PMID- 29602116 TI - Increasing atmospheric deposition nitrogen and ammonium reduced microbial activity and changed the bacterial community composition of red paddy soil. AB - Atmospheric deposition nitrogen (ADN) increases the N content in soil and subsequently impacts microbial activity of soil. However, the effects of ADN on paddy soil microbial activity have not been well characterized. In this study, we studied how red paddy soil microbial activity responses to different contents of ADN through a 10-months ADN simulation on well managed pot experiments. Results showed that all tested contents of ADN fluxes (27, 55, and 82kgNha-1 when its ratio of NH4+/NO3--N (RN) was 2:1) enhanced the soil enzyme activity and microbial biomass carbon and nitrogen and 27kgNha-1 ADN had maximum effects while comparing with the fertilizer treatment. Generally, increasing of both ADN flux and RN (1:2, 1:1 and 2:1 with the ADN flux of 55kgNha-1) had similar reduced effects on microbial activity. Furthermore, both ADN flux and RN significantly reduced soil bacterial alpha diversity (p<0.05) and altered bacterial community structure (e.g., the relative abundances of genera Dyella and Rhodoblastus affiliated to Proteobacteria increased). Redundancy analysis demonstrated that ADN flux and RN were the main drivers in shaping paddy soil bacteria community. Overall, the results have indicated that increasing ADN flux and ammonium reduced soil microbial activity and changed the soil bacterial community. The finding highlights how paddy soil microbial community response to ADN and provides information for N management in paddy soil. PMID- 29602117 TI - Relevance between chemical structure and pyrolysis behavior of palm kernel shell lignin. AB - Palm kernel shell (PKS) lignin obtained by enzymatic/mild acid hydrolysis (EMAL) was thoroughly elucidated by FTIR (fourier transform infrared), 13C-1H 2D-NMR (nuclear magnetic resonance), quantitative 31P NMR combined with DFRC (derivatization followed by reductive cleavage), and Py-GC/MS (pyrolysis-gas chromatography/mass spectrometry) with and without TMAH (tetramethylammonium hydroxide). Pyrolysis behavior was then characterized by TG-FTIR-MS (thermo gravimetric-FTIR-mass spectrometry) and Py-GC/MS. The PKS lignin is demonstrated to be a p-hydroxyphenyl-guaiacyl-syringyl (H-G-S) lignin with abundances of p hydrobenzoates and low S/G ratio of 0.15. 2D-NMR indicated that the main substructures are beta-O-4-ethers (~85%), and 31P NMR/DFRC quantified the total beta-O-4 content of 2295MUmol/g. Py-GC/MS with and without TMAH confirmed that phenol mainly originated from p-hydroxybenzoates units. Thermal-stability, evolution behavior of typical volatiles, and selectivity of phenolic compounds (H , G-, S-, C-type) during PKS lignin pyrolysis were explored. Relationship between chemical structure and pyrolysis behavior are also obtained. This work will provide a deep insight to the effective utilization of PKS. PMID- 29602118 TI - Fertilizer N application rate impacts plant-soil feedback in a sanqi production system. AB - Replant failure caused by negative plant-soil feedback (NPFS) in agricultural ecosystems is a critical factor restricting the development of sustainable agriculture. Soil nutrient availability has the capacity to affect plant-soil feedback. Here, we used sanqi (Panax notoginseng), which is severely threatened by NPSF, as a model plant to decipher the overall effects of nitrogen (N) rates on NPSF and the underlying mechanism. We found that a high rate of N at 450kgNha 1 (450N) aggravated the NPSF through the accumulation of pathogens in the soil compared with the optimal 250N. The increased N rates resulted in a significant increase in the soil electrical conductivity and available nitrogen but a decrease in the soil pH and C/N ratio. GeoChip 5.0 data demonstrated that these changed soil properties caused the soil to undergo stress (acidification, salinization and carbon starvation), as indicated by the enriched soil microbial gene abundances related to stress response and nutrition cycling (N, C and S). Accordingly, increased N rates reduced the richness and diversity of soil fungi and bacteria and eventually caused a shift in soil microbes from a bacterial dominant community to a fungal-dominant community. In particular, the high 450N treatment significantly suppressed the abundance of copiotrophic bacteria, including beneficial genera Bacillus and Pseudomonas, thus weakening the antagonistic activity of these bacteria against fungal pathogens. Moreover, 450N application significantly enriched the abundance of pathogen pathogenicity related genes. Once sanqi plants were grown in this N-stressed soil, their host specific fungal pathogen Fusarium oxysporum significantly accumulated, which aggravated the process of NPSF. This study suggested that over-application of nitrogen is not beneficial for disease management or the reduction of fungicide application in agricultural production. PMID- 29602119 TI - A systematic review on the management and treatment of mercury in artisanal gold mining. AB - Artisanal gold mining (AGM) continues to be a pervasive global health issue. While there are various problems associated with AGM, mercury exposure is the primary hazard contributing to adverse health effects in exposed human populations. Over the last several decades, many interventions have been developed and implemented to curb mercury emissions and releases, notwithstanding a comprehensive review of context specific effectiveness. A systematic review was conducted in order to specifically assess the impact of current mercury interventions within the AGM sector worldwide. To aid in this review, a resource pool of information on AGM and mercury, treatment and management of emissions and releases, and interventions was assembled through a search conducted via multiple search engines. This search determined that there have been many strategies used to reduce or eliminate mercury, through interventions or programs focusing on education, processing centers, or mercury alternative techniques. Education has focused on environment or health awareness or more specifically on cleaner or alternative techniques. Processing centers offered artisanal miners rudimentary equipment for grinding and amalgamation that extract less than 30% of the gold as an exchange for their tailings. Some techniques reduced mercury releases including retorts, mill leaching, vat-leaching, and others replaced mercury from the process such as magnets, direct smelting, sluices, and borax. There are both positive and negative outcomes associated with every intervention. Novel and comprehensive strategies-including mercury removal technology, miner education on mercury hazards, economic gains, and policy-are needed to address mercury public health issues associated with AGM. PMID- 29602120 TI - Phosphorus removal from eutrophic water using modified biochar. AB - Increasing problems related to water eutrophication, commonly caused by the high concentration of phosphorus (P), are stimulating studies aimed at an environmentally safe solution. Moreover, some research has focused on the reuse of P due to concerns about the end of its natural reserves. Biochar appears to be a solution to both problems and may act as a recovery of eutrophic/residual water with the subsequent reuse of P in agriculture, the purpose of which is to test such an assertion. Samples of biochar from poultry manure (BPM) and sugarcane straw (BCS) had their maximum adsorption capacities of Al obtained by Langmuir isotherm. These values were used to conduct the so-called post-doping process, conferring P adsorption capacity to the pyrolysed materials. Langmuir and Freundlich isotherms were adjusted for the same biochar types (Al-doped) at increasing P concentrations, in order to obtain their maximum P adsorption capacities (MPAC) and their parameters. The desorption of the adsorbed P in its MPAC was tested by three extractors: H2SO4, NaHCO3, and H2O. Finally, these biochars were used in competitive adsorption assays of phosphate, sulfate, chloride and nitrate anions and applied in a synthetic eutrophic water. The high values of MPAC of the powder materials (701.65 and 758.96mgg-1 of P for BPM and BCS, respectively) are reduced by almost half for the fragment materials (356.04 and 468.84mgg-1 of P for BPM and BCS, respectively), these values being almost entirely extracted the extractors. Its application in eutrophic/residual water, in addition to presenting a good MPAC, these materials adsorbed, in equal proportions, phosphates and sulfates, as well as to a lesser extent, nitrates and chlorides. Thus, biochar from poultry manure and sugarcane straw, after post doping with Al, have high MPAC, being excellent materials for the recovery of waters and subsequent reuse in agriculture. PMID- 29602121 TI - Three-dimensional spatial variability of arsenic-containing soil from geogenic source in Hong Kong: Implications on sampling strategies. AB - Soil contamination by trace elements such as arsenic (As) can pose considerable threats to human health, and need to be carefully identified through site investigation before the soil remediation and development works. However, due to the high costs of soil sampling and testing, decisions on risk management or mitigation strategies are often based on limited data at the site, with substantial uncertainty in the spatial distributions of potentially toxic elements. This study incorporates the restricted maximum likelihood method with three-dimensional spatial autocovariance structure, to investigate the spatial variability features of As-containing soils of geogenic origin. A recent case study in Hong Kong is presented, where >550 samples were retrieved and tested for distributions of As concentrations. The proposed approach is applied to characterize their spatial correlation patterns, to predict the As concentrations at unsampled locations, and to quantify the uncertainty of such estimates. The validity of the approach is illustrated by utilizing the multi-stage site investigation data, through which the advantages of the approach over traditional geostatistical methods are revealed and discussed. The new approach also quantifies the effectiveness of soil sampling on reduction of uncertainty levels across the site. This can become a useful indicator for risk management or mitigation strategies, as it is often necessary to balance between the available resources for soil sampling at the site and the needs for proper characterization of contaminant distributions. PMID- 29602122 TI - Atmospheric metal pollution records in the Kovarska Bog (Czech Republic) as an indicator of anthropogenic activities over the last three millennia. AB - Three peat cores were extracted from the Kovarska Bog in the central Ore Mountains to study anthropogenic pollution generated by mining and metallurgy. The core profiles were 14C dated, and concentrations of selected elements were determined by ICP MS and HG-AAS. Principal component analysis indicated that Pb, Cu, As and Ag may be useful elements for the reconstruction of historical atmospheric pollution. Total and anthropogenic accumulation rates (ARs) of Pb, Cu and As estimated for the last ca. 3500years showed similar chronologies, and revealed twelve periods of elevated ARs of Pb, As and Cu related to possible mining and metallurgic activities. In total, four periods of elevated ARs of Pb, Cu and As were detected during the Middle and Late Bronze Ages, including a distinct Late Bronze Age pollution event between 1030BCE and 910BCE. The Iron Age included three episodes of increased ARs of Pb and As; the first and the most distinctive episode, recorded between 730 and 440BCE, was simultaneous with the Bylany culture during the Hallstatt Period. The Roman Age was characterized by one pollution event, two events were detected in the Middle Ages, and the last two during the modern period. Enhanced element ARs in the late 12th and 15th centuries clearly documented the onset of two periods of intense mining in the Ore Mountains. Metal ARs culminated in ca. 1600CE, and subsequently decreased after the beginning of the Thirty Years' War. The last boom of mining between 1700CE and 1830CE represented the last period of important metallurgical operations. Late Medieval and modern period metal ARs are in good agreement with written documents. Earlier pollution peaks suggest that local metal production could have a much longer tradition than commonly believed; however, archaeological or written evidence is scarce or lacking. PMID- 29602123 TI - Fishing in troubled waters: Revealing genomic signatures of local adaptation in response to freshwater pollutants in two macroinvertebrates. AB - Local adaptation is of fundamental importance for populations to cope with fast, human-mediated environmental changes. In the past, analyses of local adaptation were restricted to few model species. Nowadays, due to the increased affordability of high-throughput sequencing, local adaptation can be studied much easier by searching for patterns of positive selection using genomic data. In the present study, we analysed effects of wastewater treatment plant and ore mining effluents on stream invertebrate populations. The two different anthropogenic stressors have impacted on stream ecosystems over different time scales and with different potencies. As target organisms we selected two macroinvertebrate species with different life histories and dispersal capacities: the caddisfly Glossosoma conformis and the flatworm Dugesia gonocephala. We applied a genome wide genetic marker technique, termed ddRAD (double digest restriction site associated DNA) sequencing, to identify local adaptation. Ten and 18% of all loci were identified as candidate loci for local adaptation in D. gonocephala and G. conformis, respectively. However, after stringent re-evaluation of the genomic data, strong evidence for local adaptation remained only for one population of the flatworm D. gonocephala affected by high copper concentration from ore mining. One of the corresponding candidate loci is arnt, a gene associated with the response to xenobiotics and potentially involved in metal detoxification. Our results support the hypotheses that local adaptation is more likely to play a central role in environments impacted by a stronger stressor for a longer time and that it is more likely to occur in species with lower migration rates. However, these findings have to be interpreted cautiously, as several confounding factors may have limited the possibility to detect local adaptation. Our study highlights how genomic tools can be used to study the adaptability and thus resistance of natural populations to changing environments and we discuss prospects and limitations of the methods. PMID- 29602124 TI - Radiative response of biomass-burning aerosols over an urban atmosphere in northern peninsular Southeast Asia. AB - A large concentration of finer particulate matter (PM2.5), the primary air quality concern in northern peninsular Southeast Asia (PSEA), is believed to be closely related to large amounts of biomass burning (BB) particularly in the dry season. In order to quantitatively estimate the contributions of BB to aerosol radiative effects, we thoroughly investigated the physical, chemical, and optical properties of BB aerosols through the integration of ground-based measurements, satellite retrievals, and modelling tools during the Seven South East Asian Studies/Biomass-burning Aerosols & Stratocumulus Environment: Lifecycles & Interactions Experiment (7-SEAS/BASELInE) campaign in 2014. Clusters were made on the basis of measured BB tracers (Levoglucosan, nss-K+, and NO3-) to classify the degree of influence from BB over an urban atmosphere, viz., Chiang Mai (18.795 degrees N, 98.957 degrees E, 354m.s.l.), Thailand in northern PSEA. Cluster-wise contributions of BB to PM2.5, organic carbon, and elemental carbon were found to be 54-79%, 42-79%, and 39-77%, respectively. Moreover, the cluster-wise aerosol optical index (aerosol optical depth at 500nm~0.98-2.45), absorption (single scattering albedo ~0.87-0.85; absorption aerosol optical depth ~0.15-0.38 at 440nm; absorption Angstrom exponent ~1.43-1.57), and radiative impacts (atmospheric heating rate ~1.4-3.6Kd-1) displayed consistency with the degree of BB. PM2.5 during Extreme BB (EBB) was ~4 times higher than during Low BB (LBB), whereas this factor was ~2.5 for the magnitude of radiative effects. Severe haze (visibility~4km) due to substantial BB loadings (BB to PM2.5~79%) with favorable meteorology can significantly impact the local-to-regional air quality and the, daily life of local inhabitants as well as become a respiratory health threat. Additionally, such enhancements in atmospheric heating could potentially influence the regional hydrological cycle and crop productivity over Chiang Mai in northern PSEA. PMID- 29602125 TI - Validation and updating of QSAR models for partitioning coefficients of ionic liquids in octanol-water and development of a new LFER model. AB - Since estimating the octanol-water partitioning coefficients (log P) of numerous ionic liquids (ILs) is tedious, time & material consuming and labor intensive, predicting by quantitative structure-activity relationship (QSAR) approach is necessary. Although several researchers presented the QSAR models for the property, validation assessment of the models were not sufficiently performed due to lack of log P dataset. In this study, the log P values of external ILs were measured by a shaking-flask method or collected from literatures. The newly obtained external log P values were applied for the validation study of previous models. In results, it was found that previous models showed rather low predictabilities and/or non-ignorable prediction limits to some IL structures whose anions were not involved in the previous studies. Accordingly, to achieve better predictability, the parameters used for previous modeling were re-selected and also their coefficients were re-calculated by multiple linear regression analysis with an inclusion of the external validation set to previous training set. Moreover, for reasonable understanding of chemical meanings in octanol-water partitioning behavior of ILs, we developed a new prediction model with a few number of descriptors, which has a good accuracy of R2 = 0.862 and standard error = 0.564 log units. PMID- 29602126 TI - A framework for identifying and selecting long term adaptation policy directions for deltas. AB - Deltas are precarious environments experiencing significant biophysical, and socio-economic changes with the ebb and flow of seasons (including with floods and drought), with infrastructural developments (such as dikes and polders), with the movement of people, and as a result of climate and environmental variability and change. Decisions are being taken about the future of deltas and about the provision of adaptation investment to enable people and the environment to respond to the changing climate and related changes. The paper presents a framework to identify options for, and trade-offs between, long term adaptation strategies in deltas. Using a three step process, we: (1) identify current policy led adaptations actions in deltas by conducting literature searches on current observable adaptations, potential transformational adaptations and government policy; (2) develop narratives of future adaptation policy directions that take into account investment cost of adaptation and the extent to which significant policy change/political effort is required; and (3) explore trade-offs that occur within each policy direction using a subjective weighting process developed during a collaborative expert workshop. We conclude that the process of developing policy directions for adaptation can assist policy makers in scoping the spectrum of options that exist, while enabling them to consider their own willingness to make significant policy changes within the delta and to initiate transformative change. PMID- 29602127 TI - Overexpression of lncRNA DANCR positively affects progression of glioma via activating Wnt/beta-catenin signaling. AB - Long non-coding RNA DANCR has been certified to act as an effective regulator in the tumorigenesis of several types of tumors. In this study, the special role of DANCR in glioma progression was explored. It was speculated that high expression of DANCR in glioma tissues and cells might be an oncogenic factor. To understand the correlation between the expression pattern of DANCR and the overall survival of glioma patients, the Kaplan Meier method was used for analysis. The result showed that high expression of DANCR might be a poor prognostic factor in glioma patients. The effects of DANCR expression on proliferation and migration of glioma cells were detected through performing MTT assay, colony formation assay and transwell assays. Results of loss-of function assay suggested that downregulated DANCR could inhibited glioma cell proliferation and migration. Additionally, western blot assay was conducted in glioma cells to demonstrate that the protein levels of the Wnt/beta-catenin pathway related proteins was negatively modulated by si-DANCR. Finally, and the increased proliferation and migration of glioma cells were observed after the Wnt/beta-catenin signals were activated. However, this tendency was reduced by si-DANCR. In conclusion, DANCR positively affected glioma progression via activating Wnt/beta-catenin signaling pathway. PMID- 29602128 TI - Targeted cancer therapy through 17-DMAG as an Hsp90 inhibitor: Overview and current state of the art. AB - Heat shock protein 90 (Hsp90) is an evolutionary preserved molecular chaperone which mediates many cellular processes such as cell transformation, proliferation, and survival in normal and stress conditions. Hsp90 plays an important role in folding, maturation, stabilization and activation of Hsp90 client proteins which all contribute to the development, and proliferation of cancer as well as other inflammatory diseases. Functional inhibition of Hsp90 can have a massive effect on various oncogenic and inflammatory pathways, and will result in the degradation of their client proteins. This turns it into an interesting target in the treatment of different malignancies. 17 dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) as a semi-synthetic derivative of geldanamycin, has several advantages over 17-Allylamino-17 demethoxygeldanamycin (17-AAG) such as higher water solubility, good bioavailability, reduced metabolism, and greater anti-tumour capability. 17-DMAG binds to the Hsp90, and inhibits its function which eventually results in the degradation of Hsp90 client proteins. Here, we reviewed the pre-clinical data and clinical trial data on 17-DMAG as a single agent, in combination with other agents and loaded on nanomaterials in various cancers and inflammatory diseases. PMID- 29602129 TI - Sanyang Xuedai enhances the radiosensitivity of human non-small cell lung cancer cells via increasing iNOS/NO production. AB - OBJECTIVE: In this research, we aimed at finding out how San Yang Xue Dai (SYKT) promotes the radiosensitivity of non-small cell lung cancer (NSCLC) cell line NCI H460. METHODS: Survival rate of NSCLC cells (A549, NCI-H460, NCI-H1650 and NCI H1975) after the SYKT treatment or irradiation (IR) was calculated by the MTT assay. The radiosensitization of SYKT (0.5 g/mL and 1.0 g/mL) on cell line NCI H460 and the radioresistant cell line NCI-H460R was studied by MTT assay and clone formation assay. The protein expression levels of iNOS, Cyclin B1 and CDC2 were determined by western blot, and the expression of NO was measured by Griess method. Finally, cell cycle and apoptotic rate of NSCLC cell line NCI-H460 were accessed by flow cytometry assay. BrdU staining was also applied to detect the cell proliferation after IR with or without SYKT treatment. RESULTS: The IC10 value of SYKT for NCI-H460 cells was 1.03 g/mL. After 1.0 g/mL SYKT treatment, the radiosensitivity of NCI-H460R cells was enhanced. The level of iNOS in the cells was found decreased after IR. We also found that SYKT could enhance iNOS and NO expressions while inhibit cyclin B1 and CDC2 expressions in radiation resistant cells. Combining beta-irradiation with SYKT caused cell cycle arrest in G2/M phase and increased cell apoptosis. CONCLUSION: SYKT resensitized radioresistant NCI-H460R cells via increasing cell apoptosis and cell cycle arrest. This was due to an elevated NO level caused by accumulating iNOS and effects of SYKT on radiosensitization of NSCLC should be further investigated in clinical application. PMID- 29602130 TI - The mechanisms involved in miR-9 regulated apoptosis in cervical cancer by targeting FOXO3. AB - As a seriously global health problem, cervical cancer is a great risk to women which threatens their lives. Approximately 30% patients who received definitive treatment may fail to recover from this disease. Accordingly, there is an imperatively need to explore alternative therapeutic approaches for this disease. Several studies have revealed that miR-9 was a critical regulator during cervical cancer growth. Here, we reported that the miR-9 was overexpressed in cervical tumor tissue and exerted a promoting effect on human cervical cancer cell (SiHa) growth. Both in vitro and in vivo experiments confirmed that miR-9 could stimulate the proliferation and migration of SiHa cells. In contrast, inhibition of miR-9 induced apoptosis in SiHa cells. In addition, dual luciferase reporter system assay verified that there was a strong target relationship between miR-9 and FOXO3. Result of western blot assay showed that the inhibition of miR-9 increased the expression of FOXO3. Moreover, miR-9 regulated FOXO3 downstream proteins Bax, Bcl-2 and p-Akt expressions, which suggesting that miR-9 was involved in the SiHa cells apoptosis. In conclusion, our results suggest that the inhibition of miR-9 could induce apoptosis in cervical cancer by targeting FOXO3 and presented a potential molecular target for the treatment of cervical cancer patients. PMID- 29602131 TI - Effects of cholecalciferol cholesterol emulsion on renal fibrosis and aquaporin 2 and 4 in mice with unilateral ureteral obstruction. AB - There was evidence that 1,25(OH)2D3 regulated aquaporin (AQP) 2 and 4 expression while ameliorating renal fibrosis. This study investigated whether cholecalciferol cholesterol emulsion (CCE), a precursor of 1,25(OH)2D3, has similar effects. The impact of CCE on renal fibrosis and AQP2 and AQP4 expression were studied in a unilateralureteral obstruction (UUO) mouse nephropathy model. CCE reduced both the extent of fibrosis and transforming growth factor (TGF)-beta signaling compared with vehicle-treated UUO model controls. AQP2 protein expression was higher and AQP4 expression was lower in UUO-model mice treated with CCE than in vehicle-treated control mice. The results showed that CCE attenuated renal fibrosis by inhibiting TGF-beta signaling, and regulated AQP2 and AQP4 expression in this UUO mouse model. PMID- 29602132 TI - Increased expression of circRNA_102231 in lung cancer and its clinical significance. AB - Circular RNAs (circRNAs) are a type of endogenous non-coding RNAs which implicated in the progression of cancers. However, the role of circRNA_102231 in lung cancer remains unclear. Gene Expression Omnibus (GEO) datasets were used to investigate aberrantly expressed circRNAs in lung cancer. CircRNA_102231 expression in lung adenocarcinoma (LAC) tissues was dertermined by qRT-PCR. Furthermore, we explored the functions of circRNA_102231 on lung cancer cells progression. In the present study, circRNA_102231 was found to be one of the most significantly upregulated circRNAs in the GEO datasets analysis (GSE101586). QRT PCR showed that circRNA_102231 expression was significantly upregulated in LAC tissues and associated with the advanced TNM stage, lymph node metastasis, and poor overall survival of lung cancer patients. The area under the receiver operating characteristic curve (ROC) was 0.897. in addition, function assays showed that circRNA_102231 inhibition significantly suppressed lung cancer cells proliferation and invasion ability in vitro. In conclusion, our study demonstrated that circRNA_102231 could act as a potential biomarker and therapeutic target for lung cancer patients. PMID- 29602133 TI - Penconazole alters redox status, cholinergic function and lung's histoarchitecture of adult rats: Reversal effect of vitamin E. AB - The present study pertains to the possible adverse effects of penconazole exposure on the lung of adult rats, and to the potential ability of vitamin E (Vit E) in mitigating the toxicity induced by this fungicide. Male Wistar rats were divided into four groups of six animals each: Group I (Controls): rats drank distilled water; Group II (PEN): rats received, by gavage, 50 mg/kg body weight (1/40 LD50) of penconazole every 2 days during 10 days; Group III (Vit E): rats received daily 100 mg alpha-tocopherol acetate/kg body weight during 10 days by gavage; and Group IV (Vit E + PEN): rats received both vitamin E (100 mg alpha tocopherol acetate/kg body weight) and penconazole (50 mg/kg body weight), being vitamin E given as a daily dosage and penconazole every 2 days, by gavage during 10 days. Results showed that penconazole induced oxidative stress in the lung demonstrated by an increase in malondialdehyde (+77%), hydrogen peroxide (+58%) and advanced oxidation protein product (+22%) levels, as compared to the controls. Furthermore, a decrease in the activities of catalase (-41%), superoxide dismutase (-45%), glutathione peroxidase (-23%) and acetylcholinesterase (-67%), and an increase in the levels of non-protein thiols (+17%), glutathione (+7%) and vitamin C (+44%) were registered. Abnormalities in lung histological sections such as alveolar edema, infiltration of inflammatory cells (leukocytes) and emphysema, were also observed following penconazole exposure. Vitamin E ameliorated the biochemical parameters, as well as the histological impairments induced by this fungicide. In conclusion, our study demonstrated that vitamin E, a natural antioxidant, was effective in alleviating penconazole-induced lung damage in Wistar rats. PMID- 29602134 TI - In vitro influence of selenium on the proliferation of and steroidogenesis in goat luteinized granulosa cells. AB - In this study, we investigated the effects of Selenium (Se) on the proliferation of and steroidogenesis in goat luteinized granulosa cells (LGCs) and elucidated the mechanisms underlying these effects. Our results showed that proliferating cell nuclear antigen (PCNA), Akt, and phosphoinositide 3-kinase (PI3K) were expressed mainly in ovarian oocytes and granulosa cells (GCs). We observed that 5 ng/mL Se significantly stimulated LGC proliferation, which could be attributed to increases in PCNA, cyclin-dependent kinase 1 (CDK1), phosphorylated adenosine monophosphate-activated protein kinase (p-AMPK; Thr172), and phosphorylated Akt (p-Akt; Ser473) and decreases in p21 (P < 0.05). Se treatment also significantly increased estradiol (E2) production, which could be, at least partially, due to increased levels of 3beta-hydroxysteroid dehydrogenase(3beta-HSD), steroidogenic acute regulatory protein (StAR), p-Akt (Ser473), and cyclic adenosine monophosphate (cAMP) (P < 0.05); however, follicle-stimulating hormone (FSH) significantly enhanced the production of E2, progesterone (P4) and cAMP (P < 0.05). Moreover, Se treatment stimulated proliferation and the synthesis of E2 and cAMP in the presence of FSH (P < 0.05). Additionally, the expression of antioxidant-related genes [glutathione peroxidase (GSH-Px) and superoxide dismutase 2 (SOD2)] and the activity of GSH-Px and SOD were progressively elevated by Se treatment (P < 0.05). These data suggested that Se plays an important role in the proliferation of and steroidogenesis in LGC by activating the PI3K/Akt and AMPK pathways, thereby increasing the expression of its downstream cell-cycle- and steroid-synthesis-related genes, as well as regulating cellular oxidative stress. PMID- 29602135 TI - Reference range of gestational uterine artery resistance index in small canine breeds. AB - The objectives of this study were to evaluate the uterine artery blood flow during the second half of normal pregnancy in small breed dogs and to determine the RI reference values of this artery in these bitches. Fifty-two, 1.5-6.5 kg, purebred healthy pregnant bitches were included in this study. Doppler ultrasonographic examinations of the uterus were performed every 10 days from Day 30 of the estrous cycle to parturition. Peak systolic velocity (PSV) and end diastolic velocity (EDV) of the uterine artery were measured while RI [(PSV EDV)/PSV] was automatically calculated. Values of PSV, EDV and RI were analyzed by repeated measures ANOVA followed by Tukey test using age, body weight, litter size and parity as covariates. Resistance index reference ranges were constructed by regressing this index on gestational age. Equation of the polynomial regression curves was used to calculate the mean, 95th and 5th centiles for each gestational age (GA). A gradual increase of PSV (P < 0.01) and EDV (P < 0.01) and a decrease in RI (P < 0.01) were found throughout the study period. PSV and EDV were influenced by litter size (P < 0.05), while RI was not. None of the Doppler parameters were influenced by age, body weight or parity. A second-degree polynomial described the relationship between RI of uterine artery and GA in the different time points: [RI = 0.993 + 8.4x10-5 x GA2- 0.0117 x GA]. It is concluded that uterine artery blood flow progressively increased throughout normal pregnancy in small breed bitches. In addition, reference ranges of uterine artery RI were 0.64-0.79, 0.57 to 0.75, 0.53 to 0.71 and 0.52 to 0.66 on Days 30, 40, 50 and 60 of gestation, respectively. PMID- 29602136 TI - Influence of polygamous versus monogamous mating on embryo production in four different strains of mice after superovulatory treatment. AB - We determined the effect of monogamous or polygamous mating with 2 females on vaginal plug (VP) rate, embryo donors (ED), 2-cell embryo production, and male performance after superovulation of females aging 24d or 45-48d. C57BL/6NCrl (B6N), BALB/cAnCrl (BALB/cN), FVB/NCrl (FVB/N), and Crl:CD1(ICR) (CD-1) females received 5 IU eCG and 5 IU hCG (24d) or 7.5 IU eCG and 7.5 IU hCG (45-48d) 48 h apart. After the hCG injection, females were paired with males, which alternated weekly in monogamous or polygamous mating. Significant differences in the percentage of VP-positive females between monogamous and polygamous mating were observed for B6N (71% vs. 49%), FVB/N (77% vs. 51%), and CD-1 (90% vs. 67%) at 45 48d. BALB/cN and CD-1 showed higher VP rates than B6N and FVB/N. A significantly higher percentage of ED was found for monogamous than for polygamous mating for FVB/N (87% vs. 61%) at 24d and for B6N (91% vs. 53%) and CD-1 (90% vs. 68%) at 45 48d. In all strains of mice and in both age groups, no significant differences were observed in the number of intact 2-cells per VP-positive female, ED or treated female between monogamous and polygamous mating except in the B6N strain where monogamous mating resulted in a significantly higher number of intact 2 cell embryos per treated female than polygamous mating at both ages. The present results imply that polygamous mating can be implemented for 2-cell embryo production in all strains studied except for B6N when all females are euthanized. However, when only VP+ females are sacrificed polygamous mating can be employed for all 4 strains studied. PMID- 29602137 TI - Examining stress perceptions and coping strategies among Saudi nursing students: A systematic review. AB - OBJECTIVES: Stress is a perennial problem in nursing education and Saudi student nurses are not immune. Despite the growing literature examining stress in Saudi student nurses, a broader perspective on this concept has not been explored. This paper is a report of a review systematically appraising and synthesizing existing scientific articles reporting stress perceptions and coping styles in Saudi student nurses. DESIGN: A systematic review method guided this review. DATA SOURCES: Four (SCOPUS, CINAHL, PubMed, Ovid) bibliographic databases were searched to locate relevant articles. REVIEW METHODS: An electronic database search was performed in August 2017 to locate studies published from 2010 onwards. The search words included: "stress" OR "psychological stress", "coping" OR "psychological adaptation", "Saudi Arabia", "student", and "nurse". Eleven (11) articles met the inclusion criteria. RESULTS: Review of the findings showed moderate to high stress levels in Saudi student nurses that originated mainly from heavy workloads and taking care of patients. However, when the students' demographic characteristics were taken into account, inconclusive results were found, although some evidence showed higher stress levels in higher level students. Both active and passive coping styles were used by nursing students when dealing with stress. CONCLUSIONS: Consistent with international studies, Saudi student nurses experience a considerable levels of stress from various sources. Findings may provide a direction for nursing faculty in formulating stress interventions that are empirically tested and culturally appropriate. PMID- 29602138 TI - The effectiveness of mindfulness meditation for nurses and nursing students: An integrated literature review. AB - BACKGROUND: A growing body of literature has identified a range of beneficial physiological and psychological outcomes from the regular practice of mindfulness meditation. For healthcare professionals, mindfulness meditation is claimed to reduce stress, anxiety and burnout, and enhance resilience. OBJECTIVE: The objective of this integrative review was to critically appraise the literature that related to the effectiveness of mindfulness meditation programs for nurses and nursing students. DESIGN: This review was conducted using Whittemore and Knafl's framework for integrated reviews. DATA SOURCES: Using the terms mindfulness, mindfulness-based-stress reduction, Vipassana, nurses, and nurse education a comprehensive search of the following electronic databases was conducted: CINAHAL, Medline, PsycINFO, EMBASE. EMCARE, ERIC and SCOPUS. REVIEW METHODS: The initial search located 1703 articles. After screening and checking for eligibility 20 articles were critically appraised using the Critical Appraisal Skills Program checklist for qualitative papers and McMaster's Critical appraisal form for quantitative papers. The final number of papers included in the review was 16. RESULTS: The results of this review identified that mindfulness meditation has a positive impact on nurses' and nursing students' stress, anxiety, depression, burnout, sense of well-being and empathy. However, the majority of the papers described small scale localised studies which limits generalisability. CONCLUSION: Contemporary healthcare is challenging and complex. This review indicated that mindfulness meditation is an effective strategy for preventing and managing the workplace stress and burnout, which so often plague nursing staff and students. Further studies with larger sample sizes using rigorous research methods would be useful in extending this work. PMID- 29602139 TI - New methods to image unstable atherosclerotic plaques. AB - Atherosclerotic plaque rupture is the primary mechanism responsible for myocardial infarction and stroke, the top two killers worldwide. Despite being potentially fatal, the ubiquitous prevalence of atherosclerosis amongst the middle aged and elderly renders individual events relatively rare. This makes the accurate prediction of MI and stroke challenging. Advances in imaging techniques now allow detailed assessments of plaque morphology and disease activity. Both CT and MR can identify certain unstable plaque characteristics thought to be associated with an increased risk of rupture and events. PET imaging allows the activity of distinct pathological processes associated with atherosclerosis to be measured, differentiating patients with inactive and active disease states. Hybrid integration of PET with CT or MR now allows for an accurate assessment of not only plaque burden and morphology but plaque biology too. In this review, we discuss how these advanced imaging techniques hold promise in redefining our understanding of stable and unstable coronary artery disease beyond symptomatic status, and how they may refine patient risk-prediction and the rationing of expensive novel therapies. PMID- 29602140 TI - Effect of simvastatin and ezetimibe on suPAR levels and outcomes. AB - BACKGROUND AND AIMS: Soluble urokinase plasminogen activator receptor (suPAR) is an inflammatory marker associated with cardiovascular disease. Statins lower both low-density lipoprotein (LDL)-cholesterol and C-reactive protein (CRP), resulting in improved outcomes. However, whether lipid-lowering therapy also lowers suPAR levels is unknown. METHODS: We investigated whether treatment with Simvastatin 40 mg and Ezetimibe 10 mg lowered plasma suPAR levels in 1838 patients with mild moderate, asymptomatic aortic stenosis, included in the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) study, using a pattern mixture model. A 1-year Cox analysis, adjusted for established cardiovascular risk factors, allocation to study treatment, peak aortic valve velocity and baseline suPAR, was performed to evaluate relationships between change in suPAR with all-cause mortality and the composite endpoint of major cardiovascular events (MCE) composed of ischemic cardiovascular events (ICE) and aortic valve related events (AVE). RESULTS: After 4.3 years of follow-up, suPAR levels had increased by 9.2% (95% confidence interval [CI]: 7.0%-11.5%) in the placebo group, but only by 4.1% (1.9%-6.2%) in the group with lipid-lowering treatment (p<0.001). In a multivariate 1-year analysis, 1-year suPAR was strongly associated with all-cause mortality, hazard ratio (HR) = 2.05 (1.17-3.61); MCE 1.40 (1.01-1.92); and AVE 1.42 (1.02-1.99) (all p<0.042) for each doubling of suPAR; but was not associated with ICE. CONCLUSIONS: Simvastatin and Ezetimibe treatment impeded the progression of the time-related increase in plasma suPAR levels. Year-1 suPAR was associated with all-cause mortality, MCE, and AVE irrespective of baseline levels (SEAS study: NCT00092677). PMID- 29602142 TI - Predictive factor for volume reduction of uterine fibroids after short-term use of ulipristal acetate. AB - OBJECTIVES: Ulipristal acetate (UPA) is a selective progesterone receptor modulator, which has been used to treat uterine fibroids. Many published reports about the outcomes indicate effective control of bleeding and reduction in the fibroid volume following both short- and long-term therapy. However, the reported volume reduction varies across different reports. Therefore, the purpose of this study was to investigate the factors that can affect the volume reduction of uterine fibroids, after short-term UPA therapy in patients with symptomatic uterine fibroids. STUDY DESIGN: Women treated with UPA for 3 months, between November 2013 and February 2017, for symptomatic uterine fibroids were evaluated retrospectively. The fibroid volume was measured using ultrasonography or magnetic resonance imaging. Response was defined as any reduction in volume after treatment and non-response was defined as no change or increase in volume. RESULTS: Totally, 152 women were treated with UPA and the median volume reduction was 13.1% (interquartile range [IQR] -16.8 to 36.7). Response to treatment was seen in 92 of 152 (60.5%) patients, while 60 women (39.5%) showed no response. Median number of fibroids in the response group was less than that in the non response group (P = 0.030; median 2, IQR 1-4 vs. median 4, IQR 1-6). On multivariate regression analysis, fewer number of uterine fibroids was an independent factor for predicting a good response to UPA (odds ratio 0.830, CI: 0.710-0.969, P = 0.019). CONCLUSION: An independent factor that can affect the volume reduction after a 3-month UPA therapy in women with uterine fibroids was the number of fibroids. This indicates that UPA might be ineffective for volume reduction in cases with multiple leiomyomas. However, future prospective studies comparing solitary and multiple leiomyomas for response to UPA are necessary. PMID- 29602141 TI - Is thromboprophylaxis cost effective in ovarian hyperstimulation syndrome: A systematic review and cost analysis. AB - BACKGROUND: The majority of serious thromboembolic events occurring in assisted reproductive technologies (ART) are in women with ovarian hyperstimulation syndrome (OHSS). OBJECTIVES: The purpose of this study was to present a thorough review and cost analysis regarding the use of venous thromboembolism (VTE) prophylaxis in OHSS to inform clinical management. DATA SOURCES: Databases used were Pubmed and Embase, in addition to checking reference lists of retrieved articles (inception to November 2017). METHODS: The systematic search strategy identified 365 titles and abstracts. Articles included in the qualitative synthesis had identified venous thrombosis incidence rates or ratios. A separate search for the cost model was conducted recognizing all associated complications of VTE. The decision tree was modeled to best fit the patient population and a sensitivity analysis was performed over a range of variables. RESULTS: The cost of VTE event per OHSS patient not on prophylaxis was ?5940 (range ?3405 to ?38,727), versus ?4134 (?2705 to ?23,192) per event per patient on prophylaxis, amounting to a saving of (?19 to ?23,192) per VTE per patient. Sensitivity analysis found VTE prophyaxis to be cost effective if the incidence of VTE in the OHSS population was greater than 2.79%. Prophylactic therapy was cost effective through 16 weeks of treatment. LIMITATIONS: OHSS is infrequent and hence, the incidence of VTE in patients with OHSS is low; therefore, the data used to inform the incidence of VTE in OHSS in the model carry some uncertainty. Further, low molecular weight heparin (LMWH) has side effects therefore individualization of care must be considered. CONCLUSIONS: With the increasing incidence of infertility and requirement for ART, thromboembolism in OHSS poses a major health threat for patients. VTE prophylaxis using enoxaparin was cost effective in patients with severe OHSS over a wide range of costs and incidences. Prophylaxis was also cost effective through the completion of the first trimester of pregnancy. PMID- 29602143 TI - 2017 update of the European Federation for Colposcopy (EFC) performance standards for the practice of colposcopy. AB - A refinement of quality indicators (QIs) is described whereby the quality of care can be measured across colposcopy services in different countries and healthcare settings. A five-round Delphi process was conducted at successive satellite meetings from 2011 to 2015 of leading European colposcopists to refine the most high-scoring QIs relevant to colposcopic practice. A review and refinement of the wording of the standards and their criteria was undertaken by national society representatives. Six quality indicators were identified and refined. "Documentation of whether the squamocolumnar junction (SCJ) has been visible or not" was changed into "for cervical colposcopy transformation zone (TZ) type (1, 2 or 3) should be documented". The standard "percentage of cases having a colposcopic examination prior to treatment for abnormal cytology" was changed to "percentage of cases having a colposcopic examination prior to treatment for abnormal cervical screening test". The standard "percentage of all excisional treatments/conizations containing CIN2+ (cervical intra-epithelial neoplasia grade two or worse)" was changed into "percentage of excisional treatments/conizations having a definitive histology of CIN2+. Definitive histology is highest grade from any diagnostic or therapeutic biopsies". The standard "percentage of excised lesions/conizations with clear margins" was unchanged. The remaining two QIs define the minimum caseloads required for colposcopists. However, "cytology" was replaced by "screening results" to acknowledge the introduction of human papillomavirus testing to European screening programmes. Six QIs were identified to define good practice in colposcopy. PMID- 29602144 TI - Weird Laughing in Hyperekplexia: A new phenotype associated with a novel mutation in the GLRA1 gene? AB - Hyperekplexia (HPX) or startle disease is a rare hereditary neurological disorder characterized by generalized stiffness, excessive startle reflex to unexpected stimuli and a short period of generalized stiffness following the startle response, and can be complicated by umbilical or inguinal hernia, developmental delay and apnea spell. HPX is caused mainly by mutations in the GLRA1 gene, and has a good response to clonazepam. In this short communication we describe an 11 year-old girl with excessive startle reflex, weird laughing and developmental delay since early infancy. She also suffered from infantile spasms and generalized tonic-clonic seizures, and became seizure-free with antiepileptic drugs treatment. However, the weird laughing was still present during the treatment. Her mother also appeared excessive startle reflex during early infancy. A novel mutation in GLRA1 was detected in the girl and her mother. Consequently, she was diagnosed with HPX, and clonazepam was added. The weird laughing was dramatic improved, which hasn't been reported in HPX. This is the first report of weird laughing in a hyperekplexia patient carrying a novel GLRA1 mutation, and expanded the phenotype spectrum of HPX. PMID- 29602145 TI - Epilepsy in neuropathologically verified Alzheimer's disease. AB - PURPOSE: Subjects with Alzheimer's disease (AD) have been shown to be at a higher risk for epilepsy. The vast majority of the previous studies have not included a full neuropathological examination. METHODS: The objective of this study was to assess the prevalence of epilepsy and clinicopathological characteristics in a well-defined study group of 64 subjects with AD. We evaluated the clinicopathological findings in 64 subjects (mean age at death 85 +/- 8.6 years) from a longitudi-nal study cohort of patients with dementia. RESULTS: Eleven out of the 64 subjects (17%) had a history of epilepsy, which is comparable to previous studies. The subjects with AD and epilepsy were significantly younger at the time of AD diagnosis and at the time of hospitalisation. In addition, their duration of AD was longer. Concomitant neuropathology in addition to AD was common in both groups and the ApoE genotypes did not differ significantly between the groups. CONCLUSION: The strength of this study is a thorough neuropathological examination of all study subjects. Our findings support the previous literature regarding the prevalence of epilepsy in subjects with AD. We have shown that the subjects with AD and epilepsy differ significantly from the subjects without epilepsy. PMID- 29602146 TI - Morphometric investigations to assess the compatibility of mandible and skull. AB - When a morphologically separated skull and mandible are found in the same case context, the possibility of a match arises. Two criteria with which to determine a match are the rough articulation between the mandibular condyles and cranial base itself and, most importantly, the fit of the teeth. However, when there has been intravital or postmortem tooth loss, this important criterion is not available. To date, only Reichs (1989) has investigated further compatibility criteria to solve the question of putative commingling in a case where a mandible seemed to originate from a female, while all other bones originated from a male individual. In a different reported case (Preibetaler et al. 2017), a mandible seemed too big for a skull; DNA analysis, however, confirmed that both originated from the same female individual. To investigate the metric relationship between mandible and skull we measured the postmortem CT data records of 223 corpses (virtual skulls) in OsiriX(c) MD for the following linear parameters: bicondylar breadth (KDB), biradicular breadth (AUB), and bizygomatic breadth (ZYB). The indices KDB/ZYB and KDB/AUB were developed and used to define ranges for matches and mismatches. Furthermore, the intra-observer reliability for the method was assessed. An intraclass correlation coefficient of >0.99 for every parameter showed that the used measurements are highly reliable. The 2.5-97.5 percentile for the KDB/AUB index lay between 0.91 and 1.05, while the range for the KDB/ZYB index was between 0.87 and 1.00. Within these ranges, it is possible to roughly assess whether or not a mandible and skull might be compatible, even if this can only be verified by forensic DNA analysis. If an index value lies outside these ranges, it can be assumed that skull and mandible do not match. Future studies should include more samples from a broader population spectrum so that these metric relationships can be used for different populations. PMID- 29602147 TI - Isolation and structural characterization of a novel sibutramine analogue, chlorosipentramine, in a slimming dietary supplement, by using HPLC-PDA, LC-Q TOF/MS, FT-IR, and NMR. AB - A novel sibutramine analogue was detected in a slimming formula by high performance liquid chromatography with a photo diode detector array (HPLC-PDA). The unknown compound exhibited an ultraviolet (UV) spectrum that was similar to that of chlorosibutramine, despite having a different HPLC retention time. Further analysis of the slimming formula by LC-quadrupole time-of-flight mass spectrometry (LC-Q-TOF/MS) showed that the unknown compound had the formula C18H27Cl2N. To elucidate the structure of this new sibutramine analogue, the target compound in the slimming formula was isolated on a preparative-LC system equipped with a PDA. After analysis by fourier transform infrared (FT-IR) and nuclear magnetic resonance (NMR) spectroscopy, the unknown compound was identified as a sibutramine analogue in which the iso-butyl group on the side chain is replaced with an iso-pentyl group. This new sibutramine analogue was identified to be 1-(1-(3,4-dichlorophenyl)cyclobutyl)-N,N,4-trimethylpentan-1 amine and has been named as chlorosipentramine. PMID- 29602148 TI - Delta-9-tetrahydrocannabinolic acid A (THC-A) in urine of a 15-month-old child: A case report. AB - INTRODUCTION: The acidic forms of cannabinoids, THC-A and CBD-A are naturally present in cannabis plants and preparations and are generally decarboxylated to the active compounds before the use (e.g. thermally decarboxylated through smoking). Hence, the identification of the acidic compounds in urine could be an evidence of cannabis ingestion rather than a passive exposure to smoke. This case report described a 15-month-old child that suffered an acute intoxication by accidental cannabis ingestion. It is important to assess the ingestion and to discriminate it from a passive exposure to better interpret the clinical findings and to establish the correct therapeutic procedure. METHODS: Urine samples were simply diluted in deionized water and directly injected in the LC-MS/MS system. D3-THCCOOH was used as internal standard. Chromatographic separation of THCCOOH, THC-A and CBD-A was carried out in reversed phase on a c18 column. A triple quad in MRM negative mode was used to monitor the three analytes. RESULTS AND DISCUSSION: The developed LC-MS/MS method was simple and fast. A LOD of 3.0ng/mL and a LOQ of 10.0ng/mL were measured for the three compounds. The analytical procedure was validated accordingly to international guidelines. The two urine samples collected from the 15-month-old child at the hospitalization and after three days provided positive results for THCCOOH (130.0 and 10.0ng/mL respectively). THC-A was found only in the urine sample collected at the hospitalization (concentration: 70.0ng/mL). CONCLUSION: THC-A was detected and quantitated in a urine sample of a 15-month-old child. PMID- 29602149 TI - Chromatographic fingerprinting through chemometric techniques for herbal slimming pills: A way of adulterant identification. AB - In the current study, gas chromatography-mass spectrometry (GC-MS) fingerprinting of herbal slimming pills assisted by chemometric methods has been presented. Deconvolution of two-way chromatographic signals of nine herbal slimming pills into pure chromatographic and spectral patterns was performed. The peak clusters were resolved using multivariate curve resolution-alternating least squares (MCR ALS) by employing appropriate constraints. It was revealed that more useful chemical information about the composition of the slimming pills can be obtained by employing sophisticated GC-MS method coupled with proper chemometric tools yielding the extended number of identified constituents. The thorough fingerprinting of the complex mixtures proved the presence of some toxic or carcinogen components, such as toluene, furfural, furfuryl alcohol, styrene, itaconic anhydride, citraconic anhydride, trimethyl phosphate, phenol, pyrocatechol, p-propenylanisole and pyrogallol. In addition, some samples were shown to be adulterated with undeclared ingredients, including stimulants, anorexiant and laxatives such as phenolphthalein, amfepramone, caffeine and sibutramine. PMID- 29602150 TI - Identification of deceased based on sternal bone computed tomography features. AB - Identification of deceased with unclear identity is a common problem in forensic science, whereby radiologic comparison can be applied as method for identification. As this comparison is mostly made on a visual basis, it is highly dependent on the examiner and often lacks standardized procedures and statistical support. The aim of this study therefore was to develop a reproducible and examiner independent method for radiologic identification (RADid) based on morphometric and morphological features of sternal bone computed tomography (CT). Furthermore, the feasibility of an automated comparison of a post-mortem (PM) case against a database of ante-mortem (AM) cases was evaluated. 44 in situ PM CT scans of sternal bone and their corresponding AM CT scans were analysed and reproducible features were selected based on intra- and interrater reliability assessments. The selected features were further tested by contrasting AM and PM data. Moreover, an automated identity evaluation was developed by calculating the number of matching features between each PM case and an AM database consisting of 94 cases including the 44 with corresponding PM scans. Several features showed to be reliable according to their resulting correlation coefficient values (greater or equal to 0.60). The suitability and stability of these features was confirmed by contrasting AM and PM CT scans. Finally, the automated comparison was successful in 76.7% of the cases, whereby an unambiguous identification was possible in 65.1%. The present study reflects the benefits of a standardized and statistically established identification method and demonstrates the high potential of the sternal bone as a suitable structure for RADid. PMID- 29602152 TI - How to recognize the traces left on a crime scene by a 3D-printed Liberator?: Part 1. Discharge, exterior ballistic and wounding potential. AB - The Liberator is a firearm that can be manufactured from its blueprints, using a 3D-printer. This weapon made of nineteen pieces - eighteen in printed plastic and one metallic nail - raises questions such as its ability to fire a round, its wounding potential and the traces produced by its discharge. In particular, knowledge must be gained to infer that a 3D-printed handgun was used, reconstruct the shooting event involving such handgun, and gather information related to the type of 3D-printed handgun used. This study focused on the traces that could orientate forensic investigations when the use of a 3D-printed Liberator is suspected. In a first step, the Liberator was investigated to study its behaviour during the discharge and characterize traces produced by the discharge. To fulfil this goal, some Liberators were printed and assembled. Six Liberators fired a round. The discharge of the weapons was done under specific conditions allowing to collect ballistics data and traces produced by the shooting. The results showed that the barrel tended to break between the ignition of the primer and the moment the projectile exited the muzzle. The speed of the projectiles reached 140m/s when the barrel broke, while it was about 170m/s when barrel remained intact. The trajectory of the projectiles was sometimes disrupted, and the projectile tumbled on itself. It was thus very difficult to characterize the trajectory. The cavity wound caused by the fastest bullet was typical of a handgun wound firing a FMJ projectile (penetration of 21cm in ballistics soap). On the other hand, the cavity caused by the slowest bullet was more representative of a splinter wound (penetration of 14cm in ballistics soap). The study of gunshot residues collected on adhesive targets showed the presence of unburnt particles and small perforations caused by polymer pieces that concentrated around the entry holes. PMID- 29602151 TI - Usefulness of hair analysis and psychological tests for identification of alcohol and drugs of abuse consumption in driving license regranting. AB - The implementation of the points-based driving license helps to change the drivers' behavior and is related to a reduction of traffic accidents and fatalities. In Spain, when a driver loses all points, the driving license is revoked, so the driver must enroll on a Driver Awareness and Re-education (DARE) course. However, at the moment offenders are not submitted to any test to confirm absence of alcohol or drugs of abuse consumption, even when 9% of Spanish drivers lose their driving license for driving under the influence (DUI). The objective of this pilot study was the comparison of the usefulness of psychological tests and hair analysis to identify those individuals with a chronic consumption of alcohol and drugs of abuse among drivers performing DARE courses. Volunteers were submitted to the AUDIT and DAST-10 tests. Also a hair sample was collected and analyzed for ethylglucuronide (EtG) (LOQ 5pg/mg) and 35 licit and illicit drugs (LOQ 5-50pg/mg) by LC-MS/MS. Sixty-one participants with a mean age of 37.2+/ 11.6years, and mainly men (90.2%), were recruited and performed AUDIT and DAST-10 tests. All hair samples were analyzed for EtG and 17 samples for licit and illicit drugs. Mean AUDIT score was 9.6 (SD=7.5), showing a value >=8 (indicator of hazardous and harmful alcohol use) in 52.4% of cases. Mean DAST-10 score was 2.9 (SD=3.3), but a score >=6 was detected in 21.3% of cases (indicating drug abuse or dependence). Twenty-two samples were positive for EtG, 8 for drugs of abuse (8 cocaine, 2 opioids, 1 amphetamines, 1 cannabis), and 3 for medicines. EtG concentration (20.7-1254.1pg/mg) was higher than the Society of Hair Testing (SoHT) cut-off for chronic alcohol consumption (>=30pg/mg) in 21 cases. All positive cases for methadone and cannabis, and half of positive cases for opioids and cocaine presented higher concentrations than SoHT cut-offs for chronic consumption. Higher AUDIT score and higher EtG concentration in hair were statistically associated with declaration of alcohol consumption >=4 times/month and with previous fine for DUI of alcohol. In addition, AUDIT scores and EtG concentration in hair had a moderate but significant Spearman correlation (r=0.331, p<0.05). The combination of psychological tests and hair analysis seems to be a promising tool to identify individuals with chronic and problematic consumption of alcohol and drugs of abuse. Moreover, their application during driving license regranting procedures could increase the effectiveness of DARE courses, reduce recidivism and improve road safety. PMID- 29602153 TI - Lymphocytic choriomeningitis virus infection of dendritic cells interferes with TLR-induced IL-12/IL-23 cytokine production in an IL-10 independent manner. AB - Dendritic cells produce IL-12 and IL-23 in response to viral and bacterial infection and these cytokines are responsible for successful pathogen clearance. How sequential viral and bacterial infections affect the production of IL-12 and IL-23 is currently not known. Our study demonstrates that in dendritic cells infected with Lymphocytic choriomeningitis virus (LCMV), TLR activation with bacterial PAMPs resulted in reduced IL-12 and IL-23 expression compared to non infected cells. Furthermore, expression of other proinflammatory cytokines, TNF alpha and IL-6, were not inhibited under these conditions. We discovered that TLR induced phosphorylation of p38 was significantly inhibited in LCMV-infected cells. We detected enhanced expression of suppressor of cytokine signalling (SOCS)-3 and IL-10. Yet, neutralizing IL-10 did not restore IL-12/IL-23 expression. Taken together, these results show that virus infection interferes with the magnitude of TLR-mediated inflammatory responses by repressing specific cytokine expression. PMID- 29602154 TI - The association of IL-33 and Foxp3 gene polymorphisms with recurrent pregnancy loss in Egyptian women. AB - Deregulated immunity is one of the most important factors implicated in recurrent pregnancy loss (RPL). The possible role of interleukin-33 (IL-33) and forkhead/winged helix transcription factor (Foxp3) in RPL have not been fully investigated. We aimed to evaluate IL-33 rs1929992 and Foxp3 rs2232365 single nucleotide polymorphisms (SNPs) and their serum levels in Egyptian RPL females. Blood samples were collected from 142 RPL patients and 123 women as healthy controls. IL-33 rs1929992 SNP was determined by polymerase chain reaction restriction fragment length polymorphism and Foxp3 rs2232365 SNP was determined using allele specific polymerase chain reaction. The serum IL-33 and Foxp3 levels were measured by enzyme linked immunosorbent assay. Foxp3 rs2232365 SNP showed statistically significant association with RPL. The risk of RPL was significantly higher in women carrying Foxp3 G allele than those carrying A allele. Lower serum levels of Foxp3 and IL-33 were observed in RPL patients than controls (P < 0.001). Foxp3 serum levels were much lower in carriers of G allele than those carrying A allele in all studied groups. Foxp3 rs2232365 SNP could be considered as a risk factor for RPL. The lowered serum levels of IL-33 and Foxp3 in RPL patients suggested that they might have an important role in the pathogenesis of the disease. Therefore, we hypothesized that Foxp3 polymorphisms may be important in RPL pathogenesis. PMID- 29602155 TI - Cytokine profile in autistic patients. AB - The etiology of Autism Spectrum Disorders (ASDs) as severe neurodevelopmental ailments is not known. However, several evidences point to dysregulation of immune system as an underlying cause of ASD. In the present study we evaluated the mRNA expression levels of TNF-alpha, TGF-beta, IFN-gamma, CXCL8, IL-1beta, IL 2, 1L-4, IL-6, IL-17 in whole blood samples of 30 ASD patients and 41 age and sex matched healthy subjects with means of real-time PCR. TNF-alpha, IL-6 and IL-17 have been shown to be significantly up-regulated in ASD patients compared with healthy subjects (P < 0.0001, P = 0.001 and P < 0.0001 respectively). IL-2 has been shown to be significantly down-regulated in total ASD patients (P < 0.0001). No significant difference has been found in expression levels of other cytokines between patients and healthy subjects. The present study provides further evidences for dysregulation of immune response in ASD patients. PMID- 29602156 TI - Interferon-gamma in mobilized stem cells: A possible prognostic marker in early post-transplant management in multiple myeloma. AB - INTRODUCTION: A complex network of cytokines in the bone marrow microenvironment has been implicated as an important factor in the pathogenesis of multiple myeloma (MM). Different cytokines have been studied in MM, both in peripheral blood and/or bone marrow, but there are few data correlating cytokines in leukapheresis product with post-transplant response depth to treatment. MATERIALS AND METHODS: In a retrospective cross-sectional study, levels of tumor necrosis factor alpha (TNF-alpha), transforming growth factor beta-1 (TGF-beta1) and interferon gamma (IFN-gamma) in peripheral hematopoietic stem cells/leukapheresis product (PHSC) of patients with MM eligible for transplantation were evaluated. Association of these cytokines with certain factors such as mobilized CD34 + cells/kg, staging, response to treatment and outcome were analyzed. RESULTS: The median baseline IFN-gamma level was 826.4 pg/mL. IFN-gamma levels in the leukapheresis product were significantly lower in patients who achieved complete response (CR) three months post-transplant when compared to patients with very good partial response (VGPR) (674.75 +/- 80.32 pg/mL versus 939.6 +/- 106.8 pg/mL, p = 0.02), respectively. Patients who lost depth of response at the third month post-transplant had a median level of IFN-gamma 1133, being considered "high-expressors" of IFN-gamma, while those reaching improved response were called "low-expressors" (median level IFN-gamma 485 pg/mL). Overall and progression-free survival did not have a statistically significant correlation with TNF-alpha, TGF-beta1 or IFN-gamma, as well as TNF-alpha and TGF-beta1 levels in post-transplant response assessment. CONCLUSION: IFN-gamma in PHSC seems to be an important biomarker of loss of response in MM, suggesting a role in early post transplant therapeutic management. PMID- 29602158 TI - Associations between friend conflict and affective states in the daily lives of adolescents. AB - This study examined the associations between friend conflict, defined as arguments with friends, and affective states using a daily diary design in a community sample of adolescents. Participants were 100 U.S. adolescents (13-17 years; 40% girls; 79% white). Adolescents completed an online survey on 14 consecutive evenings. Adolescents reported significantly higher anger/hostility, confusion, and tension/anxiety and less friendliness on days during which they experienced friend conflict relative to no-conflict days. However, no same-day associations for depressed affect, fatigue, or vigor were found. Adolescents experiencing friend conflict reported increased next-day anger/hostility, depressed affect, and tension/anxiety, but not other affective states. Higher levels of anger/hostility and depressed affect predicted an increased likelihood of next-day friend conflict. Conversely, higher levels of friendliness and vigor predicted a decreased likelihood of next-day friend conflict. These findings suggest that directional relationships between adolescents' friend conflicts and their affective states vary by affective domain. PMID- 29602157 TI - How lipids contribute to ion channel function, a fat perspective on direct and indirect interactions. AB - Membrane lipid composition and remodeling influence the function of ion channels. Polyunsaturated fatty acids (PUFAs) and their derivatives modulate ion channel function; whether this effect occurs directly by binding to the protein or indirectly through alteration of membranes' mechanical properties has been difficult to distinguish. There are a large number of studies addressing the effect of fatty acids; recent structural and functional analyses have identified binding sites and provided further evidence for the role of the plasma membrane in ion channel function. Here, we review cation channels that do not share a common topology or lipid-binding signature sequence, but for which there are recent compelling data that support both direct and indirect modulation by PUFAs or their derivatives. PMID- 29602159 TI - The longitudinal association between cognitive control capacities, suicidality, and depression during late adolescence and young adulthood. AB - This study examined the association between cognitive control capacities, suicidal thoughts and attempts, and depressive symptoms during late adolescence and young adulthood. The sample included 4192 participants (55.5% female) from the United States who participated in Waves III (2001-2002; respondent age 18-26 years) and IV (2007-2008; respondent age 24-33 years) of the National Longitudinal Study of Adolescent to Adult Health. Data were analyzed using structural equation modeling. Suicidality in late adolescence predicted depressive symptoms in young adulthood. Depressive symptoms were not predictive of later suicide ideation nor attempts. Working memory was associated with lower depressive symptoms. Higher verbal ability was associated with more suicidal thoughts but not attempts. Internal locus of control was associated with decreased depressive symptoms and suicidal thoughts/attempts in young adulthood. Findings suggest that cognitive control capacities developed in adolescence differentially predict depressive symptoms, suicidal thoughts, and suicide attempts in young adulthood. PMID- 29602160 TI - Stigma associated with autism among college students in Japan and the United States: An online training study. AB - Misconceptions and stigma associated with autism vary across cultures and may be influenced by various factors. Undergraduates in Japan (N = 212) and the United States (US) (N = 365) completed an online autism training, with pre- and posttest surveys assessing autism-related stigma (i.e., social distance) and knowledge. Aims were to examine differences in autism stigma and knowledge in Japan and the US, while extending prior research demonstrating benefits of an online autism training in the US and Lebanon to Japan. The results revealed that Japanese students indicated greater autism-related stigma than US students, which was not attributable to differences in autism knowledge, prior experience with autism, or college major. In both countries, students majoring in "helping professions" exhibited greater willingness to engage with people with autism. Japanese and US students varied in their misconceptions about autism, with significant differences on about half of the knowledge items. Japanese students showed decreased stigma after completing the autism training, yet continued to exhibit greater social distance towards people with autism relative to US students. Future research should focus on identifying specific cultural factors (e.g., conformity to social norms and homogeneity within communities) that contribute to fear and exclusion of people with autism in different societies. PMID- 29602162 TI - Reuma.pt - structure and innovation. PMID- 29602161 TI - Reuma.pt - the start and the purpose. PMID- 29602163 TI - Portuguese recommendations for the prevention, diagnosis and management of primary osteoporosis - 2018 update. AB - BACKGROUND: Advances in osteoporosis (OP)case definition, treatment options, optimal therapy duration and pharmacoeconomic evidence in the national context motivated the Portuguese Society of Rheumatology (SPR) to update the Portuguese recommendations for the diagnosis and management of osteoporosis published in 2007. METHODS: SPR bone diseases' working group organized meetings involving 55 participants (rheumatologists, rheumatology fellows and one OP specialist nurse) to debate and develop the document. First, the working group selected 11 pertinent clinical questions for the diagnosis and management of osteoporosis in standard clinical practice. Then, each question was investigated through literature review and draft recommendations were built through consensus. When insufficient evidence was available, recommendations were based on experts' opinion and on good clinical practice. At two national meetings, the recommendations were discussed and updated. A draft of the recommendations full text was submitted to critical review among the working group and suggestions were incorporated. A final version was circulated among all Portuguese rheumatologists before publication and the level of agreement was anonymously assessed using an online survey. RESULTS: The 2018 SPR recommendations provide comprehensive guidance on osteoporosis prevention, diagnosis, fracture risk assessment, pharmacological treatment initiation, therapy options and duration of treatment, based on the best available evidence. They attained desirable agreement among Portuguese rheumatologists. As more evidence becomes available, periodic revisions will be performed. Target audience and patient population: The target audience for these guidelines includes all clinicians. The target patient population includes adult Portuguese people. Intended use: These recommendations provide general guidance for typical cases. They may not be appropriate in all situations - clinicians are encouraged to consider this information together with updated evidence and their best clinical judgment in individual cases. PMID- 29602164 TI - The impact of patient global assessment in the definition of remission as a predictor of long-term radiographic damage in patients with rheumatoid arthritis: protocol for an individual patient data meta-analysis. AB - BACKGROUND: Remission is the target for management of rheumatoid arthritis (RA) and intensification of immunosuppressive therapy is recommended for those that do not achieve this status. Patient global assessment (PGA) is the single patient reported outcome considered in the American College of Rheumatology/European League Against Rheumatism remission criteria, but its use as target has been questioned. The primary aim of this study is to assess whether excluding PGA from the definition of disease remission changes the association of disease remission with long-term radiographic damage and physical function in patients with RA. METHODS: Individual Patient Data Meta-analysis using data from randomized controlled trials of biological and targeted synthetic agents, identified through ClinicalTrials.gov and PubMed. Different remission states will be defined: (i) 4v remission [tender (TJC28) and swollen 28-joint counts (SJC28) both<=1, C-reactive protein (CRP)<=1 (mg/dl), and PGA<=1 (0-10 scale)], (ii) 4v-near-remission (TJC28<=1, SJC28<=1, CRP<=1, and PGA>1), (iii) non-remission (TJC28>1 or SJC28>1 or CRP>1), all mutually exclusive, and (iv) 3v-remission (TJC28<=1, SJC28<=1, CRP<=1). Likelihood ratios will be used to descriptively compare whether meeting the 3v and 4v-remission criteria in a single visit (at 6 or 12 months) predicts good outcome in the second year (1-2y). Differences in the predictive value of PGA in the definition of remission will be assessed by comparing the three mutually exclusive disease states using logistic regression analysis. Good outcome is defined primarily by radiographic damage (no deterioration in radiographic scores, whatever the instrument used in each trial), and secondarily by functional disability (Health Assessment Questionnaire consistently <=0.5 and no deterioration), and their combination ("overall good outcome"). Additional analyses will consider longer periods over which to (concurrently) define remission status and outcome (between 1-5y and 1-10y), different cut-offs to define good radiographic outcome (change <=0.5, <=3 and <=5 in radiographic score), sustained remission and the influence of treatment and other clinical factors. DISCUSSION: If 4v-remission and 4v-near-remission are associated with a similar probability of good outcomes, particularly regarding structural damage, the 3v-remission (excluding PGA) could be adopted as the target for immunosuppressive therapy. Patients' perspectives would remain essential, but assessed separately from disease activity, using instruments adequate to guide adjunctive therapies. Systematic review registration: PROSPERO, CRD42017057099. PMID- 29602165 TI - Sonographic evaluation of salivary glands in juvenile Sjogren's syndrome. AB - : IIntroduction: Sjogren's syndrome in childhood is a rare autoimmune disease and mostly under-diagnosed. The aim of this study is to highlight the importance of ultrasonographic assessment of the salivary glands in children with recurrent parotitis and positive autoantibodies. Two cases of ultrasonographic patterns typical of Sjogren's syndrome have been described below. Case 1: Female, 7 years old, reporting for 2 years recurrent parotitis, xerophthalmia, xerostomia, polyarthralgia and fever. Immunological tests were positive for antinuclear antibodies, rheumatoid factor, anti-SSA/Ro and anti-SSB/La. Salivary glands ultrasound was consistent with Grade 4 by the B-mode method and the spectral Doppler with presence of intense Power Doppler signal and decreased vessels internal resistance, supporting the diagnosis of juvenile Sjogren's syndrome. Case 2: Female, 10 years old, reporting recurrent parotitis for 1 year and polyarthritis for 10 days. The supplementary tests revealed positive antibodies for Sjogren's syndrome. Salivary glands Ultrasound and Spectral Doppler were consistent with chronic and active inflammatory process of the salivary glands in the juvenile Sjogren's syndrome. DISCUSSION: Salivary glands ultrasound can be a useful exam in the diagnosis of juvenile Sjogren's syndrome. PMID- 29602166 TI - More than Ankylosing Spondylitis. PMID- 29602167 TI - A re-audit of cervical screening uptake in a dermatology cohort on immunosuppressive medications. PMID- 29602168 TI - Effect of SO2 on sugars, indicators of Maillard reaction, and browning in dried apricots during storage. AB - BACKGROUND: The effect of sulfur dioxide (SO2 ) concentration was determined on sugars and indicators in the Maillard reaction (MR), and on browning, in sulfured, dried apricots (SDAs) during storage at 4, 20 and 30 degrees C for 379 days. RESULTS: As SO2 concentration increased, the content of reducing sugars involved in the MR also increased. The preventive effect of SO2 on the MR could not result from the binding of SO2 to reducing sugars. Before storage, furosine was detected in the non-SDAs but 5-hydroxymethylfurfural (HMF) was not detected. Even the lowest SO2 concentration (451 mg kg-1 ) was sufficient to prevent the formation of furosine and HMF during drying of apricots. CONCLUSION: Formation of furosine and HMF in all samples during storage at 20 and 30 degrees C for 379 days indicated that SO2 could not prevent the first and intermediate stages of MR in SDAs during storage. Thus, the main prevention effect of SO2 on browning in SDAs occurred during drying, not storage. (c) 2018 Society of Chemical Industry. PMID- 29602169 TI - Allergic phenotype of chronic rhinosinusitis based on radiologic pattern of disease. AB - OBJECTIVES/HYPOTHESIS: Polypoid edema of the middle turbinate is a marker of inhalant allergy. Extensive edematous changes may result in limited central nasal and sinus disease, which has been called central compartment atopic disease (CCAD). Radiologically, this is seen as soft tissue thickening in the central portion of the sinonasal cavity with or without paranasal sinus involvement. When the sinuses are involved, the soft tissue thickening spares the sinus roof or lateral wall (centrally limited). This centrally limited radiological pattern was assessed among chronic rhinosinusitis (CRS) patients and compared to allergy status. STUDY DESIGN: Diagnostic cross-sectional study. METHODS: This study included consecutive CRS patients without prior sinus surgery. Computed tomography (CT) scans of the paranasal sinuses were blindly assessed and allergy status was confirmed by serum or skin testing. Individual sinus cavities were defined as either centrally limited or diffuse disease. The radiological pattern that may predict allergy was determined, and its diagnostic accuracy was calculated. RESULTS: One hundred twelve patients diagnosed to have CRS, representing 224 sides, were assessed (age 46.31 +/- 13.57 years, 38.39% female, 41.07% asthma, Lund-Mackay CT score 15.88 +/- 4.35, 56.25% atopic). The radiological pattern defined by centrally limited changes in all of the paranasal sinuses was associated with allergy status (73.53% vs. 53.16%, P = .03). This predicted atopy with 90.82% specificity, 73.53% positive predictive value, likelihood positive ratios of 2.16, and diagnostic odds ratio of 4.59. CONCLUSIONS: A central radiological pattern of mucosal disease is associated with inhalant allergen sensitization. This group may represent a CCAD subgroup of patients with mainly allergic etiology. LEVEL OF EVIDENCE: 3b Laryngoscope, 128:2015-2021, 2018. PMID- 29602170 TI - Effects of temperature and water availability on light energy utilization in photosynthetic processes of Deschampsia antarctica. AB - Regional climate change in Antarctica would favor the carbon assimilation of Antarctic vascular plants, since rising temperatures are approaching their photosynthetic optimum (10-19 degrees C). This could be detrimental for photoprotection mechanisms, mainly those associated with thermal dissipation, making plants more susceptible to eventual drought predicted by climate change models. With the purpose to study the effect of temperature and water availability on light energy utilization and putative adjustments in photoprotective mechanisms of Deschampsia antarctica Desv., plants were collected from two Antarctic provenances: King George Island and Lagotellerie Island. Plants were cultivated at 5, 10 and 16 degrees C under well-watered (WW) and water-deficit (WD, at 35% of the field capacity) conditions. Chlorophyll fluorescence, pigment content and de-epoxidation state were evaluated. Regardless of provenances, D. antarctica showed similar morphological, biochemical and functional responses to growth temperature. Higher temperature triggered an increase in photochemical activity (i.e. electron transport rate and photochemical quenching), and a decrease in thermal dissipation capacity (i.e. lower xanthophyll pool, Chl a/b and beta carotene/neoxanthin ratios). Leaf mass per unit area was reduced at higher temperature, and was only affected in plants exposed to WD at 16 degrees C and exhibiting lower electron transport rate and amount of chlorophylls. D. antarctica is adapted to frequent freezing events, which may induce a form of physiological water stress. Photoprotective responses observed under WD contribute to maintain a stable photochemical activity. Thus, it is possible that short-term temperature increases could favor the photochemical activity of this species. However, long-term effects will depend on the magnitude of changes and the plant's ability to adjust to new growth temperature. PMID- 29602171 TI - Appendicectomy during pregnancy and the risk of preterm birth: A population data linkage study. AB - BACKGROUND: Suspected appendicitis is a common non-obstetric indication for emergency abdominal surgery during pregnancy. AIMS: Assess the risk of preterm birth and other maternal and neonatal adverse birth outcomes following appendicectomy during pregnancy. MATERIALS AND METHODS: Population-based data linkage study of women with singleton births in New South Wales, Australia, 2002 2014. Pregnancies with appendicitis and appendicectomy were compared to pregnancies without appendicitis. Crude and adjusted hazard ratios (aHR) with 95% confidence intervals (CI) for preterm birth were estimated. Modified Poisson regression with robust variance was used to estimate crude and adjusted risk ratios (aRR) with 99% CI for other outcomes. RESULTS: Of 1 124 551 eligible pregnancies, 1024 (0.9/1000 pregnancies) had appendicitis and appendicectomy. Of these, 566 (55.3%) had laparoscopic and 458 (44.7%) had open appendicectomy. Appendicectomy at later gestational ages was associated with increasing rates of preterm birth. After adjustment for maternal and pregnancy factors, appendicectomy was associated with increased risk of preterm birth (overall aHR 1.73, 95% CI 1.42-2.09; planned aHR 2.08, 95% CI 1.60-2.72), maternal morbidity (aRR 2.68, 99% CI 1.88-3.83) and neonatal morbidity (aRR 1.42, 99% CI 1.03-1.94). However, there was no difference in perinatal mortality rates. CONCLUSION: Appendicectomy during pregnancy is associated with increased risk of spontaneous and planned preterm birth, maternal and neonatal morbidity. Availability of resources to prevent or manage preterm labour should be considered when appendicectomy is performed at gestational ages of 20 weeks or more. PMID- 29602172 TI - No differences in olanzapine- and risperidone-related weight gain between women and men: a meta-analysis of short- and middle-term treatment. AB - OBJECTIVE: A plethora of data deriving from single studies as well as meta analyses demonstrates that weight gain is associated with the exposure to the majority of antipsychotics (AP). However, potential sex differences have widely evaded the attention of AP treatment trials. It is hypothesised that female patients gain more weight compared with male patients due to their enhanced susceptibility to adverse drug reactions. METHOD: A meta-analysis was conducted using clinical trials of AP that reported weight change separately for female and male patients. Duration of AP use was stratified in four categories: <6 weeks, 6 16 weeks, 16-38 weeks and >38 weeks. Forest plots were generated for men and women separately, stratified by AP as well as by duration of use. Sex differences were tested by performing meta-regression. RESULTS: Data of 26 studies were used in the present analysis because sufficient data were available only for olanzapine, risperidone and the no-medication group. Both female and male patients showed considerable weight gain after switch or initiate of olanzapine or risperidone, but meta-regression analyses did not show significant sex differences. CONCLUSION: The present meta-analysis revealed that sex differences in AP-related weight gain have been under investigated hampering the detection of sex-specific patterns. In chronic patients switching to olanzapine or risperidone receiving short-or middle-term treatment, AP were associated with weight gain in both sex subgroups and no significant differences were reported. PMID- 29602173 TI - Antifungal effect of phenolic extract of fermented rice bran with Rhizopus oryzae and its potential use in loaf bread shelf life extension. AB - BACKGROUND: In this study the antifungal potential of a phenolic extract obtained from rice bran fermented with Rhizopus oryzae CECT 7560 and its application in the elaboration of bread was assessed. RESULTS: Eighteen compounds with antifungal potential were identified by LC-ESI-qTOF-MS in the extract: organic acids, gallates and gallotannins, flavonoids, ellagic acid and benzophenone derivatives. The extract was active against strains of Fusarium, Aspergillus and Penicillium, with minimum inhibitory concentration ranging from 390 to 3100 ug mL 1 and minimum fungicidal concentration variable from 780 to 6300 ug mL-1 . The strains that were most sensitive to the phenolic extract were F. graminearum, F. culmorum, F. poae, P. roqueforti, P. expansum and A. niger. The phenolic extract added at 5 and 1 g kg-1 concentrations in the preparation of bread loaves contaminated with P. expansum produced a reduction of 0.6 and 0.7 log CFU g-1 . The bread loaves treated with calcium propionate and 10 g kg-1 of the phenolic extract evidenced an improvement in their shelf lives of 3 days. CONCLUSION: The phenolic extract assessed in this study could be considered as an alternative for inhibiting toxigenic fungi and as a substitute for synthetic compounds in food preservation. (c) 2018 Society of Chemical Industry. PMID- 29602174 TI - Expression of programmed death ligand 1 is associated with poor prognosis in myeloid sarcoma patients. AB - Myeloid sarcoma (MS) is a rare condition and is an extramedullary tumour of immature myeloid cells. It is now known that the programmed death 1 (PD 1)/programmed death ligand 1 (PD-L1) pathway suppresses the host antitumor responses and that these products are expressed on both tumour cells and tumour infiltrating cells in various malignancies. However, little is known about the significance of PD-1/PD-L1 expression on tumour cells and tumour microenvironmental cells in MS. To investigate the clinicopathological significance of PD-1/PD-L1 expression in MS, we analyzed 98 patients by immunohistochemistry. Of these, 10.2% of cases had neoplastic tumour cells positive for PD-L1 (nPD-L1+ ). However, the rate of nPD-L1+ was <5% (range: 0.27 to 2.97%). On the other hand, PD-L1 expression on 1 or more of stromal cells in the tumour microenvironment (miPD-L1+ ) was observed in 37.8% of cases. Because all nPD-L1+ cases expressed PD-1 on less than 5% of tumour cells, we compared the miPD-L1+ and miPD-L1- groups. There was a correlation between miPD-L1+ status and the number of PD-1-expressing tumour -infiltrating lymphocytes (PD-1+ TILs; P = .0229). miPD-L1+ was found to be associated with poorer overall survival and progression-free survival (P = .00392, P = .00261, respectively). Multivariate analysis also confirmed miPD-L1+ to be an independent poor prognostic factor. In conclusion, our study indicated that the immunotherapy blocking the PD-1/PD-L1 pathway may improve the clinical outcome of MS. PMID- 29602175 TI - Effect of Anemia on Prognosis in Patients on Extracorporeal Membrane Oxygenation. AB - Anemia is a component of the pathological triangle in cardiorenal anemia syndrome and is a risk factor for mortality in acute respiratory distress syndrome. This study assessed the predictive value of anemia for outcomes in critically ill patients receiving extracorporeal membrane oxygenation (ECMO) support. This retrospective study analyzed patients who received ECMO support at the cardiovascular surgery intensive care unit in the study institute between July 2003 and March 2012. Patient data, such as demographic information, etiologies of ECMO implementation, clinical parameters, and in-hospital and 6-month mortality rates, were statistically analyzed. The overall in-hospital mortality rate among the enrolled 295 patients was 55.6%. Multivariate logistical regression analysis indicated that age, albumin levels, sequential organ failure assessment (SOFA) score, and hemoglobin (Hb) level on ECMO day 1 exhibited independent prognostic significance for predicting in-hospital mortality rate. The SOFA score exhibited the highest areas under the receiver operating characteristic curve value (0.812 +/- 0.025). The Hb level on ECMO day 1 exhibited satisfactory calibration and discriminatory power. The cumulative 6-month survival rates differed significantly between patients with Hb levels less than and more than 8.85 g/dL (30.6 vs. 54.0%, respectively, P < 0.001). This study indicated that old age, low albumin levels, low Hb levels, and higher SOFA scores on ECMO day 1 increased the risk of mortality. The Hb level is a readily measurable parameter and with good predictive power for critical patients on ECMO. PMID- 29602176 TI - Wang's Forceps-Assisted Percutaneous Insertion and Fixation of Peritoneal Dialysis Catheter. AB - Percutaneous insertion of peritoneal dialysis catheters is theoretically most preferred by nephrologists because of the advantages of bedside performing, surgery independence, and minimal injury over other procedures of catheter placement such as open surgical dissection or laparoscopic operation. However, blindly placing catheters in the percutaneous procedure brings the risk of catheter malposition or bowel perforation; this largely retarded it's implementation. We had previously developed a novel technique termed "Wang's forceps-assisted catheter insertion and fixation," which had been successfully applied in the open surgical catheter insertion and displaced catheter reposition in our center. In this study, we further explored the possibility of applying the Wang's forceps in the procedure of percutaneous catheter insertion both in porcine model and patients with end stage renal disease (ESRD). A total of three miniature pigs successfully received percutaneous catheter insertion using Seldinger's technique with Wang's forceps assistance. The catheters were all placed in the right position and functioning well in dialysate drainage. This novel method of percutaneous catheter insertion was then performed on 20 ESRD patients. The procedure showed effective time-saving with the average operating time of 29.2 +/- 3.53 min and was well tolerated by patients with minimal pain and injury. During a follow-up time of 6 months, no complications of catheter displacement, leakage, or blockade occurred. Our preliminary observation demonstrates that utilization of Wang's forceps in a percutaneous procedure conferred benefits of accurately placing and fixing catheters while preserving the merits of minimal invasion and simple performance. PMID- 29602177 TI - Hospitalization among migrants in Italy: Access to health care as an opportunity for integration and inclusion. AB - This paper analyzes migrant access to health care by comparing hospitalizations of native and immigrant population with respect the Tuscany Region (Italy). In the analyses, a critical gap both for legal and undocumented migrant population is highlighted. Indeed, we found some key differences between the migrant and native populations related to the use of specific hospital services in Tuscany and, indirectly, of community and primary care services. Moreover, especially for undocumented migrants, hospitals seem to be the only point of access to the health-care system for migrant populations. The results suggest that the Italian health-care system is unable to ensure an equitable access to health services. In this context, maternity care could be a key point of access to the welfare system that allows participation in the health system not only for mothers but also for all migrant family members. PMID- 29602179 TI - A comparison of two centrifuge techniques for constructing vulnerability curves: insight into the 'open-vessel' artifact. AB - A vulnerability curve (VC) describes the extent of xylem cavitation resistance. Centrifuges have been used to generate VCs for decades via static- and flow centrifuge methods. Recently, the validity of the centrifuge techniques has been questioned. Researchers have hypothesized that the centrifuge techniques might yield unreliable VCs due to the open-vessel artifact. However, other researchers reject this hypothesis. The focus of the dispute is centered on whether exponential VCs are more reliable when the static-centrifuge method is used rather than the flow-centrifuge method. To further test the reliability of the centrifuge technique, two centrifuges were manufactured to simulate the static- and flow-centrifuge methods. VCs of three species with open vessels of known lengths were constructed using the two centrifuges. The results showed that both centrifuge techniques produced invalid VCs for Robinia because the water flow through stems under mild tension in centrifuges led to an increasing loss of water conductivity. In addition, the injection of water in the flow-centrifuge exacerbated the loss of water conductivity. However, both centrifuge techniques yielded reliable VCs for Prunus, regardless of the presence of open vessels in the tested samples. We conclude that centrifuge techniques can be used in species with open vessels only when the centrifuge produces a VC that matches the bench dehydration VC. PMID- 29602178 TI - Ethanol Exposure History and Alcoholic Reward Differentially Alter Dopamine Release in the Nucleus Accumbens to a Reward-Predictive Cue. AB - BACKGROUND: Conditioned stimuli (CS) that predict reward delivery acquire the ability to induce phasic dopamine release in the nucleus accumbens (NAc). This dopamine release may facilitate conditioned approach behavior, which often manifests as approach to the site of reward delivery (called "goal-tracking") or to the CS itself (called "sign-tracking"). Previous research has linked sign tracking in particular to impulsivity and drug self-administration, and addictive drugs may promote the expression of sign-tracking. Ethanol (EtOH) acutely promotes phasic release of dopamine in the accumbens, but it is unknown whether an alcoholic reward alters dopamine release to a CS. We hypothesized that Pavlovian conditioning with an alcoholic reward would increase dopamine release triggered by the CS and subsequent sign-tracking behavior. Moreover, we predicted that chronic intermittent EtOH (CIE) exposure would promote sign-tracking while acute administration of naltrexone (NTX) would reduce it. METHODS: Rats received 14 doses of EtOH (3 to 5 g/kg, intragastric) or water followed by 6 days of Pavlovian conditioning training. Rewards were a chocolate solution with or without 10% (w/v) alcohol. We used fast-scan cyclic voltammetry to measure phasic dopamine release in the NAc core in response to the CS and the rewards. We also determined the effect of NTX (1 mg/kg, subcutaneous) on conditioned approach. RESULTS: Both CIE and alcoholic reward, individually but not together, associated with greater dopamine to the CS than control conditions. However, this increase in dopamine release was not linked to greater sign-tracking, as both CIE and alcoholic reward shifted conditioned approach from sign-tracking behavior to goal tracking behavior. However, they both also increased sensitivity to NTX, which reduced goal-tracking behavior. CONCLUSIONS: While a history of EtOH exposure or alcoholic reward enhanced dopamine release to a CS, they did not promote sign tracking under the current conditions. These findings are consistent with the interpretation that EtOH can stimulate conditioned approach, but indicate that the conditioned response may manifest as goal-tracking. PMID- 29602180 TI - What, where and when? Using Google Trends and Google to investigate patient needs and inform pharmacy practice. AB - OBJECTIVES: The aim was to provide a comprehensive overview (using pertinent examples) of the various ways that Google Trends and Google data could inform pharmacy practice. The objectives were to: examine what type of information people search for in relation to a common class of medicines; ascertain where people are directed to (websites) following an initial search for a medicine or medical condition; and establish information about when they search. METHODS: The methodology differed depending on whether Google Trends or Google was being interrogated, but the search domain was always limited to the United Kingdom. Google Trends was queried, typically for a 5-year time frame, and data downloaded for many search inputs relating to medical conditions (self-treatable and non self-treatable) and medicines (bought over-the-counter and prescribed). Google was queried and data collected for searches related to 'antibiotics'. KEY FINDINGS: Google Trends revealed a previously unknown seasonality pattern for irritable bowel syndrome. Related searches for 'antibiotics' revealed a high level of interest in the appropriateness of concomitant alcohol consumption and queries about what antibiotics are. Largely, people were being directed to reputable websites following their initial search input about a prescription-only medicine. However, searches for over-the-counter medicines were more likely to lead to commercial domains. CONCLUSIONS: This is one of the first studies to investigate use of Google Trends and Google in a pharmacy-specific context. It is relevant for practice as it could inform marketing strategies, public health policy and help tailor patient advice and counselling. PMID- 29602181 TI - Highly Efficient Spectrally Stable Red Perovskite Light-Emitting Diodes. AB - Perovskite light-emitting diodes (LEDs) have recently attracted great research interest for their narrow emissions and solution processability. Remarkable progress has been achieved in green perovskite LEDs in recent years, but not blue or red ones. Here, highly efficient and spectrally stable red perovskite LEDs with quasi-2D perovskite/poly(ethylene oxide) (PEO) composite thin films as the light-emitting layer are reported. By controlling the molar ratios of organic salt (benzylammonium iodide) to inorganic salts (cesium iodide and lead iodide), luminescent quasi-2D perovskite thin films are obtained with tunable emission colors from red to deep red. The perovskite/polymer composite approach enables quasi-2D perovskite/PEO composite thin films to possess much higher photoluminescence quantum efficiencies and smoothness than their neat quasi-2D perovskite counterparts. Electrically driven LEDs with emissions peaked at 638, 664, 680, and 690 nm have been fabricated to exhibit high brightness and external quantum efficiencies (EQEs). For instance, the perovskite LED with an emission peaked at 680 nm exhibits a brightness of 1392 cd m-2 and an EQE of 6.23%. Moreover, exceptional electroluminescence spectral stability under continuous device operation has been achieved for these red perovskite LEDs. PMID- 29602182 TI - Disease site as a determinant of survival outcome in patients with systemic anaplastic lymphoma kinase positive anaplastic large cell lymphoma with extranodal involvement: an analysis of 1306 cases from the US National Cancer Database. AB - Systemic anaplastic lymphoma kinase positive (ALK+) anaplastic large cell lymphoma with extranodal involvement (ALCL-E) is a rare form of non-Hodgkin lymphoma. No large study in the literature has compared the survival outcomes among different primary extranodal sites of involvement in ALK+ ALCL-E. We identified 1306 patients with ALK+ ALCL-E diagnosed between 2004 and 2014 in the US National Cancer Database, among whom 387 had primary extranodal site in the chest/abdomen/pelvis, 103 in the bone, 62 in the central nervous system, 134 in the head and neck and 620 in the cutaneous/soft tissue. Younger age, lower Charlson-Deyo score, lower clinical stage, receipt of chemotherapy and receipt of radiotherapy were predictors of longer overall survival. Patients with extranodal involvement of central nervous system and chest/abdomen/pelvis had shorter overall survival than those with involvement of head and neck, bone, and cutaneous/subcutaneous tissue after adjusting for confounding variables. We recommend treating these patients upfront with more aggressive therapy. PMID- 29602183 TI - Gene expression profiling in healthy newborns from diverse localities of the Czech Republic. AB - Prenatal exposure to air pollution is associated with intrauterine growth restriction and low birth weight. Gene expression changes in newborns in relation to air pollution have not been sufficiently studied. We analyzed whole genome expression in cord blood leukocytes of 202 newborns from diverse localities of the Czech Republic, differing among other factors in levels of air pollution: the district of Karvina (characterized by higher concentration of air pollutants) and Ceske Budejovice (lower air pollution levels). We aimed to identify differentially expressed genes (DEGs) and pathways in relation to locality and concentration of air pollutants. We applied the linear model to identify the specific DEGs and the correlation analysis, to investigate the relationship between the concentrations of air pollutants and gene expression data. An analysis of biochemical pathways and gene set enrichment was also performed. In general, we observed modest changes of gene expression, mostly attributed to the effect of the locality. The highest number of DEGs was found in samples from the district of Karvina. A pathway analysis revealed a deregulation of processes associated with cell growth, apoptosis or cellular homeostasis, immune response related processes or oxidative stress response. The association between concentrations of air pollutants and gene expression changes was weak, particularly for samples collected in Karvina. In summary, as we did not find a direct effect of exposure to air pollutants, we assume that the general differences in the environment, rather than actual concentrations of individual pollutants, represent a key factor affecting gene expression changes at delivery. Environ. Mol. Mutagen. 59:401-415, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29602184 TI - Twisted Acoustics: Metasurface-Enabled Multiplexing and Demultiplexing. AB - Metasurfaces are used to enable acoustic orbital angular momentum (a-OAM)-based multiplexing in real-time, postprocess-free, and sensor-scanning-free fashions to improve the bandwidth of acoustic communication, with intrinsic compatibility and expandability to cooperate with other multiplexing schemes. The metasurface-based communication relying on encoding information onto twisted beams is numerically and experimentally demonstrated by realizing real-time picture transfer, which differs from existing static data transfer by encoding data onto OAM states. With the advantages of real-time transmission, passive and instantaneous data decoding, vanishingly low loss, compact size, and high transmitting accuracy, the study of a-OAM-based information transfer with metasurfaces offers new route to boost the capacity of acoustic communication and great potential to profoundly advance relevant fields. PMID- 29602185 TI - Stakeholder perspectives regarding transfer of free maternity services to National Health Insurance Fund in Kenya: Implications for universal health coverage. AB - BACKGROUND: Kenya is developing strategies to finance health care through prepayment to achieve universal health coverage (UHC). Plans to transfer free maternity services (FMS) from the Ministry of Health to the National Health Insurance Fund (NHIF) are a step towards UHC. We examined views of health workers and women regarding the transition of FMS to NHIF to inform the process. METHODS: In-depth interviews among 14 facility-level managers and providers, 11 county level managers, and 21 focus group discussions with women who gave birth before and after the introduction of FMS. Data were analyzed thematically. RESULTS: The transfer is a mechanism of achieving UHC, eliminating dependency on free services, and encouraging people to take responsibility of their health. However, skepticism regarding the efficiency of NHIF may limit support. Diverse and robust systems were recommended for enrollment of clients while standardization of services through accreditation and quality assurance linked to performance-based reimbursement would improve greater predictability in the payment schedule and better coverage of referrals and complications. CONCLUSION: Transitioning FMS to NHIF provides an opportunity for the Ministry of Health to sharpen its role as policymaker and develop a comprehensive health care financing strategy for the country towards achieving UHC. PMID- 29602187 TI - Metformin blocks mitochondrial membrane potential and inhibits sperm motility in fresh and refrigerated boar spermatozoa. AB - Metformin is clinically used to treat diabetes. Given its role-impacting metabolism, metformin has been also added to semen cryopreservation media showing specie-dependent effects. We aimed to investigate metformin effects in both fresh (38.5 degrees C for 2, 24 hr) and refrigerated (17 degrees C for 10 days) boar spermatozoa. Metformin (2 hr) does not affect fresh sperm viability, membrane lipid organization nor acrosome integrity. However, metformin (24 hr) blocks sperm DeltaPsim and significantly reduces % motile spermatozoa (65%), % progressive spermatozoa (50%), % rapid (100%), velocities VCL (69%), VSL (86%), VAP (78%) and motility coefficients. Metformin-including extender does not modify sperm viability, membrane lipid organization or acrosome integrity. Furthermore, it significantly reduces high DeltaPsi-population spermatozoa at refrigeration day 4. Metformin also significantly reduces sperm motility during refrigeration. Summarizing, metformin inhibits both boar sperm DeltaPsi and motility in any sperm condition studied: fresh and refrigerated. These findings dissuade metformin as an additive to improve boar sperm quality. PMID- 29602186 TI - Molecular mechanisms underlying striatal synaptic plasticity: relevance to chronic alcohol consumption and seeking. AB - The striatum, the input structure of the basal ganglia, is a major site of learning and memory for goal-directed actions and habit formation. Spiny projection neurons of the striatum integrate cortical, thalamic, and nigral inputs to learn associations, with cortico-striatal synaptic plasticity as a learning mechanism. Signaling molecules implicated in synaptic plasticity are altered in alcohol withdrawal, which may contribute to overly strong learning and increased alcohol seeking and consumption. To understand how interactions among signaling molecules produce synaptic plasticity, we implemented a mechanistic model of signaling pathways activated by dopamine D1 receptors, acetylcholine receptors, and glutamate. We use our novel, computationally efficient simulator, NeuroRD, to simulate stochastic interactions both within and between dendritic spines. Dopamine release during theta burst and 20-Hz stimulation was extrapolated from fast-scan cyclic voltammetry data collected in mouse striatal slices. Our results show that the combined activity of several key plasticity molecules correctly predicts the occurrence of either LTP, LTD, or no plasticity for numerous experimental protocols. To investigate spatial interactions, we stimulate two spines, either adjacent or separated on a 20-MUm dendritic segment. Our results show that molecules underlying LTP exhibit spatial specificity, whereas 2-arachidonoylglycerol exhibits a spatially diffuse elevation. We also implement changes in NMDA receptors, adenylyl cyclase, and G protein signaling that have been measured following chronic alcohol treatment. Simulations under these conditions suggest that the molecular changes can predict changes in synaptic plasticity, thereby accounting for some aspects of alcohol use disorder. PMID- 29602188 TI - Laser Rewritable Dichroics through Reconfigurable Organic Charge-Transfer Liquid Crystals. AB - Charge-transfer materials based on the self-assembly of aromatic donor-acceptor complexes enable a modular organic-synthetic approach to develop and fine-tune electronic and optical properties, and thus these material systems stand to impact a wide range of technologies. Through laser-induction of temperature gradients, in this study, user-defined patterning of strongly dichroic and piezoelectric organic thin films composed of donor-acceptor columnar liquid crystals is shown. Fine, reversible control over isotropic versus anisotropic regions in thin films is demonstrated, enabling noncontact writing/rewriting of micropolarizers, bar codes, and charge-transfer based devices. PMID- 29602189 TI - e-Screening revolution: A novel approach to developing a delirium screening tool in the intensive care unit. AB - OBJECTIVES: Delirium is common in the intensive care unit (ICU), often affecting older patients. A bedside electronic tool has the potential to revolutionise delirium screening. Our group describe a novel approach to the design and development of delirium screening questions for the express purpose of use within an electronic device. Preliminary results are presented. METHODS: Our group designed a series of tests which targeted the clinical criteria for delirium according to Diagnostic and Statistical Manual of Mental Disorders - Fifth Edition (DSM-5) criteria against predefined requirements, including applicability to older patients. RESULTS: Candidate questions, including tests of attention and awareness, were devised and then refined by an expert multidisciplinary group, including geriatricians. A scoring scheme was constructed, with testing to failure an indicator of delirium. The device was tested in healthy controls, aged 20-80 years, who were recorded as being without delirium. CONCLUSION: e-Screening for delirium requires a novel approach to instrument design but may revolutionise recognition of delirium in ICU. PMID- 29602190 TI - Out-of-hours intensive care unit admission and 90-day mortality: a Danish nationwide cohort study. AB - BACKGROUND: Mortality rates in critically ill adult patients admitted to the intensive care unit (ICU) remains high, and numerous patient- and disease-related adverse prognostic factors have been identified. In recent years, studies in a variety of emergency conditions suggested that outcome is dependent on the time of hospital admission. The importance of out-of-hours admission to the ICU has been sparsely evaluated and with ambiguous findings. We assessed the association between out-of-hours (16:00 to 07:00) and weekend admission to the ICU, respectively, and 90-day mortality in a nationwide cohort. METHODS: We included all Danish adult patients admitted to the ICU between 1 January 2011 and 30 June 2014, with an ICU stay > 24 h. The crude and adjusted association between out-of hours and weekend admission and 90-day mortality was assessed (odds ratio (ORs) with 95% confidence intervals (CI)). RESULTS: A total of 44,797 patients were included, 53.3% were admitted out-of-hours, and 22.6% during weekends. Median age was 67 years (interquartile range (IQR) 55-76), and median SAPS II was 42 (IQR 30 54). Patients admitted in-hours vs. out-of-hours displayed a 90-day mortality rate of 41.0% vs. 44.2%. The adjusted association (OR with 95% CI) between out-of hours admission and 90-day mortality was 1.07 (1.02-1.11), and the adjusted association (OR with 95% CI) between weekend admission and 90-day mortality was 1.10 (1.05-1.15). CONCLUSION: This nationwide study suggests that critically ill adult patients admitted to the ICU during weekends and out-of-hours, and with an ICU stay > 24 h are at slightly increased risk of mortality. PMID- 29602191 TI - Perinatal substance use, residential instability, and negative behavioral outcomes among adolescents: Lessons from the maternal lifestyle study. AB - PROBLEM: Both housing instability and prenatal substance use are known risk factors for behavioral problems among adolescents. METHODS: The purpose of this study was to investigate the association between residential instability (residential mobility and homelessness) and delinquent behaviors among adolescents enrolled in the maternal lifestyle study (MLS), a 16-year research study that explored short-term and long-term effects of in-utero exposure to cocaine and/or opiates (N = 736). Logistic regression was used to measure the association between housing problems with youth crimes, school delinquency, and substance use at 11, 15, and 16 years of age. FINDINGS: Both high-frequency residential mobility and homelessness were associated with deviant behaviors across the entire sample of children born with in-utero cocaine/opiate exposure and those without. CONCLUSIONS: Psychiatric nursing care of youth should include a comprehensive assessment of residential instability to identify risk and target potential interventions. PMID- 29602192 TI - Ultralarge Nanosheets Fabricated by the Hierarchical Self-Assembly of Porphyrin Ended Hyperbranched Poly (ether amine) (TPP-hPEA). AB - An ultralarge sheet with remarkable lateral dimensions of 10 um * 10 um-20 um * 20 um is fabricated by the hierarchical self-assembly of porphyrin-ended hyperbranched poly(ether amine) (tetraphenylporphyrin (TPP)-hPEA) in solution. The obtained TPP-hPEA amphiphiles can self-assemble from ultrathin single-layered nanosheets with a thickness of 4 nm to ultralarge multilayered nanosheets with thicknesses from 30 to 70 nm. The lateral dimensions increase from 2 * 2 um to 5 * 5 um, and eventually to 10 * 10 um. In-situ dynamic light scattering and UV-vis spectroscopy studies suggest a hierarchical growth self-assembly mechanism with a self-assembly process that relies on pi-pi stacking. This 2D self-assembly method provides a significant potential guide for the preparation of ultralarge nanosheets in solution. PMID- 29602193 TI - Microvascular endothelial function is an independent predictor for albuminuria progression among Asians with type 2 diabetes-A prospective cohort study. AB - OBJECTIVE: We aim to investigate whether microvascular endothelial dysfunction is an independent predictor for future albuminuria progression in T2DM cohort. METHODS: A total of 1098 patients with T2DM were clinically assessed at baseline and 3.2-year follow-up. Progression was defined as transition from normoalbuminuria (ACR <30 mg/g) to microalbuminuria (ACR = 30-299 mg/g) or macroalbuminuria (ACR >300 mg/g), or microalbuminuria to macroalbuminuria. Microvascular endothelial vasodilation at baseline was quantified using LDF. The increase in perfusion in response to ACh and NaNP was calculated. Logistic regression model was used to estimate the OR for albuminuria progression. RESULTS: Albuminuria progression occurred in 226 (20.6%) patients. Baseline ACh was significantly higher in nonprogression than progression group (80.0 +/- 53.2% vs 72.0 +/- 49.7%, P = .04). There is no significant difference in NaNP between the two groups (111.1 +/- 80.3% vs 121.1 +/- 87.4%, P = .12). After multivariable adjustment, 1-SD increase in ACh was marginally associated with albuminuria progression (OR = 0.87, 95% CI, 0.72-1.02, P = .08) in all patients. When stratified by baseline albuminuria, 1-SD increase in ACh was significantly associated with albuminuria progression in normoalbuminuria (OR = 0.76, 95% CI, 0.59-0.97, P = .03), but not in microalbuminuria patients (OR = 1.18, 95% CI, 0.81-1.70, P = .39). CONCLUSIONS: Impaired endothelial-dependent microvascular reactivity predicts the onset of albuminuria progression among T2DM patients with normoalbuminuria. PMID- 29602194 TI - Genome-wide association studies for two exterior traits in Chinese Dongxiang spotted pigs. AB - Pigs show extensive variation in exterior appearance. This variation has been explored as one of the selection targets to form breeding features in the pig industry. In this study, a customized Affymetrix Axiom Pig1.4M array plate was used to conduct genome-wide association studies (GWAS) for two exterior traits spotted coat color (SC) and facial type (FT)-in Chinese Dongxiang spotted pigs. Two and 12 single nucleotide polymorphisms (SNPs) were identified to be associated with SC and FT at the 5% genome-wide significant level, respectively. Of these SNPs, two associated with SC were located around the DACH1 gene on Sus Scrofa chromosome (SSC)11. Eleven SNPs associated with FT were located within a 7.68 Mb region (29.03-36.71 Mb) on SSC7. Based on the GWAS results and the biological functions of genes, we highlight EDNRB as a candidate gene for SC and HMGA1 and RPS10 as the potential genes affecting facial variation. The findings contribute to the final characterization of causative genes and mutations underlying the effects of the SSC7 and SSC11 loci and improve our understanding of the genetic basis of phenotypic variation in Chinese indigenous pigs. PMID- 29602195 TI - GreenCut protein CPLD49 of Chlamydomonas reinhardtii associates with thylakoid membranes and is required for cytochrome b6 f complex accumulation. AB - The GreenCut encompasses a suite of nucleus-encoded proteins with orthologs among green lineage organisms (plants, green algae), but that are absent or poorly conserved in non-photosynthetic/heterotrophic organisms. In Chlamydomonas reinhardtii, CPLD49 (Conserved in Plant Lineage and Diatoms49) is an uncharacterized GreenCut protein that is critical for maintaining normal photosynthetic function. We demonstrate that a cpld49 mutant has impaired photoautotrophic growth under high-light conditions. The mutant exhibits a nearly 90% reduction in the level of the cytochrome b6 f complex (Cytb6 f), which impacts linear and cyclic electron transport, but does not compromise the ability of the strain to perform state transitions. Furthermore, CPLD49 strongly associates with thylakoid membranes where it may be part of a membrane protein complex with another GreenCut protein, CPLD38; a mutant null for CPLD38 also impacts Cytb6 f complex accumulation. We investigated several potential functions of CPLD49, with some suggested by protein homology. Our findings are congruent with the hypothesis that CPLD38 and CPLD49 are part of a novel thylakoid membrane complex that primarily modulates accumulation, but also impacts the activity of the Cytb6 f complex. Based on motifs of CPLD49 and the activities of other CPLD49 like proteins, we suggest a role for this putative dehydrogenase in the synthesis of a lipophilic thylakoid membrane molecule or cofactor that influences the assembly and activity of Cytb6 f. PMID- 29602196 TI - Village-scale (Phase III) evaluation of the efficacy and residual activity of SumiShield(r) 50 WG (Clothianidin 50%, w/w) for indoor spraying for the control of pyrethroid-resistant Anopheles culicifacies Giles in Karnataka state, India. AB - OBJECTIVE: There is an urgent need to test and incorporate new molecules with promising efficacy and novel mode of action to control insecticide-resistant mosquito vectors for disease control. We tested a new compound, clothianidin (SumiShield 50 WG), for its efficacy as an indoor residual spray (IRS) for the control of pyrethroid-resistant Anopheles culicifacies (Diptera: Culicidae) in comparison with pirimiphos methyl (Actellic CS) as a positive control. METHODS: Ten villages were selected, five each for IRS with clothianidin (300 mg AI/m2 ) and pirimiphos methyl (1000 mg AI/m2 ) in Almatti Dam catchment area in Karnataka state, India. Entomological parameters were monitored in these sprayed villages using standard methods. Assessment of quality of spray was performed by analysing the insecticide content in the filter paper samples collected from sprayed houses. Perceptions of spray men and inhabitants were recorded post-spray on safety of these molecules. RESULTS: The mean applied to target ratio of content was 1.7 (n = 29) for clothianidin and 1.8 (n = 50) for pirimiphos methyl on filter paper samples analysed. Residual activity (>=80% mortality in exposed mosquitoes) after 24 h post-exposure of SumiShield WG was 5 months and increased to 6 months when the holding period was extended to 120 h and that of Actellic CS was 3 months at 24-h holding period and extended to 4 months at 120-h extended holding period. The mean densities of An. culicifacies in both arms fell drastically post-spray. In light trap collections, density of mosquitoes collected indoors was lower than outdoors in both arms indicating effectiveness of IRS. SumiShield WG was more efficacious in reducing the per-structure density than Actellic CS. The proportion of nulliparous mosquitoes was higher than that of parous mosquitoes during post-spray collections in both arms. The majority of adverse events reported were transitory and subsided without medication. CONCLUSION: Indoor residual spraying with SumiShield WG was found effective, operationally feasible and safe, and it is effective for up to 6 months. PMID- 29602197 TI - Couples coping with sensory loss: A dyadic study of the roles of self- and perceived partner acceptance. AB - OBJECTIVES: Hearing-, vision-, and dual-sensory loss have been linked to relational and psychological distress among adults with sensory loss (AWSLs) and their spouses. Regardless, research on factors associated with couples' adjustment is lacking. This study examined the stability and strength of associations between self-acceptance of sensory loss, perceived partner acceptance of sensory loss, and relationship satisfaction and psychological distress among AWSLs and their spouses over time. DESIGN: A total of 122 AWSLs and their spouses completed an online survey at two time points over a 6-month period. METHODS: A multigroup (i.e., time 1 and time 2) actor-partner interdependence model assessed the stability and strength of actor and partner effects of self-acceptance and perceived partner acceptance on each partner's relationship satisfaction and psychological distress over time. RESULTS: No moderation by time was identified, indicating stability in associations over the 6-month period. Overall, both actor and partner effects were evident. Specifically, self-acceptance among AWSLs was inversely associated with own psychological distress and the relationship satisfaction of spouses. Self acceptance by spouses was inversely associated with the psychological distress of AWSLs and spouses. Perception of spouse acceptance by AWSLs was positively associated with own and spouse relationship satisfaction. CONCLUSIONS: Interventions targeting acceptance that incorporate a family systems perspective may be beneficial in alleviating psychological and relational distress among couples coping with sensory loss. Statement of contribution What is already known on this subject? The experience of hearing and/or vision loss has been linked to heightened distress both psychologically and within intimate relationships. Prior research has demonstrated a link between an individual's ability to accept their sensory loss and healthier well-being. What does this study add? This is the first dyadic study of sensory loss acceptance and its link to relationship satisfaction and distress. Acceptance operates interpersonally protecting against distress for those with sensory loss and their spouses. Perceiving that one's spouse accepts the sensory loss is important for both partner's relationship satisfaction. PMID- 29602198 TI - Severity of olfactory deficits is reflected in functional brain networks-An fMRI study. AB - Even though deficits in olfactory function affect a considerable part of the population, the neuronal basis of olfactory deficits remains scarcely investigated. To achieve a better understanding of how smell loss affects neural activation patterns and functional networks, we set out to investigate patients with olfactory dysfunction using functional magnetic resonance imaging (fMRI) and olfactory stimulation. We used patients' scores on a standardized olfactory test as continuous measure of olfactory function. 48 patients (mean olfactory threshold discrimination identification (TDI) score = 16.33, SD = 6.4, range 6 - 28.5) were investigated. Overall, patients showed piriform cortex activation during odor stimulation compared to pure sniffing. Group independent component analysis indicated that the recruitment of three networks during odor stimulation was correlated with olfactory function: a sensory processing network (including regions such as insula, thalamus and piriform cortex), a cerebellar network and an occipital network. Interestingly, recruitment of these networks during pure sniffing was related to olfactory function as well. Our results support previous findings that sniffing alone can activate olfactory regions. Extending this, we found that the severity of olfactory deficits is related to the extent to which neural networks are recruited both during olfactory stimulation and pure sniffing. This indicates that olfactory deficits are not only reflected in changes in specific olfactory areas but also in the recruitment of occipital and cerebellar networks. These findings pave the way for future investigations on whether characteristics of these networks might be of use for the prediction of disease prognosis or of treatment success. PMID- 29602199 TI - Elevated CRB3 expression suppresses breast cancer stemness by inhibiting beta catenin signalling to restore tamoxifen sensitivity. AB - Tamoxifen is a first-line drug for hormone therapy (HT) in oestrogen receptor positive breast cancer patients. However, 20% to 30% of those patients are resistant to tamoxifen treatment. Cancer stem cells (CSCs) have been implicated as one of the mechanisms responsible for tamoxifen resistance. Our previous study indicated that decreased expression of the CRB3 gene confers stem cell characteristics to breast cancer cells. In the current investigation, we found that most of the breast cancer patient tissues resistant to tamoxifen were negative for CRB3 protein and positive for beta-catenin protein, in contrast to their matched primary tumours by immunohistochemical analysis. Furthermore, expression of CRB3 mRNA and protein was low, while expression of beta-catenin mRNA and protein was high in tamoxifen resistance cells (LCC2 and T47D TamR) contrast to their corresponding cell lines MCF7 and T47D. Similarly, CRB3 overexpression markedly restored the tamoxifen sensitivity of TamR cells by the MTT viability assay. Finally, we found that CRB3 suppressed the stemness of TamR cells by inhibiting beta-catenin signalling, which may in turn lead to a decrease in the breast cancer cell population. Furthermore, these findings indicate that CRB3 is an important regulator for breast cancer stemness, which is associated with tamoxifen resistance. PMID- 29602200 TI - Inhibition is associated with metabolic syndrome and depression through inflammation. AB - Inhibition is the ability to stop one's self from responding, or paying attention, to tempting/distracting stimuli or thoughts. Those with poor inhibition are at greater risk of depression and a variety of diseases of older adulthood than those with better inhibition. Inflammation may be a mechanism underlying these links. A total of 840 participants from the Midlife in the United States study completed a neuropsychological measure of inhibition, a self report measure of depressive symptoms, and a blood draw. Results indicated that poor inhibition was associated with high interleukin-6 (IL-6). Inhibition was indirectly associated with metabolic syndrome incidence and depressive symptoms through IL-6. Findings suggest that IL-6 may be a mechanism linking inhibition with metabolic syndrome and depression. PMID- 29602201 TI - New BiVO4 Dual Photoanodes with Enriched Oxygen Vacancies for Efficient Solar Driven Water Splitting. AB - Bismuth vanadate (BiVO4 ) is a promising photoanode material for photoelectrochemical (PEC) water splitting. However, owing to the short carrier diffusion length, the trade-off between sufficient light absorption and efficient charge separation often leads to poor PEC performance. Herein, a new electrodeposition process is developed to prepare bismuth oxide precursor films, which can be converted to transparent BiVO4 films with well-controlled oxygen vacancies via a mild thermal treatment process. The optimized BiVO4 film exhibits an excellent back illumination charge separation efficiency mainly due to the presence of enriched oxygen vacancies which act as shallow donors. By loading FeOOH/NiOOH as the cocatalysts, the BiVO4 dual photoanodes exhibit a remarkable and highly stable photocurrent density of 5.87 mA cm-2 at 1.23 V versus the reversible hydrogen electrode under AM 1.5 G illumination. An artificial leaf composed of the BiVO4 /FeOOH/NiOOH dual photoanodes and a single sealed perovskite solar cell delivers a solar-to-hydrogen conversion efficiency as high as 6.5% for unbiased water splitting. PMID- 29602202 TI - Renal Resistance Trend During Hypothermic Machine Perfusion Is More Predictive of Postoperative Outcome Than Biopsy Score: Preliminary Experience in 35 Consecutive Kidney Transplantations. AB - Hypothermic machine perfusion (HPM) grants a better postoperative outcome in transplantation of organs procured from extended criteria donors (ECDs) and donors after cardiac death (DCD). So far, the only available parameter for outcome prediction concerning those organs is pretransplant biopsy score. The aim of this study is to evaluate whether renal resistance (RR) trend during HPM may be used as a predictive marker for post-transplantation outcome. From December 2015 to present, HMP has been systematically applied to all organs from ECDs and DCD. All grafts underwent pretransplantation biopsy evaluation using Karpinski's histological score. Only organs that reached RR value <=1.0 within 3 hours of perfusion were transplanted. Single kidney transplantation (SKT) or double kidney transplantation (DKT) were performed according to biopsy score results. Sixty five HMPs were performed (58 from ECDs and 7 from DCD/ECMO donors). Fifteen kidneys were insufficiently reconditioned (RR > 1) and were therefore discarded. Forty-nine kidneys were transplanted, divided between 21 SKT and 14 DKT. Overall primary nonfunction (PNF) and delayed graft function (DGF) rate were 2.9 and 17.1%, respectively. DGF were more common in kidneys from DCD (67 vs. 7%; P = 0.004). Biopsy score did not correlate with PNF/DGF rate (P = 0.870) and postoperative creatinine trend (P = 0.796). Recipients of kidneys that reached RR <= 1.0 within 1 hour of HMP had a lower PNF/DGF rate (11 vs. 44%; P = 0.033) and faster serum creatinine decrease (POD10 creatinine: 1.79 mg/dL vs. 4.33 mg/dL; P = 0.019). RR trend is more predictive of post-transplantation outcome than biopsy score. Hence, RR trend should be taken into account in the pretransplantation evaluation of the organs. PMID- 29602203 TI - LncRNA NR2F1-AS1 regulates hepatocellular carcinoma oxaliplatin resistance by targeting ABCC1 via miR-363. AB - Emerging evidence has validated the vital role of long non-coding RNA (lncRNA) in the chemoresistance of cancer treatment. In the present study, we investigate the function of lncRNA NR2F1-AS1 on oxaliplatin (OXA) resistance of hepatocellular carcinoma (HCC) and discover the underlying molecular mechanism. Results revealed that lncRNA NR2F1-AS1 was up-regulated in oxaliplatin-resistant HCC tissue and cells using microarray analysis and RT-PCR. Meanwhile, ABCC1 protein was overexpressed in OXA-resistant HCC cells (Huh7/OXA and HepG2/OXA). In vitro, NR2F1-AS1 knockdown reduced the invasion, migration, drug-resistant gene (MDR1, MRP5, LRP1) and IC50 value in Huh7/OXA and HepG2/OXA cells. In vivo, NR2F1-AS1 knockdown decreased the tumour weight of HCC cells. Bioinformatics tools and luciferase reporter assay confirmed miR-363 targeted the 3'-UTR of NR2F1-AS1 and ABCC1 mRNA, presenting that NR2F1-AS1 promoted ABCC1 expression through endogenous sponging miR-363. In summary, results conclude that NR2F1-AS1 regulates HCC OXA resistance through targeting miR-363-ABCC1 pathway, providing a vital theoretic mechanism and therapeutic target for HCC chemoresistance. PMID- 29602204 TI - High levels of fecundity in small and isolated populations of a self-compatible Aloe pollinated by opportunistic birds and bees. AB - Plant species that are effective colonisers of transient habitats are expected to have a capacity for uniparental reproduction and show flexibility in pollination systems. Such traits may enable populations to be established from a small number of founding individuals without these populations succumbing to reductions in fecundity arising from pollinator limitation. We tested these predictions for Aloe thraskii (Xanthorrhoeaceae), a succulent treelet that colonises shifting coastal dunes and has both bird and bee pollinators. We performed hand pollination experiments, and selectively excluded bird visitors to determine differences in pollinator effectiveness. We measured pollinator visitation rates and fecundity in populations varying in their size, density and isolation distance. Controlled hand-pollinations revealed that unlike most other Aloe species, A. thraskii is self-compatible and thus capable of uniparental reproduction. The species does however depend on pollinators and is visited by various bird species as well as by bees. Fruit and seed set are not affected by selective exclusion of birds, thus indicating that bees are effective pollinators. Bird visitation rates increased with increasing plant height and population size, while bee visitation rates increased with increasing population size and density. We found that seed set per flower was lower in large populations than in small populations. These results suggest that establishment of populations of A. thraskii from a small number of individuals is unlikely to be limited by the fecundity of individual plants. PMID- 29602205 TI - Noncanonical Hox, Etv4, and Gli3 gene activities give insight into unique limb patterning in salamanders. AB - Limb development in salamanders is unique among tetrapods in significant ways. Not only can salamanders regenerate lost limbs repeatedly and throughout their lives, but also the preaxial zeugopodial element and digits form before the postaxial ones and, hence, with a reversed polarity compared to all other tetrapods. Moreover, in salamanders with free-swimming larval stages, as exemplified by the axolotl (Ambystoma mexicanum), each digit buds independently, instead of undergoing a paddle stage. Here, we report gene expression patterns of Hoxa and d clusters, and other crucial transcription factors during axolotl limb development. During early phases of limb development, expression patterns are mostly similar to those reported for amniotes and frogs. Likewise, Hoxd and Shh regulatory landscapes are largely conserved. However, during late digit-budding phases, remarkable differences are present: (i) the Hoxd13 expression domain excludes developing digits I and IV, (ii) we expand upon previous observation that Hoxa11 expression, which traditionally marks the zeugopodium, extends distally into the developing digits, and (iii) Gli3 and Etv4 show prolonged expression in developing digits. Our findings identify derived patterns in the expression of key transcription factors during late phases of salamander limb development, and provide the basis for a better understanding of the unique patterning of salamander limbs. PMID- 29602206 TI - Impact of HAS-BLED score to predict trans femoral transcatheter aortic valve replacement outcomes. AB - BACKGROUND: Predictors of bleeding and mortality after trans femoral transcatheter aortic valve replacement (TF-TAVR) has not been thoroughly investigated. OBJECTIVE: The aim of this study was to assess whether Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/alcohol concomitantly (HAS-BLED) score has predictive value for bleeding and mortality in patients after TAVR. METHODS: Between October 2013 and April 2016, 969 patients underwent TF-TAVI were prospectively included in the OCEAN-TAVI registry from Japan. The primary outcomes were severe bleeding (including life-threatening and major bleeding defined in The Valve Academic Research Consortium-2 criteria) and mortality within 1 year after TAVR. RESULTS: Elderly (84 +/- 5 years) and high surgical risk patients (The Society of Thoracic Surgery Risk Score 6.7 [4.6-9.3]) were enrolled. Severe bleeding and mortality had occurred in 177 patients (18.2%) and 66 patients (6.8%), respectively. On multivariate analysis, HAS-BLED score was associated with severe bleeding (hazard ratio [HR], 1.82; 95% confidence interval [CI], 1.41-2.00; p < 0.001) and mortality (HR, 2.04, 95% CI, 1.56-2.69, P < 0.001). A HAS-BLED score threshold of 4 points (area under the curve 0.71 for severe bleeding, 0.72 for mortality) predicted a higher rate of severe bleeding (25.3% vs. 14.4%, P < 0.001) and mortality (16.2% vs. 4.0%, P < 0.001). CONCLUSIONS: HAS-BLED score could predict the risk of severe bleeding and mortality in patients who underwent TF-TAVR independent of the presence of atrial fibrillation. PMID- 29602207 TI - Associations of lifetime traumatic experience with dysfunctional eating patterns and postsurgery weight loss in adults with obesity: A retrospective study. AB - This study aimed to examine the associations of lifetime traumatic experience with presurgery and postsurgery eating pathology and postoperative weight loss in a sample of adult bariatric surgery patients using electronic medical record (EMR) data. Presurgery lifetime exposure to traumatic event, presurgery and postsurgery dysfunctional eating patterns, and post-operative total and excess weight losses were extracted from electronic medical records of 200 adult bariatric surgery patients in 2013 and 2014. Logistic regression analyses were conducted. During their lifetime, 60.5% of the patients (81.5% women, age = 44.4 +/- 11.5 years; BMIpre = 44.9 +/- 5.5 kg/m2 ) reported that they were exposed to a traumatic event. Before surgery, trauma exposure was associated with impulsive, compulsive, or restrictive eating patterns (OR = 2.40), overeating or disturbed eating (OR = 1.55), and grazing or night eating behaviours (OR = 1.72). After surgery, trauma exposure was associated with lower total weight loss at 6 (OR = 2.06) and 24 months (OR = 2.06), and to overeating or disturbed eating (OR = 1.53) 12 months after surgery. Bariatric surgery candidates with a history of trauma exposure could benefit from closer medical, dietetic, and/or psychological follow-up care to avoid insufficient postoperative weight loss as well as reappearance of dysfunctional eating patterns after surgery. PMID- 29602208 TI - Recurrent histone mutations in T-cell acute lymphoblastic leukaemia. PMID- 29602209 TI - Characterization of Atomic Structures of Nanosized Intermetallic Compounds Using Electron Diffraction Methods. AB - In metallurgy, many intermetallic compounds crystallize as nanosized particles in metallic matrices. These particles influence dramatically the physical properties of engineering materials such as alloys and steels. Since properties and crystal structure are intimately linked, characterization of the atomic model of these intermetallides is crucial for the development of new alloys. However, this structural information usually cannot be attained using traditional X-ray diffraction methods, limited by the small volume and size of the precipitates. In these cases, electron diffraction (ED) is the most suitable method. In the last few decades, ED has experienced a tremendous leap forward. Many structures, including intermetallides, are solved using these methods. The class of intermetallides should be discussed independently since these phases do not comprise regular polyhedrals; moreover, the interatomic distances and angles vary drastically even in the same compositional system. These facts point to difficulties that have to be overcome during the solution path. Furthermore, intermetallic compounds can be of high complexity-possessing hundreds of atoms in the unit cell. Here, this topic is expanded with an emphasis on novel developments in the field. PMID- 29602210 TI - Predicting neo-adjuvant chemotherapy response and progression-free survival of locally advanced breast cancer using textural features of intratumoral heterogeneity on F-18 FDG PET/CT and diffusion-weighted MR imaging. AB - Predicting response to neo-adjuvant chemotherapy (NAC) and survival in locally advanced breast cancer (LABC) is important. This study investigated the prognostic value of tumor heterogeneity evaluated with textural analysis through F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) and diffusion weighted imaging (DWI). We enrolled 83 patients with LABC who had completed NAC and curative surgery. Tumor texture indices from pretreatment FDG PET and DWI were extracted from histogram analysis and 7 different parent matrices: co occurrence matrix, the voxel-alignment matrix, neighborhood intensity difference matrix, intensity size-zone matrix (ISZM), normalized gray-level co-occurrence matrix (NGLCM), neighboring gray-level dependence matrix (NGLDM), and texture spectrum matrix. The predictive values of textural features were tested regarding both pathologic NAC response and progression-free survival. Among 83 patients, 46 were pathologic responders, while 37 were nonresponders. The PET texture indices from 7 parent matrices, DWI texture indices from histogram, and 1 parent matrix (NGLCM) showed significant differences according to NAC response. On multivariable analysis, number nonuniformity of PET extracted from the NGLDM was an independent predictor of pathologic response (P = .009). During a median follow-up period of 17.3 months, 14 patients experienced recurrence. High intensity zone emphasis (HIZE) and high-intensity short-zone emphasis (HISZE) from PET extracted from ISZM were significant textural predictors (P = .011 and P = .033). On Cox regression analysis, only HIZE was a significant predictor of recurrence (P = .027), while HISZE showed borderline significance (P = .107). Tumor texture indices are useful for NAC response prediction in LABC. Moreover, PET texture indices can help to predict disease recurrence. PMID- 29602211 TI - Genetic effects of the transcription factors-sal-like 1 and spalt-like transcription factor 3 on egg production-related traits in Chinese Dagu hens. AB - Transcription factors (TFs) encoded by SALL1 and SALL3 genes play central roles in the regulation of ovarian development in hens. The present study aimed to examine polymorphisms of these two genes in Chinese Dagu chickens, and to identify the effects of TFs on the laying performance. Among the population, two novel single-nucleotide polymorphisms (SNPs) were identified by single-strand conformation polymorphism (SSCP) in the amplicons of the candidate genes. The effect of the SNP (729C > A) in exon 2 of SALL1 gene on egg production at 43, 57, and 66 weeks and EW at 30 and 43 weeks were the most significant in the 360 samples (P < 0.05). Moreover, for the SNP 1014T > A (in exon 2 of SALL3), the TT genotype was significantly correlated with higher egg production and EW (P < 0.05). Furthermore, four combined genotypes were reconstructed based on the two SNPs. The combined genotype TATT was correlated with the highest egg production at 43-66 weeks and with higher EW at 30, 43 weeks (P < 0.05). The polymorphisms of the two TFs studied are potential molecular genetic markers for chicken breeding, which might help in understanding the genetic structure of laying performance and improving these traits directly by marker-assisted selection (MAS). PMID- 29602212 TI - A more randomly organized grey matter network is associated with deteriorating language and global cognition in individuals with subjective cognitive decline. AB - OBJECTIVES: Grey matter network disruptions in Alzheimer's disease (AD) are associated with worse cognitive impairment cross-sectionally. Our aim was to investigate whether indications of a more random network organization are associated with longitudinal decline in specific cognitive functions in individuals with subjective cognitive decline (SCD). EXPERIMENTAL DESIGN: We included 231 individuals with SCD who had annually repeated neuropsychological assessment (3 +/- 1 years; n = 646 neuropsychological investigations) available from the Amsterdam Dementia Cohort (54% male, age: 63 +/- 9, MMSE: 28 +/- 2). Single-subject grey matter networks were extracted from baseline 3D-T1 MRI scans and we computed basic network (size, degree, connectivity density) and higher order (path length, clustering, betweenness centrality, normalized path length [lambda] and normalized clustering [gamma]) parameters at whole brain and/or regional levels. We tested associations of network parameters with baseline and annual cognition (memory, attention, executive functioning, language composite scores, and global cognition [all domains with MMSE]) using linear mixed models, adjusted for age, sex, education, scanner and total gray matter volume. PRINCIPAL OBSERVATIONS: Lower network size was associated with steeper decline in language (beta +/- SE = 0.12 +/- 0.05, p < 0.05FDR). Higher-order network parameters showed no cross-sectional associations. Lower gamma and lambda values were associated with steeper decline in global cognition (gamma: beta +/- SE = 0.06 +/ 0.02); lambda: beta +/- SE = 0.06 +/- 0.02), language (gamma: beta +/- SE = 0.11 +/- 0.04; lambda: beta +/- SE = 0.12 +/- 0.05; all p < 0.05FDR). Lower path length values in precuneus and fronto-temporo-occipital cortices were associated with a steeper decline in global cognition. CONCLUSIONS: A more randomly organized grey matter network was associated with a steeper decline of cognitive functioning, possibly indicating the start of cognitive impairment. PMID- 29602213 TI - Expression of the Sox9, Foxl2, Vasa, and TRPV4 genes in the ovaries and testes of the Morelet's crocodile, Crocodylus moreletii. AB - The Sox9 gene is important for determining sex in vertebrates, as well as for maintaining testis morphology and fertility during adult life. In the same way, Vasa is an important gene for the maintenance of the germinal lineage and has been highly conserved throughout evolution, as it is expressed in germ cells of both vertebrates and invertebrates. In the particular case of crocodiles, the expression of Sox9 during gonadal morphogenesis and in the testes of 3-month-old Alligator mississippiensis has been studied. However, it is interesting to carry out studies on other species of crocodiles in relation to their particular mechanism for sex determination influenced by temperature. In this work, we investigated the expression of the Sox9, Vasa, Foxl2, and TRPV4 genes in the ovaries and testes of 5-year-old juvenile crocodiles from Crocodylus moreletii. As expected, Sox9 expression was found in males, but surprisingly, it was also found in females. For the first time, the expression of Vasa was reported in spermatogonia, oogonia, and oocytes of 5-year-old crocodiles. Foxl2 is important for the development and maintenance of the ovary during adult life in vertebrates; moreover, Foxl2 protein and transcripts are both highly expressed in the ovaries compared to the testes. A possible upstream regulator of the Sox9 gene in reptiles has not yet been discovered; as such, the expression of the TRPV4 ion channel was evaluated. The TRPV4 ion channel was expressed in the cytoplasm of Sertoli and follicular cells and was therefore proposed as a possible regulator of SOX9. PMID- 29602214 TI - Self-Activating, Capacitive Anion Intercalation Enables High-Power Graphite Cathodes. AB - Developing high-power cathodes is crucial to construct next-generation quick charge batteries for electric transportation and grid applications. However, this mainly relies on nanoengineering strategies at the expense of low scalability and high battery cost. Another option is provided herein to build high-power cathodes by exploiting inexpensive bulk graphite as the active electrode material, where anion intercalation is involved. With the assistance of a strong alginate binder, the disintegration problem of graphite cathodes due to the large volume variation of >130% is well suppressed, making it possible to investigate the intrinsic electrochemical behavior and to elucidate the charge storage kinetics of graphite cathodes. Ultrahigh power capability up to 42.9 kW kg-1 at the energy density of >300 Wh kg-1 (based on graphite mass) and long cycling life over 10 000 cycles are achieved, much higher than those of conventional cathode materials for Li-ion batteries. A self-activating and capacitive anion intercalation into graphite is discovered for the first time, making graphite a new intrinsic intercalation pseudocapacitance cathode material. The finding highlights the kinetical difference of anion intercalation (as cathode) from cation intercalation (as anode) into graphitic carbon materials, and new high-power energy storage devices will be inspired. PMID- 29602215 TI - Reduction of catheter kinks and knots via radial approach. AB - Coronary angiography and percutaneous coronary intervention using the radial approach are becoming more frequent. Pronounced guide catheter manipulation in cases with tortuous access routes may lead to severe catheter kinking or knotting. The purpose of this review article is to present several techniques to resolve radial access catheter knots and kinks. First, simple maneuvers such as gentle traction, rotation, and guidewire advancement can often resolve minor kinking; however, complex loops and kinks are often not reversible with these simple maneuvers. Second, fixing the distal catheter tip using external compression, encasing the knot with a larger sheath, or untwisting the knot with hydraulic pressure can be useful. Finally, internal fixation by grasping the kinked catheter with a snare introduced via the femoral artery allows both ends of the catheter to be rotated in opposite directions to untwist the catheter for safe removal. PMID- 29602216 TI - Transoral resection of extensive pediatric supraglottic neurofibroma. AB - This case report describes the novel use of transoral robotic surgery (TORS) with delayed transoral laser microsurgery (TLM) for residual disease in the resection of a pediatric neurofibroma with supraglottic and parapharyngeal space extension. Postoperatively, the patient had excellent functional outcomes. This case demonstrates that pediatric TORS is feasible, safe, and complementary to TLM. Neurofibroma is just one of the diverse pathologic processes of the pediatric airway that can be managed via transoral surgery, and applications of TORS with TLM will continue to broaden as our experience develops. Laryngoscope, 2525-2528, 2018. PMID- 29602217 TI - A fluorescently labeled undecapeptide derived from a protein in royal jelly of the honeybee-royalisin-for specific detection of oxidized low-density lipoprotein. AB - The probes for detection of oxidized low-density lipoprotein (ox-LDL) in plasma and in atherosclerotic plaques are expected to facilitate the diagnosis, prevention, and treatment of atherosclerosis. Recently, we have reported that a heptapeptide (Lys-Trp-Tyr-Lys-Asp-Gly-Asp, KP6) coupled through the epsilon-amino group of N-terminal Lys to fluorescein isothiocyanate (FITC), (FITC)KP6, can be useful as a fluorescent probe for specific detection of ox-LDL. In the present study, to develop a novel fluorescent peptide for specific detection of ox-LDL, we investigated the interaction (with ox-LDL) of an undecapeptide corresponding to positions 41 to 51 of a potent antimicrobial protein (royalisin, which consists of 51 residues; from royal jelly of honeybees), conjugated at the N terminus to FITC in the presence of 6-amino-n-caproic acid (AC) linker, (FITC-AC) royalisin P11, which contains both sequences, Phe-Lys-Asp and Asp-Lys-Tyr, similar to Tyr-Lys-Asp in (FITC)KP6. The (FITC-AC)-royalisin P11 bound with high specificity to ox-LDL in a dose-dependent manner, through the binding to major lipid components in ox-LDL (lysophosphatidylcholine and oxidized phosphatidylcholine). In contrast, a (FITC-AC)-shuffled royalisin P11 peptide, in which sequences Phe-Lys-Asp and Asp-Lys-Tyr were modified to Lys-Phe-Asp and Asp Tyr-Lys, respectively, hardly bound to LDL and ox-LDL. These findings strongly suggest that (FITC-AC)-royalisin P11 may be an effective fluorescent probe for specific detection of ox-LDL and that royalisin from the royal jelly of honeybees may play a role in the treatment of atherosclerosis through the specific binding of the region at positions 41 to 51 to ox-LDL. PMID- 29602218 TI - Treatment of canine sinonasal aspergillosis with clotrimazole infusion in patients with cribriform plate lysis. AB - OBJECTIVE: To describe the treatment of sinonasal aspergillosis with topical 1% clotrimazole solution in dogs with cribriform plate lysis. MATERIALS AND METHODS: This retrospective study includes data retrieval from medical records of dogs with sinonasal aspergillosis and cribriform plate lysis that underwent topical treatment with 1% clotrimazole solution. RESULTS: Five dogs with sinonasal aspergillosis, cribriform plate lysis diagnosed on CT scans, and normal neurologic examinations were treated with a single (n=3) or multiple (n=2) infusions of clotrimazole solution. No dogs developed clinical neurologic disease after therapy. CLINICAL SIGNIFICANCE: In this study, a topical clotrimazole solution was not associated with adverse neurologic effects in neurologically normal dogs with sinonasal aspergillosis and cribriform plate lysis. PMID- 29602219 TI - CD200 included in a 4-marker modified Matutes score provides optimal sensitivity and specificity for the diagnosis of chronic lymphocytic leukaemia. AB - CD200, a transmembrane type Ia glycoprotein belonging to the immunoglobulin superfamily, has been shown to have a differential expression in B-cell neoplasms. Here, we retrospectively assessed the diagnostic relevance of CD200 on 427 patients with B-cell chronic neoplasms in leukemic phase (median age, 69 y; range, 35-97 y). The final diagnosis based on the investigator's assessment was chronic lymphocytic leukaemia (CLL) in 75% of cases and non-CLL in 25% of cases. Sensitivity and specificity for the diagnosis of CLL (vs non-CLL) were calculated for the following markers: CD200, CD5, CD22, CD23, CD79b, FMC7, and SmIg. CD23 was the only marker without a statistically significant difference between the investigator assessment and the flowcytometric analysis. The other markers were unable-when individually evaluated-to discriminate between CLL and non-CLL, requiring the integration into a scoring system. The modified score no. 1 (addition of CD200) showed superimposable sensitivity and specificity compared with the Matutes score. The substitution of CD79b (modified score no. 2), surface membrane immunoglobulins (SmIg) (modified score no. 3), and CD79b and FMC7 (modified score no. 4) with CD200 showed that only the modified score no. 4 had both higher sensitivity and higher specificity compared with standard Matutes score. In conclusion, this work defines a simplified score, compared with the classical Matutes score, for the differential diagnosis of chronic B-cell leukaemia-which only requires 4 markers instead of 5 (CD5, CD23, CD200, and SmIg). PMID- 29602220 TI - Degenerative mitral regurgitation predicts worse outcomes in patients undergoing transcatheter aortic valve replacement. AB - OBJECTIVES: To evaluate the role mitral regurgitation (MR) etiology and severity play in outcomes for patients undergoing transcatheter aortic valve replacement (TAVR). BACKGROUND: Multiple prior studies have investigated the influence of MR severity on outcomes for patients undergoing TAVR. Less has been published regarding the effects of MR etiology on outcomes, including its impact on heart failure hospitalization. METHODS: Two hundred and seventy patients undergoing TAVR at 2 hospitals were enrolled. Each patient had a baseline and follow-up (within 30 days of TAVR) echocardiogram that was analyzed. MR was graded as none, mild, moderate, or severe, as well as functional or degenerative. We compared patient outcomes, including death and heart failure hospitalization, among none mild MR, moderate-severe functional MR, and moderate-severe degenerative MR groups. RESULTS: Two hundred and seventy patients underwent TAVR, reducing mean aortic valve gradients from 45 +/- 15 mm Hg to 9 +/- 4 mm Hg. On multivariable analysis, only patients with moderate-severe degenerative MR had decreased survival free of death or CHF hospitalization compared to those with none-mild MR (P = .011). Subanalysis showed patients with moderate-severe degenerative MR were more likely to be hospitalized for heart failure at 2 years compared to those with moderate-severe functional MR (P = .02). Patients with moderate-severe degenerative MR were also less likely to have improvement in MR severity at follow up (P = .01). CONCLUSIONS: Special consideration should be given to patients with moderate-severe degenerative MR undergoing TAVR. As transcatheter approaches for mitral valve repair and replacement continue to evolve, moderate severe degenerative MR patients may benefit from consideration of double valve intervention. PMID- 29602221 TI - Elucidating the Structure-Reactivity Correlations of Phenothiazine-Based Fluorescent Probes toward ClO. AB - In this work, with the aim of developing effective molecular probes and investigating the structure-reactivity correlation, a short series of phenothiazine-based fluorescent probes are designed for the detection of ClO- with differing electron push-pull groups. Sensing experiment results and single crystal X-ray analysis with the aid of time-dependent DFT (TD-DFT) calculations reveal that substituting groups with increasing electron-withdrawing ability can increase the dihedral angle of the phenothiazine moiety and reduce the gap energy of the probes, leading to enhanced reactivity toward ClO- . Both PT1 and PT2 show two-color switching upon detection of ClO- . PT1, with the strong electron donating group thiophene, shows a fluorescence color switch from salmon to blue. PT2, with a medium electron-donating/accepting group benzothiazole, shows a fluorescence color switch from red to green. However, both PT1 and PT2 show almost no response to ONOO- . Through the introduction of strong electron withdrawing ketone combined with a cyano group, PT3 shows a cyan emission upon detection of ClO- and weak red emission upon detection of ONOO- . HRMS and 1 H NMR results confirm that PT1 and PT2 have the same sensing mode, in which the divalent sulfur of phenothiazine can be oxidized to sulfoxide by ClO- . Upon reaction with ClO- , PT3 experiences two-step reactions. It is first oxidized into the sulfone structure by ClO- , and then transformed into sulfoxide phenothiazine aldehyde. Upon encountering ONOO- , PT3 changes into an aldehyde structure and some nonfluorescent byproducts. Owing to their special selectivity and high sensitivity, PT1 and PT2 are applied to image the endogenous ClO- in macrophage cells and zebrafish larvae. This study is expected to provide useful guidelines for probe design for various applications. PMID- 29602222 TI - Novel acquisitions on biology and management of transformed follicular lymphoma. AB - Follicular lymphoma (FL) generally has an indolent clinical course, but in some patients, a histological transformation (HT) into aggressive entities may take place and often lead to a poorer survival. The rituximab era has seen an improved outcome of FL, including those with HT. The current treatment strategies for transformed FL are based on immunochemotherapy for the cases with HT at the time of diagnosis or as the first event after watchful waiting. Patients transforming after prior treatment of FL usually benefit from autologous stem cell transplant. Unfortunately, early assessment of the transformation risk remains elusive. Recent studies delved the mechanisms of HT, showing that this is a complex process, resulting from a number of epigenetic and genetic lesions occurring in the tumour cell population as well as progressive changes in the tumour microenvironment. This novel knowledge has prompted clinical investigations on a variety of new therapeutic strategies. PMID- 29602223 TI - Cost-effectiveness of sialendoscopy versus medical management for radioiodine induced sialadenitis. AB - OBJECTIVES/HYPOTHESIS: The medical management and radiographic identification of radioiodine-induced sialadenitis (RAIS) is challenging. This study utilizes a cost-effectiveness analysis to compare upfront sialendoscopy as both a diagnostic and therapeutic option versus multiple modalities of diagnostic radiography along with medical management. STUDY DESIGN: Literature review and cost-effectiveness analysis. METHODS: A literature review was performed to identify the outcomes of medical management, sialendoscopy, diagnostic radiography, and surgical complications. All charges were obtained from the University of Mississippi Budget Office in 2017 US dollars and converted to costs using the 2017 Medicare Cost-to-Charge Ratio for urban medical centers. A cost-effectiveness analysis was used to evaluate the four treatment arms-sialendoscopy, medical management- ultrasound, medical management-computed tomography (CT) sialography, and medical management-magnetic resonance (MR) sialography. Sensitivity analyses were used to evaluate the confidence levels of the economic evaluation. RESULTS: The incremental cost-effectiveness ratio for upfront sialendoscopy versus medical management-ultrasound was $30,402.30, which demonstrates that sialendoscopy is the more cost-effective option given a willingness-to-pay threshold of $50,000. The probability that this decision is correct at a willingness-to-pay of $50,000 is 64.5%. Sialendoscopic improvement was the most sensitive variable requiring a threshold of 0.70. Of the three imaging modalities, ultrasound dominated MR and CT sialography, both of which required a willingness-to-pay of greater than $90,000 to realize a difference. CONCLUSIONS: Upfront sialendoscopy is more cost effective compared to medical management utilizing diagnostic ultrasound assuming a willingness-to-pay threshold of $50,000. There is a clear cost-effectiveness to using ultrasound with medical management over CT and MR sialography in the diagnosis and management of RAIS. LEVEL OF EVIDENCE: NA. Laryngoscope, 1822-1828, 2018. PMID- 29602224 TI - The PP2A-interactor TIP41 modulates ABA responses in Arabidopsis thaliana. AB - Modulation of growth in response to environmental cues is a fundamental aspect of plant adaptation to abiotic stresses. TIP41 (TAP42 INTERACTING PROTEIN OF 41 kDa) is the Arabidopsis thaliana orthologue of proteins isolated in mammals and yeast that participate in the Target-of-Rapamycin (TOR) pathway, which modifies cell growth in response to nutrient status and environmental conditions. Here, we characterized the function of TIP41 in Arabidopsis. Expression analyses showed that TIP41 is constitutively expressed in vascular tissues, and is induced following long-term exposure to NaCl, polyethylene glycol and abscisic acid (ABA), suggesting a role of TIP41 in adaptation to abiotic stress. Visualization of a fusion protein with yellow fluorescent protein indicated that TIP41 is localized in the cytoplasm and the nucleus. Abolished expression of TIP41 results in smaller plants with a lower number of rosette leaves and lateral roots, and an increased sensitivity to treatments with chemical TOR inhibitors, indicating that TOR signalling is affected in these mutants. In addition, tip41 mutants are hypersensitive to ABA at germination and seedling stage, whereas over-expressing plants show higher tolerance. Several TOR- and ABA-responsive genes are differentially expressed in tip41, including iron homeostasis, senescence and ethylene-associated genes. In yeast and mammals, TIP41 provides a link between the TOR pathway and the protein phosphatase 2A (PP2A), which in plants participates in several ABA-mediated mechanisms. Here, we showed an interaction of TIP41 with the catalytic subunit of PP2A. Taken together, these results offer important insights into the function of Arabidopsis TIP41 in the modulation of plant growth and ABA responses. PMID- 29602225 TI - Oral microbiota maturation during the first 7 years of life in relation to allergy development. AB - BACKGROUND: Allergic diseases have become a major public health problem in affluent societies. Microbial colonization early in life seems to be critical for instructing regulation on immune system maturation and allergy development in children. Even though the oral cavity is the first site of encounter between a majority of foreign antigens and the immune system, the influence of oral bacteria on allergy development has not yet been reported. OBJECTIVE: We sought to determine the bacterial composition in longitudinally collected saliva samples during childhood in relation to allergy development. METHODS: Illumina sequencing of the 16S rDNA gene was used to characterize the oral bacterial composition in saliva samples collected at 3, 6, 12, 24 months, and 7 years of age from children developing allergic symptoms and sensitization (n = 47) and children staying healthy (n = 33) up to 7 years of age. RESULTS: Children developing allergic disease, particularly asthma, had lower diversity of salivary bacteria together with highly divergent bacterial composition at 7 years of age, showing a clearly altered oral microbiota in these individuals, likely as a consequence of an impaired immune system during infancy. Moreover, the relative amounts of several bacterial species, including increased abundance of Gemella haemolysans in children developing allergies and Lactobacillus gasseri and L. crispatus in healthy children, were distinctive during early infancy, likely influencing early immune maturation. CONCLUSION: Early changes in oral microbial composition seem to influence immune maturation and allergy development. Future experiments should test the probiotic potential of L. gasseri and L. crispatus isolates. PMID- 29602226 TI - Histological and immunohistochemical investigations of ovarian interstitial glands during non-breeding season in camels (Camelus dromedarius). AB - The aim of this was to investigate the histology and immunohistochemistry of interstitial glands during non-breeding season in camel ovaries. A total of 21 mature, non-pregnant and apparently healthy camels aged between 8 and 12 years were slaughtered. The ovaries were removed within 15 min, cleaned from adipose tissue, weighted and examined grossly. The histological preparation was made, and then, the blocks were cut at 3-5 microns thickness and stained by H&E for histological examinations. Moreover, some sections were stained with Sudan Black for lipid detection. Immunohistochemical analysis of paraffin-embedded ovarian tissues was performed to detect the localization of S-100, vimentin, progesterone receptors (PR) and oestrogen receptors (ER). Immunoreactive signals were detected using UltraVision Detection System. The results revealed that the interstitial glands were located in the cortical region and they were arranged in various arrangements either single, in couple or in groups rich in lipid droplet. All interstitial gland arrangements were enclosed by connective tissue capsules containing fibroblasts and collagenous fibres separated them from the surrounding ovarian structures. Both interstitial glands and their surrounding CT were penetrated by several blood vessels. There was a strong immunoreactive signal for S-100 in the nuclei of interstitial cells, and no signals were detected either in cells of the interstitial glands or their connective tissue with PR. We could conclude that the interstitial gland is distinct in ovary of camel and further studies are needed to elucidate its rule in steroid synthesis. PMID- 29602227 TI - The performance of five fruit-derived and freeze-dried potentially probiotic Lactobacillus strains in apple, orange, and grape juices. AB - BACKGROUND: This study assessed the survival of the fruit-derived and freeze dried L. plantarum 49, L. brevis 59, L. paracasei 108, L. fermentum 111 and L. pentosus 129 strains during frozen storage and when incorporated into apple, orange, and grape juice stored under refrigeration. Physicochemical parameters of juices containing the freeze-dried Lactobacillus strains and the survival of the test strains in the fruit juices during in vitro digestion were also evaluated. RESULTS: No decreases in survival rates (log N/log N0) of the freeze-dried cells were observed in up to 1 month of storage. The survival rates of the freeze-dried strains L. plantarum 49 and L. paracasei 108 were > 0.75 in up to 4 months of storage. All freeze-dried strains exhibited survival rates of >0.75 in up to 2 weeks of storage in apple juice; only L. plantarum 49 and L. paracasei 108 showed similar survival rates in orange and grape juices in up to 2 weeks of storage. The contents of the monitored organic acids or sugars during storage varied depending on the added strain and the type of fruit juice. At the end of in vitro digestion, L. brevis 59, L. paracasei 108 and L. fermentum 111 showed survival rates of >0.80 in apple juice. CONCLUSION: Apple juice was the best substrate for the survival of the tested freeze-dried Lactobacillus strains over time. L. paracasei 108 and L. plantarum 49 were the strains presenting the best performance for incorporation in potentially probiotic fruit juices. (c) 2018 Society of Chemical Industry. PMID- 29602228 TI - Low serum level of epidermal growth factor in chronic ketamine users. AB - BACKGROUND: Growth factors play an important role in brain development. Whether epidermal growth factor (EGF) plays a role in the pathophysiology of ketamine related disorders is unexplored. In this study, we examined the serum levels of EGF in chronic ketamine users as compared with healthy controls. The possible correlation between serum EGF levels with the demographic, ketamine use characteristics and psychopathological symptoms were analyzed. METHODS: Sixty seven chronic ketamine users and 40 healthy subjects were recruited. Serum EGF levels were measured by enzyme-linked immunosorbent assay. Psychopathological symptoms were assessed using Positive and Negative Syndrome Scale, Beck Depression Inventory and Beck Anxiety Inventory. RESULTS: The serum level of EGF in the chronic ketamine users was significantly lower than that of healthy subjects (22.34 +/- 4.81 pg/ml vs. 87.10 +/- 2.96 pg/ml, F = 15.169, p < 0.01). The serum EGF level was negatively correlated with the current average dose of ketamine consumption per day of use (p = 0.015), and positively associated with the Positive and Negative Syndrome Scale positive symptom score (p = .022). CONCLUSIONS: Serum level of EGF decreased in chronic ketamine users compared with healthy subjects, which may play a role in the pathophysiology of ketamine related disorders. PMID- 29602229 TI - Prospective evaluation of hematocrit in gender-affirming hormone treatment: results from European Network for the Investigation of Gender Incongruence. AB - In trans persons on gender-affirming hormonal treatment, a decrease (in trans women) or increase (in trans men) in hematocrit is often observed. Reference ranges for evaluation of hematocrit levels in trans persons have not been established. This prospective cohort study is part of the European Network for the Investigation of Gender Incongruence (ENIGI). At the Ghent and Amsterdam sites, we included 625 hormone-naive trans persons. Gender-affirming hormonal treatment was initiated at the first visit. In trans men, serum hematocrit (Hct) levels increased during the first year (+4.9 Hct %, 95% CI 3.82-5.25), with the most pronounced increase during the first 3 months (+2.7 Hct %, 95% CI 1.94 3.29). Trans men receiving testosterone esters had a larger increase in serum hematocrit levels compared to trans men receiving testosterone undecanoate (Delta 0.8 Hct %). Of 192 trans men, 22 (11.5%) developed serum hematocrit levels >=50.0%. Trans men on testosterone undecanoate were less likely to develop hematocrit levels >=50% or >=52%, compared to trans men on testosterone esters, and were less likely to develop hematocrit levels >=50%, compared to trans men on testosterone gel. In trans women, serum hematocrit had dropped by 4.1 Hct % (95% CI 3.50-4.37) after 3 months, after which only small decreases were observed. In conclusion, serum hematocrit levels can be found in the reference range of the perceived gender as from 3 months after the initiation of gender-affirming hormonal treatment. PMID- 29602230 TI - Alterations of polyunsaturated fatty acid metabolism in ovarian tissues of polycystic ovary syndrome rats. AB - The metabolism of polyunsaturated fatty acids (PUFAs) remains poorly characterized in ovarian tissues of patients with polycystic ovary syndrome (PCOS). This study aimed to explore alterations in the levels of PUFAs and their metabolites in serum and ovarian tissues in a PCOS rat model treated with a high fat diet and andronate. Levels of PUFAs and their metabolites were measured using gas/liquid chromatography-mass spectrometry after the establishment of a PCOS rat model. Only 3 kinds of PUFAs [linoleic acid, arachidonic acid (AA) and docosahexaenoic acid] were detected in both the circulation and ovarian tissues of the rats, and their concentrations were lower in ovarian tissues than in serum. Moreover, significant differences in the ovarian levels of AA were observed between control, high-fat diet-fed and PCOS rats. The levels of prostaglandins, AA metabolites via the cyclooxygenase (COX) pathway, in ovarian tissues of the PCOS group were significantly increased compared to those in the controls. Further studies on the mechanism underlying this phenomenon showed a correlation between decreased expression of phosphorylated cytosolic phospholipase A2 (p-cPLA2) and increased mRNA and protein expression of COX2, potentially leading to a deeper understanding of altered AA and prostaglandin levels in ovarian tissues of PCOS rats. PMID- 29602231 TI - Eosinophil phagocytosis in advanced systemic mastocytosis with eosinophilia. PMID- 29602232 TI - Long-term survival in locally advanced non-small cell lung cancer invading the great vessels and heart. AB - BACKGROUND: The aim of this study was to analyze the surgical outcomes of locally advanced lung cancer invading the great vessels or heart, according to the extension of cancer invasion. METHODS: From 1995 to 2015, 59 patients who were surgically treated and pathologically diagnosed with T4N0-1 non-small cell lung cancer with invasion to the great vessels or heart were enrolled. Surgical outcomes were compared between patient groups with and without intrapericardial invasion. RESULTS: The median age was 64 years (interquartile range [IQR] 57-68) and 56 patients (95%) were male. In-hospital mortality was 9% and median overall survival was 30 months (IQR 12-83). One and five-year overall survival rates were 75% and 44%, respectively. The median overall survival in patients with lung cancer invasion to the intrapericardial space (n = 45) was 27 months (IQR 10-63), while it was 42 months (IQR 18-104) in patients without intrapericardial invasion (n = 14). Median disease-free survival was significantly poorer in patients with intrapericardial invasion (12 months; IQR 6-55), especially in patients with heart invasion (n = 11, 7 months, IQR 5-27), than in patients without intrapericardial invasion (30 months, IQR 13-103). CONCLUSION: Patients with lung cancer invading the intrapericardial space showed worse surgical outcomes in both overall and disease-free survival. Therefore, surgical management should be carefully considered in patients with intrapericardial invasion. PMID- 29602233 TI - Dose-dependent modulation of the visually evoked N1/N170 by perceptual surprise: a clear demonstration of prediction-error signalling. AB - Prediction-error checking processes play a key role in predictive coding models of perception. However, neural indices of such processes have yet to be unambiguously demonstrated. To date, experimental paradigms aiming to study such phenomena have relied upon the relative frequency of stimulus repeats and/or 'unexpected' events that are physically different from 'expected' events. These features of experimental design leave open alternative explanations for the observed effects. A definitive demonstration requires that presumed prediction error-related responses should show contextual dependency (rather than simply effects of frequency or repetition) and should not be attributable to low-level stimulus differences. Most importantly, prediction-error signals should show dose dependency with respect to the degree to which expectations are violated. Here, we exploit a novel experimental paradigm specifically designed to address these issues, using it to interrogate early latency event-related potentials (ERPs) to contextually expected and unexpected visual stimuli. In two electroencephalography (EEG) experiments, we demonstrate that an N1/N170 evoked potential is robustly modulated by unexpected perceptual events ('perceptual surprise') and shows dose-dependent sensitivity with respect to both the influence of prior information and the extent to which expectations are violated. This advances our understanding of perceptual predictions in the visual domain by clearly identifying these evoked potentials as an index of visual surprise. PMID- 29602234 TI - A new insight into cystatin C contained in milk basic protein to bone metabolism: Effects on osteoclasts and osteoblastic MC3T3-E1 cells in vitro. AB - A milk protein fraction possessing alkaline isoelectric points (milk basic protein [MBP]) improves bone metabolism in vivo, and it inhibits bone resorption by osteoclasts and promotes mouse osteoblastic MC3T3-E1 cells proliferation in vitro. Cystatin C (CysC) is a component of MBP and shows bone resorption inhibitory activity. Therefore, it is likely that MBP with higher CysC content improves bone metabolism more effectively. In this study, we prepared MBP with low and high contents of CysC and compared its effects on bone metabolism with standard MBP in vitro. Our results showed that the CysC content in MBP was positively related to not only bone resorption inhibitory activity but also MC3T3 E1 cells proliferative activity. Furthermore, purified CysC stimulated MC3T3-E1 cells proliferation. These results indicate that CysC contributes to promotion of MC3T3-E1 cells proliferation, and MBP with higher CysC content shows enhanced bone resorption inhibitory activity and MC3T3-E1 cells proliferative activity. CysC is considered an important factor in the effect on bone metabolism of MBP. PMID- 29602235 TI - Conceptualising women's motivations for social egg freezing and experience of reproductive delay. AB - As the average age of motherhood in many Western countries continues to rise, the spectacle of the older mother and the trend towards delayed childbearing has been the subject of much public debate and interest. Concurrent to this trend has been the development and use of a new form of fertility preservation - social egg freezing - a technology which by its very nature is meant to enable reproductive delay. Whilst previous studies have been able to provide insights into the complex and often interrelating structural, economic, and relational factors shaping the timing of motherhood, and in some cases women's use of social egg freezing, fewer studies have clearly demonstrated the way these factors themselves, as well as the accounts of individual women, can be seen as being shaped by ideological and discursive forces. Drawing on interviews with 31 users of social egg freezing this article will demonstrate how women's accounts of reproductive delay and use of egg freezing technology can be seen as being shaped by neoliberal rationality, heteronormativity, discourses of 'appropriate parenting' and gendered ideologies of parenthood. PMID- 29602236 TI - Evaluating glaucomatous abnormality in peripapillary optical coherence tomography enface visualisation of the retinal nerve fibre layer reflectance. AB - PURPOSE: Optical coherence tomography (OCT) enface visualisation of the retinal nerve fibre layer (RNFL) reflectance has been found to have some advantages over retinal thickness measures. However, it is not yet clear how abnormalities on enface images relate to findings of abnormalities from other clinical measures such as the circumpapillary retinal nerve fibre layer thickness (cRNFLT). We developed a technique to analyse the RNFL reflectance on the OCT enface images, and to investigate its relation with the cRNFLT. METHODS: Spectralis (www.heidelbergengineering.com) OCT scans of the central retinal +/-24 degrees were analysed in the study eye of 31 controls and 33 patients, ages 61 (+/-9) and 69 (+/-8) years respectively. Enface slab-images were extracted at 16-24, 24-36, and 24-52 MUm from the inner limiting membrane in the temporal raphe, perifoveal and disc regions respectively. Reflectance probability maps were generated for the patients based on the control data. Glaucomatous abnormality was defined on the slab-images when the slab-area with reflectance abnormality was greater than the 95th percentile, and on the cRNFLT when the thickness measure was less than the fifth percentile, of that found in controls. The fraction of slab-image showing reflectance abnormality was compared to cRNFLT in the patient group, using Spearman's rho. Agreement between the findings of abnormality based on cRNFLT and slab-image reflectance was assessed using Cohen's kappa. RESULTS: Slab image and cRNFLT findings were in agreement for 26/33 eyes; four subjects showed cRNFLT abnormality but not slab-image abnormality, and three subjects showed slab image abnormality but not cRNFLT abnormality. Spearman's rho found rs (31) = 0.82. The reflectance findings and cRNFLT findings were consistent in 27/33 for both the superior temporal (ST) and inferior temporal (IT) sectors, and Cohen's kappa found 0.53 and 0.61 respectively. CONCLUSION: The surface area of enface slab-images showing RNFL reflectance were strongly related to the cRNFLT measures, and the classification of a subject with glaucoma based on enface reflectance findings and cRNFLT findings had a generally good agreement. The larger retinal area assessed by the enface method preserves the spatial location of the RNFL abnormalities, and makes the technique a useful approach for identifying regions of potential RNFL abnormality for targeted perimetry. PMID- 29602237 TI - NEFA-induced ROS impaired insulin signalling through the JNK and p38MAPK pathways in non-alcoholic steatohepatitis. AB - The aim of this study was to investigate the changes in hepatic oxidative phosphorylation (OXPHOS) complexes (COs) in patients and cows with non-alcoholic steatohepatitis (NASH) and to investigate the mechanism that links mitochondrial dysfunction and hepatic insulin resistance induced by non-esterified fatty acids (NEFAs). Patients and cows with NASH displayed high blood NEFAs, TNF-alpha and IL 6 concentrations, mitochondrial dysfunction and insulin resistance. The protein levels of peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC-1alpha), mitofusin-2 (Mfn-2) and OXPHOS complexes (human: COI and COIII; cow: COI-IV) were significantly decreased in patients and cows with NASH. NEFA treatment significantly impaired mitochondrial function and, increased reactive oxygen species (ROS) production, and excessive ROS overactivated the JNK and p38MAPK pathways and induced insulin resistance in cow hepatocytes. PGC-1alpha and Mfn-2 overexpression significantly decreased the NEFA-induced ROS production and TNF-alpha and IL-6 mRNA expressions, reversed the inhibitory effect of NEFAs on mitochondrial function and attenuated the overactivation of the ROS JNK/p38MAPK pathway, alleviated insulin resistance induced by NEFAs in cow hepatocytes and HepG2 cells. These findings indicate that NEFAs induce mitochondrial dysfunction and insulin resistance mediated by the ROS-JNK/p38MAPK pathway. PGC-1alpha or Mfn-2 overexpression reversed the lipotoxicity of NEFAs on mitochondrial dysfunction and insulin resistance. Our study clarified the mechanism that links hepatic mitochondrial dysfunction and insulin resistance in NASH. PMID- 29602238 TI - Improving health literacy in a Japanese community population-A pilot study to develop an educational programme. AB - OBJECTIVE: Although a growing number of interventional studies on health literacy have been conducted recently, the majority were designed in clinical settings, focusing mainly on functional health literacy. This study evaluated a programme designed to improve health literacy in a community population, with a scope of going beyond functional health literacy. METHODS: In collaboration with an Approved Specified Nonprofit organization (NPO), we evaluated a five-session programme designed to provide basic knowledge on health-care policy and systems, current issues in health care in Japan, patient roles and relationships with health-care providers and interpersonal skills. In total, 67 of 81 programme participants agreed to participate in the study, and 54 returned the completed questionnaires at baseline and at follow-up. Health literacy and trust in the medical profession were measured at baseline and at follow-up. Participants' learning through the programme was qualitatively analysed by thematic analysis. RESULTS: Quantitative examinations of the changes in health literacy and degree of trust in medical professionals between the baseline and follow-up suggested that health literacy significantly improved after implementing the programme. The thematic analysis of participants' learning throughout the programme suggested that they not only acquired knowledge and skills but also experienced a shift in their beliefs and behaviours. DISCUSSION: Providing individuals who are motivated to learn about health-care systems and collaborate with health-care providers with the necessary knowledge and skills may improve their health literacy, which could enable them to maintain and promote their health and that of their family and other people around them. PMID- 29602239 TI - Inflammatory factor receptor Toll-like receptor 4 controls telomeres through heterochromatin protein 1 isoforms in liver cancer stem cell. AB - Toll-like receptor 4 (TLR4) which acts as a receptor for lipopolysaccharide (LPS) has been reported to be involved in carcinogenesis. However, the regulatory mechanism of it has not been elucidated. Herein, we demonstrate that TLR4 promotes the malignant growth of liver cancer stem cells. Mechanistically, TLR4 promotes the expression of histone-lysine N-methyltransferase (SUV39 h2) and increases the formation of trimethyl histone H3 lysine 9-heterochromatin protein 1-telomere repeat binding factor 2 (H3K9me3-HP1-TRF2) complex at the telomeric locus under mediation by long non coding RNA urothelial cancer-associated 1 (CUDR). At the telomeric locus, this complex promotes binding of POT1, pPOT1, Exo1, pExo1, SNM1B and pSNM1B but prevents binding of CST/AAF to telomere, thus controlling telomere and maintaining telomere length. Furthermore, TLR4 enhances interaction between HP1alpha and DNA methyltransferase (DNMT3b), which limits RNA polymerase II deposition on the telomeric repeat-containing RNA (TERRA) promoter region and its elongation, thus inhibiting transcription of TERRA. Ultimately, TLR4 enhances the telomerase activity by reducing the interplay between telomerase reverse transcriptase catalytic subunit (TERT) and TERRA. More importantly, our results reveal that tri-complexes of HP1 isoforms (alpha, beta and gamma) are required for the oncogenic action of TLR4. This study elucidates a novel protection mechanism of TLR4 in liver cancer stem cells and suggests that TLR4 can be used as a novel therapeutic target for liver cancer. PMID- 29602240 TI - Optimizing outcomes with polymethylmethacrylate fillers. AB - INTRODUCTION: The ideal filler should be long-lasting, biocompatible, chemically inert, soft and easy to use, and have a long history of safety. This review focuses on the evolution and development of the PMMA-collagen gel, Bellafill, and the 10 years of postmarketing experience of Bellafill since it received premarket approval (PMA) from the FDA as Artefill in 2006. Artefill was rebranded to Bellafill in 2015. METHODS: The authors conducted a literature search on PubMed for key articles describing the steps in which Arteplast, a PMMA filler developed in 1989, led to the development of Bellafill, the only PMMA filler approved by the US FDA for the treatment of nasolabial folds and acne scar correction. The factors governing efficacy and safety were also evaluated for the major PMMA fillers available in the world. RESULTS: The process of manufacturing and purifying PMMA has played a major role in minimizing adverse events for Bellafill. Postmarketing surveillance data for the 2007-2016 period show that for more than 530 000 Bellafill syringes distributed worldwide, 11 confirmed granulomas (excluding clinical trial data) (0.002% of syringes sold) have been reported. Data on other PMMA fillers are limited and inconsistent. The authors suggest that adverse events are often attributable to lack of proficiency in treatment technique and other factors. CONCLUSION: Bellafill has demonstrated an excellent safety and effectiveness profile in multiple clinical studies, customer feedback, and 10 years of postmarketing surveillance experience. Adverse events occur with all fillers for a variety of reasons. In addition to quality of the product, injector skill and technique are critical to ensuring good clinical outcomes. PMID- 29602242 TI - Reply to Wjst. PMID- 29602241 TI - Incidence of and associated factors for bacterial colonization of intravenous catheters removed from dogs in response to clinical complications. AB - BACKGROUND: Infection rate associated with intravenous (IV) catheter placement is emerging as an important issue in small animal veterinary medicine, mostly because of the economic costs associated with these infections. Identification of possible associated factors may provide useful information for the surveillance and prevention of such infections. OBJECTIVES: To determine the incidence of positive bacterial cultures obtained from IV catheters used in dogs hospitalized for at least 48 hours and removed because of clinical complication. To identify the bacteria involved and factors associated with bacterial colonization. ANIMALS: One-hundred eighty-two dogs that underwent IV catheterization from January 2015 to July 2015 at the Veterinary Teaching Hospital of Alfonso X el Sabio University of Madrid were enrolled in the study. RESULTS: The bacterial colonization rate of all IV catheters removed in response to clinical complications was 39.6%, the cumulative proportion of catheters that remained in place at 24, 48, and 72 hours after placement was 89.5, 78, and 59.4%, respectively. Multivariable Cox proportional hazards regression indicated significant associations for staff who performed catheterization (junior, P = .002; student, P = .034) and use of steroidal anti-inflammatory drugs (P = .036). The most frequently isolated bacterium was Acinetobacter spp. (21.7%). CONCLUSIONS AND CLINICAL IMPORTANCE: The bacterial colonization incidence related to IV catheter placement was slightly higher than the incidence described in other veterinary studies. Associated factors not previously described in veterinary medicine were found. The most frequently isolated organism was Acinetobacter spp., indicating its importance as an emerging pathogen in catheter colonization. PMID- 29602243 TI - Over 14% Efficiency in Polymer Solar Cells Enabled by a Chlorinated Polymer Donor. AB - Fluorine-contained polymers, which have been widely used in highly efficient polymer solar cells (PSCs), are rather costly due to their complicated synthesis and low yields in the preparation of components. Here, the feasibility of replacing the critical fluorine substituents in high-performance photovoltaic polymer donors with chlorine is demonstrated, and two polymeric donors, PBDB-T-2F and PBDB-T-2Cl, are synthesized and compared in parallel. The synthesis of PBDB-T 2Cl is much simpler than that of PBDB-T-2F. The two polymers have very similar optoelectronic and morphological properties, except the chlorinated polymer possess lower molecular energy levels than the fluorinated one. As a result, the PBDB-T-2Cl-based PSCs exhibit higher open circuit voltage (Voc ) than the PBDB-T 2F-based devices, leading to an outstanding power conversion efficiency of over 14%. This work establishes a more economical design paradigm of replacing fluorine with chlorine for preparing highly efficient polymer donors. PMID- 29602244 TI - Internalized stigma in adults with early phase versus prolonged psychosis. AB - AIM: Although internalized stigma is associated with negative outcomes among those with prolonged psychosis, surprisingly little work has focused on when in the course of one's illness stigma is internalized and the impact of internalization on symptoms or social functioning over the course of the illness. Therefore, this study investigated whether (1) internalized stigma is greater among those later in the course of psychosis and (2) whether internalized stigma has a stronger negative relationship with social functioning or symptoms among those with prolonged compared to early phase psychosis. METHODS: Individuals with early phase (n = 40) and prolonged psychosis (n = 71) who were receiving outpatient services at an early-intervention clinic and a VA medical center, respectively, completed self-report measures of internalized stigma and interview rated measures of symptoms and social functioning. RESULTS: Controlling for education, race and sex differences, internalized stigma was significantly greater among those with prolonged psychosis compared to early phase. Internalized stigma was negatively related to social functioning and positively related to symptoms in both groups. Furthermore, the magnitude of the relationship between cognitive symptoms and internalized stigma was significantly greater among those with early phase. Stereotype endorsement, discrimination experiences and social withdrawal also differentially related to symptoms and social functioning across the 2 samples. CONCLUSIONS: Findings suggest that internalized stigma is an important variable to incorporate into models of early psychosis. Furthermore, internalized stigma may be a possible treatment target among those with early phase psychosis. PMID- 29602246 TI - Effect of European Medicines Agency's regulatory measures on nimesulide utilization in Portugal. PMID- 29602245 TI - Reactive glia promote development of CD103+ CD69+ CD8+ T-cells through programmed cell death-ligand 1 (PD-L1). AB - INTRODUCTION: Previous work from our laboratory has demonstrated in vivo persistence of CD103+ CD69+ brain resident memory CD8+ T-cells (bTRM ) following viral infection, and that the PD-1: PD-L1 pathway promotes development of these TRM cells within the brain. Although glial cells express low basal levels of PD L1, its expression is upregulated upon IFN-gamma-treatment, and they have been shown to modulate antiviral T-cell effector responses through the PD-1: PD-L1 pathway. METHODS: We performed flow cytometric analysis of cells from co-cultures of mixed glia and CD8+ T-cells obtained from wild type mice to investigate the role of glial cells in the development of bTRM . RESULTS: In this study, we show that interactions between reactive glia and anti-CD3 Ab-stimulated CD8+ T-cells promote development of CD103+ CD69+ CD8+ T-cells through engagement of the PD-1: PD-L1 pathway. These studies used co-cultures of primary murine glial cells obtained from WT animals along with CD8+ T-cells obtained from either WT or PD-1 KO mice. We found that alphaCD3 Ab-stimulated CD8+ T-cells from WT animals increased expression of CD103 and CD69 when co-cultured with primary murine glial cells. In contrast, significantly reduced expression of CD103 and CD69 was observed using CD8+ T-cells from PD-1 KO mice. We also observed that reactive glia promoted high levels of CD127, a marker of memory precursor effector cells (MPEC), on CD69+ CD8+ T-cells, which promotes development of TRM cells. Interestingly, results obtained using T-cells from PD-1 KO animals showed significantly reduced expression of CD127 on CD69+ CD8+ cells. Additionally, blocking of glial PD-L1 resulted in decreased expression of CD103, along with reduced CD127 on CD69+ CD8+ T-cells. CONCLUSIONS: Taken together, these results demonstrate a role for activated glia in promoting development of bTRM through the PD-1: PD-L1 pathway. PMID- 29602247 TI - Mortality in rabbits transported for slaughter. AB - During transport rabbits may be exposed to various stressors which can compromise both their welfare and meat quality. Mortality related to the commercial transport of rabbits for slaughter was analyzed in the Czech Republic in the period from 2009 to 2016. The overall transport-related mortality of rabbits was 0.19%. Transport distance was found to have an impact on rabbit mortality; significantly (p < .001) greater losses were found in rabbits transported over longer distances. Mortality rates ranged from 0.02% in rabbits transported over distances of less than 50 km to 0.29% in rabbits transported over distances exceeding 400 km. A significantly (p < .001) increased risk was also associated with shipments in which 500 and more rabbits were delivered per batch. No effect of season was found. Our results show that rabbits can be transported within a wide range of temperatures (from -5 to 19.9 degrees C) with no negative impact on mortality in transit. However, journeys carried out at temperatures below -5 degrees C and above 20 degrees C were associated with increased death losses (0.17% and 0.15%, respectively). PMID- 29602248 TI - Consequences of an early catheter-based intervention on pulmonary artery growth and right ventricular myocardial function in a pig model of pulmonary artery stenosis. AB - OBJECTIVE: To determine the consequences of an early catheter-based intervention on pulmonary artery (PA) growth and right ventricular (RV) myocardial function in an animal model of branch PA stenosis. BACKGROUND: Acute results and safety profiles of deliberate stent fracture within the pulmonary vasculature have been demonstrated. The long-term impact of early stent intervention and deliberate stent fracture on PA growth and myocardial function is not understood. METHODS: Implantation of small diameter stents was performed in a pig model of left PA stenosis at 6 weeks (10 kg) followed by dilations at 10 (35 kg) and 18 weeks (65 kg) with intent to fracture and implant large diameter stents. Hemodynamics, RV contractility, and 2D/3D angiography were performed with each intervention. The heart and pulmonary vasculature were histologically assessed. RESULTS: Stent fracture occurred in 9/12 and implantation of large diameter stents was successful in 10/12 animals with no PA aneurysms or dissections. The final stented PA segment and distal left PA branch origins equaled the corresponding PA diameters of sham controls. Growth of left PA immediately beyond the stent was limited and there was diffuse fibro-intimal proliferation within the distal left and right PA. RV contractility was diminished in the intervention group and the response to dobutamine occurred uniquely via increases in heart rate. CONCLUSIONS: Early stent intervention in this surgically created PA stenosis model was associated with improved growth of the distal PA vasculature but additional investigation of PA vessel physiology and impact on the developing heart are needed. PMID- 29602249 TI - The first transapical transcatheter aortic valve-in-valve implantation using the J-valve system into a failed biophysio aortic prosthesis in a patient with high risk of coronary obstruction. AB - We report the first successful valve-in-valve (ViV) implantation into a failed Edwards Biophysio surgical prosthesis (Edwards Lifesciences, Irvine, CA) and also the first use of the J-Valve system (Jie Cheng Medical Technologies, Suzhou, China) in a ViV configuration. A 77-year old male had symptomatic severe aortic stenosis secondary to failure of a 25 mm Biophysio bioprosthetic valve implanted 11 years previously, along with concomitant coronary artery bypass grafting. Transthoracic echocardiography (TTE) revealed calcified leaflets, a mean aortic gradient of 50 mm Hg, and an estimated valve area of 0.9 cm2 with no aortic insufficiency. The patient had low coronary ostial height with the right coronary artery arising only 8.5 mm from the valve annulus and the left main coronary artery arising only 9.4 mm from the valve annulus. Risk of coronary ostial obstruction was especially concerning in context of both the patient's extremely low coronary ostial height and the unique structure of the Biophysio valve. Under general anesthesia, transapical transcatheter aortic ViV implantation with a 25 mm J-Valve was performed in a hybrid operating room. The J-Valve prosthesis was deployed in the 25 mm Biophysio surgical valve without difficulty or complications. There were no intraoperative or postoperative complications. The patient was discharged home after 3 days. TTE at 1 year showed a mean aortic valve gradient of 14 mm Hg, and no aortic insufficiency. This case demonstrated that J-Valve implantation may be a new option for patients at high risk for coronary obstruction. PMID- 29602251 TI - Tim-3 blockade promotes iNKT cell function to inhibit HBV replication. AB - Increased expression of T cell immunoglobulin and mucin domain-3 (Tim-3) on invariant natural killer T (iNKT) cells is reported in chronic hepatitis B virus (HBV) infection. However, whether Tim-3 regulates iNKT cells in chronic HBV condition remains unclear. In this study, our results showed that the expression of Tim-3 was up-regulated on hepatic iNKT cells from HBV-transgenic (Tg) mice or iNKT cells stimulated with alpha-galactosylceramide (alpha-Galcer). Compared with Tim-3- iNKT cells, Tim-3+ iNKT cells expressed more IFN-gamma, IL-4 and CD107a, indicating a strong relationship between Tim-3 and iNKT cell activation. Constantly, treatment of Tim-3 blocking antibodies significantly enhanced the production of IFN-gamma, TNF-alpha, IL-4 and CD107a in iNKT cells both in vivo and in vitro. This Tim-3- mediated suppression of iNKT cells was further confirmed in Tim-3 knockout (KO) mice. Moreover, Tim-3 blockade promoted alpha Galcer-triggered inhibition of HBV replication, displaying as the decreased HBV DNA and HBsAg level in serum, and down-regulated pgRNA expression in liver tissues. Collectively, our data, for the first time, demonstrated the potential role of Tim-3 blockade in promoting iNKT cell-mediated HBV inhibition. Therefore, combination of alpha-Galcer with Tim-3 blockade might be a promising approach in chronic hepatitis B therapy. PMID- 29602252 TI - The Swedish policy approach to directed mutagenesis in a European context. AB - This review describes the Swedish approach to directed mutagenesis in plants and puts it in a comparative European perspective. Directed mutagenesis is accomplished by a number of genome editing techniques; however, the legal status of these techniques and their resulting products is uncertain in the European Union (EU) as there is no political consensus on whether or not these should be regulated as genetically modified organisms (GMOs). A number of cases have developed over the past few years, putting the GMO regulatory framework to the test. These include oilseed rape developed by oligonucleotide-directed mutagenesis, Arabidopsis developed by clustered regularly interspaced short palindromic repeat-Cas9, and the case on mutagenesis for which the French Court requested a preliminary ruling from the Court of Justice of the EU. In this review, the involvement of the Swedish Government and governmental authorities in these cases is described and compared with that of other EU member states and/or EU entity statements and reports. Various approaches to the definition of recombinant nucleic acids are also discussed, as this is crucial for the EU GMO definition thus affecting the legal status of products developed by directed mutagenesis. PMID- 29602250 TI - The role of septin 7 in physiology and pathological disease: A systematic review of current status. AB - Septins are a conserved family of cytoskeletal GTPases present in different organisms, including yeast, drosophila, Caenorhabditis elegans and humans. In humans, septins are involved in various cellular processes, including exocytosis, apoptosis, leukemogenesis, carcinogenesis and neurodegeneration. Septin 7 is unique out of 13 human septins. Mammalian septin 6, septin 7, septin 2 and septin 9 coisolate together in complexes to form the core unit for the generation of the septin filaments. Physiological septin filaments are hetero-oligomeric complexes consisting of core septin hexamers and octamers. Furthermore, septin 7 plays a crucial role in cytokinesis and mitosis. Septin 7 is localized to the filopodia and branches of developing hippocampal neurons, and is the most abundant septin in the adult rat forebrain as well as a structural component of the human and mouse sperm annuli. Septin 7 is crucial to the spine morphogenesis and dendrite growth in neurons, and is also a structural constituent of the annulus in human and mouse sperm. It can suppress growth of some tumours such as glioma and papillary thyroid carcinoma. However, the molecular mechanisms of involvement of septin 7 in human disease, especially in the development of cancer, remain unclear. This review focuses on the structure, function and mechanism of septin 7 in vivo, and summarizes the role of septin 7 in cell proliferation, cytokinesis, nervous and reproductive systems, as well as the underlying molecular events linking septin 7 to various diseases, such as Alzheimer's disease, schizophrenia, neuropsychiatric systemic lupus erythematosus, tumour and so on. PMID- 29602253 TI - Ultrafast Acoustofluidic Exfoliation of Stratified Crystals. AB - While the remarkable properties of 2D crystalline materials offer tremendous opportunities for their use in optics, electronics, energy systems, biotechnology, and catalysis, their practical implementation largely depends critically on the ability to exfoliate them from a 3D stratified bulk state. This goal nevertheless remains elusive, particularly in terms of a rapid processing method that facilitates high yield and dimension control. An ultrafast multiscale exfoliation method is reported which exploits the piezoelectricity of stratified materials that are noncentrosymmetric in nature to trigger electrically-induced mechanical failure across weak grain boundaries associated with their crystal domain planes. In particular, it is demonstrated that microfluidic nebulization using high frequency acoustic waves exposes bulk 3D piezoelectric crystals such as molybdenum disulphide (MoS2 ) and tungsten disulphide (WS2 ) to a combination of extraordinarily large mechanical acceleration (~108 m s-2 ) and electric field (~107 V m-1 ). This results in the layered bulk material being rapidly cleaved into pristine quasi-2D-nanosheets that predominantly comprise single layers, thus constituting a rapid and high throughput chip-scale method that opens new possibilities for scalable production and spray coating deposition. PMID- 29602254 TI - Nanomedicine Approaches Against Parasitic Worm Infections. AB - Nanomedicine approaches have the potential to transform the battle against parasitic worm (helminth) infections, a major global health scourge from which billions are currently suffering. It is anticipated that the intersection of two currently disparate fields, nanomedicine and helminth biology, will constitute a new frontier in science and technology. This progress report surveys current innovations in these research fields and discusses research opportunities. In particular, the focus is on: (1) major challenges that helminth infections impose on mankind; (2) key aspects of helminth biology that inform future research directions; (3) efforts to construct nanodelivery platforms to target drugs and genes to helminths hidden in their hosts; (4) attempts in applying nanotechnology to enable vaccination against helminth infections; (5) outlooks in utilizing nanoparticles to enhance immunomodulatory activities of worm-derived factors to cure allergy and autoimmune diseases. In each section, achievements are summarized, limitations are explored, and future directions are assessed. PMID- 29602255 TI - Monitoring and control of amygdala neurofeedback involves distributed information processing in the human brain. AB - Brain-computer interfaces provide conscious access to neural activity by means of brain-derived feedback ("neurofeedback"). An individual's abilities to monitor and control feedback are two necessary processes for effective neurofeedback therapy, yet their underlying functional neuroanatomy is still being debated. In this study, healthy subjects received visual feedback from their amygdala response to negative pictures. Activation and functional connectivity were analyzed to disentangle the role of brain regions in different processes. Feedback monitoring was mapped to the thalamus, ventromedial prefrontal cortex (vmPFC), ventral striatum (VS), and rostral PFC. The VS responded to feedback corresponding to instructions while rPFC activity differentiated between conditions and predicted amygdala regulation. Control involved the lateral PFC, anterior cingulate, and insula. Monitoring and control activity overlapped in the VS and thalamus. Extending current neural models of neurofeedback, this study introduces monitoring and control of feedback as anatomically dissociated processes, and suggests their important role in voluntary neuromodulation. PMID- 29602256 TI - Exploring governance for a One Health collaboration for leptospirosis prevention and control in Fiji: Stakeholder perceptions, evidence, and processes. AB - : Fiji has a high burden of leptospirosis, with endemic infection and epidemic outbreaks with high mortality, often associated with flooding and cyclones. As a zoonosis, leptospirosis control requires interventions in sectors beyond the usual control of health-in Fiji, the dairy and sugar industries, and water and sanitation and rodent control in communities. This paper presents the findings of qualitative research to inform policy around governance for a One Health multisectoral approach to leptospirosis control. METHODS: Key informants from relevant government agencies and industry organizations were interviewed in late 2014, and the interviews analyzed and triangulated with documentary analysis. FINDINGS: The analysis identified 5 themes: perceptions of the impact of leptospirosis, governance processes, models for collaboration, leptospirosis control, and preferred leadership for leptospirosis management. Data were limited, with poor communication between ministries, and limited awareness of leptospirosis outside outbreaks. Collaboration during outbreaks was positive but not sustained in endemic periods. Mechanism for enhanced collaboration was developed for endemic and outbreak situations. CONCLUSION: The findings informed a One Health governance approach to leptospirosis, framed within a National Strategic Plan, with a specific National Action Plan for Leptospirosis. The process provides a research based One Health template for application to other zoonotic diseases. PMID- 29602257 TI - Neonatal oesophageal perforation: The role for non-operative management. AB - AIM: Isolated oesophageal perforation in neonates is a rare but potentially life threatening condition. Although management has historically been operative, conservative management (antibiotics, bowel rest, parenteral nutrition) is now more routinely used. The aim of this study was to evaluate the management of this condition in two large neonatal surgical centres. METHODS: A retrospective cohort study was conducted for neonates admitted to The Hospital for Sick Children (Toronto, Canada) or The Royal Children's Hospital (Melbourne, Australia) with a diagnosis of oesophageal perforation, from 2006 to 2016. Patients with oesophageal atresia or tracheo-oesophageal fistula were excluded. Data were collected from chart review regarding demographics, clinical course, management and outcomes. RESULTS: Eleven neonates with oesophageal perforation were identified over a 10-year period at the two centres. Median gestational age at birth was 25.3 weeks (interquartile range 24.2-28.8) and the majority (7/11, 64%) of neonates were extremely low birthweight. Diagnosis was made on day 1 of life for 9 of 11 (81%) neonates and was secondary to nasogastric tube insertion in 10 of 11 (91%) neonates. Only four (36%) neonates had symptomatic complications. All neonates were managed with bowel rest and intravenous antibiotics for a median of 7 days (interquartile range 7-10); two patients required operative intervention. Three neonates (27%) developed chronic lung disease and two (19%) died prior to discharge. CONCLUSIONS: Oesophageal perforation is severe complication secondary to instrumentation of the upper gastrointestinal tract in neonates. Prompt and accurate diagnosis is crucial. Non-operative management is effective for the majority, though morbidity is common. PMID- 29602258 TI - Patent foramen ovale (PFO) closure versus medical therapy for prevention of recurrent stroke in patients with prior cryptogenic stroke: A systematic review and meta-analysis of randomized controlled trials. AB - OBJECTIVES: We performed a systematic review and meta-analysis of randomized controlled trials to assess the effect of closure of a patent foramen ovale (PFO) compared with medical therapy for the prevention of stroke in patients with prior cryptogenic stroke. BACKGROUND: The role of PFO closure in reducing risk of stroke in patients with prior cryptogenic stroke has been controversial. METHODS: We searched PubMed, Embase, CINAHL, and CENTRAL for randomized trials investigating PFO closure versus medical therapy. We assessed trial bias and the quality of evidence for main outcomes was rated using GRADE. The primary outcome of interest was the occurrence of stroke. Estimates of effect were pooled with a random-effects model. This study is registered with PROSPERO (CRD42017081579). RESULTS: We included five trials, comprising data for 3,440 adults randomized to receive PFO closure (n = 1,829) or medical therapy (n = 1,611). Mean follow-up ranged from 2 years to 5.4 years across the trials. Patients treated with PFO closure had a lower risk of stroke (RR 0.39, 95% CI 0.18-0.88, I2 = 57%, P = 0.02) compared with those treated with medical therapy. Subgroup analyses showed that the beneficial effect of PFO closure on a composite outcome of cerebrovascular events is more pronounced in patients with a large PFO shunt (RR 0.25, 95% CI 0.12-0.54, I2 = 0%, P = 0.0004), male patients (RR 0.34, 95% CI 0.15-0.75, I2 = 36%, P = 0.07), and those aged <=45 years (RR 0.35, 95% CI 0.15 0.79, I2 = 0%, P = 0.01). CONCLUSIONS: PFO closure reduced risk of stroke compared with medical therapy. PFO closure is a therapeutic option that should be offered to adults with cryptogenic stroke. PMID- 29602259 TI - An algorithmic approach for the management of ostial right coronary artery chronic total occlusions. AB - Treatment of ostial chronic total occlusions (CTOs) of the right coronary artery (RCA) can be challenging. We present an algorithmic approach to the management of such lesions that incorporates all contemporary equipment and techniques. If the RCA ostium can be engaged with a guide catheter then antegrade crossing attempts should be performed. If the antegrade guidewire enters the subintimal space, re entry into the distal true lumen is performed provided that the antegrade guide catheter provides enough support. If re-entry cannot be achieved, the antegrade wire is left in place to facilitate retrograde recanalization attempts (usually performed using the reverse controlled antegrade and retrograde tracking and dissection-reverse CART-technique). If the RCA ostium cannot be engaged with a guide catheter (for example in flush ostial occlusions) or if the guide catheter does not provide sufficient support, a primary retrograde approach is required, aiming for retrograde guidewire puncture into the aorta, followed by snaring and externalization. Retrograde guidewire puncture can be challenging, requiring use of stiff, highly penetrating guidewires or occasionally use of the Carlino technique. The aforementioned algorithm can facilitate crossing of ostial RCA CTOs. PMID- 29602260 TI - C-reactive protein and immature-to-total neutrophil ratio have no utility in guiding lumbar puncture in suspected neonatal sepsis. AB - AIM: Meningitis may complicate neonatal sepsis, but there is scant evidence to inform the decision to perform a lumbar puncture (LP) and considerable variation in practice. We investigated whether inflammatory markers - C-reactive protein (CRP) and immature-to-total neutrophil ratio (ITR) - were predictive of meningitis or significant cerebrospinal fluid (CSF) pleocytosis and useful in guiding the decision to perform a LP. METHODS: We studied all inpatients in a single tertiary neonatal unit who were <6 months of age who had a LP performed between March 2011 and October 2014. We categorised CSF results as follows: (i) culture-positive meningitis; (ii) probable culture-negative meningitis but meeting a priori criteria for significant CSF leucocytosis; or (iii) no evidence of meningitis. CRP and ITR obtained within 48 h of LP were analysed. We assessed the test performance of CRP and ITR by area under receiver operating characteristic curves. RESULTS: A total of 757 (male 471, 62.2%) infants were included. The median (interquartile range) gestational age was 38.4 weeks (30 40.3), and birthweight was 2940 g (1330-3560). Ten (1.3%) infants had culture positive meningitis; 71 (9.4%) were classified as probable culture-negative meningitis and 676 (89.3%) as non-meningitis. The area under receiver operating characteristic curve for culture-positive and probable culture-negative meningitis was 0.43 for CRP (95% confidence interval 0.36-0.51) and 0.58 for ITR (0.51-0.65). At a CRP threshold of 30 mg/L, there was a positive likelihood ratio (LR) of 0.77 and a negative LR of 1.44. CONCLUSIONS: CRP and ITR perform poorly in identifying infants with confirmed or probable meningitis. The decision to perform an LP should be more focused on clinical grounds and/or a positive blood culture and less on inflammatory or haematological markers in isolation. PMID- 29602261 TI - Post-acute care use after major head and neck oncologic surgery with microvascular reconstruction. AB - OBJECTIVES: Post-acute care (PAC) centers, such as skilled nursing facilities, unskilled nursing facilities, lower acuity hospitals, and rehabilitation centers, serve to optimize recovery after acute care hospitalization. We aimed to identify factors associated with PAC utilization among patients undergoing head and neck cancer surgery with microvascular reconstruction because it may be helpful for patient decision making, discharge planning, and resource allocation. METHODS: Retrospective linked analysis of the 2011 to 2015 National Surgical Quality Improvement Program. Eligible patients were identified and stratified by discharge disposition (home or PAC) after their postoperative acute-care hospitalization. After an initial univariate screen of demographic and clinical variables, a multivariable logistic regression analysis was performed modelling discharge to PAC. RESULTS: Of the 1,652 identified patients, 261 (15.8%) were discharged to PAC. Those admitted to PAC were older, had a higher burden of comorbidity, and were more likely to be functionally dependent. They also had longer surgeries, longer hospitalizations, higher rates of reoperation, and higher rates of postoperative complications. After multivariate analysis, factors independently associated with PAC discharge included increasing age (odds ratio [OR] 2.12 per 10-year increase; 95% confidence interval [CI], 1.81-2.48), active smoking status (odds ratio (OR) 1.61; 95% confidence interval (CI), 1.13-2.29), prolonged hospitalization (OR 1.04; 95% CI, 1.02-1.07), and postoperative pulmonary complications (OR 2.02; 95% CI, 1.36-2.99). CONCLUSION: Of the patients undergoing surgery for head and neck cancers with microvascular reconstruction, 15.8% are discharged to PAC. Age, active smoking status, prolonged hospitalization, and postoperative pulmonary complications (vs. comorbidity, functional status, or primary tumor site) are independently associated with discharge to PAC. LEVEL OF EVIDENCE: Level 2c. Laryngoscope, 2532-2538, 2018. PMID- 29602262 TI - False lumen intervention to promote remodelling and thrombosis-The FLIRT concept in aortic dissection. AB - OBJECTIVE: Thoracic endovascular aortic repair (TEVAR) has changed the management of aortic dissection by induced remodelling. Beyond reconstructing the true lumen, we describe the concept of False Lumen Intervention to promote Remodelling and Thrombosis (FLIRT) in both type A and B aortic dissection. METHODS: Between 2011 and 2017, 10 patients with aortic dissection (5 type A; 5 type B) underwent FLIRT using a combination of patent foramen ovale (PFO) or atrial septal defect (ASD) occluders, coils and glue. Patients were followed by computed tomography (CT) angiogram prior to, and 6 months following, discharge to evaluate false lumen (FL) thrombosis and aortic remodelling. Outcomes analyzed comprised successful device delivery, completeness of FL thrombosis and aortic remodelling, procedure related complications and mortality. RESULTS: FLIRT induced aortic remodelling in all cases of proximal dissection, with aortic shrinkage from 63.8 +/- 7.5 pre-FLIRT, to 50.2 +/- 6.6 mm (P = 0.057) and an increase in true lumen area from 5.8 +/- 3.6 to 11.4 +/- 2.5 cm2 (P = 0.006). In distal dissection (after previous TEVAR with residual FL flow), FLIRT successfully induced FL thrombosis in 4 of 5 cases at first attempt (1 case required additional coiling of the gutter between left subclavian artery and stent-graft for complete thrombosis). While maximal aortic diameter remained unchanged (55.6 +/- 9.1 pre FLIRT and 54.4 +/- 13.7 mm at follow-up), true lumen area increased from 7.8 +/- 2.3 pre-procedure, to 10.6 +/- 1.5 cm2 at follow-up (P = 0.016), consistent with remodelling. CONCLUSION: Interventional FL management, using the FLIRT concept, is feasible in selected cases of aortic dissection, promotes FL thrombosis and induces successful remodelling. PMID- 29602263 TI - Applications of dissolution dynamic nuclear polarization in chemistry and biochemistry. AB - Sensitivity of detection is one of the most limiting aspects when applying NMR spectroscopy to current problems in the molecular sciences. A number of hyperpolarization methods exist for increasing the population difference between nuclear spin Zeeman states and enhance the signal-to-noise ratio by orders of magnitude. Among these methods, dissolution dynamic nuclear polarization (D-DNP) is unique in its capability of providing high spin polarization for many types of molecules in the liquid state. Originally proposed for biomedical applications including in vivo imaging, applications in high resolution NMR spectroscopy are now emerging. These applications are the focus of the present review. Using D DNP, a small sample aliquot is first hyperpolarized as a frozen solid at low temperature, followed by dissolution into the liquid state. D-DNP extends the capabilities of liquid state NMR spectroscopy towards shorter timescales and enables the study of nonequilibrium processes, such as the kinetics and mechanisms of reactions. It allows the determination of intermolecular interactions, in particular based on spin relaxation parameters. At the same time, a challenge in the application of this hyperpolarization method is that spin polarization is nonrenewable. Substantial effort has been devoted to develop methods for enabling rapid correlation spectroscopy, the measurement of time dependent signals, and the extension of the observable time window. With these methods, D-DNP has the potential to open new application areas in the chemical and biochemical sciences. PMID- 29602265 TI - R(NA)-tistic expression: The art of matching unknown mRNA and proteins to environmental response in ecological genomics. AB - A challenge of modern ecological genomics is reducing uncertainty surrounding the biological inferences from gene expression. For example, approximately 40% of proteins in eukaryotic model organisms do not contain characterized domains (Gollery et al., 2006). Even proteins of "known function" are typically only characterized in the sense that they have a domain function, but provide no information on their biological role within the cell (e.g., activation, pathways or targets). Yet, as molecular ecologists, a common objective is to elucidate how organisms respond to environmental variation through changes in gene expression, including homoeostatic, acclimatory, and adaptive responses to environmental stressors, a challenge increased by poor protein ecological annotation. Now, in this issue of Molecular Ecology, Orsini et al. (2017) use the quintessential Daphnia system to characterize the differences in stress response in three genotypic backgrounds to common biotic and abiotic stressors found in nature. Using an optimized weighted gene co-expression network analysis, they link genes of unknown function to genes that they co-activate with and enrich for gene ontology. Determining the functional networks of genes that behave in genotype- and treatment-specific responses gives insight into possible pathways and respective ecological roles, helping pave the way for the next generation of transcriptomic studies in molecular ecology. PMID- 29602264 TI - The cyclin-dependent kinase G group defines a thermo-sensitive alternative splicing circuit modulating the expression of Arabidopsis ATU2AF65A. AB - The ability to adapt growth and development to temperature variations is crucial to generate plant varieties resilient to predicted temperature changes. However, the mechanisms underlying plant response to progressive increases in temperature have just started to be elucidated. Here, we report that the cyclin-dependent kinase G1 (CDKG1) is a central element in a thermo-sensitive mRNA splicing cascade that transduces changes in ambient temperature into differential expression of the fundamental spliceosome component, ATU2AF65A. CDKG1 is alternatively spliced in a temperature-dependent manner. We found that this process is partly dependent on both the cyclin-dependent kinase G2 (CDKG2) and the interacting co-factor CYCLIN L1 (CYCL1), resulting in two distinct messenger RNAs. The relative abundance of both CDKG1 transcripts correlates with ambient temperature and possibly with different expression levels of the associated protein isoforms. Both CDKG1 alternative transcripts are necessary to fully complement the expression of ATU2AF65A across the temperature range. Our data support a previously unidentified temperature-dependent mechanism based on the alternative splicing (AS) of CDKG1 and regulated by CDKG2 and CYCL1. We propose that changes in ambient temperature affect the relative abundance of CDKG1 transcripts, and this in turn translates into differential CDKG1 protein expression coordinating the AS of ATU2AF65A. PMID- 29602266 TI - Cytomegalovirus infection in heart transplantation: A single center experience. AB - BACKGROUND: Cytomegalovirus (CMV) infection remains a major complication after heart transplantation with varying prophylaxis strategies employed. We sought to determine the impact of valganciclovir (VGC) duration on the epidemiology of CMV infections after heart transplantation. METHODS: We performed a prospective cohort study of CMV donor (D) or recipient (R) seropositive heart transplant recipients from 2005 to 2012 who completed VGC prophylaxis, ranging from 3 to 12 months according to serostatus and induction immunosuppression. Univariate and multivariate logistic regression was performed. RESULTS: Among 159 heart transplant recipients during the study period, 130 (82%) were eligible for VGC prophylaxis. CMV D/R serostatus was as follows: 24% D+/R-, 30% D+/R+, and 29% D /R+. 65% and 21% received basiliximab and thymoglobulin induction, respectively, followed by maintenance tacrolimus, mycophenolate mofetil, and prednisone. Twenty one (16%) recipients suffered CMV infection. There was no association with comorbidities including diabetes mellitus, chronic kidney disease, or mechanical assist devices, nor were there associations with rejection, treatments of rejection, or mortality. When VGC prophylaxis duration was stratified by <=6 vs >=12 months, time from heart transplantation to CMV infection was delayed (median 247 vs 452 days, P = .002) but there was no difference in days from VGC discontinuation to onset of CMV infection (median 72 vs 83 days, P = .31). CMV infection occurred most frequently within 6-16 weeks of VGC cessation, and 95% of infections occurred during the 6 months post-prophylaxis period. CONCLUSIONS: Relative to <=6 months, >=12 months of VGC did not reduce incidence of CMV infection and only delayed time to onset. 95% of CMV infection occurs within 6 months after cessation of VGC. PMID- 29602267 TI - Structural Model for Viscoelastic Properties of Pericardial Bioprosthetic Valves. AB - The benefit of bioprosthetic aortic valve over mechanical valve replacements is the release of thromboembolism and digression of long-term anticoagulation treatment. The function of bioprostheses and their efficiency is known to depend on the mechanical properties of the leaflet tissue. So it is necessary to select a suitable tissue for the bioprosthesis. The purpose of the present study is to clarify the viscoelastic behavior of bovine, equine, and porcine pericardium. In this study, pericardiums were compared mechanically from the viscoelastic aspect. After fixation of the tissues in glutaraldehyde, first uniaxial tests with different extension rates in the fiber direction were performed. Then, the stress relaxation tests in the fiber direction were done on these pericardial tissues by exerting 20, 30,40, and 50% strains. After evaluation of viscoelastic linearity, the Prony series, quasilinear viscoelastic (QLV) and modified superposition theory were applied to the stress relaxation data. Finally, the parameters of these constitutive models were extracted for each pericardium tissue. All three tissues exhibited a decrease in relaxation rate with elevating strain, indicating the nonlinear viscoelastic behavior of these tissues. The three-term Prony model was selected for describing the linear viscoelasticity. Among different models, the QLV model was best able to capture the relaxation behavior of the pericardium tissues. More stiffness of porcine pericardium was observed in comparison to the two other pericardium tissues. The relaxation percentage of porcine pericardium was less than the two others. It can be concluded that porcine pericardium behaves more as an elastic and less like a viscous tissue in comparison to the bovine and equine pericardium. PMID- 29602268 TI - Social participation and the onset of hypertension among the middle-aged and older population: Evidence from the China Health and Retirement Longitudinal Study. AB - AIM: While previous studies have examined the association between health-related behaviors and hypertension, comparatively little attention has been paid to the role of social participation (i.e. participating in community organizations). The aim of the present study was to investigate the longitudinal association between social participation and hypertension among the middle-aged and older population (aged >=45 years) in China where the prevalence of hypertension has been increasing rapidly in the past few decades. METHODS: Data came from the China Health and Retirement Longitudinal Study waves 2011 and 2013. Information was obtained from 5483 participants on blood pressure, social participation and covariates. A sex-stratified Poisson regression model with a robust variance estimator was used to examine the associations. RESULTS: During the period between 2011 and 2013, 20.6% of men and 17.2% of women developed hypertension. A Poisson regression model showed that participating in community organizations once a week or more frequently was inversely associated with the onset of hypertension in women (incidence rate ratio 0.80, 95% confidence interval 0.67 0.95, P = 0.012). Among men, no such association was found. CONCLUSION: The present study suggests that promoting social participation might help mitigate the disease burden associated with hypertension in China, particularly among women. Geriatr Gerontol Int 2018; 18: 1093-1099. PMID- 29602269 TI - Risk for interspecies transmission of zoonotic pathogens during poultry processing and pork production in Peru: A qualitative study. AB - Interspecies transmission of pathogens is an unfrequent but naturally occurring event and human activities may favour opportunities not previously reported. Reassortment of zoonotic pathogens like influenza A virus can result from these activities. Recently, swine and birds have played a central role as "mixing vessels" for epidemic and pandemic events related to strains like H1N1 and H5N1. Unsafe practices in poultry markets and swine farms can lead to interspecies transmission, favouring the emergence of novel strains. Thus, understanding practices that lead to interspecies interactions is crucial. This qualitative study aimed to evaluate poultry processing practices in formal and informal markets and the use of leftovers by swine farmers in three Peruvian cities: Lima (capital), Tumbes (coastal) and Tarapoto (jungle). We conducted 80 direct observations at formal and informal markets and interviewed 15 swine farmers. Processors slaughter and pluck chickens and vendors and/or processors eviscerate chickens. Food safety and hygiene practices were suboptimal or absent, although some heterogeneity was observed between cities and chicken vendors versus processors. Both vendors (76%) and processors (100%) sold the chicken viscera leftovers to swine farmers, representing the main source of chicken viscera for swine farms (53%). Swine farmers fed the chicken viscera to their swine. Chicken viscera cooking times varied widely and were insufficient in some cases. Non abattoired poultry leads to the sale of poultry leftovers to small-scale swine farms, resulting in indirect but frequent interspecies contacts that can lead to interspecies transmission of bacterial pathogens or the reassortment of influenza A viruses. These interactions are exacerbated by suboptimal safety and hygiene conditions. People involved in these activities constitute an at-risk population who could play a central role in preventing the transmission of pathogens between species. Educational interventions on hygiene and food safety practices will be important for reducing the risk of interspecies influenza transmission. PMID- 29602270 TI - Injectable Granular Hydrogels with Multifunctional Properties for Biomedical Applications. AB - Injectable hydrogels are useful for numerous biomedical applications, such as to introduce therapeutics into tissues or for 3D printing. To expand the complexity of available injectable hydrogels, shear-thinning and self-healing granular hydrogels are developed from microgels that interact via guest-host chemistry. The microgel properties (e.g., degradation, molecule release) are tailored through their crosslinking chemistry, including degradation in response to proteases. When microgels of varied formulations are mixed, complex release and degradation behaviors are observed, including after injection to permit cellular invasion. PMID- 29602271 TI - Microbial diversity of thermophiles with biomass deconstruction potential in a foliage-rich hot spring. AB - The ability of thermophilic microorganisms and their enzymes to decompose biomass have attracted attention due to their quick reaction time, thermostability, and decreased risk of contamination. Exploitation of efficient thermostable glycoside hydrolases (GHs) could accelerate the industrialization of biofuels and biochemicals. However, the full spectrum of thermophiles and their enzymes that are important for biomass degradation at high temperatures have not yet been thoroughly studied. We examined a Malaysian Y-shaped Sungai Klah hot spring located within a wooded area. The fallen foliage that formed a thick layer of biomass bed under the heated water of the Y-shaped Sungai Klah hot spring was an ideal environment for the discovery and analysis of microbial biomass decay communities. We sequenced the hypervariable regions of bacterial and archaeal 16S rRNA genes using total community DNA extracted from the hot spring. Data suggested that 25 phyla, 58 classes, 110 orders, 171 families, and 328 genera inhabited this hot spring. Among the detected genera, members of Acidimicrobium, Aeropyrum, Caldilinea, Caldisphaera, Chloracidobacterium, Chloroflexus, Desulfurobacterium, Fervidobacterium, Geobacillus, Meiothermus, Melioribacter, Methanothermococcus, Methanotorris, Roseiflexus, Thermoanaerobacter, Thermoanaerobacterium, Thermoanaerobaculum, and Thermosipho were the main thermophiles containing various GHs that play an important role in cellulose and hemicellulose breakdown. Collectively, the results suggest that the microbial community in this hot spring represents a good source for isolating efficient biomass degrading thermophiles and thermozymes. PMID- 29602273 TI - Rebuttal: Comparative prognostic value of postprocedural creatine kinase myocardial band and high-sensitivity troponin T in patients with non-ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention. PMID- 29602272 TI - Connectivity dynamics in typical development and its relationship to autistic traits and autism spectrum disorder. AB - Recent advances in neuroimaging techniques have provided significant insights into developmental trajectories of human brain function. Characterizations of typical neurodevelopment provide a framework for understanding altered neurodevelopment, including differences in brain function related to developmental disorders and psychopathology. Historically, most functional connectivity studies of typical and atypical development operate under the assumption that connectivity remains static over time. We hypothesized that relaxing stationarity assumptions would reveal novel features of both typical brain development related to children on the autism spectrum. We employed a "chronnectomic" (recurring, time-varying patterns of connectivity) approach to evaluate transient states of connectivity using resting-state functional MRI in a population-based sample of 774 6- to 10-year-old children. Dynamic connectivity was evaluated using a sliding-window approach, and revealed four transient states. Internetwork connectivity increased with age in modularized dynamic states, illustrating an important pattern of connectivity in the developing brain. Furthermore, we demonstrated that higher levels of autistic traits and ASD diagnosis were associated with longer dwell times in a globally disconnected state. These results provide a roadmap to the chronnectomic organization of the developing brain and suggest that characteristics of functional brain connectivity are related to children on the autism spectrum. PMID- 29602274 TI - Blackouts as a Moderator of Young Adult Veteran Response to Personalized Normative Feedback for Heavy Drinking. AB - BACKGROUND: Blackouts-or periods of alcohol-induced amnesia for all or part of a drinking event-have been identified as independent predictors of alcohol-related harm that may be used to identify individuals who would benefit from intervention. However, little is known about the prevalence and impact of blackouts among Veterans. This study examined blackouts as a moderator of young adult veteran response to a brief, online personalized normative feedback (PNF) intervention for heavy drinking. METHODS: Veterans scoring >=3/4 (women/men) on the Alcohol Use Disorders Identification Test completed a baseline and 1-month assessment as part of a larger intervention trial (N = 571; 83% male; age M = 28.9, SD = 3.3). Participants were randomized to alcohol PNF (n = 285) or a video game attention control (n = 286). Hierarchical regression was used to examine the interaction between intervention condition and blackouts on alcohol-related outcomes at 1-month follow-up. RESULTS: At baseline, 26% of participants reported loss of memory for drinking events in the past 30 days. The interaction between condition and blackouts was significant, such that PNF participants who had experienced blackouts at baseline reported greater decreases in drinking quantity at 1 month than those who had not, and only PNF participants who had experienced baseline blackouts reported a decrease in alcohol problems at follow-up. CONCLUSIONS: PNF appears to be particularly effective for individuals who have experienced alcohol-induced blackout, perhaps because blackouts prime them for feedback on their alcohol use. While other negative consequences may also prime individuals for behavior change, blackouts are posited as a particularly useful screening tool because they are prevalent among young adults, have a strong association with alcohol-related harm, and are assessed in widely used clinical measures. PMID- 29602275 TI - Study of the effects of 0.15 terahertz radiation on genome integrity of adult fibroblasts. AB - The applications of Terahertz (THz) technologies have significantly developed in recent years, and the complete understanding of the biological effects of exposure to THz radiation is becoming increasingly important. In a previous study, we found that THz radiation induced genomic damage in fetal fibroblasts. Although these cells demonstrated to be a useful model, exposure of human foetuses to THz radiation is highly improbable. Conversely, THz irradiation of adult dermal tissues is cause of possible concern for some professional and nonprofessional categories. Therefore, we extended our study to the investigation of the effects of THz radiation on adult fibroblasts (HDF). In this work, the effects of THz exposure on HDF cells genome integrity, cell cycle, cytological ultrastructure and proteins expression were assessed. Results of centromere negative micronuclei frequencies, phosphorylation of H2AX histone, and telomere length modulation indicated no induction of DNA damage. Concordantly, no changes in the expression of proteins associated with DNA damage sensing and repair were detected. Conversely, our results showed an increase of centromere-positive micronuclei frequencies and chromosomal nondisjunction events, indicating induction of aneuploidy. Therefore, our results indicate that THz radiation exposure may affect genome integrity through aneugenic effects, and not by DNA breakage. Our findings are compared to published studies, and possible biophysical mechanisms are discussed. Environ. Mol. Mutagen. 59:476-487, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29602276 TI - Octreotide for congenital and acquired chylothorax in newborns: A systematic review. AB - AIM: Chylothorax is a rare but life-threatening condition in newborns. Octreotide, a somatostatin analogue, is widely used as a therapeutic option in neonates with congenital and acquired chylothorax, but its therapeutic role has not been clarified yet. METHODS: We performed a systematic review to assess the efficacy and safety of octreotide in the treatment of congenital and acquired chylothorax in newborns. Comprehensive research, updated till 31 October 2017, was performed by searching in PubMed, MEDLINE, EMBASE and the Cochrane Central Register of Controlled Trials (CENTRAL) databases using the MeSH terms 'octreotide' and 'chylothorax'. Both term and preterm newborns with congenital or acquired chylothorax treated with octreotide within the 30th day of life were included. Octreotide treatment was considered effective if a progressive reduction/ceasing in drained chylous effusion occurred. RESULTS: A total of 39 articles were included. Octreotide was effective in 47% of patients, with a slight but not significant difference between congenital (30/57; 53.3%) and acquired (9/27; 33.3%) chylothorax (P = 0.10). Marked variation in octreotide regimen was observed. The most common therapeutic scheme was intravenous infusion at a starting dose of 1 MUg/kg/h, gradually increasing to 10 MUg/kg/h according to the therapeutic response. Side effects were reported in 12 of 84 patients (14.3%). Only case reports were included in this review due to the lack of randomised controlled trials. CONCLUSION: Octreotide is a relatively effective and safe treatment option in neonates with chylothorax, especially for the congenital forms. PMID- 29602277 TI - Suspected coronary fat embolism after liposuction. AB - A 38-year-old female presented with chest pain and ST elevation on electrocardiogram after an outpatient liposuction procedure. Emergent coronary angiography revealed complete occlusion of multiple coronary arteries, with fat embolism as the suspected etiology. Attempts to restore distal coronary flow with balloon dilatation, aspiration with Pronto catheter, and distal adenosine administration resulted in minimal improvement in flow. The material aspirated was consistent with fat. With supportive therapy, including Impella CP support, the patient's clinical condition improved. To our knowledge, this is the first reported case of multiple coronary occlusion after liposuction. PMID- 29602278 TI - DARK Classics in Chemical Neuroscience: Methamphetamine. AB - Methamphetamine has the second highest prevalence of drug abuse after cannabis, with estimates of 35 million users worldwide. The ( S)-(+)-enantiomer is the illicit drug, active neurostimulant, and eutomer, while the ( R)-(-)-enantiomer is contained in over the counter decongestants. While designated a schedule II drug in 1970, ( S)-(+)-methamphetamine is available by prescription for the treatment of attention-deficit disorder and obesity. The illicit use of ( S)-(+) methamphetamine results in the sudden "rush" of stimulation to the motivation, movement, pleasure, and reward centers in the brain, caused by rapid release of dopamine. In this review, we will provide an overview of the synthesis, pharmacology, adverse effects, and drug metabolism of this widely abused psychostimulant that distinguish it as a DARK classic in Chemical Neuroscience. PMID- 29602279 TI - Isolation and Sequencing of Salsolinol Synthase, an Enzyme Catalyzing Salsolinol Biosynthesis. AB - Salsolinol (1-methyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline), a derivate of dopamine, is suspected to be the most probable neurotoxin in the degeneration of dopaminergic neurons. Numerous hypotheses regarding its pathophysiological roles have been raised, especially related to Parkinson's disease and alcohol addiction. In the mammalian brain, salsolinol may be enzymatically synthesized by salsolinol synthase from dopamine and acetaldehyde. However, the direct evidence of its biosynthesis was still missing. In this study, we purified salsolinol synthase from rat brain by a systematical procedure involving acid precipitation, ultrafiltration, and hydrophilic interaction chromatography. The molecular weight of salsolinol synthase determined by MALDI-TOF MS is 8622.29 Da, comprising 77 amino acids (MQIFVKTLTG KTITLEVEPS DTIKNVKAKI QDKEGIPPDQ QRLIFAGKQL EDGRTLSDYN IQKKSTLHLV LRLRVDY). Homology analysis showed that the enzyme is a ubiquitin-like protein, with a difference of four amino acids, which suggests it is a novel protein. After it was overexpressed in eukaryotic cells, the production of salsolinol was significantly increased as compared with control, confirming the catalytic function of this enzyme. To our knowledge, it is the first systematic purification and sequencing of salsolinol synthase. Together, this work reveals a formerly anonymous protein and urges further exploration of its possible prognostic value and implications in Parkinson's disease and other related disorders. PMID- 29602280 TI - Air-Water Interfacial Properties of Chloroform-Spread versus Water-Spread Poly((d,l-lactic acid- co-glycolic acid)- block-ethylene glycol) (PLGA-PEG) Polymers. AB - Polymers at fluid interfaces are used for a number of applications that include coatings, electronics, separation, energy, cosmetics, and medicines. Here, we present a study on an amphiphilic block copolymer, poly((d,l-lactic acid- co glycolic acid)- block-ethylene glycol) (PLGA-PEG), at the air-water interface. PLGA-PEG at the air-water interface prepared by using an organic spreading solvent exhibits an extremely high surface pressure without the occurrence of desorption, making it an attractive candidate for a variety of uses in the areas mentioned above. The origin of this high surface pressure increase was shown to be due to the glass transition of the PLGA segments. The temperature at which this glass transition occurs for the PLGA segments of PLGA-PEG at the air-water interface was measured to be about 290 K by thermodynamic analysis based on the two-dimensional Maxwell relations. However, from an applications standpoint, spreading by an organic solvent greatly limits its scope of feasible uses. To explore the possibility of maintaining the excellent surface mechanical properties of the PLGA-PEG at the air-water interface while not using an organic solvent, we investigated the air-water interfacial properties of water-spread PLGA-PEG. When spread with water, it was shown that the initial micelles that form in the aqueous spreading solution remain intact even after being spread onto the air-water interface. Due to this different morphology, the surface pressure and monolayer stability were greatly reduced for the water-spread PLGA-PEG at the air-water interface. We used the Daoud and Cotton's blob scaling model to describe the desorption process of the water-spread PLGA-PEG at the air-water interface. From the scaling concept, it was shown that with higher PEG molecular weight and larger micelle size, the adsorption energy of the water-spread PLGA PEG to the air-water interface was increased. PMID- 29602282 TI - Comparison between thaw-mounting and use of conductive tape for sample preparation in ToF-SIMS imaging of lipids in Drosophila microRNA-14 model. AB - Time-of-flight secondary ion mass spectrometry (ToF-SIMS) imaging elucidates molecular distributions in tissue sections, providing useful information about the metabolic pathways linked to diseases. However, delocalization of the analytes and inadequate tissue adherence during sample preparation are among some of the unfortunate phenomena associated with this technique due to their role in the reduction of the quality, reliability, and spatial resolution of the ToF-SIMS images. For these reasons, ToF-SIMS imaging requires a more rigorous sample preparation method in order to preserve the natural state of the tissues. The traditional thaw-mounting method is particularly vulnerable to altered distributions of the analytes due to thermal effects, as well as to tissue shrinkage. In the present study, the authors made comparisons of different tissue mounting methods, including the thaw-mounting method. The authors used conductive tape as the tissue-mounting material on the substrate because it does not require heat from the finger for the tissue section to adhere to the substrate and can reduce charge accumulation during data acquisition. With the conductive-tape sampling method, they were able to acquire reproducible tissue sections and high quality images without redistribution of the molecules. Also, the authors were successful in preserving the natural states and chemical distributions of the different components of fat metabolites such as diacylglycerol and fatty acids by using the tape-supported sampling in microRNA-14 (miR-14) deleted Drosophila models. The method highlighted here shows an improvement in the accuracy of mass spectrometric imaging of tissue samples. PMID- 29602281 TI - Time of flight secondary ion mass spectrometry-A method to evaluate plasma modified three-dimensional scaffold chemistry. AB - Biopolymers are used extensively in the manufacture of porous scaffolds for a variety of biological applications. The surfaces of these scaffolds are often modified to encourage specific interactions such as surface modification of scaffolds to prevent fouling or to promote a cell supportive environment for tissue engineering implants. However, few techniques can effectively characterize the uniformity of surface modifications in a porous scaffold. By filling the scaffold pores through polymer embedding, followed by analysis with imaging time of-flight secondary ion mass spectrometry (ToF-SIMS), the distribution and composition of surface chemical species though complex porous scaffolds can be characterized. This method is demonstrated on poly(caprolactone) scaffolds modified with a low-fouling plasma-deposited coating from octafluoropropane via plasma enhanced chemical vapor deposition. A gradient distribution of CF+/CF3+ is observed for scaffolds plasma treated for 5 min, whereas a 20 min treatment results in more uniform distribution of the surface modification throughout the entire scaffold. The authors expect this approach to be widely applicable for ToF SIMS analysis of scaffolds modified by multiple plasma processing techniques as well as alternative surface modification approaches. PMID- 29602283 TI - Korean mistletoe lectin enhances natural killer cell cytotoxicity via upregulation of perforin expression. AB - BACKGROUND: Natural killer (NK) cells are crucial components of the innate immune system, providing the first line of defense against pathogens. In a previous study, we demonstrated prophylactic activity of water extract of Korean mistletoe (Viscum album coloratum) on tumor metastasis. However, the leading compound from water extract of Korean mistletoe was not clearly addressed. OBJECTIVE: The purpose of this research was mainly focused on addressing the effect of Korean mistletoe lectin (KMLC) on NK cell cytotoxicity, and the ability of cytokine secretion as well as its signal transduction, mitogen-activated protein kinase (MAPK) pathway. METHODS: KMLC was used to test NK cell-mediated cytotoxicity in vitro and in vivo. Non-isotope cytotoxicity assay (bis-N,N,N',N'-tetraacetic acid (BATDA) release assay) was performed to test the cytotoxicity of NK cells against target tumor cells. Receptor expression was checked by flow cytometry analysis and MAPK signal molecules were analyzed by immunoblotting. RESULTS AND CONCLUSIONS: KMLC at 200 ng/mL increased the cytotoxicity of NK92 cells by 35% compared with untreated cells. KMLC-treated (at 100 ng/mL) mice splenocytes showed a 20% increase in cytotoxic activity. Also, the B chain, one of the subchains of KMLC, increases perforin expression. We demonstrated that the signal transduction controlling NK cell cytotoxicity was mediated by upregulation of the NKG2D receptor and expression of a cytotoxic effector molecule. These results suggested that KMLC possessed immunological activity, mediated by NK cell activation. PMID- 29602284 TI - Common antibody dependent cell mediated cytotoxicity (ADCC) antibody epitopes of HIV-1 CRF01_AE Env and Gag in early HIV-1 infected individuals. AB - BACKGROUND: There have been a few studies aimed at identifying epitopes of ADCC inducing antibodies when compared to those of neutralizing antibodies and cytotoxic T lymphocytes against a variety of HIV-1 clades. OBJECTIVE: To map the common ADCC epitopes of HIV-1 CRF01_AE. METHODS: We screened 65 sera of confirmed early HIV-1 CRF01_AE infected individuals for ADCC antibody against gp120 utilizing an EGFP-CEM-NKr flow cytometric assay. Sera with high ADCC antibody were then examined against ADCC epitopes using the complete HIV-1 CRF01_AE gp160- and subtype A Gag-overlapping peptide sets which were divided into 7 pools:E1-E7 and 5 pools:G1-G5, respectively. Each positive peptide pool was further investigated for fine ADCC epitope mapping using matrix formats. RESULTS: Twenty, 25 and 20 sera demonstrated the high-, medium- and low-ADCC antibody activities against gp120, respectively. Interestingly, 11 Env- and 6 Gag-peptides of pools E3, E4, E7 and pools G1, G2, G4 with high ADCC responses were also responded by at least 20%, 12% and 5%, 10% of medium- and low-ADCC antibody sera, respectively. These eleven common Env ADCC epitopes were localized at C2-V3-C3-V4 regions of gp120 and cytoplasmic tail of gp41 while six common Gag ADCC epitopes were localized at p17-p24-p2 regions. CONCLUSIONS: Although the degree of ADCC antibody responses to the gp120 protein varied from high to low, there were certain consensus Env and Gag peptides that could induce the ADCC antibody responses of 21.54-58.46% and 23.08-41.54%, respectively of the early infected individuals. This epitope information should be useful as the new antibody-based vaccine immunogens. PMID- 29602285 TI - Prevalence of allergen sensitization among 15,534 patients with suspected allergic diseases in Henan Province, China. AB - BACKGROUND: The prevalence of allergen sensitization varies in different geographic areas and population subsets. This study investigated the prevalence and distribution of inhaled and food allergens among allergic patients in Henan Province, China. METHOD: The prevalence and distribution of 19 inhaled and food allergens among 15,534 patients with suspected allergic diseases were retrospectively analyzed in Henan Province, China between December 2012 and August 2016. Reactivity of their serum-specific immunoglobulin E (sIgE) to allergens was tested using the AllergyScreen test. RESULTS: Of the 15,534 patients tested, the sIgE of 6520 (41.97%) was tested positive for at least one of the 19 tested allergens. Dermatophagoides pteronyssinus (3540, 22.79%), cockroach (1398, 9.00%), and mold mix (1301, 8.38%) were the most frequently tested inhaled allergens, while cashew nut (1320, 8.50%), mango (768, 4.94%) and cow's milk (748, 4.82%) were the most frequently tested food allergens. The overall sIgE positive rate was higher in males than that in females (p < 0.05). Moreover, the sIgE positive rates to the most of the inhaled and food allergens were statistically different between age groups (p < 0.05). The sIgE positive rates of the main inhaled allergens increased with age. However, the sIgE positive rates for the primary food allergens were higher in the younger groups and lower in the older groups. CONCLUSIONS: The characteristics of allergen sensitization revealed in this study in Henan Province would facilitate the prevention, diagnosis, and management of allergic diseases in this region. PMID- 29602286 TI - Comparison of Th17 cells mediated immunological response among asthmatic children with or without allergic rhinitis. AB - OBJECTIVE: To investigate whether there were differences in Th17 cells mediated immunological responses among asthmatics with or without allergic rhinitis. METHODS: A case-control comparison was conducted in a cohort of 67 children with asthma (AS), 50 children with allergic rhinitis (AR), 52 children with both AS and AR (ASR), 25 infectious rhinitis (IR), and 55 healthy controls (HC). The percentages of circulating Th17 cells were determined by flow cytometry. The Th2- and Th17-related cytokines in plasma and culture supernatants were measured by enzyme-linked immunosorbent assay. The effect of proinflammation cytokine IL-17E on Th2 cytokines production from human T helper (Th) lymphocytes was analyzed. RESULTS: (1) A inter-group comparison revealed that Th17 cells levels were highest in ASR group [(0.89% +/- 0.27) %], following by AS group [(0.82 +/- 0.29) %] and AR group[(0.78 +/- 0.17) %] (P< 0.05). (2) After in-vitro stimulation with house dust mite (HDM) antigen, the levels of IL-4 and IL-17E in culture supernatants of PBMCs from allergic children (AS group, AR group and ASR group) were significantly enhanced. (3) The release of Th2 cytokines from IL-17E treated Th cells of allergic children (AS group, AR group and ASR group) were significantly induced, no similar result was observed in IR group and HC group. CONCLUSION: Our findings preliminarily revealed that Th17 cell and its related cytokines might be involved in pathogenesis of airway inflammation diseases, and also presenting varying immunological characteristics among asthmatic children with or without allergic rhinitis. PMID- 29602287 TI - Evaluation of signs, symptoms, and occlusal factors among patients with temporomandibular disorders according to Helkimo index. AB - Objective This study sought to assess the clinical signs and subjective symptoms of TMD, including the occlusal condition. Methods Recruited individuals included 123 patients (58 men, 65 women) aged 15 to 65 years (mean 38.6 years) who had been referred to the TMD department. Helkimo dysfunction, occlusal, and anamnestic indices were used to assess signs of TMD, occlusal condition, and symptoms, respectively. Relationships of occlusal factors with signs and symptoms of TMD were evaluated by Spearman's correlation test. Associations of TMD with sex and age distributions were assessed by Mann-Whitney and Spearman's test, respectively. Results The prevalence of signs and symptoms was as high as 75%. Occlusal factors had significant associations with signs and symptoms of TMD. Conclusion Prevalence of TMD in the study population was high, without preference for age or sex. Occlusal factors may play a role in the etiology of TMD. PMID- 29602288 TI - Preclinical, phase I, and phase II investigational clinical trials for treatment of progressive supranuclear palsy. AB - INTRODUCTION: Our understanding of the pathological basis of progressive supranuclear palsy (PSP), as the most common atypical parkinsonian syndrome, has greatly increased in recent years and a number of disease-modifying therapies are under evaluation as a result of these advances. Areas covered: In this review, we discuss disease-modifying therapeutic options which are currently under evaluation or have been evaluated in preclinical or clinical trials based on their targeted pathophysiologic process. The pathophysiologic mechanisms are broadly divided into three main categories: genetic mechanisms, abnormal post translational modifications of tau protein, and transcellular tau spread. Expert opinion: Once the best therapeutic approaches are identified, it is likely that some combination of interventions will need to be evaluated, but this will take time. It is critical to treat patients at early stages, and development of the Movement Disorder Society PSP diagnostic criteria is an important step in this direction. In addition, development of biological biomarkers such as tau PET and further refinement of tau ligands may help both diagnose early and measure disease progression. In the meantime, a comprehensive, personalized interdisciplinary approach to this disease is absolutely necessary. PMID- 29602289 TI - Effect of iloprost on contractile impairment and mitochondrial degeneration in ischemia-reperfusion of skeletal muscle. AB - Purpose Acute lower extremity ischemia is still a main cause of mortality and morbidity in orthopedic traumatology and reconstructive surgery. In acute lower extremity ischemia, the skeletal muscles are the tissues that are the most vulnerable to ischemia. The aim of this study was to evaluate the effects of iloprost (IL) therapy on skeletal muscle contractile impairment and mitochondrial degeneration in an acute lower extremity ischemia-reperfusion rat model. Main Methods Forty Wistar albino rats were randomly divided into a control group and four experimental groups. Experimental groups were either subjected to 2 h of lower extremity ischemia followed by a 4-h reperfusion period or to 4 h of ischemia followed by an 8-h reperfusion period. Except for the animals in the control group, all animals received IL (1 ng/kg/min) or saline (1 ml/kg) by intraperitoneal infusion for 10 min immediately before reperfusion. At the end of the recording of skeletal muscle electrical activity and contractility, all rats were sacrificed by decapitation and muscle samples of lower extremity were immediately harvested for histopathologic analyses. Results After ischemia reperfusion, a breakdown in the force-frequency curves of extensor digitorum longus muscle was observed, showing the diminished muscle contractility. However, IL significantly improved muscle contractility following injury induced by 2 h of ischemia followed by a 4-h reperfusion period. In addition, IL partially ameliorated mitochondrial degeneration in the muscle cells of ischemia groups. Conclusion This study indicates that immediate IL therapy repairs muscle damage especially after 2 h of ischemia and 4 h of reperfusion and therefore that IL improves contractile function. PMID- 29602290 TI - What we do and do not know about women and kidney diseases; Questions unanswered and answers unquestioned: Reflection on World Kidney Day and International Woman's Day. AB - Chronic kidney disease (CKD) affects approximately 10% of the world's adult population; it is within the top 20 causes of death worldwide, and its impact on patients and their families can be devastating. World Kidney Day and International Women's Day in 2018 coincide, thus offering an opportunity to reflect on the importance of women's health and specifically their kidney health, on the community, and the next generations, as well as to strive to be more curious about the unique aspects of kidney disease in women so that we may apply those learnings more broadly. Girls and women, who make up approximately 50% of the world's population, are important contributors to society and their families. Gender differences continue to exist around the world in access to education, medical care, and participation in clinical studies. Pregnancy is a unique state for women, which not only offers an opportunity for diagnosis of kidney disease, but also states where acute and chronic kidney diseases may manifest, and which may impact future generations with respect to kidney health. There are various autoimmune and other conditions that are more likely to impact women with profound consequences for childbearing, and on the fetus. Women have different complications on dialysis than men and are more likely to be donors than recipients of kidney transplants. In this editorial, we focus on what we do and do not know about women, kidney health, and kidney disease and what we might learn in the future to improve outcomes worldwide. PMID- 29602291 TI - Surface electromyographic evaluation of the neuromuscular activation of the inspiratory muscles during progressively increased inspiratory flow under inspiratory-resistive loading. AB - This study aimed to evaluate neuromuscular activation in the scalene and sternocleidomastoid muscles using surface electromyography (EMG) during progressively increased inspiratory flow, produced by increasing the respiratory rate under inspiratory-resistive loading using a mask ventilator. Moreover, we attempted to identify the EMG inflection point (EMGIP) on the graph, at which the root mean square (RMS) of the EMG signal values of the inspiratory muscles against the inspiratory flow velocity acceleration abruptly increases, similarly to the EMG anaerobic threshold (EMGAT) reported during incremental-resistive loading in other skeletal muscles. We measured neuromuscular activation of healthy male subjects and found that the inspiratory flow velocity increased by approximately 1.6-fold. We successfully observed an increase in RMS that corresponded to inspiratory flow acceleration with rho >= 0.7 (Spearman's rank correlation) in 17 of 27 subjects who completed the experimental protocol. To identify EMGIP, we analyzed the fitting to either a straight or non-straight line related to the increasing inspiratory flow and RMS using piecewise linear spline functions. As a result, EMGIP was identified in the scalene and sternocleidomastoid muscles of 17 subjects. We believe that the identification of EMGIP in this study infers the existence of EMGAT in inspiratory muscles. Application of surface EMG, followed by identification of EMGIP, for evaluating the neuromuscular activation of respiratory muscles may be allowed to estimate the signs of the respiratory failure, including labored respiration, objectively and non-invasively accompanied using accessory muscles in clinical respiratory care. PMID- 29602292 TI - Heat shock proteins and cardiovascular disease. AB - The development of stress drives a host of biological responses that include the overproduction of a family of proteins named heat shock proteins (HSPs), because they were initially studied after heat exposure. HSPs are evolutionarily preserved proteins with a high degree of interspecies homology. HSPs are intracellular proteins that also have extracellular expression. The primary role of HSPs is to protect cell function by preventing irreversible protein damage and facilitating molecular traffic through intracellular pathways. However, in addition to their chaperone role, HSPs are immunodominant molecules that stimulate natural as well as disease-related immune reactivity. The latter may be a consequence of molecular mimicry, generating cross-reactivity between human HSPs and the HSPs of infectious agents. Autoimmune reactivity driven by HSPs could also be the result of enhancement of the immune response to peptides generated during cellular injury and of their role in the delivery of peptides to the major histocompatibility complex in antigen-presenting cells. In humans, HSPs have been found to participate in the pathogenesis of a large number of diseases. This review is focused on the role of HSPs in atherosclerosis and essential hypertension. PMID- 29602293 TI - Swimming exercise demonstrates advantages over running exercise in reducing proteinuria and glomerulosclerosis in spontaneously hypertensive rats. AB - Experimental studies in animal models have described the benefits of physical exercise (PE) to kidney diseases associated with hypertension. Land- and water based exercises induce different responses in renal function. Our aim was to evaluate the renal alterations induced by different environments of PE in spontaneously hypertensive rats (SHRs). The SHRs were divided into sedentary (S), swimming exercise (SE), and running exercise (RE) groups, and were trained for 8 weeks under similar intensities (60 min/day). Arterial pressure (AP) and heart rate (HR) were recorded. The renal function was evaluated through urinary volume at each week of training; sodium and potassium excretions, plasma and urinary osmolarities, glomerular filtration rate (GFR), levels of proteinuria, and renal damage were determined. SE and RE rats presented reduced mean AP, systolic blood pressure, and HR in comparison with S group. SE and RE rats showed higher urine osmolarity compared with S. SE rats showed higher free water clearance (P < 0.01), lower urinary density (P < 0.0001), and increased weekly urine volume (P < 0.05) in comparison with RE and S groups. GFR was increased in both SE and RE rats. The proteinuria of SE (7.0 +/- 0.8 mg/24 h) rats was decreased at the 8th week of the PE in comparison with RE (9.6 +/- 0.8 mg/24 h) and S (9.8 +/- 0.5 mg/24 h) groups. The glomerulosclerosis was reduced in SE rats (P < 0.02). SE produced different response in renal function in comparison with RE, in which only swimming-trained rats had better profile for proteinuria and glomerulosclerosis. PMID- 29602294 TI - Melatonin ameliorates brain oxidative stress and upregulates senescence marker protein-30 and osteopontin in a rat model of vascular dementia. AB - The aim of this study was to investigate the effect of melatonin on oxidative stress and senescence marker protein-30 (SMP30) as well as osteopontin (OPN) expression in the hippocampus of rats subjected to vascular dementia (VD). A total of 72 male rats were divided into six groups (n = 12 each) as follows: (i) untreated control (CON), (ii) sham-operated group, (iii) sham-operated + melatonin, (iv) rats exposed to VD induced by permanent bilateral occlusion of the common carotid arteries (BCCAO) leading to chronic cerebral hypoperfusion, (v) rats exposed to VD + melatonin, and (vi) rats exposed to VD + donepezil (DON). At the end of experiment, the hippocampal levels of acetylcholine (ACh), norepinephrine (NE), and dopamine (Dop) were measured. Expression of OPN was determined using immunohistochemistry, and SMP30 expression was determined using real-time PCR in the hippocampus. Hippocampal thiobarbituric acid reactive substances (TBARS) and total antioxidant capacity (TAC) were evaluated. The BCCAO group showed significantly decreased TAC (p < 0.05) and significantly increased in TBARS levels compared with the CON group. In addition, BCCAO significantly decreased (p < 0.05) the expression of both OPN and SMP30 and the levels of ACh, NE, and Dop in the hippocampus compared with CON treatment. Treatment with melatonin significantly increased OPN and SMP30 expression and ACh, NE, and Dop levels in the hippocampus with amelioration of the oxidative stress compared with BCCAO rats. Melatonin might produce a neuroprotective effect through its antioxidant action and by increasing the expression of SMP30 and OPN that is not comparable with that of DON. PMID- 29602295 TI - Moderate hypothermia and responses to calcium channel blockers - Role of the nitric oxide. AB - Moderate hypothermia (25-31 degrees C) may have a significant influence on vascular tone. At present, very little is known about the role of endothelial nitric oxide on the hypothermia-induced responses. In this study, we investigated the effect of hypothermia (to 28 degrees C) on the vasodilatation induced by verapamil, a phenylalkylamine calcium channel blocker (10-9-3 * 10-4 M) and dihydropyridines, amlodipine (10-9-3 * 10-4 M), and benidipine (10-9-10-3 M) on 5 hydroxytryptamine (5-HT or serotonin) precontracted calf cardiac veins. Furthermore, the role of nitric oxide in the hypothermia-induced responses was analyzed. Ring preparations of veins obtained from calf hearts were suspended in organ baths containing 15 ml of Krebs-Henseleit solution, maintained at 37 degrees C, and continuously gassed with 95% O2-5% CO2. After a resting period, verapamil, amlodipine, and benidipine were applied cumulatively on serotonin (10 6 M) precontracted calf cardiac vein rings and induced concentration-dependent relaxations. In another part of the study, the medium temperature was decreased to 28 degrees C after the preparations were contracted with 5-HT, then cumulative concentrations of verapamil, amlodipine, or benidipine were added. During hypothermia, the pIC50 value, but not the maximal response, to all blockers were significantly higher than at 37 degrees C. Hypothermia in the presence of NG-nitro-l-arginine methyl ester (L-NAME, 10-4 M) decreased the pIC50 and Emax values to verapamil, amlodipine, and benidipine. Only one blocker was tested in each preparation. These results suggest that nitric oxide may play a role in the hypothermia-induced changes in vasodilation caused by verapamil, amlodipine, and benidipine in calf cardiac vein, but further research is needed to explain the complete mechanism. PMID- 29602296 TI - Transcriptomic analysis reveals inflammatory and metabolic pathways that are regulated by renal perfusion pressure in the outer medulla of Dahl-S rats. AB - Studies exploring the development of hypertension have traditionally been unable to distinguish which of the observed changes are underlying causes from those that are a consequence of elevated blood pressure. In this study, a custom designed servo-control system was utilized to precisely control renal perfusion pressure to the left kidney continuously during the development of hypertension in Dahl salt-sensitive rats. In this way, we maintained the left kidney at control blood pressure while the right kidney was exposed to hypertensive pressures. As each kidney was exposed to the same circulating factors, differences between them represent changes induced by pressure alone. RNA sequencing analysis identified 1,613 differently expressed genes affected by renal perfusion pressure. Three pathway analysis methods were applied, one a novel approach incorporating arterial pressure as an input variable allowing a more direct connection between the expression of genes and pressure. The statistical analysis proposed several novel pathways by which pressure affects renal physiology. We confirmed the effects of pressure on p-Jnk regulation, in which the hypertensive medullas show increased p-Jnk/Jnk ratios relative to the left (0.79 +/- 0.11 vs. 0.53 +/- 0.10, P < 0.01, n = 8). We also confirmed pathway predictions of mitochondrial function, in which the respiratory control ratio of hypertensive vs. control mitochondria are significantly reduced (7.9 +/- 1.2 vs. 10.4 +/- 1.8, P < 0.01, n = 6) and metabolomic profile, in which 14 metabolites differed significantly between hypertensive and control medullas ( P < 0.05, n = 5). These findings demonstrate that subtle differences in the transcriptome can be used to predict functional changes of the kidney as a consequence of pressure elevation. PMID- 29602297 TI - Similarity and variation in the insulin-like growth factor 2 - H19 locus in primates. AB - Insulin-like growth factor 2 (IGF2), a small, secreted protein, is critical for fetal and prenatal growth in humans and other mammals. The IGF2 gene and its mouse homolog comprise part of a conserved linkage group that is regulated by parental imprinting, with IGF2/ Igf2 being expressed from the paternal chromosome, and the adjacent H19 gene from the maternal chromosome. By using information extracted from public genomic and gene expression databases, I have now analyzed this locus in nine nonhuman primate species representing over 60 million years of evolutionary divergence from a common progenitor. Both IGF2 and H19 genes and the entire locus have been conserved among these primates. Each primate IGF2 gene except for gibbon and marmoset is composed of 10 exons and contains five potential promoters, each with distinctive 5'-untranslated exons. Similarly, except for marmoset and mouse lemur, H19 consists of six exons and has two promoters. DNA sequence conservation is high, not only in orthologous exons and promoters, but also in a putative imprinting control region located 5' to H19 and in multiple potential distal enhancer elements found 3' to H19. Collectively, these results support the hypothesis that common regulatory processes shaped the IGF2 - H19 locus before the onset of primate speciation more than 85 million years ago. This study also leads to the conclusion that inaccuracies in data presentation in genetic repositories could limit our ability to develop novel insights about roles of individual genes and multigene loci in mammalian physiology and disease. PMID- 29602298 TI - The perplexing pregnancy disorder preeclampsia: what next? AB - Preeclampsia occurs in 3-5% of pregnancies and is a leading cause of deaths of mothers and their infants worldwide. It was initially described over 100 yr ago as a pregnancy abnormality defined by new-onset hypertension and proteinuria. Progress in understanding the pathophysiology was impeded by attention to these diagnostic findings. Hypertension and proteinuria were actually serendipitously recognized components of a complex multisystemic syndrome and not especially pertinent to outcome. With the recognition of inflammatory activation with consequent endothelial dysfunction 30 yr ago redirection of research resulted in an explosive increase in understanding of the disorder. The immunological origins, the role of the placenta and its functional alterations due to endoplasmic reticulum and oxidative stress, identification of placental products linking placental dysfunction to maternal systemic pathophysiology, and the role of the maternal constitution have been elegantly demonstrated by clinical, fundamental, and epidemiological findings and clever animal experimentation. Nonetheless, this increase in knowledge has not translated into improved prediction and prevention of preeclampsia. In this presentation the likelihood is discussed that this is secondary to a much greater complexity than has been previously considered and the existence of subtypes of preeclampsia that may not share an identical pathophysiology. The necessity for collaboration with data, sample, and intellectual sharing is addressed. An approach to addressing the challenges posed to such collaboration exemplified by the Global Pregnancy Collaboration is presented. PMID- 29602299 TI - Identification of human skeletal muscle miRNA related to strength by high throughput sequencing. AB - The loss of muscle size, strength, and quality with aging is a major determinant of morbidity and mortality in the elderly. The regulatory pathways that impact the muscle phenotype include the translational regulation maintained by microRNAs (miRNA). Yet the miRNAs that are expressed in human skeletal muscle and relationship to muscle size, strength, and quality are unknown. Using next generation sequencing, we selected the 50 most abundantly expressed miRNAs and then analyzed them in vastus lateralis muscle, obtained by biopsy from middle aged males ( n = 48; 50.0 +/- 4.3 yr). Isokinetic strength testing and midthigh computed tomography was undertaken for muscle phenotype analysis. Muscle attenuation was measured by computerized tomography and is inversely proportional to myofiber lipid content. miR-486-5p accounted for 21% of total miR sequence reads, with miR-10b-5p, miR-133a-3p, and miR-22-3p accounting for a further 15, 12, and 10%, respectively. Isokinetic knee extension strength and muscle cross sectional area were positively correlated with miR-100-5p, miR-99b-5p, and miR 191-5p expression. Muscle attenuation was negatively correlated to let-7f-5p, miR 30d-5p, and miR-125b-5p expression. In silico analysis implicates miRNAs related to strength and muscle size in the regulation of mammalian target of rapamycin, while miRNAs related to muscle attenuation may have potential roles regulating the transforming growth factor-beta/SMAD3 pathway. PMID- 29602300 TI - Corrigendum. PMID- 29602301 TI - Sensitivity of corneal biomechanical and optical behavior to material parameters using design of experiments method. AB - The optical performance of the human cornea under intraocular pressure (IOP) is the result of complex material properties and their interactions. The measurement of the numerous material parameters that define this material behavior may be key in the refinement of patient-specific models. The goal of this study was to investigate the relative contribution of these parameters to the biomechanical and optical responses of human cornea predicted by a widely accepted anisotropic hyperelastic finite element model, with regional variations in the alignment of fibers. Design of experiments methods were used to quantify the relative importance of material properties including matrix stiffness, fiber stiffness, fiber nonlinearity and fiber dispersion under physiological IOP. Our sensitivity results showed that corneal apical displacement was influenced nearly evenly by matrix stiffness, fiber stiffness and nonlinearity. However, the variations in corneal optical aberrations (refractive power and spherical aberration) were primarily dependent on the value of the matrix stiffness. The optical aberrations predicted by variations in this material parameter were sufficiently large to predict clinically important changes in retinal image quality. Therefore, well characterized individual variations in matrix stiffness could be critical in cornea modeling in order to reliably predict optical behavior under different IOPs or after corneal surgery. PMID- 29602302 TI - Assessing Outcomes in People With Chronic Ankle Instability: The Ability of Functional Performance Tests to Measure Deficits in Physical Function and Perceived Instability. AB - Study Design Laboratory-based, cross-sectional study. Background Functional performance tests (FPTs) assess short bouts of unilateral hops for either distance or speed. More research is needed to identify specific FPTs that may be useful for measuring asymmetry outcomes related to functional performance and perceived instability deficits in individuals with chronic ankle instability (CAI). Objectives To identify FPTs that are sensitive to subjective and objective deficits associated with CAI. Methods Twenty-four subjects with unilateral CAI (10 male, 14 female; mean +/- SD age, 20.7 +/- 3.0 years) and 24 healthy, matched controls (10 male, 14 female; age, 20.1 +/- 2.6 years) completed 5 unilateral FPTs in random order. Mean FPT scores and functional symmetry percentages were calculated and compared between groups using 2 separate 1-way multivariate analyses of variance (MANOVAs). Perceived instability symmetry percentages were compared between groups using a Mann-Whitney U analysis. Results There were no differences in the mean FPT scores (P>.05) or functional symmetry percentages (P>.05) between groups for any of the 5 FPTs. However, participants with CAI perceived greater instability when using their involved limb during the side hop (P = .02), 6-meter crossover hop (P = .003), lateral hop (P = .007), and figure of-eight hop (P = .008). Conclusion There were no differences in mean functional scores between groups for all 5 FPTs, and each group performed symmetrically. Regardless, administering a visual analog scale following the completion of the side hop, 6-meter crossover hop, lateral hop, and figure-of-eight hop tests captures subjective reports of perceived instability in the involved limb that can be compared bilaterally throughout treatment. J Orthop Sports Phys Ther 2018;48(5):372-380. Epub 30 Mar 2018. doi:10.2519/jospt.2018.7514. PMID- 29602303 TI - Hop Distance Symmetry Does Not Indicate Normal Landing Biomechanics in Adolescent Athletes With Recent Anterior Cruciate Ligament Reconstruction. AB - Background Return-to-sport protocols after anterior cruciate ligament reconstruction (ACLR) often include assessment of hop distance symmetry. However, it is unclear whether movement deficits are present, regardless of hop symmetry. Objectives To assess biomechanics and symmetry of adolescent athletes following ACLR during a single-leg hop for distance. Methods Forty-six patients with ACLR (5-12 months post surgery; 27 female; mean +/- SD age, 15.6 +/- 1.7 years) were classified as asymmetric (operative-limb hop distance less than 90% that of nonoperative limb [n = 17]) or symmetric (n = 29) in this retrospective cohort. Lower extremity biomechanics were compared among operative and contralateral limbs and 24 symmetric controls (12 female; mean +/- SD age, 14.7 +/- 1.5 years) using analysis of variance. Results Compared to controls, asymmetric patients hopped a shorter distance on their operative limb (P<.001), while symmetric patients hopped an intermediate distance on both sides (P>=.12). During landing, the operative limb, regardless of hop distance, exhibited lower knee flexion moments compared to controls and the contralateral side (P<=.04), with lower knee energy absorption than the contralateral side (P<=.006). During takeoff, both symmetric and asymmetric patients had less hip extension and smaller ankle range of motion on the operative side compared with controls (P<=.05). Asymmetric patients also had lower hip range of motion on the operative, compared with the contralateral, side (P = .001). Conclusion Both symmetric and asymmetric patients offloaded the operative knee; symmetric patients achieved symmetry, in part, by hopping a shorter distance on the contralateral side. Therefore, hop distance symmetry may not be an adequate test of single-limb function and return-to-sport readiness. J Orthop Sports Phys Ther 2018;48(8):622-629. Epub 30 Mar 2018. doi:10.2519/jospt.2018.7817. PMID- 29602304 TI - Effectiveness of the McKenzie Method of Mechanical Diagnosis and Therapy for Treating Low Back Pain: Literature Review With Meta-analysis. AB - Study Design Literature review with meta-analysis. Background The McKenzie Method of Mechanical Diagnosis and Therapy (MDT), a classification-based system, was designed to classify patients into homogeneous subgroups to direct treatment. Objectives To examine the effectiveness of MDT for improving pain and disability in patients with either acute (less than 12 weeks in duration) or chronic (greater than 12 weeks in duration) low back pain (LBP). Methods Randomized controlled trials examining MDT in patients with LBP were identified from 6 databases. Independent investigators assessed the studies for exclusion, extracted data, and assessed risk of bias. The standardized mean difference (SMD) and 95% confidence interval were calculated to compare the effects of MDT to those of other interventions in patients with acute or chronic LBP. Results Of the 17 studies that met the inclusion criteria, 11 yielded valid data for analysis. In patients with acute LBP, there was no significant difference in pain resolution (P = .11) and disability (P = .61) between MDT and other interventions. In patients with chronic LBP, there was a significant difference in disability (SMD, -0.45), with results favoring MDT compared to exercise alone. There were no significant differences between MDT and manual therapy plus exercise (P>.05) for pain and disability outcomes. Conclusion There is moderate- to high-quality evidence that MDT is not superior to other rehabilitation interventions for reducing pain and disability in patients with acute LBP. In patients with chronic LBP, there is moderate- to high-quality evidence that MDT is superior to other rehabilitation interventions for reducing pain and disability; however, this depends on the type of intervention being compared to MDT. Level of Evidence Therapy, level 1a. J Orthop Sports Phys Ther 2018;48(6):476-490. Epub 30 Mar 2018. doi:10.2519/jospt.2018.7562. PMID- 29602305 TI - Rasch Analysis of the Activities-Specific Balance Confidence Scale in Older Adults Seeking Outpatient Rehabilitation Services. AB - Background The Activities-specific Balance Confidence (ABC) scale measures confidence in performing various ambulatory activities without falling or experiencing a sense of unsteadiness. Objectives This study (1) examined the ABC scale (0-100) using Rasch analysis, (2) assessed statistically reliable change, and (3) developed a functional staging to guide clinical interpretation of a patient's improvement. Methods The authors examined rating-scale structure, item difficulty hierarchy, item fit, person-item match, separation index, differential item functioning, test precision, and unidimensionality. Additionally, this cross sectional study of 5012 older patients seeking outpatient rehabilitation therapy in 123 clinics estimated the minimal detectable change and developed a functional staging. Results The item "walk outside on icy sidewalks" was the most difficult item, while the item "reach for a small can off a shelf at eye level" was the easiest item. Overall, average patient ability estimates of 56.2 +/- 20.3 were slightly higher than the average item difficulty estimates of 45.9 +/- 7.8. With a separation index equal to 3.65, the ABC scale items can differentiate individuals into 5.2 statistically distinct strata. Most ABC scale items were free of differential item functioning. For example, "walk outside on icy sidewalks" was easier for patients who were underweight. Results supported unidimensionality of the ABC scale, with the first factor explaining 77% of the total variance. The estimated minimal detectable change was 15 points. The authors provided an example of functional staging application. Conclusion Results supported sound psychometric properties and clinical usage of the ABC scale for older adults seeking outpatient rehabilitation therapy. J Orthop Sports Phys Ther 2018;48(7):574-583. Epub 30 Mar 2018. doi:10.2519/jospt.2018.8023. PMID- 29602306 TI - Coronary artery fistula with associated Takotsubo cardiomyopathy: a case report. AB - BACKGROUND: Coronary artery fistula, first described by Krause in 1865, is an abnormal communication between the coronary artery and one of the four chambers of the heart or one of the great vessels. The communications are often congenital but may also be acquired from trauma or invasive cardiovascular procedures. Half of the cases present with angina pectoris whereas the remaining half are incidentally detected on echocardiogram or angiogram performed for an unrelated reason. Takotsubo cardiomyopathy or stress-induced cardiomyopathy is characterized by transient left ventricular dysfunction with minimal elevation of cardiac biomarkers in the absence of underlying coronary artery disease. Almost 90% of reported patients are postmenopausal women with a history of recent emotional or physical stress. CASE PRESENTATION: We report an unusual case of a 64-year-old Hispanic woman presenting with typical symptoms suggestive of acute coronary syndrome after an extreme familial conflict. There was mild troponin elevation. Cardiac catheterization revealed microfistulas originating from the third portion of the left anterior descending artery draining to the left ventricular cavity. The ventriculogram demonstrated the apical ballooning. We postulate that high local concentration of catecholamine triggered by stress resulted in angina pectoris due to worsening coronary steal from the coronary fistula. Also, the stress-induced adrenergic stimulation unmasked the classical akinetic apex and apical ballooning characteristic of Takotsubo cardiomyopathy. CONCLUSIONS: This case report highlights the rare but important association between two uncommon conditions. To the best of our knowledge, only one similar case has been reported describing a patient with microfistulas to left ventricular cavity and concurrent Takotsubo cardiomyopathy. PMID- 29602307 TI - Nanoparticles engineered to bind cellular motors for efficient delivery. AB - BACKGROUND: Dynein is a cytoskeletal molecular motor protein that transports cellular cargoes along microtubules. Biomimetic synthetic peptides designed to bind dynein have been shown to acquire dynamic properties such as cell accumulation and active intra- and inter-cellular motion through cell-to-cell contacts and projections to distant cells. On the basis of these properties dynein-binding peptides could be used to functionalize nanoparticles for drug delivery applications. RESULTS: Here, we show that gold nanoparticles modified with dynein-binding delivery sequences become mobile, powered by molecular motor proteins. Modified nanoparticles showed dynamic properties, such as travelling the cytosol, crossing intracellular barriers and shuttling the nuclear membrane. Furthermore, nanoparticles were transported from one cell to another through cell to-cell contacts and quickly spread to distant cells through cell projections. CONCLUSIONS: The capacity of these motor-bound nanoparticles to spread to many cells and increasing cellular retention, thus avoiding losses and allowing lower dosage, could make them candidate carriers for drug delivery. PMID- 29602308 TI - Gold nanoparticles stabilize peptide-drug-conjugates for sustained targeted drug delivery to cancer cells. AB - BACKGROUND: Peptide-drug-conjugates (PDCs) are being developed as an effective strategy to specifically deliver cytotoxic drugs to cancer cells. However one of the challenges to their successful application is the relatively low stability of peptides in the blood, liver and kidneys. Since AuNPs seem to have a longer plasma half-life than PDCs, one approach to overcoming this problem would be to conjugate the PDCs to gold nanoparticles (AuNPs), as these have demonstrated favorable physico-chemical and safety properties for drug delivery systems. We set out to test whether PEG coated-AuNPs could provide a suitable platform for the non-covalent loading of pre-formed PDCs and whether this modification would affect the bioavailability of the PDCs and their cytotoxicity toward target cancer cells. METHODS: Peptides specifically internalized by A20 murine lymphoma cells were isolated from a phage library displaying 7mer linear peptides. Peptide specificity was validated by flow cytometry and confocal microscopy. PDCs were synthesized containing a selected peptide (P4) and either chlorambucil (Chlor), melphalan (Melph) or bendamustine (Bend). Gold nanoparticles were sequentially coated with citrate, PEG-6000 and then PDC (PDC-PEG-AuNP). The physico-chemical properties of the coated particles were analyzed by electrophoresis, TEM, UV-VIS and FTIR. Stability of free and PDC-coated AuNP was determined. RESULTS: Biopanning of the phage library resulted in discovery of several novel peptides that internalized into A20 cells. One of these (P4) was used to synthesize PDCs containing either Chlor, Melph or Bend. All three PDCs specifically killed A20 target cells, however they had short half-lives ranging from 10.6 to 15.4 min. When coated to PEG-AuNPs, the half-lives were extended to 21.0-22.3 h. The PDC PEG-AuNPs retained cytotoxicity towards the target cells. Moreover, whereas pre incubation for 24 h of free PDCs almost completely abolished their cytotoxic activity, the PDC-PEG-AuNPs were still active even after 72 h pre-incubation. CONCLUSIONS: Peptide-drug-conjugates hold potential for improving the target efficacy of chemotherapeutic drugs, however their short half-lives may limit their application. This hurdle can be overcome by easily conjugating them to gold nanoparticles. This conjugation also opens up the possibility of developing slow release formulations of targeted drug delivery systems containing PDCs. PMID- 29602310 TI - Correction to: Esophagus perforation and myocardial penetration caused by swallowing of a foreign body leading to a misdiagnosis of acute coronary syndrome: a case report. AB - In the publication of this article [1], the Acknowledgements section was missing. PMID- 29602309 TI - Regenerative abilities of mesenchymal stem cells through mitochondrial transfer. AB - The past decade has witnessed an upsurge in studies demonstrating mitochondrial transfer as one of the emerging mechanisms through which mesenchymal stem cells (MSCs) can regenerate and repair damaged cells or tissues. It has been found to play a critical role in healing several diseases related to brain injury, cardiac myopathies, muscle sepsis, lung disorders and acute respiratory disorders. Several studies have shown that various mechanisms are involved in mitochondrial transfer that includes tunnel tube formation, micro vesicle formation, gap junctions, cell fusion and others modes of transfer. Few studies have investigated the mechanisms that contribute to mitochondrial transfer, primarily comprising of signaling pathways involved in tunnel tube formation that facilitates tunnel tube formation for movement of mitochondria from one cell to another. Various stress signals such as release of damaged mitochondria, mtDNA and mitochondrial products along with elevated reactive oxygen species levels trigger the transfer of mitochondria from MSCs to recipient cells. However, extensive cell signaling pathways that lead to mitochondrial transfer from healthy cells are still under investigation and the changes that contribute to restoration of mitochondrial bioenergetics in recipient cells remain largely elusive. In this review, we have discussed the phenomenon of mitochondrial transfer from MSCs to neighboring stressed cells, and how this aids in cellular repair and regeneration of different organs such as lung, heart, eye, brain and kidney. The potential scope of mitochondrial transfer in providing novel therapeutic strategies for treatment of various pathophysiological conditions has also been discussed. PMID- 29602311 TI - Cardiomyocyte-targeted and 17beta-estradiol-loaded acoustic nanoprobes as a theranostic platform for cardiac hypertrophy. AB - BACKGROUND: Theranostic perfluorocarbon nanoprobes have recently attracted attention due to their fascinating versatility in integrating diagnostics and therapeutics into a single system. Furthermore, although 17beta-estradiol (E2) is a potential anti-hypertrophic drug, it has severe non-specific adverse effects in various organs. Therefore, we have developed cardiomyocyte-targeted theranostic nanoprobes to achieve concurrent targeted imaging and treatment of cardiac hypertrophy. RESULTS: We had successfully synthesized E2-loaded, primary cardiomyocyte (PCM) specific peptide-conjugated nanoprobes with perfluorocarbon (PFP) as a core (PCM-E2/PFPs) and demonstrated their stability and homogeneity. In vitro and in vivo studies confirmed that when exposed to low-intensity focused ultrasound (LIFU), these versatile PCM-E2/PFPs can be used as an amplifiable imaging contrast agent. Furthermore, the significantly accelerated release of E2 enhanced the therapeutic efficacy of the drug and prevented systemic side effects. PCM-E2/PFPs + LIFU treatment also significantly increased cardiac targeting and circulation time. Further therapeutic evaluations showed that PCM E2/PFPs + LIFU suppressed cardiac hypertrophy to a greater extent compared to other treatments, revealing high efficiency in cardiac-targeted delivery and effective cardioprotection. CONCLUSION: Our novel theranostic nanoplatform could serve as a potential theranostic vector for cardiac diseases. PMID- 29602312 TI - Clinical Natural Language Processing in languages other than English: opportunities and challenges. AB - BACKGROUND: Natural language processing applied to clinical text or aimed at a clinical outcome has been thriving in recent years. This paper offers the first broad overview of clinical Natural Language Processing (NLP) for languages other than English. Recent studies are summarized to offer insights and outline opportunities in this area. MAIN BODY: We envision three groups of intended readers: (1) NLP researchers leveraging experience gained in other languages, (2) NLP researchers faced with establishing clinical text processing in a language other than English, and (3) clinical informatics researchers and practitioners looking for resources in their languages in order to apply NLP techniques and tools to clinical practice and/or investigation. We review work in clinical NLP in languages other than English. We classify these studies into three groups: (i) studies describing the development of new NLP systems or components de novo, (ii) studies describing the adaptation of NLP architectures developed for English to another language, and (iii) studies focusing on a particular clinical application. CONCLUSION: We show the advantages and drawbacks of each method, and highlight the appropriate application context. Finally, we identify major challenges and opportunities that will affect the impact of NLP on clinical practice and public health studies in a context that encompasses English as well as other languages. PMID- 29602313 TI - Lasiopodomys fuscus as an important intermediate host for Echinococcus multilocularis: isolation and phylogenetic identification of the parasite. AB - BACKGROUND: Echinococcus multilocularis causes alveolar echinococcosis (AE) and is widely prevalent in Qinghai Province, China, where a number of different species have been identified as hosts. However, limited information is available on the Qinghai vole (Lasiopodomys fuscus), which is hyper endemic to Qinghai Province and may represent a potential intermediate host of E. multilocularis. Thus, L. fuscus could contribute to the endemicity of AE in the area. METHODS: Fifty Qinghai voles were captured from Jigzhi County in Qinghai Province for the clinical identification of E. multilocularis infection via anatomical examination. Hydatid fluid was collected from vesicles of the livers in suspected voles and subjected to a microscopic examination and PCR assay based on the barcoding gene of cox 1. PCR-amplified segments were sequenced for a phylogenetic analysis. E. multilocularis-infected Qinghai voles were morphologically identified and subjected to a phylogenetic analysis to confirm their identities. RESULTS: Seventeen of the 50 Qinghai voles had E. multilocularis-infection-like vesicles in their livers. Eleven out of the 17 Qinghai voles presented E. multilocularis infection, which was detected by PCR and sequencing. The phylogenetic analysis showed that all 11 positive samples belonged to the E. multilocularis Asian genotype. A morphological identification and phylogenetic analysis of the E. multilocularis-infected Qinghai voles confirmed that all captured animals were L. fuscus. CONCLUSIONS: L. fuscus can be infected with E. multilocularis and plays a potential role in the life cycle and epidemiology of E. multilocularis in the Qinghai-Tibetan Plateau of China. PMID- 29602314 TI - Use of cilomilast-loaded phosphatiosomes to suppress neutrophilic inflammation for attenuating acute lung injury: the effect of nanovesicular surface charge. AB - BACKGROUND: Cilomilast is a phosphodiesterase 4 (PDE4) inhibitor for treating inflammatory lung diseases. This agent has a narrow therapeutic index with significant adverse effects on the nervous system. This study was conducted to entrap cilomilast into PEGylated phosphatidylcholine-rich niosomes (phosphatiosomes) to improve pulmonary delivery via the strong affinity to pulmonary surfactant film. Neutrophils were used as a cell model to test the anti inflammatory activity of phosphatiosomes. In an in vivo approach, mice were given lipopolysaccharide to produce acute lung injury. The surface charge in phosphatiosomes that influenced the anti-inflammatory potency is discussed in this study. RESULTS: The average diameter of the phosphatiosomes was about 100 nm. The zeta potential of anionic and cationic nanovesicles was - 35 and 32 mV, respectively. Cilomilast in both its free and nanocapsulated forms inhibited superoxide anion production but not elastase release in activated neutrophils. Cationic phosphatiosomes mitigated calcium mobilization far more effectively than the free drug. In vivo biodistribution evaluated by organ imaging demonstrated a 2-fold ameliorated lung uptake after dye encapsulation into the phosphatiosomes. The lung/brain distribution ratio increased from 3 to 11 after nanocarrier loading. The intravenous nanocarriers deactivated the neutrophils in ALI, resulting in the elimination of hemorrhage and alveolar wall damage. Only cationic phosphatiosomes could significantly suppress IL-1beta and TNF-alpha in the inflamed lung tissue. CONCLUSIONS: These results suggest that phosphatiosomes should further be investigated as a potential nanocarrier for the treatment of pulmonary inflammation. PMID- 29602315 TI - Percentage of Deaths Associated With Inadequate Physical Activity in the United States. AB - INTRODUCTION: Current physical activity guidelines recommend that adults participate weekly in at least 150 minutes of moderate-intensity equivalent aerobic physical activity to achieve substantial health benefits. We used a nationally representative sample of data of US adults to estimate the percentage of deaths attributable to levels of physical activity that were inadequate to meet the aerobic guideline. METHODS: Data from the 1990 to 1991 National Health Interview Survey for adults aged 25 years or older were linked with mortality data up until December 31, 2011, from the National Death Index (N = 67,762 persons and 18,796 deaths). Results from fully adjusted Cox proportional hazards models were used to estimate hazard ratios and population attributable fractions for inadequate levels of physical activity (ie, less than 150 minutes per week of moderate-intensity equivalent aerobic activity). RESULTS: Overall, 8.3% (95% confidence interval [CI], 6.4-10.2) of deaths were attributed to inadequate levels of physical activity. The percentage of deaths attributed to inadequate levels was not significant for adults aged 25 to 39 years (-0.2%; 95% CI, -8.8% to 7.7%) but was significant for adults aged 40 to 69 years (9.9%; 95% CI, 7.2% 12.6%) and adults aged 70 years or older (7.8%; 95% CI, 4.9%-10.7%). CONCLUSIONS: A significant portion of deaths was attributed to inadequate levels of physical activity. Increasing adults' physical activity levels to meet current guidelines is likely one way to reduce the risk of premature death in the United States. PMID- 29602316 TI - Effect of Cytochrome P450 (CYP) 2D6 Genetic Polymorphism on the Inhibitory Action of Antidepressants on CYP2D6-Mediated Dopamine Formation from p-Tyramine. AB - PURPOSE: The inhibitory effects of antidepressants, such as imipramine, desipramine, and fluvoxamine, on dopamine formation from p-tyramine catalyzed by cytochrome P450 (CYP) 2D6.2 (Arg296Cys, Ser486Thr) and CYP2D6.10 (Pro34Ser, Ser486Thr), were compared with those on dopamine formation catalyzed by CYP2D6.1 (wild type), to investigate the effect of a CYP2D6 polymorphism on neuroactive amine metabolism in the brain. METHODS: Inhibition constants (Ki) of the antidepressants toward dopamine formation catalyzed by CYP2D6.1, CYP2D6.2, and CYP2D6.10, which were expressed in recombinant Escherichia coli, were compared. RESULTS: Imipramine and desipramine competitively or non-competitively inhibited dopamine formation mediated by CYP2D6.1, CYP2D6.2, and CYP2D6.10 with Ki values of 3.9-4.9, 5.9-9.6, and 26.7-37.5 uM, respectively. The maximal velocity (Vmax) values for dopamine formation by all CYP2D6 variants gradually increased with increasing fluvoxamine concentrations up to 40-100 uM, indicating that fluvoxamine stimulated dopamine formation. CONCLUSIONS: These results suggest that the inhibition/stimulation of CYP2D6-mediated dopamine formation by these antidepressants would be affected by CYP2D6 polymorphism in the brain. This article is open to POST-PUBLICATION REVIEW. Registered readers (see "For Readers") may comment by clicking on ABSTRACT on the issue's contents page. PMID- 29602317 TI - Blastocystis sp., an emerging parasite with controversial pathogenicity. Should all human cases be treated? PMID- 29602318 TI - Predicting the course of persistent physical symptoms: Development and internal validation of prediction models for symptom severity and functional status during 2 years of follow-up. AB - OBJECTIVE: Increased knowledge about predictors of the course of persistent physical symptoms (PPS) is needed to identify patients at risk for long-term PPS in clinical settings. Therefore, we developed prediction models for the course of PPS in terms of symptom-severity and related functional status during a 2-year follow-up period. METHODS: We used data of the PROSPECTS cohort study, consisting of 325 PPS patients from several health care settings. Symptom severity (PHQ-15), physical functioning (RAND 36 PCS) and mental functioning (RAND 36 MCS) were assessed at baseline and 6, 12 and 24 months afterwards. We applied mixed model analyses to develop prediction models for all outcomes, using all follow-up measurements. Potential predictors were based on empirical and theoretical literature and measured at baseline. RESULTS: For symptom severity, physical functioning and mental functioning we identified predictors for the adverse course of PPS included physical comorbidity, higher severity and longer duration of PPS at baseline, anxiety, catastrophizing cognitions, embarrassment and fear avoidance cognitions, avoidance or resting behaviour and neuroticism. Predictors of a favourable course included limited alcohol use, higher education, higher levels of physical and mental functioning at baseline, symptom focusing, damage cognitions and extraversion. Explained interpersonal variance for all three models varied between 70.5 and 76.0%. Performance of the models was comparable in primary and secondary/tertiary care. CONCLUSION: The presented prediction models identified several relevant demographic, medical, psychological and behavioural predictors for adverse and favourable courses of PPS. External validation of the presented models is needed prior to clinical implementation. PMID- 29602319 TI - A step towards a new delimitation of functional somatic syndromes: A latent class analysis of symptoms in a population-based cohort study. AB - OBJECTIVES: The current delimitation of functional somatic syndromes (FSS) is inconsistent. We aimed to investigate somatic symptom profiles in the general adult population to contribute to a new, data-driven delimitation of FSS. METHODS: Information on 31 self-reported somatic symptoms used in the delimitation of various FSS and bodily distress syndrome (BDS) was obtained from the DanFunD study-a population-based cohort study on 9656 adults (participation 33.6%) from Greater Copenhagen, Denmark. Latent class analysis was used to identify symptom profiles. The profiles were described by their relation with sex, age, chronic disease, self-perceived health, symptom impact, self-reported FSS, and BDS case-status. RESULTS: Eight symptom profiles were identified. The largest profile had no symptoms (49% of the population). Three profiles were characterized by a few, specific symptoms: muscle and joint pain (17%), gastrointestinal symptoms (6%), and general symptoms (13%). Three profiles had multiple symptoms in specific combinations: musculoskeletal and general symptoms (7%); fatigue, musculoskeletal and gastrointestinal symptoms (3%); and cardiopulmonary, gastrointestinal and general symptoms (3%). Lastly, one profile (2%) had high probability of all symptoms. The last four profiles (15%) were strongly associated with BDS case-status, poor self-perceived health and high impact of symptoms. Analyses excluding persons with multi-symptomatic chronic disease showed similar results. CONCLUSIONS: We identified eight symptom profiles characterized by specific combinations of symptoms. Four of these had multiple symptoms from several bodily systems showing large overlap with BDS, possibly indicating subtypes of FSS. The profiles contribute to a new delimitation of FSS by illustrating the importance of specific symptom combinations. PMID- 29602320 TI - Pre-treatment anxiety is associated with persistent chemotherapy-induced peripheral neuropathy in women treated with neoadjuvant chemotherapy for breast cancer. AB - OBJECTIVE: Chemotherapy-induced peripheral neuropathy (CIPN) is a frequent adverse reaction caused by chemotherapeutic agents, especially the taxanes. CIPN can persist from months to years after completion of chemotherapy, decreasing quality of life for cancer survivors. The aim of this study was to explore the incidence and risk factors of persistent CIPN among women with breast cancer receiving neoadjuvant chemotherapy. METHODS: In this prospective study, we recruited women with breast cancer receiving neoadjuvant chemotherapy, including four cycles of docetaxel. Participants reported neuropathic symptoms of tingling/numbness at baseline, at the end of chemotherapy treatment, and at 8 months after completion of chemotherapy. Candidate factors associated with CIPN were assessed before chemotherapy. RESULTS: Among 111 participants, 50 (45.0%) experienced CIPN during chemotherapy, and 21 (18.9%) reported persistent CIPN after chemotherapy. Univariate logistic regression analysis revealed that development of CIPN was significantly associated with pre-treatment numbness (odds ratio [OR], 4.02; 95% confidence interval [CI], 1.09-7.40; p = .033), and persistent CIPN was significantly associated with pre-treatment numbness (OR, 3.60; 95% CI, 1.12-11.61; p = .032) and pre-treatment anxiety (OR, 5.02; 95% CI, 1.84-13.70; p = .002). Multivariate analysis indicated that pre-treatment anxiety remained significantly associated with persistent CIPN (OR, 4.01; 95% CI, 1.25 12.87; p = .020). CONCLUSION: Our results suggested that pre-treatment anxiety might be related to a patient's risk for persistent CIPN in women with breast cancer undergoing neoadjuvant chemotherapy. Further research is required to investigate if interventions targeting pre-treatment anxiety could provide prevention and management for persistent CIPN. PMID- 29602321 TI - Towards a Swedish identity in consultation-liaison (CL) psychiatry and psychosomatics - Re-foundation of the Swedish Association of CL Psychiatry. PMID- 29602322 TI - A systematic review of the quality of randomized controlled trials of psychological treatments for emotional distress in breast cancer. AB - OBJECTIVE: Meta-analyses of trials of psychological treatments for emotional distress in breast cancer (BCa) conclude that efficacious treatments exist. Subsequently, their implementation in routine care is widely promoted by health policy. However, the methodological quality of these trials has not been systematically evaluated. The present review investigates this issue. METHOD: A systematic search identified randomized controlled trials of psychological treatments for emotional distress in BCa. The Psychotherapy Outcome Study Methodology Rating Form was used to assess the quality of trials. Generic design elements, including representativeness of sample, control of concomitant treatments, reporting clinical significance outcomes, and design elements specific to psychotherapy trials, including manualisation, therapist training, and therapist adherence and competence were evaluated. RESULTS: 91 trials were eligible. Overall, methodological quality was low. Generic design elements were limited in most trials: 15% specified as an inclusion criterion that participants were distressed; 10% controlled for concomitant treatments; and 11% reported the clinical significance of findings. Design elements specific to psychotherapy trials were also implemented poorly: 51% used treatment manuals; 8% used certified trained therapists; and monitoring of adherence and competence occurred in 15% and 4%, respectively. CONCLUSION: The methodological quality of psychological treatment trials for emotional distress in BCa is improving. However, if relevant health policies are to be adequately empirically informed, trials of greater methodological rigour are essential. Trials should include participants with clinical levels of distress, control for concomitant treatments and report the clinical significance of findings. Trialists must also consider the specific requirements of psychotherapy trials. PMID- 29602323 TI - The factor structure of the Medical Outcomes Study-Social Support Survey: A comparison of different models in a sample of recently diagnosed cancer patients. AB - OBJECTIVE: To analyse the factor structure and psychometric properties of the original and abbreviated versions of the Medical Outcomes Study-Social Support Survey (MOS-SSS) in recently-diagnosed cancer patients. METHOD: A sample of 128 newly-diagnosed cancer patients were assessed with the Spanish versions of the MOS-SSS and the Hospital Anxiety and Depression Scale (HADS). Confirmatory factor analyses were conducted to analyse six different factor structures. Internal consistency and convergent validity indexes were calculated. The models tested included all of the following: 1) the original five-factor model (comprised of the following dimensions: emotional, informational, and tangible support, positive social interaction, and affection); 2) a four-factor empirical solution; 3 & 4) two different three-factor structures obtained in studies conducted in cancer patients; and 5 & 6) a two-factor solution for the abbreviated 8-item form and a one-factor solution for the 6-item form. RESULTS: The original five-factor structure showed a better fit index than the three and four factor models. Both the 6- and 8-item versions showed excellent goodness-of-fit, with adequate internal consistency and convergent validity indexes. CONCLUSION: The MOS-SSS is a powerful, highly flexible instrument to assess social support in cancer patients. The full 19-item scale allows for a comprehensive assessment of the essential dimensions of social support, while the abbreviated versions permit a quick assessment that minimizes the burden on patients. PMID- 29602324 TI - The relationship between attachment orientations and the course of depression in coronary artery disease patients: A secondary analysis of the SPIRR-CAD trial. AB - OBJECTIVE: The relationship between attachment orientations and the recovery from depressive symptoms in patients diagnosed with coronary artery disease (CAD) with and without a psychotherapeutic intervention was examined in this study. METHODS: In a multicenter trial of 570 depressed CAD patients (SPIRR-CAD), assigned to usual care plus either a stepwise psychotherapy intervention or one information session, 522 patients provided attachment data at baseline. Attachment was measured with the Relationship Scales Questionnaire (RSQ), yielding four attachment orientations. The primary outcome was change in Hospital Anxiety and Depression Scale depression (HADS-D) scores from baseline to follow-up at 18 months. Secondary outcomes were HADS-D scores at 1, 6, 12, and 24 months. RESULTS: Independent of treatment assignment, attachment was related to change in depression at 18 months (p < 0.01) with secure attachment resulting in a significant reduction (-2.72, SE = 0.27) in depression compared to dismissive avoidant (-1.51, SE = 0.35, p = 0.040) and fearful-avoidant (-0.65, SE = 0.61, p = 0.012) attachment. Patients with anxious-preoccupied attachment showed changes similar to secure attachment (-2.01, SE = 0.47). An explorative subgroup analysis across all assessment time points revealed patients with a dismissive-avoidant attachment benefitted from psychotherapy (average mean difference = 0.93, SE = 0.47, p = 0.048). CONCLUSION: Attachment played an important role for improvement in depressive symptoms. Only dismissive-avoidant patients seemed to benefit from the intervention. The lack of improvement in fearful-avoidant patients shows a need for specific interventions for this group. TRIAL REGISTRATION: www.clinicaltrials.govNCT00705965; www.isrctn.com ISRCTN76240576. PMID- 29602325 TI - A register-based case-control study of health care utilization and costs in binge eating disorder. AB - OBJECTIVE: Capturing trends in healthcare utilization may help to improve efficiencies in the detection and diagnosis of illness, to plan service delivery, and to forecast future health expenditures. For binge-eating disorder (BED), issues include lengthy delays in detection and diagnosis, missed opportunities for recognition and treatment, and morbidity. The study objective was to compare healthcare utilization and expenditure in people with and without BED. METHODS: A case-control design and nationwide registers were used. All individuals diagnosed with BED at eating disorder clinics in Sweden between 2005 and 2009 were included (N = 319, 97% female, M age = 22 years). Ten controls (N = 3190) were matched to each case on age-, sex-, and location of birth. Inpatient, hospital-based outpatient, and prescription medication utilization and expenditure were analyzed up to eight years before and four years after the index date (i.e., date of diagnosis of the BED case). RESULTS: Cases had significantly higher inpatient, hospital-based outpatient, and prescription medication utilization and expenditure compared with controls many years prior to and after diagnosis of BED. Utilization and expenditure for controls was relatively stable over time, but for cases followed an inverted U-shape and peaked at the index year. Care for somatic conditions normalized after the index year, but care for psychiatric conditions remained significantly higher. CONCLUSION: Individuals with BED had substantially higher healthcare utilization and costs in the years prior to and after diagnosis of BED. Since previous research shows a delay in diagnosis, findings indicate clear opportunities for earlier detection and clinical management. Training of providers in detection, diagnosis, and management may help curtail morbidity. A reduction in healthcare utilization was observed after BED diagnosis. This suggests that earlier diagnosis and treatment could improve long-term health outcomes and reduce the economic burden associated with BED. PMID- 29602326 TI - Type D personality and coronary atherosclerotic plaque vulnerability: The potential mediating effect of health behavior. AB - OBJECTIVE: The association between type D personality and coronary plaque vulnerability has been suggested. The objective of the study was to evaluate the potential mediating effects of health behavior on the association between type D personality and plaque vulnerability in coronary artery disease (CAD) patients. METHODS: A total of 319 CAD patients were assessed for type D personality and health behavior via self-administered questionnaires. The plaque vulnerability, evaluated according to characteristics, accompaniment, and outcomes of plaque, was assessed by optical coherence tomography. RESULTS: Regression analysis showed that type D personality was independently associated with lipid plaque (odds ratio [OR] = 2.387, p = 0.001), thin cap fibroatheroma (TCFA) (OR = 2.366, p = 0.001), rupture (OR = 2.153, p = 0.002), and lipid arc (beta = -0.291, p < 0.001). Mediation analyses showed that aspects of health behavior were significant mediators of the relationship between type D personality and plaque vulnerability. Psychological stress mediated the relationship between type D and lipid plaque (p = 0.030), TCFA (p = 0.034), and rupture (p = 0.013). Living habits significantly mediated the relationship between type D and lipid plaque (p = 0.028), TCFA (p = 0.036), but not rupture (p = 0.066). Participating in activities was not a significant mediator of the relationship between type D personality and lipid plaque (p = 0.115), TCFA (p = 0.115), or rupture (p = 0.077). CONCLUSIONS: Health behaviors (psychological stress and living habits) may be mediators of the association between type D personality and plaque vulnerability. PMID- 29602327 TI - Transdiagnostic internet-delivered cognitive-behaviour therapy (CBT) for adults with functional gastrointestinal disorders (FGID): A feasibility open trial. AB - Many people with functional gastrointestinal disorders (FGIDs) face significant barriers in accessing psychological treatments that are known to reduce symptoms and their psychological sequelae. This study examined the feasibility and initial outcomes of a transdiagnostic and internet-delivered cognitive behaviour therapy (iCBT) intervention, the Chronic Conditions Course, for adults with functional gastrointestinal disorders (FGIDs). A single-group feasibility open trial design was employed and administered to twenty seven participants. The course ran for 8 weeks and was provided with weekly contact from a Clinical Psychologist. Seventy percent of participants completed the course within the 8 weeks and 81.5% provided data at post-treatment. High levels of satisfaction were observed and relatively little clinician time (M = 42.70 min per participant; SD = 46.25 min) was required. Evidence of clinical improvements in FGID symptoms (ds >= 0.46; avg. improvement >=21%), anxiety symptoms (ds >= 0.99; avg. improvement >=42%), and depression symptoms (ds >= 0.75; avg. improvement >=35%) were observed, which either maintained or continued to improve to 3-month follow-up. Evidence of improvement was also observed in pain catastrophising and mental-health related quality of life, but not physical-health related quality of life. These findings highlight the potential value of transdiagnostic internet-delivered programs for adults with FGIDs and support for the conduct of larger-scale controlled studies. PMID- 29602328 TI - The joint influence of emotional reactivity and social interaction quality on cardiovascular responses to daily social interactions in working adults. AB - OBJECTIVE: Social interaction quality is related to cardiovascular functioning. Trait emotional reactivity may amplify cardiovascular responses to social interactions, but is often examined as a tendency to react to negative events. We took a broader approach by examining the joint effects of positive and negative emotional reactivity and social interaction quality on ambulatory blood pressure (ABP) and heart rate (HR) responses to daily social interactions. METHODS: Participants were part of a larger study on BP and cardiovascular health (N = 805; MAge = 45.3; 40.1% male). Participants completed a measure of emotional reactivity (BIS/BAS) and 24-hour ABP monitoring accompanied by ecological momentary assessments (EMA) about just-experienced social interactions and their pleasantness. Multilevel models tested the associations of emotional reactivity, average pleasantness, and momentary pleasantness with BP and HR. RESULTS: Participants who reported more pleasant interactions on average had lower BP (systolic BP: B = -0.51 mmHg; diastolic BP: B = -0.46 mmHg). These effects did not depend on emotional reactivity. The effect of momentary pleasantness depended on BIS/BAS; in less reactive participants, greater pleasantness was associated with lower HR, B = -0.13 bpm; in more reactive participants, greater pleasantness was associated with increased HR, B = 0.16). CONCLUSIONS: Participants who had more pleasant social interactions throughout the day had lower mean ABP. The acute effect of a given social interaction on HR depended on emotional reactivity: HR increased for participants high in emotional reactivity during pleasant interactions. Thus, emotional reactivity may influence cardiovascular responses to social stimuli. PMID- 29602329 TI - Psychological abuse, substance abuse distress, dissatisfaction with friendships, and incident psychiatric problems. AB - OBJECTIVE: The aim of this study was to assess the mediating role of dissatisfaction with friendships in adulthood in the associations between psychological abuse in childhood, substance abuse distress in childhood, and incident psychiatric problems (IPPs) in adulthood over 13 years of follow-up. METHODS: We used data collected from 1994 to 2008 within the framework of the Tromso Study (N = 9502), a representative, longitudinal, prospective cohort study. Poisson regression analysis was used to assess the associations between psychological abuse, substance abuse distress, dissatisfaction with friendships in adulthood, and IPPs in adulthood. Indirect effects and proportion mediated (%) were assessed with the difference-in-coefficients method. RESULTS: Psychological abuse (relative risk [RR] = 1.66, 95% confidence interval [CI]: 1.45-1.89) and substance abuse distress in childhood (RR = 1.38, 95% CI: 1.18-1.62) were associated with an increased risk of dissatisfaction with friendships in adulthood. Dissatisfaction with friendships in adulthood was associated with an increased risk of IPPs in adulthood (RR = 1.71, 95% CI: 1.33-2.20). Moreover, dissatisfaction with friendships in adulthood mediated 9.31% (95% CI: 4.25-14.57) of the association between psychological abuse in childhood and IPPs in adulthood, and 9.17% (95% CI: 4.35-16.33) of the association between substance abuse distress in childhood and IPPs in adulthood. CONCLUSIONS: Dissatisfaction with friendships in adulthood mediates a minor proportion of the associations between psychological abuse, substance abuse distress, and IPPs in adulthood. Interventions aimed at decreasing dissatisfaction with friendships may dampen some of the effect of psychological abuse and substance abuse distress in childhood on IPPs in adulthood. PMID- 29602330 TI - The association between depression and eating styles in four European countries: The MooDFOOD prevention study. AB - OBJECTIVE: Depression, one of the most prevalent and disabling disorders in Europe, is thought to be associated with unhealthy eating styles. As prevalence of depression and eating styles potentially differ across Europe, the current study aimed to investigate in a large, European sample, the associations of history of major depressive disorder and depression severity with unhealthy eating styles. METHODS: Baseline data of the MooDFOOD prevention study was used. The current analysis included 990 participants of four European countries (The Netherlands, United Kingdom, Germany, Spain). Analyses of Covariance and linear regression analyses were performed with depression history or depression severity as determinants, and emotional, uncontrolled, and cognitive restrained eating (Three Factor Eating Questionnaire Revised, 18 item) as outcomes. RESULTS: Depression history and severity were associated with more emotional and uncontrolled eating and with less cognitive restrained eating. Mood, somatic, and cognitive symptom clusters were also associated with more emotional and uncontrolled eating, and with less cognitive restrained eating. The somatic depressive symptoms "increased appetite" and "increased weight" were more strongly associated to unhealthy eating styles compared to other symptoms. No differences in associations between depression and unhealthy eating were found between European countries. CONCLUSION: Our results suggest that depression is related to more unhealthy eating styles. Diminishing unhealthy eating styles in subthreshold depressed persons could potentially reduce adverse health consequences like weight gain, unhealthy dietary patterns and weight-related diseases. It is also possible that interventions that decrease depressive symptoms can lead to a decrease in unhealthy eating styles. PMID- 29602331 TI - The association of omega-3 fatty acid levels with personality and cognitive reactivity. AB - OBJECTIVE: Low omega (n)-3 polyunsaturated fatty acid (PUFA) levels have been found in patients with various major psychiatric disorders. This study aims to identify whether psychological vulnerabilities (personality and cognitive reactivity) underlying these psychiatric conditions are also associated with n-3 PUFA blood levels. METHODS: Data was used from 2912 subjects (mean age 41.9 years, 66.4% female) from the Netherlands Study of Depression and Anxiety (NESDA). Five personality dimensions (NEO Five Factor Inventory) and cognitive reactivity measures (Leiden Index of Depression Sensitivity-Revised and Anxiety Sensitivity Index) were assessed. Plasma n-3 PUFA and docosahexaenoic acid (DHA) levels (as ratios against total fatty acids; mmol%) were assessed using a nuclear magnetic resonance platform. RESULTS: Low n-3 PUFA and DHA levels were associated with high neuroticism (Standardized beta (Beta) = -0.045, 95% Confidence Interval (CI) = -0.079 to -0.010, p = 0.011; Beta = -0.058, 95%CI = -0.093 to -0.022, p = 0.001), low extraversion (Beta = 0.065, 95%CI = 0.031 to 0.099, p < 0.001; Beta = 0.074, 95%CI = 0.039 to 0.109, p < 0.001) and low conscientiousness (Beta = 0.060, 95%CI = 0.027 to 0.093, p < 0.001; Beta = 0.074, 95%CI = 0.039 to 0.108, p < 0.001). Low n-3 PUFA and DHA levels were related to high hopelessness/suicidality (Beta = -0.059, 95%CI = -0.096 to -0.023, p = 0.001; Beta = -0.078, 95%CI = -0.116 to -0.041, p < 0.001), but not with other cognitive reactivity measures. Directions of associations were generally consistent in subjects with and without a current depressive disorder. CONCLUSION: Low n-3 PUFA and DHA levels are associated with personality (high neuroticism, low extraversion and low conscientiousness) and cognitive reactivity (high hopelessness/suicidality). Effect sizes were rather small, but in line with previous research on personality and chronic diseases. Future research should examine which lifestyle and/or biological pathways underlie these associations. PMID- 29602332 TI - An Enduring Dialogue between Computational and Empirical Vision. AB - In the late 1970s, key discoveries in neurophysiology, psychophysics, computer vision, and image processing had reached a tipping point that would shape visual science for decades to come. David Marr and Ellen Hildreth's 'Theory of edge detection', published in 1980, set out to integrate the newly available wealth of data from behavioral, physiological, and computational approaches in a unifying theory. Although their work had wide and enduring ramifications, their most important contribution may have been to consolidate the foundations of the ongoing dialogue between theoretical and empirical vision science. PMID- 29602333 TI - Retinal Cell Fate Specification. AB - How are different neural cell types generated from progenitor cells? In 1990, Turner et al. used new lineage tracing techniques to show that different cells in the mammalian retina share their progenitor origin. The findings established a key step toward our understanding of how multipotent progenitor cells give rise to complex circuitry in the retina. PMID- 29602334 TI - The Song Remains the Same. AB - Deafness causes speech to deteriorate, but whether this deterioration reflects an active or passive process is unclear. Birdsong - a learned vocal behavior that resembles speech in its dependence on auditory feedback - also deteriorates following deafening. In their 2000 paper, Brainard and Doupe showed that, following deafening, birdsong deteriorates through an active process mediated by a cortex-basal ganglia (BG) circuit. PMID- 29602335 TI - Neuronal Variability as a Proxy for Network State. AB - Characterizing how network state modulates cortical dynamics and information processing is an important step for understanding the neural code. In 2010, Churchland et al. reported wide experimental evidence showing that spontaneous and stimulus-evoked conditions are two distinct states, as indicated by a marked reduction of neuronal variability after stimulus onset. PMID- 29602336 TI - Extraction of maxillary canines. PMID- 29602337 TI - The personal touch. PMID- 29602338 TI - Effects of supplemental vibrational force on space closure, treatment duration, and occlusal outcome: A multicenter randomized clinical trial. AB - INTRODUCTION: A multicenter parallel 3-arm randomized clinical trial was carried out in 3 university hospitals in the United Kingdom to investigate the effect of supplemental vibratory force on space closure and treatment outcome with fixed appliances. METHODS: Eighty-one subjects less than 20 years of age with mandibular incisor irregularity undergoing extraction-based fixed appliance treatment were randomly allocated to supplementary (20 minutes/day) use of an intraoral vibrational device (AcceleDent; OrthoAccel Technologies, Houston, Tex) (n = 29), an identical nonfunctional (sham) device (n = 25), or fixed-appliance only (n = 27). Space closure in the mandibular arch was measured from dental study casts taken at the start of space closure, at the next appointment, and at completion of space closure. Final records were taken at completion of treatment. Data were analyzed blindly on a per-protocol basis with descriptive statistics, 1 way analysis of variance, and linear regression modeling with 95% confidence intervals. RESULTS: Sixty-one subjects remained in the trial at start of space closure, with all 3 groups comparable for baseline characteristics. The overall median rate of initial mandibular arch space closure (primary outcome) was 0.89 mm per month with no difference for either the AcceleDent group (difference, 0.09 mm/month; 95% CI, -0.39 to 0.22 mm/month; P = 0.57) or the sham group (difference, -0.02 mm/month; 95% CI, -0.32 to 0.29 mm/month; P = 0.91) compared with the fixed only group. Similarly, no significant differences were identified between groups for secondary outcomes, including overall treatment duration (median, 18.6 months; P >0.05), number of visits (median, 12; P >0.05), and percentage of improvement in the Peer Assessment Rating (median, 90.0%; P >0.05). CONCLUSIONS: Supplemental vibratory force during orthodontic treatment with fixed appliances does not affect space closure, treatment duration, total number of visits, or final occlusal outcome. REGISTRATION: NCT02314975. PROTOCOL: The protocol was not published before trial commencement. FUNDING: AcceleDent units were donated by OrthoAccel Technologies; no contribution to the conduct or the writing of this study was made by the manufacturer. PMID- 29602339 TI - Finite element analysis of slot wall deformation in stainless steel and titanium orthodontic brackets during simulated palatal root torque. AB - INTRODUCTION: Torque applied on anterior teeth is vital for root positioning and stability. The aim of this study was to evaluate the detailed slot wall deformation in stainless steel (SS) and titanium (Ti) edgewise brackets during palatal root torque using finite element analysis. METHODS: A finite element model was developed from a maxillary central incisor SS bracket (0.022 in). The generated torque values from an SS rectangular archwire (0.019 * 0.025 in) while twisting from 5 degrees to 40 degrees were obtained experimentally by a spine tester, and the calculated torque force was applied in the bracket slot. The deformations of the slot walls in both SS and Ti brackets were measured at various locations. RESULTS: There were gradual increases in the deformations of both bracket slot walls from the bottom to top locations. In the SS bracket slot for the 40 degrees twist, the deformations were 9.28, 36.8, and 44.8 MUm in the bottom, middle, and top slot wall locations, respectively. Similarly, in the Ti bracket slot for the 40 degrees twist, the deformations were 39.2, 62.4, and 76.2 MUm in the bottom, middle, and top slot wall locations, respectively. The elastic limits were reached at 28 degrees for SS and at 37 degrees for Ti. CONCLUSIONS: Both SS and Ti bracket slots underwent deformation during torque application. There are variations in the deformations at different locations in the slot walls and between the materials. PMID- 29602340 TI - Influence of nasoalveolar molding on skeletal development in patients with unilateral cleft lip and palate at 5 years of age. AB - INTRODUCTION: The aim of this retrospective study was to assess the influence of presurgical nasoalveolar molding (NAM) on skeletal development in patients with operated unilateral cleft lip and palate at 5 years of age. MATERIALS: Lateral cephalometric radiographs of 26 unilateral cleft lip and palate patients who had undergone presurgical NAM (NAM group) and 20 unilateral cleft lip and palate patients who did not have any presurgical NAM (non-NAM group) were analyzed. The radiographs were digitally traced using Quick Ceph Studio software (version 3.5.1.r (1151); Quick Ceph Systems, San Diego, Calif). Independent samples t tests were performed for statistical analysis. RESULTS: No significant differences were observed in sagittal and vertical skeletal measurements between the NAM and non-NAM groups. CONCLUSIONS: NAM resulted in no significant difference in skeletal development in unilateral cleft lip and palate patients compared with those without NAM in early childhood. PMID- 29602341 TI - Epidemiologic study of orthodontic retention procedures. AB - INTRODUCTION: The aims of this study were to survey current retention procedures applied by Dutch orthodontists and to examine their acquaintance with "unintentionally active retainers." METHODS: A questionnaire was sent to all 306 Dutch orthodontists involved in patient treatment. Questions were clustered in 4 parts: (1) general information, (2) retention procedures, (3) characteristics of wire materials for bonded retainers, and (4) acquaintance with "unintentionally active retainers." RESULTS: The response rate was 98%. The most applied retention modality in the maxillary arch was a combination of a removable and a bonded retainer (54%); in the mandibular arch, mainly a bonded retainer without a removable retainer was used (83%). Bonded retention was aimed to be lifelong for the maxillary arch (90%) and the mandibular arch (92%). Mean removable retention duration was 2 years. Vacuum-formed retainers were used more frequently and Hawley-type retainers less frequently. The wire materials used for bonded retainers were diverse. All orthodontists were familiar with unintentionally active retainers; 44% believed this phenomenon is caused by the properties of round multistrand wires. The opinion that unwanted changes in tooth position can arise due to the properties of round multistrand wire material was associated with changing the wire material (P <0.005). CONCLUSIONS: Lifelong retention with bonded retainers continues to increase. All orthodontists were acquainted with unintentionally active retainers and their impact. There is a need to identify all causative factors of inadvertent tooth movement in relation to bonded retainers and to prevent the onset of unintentionally active retainers. PMID- 29602342 TI - Anatomic assessment of the mandibular buccal shelf for miniscrew insertion in white patients. AB - INTRODUCTION: Cortical bone thickness, bone width, insertion depth, and proximity to nerves are important factors when planning and placing orthodontic miniscrews. The objective of this study was to anatomically assess the mandibular buccal shelf in a white patient population as the insertion site for orthodontic miniscrews by investigating these 4 variables. METHODS: Measurements were made on cone-beam computed tomography scans of 30 white patients (18 girls, 12 boys; mean age, 14.5 +/- 2 years). All measurements were taken adjacent to the distobuccal cusp of the first molar, and the mesiobuccal and distobuccal cusps of the second molar. Additionally, bone depth was measured at 2 height levels, 4 and 8 mm from the cementoenamel junction. Stereolithographic models of patients were superimposed on the cone-beam computed tomography volumes to virtually create an outline of the soft tissue on the cone-beam computed tomography image to allow identification of the purchase point height (mucogingival junction). The inferior alveolar nerve was digitally traced. Miniscrews (1.6 * 10 mm) were virtually placed at the buccal shelf, and their insertion depths and relationships to the nerve were assessed. Analysis of variance with post hoc analysis was used for data analysis. RESULTS: Insertion sites and measurement levels had significant impacts on both cortical bone thickness and bone width. Cortical bone thickness was typically greatest at the distobuccal cusp of the second molar. Bone width was also greatest at the distobuccal cusp of the second molar 8 mm from the cementoenamel junction. The greatest insertion depth was found again at the distobuccal cusp to the second molar, whereas the miniscrews had the greatest proximity to the nerve at this site also. CONCLUSIONS: The distobuccal cusp level of the mandibular second molar is the most appropriate site for miniscrew insertion at the buccal shelf in white patients. PMID- 29602343 TI - Incisor malalignment and the risk of periodontal disease progression. AB - INTRODUCTION: The objective of this study was to investigate the association between incisor crowding, irregularity, and periodontal disease progression in the anterior teeth. METHODS: Data collected over 35 years from men enrolled in the Veterans Affairs Dental Longitudinal Study included information concerning pocket depth and alveolar bone loss. Plaster casts of the maxillary (n = 400) and mandibular (n = 408) arches were available for baseline measurements. Periodontal disease in the anterior teeth was defined as per arch sum of pathologic pocket depth and sum of teeth with any alveolar bone loss in the anterior sextants. Incisor malalignment status was defined by the anterior tooth size-arch length discrepancy index and Little's Irregularity Index. Adjusted mixed effects linear models computed the beta (beta) estimates and 95% confidence intervals (95% CI) of the amounts of change in periodontal disease outcomes by the level of malalignment. RESULTS: In the anterior maxillary arch, crowding and spacing were significantly associated with an increased per-arch sum of pathologic pocket depth (beta, 0.70 mm; 95% CI, 0.20-1.21, and beta, 0.49 mm; 95% CI, 0.06-0.91, respectively). In the anterior mandibular arch, incisor crowding and irregularity were significantly associated with an increased per-arch sum of pathologic pocket depth (mild crowding: beta, 0.47 mm; 95% CI, 0.01-0.93; severe irregularity: beta, 0.94 mm; 95% CI, 0.50-1.38), and the sum number of teeth with alveolar bone loss (mild and moderate-to-severe crowding: beta, 0.45 teeth; 95% CI, 0.08-0.82; and beta, 0.45 teeth; 95% CI, 0.13-0.83, respectively; moderate irregularity: beta, 0.34 teeth; 95% CI, 0.06-0.62). CONCLUSIONS: Certain incisor malalignment traits (ie, maxillary incisor crowding, maxillary incisor spacing, mandibular incisor mild crowding, mandibular incisor moderate-to-severe crowding, mandibular incisor moderate irregularity, and mandibular incisor severe irregularity) are associated with significant periodontal disease progression. PMID- 29602344 TI - Objective assessment of the contribution of dental esthetics and facial attractiveness in men via eye tracking. AB - INTRODUCTION: Recently, greater emphasis has been placed on smile esthetics in dentistry. Eye tracking has been used to objectively evaluate attention to the dentition (mouth) in female models with different levels of dental esthetics quantified by the aesthetic component of the Index of Orthodontic Treatment Need (IOTN). This has not been accomplished in men. Our objective was to determine the visual attention to the mouth in men with different levels of dental esthetics (IOTN levels) and background facial attractiveness, for both male and female raters, using eye tracking. METHODS: Facial images of men rated as unattractive, average, and attractive were digitally manipulated and paired with validated oral images, IOTN levels 1 (no treatment need), 7 (borderline treatment need), and 10 (definite treatment need). Sixty-four raters meeting the inclusion criteria were included in the data analysis. Each rater was calibrated in the eye tracker and randomly viewed the composite images for 3 seconds, twice for reliability. RESULTS: Reliability was good or excellent (intraclass correlation coefficients, 0.6-0.9). Significant interactions were observed with factorial repeated-measures analysis of variance and the Tukey-Kramer method for density and duration of fixations in the interactions of model facial attractiveness by area of the face (P <0.0001, P <0.0001, respectively), dental esthetics (IOTN) by area of the face (P <0.0001, P <0.0001, respectively), and rater sex by area of the face (P = 0.0166, P = 0.0290, respectively). For area by facial attractiveness, the hierarchy of visual attention in unattractive and attractive models was eye, mouth, and nose, but for men of average attractiveness, it was mouth, eye, and nose. For dental esthetics by area, at IOTN 7, the mouth had significantly more visual attention than it did at IOTN 1 and significantly more than the nose. At IOTN 10, the mouth received significantly more attention than at IOTN 7 and surpassed the nose and eye. These findings were irrespective of facial attractiveness levels. For rater sex by area in visual density, women showed significantly more attention to the eyes than did men, and only men showed significantly more attention to the mouth over the nose. CONCLUSIONS: Visual attention to the mouth was the greatest in men of average facial attractiveness, irrespective of dental esthetics. In borderline dental esthetics (IOTN 7), the eye and mouth were statistically indistinguishable, but in the most unesthetic dental attractiveness level (IOTN 10), the mouth exceeded the eye. The most unesthetic malocclusion significantly attracted visual attention in men. Male and female raters showed differences in their visual attention to male faces. Laypersons gave significant visual attention to poor dental esthetics in men, irrespective of background attractiveness; this was counter to what was seen in women. PMID- 29602345 TI - Comparison of digital intraoral scanners and alginate impressions: Time and patient satisfaction. AB - INTRODUCTION: Recent technological advances have made intraoral scans and digital models a possibility and a promising alternative to conventional alginate impressions. Several factors should be examined when considering an intraoral scanner, including patient acceptance and efficiency. The objectives of this study were to assess and compare patient satisfaction and time required between 2 intraoral scanners and conventional alginate impressions. METHODS: An initial pilot study was completed to create a valid and reliable survey instrument that would measure 3 areas of patient satisfaction with the impression experience. A visual analog scale survey was developed and administered to 180 orthodontic patients receiving 1 of 3 types of impressions: (1) iTero Element intraoral scan (Align Technologies, San Jose, Calif), n = 60; (2) TRIOS Color intraoral scan (3Shape, Copenhagen, Denmark), n = 60; and (3) conventional alginate impression (imprEssix Color Change; Dentsply Sirona, York, Pa), n = 60, and the time required to obtain the impressions was recorded. RESULTS: Reliability was evaluated with intraclass correlation coefficient values for 17 paired questionnaires, and all questions were found to be reliable (intraclass correlation coefficient, >=0.65). For the main study, 180 subjects completed timed impressions and surveys. Data indicated that subjects receiving intraoral scans preferred the digital impressions, and subjects receiving alginate impressions were neutral regarding impression preference, and that efficiency varied based on the impression method. CONCLUSIONS: Intraoral scanners are accepted by orthodontic patients, and they have comparable efficiency with conventional impression methods depending on the type of scanner. PMID- 29602346 TI - Dentoskeletal effects of facemask therapy in skeletal Class III cleft patients with or without bone graft. AB - INTRODUCTION: The association between maxillary protraction and bone graft in patients with cleft lip and palate remains unclear. The purpose of this study was to investigate whether a secondary alveolar bone graft influences dentoskeletal effects of facemask therapy in unilateral cleft lip and palate patients with a skeletal Class III relationship. METHODS: In this prospective nonrandomized clinical trial, 61 consecutive boys with unilateral cleft lip and palate and skeletal Class III malocclusion were divided into 3 groups: grafted facemask group (n = 21), ungrafted facemask group (n = 20), and untreated control group (n = 20). Sixteen dentoskeletal measurements on lateral cephalometric radiographs were compared before and after therapy or observation with 1-way analysis of variance or the Mann-Whitney U test. RESULTS: After facemask therapy, the grafted group showed a statistically significantly greater advancement of Point A (S-Vert A, 4.18 +/- 1.94 mm; SNA, 3.51 degrees +/- 2.21 degrees ) than did the ungrafted group (S-Vert-A, 2.64 +/- 1.58 mm; SNA, 1.92 degrees +/- 1.05 degrees ). Furthermore, significant SNB changes were found in the grafted group when compared with those in the ungrafted group (-0.38 degrees +/- 1.77 degrees vs 1.69 degrees +/- 1.34 degrees ; P <0.05). The changes in the mandibular plane angle (MP-SN, MP-FH) in the grafted group were less pronounced than in the ungrafted group by approximately 2 degrees (P <0.05). Flaring of the maxillary incisors was more pronounced in treated subjects than in untreated subjects. The mandibular incisors proclined in both grafted (1.54 degrees +/- 4.21 degrees ) and control (0.97 degrees +/- 3.71 degrees ) patients, and were retroclined in the ungrafted group (-2.13 degrees +/- 3.68 degrees ). CONCLUSIONS: Facemask therapy performed after an alveolar bone graft produced more anterior maxillary migration (90%) and less pronounced mandibular clockwise rotation (10%) than those in the ungrafted group (50%, 50%, respectively). PMID- 29602347 TI - Orthodontic treatment in patients with aggressive periodontitis. AB - INTRODUCTION: Aggressive periodontitis (AP) is a condition that promotes breakdown of the periodontal tissues in a short time. In severe cases, pathologic migration of teeth and tooth loss can occur, producing esthetic and functional problems for the patient. Orthodontic treatment may be recommended to restore esthetics and masticatory function. We assessed the effects of orthodontic movement in the periodontal tissues of treated patients with AP. METHODS: Ten subjects (ages 25.0 +/- 5.22 years) with AP received periodontal treatment followed by orthodontic treatment. Maintenance sessions were performed monthly under a strict dental biofilm control. They were compared with 10 periodontally healthy subjects (ages 22.9 +/- 5.23 years) who received orthodontic treatment. Probing pocket depth, clinical attachment level, bleeding on probing, and dental plaque index were measured at baseline, after orthodontic treatment, and after 4 months. RESULTS: Statistical analysis showed improvement in all clinical parameters between baseline and 4 months after orthodontic treatment: probing pocket depth (0.29 mm), clinical attachment level (0.38 mm), bleeding on probing (4.0%), and dental plaque index (11%). CONCLUSIONS: The periodontal parameters of the AP patients remained stable during orthodontic treatment under strict biofilm control. PMID- 29602348 TI - Reliability and validity of mandibular posterior vertical asymmetry index in panoramic radiography compared with cone-beam computed tomography. AB - INTRODUCTION: The purposes of this study were to compare the asymmetry index using panoramic radiography and cone-beam computed tomography for detecting mandibular posterior asymmetry and to evaluate the diagnostic value of the asymmetry index on panoramic radiography. METHODS: A total of 43 patients were included in this study. Ten mandibular posterior distances were measured using panoramic radiography and cone-beam computed tomography, and 10 asymmetry index values were calculated. The reliability of each asymmetry index was assessed. For evaluating validity of each asymmetry index using panoramic radiography, the paired t test and the Bland-Altman analysis were used. The accuracy of the asymmetry index and the area under the curve of receiver operator characteristic were calculated. RESULTS: The asymmetry index of total ramal height showed good reliability (ICC, >0.888). In condylar height 1, specificity and negative predictive value were low (0.08 and 0.17, respectively), 95% limits of agreement were +/-17.9%, and area under the curve was 0.484. In total, ramal height accuracy was 0.86, and areas under the curve were 0.926 to 0.957. CONCLUSIONS: For detecting asymmetry of the condyle region, the asymmetry index using panoramic radiography had little diagnostic value, and we recommend using cone beam computed tomography images. However, the asymmetry index for total ramal height showed good reliability and relatively higher validity, and its diagnostic value was excellent. PMID- 29602349 TI - Contemporary Class II Division 2 nonextraction adult treatment. AB - Achieving ideal results when treating a difficult malocclusion is a challenge that orthodontists frequently encounter. Maintaining those results is sometimes more challenging than the correction itself. As specialists in orthodontics, we should be able to apply bone physiology concepts during the diagnosis and treatment planning process and predict how bone will react after biomechanical stimuli. Understanding bone physiology and the biology of tissue response during orthodontic tooth movement should allow us to develop the proper mechanical design and consequently the therapeutic procedures necessary to achieve the expected tooth position and bone architecture. Surgically facilitated orthodontic therapy uses basic bone biology and physiologic bone turnover procedures as well as basic orthodontic biomechanical principles to correct dental malocclusions in the shortest, safest, and most conservative manner. The correction of such malocclusions with this approach is expected to be functional and stable. PMID- 29602350 TI - Nonsurgical correction of a severe anterior open bite with mandibular molar intrusion using mini-implants and the multiloop edgewise archwire technique. AB - This article reports the case of a 24-year-old man with a large anterior open bite, mild mandibular crowding, increased overjet, no passive lip sealing, and Angle Class I malocclusion. The treatment results were achieved by mandibular molar intrusion using 1.8 * 8.5-mm mini-implants (C-implants) inserted between the mandibular first and second molars bilaterally. A 2.5-mm molar intrusion and open-bite closure occurred within 8 months. The multiloop edgewise archwire technique helped to intrude the posterior teeth. Total treatment time was 20 months. Fifty months postretention records are also presented. The patient achieved a suitable occlusion and satisfactory facial esthetics at the end of treatment and at the 50-month retention check. PMID- 29602351 TI - Expanding torque possibilities: A skeletally anchored torqued cantilever for uprighting "kissing molars". AB - Several uprighting mechanics and devices have been used for repositioning tipped molars. "Kissing molars" (KMs) are an uncommon tooth impaction involving 2 severely tipped mandibular molars with their occlusal surfaces positioned crown to crown, with the roots pointing in opposite directions. Orthodontic uprighting of KMs has not been a usual treatment protocol, and it can be a challenging task due to the severe tipping and double impaction, requiring efficient and well controlled uprighting mechanics. An innovative skeletally anchored cantilever, which uses the torque principle for uprighting tipped molars, is suggested. This torqued cantilever is easy to manufacture, install, and activate; it is a well known torque that is effective for producing root movement. A successful treatment of symptomatic KMs, involving the first and second molars, was achieved with this cantilever. Thus, clinicians should consider the suggested uprighting mechanics and orthodontic device as a more conservative alternative to extraction of KMs, depending on the patient's age, involved teeth in KMs, tipping severity, and impaction positions. PMID- 29602352 TI - Precision and reliability of Dolphin 3-dimensional voxel-based superimposition. AB - INTRODUCTION: Superimposition of 2 cone-beam computed tomography images is possible by using landmarks, surfaces, or density information (voxel-based). Voxel-based superimposition is automated and uses the most image content, providing accurate results. Until recently, this superimposition was extremely laborious, but a user-friendly voxel-based superimposition has recently been introduced. Our aim was to evaluate the precision and reliability of Dolphin 3 dimensional voxel-based superimposition (Dolphin Imaging, Chatsworth, Calif). METHODS: This was a retrospective study using existing scans of 31 surgical orthodontic patients with a mean age of 21 +/- 8 years (range, 15-47 years). Each patient had a presurgical and a postsurgical scan taken within 12 months. Surgical patients were used since the reference area for superimposition was not affected by growth or surgical procedures. The volumes were superimposed using voxel-based methods from Dolphin Imaging and a tested method used previously. This method uses 2 open-source programs and takes about 3 hours to complete, whereas the Dolphin method takes under 5 minutes. The postsurgical scan was superimposed on the presurgical scan at the cranial base. Postsurgical registrations for both methods were compared with each other using the absolute closest point color map, with emphasis on 7 regions (nasion, A-point, B-point, bilateral zygomatic arches, and bilateral gonions). RESULTS: Intraclass correlations showed excellent reliability (0.96). The mean differences between the 2 methods were less than 0.21 mm (voxel size, 0.38). The smallst difference was in the left zygomatic area at 0.09 +/- 0.07 mm, and the largest was in the right gonial region at 0.21 +/- 0.13 mm. CONCLUSIONS: Dolphin 3-dimensional voxel based superimposition, a fast and user-friendly method, is precise and reliable. PMID- 29602353 TI - Qualified immunity: Pure heart and empty head. PMID- 29602354 TI - Bittersweet progress for haemophilia A. PMID- 29602355 TI - Unravelling the diversity of mechanisms through which nutrition regulates body size in insects. AB - Insects show impressive diversity in adult body size across species, and within species adult body size is sensitive to numerous environmental conditions, particularly to changes in nutrition. Body size in adult insects correlates with a number of important fitness-related traits such as fecundity, longevity, stress resistance, and mating success. Over the past few decades, the field of insect body size regulation has made impressive progress towards understanding the signalling pathways that regulate body size in response to nutrition. These studies have shown that conserved nutrition-sensitive signalling pathways act in animals from insects to vertebrates to regulate growth. In particular, pathways like the insulin/insulin-like growth factor signalling (IIS) pathway and the Target of rapamycin (TOR) pathway respond to the levels of dietary nutrients to adjust both the rate of growth and the duration of the growth period. They do this not only by regulating organ growth, but also by modifying the rates of synthesis and circulating concentrations of key developmental hormones. Although the mechanisms through which this occurs have been well documented in one insect, the fruit fly Drosophila melanogaster, it is becoming increasingly clear that the downstream mechanisms through which IIS and TOR signalling alter size in response to nutrition differ between organs and across species. In this review, we highlight how understanding the organ-specific effects of IIS/TOR signalling are key to revealing the diversity of size control mechanisms across insects. PMID- 29602356 TI - By land, air, and sea: hemipteran diversity through the genomic lens. AB - Thanks to a recent spate of sequencing projects, the Hemiptera are the first hemimetabolous insect order to achieve a critical mass of species with sequenced genomes, establishing the basis for comparative genomics of the bugs. However, as the most speciose hemimetabolous order, there is still a vast swathe of the hemipteran phylogeny that awaits genomic representation across subterranean, terrestrial, and aquatic habitats, and with lineage-specific and developmentally plastic cases of both wing polyphenisms and flightlessness. In this review, we highlight opportunities for taxonomic sampling beyond obvious pest species candidates, motivated by intriguing biological features of certain groups as well as the rich research tradition of ecological, physiological, developmental, and particularly cytogenetic investigation that spans the diversity of the Hemiptera. PMID- 29602357 TI - Genomes of Diptera. AB - Diptera (true flies) are among the most diverse holometabolan insect orders and were the first eukaryotic order to have a representative genome fully sequenced. 110 fly species have publically available genome assemblies and many hundreds of population-level genomes have been generated in the model organisms Drosophila melanogaster and the malaria mosquito Anopheles gambiae. Comparative genomics carried out in a phylogenetic context is illuminating many aspects of fly biology, providing unprecedented insight into variability in genome structure, gene content, genetic mechanisms, and rates and patterns of evolution in genes, populations, and species. Despite the rich availability of genomic resources in flies, there remain many fly lineages to which new genome sequencing efforts should be directed. Such efforts would be most valuable in fly families or clades that exhibit multiple origins of key fly behaviors such as blood feeding, phytophagy, parasitism, pollination, and mycophagy. PMID- 29602358 TI - Endocrine regulation of a dispersal polymorphism in winged insects: a short review. AB - Changes in food availability and crowding are two critical environmental conditions that impact an animal's trajectory toward either reproduction or migration. Many insects facing this challenge have evolved wing polymorpisms that allow them to respond to changing conditions. When conditions favor reproduction, wing polymorphic species produce adults that either have no wings or short, non functional wings; however, when conditions favor migration, adults with functional wings and robust flight muscles develop. Here we review three recently reported signaling pathways regulating wing polyphenism in wing polymorphic crickets, aphids, and brown planthoppers: juvenile horomone/ecdysone signaling, insulin signaling, and Jun-N-terminal Kinase (JNK) signaling. Understanding how these pathways respond to nutrition, stress and crowding with the appropriate adaptive phenotype is an important step in understanding how life-history trade offs evolve. PMID- 29602359 TI - Epigenetics and developmental plasticity in orthopteroid insects. AB - Developmental plasticity is a key driver of the extraordinary ecological success of insects. Epigenetic mechanisms provide an important link between the external stimuli that initiate polyphenisms, and the stable changes in gene expression that govern alternative insect morphs. We review the epigenetics of orthopteroid insects, focussing on recent research on locusts and termites, two groups which display high levels of phenotypic plasticity, and for which genome sequences have become available in recent years. We examine research on the potential role of DNA methylation, histone modifications, and non-coding RNAs in the regulation of gene expression in these insects. DNA methylation patterns in orthopteroids share a number of characteristics with those of hymenopteran insects, although methylation levels are much higher, and extend to introns and repeat elements. Future examinations of epigenetic mechanisms in these insects will benefit from comparison of tissues from aged-matched individuals from alternative morphs, and adequate biological replication. PMID- 29602360 TI - Recent advances in understanding the mechanisms of sexually dimorphic plasticity: insights from beetle weapons and future directions. AB - Many traits that are sexually dimorphic, appearing either differently or uniquely in one sex, are also sensitive to an organism's condition. This phenomenon seems to have evolved to limit genetic conflict between traits that are under different selective pressures in each sex. Recent work has shed light on the molecular and developmental mechanisms that govern this condition sensitive growth, and this work has now expanded to encompass both sexual dimorphism as well as conditionally plastic growth, as it seems the two phenomena are linked on a molecular level. In all cases studied the gene doublesex, a conserved regulator of sex differentiation, controls both sexual dimorphism as well as the condition dependent plastic responses common to these traits. However, the advent of next generation -omics technologies has allowed researchers to decipher the common and diverged mechanisms of sexually dimorphic plasticity and expand investigations beyond the foundation laid by studies utilizing beetle weapons. PMID- 29602361 TI - A molecular concept of caste in insect societies. AB - The term 'caste' is used to describe the division of reproductive labour that defines eusocial insect societies. The definition of 'caste' has been debated over the last 50 years, specifically with respect to the simplest insect societies; this raises the question of whether a simple categorisation of social behaviour by reproductive state alone is helpful. Gene-level analyses of behaviours of individuals in hymenopteran social insect societies now provide a new empirical base-line for defining caste and understanding the evolution and maintenance of a reproductive division of labour. We review this literature to identify a set of potential molecular signatures that, combined with behavioural, morphological and physiological data, help define caste more precisely; these signatures vary with the type of society, and are likely to be influenced by ecology, life-history, and stage in the colony cycle. We conclude that genomic approaches provide us with additional ways to help quantify and categorise caste, and behaviour in general. PMID- 29602362 TI - Recent progress and prospects for advancing arachnid genomics. AB - Arachnids exhibit tremendous species richness and adaptations of biomedical, industrial, and agricultural importance. Yet genomic resources for arachnids are limited, with the first few spider and scorpion genomes becoming accessible in the last four years. We review key insights from these genome projects, and recommend additional genomes for sequencing, emphasizing taxa of greatest value to the scientific community. We suggest greater sampling of spiders whose genomes are understudied but hold important protein recipes for silk and venom production. We further recommend arachnid genomes to address significant evolutionary topics, including the phenotypic impact of genome duplications. A barrier to high-quality arachnid genomes are assemblies based solely on short read data, which may be overcome by long-range sequencing and other emerging methods. PMID- 29602363 TI - The distinct roles of insulin signaling in polyphenic development. AB - Many insects have the ability to develop alternative morphologies in response to specific environmental signals such as photoperiod, temperature, nutrition and crowding. These signals are integrated by the brain and result in alternative patterns of secretion of developmental hormones like ecdysone, juvenile hormone and insulin-like growth factors, which, in turn, direct alternative developmental trajectories. Insulin signaling appears to be particularly important when the polyphenism involves differences in the sizes of the body, appendages and other structures, such as wings, mandibles and horns. Here we review recent advances in understanding the role of insulin signaling, and its interaction with other hormones, in the development of polyphenisms. PMID- 29602365 TI - Beetle genomes in the 21st century: prospects, progress and priorities. AB - The order Coleoptera (beetles) is arguably the most species-rich lineage of animals. Beetles exhibit an extraordinary variety of life histories and occupy most terrestrial environments. Whole genome sequences are available for 11 beetle species, only six of which have been published. Studies of beetle genomes have revealed remarkable new insights into the genomic basis and evolution of beetle life histories and other aspects of beetle biodiversity, including the genes underlying chemoperception, detoxification, and specialized plant feeding, as well as the role of horizontal gene transfer in elaboration of the beetle trophic repertoire. Nonetheless, such studies are in their infancy. The study of beetle genomes has the potential to further revolutionize our understanding of beetle biodiversity, but genomic studies of beetles remain seriously limited in scope and resolution by the very few genomes that are currently available for study. PMID- 29602366 TI - Genes and genomic processes underpinning the social lives of ants. AB - The >15000 ant species are all highly social and show great variation in colony organization, complexity and behavior. The mechanisms by which such sociality evolved, as well as those underpinning the elaboration of ant societies since their ~140 million year old common ancestor, have long been pondered. Here, we review recent insights generated using various genomic approaches. This includes understanding the molecular mechanisms underlying caste differentiation and the diversity of social structures, studying the impact of eusociality on genomic evolutionary rates, and investigating gene expression changes associated with differences in lifespan between castes. Furthermore, functional studies involving RNAi and CRISPR have recently been successfully applied to ants, opening the door to exciting research that promises to revolutionize the understanding of the evolution and diversification of social living. PMID- 29602367 TI - The (ongoing) problem of relative growth. AB - Differential growth, the phenomenon where parts of the body grow at different rates, is necessary to generate the complex morphologies of most multicellular organisms. Despite this central importance, how differential growth is regulated remains largely unknown. Recent discoveries, particularly in insects, have started to uncover the molecular-genetic and physiological mechanisms that coordinate growth among different tissues throughout the body and regulate relative growth. These discoveries suggest that growth is coordinated by a network of signals that emanate from growing tissues and central endocrine organs. Here we review these findings and discuss their implications for understanding the regulation of relative growth and the evolution of morphology. PMID- 29602364 TI - Genomes of the Hymenoptera. AB - Hymenoptera is the second-most sequenced arthropod order, with 52 publically archived genomes (71 with ants, reviewed elsewhere), however these genomes do not capture the breadth of this very diverse order (Figure 1, Table 1). These sequenced genomes represent only 15 of the 97 extant families. Although at least 55 other genomes are in progress in an additional 11 families (see Table 2), stinging wasps represent 35 (67%) of the available and 42 (76%) of the in progress genomes. A more comprehensive catalog of hymenopteran genomes is needed for research into the evolutionary processes underlying the expansive diversity in terms of ecology, behavior, and physiological traits within this group. Additional sequencing is needed to generate an assembly for even 0.05% of the estimated 1 million hymenopteran species, and we recommend premier level assemblies for at least 0.1% of the >150,000 named species dispersed across the order. Given the haplodiploid sex determination in Hymenoptera, haploid male sequencing will help minimize genome assembly issues to enable higher quality genome assemblies. PMID- 29602369 TI - Lepidoptera genomes: current knowledge, gaps and future directions. AB - Butterflies and moths (Lepidoptera) are one of the most ecologically diverse and speciose insect orders. With recent advances in genomics, new Lepidoptera genomes are regularly being sequenced, and many of them are playing principal roles in genomics studies, particularly in the fields of phylo-genomics and functional genomics. Thus far, assembled genomes are only available for <10 of the 43 Lepidoptera superfamilies. Nearly all are model species, found in the speciose clade Ditrysia. Community support for Lepidoptera genomics is growing with successful management and dissemination of data and analytical tools in centralized databases. With genomic studies quickly becoming integrated with ecological and evolutionary research, the Lepidoptera community will unquestionably benefit from new high-quality reference genomes that are more evenly distributed throughout the order. PMID- 29602368 TI - Open access genomic resources for terrestrial arthropods. AB - Genome sequencing initiatives like the Arthropod i5k project and other biodiversity genomics research rely on access to high quality DNA and/or tissue. Global collection initiatives such as the Smithsonian Global Genome Initiative (GGI) and its partner network, the Global Genome Biodiversity Network (GGBN) aim to provide access to these resources at high-quality standards. Here, we review progress toward providing genomic resources (tissues, DNA, genomes) for terrestrial arthropods, a megadiverse animal group, and compare progress in genome sequencing to all other animals. PMID- 29602371 TI - Editorial overview: Development and regulation: Mechanisms of phenotypic plasticity one hundred years since 'On Growth and Form'. PMID- 29602370 TI - Editorial overview: Insect genomics: Arthropod genomic resources for the 21st century: It only counts if it's in the database! PMID- 29602372 TI - [The pathology of renal transplants]. AB - In order to make an objective assessment of the histopathology of a renal biopsy during a kidney transplant, all the various elements involved in the process must be understood. It is important to know the characteristics of the donor organ, especially if the donor is older than 65. The histopathological features of the donor biopsy, especially its vascular status, are often related to an initial poor function of the transplanted kidney. The T lymphocyte inflammatory response is characteristic in acute cellular rejection; the degree of tubulitis, together with the amount of affected parenchyme, are important factors. The proportion of cellular sub-populations, such as plasma cells and macrophages, is also important, as they can be related to antibody-mediated humoral rejection. Immunofluorescent or immunohistochemical studies are necessary to rule out C4d deposits or immunogloblulins. The presence of abundant deposits of C4d in tubular basement membranes supports a diagnosis of humoral rejection, as does the presence of capillaritis, glomerulitis which, together with vasculitis, are typical diagnostic findings in C4d negative cases. Interstitial fibrosis, tubular atrophy and glomerular sclerosis, although non-specific, imply a chronic phase. Transplant glomerulopathy and multilamination in more than 6 layers of the tubular and glomerular basement membranes are quasi-specific characteristics of chronic humoral rejection. Electron microscopy is essential to identify of these pathologies as well as to demonstrate the presence of other glomerular renal diseases. PMID- 29602373 TI - [Psammomatous calcification in a gastric carcinoma. A case report and a review of the literature]. AB - Dystrophic calcification in gastric carcinoma is an unusual finding usually associated with mucinous carcinomas. Psammomatous calcification is rare; indeed there are only seven cases reported to date. We present a case of a 73 year old male with tubular adenocarcinoma that revealed numerous globular shaped calcified bodies of psammomatous type within the tumor. The pathogenesis and prognostic significance are discussed. PMID- 29602374 TI - [Venolymphatic malformation with bone erosion. An unusual affectation in these lesions]. AB - A 30 year old male presented with a cutaneous lesion on the distal area of the 5th toe with involvement of the outer edges. Macroscopically, it was a 1cm violaceous and keratotic lesion. Radiography showed an increase in soft tissue, possibly due to a vascular lesion. MRI showed a hyper-intense signal with erosion of the distal phalanx compatible with a low-flow vascular malformation. The distal phalanx was amputated. Histopathology revealed a lesion formed by venous and D2-40 positive lymphatic vessels. This case highlights the fact that even minimal skin involvement in vascular malformations may conceal an important deeper lesion, such as erosion of the cortical bone. PMID- 29602375 TI - [Primary breast synovial sarcoma]. AB - Primary synovial sarcoma of the breast is very rare. We report a case of a 33 year-old woman, who had previously undergone a radical mastectomy, having been diagnosed with fusocellular breast carcinoma. Histopathology revealed a hypercellular lesion formed by spindle cells with storiform and herringbone patterns. Immunohistochemistry showed strong expression of vimentin and CD99, and focal bcl2, EMA, CK AE1-AE3, actin and desmin, with negativity for S100, CD34, CK7, CK14, CK19, hormone receptors, caldesmon and myosin. Molecular biology revealed the expression of the fusion product of the SS18 and SSX genes, indicative of the translocation t(X;18)(p11.2;q11.2), which confirmed the diagnosis of synovial sarcoma. PMID- 29602376 TI - [Cytology: we're moving on!] PMID- 29602377 TI - [The Spanish Society of Cytology: Quality control program of gynecological cytology]. AB - INTRODUCTION: In Spain, the guidelines for cervical cancer screening include a recommendation to enroll in external quality control programs. The Spanish Society of Cytology (SEC) has initiated its own quality control program of gynecological cytology (QCPGC). AIM: To describe and discuss the results of the second round of SECs QCPGC. MATERIAL AND METHOD: The cases are selected by a group of expert cytologists. The cases with an agreement of 75% of four cytopathologists were used. The cases were scanned with Aperio. The scanned cases not available were excluded. We included a total of 23 cases, 1 negative, 15 low grade lesions (4 ASCUS and 11 LSIL) and 7 high grade lesions (1 ASCH and 6 HSIL). Sixteen cases were studied with ThinPrepTM platform and in 7 cases the SurePathTM platform was used. RESULTS: Sixteen hospitals participated. The global mean concordance was 70.6%. The mean concordance in the type of lesion was 63.1%. The concordance was 71.9% in negative diagnoses, 56.2% in ASCUS, 69.5% in LSIL and 82.8% in HSIL The discordant cases were diagnosed more frequently as negative and ASCUS. 4.4% of cases had major discordances (HSIL or ASCH versus negatives). CONCLUSIONS: Our results are similar to those reported in the literature, with very few severe discordances. PMID- 29602378 TI - [MELF pattern in myometrial infiltration in endometrioid adenocarcinoma of the endometrium. A retrospective study of 70 cases]. AB - INTRODUCTION: Endometrioid adenocarcinoma of the endometrium (EAE) usually has a favorable prognosis. Recently, the MELF (microcystic, elongated and fragmented) pattern of myometrial infiltration has been described. It is associated with lymphovascular invasion and lymph node metastasis. Seventy cases of EAE were reviewed to identify the presence of MELF and its correlation with other prognostic factors. MATERIAL AND METHODS: Hysterectomies performed for EAE during a 5-year period were reviewed, searching for MELF pattern. Its presence was correlated with other variables such as histological grade, depth of myometrial infiltration, pelvic and/or aortic lymph node metastasis, peritoneal implants and evolution. RESULTS: In 17 (24%) cases MELF pattern was detected. It was more frequent in low grade tumors; it was present in four grade 3 cases. In 9 (53%) cases there was deep myometrial infiltration. Five cases had lymph node metastasis in the pelvis and three in the para-aortic region. One of the patients died, another presented a vulvar recurrence and another pulmonary metastasis. CONCLUSION: MELF pattern can be seen in high grade EAE and correlates with deep myometrial infiltration and pelvic lymph node metastasis. Its presence does not seem to influence survival. PMID- 29602379 TI - [Recommendations for biomarker testing in epithelial ovarian cancer. A national consensus statement by the Spanish Society of Pathology and the Spanish Society of Medical Oncology]. AB - Advances in the understanding of the histological and molecular characteristics of ovarian cancer now allow 5subtypes to be identified, leading to a more refined therapeutic approach and improved clinical trials. Each of the subtypes has specific histological features and a particular biomarker expression, as well as mutations in different genes, some of which have prognostic and predictive value. CA125 and HE4 are examples of ovarian cancer biomarkers used in diagnosis and follow-up. Currently, somatic or germinal mutations on BRCA1 and BRCA2 genes are the most important biomarkers in epithelial ovarian cancer, having prognostic and predictive value. In this article, a group of experts from the Spanish Society of Medical Oncology and the Spanish Society of Pathology review the histological and molecular characteristics of the 5subtypes of ovarian cancer and describe the most useful biomarkers and mutations for diagnosis, screening and tailored treatment strategy. PMID- 29602380 TI - [Consensus statement on biomarkers in breast cancer by the Spanish Society of Pathology and the Spanish Society of Medical Oncology]. AB - This consensus statement is a joint initiative of the Spanish Society of Pathology (SEAP) and the Spanish Society of Medical Oncology (SEOM). It revises and updates the recommendations for the use of biomarkers in the diagnosis and treatment of breast cancer. The group of experts recommends that, in all cases of breast cancer, the histologic grade and the alpha-estrogen receptor (ER), progesterone receptor, Ki-67 and HER2 status should be determined, in order to assist prognosis and establish therapeutic options, including hormone therapy, chemotherapy and anti-HER2 therapy. One of the four available genetic prognostic platforms (MammaPrint(r), Oncotype DX(r), Prosigna(r) or EndoPredict(r)) may be used in node-negative ER-positive patients to establish a prognostic category and decide, together with the patient, whether adjuvant treatment be limited to hormonal therapy. Newer technologies, including next generation sequencing, liquid biopsy, tumour infiltrating lymphocytes or PD-1 determination, are still investigational. PMID- 29602381 TI - Cloning, expression and characterisation of P450-Hal1 (CYP116B62) from Halomonas sp. NCIMB 172: A self-sufficient P450 with high expression and diverse substrate scope. AB - Cytochrome P450 monooxygenases are able to catalyse a range of synthetically challenging reactions ranging from hydroxylation and demethylation to sulfoxidation and epoxidation. As such they have great potential for biocatalytic applications but are underutilised due to often-poor expression, stability and solubility in recombinant bacterial hosts. The use of self-sufficient P450 s with fused haem and reductase domains has already contributed heavily to improving catalytic efficiency and simplifying an otherwise more complex multi-component system of P450 and redox partners. Herein, we present a new addition to the class VII family with the cloning, sequencing and characterisation of the self sufficient CYP116B62 Hal1 from Halomonas sp. NCIMB 172, the genome of which has not yet been sequenced. Hal1 exhibits high levels of expression in a recombinant E. coli host and can be utilised from cell lysate or used in purified form. Hal1 favours NADPH as electron donor and displays a diverse range of activities including hydroxylation, demethylation and sulfoxidation. These properties make Hal1 suitable for future biocatalytic applications or as a template for optimisation through engineering. PMID- 29602382 TI - A simplified method for active-site titration of lipases immobilised on hydrophobic supports. AB - The aim of this work was to develop a simple and accurate protocol to measure the functional active site concentration of lipases immobilised on highly hydrophobic supports. We used the potent lipase inhibitor methyl 4-methylumbelliferyl hexylphosphonate to titrate the active sites of Candida rugosa lipase (CrL) bound to three highly hydrophobic supports: octadecyl methacrylate (C18), divinylbenzene crosslinked methacrylate (DVB) and styrene. The method uses correction curves to take into account the binding of the fluorophore (4 methylumbelliferone, 4-MU) by the support materials. We showed that the uptake of the detection agent by the three supports is not linear relative to the weight of the resin, and that the uptake occurs in an equilibrium that is independent of the total fluorophore concentration. Furthermore, the percentage of bound fluorophore varied among the supports, with 50 mg of C18 and styrene resins binding approximately 64 and 94%, respectively. When the uptake of 4-MU was calculated and corrected for, the total 4-MU released via inhibition (i.e. the concentration of functional lipase active sites) could be determined via a linear relationship between immobilised lipase weight and total inhibition. It was found that the functional active site concentration of immobilised CrL varied greatly among different hydrophobic supports, with 56% for C18, compared with 14% for DVB. The described method is a simple and robust approach to measuring functional active site concentration in immobilised lipase samples. PMID- 29602383 TI - Enantioselective sulfoxidations employing the thermostable cyclohexanone monooxygenase from Thermocrispum municipale. AB - The recently discovered cyclohexanone monooxygenase from Thermocrispum municipale (TmCHMO) was employed in the preparation of different optically active sulfoxides. This novel Baeyer-Villiger monooxygenase (BVMO) shows a similar substrate specificity and selectivity when compared with the prototype CHMO from Acinetobacter calcoaceticus. Interestingly, TmCHMO is able to catalyse the asymmetric sulfoxidations at relatively high temperatures, substrate concentrations and in the presence of organic solvents while maintaining or even increasing its selectivity. This shows that this newly found biocatalyst is a promising catalyst for the synthesis of optically active sulfoxides. PMID- 29602384 TI - Characterization of regioselective flavonoid O-methyltransferase from the Streptomyces sp. KCTC 0041BP. AB - A flavonoid comprises polyphenol compounds with pronounced antiviral, antioxidant, anticarcinogenic, and anti-inflammatory effects. The flavonoid modification by methylation provides a greater stability and improved pharmacokinetic properties. The methyltransferase from plants or microorganisms is responsible for such substrate modifications in a regiospecific or a promiscuous manner. GerMIII, originally characterized as a putative methyltransferase in a dihydrochalcomycin biosynthetic gene cluster of the Streptomyces sp. KCTC 0041BP, was tested for the methylation of the substrates of diverse chemical structures. Among the various tested substrates, flavonoids emerged as the favored substrates for methylation. Further, among the flavonoids, quercetin is the most favorable substrate, followed by luteolin, myricetin, quercetin 3-O-beta-D-glucoside, and fisetin, while only a single product was formed in each case. The products were confirmed by HPLC and mass-spectrometry analyses. A detailed NMR spectrometric analysis of the methylated quercetin and luteolin derivatives confirmed the regiospecific methylation at the 4'-OH position. Modeling and molecular docking provided further insight regarding the most favorable mechanism and substrate architecture for the enzymatic catalysis. Accordingly, a double bond between the C2 and the C3 and a single-ring-appended conjugate-hydroxyl group are crucial for the favorable enzymatic conversions of the GerMIII catalysis. Thus, in this study, the enzymatic properties of GerMIII and a mechanistic overview of the regiospecific modification that was implemented for the acceptance of quercetin as the most favorable substrate are presented. PMID- 29602385 TI - Biochemical characterization and substrate profiling of a reversible 2,3 dihydroxybenzoic acid decarboxylase for biocatalytic Kolbe-Schmitt reaction. AB - Reversible benzoic acid decarboxylases are versatile biocatalysts by taking advantage of both decarboxylation and carboxylation reactions, especially for the biocatalytic Kolbe-Schmitt reaction. In the course of developing a benzoic acid decarboxylase tool-box, a putative benzoic acid decarboxylase gene from Fusarium oxysporum was heterologously over-expressed in Escherichia coli, the recombinant protein was purified and characterized. The purified enzyme exhibited relatively high catalytic efficiencies for the decarboxylation of 2, 3-dihydroxybenzoic acid and carboxylation of catechol (kcat/Km = 2.03 * 102 and 1.88 mM-1 min-1, respectively), and thus characterized as 2, 3-dihydroxybenzoic acid decarboxylase (2, 3-DHBD_Fo). The enzyme also catalyzed the decarboxylation of various substituted salicylic acids with different groups at varied positions except 5 position and the carboxylation of phenol and the substituted phenols. In a preparative reaction, catechol was carboxylated into 2, 3-dihydroxybenoic acid with 95% conversion by adding dodecyldimethylbenzylammonium chloride into the reaction system, and the product was isolated in 72% yield. These results demonstrate that 2, 3-DHBD_Fo is a valuable addition to the benzoic acid decarboxylase tool-box with potential practical applications. PMID- 29602386 TI - Fabrication of an amperometric sarcosine biosensor based on sarcosine oxidase/chitosan/CuNPs/c-MWCNT/Au electrode for detection of prostate cancer. AB - An amperometric sarcosine biosensor was fabricated based on covalent immobilization of sarcosine oxidase (SarOx) onto the nanocomposite of carboxylated multi-walled carbon nanotubes (cMWCNT)/chitosan (CHIT) and copper nanoparticles (CuNPs), electrodeposited on gold (Au) electrode. The SarOx/CHIT/CuNPs/c-MWCNT/Au electrode was characterized by scanning electron microscopy (SEM), electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV). The enzyme electrode exhibited optimum current within 2 s at a potential of 0.2 V against Ag/AgCl, pH 7.0 and 35 degrees C. A linear relationship was obtained between sarcosine concentration in the range, 0.1-100 MUM and current (mA) under optimum conditions. The biosensor exhibited a high sensitivity of 277.5 MUA/MUM/cm2, a low detection limit of 0.1 pM and excellent storage stability (180 days). The analytical recoveries of added sarcosine in sera at 0.5 MUM and at 1.0 MUM concentration were 95.5% and 97.30 respectively. The precision i.e. within and between-batch coefficients of variation (CVs) were 1.08% and 1.70% respectively. There was a good correlation (R2 = 0.99) between the level of sarcosine in sera as measured by the standard immuno kit method and the present biosensor. The biosensor measured sarcosine level in sera of prostate cancer patients, which was significantly higher than those of apparently healthy persons (p value <0.01). PMID- 29602387 TI - Engineering the residues on "A" surface and C-terminal region to improve thermostability of nitrilase. AB - Nitrilases can hydrolyze nitriles to corresponding carboxylic acids in one single step, which have great potential as valuable biocatalysts for chemical synthesis. However, the poor thermostability of the nitrilases restrict their applications in industry. In this work, error-prone PCR and site-directed mutagenesis were utilized to improve the thermostability of nitrilases. Several mutants (AcN Q339K, AcN-Q343K, AcN-T201F, AcN-T201W, AcN-T201L, AcN-T201I) were obtained with dramatically improved thermostability. The best mutant AcN-T201F/Q339K/Q343K exhibited about 14-fold longer half-life at 45 degrees C. The result of homology modeling suggested that the site 201, which was located on the "A" surface (the dimer interaction), played an important role in the oligomerization of nitrilase and the stabilization of substrate binding pocket. The Phe substitution on site 201 was selected in protein engineering of nitrilase LNIT5, which also demonstrated an improvement of thermostability. In addition, lysine substitution on Q339 and Q343 which brought positive charges to the alpha helix in the C terminal region stabilized the surface. PMID- 29602388 TI - Biosynthesis of Pd and Au as nanoparticles by a marine bacterium Bacillus sp. GP and their enhanced catalytic performance using metal oxides for 4-nitrophenol reduction. AB - Recovery of noble metals using marine bacteria is becoming an attractive research area because the marine microbes can better adapt to unfavorable environment than terrestrial microorganisms. In this study, we first reported that a marine Bacillus sp. GP was capable of producing Pd and Au NPs in the presence of sodium lactate. Ultraviolet visible spectrometer (UV-vis), transmission electron microscopy (TEM), X-ray diffraction patterns (XRD), X-ray photoelectron spectroscopy (XPS) and fourier transform infrared spectroscopy (FTIR) analyses were employed to explain the process and mechanism of Pd(II)/Au(III) reduction through GP. Additionally, we also found that bio-Pd/Au NPs could be used as catalysts in chemical reduction of 4-nitrophenol (4-NP). Moreover, the catalytic activity of bio-Pd NPs could be enhanced by Fe3O4, Al2O3 and SiO2, which is beneficial for practical application. The k1 (k2) values of Fe3O4, Al2O3 and SiO2 supplemental systems were approximately 1.28-1.69 (1.15-1.69), 1.42-1.75 (1.53 1.91) and 1.07-1.73 (1.14-1.49) fold, respectively, compared to that of control systems. PMID- 29602389 TI - Improved peroxide biosensor based on Horseradish Peroxidase/Carbon Nanotube on a thiol-modified gold electrode. AB - A new 3-dimensional (3D) network of crosslinked Horseradish Peroxidase/Carbon Nanotube (HRP/CNT) on a thiol-modified Au surface has been described in order to build up the effective electrical wiring of the enzyme units with the electrode. The synthesized 3D HRP/CNT network has been characterized with cyclic voltammetry and amperometry which results the establishment of direct electron transfer between the redox active unit of HRP and the Au surface. Electrochemical measurements reveal that the high biological activity and stability is exhibited by the immobilized HRP and a quasi-reversible redox peak of the redox centre of HRP was observed at about -0.355 and -0.275V vs. Ag/AgCl. The electron transfer rate constant, KS and electron transfer co-efficient alpha were found as 0.57s-1 and 0.42, respectively. Excellent electrocatalytic activity for the reduction of H2O2 was exhibited by the developed biosensor. The proposed biosensor modified with HRP/CNT 3D network displays a broader linear range and a lower detection limit for H2O2 determination. The linear range is from 1.0*10-7 to 1.2*10-4M with a detection limit of 2.2.0*10-8M at 3sigma. The Michaelies-Menten constant Kapp M value is estimated to be 0.19mM. Moreover, this biosensor exhibits very high sensitivity, good reproducibility and long-time stability. PMID- 29602390 TI - The effect of a lytic polysaccharide monooxygenase and a xylanase from Gloeophyllum trabeum on the enzymatic hydrolysis of lignocellulosic residues using a commercial cellulase. AB - Hydrolysis of lignocellulosic biomass depends on the concerted actions of cellulases and accessory proteins. In this work we examined the combined action of two auxiliary proteins from the brown rot fungus Gloeophyllum trabeum: a family AA9 lytic polysaccharide monooxygenase (GtLPMO) and a GH10 xylanase (GtXyn10A). The enzymes were produced in the heterologous host Pichia pastoris. In the presence of an electron source, GtLPMO increased the activity of a commercial cellulase on filter paper, and the xylanase activity of GtXyn10A on beechwood xylan. Mixtures of GtLPMO, GtXyn10A and Celluclast 1.5L were used for hydrolysis of pretreated wheat straw. Results showed that a mixture of 60% Celluclast 1.5L, 20% GtXyn10A and 20% GtLPMO increased total reducing sugar production by 54%, while the conversions of glucan to glucose and xylan to xylose were increased by 40 and 57%, respectively. This suggests that GtLPMO can contribute to lignocellulose hydrolysis, not only by oxidative activity on glycosidic bonds, but also to hemicellulose through the oxidation of xylosyl bonds in xylan. The concerted action of these auxiliary enzymes may significantly improve large-scale recovery of sugars from lignocellulose. PMID- 29602391 TI - A process for production of trehalose by recombinant trehalose synthase and its purification. AB - The process for production of trehalose using trehalose synthase (TreS) to convert maltose into trehalose in one step is highly desirable in the industry. Nonetheless, the studies on industrial-scale production of trehalose by recombinant TreS in Escherichia coli are still scarce. In this study, a TreS from Pseudomonas putida ATCC47054 was expressed in E. coli BL21(DE3) via plasmids pET15b and pET22b. pET15b-treS showed better plasmid stability and TreS expression, which revealed that the highest activity, 39866+/-1420U/(g dry cell weight) at the final lactose concentration of 4g/L for 7h at 27 degrees C in a 5 L fermentor at pH 8.0. The use of 30% (w/v) high-maltose syrup as a substrate can extend the temperature tolerance of TreS to 60 degrees C. More than 64% of maltose can be converted into trehalose by adding 200U of TreS per gram of maltose at 50 degrees C for 24h. The total sugar content of the trehalose syrup reached 95.0%+/-1.0% (w/w) after separation. The recovery rate of trehalose dehydrate reached 57.0%+/-2.0% after slow cooling, and the purity was 99.0+/ 0.2%. Our study revealed a safe and reliable process of trehalose production by recombinant TreS. PMID- 29602393 TI - Mitochondrial Dysfunction and Signaling in Diabetic Kidney Disease: Oxidative Stress and Beyond. AB - The kidneys are highly metabolic organs that produce vast quantities of adenosine triphosphate via oxidative phosphorylation and, as such, contain many mitochondria. Although mitochondrial reactive oxygen species are involved in many physiological processes in the kidneys, there is a plethora of evidence to suggest that excessive production may be a pathologic mediator of many chronic kidney diseases, including diabetic kidney disease. Despite this, results from clinical testing of antioxidant therapies have been generally underwhelming. However, given the many roles of mitochondria in cellular functioning, pathways other than reactive oxygen species production may prevail as pathologic mediators in diabetic kidney disease. Accordingly, in this review, mitochondrial dysfunction in a broader context is discussed, specifically focusing on mitochondrial respiration and oxygen consumption, intrarenal hypoxia, oxidative stress, mitochondrial uncoupling, and networking. PMID- 29602392 TI - Characterisation of novel biomass degradation enzymes from the genome of Cellulomonas fimi. AB - Recent analyses of genome sequences belonging to cellulolytic bacteria have revealed many genes potentially coding for cellulosic biomass degradation enzymes. Annotation of these genes however, is based on few biochemically characterised examples. Here we present a simple strategy based on BioBricks for the rapid screening of candidate genes expressed in Escherichia coli. As proof of principle we identified over 70 putative biomass degrading genes from bacterium Cellulomonas fimi, expressing a subset of these in BioBrick format. Six novel genes showed activity in E. coli. Four interesting enzymes were characterised further. alpha-l-arabinofuranosidase AfsB, beta-xylosidases BxyF and BxyH and multi-functional beta-cellobiosidase/xylosidase XynF were partially purified to determine their optimum pH, temperature and kinetic parameters. One of these enzymes, BxyH, was unexpectedly found to be highly active at strong alkaline pH and at temperatures as high as 100 degrees C. This report demonstrates a simple method of quickly screening and characterising putative genes as BioBricks. PMID- 29602395 TI - The Role of Peroxisome Proliferator-Activated Receptor gamma Coactivator 1alpha (PGC-1alpha) in Kidney Disease. AB - Peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha) is a key transcriptional regulator of mitochondrial biogenesis and function. Several recent studies have evaluated the role of PGC-1alpha in various renal cell types in healthy and disease conditions. Renal tubule cells mostly depend on mitochondrial fatty acid oxidation for energy generation. A decrease in PGC 1alpha expression and fatty acid oxidation is commonly observed in patient samples and mouse models with acute and chronic kidney disease. Conversely, increasing PGC-1alpha expression in renal tubule cells restores energy deficit and has been shown to protect from acute and chronic kidney disease. Other kidney cells, such as podocytes and endothelial cells, are less metabolically active and have a narrow PGC-1alpha tolerance. Increasing PGC-1alpha levels in podocytes induces podocyte proliferation and collapsing glomerulopathy development, while increasing PGC1-alpha in endothelial cells alters endothelial function and causes microangiopathy, thus highlighting the cell-type-specific role of PGC-1alpha in different kidney cells. PMID- 29602394 TI - The Warburg Effect in Diabetic Kidney Disease. AB - Diabetic kidney disease (DKD) is the leading cause of morbidity and mortality in diabetic patients. Defining risk factors for DKD using a reductionist approach has proven challenging. Integrative omics-based systems biology tools have shed new insights in our understanding of DKD and have provided several key breakthroughs for identifying novel predictive and diagnostic biomarkers. In this review, we highlight the role of the Warburg effect in DKD and potential regulating factors such as sphingomyelin, fumarate, and pyruvate kinase muscle isozyme M2 in shifting glucose flux from complete oxidation in mitochondria to the glycolytic pathway and its principal branches. With the development of highly sensitive instruments and more advanced automatic bioinformatics tools, we believe that omics analyses and imaging techniques will focus more on singular cell-level studies, which will allow in-depth understanding of DKD and pave the path for personalized kidney precision medicine. PMID- 29602396 TI - Lipidomics and Biomarker Discovery in Kidney Disease. AB - Technological advances in mass spectrometry-based lipidomic platforms have provided the opportunity for comprehensive profiling of lipids in biological samples and shown alterations in the lipidome that occur in metabolic disorders. A lipidomic approach serves as a powerful tool for biomarker discovery and gaining insight to molecular mechanisms of disease, especially when integrated with other -omics platforms (ie, transcriptomics, proteomics, and metabolomics) in the context of systems biology. In this review, we describe the workflow commonly applied to the conduct of lipidomic studies including important aspects of study design, sample preparation, biomarker identification and quantification, and data processing and analysis, as well as crucial considerations in clinical applications. We also review some recent studies of the application of lipidomic platforms that highlight the potential of lipid biomarkers and add to our understanding of the molecular basis of kidney disease. PMID- 29602397 TI - A Systems-Level View of Renal Metabolomics. AB - The measurement of select circulating metabolites such as creatinine, glucose, and cholesterol are integral to clinical medicine, with implications for diagnosis, prognosis, and treatment. Metabolomics studies in nephrology research seek to build on this paradigm, with the goal to identify novel markers and causal participants in the pathogenesis of kidney disease and its complications. This article reviews three themes pertinent to this goal. Each is rooted in long established principles of human physiology, with recent updates enabled by metabolomics and other tools. First, the kidney has a broad and heterogeneous impact on circulating metabolites, with progressive loss of kidney function resulting in a multitude of small molecule alterations. Second, an increasing number of circulating metabolites have been shown to possess functional roles, in some cases acting as ligands for specific G-protein-coupled receptors. Third, circulating metabolites traffic through varied, and sometimes complex, interorgan circuits. Taken together, these themes emphasize the importance of viewing renal metabolomics at the systems level, recognizing the diverse origins and physiologic effects of blood metabolites. However, how to synthesize these themes and how to establish clinical relevance remain uncertain and will require further investigation. PMID- 29602398 TI - Genome-Wide Association Studies of Metabolite Concentrations (mGWAS): Relevance for Nephrology. AB - Metabolites are small molecules that are intermediates or products of metabolism, many of which are freely filtered by the kidneys. In addition, the kidneys have a central role in metabolite anabolism and catabolism, as well as in active metabolite reabsorption and/or secretion during tubular passage. This review article illustrates how the coupling of genomics and metabolomics in genome-wide association analyses of metabolites can be used to illuminate mechanisms underlying human metabolism, with a special focus on insights relevant to nephrology. First, genetic susceptibility loci for reduced kidney function and chronic kidney disease (CKD) were reviewed systematically for their associations with metabolite concentrations in metabolomics studies of blood and urine. Second, kidney function and CKD-associated metabolites reported from observational studies were interrogated for metabolite-associated genetic variants to generate and discuss complementary insights. Finally, insights originating from the simultaneous study of both blood and urine or by modeling intermetabolite relationships are summarized. We also discuss methodologic questions related to the study of metabolite concentrations in urine as well as among CKD patients. In summary, genome-wide association analyses of metabolites using metabolite concentrations quantified from blood and/or urine are a promising avenue of research to illuminate physiological and pathophysiological functions of the kidney. PMID- 29602399 TI - Metabolomics and Metabolic Reprogramming in Kidney Cancer. AB - Kidney cancer, or renal cell carcinoma (RCC), is a disease of increasing incidence that commonly is seen in the general practice of nephrology. Despite this state of affairs, this fascinating and highly morbid disease frequently is under-represented, or even absent, from the curriculum of nephrologists in training and generally is underemphasized in national nephrology meetings, both scientific as well as clinical. Although classic concepts in cancer research in general had led to the concept that cancer is a disease resulting from mutations in the control of growth-regulating pathways, reinforced by the discovery of oncogenes, more contemporary research, particularly in kidney cancer, has uncovered changes in metabolic pathways mediated by those same genes that control tumor energetics and biosynthesis. This adaptation of classic biochemical pathways to the tumor's advantage has been labeled metabolic reprogramming. For example, in the case of kidney cancer there exists a near-universal presence of von Hippel-Lindau tumor suppressor (pVHL) inactivation in the most common form, clear cell RCC (ccRCC), leading to activation of hypoxia-relevant and other metabolic pathways. Studies of this and other pathways in clear cell RCC (ccRCC) have been particularly revealing, leading to the concept that ccRCC can itself be considered a metabolic disease. For this reason, the relatively new method of metabolomics has become a useful technique in the study of ccRCC to tease out those pathways that have been reprogrammed by the tumor to its maximum survival advantage. Furthermore, identification of the nodes of such pathways can lead to novel areas for drug intervention in a disease for which such targets are seriously lacking. Further research and dissemination of these concepts, likely using omics techniques, will lead to clinical trials of therapeutics specifically targeted to tumor metabolism, rather than those generally toxic to all proliferating cells. Such novel agents are highly likely to be more effective than existing drugs and to have far fewer adverse effects. This review provides a general overview of the technique of metabolomics and then discusses how it and other omics techniques have been used to further our understanding of the basic biology of kidney cancer as well as to identify new therapeutic approaches. PMID- 29602400 TI - Targeting Glucosylceramide Synthesis in the Treatment of Rare and Common Renal Disease. AB - Sphingolipids, including ceramides, glycosphingolipids, sphingomyelin, and sphingosine-1-phosphate, have been recognized as important molecules that regulate critical cellular functions. Although originally studied in the context of lysosomal storage diseases, the roles of these compounds in more common disorders involving metabolism, vascular disease, and aberrant growth has been the focus of recent studies, including in disorders that affect the kidneys. These efforts have led to new insights into Fabry disease, a classic disorder of lysosomal function that results in renal failure as well as in more common renal diseases including diabetic nephropathy and polycystic kidney disease. Pathways for glycosphingolipid synthesis can be targeted with orally available small molecule inhibitors, creating new opportunities for the treatment of both rare and common kidney diseases. PMID- 29602402 TI - Introduction: Systems Biology of Kidney Disease. PMID- 29602403 TI - Diabetes and Hypertension: The Low and High Points. PMID- 29602404 TI - Angiotensin-Converting Enzyme Inhibitors vs. Angiotensin Receptor Blockers for the Treatment of Hypertension in Adults With Type 2 Diabetes: Why We Favour Angiotensin Receptor Blockers. AB - Cardiovascular disease is the principal cause of morbidity and mortality in patients with diabetes mellitus. The incidence or progression of kidney disease is also common in these patients. Several clinical trials have established the efficacy of angiotensin receptor blockers for the prevention of adverse cardiovascular and renal outcomes in this population and are summarized in this review article. Head-to-head comparison of angiotensin receptor blockers with angiotensin-converting enzyme inhibitors has shown similar cardioprotective and renoprotective properties of both medication classes. However, angiotensin receptor blockers have an improved safety profile with fewer episodes of cough and angioedema and may be the agent of choice in patients with diabetes and hypertension. Novel therapeutic strategies, such as those that include a mineralocorticoid receptor blocker or a selective sodium-glucose cotransporter type 2 inhibitor, may further protect patients with diabetes from cardiovascular and renal complications. PMID- 29602401 TI - Contributory Role of Gut Microbiota and Their Metabolites Toward Cardiovascular Complications in Chronic Kidney Disease. AB - The gut microbiome recently has emerged as a novel risk factor that impacts health and disease. Our gut microbiota can function as an endocrine organ through its unique ability to metabolize various dietary precursors, and can fuel the systemic inflammation observed in chronic disease. This is especially important in the setting of chronic kidney disease, in which microbial metabolism can contribute directly to accumulation of circulating toxins that then can alter and shift the balance of microbiota composition and downstream functions. To study this process, advances in -omics technologies are providing opportunities to understand not only the taxonomy, but also the functional diversity of our microbiome. We also reliably can quantify en masse a wide range of uremic byproducts of microbial metabolism. Herein, we examine the bidirectional relationship between the gut microbiome and the failing kidneys. We describe potential approaches targeting gut microbiota for cardiovascular risk reduction in chronic kidney disease using an illustrative example of a novel gut-generated metabolite, trimethylamine N-oxide. PMID- 29602405 TI - Resistant Hypertension in Adults With Type 1 or 2 Diabetes: A Structured Diagnostic Approach. AB - People with diabetes often have difficulty reaching their blood pressure targets and are labelled as having resistant hypertension. Clinicians often move quickly to screen such people for secondary causes of hypertension; however, such causes are rare, and resistant hypertension usually has other explanations that are significantly more common. By using a structured approach to resistant hypertension, clinicians can assist patients to reach their target blood pressure levels. Step 1 is to determine out-of-office blood pressure measurements using home or ambulatory blood pressure monitors. Step 2 is to determine the level of adherence to prescribed medications. Step 3 is to identify interfering substances. Step 4 is to check that the prescribed medications are synergistic and optimally dosed. Finally, if all other steps fail to get patients to their blood pressure targets, we consider possible secondary causes of hypertension. This approach is particularly useful in helping people with diabetes to reach their blood pressure targets. PMID- 29602406 TI - Hypertension in Adults With Type 2 Diabetes: A Review of Blood Pressure Measurement Methods, Targets and Therapy. AB - Hypertension occurs in more than two-thirds of patients with type 2 diabetes. In a retrospective analysis of a Framingham cohort, high blood pressure was associated with a 72% increase in the risk for all-cause death and a 57% increment in the risk for any cardiovascular disease event, making hypertension the strongest driver of cardiovascular outcomes in individuals with diabetes. One of the key aspects of hypertension management is the correct measurement of blood pressure; various types of monitoring in both clinic and ambulatory settings are reviewed here. Their benefits and challenges are presented along with the resources available to support clinicians and patients in better understanding and using the monitors. Specific phenotypes, such as white-coat hypertension and masked hypertension, are also addressed. This review outlines major trials that set systolic and diastolic blood pressure thresholds for patients with diabetes and hypertension. Optimal antihypertensive therapies are described in studies supporting these recommendations. PMID- 29602407 TI - Nonpharmacological Interventions in the Management of Hypertension in the Adult Population With Type 2 Diabetes Mellitus. AB - This review discusses nonpharmacological interventions for the management of hypertension in people with diabetes. Interventions that focus on controlling weight, reducing salt intake, eating according to the Dietary Approaches to Stop Hypertension guidelines, partaking in regular physical activity, ceasing smoking and self-measuring of blood pressure can lower blood pressure in the population with diabetes. Other positive outcomes resulting from these lifestyle changes are improved glycemia levels and cardiac function and reduction in overall cardiovascular risk. PMID- 29602408 TI - An Update on Hypertension in Children With Type 1 Diabetes. AB - The prevalence of hypertension in children with type 1 diabetes is reported to be between 6% and 16%. This potentially modifiable cardiovascular risk factor may go undiagnosed and undertreated, particularly in children with type 1 diabetes. Recent updated Canadian clinical practice guidelines recommend blood pressure screening every 2 years in children with type 1 diabetes as well as routine use of ambulatory blood pressure monitoring. Risk factors for hypertension in type 1 diabetes include poor glycemic control, overweight and obesity and genetic predisposition for hypertension. In terms of pathophysiology, sustained hyperglycemia, angiotensin I and II and inflammatory cytokines have been implicated. Endothelial and vascular dysfunction, with impaired endothelial dependent vasodilation and increased carotid artery intima-media thickness, are evident in preclinical and clinical studies of children and not just in adults with type 1 diabetes. Early targeted therapy is critical to the control of hypertension and the development of related morbidity. As with hypertension in adults with type 1 diabetes, lifestyle modifications remain first-line therapy, including diet and glycemic control. Initial antihypertensive therapy should be an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker because of their associated effects of reducing microalbuminuria and improving renovascular outcomes. Pediatric hypertension in type 1 diabetes is an area of evolving study and opinion; identification and appropriate treatment is critical for the prevention of micro- and macrovascular complications in adulthood. PMID- 29602410 TI - Editorial. PMID- 29602409 TI - Single-Pill Combinations in the Treatment of Hypertension in Adults: Beyond Convenience. AB - Adequate blood pressure control in patients with hypertension remains the pillar of cardiovascular-event prevention. Smoking cessation, reduced dietary salt intake, physical exercise and weight loss contribute to better blood pressure control and reduced cardiovascular morbidity, but alone, they are often insufficient in doing so, and their success is highly dependent on individual patient motivation. Pharmacologic therapy, thus, remains necessary for most patients, and our conception of the optimal way of approaching this therapy has evolved over the past decade. Traditionally, monotherapy using a first-line drug was initiated and uptitrated, with the addition of other antihypertensive agents as needed. The latest Hypertension Canada guidelines, however, now recommend first-line treatment with single-pill combinations in patients without compelling indications for treatment. In this review, we discuss the evidence behind this recommendation and how single-pill combinations can improve patient care. PMID- 29602411 TI - High proportion of patients referred to a psychosomatic dental clinic owing to atypical odontalgia had psychiatric comorbidities, but these seemed to not be associated with pain levels. PMID- 29602412 TI - Longevity of gold cast inlays and onlays is probably associated with patients' age and number of tooth surfaces covered. PMID- 29602413 TI - Zirconia-based and metal-based single posterior crowns probably have similar clinical outcomes after 5 years. PMID- 29602414 TI - Foraminal enlargement of necrotic teeth is associated with higher levels of postoperative pain. PMID- 29602415 TI - BiOX (X = Cl, Br, I) photocatalytic nanomaterials: Applications for fuels and environmental management. AB - Energy and environmental issues are the major concerns in our contemporary "risk society". As a green technique, photocatalysis has been identified as a promising solution for above-mentioned problems. In recent decade, BiOX (X = Cl, Br, I) photocatalytic nanomaterials have sparked numerous interest as economical and efficient photocatalysts for energy conversion and environmental management. The distinctive physicochemical properties of BiOX nanomaterials, especially their energy band structures and levels as well as relaxed layered nanostructures, should be responsible for the visible-light-driven photocatalytic performance improvement, which could be utilized in dealing with the global energy and environmental challenges. In this review, recent advances for the enhancement of BiOX photocatalytic activity are detailedly summarized. Furthermore, the applications of BiOX photocatalysts in water splitting and refractory organic pollutants removal are highlighted to offer guidelines for better development in photocatalysis. Particularly, no relative reports in previous studies were documented in CO2 reduction as well as heavy metals and air pollutants removal, thus this review presented as a considerable research value. Challenges in the construction of high-performance BiOX-based photocatalytic systems are also discussed. With the exponential growth of studies on BiOX photocatalytic nanomaterials, this review provides unique and comprehensive perspectives to design BiOX-based photocatalytic systems with superior visible light photocatalytic activity. The knowledge of both the merits and demerits of BiOX photocatalysts are updated and provided as a reference. PMID- 29602416 TI - Cutaneous Rosai-Dorfman Disease: A Novel Clinical Presentation. PMID- 29602417 TI - Dermatitis of the Face and Neck: Response to Itraconazole. PMID- 29602418 TI - Nonexercise Estimated Cardiorespiratory Fitness and All-Cancer Mortality: the NHANES III Study. AB - OBJECTIVE: To examine the relationship between estimated cardiorespiratory fitness (eCRF) using nonexercise equations and all-cancer mortality in a representative sample of the US population. PARTICIPANTS AND METHODS: A total of 8506 study participants were derived from the Third National Health and Nutrition Examination Survey, conducted from October 18, 1988, to October 15, 1994. They were followed for all-cancer mortality. Participants' CRF was estimated from nonexercise models that were determined by age, body mass index, waist circumference, resting heart rate, physical activity status, and smoking status, and further grouped into quintiles. Hazard ratios (HRs) and 95% CIs were calculated from Cox proportional hazards models for the relationship between eCRF and all-cancer mortality. RESULTS: During a mean of 19.5 years of follow-up, 455 cancer deaths (263 men and 192 women) were registered. After adjustment for race/ethnicity, age, educational level, current smoking, hypertension, diabetes mellitus, and hypercholesterolemia, each 1-metabolic equivalent increase in eCRF was associated with 30% (95% CI, 24%-35%) and 27% (95% CI, 18%-36%) risk reduction for all-cancer mortality in men and women, respectively. When eCRF was categorized into quintiles, HRs (95% CIs) were 0.47 (0.24-0.95), 0.81 (0.46 1.44), 0.49 (0.26-0.93), and 0.57 (0.31-1.06) across incremental quintiles in women (quintile 1 was the reference group). However, none of the HRs reached statistical significance in men. CONCLUSION: The eCRF was inversely associated with all-cancer mortality in quintiles 2 and 4 in women. More research is needed to further understand the association between eCRF and all-cancer mortality in men. PMID- 29602419 TI - Do not miss the bridge. PMID- 29602420 TI - Albumin (but not Alvin) and the chipmunks help protect our brain! PMID- 29602421 TI - Resource use in neonatal cardiac surgery: Lacking details. PMID- 29602422 TI - Another win for multiarterial bypass grafting: What's next? PMID- 29602423 TI - Valve-sparing root surgery in congenital heart disease-Shoulda, coulda.... PMID- 29602424 TI - The father of coronary artery bypass grafting: Rene Favaloro and the 50th anniversary of coronary artery bypass grafting. PMID- 29602425 TI - Every breath you take: The value of the electronic nose (e-nose) technology in the early detection of lung cancer. PMID- 29602426 TI - Use of Berlin Heart ventricular assist devices as a total artificial heart. PMID- 29602427 TI - Erratum. PMID- 29602428 TI - Diagnostic concordance between mobile interfaces and conventional workstations for emergency imaging assessment. AB - INTRODUCTION: Mobile devices and software are now available with sufficient computing power, speed and complexity to allow for real-time interpretation of radiology exams. In this paper, we perform a multivariable user study that investigates concordance of image-based diagnoses provided using mobile devices on the one hand and conventional workstations on the other hand. METHODS: We performed a between-subjects task-analysis using CT, MRI and radiography datasets. Moreover, we investigated the adequacy of the screen size, image quality, usability and the availability of the tools necessary for the analysis. Radiologists, members of several teams, participated in the experiment under real work conditions. A total of 64 studies with 93 main diagnoses were analyzed. RESULTS: Our results showed that 56 cases were classified with complete concordance (87.69%), 5 cases with almost complete concordance (7.69%) and 1 case (1.56%) with partial concordance. Only 2 studies presented discordance between the reports (3.07%). The main reason to explain the cause of those disagreements was the lack of multiplanar reconstruction tool in the mobile viewer. Screen size and image quality had no direct impact on the mobile diagnosis process. CONCLUSION: We concluded that for images from emergency modalities, a mobile interface provides accurate interpretation and swift response, which could benefit patients' healthcare. PMID- 29602429 TI - Integrating electronic healthcare records of armed forces personnel: Developing a framework for evaluating health outcomes in England, Scotland and Wales. AB - BACKGROUND: Electronic Healthcare Records (EHRs) are created to capture summaries of care and contact made to healthcare services. EHRs offer a means to analyse admissions to hospitals for epidemiological research. In the United Kingdom (UK), England, Scotland and Wales maintain separate data stores, which are administered and managed exclusively by devolved Government. This independence results in harmonisation challenges, not least lack of uniformity, making it difficult to evaluate care, diagnoses and treatment across the UK. To overcome this lack of uniformity, it is important to develop methods to integrate EHRs to provide a multi-nation dataset of health. OBJECTIVE: To develop and describe a method which integrates the EHRs of Armed Forces personnel in England, Scotland and Wales based on variable commonality to produce a multi-nation dataset of secondary health care. METHODS: An Armed Forces cohort was used to extract and integrate three EHR datasets, using commonality as the linkage point. This was achieved by evaluating and combining variables which shared the same characteristics. EHRs representing Accident and Emergency (A&E), Admitted Patient Care (APC) and Outpatient care were combined to create a patient-level history spanning three nations. Patient-level EHRs were examined to ascertain admission differences, common diagnoses and record completeness. RESULTS: A total of 6,336 Armed Forces personnel were matched, of which 5,460 personnel had 7,510 A&E visits, 9,316 APC episodes and 45,005 Outpatient appointments. We observed full completeness for diagnoses in APC, whereas Outpatient admissions were sparsely coded; with 88% of diagnoses coded as "Unknown/unspecified cause of morbidity". In addition, A&E records were sporadically coded; we found five coding systems for identifying reason for admission. CONCLUSION: At present, EHRs are designed to monitor the cost of treatment, enable administrative oversight, and are not currently suited to epidemiological research. However, only small changes may be needed to take advantage of what should be a highly cost-effective means of delivering important research for the benefit of the NHS. PMID- 29602430 TI - Feasibility of mobile health game "Fume" in supporting tobacco-related health literacy among early adolescents: A three-armed cluster randomized design. AB - OBJECTIVE: New interventions supporting health literacy and a tobacco-free lifestyle in adolescence are needed to narrow the widening gap in existing health inequalities. Health games offer potential and could be utilized for example in school healthcare, but more research is needed to increase the understanding of the effects of game elements in health interventions. The aim of this feasibility study is to determine the short-term effectiveness of the tobacco-related mobile health game Fume and a non-gamified website in comparison with a no-intervention control group, regarding tobacco-related health literacy among 10-13-year-old early adolescents. In addition, we compare the demand for and acceptability of Fume to that of the website. METHODS: In total, 151 early adolescents participated in this single-blinded, three-armed cluster randomized trial. The participants from three municipalities in southwest Finland were randomly allocated between a group with access to the health game Fume (n = 61), a group with access to the website (n = 47), and a group with no intervention (n = 43). The intervention groups first participated in a 20-min training session with Fume/the website, and then had two weeks to use Fume/the website based on their own interest. Short-term effectiveness was measured by primary (anti-smoking self efficacy) and secondary (smoking outcome expectations, attitudes towards tobacco use, tobacco-use motives, motivation to decline tobacco use in the future, and knowledge about tobacco) outcomes derived from the theory-based determinants of tobacco-related health literacy and evaluated with self-assessment questionnaires at baseline and post-intervention (after a two-week follow-up). For evaluating the demand, the actual use of Fume/the website was tracked during the two-week period. Regarding acceptability, the raised interest towards Fume/the website and opinions about the interventions were evaluated post-intervention. Differences were tested with the McNemar, Fisher exact, and non-parametric tests. RESULTS: Statistically significant favorable changes during the study period were found for positive (P = 0.002) and negative (P = 0.02) smoking outcome expectations and attitudes towards cigarette smoking (P = 0.01) within the group using Fume. No statistically significant changes were detected within the website or control groups. Statistically significant differences were not found for the change in outcome variables among the three groups. The number of visits (P < 0.001), number of separate visit days (P < 0.001) and total duration of use (P < 0.001) were larger for the group using Fume than for that using the website. Fume sparked more interest in early adolescents than the website did (P < 0.001). There were no statistically significant differences in opinions about Fume and those regarding the website. CONCLUSIONS: The intervention with embedded game elements, the health game Fume, was found to be more feasible as a tobacco related health education intervention than the non-gamified website among early adolescents in light of demand and acceptability (raised interest). Even though no change in anti-smoking self-efficacy was found, the results of this feasibility study demonstrated favorable short-term changes with Fume in some other theory-based determinants of tobacco-related health literacy. PMID- 29602431 TI - Evaluating the usability of speech recognition to create clinical documentation using a commercial electronic health record. AB - OBJECTIVE: To conduct a usability study exploring the value of using speech recognition (SR) for clinical documentation tasks within an electronic health record (EHR) system. METHODS: Thirty-five emergency department clinicians completed a system usability scale (SUS) questionnaire. The study was undertaken after participants undertook randomly allocated clinical documentation tasks using keyboard and mouse (KBM) or SR. SUS scores were analyzed and the results with KBM were compared to SR results. RESULTS: Significant difference in SUS scores between EHR system use with and without SR were observed (KBM 67, SR 61; P = 0.045; CI, 0.1 to 12.0). Nineteen of 35 participants scored higher for EHR with KBM, 11 higher for EHR with SR and 5 gave the same score for both. Factor analysis showed no significant difference in scores for the sub-element of usability (EHR with KBM 65, EHR with SR 62; P = 0.255; CI, -2.6 to 9.5). Scores for the sub-element of learnability were significantly different (KBM 72, SR 55; P < 0.001; CI, 9.8 to 23.5). A significant correlation was found between the perceived usability of the two system configurations (EHR with KBM or SR) and the efficiency of documentation (time to document) (P = 0.002; CI, 10.5 to -0.1) but not with safety (number of errors) (P = 0.90; CI, -2.3 to 2.6). DISCUSSION: SR was associated with significantly reduced overall usability scores, even though it is often positioned as ease of use technology. SR was perceived to impose larger costs in terms of learnability via training and support requirements for EHR based documentation when compared to using KBM. Lower usability scores were significantly associated with longer documentation times. CONCLUSION: The usability of EHR systems with any input modality is an area that requires continued development. The addition of an SR component to an EHR system may cause a significant reduction in terms of perceived usability by clinicians. PMID- 29602433 TI - Improving resident's skills in the management of circulatory shock with a knowledge-based e-learning tool. AB - BACKGROUND: Correct clinical management of circulatory shock in emergency departments (ER) and intensive care units (ICU) is critical. In this context, the transmission of professional skills by means of the practical supervision of real cases at the point of care entails important issues that can be widely overcome with the use of computer knowledge-based e-learning tools. OBJECTIVE: Shock Instructor is a web-based e-learning tool implementing the already tested training program model (TPM) that uses a knowledge base about the evidence found in the clinical practice guidelines about seven types of shock. This tool is expected to reduce the learning times and to improve the skills of hospital residents with regard to both the correct application of the guidelines and patient recovery, suppressing the risks of direct interventions. METHODS: Shock Instructor has been used to train residents in the Emergency Department of the Hospital Clinic de Barcelona (Spain) in order to reduce the learning cycle without affecting quality. A case-base with the description of 51 cases with shock and a knowledge-base with 137 clinical rules about the treatment of shock were incorporated to the Shock-Instructor system. A group of 33 residents was involved in a randomized controlled trial to check whether the use of Shock Instructor can significantly improve the skills of clinicians after one week of problem-based training. RESULTS: No significant differences were found in the skill levels of the intervention (IG) and control (CG) groups prior to learning. However, we observed an improvement of the IG clinicians capacity to stabilize patients with shock in better clinical conditions (5% improvement, p = 0.004), and to reduce the risk of death in 19.52% (p = 0.004), after training. First-year residents in IG enhanced 14.3% their sensitivity in the correct application of guidelines (p = 0.01), and 14.9% the mean survival rate of their patients (p = 0.01), after being trained with Shock-Instructor for a week. Residents with specialties different from ER and ICU enhanced 16.1% their application of guidelines (p = 0.04), and 14.5% the survival rate of the cases attended (p = 0.01). CONCLUSIONS: Web-oriented knowledge-based e-learning computer tools such as Shock-Instructor can significantly reduce the learning time of ER and ICU residents, while enhancing their assimilation of evidence-based medicine and both the survival rate and health condition of patients with shock. PMID- 29602432 TI - Health literacy and patient web portals. AB - OBJECTIVES: There is limited evidence about the association between health literacy and use of patient web portals in patients with chronic illnesses. The objective of this review was to learn more about health literacy and use of patient web portals. METHODS: Bibliographic searches were conducted in PubMed and CINAHL using relevant MeSH search terms and Boolean algebra commands. RESULTS: Qualitative studies and studies with a cross-sectional, cohort, or pre-/post-test design have shown that persons with limited health literacy are less likely to use patient web portals, although there is inconsistency in the association across studies. CONCLUSIONS: The conflicting findings may be partially due to racial and ethnic differences in health literacy or level of comfort in sharing private health information using mobile technologies. Several opportunities exist to improve the usability and acceptability of web portals for patients with limited health literacy including enhancements in the design of the portals, patient and provider education and training, and engagement of proxies such as caregivers and close family members. PMID- 29602434 TI - Clinical decision support tool for Co-management signalling. AB - INTRODUCTION: Co-management between internists and surgeons of selected patients is becoming one of the pillars of modern clinical management in large hospitals. Defining the patients to be co-managed is essential. The aim of this study is to create a decision tool using real-world patient data collected in the preoperative period, to support the decision on which patients should have the co management service offered. METHODS: Data was collected from the electronic clinical health records of patients who had an International Classification of Diseases, 9th edition (ICD-9) code of colorectal surgery during the period between January 2012 and October 2014 in a 200 bed private teaching hospital in Lisbon. ICD-9 codes of colorectal surgery [48.5 and 48.6 (anterior rectal resection and abdominoperineal resection), 45.7 (partial colectomy), 45.8 (Total Colectomy), and 45.9 (Bowel Anastomosis)] were used. Only patients above 18 years old were considered. Patients with more than one procedure were excluded from the study. From these data the authors investigated the construction of predictive models using logistic regression and Takagi-Sugeno fuzzy modelling. RESULTS: Data contains information obtained from the clinical records of a cohort of 344 adult patients. Data from 398 emergent and elective surgeries were collected, from which 54 were excluded because they were second procedures for the same patients. Four preoperative variables were identified as being the most predictive of co management, in multivariable regression analysis. The final model performed well after being internally validated (0.81 AUC, 77% accuracy, 74% sensitivity, 78% specificity, 93% negative predictive value). The results indicate that the decision process can be more objective and potentially automated. CONCLUSIONS: The authors developed a prediction model based on preoperative characteristics, in order to support the decision for the co-management of surgical patients in the postoperative ward setting. The model is a simple bedside decision tool that uses only four numerical variables. PMID- 29602436 TI - Assessing mobile health applications with twitter analytics. AB - INTRODUCTION: Advancement in the field of information technology and rise in the use of Internet has changed the lives of people by enabling various services online. In recent times, healthcare sector which faces its service delivery challenges started promoting and using mobile health applications with the intention of cutting down the cost making it accessible and affordable to the people. OBJECTIVES: The objective of the study is to perform sentiment analysis using the Twitter data which measures the perception and use of various mobile health applications among the citizens. METHODS: The methodology followed in this research is qualitative with the data extracted from a social networking site "Twitter" through a tool RStudio. This tool with the help of Twitter Application Programming Interface requested one thousand tweets each for four different phrases of mobile health applications (apps) such as "fitness app", "diabetes app", "meditation app", and "cancer app". Depending on the tweets, sentiment analysis was carried out, and its polarity and emotions were measured. RESULTS: Except for cancer app there exists a positive polarity towards the fitness, diabetes, and meditation apps among the users. Following a system thinking approach for our results, this paper also explains the causal relationships between the accessibility and acceptability of mobile health applications which helps the healthcare facility and the application developers in understanding and analyzing the dynamics involved the adopting a new system or modifying an existing one. PMID- 29602435 TI - Physician nurse care: A new use of UMLS to measure professional contribution: Are we talking about the same patient a new graph matching algorithm? AB - BACKGROUND: Physician and nurses have worked together for generations; however, their language and training are vastly different; comparing and contrasting their work and their joint impact on patient outcomes is difficult in light of this difference. At the same time, the EHR only includes the physician perspective via the physician-authored discharge summary, but not nurse documentation. Prior research in this area has focused on collaboration and the usage of similar terminology. OBJECTIVE: The objective of the study is to gain insight into interprofessional care by developing a computational metric to identify similarities, related concepts and differences in physician and nurse work. METHODS: 58 physician discharge summaries and the corresponding nurse plans of care were transformed into Unified Medical Language System (UMLS) Concept Unique Identifiers (CUIs). MedLEE, a Natural Language Processing (NLP) program, extracted "physician terms" from free-text physician summaries. The nursing plans of care were constructed using the HANDS(c) nursing documentation software. HANDS(c) utilizes structured terminologies: nursing diagnosis (NANDA-I), outcomes (NOC), and interventions (NIC) to create "nursing terms". The physician's and nurse's terms were compared using the UMLS network for relatedness, overlaying the physician and nurse terms for comparison. Our overarching goal is to provide insight into the care, by innovatively applying graph algorithms to the UMLS network. We reveal the relationships between the care provided by each professional that is specific to the patient level. RESULTS: We found that only 26% of patients had synonyms (identical UMLS CUIs) between the two professions' documentation. On average, physicians' discharge summaries contain 27 terms and nurses' documentation, 18. Traversing the UMLS network, we found an average of 4 terms related (distance less than 2) between the professions, leaving most concepts as unrelated between nurse and physician care. CONCLUSION: Our hypothesis that physician's and nurse's practice domains are markedly different is supported by the preliminary, quantitative evidence we found. Leveraging the UMLS network and graph traversal algorithms, allows us to compare and contrast nursing and physician care on a single patient, enabling a more complete picture of patient care. We can differentiate professional contributions to patient outcomes and related and divergent concepts by each profession. PMID- 29602437 TI - A computer vision-based system for monitoring Vojta therapy. AB - A neurological illness is t he disorder in human nervous system that can result in various diseases including the motor disabilities. Neurological disorders may affect the motor neurons, which are associated with skeletal muscles and control the body movement. Consequently, they introduce some diseases in the human e.g. cerebral palsy, spinal scoliosis, peripheral paralysis of arms/legs, hip joint dysplasia and various myopathies. Vojta therapy is considered a useful technique to treat the motor disabilities. In Vojta therapy, a specific stimulation is given to the patient's body to perform certain reflexive pattern movements which the patient is unable to perform in a normal manner. The repetition of stimulation ultimately brings forth the previously blocked connections between the spinal cord and the brain. After few therapy sessions, the patient can perform these movements without external stimulation. In this paper, we propose a computer vision-based system to monitor the correct movements of the patient during the therapy treatment using the RGBD data. The proposed framework works in three steps. In the first step, patient's body is automatically detected and segmented and two novel techniques are proposed for this purpose. In the second step, a multi-dimensional feature vector is computed to define various movements of patient's body during the therapy. In the final step, a multi-class support vector machine is used to classify these movements. The experimental evaluation carried out on the large captured dataset shows that the proposed system is highly useful in monitoring the patient's body movements during Vojta therapy. PMID- 29602438 TI - Physicians' perceptions of the impact of the EHR on the collection and retrieval of psychosocial information in outpatient diabetes care. AB - BACKGROUND: Psychosocial information informs clinical decisions by providing crucial context for patients' barriers to recommended self-care; this is especially important in outpatient diabetes care because outcomes are largely dependent upon self-care behavior. Little is known about provider perceptions of use of psychosocial information. Further, while EHRs have dramatically changed how providers interact with patient health information, the EHRs' role in collection and retrieval of psychosocial information is not understood. METHODS: We designed a qualitative study. We used semi-structured interviews to investigate physicians' (N = 17) perspectives on the impact of EHR for psychosocial information use for outpatient Type II diabetes care decisions. We selected the constant comparative method to analyze the data. FINDINGS: Psychosocial information is perceived as dissimilar from other clinical information such as HbA1c and prescribed medications. Its narrative form conveys the patient's story, which elucidates barriers to following self-care recommendations. The narrative is abstract, and requires interpretation of patterns. Psychosocial information is also circumstantial; hence, the patients' context determines influence on self-care. Furthermore, EHRs can impair the collection of psychosocial information because the designs of EHR tools make it difficult to document, search for, and retrieve it. Templates do not enable users from collecting the patient's 'story', and using free text fields is time consuming. Providers therefore had low use of, and confidence in, the accuracy of psychosocial information in the EHR. PRINCIPAL CONCLUSIONS: Workflows and EHR tools should be re-designed to better support psychosocial information collection and retrieval. Tools should enable recording and summarization of the patient's story, and the rationale for treatment decisions. PMID- 29602439 TI - Foreword. PMID- 29602440 TI - Circadian Distribution of Acute Myocardial Infarction in Different Age Groups. AB - Many epidemiologic studies reported a morning peak in the incidence of acute myocardial infarction (AMI). However, clinical outcomes and the relation between age distribution and circadian pattern have not been fully investigated in a large number of patients. Our study aimed to clarify the impacts of onset time in circadian variation on incidence and clinical outcomes of AMI according to age. From the Korea Acute Myocardial Infarction Registry, we gathered data of 20,685 patients from 53 centers in Republic of Korea. Data from a total of 19,915 patients (11,339 ST elevation myocardial infarction, 8,576 non-ST elevation myocardial infarction) were analyzed from the registry, after exclusion of diagnoses other than AMI. A morning-dominant incidence was shown by sinusoidal function, in all patients and in all separate age groups (age < 55, 55 <= age < 75, 75 <= age). In-hospital mortality and major adverse cardiovascular events (MACEs), including cardiac deaths, noncardiac deaths, recurrent myocardial infarction, repeated percutaneous coronary intervention, and coronary artery bypass graft at 1, 12, and 24 months' follow-up, were compared in 4 periods (00:00~05:59, 06:00~11:59, 12:00~17:59, and 18:00~23:59), and no significant difference was noted. Kaplan-Meier curve was drawn for death and MACE-free survival, and no significant different event-free survival was depicted (p value = 0.31). In conclusion, the incidences of myocardial infarction by onset time were uneven in 24 hours, in all patients and age groups, by sinusoidal function. However, there were no significant differences in in-hospital mortality or MACEs in the 4 time periods during 24 months of follow-up. PMID- 29602441 TI - Relation of Perceived Health Competence to Physical Activity in Patients With Coronary Heart Disease. AB - Physical inactivity is highly associated with mortality, especially in patients with coronary heart disease. We evaluated the effect of perceived health competence, a patient's belief in his or her ability to achieve health-related goals, on cumulative physical activity levels in the Mid-South Coronary Heart Disease Cohort Study. The Mid-South Coronary Heart Disease Cohort Study consists of 2,587 outpatients (32% were female) with coronary heart disease at an academic medical center network in the United States. Cumulative physical activity was quantified in metabolic equivalent (MET)-minutes per week with the International Physical Activity Questionnaire. We investigated associations between the 2-item Perceived Health Competence Scale (PHCS-2) and MET-minutes/week after adjusting for co-morbidities and psychosocial factors with linear regression. Nearly half of participants (47%) exhibited low physical activity levels (<600 MET minutes/week). Perceived health competence was highly associated with physical activity after multivariable adjustment. A nonlinear relation was observed, with the strongest effect on physical activity occurring at lower levels of perceived health competence. There was effect modification by gender (p = 0.03 for interaction). The relation between perceived health competence and physical activity was stronger in women compared with men; an increase in the PHCS-2 from 3 to 4 was associated with a 73% increase in MET-minutes/week in women (95% confidence interval 43% to 109%, p <0.0001) compared with a 53% increase in men (95% confidence interval 27% to 84%, p <0.0001). In conclusion, low perceived health competence was strongly associated with less physical activity in patients with coronary heart disease and may represent a potential target for behavioral interventions. PMID- 29602442 TI - [Tropical endomyocardial fibrosis: Perspectives]. AB - Tropical endomyocardial fibrosis (FET) is a leading cause of heart failure and the most common restrictive cardiomyopathy worldwide. Extensive fibrosis of the ventricular endocardium causing architectural distortion, impaired filling and valvular insufficiency define the disease. Confined to peculiar and limited geographical areas, the aetiology remains blurred and it carries a grim prognosis. The changing burden reported recently in some endemic areas and the refinement of diagnostic tools have emphasized alternative routes for understanding and treatment of the disease. PMID- 29602443 TI - [Resistance to vitamin K antagonist revealing interaction with soy lecithin]. AB - Vitamin K antagonists (VKA) are difficult to use because of a narrow therapeutic index and of a marked inter- and intra-individual variability among patients in the required dosage. This drug may interact with many other drugs and same with certain food compounds. We report the case of potential interaction between soy lecithin and Vitamin K antagonists in a 46 years-old woman. Subtherapeutic INR values were detected despite the increase gradually in dose and replacing acenocoumarol by fluindione. An enquiry of pharmacovigilance was conducted found the consumption of soy lecithin capsules. Fifteen days after its stopping, the INR values have really increased. Clinicians should think to the possibility of interaction between oral anticoagulants and food supplement that is increasingly used. PMID- 29602445 TI - Galectins: Multitask signaling molecules linking fibroblast, endothelial and immune cell programs in the tumor microenvironment. AB - Tumor cells corrupt surrounding normal cells instructing them to support proliferative, pro-angiogenic and immunosuppressive networks that favor tumorigenesis and metastasis. This dynamic cross-talk is sustained by a range of intracellular signals and extracellular mediators produced by both tumoral and non-tumoral cells. Galectins -whether secreted or intracellularly expressed- play central roles in the tumorigenic process by delivering regulatory signals that contribute to reprogram fibroblasts, endothelial and immune cell programs. Through glycosylation-dependent or independent mechanisms, these endogenous lectins control a variety of cellular events leading to tumor cell proliferation, survival, migration, inflammation, angiogenesis and immune escape. Here we discuss the role of galectin-driven pathways, particularly those activated in non tumoral stromal cells, in modulating tumor progression. PMID- 29602444 TI - Tromboc@t Working Group recommendations for management in patients receiving direct oral anticoagulants. AB - BACKGROUND AND OBJECTIVES: In recent years, direct oral anticoagulants (DOACs) have become an alternative to vitamin K antagonists (VKA) for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (NVAF) as well as for prevention and treatment of deep venous thrombosis. Pivotal trials have demonstrated non-inferiority and potential superiority compared to warfarin, which increases the options of anticoagulant treatment. In our setting, the Anticoagulant Treatment Units (ATUs) and Primary Care Centres (PCCs) play an important role in the education, follow-up, adherence control and management in special situations of anticoagulated patients. These considerations have motivated us to elaborate the present consensus document that aims to establish clear recommendations that incorporate the findings of scientific research into clinical practice to improve the quality of care in the field of anticoagulation. MATERIAL AND METHODS: A group of experts from the Catalan Thrombosis Group (TROMBOC@T) reviewed all published literature from 2009 to 2016, in order to provide recommendations based on clinical evidence. RESULTS: As a result of the project, a set of practical recommendations have been established that will facilitate treatment, education, follow-up and management in special situations of anticoagulated patients with ACODs. CONCLUSIONS: Progressive increase in the use of DOACs calls for measures to establish and homogenise clinical management guidelines for patients anticoagulated with DOACs in ATUs and PCCs. PMID- 29602446 TI - Margo McCaffery: Resolute and Visionary. PMID- 29602447 TI - Use of tocilizumab in systemic sclerosis: A brief literature review. AB - The available treatments for systemic sclerosis (SS) have limited effectiveness. Treatment with tocilizumab (TCZ), a biological drug that inhibits interleukin 6 (IL-6), has recently been proposed. In this study, we conducted a literature review to assess the safety and efficacy of TCZ in SS. We found 52 articles, 10 of which we selected after evaluating the articles. In a randomised clinical trial, TCZ showed a nonsignificant improvement in the degree of skin induration, while another observational study showed neutral results. In this same clinical trial, the functional respiratory parameters showed a certain degree of stabilization. The safety profile of TCZ is acceptable; however, the current evidence regarding treatment of SS with TCZ is highly limited, although the drug could have a beneficial effect in skin disorder. New clinical trials are needed to determine the usefulness of TCZ in SS. PMID- 29602448 TI - Reducing toxic stress experienced by children living in poverty. PMID- 29602449 TI - Moving ahead with the transition to the doctor of nursing practice. PMID- 29602450 TI - Impact of environmental adaptation on tear film assessments. AB - PURPOSE: The purpose of this study was to investigate the effect of ocular environmental adaptation on clinical tear film assessment. METHOD: Thirty subjects (male, mean age 23+/-2.5) participated in this study. A number of clinical tear film tests were applied, including: fluorescein tear break-up time (FTBUT), Schirmer test and tear prism height test (TPH). The tear physiology of each subject was evaluated twice, once immediately when they arrived from the external environment, and then after 30minutes adaptation in the exam room environment. RESULTS: The mean values were: Schirmer test A (22.1+/-2.99), Schirmer test B (24.2+/-2.63), FTBUT A (8.00+/-1.94), FTBUT B (9.13+/-2.04), TPH A (0.179+/-0.026) and TPH B* (0.187+/-0.023). Statistical testing using Wilcoxon signed rank test showed a significant difference between the Schirmer test results measured at the different times (P=0.008). Also, the FTBUT and tear prism height test results showed significant differences between the two evaluation times, (P=0.001, 0.011, respectively) (A: tear assessed when the subject comes from the outside environment, B: tear film assessed after 30min adaptation in the clinical environment). CONCLUSION: This study showed a significant difference between the tear film test results evaluated when the subjects were assessed immediately from the outside environment and after an adaptation time in the clinic environment. Practitioners must consider the effect of differences between external and clinical environment adaptation on clinical tear film physiology. PMID- 29602452 TI - Male pattern hair loss: Taking one for the team: The selfless gene. AB - Male pattern hair loss (MPHL) is exceedingly common. It is characterised by onset in early adulthood and progression with age. It has a strong heritable component. The reason for its existence remains unexplained. Given that MPHL is progressive and has its earliest manifestations in young adults it may be a barometer of age. Here we suggest that MPHL may have atavistically allowed women in our species and ancestor species to select younger (but not necessarily the youngest) adult mates. Evidence suggests that conceptions by younger fathers are more likely to lead to live births and less likely to result in miscarriage. Further children fathered by younger men may have improved health and be less likely to suffer from a number of co-morbidities. This is collectively known as the "paternal age affect". Hence the selection of younger males mediated by the MPHL may improve the fitness of the population and of the species at the expense of the individual. Indeed MPHL may have been an evolutionary "nudge" directing women to favour younger partners. It is conceivable that for a species whose success is predicated upon co-operation, collaboration and altruism the gene cannot be exclusively selfish and must have a selfless allele. PMID- 29602451 TI - [Autologous serum tears: Long-term treatment in dry eye syndrome]. AB - INTRODUCTION: Dry eye disease is a multifactorial pathology of the ocular surface. The high incidence of this pathology, as well as its significant impact on quality of life and vision and its financial cost, makes it a real public health problem. While the treatment of mild cases is generally simple and effective, treatment of severe forms is often disappointing. The use of autologous serum tears (AST) represents a therapeutic alternative for the most severe cases. The purpose of our study is to evaluate the efficacy of long-term AST treatment in patients with severe dry eye disease refractory to conventional treatment or secondary to systemic diseases such as Sjogren's syndrome or Graft versus Host disease (GVH), or ocular pathologies such as neurotrophic keratitis, chemical burns and ocular cicatricial pemphigoid. PATIENTS AND METHODS: This is a monocentric retrospective observational study conducted on 47 patients, with 83 eyes treated with autologous serum eye drops for isolated or secondary dry eye disease at the Marseille Public Hospitals between April 2014 and April 2017. The patients' subjective symptoms (ocular surface disease index [OSDI] score), their degree of satisfaction and the side effects were collected using questionnaires. Tear Break Up Time (BUT) and Schirmer scores were noted. A clinical evaluation based on fluorescein staining (Oxford score) was carried out prior to treatment with AST at P0 followed by 5 periods: P1 (between 1 and 3 months), P2 (3 to 9 months), P3 (9 to 15 months), P4 (15 months to 24 months), and P5 (>24 months). RESULTS: Out of the 83 eyes treated, the mean age was 54.39+/-21.56. There were 20 males (42.55 %) and 27 females (57.44 %); treatment indications consisted mainly of 25.53 % GVH, 21.27 % severe dry eye disease and 19.14 % Sjogren syndrome. The mean duration of follow-up was 9.82 months+/-15.50. The OSDI score decreased by 19.32 points+/-29.37 (P<0.05) between P0 and P1 and by 23.06 points+/-18.41 (P<0.05) between P0 and P4. The Oxford clinical score showed a significant decrease by the third month of treatment, between P0 and P2, by 1.32 points+/-1.76 (P<0.05). The Schirmer test and the BUT also showed an improvement in dry eye symptoms over time with AST, significantly at P1 (P<0.05). DISCUSSION: Complementary biological analyzes on the composition of AST are under way in order to identify predictive factors of effectiveness; patients not responding to AST treatment might respond to allogeneic serum from healthy donor cord blood. CONCLUSION: On this first series of 83 eyes treated with ASD, clinical efficacy was noted in most of the patients. No infectious complications were reported, and the satisfaction rate was very high. PMID- 29602453 TI - SGLT2 inhibitor-induced euglycaemic diabetic ketoacidosis may be due to abrupt, severe and transient impaired glucose sensing in susceptible individuals with a hitherto unrecognised beta cell SGLT variant. AB - Euglycaemic diabetic ketoacidosis (EDKA) is a rare complication of treatment with SGLT2 inhibitors in patients with type 2 diabetes. Uncertainty remains about its precise mechanistic basis, but the physiological derangement is acute and profound, yet reversible with cessation of the drug. It is reminiscent of other "non type 1" presentations with DKA such as ketosis prone diabetes, except that glucose levels are usually normal. Impaired beta cell glucose sensing that mimicked a state of hypoglycaemia could theoretically lead to abrupt and transient cessation of insulin secretion. GLUT2 mediates glucose sensing in beta cells. In other tissues such as enterocytes, GLUT2 mediated glucose transport is controlled by SGLT1. Although the affinity of SGLT1 for SGLT2 inhibitors is low, hypothetically a rare variant within the SGLT family with a hitherto unrecognised role in GLUT2 mediated glucose sensing might have an affinity for the SGLT2 inhibitor ligand and thus give rise to acute, severe but reversible euglycaemic DKA in susceptible patients. PMID- 29602454 TI - Optimise the microbial flora with milk and yoghurt to prevent disease. AB - Pathogenic bacteria, which are temporary or permanent members of our microbial flora, cause or contribute to a wide range of human disease at all ages. Conditions include Alzheimer's disease, atherosclerosis, diabetes mellitus, obesity, cancer, autoimmunity and psychosis, amongst others. The mechanism of damage is inflammation which can be chronic or acute. An optimal microbial flora includes a wide range of pathogenic bacteria in low dose. This allows specific immunity to be developed and maintained with minimal inflammatory damage. Human milk has evolved to deliver an optimal microbial flora to the infant. Cow's milk has the potential, following appropriate fortification, to maintain an optimal human microbial flora throughout life. Yoghurt is a fermented milk product in which bacteria normally present in milk convert sugars to lactic acid. The acid suppresses the growth of pathogens in the oral cavity, oropharynx and oesophagus. Thus yoghurt can restore an optimal flora in these regions in the short term. Since bacteria are transported between epithelial surfaces, yoghurt will also optimise the flora elsewhere. The judicious use of milk and yogurt could prevent a high proportion of human disease. PMID- 29602455 TI - Human chorionic gonadotropin levels of pregnant women can be an indicator of boys with cryptorchidism. PMID- 29602456 TI - Are human ATP-binding cassette transporter C11 and earwax associated with the incidence of cholesteatoma? AB - Cholesteatoma is an ear disease based on a locally destructive noncancerous conglomerate of epidermis and keratin debris. Abnormal growth of stratified keratinized squamous epithelium in the temporal bone causes destruction of the outer and middle ear, potentially leading to hearing impairment, facial palsy, vertigo, lateral sinus thrombosis, and intracranial complications. Although cholesteatoma is effectively treated by surgical resection (mastoidectomy), the lack of effective and nonsurgical therapies potentially results in fatal consequences, establishing the need for a comprehensive investigation of cholesteatoma pathogenesis. Although its etiology is still being debated, interestingly, we found that the trend associated with the 538G allele frequency of the adenosine triphosphate-binding cassette transporter C11 (ABCC11) gene, the determinant of wet-type earwax, and ethnic groups was similar to that between the incidence of cholesteatoma and ethnic groups (countries). The incidences of cholesteatoma in Europe (Denmark, Finland, and Scotland) are higher than in East Asia (Japan), and the frequencies of the ABCC11 538G allele in African, American, and European (Finland and Scotland) populations are higher than those in East Asian populations (Japan). Additionally, a single-nucleotide polymorphism in the ABCC11 gene (rs17822931, 538G > A; Gly180Arg) is closely related to earwax morphotypes. While earwax is often beneficial to ear health, it is sometimes harmful in cases where it causes hearing impairment. Based on independent findings of associations between ABCC11 and the physiological environment of the auditory canal, we hypothesize a possible link between ABCC11, earwax, and the incidence of cholesteatoma. PMID- 29602457 TI - Optical illusions and life-threatening traffic crashes: A perspective on aerial perspective. AB - Aerial perspective illusion is a feature of visual perception where landscapes appear relatively close in clear light and distant in dim light. We hypothesized that bright sunlight might cause drivers to perceive distant terrain as relatively close and misinterpret the approach speed of surrounding landscape as unduly slow. This hypothesis would mean, in turn, that drivers in bright sunlight may underestimate their progress on the road, compensate by traveling at a faster baseline speed, and ultimately increase the prevailing risk of a life-threatening traffic crash. We conducted three pilot studies to illustrate how the illusion might contribute to a life- threatening traffic crash. The first illustration used a questionnaire to demonstrate that most respondents were mistaken when judging the distance between simple balls in different positions. The second illustration involved an experimental manipulation to assess whether aerial perspective influenced judgments about the relative positions of vehicles in traffic. The third illustration analyzed a segment of high-volume fast-speed traffic and found an increased frequency of speeding under bright sunlight. Together with past work based on the visual arts, these examples illustrate how an aerial perspective illusion can affect distance perception, may appear in realistic traffic situations, and could potentially contribute to the risk of a life-threatening traffic crash. An awareness of this hypothesis might lead to applications on how optical illusions could extend to everyday traffic and might potentially inform safety warnings to prevent life- threatening crashes. PMID- 29602458 TI - Eukaryotic (translation) initiation factor 4A (eIF4A) inhibition may be used to treat Huntington's disease by decreasing the expression of huntingtin. PMID- 29602459 TI - Potential role of lipoic acid as a chelator in prevention and treatment of gadolinium brain retention. PMID- 29602460 TI - Preoperative gastric lavage in gastric cancer patients undergoing surgical, endoscopic or minimally invasive treatment: An oncological measure preventing peritoneal spillage of intragastric cancer cells and development of related metastases. AB - In addition to classical metastatic pathways, recently gastric cancer was described having an alternative route called "endoluminal exfoliation". Provisional analyses demonstrated, in fact, this kind of shedding is associated with several clinico-pathological features indicative of aggressive behavior and resulted to be an independent prognostic factor entailing poor prognosis. Compared with non-sowing counterparts, in fact, patients affected with exfoliating early and advanced gastric carcinomas met with shorter overall survival, disease free survival, progression free survival and time to tumor progression. In spite of these interesting results, however, the clinico pathological and oncological significance of this unconventional metastatic route is still to be clarified. Such an investigation is further urged by the increasing widespread employment of minimally invasive treatments for gastric cancer which include a wide spectrum of intragastric interventions and maneuvers. Indeed, endoscopic mucosal resection, endoscopic submucosal dissection, endoscopic full-thickness resection, intragastric laparoscopic surgery and hybrid procedures all take place inside of the stomach. However, iatrogenic perforations can occur during execution of these treatments leading to spillage of malignant cells from gastric to the peritoneal cavity or trocar insertion sites. Furthermore, many other gastric conditions and interventions can collide with endogastric presence of floating cancer cells: spontaneous ulceration or perforation, laparotomy surgery, gastrointestinal occlusion, diverticula. Viability, migration and intraluminal transportability of the intragastric floating cancer cells represents another original and intriguing topic. All these considerations led us to entertain the hypothesis that removing the exfoliated cancer cells from the gastric lumen could save patients from the dreaded potential risk of spillage. Performing gastric lavage before starting any kind of tumor intervention could be the most appropriate procedure to adopt with prophylactic intent. Should our speculation prove to be clinically significant, preoperative gastric lavage should be pointed out as a simple but cogent method useful for preventing oncological mishaps such as spillage of gastric cancer cells and development of related recurrences or metastases. PMID- 29602461 TI - Left ventricular hypertrophy as protective factor after bypass grafting. AB - Left ventricular hypertrophy (LVH) is a well established cardiovascular risk factor, accounting for an increase in cardiovascular morbid-mortality, although how much the magnitude and the kind of LVH could affect cardiovascular outcomes is in large part unknown. We speculate that mild LVH in absence of left ventricular (LV) chamber dilation, could play a protective role towards functional capacity, clinical outcome, cardiovascular and total morbi-mortality in conditions in which LV systolic function is generally reduced. Accordingly to many epidemiological observations, the availability of extra-quote of systolic function could lead to a significative improvement in the final outcome of some kinds of heart patients, as those undergoing bypass-grafting, where the stress for heart and cardiovascular system is always high. We suppose that the functional reserve available for patients with LVH could make the difference with respect to other patients undergoing myocardial revascularization. Similarly, the availability of a contractile reserve warranted by LVH could ensure a little gain in the outcome for patients after other major cardiovascular events (such as myocardial infarction or other heart surgery as surgical valve replacement). However, our hypothesis only involves mild LVH without LV chamber dilation, that is the initial stage of "non-dilated concentric" LVH and "non-dilated eccentric" LVH according to the new four-tiered classification of LVH based on relative wall thickness and LV dilation. Support for our hypothesis derives from the well-known protective role of systolic function that is a major factor in almost all cardiovascular diseases, where LV ejection fraction (LVEF) has shown to significantly improve quality of life, as well as morbidity and mortality. The knowledge that mild LVH in absence of LV chamber dilation is not as harmful in such conditions as believed at present could make avoidable some drugs prescription in some stages of the disease. Furthermore, it may allow a better evaluation of the risk profile of patients with LVH undergoing some cardiovascular major events like bypass grafting, myocardial infarction or surgical heart valve replacement. PMID- 29602462 TI - Dual antithrombotic plus adjunctive antiinflammatory therapy to improve cardiovascular outcome in atrial fibrillation patients with concurrent acute coronary syndrome: A triple-pathway strategy. AB - The concurrence of atrial fibrillation and acute coronary syndrome poses a conundrum in the antithrombotic management as intensification of anticoagulation or antiplatelet therapy inevitably comes at the price of an increased bleeding risk. Various antithrombotic combinations have been attempted to prevent the recurrent cardiovascular events, however, there has been limited success in effective risk reduction for this high risk population. Given the overarching effect of interleukin 1beta-driven inflammation on the arrhythmogenesis, thrombogenesis, and hypercoagulability, we hypothesize that the triple-pathway strategy (i.e., incorporating antiinflammatory therapy into anticoagulant and antiplatelet therapy) would grant incremental cardiovascular benefits for atrial fibrillation patients with coexisting acute coronary syndrome and stent placement. PMID- 29602463 TI - Treating patients suffering from myalgic encephalopathy/chronic fatigue syndrome (ME/CFS) with sodium dichloroacetate: An open-label, proof-of-principle pilot trial. AB - Twenty-two consecutive patients suffering from refractory myalgic encephalitis/chronic fatigue syndrome (ME/CFS) were treated with an innovative nutriceutical containing sodium dichloroacetate in a proof-of-principle, pilot, open-label prospective cohort trial. Ten patients experienced significant improvement of their health condition with reduction to almost half of their score in the fatigue severity scale. In twelve patients treatment failed to exert any beneficial effect. In the latter patients several other diseases have commonly been revealed by extensive biological and imaging investigations. These preliminary findings sustain the hypothetical role of mitochondrial hypo metabolism due to inhibition of the activity of the pyruvate dehydrogenase in the pathogenesis of primary ME/CFS, and suggest a possible benefit of nutriceutical treatment by sodium dichloroacetate. PMID- 29602464 TI - Use of Lactobacillus spp. to prevent recurrent urinary tract infections in females. AB - Urinary tract infections (UTIs) are the most common bacterial infections seen in the community, especially amongst females. The widespread use of antibiotics has led to the increased occurrence of E. coli resistant isolates worldwide. A promising non-antibiotic approach is the use of probiotic lactobacilli strains. This paper hypothesizes that Lactobacillus spp. containing products are able to prevent recurrent urinary tract infections in females. Using the keywords [lactobacillus OR lactobacilli OR probiotic] and [urinary tract infection OR UTI OR cystitis], a preliminary search on the PubMed, Ovid, Google Scholar and ClinicalTrials.gov database yielded 1,647 papers published in English between 1 Jan-1960 and 1-May-2017. 9 clinical trials with a total of 726 patients were reviewed. Different lactobacilli strains (in either oral or suppository formulation) were utilized and they demonstrated varying efficacy in the prevention of recurrent UTIs. Using a random-effects model, pooled risk ratio of at least one recurrent UTI episode during the entire study duration was 0.684 (95% CI 0.438 to 0.929, p < 0.001), per-protocol analysis. However, key limitations include significant inter-study variability and the limited duration of follow-up of most studies. Our hypothesis on the chemoprophylactic effects of probiotics for UTIs is plausible and supported by current data. Lactobacillus rhamnosus GR1 and Lactobacillus reuteri RC14 were the most commonly studied lactobacilli strains. Further and more robust randomized controlled trials with standardized lactobacilli strains and formulation are required for confirmation of effects. PMID- 29602465 TI - The presence of tumor extrachomosomal circular DNA (ecDNA) as a component of liquid biopsy in blood. AB - In molecular biology covalently closed circular DNAs are able to passthrough double layer of eukaryotic cellular membrane. Very recently the presence of circular extra chromosomal DNA (ecDNA) has been shown which are different in seventeen different types of cancers. In fact, ecDNA are the tricky way of oncogenes to increase their copy number. We hypothesis the presence of ecDNA in the blood of cancer patients as a subpopulation of liquid biopsy. On the occasion of their presence in blood they will be very beneficial to cover the small amount of cell frees DNA (cfDNA). Isolation and characterization of ecDNA will be possible by a sensitive method entitled Circle-Seq. The origin of tumor more than its prognosis and diagnosis will be possible in the easiest way by using ecDNA. PMID- 29602466 TI - PVDF piezoelectric neural conduit incorporated pre-differentiated adipose-derived stem cells may accelerate the repair of peripheral nerve injury. AB - Peripheral nerve injury is a common trauma disease which often results in sensory and motor dysfunction. However, the surgical repair for peripheral nerve injury, especially for large segmental defects, is not satisfactory. Growing evidences suggest that artificial neural conduit combined with stem cells is potential tissue engineering remediation method for peripheral nerve injury. But, selections of biomaterials and stem cells are still being debated. Based on the findings from previous studies, we hypothesize that PVDF piezoelectric neural conduit incorporated Schwann-like cells which pre-differentiated from adipose derived stem cells may substantially promote the repair of peripheral nerve injury. This novel technique may help clinical surgeons cure the seriously injured patients better and point out a new direction for neural tissue engineering researchers select the suitable biomaterials and seed cells. PMID- 29602467 TI - Role of Apolipoprotein E in the tangled mystery of pain. AB - Pain is one of the common and debilitating health manifestations associated with the majority of diseased conditions, thus making it a serious health concern worldwide. While trying to decipher the cryptic mechanism of pain in hope to provide better gene-based therapeutics, researchers have concluded pain to be of multigenic origin making it hard to cure. Apolipoprotein E is a protein coded by APOE gene containing 4 exons, located on chromosome 19q13.2. It is among the key regulators of various crucial body functions such as lipid transport, apoptosis, vitamin k pathway, and cognition, hence, it is highly suspected to play a pivotal role in the nociception process. However, very few studies have tried and succeeded to find a direct involvement of APOE in pain processing. The current article attempts to throw light on some of the major clinical research findings which strengthen the hypothesis stating that apolipoprotein E has a concealed yet deeply embedded association with the pain regulating pathways, through several underlying physiological, biochemical and neurological processes, that in turn, decide the fate of pain sensation in a complex manner. PMID- 29602468 TI - Do the key prognostic factors for non-specific neck pain have moderation effects? - A study protocol. AB - Neck pain is one of the common musculoskeletal conditions prevalent in the general population in Norway. Patients with neck pain, seek treatment from different health professionals such as general practitioners, physiotherapists, chiropractors and alternative medicine practitioners. The interventions for neck pain are typically provided in a primary care or specialised healthcare setting depending on the general practitioners' referral patterns. Clinicians are interested to know the various prognostic factors that can explain the recovery from neck pain. In order to know this, studies have explored and reported on a range of prognostic factors that contribute to the outcomes in patients with neck pain. This information is currently available only for neck pain following whiplash injury that has a traumatic origin. There is limited information on the role of prognostic factors specifically for non-specific neck pain without a traumatic episode. Moreover, there is a lack of data on whether there are interactions (moderation effects) between the prognostic factors. Therefore, we propose a hypothesis to elucidate whether the same set of prognostic factors found in neck pain associated with whiplash injuries are also identified in patients with neck pain without trauma. Additionally, we hypothesize that the association between a prognostic factor and the outcome variable (s) would be dependent on the third variable, thereby confirming the moderation effects. Clinicians could make informed decisions in the clinical management of neck pain with the knowledge of prognostic factors that explain the outcomes. It could also be used for the development of new interventions or for modifying the existing ones. PMID- 29602469 TI - Seminal cell-free DNA molecular profile as a novel diagnostic and prognostic prostate cancer biomarkers. PMID- 29602470 TI - The possible role of stress induced hormonal disbalance in the patophysiology of insulin resistane in lean individuals. AB - Insulin resistance (IR) is a common denominator of metabolic and hemodynamic disorders simultaneously present in one person and responsible for elevated risk of developing type 2 diabetes (T2DM) and cardiovascular incidents. According to the latest research, IR is present in 25-45% of the general population. Therefore, the mechanism of its development is in the center of scientific and professional interest. Established or acquired factors, or combinations thereof, which disturb any step of the physiological insulin action mechanism: its binding to the cellular receptor, through the complex cascade of intracellular signaling pathways might cause IR. Although the adiposity and its underlying risk factors are considered to be the primary cause of IR, it is present in a great porportion in lean individuals as well. There are insights of the possible role of psychological factors: exposure to stress and deprssion to IR development, although the mechanism of this relationship has not been comperhensively studied. Data driven from cell cultures and experimental animal models suggest that there is an elevated level of counter-regulatory insulin hormones: growth hormone, prolactin and cortisol due to acute stress exposure. However, the relationship between these psychological disorders with the hyperreactivity of the axis of the hypothalamic-pituitaryadrenal axis as the underlying mechanism in the patophysiology of IR in lean individuals has not been systematically investigated. Based on the aforementioned, we hypothesise that this mechanism would be responsible for the formation of IR, and consequently, T2DM in lean individuals. The possible effect of the amount of stress in conjunction with the serum concentration of growth hormone, cortisol, prolactin and dehydroepiandrostendone to the abnormal 5-h oral glucose tollerance test results could contribute to the primary prevention of diabetes and its complications. PMID- 29602471 TI - Early and midterm outcome of Multilayer Flow Modulator stent for complex aortic aneurysm treatment in Germany. AB - OBJECTIVE: The objective of this study was to assess the early and midterm outcomes of endovascular repair of complex aortic aneurysm cases using the Multilayer Flow Modulator (MFM; Cardiatis, Isnes, Belgium) endograft in Germany. METHODS: A retrospective study including patients presenting with abdominal aortic aneurysm (AAA), thoracic aortic aneurysm, or thoracoabdominal aortic aneurysm treated with the MFM was conducted in Germany. Mortality and morbidity (in terms of spinal cord ischemia, visceral ischemia, and stroke) at 30 days postoperatively were evaluated. In addition, during follow-up, freedom from reintervention, rupture, and failure mode were also assessed. RESULTS: Between 2009 and 2014, a total of 61 patients with AAA, thoracoabdominal aortic aneurysm, or thoracic aortic aneurysm were treated with the MFM endograft in 29 hospitals around Germany. However, data of 40 patients with a mean age of 73.4 +/- 11.2 years (72.5% male; 29/40) and mean aortic aneurysm diameter of 60.3 +/- 16.6 mm from 14 hospitals were available for this retrospective study. Thirty-seven (93%) patients were treated urgently. In 12 cases (12/40 [30%]), patients were treated outside instructions for use because of aortic aneurysm diameter >65 mm. A total of 69 MFM stents were used (1.7/patient). The technical success rate was 95% (38/40). Postoperatively, no patient presented with spinal cord ischemia, renal function deterioration, stroke, or intestinal ischemia, except for one patient who developed multiorgan failure because of early stent migration. The intraoperative and 30-day mortality rate was 0% and 2.5%, respectively. The mean follow-up was 12.9 months (+/-14.9 months), with a survival rate at 1 month, 6 months, and 12 months of 97%, 78%, and 70%, respectively. Freedom from failure mode (type I or II) at 1 month, 6 months, and 12 months was 97.5%, 88%, and 86%, respectively, and visceral vessel patency was 99.3% (155/156 available). During follow-up, 4 patients (4/39 [10%]) had an aneurysm sac rupture and 10 (10/39 [25%]) underwent a reintervention. Freedom from rupture and freedom from reintervention at 1 month, 6 months, and 12 months were 97.5% and 100%, 96% and 84%, and 86% and 75%, respectively. CONCLUSIONS: The use of the MFM for endovascular treatment of complex aortic aneurysm in urgent cases appears to be technically feasible in terms of mortality and morbidity, with moderate 30-day and acceptable midterm outcomes. Reinterventions may be needed to expand the utility of outcomes. PMID- 29602472 TI - Local anesthesia for percutaneous endovascular abdominal aortic aneurysm repair is associated with fewer pulmonary complications. AB - OBJECTIVE: Percutaneous endovascular aneurysm repair (EVAR) can be performed with general anesthesia (GA) or local anesthesia (LA). Our goal was to assess perioperative outcomes comparing anesthesia type in percutaneous EVAR. METHODS: The Vascular Quality Initiative database was queried for all exclusively percutaneous EVAR procedures. Univariable analysis was used to compare which patients were offered LA. Multivariable analysis was used to determine the independent effect of anesthesia type. RESULTS: There were 8141 percutaneous EVARs identified in the Vascular Quality Initiative database. Average age was 73 years, and 83% were male. GA and LA were used in 7387 (90.7%) and 754 (9.3%) cases, respectively. GA was used more often in patients who were younger (72.8 +/ 8 vs 74.3 +/- 9), white (89% vs 84.5%), and on Medicare (62% vs 61.5%); in patients with higher body mass index (28.3 +/- 6 vs 27.3 +/- 7), hypertension (81.5% vs 77.8%), diabetes (20.5% vs 17.4%), and previous lower extremity bypass (1.7% vs 0.5%); and in patients undergoing elective repair (86.4% vs 81.3%). Use of GA was associated with lower rates of preoperative congestive heart failure (11.6% vs 16.1%), preoperative anticoagulation (11.7% vs 14.2%), and less use of ultrasound guidance (81.5% vs 88.8%; P < .05). There was no difference in patients with chronic obstructive pulmonary disease, coronary artery disease, previous aneurysm repair, and concomitant iliac aneurysm repair. Multivariable analysis showed that GA compared with LA was associated with more pulmonary complications (odds ratio, 2.8; 95% confidence interval, 1.49-5.43; P = .002) and prolonged operative time (means ratio, 1.11; 95% confidence interval, 1.08-1.52; P < .001). There was no independent effect on overall complications, cardiac complications, or mortality. CONCLUSIONS: Although it was used in only 1 in 10 cases of percutaneous EVAR, LA was associated with fewer pulmonary complications after adjustment for patient factors. Surgeons should consider expanding the use of LA for percutaneous EVAR when feasible. PMID- 29602473 TI - Early outcomes with a single-sided access endovascular stent. AB - OBJECTIVE: The objective of this study was to report the 1-year follow-up study results of the new Horizon stent graft (Endospan, Herzliya, Israel) from two different prospective consecutive trials. The Horizon abdominal aortic aneurysm stent graft system is a 14F profile system requiring only a single access site. It consists of three modules, introduced separately: base limb (iliac to iliac limb); distal aortic limb; and proximal aortic limb with a bare suprarenal crown and active fixation. METHODS: Data from the first in man (FIM) clinical study with 10 patients enrolled and the pivotal study with 30 patients were analyzed. Outcomes measured were freedom from major adverse events (MAEs) including all cause mortality, myocardial infarction, renal failure, respiratory failure, paraplegia, stroke, bowel ischemia, and procedural blood loss >=1000 mL. Performance end points included successful delivery and deployment of the device, freedom from aneurysm growth >=5 mm, type I or type III endoleak, stent graft occlusion, conversion to open surgery, rupture, and stent graft migration. RESULTS: In the FIM study, one conversion to open surgery with >1000 mL of blood loss was registered perioperatively. In the pivotal study, no perioperative MAE was registered. Overall, at 1-year follow-up, two deaths and one aneurysm growth unrelated to endoleak were registered. CONCLUSIONS: The results of both the FIM and pivotal studies demonstrated that 39 of 40 procedures were successful for delivery and deployment of the Horizon stent graft. No MAE was registered during the follow-up. The primary safety and performance end points were met in both studies. PMID- 29602474 TI - Quantification of gait parameters with inertial sensors and inverse kinematics. AB - : Measuring human gait is important in medicine to obtain outcome parameter for therapy, for instance in Parkinson's disease. Recently, small inertial sensors became available which allow for the registration of limb-position outside of the limited space of gait laboratories. The computation of gait parameters based on such recordings has been the subject of many scientific papers. We want to add to this knowledge by presenting a 4-segment leg model which is based on inverse kinematic and Kalman filtering of data from inertial sensors. To evaluate the model, data from four leg segments (shanks and thighs) were recorded synchronously with accelerometers and gyroscopes and a 3D motion capture system while subjects (n = 12) walked at three different velocities on a treadmill. Angular position of leg segments was computed from accelerometers and gyroscopes by Kalman filtering and compared to data from the motion capture system. The four segment leg model takes the stance foot as a pivotal point and computes the position of the remaining segments as a kinematic chain (inverse kinematics). Second, we evaluated the contribution of pelvic movements to the model and evaluated a five segment model (shanks, thighs and pelvis) against ground-truth data from the motion capture system and the path of the treadmill. RESULTS: We found the precision of the Kalman filtered angular position is in the range of 2 6 degrees (RMS error). The 4-segment leg model computed stride length and length of gait path with a constant undershoot of 3% for slow and 7% for fast gait. The integration of a 5th segment (pelvis) into the model increased its precision. The advantages of this model and ideas for further improvements are discussed. PMID- 29602475 TI - Concurrent validation of an inertial measurement system to quantify kicking biomechanics in four football codes. AB - Wearable inertial measurement systems (IMS) allow for three-dimensional analysis of human movements in a sport-specific setting. This study examined the concurrent validity of a IMS (Xsens MVN system) for measuring lower extremity and pelvis kinematics in comparison to a Vicon motion analysis system (MAS) during kicking. Thirty footballers from Australian football (n = 10), soccer (n = 10), rugby league and rugby union (n = 10) clubs completed 20 kicks across four conditions. Concurrent validity was assessed using a linear mixed-modelling approach, which allowed the partition of between and within-subject variance from the device measurement error. Results were expressed in raw and standardised units for assessments of differences in means and measurement error, and interpreted via non-clinical magnitude-based inferences. Trivial to small differences were found in linear velocities (foot and pelvis), angular velocities (knee, shank and thigh), sagittal joint (knee and hip) and segment angle (shank and pelvis) means (mean difference: 0.2-5.8%) between the IMS and MAS in Australian football, soccer and the rugby codes. Trivial to small measurement errors (from 0.1 to 5.8%) were found between the IMS and MAS in all kinematic parameters. The IMS demonstrated acceptable levels of concurrent validity compared to a MAS when measuring kicking biomechanics across the four football codes. Wearable IMS offers various benefits over MAS, such as, out-of-laboratory testing, larger measurement range and quick data output, to help improve the ecological validity of biomechanical testing and the timing of feedback. The results advocate the use of IMS to quantify biomechanics of high-velocity movements in sport-specific settings. PMID- 29602476 TI - Ultrasound estimates of Achilles tendon exhibit unexpected shortening during ankle plantarflexion. AB - The purpose of this study was to investigate Achilles tendon (AT) length changes during a series of tasks that involved combinations of higher/lower force, and larger/smaller length changes of the medial gastrocnemius muscle-tendon unit (MTU). We sought to determine if common ultrasound-based estimates of AT length change were consistent with expectations for a passive elastic tendon acting in series with a muscle. We tested 8 healthy individuals during restricted joint calf contractions (high force, low displacement), ankle dorsi-/plantar-flexion (DF/PF) with the foot in the air (low force, high displacement), and heel raises (high force, high displacement). We experimentally estimated AT length change using two ultrasound methods, one based on muscle-tendon junction (MTJ) tracking and one based on muscle fascicle (MF) tracking. Estimates of AT length change were consistent with model expectations during restricted calf contractions, when the MTU underwent minimal length change. However, estimates of AT length changes were inconsistent with model expectations during the ankle DF/PF and heel raise tasks. Specifically, the AT was estimated to shorten substantially, often 10-20 mm, when the ankle plantarflexed beyond neutral position, despite loading conditions in which a passive, stiff spring would be expected to either lengthen (under increasing force) or maintain its length (under low force). These unexpected findings suggest the need for improvements in how we conceptually model and/or experimentally estimate MTU dynamics in vivo during motion analysis studies, particularly when the ankle plantarflexes beyond neutral. PMID- 29602477 TI - Flow instability detected in ruptured versus unruptured cerebral aneurysms at the internal carotid artery. AB - Flow instability has emerged as a new hemodynamic metric hypothesized to have potential value in assessing the rupture risk of cerebral aneurysms. However, diverse findings have been reported in the literature. In the present study, high resolution hemodynamic simulations were performed retrospectively on 35 aneurysms (10 ruptured & 25 unruptured) located at the internal carotid artery (ICA). Simulated hemodynamic parameters were statistically compared between the ruptured and unruptured aneurysms, with emphasis on examining the correlation of flow instability with the status of aneurysm rupture. Pronounced flow instability was detected in 20% (2 out of 10) of the ruptured aneurysms, whereas in 44% (11 out of 25) of the unruptured aneurysms. Statistically, the flow instability metric (quantified by the temporally and spatially averaged fluctuating kinetic energy over the aneurysm sac) did not differ significantly between the ruptured and unruptured aneurysms. In contrast, low wall shear stress area (LSA) and pressure loss coefficient (PLC) exhibited significant correlations with the status of aneurysm rupture. In conclusion, the present study suggests that the presence of flow instability may not correlate closely with the status of aneurysm rupture, at least for ICA aneurysms. On the other hand, the retrospective nature of the study and the small sample size may have to some extent compromised the reliability of the conclusion, and therefore large-scale prospective studies would be needed to further address the issue. PMID- 29602478 TI - [Post-traumatic pulmonary aspergilloma]. AB - INTRODUCTION: Aspergillomas occur due to colonization of a pre-existing pulmonary, bronchial or pleural cavity by Aspergillus spp. Often asymptomatic, this pathology can reveal itself by recurrent haemoptysis or when bacterial superinfections occur. Aspergillomas occurring in post-traumatic cavities are rare and their management is poorly codified. CASE REPORT: A child suffered from a chest wound at the age of 13 years. Two years later, investigation of recurrent haemoptysis revealed a residual pneumatocele in the right lower lobe colonized by Aspergillus spp. Initial treatment with systemic azole antifungals was unsuccessful because of digestive and ophthalmological intolerance. Surgical treatment by right lower lobectomy was finally decided on by the multidisciplinary team. This revealed an intrabronchial foreign body of vegetal type with cellulosic reinforcement, causing a polymorphic granulomatous reaction around, and associated with a proliferation of filamentous fungi including Aspergillus fumigatus. Surgery was followed by liposomal amphotericin B treatment for three weeks with a favourable outcome. CONCLUSIONS: This clinical case illustrates the benefits of surgical management of post-traumatic aspergillomas, even in children, in order to eradicate the aspergillus implant and to remove any foreign body to prevent recurrence. PMID- 29602479 TI - [Asthma and socioeconomic characteristics in France in 2012]. AB - INTRODUCTION: The prevalence of adult asthma is around 6-7% in France. This disease is multifactorial and is related in particular to occupational factors. Using data from The French Health, Health Care and Insurance Survey (ESPS), this study aimed to describe asthma prevalence in France according to socio-economic status in 2012. METHODS: This analysis included the population aged 15 years and over. Current asthma, defined by a declaration of having asthma in the last 12 months, was analyzed according to socio-economic variables available in the ESPS survey. RESULTS: Among the 23,047 subjects interviewed, 12,565 were included in the analysis. Current asthma frequency was 7.4%. Higher risk of asthma was observed in unemployed, non-qualified persons, with a lower income, or having free healthcare insurance. Regarding occupations, in men, trade and commerce employees, personal services employees and administrative employees were associated with a higher level of current asthma prevalence. CONCLUSIONS: These results show that subjects with lower socio-economic status are more likely to suffer from asthma. New epidemiological tools in France, including cohorts (Constances, COSET) will be helpful to study more precisely the associations between asthma and occupational factors. PMID- 29602480 TI - [Tunnelled central venous catheter infection during treatment with epoprostenol]. AB - INTRODUCTION: Pulmonary arterial hypertension is a pulmonary vascular disease with a poor prognosis. Continuous intravenous treatment with prostacyclin analogues requires the placement of a tunnelled catheter. The occurrence of catheter-related infections in this context is unusual due to the alkaline pH of the prostacyclin analogue solutions. OBSERVATION: A 50-year-old patient with inherited pulmonary artery hypertension, treated with bosentan, sildenafil and epoprostenol, experienced generalized malaise associated with a weight loss of 9kg over a 12-month period without evidence of a source of infection or malignancy. There was no evidence of hemodynamic disturbance. The diagnosis was made after 1 year of follow-up, when the patient presented with a 38 degrees fever and a biological inflammatory syndrome. Repeated peripheral blood cultures were positive for Dietzia, an alkalophilic coryneform bacillus. The patient's condition responded favourably to antibiotic therapy. CONCLUSION: Infection of a tunneled intravenous catheter should be considered in the case of non-specific symptoms or where there is evidence of sepsis, in patients treated with intravenous prostacyclin analogues administered intravenously. In this context, the laboratory should be warned to search for slow-growing organisms. PMID- 29602481 TI - [Asthma: Adapting the therapeutic follow-up according to the medical and psychosocial profiles]. AB - INTRODUCTION: This work is based on the data of REALISETM, a survey conducted among 8000 European patients to identify the profiles of adult asthma patients and how these are linked with treatment adherence behaviors. METHODS: A cluster analysis was performed by combining data in three ways: control of asthma, attitude towards the disease, compliance with treatment. A multidisciplinary group analyzed the results for the 1024 French survey respondents. RESULTS: Four patient profiles were identified: "rather confident" (28% of patients), rather young patients with a low level of concern about their asthma. "Rather committed" (23%) patients considering themselves to be mostly healthy, reporting better therapeutic declared. "Rather questing" (26%), patients poorly controlled, seeking to manage their asthma themselves. "Rather concerned" profile (23%), a bit older, with poor clinical control, considering their asthma to be severe. CONCLUSIONS: Cluster analysis provides a multidimensional approach to understand the therapeutic behavior of the different patient profiles better and so adjust communication by and education of healthcare professionals. PMID- 29602482 TI - [Neurofibromatosis as a cause of breathlessness]. AB - INTRODUCTION: Type 1 neurofibromatosis, also called "Recklinghausen's disease" is among the most frequent autosomal dominant genetic disorders, with an incidence of 1:3500 births. It mainly affects the skin and peripheral nervous system. However, in its less frequent manifestations, are tumors such as meningocele and skeletal dysplasias leading to severe clinical presentation. CASE REPORT: We report the case of a 55-year-old patient with type 1 neurofibromatosis and dyspnea due to a large left thoracic meningocele combined with a significant kyphoscoliosis, causing a severe restrictive ventilatory defect, complicated by chronic respiratory failure and pulmonary hypertension. Symptomatic treatment with non-invasive ventilation permitted an improvement of the clinical situation. CONCLUSIONS: Our observation shows the complexity of the therapeutic support of the neurofibromatosis of type 1. The contribution of non-invasive ventilation was illustrated by the arterial blood gas and clinical improvements as well as improved quality of life, with an acceptable level of inconvenience to the patient. PMID- 29602483 TI - [Spotting the GLObalRIsk of severe outcomes in undiagnosed COPD patients (GLORI COPD)]. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a severe chronic disease and its prevalence is increasing. Nevertheless, mortality linked to moderate and mild COPD without comorbidities is low. The aim of the study is to create and validate a questionnaire in primary care to spot patients with undiagnosed COPD who are at high risk of severe complications considering the severity of their COPD and their comorbidities. METHODS: The development of the questionnaire has three steps. The first is the selection of the items which can be included in the questionnaire with a two-round Delphi method. The second step is a cross-sectional study to assess the link between spirometry and the selected items in the first step. The last step is the validation of the questionnaire in a prospective study in primary care. EXPECTED RESULTS: Identifying undiagnosed COPD patients with a high global risk of complications in primary care will help to establish which patients have to be diagnosed as a priority. This is particularly useful in general practice as the patient is considered globally and not just on the basis of respiratory criteria. It should allow better selection of patients who need specialised follow up. PMID- 29602484 TI - [Blue rubber bleb naevus syndrome involving the pleura]. AB - Bean's syndrome ('blue rubber bleb nevus syndrome') is a rare disease characterized by venous malformations involving various organs. Most often these lesions are localized to the skin and the digestive system. Gastro-intestinal bleeding is the most frequent presentation. Though other organs can be affected, chest localizations are infrequent and pleural localization is exceptional. We report the case of an asbestos-exposed patient with Bean's syndrome with characteristic skin lesions, smoker, hospitalized for the investigation of a hemorrhagic pleural effusion. A medical thoracoscopy revealed pleural lesions similar to the cutaneous lesions and compatible with a pleural localization of the disease. This is the first documented case of this disease involving the pleura. A review of the literature was carried out on account of this clinical case. PMID- 29602486 TI - Comparison of arthroscopic reduction and percutaneous fixation and open reduction and internal fixation for tibial plateau fractures. AB - PURPOSE: To conduct a meta-analysis with randomized controlled trials (RCTs) published in full text to demonstrate database to show the associations of perioperative, postoperative outcomes of arthroscopic reduction and percutaneous fixation(ARPF) and open reduction and internal fixation(ORIF) for tibial plateau fractures to provide the predictive diagnosis for clinic. METHODS: Literature search was performed in PubMed, Embase, Web of Science and Cochrane Library for information from the earliest date of data collection to June 2017. RCTs comparing the benefits and risks of ARPF with those of ORIF in tibial plateau fractures were included. Statistical heterogeneity was quantitatively evaluated by X2 test with the significance set P < 0.10 or I2 > 50%. RESULTS: Seven RCTs consisting of 571 patients were included.(288 ARPF patients; 283 ORIF patients;). Pooled results showed that ORIF was related to a greater increase in operative time, incision length, hospital stay, perioperative complications, and full weight bearing compared with ARPF. The results showed that ARPF was related to a greater increase in ROM Rasmussen Scores compared with ORIF (WMD = 10.38; 95% CI, 8.31, 12.45; P < 0.10). CONCLUSION: This meta-analysis showed that arthroscopic reduction and percutaneous fixation for tibial plateau fractures, compared with open reduction and internal fixation, could demonstrate an decreased risk of perioperative and postoperative complications and improve clinical outcome in operative time, incision length, hospital stay, perioperative complications, full weight bearing and Rasmussen Scores. PMID- 29602485 TI - [Occurrence of delayed symptoms after a challenge test with methacholine]. AB - There are few prospective studies available on the development of delayed symptoms following challenge tests with methacholine (MCT) at the currently recommended doses. The objective of this study was to describe the nature and frequency of respiratory symptoms suggestive of bronchospasm developing within 24hours after a MCT. The study was offered to adult patients who underwent MCT seen consecutively between June and October 2015. Following the test, a questionnaire adapted from the GINA asthma control questionnaire bearing on diurnal and nocturnal symptoms (cough, dyspnoea, wheeze and tightness), was delivered to the patient and the replies collected by telephone 24hours later. Of the 101 patients included (initial FEV1 2.82+/-0.79L), 46 (46 %) were MCT+ and 55 (54 %) MCT-. Among the MCT-, 4 (7 %) presented with immediate symptoms (S+) and 4 (7 %) with delayed symptoms. Among the MCT+ patients, 36 (78 %) presented with immediate symptoms (P<0.001 compared with the MCT- patients), and 39 (85 %) with delayed symptoms (P<0.001 compared with the MCT- patients). Delayed symptoms developed with a mean of 5h30 after the provocation test. Immediate and delayed symptoms were more frequent in subjects having significant non-specific bronchial hyper-reactivity. Informing patients of the risk of developing delayed symptoms seems useful and allows optimization of their management after a MCT. PMID- 29602487 TI - Should we bury K-wires after metacarpal and phalangeal fracture osteosynthesis? AB - BACKGROUND: Burying Kirschner wires (K-wires) under the skin after metacarpal and phalangeal fracture osteosynthesis may reduce risk of infection, but it might also complicate later removal. PURPOSE/AIM OF STUDY: To examine infection and reoperation rates after metacarpal and phalangeal fracture osteosynthesis with buried versus exposed K-wires. MATERIALS AND METHODS: Metacarpal and phalangeal fractures treated with K-wire osteosynthesis at our institution from 1st of January, 2009 to 1st of February, 2015 were identified retrospectively. The final study population included 444 patients, 331 with metacarpal, 109 phalangeal and 4 with mixed fractures. Surgical and patient records were examined 90 days postoperatively. FINDINGS/RESULTS: 337 patients (75.9%) were treated with buried K-wires and 107 patients (24.1%) with exposed (non-buried) K-wires. 14 patients (4.1%) treated with buried K-wires presented with postoperative infection, opposed to 7 patients (6,5%) treated with non-buried K-wires (p = 0.311). None of the postoperative infections caused re-operation. Only one case of deep/severe infection was recorded in a patient treated with buried K-wires requiring intravenous antibiotic treatment. In 58 of 337 patients (17.2%) treated with buried K-wires, removal was not possible in the outpatient clinic and required readmission for removal in the operation theatre. All exposed K-wires could be removed in the out-patient clinic without re-operation. CONCLUSIONS: We found no difference in postoperative infection rate between metacarpal and phalangeal fracture osteosynthesis with buried versus exposed K-wires. However, the high readmission and reoperation rate (17.2%) after burying K-wires should call for reconsideration of surgical strategies. PMID- 29602488 TI - Femoral arterial and central venous catheters in the trauma resuscitation room. AB - BACKGROUND: Arterial and central venous femoral catheters (fAC-CVC) use during the initial management of severe trauma patients is not a standard technique in most trauma centers. Arguments in favor of their use are: continuous monitoring of blood pressure, safe drug administration, easy blood sampling and potentially large bore venous access. The lack of evidence makes the practice heterogeneous. The aim of the present study was to describe the use and complications of fAC-CVC in the trauma bay in two centers where they are routinely used. METHODS: This was a retrospective analysis of routine fAC-CVC use from two French trauma centers. All patients admitted directly to the trauma resuscitation room were included. Demographic, clinical and biological data were collected from the scene to discharge to describe the use of catheters during initial trauma management including infectious, mechanical and thrombotic complications. RESULTS: 243 pairs of femoral catheters were inserted among 692 patients admitted in both trauma centers. Femoral AC-CVC use was more frequent in critically ill patients with higher ISS 26 [17; 41] vs 13 [8; 24], p < 0.001(median [quartile 1-3]), severe traumatic brain injury (AIS head 1[0-4] vs 0[0-3], p < 0.001), lower systolic blood pressure, 92 (37) vs 113 (28) mmHg, p < 0.001 mean (standard deviation), lower haemoglobin on arrival, 10.9 (3) vs 13.3 (2.1) g/dL (p < 0.001), and higher blood lactate concentration, 4.0 (3.9) vs 2.1 (1.8) mmol/L (p < 0.001). In patients with fAC-CVC use time in the trauma room was longer, 46 [40;60] vs 30 [20;40] minutes (p < 0.05). In total 52 colonizations and 3 bloodstream infections were noted in 1000 catheter days. An incidence of 12% of mechanical complications and of 42% deep venous thromboses were observed. Of the latter none was associated with confirmed pulmonary embolism. CONCLUSION: Femoral AC-CVC appeared to be deployed more often in critically ill patients, presenting with shock and/or traumatic brain injury in particular. The observed rate of complications in this sample seems to be low compared to reported rates. PMID- 29602489 TI - Beliefs and expectations of rural hospital practitioners towards a developing trauma system: A qualitative case study. AB - BACKGROUND: An understanding of stakeholders' views is key to the successful development and operation of a rural trauma system. Scotland, which has large remote and rural areas, is currently implementing a national trauma system. The aim of this study was to identify key barriers and enablers to the development of an effective trauma system from the perspective of rural healthcare professionals. METHODS: This is a qualitative study, which was conducted in rural general hospitals (RGH) in Scotland, from April to June 2017. We used an opportunistic sampling strategy to include hospital providers of rural trauma care across the region. Semi-structured interviews were conducted, recorded, and transcribed. Thematic analysis was used to identify and group participant perspectives on key barriers and enablers to the development of the new trauma system. RESULTS: We conducted 15 interviews with 18 participants in six RGHs. Study participants described barriers and enablers across three themes: 1) quality of care, 2) interfaces within the system and 3) interfaces with the wider healthcare system. For quality of care, enablers included confidence in basic trauma management, whilst a perceived lack of change from current management was seen as a barrier. The theme of interfaces within the system identified good interaction with other services and a single point of contact for referral as enablers. Perceived barriers included challenges in referring to tertiary care. The final theme of interfaces with the wider healthcare system included an improved transport system, increased audit resource and coordinated clinical training as enablers. Perceived barriers included a rural staffing crisis and problematic patient transfer to further care. CONCLUSIONS: This study provides insight into rural professionals' perceptions regarding the implementation of a trauma system in rural Scotland. Barriers included practical issues, such as retrieval, transfer and referral processes. Importantly, there is a degree of uncertainty, discontent and disengagement towards trauma system development, and concerns regarding staffing levels and governance. These issues are unlikely to be unique to Scotland and warrant further study to inform service planning and the effective delivery of rural trauma systems. PMID- 29602490 TI - Epidermal growth factor regulates apoptosis and oxidative stress in a rat model of spinal cord injury. AB - Spinal cord injury (SCI) leads to vascular damage and disruption of blood-spinal cord barrier which participates in secondary nerve injury. Epidermal growth factor (EGF) is an endogenous protein which regulates cell proliferation, growth and differention. Previous studies reported that EGF exerts neuroprotective effect in spinal cord after SCI. However, the molecular mechanisms underlying EGF mediated protection in different regions of nervous system have not shown yet. In this study, we aimed to examine possible anti-apoptotic and protective roles of EGF not only in spinal cord but also in brain following SCI. Twenty-eight adult rats were divided into four groups of seven animals each as follows: sham, trauma (SCI), SCI + EGF and SCI + methylprednisolone (MP) groups. The functional neurological deficits due to the SCI were assessed by behavioral analysis using the Basso, Beattie and Bresnahan (BBB) open-field locomotor test. The alterations in pro-/anti-apoptotic protein levels and antioxidant enzyme activities were measured in spinal cord and frontal cortex. In our study, EGF promoted locomotor recovery and motor neuron survival of SCI rats. EGF treatment significantly decreased Bax and increased Bcl-2 protein expressions both in spinal cord and brain when compared to SCI group. Moreover, antioxidant enzyme activities including catalase, superoxide dismutase (SOD) and glutathione peroxidase (GPx) were increased following EGF treatment similar to MP treatment. Our experiment also suggests that alteration of the ratio of Bcl-2 to Bax may result from decreased apoptosis following EGF treatment. As a conclusion, these results show, for the first time, that administration of EGF exerts its protection via regulating apoptotic and oxidative pathways in response to spinal cord injury in different regions of central nervous system. PMID- 29602491 TI - The Complementary Role of Real World Evidence: Focus on Oral Anticoagulants. PMID- 29602492 TI - Defining Hypertension - A Storm Across the Pacific. PMID- 29602493 TI - Should We Push the Frontier? Easier Said Than Done. PMID- 29602494 TI - Motor coordination and synaptic plasticity deficits are associated with increased cerebellar activity of NADPH oxidase, CAMKII, and PKC at preplaque stage in the TgCRND8 mouse model of Alzheimer's disease. AB - Numerous studies indicate that the cerebellum undergoes structural and functional neurodegenerative changes in Alzheimer's disease. The purpose of this study was to examine the extent of cerebellar alterations at early, preplaque stage of the pathology in TgCRND8 mice through behavioral, electrophysiological, and molecular analysis. Balance beam test and foot-printing analysis revealed significant motor coordination and balance deficits in 2-month-old TgCRND8 mice compared to their littermates. Patch-clamp recordings performed on cerebellar slices of transgenic mice showed synaptic plasticity deficit and loss of noradrenergic modulation at parallel fiber-Purkinje cell synapse suggesting an early dysfunction of the cerebellar circuitry due to amyloid precursor protein overexpression. Finally, western blot analysis revealed an enhanced expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunits p47phox and p67phox as well as Ca2+/calmodulin-dependent protein kinase and protein kinase C alpha in the cerebellum of 2-month-old transgenic mice. Therefore, we propose the existence of self-sustaining feedback loop involving the formyl peptide receptor 2-reactive oxygen species-Ca2+/calmodulin-dependent protein kinase II-protein kinase C alpha pathway that may promote reactive oxygen species generation in the early stage of Alzheimer's disease and eventually contribute to the exacerbation of pathological phenotype. PMID- 29602496 TI - A systematic review to evaluate the evidence base for the World Health Organization's adopted hand hygiene technique for reducing the microbial load on the hands of healthcare workers. AB - BACKGROUND: Effective hand hygiene prevents healthcare-associated infections. This systematic review evaluates the evidence for the World Health Organization's (WHO) technique in reducing the microbial load on the hands of healthcare workers (HCWs). METHODS: This study was conducted in accordance with Joanna Briggs Protocol 531. Index and free-text terms for technique, HCW, and microbial load were searched in CINAHL, Medline, Web of Science, Mednar, Proquest, and Google Scholar. Inclusion criteria were articles in English that evaluated the WHO 6 step hand hygiene technique for healthcare staff. Two reviewers independently performed quality assessment and data extraction. RESULTS: All 7 studies found that the WHO technique reduced bacterial load on HCW hands, but the strongest evidence came from 3 randomized controlled trials, which reported conflicting evidence. One study found no difference in the effectiveness of the WHO 6-step technique compared to the Centers for Disease Control and Prevention's 3-step technique (P = .08); another study found the WHO 6-step technique to be more effective (P = .02); and the third study found that a modified 3-step technique was more effective than the 6-step technique (P = .021). CONCLUSIONS: This review provides evidence of the effectiveness of the WHO technique but does not identify the most effective hand hygiene technique. Questions to be addressed by further research are identified. Meanwhile, current practices should continue. PMID- 29602497 TI - Comparison of loop-mediated isothermal amplification with hyperbranched rolling circle amplification as a simple detection method for Heterosigma akashiwo. AB - The fish-killing alga Heterosigma akashiwo is a globally distributed, toxic, and bloom-forming raphidophyte that has caused great losses to the fishing industry in many coastal countries. Therefore, rapid and sensitive detection methods should be developed to present timely warning of harmful algal blooms. In this study, hyperbranched rolling circle amplification (HRCA) was established for the detection of H. akashiwo and compared with loop-mediated isothermal amplification (LAMP) in terms of specificity and sensitivity. The partial D1-D2 sequence of the large subunit (LSU) of rDNA of H. akashiwo was used to design a specific padlock probe for HRCA and two pairs of specific primers for LAMP. The parameters for HRCA were optimized. Cross-reactivity tests showed that the specificity of the developed HRCA for H. akashiwo was greater than that of LAMP in this study. The sensitivities of HRCA and LAMP were comparable and were 10-fold higher than that of regular PCR. These methods also yielded a detection limit of 20 fg/MUL for the recombinant plasmid containing the target LSU D1-D2 and 1 cell for target species. The test with the simulated field samples indicated that the developed HRCA obtained a detection limit of 5 cells mL-1, which was lower than the warning cell density (100 cells mL-1) of H. akashiwo. The visual detection of positive HRCA could be achieved via coloration reaction with the addition of fluorescent SYBR Green I dye to the amplification products. The developed HRCA was also efficient for field samples with target cell densities ranging from 10 cells mL-1 to 1000 cells mL-1. Therefore, the proposed HRCA detection protocols are possibly applicable to the field monitoring of H. akashiwo. PMID- 29602495 TI - Longitudinal accrual of neocortical amyloid burden is associated with microstructural changes of the fornix in cognitively normal adults. AB - The fornix and parahippocampal cingulum are 2 major limbic tracts in the core memory network of the hippocampus. Although these fiber tracts are known to degrade with Alzheimer's disease (AD), little is known about their vulnerability in the asymptomatic phase of AD. In this longitudinal study of cognitively normal adults, we assessed amyloid-beta (Abeta) plaques using positron emission tomography and white matter microstructure using diffusion tensor imaging. We found that an increase of neocortical Abeta burden over time was associated with an increase of radial diffusivity in the fornix but not in the parahippocampal cingulum. The effect of increasing neocortical Abeta burden on the fornix remained significant after controlling for baseline measures, head motion, global brain atrophy, regional Abeta burden in the hippocampus, or microstructural changes in the global white matter. In addition, microstructural changes in the fornix were not associated with decline of episodic memory or other cognitive abilities. Our findings suggest that microstructural changes in the fornix may be an early sign in the asymptomatic phase of AD. PMID- 29602498 TI - Time series models of decadal trends in the harmful algal species Karlodinium veneficum in Chesapeake Bay. AB - The harmful dinoflagellate, Karlodnium veneficum, has been implicated in fish kill and other toxic, harmful algal bloom (HAB) events in waters worldwide. Blooms of K. veneficum are known to be related to coastal nutrient enrichment but the relationship is complex because this HAB taxon relies not only on dissolved nutrients but also particulate prey, both of which have also changed over time. Here, applying cross-correlations of climate-related physical factors, nutrients and prey, with abundance of K. veneficum over a 10-year (2002-2011) period, a synthesis of the interactive effects of multiple factors on this species was developed for Chesapeake Bay, where blooms of the HAB have been increasing. Significant upward trends in the time series of K. veneficum were observed in the mesohaline stations of the Bay, but not in oligohaline tributary stations. For the mesohaline regions, riverine sources of nutrients with seasonal lags, together with particulate prey with zero lag, explained 15%-46% of the variation in the K. veneficum time series. For the oligohaline regions, nutrients and particulate prey generally showed significant decreasing trends with time, likely a reflection of nutrient reduction efforts. A conceptual model of mid-Bay blooms is presented, in which K. veneficum, derived from the oceanic end member of the Bay, may experience enhanced growth if it encounters prey originating from the tributaries with different patterns of nutrient loading and which are enriched in nitrogen. For all correlation models developed herein, prey abundance was a primary factor in predicting K. veneficum abundance. PMID- 29602499 TI - Thermal acclimation affects growth and lipophilic toxin production in a strain of cosmopolitan harmful alga Dinophysis acuminata. AB - Species of the harmful algal bloom (HAB) genera Dinophysis are causative of one of the most widespread and expanding HAB events associated with the human intoxication, diarrheic shellfish poisoning (DSP). The effects of warming temperature on the physiology and toxinology of these mixotrophic species remain intractable due to their low biomass in nature and difficulties in establishing and maintaining them in culture. Hence, the present study investigated the influence of warming temperature, encompassing present and predicted climate scenarios, on growth and toxin production in a strain of the most cosmopolitan DSP-causative species, Dinophysis acuminata. The strain was isolated from western Japan, acclimated, and cultured over extended time spans. The specific growth and toxin production rates were highest at 20-26 degrees C and 17-29 degrees C, respectively, and had significant linear relationships during exponential phase. The cellular toxin production of okadaic acid and pectenotoxin-2 were highest during early exponential growth phase at temperatures <=17 degrees C but highest during late stationary phase at temperatures >=20 degrees C. The cellular toxin production of Dinophysistoxin-1, however, increased from early exponential to late stationary growth phase independently from temperature. The net toxin productions were not affected by acclimation temperature but significantly affected by growth and were highest during early exponential growth phase. Warming water temperatures increase growth and promote toxin production of D. acuminata, potentially increasing incidence of diarrheic shellfish poisoning events and closures of shellfish production. It is likely that D. acuminata is more toxic at low cell densities during bloom initiation in winter, and at high cell densities during bloom termination in spring-autumn. The results of the present research are also of importance for the mass production of D. acuminata for subsequent studies of the toxicological and pharmacological bioactivities of DSTs and PTX2, and the fate of these toxins in the natural environment and the vectoring shellfish molluscs. PMID- 29602500 TI - Differential toxin response of Pseudo-nitzschia multiseries as a function of nitrogen speciation in batch and continuous cultures, and during a natural assemblage experiment. AB - The toxigenic diatom Pseudo-nitzschia multiseries Hasle, isolated from the U.S. Pacific Northwest, was examined in unialgal laboratory cultures and in natural assemblages during shipboard experiments, to examine cellular growth and domoic acid (DA) production as a function of nitrogen (N) substrate and availability expected during bloom development and decline. Laboratory experiments utilizing batch cultures conducted at saturating (120 MUmol photons m-2 s-1) photosynthetic photon flux density (PPFD), demonstrated that P. multiseries (strain NWFSC-245) grows equally well on the three N substrates tested (nitrate [NO3-], ammonium [NH4+] and urea), and achieved an average specific growth rate of 0.83 d-1. Despite equivalent growth rates, cellular toxicity (particulate DA concentration normalized to cell abundance) varied as a function of N substrate, with urea grown cells demonstrating 1.3- and 3.4-fold more toxicity than both NH4+- and NO3 -grown cells. Cellular toxicity of the N-limited chemostat cultures, grown at a dilution rate of 0.48 d-1, were less than the cellular toxicity measured for the N-replete batch cultures for all three N substrates, but again cellular toxicity varied as a function of N substrate and the urea-supported cells were 3.5- and 4.3-fold more toxic than the respective NH4+- and NO3--supported cells. Starved cultures of P. multiseries showed no decline in cellular toxicity or change in the order of toxicity as a function of N substrate, and cells previously supported by urea were 13- and 5-fold more toxic than NH4+- and NO3--supported cells. At all three levels of N-sufficiency, the urea-grown cells consistently produced the highest concentration of particulate DA per cell compared to cells grown on either NO3- or NH4+. Shipboard N enrichment experiments using natural phytoplankton assemblages were conducted off the west coast of Washington in an area characterized by elevated concentrations of macronutrients and iron. All N (NO3-, NH4+ and urea) treatments showed significant increases in biomass (as measured by total and size-fractionated chlorophyll a) and the abundance of Pseudo-nitzschia species over the 6-d experiment. As with the unialgal laboratory experiments, cellular toxicity varied as a function of the N source supporting growth, and the planktonic assemblages enriched with either NH4+ or urea demonstrated greater cellular toxicity than the assemblages supported solely by NO3-. These laboratory and field results demonstrate that N substrate can regulate the toxicity of Pseudo-nitzschia species, and that N source should be considered when evaluating the potential effects of cultural eutrophication on the growth of toxigenic diatoms. PMID- 29602501 TI - Remote quantification of Cochlodinium polykrikoides blooms occurring in the East Sea using geostationary ocean color imager (GOCI). AB - Accurate and timely quantification of widespread harmful algal bloom (HAB) distribution is crucial to respond to the natural disaster, minimize the damage, and assess the environmental impact of the event. Although various remote sensing based quantification approaches have been proposed for HAB since the advent of the ocean color satellite sensor, there have been no algorithms that were validated with in-situ quantitative measurements for the red tide occurring in the Korean seas. Furthermore, since the geostationary ocean color imager (GOCI) became available in June 2010, an algorithm that exploits its unprecedented observation frequency (every hour during the daytime) has been highly demanded to better track the changes in spatial distribution of red tide. This study developed a novel red tide quantification algorithm for GOCI that can estimate hourly chlorophyll-a (Chl a) concentration of Cochlodinium (Margalefidinium) polykrikoides, one of the major red tide species around Korean seas. The developed algorithm has been validated using in-situ Chl a measurements collected from a cruise campaign conducted in August 2013, when a massive C. polykrikoides bloom devastated Korean coasts. The proposed algorithm produced a high correlation (R2=0.92) with in-situ Chl a measurements with robust performance also for high Chl a concentration (300mg/m3) in East Sea areas that typically have a relatively low total suspended particle concentration (<0.5mg/m3). PMID- 29602502 TI - Blurred lines: Multiple freshwater and marine algal toxins at the land-sea interface of San Francisco Bay, California. AB - San Francisco Bay (SFB) is a eutrophic estuary that harbors both freshwater and marine toxigenic organisms that are responsible for harmful algal blooms. While there are few commercial fishery harvests within SFB, recreational and subsistence harvesting for shellfish is common. Coastal shellfish are monitored for domoic acid and paralytic shellfish toxins (PSTs), but within SFB there is no routine monitoring for either toxin. Dinophysis shellfish toxins (DSTs) and freshwater microcystins are also present within SFB, but not routinely monitored. Acute exposure to any of these toxin groups has severe consequences for marine organisms and humans, but chronic exposure to sub-lethal doses, or synergistic effects from multiple toxins, are poorly understood and rarely addressed. This study documents the occurrence of domoic acid and microcystins in SFB from 2011 to 2016, and identifies domoic acid, microcystins, DSTs, and PSTs in marine mussels within SFB in 2012, 2014, and 2015. At least one toxin was detected in 99% of mussel samples, and all four toxin suites were identified in 37% of mussels. The presence of these toxins in marine mussels indicates that wildlife and humans who consume them are exposed to toxins at both sub-lethal and acute levels. As such, there are potential deleterious impacts for marine organisms and humans and these effects are unlikely to be documented. These results demonstrate the need for regular monitoring of marine and freshwater toxins in SFB, and suggest that co-occurrence of multiple toxins is a potential threat in other ecosystems where freshwater and seawater mix. PMID- 29602503 TI - Population dynamic of bloom-forming Microcystis aeruginosa in the presence of the invasive bivalve Limnoperna fortunei. AB - Aquatic ecosystems have been severely altered by invasive species and a connection has been observed between bivalve invasions and an increase in frequency of cyanobacteria toxic blooms. In South America, the invasive golden mussel, Limnoperna fortunei, has caused serious environmental and economic impacts, because of its high filtration rates, high population densities and rapid dispersion. Changes in the plankton community have been detected at sites invaded by this species. The aim of the present study was to investigate the possible effects of this mussel on the growth of the bloom-forming cyanobacterium Microcystis aeruginosa, in laboratory experiments under controlled light and temperature conditions. The cyanobacterium M. aeruginosa and a chlorophyte (Pseudokirchneriella sp.) were used either together or alone as food for the mussels. Density measurements of M. aeruginosa and Pseudokirchneriella sp. growing in vessels with and without mussels were performed daily, and nutrient concentrations in the water were assessed at the beginning and end of the experiment. The results indicated that Pseudokirchneriella sp. acted as a competitor, contributing to reduce densities and growth rates of M. aeruginosa. These effects, however, did not occur in the presence of the golden mussel, when the densities of Pseudokirchneriella sp. were significantly lower, possibly due to selective grazing. Phosphate and nitrate concentrations were always higher in the presence of the bivalves. As previously observed for other invasive mollusks, our results suggest that the golden mussel may have a positive effect on M. aeruginosa by the exclusion of potential competitors as well as by increasing nutrient supply. PMID- 29602504 TI - Genome variation in nine co-occurring toxic Cylindrospermopsis raciborskii strains. AB - Cyanobacteria form harmful algal blooms and are highly adapted to a range of habitats, in part due to their phenotype plasticity. This plasticity is partially the result of co-existence of multiple strains within a single population. The toxic cyanobacterium Cylindrospermopsis raciborskii has remarkable phenotypic plasticity, strain variation and environmental adaptation resulting in an expansion of its global range. To understand the genetic basis of the high level of plasticity within a C. raciborskii population, the genomes of nine co occurring strains were compared. The strains differed in morphology, toxin cell quotas and physiology, despite being obtained from a single water sample. Comparative genomics showed that three coiled strains were 3.9 Mbp in size, with 3544 +/- 11 genes, while straight strains were 3.8 Mbp in size, with 3485 +/- 20 genes. The core proteome comprised 86% of the genome and consisted of 2891 orthologous groups (OGs), whereas the variable genome comprised ~14% (847 OGs), and the strain specific genome only ~1% (433 OGs).There was a high proportion of variable strain-specific genes for the very closely related strains, which may underpin strain differentiation. The variable genes were associated with environmental responses and adaptation, particularly phage defence, DNA repair, membrane transport, and stress, illustrative of the adaptability of the strains in response to environmental and biological stressors. This study shows that high genomic variability exists between co-occurring strains and may be the basis of strain phenotypic differences and plasticity of populations. Therefore management and prediction of blooms of this harmful species requires different approaches to capture this strain variability. PMID- 29602505 TI - Consortial brown tide - picocyanobacteria blooms in Guantanamo Bay, Cuba. AB - A brown tide bloom of Aureoumbra lagunensis developed in Guantanamo Bay, Cuba during a period of drought in 2013 that followed heavy winds and rainfall from Hurricane Sandy in late October 2012. Based on satellite images and water turbidity measurements, the bloom appeared to initiate in January 2013. The causative species (A. lagunensis) was confirmed by microscopic observation, and pigment and genetic analyses of bloom samples collected on May 28 of that year. During that time, A. lagunensis reached concentrations of 900,000 cells ml-1 (28 ppm by biovolume) in the middle portion of the Bay. Samples could not be collected from the northern (Cuban) half of the Bay because of political considerations. Subsequent sampling of the southern half of the Bay in November 2013, April 2014, and October 2014 showed persistent lower concentrations of A. lagunensis, with dominance shifting to the cyanobacterium Synechococcus (up to 33 ppm in April), an algal group that comprised a minor bloom component on May 28. Thus, unlike the brown tide bloom in Laguna Madre, which lasted 8 years, the bloom in Guantanamo Bay was short-lived, much like recent blooms in the Indian River, Florida. Although hypersaline conditions have been linked to brown tide development in the lagoons of Texas and Florida, observed euhaline conditions in Guantanamo Bay (salinity 35-36) indicate that strong hypersalinity is not a requirement for A. lagunensis bloom formation. Microzooplankton biomass dominated by ciliates was high during the observed peak of the brown tide, and ciliate abundance was high compared to other systems not impacted by brown tide. Preferential grazing by zooplankton on non-brown tide species, as shown in A. lagunensis blooms in Texas and Florida, may have been a factor in the development of the Cuban brown tide bloom. However, subsequent selection of microzooplankton capable of utilizing A. lagunensis as a primary food source may have contributed to the short-lived duration of the brown tide bloom in Guantanamo Bay. PMID- 29602506 TI - Life histories of microalgal species causing harmful blooms: Haploids, diploids and the relevance of benthic stages. AB - In coastal and offshore waters, Harmful Algal Blooms (HABs) currently threaten the well-being of coastal countries. These events, which can be localized or involve wide-ranging areas, pose risks to human health, marine ecosystems, and economic resources, such as tourism, fisheries, and aquaculture. Dynamics of HABs vary from one site to another, depending on the hydrographic and ecological conditions. The challenge in investigating HABs is that they are caused by organisms from multiple algal classes, each with its own unique features, including different life histories. The complete algal life cycle has been determined in <1% of the described species, although elucidation of the life cycles of bloom-forming species is essential in developing preventative measures. The knowledge obtained thus far has confirmed the complexity of the algal life cycle, which is composed of discrete life stages whose morphology, ecological niche (plankton/benthos), function, and lifespan vary. The factors that trigger transitions between the different stages in nature are mostly unknown, but it is clear that an understanding of this process provides the key to effectively forecasting bloom recurrence, maintenance, and decline. Planktonic stages constitute an ephemeral phase of the life cycle of most species whereas resistant, benthic stages enable a species to withstand adverse conditions for prolonged periods, thus providing dormant reservoirs for eventual blooms and facilitating organismal dispersal. Here we review current knowledge of the life cycle strategies of major groups of HAB producers in marine and brackish waters. Rather than providing a comprehensive discussion, the objective was to highlight several of the research milestones that have changed our understanding of the plasticity and frequency of the different life cycle stages as well as the transitions between them. We also discuss the relevance of benthic and planktonic forms and their implications for HAB dynamics. PMID- 29602507 TI - Phylogeny and salt-tolerance of freshwater Nostocales strains: Contribution to their systematics and evolution. AB - Phylogenetic relationships among heterocytous genera (the Nostocales order) have been profoundly modified since the use of polyphasic approaches that include molecular data. There is nonetheless still ample scope for improving phylogenetic delineations of genera with broad ecological distributions, particularly by integrating specimens from specific or up-to-now poorly sampled habitats. In this context, we studied 36 new isolates belonging to Chrysosporum, Dolichospermum, Anabaena, Anabaenopsis, and Cylindrospermopsis from freshwater ecosystems of Burkina-Faso, Senegal, and Mayotte Island. Studying strains from these habitats is of particular interest as we suspected different range of salt variations during underwent periods of drought in small ponds and lakes. Such salt variation may cause different adaptation to salinity. We then undertook a polyphasic approach, combining molecular phylogenies, morphological analyses, and physiological measurements of tolerance to salinity. Molecular phylogenies of 117 Nostocales sequences showed that the 36 studied strains were distributed in seven lineages: Dolichospermum, Chrysosporum, Cylindrospermopsis/Raphidiopsis, Anabaenopsis, Anabaena sphaerica var tenuis/Sphaerospermopsis, and two independent Anabaena sphaerica lineages. Physiological data were congruent with molecular results supporting the separation into seven lineages. In an evolutionary context, salinity tolerance can be used as an integrative marker to reinforce the delineation of some cyanobacterial lineages. The history of this physiological trait contributes to a better understanding of processes leading to the divergence of cyanobacteria. In this study, most of the cyanobacterial strains isolated from freshwater environments were salt-tolerant, thus suggesting this trait constituted an ancestral trait of the heterocytous cyanobacteria and that it was probably lost two times secondarily and independently in the ancestor of Dolichospermum and of Cylindrospermopsis. PMID- 29602508 TI - Revealing the distinct habitat ranges and hybrid zone of genetic sub-populations within Pseudo-nitzschia pungens (Bacillariophyceae) in the West Pacific area. AB - Genetic sub-populations (clades) of cosmopolitan marine diatom Pseudo-nitzschia pungens might have distinct habitats, and their hybrid zone is suspected in higher latitude area of the West Pacific area, however, it is still unrevealed because of technical difficulties and lack of evidences in natural environments. The aim of this study is to investigate the habitat characteristics of each clade of P. pungens on geographical distribution with the habitat temperature ranges of each clade and to reveal their hybrid zone in the West Pacific area. We employed the 137 number of nucleotide sequences of P. pungens and its sampling data (spatial and temporal scale) originated from the West Pacific area, and used field application of qPCR assay for intra-specific level of P. pungens. Only two genotypes, clade I and III, were identified in the West Pacific area. Clade I was distributed from 39 to 32.3 degrees N, and clade III were from 1.4 to 34.4 degrees N. The estimated habitat temperature for the clade I and clade III ranges were 8.1-26.9 degrees C and 24.2-31.2 degrees C, respectively. The latitudinal distributions and temperature ranges of each clade were significantly different. The qPCR assay employed, and results suggested that the hybrid zone for clade I and III has been observed in the southern Korean coasts, and clade III might be introduced from the Southern Pacific area. The cell abundances of clade III were strongly related with the higher seawater temperature and warm current force. This study has defined distinct habitat characteristics of genetically different sub-populations of P. pungens, and revealed its hybrid zone in natural environment for the first time. We also provided strong evidences about dispersion of the population of clade III to higher latitude in the West Pacific area. PMID- 29602509 TI - Interactions between nitrogen form, loading rate, and light intensity on Microcystis and Planktothrix growth and microcystin production. AB - The toxin-producing, bloom-forming cyanobacterial genera Microcystis and Planktothrix require fixed nitrogen (N), such as nitrate, ammonium, or organic N (e.g., urea) for growth and production of microcystins (MC). Bioavailable N can enter lakes in pulses via tributary discharge and through in-lake recycling, which can maintain low N concentrations. Additionally, light intensity has been suggested to play a role in MC production. This study examined how three forms of N (nitrate, ammonium, and urea) interacted with N loading rate (one large pulse vs. many small pulses) and light intensity to stimulate Microcystis and Planktothrix growth and MC production using nutrient enrichment experiments. Enrichments of nitrate, ammonium, and urea resulted in greater cyanobacterial biovolumes and MC concentrations than phosphorus-only enrichments, and there was no difference between pulse (100 MUmol/L) and press treatments (8.3 MUmol/L every 4 h). Analysis of mcyD transcripts showed significant up-regulation within 4 h of ammonium and urea enrichment. High light intensities (300 MUmol photons/m2/s) with N enrichment resulted in greater cyanobacterial biovolumes and MC concentrations than lower light intensities (30 and 3 MUmol photons/m2/s). Overall, the results suggest Microcystis and Planktothrix can use many forms of N and that high light intensities enhance MC production during elevated N concentrations. Moreover, the results here further demonstrate the importance of considering N, as well as P, in management strategies aimed at mitigating cyanobacterial blooms. PMID- 29602510 TI - Feeding and grazing impact by the bloom-forming euglenophyte Eutreptiella eupharyngea on marine eubacteria and cyanobacteria. AB - The phototrophic euglenophyte Eutreptiella eupharyngea often causes blooms in the coastal waters of many countries, but its mode of nutrition has not been assessed. This species has previously been considered as exclusively auxotrophic. To explore whether E. eupharyngea is a mixotrophic species, the protoplasm of E. eupharyngea cells were examined using light, epifluorescence, and transmission electron microscopy after eubacteria, the cyanobacterium Synechococcus sp., and diverse algal species were provided as potential prey. Furthermore, the ingestion rates of E. eupharyngea KR on eubacteria or Synechococcus sp. as a function of prey concentration were measured. In addition, grazing by natural populations of euglenophytes on natural populations of eubacteria in Masan Bay was investigated. This study is the first to report that E. eupharyngea is a mixotrophic species. Among the potential prey organisms offered, E. eupharyngea fed only on eubacteria and Synechococcus sp., and the maximum ingestion rates of these two organisms measured in the laboratory were 5.7 and 0.7 cells predator-1 h-1, respectively. During the field experiments, the maximum ingestion rates and grazing impacts of euglenophytes, including E. eupharyngea, on natural populations of eubacteria were 11.8 cells predator-1 h-1 and 1.228 d-1, respectively. Therefore, euglenophytes could potentially have a considerable grazing impact on marine bacterial populations. PMID- 29602511 TI - Co-design for implementing patient participation in hospital services: A discussion paper. PMID- 29602512 TI - Emerging Roles of DHHC-mediated Protein S-palmitoylation in Physiological and Pathophysiological Context. AB - Protein S-palmitoylation refers to a post-translational modification (PTM) wherein palmitic acid, a 16-carbon long saturated fatty acid gets covalently attached to Cys sidechain of a protein. It has been known to the literature for almost 50 years and in general, this PTM is believed to facilitate membrane attachments of proteins for the obvious hydrophobicity of the palmitoyl group. But after the discovery of the protein palmitoyl acyltransferases (PATs, also known as DHHC-PATs), a major paradigm shift has been observed in the field of protein S-palmitoylation. A family of 23 mammalian DHHC-PATs has been identified and the majority of them are associated with many human diseases spanning from neuropsychiatric diseases to cancers. Novel unique and essential role of DHHC mediated protein S-palmitoylation has been revealed apart from its membrane trafficking role. Biomedical importance of DHHCs has also been reiterated with small molecule inhibitors for DHHCs as well as in DHHC-knockout mice or mouse Xenograft models. In this review, we present recent advances in the field of protein S-palmitoylation and the involvement of individual DHHC isoforms in human diseases. In addition, the recent development of the analytical tools to study S palmitoylation and their inhibitors are discussed in detail. We also highlight the issues that need to be addressed in detail to further develop our understanding on protein S-palmitoylation and strongly believe that pharmacological modulation of DHHC-mediated protein S-palmitoylation has a massive potential to emerge as a novel therapeutic strategy for human diseases. It will not be surprising if reversible protein S-palmitoylation prove to be an indispensable PTM that regulates a host of cellular processes, just like protein phosphorylation or ubiquitination. PMID- 29602513 TI - Validation of standard method EN ISO 11290 - Part 1 - Detection of Listeria monocytogenes in food. AB - The reference method for the detection and enumeration of L. monocytogenes in food (Standards EN ISO 11290-1&2) has been validated by inter-laboratory studies in the frame of the Mandate M381 from European Commission to CEN. In this paper, the collaborative studies led in 2013 on 5 matrices (cold-smoked salmon, milk powdered infant food formula, vegetables, environment, and cheese) to validate the recently revised Standard EN ISO 11290-Part 1 are reported. According to the results obtained, the revised Standard EN ISO 11290-1 can be considered as a good method for the detection of L. monocytogenes in foods and food processing environments, in particular for the matrices included in the study. According to the matrices, the sensitivity rate varied from 91.1% to 100%, and the specificity rate varied from 97.6% to 100%. Positive samples were most often detected after 24 h half-Fraser enrichment. PMID- 29602514 TI - The highs and lows of cardiovascular disease prevention. PMID- 29602515 TI - The critical role of C5a as an initiator of neutrophil-mediated autoimmune inflammation of the joint and skin. AB - The deposition of IgG autoantibodies in peripheral tissues and the subsequent activation of the complement system, which leads to the accumulation of the anaphylatoxin C5a in these tissues, is a common hallmark of diverse autoimmune diseases, including rheumatoid arthritis (RA) and pemphigoid diseases (PDs). C5a is a potent chemoattractant for granulocytes and mice deficient in its precursor C5 or its receptor C5aR1 are resistant to granulocyte recruitment and, consequently, to tissue inflammation in several models of autoimmune diseases. However, the mechanism whereby C5a/C5aR regulates granulocyte recruitment in these diseases has remained elusive. Mechanistic studies over the past five years into the role of C5a/C5aR1 in the K/BxN serum arthritis mouse model have provided novel insights into the mechanisms C5a/C5aR1 engages to initiate granulocyte recruitment into the joint. It is now established that the critical actions of C5a/C5aR1 do not proceed in the joint itself, but on the luminal endothelial surface of the joint vasculature, where C5a/C5aR1 mediate the arrest of neutrophils on the endothelium by activating beta2 integrin. Then, C5a/C5aR1 induces the release of leukotriene B4 (LTB4) from the arrested neutrophils. The latter, subsequently, initiates by autocrine/paracrine actions via its receptor BLT1 the egress of neutrophils from the blood vessel lumen into the interstitial. Compelling evidence suggests that this C5a/C5aR1-LTB4/BLT1 axis driving granulocyte recruitment in arthritis may represent a more generalizable biological principle critically regulating effector cell recruitment in other IgG autoantibody-induced diseases, such as in pemphigoid diseases. Thus, dual inhibition of C5a and LTB4, as implemented in nature by the lipocalin coversin in the soft-tick Ornithodoros moubata, may constitute a most effective therapeutic principle for the treatment of IgG autoantibody-driven diseases. PMID- 29602516 TI - Simulation as a surgical teaching model. PMID- 29602517 TI - This letter corrects factual errors and omissions in Ellen K. Silbergeld's commentary on "Managing hazards in place: The risks of residual risk". PMID- 29602518 TI - Comorbid mental disorders among adults in the mental health surveillance survey. AB - PURPOSE: To examine the prevalence and correlates of mental disorder comorbidity in the adult U.S. household population. METHODS: Data are from a nationally representative sample of noninstitutionalized, civilian adults aged 18 years or older (n = 5653) who participated in the 2008-2012 Mental Health Surveillance Study. Mental disorders, including substance use disorders, were assessed by clinical interviewers using a semistructured diagnostic instrument. Analyses examined co-occurrence of mental disorders and associations with sociodemographic, functional impairment, and treatment correlates. RESULTS: Approximately one-third of adults (31.1%, or more than 15 million) with a past year mental disorder had a co-occurring mental disorder. Correlates of comorbidity in adjusted models included being of young age, being of non-Hispanic white race/ethnicity, having low family income, and living in a large metropolitan area. Adults with comorbid mental disorders had lower mean levels of functioning and were more likely to report past-year treatment than adults with a single disorder; they also had higher estimates of past-year perceived unmet need for care (21.7% vs. 11.6%, P < .01). CONCLUSIONS: About one in three adults with a mental disorder have a co-occurring mental disorder. Elucidating factors associated with co-occurrence may lend clues to shared etiologies, help improve prevention efforts, facilitate early identification, and improve treatment regimens. PMID- 29602519 TI - A light in the control of secondary hyperparathyroidism. Etelcalcetide IV in hemodialysis. PMID- 29602520 TI - The Knowledge of and Attitudes Toward First Aid and Cardiopulmonary Resuscitation Among Parents. AB - PURPOSE: To determine the level of knowledge of first aid and cardiopulmonary resuscitation (CPR) among the parents of children who attended our Pediatric Emergency Department and to identify the factors that affect this knowledge. DESIGN AND METHODS: Descriptive, transversal study. A questionnaire was distributed anonymously among parents to collect data about their previous CPR training, knowledge and experience. RESULTS: A total 405 valid questionnaires were returned. The mean age of the sample was 38.08 (SD 7.1) years, and 66.9% of participants were female. The mean score of correctly answered questions was 6.76 out of 19 questions. Parents with a university education received a mean score of 7.16 versus 6.24 for those with a primary education (p = 0.022). Parents with previous training received a higher mean score (8.04 vs 6.17, respectively, p < 0.01). Parents with jobs related to healthcare or education received a higher mean score compared to those who did not (8.63, p < 0.01 and 7.16, p = 0.0013, respectively). No significant differences among parents with chronically ill children (p = 0.76) or related to the number of children (rho = -0.101) were observed. Furthermore, 77.3% of parents expressed an interest in receiving further training. CONCLUSIONS: Knowledge of first aid among the general population is lacking. Parents with previous training in this field, those with a university-level education, and those who are healthcare providers and educational professionals received significantly higher scores. PRACTIC IMPLICATIONS: Studies based on surveys can be useful in estimating a population's knowledge base, allowing the development of community-based training activities. PMID- 29602521 TI - Animal Models of Addiction and Neuropsychiatric Disorders and Their Role in Drug Discovery: Honoring the Legacy of Athina Markou. AB - Each of the co-authors worked with Athina Markou, at different stages of our careers and in different capacities, to develop, optimize, and use animal models of drug addiction and, more generally, mental health disorders such as anxiety, depression, and schizophrenia. Here, we briefly summarize some of our work with Athina, primarily involving the use of the intracranial self-stimulation and intravenous drug self-administration procedures. This work established that excessive consumption of addictive drugs can induce profound dysfunction in brain reward circuits. Such drug-induced reward deficits are likely to play a key role in precipitating the emergence of compulsive drug-seeking behaviors. We also summarize findings suggesting that perturbations in glutamatergic transmission contribute to brain reward deficits in drug-dependent animals and that metabotropic glutamate receptors are potential targets for the development of novel medications to facilitate long-term drug abstinence and prevention of relapse. PMID- 29602522 TI - High Glycemic Index Metabolic Damage - a Pivotal Role of GIP and GLP-1. AB - When glucose-fructose dimers are supplied as the slowly digestible, completely absorbable, low glycemic index (GI) sugar isomaltulose, the detrimental effects of high GI sucrose are avoided. This difference requires the presence of intact glucose-induced insulinotropic peptide receptor (GIPR) and is mediated by the rapid uptake of glucose and the stimulation of GIP release from K cells in the upper small intestine. GIP promotes lipogenesis, fatty liver, insulin resistance, and postprandial inflammation, and reduces fat oxidation in skeletal muscle, partly by hypothalamic interference with energy partitioning and epigenetic programming. GIP is similarly required for the detrimental metabolic effects of other high GI carbohydrates. We therefore propose that the release of GIP in the upper small intestine is an important determinant of the metabolic quality of carbohydrates. PMID- 29602523 TI - Endocrine, Paracrine, and Autocrine Signaling Pathways That Regulate Ovulation. AB - The central role of luteinizing hormone (LH) and its receptor (LHCGR) in triggering ovulation has been recognized for decades. Because the LHCGR is present in the mural (outermost) granulosa cell layer of preovulatory follicles (POFs), the LH-initiated signal has to be transmitted to another somatic cell type (cumulus granulosa cells) and the oocyte to release a fertilizable oocyte. Recent studies have shown that activation of the LHCGR initiates vectorial transfer of information among the two somatic cell types and the oocyte and the molecules and signaling pathways involved are now better understood. This review summarizes the newer developments on the complex signaling pathways that regulate ovulation. PMID- 29602524 TI - Individual data meta-analysis for the study of survival after pulmonary metastasectomy in colorectal cancer patients: A history of resected liver metastases worsens the prognosis. AB - OBJECTIVES: To assess the impact of a history of liver metastases on survival in patients undergoing surgery for lung metastases from colorectal carcinoma. METHODS: We reviewed recent studies identified by searching MEDLINE and EMBASE using the Ovid interface, with the following search terms: lung metastasectomy, pulmonary metastasectomy, lung metastases and lung metastasis, supplemented by manual searching. Inclusion criteria were that the research concerned patients with lung metastases from colorectal cancer undergoing surgery with curative intent, and had been published between 2007 and 2014. Exclusion criteria were that the paper was a review, concerned surgical techniques themselves (without follow-up), and included patients treated non-surgically. Using Stata 14, we performed aggregate data and individual data meta-analysis using random-effect and Cox multilevel models respectively. RESULTS: We collected data on 3501 patients from 17 studies. The overall median survival was 43 months. In aggregate data meta-analysis, the hazard ratio for patients with previous liver metastases was 1.19 (95% CI 0.90-1.47), with low heterogeneity (I2 4.3%). In individual data meta-analysis, the hazard ratio for these patients was 1.37 (95% CI 1.14-1.64; p < 0.001). Multivariate analysis identified the following factors significantly affecting survival: tumour-infiltrated pulmonary lymph nodes (p < 0.001), type of resection (p = 0.005), margins (p < 0.001), carcinoembryonic antigen levels (p < 0.001), and number and size of lung metastases (both p < 0.001). CONCLUSIONS: A history of liver metastases is a negative prognostic factor for survival in patients with lung metastases from colorectal cancer. We registered the meta analysis protocol in PROSPERO (CRD42015017838). PMID- 29602525 TI - Access to childhood immunisation services and its determinants among recent and settled migrants in Delhi, India. AB - OBJECTIVES: Childhood immunisation is one of the important public health interventions, and poor migrants are vulnerable to forego these services. The objective of the study is to understand the access of childhood immunisation services to the socio-economically disadvantaged migrants and the determinants of full immunisation uptake up to the age of 1 year. METHODS: In a cross-sectional survey, 458 migrant households with a child aged up to 2 years were identified. Data on sociodemographics, migration history, receipt of various vaccines and maternal healthcare services were collected through interviewer-administered pretested questionnaires. Multiple logistic regression analysis was performed to identify the determinants of full immunisation status. RESULTS: Childhood immunisation coverage rates were low as only 31% of recent-migrant children and 53% of settled-migrant children were fully immunised against seven vaccine preventable diseases (VPDs) by 12 months of age. Lack of awareness of the immunisation schedule and location of health facilities, mobility, illness of the child, fear of vaccines and side-effects were the main reasons for incomplete or no immunisation. Mother's educational attainment, TV viewership, hospital birth and receipt of information on childhood immunisation from the health workers during postnatal visits increased chances of getting the child fully immunised against seven VPDs by 1 year of age. CONCLUSION: The migrants, particularly the recent migrants, are at the risk of foregoing immunisation services because of livelihood insecurity, mobility and non-familiarity of services in the new urban environment. There is a need to deliver services with a focus on recent migrants. Investing in education and socio-economic development and providing secured livelihoods and equitable services are important to improve and sustain access to healthcare services in the long run. PMID- 29602526 TI - Differences in the health-age profile across rural and urban sectors: a study on migrants and non-migrants in China. AB - OBJECTIVES: The objective of this study is to examine age-health differentials between migrants and non-migrants in the context of migration in China. STUDY DESIGN: We use nationally representative data from the China Labor-force Dynamics Survey to analyze the relationship between age and health across different migration status groups. METHODS: We used a comprehensive measure of perceived health from factor analysis and structural equation models to take multiple dimensions of subjective health into consideration. RESULTS: We found a difference in the association between age and health (net of controls) at age 46 years and above but not for younger age groups. That is, there is a health disadvantage between those who had ever migrated and urban non-migrants in older adulthood but not for young adulthood. However, the age-health profile of rural ever-migrants is not different from that of rural non-migrants. CONCLUSIONS: These results highlight the effect of migration on health at different ages, which reflects the toll that migration takes on health over time. Our results imply that researchers should take into consideration life stages when examining the migration-health nexus. We also argue that there are potential influences related to China's longstanding division between rural and urban sectors. PMID- 29602527 TI - Abdominal Cutaneous Nerve Entrapment Syndrome: The Cause of Localized Abdominal Pain in a Young Pregnant Woman. AB - BACKGROUND: Despite the broad differential diagnosis in any patient referring with symptoms involving the chest or abdomen, a small number of conditions overshadow the rest by their probability. Chest and abdominal wall pain continues to constitute a common and expensive overlooked source of pain of unknown cause. In particular, cutaneous nerve entrapment syndrome is commonly encountered but not easily diagnosed unless its specific symptoms are sought and the precise physical examination undertaken. CASE REPORT: A primigravida woman with unbearable abdominal pain was referred repeatedly seeking a solution for her suffering. Numerous laboratory and imaging studies were employed in order to elucidate the cause of her condition. After numerous visits and unnecessary delay, the diagnosis was finally made by a physician fully versed in the field of torso wall pain. The focused physical examination disclosed abdominal cutaneous nerve entrapment syndrome as the diagnosis, and anesthetic infiltration led to immediate alleviation of her pain. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Cutaneous nerve entrapment is a common cause of abdominal pain that is reached on the basis of thorough history and physical examination alone. Knowledge dissemination of the various torso wall syndromes is imperative for prompt delivery of suitable care. All emergency physicians should be fully aware of this entity because the diagnosis is based solely on physical examination, and immediate relief can be provided in the framework of the first visit. Wider recognition of this syndrome will promise that such mishaps are not repeated in the future. PMID- 29602528 TI - Subacute Combined Degeneration from Recreational Nitrous Oxide Inhalation. PMID- 29602529 TI - Neurosyphilis as a Cause of Transverse Myelitis in a Teenage Girl. AB - BACKGROUND: Syphilis is a sexually transmitted infection that was nearly eradicated in 2001 but is now making a resurgence. It has a wide range of clinical manifestations depending on disease stage. Neurosyphilis is an infrequently seen infectious disease with central nervous system involvement that can occur in either early- or late-stage syphilis. The diagnosis of neurosyphilis is challenging, primarily because Treponema pallidum, the infecting organism, cannot be cultured in vitro. This article describes a patient with neurosyphilis and reviews the epidemiology and clinical manifestations, diagnostics, and treatment of neurosyphilis. CASE REPORT: In compliance with the request of the Privacy Board of our institution, the numerical age of this patient has been omitted. A sexually active teenage girl who was treated for primary syphilis 2 years earlier presented to a tertiary children's hospital with paresthesia and weakness of her right leg, left arm, and neck. Magnetic resonance imaging revealed cervical intramedullary cord edema consistent with transverse myelitis. Serum studies showed positive syphilis enzyme immunoassay, T. pallidum particle agglutination assay, and fluorescent treponemal antibody absorption. A serum rapid plasma reagin test was negative. A lumbar puncture was performed with normal cell count and protein. A cerebrospinal fluid Venereal Disease Research Laboratory test was negative. She was diagnosed with neurosyphilis and treated with intravenous steroids and penicillin G, with near complete resolution of symptoms. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: The Centers for Disease Control and prevention has noted a steady rise of the incidence of syphilis since 2002. Emergency physicians should be familiar with the spectrum of the clinical manifestations of syphilis, challenges in diagnostics, and appropriate treatment course. PMID- 29602530 TI - Hydrogel Arrays and Choroidal Neovascularization Models for Evaluation of Angiogenic Activity of Vital Pulp Therapy Biomaterials. AB - INTRODUCTION: This study intended to evaluate the angiogenic properties of vital pulp therapy materials including white mineral trioxide aggregate (WMTA), calcium hydroxide (Ca[OH]2), Geristore (Den-Mat, Santa Maria, CA), and nano WMTA biomaterials. METHODS: WMTA, Ca(OH)2, Geristore, and nano WMTA disks were prepared, dispersed into 2 mL Milli-Q (Millipore, ThermoFisher, Hanover Park, IL) distilled water, and centrifuged to obtain 2 mL supernatant elution. Thirty-five wells of polyethylene glycol hydrogel arrays were prepared and divided into 5 groups of 7 (n = 7). Mice molar endothelial cells (ECs) were placed on hydrogel arrays. The elution prepared from each sample was diluted in growth medium (1:3) and added to the hydrogel arrays. The EC medium alone was used for the control. For the choroidal neovascularization (CNV) model, thirty-five 6-week-old female mice were lasered and divided into 5 groups, and elution from each sample (2 MUL) or saline (control) was delivered by intravitreal injection on the day of the laser treatment and 1 week later. The mean number of nodes, the total length of the branches in the hydrogel arrays, and the mean area of CNV were calculated using ImageJ software (National Institutes of Health, Bethesda, MD) and analyzed by 1-way analysis of variance and post hoc Tukey honest significant difference tests. RESULTS: The comparison of results regarding the number of nodes showed the values of control > Geristore > nano WMTA > WMTA > Ca(OH)2. Regarding the total branch length and the CNV area, the comparison of results showed values of Geristore > control > nano WMTA > WMTA > Ca(OH)2. CONCLUSIONS: All tested materials showed minimal antiangiogenic activity, whereas Geristore and nano WMTA showed a higher proangiogenic activity than WMTA and Ca(OH)2. PMID- 29602531 TI - Methodological and Reporting Quality of Systematic Reviews and Meta-analyses in Endodontics. AB - INTRODUCTION: The aim of this systematic review (SR) was to evaluate the quality of SRs and meta-analyses (MAs) in endodontics. METHODS: A comprehensive literature search was conducted to identify relevant articles in the electronic databases from January 2000 to June 2017. Two reviewers independently assessed the articles for eligibility and data extraction. SRs and MAs on interventional studies with a minimum of 2 therapeutic strategies in endodontics were included in this SR. Methodologic and reporting quality were assessed using A Measurement Tool to Assess Systematic Reviews (AMSTAR) and Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA), respectively. The interobserver reliability was calculated using the Cohen kappa statistic. Statistical analysis with the level of significance at P < .05 was performed using Kruskal-Wallis tests and simple linear regression analysis. RESULTS: A total of 30 articles were selected for the current SR. Using AMSTAR, the item related to the scientific quality of studies used in conclusion was adhered by less than 40% of studies. Using PRISMA, 3 items were reported by less than 40% of studies, which were on objectives, protocol registration, and funding. No association was evident comparing the number of authors and country with quality. Statistical significance was observed when quality was compared among journals, with studies published as Cochrane reviews superior to those published in other journals. AMSTAR and PRISMA scores were significantly related. CONCLUSIONS: SRs in endodontics showed variability in both methodologic and reporting quality. PMID- 29602532 TI - Cross-Species Neuromodulation from High-Intensity Transcranial Electrical Stimulation. AB - Transcranial electrical stimulation (TES) is a proposed tool for noninvasively modulating human brain circuits, but its ability to affect cortical physiology remains unclear. A recent study merged TES with live animal and human cadaveric recordings to verify intracranial electrical effects, then used these findings to develop a novel neuromodulation protocol. PMID- 29602533 TI - The neurocognitive nature of children with ADHD comorbid sluggish cognitive tempo: Might SCT be a disorder of vigilance? AB - : Sluggish Cognitive Tempo (SCT) refers to a clinical construct including several symptoms such as sluggishness, absentmindedness, low energy. In the present study, we compared neurocognitive laboratory outcomes of ADHD children with or without SCT. METHOD: The CNS Vital Signs Battery was utilized to measure neurocognitive measure of the participants. The SCT+ADHD group comprised of 42 subjects, ADHD group was 41 subjects and control group was 24 subjects. RESULTS: The cognitive flexibility score was found to be more severely impaired in ADHD children with SCT in comparison to the ADHD-only. Additionally, greater deficits in the Shifting Attention Test (p = 0.014) and the Continuous Performance Test (reaction time score, p < 0.01) were found in the SCT+ADHD group relative to ADHD group. Processing speed, visual/auditory memory, psychomotor speed and reaction time were not found to more impaired in those comorbid with SCT. CONCLUSION: Impairments in the cognitive flexibility and more specifically shifting attention and continuous performance may be indicative of vigilance and orientation problems rather than executive functions for the SCT construct. PMID- 29602534 TI - An investigation of emotion recognition training to reduce symptoms of social anxiety in adolescence. AB - This study aimed to examine the effect of emotion recognition training on social anxiety symptoms among adolescents, aged 15-18 years. The study included a screening session, which identified participants who scored above a cut-off on a self-report measure of social anxiety for enrolment into a randomized controlled trial (Clinical Trials ID: NCT02550379). Participants were randomized to an intervention condition designed to increase the perception of happiness over disgust in ambiguous facial expressions or a sham intervention control condition, and completed self-report measures of social anxiety, fear of negative evaluation, anxiety-related disorders, and depressive symptoms. The intervention group demonstrated a strong shift in the balance point at which they perceived happiness over disgust in ambiguous facial expressions. This increase in positive perception was not associated with any changes in the primary outcome of social anxiety; however, some evidence of improvement in symptomatology was observed on one of a number of secondary outcomes. Those in the intervention group had lower depression symptoms at 2-week follow-up, compared to those in the control group who received the sham intervention training. Potential reasons for why the shift in balance point measurement was not associated with a concurrent shift in symptoms of social anxiety are discussed. PMID- 29602536 TI - Contemporary Dual Mobility Head Penetration at Five Years: Concern for the Additional Convex Bearing Surface? AB - BACKGROUND: Dual mobility (DM) bearings are increasingly popular and second generation designs contain highly cross-linked polyethylene. The purpose of this study is to report head penetration rates in modern DM bearings. METHODS: A review of 63 consecutive DM bearings was performed. Radiographs were analyzed for head penetration using Martell methodology at regular postoperative intervals. RESULTS: Thirty-four DM bearings were analyzed. Mean linear head penetration was 1.59 mm/y at 1 year, 1.07 mm/y at 2 years, and 0.27 mm/y at 5 years following an exponential regression model (R2 = 0.999). Mean volumetric wear was 783 mm3/y at 1 year, 555 mm3/y at 2 years, and 104 mm3/y at 5 years following an exponential regression model (R2 = 0.986). CONCLUSION: Initial head penetration of DM bearings is larger than contemporary cross-linked polyethylene bearings; however, rates approach steady state after 2 years, analogous to traditional bearings. The larger "bedding-in" head penetration may be due to the additional convex bearing surface, creating 2 surfaces for deformation/wear. PMID- 29602535 TI - Wastewater-based epidemiology generated forensic information: Amphetamine synthesis waste and its impact on a small sewage treatment plant. AB - Chemical analysis of domestic wastewater can reveal the presence of illicit drugs either consumed by a population or directly discharged into the sewer system. In the search for causes of a recent malfunctioning of a small domestic wastewater treatment plant aberrantly high loads of amphetamine were observed in the influent of the plant. Direct discharges of chemical waste from illegal production sites were suspected to be the cause. Illegal manufacturing of amphetamines creates substantial amounts of chemical waste. Here we show that fly tipping of chemical waste originating from an amphetamine synthesis in the catchment of a small sewage treatment plant resulted in failure of the treatment process. Target analysis of drugs of abuse and non-target screening using high resolution mass spectrometry provided evidence for the presence of amphetamine produced from the precursor 1-phenylpropan-2-one by the Leuckart process through specific synthesis markers. Furthermore the identity and presence of the pre precursor 3-oxo-2-phenylbutanamide was confirmed and a route specific marker was proposed. This is the first study that demonstrates that non-target screening of wastewater can identify intermediates, impurities and by products of the synthesis routes used in illegal manufacturing of amphetamine. The profiles of chemicals thus obtained can be used in tracking productions sites within the corresponding sewer catchment. PMID- 29602537 TI - Intraoperative Comparison of Measured Resection and Gap Balancing Using a Force Sensor: A Prospective, Randomized Controlled Trial. AB - BACKGROUND: For establishing femoral component position, gap-balancing (GB) and measured resection (MR) techniques were compared using a force sensor. METHODS: Ninety-one patients were randomized to undergo primary total knee arthroplasty using either MR (n = 43) or GB (n = 48) technique using a single total knee arthroplasty design. GB was performed with an instrumented tensioner. Force sensor data were obtained before the final implantation. RESULTS: GB resulted in greater range of femoral component rotation vs MR (1.5 degrees +/- 2.9 degrees vs 3.1 degrees +/- 0.5 degrees , P < .05) and posterior condylar cut thickness medially (10.2 +/- 2.0 mm vs 9.0 +/- 1.3 mm) and laterally (8.5 +/- 1.9 mm vs 6.4 +/- 1.0 mm). Force sensor data showed a decreased intercompartmental force difference at full flexion in GB (.8 +/- 2.3 vs 2.0 +/- 3.3u, 1u ~ 15 N, P < .05). CONCLUSION: GB resulted in a greater range of femoral component rotation and thicker posterior condylar cuts resulting in an increased flexion space relative to MR. Intercompartmental force difference trended toward a more uniform distribution between full extension and full flexion in the GB vs MR group. PMID- 29602538 TI - A comparison of computer-assisted detection (CAD) programs for the identification of colorectal polyps: performance and sensitivity analysis, current limitations and practical tips for radiologists. AB - AIM: To directly compare the accuracy and speed of analysis of two commercially available computer-assisted detection (CAD) programs in detecting colorectal polyps. MATERIALS AND METHOD: In this retrospective single-centre study, patients who had colorectal polyps identified on computed tomography colonography (CTC) and subsequent lower gastrointestinal endoscopy, were analysed using two commercially available CAD programs (CAD1 and CAD2). Results were compared against endoscopy to ascertain sensitivity and positive predictive value (PPV) for colorectal polyps. Time taken for CAD analysis was also calculated. RESULTS: CAD1 demonstrated a sensitivity of 89.8%, PPV of 17.6% and mean analysis time of 125.8 seconds. CAD2 demonstrated a sensitivity of 75.5%, PPV of 44.0% and mean analysis time of 84.6 seconds. CONCLUSION: The sensitivity and PPV for colorectal polyps and CAD analysis times can vary widely between current commercially available CAD programs. There is still room for improvement. Generally, there is a trade-off between sensitivity and PPV, and so further developments should aim to optimise both. Information on these factors should be made routinely available, so that an informed choice on their use can be made. This information could also potentially influence the radiologist's use of CAD results. PMID- 29602539 TI - Ultrasound and Stars. PMID- 29602541 TI - Kanapoi revisited: Paleoecological and biogeographical inferences from the fossil fish. AB - Fish fossils were recovered from three different depositional contexts at the Pliocene Kanapoi site to: 1) test the assumption that habitat and ecology of modern fish taxa can predict habitat and ecology of fossil taxa; 2) reconstruct the lake and river environments in the Kanapoi Formation, with reference to fish fossils from the nearby Lothagam site deposits; and 3) investigate biogeographical inferences from the fossils. We compare the Kanapoi fish taxa and their depositional environments with the taxa and environments in modern Lake Turkana, and with another Plio-Pleistocene fauna from the eastern Turkana Basin. Taphonomic caveats are discussed. Our results support the use of ecological preferences of modern fish to predict past preferences. Our analysis of the Kanapoi fossils also indicates that the Pliocene Lonyumun Lake had a diverse fauna, with an unusual mix of taxa compared to the modern lake. The presence of possibly endemic species in the Pliocene lake may additionally represent a period of isolation during this epoch. Few fish fossils were recovered in the deposits of the ancestral Kerio River, a primary affluent of Lonyumun Lake then as now, but those present indicate a different ecology than that interpreted for the modern lake. Previously unknown fish taxa which enter the lake during the Pliocene suggest the existence of a connection between the Nile River and the Turkana Basin, which may have been viable for other vertebrates, including hominins. PMID- 29602540 TI - Accelerated Clearance of Ultrasound Contrast Agents Containing Polyethylene Glycol is Associated with the Generation of Anti-Polyethylene Glycol Antibodies. AB - Emerging evidence suggests that the immune system can recognize polyethylene glycol (PEG), leading to the accelerated blood clearance (ABC) of PEGylated particles. Our aim here was to study the generation of anti-PEG immunity and changes in PEGylated microbubble pharmacokinetics during repeated contrast enhanced ultrasound imaging in rats. We administered homemade PEGylated microbubbles multiple times over a 28-d period and observed dramatically accelerated clearance (4.2 * reduction in half-life), which was associated with robust anti-PEG IgM and anti-PEG IgG antibody production. Dosing animals with free PEG as a competition agent before homemade PEGylated microbubble administration significantly prolonged microbubble circulation, suggesting that ABC was largely driven by circulating anti-PEG antibodies. Experiments with U.S. Food and Drug Administration-approved Definity microbubbles similarly resulted in ABC and the generation of anti-PEG antibodies. Experiments repeated with non PEGylated Optison microbubbles revealed a slight shift in clearance, indicating that immunologic factors beyond anti-PEG immunity may play a role in ABC, especially of non-PEGylated agents. PMID- 29602542 TI - Decreased interhemispheric homotopic connectivity in Parkinson's disease patients with freezing of gait: A resting state fMRI study. AB - INTRODUCTION: Freezing of gait is a common complaint in patients with Parkinson's disease (PD). However, the neural bases of freezing of gait in PD remain uncertain. Existing studies on PD patients with freezing of gait (PD-FOG+) have reported damage of the corpus callosum, the largest commissural bundle of the brain. Thus, in this study we explored homotopic connectivity to investigate FOG related interehemispheric alterations METHODS: A total of 21 PD-FOG + patients, 33 PD patients without freezing of gait (PD-FOG-), and 24 matched healthy controls were recruited. All PD patients were evaluated via the FOG questionnaire (FOGQ) and all subjects had a resting state functional magnetic resonance imaging (rs-fMRI) scan. The pattern of the homotopic connectivity was measured with the voxel-mirrored homotopic connectivity (VMHC) approach. RESULT: The PD-FOG + patients showed decreased VMHC values in the inferior parietal lobe (IPL) compared to both PD-FOG-patients and healthy controls. In PD-FOG + patients, the mean VMHC values in the IPL were negatively correlated with the FOGQ scores. Receiver operating characteristic curves analyses revealed that the VMHC in the IPL had discriminatory function distinguishing PD-FOG + patients from PD-FOG patients or healthy controls. CONCLUSION: Decreased VMHC values of PD-FOG + patients relative to PD-FOG- and healthy controls in IPL maybe a unique feature for PD-FOG+ and it may have the ability to separate PD-FOG + patients from PD-FOG and healthy controls. PMID- 29602543 TI - The Gun Violence Epidemic: Time for Perioperative Physicians to Act. PMID- 29602544 TI - Integrated strategy for identifying minor components in complex samples combining mass defect, diagnostic ions and neutral loss information based on ultra performance liquid chromatography-high resolution mass spectrometry platform: Folium Artemisiae Argyi as a case study. AB - Ultra-performance liquid chromatography coupled to high-resolution mass spectrometry (UPLC-HRMS) has been used as a powerful tool to profile chemicals in traditional Chinese medicines. However, identification of potentially bioactive compounds is still a challenging work because of the large amount of information contained in the raw UPLC-HRMS data. Especially the ubiquitous matrix interference makes it more difficult to characterize the minor components. Therefore, rapid recognition and efficient extraction of the corresponding parent ions is critically important for identifying the attractive compounds in complex samples. Herein, we propose an integrated filtering strategy to remove un-related or interference MS1 ions from the raw UPLC-HRMS data, which helps to retain the MS features of the target components and expose the compounds of interest as effective as possible. The proposed strategy is based on the use of a combination of different filtering methods, including nitrogen rule, mass defect, and neutral loss/diagnostic fragment ions filtering. The strategy was validated by rapid screening and identification of 16 methoxylated flavonoids and 55 chlorogenic acids analogues from the raw UPLC-HRMS dataset of Folium Artemisiae Argyi. Particularly, successful detection of several minor components indicated that the integrated strategy has obvious advantages over individual filtering methods, and it can be used as a promising method for screening and identifying compounds from complex samples, such as herbal medicines. PMID- 29602545 TI - Utility of a high coverage phenyl-bonding and wide-pore superficially porous particle for the analysis of monoclonal antibodies and related products. AB - A wide-pore silica-based superficially porous material with a high coverage phenyl bonding was evaluated for the analysis of monoclonal antibodies and antibody-drug conjugates. This new material is based on 2.7 MUm particles having a shell thickness of 0.40 MUm and average pore size of approximately 450 A. Various important features of this reversed phase column technology were explored, including kinetic performance for large biomolecules (i.e. speed of analysis, efficiency and peak capacity), recovery of proteins, selectivity for resolving modifications, and the possibility to reduce the amount of trifluoroacetic acid in the mobile phase. A systematic comparison was also performed with other existing modern wide-pore phases possessing differences in structure/morphology and chemistry. If all these figures of merit are considered, it is clear that this phenyl bonded wide-pore superficially porous stationary phase is one of the most promising materials to have been developed in recent years. Indeed, it offers kinetic performance comparable to the most efficient wide-pore SPP column on the market. In terms of protein recovery, this new phase was found to be superior to silica-based and silica-hybrid C4 bonded materials, particularly with separations performed at sub-80 degrees C temperature. Under such conditions, it in fact shows recoveries that are quite similar to a divinyl benzene (DVB) polymer-based material. More importantly, due to its unique, high coverage phenyl bonding, it offers additional steric effects and potentially even pi-pi interactions that yield advantageous selectivity for mAb sub-unit peaks and ADC species as compared to commonly used C4 or C18 bonded phases. Last but not least, mobile phases consisting of only 0.02-0.05% trifluoroacetic acid can be successfully used with this column, without significant loss in recovery and peak capacity. PMID- 29602546 TI - Decreased expression of TFAP2B in endometrial cancer predicts poor prognosis: A study based on TCGA data. AB - BACKGROUND: Transcription factor activator protein-2beta (TFAP-2beta) was previously reported to constituted promoter activity in endometrial carcinoma (EC). We evaluated the role of TFAP2B in ECs using publicly available data from The Cancer Genome Atlas (TCGA). METHODS: The relationship between clinical pathologic features and TFAP2B were analyzed with the Wilcoxon signed-rank test and logistic regression. Clinicopathologic characteristics associated with overall survival in TCGA patients using Cox regression and the Kaplan-Meier method. Gene Set Enrichment Analysis (GSEA) was performed using TCGA data set. RESULTS: Reduced TFAP2B expression in EC was significantly associated with high grade (OR=2.2 for well, moderate vs. poor), stage (OR=2.5 for I vs. IV), histology (OR=1.8 for serous vs. endometrioid), distant metastasis (OR=2.4 for positive vs. negative) (all p-values<0.05). Kaplan-Meier survival analysis showed that EC with TFAP2B-low had a worse prognosis than that with TFAP2B-high (p=0.013). The univariate analysis revealed that TFAP2B-low correlated significantly with a poor overall survival (OS) (HR: 2.35; 95% confidence interval [CI]: 1.17-4.73; p=0.016). The multivariate analysis revealed that TFAP2B remained independently associated with overall survival, with a HR of 4.42 (CI: 1.25-12.64; p=0.021). GSEA show that p53/hypoxia pathway, androgen response, notch signaling, fatty acid metabolism, glycolysis and estrogen response late are differentially enriched in TFAP2B high expression phenotype. CONCLUSIONS: TFAP2B expression may be a potential prognostic molecular marker of poor survival in endometrial cancer, Moreover, the p53/hypoxia, androgen response and notch signaling pathway may be the key pathway regulated by TFAP2B in EC. PMID- 29602547 TI - Ostomy in continuity: A novel approach for the management of children with complex short bowel syndrome. AB - INTRODUCTION: Despite medical and surgical management, a subset of children with short bowel syndrome (SBS) who have discrepancy between proximal small bowel and distal colon have persistent feeding intolerance. We propose the use of an Ostomy in Continuity (OIC) (Bishop-Koop or Santulli) as a salvage procedure to decompress the proximal bowel while still maintaining maximal intestinal length, in these patients. METHODS: A retrospective chart review of 104 SBS patients identified sixteen patients who underwent an OIC. Measures of reliance on parenteral nutrition (PN), growth, intestinal failure associated liver disease, the rate of central venous catheter infections and enterocolitis were collected. These parameters were compared before and after the placement of OIC in the same patients at a median follow-up period of 24months (range 3-52months). Outcome measures include intestinal autonomy and survival without intestinal and liver transplant. RESULTS: All 16 patients showed significant improvement in their enteral tolerance after OIC. The mean PN caloric requirement decreased from 95% to 21% (p=0.0001). The median weight Z score improved from -1.18 to 0.20 (p=0.0006) and the median height Z score improved from -2.74 to -1 (p=0.0001). The mean conjugated bilirubin decreased from 10.3mg/dl to 0.3mg/dl (p=0.0001) in nine patients with hyperbilirubinemia. There was no decrease in central venous catheter infections (CVCI) but there was a decrease in the rate of enterocolitis. None of the patients required intestinal or liver transplant. There was one minor skin excoriation complication in one patient with a Bishop-Koop stoma. CONCLUSIONS: The application of an ostomy in continuity within a comprehensive intestinal rehabilitation program is a novel approach in the treatment of refractory short bowel syndrome that improves intestinal autonomy and decreases the rate of enterocolitis. TYPE OF STUDY: Case Series. LEVEL OF EVIDENCE: IV (Cohort Study). PMID- 29602548 TI - Endoscopic pilonidal sinus treatment versus total excision with primary closure for sacrococcygeal pilonidal sinus disease in the pediatric population. AB - PURPOSE: To evaluate the effectiveness and safety of Endoscopic Pilonidal Sinus Treatment (EPSiT) in the pediatric population and compare it with excision followed by primary closure (EPC) regarding intra- and postoperative outcomes. METHODS: A retrospective analysis of all patients with chronic sacrococcygeal pilonidal sinus submitted to EPSiT and EPC during a 12-month period in our institution was performed. Data concerning patients' demographics and surgical outcomes were collected and compared between the two groups. RESULTS: We analyzed a total of 21 cases that underwent EPSiT and 63 cases of EPC, both groups with similar demographic characteristics. Operative time was similar for both groups (30 vs. 38min; p>0.05). No major intraoperative complications were reported. Wound infection rate was lower for EPSiT ((5.2% [n=1] vs. 20.0% [n=12]); p>0.05). Healing time was similar for both groups (28 vs. 37.5days). Recurrence occurred in 18,9% (n=15), with 2 cases (10.5%) reported in the EPSiT group versus 13 (21.6%) in EPC. There were no differences between groups regarding postoperative complications, complete wound healing and recurrence rates or healing time (p>0.05). CONCLUSIONS: Our results suggest that EPSiT is as viable as excision followed by primary closure in the management of sacrococcygeal pilonidal sinus in the pediatric population. LEVEL OF EVIDENCE: Therapeutic study - level III. PMID- 29602549 TI - Early detection of necrotizing enterocolitis using broadband optical spectroscopy. AB - PURPOSE: The definitive diagnosis of necrotizing enterocolitis (NEC) is typically at an advanced stage, indicating the need for sensitive and noninvasive diagnostic modalities. Near infrared spectroscopy (NIRS) has been utilized to noninvasively measure intraabdominal tissue oxygenation and to diagnose NEC, but specificity is lacking, in part because sensors are limited to a narrow band of the electromagnetic spectrum. Here, we introduce the concept of broadband optical spectroscopy (BOS) as a noninvasive method to characterize NEC. METHODS: NEC was induced in 7-day old mice by gavage feeding with formula supplemented with enteric bacteria plus hypoxia. Transabdominal spectroscopy was performed daily using a broad-spectrum halogen light source coupled with a spectroradiometer capable of detection from 400 to 1800nm. RESULTS: A feature extraction algorithm was developed based on the spectral waveforms from mice with NEC. When subsequently tested on cohorts of diseased and control mice by a blinded examiner, noninvasive BOS was able to detect disease with 100% specificity and sensitivity. CONCLUSIONS: We reveal that the use of BOS is able to accurately and noninvasively discriminate the presence of NEC in a mouse model, thus introducing a noninvasive early diagnostic modality for this devastating disease. PMID- 29602550 TI - Minimally invasive repair of pectus excavatum: Analysis of the NSQIP database and the use of thoracoscopy. AB - BACKGROUND: The minimally invasive repair of pectus excavatum (MIRPE) has been widely accepted and has become a viable alternative to the open Ravitch technique. MIRPE has evolved over time with some advocating that a safe repair can be accomplished without direct visualization utilizing thoracoscopy. The MIRPE with and without a thoracoscopic approach has not been previously analyzed from a nationwide database to determine differences in safety and short-term outcomes. METHODS: The American College of Surgeons National Surgical Quality Improvement Program-Pediatric (NSQIP-P) 2012-2015 database was used in identifying patients that had MIRPE using Current Procedural Terminology (CPT) codes and ICD-9CM/ICD-10CM postoperative diagnosis codes. Outcomes of interest were readmissions, reoperations, complications, cardiothoracic injury, operative time, and duration of hospital stay after surgery for MIRPE with and without thoracoscopy. Descriptive statistics, simple and multivariable logistic regressions, Fisher's exact, and Wilcoxon rank sum test were used to determine any differences in 30-day postoperative outcomes. RESULTS: There were 1569 MIRPE cases included. 15.9% (N=249) of MIRPE were done without thoracoscopy. There were no significant differences with the use of thoracoscopy compared to without thoracoscopy in the rate of readmissions (2.5 vs 4.8%; p=0.06), reoperations (1.4 vs 2.0%; p=0.57), postoperative complications (2.6% vs 3.2%; p=0.52), and cardiothoracic injuries (0.2% vs 0.0%; p=1.00). Unadjusted odds ratios (ORs) for readmission and reoperation comparing MIRPE with thoracoscopy to MIRPE without thoracoscopy were 0.51 (p<0.05) and 0.71 (p=0.50), respectively. Adjusted ORs were 0.49 (p=0.04) and 0.71 (p=0.50), respectively. There were no reported deaths, but two cardiothoracic injuries were recorded in the group with thoracoscopy. MIRPE with thoracoscopy was associated with longer operative time (mean 13.0min; p=0.00) and longer hospital stay (mean 0.37days; p<0.01) compared to MIRPE without thoracoscopy. No data were available for the severity of the pectus defect. CONCLUSION: MIRPE has a low adverse event rate with no difference in reoperations, postoperative complications, and cardiothoracic injuries with or without the use of thoracoscopy. There may be a higher rate of readmissions in the nonthoracoscopic group. While the technique used remains the surgeon's decision, the use of thoracoscopy may be unnecessary and is at an added cost. TYPE OF STUDY: Treatment study (retrospective comparative study). LEVEL OF EVIDENCE: Level III. PMID- 29602551 TI - Relationship between perioperative blood transfusion and surgical site infections in pediatric general and thoracic surgical patients. AB - BACKGROUND: Recently, perioperative transfusions were demonstrated to be associated with higher rate of surgical site infections (SSIs) in neonates. We sought to examine whether a similar relationship exists between perioperative blood transfusions and SSI among non-neonatal pediatric general surgical patients. METHODS: We conducted an IRB-approved retrospective study reviewing non neonatal patients (age greater than 28days and less than 18years) who underwent a general or thoracic surgical procedure in 2012, 2013, 2014, in the American College of Surgeons National Safety and Quality Improvement Project-Pediatric (ACS-NSQIP-P) Participant User Files. We used Chi-square analyses to perform a bivariate analysis comparing proportions of SSI's between patients who received blood transfusion to those who did not. Multiple logistic regression analyses compared the odds of SSIs in transfused versus nontransfused patients controlling for organ failure, steroid use, nutritional status, current infection, American Society of Anesthesiologists (ASA) Physical Status classification, and wound classification. RESULTS: There were 55,133 patients with 1779 patients who received blood transfusion (>=25ml/kg body weight) during or within 72h of surgery. Bivariate analysis showed at least twice the rate of infection in transfused patients compared to nontransfused patients (p<0.01): superficial SSI 3.5% vs 1.5%; deep SSI 0.8% vs 0.2%, organ space SSI 3.8% vs 1.6%; deep dehiscence 2% vs 0.3%. Total wound infections and dehiscence for transfused patients were 10.5% vs 3.8% in nontransfused patients (p<0.01). Multiple regression analysis showed that nutritional issue, current infection, and wounds not classified as "clean" have statistically significant correlation with SSI. Although there was significant interaction between ASA and transfusion (p<0.0001), we found statistically significant associations between transfusions and SSI for ASA class 1-2 (OR=5.51, 95% CI 3.47-7.52), ASA class 3 (OR=2.06, 95% CI 1.63-2.61), and ASA class 4-5 (OR=1.67, 95% CI 1.15-2.42). CONCLUSION: In non newborn pediatric general and thoracic surgery patients, transfusions were associated with higher risk of SSI or wound dehiscence. Although there was a significant interaction between ASA and transfusion, OR for SSI was stronger for lower ASA classes. TYPE OF STUDY: Retrospective Review. LEVEL OF EVIDENCE: II. PMID- 29602552 TI - Screening practices and associated anomalies in infants with anorectal malformations: Results from the Midwest Pediatric Surgery Consortium. AB - BACKGROUND: This study evaluates screening practices and the incidence of associated anomalies in infants with anorectal malformations (ARM). METHODS: We performed a multi-institutional retrospective cohort study of children born between 2007 and 2011 who underwent surgery for ARM at 10 children's hospitals. ARM type was classified based on the location of the distal rectum, and all screening studies were reviewed. RESULTS: Among 506 patients, the most common ARM subtypes were perineal fistula (40.7%), no fistula (11.5%), and vestibular fistula (10.1%). At least 1 screening test was performed in 96.6% of patients, and 11.3% of patients underwent all. The proportion of patients with >=1 abnormal finding on any screening test varied by type of ARM (p<0.001). Screening rates varied from 15.2% for limb anomalies to 89.7% for renal anomalies. The most commonly identified anomalies by screening category were: spinal: tethered cord (20.6%); vertebral: sacral dysplasia/hemisacrum (17.8%); cardiac: patent foramen ovale (58.0%); renal: hydronephrosis (22.7%); limb: absent radius (7.9%). CONCLUSION: Screening practices and the incidence of associated anomalies varied by type of ARM. The rate of identifying at least one associated anomaly was high across all ARM subtypes. Screening for associated anomalies should be considered standard of care for all ARM patients. TYPE OF STUDY: Multi-institutional retrospective cohort study. LEVEL OF EVIDENCE: III. PMID- 29602553 TI - Surgical lung biopsy in children after hematopoietic cell transplantation. AB - BACKGROUND/PURPOSE: Pulmonary complications are some of the leading causes of morbidity and mortality in immunocompromised pediatric patients. We sought to assess the value of surgical lung biopsy (SLB) in hematopoietic cell transplantation (HCT) pediatric patients. METHODS: A retrospective review of patients who underwent SLB within one year of HCT between 1999 and 2015 was performed. RESULTS: Twenty-nine patients (15 females, 14 males) with a median age of 10years (range, 0.6-23) were identified. Median interval between HCT and SLB was 114.8days (range, 16-302). At surgery, 11 (38%) patients were intubated, and 7 (24%) were receiving supplemental oxygen. The most common histological finding was cryptogenic organizing pneumonia in 8 cases (27%), followed by infection in 7 (24%). Perioperative complications (17%) included bronchopleural fistula (n=2), splenic laceration from a trocar injury (n=2), and hemothorax (n=1). Changes in therapy occurred in 25 patients (86%). Twenty-four (83%) patients survived more than 30days post SLB, and the overall survival rate was 41% with a median follow up of 8.5years (range, 1-13). CONCLUSION: SLB appears to be safe and informative in pediatric patients after HCT and led to changes in therapy in most patients. However, long-term survival after this procedure was <50%, reinforcing the fact that pulmonary complications are some of the leading causes of mortality in these patients. TYPE OF STUDY: Retrospective analysis. LEVEL OF EVIDENCE: Level IV. PMID- 29602554 TI - Incidence and outcomes of pediatric extremity melanoma: A propensity score matched SEER study. AB - BACKGROUND: There is a paucity of literature on treatment of melanoma in children with surgical management extrapolated from adult experience. The incidence and clinical outcomes of pediatric extremity melanoma were studied. METHODS: SEER registry was analyzed between 1973 and 2010 for patients <20years old with extremity melanoma. Multivariate and propensity-score matched analyses were performed to identify independent predictors of survival. RESULTS: Overall, 917 patients were identified with an age-adjusted incidence of 0.2/100,000 persons, annual percent change 0.96. Most had localized disease (77%), histology revealing melanoma-not otherwise specified (52%). Surgical procedures performed included wide local excision (50%), excisional biopsy (32%), lymphadenectomy (LA) (28%), and sentinel lymph node biopsy (SLNB) (15%). Overall, 30-year disease specific mortality was 7% with lower survival for extremity melanoma (90%), males (89%), nodular histology (69%), and distant disease (36%) (all P<0.05). Post-treatment multivariate analysis revealed localized disease (HR 9.76; P=0.006) as an independent prognosticator of survival; earlier diagnostic years 1988-1999 (HR 2.606; P=0.017) were a negative prognosticator of survival. Propensity-score matched analysis found no difference in survival between SLNB/LA vs no sampling for regional/distant disease. CONCLUSIONS: Pediatric extremity melanoma in SEER demonstrate no survival advantage between children undergoing sampling procedures vs no sampling for regional/distant disease. TYPE OF STUDY: Retrospective, prognostic study. LEVEL OF EVIDENCE: III. PMID- 29602556 TI - Long-term functional outcomes after pylorus preserving pancreaticoduodenectomy from childhood through middle age: 30-year follow-up of nutritional status, pancreatic function, and morphological changes of the pancreatic remnant. PMID- 29602555 TI - Surgical practice and outcome in 711 neonates and infants undergoing hernia repair in a large multicenter RCT: Secondary results from the GAS Study. AB - BACKGROUND: The GAS study is an international RCT to evaluate neurodevelopmental outcome comparing general plus regional anesthesia versus regional anesthesia alone in 722 neonates and infants who had inguinal hernia repair up to 60 weeks of postmenstrual age. This paper comprises a secondary descriptive analysis of hernias, aspects of surgery and outcomes. METHODS: The incidence of unilateral and bilateral hernias, side preponderance, predictive factors for bilateral hernias and surgical approaches were collated. Follow-up outcome data were examined at 2 years. RESULTS: Of 711 eligible patients, there were 679 with hernia data showing that 321 hernias were right-sided, 190 left and 168 bilateral. Male to female ratio was 5:1. Of those with unilateral hernias, 25.8% underwent contralateral exploration and in these cases a patent processus vaginalis was found in 68.9%. Bilateral hernias were more common in younger and female patients. At 2 years there was a recurrence rate of 0.99% and in 2.7% of patients a hernia was evident on the contralateral side (metachrony), and this was unrelated to the anesthesia technique. CONCLUSIONS: Bilateral hernias are associated with lower gestational age at birth and female gender. There was a low incidence of complications and the anesthesia technique did not affect surgical outcome. LEVEL OF EVIDENCE: Level 1 evidence from prospective treatment study. PMID- 29602557 TI - Colicky pain and related complications after cholecystectomy for mild gallstone pancreatitis. AB - BACKGROUND: Same-admission cholecystectomy is advised after gallstone pancreatitis to prevent recurrent pancreatitis, colicky pain and other complications, but data on the incidence of symptoms and complications after cholecystectomy are lacking. METHODS: This was a prospective cohort study during the previously published randomized controlled PONCHO trial on timing of cholecystectomy after mild gallstone pancreatitis. Data on healthcare consumption and questionnaires focusing on colicky pain and biliary complications were obtained during 6 months after cholecystectomy. Main outcomes were (i) postoperative colicky pain as reported in questionnaires and (ii) medical treatment for postoperative symptoms and gallstone related complications. RESULTS: Among 262 patients who underwent cholecystectomy after mild gallstone pancreatitis, 28 of 191 patients (14.7%) reported postoperative colicky pain. The majority of these were reported within 2 months after surgery and were single events. Overall, 25 patients (9.5%) required medical treatment for symptoms or gallstone related complications. Acute readmission was required in seven patients (2.7%). No predictors for the development of postoperative colicky pain were identified. DISCUSSION: Some 15% of patients experienced colicky pain after cholecystectomy for mild gallstone pancreatitis, which were mostly single events and rarely required readmission. These data may be used to better inform patients undergoing cholecystectomy for mild gallstone pancreatitis. PMID- 29602558 TI - Does nailfold capillaroscopy help predict future outcomes in systemic sclerosis? A systematic literature review. AB - BACKGROUND: Nailfold capillaroscopy (NC) is an important diagnostic tool in systemic sclerosis (SSc). Confirmation of NC as a prognostic factor could facilitate earlier intervention and slow disease progression in SSc. We undertook a systematic literature review to evaluate the prognostic value of NC in predicting SSc disease progression. METHODS: Standardised searches of EMBASE and MEDLINE were undertaken to identify longitudinal studies of adult subjects with SSc reporting the prognostic value of NC for any aspect of disease progression and/or survival. Non-English, non-original research, animal studies, non-adult studies and non-full length reports were excluded from the analysis (PROSPERO 2017:CRD42017071719). Wide heterogeneity in study design, prognostic factor measurement and study outcomes necessitated a qualitative data synthesis. The "QUality In Prognosis Studies" (QUIPS) risk-of-bias tool was used to assess study quality. Study selection, data extraction and risk-of-bias assessment were each undertaken independently by 2 reviewers and consensus reached where necessary. RESULTS: Of 942 retrieved articles, 18 studies fulfilled the inclusion criteria. The majority of studies (17/18, 94%) reported positive associations between baseline NC appearances (using a variety of qualitative, semi-quantitative and quantitative NC endpoints) and clinical outcomes including digital ulcer (DU) occurrence/healing, survival, disease progression (using domains of Medsger disease severity scale), calcinosis, skin progression, pulmonary arterial hypertension (PAH), and/or a composite analysis of "cardiovascular events". Application of the QUIPS tool identified a moderate-high risk of potential bias in 6/18 studies for study participation, 3/18 studies for study attrition, 10/18 for prognostic factor measurement, 5/18 for outcome measurement, 13/18 for confounders and 13/18 for statistical analyses. Study quality limited the strength of the conclusions drawn from these studies. The most important source of potential bias across the studies was insufficient adjustment for potential confounders; such as existing DU disease in studies evaluating future DU occurrence. Recent work suggests NC evolution is an important predictor of disease progression in SSc. CONCLUSIONS: High levels of potential bias relating to study confounding and statistical analysis make it difficult to draw conclusions regarding the prognostic role of NC in SSc. There is strong evidence supporting an association between NC abnormalities (particularly capillary loss) and disease severity (particularly vascular manifestations such as DU, calcinosis and PAH). Evolution of NC appearances may represent a more important predictor of disease progression which could have important implications for the future use of NC in the routine longitudinal assessment and management of SSc. PMID- 29602559 TI - Predictive value of early structural changes on radiographs and MRI for incident clinical and radiographic knee osteoarthritis in overweight and obese women. AB - OBJECTIVE: To determine the predictive value of tibiofemoral (TF), patellofemoral (PF) MRI osteoarthritis (OA), and Kellgren and Lawrence grade 1 (KLG1) for the incidence of knee OA (clinical and/or radiological signs) at 2.5 and 6.5 years follow-up in a high-risk cohort. METHODS: Data of the PROOF study were used, consisting of middle-aged obese women without clinical (ACR-criteria) knee OA and free of radiographic signs (KLG < 2) at baseline. To determine the relation between MRI defined knee OA and KLG1 at baseline with clinical (ACR criteria) or radiographic OA (KLG >= 2) at the follow-up points, sensitivity, specificity, likelihood ratios and pre-test and post-test probabilities were calculated. RESULTS: The baseline prevalence of KLG1 (42.9%) was higher than TF MRI OA (14.6%) and PF MRI OA (10.0%). All diagnostic performance statistics indicated better prediction for radiographic OA than for clinical OA. For both outcomes and time points, the absolute difference between pre-test and post-test probabilities was the highest for TF MRI OA. The number needed to screen to obtain a certain number of cases with definite knee OA after a given follow-up period was higher (16-524%) for MRI OA, than for KLG1. CONCLUSIONS: When comparing the associations and post-test probabilities, TF MRI OA was more strongly related to the development of radiographic knee OA than KLG1. However, for the selection of people at high risk for developing knee OA, for instance for preventive trials, radiography seems to be sufficient, due to the high baseline prevalence. PMID- 29602560 TI - Strategies for MSC expansion and MSC-based microtissue for bone regeneration. AB - Mesenchymal stem cells (MSCs) have gained increasing attention as a potential approach for the treatment of bone injuries due to their multi-lineage differentiation potential and also their ability to recognize and home to damaged tissue sites, secreting bioactive factors that can modulate the immune system and enhance tissue repair. However, a wide gap between the number of MSCs obtainable from the donor site and the number required for implantation, as well as the lack of understanding of MSC functions under different in vitro and in vivo microenvironment, hinders the progression of MSCs toward clinical settings. The clinical translation of MSCs pre-requisites a scalable expansion process for the biomanufacturing of therapeutically qualified cells. This review briefly introduces the features of implanted MSCs to determine the best strategies to optimize their regenerative capacity, as well as the current MSC implantation for bone diseases. Current achievements for expansion of MSCs using various culturing methods, bioreactor technologies, biomaterial platforms, as well as microtissue based expansion strategies are also discussed, providing new insights into future large-scale MSC expansion and clinical applications. PMID- 29602561 TI - Molecular bottlebrush as a unimolecular vehicle with tunable shape for photothermal cancer therapy. AB - Morphology of delivery nanovehicle plays a significant role in bioavailability of drug. Molecular bottlebrush (MBB)-based unimolecular micelle, with tunable morphologies including sphere, rod, and worm, offers a new aspect to uncover the relationship between morphology and bio-behaviors. In this study, a series of MBB as unimolecular micelle with core-shell structures were tailor-made through controlled/living polymerization and click chemistry, and served as carriers of IR780 photothermal agent. With an excellent IR780 loading content of up to ca. 25%, these molecular nanovehicles still maintained their molecular morphologies and did not aggregate in cell culture medium. Among three MBB, the rodlike one exhibited best performance in cell uptake in the 2D and also in spheroid penetration in 3D cell culture. Furthermore, this rodlike system had preferential accumulation in tumor in vivo and excellent effect on photothermal cancer therapy which effectively inhibited tumor growth. These results demonstrated an important role of nanoparticle shape on bio-behaviors and the unimolecular micelle could be a promising nanovehicle with precisely defined structure for biomedicine applications. PMID- 29602562 TI - Design of drug delivery systems for physical energy-induced chemical surgery. AB - Physical energy-induced chemical surgery, a technique that induces antitumor effects by delivering a drug that exerts a therapeutic effect in response to physical energy and irradiating the diseased part with the corresponding physical energy, is a useful method to treat cancers with minimal systemic side effects. Among chemical surgery, photodynamic therapy (PDT) and neutron capture therapy (NCT) require a system that selectively delivers drugs to the diseased site. Although PDT and NCT have a similar concept, drug delivery systems (DDSs) for their purpose need different functions to solve the unique problems derived from the characteristics of respective physical energy. In this review, we will describe recent chemistry-based solutions including ours to overcome these challenges. PMID- 29602563 TI - Author Reply. PMID- 29602564 TI - Author Reply. PMID- 29602565 TI - Editorial Comment. PMID- 29602566 TI - Editorial Comment. PMID- 29602568 TI - Evaluation of Ophthalmic Surgical Instrument Sterility Using Short-Cycle Sterilization for Sequential Same-Day Use. AB - PURPOSE: The common practice of short-cycle sterilization for ophthalmic surgical instrumentation has come under increased regulatory scrutiny. This study was undertaken to evaluate the efficacy of short-cycle sterilization processing for consecutive same-day cataract procedures. DESIGN: Testing of specific sterilization processing methods by an independent medical device validation testing laboratory. PARTICIPANTS: Phaco handpieces from 3 separate manufacturers were tested along with appropriate biologic indicators and controls using 2 common steam sterilizers. METHODS: A STATIM 2000 sterilizer (SciCan, Canonsburg, PA) with the STATIM metal cassette, and an AMSCO Century V116 pre-vacuum sterilizer (STERIS, Mentor, OH) using a Case Medical SteriTite container (Case Medical, South Hackensack, NJ) rigid container were tested using phaco tips and handpieces from 3 different manufacturers. Biological indicators were inoculated with highly resistant Geobacillus stearothermophilus, and each sterility verification test was performed in triplicate. Both wrapped and contained loads were tested with full dry cycles and a 7-day storage time to simulate prolonged storage. In adherence with the manufacturers' instructions for use (IFU), short cycles (3.0-3.5-minute exposure times) for unwrapped and contained loads were also tested after only 1 minute of dry time to simulate use on a consecutive case. Additional studies were performed to demonstrate whether any moisture present in the load containing phaco handpieces postprocessing was sterile and would affect the sterility of the contents after a 3-minute transit/storage time. This approximated the upper limit of time needed to transfer a containment device to the operating room. MAIN OUTCOME MEASURES: Presence or absence of microbial growth from cultured test samples. RESULTS: All inoculated test samples from both sterilizers were negative for growth of the target organism whether the full dry phase was interrupted or not. Pipetted postprocessing moisture samples and swabs of the handpieces were also negative for growth after a 3-minute transit/storage time. CONCLUSIONS: These studies support the use of unwrapped, short-cycle sterilization that adheres to the IFU of these 2 popular Food and Drug Administration-cleared sterilizers for sequential same-day cataract surgeries. A full drying phase is not necessary when the instruments are kept within the covered sterilizer containment device for prompt use on a sequential case. PMID- 29602567 TI - Determinants of Outcomes of Adenoviral Keratoconjunctivitis. AB - PURPOSE: To determine host and pathogen factors predictive of outcomes in a large clinical cohort with keratoconjunctivitis. DESIGN: Retrospective analyses of the clinical and molecular data from a randomized, controlled, masked trial for auricloscene for keratoconjunctivitis (NVC-422 phase IIB, NovaBay; clinicaltrials.gov identifier, NCT01877694). PARTICIPANTS: Five hundred participants from United States, India, Brazil, and Sri Lanka with clinical diagnosis of keratoconjunctivitis and positive rapid test results for adenovirus. METHODS: Clinical signs and symptoms and bilateral conjunctival swabs were obtained on days 1, 3, 6, 11, and 18. Polymerase chain reaction (PCR) analysis was performed to detect and quantify adenovirus in all samples. Regression models were used to evaluate the association of various variables with keratoconjunctivitis outcomes. Time to resolution of each symptom or sign was assessed by adenoviral species with Cox regression. MAIN OUTCOME MEASURES: The difference in composite scores of clinical signs between days 1 and 18, mean visual acuity change between days 1 and 18, and time to resolution of each symptom or sign. RESULTS: Of 500 participants, 390 (78%) showed evidence of adenovirus by PCR. Among adenovirus-positive participants, adenovirus D species was most common (63% of total cases), but a total of 4 species and 21 different types of adenovirus were detected. Adenovirus D was associated with more severe signs and symptoms, a higher rate of subepithelial infiltrate development, and a slower decline in viral load compared with all other adenovirus species. The clinical courses of all patients with non-adenovirus D species infection and adenovirus-negative keratoconjunctivitis were similar. Mean change in visual acuity between days 1 and 18 was a gain of 1.9 letters; worse visual outcome was associated with older age. CONCLUSIONS: A substantial proportion of keratoconjunctivitis is not associated with a detectable adenovirus. The clinical course of those with adenovirus D keratoconjunctivitis is significantly more severe than those with non-adenovirus D species infections or adenovirus-negative keratoconjunctivitis; high viral load at presentation and non-United States origin of participants is associated with poorer clinical outcome. PMID- 29602569 TI - Ten-Year Progression of Myopic Maculopathy: The Beijing Eye Study 2001-2011. AB - PURPOSE: To investigate the progression pattern of myopic maculopathy and associated factors in a population-based study. DESIGN: Population-based longitudinal study. PARTICIPANTS: The Beijing Eye Study including 4439 participants in 2001 was repeated in 2011, with 2695 individuals (66.4%) being re examined in 2011. METHODS: The study participants underwent detailed ophthalmic and general examinations. Using fundus photographs obtained in 2001 and 2011, we assessed the progression of myopic maculopathy in highly myopic eyes with a refractive error >=-6 diopters in 2001. Myopic maculopathy was differentiated into tessellated fundus (category 1), diffuse chorioretinal atrophy (category 2), patchy chorioretinal atrophy (category 3), and macular atrophy (category 4), with lacquer cracks and choroidal neovascularization as additional plus signs. MAIN OUTCOME MEASURES: Progression pattern of myopic maculopathy. RESULTS: Of 110 highly myopic eyes (70 individuals) at baseline, 39 eyes (35.5%) showed progression observed in 15 of 79 eyes (19%) with tessellated fundus at baseline, in 17 of 24 eyes (71%) with diffuse chorioretinal atrophy, in all 6 eyes with patchy chorioretinal atrophy, and the 1 eye with macular atrophy. Lacquer cracks detected in 2 eyes in 2001 developed into a small patchy atrophy (1 eye) or widened during the follow-up (1 eye). Five eyes demonstrated new lacquer cracks. In binary regression analysis, progression of myopic maculopathy was associated with longer axial length (P < 0.001; odds ratio [OR], 7.13; 95% confidence interval [CI], 2.49-20.4), older age (P = 0.001; OR, 1.25; 95% CI, 1.10-1.42), higher prevalence of staphylomas (P = 0.03; OR, 24.3; 95% CI, 2.89-204), smaller parapapillary gamma-zone in 2011 (P = 0.01; OR, 0.61; 95% CI, 0.41-0.91), and female gender (P = 0.04; OR, 9.78; 95% CI, 1.06-90.6). CONCLUSIONS: The 10-year progression rate of myopic maculopathy in this elderly Chinese population was 35.5%, increasing from 15 of 79 eyes (19%) in category 1 of myopic maculopathy at baseline to 17 of 24 eyes (71%) in category 2 and 6 of 6 eyes (100%) in category 3. Risk factors for myopic maculopathy progression were longer axial length, pre existing staphylomata, smaller parapapillary gamma-zone, older age, and female gender. PMID- 29602571 TI - The APEX Approaches: A Unified LRR-RK Network Revealed. AB - Leucine-rich repeat receptor kinases (LRR-RKs) represent a large and functionally diverse family of transmembrane proteins critical for signal recognition and transduction at the plant cell plasma membrane. Here, we discuss a recent report which used a systems-level approach to validate key paradigms by constructing an LRR-RK interaction network model. PMID- 29602570 TI - Successful Optimization of Adalimumab Therapy in Refractory Uveitis Due to Behcet's Disease. AB - PURPOSE: To assess efficacy, safety, and cost-effectiveness of adalimumab (ADA) therapy optimization in a large series of patients with uveitis due to Behcet disease (BD) who achieved remission after the use of this biologic agent. DESIGN: Open-label multicenter study of ADA-treated patients with BD uveitis refractory to conventional immunosuppressants. SUBJECTS: Sixty-five of 74 patients with uveitis due to BD, who achieved remission after a median ADA duration of 6 (range, 3-12) months. ADA was optimized in 23 (35.4%) of them. This biologic agent was maintained at a dose of 40 mg/subcutaneously/2 weeks in the remaining 42 patients. METHODS: After remission, based on a shared decision between the patient and the treating physician, ADA was optimized. When agreement between patient and physician was reached, optimization was performed by prolonging the ADA dosing interval progressively. Comparison between optimized and nonoptimized patients was performed. MAIN OUTCOME MEASURES: Efficacy, safety, and cost effectiveness in optimized and nonoptimized groups. To determine efficacy, intraocular inflammation (anterior chamber cells, vitritis, and retinal vasculitis), macular thickness, visual acuity, and the sparing effect of glucocorticoids were assessed. RESULTS: No demographic or ocular differences were found at the time of ADA onset between the optimized and the nonoptimized groups. Most ocular outcomes were similar after a mean +/- standard deviation follow-up of 34.7+/-13.3 and 26+/-21.3 months in the optimized and nonoptimized groups, respectively. However, relevant adverse effects were only seen in the nonoptimized group (lymphoma, pneumonia, severe local reaction at the injection site, and bacteremia by Escherichia coli, 1 each). Moreover, the mean ADA treatment costs were lower in the optimized group than in the nonoptimized group (6101.25 euros/patient/year vs. 12 339.48; P < 0.01). CONCLUSION: ADA optimization in BD uveitis refractory to conventional therapy is effective, safe, and cost-effective. PMID- 29602573 TI - Corrigendum to "LncRNA LOC730101 promotes osteosarcoma cell survival under energy stress" [Biochem. Biophys. Res. Commun. 496 (1) (2018) 1-6]. PMID- 29602572 TI - Non-specific gastrointestinal features: Could it be Fabry disease? AB - Non-specific gastrointestinal symptoms, including pain, diarrhoea, nausea, and vomiting, can be the first symptoms of Fabry disease. They may suggest more common disorders, e.g. irritable bowel syndrome or inflammatory bowel disease. The confounding clinical presentation and rarity of Fabry disease often cause long diagnostic delays and multiple misdiagnoses. Therefore, specialists involved in the clinical evaluation of non-specific upper and lower gastrointestinal symptoms should recognize Fabry disease as a possible cause of the symptoms, and should consider Fabry disease as a possible differential diagnosis. When symptoms or family history suggest Fabry disease, in men, low alpha-galactosidase A enzyme levels, and in women, specific Fabry mutations confirm the diagnosis. In addition to symptomatic treatments, disease-specific enzyme replacement therapy with recombinant human alpha-galactosidase A enzyme or chaperone therapy (migalastat) in patients with amenable mutations can improve the disease, including gastrointestinal symptoms, and should be initiated as early as possible after Fabry disease has been confirmed; starting enzyme replacement therapy at as young an age as possible after diagnosis improves long-term clinical outcomes. Improved diagnostic tools, such as a modified gastrointestinal symptom rating scale, may facilitate diagnosing Fabry disease in patients with gastrointestinal symptoms of unknown cause and thus assure timely initiation of disease-specific treatment. PMID- 29602574 TI - IgE and T-cell responses to house dust mite allergen components. AB - Using the terminology for Dermatophagoides pteronyssinus, IgE responses to house dust mites have been shown to be mostly directed to the serodominant Der p 1, 2 and 23 allergen components with mid -tier responses to Der p 4, 5, 7 and 21 that are made by 30-50% of subjects with titers proportional to those of the serodominant specificities. This pattern can be seen to evolve in childhood and although responses to minor allergens appear to contribute little to the total IgE they are at least markers for a greater propensity to develop disease. While Der p 23 is a component that induces prevalent IgE responses, sometimes in the absence of responses to Der p 1and 2, not all studies have found high titers so further investigation is needed. From limited knowledge adult onset IgE responses might have a different pattern that is not so centered on Der p 1 and 2. Responses that induce under 3.5 IU/ml of IgE antibody are not usually associated with disease and should be examined for cross reactivity expected from IgE responses to other allergens and antigens of infectious agents. Scabies that has 40% endemicity in some regions and is spread by immigration can give rise to high titer binding that can be recognized by component resolved diagnosis. Recent studies with synthetic peptides representing allergens and non-allergenic HDM proteins now offer new research avenues on HDM induced immune responses, including the ability to use peptides representing the serodominant allergens as defined reagents for long overdue reproducible T-cell investigations. PMID- 29602575 TI - Relationship between age and nerve dimensions in Charcot-Marie-Tooth disease. Do we know the reality? PMID- 29602576 TI - Training and practical issues of breech and twin deliveries in the Netherlands. PMID- 29602577 TI - Does multimorbidity still remain a matter of the elderly: Lithuanian national data analysis. AB - INTRODUCTION: Multimorbidity - the coexistence of >=2 chronic conditions in same individual is usually associated with older age. There is an increase in its prevalence at a much younger age, however with very limited research specifying that. OBJECTIVE: To identify age breaking points for the occurrence of multimorbidity. METHODS: The study included patients, who used any healthcare services between the 01/01/2012 and 30/06/2014. Patients were divided into two groups - with single chronic condition and with multimorbidity. Age-specific proportion of multimorbidity, rate of primary and outpatient visits, number of hospitalizations and prescribed reimbursed medications between these groups were analyzed. RESULTS: The study included 452578 patients, 94.63% of them had more than one chronic condition. The risk increase with every consecutive year for developing multimorbidity was between the age of 28 and 39 years. The age breaking point for the rapid increase in hospitalizations was about 29 years in multimorbidity group. The proportion of patients with multimorbidity using expensive medications starts to increase at the age of 41. CONCLUSIONS: The risk of acquiring an additional chronic condition rises exponentially from the age of 29 years and platos between the age of 51 and 57. Patients with multimorbidity require increasing amounts of primary healthcare resources, where patients with single chronic condition require decreasing primary care usage, possibly attributed to successful patient empowerment. PMID- 29602578 TI - Recent advancement in the mechanism of basophil activation. AB - Basophils have been recognized as crucial players in allergic inflammation. Basophils have the potential to initiate and expand inflammation through the production of specific cytokines and proteases, and are associated with T helper 2 (Th2) immune responses. In addition, recent studies revealed the heterogeneity in basophil populations. Basophils have been clarified important roles in not only IgE-mediated allergic inflammation but also TSLP-mediated and IgE independent inflammation. Moreover, basophils infiltrate in many human cutaneous diseases. Basophils are responsible for recruiting other inflammatory cells such as macrophages, eosinophils, and fibroblasts. In this review, we discuss recent advances in our understanding of basophil activation and migration in allergic inflammation. PMID- 29602579 TI - Continued uncertainty regarding treatment of patent ductus arteriosus in premature infants and the role of clinical trials. AB - Despite several decades of research into treatments for patent ductus arteriosus (PDA), there is continued uncertainty regarding whether, when, and how best to treat PDA and the long-term consequences. There are almost 5000 babies enrolled into clinical trials, but the questions remain largely unanswered. Many of the trials performed over the period were well designed and addressed important clinical questions, but the results are not necessarily directly applicable to the clinical management dilemmas of today since perinatal care has improved over time per se, the patient population is typically more premature, and there have been technological advances in diagnosis. This article examines some of the approaches taken, how trial designs evolved over time, especially in terms of the patient population and outcomes evaluated, and it offers points to consider when planning future research. PMID- 29602580 TI - Effects of chronic kidney disease on clinical outcomes in patients with peripheral artery disease undergoing endovascular treatment: Analysis from the K VIS ELLA registry. AB - OBJECTIVES: Chronic kidney disease (CKD) is a risk factor for peripheral artery disease (PAD), but the impact of CKD in PAD patients who received endovascular treatment (EVT) is not well studied. Aim of this study is to clarify the impact of CKD in patients with PAD in real EVT era. METHODS: Using the Korean Vascular Intervention Society (K-VIS) endovascular therapy in lower limb artery disease registry (ELLA) registry, we analyzed 3434 patients who underwent EVT. Baseline characteristics, in-hospital events, and overall- and major adverse limb events (MALE)-free survival were analyzed. RESULTS: 2739 patients (3548 target limbs) were included. 272 patients featured CKD (9.9%). Limbs in CKD patients had higher Rutherford scores, higher prevalence of critical limb ischemia (CLI). There were no differences in technical success rates in non-CKD vs. CKD group comparison and non-severe CKD vs. severe CKD group comparison (p = 0.050, 0.581, respectively). In-hospital death (p < 0.001) and short-term unexpected amputation (p = 0.028) were more frequent in the CKD group. The short-term outcome differences between severe and non-severe CKD were insignificant. Kaplan-Meier curves favored overall and MALE-free survival in non-CKD patients compared with CKD patients, but there was no difference in overall- or MALE-free survival between non-severe CKD and severe CKD groups. CONCLUSION: PAD patients with CKD showed worse short-term mortality, short-term unexpected amputation outcome, and overall- and MALE-free survival than those without CKD in real EVT era. These findings might provide additive prognostic information for PAD patients with CKD who will be treated with EVT. PMID- 29602581 TI - Macrophage migration inhibitory factor (MIF) is associated with degree of collateralization in patients with totally occluded coronary arteries. AB - BACKGROUND: Collaterals in patients with coronary artery disease (CAD) limit myocardial infarction and improve survival. Macrophage migration inhibitory factor (MIF) might play a role in collateral development. We aimed this study to evaluate the association of Macrophage migration Inhibitory Factor (MIF) with the extent of collateralization in patients with coronary occlusion. METHODS AND RESULTS: We consecutively enrolled: a) 40 patients undergoing PCI of a chronic coronary total occlusion (CTO); b) 26 patients with ST-elevation myocardial infarction (STEMI) undergoing primary PCI (pPCI) of the infarct-related artery (IRA); c) 12 control patients undergoing angiography without significant coronary artery disease (CTRL). CTO patients were grouped in high (HCG) or low collateralization group (LCG). STEMI patients were grouped in COLL+ or COLL- group depending on the presence of collaterals to the IRA. Blood sampling was performed from the arterial sheath (SYSTEMIC), and distal to the occlusion (LOCAL). SYSTEMIC and LOCAL levels were significantly different between the 3 groups. A progressive increase in MIF ratio (defined as: % (LOCAL SYSTEMIC)/SYSTEMIC) was observed (CTRL: -0.5[-23;28] vs. CTO: 4[-19;32] vs. STEMI: 55[37;87], p < 0.01). In CTO, MIF ratio was significantly higher in HCG vs. LCG (68 [45;120] vs. 46 [29;66], p = 0.02). In STEMI, MIF ratio was not different between COLL+ and COLL- patients; however, in COLL+, LOCAL was significantly higher as compared with SYSTEMIC (83 ng/ml [63;100] vs. 67 ng/ml [40;79], p = 0.04). CONCLUSIONS: Local MIF is significantly associated with the extent of collateralization in both acute and chronic total coronary occlusions. PMID- 29602582 TI - Relationship between CHA2DS2-VASc score, coronary artery disease severity, residual platelet reactivity and long-term clinical outcomes in patients with acute coronary syndrome. AB - BACKGROUND: The CHA2DS2-VASc score predicts stroke risk in patients with atrial fibrillation, but recently has been reported to have a prognostic role even in patients with ACS. We sought to assess the ability of the CHA2DS2-VASc score to predict the severity of coronary artery disease, high residual platelet reactivity and long-term outcomes in patients with acute coronary syndrome (ACS). METHODS: Overall, 1729 consecutive patients with ACS undergoing invasive management were included in this prospective registry. We assessed platelet reactivity via light transmittance aggregometry after clopidogrel loading. Patients were divided according to the CHA2DS2-VASc score: group A = 0, B = 1, C = 2, D = 3, E = 4 and F >= 5. RESULTS: Patients with higher CHA2DS2-VASc score were more likely to have a higher rate of multivessel CAD (37%, 47%, 55%, 62%, 67 and 75% in Group A, B, C, D, E and F; p < 0.001); moreover, CHA2DS2-VASc score correlated linearly with residual platelet reactivity (R = 0.77; p < 0.001). At long-term follow-up, estimated adverse event rates (MACCE: cardiac death, MI, stroke or any urgent coronary revascularization) were 3%, 8%, 10%, 14%, 19% and 24% in group A, B, C, D, E and F; p < 0.001. Multivariable analysis demonstrated CHA2DS2-VASc to be an independent predictor of severity of coronary artery disease, of high residual platelet reactivity and of MACCE. CONCLUSIONS: In a cohort of patients with ACS, CHA2DS2-VASc score correlated with coronary disease severity and residual platelet reactivity, and therefore it predicted the risk of long-term adverse events. PMID- 29602583 TI - Corrigendum to "Changes in natriuretic peptides after acute hospital presentation for heart failure with preserved ejection fraction: A feasible surrogate trial endpoint? A report from the prospective Karen study" [Int. J. Cardiol. 226 (2017) 65-70]. PMID- 29602584 TI - Stomach Dose-Volume Predicts Acute Gastrointestinal Toxicity in Chemoradiotherapy for Locally Advanced Pancreatic Cancer. AB - AIMS: Gastrointestinal toxicity impedes dose escalation in chemoradiotherapy for hepatobiliary malignancies. Toxicity risk depends on clinical and radiotherapy metrics. We aimed to identify predictive factors using data from two prospective phase II clinical trials of locally advanced pancreatic cancer (LAPC). MATERIALS AND METHODS: Ninety-one patients with available data from the ARCII (59.4 Gy in 33 fractions with gemcitabine, cisplatin and nelfinavir, n = 23) and SCALOP (50.4 Gy in 28 fractions with capecitabine or gemcitabine, n = 74) trials were studied. The independent variables analysed comprised age, sex, performance status, baseline symptoms, tumour size, weight loss, chemotherapy regimen and dose-volume histogram of stomach and duodenum in 5 Gy bins. The outcome measures used were Common Terminology Criteria of Adverse Events (CTCAE) grade and risk of CTCAE grade >=2 acute upper gastrointestinal toxicity (anorexia, pain, nausea and/or vomiting). The risk of CTCAE grade >=2 events was modelled using multivariable logistic regression and prediction of severity grade using ordinal regression. RESULTS: CTCAE grade >=2 symptoms occurred in 38 patients (42%). On univariate analysis, stomach V35-45Gy was predictive of risk (odds ratio 1.035, 95% confidence interval 1.007-1.063) and grade (1.023, 1.003-1.044) of toxicity. The area under the curve was 0.632 (0.516-0.747) with toxicity risk 33/66 (50%) above and 5/25 (20%) below the optimal discriminatory threshold (7.1 cm3). Using a threshold of 30 cm3, risk was 13/20 (65%) versus 25/71 (35%). The optimal multivariable logistic regression model incorporated patient sex, chemotherapy regimen and stomach V35-45Gy. Receiving gemcitabine rather than capecitabine (odds ratio 3.965, 95% confidence interval 1.274-12.342) and weight loss during induction chemotherapy (1.216, 1.043-1.419) were significant predictors for the SCALOP cohort, whereas age predicted toxicity risk in ARCII only (1.344, 1.015 1.780). Duodenum dose-volume did not predict toxicity risk or severity in any cohort. CONCLUSIONS: In chemoradiotherapy for LAPC the volume of stomach irradiated to a moderately high dose (35-45 Gy) predicts the incidence and severity of acute toxicity. Other predictive factors can include age, sex, recent weight loss and concomitant chemotherapy agents. PMID- 29602585 TI - Trend in otolaryngological surgeries in an era of super-aging: Descriptive statistics using a Japanese inpatient database. AB - OBJECTIVE: To reveal the age distribution and capture the longitudinal trend in otolaryngological surgeries performed in Japan, where society is rapidly aging. METHODS: Using the Diagnosis Procedure Combination database, we extracted data on patients who were hospitalized and underwent any type of otolaryngological surgery in departments of otolaryngology or head and neck surgery from fiscal year 2007 to fiscal year 2013. Type of surgery, patient's age, and fiscal year were compared. We categorized >200 types of surgeries into eight specialties: ear surgery, functional endoscopic sinus surgery (FESS), other types of paranasal surgery (except for malignancy), head and neck cancer surgery, benign tumor surgery, upper airway surgery (including pharynx and larynx), removal of foreign body, and other. RESULTS: In total, 558,732 patients were included. The proportions of patients in each age category formed two peaks in middle age and in children aged <=9years. The proportion of all surgeries made up by FESS, other paranasal surgery, benign tumor surgery, and head and neck cancer surgery gradually increased with age, forming a peak in patients in their 60s. The proportion of ear surgery was highest in patients aged <=9years (34.0% of all surgeries, mostly myringotomy and transtympanic ventilation tube insertion) and formed a gradual peak in patients in their 60s (mostly tympanoplasty). The proportion of upper airway surgery (tonsillectomy and adenoidectomy) was highest in patients aged <=9years (25.3% of all surgeries). The proportion of foreign body removal was highest in patients aged <=9years (52.2% of all surgeries) and increased slightly with age. In 2013, compared with 2007, those aged 65-74 years and >=75years made up a larger percentage of patients undergoing each specific surgery, including tympanoplasty, stapedectomy/stapedotomy, FESS, head and neck cancer surgery, pharyngolaryngectomy, total/subtotal glossectomy, thyroid lobectomy, parotidectomy (for a benign tumor), submandibular gland resection, tonsillectomy, and vocal fold polypectomy. CONCLUSION: The age distribution of otolaryngological surgeries varied by specialty. We found an increased proportion of patients aged 65-74 and >=75years in most specific surgeries. PMID- 29602586 TI - Analysis of the effects of high-fidelity simulation on nursing students' perceptions of their preparedness for disasters. AB - INTRODUCTION: As disasters may occur any time, health care staff and institutions should be prepared to manage these events. The aim of study is to analyze the effects of high-fidelity simulation on the perceptions of senior nursing students regarding their preparedness for disasters. METHODS: This study used a pretest posttest design and was conducted as a quasi-experimental investigation. RESULTS: Slightly less than the half of the students (42.5%) expressed that they were prepared to face a disaster. There was a statistically significant difference in their scores on the Scale of Perception of Disaster Preparedness among Nurses between the pre-intervention and postdisaster stage (p < 0.05). CONCLUSION: Supporting simulation activities with drills positively affected nurses' perceptions of disasters. PMID- 29602587 TI - Off-line and real-time monitoring of acetaminophen photodegradation by an electrochemical sensor. AB - The photochemistry of N-acetyl-para-aminophenol (acetaminophen, APAP) is here investigated by using differential pulse voltammetry (DPV) analysis to monitor APAP photodegradation upon steady-state irradiation. The purpose of this work is to assess the applicability of DPV to monitor the photochemical behaviour of xenobiotics, along with the development of an electrochemical set-up for the real time monitoring of APAP photodegradation. We here investigated the APAP photoreactivity towards the main photogenerated reactive transients species occurring in sunlit surface waters (hydroxyl radical HO, carbonate radical CO3-, excited triplet state of anthraquinone-2-sulfonate used as proxy of the chromophoric DOM, and singlet oxygen 1O2), and determined relevant kinetic parameters. A standard procedure based on UV detection coupled with liquid chromatography (HPLC-UV) was used under identical experimental conditions to compare and verify the DPV-based results. The latter were in agreement with HPLC data, with the exception of the triplet-sensitized processes. In the other cases, DPV could be used as an alternative to the well-tested but more costly and time consuming HPLC-UV technique. We have also assessed the reaction rate constant between APAP and HO by real-time DPV, which allowed for the monitoring of APAP photodegradation inside the irradiation chamber. Unfortunately, real-time DPV measurements are likely to be affected by temperature variations of the irradiated samples. Overall, DPV appeared as a fast, cheap and reasonably reliable technique when used for the off-line monitoring of APAP photodegradation. When a suitable real-time procedure is developed, it could become a very straightforward method to study the photochemical behaviour of electroactive xenobiotics. PMID- 29602588 TI - [Transesophageal echocardiography in perioperative period guiding the decision making during hemodynamic instability due to atrial fibrillation]. AB - BACKGROUND AND OBJECTIVE: Atrial fibrillation is the most common cardiac arrhythmia, which may occur during the perioperative period and lead to hemodynamic instability due to loss of atrial systolic function. During atrial fibrillation management, electrical cardioversion is one of the therapeutic options in the presence of hemodynamic instability; however, it exposes the patient to thromboembolic event risks. Transesophageal echocardiography is a diagnostic tool for thrombi in the left atrium and left atrial appendage with high sensitivity and specificity, allowing early and safe cardioversion. The present case describes the use of transesophageal echocardiography to exclude the presence of thrombi in the left atrium and left atrial appendage in a patient undergoing non-cardiac surgery with atrial fibrillation of unknown duration and hemodynamic instability. CASE REPORT: Male patient, 74 years old, hypertensive, with scheduled abdominal surgery, who upon cardiac monitoring in the operating room showed atrial fibrillation undiagnosed in preoperative electrocardiogram, but hemodynamic stable. During surgery, the patient showed hemodynamic instability requiring norepinephrine at increasing doses, with no response to heart rate control. After the end of the surgery, transesophageal echocardiography was performed with a thorough evaluation of the left atrium and left atrial appendage and pulsed Doppler analysis of the left atrial appendage with mean velocity of 45cm.s-1. Thrombus in the left atrium and left atrial appendage and other cardiac causes for hemodynamic instability were excluded. Therefore, electrical cardioversion was performed safely. After returning to sinus rhythm, the patient showed improvement in blood pressure levels, with noradrenaline discontinuation, extubation in the operating room, and admission to the intensive care unit. CONCLUSION: In addition to a tool for non-invasive hemodynamic monitoring, perioperative transesophageal echocardiography may be valuable in clinical decision making. In this report, transesophageal echocardiography allowed the performance of early and safely cardioversion, with reversal of hemodynamic instability, and without thromboembolic sequelae. PMID- 29602589 TI - Adaptive radiation therapy. PMID- 29602590 TI - Magnitude and phase of three-dimensional (3D) velocity vector: Application to measurement of cochlear promontory motion during bone conduction sound transmission. AB - Recent measurements of vibrational motion to assess sound transmission through ear structures and skull contents have included three-dimensional (3D) behavior. The 3D motion of a point has been described with the three orthogonal components in the 3D space. In this article, a method to represent the 3D velocity with the magnitude and phase of the resultant velocity is introduced. This method was applied to the measurement of cochlear promontory motion as an indication of bone conduction (BC) sound transmission. The promontory motions were measured on the ipsilateral and contralateral sides, and the transcranial attenuation and phase delay of the contralateral side relative to the ipsilateral side were calculated. The transcranial attenuation and phase delay calculated with the maximum magnitudes and corresponding phases of the resultant were a better fit to the interaural threshold difference and transcranial time interval between the ipsilateral and contralateral sides as reported in the literature, than the attenuation and phase delay calculated with any individual Cartesian motion component. PMID- 29602591 TI - Clinical trials for inner ear drugs: Design and execution challenges. AB - The development of therapies for the inner ear presents unique opportunities and challenges. On the one hand, the ear presents an opportunity for localized drug delivery to avoid systemic side effects. However, we do not understand the pathobiology of many common ear disorders clearly enough to develop rational therapeutic solutions. Further, identification of biomarkers beyond conventional audiometry and balance testing to track disease progress and recovery remain elusive. Because of the comparatively low incidence and prevalence of many inner ear disorders, as well as issues with respect to timing of drug delivery for certain diseases, multi-center, multi-investigator collaborative networks are required to promote effective clinical trial design. PMID- 29602593 TI - Effect of age and hearing loss on auditory stream segregation of speech sounds. AB - Segregating and understanding speech in complex environments is a major challenge for hearing-impaired (HI) listeners. It remains unclear to what extent these difficulties are dominated by direct interference, such as simultaneous masking, or by a failure of the mechanisms of stream segregation. This study compared older HI listeners' performance with that of young and older normal-hearing (NH) listeners in stream segregation tasks involving speech sounds. Listeners were presented with sequences of speech tokens, each consisting of a fricative consonant and a voiced vowel (CV). The CV tokens were concatenated into interleaved sequences that alternated in fundamental frequency (F0) and/or simulated vocal tract length (VTL). Each pair of interleaved sequences was preceded by a "word" consisting of two random tokens. The listeners were asked to indicate whether the word was present in the following interleaved sequences. The word, if present, occurred within one of the interleaved sequences, so that performance improved if the listeners were able to perceptually segregate the two sequences. Although HI listeners' identification of the speech tokens in isolation was poorer than that of the NH listeners, HI listeners were generally able to use both F0 and VTL cues to segregate the interleaved sequences. The results suggest that the difficulties experienced by HI listeners in complex acoustic environments cannot be explained by a loss of basic stream segregation abilities. PMID- 29602592 TI - Addressing variability in the acoustic startle reflex for accurate gap detection assessment. AB - The acoustic startle reflex (ASR) is subject to substantial variability. This inherent variability consequently shapes the conclusions drawn from gap-induced prepulse inhibition of the acoustic startle reflex (GPIAS) assessments. Recent studies have cast doubt as to the efficacy of this methodology as it pertains to tinnitus assessment, partially, due to variability in and between data sets. The goal of this study was to examine the variance associated with several common data collection variables and data analyses with the aim to improve GPIAS reliability. To study this the GPIAS tests were conducted in adult male and female CBA/CaJ mice. Factors such as inter-trial interval, circadian rhythm, sex differences, and sensory adaptation were each evaluated. We then examined various data analysis factors which influence GPIAS assessment. Gap-induced facilitation, data processing options, and assessments of tinnitus were studied. We found that the startle reflex is highly variable in CBA/CaJ mice, but this can be minimized by certain data collection factors. We also found that careful consideration of temporal fluctuations of the ASR and controlling for facilitation can lead to more accurate GPIAS results. This study provides a guide for reducing variance in the GPIAS methodology - thereby improving the diagnostic power of the test. PMID- 29602594 TI - Standard metabolic rates of early life stages of the diamondback terrapin (Malaclemys terrapin), an estuarine turtle, suggest correlates between life history changes and the metabolic economy of hatchlings. AB - I estimated standard metabolic rates (SMR) using measurements of oxygen consumption rates of embryos and unfed, resting hatchlings of the diamondback terrapin (Malaclemys terrapin) three times during embryonic development and twice during the early post-hatching period. The highest observed SMRs occurred during mid to late embryonic development and the early post-hatching period when hatchlings were still reliant on yolk reserves provided by the mother. Hatchlings that were reliant on yolk displayed per capita SMR 135 % higher than when measured 25 calendar days later after they became reliant on exogenous resources. The magnitude of the difference in hatchling SMR between yolk-reliant and exogenously feeding stages was much greater than that attributed to costs of digestion (specific dynamic action) observed in another emydid turtle, suggesting that processing of the yolk was not solely responsible for the observed difference. The pre-feeding period of yolk reliance of hatchlings corresponds with the period of dispersal from the nesting site, suggesting that elevated SMR during this period could facilitate dispersal activities. Thus, I hypothesize that the reduction in SMR after the development of feeding behaviors may reflect an energy optimization strategy in which a high metabolic expenditure in support of development and growth of the embryo and dispersal of the hatchling is followed by a substantial reduction in metabolic expenditure coincident with the individual becoming reliant on exogenous resources following yolk depletion. PMID- 29602595 TI - Lipid and lipoprotein parameters for detection of familial hypercholesterolemia in childhood. The DECOPIN Project. AB - BACKGROUND: Familial hypercholesterolaemia (FH) in children is under-detected and is difficult to diagnose in clinical practice. The aim of this study was to evaluate clinical, biochemical and vascular imaging variables in order to detect children and adolescents with FH. METHODS: A total of 222 children aged 4-18 years old were recruited to participate in a project for the early detection of FH (The DECOPIN Project). They were distributed into 3groups: FH, if genetic study or clinical criteria were positive (n=91); Polygenic hypercholesterolaemia (PH) if LDL-Cholesterol >135mg/dL without FH criteria (n=23), and Control group (CG) if LDL-C <135mg/dL (n=108). Data were collected from family history, anthropometric data, and clinical variables. The usual biochemical parameters, including a complete lipid profile were analysed. The carotid intima-media thickness (cIMT) and thickness of Achilles tendons were determined using ultrasound in all participants. RESULTS: A total of 91 children had a diagnosis of FH, 23 with PH, and 108 with CG. Children with FH had higher concentrations of total cholesterol, LDL-C, ApoB/ApoA1 ratio, and cholesterol-year score, than the other groups. HDL-C was lower in the FH group than in the CG. Thickness of the Achilles tendon and cIMT did not show any differences between groups, although a greater cIMT trend was observed in the FH group. ApoB/ApoA1 ratio >0.82 was the parameter with the highest sensitivity and specificity to predict the presence of mutation in children with FH. CONCLUSIONS: Although LDL-C is the main biochemical parameter used to define FH, the ApoB/ApoA1 ratio (>0.82) may be a useful tool to identify children with FH and a positive mutation. PMID- 29602596 TI - Mechanisms of vascular aging: What can we learn from Hutchinson-Gilford progeria syndrome? AB - Aging is the main risk factor for cardiovascular disease (CVD). The increased prevalence of CVD is partly due to the global increase in life expectancy. In this context, it is essential to identify the mechanisms by which aging induces CVD, with the ultimate aim of reducing its incidence. Both atherosclerosis and heart failure significantly contribute to age-associated CVD morbidity and mortality. Hutchinson-Gilford progeria syndrome (HGPS) is a rare genetic disorder caused by the synthesis of progerin, which is noted for accelerated aging and CVD. This mutant form of prelamin A induces generalised atherosclerosis, vascular calcification, and cardiac electrophysiological abnormalities, leading to premature aging and death, mainly due to myocardial infarction and stroke. This review discusses the main vascular structural and functional abnormalities during physiological and premature aging, as well as the mechanisms involved in the exacerbated CVD and accelerated aging induced by the accumulation of progerin and prelamin A. Both proteins are expressed in non-HGPS individuals, and physiological aging shares many features of progeria. Research into HGPS could therefore shed light on novel mechanisms involved in the physiological aging of the cardiovascular system. PMID- 29602597 TI - Baseline serum vascular endothelial growth factor levels predict treatment response to antipsychotic medication in patients with schizophrenia. AB - Vascular endothelial growth factor (VEGF) is implicated in angiogenesis, blood flow, and neuroplasticity, which have previously been shown to contribute to schizophrenia and the mechanisms of action of antipsychotic medication. The aim of the present study was to investigate whether baseline serum VEGF levels predict treatment responses to antipsychotic medication. Drug-free adults with schizophrenia were administered monotherapy with atypical antipsychotic drugs for 6 weeks. Participants' psychiatric symptoms were assessed using the positive and negative symptom scale (PANSS) before and after treatment. Blood samples for VEGF measurements were collected from 201 participants comprising 83 healthy controls and 118 patients (i.e. only on admission). Baseline VEGF levels in adults with schizophrenia were significantly lower than those in the control group (t = 3.656, df = 199, P < 0.001). In particular, pretreatment VEGF levels were significantly higher in patients responding to drug treatment at follow-up (>= 50% reduction in initial PANSS total) (t = 4.743, df = 116, P < 0.001). The predictive power of serum VEGF levels was investigated using receiver operating characteristic curves. The area under the curve was 0.774 (95% confidence interval 0.688-0.846); for fixed specificity of 78.8%, the corresponding sensitivity was 63.5%. Results from this preliminary experiment suggest high baseline serum concentrations of VEGF may predict a better response to antipsychotic medications in adults with schizophrenia. Further studies using larger sample sizes are needed to verify the findings. PMID- 29602598 TI - Development of a novel methodology for QA of respiratory-gated and VMAT beam delivery using Octavius 4D phantom. AB - The objective of this study was to develop and evaluate a series of quality assurance (QA) techniques based on Octavius 4D phantom for testing of respiratory gated treatment delivery, integrity of dose rate vs gantry speed in volumetric modulated arc therapy (VMAT) commissioning, and multileaf collimator (MLC) positioning accuracy of a linear accelerator. An Octavius 4D phantom capable of rotating with the gantry and recording the detector signal with a sampling rate of 10 Hz was isocentrally set up and an inclinometer was also installed to measure the gantry angle simultaneously. A simple arc test was created and delivered with gating function activated to measure the timing accuracy of the gating window. A tailor-made dose rate vs gantry speed plan was also designed to test the accuracy of measured dose rate, gantry speed, and actual control points. All experiments were conducted while machine log files were collected for comparison. The variations of beam flatness, symmetry, and field size were analyzed as a function of gantry angle to evaluate the influence from the modulation of dose rate and gantry speed. MLC position accuracy was evaluated based on specific garden fence plans. The time of gating window was measured to be less than 10-millisecond deviation from the log data. Gantry backlash was observed and quantified to be 1.72 degrees with an extra stabilization time of 1.16 seconds for a gating arc with gantry speed of 6 degrees /s. In the dose rate vs gantry speed test, the mean deviation between measured gantry angle and log data was less than 0.2 degrees after a time delay of 0.25 second was corrected. The measured dose rate agreed with the log data very well with a mean deviation of 0.05%, and even the transit of modulation was tracked successfully. There was a statistically significant difference on the variation of beam parameters between a VMAT plan and a simple arc plan. The induced MLC position errors were detected with an accuracy of 0.05 mm. The leaf position reproducibility was found to be better than 0.02 mm, whereas the routine MLC position accuracy was better than 0.1 mm. A time-resolved method using Octavius 4D phantom has been developed and proven to be convenient for respiratory gating QA, dose rate vs gantry speed test, and MLC QA. Gating time, dose rate, and gantry speed-induced leave position error could be directly measured with high accuracy after comparison with the machine log data. This study also highlights the capability of the phantom in quantifying the variation of flatness, symmetry, and field size during gantry rotation. PMID- 29602599 TI - Comments on "High Radon Areas and lung cancer prevalence: Evidence from Ireland". PMID- 29602600 TI - Usefulness of rapid urease test samples for molecular analysis of clarithromycin resistance in Helicobacter pylori. AB - Helicobacter pylori is a gastric pathogen that is widely recognized as a causative agent of gastric disease. Its eradication is variable, mainly due to increased resistance to clarithromycin. Our objective was: to evaluate (i) if the biopsy specimen used for the rapid urease test is a useful sample to detect resistance to clarithromycin by PCR-RFLP and (ii) the distribution of A2142G and A2143G point mutations in the 23S rRNA gene, in relation to virulence factors in our region. Gastric specimens were collected from adult dyspeptic patients (n=141) and H. pylori was investigated by the rapid urease test, histopathological analysis and PCR for the hsp60 gene. Clarithromycin resistance was detected by PCR-RFLP in 62 H. pylori (+) paired biopsy specimens submitted to molecular analysis and the rapid urease test. H. pylori virulence factors were analyzed by multiplex PCR using specific primers for the cagA, vacA and babA2 genes. Thirteen out of 62 strains (20.9%) were resistant to clarithromycin: 6/13 (46.2%) harbored the A2143G mutation whereas 7/13 (53.8%) carried the A2142G point mutation. vacA m1s1 was the most frequent genotype among the resistant strains. In conclusion, the biopsy specimens used for the rapid urease test were suitable samples for clarithromycin resistance detection in patients infected with H. pylori, which became especially useful in cases where the number or size of the biopsies is limited. In addition, this is the first report of a molecular analysis for clarithromycin resistance performed directly from gastric biopsies in our region. PMID- 29602601 TI - Dioscorea zingiberensis C. H. Wright: An overview on its traditional use, phytochemistry, pharmacology, clinical applications, quality control, and toxicity. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Dioscorea zingiberensis C. H. Wright (D. zingiberensis), Dioscoreaceae, is used extensively in traditional Chinese medicines. The aim of the current review paper is to give a comprehensive overview of the traditional usage and phytochemistry of the plant. Clinical studies performed and products prepared from the plant and active principles will be mentioned. In addition a review of the taxonomy of the genus Dioscorea is given. MATERIALS AND METHODS: A systematic search on literature has been performed in databases like Google Scholar, Science Direct, Scifinder, Web of Science, and in Chinese databases (China Knowledge Resource Integrated, i.e., CNKI and Wanfang) including Ph.D. and M.Sc. dissertations. These from the period 1983-2016 have been searched. RESULTS: D. zingiberensis is an endemic plant in China widely distributed in some provinces, especially Hubei and Shaanxi. The rhizomes are the medicinal part in Dun-Ye-Guan-Xin-Ning tablets and are used for isolation of diosgenin. Steroidal saponins are believed to be the active principles. More than 70 compounds have been identified. Several of these have been tested in preclinical assays and clinical trials. A wide spectrum of biological effects including cardiovascular, anti-thrombosis, hyperlipidemia, neuroprotection, anti-inflammatory, and anthelmintic effect has been verified. CONCLUSIONS: Because of the promising results from the investigations on the plant material of D. zingiberensis, further in depth analyses ought to be performed to evaluate its potential as either a traditional drug or a source of bioactive principle. The presently performed studies do not explain mechanism of action, pharmacokinetics (ADME properties), or toxicity. All of these topics need more elaborate investigations. PMID- 29602603 TI - Assessing the influence of subventricular zone contact of glioblastomas with gross total resection on patient survival. PMID- 29602602 TI - Pediatric pharmacology. PMID- 29602604 TI - Hair sparing does not compromise real-time magnetic resonance imaging guided stereotactic laser fiber placement for temporal lobe epilepsy. AB - Pre-operative scalp shaving is conventionally thought to simplify postoperative cranial wound care, lower the rate of wound infections, and ease optimal incision localization. Over the past few decades, some neurosurgeons have refrained from scalp shaving in order to improve patient satisfaction with brain surgery. However, this hair-sparing approach has not yet been explored in the growing field of magnetic resonance-guided laser interstitial thermal therapy (MRgLITT). This study investigated the initial impact of a no-shave technique on post operative wound infection rate as well as on entry and target accuracy in MRgLITT for mesial temporal epilepsy. Eighteen patients selected by the Stanford Comprehensive Epilepsy Program between November 2015 and August 2017 were included in the study. All patients underwent functional selective amygdalohippocampotomies using MRgLITT entirely within a diagnostic MRI suite. No hair was removed and no additional precautions were taken for hair or scalp care. Otherwise, routine protocols for surgical preparations and wound closure were followed. The study was performed under approval from Stanford University's Internal Review Board (IRB-37830). No post-operative wound infections or erosions occurred for any patient. The mean entry point error was 2.87 +/- 1.3 mm and the mean target error was 1.0 +/- 0.9 mm. There have been no other complications associated with this hair-sparing approach. The study's results suggest that hair sparing in MRgLITT surgery for temporal epilepsy does not increase the risk of wound complications or compromise accuracy. This preferred cosmetic approach may thus appeal to epilepsy patients considering such interventions. PMID- 29602605 TI - Asian American adult brain tumor patients treated in Los Angeles County. PMID- 29602606 TI - A surgical strategy to prevent delayed epidural hematoma after posterior fossa surgery using lateral suboccipital retrosigmoid approach. AB - Although non-traumatic postoperative delayed epidural hematoma (EDH) after posterior fossa surgery is rare, measures to prevent it need to be pursued due to its catastrophic results. In this report, we describe a surgical strategy to prevent delayed EDH after posterior fossa surgery. Key dural tacking sutures were performed at the medial and cephalic margin of the dura. We have performed key dural tacking sutures on 454 patients with neurovascular compression syndrome during microvascular decompression surgeries since April 2016, and no hemorrhagic complication, including delayed EDH, occurred. We discovered that key dural tacking sutures can be helpful in preventing postoperative posterior fossa delayed EDH. PMID- 29602607 TI - Surgical management of adult type 1 split cord malformation. Report of two cases with literature review. AB - Split cord malformation (SCM) is a rare form of spinal dysraphism wherein the spinal cord is divided longitudinally into two distinct hemicords. Surgery is usually performed in children while management in adults, who rarely manifest symptoms, remains controversial. Both expectant management and prophylactic surgery have been variously advocated. The present article describes our experience in two adult patients with predominant pain-related complaints who underwent surgical excision of type 1 SCM lesions. A comprehensive review of the literature on SCM in adults is also provided. While pain, disability, and quality of life scores improved in these two patients, further larger studies will be required to define the role of surgery in adults with type 1 SCM and a pain dominant presentation. PMID- 29602608 TI - Hospital-Treated Snow Sport Injury in Victoria, Australia: A Summary of 2003 2012. AB - INTRODUCTION: To determine the incidence rate and changes over time for ice and snow sports injury in Victoria, Australia, from 2003 to 2012 and describe the most common types and causes of these injuries. METHODS: Retrospective data from the Victorian Injury Surveillance Unit describing hospital admissions and emergency department presentations were extracted for the 10-year period of 2003 to 2012 for all ice- and snow-related injury. Descriptive injury data and participation-adjusted trend analyses using log-linear regression modelling of data (statistical significance, P<0.05) from the Exercise, Recreation and Sport Survey 2003 to 2010 are presented. RESULTS: Overall, there were 7387 ice- and snow-related injuries, with a significant increase in hospital-treated snowboard injuries and a (nonsignificant) decline in hospital-treated ski injuries over the 10 years. Skiing (39%) and snowboarding (37%) had the highest incidence of hospital-treated injury, with males aged 15 to 24 years injured most frequently in both sports. Falls were the most common cause of injury in both skiing (68%) and snowboarding (78%). CONCLUSIONS: Patterns of snow sports injury in Australia during 2003 to 2012 remain similar to findings of national studies conducted decades earlier. More importantly, however, Australian injury patterns are comparable to international statistics and thus may be generalizable internationally. Head injuries, although infrequent, are associated with great injury severity due to a high frequency of hospitalization. Furthermore, research into the use of personal protective equipment and other injury prevention measures among Australian participants, particularly by young, male snowboarders, is required. Given the similar injury patterns, injury prevention measures implemented internationally could reasonably translate to an Australian setting. PMID- 29602609 TI - [Uveitis: From diagnosis to treatment]. PMID- 29602610 TI - Successful microdissection testicular sperm extraction for men with non obstructive azoospermia. AB - Non-obstructive azoospermia (NOA) is the most severe form of male infertility, defined by lack of spermatozoa in the ejaculate caused by impaired spermatogenesis. The chance of biological fatherhood of these men has been improved since the introduction of microdissection testicular sperm extraction (MD-TESE) combined with intracytoplasmic sperm injection. A thorough patient evaluation preoperatively is essential to recognize any underlying conditions, and to assist in patient counseling on the sperm recovery rate and pregnancy results. This review article summarizes the present data on MD-TESE to reach optimal results is treating men with NOA. PMID- 29602611 TI - Effects of melatonin supplementation prior to Ovsynch protocol on ovarian activity and conception rates in anestrous Murrah buffalo heifers during out of breeding season. AB - Buffalo heifers have tendency to show anestrus during summer season. Melatonin has been used for correcting summer dependent anestrous via inducing resumption of ovarian activity. Therefore, the investigation was conducted to compare efficacy of melatonin for induction of estrus and conception rate with Ovsynch protocol in summer anestrous Murrah buffalo heifers. Thirty, summer anestrous Murrah buffalo heifers were selected and divided into two groups- treatment (n = 20; 12 melatonin implants) and control (n = 10; no treatment). On day 28 post implant insertion, animals of both the groups were subjected to Ovsynch protocol. Blood sampling and ovarian ultrasonography were conducted to measure plasma melatonin, progesterone concentration and ovarian dynamics, respectively. No animal in either group showed estrus during first 28 days post-implant insertion. However, estrus induction rate was 100% after Ovsynch protocol in both groups. As compared to controls, treatment group exhibited higher (p < 0.05) plasma melatonin on days 1, 4, 8, 15, 22 and 28 post-melatonin, with highest concentration on day 4. The progesterone concentration increased (p < 0.05) on days 15 and 22 post-melatonin treatment. The treatment group had larger (p < 0.05) preovulatory follicle on day of AI, subsequently developed larger (p < 0.05) corpus luteum and higher plasma progesterone concentrations by day 12 post AI as compared to the control group. The overall conception rate was 50 and 20% in treatment and control groups, respectively. In conclusion, melatonin treatment along with Ovsynch protocol improved the luteal profiles as well as the conception rate in buffalo heifers when compared with animals treated with Ovsynch protocol alone during summer season. PMID- 29602612 TI - To chelate or not to chelate in MDS: That is the question! AB - Myelodysplastic syndromes (MDS) are a heterogeneous group of hemopathies that exhibit physical manifestations with clinical consequences of bone marrow failure and inherent risk of progression to acute myeloid leukemia. Iron overload (IO) is common in MDS due to chronic transfusion support and disease-related alterations in iron metabolism. IO has been conclusively associated with inferior outcomes among MDS patients. Despite lack of randomized trials showing a survival impact of iron chelation therapy (ICT), ICT is recommended by experts and guidelines for select MDS patients with IO and is often used. The availability of effective oral ICT agents has reignited the controversy regarding ICT use in patients with MDS and IO. Here we summarize the studies evaluating the value of ICT in MDS and suggest a practical approach for use of these therapies. We also highlight controversies regarding use of ICT in MDS and discuss some ongoing efforts to answer these questions. PMID- 29602613 TI - Noninvasive Echocardiographic Measures of Pulmonary Vascular Resistance in Children and Young Adults with Cardiomyopathy. AB - BACKGROUND: Patients with cardiomyopathy (CM) are at increased risk for pulmonary hypertension (PH). Data are lacking on the use of noninvasive PH measures by echocardiography in patients with CM. The aim of this study was to evaluate the correlation between Doppler-derived echocardiographic indices and catheterization based measurement of pulmonary vascular resistance (PVR) in children and young adults with CM. METHODS: Imaging studies were retrospectively reviewed from pediatric patients with CM who underwent both echocardiography and cardiac catheterization within a 72-hour period. The ratio of peak tricuspid regurgitation velocity to right ventricular outflow tract velocity-time integral, the S/D ratio, and right ventricular myocardial performance index were correlated with invasive PVR. Receiver operating characteristic curves were developed to determine cutoffs for detecting PVR >= 6 indexed Wood units, a value associated with higher heart transplantation risk. RESULTS: Twenty-three patients with CM (median age, 11.7 years; range, 0.5-21 years) met the criteria for analysis, the majority (n = 17 [74%]) of whom had dilated CM. Linear regression showed significant correlations between echocardiography-based ratio of peak tricuspid regurgitation velocity to right ventricular outflow tract velocity-time integral, S/D ratio, and right ventricular myocardial performance index versus invasive PVR (r = 0.84, r = 0.72, and r = 0.72, respectively, P < .001). All echocardiographic measures showed high sensitivity, specificity, and predictive values to detect PVR >= 6 indexed Wood units, with ratio of peak tricuspid regurgitation velocity to right ventricular outflow tract velocity-time integral demonstrating the highest area under the curve (0.958; 95% CI, 0.866-1). CONCLUSIONS: Right-sided Doppler-derived echocardiographic indices correlate with PVR measured by cardiac catheterization in children and young adults with CM. These parameters may serve as useful adjuncts in serial assessment of right ventricular hemodynamics in this population. PMID- 29602615 TI - Response to Letter to the Editor Regarding "Yield of Computed Tomography (CT) Angiography in Patients with Acute Headache, Normal Neurological Examination, and Normal Non Contrast CT: A Meta-Analysis." PMID- 29602616 TI - Intracranial Large and Medium Artery Atherosclerotic Disease and Stroke. AB - BACKGROUND: Intracranial atherosclerotic disease (ICAD) is one of the most common causes of stroke worldwide and is associated with a high risk of stroke recurrence. We sought to perform a literature review of the epidemiology, pathophysiology, and treatment options. METHODS: A literature review on recent studies evaluating the epidemiology, risk factors, clinical presentation, and treatment was reviewed. ICAD is particularly common in Africa and Asia. RESULTS: Although the medical management of ICAD has improved over the past decade, a subgroup of patients with ICAD remains at significantly high risk of stroke recurrence, and newer studies that aim at improving our understanding of ICAD and evaluating new treatment methods are currently under way. CONCLUSION: ICAD remains a common cause of stroke worldwide; further studies evaluating treatment options to prevent stroke recurrence are urgently needed. PMID- 29602614 TI - Estradiol Protects White Matter of Male C57BL6J Mice against Experimental Chronic Cerebral Hypoperfusion. AB - BACKGROUND AND PURPOSE: Estradiol is a sex steroid hormone known to protect the brain against damage related to transient and global cerebral ischemia. In the present study, we leverage an experimental murine model of bilateral carotid artery stenosis (BCAS) to examine the putative effects of estradiol therapy on chronic cerebral hypoperfusion. We hypothesize that long-term estradiol therapy protects against white matter injury and declarative memory deficits associated with chronic cerebral hypoperfusion. METHODS: Adult male C57BL/6J mice underwent either surgical BCAS or sham procedures. Two days after surgery, the mice were given oral estradiol (Sham+E, BCAS+E) or placebo (Sham+P, BCAS+P) treatments daily for 31-34 days. All mice underwent Novel Object Recognition (NOR) testing 31-34 days after the start of oral treatments. Following sacrifice, blood was collected and brains fixed, sliced, and prepared for histological examination of white matter injury and extracellular signal-regulated kinase (ERK) expression. RESULTS: Animals receiving long-term oral estradiol therapy (BCAS-E2 and Sham-E2) had higher plasma estradiol levels than those receiving placebo treatment (BCAS-P and Sham-P). BCAS-E2 mice demonstrated less white matter injury (Kluver-Barrera staining) and performed better on the NOR task compared to BCAS-P mice. ERK expression in the brain was increased in the BCAS compared to sham cohorts. Among the BCAS mice, the BCAS-E2 cohort had a greater number of ERK + cells. CONCLUSION: This study demonstrates a potentially protective role for oral estradiol therapy in the setting of white matter injury and declarative memory deficits secondary to murine chronic cerebral hypoperfusion. PMID- 29602617 TI - Association between Delirium and Prehospitalization Medication in Poststroke Patients. AB - PURPOSE: Medication is an important risk factor for delirium; however, the association between delirium and prehospitalization medication is unclear. We investigated the association between prestroke medication and poststroke delirium. MATERIALS AND METHODS: All patients hospitalized in the stroke care unit from September 2011 to September 2012 were selected, and their delirium symptoms, patient information, and pre- and poststroke medications were analyzed. Delirium was defined as a score of 4 or higher on the Intensive Care Delirium Screening Checklist. Factors that were related to delirium were extracted using univariate analysis, and the independent risk factors were determined using multivariate analysis. RESULTS: Of the 269 patients analyzed, 97 (36%) experienced delirium. Univariate analysis revealed significant differences between the delirium and nondelirium groups in age, dementia, previous cerebrovascular disease, craniotomy, all insertion-tube types, and 6 categories of prestroke medication. Prestroke polypharmacy was associated with poststroke delirium (P = .002). Multivariate analysis showed that taking antianxiety agents or sleep aids was an independent risk factor for delirium (odds ratio: 3.17, 95% confidence interval: 1.16-8.82). CONCLUSIONS: The present study suggests that prestroke medication affects the onset of poststroke delirium. These findings can contribute to the prediction and prevention of this condition. PMID- 29602618 TI - Thrombosed Aneurysm of the Posterior Inferior Cerebellar Artery and Lateral Medullary Ischemia as the Initial Presentation of Polyarteritis Nodosa: Case Report and Literature Review. AB - A 27-year-old woman with a previously undiagnosed polyarteritis nodosa (PAN) developed lateral medullary stroke related to a thrombosed posterior inferior cerebellar artery (PICA)-origin aneurysm. A concurrent thrombosis of the PICA was identified on high-resolution 3-dimensional CUBE T1 magnetic resonance imaging sequence at 3 T. Body computed tomography angiography, magnetic resonance imaging magnetic resonance angiography, and digital angiography revealed multiple tiny aneurysms of the visceral arteries and bilateral kidney infarcts. On the basis of these findings and of laboratory data, the patient was diagnosed as having PAN. Intracranial aneurysms (IAs) are extremely rare in PAN and usually manifest as subarachnoid or cerebral hemorrhage. Ischemic manifestation of small thrombosed IA is a rare occurrence. This case highlights (1) an uncommon complication in patients with PAN (16 other cases of IAs in patients with PAN found in the literature), (2) an unusual initial presentation of PAN, and (3) a thrombosed PICA-origin aneurysm responsible for an ischemic stroke and for secondary thrombosis of the parent vessel. PMID- 29602619 TI - Structure of Herpesvirus Capsid Sheds Light on Drug Discovery. AB - The atomic resolution structure of Kaposi's sarcoma-associated herpesvirus (KSHV) capsid reveals that protein-protein interfaces (PPIs) are essential for its structural stability. This structural information guided a mutagenesis study that identified novel drug targets interrupting PPIs essential for capsid assembly. PMID- 29602620 TI - Full-chain health impact assessment of traffic-related air pollution and childhood asthma. AB - BACKGROUND: Asthma is the most common chronic disease in children. Traffic related air pollution (TRAP) may be an important exposure contributing to its development. In the UK, Bradford is a deprived city suffering from childhood asthma rates higher than national and regional averages and TRAP is of particular concern to the local communities. AIMS: We estimated the burden of childhood asthma attributable to air pollution and specifically TRAP in Bradford. Air pollution exposures were estimated using a newly developed full-chain exposure assessment model and an existing land-use regression model (LUR). METHODS: We estimated childhood population exposure to NOx and, by conversion, NO2 at the smallest census area level using a newly developed full-chain model knitting together distinct traffic (SATURN), vehicle emission (COPERT) and atmospheric dispersion (ADMS-Urban) models. We compared these estimates with measurements and estimates from ESCAPE's LUR model. Using the UK incidence rate for childhood asthma, meta-analytical exposure-response functions, and estimates from the two exposure models, we estimated annual number of asthma cases attributable to NO2 and NOx in Bradford, and annual number of asthma cases specifically attributable to traffic. RESULTS: The annual average census tract levels of NO2 and NOx estimated using the full-chain model were 15.41 and 25.68 MUg/m3, respectively. On average, 2.75 MUg/m3 NO2 and 4.59 MUg/m3 NOx were specifically contributed by traffic, without minor roads and cold starts. The annual average census tract levels of NO2 and NOx estimated using the LUR model were 21.93 and 35.60 MUg/m3, respectively. The results indicated that up to 687 (or 38% of all) annual childhood asthma cases in Bradford may be attributable to air pollution. Up to 109 cases (6%) and 219 cases (12%) may be specifically attributable to TRAP, with and without minor roads and cold starts, respectively. CONCLUSIONS: This is the first study undertaking full-chain health impact assessment of TRAP and childhood asthma in a disadvantaged population with public concern about TRAP. It further adds to scarce literature exploring the impact of different exposure assessments. In conservative estimates, air pollution and TRAP are estimated to cause a large, but largely preventable, childhood asthma burden. Future progress with childhood asthma requires a move beyond the prevalent disease control-based approach toward asthma prevention. PMID- 29602621 TI - Do Many Hands Make Outcomes Better? Commentary on "Use of an Assistant Surgeon Does Not Mitigate the Effect of Lead Surgeon Volume on Outcomes Following Open Repair of Intact Abdominal Aneurysms". PMID- 29602622 TI - The application of simple metrics in the assessment of glycaemic variability. AB - The assessment of glycaemic variability (GV) remains a subject of debate with many indices proposed to represent either short- (acute glucose fluctuations) or long-term GV (variations of HbA1c). For the assessment of short-term within-day GV, the coefficient of variation for glucose (%CV) defined as the standard deviation adjusted on the 24-h mean glucose concentration is easy to perform and with a threshold of 36%, recently adopted by the international consensus on use of continuous glucose monitoring, separating stable from labile glycaemic states. More complex metrics such as the Low Blood Glucose Index (LBGI) or High Blood Glucose Index (HBGI) allow the risk of hypo or hyperglycaemic episodes, respectively to be assessed although in clinical practice its application is limited due to the need for more complex computation. This also applies to other indices of short-term intraday GV including the mean amplitude of glycemic excursions (MAGE), Shlichtkrull's M-value and CONGA. GV is important clinically as exaggerated glucose fluctuations are associated with an enhanced risk of adverse cardiovascular outcomes due primarily to hypoglycaemia. In contrast, there is at present no compelling evidence that elevated short-term GV is an independent risk factor of microvascular complications of diabetes. Concerning long-term GV there are numerous studies supporting its association with an enhanced risk of cardiovascular events. However, this association raises the question as to whether the impact of long-term variability is not simply the consequence of repeated exposure to short-term GV or ambient chronic hyperglycaemia. The renewed emphasis on glucose monitoring with the introduction of continuous glucose monitoring technologies can benefit from the introduction and application of simple metrics for describing GV along with supporting recommendations. PMID- 29602623 TI - Interstitial Pulmonary Edema and Acetazolamide in High-Performance Sport: A Case Report. PMID- 29602624 TI - Primary Endobronchial Tumors in Childhood. PMID- 29602625 TI - Microcystic adnexal carcinoma-diagnostic criteria and therapeutic methods: case report and review of the literature. AB - Microcystic adnexal carcinoma (MAC) is a rare, infiltrating, locally aggressive cutaneous neoplasm of combined follicular and eccrine/apocrine histogenesis, usually presenting on the upper lip or face. Differentiation from other adnexal tumours is very important because the clinical management of these tumours is radically different, and misdiagnosis may lead to incorrect treatment. A case of recurrent MAC in the upper lip, treated with multiple excisions and postoperative radiation therapy (PORT), is presented herein. There have been no signs or symptoms of recurrence since the subsequent reconstructive surgery and PORT. Based on reports in the literature it appears that although immunohistochemistry can be helpful in distinguishing between MAC and other adnexal tumours, careful histopathological examination is essential for an accurate diagnosis. Perineural and intramuscular invasion strongly suggest the diagnosis of MAC. Its predilection for the facial area often limits the width of surgical excision. In such cases, PORT may be considered. PMID- 29602626 TI - Intra-alveolar epsilon-aminocaproic acid for the control of post-extraction bleeding in anticoagulated patients: randomized clinical trial. AB - The aim of this study was to compare the effectiveness of the intra-alveolar administration of epsilon-aminocaproic acid (EACA) and daily gentle rinsing with EACA mouthwash with that of routine postoperative procedures for the control of bleeding after tooth extraction in anticoagulated patients. A randomized clinical trial was conducted involving 52 patients submitted to 140 tooth extractions, assigned randomly to two groups. The intervention group was treated with intra alveolar administration of EACA immediately after surgery and gentle rinsing with EACA mouthwash during the postoperative period. The control group received routine postoperative recommendations. A single episode of immediate bleeding occurred in the intervention group. Late bleeding episodes occurred in 23 procedures (16.4%): 11 (15.7%) in the intervention group and 12 (17.1%) in the control group. Among the patients with late bleeding, 18 (78.3%) events were classified as moderate and were controlled by the patient applying pressure to a gauze pack placed over the extraction socket. The remaining five cases (21.7%) required re-intervention. No statistically significant difference in the frequency of postoperative bleeding was observed between the groups. Thus, routine measures were as effective for the control of bleeding after simple tooth extractions in anticoagulated patients as the topical administration of EACA. PMID- 29602627 TI - Treatment of diabetes in the elderly. Is there anything to improve? PMID- 29602628 TI - Historical and Current Advances That Incorporate Competing Risk for Benefit and Mortality in Older Patients With Cancer. AB - Competing risk occurs when patients have >1 disease or condition that can affect an important outcome, such as mortality. In older adults who develop cancer, the presence of comorbid chronic diseases or functional impairments can change the likelihood that the cancer will lead to an adverse outcome. The recognition and incorporation of competing risk into oncology research started during the experimental development of chemotherapy. A related concept of considering performance status in clinical trials of cancer therapies also occurred in the context of treatment interventions using chemotherapy. Statistical methodologies for competing risk have advanced substantially over time, and a patient's performance measurements remain common in deciding how best to care for older patients with cancer. The historical development of these 2 uses of competing risk, statistical adjustment in research and patient performance measurement, is explained. Furthermore, this article discusses more recent advances in merging these 2 approaches. Particular attention is given to advances in calculating life expectancy that are specific to a patient's condition, status, or setting, and to describing how these estimates might be used to inform decisions about cancer care in older patients. Frameworks for moving beyond mortality as the only considered competing outcome to describe other outcomes, such as functional loss or the need for institutionalization, are also described. Finally, approaches that could more fully leverage the advanced methods for incorporating competing risks into clinical decision making are presented. PMID- 29602629 TI - The role of digital health in supporting the achievement of the Sustainable Development Goals (SDGs). PMID- 29602630 TI - Medicare Costs Associated With Arteriovenous Fistulas Among US Hemodialysis Patients. AB - BACKGROUND: An arteriovenous fistula (AVF) is the recommended vascular access for hemodialysis (HD). Previous studies have not examined the resources and costs associated with creating and maintaining AVFs. STUDY DESIGN: Retrospective observational study. SETTING & PARTICIPANTS: Elderly US Medicare patients initiating hemodialysis therapy during 2010 to 2011. PREDICTOR: AVF primary and secondary patency and nonuse in the first year following AVF creation. OUTCOMES: Annualized vascular access costs per patient per year. RESULTS: Among patients with only a catheter at HD therapy initiation, only 54% of AVFs were successfully used for HD, 10% were used but experienced secondary patency loss within 1 year of creation, and 83% experienced primary patency loss within 1 year of creation. Mean vascular access costs per patient per year in the 2.5 years after AVF creation were $7,871 for AVFs that maintained primary patency in year 1, $13,282 for AVFs that experienced primary patency loss in year 1, $17,808 for AVFs that experienced secondary patency loss in year 1, and $31,630 for AVFs that were not used. Similar patterns were seen among patients with a mature AVF at HD therapy initiation and patients with a catheter and maturing AVF at HD therapy initiation. Overall, in 2013, fee-for-service Medicare paid $2.8 billion for dialysis vascular access-related services, ~12% of all end-stage renal disease payments. LIMITATIONS: Lack of granularity with certain billing codes. CONCLUSIONS: AVF failure in the first year after creation is common and results in substantially higher health care costs. Compared with patients whose AVFs maintained primary patency, vascular access costs were 2 to 3 times higher for patients whose AVFs experienced primary or secondary patency loss and 4 times higher for patients who never used their AVFs. There is a need to improve AVF outcomes and reduce costs after AVF creation. PMID- 29602631 TI - A Randomized Trial of a Multicomponent Intervention to Promote Medication Adherence: The Teen Adherence in Kidney Transplant Effectiveness of Intervention Trial (TAKE-IT). AB - BACKGROUND: Poor adherence to immunosuppressive medications is a major cause of premature graft loss among children and young adults. Multicomponent interventions have shown promise but have not been fully evaluated. STUDY DESIGN: Unblinded parallel-arm randomized trial to assess the efficacy of a clinic-based adherence-promoting intervention. SETTING & PARTICIPANTS: Prevalent kidney transplant recipients 11 to 24 years of age and 3 or more months posttransplantation at 8 kidney transplantation centers in Canada and the United States (February 2012 to May 2016) were included. INTERVENTION: Adherence was electronically monitored in all participants during a 3-month run-in, followed by a 12-month intervention. Participants assigned to the TAKE-IT intervention could choose to receive text message, e-mail, and/or visual cue dose reminders and met with a coach at 3-month intervals when adherence data from the prior 3 months were reviewed with the participant. "Action-Focused Problem Solving" was used to address adherence barriers selected as important by the participant. Participants assigned to the control group met with coaches at 3-month intervals but received no feedback about adherence data. OUTCOMES: The primary outcomes were electronically measured "taking" adherence (the proportion of prescribed doses of immunosuppressive medications taken) and "timing" adherence (the proportion of doses of immunosuppressive medications taken between 1 hour before and 2 hours after the prescribed time of administration) on each day of observation. Secondary outcomes included the standard deviation of tacrolimus trough concentrations, self-reported adherence, acute rejection, and graft failure. RESULTS: 81 patients were assigned to intervention (median age, 15.5 years; 57% male) and 88 to the control group (median age, 15.8 years; 61% male). Electronic adherence data were available for 64 intervention and 74 control participants. Participants in the intervention group had significantly greater odds of taking prescribed medications (OR, 1.66; 95% CI, 1.15-2.39) and taking medications at or near the prescribed time (OR, 1.74; 95% CI, 1.21-2.50) than controls. LIMITATIONS: Lack of electronic adherence data for some participants may have introduced bias. There was low statistical power for clinical outcomes. CONCLUSIONS: The multicomponent TAKE-IT intervention resulted in significantly better medication adherence than the control condition. Better medication adherence may result in improved graft outcomes, but this will need to be demonstrated in larger studies. TRIAL REGISTRATION: Registered at ClinicalTrials.gov with study number NCT01356277. PMID- 29602632 TI - Urinary Biomarkers of Kidney Tubular Damage and Risk of Cardiovascular Disease and Mortality in Elders. AB - RATIONALE & OBJECTIVE: Novel urinary biomarkers have enabled earlier detection of kidney tubular damage, but their prognostic value for adverse cardiovascular outcomes is uncertain. We hypothesized that tubular damage, measured by urine alpha1-microglobulin (A1M), amino-terminal propeptide of type III procollagen (PIIINP), and neutrophil gelatinase-associated lipocalin (NGAL), would be associated with higher risks for cardiovascular events and mortality among elders. STUDY DESIGN: Case-cohort study. SETTING & PARTICIPANTS: This study included a randomly selected subcohort (n=502), cardiovascular disease (CVD) cases (n=245), and heart failure cases (n=220) from the Health, Aging, and Body Composition (Health ABC) Study. PREDICTORS: Baseline urine A1M, PIIINP, and NGAL concentrations. OUTCOMES: Incident CVD, heart failure, and all-cause mortality. ANALYTICAL APPROACH: Cox proportional hazards models were used to evaluate biomarker associations with each outcome. RESULTS: At baseline, mean age was 74 years and estimated glomerular filtration rate was 73mL/min/1.73m2. After adjustment for demographics, estimated glomerular filtration rate, albumin creatinine ratio, and other cardiovascular risk factors, each doubling in biomarker concentration was associated with the following adjusted HRs for CVD: A1M, 1.51 (95% CI, 1.16-1.96); PIIINP, 1.21 (95% CI, 1.00-1.46); and NGAL, 1.12 (95% CI, 1.05-1.20). There were 248 deaths in the subcohort during a median follow-up of 12.4 years. Adjusted associations of each biomarker (HR per doubling) with all-cause mortality were: A1M, 1.29 (95% CI, 1.10-1.51); PIIINP, 1.05 (95%, 0.94-1.18); and NGAL, 1.07 (95% CI, 1.02-1.12). Biomarker concentrations did not have statistically significant associations with heart failure after multivariable adjustment. LIMITATIONS: Urine biomarkers were measured at a single time point; no validation cohort available. CONCLUSIONS: Kidney tubular damage is an independent risk factor for CVD and death among elders. Future studies should investigate mechanisms by which kidney tubular damage may adversely affect cardiovascular risk. PMID- 29602633 TI - The lateralization and distalization shoulder angles are important determinants of clinical outcomes in reverse shoulder arthroplasty. AB - BACKGROUND: Reverse shoulder arthroplasty (RSA) designs vary in the lateralization and distalization geometry, which may affect functional outcomes. The purpose was to determine the effect of RSA lateralization and distalization on final functional outcomes by using the "lateralization shoulder angle" (LSA) and the "distalization shoulder angle" (DSA). METHODS: Forty-six consecutive patients who underwent RSA for cuff tear arthropathy were retrospectively evaluated. Functional outcome and radiographs were evaluated at a minimum of 2 years postoperatively and compared between implants with or without glenoid lateralization and with or without humeral-sided lateralization. Anteroposterior shoulder radiographs were used to evaluate the LSA and DSA. RESULTS: Both angles showed substantial to almost perfect intrarater and inter-rater agreement. Higher LSA values were found in more lateralized RSAs (P = .027), and values between 75 degrees and 95 degrees were correlated with better active external rotation (quadratic regression analysis R2 = 0.553, P < .001). Postoperative active anterior elevation (R2 = 0.2, P = .008), Constant (rs = 0.29, P = .05), and Activities of Daily Living Requiring External Rotation scores (rs = 0.4 P = .007) had a positive correlation with the LSA. The quadratic regression analysis also showed that a DSA between 40 degrees and 65 degrees resulted in better active anterior elevation (R2 = 0.4, P < .001) and abduction (R2 = 0.4, P < .001). The negative correlation between the LSA and DSA (rs = -0.7, P < .001) revealed that, according to the implant used, the more distally the RSA is placed the less lateralization is achieved. CONCLUSIONS: The LSA and the DSA are reproducible measurements that may be used to estimate "lateralization and distalization" after RSA. These measurements are correlated with postoperative clinical outcomes. PMID- 29602634 TI - Scapular kinematic alterations during arm elevation with decrease in pectoralis minor stiffness after stretching in healthy individuals. AB - BACKGROUND: Pectoralis minor tightness may be seen in individuals with scapular dyskinesis, and stretching is used for the treatment of altered scapular motion in sports and clinical fields. However, few researchers have reported on the effects of pectoralis minor stiffness on scapular motion during arm elevation. This study investigated whether an acute decrease of pectoralis minor stiffness after stretching changes the scapular motion during arm elevation. METHODS: The study allocated 15 dominant and 15 nondominant upper limbs in healthy men as control and interventional limbs, respectively. In the intervention limb group, the shoulder was passively and horizontally abducted at 150 degrees of elevation for 5 minutes to stretch the pectoralis minor muscle. Before and after stretching, an electromagnetic sensor was used to examine 3-dimensional scapular motion during abduction and scaption. Ultrasonic shear wave elastography was used to measure pectoralis minor stiffness before and immediately after stretching and after arm elevation. RESULTS: In the interventional limb, pectoralis minor stiffness decreased by 3.2 kPa immediately after stretching and by 2.5 kPa after arm elevation. The maximal changes in scapular kinematics after stretching were 4.8 degrees of external rotation and 3.3 degrees of posterior tilt in abduction, and 4.5 degrees of external rotation and 3.7 degrees of posterior tilt in scaption. Upward rotation in abduction or scaption did not change. CONCLUSIONS: Stretching for the pectoralis minor muscle increases external rotation and posterior tilt of the scapula during arm elevation. PMID- 29602635 TI - Yeasts and filamentous fungi associated with some dairy products in Egypt. AB - This work aimed to identify and evaluate the diversity of yeasts and filamentous fungi that contaminate some dairy products (fresh buffalo milk, plain yoghurt, butter and Kareisk cheese) in Assiut city, Egypt. The identification was based on phenotypic characteristics, and genotypically in case of yeasts. The pHs of all dairy products lie within the acidic range, but yoghurt registered the highest value. A total of 41 genera and 89 species+3 varieties were recovered from all dairy products investigated on DRBC (26 genera representing 59 species+1 variety), DG18 (32 genera, 56 species+2 varieties) and MY50G (31 genera, 64 species+2 varieties). From these, filamentous fungi were represented by 21 genera and 59 species+2 varieties, and yeasts by 20 genera and 30 species+1 variety. In all products except yoghurt, the xerophilic media (DG18 and MY50G) supported more diversity of fungal species than the general medium (DRBC). Reversely, DRBC supported more propagules originated from all products than DG18 and DRBC. On the other hand, the highest numbers of propagules were recovered from Kareish cheese and butter on MY50G, while the lowest numbers were recorded from yoghurt and raw milk on MY50G. Moreover, yeasts constituted the greatest part of propagules from the four products on the three isolation media except the raw milk on MY50G. From yeasts, Candida, Cyberlindnera, Debaryomyces, Galactomyces, Kazachstania, Kluyveromyces, Myerozyma, Pichia, Rhodotorula, Trichosporon; and from filamentous fungi, only Aspergillus, Cladosporium, Mucor and Penicillium were found contaminating all dairy products. Possible medical problems related to the presence of these fungi or to their metabolic products are discussed. PMID- 29602636 TI - Oropharyngeal candidiasis in head and neck cancer patients in Iran: Species identification, antifungal susceptibility and pathogenic characterization. AB - OBJECTIVE: Oropharyngeal candidiasis (OPC) is the most frequent opportunistic fungal infection in head and neck cancer patients. This study was done to identify the Candida species, which cause OPC, and to evaluate their antifungal susceptibility pattern and pathogenic characteristics in Iranian head and neck cancer patients treated by radiotherapy. MATERIAL AND METHODS: The oral clinical samples were determined by culturing on CHROMagar, carbohydrate assimilation and ITS sequencing methods. Biofilm formation, phospholipase and proteinase activity and antifungal susceptibility were examined too. RESULTS: Among 54 patients with confirmed OPC, 39 (72.22%) patients were male and 15 (27.77%) were female. The most frequently Candida species from a total of 60 isolates was C. albicans (53.3%), followed by C. tropicalis (21.66%), C. glabrata (15%), C. kefyr (5%) and C. dubliniensis (1.66%). All the isolates were high-producers of biofilm. All of Candida isolates were proteinase positive and 47 isolates (81.04%) represented phospholipase activity. The maximum and minimum rates of antifungal resistance belonged to ketoconazole (93.75% of C. albicans and 89.28% of Candida non albicans) and fluconazole (62.50% and 42.85% of C. albicans and Candida non albicans), respectively. The most effective antifungal against all candida isolates was fluconazole. CONCLUSION: Our data can estimate abundance of OPC in male and female head and neck cancer patients and is helpful to use effective strategies for antifungal treatment, prophylaxis, and preventive therapies in these patients. PMID- 29602637 TI - Importin-11 overexpression promotes the migration, invasion, and progression of bladder cancer associated with the deregulation of CDKN1A and THBS1. AB - OBJECTIVES: We recently determined that a novel oncogene, IPO11 from 5q12, participates in bladder cancer (BCa) progression. However, the biological function of IPO11 and the molecular mechanisms through which it contributes to BCa progression remain unclear. The aim of this study was to investigate the role of IPO11 in BCa aggressiveness and elucidate the molecular mechanisms underlying its effects in BCa. MATERIALS AND METHODS: The mRNA expression levels of IPO11 in BIU-87, RT4, UMUC3, EJ, 5637, T24, J82, and HT-1376 cell lines were determined using quantitative real-time polymerase chain reaction. Expression of importin-11 was detected in 134 formalin-fixed and paraffin-embedded (FFPE) BCa tissues and 10 paired nonneoplastic bladder tissue specimens by immunohistochemistry. The copy number of IPO11 was examined in 25 FFPE BCa specimens using fluorescent in situ hybridization. The effects of IPO11 on migration, invasion, and cell proliferation were investigated in EJ and 5637 cell lines using RNA interference. Potential molecular mechanisms were investigated using whole transcriptome sequencing and bioinformatic approaches in EJ cells and IPO11-silenced EJ cells and verified using quantitative real-time polymerase chain reaction. RESULTS: Endogenous IPO11 mRNA was highly expressed in 6 invasive BCa cell lines (EJ, HT 1376, UMUC3, 5637, J82, and T24) but had a low expression in the noninvasive BCa cell line BIU-87 and the papillary BCa cell line RT4. Immunohistochemical staining revealed that 87 (64.9%) of 134 FFPE BCa tissues displayed importin-11 overexpression. Moreover, importin-11 overexpression was positively associated with increased tumor stages and tumor grades, lymphatic invasion, and lymph node metastasis. Furthermore, importin-11 overexpression was detected in 100% (14/14) of BCa tissues with IPO11 amplification, and IPO11 amplification was not observed in 2 additional BCa tissues with importin-11 overexpression. Small interfering RNA-mediated knockdown of IPO11 is sufficient to inhibit the motility and invasiveness of EJ and 5637 cells. IPO11 knockdown also inhibited cell proliferation in EJ cells, whereas this was not observed in 5637 cells or the in vivo experiments. Using whole transcriptome sequencing, we found that 22 genes (including IPO11) were differentially expressed in IPO11-silenced EJ cells compared with wild-type EJ cells, 4 of which were upregulated, and 18 of which were downregulated. KEGG pathway enrichment analysis of the significantly differentially expressed genes showed that the proteoglycans in cancer pathway (pathway Id: hsa05205) was most significantly enriched among 10 genetically altered pathways and referred to 6 significantly altered genes (CDKN1A, HBEGF, PTK2, THBS1, CCNG2, and EGR1). The next 3 most significantly enriched pathways in order were the p53, ErbB, and BCa pathways. CDKN1A and THBS1 were the most 2 frequently covered genes and were involved in 9 and 6 pathways, respectively. They were also 2 key proteins in the BCa pathway (pathway Id: hsa05219) that were downregulated in IPO11-knockdown EJ cells compared with wild-type EJ cells. CONCLUSIONS: Importin-11 overexpression can promote BCa cell invasiveness, probably associated with the deregulation of CDKN1A and THBS1 primarily through the activation of the proteoglycans in cancer pathway and the classical BCa pathway. Importin-11 may be a useful target through which the progression of noninvasive BCa to invasive BCa can be blocked. PMID- 29602638 TI - Pattern of node metastases in patients treated with radical cystectomy and extended or superextended pelvic lymph node dissection due to bladder cancer. AB - BACKGROUND: Pelvic lymph node dissection (PLND) has a diagnostic and therapeutic role during radical cystectomy in bladder cancer patients. However, at the time, no prospective data supports the value of extended PLND in improving survival expectances. We sought to describe incidence and location of node metastases in patients treated with extended and superextended PLND. METHODS: We evaluated 653 contemporary patients with clinically nonmetastatic high risk nonmuscle invasive or muscle-invasive bladder cancer treated with radical cystectomy and extended or superextended PLND without neoadjuvant chemotherapy at a single tertiary referral center between 1990 and 2013. Limited PLND is defined as the removal of obturator and internal iliac nodes. Standard included also the external iliac nodes. Extended includes also common and presacral nodes. Finally, superextended PLND includes all the nodes removed along the inferior mesenteric artery. We evaluated incidence of pathologically node metastases. Logistic regression analyses evaluate preoperative and pathologic characteristics to the risk of harboring node metastases in the extended and superextended template. RESULTS: Overall, 191 (29.3%) patients were found with pathologically node confirmed metastases. Of these, 56 (29.3%) patients were found with a single node metastasis, while 135 (70.7%) had multiple node metastases. The vast majority of patients were found with node metastases standard template (n = 172, 26.3%), on the other hand 30 (4.6%) and 21 (3.2%) patients had node metastases in extended and superextended templates, respectively. However, of these only 2 patients were found without concomitant lymph node metastases in the limited or standard templates. On multivariable analyses, cN+ status (odds ratio = 4.40, P<0.001) and cT3-4 vs. cT1 2 (odds ratio = 2.25, P<0.001) were associated with an increased risk of harboring node metastases in the extended or superextended template. CONCLUSIONS: We found that the majority of patients harbored node disease in the limited or standard node dissection pattern. On the other hand, only a minority of patient were found with a disease in extended or superextended template without harboring a concomitant node disease in the limited pattern. PMID- 29602639 TI - Role of lymph node dissection in renal cell cancer. AB - Lymph node metastasis in renal cell cancer (RCC) portends an extremely poor prognosis. Despite proven staging benefit, the therapeutic value of lymph node dissection in RCC remains questionable. The only prospective randomized trial examining its role failed to show any benefit. However, subsequent retrospective publications have attempted to identify high-risk cohorts and clinical scenarios where removal of nodes may improve survival. The aim of this article is to provide a comprehensive review looking at the role of lymph node dissection in RCC if any, the ideal extent of dissection, and also tools a clinician could employ to identify those who would most likely benefit from this exercise. PMID- 29602640 TI - Protein complex prediction by date hub removal. AB - Proteins physically interact with each other and form protein complexes to perform their biological functions. The prediction of protein complexes from protein-protein interaction (PPI) network is usually difficult when the complexes are overlapping with each other in a dense region of the network. To address the problem of predicting overlapping complexes, a previously proposed network decomposition approach is promising. It decomposes a PPI network by e.g. removing proteins with high degree (hubs) which may participate in different complexes. This motivates us to examine a list of proteins, which bind their different partners at different time or at different location (viz. date hubs), manually collected from literature, for network decomposition. Results show that the CMC complex discovery algorithm after removing date hubs recalls more overlapping complexes that were missed earlier. Further improvement in performance is achieved when we predict date hub proteins based on simple network features and remove them from PPI networks. PMID- 29602641 TI - Schizophrenia moderates the relationship between white matter integrity and cognition. AB - Cognitive impairment is a primary feature of schizophrenia, with alterations in several cognitive domains appearing in the pre-morbid phase of the disorder. White matter microstructure is also affected in schizophrenia and considered to be related to cognition, but the relationship of the two is unclear. As interaction between cognition and white matter structure involves the interplay of several brain structures and cognitive abilities, investigative methods which can examine the interaction of multiple variables are preferred. A multiple groups structural equation model (SEM) was used to assess the relationship between diffusion tension imaging data (fractional anisotropy of selected white matter tracts) and cognitive abilities of 196 subjects - 135 healthy subjects and 61 patients with schizophrenia. It was found that multiple-indicators, multiple causes model best fitted the data analysed. Schizophrenia moderated the relation of white matter function on cognition with a large effect size. This paper extends previous work on modelling intelligence within a SEM framework by incorporating neurological elements into the model, and shows that white matter microstructure in patients with schizophrenia interacts with cognitive abilities. PMID- 29602642 TI - Persistent tachycardia in clozapine treated patients: A 24-hour ambulatory electrocardiogram study. AB - Tachycardia is associated with cardiovascular mortality. Tachycardia is also a known clozapine adverse effect. However, whether clozapine-associated tachycardia is persistent is not known. Thirty clozapine-treated patients with clinical tachycardia were investigated with 24-hour ambulatory electrocardiography (ECG). Baseline peripheral heart rate (HR) was 106.7+/-7.8. The ambulatory ECG 24-hour HR was 98.7+/-9.7. Baseline HR and 24-hour-HR correlated strongly (r=0.74, p=0.000003). Daytime HR was 106.4+/-9.9 and nighttime HR 89.2+/-12.0. Low dose bisoprolol reduced HR significantly. The high 24-hour-HR indicates a persistent tachycardia. Tachycardia should not discourage from clozapine use but the findings indicate a need of guidelines for detection and treatment of clozapine associated tachycardia. PMID- 29602643 TI - LC-MS analysis and cytoprotective effect against the mercurium and aluminium toxicity by bioactive products of Psidium brownianum Mart. ex DC. AB - This study aimed to verify the chelating, antioxidant and cytoprotective activities of Psidium brownianum Mart. Ex DC against mercury and aluminum. The ethanolic extract, as well as the tannic and flavonoid fractions, were prepared and subjected to liquid chromatography-mass spectrometry analysis. Ferric ion reduction and antioxidant activity measurement using the FRAP method were performed with P. brownianum. After determining the sub-allelopathic doses, germination tests using Lactuca sativa (lettuce) seeds were performed. The main compounds identified in the extract and fractions were: quercetin and its derivatives; myricetin and its derivatives; gallic acid; ellagic acid; quinic acid and gallocatechin. The Minimum Inhibitory Concentration (MIC) for all samples were >= 1024 MUg/mL. The flavonoid fraction in association with mercury chloride demonstrated cytoprotection (p < 0.001). The sub-allelopathic concentration used was 64 MUg/mL. The extract and fractions were cytoprotective for radicles and caulicles when assayed in association with mercury and against aluminum for radicles. This suggests that the P. brownianum extract and its fractions present cytoprotective activity, possibly related to the antioxidant effect of secondary metabolites, especially flavonoids. PMID- 29602644 TI - Who Is Responsible? A Man With Dementia Wanders From Home, Is Hit by a Train, and Dies. AB - The impact of dementia and Alzheimer's disease extends far beyond the healthcare needs of the person with dementia. As the disease progresses, individuals with dementia often require ongoing formal or informal care for their basic daily routine because of behavior changes and continuing loss of cognitive function. Most of the care for people with dementia takes place at home, and the unpaid, informal caregivers are often spouses or other relatives. Providing long-term informal care at home for someone with dementia is psychologically, physically, and financially draining. The tragedy described in this case elucidates the far reaching societal impact of dementia care and the implicit health policy considerations. In 2007, a 91-year-old Japanese man with dementia was in the care of his wife when he wandered from home, was hit by a train, and died, immediately affecting the Central Japan Railway Company operations and, subsequently, legal practice as well as Japanese elder care policy. The railway sued the man's wife and son for negligence and lost revenue, winning both trials at the local and district courts. This ruling shocked families and caregivers in Japan, where care for elderly parents traditionally falls on the oldest son, and brought attention to the complex issues related to dementia care. A decade later, we revisit this case to provoke a renewed dialogue about the matrix of responsibilities and liabilities associated with caregiving; to illuminate the unmet needs of the person with dementia, as well as his or her informal caregivers; and the financial implications related to long-term care policy. We close with 2 practical suggestions which preserve the dignity of the individual and provide reassurance for caregivers. PMID- 29602645 TI - Changing the standard of care for treating melanoma brain metastases. PMID- 29602646 TI - Combination nivolumab and ipilimumab or nivolumab alone in melanoma brain metastases: a multicentre randomised phase 2 study. AB - BACKGROUND: Nivolumab monotherapy and combination nivolumab plus ipilimumab increase proportions of patients achieving a response and survival versus ipilimumab in patients with metastatic melanoma; however, efficacy in active brain metastases is unknown. We aimed to establish the efficacy and safety of nivolumab alone or in combination with ipilimumab in patients with active melanoma brain metastases. METHODS: This multicentre open-label randomised phase 2 trial was done at four sites in Australia, in three cohorts of immunotherapy naive patients aged 18 years or older with melanoma brain metastases. Patients with asymptomatic brain metastases with no previous local brain therapy were randomly assigned using the biased coin minimisation method, stratified by site, in a 30:24 ratio (after a safety run-in of six patients) to cohort A (nivolumab plus ipilimumab) or cohort B (nivolumab). Patients with brain metastases in whom local therapy had failed, or who had neurological symptoms, or leptomeningeal disease were enrolled in non-randomised cohort C (nivolumab). Patients in cohort A received intravenous nivolumab 1 mg/kg combined with ipilimumab 3 mg/kg every 3 weeks for four doses, then nivolumab 3 mg/kg every 2 weeks; patients in cohort B or cohort C received intravenous nivolumab 3 mg/kg every 2 weeks. The primary endpoint was intracranial response from week 12. Primary and safety analyses were done on an intention-to-treat basis in all patients who received at least one dose of the study drug. This trial is registered with ClinicalTrials.gov, number NCT02374242, and is ongoing for the final survival analysis. FINDINGS: Between Nov 4, 2014, and April 21, 2017, 79 patients were enrolled; 36 in cohort A, 27 in cohort B, and 16 in cohort C. One patient in cohort A and two in cohort B were found to be ineligible and excluded from the study before receiving the study drug. At the data cutoff (Aug 28, 2017), with a median follow up of 17 months (IQR 8-25), intracranial responses were achieved by 16 (46%; 95% CI 29-63) of 35 patients in cohort A, five (20%; 7-41) of 25 in cohort B, and one (6%; 0-30) of 16 in cohort C. Intracranial complete responses occurred in six (17%) patients in cohort A, three (12%) in cohort B, and none in cohort C. Treatment-related adverse events occurred in 34 (97%) of 35 patients in cohort A, 17 (68%) of 25 in cohort B, and eight (50%) of 16 in cohort C. Grade 3 or 4 treatment-related adverse events occurred in 19 (54%) patients in cohort A, four (16%) in cohort B, and two (13%) in cohort C. No treatment-related deaths occurred. INTERPRETATION: Nivolumab combined with ipilimumab and nivolumab monotherapy are active in melanoma brain metastases. A high proportion of patients achieved an intracranial response with the combination. Thus, nivolumab combined with ipilimumab should be considered as a first-line therapy for patients with asymptomatic untreated brain metastases. FUNDING: Melanoma Institute Australia and Bristol-Myers Squibb. PMID- 29602647 TI - Bronchiectasis, Chronic Suppurative Lung Disease and Protracted Bacterial Bronchitis. AB - Bronchiectasis is a structural airway disease characterized by dilated bronchi and bronchioles due to severe or recurrent lower airways inflammation. Bronchiectasis can occur as a result of chronic pulmonary aspiration. Bronchiectasis may also be associated with a wide variety of systemic diseases, which should be considered in the differential diagnosis. Children with bronchiectasis typically have a chronic or recurrent productive cough and carry a significant burden of disease with a considerable impact on quality of life. The diagnosis of bronchiectasis is made by high-resolution chest computerized tomography. Aggressive management of bronchiectasis is necessary to reduce the daily symptom burden and frequency of exacerbations. Chronic suppurative lung disease may be a precursor to bronchiectasis, only lacking the defining radiographic features of bronchiectasis. Children with chronic suppurative lung disease may have the same symptoms as children with bronchiectasis and should be treated similarly. Protracted bacterial bronchitis is defined as a cough lasting at least four weeks that responds to antibiotic therapy. Protracted bacterial bronchitis may occur following a viral respiratory tract infection. Protracted bacterial bronchitis can be treated with a prolonged course of empiric antibiotics. Further evaluation is necessary if a child with suspected protracted bacterial bronchitis does not adequately respond to antibiotics as chronic suppurative lung disease or bronchiectasis must be considered. PMID- 29602648 TI - Dual antiplatelet therapy after coronary stent implantation: Individualizing the optimal duration. AB - Dual antiplatelet therapy (DAPT) with a P2Y12 receptor antagonist in addition to aspirin is the antiplatelet treatment of choice in patients undergoing percutaneous coronary intervention. Despite DAPT being one of the most widely investigated treatment strategies in the cardiology field, its optimal duration after coronary stenting remains controversial. The balance between the possible benefit of preventing a thrombotic event and the risk of suffering a bleeding complication due to maintenance of therapy is of critical relevance to determine the duration of DAPT in a given patient. Indeed, extended DAPT is associated with a reduction in non-fatal ischemic outcomes, at the cost of increasing the risk of bleeding events. Of note, several factors related to the patient, the procedure, or the device implanted may influence the ischemic and/or bleeding risk profiles of a given patient. Therefore, it is reasonable to recommend that the decision on DAPT duration should be individualized on a case-to-case basis. This review aims to provide a comprehensive overview of the current status of knowledge on duration of DAPT after coronary stenting, focusing on the evidence provided mainly by randomized clinical trials, as well as to discuss the factors that may influence the individual ischemic and bleeding risk profiles for a given patient, and whether the use of risk scores may inform the decision-making process for determining DAPT duration. PMID- 29602649 TI - Time-dependent depressive symptoms and risk of cardiovascular and all-cause mortality among the Chinese elderly: The Beijing Longitudinal Study of Aging. AB - BACKGROUND: Depressive symptoms tend to fluctuate over time. Data on the relationship between time-dependent depressive symptoms and the risk of cardiovascular and all-cause mortality among the elderly in China are lacking. METHODS AND RESULTS: A prospective cohort of 1999 subjects aged >=55 years were enrolled in the Beijing Longitudinal Study of Aging since 1992. Depressive symptoms were assessed at baseline (0 years) and after 2, 5, 8, and 12 years, defined as a score of >=16 on the 20-item Center for Epidemiological Studies Depression Scale. Mortality status was obtained from the local death registry until December 31st, 2012. Hazard ratio (HR) for all-cause mortality and sub distribution HR (SHR) for cardiovascular mortality were respectively deduced from time-dependent Cox and competing risk models. During 19,658 person-years of follow-up, 1127 (55.65%) deaths were recorded, of which 483 (23.85%) were attributable to cardiovascular inclinations. Baseline depressive symptoms were neither associated with all-cause mortality (adjusted HR: 1.12, 95% confident interval, CI: 0.94-1.33) nor cardiovascular mortality (adjusted SHR: 1.10, 95% CI: 0.82-1.46) after adjustment of potential cardiac-risk factors. When depressive symptoms were used as time-dependent variable updated from 1992 to 2004, the associations were significant for both all-cause mortality (adjusted HR: 1.48, 95% CI: 1.26-1.73) and cardiovascular mortality (adjusted SHR: 1.40, 95% CI: 1.08-1.82) in the full adjusted model. CONCLUSIONS: Time-dependent depressive symptoms increased the risk of all-cause and cardiovascular mortality among the elderly in China. PMID- 29602650 TI - Anomalous Forearm Muscles and Their Clinical Relevance. AB - Despite their relatively low prevalence in the population, anomalous muscles of the forearm may be encountered by nearly all hand and wrist surgeons over the course of their careers. We discuss 6 of the more common anomalous muscles encountered by hand surgeons: the aberrant palmaris longus, anconeus epitrochlearis, palmaris profundus, flexor carpi radialis brevis, accessory head of the flexor pollicis longus, and the anomalous radial wrist extensors. We describe the epidemiology, anatomy, presentation, diagnosis, and treatment of patients presenting with an anomalous muscle. Each muscle often has multiple variations or subtypes. The presence of most anomalous muscles is difficult to diagnose based on patient history and examination alone, given that symptoms may overlap with more common pathologies. Definitive diagnosis typically requires soft tissue imaging or surgical exploration. When an anomalous muscle is present and symptomatic, it often requires surgical excision for symptom resolution. PMID- 29602652 TI - Intramuscular Epithelioid Sarcoma Presenting as Extrinsic Flexor Tightness in the Forearm. AB - Epithelioid sarcoma is an uncommon soft tissue sarcoma involving predominantly the distal extremities of adolescents and young adults. Its rarity makes it difficult to diagnose accurately and treat properly in the early stages. We discuss the delayed diagnosis of a 37-year-old man who presented with extrinsic flexor tightness of the wrist and fingers. We initially thought that the lesion resulted from inflamed soft tissue of the flexor muscles causing contracture. However, histological examination of a biopsy specimen revealed nodular proliferation of epithelioid and spindle cells, which were immunoreactive to epithelial and nonepithelial markers, respectively, leading to the final diagnosis of epithelioid sarcoma. PMID- 29602651 TI - Anatomical Variation of the Radial Artery Associated With Clinically Significant Ischemia. AB - PURPOSE: The purpose of this retrospective review was to investigate the incidence of radial artery anatomical variations in patients with clinically significant distal upper extremity (UE) ischemia. Available anatomical studies report that high takeoff of the radial artery occurs in up to 15% of the population. We hypothesized that there is a higher incidence of high origin of the radial artery in patients with clinically significant ischemia compared with the reported frequency in the general population. METHODS: We performed a retrospective review of all patients who underwent UE angiography for clinically significant hand and digital ischemia in our institution from 2012 to 2016. Data collected included patient age, sex, comorbidities, and modality of treatment. RESULTS: Twenty-six angiograms were performed for UE ischemia meeting inclusion criteria. Eight patients had Raynaud disease or scleroderma. Ten patients (38%) had high radial artery takeoff with radial artery origin proximal to the antecubital fossa. The need for surgical intervention was similar in patients with normal anatomy and those with high takeoff of the radial artery. CONCLUSIONS: Incidence of high radial artery takeoff was found more frequently in patients with distal UE ischemia requiring angiogram than in reported population data. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic IV. PMID- 29602653 TI - The Use of Medicinal Leeches for the Treatment of Venous Congestion in Replanted or Revascularized Digits. AB - PURPOSE: A noteworthy cause of failure in digital replantation is venous insufficiency. External bloodletting with medicinal leeches is a common treatment for venous insufficiency after distal digital replantations. The objective of this study was to evaluate the salvage rate of digits replanted proximal to the distal interphalangeal (DIP) joint that were treated with medicinal leeches for venous congestion. METHODS: We retrospectively reviewed the charts of patients with complete or incomplete digit amputation admitted between January, 2008 and April, 2014. We included all patients with venous congestion in one or more digits replanted or revascularized at the middle or proximal phalangeal level, who were treated with medicinal leeches. Treatment initiation and duration were based on clinical judgment. Demographic, therapy, and surgical data were collected. RESULTS: Of 145 patients with 205 digits that were replanted or revascularized, 25 digits were treated with medicinal leeches for venous congestion. Venous congestion was diagnosed later than 48 hours after operation in 24 of the 25 digits. Of the 25 digits, 11 survived (44.4%) (8 of 22 replanted digits and all 3 revascularized digits). No complications were recorded except for substantial blood loss requiring transfusion in one patient. CONCLUSIONS: External bloodletting with medical leeches might be less effective with late treatment or with a higher volume of congested tissue, as is characteristic of proximal finger replantation. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 29602654 TI - An Evaluation of the Reliability of Wrist Arthroscopy in the Assessment of Tears of the Triangular Fibrocartilage Complex. AB - PURPOSE: Wrist arthroscopy is generally considered the reference standard in the diagnosis of triangular fibrocartilage complex (TFCC) injuries. There is a paucity of data examining the reliability of wrist arthroscopy as a diagnostic modality for TFCC injuries. The goal of this study was to evaluate the interobserver and intraobserver reliability of the diagnosis of TFCC pathology during wrist arthroscopy. METHODS: Twenty-five intraoperative digital videos were captured by the senior author during diagnostic and surgical arthroscopy of the wrist joint for known or suspected articular pathology. The senior author (P.K.B.) confirmed TFCC resilience on visual inspection and ballottement (trampoline effect) to make the diagnosis. Two videos were excluded for poor quality and inadequate visualization. Three hand surgeons subsequently reviewed the remaining 23 videos in a blinded fashion at 2 time points separated by 4 weeks. The reviewers determined if the trampoline test was positive and if a TFCC tear was present. Tears were classified using a morphologic classification. Statistical measures of reliability including percentage agreement and kappa coefficients were calculated. RESULTS: Agreement between observers for the presence or absence of a tear was 66.7%. The average intraobserver agreement regarding the presence or absence of a tear was 67.4% The kappa value for interobserver agreement was 0.33, whereas the intrarater agreement was 0.88. The 3 reviewers identified an average of 11.3 positive trampoline tests. Agreement between observers for a positive trampoline test was 65.2%. The average percentage of intraobserver agreement regarding a positive trampoline test was 49.3%. In cases where all 3 reviewers agreed on the presence of a TFCC tear, the agreement regarding tear location was 76.6%. CONCLUSIONS: Wrist arthroscopy remains instrumental in the treatment of TFCC tears. However, given that inter rater reliability in the assessment of these tears is probably too low, reconsideration should be given to arthroscopy as the reference standard in the diagnosis of these tears. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic III. PMID- 29602655 TI - Correlation of the Lateral Wrist Radiograph to Ulnar Variance: A Cadaveric Study. AB - PURPOSE: Both positive and negative ulnar variance have been implicated in a variety of wrist disorders. Surgery aims to correct the variance in these pathologic conditions. This necessitates accurate and reproducible measuring tools; however, the most accurate radiographic measurement technique remains unclear. The purposes of this study were to evaluate 3 methods for determining ulnar variance and to compare each with direct anatomic measurement in a cadaver model. METHODS: We fixed 10 fresh above-elbow cadaver specimens in neutral rotation and obtained standardized fluoroscopic posteroanterior and lateral wrist images. A dorsal approach was performed and two independent investigators directly measured ulnar variance using digital calipers with the cartilage both intact and denuded. Ulnar variance was measured radiographically using the lateral, perpendicular, and central reference point methods. The reliability of each set of measurements (within a 1-mm cutoff) was assessed by the intraclass coefficient; agreement between radiographic and direct measurements was evaluated by the Bland-Altman method. RESULTS: Each method of determining ulnar variance demonstrated near perfect agreement by the intraclass coefficient. The lateral radiograph method correlated highly with the directly measured ulnar variance with the cartilage denuded with an average measurement difference of 0.06 mm. No radiographic measurement technique demonstrated consistent agreement within 1 mm of the measured ulnar variance with the cartilage intact. CONCLUSIONS: Ulnar variance measured by the lateral wrist radiograph technique correlates highly with the directly measured osseous ulnar variance. The remaining measurement techniques did not correlate reliably to within 1 mm of the directly measured ulnar variance with 95% confidence. No method was able to account accurately for the articular cartilage thicknesses at the lunate facet of the radius or the distal ulnar head, which we found to vary in an unpredictable manner. Whereas the lateral radiograph has been shown to allow for more reliable standardization of wrist position compared with the posteroanterior view, this study also highlights the inherent limitations of using static radiographic images in evaluating ulnar variance. CLINICAL RELEVANCE: The results of the current study demonstrate the utility of the lateral wrist radiograph for assessing bony ulnar variance. PMID- 29602656 TI - Opioid Use After Upper Extremity Surgery. AB - Ever since the institution of pain as the fifth vital sign, there has been a rising opioid epidemic in the United States, with Americans now consuming 80% of the global opioid supply while representing only 5% of the world's population. Surgeons are tasked with the duty of both managing patients' pain in the perioperative period and following responsible prescribing behaviors. Several articles have been published with the goal of evaluating opioid use after upper extremity surgery, risk factors for opioid misuse/abuse, the impact of anesthetic type, and the role of multimodal pain management regimens. These studies have found that, on average, surgeons prescribe 2 to 5 times more opioids than patients consume. Multimodal pain management strategies are effective for decreasing postoperative opioid consumption. Risk factors for prolonged opioid use and/or misuse are younger age, history of substance abuse, psychological disorders, and previous pain diagnoses. Use of regional blockade anesthesia, particularly with long-acting agents or indwelling catheters, can be helpful in the management of postoperative pain. This review article summarizes the available literature regarding opioid use after upper extremity surgery to provide the surgeon with additional information to make informed decisions regarding postoperative opioid prescription. PMID- 29602657 TI - Tendon Adhesions: A Novel Method of Objectively Measuring Adhesions by Assessing Tendon Glide Through a Soft Tissue Envelope in a Rat Model. AB - PURPOSE: To develop a rat model of extra-synovial tendon adhesions that will enable accurate testing of scar barriers and adhesion inhibiting treatments to facilitate future research. METHODS: Thirty-six 6-month-old male Sprague-Dawley rats were randomized to one of the 3 groups of 12. In Group A, the middle one third portion of the left Achilles tendon was excised. In Group B, the tendon and soft tissue bed was abraded with steel wool. In Group C, a silk suture was sewn along the tendon. The right hind limbs served as controls. At 4 weeks, biomechanical testing was performed on the bilateral hind limbs. The Achilles tendon was cut at the gastrocnemius-tendon junction proximal to the "adhesion zone" (or analogous level in the control limb). The calcaneal insertion of the Achilles was attached to a tensiometer. The force needed to pull the tendon out of its soft tissue envelope at a fixed rate was measured. RESULTS: Three rats were excluded because of complications during data collection. Pair-wise comparison testing was performed, comparing the mean peak force to pull the Achilles tendon from its soft tissue envelope in 33 control limbs and the contralateral limb from each group. The average peak force for the cut tendon group (A) was 20.1 N, 18.8 N in the steel wool group (B), and 21.1 N in the suture group (C). The average peak force in the control limbs was 15.6 N. There was a significant difference noted in peak forces between the control limbs and each experimental group. CONCLUSIONS: A consistent and statistically increased force was necessary to pull a rodent Achilles tendon from an adhesion-induced tissue bed compared with controls. No statistical difference was detected between experimental groups. CLINICAL RELEVANCE: Our study demonstrates an objective method of biomechanical tendon adhesion assessment in a rat model. PMID- 29602658 TI - Effects of the Affordable Care Act on Payer Mix and Physician Reimbursement in Hand Surgery. AB - PURPOSE: To evaluate the effect of the Affordable Care Act (ACA) on the payer distribution and reimbursement rate for hand surgery at our institution. METHODS: We reviewed records of 4,257 patients who underwent hand surgery at our institution between January 2008 and June 2016; 2,601 patients underwent surgery before the implementation of the ACA, and 1,656 patients after. Type of procedure, insurance status, amount of money billed, and amount collected were recorded. RESULTS: After the implementation of the ACA, we performed fewer metacarpal fracture repairs, distal radius fracture repairs, and abscess incision and drainage procedures. We performed more endoscopic carpal tunnel releases. The proportion of uninsured patients decreased significantly (15% to 6.4%), and the proportion of patients on Medicare (15.4% to 20.3%) and Medicaid (9.5% to 17.8%) increased significantly. The overall reimbursement rate did not change significantly (32.3% to 30.3%) between the 2 time periods. CONCLUSIONS: After the implementation of the ACA, we observed a significant reduction in the number of uninsured patients and an increase in Medicaid and Medicare patients. However, this led to no significant change in reimbursement rates. TYPE OF STUDY/LEVEL OF EVIDENCE: Economic and design analysis II. PMID- 29602659 TI - A national approach to pharmacovigilance: The case of India as a growing hub of global clinical trials. AB - Pharmacovigilance is the pharmacological science associated with the detection, understanding and prevention of adverse effects, especially long-term and short term adverse effects of medicines. In the present day pharmaceutical scenario, where the development and marketing of an ever-growing array of medicines has rendered their safety and therapeutic efficacy key to determining the success of a drug, pharmacovigilance has come about to play a critical and significant part. While pharmacovigilance, as a system, has witnessed considerable progress and evolution in the West, not as much has been accomplished in India. With India now being recognised as a hub of global clinical trials and with an increasing number of clinical trials and clinical research studies being conducted actively, the need for a dynamic pharmacovigilance network with an efficient and prudent operation methodology is felt, now more than ever. This article observes the evolution of the pharmacovigilance system in India, with a fundamental overview of the present system in place and also various schemes and proposals to establish and sustain the same. It also examines the challenges faced in the execution of an effective pharmacovigilance network as well as the future prospects with regards to the Indian market. PMID- 29602660 TI - Management of treatment failure in restless legs syndrome (Willis-Ekbom disease). AB - Dopaminergic drugs have been widely used over the last decades for the treatment of restless legs syndrome (RLS)/Willis-Ekbom disease (WED). While the majority of studies show an initial improvement in symptoms, longer studies and clinical experience show that either treatment efficacy decreases with time, and/or augmentation develops: dopaminergic augmentation has been reported to be the main reason for treatment discontinuation and treatment failure in RLS/WED. The current review discusses the main reasons for treatment failure in RLS/WED and outlines the most recent expert-based strategies to prevent and manage it. The main strategy for preventing augmentation is to consider non-dopaminergic medications such as alpha2delta ligands for initial RLS/WED treatment; these effective drugs have been shown to have little risk of augmentation. Alternatively, should dopaminergic drugs be elected as initial treatment, then the daily dose should be kept low and not exceed maximum recommended doses, however, it should be kept in mind that even low dose dopaminergics can cause augmentation. Patients with low iron stores should be given appropriate iron supplementation. Daily treatment should start only when symptoms significantly impact quality of life in terms of frequency and severity; while intermittent treatment might be considered in intermediate cases. Treatment of existing augmentation should be initiated, where possible, with the elimination/correction of extrinsic exacerbating factors (iron levels, antidepressants, antihistamines, etc.). In cases of mild augmentation, dopamine agonist therapy can continue by dividing or advancing the dose, or increasing the dose if there are breakthrough nighttime symptoms. Alternatively, the patient can be switched to an alpha2delta ligand or rotigotine. For severe augmentation, the patient can be switched to an alpha2delta ligand or rotigotine, noting that rotigotine may produce augmentation at higher doses with long-term use. In more severe cases of augmentation an opioid may be considered, bypassing alpha2delta ligands and rotigotine. PMID- 29602661 TI - 3-Tesla MRI-assisted detection of compression points in ulnar neuropathy at the elbow in correlation with intraoperative findings. AB - INTRODUCTION: Releasing the ulnar nerve from all entrapments is the primary objective of every surgical method in ulnar neuropathy at the elbow (UNE). The aim of this retrospective diagnostic study was to validate preoperative 3-Tesla MRI results by comparing the MRI findings with the intraoperative aspects during endoscopic-assisted or open surgery. METHODS: Preoperative MRI studies were assessed by a radiologist not informed about intraoperative findings in request for the exact site of nerve compression. The localizations of compression were then correlated with the intraoperative findings obtained from the operative records. Percent agreement and Cohen's kappa (kappa) values were calculated. RESULTS: From a total of 41 elbows, there was a complete agreement in 27 (65.8%) cases and a partial agreement in another 12 (29.3%) cases. Cohen's kappa showed fair-to-moderate agreement. CONCLUSION: High-resolution MRI cannot replace thorough intraoperative visualization of the ulnar nerve and its surrounding structures but may provide valuable information in ambiguous cases or relapses. PMID- 29602662 TI - System-wide process changes improve procedural sedation billing in the pediatric emergency department. PMID- 29602663 TI - Interprofessional simulation for rapid response system should be developed with step by step process to multiple learning purposes. PMID- 29602664 TI - Rate of patients at elevated risk of opioid overdose visiting the emergency department. AB - OBJECTIVE: To determine the rate of patients visiting the emergency department who are at risk of opioid overdose. METHODS: The electronic records of a 412 bed tertiary care county teaching hospital were searched for emergency department (ED) visits from January 1, 2013 to October 31, 2016 to find patients on at least 100mg morphine equivalents (MME) of oral opioid therapy, or an opioid in combination with a benzodiazepine. Records were also searched for patients with a positive urinalysis for opioids when no opioid was present on their home medication list. Medication reconciliations were searched for patients at risk of opioid overdose who were subsequently discharged on naloxone. RESULTS: An analysis of 2521 patients visiting the ED was performed, and the overall rate of risk of opioid overdose increased from 25.84% to 47.41% (p<0.0001) in patients meeting inclusion criteria from 2013 to 2016. For patients on opioids, the rate of patients on 100 MME daily or greater increased from 9.72% to 28.24% (p<0.0001) from 2013 to 2016. The rate of patients on opioid therapy in combination with benzodiazepine therapy did not change significantly from 2013 to 2016. When comparing patients at risk of opioid overdose to total emergency department visits, we found the rate of at risk patients increased significantly from 0.12% to 0.56% (p<0.0001) from 2013 to 2016. CONCLUSIONS: The rate of patients visiting the emergency department at risk of opioid overdose increased significantly from 2013 to 2016. Naloxone was not routinely prescribed to this patient cohort. PMID- 29602665 TI - Relocation of blood gas laboratory to the emergency department helps decrease lactic acid values. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.ajem.2018.03.017. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal. PMID- 29602666 TI - Out of hospital extracorporeal life support (ECLS) implantation in cardiogenic shock after cardiac arrest. AB - We report the use of out-of-hospital extracorporeal life support (ECLS) in a 62 year-old patient with severe cardiogenic shock after cardiac arrest. The patient was successfully stabilized using the ECLS system in the pre-hospital setting. Hospital discharge with a good neurological outcome was possible after 23days. PMID- 29602667 TI - Retrospective assessment of succinylcholine use in acute stroke care: What are the risks? PMID- 29602668 TI - Sleep hygiene practices and its effects on job satisfaction in emergency medicine physicians and physicians-in-training. PMID- 29602669 TI - Displaced anterior pelvic fracture on initial pelvic radiography predicts massive hemorrhage. AB - INTRODUCTION: Massive hemorrhage is often associated with unstable pelvic fractures with posterior ring injury. Initial pelvic radiography alone may not detect these posterior lesions. We examined whether the presence of an anterior pelvic fracture on initial pelvic radiography alone may identify patients who are at a high risk of major hemorrhage. MATERIALS AND METHODS: A total of 288 patients with pelvic fractures were admitted to the Fukui Prefectural Hospital during an 11-year period. After excluding 33 patients who were in cardiopulmonary arrest on arrival and nine with concomitant abdominal organ injuries requiring emergency laparotomy, 246 eligible patients were retrospectively reviewed. Anterior pelvic fractures were defined as displacement of the obturator ring, obturator ring with laterality, or displacement of the pubic symphysis on pelvic radiography. RESULTS: Massive hemorrhage was identified in 106 of 246 patients. Patients with massive hemorrhage had a higher frequency of anterior pelvic fractures on pelvic radiography and higher frequency of posterior pelvic fractures on computed tomography than those without massive hemorrhage. Logistic regression analysis identified displacement of the obturator ring by >=5mm, obturator ring with laterality of >=5mm, and displacement of the pubic symphysis by >=4mm on pelvic radiography as predictors of massive pelvic hemorrhage. CONCLUSION: The results of the present study suggested that the presence of displaced anterior lesions of the pelvic ring on pelvic radiography alone, without the use of computed tomography during the initial treatment stage, may promptly identify patients at high risk of massive pelvic hemorrhage who require intervention for hemorrhage control. PMID- 29602670 TI - Topical tranexamic acid for the treatment of acute epistaxis in the emergency department. AB - OBJECTIVE: To evaluate the effectiveness and potential benefits of topical tranexamic acid (TXA) in the management of acute epistaxis. METHODS: Retrospective review was performed among all patients presenting to the institution's emergency department (ED) with epistaxis between September 2014 and August 2016. Patients achieving hemostasis with standard of care agents, such as oxymetazoline, lidocaine, or epinephrine were excluded. The primary outcome was the ED length of stay (LOS). Secondary outcomes included the incidence of hospital admission, otolaryngologist consultation, nasal packing, prophylactic antibiotic use, and ED visit for rebleeding within seven days of treatment. RESULTS: Among 122 patients, 30 received topical TXA (500mg injectable solution soaked onto packing material and applied to the affected nostril) and 92 were managed with standard care. Nearly half (46.7%) of TXA-treated subjects received TXA either alone or in combination with standard of care agents as their initial treatment strategy. No significant difference was observed in the ED LOS (272 vs 232min in TXA and standard care arms, respectively, p=0.26). However, TXA was associated with a significant reduction in otolaryngologist consults (30.0% vs 65.2%, p=0.002) and nasal packing (16.7% vs 23.9%, p=0.003). CONCLUSIONS: This investigation did not demonstrate a significant difference in ED LOS among patients with acute epistaxis treated with topical TXA or standard care. However, this data does add to existing evidence that TXA may be associated with a reduction in resource utilization, suggesting it may provide more effective bleeding control. Overall, more data is needed to confirm the potential benefits of this practice. PMID- 29602671 TI - Dover sole. AB - Negative pressure pulmonary edema (NPPE) is a clinical syndrome well described in the literature and easy to recognize in cases of suspicion, but probably underdiagnosed. It can be a cause of morbidity and admission to the intensive care unit of healthy young individuals. It is present in approximately one in every thousand anesthetics and in 10% of the episodes of upper airway obstruction that are observed in routine clinical practice. It is a non-cardiogenic form of pulmonary oedema thought to be caused by the highly negative intra-thoracic pressure generated when trying to breathe against an acute obstruction. We report a case of NPPE after an airway obstruction in a young male patient. PMID- 29602672 TI - Serum levels of miRNA in patients with hepatitis B virus-associated acute-on chronic liver failure. AB - BACKGROUND: Hepatitis B virus (HBV)-associated acute-on-chronic liver failure (HBV-ACLF) is a life-threatening condition and its exact pathophysiology and progression remain unclear. The present study aimed to assess the role of serum miRNAs in the evaluation of HBV-ACLF and to develop a model to predict the outcomes for ACLF. METHODS: Serum was collected from 41 chronic hepatitis B and 55 HBV-ACLF patients in addition to 30 chronic asymptomatic HBV carriers as controls. The miRNAs expressions were measured by real-time quantitative PCR (q PCR). Statistical analyses were conducted to assess the ability of differentially expressed miRNAs and other prognostic factors in identifying ACLF prognosis and to develop a new predictive model. RESULTS: Real-time q-PCR indicated that serum miR-146a-5p, miR-122-3p and miR-328-3p levels were significantly upregulated in ACLF patients compared to chronic hepatitis B and chronic asymptomatic HBV carriers patients. In addition, multivariate regression analyses indicated that Na+, INR, gastrointestinal bleeding and miR-122-3p are all independent factors that are reliable and sensitive to the prognosis of HBV-ACLF. Therefore, we developed a new model for the prediction of HBV-ACLF disease state: Y = 0.402 * Na+ - 1.72 * INR - 4.963 * gastrointestinal bleeding (Yes = 0; No = 1)-0.278 * (miR-122-3p) + 50.449. The predictive accuracy of the model was 95.3% and the area under the receiver operating characteristic curve (AUROC) was 0.847. CONCLUSIONS: Expression levels of these miRNAs (miR-146a-5p, miR-122-3p and miR 328-3p) positively correlate with the severity of liver inflammation in patients with ACLF and may be useful to predict HBV-ACLF severity. PMID- 29602673 TI - Building bridges for highly selective, potent and stable oxytocin and vasopressin analogs. AB - Oxytocin (OT) is an exciting potential therapeutic agent, but it is highly sensitive to modification and suffers extensive degradation at elevated temperature and in vivo. Here we report studies towards OT analogs with favorable selectivity, affinity and potency towards the oxytocin receptor (OTR), in addition to improving stability of the peptide by bridging the disulfide region with substituted dibromo-xylene analogs. We found a sensitive structure-activity relationship in which meta-cyclized analogs (dOTmeta) gave highest affinity (50 nM Ki), selectivity (34-fold), and agonist potency (34 nM EC50, 87-fold selectivity) towards OTR. Surprisingly, ortho-cyclized analogs demonstrated OTR and vasopressin V1a receptor subtype affinity (220 nM and 69 nM, respectively) and pharmacological activity (294 nM and 35 nM, respectively). V1a binding and selectivity for ortho-cyclized peptides could be improved 6-fold by substituting a neutral residue at position 8 with a basic amino acid, providing potent antagonists (14 nM IC50) that displayed no activation of the OTR. Furthermore, xylene-bridged analogs demonstrated increased stability compared to OT at elevated temperature, demonstrating promising therapeutic potential for these analogs which warrants further study. PMID- 29602674 TI - Design, synthesis, and biological evaluation of new B-RafV600E kinase inhibitors. AB - The association of deregulated signal pathways with various diseases has long been a research hotspot. One of the most important signal pathways, the MAPK (mitogen-activated protein kinase) signal pathway, plays a vital role in transducing extracellular signals into vital intracellular mechanisms. While mutations on its key component Raf kinase lead to sever diseases, targeted inhibition has thereby become an attractive therapeutic strategy. Several drugs have been approved for the treatment of Raf relevant diseases, yet more candidates are ever needed as the known drugs have confronted resistance and side effects. In the present study, we primarily investigated the binding modes of type I/II and type II inhibitors with B-Raf kinase. Based on the current knowledge, these ligands were fragmented and recombined to provide new interesting insights. Afterwards, a series of derivatives has been synthesized after the validation of hit compound. In addition, in vitro assays were carried out to profile the pharmacological properties of all the entities. Of all the compounds, compound 5h showed the best profile and may be used in the future study. PMID- 29602675 TI - DNA sequence-specific ligands. XVII. Synthesis, spectral properties, virological and biochemical studies of fluorescent dimeric bisbenzimidazoles DBA(n). AB - A series of DNA minor groove binding fluorescent dimeric bisbenzimidazoles DBA(n) bearing linkers of various length were synthesized and their biochemical and antiviral activities were evaluated. Their antiviral activity was assessed in model cell systems infected with human herpes simplex virus (HSV-1) and cytomegalovirus (CMV). Compounds DBA(1) and DBA(7) demonstrated in vitro inhibitory properties towards HSV-1, and DBA(7) completely blocked the viral infection. Compound DBA(11) displayed the in vitro therapeutic activity towards both HSV-1 and CMV. All of the DBA(n) could fluoresce, were well soluble in water, not cytotoxic to a concentration of 240 uM, penetrated well into cell nuclei by binding to DNA and could inhibit topo-I at low micromolecular concentrations. PMID- 29602676 TI - Structure-activity relationships in a new class of non-substrate-like covalent inhibitors of the bacterial glycosyltransferase LgtC. AB - Lipooligosaccharide (LOS) structures in the outer core of Gram-negative mucosal pathogens such as Neisseria meningitidis and Haemophilus influenzae contain characteristic glycoepitopes that contribute significantly to bacterial virulence. An important example is the digalactoside epitope generated by the retaining alpha-1,4-galactosyltransferase LgtC. These digalactosides camouflage the pathogen from the host immune system and increase its serum resistance. Small molecular inhibitors of LgtC are therefore sought after as chemical tools to study bacterial virulence, and as potential candidates for anti-virulence drug discovery. We have recently discovered a new class of non-substrate-like inhibitors of LgtC. The new inhibitors act via a covalent mode of action, targeting a non-catalytic cysteine residue in the LgtC active site. Here, we describe, for the first time, structure-activity relationships for this new class of glycosyltransferase inhibitors. We have carried out a detailed analysis of the inhibition kinetics to establish the relative contribution of the non-covalent binding and the covalent inactivation steps for overall inhibitory activity. Selected inhibitors were also evaluated against a serum-resistant strain of Haemophilus influenzae, but did not enhance the killing effect of human serum. PMID- 29602677 TI - Mobility one week after a hip fracture - can it be predicted? AB - OBJECTIVE: Better patient outcomes and more efficient healthcare could be achieved by predicting post hip fracture function at an early stage. This study aimed to identify independent predictors of mobility outcome one week post hip fracture surgery. METHODS: All hip fracture inpatients (n=77) were included in this 6 month prospective observational cohort study. Predictor variables were obtained on the first postoperative day and included premorbid function using the New Mobility Score (NMS). Mobility outcome measures one week postoperatively included the Cumulated Ambulatory Score (CAS). Data were analysed with SPSS using binary multiple logistic regression analysis RESULTS: Patients who fell outdoors (OR 3.848; 95% CI, 1.053-14.061), had no delay to surgery (OR 5.472; 95% CI, 1.073-27.907) and had high pre-fracture function (OR3.366; 95% CI, 1.042-10.879) were predicted to achieve independent mobility (CAS = 6) one week postoperatively. CONCLUSION: Fall location, time to surgery and baseline function predict independent mobility one week after hip fracture, and can be used for early rehabilitation stratification. The NMS and CAS are recommended as standardised hip fracture clinical measures. Orthogeriatric and physiotherapy service initiatives may improve early functional outcome. PMID- 29602678 TI - Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome due to ethambutol. PMID- 29602679 TI - A new target for Alzheimer's disease: A small molecule SERCA activator is neuroprotective in vitro and improves memory and cognition in APP/PS1 mice. AB - Amongst the cellular cacophony of altered signals in Alzheimer's disease (AD), disrupted Ca2+ homeostasis and consequential endoplasmic reticulum (ER) stress signals have been recognized as key determinants of neuron fate. This altered Ca2+ state is accompanied by a failing sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pump, which has been recognized as a causal feature of the underlying disease state. Repair of the Ca2+ dyshomeostasis represents a putative drug target via alleviation of ER stress and rescue of injured neurons, effectively modifying the AD state. Herein, we report a small molecule SERCA activator that rescues brain cells and raises ER Ca2+ in vitro, and shows efficacy in the APP/PS1 double transgenic mouse model of Alzheimer's disease. These results support SERCA activation as a therapeutic target for AD. PMID- 29602680 TI - Towards new antibiotics targeting bacterial transglycosylase: Synthesis of a Lipid II analog as stable transition-state mimic inhibitor. AB - Described here is the asymmetric synthesis of iminosugar 2b, a Lipid II analog, designed to mimic the transition state of transglycosylation catalyzed by the bacterial transglycosylase. The high density of functional groups, together with a rich stereochemistry, represents an extraordinary challenge for chemical synthesis. The key 2,6-anti- stereochemistry of the iminosugar ring was established through an iridium-catalyzed asymmetric allylic amination. The developed synthetic route is suitable for the synthesis of focused libraries to enable the structure-activity relationship study and late-stage modification of iminosugar scaffold with variable lipid, peptide and sugar substituents. Compound 2b showed 70% inhibition of transglycosylase from Acinetobacter baumannii, providing a basis for further improvement. PMID- 29602681 TI - Design, synthesis, neuroprotective, antibacterial activities and docking studies of novel thieno[2,3-d]pyrimidine-alkyne Mannich base and oxadiazole hybrids. AB - A series of thieno[2,3-d]pyrimidine alkyne Mannich base derivatives (7a-e, 8a-e) and thieno[2,3-d]pyrimidine 1,3,4-oxadiazole derivatives (9a-e, 10a-e) have been synthesized and evaluated for their neuroprotective and neurotoxicity activities where 9a, 10d displayed good neuroprotection 10.6 and 11.88 ug/mL respectively against the H2O2 induced cell death at the EC50 values and 9b, 9d showed respective toxic effects on PC12 cells at CC50 86.12 and 94.16 ug/mL. Compounds 9a, 9e, 10a and 10b showed strong antibacterial activity against two gram positive (S. aureus, B. subtilis) and two gram-negative strains (E. coli, P. aeruginosa) and showed good binding affinities with C(30) carotenoid dehydrosqualene synthase, Gyrase A and LpxC. This is the first report for the demonstration of thieno[2,3-d] pyrimidine derivatives as promising neuroprotective agents against H2O2 induced neurotoxicity on PC12 cells. PMID- 29602682 TI - Designing novel inhibitors against falcipain-2 of Plasmodium falciparum. AB - Coumarin containing pyrazoline derivatives have been synthesized and tested as inhibitors of in vitro development of a chloroquine-sensitive (MRC-02) and chloroquine-resistant (RKL-2) strain of Plasmodium falciparum and in vivo Plasmodium berghei malaria. Docking study was also done on cysteine protease falcipain-2 which showed that the binding pose of C-14 molecule and epoxysuccinate, inhibitor of falcipain-2, binds in the similar pattern. The most active antimalarial compound was 3-(1-benzoyl-5-(4-flurophenyl)-4,5-dihydro-1H pyrazol-3yl)-7-(diethyamino)-2H-chromen-2-one C-14, with an IC50 of 4.21 ug/ml provided complete protection to the infected mice at 24 mg/kg X 4 days respectively. PMID- 29602684 TI - Corrections. PMID- 29602683 TI - Studies on synthesis of novel pyrido[2,3-d]pyrimidine derivatives, evaluation of their antimicrobial activity and molecular docking. AB - A series of novel pyrido[2,3-d]pyrimidine derivatives 6 were prepared starting from 2-amino-3-cyano-4-trifluoromethyl-6-phenyl pyridine 3 via Grignard's reaction, cyclization followed by coupling with aliphatic and cyclic amines. All the compounds 6 were screened for antibacterial, minimum bactericidal concentration (MBC), biofilm inhibition activity as well as antifungal and minimum fungicidal concentration (MFC) activities. Among the screened compounds, the compounds 6e, 6f, and 6m which showed exhibiting promising activity have been identified. The results reveal that the compound pyrido[2,3-d]pyrimidine derivative 6e altered the sterol profile which may exert its antifungal activity through inhibition of ergosterol biosynthesis and could be an ideal candidate for antifungal therapy. The molecular docking results also validated the antifungal results. PMID- 29602685 TI - Intrathecal expression of IL-5 and humoral response in patients with tick-borne encephalitis. AB - AIM: The aim of the study was to assess the role of an early specific humoral response in human infection with a tick-borne encephalitis virus (TBEV) and the role of IL-5 as its potential mediator and marker. MATERIALS AND METHODS: The retrospective study involved a cohort of 199 patients diagnosed with TBE, in whom anti-TBEV IgM and IgG antibody titers were analyzed on admission and compared with clinical presentation and basic laboratory parameters. The prospective study included 50 TBE patients in whom IL-5 serum and CSF concentration was measured with ELISA on admission in the TBE neurologic phase and in selected patients before discharge, at follow-up or in samples obtained before the neurologic phase onset. RESULTS: The serum anti-TBEV IgM correlated with good clinical outcome and the CSF anti-TBEV IgM with more pronounced CSF inflammation on admission, but also with its more complete resolution on follow-up. The serum anti-TBEV IgG correlated with milder presentation and better outcome. Concentration of IL-5 was increased in CSF but not in the serum of TBE patients. IL-5 concentration index on admission favored its intrathecal synthesis. IL-5 did not correlate significantly with clinical presentation and specific IgM and IgG titers. CONCLUSIONS: Specific anti-TBEV IgM systemic and intrathecal response and IgG systemic response are protective, together favoring milder presentation, better outcome and resolution of central nervous system (CNS) inflammation. IL-5 is expressed intrathecally in TBE, but its pathogenetic role remains unclear. PMID- 29602686 TI - Prevalence of esophoria in concussed patients. AB - PURPOSE: To assess the prevalence of esophoria at near in concussed patients in a neuro-optometric private practice setting. METHODS: A retrospective analysis was performed involving a chart review in a neuro-optometric, private practice setting of consecutive patients with a medical diagnosis of concussion from January 1st 2016 to December 31st 2016. A total of 71 patients were included in the analysis. All received a comprehensive vision examination, with a near vision emphasis. The near horizontal phoria was assessed with the cover test and the von Graefe test. RESULTS: Approximately 30% of the patients with a medically based diagnosis of concussion exhibited esophoria at near, with good agreement (95%) between the two tests. Mean esophoria was 5.2 (SD=2.8) prism diopters (pd), with a range from 2pd to 14pd of esophoria. Convergence excess was diagnosed in 23%. DISCUSSION: Near esophoria was found in nearly one-third of this practice-based sample of concussed patients. Thus, it was more common than typically believed to be the case. Two proposed oculomotor-based mechanisms related to these symptomatic esophoric patients included phoria decompensation and excessive accommodative vergence. PMID- 29602687 TI - Effect of phenylephrine on static and dynamic accommodation. AB - PURPOSE: We tested the hypothesis that changes in accommodation after instillation of Phenylephrine Hydrochloride (PHCl) observed in some studies could be caused by changes in optics. METHODS: We performed two experiments to test the effects of PHCl on static and on dynamic accommodation in 8 and 6 subjects, respectively. Objective wavefront measurements were recorded of the static accommodation response to a stimulus at different distances or dynamic accommodation response to a sinusoidally moving stimulus (between 1 and 3 D of accommodative demand at 0.2Hz). The responses were characterized using two methods: one that takes into account the mydriatic optical effects on the accommodation produced by higher-order aberrations of the eye and another that takes into account only power changes paraxially due to the action of the ciliary muscle and regardless of the pupil size. RESULTS: When mydriatic optical effects were taken into account, differences in responses before and after PHCl instillation were 0.51+/-0.53 D, and 0.12+/-0.15, for static and dynamic accommodation, respectively, and were statistically significant (p<0.039). When mydriatic optical effects were not taken into account, the differences in responses before and after PHCl instillation were -0.20+/-0.51 D, and -0.05+/ 0.14, for static and dynamic accommodation, respectively, and were not statistically significant (p>0.313). CONCLUSIONS: The mydriatic effect of the PHCl causes optical changes in the eye that can reduce the objective and subjective measurement of accommodation. PMID- 29602688 TI - EGFR is not amplified in ameloblastoma. AB - OBJECTIVE: The aim of this study was to investigate alterations in the EGFR gene and its protein expression for a better understanding of the biologic behavior of ameloblastoma. STUDY DESIGN: Twenty-five samples of ameloblastoma were selected, and dual-color fluorescence in situ hybridization assay was performed. The results of the assay and immunohistochemistry reaction for EGFR and Ki67 were associated with clinicopathologic features and recurrence. RESULTS: All analyzed cases presented disomy without any gene polysomy or amplification. With regard to EGFR immunoexpression, 3 cases (12%) were considered negative, and 22 (88%) were positive, of which 13 (52%) were weak and 9 (36%) were strong. All samples presented low positivity for Ki67. There was no association between EGFR expression and clinicopathologic features or recurrence (P > .05). In some cases, EGFR immunoexpression was observed without gene amplification. CONCLUSIONS: Ameloblastoma development, progression, or recurrence does not appear to be related to EGFR amplification or polysomy. PMID- 29602689 TI - Benefits of caseload midwifery to prevent fetal alcohol spectrum disorder: A discussion paper. AB - BACKGROUND: Exposure to alcohol prenatally can result in a child being diagnosed with fetal alcohol spectrum disorder. Affected infants experience lifelong impairments that can involve, physical, cognitive, behavioural and emotional difficulties that impact on their functional capacity. Effective prevention of fetal alcohol spectrum disorder is critically needed in Australia. Reduction in the prevalence of this disorder will only be possible if we prevent alcohol consumption during pregnancy. AIM: This paper provides an overview of fetal alcohol spectrum disorder and discusses the role of caseload midwifery as part of a multi-level prevention approach. FINDINGS: Drawing on previous research, caseload midwifery has potential to support the prevention of fetal alcohol spectrum disorder through continuity of care. CONCLUSION: Prevention of fetal alcohol spectrum disorder will be more likely if women experience a supportive relationship with a known midwife, who has received appropriate training and can enable women to feel comfortable in discussing and addressing alcohol use. PMID- 29602691 TI - The relationship between elevated prehospital point-of-care lactate measurements, intensive care unit admission, and mortality: A retrospective review of adult patients. AB - OBJECTIVE: To determine whether prehospital point-of-care lactate (pLA) is associated with mortality, admission, and duration of hospital stay. DESIGN: A retrospective clinical audit, where elevated lactate was defined as >=2 mmol/L. SETTING: The ambulance service and primary referral hospital in the Australian Capital Territory from 1st July 2014 to 30th June 2015. PARTICIPANTS: Adult patients (>=18 years) who had pLA measured and were transported to the primary referral hospital. MAIN OUTCOME MEASURES: Mortality, admission, and duration of hospital stay. RESULTS: Two hundred fifty-three patients with a median pLA of 2.5 mmol/L (interquartile range [IQR]: 1.5-3.7) were analysed. Overall mortality was 8.3%; 68% were admitted to the hospital; 8.3% to the intensive care unit (ICU). pLA was non-significantly higher in those who died compared to survivors (3.5 [IQR: 2.75-5.85] vs 2.4 [1.5-3.6]; W = 1631.5; p = 0.053). pLA was higher for those admitted to the hospital (2.9 [1.9-3.9] vs 2.0 [1.4-3.1]; W = 5094.5, p = 0.001) and the ICU (3.2 [2.4-5.7] vs 2.4 [1.5-3.6]; W = 1578.5; p = 0.008). There was no relationship between pLA and duration of stay. Considered as a screening tool, at a cut-off of 2.5 mmol/L, pLA had a likelihood ratio+ of 1.61 for mortality and 1.44 for ICU admission; the odds ratio for mortality was 3.76 (95% confidence interval = 1.30, 13.89). CONCLUSIONS: Elevated prehospital lactate was associated with significantly increased ICU and hospital admissions. There may be value in pLA as a screening tool. PMID- 29602690 TI - Steroids, atosiban and pulmonary oedema: are or may be a cause? PMID- 29602692 TI - [CNGOF-HAS Endometriosis guidelines: Aim, method, organisation and limits]. PMID- 29602693 TI - [Between "pragmatic" interpretation and "disturbing" understanding: Embryonic cryopreservation for IVF patients]. AB - OBJECTIVES: The aim of this article is to question the feeling of IVF patients towards embryonic cryopreservation, in order to understand their potential reluctance to freeze embryos and their difficulties to consider the fate of their frozen embryos once their parental project completed. METHODS: Twenty-seven semi directive interviews with homologous IVF patients were conducted. These persons were followed in two fertility centres in Marseille. RESULTS: If all the patients interviewed have accepted embryonic cryopreservation or have accepted on principle, a majority have an ambivalent attitude towards this technique. If some share the "pragmatic" vision of professionals (embryologists, technicians and gynaecologists), they are numerous to worry about a possible deterioration of embryonic quality, or again about a disrupted order of generation. Finally, it appears that patients do not anticipate the possible fate of their frozen embryos if they are uninscribed from their parental project. CONCLUSIONS: Patients are mainly ambivalent towards embryonic cryopreservation. They prioritize different rationality depending on the situations and issues they are dealing with. PMID- 29602694 TI - [Early and later intrahepatic cholestasis of pregnancy (ICP): Study of adverse pregnancy outcomes]. AB - OBJECTIVE: To compare the risk for adverse pregnancy and fetal outcomes in early or late-onset intrahepatic cholestasis of pregnancy (ICP). METHODS: In a retrospective and unicentric analysis, data were collected for all women with ICP (serum bile acid level over 8mol/L) between June 1, 2008 and January 1, 2015. Patients were divided in early-onset ICP (pregnancy duration at diagnosis<33 weeks) and late-onset ICP (pregnancy duration at diagnosis>=33 weeks). The frequency of adverse pregnancy and fetal outcomes was assessed. RESULTS: Among 138 eligible women, 40 were in the early-onset group and 98 in the late-onset group. Adverse pregnancy or fetal outcomes affected significantly more patients in early-onset ICP group (45% versus 17.3%, P<0.05). Threatened preterm birth (30% versus 10.0%, P<0.05) was significantly increased in early-onset ICP group. Prematurity was higher in early-onset group (40.0% versus 28.0%, P=0.23). Early onset and severe ICP were not significantly linked (P=0.16). CONCLUSION: Early onset ICP diagnosed before 33 Weeks is associated with adverse pregnancy outcomes, particularly threatened preterm birth. PMID- 29602695 TI - [Radiotherapy of bone metastases in France: A descriptive monocentric retrospective study]. AB - PURPOSE: Bone metastases cause pain and affect patients' quality of life. Radiation therapy is one of the reference analgesic treatments. The objective of this study was to compare the current practices of a French radiotherapy department for the treatment of uncomplicated bone metastases with data from the literature in order to improve and optimize the management of patients. MATERIAL AND METHODS: A retrospective monocentric study of patients who underwent palliative irradiation of uncomplicated bone metastases was performed. RESULTS: Ninety-one patients had 116 treatments of uncomplicated bone metastases between January 2014 and December 2015, including 44 men (48%) and 47 women (52%) with an average age of 63years (25-88years). Primary tumours most commonly found were breast cancer (35%), lung cancer (16%) and prostate cancer (12%). The regimens used were in 29% of cases 30Gy in ten fractions (group 30Gy), in 21% of cases 20Gy in five fractions (group 20Gy), in 22% of cases 8Gy in one fraction (group 8Gy) and in 28% of cases 23.31Gy in three fractions of stereotactic body irradiation (stereotactic group). The general condition of the patient (P<0.001), pain score and analgesic (P<0.001), oligometastatic profile (P=0.003) and practitioner experience (P<0.001) were factors influencing the choice of the regimen irradiation. Age (P=0.46), sex (P=0.14), anticancer treatments (P=0.56), concomitant hospitalization (P=0.14) and the distance between the radiotherapy centre and home (P=0.87) did not influence the decision significantly. A total of three cases of spinal compression and one case of post-therapeutic fracture were observed, occurring between one and 128days and 577days after irradiation, respectively. Eight percent of all irradiated metastases were reirradiated with a delay ranging between 13 and 434days after the first irradiation. The re irradiation rate was significantly higher after 8Gy (P=0.02). The rate of death was significantly lower in the stereotactic arm (P<0.001) and overall survival was significantly greater in the stereotactic arm (P<0.001). CONCLUSION: This study showed that patients' analysed was comparable to the population of different studies. Predictive factors for the choice of the treatment regimen were identified. Non-fractionnated therapy was underutilised while stereotactic treatment was increasingly prescribed, showing an evolution in the management of patients. PMID- 29602696 TI - Preoperative assessment of peritoneal carcinomatosis of colorectal origin. AB - The goal of preoperative assessment of patients with peritoneal carcinomatosis (PC) from colorectal origin is to select candidates for curative surgery by evaluating the possibility of complete resection, and to plan the surgical procedure. Quantitative and qualitative evaluation of lesional localization remains difficult even with current technical progress in imaging. Computed tomography (CT), the reference imaging technique, allows detection of both peritoneal and extra-peritoneal lesions. Sensitivity and specificity for detecting PC are 83% (95%CI: 79-86%) and 86% (95%CI: 82-89%), respectively. Functional imaging, with diffusion-weighted magnetic resonance imaging (MRI) and positron emission tomography PET-CT allows efficient exploration of peritoneal lesions. MRI is operator-dependent, with a long learning curve, and is, at present, essentially used only in expert centers. A standardized protocol provided by the radiologists working with the French National Center for rare peritoneal tumors RENA-RAD (http://www.renape-online.fr/fr/espace professionnel/rena-rad.html) is however available on line. PET-CT is particularly useful for identifying and defining extra-peritoneal disease. Combining imaging techniques, particular CT with MRI, seems to improve the calculation of the Peritoneal Cancer Index compared to CT alone. Surgical exploration is the reference technique to evaluate PC. Currently, the literature cannot confirm whether laparoscopy performs as well as laparotomy, but laparoscopy is, de facto, the fundamental tool to decrease the number of unnecessary laparotomies in these patients. To optimize the pre-, intra- and postoperative reporting of the extent of PC, the French National Network for management of PC (RENAPE and BIG-RENAPE: http://www.e-promise.org/) has offered on-line a free-of-charge, standardized, multidisciplinary and transversal software. PMID- 29602698 TI - Novel insights into the functional metabolic impact of an apparent de novo m.8993T>G variant in the MT-ATP6 gene associated with maternally inherited form of Leigh Syndrome. AB - In this study, we report a novel perpective of metabolic consequences for the m.8993T>G variant using fibroblasts from a proband with clinical symptoms compatible with Maternally Inherited Leigh Syndrome (MILS). Definitive diagnosis was corroborated by mitochondrial DNA testing for the pathogenic variant m.8993T>G in MT-ATP6 subunit by Sanger sequencing. The long-range PCR followed by massively parallel sequencing method detected the near homoplasmic m.8993T>G variant at 83% in the proband's fibroblasts and at 0.4% in the mother's fibroblasts. Our results are compatible with very low levels of germline heteroplasmy or an apparent de novo mutation. Our mitochondrial morphometric analysis reveals severe defects in mitochondrial cristae structure in the proband's fibroblasts. Our live-cell mitochondrial respiratory analyses show impaired oxidative phosphorylation with decreased spare respiratory capacity in response to energy stress in the proband's fibroblasts. We detected a diminished glycolysis with a lessened glycolytic capacity and reserve, revealing a stunted ability to switch to glycolysis upon full inhibition of OXPHOS activities. This dysregulated energy reprogramming results in a defective interplay between OXPHOS and glycolysis during an energy crisis. Our study sheds light on the potential pathophysiologic mechanism leading to chronic energy crisis in this MILS patient harboring the m.8993T>G variant. PMID- 29602699 TI - Intramedullary versus extramedullary internal fixation for unstable intertrochanteric fracture, a meta-analysis. AB - OBJECTIVE: The aim of this meta-analysis was to explore the difference between and compare intramedullary fixation (IF) and extramedullary fixation (EF) for unstable intertrochanteric fractures. METHODS: We searched Pubmed database and Cochrane library following by including and excluding articles based from inception to December, 2016. All randomized controlled trials (RCTs) comparing IF and EF for unstable intertrochanteric fractures were assessed and selected by two researchers independently. Data were analyzed using Review Manager 5.1 version. RESULTS: 17 RCTs were enrolled in our meta-analysis comparing IF and EF and showed evidence that IF had lower rate of implant failure RR = 0.2695%CI 0.13 0.51, P < 0.0001 and re-operation (RR = 0.60, 95%CI 0.37-0.98, P = 0.04), while there was no statistical differences of cut-out, postoperative infections and other complications. Moreover, PPM scores verified that IF had better postoperative hip mobility recovery (MD = 0.87, 95%CI 0.08-1.66, P = 0.03). CONCLUSION: IF has lower incidence of failure of implant and reoperation and shows better postoperative functional recovery when treating adult unstable intertrochanteric fracture while the most postoperative complications were not statistically different from EF. LEVEL OF EVIDENCE: Level I, therapeutic study. PMID- 29602700 TI - Poor knowledge of vaccination recommendations and negative attitudes towards vaccinations are independently associated with poor vaccination uptake among adults - Findings of a population-based panel study in Lower Saxony, Germany. AB - OBJECTIVES: The aims of this study were to (a) assess knowledge of official vaccination recommendations and attitudes towards vaccinations among adults and (b) examine their association with vaccination uptake among adults. METHODS: This study was part of the HaBIDS study (Hygiene and Behaviour Infectious Diseases Survey), which is an online panel established in March 2014 in Lower Saxony, Germany with males and females aged between 15 and 69 years (n = 2379). Every few months, participants completed questionnaires on different aspects of infectious diseases. In September 2014, knowledge of vaccination recommendations, attitudes towards vaccinations and information on uptake of vaccinations in the last 10 years (practice) were collected using a knowledge-attitude-practice (KAP) questionnaire. Multiple correspondence analysis was applied to identify underlying structures in each KAP domain and fractional polynomial regression analysis to examine the associations of knowledge and attitudes with vaccination uptake. RESULTS: Of the 2379 panel members, 1698 (71%) completed the KAP questionnaire on vaccinations. The majority of participants (80%) knew that the vaccine against diphtheria and tetanus should be administered every 10 years. Regarding other recommendations, the proportion of correct answers varied between 35% and 60%. 82% of participants agreed that adult vaccinations should be mandatory for selected groups such as health care workers and 40% stated that vaccinations should be mandatory for all adults. For the different vaccines, the odds of being unvaccinated were 1.5- to 5-times higher among participants with poor knowledge of vaccination recommendations compared to participants with good knowledge. Participants with negative attitudes towards vaccinations were also more likely to be unvaccinated. CONCLUSIONS: Efforts should be undertaken to improve knowledge of official vaccination recommendations in the general population and reduce common misconceptions about vaccinations. This information can be provided during general practitioner visits or through media campaigns. PMID- 29602701 TI - Delineating the serotype-specific neutralizing antibody response to a live attenuated tetravalent dengue vaccine. AB - The dengue virus (DENV) vaccines that are licensed or in clinical development consist of DENV serotype 1-4 tetravalent formulations given simultaneously and are not acquired sequentially like natural infections. It is unclear what effect this has on development of protective levels of immunity to all four serotypes. Serotype-specific neutralizing antibody (NAb) is considered the most relevant correlate of protection from dengue disease. Here we assessed levels of serotype specific and cross-reactive NAb in immune sera from 10 subjects vaccinated with a live attenuated tetravalent DENV vaccine developed at the Walter Reed Army Institute of Research. The majority of subjects NAb responses to DENV-2 and DENV 4 were type-specific, while their NAb responses to DENV-1 and DENV-3 were primarily cross-reactive. Vaccine virus RNAemia has been most frequently detected for DENV-2 and DENV-4 in vaccinated subjects, strongly suggesting that replication is important for eliciting serotype-specific immunity. PMID- 29602697 TI - Protein Phase Separation: A New Phase in Cell Biology. AB - Cellular compartments and organelles organize biological matter. Most well-known organelles are separated by a membrane boundary from their surrounding milieu. There are also many so-called membraneless organelles and recent studies suggest that these organelles, which are supramolecular assemblies of proteins and RNA molecules, form via protein phase separation. Recent discoveries have shed light on the molecular properties, formation, regulation, and function of membraneless organelles. A combination of techniques from cell biology, biophysics, physical chemistry, structural biology, and bioinformatics are starting to help establish the molecular principles of an emerging field, thus paving the way for exciting discoveries, including novel therapeutic approaches for the treatment of age related disorders. PMID- 29602702 TI - Human papillomavirus vaccination coverage in Luxembourg - Implications of lowering and restricting target age groups. AB - BACKGROUND: In Luxembourg, a national Human Papillomavirus (HPV) vaccination programme was introduced in 2008, targeting 12-17 year old girls offering a choice of bivalent or quadrivalent vaccine free of charge. In 2015, the programme was changed offering the bivalent vaccine only to 11-13 year old girls. The aim of this study was to evaluate the HPV vaccination coverage, to assess the impact of age target changes and compare vaccination coverage to other European countries. METHODS: Anonymous HPV vaccination records consisting of individual vaccine doses obtained free of charge in pharmacies between 2008 and 2016 were extracted from the Luxembourgish Social Security database. Additional aggregate tables by nationality and municipality were analysed. RESULTS: Of the target cohort of 39,610 girls born between 1991 and 2003 residing in Luxembourg, 24,550 (62.0%) subjects obtained at least one dose, 22,082 (55.7%) obtained at least two doses, and 17,197 (43.4%) obtained three doses of HPV vaccine. The mean age at first dose was 13.7 years during 2008-14 and 12.7 years in 2016 after the age target change. Coverage varied significantly by nationality (p < 0.0001): Portuguese (80%), former Yugoslavs (74%), Luxembourgish (54%), Belgian (52%), German (47%), French (39%) and other nationalities (51%). Coverage varied also by geographical region, with lower rates (<50%) noted in some Northern and Central areas of Luxembourg (range: 38% to 78%). CONCLUSION: Overall HPV vaccination coverage in Luxembourg is moderate and varied by nationality and region. The policy changes in 2015 did not have a substantial impact except lowering age at initiating vaccination. Options to improve coverage deserve further investigation. PMID- 29602703 TI - Pertussis in Africa: Findings and recommendations of the Global Pertussis Initiative (GPI). AB - Pertussis remains a major cause of morbidity and mortality, particularly in infants and young children, and despite the availability of vaccines and pertinent national and international guidelines. The disease burden is more severe in low- and middle-income countries (LMICs), especially in the African continent. Pertussis is more prevalent among young infants in Africa. Poor or no pertussis surveillance, lack of disease awareness, diagnostic limitations, and competing health priorities are considered key contributory factors for this high pertussis burden in Africa. Most African countries use whole-cell pertussis (wP) vaccines, but coverage with three primary doses of diphtheria-tetanus-pertussis vaccines falls short of the World Health Organization's recommended goal of >90%. The Global Pertussis Initiative (GPI) works toward developing recommendations through systematic evaluation and prioritization of strategies to prevent pertussis-related infant and child deaths, as well as reducing global disease burden to acceptable national, regional, and local levels. For countries using wP vaccines, the GPI recommends continuing to use wP to improve primary and toddler booster vaccination coverage. Vaccination during pregnancy is the next priority when acellular pertussis (aP) vaccines and other resources are available that directly protect newborns too young to be vaccinated, followed by, in order of priority, booster doses in older children, adolescents, healthcare workers and finally, all adults. Improved surveillance should be a high priority for African LMICs assessing true disease burden and vaccine effectiveness to inform policy. More research is warranted to evaluate the safety and efficacy of wP and aP vaccines and strategies, and to determine their optimal use. PMID- 29602704 TI - Sequential pulmonary immunization with heterologous recombinant influenza A virus tuberculosis vaccines protects against murine M. tuberculosis infection. AB - Tuberculosis (TB) infection affects a quarter of the global population resulting in a large burden of TB disease and mortality. The long-term control of TB requires vaccines with greater efficacy and durability than the current Mycobacterium bovis Bacille Calmette-Guerin (BCG). Pulmonary immunization may increase and prolong immunity at the site of Mycobacterium tuberculosis infection. We have investigated recombinant influenza A viruses (rIAVs) expressing the p25 CD4+ T cell epitope of M. tuberculosis Ag85B240-254 for single and sequential immunization against M. tuberculosis infection. Intranasal immunization with single dose of rIAV X31 (H3N2 strain) expressing the p25 epitope (X31-p25), induced p25-specific CD4+ T cells and conferred protection against aerosol delivery of M. tuberculosis infection in the lungs. To enhance this effect, prime-boost immunization with hetero-subtypic rIAVs was examined. Sequential immunization with X31-p25 and a second rIAV, PR8 (H1N1 strain) expressing the same epitope (PR8-p25), increased the frequency of p25-specific IFN-gamma T cell responses and polyfunctional CD4+ T cells producing IFN-gamma, IL-2, and TNF, compared to immunization with each rIAV alone. This combination resulted in protection against M. tuberculosis in both the lungs and spleen. Therefore, our study revealed that rIAV is not only an efficient vector to induce protective immunity in the lungs, but also has a potential use for sequential immunization with heterologous rIAV to boost the immunogenicity and improve the protection against M. tuberculosis. PMID- 29602705 TI - Immune mechanisms induced by an HSV-1 mutant strain: Discrepancy analysis of the immune system gene profile in comparison with a wild-type strain. AB - Herpes simplex virus is a prevalent pathogen of humans of various age groups. The fact that no prophylactic or therapeutic vaccine is currently available suggests a significant need to further investigate the immune mechanisms induced by the virus and various vaccine candidates. We previously generated an HSV-1 mutant strain, M3, with partial deletions in ul7, ul41 and LAT that produced an attenuated phenotype in mice. In the present study, we performed a comparative analysis to characterize the immune responses induced by M3 versus wild-type HSV 1 in a mouse model. Infection with wild-type HSV-1 triggered an inflammatory dominated response and adaptive immunity suppression and was accompanied by severe pathological damage. In contrast, infection with M3 induced a systematic immune response involving full activation of both innate and adaptive immunity and was accompanied by no obvious pathological changes. Furthermore, the immune response induced by M3 protected mice from lethal challenge with wild-type strains of HSV-1 and restrained virus proliferation and impaired latency. These data are useful for further HSV-1 vaccine development using a mutant strain construction strategy. PMID- 29602706 TI - Baseline lung allograft dysfunction is associated with impaired survival after double-lung transplantation. AB - BACKGROUND: The prognostic value of defining normal vs abnormal baseline post transplant lung function (or baseline lung allograft dysfunction [BLAD]) has not been studied using standardized reference values of percent predicted of the population. Our aim was to assess the association between BLAD and survival in double-lung transplant recipients and assess for potential pre-transplant donor and recipient risk factors for BLAD. METHODS: We conducted a retrospective cohort study of double-lung transplant recipients in our program during the period 2004 to 2009. We defined normal baseline function as both forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) >=80% predicted on at least 2 consecutive tests >=3 weeks apart; we defined BLAD as failure to meet these criteria. We used a Cox regression model to assess the association between BLAD and survival. We used logistic regression to assess potential pre-transplant donor and recipient factors associated with BLAD. RESULTS: Of 178 patients double lung transplant recipients eligible for study, 75 (42%) met the criteria for BLAD. BLAD was associated with impaired survival (hazard ratio [HR] 2.23, 95% confidence interval [CI] 1.41 to 3.54]) via Cox regression compared to patients with normal baseline, and lower baseline was associated with greater risk of death in a dose-dependent fashion. Pre-transplant factors associated with BLAD included interstitial lung disease (ILD) as an indication for transplant (odds ratio [OR] 2.66, 95% CI 1.17 to 6.15) and heavy donor smoking history (OR 3.07, 95% CI 1.17 to 8.43). CONCLUSIONS: BLAD is dynamic risk state associated with impaired survival after double-lung transplantation, and should be considered when physiologically phenotyping patients. PMID- 29602707 TI - Neutrophil extracellular traps were released during intraoperative blood salvage in posterior lumbar surgery. AB - The formation of neutrophil extracellular traps (NETs) has been associated with endothelial damage and severe pulmonary dysfunction. The present study aimed to investigate whether this NETosis occurs during intraoperative blood salvage (IBS), and whether the washing procedures before re-transfusion of autologous blood could remove the NET components, including DNA, histones, and myeloperoxidase. The study was performed using blood samples from 20 patients who underwent posterior lumbar surgery at the Beijing Friendship Hospital. The samples were obtained at three time points/sources: peripheral venous blood prior to surgery (baseline), cell salvage collection reservoir (reservoir), and filtered salvaged blood prior to re-transfusion (pre-transfusion); blood salvage was accomplished with a Cell Saver 5 system. The plasma was collected after centrifugation of the blood sample. Then the DNA amount was measured using SYTOX Green labeling; the integrity and length of the DNA were roughly evaluated by agarose gel electrophoresis; and the levels of nucleosomes (DNA and histones) and myeloperoxidase were detected using commercial ELISA kits. Extracellular DNA, nucleosomes, and myeloperoxidase were found higher in the reservoir samples and pre-transfusion samples, as compared to the baseline samples. The DNA was primarily non-fragmented with high molecular weight (>15 kb). And lower levels of these NET components were observed in pre-transfusion samples, compared with the reservoir samples. In conclusion, DNA, histones, and myeloperoxidase were released during IBS, indicating the NET formation by activated neutrophils. Pre transfusion processing could reduce the NET components but the levels remained significantly elevated compared to the baseline. PMID- 29602708 TI - Curcumin and its demethoxy derivatives possess p300 HAT inhibitory activity and suppress hypertrophic responses in cardiomyocytes. AB - The natural compound, curcumin (CUR), possesses several pharmacological properties, including p300-specific histone acetyltransferase (HAT) inhibitory activity. In our previous study, we demonstrated that CUR could prevent the development of cardiac hypertrophy by inhibiting p300-HAT activity. Other major curcuminoids isolated from Curcuma longa including demethoxycurcumin (DMC) and bisdemethoxycurcumin (BDMC) are structural analogs of CUR. In present study, we first confirmed the effect of these three curcuminoid analogs on p300-HAT activity and cardiomyocyte hypertrophy. Our results showed that DMC and BDMC inhibited p300-HAT activity and cardiomyocyte hypertrophy to almost the same extent as CUR. As the three compounds have structural differences in methoxy groups at the 3-position of their phenol rings, our results suggest that these methoxy groups are not involved in the inhibitory effects on p300-HAT activity and cardiac hypertrophy. These findings provide useful insights into the structure-activity relationship and biological activity of curcuminoids for p300 HAT activity and cardiomyocyte hypertrophy. PMID- 29602709 TI - Comparative study on fixation of central venous catheter by suture versus adhesive device. AB - OBJECTIVES: To assess the efficacy of a central venous catheter adhesive fixation device (CVC) to prevent associated complications. To establish the need for dressing changes, number of days' catheterization and reasons for catheter removal in both study groups. To assess the degree of satisfaction of personnel with the adhesive system. METHOD: A, randomized, prospective and open pilot study, of parallel groups, with comparative evaluation between CVC fixation with suture and with an adhesive safety system. The study was performed in the Coronary Unit of the Universitari de Bellvitge Hospital, between April and November 2016. The population studied were patients with a CVC. The results were analyzed using SPSS Statistics software. The study was approved by the Clinical Research Ethics Committee. RESULTS: 100 patients (47 adhesive system and 53 suture) were analyzed. Both groups were homogeneous in terms of demographic variables, anticoagulation and days of catheterization. The frequency of complications in the adhesive system group was 21.3%, while in the suture group it was 47.2% (P=.01). The suture group had a higher frequency of local signs of infection (p=.006), catheter displacement (p=.005), and catheter-associated bacteraemia (P=.05). The use of adhesive fixation was associated with a lower requirement for dressing changes due to bleeding (P=.006). Ninety-six point seven percent of the staff recommended using the adhesive safety system. CONCLUSIONS: The catheters fixed with adhesive systems had fewer infectious complications and less displacement. PMID- 29602710 TI - Psychometric properties of the parents perception uncertainty in illness scale, spanish version. AB - OBJECTIVE: To analyze the psychometric properties of the Parents' Perception of Uncertainty in Illness Scale, parents/children, adapted to Spanish. METHOD: A descriptive methodological study involving the translation into Spanish of the Parents' Perception of Uncertainty in Illness Scale, parents/children, and analysis of their face validity, content validity, construct validity and internal consistency. RESULTS: The original version of the scale in English was translated into Spanish, and approved by its author. Six face validity items with comprehension difficulty were reported; which were reviewed and adapted, keeping its structure. The global content validity index with expert appraisal was 0.94. In the exploratory analysis of factors, 3 dimensions were identified: ambiguity and lack of information, unpredictability and lack of clarity, with a KMO=0.846, which accumulated 91.5% of the explained variance. The internal consistency of the scale yielded a Cronbach alpha of 0.86 demonstrating a good level of correlation between items. CONCLUSION: The Spanish version of "Parent's Perception of Uncertainty in Illness Scale" is a valid and reliable tool that can be used to determine the level of uncertainty of parents facing the illness of their children. PMID- 29602711 TI - Tenofovir disoproxil fumarate co-administered with lopinavir/ritonavir is strongly associated with tubular damage and chronic kidney disease. AB - BACKGROUD: With expanding antiretroviral therapy (ART) in a resource-limited setting, the use of second line ART with ritonavir boosted lopinavir (LPV/r) is increasing. However, little is known regarding the renal safety of tenofovir (TDF) co-administered with LPV/r. METHODS: In total 1382 HIV-infected patients were enrolled and data were recorded twice (October 2014 and 2015) in Vietnam. Tubular dysfunction (TD) was defined as urinary beta 2 microglobulin (beta2MG) > 1000 MUg/L at both timepoints or increase in beta2MG by > 2000 MUg/L. Chronic kidney disease (CKD) was defined as creatinine clearance <=60 ml/min or urinary protein/creatinine ratio >= 0.15 g/gCre at both timepoints. RESULTS: The patients'mean weight and age were 55.9 kg and 38.4 years, respectively, and 41.5% were female. Additionally, 98.2% were on ART, 76.3% were on TDF (mean exposure duration was 35.4 months), and 22.4% had never TDF exposure. TD and CKD were diagnosed in 13% and 8.3% of all patients, respectively. In multivariate analyses, age (OR = 1.057; 95%CI, 1.034-1.081), being female (OR = 0.377; 95%CI, 0.221-0.645), HBsAg positive (OR = 1.812; 95%CI, 1.134-2.894), HCVAb positive (OR = 1.703; 95%CI, 1.100-2.635), TDF exposure (OR = 9.226; 95%CI, 2.847-29.901) and LPV/r exposure (OR = 5.548; 95%CI, 3.313-9.293) were significantly associated with TD. Moreover, age (OR = 1.093; 95%CI, 1.068-1.119), being female (OR = 0.510; 95%CI, 0.295-0.880), weight (OR = 0.909; 95%CI, 0.879-0.939), hypertension (OR = 3.027; 95%CI, 1.714-5.347), TDF exposure (OR = 1.963; 95%CI, 1.027-3.7 53) and LPV/r exposure (OR = 3.122; 95%CI, 1.710-5.699) were significantly associated with CKD. CONCLUSIONS: TDF and LPV/r exposure were strongly associated with TD and CKD, in addition to their known risks. Therefore, attention to renal safety for patients on second line ART is necessary. PMID- 29602712 TI - Hierarchical Bayesian models of delusion. PMID- 29602713 TI - Antral resection versus antral preservation during laparoscopic sleeve gastrectomy for severe obesity: Systematic review and meta-analysis. AB - Although laparoscopic sleeve gastrectomy is an established operation for severe obesity, there is controversy regarding the extent to which the antrum is excised. The objective of this systematic review was to investigate the effect on perioperative complications and medium-term outcomes of antral resecting versus antral preserving sleeve gastrectomy. MEDLINE, EMBASE, and Cochrane databases were searched from 1946 to April 2017. Eligible studies compared antral resection (staple line commencing 2-3 cm from pylorus) with antral preservation (>5 cm from pylorus) in patients undergoing primary sleeve gastrectomy for obesity. Meta analyses were performed with a random-effects model, and risk of bias within and across studies was assessed using validated scoring systems. Eight studies (619 participants) were included: 6 randomized controlled trials and 2 cohort studies. Overall follow-up was 94% for the specified outcomes of each study. Mean percentage excess weight loss was 62% at 12 months (7 studies; 574 patients) and 67% at 24 months (4 studies; 412 patients). Antral resection was associated with significant improvement in percentage excess weight loss at 24-month follow-up (mean 70% versus 61%; standardized mean difference .95; confidence interval .35 1.58, P<.005), an effect that remained significant when cohort studies were excluded. There was no difference in incidence of perioperative bleeding, leak, or de novo gastroesophageal reflux disease. According to the available evidence, antral resection is associated with better medium-term weight loss compared with antral preservation, without increased risk of surgical complications. Further randomized clinical trials are indicated to confirm this finding. PMID- 29602714 TI - The importance of determining the clinical significance of research results in physical therapy clinical research. PMID- 29602715 TI - Original and modified technique of tie-over dressing: Method and application in burn patients. AB - In burn patients, meshed split thickness skin grafts are commonly used on large and non-flat areas whom immobilization is difficult to achieve. The frequent mobilizations of burn patients can make the graft slip and prevent the revascularization and therefore the taking of the skin graft. In order to prevent this pitfall, we modified and adapted the tie-over dressing procedure. The giant running tie-over dressing enables large skin grafts to be applied to their wound bed and therefore helps revascularization. Some cautions are necessary in order to avoid any infection. This original and easy-to-perform procedure answers to the difficulties of large split-thickness skin grafts in burn patients. PMID- 29602716 TI - A review of campfire burns in children: The QLD experience. AB - INTRODUCTION: Campfire burns in children are a significant health issue. It is imperative that the extent of the problem is examined and strategies discussed to inform future prevention campaigns. METHOD: A retrospective review of data from the Queensland Paediatric Burns Registry for all children presenting with campfire burns between January 2013 and December 2014 (inclusive). Information collected included patient demographics, detail regarding mechanism of injury, first aid, Total Body Surface Area (TBSA), burn depth, and treatment. RESULTS: Seventy-five children with campfire burns were seen in our paediatric burns centre during this 2-year period. The median age of patients was 3 years (range 10 days-14 years). The hands and feet were the areas most commonly affected. Eleven percent of patients suffered flame burns, whilst 89% suffered contact burns from the hot coals or ashes. Of the latter group, approximately half experienced burns from campfires that had been extinguished for at least one night. Thirteen percent of patients underwent split thickness skin grafting. The incidence of burns was increased during school holiday months. DISCUSSION: We have previously demonstrated the effectiveness of targeted campaigns in reducing the incidence of campfire burns. A significant portion of patients sustained burns from incorrectly extinguished campfires. These injuries are likely to be preventable with ongoing public awareness campaigns. PMID- 29602718 TI - Defining chronic Pseudomonas aeruginosa infection in cystic fibrosis. PMID- 29602717 TI - Skin xenotransplantation: Historical review and clinical potential. AB - Half a million patients in the USA alone require treatment for burns annually. Following an extensive burn, it may not be possible to provide sufficient autografts in a single setting. Pig skin xenografts may provide temporary coverage. However, preformed xenoreactive antibodies in the human recipient activate complement, and thus result in rapid rejection of the graft. Because burn patients usually have some degree of immune dysfunction and are therefore at increased risk of infection, immunosuppressive therapy is undesirable. Genetic engineering of the pig has increased the survival of pig heart, kidney, islet, and corneal grafts in immunosuppressed non-human primates from minutes to months or occasionally years. We summarize the current status of research into skin xenotransplantation for burns, with special emphasis on developments in genetic engineering of pigs to protect the graft from immunological injury. A genetically engineered pig skin graft now survives as long as an allograft and, importantly, rejection of a skin xenograft is not detrimental to a subsequent allograft. Nevertheless, currently, systemic immunosuppressive therapy would still be required to inhibit a cellular response, and so we discuss what further genetic manipulations could be carried out to inhibit the cellular response. PMID- 29602719 TI - Reincarnation Type Presentations of Children with High-Functioning Autism in Sri Lanka. AB - Autism is characterised by impaired social communication and restricted repetitive behaviours. However, language and intelligence are spared in high functioning individuals. The symptomatology is complex and culturally diverse. Buddhists and Hindus believe in rebirth and reincarnation type presentations in children are frequently seen among these populations. Here we describe three children from Sri Lanka claiming memories of their past lives and later diagnosed to have high-functioning autism. The first, a seven-year-old Buddhist believes he was killed by terrorists as a soldier in his previous life and attributed his birthmark to be an injury which caused death. The second, a five-year-old Catholic girl suffering from asthma claiming she died of breathing difficulties in her previous life where she was a Buddhist grandmother. The third, an eight year-old academically superior child claims he was a monk in his previous life and demands parents to allow him to enter the priesthood. PMID- 29602720 TI - Musculoskeletal training injury prevention in the U.S. Army: Evolution of the science and the public health approach. AB - Injuries cause more morbidity among soldiers in the U.S. Army than any other health condition. Over two-thirds of U.S. soldiers' injuries occur gradually from cumulative micro-traumatic damage to the musculoskeletal system as a result of physical training activities. Paradoxically, the very physical training activities required to improve soldier performance also result in injury. Determining the amounts and types of physical training that maximize performance while minimizing injuries requires scientific evidence. This evidence must be incorporated into a framework that ensures scientific gaps are addressed and prevention efforts are evaluated. The five-step public health approach has proven to be an effective construct for Army public health to organize and build an injury prevention program. Steps include: 1) surveillance to define the magnitude of the problem, 2) research and field investigations to identify causes and risk factors, 3) intervention trials and systematic reviews to determine what works to address leading risk factors, 4) program and policy implementation to execute prevention, and 5) program evaluation to assess effectiveness. Dissemination is also needed to ensure availability of scientific lessons learned. Although the steps may not be conducted in order, the capability to perform each step is necessary to sustain a successful program and make progress toward injury control and prevention. As with many U.S. public health successes (e.g., seatbelts, smoking cessation), the full process can take decades. As described in this paper, the U.S. Army uses the public health approach to assure that, as the science evolves, it is translated into effective prevention. PMID- 29602721 TI - Efficacy and Safety of Tadalafil 5 mg Once Daily for the Treatment of Erectile Dysfunction After Robot-Assisted Laparoscopic Radical Prostatectomy: A 2-Year Follow-Up. AB - BACKGROUND: Although nerve-sparing robot-assisted radical prostatectomy (NS-RALP) is performed, a large number of patients still experience erectile dysfunction (ED) after surgery. AIM: To evaluate the efficacy and safety of tadalafil 5 mg once daily (OaD) in ED treatment over 2 years and investigate the cause of vascular ED after NS-RARP. METHODS: We retrospectively evaluated 95 men who underwent NS-RARP and had a penile rehabilitation treatment with tadalafil 5 mg OaD. They were classified into 3 groups: tadalafil 5 mg OaD for 2 years (group I), tadalafil 5 mg OaD for 1 year (group II), and no tadalafil (group III). All patients in group I underwent penile color duplex ultrasound to evaluate the cause of vascular ED. OUTCOMES: Patients were surveyed using the abridged 5-item International Index of Erectile Function (IIEF-5). RESULTS: Statistically significant improvements were observed in group I for all IIEF-5 domain scores (P = .000). There was no statistically significant difference in recovery of erectile function (EF) the 2-year follow-up between groups I and II. Sub-analysis based on NS status showed no difference in recovery of EF. However, group I showed better trends in EF improvement. Those with venogenic ED had poor responses compared with those with arteriogenic ED or unremarkable findings with tadalafil 5-mg OaD treatment (14.2% vs 55.0% vs 53.3%). The overall side effects included hot flushing in 9.5%, headache in 7.1%, and dizziness in 2.3% of patients. CLINICAL IMPLICATIONS: Long-term usage of tadalafil 5 mg OaD after RARP can be an effective option for penile rehabilitation. STRENGTHS AND LIMITATIONS: The present study is a retrospective study with a relatively small sample. CONCLUSIONS: Although the responses of patients with venogenic ED were limited compared with those with arteriogenic ED, tadalafil 5-mg OaD treatment was well tolerated and significantly improved EF up to 2 years after NS-RARP. Kim S, Sung GT. Efficacy and Safety of Tadalafil 5 mg Once Daily for the Treatment of Erectile Dysfunction After Robot-Assisted Laparoscopic Radical Prostatectomy: A 2 Year Follow-Up. Sex Med 2018;6:108-114. PMID- 29602722 TI - Incidental Thyroid Nodules in the National Lung Screening Trial: Estimation of Prevalence, Malignancy Rate, and Strategy for Workup. AB - RATIONALE AND OBJECTIVES: There is limited research on the prevalence of incidental thyroid nodules (ITNs) in the United States screening population and on the appropriate evaluation of computed tomography (CT)-detected ITNs. The purpose of this study is to determine the prevalence of ITNs in the National Lung Screening Trial (NLST) and develop a workup strategy for ITNs. MATERIALS AND METHODS: CT images were obtained for subjects with documented thyroid abnormalities in the CT screening arm of the NLST, subjects diagnosed with thyroid malignancies, and control subjects. Several size thresholds were compared to determine how many nodules would be further evaluated and how many thyroid malignancies would be missed had each threshold been applied at the time of workup. RESULTS: Thyroid nodules were reported in 0.7% (117 of 17,309 subjects). In 663 control subjects without reported thyroid nodules, thyroid nodules were identified in 78 (11.8%). Reported nodules were larger than unreported nodules (21.3 vs 16.9 mm, P = .03). Thyroid malignancies were diagnosed in 0.1% (22 of 17,309). If a 20-mm rather than a 10-mm cutoff were used to determine which nodules should be further evaluated, all malignancies would be detected, but 24 rather than 62 patients would require workup, for a workup reduction rate of 48.7% (38 of 78). CONCLUSIONS: Less than 1% of subjects in the NLST had reported ITNs. The true prevalence of ITNs was estimated to be 11.8%, which provides a better approximation of the number of patients who could potentially receive workup. A 20-mm rather than a 10-mm cutoff would reduce the workup rate by almost 50% while still capturing all malignancies. PMID- 29602723 TI - Impact of a New Adaptive Statistical Iterative Reconstruction (ASIR)-V Algorithm on Image Quality in Coronary Computed Tomography Angiography. AB - RATIONALE AND OBJECTIVES: A new postprocessing algorithm named adaptive statistical iterative reconstruction (ASIR)-V has been recently introduced. The aim of this article was to analyze the impact of ASIR-V algorithm on signal, noise, and image quality of coronary computed tomography angiography. MATERIALS AND METHODS: Fifty consecutive patients underwent clinically indicated coronary computed tomography angiography (Revolution CT; GE Healthcare, Milwaukee, WI). Images were reconstructed using filtered back projection and ASIR-V 0%, and a combination of filtered back projection and ASIR-V 20%-80% and ASIR-V 100%. Image noise, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) were calculated for left main coronary artery (LM), left anterior descending artery (LAD), left circumflex artery (LCX), and right coronary artery (RCA) and were compared between the different postprocessing algorithms used. Similarly a four point Likert image quality score of coronary segments was graded for each dataset and compared. A cutoff value of P < .05 was considered statistically significant. RESULTS: Compared to ASIR-V 0%, ASIR-V 100% demonstrated a significant reduction of image noise in all coronaries (P < .01). Compared to ASIR-V 0%, SNR was significantly higher with ASIR-V 60% in LM (P < .01), LAD (P < .05), LCX (P < .05), and RCA (P < .01). Compared to ASIR-V 0%, CNR for ASIR-V >=60% was significantly improved in LM (P < .01), LAD (P < .05), and RCA (P < .01), whereas LCX demonstrated a significant improvement with ASIR-V >=80%. ASIR-V 60% had significantly better Likert image quality scores compared to ASIR-V 0% in segment , vessel-, and patient-based analyses (P < .01). CONCLUSIONS: Reconstruction with ASIR-V 60% provides the optimal balance between image noise, SNR, CNR, and image quality. PMID- 29602724 TI - Relationship between Background Parenchymal Enhancement on High-risk Screening MRI and Future Breast Cancer Risk. AB - RATIONALE AND OBJECTIVES: To determine if background parenchymal enhancement (BPE) on screening breast magnetic resonance imaging (MRI) in high-risk women correlates with future cancer. MATERIALS AND METHODS: All screening breast MRIs (n = 1039) in high-risk women at our institution from August 1, 2004, to July 30, 2013, were identified. Sixty-one patients who subsequently developed breast cancer were matched 1:2 by age and high-risk indication with patients who did not develop breast cancer (n = 122). Five fellowship-trained breast radiologists independently recorded the BPE. The median reader BPE for each case was calculated and compared between the cancer and control cohorts. RESULTS: Cancer cohort patients were high-risk because of a history of radiation therapy (10%, 6 of 61), high-risk lesion (18%, 11 of 61), or breast cancer (30%, 18 of 61); BRCA mutation (18%, 11 of 61); or family history (25%, 15 of 61). Subsequent malignancies were invasive ductal carcinoma (64%, 39 of 61), ductal carcinoma in situ (30%, 18 of 61) and invasive lobular carcinoma (7%, 4of 61). BPE was significantly higher in the cancer cohort than in the control cohort (P = 0.01). Women with mild, moderate, or marked BPE were 2.5times more likely to develop breast cancer than women with minimal BPE (odds ratio = 2.5, 95% confidence interval: 1.3-4.8, P = .005). There was fair interreader agreement (kappa = 0.39). CONCLUSIONS: High-risk women with greater than minimal BPE at screening MRI have increased risk of future breast cancer. PMID- 29602725 TI - Gallbladder Scalloping, Mammillated Caudate Lobe, and Inferior Vena Cava Scalloping: Three Novel Ultrasound Signs of Cirrhosis. AB - PURPOSE: We aimed to present three new ultrasound signs-gallbladder scalloping, mammillated caudate lobe, and inferior vena cava scalloping-and determine their accuracy in diagnosing liver cirrhosis. MATERIALS AND METHODS: A total of 201 consecutive patients with a history of chronic liver disease who had undergone ultrasound imaging and liver biopsy were identified. A senior ultrasound radiologist blindly reviewed the ultrasound examinations. Specificity, sensitivity, positive predictive value, and negative predictive value of diagnosing cirrhosis were calculated for all evaluated ultrasound signs and selected combinations of signs, using the liver biopsy results as the reference standard. RESULTS: Of the 201 patients, 152 (76%) had either pathology-proven cirrhosis or significant fibrosis. Caudate lobe hypertrophy was the most specific (88%) and most positive predictor (90%) for cirrhosis, whereas mammillated caudate lobe was the most sensitive (78%). Inferior vena cava scalloping was the most specific (78%) of the three proposed ultrasound signs. When signs were combined, the presence of either gallbladder scalloping or liver surface nodularity was highly sensitive for cirrhosis (87%), whereas the presence of either gallbladder scalloping or inferior vena cava scalloping with caudate lobe hypertrophy was highly specific (93%). CONCLUSIONS: Gallbladder scalloping, mammillated caudate lobe, and inferior vena cava scalloping are three novel signs that improve the accuracy of ultrasound in diagnosing cirrhosis. PMID- 29602726 TI - Does Enhancement or Perfusion on Preprocedure CT Predict Outcomes After Embolization of Hepatocellular Carcinoma? AB - RATIONALE AND OBJECTIVE: The objective of this study was to evaluate whether quantitative enhancement or perfusion measurements on preprocedure triphasic computed tomography (CT) can be used to predict response or overall survival after embolization of hepatocellular carcinoma. MATERIALS AND METHODS: The institutional review board approved this retrospective review of 63 patients with hepatocellular carcinoma treated with particle embolization between March 2009 and December 2014. Quantitative enhancement and perfusion measurements were performed on the target tumor and the background liver on the triphasic CT performed before treatment. Microvascular invasion (MVI) and degree of differentiation were determined from a core biopsy specimen. Quantitative enhancement and perfusion values were then correlated with pathology (two-tailed t test), response to embolization on modified Response Evaluation Criteria In Solid Tumors (two-tailed t test), and overall survival after embolization (Cox proportional hazards model). RESULTS: Arterial enhancement did not predict immediate response or overall survival after embolization. The degree of differentiation or presence of MVI also did not predict immediate response or overall survival after embolization. However, high hepatic artery coefficient or low portal vein coefficient, both in the tumor (P = .011 and P = .004) and in the background liver (P = .015 and P = .009), were associated with worse survival. Hepatic artery coefficient, both in the tumor (P = .025) and in the background liver (P = .013), were independent predictors of survival in a multivariate model including the Child-Pugh score and the BCLC stage. CONCLUSIONS: Tumor and liver perfusion parameters estimated from preprocedure triphasic CT were predictive of survival after embolization. Arterial-phase enhancement and histology (degree of differentiation or MVI) did not predict immediate response or overall survival after particle embolization. PMID- 29602727 TI - The applicable scope of dual trigger: which protocol shall we compare with? PMID- 29602728 TI - Imaging the ovary. AB - During each reproductive cycle, the ovary exhibits tissue remodelling and cyclic vasculature changes associated with hormonally regulated folliculogenesis, follicle rupture, luteal formation and regression. However, the relationships among different types of follicles and corpora lutea are unclear, and the role of ovarian vasculature in folliculogenesis and luteal dynamics has not been extensively investigated. Understanding of ovarian physiology and pathophysiology relies upon elucidation of ovarian morphology and architecture. This paper summarizes the literature on traditional approaches to the imaging of ovarian structures and discusses recent advances in ovarian imaging. Traditional in-vivo ultrasound, together with histological and electron microscopic approaches provide detailed views of the ovary at organ, tissue and molecular levels. However, in-vivo imaging is limited to antral and larger follicles whereas histological imaging is mainly two-dimensional in nature. Also discussed are emerging approaches in the use of near-infrared fluorophores to image follicles in live animals to detect preantral follicles as well as visualizing ovarian structures using CLARITY in fixed whole ovaries to elucidate three-dimensional interrelationships among follicles, corpora lutea and ovarian vasculature. Advances in ovarian imaging techniques provide new understanding of ovarian physiology and allow for the development of better tools to diagnose ovarian pathophysiology. PMID- 29602729 TI - Sperm count and motility are quantitatively affected by functional polymorphisms of HTR2A, MAOA and SLC18A. AB - Spermatozoa and neurones share similar membrane characteristics and features. Associations of multiple polymorphisms traditionally related to neurotransmission were investigated. Infertile men were grouped into controls with normospermia (n = 182) and idiopathic infertile men with asthenozoospermia (n = 103), and analysed as a case-control study and as a quantitative association of each genotype. Ten neurotransmission-associated genetic variants were mapped by SNP analysis using quantitative polymerase chain reaction with TaqMan probes. Men with HTR2A rs6313 had a higher risk of asthenozoospermia (OR = 2.14; P = 0.04). MAOA rs3788862 G carriers displayed an increased risk of asthenozoospermia (OR = 2.29; P = 0.02). The SLC18A1 rs1390938 G allele was more frequent among such cases (0.75 versus 0.87; P < 0.01 and P < 0.01 for Armitage trend test); for SLC18A1 rs2270641 P = 0.02 (case-control frequency) and P = 0.01 (Armitage trend test). MAOA rs3788862 was correlated with sperm motility (Spearman rho = 0.14; P = 0.02); SLC18A1 rs1390938 was correlated with sperm count and motility (Spearman rho = 0.20; P < 0.01). Gene polymorphisms of HTR2A, MAOA and SLC18A1, related to neurotransmission, are individually associated with asthenozoospermia through variation in sperm count and motility, without detectable allelic or genotype interaction. PMID- 29602730 TI - Response: The applicable scope of dual trigger. PMID- 29602731 TI - Artificial blastocoel collapse of human blastocysts before vitrification and its effect on re-expansion after warming. PMID- 29602732 TI - [Impact of obesity in kidney transplantation: Monocentric cohort study and review of the literature]. AB - Post-kidney transplantation outcomes in obese patients remain uncertain. The aim of this study is to compare patient and graft survival and post-transplant complications in obese patients and non-obese patients. We performed a retrospective analysis of a sample of 245kidney transplantations performed between 2008 and 2014 in Clermont-Ferrand. Obese patients and non-obese patients have been compared. Then we compared obese patients who have lost at least 5% of their weight (OPP) with obese patients who did not lose weight (OPS), and non obese patients who have lost at least 5% of their weight (NOPP) with non-obese patients who did not lose weight (NOPS). Patient survival at 5years is similar between obese and non obese (84.06% versus 90.96%; P=0.49), between OPP and OPS (88.89% versus 81.82%; P=0.34) and between NOPP and NOPS (89.19% versus 91.05%; P=0.73). At 5years, graft survival is also comparable between obese and non obese (88.82% versus 81.86%; P=0.58), between OPP and OPS (85.56% versus 91.06%; P=0.98) and between NOPP and NOPS (88% versus 80.12%; P=0.31). The length of hospitalization and the rate of complications seem similar between obese and non obese and between OPP and OPS. Post-transplantation outcomes are similar between obese and non-obese patients and a weight loss for obese patients does not seem to decrease the risk of post-transplant complication. PMID- 29602734 TI - Treatment outcomes in older patients with advanced gastrointestinal stromal tumor (GIST). AB - BACKGROUND: The aim of the study was to analyze the treatment results of advanced GIST in the largest, homogenous series of older patients. METHODS: Between 2001 and 2016, 686 patients with metastatic/unresectable GIST were treated initially with imatinib and 656 were included in the analysis. Subsequently 232 patients were treated with sunitinib after imatinib failure. We have analyzed the outcomes of patients who have been treated with the tyrosine kinase inhibitor at the age >= 70 years and compared to control group of patients younger than 70 years old. RESULTS: In the group of patients treated with imatinib, 139 (21%) started therapy at the age of at least 70 years (median age of the entire cohort: 60). Median progression-free survival (PFS) on 1st line imatinib did not differ between patients >=70 yo (years old) and < 70yo (38.5 vs 44.9 months), but median overall survival (OS) was significantly better for younger patients (81 months vs. 50; p = 0.0001; although disease-specific survival - DSS was similar). Distribution of primary tumor mutational status was generally similar in older and younger patients. Permanent dose reduction (300-100 mg/day) was required for 23 patients (16.9%) in the older group and was significantly more frequent as compared to younger patients (5%). Drug-related adverse events were mainly of grades 1/2, but grade 3/4 toxicity occurred more frequently in older (14.7%) than in younger patients (3.8%). Similarly in group of patients treated with second line sunitinib median PFS and DSS were comparable in groups of patients >=70 yo (n = 55) and < 70yo (9.7 months vs 10.3 months; p = 0.7, and 21.5 vs 22.9 months). >40% of patients in both groups required dose adjustments to 37.5-25 mg daily. CONCLUSIONS: Our study confirms that current therapy of advanced GIST with tyrosine kinase inhibitors (both in 1st and 2nd line) in older patients enable to achieve the similar disease control rate and final outcomes as in younger patients, but it demands close cooperation of experienced oncologist with patients for dose modifications and side effects management. Limitation of our study is that the patients did not undergo a comprehensive geriatric assessment, what might be helpful for personalized management of patients. Nevertheless, we confirm that older patients with GIST should not receive less treatment irrespective of comorbidities. PMID- 29602733 TI - What features of stigma do the public most commonly attribute to Alzheimer's disease dementia? Results of a survey of the U.S. general public. AB - INTRODUCTION: Understanding the prevalence of beliefs, attitudes, and expectations about Alzheimer's disease dementia in the public could inform strategies to mitigate stigma. METHODS: Random sample of 317 adults from the U.S. public was analyzed to understand reactions toward a man with mild-stage Alzheimer's disease dementia. RESULTS: In adjusted analyses, over half of respondents expected the person to be discriminated against by employers (55.3%; 95% confidence interval [CI] = 47.0-65.2) and be excluded from medical decision making (55.3%; 95% CI = 46.9-65.4). Almost half expected his health insurance would be limited based on data in the medical record (46.6%; 95% CI = 38.0-57.2), a brain imaging result (45.6%, 95% CI = 37.0-56.3), or genetic test result (44.7%; 95% CI = 36.0-55.4). DISCUSSION: Public education and policies are needed to address concerns about employment and insurance discrimination. Studies are needed to discover how advances in diagnosis and treatment may change Alzheimer's disease stigma. PMID- 29602736 TI - Current Status of the Relationship Between Metabolic Syndrome and Lower Urinary Tract Symptoms. AB - : Although the exact nature of the association between metabolic syndrome (MetS) and lower urinary tract symptoms (LUTS) is still not completely understood, findings that men with metabolic alterations experience faster-developing LUTS or are more frequently candidates for benign prostatic enlargement (BPE) surgery support the hypothesis that metabolic and pathological derangements characterizing MetS can promote the development and progression of BPE and LUTS. The strong evidence that MetS is associated with larger prostate size supports a role for metabolic derangements in the development and progression of BPE. However, the relationship between MetS and LUTS is currently based on conflicting results. Most of the US and European population-based studies demonstrate a positive association between MetS and LUTS, but Asian studies often show opposite results. These findings indicate that ethnicity, diet and lifestyle could represent a central issue for the association between MetS and LUTS. PATIENT SUMMARY: The strong evidence that metabolic syndrome is associated with greater prostate size supports a role for metabolic derangements in the development and progression of benign prostatic enlargement. Ethnicity, diet, and lifestyle could represent central issues for the association between metabolic syndrome and lower urinary tract symptoms. PMID- 29602735 TI - The preference to receive chemotherapy and cancer-related outcomes in older adults with breast cancer CALGB 49907 (Alliance). AB - OBJECTIVE: Chemotherapy preference refers to a patient's interest in receiving chemotherapy. This study examined whether chemotherapy preference was associated with toxicity, efficacy, quality of life (QoL), and functional outcomes during and after completion of adjuvant chemotherapy in older women with breast cancer. MATERIALS AND METHODS: This study is a secondary analysis of CALGB 49907, a randomized trial that compared standard adjuvant chemotherapy versus capecitabine in patients age 65 years or older with breast cancer. A subset of 145 patients completed a questionnaire to describe chemotherapy preference pre-treatment. The association of this pre-treatment preference with the patient's perception of self-health, predicted and actual QoL, patient- and professional-reported toxicity, mental health, self-rated function, and survival was studied during and after treatment. RESULTS: The median age of patients was 71 years and 47% had a high preference for chemotherapy. On baseline demographics, the low preference group had a higher proportion of white patients (95% vs. 78%, p = 0.004). Before treatment, low chemotherapy preference was associated with greater nausea/vomiting (p = 0.008). Mid-treatment, low preference was associated with lower QoL, worse social, emotional and physical function (all p <= 0.02) and worse nausea/vomiting, cancer symptoms and financial worries (all p < 0.05). The association noted mid-treatment, resolved after treatment completion except with financial worries which persisted at 24 months. Low preference was associated with higher rates of grade 3-5 adverse events (53% vs. 34%, p = 0.02) but was not associated with survival. CONCLUSIONS: Low chemotherapy preference prior to treatment initiation was associated with lower QoL, worse physical symptoms and self-rated function and more adverse events mid-treatment. There is no association of chemotherapy preference with survival. PMID- 29602737 TI - Polymorphism in the promoter region of lncRNA GAS5 is functionally associated with the risk of gastric cancer. AB - BACKGROUND AND AIMS: Previous studies showed that down-regulation of GAS5 was involved in the development of gastric cancer (GC). However, the regulatory mechanism of down-expressed GAS5 in GC remains obscure. We aimed to investigate the role of rs145204276 of GAS5 in the development and metastasis process of GC. METHODS: 853 GC patients and 954 healthy controls were recruited. The variant rs145204276 was genotyped and the Chi2 test was used to compare the frequency of the genotype and the allele between the patients and the controls. Odds ratio (OR) and 95% confidence intervals (95% CIs) were calculated to estimate the association of rs145204276 with the risk of development and metastasis of GC. RESULTS: Patients were found to have significantly lower rate of genotype del/del than the controls (7.2% vs. 8.9%, P=0.016). The allele del was significantly associated with a decreased risk of GC (26.4% vs. 30.7%, P=0.005) with an OR of 0.81 (95% CI=0.70-0.94). Patients with allele del were less likely to develop lymph node metastasis (P=0.01), with an OR of 0.75 (95% CI=0.60-0.93). Comparably, rs145204276 was also significantly associated with a decreased risk of distant metastasis of GC (P=0.007; OR=0.55). CONCLUSION: We confirmed that rs145204276 of GAS5 is a functional variant associated with the susceptibility and metastasis of GC. It plays a protective role in the development of GC possibly through the regulation of GAS5. PMID- 29602738 TI - Why randomised controlled trials of psychological treatments are still essential. PMID- 29602739 TI - Negative symptoms of schizophrenia: new developments and unanswered research questions. AB - Negative symptoms of schizophrenia are associated with poor functional outcome and place a substantial burden on people with this disorder, their families, and health-care systems. We summarise the evolution of the conceptualisation of negative symptoms, the most important findings, and the remaining open questions. Several studies have shown that negative symptoms might be primary to schizophrenia or secondary to other factors, and that they cluster in the domains of avolition-apathy and expressive deficit. Failure to take this heterogeneity into account might hinder progress in research on neurobiological substrates and discoveries of treatments for primary or enduring negative symptoms. Improvement in recognition and routine assessment of negative symptoms is instrumental for correct management of secondary negative symptoms that are amenable to treatment. If substantial progress is to be made in the understanding and treatment of negative symptoms, then advances in concepts and assessment should be integrated into the design of future studies of these symptoms. PMID- 29602740 TI - Changing the topic does not change the facts. PMID- 29602741 TI - Changing the topic does not change the facts - Authors' reply. PMID- 29602743 TI - Shared care planning: Realizing the promise of team-based person-centered care. PMID- 29602742 TI - Cas4-Dependent Prespacer Processing Ensures High-Fidelity Programming of CRISPR Arrays. AB - CRISPR-Cas immune systems integrate short segments of foreign DNA as spacers into the host CRISPR locus to provide molecular memory of infection. Cas4 proteins are widespread in CRISPR-Cas systems and are thought to participate in spacer acquisition, although their exact function remains unknown. Here we show that Bacillus halodurans type I-C Cas4 is required for efficient prespacer processing prior to Cas1-Cas2-mediated integration. Cas4 interacts tightly with the Cas1 integrase, forming a heterohexameric complex containing two Cas1 dimers and two Cas4 subunits. In the presence of Cas1 and Cas2, Cas4 processes double-stranded substrates with long 3' overhangs through site-specific endonucleolytic cleavage. Cas4 recognizes PAM sequences within the prespacer and prevents integration of unprocessed prespacers, ensuring that only functional spacers will be integrated into the CRISPR array. Our results reveal the critical role of Cas4 in maintaining fidelity during CRISPR adaptation, providing a structural and mechanistic model for prespacer processing and integration. PMID- 29602744 TI - Description and comparison of medication diversion in pharmacies by pharmacists, interns, and pharmacy technicians. AB - OBJECTIVES: 1) To describe reported medication diversion within the practice of pharmacy; and 2) to compare diversion by employee type. DESIGN: Retrospective study. SETTING: A sample of state board of pharmacy records was examined from 9 states. Disciplinary actions were obtained from the records for the time period of May 2008 to May 2013. PARTICIPANTS: Pharmacy employees (pharmacist, technician, interns). INTERVENTION: Not applicable. MAIN OUTCOME MEASURES: When a diversion case was identified, the following items were obtained for each case of medication diversion: 1) category of pharmacy employee (pharmacist, technician, intern); 2) type of substance (control, noncontrol, both); 3) use of diverted substance (sale, personal use, both, undetermined); and 4) action taken by the board. RESULTS: A total of 811 medication diversion cases in 9 states were identified. Most cases involved a pharmacy technician (71.4%), controlled substances only (94.2%), and diversion for personal use (46.6%) and resulted in license or registration revocation or surrender (62.5%). When examining medication diversion use by purpose for diversion, there were significant differences by pharmacy employee type (sale use: P = 0.003; personal use: P = 0.032; unknown use: P < 0.001). CONCLUSION: Medication diversion is a pressing problem. There were 811 cases examined by 9 state boards, and many cases may be unreported. Technicians represent nearly three-fourths of diversions. It is essential that the practice of pharmacy identifies and assesses strategies to reduce medication diversion. PMID- 29602745 TI - Implementation of a pharmacist-led pharmacogenomics service for the Program of All-Inclusive Care for the Elderly (PHARM-GENOME-PACE). AB - OBJECTIVES: To determine the feasibility of implementing a pharmacist-led pharmacogenomics (PGx) service for the Program of All-Inclusive Care for the Elderly (PACE). SETTING: A national centralized pharmacy providing PGx services to community-based PACE centers. PRACTICE DESCRIPTION: Individuals 55 years of age and older enrolled in PACE who underwent PGx testing as part of their medical care (n = 296). PRACTICE INNOVATION: Pharmacist-led PGx testing, interpreting, and consulting. EVALUATION: Implementation processes and roles were ascertained by reviewing policies and procedures for the PGx service and documented observations made by pharmacists providing the service. Genetic variants and drug gene interactions (DGIs) were determined by interpretations of PGx test results. Types of recommendations provided by pharmacists were ascertained from PGx consultations. Prescribers' acceptance of recommendations were ascertained by documented responses or drug changes made after PGx consultations. RESULTS: Challenges to implementation included lack of systems interoperability, limited access to medical electronic health records, determining prescribers' responses, and knowledge and competency gaps in PGx. Pharmacist roles most essential to overcoming challenges were interpreting and applying PGx data, determining how to disseminate those data to prescribers, advocating for appropriate PGx testing, and educating about the application of test results to clinical practice. Participants frequently used drugs posing DGI risks, with the majority (73.6%) reporting more than 1 interaction. The overwhelming majority (89.0%) of pharmacists' recommendations to mitigate risks were accepted by referring prescribers. CONCLUSION: Implementing a pharmacist-led PGx service for PACE is feasible. Implementation of this service highlights the leadership role of pharmacists in moving PGx from research to practice. PMID- 29602746 TI - An appointment-based model to systematically assess and administer vaccinations. AB - OBJECTIVES: To incorporate the assessment of vaccination status and administration of vaccines in an appointment-based model (ABM) and measure the impact on vaccinations administered and patient and pharmacist satisfaction with the appointment-based model. PRACTICE DESCRIPTION: An ABM was implemented to systematically assess vaccination status and administer vaccines. Patients made an appointment to pick up synchronized prescriptions, and pharmacists assessed vaccination histories and administered vaccinations during the appointment. In addition, pharmacists could access the statewide immunization information system to objectively determine vaccination histories and document administered vaccines. SETTINGS AND PARTICIPANTS: This project was conducted at 24 Kroger Pharmacies in the Cincinnati-Dayton Area. Any patient filling more than 1 maintenance medication was eligible for the ABM program. Pharmacists were encouraged to target patients at high risk for medication problems and vaccine preventable diseases, including patients 60 years of age or older with more than 5 medications and high-risk disease states such as diabetes, asthma, and chronic obstructive pulmonary disease. EVALUATION: Pharmacies were randomized, and an a priori analysis was conducted to ensure that the 24 intervention and 78 control stores were similar at baseline. Postimplementation data on the mean number of vaccines per store were compared between the intervention stores and the control stores from September 2014 through December 2015. Patient and pharmacist satisfaction with the ABM was assessed via surveys. RESULTS: The pharmacist vaccine assessment as part of the ABM program showed higher overall mean vaccinations per store compared with the control group during the project period (1810.71 +/- 500.88 vs. 1455.09 +/- 754.43; P = 0.01). Patients and pharmacists felt that the ABM program facilitated vaccine discussions. CONCLUSION: The ABM program with a focus on vaccinations allowed pharmacists to systematically assess patient vaccination histories and administer vaccines in the pharmacy. Patients and pharmacists appreciated the dedicated time to discuss vaccinations. PMID- 29602747 TI - The predictive ability of the STarT Back Tool was limited in people with chronic low back pain: a prospective cohort study. AB - QUESTIONS: In people with chronic non-specific low back pain (LBP), what is the predictive and discriminative validity of the STarT Back Tool (SBT) for pain intensity, self-reported LBP-related disability, and global self-perceived change at 1-year follow-up? What is the profile of the SBT risk subgroups with respect to demographic variables, pain intensity, self-reported LBP-related disability, and psychological measures? DESIGN: Prospective cohort study. PARTICIPANTS: A total of 290 adults with dominant axial LBP of>=3months' duration recruited from the general community, and private physiotherapy, psychology, and pain-management clinics in Western Australia. OUTCOME MEASURES: The 1-year follow-up measures were pain intensity, LBP-related disability, and global self-perceived change. RESULTS: Outcomes were collected on 264 participants. The SBT categorised 82 participants (28%) as low risk, 116 (40%) as medium risk, and 92 (32%) as high risk. The risk subgroups differed significantly (p<0.05) on baseline pain, disability, and psychological scores. The SBT's predictive ability was strongest for disability: RR was 2.30 (95% CI 1.28 to 4.10) in the medium-risk group and 2.86 (95% CI 1.60 to 5.11) in the high-risk group. The SBT's predictive ability was weaker for pain: RR was 1.25 (95% CI 1.04 to 1.51) in the medium-risk group and 1.26 (95% CI 1.03 to 1.52) in the high-risk group. For the SBT total score, the AUC was 0.71 (95% CI 0.64 to 0.77) for disability and 0.63 (95% CI 0.55 to 0.71) for pain. CONCLUSION: This was the first large study to investigate the SBT in a population exclusively with chronic LBP. The SBT provided an acceptable indication of 1-year disability, had poor predictive and discriminative ability for future pain, and was unable to predict or discriminate global perceived change. In this cohort with chronic non-specific LBP, the SBT's predictive and discriminative abilities were restricted to disability at 1year. [Kendell M, Beales D, O'Sullivan P, Rabey M, Hill J, Smith A (2018) The predictive ability of the STarT Back Tool was limited in people with chronic low back pain: a prospective cohort study. Journal of Physiotherapy 64: 107-113]. PMID- 29602748 TI - Progressive resistance training increases strength after stroke but this may not carry over to activity: a systematic review. AB - QUESTION: Does progressive resistance training improve strength and activity after stroke? Does any increase in strength carry over to activity? DESIGN: Systematic review of randomised trials with meta-analysis. PARTICIPANTS: Adults who have had a stroke. INTERVENTION: Progressive resistance training compared with no intervention or placebo. OUTCOME MEASURES: The primary outcome was change in strength. This measurement had to be of maximum voluntary force production and performed in muscles congruent with the muscles trained in the intervention. The secondary outcome was change in activity. This measurement had to be a direct measure of performance that produced continuous or ordinal data, or with scales that produced ordinal data. RESULTS: Eleven studies involving 370 participants were included in this systematic review. The overall effect of progressive resistance training on strength was examined by pooling change scores from six studies with a mean PEDro score of 5.8, representing medium quality. The effect size of progressive resistance training on strength was 0.98 (95% CI 0.67 to 1.29, I2=0%). The overall effect of progressive resistance training on activity was examined by pooling change scores from the same six studies. The effect size of progressive resistance training on activity was 0.42 (95% CI -0.08 to 0.91, I2=54%). CONCLUSION: After stroke, progressive resistance training has a large effect on strength compared with no intervention or placebo. There is uncertainty about whether these large increases in strength carry over to improvements in activity. REVIEW REGISTRATION: PROSPERO CRD42015025401. [Dorsch S, Ada L, Alloggia D (2018) Progressive resistance training increases strength after stroke but this may not carry over to activity: a systematic review. Journal of Physiotherapy 64: 84-90]. PMID- 29602749 TI - Opportunities for cross-disciplinary care partnerships in physiotherapy. PMID- 29602750 TI - Standard restrictive sternal precautions and modified sternal precautions had similar effects in people after cardiac surgery via median sternotomy ('SMART' Trial): a randomised trial. AB - QUESTION: In people who have undergone cardiac surgery via median sternotomy, does modifying usual sternal precautions to make them less restrictive improve physical function, pain, kinesiophobia and health-related quality of life? DESIGN: Two-centre, randomised, controlled trial with concealed allocation, blinded assessors and intention-to-treat analysis. PARTICIPANTS: Seventy-two adults who had undergone cardiac surgery via a median sternotomy were included. INTERVENTION: Participants were randomly allocated to one of two groups at 4 (SD 1) days after surgery. The control group received the usual advice to restrict their upper limb use for 4 to 6 weeks (ie, restrictive sternal precautions). The experimental group received advice to use pain and discomfort as the safe limits for their upper limb use during daily activities (ie, less restrictive precautions) for the same period. Both groups received postoperative individualised education in hospital and via weekly telephone calls for 6 weeks. OUTCOME MEASURES: The primary outcome was physical function assessed by the Short Physical Performance Battery. Secondary outcomes included upper limb function, pain, kinesophobia, and health-related quality of life. Outcomes were measured before hospital discharge and at 4 and 12 weeks postoperatively. Adherence to sternal precautions was recorded. RESULTS: There were no statistically significant differences in physical function between the groups at 4 weeks (MD 1.0, 95% CI -0.2 to 2.3) and 12 weeks (MD 0.4, 95% CI -0.9 to 1.6) postoperatively. There were no statistically significant between-group differences in secondary outcomes. CONCLUSION: Modified (ie, less restrictive) sternal precautions for people following cardiac surgery had similar effects on physical recovery, pain and health-related quality of life as usual restrictive sternal precautions. Similar outcomes can be anticipated regardless of whether people following cardiac surgery are managed with traditional or modified sternal precautions. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ANZCTRN12615000968572. [Katijjahbe MA, Granger CL, Denehy L, Royse A, Royse C, Bates R, Logie S, Nur Ayub MA, Clarke S, El-Ansary D (2018) Standard restrictive sternal precautions and modified sternal precautions had similar effects in people after cardiac surgery via median sternotomy ('SMART' Trial): a randomised trial. Journal of Physiotherapy 64: 97-106]. PMID- 29602751 TI - Safety and mosquitocidal efficacy of high-dose ivermectin when co-administered with dihydroartemisinin-piperaquine in Kenyan adults with uncomplicated malaria (IVERMAL): a randomised, double-blind, placebo-controlled trial. AB - BACKGROUND: Ivermectin is being considered for mass drug administration for malaria due to its ability to kill mosquitoes feeding on recently treated individuals. However, standard, single doses of 150-200 MUg/kg used for onchocerciasis and lymphatic filariasis have a short-lived mosquitocidal effect (<7 days). Because ivermectin is well tolerated up to 2000 MUg/kg, we aimed to establish the safety, tolerability, and mosquitocidal efficacy of 3 day courses of high-dose ivermectin, co-administered with a standard malaria treatment. METHODS: We did a randomised, double-blind, placebo-controlled, superiority trial at the Jaramogi Oginga Odinga Teaching and Referral Hospital (Kisumu, Kenya). Adults (aged 18-50 years) were eligible if they had confirmed symptomatic uncomplicated Plasmodium falciparum malaria and agreed to the follow-up schedule. Participants were randomly assigned (1:1:1) using sealed envelopes, stratified by sex and body-mass index (men: <21 vs >=21 kg/m2; women: <23 vs >=23 kg/m2), with permuted blocks of three, to receive 3 days of ivermectin 300 MUg/kg per day, ivermectin 600 MUg/kg per day, or placebo, all co-administered with 3 days of dihydroartemisinin-piperaquine. Blood of patients taken on post-treatment days 0, 2 + 4 h, 7, 10, 14, 21, and 28 was fed to laboratory-reared Anopheles gambiae sensu stricto mosquitoes, and mosquito survival was assessed daily for 28 days after feeding. The primary outcome was 14-day cumulative mortality of mosquitoes fed 7 days after ivermectin treatment (from participants who received at least one dose of study medication). The study is registered with ClinicalTrials.gov, number NCT02511353. FINDINGS: Between July 20, 2015, and May 7, 2016, 741 adults with malaria were assessed for eligibility, of whom 141 were randomly assigned to receive ivermectin 600 MUg/kg per day (n=47), ivermectin 300 MUg/kg per day (n=48), or placebo (n=46). 128 patients (91%) attended the primary outcome visit 7 days post treatment. Compared with placebo, ivermectin was associated with higher 14 day post-feeding mosquito mortality when fed on blood taken 7 days post treatment (ivermectin 600 MUg/kg per day risk ratio [RR] 2.26, 95% CI 1.93-2.65, p<0.0001; hazard ratio [HR] 6.32, 4.61-8.67, p<0.0001; ivermectin 300 MUg/kg per day RR 2.18, 1.86-2.57, p<0.0001; HR 4.21, 3.06-5.79, p<0.0001). Mosquito mortality remained significantly increased 28 days post treatment (ivermectin 600 MUg/kg per day RR 1.23, 1.01-1.50, p=0.0374; and ivermectin 300 MUg/kg per day 1.21, 1.01-1.44, p=0.0337). Five (11%) of 45 patients receiving ivermectin 600 MUg/kg per day, two (4%) of 48 patients receiving ivermectin 300 MUg/kg per day, and none of 46 patients receiving placebo had one or more treatment-related adverse events. INTERPRETATION: Ivermectin at both doses assessed was well tolerated and reduced mosquito survival for at least 28 days after treatment. Ivermectin 300 MUg/kg per day for 3 days provided a good balance between efficacy and tolerability, and this drug shows promise as a potential new tool for malaria elimination. FUNDING: Malaria Eradication Scientific Alliance (MESA) and US Centers for Disease Control and Prevention (CDC). PMID- 29602752 TI - Corrections. PMID- 29602753 TI - Ivermectin: repurposing an old drug to complement malaria vector control. PMID- 29602754 TI - Patent Foramen Ovale Closure Versus Medical Therapy for Cryptogenic Stroke: Meta Analysis of Randomised Trials. AB - BACKGROUND: Patent foramen ovale (PFO) is a common anatomic variant associated with cryptogenic stroke. Percutaneous PFO closure in these patients to prevent recurrent neurological events has been controversial for decades, and mixed results have been reported from past and recent observational and randomised studies. This meta-analysis of randomised trials aims to compare the efficacy and safety of PFO closure with medical therapy for cryptogenic stroke patients. METHODS: Medline, PubMed, EMBASE, Scopus and Cochrane were searched from January 1980 to September 2017 by two authors independently to include original randomised trials comparing PFO closure with medical therapy for secondary stroke prevention. Relevant study and baseline characteristics and outcomes were extracted and pooled using random-effects models. RESULTS: Amongst 619 articles searched giving 10 full-texts assessed, six studies reporting five randomised trials and totalling 1829 PFO closure and 1611 medical therapy patients were included. Pooled hazards ratios (95% confidence interval, p-value) ischaemic stroke, transient ischaemic attack (TIA) and composite neurovascular or mortality events were 0.41 (0.19-0.90, p=0.03), 0.77 (0.51-1.14, p=0.19) and 0.60 (0.44 0.81, p<0.001) for PFO closure compared to medical therapy. Any adverse events, major bleeding and all-cause mortality were similar between modalities (p=0.37 0.95), however PFO closure had higher rates of new onset atrial fibrillation at 4.6 times (p<0.001). CONCLUSION: Our meta-analysis found that, in patients with cryptogenic stroke, percutaneous PFO closure is beneficial at reducing ischaemic stroke and composite neurovascular or mortality events, with a higher incidence of new atrial fibrillation, compared to medical therapy. PMID- 29602755 TI - Pathoanatomic Findings and Treatment During Hypertrophic Obstructive Cardiomyopathy Surgery: The Role of Mitral Valve. AB - BACKGROUND: To assess the role of the mitral valve apparatus (leaflets, chordae and papillary muscles, PM) in left ventricle outflow tract (LVOT) obstruction, and results of the surgical treatment for hypertrophic obstructive cardiomyopathy (HOCM). METHODS: Twenty-eight consecutive patients (58+/-11years, 53% female) undergoing HOCM surgery from 2007 to 2016 at our institute were retrospectively reviewed. Endpoints included the involvement of the mitral valve in LVOT obstruction, mortality, and changes in clinical and echocardiographic characteristics after HOCM surgery. RESULTS: Secondary chordae tendineae tractioning the anterior mitral leaflet to the interventricular septum, and systolic anterior motion were detected in 78% of the patients. Anomalous, hypertrophied, and fused PM with muscularis trabeculae hypertrophy were found in 50%, 25%, and 35% of the patients, respectively. Four patients had posterior leaflet redundancy. Secondary chordae (92%), PM, and muscularis trabeculae resection (71%), and PM splitting and elongation (28%) were added variably to septal myectomy (100%). Nine procedures (32%) on mitral valve leaflets were performed, involving six posterior and three anterior mitral leaflets. Long-term follow-up was 4+/-2.8years. There was no hospital mortality, and NYHA was reduced from 3+/-0.5 to 1+/-0.7 (p<0.0001), the LVOT gradient from 88+/-35 to 20+/-18mmHg (p<0.0001), mitral valve regurgitation from grade 3+/-1 to 1+/-0.7 (p<0.0001), and septum thickness from 18+/-3 to 14+/-2mm (p<0.0001). CONCLUSIONS: The mitral valve apparatus contributes with all its components variably to LVOT dynamic obstruction thus surgical correction in addition to extended myectomy is recommended to achieve the best outcome. PMID- 29602756 TI - Tolvaptan for Heart Failure in Chronic Kidney Disease Patients: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Heart failure (HF) is frequently associated with renal impairment. Tolvaptan is reported to be effective in treating congestion in HF without significant electrolyte loss compared to conventional diuretics. However, the safety and efficacy of its use in patients with chronic kidney disease (CKD) is uncertain. This systematic review and meta-analysis evaluated the efficacy and safety outcomes of tolvaptan for HF management in patients with CKD, with a focus at a physiologic basis related to safety. METHODS: We searched for observational studies and randomised clinical trials (RCTs) that assessed the effects of tolvaptan against placebo or standard care in adult patients with HF and CKD. Our protocol was registered with PROSPERO (number CRD42017052775). RESULTS: Seventeen studies were included in the qualitative review and six in the meta-analysis involving 1597 patients. Tolvaptan was associated with an increase in sodium concentration. No significant differences in change of eGFR and serum creatinine were found between tolvaptan and control groups. Urine flow rate appears to increase significantly with tolvaptan compared to baseline (p<0.0001). The meta analysis demonstrated no heterogeneity between studies but the possibility of publication bias due to incomplete reporting in excluded studies and lack of RCTs. CONCLUSIONS: The safety profile of tolvaptan appears acceptable for patients with HF and CKD. There is evidence for an improvement in serum sodium and reduction in body water without deterioration in renal function. Further research is needed to elucidate the long-term benefits of tolvaptan as an adjunct or alternative to diuretics in such patients. PMID- 29602757 TI - The staff and patient perspectives on compliance with mechanical prophylaxis for venous thromboembolism. AB - BACKGROUND: This study evaluated the accuracy of assessment and compliance with proper use of intermittent pneumatic compression (IPC) devices before and after implementation of education, accountability, and oversight measures for health care providers. METHODS: Prospective analysis of randomly selected, emergently hospitalized adult patients was performed (group 1). IPC use was observed by random visual inspections. These patients underwent independent venous thromboembolism (VTE) risk assessments by the admitting service and a VTE consult service. Mechanical prophylaxis orders were subsequently reviewed. Next, strategies to improve compliance were implemented. One year later, prospective analysis of a similar cohort (group 2) was performed, followed by surveys of staff and patients to identify barriers to compliance. RESULTS: In group 1, VTE risk assessments were accurate and IPC was appropriately ordered. Of patients who needed IPC, 24 had IPC correctly applied and 72 did not. In group 2, VTE risk assessments were accurate and IPC was appropriately ordered. Of patients who needed IPC, 26 had IPC correctly applied and 74 did not. Surveys revealed that most providers are aware of the indications, order appropriately, and make efforts to ensure application. Most nurses reported that orders were placed and that IPC was applied. Most patients claimed to have knowledge of VTE and IPC use, but half reported that they were not educated and complained of sleep interference. CONCLUSIONS: Even with implementation of strategies to improve compliance, most patients do not receive adequate mechanical prophylaxis. Health care providers appropriately order prophylactic measures but do not follow up to ensure application. Discomfort and lack of education of the patient were important barriers to prophylaxis. PMID- 29602758 TI - New method for ultrasound-guided inferior vena cava filter placement. AB - OBJECTIVE: Transabdominal ultrasound (TAUS)-guided inferior vena cava filter (IVCF) placement currently uses an inferior vena cava (IVC) longitudinal plane with cross-section of the right renal artery or the transverse plane of the right renal vein (RRV)-IVC intersection. The goal of this study was to introduce a new method for TAUS-guided IVCF placement. METHODS: The study enrolled patients who were at high risk for or had pulmonary embolism from October 22, 2010, to June 30, 2016. The probe was positioned on the right flank to centralize the RRV-IVC junction during imaging and to permit a straight line through the midpoint of the probe on the surface and a parallel line 1.0 cm below the straight line as a marker. The probe was subsequently placed on the abdominal wall with the upper edge at the marker line to show the long axis of the IVC during the process of filter placement. The upper edge of the probe was considered the filter tip position. RESULTS: A total of 1029 patients were evaluated, and 98 patients (9.5%) were excluded because of poor IVC visualization (n = 14 [1.4%]), IVC or bilateral iliac vein thrombosis (n = 79 [7.7%]), and unsuitable anatomy (n = 5 [0.5%]). The remaining 931 patients (90.5%) were selected for TAUS-guided IVCF placement, and all filters (100%) were successfully placed. There were no procedure-related complications. Suprarenal IVCF was observed in 4 patients (0.4%) by computed tomography, and the filter tip exceeded the upper edge of L2 in 15 patients (1.6%) by plain film radiography; one of them had two RRVs. Severe filter tilting (20.8 degrees) occurred in one patient. CONCLUSIONS: This new method of TAUS-guided IVCF placement was simple, safe, and effective. It may be widely applied for the bedside placement of vena cava filters. PMID- 29602759 TI - Economic implications of endovenous great saphenous ablation in a public health care system. AB - BACKGROUND: In mid-2007, endovenous ablation (EVA) of the great saphenous vein was introduced into the publicly funded health care system in Saskatchewan, Canada. We hypothesize that the introduction of EVA resulted in a decrease in use of high ligation and stripping (HL/S), decreased costs to the health care system, and increased demand of patients for great saphenous vein ablative procedures. METHODS: We retrospectively reviewed administrative data to capture cases of HL/S between 2003 and 2014 and cases of EVA of the great saphenous vein (endovenous laser treatment and radiofrequency ablation) between 2007 and 2014. Accounting for the change in practice pattern that occurred slowly between 2007 and 2009, we divided our patients into the pre-EVA era (2003-2006) and the post-EVA era (2010 2014). Procedure costs were determined with models used by our health region for this purpose. RESULTS: Utilization rates for great saphenous vein intervention remained similar in the pre-EVA (90 procedures per year) and post-EVA (92 procedures per year; P = .83) eras. Case costs of HL/S ($1965.12/case) were higher than those of EVA (endovenous laser treatment, $1295.08/case; radiofrequency ablation, $1410.54/case). The total annual costs of great saphenous vein intervention decreased from $176,861 in the pre-EVA era to $134,525 (P = .02). CONCLUSIONS: Introduction of publicly funded EVA has reduced rates of HL/S and reduced costs to our health system by approximately $42,000 per year, without increasing great saphenous vein intervention rates. PMID- 29602760 TI - Preventing the development and progression of diabetic kidney disease: Where do we stand? AB - Diabetic kidney disease (DKD) is a major factor associated with increased cardiovascular (CV) and all-cause mortality and morbidity in patients with diabetes. Current standard therapy includes intensive management of hyperglycemia and blood pressure control with renin-angiotensin-aldosterone system (RAAS) blockers. Despite the implementation of this strategy, DKD remains the leading cause of end-stage renal disease (ESRD), mainly because of the increasing burden of diabetes mellitus. The aim of this review is to evaluate the available evidence, focusing on the benefit of current treatment in the development and progression of DKD. PMID- 29602761 TI - Prevalence and related risk factors of diabetic foot ulcer in Ahvaz, south west of Iran. AB - AIMS: The aim of this study was to evaluate the prevalence of diabetic foot ulcer and its related risk factors. MATERIALS AND METHODS: In this descriptive cross sectional study, 605 patients with diabetes were evaluated in July 2014. A checklist was used to obtain demographic data, diabetes related data, past medical history, and physical examination data. RESULTS: The prevalence of diabetic foot ulcer was 6.4% (95% CI: 4.64-8.73). Seventeen cases of them were female (4.9%). In univariate analysis, the following variables had statistically significant relationship with DFU prevalence: diabetes duration, educational level, 10 g monofilament sensation, Ankle Brachial Index (ABI) and Body Mass Index (BMI). Patients' age, glycemic control and smoking did not show any significant relationship with DFU. After logistic regression analysis, the patients with decreased 10 g monofilament sensation had DFU more than patients with normal sensation (OR = 8.84, 95% CI: 3.5-22.3). Abnormal ABI increased the odds of DFU (OR = 5.6, 95% CI: 1.3-24.18). The DFU prevalence in patients with diabetes duration of 11-20 years, was more than patients with <=5 years (OR = 3.8, 95% CI: 1.33-10.8).The odds of DFU development in educated patients compared with illiterate patients was 0.27(95% CI: 0.12-0.57). BMI had a significant relationship with DFU prevalence. The odds in overweight patients was 0.259(95% CI: 0.108-0.623) and in obese patients was 0.263 (95% CI: 0.1-0.687). CONCLUSION: The prevalence of DFU was 6.4% in this study. Final associated risk factors of DFU were decreased 10 g monofilament sensation, abnormal ABI, diabetes duration, educational level and BMI. PMID- 29602762 TI - Insulin-induced upregulation of lipoprotein lipase in Schwann cells during diabetic peripheral neuropathy. AB - Diabetic peripheral neuropathy (DPN) is one of the major complications associated with diabetes. It is characterized by the degeneration of the myelin sheath around axons, referred to as demyelination. Such demyelinations are often caused by reduced lipid component of the myelin sheath. Since, lipoprotein lipase (LPL) provides the lipid for myelin sheath by hydrolysing the triglyceride rich lipoproteins, and also helps in the uptake of lipids by the Schwann cells (SCs) for its utilization, LPL is considered as the important factor in the regeneration of myelin sheath during diabetic neuropathy. Earlier reports from our laboratory have provided the insights of insulin and its receptor in SCs during diabetic neuropathy. In order to evaluate the long term effect of insulin on lipid metabolism during diabetic neuropathy, in this study, we analyzed the expression of LPL in SCs under normal, high glucose and insulin treated conditions. A decrease in the expression of LPL was observed in SCs of high glucose condition and it was reversed upon insulin treatment. Histochemical observations of sciatic nerve of insulin treated neuropathy subjects showed the improved nerve morphology, signifying the importance of insulin in restoring the pathophysiology of diabetic neuropathy. PMID- 29602763 TI - Advances in the treatment of extranodal NK/T-cell lymphoma, nasal type. AB - Extranodal natural killer/T-cell lymphoma, nasal type (ENKL) is a subtype of mature T- and natural killer cell lymphomas characterized by its association with Epstein-Barr virus and extranodal involvement. Although there is geographic variance in the frequency of ENKL, its clinical features are similar between Western countries and endemic areas, such as East Asia. Anthracycline-containing chemotherapy is not recommended to treat ENKL. No standard treatment has been established based on the results of randomized controlled trials. In patients with localized disease, radiotherapy is a core component of the recommended first line therapy. Radiotherapy administered at 50 to 54 Gy, extended involved-site radiotherapy considering tumor invasiveness, and the use of intensity modulated radiation therapy or volumetric modulated arc therapy are associated with efficacy of radiotherapy. Although the use of concurrent chemoradiotherapy has been supported by the results of clinical trials, accumulating evidence supports the use of sequential chemoradiotherapy with non-anthracycline-containing regimens that include l-asparaginase and/or platinum anticancer agents. l asparaginase-containing chemotherapy is a key component of first-line treatments for systemic ENKL. Hematopoietic stem cell transplantation is recommended as a front-line consolidation therapy for newly diagnosed advanced-stage ENKL. Newer agents including immune checkpoint inhibitors are being investigated for treating ENKL. In this modern ENKL treatment era, multidisciplinary efforts are needed to identify the best timing and sequencing of radiotherapy, l-asparaginase, platinum, newer agents, and hematopoietic stem cell transplantation. PMID- 29602764 TI - Association of Left Atrial Function Index with Atrial Fibrillation and Cardiovascular Disease: The Framingham Offspring Study. AB - BACKGROUND: Left atrial (LA) size, a marker of atrial structural remodeling, is associated with increased risk for atrial fibrillation (AF) and cardiovascular disease (CVD). LA function may also relate to AF and CVD, irrespective of LA structure. We tested the hypothesis that LA function index (LAFI), an echocardiographic index of LA structure and function, may better characterize adverse LA remodeling and predict incident AF and CVD than existing measures. METHODS AND RESULTS: In 1786 Framingham Offspring Study eighth examination participants (mean age, 66+/-9 years; 53% women), we related LA diameter and LAFI (derived from the LA emptying fraction, left ventricular outflow tract velocity time integral, and indexed maximal LA volume) to incidence of AF and CVD on follow-up. Over a median follow-up of 8.3 years (range, 7.5-9.1 years), 145 participants developed AF and 139 developed CVD. Mean LAFI was 34.5+/-12.7. In adjusted Cox regression models, lower LAFI was associated with higher risk of incident AF (hazard ratio=3.83, 95% confidence interval=2.23-6.59, lowest [Q1] compared with highest [Q4] LAFI quartile) and over 2-fold higher risk of incident CVD (hazard ratio=2.20, 95% confidence interval=1.32-3.68, Q1 versus Q4). Addition of LAFI, indexed maximum LA volume, or LA diameter to prediction models for AF or CVD did not significantly improve model discrimination for either outcome. CONCLUSIONS: In our prospective investigation of a moderate-sized community-based sample, LAFI, a composite measure of LA size and function, was associated with incident AF and CVD. Addition of LAFI to the risk prediction models for AF or CVD, however, did not significantly improve their performance. PMID- 29602765 TI - Left Atrium and Cardiovascular Risk: Does Functionality Matter More Than Size? PMID- 29602766 TI - Predictors of Acute Failure Ablation of Intra-atrial Re-entrant Tachycardia in Patients With Congenital Heart Disease: Cardiac Disease, Atypical Flutter, and Previous Atrial Fibrillation. AB - BACKGROUND: Intra-atrial re-entrant tachycardia (IART) in patients with congenital heart disease (CHD) increases morbidity and mortality. Radiofrequency catheter ablation has evolved as the first-line treatment. The aim of this study was to analyze the acute success and to identify predictors of failed IART radiofrequency catheter ablation in CHD. METHODS AND RESULTS: The observational study included all consecutive patients with CHD who underwent a first ablation procedure for IART at a single center from January 2009 to December 2015 (94 patients, 39.4% female, age: 36.55+/-14.9 years). In the first procedure, 114 IART were ablated (acute success: 74.6%; 1.21+/-0.41 IART per patient) with an acute success of 74.5%. Cavotricuspid isthmus-related IART was the only arrhythmia in 51%; non-cavotricuspid isthmus-related IART was the only mechanism in 27.7% and 21.3% of the patients had both types of IART. Predictors of acute radiofrequency catheter ablation failure were as follows: nonrelated cavotricuspid isthmus IART (odds ratio 7.3; confidence interval [CI], 1.9-17.9; P=0.04), previous atrial fibrillation (odds ratio 6.1; CI, 1.3-18.4; P=0.02), transposition of great arteries (odds ratio, 4.9; CI, 1.4-17.2; P=0.01) and systemic ventricle dilation (odds ratio 4.8; CI, 1.1-21.7; P=0.04) with an area under the receiver operating characteristic curve of 0.83+/-0.056 (CI, 0.74-0.93, P=0.001). After a mean follow-up longer than 3.5 years, 78.3% of the patients were in sinus rhythm (33.1% of the patients required more than 1 radiofrequency catheter ablation procedure). CONCLUSIONS: Although ablation in CHD is a challenging procedure, acute success of 75% can be achieved in moderate-highly complex CHD patients in a referral center. Predictors of failed ablation are IART different from cavotricuspid isthmus, previous atrial fibrillation, and markers of complex CHD (transposition of great arteries, systemic ventricle dilation). PMID- 29602767 TI - In-Hospital Outcomes of Dual Loading Antiplatelet Therapy in Patients 75 Years and Older With Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention: Findings From the CCC-ACS (Improving Care for Cardiovascular Disease in China-Acute Coronary Syndrome) Project. AB - BACKGROUND: Elderly patients with acute coronary syndrome (ACS) are at high risk for ischemic and bleeding events. This study aimed to evaluate the clinical effectiveness and safety of dual loading antiplatelet therapy for patients 75 years and older undergoing percutaneous coronary intervention for ACS. METHODS AND RESULTS: The Improving Care for Cardiovascular Disease in China-ACS project was a collaborative study of the American Heart Association and Chinese Society of Cardiology. A total of 5887 patients 75 years and older with ACS who had percutaneous coronary intervention and received dual antiplatelet therapy with aspirin and P2Y12 inhibitors (clopidogrel or ticagrelor) between November 2014 and June 2017 were enrolled. The primary effectiveness and safety outcomes were in-hospital major adverse cardiovascular events and major bleeding. Hazard ratios (HRs) of in-hospital outcomes with different loading statuses of antiplatelet therapy were estimated using Cox proportional hazard models with multivariate adjustment. A propensity score-matched analysis was also conducted. Compared with patients receiving a dual nonloading dose, patients taking a dual loading dose had increased risks of both major adverse cardiovascular events (HR, 1.66, 95% confidence interval, 1.13-2.44; [P=0.010]) and major bleeding (HR, 2.34, 95% confidence interval, 1.75-3.13; [P<0.001]). Among 3284 propensity score-matched patients, a dual loading dose was associated with a 1.36-fold risk of major adverse cardiovascular events (HR, 1.36; 95% confidence interval, 0.88-2.11 [P=0.168]) and a 2.08-fold risk of major bleeding (HR, 2.08; 95% confidence interval, 1.47-2.93 [P<0.001]). CONCLUSIONS: A dual loading dose of antiplatelet therapy was associated with increased major bleeding risk but not with decreased major adverse cardiovascular events risk among patients 75 years and older undergoing percutaneous coronary intervention for ACS in China. CLINICAL TRIAL REGISTRATION: URL: http://www.ClinicalTrials.gov. Unique identifier: NCT02306616. PMID- 29602768 TI - Association of Electronic Health Record Use With Quality of Care and Outcomes in Heart Failure: An Analysis of Get With The Guidelines-Heart Failure. AB - BACKGROUND: Adoption of electronic health record (EHR) systems has increased significantly across the nation. Whether EHR use has translated into improved quality of care and outcomes in heart failure (HF) is not well studied. METHODS AND RESULTS: We examined participants from the Get With The Guidelines-HF registry who were admitted with HF in 2008 (N=21 222), using various degrees of EHR implementation (no EHR, partial EHR, and full EHR). We performed multivariable logistic regression to determine the relation between EHR status and several in-hospital quality metrics and outcomes. In a substudy of Medicare participants (N=8421), we assessed the relation between EHR status and rates of 30-day mortality, readmission, and a composite outcome. In the cohort, the mean age was 71+/-15 years, 49% were women, and 64% were white. The mean ejection fraction was 39+/-17%. Participants were admitted to hospitals with no EHR (N=1484), partial EHR (N=13 473), and full EHR (N=6265). There was no association between EHR status and several quality metrics (aside from beta blocker at discharge) or in-hospital outcomes on multivariable adjusted logistic regression (P>0.05 for all comparisons). In the Medicare cohort, there was no association between EHR status and 30-day mortality, readmission, or the combined outcome. CONCLUSIONS: In a large registry of hospitalized patients with HF, there was no association between degrees of EHR implementation and several quality metrics and 30-day postdischarge death or readmission. Our results suggest that EHR may not be sufficient to improve HF quality or related outcomes. PMID- 29602769 TI - Whole-exome sequencing identifies germline mutation in TP53 and ATRX in a child with genomically aberrant AT/RT and her mother with anaplastic astrocytoma. AB - Brain tumors typically arise sporadically and do not affect several family members simultaneously. In the present study, we describe clinical and genetic data from two patients, a mother and her daughter, with familial brain tumors. Exome sequencing revealed a germline missense mutation in the TP53 and ATRX genes in both cases, and a somatic copy-neutral loss of heterozygosity (LOH) in TP53 in both atypical teratoid/rhabdoid tumor (AT/RT) and astrocytoma tumors. ATRX mutation was associated with the loss of ATRX protein expression. In the astrocytoma case, R132C missense mutation was found in the known hotspot site in isocitrate dehydrogenase 1 (IDH1) and LOH was detected in TP53 The mother carried few other somatic alterations, suggesting that the IDH1 mutation and LOH in TP53 were sufficient to drive tumor development. The genome in the AT/RT tumor was atypically aneuploid: Most chromosomes had experienced copy-neutral LOH or whole chromosome gains. Only Chromosome 18 had normal diploid status. INI1/hSNF5/SMARCB1 was homozygously deleted in the AT/RT tumor. This report provides further information about tumor development in a predisposed genetic background and describes two special Li-Fraumeni cases with a familial brain tumor. PMID- 29602770 TI - Lipocalin 2 Plays an Important Role in Regulating Inflammation in Retinal Degeneration. AB - It has become increasingly important to understand how retinal inflammation is regulated because inflammation plays a role in retinal degenerative diseases. Lipocalin 2 (LCN2), an acute stress response protein with multiple innate immune functions, is increased in ATP-binding cassette subfamily A member 4 (Abca4) -/- retinol dehydrogenase 8 (Rdh8) -/- double-knockout mice, an animal model for Stargardt disease and age-related macular degeneration (AMD). To examine roles of LCN2 in retinal inflammation and degeneration, Lcn2-/-Abca4-/-Rdh8-/- triple knockout mice were generated. Exacerbated inflammation following light exposure was observed in Lcn2-/-Abca4-/-Rdh8-/- mice as compared with Abca4-/-Rdh8-/- mice, with upregulation of proinflammatory genes and microglial activation. RNA array analyses revealed an increase in immune response molecules such as Ccl8, Ccl2, and Cxcl10 To further probe a possible regulatory role for LCN2 in retinal inflammation, we examined the in vitro effects of LCN2 on NF-kappaB signaling in human retinal pigmented epithelial (RPE) cells differentiated from induced pluripotent stem cells derived from healthy donors. We found that LCN2 induced expression of antioxidant enzymes heme oxygenase 1 and superoxide dismutase 2 in these RPE cells and could inhibit the cytotoxic effects of H2O2 and LPS. ELISA revealed increased LCN2 levels in plasma of patients with Stargardt disease, retinitis pigmentosa, and age-related macular degeneration as compared with healthy controls. Finally, overexpression of LCN2 in RPE cells displayed protection from cell death. Overall these results suggest that LCN2 is involved in prosurvival responses during cell stress and plays an important role in regulating inflammation during retinal degeneration. PMID- 29602771 TI - Transcriptomic Analysis of CD4+ T Cells Reveals Novel Immune Signatures of Latent Tuberculosis. AB - In the context of infectious diseases, cell population transcriptomics are useful to gain mechanistic insight into protective immune responses, which is not possible using traditional whole-blood approaches. In this study, we applied a cell population transcriptomics strategy to sorted memory CD4 T cells to define novel immune signatures of latent tuberculosis infection (LTBI) and gain insight into the phenotype of tuberculosis (TB)-specific CD4 T cells. We found a 74-gene signature that could discriminate between memory CD4 T cells from healthy latently Mycobacterium tuberculosis-infected subjects and noninfected controls. The gene signature presented a significant overlap with the gene signature of the Th1* (CCR6+CXCR3+CCR4-) subset of CD4 T cells, which contains the majority of TB specific reactivity and is expanded in LTBI. In particular, three Th1* genes (ABCB1, c-KIT, and GPA33) were differentially expressed at the RNA and protein levels in memory CD4 T cells of LTBI subjects compared with controls. The 74-gene signature also highlighted novel phenotypic markers that further defined the CD4 T cell subset containing TB specificity. We found the majority of TB-specific epitope reactivity in the CD62L-GPA33- Th1* subset. Thus, by combining cell population transcriptomics and single-cell protein-profiling techniques, we identified a CD4 T cell immune signature of LTBI that provided novel insights into the phenotype of TB-specific CD4 T cells. PMID- 29602772 TI - Cutting Edge: Mitochondrial Assembly of the NLRP3 Inflammasome Complex Is Initiated at Priming. AB - The NLRP3 inflammasome is activated in response to microbial and danger signals, resulting in caspase-1-dependent secretion of the proinflammatory cytokines IL 1beta and IL-18. Canonical NLRP3 inflammasome activation is a two-step process requiring both priming and activation signals. During inflammasome activation, NLRP3 associates with mitochondria; however, the role for this interaction is unclear. In this article, we show that mouse NLRP3 and caspase-1 independently interact with the mitochondrial lipid cardiolipin, which is externalized to the outer mitochondrial membrane at priming in response to reactive oxygen species. An NLRP3 activation signal is then required for the calcium-dependent association of the adaptor molecule ASC with NLRP3 on the mitochondrial surface, resulting in inflammasome complex assembly and activation. These findings demonstrate a novel lipid interaction for caspase-1 and identify a role for mitochondria as supramolecular organizing centers in the assembly and activation of the NLRP3 inflammasome. PMID- 29602773 TI - PD-L1-Independent Mechanisms Control the Resistance of Melanoma to CD4+ T Cell Adoptive Immunotherapy. AB - Immunotherapy is becoming the standard of care for melanoma. However, resistance to therapy is a major problem. Previously, we showed that tumor-specific, cytotoxic CD4+ T cells from tyrosinase-related protein 1 transgenic mice could overcome secondary resistance to recurring melanoma when anti-programmed cell death 1 ligand (PD-L1) checkpoint blockade was combined with either anti lymphocyte-activated gene 3 (LAG-3) Abs or depletion of tumor-specific regulatory T (Treg) cells. In this study, we show that PD-L1 expressed by the host, not B16 melanoma, plays a major role in the early stages of exhaustion or primary resistance. We observed durable regression of melanoma in tumor-bearing PD-L1-/ RAG-/- mice with transfer of naive tumor-specific CD4+ T cells. However, exhausted tumor-specific CD4+ T cells, which included tumor-specific Treg cells, failed to maintain durable regression of tumors in PD-L1-/-RAG-/- mice unless tumor-specific Treg cells were eliminated, showing nonredundant pathways of resistance to immunotherapy were present. Translating these findings to a clinically relevant model of cancer immunotherapy, we unexpectedly showed that anti-PD-L1 checkpoint blockade mildly improved immunotherapy with tumor-specific CD4+ T cells and irradiation in wild-type mice. Instead, anti-LAG-3 checkpoint blockade, in combination with tumor-specific CD4+ T cells and irradiation, overcame primary resistance and treated established tumors resulting in fewer recurrences. Because LAG-3 negatively regulates effector T cell function and activates Treg cells, LAG-3 blockade may be more beneficial in overcoming primary resistance in combination immunotherapies using adoptive cellular therapy and irradiation than blockade of PD-L1. PMID- 29602774 TI - Downregulation of CD3zeta in NK Cells from Systemic Lupus Erythematosus Patients Confers a Proinflammatory Phenotype. AB - Cytotoxic function and cytokine profile of NK cells are compromised in patients with systemic lupus erythematosus (SLE). CD3zeta, an important molecule for NK cell activation, is downregulated in SLE T cells and contributes to their altered function. However, little is known about the role of CD3zeta in SLE NK cells. We studied CD3zeta levels and its contribution to cytotoxic, degranulation, and cytokine production capacity of NK cells from patients with SLE. Furthermore, we studied the human NK cell line, NKL, in which manipulation of CD3zeta levels was achieved using small interfering RNA and NK cells from Rag2 mice deficient in CD3zeta. We found reduced CD3zeta expression in NK cells from SLE patients independent of disease activity. Downregulation of CD3zeta expression in NK cells is mediated, at least in part, by Caspase 3, the activity of which is higher in NK cells from patients with SLE compared with NK cells from healthy donors. CD3zeta levels correlated inversely with natural cytotoxicity and the percentage of cells capable of producing the proinflammatory cytokines IFN-gamma and TNF. In contrast, CD3zeta levels showed a direct correlation with levels of Ab-dependent cellular cytotoxicity. Experiments performed in CD3zeta-silenced NKL and CD3zeta deficient NK cells from Rag2 mice confirmed the dependence of NK cell function on CD3zeta levels. Our results demonstrate a differential role for CD3zeta in natural cytotoxicity and Ab-dependent cellular cytotoxicity. We conclude that downregulated CD3zeta confers a proinflammatory phenotype to SLE NK cells and contributes to their altered function in patients with SLE. PMID- 29602775 TI - Canonical Wnt Signaling in CD11c+ APCs Regulates Microbiota-Induced Inflammation and Immune Cell Homeostasis in the Colon. AB - Aberrant Wnt/beta-catenin signaling occurs in several inflammatory diseases, including inflammatory bowel disease and inflammatory bowel disease-associated colon carcinogenesis. However, its role in shaping mucosal immune responses to commensals in the gut remains unknown. In this study, we investigated the importance of canonical Wnt signaling in CD11c+ APCs in controlling intestinal inflammation. Using a mouse model of ulcerative colitis, we demonstrated that canonical Wnt signaling in intestinal CD11c+ APCs controls intestinal inflammation by imparting an anti-inflammatory phenotype. Genetic deletion of Wnt coreceptors, low-density lipoprotein receptor-related proteins 5 and 6 (LRP5/6) in CD11c+ APCs in LRP5/6DeltaCD11c mice, resulted in enhanced intestinal inflammation with increased histopathological severity of colonic tissue. This was due to microbiota-dependent increased production of proinflammatory cytokines and decreased expression of immune-regulatory factors such as IL-10, retinoic acid, and IDO. Mechanistically, loss of LRP5/6-mediated signaling in CD11c+ APCs resulted in altered microflora and T cell homeostasis. Furthermore, our study demonstrates that conditional activation of beta-catenin in CD11c+ APCs in LRP5/6DeltaCD11c mice resulted in reduced intestinal inflammation with decreased histopathological severity of colonic tissue. These results reveal a mechanism by which intestinal APCs control intestinal inflammation and immune homeostasis via the canonical Wnt-signaling pathway. PMID- 29602776 TI - Mitocryptides from Human Mitochondrial DNA-Encoded Proteins Activate Neutrophil Formyl Peptide Receptors: Receptor Preference and Signaling Properties. AB - Phagocytic neutrophils express formyl peptide receptors (FPRs; FPR1 and FPR2) that distinctly recognize peptides starting with an N-formylated methionine (fMet). This is a hallmark of bacterial metabolism; similar to prokaryotes, the starting amino acid in synthesis of mitochondrial DNA-encoded proteins is an fMet. Mitochondrial cryptic peptides (mitocryptides; MCTs) with an N-terminal fMet could be identified by our innate immune system; however, in contrast to our knowledge about bacterial metabolites, very little is known about the recognition profiles of MCTs. In this study, we determined the neutrophil-recognition profiles and functional output of putative MCTs originating from the N termini of the 13 human mitochondrial DNA-encoded proteins. Six of the thirteen MCTs potently activated neutrophils with distinct FPR-recognition profiles: MCTs from ND3 and ND6 have a receptor preference for FPR1; MCTs from the proteins ND4, ND5, and cytochrome b prefer FPR2; and MCT-COX1 is a dual FPR1/FPR2 agonist. MCTs derived from ND2 and ND4L are very weak neutrophil activators, whereas MCTs from ND1, ATP6, ATP8, COX2, and COX3, do not exert agonistic or antagonistic FPR effects. In addition, the activating MCTs heterologously desensitized IL-8R but primed the response to the platelet-activating factor receptor agonist. More importantly, our data suggest that MCTs have biased signaling properties in favor of activation of the superoxide-generating NADPH oxidase or recruitment of beta arrestin. In summary, we identify several novel FPR-activating peptides with sequences present in the N termini of mitochondrial DNA-encoded proteins, and our data elucidate the molecular basis of neutrophil activation by MCTs. PMID- 29602777 TI - Attention-deficit/hyperactivity disorder: variation by socioeconomic deprivation. AB - BACKGROUND: In England, there is a discrepancy between the prevalence of attention-deficit/hyperactivity disorder (ADHD) ascertained from medical records and community surveys. There is also a lack of data on variation in recorded prevalence by deprivation and geographical region; information that is important for service development and commissioning. METHODS: Cohort study using data from the Clinical Practice Research Datalink comprising 5196 children and young people aged 3-17 years with ADHD and 490 016 without, in 2012. RESULTS: In 2012, the recorded prevalence of ADHD was 1.06% (95% CI 1.03 to 1.09). Prevalence in the most deprived areas was double that of the least deprived areas (prevalence rate ratio 2.58 (95% CI 2.36 to 2.83)), with a linear trend from least to most deprived areas across all regions in England. CONCLUSIONS: The low prevalence of ADHD in medical records may indicate considerable underdiagnosis. Higher rates in more disadvantaged areas indicate greater need for services in those areas. PMID- 29602778 TI - Clinical imaging in dementia with Lewy bodies. AB - Dementia with Lewy bodies (DLB) is a common neurodegenerative dementia in older people; however, the clinical features, particularly cognitive fluctuations and rapid eye movement sleep disorder, are often hard to elicit, leading to difficulty in making the diagnosis clinically. Here we examine the literature for the evidence behind imaging modalities that could assist in making the diagnosis. Dopamine transporter (DAT) imaging remains the best modality for differentiation from dementia of Alzheimer's type with high sensitivity and specificity reported based on pathological diagnoses. 123Iodine-metaiodobenzylguanidine myocardial scintigraphy (MIBG) however is rapidly becoming an alternative imaging modality for the diagnosis of DLB, though studies assessing its accuracy with postmortem verification are still awaited. However, there are suggestions that MIBG may be better in the differentiation of vascular parkinsonism from DLB than DAT scans but may have lower sensitivity for detecting DLB compared with the 80% sensitivity seen in DAT imaging. Structural MRI scans have long been used for the diagnosis of dementia; however, their utility in DLB is limited to revealing the presence of coexisting Alzheimer's disease. Fluorodeoxyglucose (FDG) PET is an alternative biomarker that can also differentiate Alzheimer's disease and DLB but lacks the evidence base of both DAT and MIBG scans. PMID- 29602779 TI - Time-Centered Approach to Understanding Risk Factors for the Progression of CKD. AB - BACKGROUND AND OBJECTIVES: Traditional approaches to modeling risk of CKD progression do not provide estimates of the time it takes for disease progression to occur, which could be useful in guiding therapeutic interactions between patients and providers. Our objective was to estimate median time spent in each of CKD stages 3a-5 and how the time differs according to risk factors associated with progression of disease. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We included 3682 participants of the Chronic Renal Insufficiency Cohort in mixed models to estimate person-specific trajectories of function, and used these trajectories to estimate time spent in each CKD stage. RESULTS: During 9.5 years of median follow-up, participants spent longer in earlier rather than later CKD stages, ranging from a median of 7.9 years (interquartile range, 2.3 to >12 years) in stage 3a to 0.8 years (interquartile range, 0.3-1.6) in stage 5. Known risk factors for CKD progression were also associated with larger differences in time until progression to the next CKD stage in earlier versus later stages of disease. For example, compared with systolic BP <140 mm Hg, systolic BP >=140 mm Hg was associated with 6.1 years shorter time (95% confidence interval [95% CI], 4.5 to 7.5) spent in stage 3a, 3.3 years shorter time (95% CI, 2.7 to 4.0) in stage 3b, but only 2.4 months shorter time (95% CI, 0.8 to 3.6) in stage 5. Compared with those with proteinuria <1 g/g, proteinuria >=1 g/g was associated with 8 years shorter time spent (95% CI, 6.8 to 9.6) in stage 3a, 5.6 years shorter time (95% CI, 5.0 to 6.4) in stage 3b, but only 6 months shorter time (95% CI, 3.8 to 8) in stage 5. CONCLUSIONS: There are marked variations in the time spent in the different stages of CKD, according to risk factors and stage of disease. PMID- 29602781 TI - Amelanotic melanoma: a unique case study and review of the literature. AB - Amelanotic melanoma (AM) is a rare form of melanoma which lacks visible pigment. Due to the achromic manifestation of this atypical cutaneous malignancy, it has been difficult to establish clinical criteria for diagnosis. Thus, AM often progresses into an invasive disease due to delayed diagnosis. In this report, we describe the case of a 72-year-old Caucasian woman who had been diagnosed with AM after 3 years of failed treatments for what presented as a periorbital dermatitis. Her Clark's level 4, 1.30 mm thick melanoma required nine surgeries for successful resection and reconstruction. This case exemplifies the diagnostic pitfall of AM and the need for new criteria for early detection and management. PMID- 29602780 TI - Development of a new patient-derived xenograft humanised mouse model to study human-specific tumour microenvironment and immunotherapy. AB - OBJECTIVE: As the current therapeutic strategies for human hepatocellular carcinoma (HCC) have been proven to have limited effectiveness, immunotherapy becomes a compelling way to tackle the disease. We aim to provide humanised mouse (humice) models for the understanding of the interaction between human cancer and immune system, particularly for human-specific drug testing. DESIGN: Patient derived xenograft tumours are established with type I human leucocyte antigen matched human immune system in NOD-scid Il2rg-/- (NSG) mice. The longitudinal changes of the tumour and immune responses as well as the efficacy of immune checkpoint inhibitors are investigated. RESULTS: Similar to the clinical outcomes, the human immune system in our model is educated by the tumour and exhibits exhaustion phenotypes such as a significant declination of leucocyte numbers, upregulation of exhaustion markers and decreased the production of human proinflammatory cytokines. Notably, cytotoxic immune cells decreased more rapidly compared with other cell types. Tumour infiltrated T cells have much higher expression of exhaustion markers and lower cytokine production compared with peripheral T cells. In addition, tumour-associated macrophages and myeloid derived suppressor cells are found to be highly enriched in the tumour microenvironment. Interestingly, the tumour also changes gene expression profiles in response to immune responses by upregulating immune checkpoint ligands. Most importantly, in contrast to the NSG model, our model demonstrates both therapeutic and side effects of immune checkpoint inhibitors pembrolizumab and ipilimumab. CONCLUSIONS: Our work provides a model for immune-oncology study and a useful parallel-to-human platform for anti-HCC drug testing, especially immunotherapy. PMID- 29602782 TI - Kite surfing: epidemiology of trauma. AB - Kite surfing has become an increasingly popular recreational activity worldwide. Thrill seekers can span the water at high speeds and reach great heights risking injury and death. We report the case of a young kite surfer who sustained a fracture dislocation of the right acetabulum that required specialised surgical management. We present this case with a review of the literature outlining the incidence of pelvic and acetabular fractures in the kitesurfing community. Overall, there is a low incidence of pelvic fractures in comparison with other orthopaedic traumas reported among kite surfers, and the most commonly injured sites are the foot and ankle. Emergency departments should be alert to this activity and its associated injury patterns due to its ever-increasing popularity. PMID- 29602783 TI - Quantitative Imaging Flow Cytometry of Legionella-Infected Dictyostelium Amoebae Reveals the Impact of Retrograde Trafficking on Pathogen Vacuole Composition. AB - The ubiquitous environmental bacterium Legionella pneumophila survives and replicates within amoebae and human macrophages by forming a Legionella containing vacuole (LCV). In an intricate process governed by the bacterial Icm/Dot type IV secretion system and a plethora of effector proteins, the nascent LCV interferes with a number of intracellular trafficking pathways, including retrograde transport from endosomes to the Golgi apparatus. Conserved retrograde trafficking components, such as the retromer coat complex or the phosphoinositide (PI) 5-phosphatase D. discoideum 5-phosphatase 4 (Dd5P4)/oculocerebrorenal syndrome of Lowe (OCRL), restrict intracellular replication of L. pneumophila by an unknown mechanism. Here, we established an imaging flow cytometry (IFC) approach to assess in a rapid, unbiased, and large-scale quantitative manner the role of retrograde-linked PI metabolism and actin dynamics in the LCV composition. Exploiting Dictyostelium discoideum genetics, we found that Dd5P4 modulates the acquisition of fluorescently labeled LCV markers, such as calnexin, the small GTPase Rab1 (but not Rab7 and Rab8), and retrograde trafficking components (Vps5, Vps26, Vps35). The actin-nucleating protein and retromer interactor WASH (Wiskott-Aldrich syndrome protein [WASP] and suppressor of cAMP receptor [SCAR] homologue) promotes the accumulation of Rab1 and Rab8 on LCVs. Collectively, our findings validate IFC for the quantitative and unbiased analysis of the pathogen vacuole composition and reveal the impact of retrograde linked PI metabolism and actin dynamics on the LCV composition. The IFC approach employed here can be adapted for a molecular analysis of the pathogen vacuole composition of other amoeba-resistant pathogens.IMPORTANCELegionella pneumophila is an amoeba-resistant environmental bacterium which can cause a life-threatening pneumonia termed Legionnaires' disease. In order to replicate intracellularly, the opportunistic pathogen forms a protective compartment, the Legionella containing vacuole (LCV). An in-depth analysis of the LCV composition and the complex process of pathogen vacuole formation is crucial for understanding the virulence of L. pneumophila Here, we established an imaging flow cytometry (IFC) approach to assess in a rapid, unbiased, and quantitative manner the accumulation of fluorescently labeled markers and probes on LCVs. Using IFC and L. pneumophila infected Dictyostelium discoideum or defined mutant amoebae, a role for phosphoinositide (PI) metabolism, retrograde trafficking, and the actin cytoskeleton in the LCV composition was revealed. In principle, the powerful IFC approach can be used to analyze the molecular composition of any cellular compartment harboring bacterial pathogens. PMID- 29602784 TI - Stable Isotope Probing for Microbial Iron Reduction in Chocolate Pots Hot Spring, Yellowstone National Park. AB - Chocolate Pots hot springs (CP) is a circumneutral-pH Fe-rich geothermal feature located in Yellowstone National Park. Previous Fe(III)-reducing enrichment culture studies with CP sediments identified close relatives of known dissimilatory Fe(III)-reducing bacterial (FeRB) taxa, including Geobacter and Melioribacter However, the abundances and activities of such organisms in the native microbial community are unknown. Here, we used stable isotope probing experiments combined with 16S rRNA gene amplicon and shotgun metagenomic sequencing to gain an understanding of the in situ Fe(III)-reducing microbial community at CP. Fe-Si oxide precipitates collected near the hot spring vent were incubated with unlabeled and 13C-labeled acetate to target active FeRB. We searched reconstructed genomes for homologs of genes involved in known extracellular electron transfer (EET) systems to identify the taxa involved in Fe redox transformations. Known FeRB taxa containing putative EET systems (Geobacter, Ignavibacteria) increased in abundance under acetate-amended conditions, whereas genomes related to Ignavibacterium and Thermodesulfovibrio that contained putative EET systems were recovered from incubations without electron donor. Our results suggest that FeRB play an active role in Fe redox cycling within Fe-Si oxide-rich deposits located at the hot spring vent.IMPORTANCE The identification of past near-surface hydrothermal environments on Mars emphasizes the importance of using modern Earth environments, such as CP, to gain insight into potential Fe-based microbial life on other rocky worlds, as well as ancient Fe-rich Earth ecosystems. By combining stable carbon isotope probing techniques and DNA sequencing technology, we gained insight into the pathways of microbial Fe redox cycling at CP. The results suggest that microbial Fe(III) oxide reduction is prominent in situ, with important implications for the generation of geochemical and stable Fe isotopic signatures of microbial Fe redox metabolism within Fe-rich circumneutral-pH thermal spring environments on Earth and Mars. PMID- 29602785 TI - The pyrroloquinoline-quinone dependent pyranose dehydrogenase from Coprinopsis cinerea (CcPDH) drives lytic polysaccharide monooxygenase (LPMO) action. AB - Fungi secrete a set of glycoside hydrolases and oxidoreductases, including lytic polysaccharide monooxygenases (LPMOs), for the degradation of plant polysaccharides. LPMOs catalyze the oxidative cleavage of glycosidic bonds after activation by an external electron donor. So far, only flavin-dependent oxidoreductases (from the auxiliary activity family AA3) have been shown to activate LPMOs. Here we present LPMO activation by a pyrroloquinoline-quinone (PQQ)-dependent pyranose dehydrogenase (PDH) from Coprinopsis cinerea, CcPDH, the founding member of the recently discovered auxiliary activity family AA12. CcPDH contains a C-terminal family 1 carbohydrate binding module (CBM1), an N-terminal family AA8 cytochrome domain, and a central AA12 dehydrogenase domain. We have studied the ability of full length CcPDH and its truncated variants to drive catalysis by two Neurospora crassa LPMOs. The results show that CcPDH indeed can activate the C1-oxidizing NcLPMO9F and the C4-oxidizing NcLPMO9C, that this activation depends on the cytochrome domain, and that the dehydrogenase and the LPMO reactions are strongly coupled. The two tested CcPDH-LPMO systems showed quite different efficiencies and this difference disappeared upon addition of free PQQ acting as a diphenol/quinone redox mediator, showing that LPMOs differ when it comes to their direct interactions with the cytochrome domain. Surprisingly, removal of the CBM domain from CcPDH had a considerable negative impact on the efficiency of the CcPDH-LPMO systems, suggesting that electron transfer in the vicinity of the substrate is beneficial. CcPDH does not oxidize cello-oligosaccharides, which makes this enzyme a useful tool for studying cellulose-oxidizing LPMOs.IMPORTANCE Lytic polysaccharide monooxygenases (LPMOs) are currently receiving increasing attention because of their importance in degrading recalcitrant polysaccharides and their potential roles in biological processes such as bacterial virulence. LPMO action requires an external electron donor, and fungi growing on biomass secrete various so-called GMC oxidoreductases, including cellobiose dehydrogenase, which can donate electrons to LPMOs. This paper describes how an enzyme not belonging to the GMC oxidoreductase family, CcPDH, can activate LPMOs and provides new insights into the activation process by 1) describing the roles of individual CcPDH domains (a dehydrogenase, a cytochrome and a carbohydrate-binding domain), 2) showing that the PDH and LPMO enzyme reactions are strongly coupled, 3) demonstrating that LPMOs differ in terms of the efficiency of activation by the same activator, and 4) providing indications that electron transfer close to the substrate surface is beneficial for the overall efficiency of the CcPDH-LPMO system. PMID- 29602786 TI - Sensitive and Specific Recombinase Polymerase Amplification Assays for Fast Screening, Detection, and Identification of Bacillus anthracis in a Field Setting. AB - Four isothermal recombinase polymerase amplification (RPA) assays were developed for fast in-field identification of Bacillus anthracis The RPA assays targeted three specific sequences (i.e., the BA_5345 chromosomal marker, the lethal factor lef [from pXO1], and the capsule-biosynthesis-related capA [from pXO2]) and a conserved sequence in the adenylate cyclase gene (adk) for the Bacillus cereus group. B. anthracis-specific RPA assays were tested first with purified genomic DNAs (n = 60), including 11 representatives of B. anthracis, and then with soil (n = 8) and white powder (n = 8) samples spiked with inactivated B. anthracis spores and/or other biological agents. The RPA assays were also tested in another laboratory facility, which blindly provided DNA and lysate samples (n = 30, including 20 B. anthracis strains). RPA assays displayed 100% specificity and sensitivity. The hands-off turnaround times at 42 degrees C ranged from 5 to 6 min for 102 genomic copies. The analytical sensitivity of each RPA assay was ~10 molecules per reaction. In addition, the BA_5345 and adk RPA assays were assessed under field conditions with a series of surface swabs (n = 13, including 11 swabs contaminated with B. thuringiensis spores) that were blindly brought to the field laboratory by a chemical, biological, radiological, and nuclear (CBRN) sampling team. None of the 13 samples, except the control, tested positive for B. anthracis, and all samples that had been harvested from spore-contaminated surfaces tested positive with the adk RPA assay. All three B. anthracis-specific RPA assays proved suitable for rapid and reliable identification of B. anthracis and therefore could easily be used by first responders under field conditions to quickly discriminate between a deliberate release of B. anthracis spores and a hoax attack involving white powder.IMPORTANCE In recent decades, particularly following the 11 September 2001 and Amerithrax attacks, the world has experienced attempts to sow panic and chaos in society through thousands of white-powder copycats using household powders to mimic real bioterrorism attacks. In such circumstances, field-deployable detection methods are particularly needed to screen samples collected from the scene. The aim is to test the samples directly using a fast and reliable assay for detection of the presence of B. anthracis While this would not preclude further confirmatory tests from being performed in reference laboratories, it would bring useful, timely, and relevant information to local crisis managers and help them make appropriate decisions without having to wait for quantitative PCR results (with turnaround times of a few hours) or phenotypic identification and sequencing (with turnaround times of a few days). In the current investigation, we developed a set of isothermal RPA assays for the rapid screening and identification of B. anthracis in powders and soil samples, with the purpose of discriminating a deliberate release of B. anthracis spores from a hoax attack involving white powder; this would also apply to dispersion by spraying of aerosolized forms of B. anthracis Further work is now ongoing to confirm the first observations and validate the on-site use of these assays by first responders. PMID- 29602787 TI - High-Yield Production of Herbicidal Thaxtomins and Thaxtomin Analogs in a Nonpathogenic Streptomyces Strain. AB - Thaxtomins are virulence factors of most plant-pathogenic Streptomyces strains. Due to their potent herbicidal activity, attractive environmental compatibility, and inherent biodegradability, thaxtomins are key active ingredients of bioherbicides approved by the U.S. Environmental Protection Agency. However, the low yield of thaxtomins in native Streptomyces producers limits their wide agricultural applications. Here, we describe the high-yield production of thaxtomins in a heterologous host. The thaxtomin gene cluster from S. scabiei 87.22 was cloned and expressed in S. albus J1074 after chromosomal integration. The production of thaxtomins and nitrotryptophan analogs was observed using liquid chromatography-mass spectrometry (LC-MS) analysis. When the engineered S. albus J1074 was cultured in the minimal medium Thx defined medium supplemented with 1% cellobiose (TDMc), the yield of the most abundant and herbicidal analog, thaxtomin A, was 10 times higher than that in S. scabiei 87.22, and optimization of the medium resulted in the highest yield of thaxtomin analogs at about 222 mg/liter. Further engineering of the thaxtomin biosynthetic gene cluster through gene deletion led to the production of multiple biosynthetic intermediates important to the chemical synthesis of new analogs. Additionally, the versatility of the thaxtomin biosynthetic system in S. albus J1074 was capitalized on to produce one unnatural fluorinated analog, 5-fluoro-thaxtomin A (5-F-thaxtomin A), whose structure was elucidated by a combination of MS and one-dimensional (1D) and 2D nuclear magnetic resonance (NMR) analyses. Natural and unnatural thaxtomins demonstrated potent herbicidal activity in radish seedling assays. These results indicated that S. albus J1074 has the potential to produce thaxtomins and analogs thereof with high yield, fostering their agricultural applications.IMPORTANCE Thaxtomins are agriculturally valuable herbicidal natural products, but the productivity of native producers is limiting. Heterologous expression of the thaxtomin gene cluster in S. albus J1074 resulted in the highest yield of thaxtomins ever reported, representing a significant leap forward in its wide agricultural use. Furthermore, current synthetic routes to thaxtomins and analogs are lengthy, and two thaxtomin biosynthetic intermediates produced at high yields in this work can provide precursors and building blocks to advanced synthetic routes. Importantly, the production of 5-F-thaxtomin A in engineered S. albus J1074 demonstrated a viable alternative to chemical methods in the synthesis of new thaxtomin analogs. Moreover, our work presents an attractive synthetic biology strategy to improve the supply of herbicidal thaxtomins, likely finding general applications in the discovery and production of many other bioactive natural products. PMID- 29602788 TI - Catabolism of 2-Hydroxypyridine by Burkholderia sp. Strain MAK1: a 2 Hydroxypyridine 5-Monooxygenase Encoded by hpdABCDE Catalyzes the First Step of Biodegradation. AB - Microbial degradation of 2-hydroxypyridine usually results in the formation of a blue pigment (nicotine blue). In contrast, the Burkholderia sp. strain MAK1 bacterium utilizes 2-hydroxypyridine without the accumulation of nicotine blue. This scarcely investigated degradation pathway presumably employs 2 hydroxypyridine 5-monooxygenase, an elusive enzyme that has been hypothesized but has yet to be identified or characterized. The isolation of the mutant strain Burkholderia sp. MAK1 DeltaP5 that is unable to utilize 2-hydroxypyridine has led to the identification of a gene cluster (designated hpd) which is responsible for the degradation of 2-hydroxypyridine. The activity of 2-hydroxypyridine 5 monooxygenase has been assigned to a soluble diiron monooxygenase (SDIMO) encoded by a five-gene cluster (hpdA, hpdB, hpdC, hpdD, and hpdE). A 4.5-kb DNA fragment containing all five genes has been successfully expressed in Burkholderia sp. MAK1 DeltaP5 cells. We have proved that the recombinant HpdABCDE protein catalyzes the enzymatic turnover of 2-hydroxypyridine to 2,5-dihydroxypyridine. Moreover, we have confirmed that emerging 2,5-dihydroxypyridine is a substrate for HpdF, an enzyme similar to 2,5-dihydroxypyridine 5,6-dioxygenases that are involved in the catabolic pathways of nicotine and nicotinic acid. The proteins and genes identified in this study have allowed the identification of a novel degradation pathway of 2-hydroxypyridine. Our results provide a better understanding of the biodegradation of pyridine derivatives in nature. Also, the discovered 2-hydroxypyridine 5-monooxygenase may be an attractive catalyst for the regioselective synthesis of various N-heterocyclic compounds.IMPORTANCE The degradation pathway of 2-hydroxypyridine without the accumulation of a blue pigment is relatively unexplored, as, to our knowledge, no genetic data related to this process have ever been presented. In this paper, we describe genes and enzymes involved in this little-studied catabolic pathway. This work provides new insights into the metabolism of 2-hydroxypyridine in nature. A broad-range substrate specificity of 2-hydroxypyridine 5-monooxygenase, a key enzyme in the degradation, makes this biocatalyst attractive for the regioselective hydroxylation of pyridine derivatives. PMID- 29602789 TI - Protein- and RNA-Enhanced Fermentation by Gut Microbiota of the Earthworm Lumbricus terrestris. AB - Earthworms are a dominant macrofauna in soil ecosystems and have determinative effects on soil fertility and plant growth. These invertebrates feed on ingested material, and gizzard-linked disruption of ingested fungal and bacterial cells is conceived to provide diverse biopolymers in the anoxic alimentary canals of earthworms. Fermentation in the gut is likely important to the utilization of ingested biopolymer-derived compounds by the earthworm. This study therefore examined the fermentative responses of gut content-associated microbes of the model earthworm Lumbricus terrestris to (i) microbial cell lysate (to simulate gizzard-disrupted cells) and (ii) dominant biopolymers of such biomass, protein, and RNA. The microbial cell lysate augmented the production of H2, CO2, and diverse fatty acids (e.g., formate, acetate, propionate, succinate, and butyrate) in anoxic gut content microcosms, indicating that the cell lysate triggered diverse fermentations. Protein and RNA also augmented diverse fermentations in anoxic microcosms of gut contents, each yielding a distinct product profile (e.g., RNA yielded H2 and succinate, whereas protein did not). The combined product profile of protein and RNA treatments was similar to that of cell lysate treatments, and 16S rRNA-based analyses indicated that many taxa that responded to cell lysate were similar to taxa that responded to protein or RNA. In particular, protein stimulated Peptostreptococcaceae, Clostridiaceae, and Fusobacteriaceae, whereas RNA stimulated Aeromonadaceae These findings demonstrate the capacity of gut-associated obligate anaerobes and facultative aerobes to catalyze biopolymer-driven fermentations and highlight the potential importance of protein and RNA as substrates linked to the overall turnover dynamics of organic carbon in the alimentary canal of the earthworm.IMPORTANCE The subsurface lifestyle of earthworms makes them an unnoticed component of the terrestrial biosphere. However, the propensity of these invertebrates to consume their home, i.e., soil and litter, has long-term impacts on soil fertility, plant growth, and the cycling of elements. The alimentary canals of earthworms can contain up to 500 ml anoxic gut content per square meter of soil, and ingested soil may contain 109 or more microbial cells per gram dry weight, considerations that illustrate that enormous numbers of soil microbes are subject to anoxia during gut passage. Feeding introduces diverse sources of biopolymers to the gut, and the gut fermentation of biopolymers could be important to the transformation of matter by the earthworm and its capacity to utilize fermentation-derived fatty acids. Thus, this study examined the capacity of microbes in earthworm gut contents to ferment protein and RNA, dominant biopolymers of cells that become disrupted during gut passage. PMID- 29602792 TI - Association between changes in lifestyle and all-cause mortality: the Health and Lifestyle Survey. AB - BACKGROUND: To examine the combined influence of changes in physical activity, diet, smoking and alcohol consumption on all-cause mortality. METHODS: Health behaviours were assessed in 1984/1985 and 1991/1992 in 8123 adults from the UK (4666 women, median age 41.0 years). An unhealthy lifestyle score was calculated, allocating one point for smoking, fruits and vegetables <3 times a day, physical activity <2 hours a week and >14 units (women) or >21 units of alcohol (men) per week. RESULTS: There were 2003 deaths over a median follow-up of 6.6 years (IQR 5.9-7.2) following the resurvey. The modal change in the unhealthy lifestyle score was zero, 41.8% had the same score, 35.5% decreased and 22.7% increased score between surveys. A one unit decrease in the unhealthy lifestyle score was not associated with a beneficial effect on mortality (HR 0.93; 95% CI 0.83 to 1.04). A one unit increase in the unhealthy lifestyle score increased the risk of mortality (adjusted HR 1.09; 95% CI 1.01 to 1.18). CONCLUSIONS: In this general population sample, the adoption of an unhealthy lifestyle was associated with an increased risk of mortality. PMID- 29602790 TI - Retrospective natural history of thymidine kinase 2 deficiency. AB - BACKGROUND: Thymine kinase 2 (TK2) is a mitochondrial matrix protein encoded in nuclear DNA and phosphorylates the pyrimidine nucleosides: thymidine and deoxycytidine. Autosomal recessive TK2 mutations cause a spectrum of disease from infantile onset to adult onset manifesting primarily as myopathy. OBJECTIVE: To perform a retrospective natural history study of a large cohort of patients with TK2 deficiency. METHODS: The study was conducted by 42 investigators across 31 academic medical centres. RESULTS: We identified 92 patients with genetically confirmed diagnoses of TK2 deficiency: 67 from literature review and 25 unreported cases. Based on clinical and molecular genetics findings, we recognised three phenotypes with divergent survival: (1) infantile-onset myopathy (42.4%) with severe mitochondrial DNA (mtDNA) depletion, frequent neurological involvement and rapid progression to early mortality (median post-onset survival (POS) 1.00, CI 0.58 to 2.33 years); (2) childhood-onset myopathy (40.2%) with mtDNA depletion, moderate-to-severe progression of generalised weakness and median POS at least 13 years; and (3) late-onset myopathy (17.4%) with mild limb weakness at onset and slow progression to respiratory insufficiency with median POS of 23 years. Ophthalmoparesis and facial weakness are frequent in adults. Muscle biopsies show multiple mtDNA deletions often with mtDNA depletion. CONCLUSIONS: In TK2 deficiency, age at onset, rate of weakness progression and POS are important variables that define three clinical subtypes. Nervous system involvement often complicates the clinical course of the infantile-onset form while extraocular muscle and facial involvement are characteristic of the late onset form. Our observations provide essential information for planning future clinical trials in this disorder. PMID- 29602791 TI - Endogenous Glucose Production and Hormonal Changes in Response to Canagliflozin and Liraglutide Combination Therapy. AB - The decrement in plasma glucose concentration with SGLT2 inhibitors (SGLT2i) is blunted by a rise in endogenous glucose production (EGP). We investigated the ability of incretin treatment to offset the EGP increase. Subjects with type 2 diabetes (n = 36) were randomized to 1) canagliflozin (CANA), 2) liraglutide (LIRA), or 3) CANA plus LIRA (CANA/LIRA). EGP was measured with [3-3H]glucose with or without drugs for 360 min. In the pretreatment studies, EGP was comparable and decreased (2.2 +/- 0.1 to 1.7 +/- 0.2 mg/kg ? min) during a 300- to 360-min period (P < 0.01). The decrement in EGP was attenuated with CANA (2.1 +/- 0.1 to 1.9 +/- 0.1 mg/kg ? min) and CANA/LIRA (2.2 +/- 0.1 to 2.0 +/- 0.1 mg/kg ? min), whereas with LIRA it was the same (2.4 +/- 0.2 to 1.8 +/- 0.2 mg/kg ? min) (all P < 0.05 vs. baseline). After CANA, the fasting plasma insulin concentration decreased (18 +/- 2 to 12 +/- 2 MUU/mL, P < 0.05), while it remained unchanged in LIRA (18 +/- 2 vs. 16 +/- 2 MUU/mL) and CANA/LIRA (17 +/- 1 vs. 15 +/- 2 MUU/mL). Mean plasma glucagon did not change during the pretreatment studies from 0 to 360 min, while it increased with CANA (69 +/- 3 to 78 +/- 2 pg/mL, P < 0.05), decreased with LIRA (93 +/- 6 to 80 +/- 6 pg/mL, P < 0.05), and did not change in CANA/LIRA. LIRA prevented the insulin decline and blocked the glucagon rise observed with CANA but did not inhibit the increase in EGP. Factors other than insulin and glucagon contribute to the stimulation of EGP after CANA induced glucosuria. PMID- 29602793 TI - Effects of Smoking Versus Nonsmoking on Postprandial Glucose Metabolism in Heavy Smokers Compared With Nonsmokers. AB - OBJECTIVE: Epidemiological studies suggest that smoking increases the risk of type 2 diabetes. We hypothesized that smoking-derived nicotine and ensuing activation of nicotinic cholinergic receptors in the gastrointestinal tract and the autonomic nervous system would have a detrimental effect on postprandial glucose metabolism and, thus, potentially constitute a link between smoking and the development of type 2 diabetes. RESEARCH DESIGN AND METHODS: We subjected 11 male heavy smokers to two identical 4-h liquid mixed-meal tests: one with concomitant cigarette smoking (immediately before and after meal intake) and one without smoking. Twelve age-, sex-, and BMI-matched nonsmokers underwent an identical meal test without smoking. RESULTS: The smokers were characterized by higher fasting plasma concentrations of glucagon compared with the nonsmokers. Among smokers, cigarette smoking before and after the meal significantly reduced postprandial plasma glucose excursions. There were no differences in gut or pancreatic hormone concentrations between the test days in the smoking group, and the responses were similar to those in the control group. CONCLUSIONS: Our results suggest that smoking in association with meal intake decreases the postprandial plasma glucose concentrations, possibly through decreased gastric emptying, and that elevated fasting glucagon concentrations rather than smoking induced alterations in postprandial glucose and hormone responses may be associated with the elevated risk of type 2 diabetes in chronic smokers. PMID- 29602795 TI - Disease-modifying drugs for multiple sclerosis and infection risk: a cohort study. AB - OBJECTIVE: Little is known about disease-modifying treatments (DMTs) for multiple sclerosis (MS) and infection risk in clinical practice. We examined the association between DMTs and infection-related medical encounters. METHODS: Using population-based administrative data from British Columbia, Canada, we identified MS cases and followed them from their first demyelinating event (1996-2013) until emigration, death or study end (December 2013). Associations between DMT exposure (by DMT generation or class) and infection-related physician or hospital claims were assessed using recurrent time-to-events models, adjusted for age, sex, socioeconomic status, index year and comorbidity count. Results were reported as adjusted HRs (aHRs). RESULTS: Of 6793 MS cases, followed for 8.5 years (mean), 1716 (25.3%) were DMT exposed. Relative to no DMT, exposure to any first generation DMT (beta-interferon or glatiramer acetate) was not associated with infection-related physician claims (aHR: 0.96; 95% CI 0.89 to 1.02), nor was exposure to these drug classes when assessed separately. Exposure to any second generation DMT (oral DMT or natalizumab) was associated with an increased hazard of an infection-related physician claim (aHR: 1.47; 95% CI 1.16 to 1.85); when assessed individually, the association was significant for natalizumab (aHR: 1.59; 95% CI 1.19 to 2.11) but not the oral DMTs (aHR: 1.17; 95% CI 0.88 to 1.56). While no DMTs were associated with infection-related hospital claims, these hospitalisations were also uncommon. CONCLUSION: Exposure to first generation DMTs was not associated with an altered infection risk. However, exposure to the second-generation DMTs was, with natalizumab associated with a 59% increased risk of an infection-related physician claim. Continued pharmacovigilance is warranted, including an investigation of the DMT-associated infection burden on patient outcomes. PMID- 29602794 TI - Specific Hepatic Sphingolipids Relate to Insulin Resistance, Oxidative Stress, and Inflammation in Nonalcoholic Steatohepatitis. AB - OBJECTIVE: Insulin resistance and nonalcoholic fatty liver disease have been linked to several lipid metabolites in animals, but their role in humans remains unclear. This study examined the relationship of sphingolipids with hepatic and peripheral metabolism in 21 insulin-resistant obese patients without (NAFL-) or with (NAFL+) nonalcoholic fatty liver and nonalcoholic steatohepatitis (NASH) and 7 healthy lean individuals undergoing tissue biopsies during bariatric or elective abdominal surgery. RESEARCH DESIGN AND METHODS: Hyperinsulinemic euglycemic clamps with d-[6,6-2H2]glucose were performed to quantify tissue specific insulin sensitivity. Hepatic oxidative capacity, lipid peroxidation, and the phosphorylated-to-total c-Jun N-terminal kinase (pJNK-to-tJNK) ratio were measured to assess mitochondrial function, oxidative stress, and inflammatory activity. RESULTS: Hepatic total ceramides were higher by 50% and 33% in NASH compared with NAFL+ and NAFL-, respectively. Only in NASH were hepatic dihydroceramides (16:0, 22:0, and 24:1) and lactosylceramides increased. Serum total ceramides and dihydroceramides (hepatic dihydroceramides 22:0 and 24:1) correlated negatively with whole-body but not with hepatic insulin sensitivity. Hepatic maximal respiration related positively to serum lactosylceramide subspecies, hepatic sphinganine, and lactosylceramide 14:0. Liver lipid peroxides (total ceramides, sphingomyelin 22:0) and the pJNK-to-tJNK ratio (ceramide 24:0; hexosylceramides 22:0, 24:0, and 24:1) all positively correlated with the respective hepatic sphingolipids. CONCLUSIONS: Sphingolipid species are not only increased in insulin-resistant humans with NASH but also correlate with hepatic oxidative stress and inflammation, suggesting that these lipids may play a role during progression of simple steatosis to NASH in humans. PMID- 29602796 TI - Survival rate and predictors of mortality in patients hospitalised with heart failure: a cohort study on the data of Persian registry of cardiovascular disease (PROVE). AB - OBJECTIVES: Heart failure (HF) has a high rate of hospitalisation and mortality. We examined its risk factors, survival rate and the predictors. METHODS: In this prospective cohort study, demographic, clinical and treatment data of 1223 patients hospitalised with HF were extracted from the Persian Registry Of cardio Vascular diseasE (PROVE)/HF registry. Survival rate and HR and their association with other variables were assessed. RESULTS: 835 (68.3%) were censored, while 388 (31.7%) patients were deceased. Mean age and frequency of hypotension during hospitalisation, tachycardia, pulmonary hypertension and anaemia, hyponatremia, heart valve disease and renal disease of the deceased patients was significantly higher than censored patients (15.2vs6.1%, 51.1vs40.1%, 24.4vs16.7%, 39.0vs31.8%, respectively, p<0.05). ACE inhibitor (ACEI)/angiotensin receptor blocker (ARB) (89.8%vs82.1%, respectively) and beta blocker (BB) (81.1%vs75.5%, respectively) were higher in follow-up in the censored group (p<0.001 and 0.02, respectively). Crude Cox regression analysis identified age, tachycardia, hypotension, anaemia, pulmonary hypertension and heart valve disease as predictors of mortality (HR >1) and using ACEI/ARB and BB as predictors of life (HR <1, p<0.05). After adjustment, all variables lost their significance, except BB (HR 0.63, p=0.03) and tachycardia (HR 1.74, p=0.01) and New York Heart Association (NYHA) class IV (HR 1.90, p=0.04) became significant predictors. CONCLUSIONS: We found a high mortality rate (31.7%). As NYHA class IV and tachycardia were significant predictors of mortality after adjustment, an effective measure can be treatment of underlying diseases, which deteriorate patients' conditions. Monitoring of medications for at-risk group, especially BB that predicts life, is important. PMID- 29602797 TI - Formation of Both Heme and Apoprotein Adducts Contributes to the Mechanism-Based Inactivation of Human CYP2J2 by 17alpha-Ethynylestradiol. AB - 17alpha-Ethynylestradiol (EE), a major component of many oral contraceptives, affects the activities of a number of the human cytochrome P450 (P450) enzymes. Here, we characterized the effect of EE on CYP2J2, a major human P450 isoform that participates in metabolism of arachidonic acid. EE inactivated the hydroxyebastine carboxylation activity of CYP2J2 in a reconstituted system. The loss of activity is time and concentration dependent and requires NADPH. The KI and kinact values for the inactivation were 3.6 MUM and 0.08 minute-1, respectively. Inactivation of CYP2J2 by EE was due to formation of a heme adduct as well as an apoprotein adduct. Mass spectral analysis of CYP2J2 partially inactivated by EE showed two distinct protein masses in the deconvoluted spectrum that exhibited a mass difference of approximately 312 Da, which is equivalent to the sum of the mass of EE and one oxygen atom. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis revealed a heme adduct with MH+ ion at m/z 875.5, corresponding to alkylation of an iron-depleted prosthetic heme by EE plus one oxygen atom. The reactive intermediate responsible for covalently modifying both the prosthetic heme and apoprotein was characterized by trapping with glutathione (GSH). LC-MS/MS analysis revealed two GSH conjugate isomers with MH+ ions at m/z 620, which were formed by reaction between GSH and EE with the oxygen being added to either the internal or terminal carbon of the ethynyl moiety. High pressure liquid chromatography analysis revealed that three other major metabolites were formed during EE metabolism by CYP2J2. PMID- 29602799 TI - Drawing the line in clinical treatment of companion animals: recommendations from an ethics working party. AB - Modern veterinary medicine offers numerous options for treatment and clinicians must decide on the best one to use. Interventions causing short-term harm but ultimately benefitting the animal are often justified as being in the animal's best interest. Highly invasive clinical veterinary procedures with high morbidity and low success rates may not be in the animal's best interest. A working party was set up by the European College of Veterinary Anaesthesia and Analgesia to discuss the ethics of clinical veterinary practice and improve the approach to ethically challenging clinical cases. Relevant literature was reviewed. The 'best interest principle' was translated into norms immanent to the clinic by means of the 'open question argument'. Clinical interventions with potential to cause harm need ethical justification, and suggest a comparable structure of ethical reflection to that used in the context of in vivo research should be applied to the clinical setting. To structure the ethical debate, pertinent questions for ethical decision-making were identified. These were incorporated into a prototype ethical tool developed to facilitate clinical ethical decision-making. The ethical question 'Where should the line on treatment be drawn' should be replaced by 'How should the line be drawn?' PMID- 29602798 TI - Hepatic Abundance and Activity of Androgen- and Drug-Metabolizing Enzyme UGT2B17 Are Associated with Genotype, Age, and Sex. AB - The major objective of this study was to investigate the association of genetic and nongenetic factors with variability in protein abundance and in vitro activity of the androgen-metabolizing enzyme UGT2B17 in human liver microsomes (n = 455). UGT2B17 abundance was quantified by liquid chromatography-tandem mass spectrometry proteomics, and enzyme activity was determined by using testosterone and dihydrotestosterone as in vitro probe substrates. Genotyping or gene resequencing and mRNA expression were also evaluated. Multivariate analysis was used to test the association of UGT2B17 copy number variation, single nucleotide polymorphisms (SNPs), age, and sex with its mRNA expression, abundance, and activity. UGT2B17 gene copy number and SNPs (rs7436962, rs9996186, rs28374627, and rs4860305) were associated with gene expression, protein levels, and androgen glucuronidation rates in a gene dose-dependent manner. UGT2B17 protein (mean +/- S.D. picomoles per milligram of microsomal protein) is sparsely expressed in children younger than 9 years (0.12 +/- 0.24 years) but profoundly increases from age 9 years to adults (~10-fold) with ~2.6-fold greater abundance in males than in females (1.2 vs. 0.47). Association of androgen glucuronidation with UGT2B15 abundance was observed only in the low UGT2B17 expressers. These data can be used to predict variability in the metabolism of UGT2B17 substrates. Drug companies should include UGT2B17 in early phenotyping assays during drug discovery to avoid late clinical failures. PMID- 29602800 TI - The microRNA-200 family coordinately regulates cell adhesion and proliferation in hair morphogenesis. AB - The microRNA (miRNA)-200 (miR-200) family is highly expressed in epithelial cells and frequently lost in metastatic cancer. Despite intensive studies into their roles in cancer, their targets and functions in normal epithelial tissues remain unclear. Importantly, it remains unclear how the two subfamilies of the five miRNA family, distinguished by a single nucleotide within the seed region, regulate their targets. By directly ligating miRNAs to their targeted mRNA regions, we identify numerous miR-200 targets involved in the regulation of focal adhesion, actin cytoskeleton, cell cycle, and Hippo/Yap signaling. The two subfamilies bind to largely distinct target sites, but many genes are coordinately regulated by both subfamilies. Using inducible and knockout mouse models, we show that the miR-200 family regulates cell adhesion and orientation in the hair germ, contributing to precise cell fate specification and hair morphogenesis. Our findings demonstrate that combinatorial targeting of many genes is critical for miRNA function and provide new insights into miR-200's functions. PMID- 29602801 TI - Tumor-Derived GM-CSF Promotes Granulocyte Immunosuppression in Mesothelioma Patients. AB - Purpose: The cross-talk between tumor cells, myeloid cells, and T cells can play a critical role in tumor pathogenesis and response to immunotherapies. Although the etiology of mesothelioma is well understood, the impact of mesothelioma tumor cells on the surrounding immune microenvironment is less well studied. In this study, the effect of the mesothelioma tumor microenvironment on circulating and infiltrating granulocytes and T cells is investigated.Experimental Design: Tumor tissues and peripheral blood from mesothelioma patients were evaluated for presence of granulocytes, which were then tested for their T-cell suppression potential. Different cocultures of granulocytes and/or mesothelioma tumor cells and/or T cells were set up to identify the mechanism of T-cell inhibition.Results: Analysis of human tumors showed that the mesothelioma microenvironment is enriched in infiltrating granulocytes, which inhibit T-cell proliferation and activation. Characterization of the whole blood at diagnosis identified similar, circulating, immunosuppressive CD11b+CD15+HLADR- granulocytes at increased frequency compared with healthy controls. Culture of healthy-donor granulocytes with human mesothelioma cells showed that GM-CSF upregulates NOX2 expression and the release of reactive oxygen species (ROS) from granulocytes, resulting in T-cell suppression. Immunohistochemistry and transcriptomic analysis revealed that a majority of mesothelioma tumors express GM-CSF and that higher GM CSF expression correlated with clinical progression. Blockade of GM-CSF with neutralizing antibody, or ROS inhibition, restored T-cell proliferation, suggesting that targeting of GM-CSF could be of therapeutic benefit in these patients.Conclusions: Our study presents the mechanism behind the cross-talk between mesothelioma tumors and the immune microenvironment and indicates that targeting GM-CSF could be a novel treatment strategy to augment immunotherapy in patients with mesothelioma. Clin Cancer Res; 24(12); 2859-72. (c)2018 AACR. PMID- 29602802 TI - SMAD4 Gene Mutation Renders Pancreatic Cancer Resistance to Radiotherapy through Promotion of Autophagy. AB - Purpose: Understanding the mechanism of radioresistance could help develop strategies to improve therapeutic response of patients with PDAC. The SMAD4 gene is frequently mutated in pancreatic cancer. In this study, we investigated the role of SMAD4 deficiency in pancreatic cancer cells' response to radiotherapy.Experimental Design: We downregulated SMAD4 expression with SMAD4 siRNA or SMAD4 shRNA and overexpressed SMAD4 in SMAD4 mutant pancreatic cancer cells followed by clonogenic survival assay to evaluate their effects on cell radioresistance. To study the mechanism of radioresistance, the effects of SMAD4 loss on reactive oxygen species (ROS) and autophagy were determined by flow cytometry and immunoblot analysis, respectively. Furthermore, we measured radioresistance by clonogenic survival assay after treatment with autophagy inhibitor (Chloroquine) and ROS inhibitor (N-acetyl-l-cysteine) in SMAD4-depleted pancreatic cancer cells. Finally, the effects of SMAD4 on radioresistance were also confirmed in an orthotopic tumor model derived from SMAD4-depleted Panc-1 cells.Results:SMAD4-depleted pancreatic cancer cells were more resistant to radiotherapy based on clonogenic survival assay. Overexpression of wild-type SMAD4 in SMAD4-mutant cells rescued their radiosensitivity. Radioresistance mediated by SMAD4 depletion was associated with persistently higher levels of ROS and radiation-induced autophagy. Finally, SMAD4 depletion induced in vivo radioresistance in Panc-1-derived orthotopic tumor model (P = 0.038). More interestingly, we observed that the protein level of SMAD4 is inversely correlated with autophagy in orthotopic tumor tissue samples.Conclusions: Our results demonstrate that defective SMAD4 is responsible for radioresistance in pancreatic cancer through induction of ROS and increased level of radiation induced autophagy. Clin Cancer Res; 24(13); 3176-85. (c)2018 AACR. PMID- 29602803 TI - Comment on "Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis". AB - Discrepancies on the role of citrullination in the induction of experimental arthritis by neutrophils extracellular traps. PMID- 29602804 TI - Response to comment on "Synovial fibroblast-neutrophil interactions promote pathogenic adaptive immunity in rheumatoid arthritis". AB - The citrullinome cargo in neutrophil extracellular traps varies according to disease condition and stimulation conditions. PMID- 29602805 TI - Geographic Inequalities in Progress against Lung Cancer among Women in the United States, 1990-2015. AB - Background: Lung cancer-related death rates in the United States have declined steadily since 1990 in men but not until the mid-2000s in women, with the gap in mortality narrowing during the most recent time period. We examined variation in the declining trend among women by county, where many tobacco control policies are implemented.Methods: We obtained county-level lung cancer death rates among women from the National Center for Health Statistics mortality file and calculated relative changes from 1990-1999 to 2006-2015. Optimized hotspot analysis identified contiguous counties with small declines or increases in death rates.Results: We identified two distinct clusters of counties: 669 in Appalachia and the Midwest (Hotspot 1) and 81 in the northern Midwest (Hotspot 2). From 1990 1999 to 2006-2015, death rates among women increased by 13% in Hotspot 1 and by 7% in Hotspot 2 counties, while rates decreased by 6% in the non-hotspot United States. From 1990-2015, death rate ratios (RRs) in hotspot versus non-hotspot counties changed from 4% lower (RR, 0.96; 95% CI, 0.94-0.99) to 28% higher [RR, 1.28; 95% confidence interval (CI), 1.25-1.31] for Hotspot 1 counties and from 18% lower (RR, 0.82; 95% CI, 0.76-0.89) to unity (RR, 0.99; 95% CI, 0.93-1.05) for Hotspot 2 counties.Conclusions: We identified areas in the Midwest and Appalachia where progress against lung cancer mortality among women has lagged compared with a steady national decline.Impact: Targeted tobacco control programs could reduce the excess burden of lung cancer among women living in hotspot counties and prevent widening geographic inequity. Cancer Epidemiol Biomarkers Prev; 27(11); 1261-4. (c)2018 AACR. PMID- 29602806 TI - Oversized galactosides as a probe for conformational dynamics in LacY. AB - Binding kinetics of alpha-galactopyranoside homologs with fluorescent aglycones of different sizes and shapes were determined with the lactose permease (LacY) of Escherichia coli by FRET from Trp151 in the binding site of LacY to the fluorophores. Fast binding was observed with LacY stabilized in an outward-open conformation (kon = 4-20 MUM-1.s-1), indicating unobstructed access to the binding site even for ligands that are much larger than lactose. Dissociation rate constants (koff) increase with the size of the aglycone so that Kd values also increase but remain in the micromolar range for each homolog. Phe27 (helix I) forms an apparent constriction in the pathway for sugar by protruding into the periplasmic cavity. However, replacement of Phe27 with a bulkier Trp does not create an obstacle in the pathway even for large ligands, since binding kinetics remain unchanged. High accessibility of the binding site is also observed in a LacY/nanobody complex with partially blocked periplasmic opening. Remarkably, E. coli expressing WT LacY catalyzes transport of alpha- or beta-galactopyranosides with oversized aglycones such as bodipy or Aldol518, which may require an extra space within the occluded intermediate. The results confirm that LacY specificity is strictly directed toward the galactopyranoside ring and also clearly indicate that the opening on the periplasmic side is sufficiently wide to accommodate the large galactoside derivatives tested here. We conclude that the actual pathway for the substrate entering from the periplasmic side is wider than the pore diameter calculated in the periplasmic-open X-ray structures. PMID- 29602807 TI - Insight from the maximal activation of the signal transduction excitable network in Dictyostelium discoideum. AB - Cell migration requires the coordination of an excitable signal transduction network involving Ras and PI3K pathways with cytoskeletal activity. We show that expressing activated Ras GTPase-family proteins in cells lacking PTEN or other mutations which increase cellular protrusiveness transforms cells into a persistently activated state. Leading- and trailing-edge markers were found exclusively at the cell perimeter and the cytosol, respectively, of the dramatically flattened cells. In addition, the lifetimes of dynamic actin puncta were increased where they overlapped with actin waves, suggesting a mechanism for the coupling between these two networks. All of these phenotypes could be reversed by inhibiting signal transduction. Strikingly, maintaining cells in this state of constant activation led to a form of cell death by catastrophic fragmentation. These findings provide insight into the feedback loops that control excitability of the signal transduction network, which drives migration. PMID- 29602808 TI - Genome-Wide Association Mapping Uncovers Fw1, a Dominant Gene Conferring Resistance to Fusarium Wilt in Strawberry. AB - Fusarium wilt, a soil-borne disease caused by the fungal pathogen Fusarium oxysporum f. sp. fragariae, threatens strawberry (Fragaria * ananassa) production worldwide. The spread of the pathogen, coupled with disruptive changes in soil fumigation practices, have greatly increased disease pressure and the importance of developing resistant cultivars. While resistant and susceptible cultivars have been reported, a limited number of germplasm accessions have been analyzed, and contradictory conclusions have been reached in earlier studies to elucidate the underlying genetic basis of resistance. Here, we report the discovery of Fw1, a dominant gene conferring resistance to Fusarium wilt in strawberry. The Fw1 locus was uncovered in a genome-wide association study of 565 historically and commercially important strawberry accessions genotyped with 14,408 SNP markers. Fourteen SNPs in linkage disequilibrium with Fw1 physically mapped to a 2.3 Mb segment on chromosome 2 in a diploid F. vesca reference genome. Fw1 and 11 tightly linked GWAS-significant SNPs mapped to linkage group 2C in octoploid segregating populations. The most significant SNP explained 85% of the phenotypic variability and predicted resistance in 97% of the accessions tested-broad-sense heritability was 0.96. Several disease resistance and defense-related gene homologs, including a small cluster of genes encoding nucleotide-binding leucine rich-repeat proteins, were identified in the 0.7 Mb genomic segment predicted to harbor Fw1 DNA variants and candidate genes identified in the present study should facilitate the development of high-throughput genotyping assays for accurately predicting Fusarium wilt phenotypes and applying marker-assisted selection. PMID- 29602809 TI - Genome-Wide Analysis of Mycoplasma bovirhinis GS01 Reveals Potential Virulence Factors and Phylogenetic Relationships. AB - Mycoplasma bovirhinis is a significant etiology in bovine pneumonia and mastitis, but our knowledge about the genetic and pathogenic mechanisms of M. bovirhinis is very limited. In this study, we sequenced the complete genome of M. bovirhinis strain GS01 isolated from the nasal swab of pneumonic calves in Gansu, China, and we found that its genome forms a 847,985 bp single circular chromosome with a GC content of 27.57% and with 707 protein-coding genes. The putative virulence determinants of M. bovirhinis were then analyzed. Results showed that three genomic islands and 16 putative virulence genes, including one adhesion gene enolase, seven surface lipoproteins, proteins involved in glycerol metabolism, and cation transporters, might be potential virulence factors. Glycerol and pyruvate metabolic pathways were defective. Comparative analysis revealed remarkable genome variations between GS01 and a recently reported HAZ141_2 strain, and extremely low homology with others mycoplasma species. Phylogenetic analysis demonstrated that M. bovirhinis was most genetically close to M. canis, distant from other bovine Mycoplasma species. Genomic dissection may provide useful information on the pathogenic mechanisms and genetics of M. bovirhinis. PMID- 29602810 TI - Effects of Larval Density on Gene Regulation in Caenorhabditis elegans During Routine L1 Synchronization. AB - Bleaching gravid C. elegans followed by a short period of starvation of the L1 larvae is a routine method performed by worm researchers for generating synchronous populations for experiments. During the process of investigating dietary effects on gene regulation in L1 stage worms by single-worm RNA-Seq, we found that the density of resuspended L1 larvae affects expression of many mRNAs. Specifically, a number of genes related to metabolism and signaling are highly expressed in worms arrested at low density, but are repressed at higher arrest densities. We generated a GFP reporter strain based on one of the most density dependent genes in our dataset - lips-15 - and confirmed that this reporter was expressed specifically in worms arrested at relatively low density. Finally, we show that conditioned media from high density L1 cultures was able to downregulate lips-15 even in L1 animals arrested at low density, and experiments using daf-22 mutant animals demonstrated that this effect is not mediated by the ascaroside family of signaling pheromones. Together, our data implicate a soluble signaling molecule in density sensing by L1 stage C. elegans, and provide guidance for design of experiments focused on early developmental gene regulation. PMID- 29602812 TI - A Whole Genome Assembly of the Horn Fly, Haematobia irritans, and Prediction of Genes with Roles in Metabolism and Sex Determination. AB - Haematobia irritans, commonly known as the horn fly, is a globally distributed blood-feeding pest of cattle that is responsible for significant economic losses to cattle producers. Chemical insecticides are the primary means for controlling this pest but problems with insecticide resistance have become common in the horn fly. To provide a foundation for identification of genomic loci for insecticide resistance and for discovery of new control technology, we report the sequencing, assembly, and annotation of the horn fly genome. The assembled genome is 1.14 Gb, comprising 76,616 scaffolds with N50 scaffold length of 23 Kb. Using RNA-Seq data, we have predicted 34,413 gene models of which 19,185 have been assigned functional annotations. Comparative genomics analysis with the Dipteran flies Musca domestica L., Drosophila melanogaster, and Lucilia cuprina, show that the horn fly is most closely related to M. domestica, sharing 8,748 orthologous clusters followed by D. melanogaster and L. cuprina, sharing 7,582 and 7,490 orthologous clusters respectively. We also identified a gene locus for the sodium channel protein in which mutations have been previously reported that confers target site resistance to the most common class of pesticides used in fly control. Additionally, we identified 276 genomic loci encoding members of metabolic enzyme gene families such as cytochrome P450s, esterases and glutathione S-transferases, and several genes orthologous to sex determination pathway genes in other Dipteran species. PMID- 29602814 TI - Polysomnography versus limited respiratory monitoring and nurse-led titration to optimise non-invasive ventilation set-up: a pilot randomised clinical trial. AB - : Polysomnography (PSG) is recommended for non-invasive ventilation (NIV) set-up in patients with chronic respiratory failure. In this pilot randomised clinical trial, we compared the physiological effectiveness of NIV set-up guided by PSG to limited respiratory monitoring (LRM) and nurse-led titration in patients with COPD-obstructive sleep apnoea (OSA) overlap. The principal outcome of interest was change in daytime arterial partial pressure of carbon dioxide (PaCO2) at 3 months. Fourteen patients with daytime PaCO2 >6 kPa and body mass index >30 kg/m2 were recruited. At 3 months, PaCO2 was reduced by -0.88 kPa (95% CI -1.52 to 0.24 kPa) in the LRM group and by -0.36 kPa (95% CI -0.96 to 0.24 kPa) in the PSG group. These pilot data provide support to undertake a clinical trial investigating the clinical effectiveness of attended limited respiratory monitoring and PSG to establish NIV in patients with COPD-OSA overlap. TRIAL NUMBER: Results, NCT02444806. PMID- 29602813 TI - Lung cancer risk to personalise annual and biennial follow-up computed tomography screening. AB - BACKGROUND: All lung cancer CT screening trials used fixed follow-up intervals, which may not be optimal. We developed new lung cancer risk models for personalising screening intervals to 1 year or 2 years, and compared these with existing models. METHODS: We included participants in the CT arm of the National Lung Screening Trial (2002-2010) who underwent a baseline scan and a first annual follow-up scan and were not diagnosed with lung cancer in the first year. True and false positives and the area under the curve of each model were calculated. Internal validation was performed using bootstrapping. RESULTS: Data from 24 542 participants were included in the analysis. The accuracy was 0.785, 0.693, 0.697, 0.666 and 0.727 for the polynomial, patient characteristics, diameter, Patz and PanCan models, respectively. Of the 24 542 participants included, 174 (0.71%) were diagnosed with lung cancer between the first and the second annual follow ups. Using the polynomial model, 2558 (10.4%, 95% CI 10.0% to 10.8%), 7544 (30.7%, 30.2% to 31.3%), 10 947 (44.6%, 44.0% to 45.2%), 16 710 (68.1%, 67.5% to 68.7%) and 20 023 (81.6%, 81.1% to 92.1%) of the 24 368 participants who did not develop lung cancer in the year following the first follow-up screening round could have safely skipped it, at the expense of delayed diagnosis of 0 (0.0%, 0.0% to 2.7%), 8 (4.6%, 2.2% to 9.2%), 17 (9.8%, 6.0% to 15.4%), 44 (25.3%, 19.2% to 32.5%) and 70 (40.2%, 33.0% to 47.9%) of the 174 lung cancers, respectively. CONCLUSIONS: The polynomial model, using both patient characteristics and baseline scan morphology, was significantly superior in assigning participants to 1-year or 2-year screening intervals. Implementing personalised follow-up intervals would enable hundreds of participants to skip a screening round per lung cancer diagnosis delayed. PMID- 29602811 TI - Identification of Proteins Required for Precise Positioning of Apc2 in Dendrites. AB - In Drosophila neurons, uniform minus-end-out polarity in dendrites is maintained in part by kinesin-2-mediated steering of growing microtubules at branch points. Apc links the kinesin motor to growing microtubule plus ends and Apc2 recruits Apc to branch points where it functions. Because Apc2 acts to concentrate other steering proteins to branch points, we wished to understand how Apc2 is targeted. From an initial broad candidate RNAi screen, we found Miro (a mitochondrial transport protein), Ank2, Axin, spastin and Rac1 were required to position Apc2 GFP at dendrite branch points. YFP-Ank2-L8, Axin-GFP and mitochondria also localized to branch points suggesting the screen identified relevant proteins. By performing secondary screens, we found that energy production by mitochondria was key for Apc2-GFP positioning and spastin acted upstream of mitochondria. Ank2 seems to act independently from other players, except its membrane partner, Neuroglian (Nrg). Rac1 likely acts through Arp2/3 to generate branched actin to help recruit Apc2-GFP. Axin can function in a variety of wnt signaling pathways, one of which includes heterotrimeric G proteins and Frizzleds. Knockdown of Galphas, Galphao, Fz and Fz2, reduced targeting of Apc2 and Axin to branch points. Overall our data suggest that mitochondrial energy production, Nrg/Ank2, branched actin generated by Arp2/3 and Fz/G proteins/Axin function as four modules that control localization of the microtubule regulator Apc2 to its site of action in dendrite branch points. PMID- 29602815 TI - Modern Radiopharmaceutical Dosimetry Should Include Robust Biodistribution Reporting. AB - Radiopharmaceutical dosimetry is an important area of nuclear medicine, and its advances have the potential to affect imaging and radiotherapy development and application protocols. Dosimetry is a computationally intensive, assumption-based process, and not all dosimetry is created equal. In this brief communication, we present biodistribution measurements as a valuable part of radiopharmaceutical dosimetry that is worthy of robust documentation. Biodistribution data are routinely collected in every dosimetry case and are integral to the subsequent dosimetry calculations. Standard documentation of these data may help us understand the value and limitations of our dosimetry estimates, identify errors, resolve discrepancies, and enable the reproducibility of results. We may also recognize that the modern digital landscape provides both opportunity and motivation to usher in the evolution of standards in our field. Ultimately, these steps may improve the current generally poor acceptance of dosimetry procedures by clinicians. PMID- 29602816 TI - Cost-Effectiveness of Bone SPECT/CT in Painful Total Knee Arthroplasty. AB - The purpose of this study was to quantify the economic value of bone SPECT/CT versus CT or metal artifact reduction sequence (MARS)-MRI for the diagnostic assessment of recurrent moderate-to-severe pain after total knee arthroplasty (TKA). Methods: An Excel-based simulation model was developed to compare bone SPECT/CT versus CT or MARS-MRI from a payer perspective. Clinical endpoints (diagnosis-delayed or otherwise, and the subsequent treatment and complications) and their corresponding cost data (2017 U.S. dollars) were obtained by performing a best evidence review of the published literature. Studies were pooled and parameters weighted by sample size. A cost-utility analysis was performed estimating the incremental cost per quality-adjusted life years gained between bone SPECT/CT and the comparative scans. One-way (+/-25%) sensitivity analysis was performed to gauge the model robustness. Results: For every 1,000 TKA patients, diagnostic bone SPECT/CT was expected to lead to 3-y cost savings up to $1,867,695 versus CT (or $622.6 per patient per year) and $1,723,435 versus MARS MRI (or $574.5 per patient per year) for a payer. With corresponding incremental quality-adjusted life years gains of 39.7 and 41.0 against CT and MARS-MRI, SPECT/CT can be considered as a cost-saving and dominant strategy in the workup of persistent/recurrent pain in TKA patients. The model was limited by the still sparse literature data, was most sensitive to imaging-related sensitivity/specificity, but proved robust for varying prevalence of surgical/nonsurgical causes of pain. Conclusion: Bone SPECT/CT is a potentially highly cost-saving and dominant imaging intervention versus CT or MARS-MR scanning in patients with recurrent and persistent knee pain after TKA. PMID- 29602817 TI - Somatostatin Receptor Imaging of Neuroendocrine Tumors: From Agonists to Antagonists. PMID- 29602818 TI - Perspective on How the FDA Should Review Diagnostic Radiopharmaceuticals. PMID- 29602819 TI - Detection Threshold and Reproducibility of 68Ga-PSMA11 PET/CT in a Mouse Model of Prostate Cancer. AB - To improve prostate-specific membrane antigen (PSMA)-targeted theranostic approaches, robust murine models of prostate cancer are needed. However, important characteristics of preclinical PSMA imaging-that is, the reproducibility of the imaging signal and the relationship between quantitative cell surface PSMA expression and lesion detectability with small-animal PET/CT have not been defined yet. Methods: Murine prostate cancer RM1 sublines (ras myc transformed cells of C57BL/6 prostate origin) expressing varying levels of human PSMA were injected into the shoulder of C57BL/6 mice on day 0. 68Ga-PSMA11 PET/CT was performed on days 7 and 8 and interpreted by 2 masked readers to determine interday and interreader reproducibility. PSMA expression was quantified on days 7 and 8 by flow cytometry of fine-needle aspiration tumor biopsy samples. Cell surface PSMA expression was correlated with PET signal. The threshold for PET positivity was based on the clinical Prostate Cancer Molecular Imaging Standardized Evaluation (PROMISE) criteria. Results: The maximum and average percentages of injected 68Ga-PSMA11 activity per gram of tissue (%IA/g) correlated nearly perfectly as determined by 2 independent readers and on 2 separate days (intraclass correlation coefficient, 1.00/0.89 and 0.95/0.88, respectively). The number of PSMA molecules per cell increased from the RM1 yellow fluorescent protein subline (PSMA-; 2,000/cell) to the RM1-low subline (PSMA+; 17,000/cell), the RM1-medium subline (PSMA++; 22,000/cell), and the RM1 PGLS subline (PSMA-positive, green fluorescent protein-positive, and luciferase positive; PSMA+++; 45,000/cell). Expression levels correlated with the visual positivity rate on 68Ga-PSMA11 PET and with the PSMA PET %IA/g. The PSMA threshold for PET positivity was approximately 20,000 per cell. Signal correlation was close at lower PSMA levels (RM1-low to RM1-medium; 10-23 %IA/g) but was lost at higher PSMA levels (RM1-medium to RM1-PGLS; 23-27 %IA/g). Conclusion: The in vivo relationship between 68Ga-PSMA11 PET/CT and PSMA expression level in a murine model of prostate cancer was robust for lower cell surface PSMA expression levels (<=22,000/cell). Thus, preclinical 68Ga-PSMA11 PET/CT can be used as an imaging biomarker to test PSMA-targeted interventions in murine models. PMID- 29602820 TI - Dual-Modality Immuno-PET and Near-Infrared Fluorescence Imaging of Pancreatic Cancer Using an Anti-Prostate Stem Cell Antigen Cys-Diabody. AB - Pancreatic cancer has a high mortality rate due to late diagnosis and the tendency to invade surrounding tissues and metastasize at an early stage. A molecular imaging agent that enables both presurgery antigen-specific PET (immuno PET) and intraoperative near-infrared fluorescence (NIRF) guidance might benefit diagnosis of pancreatic cancer, staging, and surgical resection, which remains the only curative treatment. Methods: We developed a dual-labeled probe based on A2 cys-diabody (A2cDb) targeting the cell-surface prostate stem cell antigen (PSCA), which is expressed in most pancreatic cancers. Maleimide-IRDye800CW was site-specifically conjugated to the C-terminal cys-tag (A2cDb-800) without impairing integrity or affinity (half-maximal binding, 4.3 nM). Direct radioiodination with 124I (124I-A2cDb-800) yielded a specific activity of 159 +/- 48 MBq/mg with a radiochemical purity exceeding 99% and 65% +/- 4.5% immunoreactivity (n = 3). In vivo specificity for PSCA-expressing tumor cells and biodistribution of the dual-modality tracer were evaluated in a prostate cancer xenograft model and compared with single-labeled 124I-A2cDb. Patient-derived pancreatic ductal adenocarcinoma xenografts (PDX-PDACs) were grown subcutaneously in NSG mice and screened for PSCA expression by immuno-PET. Small-animal PET/CT scans of PDX-PDAC-bearing mice were obtained using the dual-modality 124I-A2cDb 800 followed by postmortem NIRF imaging with the skin removed. Tumors and organs were analyzed ex vivo to compare the relative fluorescent signals without obstruction by other organs. Results: Specific uptake in PSCA-positive tumors and low nonspecific background activity resulted in high-contrast immuno-PET images. Concurrent with the PET studies, fluorescent signal was observed in the PSCA positive tumors of mice injected with the dual-tracer 124I-A2cDb-800, with low background uptake or autofluorescence in the surrounding tissue. Ex vivo biodistribution confirmed comparable tumor uptake of both 124I-A2cDb-800 and 124I A2cDb. Conclusion: Dual-modality imaging using the anti-PSCA cys-diabody resulted in high-contrast immuno-PET/NIRF images of PDX-PDACs, suggesting that this imaging agent might offer both noninvasive whole-body imaging to localize PSCA positive pancreatic cancer and fluorescence image-guided identification of tumor margins during surgery. PMID- 29602822 TI - 18F-Fluoroestradiol Tumor Uptake Is Heterogeneous and Influenced by Site of Metastasis in Breast Cancer Patients. AB - Heterogeneity of estrogen receptor (ER) expression in breast cancer is recognized. However, knowledge about varying expression across metastases and surrounding normal tissue in patients is scarce. We therefore analyzed 16alpha 18F-fluoro-17beta-estradiol (18F-FES) PET to assess ER expression heterogeneity. Methods:18F-FES PET on accredited PET/CT camera systems performed in patients with ER-positive metastatic breast cancer November 2009-December 2014 was analyzed. Lesions with an SUVmax 1.5 or more were considered ER-positive, but liver lesions were excluded given high background liver signal. CT lesions with a diameter 10 mm or more were included. We used multilevel linear-mixed models to evaluate determinants of 18F-FES uptake. Cluster analysis was performed with different imaging features per patient as input variables. Results: In 91 patients, 1,617 metastases in bone (78%), lymph node (15%), lung (4%), or liver (2%) were identified by CT (11.2%), PET (56.6%), or both (32.2%). Median tumor uptake varied greatly between patients (SUVmax, 0.54-14.21). 18F-FES uptake in bone metastases was higher than in lymph node and lung metastases (geometric mean SUVmax, 2.61 [95% confidence interval (CI), 2.31-2.94] vs. 2.29 [95% CI, 2.00 2.61; P < 0.001] vs. 2.23 [95% CI, 1.88-2.61; P = 0.021]), respectively. Cluster analysis identified 3 subgroups of patients characterized by particular metastatic sites and 18F-FES PET/CT features. SUVmax in surrounding normal tissue, highest in the bones, varied per patient (range, 0.7-3.3). Conclusion:18F FES uptake is heterogeneous in tumor and normal tissue and influenced by anatomic site. Different patterns can be distinguished, possibly identifying biologically relevant ER-positive metastatic breast cancer patient subgroups. PMID- 29602821 TI - A Prospective Comparison of 18F-Sodium Fluoride PET/CT and PSMA-Targeted 18F DCFBC PET/CT in Metastatic Prostate Cancer. AB - The purpose of this study was to compare the diagnostic performance of 18F-DCFBC PET/CT, a first-generation 18F-labeled prostate-specific membrane antigen (PSMA) targeted agent, and 18F-NaF PET/CT, a sensitive marker of osteoblastic activity, in a prospective cohort of patients with metastatic prostate cancer. Methods: Twenty-eight prostate cancer patients with metastatic disease on conventional imaging prospectively received up to 4 PET/CT scans. All patients completed baseline 18F-DCFBC PET/CT and 18F-NaF PET/CT scans, and 23 patients completed follow-up imaging, with a median follow-up interval of 5.7 mo (range, 4.2-12.6 mo). Lesion detection was compared across the 2 PET/CT agents at each time point. Detection and SUV characteristics of each PET/CT agent were compared with serum prostate-specific antigen (PSA) levels and treatment status at the time of baseline imaging using nonparametric statistical testing (Spearman correlation, Wilcoxon rank). Results: Twenty-six patients had metastatic disease detected on 18F-NaF or 18F-DCFBC at baseline, and 2 patients were negative on both scans. Three patients demonstrated soft tissue-only disease. Of 241 lesions detected at baseline, 56 were soft-tissue lesions identified by 18F-DCFBC only and 185 bone lesions detected on 18F-NaF or 18F-DCFBC. 18F-NaF detected significantly more bone lesions than 18F-DCFBC (P < 0.001). Correlation of PSA with patient-level SUV metrics was strong in 18F-DCFBC (rho > 0.5, P < 0.01) and poor in 18F-NaF (rho < 0.3, P > 0.1). When PSA levels were combined with treatment status, patients with below-median levels of PSA (<2 ng/mL) on androgen deprivation therapy (n = 11) demonstrated more lesions on 18F-NaF than 18F-DCFBC (P = 0.02). In PSA greater than 2 ng/mL, patients on androgen deprivation therapy (n = 8) showed equal to or more lesions on 18F-DCFBC than on 18F-NaF. Conclusion: The utility of PSMA-targeting imaging in metastatic prostate cancer appears to depend on patient disease course and treatment status. Compared with 18F-NaF PET/CT, 18F DCFBC PET/CT detected significantly fewer bone lesions in the setting of early or metastatic castrate-sensitive disease on treatment. However, in advanced metastatic castrate-resistant prostate cancer, 18F-DCFBC PET/CT shows good concordance with NaF PET/CT. PMID- 29602824 TI - Inhibiting PTPN12-Regulated RTKs May Be Therapeutic in TNBC. AB - PTPN12 deficiency may confer sensitivity to tyrosine kinase inhibitor combinations in TNBC. PMID- 29602823 TI - Urinary excretion of platinum from South African precious metals refinery workers. AB - BACKGROUND: Urinary platinum (Pt) excretion is a reliable biomarker for occupational Pt exposure and has been previously reported for precious metals refinery workers in Europe but not for South Africa, the world's largest producer of Pt. OBJECTIVE: This study aimed to quantify the urinary Pt excretion of South African precious metals refinery workers. METHODS: Spot urine samples were collected from 40 workers (directly and indirectly exposed to Pt) at two South African precious metals refineries on three consecutive mornings prior to their shifts. Urine samples were analysed for Pt using inductively coupled plasma-mass spectrometry and were corrected for creatinine content. RESULTS: The urinary Pt excretion of workers did not differ significantly between sampling days. Urinary Pt excretions ranged from <0.1 to 3.0 ug Pt/g creatinine with a geometric mean of 0.21 ug Pt/g creatinine (95% CI 0.17 to 0.26 ug Pt/g creatinine). The work area (P=0.0006; eta2=0.567) and the number of years workers were employed at the refineries (P=0.003; eta2=0.261) influenced their urinary Pt excretion according to effect size analyses. Directly exposed workers had significantly higher urinary Pt excretion compared with indirectly exposed workers (P=0.007). CONCLUSION: The urinary Pt excretion of South African precious metals refinery workers reported in this study is comparable with that of seven other studies conducted in precious metals refineries and automotive catalyst plants in Europe. The Pt body burden of workers is predominantly determined by their work area, years of employment in the refineries and whether they are directly or indirectly exposed to Pt. PMID- 29602825 TI - Loss of NF-kappaB1 Promotes Inflammation and Immune Checkpoint Regulators. AB - Polymorphisms that reduce NF-kappaB1 in epithelial and hematopoietic cells promote gastric cancer. PMID- 29602826 TI - Increasing FcgammaR Binding Activity May Enhance Anti-CTLA4 Efficacy. AB - Anti-CTLA4 antibodies induce an FcgammaR-dependent depletion of Tregs to promote tumor rejection. PMID- 29602827 TI - Machine Learning Improves Diagnosis of CNS Cancers. AB - A new machine-learning algorithm that recognizes patterns in genome-wide DNA methylation data can help pathologists classify brain and spinal cord tumors. The diagnostic tool is freely available online, and could prove valuable for histologically ambiguous cases. PMID- 29602828 TI - LHPP Is a Histidine Phosphatase and a Tumor Suppressor. AB - Deregulated histidine phosphorylation may promote tumorigenesis in hepatocellular carcinoma (HCC). PMID- 29602830 TI - 3beta-Methyl-Neurosteroid Analogs Are Preferential Positive Allosteric Modulators and Direct Activators of Extrasynaptic delta-Subunit gamma-Aminobutyric Acid Type A Receptors in the Hippocampus Dentate Gyrus Subfield. AB - Neurosteroids are powerful modulators of gamma-aminobutyric acid (GABA)-A receptors. Ganaxolone (3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one, GX) and synthetic analogs of the neurosteroid allopregnanolone (AP) are designed to treat epilepsy and related conditions. However, their precise mechanism of action in native neurons remains unclear. Here, we sought to determine the mode of action of GX and its analogs at GABA-A receptors in native hippocampal neurons by analyzing extrasynaptic receptor-mediated tonic currents and synaptic receptor mediated phasic currents. Concentration-response profiles of GX were determined in two cell types: delta-containing dentate gyrus granule cells (DGGCs) and gamma2-containing CA1 pyramidal cells (CA1PCs). GX produced significantly greater potentiation of the GABA-A receptor-activated chloride currents in DGGCs (500%) than CA1PCs (200%). In the absence of GABA, GX evoked 2-fold greater inward currents in DGGCs than CA1PCs, which were 2-fold greater than AP within DGGCs. In hippocampus slices, GX potentiated and directly activated tonic currents in DGGCs. These responses were significantly diminished in DGGCs from delta-subunit knockout (deltaKO) mice, confirming GX's selectivity for deltaGABA-A receptors. Like AP, GX potentiation of tonic currents was prevented by protein kinase C inhibition. Furthermore, GX's protection against hippocampus-kindled seizures was significantly diminished in deltaKO mice. GX analogs exhibited greater potency and efficacy than GX on deltaGABA-A receptor-mediated tonic inhibition. In summary, these results provide strong evidence that GX and its analogs are preferential allosteric modulators and direct activators of extrasynaptic deltaGABA-A receptors regulating network inhibition and seizures in the dentate gyrus. Therefore, these findings provide a mechanistic rationale for the clinical use of synthetic neurosteroids in epilepsy and seizure disorders. PMID- 29602831 TI - Bioengineered Noncoding RNAs Selectively Change Cellular miRNome Profiles for Cancer Therapy. AB - Noncoding RNAs (ncRNAs) produced in live cells may better reflect intracellular ncRNAs for research and therapy. Attempts were made to produce biologic ncRNAs, but at low yield or success rate. Here we first report a new ncRNA bioengineering technology using more stable ncRNA carrier (nCAR) containing a pre-miR-34a derivative identified by rational design and experimental validation. This approach offered a remarkable higher level expression (40%-80% of total RNAs) of recombinant ncRNAs in bacteria and gave an 80% success rate (33 of 42 ncRNAs). New FPLC and spin-column based methods were also developed for large- and small scale purification of milligrams and micrograms of recombinant ncRNAs from half liter and milliliters of bacterial culture, respectively. We then used two bioengineered nCAR/miRNAs to demonstrate the selective release of target miRNAs into human cells, which were revealed to be Dicer dependent (miR-34a-5p) or independent (miR-124a-3p), and subsequent changes of miRNome and transcriptome profiles. miRNA enrichment analyses of altered transcriptome confirmed the specificity of nCAR/miRNAs in target gene regulation. Furthermore, nCAR assembled miR-34a-5p and miR-124-3p were active in suppressing human lung carcinoma cell proliferation through modulation of target gene expression (e.g., cMET and CDK6 for miR-34a-5p; STAT3 and ABCC4 for miR-124-3p). In addition, bioengineered miRNA molecules were effective in controlling metastatic lung xenograft progression, as demonstrated by live animal and ex vivo lung tissue bioluminescent imaging as well as histopathological examination. This novel ncRNA bioengineering platform can be easily adapted to produce various ncRNA molecules, and biologic ncRNAs hold the promise as new cancer therapeutics. PMID- 29602832 TI - Intracellular Chloride and Scaffold Protein Mo25 Cooperatively Regulate Transepithelial Ion Transport through WNK Signaling in the Malpighian Tubule. AB - Background With No Lysine kinase (WNK) signaling regulates mammalian renal epithelial ion transport to maintain electrolyte and BP homeostasis. Our previous studies showed a conserved role for WNK in the regulation of transepithelial ion transport in the Drosophila Malpighian tubule.Methods Using in vitro assays and transgenic Drosophila lines, we examined two potential WNK regulators, chloride ion and the scaffold protein mouse protein 25 (Mo25), in the stimulation of transepithelial ion flux.ResultsIn vitro, autophosphorylation of purified Drosophila WNK decreased as chloride concentration increased. In conditions in which tubule intracellular chloride concentration decreased from 30 to 15 mM as measured using a transgenic sensor, Drosophila WNK activity acutely increased. Drosophila WNK activity in tubules also increased or decreased when bath potassium concentration decreased or increased, respectively. However, a mutation that reduces chloride sensitivity of Drosophila WNK failed to alter transepithelial ion transport in 30 mM chloride. We, therefore, examined a role for Mo25. In in vitro kinase assays, Drosophila Mo25 enhanced the activity of the Drosophila WNK downstream kinase Fray, the fly homolog of mammalian Ste20-related proline/alanine-rich kinase (SPAK), and oxidative stress-responsive 1 protein (OSR1). Knockdown of Drosophila Mo25 in the Malpighian tubule decreased transepithelial ion flux under stimulated but not basal conditions. Finally, whereas overexpression of wild-type Drosophila WNK, with or without Drosophila Mo25, did not affect transepithelial ion transport, Drosophila Mo25 overexpressed with chloride-insensitive Drosophila WNK increased ion flux.Conclusions Cooperative interactions between chloride and Mo25 regulate WNK signaling in a transporting renal epithelium. PMID- 29602833 TI - Post-Transplant Natural Antibodies Associate with Kidney Allograft Injury and Reduced Long-Term Survival. AB - Background The development of antibodies specific to HLA expressed on donor tissue (donor-specific antibodies [DSAs]) is a prominent risk factor for kidney graft loss. Non-HLA antibodies with pathogenic potential have also been described, including natural antibodies (Nabs). These IgG Nabs bind to immunogenic self-determinants, including oxidation-related antigens.Methods To examine the relationship of Nabs with graft outcomes, we assessed Nabs in blinded serum specimens collected from a retrospective cohort of 635 patients who received a transplant between 2005 and 2010 at Necker Hospital in Paris, France. Serum samples were obtained immediately before transplant and at the time of biopsy-proven rejection within the first year or 1 year after transplant. Nabs were detected by ELISA through reactivity to the generic oxidized epitope malondialdehyde.Results Univariate Cox regression analysis identified the development of post-transplant Nabs (defined as 50% increase in reactivity to malondialdehyde) as a significant risk factor for graft loss (hazard ratio, 2.68; 95% confidence interval, 1.49 to 4.82; P=0.001). Post-transplant Nabs also correlated with increased mean Banff scores for histologic signs of graft injury in post-transplant biopsy specimens. Multivariable Cox analyses confirmed Nabs development as a risk factor independent from anti-HLA DSAs (hazard ratio, 2.07; 95% confidence interval, 1.03 to 4.17; P=0.04). Moreover, patients with Nabs and DSAs had a further increased risk of kidney graft loss.Conclusions These findings reveal an association between Nabs, kidney graft injury, and eventual graft failure, suggesting the involvement of Nabs in immune mechanisms of rejection. PMID- 29602834 TI - Nephrin-Binding Ephrin-B1 at the Slit Diaphragm Controls Podocyte Function through the JNK Pathway. AB - Background B-type ephrins are membrane-bound proteins that maintain tissue function in several organs. We previously reported that ephrin-B1 is localized at the slit diaphragm of glomerular podocytes. However, the function of ephrin-B1 at this location is unclear.Methods We analyzed the phenotype of podocyte-specific ephrin-B1 knockout mice and assessed the molecular association of ephrin-B1 and nephrin, a key molecule of the slit diaphragm, in HEK293 cells and rats with anti nephrin antibody-induced nephropathy.Results Compared with controls, ephrin-B1 conditional knockout mice displayed altered podocyte morphology, disarrangement of the slit diaphragm molecules, and proteinuria. Ephrin-B1 expressed in HEK293 cells immunoprecipitated with nephrin, which required the basal regions of the extracellular domains of both proteins. Treatment of cells with an anti-nephrin antibody promoted the phosphorylation of nephrin and ephrin-B1. However, phosphorylation of ephrin-B1 did not occur in cells expressing a mutant nephrin lacking the ephrin-B1 binding site or in cells treated with an Src kinase inhibitor. The phosphorylation of ephrin-B1 enhanced the phosphorylation of nephrin and promoted the phosphorylation of c-Jun N-terminal kinase (JNK), which was required for ephrin-B1-promoted cell motility in wound-healing assays. Notably, phosphorylated JNK was detected in the glomeruli of control mice but not ephrin-B1 conditional knockout mice. In rats, the phosphorylation of ephrin-B1, JNK, and nephrin occurred in the early phase (24 hours) of anti-nephrin antibody induced nephropathy.Conclusions Through interactions with nephrin, ephrin-B1 maintains the structure and barrier function of the slit diaphragm. Moreover, phosphorylation of ephrin-B1 and, consequently, JNK are involved in the development of podocyte injury. PMID- 29602835 TI - Assessing the health effects associated with occupational radiation exposure in Korean radiation workers: protocol for a prospective cohort study. AB - INTRODUCTION: The cancer risk of radiation exposure in the moderate-to-high dose range has been well established. However, the risk remains unclear at low-dose ranges with protracted low-dose rate exposure, which is typical of occupational exposure. Several epidemiological studies of Korean radiation workers have been conducted, but the data were analysed retrospectively in most cases. Moreover, groups with relatively high exposure, such as industrial radiographers, have been neglected. Therefore, we have launched a prospective cohort study of all Korean radiation workers to assess the health effects associated with occupational radiation exposure. METHODS AND ANALYSIS: Approximately 42 000 Korean radiation workers registered with the Nuclear Safety and Security Commission from 2016 to 2017 are the initial target population of this study. Cohort participants are to be enrolled through a nationwide self-administered questionnaire survey between 24 May 2016 and 30 June 2017. As of 31 March 2017, 22 982 workers are enrolled in the study corresponding to a response rate of 75%. This enrolment will be continued at 5-year intervals to update information on existing study participants and recruit newly hired workers. Survey data will be linked with the national dose registry, the national cancer registry, the national vital statistics registry and national health insurance data via personal identification numbers. Age-specific and sex-specific standardised incidence and mortality ratios will be calculated for overall comparisons of cancer risk. For dose-response assessment, excess relative risk (per Gy) and excess absolute risk (per Gy) will be estimated with adjustments for birth year and potential confounders, such as lifestyle factors and socioeconomic status. ETHICS AND DISSEMINATION: This study has received ethical approval from the institutional review board of the Korea Institute of Radiological and Medical Sciences (IRB No. K-1603-002-034). All participants provided written informed consent prior to enrolment. The findings of the study will be disseminated through scientific peer reviewed journals and be provided to the public, including radiation workers, via the study website (http://www.rhs.kr/) and onsite radiation safety education. PMID- 29602836 TI - Distribution and predictors of hospital charges for haemorrhagic stroke patients in Beijing, China, March 2012 to February 2015: a retrospective study. AB - OBJECTIVES: The purpose of this study is to analyse hospital charges for patients with haemorrhagic stroke in China and investigate potential factors associated with inpatient charges. METHODS: The study participants were in-hospital patients with a primary diagnosis of haemorrhagic stroke from all the secondary and tertiary hospitals in Beijing during the period from 1 March 2012 to 28 February 2015. Distribution characteristics of detailed hospital charges were analysed. The influence of potential factors on hospital charges was researched using a stepwise multiple regression model. RESULTS: A total of 34 890 patients with haemorrhagic stroke of mean age 61.19+/-14.37 years were included in the study, of which 37.2% were female. Median length of hospital stay (LOHS) was 15 days (IQR 9-23) and median hospital cost was 18 577 Chinese yuan (CNY) (IQR 10 442-39 784). The hospital costs for patients in Western medicine hospitals (median 19 651 CNY) were significantly higher (P<0.01) than those in traditional Chinese medicine hospitals (median 14 560 CNY), and were significantly higher (P<0.01) for Level 3 hospitals (median 20 029 CNY) than for Level 2 hospitals (median 16 095 CNY). The proportion of medicine fees and bed fees within total hospital charges showed a decreasing trend during the study period. With stepwise multiple regression, the major factors associated with hospital charges were LOHS, surgery, pulmonary infection, ventilator usage, hospital level, occupation, hyperlipidaemia, hospital type, in-hospital death, sex and age. CONCLUSION: We conclude that medicines form the largest part of hospital charges but are showing a decreasing trend, and LOHS is strongly associated with patient charges for haemorrhagic stroke in China. This implies that the cost structure is very unreasonable in China and medical technology costs fail to be fully manifested. A reasonable decrease in medicine charges and shortening LOHS may be effective ways to reduce hospital charges. PMID- 29602837 TI - Trends in initiation of direct oral anticoagulant therapies for atrial fibrillation in a national population-based cross-sectional study in the French health insurance databases. AB - OBJECTIVE: Unlike several other national health agencies, French health authorities recommended that the newer direct oral anticoagulant (DOAC) agents only be prescribed as second choice for the treatment of newly diagnosed non valvular atrial fibrillation (NVAF), with vitamin K antagonists (VKA) remaining the first choice. We investigated the patterns of use of DOACs versus VKA in the treatment of NVAF in France over the first 5 years of DOAC availability. We also identified the changes in patient characteristics of those who initiated DOAC treatment over this time period. METHODS: Based on the French National Health Administrative Database, we constituted a population-based cohort of all patients who were newly treated for NVAF between January 2011 and December 2015. Trends in drug use were described as the percentage of patients initiating each drug at the time of treatment initiation. A multivariate analysis using logistic regression model was performed to identify independent sociodemographic and clinical predictors of initial anticoagulant choice. RESULTS: The cohort comprised 814 446 patients who had received a new anticoagulant treatment for NVAF. The proportion of patients using DOACs as initial anticoagulant therapy reached 54% 3 months after the Health Ministry approved the reimbursement of dabigatran for NVAF, and 61% by the end of 2015, versus VKA use. In the multivariate analysis, we found that DOAC initiators were younger and healthier overall than VKA initiators, and this tendency was reinforced over the 2011-2014 period. DOACs were more frequently prescribed by cardiologists in 2012 and after (adjusted OR in 2012: 2.47; 95% CI 2.40 to 2.54). CONCLUSION: Despite recommendations from health authorities, DOACs have been rapidly and massively adopted as initial therapy for NVAF in France. Observational studies should account for the fact that patients selected to initiate DOAC treatment are healthier overall, as failure to do so may bias the risk-benefit assessment of DOACs. PMID- 29602838 TI - Measuring quality of life of people with predementia and dementia and their caregivers: a systematic review protocol. AB - INTRODUCTION: Dementia is the fastest growing major cause of disability globally and may have a profound impact on the health-related quality of life (HRQoL) of both the patient with dementia and those who care for them. This review aims to systematically identify and synthesise the measurements of HRQoL for people with, and their caregivers across the full spectrum of, dementia from its preceding stage of predementia to end of life. METHODS AND ANALYSIS: A systematic literature review was conducted in Medical Literature Analysis and Retrieval System Online , ExcerptaMedicadataBASE, Cochrane Database of Systematic Reviews , Cochrane Central Register of Controlled Trials, Database of Abstracts of Reviews of Effect, National Health Service Economic Evaluation Database and PsycINFO between January 1990 and the end of April 2017. Two reviewers will independently assess each study for inclusion and disagreements will be resolved by a third reviewer. Data will be extracted using a predefined data extraction form following best practice. Study quality will be assessed with the Effective Public Health Practice Project quality assessment tool. HRQoL measurements will be presented separately for people with dementia and caregivers by instrument used and, when possible, HRQoL will be reported by disease type and stage of the disease. Descriptive statistics of the results will be provided. A narrative synthesis of studies will also be provided discussing differences in HRQoL measurements by instrument used to estimate it, type of dementia and disease severity. ETHICS AND DISSEMINATION: This systematic literature review is exempt from ethics approval because the work is carried out on published documents. The findings of the review will be disseminated in a related peer-reviewed journal and presented at conferences. They will also contribute to the work developed in the Real World Outcomes across the Alzheimer's disease spectrum for better care: multimodal data access platform (ROADMAP). TRIAL REGISTRATION NUMBER: CRD42017071416. PMID- 29602839 TI - Association of allergic diseases with children's life satisfaction: population based study in Finland. AB - OBJECTIVE: To assess the impact of allergic diseases on the subjective well-being and life satisfaction of primary-school children. DESIGN: Population-based cohort. SETTING: Finnish sample of children ages 10 and 12 from the International Survey of Children's Well-Being. PARTICIPANTS: Nationally representative sample of 1947 school children. MAIN OUTCOME MEASURE: Two different instruments to assess the child's own perception of well-being, the short version of the Student Life Satisfaction Scale (SLSS) and the Brief Multidimensional Student Life Satisfaction Scale (BMSLSS). RESULTS: Altogether, 51.4% of children reported having at least one allergic condition (10.1% asthma, 23.8% eczema and 40.3% seasonal allergic rhinitis). A statistically significant distinction in life satisfaction emerged between non-allergic and allergic children (inferior in the latter). In particular, children with eczema were more likely to report a reduction in life satisfaction compared with non-allergic children (SLSS beta= 128.220; BMSLSS beta=-90.694; p<0.01). Apart from freedom from eczema, good life satisfaction was associated with a physically active lifestyle. CONCLUSIONS: Active allergic disease reduces the child's own perception of well-being. During clinical visits, more attention should be paid to the child's psychosocial status and impairments, which may differ substantially from those of parents or medical authorities. PMID- 29602840 TI - Vitamin D, obesity and leptin in relation to bladder cancer incidence and survival: prospective protocol study. AB - INTRODUCTION: Bladder cancer (BC) (including renal pelvis, ureter and urethra) is one of the most common urogenital cancers and the fourth most frequent cancer in men in the USA. In Norway, the incidence of BC has increased over the last decades. The age-standardised incidence rates per 100 000 for 2011-2015 were 53.7 in men and 16.5 in women. Compared to the 5-year period 2006-2010, the percentage increase in incidence was 6.1% in men and 12.3% in women. The recurrence rate of BC is over 50%, the highest recurrence rate of any malignancy. Smoking and occupational exposure to aromatic amines are recognised as the major risk factors. Recently, low-serum level of 25-hydroxy vitamin D (25(OH)D) and obesity have been suggested to increase the BC risk, and leptin, which is important in weight regulation, may be involved in bladder carcinogenesis. More knowledge on potential risk factors for BC is necessary for planning and implementing primary prevention measures. METHODS AND ANALYSES: Cohort and nested case-control studies will be carried out using the population-based Janus Serum Bank Cohort consisting of prediagnostic sera, clinical measurement data (body height and weight, body surface area and weight change over time, blood pressure, cholesterol and triglycerides) and self-reported information on lifestyle factors (smoking, physical activity). Participants were followed from cohort inclusion (1972-2003) through 2014. The cohort will be linked to the Cancer Registry of Norway (cancer data), the National Cause of Death Registry (date and cause of death), National Population Registry (vital status) and Statistic Norway (education and occupation). Serum samples will be analysed for 25(OH)D, vitamin D binding protein, leptin, albumin, calcium and parathyroid hormone. Cox regression and conditional logistic regression models and mediation analysis will be used to estimate association between the exposures and BC. ETHICS AND DISSEMINATION: The study has been approved by the Regional Committee for Medical Research Ethics and is funded by the Norwegian Cancer Society. Results will be published in peer reviewed journals, at scientific conferences and through press releases. PMID- 29602841 TI - Effect of levosimendan on mortality in severe sepsis and septic shock: a meta analysis of randomised trials. AB - OBJECTIVE: We aim to synthesise up-to-date randomised trials to investigate the effects of levosimendan on mortality and clinical outcomes in severe sepsis and septic shock. METHODS: A collection of databases including PubMed, EMBASE, Cochrane Central Register and Web of Science were searched updated to August 2017. Randomised trials were included when they pertain to the use of levosimendan in severe sepsis or septic shock compared with any category of inotropes, or as an adjunct to standard therapy with mortality reported. The primary outcome was mortality, and the secondary outcomes were clinical performances including serum lactate, cardiac function, vasopressor requirement and fluid infusion. RESULTS: A total of 10 studies with 1036 patients were included in this meta-analysis. The results revealed that levosimendan could not reduce mortality significantly in severe sepsis and septic shock (OR 0.89, 95% CI 0.69 to 1.16, P=0.39). Levosimendan use could reduce serum lactate more effectively, and enhance cardiac contractibility with increased cardiac index and left ventricular ejection fraction. However, its use could also increase fluid infusion but not reduce norepinephrine dose. No significant benefit in mortality could be observed of levosimendan versus dobutamine use, or in patients with proven cardiac dysfunction. CONCLUSIONS: Current evidence is not sufficient to support levosimendan as superior to dobutamine or as an optimal adjunct in severe sepsis and septic shock. More large-scale randomised trials are necessary to validate levosimendan use in sepsis. PMID- 29602842 TI - Hyponatraemia, hyperglycaemia and worsening renal function at first blood sample on emergency department admission as predictors of in-hospital death in patients with dyspnoea with suspected acute heart failure: retrospective observational analysis of the PARADISE cohort. AB - OBJECTIVES: To assess the prognostic value of hyponatraemia, hyperglycaemia and impaired estimated glomerular filtration rate (eGFR) in predicting in-hospital death in patients with acute heart failure (AHF) admitted for acute dyspnoea in the emergency department. DESIGN: Retrospective observational study. SETTING: Emergency Department of the University Hospital of Nancy. Data were collected from August 2013 to October 2015. PARTICIPANTS: The analysis included 405 patients with AHF admitted for acute dyspnoea in an emergency department. RESULTS: The population was elderly (mean age 82 years), 20.1% had hyponatraemia, 45.1% had hyperglycaemia and 48.6% had eGFR <50 mL/min/1.73 m2. Sixty-one patients (15.1%) died in hospital, mostly due to cardiac aetiology (58.3%). In multivariable analysis adjusted for key potential confounders, adjusted hyponatraemia (OR=2.40, (1.16 to 4.98), p=0.02), hyperglycaemia (OR=2.00, 1.06 to 3.76, p=0.03) and eGFR <50 mL/min/1.73 m2 (OR=1.97 (1.00 to 3.80), p=0.04*) were all identified as significant independent predictors of in-hospital death. CONCLUSIONS: Results of basic routine laboratory tests (hyponatraemia, hyperglycaemia and impaired eGFR) performed on admission in the emergency department are independently associated with in-hospital death. These inexpensive tests, performed as early as patient admission in the emergency department, could allow the early identification of patients admitted for AHF who are at high risk of in-hospital death. TRIAL REGISTRATION NUMBER: NCT02800122. PMID- 29602843 TI - Dementia and vagotomy in Taiwan: a population-based cohort study. AB - OBJECTIVE: Truncal vagotomy is associated with a decreased risk of subsequent Parkinson disease (PD), although the effect of vagotomy on dementia is unclear. In response, we investigated the risk of dementia in patients who underwent vagotomy. SETTING: Population-based cohort study. PARTICIPANTS: A total of 155 944 patients who underwent vagotomy (vagotomy cohort) and 155 944 age-matched, sex-matched and comorbidity-matched controls (non-vagotomy cohort) were identified between 2000 and 2011. PRIMARY AND SECONDARY OUTCOME MEASURES: All patient data were tracked until the diagnosis of dementia, death or the end of 2011. The cumulative incidence of subsequent dementia and HRs were calculated. RESULTS: The mean ages of the study patients in the vagotomy and non-vagotomy cohorts were 56.6+/-17.4 and 56.7+/-17.3 years, respectively. The overall incidence density rate for dementia was similar in the vagotomy and non-vagotomy cohorts (2.43 and 2.84 per 1000 person-years, respectively). After adjustment for age, sex and comorbidities such as diabetes, hypertension, hyperlipidaemia, stroke, depression, coronary artery disease and PD, the patients in the vagotomy cohort were determined to not be at a higher risk of dementia than those in the non-vagotomy cohort (adjusted HR=1.09, 95% CI 0.87 to 1.36). Moreover, the patients who underwent truncal vagotomy were not associated with risk of dementia (adjusted HR=1.04, 95% CI 0.87 to 1.25), compared with the patients who did not undergo vagotomy. CONCLUSION: Vagotomy, either truncal or selective, is not associated with risk of dementia. PMID- 29602844 TI - Impact of gestational weight gain and prepregnancy body mass index on the prevalence of large-for-gestational age infants in two cohorts of women with type 1 insulin-dependent diabetes: a cross-sectional population study. AB - OBJECTIVES: Despite improvements in treatment modalities, large-for-gestational age (LGA) prevalence has remained between 30% and 40% among infants of mothers with type 1 insulin-dependent diabetes mellitus (TIDM). Our objective was to estimate LGA prevalence and examine the association between gestational weight gain (GWG) and prepregnancy body mass index (BMI) with LGA among mothers with TIDM. DESIGN: Cross-sectional study. SETTING: Regional data in Cincinnati, Ohio, from the Diabetes in Pregnancy Program Project (PPG), a prospective cohort for the period 1978-1993; national data from Consortium on Safe Labor (CSL), a multicentre cross-sectional study for the period 2002-2008. PARTICIPANTS: The study included 333 pregnancies in the PPG and 358 pregnancies in the CSL. Pregnancies delivered prior to 23 weeks' gestation were excluded. Women with TIDM in the PPG were identified according to physician confirmation of ketoacidosis, and/or c-peptide levels, and by International Classification of Diseases, ninth version codes within the CSL. LGA was identified as birth weight >90th percentile according to gestational age, race and sex. MAIN OUTCOME MEASURES: LGA at birth. RESULTS: Mean+/-SD maternal age at delivery was 26.4+/-5.1 years for PPG women and 27.5+/-6.0 years for CSL women, p=0.008. LGA prevalence did not significantly differ between cohorts (PPG: 40.2% vs CSL: 36.6%, p=0.32). More women began pregnancy as overweight in the later cohort (PPG (16.8%) vs CSL (27.1%), p<0.001). GWG exceeding Institute of Medicine (IOM) guidelines was higher in the later CSL (56.2%) vs PPG (42.3%) cohort, p<0.001. Normal-weight women with GWG within IOM guidelines had a lower LGA prevalence in CSL (PPG: 30.6% vs CSL: 13.7%), p=0.001. CONCLUSIONS: Normal-weight women with GWG within IOM guidelines experienced a lower LGA prevalence, supporting the importance of adherence to IOM guidelines for GWG to reduce LGA. High BMI and GWG may be hindering a reduction in LGA prevalence. PMID- 29602845 TI - Dentists' intention to report suspected violence: a cross-sectional study in eight Arab countries. AB - OBJECTIVES: This study assessed dentists' intention in eight Arab countries to report suspected exposure to violence among patients and factors associated with this intention based on the theory of planned behaviour. METHODS: A cross sectional study was conducted in 2016 including a convenience sample of dentists practising in public, private and academic sectors in Algeria, Egypt, Jordan, Kuwait, Libya, Palestine, Saudi Arabia and Yemen. Respondents answered a self administered questionnaire collecting information about personal and professional background and perceived ability to identify victims of violence. The questionnaire assessed (on a scale from 1 to 10 using six negative statements) dentists' perception of healthcare system mandated reporting of suspected violence. Six statements were used to assess professional attitude towards reporting suspected violence. Logistic regression was used to assess the association between intention to report suspected violence and perceived ability, perception and attitude adjusting for confounders. RESULTS: The response rate was 65.2% (n=2936/4506) from general practitioners (70.9%) of mean age=31 years with 56.7% women. Of those, 68.8% intended to report and 52.2% considered themselves able to identify violence victims. The mean (SD) negative perception score=5.3/10 (2.1) and the mean (SD) professional attitude score=7.5/10 (1.9). In multivariate regression, intention to report was associated with professional attitude (OR 1.08, 95% CI 1.03 to 1.14), ability to identify violence victims (OR 1.76, 95% CI 1.45 to 2.12) and negative perception that reporting is not mandated (OR 0.89, 95% CI 0.85 to 0.94). Significant differences existed among countries in intention to report. CONCLUSION: Most dentists intended to report suspected violence and their intention could be explained by the theory of planned behaviour which offers a framework for professional development to support violence victims. Sharing of training resources, policies and guidelines is needed to ensure that practices similar to international guidelines are consistently adopted by dentists across Arab countries. PMID- 29602846 TI - Protocol to assess the impact of tobacco-induced volatile organic compounds on cardiovascular risk in a cross- sectional cohort: Cardiovascular Injury due to Tobacco Use study. AB - INTRODUCTION: Tobacco use leads to increased mortality, the majority of which is attributed to cardiovascular disease. Despite this knowledge, the early cardiovascular impact of tobacco product use is not well understood. Tobacco use increases exposure to harmful and potentially harmful constituents including volatile organic compounds (VOCs) such as acrolein and crotonaldehyde, which may contribute to cardiovascular risk. The link between exposure patterns, risk profiles and demographic distribution of tobacco product users, particularly users of new and emerging products, are not well known. Therefore, we designed the Cardiovascular Injury due to Tobacco Use (CITU) study to assess population characteristics, demographic features, exposure patterns and cardiovascular risk in relation to tobacco. METHODS AND ANALYSIS: We present the design and methodology of the CITU study, a cross-sectional observational tobacco study conducted in Boston, Massachusetts and Louisville, Kentucky starting in 2014. Healthy participants 21-45 years of age who use tobacco products, including electronic nicotine devices, or who never used tobacco are being recruited. The study aims to recruit an evenly split cohort of African-Americans and Caucasians, that is, sex balanced for evaluation of self-reported tobacco exposure, VOC exposure and tobacco-induced injury profiling. Detailed information about participant's demographics, health status and lifestyle is also collected. ETHICS AND DISSEMINATION: The study protocol was approved institutional review boards at both participating universities. All study protocols will protect participant confidentiality. Results from the study will be disseminated via peer-reviewed journals and presented at scientific conferences. PMID- 29602847 TI - Protocol for the mixed-methods process and context evaluation of the TB & Tobacco randomised controlled trial in Bangladesh and Pakistan: a hybrid effectiveness implementation study. AB - INTRODUCTION: Tuberculosis (TB) remains a significant public health problem in South Asia. Tobacco use increases the risks of TB infection and TB progression. The TB& Tobacco placebo-controlled randomised trial aims to (1) assess the effectiveness of the tobacco cessation medication cytisine versus placebo when combined with behavioural support and (2) implement tobacco cessation medication and behavioural support as part of general TB care in Bangladesh and Pakistan. This paper summarises the process and context evaluation protocol embedded in the effectiveness-implementation hybrid design. METHODS AND ANALYSIS: We are conducting a mixed-methods process and context evaluation informed by an intervention logic model that draws on the UK Medical Research Council's Process Evaluation Guidance. Our approach includes quantitative and qualitative data collection on context, recruitment, reach, dose delivered, dose received and fidelity. Quantitative data include patient characteristics, reach of recruitment among eligible patients, routine trial data on dose delivered and dose received, and a COM-B ('capability', 'opportunity', 'motivation' and 'behaviour') questionnaire filled in by participating health workers. Qualitative data include semistructured interviews with TB health workers and patients, and with policy makers at district and central levels in each country. Interviews will be analysed using the framework approach. The behavioural intervention delivery is audio recorded and assessed using a predefined fidelity coding index based on behavioural change technique taxonomy. ETHICS AND DISSEMINATION: The study complies with the guidelines of the Declaration of Helsinki. Ethics approval for the study and process evaluation was granted by the University of Leeds (qualitative components), University of York (trial data and fidelity assessment), Bangladesh Medical Research Council and Bangladesh Drug Administration (trial data and qualitative components) and Pakistan Medical Research Council (trial data and qualitative components). Results of this research will be disseminated through reports to stakeholders and peer-reviewed publications and conference presentations. TRIAL REGISTRATION NUMBER: ISRCTN43811467; Pre-results. PMID- 29602848 TI - Online stroke forum as source of data for qualitative research: insights from a comparison with patients' interviews. AB - OBJECTIVE: To determine the appropriateness of an online forum compared with face to-face interviews as a source of data for qualitative research on adherence to secondary prevention medications after stroke. DESIGN: A comparison of attributes of two data sources, interviews and a forum, using realistic evaluation; a comparison of themes around adherence according to the Perceptions and Practicalities Approach (PAPA) framework. SETTING: Interviews were conducted in UK GP practices in 2013 and 2014; online posts were written by UK stroke survivors and family members taking part in the online forum of the Stroke Association between 2004 and 2011. PARTICIPANTS: 42 interview participants: 28 stroke survivors (age range 61-92 years) and 14 caregivers (85% spouses). 84 online forum participants: 49 stroke survivors (age range 32-72 years) and 33 caregivers (60% sons/daughters). RESULTS: 10 attributes were identified within the two data sources and categorised under three domains (context, mechanisms and outcomes). Participants' characteristics of forum users were often missing. Most forum participants had experienced a stroke within the previous 12 months, while interviewees had done so 1-5 years previously.All interview themes could be matched with corresponding themes from the forum. The forum yielded three additional themes: influence of bad press on taking statins, criticisms of clinicians' prescribing practices and caregiver burden in assisting with medications and being advocates for survivors with healthcare professionals. CONCLUSIONS: An online forum is an appropriate source of data for qualitative research on patients' and caregivers' issues with adherence to secondary prevention stroke medications and may offer additional insights compared with interviews, which can be attributed to differences in the approach to data collection. PMID- 29602849 TI - A cross-sectional survey of physical strains among offshore wind farm workers in the German exclusive economic zone. AB - OBJECTIVES: To assess the physical strains of employees in the German offshore wind industry, according to job type and phase of the wind farm (under construction or operation). DESIGN: Web-based cross-sectional survey. SETTING: Offshore wind farm companies operating within the German exclusive economic zone. PARTICIPANTS: Male workers with regular offshore commitments and at least 28 days spent offshore in the past year (n=268). OUTCOME MEASURES: Physical strains (eg, climbing, noise, working overhead, with twisted upper body or in confined spaces, vibration, heavy lifting, humidity, odours). RESULTS: The most frequently mentioned physical strain was 'climbing' with 63.8% of the respondents reporting to be always or frequently confronted with climbing and ascending stairs during offshore work. Work as a technician was associated with a greater exposition to noise, vibrations, humidity, cold, heat, chemical substances, lifting/carrying heavy loads, transport of equipment, working in non-ergonomic positions and in cramped spaces, as well as climbing.Indeed, statistical analyses showed that, after adjusting for phase of the wind farm, age, nationality, offshore experience, work schedule and type of shift, compared with non-technicians, working as a technician was associated with more frequently lifting/carrying of heavy loads (OR 2.58, 95% CI 1.58 to 4.23), transport of equipment (OR 2.06 95% CI 1.27 to 3.33), working with a twisted upper body (OR 2.85 95% CI 1.74 to 4.69), working overhead (OR 2.77 95% CI 1.67 to 4.58) and climbing (OR 2.30 95% CI 1.40 to 3.77). Working in wind farms under construction was strongly associated with increased and decreased exposure to humidity (OR 2.32 95% CI 1.38 to 3.92) and poor air quality (OR 0.58 95% CI 0.35 to 0.95), respectively. CONCLUSIONS: Workers on offshore wind farms constitute a heterogeneous group, including a wide variety of occupations. The degree of exposure to detrimental physical strains varies depending on the type of job. Technicians are more exposed to ergonomic challenges than other offshore workers. PMID- 29602850 TI - Thyroid disorders and breast cancer risk in Asian population: a nationwide population-based case-control study in Taiwan. AB - OBJECTIVE: To evaluate whether hyperthyroidism or hypothyroidism increases the risk of subsequent breast cancer in an Asian population. DESIGN: Nationwide population-based case-control study. SETTING: All healthcare facilities in Taiwan. PARTICIPANTS: A total of 103 466 women (mean age 53.3 years) were enrolled. METHODS: 51 733 adult women with newly diagnosed primary breast cancer without a previous cancer history between 2006 and 2011 were identified and included in our study. 51 733 women with no cancer diagnosis prior to the index date were age matched as controls. Diagnosis of hyperthyroidism or hypothyroidism prior to the diagnosis of breast cancer or the same index date was identified, age, histories of thyroid disease treatment, oestrogen use and radioactive iodine treatment were adjusted. MAIN OUTCOME MEASURES: To identify risk differences in developing breast cancer among patients with a medical history of hyperthyroidism or hypothyroidism. RESULTS: There was a significantly increased risk of breast cancer in women with hyperthyroidism under the age of 55 years (age <45: OR 1.16, P=0.049; age 45-55: OR 1.15, P=0.019). Patients with hypothyroidism also showed an increased risk of breast cancer (OR 1.19, P=0.029) without statistical significance after stratification by age group (age <45, 45-55, >55 years). Treatment for thyroid disorders did not alter the association in subgroup analyses (P=0.857; 0.262, respectively). CONCLUSIONS: Asian women under 55 years of age with history of hyperthyroidism have a significantly increased risk of breast cancer regardless of treatment. Women with history of hypothyroidism may also have an increased risk. PMID- 29602851 TI - Patient perspectives on the HIV continuum of care in London: a qualitative study of people diagnosed between 1986 and 2014. AB - OBJECTIVES: To describe the experiences of the HIV treatment cascade of diagnosis, engagement with care and initiation of treatment from the perspective of patients; we explored whether this differed according to the year of their diagnosis, for example, whether they had experienced HIV care in the pretreatment era. DESIGN: Qualitative interview study with framework analysis. SETTING: Two large HIV adult outpatient clinics in central London. PARTICIPANTS: 52 HIV positive individuals, 41 men, 11 women, purposively sampled to include people who had been diagnosed at different stages in the history of the epidemic classified as four 'generations': pre-1996 (preantiretroviral therapy (ART)), 1997-2005 (complex ARTs), 2006-2012 (simpler ARTs) and 2013 onwards (recent diagnoses). RESULTS: Some important differences were identified; for earlier generations, the visible illness and deaths from AIDS made it harder to engage with care following diagnosis. Subsequent decisions about starting treatment were deeply influenced by the fear of severe side effects from early ART. However, despite improvements in ART and life expectancy over the epidemic, we found a striking similarity across participants' accounts of the key stages of the care continuum, regardless of when they were diagnosed. Diagnosis was a major traumatic life event for almost everyone. Fear of testing positive or having low self-perceived risk affected the timing of testing and diagnosis. Engaging with care was facilitated by a flexible approach from services/clinicians. Initiating treatment was a major life decision. CONCLUSION: We found patients' experiences are influenced by when they were diagnosed, with earliest cohorts facing substantial challenges. However, being diagnosed with HIV and starting treatment continue to be significant life-altering events even in the era of effective, simple treatments. Despite the advances of biomedical treatment, services should continue to recognise the needs of patients for whom the diagnosis and treatment remain significant challenges. PMID- 29602852 TI - Factors associated with 30-day readmission after hospitalisation for community acquired pneumonia in older patients: a cross-sectional study in seven Spanish regions. AB - OBJECTIVE: Hospital readmission in patients admitted for community-acquired pneumonia (CAP) is frequent in the elderly and patients with multiple comorbidities, resulting in a clinical and economic burden. The aim of this study was to determine factors associated with 30-day readmission in patients with CAP. DESIGN: A cross-sectional study. SETTING: The study was conducted in patients admitted to 20 hospitals in seven Spanish regions during two influenza seasons (2013-2014 and 2014-2015). PARTICIPANTS: We included patients aged >=65 years admitted through the emergency department with a diagnosis compatible with CAP. Patients who died during the initial hospitalisation and those hospitalised more than 30 days were excluded. Finally, 1756 CAP cases were included and of these, 200 (11.39%) were readmitted. MAIN OUTCOME MEASURES: 30-day readmission. RESULTS: Factors associated with 30-day readmission were living with a person aged <15 years (adjusted OR (aOR) 2.10, 95% CI 1.01 to 4.41), >3 hospital visits during the 90 previous days (aOR 1.53, 95% CI 1.01 to 2.34), chronic respiratory failure (aOR 1.74, 95% CI 1.24 to 2.45), heart failure (aOR 1.69, 95% CI 1.21 to 2.35), chronic liver disease (aOR 2.27, 95% CI 1.20 to 4.31) and discharge to home with home healthcare (aOR 5.61, 95% CI 1.70 to 18.50). No associations were found with pneumococcal or seasonal influenza vaccination in any of the three previous seasons. CONCLUSIONS: This study shows that 11.39% of patients aged >=65 years initially hospitalised for CAP were readmitted within 30 days after discharge. Rehospitalisation was associated with preventable and non-preventable factors. PMID- 29602853 TI - Association between refill adherence to lipid-lowering medications and the risk of cardiovascular disease and mortality in Swedish patients with type 2 diabetes mellitus: a nationwide cohort study. AB - OBJECTIVES: To analyse the association between refill adherence to lipid-lowering medications, and the risk of cardiovascular disease (CVD) and mortality in patients with type 2 diabetes mellitus. DESIGN: Cohort study. SETTING: National population-based cohort of Swedish patients with type 2 diabetes mellitus. PARTICIPANTS: 86 568 patients aged >=18 years, registered with type 2 diabetes mellitus in the Swedish National Diabetes Register, who filled at least one prescription for lipid-lowering medication use during 2007-2010, 87% for primary prevention. EXPOSURE AND OUTCOME MEASURES: Refill adherence of implementation was assessed using the medication possession ratio (MPR), representing the proportion of days with medications on hand during an 18-month exposure period. MPR was categorised by five levels (<=20%, 21%-40%, 41%-60%, 61%-80% and >80%). Patients without medications on hand for >=180 days were defined as non-persistent. Risk of CVD (myocardial infarction, ischaemic heart disease, stroke and unstable angina) and mortality by level of MPR and persistence was analysed after the exposure period using Cox proportional hazards regression and Kaplan-Meier, adjusted for demographics, socioeconomic status, concurrent medications and clinical characteristics. RESULTS: The hazard ratios for CVD ranged 1.33-2.36 in primary prevention patients and 1.19-1.58 in secondary prevention patients, for those with MPR <=80% (p<0.0001). The mortality risk was similar regardless of MPR level. The CVD risk was 74% higher in primary prevention patients and 33% higher in secondary prevention patients, for those who were non-persistent (p<0.0001). The mortality risk was 6% higher in primary prevention patients and 18% higher in secondary prevention patients, for non-persistent patients (p<0.0001). CONCLUSIONS: Higher refill adherence to lipid-lowering medications was associated with lower risk of CVD in primary and secondary prevention patients with type 2 diabetes mellitus. PMID- 29602854 TI - Acupuncture for constipation in patients with stroke: protocol of a systematic review and meta-analysis. AB - INTRODUCTION: Constipation is one of the most common complications in patients with stroke. Acupuncture has gained increased popularity for the management of constipation. However, there is a lack of supportive evidence on the efficacy of acupuncture for poststroke constipation. This systematic review aims to collect and critically appraise all the available evidence about the efficacy and safety of the acupuncture for constipation in poststroke patients. METHODS AND ANALYSIS: A comprehensive search of Pubmed, Embase, Cochrane Central Register of Controlled Trials, Web of Science, four Chinese databases (National Knowledge Infrastructure (CNKI), Chinese Biomedical Literatures database (CBM), Wanfang Digital Periodicals (WANFANG) and Chinese Science and Technology Periodicals (VIP) database), one Japanese medical database (National Institute of Informatics, CiNii) and one Korean medical database (Oriental Medicine Advanced Searching Integrated System, OASIS) will be conducted to identify randomised controlled trials of acupuncture for constipation in poststroke patients. There is no restriction on language or publication status. The primary outcome measure will be frequency of bowel movement. The risk of bias will be assessed using the approach recommended by Cochrane Handbook for Systematic Reviews of Interventions. We will conduct the meta-analysis to synthesise the evidence for each outcome, if possible. The heterogeneity will be statistically assessed using a chi2 test and I2 statistic. This protocol is developed following the guideline of Preferred Reporting Items for Systematic Reviews and Meta-analyses Protocols 2015. ETHICS AND DISSEMINATION: The ethical approval is not required because no primary data are collected. The findings will be presented at scientific conferences or a peer-reviewed scientific journal. PROSPERO REGISTRATION NUMBER: CRD42017076880. PMID- 29602855 TI - How will South Africa's mandatory salt reduction policy affect its salt iodisation programme? A cross-sectional analysis from the WHO-SAGE Wave 2 Salt & Tobacco study. AB - OBJECTIVE: The WHO's global targets for non-communicable disease reduction recommend consumption of<5 g salt/day. In 2016, South Africa was the first country to legislate maximum salt levels in processed foods. South Africa's salt iodisation fortification programme has successfully addressed iodine deficiency but information is dated. Simultaneous monitoring of sodium reduction and iodine status is required to ensure compatibility of the two public health interventions. DESIGN/SETTING/PARTICIPANTS: A nested cohort design within WHO's 2015 Study on global AGEing and adult health (n=2887) including individuals from households across South Africa. Randomly selected adults (n=875) provided 24-hour and spot urine samples for sodium and iodine concentration analysis (the primary and secondary outcome measures, respectively). Median 24-hour urinary iodine excretion (UIE) and spot urinary iodine concentrations (UIC) were compared by salt intakes of <5g/day, 5-9g/dayand >9 g/day. RESULTS: Median daily sodium excretion was equivalent to 6.3 g salt/day (range 1-43 g/day); 35% had urinary sodium excretion values within the desirable range (<5 g salt/day), 37% had high values (5-9 g salt/day) and 28% had very high values (>9 g salt/day). Median UIC was 130 ug/L (IQR=58-202), indicating population iodine sufficiency (>=100 ug/L). Both UIC and UIE differed across salt intake categories (p<0.001) and were positively correlated with estimated salt intake (r=0.166 and 0.552, respectively; both p<0.001). Participants with salt intakes of <5 g/day were not meeting the Estimated Average Requirement for iodine intake (95 ug/day). CONCLUSIONS: In a nationally representative sample of South African adults, the association between indicators of population iodine status (UIC and UIE) and salt intake, estimated using 24-hour urinary sodium excretion, indicate that low salt intakes may compromise adequacy of iodine intakes in a country with mandatory iodisation of table salt. The iodine status of populations undergoing salt reduction strategies needs to be closely monitored to prevent re-emergence of iodine deficiency. PMID- 29602856 TI - Urban-rural differences in the prevalence of diabetes mellitus among 25-74 year old adults of the Yangon Region, Myanmar: two cross-sectional studies. AB - OBJECTIVES: To investigate the association between urban-rural location and the occurrence of diabetes mellitus (DM) in the Yangon Region, and to estimate the proportion of urban and rural participants already diagnosed with DM, and of those, the proportion under treatment and under control. DESIGN: Two cross sectional studies, using the WHO STEPs methodology. SETTING: The Yangon Region of Myanmar, urban and rural areas. PARTICIPANTS: Men and women, aged 25-74 years, included during the study period from September-November 2013 (urban) and 2014 (rural areas) (n=1372). Institutionalised people, physically and mentally ill person, monks and nuns were excluded. RESULTS: The age-standardised prevalence of DM was 12.1% in urban and 7.1% in rural areas (p=0.039). In urban areas, the prevalence of DM was lowest in the highest educational groups (p<0.001). There were no differences in DM prevalence between gender or income levels. In rural areas, those who were physically inactive had a low intake of fruit and vegetable and were overweight/obese had a higher DM prevalence than others. In a logistic regression, the OR for DM in rural compared with urban areas was 0.38 (0.22, 0.65), adjusted for sociodemographic variables and behavioural risk factors. In urban areas, 43.1% of participants had the experience of receiving blood glucose measurements by a doctor or health worker, and 61.5% of all cases of DM were already diagnosed, 78.7% were under treatment and 45.8% were under control. The corresponding proportions in rural areas were 26.4%, 52.4%, 78.1% and 32.0%, respectively. CONCLUSION: The prevalence of DM in the Yangon Region was high, and significantly higher in urban than in rural areas. More health services are needed to serve this population with a large proportion of undiagnosed diabetes. Preventive measures to halt and reduce the prevalence of DM are urgently needed. PMID- 29602858 TI - Incidence of adverse events in Sweden during 2013-2016: a cohort study describing the implementation of a national trigger tool. AB - OBJECTIVES: To describe the implementation of a trigger tool in Sweden and present the national incidence of adverse events (AEs) over a 4-year period during which an ongoing national patient safety initiative was terminated. DESIGN: Cohort study using retrospective record review based on a trigger tool methodology. SETTING AND PARTICIPANTS: Patients >=18 years admitted to all somatic acute care hospitals in Sweden from 2013 to 2016 were randomised into the study. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome measure was the incidence of AEs, and secondary measures were type of injury, severity of harm, preventability of AEs, estimated healthcare cost of AEs and incidence of AEs in patients cared for in another type of unit than the one specialised for their medical needs ('off-site'). RESULTS: In a review of 64 917 admissions, the average AE rates in 2014 (11.6%), 2015 (10.9%) and 2016 (11.4%) were significantly lower than in 2013 (13.1%). The decrease in the AE rates was seen in different age groups, in both genders and for preventable and non-preventable AEs. The decrease comprised only the least severe AEs. The types of AEs that decreased were hospital-acquired infections, urinary bladder distention and compromised vital signs. Patients cared for 'off-site' had 84% more preventable AEs than patients cared for in the appropriate units. The cost of increased length of stay associated with preventable AEs corresponded to 13%-14% of the total cost of somatic hospital care in Sweden. CONCLUSIONS: The rate of AEs in Swedish somatic hospitals has decreased from 2013 to 2016. Retrospective record review can be used to monitor patient safety over time, to assess the effects of national patient safety interventions and analyse challenges to patient safety such as the increasing care of patients 'off-site'. It was found that the economic burden of preventable AEs is high. PMID- 29602857 TI - Opportunities and challenges to improving antibiotic prescribing practices through a One Health approach: results of a comparative survey of doctors, dentists and veterinarians in Australia. AB - OBJECTIVES: To explore and compare the knowledge, attitudes and experiences of doctors, dentists and veterinarians (as prescribers) in relation to antibiotic use and antibiotic resistance (AbR), and to consider the implications of these for policy-making that support a One Health approach. DESIGN: A cross-sectional survey conducted online. SETTING: Doctors, dentists and veterinarians practising in primary, secondary or tertiary care in Australia. PARTICIPANTS: 547 doctors, 380 dentists and 403 veterinarians completed the survey. MAIN OUTCOME MEASURES: Prescribers' knowledge, attitudes and perceptions of AbR, the extent to which a range of factors are perceived as barriers to appropriate prescribing practices, and perceived helpfulness of potential strategies to improve antibiotic prescribing in practice. RESULTS: There was substantial agreement across prescriber groups that action on AbR is required by multiple sectors and stakeholders. However, prescribers externalised responsibility to some extent by seeing the roles of others as more important than their own in relation to AbR. There were common and context-specific barriers to optimal prescribing across the prescriber groups. Prescriber groups generally perceived restrictive policies as unhelpful to supporting appropriate prescribing in their practice. CONCLUSIONS: The results have implications for implementing a One Health approach that involves doctors, dentists and veterinarians as key players to tackling the crisis of AbR. The findings are that (1) prescribers understand and are likely receptive to a One Health policy approach to AbR, (2) policy development should be sensitive to barriers that are specific to individual prescriber groups and (3) the development and introduction of interventions that might be perceived as reducing prescriber autonomy will need to be carefully designed and implemented. PMID- 29602859 TI - Prevalence of childhood hearing impairment of different severities in urban and rural areas: a nationwide population-based study in Taiwan. AB - OBJECTIVE: Childhood hearing impairment (CHI) is a major developmental disability, but data at the national level are limited, especially those on different severities. We conducted a study to fill this data gap. DESIGN: A nationwide study on the basis of a reporting system. SETTING: To provide services to disabled citizens, the Taiwanese government maintains a registry of certified cases. Using data from this registry, we estimated prevalence rates of CHI of different severities from 2004 to 2010 and made comparisons between urban and rural areas. PARTICIPANTS: Taiwanese citizens <=17 years old. PRIMARY OUTCOME MEASURES: To qualify for CHI disability benefits, a child must have an unaided pure-tone better ear hearing level at 0.5, 1 and 2 kHz with an average >=55 decibels (dB), confirmed by an otolaryngologist. The severity was classified by pure-tone better ear hearing level as mild (55-69 dB), moderate (70-89 dB) and severe (>=90 dB). RESULTS: The registered cases under 17 years old decreased annually from 4075 in 2004 to 3533 in 2010, but changes in the prevalence rate were small, ranging from 7.62/10 000 in 2004 to 7.91/10 000 in 2006. The prevalence rates of mild CHI increased in all areas over time, but not those of moderate or severe CHI. Rural areas had higher overall prevalence rates than urban areas in all years, with rate ratios (RRs) between 1.01 and 1.09. By severity, rural areas had higher prevalence rates of mild (RRs between 1.08 and 1.25) and moderate (RRs between 1.06 and 1.21) CHI but had lower prevalence rates of severe CHI (RRs between 0.92 and 0.99). CONCLUSION: While rural areas had higher overall prevalence rates of CHI than urban areas, the RRs decreased with CHI severity. Further studies that identify factors affecting the rural-urban difference might help the prevention of CHI. PMID- 29602860 TI - Protocol for the trismus trial-therabite versus wooden spatula in the amelioration of trismus in patients with head and neck cancer: randomised pilot study. AB - INTRODUCTION: Patients can develop trismus from their head and neck cancer or as a result of treatment. Trismus affects the jaw muscles and makes mouth opening difficult. To potentially combat trismus, patients could undertake proactive jaw stretching exercises prior to, during and after radiotherapy, although currently these are not the standard of care. METHODS AND ANALYSIS: This is a randomised, open-label, controlled, two-centre feasibility study, to assess the objective and subjective effectiveness and cost-effectiveness of therabite use compared with wooden spatula in ameliorating trismus in patients treated for stage 3 and 4 oral and oropharyngeal cancer, managed either by primary surgery followed by (chemo)radiotherapy or primary (chemo)radiotherapy. The principal objective assessment is measurement of maximum jaw opening. Assessments in all cases will be performed preradiotherapy and again at 3 and 6 months postintervention.Secondary aims of the study will be (1) to assess whether therabite or the wooden spatula intervention improves patients' quality of life, (2) reduce the level of post-treatment clinical management/healthcare use and (3) a nested qualitative study will explore the experience of the patient taking part in the intervention; data will be transcribed verbatim and analysis will be based on content analysis methods using the interview questions as the framework for examination. ETHICS AND DISSEMINATION: North West Greater Manchester granted ethical approval (REC Reference 11/NW/0744). Good Clinical Practice and the Declaration of Helsinki have been adhered to. The results will be presented internationally and submitted to a peer-reviewed journal. Head and neck cancer charities and information websites will also be approached. TRIAL REGISTRATION NUMBER: NCT01733797. PMID- 29602861 TI - Relationship between stroke recurrence, infarct pattern, and vascular distribution in patients with symptomatic intracranial stenosis. AB - OBJECTIVE: In view of recent literature suggesting that stroke recurrence and risks related to intervention may be related to plaque physiology/instability, our study sought to discern the pattern of stroke and rates of stoke recurrence as they relate to the anatomy and presentation of the underlying stenosis. METHODS: Retrospective chart as well as CT and MR angiographic imaging review of patients in the institutional stroke database was performed, including identification of patient risk factors, medical therapeutic optimization, compliance, serum cholesterol (low density lipoprotein) levels, blood pressure, physical therapy referrals, follow-up clinical status (using the modified Rankin Scales), and rate of recurrent stroke. 39 patients met the inclusion criteria. We evaluated infarct pattern (embolic, adjacent perforator, or watershed) and vascular distribution. RESULTS: Basilar artery stenosis was most likely to present as a perforator stroke and least likely to recur. Patients discharged with suboptimal medical therapy were twice as likely to have a recurrent stroke. Among patients with optimized medical therapy, no recurrent strokes were seen in patients with an embolic infarct pattern, while a 57% recurrence rate was seen in patients with a watershed infarct pattern. CONCLUSIONS: Our results suggest that hemodynamic intracranial vascular stenoses may be less responsive to medical therapy, while stenotic lesions caused by plaque destabilization or in perforator territories may benefit from aggressive medical management with delayed or staged endovascular therapy. Recurrence of stroke may be affected both by vascular territory and by aggressive risk factor control, although the latter remains difficult to evaluate. PMID- 29602863 TI - The Coming-of-Age of Subcutaneous Injectable Contraception. PMID- 29602862 TI - Safety and efficacy of mechanical thrombectomy in acute ischemic stroke of anticoagulated patients. AB - BACKGROUND: Anticoagulated patients (APs) are currently excluded from acute ischemic stroke reperfusion therapy with intravenous recombinant tissue plasminogen activator (IV-rtPA); however, these patients could benefit from mechanical thrombectomy (MT). Evidence for MT in this condition remains scarce. The aim of this study was to analyze the safety and efficacy of MT in APs. METHODS: We analyzed three patient groups from two prospective registries: APs with MT (AP-MT group), non-anticoagulated patients treated with MT (NAP-MT group), and non-anticoagulated patients treated with IV-rtPA and MT (NAP-IVTMT group). Univariate and multivariate logistic regression were used to evaluate treatment efficacy with modified Rankin Scale (mRS) <=2 and safety (radiologic intracranial hemorrhage (rICH), symptomatic intracranial hemorrhage (sICH) and death rate at 3 months) between groups. RESULTS: 333 patients were included in the study, with 44 (12%) in the AP-MT group, 105 (31%) in the NAP-MT group, and 188 (57%) in the NAP-IVTMT group. Univariate analysis showed that the AP-MT group was older (P<0.001), more often had atrial fibrillation (P<0001), and had a higher ASPECTS (P<0.006 and P<0.002) compared with the NAP-MT group and NAP-IVTMT groups, respectively. Multivariate analysis showed that the AP-MT group had a lower risk of rICH (OR 2.77, 95% CI 1.01 to 7.61, P=0.05) but a higher risk of death at 3 months (OR 0.26, 95% CI 0.09 to 0.76, P=0.01) compared with the NAP IVTMT group. No difference was found between the AP-MT and NAP-MT groups. CONCLUSIONS: With regard to intracranial bleeding and functional outcome at 3 months, MT in APs seems as safe and efficient as in NAPs. However, there is a higher risk of death at 3 months in the AP-MT group compared with the NAP-IVTMT group. PMID- 29602864 TI - Human Resources for Health: The Best Learning, the Best Skill Mix, and the Most Impact. PMID- 29602865 TI - Family Planning in the Democratic Republic of the Congo: Encouraging Momentum, Formidable Challenges. AB - Momentum for family planning in the Democratic Republic of the Congo (DRC) is evident in multiple ways: strong political will, increasing donor support, a growing number of implementing organizations, innovative family planning programming, and a cohesive family planning stakeholder group. Between 2013 and 2017, the modern contraceptive prevalence rate (mCPR) in the capital city of Kinshasa increased from 18.5% to 26.7% among married women, but as of 2013-14, it was only 7.8% at the national level. The National Multisectoral Strategic Plan for Family Planning: 2014-2020 calls for achieving an mCPR of 19.0% by 2020, an ambitious goal in light of formidable challenges to family planning in the DRC. Of the 16,465 health facilities reporting to the national health information system in 2017, only 40% offer family planning services. Key challenges include uncertainty over the political situation, difficulties of ensuring access to family planning services in a vast country with a weak transportation infrastructure, funding shortfalls for procuring adequate quantities of contraceptives, weak contraceptive logistics and supply chain management, strong cultural norms that favor large families, and low capacity of the population to pay for contraceptive services. This article describes promising initiatives designed to address these barriers, consistent with the World Health Organization's framework for health systems strengthening. For example, the national family planning coordinating mechanism is being replicated at the provincial level to oversee the expansion of family planning service delivery. Promising initiatives are being implemented to improve the supply and quality of services and generate demand for family planning, including social marketing of subsidized contraceptives at both traditional and non-traditional channels and strengthening of services in military health facilities. To expand contraceptive access, family planning is being institutionalized in nursing schools, allowing students to operate as community-based distributors. While major challenges remain, significant progress in family planning has been made in the DRC, which should be judged not in comparison with sub-Saharan African countries with high mCPR and mature programs, but rather with those starting from much further behind. PMID- 29602866 TI - Expanding Access to Injectable Contraception: Results From Pilot Introduction of Subcutaneous Depot Medroxyprogesterone Acetate (DMPA-SC) in 4 African Countries. AB - PATH partnered with the United Nations Population Fund (UNFPA) and country ministries of health (MOHs) to coordinate pilot introductions of subcutaneous depot medroxyprogesterone acetate (subcutaneous DMPA or DMPA-SC, brand name Sayana Press) in Burkina Faso, Niger, Senegal, and Uganda from July 2014 through June 2016 in order to expand the range of methods available to women, particularly in remote locations. The pilot introductions aimed to answer key questions that would inform decisions about future investments in DMPA-SC and scaling up product availability and service-delivery innovations nationally. These questions included the extent to which DMPA-SC would appeal to first-time users of modern contraception, as well as adolescent girls and young women; whether DMPA-SC would add value to family planning programs or simply replace DMPA-IM or other modern methods; and the trends in injectables use when introducing DMPA-SC (or any injectable) at the community level for the first time. We implemented a multicountry monitoring system to track key indicators, including the number of doses administered by category of user (e.g., new users, by client age group) or delivery channel. Providers generally collected these data using their national programs' standard family planning registers. Data were analyzed for cumulative information and to examine trends over time using Microsoft Power Query for Excel and Tableau. Across the 4 countries, nearly half a million DMPA-SC doses were administered and approximately 135,000 first-time users of modern contraception were reached. Furthermore, 44% of the doses administered in 3 of the countries with data were to adolescent girls and young women under age 25. Switching from DMPA-IM to DMPA-SC was not widespread, ranging from 7% in Burkina Faso to 16% in Uganda. Results from these pilot introductions demonstrate that DMPA-SC has the potential to expand community-level access to injectables, maximize task-sharing strategies, and reach young women and new acceptors of family planning. Considered within the context of each country's setting, training approach, and introduction strategy, these results can help stakeholders in other countries make informed decisions about whether and how to include this contraceptive option in their family planning programs. PMID- 29602867 TI - Medical Education Partnership Initiative (MEPI) in Zimbabwe: Outcomes and Challenges. AB - BACKGROUND: Sub-Saharan Africa has an inadequate number of health professionals, leading to a reduced capacity to respond to health challenges, including HIV/AIDS. From 2010 to 2015, the Medical Education Partnership Initiative (MEPI) sponsored by the U.S. Presidents Emergency Plan for AIDS Relief (PEPFAR) and the National Institutes of Health (NIH)-was enthusiastically taken up by the University of Zimbabwe College of Health Sciences (UZCHS) and 12 other sub Saharan African universities to develop models of training to improve medical education and research capacity. In this article, we describe the outcomes and challenges of MEPI in Zimbabwe. METHODS: UZCHS in partnership with the University of Colorado, Denver; Stanford University; University of Cape Town; University College London; and King's College London designed the Novel Education Clinical Trainees and Researchers (NECTAR) program and 2 linked awards addressing cardiovascular disease and mental health to pursue MEPI objectives. A range of medical education and research capacity-focused programs were implemented, including faculty development, research support, mentored scholars, visiting professors, community-based education, information and technology support, cross cutting curricula, and collaboration with partner universities and the ministries of health and education. We analyzed quantitative and qualitative data from several data sources, including annual surveys of faculty, students, and other stakeholders; workshop exit surveys; and key informant interviews with NECTAR administrators and leaders and the UZCHS dean. FINDINGS: Improved Internet connectivity and electronic resource availability were early successes of NECTAR. Over the 5-year period, 69% (115 of 166) of faculty members attended at least 1 of 15 faculty development workshops. Forty-one faculty members underwent 1-year advanced faculty development training in medical education and leadership. Thirty three mentored research scholars were trained under NECTAR, and 52 and 12 in cardiovascular and mental health programs, respectively. Twelve MEPI scholars had joined faculty by 2015. Full-time faculty grew by 36% (122 to 166), annual postgraduate and medical student enrollment increased by 61% (75 to 121) and 71% (123 to 210), respectively. To institutionalize and sustain MEPI innovations, the Research Support Center and the Department of Health Professions Education were established at UZCHS. CONCLUSION: MEPI has synergistically revitalized medical education, research capacity, and leadership at UZCHS. Investments in creating a new research center, health professions education department, and, programs have laid the foundation to help sustain faculty development and research capacity in the country. PMID- 29602868 TI - Community-Based Management of Acute Malnutrition to Reduce Wasting in Urban Informal Settlements of Mumbai, India: A Mixed-Methods Evaluation. AB - BACKGROUND: We evaluated an adaptation of a large-scale community-based management of acute malnutrition program run by an NGO with government partnerships, in informal settlements of Mumbai, India. The program aimed to reduce the prevalence of wasting among children under age 3 and covered a population of approximately 300,000. METHODS: This study used a mixed-methods approach including a quasi-experimental design to compare prevalence estimates of wasting in intervention areas with neighboring informal settlements. Cross sectional data were collected from March through November 2014 for the baseline and October through December 2015 for the endline. Endline data were analyzed using mixed-effects logistic regression models, adjusting for child, maternal, and household characteristics. In addition, we conducted in-depth interviews with 37 stakeholders (13 staff and 24 mothers) who reported on salient features that contributed to successful implementation of the program. RESULTS: We interviewed 2,578 caregivers at baseline and 3,455 at endline in intervention areas. In comparison areas, we interviewed 2,082 caregivers at baseline and 2,122 at endline. At endline, the prevalence of wasting decreased by 28% (18% to 13%) in intervention areas and by 5% (16.9% to 16%) in comparison areas. Analysis of the endline data indicated that children in intervention areas were significantly less likely to be malnourished (adjusted odds ratio, 0.81; confidence interval, 0.67 to 0.99). Stakeholders identified 4 main features as contributing to the success of the program: (1) tailoring and reinforcement of information provided to caregivers in informal settings, (2) constant field presence of staff, (3) holistic case management of issues beyond immediate malnourishment, and (4) persistence of field staff in persuading reluctant families. Staff capabilities were enhanced through training, stringent monitoring mechanisms, and support from senior staff in tackling difficult cases. CONCLUSION: NGO-government partnerships can revitalize existing community-based programs in urban India. Critical to success are processes that include reinforced knowledge-building of caregivers, a high level of field support and encouragement to the community, and constant monitoring and follow-up of cases by all staff levels. PMID- 29602869 TI - Evolution and Resistance to Sexuality Education in Mexico. AB - BACKGROUND: Since the 1930s, Mexico has made substantial progress in providing adolescents with sexuality education through an evolving national school-based program. As part of a broader effort to document strategies to build support for and deal with resistance to sexuality education, this analysis uses a historical lens to answer 2 key questions: (1) How has the nature of sexuality education in Mexico evolved from the 1930s to the 2010s? (2) How have the drivers, responses, support, and resistance to sexuality education impacted Mexico's experience implementing and sustaining school-based sexuality education? METHODS: The analysis was informed by a review of peer-reviewed and gray literature as well as the personal experience and documents of one of the authors, who has played a central role in Mexico's sexuality education effort for 50 years. The findings were organized according to 4 time periods-the 1930s, the 1970s, the 1990s, and the first 2 decades of the 21st century-that emerged during the analysis as distinct periods with regard to the social and political context of school-based sexuality education. Within each of these time periods, the following 4 thematic aspects were assessed: drivers, responses, support, and resistance, with a particular focus on the rationales and strategies of resistance over time.Findings: This analysis identified determined support for school-based sexuality education in the 4 historical time periods from a range of governmental and nongovernmental stakeholders. However, opposition to sexuality education also steadily rose in the time period considered, with a growing range of more organized and well-financed actors. The Mexican government's commitment to delivering school-based sexuality education has driven its inclusion in public schools, along with expansion of its curricula from primarily biological content to a more comprehensive approach. CONCLUSION: Mexico's experience with sexuality education can inform other countries' efforts to consider the drivers, responses, support, and resistance that may be present in their own contexts. This type of analysis can contribute to strategic, well-informed, and well-conceived programmatic design and implementation to build support for sexuality education and deal with resistance. PMID- 29602870 TI - Using Program Data to Improve Access to Family Planning and Enhance the Method Mix in Conflict-Affected Areas of the Democratic Republic of the Congo. AB - Unmet need for family planning in the conflict-affected area of eastern Democratic Republic of the Congo (DRC) has been reported to be as high as 38%, and women in such conflict settings are often the most at risk for maternal mortality. The International Rescue Committee implements the Family Planning and Post-Abortion Care in Emergencies program in 3 provinces of eastern DRC to provide women and couples access to family planning, including long-acting reversible contraceptives (LARCs). This article presents routine program data from June 2011 through December 2013 from 2 health zones as well as results from a qualitative assessment of family planning clients and of male and female non users, conducted in 2013. It then describes how these findings were used to make program adjustments to improve access to family planning services and client informed choice and assesses the effects of the program design changes on family planning uptake and method mix using routine program data from January 2014 through December 2016. Between 2011 and 2013, 8,985 clients adopted family planning, with an average 14 clients adopting a method per facility, per month. The method mix remained stable during this period, with implants dominating at 48%. Barriers to uptake identified from the qualitative research were both supply and demand-related, including misconceptions about certain modern contraceptive methods on the part of providers, users, and other community members. The program implemented several program changes based on the assessment findings, including clinical coaching and supportive supervision to improve provider skills and attitudes, introduction of immediate postpartum insertion of the intrauterine device (IUD) and the levonorgestrel-releasing intrauterine system (LNG-IUS), and behavior change communication campaigns to raise awareness about family planning. After these program changes, the mean number of clients adopting modern family planning per facility, per month increased from 14 to 37 and the percentage of family planning adopters choosing LARCs increased from 50% to 66%. While implants continued to be the most dominant method, reaching 60% of the method mix in 2016, the percentage of clients adopting IUDs increased each year, from 3% in 2014 to 13% in 2016. In total, 39,399 clients started family planning methods during the post-program design change period (2014-2016). Our experience in eastern DRC demonstrates that women and their partners affected by conflict want family planning, and that it is feasible to deliver the full range of modern contraceptive methods when programs are adapted and sensitive to the local context. PMID- 29602871 TI - Effective Collaboration for Scaling Up Health Technologies: A Case Study of the Chlorhexidine for Umbilical Cord Care Experience. AB - The global health field is replete with examples of cross-organizational collaborative partnerships, such as networks, alliances, coalitions, task forces, and working groups, often established to tackle a shared global health concern, condition, or threat affecting low-income countries or communities. The purpose of this article is to review factors influencing the effectiveness of a multi agency global health collaborative effort using the Chlorhexidine Working Group (CWG) as our case study. The CWG was established to accelerate the introduction and global scale-up of chlorhexidine for umbilical cord care to reduce infection related neonatal morbidity and mortality in low-income countries. Questions included: how current and past CWG members characterized the effectiveness, productivity, collaboration, and leadership of the CWG; what factors facilitated or hindered group function; institutional or individual reasons for participating and length of participation in the CWG; and lessons that might be relevant for future global collaborative partnerships. Data were collected through in-depth, semistructured individual interviews with 19 group members and a review of key guiding documents. Six domains of internal coalition functioning (leadership, interpersonal relationships, task focus, participant benefits and costs, sustainability planning, and community support) were used to frame and describe the functioning of the CWG. Collaboration effectiveness was found to depend on: (1) leadership that maintained a careful balance between discipline and flexibility, (2) a strong secretariat structure that supported the evolution of trust and transparent communication in interpersonal relationships, (3) shared goals that allowed for task focus, (4) diverse membership and active involvement from country-level participants, which created a positive benefit-cost ratio for participants, (5) sufficient resources to support the partnership and build sustainable capacity for members to accelerate the transfer of knowledge, and (6) support from the global health community across multiple organizations. Successful introduction and scale-up of new health interventions require effective collaboration across multiple organizations and disciplines, at both global and country levels. The participatory collaborative partnership approach utilized by the Chlorhexidine Working Group offers an instructive learning case. PMID- 29602872 TI - Palm Oil in Myanmar: A Spatiotemporal Analysis of the Effects of Industrial Farming on Biodiversity Loss. AB - BACKGROUND: Palm oil consumption is potentially deleterious to human health, and its production has resulted in 11 million hectares of deforestation globally. Importing roughly 394,000 metric tons of palm oil in 2012 alone, the Burmese government has recently pushed for intensive oil palm development to sate domestic demand for consumption and become international market players. Given well-studied linkages between biodiversity loss and ecosystem instability, this study aims to characterize the nature of deforestation for oil palm production in Myanmar, its relationship to increased biodiversity loss, and contextualize the potential impacts of this loss on diets and human health in rural Myanmar. METHODS: First, a GIS land suitability analysis overlaying spatial data on rainfall, elevation, and slope was conducted in order to identify areas of Myanmar best suited to oil palm tree growth. Second, after narrowing the geographic range, vegetation indices using varying spectral band models in ENVI (Environment for Visualizing Images) allowed a more granular examination of changes in vegetation phenology from 1975 to 2015. Lastly, ground truthing permitted an in-person verification of GIS and ENVI results and provided contextual understanding of oil palm development in Myanmar. RESULTS: GIS analysis revealed that the Tanintharyi Region, one of the most biodiverse regions in Myanmar, is highly suitable for oil palm growth. Next, vegetation indices revealed a progressive shift from smallholder farming, with little observable deforestation between 1975 and 1990, to industrial oil palm plantations all throughout Tanintharyi starting around 2000-a shift concomitant with biodiversity loss of primary forestland. Ground truthing indicated that plantation development has advanced rapidly, though not without barriers to growth. CONCLUSIONS: If these trends of Burmese oil palm intensification continue, 4 key outcomes may follow: (1) even higher levels of biodiversity loss, (2) increased access and affordability of edible palm oil, (3) decreased importing of palm oil, and (4) large profits made from selling excess palm oil on the international market. Although the first 2 outcomes may adversely affect low-income Burmese populations, the latter 2 may bode well for the domestic economy and international trade partners, thus encouraging competing interests. This increased domestic access and affordability of palm oil may increase consumption and cause increased prevalence of cardiovascular disease, diabetes, and obesity. Finally, this biodiversity loss concurrent with industrial deforestation may disproportionately impact vulnerable, rural communities. PMID- 29602873 TI - Yazidi Women: Healing the Invisible Wounds. PMID- 29602874 TI - Update of: Kara et al., The BetterBirth Program: Pursuing Effective Adoption and Sustained Use of the WHO Safe Childbirth Checklist Through Coaching-Based Implementation in Uttar Pradesh, India. PMID- 29602876 TI - Supple bodies, healthy minds: yoga, psychedelics and American mental health. AB - Much discussion about mental health has revolved around treatment models. As interdisciplinary scholarship has shown, mental health knowledge, far from being a neutral product detached from the society that generated it, was shaped by politics, economics and culture. By drawing on case studies of yoga, religion and fitness, this article will examine the ways in which mental health practices sometimes scientific, sometimes spiritual-have been conceived, debated and applied by researchers and the public. More specifically, it will interrogate the relationship between yoga, psychedelics, South Asian and Eastern religion (as understood and practiced in the USA) and mental health. PMID- 29602875 TI - Update of: Marx Delaney et al., Improving Adherence to Essential Birth Practices Using the WHO Safe Childbirth Checklist With Peer Coaching: Experience From 60 Public Health Facilities in Uttar Pradesh, India. PMID- 29602877 TI - Taking a position on intramembrane proteolysis. AB - Decades of work have contributed to our in-depth mechanistic understanding of soluble proteases, but much less is known about the catalytic mechanism of intramembrane proteolysis due to inherent difficulties in both preparing and analyzing integral membrane enzymes and transmembrane substrates. New work from Naing et al. tackles this challenge by examining the catalytic parameters of an aspartyl intramembrane protease homologous to the enzyme that cleaves amyloid precursor protein, finding that both chemistry and register contribute to specificity in substrate cleavage. PMID- 29602879 TI - Engineering and dissecting the glycosylation pathway of a streptococcal serine rich repeat adhesion. PMID- 29602880 TI - Exercise increases mitochondrial PGC-1 alpha content and promotes nuclear mitochondrial cross-talk to coordinate mitochondrial biogenesis. PMID- 29602878 TI - Molecular basis for the structural diversity in serogroup O2-antigen polysaccharides in Klebsiella pneumoniae. AB - Klebsiella pneumoniae is a major health threat. Vaccination and passive immunization are considered as alternative therapeutic strategies for managing Klebsiella infections. Lipopolysaccharide O antigens are attractive candidates because of the relatively small range of known O-antigen polysaccharide structures, but immunotherapeutic applications require a complete understanding of the structures found in clinical settings. Currently, the precise number of Klebsiella O antigens is unknown because available serological tests have limited resolution, and their association with defined chemical structures is sometimes uncertain. Molecular serotyping methods can evaluate clinical prevalence of O serotypes but require a full understanding of the genetic determinants for each O antigen structure. This is problematic with Klebsiella pneumoniae because genes outside the main rfb (O-antigen biosynthesis) locus can have profound effects on the final structure. Here, we report two new loci encoding enzymes that modify a conserved polysaccharide backbone comprising disaccharide repeat units [->3) alpha-d-Galp-(1->3)-beta-d-Galf-(1->] (O2a antigen). We identified in serotype O2aeh a three-component system that modifies completed O2a glycan in the periplasm by adding 1,2-linked alpha-Galp side-group residues. In serotype O2ac, a polysaccharide comprising disaccharide repeat units [->5)-beta-d-Galf-(1->3) beta-d-GlcpNAc-(1->] (O2c antigen) is attached to the non-reducing termini of O2a antigen chains. O2c-polysaccharide synthesis is dependent on a locus encoding three glycosyltransferase enzymes. The authentic O2aeh and O2c antigens were recapitulated in recombinant Escherichia coli hosts to establish the essential gene set for their synthesis. These findings now provide a complete understanding of the molecular genetic basis for the known variations in Klebsiella O-antigen carbohydrate structures based on the O2a backbone. PMID- 29602881 TI - ERK and the F-box protein beta TRCP target STAT1 for degradation. PMID- 29602882 TI - 'Gaps' in targeted ischaemic injury therapies in ST-elevation myocardial infarction. PMID- 29602883 TI - Danegaptide for primary percutaneous coronary intervention in acute myocardial infarction patients: a phase 2 randomised clinical trial. AB - OBJECTIVES: Reperfusion immediately after reopening of the infarct-related artery in ST-segment elevation myocardial infarction (STEMI) may cause myocardial damage in addition to the ischaemic insult (reperfusion injury). The gap junction modulating peptide danegaptide has in animal models reduced this injury. We evaluated the effect of danegaptide on myocardial salvage in patients with STEMI. METHODS: In addition to primary percutaneous coronary intervention in STEMI patients with thrombolysis in myocardial infarction flow 0-1, single vessel disease and ischaemia time less than 6 hours, we tested, in a clinical proof-of concept study, the therapeutic potential of danegaptide at two-dose levels. Primary outcome was myocardial salvage evaluated by cardiac MRI after 3 months. RESULTS: From November 2013 to August 2015, a total of 585 patients were randomly enrolled in the trial. Imaging criteria were fulfilled for 79 (high dose), 80 (low dose) and 84 (placebo) patients eligible for the per-protocol analysis. Danegaptide did not affect the myocardial salvage index (danegaptide high (63.9+/ 14.9), danegaptide low (65.6+/-15.6) and control (66.7+/-11.7), P=0.40), final infarct size (danegaptide high (19.6+/-11.4 g), danegaptide low (18.6+/-9.6 g) and control (21.4+/-15.0 g), P=0.88) or left ventricular ejection fraction (danegaptide high (53.9%+/-9.5%), danegaptide low (52.7%+/-10.3%) and control (52.1%+/-10.9%), P=0.64). There was no difference between groups with regard to clinical outcome. CONCLUSIONS: Administration of danegaptide to patients with STEMI did not improve myocardial salvage. TRIAL REGISTRATION NUMBER: NCT01977755; Pre-results. PMID- 29602884 TI - Meta-analysis: mistake or milestone in medicine? PMID- 29602885 TI - Beckwith-Weidemann syndrome with IC2 (KvDMR1) hypomethylation defect: a novel mutation. AB - The Beckwith-Wiedemann syndrome (BWS) is a rare genetic syndrome. However, this is one of the most common overgrowth syndromes. This is a genetically and clinically heterogeneous syndrome. Here, we report a case of Beckwith-Weidemann syndrome without macrosomia, visceromegaly and hemihyperplasia but having macroglossia, omphalocele and anterior linear ear lobe creases. The diagnosis was confirmed by gene analysis suggestive of imprinting centre 2 (KvDMR1) hypomethylation defect. PMID- 29602886 TI - Rapid onset of multiple concurrent squamous cell carcinomas associated with the use of an arsenic-containing traditional medicine for chronic plaque psoriasis. AB - We report a case of a 46-year-old Vietnamese man who developed widespread, numerous and concurrent cutaneous squamous cell carcinomas (SCCs) in non-sun exposed skin areas after taking a traditional medicine (TM) formulation for chronic plaque psoriasis. The SCC lesions began to develop within 12-15 months after beginning the arsenic-containing TM. The patient experienced both acute and chronic symptoms consistent with arsenic exposure. Laboratory investigation of a collected hair sample showed a significant arsenic level. The TM formulation used by the patient was tested and demonstrated an extremely high concentration of arsenic. PMID- 29602887 TI - Proximal tibiofibular joint dislocation treated using flexible and permanent syndesmosis fixation. AB - We present the case of a 40-year-old man who suffered an isolated proximal tibiofibular dislocation of the left knee after a trauma during a soccer game. Physical examination and radiographic imaging revealed an anterolateral dislocation of the proximal fibula. The diagnosis was confirmed by MRI. The treatment choice was open reduction and internal fixation under direct visualisation using flexible and permanent internal fixation. Postoperative treatment includes knee immobilisation during the first week, and partial weight was allowed for 2 weeks progressing to full weight bearing over 4 weeks. The patient started a gradual and progressive physical therapy programme with range of motion exercises, muscle strengthening and gait training. Full knee range of motion was achieved after 4 weeks. No complaint of pain or hardware discomfort was reported, and the patient is back to daily life and sports activities after 6 months of surgical treatment. PMID- 29602888 TI - Pseudotumor cerebri as the presentation of Lyme disease in a non-endemic area. AB - Intracranial hypertension is a rare entity in prepubertal children, and its differential diagnosis includes a number of systemic diseases, drugs, vitamin deficiencies and excesses, and hereditary conditions. Infectious aetiology is rare. The case of a 9-year-old boy with intracranial hypertension secondary to acute neuroborreliosis is described. He presented with daily pulsatile frontotemporal headache, pallor, photophobia and phonophobia. His neurological examination revealed papilledema with no nuchal rigidity. The lumbar puncture showed increased pressure (50 cm H2O) and lymphocytic pleocytosis. Serum and cerebrospinal fluid (CSF) Borrelia burgdorferi antibodies were positive. This kind of infection is rare in Portugal but a trip to an endemic area was identified. A careful history, considering the exposure to rural areas together with the intracranial hypertension and inflammatory CSF, are important clues to the diagnosis, allowing the institution to select appropriate treatment. PMID- 29602889 TI - Adult scurvy associated with psychiatric disorders and breast feeding. AB - Scurvy is a nutritional disease caused by ascorbic acid deficiency and is potentially fatal. It was originally described in the 18th century by James Lind and associated with long sea voyages and insufficient citrus consumption. Its prevalence has declined markedly over the years but has still been described sporadically in certain countries. A 22-year-old woman with an anxiety disorder and anorexia nervosa, recent pregnancy and ongoing breast feeding, presented with a 10-day history of spontaneous haematomas in the lower limbs, gingivorrhagia and fatigue. The examination was remarkable for signs of minor bleeding without haemodynamic compromise, gonalgia and pale skin. Work-up studies revealed the presence of anaemia. Direct anamnesis identified a diet based solely of tea and carbohydrates due to distorted body image. With the working diagnosis of scurvy, nutritional support and oral vitamin C supplementation was initiated. Her symptoms and anaemia resolved in 30 days and the diagnosis was confirmed biochemically. PMID- 29602890 TI - Childhood obesity in Mexico: social determinants of health and other risk factors. AB - Approximately 50 million children and adolescents in Latin America are affected by the childhood obesity pandemic. We present the case of a 5-year-old Mexican girl with obesity and gastro-oesophageal reflux disease (GORD), in whom prenatal, lifestyle and environmental risk factors were identified. Here, we demonstrate how childhood obesity is rooted since pregnancy and the perinatal stage, and how the social determinants of health like unsafe outdoor conditions, lack of infrastructure to exercise and a suboptimal physical activity curriculum in government schools strongly influence the development and maintenance of childhood obesity and complicate management. PMID- 29602891 TI - High-dose thiamine and essential tremor. AB - Essential tremor is a common neurological disease. The medical treatment of this affection currently involves the use of propranolol, primidone and other drugs. These drugs, however, are often not effective in reducing tremor and cause side effects in a large share of the patients treated. The treatment with intramuscular high-dose thiamine has led to a rapid, remarkable and persistent improvement of the symptoms in two patients with essential tremor. This result suggests the possibility that high doses of intramuscular thiamine may be an affordable alternative, highly effective and long-lasting medical treatment that has shown no relevant side effect. PMID- 29602892 TI - Essential thrombocytosis 40 years after splenectomy. PMID- 29602893 TI - Synovial sarcoma of the transverse colon: a rare cause of intussusception. AB - We report a third case of a primary intramural synovial sarcoma of the lower gastrointestinal tract. A 50-year-old woman presented with hematochezia, dizziness and shortness of breath. CT imaging revealed a transverse colo-colonic intussusception with a colonic mass serving as a lead point. A subtotal colectomy was performed with oncologic resection of a sausage-like mass in the mid transverse colon. Pathological assessment showed a biphasic synovial sarcoma. The postoperative hospital course was without complications and the patient was discharged home with plans for postoperative surveillance. PMID- 29602894 TI - Apixaban-induced subdural bleeding: case presentation and literature review. AB - Apixaban is a factor Xa inhibitor which is a non-vitamin K dependent oral anticoagulant known tocause the lowest rate of intracranial bleeding among the same kind of inibitors. In this paper, we report a rare case in a 60-year-old man with a history of hypertension and oligodendroglioma on apixaban for deep venous thrombosis who presented to our hospital with decreased level of consciousness and slurred speech with rapid deterioration. We highlight the risk of subdural bleeding requiring immediate neurosurgical intervention due to apixaban, with literature review. PMID- 29602895 TI - Acute brainstem compression. PMID- 29602896 TI - Newborn health benefits or financial risk protection? An ethical analysis of a real-life dilemma in a setting without universal health coverage. AB - INTRODUCTION: High healthcare costs make illness precarious for both patients and their families' economic situation. Despite the recent focus on the interconnection between health and financial risk at the systemic level, the ethical conflict between concerns for potential health benefits and financial risk protection at the household level in a low-income setting is less understood. METHODS: Using a seven-step ethical analysis, we examine a real-life dilemma faced by families and health workers at the micro level in Ethiopia and analyse the acceptability of limiting treatment for an ill newborn to protect against financial risk. We assess available evidence and ethical issues at stake and discuss the dilemma with respect to three priority setting criteria: health maximisation, priority to the worse-off and financial risk protection. RESULTS: Giving priority to health maximisation and extra priority to the worse-off suggests, in this particular case, that limiting treatment is not acceptable even if the total well-being gain from reduced financial risk is taken into account. Our conclusion depends on the facts of the case and the relative weight assigned to these criteria. However, there are problematic aspects with the premise of this dilemma. The most affected parties-the newborn, family members and health worker-cannot make free choices about whether to limit treatment or not, and we thereby accept deprivations of people's substantive freedoms. CONCLUSION: In settings where healthcare is financed largely out-of-pocket, families and health workers face tragic trade-offs. As countries move towards universal health coverage, financial risk protection for high-priority services is necessary to promote fairness, improve health and reduce poverty. PMID- 29602897 TI - Accelerated Cardiomyocyte Proliferation in the Heart of a Neonate With LEOPARD Syndrome-Associated Fatal Cardiomyopathy. PMID- 29602898 TI - Pan RJ. Restoring Community Immunity in America. Pediatrics. 2018;141(1): e20173449. PMID- 29602899 TI - Re: Errata for Prevention of Childhood Lead Toxicity. PMID- 29602900 TI - Anxiety and Mood Disorder in Children With Autism Spectrum Disorder and ADHD. AB - OBJECTIVES: Autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD) frequently co-occur. Understanding the endophenotype of children with both ASD and ADHD may impact clinical management. In this study, we compare the comorbidity of anxiety and mood disorders in children with ASD, with and without ADHD. METHODS: We performed a cross-sectional study of children with ASD who were enrolled in the Interactive Autism Network, an Internet-mediated, parent report, autism research registry. Children ages 6 to 17 years with a parent reported, professional, and questionnaire-verified diagnosis of ASD were included. Data were extracted regarding parent-reported diagnosis and/or treatment of ADHD, anxiety disorder, and mood disorder. ASD severity was measured by using Social Responsiveness Scale total raw scores. RESULTS: There were 3319 children who met inclusion criteria. Of these, 1503 (45.3%) had ADHD. Comorbid ADHD increased with age (P < .001) and was associated with increased ASD severity (P < .001). A generalized linear model revealed that children with ASD and ADHD had an increased risk of anxiety disorder (adjusted relative risk 2.20; 95% confidence interval 1.97-2.46) and mood disorder (adjusted relative risk 2.72; 95% confidence interval 2.28-3.24) compared with children with ASD alone. Increasing age was the most significant contributor to the presence of anxiety disorder and mood disorder. CONCLUSIONS: Co-occurrence of ADHD is common in children with ASD. Children with both ASD and ADHD have an increased risk of anxiety and mood disorders. Physicians who care for children with ASD should be aware of the coexistence of these treatable conditions. PMID- 29602901 TI - Re: Disparities Between Parental Expectations and Pediatric Antibiotic Prescribing. PMID- 29602902 TI - Xu A, Ganapathy V, Morain SR. Delay in State Adoption of Newborn Screening Tests. Pediatrics. 2018;141(1):e20170300. PMID- 29602903 TI - The Atacama skeleton. PMID- 29602904 TI - A trapped human PPM1A-phosphopeptide complex reveals structural features critical for regulation of PPM protein phosphatase activity. AB - Metal-dependent protein phosphatases (PPM) are evolutionarily unrelated to other serine/threonine protein phosphatases and are characterized by their requirement for supplementation with millimolar concentrations of Mg2+ or Mn2+ ions for activity in vitro The crystal structure of human PPM1A (also known as PP2Calpha), the first PPM structure determined, displays two tightly bound Mn2+ ions in the active site and a small subdomain, termed the Flap, located adjacent to the active site. Some recent crystal structures of bacterial or plant PPM phosphatases have disclosed two tightly bound metal ions and an additional third metal ion in the active site. Here, the crystal structure of the catalytic domain of human PPM1A, PPM1Acat, complexed with a cyclic phosphopeptide, c(MpSIpYVA), a cyclized variant of the activation loop of p38 MAPK (a physiological substrate of PPM1A), revealed three metal ions in the active site. The PPM1Acat D146E c(MpSIpYVA) complex confirmed the presence of the anticipated third metal ion in the active site of metazoan PPM phosphatases. Biophysical and computational methods suggested that complex formation results in a slightly more compact solution conformation through reduced conformational flexibility of the Flap subdomain. We also observed that the position of the substrate in the active site allows solvent access to the labile third metal-binding site. Enzyme kinetics of PPM1Acat toward a phosphopeptide substrate supported a random-order, bi-substrate mechanism, with substantial interaction between the bound substrate and the labile metal ion. This work illuminates the structural and thermodynamic basis of an innate mechanism regulating the activity of PPM phosphatases. PMID- 29602905 TI - The plant defense signal galactinol is specifically used as a nutrient by the bacterial pathogen Agrobacterium fabrum. AB - The bacterial plant pathogen Agrobacterium fabrum uses periplasmic-binding proteins (PBPs) along with ABC transporters to import a wide variety of plant molecules as nutrients. Nonetheless, how A. fabrum acquires plant metabolites is incompletely understood. Using genetic approaches and affinity measurements, we identified here the PBP MelB and its transporter as being responsible for the uptake of the raffinose family of oligosaccharides (RFO), which are the most widespread d-galactose-containing oligosaccharides in higher plants. We also found that the RFO precursor galactinol, recently described as a plant defense molecule, is imported into Agrobacterium via MelB with nanomolar range affinity. Structural analyses and binding mode comparisons of the X-ray structures of MelB in complex with raffinose, stachyose, galactinol, galactose, and melibiose (a raffinose degradation product) revealed how MelB recognizes the nonreducing end galactose common to all these ligands and that MelB has a strong preference for a two-unit sugar ligand. Of note, MelB conferred a competitive advantage to A. fabrum in colonizing the rhizosphere of tomato plants. Our integrative work highlights the structural and functional characteristics of melibiose and galactinol assimilation by A. fabrum, leading to a competitive advantage for these bacteria in the rhizosphere. We propose that the PBP MelB, which is highly conserved among both symbionts and pathogens from Rhizobiace family, is a major trait in these bacteria required for early steps of plant colonization. PMID- 29602906 TI - Thylakoid membranes contain a non-selective channel permeable to small organic molecules. AB - The thylakoid lumen is a membrane-enclosed aqueous compartment. Growing evidence indicates that the thylakoid lumen is not only a sink for protons and inorganic ions translocated during photosynthetic reactions but also a place for metabolic activities, e.g. proteolysis of photodamaged proteins, to sustain efficient photosynthesis. However, the mechanism whereby organic molecules move across the thylakoid membranes to sustain these lumenal activities is not well understood. In a recent study of Cyanophora paradoxa chloroplasts (muroplasts), we fortuitously detected a conspicuous diffusion channel activity in the thylakoid membranes. Here, using proteoliposomes reconstituted with the thylakoid membranes from muroplasts and from two other phylogenetically distinct organisms, cyanobacterium Synechocystis sp. PCC 6803 and spinach, we demonstrated the existence of nonselective channels large enough for enabling permeation of small organic compounds (e.g. carbohydrates and amino acids with Mr < 1500) in the thylakoid membranes. Moreover, we purified, identified, and characterized a muroplast channel named here CpTPOR. Osmotic swelling experiments revealed that CpTPOR forms a nonselective pore with an estimated radius of ~1.3 nm. A lipid bilayer experiment showed variable-conductance channel activity with a typical single-channel conductance of 1.8 nS in 1 m KCl with infrequent closing transitions. The CpTPOR amino acid sequence was moderately similar to that of a voltage-dependent anion-selective channel of the mitochondrial outer membrane, although CpTPOR exhibited no obvious selectivity for anions and no voltage dependent gating. We propose that transmembrane diffusion pathways are ubiquitous in the thylakoid membranes, presumably enabling rapid transfer of various metabolites between the lumen and stroma. PMID- 29602907 TI - An N-terminally truncated form of cyclic GMP-dependent protein kinase Ialpha (PKG Ialpha) is monomeric and autoinhibited and provides a model for activation. AB - The type I cGMP-dependent protein kinases (PKG I) serve essential physiological functions, including smooth muscle relaxation, cardiac remodeling, and platelet aggregation. These enzymes form homodimers through their N-terminal dimerization domains, a feature implicated in regulating their cooperative activation. Previous investigations into the activation mechanisms of PKG I isoforms have been largely influenced by structures of the cAMP-dependent protein kinase (PKA). Here, we examined PKG Ialpha activation by cGMP and cAMP by engineering a monomeric form that lacks N-terminal residues 1-53 (Delta53). We found that the construct exists as a monomer as assessed by whole-protein MS, size-exclusion chromatography, and small-angle X-ray scattering (SAXS). Reconstruction of the SAXS 3D envelope indicates that Delta53 has a similar shape to the heterodimeric RIalpha-C complex of PKA. Moreover, we found that the Delta53 construct is autoinhibited in its cGMP-free state and can bind to and be activated by cGMP in a manner similar to full-length PKG Ialpha as assessed by surface plasmon resonance (SPR) spectroscopy. However, we found that the Delta53 variant does not exhibit cooperative activation, and its cyclic nucleotide selectivity is diminished. These findings support a model in which, despite structural similarities, PKG Ialpha activation is distinct from that of PKA, and its cooperativity is driven by in trans interactions between protomers. PMID- 29602909 TI - Age-dependent sex ratios of motor neuron disease: French nationwide study and meta-analysis. AB - OBJECTIVE: To examine the relation of age with male-to-female (M/F) ratios and incidence rates of motor neuron disease (MND) in a French nationwide study and meta-analysis of incidence studies. METHODS: We used data from the French National Health Insurance databases. Patients with incident MND (2010-2014) were identified based on drug claims (riluzole), hospitalization records, death records, and long-term chronic disease benefits. We estimated age-specific M/F incidence ratios using Poisson regression. Poisson, Gompertz, and multistep models were used to model the relation between age and incidence. We performed a meta-analysis (n = 28 studies) and used meta-regression to examine the relation of age with incidence rates and ratios. RESULTS: In France, we identified 10,848 patients with incident MND (6,021 men, 4,827 women). Incidence was higher in men than in women in all age groups. M/F ratios were significantly different across age groups and followed a quadratic trend (p < 0.001). Between 20 and 49 years, the average M/F ratio was 2.26 (95% confidence interval [CI] = 1.96-2.62); it was 1.41 (95% CI = 1.35-1.47) between 50 and 84 years, and 1.88 (95% CI = 1.64-2.17) after 85 years. Incidence was lower in women than men at younger ages, but increased more steeply in women than men. Similar patterns were observed in the meta-analysis of incidence studies, especially in 19 higher-quality studies. CONCLUSION: The relation between age and M/F incidence ratios of MND follows a quadratic U-shaped pattern with an abrupt drop after the fifth decade. The change in M/F ratios before and after menopause suggests that reproductive/hormonal protective factors have a role in women and should prompt further studies to explore this hypothesis. PMID- 29602910 TI - Neurocognition, sleep, and PET findings in type 2 vs type 1 narcolepsy. AB - OBJECTIVE: To analyze differences in functional brain images collected in patients with type 2 and type 1 narcolepsy compared to normal controls and the relationship among brain images, objective neuropsychologic tests, and sleep findings. METHODS: Data collection included comprehensive clinical investigation, study of sleep/wake with actigraphy, polysomnography, Multiple Sleep Latency Test, human leukocyte antigen typing, 18F-fluorodeoxyglucose PET, and cognitive tests obtained from 29 patients with type 2 narcolepsy, 104 patients with type 1 narcolepsy, and 26 sex- and age-matched normal control individuals. Conners' Continuous Performance Test (CPT II) and Wisconsin Card-Sorting Task were performed simultaneously with the FDG-PET examination. After analyses of variance, data between patients with type 1 and type 2 narcolepsy were compared by post hoc analysis, and correlation between functional brain imaging findings and results of neurocognitive tests was obtained. RESULTS: All patients with narcolepsy presented with at least 2 sleep-onset REM periods (SOREMP) and subjective sleepiness. Patients with type 2 narcolepsy compared to patients with type 1 narcolepsy had significantly less SOREMP, longer mean sleep latencies, and lower body mass indexes, apnea-hypopnea indexes, and frequency of human leukocyte antigen DQ-Beta1*0602. In patients with type 2 narcolepsy, FDG-PET studies showed significantly less hypermetabolism in the fusiform gyrus, striatum, hippocampus, thalamus, basal ganglia, and cerebellum than in patients with type 1 narcolepsy, and significantly less hypometabolism in the regions of frontal lobe, posterior cingulum, angular gyrus, and part of the parietal lobe; these changes were associated with fewer errors on the CPT. CONCLUSION: Young patients with type 2 narcolepsy have fewer clinical impairments and less distinct brain functional abnormalities than patients with type 1 narcolepsy, who are significantly more affected. PMID- 29602908 TI - A Review of Promising Natural Chemopreventive Agents for Head and Neck Cancer. AB - Head and neck squamous cell carcinoma (HNSCC) accounts for 300,000 deaths per year worldwide, and overall survival rates have shown little improvement over the past three decades. Current treatment methods including surgery, chemotherapy, and radiotherapy leave patients with secondary morbidities. Thus, treatment of HNSCC may benefit from exploration of natural compounds as chemopreventive agents. With excellent safety profiles, reduced toxicities, antioxidant properties, and general acceptance for use as dietary supplements, natural compounds are viewed as a desirable area of investigation for chemoprevention. Though most of the field is early in development, numerous studies display the potential utility of natural compounds against HNSCC. These compounds face additional challenges such as low bioavailability for systemic delivery, potential toxicities when consumed in pharmacologic doses, and acquired resistance. However, novel delivery vehicles and synthetic analogues have shown to overcome some of these challenges. This review covers 11 promising natural compounds in the chemoprevention of HNSCC including vitamin A, curcumin, isothiocyanate, green tea, luteolin, resveratrol, genistein, lycopene, bitter melon, withaferin A, and guggulsterone. The review discusses the therapeutic potential and associated challenges of these agents in the chemopreventive efforts against HNSCC. Cancer Prev Res; 11(8); 441-50. (c)2018 AACR. PMID- 29602911 TI - Rare side effects of alemtuzumab remind us of the need for postmarketing surveillance. PMID- 29602912 TI - Acute acalculous cholecystitis: A new safety risk for patients with MS treated with alemtuzumab. AB - OBJECTIVE: To evaluate acute acalculous cholecystitis (AAC) as a potential safety risk for patients treated with alemtuzumab. METHODS: The Food and Drug Administration Adverse Event Reporting System and the medical literature were searched for cases of AAC in conjunction with alemtuzumab for all clinical indications. RESULTS: Eight spontaneously reported cases meeting the case definition of AAC in close temporal association with alemtuzumab use were identified. Based on established criteria within the Food and Drug Administration Division of Pharmacovigilance for causality assessment, 4 cases were assessed as probable while 4 were possible. All cases occurred in patients with relapsing remitting multiple sclerosis. Seven of the 8 cases presented with AAC during or shortly after alemtuzumab treatment, thereby suggesting an acute cytokine release syndrome as a putative pathogenic mechanism. The cases identified in this review differ from the typical AAC cases described in the medical literature based on female preponderance, lack of concurrent critical illnesses, inconsistent presence of other risk factors, and resolution with conservative treatment in the majority of cases. CONCLUSIONS: AAC represents a new and potentially life threatening adverse event associated with alemtuzumab use in relapsing-remitting multiple sclerosis. In cases seen to date, early and conservative treatment resulted in good clinical outcome, although the natural history of AAC in this population without critical illness is not well defined. Awareness of this safety risk by general and specialty neurologists is important for prompt recognition and optimal management. PMID- 29602913 TI - Sensory cortex hyperexcitability predicts short survival in amyotrophic lateral sclerosis. AB - OBJECTIVE: To investigate somatosensory cortex excitability and its relationship to survival prognosis in patients with amyotrophic lateral sclerosis (ALS). METHODS: A total of 145 patients with sporadic ALS and 73 healthy control participants were studied. We recorded compound muscle action potential and sensory nerve action potential of the median nerve and the median nerve somatosensory evoked potential (SEP), and we measured parameters, including onset to-peak amplitude of N13 and N20 and peak-to-peak amplitude between N20 and P25 (N20p-P25p). Clinical prognostic factors, including ALS Functional Rating Scale Revised, were evaluated. We followed up patients until the endpoints (death or tracheostomy) and analyzed factors associated with survival using multivariate analysis in the Cox proportional hazard model. RESULTS: Compared to controls, patients with ALS showed a larger amplitude of N20p-P25p in the median nerve SEP. Median survival time after examination was shorter in patients with N20p-P25p >=8 MUV (0.82 years) than in those with N20p-P25p <8 MUV (1.68 years, p = 0.0002, log rank test). Multivariate analysis identified a larger N20p-P25p amplitude as a factor that was independently associated with shorter survival (p = 0.002). CONCLUSION: Sensory cortex hyperexcitability predicts short survival in patients with ALS. PMID- 29602914 TI - Hemophagocytic lymphohistiocytosis in 2 patients with multiple sclerosis treated with alemtuzumab. PMID- 29602915 TI - Acute coronary syndrome associated with alemtuzumab infusion in multiple sclerosis. PMID- 29602917 TI - Correction to "Investigation into the Mechanism of Homo- and Heterodimerization of Angiotensin-Converting Enzyme". PMID- 29602916 TI - Insulin resistance and clinical outcomes after acute ischemic stroke. AB - OBJECTIVE: In this study, we aimed to determine whether insulin resistance is associated with clinical outcomes after acute ischemic stroke. METHODS: We enrolled 4,655 patients with acute ischemic stroke (aged 70.3 +/- 12.5 years, 63.5% men) who had been independent before admission; were hospitalized in 7 stroke centers in Fukuoka, Japan, from April 2009 to March 2015; and received no insulin therapy during hospitalization. The homeostasis model assessment of insulin resistance (HOMA-IR) score was calculated using fasting blood glucose and insulin levels measured 8.3 +/- 7.8 days after onset. Study outcomes were neurologic improvement (>=4-point decrease in NIH Stroke Scale score or 0 at discharge), poor functional outcome (modified Rankin Scale score of >=3 at 3 months), and 3-month prognosis (stroke recurrence and all-cause mortality). Logistic regression analysis was used to evaluate the association of the HOMA-IR score with clinical outcomes. RESULTS: The HOMA-IR score was associated with neurologic improvement (odds ratio, 0.68 [95% confidence interval, 0.56-0.83], top vs bottom quintile) and with poor functional outcome (2.02 [1.52-2.68], top vs bottom quintile) after adjusting for potential confounding factors, including diabetes and body mass index. HOMA-IR was not associated with stroke recurrence or mortality within 3 months of onset. The associations were maintained in nondiabetic or nonobese patients. No heterogeneity was observed according to age, sex, stroke subtype, or stroke severity. CONCLUSIONS: These findings suggest that insulin resistance is independently associated with poor functional outcome after acute ischemic stroke apart from the risk of short-term stroke recurrence or mortality. PMID- 29602918 TI - The evaluation of teeth loosening of the upper jaw in adaptive period of orthodontic treatment by braces. AB - OBJECTIVE: Introduction: Tooth loosening is divided into physiological and pathological one, but there is tooth loosening that occurs during orthodontic treatment (OT) and depends on the tissues of parodontium and strength of orthodontic apparatus. The aim of the research is to evaluate teeth loosening of the upper jaw during adaptive period in patients with permanent bite who were treated by braces. PATIENTS AND METHODS: Materials and methods: Periostometry (device "Periotest") of teeth to 30 patients who are from 14 to 27 years old with the pathology of the first type based Angle's classification. The evaluation of teeth loosening was done before OT, in 1 month, in 3 months and in 6 months. RESULTS: Results: The average index of teeth loosening before OT in patients included 3,08+/-1,29, so it corresponded to norm indices. In 1 month after braces fixation indices of tooth loosening were increased. Middle index of teeth loosening on the third month of OT was 5,84+/-0,77 relative units, that in 1,9 times more than periostometric indices before OT. CONCLUSION: Conclusions: Changes of teeth loosening during OT by braces during the first month after fixation. It should be noted that during the first month of OT data of periostometry determine the enlargement of teeth loosening of all teeth in 1,38, in 3 months there is decrease of teeth loosening for all types of teeth. On the 6th month of OT indices of teeth loosening continue decreasing but with lesser intensity and not achieve such level which was to the beginning of OT. PMID- 29602919 TI - Effect of prolonged and intermittent treatment on the clinical course of peptic ulcer. AB - OBJECTIVE: Introduction: The number of patients with peptic ulcer increases annually. According to published data, patients with peptic ulcer constitute about 15% of those hospitalized with gastrointestinal diseases. The aim: That is why we set the task to evaluate the methods of preventive treatment and to choose the most effective one. PATIENTS AND METHODS: Materials and methods: For this purpose, we selected 103 patients with peptic ulcer without severe exacerbations and complications from one region (main group) and 101 patients from another region (control group) for observations. Making diagnosis was based on the study of complaints, anamnestic data, physical examination of the patient, evaluation of the functional state of the gastroduodenal system, as well as the X-ray and endoscopic examination. The sources of the study were medical records of outpatients, control cards for dispensary surveillance, registers of temporary disability records, sick leave records and others. RESULTS: Results: Most patients, from both the main and control groups, who were on prophylactic treatment, noticed that they had an increased working capacity, normalized sleep, better appetite and fewer dyspeptic disorders. Patients in the main group for two years were on prolonged prophylactic treatment according to the method that we had developed. by us. Patients in the control group received an intermittent preventive treatment twice a year (in spring and autumn). In the complex of therapeutic measures the following were used: dietary recommendations, antacids, cholinolytics, multivitamins, etc. CONCLUSION: Conclusions: Prolonged prophylactic treatment is an effective means to combat exacerbations and complications of peptic ulcer and can be recommended for implementation in practice. PMID- 29602920 TI - [The influence of stress-strain processes in tooth enamel on the marginal permeability of class i restorations with a different design of the edge of the carious cavity]. AB - OBJECTIVE: Introduction: Of the factors affecting the marginal permeability of restorations in the teeth, the state of stress-strain processes in the enamel with different design of the edge of the carious cavity has been poorly studied. The aim of this research was to study the influence of stress-strain processes in tooth enamel on the marginal permeability of class I restorations with a different design of the edge of the carious cavity. PATIENTS AND METHODS: Materials and methods: We have examined 45 pulled out intact third molars, which were divided into three groups of 15 each, depending on class 1 carious cavities formed in them. In I group we formed a carious cavity without a bevel of enamel, in II - with external bevel of enamel, in III - with internal bevel of enamel. Carious cavities were restored with a microhybrid composite light curing material. The teeth were undergone thermocycling and a single vertical mechanical load, were covered with nail polish, placed in a 1% aqueous solution of methylene blue, separated in the medio-distal direction, and the depth of dye penetration was studied. The stress-strain state of the enamel was modelled by the finite elements method. RESULTS: Results: Nonparametric statistical analysis showed that there is a close relationship between the values of stress and strain in enamel and the marginal permeability of restorations. The higher are these values, the deeper is the penetration of the dye. When the edge of the carious cavity is formed with external bevel of enamel, the lowest penetration of the dye is observed, with the internal bevel - the maximal. The results obtained can be useful for clinicians in the preparation of class I carious cavities. CONCLUSION: Conclusions: The higher the values of stress and strain in enamel, the deeper the marginal permeability of restorations. When the external bevel of the enamel is formed, the dye penetrates least, and when the internal bevel is formed - the maximal. PMID- 29602921 TI - The influence of the manual thrombus aspiration on the short term effectiveness of the percutaneous revascularization in patients with coronary artery thrombosis. AB - OBJECTIVE: Introduction: Percutaneous coronary intervention (PCI) is one of the main issues in treatment of acute coronary syndrome with ST segment elevation (STEMI). The manual thrombus aspiration was believed to improve the results of intervention especially in patients with coronary thrombosis. The aim: To explore the influence of manual thrombus aspiration on the short-termed prognosis after PCI in patients with STEMI and visible coronary thrombosis. PATIENTS AND METHODS: Materials and methods: 50 patients with STEMI and visible coronary thrombosis were included for exploration. Main group (MG) consists of 25 patients to whom manual thrombus aspiration was performed and comparison group (CG) of 25 patients whom were performed just conventional PCI. RESULTS: Results: In the 84% patients of the MG and in 72% CG was gained TIMI 3 flow grade after the procedure (r=0.5). MBG 3 was reached in similar number of patients from both groups ( r=0.37). Comparison of the ejection fraction of the LV and its' wall motion score brought the same results. The trend to better indexes of glomerular filtration rate was observed in the patients of the MG (r=0.18). Need of the balloon angioplasty before stenting was the unique index improved by the manual thrombus aspiration (r=0.02). CONCLUSION: Conclisions: No significant advantages of the manual thrombus aspiration usage weren't revealed compearing to conventional PCI in our study in the patients with STEMI and visible coronary thrombosis. At the same time few insignificant trends were reveled. So the more powerful trial is needed to solve this problem. PMID- 29602922 TI - Indicators of phagocytosis in women with acne during comprehensive treatment that included immunotherapy and probiotics. AB - OBJECTIVE: Introduction: Acne is one of the most common dermatological diseases. It may have a chronic course, leaving permanent marks, and in last years has been tending to have more and more severe clinical course with widespread skin lesions. According to recent studies, the development of acne is due to the combined effect of endogenous and exogenous factors, among which endocrine diseases (quite a significant aspect), disorders of metabolic processes, reduced systemic immunity and phagocytic ability of mononuclear phagocytes and granulocytes at various stages of phagocytosis of pyogenic cocci, which contributes to more severe clinical course, and frequent relapse of this diseases. It was also proved that the intestinal microbiota plays an important role in the formation of homeostasis and immune response. The aim of the studyis to determine the evolution of phagocytosis indices in patients with acne under differentcomprehensive treatments, using oral antibiotics, immunotherapy, probiotics and low-dose birth control pills. PATIENTS AND METHODS: Materials and methods: We observed 93 women with acne aged from 18 to 25 years old. In 19 (20,43 %) patients mild acne was diagnosed, in 41 (44.09%) - moderate acne, in 33 (35.48 %) persons - severe acne, 54 (58,06%) persons suffered from acne up to 1 year, 39 (41,93%) - from 1 to 3 years. To assess the state of phagocytosis in patients with acne vulgaris, we determined phagocytic activity (PA) and phagocytic index (PI) of polymorphonuclear leukocytes, nitro blue tetrazolium recovery test (NBT test spontaneous) and NBT-test pyrogenal stimulated by the recognized methods. RESULTS: Results: Analysis of the studied parameters of phagocytosis at the end of treatment showed a significant increase in patients of the core group who were administered a comprehensive treatment which included oral antibiotic, probiotic, low-dose birth control pills and autohemotherapy, as compared with the patients of other groups under study. CONCLUSION: Conclusions: Using combined therapy for women with acne occurring against the backdrop of a sluggish process of phagocytosis and concomittant intestinal dysbiosis leads to normalization of the leading indices of phagocytosis (PI, PA, NBT tests both spontaneous and stimulated), and enchances their phagocytic activity both during capture and formation of bactericidal activity and in the final stages of phagocytosis justifying the feasibility of a combined use of antibiotics, probiotic, low-dose birth control pills and autohemotherapy in the treatment of acne. PMID- 29602923 TI - [The role of genes of renin-angiotensin system in the development of adverse outcomes of treatment in severe intraventricular hemorrhages in premature infants]. AB - OBJECTIVE: Introduction: Intraventricular hemorrhage (IVH) causes increased morbidity and mortality in premature infants and is associated with adverse neurological outcomes. The aim of the research is to confirm the role of genes of renin-angiotensin system in the development of adverse outcomes of treatment of severe IVC in preterm. PATIENTS AND METHODS: Materials and methods: A prospective study was conducted, which included 58 premature infants (average birth weight 1016.8 +/- 52.59 g, gestational age 26.96 +/-0.33 weeks), who were treated at medical institutions in Poltava region during 2012-2015. I/D polymorphism of ACE gene, A/C polymorphism of AGT2R1 gene and 4a/b polymorphism of the eNOS gene were studied. The distribution of the genotype was compared between groups using the chi2 analysis. RESULTS: Results: Out of 58 children enrolled in the study, 33 (56.9%) of infants developed ventricular dilatation, which in 8 (13.8%) of the newborns progressed to hydrocephalus. Thirty-four (58.6%) infants with severe IVHs died. The average (median) time of death of infants was 10.6 days. Among children who died, a combination of genotypes ID & DD of the gene ACE +4ab & 4AA of the eNOS gene was found significantly more often than in children who survived, and at the border of statistical significance - the isolated genotype 4ab & 4 aa of the eNOS gene. The combination of genotype ID+DD of the ACE gene and the AC + CC genotype of the AGTR1 gene was significantly more frequent among children with ventricular dilatation than in children without it. The weight at birth have negative correlation trends with lethal outcomes and do not have with ventricular dilatation and hydrocephalus. CONCLUSION: Conclusions: Lethal outcomes in children with IVH are associated with weight at birth, as well as the presence of a combination of genotypes ID+DD of the ACE gene and 4ab+4aa of the eNOS gene. PMID- 29602924 TI - The study of leukocyte phagocytic activity in the presence of herpetic infection and stroke. AB - OBJECTIVE: Inrtoduction: Post-stroke complications are one of the urgent and insufficiently resolved problems. According to different literature data 23% to 65% of patients suffer from the post-stroke development of an infectious process. Herpes simplex virus type 1 and 2 can also be etiological factors of stroke development, however their reactivation is seldom mentioned in clinical observations. The development of immune suppression is considered to be the cause of these complications. The aim: The current study aims at determining post stroke changes in leukocyte component of the immunity and in the presence of concomitant herpetic infection as well as at finding changes in phagocytosis parameters during antiviral treatment. PATIENTS AND METHODS: Materials and methods: The experiments were carried out on mice of the Balb/s line. The animals were infected with the herpes simplex virus type I, and 30 days later hemorrhagic stroke was simulated by administering 0.1 ml of autoblood into the right hemisphere. Following the acute stroke some animals were given acyclovir, proteflazid or altabor. From the animals' blood leukocytes were obtained and phagocytic activity and production of reactive oxygen species of granulocytes and agranulocytes in relation to fluorescent E.coli bacteria were studied by flow cytometry. RESULTS: Results: The experiment revealed significant changes in the redistribution between two major types of leukocytes in mice with stroke (an increased number of agranulocytes by 19.9%) and decreased phagocytosis activity, in the animals infected with herpes simplex virus type I in particular. Ischemic brain damage had an immunosuppressive effect on blood leukocytes. For comparison a significant increase in phagocyte count in leukocytes was found in the case of viral infection. The use of drugs with antiviral effects did not affect the activity of granulocytes / agranulocytes. CONCLUSION: Conclusion: Stroke can be the cause of latent herpes virus infection reactivation and has essential negative effect on immune characteristics of leukocytes that remain unchanged with the use of antiviral agents. PMID- 29602925 TI - [Risk factors for adverse course of gastric and duodenal peptic ulcer]. AB - OBJECTIVE: Introduction: High morbidity rate, frequent relapses, and significant economic losses give reasons for highlighting the peptic ulcer disease as the most topical medical-statistical problem. The aim of the study is to assess the influence of the main risk factors on the course of gastric and duodenal peptic ulcer. PATIENTS AND METHODS: Materials and methods: We formed up the risk groups consisted of patients with 12 modified (4) and regular (8) factors, each characterized with its own signs and gradations. We performed the quantitative evaluation of the factors and scored the signs thereof, the results of which were used for determination of the most informative ones. RESULTS: Results: Among the regular factors, we placed emphasis on gender, age, burdened heredity, and 0(I), Rh+ blood type. The risk of peptic ulcer in hereditary tainted young men of the working age with parental lineage (+2.3) and in males with 0(I) Rh+ blood type (+1.4) was proved. Helicobacter pylori (Hp) infection is a key contributor (a predictor of) to severity of the disease course (+9.7) among the modified risk factors. Negative effect of a concomitant pathology (+5.0), including hepatobiliary lesions (+3.8), hypertension (+4.0), and diabetes mellitus (+1.3) is also significant. Diet violation (+3.7), tobacco smoking (+3.2) and stress (+3.0) were ranked third. CONCLUSION: Conclusions: The results of quantitative evaluation of the factors scoring suggest of the underlying H.pylori infection (the significance of which is growing along with the growth of the disease incidence) and irrational diet as the most informatively important ones. We have established the direct dependence between the most important peptic ulcer risk factors, severity of the disease, and duration and periodicity of treatment thereof. PMID- 29602926 TI - Health of ophthalmologists as a prerequisite of quality medical services. AB - OBJECTIVE: Introduction: The effectiveness and efficiency of the medical sector workforce directly depend on health of medical professionals. Scientific literature pays considerable attention to the health of surgeons, physicians, obstetricians, gynecologists, infectionists and dentists paying very little, if any, attention to health problems of ophthalmologists. This study is intended to bridge this gap. The aim at revealing the current situation and characteristics of health status of ophthalmologists using the results of sociological research and identifying health problems of the respondents in order to determine reliable preventive measures. PATIENTS AND METHODS: Materials and methods: The authors used bibliographic, medical-statistical, sociological and informational analytical methods as well as analyzed questionnaires of the sociological survey conducted among ophthalmologists from various regions of Ukraine. RESULTS: Results: The results of the sociological survey allowed determining the main medical-demographic and occupational characteristics of the ophthalmologists working at health facilities. It was found that11,1+/-2,1 per 100 respondents assess their health condition as very good and 34,3+/-3,2 per 100 respondents - as good. At the same time every third respondent reports own health condition as satisfactory, 18,5+/-2,6 per 100 respondents report their health condition as bad and 2,8+/-1,2 per 100 respondents - as very bad. Chronic diseases in the history were confirmed by 52,8+/-3,4 per 100 ophthalmologists, recurrent acute diseases were reported by 48,6+/-3,4 per 100 respondents. Some ophthalmologists reported their low medical activity due to a number of reasons. The main factors that adversely affect the health of ophthalmologists include considerable workload, the need to work part-time for subsistence, neuro-emotional stress, insufficiently equipped medical and diagnostic process lacking modern technologies, poor team atmosphere, lack of comfort at the workplace and others. CONCLUSION: Conclusions: Own health condition assessed by ophthalmologists, the prevalence of chronic and acute pathology, factors of the working environment affecting health serve as the ground for improving prophylaxis activities among ophthalmologists and strengthening their health as a prerequisite for the quality medical services. PMID- 29602927 TI - [Features of local immunity in local inflammatory reactions in pregnant, depending on the implementation of intrauterine infection]. AB - OBJECTIVE: Introduction: Vaginal protective systems function independently of other systemic mechanisms and impairments of local immune mechanisms of the vaginal mucosa are the cause of infectious disorders of the reproductive system The aim: To assess characteristics of local immunity in local inflammatory reactions in pregnant, depending on the implementation of intrauterine infection. PATIENTS AND METHODS: Materials and methods: The study comprised Group 1 of pregnant women with the presence of bacterial infections with and without implementation of IUI, Group 2 with the presence of viral infections with and without implementation of IUI, Group 3 with the presence of infections of combined polyetiological structure with and without implementation of IUI and control group included pregnant women with physiological pregnancy. The study implied evaluation of the number of leukocytes in vaginal contents, concentration of IgA, IgM, IgG, sIgA, concentration of cytokines-IL-1 beta , IL-6, IL-10, TNF- alpha in vaginal swabs. RESULTS: Results: Women with the presence of an infectious process without its implementation, regardless of the etiologic factor, were found to have more expressed inflammatory reactions. In the presence of a viral infection, changes in the humoral link of local immunity were less expressed. In Group 1 without implementation of IUI, the concentration of IL-1 beta was (73.68 +/- 10.23) pg / ml, IL-6 was (53.3 +/- 6.8) pg / ml. In Group 2 with implementation of IUI, concentration of IL-10 was (26.72 +/- 4.35) pg / ml. In Group 2 without implementation of IUI, the content of TNF-alpha was (575.25 +/ 69.03) pg / ml. CONCLUSION: Conclusions: The study showed the differences between the groups of pregnant women with different outcome of IUI in the content of proinflammatory and anti-inflammatory cytokines. PMID- 29602928 TI - Comparative hygienic assessment of active ingredients content in the air environment after treatment of cereal spiked crops by combined fungicides. AB - OBJECTIVE: Introduction: The quality of the air environment significantly affects the health of the population. Chemical plant protection products in the spring and summer time may be the main pollutants of the air environment in rural areas. Chemical plant protection products are dangerous substances of anthropogenic origin. If applying pesticides in high concentrations, the risk of poisoning by active ingredients of pesticide preparations in workers directly contacting with it increases. The aim: Comparative hygienic assessment of active ingredients content in the air environment after treatment of cereal spiked crops by combined fungicides was the aim of the work. PATIENTS AND METHODS: Materials and methods: Active ingredients of the studied combined fungicides, samples of air, and swabs from workers' skin and stripes from overalls were materials of the research. Methods of full-scale in-field hygienic experiment, gas-liquid chromatography, high-performance liquid chromatography, as well as statistical and bibliographic methods were used in the research. RESULTS: Results and conclusions: Active ingredients of the studied combined fungicides were not detected in the working zone air and atmospheric air at the levels exceeding the limits of its detection by appropriate chromatography methods. Findings confirmed the air environment safety for agricultural workers and rural population if studied combined fungicides are applied following the hygienically approved suggested application rates and in accordance of good agricultural practice rules. However the possible complex risk for workers after certain studied fungicides application may be higher than acceptable due to the elevated values for dermal effects. The complex risk was higher than acceptable in eru case of aerial spraying of both studied fungicides, meanwhile only one combination of active ingredients revealed possible risk for workers applying fungicides by rod method of cereal spiked crops treatment. PMID- 29602929 TI - Clinical and laboratory characteristics of hepatitis d in Republic of Sakha (Yakutia). AB - OBJECTIVE: Inrtroduction: The epidemiological situation for hepatitis D has changed significantly. Reduced population authors infection due to a sharp decline in hospitalizations from Central Asia regions, the Caucasus and Moldova, which are known to be endemic for hepatitis D. Currently, the incidence of chronic hepatitis D (HGD) in Russia is 1%, while in the countries of Central Asia, and in particular in Turkmenistan, the share of HGD among chronic viral hepatitis is 8%. The aim of research was to establish the clinical features, depending on the activity of the replication of hepatitis viruses B and D. PATIENTS AND METHODS: Materials and Methods: We studied 26 patients with viral hepatitis D with a determined activity replicative virus by PCR (polymerase chain reaction). The age of patients ranged from 28 to 78 years. The patients performed the ELISA (enzyme-linked immunosorbent assay) study for the presence of markers of parenteral viral hepatitis (HBsAg, a-HCV and a-HDV), the standard general clinical biochemical blood tests. of the instrumental methods survey used ultrasonography (ultrasound), EGD (fibrogastroduodenoscopy). Grading the severity of liver cirrhosis established by Child-Pugh (eng. Child-Pugh, Child-Turcotte, Child-Turcotte-Pugh, sometimes Child-Paquet) is designed to assess the severity of cirrhosis. The severity of liver cirrhosis is assessed on a point system, which are calculated from 5 or 6 parameters. RESULTS: Results: It is established that most HGD more prevalent among young people bodied (69%) and occurs mainly in severe symptoms and portal hypertension leading to the rapid development of liver cirrhosis (53%). It showed that hyperenzymemia reaches high levels of ALT to 1715 U / L. with a high viral DNA load virus (HBV) 2648226,0 +/- 953892,7 copies / ml in the presence of an RNA virus D (HDV +). CONCLUSION: Conclusion: Thus, the main feature of chronic hepatitis D is its predominant tsirrogennost. PMID- 29602930 TI - Stereomorphology of the glandular parenchyma of the inferoposterolateral area of human prostate gland. AB - OBJECTIVE: Introduction: The human prostate gland contains numerous tubular masses of different calibers in its parenchyma. They form the tubuloalveolar prostate glandules, constituting from numerous prostatic excretory ductules as well as major excretory ducts. The aim: The study was aimed at 3D visualization of individual microelements of the tubuloalveolar aggregations, localized within the peripheral area. PATIENTS AND METHODS: Materials and methods: To meet the objectives of the study a series of paraffin plane-parallel 4 MUm sections has been obtained in the peripheral prostate area. The serial sections were stained with hematoxylin and eosin. After the analysis of the series of sections, the graphical two-dimensional and plastic 3D reconstructions of the investigated microobjects have been made sequentially in depth. RESULTS: Results: Presence of the epithelial creases and invaginations of the wall in the luminal contour of tubuloalveolar aggregations of the prostate has been found. Creases can be solitary, multiple, or wavy; they can be localized both symmetrically and asymmetrically, with different heights and thicknesses. Intraluminal invaginations, along with the epithelial crease, contain a stromal muscle component with localized blood loop-shaped microvessel. The creases of the glandular epithelium and intraluminal invaginations can "overlap" the lumens of the tubuloalveolar aggregations up to 2/3 of the width, making the inner lumen sinuous that influences the laminar flow of the liquid. CONCLUSION: Conclusions: Alternation of the considerable enlargement and narrowing of the inner diameter is common for the tubuloalveolar aggregations which can affect the secreta deposition and movement. PMID- 29602931 TI - characterization of lepr gene Q223R (RS1137101) genotypes in patients with knee joint osteoarthritis of different radiographic stages. AB - OBJECTIVE: Introduction: Osteoarthritis is a multifactorial joint disease with a significant role of the genetic factor. The numerous studies have demonstrated that genetic dependence is specific for individual hand, hip and knee regions with a genetic contribution to the pathogenesis of osteoarthrosis varying from 40% to 65%. To assess the role of leptin gene receptor functional activity disturbance in the pathogenesis of osteoarthrosis, it is important to study the relationship between the LEPR gene polymorphism and a number of clinical and laboratory parameters. The study objective was to determine the relationship between the LEPR gene Q223R (rs1137101) polymorphism and the radiographic stage of osteoarthrosis of the knee in female patients of the Ukrainian population. PATIENTS AND METHODS: Materials and methods: The rs1137101 polymorphism was genotyped in 99 female patients diagnosed with osteoarthrosis of the knee using polymerase chain reaction in a real-time mode. RESULTS: Results: It was a tendency of lower prevalence of AA homozygotes and higher prevalence of AG heterozygotes with growing the severity of the disease. The high prevalence of homozygous carriers of the variant allele G in radiographic Stage I patients preconditioned the absence of statistically significant differences in the distribution of genotypes between the groups. CONCLUSION: Conclusion: No statistically significant differences in the distribution of prevalence of alleles and LEPR gene Q223R (rs1137101) genotypes in the groups of patients with the knee OA of different radiographic stages have been revealed. PMID- 29602932 TI - [The epidemiology of sudden cardiac arrest in prehospital care in the area of the silesian voivodeship]. AB - OBJECTIVE: Introduction: Sudden cardiac arrest (SCA) is a serious medical and social issue. The incidence of SCA varies depending on the location and the circumstances. The aim: A retrospective analysis of non-hospital SCA cases from an epidemiological perspective. The research involved the population monitored by the Voivodeship Rescue Service (VRS) in Katowice. PATIENTS AND METHODS: Material and methods The analysis covered dispatch order forms and emergency medical procedure forms of the VRS in Katowice in 2016 (n = 249 872). The retrospective analysis involved cases of non-hospital SCA in adults (n = 1603). Quantitative parameters have been presented as average values with standard deviation. Non metric variables have been described by means of structure indicators. A comparative analysis was conducted by means of the Student's T-test for the quantitative variables and the Pearson's chisquared test for the non-metric variables. The statistical significance adopted for the purpose of all analyses was 0.05. RESULTS: Results: There were 1005 men (62.7%), 566 women (35.3%) and 32 cases (2.0%) where gender identification was not reported. Female individuals were generally older than male individuals (p = 0.000). Patients' average age was 65.7 years. The SCA attack rate was 59.37/100 000. SCA cases were usually reported in domestic conditions (71.1%, p = 0.000). In a majority of cases, the incident was witnessed by a third person (about 70.0% of cases, p= 0.000). Most of the SCA cases were reported in the first quarter of the year whereas the lowest number of cases was noticed in the third quarter (28.4 % vs 22.5 %). SCA was most frequent during the day. Restoration of spontaneous circulation was reported in 33.4% of the cases. CONCLUSION: Conclusions: The incidence of SCA is occasional in the context of all analyzed emergency cases in the period under research. However, SCA cases are related with a high risk of failure. Acting according to the currently available knowledge will probably cause an increase of the restoration of spontaneous circulation (ROSC) rate. PMID- 29602933 TI - International medical law and its impact on the ukrainian health care legislation. AB - OBJECTIVE: Introduction: The Ukrainian state has an urgent necessity of rapid search for essentially new legal and organizational forms of the healthcare system, reform of the legal regulation of healthcare services provision. In the context of European integration, the advancement of the medical industry reform is closely related to consideration of international standards and norms of health care. The aim: To study the impact of international medical law on the Ukrainian health care legislation. PATIENTS AND METHODS: Materials and methods: International and Ukrainian regulations and documents on health care were used in the research. System and structural, functional and legal comparative methods as well as systematization, analysis and synthesis were determinative in the research process. RESULTS: Review: Systematization of international documents on health care was made. The major problems in the Ukrainian health care legislation were determined in terms of their conformity with the international legislative norms. The expediency of the Medical Code adoption was grounded and its structure was defined. CONCLUSION: Conclusions: Most health care international acts are ratified by Ukraine and their provisions are implemented in the legislation. Simultaneously, there is a row of problems, which hinder the Ukrainian health care development and place obstacles in the way of European integration. To remove these obstacles, it is expedient to create a codified act - the Medical Code, which would systematize the provisions of the current medical laws and regulations and fill in the existing gaps in the legal regulation of health care. PMID- 29602934 TI - [The main directions of reforming the service of medical statistics in Ukraine]. AB - OBJECTIVE: Introduction: Implementation of new methods of information support of managerial decision-making should ensure of the effective health system reform and create conditions for improving the quality of operational management, reasonable planning of medical care and increasing the efficiency of the use of system resources. Reforming of Medical Statistics Service of Ukraine should be considered only in the context of the reform of the entire health system. The aim: This work is an analysis of the current situation and justification of the main directions of reforming of Medical Statistics Service of Ukraine. PATIENTS AND METHODS: Material and methods: In the work is used a range of methods: content analysis, bibliosemantic, systematic approach. The information base of the research became: WHO strategic and program documents, data of the Medical Statistics Center of the Ministry of Health of Ukraine. RESULTS: Review: The Medical Statistics Service of Ukraine has a completed and effective structure, headed by the State Institution "Medical Statistics Center of the Ministry of Health of Ukraine." This institution reports on behalf of the Ministry of Health of Ukraine to the State Statistical Service of Ukraine, the WHO European Office and other international organizations. An analysis of the current situation showed that to achieve this goal it is necessary: to improve the system of statistical indicators for an adequate assessment of the performance of health institutions, including in the economic aspect; creation of a developed medical and statistical base of administrative territories; change of existing technologies for the formation of information resources; strengthening the material-technical base of the structural units of Medical Statistics Service; improvement of the system of training and retraining of personnel for the service of medical statistics; development of international cooperation in the field of methodology and practice of medical statistics, implementation of internationally accepted methods for collecting, processing, analyzing and disseminating medical and statistical information; the creation of a medical and statistical service that adapted to the specifics of market relations in health care, flexible and sensitive to changes in international methodologies and standards. CONCLUSION: Conclusions: The data of medical statistics are the basis for taking managerial decisions by managers at all levels of health care. Reform of Medical Statistics Service of Ukraine should be considered only in the context of the reform of the entire health system. The main directions of the reform of the medical statistics service in Ukraine are: the introduction of information technologies, the improvement of the training of personnel for the service, the improvement of material and technical equipment, the maximum reuse of the data obtained, which provides for the unification of primary data and a system of indicators. The most difficult area is the formation of information funds and the introduction of modern information technologies. PMID- 29602935 TI - Factors of the medical career choice within the context of ukrainian healthcare reforms. AB - OBJECTIVE: Introduction: The article is dedicated to the motives of medical career choice studied by Ukrainian and foreign scientists, and by the authors themselves. The authors define the main motives, grouped into the pragmatic, social, scientific and professional ones, paying particular attention to the proposed reforms of the Healthcare of Ukraine "Health 2020". The aim: The study has been aimed at detection of the medical career choice factor groups and their possible correction during the medical training, defining possible influence of the Ukrainian Healthcare reformation onto alterations of the medical career choice. PATIENTS AND METHODS: Materials and methods: This article is based on bibliosemantic, dialectical, comparative, analytic, synthetic and comprehensive research methods. RESULTS: Review and conclusion: The authors have analyzed medical career motives according to the A. Maslow hierarchy of needs, comparing the present motives with the motives to be changed after reforming the Ukrainian healthcare. The authors conclude that according to the Maslow's hierarchy of needs, the medical career choice corresponding to the first, second and third needs level would be directly related to the pragmatic, social and scientific motives, further disappointment in career, low professional performance and professional "burnout". The career choice corresponding to the last levels of the needs hierarchy is related to the professional motives and self-actualization, but, due to the applicants' age and financial status of medical specialists in Ukraine, is not likely to occur. Positive changes in medical specialists' salary rise, social protection offered by the State and state support of the profession will provide for correction of motives onto the higher level, in this way, benefiting the patients. PMID- 29602936 TI - Pharmaceutical terms with onomastic component: quantitative, structural and lexico-semantic analysis. AB - OBJECTIVE: Introduction: The present paper examines the prevalence and role of eponymic terms in the Latin and English pharmaceutical terminologies. The aim: The authors aim to conduct the quantitative, structural and lexico-semantic analysis of the names of medications with the proprial component. PATIENTS AND METHODS: Materials and methods: The research material in the amount of 147 units was obtained by the continuous sampling from the dictionaries, guidebooks and manuals on prescription-writing using the narrative and component analysis methods, by means of which the arrangement, systematization, classification and interpretation of the structural, semantic and functional features of the units under consideration have been conducted. RESULTS: Review and conclusions: The research has resulted in the delineation of the following groups of eponymic terms in the pharmaceutical terminologies of Latin and English: (1) semisolid dosage forms (formae medicamentorum molles): 81 title (55.1%); (2) liquid dosage forms (formae medicamentorum fluidae): 60 lexical units (40.8%); (3) solid dosage forms (formae medicamentorum solidae): 6 cases (4.1%). The analysis of 147 units showed that the most extensive group of pharmaceutical terminology units with the eponymic component are the names that specify the dosage form of medication. The prospects for research are in the further in-depth study to examine the tendencies of eponymization in both synchronic and diachronic aspects. PMID- 29602937 TI - Influence of risk factors on development of chronic obstructive pulmonary disease and legislative foundations for copd medical care in Ukraine. AB - OBJECTIVE: Introduction: Out of all respiratory diseases COPD is the leading cause of death and is characterized with diffuse non-reversible airway obstruction. Many various components play role in development and progression of this disease, while COPD risk factors play the most prominent role. Further progress in healthcare system development around COPD in Ukraine requires analysis of legislation, regulating pulmonological medical service in Ukraine. The aim: To analyze the influence of major risk factors on the development of chronic obstructive pulmonary disease and to determine key legislative aspects of the organization of medical care for COPD patients in Ukraine. PATIENTS AND METHODS: Materials and methods: 50 medical literature sources were systematically reviewed as the material for the research of COPD risk factors and their impact on studies disease. Also, an analysis of existing legislative acts regulating the pulmonological medical care in Ukraine, specifically, in patients with COPD, was conducted. CONCLUSION: Conclusions: There is a need to develop and implement a set of organizational and medical measures aiming at addressing the priorities of public healthcare, and specifically improvement of the quality of medical care for patients with chronic obstructive pulmonary disease in Ukraine. PMID- 29602938 TI - Ensuring right to organic food in public health system. AB - OBJECTIVE: Introduction: Human health directly depends on safety and quality of food. In turn, quality and safety of food directly depend on its production conditions and methods. There are two main food production methods: traditional and organic. Organic food production is considered safer and more beneficial for human health. Aim: to determine whether the organic food production method affects human health. PATIENTS AND METHODS: Materials and methods: international acts, data of international organizations and conclusions of scientists have been examined and used in the study. The article also summarizes information from scientific journals and monographs from a medical and legal point of view with scientific methods. This article is based on dialectical, comparative, analytic, synthetic and comprehensive research methods. The problems of effects of food production methods and conditions on human health have been analyzed within the framework of the system approach. CONCLUSION: Conclusions: Food production methods and conditions ultimately affect the state and level of human health. The organic method of production activity has a positive effect on human health. PMID- 29602939 TI - [Personality traits of perpetrators of various types of crimes]. AB - This study was conducted in Nowy Wisnicz, with prisoners sentenced for: murders, sex crimes, theft and robbery, maintenance, bullying. A Polish adaptation of PAI test, made by the author of the study, was used. The study results and its statistical analysis showed characteristic personality features of particular criminal groups can be used in rehabilitation of disturbed people, addicts, and become the basis for preparing actions reducing frequency of committing crimes. PMID- 29602940 TI - Morphological and crystal chemical characteristic of pansreatic lithiasis. AB - OBJECTIVE: Introduction: Information on chemical and phase composition of pancreoliths is limited and discrepant. There are reports, that pancreoliths are composed by calcium, phosphate, calcium carbonate or combination of calcium with fatty acids The aim of the work is studying of structural characteristics of pancreatoliths in 5 clinical cases. PATIENTS AND METHODS: Materials and methods: Morphological and crystal-chemical study of five cases of pathological biomineralization in the pancreas were conducted in the work. RESULTS: Results: Two stones were located in the pancreatic duct, in other cases - in the ductal system of pancreas. Concretion sizes ranged from 0.5 to 1.5 cm in diameter. Pancreatic lithiasis' form depended on the location: in the duct of Wirsung single concretions were found (they were relatively large, oval stones with smooth, regular edges); multiple, small concretions with irregular edges, coral like stones dominated in the ductal system of pancreas. Histological study of pancreas showed the signs of chronic pancreatitis, tissue fibrosis, atrophy and edema of glandular component, system distension of ducts, nidal mix-cell inflammatory infiltrates, vessels' plethora. Structural phase and chemical analysis of pathological biominerals responded calcite in all studied cases. CONCLUSION: Conclusion: The presence of pancreatic lithiasis was found to be accompanied by significant morphological changes of the pancreas. The pancreatolith crystal phase was established to be calcium carbonate in the form of calcite. PMID- 29602941 TI - Opisthorchiasis and viral hepatitis b: clinical cases. AB - OBJECTIVE: Introduction: Among the cases of biohelminthosis, which are registered in Ukraine, opisthorchiasis is the most common and constitutes the second largest centre in Europe. Due to the growth of migration processes and global tourism, opisthorchiasis is becoming increasingly relevant for the countries of the European Union and the United States. Under modern conditions, the clinical course of many infectious and parasitic diseases has changed. The aim: The present paper discusses and analyzes the cases of opisthorchiasis and hepatitis B virus which are challenging in terms of diagnostics and choice of treatment tactics. CONCLUSION: Conclusion: The course of acute infections, the formation of results and the effectiveness of treatment are influenced by a number of factors, among which mixed infections are of particular interest. PMID- 29602942 TI - Public health and social supervision issues within public administration of ukrainian territories in the late 8th- early 9th centuries. AB - OBJECTIVE: Introduction: The public health system modernization history is based upon the progress in state country administration and administration of healthcare within the sectorwide approach. The WHO European Bureau pays much attention to the National Health Service systems development while implementing their basic policies. The Ukrainian state health service management was founded basing on the regulatory field of the Russian Empire, using the European healthcare promotion experience. Aim: of the article is the analysis of the regulatory field of police and amenity authorities of the Russian Empire and Ukraine within the medical and social service in the 18th-19th centuries. PATIENTS AND METHODS: Materials and methods: The structure of the article corresponds to the problem city and chronology principles, using the following methods and techniques of scientific learning: the systemic, historic, regulatory comparative, logical and structural-functional analysis of the studied medical legal phenomena. The study sources are the scientific publications, collections of laws and executive orders of the Russian Empire and Ukraine in the 18th-19th centuries. RESULTS: Review: As a result of the performed work it can be determined were the main directions of the police competence in late 18th- early 19th centuries. CONCLUSION: Conclusion: Preserving health, treatment of the ill and injured, management of medical and social service of those in need, holding various preventive activities and supporting safe environment and regulating the safety of food were the main directions of the police competence in late 18th- early 19th centuries. PMID- 29602943 TI - Hemoptysis After CardioMEMS Implantation: Case Report and Review. AB - BACKGROUND The CardioMEMS heart failure system is a small sensor that is placed in a branch pulmonary artery for ambulatory monitoring of pulmonary artery pressures. CardioMEMS has been approved for use in the United States in patients with New York Heart Association (NYHA) class III heart failure and frequent hospitalizations. In this report we describe a patient who had hemoptysis after CardioMEMS implantation. Further, we discuss possible etiologies for the occurrence of hemoptysis and suggest strategies to minimize this risk. CASE REPORT The patient was a 79-year-old female with NYHA class III heart failure with non-ischemic cardiomyopathy (LVEF 40%) and chronic atrial fibrillation who was referred for CardioMEMS implantation. The procedure was completed uneventfully. The patient was transferred out of the procedure suite to the recovery area where she developed a slight cough approximately 20 minutes after the implantation. Within a few coughs the patient started having hemoptysis. She was transferred to the cardiac intensive care unit for observation. She was kept off warfarin and aspirin and her hemoptysis resolved 3 days later. While the exact etiology of hemoptysis in this patient was unclear, we felt that it may have been precipitated by a minor wire-induced distal branch pulmonary artery injury. CONCLUSIONS Our report discusses hemoptysis as a potential life threatening complication of CardioMEMS sensor implantation while suggesting possible etiologies and avoidance strategies. As the utilization of this technology expands in the years to come, a more comprehensive national registry for surveillance of device related complications will be crucial. PMID- 29602944 TI - Ventricular diastolic dimension over maximal myocardial thickness is robust landmark of systolic impairment in patients with hypertrophic cardiomyopathy. AB - BACKGROUND The effects of focal hypertrophy on geometry of the left ventricle and systolic function have not been studied in patients with hypertrophic cardiomyopathy (HCM), despite the fact that the former is the most prominent disease characteristic. The aim of our study was to analyze systolic function over ventricle geometry, generating a functional index made from left ventricle end diastolic dimension (LVEDD) divided by end diastolic thickness of the region with maximal extent of hypertrophy and interventricular septum. MATERIAL AND METHODS Our hospital database of cardiac magnetic resonance was screened for HCM. Geometric functional index (GFI) was calculated for LVEDD over maximal end diastolic thickness (MaxEDT) giving GFI-M, while LVEDD over interventricular septum was expressed as GFI-I. There were 55 consecutive patients with HCM. RESULTS There were 43 males (78.2%) and 12 females (21.8%). The mean age was 52.3+/-16.7 years (range: 15.5-76.4 years). A significant difference of GFI was found for preserved versus impaired systolic function of the left ventricle (preserved systolic function); GFI-M 2.28+/-0.60 versus 3.66+/-0.50 (p<0.001), and GFI-I 2.75+/-0.88 versus 3.81+/-0.87 (p<0.001), respectively. Diagnostic value was tested using receiver operating curve (ROC) analyzes, with GFI-M area under curve (AUC)=0.959 (95% CI: 0.868-0.994); (p<0.001) and GFI-I-AUC=0.847 (0.724-0.930); (p<0.001). GFI-M was superior to GFI-I for appraisal of left ventricle systolic dysfunction in HCM; DeltaAUC=0.112 (0.018-0.207); (p=0.020). CONCLUSIONS GFI is a simple tool, with high sensitivity and specificity for detecting impairment of systolic function in patients with HCM. Further studies would be necessary to investigate its clinical and prognostic impacts, as well as reproducibility with prospective validation. PMID- 29602945 TI - Biosynthesis of fragin is controlled by a novel quorum sensing signal. AB - Members of the diazeniumdiolate class of natural compounds show potential for drug development because of their antifungal, antibacterial, antiviral, and antitumor activities. Yet, their biosynthesis has remained elusive to date. Here, we identify a gene cluster directing the biosynthesis of the diazeniumdiolate compound fragin in Burkholderia cenocepacia H111. We provide evidence that fragin is a metallophore and that metal chelation is the molecular basis of its antifungal activity. A subset of the fragin biosynthetic genes is involved in the synthesis of a previously undescribed cell-to-cell signal molecule, valdiazen. RNA-Seq analyses reveal that valdiazen controls fragin biosynthesis and affects the expression of more than 100 genes. Homologs of the valdiazen biosynthesis genes are found in various bacteria, suggesting that valdiazen-like compounds may constitute a new class of signal molecules. We use structural information, in silico prediction of enzymatic functions and biochemical data to propose a biosynthesis route for fragin and valdiazen. PMID- 29602947 TI - High-risk screening for Gaucher disease in patients with neurological symptoms. AB - Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by the deficiency of glucocerebrosidase enzyme activity. Clinical phenotypes of GD are categorized into three groups: (i) non-neuronopathic GD (type 1), (ii) acute neuronopathic GD (type 2) and (iii) subacute neuronopathic GD (type 3). The high-risk screening of neuronopathic GD has been performed using an enzymatic assay on the dried blood spot (DBS) samples. We enrolled a total of 102 individuals (47 females, 55 males; 0-57 years old; median age 10.5 years) with various neurological symptoms. We detected two patients with very low enzyme activity and they were diagnosed with the disease by using glucocerebrosidase gene analysis. Patient 1 was found to be compound heterozygous for the p.R159W/p.R170C locus and patient 2 was found to harbor two mutations at the IVS7+1G>T (c.999+1G>T) and p.L483P sites. This simple screening protocol using DBS samples is useful for early diagnosis of GD in high-risk and underdiagnosed patients suffering from various neurological symptoms. PMID- 29602946 TI - Biomimetic temporal self-assembly via fuel-driven controlled supramolecular polymerization. AB - Temporal control of supramolecular assemblies to modulate the structural and transient characteristics of synthetic nanostructures is an active field of research within supramolecular chemistry. Molecular designs to attain temporal control have often taken inspiration from biological assemblies. One such assembly in Nature which has been studied extensively, for its well-defined structure and programmable self-assembly, is the ATP-driven seeded self-assembly of actin. Here we show, in a synthetic manifestation of actin self-assembly, an ATP-selective and ATP-fuelled, controlled supramolecular polymerization of a phosphate receptor functionalised monomer. It undergoes fuel-driven nucleation and seeded growth that provide length control and narrow dispersity of the resultant assemblies. Furthermore, coupling via ATP-hydrolysing enzymes yielded its transient characteristics. These results will usher investigations into synthetic analogues of important biological self-assembly motifs and will prove to be a significant advancement toward biomimetic temporally programmed materials. PMID- 29602948 TI - Virtual Issue #2: Contribution of Chinese research to the field of environmental contamination and toxicology: The most cited papers published in BECT from 2012 2017. PMID- 29602949 TI - Matrix Effect Evaluation and Method Validation of Azoxystrobin and Difenoconazole Residues in Red Flesh Dragon Fruit (Hylocereus polyrhizus) Matrices Using QuEChERS Sample Preparation Methods Followed by LC-MS/MS Determination. AB - Production of red flesh dragon fruit (Hylocereus polyrhizus) was hampered by Colletotrichum sp. Pre-harvest application of azoxystrobin and difenoconazole mixture is recommended, therefore, a selective and sensitive multi residues analytical method is required in monitoring and evaluating the commodity's safety. LC-MS/MS is a well-established analytical technique for qualitative and quantitative determination in complex matrices. However, this method is hurdled by co-eluted coextractives interferences. This work evaluated the pH effect of acetate buffered and citrate buffered QuEChERS sample preparation in their effectiveness of matrix effect reduction. Citrate buffered QuEChERS proved to produce clean final extract with relative matrix effect 0.4%-0.7%. Method validation of the selected sample preparation followed by LC-MS/MS for whole dragon fruit, flesh and peel matrices fortified at 0.005, 0.01, 0.1 and 1 g/g showed recoveries 75%-119%, intermediate repeatability 2%-14%. The expanded uncertainties were 7%-48%. Based on the international acceptance criteria, this method is valid. PMID- 29602950 TI - Arsenic-containing hydrocarbons: effects on gene expression, epigenetics, and biotransformation in HepG2 cells. AB - Arsenic-containing hydrocarbons (AsHCs), a subgroup of arsenolipids found in fish and algae, elicit substantial toxic effects in various human cell lines and have a considerable impact on cellular energy levels. The underlying mode of action, however, is still unknown. The present study analyzes the effects of two AsHCs (AsHC 332 and AsHC 360) on the expression of 44 genes covering DNA repair, stress response, cell death, autophagy, and epigenetics via RT-qPCR in human liver (HepG2) cells. Both AsHCs affected the gene expression, but to different extents. After treatment with AsHC 360, flap structure-specific endonuclease 1 (FEN1) as well as xeroderma pigmentosum group A complementing protein (XPA) and (cytosine 5)-methyltransferase 3A (DNMT3A) showed time- and concentration-dependent alterations in gene expression, thereby indicating an impact on genomic stability. In the subsequent analysis of epigenetic markers, within 72 h, neither AsHC 332 nor AsHC 360 showed an impact on the global DNA methylation level, whereas incubation with AsHC 360 increased the global DNA hydroxymethylation level. Analysis of cell extracts and cell media by HPLC-mass spectrometry revealed that both AsHCs were considerably biotransformed. The identified metabolites include not only the respective thioxo-analogs of the two AsHCs, but also several arsenic-containing fatty acids and fatty alcohols, contributing to our knowledge of biotransformation mechanisms of arsenolipids. PMID- 29602953 TI - Indole-3-carbinol improves neurobehavioral symptoms in a cerebral ischemic stroke model. AB - Stroke is one of the most common causes of death worldwide and also responsible for permanent disability. Ischemic stroke has been found to affect 80% of stroke patients. Recombinant tissue plasminogen activator (rtPA) is the widely used drug for the ischemic stroke with narrow therapeutic window. Indole-3-carbinol (I3C) is a natural compound obtained from brassica species having antithrombotic activity. Middle cerebral artery occlusion (MCAO) model was used followed by reperfusion after 2 h of ischemia for the evaluation of the I3C against ischemic stroke. After reperfusion, I3C (12.5, 25, and 50 mg/kg) was given by oral route once daily and continued up to the 14th day. Behavioral studies including postural reflex, forelimb placing, and cylinder tests showed I3C attenuated the MCAO-induced increase in average score and asymmetry score efficiently. Mean cerebral blood flow (CBF) was improved by treatment with I3C (12.5 mg/kg) by 60% of baseline at 6 h. I3C inhibited ADP-induced platelet aggregation and reduced ischemic volume significantly. It also inhibited in vitro the ADP-induced platelet aggregation in healthy human volunteers. I3C improves behavioral scores and mean CBF after focal cerebral ischemia in rats. Furthermore, I3C showed prophylactic anti-thrombotic activity against carrageenan induced tail thrombosis. Therefore, preclinical evidence points to I3C as a potential candidate for use in cerebral ischemic stroke. PMID- 29602952 TI - Regulation of the Hippo pathway in cancer biology. AB - The Hippo tumor suppressor pathway, which is well conserved from Drosophila to humans, has emerged as the master regulator of organ size, as well as major cellular properties, such as cell proliferation, survival, stemness, and tissue homeostasis. The biological significance and deregulation of the Hippo pathway in tumorigenesis have received a surge of interest in the past decade. In the current review, we present the major discoveries that made substantial contributions to our understanding of the Hippo pathway and discuss how Hippo pathway components contribute to cellular signaling, physiology, and their potential implications in anticancer therapeutics. PMID- 29602951 TI - A latent ability to persist: differentiation in Toxoplasma gondii. AB - A critical factor in the transmission and pathogenesis of Toxoplasma gondii is the ability to convert from an acute disease-causing, proliferative stage (tachyzoite), to a chronic, dormant stage (bradyzoite). The conversion of the tachyzoite-containing parasitophorous vacuole membrane into the less permeable bradyzoite cyst wall allows the parasite to persist for years within the host to maximize transmissibility to both primary (felids) and secondary (virtually all other warm-blooded vertebrates) hosts. This review presents our current understanding of the latent stage, including the factors that are important in bradyzoite induction and maintenance. Also discussed are the recent studies that have begun to unravel the mechanisms behind stage switching. PMID- 29602955 TI - Isolated rupture of the accessory soleus tendon: an original and confusing picture. AB - The accessory soleus muscle is an uncommon congenital anatomical variant with a prevalence ranging from 0.7 to 5.5%. Although intermittent and exertional symptoms caused by this supernumerary muscle have been well documented, acute injuries have not. We present a case of an isolated rupture of the accessory soleus tendon with myotendinous retraction, mimicking clinically a "tennis leg." A 29-year-old woman sustained a hyperdorsal flexion injury of the right ankle with a severe and sudden pain in the middle part of the calf. Radiographs were normal and the diagnosis of "tennis leg" was clinically suspected. Ultrasound demonstrated bilateral accessory soleus muscles. On the symptomatic side, there was a complete isolated rupture of the accessory soleus tendon with myotendinous retraction. These findings were confirmed by magnetic resonance imaging (MRI), which showed no other abnormality. To our knowledge, this acute and misleading presentation has not been reported previously. PMID- 29602954 TI - DL-3-n-butylphthalide improves ventricular function, and prevents ventricular remodeling and arrhythmias in post-MI rats. AB - DL-3-n-butylphthalide (NBP) is used in the treatment of ischemic stroke. It was demonstrated NBP also has a cardioprotective effect in acute myocardial infarction (MI) model. However, the chronic effects of NBP on ventricular function, remodeling, and arrhythmias in post-MI stage are unknown. This study was to investigate the effect of NBP on reducing ventricular remodeling and arrhythmias in post-MI stage. Post-MI rats were randomly treated with 100 mg/kg NBP daily (n = 21) or vehicle (n = 21) for 5 weeks. Sham-operated rats were treated with the same dose vehicle (n = 18). Echocardiographic assessment, ventricular arrhythmias inducibility test, morphological and collagen analysis, immunohistochemistry, and western blot were studied. NBP significantly improved cardiac function, inhibited the severity and inducibility of ventricular arrhythmias, reduced cardiac index, fibrosis and hypertrophy, improved the protein expression and distribution of Cx43 gap junction, and upregulated PI3k/Akt/Nrf2 pathway and the downstream antioxidant response elements (ARE), including heme oxygenase-1, Glutathione, Cu-Zn superoxide dismutase, and Fe/Mn superoxide dismutase. These results suggest NBP improves LV function and reduces ventricular arrhythmias by mitigating LV fibrosis, hypertrophy, and Cx43 gap junction remodeling. PI3k/Akt/Nrf2/ARE signaling pathway may contribute to its anti-ventricular remodeling effects. PMID- 29602956 TI - Effects of vitamin D supplementation on FGF23: a randomized-controlled trial. AB - PURPOSE: Fibroblast growth factor-23 (FGF23) is critical for phosphate homeostasis. Considering the high prevalence of vitamin D deficiency and the association of FGF23 with adverse outcomes, we investigated effects of vitamin D3 supplementation on FGF23 concentrations. METHODS: This is a post-hoc analysis of the Styrian Vitamin D Hypertension trial, a single-center, double-blind, randomized, placebo-controlled trial, conducted from 2011 to 2014 at the Medical University of Graz, Austria. Two hundred subjects with 25(OH)D concentrations < 30 ng/mL and arterial hypertension were randomized to receive either 2800 IU of vitamin D3 daily or placebo over 8 weeks. Primary outcome was the between-group difference in FGF23 levels at study end while adjusting for baseline values. RESULTS: Overall, 181 participants (mean +/- standard deviation age, 60.1 +/- 11.3; 48% women) with available c-term FGF23 concentrations were considered for the present analysis. Mean treatment duration was 54 +/- 10 days in the vitamin D3 group and 54 +/- 9 days in the placebo group. At baseline, FGF23 was significantly correlated with serum phosphate (r = 0.135; p = 0.002). Vitamin D3 supplementation had no significant effect on FGF23 in the entire cohort (mean treatment effect 0.374 pmol/L; 95% confidence interval - 0.024 to 0.772 pmol/L; p = 0.065), but increased FGF23 concentrations in subgroups with baseline 25(OH)D concentrations below 20 ng/mL (n = 70; mean treatment effect 0.973 pmol/L; 95% confidence interval - 0.032 to 1.979 pmol/L; p = 0.019) and 16 ng/mL (n = 40; mean treatment effect 0.593 pmol/L; 95% confidence interval 0.076 to 1.109; p = 0.022). CONCLUSIONS: Vitamin D3 supplementation had no significant effect on FGF23 in the entire study cohort. We did, however, observe an increase of FGF23 concentrations in subgroups with low baseline 25(OH)D. PMID- 29602957 TI - Nanotechnology: the scope and potential applications in orthopedic surgery. AB - Nanotechnology involves manipulation of matter measuring 1-100 nm in at least one of its dimensions at the molecular level. Engineering and manipulation of matter at the molecular level has several advantages in the field of medicine (nanomedicine) since most of the biological molecules exist and function at a nanoscale. Though promising, questions still remain on how much of this will ultimately translate into achieving better patient care. Concerns of cost effectiveness and nanotechnology safety still remain unclear. Orthopedics is an attractive area for the application of nanotechnology since the bone, and its constituents such as hydroxyapatite, Haversian systems, and the collagen fibrils are nanocompounds. The major orthopedic applications of nanotechnology involve around (i) effective drug delivery systems for antibiotics and chemotherapeutic agents, (ii) surface preparation of implants and prosthesis to improve osteointegration and reduce biofilm formation, (iii) controlled drug eluting systems to combat implant-related infections, (iv) tissue engineering for scaffolds preparation to deal with bone and cartilage defects, and (v) diagnostic applications in the field of oncology and musculoskeletal infections. PMID- 29602958 TI - HLA-G peptide preferences change in transformed cells: impact on the binding motif. AB - HLA-G is known for its strictly restricted tissue distribution. HLA-G expression could be detected in immune privileged organs and many tumor entities such as leukemia, multiple myeloma, and non-Hodgkin and Hodgkin's lymphoma. This functional variability from mediation of immune tolerance to facilitation of tumor immune evasion strategies might translate to a differential NK cell inhibition between immune-privileged organs and tumor cells. The biophysical invariability of the HLA-G heavy chain and its contrary diversity in immunity implicates a strong influence of the bound peptides on the pHLA-G structure. The aim was to determine if HLA-G displays a tissue-specific peptide repertoire. Therefore, using soluble sHLA-G technology, we analyzed the K562 and HDLM-2 peptide repertoires. Although both cell lines possess a comparable proteome and recruit HLA-G-restricted peptides through the same peptide-loading pathway, the peptide features appear to be cell specific. HDLM-2 derived HLA-G peptides are anchored by an Arg at p1 and K562-derived peptides are anchored by a Lys. At p2, no anchor motif could be determined while peptides were anchored at pOmega with a Leu and showed an auxiliary anchor motif Pro at p3. To appreciate if the peptide anchor alterations are due to a cell-specific differential peptidome, we performed analysis of peptide availability within the different cell types. Yet, the comparison of the cell-specific proteome and HLA-G-restricted ligandome clearly demonstrates a tissue-specific peptide selection by HLA-G molecules. This exclusive and unexpected observation suggests an exquisite immune function of HLA G. PMID- 29602959 TI - Antiplatelet and anticoagulant agents in vitreoretinal surgery: a prospective multicenter study involving 804 patients. PMID- 29602962 TI - Antiplatelet and anticoagulant agents in vitreoretinal surgery: a prospective multicenter study involving 804 patients. PMID- 29602960 TI - Impact of same-session trabectome surgery on Ahmed glaucoma valve outcomes. AB - PURPOSE: To evaluate the efficacy and survival rates of same session ab interno trabeculectomy with the trabectome and Ahmed glaucoma valve implant (AT) in comparison to the Ahmed glaucoma valve alone (A). METHOD: A total of 107 eyes undergoing primary glaucoma surgery were enrolled in this retrospective comparative case series, including 48 eyes which underwent AT and 59 eyes which received A alone. Participants were identified using the procedural terminology codes, and their medical records were reviewed. The primary outcome measure was success defined as IOP > 5 mmHg, <= 21 mmHg and >= 20% reduction of IOP from baseline at two consecutive visits after 3 months, and no need for glaucoma reoperation. Secondary outcome measures were IOP, the number of glaucoma medications, incidence of a hypertensive phase, and best corrected visual acuity (BCVA). RESULTS: The cumulative probability of success at 1 year was 70% in AT, and 65% in A (p = 0.85). IOP decreased significantly from 26.6 +/- 10.1 mmHg at baseline to 14.7 +/- 3.3 mmHg at the final follow-up in AT (p = 0.001). The corresponding numbers for A were 27.8 +/- 10.2 and 16.7 +/- 4.9, respectively (p = 0.001). The final IOP was significantly lower in AT (p = 0.022). The number of medications at baseline was comparable in both groups (2.6 +/- 1.2 in AT and 2.5 +/- 1.3 in A, p = 0.851). Corresponding number at 1 year visit was 1.2 +/- 2 in AT and 2.8 +/- 1.8 in A (p = 0.001). The incidence of a hypertensive phase was 18.7% in AT and 35.5% in A (p = 0.05). HP resolved in only 30% of eyes. The criteria for HP resolution were fulfilled in 9 eyes (30%). There was no difference in the rate of resolution of the hypertensive phase between AT and A (33.3 and 28.5%, respectively, p = 0.67). CONCLUSION: Ahmed glaucoma valve implant with same session trabectome surgery significantly decreased the rate of the hypertensive phase and postoperative IOP as well as the number of glaucoma medications. PMID- 29602963 TI - Evaluation of superior concha bullosa by computed tomography. AB - OBJECTIVE: Concha bullosa is generally regarded as pneumatisation of the middle turbinate in the nose. However, pneumatisation may also be seen in the superior and inferior turbinate. Computed tomography (CT) of paranasal sinuses is extremely helpful for the examination of this inaccessible area. Coronal CT sections of paranasal sinuses are particularly useful for surgical anatomy, as these images show nearly the same regions as the endoscopic examinations. The aim of this retrospective study was to evaluate the presence, incidence and unilaterality-bilaterality of superior turbinate pneumatisation and concomitant nasal pathologies. METHODS: A total of 1000 patients who underwent CT of the paranasal sinuses because of headaches, nasal obstructions, anosmia, facial pain or facial trauma were evaluated retrospectively. RESULTS: Among the 1000 patients, superior pneumatized turbinate was seen on CT images of the paranasal sinuses in 149 (14.9%) cases. Of these patients, 84 were female, 65 were male, and the mean age was 38.14 years. Among 149 patients, 58 patients had bilateral superior pneumatized turbinate and the remaining 91 patients had unilateral superior pneumatized turbinate. 60.4% of the patients with superior pneumatized turbinate also had middle pneumatized turbinate. CONCLUSION: The superior pneumatized turbinate is an anatomical variation with an incidence ranging from 12.2 to 50%. The present study revealed that there is no relationship between volume size of the superior pneumatized turbinates and sinusitis, nasal septum deviation and paradoxical middle concha. It is very important to define anatomical variations in the preoperative CT evaluation of the paranasal sinuses. PMID- 29602964 TI - Human cold stress of strong local-wind "Hijikawa-arashi" in Japan, based on the UTCI index and thermo-physiological responses. AB - We investigated the cold stress caused by a strong local wind called "Hijikawa arashi," through in situ vital measurements and the Universal Thermal Climate Index (UTCI). This wind is a very interesting winter phenomenon, localized in an area within 1 km of the seashore in Ozu City, Ehime Prefecture in Japan. When a strong Hijikawa-arashi (HA) occurred at 14-15 m s-1, the UTCI decreased to - 30 degrees C along the bridge where commuting residents are the most exposed to strong and cold winds. On the bridge, most participants in our experiment felt "very cold" or "extremely cold." The UTCI of HA can be predicted from a multiple regression equation using wind speed and air temperature. The cold HA wind is also harmful to human thermo-physiological responses. It leads to higher blood pressure and increased heart rate, both of which act as cardiovascular stress triggers. Increases of 6-10 mmHg and 3-6 bpm for every 10 degrees C reduction in UTCI were seen on all observational days, including HA and non-HA days. In fact, the participants' body skin temperatures decreased by approximately 1.2 to 1.7 degrees C for every 10 degrees C reduction in UTCI. Thus, the UTCI variation due to the HA outbreak corresponded well with the cold sensation and thermo physiological responses in humans. This result suggests that daily UTCI monitoring enables the prediction of thermo-physiological responses to the HA cold stress. PMID- 29602965 TI - The impact of climatic variations on the reproductive success of Gentiana lutea L. in a Mediterranean mountain area. AB - Increases in temperature have been predicted and reported for the Mediterranean mountain ranges due to global warming and this phenomenon is expected to have profound consequences on biodiversity and ecosystem functioning. We hereby present the case of Gentiana lutea L. subsp. lutea, a rhizomatous long-lived plant living in Central-Southern Europe, which is at the edge of its ecological and distributional range in Sardinia. Concretely, we analysed the reproductive success experienced during three phenological cycles (2013/2014, 2014/2015 and 2015/2016) in four representative populations, with particular attention to the phenological cycle of 2014/2015, which has been recorded as one of the warmest periods of the last decades. The Smirnov-Grubbs test was used to evaluate differences in temperature and precipitation regimes among historical data and the analysed years, while the Kruskal-Wallis followed by the Wilcoxon test was used to measure differences between anthesis and reproductive performances among cycles and populations. In addition, generalised linear models were carried out to check relationships between climate variables and reproductive performance. Significant differences among climate variables and analysed cycles were highlighted, especially for maximum and mean temperatures. Such variations determined a non-flowering stage in two of the four analysed populations in 2014/2015 and significant differences of further five reproductive traits among cycles. These results confirmed that in current unstable climatic conditions, which are particularly evident in seasonal climates, reproductive success can be a sensitive and easily observable indicator of climatic anomalies. Considering the importance of this issue and the ease and cost-effectiveness of reproductive success monitoring, we argue that research in this sense can be a supporting tool for the enhancement of future crucial targets such as biodiversity conservation and the mitigation of global warming effects. PMID- 29602966 TI - The role of perceived air pollution and health risk perception in health symptoms and disease: a population-based study combined with modelled levels of PM10. AB - PURPOSE: Adverse health impact of air pollution on health may not only be associated with the level of exposure, but rather mediated by perception of the pollution and by top-down processing (e.g. beliefs of the exposure being hazardous), especially in areas with relatively low levels of pollutants. The aim of this study was to test a model that describes interrelations between air pollution (particles < 10 [Formula: see text]m, PM10), perceived pollution, health risk perception, health symptoms and diseases. METHODS: A population-based questionnaire study was conducted among 1000 Estonian residents (sample was stratified by age, sex, and geographical location) about health risk perception and coping. The PM10 levels were modelled in 1 * 1 km grids using a Eulerian air quality dispersion model. Respondents were ascribed their annual mean PM10 exposure according to their home address. Path analysis was performed to test the validity of the model. RESULTS: The data refute the model proposing that exposure level significantly influences symptoms and disease. Instead, the perceived exposure influences symptoms and the effect of perceived exposure on disease is mediated by health risk perception. This relationship is more pronounced in large cities compared to smaller towns or rural areas. CONCLUSIONS: Perceived pollution and health risk perception, in particular in large cities, play important roles in understanding and predicting environmentally induced symptoms and diseases at relatively low levels of air pollution. PMID- 29602967 TI - Pharyngocutaneous and tracheoesophageal fistula closure using supraclavicular artery island flap. AB - BACKGROUND: Pharyngocutaneous fistula is a common complication of laryngopharyngeal surgery, being associated with increased morbidity and mortality. Classical regional and free flaps, frequently used in the treatment of this complication, have several limitations, including bulking, donor site morbidity and long operative time. The supraclavicular artery island flap (SCAIF) is a fasciocutaneous flap and presents as an alternative option with good results and without the previously stated limitations. We describe our experience with SCAIF in pharyngocutaneous and tracheoesophageal fistula closure. METHODS: Between April and December 2017, four patients with pharyngocutaneous and two patients with tracheoesophageal fistula underwent fistula closure with SCAIF. Clinical records were retrospectively reviewed. RESULTS: Pharyngocutaneous fistulae were associated with anterior esophageal wall defects ranging from 4 to 13.5 cm2. Tracheoesophageal fistulae defects were smaller (approximately 2 cm2). Fistula closure was achieved in all patients, oral diet was started on the 14th day post-operative and there were no signs of recurrence during follow-up. The donor area was complicated with the formation of hematoma in two patients. CONCLUSIONS: The SCAIF has unique features that makes it an ideal option for pharyngocutaneous and tracheoesophageal fistula closure, namely, reliable perfusion, quick and simple dissection, pliability and minor donor site morbidity. Local complications do not significantly affect long term morbidity of the donor area and can be avoided with simple measures. PMID- 29602969 TI - Raman spectroscopy reveals differences in molecular structure between human femoral heads affected by steroid-associated and alcohol-associated osteonecrosis. AB - PURPOSE: The purposes of this study were to document novel Raman spectroscopic findings in femoral heads affected by osteonecrosis and to identify molecular structure differences based on aetiology. METHODS: We obtained 13 femoral heads with osteonecrosis from 13 different patients who underwent total hip arthroplasty. Comparisons were made between the viable zones of each femoral head examined. The samples were scanned with X-ray micro-CT for structural mapping and a central coronal section slab was prepared for Raman spectroscopy and histological analyses. Raman spectra were collected at different locations, including the viable and necrotic zones of the femoral head, using a highly spectrally resolved Raman microprobe. RESULTS: Significant alterations in the spectral morphology in the high wavenumber region were found, with a pronounced inhibition of peculiar lipid signals in the frequency interval 2851 ~ 2890 cm-1 and at ~ 1750 cm-1. The necrotic zone in steroid-associated osteonecrosis showed an increase in the ratio of lipid-related bands to protein-related bands, while alcohol-associated osteonecrosis exhibited a decrease in this ratio. CONCLUSIONS: We systematically found a decrease in Raman intensity for sphingomyelin and phenylalanine fingerprint bands in the necrotic zones, and these differences may be related to the etiology of osteonecrosis. PMID- 29602968 TI - Comparison of abdominal radiographs and sonography in prognostic prediction of infants with necrotizing enterocolitis. AB - PURPOSE: The purpose of this study was to investigate the comparison of AR and AUS in predicting prognosis in infants with necrotizing enterocolitis. METHODS: All patients were diagnosed as NEC at the department of general surgery and neonatal surgery, Qilu children's hospital between 1st, Jun, 2010 and 30th, Dec, 2016. The logistic regression analysis and the area under ROC curve (AUC)s were also used to compare the prognostic values of radiograph and sonograph for NEC. RESULTS: Throughout the study period, 86 preterm neonates were hospitalized with diagnosis of definite NEC. Among these patients, 39 infants (45.3%) required surgical treatment. After adjusting for competing sonographic factors, we identified that thick bowel wall (more than 2.5 mm) (p = 0.001, HR: 1.849), intramural gas (pneumatosis intestinalis) (p = 0.017, HR: 1.265), portal venous gas (p = 0.002, HR: 1.824), and reduced peristalsis (p = 0.021, HR: 1.544) were independent prognostic factors associated with NEC. After adjusting for competing radiographic factors, we identified that free peritoneal gas (p = 0.007, HR: 1.472), portal venous gas (p = 0.012, HR: 1.649), and dilatation and elongation (p = 0.025, HR: 1.327). Moreover, we found that the AUROC for AR logistic model was 0.745 (95% CI 0.629-0.812), which was significant lower than the AUS logistic model (AUROC: 0.857, 95% CI 0.802-0.946) for predicting prognosis of NEC. CONCLUSIONS: In conclusion, we found that several radiographic and sonographic parameters were associated with the prognosis of patients with NEC. The AUS model based on the logistic regression analysis was significant superior to the AR model in the prognostic prediction of NEC. PMID- 29602970 TI - More accurate correction can be obtained using a three-dimensional printed model in open-wedge high tibial osteotomy. AB - PURPOSE: The purpose of this study was to compare the accuracy of the preoperative planning method using a three-dimensional (3D) printed model with that of a method using picture archiving and communication system (PACS) images in high tibial osteotomy (HTO). METHODS: Patients who underwent HTO using a 3D printed model (20 patients) and a method based on PACS images (20 patients) from 2012 to 2016 were compared. After obtaining the correction angle, in the 3D printed method, the wedge-shaped 3D printed model was designed. The PACS method used preoperative radiographs. The accuracy of HTO for each method was compared using radiographs obtained at the first postoperative year. The preoperative and postoperative posterior tibial slope angles were also compared. RESULTS: The weight-bearing line was corrected 21.2 +/- 11.8% from preoperatively to 61.6 +/- 3.3% postoperatively in the 3D group and from 19.4 +/- 12.3% to 61.3 +/- 8.1% in the PACS group. The mean absolute difference with the target point was lower in the 3D group (2.3 +/- 2.5) than in the PACS group (6.2 +/- 5.1; p = 0.005). The number of patients in an acceptable range was higher in the 3D group than in the PACS group. The posterior tibial slope angle was not significantly different in the 3D group (8.6 degrees -8.9 degrees ), but was significantly different in the PACS group (9.9 degrees -10.5 degrees , p = 0.042). CONCLUSIONS: In open-wedge HTO, a more accurate correction for successful results could be obtained using the 3D printed model. LEVEL OF EVIDENCE: IV. PMID- 29602971 TI - Distribution of the acanthocephalan Neoechinorhynchus buttnerae and semiquantitative analysis of histopathological damage in the intestine of tambaqui (Colossoma macropomum). AB - In this paper, we have described for the first time a semiquantitative method to evaluate histopathological damage, taking the degree of Neoechinorhynchus buttnerae attachment to the intestinal wall of the tambaqui (Colossoma macropomum), an important species in Brazilian aquaculture, into account. Twelve specimens of tambaqui were collected from a fish farm. Their bowels were removed and divided into seven morphologically distinct portions according to density and distribution of the parasite studies. Fragments from each fraction were histologically processed and analyzed. There was a clear preference on the part of N. buttnerae for the intermediate regions of the intestinal tube, where the highest densities were recorded. The intensity of damage to the host, estimated by calculating the Histopathological Alteration Index (HAI), showed severe and irreversible changes only where the parasite had its proboscis penetrated into the intestine wall. PMID- 29602972 TI - The potential role of toll-like receptor 4 Asp299Gly polymorphism and its association with recurrent cystic echinococcosis in postoperative patients. AB - The study of pathogenesis mechanisms of larval stages in the Taeniidae has recently focused on host genetic factors, particularly toll-like receptor (TLR) variations. However, the potential role of TLR4 polymorphism in hydatidosis has not yet been sufficiently elucidated in postoperative patients. In this case control investigation, 80 patients from Iran, including 40 with acute hydatidosis (AH) and 40 with recurrent hydatidosis (RH), and 80 ethnically matched controls were evaluated from February 2015 to February 2017. Hydatidosis patients were confirmed using radiological, immunological, and histopathological examinations. Genotyping of Asp299Gly and Thr399Ile of TLR4 single-nucleotide polymorphisms was determined by restriction fragment length polymorphism, sequencing, and phylogenetic strategies. The heterozygous mutant-type TLR4 Asp299Gly genotype indicated a tendency to be associated with the occurrence of RH (P = 0.060) and conferred a 3-fold risk for susceptibility. There was no difference in genotype frequency of Asp299Gly between patients with AH and healthy controls (P = 0.42; OR, 1.82; 95% CI, 0.11-30.1%). Interestingly, a frequency of the G allele (12%: Gly) was observed to be a risk factor for susceptibility to RH patients (P = 0.050; OR, 7.08; 95% CI, 0.97-51.5%). A relative genetic variability of TLR4 Asp299Gly was found in RH patients (haplotype diversity: 0.700) compared to AH patients and healthy controls (Hd: 0.000). The Asp299Gly genotype was dominantly identified in patients with hepatic hydatid cysts. The TLR4 Thr399Ile codon was not detected except in a patient with a pulmonary hydatid cyst. The current findings enhance our knowledge regarding the TLR4 Asp299Gly polymorphism potentially leading to the development of RH, by skewing the immune system towards a Th2 response. Identification of the Asp299Gly codon may be a diagnostic hallmark in RH patients who have undergone unsuccessful postoperative intervention. However, further studies with a higher case number are needed on ethnic population from various geographic regions, in order to confirm this hypothesis. PMID- 29602973 TI - Sunitinib shrinks NET-G3 pancreatic neuroendocrine neoplasms. AB - PURPOSE: The 2017 revised World Health Organization classification of pancreatic neuroendocrine neoplasms classified conventional G3 tumors into well differentiated (NET-G3) and poorly differentiated (NEC-G3) tumors. However, guidelines for selection of drug therapy were not established in the 2017 revision. This study aimed to elucidate the rates of maximum tumor reduction of sunitinib, progression-free survival, and overall survival in the new classification. METHODS: We investigated the reduction rate over time using computed tomography for 60 patients with unresectable or distant metastatic pancreatic neuroendocrine neoplasms who received 37.5 mg of sunitinib in our department from April 2013 to November 2017. RESULTS: Of the 60 cases, 42, 10, and 5 were NET-G1/G2, NET-G3, and NEC-G3, respectively. The prognostic factors were analyzed according to clinicopathological factors using the Cox hazard model. The median observation period was 19 months, and the median duration of sunitinib administration was 7 months. The median maximum reduction rate of sunitinib was 18.3%. Tumor response was classified according to the Response Evaluation Criteria in Solid Tumors: 20 cases (33.3%) showed partial response, 29 cases (48.3%) showed stable disease, and 11 cases (18.3%) showed progressive disease. In a multivariate analysis of factors contributing to progression-free survival from the start of sunitinib administration, only histologically poor differentiation was a significant factor (p = 0.010). Progression-free survival and overall survival were significantly better in patients with NET-G3 than that in patients with NEC-G3 (p = 0.005, p = 0.012), while it was not different between those with NET-G3 and those with NET-G1/2. CONCLUSION: Our results indicate that sunitinib is as effective for NET-G3 as for NET-G1/2. PMID- 29602974 TI - High prevalence of PCV2d in Hunan province, China: a retrospective analysis of samples collected from 2006 to 2016. AB - Porcine circovirus 2 (PCV2) has been widely prevailing in China since the first report in 2001, causing huge economic losses to the pig industry. In the present study, 674 samples were collected from 2006 to 2016 in Hunan province, and 62% were positive for PCV2. An increase was observed from 2006 to 2011 (72.1%-89.1%), and a decrease was observed from 2012 to 2016 (78.9%-36.8%). The prevalence of genotype PCV2a, PCV2b, and PCV2d was 0, 44.7% and 67%, respectively. During 2006 2007, PCV2b was the main genotype circulating in Hunan, while, in 2008, PCV2d became the predominant one. Coinfection with PCV2b and PCV2d was observed frequently, and the positive rates of coinfection ranged from 6.3% to 18.9% during 2006-2016. The complete genome was sequenced for 54 positive samples, and four were identified as PCV2b-1, 22 as PCV2b-2, four as PCV2d-1 and 24 as PCV2d 2, based on phylogenetic analysis of the complete genome and ORF2 region. Recombination analysis using the complete genome sequences of these isolates revealed a high recombination rate of 27.7% (17/54), and showed that recombination occurred mainly in the ORF1 region. This shows that the prevalence of PCV2 has clearly decreased in recent years and that PCV2d has become a predominant genotype since 2008. In addition, frequent recombination events were observed in the PCV2 isolates from Hunan, China. PMID- 29602975 TI - Standardization of surgical procedures to reduce risk of anastomotic leakage, reoperation, and surgical site infection in colorectal cancer surgery: a retrospective cohort study of 1189 patients. AB - PURPOSE: Anastomotic leakage (AL) and surgical site infection (SSI) are prevalent complications of colorectal surgery. To lower this risk, we standardized our surgical procedures in 2012, with a preferential use of laparoscopic approach (LS) for both colon and rectal surgery, combined with triangulating anastomosis (TA) for colon surgery and defunctioning ileostomy (DI) for low anterior resection. Our aim was to evaluate the outcomes of our standardized procedures. METHODS: The incidence rate of AL (primary outcome) and of reoperation and SSI (secondary outcome) was compared before (early period, n = 648) and after (late period, n = 541) standardization, through a retrospective analysis. RESULTS: The incidence rate of AL (6.6 versus 1.8%; P = 0.001), reoperation (3.5 versus 0.7%; P = 0.0012), and SSI (7.7 versus 4.6%; P = 0.029) was lower in late than in the early period. For colon cancer, TA and LS reduced the risk of AL (2.1 versus 0.3%, P = 0.020, for TA, and 3.2 versus 0.4%, P = 0.0027, for LS) and reoperation (2.9 versus 0.3%, P = 0.003, for TA, and 2.5 versus 0.2%, P = 0.0040, for LS). For rectal cancer, the incidence of all adverse outcomes (AL, reoperation, and SSI) was lower in cases treated by LS. However, the incidence of AL was lower in the late than in early period (P = 0.002) and with LS (P = 0.002). On multivariate analysis, late period and LS were independent factors of a lower risk of adverse outcomes. CONCLUSIONS: Our surgical standardization seems to be effective in lowering the risks of AL, reoperation, and SSI after colorectal cancer surgery. PMID- 29602976 TI - Do clinical criteria reflect pathologic complete response in rectal cancer following neoadjuvant therapy? AB - BACKGROUND: Clinical complete response (cCR) in rectal cancer is being evaluated as a tool to identify patients who would not require surgery in the curative management of rectal cancer. Our study reviews mucosal changes after neoadjuvant therapy for rectal cancer in patients treated at our center. METHODS: Pathology reports were retrieved for patients treated with neoadjuvant chemoradiation therapy (CRT) or high-dose rate brachytherapy (HDRBT). The macroscopic appearance of the specimen was compared with pathologic staging. RESULTS: This study included 282 patients: 88 patients underwent neoadjuvant CRT and 194 patients underwent HDRBT; all patients underwent total mesorectal excision (TME). There were 160 male and 122 female patients with a median age of 65 years (range 29 87). The median time between neoadjuvant therapy and surgery was 50 and 58 days. Sixty patients (21.2%) were staged as ypT0N0, 21.2% had a pathologic complete response (pCR), and only 3.2% had a cCR. Of the 67 patients with initial involvement of the circumferential radial margin (CRM), 44 converted to pathologic CRM-. Two hundred seventy-three patients (96.8%) had mucosal abnormalities. Of the 222 patients with residual tumor, 70 patients had no macroscopic tumor visualized but an ulcer in its place. CONCLUSION: Most patients undergoing neoadjuvant therapy for rectal cancer have residual mucosal abnormalities which preclude to a cCR as per published criteria from Brazil. Further studies are required to optimize clinical evaluation and MRI imaging in selected patients. PMID- 29602977 TI - Ulcerative colitis and the aging-related development of colonic diverticula. AB - PURPOSE: Aim of this observational case-control study was to assess the prevalence, features, and risk factors of colonic diverticula in patients with ulcerative colitis (UC). METHODS: The data of 896 UC patients aged >= 30 years from Brescia IBD database were retrospectively analyzed. Individuals with colonic diverticula were identified and prevalence was compared with that of control patients undergoing screening colonoscopy after gender/age matching. A nested cohort study was then conducted among UC patients in order to define eventual association of diverticula with specific clinico-pathologic parameters. RESULTS: Prevalence of subjects with diverticula was 11.4% among 465 UC patients aged 49 years and older, significantly lower than 35.1% prevalence in control patients of same age and gender (p < 0.001). Advancing age was a significant risk factor for diverticula development in both groups. Among UC patients, a short duration and a late onset of UC were both significantly associated to the presence of diverticula. Moreover, UC patients with diverticula had a significantly lower frequency of flares per year, even if maximal flare severity and frequency of hospital admission were similar to those of subjects without diverticula. UC patients with diverticula had a trend toward more frequent extension of UC to the left colon, possibly because of their older age. The majority of those patients had few sigmoid diverticula without symptoms. CONCLUSIONS: Development of colonic diverticula is substantially reduced in patients with UC, markedly among those with an early onset, a long history of inflammatory disease, and a high flare frequency. This study reinforces the hypothesis sustaining a protective role of UC against colonic diverticula. PMID- 29602978 TI - Effect of Diane-35, alone or in combination with orlistat or metformin in Chinese polycystic ovary syndrome patients. AB - OBJECTIVE: To evaluate the effect of Diane-35, alone or in combination with orlistat or metformin, on androgen and body fat percentage parameters in Chinese overweight and obese polycystic ovary syndrome (PCOS) patients with insulin resistance. METHODS: A total of 240 PCOS women were randomly allocated to receive Diane-35 alone (D group), Diane-35 plus orlistat (DO group), Diane-35 plus metformin (DM group), or Diane-35 plus orlistat plus metformin (DOM group). Serum TT, DHEA-S, androstenedione, SHBG, FT, FAI, body fat, and body fat percentage were assessed at baseline and after 12 weeks of treatment. RESULTS: Significant changes in serum TT, SHBG, and FAI were observed in all treatment groups compared with baseline. DHEA-S and androstenedione significantly decreased in the DO, DM, and DOM groups after treatment. FT only significantly decreased in the DOM group. Body fat and body fat percentage significantly decreased in the DO and DOM groups. Compared with the D group, DHEA-S significantly decreased in the DO, DM, and DOM groups (F = 4.081, p = 0.008); SHBG significantly increased in the DOM group (F = 3.019, p = 0.031); and FAI significantly decreased in the DO group (chi2 = 12.578, p = 0.006). There were significant differences between groups in body fat percentage (chi2 = 23.590, p < 0.001). Side-effects were less with orlistat than metformin. CONCLUSIONS: Diane-35 in combination with orlistat or metformin is more effective in reducing androgen than Diane-35 alone. Orlistat is more effective in reducing body fat percentage than metformin. In addition, orlistat has mild side-effects and is better tolerated compared with metformin. PMID- 29602979 TI - Influence of training level on cervical cone size and resection margin status at conization: a retrospective study. AB - OBJECTIVE: To explore whether a surgeon's training level influences the rate of incomplete resections or the amount of resected cervical tissue in women treated with large loop excision of the transformation zone (LLETZ). METHODS: The present study is a retrospective analysis of the data of women who had undergone LLETZ for cervical intraepithelial neoplasia (CIN) within the years 2004-2008 at the Medical University of Vienna. Women were grouped according to the level of training of the operating surgeon (i.e, resident or staff gynecologist) and univariate and multivariable analyses were performed to identify independent risk factors for excessive cone volume, depth and incomplete resection (i.e., positive resection margin). RESULTS: Data of 912 women were analysed. Residents had a significantly larger cone volume [median 2681 (interquartile range 1472-4109) mm3] than staff gynecologists [2094 (1309-3402) mm3] (p = 0.001) in univariate analysis. The depth of resection and the rate of incomplete resection were comparable between both groups. In a binary logistic multivariable analysis, the level of training as well as patient's age was significantly associated with a cone volume larger than 2500 mm3. CONCLUSION: Conization performed by residents as opposed to staff gynecologists does not compromise the procedure's effectiveness but may expose women to a potential additional risk for adverse obstetrical outcomes due to excessive resection of cervical tissue. PMID- 29602980 TI - Placenta previa and placental abruption after assisted reproductive technology in patients with endometriosis: a systematic review and meta-analysis. AB - INTRODUCTION: Recent evidence suggests that assisted reproductive technology (ART) increases the risk of adverse pregnancy outcomes, including placental disorders. Similarly, endometriosis resulted detrimental on placenta previa. However, up to 50% of women with endometriosis suffer from infertility, thus requiring ART. The aim of our metanalysis is to compare women with and without endometriosis undergoing ART in terms of placenta disorders events, to establish if ART itself or endometriosis, as an indication to ART, increases the risk of placenta previa. METHODS: Literature searches were conducted in January 2018 using electronic databases (PubMed, Medline, Scopus, Embase, Science Direct, and the Cochrane Library Scopus). Series comparing pregnancy outcome after ART in women with and without endometriosis were screened and data on placenta previa and placental abruption were extracted. RESULTS: Five retrospective case-control studies met the inclusion criteria. The meta-analysis revealed that endometriosis is associated with an increased risk of placenta previa in pregnancies achieved through ART (OR 2.96 (95% CI 1.25-7.03); p = 0.01, I2 =69%, random-effect model). No differences in placental abruption incidence were found (OR 0.44 (95% CI 0.10 1.87); p = 0.26, I2 = 0%, fixed-effect model). CONCLUSION: Patients with endometriosis undergoing ART may have additional risk of placenta previa. Despite the inability to determine if endometriosis alone or endometriosis plus ART increase the risk, physicians should be aware of the potential additional risk that endometriosis patients undergoing ART harbor. PMID- 29602981 TI - Population pharmacokinetics of vancomycin and AUC-guided dosing in Chinese neonates and young infants. AB - OBJECTIVES: To develop a population pharmacokinetic (PK) model for vancomycin in Chinese neonates and infants less than 2 months of age (young infants) with a wide gestational age range, in order to determine the appropriate dosing regimen for this population. METHODS: We performed a retrospective chart review of patients from the neonatal intensive care unit (NICU) at Children's Hospital of Fudan University to identify neonates and young infants treated with vancomycin from May 2014 to May 2017. Vancomycin concentrations and covariates were utilized to develop a one-compartment model with first-order elimination. The predictive performance of the final model was assessed by both internal and external evaluation, and the relationship between trough concentration and AUC0-24 was investigated. Monte Carlo simulations were performed to design an initial dosing schedule targeting an AUC0-24 >= 400. RESULTS: The analysis included a total of 330 concentration-time data points from 213 neonates and young infants with gestational age (GA) and body weight of 25-42 weeks and 0.88-5.1 kg, respectively. Body weight, postmenstrual age (PMA) and serum creatinine level were found to be important factors explaining the between-subject variability in vancomycin PK parameters for this population. Both internal and external evaluation supported the prediction of the final vancomycin PK model. The typical population parameter estimates of clearance and distribution volume for an infant weighing 2.73 kg with a PMA of 39.8 weeks and serum creatinine of 0.28 mg/dL were 0.103 L/h/kg and 0.58 L/kg, respectively. Although vancomycin serum trough concentrations were predictive of the AUC, considerable variability was observed in the achievement of an AUC0-24/MIC of >=400. For MIC values of <=0.5 mg/L, AUC0 24/MIC >=400 was achieved for 95% of the newborn infants with vancomycin troughs of 5-10 mg/L. When the MIC increased to 1 mg/L, only 15% of the patients with troughs of 5-10 mg/L achieved AUC0-24/MIC >=400. For MIC values of 2 mg/L, no infants achieved the target. Simulations predicted that a dose of at least 14 and 15 mg/kg every 12 h was required to attain the target AUC0-24 >= 400 in 90% of infants with a PMA of 30-32 and 32-34 weeks, respectively. This target was also achieved in 93% of simulated infants in the oldest PMA groups (36-38 and 38-40 weeks, respectively) when the dosing interval was extended to 8 h. For infants with a PMA >=44 weeks, a dose increase to 18 mg/kg every 8 h was needed. The trough concentrations of 5-15 mg/L were highly predictive of an AUC0-24 of >=400 when treating invasive MRSA infections with an MIC of <=1 mg/L. CONCLUSIONS: The PK parameters for vancomycin in Chinese infants younger than 2 months of age were estimated using the model developed herein. This model has been used to predict individualized dosing regimens in this vulnerable population in our hospital. A large external evaluation of our model will be conducted in future studies. PMID- 29602982 TI - Ficellomycin: an aziridine alkaloid antibiotic with potential therapeutic capacity. AB - Ficellomycin is an aziridine antibiotic produced by Streptomyces ficellus, which displays high in vitro activity against Gram-positive bacteria including multidrug resistant strains of Staphylococcus aureus. Compared to currently available antibiotics, ficellomycin exhibits a unique mechanism of action-it impairs the semiconservative DNA replication by inducing the formation of deficient 34S DNA fragments, which lack the ability to integrate into larger DNA pieces and eventually the complete bacterial chromosome. Until recently, some important progress has been made in research on ficellomycin synthesis and biosynthesis, opening the perspective to develop a new generation of antibiotics with better clinical performance than the currently used ones. In this review, we will cover the discovery and biological activity of ficellomycin, its biosynthesis, mode of action, and related synthetic analogs. The role of ficellomycin and its analogs as an important source of drug prototypes will be discussed together with future research prospects. PMID- 29602983 TI - Genome-guided exploration of metabolic features of Streptomyces peucetius ATCC 27952: past, current, and prospect. AB - Streptomyces peucetius ATCC 27952 produces two major anthracyclines, doxorubicin (DXR) and daunorubicin (DNR), which are potent chemotherapeutic agents for the treatment of several cancers. In order to gain detailed insight on genetics and biochemistry of the strain, the complete genome was determined and analyzed. The result showed that its complete sequence contains 7187 protein coding genes in a total of 8,023,114 bp, whereas 87% of the genome contributed to the protein coding region. The genomic sequence included 18 rRNA, 66 tRNAs, and 3 non-coding RNAs. In silico studies predicted ~ 68 biosynthetic gene clusters (BCGs) encoding diverse classes of secondary metabolites, including non-ribosomal polyketide synthase (NRPS), polyketide synthase (PKS I, II, and III), terpenes, and others. Detailed analysis of the genome sequence revealed versatile biocatalytic enzymes such as cytochrome P450 (CYP), electron transfer systems (ETS) genes, methyltransferase (MT), glycosyltransferase (GT). In addition, numerous functional genes (transporter gene, SOD, etc.) and regulatory genes (afsR-sp, metK-sp, etc.) involved in the regulation of secondary metabolites were found. This minireview summarizes the genome-based genome mining (GM) of diverse BCGs and genome exploration (GE) of versatile biocatalytic enzymes, and other enzymes involved in maintenance and regulation of metabolism of S. peucetius. The detailed analysis of genome sequence provides critically important knowledge useful in the bioengineering of the strain or harboring catalytically efficient enzymes for biotechnological applications. PMID- 29602984 TI - Interactions between carbon and nitrogen sources depend on RIM15 and determine fermentative or respiratory growth in Saccharomyces cerevisiae. AB - Nutritional homeostasis is fundamental for alcoholic fermentation in Saccharomyces cerevisiae. Carbon and nitrogen have been related to this metabolic process; nevertheless, little is known about their interactions with the media and the energetic metabolism. Rim15p kinase is a point of convergence among different nutrient-activated signaling pathways; this makes it a target to investigate the relationship between nutritional status and energetic metabolism. To improve the current knowledge of nutrient interactions and their association with RIM15, we validated the doubling time as an indicator of growth phenotype, confirming that this kinetic parameter can be related to the cellular bioenergetic status. This endorses the usefulness of a threshold in doubling time values as an indicator of fermentative (<= 6.5 h) and respiratory growth (>= 13.2 h). Using the doubling time as response variable, we find that (i) two second order interactions between type and concentration of carbon and nitrogen sources significantly affected the growth phenotype of S. cerevisiae; (ii) these metabolic interactions changed when RIM15 was deleted, suggesting a dependence on this gene; (iii) high concentration of ammonium (5% w/v) is toxic for S. cerevisiae cells; (iv) proline prompted fermentative growth phenotype regardless presence or absence of RIM15; (v) RIM15 deletion reverted ammonium toxicity when cells were grown in glucose (10% w/v); and (vi) RIM15 deletion improves fermentative metabolism probably by a partial inhibition of the respiration capacity. This study reveals the existence of synergic and diverse roles of carbon and nitrogen sources that are affected by RIM15, influencing the fermentative and respiratory growth of S. cerevisiae. PMID- 29602985 TI - Rendezvous endoscopic recanalization for complete esophageal obstruction. AB - BACKGROUND AND STUDY AIM: Complete esophageal obstruction after (chemo)radiation for head and neck cancers is rare. However, inability to swallow one's own saliva strongly inflicts upon quality of life. Techniques for endoscopic recanalization in complete obstruction are not well established. We assessed the efficacy and safety of rendezvous recanalization. PATIENTS AND METHODS: We performed a retrospective review of all patients who underwent endoscopic recanalization of complete proximal esophageal obstruction after radiotherapy between January 2009 and June 2016. Technical success was defined as an ability to pass an endoscope across the recanalized lumen, clinical success by changes in the dysphagia score. Adverse events were recorded prospectively. RESULTS: 19 patients with complete obstruction (dysphagia IV degrees ), all of whom had failed at least one trial of conventional dilatation, underwent recanalization by endoscopic rendezvous, a combined approach through a gastrostomy and perorally under fluoroscopic control. Conscious sedation was used in all patients. In 18/19 patients (94.7%), recanalization was technically successful. In 14/18 patients (77.8%), the post intervention dysphagia score changed to <= II. Three patients had their PEG removed. Factors negatively associated with success were obstruction length of 50 mm; and tumor recurrence for long-term success. No severe complications were recorded. CONCLUSIONS: Rendezvous recanalization for complete esophageal obstruction is a reliable and safe method to re-establish luminal patency. Differences between technical and clinical success rates highlight the importance of additional functional factors associated with dysphagia. Given the lack of therapeutic alternatives, rendezvous recanalization is a valid option to improve dysphagia. PMID- 29602986 TI - Transferability of laparoscopic skills using the virtual reality simulator. AB - BACKGROUND: Skill transfer represents an important issue in surgical education, and is not well understood. The aim of this randomized study is to assess the transferability of surgical skills between two laparoscopic abdominal procedures using the virtual reality simulator in surgical novices. METHODS: From September 2016 to July 2017, 44 surgical novices were randomized into two groups and underwent a proficiency-based basic training consisting of five selected simulated laparoscopic tasks. In group 1, participants performed an appendectomy training on the virtual reality simulator until they reached a defined proficiency. They moved on to the tutorial procedural tasks of laparoscopic cholecystectomy. Participants in group 2 started with the tutorial procedural tasks of laparoscopic cholecystectomy directly. Finishing the training, participants of both groups were required to perform a complete cholecystectomy on the simulator. Time, safety and economy parameters were analysed. RESULTS: Significant differences in the demographic characteristics and previous computer games experience between the two groups were not noted. Both groups took similar time to complete the proficiency-based basic training. Participants in group 1 needed significantly less movements (388.6 +/- 98.6 vs. 446.4 +/- 81.6; P < 0.05) as well as shorter path length (810.2 +/- 159.5 vs. 945.5 +/- 187.8 cm; P < 0.05) to complete the cholecystectomy compared to group 2. Time and safety parameters did not differ significantly between both groups. CONCLUSION: The data demonstrate a positive transfer of motor skills between laparoscopic appendectomy and cholecystectomy on the virtual reality simulator; however, the transfer of cognitive skills is limited. Separate training curricula seem to be necessary for each procedure for trainees to practise task-specific cognitive skills effectively. Mentoring could help trainees to get a deeper understanding of the procedures, thereby increasing the chance for the transfer of acquired skills. PMID- 29602987 TI - Safety and curability of laparoscopic gastrectomy in elderly patients with gastric cancer. AB - BACKGROUND: Elderly patients are often considered as a high-risk population for major abdominal surgery due to reduced functional reserve and increased comorbidities. The aim of this study was to assess the safety and curability of laparoscopic gastrectomy in elderly patients with gastric cancer compared with short- and long-term outcomes in non-elderly patients. METHODS: We retrospectively investigated 386 patients who underwent laparoscopic gastrectomy for gastric cancer between January 2007 and December 2015 at the Digestive Disease Center, Showa University, Northern Yokohama Hospital. We categorized the patients into two groups by age: the elderly patients (>= 75 years old) and the non-elderly patients (< 74 years old). Patient characteristics, clinicopathologic and operative findings, and short- and long-term outcomes were investigated and compared between the two groups. RESULTS: The elderly group showed a significantly higher rate of comorbidities (73.1 vs. 49.2%, P < 0.001), and American Society of Anesthesiologists (ASA) scores >= 2 (76.3 vs. 43.7%, P < 0.001), and using anticoagulant agents (25.8 vs. 7.9%, P < 0.001) than the non elderly group. The postoperative morbidity and mortality did not differ between the two groups (19.4 vs. 18.8%; P = 0.880, 2.2 vs. 0%; P = 0.058). In the multivariate analysis, male sex was the only risk factor for postoperative morbidity after laparoscopic gastrectomy. However, age was not found to be a risk factor. The 5-year overall survival ratio was significantly lower in the elderly group than in the non-elderly group (67.7 vs. 85.0%; P < 0.001). However, the 5 year disease-specific survival ratio was similar in the two groups (84.8 vs. 89.1%; P = 0.071). CONCLUSION: Laparoscopic gastrectomy for gastric cancer could be safely performed in elderly patients with acceptable postoperative morbidity and curability. PMID- 29602988 TI - Mobile, real-time, and point-of-care augmented reality is robust, accurate, and feasible: a prospective pilot study. AB - BACKGROUND: Augmented reality (AR) systems are currently being explored by a broad spectrum of industries, mainly for improving point-of-care access to data and images. Especially in surgery and especially for timely decisions in emergency cases, a fast and comprehensive access to images at the patient bedside is mandatory. Currently, imaging data are accessed at a distance from the patient both in time and space, i.e., at a specific workstation. Mobile technology and 3 dimensional (3D) visualization of radiological imaging data promise to overcome these restrictions by making bedside AR feasible. METHODS: In this project, AR was realized in a surgical setting by fusing a 3D-representation of structures of interest with live camera images on a tablet computer using marker-based registration. The intent of this study was to focus on a thorough evaluation of AR. Feasibility, robustness, and accuracy were thus evaluated consecutively in a phantom model and a porcine model. Additionally feasibility was evaluated in one male volunteer. RESULTS: In the phantom model (n = 10), AR visualization was feasible in 84% of the visualization space with high accuracy (mean reprojection error +/- standard deviation (SD): 2.8 +/- 2.7 mm; 95th percentile = 6.7 mm). In a porcine model (n = 5), AR visualization was feasible in 79% with high accuracy (mean reprojection error +/- SD: 3.5 +/- 3.0 mm; 95th percentile = 9.5 mm). Furthermore, AR was successfully used and proved feasible within a male volunteer. CONCLUSIONS: Mobile, real-time, and point-of-care AR for clinical purposes proved feasible, robust, and accurate in the phantom, animal, and single trial human model shown in this study. Consequently, AR following similar implementation proved robust and accurate enough to be evaluated in clinical trials assessing accuracy, robustness in clinical reality, as well as integration into the clinical workflow. If these further studies prove successful, AR might revolutionize data access at patient bedside. PMID- 29602989 TI - An in vivo analysis of safe laparoscopic grasping thresholds for colorectal surgery. AB - BACKGROUND: Analysis of safe laparoscopic grasping thresholds for the colon has not been performed. This study aimed to analyse tissue damage thresholds when the colon is grasped laparoscopically, correlating histological changes to mechanical compressive forces. METHODS: An instrumented laparoscopic grasper was used to measure the forces applied to porcine colon, with data captured and plotted as a force-time (f-t) curve. Haematoxylin and eosin histochemistry of tissue subjected to 10, 20, 40, 50 and 70 N for 5, 30 and 60 s was performed, and the area of colonic circular and longitudinal muscle was compared in grasped and un-grasped regions. The area under the f-t curve was calculated as a measure of the accumulated force applied, known as the force-time product (FTP). RESULTS: FTP ranged from 55.7 to 3793 N.s. Significant differences were observed between the muscle area of the grasped and un-grasped regions in both longitudinal and circular muscle at 50 N and above for all grasping times. For the longitudinal muscle, significant differences were observed between grasped and un-grasped areas at 20 N force for 30 s (mean difference = 59 mm2, 95% CI 41-77 mm2, P = 0.04), 20 N force for 60 s (mean difference = 31 mm2, 95% CI 21.5-40.5 mm2, P = 0.006) and 40 N force for 30 s (mean difference 37 mm2, 95% CI 27-47 mm2, P = 0.006). Changes in histology correlated with mechanical forces applied to the longitudinal muscle at a FTP over 300 N s. CONCLUSIONS: This study characterizes the grasping forces that result in histological changes to the colon and correlates these with a mechanical measurement of the applied force. The findings will contribute to the development of smart laparoscopic graspers with active constraints to prevent excessive grasping and tissue injury. PMID- 29602990 TI - Safety of laparoscopic fundoplication in children under 5 kg: a comparative study. AB - BACKGROUND: Laparoscopic fundoplication in children under 5 kg is still debated. Our objective was to evaluate the safety and efficacy of laparoscopic fundoplication (LF) in children under 5 kg. METHODS: We reviewed the cases of 96 children treated by laparoscopic fundoplication between 2005 and 2014. Thirty five patients had a weight of 5 kg or less at the time of LF (Low Weight Group) and 61 patients had a weight between 5.1 and 10 kg (High Weight Group). The pre operative, peri-operative, post-operative data regarding surgery and anesthesia were compared between groups. RESULTS: Mean weight was 3.9 +/- 0.8 kg in the LWG and 7.8 +/- 1.5 kg in the HWG. Children in the LWG were more prone to pre operative respiratory management (40% mechanical ventilation and 42.9% oxygen therapy). The operating times (82 +/- 28 min for LWG and 85 +/- 31 min for HWG) and respiratory parameters during the procedure (PCO2) were comparable between groups. Post-operative complications were 1 gastric perforation with peritonitis and 1 small bowel obstruction in the LWG, 2 cases of gastric perforation with peritonitis in the HWG. Mean follow-up was 67 +/- 44 months. Significant recurrence of GERD requiring a redo fundoplication was noted in 3 patients in the LWG and 1 patient in the HWG. CONCLUSION: Laparoscopic fundoplication is a safe procedure in infants <= 5 kg without increase of post-operative complications, recurrence, or mean operative time. PMID- 29602991 TI - Logistical considerations for establishing reliable surgical telementoring programs: a report of the SAGES Project 6 Logistics Working Group. AB - Surgical telementoring programs (STMPs) as educational tools have consistently demonstrated success in the training of surgeons in a variety of surgical disciplines. The goal of an STMP is to train and educate practicing surgeons by improving or remediating surgical skills or assisting in the safe adoption of new procedures. STMPs may even have a role in assisting with recertification. In 2015, the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES) launched the SAGES Telementoring Initiative at the Project 6 Summit. Herein, we provide a report on the SAGES Project 6 Logistics working group and lay out a plan for the recommended logistical framework to carry out an STMP. PMID- 29602992 TI - Updated panel report: best practices for the surgical treatment of obesity. AB - BACKGROUND: During the 2004 annual meeting of the Society of American Gastrointestinal and Endoscopic Surgeons (SAGES), a panel of experts convened to provide updated information on best practices in bariatric surgery. The rapid evolution of endoluminal technologies, surgical indications, and training in bariatric surgery since 2004 has led to new questions and concerns about optimal treatment algorithms, patient selection, and the preparation of our current and future bariatric workforce. METHODS: An expert panel was convened at the SAGES 2017 annual meeting to provide a summative update on current practice patterns, techniques, and training in bariatric surgery in order to review and establish best practices. This was a joint effort by SAGES, International Society for the Perioperative Care of the Obese Patient, and the American Society for Metabolic and Bariatric Surgery. RESULTS: On March 23, 2017, seven expert faculty convened to address current areas of controversy in bariatric surgery and provide updated guidelines and practice recommendations. Areas addressed included the expanded indications for use of metabolic surgery in the treatment of diabetes, the safety and efficacy of new and investigational endoluminal procedures, updates on new guidelines for the management of airway and sleep apnea in the obese patient, the development of clinical pathways to reduce variation in the management of the bariatric patient, and new guidelines for training, credentialing, and bariatric program accreditation. The following article is a summary of this panel. CONCLUSION: Bariatric surgery is a field that continues to evolve. A timely, systematic approach, such as described here, that coalesces data and establishes best practices on the current body of available evidence is imperative for optimal patient care and to inform provider, insurer, and policy decisions. PMID- 29602993 TI - SAGES climate survey: results and strategic planning for our future. AB - BACKGROUND: While SAGES prides itself on diversity and inclusivity, we also recognize that as an organization we are not impervious to blind spots impacting equity within the membership. To address this, the We R Sages task force was formed to identify the barriers and facilitators to creating a diverse organization and develop a strategic plan for the implementation of programing and opportunities that promote diversity and inclusivity within our membership. As the first step in the process, a survey was administered to gauge the current organizational climate. METHODS: In September of 2017, a validated climate survey was administered to 704 SAGES committee members via SurveyMonkey(r). Climate was assessed on: overall SAGES experience, consideration of leaving the organization, mentorship within the organization, resources and opportunities within the organization, and attitudes and experiences within the organization. Additional free text responses were encouraged to generate qualitative themes. RESULTS: The survey response rate was 52.1% (n = 367). Respondent self-identified demographics were: male (73%), white (63%), heterosexual (95.5%), and non-disabled (98%). Average overall satisfaction was 8.1/10. 12.5% of respondents had considered leaving the organization and 74.4% had not identified a formal mentor within the organization. Average agreement with equitable distribution of resources and opportunities was 5.8/10. 93.6% of respondents had not experienced bias within the organization. CONCLUSION: Overall SAGES has a very positive climate; however, several key issues were identified from the quantitative survey as well as the free text responses. Strategic planning to address issues of membership recruitment, committee engagement, advancement transparency, diversity awareness, leadership development, and formal mentorship are being implemented. PMID- 29602994 TI - Examining the impact of surgical coaching on trainee physiologic response and basic skill acquisition. AB - BACKGROUND: We examined how problem-solving coaching impacts trainee skill acquisition and physiologic stress as well as how trainee sensitivity to feedback, known as self-monitoring ability, impacts coaching effectiveness. METHODS: Medical students completed a pre-training demographics questionnaire, a 12-item self-monitoring ability scale (1 = always false, 5 = always true), and baseline FLS Task 5 with physiologic sensors. After watching a laparoscopic suturing instructional video, students practiced the task for 30 min, either with a surgical coach, or alone, depending on condition. The coach logged frequency of coaching behaviors according to a task-specific coaching script. Trainees then completed FLS Task 5 with physiologic sensors, a post-training questionnaire, and a 12-item coaching quality evaluation (1 = poor, 5 = very good). RESULTS: Twenty four students (age 24.5 +/- 1.4; 54% men; 58% MS4) participated in the study. All were fairly high self-monitors (3.8 +/- 0.76). No differences in baseline suturing skills between the groups emerged. Improvement in the coaching group's suturing (N = 12; 285.0 +/- 79.9) was significantly higher than the control group (N = 12; 200.9 +/- 110.3). One measure of physiologic stress (rMSSD) was significantly higher in the coaching group. Trainees who received more coaching demonstrated larger improvements (r = 0.7, p < 0.05). Overall ,perceived quality of the coaching relationship was high (4.4 +/- 0.6). There was no correlation between trainee self-monitoring ability and skill improvement. CONCLUSIONS: This work suggests that coaching may increase heart rate variability of trainees, indicating coping well with training. Trainee disposition toward feedback did not play a role in this relationship. PMID- 29602995 TI - Learning curve for performing choledochotomy bile duct exploration with primary closure after laparoscopic cholecystectomy. AB - BACKGROUND: Primary closure after laparoscopic cholecystectomy (LC) and laparoscopic common bile duct exploration (LCBDE) is a safe and effective approach for treating cholecystolithiasis with choledocholithiasis. The aim of this study was to evaluate the learning curve of performing primary closure after LC+LCBDE. METHODS: We retrospectively identified all patients who underwent primary closure after LC+LCBDE performed by a single surgeon from January 2009 to April 2015 in our institution, and analyzed preoperative, intraoperative, and postoperative data using the cumulative sum (CUSUM) analysis to evaluate the learning curve for this procedure. RESULTS: Overall, there were 390 patients. The total postoperative complications rate was 7.2%, including bile leakage in 9 (2.3%) patients and retained common bile duct stone in 3 (0.8%) patients. The CUSUM operating time (OT) learning curve was best modeled by the equation: CUSUMOT = 312.209 * procedure0.599 * e(-0.011*procedure) + 122.608 (R2 = 0.96). The learning curve was composed of two phases, phase 1 (the initial 54 patients) and phase 2 (the remaining 336 patients). A significant decrease in the OT (116.8 +/- 22.4 vs. 93.8 +/- 17.8 min; p < 0.001) and complication rate (16.7 vs. 5.7%; p < 0.01) including the rate of bile leakage (7.4 vs. 1.5%; p < 0.01) and retained stone (3.7 vs. 0.3%; p < 0.01) was observed between the two phases. In addition, 20 patients had conversion to open surgery. Impacted stones were independently associated with conversion, as indicated by a multivariable analysis. CONCLUSION: The data suggest that the learning curve of this procedure was achieved in approximately 54 cases. An impacted stone was the only risk factor that affected the conversion rate. PMID- 29602996 TI - Laparoscopic pancreaticoduodenectomy with major venous resection and reconstruction: anterior superior mesenteric artery first approach. AB - BACKGROUND: The en bloc resection of the superior mesenteric or portal vein with concomitant venous reconstruction may be required in patients with borderline resectable pancreatic cancer. However, performing laparoscopic pancreaticoduodenectomy (LPD) with major venous resection and reconstruction is technically challenging. Herein, we introduced a safe and feasible technique to perform LPD with major venous resection. METHODS: Over the period of November 2015 to November 2016, 18 patients underwent laparoscopic pancreaticoduodenectomy with major venous resection and reconstruction using the anterior superior mesenteric artery (SMA)-first approach at our institution. Demographic characteristics, intraoperative and postoperative variables, and follow-up outcomes were prospectively collected. RESULTS: Eighteen male and ten female patients were included in this study. The median age of the patients was 58 years (range 49-76 years). Eight cases of wage resections, six cases of end-to-end anastomosis, and four cases of artificial grafts were performed in our series. Only one patient (5.6%) required conversion because of uncontrolled bleeding from the splenic vein. The average operative time was 448 min (range 420-570 min). The mean time for blood occlusion was 32 min, including 17 min for wage resections, 28 min for end-to-end anastomosis, and 48 min for artificial grafts. Thirty-day mortality was not observed in our series. The median postoperative hospital stay was 13 days (range 9-18 days). Three patients suffered from pancreatic fistula (Grade A), and one suffered from abdominal bleeding after subcutaneous injection with low-molecular heparin. In this case, abdominal bleeding was stopped through conservative therapies. CONCLUSION: Laparoscopic pancreaticoduodenectomy with major venous resection and reconstruction can be safely and feasibly performed. The anterior SMA-first approach can facilitate this procedure and decrease operative time and blood occlusion duration. PMID- 29602997 TI - Laparoscopic Hill repair: 25-year follow-up. AB - BACKGROUND: The open Hill repair for gastroesophageal reflux disease and hiatal hernia is remarkably durable, with a median 10-year reoperation rate of only 3% and satisfaction of 93%. No long-term data exist for the laparoscopic Hill repair (LHR). METHODS: Patients who underwent primary LHR at Swedish Medical Center for reflux and/or hiatal hernia at least 5 years earlier (1992-2010) were identified from an IRB-approved database. There were 727 patients who met inclusion criteria, including 648 undergoing repair for reflux and 79 for paraesophageal hernia. Two questionnaires were administered via mail to evaluate long-term quality of life using validated GERD-HRQL, Swallowing score, and global satisfaction score. Outcomes were defined by GERD-HRQL score, Swallowing score, resumption of proton pump inhibitor (PPI) therapy, need for reoperation, and global satisfaction with overall results. RESULTS: Two hundred forty-two patients completed and returned the survey (226 lost to follow-up, 90 deceased, 3 denied undergoing LHR, 166 non-responders), of which 52% were male. The average age at the time of surgery was 49.5 years. Median follow-up was 18.5 years (range 6.2 24.7). The average GERD-HRQL score (7.1) and the average Swallowing score (39.9) both indicated excellent symptomatic outcomes. 30% of patients are using daily PPIs. 24 patients (9.9%) required reoperation for failure during the follow-up period, 21 in the reflux group and 3 in the paraesophageal hernia group. Overall, 85% reported good to excellent results, and 76% would recommend the operation. CONCLUSION: LHR shows excellent long-term durability and quality of life similar to the open Hill repair, with 85% good to excellent results at a median follow-up of 19 years and a reoperation rate under 10%. It is surmised that Hill suture fixation of the gastroesophageal junction to the preaortic fascia may confer unique structural integrity compared to other repairs. PMID- 29602998 TI - Clinical feasibility of a new full-thickness endoscopic plication device (GERDxTM) for patients with GERD: results of a prospective trial. AB - BACKGROUND: Previous studies suggest clinical effectiveness of endoscopic full thickness plication in selected patients with gastroesophageal reflux disease (GERD). The aim of this study was to assess the clinical safety and efficiency of the GERDxTM device by evaluating clinical parameters, reflux symptom scores, and quality of life (QoL). METHODS: Prospective one-arm trial evaluating the outcome of forty patients with GERD subjected to endoscopic plication with the GERDxTM device. We included patients with at least one typical reflux symptom despite treatment with a PPI for > 6 months, pathologic esophageal acid exposure, hiatal hernia of size < 2 cm, and endoscopic Hill grade II-III. Evaluation of Gastrointestinal Quality of Life Index (GIQLI), symptom scores, esophageal manometry, and impedance-pH-monitoring were performed at baseline and at 3 months after surgery. (Trial Registration: ClinicalTrials.gov NCT 01798212.) RESULTS: There were no intraoperative complications. Four out of forty patients experienced postoperative complications requiring intervention. Seven of forty patients were subjected to laparoscopic fundoplication 3 months after endoscopic plication due to persistent symptoms and were lost to further follow-up. Thirty out of forty patients were available at 3-month follow-up. There was an improvement of the GIQLI score, from a mean of 92.45 +/- 18.47 to 112.03 +/- 13.11 (p < 0.001). The general reflux-specific score increased from a mean of 49.84 +/- 24.83 to 23.93 +/- 15.63 (p < 0.001), and the DeMeester score from a mean of 46.48 +/- 30.83 to 20.03 +/- 23.62 (p < 0.001). There was no significant change in manometric data after intervention. Three of thirty patients continued daily antireflux medication. CONCLUSIONS: Endoscopic plication with the GERDxTM device reduced distal acid exposure of the esophagus, reflux-related symptoms, and improved GIQLI scores with minimal side effects in a selected cohort of patients and may be a safe alternative in the treatment of GERD. PMID- 29602999 TI - Long-term oncologic outcomes after laparoscopic vs. open colon cancer resection: a high-quality population-based analysis in a Southern German district. AB - BACKGROUND: Over 20 years after the introduction of laparoscopic surgery for colon cancer, many surgeons still prefer the open approach. Whereas randomized controlled trials (RCTs) have proven the oncologic safety of laparoscopy, long term data depicting daily clinical routine are scarce. METHODS: This population based cohort study compares 5-year overall, relative, and recurrence-free survival rates after laparoscopic and open colon carcinoma surgery. Data derive from an independent German cancer registry encompassing all tumor patients within a political district of 1.1 million inhabitants. The final analysis included 2669 patients with major elective resection of primary non-metastatic colonic adenocarcinoma between January 1, 2004 and December 31, 2013. Survival rates were compared using Kaplan-Meier analyses, relative survival models, and multivariate Cox regression. Sensitivity analysis quantified selection bias. RESULTS: The proportion of laparoscopic procedures increased from 9.7 to 25.8% in 2011 and dropped again to 15.8% at the end of observation period. Laparoscopy patients were younger, had a lower tumor stage, and were more likely to receive postoperative chemotherapy. Overall, relative, and recurrence-free survival was significantly superior or equivalent in Kaplan-Meier analysis (5-year overall survival rate open vs. laparoscopic: 69.0 vs. 80.2%, p < 0.001). The superiority of laparoscopy mostly remained stable after adjusting for confounders, although significance was only reached in T1-3 patients without lymph node metastases (overall survival: hazard ratio (HR) 0.654; 95% confidence interval (CI) 0.446 0.958; p = 0.029). CONCLUSION: Laparoscopy is a safe and promising alternative to the open approach in daily clinic practice. These favorable outcomes require future confirmation by high-quality studies outside the setting of RTCs. PMID- 29603000 TI - Prospective histological evaluation of a 20G core trap with a forward-cutting bevel needle for EUS-FNA of pancreatic lesions. AB - BACKGROUND: Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) has been established as a method to obtain tissues of various organs. To obtain sufficient tissue has clinical impact to facilitate the diagnosis by clinical pathologists, the assessment and subtyping of various neoplasms, and for further immunohistochemical investigations of tumor type. Recently, a novel 20G core trap with a forward-cutting beveled FNA needle (ProC-F) has become available. The aim of this prospective study was to evaluate the feasibility and diagnostic yield of EUS-FNA for pancreatic lesions using this needle. PATIENTS AND METHOD: In this study, the first puncture was performed using the ProC-F. Only tissue obtained with the first puncture using the ProC-F was used to evaluate diagnostic yield of ProC-F. The second puncture was performed using a 22G standard FNA needle using the same technique as for the first puncture. Second puncture was performed if the endosonographer did not feel that sufficient tissue had not been obtained by first puncture. RESULTS: Fifty-three consecutive patients who underwent EUS-FNA for pancreatic lesions were prospectively enrolled. The technical success rate of EUS-FNA using the ProC-F was 98.1% (52/53). The rate of adequate tissue obtained by ProC-F was 96.2% (50/52). On the other hand, the rate of adequate tissue obtained by the standard needle was 71.1%. The sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV), and accuracy of the ProC F and the standard needle were 92.5, 100, 100, 76.9, and 94.0%, and 85.2, 100, 100, 55.6, and 87.5%, respectively. Diagnostic yield of ProC-F about sensitivity (P = 0.027), NPV (P = 0.035), and accuracy (P = 0.004) was significantly higher than of standard needle. Adverse events were not seen in any patients. CONCLUSIONS: Although only tissue obtained by the first puncture was evaluated, the rate of adequate tissue and the histologic diagnostic yield for pancreatic lesions were extremely high using the ProC-F. PMID- 29603001 TI - Oncological outcome following laparoscopic versus open surgery for cancer in the transverse colon: a nationwide cohort study. AB - BACKGROUND: The literature on transverse colonic cancer resection is sparse. The optimal surgical approach for this disease is thus unknown. This study aimed to examine laparoscopic versus open surgery for transverse colonic cancer. METHODS: This study was a nationwide, retrospective cohort study of all patients registered with a transverse colonic cancer in Denmark between 2010 and 2013. Data were obtained from the Danish Colorectal Cancer Group, the Danish Pathology Registry, Danish National Patient Registry, and patients' records. Main outcome measures were surgical resection plane, lymph node yield, and long-term cancer recurrence and survival. RESULTS: In total, 357 patients were included. Non mesocolic resection was more frequent with laparoscopic compared with open resection (adjusted odds ratio 2.44, 95% CI 1.29-4.60, P = 0.006). Median number of harvested lymph nodes was higher after open compared with laparoscopic resection (22 versus 19, P = 0.03). Non-mesocolic resection (adjusted hazard ratio 2.45, 95% CI 1.25-4.79, P = 0.01) and increasing tumor stage (P < 0.001) were factors associated with recurrence. Cancer recurrence was significantly associated with an increased risk of mortality (adjusted hazard ratio 4.32, 95% CI 2.75-6.79, P < 0.001). Overall mortality was, however, not associated with the surgical approach or surgical plane. CONCLUSIONS: Although associated with a lower rate of mesocolic resection plane and fewer lymph nodes harvested, laparoscopic surgery for transverse colonic cancers led to similar long-term results compared with open resection. PMID- 29603002 TI - Computer tomographic analysis of organ motion caused by respiration and intraoperative pneumoperitoneum in a porcine model for navigated minimally invasive esophagectomy. AB - BACKGROUND: Navigation systems have the potential to facilitate intraoperative orientation and recognition of anatomical structures. Intraoperative accuracy of navigation in thoracoabdominal surgery depends on soft tissue deformation. We evaluated esophageal motion caused by respiration and pneumoperitoneum in a porcine model for minimally invasive esophagectomy. METHODS: In ten pigs (20-34 kg) under general anesthesia, gastroscopic hemoclips were applied to the cervical (CE), high (T1), middle (T2), and lower thoracic (T3) level, and to the gastroesophageal junction (GEJ) of the esophagus. Furthermore, skin markers were applied. Three-dimensional (3D) and four-dimensional (4D) computed tomography (CT) scans were acquired before and after creation of pneumoperitoneum. Marker positions and lung volumes were analyzed with open source image segmentation software. RESULTS: Respiratory motion of the esophagus was higher at T3 (7.0 +/- 3.3 mm, mean +/- SD) and GEJ (6.9 +/- 2.8 mm) than on T2 (4.5 +/- 1.8 mm), T1 (3.1 +/- 1.8 mm), and CE (1.3 +/- 1.1 mm). There was significant motion correlation in between the esophageal levels. T1 motion correlated with all other esophagus levels (r = 0.51, p = 0.003). Esophageal motion correlated with ventilation volume (419 +/- 148 ml) on T1 (r = 0.29), T2 (r = 0.44), T3 (r = 0.54), and GEJ (r = 0.58) but not on CE (r = - 0.04). Motion correlation of the esophagus with skin markers was moderate to high for T1, T2, T3, GEJ, but not evident for CE. Pneumoperitoneum led to considerable displacement of the esophagus (8.2 +/- 3.4 mm) and had a level-specific influence on respiratory motion. CONCLUSIONS: The position and motion of the esophagus was considerably influenced by respiration and creation of pneumoperitoneum. Esophageal motion correlated with respiration and skin motion. Possible compensation mechanisms for soft tissue deformation were successfully identified. The porcine model is similar to humans for respiratory esophageal motion and can thus help to develop navigation systems with compensation for soft tissue deformation. PMID- 29603003 TI - Validity evidence for procedural competency in virtual reality robotic simulation, establishing a credible pass/fail standard for the vaginal cuff closure procedure. AB - BACKGROUND: The use of robotic surgery for minimally invasive procedures has increased considerably over the last decade. Robotic surgery has potential advantages compared to laparoscopic surgery but also requires new skills. Using virtual reality (VR) simulation to facilitate the acquisition of these new skills could potentially benefit training of robotic surgical skills and also be a crucial step in developing a robotic surgical training curriculum. The study's objective was to establish validity evidence for a simulation-based test for procedural competency for the vaginal cuff closure procedure that can be used in a future simulation-based, mastery learning training curriculum. METHODS: Eleven novice gynaecological surgeons without prior robotic experience and 11 experienced gynaecological robotic surgeons (> 30 robotic procedures) were recruited. After familiarization with the VR simulator, participants completed the module 'Guided Vaginal Cuff Closure' six times. Validity evidence was investigated for 18 preselected simulator metrics. The internal consistency was assessed using Cronbach's alpha and a composite score was calculated based on metrics with significant discriminative ability between the two groups. Finally, a pass/fail standard was established using the contrasting groups' method. RESULTS: The experienced surgeons significantly outperformed the novice surgeons on 6 of the 18 metrics. The internal consistency was 0.58 (Cronbach's alpha). The experienced surgeons' mean composite score for all six repetitions were significantly better than the novice surgeons' (76.1 vs. 63.0, respectively, p < 0.001). A pass/fail standard of 75/100 was established. Four novice surgeons passed this standard (false positives) and three experienced surgeons failed (false negatives). CONCLUSION: Our study has gathered validity evidence for a simulation-based test for procedural robotic surgical competency in the vaginal cuff closure procedure and established a credible pass/fail standard for future proficiency-based training. PMID- 29603004 TI - Single-stage laparoscopic common bile duct exploration and cholecystectomy versus two-stage endoscopic stone extraction followed by laparoscopic cholecystectomy for patients with gallbladder stones with common bile duct stones: systematic review and meta-analysis of randomized trials with trial sequential analysis. AB - BACKGROUND: The ideal management of common bile duct (CBD) stones associated with gall stones is a matter of debate. We planned a meta-analysis of randomized trials comparing single-stage laparoscopic CBD exploration and cholecystectomy (LCBDE) with two-stage preoperative endoscopic stone extraction followed by cholecystectomy (ERCP + LC). METHODS: We searched the Pubmed/Medline, Web of science, Science citation index, Google scholar and Cochrane Central Register of Controlled trials electronic databases till June 2017 for all English language randomized trials comparing the two approaches. Statistical analysis was performed using Review Manager (RevMan) [Computer program], Version 5.3. Copenhagen: The Nordic Cochrane Centre, The Cochrane Collaboration, 2014 and results were expressed as odds ratio for dichotomous variables and mean difference for continuous. p value <= 0.05 was considered significant. Trial sequential analysis (TSA) was performed using TSA version 0.9.5.5 (Copenhagen: The Copenhagen Trial Unit, Centre for Clinical Intervention Research, 2016). PROSPERO trial registration number is CRD42017074673. RESULTS: A total of 11 trials were included in the analysis, with a total of 1513 patients (751-LCBDE; 762-ERCP + LC). LCBDE was found to have significantly lower rates of technical failure [OR 0.59, 95% CI (0.38, 0.93), p = 0.02] and shorter hospital stay [MD - 1.63, 95% CI (- 3.23, - 0.03), p = 0.05]. There was no significant difference in mortality [OR 0.37, 95% CI (0.09, 1.51), p = 0.17], morbidity [OR 0.97, 95% CI (0.70, 1.33), p = 0.84], cost [MD - 379.13, 95% CI (- 784.80, 111.2), p = 0.13] or recurrent/retained stones [OR 1.01, 95% CI (0.38, 2.73), p = 0.98]. TSA showed that although the Z-curve crossed the boundaries of conventional significance, the estimated information size is yet to be achieved. CONCLUSIONS: Single-stage LCBDE is superior to ERCP + LC in terms of technical success and shorter hospital stay in good-risk patients with gallstones and CBD stones, where expertise, operative time and instruments are available. PMID- 29603005 TI - The effect on surgical skills of expert surgeons using 3D/HD and 2D/4K resolution monitors in laparoscopic phantom tasks. AB - BACKGROUND: Recently, several new imaging technologies, such as three-dimensional (3D)/high-definition (HD) stereovision and high-resolution two-dimensional (2D)/4K monitors, have been introduced in laparoscopic surgery. However, it is still unclear whether these technologies actually improve surgical performance. METHODS: Participants were 11 expert laparoscopic surgeons. We designed three laparoscopic suturing tasks (task 1: simple suturing, task 2: knotting thread in a small box, and task 3: suturing in a narrow space) in training boxes. Performances were recorded by an optical position tracker. All participants first performed each task five times consecutively using a conventional 2D/HD monitor. Then they were randomly divided into two groups: six participants performed the tasks using 3D/HD before using 2D/4K; the other five participants performed the tasks using a 2D/4K monitor before the 3D/HD monitor. After the trials, we evaluated the performance scores (operative time, path length of forceps, and technical errors) and compared performance scores across all monitors. RESULTS: Surgical performances of participants were ranked in decreasing order: 3D/HD, 2D/4K, and 2D/HD using the total scores for each task. In task 1 (simple suturing), some surgical performances using 3D/HD were significantly better than those using 2D/4K (P = 0.017, P = 0.033, P = 0.492 for operative time, path length, and technical errors, respectively). On the other hand, with operation in narrow spaces such as in tasks 2 and 3, performances using 2D/4K were not inferior to 3D/HD performances. The high-resolution images from the 2D/4K monitor may enhance depth perception in narrow spaces and may complement stereoscopic vision almost as well as using 3D/HD. CONCLUSIONS: Compared to a 2D/HD monitor, a 3D/HD monitor improved the laparoscopic surgical technique of expert surgeons more than a 2D/4K monitor. However, the advantage of 2D/4K high-resolution images may be comparable to a 3D/HD monitor especially in narrow spaces. PMID- 29603006 TI - Customized airway stenting for bronchopleural fistula after pulmonary resection by interventional technique: single-center study of 148 consecutive patients. AB - BACKGROUND: Bronchopleural fistula after pulmonary resection is a serious complication, with major impact on the quality of life and survival. This study aims to evaluate the efficacy and safety of customized airway stenting in the treatment of bronchopleural fistula. METHODS: A series of airway stents for dedicated bronchopleural fistula occlusion were designed after taking into account the anatomical and pathophysiological features of post-pulmonary resection fistulas and the shortcomings of airway stents currently available. The fistulas were occluded with the bullet head or a special part of the covered airway stent. Successful stenting was defined as immediate cessation of air leak from the residual cavity after stenting. The results were retrospectively analyzed. RESULTS: Airway occlusion stenting was successful on the first attempt in 143/148 (96.6%) patients with bronchopleural fistulas. In the remaining 5 patients, occlusion was successful only on the second try. At follow-up 30 days after stenting, 141 patients reported relief in symptoms. No choking, laryngeal edema, or airway rupture occurred in any patient during stent insertion or removal; 2 patients developed hemorrhage during stent removal. CONCLUSIONS: Airway occlusion stenting appears to be a feasible and effective technique for treatment of bronchopleural fistula. PMID- 29603007 TI - A novel assessment tool for evaluating competence in video-assisted thoracoscopic surgery lobectomy. AB - BACKGROUND: Specific assessment tools can accelerate trainees' learning through structured feedback and ensure that trainees attain the knowledge and skills required to practice as competent, independent surgeons (competency-based surgical education). The objective was to develop an assessment tool for video assisted thoracoscopic surgery (VATS) lobectomy by achieving consensus within an international group of VATS experts. METHOD: The Delphi method was used as a structured process for collecting and distilling knowledge from a group of internationally recognized VATS experts. Opinions were obtained in an iterative process involving answering repeated rounds of questionnaires. Responses to one round were summarized and integrated into the next round of questionnaires until consensus was reached. RESULTS: Thirty-one VATS experts were included and four Delphi rounds were conducted. The response rate for each round were 68.9% (31/45), 100% (31/31), 96.8% (30/31), and 93.3% (28/30) for the final round where consensus was reached. The first Delphi round contained 44 items and the final VATS lobectomy Assessment Tool (VATSAT) comprised eight items with rating anchors: (1) localization of tumor and other pathological tissue, (2) dissection of the hilum and veins, (3) dissection of the arteries, (4) dissection of the bronchus, (5) dissection of lymph nodes, (6) retrieval of lobe in bag, (7) respect for tissue and structures, and (8) technical skills in general. CONCLUSION: A novel and dedicated assessment tool for VATS lobectomy was developed based on VATS experts' consensus. The VATSAT can support the learning of VATS lobectomy by providing structured feedback and help supervisors make the important decision of when trainees have acquired VATS lobectomy competencies for independent performance. PMID- 29603008 TI - The change in groin pain perception after transabdominal preperitoneal inguinal hernia repair with glue fixation: a prospective trial of a single surgeon's experience. AB - BACKGROUND: Although inguinal hernia is one of the most common conditions requiring surgical treatment, no reliable information is available on the quality of life of patients with inguinal hernias before surgery. Additionally, patients with intense inguinal pain prior to surgery are more susceptible to postoperative chronic pain. In such cases, less invasive laparoscopic techniques can be used, allowing atraumatic mesh fixation to reduce postoperative pain. The aim of the study was to determine, whether these treatments for patients with preoperative pain would minimize upsetting experiences after surgery. MATERIALS AND METHODS: Data were gathered prospectively from the National Hernia Repair Register for 146 patients who underwent TAPP repairs in the general surgery department (2013 2016). The demographic data were recorded, the pain intensity was determined and patients described the occurrence of pain during ten everyday activities. RESULTS: The average surgery time was 56.4 min. The follow-up was 23.4 months. The pain before surgery was 4.28 and 12 months after surgery 0.38 (p < 0.001). Pain intensity before surgery was scored as 4.1, 4.3, and 4.9 among patients who had a hernia < 12 months, > 1 year, and > 5 years, respectively (p = 0.028). Twelve months after surgery, the pain was 0.26, 0.34, and 0.40 (p = 0.037), respectively. Patients < 40 years experienced pain before the surgery more often. The intensity of pre-/postoperative pain was significantly higher < 40 years (4.9/0.63) than > 60 years (3.8/0.29). CONCLUSIONS: TAPP inguinal hernia repair with glue fixation significantly decreased the frequency and intensity of the pain compared to that experienced preoperatively. After TAPP repair, the influence of pain on basic everyday activities is substantially lower. Patients under 40 years of age experience frequent and intense pre- and postoperative pain. A longer hernia duration prior to surgery causes increased pre- and postoperative pain. PMID- 29603009 TI - Endoscopic pilonidal sinus treatment: a systematic review and meta-analysis. AB - BACKGROUND: Sacrococcygeal pilonidal disease (SPD) is a common surgical condition for which a multitude of surgical treatments have been described. The present review aimed to evaluate the efficacy and safety of a novel endoscopic procedure for the treatment of SPD. METHODS: An organized literature search was conducted. Electronic databases including PubMed/Medline, Scopus, Embase, and Cochrane library were searched for articles that assessed the endoscopic treatment for SPD. The main outcome parameters were failure of the technique including persistence and recurrence of SPD, postoperative complications and pain, time to complete healing, and time to return to work. RESULTS: Nine studies with a total of 497 patients were included. Mean age of patients was 24.8 years. Mean operation time was 34.7 min. The procedure was performed as day-case surgery in all studies. The mean Visual analogue score of pain within the first week was 1.35. Failure of the technique was recorded in 40 (8.04%) patients, 20 (4.02%) had persistent SPD and 20 (4.02%) developed recurrence. The weighted mean failure rate of the technique was 6.3% (95% CI 3.6-9.1). Mean weighted complication rate was 1.1% (95% CI 0.3-2.4). Mean time to complete healing was 32.9 days and mean time to return to work was 2.9 days. CONCLUSION: The endoscopic treatment of pilonidal sinus is a promising and safe method of treatment of SPD. The main advantages of the endoscopic treatment as compared to conventional surgery are the minimal postoperative pain, quick healing, and short time to return to work and daily activities. PMID- 29603010 TI - A prospective, single-arm study on the use of the da Vinci(r) Table Motion with the Trumpf TS7000dV operating table. AB - BACKGROUND: The da Vinci(r) Table Motion (dVTM) comprises a combination of a unique operating table (Trumpf MedicalTM TruSystem(r) 7000dV) capable of isocenter motion connected wirelessly with the da Vinci Xi(r) robotic platform, thereby enabling patients to be repositioned without removal of instruments and or undocking the robot. MATERIALS AND METHODS: Between May 2015 to October 2015, the first human use of dVTM was carried out in this prospective, single-arm, post market study in the EU, for which 40 patients from general surgery (GS), urology (U), or gynecology (G) were enrolled prospectively. Primary endpoints of the study were dVTM feasibility, efficacy, and safety. RESULTS: Surgeons from the three specialties obtained targeting success and the required table positioning in all cases. Table movement/repositioning was necessary to gain exposure of the operating field in 106/116 table moves (91.3%), change target in 2/116 table moves (1.7%), achieve hemodynamic relief in 4/116 table moves (3.5%), and improve external access for tumor removal in 4/116 table moves (3.5%). There was a significantly higher use of tilt and tilt plus Trendelenburg in GS group (GS vs. U p = 0.055 and GS vs. G p = 0.054). There were no dVTM safety-related or adverse events. CONCLUSIONS: The dVTM with TruSystem 7000dV operating table in wireless communication with the da Vinci Xi is a perfectly safe and effective synergistic combination, which allows repositioning of the patient whenever needed without imposing any delay in the execution of the operation. Moreover, it is helpful in avoiding extreme positions and enables the anesthesiologist to provide immediate and effective hemodynamic relief to the patient when needed. PMID- 29603011 TI - Post-operative regression of retro-odontoid pseudotumors treated with and without fusion. AB - PURPOSE: Retro-odontoid pseudotumor is common in elderly people and is a cause of cervical myelopathy. The goal of the study was to investigate surgical procedures, outcomes, and post-operative spontaneous regression of posterior cervical retro-odontoid pseudotumors. METHODS: The subjects were 29 patients who underwent surgery for myelopathy due to a retro-odontoid pseudotumor around the craniocervical region at 9 facilities and were followed-up for an average of 54 months (range 12-96 months). Data were collected in a multicenter review of a retrospective database. Comparisons were performed between cases treated with and without fusion. RESULTS: The JOA recovery rate at final follow-up did not differ significantly between the fusion (n = 17, including all 15 patients with atlantoaxial subluxation) and non-fusion (n = 12) groups. However, pseudotumor regression was significantly more frequent in the fusion group (100% vs. 42%, p < 0.01). In all patients, regression cases had significantly higher rates of contrast enhancement of the pseudotumor on pre-operative T1 gadolinium-enhanced MRI (68% vs. 14%, p = 0.013) and of JOA recovery (50% vs. 30%, p < 0.01). CONCLUSIONS: Regression of pseudotumor occurred in all cases treated with fusion surgery. There was a significant difference in pseudotumor regression with or without fusion, and regression was significantly related to gadolinium enhancement on MRI. Therefore, it is preferable to use fusion surgery for a retro odontoid pseudotumor that shows contrast enhancement, even if there is no apparent instability pre-operatively. These slides can be retrieved under Electronic Supplementary Material. PMID- 29603012 TI - Decision-making factors in the treatment of adult spinal deformity. AB - PURPOSE: We aimed to elucidate the factors for the decision-making process in the treatment of adult spinal deformity (ASD), including sagittal parameters, that impact health-related quality of life (HRQOL). METHODS: A multicenter prospective ASD database was retrospectively reviewed. The demographic data, HRQOL, and radiographic measures were analyzed using multivariate analyses in younger (<= 50 years) and older (> 50 years) age groups. RESULTS: This study included 414 patients (134 surgical and 280 nonsurgical; mean age 30.7 years) in the younger age group and 575 patients (323 surgical and 252 nonsurgical; mean age 65.8 years) in the older age group. Worse HRQOL measures drove surgical treatment, both in younger and older patients. The SRS-22 self-image score was the most differentiating domain, both in the younger and older age groups, and an additional significant factor in the older age group was pain and disability. Coronal deformity drove surgical treatment for the younger age group; however, older surgical patients were less likely to have coronal malalignment. Sagittal parameters were associated with the decision-making process. Greater pelvic incidence minus lumbar lordosis mismatch in the younger age group and smaller lumbar lordosis index in the older age group were most correlated with the decision to undergo surgery. CONCLUSIONS: Aside from the HRQOL measures and coronal deformity, sagittal parameters were identified as significant factors for the decision-making process in the ASD population, and the lack of lumbar lordosis in relation to pelvic incidence was a strong driver to pursue surgical treatment. These slides can be retrieved under Electronic Supplementary Material. PMID- 29603013 TI - External validation of the adult spinal deformity (ASD) frailty index (ASD-FI). AB - PURPOSE: To assess the ability of the recently developed adult spinal deformity frailty index (ASD-FI) to predict odds of perioperative complications, odds of reoperation, and length of hospital stay after adult spinal deformity (ASD) surgery using a database other than the one used to create the index. METHODS: We used the ASD-FI to calculate frailty scores for 266 ASD patients who had minimum postoperative follow-up of 2 years in the European Spine Study Group (ESSG) database. Patients were enrolled from 2012 through 2013. Using ASD-FI scores, we categorized patients as not frail (NF) (< 0.3 points), frail (0.3-0.5 points), or severely frail (SF) (> 0.5 points). Multivariable logistic regression, adjusted for preoperative and surgical factors such as operative time and blood loss, was performed to determine the relationship between ASD-FI category and odds of major complications, odds of reoperation, and length of hospital stay. RESULTS: We categorized 135 patients (51%) as NF, 90 patients (34%) as frail, and 41 patients (15%) as SF. Overall mean ASD-FI score was 0.29 (range 0-0.8). The adjusted odds of experiencing a major intraoperative or postoperative complication (OR 4.5, 95% CI 2.0-10) or having a reoperation (OR 3.9, 95% CI 1.7-8.9) were higher for SF patients compared with NF patients. Mean hospital stay was 2.1 times longer (95% CI 1.8-2.4) for SF patients compared with NF patients. CONCLUSIONS: Greater patient frailty, as measured by the ASD-FI, is associated with longer hospital stays and greater odds of major complications and reoperation. These slides can be retrieved under Electronic Supplementary Material. PMID- 29603014 TI - Impact of formulation on the iontophoretic delivery of the FOLFIRINOX regimen for the treatment of pancreatic cancer. AB - PURPOSE: Effective treatment of patients with locally advanced pancreatic cancer is a significant unmet clinical need. One major hurdle that exists is inadequate drug delivery due to the desmoplastic stroma and poor vascularization that is characteristic of pancreatic cancer. The local iontophoretic delivery of chemotherapies provides a novel way of improving treatment. With the growing practice of highly toxic combination therapies in the treatment of pancreatic cancer, the use of iontophoresis for local delivery can potentiate the anti cancer effects of these therapies while sparing unwanted toxicity. The objective of this study was to investigate the impact of formulation on the electro transport of the FOLFIRINOX regimen for the development of a new treatment for pancreatic cancer. METHODS: Three formulations of the FOLFIRINOX regimen (5 fluorouracil, leucovorin, irinotecan, and oxaliplatin) were generated at a fixed pH of 6.0 and were referred to as formulation A (single drug solution with all four drugs combined), formulation B (two drug solutions with two drugs per solution), and formulation C (four individual drug solutions). Anodic iontophoresis of the three different formulations was evaluated in orthotopic patient-derived xenografts of pancreatic cancer. RESULTS: Iontophoretic transport of the FOLFIRINOX drugs was characterized according to organ exposure after a single device treatment in vivo. We report that the co-iontophoresis of two drug solutions, leucovorin + oxaliplatin and 5-fluorouracil + irinotecan, resulted in the highest levels of cytotoxic drugs in the tumor compared to drugs delivered individually or combined into one solution. There was no significant difference in plasma, pancreas, kidney, and liver exposure to the cytotoxic drugs delivered by the three different formulations. In addition, we found that reducing the duration of iontophoretic treatment from 10 to 5 min per solution resulted in a significant decrease in drug concentrations. CONCLUSIONS: Underlying the difference in drug transport of the formulations was electrolyte concentrations, which includes both active and inactive components. Electrolyte concentrations can hinder or improve drug electro-transport. Overall, balancing electrolyte concentration is needed for optimal electro-transport. PMID- 29603015 TI - Effect of ulixertinib, a novel ERK1/2 inhibitor, on the QT/QTc interval in patients with advanced solid tumor malignancies. AB - PURPOSE: The aim of this analysis was to investigate the potential for ulixertinib (BVD-523) to prolong cardiac repolarization. The mean prolongation of the corrected QT (QTc) interval was predicted at the mean maximum drug concentrations of the recommended phase 2 dose (RP2D; 600 mg BID) and of higher concentrations. In addition, the effect of ulixertinib on other quantitative ECG parameters was assessed. METHODS: In a two-part, phase 1, open-label study in adults with advanced solid tumors, 105 patients [24 in Part 1 (dose escalation) and 81 in Part 2 (cohort expansion)] were included in a QT prolongation analysis. Electrocardiograms (ECGs) extracted from 12-lead Holter monitors, along with time matched pharmacokinetic blood samples, were collected over 12 h on cycle 1 day 1 and cycle 1 day 15 and analyzed by a core ECG laboratory. RESULTS: A small increase in heart rate was observed on both study days (up to 5.6 bpm on day 1 and up to 7 bpm on day 15). The estimated mean changes from baseline in the study specific QTc interval (QTcSS), at the ulixertinib Cmax, were - 0.529 ms (90% CI - 6.621, 5.562) on day 1 and - 9.202 ms (90% CI - 22.505, 4.101) on day 15. The concentration: QTc regression slopes were mildly positive but not statistically significant [0.53 (90% CI - 1.343, 2.412) and 1.16 (90% CI - 1.732, 4.042) ms per ug/mL for days 1 and 15, respectively]. Ulixertinib had no meaningful effect on PR or QRS intervals. CONCLUSIONS: Ulixertinib administered to patients with solid tumors at clinically relevant doses has a low risk for QT/QTc prolongation or any other effects on ECG parameters. REGISTRATION: The study is registered at Clinicaltrials.gov (NCT01781429) and was sponsored by BioMed Valley Discoveries. PMID- 29603016 TI - Ischaemia reperfusion injury: mechanisms of progression to chronic graft dysfunction. AB - The increasing use of extended criteria organs to meet the demand for kidney transplantation raises an important question of how the severity of early ischaemic injury influences long-term outcomes. Significant acute ischaemic kidney injury is associated with delayed graft function, increased immune associated events and, ultimately, earlier deterioration of graft function. A comprehensive understanding of immediate molecular events that ensue post ischaemia and their potential long-term consequences are key to the discovery of novel therapeutic targets. Acute ischaemic injury primarily affects tubular structure and function. Depending on the severity and persistence of the insult, this may resolve completely, leading to restoration of normal function, or be sustained, resulting in persistent renal impairment and progressive functional loss. Long-term effects of acute renal ischaemia are mediated by several mechanisms including hypoxia, HIF-1 activation, endothelial dysfunction leading to vascular rarefaction, sustained pro-inflammatory stimuli involving innate and adaptive immune responses, failure of tubular cells to recover and epigenetic changes. This review describes the biological relevance and interaction of these mechanisms based on currently available evidence. PMID- 29603017 TI - An open-label pilot study of a home wearable light therapy device for postpartum depression. AB - We sought to establish the feasibility and preliminary effects of home-wearable light therapy for postpartum depression, and its effects on circadian measures. Eight women within 6 months postpartum were prescribed 60 min of daily morning light therapy for 5 weeks. The device was well tolerated. Significant improvements were observed in self-report and clinician-rated depression symptoms, with little change in objective circadian measures. Home-wearable light therapy is feasible for postpartum women and may be a promising treatment for postpartum depression. Clinicaltrials.gov Identifier: NCT02769858. PMID- 29603018 TI - Expression of inflammatory markers in women with perinatal depressive symptoms. AB - Perinatal depression affects 10-20% of women and is associated with poor outcomes for mother and child. Inflammation is associated with depression in non-pregnant adults. Perinatal depression and inflammation in pregnancy are independently associated with morbidities including obesity, gestational diabetes, preeclampsia, and preterm birth. The role of inflammation in perinatal depression has received little attention. We hypothesized an association between self reported perinatal depressive symptoms and serum inflammatory biomarkers TNF alpha, IL-6, IL-1beta, and CRP. 110 healthy gravidas were recruited in third trimester from an academic medical center, with a baseline study visit at a mean of 32.5 (SD +/- 1.8) weeks gestational age. Sixty-three participants completed the Edinburgh Postnatal Depression Scale (EPDS) and provided demographic information and serum samples upon enrollment and at 3 and 6 months postpartum. Serum inflammatory markers were quantified by multiplex array. Multiple linear mixed effects models were used to evaluate trends of biomarkers with the EPDS score in the third trimester of pregnancy and the postpartum period. Elevated serum TNF-alpha was associated with lower EPDS total score (beta = - 0.90, p = 0.046) after adjusting for demographics and medication use. In contrast, IL-6, CRP, and IL-1beta did not demonstrate statistically significant associations with depressive symptoms by the EPDS in either crude or adjusted models. Study findings showed no association or an inverse (TNF-alpha) association between inflammatory markers and perinatal depressive symptoms. Relevant literature evaluating a role for inflammation in depression in the unique context of pregnancy is both limited and inconsistent, and further exploration is merited. PMID- 29603019 TI - Assessment of surface water quality using a growing hierarchical self-organizing map: a case study of the Songhua River Basin, northeastern China, from 2011 to 2015. AB - The analysis of a large number of multidimensional surface water monitoring data for extracting potential information plays an important role in water quality management. In this study, growing hierarchical self-organizing map (GHSOM) was applied to a water quality assessment of the Songhua River Basin in China using 22 water quality parameters monitored monthly from 13 monitoring sites from 2011 to 2015 (14,782 observations). The spatial and temporal features and correlation between the water quality parameters were explored, and the major contaminants were identified. The results showed that the downstream of the Second Songhua River had the worst water quality of the Songhua River Basin. The upstream and midstream of Nenjiang River and the Second Songhua River had the best. The major contaminants of the Songhua River were chemical oxygen demand (COD), ammonia nitrogen (NH3-N), total phosphorus (TP), and fecal coliform (FC). In the Songhua River, the water pollution at downstream has been gradually eased in years. However, FC and biochemical oxygen demand (BOD5) showed growth over time. The component planes showed that three sets of parameters had positive correlations with each other. GHSOM was found to have advantages over self-organizing maps and hierarchical clustering analysis as follows: (1) automatically generating the necessary neurons, (2) intuitively exhibiting the hierarchical inheritance relationship between the original data, and (3) depicting the boundaries of the classification much more clearly. Therefore, the application of GHSOM in water quality assessments, especially with large amounts of monitoring data, enables the extraction of more information and provides strong support for water quality management. PMID- 29603021 TI - Microstructure and chemical analysis of four calcium silicate-based cements in different environmental conditions. AB - OBJECTIVE: The objective of this study was to analyze the microstructure and crystalline structures of ProRoot MTA, Biodentine, CEM Cement, and Retro MTA when exposed to phosphate-buffered saline, butyric acid, and blood. METHODS AND MATERIALS: Mixed samples of ProRoot MTA, Biodentine, CEM Cement, and Retro MTA were exposed to either phosphate-buffered saline, butyric acid, or blood. Scanning electron microscope (SEM) and energy-dispersive X-ray spectroscopic (EDX) evaluations were conducted of specimens. X-ray diffraction (XRD) analysis was also performed for both hydrated and powder forms of evaluated calcium silicate cements. RESULTS: The peak of tricalcium silicate and dicalcium silicate detected in all hydrated cements was smaller than that seen in their unhydrated powders. The peak of calcium hydroxide (Ca(OH)2) in blood- and acid-exposed ProRoot MTA, CEM Cement, and Retro MTA specimens were smaller than that of specimens exposed to PBS. The peak of Ca(OH)2 seen in BiodentineTM specimens exposed to blood was similar to that of PBS-exposed specimens. On the other hand, those exposed to acid exhibited smaller peaks of Ca(OH)2. CONCLUSION: Exposure to blood or acidic pH decreased Ca(OH)2 crystalline formation in ProRoot MTA, CEM Cement and Retro MTA. However, a decrease in Ca(OH)2 was only seen when BiodentineTM exposed to acid. CLINICAL RELEVANCE: The formation of Ca(OH)2 which influences the biological properties of calcium silicate cements was impaired by blood and acid exposures in ProRoot MTA, CEM Cement, and Retro MTA; however, in the case of Biodentine, only exposure to acid had this detrimental effect. PMID- 29603020 TI - A water-soluble, mucoadhesive quaternary ammonium chitosan-methyl-beta cyclodextrin conjugate forming inclusion complexes with dexamethasone. AB - The ocular bioavailability of lipophilic drugs, such as dexamethasone, depends on both drug water solubility and mucoadhesion/permeation. Cyclodextrins and chitosan are frequently employed to either improve drug solubility or prolong drug contact onto mucosae, respectively. Although the covalent conjugation of cyclodextrin and chitosan brings to mucoadhesive drug complexes, their water solubility is restricted to acidic pHs. This paper describes a straightforward grafting of methyl-beta-cyclodextrin (MCD) on quaternary ammonium chitosan (QA Ch60), mediated by hexamethylene diisocyanate. The resulting product is a water soluble chitosan derivative, having a 10-atom long spacer between the quaternized chitosan and the cyclodextrin. The derivative is capable of complexing the model drug dexamethasone and stable complexes were also observed for the lyophilized products. Furthermore, the conjugate preserves the mucoadhesive properties typical of quaternized chitosan and its safety as solubilizing excipient for ophthalmic applications was preliminary assessed by in vitro cytotoxicity evaluations. Taken as a whole, the observed features appear promising for future processing of the developed product into 3D solid forms, such as controlled drug delivery systems, films or drug eluting medical devices. PMID- 29603022 TI - Cytotoxic effects to mouse and human gingival fibroblasts of a nanohybrid ormocer versus dimethacrylate-based composites. AB - OBJECTIVES: Tooth-colored composites have emerged as a standard restorative material in caries therapy and have largely replaced materials such as silver amalgam or glass ionomer cements. In addition to their superior esthetics and desirable mechanical properties, composites also comprise negative characteristics, such as wear, shrinkage, and an adverse biocompatibility. Modifications of classic resin-based dental composites have been developed to overcome these shortcomings. For example, ormocers are innovative inorganic organic hybrid polymers that form a siloxane network modified by the incorporation of organic groups. Recently, a new ormocer, Admira Fusion (VOCO), was introduced to composite technology. The absence of cytotoxic matrix monomers leads to the hypothesis that ormocers have improved biocompatibility compared to resin-based dental restorative materials. MATERIALS AND METHODS: The aim of this study was to compare the cytotoxic effects of Admira Fusion to a nanohybrid composite (GrandioSO, VOCO) and a nanofiller composite (Filtek Supreme XTE, 3M Espe) on the standard dermal mouse fibroblasts (L929) and human gingival fibroblasts (GF-1) via a Cell Counting Kit-8 (CCK-8) assay. RESULTS: Admira Fusion was significantly less cytotoxic than GrandioSO and Filtek Supreme XTE to both the standard mouse dermal fibroblasts (L929) and human gingival fibroblasts. CONCLUSIONS: Compared to other resin-based dental restorative materials, the ormocer (Admira Fusion) possesses a superior biocompatibility in vitro. Future research studies are needed to confirm our results. CLINICAL SIGNIFICANCE: Clinically, dental practitioners and their patients might benefit from Admira Fusion in terms of reduced adverse biologic reactions compared to resin-based dental restorative materials. PMID- 29603023 TI - Investigation on the in vitro cytocompatibility of Mg-Zn-Y-Nd-Zr alloys as degradable orthopaedic implant materials. AB - Mg-Zn-Y-Nd-Zr alloy has been developed as a new type of biodegradable orthopaedic implant material by the authors' research group with its excellent mechanical properties and controllable degradation rate. In this study, the cytocompatibility of Mg-Zn-Y-Nd-Zr alloy was systematically evaluated through in vitro cell culture method. MTT assay was applied to evaluate the cytotoxicity of Mg-Zn-Y-Nd-Zr alloy and no toxic effect was observed on L929 and MC3T3-E1 cells followed the protocol of ISO 10993 standard. Considering the potential ion accumulation in the bony environment, this study further investigated the cytotoxic effect of accumulated metallic ions during the alloy degradation by extending the extract preparation time. When the extract preparation time was prolonged to 1440 h, the accumulated metallic ions leaded to severe cell apoptosis, of which the combined ion concentration was determined as 39.5-65.8 uM of Mg2+, 3.5-5.9 uM of Zn2+, 0.44-0.74 uM of Y3+, 0.3-0.52 uM of Nd3+ and 0.11 0.18 uM of Zr4+ for L929, and 65.8-92.2 uM of Mg2+, 5.9-8.3 uM of Zn2+, 0.74-1.04 uM of Y3+, 0.52-0.73 uM of Nd3+ and 0.18-0.25 uM of Zr4+ for MC3T3-E1 cells. Besides the cell viability assessment, high expression of ALP activity and calcified nodules implied that metal elements in Mg-Zn-Y-Nd-Zr alloys can promote the osteogenic differentiation. Hence, excellent cytocompatibility has equipped Mg-Zn-Y-Nd-Zr alloy as a promising candidate for orthopaedic implant application, which can remarkably guide the magnesium-based alloy design and provide scientific evidence for clinical practice in future. PMID- 29603024 TI - Effect of cultivation mode on the production of docosahexaenoic acid by Tisochrysis lutea. AB - In this study, Tisochrysis lutea was cultivated in mixotrophic and heterotrophic cultures with glycerol as a carbon source and with glucose and acetate for comparison; autotrophic cultivation was the control group without a carbon source. It was found that T. lutea used glycerol and did not use glucose and acetate under mixotrophy. Mixotrophy slightly elevated the docosahexaenoic acid (DHA) and total fatty acids (TFA) content in the dry-weight and enhanced the DHA and TFA production in medium (41.3 and 31.9% respectively) at the end of a 16-day cultivation, while heterotrophy reduced the DHA content and TFA production. Under the mixotrophy, the glycerol contribution to the DHA production (16.19 mg/L) and the TFA production (97.8 mg/L) was not very high and the DHA yield [2.63% chemical oxygen demand (COD)] and TFA yield (13.1% COD) were also very low. Furthermore, T. lutea using glycerol had a period of adaptation, indicating that T. lutea was not an ideal microalga for organic carbon utilization. PMID- 29603025 TI - Effect of Chemical Binding of Doxorubicin Hydrochloride to Gold Nanoparticles, Versus Electrostatic Adsorption, on the In Vitro Drug Release and Cytotoxicity to Breast Cancer Cells. AB - PURPOSE: The selective delivery of chemotherapeutic agent to the affected area is mainly dependent on the mode of drug loading within the delivery system. This study aims to compare the physical method to the chemical method on the efficiency of loading DOX.HCl to GNPs and the specific release of the loaded drug at certain tissue. METHOD: Bifunctional polyethylene glycol with two different functionalities, the alkanethiol and the carboxyl group terminals, was synthesized. Then, DOX.HCl was covalently linked via hydrazone bond, a pH sensitive bond, to the carboxyl functional group and the produced polymer was used to prepare drug functionalized nanoparticles. Another group of GNPs was coated with carboxyl containing polymer; loading the drug into this system by the means of electrostatic adsorption. Finally, the prepared system were characterized with respect to size, shape and drug release in acetate buffer pH 5 and PBS pH 7.4 Also, the effect of DOX.HCl loaded systems on cell viability was assessed using MCF-7 breast cancer cell line. RESULTS: The prepared nanoparticles were spherical in shape, small in size and monodisperse. The release rate of the chemically bound drug in the acidic pH was higher than the electrostatically adsorbed one. Moreover, both systems show little release at pH 7.4. Finally, cytotoxicity profiles against human breast adenocarcinoma cell line (MCF-7) exhibited greater cytotoxicity of the chemically bound drug over the electrostatically adsorbed one. CONCLUSION: Chemical binding of DOX.HCl to the carboxyl group of PEG coating GNPs selectively delivers high amount of drug to tumour-affected tissue which leads to reducing the unwanted effects of the drug in the non-affected ones. PMID- 29603026 TI - Wall thickness control in biotubes prepared using type-C mold. AB - A type-C mold based on in-body tissue architecture was previously developed for preparing small-diameter biotube vascular grafts with a 2-mm diameter and approximately 1-mm wall thickness. In this study, the type-C mold was modified for preparing large-diameter biotubes with controlled wall thicknesses. Four types of molds were assembled by inserting silicone center rods (outer diameters 11, 13, 15, 17 mm) into stainless steel cages (inner diameter 19 mm) and surgically embedded in the abdominal subcutaneous pouches of Holstein cows. After 8-12 weeks, connective tissues occupied the rod-cage gap in the molds to form biotubes. The wall thickness of the biotubes obtained after removing the molds was approximately 1-3 mm, which corresponded to approximately 80% of each gap distance. The breaking strength almost linearly increased with the wall thickness of the biotubes. The strength of the biotubes with wall thickness over 1.5 mm was higher than that of beagle blood vessels. The thickest biotubes were as strong as bovine pericardium and can be used as an alternative trachea graft because of their adequate lumen-holding force. PMID- 29603027 TI - Modulating Sticking Propensity of Pharmaceuticals Through Excipient Selection in a Direct Compression Tablet Formulation. AB - PURPOSE: To investigate how excipient matrix affects punch sticking propensity of active pharmaceutical ingredients (API), with the focus on the effect of bonding interactions between API-API (F2) and API-excipient (F3). METHOD: Sticking kinetics of direct compression formulations, consisting of 20% of celecoxib (CEL) or ibuprofen (IBN) in different excipient matrices, i.e., microcrystalline cellulose (Avicel PH102 and Avicel PH105 dry coated with nano-sized silica (PH105(n)), hypromellose (K15 M), and a 3:1 mixture between starch and Avicel PH102 (S3P1), was assessed using a removable punch tip on a compaction simulator. The amount of material transferred to punch was determined gravimetrically every 10 compressions up to 50 compactions. RESULTS: CEL exhibited higher F2 than IBN. CEL also exhibited more sticking under otherwise identical compaction conditions in the same excipient matrix. Among different excipient matrices, sticking propensity of both APIs followed the ascending order: PH105(n) < PH102 < K15 M < S3P1. This order was exactly opposite to the order of F3, confirming that greater bonding strength of the formulation favors lower sticking propensity of a given API. CONCLUSION: For an API prone to punch sticking, judicious use of excipients to render higher tablet mechanical strength can mitigate severity of punch sticking. PMID- 29603028 TI - Comparison of early osseointegration between laser-treated/acid-etched and sandblasted/acid-etched titanium implant surfaces. AB - This study was designed to compare the early osseointegration of titanium surfaces prepared via laser-treated/acid-etched (LA) and sandblasted/acid-etched (SLA) in dogs. Titanium implants were divided into two groups: Surfaces of the experimental group were treated via LA, while in the control group, surfaces were treated via SLA. The physical and chemical properties of LA and SLA surfaces were tested and compared. Sixteen implants with LA or SLA surfaces were placed into the tibias of four beagle dogs, each treatment group received two implants per single tibia. The dogs were sacrificed two and four weeks after implant placement. Scanning electron microscopy showed that both the LA and SLAs surface exhibited rough structures with micro pores sized 1-3 MUm. In the LA surface, regular melting points were observed. However, in the SLA surface, the structure was irregular and few oxide aluminum particles still remained. Only titanium and a small amount of titanium compounds were detected on LA surfaces, while Al was found of SLA surfaces. The LA surface roughness was above that of SLA surfaces (LA: Ra: 2.1 MUm; SLA: Ra :1.53 MUm; P < 0.01). Both groups exhibited good osseointegration and no significant differences were found in the BIC% at two or four weeks between both groups (P > 0.05). Both groups exhibited good osseointegration; however, the LA surface was cleaner and more uniform than the SLA surface, and no significant differences were found between both groups. PMID- 29603029 TI - Comparing a genetic and a psychological factor as correlates of anxiety, depression, and chronic stress in men with prostate cancer. AB - PURPOSE: Some prostate cancer (PCa) patients become clinically anxious or depressed after diagnosis and treatment. Some also show the physiological signs of chronic stress. However, there are currently no data describing how these particular patients might be identified at intake. This study tested the individual and combined predictive power of a psychological factor and a genetic factor as potential predictors of anxiety, depression, and chronic stress in a sample of PCa patients. METHODS: Ninety-five PCa patients completed psychological inventories for anxiety, depression, and psychological resilience (PR) and also gave a saliva sample for cortisol and a mouthwash sample for genetic testing for the presence of the BDNF Val66Met polymorphism. RESULTS: High PR patients had significantly lower anxiety and depression than low PR patients, but showed no significant differences in their salivary cortisol. Carriers of the Met allele of the BDNF Val66Met polymorphism had significantly higher salivary cortisol concentrations than patients who did not carry this allele. CONCLUSIONS: Each of these two factors may provide valuable information regarding the vulnerability of PCa patients to anxiety, depression, or chronic stress. Suggestions are made for their inclusion in clinical settings. PMID- 29603030 TI - Conventional versus pigtail chest tube-are they similar for treatment of malignant pleural effusions? AB - INTRODUCTION: The optimal chest tube type and size for drainage and chemical pleurodesis of malignant pleural effusions remains controversial. This retrospective study was conducted to compare the efficacy of conventional versus pigtail chest tube in the treatment of malignant pleural effusions. METHODS: Patients submitted to chest tube drainage and slurry talc pleurodesis due to malignant pleural effusion in our pulmonology ward from 2012 to 2016 were eligible. According to the type of chest tube, they were divided into two groups: group I-conventional chest tube and group II-pigtail chest tube. Number of deaths, recurrence of malignant pleural effusion, and timelines associated with the procedures were reviewed and compared between groups. RESULTS: Out of the 61 included patients, 46 (75.4%) were included in group I and 15 (24.6%) in group II. Only one patient had pigtail chest tube obstruction, with posterior insertion of conventional chest tube. Death during hospital stay and up to 3 months, recurrence at 4 weeks, total duration of hospital stay, time from chest tube insertion to pleurodesis, and time from chest tube insertion to removal were not significantly different between the two groups (all p > 0.05). DISCUSSION: These findings suggest that pigtail chest tube can be an alternative on palliation, with no compromise in pleurodesis performance. PMID- 29603031 TI - Does the subspecialty of an intensive care unit (ICU) has an impact on outcome in patients suffering from aneurysmal subarachnoid hemorrhage? AB - We retrospectively compared the outcome of aneurysmal subarachnoid hemorrhage (aSAH) patients treated in a neurosurgical ICU (nICU) between 1990 and 2005 with that of patients treated in a general ICU (gICU) between 2005 and 2013 with almost identical treatment strategies. Among other parameters, we registered the initial Hunt and Hess grade, Fisher score, the incidence of vasospasm, and outcome. A multivariate analysis (logistic regression model) was performed to adjust for different variables. In total, 755 patients were included in this study with 456 patients assigned to the nICU and 299 patients to the gICU. Multivariate logistic regression analysis revealed no significant difference between the patient outcome treated in a nICU versus gICU after adjusting for different variables. The outcome of patients after aSAH is not influenced by the type of ICU (gICU versus nICU). The data do not allow claiming that aSAH patients need to be treated in a specialized ICU for obtaining better results. Parameters which might differ from hospital to hospital, especially warranty of neurosurgical expertise on gICU, have the potential to influence the results. PMID- 29603032 TI - Association of reproductive history with breast tissue characteristics and receptor status in the normal breast. AB - INTRODUCTION: Reproductive history has been associated with breast cancer risk, but more knowledge of the underlying biological mechanisms is needed. Because of limited data on normal breast tissue from healthy women, we examined associations of reproductive history and established breast cancer risk factors with breast tissue composition and markers of hormone receptors and proliferation in a nested study within the Karolinska Mammography project for risk prediction for breast cancer (Karma). MATERIALS AND METHODS: Tissues from 153 women were obtained by ultrasound-guided core needle biopsy as part of the Karma project. Immunohistochemical staining was used to assessed histological composition of epithelial, stromal and adipose tissue, epithelial and stromal oestrogen receptor (ER) and progesterone receptor (PR) status, and Ki-67 proliferation status. An individualised reproductive score including parity, number of pregnancies without birth, number of births, age at first birth, and duration of breastfeeding, was calculated based on self-reported reproductive history at the time of the Karma study entry. All analyses were adjusted for age and BMI. RESULTS: Cumulated reproductive score was associated with increased total epithelial content and greater expression of epithelial ER. Parity was associated with greater epithelial area, increased epithelial-stromal ratio, greater epithelial ER expression and a lower extent of stromal proliferation. Increasing numbers of pregnancies and births were associated with a greater epithelial area in the entire study set, which remained significant among postmenopausal women. Increasing numbers of pregnancies and births were also associated with a greater expression of epithelial ER among postmenopausal women. Longer duration of breastfeeding was associated with greater epithelial area and greater expression of epithelial PR both in the entire study set and among postmenopausal women. Breastfeeding was also positively associated with greater epithelial ER expression among postmenopausal women. Prior use of oral contraceptives was associated with lower epithelial-stromal ratio amongst all participants and among pre- and postmenopausal women separately. CONCLUSION: Reproductive risk factors significantly influence the epithelial tissue compartment and expression of hormone receptors in later life. These changes remain after menopause. This study provides deeper insights of the biological mechanisms by which reproductive history influences epithelial area and expression of hormone receptors, and as a consequence the risk of breast cancer. PMID- 29603033 TI - Factorial Validity of the Toronto Alexithymia Scale (TAS-20) in Clinical Samples: A Critical Examination of the Literature and a Psychometric Study in Anorexia Nervosa. AB - There is extensive use of the 20-item Toronto Alexithymia Scale (TAS-20) in research and clinical practice in anorexia nervosa (AN), though it is not empirically established in this population. This study aims to examine the factorial validity of the TAS-20 in a Portuguese AN sample (N = 125), testing four different models (ranging from 1 to 4 factors) that were identified in critical examination of existing factor analytic studies. Results of confirmatory factor analysis (CFA) suggested that the three-factor solution, measuring difficulty identifying (DIF) and describing feelings (DDF), and externally oriented thinking (EOT), was the best fitting model. The quality of measurement improves if two EOT items (16 and 18) are eliminated. Internal consistency of EOT was low and decreased with age. The results provide support for the factorial validity of the TAS-20 in AN. Nevertheless, the measurement of EOT requires some caution and may be problematic in AN adolescents. PMID- 29603034 TI - Development of EUCAST zone diameter breakpoints and quality control criteria for ceftazidime-avibactam 10-4 MUg. AB - Ceftazidime-avibactam disk studies were performed for disk mass selection and for establishing EUCAST quality control ranges and zone diameter breakpoints. The disk mass study included disk diffusion testing with ceftazidime-avibactam 10-4 and 10-6 MUg disks and broth microdilution MIC testing for challenge set of 94 Enterobacteriaceae and 45 Pseudomonas aeruginosa. EUCAST SOP 9.0-based QC and MIC disk correlations studies were followed for development of ceftazidime-avibactam 10-4 MUg ranges for Escherichia coli ATCC 25922, P. aeruginosa ATCC 27583, and Klebsiella pneumoniae ATCC 700603 and for zone diameter breakpoint determination. The ceftazidime-avibactam 10-4 and 10-6 MUg disks performed similar in comparison to broth microdilution, with zones <= 14 mm for all resistant strains. The 10-4 MUg disk was selected and used in QC and breakpoint studies. There was minimal variation of ceftazidime-avibactam 10-4 MUg QC study results between disks, media, and sites. The QC ranges were within 7 mm for all strains. The zone diameter breakpoint study demonstrated good correlation of MIC and disk results. The established zone diameter breakpoints resulted in false susceptible rates of 1.6 and 4.0% for Enterobacteriaceae and P. aeruginosa. EUCAST selected the ceftazidime-avibactam 10-4 MUg disk and established QC ranges for E. coli 25922 of 24-30 mm, P. aeruginosa ATCC 27853 of 21-27 mm, and K. pneumoniae ATCC 700603 of 18-24 mm. The zone diameter breakpoints that correlated best with the MIC breakpoints of susceptible <= 8 mg/L and resistant > 8 mg/L were Enterobacteriaceae (S >= 13, R < 13 mm) and P. aeruginosa (S >= 17, R < 17 mm). PMID- 29603035 TI - Clinical characteristics of infections caused by Mycoplasma pneumoniae P1 genotypes in children. AB - Mycoplasma pneumoniae (M. pneumoniae) isolates can be classified into two major genetic groups, P1 type 1 (MP1) and P1 type 2 (MP2), based on the DNA sequence of the P1 adhesion protein gene. The aim of our study was to determine if M. pneumoniae P1 genotype is associated with disease manifestation and severity of acute M. pneumoniae infection. We compared epidemiological and clinical data of children infected with either MP1 or MP2. In addition, we separately analysed data of patients presenting with individual manifestations of M. pneumoniae infection. Data of 356 patients infected with MP1 were compared with those of 126 patients infected with MP2. MP2-infected children presented with higher median baseline C-reactive protein levels and were admitted to the hospital more often. The distribution of P1 genotype varied among groups of patients with different manifestations of M. pneumoniae infection. MP2 was more common than MP1 among patients with neurological and cardiovascular manifestations, whereas MP1 was more prevalent in other manifestations. The results from our large cohort indicate that the two P1 subtypes may have different pathogenic potential and that infections with MP2 strains could be more virulent than those with MP1 strains. PMID- 29603036 TI - Is elevated body mass index protective against cervical spine injury in adults? AB - PURPOSE: Correlate body mass index (BMI) with incidence and type of cervical spine injury seen on CT in adult patients presenting with blunt trauma. MATERIALS AND METHODS: Retrospective chart review of all adult blunt trauma patients who had a cervical spine CT performed at our level 1 trauma center during an approximately 3-year period. RESULTS: A statistically significant (p = 0.01) difference in cervical spine injury incidence was present between different BMI groups. Cervical spine injury incidence was 7.7% for underweight (BMI <= 18) patients, 7.1% for normal weight (BMI 18-25) patients, 6.2% for overweight/obese (BMI 25-35) patients, and 4.7% for morbidly obese (BMI > 35) patients. Using BMI > 18-25 as a reference group, females with BMI > 25-35 had an adjusted odds ratio (aOR) of 0.56 (CI 0.41-0.75) and females with BMI > 35 had an aOR of 0.42 (CI 0.26-0.70). Males with a BMI <= 18 had an aOR of 2.20 (CI 1.12-4.32) and males with BMI > 35 had an aOR of 0.66 (CI 0.46-0.95). A particularly low incidence of cervical spine injury was observed in patients older than 65 in the obese group with a cervical spine injury rate of only 1.4% in this patient population. No statistical significant difference was seen in injury morphology across the BMI groups. CONCLUSION: An inverse relationship exists between BMI and the overall incidence of cervical spine injury. This protective effect appears to be influenced by gender with elevated BMI having lower relative odds of cervical spine injury in women than in men. A particularly low rate of cervical spine injury was identified in obese patients over the age of 65. Routine imaging of all elderly, obese trauma patients with low energy mechanism of injury may not be warranted. PMID- 29603037 TI - Adopted Individuals' Views on the Utility and Value of Expanded Carrier Screening. AB - Adoptees may not have family medical history and ethnicity information. Carrier screening assesses reproductive risk. Expanded carrier screening (ECS) screens for many genetic conditions regardless of a patient's knowledge of family history and ethnicity. This study aimed to better understand the opinions and attitudes of adopted individuals on the use of ECS in determining a patient's reproductive genetic risks. Specifically, the study assessed how adopted individuals feel that results of ECS may be useful to them and whether adoptees feel that meeting with a genetics professional in the process of undergoing ECS would be useful. Adult adoptees (N = 124) were recruited online. Their opinions on ECS were explored. The majority reported they had never been offered carrier screening (92%). The majority of adoptees wanted ECS (76%). Neither the amount of contact with biological relatives nor having medical knowledge about biological relatives was significantly associated with adoptees' desire to pursue ECS. There was a significant positive correlation between adoptees of higher education levels and the amount they would pay for ECS (p = 0.004). The majority of participants (95%) indicated a genetics professional would be helpful when undergoing ECS. The findings suggest this population may want ECS and support from genetics healthcare professionals. Advocacy for genetic counseling and testing for adoptees appears justifiable. PMID- 29603038 TI - Associations of CTLA4 +49 A/G Dimorphism and HLA-DRB1*/DQB1* Alleles With Type 1 Diabetes from South India. AB - The aim of present study was to elucidate the association of CTLA4 +49 A/G and HLA-DRB1*/DQB1* gene polymorphism in south Indian T1DM patients. The patients and controls (n = 196 each) were enrolled for CTLA4 and HLA-DRB1*/DQB1* genotyping by RFLP/PCR-SSP methods. The increased frequencies of CTLA4 'AG' (OR = 1.99; p = 0.001), 'GG' (OR = 3.94; p = 0.001) genotypes, and 'G' allele (OR = 2.42; p = 9.26 * 10-8) were observed in patients. Reduced frequencies of 'AA' (OR = 0.35; p = 7.19 * 10-7) and 'A' (OR = 0.41; p = 9.26 * 10-8) in patients revealed protective association. Among HLA-DRB1*/DQB1* alleles, DRB1*04 (OR = 3.29; p = 1.0 * 10-5), DRB1*03 (OR = 2.81; p = 1.9 * 10-6), DQB1*02:01 (OR = 2.93; p = 1.65 * 10-5), DQB1*02:02 (OR = 3.38; p = 0.0003), and DQB1*03:02 (OR = 7.72; p = 0.0003) were in susceptible association. Decreased frequencies of alleles, DRB1*15 (OR = 0.32; p = 2.55 * 10-7), DRB1*10 (OR = 0.45; p = 0.002), DQB1*06:01 (OR = 0.43; p = 0.0001), and DQB1*05:02 (OR = 0.28; p = 2.1 * 10-4) in patients were suggested protective association. The combination of DRB1*03+AG (OR = 5.21; p = 1.4 * 10-6), DRB1*04+AG (OR = 2.14; p = 0.053), DRB1*04+GG (OR = 5.21; p = 0.036), DQB1*02:01+AG (OR = 4.44; p = 3.6 * 10-5), DQB1*02:02+AG (OR = 20.9; p = 9.5 * 10-4), and DQB1*02:02+GG (OR = 4.06; p = 0.036) revealed susceptible association. However, the combination of DRB1*10+AA (OR = 0.35; p = 0.003), DRB1*15+AA (OR = 0.22; p = 5.3 * 10-7), DQB1*05:01+AA (OR = 0.45; p = 0.007), DQB1*05:02+AA (OR = 0.17; p = 1.7 * 10-4), DQB1*06:01+AA (OR = 0.40; p = 0.002), and DQB1*06:02+AG (OR = 0.34; p = 0.001) showed decreased frequency in patients, suggesting protective association. In conclusion, CTLA4/HLA-DR/DQ genotypic combinations revealed strong susceptible/protective association toward T1DM in south India. A female preponderance in disease associations was also documented. PMID- 29603040 TI - Screening for childhood adversity: the what and when of identifying individuals at risk for lifespan health disparities. AB - Existing research on childhood adversity and health risk across the lifespan lacks specificity regarding which types of exposures to assess and when. The purpose of this study was to contribute to an empirically-supported framework to guide practitioners interested in identifying youth who may be at greatest risk for a lifelong trajectory of health disparities. We also sought to identify the point in childhood at which screening for adversity exposure would capture the largest group of at risk individuals for triage to prevention and intervention services. Participants (n = 4036) collected as part of the Midlife in the United States study reported their medical status and history including physical (cardiovascular disease, hypertension, obesity, diabetes, cancer) and mental health (depression, substance use problems, sleep problems). Participants indicated whether they were exposed to 7 adversities at any point in childhood and their age of exposure to 19 additional lifetime adversities before the age of 18. Parent drug abuse, dropping out or failing out of school, being fired from a job, and sexual assault during childhood exhibited the largest effect sizes on health in adulthood, which were comparable to the effects of childhood maltreatment. Childhood adversity screening in early adolescence may identify the largest proportion of youth at risk for negative health trajectories. The results of this descriptive analysis provide an empirical framework to guide screening for childhood adversity in pediatric populations. We discuss the implications of these observations in the context of prevention science and practice. PMID- 29603042 TI - A transvaginal approach to rectovaginal fistulae for the colorectal surgeon: technical notes and case series. AB - Rectovaginal fistulae (RVF) are not uncommonly seen by the colorectal surgeon and gynaecologist, often debilitating for patients and typically managed with multiple operative procedures, achieving control rather than cure. Transvaginal repair is the least common surgical approach but has clear advantages and equivalent healing rates to other approaches. Here, we describe a simple, safe and effective flapless transvaginal technique for the repair of primary and recurrent low- and mid-level RVF of varying aetiology. We report 15 cases of RVF (nine recurrent) treated by this technique at a single UK centre. The healing rate was 67%. There were no major complications. Median follow-up was 48 months. PMID- 29603041 TI - A tandem array of UDP-glycosyltransferases from the UGT73C subfamily glycosylate sapogenins, forming a spectrum of mono- and bisdesmosidic saponins. AB - KEY MESSAGE: This study identifies six UGT73Cs all able to glucosylate sapogenins at positions 3 and/or 28 which demonstrates that B. vulgaris has a much richer arsenal of UGTs involved in saponin biosynthesis than initially anticipated. The wild cruciferous plant Barbarea vulgaris is resistant to some insects due to accumulation of two monodesmosidic triterpenoid saponins, oleanolic acid 3-O-beta cellobioside and hederagenin 3-O-beta-cellobioside. Insect resistance depends on the structure of the sapogenin aglycone and the glycosylation pattern. The B. vulgaris saponin profile is complex with at least 49 saponin-like metabolites, derived from eight sapogenins and including up to five monosaccharide units. Two B. vulgaris UDP-glycosyltransferases, UGT73C11 and UGT73C13, O-glucosylate sapogenins at positions 3 and 28, forming mainly 3-O-beta-D-glucosides. The aim of this study was to identify UGTs responsible for the diverse saponin oligoglycoside moieties observed in B. vulgaris. Twenty UGT genes from the insect resistant genotype were selected and heterologously expressed in Nicotiana benthamiana and/or Escherichia coli. The extracts were screened for their ability to glycosylate sapogenins (oleanolic acid, hederagenin), the hormone 24 epibrassinolide and sapogenin monoglucosides (hederagenin and oleanolic acid 3-O beta-D-glucosides). Six UGTs from the UGT73C subfamily were able to glucosylate both sapogenins and both monoglucosides at positions 3 and/or 28. Some UGTs formed bisdesmosidic saponins efficiently. At least four UGT73C genes were localized in a tandem array with UGT73C11 and possibly UGT73C13. This organization most likely reflects duplication events followed by sub- and neofunctionalization. Indeed, signs of positive selection on several amino acid sites were identified and modelled to be localized on the UGT protein surface. This tandem array is proposed to initiate higher order bisdesmosidic glycosylation of B. vulgaris saponins, leading to the recently discovered saponin structural diversity, however, not directly to known cellobiosidic saponins. PMID- 29603043 TI - Hoeflea prorocentri sp. nov., isolated from a culture of the marine dinoflagellate Prorocentrum mexicanum PM01. AB - A Gram-stain negative, aerobic, rod-shaped, non-motile, yellow-pigmented and non spore-forming bacterial strain, designated PM5-8T, was isolated from a culture of a marine toxigenic dinoflagellate Prorocentrum mexicanum PM01. Strain PM5-8T grew at 15-35 degrees C (optimum, 25-30 degrees C) and pH 6-11 (optimum, 7.5-8). Cells required at least 1.5% (w/v) NaCl for growth, and can tolerate up to 7.0% with the optimum of 4%. Phylogenetic analysis based on 16S rRNA gene sequence revealed that the strain PM5-8T is closely related to members of the genus Hoeflea, with high sequence similarities with Hoeflea halophila JG120-1T (97.06%) and Hoeflea alexandrii AM1V30T (97.01%). DNA-DNA hybridization values between the isolate and other type strains of recognized species of the genus Hoeflea were between 11.8 and 25.2%, which is far below the value of 70% threshold for species delineation. The DNA G + C content was 50.3 mol%. The predominant cellular fatty acids of the strain were identified as summed feature 8 (C16:1 omega7c and/or C16:1 omega6c; 51.5%), C18:1 omega7c 11-methyl (20.7%), C16:0 (17.2%) and C18:0 (5.7%). The major respiratory quinone was Q-10. Polar lipids profiles contained phosphatidylcholine, phosphatidylglycerol, sulfoquinovosyl diacylglycerol, phosphatidylmono- methylethanolamine, phosphatidylethanolamine and four unidentified lipids. On the basis of the polyphasic taxonomic data presented, strain PM5-8T (= CCTCC AB 2016294T = KCTC 62490T) represents a novel species of the genus Hoeflea, for which the name Hoeflea prorocentri sp. nov. is proposed. PMID- 29603044 TI - Genipin-Cross-Linked Chitosan Nerve Conduits Containing TNF-alpha Inhibitors for Peripheral Nerve Repair. AB - Tissue engineered nerve grafts (TENGs) are considered a promising alternative to autologous nerve grafting, which is considered the "gold standard" clinical strategy for peripheral nerve repair. Here, we immobilized tumor necrosis factor alpha (TNF-alpha) inhibitors onto a nerve conduit, which was introduced into a chitosan (CS) matrix scaffold utilizing genipin (GP) as the crosslinking agent, to fabricate CS-GP-TNF-alpha inhibitor nerve conduits. The in vitro release kinetics of TNF-alpha inhibitors from the CS-GP-TNF-alpha inhibitor nerve conduits were investigated using high-performance liquid chromatography. The in vivo continuous release profile of the TNF-alpha inhibitors released from the CS GP-TNF-alpha inhibitor nerve conduits was measured using an enzyme-linked immunosorbent assay over 14 days. We found that the amount of TNF-alpha inhibitors released decreased with time after the bridging of the sciatic nerve defects in rats. Moreover, 4 and 12 weeks after surgery, histological analyses and functional evaluations were carried out to assess the influence of the TENG on regeneration. Immunochemistry performed 4 weeks after grafting to assess early regeneration outcomes revealed that the TENG strikingly promoted axonal outgrowth. Twelve weeks after grafting, the TENG accelerated myelin sheath formation, as well as functional restoration. In general, the regenerative outcomes following TENG more closely paralleled findings observed with autologous grafting than the use of the CS matrix scaffold. Collectively, our data indicate that the CS-GP-TNF-alpha inhibitor nerve conduits comprised an elaborate system for sustained release of TNF-alpha inhibitors in vitro, while studies in vivo demonstrated that the TENG could accelerate regenerating axonal outgrowth and functional restoration. The introduction of CS-GP-TNF-alpha-inhibitor nerve conduits into a scaffold may contribute to an efficient and adaptive immune microenvironment that can be used to facilitate peripheral nerve repair. PMID- 29603039 TI - Could use of Selective Serotonin Reuptake Inhibitors During Lactation Cause Persistent Effects on Maternal Bone? AB - The lactating mammary gland elegantly coordinates maternal homeostasis to provide calcium for milk. During lactation, the monoamine serotonin regulates the synthesis and release of various mammary gland-derived factors, such as parathyroid hormone-related protein (PTHrP), to stimulate bone resorption. Recent evidence suggests that bone mineral lost during prolonged lactation is not fully recovered following weaning, possibly putting women at increased risk of fracture or osteoporosis. Selective Serotonin Reuptake Inhibitor (SSRI) antidepressants have also been associated with reduced bone mineral density and increased fracture risk. Therefore, SSRI exposure while breastfeeding may exacerbate lactational bone loss, compromising long-term bone health. Through an examination of serotonin and calcium homeostasis during lactation, lactational bone turnover and post-weaning recovery of bone mineral, and the effect of peripartum depression and SSRI on the mammary gland and bone, this review will discuss the hypothesis that peripartum SSRI exposure causes persistent reductions in bone mineral density through mammary-derived PTHrP signaling with bone. PMID- 29603045 TI - Wnt/beta-catenin signaling pathway in severe preeclampsia. AB - This study aims to elucidate the mechanisms of Wnt/beta-catenin signaling pathway in the development of preeclampsia (PE). The mRNA levels of Wnt1, beta-catenin, c myc and cyclinD1 were determined by real-time PCR in the placentas. Moreover, the expression levels of Wnt1, beta-catenin, Dickkopf-1 (DKK1) and glycogen synthase kinase 3beta (GSK-3beta) proteins were detected by Western blot. Immunohistochemistry was used in placental tissue microarray to localize the expression of Wnt1, beta-catenin, DKK1 proteins in the placentas of two groups. Compared with the control placentas, the mRNA levels of Wnt1, beta-catenin, c-myc and cyclinD1 were decreased in the severe preeclamptic placentas. The Western blot results showed that the expression levels of Wnt1, beta-catenin, and GSK 3beta proteins were significantly elevated in the control group, while the expression level of DKK1 was significantly decreased. In addition, the staining intensity of Wnt1, beta-catenin were weaker in the placentas of the severe PE group while the staining intensity of DKK1 was significantly stronger in the placentas of the severe PE group. Wnt/beta-catenin signaling pathway may play a significant role in the pathogenesis of PE by regulating the invasion and proliferation of trophoblast. PMID- 29603046 TI - Bayes factors for choosing among six common survival models. AB - A super model that includes proportional hazards, proportional odds, accelerated failure time, accelerated hazards, and extended hazards models, as well as the model proposed in Diao et al. (Biometrics 69(4):840-849, 2013) accounting for crossed survival as special cases is proposed for the purpose of testing and choosing among these popular semiparametric models. Efficient methods for fitting and computing fast, approximate Bayes factors are developed using a nonparametric baseline survival function based on a transformed Bernstein polynomial. All manner of censoring is accommodated including right, left, and interval censoring, as well as data that are observed exactly and mixtures of all of these; current status data are included as a special case. The method is tested on simulated data and two real data examples. The approach is easily carried out via a new function in the spBayesSurv R package. PMID- 29603047 TI - A novel MR-compatible sensor to assess active medical device safety: stimulation monitoring, rectified radio frequency pulses, and gradient-induced voltage measurements. AB - PURPOSE: To evaluate the function of an active implantable medical device (AIMD) during magnetic resonance imaging (MRI) scans. The induced voltages caused by the switching of magnetic field gradients and rectified radio frequency (RF) pulse were measured, along with the AIMD stimulations. MATERIALS AND METHODS: An MRI compatible voltage probe with a bandwidth of 0-40 kHz was designed. Measurements were carried out both on the bench with an overvoltage protection circuit commonly used for AIMD and with a pacemaker during MRI scans on a 1.5 T (64 MHz) MR scanner. RESULTS: The sensor exhibits a measurement range of +/- 15 V with an amplitude resolution of 7 mV and a temporal resolution of 10 us. Rectification was measured on the bench with the overvoltage protection circuit. Linear proportionality was confirmed between the induced voltage and the magnetic field gradient slew rate. The pacemaker pacing was recorded successfully during MRI scans. CONCLUSION: The characteristics of this low-frequency voltage probe allow its use with extreme RF transmission power and magnetic field gradient positioning for MR safety test of AIMD during MRI scans. PMID- 29603048 TI - Optimization of diffusion-weighted single-refocused spin-echo EPI by reducing eddy-current artifacts and shortening the echo time. AB - OBJECTIVE: The purpose of this work was to optimize the acquisition of diffusion weighted (DW) single-refocused spin-echo (srSE) data without intrinsic eddy current compensation (ECC) for an improved performance of ECC postprocessing. The rationale is that srSE sequences without ECC may yield shorter echo times (TE) and thus higher signal-to-noise ratios (SNR) than srSE or twice-refocused spin echo (trSE) schemes with intrinsic ECC. MATERIALS AND METHODS: The proposed method employs dummy scans with DW gradients to drive eddy currents into a steady state before data acquisition. Parameters of the ECC postprocessing algorithm were also optimized. Simulations were performed to obtain minimum TE values for the proposed sequence and sequences with intrinsic ECC. Experimentally, the proposed method was compared with standard DW-trSE imaging, both in vitro and in vivo. RESULTS: Simulations showed substantially shorter TE for the proposed method than for methods with intrinsic ECC when using shortened echo readouts. Data of the proposed method showed a marked increase in SNR. A dummy scan duration of at least 1.5 s improved performance of the ECC postprocessing algorithm. CONCLUSION: Changes proposed for the DW-srSE sequence and for the parameter setting of the postprocessing ECC algorithm considerably reduced eddy current artifacts and provided a higher SNR. PMID- 29603049 TI - Profiles of Language Brokering Experiences and Contextual Stressors: Implications for Adolescent Outcomes in Mexican Immigrant Families. AB - Adolescents from Mexican immigrant families are often embedded in a challenging social environment and experience multiple contextual stressors, including economic stress, discrimination, and foreigner stress. We consider how the effects of these contextual stressors may be amplified or diminished for adolescents who function as language brokers, interpreting and mediating for their English-limited parents. Using two waves of survey data collected from a sample (N = 604 at Wave 1; N = 483 at Wave 2) of Mexican American adolescents with ages ranging from 11 to 15 (Mage = 12.41, 54% female), four distinct brokering-stress profiles were identified. Latent profile analyses revealed that with moderate levels of contextual stress, adolescents with more positive language brokering experiences (protective group) demonstrated more favorable outcomes than those with neutral language brokering experiences (moderate group) and those who did not involve themselves as frequently in language brokering activities (less-involved group). In contrast, high levels of contextual stress, coupled with more negative language brokering experiences (risk group), produced the least favorable outcomes among adolescents. PMID- 29603052 TI - Biodegradation of pentafluorosulfanyl-substituted aminophenol in Pseudomonas spp. AB - The pentafluorosulfanyl (SF5-) substituent conveys properties that are beneficial to drugs and agrochemicals. As synthetic methodologies improve the number of compounds containing this group will expand and these chemicals may be viewed as emerging pollutants. As many microorganisms can degrade aromatic xenobiotics, we investigated the catabolism of SF5-substituted aminophenols by bacteria and found that some Pseudomonas spp. can utilise these compounds as sole carbon and energy sources. GC-MS analysis of the culture supernatants from cultures grown in 5 (pentafluorosulfanyl) 2-aminophenol demonstrated the presence of the N-acetylated derivative of the starting substrate and 4-(pentafluorosulfanyl)catechol. Biotransformation experiments with re-suspended cells were also conducted and fluorine-19 NMR analyses of the organic extract and aqueous fraction from suspended cell experiments revealed new resonances of SF5-substituted intermediates. Supplementation of suspended cell cultures with yeast extract dramatically improved the degradation of the substrate as well as the release of fluoride ion. 4-(Pentafluorosulfanyl)catechol was shown to be a shunt metabolite and toxic to some of the bacteria. This is the first study to demonstrate that microorganisms can biodegrade SF5-substituted aromatic compounds releasing fluoride ion, and biotransform them generating a toxic metabolite. PMID- 29603053 TI - Policy Implications and Research Recommendations: A Review of Hookah Use Among US College Students. AB - The rate of Hookah use among college students during the last decade is about 30%. Although college students perceive hookah use as a safer alternative to conventional cigarettes, hookah use increases the risk of disease and nicotine dependence, and therefore remains an area of concern. Presently, the US Food and Drug Administration (FDA) has little regulation for the manufacture, distribution, or sale of hookah. This review attempts to assess empirical literature relating to hookah use while focusing on the consequences for regulatory policy. PubMed (including MEDLINE 2010-2017), PsycINFO, EBSCO, Scopus (Elsevier) databases were examined to pinpoint articles published in English. The following terms were used in the searches: Hookah or Waterpipe or nargile or "arghile" or "shisha" or "hubble bubble" or "alternative tobacco product" or "flavored tobacco". Hookah use may initiate smoking among tobacconaive college students. College students who use hookah are generally not aware of the increased risks for tobacco related diseases as it relates to their behavior. In addition, few public health messages target college-age adults with anti-hookah messages. A lack of information regarding the dangers and potential harms of hookah use may be misinterpreted as a sign of "safety" which inadvertently may imply a suggestion of no need for safety measures. Hence, a research agenda that would inform about health policy actions has been proposed. PMID- 29603054 TI - Autolytic hydrolases affect sexual and asexual development of Aspergillus nidulans. AB - Radial growth, asexual sporulation, and cleistothecia formation as well as extracellular chitinase and proteinase formation of Aspergillus nidulans were monitored in surface cultures in order to study the physiological role of extracellular hydrolase production in carbon-stressed cultures. We set up carbon stressed and carbon-overfed experimental conditions by varying the starting glucose concentration within the range of 2.5 and 40 g/L. Glucose starvation induced radial growth and hydrolase production and enhanced the maturation of cleistothecia; meanwhile, glucose-rich conditions enhanced mycelial biomass, conidia, and cleistothecia production. Double deletion of chiB and engA (encoding an extracellular endochitinase and a beta-1,3-endoglucanase, respectively) decreased conidia production under carbon-stressed conditions, suggesting that these autolytic hydrolases can support conidia formation by releasing nutrients from the cell wall polysaccharides of dead hyphae. Double deletion of prtA and pepJ (both genes encode extracellular proteases) reduced the number of cleistothecia even under carbon-rich conditions except in the presence of casamino acids, which supports the view that sexual development and amino acid metabolism are tightly connected to each other in this fungus. PMID- 29603055 TI - Post-deployment Mental Health Screening: A Systematic Review of Current Evidence and Future Directions. AB - Population-based post-deployment screening programs within the Departments of Defense and Veterans Affairs have been implemented to assess for mental health conditions and traumatic brain injury. The purpose of this paper is to systematically review the literature on post-deployment screening within this context and evaluate evidence compared to commonly accepted screening implementation criteria. Findings reflected highly variable psychometric properties of the various screens, variable treatment referral rates following screening, low to moderate treatment initiation rates following screening, and no information on treatment completion or long-term outcomes following screening. In sum, the evidence supporting population based post-deployment screening is inconclusive. Implications are discussed. PMID- 29603056 TI - Pain Knowledge and Attitudes Among Nurses in Cancer Care in Norway. AB - The purpose of this study was to survey knowledge on, and attitudes to, pain and pain management among a cohort of Norwegian Nurses in cancer care, and to explore whether there is any association between various demographic variables and knowledge level. This is a web-based survey and nurses were recruited from the Forum for Cancer Nursing. Nurses completed the questionnaire "Nurses' Knowledge and Attitudes Survey Regarding Pain (NKAS)". Univariate and multivariate linear regression analysis were used to evaluate the association between knowledge and attitudes and demographic variables. Nurses from all over Norway answered. The majority were women and most had education above bachelor level. Mean NKAS total score was 31 points (75%). Significant associations were found between NKAS total score and pain management course (p = 0.01) and workplace (p = 0.04). Nurses in cancer care in Norway have relatively good pain knowledge. The potential for improvement is the greatest with regard to pharmacology and nurses' attitudes to how patients express pain. Our findings suggest that an extensive pain management course with patient histories may result in more theoretical knowledge being applied to the patients. In a time with large migration among nurses, our findings indicate that pain management courses should be aware of cultural differences in the educational training. PMID- 29603057 TI - The Dysphagia in Stroke Protocol Reduces Aspiration Pneumonia in Patients with Dysphagia Following Acute Stroke: a Clinical Audit. AB - Cough reflex testing has been evaluated as a component of the clinical swallowing assessment as a means of identifying patients at risk of aspiration during swallowing. A previous study by our research group found good sensitivity and specificity of the cough reflex test for identifying patients at risk of aspiration post-stroke, yet its use did not decrease pneumonia rates, contrary to previous reports. The aim of this study was to expand on our earlier work by implementing a clinical management protocol incorporating cough reflex testing within the same healthcare setting and compare patient outcomes to those from the original study and to evaluate clinical outcomes in patients with acute stroke who were managed using the Dysphagia in Stroke Protocol (DiSP). Secondarily, to compare those outcomes to historical data prior to implementation of the DiSP. This clinical audit measured outcomes from 284 patients with acute stroke managed per the DiSP, which guides use of videofluoroscopic swallowing study and patient management based on clinical exam with cough reflex testing. Data from our previous trial were included for comparison of pre- and post-DiSP patient outcomes. Data collection took place between November 2012 and April 2016 at four urban hospitals within New Zealand. Following implementation of the DiSP, the rate of aspiration pneumonia (10%) was substantially lower than the pre-DiSP rate (28%), with no pneumonia readmissions within 3 months. Pneumonia-related mortality was unchanged. By 3 months, 81% of the patients were on a normal diet and 67% had returned home, compared to pre-DiSP outcomes of 55% and 55% respectively. Previous work has suggested that simply implementing cough reflex testing in dysphagia management may not be sufficient to improve patient outcomes. The present study adds to this picture by suggesting that the true variable of influence may be the way in which the results of the test are applied to patient care. There is a strong case to support the use of a structured protocol if cough reflex testing is to be implemented in clinical practice. PMID- 29603058 TI - Discrimination of Isomers of Released N- and O-Glycans Using Diagnostic Product Ions in Negative Ion PGC-LC-ESI-MS/MS. AB - Profiling cellular protein glycosylation is challenging due to the presence of highly similar glycan structures that play diverse roles in cellular physiology. As the anomericity and the exact linkage type of a single glycosidic bond can influence glycan function, there is a demand for improved and automated methods to confirm detailed structural features and to discriminate between structurally similar isomers, overcoming a significant bottleneck in the analysis of data generated by glycomics experiments. We used porous graphitized carbon-LC-ESI MS/MS to separate and detect released N- and O-glycan isomers from mammalian model glycoproteins using negative mode resonance activation CID-MS/MS. By interrogating similar fragment spectra from closely related glycan isomers that differ only in arm position and sialyl linkage, product fragment ions for discrimination between these features were discovered. Using the Skyline software, at least two diagnostic fragment ions of high specificity were validated for automated discrimination of sialylation and arm position in N glycan structures, and sialylation in O-glycan structures, complementing existing structural diagnostic ions. These diagnostic ions were shown to be useful for isomer discrimination using both linear and 3D ion trap mass spectrometers when analyzing complex glycan mixtures from cell lysates. Skyline was found to serve as a useful tool for automated assessment of glycan isomer discrimination. This platform-independent workflow can potentially be extended to automate the characterization and quantitation of other challenging glycan isomers. Graphical Abstract ?. PMID- 29603059 TI - Adiponectin Reverses the Proliferative Effects of Estradiol and IGF-1 in Human Epithelial Ovarian Cancer Cells by Downregulating the Expression of Their Receptors. AB - The expression of adiponectin receptors AdipoR1 and AdipoR2 has been reported in the human ovary and ovarian cancer tissues. Moreover, adiponectin has been reported to act as an anti-tumor factor by inhibiting cancer cell proliferation. Thus, we investigate whether adiponectin and its receptors influence ovarian cancer development. In the present study, we found that adiponectin was not expressed in the granulosa cell line (COV434), and epithelial ovarian cancer cell lines (OVCAR-3, SKOV-3, and Caov-3). Additionally, we found that AdipoR1 and AdipoR2 expression is lower in epithelial ovarian cancer cells than in granulosa tumor cells. Endogenous 17beta-estradiol as well as exogenous estrogens, such as bisphenol A and its chlorinated and brominated analogs do not affect adiponectin receptor expression. We found that adiponectin inhibited the growth of OVCAR-3 and SKOV-3 cells, and that this effect was independent of apoptosis. Moreover, adiponectin reverses the stimulatory effects of 17beta-estradiol and insulin-like growth factor 1 on cell proliferation by downregulating the expression of their receptors, whereas progesterone increased the sensitivity of cancer cells to adiponectin by upregulating AdipoR1 and AdipoR2 expression. These results suggest interactions between adiponectin and various ovarian steroid hormone and growth factor pathways in ovarian cancer cells. PMID- 29603060 TI - Correction to: Global and Japanese regional variations in radiologist potential workload for computed tomography and magnetic resonance imaging examinations. AB - In Results of Abstract, the first sentence should read as: The radiologist potential workload in Japan was 2.78-4.17 times higher than those in other countries. PMID- 29603061 TI - Aiding the Detection of QRS Complex in ECG Signals by Detecting S Peaks Independently. AB - In this paper, a novel algorithm for the accurate detection of QRS complex by combining the independent detection of R and S peaks, using fusion algorithm is proposed. R peak detection has been extensively studied and is being used to detect the QRS complex. Whereas, S peaks, which is also part of QRS complex can be independently detected to aid the detection of QRS complex. In this paper, we suggest a method to first estimate S peak from raw ECG signal and then use them to aid the detection of QRS complex. The amplitude of S peak in ECG signal is relatively weak than corresponding R peak, which is traditionally used for the detection of QRS complex, therefore, an appropriate digital filter is designed to enhance the S peaks. These enhanced S peaks are then detected by adaptive thresholding. The algorithm is validated on all the signals of MIT-BIH arrhythmia database and noise stress database taken from physionet.org. The algorithm performs reasonably well even for the signals highly corrupted by noise. The algorithm performance is confirmed by sensitivity and positive predictivity of 99.99% and the detection accuracy of 99.98% for QRS complex detection. The number of false positives and false negatives resulted while analysis has been drastically reduced to 80 and 42 against the 98 and 84 the best results reported so far. PMID- 29603062 TI - Peripheral Blood Cell Interactions of Cancer-Derived Exosomes Affect Immune Function. AB - Cancer-derived exosomes are constitutively produced and secreted into the blood and biofluids of their host patients providing a liquid biopsy for early detection and diagnosis. Given their ubiquitous nature, cancer exosomes influence biological mechanisms that are beneficial to the tumor cells where they are produced and the microenvironment in which these tumors exist. Accumulating evidence suggests that exosomes transport proteins, lipids, DNA, mRNA, miRNA and long non coding RNA (lncRNA) for the purpose of cell-cell and cell-extracellular communication. These exosomes consistently reflect the status as well as identity of their cell of origin and as such may conceivably be affecting the ability of a functional immune system to recognize and eliminate cancer cells. Recognizing and mapping the pathways in which immune suppression is garnered through these tumor derived exosome (TEX) may lead to treatment strategies in which specific cell membrane proteins or receptors may be targeted, allowing for immune surveillance to once again help with the treatment of cancer. This Review focuses on how cancer exosomes interact with immune cells in the blood. PMID- 29603063 TI - Deep Learning for Drug Design: an Artificial Intelligence Paradigm for Drug Discovery in the Big Data Era. AB - Over the last decade, deep learning (DL) methods have been extremely successful and widely used to develop artificial intelligence (AI) in almost every domain, especially after it achieved its proud record on computational Go. Compared to traditional machine learning (ML) algorithms, DL methods still have a long way to go to achieve recognition in small molecular drug discovery and development. And there is still lots of work to do for the popularization and application of DL for research purpose, e.g., for small molecule drug research and development. In this review, we mainly discussed several most powerful and mainstream architectures, including the convolutional neural network (CNN), recurrent neural network (RNN), and deep auto-encoder networks (DAENs), for supervised learning and nonsupervised learning; summarized most of the representative applications in small molecule drug design; and briefly introduced how DL methods were used in those applications. The discussion for the pros and cons of DL methods as well as the main challenges we need to tackle were also emphasized. PMID- 29603064 TI - LV function validation of computer-assisted interventional system for cardiac resyncronisation therapy. AB - PURPOSE: Cardiac resynchronisation therapy (CRT) is an established treatment for symptomatic patients with heart failure, a prolonged QRS duration, and impaired left ventricular (LV) function; however, non-response rates remain high. Recently proposed computer-assisted interventional platforms for CRT provide new routes to improving outcomes. Interventional systems must process information in an accurate, fast and highly automated way that is easy for the interventional cardiologists to use. In this paper, an interventional CRT platform is validated against two offline diagnostic tools to demonstrate that accurate information processing is possible in the time critical interventional setting. METHODS: The study consisted of 3 healthy volunteers and 16 patients with heart failure and conventional criteria for CRT. Data analysis included the calculation of end diastolic volume, end-systolic volume, stroke volume and ejection fraction; computation of global volume over the cardiac cycle as well as time to maximal contraction expressed as a percentage of the total cardiac cycle. RESULTS: The results showed excellent correlation ([Formula: see text] values of [Formula: see text] and Pearson correlation coefficient of [Formula: see text]) with comparable offline diagnostic tools. CONCLUSION: Results confirm that our interventional system has good accuracy in everyday clinical practice and can be of clinical utility in identification of CRT responders and LV function assessment. PMID- 29603065 TI - Fast 5DOF needle tracking in iOCT. AB - PURPOSE: Intraoperative optical coherence tomography (iOCT) is an increasingly available imaging technique for ophthalmic microsurgery that provides high resolution cross-sectional information of the surgical scene. We propose to build on its desirable qualities and present a method for tracking the orientation and location of a surgical needle. Thereby, we enable the direct analysis of instrument-tissue interaction directly in OCT space without complex multimodal calibration that would be required with traditional instrument tracking methods. METHOD: The intersection of the needle with the iOCT scan is detected by a peculiar multistep ellipse fitting that takes advantage of the directionality of the modality. The geometric modeling allows us to use the ellipse parameters and provide them into a latency-aware estimator to infer the 5DOF pose during needle movement. RESULTS: Experiments on phantom data and ex vivo porcine eyes indicate that the algorithm retains angular precision especially during lateral needle movement and provides a more robust and consistent estimation than baseline methods. CONCLUSION: Using solely cross-sectional iOCT information, we are able to successfully and robustly estimate a 5DOF pose of the instrument in less than 5.4 ms on a CPU. PMID- 29603066 TI - Culture Supernatants of Lactobacillus gasseri and L. crispatus Inhibit Candida albicans Biofilm Formation and Adhesion to HeLa Cells. AB - PURPOSE: Vulvovaginal candidiasis (VVC) is a common superficial infection of the vaginal mucous membranes caused by the fungus Candida albicans. The aim of this study was to assess the mechanisms underlying the inhibitory effects of the culture supernatants of Lactobacillus gasseri and L. crispatus, the predominant microbiota in Asian healthy women, on C. albicans biofilm formation. The inhibition of C. albicans adhesion to HeLa cells by Lactobacillus culture supernatant was also investigated. METHODS: Candida albicans biofilm was formed on polystyrene flat-bottomed 96-well plates, and the inhibitory effects on the initial colonization and maturation phases were determined using the XTT reduction assay. The expression levels of biofilm formation-associated genes (HWP1, ECE1, ALS3, BCR1, EFG1, TEC1, and CPH1) were determined by reverse transcription quantitative polymerase chain reaction. The inhibition of C. albicans adhesion to HeLa cells by Lactobacillus culture supernatant was evaluated by enumerating viable C. albicans cells. RESULTS: The culture supernatants of both Lactobacillus species inhibited the initial colonization and maturation of C. albicans biofilm. The expression levels of all biofilm formation related genes were downregulated in the presence of Lactobacillus culture supernatant. The culture supernatant also inhibited C. albicans adhesion to HeLa cells. CONCLUSION: The culture supernatants of L. gasseri and L. crispatus inhibited C. albicans biofilm formation by downregulating biofilm formation related genes and C. albicans adhesion to HeLa cells. These findings support the notion that Lactobacillus metabolites may be useful alternatives to antifungal drugs for the management of VVC. PMID- 29603068 TI - The significance and application of vascular niche in the development and maintenance of hematopoietic stem cells. AB - Deriving hematopoietic stem cells (HSCs) from human pluripotent stem cells is one of major goals in stem cell and hematological research. To induce HSCs from human pluripotent stem cells, many attempts to mimic embryonic development through stepwise exposure to morphogens. HSCs arise from dorsal aorta of embryos then migrate and settle in the bone marrow. Development and maintenance of HSCs are controlled by the microenvironmental cues around the blood vessels (called vascular niche) through morphogens and cytokines. Vascular niche serves as a common mechanism from embryo development to life-long maintenance of HSCs. In this chapter, I discuss that how vascular niche regulates development and maintenance of HSCs and exemplify the role of vascular niche to exquisitely induce HSCs from human pluripotent stem cells. PMID- 29603067 TI - Secretome of Differentiated PC12 Cells Restores the Monocrotophos-Induced Damages in Human Mesenchymal Stem Cells and SHSY-5Y Cells: Role of Autophagy and Mitochondrial Dynamics. AB - A perturbed cellular homeostasis is a key factor associated with xenobiotic exposure resulting in various ailments. The local cellular microenvironment enriched with secretory components aids in cell-cell communication that restores this homeostasis. Deciphering the underlying mechanism behind this restorative potential of secretome could serve as a possible solution to many health hazards. We, therefore, explored the protective efficacy of the secretome of differentiated PC12 cells with emphasis on induction of autophagy and mitochondrial biogenesis. Monocrotophos (MCP), a widely used neurotoxic organophosphate, was used as the test compound at sublethal concentration. The conditioned medium (CM) of differentiated PC12 cells comprising of their secretome restored the cell viability, oxidative stress and apoptotic cell death in MCP-challenged human mesenchymal stem cells and SHSY-5Y, a human neuroblastoma cell line. Delving further to identify the underlying mechanism of this restorative effect we observed a marked increase in the expression of autophagy markers LC3, Beclin-1, Atg5 and Atg7. Exposure to autophagy inhibitor, 3 methyladenine, led to a reduced expression of these markers with a concomitant increase in the expression of pro-apoptotic caspase-3. Besides that, the increased mitochondrial fission in MCP-exposed cells was balanced with increased fusion in the presence of CM facilitated by AMPK/SIRT1/PGC-1alpha signaling cascade. Mitochondrial dysfunctions are strongly associated with autophagy activation and as per our findings, cellular secretome too induces autophagy. Therefore, connecting these three potential apices can be a major breakthrough in repair and rescue of xenobiotic-damaged tissues and cells. PMID- 29603069 TI - Higher free triiodothyronine concentration is associated with lower prevalence of microangiopathic complications and better metabolic control in adult euthyroid people with type 1 diabetes. AB - PURPOSE: Type 1 diabetes mellitus (T1DM) is a disorder of insulin deficiency but with a wide range of hormones simultaneously disturbed. The study was performed to explore relation of free triiodothyronine (FT3) with metabolic control and occurrence of microangiopathic complications. METHODS: A total of 266 adult T1DM participants [56% men; 32 (interquartile range, IQR: 25-39) years and disease duration 13 (IQR: 8-19) years] in euthyroid state with negative history for hypothyroidism were included to the study. Participants were screened for thyroid stimulating hormone (TSH), free thyroxine (FT4) and FT3. Moreover, microangiopathic complications (retinopathy, diabetic kidney disease, peripheral and autonomic neuropathy), markers of metabolic control such as glycated hemoglobin (HbA1c) were evaluated. RESULTS: A total of 114 (42.9%) people had diagnosed at least one microangiopathic complication. In multivariable linear regression higher HbA1c was statistically significant independent predictor of lower FT3 (beta = -0.25; p < 0.0001) after adjustment for sex, T1DM duration, HbA1c, waist-to-hip ratio (WHR) (R2 = 0.15, p < 0.0001). Higher FT3 was simultaneously a predictor of lower prevalence of microangiopathy in multivariate logistic regression analysis (odds ratio, 0.51; 95% confidence interval, 0.27 0.98; p = 0.04) after an adjustment for: age, hypertension, HbA1c, WHR and total cholesterol (TC). CONCLUSIONS: FT3 as tissue active hormone plays a clinically important role in T1DM people. The higher FT3 concentration is related to the lower prevalence of microangiopathy and better metabolic control of the disease in adult euthyroid people with T1DM. PMID- 29603070 TI - High calcium, phosphate and calcitriol supplementation leads to an osteocyte-like phenotype in calcified vessels and bone mineralisation defect in uremic rats. AB - A link between vascular calcification and bone anomalies has been suggested in chronic kidney disease (CKD) patients with low bone turnover disease. We investigated the vascular expression of osteocyte markers in relation to bone microarchitecture and mineralization defects in a model of low bone turnover CKD rats with vascular calcification. CKD with vascular calcification was induced by 5/6 nephrectomy followed by high calcium and phosphate diet, and vitamin D supplementation (Ca/P/VitD). CKD + Ca/P/VitD group (n = 12) was compared to CKD + normal diet (n = 12), control + normal diet (n = 8) and control + Ca/P/VitD supplementation (n = 8). At week 6, tibia, femurs and the thoracic aorta were analysed by Micro-Ct, histomorphometry and for expression of osteocyte markers. High Ca/P/VitD treatment induced vascular calcification only in CKD rats, suppressed serum parathyroid hormone levels and led to higher sclerostin, DKK1 and FGF23 serum levels. Expression of sclerostin, DKK1 and DMP1 but not FGF23 were increased in calcified vessels from CKD + Ca/P/VitD rats. Despite low parathyroid hormone levels, tibia bone cortical thickness was significantly lower in CKD + Ca/P/VitD rats as compared to control rats fed a normal diet, which is likely the result of radial growth impairment. Finally, Ca/P/VitD treatment in CKD rats induced a bone mineralization defect, which is likely explained by the high calcitriol dose. In conclusion, Ca/P/VitD supplementation in CKD rats induces expression of osteocyte markers in vessels and bone mineralisation anomalies. Further studies should evaluate the mechanisms of high dose calcitriol induced bone mineralisation defects in CKD. PMID- 29603071 TI - Serum homocysteine levels are affected by renal function during a 3-year period of minodronate therapy in female osteoporotic patients. AB - Serum homocysteine is a possible marker to indicate bone quality. However, it is not clear whether changes are seen in serum homocysteine levels with long-term bisphosphonate therapy. We aimed to investigate the factors affecting serum homocysteine levels during a 3-year period of monthly minodronate therapy in osteoporotic women, and to examine if the serum homocysteine levels could reflect some aspects of bone metabolism. The study included 43 patients (age 72.3 +/- 7.0 years) undergoing treatment for osteoporosis for the first time (New group) and 35 patients (age 74.4 +/- 8.2 years) who switched from alendronate or risedronate to minodronate (Switch group). Minodronate (50 mg/every 4 weeks) was administered for 36 months. Lumbar, femoral neck, and total hip bone mineral densities (BMD), and serum homocysteine levels were monitored at baseline and after 9, 18, 27, and 36 months of treatment. Lumbar BMD increased significantly in both groups (New group 11.4%, Switch group 6.2%). However, femoral neck and total hip BMDs increased only in the New group (femoral neck 3.6%, total hip 4.1%). Serum homocysteine levels increased significantly at 18 and 27 months in all subjects. Multiple linear regression analysis revealed that changes in homocysteine levels during 18, 27, and 36 months significantly correlated with changes in creatinine clearance during the same corresponding periods (18 months: B = - 0.472, p = 0.003; 27 months: B = - 0.375, p = 0.021; 36 months: B = - 0.445, p = 0.012). Thus, serum homocysteine levels possibly reflect renal function instead of bone metabolism during minodronate therapy. PMID- 29603072 TI - Comment on: "Effects of interventions with a physical activity component on bone health in obese children and adolescents: a systematic review and meta-analysis". PMID- 29603073 TI - Predictors of self-medication in Serbian adult population: cross-sectional study. AB - Background In spite of many benefits for individuals and community, self medication has a number of potential risks. Objective To identify predictors of self-medication with over-the-counter and prescription (Rx) medicines without doctor's prescription. Setting Serbian population of 15 years of age and over. Method This was crosssectional, epidemiological study. Data have been drawn from Serbian National Health Survey 2013 database. Predictors of self-medication were determined among sociodemographic, health related and health services related factors, using multivariate logistic regression models. Main outcome measure Prevalence and predictors of selfmedication. Results The study included 14,623 participants. The prevalence of selfmedication was 27.1 and 24% after exclusion of vitamins, minerals and herbal preparations. Medicines for pain relief were the mostly used medicines without doctors' prescription in 18.4% of participants. A relatively high prevalence of self-medication with Rx medicines, (1) tranquilizers and sleeping pills, (2) antibiotics and (3) antihypertensives, was found, 4, 2.5 and 1.9%, respectively. Socio-demographic factors (middle age, female gender, higher level of education), health related factors (chronic disease, stress, physical pain), and health service related factors (nonrealized healthcare needs due to long waiting, dissatisfaction with publicly funded health services) have been found as significantly associated with self-medication. Conclusion Self-medication in Serbia is predicted by socio-demographic and health related factors, unmet needs for healthcare and dissatisfaction with publicly funded healthcare services. Improvements in healthcare system, particularly, shortening of long waiting for healthcare services and improvements in pharmaceutical services, particularly better control of Rx medicines dispensing, could contribute in improvement of responsible self-medication. PMID- 29603074 TI - Impact of the clinical pharmacist interventions on prevention of pharmacotherapy related problems in the paediatric intensive care unit. AB - Background Problems related to pharmacotherapy are common in patients admitted to the paediatric intensive care unit (PICU) and are associated with increased healthcare costs. Data on the impact of clinical pharmacist interventions to prevent pharmacotherapy-related problems and to minimize costs in the PICU are limited. Objectives To evaluate the number and type of clinical pharmacist interventions in the PICU and to determine cost savings associated with them. Setting a ten bed PICU of a tertiary-care university hospital in Brazil. Method This was a prospective, observational study conducted over 1-year. The Failure Mode and Effects Analysis (FMEA) tool was applied at the beginning of the study to assess drug-related risks in the PICU and to guide clinical pharmacist interventions. Main outcome measure Number and type of clinical pharmacist interventions and healthcare-related costs. Results One hundred sixty-two children were followed-up by the clinical pharmacist and 1586 prescriptions were evaluated; pharmacotherapy-related problems were identified in 12.4% of them. Sixteen of 75 failure modes identified by FMEA were potentially reduced by the clinical pharmacist interventions. There were 197 interventions with a cost saving of R$ 15,118.73 (US$ 4828.00). Clinical pharmacist interventions were related to drug interaction and therapeutic monitoring (34.5%), drug selection (22.3%), dosing and frequency (16.8%), prescription (13.2%) and administration (13.2%). Ninety-seven per cent of the clinical pharmacist interventions were accepted by the medical team. The interventions with larger cost savings were related to administration (39%). Conclusion The clinical pharmacist interventions minimized the risks of pharmacotherapy-related problems and contributed to the reduction of costs associated with medical prescription. PMID- 29603075 TI - Promoting Colorectal Cancer Screening in Foreign-Born Chinese-American Women: Does Racial/Ethnic and Language Concordance Matter? AB - Chinese Americans are one of the fastest-growing and largest Asian-American subgroups. Approximately 70% of Chinese Americans are immigrants with 46% being of limited English proficiency. Despite colorectal cancer (CRC) being the second leading cause of cancer death in Chinese Americans, Chinese Americans have lower CRC screening rates than other Asian subgroups, and only 40% of CRC cases among Chinese Americans are diagnosed early. Furthermore, CRC is the second most common cancer among Chinese American women. Race/ethnicity concordant providers may process culturally specific knowledge, skills, and experience that may facilitate better communication. Although using an interpreter can help to overcome language barriers between providers and patients, it may not achieve the same level of communication as a language concordant provider. The purpose of this study was to test a community education intervention, taking into account the racial/ethnic and language concordance of the presenter, to increase CRC screening uptake among foreign-born Chinese American women. This study used a quasi-experimental design and a convenience sample of 198 foreign-born Chinese-American women. Logistic regression was used to examine the effect of racial/ethnic and language concordance of the presenter on the return of completed FOBT kits for testing. The Chinese/English-speaking presenter had the highest return rate (73%), followed by the White/English-speaking presenter (61%), and the Chinese/Chinese speaking presenter (48%), and the differences were statistically significant. Post-education intention to screen was also a significant predictor for returning the FOBT kit for testing. The use of an interpreter did not decrease the effectiveness of the educational intervention. PMID- 29603077 TI - Minimal water volume for intensively producing male Siamese fighting fish (Betta splendens Regan, 1910). AB - Water volume is a key parameter affecting the individual rearing of male Siamese fighting fish (Betta splendens Regan, 1910). In this study, minimization of water volume was pursued by assessing growth, feed utilization, digestive enzyme activities, color coordinates, muscle quality, and carcass composition. One-month old solid-red male fish (0.97 +/- 0.01 g initial body weight) were distributed individually into glass aquaria with five alternative water volumes (100, 150, 200, 250, and 300 mL), comprising 15 fish per treatment (n = 15), over 8 weeks duration. No mortality of the reared fish was found during the study. Growth performance and feed utilization of the fish reared in 150 mL water were superior to the other treatments. The water volume significantly affected specific activities of the digestive enzymes (P ? 0.05), except for amylase, and no differences in enzyme activities were observed between fish reared in 150 and in 300 mL water. The preferred treatment maintained skin lightness (L*) and had the highest redness (a* and a*/b*) among the treatments. Protein synthesis (RNA concentration) and its turnover rate (RNA/protein ratio) and myosin and actin in muscle also benefited from this treatment. Carcass composition, in terms of moisture, crude protein, and crude ash, was maintained, but the amount of crude lipid fluctuated with water volume. Based on our experiments, the preferred minimal water volume for individual rearing of male Siamese fighting fish should be about 150 mL. PMID- 29603076 TI - Effects of Rhizoma Alismatis extract on biochemical indices and adipose gene expression in oleic acid-induced hepatocyte injury in Jian carp (Cyprinus carpio var. Jian). AB - Fatty liver is an increasingly serious disease of fish in aquaculture. However, the mechanisms responsible for the occurrence of fatty liver remain unclear, and no effective methods for the prevention and treatment of this disease have yet been found. In the present study, we aimed to develop an in vitro model of hepatocyte injury using oleic acid as hepatotoxicant and evaluate the protective effects of Rhizoma Alismatis extract (RAE) in Jian carp using this model. Primary hepatocytes from Jian carp were isolated and purified and cultured in vitro. The result indicated that 0.4 mmol L-1 oleic acid and 48 h could be the optimal conditions to induce hepatocyte injury model in cultured hepatocytes. Hepatocytes were exposed to oleic acid, followed by the addition of RAE at 0, 1, 5, 10, 20, or 50 MUg mL-1. The hepatocytes and supernatant were then analyzed. RAE suppressed oleic acid-induced elevations in aspartate aminotransferase, alanine aminotransferase, triglycerides, total cholesterol, lactate dehydrogenase, alkaline phosphatase, cholinesterase, malondialdehyde, gamma-glutamyl transferase, cytochrome P450 1A, cytochrome P450 2E1, liver-type fatty acid binding protein, free fatty acid, fatty acid synthetase, and tumor necrosis factor-alpha (P < 0.01 or P < 0.05); reduced protein levels of cytochrome P450 1A, nuclear factor (NF)-kappaB p65, and NF-kappaB c-Rel; and inhibited cytochrome P4503A, NF-kappaB c-Rel, nuclear factor erythroid-related factor 2, peroxisome proliferator-activated receptor-alpha, and cytochrome P4501A mRNA levels. In conclusion, RAE exhibited a protective effect against hepatocyte injury in Jian carp. Further in vivo studies are needed to provide more evidence for the use of RAE as a hepatoprotective agent for the treatment of hepatocyte injury. PMID- 29603078 TI - Estimated expenditures for hip fractures using merged healthcare insurance data for individuals aged >= 75 years and long-term care insurance claims data in Japan. AB - : Little is known about hip fracture expenditure in Japan. Using claims data obtained from a core city near Tokyo, we estimated the mean healthcare expenditure and monthly long-term care expenditure post-hip fracture to be Y2,600,000 (US$29,500) and Y113,000 (US$1290), respectively. PURPOSE: We aimed to estimate healthcare and long-term care expenditures post-hip fracture in Japan. METHODS: Healthcare insurance claims data for adults aged >= 75 years were merged with long-term care insurance claims data. We analyzed the data of hip fracture patients who were admitted to non-diagnosis procedure combination/per diem payment system (DPC/PDPS) hospitals in a core city near Tokyo between April 2012 and September 2013. We estimated healthcare expenditure, namely, the difference between total payments 6 months pre- and 6 months post-hip fracture, and monthly long-term care expenditure for those who did not use long-term care insurance pre-hip fracture, but who commenced long-term care insurance post-hip fracture. We also performed multiple linear regressions to examine the associations of healthcare or long-term care expenditure with various factors. RESULTS: The estimated mean healthcare (n = 78) and monthly long-term care (n = 42) expenditures post-hip fracture were Y2,600,000 (US$29,500) and Y113,000 (US$1290), respectively. In multiple linear regressions, healthcare expenditure was positively associated with longer duration of hospital stay (p = 0.036), and negatively associated with higher Charlson Comorbidity Index scores (p = 0.015). Monthly long-term care expenditure was positively associated with higher care needs level post-hip fracture (p = 0.022), and usage of institutional care services (p < 0.001). CONCLUSIONS: This is the first study to estimate healthcare and long-term care expenditures post-hip fracture using claims data in Japan. Further studies are needed that include healthcare claims data at both DPC/PDPS and non-DPC/PDPS hospitals to capture the lifelong course of long-term care required post-hip fracture. PMID- 29603079 TI - Effects of Breast and Prostate Cancer Metastases on Lumbar Spine Biomechanics: Rapid In Silico Evaluation. AB - Metastases to distant organs are a frequent occurrence in cancer diseases. The skeletal system, especially the spine, is one such organ. The objective of this study was to apply a numerical modeling, using a finite element method (FEM), for the evaluation of deformation and stress in lumbar spine in bone metastases to the spine. We investigated 20 patients (10 women and 10 men) aged 38-81 years. In women, osteolytic lesions in lumbar spine accompanied breast cancer, in men it was prostate cancer. Geometry of FEM models were built based on CT scans of metastatic lumbar spine. We made the models for osteolytic metastases, osteosclerotic metastases, and metastases after surgery. Images were compared. We found a considerable concentration of strain, especially located in the posterior part of the vertebral body. In osteolytic lesions, the strain was located below the vertebral body with metastases. In osteosclerotic lesions, the strain was located in the anterior and posterior parts in and below the vertebral body with metastases. Surgery abolished the pathological strain. We conclude that metastases to the lumbar spine introduce a pathological strain on the lumbar body. The immobilization of the vertebral body around fractures abolished the strain. PMID- 29603080 TI - Neuroimaging classification of progression patterns in glioblastoma: a systematic review. AB - BACKGROUND: Our primary objective was to report the current neuroimaging classification systems of spatial patterns of progression in glioblastoma. In addition, we aimed to report the terminology used to describe 'progression' and to assess the compliance with the Response Assessment in Neuro-Oncology (RANO) Criteria. METHODS: We conducted a systematic review to identify all neuroimaging studies of glioblastoma that have employed a categorical classification system of spatial progression patterns. Our review was registered with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) registry. RESULTS: From the included 157 results, we identified 129 studies that used labels of spatial progression patterns that were not based on radiation volumes (Group 1) and 50 studies that used labels that were based on radiation volumes (Group 2). In Group 1, we found 113 individual labels and the most frequent were: local/localised (58%), distant/distal (51%), diffuse (20%), multifocal (15%) and subependymal/subventricular zone (15%). We identified 13 different labels used to refer to 'progression', of which the most frequent were 'recurrence' (99%) and 'progression' (92%). We identified that 37% (n = 33/90) of the studies published following the release of the RANO classification were adherent compliant with the RANO criteria. CONCLUSIONS: Our review reports significant heterogeneity in the published systems used to classify glioblastoma spatial progression patterns. Standardization of terminology and classification systems used in studying progression would increase the efficiency of our research in our attempts to more successfully treat glioblastoma. PMID- 29603081 TI - Evolution of photosynthetic reaction centers: insights from the structure of the heliobacterial reaction center. AB - The proliferation of phototrophy within early-branching prokaryotes represented a significant step forward in metabolic evolution. All available evidence supports the hypothesis that the photosynthetic reaction center (RC)-the pigment-protein complex in which electromagnetic energy (i.e., photons of visible or near infrared light) is converted to chemical energy usable by an organism-arose once in Earth's history. This event took place over 3 billion years ago and the basic architecture of the RC has diversified into the distinct versions that now exist. Using our recent 2.2-A X-ray crystal structure of the homodimeric photosynthetic RC from heliobacteria, we have performed a robust comparison of all known RC types with available structural data. These comparisons have allowed us to generate hypotheses about structural and functional aspects of the common ancestors of extant RCs and to expand upon existing evolutionary schemes. Since the heliobacterial RC is homodimeric and loosely binds (and reduces) quinones, we support the view that it retains more ancestral features than its homologs from other groups. In the evolutionary scenario we propose, the ancestral RC predating the division between Type I and Type II RCs was homodimeric, loosely bound two mobile quinones, and performed an inefficient disproportionation reaction to reduce quinone to quinol. The changes leading to the diversification into Type I and Type II RCs were separate responses to the need to optimize this reaction: the Type I lineage added a [4Fe-4S] cluster to facilitate double reduction of a quinone, while the Type II lineage heterodimerized and specialized the two cofactor branches, fixing the quinone in the QA site. After the Type I/II split, an ancestor to photosystem I fixed its quinone sites and then heterodimerized to bind PsaC as a new subunit, as responses to rising O2 after the appearance of the oxygen-evolving complex in an ancestor of photosystem II. These pivotal events thus gave rise to the diversity that we observe today. PMID- 29603082 TI - 15N photo-CIDNP MAS NMR analysis of reaction centers of Chloracidobacterium thermophilum. AB - Photochemically induced dynamic nuclear polarization (photo-CIDNP) has been observed in the homodimeric, type-1 photochemical reaction centers (RCs) of the acidobacterium, Chloracidobacterium (Cab.) thermophilum, by 15N magic-angle spinning (MAS) solid-state NMR under continuous white-light illumination. Three light-induced emissive (negative) signals are detected. In the RCs of Cab. thermophilum, three types of (bacterio)chlorophylls have previously been identified: bacteriochlorophyll a (BChl a), chlorophyll a (Chl a), and Zn bacteriochlorophyll a' (Zn-BChl a') (Tsukatani et al. in J Biol Chem 287:5720 5732, 2012). Based upon experimental and quantum chemical 15N NMR data, we assign the observed signals to a Chl a cofactor. We exclude Zn-BChl because of its measured spectroscopic properties. We conclude that Chl a is the primary electron acceptor, which implies that the primary donor is most likely Zn-BChl a'. Chl a and 81-OH Chl a have been shown to be the primary electron acceptors in green sulfur bacteria and heliobacteria, respectively, and thus a Chl a molecule serves this role in all known homodimeric type-1 RCs. PMID- 29603083 TI - First Development, Optimization, and Stability Control of a Pediatric Oral Atenolol Formulation. AB - Liquid formulations can be used in children of different ages by varying the volume of the administered dose in order to ensure an exact dosage. The aim of this work was to develop and to optimize a safe liquid atenolol formulation and to carry out the corresponding chemical and microbiological stability studies. A Plackett-Burman design was used to determine the factors that could be critical in the development of the formulations, and a central composite design was used to determine the optimal working conditions. As a result of these analyses, three formulations were selected and their stability studied in three storage conditions, 4, 25, and 40 degrees C. After 6 months of stability testing, the optimal systems showed no pH change or atenolol loss; however, only glycerin based formulations showed no microbial development. These systems, employing excipients in a range that the EMA has recommended, showed chemical and microbiological stability for at least 6 months even at the worst storage conditions. PMID- 29603084 TI - Multi-faceted Characterization of Wet-milled Griseofulvin Nanosuspensions for Elucidation of Aggregation State and Stabilization Mechanisms. AB - Characterization of wet-milled drug suspensions containing neutral polymer anionic surfactant as stabilizers poses unique challenges in terms of assessing the aggregation state and examining the stabilization mechanisms. Using a multi faceted characterization method, this study aims to assess the aggregation state of wet-milled griseofulvin (GF) nanosuspensions and elucidate the stabilization mechanisms and impact of stabilizers. Two grades, SSL and L, of hydroxypropyl cellulose (HPC) with molecular weights of 40 and 140 kg/mol, respectively, were used as a neutral stabilizer at concentrations varying from 0 to 7.5% (w/w) without and with 0.05% (w/w) sodium dodecyl sulfate (SDS). The aggregation state was examined via laser diffraction, scanning electron microscope (SEM) imaging, and rheometry. Zeta potential, stabilizer adsorption, surface tension, and drug wettability were used to elucidate the stabilization mechanisms. The results suggest that deviation from a uni-modal PSD and pronounced pseudoplasticity with power-law index lower than one signify severe aggregation. Polymer or surfactant alone was not able to prevent GF nanoparticle aggregation, whereas HPC-SDS combination led to synergistic stabilization. The effect of polymer concentration was explained mainly by the stabilizer adsorption and partly by surface tension. The synergistic stabilization afforded by HPC-SDS, traditionally explained by electrosteric mechanism, was attributed to steric stabilization provided by HPC and enhanced GF wettability/reduced surface tension provided by SDS. Zeta potential results could not explain the mitigation of aggregation by HPC-SDS. Overall, this study has demonstrated that the elucidation of the complex effects of HPC-SDS on GF nanosuspension stability entails a multi-faceted and comprehensive characterization approach. PMID- 29603085 TI - Risk assessment of bioaccessible arsenic and cadmium exposure through rice consumption in local residents of the Mae Tao Sub-district, Northwestern Thailand. AB - Consumption of contaminated rice is a toxin exposure route in Asian populations. Since total concentrations generally overestimate health risks, the objectives of this study were to determine the levels of bioaccessible As and Cd in rice cultivated in the Mae Tao, Tak Province and evaluate their potential health impacts in local adults. In total, 59 locally grown rice samples were analyzed for their total and bioaccessible concentrations. Bioaccessible concentrations were obtained from an in vitro digestion process. Inorganic As concentrations were estimated assuming that 63.2-63.5% of the total As is inorganic As. Rice contained inorganic As (45.2% of white rice and 57.1% of sticky rice) and Cd (51.6% of white rice and 32.1% of sticky rice) levels exceeding the Codex standards. The bioaccessibilities of As (16.3-70.0%) and Cd (Null to 83.7%) in rice varied widely. The concentrations of bioaccessible As, which were 1-1.2 times greater than those of bioaccessible Cd, indicate a higher possibility of As absorption into the human body. Positive significant relationships were found between total and bioaccessible As (R2 = 0.568 for white rice and R2 = 0.704 for sticky rice) and Cd (R2 = 0.874 for white rice and R2 = 0.862 for sticky rice). The hazard quotient (HQ) of inorganic As exposure accounted for approximately 93.4% of hazard index (HI). Approximately 2-6 in 10,000 residents over a lifetime of 75 years could suffer from cancer as a result of daily rice consumption. Therefore, the consumption of the home-grown rice in this study should be limited. PMID- 29603086 TI - Temporal and spatial variations of PM2.5 organic and elemental carbon in Central India. AB - This study describes spatiotemporal patterns from October 2015 to September 2016 for PM2.5 mass and carbon measurements in rural (Kosmarra), urban (Raipur), and industrial (Bhilai) environments, in Chhattisgarh, Central India. Twenty-four hour samples were acquired once every other week at the rural and industrial sites. Twelve-hour daytime and nighttime samples were acquired either a once a week or once every other week at the urban site. Each site was equipped with two portable, battery-powered, miniVol air samplers with PM2.5 inlets. Annual average PM2.5 mass concentrations were 71.8 +/- 27 ug m-3 at the rural site, 133 +/- 51 ug m-3 at the urban site, and 244.5 +/- 63.3 ug m-3 at the industrial site, ~ 2-6 times higher than the Indian Annual National Ambient Air Quality Standard of 40 ug m-3. Average monthly nighttime PM2.5 and carbon concentrations at the urban site were consistently higher than those of daytime from November 2015 to April 2016, when temperatures were low. Annual average total carbon (TC = OC + EC) at the urban (46.8 +/- 23.8 ug m-3) and industrial (98.0 +/- 17.2 ug m-3) sites also exceeded the Indian PM2.5 NAAQS. TC accounted for 30-40% of PM2.5 mass. Annual average OC ranged from 17.8 +/- 6.1 ug m-3 at the rural site to 64 +/- 9.4 ug m-3 at the industrial site, with EC ranging from 4.51 +/- 2.2 to 34.01 +/- 7.8 ug m 3. The average OC/EC ratio at the industrial site (1.88) was 18% lower than that at the urban site and 52% lower than that at the rural site. OC was attributed to 43.0% of secondary organic carbon (SOC) at the rural site, twice that estimated for the urban and industrial sites. Mortality burden estimates for PM2.5 EC are 4416 and 6196 excess deaths at the urban and industrial sites, respectively, during 2015-2016. PMID- 29603087 TI - Using the Children with Special Health Care Needs Screener with Immigrant Families: An Analysis of the National Survey of Children's Health. AB - Children in immigrant families are less likely to screen positive with the Children with Special Health Care Needs Screener (CSHCN-S). This may indicate that children in immigrant families are healthier or require fewer health services than non-immigrant peers. Alternatively, the screener may under-identify special healthcare needs in this population. Using the 2011-2012 National Survey of Children's Health, we examined the prevalence of a positive CSHCN-S among children from first, second, and third generation households with an equivalent number of currently diagnosed chronic conditions (0, 1, 2+). Multivariate analyses controlled for sociodemographic factors. Among children with an equivalent number of chronic conditions, fewer children from first and second generation households screened positive with the CSHCN-S relative to children from third generation households. This association remained after adjusting for covariates. The CSHCN Screener may under-identify children from immigrant households, allowing for missed opportunities to allocate health resources. PMID- 29603088 TI - Black-White Differences in Willingness to Participate and Perceptions About Health Research: Results from the Population-Based HealthStreet Study. AB - Health research participation of racial and ethnic minorities is significantly lower than their counterparts, impeding the testing and development of evidence based clinical and public health interventions for these populations. The purpose of this study was to determine African-Americans' (AAs) perceptions about health research, past participation in health research, and willingness to participate in health research studies compared to White adults from a large socio economically disadvantaged population. Community members ages 18 years or older enrolled in HealthStreet, an innovative community engagement research program comprised the source of study population. A total of 7809 community members (58.6% females) participated in the study with 65.8% AAs and 34.2% Whites. AAs were statistically significantly less likely to have previously participated in a research study, be willing to volunteer for any type of health research study, or to trust research or researchers compared to Whites. AAs also desired significantly higher compensation amounts to participate compared with Whites adults. In logistic regression analysis, education, age, gender, visits to healthcare practitioners and facilities were statistically significant predictors for AAs participation in health research. Keeping in view the findings of our study, clinical and public health researchers and practitioners should use special recruitment and retention strategies to increase the participation of AAs in health research studies. PMID- 29603089 TI - Neighborhood Racial Diversity and Metabolic Syndrome: 2003-2008 National Health and Nutrition Examination Survey. AB - This study investigated the independent association between neighborhood racial/ethnic diversity and metabolic syndrome among US adults, and focused on how this association differed across individual and neighborhood characteristics (i.e., race/ethnicity, sex, age, urbanity, neighborhood poverty). Objectively measured biomarker data from 2003 to 2008 National Health and Nutrition Examination Survey were linked to census-tract profiles from 2000 decennial census (N = 10,122). Multilevel random intercept logistic regression models were estimated to examine the contextual effects of tract-level racial/ethnic diversity on individual risks of metabolic syndrome. Overall, more than 20% of the study population were identified as having metabolic syndrome, although the prevalence also varied across demographic subgroups and specific biomarkers. Multilevel analyses showed that increased racial/ethnic diversity within a census tract was associated with decreased likelihood of having metabolic syndrome (OR 0.71, 95% CI 0.52-0.96), particularly among female (OR 0.64; 95% CI 0.43-0.96), young adults (OR 0.60; 95% CI 0.39-0.93), and residents living in urban (OR 0.67; 95% CI 0.48-0.93) or poverty neighborhoods (OR 0.54; 95% CI 0.31-0.95). The findings point to the potential benefits of neighborhood racial/ethnic diversity on individual health risks. PMID- 29603090 TI - Socioeconomic Status and Glycemic Index Among Punjabis in Kuala Lumpur, Malaysia: Possible Association with Metabolic Syndrome. AB - There are only limited reports on Punjabi's health status in Malaysia. This cross sectional study assessed the prevalence of metabolic syndrome (Mets) and its risk factors among 277 subjects recruited from the Malaysian Punjabi community. Overall prevalence of Mets was 43%, but 61% among females. Subjects classified with Mets had significantly (p < 0.05) higher body mass index, visceral fat and percentage of body fat. Daily carbohydrate and glycemic index (GI) were also higher among Mets subjects (p < 0.05). Logistics regression analysis showed that primary level of education (OR 5.57, CI 1.29-23.97, p = 0.021) was a factor associated with Mets, followed by middle household income (OR 2.30, CI 1.01-5.20, p = 0.046), GI (OR 1.03, CI 1.00-1.06, p = 0.026), and age (OR 1.03, CI 1.00 1.05, p = 0.023). Mets shows high prevalence among the studied Punjabi population, prompting the consideration of adequate preventive measures, primarily among lower socioeconomic groups. PMID- 29603091 TI - Platelet Proteomic Analysis Revealed Differential Pattern of Cytoskeletal- and Immune-Related Proteins at Early Stages of Alzheimer's Disease. AB - Platelets are considered a good model system to study a number of elements associated with neuronal pathways as they share biochemical similarities. Platelets represent the major source of amyloid-beta (Abeta) in blood contributing to the Abeta accumulation in the brain parenchyma and vasculature. Peripheral blood platelet alterations including cytoskeletal abnormalities, abnormal cytoplasmic calcium fluxes or increased oxidative stress levels have been related to Alzheimer's disease (AD) pathology. Therefore, platelets can be considered a peripheral model to study metabolic mechanisms occurring in AD. To investigate peripheral molecular alterations, we examined platelet protein expression in a cohort of 164 subjects, including mild cognitive impairment (MCI), and AD patients, and healthy aged-matched controls. A two-dimensional difference gel electrophoresis (2D-DIGE) discovery phase revealed significant differences between patients and controls in five proteins: talin, vinculin, moesin, complement C3b and Rho GDP, which are known to be involved in cytoskeletal regulation including focal adhesions, inflammation and immune functions. Western blot analysis verified that talin was found to be increased in mild and moderate AD groups versus control, while the other three were found to be decreased. We also analysed amyloid precursor protein (APP), amyloid-beta 1-40 (Abeta40) and 1-42 (Abeta42) levels in platelets from the same groups of subjects. Upregulation of platelet APP and Abeta peptides was found in AD patients compared to controls. These findings complement and expand previous reports concerning the morphological and functional alterations in AD platelets, and provide more insights into possible mechanisms that participate in the multifactorial and systemic damage in AD. PMID- 29603092 TI - MicroRNA Expression Levels Are Altered in the Cerebrospinal Fluid of Patients with Young-Onset Alzheimer's Disease. AB - Clinical diagnosis of Alzheimer's disease (AD) prior to the age of 65 years is classified as young-onset (YOAD), whereas diagnosis after the age of 65 years is considered late-onset (LOAD). Although rare autosomal mutations more commonly associate with YOAD, most YOAD and LOAD cases are sporadic. YOAD and LOAD share amyloid and tau pathology, but many YOAD patients show increased disease severity and rate of progression. The current study examined the microRNA (miRNA) expression profile from exosomes isolated from the cerebrospinal fluid (CSF) of YOAD patients with biomarker-confirmed AD. Results uncovered miR-16-5p, miR-125b 5p, miR-451a, and miR-605-5p as differentially expressed in the CSF-derived exosomes of YOAD patients when compared with healthy controls (HC). In a cohort of LOAD patients, miR-125b-5p, miR-451a, and miR-605-5p were similarly altered in expression, but miR-16-5p showed similar expression to control. Analysis of the mRNA targets of these miRNAs revealed transcripts enriched in biological processes relevant to the post-mortem posterior cingulate cortex transcriptome in YOAD from a previously published microarray study, including those related to neuron projections, synaptic signaling, metabolism, apoptosis, and the immune system. Hence, these miRNAs represent novel targets for uncovering disease mechanisms and for biomarker development in both YOAD and LOAD. PMID- 29603093 TI - Oxaliplatin Modulates the Characteristics of Voltage-Gated Calcium Channels and Action Potentials in Small Dorsal Root Ganglion Neurons of Rats. AB - Oxaliplatin is important for treating colorectal cancer. Although oxaliplatin is highly effective, it has severe side effects, of which neurotoxicity in dorsal root ganglion (DRG) neurons is one of the most common. The key mechanisms of this neurotoxicity are still controversial. However, disturbances of calcium homeostasis in DRG neurons have been suggested to mediate oxaliplatin neurotoxicity. By using whole-cell patch-clamp and current-clamp techniques, as well as immunocytochemical staining, we examined the influence of short- and long term exposure to oxaliplatin on voltage-gated calcium channels (VGCC) and different VGCC subtypes in small DRG neurons of rats in vitro. Exposure to oxaliplatin reduced VGCC currents (ICa(V)) in a concentration-dependent manner (1 500 MUM; 13.8-63.3%). Subtype-specific measurements of VGCCs showed differential effects on ICa(V). While acute treatment with oxaliplatin led to a reduction in ICa(V) for P/Q-, T-, and L-type VGCCs, ICa(V) of N-type VGCCs was not affected. Exposure of DRG neurons to oxaliplatin (10 or 100 MUM) for 24 h in vitro significantly increased the ICa(V) current density, with a significant influence on L- and T-type VGCCs. Immunostaining revealed an increase of L- and T-type VGCC protein levels in DRG neurons 24 h after oxaliplatin exposure. This effect was mediated by calcium-calmodulin-protein kinase II (CaMKII). Significant alterations in action potentials (AP) and their characteristics were also observed. While the amplitude increased after oxaliplatin treatment, the rise time and time-to-peak decreased, and these effects were reversed by treatment with pimozide and nimodipine, which suggests that VGCCs are critically involved in oxaliplatin-mediated neurotoxicity. PMID- 29603094 TI - HERC1 Ubiquitin Ligase Is Required for Normal Axonal Myelination in the Peripheral Nervous System. AB - A missense mutation in HERC1 provokes loss of cerebellar Purkinje cells, tremor, and unstable gait in tambaleante (tbl) mice. Recently, we have shown that before cerebellar degeneration takes place, the tbl mouse suffers from a reduction in the number of vesicles available for release at the neuromuscular junction (NMJ). The aim of the present work was to study to which extent the alteration in HERC1 may affect other cells in the nervous system and how this may influence the motor dysfunction observed in these mice. The functional analysis showed a consistent delay in the propagation of the action potential in mutant mice in comparison with control littermates. Morphological analyses of glial cells in motor axons revealed signs of compact myelin damage as tomacula and local hypermyelination foci. Moreover, we observed an alteration in non-myelinated terminal Schwann cells at the level of the NMJ. Additionally, we found a significant increment of phosphorylated Akt-2 in the sciatic nerve. Based on these findings, we propose a molecular model that could explain how mutated HERC1 in tbl mice affects the myelination process in the peripheral nervous system. Finally, since the myelin abnormalities found in tbl mice are histological hallmarks of neuropathic periphery diseases, tbl mutant mice could be considered as a new mouse model for this type of diseases. PMID- 29603096 TI - Phosphorus and species regulate N2 fixation by herbaceous legumes in longleaf pine savannas. AB - Longleaf pine savannas house a diverse community of herbaceous N2-fixing legume species that have the potential to replenish nitrogen (N) losses from fire. Whether legumes fill this role depends on the factors that regulate symbiotic fixation, including soil nutrients such as phosphorus (P) and molybdenum (Mo) and the growth and fixation strategies of different species. In greenhouse experiments, we determined how these factors influence fixation for seven species of legumes grown in pure field soil from two different regions of the southeastern US longleaf pine ecosystem. We first added P and Mo individually and in combination, and found that P alone constrained fixation. Phosphorus primarily influenced fixation by regulating legume growth. Second, we added N to plants and found that species either downregulated fixation (facultative strategy) or maintained fixation at a constant rate (obligate strategy). Species varied nearly fourfold in fixation rate, reflecting differences in growth rate, taxonomy and fixation strategy. However, fixation responded strongly to P addition across all species in our study, suggesting that the P cycle regulates N inputs by herbaceous legumes. PMID- 29603095 TI - Heritable plant phenotypes track light and herbivory levels at fine spatial scales. AB - Organismal phenotypes often co-vary with environmental variables across broad geographic ranges. Less is known about the extent to which phenotypes match local conditions when multiple biotic and abiotic stressors vary at fine spatial scales. Bittercress (Brassicaceae: Cardamine cordifolia), a perennial forb, grows across a microgeographic mosaic of two contrasting herbivory regimes: high herbivory in meadows (sun habitats) and low herbivory in deeply shaded forest understories (shade habitats). We tested for local phenotypic differentiation in plant size, leaf morphology, and anti-herbivore defense (realized resistance and defensive chemicals, i.e., glucosinolates) across this habitat mosaic through reciprocal transplant-common garden experiments with clonally propagated rhizomes. We found habitat-specific divergence in morphological and defensive phenotypes that manifested as contrasting responses to growth in shade common gardens: weak petiole elongation and attenuated defenses in populations from shade habitats, and strong petiole elongation and elevated defenses in populations from sun habitats. These divergent phenotypes are generally consistent with reciprocal local adaptation: plants from shade habitats that naturally experience low herbivory show reduced investment in defense and an attenuated shade avoidance response, owing to its ineffectiveness within forest understories. By contrast, plants from sun habitats with high herbivory show shade-induced elongation, but no evidence of attenuated defenses canonically associated with elongation in shade-intolerant plant species. Finally, we observed differences in flowering phenology between habitat types that could potentially contribute to inter-habitat divergence by reducing gene flow. This study illuminates how clonally heritable plant phenotypes track a fine-grained mosaic of herbivore pressure and light availability in a native plant. PMID- 29603097 TI - Correction to: Dynamic susceptibility contrast (DSC) perfusion MRI in differential diagnosis between radionecrosis and neoangiogenesis in cerebral metastases using rCBV, rCBF and K2. AB - In the original publication of the article, the name of the last author was incorrect. The correct name should read as given below. PMID- 29603098 TI - DNA methylation of genes regulating appetite and prediction of weight loss after bariatric surgery in obese individuals. AB - PURPOSE: Epigenetic traits are influenced by clinical variables; interaction between DNA methylation (DNAmeth) and bariatric surgery-induced weight loss has been scarcely explored. We investigated whether DNAmeth of genes encoding for molecules/hormones regulating appetite, food intake or obesity could predict successful weight outcome following Roux-en-Y gastric bypass (RYGB). METHODS: Forty-five obese individuals with no known comorbidities were stratified accordingly to weight decrease one-year after RYGB (excess weight loss, EWL >= 50%: good responders, GR; EWL < 50%: worse responders, WR). DNAmeth of leptin (LEP), ghrelin (GHRL), ghrelin receptor (GHSR) and insulin-growth factor-2 (IGF2) was assessed before intervention. Single nucleotide polymorphisms of genes affecting DNAmeth, DNMT3A and DNMT3B, were also determined. RESULTS: At baseline, type 2 diabetes was diagnosed by OGTT in 13 patients. Post-operatively, GR (n = 23) and WR (n = 22) achieved an EWL of 67.7 +/- 9.6 vs 38.2 +/- 9.0%, respectively. Baseline DNAmeth did not differ between GR and WR for any tested genes, even when the analysis was restricted to subjects with no diabetes. A relationship between GHRL and LEP methylation profiles emerged (r = 0.47, p = 0.001). Searching for correlation between DNAmeth of the studied genes with demographic characteristics and baseline biochemical parameters of the studied population, we observed a correlation between IGF2 methylation and folate (r = 0.44, p = 0.003). Rs11683424 for DNMT3A and rs2424913 for DNMT3B did not correlate with DNAmeth of the studied genes. CONCLUSIONS: In severely obese subjects, the degree of DNAmeth of some genes affecting obesity and related conditions does not work as predictor of successful response to RYGB. PMID- 29603099 TI - Selenium-Rich Yeast Protects Against Aluminum-Induced Renal Inflammation and Ionic Disturbances. AB - The aim of this study was to evaluate the protective effects of SeY (selenium rich yeast) against Al (aluminum)-induced inflammation and ionic imbalances. Male Kunming mice were treated with Al (10 mg/kg) and/or SeY (0.1 mg/kg) by oral gavage for 28 days. The degree of inflammation was assessed by mRNA expression of inflammatory biomarkers. Ionic disorders were assessed by determining the Na+, K+, and Ca2+ content, as well as the alteration in ATP-modifying enzymes (ATPases), including Na+K+-ATPase, Ca2+-ATPase, Mg2+-ATPase, Ca2+Mg2+-ATPase, and the mRNA levels of ATPase's subunits in kidney. It was observed here that SeY exhibited a significant protective effect on the kidney against the Al-induced upregulation of pro-inflammatory and downregulation of anti-inflammatory cytokines. Furthermore, a significant effect of Al on the Na+, K+, Ca2+, and Mg2+ levels in kidney was observed, and Al was observed to decrease the activities of Na+K+-ATPase, Mg2+-ATPase, and Ca2+Mg2+-ATPase. The mRNA expression of the Na+K+ ATPase subunits and Ca2+-ATPase subunits was regulated significantly by Al. Notably, SeY modulated the Al-induced alterations of ion concentrations, ATPase activity, and mRNA expression of their subunits. These results suggest that SeY prevents renal toxicity caused by Al via regulation of inflammatory responses, ATPase activities, and transcription of their subunits. PMID- 29603100 TI - Relationship of Dietary and Serum Zinc with Depression Score in Iranian Adolescent Girls. AB - Zinc deficiency, which is common among Iranian populations, is believed to play a crucial role in the onset and progression of mood disorders such as depression in different stages of life. We have therefore investigated the relationship between serum/dietary zinc status and depression scores among adolescent girls living in northeastern Iran. Serum zinc was measured by flame atomic absorption (Varian AA240FS) and the mean zinc intake was assessed using 3-day food record. A validated Persian version of the Beck Depression Inventory (BDI) was used to determine the severity of depressive symptoms for all subjects. Data were analyzed using SPSS 18 software. There was a statistically significant correlation between dietary zinc intake and serum zinc concentration (r = 0.117, p = 0.018). Dietary intake of zinc (7.04 +/- 4.28 mg/day) was significantly lower among subjects with mild to severe depression symptoms than those with no or minimal depression symptoms (8.06 +/- 3.03 mg/day). Dietary zinc intake was inversely correlated with depression score (r = 0.133, p = 0.008). However, there was no significant difference in serum zinc concentrations among individuals with no or minimal and mild to severe depression symptoms (p = 0.5). Dietary zinc intake, but not serum zinc concentration, was inversely associated with depression symptoms. Therefore, controlled clinical trials are needed to determine the efficacy of zinc supplementation in the treatment of depression disorders. PMID- 29603101 TI - Introducing and evaluating a knowledge transfer approach to support problem solving in and around protected areas. AB - Protected areas (PAs) can generate many benefits inside and outside their borders, and achieving objectives for diverse stakeholders raises many challenges. There are many examples of successful PA management around the globe, although a systematic and comprehensive approach to developing and sharing these solutions has been lacking. We present "solutioning" as a structured process of peer-learning, which can inform management strategies in and around protected areas. We explain how the PANORAMA-Solutions for a Healthy Planet initiative has put solutioning into practice through an interactive community and web portal to learn about protected area solutions around the globe. Unlike other web platforms and initiatives reviewed, PANORAMA facilitates adaptation of solution elements (i.e., building blocks) for novel implementation. Supported by theories of resilience and peer-learning, PANORAMA appears to have potential to promote efficiency and equitable benefits for PAs and associated stakeholders focused on nature conservation and sustainable development, although further research is needed to assess whether this learning leads to better solutions or more effective PA management. PMID- 29603102 TI - Soil surface Hg emission flux in coalfield in Wuda, Inner Mongolia, China. AB - Hg emission flux from various land covers, such as forests, wetlands, and urban areas, have been investigated. China has the largest area of coalfield in the world, but data of Hg flux of coalfields, especially, those with coal fires, are seriously limited. In this study, Hg fluxes of a coalfield were measured using the dynamic flux chamber (DFC) method, coupled with a Lumex multifunctional Hg analyzer RA-915+ (Lumex Ltd., Russia). The results show that the Hg flux in Wuda coalfield ranged from 4 to 318 ng m-2 h-1, and the average value for different areas varied, e.g., coal-fire area 99 and 177 ng m-2 h-1; no coal-fire area 19 and 32 ng m-2 h-1; and backfilling area 53 ng m-2 h-1. Hg continued to be emitted from an underground coal seam, even if there were no phenomena, such as vents, cracks, and smog, of coal fire on the soil surface. This phenomenon occurred in all area types, i.e., coal-fire area, no coal-fire area, and backfilling area, which is universal in Wuda coalfield. Considering that many coalfields in northern China are similar to Wuda coalfield, they may be large sources of atmospheric Hg. The correlations of Hg emission flux with influence factors, such as sunlight intensity, soil surface temperature, and atmospheric Hg content, were also investigated for Wuda coalfield. Graphical abstract ?. PMID- 29603103 TI - Screening of seaweeds in the East China Sea as potential bio-monitors of heavy metals. AB - Seaweeds are good bio-monitors of heavy metal pollution and have been included in European coastal monitoring programs. However, data for seaweed species in China are scarce or missing. In this study, we explored the potential of seaweeds as bio-monitor by screening the natural occurring seaweeds in the "Kingdom of seaweed and shellfish" at Dongtou Islands, the East China Sea. Totally, 12 seaweed species were collected from six sites, with richness following the sequence of Rhodophyta > Phaeophyta > Chlorophyta. The concentration of heavy metals (Cu, Cr, Ni, Zn, Pb, Cd, As) in the seaweeds was determined, and the bioaccumulation coefficient was calculated. A combination of four seaweeds, Pachydictyon coriaceum, Gelidium divaricatum, Sargassum thunbergii, and Pterocladiella capillacea, were proposed as bio-monitors due to their high bioaccumulation capabilities of specific heavy metals in the East China Sea and hence hinted the importance of using seaweed community for monitoring of pollution rather than single species. Our results provide first-hand data for the selection of bio-monitor species for heavy metals in the East China Sea and contribute to selection of cosmopolitan bio-monitor communities over geographical large area, which will benefit the establishment of monitoring programs for coastal heavy metal contamination. PMID- 29603104 TI - Modelling equilibrium adsorption of single, binary, and ternary combinations of Cu, Pb, and Zn onto granular activated carbon. AB - Elevated concentrations of heavy metals in water can be toxic to humans, animals, and aquatic organisms. A study was conducted on the removal of Cu, Pb, and Zn by a commonly used water treatment adsorbent, granular activated carbon (GAC), from three single, three binary (Cu-Pb, Cu-Zn, Pb-Zn), and one ternary (Cu-Pb-Zn) combination of metals. It also investigated seven mathematical models on their suitability to predict the metals adsorption capacities. Adsorption of Cu, Pb, and Zn increased with pH with an abrupt increase in adsorption at around pH 5.5, 4.5, and 6.0, respectively. At all pHs tested (2.5-7.0), the adsorption capacity followed the order Pb > Cu > Zn. The Langmuir and Sips models fitted better than the Freundlich model to the data in the single-metal system at pH 5. The Langmuir maximum adsorption capacities of Pb, Cu, and Zn (mmol/g) obtained from the model's fits were 0.142, 0.094, and 0.058, respectively. The adsorption capacities (mmol/g) for these metals at 0.01 mmol/L equilibrium liquid concentration were 0.130, 0.085, and 0.040, respectively. Ideal Adsorbed Solution (IAS)-Langmuir and IAS-Sips models fitted well to the binary and ternary metals adsorption data, whereas the Extended Langmuir and Extended Sips models' fits to the data were poor. The selectivity of adsorption followed the same order as the metals' capacities and affinities of adsorption in the single-metal systems. PMID- 29603105 TI - Metal accumulation in Raphanus sativus and Brassica rapa: an assessment of potential health risk for inhabitants in Punjab, Pakistan. AB - Pakistan is an agricultural country and due to the shortage of clean water, most of the irrigated area (32,500 ha) of Pakistan was supplied with wastewater (0.876 * 109 m3/year). Concentrations of heavy metals in radish (Raphanus sativus) and turnip (Brassica rapa) taken from vegetable fields in Sargodha, Pakistan, were measured. Untreated wastewater was used persistently for a long time to irrigate these vegetable fields. A control site was selected that had a history of fresh groundwater irrigation. Mean metal concentrations were found for irrigation water, soil, and vegetables. In irrigation water, concentrations of Mo and Pb at three sites and Se at sites II and III were higher than the recommended limits. In vegetables, concentrations of Mo and Pb were above the maximum permissible limits. High bioconcentration factor was observed for Zn (12.61 in R. sativus and 11.72 in B. rapa) at site I and high pollution load index was found for Pb (3.89 in R. sativus and 3.87 in B. rapa) at site II. The differences in metal concentrations found in samples depended upon different soil nature and assimilation capacities of vegetables at different sites which in turn depended upon different environmental cues. The entrance of metal and metalloids to human body may happen through different pathways; however, the food chain is the chief route through which metals are transferred from vegetables to individuals. Health risk index observed for metals, (Mo, As, Ni, Cu, and Pb) higher than 1 indicated high risk through consumption of these vegetables at three sites. PMID- 29603106 TI - Insect community composition and functional roles along a tropical agricultural production gradient. AB - High intensity agricultural production systems are problematic not only for human health and the surrounding environment, but can threaten the provision of ecosystem services on which farm productivity depends. This research investigates the effects of management practices in Costa Rica on on-farm insect diversity, using three different types of banana farm management systems: high-input conventional system, low-input conventional system, and organic system. Insect sampling was done using pitfall and yellow bowl traps, left for a 24-h period at two locations inside the banana farm, at the edge of the farm, and in adjacent forest. All 39,091 individual insects were classified to family level and then morphospecies. Insect species community composition and diversity were compared using multivariate statistics with ordination analysis and Monte Carlo permutation testing, and revealed that each of the management systems were significantly different from each other for both trap types. Insect diversity decreased as management intensity increased. Reduced insect diversity resulted in fewer functional groups and fewer insect families assuming different functions essential to ecosystem health. Organic farms had similar species composition on the farm compared to adjacent forest sites, whereas species composition increasingly differed between farm and forest sites as management intensity increased. We conclude that while organic production has minimal impact on insect biodiversity, even small reductions in management intensity can have a significantly positive impact on on-farm insect biodiversity and functional roles supported. PMID- 29603107 TI - Low-level laser irradiation at a high power intensity increased human endothelial cell exosome secretion via Wnt signaling. AB - The distinct role of low-level laser irradiation (LLLI) on endothelial exosome biogenesis remains unclear. We hypothesize that laser irradiation of high dose in human endothelial cells (ECs) contributes to the modulation of exosome biogenesis via Wnt signaling pathway. When human ECs were treated with LLLI at a power density of 80 J/cm2, the survival rate reduced. The potential of irradiated cells to release exosomes was increased significantly by expressing genes CD63, Alix, Rab27a, and b. This occurrence coincided with an enhanced acetylcholine esterase activity, pseudopodia formation, and reduced zeta potential value 24 h post irradiation. Western blotting showed the induction of LC3 and reduced level of P62, confirming autophagy response. Flow cytometry and electron microscopy analyses revealed the health status of the mitochondrial function indicated by normal DeltaPsi activity without any changes in the transcription level of PINK1 and Optineurin. When cells exposed to high power laser irradiation, p-Akt/Akt ratio and in vitro tubulogenesis capacity were blunted. PCR array and bioinformatics analyses showed the induction of transcription factors promoting Wnt signaling pathways and GTPase activity. Thus, LLLI at high power intensity increased exosome biogenesis by the induction of autophagy and Wnt signaling. LLLI at high power intensity increases exosome biogenesis by engaging the transcription factors related to Wnt signaling and autophagy stimulate. PMID- 29603109 TI - Use of Proton Pump Inhibitors and the Risk of Acute Kidney Injury Among Patients with Rheumatoid Arthritis: Cohort Study. AB - INTRODUCTION: Recent observational studies have indicated that use of proton pump inhibitors may be associated with adverse renal outcomes. The objective of this study was to investigate whether the use of proton pump inhibitors increases the risk of acute kidney injury among patients with rheumatoid arthritis. METHODS: We conducted the study as a historical prospective cohort study, including patients with rheumatoid arthritis, 30-84 years of age, during 2004-2015. Among these, we identified and matched episodes of use and non-use of proton pump inhibitors (control episodes) 1:4 on the propensity score, including 24,579 episodes of use of proton pump inhibitors and 98,230 control episodes. The primary outcome was a first diagnosis of acute kidney injury and the secondary outcome was any serious renal event (acute kidney injury or chronic kidney disease). The primary time point for analysis was 120 days after study entry. RESULTS: The incidence rate of acute kidney injury was 2.2 per 1000 person-years during episodes of use of proton pump inhibitors and 0.9 during control episodes. Use of proton pump inhibitors was associated with a significantly increased risk of acute kidney injury (hazard ratio 2.30, 95% confidence interval 1.26-4.20). The absolute risk difference was 40 (95% confidence interval 8-99) events of acute kidney injury per 100,000 episodes of use of proton pump inhibitors. Use of proton pump inhibitors was also associated with a significantly increased risk of the secondary outcome of any serious renal event (hazard ratio 2.61, 95% confidence interval 1.80-3.80). CONCLUSIONS: This cohort study among patients with rheumatoid arthritis found a significantly increased risk of acute kidney injury associated with the use of proton pump inhibitors. These findings may help inform clinical decision making when considering the risks and benefits of proton pump inhibitor treatment in rheumatoid arthritis. PMID- 29603108 TI - Should open excisions and sutured incisions be treated differently? A review and meta-analysis of animal wound models following low-level laser therapy. AB - Although low-level laser therapy (LLLT) was discovered already in the 1960s of the twentieth century, it took almost 40 years to be widely used in clinical dermatology/surgery. It has been demonstrated that LLLT is able to increase collagen production/wound stiffness and/or improve wound contraction. In this review, we investigated whether open and sutured wounds should be treated with different LLLT parameters. A PubMed search was performed to identify controlled studies with LLLT applied to wounded animals (sutured incisions-tensile strength measurement and open excisions-area measurement). Final score random effects meta analyses were conducted. Nineteen studies were included. The overall result of the tensile strength analysis (eight studies) was significantly in favor of LLLT (SMD = 1.06, 95% CI 0.66-1.46), and better results were seen with 30-79 mW/cm2 infrared laser (SMD = 1.44, 95% CI 0.67-2.21) and 139-281 mW/cm2 red laser (SMD = 1.52, 95% CI 0.54-2.49). The overall result of the wound contraction analysis (11 studies) was significantly in favor of LLLT (SMD = 0.99, 95% CI 0.38-1.59), and the best results were seen with 53-300 mW/cm2 infrared laser (SMD = 1.18, 95% CI 0.41-1.94) and 25-90 mW/cm2 red laser (SMD = 1.6, 95% CI 0.27-2.93). Whereas 1-15 mW/cm2 red laser had a moderately positive effect on sutured wounds, 2-4 mW/cm2 red laser did not accelerate healing of open wounds. LLLT appears effective in the treatment of sutured and open wounds. Statistical heterogeneity indicates that the tensile strength development of sutured wounds is more dependent on laser power density compared to the contraction rate of open wounds. PMID- 29603111 TI - Perceived Social Norms About Oral PrEP Use: Differences Between African-American, Latino and White Gay, Bisexual and Other Men Who Have Sex with Men in Texas. AB - Correct and consistent condom use has been the primary method of HIV prevention until the FDA approve the use of PrEP in 2012. While strong evidence existing regarding the efficacy of PrEP, uptake has remained slower than anticipated. While work is underway to better understand the factors impacting uptake, the majority of this work as been focused on white gay, bisexual, and other men who have sex with men (GBMSM) living in metropolitan regions of the coastal U.S. The current study used a community-based framework to assess perceived social norms through a elicitation survey. A total of 104 GBMSM met inclusion criteria for the study. Several analytic categories emerged across questions and a number of differences were found across race and ethnicity such as who would approve or disapprove off PrEP and who would be likely to use PrEP. Further, we found differences between injunctive and descriptive norms. These findings suggest that there are unique factors contributing to PrEP uptake among racial and ethnic minority GBMSM and that to fully understand uptake a more robust measure of perceived norms may be needed. PMID- 29603110 TI - Patterns of Gender-Based Violence and Associations with Mental Health and HIV Risk Behavior Among Female Sex Workers in Mombasa, Kenya: A Latent Class Analysis. AB - Gender-based violence (GBV) is common among female sex workers (FSWs) and is associated with multiple HIV risk factors, including poor mental health, high risk sexual behavior, and sexually transmitted infections (STIs). Prior studies have focused on GBV of one type (e.g. physical or sexual) or from one kind of perpetrator (e.g., clients or regular partners), but many FSWs experience overlapping types of violence from multiple perpetrators, with varying frequency and severity. We examined the association between lifetime patterns of GBV and HIV risk factors in 283 FSWs in Mombasa, Kenya. Patterns of GBV were identified with latent class analysis based on physical, sexual, or emotional violence from multiple perpetrators. Cross-sectional outcomes included depressive symptoms, post-traumatic stress disorder (PTSD) symptoms, disordered alcohol and other drug use, number of sex partners, self-reported unprotected sex, prostate-specific antigen (PSA) in vaginal secretions, and a combined unprotected sex indicator based on self-report or PSA detection. We also measured HIV/STI incidence over 12 months following GBV assessment. Associations between GBV patterns and each outcome were modeled separately using linear regression for mental health outcomes and Poisson regression for sexual risk outcomes. Lifetime prevalence of GBV was 87%. We identified 4 GBV patterns, labeled Low (21% prevalence), Sexual (23%), Physical/Moderate Emotional (18%), and Severe (39%). Compared to women with Low GBV, those with Severe GBV had higher scores for depressive symptoms, PTSD symptoms, and disordered alcohol use, and had more sex partners. Women with Sexual GBV had higher scores for disordered alcohol use than women with Low GBV, but similar sexual risk behavior. Women with Physical/Moderate Emotional GBV had more sex partners and a higher prevalence of unprotected sex than women with Low GBV, but no differences in mental health. HIV/STI incidence did not differ significantly by GBV pattern. The prevalence of GBV was extremely high in this sample of Kenyan FSWs, and different GBV patterns were associated with distinct mental health and sexual risk outcomes. Increased understanding of how health consequences vary by GBV type and severity could lead to more effective programs to reduce HIV risk in this vulnerable population. PMID- 29603112 TI - Identifying Spatial Variation Along the HIV Care Continuum: The Role of Distance to Care on Retention and Viral Suppression. AB - Distance to HIV care may be associated with retention in care (RIC) and viral suppression (VS). RIC (>= 2 HIV visits or labs >= 90 days apart in 12 months), prescribed antiretroviral therapy (ART), VS (< 200 copies/mL at last visit) and distance to care were estimated among 3623 DC Cohort participants receiving HIV care in 13 outpatient clinics in Washington, DC in 2015. Logistic regression models and geospatial statistics were computed. RIC was 73%; 97% were on ART, among whom 77% had VS. ZIP code-level clusters of low RIC and high VS were found in Northwest DC, and low VS in Southeast DC. Those traveling >= 5 miles had 30% lower RIC (adjusted odds ratio (aOR) 0.71, 95% CI 0.58, 0.86) and lower VS (OR 0.70, 95% CI 0.52, 0.94). Geospatial clustering of RIC and VS was observed, and distance may be a barrier to optimal HIV care outcomes. PMID- 29603114 TI - Maternal quality of life in routine labor epidural analgesia versus labor analgesia on request: results of a randomized trial. AB - INTRODUCTION: The purpose of this study was to evaluate the changes in maternal quality of life (QOL) from pregnancy to 6 weeks after delivery between routine labor epidural analgesia (EA) and pain relief on maternal request only. METHODS: ?Women delivering of a singleton in cephalic presentation beyond 36 + 0 weeks' gestation were randomly allocated to EA as a routine during labor (routine EA group), or to any kind of analgesia on request only (control group). The Short Form health survey (SF-36) was used to assess women's QOL before randomization, and 6 weeks postpartum. Data were analyzed according to the intention to treat principle. RESULTS: A total of 488 women were included, and antepartum as well as postpartum SF-36 questionnaires were filled in by 356 (73.0%) women, 176 (49.4%) in the routine EA group, and 180 (50.6%) in the control group. Changes from the QOL antepartum to the QOL 6 weeks postpartum were comparable between both groups, also in the subgroup of women in the control group who gave birth without any pain medication (n = 41, 22.8%). Maternal age and the incidence of adverse events related to EA, which were both higher in the routine EA group, had no influence on the changes in QOL. Differences in request for pain relief were comparable with other studies. CONCLUSION: Routine administration of EA during labor and pain relief on maternal request only are associated with comparable changes of women's QOL antepartum to 6 weeks postpartum. PMID- 29603115 TI - Chinese Children's Knowledge of Topicalization: Experimental Evidence from a Comprehension Study. AB - There is a debate as to whether topic structures in Chinese involve A'-movement or result from base-generation of the topic in the left periphery. If Chinese topicalization was derived by movement, under the assumptions of Friedmann et al.'s Relativized Minimality (Lingua 119:67-88, 2009), we would expect children's comprehension of object topicalization (with OSV order) to be worse than their comprehension of subject topicalization (with SVO order). This study examined 146 Mandarin-speaking children from age three to age six by means of a picture sentence matching task with an appropriate context. The results showed a subject/object asymmetry when the topic marker is overt, and no asymmetry when the topic marker is covert. This suggests that the presence or absence of topic markers play an important role in children's comprehension of topicalization. We propose that both structures involve movement in the adult grammar, but not in the child grammar, at least initially. Sentences without overt topic markers are base-generated on a par with gapless sentences with a topic, and the base generation analysis is abandoned as soon as children learn the syntax and semantics of topic markers, which function as attractors of topics. PMID- 29603113 TI - Fucoxanthin Elicits Epigenetic Modifications, Nrf2 Activation and Blocking Transformation in Mouse Skin JB6 P+ Cells. AB - Nuclear factor erythroid-2-related factor-2 (Nrf2 or NFE2L2) is a master regulator of the anti-oxidative stress response, which is involved in the defense against many oxidative stress/inflammation-mediated diseases, including anticancer effects elicited by an increasing number of natural products. Our previous studies showed that the epigenetic modification of the Nrf2 gene plays a key role in restoring the expression of Nrf2. In this study, we aimed to investigate the epigenetic regulation of Nrf2 by astaxanthin (AST) and fucoxanthin (FX), carotenoids which are abundant in microalgae and seaweeds, in mouse skin epidermal JB6 P+ cells. FX induced the anti-oxidant response element (ARE)-luciferase and upregulated the mRNA and protein levels of Nrf2 and Nrf2 downstream genes in HepG2-C8 cells overexpressing the ARE-luciferase reporter. Both FX and AST decreased colony formation in 12-Otetradecanoylphorbol-13-acetate (TPA)-induced transformation of JB6 P+ cells. FX decreased the methylation of the Nrf2 promoter region in the JB6 P+ cells by the bisulfite conversion and pyrosequencing. Both FX and AST significantly reduced DNA methyltransferase (DNMT) activity but did not affect histone deacetylase (HDAC) activity in JB6 P+ cells. In summary, our results show that FX activates the Nrf2 signaling pathway, induces the epigenetic demethylation of CpG sites in Nrf2 and blocks the TPA induced transformation of JB6 P+ cells, indicating the potential health-promoting effects of FX in skin cancer prevention. PMID- 29603117 TI - Neurocognitive mechanisms behind emotional attention: Inverse effects of anodal tDCS over the left and right DLPFC on gaze disengagement from emotional faces. AB - BACKGROUND: Attention to relevant emotional information in the environment is an important process related to vulnerability and resilience for mood and anxiety disorders. In the present study, the effects of left and right dorsolateral prefrontal cortex (i.e., DLPFC) stimulation on attentional mechanisms of emotional processing were tested and contrasted. METHODS: A sample of 54 healthy participants received 20 min of active and sham anodal transcranial direct current stimulation (i.e., tDCS) either of the left (n = 27) or of the right DLPFC (n = 27) on two separate days. The anode electrode was placed over the left or the right DLPFC, the cathode over the corresponding contra lateral supraorbital area. After each neurostimulation session, participants completed an eye-tracking task assessing direct processes of attentional engagement towards and attentional disengagement away from emotional faces (happy, disgusted, and sad expressions). RESULTS: Compared to sham, active tDCS over the left DLPFC led to faster gaze disengagement, whereas active tDCS over the right DLPFC led to slower gaze disengagement from emotional faces. Between-group comparisons showed that such inverse change patterns were significantly different and generalized for all types of emotion. CONCLUSIONS: Our findings support a lateralized role of left and right DLPFC activity in enhancing/worsening the top-down regulation of emotional attention processing. These results support the rationale of new therapies for affective disorders aimed to increase the activation of the left over the right DLPFC in combination with attentional control training, and identify specific target attention mechanisms to be trained. PMID- 29603116 TI - Methylene Blue Counteracts H2S-Induced Cardiac Ion Channel Dysfunction and ATP Reduction. AB - We have previously demonstrated that methylene blue (MB) counteracts the effects of hydrogen sulfide (H2S) cardiotoxicity by improving cardiomyocyte contractility and intracellular Ca2+ homeostasis disrupted by H2S poisoning. In vivo, MB restores cardiac contractility severely depressed by sulfide and protects against arrhythmias, ranging from bundle branch block to ventricular tachycardia or fibrillation. To dissect the cellular mechanisms by which MB reduces arrhythmogenesis and improves bioenergetics in myocytes intoxicated with H2S, we evaluated the effects of H2S on resting membrane potential (Em), action potential (AP), Na+/Ca2+ exchange current (INaCa), depolarization-activated K+ currents and ATP levels in adult mouse cardiac myocytes and determined whether MB could counteract the toxic effects of H2S on myocyte electrophysiology and ATP. Exposure to toxic concentrations of H2S (100 uM) significantly depolarized Em, reduced AP amplitude, prolonged AP duration at 90% repolarization (APD90), suppressed INaCa and depolarization-activated K+ currents, and reduced ATP levels in adult mouse cardiac myocytes. Treating cardiomyocytes with MB (20 ug/ml) 3 min after H2S exposure restored Em, APD90, INaCa, depolarization-activated K+ currents, and ATP levels toward normal. MB improved mitochondrial membrane potential (?psim) and oxygen consumption rate in myocytes in which Complex I was blocked by rotenone. We conclude that MB ameliorated H2S-induced cardiomyocyte toxicity at multiple levels: (1) reversing excitation-contraction coupling defects (Ca2+ homeostasis and L-type Ca2+ channels); (2) reducing risks of arrhythmias (Em, APD, INaCa and depolarization-activated K+ currents); and (3) improving cellular bioenergetics (ATP, ?psim). PMID- 29603119 TI - The 'other' London effect: the diversification of London's suburban grammar schools and the rise of hyper-selective elite state schools. AB - This paper examines the rise of a new elite of 'super-state' schools in London, revealing a growing divide within the state sector which problematizes claims that the capital is a 'hotspot' for social mobility (Social Mobility Commission ). Although recent research has revealed a 'London effect' in which students in the capital on Free School Meals outperform their peers in other regions (Greaves, Macmillan and Sibieta ), inequalities between London's schools in access to elite universities have been overlooked. Drawing on a case study of a suburban London grammar school, 'King Henry's School', I show how ethnic-minority suburbanization has combined with an institutional strategy to compete with elite private schools. Strategies of selection have been mobilized alongside elements of elite 'gentlemanly' educational culture in order to reposition the school within the hierarchy of London's schools. The result is a hyper-selective school which provides a conduit to elite universities for upwardly mobile British-Asian students. I show that this strategy has strong parallels with the school's attempts in the early twentieth century to compete with London's fee-paying 'public' schools. The continuing symbolic value of 'traditional' forms of elite educational culture to a school seeking to reposition itself within the field reflects deep structural patterns of inequality in English education. To understand how apparent improvements in social mobility can sit alongside deepening inequalities between state schools, there is a need for a historical sociological approach that takes account of long-term processes of institutional change (Savage ; Inglis ). PMID- 29603118 TI - Magnetic resonance imaging of vaginal support structure before and after Vecchietti procedure in women with Mayer-Rokitansky-Kuster-Hauser syndrome. AB - INTRODUCTION: It is unclear how pelvic floor supporting structures might be affected by the absence of the vagina. It was the aim of this prospective study to analyze the magnetic resonance imaging morphology of pelvic support prior and after a Vecchietti procedure in women suffering Mullerian agenesis (Mayer Rokitansky-Kuster-Hauser syndrome). MATERIAL AND METHODS: 26 women with a diagnosis of Mayer-Rokitansky-Kuster-Hauser syndrome associated vaginal agenesis were recruited prospectively prior to the laparoscopic creation of a neovagina according to the Vecchietti procedure. The primary outcome measure was the magnetic resonance imaging morphology of supporting structures. Secondary outcome measures were anatomical and functional vaginal length. Follow up was conducted six months after surgery. RESULTS: Twenty-six women were analyzed. Mean age was 19.8 +/- 4.4 years (+/-SD) and mean body mass index was 23.7 +/- 4.3 kg/m2 (+/ SD). All were Caucasian. Supporting structures consistent with cardinal and uterosacral ligaments were visible on magnetic resonance imaging in all cases (100%). There were no levator ani defects. The vaginal apex could be visualized postoperatively in 12 women (46.2%) reaching up to Level I. The vagina was visible in both Level II and III with normal relations to the pelvic walls in all cases. On gynecological examination, vaginal length was 8.8 +/- 2.1 cm (mean +/- SD) anatomically and 10.2 +/- 2.2 cm (mean +/- SD) functionally. CONCLUSIONS: The preoperative presence of pelvic support structures into which the vagina is lengthened by the surgery likely explains the uncommon occurrence of vaginal prolapse in women who had the Vecchietti procedure. PMID- 29603120 TI - Analysis of sports-relevant polymorphisms in a large Brazilian cohort of top level athletes. AB - In recent years, there have been an increasing number of genetic variants associated with athletic phenotypes. Here, we selected a set of sports-relevant polymorphisms that have been previously suggested as genetic markers for human physical performance, and we examined their association with athletic status in a large cohort of Brazilians. We evaluated a sample of 1,622 individuals, in which 966 were nonathletes, and 656 were athletes: 328 endurance athletes and 328 power athletes. Only the AGT M268T minor allele was nominally associated with the endurance status. Conversely, we found that seven polymorphisms are more frequent in power athletes (MCT1 D490E, AGT M268T, PPARG P12A, PGC1A G482S, VEGFR2 Q472H, NOS3 C/T, and ACTN3 R577X). For all of these polymorphisms, power athletes were more likely than nonathletes or endurance athletes to carry the major allele or the homozygous genotype for the major allele. In particular, MCT1 D490E, AGT M268T, NOS3 C/T, and ACTN3 R577X showed stronger associations. Our findings support a role for these variants in the achievement of power athletic status in Brazilians: MCT1 D490E (T allele), AGT M268T (G allele), PPARG (C allele), PGC1A G482S (C allele), VEGFR2 Q472H (T allele), NOS3 C/T (T allele), and ACTN3 R577X (R allele). PMID- 29603121 TI - Mobility closure in the upper class: assessing time and forms of capital. AB - Most understandings of the ways classes become social groupings centre on processes of mobility closure whereby mutual appreciation and recognition within classes arise from homogenous experiences over time. The mapping of such structured biographies, however, remains understudied. This paper explores intra- and intergenerational mobility patterns in the upper strata of the Norwegian class structure and aims to include temporal processes and multiple forms of capital in the quantification of class trajectories. By combining multiple correspondence analysis and social sequence analysis, two important but often neglected aspects of recruitment to the upper class are emphasized: first, by introducing multiple forms of capital, different ways of maintaining mobility closure are demonstrated; second, different pathways to power are highlighted by distinguishing between divergent class careers. A key aim of the analysis is to explore internal divisions within the upper class in forms of parental capital (an 'origin space') and link these divisions to a typology of 'destination careers' in adulthood. The analysis suggests that individuals from modest origins are more likely to have careers that feature a biographically late arrival and/or short-term affiliations to upper-class positions whereas individuals from families rich in capital are more likely to have stable careers in the upper class fractions from which they originate. The analysis thus reveals important divisions in the trajectories of Norwegians who reach the upper class; not only are there differences in their upbringing in terms of the availability of different amounts and types of capital but such divisions also seem linked to their own class careers later in adulthood. PMID- 29603122 TI - Postconditioning effects of argon or xenon on early graft function in a porcine model of kidney autotransplantation. AB - BACKGROUND: Ischaemia-reperfusion injury is inevitable during renal transplantation and can lead to delayed graft function and primary non-function. Preconditioning, reconditioning and postconditioning with argon and xenon protects against renal ischaemia-reperfusion injury in rodent models. The hypothesis that postconditioning with argon or xenon inhalation would improve graft function in a porcine renal autotransplant model was tested. METHODS: Pigs (n = 6 per group) underwent left nephrectomy after 60 min of warm ischaemia (renal artery and vein clamping). The procured kidney was autotransplanted in a separate procedure after 18 h of cold storage, immediately after a right nephrectomy. Upon reperfusion, pigs were randomized to inhalation of control gas (70 per cent nitrogen and 30 per cent oxygen), argon (70 per cent and 30 per cent oxygen) or xenon (70 per cent and 30 per cent oxygen) for 2 h. The primary outcome parameter was peak plasma creatinine; secondary outcome parameters included further markers of graft function (creatinine course, urine output), graft injury (aspartate aminotransferase, heart-type fatty acid-binding protein, histology), apoptosis and autophagy (western blot, terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) staining), inflammatory mediators and markers of cell survival/growth (mRNA and tissue protein quantification), and animal survival. Results are presented as median (i.q.r.). ANOVA and Kruskal Wallis tests were used where indicated. RESULTS: Peak plasma creatinine levels were similar between the groups: control 20.8 (16.4-23.1) mg/dl, argon 21.4 (17.1 24.9) mg/dl and xenon 19.4 (17.5-21.0) mg/dl (P = 0.607). Xenon was associated with an increase in autophagy and proapoptotic markers. Creatinine course, urine output, injury markers, histology, survival and inflammatory mediators were not affected by the intervention. CONCLUSION: Postconditioning with argon or xenon did not improve kidney graft function in this experimental model. Surgical relevance Ischaemia-reperfusion injury is inevitable during renal transplantation and can lead to delayed graft function and primary non-function. Based on mainly small animal experiments, noble gases (argon and xenon) have been proposed to minimize this ischaemia-reperfusion injury and improve outcomes after transplantation. The hypothesis that postconditioning with argon or xenon inhalation would improve graft function was tested in a porcine kidney autotransplantation model. The peak plasma creatinine concentration was similar in the control, argon and xenon groups. No other secondary outcome parameters, including animal survival, were affected by the intervention. Xenon was associated with an increase in autophagy and proapoptotic markers. Despite promising results in small animal models, postconditioning with argon or xenon in a translational model of kidney autotransplantation was not beneficial. Clinical trials would require better results. PMID- 29603123 TI - Exploring the impact of teacher emotions on their approaches to teaching: A structural equation modelling approach. AB - BACKGROUND: Research into teacher emotion has attracted increasing attention in the last two decades. The relevance of teacher emotion in education has been highlighted. However, evidence of how teacher emotions impact their teaching approaches is rather limited. AIMS: This study investigated the relationship between two self-report instruments - the Teacher Emotion Inventory and the Approach to Teaching. SAMPLE: There were 1,830 teachers were approached from 43 primary schools in China and 12 primary schools in Hong Kong. METHODS: Exploratory factor analysis, confirmatory factor analysis, and structural equation modelling were utilized in the analysis procedure. RESULTS: As a result, a five-factor TEI model was identified with two positive factors (Joy and Love) and three negative factors (Sadness, Anger, and Fear). A ATI model involved was confirmed with three factors (Knowledge Transmission, Student-Teacher Interaction, and Student Focus). Structural equation modelling demonstrated that more student-centred approaches are the consequence of positive teacher emotions while a teacher-centred approach is the consequence of negative teacher emotions although there are two surprising links. CONCLUSIONS: Identifying this pattern of relationships will contribute to understanding the reasons why new teaching strategies are often not adopted despite well-designed professional programs and educational reform and will provide implications for teaching improvement through teacher emotion. PMID- 29603125 TI - Molecular determinants of the interaction of EGCG with ordered and disordered proteins. AB - The aggregation process of peptides and proteins is of great relevance as it is associated with a wide range of highly debilitating disorders, including Alzheimer's and Parkinson's diseases. The natural product (-)-epigallocatechin-3 gallate (EGCG) can redirect this process away from amyloid fibrils and towards non-toxic oligomers. In this study we used nuclear magnetic resonance (NMR) spectroscopy to characterize the binding of EGCG to a set of natively structured and unstructured proteins. The results show that the binding process is dramatically dependent on the conformational properties of the protein involved, as EGCG interacts with different binding modes depending on the folding state of the protein. We used replica exchange molecular dynamics simulations to reproduce the trends observed in the NMR experiments, and analyzed the resulting samplings to identify the dominant direct interactions between EGCG and ordered and disordered proteins. PMID- 29603124 TI - Comparison of two ancient DNA extraction protocols for skeletal remains from tropical environments. AB - OBJECTIVES: The tropics harbor a large part of the world's biodiversity and have a long history of human habitation. However, paleogenomics research in these climates has been constrained so far by poor ancient DNA yields. Here we compare the performance of two DNA extraction methods on ancient samples of teeth and petrous portions excavated from tropical and semi-tropical sites in Tanzania, Mexico, and Puerto Rico (N = 12). MATERIALS AND METHODS: All samples were extracted twice, built into double-stranded sequencing libraries, and shotgun sequenced on the Illumina HiSeq 2500. The first extraction protocol, Method D, was previously designed for recovery of ultrashort DNA fragments from skeletal remains. The second, Method H, modifies the first by adding an initial EDTA wash and an extended digestion and decalcification step. RESULTS: No significant difference was found in overall ancient DNA yields or post-mortem damage patterns recovered from samples extracted with either method, irrespective of tissue type. However, Method H samples had higher endogenous content and more mapped reads after quality-filtering, but also higher clonality. In contrast, samples extracted with Method D had shorter average DNA fragments. DISCUSSION: Both methods successfully recovered endogenous ancient DNA. But, since surviving DNA in ancient or historic remains from tropical contexts is extremely fragmented, our results suggest that Method D is the optimal choice for working with samples from warm and humid environments. Additional optimization of extraction conditions and further testing of Method H with different types of samples may allow for improvement of this protocol in the future. PMID- 29603126 TI - Thirty-day mortality in patients undergoing laparotomy for small bowel obstruction. AB - BACKGROUND: Small bowel obstruction (SBO) is a common indication for emergency laparotomy. There are currently variations in the timing of surgery for patients with SBO and limited evidence on whether delayed surgery affects outcomes. The aim of this study was to evaluate the impact of time to operation on 30-day mortality in patients requiring emergency laparotomy for SBO. METHODS: Data were collected from the National Emergency Laparotomy Audit (NELA) on all patients aged 18 years or older who underwent emergency laparotomy for all forms of SBO between December 2013 and November 2015. The primary outcome measure was 30-day mortality, with date of death obtained from the Office for National Statistics. Patients were grouped according to the time from admission to surgery (less than 24 h, 24-72 h and more than 72 h). A multilevel logistic regression model was used to explore the impact of patient factors, primarily delay to surgery, on 30 day mortality. RESULTS: Some 9991 patients underwent emergency laparotomy requiring adhesiolysis or small bowel resection for SBO. The overall mortality rate was 7.2 per cent (722 patients). Within each time group, 30-day mortality rates were significantly worse with increasing age, ASA grade, Portsmouth POSSUM score and level of contamination. Patients undergoing emergency laparotomy more than 72 h after admission had a significantly higher risk-adjusted 30-day mortality rate (odds ratio 1.39, 95 per cent c.i. 1.09 to 1.76). CONCLUSION: In patients who require an emergency laparotomy with adhesiolysis or resection for SBO, a delay to surgery of more than 72 h is associated with a higher 30-day postoperative mortality rate. PMID- 29603127 TI - The role of whole-brain radiation therapy in patients with cerebral metastases. PMID- 29603128 TI - Kaposiform haemangioendothelioma: clinical features, complications and risk factors for Kasabach-Merritt phenomenon. AB - BACKGROUND: Few studies have reported the clinical features, complications and predictors of Kasabach-Merritt phenomenon (KMP) associated with Kaposiform haemangioendothelioma (KHE). OBJECTIVES: To determine the clinical characteristics present at diagnosis and to identify features that may aid clinicians in managing KHE. METHODS: We conducted a cohort study of 146 patients diagnosed with KHE. RESULTS: KHE precursors or lesions were present at birth in 52.1% of patients. In 91.8% of patients, lesions developed within the first year of life. The median age at diagnosis of KHE was 2.3 months (interquartile range 1.0-6.0). The extremities were the dominant location, representing 50.7% of all KHEs. Among KHEs in the cohort, 63.0% were mixed lesions (cutaneous lesions with deep infiltration). Approximately 70% of patients showed KMP. A KHE diagnosis was delayed by >= 1 month in 65.7% of patients with KMP. Patients with KMP were more likely to have major complications than patients without KMP (P = 0.023). Young age (< 6 months), trunk location, large lesion size (> 5.0 cm) and mixed lesion type were associated with KMP in a univariate analysis. In the multivariate analysis, only age [odds ratio (OR) 11.9, 95% confidence interval (CI) 4.07-34.8; P < 0.001], large lesion size (OR 5.08, 95% CI 2.24-11.5; P < 0.001) and mixed lesion type (OR 2.96, 95% CI 1.23-7.13; P = 0.016) were associated with KMP. CONCLUSIONS: Most KHEs appeared before 12 months of age. KHEs are associated with various major complications, which can occur in combination and develop early in the disease process. Young age, large lesion size and mixed lesion type are important predictors of KMP. PMID- 29603130 TI - Multicentre randomized clinical trial of inspiratory muscle training versus usual care before surgery for oesophageal cancer. AB - BACKGROUND: Up to 40 per cent of patients undergoing oesophagectomy develop pneumonia. The aim of this study was to assess whether preoperative inspiratory muscle training (IMT) reduces the rate of pneumonia after oesophagectomy. METHODS: Patients with oesophageal cancer were randomized to a home-based IMT programme before surgery or usual care. IMT included the use of a flow-resistive inspiratory loading device, and patients were instructed to train twice a day at high intensity (more than 60 per cent of maximum inspiratory muscle strength) for 2 weeks or longer until surgery. The primary outcome was postoperative pneumonia; secondary outcomes were inspiratory muscle function, lung function, postoperative complications, duration of mechanical ventilation, length of hospital stay and physical functioning. RESULTS: Postoperative pneumonia was diagnosed in 47 (39.2 per cent) of 120 patients in the IMT group and in 43 (35.5 per cent) of 121 patients in the control group (relative risk 1.10, 95 per cent c.i. 0.79 to 1.53; P = 0.561). There was no statistically significant difference in postoperative outcomes between the groups. Mean(s.d.) maximal inspiratory muscle strength increased from 76.2(26.4) to 89.0(29.4) cmH2 O (P < 0.001) in the intervention group and from 74.0(30.2) to 80.0(30.1) cmH2 O in the control group (P < 0.001). Preoperative inspiratory muscle endurance increased from 4 min 14 s to 7 min 17 s in the intervention group (P < 0.001) and from 4 min 20 s to 5 min 5 s in the control group (P = 0.007). The increases were highest in the intervention group (P < 0.050). CONCLUSION: Despite an increase in preoperative inspiratory muscle function, home-based preoperative IMT did not lead to a decreased rate of pneumonia after oesophagectomy. Registration number: NCT01893008 (https://www.clinicaltrials.gov). PMID- 29603132 TI - Meta-analysis of neoadjuvant therapy and its impact in facilitating breast conservation in operable breast cancer. AB - BACKGROUND: Neoadjuvant therapy (NAT) for operable breast cancer may facilitate more breast-conserving surgery (BCS). It seems, however, that this benefit is not being realized fully. METHODS: A systematic review of the literature was performed. RCTs were included. The criteria for inclusion were: documentation of surgical assessment before and after NAT, surgery performed (BCS or mastectomy), and clinical and pathological responses. RESULTS: A total of 1452 patients from seven RCTs met the inclusion criteria. After NAT, the feasibility of BCS increased from 43.3 to 60.4 per cent (P < 0.001), but BCS was performed in only 51.8 per cent (P = 0.04). Only 31 per cent of patients who became eligible for BCS (assessed on clinical response) underwent BCS (pooled rate ratio 0.31, 95 per cent c.i. 0.22 to 0.44; P < 0.001). Of the mastectomy candidates who achieved a pathological complete response after NAT, only 41 per cent underwent BCS (pooled rate ratio 0.41, 0.23 to 0.74; P = 0.003). The main factors that influenced the decision not to shift to BCS, even though it was feasible, were clinical assessment before NAT, multicentricity and tumour size at presentation. CONCLUSION: Breast surgery performed after NAT does not reflect tumour response, resulting in potentially unnecessary radical surgery, especially mastectomy. The barriers to maximizing the surgical benefits of NAT need to be better understood and explored. PMID- 29603133 TI - Surgery 3.0, artificial intelligence and the next-generation surgeon. PMID- 29603134 TI - Anatomy lesson of the brain and cerebral membranes captured on canvas by Rembrandt in 1656. AB - The Anatomy Lesson of Jan Deijman, painted by Rembrandt in 1656, is one of the most extraordinary historical paintings recording an anatomical demonstration of the brain and the cerebral membranes. This painting belongs to the series of group portraits made for the Amsterdam Guild of Surgeons in the 17th and 18th centuries. Unfortunately, the painting was seriously damaged by a fire in the boardroom of the Surgeons' Guild in 1723. The original painting once measured at least five times the size of what is left of it today after large pieces of burned canvas had to be removed during the restoration process. Lying on the dissection table is the body of an executed criminal. Doctor Deijman, lecturer in anatomy of the Surgeons' Guild, is standing behind the corpse while performing the anatomical dissection. The abdominal organs have been removed, and the brain and cerebral membranes are about to be dissected. The nature of the depicted anatomical structures was assessed recently. This revealed that, by showing the falx cerebri, Rembrandt at the same time probably concealed a memento mori message in his masterpiece. PMID- 29603135 TI - Treatment efficacy for idiopathic recurrent pregnancy loss - a systematic review and meta-analyses. AB - INTRODUCTION: Medical treatment of women with idiopathic recurrent pregnancy loss is controversial. The objective was to assess the effects of different treatments on live birth rates and complications in women with unexplained recurrent pregnancy loss. MATERIAL AND METHODS: We searched MEDLINE, Embase and the Cochrane Library, and identified 1415 publications. This systematic review included 21 randomized controlled trials regarding acetylsalicylic acid, low molecular-weight heparin, progesterone, intravenous immunoglobulin or leukocyte immune therapy in women with three or more consecutive miscarriages of unknown cause. The study quality was assessed and data was extracted independently by at least two authors. RESULTS: No significant difference in live birth rate was found when acetylsalicylic acid was compared with low-molecular-weight heparin or with placebo. Meta-analyses of low-molecular-weight heparin vs. control found no significant differences in live birth rate [risk ratio (RR) 1.47, 95% CI 0.83 2.61]. Treatment with progesterone starting in the luteal phase seemed effective in increasing live birth rate (RR 1.18, 95% CI 1.09-1.27) but not when started after conception. Intravenous immunoglobulin showed no effect on live birth rate compared with placebo (RR 1.07, 95% CI 0.91-1.26). Paternal immunization compared with autologous immunization showed a significant difference in outcome (RR 1.8, 95% CI 1.34-2.41), although the studies were small and at high risk of bias. CONCLUSION: The literature does not allow advice on any specific treatment for idiopathic recurrent pregnancy loss, with the exception of progesterone starting from ovulation. We suggest that any treatment for recurrent pregnancy loss should be used within the context of a randomized controlled trial. PMID- 29603136 TI - Anti-thymocyte globulin improves survival free from relapse and graft-versus-host disease after allogeneic peripheral blood stem cell transplantation in patients with Philadelphia-negative acute lymphoblastic leukemia: An analysis by the Acute Leukemia Working Party of the EBMT. AB - BACKGROUND: Mobilized peripheral blood stem cells are currently the predominant source of grafts for allogeneic transplantation (allogeneic peripheral blood stem cell transplantation [allo-PBSCT]), although, in comparison with bone marrow, their use is associated with an increased risk of chronic graft-versus-host disease (cGVHD). Attempts to reduce the incidence of cGVHD include the addition of anti-thymocyte globulin (ATG) to the pretransplant conditioning regimen. METHODS: The goal of this retrospective study was to analyze the effect of ATG on allo-PBSCT outcomes for adults with Philadelphia-negative acute lymphoblastic leukemia (Ph-neg ALL). The primary endpoint was survival free from relapse, grade 3 to 4 acute graft-versus-host disease (aGVHD), and cGVHD (ie, graft-versus-host disease-free/relapse-free survival [GRFS]). Nine-hundred twenty-four patients who underwent unmanipulated allo-PBSCT in their first complete remission between 2007 and 2016 were included. ATG was used in 97 of the 494 transplants from matched sibling donors (20%) and in 307 of the 430 transplants from human leukocyte antigen-matched (8 of 8 loci) unrelated donors (71%). RESULTS: The use of ATG was an independent factor for an improved chance of GRFS (hazard ratio [HR], 0.70; P = .0009). Furthermore, it was associated with a reduced risk of both grade 2 to 4 (HR, 0.66; P = .005) and grade 3 to 4 aGVHD (HR, 0.58; P = .03). Similarly, its addition reduced the incidence of both total (HR, 0.45; P < 10-5 ) and extensive cGVHD (HR, 0.30; P < 10-5 ) as well as nonrelapse mortality (HR, 0.58; P = .01). No significant effect was found with respect to leukemia-free or overall survival. However, an increased risk of relapse was noted for those who received ATG (HR, 1.40; P = .04). CONCLUSIONS: Patients with Ph-neg ALL treated with allo PBSCT benefit from the use of ATG in terms of improved GRFS. Its use may, therefore, be considered in this setting. Cancer 2018;124:2523-33. (c) 2018 American Cancer Society. PMID- 29603137 TI - The thermoregulatory function of the human hand: How do palm and digit proportions affect heat loss? AB - OBJECTIVES: The current study assessed whether ecogeographical patterns seen in hand proportions correlate with heat loss directly. Using a brief severe cold immersion experiment on the hand, the influence of hand and digit dimensions on heat loss was evaluated. MATERIALS AND METHODS: A sample of 113 living individuals were tested. Two-dimensional and three-dimensional scanning techniques were used to assess hand and digit dimensions. Thermal imaging analysis was used to quantify heat loss during a 3-min ice-water immersion of the hands. RESULTS: When body size was accounted for, hand width and digit length relative to total hand length were significant predictors of heat loss from the hand. DISCUSSION: The current study provides empirical evidence to support the link between thermodynamic principles relating to surface area-to-volume ratio, and ecogeographical patterns associated with temperature. PMID- 29603139 TI - A direct-to-patient telemedicine abortion service in Australia: Retrospective analysis of the first 18 months. AB - BACKGROUND: In 2015, the Tabbot Foundation launched a nationwide direct-to patient telemedicine service to enable women to obtain medical abortion without visiting an abortion provider. AIMS: We aimed to describe results from the first 18 months of this service. MATERIALS AND METHODS: To have an abortion through the Foundation, a woman obtained screening tests locally and had a telephone consultation with a Foundation doctor. If she was eligible, mifepristone, misoprostol and other medications were sent to her by mail. After taking the drugs, the woman obtained follow-up tests at local facilities and had a consultation with Foundation professionals. The Foundation charged $250 to patients with Medicare eligibility and $600 otherwise. We summarised clinical data collected by the service. RESULTS: Between June 2015 and December 2016, 1010 women received medications, of whom 56% lived outside of major cities. Ninety five percent of packages were sent within 15 days after registration. Of the 965 women who took misoprostol, outcomes were definitively documented for 754 (78%), of whom 96% had a complete abortion without surgical intervention, and 95% had no face-to-face clinical encounter after treatment. Of women with Medicare cards, 72% paid no out-of-pocket charges other than to the Foundation. Nearly all women (781/802; 97%) were highly satisfied. CONCLUSIONS: The direct-to-patient telemedicine medical abortion service was effective, safe, inexpensive and satisfactory. It disproportionately served women in parts of Australia with limited access to abortion facilities. This experience may be instructive for others desiring to use telemedicine to enhance access to abortion. PMID- 29603138 TI - A roadmap for global synthesis of the plant tree of life. AB - Providing science and society with an integrated, up-to-date, high quality, open, reproducible and sustainable plant tree of life would be a huge service that is now coming within reach. However, synthesizing the growing body of DNA sequence data in the public domain and disseminating the trees to a diverse audience are often not straightforward due to numerous informatics barriers. While big synthetic plant phylogenies are being built, they remain static and become quickly outdated as new data are published and tree-building methods improve. Moreover, the body of existing phylogenetic evidence is hard to navigate and access for non-experts. We propose that our community of botanists, tree builders, and informaticians should converge on a modular framework for data integration and phylogenetic analysis, allowing easy collaboration, updating, data sourcing and flexible analyses. With support from major institutions, this pipeline should be re-run at regular intervals, storing trees and their metadata long-term. Providing the trees to a diverse global audience through user-friendly front ends and application development interfaces should also be a priority. Interactive interfaces could be used to solicit user feedback and thus improve data quality and to coordinate the generation of new data. We conclude by outlining a number of steps that we suggest the scientific community should take to achieve global phylogenetic synthesis. PMID- 29603140 TI - Differences in the placebo response in duloxetine and venlafaxine trials. AB - OBJECTIVE: Our analysis aimed at comparing the placebo effect sizes from randomized controlled trials (RCTs) of two widely prescribed antidepressants, namely duloxetine and venlafaxine, and at analysing a potential influence of the investigated drugs on the placebo response. METHOD: We conducted a comprehensive systematic review and meta-analysis of placebo-controlled, double-blind RCTs, which examined the efficacy of duloxetine and venlafaxine in the acute treatment of major depressive disorder. RESULTS: We included 71 studies (29 duloxetine trials and 43 venlafaxine trials; one study provided data for the duloxetine and the venlafaxine data set). The placebo effect sizes, defined as pre-postscore change divided by baseline standard deviation, differed significantly between venlafaxine and duloxetine studies (-2.51 vs. -2.09; test for subgroup differences P = 0.028; high heterogeneity). The analysis of effect modifiers and the metaregression analyses confirmed the drug, next to baseline depression severity and publication status, as the most influential independent predictor. CONCLUSION: Our analyses show a significant difference in the placebo response between venlafaxine and duloxetine trials and suggest that the investigated drug has an influence on the placebo response that is not related to baseline severity, changes over the years or other variables we included. PMID- 29603141 TI - Population-based cohort study of surgical myotomy and pneumatic dilatation as primary interventions for oesophageal achalasia. AB - BACKGROUND: The aim of this national population-based cohort study was to compare rates of reintervention after surgical myotomy versus sequential pneumatic dilatation for the primary management of oesophageal achalasia. METHODS: Patients with oesophageal achalasia diagnosed between 2002 and 2012, and without an intervention in the preceding 5 years were identified from the Hospital Episode Statistics database. Patients were divided into two groups based on the primary treatment, and propensity score matching was used to compensate for differences in baseline characteristics. RESULTS: Some 14 705 patients were diagnosed with oesophageal achalasia, of whom 7487 (50.9 per cent) received interventional treatment: 1742 (23.3 per cent) surgical myotomy, 4534 (60.6 per cent) pneumatic dilatation and 1211 (16.2 per cent) endoscopic botulinum toxin injection. As age increased, the proportion of patients receiving myotomy decreased and the proportion undergoing dilatation increased. Patients who underwent surgical myotomy were younger (mean age 44.8 years versus 58.5 years among those who had pneumatic dilatation; P < 0.001), a greater proportion had a Charlson co morbidity index score of 0 (90.1 versus 87.7 per cent; P = 0.003) and they were more commonly men (55.6 versus 51.8 per cent; P = 0.020). Following propensity score matching, the safety of the two initial treatment approaches was equivalent, with no difference in incidence of oesophageal perforation (1.3 and 1.4 per cent after myotomy and dilatation respectively; P = 0.750). However, dilatation was associated with increased need for reintervention (59.6 versus 13.8 per cent; P < 0.001) and frequency of reinterventions (mean 0.34 versus 0.06 per year; P < 0.001). CONCLUSION: Surgical myotomy was associated with a lower rate of reintervention and could be offered as primary treatment in patients with oesophageal achalasia who are fit for surgery. For those unfit for surgery, pneumatic dilatation may provide symptomatic relief with approximately 60 per cent of patients requiring reintervention. PMID- 29603143 TI - Plastid phylogenomic analysis of green plants: A billion years of evolutionary history. AB - PREMISE OF THE STUDY: For the past one billion years, green plants (Viridiplantae) have dominated global ecosystems, yet many key branches in their evolutionary history remain poorly resolved. Using the largest analysis of Viridiplantae based on plastid genome sequences to date, we examined the phylogeny and implications for morphological evolution at key nodes. METHODS: We analyzed amino acid sequences from protein-coding genes from complete (or nearly complete) plastomes for 1879 taxa, including representatives across all major clades of Viridiplantae. Much of the data used was derived from transcriptomes from the One Thousand Plants Project (1KP); other data were taken from GenBank. KEY RESULTS: Our results largely agree with previous plastid-based analyses. Noteworthy results include (1) the position of Zygnematophyceae as sister to land plants (Embryophyta), (2) a bryophyte clade (hornworts, mosses + liverworts), (3) Equisetum + Psilotaceae as sister to Marattiales + leptosporangiate ferns, (4) cycads + Ginkgo as sister to the remaining extant gymnosperms, within which Gnetophyta are placed within conifers as sister to non-Pinaceae (Gne-Cup hypothesis), and (5) Amborella, followed by water lilies (Nymphaeales), as successive sisters to all other extant angiosperms. Within angiosperms, there is support for Mesangiospermae, a clade that comprises magnoliids, Chloranthales, monocots, Ceratophyllum, and eudicots. The placements of Ceratophyllum and Dilleniaceae remain problematic. Within Pentapetalae, two major clades (superasterids and superrosids) are recovered. CONCLUSIONS: This plastid data set provides an important resource for elucidating morphological evolution, dating divergence times in Viridiplantae, comparisons with emerging nuclear phylogenies, and analyses of molecular evolutionary patterns and dynamics of the plastid genome. PMID- 29603144 TI - Pain management for patients with cancer. PMID- 29603142 TI - Optimal pain management for patients with cancer in the modern era. AB - Pain is a common symptom among patients with cancer. Adequate pain assessment and management are critical to improve the quality of life and health outcomes in this population. In this review, the authors provide a framework for safely and effectively managing cancer-related pain by summarizing the evidence for the importance of controlling pain, the barriers to adequate pain management, strategies to assess and manage cancer-related pain, how to manage pain in patients at risk of substance use disorder, and considerations when managing pain in a survivorship population. CA Cancer J Clin 2018;68:182-196. (c) 2018 American Cancer Society. PMID- 29603145 TI - Natural cause mortality in persons with serious mental illness. AB - OBJECTIVE: To identify the determinants of natural cause mortality in a cohort of individuals with serious mental illness assessed prospectively. METHOD: Persons with schizophrenia (n = 789) and bipolar disorder (n = 498), mean age of 38 (s.d. 12.6) years, underwent an in-person clinical assessment. They also had a blood sample drawn from which infectious disease markers were measured. Mortality was subsequently determined utilizing data from the National Death Index following a period of up to 16.9 years. RESULTS: A total of 6.8% (87 of 1287) of persons died of natural causes. Mortality was predicted in a multivariate model by baseline cigarette smoking (RR = 6.29, 95% CI 1.41, 3.72, P = 0.00076); divorced or widowed status (RR = 1.90, CI 1.21, 2.99); reduced cognitive score (RR = 0.73, CI 0.61, 0.87); receipt of antidepressant medication (RR = 1.74, CI 1.12, 2.71); elevated levels of antibodies to Epstein-Barr virus (EBV) (RR = 1.29, CI 1.01, 1.66); and a genitourinary (RR = 1.82, CI 1.16, 2.86), respiratory (RR = 1.82, CI 1.16, 2.86), or cardiac (RR = 2.09, CI 1.33, 3.29) condition. There was an additive effect of smoking and both a cardiac and a respiratory condition but not elevated EBV antibody levels. CONCLUSION: Smoking is a modifiable behaviour which is associated with mortality in this population. PMID- 29603146 TI - Structural determinants of ligand binding in truncated hemoglobins: Resonance Raman spectroscopy of the native states and their carbon monoxide and hydroxide complexes. AB - The ligand binding characteristics of heme-containing proteins are determined by a number of factors, including the nature and conformation of the distal residues and their capability to stabilize the heme-bound ligand via hydrogen-bonding and electrostatic interactions. In this regard, the heme pockets of truncated hemoglobins (TrHbs) constitute an interesting case study as they share many common features, including a number of polar cavity residues. In this review, we will focus on three proteins of group II TrHbs, from Thermobifida fusca (Tf-HbO) and Pseudoalteromonas haloplanktis TAC125 (Ph-HbO). Although the residues in positions G8 (Trp) and B10 (Tyr) are conserved in all three proteins, the CD1 residue is a Tyr in T. fusca and a His in P. haloplanktis. Comparison of the ligand binding characteristics of these proteins, in particular the hydroxo and CO ligands by means of resonance Raman spectroscopy, reveals that this single difference in the key heme cavity residues markedly affects their ligand binding capability and conformation. Furthermore, although the two Ph-HbOs (Ph-HbO-2217 and Ph-HbO-0030) have identical key cavity residues, they display distinct ligand binding properties. PMID- 29603148 TI - The Place of Radiation Therapy in the Treatment of Carcinoma of the Distal End of the Penis. AB - Carcinoma of the penis is a rare disease in the mainland United States. It occurs almost exclusively in uncircumcised men, very rarely before age 30, usually after age 50, and is generally associated with phimosis and resulting difficult or poor hygiene. It tends to remain localized for considerable lengths of time, but undifferentiated tumors and tumors in younger patients may be quite aggressive. Primary treatment may be surgical extirpation or irradiation. The latter is followed by surgery in the event of failure to control the tumor or for a radiation complication. Irradiation alone, if successful, avoids the functional disability and the psychological distress caused by loss of the penis, so if control is comparable, obviously this is the treatment of choice. Many authors have published results of treatment by primary surgery or radiotherapy. We wish to report on the treating of carcinoma of the penis by radiotherapy alone or in planned combination with surgery. The M. D. Anderson Hospital and Tumor Institute's experience with conservative management of carcinoma of the distal end of the penis by radiotherapy is reviewed, and compared with more drastic methods that combine preoperative irradiation with partial or total amputation. PMID- 29603149 TI - Combined Interstitial and External Radiotherapy in the Definitive Management of Carcinoma of the Prostate. AB - Five hundred and forty-two patients have been treated for prostatic carcinoma with radiotherapy between 1965 and 1976 at our institution. All patients have been followed for longer than one year. Two hundred and ninety-five patients have been subjected to surgical exploration to document the precise stage of their disease and undergone staging pelvic lymphadenectomy at the time of interstitial implantation of radioactive gold grains. Postoperatively, these patients have received an average of 4500 rad, given over one month, external beam radiotherapy to the prostate. Excellent survival data are presented including the results of post treatment needle biopsy in a selected number of patients. PMID- 29603150 TI - Cancer of the Penis. AB - Cancer of the penis is infrequent in the United States because of good genital hygiene and circumcision of male babies at birth. In other countries, it represents 11-12% of all cancer in males. Tumors of the penis consist mainly of squamous cell carcinoma. Mesenchymal tumors are rare. The treatment is based on the surgical excision of the penis (partial or total) with or without regional lymphadenectomy. Radiotherapy alone or in conjunction with surgery is also used. Chemotherapy with bleomycin and/or methotrexate has been effective in advanced disease. The prognosis is directly related to the stage of the tumor at the time of the treatment. Patients without lymphatic metastases remain alive and free of disease at ten years of follow-up. Meanwhile, patients with microscopic lymphatic spread, survive an average of 2.5 years (Roswell Park Memorial Institute). These data emphasize the importance of early diagnosis and treatment to achieve long survival. PMID- 29603147 TI - Timely follow-up of positive cancer screening results: A systematic review and recommendations from the PROSPR Consortium. AB - Timely follow-up for positive cancer screening results remains suboptimal, and the evidence base to inform decisions on optimizing the timeliness of diagnostic testing is unclear. This systematic review evaluated published studies regarding time to follow-up after a positive screening for breast, cervical, colorectal, and lung cancers. The quality of available evidence was very low or low across cancers, with potential attenuated or reversed associations from confounding by indication in most studies. Overall, evidence suggested that the risk for poorer cancer outcomes rises with longer wait times that vary within and across cancer types, which supports performing diagnostic testing as soon as feasible after the positive result, but evidence for specific time targets is limited. Within these limitations, we provide our opinion on cancer-specific recommendations for times to follow-up and how existing guidelines relate to the current evidence. Thresholds set should consider patient worry, potential for loss to follow-up with prolonged wait times, and available resources. Research is needed to better guide the timeliness of diagnostic follow-up, including considerations for patient preferences and existing barriers, while addressing methodological weaknesses. Research is also needed to identify effective interventions for reducing wait times for diagnostic testing, particularly in underserved or low resource settings. CA Cancer J Clin 2018;68:199-216. (c) 2018 American Cancer Society. PMID- 29603151 TI - The Pathology of Human Bladder Cancer. AB - The pathologist plays a key role in the detection and diagnosis of bladder cancer, as well as in the development of strategies for the clinical management of this disease by the urologist. In order to make appropriate decisions, the urologist needs help from the pathologist in determining: 1) whether or not a bladder tumor is present; 2) if present, its histologic type, grade, depth of invasion and evidence of lymphatic or blood vessel invasion; 3) whether or not there are associated neoplastic lesions elsewhere in the bladder -or elsewhere in the lower urinary tract; and 4) if some therapeutic modality has been directed toward the neoplastic tissue, the completeness of tumor removal or destruction. It is recommended that the WHO classification of bladder tumors be used by pathologists in their reports to facilitate communication among pathologists, urologists, radiation therapists, medical oncologists, and others involved in the management of bladder cancer patients. In addition, the pathologist should make a definite statement regarding the presence or absence of muscle tissue in every bladder biopsy specimen containing tumor. After one or more superficial tumors are identified by the urologist and treated by transurethral means, management of the patient will depend not only on the microscopic evaluation of the resected tumor but also on an accurate assessment of the neoplastic potential of the remaining epithelium. The cytopathologic examination of urine samples or bladder washings aids this assessment. PMID- 29603152 TI - Chemotherapy Programs of the National Prostatic Cancer Project (NPCP). AB - Results of the first nationally randomized trial of the National Prostatic Cancer Project revealed a demonstrable advantage for chemotherapy in the management of advanced disease (Stage D in relapse from endocrine therapy). Both cyclophosphamide and 5-Fluorouracil showed improved activity over standard therapy. A second trial for patients previously irradiated, with less tolerance to myelosuppressive agents, revealed an advantage for estramustine phosphate and streptozotocin over standard therapy. Subsequently completed trials have revealed activity for prednimustine and imidazole carboxamide (DTIC). Trials currently underway for newly-diagnosed Stage D and for Stage D disease clinically stable to diethylstilbestrol (DES) show promising activity for DES combined with cyclophosphamide. Current trials with single agents in advanced disease are comparing methyl-CCNU and hydroxyurea with cyclophosphamide; another is evaluating estramustine phosphate and vincristine alone and in combination. The use of chemotherapy in earlier staged patients as adjuvants to definitive surgery or irradiation is underway in two clinical trials, where the effect of cyclophosphamide and estramustine phosphate as long-term therapies is compared with no additional treatment. PMID- 29603153 TI - The Management of Superficial Bladder Cancer. AB - Superficial bladder cancer includes tumors confined to the mucosa and lamina propria. They may be papillary or sessile. Tumors confined to the mucosa include papillomas, papillary carcinomas, or carcinoma in situ. Therapy must be individualized for each patient taking into consideration the histologic type, cytologic grade, location, number, prior history, and presence of atypia or carcinoma in situ in other areas of the bladder. Although the five-year survival rates are good (62-88 percent), the 48-70 percent incidence of subsequent tumors requires constant surveillance. This high incidence is primarily due to the multifocal origin of urothelial tumors, but implantation of tumor cells following local resection may be a contributing factor. Current efforts to reduce this recurrence rate emphasize intravesical chemotherapy. Thio-tepa and epodyl are effective in eradicating one-third of tumors when used for definitive therapy. Most studies demonstrate a reduction in the recurrence rate when they are initiated following endoscopic resection of all visible tumor. A number of other drugs are being investigated for both definitive and prophylactic intravesical chemotherapy. Surgical procedures consist of transurethral resection, transvesical radium implantation, segmental cystectomy, and cystoprostatectomy. Each procedure has its own indications, and the surgeon must be discriminating in their use. PMID- 29603154 TI - Testicular Cancer: Risk Factors and the Role of Adjuvant Chemotherapy. AB - Advances in therapeutic results due to chemotherapy in metastatic non seminomatous germinal cell tumors of the testes are stimulating investigations that assess the role of chemotherapy as an adjuvant to surgery and/or radiotherapy in early stages of disease. In current series, complete responses are obtained in 70-80% of patients with metastatic disease; the relapse rate is 15-20%. Toxicity is significant but acceptable. The current literature reveals that surgery and/or radiation to the periaortic lymph nodes for clinical Stage I disease results in a 2+ year disease-free survival rate of about 90%. For clinical Stage II disease, the rate is about 50%. Patients with non-seminomatous testicular carcinoma Stage II are at significant risk to develop distant metastases and are candidates for an intergroup protocol that randomizes patients to receive either adjuvant combination chemotherapy or combination chemotherapy at first recurrence. All patients with testicular cancer should be considered curable. This requires careful assessment and monitoring, and can best be approached in controlled clinical trials. PMID- 29603155 TI - Detection of Carcinoma of the Prostate Utilizing Biochemical Observations. AB - This review presents the current status of attempts to identify individuals with a high risk of carcinoma of the prostate by using biochemical, immunochemical, and immunologic studies of body fluids. Blood, urine, and prostatic fluid have been subjected to a variety of analyses in attempts to find alterations that are sufficiently specific and sensitive enough to be useful in the early recognition of patients with a high probability of localized or disseminated carcinoma of the prostate. A variety of immunologic and immunochemical techniques to identify and quantify acid phosphatase of prostatic origin in the serum are currently being explored for this purpose; as yet, none has achieved the specificity-sensitivity relationship necessary for widespread clinical application. Biochemical studies of prostatic fluid have disclosed a reversal of the lactic dehydrogenase (LDH) isoenzyme pattern with a predominance of LDH-V and increased levels of transferrin, complement C3 and possibly complement C4 in association with carcinoma of the prostate. The value of these non-specific changes is increased by the probable direct relationship between prostatic epithelial cell metabolism and changes in prostatic fluid composition. These approaches to identify individuals with a high risk of carcinoma of the prostate hold promise; they should be continued and expanded. PMID- 29603156 TI - Pathology of Germ Cell Tumors of Testis: A Progress Report. AB - Since the last National Conference on Urological Tumors, there has been major progress in pathology of testicular tumors. An international histological classification of these tumors has been proposed, which is based on the sound principle that pathological examination must specify the exact components that are present in a tumor and give an estimate of relative proportions of each. The WHO classification, using generally accepted principles of tumor typing, has provided a standard method of pathological reporting of these tumors so that results of research from different parts of the world can be compared. The WHO system published in 1977 is readily convertible to the system in use in the American Testicular Tumor Registry. Its convertibility to the Friedman-Moore and Pugh-Cameron Testicular Tumor classifications is limited. Though it is generally believed that embryonal carcinoma can differentiate along extra-embryonic lines to form yolk sac tumor and choriocarcinoma or along embryonic lines to form teratoma, the malignant germ cell itself seems to have the potential to develop along any of these lines without first going through the embryonal carcinoma phase. Seminomas with high mitotic index and seminomas that contain syncytiotrophoblasts appear to have a less favorable prognosis than classic seminomas or spermatocytic seminomas. HCG is readily demonstrable in syncytiotrophoblasts whether alone or forming choriocarcinoma. AFP is demonstrable in yolk sac tumors and in some embryonal carcinomas. Histological demonstration of AFP and HCG can and should be correlated with clinical findings. Such correlation can readily be made with the WHO histological classification of these tumors. PMID- 29603157 TI - Carcinoma of the Bladder: Predictors. AB - The natural history of carcinoma of the bladder is unpredictable. In some patients, invasive (potentially lethal) carcinomas represent their initial clinical presentation, whereas in others, a protracted clinical course characterized by multiple recurrent tumors is witnessed. This latter population of patients is the most vexing to the urologist. The prediction of the patient's "state of risk" from the tumor has historically been based on clinical pathologic staging employing grade and stage. Predictive clinical evidence for the development of invasive (potentially lethal) carcinoma has been gleaned from observations of the rapidity and pattern of tumor recurrence (single vs. multiple), tumor characteristics (grade, shape, and presence of lymphatic or venous invasion) and the presence of carcinoma in situ at preselected endoscopically normal biopsy sites. Currently available "objective" predictors such as blood group isoantigen deletion from bladder urothelium of patients with invasive bladder carcinoma are provocative. Presently, this technique cannot pinpoint when tumor invasion will occur in a particular patient. However, the application of this methodology in a prospective study (including examination of preselected endoscopically normal mucosal biopsies) is well as resected tumor tissue may prove valuable. At the ultrastructure level as studied with the electron microscope and immunofluorescent probes, alterations in the plasma membrane have been defined that are associated with malignant transformation and abnormal growth patterns (potentially predictive of tumor invasion). Certain Of these techniques appropriately applied to a population at high risk may ultimately assist the surgeon in timing extirpative surgery. PMID- 29603158 TI - Management of Stages I and II Nonseminomatous Germ Cell Tumors of the Testis. AB - Management of Stages I and II nonseminomatous tumors of the testis is in a state of flux as a result of improvement in the major modalities for patient treatment. Both radiotherapy and retroperitoneal lymphadenectomy, used alone, are providing five-year survival rates in the range of 75 to 90% for patients with localized disease (Stage 1). However, since current staging methods fail to detect regional disease (Stage II) in 15 to 20% of the patients before therapy, lymphadenectomy provides a distinct and additional advantage, both by removing possible unseen metastases and by determining pathologically which patients may benefit from adjuvant therapy. Both surgery and radiotherapy, when used alone to combat extensive retroperitoneal disease, have proved unsatisfactory; surgery is frequently difficult or impossible, and persistent disease is common following radiotherapy. Therefore, patients with extensive Stage II disease are best treated with either preoperative chemotherapy or preoperative radiotherapy (2500 to 3000 rads over three to four weeks) before resection of the retroperitoneal disease. The benefits of adjuvant chemotherapy for patients with Stages I and II disease is under continuing investigation. PMID- 29603160 TI - The Management of Testicular Seminomas, 1979. AB - The reported results from throughout the world of modern treatment of testicular seminoma are reviewed for the various clinical stages of disease. The three-year survival rate for 1,346 patients with Stage 1 and 2 disease is 91%. Since the review reveals considerable differences in staging methods, a clinically useful staging system is proposed. Treatment methods are described and discussed. Recommendations are made assuming that patients so treated are clinically evaluated for extent of disease before treatment with currently available techniques, including lymphangiography, CT scanning, perhaps ultrasonography, and serum marker determinations. Although the role of cytoreductive surgery in patients with seminoma, even bulky seminoma, now is limited, occasionally when laparotomy is done, debulking may also be helpful. Effective combination chemotherapy regimens have not been identified. The 28% three-year survival rate of patients with Stage 3 disease establishes the real need to identify such therapy. Finally, anaplastic seminoma is considered; a recent review by Percarpio indicates that this subtype perhaps is not unlike classical seminoma as far as stage distribution and prognosis is concerned. PMID- 29603159 TI - Current Status of Classification and Staging of Prostate Cancer. AB - The international TNM classification system for prostatic cancer has been recently revised and is most helpful for comparisons between various groups of patients. Today in the United States, the evaluation of certain factors related to clinical and pathologic staging are being further altered. These include primary grade of tumor and the extent and techniques of tumor staging. New tests for acid phosphatase and alkaline phosphatase isozymes are being concurrently evaluated. Advances in the past six years have contributed to further redefinition and subgrouping of previous conventional staging or prognostic assessment of prostatic cancer. Localized (Stage B, C), occult (Stage A), or generalized (Stage D) tumors are being subdivided. Although grade of the primary tumor has been thought to be important only recently has a consensus been achieved by the National Prostatic Cancer Project for a system of assessment that uses cellular patterns and nuclear changes. Aspiration cytology may be a useful adjuvant. The role and type of pelvic lymph node assessment, whether operative, radiographic, or by thin needle percutaneous aspiration, is undergoing additional study. In dealing with the so-called occult (Stage A) lesions, a further subdivision, Stage A,/A2 has been employed. Similar changes in so-called B1 /B2 , C1 /C2 , and D1 /D2 also exist. These are valid attempts to further define extent of disease and overall true tumor burden. Nevertheless, it is still the privilege of the physician to determine the necessity and extent of the use of such classification. Today, the decision to provide therapeutic care based only on a clinical stage must be made with the knowledge of these variations of classification and staging as well as of other developments. PMID- 29603161 TI - Urethral Cancer. AB - Primary cancer of the urethra is an uncommon lesion with only slightly more than 400 cases in men, and slightly less than 1,100 cases in females reported in the literature. Review of these cases allows some generalizations. The most common tumor type in both sexes is squamous cell carcinoma. Signs and symptoms are varied and nonpathognomonic. Anterior or distal lesions in both sexes, in general, drain into inguinal lymph nodes, while posterior or proximal lesions drain into pelvic nodes; obviously some overlapping can occur. Anterior lesions are discovered earlier, are usually of lower stage, and can be controlled by less radical means than posterior tumors. They have a much better prognosis than posterior lesions. Although these cancers are rare, the diagnosis should always be considered in any patient with urethral complaints. PMID- 29603162 TI - The Diagnosis and Treatment of Renal Cell Carcinoma. AB - Surgical excision remains the only method of curing renal cell carcinoma. Early ligation of the renal artery and vein, followed by radical nephrectomy with regional lymphadenectomy, seems to offer the best method of cure for patients with localized disease. Results of more extensive surgery have been encouraging, and surgical extirpation should be attempted even when the tumor involves the vena cava, adjacent organs, or a solitary kidney. Radiotherapy as a post operative adjuvant has not been effective, and when used pre-operatively, may decrease local recurrence but does not appear to improve five-year survival. A chemotherapeutic agent capable of significantly altering the course of metastastic renal cell carcinoma has not been identified. Vinblastine, the most effective currently available drug, rarely produces tumor regression. Progestational agents seldom, if ever, cause tumor regression, though newer hormonal agents may be more promising. Data continue to accumulate documenting altered immune mechanisms in renal cancer patients. These studies have provided impetus for continued trials of immunotherapy, and several agents are being studied. The management of patients with metastases at the time of diagnosis remains controversial. A better understanding of the natural history of these patients suggests that palliative nephrectomy may be inappropriate except for severe symptoms and patients with resectable metastases. Intraarterial infarction, fellowed by palliative nephrectomy, may improve survival, perhaps by stimulating a general immune response. PMID- 29603163 TI - Childhood Urologic Cancer Therapy Related Sequelae and Their Impact on Management. AB - Multidisciplinary treatment for childhood urologic cancer has resulted in improved survival. However, the sucessful results may be marred by the appearance of therapy-related sequelae. Thus, radiation therapy has produced spine deformities (kyphosis and scoliosis), ovarian failure, renal disease and abnormalities in the skin, subcutaneous tissue, and muscle. Successful treatment of pulmonary metastases has been associated with abnormalities in pulmonary physiology and chest wall deformities. Chemotherapy-related complications include hemorrhagic cystitis and possible gonadal failure. If exenteration for bladder or prostate cancer is required, the sequelae are immediately apparent and include ureterosigmoidostomy, colostomy, or iliostomy. Oncogenic sequelae comprise benign and malignant neoplasms, and many of them appear to be radiation induced. Recognition of these sequelae has lead to changes in therapy to reduce or prevent their occurrence. However, despite innovative changes, long-term survivors still appear to be a risk for the development of late complications. The importance of continued surveillance is stressed. PMID- 29603164 TI - Hormonal Therapy of Prostatic Cancer. AB - The principle goal of hormonal therapy in the treatment of prostatic cancer, as Huggins suggested in 1941, is the suppression of androgenic stimuli. Consequently, the treatment of advanced prostatic cancer has consisted of orchiectomy, estrogen administration, antiandrogen therapy, adrenalectomy or hypophysectomy, or a combination of some of these. Although the three VACURG studies are subject to several valid criticisms, they provide the best available information to date. In summary, these studies report 1) patients with low stage disease who are treated with estrogen (diethylstilbestrol 5 mg/day) have a higher death rate, mainly cardiovascular, than men not receiving estrogen and 2) in patients with high stage disease, delayed hormonal therapy is as effective as early hormonal therapy. Castration appears to be as effective as treatment with estrogens or a combination of the two and does not evoke the untoward side effects of estrogen administration. Although subjective improvement has been observed following adrenal or pituitary ablation, the duration of response is usually short, and consequently these procedures are used infrequently now. Experience with the use of antiandrogens is even more limited. Efforts must continue to develop means of predicting hormonal responsiveness. If receptor measurements prove to be an accurate means for predicting the hormonal responsiveness of prostatic cancer, as they have in breast cancer, then our current plan of treatment will need modification. In those men who are unlikely to respond to hormonal therapy, early chemotherapy should be instituted. PMID- 29603165 TI - Current Perspectives in the Management of High-Grade Invasive Bladder Cancer. AB - Optimal management of high-grade invasive bladder cancer requires aggressive therapy, usually radical cystectomy with preoperative radiation therapy. Recent prospective studies have demonstrated that five-year survival rates for deeply invasive disease have improved to 45- 55% compared to a dismal less than 20% five year survival for patients treated by definitive radiation therapy alone, or historical series in which cystectomy was used as single modality therapy. The incidence of pelvic lymph node involvement ranges from 10% in patients with P1 and P1S disease to 50% in patients with P3 disease and implies the need to treat the pelvic nodes by lymphadenectomy or adequate preoperative radiation therapy whenever cystectomy is indicated. The improvements in surgical technique, pre-, and postoperative management have resulted in operative mortality as low as 1% and early complication rates as low as 24% for patients treated by single-stage radical cystectomy with pelvic node dissection and urinary diversion. Despite these advances, 50% or more of patients with high-grade invasive bladder cancer die of distant metastases, usually within two years, implying the need to scrutinize adjuvant chemotherapy in carefull controlled prospective studies. PMID- 29603166 TI - Surgical Staging of Carcinoma of the Prostate. AB - Surgical staging (bilateral pelvic lymphadenectomy) has become a widely used and accepted procedure over the past eight years. It's utility is recognized by surgeons and radiotherapists alike. Approximately 15 to 20% of patients with small, palpable prostate cancer nodules (Stage B,) have (+) pelvic lymph nodes; over 30% of patients with larger but still intracapsular involvement (Stage B2 ) have (+) nodes. Over 50% of patients with localized capsular penetration (Stage C) have (+) nodes. Poorly-differentiated tumors metastasize to nodes with greater frequency than do well-differentiated tumors. The complication rate appears to be acceptable with lymphocele formation, thromboembolic phenomena, wound infections, and lymphedema being some of the more common problems. Operative mortality due to pelvic lymphadenectomy is extremely rare. Multiple positive nodes are a bad prognostic sign, whereas one or two nodes with minimal tumor volume are much less ominous. Little data is available on the therapeutic efficacy of a thorough pelvic lymphadenectomy in combination with radical prostatectomy or radiotherapy in terms of 10 or 15 year survival. Such data should become available in the next few years. PMID- 29603167 TI - Pelvic Rhabdomyosarcomas in Childhood: Diagnosis and Concepts of Management Reviewed. AB - The diagnosis of pelvic rhabdomyosarcoma in childhood may ordinarily be established without laparotomy. A search for dissemination is rarely positive at the time of discovery of the tumor. Regimens of combined therapy including 1) radical surgical excision, 2) pelvic irradiation, and 3) multiple-agent long range chemotherapy have resulted in survival rates of 60-90% in children with apparently localized disease. Satisfaction with the results of such regimens, relative to survival, is offset by the adverse effects of the exenteration procedures required and to a lesser extent by the morbidity associated with pelvic irradiation. New approaches have been developed in an attempt to avoid exenteration and radiotherapy. These include limited local surgery, i.e., partial cystectomy or tumorectomy, in rhabdomyosarcomas of the bladder, for example. The results of these procedures have been markedly better than those that followed the use of similar, limited operations before the use of effective chemotherapy. More radical departures from accepted tumor management, i.e., primary chemotherapy regimens which do not include initial surgery (except biopsy) and which may or may not include radiotherapy, have also been employed. In approximately 70% of infants and small children with pelvic rhabdomyosarcoma, tumor dissemination can be controlled by an approach that first uses only chemotherapy. On this regimen, a majority of these neoplasms will be reduced in size to the extent that a limited surgical excision is possible, or they may be treated without excisional surgery. PMID- 29603168 TI - Radical Surgery for Prostatic Cancer. AB - Radical surgical procedures for the cure of prostatic cancer are based on the premise that all cancer cells reside in the tissue to be excised and that the excision be properly accomplished. In the 75 years that have elapsed since radical prostatectomy was first performed, the criteria for the selection of surgical candidates have been refined. Based on pathologic findings and demonstrated long-term tumor-free survival, those patients apt to derive the greatest benefit from radical surgery are those with Stage B1 lesions. We were able to trace 57 patients with Stage B, disease who underwent radical perineal prostatectomy at The Johns Hopkins Hospital between the years 1951-1963. Fifteen years or more postoperatively, 29 (51%) were alive and well, 10 (17%) died of recurrent cancer, and 18 (32%) died without disease. There are no available data to prove that any other therapeutic modality can match the 15-year survival provided by radical prostatectomy in patients with this stage of disease. PMID- 29603169 TI - Classification and Staging of Bladder Carcinoma. AB - Bladder carcinoma is a chronic, heterogeneous, field-change, neoplastic diathesis in most of the patient., that it afflicts. Staging initially considered the primary lesion(s) and local nodal involvement (Jewett-Strong-Marshall), but variable disease characteristics cannot be accommodated by this system. For clinical research purposes, longitudinal observations on patients with bladder carcinoma seem useful for identifying and classifying types of patients with types of urothelial neoplasms. For general use, however, the classification of the American Joint Committee provides for common taxonomy concerning the primary tumor(s), T(m); nodal involvement, (N); metastases, (M); grade, (G); and lymphatic involvement, (L+/L-). It also provides for indicating how the information for each of these tumor characteristics or activities was obtained, i.e. clinical, (cT); surgical biopsy of a metastatic pelvic node, (sN+); or pathological evaluation of cystectomy specimen, (pTpN). This system clearly describes patients in different stages of disease treated by different modalities, using previously defined rules. It should be employed in initial and subsequent follow-up of patients, particularly when analyzing the results of treatment. PMID- 29603170 TI - Testicular Cancer in Children. AB - Management of testis cancer in children differs from that in adults due to the histological types and varying tolerances to chemotherapy agents. Embryonal adrenocarcinoma (endodermal sinus tumor, Teilum's tumor) is a tumor of infancy and young children and less aggressive than other testis cancers. Most cases require only orchiectomy for cure. Embryonal carcinoma is seen in older children and is managed by orchiectomy, regional node dissection, and chemotherapy according to stage. Teratocarcinoma is seen in older age groups. In the young children, as rhabdomyosarcoma and neuroblastoma are often present. Intensive multidisciplinary treatment is required in management. Paratesticular rhabdomyosarcoma arising in the distalcord requires pelvic and retroperitoneal node dissection in addition to orchiectomy. Chemotherapy and radiation therapy help to produce high cure rates in these tumors. Details of the treatment of these histological types and results of treatment will be presented. PMID- 29603171 TI - Carcinoma of the Adrenal Cortex. AB - Adrenal cortical carcinoma is a rare tumor that affects all ages and sexes and has a dismal prognosis. Half are functional, half are not. Early stages are uncommon and are detected by their endocrine effects, usually in females, as incidental findings at surgery or on computed tomography scans. Arteriography, venography, and CT-scan define the local disease. Endocrine evaluations may delay surgery and do not affect the treatment. Radical local surgery with wide exposure is indicated in all adrenal tumors except the radiologically defined small tumor of pure primary hyperaldosteronism. Thoracoabdominal incisions, extra-fascial dissection, nephrectomy, splenectomy, and partial pancreatectomy may be used. Adjunctive chemotherapy or radiation have not been tested. Cures are recorded only in widely-excised, low stage tumors without evidence of metastases (T 1-2 NOMO). Ortho-p-DDD is useful in less than half the cases, functional or not. Phase II studies and collaborative combined chemotherapy treatment studies are badly needed. PMID- 29603172 TI - Wilm's Tumor: An Update. AB - Major advances have been made against Wilms' tumor as a result of treatment methods developed by single institutions that then have been confirmed and extended by national cooperating groups. Better survival rates have been achieved, and therapy has been refined so that treatment can be reduced in early stage disease without jeopardizing tumor control. This results in fewer short- and long-term complications, an especially important consideration in children. Their organs and tissues are vulnerable to anti-mitotic treatments such as chemo- and radiotherapy, that can produce disabling if not lethal dysfunctions. This progress has been the result of the cooperative efforts by multiple specialists, and provides evidence of the value of such integrated studies. They have changed the outlook from a 90% death rate in the early years of this century to the 90% survival rate now possible with modern management. PMID- 29603173 TI - Staging of Early Nonseminomatous Germ-Cell Testicular Cancer. AB - The common clinical staging techniques for nonseminomatous testicular cancer fail to predict the pathologic stage in a significant number of patients with Stages I, IIS, and IIA disease. Newer techniques such as ultrasonography and computed tomography are useful in more advanced disease (Stages IIB or higher), but neither can detect microscopic metastases (Stage IIA). The accuracy of clinical staging may be improved by the discovery of new tumor markers and the devising of assays for tumor-associated antigens, but at present retroperitoneal lymphadenectomy is needed for staging as well as for treatment. PMID- 29603174 TI - The Role of Biologic Tumor Markers in Testicular Cancer. AB - Serial quantitative measurements of serum alphafetoprotein (AFP) and human chorionic gonadotropin (HCG) have been prospectively studied in 386 patients with testicular germ cell cancer during the past seven years using sensitive and specific radioimmunoassays (RIAS). When HCG and AFP was measured in patients with nonseminomatous testicular tumors (NSTT), about 90% of these patients with active tumors have elevated levels of serum HCG and/or AFP. These markers have proven valuable in reducing the clinical staging errors to 5-14% by measuring their serum levels during the pre- and post-lymphadenectomy periods. The role of these markers have been demonstrated in monitoring the therapy and determining the prognosis of patients with NSTT. Although serum AFP has not been observed in patients with seminoma, serum HCG has been observed in patients with pure seminoma. Although these markers are seen with certain other cancers, their differential diagnosis does not pose a problem. However, since most seminoma and about 10% of NSTT do not produce these markers, their value in differential diagnosis of a scrotal mass is limited. In interpretation of these markers, one should consider their biologic half-lives and their discordant behavior while the patient is under therapy. Concentrating the 24 hour urine and extracting the urinary HCG content by using a carboxy-terminal RIA enhance the potential for a more sensitive monitoring of the tumor burden and for guiding the therapy of certain patients with testicular cancer. Finally, there are a number of potential markers under investigation in our laboratory. PMID- 29603175 TI - Staging and Treatment of Neuroblastoma. AB - Advances in the treatment of neuroblastoma have been sparse in the past decade. This common tumor of childhood has not participated in the success seen in other pediatric solid tumors. Patients with local resectable tumors probably do not require irradiation (RT) or adjuvant chemotherapy. Gross residual disease (usually Stage III) does benefit from RT, and the value of chemotherapy has yet to be determined. Stage IV patients may not require resection of the primary; chemotherapy assumes a major role. Combinations, which include cyclophosphamide, vincristine, Adriamycin, and imidazole carboxamide have induced responses in more than 50% of patients. Survival though has improved little in spite of good response rates. PMID- 29603176 TI - External Radiation Therapy of Carcinoma of the Prostate. PMID- 29603177 TI - Psychological Impact of Urologic Cancer. AB - All involved in the therapeutic alliance feel stress: the patient, the family, and the care giver. Uncertainty breeds anxiety. Distress is minimized when all concerned have a shared, clear understanding of therapeutic goals and when emphasis is focused on what can be done. Openness concerning diagnosis and prognosis demands sustained and supportive follow-up. A shifting balance between denial and integration of reality usually exists. Irrespective of outcome, the patient and family cope with loss and uncertainty. In the presence of progressive illness, repeated losses compound the adjustment problem. Anticipated disfigurement due to radical surgery, alterations in body image particularly where sexual function is concerned, the necessity of urinary or fecal diversion, and side effects of therapy all require careful psychological preparation. Staff burnout may be minimized by attention to staff selection, training, supervision, support and communication. The bereaved constitute a high-risk population. Even a simple follow-up program may help them to adjust to their loss. PMID- 29603178 TI - Carcinoma in Situ of the Bladder. AB - Central to the earlier detection and effective treatment of bladder cancer is the understanding of the basic principle that in situ cancer, evolving from epithelial atypia or hyperplasia, is the early phase in the development of invasive bladder cancer. While it may be asymptomatic, irritative bladder symptoms such as frequency, urgency, and dysuria irrespective of bacteriuria are usually evident and should be evaluated with exfoliative urinary cytology to detect the presence of this cancer. Properly collected and skillfully interpreted cytologic examination of the urine is probably the most accurate screening test for this and other important varieties of bladder cancer. Improved technologic features of cystoscopy have aided in the identification of in situ cancer, particularly when multiple random cold biopsy specimens of all quadrants, including the trigone, of the bladder and of the prostatic urethra are employed. Such investigative methods recognize that in situ cancer is a generalized urothelial malignancy that very often involves ureteral, prostatic as well as all bladder mucosa. Despite the pathologic observation that this cancer shows an intense cellular activity, the temporal aspect of its transition from a superficial cancer to an invasive one remains unpredictable, although clearly finite. Treatment is controversial. Radical cystectomy should effect cure if recommended early and before it becomes clinically apparent that the disease is already invasive in some urothelial locations. If the cancer appears to be localized to a relatively small (5 cm) area of the bladder and the patient's symptoms are not excessive, intravesical chemotherapy using such preparations as Thio-tepa, mitomycin, Adriamycin, or epodyl may result in a temporary, sometimes complete, remission. PMID- 29603179 TI - T3 Bladder Cancer: The Case for Higher Radiation Dosage. AB - Examination of the published results of selected major studies of radiotherapy for T3 bladder cancer strengthens two convictions: 1) that incidence and degree of radiation-induced stage reduction are dose-dependent and 2) that higher rates and greater degrees of tumor regression preoperatively are associated with higher rates of survival, i.e. high preoperative radiation doses are more effective than low ones. PMID- 29603180 TI - Chemotherapy of Metastatic Bladder Cancer. AB - Recent disease-oriented phase II clinical trials in advanced transitional cell carcinoma of the urothelial tract have defined the therapeutic efficacy of cis diamminedichloride platinum II, Adriamycin and methotrexate. Other agents which may have some activity include cyclophosphamide, the podophyllotoxins, hexamethylmelamine, and possibly 5-flourouracil. While combination drug regimens have been reported to induce higher remission rates when compared to single agents, prospective randomized trials will be needed to document enhanced therapeutic benefit. The problems in selecting appropriate patients and in defining response criteria in clinical trials in urothelial tumors are discussed. Chemotherapy data in the treatment of bladder cancer is summarized, using strict response criteria. PMID- 29603181 TI - HOTAIR gene polymorphisms contribute to increased neuroblastoma susceptibility in Chinese children. AB - BACKGROUND: Neuroblastoma is the most frequently diagnosed extracranial solid tumor in children. Previous studies have shown that single-nucleotide polymorphisms in some genes are associated with the risk of multiple cancers, including neuroblastoma. Although Hox transcript antisense intergenic RNA (HOTAIR) gene polymorphisms have been investigated in a variety of cancers, to the authors' knowledge the relationships between HOTAIR gene polymorphisms and neuroblastoma susceptibility have not been reported to date. The objective of the current study was to evaluate the correlation between HOTAIR gene polymorphisms and neuroblastoma risk in Chinese children. METHODS: The authors genotyped 6 polymorphisms (rs920778 A>G, rs12826786 C>T, rs4759314 A>G, rs7958904 G>C, rs874945 C>T, and rs1899663 C>A) of the HOTAIR gene in 2 Chinese populations including 393 neuroblastoma cases and 812 healthy controls. The strength of the associations was evaluated using odds ratios and 95% confidence intervals. Further stratification analyses were conducted to explore the association between the HOTAIR gene polymorphisms rs12826786 C>T, rs874945 C>T, and rs1899663 C>A with neuroblastoma susceptibility in terms of age, sex, clinical stage of disease, and sites of origin. RESULTS: The authors found that the rs12826786 C>T (P =.013), rs874945 C>T (P =.020), and rs1899663 C>A (P =.029) polymorphisms were significantly associated with increased neuroblastoma risk. In stratification analyses, these associations were more predominant in females and among patients with tumor in the retroperitoneal region or mediastinum. The remaining 3 polymorphisms were not found to be related to neuroblastoma susceptibility. CONCLUSIONS: The results of the current study verified that HOTAIR gene polymorphisms are associated with increased neuroblastoma risk and suggest that HOTAIR gene polymorphisms might be a potential biomarker for neuroblastoma susceptibility. Cancer 2018;124:2599-606. (c) 2018 American Cancer Society. PMID- 29603182 TI - Collagen deposition in chronic hidradenitis suppurativa: potential role for CD163+ macrophages. PMID- 29603183 TI - Intraspecific trait variation and the leaf economics spectrum across resource gradients and levels of organization. AB - Understanding patterns of functional trait variation across environmental gradients offers an opportunity to increase inference in the mechanistic causes of plant community assembly. The leaf economics spectrum (LES) predicts global tradeoffs in leaf traits and trait-environment relationships, but few studies have examined whether these predictions hold across different levels of organization, particularly within species. Here, we asked (1) whether the main assumptions of the LES (expected trait relationships and shifts in trait values across resource gradients) hold at the intraspecific level, and (2) how within species trait correlations scale up to interspecific or among-community levels. We worked with leaf traits of saplings of woody species growing across light and soil N and P availability gradients in temperate rainforests of southern Chile. We found that ITV accounted for a large proportion of community-level variation in leaf traits (e.g., LMA and leaf P) and played an important role in driving community-level shifts in leaf traits across environmental gradients. Additionally, intraspecific leaf trait relationships were generally consistent with interspecific and community-level trait relationships and with LES predictions-e.g., a strong negative intraspecific LMA-leaf N correlation although, most trait relationships varied significantly among species, suggesting idiosyncrasies in the LES at the intraspecific level. PMID- 29603184 TI - The pot dealer state harms patients with cancer. PMID- 29603185 TI - Sex change in the dioecious palm Ceroxylon quindiuense (Arecaceae). PMID- 29603186 TI - Peristomal psoriasis: an extraintestinal manifestation of inflammatory bowel disease? PMID- 29603187 TI - Opioid Guidelines Are a Necessary Response to the Opioid Crisis. AB - Guidelines for opioid prescribing in noncancer pain have proliferated since the opioid crisis in the United States became widely recognized. The recently published Centers for Disease Control (CDC) guidelines for opioid prescribing have been controversial. Many of these concerns arise from underestimation of the scale of the opioid crisis, as well as misunderstanding what the guidelines actually say. Strict guidelines should be welcomed as a constructive approach to managing a thorny public health issue. PMID- 29603188 TI - Linking tree genetics and stream consumers: isotopic tracers elucidate controls on carbon and nitrogen assimilation. AB - Leaf litter provides an important nutrient subsidy to headwater streams, but little is known about how tree genetics influence energy pathways from litter to higher trophic levels. Despite the charge to quantify carbon (C) and nitrogen (N) pathways from decomposing litter, the relationship between litter decomposition and aquatic consumers remains unresolved. We measured litter preference (attachments to litter), C and N assimilation rates, and growth rates of a shredding caddisfly (Hesperophylax magnus, Limnephilidae) in response to leaf litter of different chemical and physical phenotypes using Populus cross types (P. fremontii, P. angustifolia, and F1 hybrids) and genotypes within P. angustifolia. We combined laboratory mesocosm studies using litter from a common garden with a field study using doubly labeled litter (13 C and 15 N) grown in a greenhouse and incubated in Oak Creek, Arizona, USA. We found that, in the lab, shredders initially chose relatively labile (low lignin and condensed tannin concentrations, rapidly decomposing) cross type litter, but preference changed within 4 d to relatively recalcitrant (high lignin and condensed tannin concentrations, slowly decomposing) litter types. Additionally, in the lab, shredder growth rates were higher on relatively recalcitrant compared to labile cross type litter. Over the course of a three-week field experiment, shredders also assimilated more C and N from relatively recalcitrant compared to labile cross type litter. Finally, among P. angustifolia genotypes, N assimilation by shredders was positively related to litter lignin and C:N, but negatively related to condensed tannins and decomposition rate. C assimilation was likewise positively related to litter C:N, and also to litter %N. C assimilation was not associated with condensed tannins or lignin. Collectively, these findings suggest that relatively recalcitrant litter of Populus cross types provides more nutritional benefit, in terms of N fluxes and growth, than labile litter, but among P. angustifolia genotypes the specific trait of litter recalcitrance (lignin or tannins) determines effects on C or N assimilation. As shredders provide nutrients and energy to higher trophic levels, the influence of these genetically based plant decomposition pathways on shredder preference and performance may affect community and food web structure. PMID- 29603189 TI - Along the speciation continuum: Quantifying intrinsic and extrinsic isolating barriers across five million years of evolutionary divergence in California jewelflowers. AB - Understanding the relative roles of intrinsic and extrinsic reproductive barriers, and their interplay within the geographic context of diverging taxa, remains an outstanding challenge in the study of speciation. We conducted a comparative analysis of reproductive isolation in California Jewelflowers (Streptanthus, s.l., Brassicaceae) by quantifying potential barriers to gene flow at multiple life history stages in 39 species pairs spanning five million years of evolutionary divergence. We quantified nine potential pre- and postzygotic barriers and explored patterns of reproductive isolation in relation to genetic distance. Intrinsic postzygotic isolation was initially weak, increased at intermediate genetic distances, and reached a threshold characterized by complete genetic incompatibility. Climatic niche differences were strong at shallow genetic distances, and species pairs with overlapping ranges showed slight but appreciable phenological isolation, highlighting the potential for ecological barriers to contribute to speciation. Geographic analyses suggest that speciation is not regionally allopatric in the California Jewelflowers, as recently diverged taxa occur in relatively close proximity and display substantial range overlap. Young pairs are characterized by incomplete intrinsic postzygotic isolation, suggesting that extrinsic barriers or fine-scale spatial segregation are more important early in the divergence process than genetic incompatibilities. PMID- 29603190 TI - Tropical herbivorous phasmids, but not litter snails, alter decomposition rates by modifying litter bacteria. AB - Consumers can alter decomposition rates through both feces and selective feeding in many ecosystems, but these combined effects have seldom been examined in tropical ecosystems. Members of the detrital food web (litter-feeders or microbivores) should presumably have greater effects on decomposition than herbivores, members of the green food web. Using litterbag experiments within a field enclosure experiment, we determined the relative effects of common litter snails (Megalomastoma croceum) and herbivorous walking sticks (Lamponius portoricensis) on litter composition, decomposition rates, and microbes in a Puerto Rican rainforest, and whether consumer effects were altered by canopy cover presence. Although canopy presence did not alter consumers' effects, focal organisms had unexpected influences on decomposition. Decomposition was not altered by litter snails, but herbivorous walking sticks reduced leaf decomposition by about 50% through reductions in high quality litter abundance and, consequently, lower bacterial richness and abundance. This relatively unexplored but potentially important link between tropical herbivores, detritus, and litter microbes in this forest demonstrates the need to consider autotrophic influences when examining rainforest ecosystem processes. PMID- 29603191 TI - Model-Informed Drug Development and Review for Generic Products: Summary of FDA Public Workshop. AB - On October 2nd and 3rd , 2017, the US Food and Drug Administration (FDA) hosted a public workshop titled "Leveraging Quantitative Methods and Modeling to Modernize Generic Drug Development and Review."1 This report summarizes Session 2 of the public workshop: "Model Informed Drug Development and Review for Generic Products." The session focused on the application of quantitative methods and modeling in modernizing the generic drug development and review. PMID- 29603192 TI - Paederus dermatitis - touched by champion flies - three clinical manifestations of pederin toxin-inflicted dermatitis. PMID- 29603193 TI - Cutaneous protothecosis in a patient on ustekinumab for psoriasis. PMID- 29603194 TI - Immune privilege disruption in folliculotropic mycosis fungoides: investigation of major histocompatibility complex antigen expression. AB - BACKGROUND: Folliculotropic mycosis fungoides (FMF) is a cutaneous T-cell lymphoma mainly affecting the hair follicle, which seems to represent a place of immune privilege phenomenon. OBJECTIVES: To explore a possible role of immune privilege (IP) in FMF analyzing the major histocompatibility complex (MHC) expression. METHODS: Immunohistochemistry for HLA-G and MHC-II was performed to formalin-fixed paraffin-embedded cutaneous skin biopsies of FMF patients (n = 43), conventional mycosis fungoides (CMF; n = 13), alopecia areata (AA; n = 13), and normal scalp skin (NS; n = 12). RESULTS: HLA-G expression was lower in FMF (34%: 14/41) and CMF (18%: 2/11) groups compared to alopecia areata (92%:11/12) and normal scalp skin group (100%: 12/12). MHC-II expression in hair follicle was greater in the FMF group (18/42: 43%) compared to AA (0%) and NS (0%). HLA-G and MHC-II expression in cellular infiltrate had no difference among FMF and CMF groups and was different compared to the AA group. CONCLUSIONS: Our data support the hypothesis of disruption of immune privilege based on the lower expression of HLA-G and higher expression of MHC-II in the follicular epithelium in mycosis fungoides compared to alopecia areata and normal scalp skin. The lack of difference between FMF and CMF groups did not support the role of these molecules as a driver of folliculotropism. The expression of MHC molecules seems to be different between neoplastic and inflammatory infiltrates. The definitive significance of expression of the MHC molecules remains unclear, and more studies are necessary to fully understand the role of these molecules in cutaneous lymphomas. PMID- 29603195 TI - A Method to Create a Horizontal Resistance Layer by Injection of a Viscous Fluid: PLAID. AB - We present a method to create a horizontal resistance layer at desired depth below soil surface to decrease seepage over a relatively large area. The layer is produced in a continuous process by means of numerous temporary screens of wells. Between each pair of screens groundwater flow is forced in horizontal direction. In the center of such flow, along virtual parallel flow lines, a chemical, viscous and dense fluid is injected that produces a clogging substance within several hours. The impact of density is overcome by the forced flow between screens. The impact of viscosity on the flow distribution is handled by adaptation of the fluxes and heads at the filters in the screens. The resulting procedure includes multistep injection and is supported by model simulations. Though a small-scale proof of concept has been successful, the composition of the optimal chemical mixture needs further research. PMID- 29603196 TI - Reply to The pot dealer state harms patients with cancer. PMID- 29603197 TI - The role of landscape connectivity in resistance, resilience, and recovery of multi-trophic microarthropod communities. AB - There is a need to find generalizable mechanisms supporting ecological resilience, resistance, and recovery. One hypothesized mechanism is landscape connectivity, a habitat configuration that allows movement of biotic and abiotic resources between local patches. Whether connectivity increases all or only one of resistance, resilience, and recovery has not been teased apart, however, and has been difficult to test at large scales and for complex trophic webs. Natural microcosms offer a complex system that can be manipulated to test questions at a landscape-scale relative to the community of study. Here, we test the role of connectivity in altering resistance, resilience, and recovery to a gradient of heating disturbance in moss microcosms. To test across trophic levels, we focused on community composition as our metric of response and applied three connectivity treatments - isolation, connected to an equally disturbed patch, and connected to an undisturbed patch. We found that connectivity between equally disturbed patches boosted resistance of communities to disturbance. Additionally, recovery was linear and rapid in communities connected to undisturbed landscapes, hump shaped when connected to equally disturbed landscapes, and linear but slow in isolated communities. We did not find thresholds on the disturbance gradient at which disturbed communities exhibited zero or increasing dissimilarity to controls through time, so were unable to draw conclusions on the role of connectivity in ecological resilience. Ultimately, isolated communities exhibited increasingly variable composition and slow recovery patterns even in control communities when compared with connected treatments. PMID- 29603198 TI - Louis R. Cantilena, MD, PhD: March 15, 1954-December 16, 2017. PMID- 29603199 TI - Indirubin and NAD+ prevent mitochondrial ischaemia/reperfusion damage in fatty livers. AB - BACKGROUND: Fatty livers are considerably more susceptible to acute stressors, such as ischaemia/reperfusion (I/R). As the incidence of I/R is high due to surgical events and some pathologies, there is an urgent need to find strategies against I/R injury (I/RI) in fatty livers. We postulate that an acute pretreatment with indirubin-3'-oxime (Ind) or NAD+ prevents mitochondrial dysfunction associated with warm I/RI in fatty livers. MATERIALS AND METHODS: Zucker fatty rats were subjected to warm ischaemia and 12 hours of reperfusion. Ind or NAD+ was administered in the hepatic artery 30 minutes before ischaemia. Hepatic mitochondrial isolation was performed, and functional assays as well as molecular analysis were performed. RESULTS: Pretreatment decreased markers of liver injury while preserving mitochondrial cytochrome c content, which is related to the prevention of calcium-induced mitochondrial permeability transition (mPT), the decline in mitochondrial respiratory state 3 and ATP content. The generation of reactive oxygen species (ROS) was also diminished. Inhibition of GSK-3beta by Ind resulted in the prevention of cyclophilin-D (CypD) phosphorylation, unabling it to bind to the adenine nucleotide translocator (ANT), thus, preventing mPT induction. Furthermore, deacetylation of CypD at Lys residue by sirtuin 3 (SIRT3) caused its dissociation from ANT, contributing to an increase in mPT threshold in NAD+ -pretreated animals. CONCLUSIONS: Pretreatment with Ind or NAD+ protects fatty livers by maintaining mitochondrial calcium homoeostasis, thus, preserving mitochondrial function and energetic balance. As such, CypD might be a new protective target against I/RI in fatty livers. PMID- 29603200 TI - CYP-Mediated Drug-Drug Interaction Is Not a Major Determinant of Attenuation of Antiplatelet Function of Clopidogrel by Vonoprazan. PMID- 29603201 TI - PR-957 mediates neuroprotection by inhibiting Th17 differentiation and modulating cytokine production in a mouse model of ischaemic stroke. AB - Acute ischaemic stroke can induce secondary brain injury by activating an inflammatory response that contributes to clinical impairment. As a specific inhibitor of the immunoproteasome subunit low molecular weight polypeptide 7 (LMP7), PR-957 may participate in regulating pathophysiological and inflammatory responses in multiple diseases of the central nervous system (CNS). We investigated the neuroprotective properties of PR-957 in a mouse model of stroke, induced by middle cerebral artery occlusion (MCAO). After MCAO and injections of PR-957 or vehicle, we evaluated mice behaviourally using modified Neurological Severity Scores (mNSS) and sensorimotor tests, including the adhesive-removal test, a foot-fault test and an inclined plane test. Infarct volume was measured 24 and 72 h after MCAO. Infiltration by different lymphocyte subpopulations was evaluated by flow cytometry and immunofluorescent staining of brain tissue from the penumbral area. Quantitative real-time polymerase chain reaction analysis and enzyme-linked immunosorbent assay were used to measure the expression of proinflammatory cytokines: interkeukin (IL)-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-10, IL-12, IL-17A, interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha, granulocyte colony-stimulating factor (GCSF) and granulocyte-macrophage colony stimulating factor (GM-CSF). Expression of phosphorylated signal transducer and activator of transcription 3 (pSTAT-3) protein levels in brain was measured by immunoblot. MCAO mice treated with PR-957 showed a significant decrease in infarct volume and had mild neurological deficits compared to vehicle-treated mice. PR-957 administration also significantly decreased IL-1beta, IL-6, IL-12, IL-17A and TNF-alpha. PR-957 provides neuroprotection via inhibiting T lymphocyte infiltration and decreasing T helper type 17 (Th17) cell differentiation in MCAO mice, which may result from the reduced expression of pSTAT-3. The neuroprotective effect of PR-957 indicates its potential utility as anti inflammatory therapy for ischaemic stroke. PMID- 29603202 TI - The Effects of a Couples-Based Health Behavior Intervention During Pregnancy on Latino Couples' Dyadic Satisfaction Postpartum. AB - Many couples tend to report steadily decreasing relationship quality following the birth of a child. However, little is known about the postpartum period for Latino couples, a rapidly growing ethnic group who are notably underserved by mental and physical health caregivers in the United States. Thus, this study investigated whether a brief couples' intervention focused on helping couples support each other while increasing healthy behaviors might improve dyadic functioning postpartum. This study presents secondary analyses of data regarding couple functioning from a larger randomized controlled trial with 348 Latino couples to promote smoking cessation. Portions of the intervention taught the couple communication and problem-solving skills to increase healthy behavior. Couples participated in four face-to-face assessments across 1 year starting at the end of the first trimester. Latent growth curve analyses revealed that the treatment group reported an increase in relationship satisfaction and constructive communication after the intervention, which diminished by 1-year follow-up, returning couples to their baseline levels of satisfaction. Results suggest that incorporating a brief couple intervention as part of a larger health intervention for Latinos may prevent postpartum decreases in relationship satisfaction. PMID- 29603204 TI - Response Time Adjustment in the Stop Signal Task: Development in Children and Adolescents. AB - Adjusting speed to maintain fast and accurate performance is critical to goal directed behavior. This study examined development of response time adjustments in the stop signal task in 13,709 individuals aged 6-17 years (49.0% Caucasian) across four trial types: correct and incorrect go, successful (stop-inhibit), and failed (stop-respond) trials. People sped more after correct than incorrect go responses and slowed more after failed than successful stop trials. Greater slowing after stop-respond but less slowing after stop-inhibit trials was associated with better response inhibition. Response time adjustments were evident in children as young as age 6, developed throughout childhood, and plateaued by age 10. Results were consistent with the predictions of the error detection and shifting goal priority hypotheses for adjustments. PMID- 29603203 TI - Association of interleukin 22 gene polymorphisms and serum IL-22 level with risk of systemic lupus erythematosus in a Chinese population. AB - The aim of this study was to investigate the association between the single nucleotide polymorphisms (SNPs) of the interleukin 22 (IL-22) gene and systemic lupus erythematosus (SLE) in a Chinese population. Three IL-22 SNPs (rs2227485, rs2227513 and rs2227491) were genotyped using SNaPshot SNP genotyping assays and identified by sequencing in 314 SLE patients and 411 healthy controls. The IL-22 level of serum was assessed by enzyme-linked immunosorbent assay (ELISA) kits. Data were analysed by spss version 17.0 software. We found that rs2227513 was associated with an increased risk of SLE [AG versus AA: adjusted odds ratio (aOR) = 2.24, 95% confidence interval (CI) = 1.22-4.12, P = 0.010; G versus. A: adjusted OR = 2.18, 95% CI = 1.20-3.97, P = 0.011]. Further analysis in patients with SLE showed that the AG genotype and G allele were associated with an increased risk of renal disorder in SLE (G versus A: aOR = 3.09, 95% CI = 1.30 7.33, P = 0.011; AG versus. AA: aOR = 3.25, 95% CI = 1.35-7.85, P = 0.009). In addition, the concentration of IL-22 was significantly lower in the rs2227513 AG genotype compared with AA genotype (P = 0.028). These results suggest that rs2227513 polymorphism might contribute to SLE susceptibility, probably by decreasing the expression of IL-22. PMID- 29603205 TI - Neuroticism and Marital Satisfaction During the Early Years of Chinese Marriage: The Mediating Roles of Marital Attribution and Aggression. AB - On the basis of three annual waves of data obtained from 268 Chinese couples, we tested an actor-partner interdependence mediation model in which spouses' neuroticism was linked to their own and partners' marital satisfaction through both intrapersonal processes (i.e., marital attribution) and interpersonal processes (i.e., marital aggression). Considering intra- and interpersonal processes simultaneously, four indirect, mediating pathways were identified: Time 1 Wives' Neuroticism -> Time 2 Wives' Attribution or Aggression, while controlling for Time 1 Wives' Attribution or Aggression -> Time 3 Wives' or Husbands' Marital Satisfaction, while controlling for Time 1 Wives' or Husbands' Marital Satisfaction. This study not only adds to a limited body of research examining why neuroticism is associated with conjugal well-being, but also extends prior research by focusing on Chinese couples and utilizing a longitudinal, dyadic mediation model. Such findings have important practical implications. Couples involving neurotic partners may benefit from interventions based on cognitive-behavioral approaches. When working with couples challenged by neuroticism, practitioners need to help them address dysfunctional interactive patterns as well as distorted cognitive styles. PMID- 29603206 TI - Critiquing the CDC Opioid Guideline: Some Light From the Heat. AB - Released in 2016, the Centers for Disease Control and Prevention (CDC) Guideline for Prescribing Opioids for Chronic Pain has been met with both praise and criticism. In this issue of the Journal, two commentaries address the guideline's strengths and limitations. While the authors differ in their assessment of the guideline, they share a common objective: safer opioid prescribing. Followed carefully, the CDC guideline will facilitate this, but followed carelessly it has the potential to cause harm. PMID- 29603207 TI - Acquired ichthyosis associated with gastric adenocarcinoma. PMID- 29603208 TI - Impacts of a Rural Subdivision on Groundwater Quality: Results of Long-Term Monitoring. AB - A rural subdivision in south central Wisconsin was instrumented with monitoring wells and lysimeters before, during, and after its construction to examine the impacts of the unsewered subdivision on groundwater quality and quantity. Prior to construction, the 78-acre (32 ha) site was farmland. Sixteen homes were constructed beginning in 2003. Initial monitoring from 2002 to 2005 showed that groundwater beneath the site had been impacted by previous agricultural use, with nitrate-N values as high as 30 mg/L and some detections of the herbicide atrazine. Our 12-year study shows that the transition from agricultural to residential land use has changed groundwater quality in both negative and positive ways. Although groundwater elevations showed typical seasonal fluctuations each year, there were no measurable changes in groundwater levels or general flow directions during the 12-year study period. Chloride values increased in many wells, possibly as a result of road salting or water softener discharge. Nitrate concentrations varied spatially and temporally over the study period, with some initial concentrations substantially above the drinking water standard. In some wells, nitrate and atrazine levels have declined substantially since agriculture ceased. However, atrazine was still present at trace concentrations throughout the site in 2014. Wastewater tracers show there are small but detectable impacts from septic effluent on groundwater quality. Particle traces based on a groundwater flow model are consistent with the hypothesis that septic leachate has impacted groundwater quality. PMID- 29603209 TI - Proximate composition, lipid utilization and validation of a non-lethal method to determine lipid content in migrating American shad Alosa sapidissima. AB - Lipid content forms the most important energy reserve in anadromous fish and can limit survival, migration and reproductive success. A fat meter was evaluated and compared with a traditional extractive method of measuring available lipid for migrating American shad Alosa sapidissima in the Connecticut River, U.S.A. The fat meter gives rapid (<10 s) and non-lethal lipid measurements, whereas traditional methods require lethal sampling that is both time consuming and expensive. The fat-meter readings had a strong relationship to traditional lipid extractions for 60 fish, 30 whole body (R2 = 0.72) and 30 fillet only (R2 = 0.81). Additional validation showed that fat-meter readings captured the gradual decrease of lipid in individual fish over time, were not affected by removal of gonads or scales and were stable for fish exposed to water or air for 24 h after death. These experiments indicate that the fat meter can be used as a reliable tool for future A. sapidissima energetic studies, allowing for larger sample sizes and non-lethal sampling. PMID- 29603210 TI - Cellular composition and organization of the spinal cord central canal during metamorphosis of the frog Xenopus laevis. AB - Studying the cellular composition and morphological changes of cells lining the central canal during Xenopus laevis metamorphosis could contribute to understand postnatal development and spinal cord regeneration. Here we report the analysis of central canal cells at different stages during metamorphosis using immunofluorescence for protein markers expression, transmission and scanning electron microscopy and cell proliferation assays. The central canal was regionalized according to expression of glial markers, ultrastructure, and proliferation in dorsal, lateral, and ventral domains with differences between larvae and froglets. In regenerative larvae, all cell types were uniciliated, have a radial morphology, and elongated nuclei with lax chromatin, resembling radial glial cells. Important differences in cells of nonregenerative froglets were observed, although uniciliated cells were found, the most abundant cells had multicilia and revealed extensive changes in the maturation and differentiation state. The majority of dividing cells in larvae corresponded to uniciliated cells at dorsal and lateral domains in a cervical-lumbar gradient, correlating with undifferentiated features. Neurons contacting the lumen of the central canal were detected in both stages and revealed extensive changes in the maturation and differentiation state. However, in froglets a very low proportion of cells incorporate 5-ethynyl-2'-deoxyuridine (EdU), associated with the differentiated profile and with the increase of multiciliated cells. Our work showed progressive changes in the cell types lining the central canal of Xenopus laevis spinal cord which are correlated with the regenerative capacities. PMID- 29603211 TI - Moving from frugivory to seed dispersal: Incorporating the functional outcomes of interactions in plant-frugivore networks. AB - There is growing interest in understanding the functional outcomes of species interactions in ecological networks. For many mutualistic networks, including pollination and seed dispersal networks, interactions are generally sampled by recording animal foraging visits to plants. However, these visits may not reflect actual pollination or seed dispersal events, despite these typically being the ecological processes of interest. Frugivorous animals can act as seed dispersers, by swallowing entire fruits and dispersing their seeds, or as pulp peckers or seed predators, by pecking fruits to consume pieces of pulp or seeds. These processes have opposing consequences for plant reproductive success. Therefore, equating visitation with seed dispersal could lead to biased inferences about the ecology, evolution and conservation of seed dispersal mutualisms. Here, we use natural history information on the functional outcomes of pairwise bird-plant interactions to examine changes in the structure of seven European plant frugivore visitation networks after non-mutualistic interactions (pulp pecking and seed predation) have been removed. Following existing knowledge of the contrasting structures of mutualistic and antagonistic networks, we hypothesized a number of changes following interaction removal, such as increased nestedness and lower specialization. Non-mutualistic interactions with pulp peckers and seed predators occurred in all seven networks, accounting for 21%-48% of all interactions and 6%-24% of total interaction frequency. When non-mutualistic interactions were removed, there were significant increases in network-level metrics such as connectance and nestedness, while robustness decreased. These changes were generally small, homogenous and driven by decreases in network size. Conversely, changes in species-level metrics were more variable and sometimes large, with significant decreases in plant degree, interaction frequency, specialization and resilience to animal extinctions and significant increases in frugivore species strength. Visitation data can overestimate the actual frequency of seed dispersal services in plant-frugivore networks. We show here that incorporating natural history information on the functions of species interactions can bring us closer to understanding the processes and functions operating in ecological communities. Our categorical approach lays the foundation for future work quantifying functional interaction outcomes along a mutualism antagonism continuum, as documented in other frugivore faunas. PMID- 29603212 TI - Health, well-being, and psychopathology in a clinical population: Structure and discriminant validity of Mental Health Continuum Short Form (MHC-SF). AB - OBJECTIVE: The literature suggests a distinction between illness (negative health) and the ability to cope with challenges such as illness (positive health). The two continua model of mental health distinguishes psychiatric symptoms (illness) from well-being (positive health). Well-being consists of hedonic, eudaimonic, and social well-being, constituting one factor that is moderately correlated with psychopathology in the general population. In a mental health care population, we examined whether the three dimensions of well-being are distinguishable and whether well-being is also moderately correlated with symptoms. METHOD: A representative sample of 1,069 patients (63% female, 47% male; mean age: 42 years) voluntarily completed the Mental Health Continuum-Short Form (MHC-SF), a 14-item test that assesses three components of well-being. RESULTS: Confirmatory factor analysis revealed a model with strong correlations between the three subscales of the MHC-SF, indicating poor discriminant validity. Furthermore, the MHC-SF was strongly correlated (r = -.71) with the symptomatic distress scale of the OQ-45. Exploratory factor analysis permitted a two-factor solution, providing support for the two continua model of mental health. However, the explained variance of the second factor (well-being) was meager in comparison with the first factor (psychopathology). The results of a canonic correlation did not confirm the two continua model, and only a model with one common canonical factor was significant. CONCLUSIONS: For patients with clinical levels of psychopathology, the level of well-being and psychopathology correlate much higher than in the general population. Well-being and psychopathology are so entwined that the supposed distinction should be seriously questioned. PMID- 29603213 TI - Associations of cigarette smoking and alcohol drinking with stomach cancer survival: A prospective patient cohort study in Japan. AB - Cigarette smoking and alcohol drinking may affect the prognosis of stomach cancer, but evidence has been inconsistent. We investigated the associations between pretreatment smoking and alcohol drinking and the risk of all-cause and stomach cancer death among 1,576 patients with histologically confirmed stomach cancer diagnosed during 1997-2010 at a single hospital in Japan. Histories of smoking and alcohol drinking were assessed using a self-administered questionnaire. The patients were followed until December 31, 2013. The Cox proportional hazards model was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). During 9,625.1 person-years, 670 all-cause and 419 stomach cancer deaths were documented. Among the patients overall, ever-drinking was significantly associated with an increased risk of all-cause death (HR: 1.25; 95% CI: 1.03-1.51), but not stomach cancer death. Positive linear associations with the frequency of drinking (ptrend = 0.02) and the amount of alcohol consumed per day (ptrend = 0.03) were observed for the risk of all-cause death. Ever-smoking was not related to either the risk of all-cause or stomach cancer death. Conversely, among the patients who underwent curative resection, a significant positive association was found between ever-smoking and the risk of stomach cancer death (HR: 2.44; 95% CI: 1.17-5.08). A positive association was also found for earlier age at start of smoking (ptrend = 0.0046). Pretreatment smoking and alcohol drinking have significant effects on stomach cancer survival. Lifestyle adjustments throughout life may improve survival. PMID- 29603214 TI - Tumor necrosis factor-alpha inhibitors and risk of non-Hodgkin lymphoma in a cohort of adults with rheumatologic conditions. AB - Based on limited evidence, the U.S. Food and Drug Administration (FDA) issued a black box warning for the use of tumor necrosis factor-alpha inhibitors (TNFIs) and risk of non-Hodgkin lymphoma (NHL). Our objective was to determine the risk of NHL associated with TNFI use by duration and type of anti-TNF agent. We performed a nested case-control study within a retrospective cohort of adults with rheumatologic conditions from a U.S. commercial health insurance database between 2009 and 2015. Use of TNFIs (infliximab, adalimumab, etanercept, golimumab and certolizumab pegol) and conventional-synthetic disease-modifying antirheumatic drugs (csDMARDs) was identified, and conditional logistic regression models were used to estimate adjusted odds ratios (OR) and 95% confidence intervals (CI) for risk of NHL. From a retrospective cohort of 55,446 adult patients, 101 NHL cases and 984 controls matched on age, gender and rheumatologic indication were included. Compared to controls, NHL cases had greater TNFI use (33% vs. 20%) but were similar in csDMARD use (70% vs. 71%). TNFI ever-use was associated with nearly two-fold increased risk of NHL (OR = 1.93; 95% CI: 1.16-3.20) with suggestion of increasing risk with duration (P trend = 0.05). TNF fusion protein (etanercept) was associated with increased NHL risk (OR = 2.73; 95% CI: 1.40-5.33), whereas risk with anti-TNF monoclonal antibodies was not statistically significant (OR = 1.77; 95% CI: 0.87-3.58). In sensitivity analyses evaluating confounding by rheumatologic disease severity, channeling bias was not likely to account for our results. Our findings support the FDA black box warning for NHL. Continued surveillance and awareness of this rare but serious adverse outcome are warranted with new TNFIs and biosimilar products forthcoming. PMID- 29603215 TI - Identifying Key Flavors in Strawberries Driving Liking via Internal and External Preference Mapping. AB - : Australian consumers desire the development of a more flavorsome Australian strawberry cultivar. To aid in the development of well-liked strawberries, the attributes driving liking need to be identified. The objective of this research is to apply Preference Mapping (PM) techniques to the descriptive profile of commercial and newly bred strawberry cultivars, together with consumer preference data to determine the flavors contributing to liking. A trained sensory panel (n = 12) used Quantitative Descriptive Analysis (QDA(r)) methodology to evaluate two appearance, seven aroma, five texture, 10 flavor and 10 aftertaste attributes of three commercial strawberry cultivars and six elite breeding lines grown in Victoria, Australia. Strawberry consumers (n = 150) assessed their liking of the same strawberry cultivars. QDA(r) significantly discriminated strawberries on 28 of the 34 sensory attributes. There were significant differences in hedonic ratings of strawberries (F(8,714) = 11.5, P = 0.0001), with Hierarchical Cluster Analysis (HCA) identifying three consumer clusters each displaying differing patterns of preference. Internal and external PM techniques were applied to the data to identify the attributes driving consumer acceptability. Sweet, berry, caramel, fruity and floral attributes were identified as most contributing to liking. Sour, citrus, green, astringent, firm and gritty attributes were conversely associated with a reduction in consumer liking. Elite Lines 2 and 6 have been identified as having the broadest appeal, satisfying between 60% and 70% of consumers in the population assessed, thus the introduction of these cultivars should satisfy the largest group of consumers in the Australian market. PRACTICAL APPLICATION: The results of this research could be applied to breeding programs, to ensure newly bred cultivars express characteristics that were identified as well-liked amongst consumers. In addition, this research provides evidence for marketing strawberries by cultivar, to assist consumers in identifying those strawberries for which they have a preference. PMID- 29603217 TI - When repetitive mental sets increase cognitive flexibility in adolescent obsessive-compulsive disorder. AB - BACKGROUND: A major facet of obsessive-compulsive disorder (OCD) is cognitive inflexibility. However, sometimes, cognitive flexibility can be needed to reuse recently abandoned mental sets. Therefore, cognitive flexibility can in certain cases be useful to reinstate some form of rigid, repetitive behavior characterizing OCD. We test the counterintuitive hypothesis that under such circumstances, cognitive flexibility is better in OCD patients than controls. METHODS: We examined N = 20 adolescent OCD patients and N = 22 controls in a backward inhibition (BI) paradigm. This was combined with event-related potential (ERP) recordings and source localization. The BI effect describes the cost of overcoming the inhibition of a recently abandoned mental set that is relevant again. Therefore, a strong BI effect is disadvantageous for cognitive flexibility. RESULTS: Compared to controls, OCD patients revealed a smaller backward inhibition effect. The EEG data revealed larger P1 amplitudes in backward inhibition trials in the OCD group, which was due to activation differences in the inferior frontal gyrus (BA47). The severity of clinical symptoms predicted these neurophysiological modulations. The power of the observed effects was about 95%. CONCLUSIONS: The study shows that cognitive flexibility can be better in OCD than controls. This may be the case in situations where superior abilities in the reactivation of repeating mental sets and difficulties to process new ones coincide. This may be accomplished by intensified inhibitory control mechanisms. The results challenge the view on OCD, since OCD is not generally associated with cognitive inflexibility. PMID- 29603216 TI - Ohmic Heating Assisted Lye Peeling of Pears. AB - : Currently, high concentrations (15% to 18%) of lye (sodium hydroxide) are used in peeling pears, constituting a wastewater handling and disposal problem for fruit processors. In this study, the effect of ohmic heating on lye peeling of pears was investigated. Pears were peeled using 0.5%, 1%, 2%, and 3% NaOH under different electric field strengths at two run times and their peeled yields were compared to that obtained at 2% and 18% NaOH with conventional heating. Results revealed that ohmic heating results in greater than 95% peeled yields and the best peel quality at much lower concentrations of lye (2% NaOH at 532 V/m and 3% NaOH at 426 and 479 V/m) than those obtained under conventional heating conditions. Treatment times of 30 and 60 s showed no significant differences. Within the studied range, the effects of increasing field strength yielded no significant additional benefits. These results confirm that the concentration of lye can be significantly lowered in the presence of ohmic heating to achieve high peeled yields and quality. PRACTICAL APPLICATION: Our work shows that lye concentrations can be greatly reduced while peeling pears, resulting in significant savings in use of caustic chemicals, reduced costs for effluent treatment and waste disposal. PMID- 29603218 TI - Caudal mesopallial neurons in female songbirds bridge sensory and motor brain regions. AB - Female songbirds use male song as an indicator of fitness and use that information to select their mate. Investigations of the female auditory system have provided evidence that the neurons within the caudal mesopallium (CM) are involved in the processing of songs that a female finds attractive, however, it is not clear how CM may exert its influence on behavioral indicators of mate choice. In the present study, anterograde tracing revealed the efferent connections of the female songbird CM. The results demonstrate connections to other auditory regions previously described in males, as well as novel connections to brain regions implicated in motor control. As in males, CM neurons in females project robustly to the lateral and medial extents of the caudal nidopallium, and to the ventral intermediate arcopallium. In a novel finding that is not present in males, CM neurons also project to the robust nucleus of the arcopallium and to the caudal striatum. Calling behavior and the expression of copulation solicitation displays are key indicators of female mate choice, and the projections found here bridge critical gaps necessary to understand how auditory perception can influence circuits related to the expression of those affiliative behaviors in female songbirds. PMID- 29603220 TI - Distribution of vesicular glutamate transporters in the brain of the turtle (Pseudemys scripta elegans). AB - The distribution of glutamatergic neurons has been extensively studied in mammalian and avian brains, but its distribution in a reptilian brain remains unknown. In the present study, the distribution of subpopulations of glutamatergic neurons in the turtle brain was examined by in situ hybridization using probes for vesicular glutamate transporter (VGLUT) 1-3. Strong VGLUT1 expression was observed in the telencephalic pallium; the mitral cells of the olfactory bulb, the medial, dorsomedial, dorsal, and lateral parts of the cerebral cortex, pallial thickening, and dorsal ventricular ridge; and also, in granule cells of the cerebellar cortex. Moderate to weak expression was found in the lateral and medial amygdaloid nuclei, the periventricular cellular layer of the optic tectum, and in some brainstem nuclei. VGLUT2 was weakly expressed in the telencephalon but was intensely expressed in the dorsal thalamic nuclei, magnocellular part of the isthmic nucleus, brainstem nuclei, and the rostral cervical segment of the spinal cord. The cerebellar cortex was devoid of VGLUT2 expression. The central amygdaloid nucleus did not express VGLUT1 or VGLUT2. VGLUT3 was localized in the parvocellular part of the isthmic nucleus, superior and inferior raphe nuclei, and cochlear nucleus. Our results indicate that the distribution of VGLUTs in the turtle brain is similar to that in the mammalian brain rather than that in the avian brain. PMID- 29603219 TI - Error-related brain activity in pediatric anxiety disorders remains elevated following individual therapy: a randomized clinical trial. AB - BACKGROUND: Anxiety disorders are associated with an overactive action monitoring system as indexed by a larger error-related negativity (ERN). This study tests whether ERN magnitude changes following treatment, predicts response to treatment, and varies by treatment type. METHODS: The sample included 130 youth (9-14 years): youth with an anxiety disorder (ANX; n = 100) and healthy control (HC; n = 30) youth with no lifetime DSM-IV disorders. ANX youth were randomized to either a manualized cognitive-behavior therapy (CBT) or a comparison child centered therapy (CCT). The ERN was assessed before and after 16 sessions of treatment and within a comparable interval for HC. Subjective ratings about making errors on the task were obtained following each testing session. The ClinicalTrials.gov identifier is NCT00774150. RESULTS: The ERN was larger in ANX than HC youth but ERN magnitude did not significantly change following treatment in the ANX youth, regardless of treatment type, and baseline ERN did not predict treatment response. Post-task ratings revealed that ANX youth worried more about task performance feedback than HC. Like the ERN, mean ratings did not significantly change following treatment. However, these ratings were not correlated with ERN amplitude. CONCLUSIONS: Findings of greater ERN in pediatric anxiety disorders are replicated in a larger sample. More importantly, findings from this randomized control trial show that a larger ERN and feeling worried about performance feedback remain unchanged following treatment and are unrelated to treatment response. Such findings suggest that action monitoring systems remain overactive in anxious youth treated with psychotherapy, suggesting the need for future investigation of whether novel complimentary cognitive and emotional training programs can modify these systems would be warranted. PMID- 29603221 TI - Primary care physicians and nurses: Targets for basic periodontal education. AB - BACKGROUND: Early diagnosis may improve patients' quality of life and reduce the lifelong social and financial burden inherent to treatment. Growing evidence supports the importance of a healthy periodontium in systemic health. Diagnosis depends on the patient and the healthcare professional. As many patients seek physicians' advice first, this study aims at assessing periodontal knowledge in a general population and their primary care physicians and nurses. METHODS: This is a cross-sectional study using an anonymous questionnaire applied to randomly selected laypersons (March to June 2016), and to physicians and nurses at their workplaces (October to December 2016) in Ourense, Spain. Sample size for the general population was determined by quota sampling. RESULTS: A total of 1,469 people entered the study. All healthcare workers and 624 (47.1%) laypersons were familiar with periodontitis. Bacterial etiology of periodontitis was recognized by 25 (4%) laypersons, 23 (34.3%) physicians, and 11 (16.6%) nurses. The following periodontal problems were experienced: 1) gingival redness: laypersons 14.4%, physicians 16.4%, and nurses 21.2%; 2) gingival bleeding: laypersons 22.2%, physicians 50.7%, and nurses 50%; 3) tooth mobility: laypersons 34.9%, physicians 7.4%, and nurses 6%; and 4) bleeding while toothbrushing: laypersons 44.3%, physicians 8.9%, and nurses 15.1%. More than a third of laypersons (37%) think periodontitis is related to other health problems, together with 53% of physicians and 47% of nurses. CONCLUSIONS: Our results show a low degree of periodontal knowledge both amongst the public and their primary care physicians and nurses and unveil unreliable targets (primary healthcare workers) for educational interventions to improve early diagnosis and treatment of periodontal disorders. PMID- 29603222 TI - The influence of aquaculture unit proximity on the pattern of Lepeophtheirus salmonis infection of anadromous Salmo trutta populations on the isle of Skye, Scotland. AB - A total of 230 anadromous Salmo trutta (brown trout) were sampled in five sheltered coastal fjords (or sea lochs) on the Isle of Skye, Scotland, U.K., in 2016 at varying distances from active Atlantic salmon Salmo salar farms. Statistical models were developed to investigate potential correlations between salmon lice Lepeophtheirus salmonis burdens on S. trutta hosts and their proximity to S. salar farm cages. Significant correlations were found between lice burdens and fish fork length and proximity to the nearest S. salar farm. The probability of the presence of L. salmonis on fish hosts increased with fish host size and with distance from the nearest S. salar farm, but total lice burdens were highest in fish sampled near S. salar farms and decreased with distance. The proportion of different life-cycle stages of L. salmonis were also dependent on S. salar farm proximity, with higher juvenile lice numbers recorded at sites near S. salar farm cages. These results highlight the complexity of the relationship between S. trutta and L. salmonis infections on wild fish and emphasize the requirement of further research to quantify these effects to better inform conservation and management strategies, particularly in areas of active S. salar farm facilities. PMID- 29603223 TI - Assessment of Beer Quality Based on a Robotic Pourer, Computer Vision, and Machine Learning Algorithms Using Commercial Beers. AB - : Sensory attributes of beer are directly linked to perceived foam-related parameters and beer color. The aim of this study was to develop an objective predictive model using machine learning modeling to assess the intensity levels of sensory descriptors in beer using the physical measurements of color and foam related parameters. A robotic pourer (RoboBEER), was used to obtain 15 color and foam-related parameters from 22 different commercial beer samples. A sensory session using quantitative descriptive analysis (QDA(r) ) with trained panelists was conducted to assess the intensity of 10 beer descriptors. Results showed that the principal component analysis explained 64% of data variability with correlations found between foam-related descriptors from sensory and RoboBEER such as the positive and significant correlation between carbon dioxide and carbonation mouthfeel (R = 0.62), correlation of viscosity to sensory, and maximum volume of foam and total lifetime of foam (R = 0.75, R = 0.77, respectively). Using the RoboBEER parameters as inputs, an artificial neural network (ANN) regression model showed high correlation (R = 0.91) to predict the intensity levels of 10 related sensory descriptors such as yeast, grains and hops aromas, hops flavor, bitter, sour and sweet tastes, viscosity, carbonation, and astringency. PRACTICAL APPLICATIONS: This paper is a novel approach for food science using machine modeling techniques that could contribute significantly to rapid screenings of food and brewage products for the food industry and the implementation of Artificial Intelligence (AI). The use of RoboBEER to assess beer quality showed to be a reliable, objective, accurate, and less time consuming method to predict sensory descriptors compared to trained sensory panels. Hence, this method could be useful as a rapid screening procedure to evaluate beer quality at the end of the production line for industry applications. PMID- 29603225 TI - Differential Decomposition Among Pig, Rabbit, and Human Remains. AB - While nonhuman animal remains are often utilized in forensic research to develop methods to estimate the postmortem interval, systematic studies that directly validate animals as proxies for human decomposition are lacking. The current project compared decomposition rates among pigs, rabbits, and humans at the University of Tennessee's Anthropology Research Facility across three seasonal trials that spanned nearly 2 years. The Total Body Score (TBS) method was applied to quantify decomposition changes and calculate the postmortem interval (PMI) in accumulated degree days (ADD). Decomposition trajectories were analyzed by comparing the estimated and actual ADD for each seasonal trial and by fuzzy cluster analysis. The cluster analysis demonstrated that the rabbits formed one group while pigs and humans, although more similar to each other than either to rabbits, still showed important differences in decomposition patterns. The decomposition trends show that neither nonhuman model captured the pattern, rate, and variability of human decomposition. PMID- 29603224 TI - Impacts of human papillomavirus vaccination for different populations: A modeling study. AB - International variations in the prevalence of HPV infection derive from differences in sexual behaviors, which are also a key factor of the basic reproductive number (R0 ) of HPV infection in different populations. R0 affects the strength of herd protection and hence the impact of a vaccination program. Similar vaccination programs may therefore generate different levels of impact depending upon the population's pre-vaccination HPV prevalence. We used IARC's transmission model to estimate (i) the overall effectiveness of vaccination versus no vaccination in women aged 15-34 years measured as percent prevalence reduction (%PR) of HPV16 and (ii) the corresponding herd protection in populations with gender-equal or traditional sexual behavior and with different levels of sexual activity, corresponding to pre-vaccination HPV16 prevalence from 1 to 8% as observed worldwide. Between populations with different levels of gender-equal sexual activity, the highest difference in %PR under girls-only vaccination is observed at 40% coverage (91%PR vs. 48%PR for 1% and 8% pre vaccination prevalence, respectively). HPV16 elimination is obtained with 55 and 97% coverage, respectively. To achieve desirable levels of HPV16 prevalence after vaccination, different levels of coverage are required in populations with different levels of pre-vaccination HPV16 prevalence, for example, in populations with gender-equal sexual behavior a decrease to 1/1000 HPV16 from pre-vaccination prevalence of 1 and 8% would require coverages of 37 and 96%, respectively. In traditional populations, corresponding coverages would need to be 28 and 93%, respectively. In conclusion, pre-vaccination HPV prevalence strongly influences herd immunity and helps predict the overall effectiveness of HPV vaccination. PMID- 29603226 TI - Are Statutory Requirements Followed in the Certification of Traumatic, Unexpected, and Unattended Deaths in Missouri? AB - Medical examiners and coroners (ME/Cs) investigate deaths important to public health. This cross-sectional study evaluated 343,412 death certificates from 2007 to 2012 in Missouri. We examined agreement between cause and manner of death by year and ME/C contact as well as 2010-2012 trends in ME/C contact. There was near perfect agreement between cause and manner of death when an ME/C was contacted (kappa=0.97, p < 0.0001) and a significant increase in the proportion of deaths with ME/C contact from 2010 to 2012 (p =< 0.0001). There was a significantly higher proportion of ME/C-certified deaths using the electronic system in 2010 2012 (aOR = 1.18, 95% CI 1.15, 1.21) compared to the manual system in 2007-2009. Black, non-Hispanic (aOR = 1.50, 95% CI 1.43,1.57) and Hispanic (aOR = 1.31, 95% CI 1.13, 1.51) deaths, compared to White, non-Hispanic deaths, were associated with a significantly greater odds of ME/C certification. Race as an independent predictor of ME/C death certification warrants further research. PMID- 29603227 TI - PLOD2 as a potential regulator of peritoneal dissemination in gastric cancer. AB - Peritoneal dissemination is the most common metastatic pattern in advanced gastric cancer (GC) and has a very poor prognosis. However, its molecular mechanism has not been elucidated. Our study investigated genes associated with peritoneal dissemination of GC. We performed combined expression analysis of metastatic GC cell lines and identified Procollagen-lysine, 2-oxoglutarate 5 dioxygenase2 (PLOD2) as a potential regulator of peritoneal dissemination. PLOD2 is regulated by hypoxia-inducible factor-1 (HIF-1) and mediates extracellular matrix remodeling, alignment, and mechanical properties. We analyzed PLOD2 expression immunohistochemically in 179 clinical samples, and found high PLOD2 expression to be significantly associated with peritoneal dissemination, leading to poor prognosis. In an in vivo-collected metastatic cell line, downregulation of PLOD2 by siRNA reduced invasiveness and migration. Hypoxia upregulated PLOD2 mediated by HIF-1, and promoted invasiveness and migration. After exposure to hypoxia, a cell line transfected with siPLOD2 exhibited significantly suppressed invasiveness and migration, despite high HIF-1 expression. These findings indicate that PLOD2 is a regulator of, and candidate therapeutic target for peritoneal dissemination of GC. Although peritoneal dissemination of GC has a very poor prognosis, its molecular mechanism has not been elucidated. We identified PLOD2 regulated by HIF-1 as a potential regulator of peritoneal dissemination of GC. Finally, we showed that PLOD2 promotes cell invasiveness and migration in GC under hypoxia and lead to peritoneal dissemination of GC. PMID- 29603228 TI - Functional Properties of a High Protein Beverage Stabilized with Oat-beta-Glucan. AB - : This study evaluated the effect of oat flour and milk protein on the functional properties and sensory acceptability of shelf stable high protein dairy beverages containing at least 0.75 g of oat-beta-glucan per serving size. Formulations adjusted to levels of 1.50% to 2.30% oat flour and 2.50% to 4.00% milk protein isolate (MPI) were thermal processed in a rotary retort. The finished product exhibited good suspension stability (>80%). The increase of oat and MPI contents lead to nectar-like beverages (51 to 100 mPas). However, oat flour was the component showing the highest effect on the viscosity coefficient values of the beverages. Sensory evaluation indicated that formulations with less than 1.9% oat flour and 2.5% MPI (thin liquid, <50 mPas) were the most accepted. Mouthfeel (perceived thickness), sweetness and aftertaste had the most influence on overall liking of the beverages. PRACTICAL APPLICATION: Overall, this study comprises the development of a functional food product. Supplementation of beverages with fiber from oats is an innovative approach to stabilize high protein beverages. Ready to drink protein beverage formulations use gums to stabilize the product and provide a desirable mouthfeel. The levels of oat-beta-glucan used in the beverage increased the thickness and meet the requirement of the FDA approved health claim for reduction of the cardiovascular disease risk (21 CFR 101.81). PMID- 29603229 TI - HRTEMFringeAnalyzer a free python module for an automated analysis of fringe pattern in transmission electron micrographs. AB - A python module (HRTEMFringeAnalyzer) is reported to evaluate the local crystallinity of samples from high-resolution transmission electron microscopy images in a mostly automated fashion. The user only selects the size of a square analyser window and a step size which translates the window in the micrograph. Together they define the resolution of the results obtained. Regions where fringe patterns are visible are identified and their lattice spacing d and direction phi as well as the corresponding mean errors sigma determined. 1/sigmad is proportional to the coherence length of the structure, whereas sigmaphi is a measure of how well the direction of the fringes is defined. Maps of these four indicators are computed. The performance of the program is demonstrated on two very different samples: ill-crystalline carbon deposits on a coked Ni/LFNO (reduced LaFe0.8 Ni0.2 O3+/-delta) catalyst and well-crystallized nanoparticles of zinc doped ceria. In the latter case, the automatic segmentation of large aggregates into individual crystalline domains is achieved by phi maps. PMID- 29603230 TI - Body fat rather than body mass index is associated with gingivitis - A southern Brazilian cross-sectional study. AB - BACKGROUND: This cross-sectional study aimed to evaluate the association between body mass index (BMI) and body fat with gingivitis in 613 adults of Porto Alegre, Brazil. METHODS: Individuals with at least four teeth were included in this study. They were identified through a multi-stage probability sampling, considering the city distribution of sex and age. Structured interviews were conducted by trained researchers in order to collect sociodemographic characteristics, behavioral habits, and systemic impaired conditions. Visible plaque and modified gingival index were assessed by a trained and calibrated examiner. Additionally, weight, height, and body fat percentage were measured. Body fat percentage was determined by bioelectrical-impedance analysis using a portable electrical micro-current monitor. The median sites with marginal bleeding was 20%, and used as a cutoff point for gingivitis. Crude and adjusted prevalence ratio by mean Poisson regression with robust variance were calculated. Two multivariable models were performed in order to associate both independent and dependent variables. RESULTS: In the multivariable analysis that included BMI, no significant association with gingivitis was detected. On the other hand, the multivariable model that included body fat showed that very high body fat category (PR 1.22; 95% CI: 1.01 to 1.49) was significantly associated with higher marginal gingival bleeding. CONCLUSION: Very high body fat category rather than BMI was significantly associated with higher positive marginal gingival bleeding in adults. PMID- 29603231 TI - Near-infrared spectroscopy allows detection and species identification of Epichloe endophytes in Lolium perenne. AB - BACKGROUND: Perennial ryegrass (Lolium perenne) is systemically infected by seed transmitted fungal endophytes (Epichloe sp.). The presence of Epichloe endophytes alters the nutritive quality of its hosts by modifying several plant traits. The aim of this research was to develop a fast method based on near-infrared reflectance spectroscopy (NIRS) to discriminate between perennial ryegrass plants infected (E+) or not infected (E-) with two endophyte species, Epichloe festucae var. lolii, and Epichloe typhina, using a heterogonous set of perennial ryegrass samples collected from wild grasslands and cultivars. Epichloe festucae var. lolii cultures show two morphotypes, M1 and M3, and Epichloe typhina cultures have a different M2 morphotype. RESULTS: Near-infrared reflectance spectra from E+ and E- ryegrass plants were recorded. Applying the best NIRS model for the detection of Epichloe, 93.3% of E+ plants were classified correctly. The NIRS morphotype classification was correct for 92.9% of M1 morphotype and 100% of M2 morphotypes. The NIRS classification of M3 morphotypes was not as accurate, but it was in accordance with the fungal species classification, identifying some M3 as M1 morphotypes. CONCLUSION: Near-infrared reflectance spectroscopy can detect the presence of Epichloe fungal endophytes directly in samples of perennial ryegrass, and it is adequate for discriminating among fungal species. (c) 2018 Society of Chemical Industry. PMID- 29603232 TI - Biodiversity of arbuscular mycorrhizal fungi and ecosystem function. AB - Contents Summary 1059 I. Introduction: pathways of influence and pervasiveness of effects 1060 II. AM fungal richness effects on ecosystem functions 1062 III. Other dimensions of biodiversity 1062 IV. Back to basics - primary axes of niche differentiation by AM fungi 1066 V. Functional diversity of AM fungi - a role for biological stoichiometry? 1067 VI. Past, novel and future ecosystems 1068 VII. Opportunities and the way forward 1071 Acknowledgements 1072 References 1072 SUMMARY: Arbuscular mycorrhizal (AM) fungi play important functional roles in ecosystems, including the uptake and transfer of nutrients, modification of the physical soil environment and alteration of plant interactions with other biota. Several studies have demonstrated the potential for variation in AM fungal diversity to also affect ecosystem functioning, mainly via effects on primary productivity. Diversity in these studies is usually characterized in terms of the number of species, unique evolutionary lineages or complementary mycorrhizal traits, as well as the ability of plants to discriminate among AM fungi in space and time. However, the emergent outcomes of these relationships are usually indirect, and thus context dependent, and difficult to predict with certainty. Here, we advocate a fungal-centric view of AM fungal biodiversity-ecosystem function relationships that focuses on the direct and specific links between AM fungal fitness and consequences for their roles in ecosystems, especially highlighting functional diversity in hyphal resource economics. We conclude by arguing that an understanding of AM fungal functional diversity is fundamental to determine whether AM fungi have a role in the exploitation of marginal/novel environments (whether past, present or future) and highlight avenues for future research. PMID- 29603233 TI - Vessel scaling in evergreen angiosperm leaves conforms with Murray's law and area filling assumptions: implications for plant size, leaf size and cold tolerance. AB - Water transport in leaf vasculature is a fundamental process affecting plant growth, ecological interactions and ecosystem productivity, yet the architecture of leaf vascular networks is poorly understood. Although Murray's law and the West-Brown-Enquist (WBE) theories predict convergent scaling of conduit width and number, it is not known how conduit scaling is affected by habitat aridity or temperature. We measured the scaling of leaf size, conduit width and conduit number within the leaves of 36 evergreen Angiosperms spanning a large range in aridity and temperature in eastern Australia. Scaling of conduit width and number in midribs and 2 degrees veins did not differ across species and habitats (P > 0.786), and did not differ from that predicted by Murray's law (P = 0.151). Leaf size was strongly correlated with the hydraulic radius of petiole conduits (r2 = 0.83, P < 0.001) and did not differ among habitats (P > 0.064), nor did the scaling exponent differ significantly from that predicted by hydraulic theory (P = 0.086). The maximum radius of conduits in petioles was positively correlated with the temperature of the coldest quarter (r2 = 0.67; P < 0.001), suggesting that habitat temperature restricts the occurrence of wide-conduit species in cold habitats. PMID- 29603234 TI - Novel green algal isolates from the Egyptian hyper-arid desert oases: a polyphasic approach with a description of Pharao desertorum gen. et sp. nov. (Chlorophyceae, Chlorophyta). AB - The biodiversity of terrestrial algae is still grossly understudied, and African deserts in particular are barely touched in this respect. Here, four coccoid green algae from oases in the Western Desert of Egypt were characterized using a combination of morphotaxonomic, ecological and 18S rDNA data, with additional carotenoid and lipid analyses for two of the strains. Three strains were identified as affiliated with known taxa: Mychonastes sp., Asterarcys sp. (first report of this genus from a desert soil), and Stichococcus cf. deasonii. The fourth strain is proposed to represent a new cryptic genus Pharao gen. nov., with the type species P. desertorum sp. nov. The new taxon is sister to the clade of uncharacterized North American desert strains of Radiococcaceae (Chlorophyceae, Chlorophyta). The pigment profile of P. desertorum gen. et sp. nov. revealed carotenoids and chlorophylls typical of green algae. Bioorganic analysis showed a complex lipidome based on phospho- (PC), galacto- (MGDG and DGDG), betaine- (DGTS), and sulfoquinovosyl- (SQDG) membrane lipids, besides significant amounts of storage neutral lipids such as diacyl- (DAG) and triacylglycerols (TAG). The presence of saturated alkyl chains within all the membrane lipid classes in P. desertorum and Asterarcys sp. appears to reflect the need to maintain membrane fluidity and viscosity. In summary, African deserts likely still harbor new taxa to be described, and lipidomic analyses of such taxa may provide clues about their ability to survive in the extremely harsh desert habitats. PMID- 29603235 TI - A novel technique for tracheal reconstruction using a resorbable synthetic mesh. PMID- 29603236 TI - Measurements of Solar Ultraviolet Radiation Exposure at Work and at Leisure in Danish Workers. AB - Exposure to solar ultraviolet radiation is the main cause of skin cancer and may well present an occupational health and safety problem. In Denmark, skin cancer is a common disease in the general population, but detailed data on solar ultraviolet radiation exposure among outdoor workers are lacking. The aim of this study was to provide objective measurements of solar ultraviolet radiation exposure on working days and at leisure and compare levels of exposure between groups of mainly outdoor, equal-parts-outdoor-and-indoor and indoor workers. To this end, UV-B dosimeters with an aluminum gallium nitride (AlGaN) photodiode detector were used to measure the solar ultraviolet radiation exposure of 457 workers in the Danish summer season. Presented as semi-annual standard erythemal dose (SED) on working days, respectively, at leisure, the results are for mainly outdoor workers 214.2 SED and 64.8 SED, equal-parts-outdoor-and-indoor workers 131.4 SED and 64.8 SED, indoor workers 55.8 SED and 57.6 SED. The daily SED by month is significantly different (alpha = 0.05) between mainly outdoor, equal parts-outdoor-and-indoor and indoor workers and across professional groups; some of which are exposed at very high levels that is roofers 361.8 SED. These findings substantiate that exposure to solar ultraviolet radiation is indeed an occupational health and safety problem in Denmark. PMID- 29603237 TI - CT cholangiography in dogs with gallbladder mucocoele. AB - OBJECTIVES: To summarise CT cholangiography findings in dogs with gallbladder mucocoele. MATERIALS AND METHODS: Each of 10 dogs with gallbladder mucocoele underwent CT cholangiography using meglumine iotroxate before cholecystectomy. The following structures of the biliary system were evaluated: the right and left hepatic ducts, common hepatic duct, cystic duct, common bile duct and gallbladder. RESULTS: The hepatic duct, cystic duct, common bile duct and gallbladder were imaged by contrast-enhanced CT cholangiography. The passage of the contrast medium through the bile duct into the duodenum was visible in nine dogs. The curved planar reformation images of two dogs showed they had filling defects in the bile duct system. In one dog with hyperbilirubinaemia due to chronic hepatitis, the bile duct system was not completely contrast-enhanced. Surgical exploration revealed no evidence of common bile duct obstruction in any dog. CLINICAL SIGNIFICANCE: CT cholangiography delineates the structural characteristics of the biliary system and partially estimates its patency in dogs with gallbladder mucocoele. Therefore this procedure may be useful as a preoperative screen of the bile duct system in dogs with gallbladder mucocoele. PMID- 29603238 TI - Cold storage of platelets in platelet additive solution: an in vitro comparison of two Food and Drug Administration-approved collection and storage systems. AB - BACKGROUND: Refrigeration of platelets (PLTs) in a PLT additive solution (PAS) reduces PLT activation compared to storage in plasma and preserves function for at least 15 days. Currently only two PASs are licensed by the Food and Drug Administration, each for use with only one apheresis platform. In this study, we compared the metabolic, functional, and activation status of PLTs collected on a Trima apheresis collection system and stored refrigerated in Isoplate (ISO) PAS to PLTs collected on an Amicus collection system and stored refrigerated in Intersol (INT) PAS. STUDY DESIGN AND METHODS: Apheresis PLTs (n = 4-7 donors) were collected on a Trima in ISO PAS or on an Amicus in INT PAS. PLTs were stored in a walk-in refrigerator (1-6 degrees C) without agitation for long-term storage. Bags were assayed at Days 1, 5, 10, and 15 of storage. Measurements included PLT counts, pH, aggregation response, rotational thromboelastometry, and activation markers. RESULTS: Cold-stored Trima-collected PLTs in ISO were slightly more hemostatic than Amicus-collected PLTs in INT and displayed better adhesion to collagen under flow conditions. Amicus-collected PLTs in INT showed increased microaggregate formation on Days 5 and 10 and a significant decrease in PLT count over storage. Trima-collected PLTs in ISO displayed better clot strength than Amicus-collected PLTs in INT. CONCLUSION: Compared to cold-stored Amicus PLTs in INT, Trima PLTs in ISO display superior in vitro function and may be better suited for treatment of bleeding patients. Clinical studies are warranted to confirm these findings. PMID- 29603239 TI - In response to Double-blind, placebo-controlled study with alginate suspension for laryngopharyngeal reflux disease. PMID- 29603240 TI - A novel superchilling storage - ice glazing (SS-IG) approach using biopolymer based composite hydrogel to delay microbiological spoilage and organic oxidation of preserved tilapia. AB - BACKGROUND: Most aquatic products are highly susceptible to deterioration and microbial spoilage during storage. Cold storage is a frequently used method to preserve them. However, products preserved by traditional frozen method are prone to suffer damage. This can significantly impair the quality of the products. To solve the problem, this work established a novel superchilling storage-ice glazing (SS-IG) approach using chitosan-catechin composite material. It can maximize the postmortem quality of preserved products during storage, avoiding damage. RESULTS: During storage at -1.5 +/- 0.2 degrees C for 25 days, the SS-IG approach using 5 g L-1 chitosan and 1~3 g L-1 catechin as IG layers can effectively enhance the postmortem quality of preserved tilapia fillets. The sensory qualities of these fillets were effectively maintained. The microbial counts in these fillets were strongly suppressed. Oxidative rancidity in these fillets was observably inhibited. Less biogenic amine was produced in these fillets. CONCLUSION: The results indicated that the SS-IG with chitosan-catechin composite-ice glazing layers can be effective in maintaining the postmortem quality of tilapia fillets. This will have a wide potential application. (c) 2018 Society of Chemical Industry. PMID- 29603241 TI - The gymnosperm ortholog of the angiosperm central cell-specification gene CKI1 provides an essential clue to endosperm origin. AB - A defining feature of angiosperms is double fertilization involving the female gametophyte central cell and formation of a nutrient-storing tissue called endosperm. The route for the evolutionary origin of endosperm from a gymnosperm ancestor, particularly the molecular steps involved, has remained elusive. Recently, the histidine kinase gene Cytokinin-Independent 1 (CKI1), an activator of cytokinin signaling, was described as a key to specification of the endosperm precursor central cell in Arabidopsis. Here, we have investigated the function and expression of a putative ortholog of CKI1 in the gymnosperm Ginkgo biloba. We demonstrate that Ginkgo CKI1 can partially rescue an Arabidopsis cki1 mutant and promote weak activation of the cytokinin signaling pathway in the Arabidopsis embryo sac, but does not confer central cell specification. Ginkgo CKI1 is expressed in both male and female gametophytes of Ginkgo. In the latter, it is expressed in the ventral canal cell, which is sister to the egg cell in the archegonium. As in Arabidopsis, Ginkgo CKI1 is not expressed in the egg cell. The similarities in expression patterns of CKI1 in Ginkgo and Arabidopsis female gametophytes suggest that extant gymnosperms possess an essential component of the molecular machinery required for angiosperm endosperm development, and provide new insights into endosperm origin from a gymnospermous ancestor. PMID- 29603242 TI - Enhancing leadership and relationships by implementing a peer mentoring program. AB - BACKGROUND: Peer-mentoring is often described as effective means to promote professional and leadership skills, yet evidence on practical models of such programs for occupational therapy students are sparse. The purpose of this study was to evaluate the outcomes of a peer-mentoring program designed for graduate occupational therapy students. METHODS: Forty-seven second-year student volunteers were randomly assigned to individually mentor first-year students in a year-long program. Students met biweekly virtually or in person to provide mentorship on everyday student issues, according to mentees' needs. Faculty-led group activities prior and during the peer-mentoring program took place to facilitate the mentorship relationships. Program effectiveness was measured using the Multi-factor Leadership Questionnaire (Avolio & Bass, MLQ: Multifactor Leadership Questionnaire, 2004) and an open-ended feedback survey. RESULTS: Results of multi-variate MANOVA for repeated measures indicating significant enhancement in several leadership skills (F(12,46) = 4.0, P = 0.001, eta2 = 0.579). Qualitative data from feedback surveys indicated that an opportunity to help; forming relationships; and structure as enabler were perceived as important participation outcomes. Students expressed high satisfaction and perceived value from their peer-mentoring experience. CONCLUSION: As we seek ways to promote our profession and the leadership of its members, it is recommended to consider student peer-mentoring to empower them to practice and advance essential career skills from the initial stages of professional development. Evidence found in this study demonstrates that peer-mentoring programs can promote leadership development and establishment of networks in an occupational therapy emerging professional community, at a low cost. The peer-mentoring blueprint and lessons learned are presented with hopes to inspire others to implement peer-mentoring programs in their settings. PMID- 29603243 TI - Functional biogeography of angiosperms: life at the extremes. AB - Nonlinear relationships between species and their environments are believed common in ecology and evolution, including during angiosperms' rise to dominance. Early angiosperms are thought of as woody evergreens restricted to warm, wet habitats. They have since expanded into numerous cold and dry places. This expansion may have included transitions across important environmental thresholds. To understand linear and nonlinear relationships between angiosperm structure and biogeographic distributions, we integrated large datasets of growth habits, conduit sizes, leaf phenologies, evolutionary histories, and environmental limits. We consider current-day patterns and develop a new evolutionary model to investigate processes that created them. The macroecological pattern was clear: herbs had lower minimum temperature and precipitation limits. In woody species, conduit sizes were smaller in evergreens and related to species' minimum temperatures. Across evolutionary timescales, our new modeling approach found conduit sizes in deciduous species decreased linearly with minimum temperature limits. By contrast, evergreen species had a sigmoidal relationship with minimum temperature limits and an inflection overlapping freezing. These results suggest freezing represented an important threshold for evergreen but not deciduous woody angiosperms. Global success of angiosperms appears tied to a small set of alternative solutions when faced with a novel environmental threshold. PMID- 29603244 TI - The Role of Neighborhood Context and School Climate in School-Level Academic Achievement. AB - In recent years, the quality of education available to children has become increasingly dependent on the social and economic demographics of neighborhoods in which the children live. This study assesses the role of community violence in explaining the relation between socio-economic status (SES) and academic outcomes and the potential of positive school climate to promote academic achievement. With a sample of 297 Chicago public elementary schools, we examine community level and school-level data and use Geographic Information Systems (GIS) mapping to illustrate how school academic achievement coincides with neighborhood economics and crime statistics. Results support the hypothesized mediation, such that lower SES was associated with lower academic achievement, and violent crime partially mediated this relation. School climate was positively associated with academic achievement, and student safety significantly moderated the relation between SES and academic achievement. Implications for theory, research, and intervention are discussed. PMID- 29603245 TI - Advanced practice registered nurses attitudes toward suicide in the 15- to 24 year-old population. AB - PURPOSE: The purpose of this study is to assess advanced practice registered nurses (APRNs) attitudes toward suicide in the 15- to 24-year-old population. DESIGN AND METHODS: A convenience sample of national psychiatric and pediatric APRNs was obtained from postings on professional websites and sending invitations to members utilizing anonymous Qualtricsc survey that included demographic questions and the Suicide Opinion Questionnaire (SOQ). FINDINGS: The pediatric APRNs demonstrated more positive attitudes toward suicide as measured by the SOQ when individual items were analyzed. PRACTICE IMPLICATIONS: One of the outcomes of this study is to raise awareness and foster prevention related to suicide for advanced practice registered nurses and the 15- to 24-year-old population. PMID- 29603246 TI - Elevated free hemoglobin and decreased haptoglobin levels are associated with adverse clinical outcomes, unfavorable physiologic measures, and altered inflammatory markers in pediatric cardiac surgery patients. AB - BACKGROUND: There are data suggesting that free hemoglobin (Hb), heme, and iron contribute to infection, thrombosis, multiorgan failure, and death in critically ill patients. These outcomes may be mitigated by haptoglobin. STUDY DESIGN AND METHODS: 164 consecutively treated children undergoing surgery for congenital heart disease were evaluated for associations between free Hb and haptoglobin and clinical outcomes, physiologic metrics, and biomarkers of inflammation RESULTS: Higher perioperative free Hb levels (and lower haptoglobin levels) were associated with mortality, nosocomial infection, thrombosis, hours of intubation and inotropes, increased interleukin-6, peak serum lactate levels, and lower nadir mean arterial pressures. The median free Hb in patients without infection (30 mg/dL; 29 interquartile range [IQR], 24-52 mg/dL) was lower than in those who became infected (39 mg/dL; IQR, 33-88 mg/ 31 dL; p = 0.0046). The median mechanical ventilation requirements were 19 (IQR, 7-72) hours in patients with higher levels of haptoglobin versus 48 (IQR, 18-144) hours in patients with lower levels (p = 0.0047). Transfusion dose, bypass duration, and complexity of surgery were all significantly correlated with Hb levels and haptoglobin levels. Multivariate analyses demonstrated that these variables were independently and significantly associated with outcomes. CONCLUSIONS: Elevated pre- and postoperative levels of free Hb and decreased levels of haptoglobin were associated with adverse clinical outcomes, inflammation, and unfavorable physiologic metrics. Transfusion, RACHS score, and duration of bypass were associated with increased free Hb and decreased haptoglobin. Further investigation of the role of hemolysis and haptoglobin as potential mediators or markers of outcomes is warranted. PMID- 29603247 TI - Optimization of ultrasound-assisted extraction of grape-seed oil to enhance process yield and minimize free radical formation. AB - BACKGROUND: Grape seeds are a relatively abundant source of oil and bioactive compounds. To use this byproduct, the current work aimed to optimize the ultrasound-assisted extraction (UAE) of grape-seed oil to obtain greater process yield and minimize free radical formation in the oil. RESULTS: The optimal condition was 15 degrees C with an ultrasonic wave amplitude of 42 um, leading to a process yield of 82.9% and content of free radicals of 14.7 * 1017 kg-1 and 3.4 * 1018 kg-1 for samples stored for 7 and 30 days, respectively. No significant differences in fatty acid composition and acidity and iodine values were observed between samples. The oil obtained by ultrasound had greater phenolic compound content and antioxidant activity by ferric reduction than the control sample (without ultrasound application). However, higher content of free radicals and peroxide value was observed. CONCLUSION: Sonication improved extraction yield when compared to the process without ultrasound application. Moreover, UAE favored the extraction of phenolic compounds. As it enhanced process yield with the minimum formation of free radicals, UAE is a promising oil extraction technology. (c) 2018 Society of Chemical Industry. PMID- 29603248 TI - Reticulocytosis in non-anaemic cats and dogs. AB - OBJECTIVE: To evaluate the proportion of blood samples diagnosed with reticulocytosis without anaemia in cats and dogs and report the aetiology and mortality rate of affected animals. MATERIALS AND METHODS: Retrospective multicentre study including haematological examination of 3956 cats and 11,087 dogs admitted to seven German veterinary clinics (2012 to 2014). The proportion of blood samples with reticulocytosis without anaemia was calculated, and after exclusion of multiple measurements of the same animal, clinical data were evaluated. Animals with reticulocytosis without anaemia were classified as healthy or diseased, and diseased patients were assigned to 12 disease groups. Pretreatment (i.e. non-steroidal anti-inflammatory drugs, glucocorticoids, dipyrone) was recorded. RESULTS: The proportion of blood samples with reticulocytosis without anaemia was 3.1% (124/3956) in cats and 4.4% (492/11,087) in dogs. Overall, 1.8% (2/111) of cats and 1.5% (7/458) of dogs with reticulocytosis without anaemia were healthy. Blood loss/anaemia, cardiac/respiratory disorders, gastrointestinal disorders and inflammatory disorders as well as cancer were the most frequent underlying diseases. Pretreatment was noted in 39.5% (43/111) of cats and 42.4% (194/458) of dogs. The mortality rate was 37.8% (42/111) in cats and 29.7% (136/458) in dogs with reticulocytosis without anaemia; the median survival time in non-survivors was 1 day (range: 0 to 376 days in cats, 0 to 444 days in dogs). CLINICAL SIGNIFICANCE: In both species, reticulocytosis without anaemia was observed in a low proportion of blood samples (dogs>cat). Though a bias towards sick animals is possible in our sample, reticulocytosis without anaemia was mainly seen in diseased animals and associated with a mortality rate of approximately one-third of patients. PMID- 29603249 TI - Cover Image, Volume 233, Number 7, July 2018. AB - Cover: The cover image, by Yin et al., is based on the Original Research Article, Mechanical unloading reduces microtubule actin crosslinking factor 1 expression to inhibit beta-Catenin Signaling and osteoblast proliferation, DOI: 10.1002/jcp.26374. PMID- 29603250 TI - What factors influence time-use of occupational therapists in the workplace? A systematic review. AB - BACKGROUND: Health-care expenditure is rapidly increasing in Australia with increasing pressure on health-care services to review processes, improve efficiency and ensure equity in service delivery. The nursing profession have improved efficiency and patient care by investigating time-use to describe current practice and support development of workforce planning models. There is, however, a lack of information to understand factors that impact on occupational therapists time-use in the clinical setting impacting the development of workforce planning models which adapt occupational therapy service delivery to match resources with demand. The objective of this review was to systematically identify known factors which impact on occupational therapists time-use in the clinical setting. METHOD: A systematic review of Medline, PsycINFO and CINAHL databases and grey literature was completed in September 2016. Two authors independently screened studies for inclusion and quality was evaluated using the Downs and Black scale. Variables impacting on occupational therapists time-use were categorised and thematically analysed to synthesise key themes. RESULTS: Twenty studies met the inclusion criteria and were included in the review. Three key categories of factors influencing time-use were identified. These were: patient-related factors (e.g. level of function, therapy required, type, complexity of injury), therapist-related factors (e.g. experience, clinical vs non-clinical responsibility), and organisational-related factors (e.g. workplace characteristics, availability of staff, presence of students). CONCLUSION: Occupational therapist time-use in clinical settings is complex and difficult to quantify in research. How occupational therapists spend their time is impacted by a number of patient, clinician and service related factors reflecting the breadth of occupational therapy practice and client-centred nature of the profession. PMID- 29603251 TI - Community water fluoridation online: an analysis of the digital media ecosystem. AB - OBJECTIVES: Research demonstrates the safety and efficacy of community water fluoridation (CWF). Yet, the digitization of communication has triggered the spread of inaccurate information online. The purpose of this study was to analyze patterns of CWF information dissemination by a network of sources on the web. METHODS: We used Media Cloud, a searchable big data platform of over 550 million stories from 50 thousand sources, along with tools to analyze that archive. We generated a network of fluoridation publishers using Media Cloud's keyword identification from August 1, 2015 to July 31, 2016. We defined the media type and sentiment toward CWF for each source and generated a network map of the most influential sources during our study period based on hyperlinking activity. RESULTS: Media Cloud detected a total of 980 stories from 325 different sources related to water fluoridation. We identified nine different media types participating in the dissemination of information: academic, government, scientific group, natural medicine, blogs, mainstream media, advocacy groups, user-generated (e.g., YouTube), and "other." We detected five sub-networks within the overall fluoridation network map, each with its own characteristics. Twenty one percent of sources were pro-fluoridation, receiving 57 percent of all inlinks, 22 percent of sources were anti-fluoridation, and the rest were neutral (54 percent). CONCLUSIONS: The dominant neutral sentiment of the network may signify that anti- and pro-sides of the debate are viewed as balanced, not just in number but also in quality of information. Despite high inlinks to pro sources, anti-fluoridation sentiment maintains influence online. PMID- 29603252 TI - Integrative and collaborative care models between pediatric oral health and primary care providers: a scoping review of the literature. AB - OBJECTIVES: Collaborative and/or integrative care between oral health and primary care providers can increase access to care to a more expansive population, helping to mitigate oral health related disease. The objective of this review was to present and evaluate different types of care models that exist between oral health and primary care providers in pediatric settings. METHODS: A literature search was conducted using five databases: MEDLINE/PubMed, ISI Web of Science, Dentistry and Oral Sciences Source, Cochrane Database, and EMBASE, to identify literature from January 1990 to January 2016. Combinations of controlled terms were utilized. Eligible sources targeted pediatric populations ages 1-17 and provided descriptions of existing collaborative and/or integrative models. RESULTS: Data related to the practice model, oral care provided, level of integration/collaboration and workflow were extracted. Sixteen articles were included that discussed 24 models of collaboration. These models provided ranges of services, but each offered a minimum of oral health risk assessment, oral health instruction, topical fluoride application and assessment for further treatment. These models included different levels of collaboration based off a ranking system created by the authors with 16.6 percent (4) classified as low, 54.2 percent (13) as medium and 29.2 percent (7) as high. CONCLUSIONS: Existing care models offered varying services and levels of integration and/or collaboration, but each offered a baseline of oral care. Most of these collaborations were based within Federally Qualified Health Centers and aimed to ease access to care issues. PMID- 29603253 TI - Scoring the home falls and accidents screening tool for health professionals (HOME FAST-HP): Evidence from one epidemiological study. AB - BACKGROUND: Falls in older people are a major public health concern. To target falls prevention interventions, screening tools need to be able to identify older people at greater risk of falling. This study aimed to investigate the screening capacity of the Home Falls and Accidents Screening Tool for health professionals (HOME FAST-HP), and to identify the best cut-off score to identify older people at higher risk of falls using the HOME FAST-HP. METHODS: The study used cross sectional data from a random sample of 650 women from the 1921 to 1926 cohort of the Australian Longitudinal Study of Women's Health (ALSWH). Selected women were sent a postal survey including the HOME FAST-HP, falls history, and other health factors. Scores on the home fast were calculated and the cut-point for optimal sensitivity and specificity of the HOME FAST-HP in relation to falls was assessed using a Receiver Operating Characteristic curve. RESULTS: A total of 567 older women participated (response rate 87%). The mean age of participants was 77.5 yrs (95% CI 77.31-77.70). A total of 153 participants (27%) reported a fall in the previous six months. The mean number of hazards using the HOME FAST-HP was 9.74 (95% CI 9.48-10.01), range 2-22. Non-fallers had a mean of 9.6 hazards (95% CI 9.32-9.91) and fallers had a mean of 10.63 hazards (95% CI 10.08-11.19) which was a significant difference (t = 3.41, P = 0.001). The area under the receiver operator curve (AUC) was 0.58 (95% CI 0.53-0.64). A HOME FAST-HP cut-off score of 9 was associated with the optimal sensitivity for falls (73.9%), with specificity (37.9%), and positive predictive value was 30.6% and negative predictive value was 79.7%. CONCLUSION: The HOME FAST-HP can be used as a screening tool to identify fallers with a cut-off score of nine indicating a higher risk of falling. PMID- 29603254 TI - Suitability of unmalted quinoa for beer production. AB - BACKGROUND: This study provides the first detailed investigation into the effect of partially substituting barley malt with quinoa (Chenopodium quinoa Willd.) on the characteristics of wort and beer. Quinoa seeds and flakes were compared in terms of their suitability for brewing. The benefits of applying a commercial enzyme mixture during beer production with quinoa were also investigated. RESULTS: These findings show that quinoa is a good starchy raw material for brewing. Even without exogenous enzymes, it is possible to substitute barley malt with up to 30% quinoa. The form in which quinoa is used has a negligible influence on the quality of the wort and beer. The foam stability of beer made with quinoa was better than that of all-malt beer, despite there being a lower level of soluble nitrogen in quinoa beer in comparison with all-malt beer and more than twice the amount of fat in quinoa in comparison to barley malt. CONCLUSION: The addition of unmalted quinoa does not give unpleasant characteristics to the beer and was even found to have a positive effect on its overall sensory quality. This offers brewers an opportunity to develop good beers with new sensory characteristics. (c) 2018 Society of Chemical Industry. PMID- 29603255 TI - Being, belonging and becoming: Development of the 3B Scale. AB - BACKGROUND: The aim of the current study was to assess the construct validity and internal consistency of a measure used by an occupation-based, mental health program. The measure was formulated according to the 3B theory of being, belong and becoming and system impacts. METHODS: The scale was administered to a sample of 122 current members of Northern Initiative for Social Action. Confirmatory factor analysis (CFA) was carried out to examine the model fit of the 3B Scale. Internal reliability was assessed using Cronbach's alpha measure of internal consistency. RESULTS: The CFA confirmed the four hypothesised underlying constructs of the 3B theory. The results of the CFA reported adequate model fit. Each factor had good to excellent internal reliability with Cronbach's alpha ranging from 0.81 to 0.91. CONCLUSION: The 3B Scale is a valid and reliable tool for measuring Being, Belonging and Becoming needs in an occupation-based mental health program. The 3B Scale is an example of an outcome measure created specifically to quantify program outcomes and demonstrates that instruments suited to unique programs can be individually configured and assist occupational therapists in their efforts to measure client perspectives. These are the essential first steps to client-centred practice and the development of practice based evidence. The 3B Scale may be useful to similar peer-led programs, as well as community-based occupational programs that foster participation. Further research is needed to determine whether the 3B Scale can detect change over time. PMID- 29603256 TI - Rare genotype advantage promotes survival and genetic diversity of a tropical palm. AB - Negative density dependence, where survival decreases as density increases, is a well-established driver of species diversity at the community level, but the degree to which a similar process might act on the density or frequency of genotypes within a single plant species to maintain genetic diversity has not been well studied in natural systems. In this study, we determined the maternal genotype of naturally dispersed seeds of the palm Oenocarpus bataua within a tropical forest in northwest Ecuador, tracked the recruitment of each seed, and assessed the role of individual-level genotypic rarity on survival. We demonstrate that negative frequency-dependent selection within this species conferred a survival advantage to rare maternal genotypes and promoted population level genetic diversity. The strength of the observed rare genotype survival advantage was comparable to the effect of conspecific density regardless of genotype. These findings corroborate an earlier, experimental study and implicate negative frequency-dependent selection of genotypes as an important, but currently underappreciated, determinant of plant recruitment and within-species genetic diversity. Incorporating intraspecific genetic variation into studies and theory of forest dynamics may improve our ability to understand and manage forests, and the processes that maintain their diversity. PMID- 29603257 TI - The non-human primate kidney transcriptome in fetal development. AB - BACKGROUND: Little is known about the repertoire of non-human primate kidney genes expressed throughout development. The present work establishes an understanding of the primate renal transcriptome during fetal development in the context of renal maturation. METHODS: The baboon kidney transcriptome was characterized at 60-day gestation (DG), 90 DG, 125 DG, 140 DG, 160 DG and adulthood (6-12 years) using gene arrays and validated by QRT-PCR. Pathway and cluster analyses were used to characterize gene expression in the context of biological pathways. RESULTS: Pathway analysis indicated activation of pathways not previously reported as relevant to kidney development. Cluster analysis also revealed gene splice variants with discordant expression profiles during development. CONCLUSIONS: This study provides the first detailed genetic analysis of the developing primate kidney, and our findings of discordant expression of gene splice variants suggest that gene arrays likely provide a simplified view and demonstrate the need to study the fetal renal proteome. PMID- 29603258 TI - "Crosstalk" technique: A comparison between two generations of cryoballoon catheter. AB - INTRODUCTION: The "Crosstalk" technique: if pulmonary vein isolation (PVI) of the superior one is not achieved due to a gap in the inferior part, it could be done during inferior vein cryoablation. This maneuver minimizes the total energy delivery time and number of lesions. We aimed to correlate the likelihood of crosstalk phenomenon with certain anatomic characteristics. METHODS: A total of 676 patients undergoing a first ablation procedure for paroxysmal or persistent atrial fibrillation (470 first-generation cryoballoon [CB] and 206 second generation CB) between June 2014 and December 2016 were included. RESULTS: "Crosstalk" phenomenon occurred in 32 patients (18 first-generation CB, 14 second generation CB). Compared to 54 control patients without crosstalk, the angle between left superior pulmonary vein (LSPV) and left atrial (LA) roof-plane, left pulmonary common ostia were significant parameters associated with crosstalk (odds ratio [OR] = 1.20, +/-95% confidence interval [CI]: 1.11-1.31, P < 0.001; OR = 5.67, +/-95% CI: 1.08-28.69, P = 0.04). As for angle between LSPV and LA roof-plane, the cut-off value was 28.68 degrees with a sensitivity of 72.22%, a specificity of 81.25%, and an area under the receiver operating characteristic curve of 0.87 to predict the possibility of crosstalk technique application to get isolated in LSPV. Among the crosstalk group, there was no statistical difference between first-generation CB and second-generation CB in pulmonary anatomic characteristics. CONCLUSION: Crosstalk technique can be effective in patients with AF undergoing CB ablation using with both first and second generation CBs. Anatomic characteristics predictive of crosstalk include a left common ostia and smaller angle between the LSPV and LA roof-plane. PMID- 29603259 TI - Overcoming infrequent electrophysiological dilemmas. PMID- 29603260 TI - Comparison between patients with norovirus-related gastroenteritis and asymptomatic carriers with respect to distribution of antibody-complexed viral particles and intestinal flora. AB - Asymptomatic carriers have a major influence on the spreading of norovirus infections. The objective of this study was to examine the characteristics of patients and asymptomatic carriers affected by norovirus-related community gastroenteritis outbreaks. No significant difference between the two groups was observed in terms of the number of norovirus-antibody complexes with respect to total numbers. Principal coordinates analysis of the intestinal flora based on beta-diversity analysis, revealed a different bacterial composition between patients and asymptomatic carriers, particularly regarding the genera Pseudomonas, Bacteroides, and Erwinia, as well as the Ruminococcaceae family. Although the proportional changes between these intestinal microorganisms were not sufficient to explain gastroenteritis symptoms, they represent possible markers shared by asymptomatic norovirus carriers. PMID- 29603261 TI - There is something wrong when you can't touch: Contact mapping. PMID- 29603262 TI - Pharmacokinetics of fentanyl citrate and norfentanyl in Holstein calves and effect of analytical performances on fentanyl parameter estimation. AB - This study describes the pharmacokinetics of intravenously administered (i.v.) fentanyl citrate, and its primary metabolite norfentanyl in Holstein calves. Eight calves (58.6 +/- 2.2 kg), aged 3-4 weeks, were administered fentanyl citrate at a single dose of 5.0 MUg/kg i.v. Blood samples were collected from 0 to 24 hr. Plasma (nor)fentanyl concentrations were determined using liquid chromatography with mass spectrometry and a lower limit of quantification (LLOQ) of 0.03 ng/ml. To explore the effect of analytical performance on fentanyl parameter estimation, the noncompartmental pharmacokinetic analysis was then repeated with a hypothetical LLOQ value of 0.05 ng/ml. Terminal elimination half life was estimated at 12.7 and 3.6 hr for fentanyl and norfentanyl, respectively. For fentanyl, systemic clearance was estimated at 2.0 L hr-1 kg-1 , volume of distribution at steady-state was 24.8 L/kg and extraction ratio was 0.42. At a hypothetical LLOQ of 0.05 ng/ml fentanyl half-life, volume of distribution at steady-state and clearance were, respectively, of 3.0 hr, 8.8 L/kg and 3.4 L kg-1 hr-1 . Fentanyl citrate administered i.v. at 5.0 MUg/kg can reach levels associated with analgesia in other species. Pharmacokinetic parameters should be interpreted with respect to LLOQ, as lower limits can influence estimated parameters, such as elimination half-life or systemic clearance and have significant impact on dosage regimen selection in clinical practice. PMID- 29603263 TI - Correlation of right ventricular multielectrode endocardial unipolar mapping and epicardial scar. PMID- 29603264 TI - The super "hidden" concealed left-sided accessory pathway. PMID- 29603265 TI - Atrial transseptal left ventricular lead implantation for cardiac resynchronization therapy using arteriovenous loop technique. AB - To date, several techniques for transseptal left ventricular (LV) endocardial pacing for cardiac resynchronization therapy (CRT) have been proposed in patients for whom routine transvenous LV pacing is infeasible. These techniques are of varying difficulty and complexity, and some requires devices not easily accessible. We herein report a simple, safe and effective approach of atrial transseptal LV lead implantation using arteriovenous loop technique in a patient for whom transvenous LV implantation lead had failed. PMID- 29603266 TI - Source and Quality of Enteral Nutrition Influences Oxidative Stress in Preterm Infants: A Prospective Cohort Study. AB - BACKGROUND: Preterm infants are at risk of oxidative stress from neonatal intensive care interventions. 8-Oxo-2'-deoxyguanosine (8-oxodG), generated by oxygen radical attack on DNA, is a potential marker of oxidative stress. The aim of the present study was to investigate the impact of quality and source of enteral nutrition (EN) on renal excretion of 8-oxodG in preterm infants. METHODS: Spontaneous urine samples were collected on postnatal days 26-31 in 33 preterm infants. Infants were fed either breast milk (BM), formula (FM), or BM/FM mixtures. Daily iron (Fe) supplementation was started day 28 +/- 1 postnatally. 8 oxodG was determined by highperformance liquid chromatography-electrochemical detection (HPLC-EC). RESULTS: The 8-oxodG/creatinine ratio was significantly higher in infants fed FM vs FM/BM (38.7 +/- 28.7 vs 16.7 +/- 12.2 nmol 8 oxodG/mmol creatinine, P < 0.0001) or BM (11.6 +/- 10.4 nmol 8-oxodG/mmol creatinine, P < 0.0001). There was no significant effect of Fe supplementation (P = 0.547). 8-OxodG excretion showed significant interindividual variation but was similar within pairs of twins. CONCLUSION: Quality and source of EN seem to influence oxidative stress in preterm infants. The underlying pathophysiological mechanism is unclear and needs further investigation. It may be speculated that other mechanisms than Fe supplementation contribute to oxidative stress, such as cow's milk protein-mediated up-regulation of the intestinal inflammatory cascade. PMID- 29603267 TI - Corrigendum. PMID- 29603268 TI - Corrigendum. PMID- 29603269 TI - Nutrition Delivery During Pediatric Extracorporeal Membrane Oxygenation Therapy. AB - BACKGROUND: Macronutrient delivery during pediatric ECMO therapy can be challenging. We examined predictors of nutrient delivery in the first 2 weeks of extracorporeal membrane oxygenation (ECMO) therapy in the pediatric intensive care unit (ICU). METHODS: Details of macronutrient delivery were recorded in children (newborn-18 years of age) who survived 24 hours after cannulation to ECMO over a 3-year period (2012-2015). RESULTS: We analyzed data from 54 consecutive eligible patients, 43% female, with median (interquartile range) ECMO duration of 8.5 (6-24) days, age 0.1 (0, 16) months, ICU length of stay 32 (21, 60) days, and 28-day mortality 13%. Median weight for age z score declined from 0.1 at admission to -1.2 at 30 days (P = 0.013). At least 80% goal energy and protein was delivered in 35 (65%) and 33 (61%) patients, respectively, by day 7; 10% of energy and 11% protein goal was delivered enterally. Parenteral nutrition (PN) was utilized in 47 (87%) patients, initiated by day 1 (1, 3). Enteral nutrition (EN) was successfully delivered in 49 (94%) patients (35% postpyloric), initiated by day 6 (2, 16). Younger age (P = 0.01) and venoarterial mode of ECMO (P = 0.0014) were associated with lower EN delivery. Use of umbilical artery catheters or vasoactive infusions did not impede EN delivery. Late PN delivery was associated with cumulative protein deficits (P = 0.019) and failure to achieve nutrient delivery goals by day 7. CONCLUSIONS: Optimal nutrient delivery was achieved in most patients by day 7, predominantly via PN. Early EN is feasible in low volumes, but PN may be essential to prevent cumulative energy and protein deficits during the first week of ECMO. PMID- 29603270 TI - Value of a novel 16-lead High-Definition ECG machine to detect conduction abnormalities in structural heart disease. AB - BACKGROUND: Depolarization abnormalities are hardly detectable by standard 12 lead electrocardiogram (ECG) in some patients. OBJECTIVE: To evaluate the value of the 16-lead High-Definition (HD)-ECG machine to record conduction abnormalities including Epsilon waves in patients with structural heart disease. METHODS: Tracings with 12-lead ECG, 16-lead HD-ECG, and signal-averaged ECG were studied. RESULTS: (1) Case of severe coronary artery disease (CAD): On 16-lead HD ECG, a tiny intra-QRS signal was noted in lead III, a prolonged P wave in lead II, and fragmentation on top of lead aVL and lead aVF. Proper automatic measurement of the prolonged P wave measuring 190 ms was noted. Signal-averaging by 16-lead HD-ECG in lead III showed the intra-QRS fragmentation and P wave prolongation of 180 ms. (2) First patient with arrhythmogenic right ventricular dysplasia (ARVD): Standard 12-lead ECG indicated Epsilon waves in lead III, V2, V3, and inverted T waves in V1-V3. 16-lead HD-ECG indicated QRS prolongation in lead II, III, aVL, aVF, V2, V3 as opposed to V6, and low amplitudes of QRS complexes in V4R and V3R as a new possible sign of ARVD. Notches in lead V2, widening of QRS complexes in all precordial leads, but shorter QRS in V8-V9 are also considered as a potential new diagnostic sign of ARVD. (3) Second ARVD patient: Notches at the end of the QRS in lead III and a negative initial deflection of the QRS in V1 and V2 were detected by standard 12-lead ECG. On 16 lead HD-ECG, a more pronounced QRS fragmentation was visible. CONCLUSION: 16-lead HD-ECG in both CAD and ARVD seems to be more sensitive than 12-lead ECG to record electrocardiographic abnormalities. PMID- 29603271 TI - Totally minimally invasive esophagectomy after neoadjuvant chemoradiotherapy: Long-term oncologic outcomes. AB - BACKGROUND AND OBJECTIVES: Minimally invasive esophagectomy is emerging with comparable short-term outcomes as open esophagectomies. Neoadjuvant chemoradiotherapy followed by surgery is considered standard of care in the Netherlands for patients with esophageal cancer. The aim of this study was to analyze the long-term oncologic outcome after neoadjuvant chemoradiotherapy followed by totally minimally invasive esophagectomy. METHODS: Neoadjuvant carboplatin and paclitaxel based chemotherapy was concomitantly given with 41.4 Gy radiotherapy. Six weeks after neoadjuvant treatment, totally minimally invasive esophagectomy was performed. RESULTS: From December 2010 until December 2015 161 patients received this combination of treatment. In 128 male and 33 female patients with median age of 65 years (58-71), 88 minimally invasive esophagectomies with intrathoracic anastomosis and 73 minimally invasive esophagectomies with cervical anastomosis were carried out. Radical (R0) resection was confirmed in 156 patients (97%). In hospital mortality occurred in 6 patients (3.7%). Overall survival was 79% and 51% at 1 and 5 years, respectively, with a median follow-up of 24.5 months (13-38). Disease-free survival was, respectively, 76% and 55%. CONCLUSIONS: Totally minimally invasive esophagectomy after neoadjuvant chemoradiotherapy for esophageal cancer is a safe treatment with low postoperative mortality rates and favorable overall and disease-free survival. PMID- 29603272 TI - Thoracic versus nonthoracic MR imaging for patients with an MR nonconditional cardiac implantable electronic device. AB - BACKGROUND: Observational studies have explored the safety of magnetic resonance (MR) scanning of patients with cardiac implantable electronic devices (CIEDs) that are not Food and Drug Administration approved for MR scanning ("nonconditional"). However, concern has been raised that MR scanning that includes the thoracic region may pose a higher risk. This study examines the safety of MR scanning of thoracic versus nonthoracic regions of patients with CIEDs. METHODS: Patients underwent MR scanning utilizing an institutional protocol. CIED variables examined included sensing value, pacing capture threshold, lead impedance, and battery voltage. Regression analysis of the CIED variable differences (pre- to immediately post-MR and pre-MR to long-term follow up) was performed to determine if CIED variable differences were dependent on region scanned (thoracic vs nonthoracic), time from CIED implant to MR scanning, or CIED type (pacemaker vs implantable cardioverter defibrillator). RESULTS: 238 patients (38% female, age 65 +/- 15 years) underwent 339 MR scans, including 99 MR scans of the thoracic region. CIED variable differences to immediately post-MR or to long-term follow-up were not significantly different from zero (P > 0.05) and there was no dependence upon region scanned (thoracic vs nonthoracic), time from CIED implant to MR scan, or CIED type. One power-on reset occurred in a patient that underwent a cardiac MR and the CIED was successfully reprogrammed. There were no clinical adverse effects. CONCLUSIONS: CIED variable differences following MR scan were not dependent on the region scanned (thoracic vs nonthoracic) and there were no clinical adverse effects in this prospective cohort. PMID- 29603273 TI - Water relations of Calycanthus flowers: Hydraulic conductance, capacitance, and embolism resistance. AB - For most angiosperms, producing and maintaining flowers is critical to sexual reproduction, yet little is known about the physiological processes involved in maintaining flowers throughout anthesis. Among extant species, flowers of the genus Calycanthus have the highest hydraulic conductance and vein densities of species measured to date, yet they can wilt by late morning under hot conditions. Here, we combine diurnal measurements of gas exchange and water potential, pressure-volume relations, functional responses of gas exchange, and characterization of embolism formation using high resolution X-ray computed microtomography to determine drought responses of Calycanthus flowers. Transpiration from flowers frequently exceeded transpiration from leaves, and flowers were unable to limit transpiration under conditions of high vapour pressure deficit. As a result, they rely heavily on hydraulic capacitance to prevent water potential declines. Despite having high water potentials at turgor loss, flowers were very resistant to embolism formation, with no embolism apparent until tepal water potentials had declined to -2 MPa. Although Calycanthus flowers remain connected to the stem xylem and have high hydraulic capacitance, their inability to curtail transpiration leads to turgor loss. These results suggest that extreme climate events may cause flower failure, potentially preventing successful reproduction. PMID- 29603274 TI - Can the epoxides of cinnamyl alcohol and cinnamal show new cases of contact allergy? AB - BACKGROUND: Cinnamyl alcohol is considered to be a prohapten and prehapten with cinnamal as the main metabolite. However, many individuals who are allergic to cinnamyl alcohol do not react to cinnamal. Sensitizing epoxides of cinnamyl alcohol and cinnamal have been identified as metabolites and autoxidation products of cinnamyl alcohol. OBJECTIVE: To investigate the clinical relevance of contact allergy to epoxycinnamyl alcohol and epoxycinnamal. METHODS: Irritative effects of the epoxides were investigated in 12 dermatitis patients. Epoxycinnamyl alcohol and epoxycinnamal were patch tested in 393 and 390 consecutive patients, respectively. In parallel, cinnamyl alcohol and cinnamal were patch tested in 607 and 616 patients, respectively. RESULTS: Both epoxides were irritants, but no more positive reactions were detected than when testing was performed with cinnamyl alcohol and cinnamal. Late allergic reactions to epoxycinnamyl alcohol were observed. In general, patients with late reactions showed doubtful or positive reactions to cinnamal and fragrance mix I at regular patch testing. CONCLUSION: The investigated epoxides are not important haptens in contact allergy to cinnamon fragrance. The high frequency of fragrance allergy among patients included in the irritancy study showed the difficulty of suspecting fragrance allergy on the basis of history; patch testing broadly with fragrance compounds is therefore important. PMID- 29603275 TI - The aroma volatile repertoire in strawberry fruit: a review. AB - Aroma significantly contributes to flavor, which directly affects the commercial quality of strawberries. The strawberry aroma is complex as many kinds of volatile compounds are found in strawberries. In this review, we describe the current knowledge of the constituents and of the biosynthesis of strawberry volatile compounds, and the effect of postharvest treatments on aroma profiles. The characteristic strawberry volatile compounds consist of furanones, such as 2,5-dimethyl-4-hydroxy-3(2H)-furanone and 4-methoxy-2,5-dimethyl-3(2H)-furanone; esters, including ethyl butanoate, ethyl hexanoate, methyl butanoate, and methyl hexanoate; sulfur compounds such as methanethiol, and terpenoids including linalool and nerolidol. As for postharvest treatment, the present review discusses the overview of aroma volatiles in response to temperature, atmosphere, and exogenous hormones, as well as other treatments including ozone, edible coating, and ultraviolet radiation. The future prospects for strawberry volatile biosynthesis and metabolism are also presented. (c) 2018 Society of Chemical Industry. PMID- 29603276 TI - Estimation of Resting Energy Expenditure Using Predictive Equations in Critically Ill Children: Results of a Systematic Review. AB - Provision of adequate energy intake to critically ill children is associated with improved prognosis, but resting energy expenditure (REE) is rarely determined by indirect calorimetry (IC) due to practical constraints. Some studies have tested the validity of various predictive equations that are routinely used for this purpose, but no systematic evaluation has been made. Therefore, we performed a systematic review of the literature to assess predictive equations of REE in critically ill children. We systematically searched the literature for eligible studies, and then we extracted data and assigned a quality grade to each article according to guidelines of the Academy of Nutrition and Dietetics. Accuracy was defined as the percentage of predicted REE values to fall within +/-10% or +/-15% of the measured energy expenditure (MEE) values, computed based on individual participant data. Of the 993 identified studies, 22 studies testing 21 equations using 2326 IC measurements in 1102 children were included in this review. Only 6 equations were evaluated by at least 3 studies in critically ill children. No equation predicted REE within +/-10% of MEE in >50% of observations. The Harris Benedict equation overestimated REE in two-thirds of patients, whereas the Schofield equations and Talbot tables predicted REE within +/-15% of MEE in approximately 50% of observations. In summary, the Schofield equations and Talbot tables were the least inaccurate of the predictive equations. We conclude that a new validated indirect calorimeter is urgently needed in the critically ill pediatric population.). PMID- 29603277 TI - CALIPER: A deformable image registration algorithm for large geometric changes during radiotherapy for locally advanced non-small cell lung cancer. AB - PURPOSE: Locally advanced non-small cell lung cancer (NSCLC) patients may experience dramatic changes in anatomy during radiotherapy and could benefit from adaptive radiotherapy (ART). Deformable image registration (DIR) is necessary to accurately accumulate dose during plan adaptation, but current algorithms perform poorly in the presence of large geometric changes, namely atelectasis resolution. The goal of this work was to develop a DIR framework, named Consistent Anatomy in Lung Parametric imagE Registration (CALIPER), to handle large geometric changes in the thorax. METHODS: Registrations were performed on pairs of baseline and mid treatment CT datasets of NSCLC patients presenting with atelectasis at the start of treatment. Pairs were classified based on atelectasis volume change as either full, partial, or no resolution. The evaluated registration algorithms consisted of several combinations of a hybrid intensity- and feature-based similarity cost function to investigate the ability to simultaneously match healthy lung parenchyma and adjacent atelectasis. These components of the cost function included a mass-preserving intensity cost in the lung parenchyma, use of filters to enhance vascular structures in the lung parenchyma, manually delineated lung lobes as labels, and several intensity cost functions to model atelectasis change. Registration error was quantified with landmark-based target registration error and post-registration alignment of atelectatic lobes. RESULTS: The registrations using both lobe labels and vasculature enhancement in addition to intensity of the CT images were found to have the highest accuracy. Of these registrations, the mean (SD) of mean landmark error across patients was 2.50 (1.16) mm, 2.80 (0.70) mm, and 2.04 (0.13) mm for no change, partial resolution, and full atelectasis resolution, respectively. The mean (SD) atelectatic lobe Dice similarity coefficient was 0.91 (0.08), 0.90 (0.08), and 0.89 (0.04), respectively, for the same groups. Registration accuracy was comparable to healthy lung registrations of current state-of-the-art algorithms reported in literature. CONCLUSIONS: The CALIPER algorithm developed in this work achieves accurate image registration for challenging cases involving large geometric and topological changes in NSCLC patients, a requirement for enabling ART in this patient group. PMID- 29603278 TI - Deep nets vs expert designed features in medical physics: An IMRT QA case study. AB - PURPOSE: The purpose of this study was to compare the performance of Deep Neural Networks against a technique designed by domain experts in the prediction of gamma passing rates for Intensity Modulated Radiation Therapy Quality Assurance (IMRT QA). METHOD: A total of 498 IMRT plans across all treatment sites were planned in Eclipse version 11 and delivered using a dynamic sliding window technique on Clinac iX or TrueBeam Linacs. Measurements were performed using a commercial 2D diode array, and passing rates for 3%/3 mm local dose/distance-to agreement (DTA) were recorded. Separately, fluence maps calculated for each plan were used as inputs to a convolution neural network (CNN). The CNNs were trained to predict IMRT QA gamma passing rates using TensorFlow and Keras. A set of model architectures, inspired by the convolutional blocks of the VGG-16 ImageNet model, were constructed and implemented. Synthetic data, created by rotating and translating the fluence maps during training, was created to boost the performance of the CNNs. Dropout, batch normalization, and data augmentation were utilized to help train the model. The performance of the CNNs was compared to a generalized Poisson regression model, previously developed for this application, which used 78 expert designed features. RESULTS: Deep Neural Networks without domain knowledge achieved comparable performance to a baseline system designed by domain experts in the prediction of 3%/3 mm Local gamma passing rates. An ensemble of neural nets resulted in a mean absolute error (MAE) of 0.70 +/- 0.05 and the domain expert model resulted in a 0.74 +/- 0.06. CONCLUSIONS: Convolutional neural networks (CNNs) with transfer learning can predict IMRT QA passing rates by automatically designing features from the fluence maps without human expert supervision. Predictions from CNNs are comparable to a system carefully designed by physicist experts. PMID- 29603279 TI - Long-Term Therapy With Teduglutide in Parenteral Support-Dependent Patients With Short Bowel Syndrome: A Case Series. AB - OBJECTIVE: To review all cases of parenteral support (PS)-dependent patients with short bowel syndrome (SBS) treated with teduglutide (Gattex, Shire) and to evaluate its efficacy and adverse effects. METHODS: This is a retrospective descriptive cohort of SBS patients treated with teduglutide. Demographics, bowel length, primary diagnosis, PS volume/duration, teduglutide dose, and side effects were collected prospectively. RESULTS: Six SBS patients (4 females, 2 males) received teduglutide. Mean age was 46.3 years (range 26-71). SBS etiology was vascular (n = 3), multiple resections (n = 2), and strangulation (n = 1). Length of residual small bowel was between 30-120 cm. The bowel anatomy was colon present (n = 3) and stoma n = 3 (ileostomy, 2; colostomy, 1). PS duration was 1.5 14 years. Weekly PS volume was mean 7.7 liters/week (1-14). Number of PS days per week ranged 1-7 days. Mean duration of teduglutide therapy was 31 months (24-36). All patients achieved >=20% reduction in PS weekly volume within 6 months. PS was weaned in all patients. Adverse effects included abdominal bloat/discomfort (n = 3), stoma enlargement (n = 3), bowel obstruction (n = 1), and congestive heart failure (n = 1). CONCLUSIONS: All PS-dependent SBS patients treated with teduglutide were weaned off PS. Patients with colon in continuity and lower PS weekly volume requirements were weaned off PS sooner than those with end-stomas and higher PS volume requirements. Teduglutide was well tolerated. Additional clinical studies of teduglutide in SBS patients with marginal PS requirements are needed. PMID- 29603280 TI - Commentary on "Fish Oil-Containing Lipid Emulsions in Adult Parenteral Nutrition: A Review of the Evidence" (https://doi.org/10.1177/0148607117721907). PMID- 29603281 TI - Association of Energy and Protein Delivery on Skeletal Muscle Mass Changes in Critically Ill Adults: A Systematic Review. AB - Critically ill patients experience significant and rapid loss of skeletal muscle mass, which has been associated with negative clinical outcomes. The aetiology of muscle wasting is multifactorial and nutrition delivery may play a role. A systematic literature review was conducted to examine the association of energy and/or protein provision on changes in skeletal muscle mass in critically ill patients. Key databases were searched up until March 2016 to identify studies that measured skeletal muscle mass and/or total body protein (TBP) at 2 or more time points during acute critical illness (up to 2 weeks after an intensive care unit [ICU] stay). Studies were included if there was documentation of participant energy balance or mean energy delivered to participants during the time period between body composition measurements. Six studies met inclusion criteria. A variety of methods were used to assess skeletal muscle mass or TBP. Participants in included studies experienced differing levels of muscle loss (0%-22.5%) during the first 2 weeks of ICU admission. No association between energy and protein delivery and changes in skeletal muscle mass were observed. This review highlights that there is currently limited high-quality evidence to clearly define the association between energy and/or protein delivery and skeletal muscle mass changes in acute critical illness. Future studies in this area should be adequately powered, account for all potential confounding factors to changes in skeletal muscle mass, and detail all sources and quantities of energy and protein delivered to participants. PMID- 29603282 TI - Sequence analysis-based characterization and identification of neurovirulence associated variants of 36 EV71 strains from China. AB - Enterovirus 71 (EV71) is the main pathogen of hand-foot-mouth disease (HFMD) and causes several neurological complications. As new strains of EV71 are constantly discovered, it is important to understand the genomic characteristics of the viruses and the mechanism of virulence. Herein, we isolated five strains of EV71 from HFMD patients with or without neurovirulence and sequenced their whole genomes. We then performed whole genome sequence analysis of totally 36 EV71 strains. The phylogenetic analysis of the VP1 region revealed all five isolated strains are clustered into C4a of C4 subgenotype. In addition, by comparing the complete genome sequences of 36 strains, 253 variable amino acid positions were found, 14 of which were identified to be associated with neurovirulence (P < 0.05). Moreover, a similar pattern of amino acid variants combination was identified in four strains without neurovirulence, indicating this type of variant pattern might be associated with avirulence. The strains with neurovirulence appeared to be distinguished from those without neurovirulence by the variants in VP1 and P2 regions, implying VP1 and P2 are the important regions associated with neurovirulence. Indeed, 3-D modeling of VP1 and P2 regions of non neurovirulent and neurovirulent strains revealed that the different variants resulted in different protein structures and amino acid composition of ligand binding site, which might account for their difference in neurovirulence. In summary, our study reveals 14 variable amino acid positions of VP1, P2 and P3 regions are related to the virulence and that mutations in the capsid proteins of EV71 might contribute to neurovirulence. PMID- 29603283 TI - JPEN Journal Club 34. Suspecting Causation in an Association. PMID- 29603284 TI - Demarcation of Viral Shelters Results in Destruction by Membranolytic GTPases: Antiviral Function of Autophagy Proteins and Interferon-Inducible GTPases. AB - A hallmark of positive-sense RNA viruses is the formation of membranous shelters for safe replication in the cytoplasm. Once considered invisible to the immune system, these viral shelters are now found to be antagonized through the cooperation of autophagy proteins and anti-microbial GTPases. This coordinated effort of autophagy proteins guiding GTPases functions against not only the shelters of viruses but also cytoplasmic vacuoles containing bacteria or protozoa, suggesting a broad immune-defense mechanism against disparate vacuolar pathogens. Fundamental questions regarding this process remain: how the host recognizes these membranous structures as a target, how the autophagy proteins bring the GTPases to the shelters, and how the recruited GTPases disrupt these shelters. In this review, these questions are discussed, the answers to which will significantly advance our understanding of the response to vacuole-like structures of pathogens, thereby paving the way for the development of broadly effective anti-microbial strategies for public health. PMID- 29603286 TI - Insights Into the Different Effects of Food on Intestinal Secretion Using Magnetic Resonance Imaging. AB - BACKGROUND: Plant foods may stimulate intestinal secretion through chemicals designed to deter herbivores, including lactucins in lettuce and rhein in rhubarb. This may increase ileostomy output and induce diarrhoea in people with intact bowels. OBJECTIVE: We aimed to determine the effect of food on intestinal water content using Magnetic Resonance Imaging (MRI). DESIGN: A three period crossover trial of isocaloric meals in adults without bowel disorders. Meals: 2 slices white bread with 10 g butter; 300 g rhubarb with 60 mL lactose free cream; 300 g lettuce with 30 mL mayonnaise. PRIMARY OUTCOME: Area under curve (AUC) small bowel water content (SBWC) using MRI. SECONDARY OUTCOMES: ascending colon water content; T1 relaxation time of ascending colon (T1AC); gastric volume; visual analogue scales of bloating and satiety (0-100). MRI analysts were blinded. Scanned fasting and hourly to 180 min postprandial. Symptoms scored half hourly. RESULTS: 9 female and 6 male subjects completed the study. AUC SBWC fell after bread but rose after lettuce and even more after rhubarb, difference from baseline being (Bread AUC -5662 (1209) ml.min vs Lettuce 3194 (1574) ml.min and Rhubarb 10586 (1629) ml.min (P < 0.01). Rhubarb induced a rise in T1AC but differences at 3 hours were not significant (P = 0.06). Gastric volume at T = 0 significantly was higher for both lettuce and rhubarb (571 +/- 92 and 558 +/- 89 mls) respectively compared to bread (314 +/- 108 mls) (p < 0.0001). Symptom scores were higher for lettuce > rhubarb > bread. CONCLUSION: Lettuce and rhubarb meals increased intestinal water content, demonstrating how different foods can alter ileal flow and stool consistency. PMID- 29603285 TI - DNA Repair: The Search for Homology. AB - The repair of chromosomal double-strand breaks (DSBs) by homologous recombination is essential to maintain genome integrity. The key step in DSB repair is the RecA/Rad51-mediated process to match sequences at the broken end to homologous donor sequences that can be used as a template to repair the lesion. Here, in reviewing research about DSB repair, I consider the many factors that appear to play important roles in the successful search for homology by several homologous recombination mechanisms. See also the video abstract here: https://youtu.be/vm7 X5uIzS8. PMID- 29603287 TI - Nuclear localisation of 53BP1 is regulated by phosphorylation of the nuclear localisation signal. AB - BACKGROUND INFORMATION: Repair of damaged DNA is essential for maintaining genomic stability. TP53-binding protein 1 (53BP1) plays an important role in repair of the DNA double-strand breaks. Nuclear localisation of 53BP1 depends on importin beta and nucleoporin 153, but the type and location of 53BP1 nuclear localisation signal (NLS) have yet to be determined. RESULTS: Here, we show that nuclear import of 53BP1 depends on two basic regions, namely 1667-KRK-1669 and 1681-KRGRK-1685, which are both needed for importin binding. Lysine 1667 is essential for interaction with importin and its substitution to arginine reduced nuclear localisation of 53BP1. Furthermore, we have found that CDK1-dependent phosphorylation of 53BP1 at S1678 impairs importin binding during mitosis. Phosphorylation-mimicking mutant S1678D showed reduced nuclear localisation, suggesting that phosphorylation of the NLS interferes with nuclear import of the 53BP1 CONCLUSIONS: We show that 53BP1 contains a classical bipartite NLS 1666 GKRKLITSEEERSPAKRGRKS-1686, which enables the importin-mediated nuclear transport of 53BP1. Additionally, we found that posttranslational modification within the NLS region can regulate 53BP1 nuclear import. SIGNIFICANCE: Our results indicate that integrity of the NLS is important for 53BP1 nuclear localisation. Precise mapping of the NLS will facilitate further studies on the effect of posttranslational modifications and somatic mutations on the nuclear localisation 53BP1 and DNA repair. PMID- 29603288 TI - Getting the Message? Native Reactive Electrophiles Pass Two Out of Three Thresholds to be Bona Fide Signaling Mediators. AB - Precision cell signaling activities of reactive electrophilic species (RES) are arguably among the most poorly-understood means to transmit biological messages. Latest research implicates native RES to be a chemically-distinct subset of endogenous redox signals that influence cell decision making through non-enzyme assisted modifications of specific proteins. Yet, fundamental questions remain regarding the role of RES as bona fide second messengers. Here, we lay out three sets of criteria we feel need to be met for RES to be considered as true cellular signals that directly mediate information transfer by modifying "first responding" sensor proteins. We critically assess the available evidence and define the extent to which each criterion has been fulfilled. Finally, we offer some ideas on the future trajectories of the electrophile signaling field taking inspiration from work that has been done to understand canonical signaling mediators. Also see the video abstract here: https://youtu.be/rG7o0clVP0c. PMID- 29603289 TI - Sole and combined vitamin C supplementation can prevent postoperative atrial fibrillation after cardiac surgery: A systematic review and meta-analysis of randomized controlled trials. AB - We undertook a systematic review and meta-analysis to evaluate the effect of vitamin C supplementation (vitamin C solely or as adjunct to other therapy) on prevention of postoperative atrial fibrillation (POAF) in patients after cardiac surgery. PubMed, Embase, Web of Science, and Cochrane Library were systematically searched to identify randomized controlled trials assessing the effect of vitamin C supplementation in adult patients undergoing cardiac surgery, and the meta analysis was performed with a random-effects model. Thirteen trials involving 1956 patients were included. Pooling estimate showed a significantly reduced incidence of POAF (relative risk [RR]: 0.68, 95% confidence interval [CI]: 0.54 to 0.87, P = 0.002) both in vitamin C alone (RR: 0.75, 95% CI: 0.63 to 0.90, P = 0.002) and as an adjunct to other therapy (RR: 0.32, 95% CI: 0.20 to 0.53, P < 0.001). The results remain stable and robust in subgroup and sensitivity analyses, and trial sequential analysis also confirmed that the evidence was sufficient and conclusive. Additionally, vitamin C could significantly decrease intensive care unit length of stay (weighted mean difference: -0.24 days, 95% CI: -0.45 to -0.03, P = 0.023), hospital length of stay (weighted mean difference: 0.95 days, 95% CI: -1.64 to -0.26, P = 0.007), and risk of adverse events (RR: 0.45, 95% CI: 0.21 to 0.96, P = 0.039). Use of vitamin C alone and as adjunct to other therapy can prevent POAF in patients undergoing cardiac surgery and should be recommended for patients receiving cardiac surgery for prevention of POAF. PMID- 29603290 TI - BET-ting on Nrf2: How Nrf2 Signaling can Influence the Therapeutic Activities of BET Protein Inhibitors. AB - BET proteins such as Brd3 and Brd4 are chromatin-associated factors, which control gene expression programs that promote inflammation and cancer. The Nrf2 transcription factor is a master regulator of genes that protect the organism against xenobiotic attack and oxidative stress. Nrf2 has demonstrated anti inflammatory activity and can support cancer cell malignancy. This review describes the discovery, mechanism and biomedical implications of the regulatory interplay between Nrf2 and BET proteins. Both Nrf2 and BET proteins are established drug targets. Small molecules that either activate or suppress these proteins are currently tested in clinical trials. The crosstalk between Nrf2 and BET proteins may have important, and until now overlooked, implications for the therapeutic effects of these drugs. Based on the information covered in this review, it should be possible to design combinatorial treatment strategies for cancer and inflammatory diseases, which may improve the efficacy of targeting a Nrf2 or BET proteins individually. PMID- 29603291 TI - Improvement in early detection of orofacial clefts using the axial view of the maxilla. AB - OBJECTIVES: To evaluate the performance of the maxilla in the axial view in detection of orofacial clefts (OC) compared with the retronasal triangle (RNT) in the coronal view and palatine line in the sagittal view at the early stage of gestation. METHODS: A total of 2982 fetuses (including 315 twins) were enrolled for the first-trimester screening in this prospective study. The maxilla in the axial view, palatine line in the sagittal view, and RNT in the coronal view were scanned by 2-dimensional ultrasound. RESULTS: Excluded 103 cases lost to follow up, 2879 fetuses were analyzed in our study. Obtaining rates of the satisfactory image of the maxilla in the axial view, RNT in the coronal view, and palatine line in the sagittal view were 95.2%, 93.8%, and 98.2% respectively. Abnormal axial view of the maxilla, coronal view of the RNT, and sagittal view of the palatine line were observed in 100% (8/8), 75% (6/8), and 50% (4/8) of the CLP cases respectively. CONCLUSIONS: The study demonstrates that using the axial view of maxilla in the diagnosis of OC is feasible and improved the detection of OC compared with the sagittal view of the palatine line and coronal view of the RNT in the first trimester. PMID- 29603292 TI - On the electrophoretic mobilities of partially charged oligosaccharides as a function of charge patterning and degree of polymerization. AB - Fully or partially charged oligosaccharide molecules play a key role in many areas of biology, where their fine structures are crucial in determining their functionality. However, the separation of specific charged oligosaccharides from similar moieties that typically coexist in extracted samples, even for those that are unbranched, and in cases where each saccharide moiety can only carry a single charge or not, is far from trivial. Typically such molecules are characterized by a degree of polymerization n and a number m (and distribution) of charged residues, and must be separated from a plethora of similar species possessing different combinations of n and m. Furthermore, the separation of the possible n!/m!(n-m)! isomers of each species of fixed n and m is a formidable challenge to analytical chemists. Herein, we report the results of molecular dynamics simulations that have been performed in order to calculate the free solution electrophoretic mobilities of galacturonides and charged oligosaccharides derived from digests of the important plant cell-wall polysaccharide pectin. The simulations are compared with an experiment and are found to correctly predict the loss of resolution of fully charged species above a critical degree of polymerization n and the ionic strength dependence of the electrophoretic mobilities of different partially charged oligosaccharides. It is expected that having a predictive tool for the calculation of the electrophoretic mobilities of differently charged oligosaccharide species in hand will allow experimental conditions that optimize the resolution of particular species to be ascertained and understood. PMID- 29603293 TI - The protective effects of sciadopitysin against methylglyoxal-induced cytotoxicity in cultured pancreatic beta-cells. AB - Increased glycation of macromolecules via the reactive dicarbonyl and alpha oxoaldehyde methylglyoxal (MG) has shown an association with diabetes and its complications. In the present study, the protective effects of sciadopitysin against MG-induced oxidative cell damage were investigated in the insulin producing pancreatic beta-cell line, RIN-m5F cells. When exposed to MG for 48 hours, RIN-m5F cells experienced significant loss of viability and impaired insulin secretion; however, treatment with sciadopitysin protected RIN-m5F cells against MG-induced cell death and decreased insulin secretion. Treatment of RIN m5F cells with sciadopitysin prevented MG-induced production of interleukin 1beta, intracellular reactive oxygen species and cardiolipin peroxidation. Furthermore, sciadopitysin increased adenosine monophosphate-activated protein kinase phosphorylation of RIN-m5F cells. Treatment of cells with sciadopitysin increased the activity of glyoxalase I and decreased the levels of MG-protein adducts, indicating that sciadopitysin protects against MG-induced protein glycation by increasing MG detoxification. Taken together, the results indicated the potential utility of sciadopitysin as an intervention against MG-induced cell damage in pancreatic beta-cells. PMID- 29603294 TI - A nonsense mutation in the FGF5 gene is associated with the long-haired phenotype in domestic guinea pigs (Cavia porcellus). PMID- 29603295 TI - Molecular identification and physiological characterization of Zymomonas mobilis strains from fuel-ethanol production plants in north-east Brazil. AB - : Zymomonas mobilis has long attracted attention owing to its capacity to ferment hexose to ethanol. From a taxonomic viewpoint, Z. mobilis is a unique species of the genus Zymomonas, separated into three subspecies, Z. mobilis subsp. mobilis, Z. mobilis subsp. pomaceae and Z. mobilis subsp. francensis on the basis of physiological tests, which are often unreliable owing to the genetic proximity among these species. Currently, the use of molecular techniques is more appropriate for identification of these bacterial subspecies. In this study, the 32 strains of Z. mobilis present in the UFPEDA bacterial collection were characterized using molecular techniques, such as sequencing of the 16S rDNA gene and its theoretical restriction profile, classifying them as members of the subspecies, Z. mobilis subsp. mobilis. In addition, anaerobic cultivations were performed, which showed the biological diversity of the strains in terms of growth, sugar consumption and ethanol production. From these results, it was possible to identify the strain Z-2-80 as a promising bacterium for use in the fermentation process. SIGNIFICANCE AND IMPACT OF THE STUDY: Zymomonas mobilis is a bacterium of great relevance to biotechnology, owing to its capacity to ferment hexose to ethanol. On a molecular basis, 32 isolates were identified as Z. mobilis subsp. mobilis. However, intraspecific diversity was identified when these were grown under strictly anaerobic conditions. The results obtained from this study suggest a strain of Z. mobilis as an alternative for use in the fermentation process. PMID- 29603296 TI - New Roles for the Nucleolus in Health and Disease. AB - Over the last decade, our appreciation of the importance of the nucleolus for cellular function has progressed from the ordinary to the extraordinary. We no longer think of the nucleolus as simply the site of ribosome production, or a dynamic subnuclear body noted by pathologists for its changes in size and shape with malignancy. Instead, the nucleolus has emerged as a key controller of many cellular processes that are fundamental to normal cell homeostasis and the target for dysregulation in many human diseases; in some cases, independent of its functions in ribosome biogenesis. These extra-nucleolar or new functions, which we term "non-canonical" to distinguish them from the more traditional role of the nucleolus in ribosome synthesis, are the focus of this review. In particular, we explore how these non-canonical functions may provide novel insights into human disease and in some cases new targets for therapeutic development. PMID- 29603298 TI - Hawaiian Drosophila as an Evolutionary Model Clade: Days of Future Past. AB - The Hawaiian Drosophila have been a model system for evolutionary, ecological, and ethological studies since the inception of the Hawaiian Drosophila Project in the 1960s. Here we review the past and present research on this incredible lineage and provide a prospectus for future directions on genomics and microbial interactions. While the number of publications on this group has waxed and waned over the years, we assert that recent systematic, biogeographic, and ecological studies have reinvigorated Hawaiian Drosophila as an evolutionary model system. The characteristics that distinguish good model clades from good model organisms (e.g., Drosophila melanogaster) are somewhat different so we first define what constitutes a good evolutionary model. We argue that the Hawaiian Drosophila possess many desired aspects of a good evolutionary model, describe how this group of geographically isolated flies have been used in the past, and propose some exciting avenues for future evolutionary research on this diverse, dynamic clade of Drosophila. PMID- 29603297 TI - Changes in photosynthetic rate and stress volatile emissions through desiccation rehydration cycles in desiccation-tolerant epiphytic filmy ferns (Hymenophyllaceae). AB - Exposure to recurrent desiccation cycles carries a risk of accumulation of reactive oxygen species that can impair leaf physiological activity upon rehydration, but changes in filmy fern stress status through desiccation and rewatering cycles have been poorly studied. We studied foliage photosynthetic rate and volatile marker compounds characterizing cell wall modifications (methanol) and stress development (lipoxygenase [LOX] pathway volatiles and methanol) through desiccation-rewatering cycles in lower-canopy species Hymenoglossum cruentum and Hymenophyllum caudiculatum, lower- to upper-canopy species Hymenophyllum plicatum and upper-canopy species Hymenophyllum dentatum sampled from a common environment and hypothesized that lower canopy species respond more strongly to desiccation and rewatering. In all species, rates of photosynthesis and LOX volatile emission decreased with progression of desiccation, but LOX emission decreased with a slower rate than photosynthesis. Rewatering first led to an emission burst of LOX volatiles followed by methanol, indicating that the oxidative burst was elicited in the symplast and further propagated to cell walls. Changes in LOX emissions were more pronounced in the upper-canopy species that had a greater photosynthetic activity and likely a greater rate of production of photooxidants. We conclude that rewatering induces the most severe stress in filmy ferns, especially in the upper canopy species. PMID- 29603299 TI - Efficacy of chlorhexidine as a final irrigant in one-visit root canal treatment: a prospective comparative study. AB - AIM: To evaluate postoperative pain and radiographic evidence of periapical healing in teeth with apical periodontitis treated in one visit with an additional final irrigation using 2% chlorhexidine (CHX) and to compare the results with conventional two-visit root canal treatment (RCT) with an intracanal calcium hydroxide (CH) dressing as a control group. METHODOLOGY: Ninety asymptomatic maxillary anterior teeth with periapical lesions were treated by a single operator. Root canals were prepared using the step-back technique with manual instrumentation with 2.5% NaOCl and 5% EDTA as irrigants. Half of the teeth were randomly assigned to the one-visit (OV) group and received an additional final rinse with 2% CHX before canal filling. The other teeth were treated in two visits (TV) with a CH paste made by mixing CH powder and distilled water as an interappointment dressing. All patients were recalled and investigated clinically and radiographically for 24 months. Postoperative pain at 24-48 h and changes in apical bone density indicating radiographic healing were evaluated statistically using the Mann-Whitney U-test followed by the Friedman and the Wilcoxon tests (alpha = 0.05). RESULTS: There were no significant differences between two groups regarding the incidence of postoperative pain at 24 h (OV group 50% no pain, 47.6% mild, 2.4% moderate pain/TV group 55% no pain, 42.5% mild, 2.5% moderate pain) and at 48 h (OV group 95% no pain, 5% mild pain/TV group 98% no pain, 2% mild pain). None of the patients reported severe postoperative pain, swelling and/or flare-ups during the follow-up period. There was no significant difference in the radiographic healing rates (OV group 97.6% PAI 1 and/or PAI 2 and 2.4% PAI 3/TV group 95% PAI 1 and/or PAI 2 and 5% PAI 3; P > 0.05). CONCLUSION: Both groups provided favourable and similar postoperative pain and periapical healing rates at 24 months. Thus, one-visit RCT with a final rinse with 2% CHX is an acceptable alternative to two-visit RCT with CH as temporary dressing in maxillary anterior teeth. PMID- 29603300 TI - Reconsidering Values in Biomedical Research. PMID- 29603302 TI - Does grip strength reflect isokinetic muscle strength in lower limbs in patients with chronic inflammatory demyelinating polyneuropathy? AB - INTRODUCTION: Grip strength (GS) is a common measure of general muscle strength in patients with chronic inflammatory demyelinating polyneuropathy (CIDP). However, it is important to investigate the correlation and responsiveness of GS compared with isokinetic muscle strength (IKS) and function of the lower limbs. METHODS: Seventy patients with CIDP were evaluated with GS, IKS, and functional measures of the lower limbs. Reevaluation was performed after 2 and 10/12 weeks. Correlation and response analyses were performed. RESULTS: GS correlated with IKS at the ankle (IKSankle ; maximum Spearman's rank-order correlation [RS ] = 0.58) and with walking performance (maximum RS = -0.38). IKSankle was more responsive to detect change (standardized response mean [SRM] = 0.57) than GS (SRM = 0.27). DISCUSSION: GS does not seem to be an appropriate surrogate measure of IKS and function of the lower limbs in patients with CIDP. Muscle Nerve 58: 449-452, 2018. PMID- 29603301 TI - Quantification of lectin fluorescence in GNE myopathy muscle biopsies. AB - INTRODUCTION: GNE myopathy is an adult-onset muscle disorder characterized by impaired sialylation of (muscle) glycans, detectable by lectin histochemistry. We describe a standardized method to quantify (lectin-) fluorescence in muscle sections, applicable for diagnosis and response to therapy for GNE myopathy. METHODS: Muscle sections were fluorescently labeled with the sialic acid-binding Sambucus nigra agglutinin (SNA) lectin and antibodies to sarcolemma residence protein caveolin-3 (CAV-3). Entire tissue sections were imaged in tiles and fluorescence was quantified. RESULTS: SNA fluorescence co-localizing with CAV-3 was ~50% decreased in GNE myopathy biopsies compared with muscle-matched controls, confirming previous qualitative results. DISCUSSION: This quantitative fluorescence method can accurately determine sialylation status of GNE myopathy muscle biopsies. This method is adaptable for expression of other membrane associated muscle proteins, and may be of benefit for disorders in which therapeutic changes in expression are subtle and difficult to assess by other methods. Muscle Nerve 58: 286-292, 2018. PMID- 29603303 TI - Patient Empowerment on the Fight Against Malnutrition. PMID- 29603304 TI - Let's Talk About Sex - Not Gender. PMID- 29603305 TI - How Does a Helicase Unwind DNA? Insights from RecBCD Helicase. AB - DNA helicases are a class of molecular motors that catalyze processive unwinding of double stranded DNA. In spite of much study, we know relatively little about the mechanisms by which these enzymes carry out the function for which they are named. Most current views are based on inferences from crystal structures. A prominent view is that the canonical ATPase motor exerts a force on the ssDNA resulting in "pulling" the duplex across a "pin" or "wedge" in the enzyme leading to a mechanical separation of the two DNA strands. In such models, DNA base pair separation is tightly coupled to ssDNA translocation of the motors. However, recent studies of the Escherichia coli RecBCD helicase suggest an alternative model in which DNA base pair melting and ssDNA translocation occur separately. In this view, the enzyme-DNA binding free energy is used to melt multiple DNA base pairs in an ATP-independent manner, followed by ATP-dependent translocation of the canonical motors along the newly formed ssDNA tracks. Repetition of these two steps results in processive DNA unwinding. We summarize recent evidence suggesting this mechanism for RecBCD helicase action. PMID- 29603306 TI - Assessing the risk of epidemic dropsy from black salve use. AB - Epidemic dropsy is a potentially life-threatening condition resulting from the ingestion of argemone oil derived from the seeds of Argemone mexicana Linn. Exposure to argemone oil is usually inadvertent, arising from mustard cooking oil adulteration. Sanguinarine, an alkaloid present in argemone oil, has been postulated as a causative agent with the severity of epidemic dropsy correlating with plasma sanguinarine levels. Cases of epidemic dropsy have also been reported following the topical application of argemone containing massage oil. Black salve, a topical skin cancer therapy also contains sanguinarine, but at significantly higher concentrations than that reported for contaminated massage oil. Although not reported to date, a theoretical risk therefore exists of black salve inducing epidemic dropsy. This literature review explores the presentation and pathophysiology of epidemic dropsy and assesses the risk of it being induced by black salve. PMID- 29603307 TI - Impact of climate change environmental conditions on the resilience of different formulations of the biocontrol agent Candida sake CPA-1 on grapes. AB - : Biocontrol agents have become components of integrated crop protection systems for controlling economically important fungal pathogens. Candida sake CPA-1 is a biocontrol agent of fungal pathogens of fruits, both pre- and post-harvest. While the efficacy of different formulations have been examined previously, few studies have considered the resilience of different formulations under changing climatic conditions of elevated temperature, drought stress and increased atmospheric CO2 . This study examined the effect of (a) temperature * RH * elevated CO2 (400 vs 1000 ppm) on the temporal establishment and viability of two dry and one liquid C. sake CPA-1 formulations on grape berry surfaces; (b) temperature stress (25 vs 35 degrees C); and (c) elevated CO2 levels. Results indicated that temperature, RH and CO2 concentration influenced the establishment and viability of the formulations but there was no significant difference between formulations. For the combined three-component factors, increased temperature (35 degrees C) and lower RH (40%) reduced the viable populations on grapes. The interaction with elevated CO2 improved the establishment of viable populations of the formulations tested. Viable populations greater than Log 4 CFUs per g were recovered from the grape surfaces suggesting that these had conserved resilience for control of Botrytis rot in grapes. SIGNIFICANCE AND IMPACT OF THE STUDY: The interaction between environmental factors that are expected to occur in response to climate change (CC) will have a significant impact on food security and availability. Little information exists on how elevated temperature, drought stress and increased CO2 will have on the efficacy of biocontrol agents. The impact of these factors on the viability of different formulations of the biocontrol yeast Candida sake on the surface of grapes berries was evaluated for the first time. Such knowledge is critical for projecting the efficacy of biocontrol under climate change conditions and to identify formulations that have the necessary resilience to perform under CC conditions. PMID- 29603308 TI - Spatial Configuration of the Uterine Artery Cervical Segment in 3-Dimensional Reconstruction at 11 to 14 Weeks' Gestation. AB - Uterine artery blood flow measurement is an important component of preeclampsia screening in the first trimester. Transabdominal measurement of the uterine artery pulsatility index has been reported to have relatively low interobserver reproducibility, mainly because the uterine artery is not sampled in the same place every time. We assessed the uterine artery pathway using 3-dimensional power Doppler reconstruction. We found that the artery always forms a loop at the level of the uterine cervix, with anterior descending and posterior ascending segments. The loop spatial position and the appearance of its segments vary according to the parity. In nullipara, the loop is most times regular, with some variations in orientation. It has an anteroposterior position above or at the level of the internal os, and it represents the most inferior point of the uterine artery at this level. In multipara, the loop is almost always rotated; its segments are tortuous and more elongated. The loop is often not the most inferior point of the uterine artery, and its anterior afferent segment sometimes descends below to the level of the loop. Three-dimensional reconstruction can clearly show the appearance of the uterine artery at the level of the cervix. Understanding the spatial arrangement of the uterine artery could enhance the performance of pulsatility index measurement. PMID- 29603309 TI - The status of Demodex cornei: description of the species and developmental stages, and data on demodecid mites in the domestic dog Canis lupus familiaris. AB - Demodecosis canina is one of the most important dog parasitoses, but its aetiology is still not well known. There are currently two known species of demodecid mite specific to the domestic dog Canis lupus familiaris Linnaeus, 1758 (Carnivora: Canidae). These are Demodex canis Leydig, 1859 (Acariformes: Demodecidae) and Demodex injai Desch & Hillier, 2003. There have also been many reports of the so-called 'short form', considered to be a separate species functioning under the name Demodex cornei nomen nudum, for which, however, no formal valid description has been documented. Taxonomic analysis of short forms of dog demodecid mites, associated with the stratum corneum, was performed, in line with the taxonomic criteria of Demodecidae systematics. This form was found to be a distinct species with features that differ from those of the other known species of this family. The species, including the adult and immature stages, is described. It is likely that different Demodex species parasitizing the domestic dog may be responsible for differentiated symptoms and different courses of demodecosis. However, the basis for clarifying this issue should be the correct, unambiguous identification of the species causing parasitosis. PMID- 29603311 TI - Delayed Allergic Reactions to Jellyfish Stings: Usefulness of Ultrasonographic Evaluation. AB - Jellyfish stings often cause immediate local skin reactions, and, less frequently, the affected individuals may develop delayed allergic reactions days or months after the sting. Here, we present 4 such cases. In all cases, color Doppler ultrasonography was performed at the time of diagnosis, and in 3 of the cases, clinical follow-ups with ultrasonographic evaluations were performed. Ultrasonography initially showed dermal thickening with decreased echogenicity that progressively normalized during follow-up. Ultrasonography was useful in quantifying inflammation by measuring the thickness of the dermis and was more precise than standard clinical follow-up of cutaneous lesions in these cases. PMID- 29603312 TI - Comparison of reports of missed nursing care: Registered Nurses vs. practical nurses in hospitals. AB - BACKGROUND: Missed nursing care is an error of omission defined as standard, required nursing care that is not completed or is seriously delayed. Study findings from around the world show that missed nursing care is a global concern. PURPOSE: The purpose of this study was to compare reports of missed nursing care by two types of nurses - registered nurses and practical nurses - in acute care hospitals in Iceland. Former studies in the USA indicate a variance in reports of missed nursing care by staff with different roles. METHODS: This was a cross sectional descriptive study using the MISSCARE Survey-Icelandic questionnaire for data collection. The questionnaire asks about the amount of missed nursing care on the unit for 24 nursing elements (Part A) and 17 reasons of care being missed (Part B). Participants were nursing staff from medical, surgical and intensive care units in all hospitals in Iceland. FINDINGS: A t-test for independent groups showed a significant difference for the overall missed nursing care score (Part A) between registered nurses (M = 2.09, SD = 0.51) and practical nurses (M = 1.82, SD = 0.59) [t(541) = 5.703, p < 0.001]. A comparison of the overall mean score for reasons of missed nursing care (Part B) between registered nurses (M = 2.32, SD = 0.38) and practical nurses (M = 2.21, SD = 0.62) indicated a significant difference in their reporting [t(299) = 2.210, p = 0.028]. In spite of the overall significant difference in ratings of the elements and reasons for missed nursing care by registered nurses and practical nurses, a pattern is evident in the ranking of the elements of nursing care being missed and reasons. CONCLUSIONS: The findings of this study point to the need to acknowledge certain aspects of missed nursing care and the different roles within nursing. They indicate a need to improve open, sincere and structured communication and mutual respect and trust within healthcare teams in Icelandic hospitals. PMID- 29603310 TI - Fetal Intelligent Navigation Echocardiography (FINE) Detects 98% of Congenital Heart Disease. AB - OBJECTIVE: Fetal intelligent navigation echocardiography (FINE) is a novel method that automatically generates and displays 9 standard fetal echocardiographic views in normal hearts by applying intelligent navigation technology to spatiotemporal image correlation (STIC) volume data sets. The main objective was to determine the sensitivity and specificity of FINE in the prenatal detection of congenital heart disease (CHD). METHODS: A case-control study was conducted in 50 fetuses with a broad spectrum of CHD (cases) and 100 fetuses with normal hearts (controls) in the second and third trimesters. Using 4-dimensional ultrasound with STIC technology, volume data sets were acquired. After all identifying information was removed, the data sets were randomly distributed to a different investigator for analysis using FINE. The sensitivity and specificity for the prenatal detection of CHD, as well as positive and negative likelihood ratios were determined. RESULTS: The diagnostic performance of FINE for the prenatal detection of CHD was: sensitivity of 98% (49 of 50), specificity of 93% (93 of 100), positive likelihood ratio of 14, and negative likelihood ratio of 0.02. Among cases with confirmed CHD, the diagnosis with use of FINE completely matched the final diagnosis in 74% (37 of 50); minor discrepancies were seen in 12% (6 of 50), and major discrepancies were seen in 14% (7 of 50). CONCLUSIONS: This is the first time the sensitivity and specificity of the FINE method in fetuses with normal hearts and CHD in the second and third trimesters has been reported. Because FINE identifies a broad spectrum of CHD with 98% sensitivity, this method could be used prenatally to screen for and diagnose CHD. PMID- 29603314 TI - Geriatric dentistry education and context in a selection of countries in 5 continents. AB - PURPOSE/AIM: To summarize and discuss how geriatric dentistry has been addressed in dental schools of different countries regarding to (1) teaching students at the predoctoral level; (2) advanced training, and (3) research. METHOD AND MATERIALS: A convenience sample of faculty members from a selection of high, upper-middle and lower-middle income countries were recruited to complete the survey. The survey had 5 open-ended main topics, and asked about (1) the size of their elderly population, (2) general information about dental education; (3) the number of dental schools teaching geriatric dentistry, and their teaching methods; (4) advanced training in geriatric dentistry; (5) scholarship/research in geriatric dentistry. RESULTS AND CONCLUSION: (1) There is great variation in the size of elderly population; (2) duration of training and content of dental education curriculum varies; (3) geriatric dentistry has not been established as a standalone course in dental schools in the majority of the countries, (4) most countries, with the exception of Japan, lack adequate number of dentists trained in geriatric dentistry as well as training programs, and (5) geriatric dentistry related research has increased in recent years in scope and content, although the majority of these papers are not in English. PMID- 29603313 TI - CD38 protein deficiency induces autoimmune characteristics and its activation enhances IL-10 production by regulatory B cells. AB - CD38 is a transmembrane protein expressed in B lymphocytes, and is able to induce responses as proliferation, differentiation or apoptosis. Several reports propose that CD38 deficiency accelerates autoimmune processes in murine models of autoimmune diabetes, lymphoproliferation and rheumatoid arthritis. Other reports have shown elevated CD38 expression in B and T cells from patients with autoimmunity; however, the role of CD38 is still unclear in the development of autoimmunity. Recently, it has been characterized as CD1dhi CD5+ regulatory B cell subpopulation able to produce IL-10, and the loss of these cells exacerbates the autoimmunity in murine models. Here, we report that CD38-/- mice exhibited elevated titres of ANAS, anti-dsDNA autoantibodies from 12 months of age and were higher by 16 months of age and mice presented kidney damage. Interestingly, there is a reduction in the survival of CD38-/- mice compared to the WT. Furthermore, CD38 is highly expressed by CD1dhigh CD5+ regulatory B cells, and the agonistic anti-CD38 stimulus plus LPS was able to increase the percentage of this cell subset and its ability to induce IL-10 production. Together, these results suggest that CD38 could play a role in the control of autoimmune diseases through their expression on regulatory B cells. PMID- 29603315 TI - Molecules and elements for quantitative bioanalysis: The allure of using electrospray, MALDI, and ICP mass spectrometry side-by-side. AB - To understand biological processes, not only reliable identification, but quantification of constituents in biological processes play a pivotal role. This is especially true for the proteome: protein quantification must follow protein identification, since sometimes minute changes in abundance tell the real tale. To obtain quantitative data, many sophisticated strategies using electrospray and MALDI mass spectrometry (MS) have been developed in recent years. All of them have advantages and limitations. Several years ago, we started to work on strategies, which are principally capable to overcome some of these limits. The fundamental idea is to use elemental signals as a measure for quantities. We began by replacing the radioactive 32 P with the "cold" natural 31 P to quantify modified nucleotides and phosphorylated peptides and proteins and later used tagging strategies for quantification of proteins more generally. To do this, we introduced Inductively Coupled Plasma Mass Spectrometry (ICP-MS) into the bioanalytical workflows, allowing not only reliable and sensitive detection but also quantification based on isotope dilution absolute measurements using poly isotopic elements. The detection capability of ICP-MS becomes particularly attractive with heavy metals. The covalently bound proteins tags developed in our group are based on the well-known DOTA chelate complex (1,4,7,10 tetraazacyclododecane-N,N',N",N'''-tetraacetic acid) carrying ions of lanthanoides as metal core. In this review, I will outline the development of this mutual assistance between molecular and elemental mass spectrometry and discuss the scope and limitations particularly of peptide and protein quantification. The lanthanoide tags provide low detection limits, but offer multiplexing capabilities due to the number of very similar lanthanoides and their isotopes. With isotope dilution comes previously unknown accuracy. Separation techniques such as electrophoresis and HPLC were used and just slightly adapted workflows, already in use for quantification in bioanalysis. Imaging mass spectrometry (MSI) with MALDI and laser ablation ICP-MS complemented the range of application in recent years. PMID- 29603316 TI - Hydrogen/deuterium exchange in mass spectrometry. AB - The isotopic exchange approach is in use since the first observation of such reactions in 1933 by Lewis. This approach allows the investigation of the pathways of chemical and biochemical reactions, determination of structure, composition, and conformation of molecules. Mass spectrometry has now become one of the most important analytical tools for the monitoring of the isotopic exchange reactions. Investigation of conformational dynamics of proteins, quantitative measurements, obtaining chemical, and structural information about individual compounds of the complex natural mixtures are mainly based on the use of isotope exchange in combination with high resolution mass spectrometry. The most important reaction is the Hydrogen/Deuterium exchange, which is mainly performed in the solution. Recently we have developed the approach allowing performing of the Hydrogen/Deuterium reaction on-line directly in the ionization source under atmospheric pressure. Such approach simplifies the sample preparation and can accelerate the exchange reaction so that certain hydrogens that are considered as non-labile will also participate in the exchange. The use of in-ionization source H/D exchange in modern mass spectrometry for structural elucidation of molecules serves as the basic theme in this review. We will focus on the mechanisms of the isotopic exchange reactions and on the application of in ESI, in-APCI, and in-APPI source Hydrogen/Deuterium exchange for the investigation of petroleum, natural organic matter, oligosaccharides, and proteins including protein-protein complexes. The simple scenario for adaptation of H/D exchange reactions into mass spectrometric method is also highlighted along with a couple of examples collected from previous studies. PMID- 29603318 TI - A New Model for Birth Weight Prediction Using 2- and 3-Dimensional Ultrasonography by Principal Component Analysis: A Chinese Population Study. AB - OBJECTIVES: To establish a new model for birth weight prediction using 2- and 3 dimensional ultrasonography (US) by principal component analysis (PCA). METHODS: Two- and 3-dimensional US was prospectively performed in women with normal singleton pregnancies within 7 days before delivery (37-41 weeks' gestation). The participants were divided into a development group (n = 600) and a validation group (n = 597). Principal component analysis and stepwise linear regression analysis were used to develop a new prediction model. The new model's accuracy in predicting fetal birth weight was confirmed by the validation group through comparisons with previously published formulas. RESULTS: A total of 1197 cases were recruited in this study. All interclass and intraclass correlation coefficients of US measurements were greater than 0.75. Two principal components (PCs) were considered primary in determining estimated fetal birth weight, which were derived from 9 US measurements. Stepwise linear regression analysis showed a positive association between birth weight and PC1 and PC2. In the development group, our model had a small mean percentage error (mean +/- SD, 3.661% +/- 3.161%). At least a 47.558% decrease in the mean percentage error and a 57.421% decrease in the standard deviation of the new model compared with previously published formulas were noted. The results were similar to those in the validation group, and the new model covered 100% of birth weights within 10% of actual birth weights. CONCLUSIONS: The birth weight prediction model based on 2- and 3-dimensional US by PCA could help improve the precision of estimated fetal birth weight. PMID- 29603319 TI - Role of melatonin in blood pressure regulation: An adjunct anti-hypertensive agent. AB - Cardiovascular diseases account for approximately one-third of all deaths each year. Of this, hypertension accounts for approximately 9.4 million deaths. Melatonin, the primary circadian hormone, has been substantiated as an effective and safe adjunct anti-hypertensive agent. In support of this, melatonin receptors have been identified within the central and peripheral nervous system, as well as the cardiovascular system, including various vascular tissues. Therefore, it is not surprising that recent research has emerged highlighting a key role of melatonin in autonomic regulation of blood pressure. In animals, pinealectomies elicit peripheral vasoconstriction and hypertension. In studies involving humans, both healthy controls and patient populations of essential and nocturnal hypertension, melatonin administration demonstrates significant hypotensive effects that yield clinically significant results. However, the precise mechanism by which melatonin elicits its hypotensive effects in humans require further investigation. This review focuses on melatonin, its role within the cardiovascular system and the emerging implications for its use as an anti hypertensive agent. Additionally, this review will discuss the current thinking on potential mechanisms behind the hypotensive effects of melatonin including: endothelium-dependent vasodilation, anti-oxidant defence mechanisms and sympatho vagal autonomic regulation. PMID- 29603317 TI - Innovative Discharge Process for Families with Pediatric Short Bowel Syndrome: A Prospective Nonrandomized Trial. AB - BACKGROUND: Home parenteral nutrition (HPN) is a life-sustaining therapy for short bowel syndrome (SBS) and other severe digestive diseases, but complications are common. We evaluated a predischarge HPN hands-on training course to reduce complications in children with SBS, including hospital readmissions. METHODS: We conducted a prospective, nonrandomized controlled research study between April 1, 2014, and April 30, 2017. Eligible participants were children aged <18 years old with SBS and anticipated HPN dependence duration >=6 months. Excluded participants had a previous history of discharge with a central venous catheter (CVC), HPN, or intravenous fluids or strictly palliative goals of care. An intervention group practiced hands-on HPN within the hospital room for 24 hours using infusion equipment. The groups received standard teaching (CVC care, home infusion pump operation, HPN preparation and administration). RESULTS: Nine children were assigned to the intervention group and 12 served as controls. The median age was 8.4 months, and length of stay (LOS) was 82 days. All participants experienced >=1 event, with a total of 47 issues related to HPN. There were no significant associations between group assignment and 30-day postdischarge events. Each additional week of LOS was associated with 11% increase in the odds of an emergency department visit (OR 1.11; 95% CI, 1.01-1.26) and 16% increase in the odds of readmission (OR 1.16; 95% CI, 1.04-1.37). CONCLUSIONS: Postdischarge events remained widespread despite HPN bedside interventions offered by this pilot intervention. With refinement of HPN discharge processes, quality benchmarks are needed. PMID- 29603320 TI - Stakeholder views of rural community-based medical education: a narrative review of the international literature. AB - CONTEXT: Rural community-based medical education (RCBME), in which medical student learning activities take place within a rural community, requires students, clinical teachers, patients, community members and representatives of health and government sectors to actively contribute to the educational process. Therefore, academics seeking to develop RCBME need to understand the rural context, and the views and needs of local stakeholders. OBJECTIVES: The aim of this review is to examine stakeholder experiences of RCBME programmes internationally. METHODS: This narrative literature review of original research articles published after 1970 utilises Worley's symbiosis model of medical education as an analysis framework. This model proposes that students experience RCBME through their intersection with multiple clinical, social and institutional relationships. This model seeks to provide a framework for considering the intersecting relationships in which RCBME programmes are situated. RESULTS: Thirty RCBME programmes are described in 52 articles, representing a wide range of rural clinical placements. One-year longitudinal integrated clerkships for penultimate-year students in Anglosphere countries were most common. Such RCBME enables students to engage in work-integrated learning in a feasible manner that is acceptable to many rural clinicians and patients. Academic results are not compromised, and a few papers demonstrate quality improvement for rural health services engaged in RCBME. These programmes have delivered some rural medical workforce outcomes to communities and governments. Medical students also provide social capital to rural communities. However, these programmes have significant financial cost and risk student social and educational isolation. CONCLUSIONS: Rural community-based medical education programmes are seen as academically acceptable and can facilitate symbiotic relationships among students, rural clinicians, patients and community stakeholders. These relationships can influence students' clinical competency and professional identity, increase graduates' interest in rural careers, and potentially improve rural health service stability. Formal prospective stakeholder consultations should be published in the literature. PMID- 29603321 TI - Incremental Value of the Tissue Motion of Annular Displacement Derived From Speckle-Tracking Echocardiography for Differentiating Chronic Constrictive Pericarditis From Restrictive Cardiomyopathy. AB - OBJECTIVES: The tissue motion of annular displacement provides an accurate and rapid assessment of left ventricular (LV) systolic function. However, it has rarely been used in patients with chronic constrictive pericarditis and restrictive cardiomyopathy. This study aimed to assess the differences in LV systolic function in patients with constrictive pericarditis and restrictive cardiomyopathy using tissue motion of annular displacement derived from speckle tracking echocardiography. METHODS: Twenty-four patients with constrictive pericarditis, 24 with restrictive cardiomyopathy, and 25 healthy volunteers (controls) were enrolled. The septal and lateral mitral annular longitudinal displacements, displacement at the midpoint, and normalized midpoint displacement of the mitral ring were calculated. RESULTS: Mitral annular tracking and quantification of the tissue motion of annular displacement were achieved within 10 seconds. In patients with constrictive pericarditis, the lateral mitral annular longitudinal displacement, displacement at the midpoint, and midpoint displacement of the mitral ring were decreased, whereas the septal mitral annular longitudinal displacement was preserved compared to controls, indicating that the reduction of systolic function in constrictive pericarditis was caused by pericardial adhesion and calcium. In patients with restrictive cardiomyopathy, tissue motion of annular displacement was more reduced compared to patients with constrictive pericarditis and controls. The correlation between the septal mitral annular longitudinal displacement and left ventricular ejection fraction was 0.67 (P < .001). A cutoff value of 8.45 mm for the septal mitral annular longitudinal displacement could effectively differentiate constrictive pericarditis from restrictive cardiomyopathy with 95.2% sensitivity and 91.7% specificity. CONCLUSIONS: The tissue motion of annular displacement was decreased in patients with constrictive pericarditis, which indicated early impairment of longitudinal function in constrictive pericarditis; adhesion and calcium in the pericardium might account for the reduction. The septal mitral annular longitudinal displacement provides a fast and effective method for the assessment of LV systolic function in patients with constrictive pericarditis and restrictive cardiomyopathy. PMID- 29603322 TI - Functional visceral fat activity evaluated by preoperative F-18 FDG PET/CT predicts regional lymph node metastasis in differentiated thyroid cancer. AB - OBJECTIVE: We investigated the predictive role of functional visceral fat activity evaluated by preoperative F-18 FDG PET/CT for regional lymph node metastasis in patients with differentiated thyroid cancer. DESIGN AND PATIENTS: Fifty-eight patients with newly diagnosed differentiated thyroid cancer were enrolled in this study, retrospectively (men 14; women 44; age 53 +/- 14.5). They all received preoperative F-18 FDG PET/CT and surgery. Functional visceral fat activity was defined as maximum standardized uptake value (SUVmax) of visceral fat divided by SUVmax of subcutaneous fat (V/S ratio). Pathology results were confirmed through the surgical specimens. RESULTS: The patients with regional lymph node metastasis showed higher functional visceral fat activity (V/S ratio) than the patients without regional lymph node metastasis (2.12 +/- 0.6 vs 1.62 +/ 0.34, P = .001). V/S ratio of 1.78 was suggested as an optimal cut-off value for predicting regional lymph node metastasis (sensitivity; 70.3%, specificity; 83.3%, area under the curve; 0.778, P < .0001). Furthermore, functional visceral fat activity was significantly associated with regional lymph node metastasis in patients with differentiated thyroid cancer by univariate and multivariate analyses. CONCLUSIONS: Functional visceral fat activity significantly affects the regional lymph node metastasis status in patients with differentiated thyroid cancer. Furthermore, it may also be useful to predict regional lymph node metastasis. PMID- 29603323 TI - Brown tumor of the jaws as a manifestation of tertiary hyperparathyroidism: A literature review and case report. AB - Brown tumor of the jaws is a manifestation of hyperparathyroidism consisting of osteolytic lesions that show proliferation of multinucleated giant cells in the maxilla and/or mandible. Differential diagnosis of these lesions from local central giant-cell granuloma is mandatory for the correct treatment of the patient. Radiographic and histopathological exams of the jaw lesion are not sufficient to determine the diagnosis, which requires laboratory tests including serum levels of calcium, alkaline phosphatase, parathyroid hormone (PTH) and phosphate, and radiographic examination of other bones as well, such as hand wrist, pelvis, and femur. We present here a brief literature review focusing on the clinical and radiographic features, diagnostic criteria and treatment of brown tumor and also report a case of the disease affecting the jaw. PMID- 29603324 TI - Complexities of perceived and actual performance in pathology interpretation: A comparison of cutaneous melanocytic skin and breast interpretations. AB - BACKGROUND: Little is known about how pathologists process differences between actual and perceived interpretations. OBJECTIVE: To compare perceived and actual diagnostic agreement before and after educational interventions. METHODS: Pathologists interpreted test sets of skin and/or breast specimens that included benign, atypical, in situ and invasive lesions. Interventions involved self directed learning, one skin and one breast, that showed pathologists how their interpretations compared to a reference diagnoses. Prior to the educational intervention, participants estimated how their interpretations would compare to the reference diagnoses. After the intervention, participants estimated their overall agreement with the reference diagnoses. Perceived and actual agreements were compared. RESULTS: For pathologists interpreting skin, mean actual agreement was 52.4% and overall pre- and postinterventional mean perceived agreement was 72.9% vs 54.2%, an overestimated mean difference of 20.5% (95% confidence interval [CI] 17.2% to 24.0%) and 1.8% (95% CI -0.5% to 4.1%), respectively. For pathologists interpreting breast, mean actual agreement was 75.9% and overall pre and postinterventional mean perceived agreement was 81.4% vs 76.9%, an overestimation of 5.5% (95% CI 3.0% to 8.0%) and 1.0% (95% CI 0.0% to 2.0%), respectively. CONCLUSIONS: Pathologists interpreting breast tissue had improved comprehension of their performance after the intervention compared to pathologists interpreting skin lesions. PMID- 29603326 TI - The impact of intraductal carcinoma of the prostate on the site and timing of recurrence and cancer-specific survival. AB - BACKGROUND: To investigate the effect of intraductal carcinoma of the prostate (IDC-P) in radical prostatectomy (RP) specimens in the context of the site of recurrence, time to recurrence, and cancer-specific survival in two academic cohorts of locally, regionally, or distantly recurrent prostate cancer. METHODS: Our cohort included men enrolled into two academic tissue repositories from 1993 to 2011, who were treated with first-line RP who later experienced local recurrence, regional recurrence, or distant metastasis (together termed clinical recurrence, CR). RP material was reviewed to identify IDC-P and to update grading to current standards. The primary endpoint was the initial location of CR. Secondary endpoints included time to CR and cancer-specific survival. Pearson's chi-square, Welch's t-test, Mann-Whitney U test and Fisher's exact test were performed for univariate analyses. Multinomial logistic regression was used for multivariate analyses. Cancer-specific survival was analyzed with the generalized Wilcoxon test and Cox regression. RESULTS: Eighty-five patients with CR were included in the analysis. IDC-P was present in 78.5% of patients from Center 1 and 70.0% from Center 2 (P = 0.547). IDC-P was independently associated with distant metastasis at initial CR (multivariate odds ratio = 6.27, P = 0.015). IDC P status did not affect time to recurrence; median survival without recurrence was at 53 months for IDC-P(+) and at 50 months for IDC-P(-) (P = 0.441). Distant metastases at the initial CR event had a 36% reduction of cancer-specific survival compared to local recurrences (P = 0.007). Additionally, prostatic-bed radiotherapy (adjuvant or salvage for biochemical recurrence before distant metastasis) was associated with a 25% reduction in cancer-specific mortality compared to no radiotherapy (P = 0.023). Similar reduction in cancer-specific mortality was observed in the subgroup of patients with distant metastasis and IDC-P when treated with radiotherapy (29%, P = 0.050). CONCLUSIONS: In our cohort, presence of IDC-P was an independent factor for distant metastasis at initial CR, but did not have a significant impact on time to CR. Furthermore, metastatic patients showed statistically reduced cancer-specific mortality when treated with radiotherapy. This reduction in cancer-specific mortality was also identified in patients with IDC-P. Future large scale validation studies should take into account the presence of IDC-P and confirm its impact on disease progression. PMID- 29603325 TI - Loss of PDK4 switches the hepatic NF-kappaB/TNF pathway from pro-survival to pro apoptosis. AB - : It has been established that nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) members promote survival by upregulating antiapoptotic genes and that genetic and pharmacological inhibition of NF-kappaB is required for tumor necrosis factor (TNF)-induced hepatocyte apoptosis. In this study, we demonstrate that this pro-survival pathway is switched to pro-apoptosis under pyruvate dehydrogenase kinase 4 (PDK4)-deficient conditions. PDK4 deficiency triggered hepatic apoptosis concomitantly with increased numbers of aberrant mitochondria, reactive oxygen species (ROS) production, sustained c-Jun N-terminal Kinase (JNK) activation, and reduction of glutathione (GSH). Interestingly, PDK4 retained p65 in cytoplasm via a direct protein-protein interaction. Disruption of PDK4-p65 association promoted p65 nuclear translocation. This, in turn, facilitated p65 binding to the TNF promoter to activate TNF-TNFR1 apoptotic pathway. Pdk4-/- livers were sensitized to Jo2 and D (+)-Galactosamine /Lipopolysaccharide (GalN/LPS)-mediated apoptotic injury which was prevented by the inhibition of p65 or TNFR1. The pro-survival activity of TNF was shifted, which was switched to a pro-apoptotic activity in Pdk4-/- hepatocytes as a result of impaired activation of pro-survival NF-kappaB targets. CONCLUSION: PDK4 is indispensable to dictate the fate of TNF/NF-kappaB-mediated hepatocyte apoptosis. (Hepatology 2018). PMID- 29603327 TI - Hepatocyte microvesicle levels improve prediction of mortality in patients with cirrhosis. AB - : Microvesicles (MVs) are extracellular vesicles released by cells following activation or apoptosis. Some MV subpopulations augment with cirrhosis severity and contribute to portal hypertension. This study aimed at determining if plasma MV levels can estimate the presence of hepatic venous pressure gradient (HVPG) >=10 mm Hg and predict mortality in patients with advanced chronic liver disease. All patients with severe fibrosis or cirrhosis undergoing liver catheterization between 2013 and 2015 at two centers were prospectively included. We measured circulating levels of annexin V+ , platelet, leukocyte, endothelial, and hepatocyte MVs. The test cohort included 139 patients. Hepatocyte MV levels were 4.0-fold and 2.2-fold higher in patients with Child-Pugh C than in those with Child-Pugh A or B liver disease, respectively. Levels of other MV subpopulations were not influenced by liver disease severity. Hepatocyte MV levels correlated with HVPG but could not identify patients with HVPG >=10 mm Hg. Hepatocyte MV level >65 U/L predicted 6-month mortality independently of Child-Pugh score and of Model for End-Stage Liver Disease (MELD). Patients with hepatocyte MV levels >65 U/L and MELD >15 had a higher 6-month mortality than other patients (23% versus 3%; P = 0.001). These findings were confirmed in a validation cohort including 103 patients. CONCLUSION: Circulating MV levels cannot identify patients with HVPG >=10 mm Hg; by contrast, hepatocyte MV levels strongly improve prediction of 6-month mortality in patients with advanced chronic liver disease; therapies associated with decreased levels of circulating hepatocyte MV might be attractive strategies in patients with severe cirrhosis. (Hepatology 2018). PMID- 29603328 TI - Critical review of the validity of patient satisfaction questionnaires pertaining to oral health care. AB - OBJECTIVES: Review the validation process reported for oral healthcare satisfaction scales that intended to measure general oral health care that is not restricted to specific subspecialties or interventions. METHODS: After preliminary searches, PUBMED and EMBASE were searched using a broad search strategy, followed by a snowball strategy using the references of the publications included from database searches. Title and abstract were screened for assessing inclusion, followed by a full-text screening of these publications. English language publications on multi-item questionnaires that report on a scale measuring patient satisfaction for oral health care were included. Publications were excluded when they did not report on any psychometric validation, or the scales were addressing specific treatments or subspecialities in oral health care. RESULTS: Fourteen instruments were identified from as many publications that report on their initial validation, while five more publications reported on further testing of the validity of these instruments. Number of items (range: 8 42) and dimension reported (range: 2-13) were often dissimilar between the assessed measurement instruments. There was also a lack of methodologies to incorporate patient's subjective perspective. Along with a limited reporting of psychometric properties of instruments, cross-cultural adaptations were limited to translation processes. CONCLUSIONS: The extent of validity and reliability of the included instruments was largely unassessed, and appropriate instruments for populations outside of those belonging to general adult populations were not present. PMID- 29603329 TI - Calcium-/calmodulin-dependent protein kinase II in occlusion-induced degenerative cartilage of rat mandibular condyle. AB - Activated calcium-/calmodulin-dependent protein kinaseII (CaMKII) is important to promote chondrocytes from proliferative to pre-hypertrophic state, which probably plays a role in osteoarthritis (OA), a widespread degeneration disease with enhanced aberrant chondrocyte differentiation. Our aim was to detect the role of CaMKII, and its relationship with the feedback loop of Indian hedgehog (Ihh) and Parathyroid-related peptide (PTHrP) in the temporomandibular joints (TMJs) OA. KN93, the competitive inhibitor of CaMKII, was added to the culture medium in vitro and was locally injected to rats TMJs (n = 54, female) every other day for 4 weeks from the beginning of the 5th and 9th week after installing of unilateral anterior crossbite (UAC), termed as 4 wk+4 wk and 8 wk+4 wk, accordingly. The RNA expression of CaMKII alpha (1.49 +/- 0.09), CaMKII beta (3.36 +/- 0.20), Ihh (1.88 +/- 0.06) and PTHrP (1.87 +/- 0.12) was all enhanced, especially at 24 dyn/cm2 in vitro (all P < .05), accompanied with downregulated expression of cartilage matrix, but upregulated markers of chondrocytes differentiation (all P < 0.05). Similarity was observed in the 4 wk+4 wk group in vivo. In the 8 wk+4 wk group, UAC upregulated the RNA expression of CaMKII alpha (1.81 +/- 0.24), CaMKII beta (1.36 +/- 0.07) and Ihh (1.70 +/- 0.21), however, down-regulated PTHrP (0.53 +/- 0.04) (all P < .05), in consonance with the protein expression. All these changes were attenuated by KN93 (all P < .05). In conclusion, CaMKII took a role, via Ihh and PTHrP pathways, in promoting biomechanically induced TMJ chondrocytes differentiation, the initiation issue of UAC stimulated osteoarthritic changes in rodent TMJs. Inhibiting CaMKII is helpful to rescue the biomechanically stimulated cartilage degradation and prospective to be a target treatment of OA. PMID- 29603331 TI - When I say ... exposure. PMID- 29603330 TI - A Clinical Decision Support System Using Ultrasound Textures and Radiologic Features to Distinguish Metastasis From Tumor-Free Cervical Lymph Nodes in Patients With Papillary Thyroid Carcinoma. AB - OBJECTIVES: This study investigated the potential of a clinical decision support approach for the classification of metastatic and tumor-free cervical lymph nodes (LNs) in papillary thyroid carcinoma on the basis of radiologic and textural analysis through ultrasound (US) imaging. METHODS: In this research, 170 metastatic and 170 tumor-free LNs were examined by the proposed clinical decision support method. To discover the difference between the groups, US imaging was used for the extraction of radiologic and textural features. The radiologic features in the B-mode scans included the echogenicity, margin, shape, and presence of microcalcification. To extract the textural features, a wavelet transform was applied. A support vector machine classifier was used to classify the LNs. RESULTS: In the training set data, a combination of radiologic and textural features represented the best performance with sensitivity, specificity, accuracy, and area under the curve (AUC) values of 97.14%, 98.57%, 97.86%, and 0.994, respectively, whereas the classification based on radiologic and textural features alone yielded lower performance, with AUCs of 0.964 and 0.922. On testing the data set, the proposed model could classify the tumor-free and metastatic LNs with an AUC of 0.952, which corresponded to sensitivity, specificity, and accuracy of 93.33%, 96.66%, and 95.00%. CONCLUSIONS: The clinical decision support method based on textural and radiologic features has the potential to characterize LNs via 2-dimensional US. Therefore, it can be used as a supplementary technique in daily clinical practice to improve radiologists' understanding of conventional US imaging for characterizing LNs. PMID- 29603332 TI - Solid papillary breast carcinomas resembling the tall cell variant of papillary thyroid neoplasms (solid papillary carcinomas with reverse polarity) harbour recurrent mutations affecting IDH2 and PIK3CA: a validation cohort. AB - AIMS: Solid papillary breast carcinoma resembling the tall cell variant of papillary thyroid neoplasms (BPTC), also known as solid papillary carcinoma with reverse polarity, is a rare histological type of breast cancer that resembles morphologically the tall cell variant of papillary thyroid carcinoma. BPTCs are characterised by IDH2 R172 hotspot somatic mutations or mutually exclusive TET2 somatic mutations, concurrently with mutations affecting PI3K pathway-related genes. We sought to characterise their histology and investigate the frequency of IDH2 and PIK3CA mutations in an independent cohort of BPTCs, as well as in conventional solid papillary carcinomas (SPCs). METHODS AND RESULTS: Six BPTCs, not previously analysed molecularly, and 10 SPCs were reviewed centrally. Tumour DNA was extracted from microdissected histological sections and subjected to Sanger sequencing of the IDH2 R172 hotspot locus and exons 9 and 20 of PIK3CA. All six BPTCs were characterised by solid, papillary and follicular architecture with circumscribed, invasive tumour nodules composed of epithelial cells with reverse polarity. IDH2 mutations were identified in all six BPTCs (three R172S, two R172T and one R172G), four of which also harboured PIK3CA mutations (two H1047R, one Q546K and one Q546R). By contrast, all SPCs lacked IDH2 mutations, while one of 10 harboured a PIK3CA mutation (H1047R). CONCLUSION: We validated the presence of IDH2 R172 hotspot mutations and PIK3CA hotspot mutations in 100% and 67% BPTCs tested, respectively, and documented absence of IDH2 R172 mutations in SPCs. These findings confirm the genotypical-phenotypical correlation reported previously in BPTC, which constitutes an entity distinct from conventional SPC. PMID- 29603333 TI - Frontal sinus ontogeny and covariation with bone structures in a modern human population. AB - In humans, the frontal sinus (FS) is located in the medial part of the supraorbital region, sometimes expanded throughout the frontal squama. It exhibits high morphological variability, but its general form appears to be constrained by surrounding structures. The goal of this study is to analyze FS growth and test for covariation between FS volume and the glabellar region, upper nasal region, bone thickness and endocranial size in a human sample from Argentina. The sample comprises 149 reconstructions derived from computed tomography images of individuals aged 0-31 years. Volume of the FS and measurements of the surrounding structures were recorded. The FS growth trajectory was assessed by parametric and nonparametric methods, and covariation was determined using correlations and partial correlations. The FS volume could be measured at an age of about 6 years and older; adults had no aplasia but hyperplasia was found in some cases. Since the most conspicuous characteristic found was variation among individuals, the nonparametric smoothing spline produced very poor fitting. The modified logistic function was the only parametric method providing significant parameters. Sexes differed in the age at which FS growth began and ended, with FS developing earlier but at a slower rate in females than in males. The FS volume did not correlate with either upper nasal width or endocranial volume, but it correlated with bone thickness measurements (mainly from the glabellar region), even when age was held constant. Expansion of the FS at the frontal poles also correlated with frontal bone thickness. Despite the difficulty in modeling and predicting the trajectory and morphology of FS, our results suggest that it is affected by its surrounding bony environment. PMID- 29603334 TI - Ultrasonography of Plantar Fibromatosis: Updated Case Series, Review of the Literature, and a Novel Descriptive Appearance Termed the "Comb Sign". AB - The purpose of this series is to review the appearance of plantar fibromatosis with high-resolution ultrasonography (US) and highlight a new imaging sign termed the "comb sign." A retrospective study was performed for patients with a clinical diagnosis of plantar fibromatosis. Charts of 43 patients (age range, 26-77 years; mean age, 54 years) were reviewed to gather patient demographics and symptoms. Several US characteristics were evaluated with emphasis on any new imaging features. A total of 57 plantar fibromas in 43 patients were examined. Plantar fibromatosis was seen as a lobular marginated oval nodule along the superficial plantar fascia involving the central or medial cord, often at the middle third (84%) of the plantar fascia, showing posterior acoustic enhancement (65%), mixed echogenicity (82%), and intralesional vascularity (53%). Slightly more than half (51%) of the lesions showed a previously unrecognized appearance, designated the comb sign. This sign was more commonly seen in the setting of larger fibromas (P < .05). Plantar fibromatosis is usually a clinical diagnosis that can be aided by a typical US appearance. Although the imaging characteristics are largely similar to prior literature, this series suggests that most show mixed echogenicity and posterior acoustic enhancement, and approximately half show internal vascularity. A new US sign, termed the comb sign, shows alternating bands of hypoechogenicity and isoechogenicity, particularly in larger plantar fibromas, and can help in further characterization. PMID- 29603335 TI - Association of neutrophil morphology with bacterial isolates in equine tracheal wash samples. AB - BACKGROUND: Tracheal wash sample neutrophilia is common in lower airway inflammation of various causes; however, relevance of cytomorphological features to culture of bacterial pathogens has not been established. OBJECTIVES: To investigate whether the presence of nondegenerate or degenerate neutrophils in tracheal washes is associated with culture of bacteria and, if so, whether this is influenced by age or temporal factors. STUDY DESIGN: Cross-sectional study. METHODS: Tracheal wash samples submitted to Rossdales LLP from 1/1/2013 to 31/7/2015 were evaluated using set criteria. Neutrophilia and degenerate neutrophilia (graded >=2/4 on Rossdales cytological scale [0-4]) were analysed in relation to bacterial isolates considered potentially pathogenic in respiratory disease. Statistical analyses included multivariable logistic regression to identify associations between two separate outcomes: 1) the presence of neutrophilia compared with no neutrophilia and 2) the presence of degenerate neutrophilia compared with nondegenerate neutrophilia and four independent variables. RESULTS: Sufficient data for inclusion in the multivariable model for nondegenerate neutrophilia were available from 1100 horses. Culture of potentially pathogenic bacteria was associated with increased odds of degenerate neutrophilia compared with samples with negative culture (OR 4.5, 95% CI 3.1, 6.4, P-value<0.001). Horses over 9 years old had lower odds of having degenerate neutrophilia than those aged 1-3 years (OR 0.6, 95% CI 0.4, 0.9, P-value<0.02). In the spring/summer, horses had reduced odds of a degenerate neutrophilia compared with winter (OR 0.4, 95% CI 0.3, 0.7, P-value <0.001). MAIN LIMITATIONS: The study relied on routine laboratory submissions, with no control over sample collection or submitted clinical history. CONCLUSIONS: Cytological evaluation of tracheal washes should include cytomorphological features of the neutrophil response. The presence of degenerate neutrophils, especially in young horses, indicates added value of culture and sensitivity for antimicrobial therapeutics. The absence of degenerate changes, in combination with clinical factors, can help support diagnosis of a nonseptic cause of airway neutrophilia. PMID- 29603336 TI - Dual anticoagulation with fondaparinux and dabigatran for treatment of cancer associated hypercoagulability. PMID- 29603337 TI - CXCR4 blockade improves leukemia eradication by allogeneic lymphocyte infusion. AB - Persistent low levels of disease in bone marrow, an immunoprivileged tissue, are responsible for relapse following allogeneic hematopoietic cell transplantation. Using mouse models carrying primary human acute lymphoblast leukemia derived from MLL-AF9-overexpressing human hematopoietic stem cells, we demonstrate that allogeneic lymphocyte infusion (ALI)-mediated graft-vs.-leukemia effects selectively spare leukemia cells in the bone marrow. The resistance of leukemia cells to ALI within bone marrow is due to the immunosuppressive status of the tissue, as ALI achieved a significantly increased complete remission rate when leukemia cells were dislodged from bone marrow by treatment with a CXCR4 antagonist AMD3100. Adoptive transfer experiments confirmed that the frequency of leukemia-initiating cells in bone marrow was significantly decreased in the recipients treated with ALI plus AMD3100 compared to those receiving ALI only. These findings indicate that the immunoprivileged nature of bone marrow is largely responsible for relapse after immunotherapies, and that treatment with AMD3100 may offer a clinically-practical approach to improving the outcome of adoptive allogeneic cell therapy. PMID- 29603338 TI - Association between prenatal psychological stress and oxidative stress during pregnancy. AB - BACKGROUND: Prenatal psychological stress during pregnancy has been associated with adverse reproductive outcomes. A growing animal literature supports an association between psychological stress and oxidative stress. We assessed this relationship in pregnant women, hypothesising that psychological stress is associated with higher concentrations of oxidative stress biomarkers during pregnancy. METHODS: Psychosocial status and stressful life events (SLE) were self reported. 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha ) was measured as a biomarker of oxidative stress in urine samples at median 32 weeks' gestation. We examined SLEs individually (ever vs never) and in summary (any vs none) and psychosocial status as measured by individual subscales and in summary (poor vs good). Linear models estimated associations between these parameters and urinary 8-iso-PGF2alpha concentrations after adjusting for covariates. RESULTS: The geometric mean of 8-iso-PGF2alpha was significantly higher among pregnant women who were non-White, smokers, had less than a college education, higher pre pregnancy BMI and were unmarried. Having ever had a death in the family (n = 39) during pregnancy was associated with a 22.9% increase in 8-iso-PGF2alpha in unadjusted models (95% confidence interval [CI] 1.50, 48.8). Poor psychosocial status was associated with a 13.1% (95% CI 2.43, 25.0) greater mean 8-iso PGF2alpha in unadjusted analyses. Associations were attenuated, but remained suggestive, after covariate adjustment. CONCLUSIONS: These data suggest that 8 iso-PGF2alpha is elevated in pregnant women with who are at a sociodemographic disadvantage and who have higher psychological stress in pregnancy. Previous studies have observed that 8-iso-PGF2alpha levels are associated with adverse birth outcomes, oxidative stress could be a mediator in these relationships. PMID- 29603339 TI - Tricin inhibits the CCL5 induction required for efficient growth of human cytomegalovirus. AB - Treatment of human embryonic lung fibroblast (HEL) cells with tricin (4', 5, 7 trihydroxy-3', 5'-dimethoxyflavone) following infection with human cytomegalovirus (HCMV) reportedly significantly suppresses HCMV replication. In the present work, the mechanisms for the anti-HCMV effects of tricin in HEL cells were examined. It was found that exposure of HEL cells to tricin inhibited HCMV replication, with concomitant decreases in amounts of transcripts of the CC chemokine RANTES (CCL5)-encoding gene and in expression of the CCL5 protein. It was also found that transcripts of HCMV immediate early 1 (IE1), and HCMV UL54 (encoding DNA polymerase) and replication of HCMV was significantly lower in CCL5 gene-knockdown cells. These results suggest that the anti-HCMV activity of tricin differs from that of ganciclovir and that CCL5 is one of the chemokines involved in HCMV replication. In addition, it is possible that chemokine CCL5 is one of the targets of tricin. PMID- 29603340 TI - Novel stepwise model of intervertebral disc degeneration with intact annulus fibrosus to test regeneration strategies. AB - Novel preclinical models that do not damage the annulus fibrosus (AF) of the intervertebral disc are required to study the efficacy of new regenerative strategies for the nucleus pulposus (NP). The aim of the study was to characterize a preclinical ovine model of intervertebral disc degeneration (IDD) induced by endplate (EP) damage and repair via the transpedicular approach, with or without partial nucleotomy, while keeping the AF intact. Twelve adult sheep were used. By the transpedicular approach, a 2 mm tunnel was drilled to the NP through the EP. A partial-nucleotomy was performed. The tunnel was sealed using a polyurethane scaffold. Lumbar discs were assigned to different groups: L1-2: nucleotomy; L2-3: EP tunnel; L3-4: nucleotomy + EP repair; L4-5: EP tunnel + repair; L5-6: control. X-Ray and MRI were performed at 0, 1, 3, and 6 months after surgery. Disc height and MRI indexes were calculated. Macro- and micro morphology were analyzed. Pfirrmann and Thompson grades were assigned. The treated discs exhibited a progressive decrease in NP signal intensity and MRI index, displaying specific grades of degeneration based on the surgical treatment. According to Pfirrmann and Thompson grades different procedures were staged as: EP tunnel + repair: grade-II; EP tunnel: grade-III, nucleotomy + EP repair: grade-IV; nucleotomy: grade-V. A new stepwise model of IDD to study and test safety and efficacy of novel strategies for NP regeneration has been characterized. The different degrees of IDD have been observed similar to Pfirrmann and Thompson grading system. The intact AF allows for loading studies and eliminating the need for AF closure. (c) 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2460-2468, 2018. PMID- 29603341 TI - Antibiotic loaded calcium sulfate bead and pulse lavage eradicates biofilms on metal implant materials in vitro. AB - Pulse lavage (PL) debridement and antibiotic loaded calcium sulfate beads (CS-B) are both used for the treatment of biofilm related periprosthetic joint infection (PJI). However, the efficacy of these alone and in combination for eradicating biofilm from orthopaedic metal implant surfaces is unclear. The purpose of the study was to understand the efficacy of PL and antibiotic loaded CS-B in eradicating bacterial biofilms on 316L stainless steel (SS) alone and in combination in vitro. Biofilms of bioluminescent strains of Pseudomonas aeruginosa Xen41 and a USA300 MRSA Staphylococcus aureus SAP231 were grown on SS coupons for 3 days. The coupons were either, (i) debrided for 3 s with PL, (ii) exposed to tobramycin (TOB) and vancomycin (VAN) loaded CS-B for 24 h, or (iii) exposed to both. An untreated biofilm served as a control. The amount of biofilm was measured by bioluminescence, viable plate count and confocal microscopy using live/dead staining. PL alone reduced the CFU count of both strains of biofilms by approximately 2 orders of magnitude, from an initial cell count on metal surface of approximately 109 CFU/cm2 . The antibiotic loaded CS-B caused an approximate six log reduction and the combination completely eradicated viable biofilm bacteria. Bioluminescence and confocal imaging corroborated the CFU data. While PL and antibiotic loaded CS-B both significantly reduced biofilm, the combination of two was more effective than alone in removing biofilms from SS implant surfaces. (c) 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2349-2354, 2018. PMID- 29603342 TI - Indeterminate pediatric acute liver failure is uniquely characterized by a CD103+ CD8+ T-cell infiltrate. AB - : The cause of pediatric acute liver failure (PALF) is unknown in up to 40% of cases. Evidence suggests that aberrant immune system activation may play a role. We hypothesized that indeterminate PALF cases would exhibit a unique pattern of hepatic inflammation. This was a retrospective and prospective study of PALF cases due to indeterminate (iPALF), autoimmune hepatitis, or known diagnosis (dPALF) etiology. Liver tissue sections were stained with immunohistochemical markers for cytotoxic T-cells (cluster of differentiation 8 [CD8]), perforin, and tissue resident memory T-cells (CD103) and scored as minimal, moderate, or dense. Lymphocytes were isolated from liver tissue for T-cell receptor beta sequencing and flow-cytometric studies. Thirty-three iPALF, 9 autoimmune hepatitis, and 14 dPALF cases were included. Dense hepatic infiltrates of CD8+ T-cells were found in 27 (82%) iPALF cases compared to 1 (7%) dPALF case (P < 0.0001). Perforin staining was dense or moderate in 19 (73%) of 26 iPALF cases compared to minimal in all 7 dPALF cases (P = 0.004); 16 (62%) of 26 iPALF cases had dense CD103 staining compared to none of the 6 dPALF cases (P = 0.001). T-cell receptor beta sequencing of iPALF cases demonstrated increased clonality compared to dPALF and control cases. Flow cytometry and immunohistochemistry revealed that iPALF intrahepatic leukocytes were predominantly tissue resident memory CD8+ T-cells. CONCLUSION: Indeterminate PALF is characterized by a dense CD8+ T-cell hepatic infiltrate consistent with expansion of a tissue resident memory T-cell phenotype; CD8+ T-cells are a biomarker of immune dysregulation in iPALF and may be used to better identify and define this group. (Hepatology 2018). PMID- 29603343 TI - Clinical findings and prognosis of interference injuries to the palmar aspect of the forelimbs in Standardbred racehorses: A study on 74 cases. AB - BACKGROUND: Information on interference injuries in racehorses is lacking. OBJECTIVE: To describe clinical findings and prognosis of palmar forelimb interference injuries in Standardbreds. STUDY DESIGN: Retrospective cohort study. METHODS: Records of 74 racehorses sustaining palmar forelimb interference injuries were studied; 7 occurred during training and 67 during racing. The number of starts before injury, hind shoeing status, gait penalties and racing speeds in cases occurring during racing were compared with negative controls (67 age, sex and speed category matched horses) from the same races. The number of starts and racing speed in 30 racing days preceding recruitment were compared with those following recruitment (negative controls) or return to racing (cases). Clinical aspects and outcome in interference-induced superficial digital flexor (SDF) tendonitis were compared with 77 horses with overstrain-induced SDF tendonitis. RESULTS: In 89% of cases, there was SDF tendonitis and this was associated with a longer time to return to racing (6 months vs. 1 months; P<0.001). The presence of gait penalties (odds ratio (OR) 11.13; 95% CI 3.74, 41.64; P<0.001) and unshod hind feet (OR = 6.26, 95% CI 2.26, 19.62; P<0.001) increased risk of interference injuries. After recruitment/return to racing, horses with interference injuries participated in a lower number of races (24 starts per racing day, interquartile range [IQR] 20-32) compared with controls (49, IQR 43-55, P<0.0001). Interference-induced tendonitis cases (n = 58) had a shorter time to return to racing (245 +/- 137 days) than overstrain-induced tendonitis cases (331 +/- 118 days, P<0.001). MAIN LIMITATIONS: Data were collected retrospectively; time of ultrasonographic assessment varied and health status of the racing controls is unknown. CONCLUSIONS: SDF tendonitis is common with palmar forelimb interference injuries in Standardbreds and increases time to return to racing. Interference-induced SDF tendonitis has a better prognosis than overstrain-induced tendonitis. PMID- 29603344 TI - The effect of 6 months or longer duration of chronic obstructive respiratory disease medication on the oral health parameters of adults. AB - The objectives of this study were to study the effect of COPD medication of 6 months or more duration on oral health parameters of adult patients. A cross sectional study was conducted to assess and compare the decayed, missing, and filled teeth (DMFT), oral hygiene index-simplified (OHI-S), periodontal disease index (PDI) scores, and presence of candida (colony-forming units [CFU]) among adult patients aged 20-45 years who had a history of 6 months or longer duration usage of chronic respiratory disease medications, with controls. A total of 170 participants each were taken in both the groups. Oral health parameters like DMFT scores (p <= 0.002), OHI-S (p <= 0.001), calculus scores (p <= 0.001), plaque scores (p <= 0.001), and CFU/ml of candida species (p <= 0.001) were higher among cases than controls. DMFT scores and candida presence were significantly higher among those whose treatment duration was greater than 5 years as compared to those with lesser duration. Gingival-periodontal component scores of PDI were lower among cases than controls (p <= 0.001). Our findings suggest the need for regular oral health maintenance for those under COPD treatment and for greater research into the possible protective role of inhaled corticosteroids in limiting periodontal disease among patients. PMID- 29603345 TI - Electron-ion reaction-based dissociation: A powerful ion activation method for the elucidation of natural product structures. AB - The structural elucidation of natural products (NPs) remains a challenge due to their structurally diversities and unpredictable functionalities, motifs, and scaffolds. Tandem mass spectrometry (MS/MS) is an effective method that assists the full elucidation of complicated NP structures. Ion activation methods play a key role in determining the fragmentation pathways and the structural information obtained from MS/MS. Electron-ion reaction-based dissociation (ExD) methods, including electron capture dissociation (ECD), electron transfer dissociation (ETD), electron-induced dissociation (EID), and electron detachment dissociation (EDD), can induce the breakage of specific chemical bonds and the generation of distinct fragment ions. This review article provides an overview of the mechanisms, instrumentation, and typical applications related to ExD MS/MS in the structural elucidation of NPs, primarly including lipids, oligosaccharides, glycoconjugates, metabolites, and pharmaceutical drugs. This work aims to reveal the capacity and potential of ExD mass spectrometry in analyzing NPs and consequently helping the NP communities to utilize the modern capabilities of MS/MS in the discovery and evaluation of novel NPs. PMID- 29603346 TI - Investigation of a new passive sampler for the detection of munitions compounds in marine and freshwater systems. AB - Over the last century, unexploded ordnances have been disposed of in marine shelf systems because of a lack of cost-effective alternatives. Underwater unexploded ordnances have the potential to leak 2,4,6-trinitrotoluene (TNT) and 1,3,5 trinitro-1,3,5-triazine (RDX), commonly used chemical munitions, and contaminate local waters, biota, and sediments. The rate at which this contamination occurs in the environment is relatively unknown, and the cost- and time-prohibitive nature of sampling across sites makes mapping difficult. In the present study we assessed the efficacy of ethylene-vinyl acetate (EVA) for sampling relatively soluble munitions compounds over a range of environmental conditions (i.e., changes in temperature and salinity) and optimized the composition of the passive sampling polymer. The EVA sampler was able to successfully detect ambient concentrations of lingering munitions compounds from field sites containing unexploded ordnances. The sampler affinity for the munitions in terms of an EVA water partition coefficient was greater than the standard octanol water values for each target compound. Partitioning of compounds onto EVA over the natural ranges of salinity did not change significantly, although uptake varied consistently and predictably with temperature. Increasing the vinyl acetate to ethylene ratio of the polymer corresponded to an increase in uptake capacity, consistent with enhanced dipole-dipole interactions between the munitions and the polymer. This sampler provides a cost-effective means to map and track leakage of unexploded ordnances both spatially and temporally. Environ Toxicol Chem 2018;37:1990-1997. (c) 2018 SETAC. PMID- 29603347 TI - The experiences and preparedness of family carers for best interest decision making of a relative living with advanced dementia: A qualitative study. AB - AIM: To explore the experience and the preparedness of family carers in their caregiving role as best interest decision-makers of a relative living with advanced dementia. BACKGROUND: The prevalence of dementia is a global issue. The role of being a carer of a relative living with dementia does not necessarily lessen once they are admitted to a nursing home. Best interest decision-making including end-of-life care decisions need to be made and reaching these choices can be challenging. The preparedness of family carers in this role needs greater understanding. DESIGN: Descriptive qualitative study. METHODS: During 2015 twenty semi-structured interviews were conducted of family carers of nursing home residents living with advanced dementia, then analysed using Braun and Clarke's thematic analysis. RESULTS: Three themes were identified: (1) Caring for someone living with dementia. The impact on the carer's holistic well-being and their experience of being a best interest decision-maker; (2) Accessing support. The influential nature of formal and informal networks; (3) Perceived knowledge and understanding of the dementia trajectory of carers and nursing staff. CONCLUSION: The experiences and preparedness of informal carers is a reflection of their personal response, but the distress experienced highlights the significant need of adequate support availability and of enhancing nursing staffs' dementia expertise to maximize their role in facilitating best interest decision-making. This has significant implications for nursing practice and for service user and nursing staff education. Considering the global impact of dementia, our findings have international relevance to similar nursing homes across the world. PMID- 29603348 TI - Landscape of immune microenvironment in hepatocellular carcinoma and its additional impact on histological and molecular classification. AB - : Immune cells constitute an important element of tumor tissue. Accumulating evidence indicates their clinicopathological significance in predicting prognosis and therapeutic efficacy. Nonetheless, the combinations of immune cells forming the immune microenvironment and their association with histological findings remain largely unknown. Moreover, it is unclear which immune cells or immune microenvironments are the most prognostically significant. Here, we comprehensively analyzed the immune microenvironment and its intratumor heterogeneity in 919 regions of 158 hepatocellular carcinomas (HCCs), and the results were compared with the corresponding histological and prognostic data. Consequently, we classified the immune microenvironment of HCC into three distinct immunosubtypes: Immune-high, Immune-mid, and Immune-low. The Immune-high subtype was characterized by increased B-/plasma-cell and T cell infiltration, and the Immune-high subtype and B-cell infiltration were identified as independent positive prognostic factors. Varying degrees of intratumor heterogeneity of the immune microenvironment were observed, some of which reflected the multistep nature of HCC carcinogenesis. However, the predominant pattern of immunosubtype and immune cell infiltration of each tumor was prognostically important. Of note, the Immune-high subtype was associated with poorly differentiated HCC, cytokeratin 19 (CK19)+ , and/or Sal-like protein 4 (SALL4)+ high-grade HCC, and Hoshida's S1/Boyault's G2 subclasses. Furthermore, patients with high-grade HCC of the predominant Immune-high subtype had significantly better prognosis. These results provide a rationale for evaluating the immune microenvironment in addition to the usual histological/molecular classification of HCC. CONCLUSION: The immune microenvironment of HCC can be classified into three immunosubtypes (Immune-high, Immune-mid, and Immune-low) with additional prognostic impact on histological and molecular classification of HCC. (Hepatology 2018). PMID- 29603349 TI - Leukocyte extracellular vesicle concentration is inversely associated with liver fibrosis severity in NAFLD. AB - The enhanced liver fibrosis (LFS) score and the nonalcoholic fatty liver disease (NAFLD) fibrosis score (NFS) are algorithmic-derived scores for diagnosing severe (F3/F4) liver fibrosis. In a pilot, substudy of the Wessex Evaluation of fatty Liver and Cardiovascular markers in NAFLD with OMacor thErapy (WELCOME) trial, we tested whether measurements of plasma platelet-, endothelial-, and leukocyte derived extracellular vesicles (EVs) counts are (a) associated with, and predict, F3/F4 fibrosis and (b) able to improve risk prediction of F3/F4 fibrosis in NAFLD, building upon LFS or NFS algorithms. Twenty-six individuals with NAFLD had liver fibrosis severity determined by Kleiner scoring after liver biopsy. Plasma samples stained with CD41a, CD42b, CD31, CD105, CD14, CD16, and CD284 antibodies were analyzed using flow cytometry to measure platelet-, endothelial-, and leukocyte-derived EVs counts. The independence of associations between EVs and F3/F4 fibrosis were tested using logistic regression. Receiver operator characteristic (ROC) curves were used to evaluate F3/F4 fibrosis prediction models. LFS was more strongly associated with F3/F4 fibrosis than NFS (chi2= 15.403, P < 0.0001, and chi2= 6.300, P = 0.012, respectively). The association between LFS and F3/F4 fibrosis was further improved by addition of CD14+ EVs (chi2=20.847,P = 0.016 vs. chi2=12.803,P = 0.015, respectively) or CD16+ EVs (chi2=22.205,P = 0.009 vs. chi2=17.559,P = 0.001, respectively), and the area under the ROC for LFS (AUC = 0.915, se = 0.055, P = 0.001) was increased by the addition of CD14+ or CD16+ EVs (AUC = 0.948, se = 0.042, and P < 0.001 and AUC = 0.967, se = 0.055, P < 0.001, respectively) as predictor variables. In this small preliminary study, CD14+ and CD16+ EV counts show potential to predict liver fibrosis severity with either marker improving the ability of the LFS to identify F3/F4 fibrosis in this small preliminary cohort study. PMID- 29603350 TI - Establishment of an in vivo turkey model for the study of flexor tendon repair. AB - Flexor tendon injuries are common and pose a clinical challenge for functional restoration. The purpose of our study was to assess the adequacy of the turkey as a large animal model for flexor tendon injuries in vivo. Twenty-four male turkeys underwent surgical flexor tendon cut and repair. Turkeys were allocated to five groups postoperatively: (1) foot casted in extension and sacrificed after 3 weeks; (2) foot casted in extension and sacrificed after 6 weeks; (3) foot casted in flexion and sacrificed after 3 weeks; (4) foot casted in flexion and sacrificed after 6 weeks; and (5) foot casted in flexion for 6 weeks and then free roaming allowed for an additional 3 weeks before sacrifice. After sacrifice, digits were collected and analyzed for adhesion formation, healing at the macrolevel and histologically, and biomechanical properties-including friction, work of flexion, stiffness, and strength of repair. All turkeys survived anesthesia and surgery. Tendon rupture occurred in all extension casts and in 11% of those casted in flexion. Friction and work of flexion were significantly higher in the repaired digit than the control digit. There was a correlation between duration of immobilization and repair strength. Histologically, the tendon healed with tenocytes migrating into the gap and producing collagen fibers. We have, for the first time, studied flexor tendon injury and repair using turkeys in terms of anesthesia, surgical procedures, postoperative care, and animal husbandry. The findings regarding functional and histological results from this novel avian model were comparable to the most commonly used mammal model. (c) 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2497-2505, 2018. PMID- 29603351 TI - Spending time outside to reduce infections at preschool may be an overrated strategy. PMID- 29603352 TI - Comparison of symmetry after smile reconstruction for flaccid facial paralysis with combined fascia lata grafts and functional gracilis transfer for static suspension or gracilis transfer alone. AB - PURPOSE: Facial paralysis has a profound impact on functionality and esthetics of the oral region. In patients with strong skin laxity and soft tissue ptosis, functional smile reconstruction is challenging due to the accentuated asymmetry at rest. Thus, the purpose of the study was to analyze facial symmetry in this patient clientele following a combination of dynamic reanimation with fascial strips for static suspension compared to functional gracilis transfer alone. METHODS: In 2014, we altered the single-stage approach for microsurgical smile reconstruction in patients with significant soft tissue ptosis by adding fascia lata grafts for static support. We evaluated 6 patients (mean age 57.8 +/- 5.2, group A) who underwent the combined procedure, and compared their results to 6 patients with flaccid facial paralysis who were treated before 2014 and received a functional gracilis transfer alone (mean age 52.5 +/- 7.5, group B). To test the efficacy of the technique, we retrospectively analyzed the correction of the oral asymmetry as well as nasal and philtral deviation by computer-assisted photograph analysis 6 months postoperatively. RESULTS: The comparative analysis revealed a significant postoperative improvement of the oral asymmetry (A: 90.0 +/- 5.0% relative correction at rest vs. B: 62.6 +/- 17.2%, P < .05), nasal (A: 0.4 +/- 0.2 vs. B: 0.7 +/- 0.4 mm, P < .05), and philtral deviation (A: 0.5 +/- 0.6 vs. B: 2.8 +/- 1.8 mm, P < .05) in group A. CONCLUSIONS: The combined procedure for dynamic facial reanimation allows for immediate correction of the oral asymmetry and improves overall outcome in patients with advanced soft tissue ptosis and oral asymmetry at rest. PMID- 29603353 TI - Antimicrobial stewardship in the neonatal unit reduces antibiotic exposure. AB - AIM: Antimicrobial stewardship plays an important role in ensuring that the appropriate drug, dose, route and duration are employed to provide adequate treatment while minimising the risks of unnecessary antibiotic use. Surveillance of antibiotic use with prescriber feedback is recommended as a high-impact stewardship intervention. The aim of this study was to reduce unnecessary antimicrobial use in a neonatal unit. METHODS: A prospective audit was performed to assess compliance with antimicrobial guidelines. Following this, educational interventions were applied, electronic prescribing was introduced to the neonatal unit, and re-audit was performed. The primary outcome was a reduction in days of therapy (DOT). RESULTS: There were 312 neonatal admissions. There was a significant overall reduction in the primary outcome of DOT/1000 patient days from 572 to 417 DOT. This represents a 27% reduction in total antibiotic use. Prolonged antibiotic treatment courses >36 hours in negative sepsis evaluations were reduced from 82 DOT to 7.5 DOT. Similarly, treatment courses greater than five days for culture-negative sepsis were reduced from 46.5 DOT to 7 DOT. CONCLUSION: Monitoring antibiotic prescribing data can provide useful insights into the trends of antibiotic use and also inform clinicians of potential areas where antibiotic use may be safely reduced. PMID- 29603354 TI - Combined multichannel intraluminal impedance-pH monitoring should be used to diagnose reflux-related otitis media with effusion in children. AB - AIM: This study investigated the diagnostic usefulness of combined multichannel intraluminal impedance-pH monitoring (MII-pH) in children with suspected reflux related otitis media with effusion (OME) as existing data were scarce. METHODS: This was a prospective study that included children up to seven years of age who underwent MII-pH due to OME lasting more than three months. The study was conducted in the Children's Hospital Zagreb, Croatia, from January 2014 to August 2016. RESULTS: The study comprised 63 children (63% male) with a mean age of 4.7 years. Gastroesophageal reflux (GER) disease was detected by impedance in 22 (35%) of the children and by pH-metry in nine (14%). In children with OME, MII-pH found a median number of 24 proximal GER episodes, of which a median of nine was acidic and a median of 11 was weakly acidic. There was a significant positive correlation between the number of GER episodes and the presence of eosinophils in nasal swabs. CONCLUSION: Both acidic and weakly acidic refluxes seemed to play a significant role in the pathogenesis of OME. Localised nasal eosinophilia may serve as a marker of extraoesophageal reflux in children with suspected reflux related OME. PMID- 29603355 TI - Apoptotic cells trigger the ABCA1/STAT6 pathway leading to PPAR-gamma expression and activation in macrophages. AB - The signal transducer and activator of transcription 6 (STAT6) transcription factor activates peroxisome proliferator-activated receptor gamma (PPAR-gamma) regulated gene expression in immune cells. We investigated proximal membrane signaling that was initiated in macrophages after exposure to apoptotic cells that led to enhanced PPAR-gamma expression and activity, using specific siRNAs for ABCA1, STAT6, and PPAR-gamma, or their antagonists. The interactions between mouse bone marrow-derived macrophages or RAW 264.7 cells and apoptotic Jurkat cells, but not viable cells, resulted in the induction of STAT6 phosphorylation as well as PPAR-gamma expression and activation. Knockdown of ATP-binding cassette transporter A1 (ABCA1) after the transfection of macrophages with ABCA1 specific siRNAs reduced apoptotic cell-induced STAT6 phosphorylation as well as PPAR-gamma mRNA and protein expression. ABCA1 knockdown also reduced apoptotic cell-induced liver X receptor alpha (LXR-alpha) mRNA and protein expression. Moreover, inhibition of STAT6 with specific siRNAs or the pharmacological inhibitor AS1517499AS reversed the induction of PPAR-gamma, LXR-alpha, and ABCA1 by apoptotic Jurkat cells. PPAR-gamma-specific siRNAs or the PPAR-gamma antagonist GW9662 inhibited apoptotic cell-induced increases in LXR-alpha and ABCA1 mRNA and protein levels. Thus, these results indicate that apoptotic cells trigger the ABCA1/STAT6 pathway, leading to the activation of the PPAR-gamma/LXR alpha/ABCA1 pathway in macrophages. PMID- 29603356 TI - Gastrointestinal: Lanthanum phosphate deposition in the gastroduodenal mucosa: An unusual cause of epigastric discomfort. PMID- 29603357 TI - Current issues with luminal subtype classification in terms of prediction of benefit from endocrine therapy in early breast cancer. AB - Endocrine therapy for oestrogen receptor-positive (ER+) breast cancer (BC) is arguably the most successful targeted cancer therapy to date. Nevertheless, resistance to endocrine therapy still occurs in a significant proportion of patients, limiting its clinical utility. ER+ or luminal BC, which represents approximately three-quarters of all breast malignancies, are biologically heterogeneous, with no distinct, clinically defined subclasses able to predict the benefit of endocrine therapy in early settings. To improve patient outcomes there is a clear need for improved understanding of the biology of the luminal BC, with subsequent translation into more effective methods of diagnosis to identify potential predictive biomarkers for endocrine therapy. This review summarises current knowledge of factors predictive of benefit of endocrine therapy and discusses why molecular classification systems of BC have yet to be translated into the clinic. PMID- 29603358 TI - Rapid review shows that probiotics and fermented infant formulas do not cause d lactic acidosis in healthy children. AB - AIM: Extensive ongoing research on probiotics and infant formulas raises a number of safety questions. One concern is the potential influence of d-lactic acid containing preparations on the health of infants and children. The aim of this review was to summarise the available knowledge on the ingestion of d-lactic acid producing bacteria, acidified infant formulas and fermented infant formulas as a potential cause of paediatric d-lactic acidosis. METHODS: A Medline database search was performed in July 2017, with no restrictions on the language, article type or publication date. The 1715 search results were screened for clinical trials, review articles, case series and case reports of relevance to the topic. RESULTS: We identified five randomised controlled trials from 2005 to 2017 covering 544 healthy infants and some case reports and experimental studies. No clinically relevant adverse effects of d-lactic acid-producing probiotics and fermented infant formulas were described in healthy children. However, a harmless, subclinical accumulation of d-lactate was theoretically possible. The only known cases of paediatric d-lactic acidosis occurred in patients with short bowel syndrome or, historically, in infants fed with acidified formulas. CONCLUSION: Our main finding was that probiotics and fermented formulas did not cause d-lactic acidosis in healthy children. PMID- 29603359 TI - Bariatric Surgery: Weighing In on Bone Loss. PMID- 29603360 TI - On the performance of adaptive preprocessing technique in analyzing high dimensional censored data. AB - Preprocessing for high-dimensional censored datasets, such as the microarray data, is generally considered as an important technique to gain further stability by reducing potential noise from the data. When variable selection including inference is carried out with high-dimensional censored data the objective is to obtain a smaller subset of variables and then perform the inferential analysis using model estimates based on the selected subset of variables. This two stage inferential analysis is prone to circularity bias because of the noise that might still remain in the dataset. In this work, I propose an adaptive preprocessing technique that uses sure independence screening (SIS) idea to accomplish variable selection and reduces the circularity bias by some popularly known refined high dimensional methods such as the elastic net, adaptive elastic net, weighted elastic net, elastic net-AFT, and two greedy variable selection methods known as TCS, PC-simple all implemented with the accelerated lifetime models. The proposed technique addresses several features including the issue of collinearity between important and some unimportant covariates, which is often the case in high dimensional setting under variable selection framework, and different level of censoring. Simulation studies along with an empirical analysis with a real microarray data, mantle cell lymphoma, is carried out to demonstrate the performance of the adaptive pre-processing technique. PMID- 29603361 TI - Gastrointestinal: Splenic abscesses-related gastrosplenic fistula: Unusual complication of melioidosis. PMID- 29603362 TI - Aged neutrophils accumulate in lymphoid tissues from healthy elderly mice and infiltrate T- and B-cell zones. AB - The average age of the human population is rising, leading to an increasing burden of age-related diseases, including increased susceptibility to infection. However, immune function can decrease with age which could impact on processes that require a functional immune system. Aging is also characterized by chronic low-grade inflammation which could further impact immune cell function. While changes to neutrophils in blood during aging have been described, little is known in aging lymphoid organs. This study used female C57BL/6J mice comparing bone marrow (BM), spleen and lymph nodes from young mice aged 2-3 months (equivalent to 18 human years) with healthy elderly mice aged 22-24 months (equivalent to 60 70 human years). Neutrophil proportions increased in BM and secondary lymphoid organs of elderly mice relative to their younger counterparts and presented an atypical phenotype. Interestingly, neutrophils from elderly spleen and lymph nodes were long lived (with decreased apoptosis via Annexin V staining and increased proportion of BrdUneg mature cells) with splenic neutrophils also demonstrating a hypersegmented morphology. Furthermore, splenic neutrophils of elderly mice expressed a mixed phenotype with increased expression of activation markers, CD11b and ICAM-1, increased proinflammatory TNFalpha, yet increased anti inflammatory transforming growth factor-beta. Elderly splenic architecture was compromised, as the marginal zone (required for clearing infections) was contracted. Moreover, neutrophils from elderly but not young mice accumulated in lymph node and splenic T- and B-cell zones. Overall, the expansion of functionally compromised neutrophils could contribute to increased susceptibility to infection observed in the elderly. PMID- 29603364 TI - A unique signal sequence of the chemokine receptor CCR7 promotes package into COPII vesicles for efficient receptor trafficking. AB - Chemokine receptors are considered to belong to the group of G protein-coupled receptors that use the first transmembrane domain as signal anchor sequence for membrane insertion instead of a cleavable N-terminal signal sequence. Chemokine recognition is determined by the N-termini of chemokine receptors. Here, we show that the chemokine receptor CCR7, which is essential for directed migration of adaptive immune cells, possesses a 24 amino acids long N-terminal signal sequence that is unique among chemokine receptors. This sequence is cleaved off the mature human and mouse protein. Introducing single point mutations in the hydrophobic core h-region or in the polar C-terminal segment (c-region) of the signal sequence to interfere with its cleavage retained CCR7 in the ER and prevented its surface expression. Furthermore, we demonstrate the correct topology of the 35 amino acids short extracellular N-tail of CCR7 in a deletion mutant lacking the natural signal sequence. This signal sequence deletion mutant of CCR7 is fully functional as it efficiently binds its ligand, elicits chemokine-induced calcium mobilization, and directs cell migration. However, we show that the signal sequence promotes efficient recruitment of the GPCR to ER exit sites, thereby controlling efficient ER to Golgi trafficking of CCR7 on its way to reach the plasma membrane. PMID- 29603363 TI - Transfusion-related adverse events are decreased in pregnant women with sickle cell disease by a change in policy from systematic transfusion to prophylactic oxygen therapy at home: A retrospective survey by the international sickle cell disease observatory. AB - Sickle cell disease (SCD) in pregnancy can be associated with adverse maternal and perinatal outcomes. Furthermore, complications of SCD can be aggravated by pregnancy. Optimal prenatal care aims to decrease the occurrence of maternal and fetal complications. A retrospective, French, two-center study compared two care strategies for pregnant women with SCD over two time periods. In the first study period (2005-2010), the women were systematically offered prophylactic transfusions. In the second study period (2011-2014), a targeted transfusion strategy was applied whenever possible, and home-based prophylactic nocturnal oxygen therapy was offered to all the pregnant women. The two periods did not differ significantly in terms of the incidence of vaso-occlusive events. Maternal mortality, perinatal mortality, and obstetric complication rates were also similar in the two periods, as was the incidence of post-transfusion complications (6.1% in 2005-2010 and 1.3% in 2011-2014, P = .15), although no de novo alloimmunizations or delayed hemolysis transfusion reactions were observed in the second period. The results of this preliminary, retrospective study indicate that targeted transfusion plus home-based prophylactic nocturnal oxygen therapy is safe and may decrease transfusion requirements and transfusion associated complications. PMID- 29603365 TI - Can the same controlled attenuation parameter cut-offs be used for M and XL probes for diagnosing hepatic steatosis? AB - BACKGROUND AND AIM: There are limited studies on controlled attenuation parameter (CAP) using Fibroscan XL probe for the diagnosis of hepatic steatosis grade. The aim of this study was to determine whether previously defined optimal cut-offs for CAP using the M probe could be applied for the XL probe. METHODS: Adult patients with chronic liver disease who had a liver biopsy and examination with both the M and XL probes were included. Previously defined optimal cut-offs for CAP using the M probe were used for the diagnosis of steatosis grades >=S1, >=S2, and S3 (248, 268, and 280 dB/m, respectively). RESULTS: Data for 180 patients were analyzed (mean age 53.7 +/- 10.8 years; central obesity 84.5%; non-alcoholic fatty liver disease 86.7%). The distribution of steatosis grades was S0, 9.4%; S1, 28.3%; S2, 43.9%, and S3, 18.3%. The sensitivity, specificity, positive predictive value, and negative predictive value of CAP using the M/XL probe for the diagnosis of steatosis grade >=S1 was 93.9%/93.3%, 58.8%/58.8%, 95.6%/95.6%, and 50.0%/47.6%, respectively. These values were 94.6%/94.6%, 41.2%/44.1%, 72.6%/73.6%, and 82.4%/83.3%, respectively, for >=S2, and 87.9%/87.9%, 27.2%/27.9%, 21.3%/21.5%, and 90.9%/91.1%, respectively, for S3. CONCLUSION: The same cut-off values for CAP may be used for the M and XL probes for the diagnosis of hepatic steatosis grade. PMID- 29603366 TI - MR imaging of magnetic ink patterns via off-resonance sensitivity. AB - PURPOSE: Printed magnetic ink creates predictable B0 field perturbations based on printed shape and magnetic susceptibility. This can be exploited for contrast in MR imaging techniques that are sensitized to off-resonance. The purpose of this work was to characterize the susceptibility variations of magnetic ink and demonstrate its application for creating MR-visible skin markings. METHODS: The magnetic susceptibility of the ink was estimated by comparing acquired and simulated B0 field maps of a custom-built phantom. The phantom was also imaged using a 3D gradient echo sequence with a presaturation pulse tuned to different frequencies, which adjusts the range of suppressed frequencies. Healthy volunteers with a magnetic ink pattern pressed to the skin or magnetic ink temporary flexible adhesives applied to the skin were similarly imaged. RESULTS: The volume-average magnetic susceptibility of the ink was estimated to be 131 +/- 3 parts per million across a 1-mm isotropic voxel (13,100 parts per million assuming a 10-MUm thickness of printed ink). Adjusting the saturation frequency highlights different off-resonant regions created by the ink patterns; for example, if tuned to suppress fat, fat suppression will fail near the ink due to the off-resonance. This causes magnetic ink skin markings placed over a region with underlying subcutaneous fat to be visible on MR images. CONCLUSION: Patterns printed with magnetic ink can be imaged and identified with MRI. Temporary flexible skin adhesives printed with magnetic ink have the potential to be used as skin markings that are visible both by eye and on MR images. PMID- 29603367 TI - Frontline Science: IL-18 primes murine NK cells for proliferation by promoting protein synthesis, survival, and autophagy. AB - Combined stimulation by IL-2 and IL-18 effectively promotes proliferation of NK cells, whereas singular stimulation does not. In this study, synergistic effects of these cytokines on NK cells proliferation was analyzed, focusing on the roles of IL-18. In splenic resting NK cells from IL-18KO mice, IL-18 rapidly activated NF-kappaB independently of IL-2, and activated or up-regulated various molecules downstream of PI3K/AKT and mTOR, including S6, Bcl-XL, ATG5, and LC3II, accompanying increases in cell growth and survival. Thus, IL-18 alone was revealed to augment various cellular processes (gene transcription, protein synthesis, survival) in the absence or presence of IL-2. Notably, combined IL-18 and IL-2 promoted autophagosome formation. In addition, priming NK cells with IL 18 augmented IL-2R, especially CD25, and enabled cells to respond to IL-2, resulting in activation of STAT3 and STAT5, followed by increase of cyclin B1 leading to proliferation. However, IL-2 alone failed to activate STAT3 or STAT5 in resting IL18KO NK cells. These results clarify the distinct roles of IL-2 and IL-18 in NK cell proliferation, and the intrinsic roles of IL-18 in various cellular processes, suggesting a range of functions of IL-18 expressed in an array of nonhematopoietic cells. PMID- 29603368 TI - Oral budesonide in gastrointestinal and liver disease: A practical guide for the clinician. AB - Oral budesonide is a second-generation steroid that allows local, selective treatment of the gastrointestinal tract and the liver, minimizing systemic exposure. The results of randomized trials comparing budesonide versus placebo or active comparators have led to expert recommendations that budesonide be used to treat mild or moderate active ileocecal Crohn's disease, microscopic colitis (including both collagenous and lymphocytic colitis), ulcerative colitis, and non cirrhotic autoimmune hepatitis. The mechanism of budesonide action obviates the need for dose tapering due to safety reasons after induction therapy. Where low dose budesonide is used to maintain remission, usually in microscopic colitis, it does not appear to have adverse safety implications other than slight reductions in cortisol levels on rare occasions. As a gut-selective and liver-selective corticosteroid, budesonide offers an appealing alternative to conventional systemic glucocorticoids in diseases of these organs. PMID- 29603369 TI - Clinical and genetic risk factors for decreased bone mineral density in Japanese patients with inflammatory bowel disease. AB - BACKGROUND AND AIM: Patients with inflammatory bowel disease (IBD) are at a high risk of low bone mineral density (BMD). Reportedly, clinical and genetic factors cause low BMD in Caucasians; however, studies in non-Caucasian populations remain scarce. METHODS: Clinical risk factors for low BMD were investigated in 266 Japanese patients with IBD, and a genome-wide association analysis (GWAS) was performed using linear regression with associated clinical factors as covariates. Genotyping was performed using a population-optimized genotyping array (Japonica array(r) ). After quality control, the genotype data of 4 384 682 single nucleotide polymorphisms (SNPs) from 254 patients with IBD were used for GWAS. RESULTS: Body mass index, age, and disease duration were independently associated with the BMD of the femoral neck (P = 1.41E - 13, 1.04E - 5, and 1.58E - 3, respectively), and body mass index and sex were associated with the BMD of the lumbar spine (P = 6.90E - 10 and 6.84E - 3, respectively). In GWAS, 118 and 42 candidate SNPs of the femoral neck and lumbar spine, respectively, were identified. Among 118, 111 candidate SNPs of the femoral neck were located within the SLC22A23 gene, which is a known IBD susceptibility gene (minimum P = 1.42E - 07). Among 42, 18 candidate SNPs of the lumbar spine were located within the MECOM gene, which is associated with osteopenia (minimum P = 5.86E - 07). Interestingly, none of the known loci showed a significant association with BMD. CONCLUSIONS: Although clinical risk factors for low BMD in IBD were similar to those in the general population, genetic risk factors were rather different. PMID- 29603370 TI - Disease Modification for Parkinson's Disease: Axonal Regeneration and Trophic Factors. AB - Disease modification and structural neuroprotection have been the holy grail for Parkinson's disease (PD) experimental therapeutics. Theoretically, there are a number of ways to implement such therapeutics, but to date all have failed. This review examines the potential of axonal regeneration and trophic factor delivery for the nigrostriatal system as 2 such approaches that historically have initiated much excitement. However, we conclude this discussion with the following question: has science passed these approaches by? (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29603371 TI - Modified Carba NP Test: Simple and rapid method to differentiate KPC- and MBL producing Klebsiella species. AB - BACKGROUND: The aim of this study was to evaluate the modified Carba NP test to differentiate KPC (Klebsiella pneumoniae carbapenemase)- and MBL (metallo-beta lactamase)-producing Klebsiella species. METHODS: A total of 508 non-duplicate clinical isolates of Klebsiella spp. were processed by modified Carba NP and combined disc tests which were further confirmed by conventional polymerase chain reaction (PCR), a gold standard method for statistical analysis. RESULTS: Modified Carba NP test demonstrated 91.7% sensitivity, 100% specificity, 100% positive predictive value (PPV) and 99.8% negative predictive value (NPV) for KPC and 96.7%, 100%, 100%, and 99.5% for MBL detection, respectively. CONCLUSION: The performance of modified Carba NP test was significantly better than combined disc test, fulfilling the requirement of simple and rapid test for clinical applications. PMID- 29603372 TI - ACVIM small animal consensus statement on safe use of cytotoxic chemotherapeutics in veterinary practice. AB - The purpose of this report is to offer a consensus opinion of ACVIM oncology diplomates and technicians on the safe use of cytotoxic chemotherapeutics in veterinary practice. The focus is on minimizing harm to the personnel exposed to the drugs: veterinary practitioners, veterinary technicians, veterinary staff, and pet owners. The safety of the patient receiving these drugs is also of paramount importance, but is not addressed in this statement. Much of the information presented is based on national recommendations by Occupational Safety and Health Administration, National Institute for Occupational Safety and Health, United States Pharmacopeia, and other published regulations. These directives reflect an abundance of caution to minimize exposure to medical personnel, but large-scale studies about the consequences of long-term occupational exposure are not available in veterinary medicine. Challenges in the delivery of optimal treatment safely and economically to veterinary patients in general practice without access to a veterinary oncologist or other specialist, because of costs or proximity, remain. PMID- 29603373 TI - Salivary levels of phosphorus and urea as indices of their plasma levels in nephropathic patients. AB - BACKGROUND: Phosphorus and urea are measurable in saliva. Measurements of saliva phosphorus (S-Pho) and saliva urea (S-Urea) could be useful because of low invasivity. Data are limited to saliva tests methodology and to correlations between plasma and saliva compositions. S-Pho and S-Urea were investigated focusing on blind duplicates, differences between collection sites, differences between collection times, freezing-thawing effects, and plasma-saliva correlations. METHODS: Tests were performed using fresh saliva collected by synthetic swap early morning after overnight fast (standard). Methodology was investigated in fifteen healthy volunteers. Plasma-saliva correlations were investigated in thirty nephropathic outpatients. RESULTS: S-Pho and S-Urea in all measurements ranged above detection limits (0.3 mmol/L). In healthy volunteers, S Pho and S-Urea were similar in duplicates (results for S-Pho and S-Urea: % difference between samples <= 4.85%; R between samples >= .976, P < .001), in samples from different mouth sites (<=4.24%; R >= .887, P < .001), and in samples of different days (<=5.61%; R >= .606, P < .01) but, compared to standard, were substantially lower in after-breakfast samples (-28.0% and -21.3%; R >= .786, P < .001) and slightly lower in frozen-thawed samples (-12.4% and -5.92%; R >= .742, P < .001). In nephropathic patients, S-Pho was higher than but correlated with plasma phosphorus (saliva/plasma ratio 4.80; R = .686, P < .001), whereas S-Urea and plasma urea were similar and correlated with each other (saliva/plasma ratio 0.96; R = .944, P < .001). Post-dialysis changes in S-Pho and S-Urea paralleled post-dialysis changes in plasma phosphorus and urea. CONCLUSION: S-Pho and S-Urea reflect plasma phosphorus and plasma urea. Early morning fasting fresh samples are advisable because collection time and freezing-thawing affect saliva tests. PMID- 29603374 TI - Validation of Nutritional Risk Screening-2002 in a Hospitalized Adult Population. AB - BACKGROUND: Malnutrition in hospitalized patients is a serious problem and is associated with a number of adverse outcomes. The Nutritional Risk Screening-2002 (NRS-2002) tool was designed to identify patients at nutrition risk. The validation of NRS-2002 compared with detailed clinical assessment of nutrition status was not studied before in hospitalized Turkish adults. The aim of this study is to determine validity, sensitivity, and specificity of the Turkish version of NRS-2002 in a hospitalized adult population. METHODS: A total of 271 consecutive hospitalized patients aged >18 years admitted to surgical and medical wards of a university hospital in Turkey were included in this single-center non interventional validity study. Assessment by geriatricians was used as the reference method. Two geriatricians experienced in the field of malnutrition interpreted the patients' nutrition status after the evaluation of several parameters. Patients were divided into "at nutrition risk" and "not at nutrition risk" groups by geriatricians. Concordance between the 2 geriatricians' clinical assessments was analyzed by kappa statistics. Excellent concordance was found; therefore, the first geriatrician's decisions were accepted as the gold standard. The correlation of nutrition status of the patients, determined with NRS-2002 and experienced geriatrician's decisions, was evaluated for the validity. RESULTS: NRS-2002 has a sensitivity of 88% and specificity of 92% when compared with professional assessment. The positive and negative predictive values were 87% and 92%, respectively. Testretest agreement was excellent as represented by a kappa coefficient of 0.956. CONCLUSIONS: NRS-2002 is a valid tool to assess malnutrition risk in Turkish hospitalized patients. PMID- 29603375 TI - Age-specific pediatric reference ranges for immunoglobulins and complement proteins on the OptiliteTM automated turbidimetric analyzer. AB - BACKGROUND: Measurement of immunoglobulins and complement proteins are frontline tests used in the assessment of immune system integrity, and reference values can vary with age. Their measurement provides an insight into the function of the innate and adaptive immune systems. METHODS: We generated pediatric reference ranges for IgG, IgA, IgM, IgD, the IgG and IgA subclasses, and C3 and C4 using the OptiliteTM turbidimetric analyzer. RESULTS: The concentrations of IgG, IgA, and IgD showed an increase with age, as expected, while IgM remained stable between the age groups. For the IgG subclasses, no significant differences were observed in IgG1 or IgG3, while IgG2 and IgG4 concentrations increased steadily with age. The concentration of IgG2 plateaued at 15-18 years, while IgG4 plateaued at 10-14 years. The trend of concentrations across all groups was IgG1 > IgG2 > IgG3 > IgG4. For both IgA1 and IgA2, concentrations increased significantly with age, plateauing at 15-18 years. The median IgA1 concentration was greater than IgA2 across all groups. There was a good correlation between the total IgG or IgA concentration and summation of their subclasses (R2 = 0.89, P < .0001, slope y = 0.98x + 14.51 mg/dL and R2 = 0.91, P < .0001, slope y = 1.35x 3.28 mg/dL, respectively). The concentration of C3 and C4 remained stable across the groups, with no significant differences observed. CONCLUSION: We have generated age-specific reference ranges in healthy children for C3, C4, IgG, IgA, IgM, IgD and the IgG and IgA subclasses using the OptiliteTM turbidimetric analyzer. These ranges will help identify individuals with abnormal concentrations, thus will aid in the diagnosis of both primary and secondary immunological disorders. PMID- 29603376 TI - The extracellular matrix: Focus on oligodendrocyte biology and targeting CSPGs for remyelination therapies. AB - The repair of myelin, termed remyelination, is a regenerative process that occurs within the central nervous system in conditions such as multiple sclerosis. Remyelination is enabled by oligodendrocytes that mature from oligodendrocyte precursor cells. Many factors influence the biology of oligodendrocytes and their capacity to reform myelin, and considerable evidence now implicates the extracellular matrix within the injured central nervous system as a major modifier of remyelination. Herein, we review current knowledge of components of the brain extracellular matrix that are beneficial or inhibitory for oligodendrocyte recruitment and maturation, and for their capacity to remyelinate where evidence exists. We highlight the detrimental roles of the chondroitin sulfate proteoglycans in remyelination and discuss approaches to alter the brain extracellular matrix for the wellbeing of oligodendrocytes and their capacity for myelin regeneration. PMID- 29603377 TI - Lipoprotein(a) level associates with coronary artery disease rather than carotid lesions in patients with familial hypercholesterolemia. AB - BACKGROUND: Lipoprotein(a) [Lp(a)] level is a novel risk factor for atherosclerotic cardiovascular disease in patients with familial hypercholesterolemia (FH), while its impact on the different sites of arteries remains undetermined. We aim to examine the associations of Lp(a) levels with coronary and carotid atherosclerosis in patients with heterozygous FH (HeFH). METHODS: A total of 148 patients with HeFH who have received carotid ultrasonography and coronary angiography due to chest pain were enrolled. Plasma Lp(a) was measured using immunoturbidimetric method. Finally, the associations between Lp(a) and coronary as well as carotid lesions were evaluated. RESULTS: Patients with Lp(a) >= 300 mg/L had similar carotid intima-media thickness (IMT, 0.782 +/- 0.16 mm vs 0.798 +/- 0.18 mm, P = .579) and plaque prevalence (66.7% vs 65%, P = .833) compared to those with Lp(a) < 300 mg/L, but had a higher prevalence of coronary artery disease (CAD, 69.7% vs 50.0%, P = .016) and higher Gensini score (GS, median 27 vs 3, P = .006). Moreover, no correlations were found between carotid mean IMT with either Lp(a) level or Lp(a) year score, while positive relation of Lp(a) with GS did. Multivariate regression analysis revealed that Lp(a), Lp(a) year score, and Lp(a) >= 300 g/L were all independent predictors for the presence of CAD (OR = 4.99, P = .007; OR = 4.73, P = .009; OR = 4.46, P = .006, respectively) but not for carotid plaques. CONCLUSIONS: This study suggested that Lp(a) level was associated with the presence and severity of CAD but not with carotid atherosclerosis in patients with HeFH. PMID- 29603378 TI - Wireless implantable coil with parametric amplification for in vivo electron paramagnetic resonance oximetric applications. AB - PURPOSE: To develop an implantable wireless coil with parametric amplification capabilities for time-domain electron paramagnetic resonance (EPR) spectroscopy operating at 300 MHz. METHODS: The wireless coil and lithium phthalocyanine (LiPc), a solid paramagnetic probe, were each embedded individually in a biocompatible polymer polydimethoxysiloxane (PDMS). EPR signals from the LiPc embedded in PDMS (LiPc/PDMS) were generated by a transmit-receive surface coil tuned to 300 MHz. Parametric amplification was configured with an external pumping coil tuned to 600 MHz and placed between the surface coil resonator and the wireless coil. RESULTS: Phantom studies showed significant enhancement in signal to noise using the pumping coil. However, no influence of the pumping coil on the oxygen-dependent EPR spectral linewidth of LiPc/PDMS was observed, suggesting the validity of parametric amplification of EPR signals for oximetry by implantation of the encapsulated wireless coil and LiPc/PDMS in deep regions of live objects. In vivo studies demonstrate the feasibility of this approach to longitudinally monitor tissue pO2 in vivo and also monitor acute changes in response to pharmacologic challenges. The encapsulated wireless coil and LiPc/PDMS engendered no host immune response when implanted for ~3 weeks and were found to be well tolerated. CONCLUSIONS: This approach may find applications for monitoring tissue oxygenation to better understand the pathophysiology associated with wound healing, organ transplantation, and ischemic diseases. PMID- 29603379 TI - Impact of prediabetes on poststroke depression in Chinese patients with acute ischemic stroke. AB - OBJECTIVE: It is unknown whether prediabetes is a predictor of poststroke depression (PSD). We aimed to explore the relationship between prediabetes and PSD in Chinese patients with acute ischemic stroke. METHODS: This is a prospective cohort study, and a total of 358 patients with acute ischemic stroke were recruited and enrolled. Patients were divided into 3 groups: normal glucose group (NGT, n = 96), prediabetes group (preDM, n = 134, impaired fasting glucose (IFG), and/or impaired glucose tolerance (IGT) and/or HbA1c (A1c) 5.7%-6.4%), and the diabetes mellitus group (DM, n = 128). At 1 month after stroke, patients with a Hamilton Depression Scale score of >=8 were diagnosed as PSD. RESULTS: In post hoc comparisons, the risk of PSD in patients with diabetes and prediabetes was higher than patients with NGT (37.5% vs 31.3% vs 14.6%, P = .001). Compared with NGT, the incidence rate of PSD in patients with prediabetes with HbA1c 5.7% to 6.4% and patients with prediabetes with IFG/IGT + HbA1c 5.7% to 6.4% was higher (35.3% vs 14.6%, 38.0% vs 14.6%; P = .006; P = .003, respectively). In logistic regression, prediabetes with HbA1c 5.7% to 6.4% and prediabetes with IFG/IGT + HbA1c 5.7% to 6.4% were a significant independent predictor of PSD after adjusting for potential confounding factors, with odd ratios of 1.731 and 1.978, respectively. CONCLUSIONS: Our study showed that prediabetes was associated with PSD and may predict its development at 1 month poststroke. In prediabetes subgroups, patients with HbA1c 5.7% to 6.4% were more likely to develop PSD compared to NGT and IFG/IGT groups. PMID- 29603380 TI - Identification of chromatin-accessible domains in non-alcoholic steatohepatitis derived hepatocellular carcinoma. AB - Non-alcoholic steatohepatitis (NASH) is becoming one of the major causes of hepatocellular carcinoma (HCC) in the United States and Western countries; however, the molecular mechanisms associated with NASH-related liver carcinogenesis are not well understood. In the present study, we investigated cancer-associated chromatin alterations using a model that resembles the development of NASH-related HCC in humans. An assay for transposase-accessible chromatin with high throughput sequencing (ATAC-seq) identified 1677 tumor specific chromatin-accessible regions in NASH-derived HCC tissue samples. Using a combined analysis of ATAC-seq and global gene expression data, we identified 199 differentially expressed genes, 139 up-regulated and 60 down-regulated. Interestingly, 15 of the 139 up-regulated genes had accessible chromatin sites within 5 Kb of the transcription start site (TSS), including Apoa4, Anxa2, Serpine1, Igfbp1, and Tubb2a, genes critically involved in the development of NASH and HCC. We demonstrate that the mechanism for the up-regulation of these genes is associated with the enrichment of chromatin-accessible regions by transcription factors, especially NFATC2, and histone H3K4me1 and H3K27ac gene transcription-activating marks. These data underline the important role of chromatin accessibility perturbations in reshaping of the chromatin landscape in NASH-related HCC. PMID- 29603382 TI - The continuum of monocyte phenotypes: Experimental evidence and prognostic utility in assessing cardiovascular risk. AB - The monocyte-macrophage cell lineage represents a major player in innate immunity, and is involved in many physiologic and pathologic conditions. Particularly, monocyte-macrophages play a very important role in atherosclerosis and cardiovascular disease. Monocyte heterogeneity is well recognized but the biologic and clinical meaning of the various monocyte subtypes is not entirely understood. Traditionally, monocytes can be divided in classical, intermediate, and nonclassical based on expression of the surface antigens CD14 and CD16. While macrophage diversity is now well recognized to organize as a continuum, monocyte subsets have long been considered as separated entities. However, mounting evidence obtained by tracking the ontology of human monocytes help clarifying that monocytes mature from classical to nonclassical ones, through an intermediate phenotype. This concept is therefore best depicted as a continuum, whereas the subdivision into discrete CD14/CD16 subsets appears an oversimplification. In this review, we discuss the evidence supporting the existence of a monocyte continuum along with the technical challenges of monocyte characterization. In particular, we describe the advantage of considering monocytes along a continuous distribution for the evaluation of cardiovascular risk. We make the point that small transition along the monocyte continuum better reflects cardiovascular risk than a simplified analysis of discrete monocyte subsets. Recognizing the monocyte continuum can be helpful to model other pathophysiologic conditions where these cells are involved. PMID- 29603381 TI - High-resolution whole-brain diffusion MRI at 7T using radiofrequency parallel transmission. AB - PURPOSE: Investigating the utility of RF parallel transmission (pTx) for Human Connectome Project (HCP)-style whole-brain diffusion MRI (dMRI) data at 7 Tesla (7T). METHODS: Healthy subjects were scanned in pTx and single-transmit (1Tx) modes. Multiband (MB), single-spoke pTx pulses were designed to image sagittal slices. HCP-style dMRI data (i.e., 1.05-mm resolutions, MB2, b-values = 1000/2000 s/mm2 , 286 images and 40-min scan) and data with higher accelerations (MB3 and MB4) were acquired with pTx. RESULTS: pTx significantly improved flip-angle detected signal uniformity across the brain, yielding ~19% increase in temporal SNR (tSNR) averaged over the brain relative to 1Tx. This allowed significantly enhanced estimation of multiple fiber orientations (with ~21% decrease in dispersion) in HCP-style 7T dMRI datasets. Additionally, pTx pulses achieved substantially lower power deposition, permitting higher accelerations, enabling collection of the same data in 2/3 and 1/2 the scan time or of more data in the same scan time. CONCLUSION: pTx provides a solution to two major limitations for slice-accelerated high-resolution whole-brain dMRI at 7T; it improves flip-angle uniformity, and enables higher slice acceleration relative to current state-of the-art. As such, pTx provides significant advantages for rapid acquisition of high-quality, high-resolution truly whole-brain dMRI data. PMID- 29603383 TI - TGF-beta-mediated LEFTY/Akt/GSK-3beta/Snail axis modulates epithelial-mesenchymal transition and cancer stem cell properties in ovarian clear cell carcinomas. AB - Advanced ovarian clear cell carcinoma (OCCCa) shows poor prognosis with chemoresistance, which is associated with epithelial-mesenchymal transition (EMT)/cancer stem cell (CSC) features. The left-right determination factor (LEFTY), a novel member of the TGF-beta superfamily, is a marker of stemness. Here we focused on the functional roles of LEFTY in OCCCas. OCCCa cell lines that were cultured in STK2, a serum-free medium for mesenchymal stem cells, or treated with TGF-beta1 underwent morphological changes toward an EMT appearance, along with increased expression of LEFTY and Snail. The cells also showed CSC properties, as demonstrated by increases in the aldehyde dehydrogenase (ALDH)1high activity population, number of spheroid formation, and expression of several CSC markers. Inhibition of LEFTY expression induced decreases in the number of spindle-shaped cells and CSC features, while cells stably overexpressing LEFTY exhibited enhancement of such EMT/CSC properties. Finally, treatment of cells with TGF-beta1 led to increased LEFTY expression and activation of Akt, which subsequently induced inactivation of GSK-3beta, while inhibition of GSK-3beta resulted in increased expression of both LEFTY and Snail. In clinical samples, LEFTY expression showed a tendency for positive associations with expression of vimentin, as well as Sox2 and ALDH1, in OCCCas with epithelial like morphology, indicating a possible relationship between LEFTY and the epithelial-mesenchymal hybrid stage of the tumors. In conclusion, TGF-beta mediated LEFTY/Akt/GSK-3beta/Snail axis may contribute to the establishment and maintenance of phenotypic characteristics of OCCCas through modulation of EMT/CSC properties. PMID- 29603384 TI - Axoglial synapses are formed onto pioneer oligodendrocyte precursor cells at the onset of spinal cord gliogenesis. AB - Virtually all oligodendrocyte precursors cells (OPCs) receive glutamatergic and/or GABAergic synapses that are lost upon their differentiation into oligodendrocytes in the postnatal and adult brain. Although OPCs are generated at mid-embryonic stages, several weeks before the onset of myelination, it remains unknown when and where OPCs receive their first synapses and become susceptible to the influence of neuronal activity. In the embryonic spinal cord, neuro epithelial precursors in the pMN domain cease generating cholinergic motor neurons (MNs) to produce OPCs when the first synapses are formed in the ventral lateral marginal zone. We discovered that when the first synapses form onto MNs, axoglial synapses also form onto the processes of neuro-epithelial precursors located in the marginal zone as they differentiate into OPCs. After leaving the neuro-epithelium, these pioneer OPCs preferentially accumulate in the marginal zone where they are contacted by functional glutamatergic and GABAergic synapses. Spontaneous activity of these axoglial synapses was significantly potentiated by cholinergic signaling acting through presynaptic nicotinic acetylcholine receptors. Moreover, we discovered that chronic nicotine treatment significantly increases early OPC proliferation and density in the marginal zone. Our results demonstrate that OPCs are contacted by functional synapses as soon as they emerge from their precursor domain and that embryonic spinal cord colonization by OPCs can be regulated by cholinergic signaling acting onto these axoglial synapses. PMID- 29603385 TI - Downregulated eosinophil activity in ulcerative colitis with concomitant primary sclerosing cholangitis. AB - Primary sclerosing cholangitis (PSC) is a chronic bile duct inflammation strongly connected to ulcerative colitis (UC). PSC is associated with an increased risk of colon cancer, but the link between the intestinal and the bile duct inflammation is still unknown. Also, the involvement of intestinal immune cells in the pathogenesis of PSC remains to be determined. The eosinophil granulocyte is one of the immune cells implicated in the inflammatory process of ulcerative colitis. This study was performed to determine how the accumulation and activation of intestinal eosinophils may differ between UC with and without concomitant PSC, and how this may be influenced by the cytokine/chemokine profile of the intestinal compartment. Eosinophils from peripheral blood and multiple parts of the colon were analyzed by flow cytometry. The intestinal level of inflammatory mediators was assessed using a multiplex proximity extension assay and a quantitative immunoassay. We found that colonic eosinophils were more abundant in both UC and PSC-UC compared with controls, but that their expression of activation markers was significantly increased in UC only. The colonic level of pro-inflammatory cytokines was increased in active UC but not in PSC-UC. In conclusion, we show for the first time that eosinophil activation phenotype discriminates between UC and PSC-UC, and that this may depend on the local cytokine profile of the colonic mucosa. PMID- 29603386 TI - Natural history of myocardial deformation in children, adolescents, and young adults exposed to anthracyclines: Systematic review and meta-analysis. AB - OBJECTIVE: Anthracyclines are widely used to treat solid and hematologic malignancies, but are known to cause cardiotoxicity. As more childhood cancer survivors reach adulthood due to improvements in oncologic treatments, they become susceptible to late and progressive anthracycline-induced cardiotoxicity. Nonetheless, diagnostic criteria for early detection of cardiac dysfunction are not well defined in children, adolescent, and young adults (CAYA, ages 1-40 years). We present a natural history of the changes in myocardial deformation in CAYA patients after anthracycline therapy. METHODS: We performed a literature review search between 2001 and 2016 using PubMed with the following search terms: strain (or deformation), torsion (or twist), children (or adolescent or young adult), cardiotoxicity (or dysfunction), and anthracyclines (or doxorubicin). A total of 23 articles were reviewed. Fourteen articles were incorporated in the meta-analysis. RESULTS: Strain abnormalities are observed at both short-term and long-term follow-up. Global longitudinal strain (GLS) abnormalities are common during or early after chemotherapy, whereas changes in global circumferential strain (GCS) are more significant and consistent on long-term follow-up. Although global radial strain and torsional parameters are also often abnormal late after chemotherapy, there are few studies evaluating these parameters. CONCLUSION: There are significant abnormalities in GLS and GCS following anthracycline therapy acutely and late after treatment. The prognostic value of these strain abnormalities warrants further investigation. PMID- 29603388 TI - Clinically Significant Change in Posttraumatic Stress Disorder Symptoms Is Associated With Lower Levels of Aggression After Residential Treatment Discharge. AB - Although the link between posttraumatic stress disorder (PTSD) and aggression has been repeatedly demonstrated, to our knowledge no research has examined whether PTSD symptom reductions are linked to less aggression after treatment. The current study aimed to address this gap in the literature by examining the association between reductions in PTSD symptoms and posttreatment aggression among 2,275 veterans in residential treatment for PTSD across 35 Veterans Health Administration sites. We estimated a multilevel model that examined the effect of clinically significant PTSD symptom change on aggression at 4-month posttreatment follow-up, and found significant within-site and between-site contextual effects of clinically significant changes in PTSD symptoms on follow-up aggression. Findings revealed that veterans who reported clinically significant changes in their PTSD symptoms had lower levels of aggression at follow-up than veterans at the same treatment site who did not report clinically significant PTSD change. After we controlled for individual clinically significant PTSD change, participants in treatment sites where the rates of clinically significant PTSD change were higher overall had lower levels of aggression at follow-up. The model explained over one-fourth of the variability in aggression, R2 = .26. Findings from the current study extend previous research that has shown associations between PTSD and aggression, by revealing that clinically significant change in PTSD during residential treatment is associated with less aggression at follow up. These findings suggest that interventions that effectively reduce PTSD symptoms may also help reduce risk for aggression. PMID- 29603387 TI - Genotype-phenotype correlations, dystonia and disease progression in spinocerebellar ataxia type 14. AB - BACKGROUND: Spinocerebellar ataxia type 14 is a rare form of autosomal dominant cerebellar ataxia caused by mutations in protein kinase Cgamma gene. Clinically, it presents with a slowly progressive, mainly pure cerebellar ataxia. METHODS: Using next generation sequencing, we screened 194 families with autosomal dominant cerebellar ataxia and normal polyglutamine repeats. In-depth phenotyping was performed using validated clinical rating scales neuroimaging and electrophysiological investigations. RESULTS: We identified 25 individuals from 13 families carrying pathogenic mutations in protein kinase Cgamma gene. A total of 10 unique protein kinase Cgamma gene mutations have been confirmed of which 5 are novel and 5 were previously described. Our data suggest that the age at onset is highly variable; disease course is slowly progressive and rarely associated with severe disability. However, one third of patients presented with a complex ataxia comprising severe focal and/or task-induced dystonia, peripheral neuropathy, parkinsonism, myoclonus, and pyramidal syndrome. The most complex phenotype is related to a missense mutation in the catalytic domain in exon 11. CONCLUSION: We present one of the largest genetically confirmed spinocerebellar ataxia type 14 cohorts contributing novel variants and clinical characterisation. We show that although protein kinase Cgamma gene mutations present mainly as slowly progressive pure ataxia, more than a third of cases had a complex phenotype. Overall, our case series extends the phenotype and suggests that protein kinase Cgamma gene mutations should be considered in patients with slowly progressive autosomal dominant cerebellar ataxia, particularly when myoclonus, dystonia, or mild cognitive impairment are present in the absence of polyglutamine expansion. (c) 2018 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society. PMID- 29603389 TI - Home Parenteral Nutrition Reimbursement and American Society for Parenteral and Enteral Nutrition Public Policy Efforts. AB - Home parenteral nutrition (HPN) has been considered a lifesaving intervention since the late 1960s for patients with gastrointestinal (GI) failure and other conditions that affect the GI tract who are well enough to be at home. Payment for this therapy under federal programs requires significant documentation and complex processes to qualify. Medicare parenteral nutrition policy, qualification processes and challenges, and advocacy supported by the American Society for Parenteral and Enteral Nutrition are reviewed with the goal of increasing clinician awareness of the complexity surrounding Medicare HPN reimbursement. PMID- 29603390 TI - Commercial scale production of RvD4 opens the resolving door to new research. PMID- 29603391 TI - Cut-off Serum Zinc Concentration Affecting the Appetite, Growth, and Nutrition Status of Undernourished Children Supplemented With Zinc. AB - BACKGROUND: Zinc supplementation has varied effects on the linear growth of children who exhibited stunted growth. MATERIALS AND METHODS: This observational study involved 761 undernourished children, aged 2-10 years, who received a 24 week course of 10-mg elemental zinc per day. The clinical parameters for evaluation included appetite, height, weight, and body mass index (BMI). Evaluation of the effect of zinc supplementation was stratified by the initial serum zinc concentration. RESULTS: The enrolled participants comprised 390 boys and 371 girls. The mean age was 5.63 years. The height-for-age, weight-for-age, and BMI-for-age z scores increased gradually during the study period. When compared with the children with a serum zinc concentration >=75 MUg/dL, the height, weight, weight-for-age, and BMI-for-age z scores increased significantly in the patients with serum zinc concentrations of <75 MUg/dL after 12- and 24 week zinc supplementation (all P < .001). BMI, height-for-age z score, and appetite also increased significantly in patients with serum zinc concentrations of <75 MUg/dL after 24-week zinc supplementation (P = .003, .019, and <.001, respectively). CONCLUSION: The findings of this study indicate that undernourished children with serum zinc concentrations of <75 MUg/dL experienced greater increments in appetite and growth as a result of zinc supplementation. PMID- 29603392 TI - Military Sexual Assault in Transgender Veterans: Results From a Nationwide Survey. AB - There is limited understanding about the frequency of military sexual assault (MSA) in transgender veterans, characteristics associated with MSA, or subsequent mental and behavioral health problems. To address this gap, we used an online national survey of 221 transgender veterans to identify prevalence of MSA and to assess its association with demographic characteristics, past history of sexual victimization, and stigma-related factors. We also evaluated the association between MSA and several mental and behavioral health problems. Overall, 17.2% of transgender veterans experienced MSA, but rates differed significantly between transgender women (15.2%) and transgender men (30.0%). Using adjusted regression models, MSA was associated with adult sexual assault prior to military service, odds ratio (OR) = 4.05, 95% CI [1.62, 10.08], and distal minority stress during military service, OR = 2.98, 95% CI [1.28, 6.91]. With respect to health outcomes, MSA was associated with past-month posttraumatic stress disorder (PTSD) symptom severity, B = 10.18, 95% CI [3.45, 16.91]; current depression symptom severity, B = 3.71, 95% CI [1.11, 6.30]; and past-year drug use, OR = 3.17, 95% CI [1.36, 7.40]. Results highlight the vulnerability of transgender veterans to MSA, and the need for military prevention programs that acknowledge transgender individuals' heightened risk. Furthermore, clinicians should consider clinical screening for PTSD, depression, and drug use in transgender veterans who have a history of MSA. PMID- 29603393 TI - Measuring Aggregated and Specific Combat Exposures: Associations Between Combat Exposure Measures and Posttraumatic Stress Disorder, Depression, and Alcohol Related Problems. AB - Research has shown combat exposure to be associated with negative mental health outcomes. Different combat exposure measures are not composed of the same combat experiences, and few combat exposure measures have been directly compared to another measure. Furthermore, research about the unique associations between specific combat experiences and mental health is lacking. We investigated associations between new-onset posttraumatic stress disorder (PTSD), new-onset depression, and alcohol-related problems and two commonly used measures of combat among a sample of 20,719 recently deployed U.S. military personnel. A 13-item measure assessed both direct and indirect combat exposures, and a 5-item measure assessed only indirect exposures. Both combat measures were associated with all outcomes in the same direction (e.g., PTSD, odds ratio [OR] = 2.97 vs. 4.01; depression, OR = 2.03 vs. 2.42; alcohol-related problems, OR = 1.41 vs. 1.62, respectively, for the 5- and 13-item measures). The 13-item measure had a stronger association with some outcomes, particularly PTSD. Each specific item had significant bivariate associations with all outcomes, ORs = 1.43-4.92. After adjusting for other combat exposures, items assessing witnessing abuse, feeling in danger, and knowing someone injured or killed remained associated with all outcomes, ORs = 1.18-2.72. After this adjustment, several items had unexpected protective associations with some mental health outcomes. Results indicated these two combat exposure measures were approximately equally effective for determining risk for negative mental health outcomes in a deployed population, despite having different content. Additional research is needed to replicate and understand how specific combat exposures affect health. PMID- 29603394 TI - An improved reference method for serum cations measurement by ion chromatography. AB - BACKGROUND: To improve the accuracy of the routine methods in laboratory medicine, ion chromatography with a simple sample treatment procedure, which can completely remove the proteins and/or organics in human serum, has been developed for the determination of serum cations. METHODS: Chromatographic conditions for the separate and simultaneous determination of K, Na, Ca, and Mg were investigated. Furthermore, various factors influencing the mineralization of human serum, such as the selection and amount of oxidant, were also examined systematically and optimized. RESULTS: The optimized experimental conditions are as follows: 1.0 mL of serum specimen digested with 2 mL nitric acid (120 degrees C) followed by 2 mL hydrogen peroxide (80 degrees C). The specimens were then redissolved and determined by ion chromatography under the optimum eluent concentration of 32 mmol/L methanesulfonic acids. The measurement accuracy and precision are less than 1.0% for all the analytes by analyzing NIST certified reference materials, IFCC-RELA specimens and serum specimens. The results were also comparable with the reference values obtained by the inductively coupled plasma mass spectrometry (ICP-MS), which were found to be in good agreement. CONCLUSIONS: Ion chromatography with a simple sample treatment procedure for the determination of cations in human serum with high sensitivity and specificity was developed. The proposed method could be recommended as a candidate reference method for the determination of serum cations. PMID- 29603395 TI - Peptidyl-prolyl cis/trans isomerase Pin1 regulates withaferin A-mediated cell cycle arrest in human breast cancer cells. AB - We have reported previously that withaferin A (WA) prevents breast cancer development in mouse mammary tumor virus-neu (MMTV-neu) transgenic mice, but the mechanism is not fully understood. Unbiased proteomics of the mammary tumors from control- and WA-treated MMTV-neu mice revealed downregulation of peptidyl-prolyl cis/trans isomerase (Pin1) protein by WA administration. The present study extends these findings to elucidate the role of Pin1 in cancer chemopreventive mechanisms of WA. The mammary tumor level of Pin1 protein was lower by about 55% in WA-treated rats exposed to N-methyl-N-nitrosourea, compared to control. Exposure of MCF-7 and SK-BR-3 human breast cancer cells to WA resulted in downregulation of Pin1 protein. Ectopic expression of Pin1 attenuated G2 and/or mitotic arrest resulting from WA treatment in both MCF-7 and SK-BR-3 cells. WA induced apoptosis was increased by Pin1 overexpression in MCF-7 cells but not in the SK-BR-3 cell line. In addition, molecular docking followed by mass spectrometry indicated covalent interaction of WA with cysteine 113 of Pin1. Overexpression of Pin1C113A mutant failed to attenuate WA-induced mitotic arrest or apoptosis in the MCF-7 cells. Furthermore, antibody array revealed upregulation of proapoptotic insulin-like growth factor binding proteins (IGFBPs), including IGFBP-3, IGFBP-4, IGFBP-5, and IGFBP-6, in Pin1 overexpressing MCF-7 cells following WA treatment when compared to empty vector transfected control cells. These data support a crucial role of the Pin1 for mitotic arrest and apoptosis signaling by WA at least in the MCF-7 cells. PMID- 29603396 TI - Video analysis of acute injuries and referee decisions during the 24th Men's Handball World Championship 2015 in Qatar. AB - Although handball is a contact sport with a high risk of acute match injuries, their mechanisms have not yet been investigated. We aimed to describe the mechanisms of acute match injuries in elite male handball and evaluate referee performance in injury situations. Based on injury surveillance from the 24th Men's Handball World Championship 2015 in Qatar, injury situations and the referee decisions were identified on video footage. A total of 55 injury situations and 37 referee decisions were included for analysis. The injury situations were analyzed individually by five handball experts, followed by a consensus meeting. An expert referee panel performed individual blinded evaluation of the referee decisions, followed by an online consensus meeting. Injuries were evenly distributed among attackers (n = 29) and defenders (n = 26). The most frequent injury cause was contact trauma due to a tackle (n = 27). At the time of injury, attackers were most frequently performing a jump shot (n = 9), while defenders were completing a tackle (n = 10). Defenders most commonly tackled the throwing arm (n = 7) or toward the head/face region (n = 6) of injured attackers, while attackers most frequently hit injured defenders with the knee during jump shots (n = 5). Agreement between the referees and the expert panel was weak (kappa: 0.22, 95% CI 0.07 to 0.36), with substantially more lenient rule interpretation by the referees. Our results suggest that stricter refereeing and rule amendments should be considered to prevent acute match injuries in elite handball, especially in relation to tackling episodes when an attacker is performing a jump shot. PMID- 29603397 TI - Role of miR-31 and SATB2 in arsenic-induced malignant BEAS-2B cell transformation. AB - Arsenic is a naturally occurring and highly potent metalloid known to elicit serious public health concerns. Today, approximately 200 million people around the globe are exposed to arsenic-contaminated drinking water at levels greater than the World Health Organization's recommended limit of 10 parts per billion. As a class I human carcinogen, arsenic exposure is known to elicit various cancers, including lung, skin, liver, and kidney. Current evidence suggests that arsenic is capable of inducing both genotoxic and cytotoxic injury, as well as activating epigenetic pathways to induce carcinogenesis. Our study identifies a novel pathway that is implicated in arsenic-induced carcinogenesis. Arsenic down regulated miRNA-31 and the release of this inhibition caused overexpression of special AT-rich sequence-binding protein 2 (SATB2). Arsenic is known to disrupt miRNA expression, and here we report for the first time that arsenic is capable of inhibiting miR-31 expression. As a direct downstream target of miR-31, SATB2 is a prominent transcription factor, and nuclear matrix binding protein implicated in many types of human diseases including lung cancer. Results from this study show that arsenic induces the overexpressing SATB2 by inhibiting miR 31 expression, which blocks the translation of SATB2 mRNA, since levels of SATB2 mRNA remain the same but protein levels decrease. Overexpression of SATB2 induces malignant transformation of human bronchial epithelial (BEAS-2B) cells indicating the importance of the expression of miR-31 in preventing carcinogenesis by suppressing SATB2 protein levels. PMID- 29603398 TI - Gastrostomy Tube Feeding in Children With Developmental or Acquired Disorders: A Longitudinal Comparison on Healthcare Provision and Eating Outcomes 4 Years After Gastrostomy. AB - BACKGROUND: Studies on long-term feeding and eating outcomes in children requiring gastrostomy tube feeding (GT) are scarce. The aim of this study was to describe children with developmental or acquired disorders receiving GT and to compare longitudinal eating and feeding outcomes. A secondary aim was to explore healthcare provision related to eating and feeding. METHODS: This retrospective cohort study reviewed medical records of children in 1 administrative region of Sweden with GT placement between 2005 and 2012. Patient demographics, primary diagnoses, age at GT placement, and professional healthcare contacts prior to and after GT placement were recorded and compared. Feeding and eating outcomes were assessed 4 years after GT placement. RESULTS: The medical records of 51 children, 28 boys and 23 girls, were analyzed and grouped according to "acquired" (n = 13) or "developmental" (n = 38) primary diagnoses. At 4 years after GT placement, 67% were still using GT. Only 6 of 37 (16%) children with developmental disorders transferred to eating all orally, as opposed to 10 of 11 (91%) children with acquired disorders. Children with developmental disorders were younger at the time of GT placement and displayed a longer duration of GT activity when compared with children with acquired disorders. CONCLUSIONS: This study demonstrates a clear difference between children with developmental or acquired disorders in duration of GT activity and age at GT placement. The study further shows that healthcare provided to children with GT is in some cases multidisciplinary, but primarily focuses on feeding rather than eating. PMID- 29603399 TI - Validation study for development of the Japan NBI Expert Team classification of colorectal lesions. AB - BACKGROUND AND AIM: The Japan narrow-band imaging (NBI) Expert Team (JNET) was organized to unify four previous magnifying NBI classifications (the Sano, Hiroshima, Showa, and Jikei classifications). The JNET working group created criteria (referred to as the NBI scale) for evaluation of vessel pattern (VP) and surface pattern (SP). We conducted a multicenter validation study of the NBI scale to develop the JNET classification of colorectal lesions. METHODS: Twenty five expert JNET colonoscopists read 100 still NBI images with and without magnification on the web to evaluate the NBI findings and necessity of the each criterion for the final diagnosis. RESULTS: Surface pattern in magnifying NBI images was necessary for diagnosis of polyps in more than 60% of cases, whereas VP was required in around 90%. Univariate/multivariate analysis of candidate findings in the NBI scale identified three for type 2B (variable caliber of vessels, irregular distribution of vessels, and irregular or obscure surface pattern), and three for type 3 (loose vessel area, interruption of thick vessel, and amorphous areas of surface pattern). Evaluation of the diagnostic performance for these three findings in combination showed that the sensitivity for types 2B and 3 was highest (44.9% and 54.7%, respectively), and that the specificity for type 3 was acceptable (97.4%) when any one of the three findings was evident. We found that the macroscopic type (polypoid or non-polypoid) had a minor influence on the key diagnostic performance for types 2B and 3. CONCLUSION: Based on the present data, we reached a consensus for developing the JNET classification. PMID- 29603400 TI - A guide to studying human dermal adipocytes in situ. AB - Dermal white adipose tissue (DWAT) is a main component of human skin, composed of individual lipid-laden mesenchymal cells known as dermal adipocytes (DAs). Besides their well-known role in lipid storage and release, DAs also promote skin immunity, wound healing and hair follicle cycling and are important players in cutaneous neuroendocrinology. The ever-growing insights into DWAT functions, albeit mostly in mice, have invited speculation that it may be involved in multiple skin diseases ranging from fibrosis to alopecia and psoriasis, thus designating human DWAT a clinically relevant, but as yet insufficiently investigated skin compartment. Therefore, this practical, user-friendly guide aims to introduce the techniques available to study human DWAT in situ and ex vivo, including immunohistochemistry, immunofluorescence microscopy and analysis via quantitative immunohistomorphometry. Here, we provide information on a collection of stains comprising pre-adipocyte (Pref1) and mature adipocyte markers (Perilipin1, Caveolin1), as well as various lipid (OilRedO, BODIPY) and histochemical stains (H&E, trichrome) available for use on human DWAT. We offer the reader guidelines on fixing, processing and staining human DAs and highlight caveats and solutions to common problems that one may encounter when studying this fascinating skin compartment. We also suggest standard methods for conducting quantitative immunohistomorphometry on human DWAT and its individual adipocytes to quantify cell size, number, lipid content and fluorescence intensity of adipose-specific markers. Finally, we briefly introduce in situ hybridization, transmission electron microscopy and essentials of magnetic resonance imaging imaging as additional tools for instructively interrogating this largest, but still least-known compartment of human skin. PMID- 29603401 TI - Platelet to lymphocyte ratio in acute aortic dissection. AB - BACKGROUND: Inflammation plays an important role in the initiation and progression of acute aortic dissection (AAD). New inflammatory indices derived from full cell blood count and its differential may be associated with increased risk. We evaluated platelet-lymphocyte (PLR), red cell distribution width (RDW) and RDW/PLT's (platelets) (RPR) in AAD. METHODS: We studied 120 consecutive patients with AAD type I admitted for emergency surgery (group I), 121 consecutive patients with aortic aneurysms of the ascending aorta prior to elective repair (group II) and 121 controls (group III), age and sex matched. RESULTS: PLR was significantly higher in group I vs both groups II and III (P < .001). There was an excellent correlation of PLR with neutrophil/lymphocyte ratio (NLR) in all three groups (P < .001 for all). After adjustment for hemoglobin, RDW did not differ but RPR remained significantly higher in group I compared to groups II and III (P < .001). The best cutoff value of PLR to predict dissection was 159 with 53% sensitivity and 86% specificity. No association between PLR, RDW, and RPR and mortality in group I was found. CONCLUSIONS: Indices derived from full cell blood count may provide diagnostic information in patients with AAD; whether these indices may contribute to prognosis assessment should be further investigated. PMID- 29603403 TI - Comparison of Calorie and Protein Intake of Very Low Birth Weight Infants Receiving Mother's Own Milk or Donor Milk When the Nutrient Composition of Human Milk Is Measured With a Breast Milk Analyzer. AB - BACKGROUND: In premature infants, donor breast milk (DBM) is assumed to provide reduced nutrients vs. mother's own milk (MOM). This study examined calorie and protein delivery when very low birth weight infants were fed fortified MOM or DBM, with a known nutrient composition, relative to established nutrition recommendations and to determine if there were differences between the groups. METHODS: A retrospective medical record review was conducted in 29 very low birth weight infants receiving MOM or DBM. Nutrient content of human milk was measured using the Calais Analyzer. Added fortifiers feeding volume, and weight were collected to determine total daily calorie and protein intake. RESULTS: 145 days of enteral feedings among 29 infants were included, 78 (53.8%) from DBM and 67 (46.2%) from MOM. Mean daily fluid intake among infants receiving DBM was significantly higher when compared with MOM, 150.6 +/- 7.6 mL/kg vs 146.8 +/- 11.3 mL/kg (P = .016). DBM feedings provided 110.1 +/- 9.0 kcals/kg/d vs 113.0 +/ 21.0 kcals/kg/d from MOM feedings (P = .275). Mean protein intake was similar, 4.1 +/- 0.5 g /kg/d on DBM days vs 4.0 +/- 0.5 g kg/d on MOM days (P = .162). A total of 46 of 78 DBM days (59.0%) and 30 of 67 MOM days (44.8%) were below the minimum established calorie needs of 110 kcals/kg/day. CONCLUSIONS: DBM provides comparable nutrient intake to MOM at a higher enteral feeding volume. However, both types of human milk failed to meet energy needs with standard fortification regimens. PMID- 29603402 TI - Expression of CRYM in different rat organs during development and its decreased expression in degenerating pyramidal tracts in amyotrophic lateral sclerosis. AB - The protein MU-crystallin (CRYM) is a novel component of the marsupial lens that has two functions: it is a key regulator of thyroid hormone transportation and a reductase of sulfur-containing cyclic ketimines. In this study, we examined changes of the expression pattern of CRYM in different rat organs during development using immunohistochemistry and immunoblotting. As CRYM is reportedly expressed in the corticospinal tract, we also investigated CRYM expression in human cases of amyotrophic lateral sclerosis (ALS) using immunohistochemistry. In the rat brain, CRYM was expressed in the cerebral cortex, basal ganglia, hippocampus and corticospinal tract in the early postnatal period. As postnatal development progressed, CRYM expression was restricted to large pyramidal neurons in layers V and VI of the cerebral cortex and pyramidal cells in the deep layer of CA1 in the hippocampus. Even within the same regions, CRYM-positive and negative neurons were distributed in a mosaic pattern. In the kidney, CRYM was expressed in epithelial cells of the proximal tubule and mesenchymal cells of the medulla in the early postnatal period; however, CRYM expression in the medulla was lost as mesenchymal cell numbers decreased with the rapid growth of the medulla. In human ALS brains, we observed marked loss of CRYM in the corticospinal tract, especially distally. Our results suggest that CRYM may play roles in development of cortical and hippocampal pyramidal cells in the early postnatal period, and in the later period, performs cell-specific functions in selected neuronal populations. In the kidney, CRYM may play roles in maturation of renal function. The expression patterns of CRYM may reflect significance of its interactions with T3 or ketimines in these cells and organs. The results also indicate that CRYM may be used as a marker of axonal degeneration in the corticospinal tract. PMID- 29603404 TI - A review of the mechanisms of action of dimethylfumarate in the treatment of psoriasis. AB - Fumaric acid esters (FAEs) such as dimethylfumarate (DMF) are used for the treatment of adults with moderate-to-severe psoriasis. The mode of action of FAEs is complex. Here, we provide a comprehensive review of the literature to describe the molecular mechanisms by which DMF and its active metabolite monomethylfumarate (MMF) exert their anti-inflammatory and immune modulatory effects. MMF can bind to the hydroxy-carboxylic acid receptor 2 (HCA2) on the cell surface and both DMF and MMF react with intracellular glutathione following cell penetration. DMF and to some extent also MMF modulate the activity of certain cellular signalling proteins such as the nuclear factor (erythroid derived 2)-like 2 (Nrf2), nuclear factor kappa B (Nf-kappaB) and the cellular concentration of cyclic adenosine monophosphate. Some studies show that DMF can also affect the hypoxia-inducible factor 1-alpha (HIF-1alpha). These actions seem to be responsible for i) the downregulation of inflammatory cytokines and ii) an overall shift from a proinflammatory Th1/Th17 response to an anti inflammatory/regulatory Th2 response. Both steps are necessary for the amelioration of psoriatic inflammation, although additional mechanisms have been proposed. There is a growing body of evidence to support the notion that DMF/MMF may also exert effects on granulocytes and non-immune cell lineages including keratinocytes and endothelial cells. A better understanding of the multiple molecular mechanisms involved in the cellular action of FAEs will help to adapt and further improve the use of such small molecules for the treatment of psoriasis and other chronic inflammatory diseases. PMID- 29603405 TI - Short- and long-term cost and utilization of health care resources in Parkinson's disease in the UK. AB - BACKGROUND: There is currently no robust long-term data on costs of treating patients with Parkinson's disease. The objective of this study was to report levels of health care utilization and associated costs in the 10 years after diagnosis among PD patients in the United Kingdom. METHODS: We undertook a retrospective population-based cohort study using linked data from the UK Clinical Practice Research Datalink and Hospital Episode Statistics databases. Total health care costs of PD patients were compared with those of a control group of patients without PD selected using 1:1 propensity score matching based on age, sex, and comorbidity. RESULTS: Between 1994 and 2013, 7271 PD patients who met study inclusion criteria were identified in linked Clinical Practice Research Datalink-Hospital Episode Statistics; 7060 were matched with controls. The mean annual health care cost difference (at 2013 costs) between PD patients and controls was L2471 (US$3716) per patient in the first year postdiagnosis (P < 0.001), increasing to L4004 (US$6021) per patient (P < 0.001) 10 years following diagnosis because of higher levels of use across all categories of health care utilization. Costs in patients with markers of advanced PD (ie, presence of levodopa-equivalent daily dose > 1100 mg, dyskinesias, falls, dementia, psychosis, hospital admission primarily due to PD, or nursing home placement) were on average higher by L1069 (US$1608) per patient than those with PD without these markers. CONCLUSIONS: This study provides comprehensive estimates of health care costs in PD patients based on routinely collected data. Health care costs attributable to PD increase in the year following diagnosis and are higher for patients with indicators of advanced disease. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29603406 TI - Metaphylactic effect of minerals on the immune response, biochemical variables and antioxidant status of newborn calves. AB - The aim of this study was to evaluate whether injectable zinc and copper affect host immune responses and antioxidant status of newborn calves. For this study, 19 newborn calves were divided into two groups. The control group consisted of 10 animals; and the treated group consisted of nine animals that received copper edetate (Cu-ed) and zinc edetate (Zn-ed) subcutaneously at the first day of life at doses of 0.3 mg/kg and 1.0 mg/kg respectively. Blood and faecal samples were collected for laboratory analyses (seric biochemistry, proteinogram, antioxidant enzymes and parasitological examination) on days 10, 20 and 30 after birth. On day 10, treated animals showed increased levels of total proteins, as well as increased globulin levels compared to the control group, a finding probably related to the increase in ceruloplasmin and IgG heavy chain. Thirty days after mineral metaphylactic administration, IgG light chain and acid glycoprotein levels significantly increased in treated animals (p < .05). There were no significant differences between groups regarding the biochemical analyses (triglycerides, cholesterol, glucose and urea). On the other hand, the superoxide dismutase and catalase activities increased on day 10 after treatment. In the control group, eight animals showed severe diarrhoea and one died 8 days after birth. Two animals from this group showed mild diarrhoea. Only three treated animals had severe diarrhoea, and six showed signs of mild diarrhoea. All animals that showed severe diarrhoea (control = 8; treated = 3) had hyperthermia (over 39.5 degrees C), and therefore, antibiotic therapy was administered (sulfadiazine and trimethoprim) for five consecutive days. In summary, Zn-ed and Cu-ed decreased the frequency and intensity of diarrhoea, modulated superoxide dismutase (SOD) and catalase (CAT) enzymes and also heightened the immune responsiveness of newborn calves, suggesting a new approach to improve cattle performance and minimize the occurrence of diarrhoea. PMID- 29603407 TI - Nutrition Support Team Guide to Maternal Diet for the Human-Milk-Fed Infant. AB - BACKGROUND: Human milk feeding is encouraged for all infants; however, the mammary gland depends on maternal dietary intake of vitamins A, B1, B2, B6, B12, D, docosahexaenoic acid (DHA), choline, and iodine. Nutrition support team knowledge of maternal feeding guidelines for these nutrient sources can therefore impact infant intake. We hypothesized that these key nutrients for lactation in the mother's diet would be less than the dietary guidelines in the United States. METHODS: This was a secondary analysis of nutrition data collected during a randomized, controlled trial. Dietary records were analyzed from 16 mothers (13 with singleton and 3 with multiple births) completing the study. Mean dietary intakes of selected nutrients were calculated and compared with the current dietary reference intakes. RESULTS: Mean maternal dietary intake for singletons was significantly (P < .05) lower than the dietary reference intakes for (vitamin A (58%), vitamin D (44%), and choline (58%);) DHA comprised only 5% of the current expert recommendation. Based on singleton recommendations, mothers to twins consumed an adequate intake except for DHA. CONCLUSIONS: Women providing breast milk for singleton preterm infants did not consume dietary reference intakes for key nutrients. Twin mothers' diets were adequate except for DHA, but these guidelines are based on singleton pregnancies and remain poorly understood for twin needs. The nutrition support team can have a unique role in maternal dietary education to impact human milk nutrient delivery to the infant. PMID- 29603408 TI - Effect of Vitamin D Level on Clinical Outcomes in Patients Undergoing Left Ventricular Assist Device Implantation. AB - BACKGROUND: Vitamin D is an important hormone that regulates cardiac myocyte function. Low levels contribute to the development of cardiovascular disease and have been implicated in immune function and the inflammatory cascade. Patients who undergo left ventricular assist device (LVAD) implantation are at risk for driveline infection, stroke, and gastrointestinal (GI) bleeding. We investigated whether serum 25-hydroxy (25-OH) vitamin D levels affect clinical outcomes after LVAD. METHODS: 212 patients who underwent LVAD implantation between 2010 and 2015 were included. We measured preoperative 25-OH vitamin D level and postoperative adverse events during the first year. Vitamin D level was classified into 3 categories: normal (>30 ng/mL), insufficient (20-30 ng/mL), and deficient (<20 ng/mL). Clinical outcomes in both insufficient and deficient categories were compared with the normal category. RESULTS: The odds ratio (OR) of being admitted >=2 times was 2.46 (95% confidence interval [CI]: 1.067-5.769) for deficiency and 2.5 (95% CI: 0.970-6.443) for insufficiency. The OR of driveline infection was 6.185 (95% CI: 0.80-49.2; P = .07) for insufficiency and 11.467 (95% CI: 1.204 109.26; P = .03) for deficiency. Vitamin D levels were not associated with GI bleeding, length of stay, or stroke. CONCLUSIONS: In patients with LVAD, both deficiency and insufficiency of 25-OH vitamin D levels are independently associated with increased postoperative driveline infection risk and higher rate of readmission. Further trials are needed to confirm whether a repletion regimen could be a promising means of decreasing the risk for these postoperative adverse events. PMID- 29603409 TI - Application of the Movement Disorder Society prodromal criteria in healthy G2019S LRRK2 carriers. AB - BACKGROUND: In 2015, the International Parkinson and Movement Disorder Society Task Force recommended research criteria for the estimation of prodromal PD. OBJECTIVES: We aimed to evaluate, for the first time, the criteria in first degree relatives of Ashkenazi Jewish G2019S-LRRK2 PD patients, who are considered a population at risk for developing PD, and assess the sensitivity and specificity of the criteria in identifying phenoconverters. METHODS: Participants were evaluated longitudinally over a period of 5 years (average follow-up: 49.2 +/- 12.3 months). Likelihood ratios and probability estimations were calculated based on the International Parkinson and Movement Disorder Society Research Criteria for Prodromal Parkinson's Disease markers and examined for each assessment point. RESULTS: One hundred twenty healthy carriers (49.53 +/- 13.4 years; 54% female) and 111 healthy noncarriers (48.43 +/- 15.79 years; 49% female) participated in this study. Probability scores were significantly higher in healthy carriers than healthy noncarriers (P < 0.0001). Of the 20 participants (8.6%) who met criteria for probable prodromal PD at baseline, 17 were healthy carriers. Participants who reached the threshold were older (P < 0.0001), had higher UPDRS-III (P < 0.001), lower cognitive function (P = 0.001), and more nonmotor symptoms (P < 0.0001), compared to those who did not. Ten participants were diagnosed with incident PD within 5 years from baseline resulting in a specificity of 91.82% (95% confidence interval: 86.69-96.94), sensitivity of 80% (95% confidence interval: 55.21-100), positive predictive value of 47.06% (95% confidence interval: 23.33-70.79), and negative predictive value of 98.06% (95% confidence interval: 95.39-100). All 10 phenoconvertors were G2019S-LRRK2 carriers. CONCLUSIONS: The results showed the utility of using the criteria and high sensitivity and specificity in identifying prodromal PD in this high-risk unique cohort. These results may be valuable for future disease modification clinical trials. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29603411 TI - Beta Oscillations and Indirect Pathway Spiny Projecting Neurons: A Selective Neuronal Mechanism Linked to Parkinsonian Pathophysiology? PMID- 29603410 TI - Low-dose oral immunotherapy for children with anaphylactic peanut allergy in Japan. AB - BACKGROUND: Oral immunotherapy (OIT) is a promising treatment for persons with allergy; however, it can also cause adverse allergic reactions. In this study, we investigated the efficacy of low-dose OIT for anaphylactic peanut allergy. METHODS: Twenty-four children (median age, 9.6 years) with anaphylaxis to peanuts were hospitalized for 5 days and then gradually fed increasing amounts of peanut powder up to 133 mg/day. One year later, they underwent an oral food challenge after 2 weeks of peanut avoidance. Those who were asymptomatic after ingesting 795 mg of peanut protein were defined as having achieved sustained unresponsiveness. We measured peanut- and Ara h2-specific immunoglobulin (Ig) E, IgG, and IgG4 levels at 0, 1, 3, 6, and 12 months in the OIT group and at 0 and 12 months in the control group. RESULTS: At baseline, all children in the OIT group and 8 in the control group had a history of anaphylaxis. The median peanut /Ara h2-specific IgE levels in the OIT and control groups were 55.4/48.6 and 58.2/38.1 kUa/L, respectively. One year later, 8 (33.3%) children in the OIT group exhibited sustained unresponsiveness, while none in the control group did. In the OIT group, the median peanut-specific IgE levels significantly increased to 194.0 kUa/L, after 1 month and then significantly decreased to 57.5 kUa/L at 12 months. Meanwhile, the median peanut- and Ara h2-specific IgG and IgG4 levels increased significantly after 1 month. CONCLUSION: Low-dose OIT induces immunological changes and has the capability of achieving sustained unresponsiveness in children with peanut anaphylaxis. PMID- 29603412 TI - Improving Nutrition Outcomes for Infants < 1500 Grams With a Progressive, Evidenced-Based Enteral Feeding Protocol. AB - BACKGROUND: Growth is essential for very low birth weight infants. The purpose of this retrospective chart review was to evaluate the impact of a new standardized, evidenced-based feeding protocol for infants born < 1500 g in correlation with growth and clinical outcomes. METHODS: Growth and nutrition data was reviewed from 2 groups of infants born < 1500 g within a level III newborn intensive care unit (NICU). Epoch 1 infants (N = 32) received care following initial implementation of a standardized enteral feeding protocol. Epoch 2 infants (N = 32) received care following aggressive modification of this initial protocol based on newly available literature that promotes earlier initiation and advancement of enteral feedings. RESULTS: Epoch 2 infants weighed more at 36 weeks (2562 vs 2304 g) with higher discharge weight percentiles (32nd vs 15th percentile). Epoch 2 infants started and achieved full enteral feedings earlier (day of life 1 vs 4; 7 vs 22, P < 0.0001) and required less days of parenteral nutrition (5.5 vs 17.5 days, P < 0.0001), with indwelling central line for parenteral access (6 vs 17.5). There were no differences in retinopathy of prematurity (17% control vs 19% study), oxygen requirement at 36 weeks (22% epoch 1 vs 43%), necrotizing enterocolitis (3% epoch 1 vs 0%), intraventricular hemorrhage grade 3-4, periventricular leukomalacia, or death. CONCLUSION: In this sample of very low birth weight infants, a progressive standardized, evidence based feeding protocol was associated with improved growth without increased risk for necrotizing enterocolitis. PMID- 29603413 TI - Optimal low-density lipoprotein concentration for cardiac allograft vasculopathy prevention. AB - Cardiac allograft vasculopathy (CAV) is a major risk factor influencing graft loss and patient survival following orthotopic heart transplant. Allograft vasculopathy is a multifactorial process, which includes both immunologic and non immunologic mechanisms. Given the non-immunological risk factors for vasculopathy, particularly hyperlipidemia, it is intuitive that reducing a patient's LDL would help attenuate the disease process. Multiple studies have shown benefits with the use of statin therapy. However, current heart transplant guidelines do not give a specific recommendation as to what LDL goal should be achieved in this patient population. This study is a retrospective cohort analysis designed to determine the relative risk of developing cardiac allograft vasculopathy with respect to different LDL goals. Median LDL level of <100 mg/dL was shown to significantly reduce the risk of developing cardiac allograft vasculopathy. Twelve of 37 patients with an LDL >=100 mg/dL (32.4%) developed CAV vs 25 of 157 patients (15.9%) with an LDL <100 mg/dL (P = .021). Furthermore, a delay in to time to cardiac allograft vasculopathy was seen when a median LDL concentration of <100 mg/dL was achieved. This benefit was not extended when a goal concentration of <70 mg/dL was targeted. PMID- 29603414 TI - GLT-1 mediates exercise-induced fatigue through modulation of glutamate and lactate in rats. AB - Glutamate has been implicated in exercise-induced fatigue, but the underlying mechanism is unknown. This study aimed to determine whether glutamate transporter 1 (GLT-1) has a key role in the regulation of exercise-induced fatigue. The expressions of GLT-1 and glial fibrillary acidic protein (GFAP) in the supplementary motor area of rats exposed to exhaustion were analyzed by immunohistochemistry. The expression of GLT-1 was further confirmed by Western blotting. The effects of GLT-1 on extracellular levels of glutamate and lactate and on exercise endurance were studied by microdialysis. GLT-1 expression was decreased in rats subjected to exercise-induced fatigue. Functional inhibition of GLT-1 using dihydrokainate and transcriptional inhibition of GLT-1 using antisense oligodeoxynucleotides led to a decrease in exercise endurance with a subsequent increase in extracellular glutamate concentration and decrease in extracellular lactate concentration. The expression of GLT-1 in the supplementary motor area is reduced after strenuous exercise, resulting in an increased extracellular glutamate concentration and decreased extracellular lactate level that may be responsible for the development of fatigue. GLT-1-mediated uptake of glutamate ameliorates exercise-induced fatigue in rat models. PMID- 29603415 TI - Wood-Inspired High-Performance Ultrathick Bulk Battery Electrodes. AB - Ultrathick electrode design is a promising strategy to enhance the specific energy of Li-ion batteries (LIBs) without changing the underlying materials chemistry. However, the low Li-ion conductivity caused by ultralong Li-ion transport pathway in traditional random microstructured electrode heavily deteriorates the rate performance of ultrathick electrodes. Herein, inspired by the vertical microchannels in natural wood as the highway for water transport, the microstructures of wood are successfully duplicated into ultrathick bulk LiCoO2 (LCO) cathode via a sol-gel process to achieve the high areal capacity and excellent rate capability. The X-ray-based microtomography demonstrates that the uniform microchannels are built up throughout the whole wood-templated LCO cathode bringing in 1.5 times lower of tortuosity and ~2 times higher of Li-ion conductivity compared to that of random structured LCO cathode. The fabricated wood-inspired LCO cathode delivers high areal capacity up to 22.7 mAh cm-2 (five times of the existing electrode) and achieves the dynamic stress test at such high areal capacity for the first time. The reported wood-inspired design will open a new avenue to adopt natural hierarchical structures to improve the performance of LIBs. PMID- 29603416 TI - Point-Defect-Passivated MoS2 Nanosheet-Based High Performance Piezoelectric Nanogenerator. AB - In this work, a sulfur (S) vacancy passivated monolayer MoS2 piezoelectric nanogenerator (PNG) is demonstrated, and its properties before and after S treatment are compared to investigate the effect of passivating S vacancy. The S vacancies are effectively passivated by using the S treatment process on the pristine MoS2 surface. The S vacancy site has a tendency to covalently bond with S functional groups; therefore, by capturing free electrons, a S atom will form a chemisorbed bond with the S vacancy site of MoS2 . S treatment reduces the charge carrier density of the monolayer MoS2 surface, thus the screening effect of piezoelectric polarization charges by free carrier is significantly prevented. As a result, the output peak current and voltage of the S-treated monolayer MoS2 nanosheet PNG are increased by more than 3 times (100 pA) and 2 times (22 mV), respectively. Further, the S treatment increases the maximum power by almost 10 times. The results suggest that S treatment can reduce free-charge carrier by sulfur S passivation and efficiently prevent the screening effect. Thus, the piezoelectric output peaks of current, voltage, and maximum power are dramatically increased, as compared with the pristine MoS2 . PMID- 29603417 TI - Antimicrobial activity of preparations after combined cultivation of lactic acid bacteria and yeast strains. AB - Use of antimicrobials in both human and animal populations over the past several decades has led to the emergence of multidrug-resistant bacteria populations that are resistant to many commercially available drugs. For example, acquired resistance to first-line antimicrobial agents increasingly complicates the management of extra-intestinal infections due to Escherichia coli, which are a major source of illness and death. The continued development of new classes of natural antimicrobial agents, possessing antibacterial activity, has become of increasing importance for medicine and veterinary. So, selection of lactic acid bacteria and yeast strains for their combined cultivation with the aim of increasing of the activity is topical. It was shown that during combined cultivation of the lactic acid bacteria with probiotic properties and yeast strains, antimicrobial activity depends on the genus and species to which the strain of lactic acid bacteria and yeast belongs. They inhibited the growth of multidrug-resistant bacteria with better efficiency. Increasing of the antimicrobial activity can be explained by the synergetic effect of products of cultures metabolism and by interaction between lactic acid bacteria cells with the cell wall of yeasts. Our data showed perspectives of combined cultivation of yeast and lactic acid bacteria for creation of a new class of antimicrobial preparations with high antibacterial activity and broad spectrum of action. Preparation can be recommended for treatment of animals. PMID- 29603418 TI - High-Gain 200 ns Photodetectors from Self-Aligned CdS-CdSe Core-Shell Nanowalls. AB - 1D core-shell heterojunction nanostructures have great potential for high performance, compact optoelectronic devices owing to their high interface area to volume ratio, yet their bottom-up assembly toward scalable fabrication remains a challenge. Here the site-controlled growth of aligned CdS-CdSe core-shell nanowalls is reported by a combination of surface-guided vapor-liquid-solid horizontal growth and selective-area vapor-solid epitaxial growth, and their integration into photodetectors at wafer-scale without postgrowth transfer, alignment, or selective shell-etching steps. The photocurrent response of these nanowalls is reduced to 200 ns with a gain of up to 3.8 * 103 and a photoresponsivity of 1.2 * 103 A W-1 , the fastest response at such a high gain ever reported for photodetectors based on compound semiconductor nanostructures. The simultaneous achievement of sub-microsecond response and high-gain photocurrent is attributed to the virtues of both the epitaxial CdS-CdSe heterojunction and the enhanced charge-separation efficiency of the core-shell nanowall geometry. Surface-guided nanostructures are promising templates for wafer-scale fabrication of self-aligned core-shell nanostructures toward scalable fabrication of high-performance compact photodetectors from the bottom-up. PMID- 29603419 TI - Prognostic implications of fibroblast growth factor receptor 4 polymorphisms in primary breast cancer. AB - Fibroblast growth factor receptor 4 (FGFR4) belongs to the receptor tyrosine kinase (RTK) family, and FGFR4 polymorphisms have been implicated in both normal development and cancer, including breast cancer. In the present study, we investigated correlations between polymorphisms in FGFR4 and breast cancer prognosis. The FGFR4 SNPs rs1966265 and rs351855 were genotyped in 747 breast cancer patients using the SNaPshot method. FGFR4 protein expression was detected by immunohistochemistry in 339 samples. SNP rs351855 was correlated with FGFR4 protein expression under dominant and co-dominant models. Lymph node metastasis (LNM), ER (estrogen receptor) status, and molecular subtype were associated with high FGFR4 expression. Univariate analysis revealed rs351855 (CC/CT: P = 0.027, CC/TT: P < 0.001, CC/CT + TT: P = 0.005) to be a prognostic predictor, and multivariate analysis indicated rs351855 (CC/TT: P = 0.005) to be an independent prognostic factor. Kaplan-Meier survival analysis showed that high FGFR4 protein expression was associated with a poor prognosis. SNP rs351855 was correlated with worse outcomes, with a dose-dependent effect. The results of this study show that FGFR4 SNP rs351855 is associated with up-regulation of FGFR4 protein expression and a worse prognosis in breast cancer. PMID- 29603420 TI - Kirigami-Inspired Nanoconfined Polymer Conducting Nanosheets with 2000% Stretchability. AB - Stretchable conductors are essential components of wearable electronics. However, such materials typically sacrifice their electronic conductivity to achieve mechanical stretchability and elasticity. Here, the nanoconfinement and air/water interfacial assembly is explored to grow freestanding mechanical endurance conducting polymer nanosheets that can be stretched up to 2000% with simultaneously high electrical conductivity, inspired by kirigami. Such stretchable conductors show remarkable electronic and mechanical reversibility and reproducibility under more than 1000 cycle durability tests with 2000% deformability, which can be accurately predicted using finite element modeling. The conductivity of nanoconfined freestanding conductor nanosheets increases by three orders of magnitude from 2.2 * 10-3 to 4.002 S cm-1 is shown, due to the charge-transfer complex formation between polymer chain and halogen, while the electrical conductance of the stretchable kirigami nanosheets can be maintained over the entire strain regime. The nanoconfined polymer nanosheets can also act as a sensor capable of sensing the pressure with high durability and real-time monitoring. PMID- 29603421 TI - Molecule-Doped Nickel Oxide: Verified Charge Transfer and Planar Inverted Mixed Cation Perovskite Solar Cell. AB - Both conductivity and mobility are essential to charge transfer by carrier transport layers (CTLs) in perovskite solar cells (PSCs). The defects derived from generally used ionic doping method lead to the degradation of carrier mobility and parasite recombinations. In this work, a novel molecular doping of NiOx hole transport layer (HTL) is realized successfully by 2,2' (perfluoronaphthalene-2,6-diylidene)dimalononitrile (F6TCNNQ). Determined by X ray photoelectron spectroscopy and ultraviolet photoelectron spectroscopy, the Fermi level (EF ) of NiOx HTLs is increased from -4.63 to -5.07 eV and valence band maximum (VBM)-EF declines from 0.58 to 0.29 eV after F6TCNNQ doping. The energy level offset between the VBMs of NiOx and perovskites declines from 0.18 to 0.04 eV. Combining with first-principle calculations, electrostatic force microscopy is applied for the first time to verify direct electron transfer from NiOx to F6TCNNQ. The average power conversion efficiency of CsFAMA mixed cation PSCs is boosted by ~8% depending on F6TCNNQ-doped NiOx HTLs. Strikingly, the champion cell conversion efficiency of CsFAMA mixed cations and MAPbI3 -based devices gets to 20.86% and 19.75%, respectively. Different from passivation effect, the results offer an extremely promising molecular doping method for inorganic CTLs in PSCs. This methodology definitely paves a novel way to modulate the doping in hybrid electronics more than perovskite and organic solar cells. PMID- 29603422 TI - 3D Printing of Bioinspired Liquid Superrepellent Structures. AB - Bioinspired re-entrant structures have been proved to be effective in achieving liquid superrepellence (including anti-penetration, anti-adhesion, and anti spreading). However, except for a few reports relying on isotropic etching of silicon wafers, most fluorination-dependent surfaces are still unable to repel liquids with extreme low surface energy (i.e., gamma < 15 mN m-1 ), especially those fluorinated solvents. Herein, triply re-entrant structures, possessing superrepellence to water (with surface tension gamma of 72.8 mN m-1 ) and various organic liquids (gamma = 12.0-27.1 mN m-1 ), are fabricated via two-photon polymerization based 3D printing technology. Such structures can be constructed both on rigid and flexible substrates, and the liquid superrepellent properties can be kept even after oxygen plasma treatment. Based on the prepared triply re entrant structures, micro open capillaries are constructed on them to realize directional liquid spreading, which may be applied in microfluidic platforms and lab-on-a-chip applications. The fabricated arrays can also find potential applications in electronic devices, gas sensors, microchemical/physical reactors, high-throughput biological sensors, and optical displays. PMID- 29603423 TI - Polarization Encoded Color Image Embedded in a Dielectric Metasurface. AB - Optical metasurfaces have shown unprecedented capabilities in the local manipulation of the light's phase, intensity, and polarization profiles, and represent a new viable technology for applications such as high-density optical storage, holography and display. Here, a novel metasurface platform is demonstrated for simultaneously encoding color and intensity information into the wavelength-dependent polarization profile of a light beam. Unlike typical metasurface devices in which images are encoded by phase or amplitude modulation, the color image here is multiplexed into several sets of polarization profiles, each corresponding to a distinct color, which further allows polarization modulation-induced additive color mixing. This unique approach features the combination of wavelength selectivity and arbitrary polarization control down to a single subwavelength pixel level. The encoding approach for polarization and color may open a new avenue for novel, effective color display elements with fine control over both brightness and contrast, and may have significant impact for high-density data storage, information security, and anticounterfeiting. PMID- 29603424 TI - A Nonaqueous Potassium-Based Battery-Supercapacitor Hybrid Device. AB - A low cost nonaqueous potassium-based battery-supercapacitor hybrid device (BSH) is successfully established for the first time with soft carbon as the anode, commercialized activated carbon as the cathode, and potassium bis(fluoro slufonyl)imide in dimethyl ether as the electrolyte. This BSH reconciles the advantages of potassium ion batteries and supercapacitors, achieving a high energy density of 120 W h kg-1 , a high power density of 599 W kg-1 , a long cycle life of 1500 cycles, and an ultrafast charge/slow discharge performance (energy density and power density are calculated based on the total mass of active materials in the anode and cathode). This work demonstrates a great potential of applying the nonaqueous BSH for low cost electric energy storage systems. PMID- 29603425 TI - Tetraphenylethylene-Interweaving Conjugated Macrocycle Polymer Materials as Two Photon Fluorescence Sensors for Metal Ions and Organic Molecules. AB - A luminescent conjugated macrocycle polymer (CMP) with strong two-photon fluorescence property, namely, P[5]-TPE-CMP, is constructed from ditriflate functionalized pillar[5]arene and a 1,1,2,2-tetrakis(4-ethynylphenyl)ethylene (TPE) linker through a Sonogashira-Hagihara cross-coupling reaction. Significantly, in sharp contrast with the corresponding conjugated microporous polymer without synthetic macrocycles, P[5]-TPE-CMP shows an outstanding stability against photobleaching and exhibits highly selective cation sensing capability toward Fe3+ at different excitation wavelengths (both UV and red-near infrared regions). Meanwhile, its fluorescence could also be sufficiently quenched by 4-amino azobenzene, a frequently used organic dye that is certified to be carcinogenic, as compared with a group of common organic compounds. This work paves a new way for enhancing the properties of porous organic polymers through the introduction of supramolecular macrocycles like macrocyclic arenes. PMID- 29603426 TI - Improved Conventional PCR Assay for Detecting Tetracapsuloides bryosalmonae DNA in Fish Tissues. AB - Conventional PCR is an established method to detect Tetracapsuloides bryosalmonaeDNA in fish tissues and to confirm diagnosis of proliferative kidney disease (PKD) caused by T. bryosalmonae. However, the commonly used PKX5f-6r primers were designed with the intention of obtaining sequence information and are suboptimal for determining parasite DNA presence. A new PCR assay to detect T. bryosalmonae 18s rDNA, PKX18s1266f-1426r, is presented that demonstrates specificity, repeatability, and enhanced sensitivity over the PKX5f-6r assay. The limit of detection of the PKX18s1266f-1426r assay at 95% confidence was 100 template copies, and the new primers detected parasite DNA more consistently at template concentrations below 100 copies than did PKX5f-6r. The PKX18s1266f-1426r also achieved 100% detection at sample DNA concentrations one order of magnitude lower than PKX5f-6r. Out of 127 salmonid fish with unknown T. bryosalmonae infection status, PKX5f-6r detected 35 positive samples, while the new assay detected 43. The discrepancy in T. bryosalmonae detection between the two primer sets may be attributed to several differences between the assays, including oligonucleotide melting temperatures, the use of a touchdown PCR thermal cycle, and amplicon length. PMID- 29603427 TI - Efficient Hydrogen Evolution Reaction Catalysis in Alkaline Media by All-in-One MoS2 with Multifunctional Active Sites. AB - MoS2 becomes an efficient and durable nonprecious-metal electrocatalyst for the hydrogen evolution reaction (HER) when it contains multifunctional active sites for water splitting derived from 1T-phase, defects, S vacancies, exposed Mo edges with expanded interlayer spacings. In contrast to previously reported MoS2 -based catalysts targeting only a single or few of these characteristics, the all-in-one MoS2 catalyst prepared herein features all of the above active site types. During synthesis, the intercalation of in situ generated NH3 molecules into MoS2 sheets affords ammoniated MoS2 (A-MoS2 ) that predominantly comprises 1T-MoS2 and exhibits an expanded interlayer spacing. The subsequent reduction of A-MoS2 results in the removal of intercalated NH3 and H2 S to form an all-in-one MoS2 with multifunctional active sites mentioned above (R-MoS2 ) that exhibits electrocatalytic HER performance in alkaline media superior to those of all previously reported MoS2 -based electrocatalysts. In particular, a hybrid MoS2 /nickel foam catalyst outperforms commercial Pt/C in the practically meaningful high-current region (>25 mA cm-2 ), demonstrating that R-MoS2 -based materials can potentially replace Pt catalysts in practical alkaline HER systems. PMID- 29603428 TI - Retrospective analysis of frontline treatment efficacy in elderly patients with diffuse large B-cell lymphoma. AB - OBJECTIVES: To investigate the effectiveness of 2 chemotherapeutic regimens, bendamustine plus rituximab (BR) or reduced-dose cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab (RD-R-CHOP), in elderly patients with treatment-naive diffuse large B-cell lymphoma. METHODS: A retrospective study was conducted to investigate the efficacy and safety of 2 frontline regimens, BR and RD-R-CHOP, in patients aged >=75 years unfit for R-CHOP. RESULTS: From January 2011 to December 2015, 26 patients received BR and 34 RD-R-CHOP. No significant difference was found in clinical background comparisons. The overall response rate was 50% and 79.4% for BR and RD-R-CHOP, respectively (P = .027). Compared with patients in RD-R-CHOP, those in BR had a lower complete remission rate (42.3% vs 70.6%, P = .036), higher progressive disease rate (38.5% vs 8.8%, P = .01), and poorer median overall survival (11.2 months vs 39 months, P = .035). The prognostic difference was mainly observed in patients with limited stage. By contrast, BR had better toxic profiles. Some patients in BR certainly showed long term survivals. CONCLUSIONS: This study demonstrated better efficacy of RD-R CHOP, indicating its administration might be considered whenever possible, especially for limited stage. However, BR is a reasonable alternative for those ineligible for anthracycline-containing regimens. Further studies are needed to guide treatment decisions. PMID- 29603429 TI - Synthetic Biology Makes Polymer Materials Count. AB - Synthetic biology applies engineering concepts to build cellular systems that perceive and process information. This is achieved by assembling genetic modules according to engineering design principles. Recent advance in the field has contributed optogenetic switches for controlling diverse biological functions in response to light. Here, the concept is introduced to apply synthetic biology switches and design principles for the synthesis of multi-input-processing materials. This is exemplified by the synthesis of a materials system that counts light pulses. Guided by a quantitative mathematical model, functional synthetic biology-derived modules are combined into a polymer framework resulting in a biohybrid materials system that releases distinct output molecules specific to the number of input light pulses detected. Further demonstration of modular extension yields a light pulse-counting materials system to sequentially release different enzymes catalyzing a multistep biochemical reaction. The resulting smart materials systems can provide novel solutions as integrated sensors and actuators with broad perspectives in fundamental and applied research. PMID- 29603430 TI - Diatomite-Templated Synthesis of Freestanding 3D Graphdiyne for Energy Storage and Catalysis Application. AB - Graphdiyne (GDY), a new kind of two-dimensional (2D) carbon allotropes, has extraordinary electrical, mechanical, and optical properties, leading to advanced applications in the fields of energy storage, photocatalysis, electrochemical catalysis, and sensors. However, almost all reported methods require metallic copper as a substrate, which severely limits their large-scale application because of the high cost and low specific surface area (SSA) of copper substrate. Here, freestanding three-dimensional GDY (3DGDY) is successfully prepared using naturally abundant and inexpensive diatomite as template. In addition to the intrinsic properties of GDY, the fabricated 3DGDY exhibits a porous structure and high SSA that enable it to be directly used as a lithium-ion battery anode material and a 3D scaffold to create Rh@3DGDY composites, which would hold great potential applications in energy storage and catalysts, respectively. PMID- 29603431 TI - Durability of the hepatitis B vaccination in pediatric renal transplant recipients. AB - Since hepatitis B virus (HBV) vaccine implementation, HBV infection has significantly decreased. However, adult renal transplant recipients show a higher rate of seroreversion compared to the general population, leading to HBV infection risk. Data are limited in pediatric renal transplant recipients. Retrospective data were collected to determine the seroprotection and durability of HBV vaccination in pediatric renal transplant patients from 2004 to 2014. One hundred subjects were categorized based on pre- and post-transplant hepatitis B surface antibody (HBsAb). Pretransplant, 85 recipients (85%) had a positive HBsAb compared to 15 (15%) with negative HBsAb. In univariable analyses, other than age (P < .05) no significant differences existed pretransplant by demographics, pretransplantation dialysis, or number of vaccinations. Of the 85 pretransplantation responders, 53 (62%) remained HBsAb positive post transplantation, 28 (32%) seroreverted, and 4 developed indeterminate titers. All seroreversions occurred within 5 years post-transplant. Receipt of a living donor organ had higher risk of reversion (P = .005). No significant differences were found in demographics, pretransplantation dialysis, vaccination number, or acute rejection. Despite vaccination, 15% of pediatric renal transplant candidates were seronegative, and an additional 32% lost seroprotection within 5 years post transplantation leaving nearly half of transplant recipients at risk for HBV infection. PMID- 29603432 TI - In vitro epidermis model mimicking IGF-1-specific age-related decline. AB - Ageing is a complex multifaceted process affecting skin functionality and structure. Several 3D organotypic skin culture models have reproduced ageing by inducing replicative senescence, glycation or oxidative stress. Yet, very few models have focused on hormonal ageing and especially the insulin-like growth factor 1 (IGF-1) signalling pathway, which has been associated with longevity in animal studies and is necessary for the early stages of skin development. In this study, we built an organotypic epidermis model with targeted IGF-1 receptor knockdown to reproduce some aspects of hormonal ageing on skin. Our model displayed morphological and functional features of aged epidermis, which were mostly attributed to a loss of function of the Stratum basale. IGF-1 receptor knockdown keratinocytes depicted an extended cell cycle, reduced proliferation potential and reduced adhesion capacities and greater sensitivity to oxidative stress than control cells. Altogether, this model represents an essential tool for further investigations into the mechanisms linked to some aspects of hormonal decline or when screening for potent anti-ageing compounds. PMID- 29603433 TI - Supplementation with sunflower seeds in beef cattle did not impact on oocyte and in vitro embryo production. AB - Supplementation with compounds rich in linoleic acid, including sunflower seed supplementation, promotes increase in conception rates in cows. We aimed to evaluate whether the sunflower seed (linoleic acid source) supplementation in beef donor females alters the plasma concentrations of cholesterol, triglycerides, HDL and LDL, increases the number and quality of oocytes, increases the cleavage rates and determines an improvement in number and quality of in vitro produced blastocysts. Thus, Nelore females were divided into two groups of 15 animals to receive supplementation with or without sunflower seed for 57 days. Females underwent follicular aspiration and the oocytes were subjected to in vitro embryo production. There was no difference (p > .1) between control group and group supplemented with sunflower seed on the number of displayed follicles; number of aspired oocytes; recovery rate; cleavage rate; number of embryos; number of blastocysts; embryos number of grades I and II; plasma concentrations of total cholesterol, triglycerides; HDL and LDL. Therefore, sunflower seed supplementation in oocyte donors did not increase the number and quality of oocytes, cleavage rates and the number and quality of blastocysts produced in vitro. PMID- 29603434 TI - Differences in in vivo muscle fascicle and tendinous tissue behavior between the ankle plantarflexors during running. AB - The primary human ankle plantarflexors, soleus (SO), medial gastrocnemius (MG), and lateral gastrocnemius (LG) are typically regarded as synergists and play a critical role in running. However, due to differences in muscle-tendon architecture and joint articulation, the muscle fascicles and tendinous tissue of the plantarflexors may exhibit differences in their behavior and interactions during running. We combined in vivo dynamic ultrasound measurements with inverse dynamics analyses to identify and explain differences in muscle fascicle, muscle tendon unit, and tendinous tissue behavior of the primary ankle plantarflexors across a range of steady-state running speeds. Consistent with their role as a force generator, the muscle fascicles of the uniarticular SO shortened less rapidly than the fascicles of the MG during early stance. Furthermore, the MG and LG exhibited delays in tendon recoil during the stance phase, reflecting their ability to transfer power and work between the knee and ankle via tendon stretch and storage of elastic strain energy. Our findings add to the growing body of evidence surrounding the distinct mechanistic functions of uni- and biarticular muscles during dynamic movements. PMID- 29603435 TI - Strongly Coupled Tin-Halide Perovskites to Modulate Light Emission: Tunable 550 640 nm Light Emission (FWHM 36-80 nm) with a Quantum Yield of up to 6.4. AB - Colloidal perovskite quantum dots represent one of the most promising materials for applications in solar cells and photoluminescences. These devices require a low density of crystal defects and a high yield of photogenerated carriers, which are difficult to realize in tin-halide perovskite because of the intrinsic instability of tin during nucleation. Here, an enhancement in the luminescent property of tin-halide perovskite nanoplates (TPNPs) that are composed of strongly coupled layered structures with the chemical formula of PEA2 SnX4 (PEA = C6 H5 (CH2 )2 NH3 , X = Br, I) is reported. TPNPs (X = I) show an emission at a wavelength of 640 nm, with high quantum yield of 6.40 +/- 0.14% and full width at half maximum (FWHM) as small as 36 nm. The presence of aliphatic carboxylic acid is found to play a key role in reducing the tin perovskite defect density, which significantly improves the emission intensity and stability of TPNPs. Upon mixing iodo- and bromo- precursors, the emission wavelength is successfully tuned from 640 nm (PEA2 SnI4 ) to 550 nm (PEA2 SnBr4 ), with a corresponding emission quantum yield and FWHM of 0.16-6.40% and 36-80 nm, respectively. The results demonstrate a major advance for the emission yield and tunability of tin-halide perovskites. PMID- 29603437 TI - Plasticizing Silk Protein for On-Skin Stretchable Electrodes. AB - Soft and stretchable electronic devices are important in wearable and implantable applications because of the high skin conformability. Due to the natural biocompatibility and biodegradability, silk protein is one of the ideal platforms for wearable electronic devices. However, the realization of skin-conformable electronic devices based on silk has been limited by the mechanical mismatch with skin, and the difficulty in integrating stretchable electronics. Here, silk protein is used as the substrate for soft and stretchable on-skin electronics. The original high Young's modulus (5-12 GPa) and low stretchability (<20%) are tuned into 0.1-2 MPa and > 400%, respectively. This plasticization is realized by the addition of CaCl2 and ambient hydration, whose mechanism is further investigated by molecular dynamics simulations. Moreover, highly stretchable (>100%) electrodes are obtained by the thin-film metallization and the formation of wrinkled structures after ambient hydration. Finally, the plasticized silk electrodes, with the high electrical performance and skin conformability, achieve on-skin electrophysiological recording comparable to that by commercial gel electrodes. The proposed skin-conformable electronics based on biomaterials will pave the way for the harmonized integration of electronics into human. PMID- 29603436 TI - Substitutional Carbon-Modified Anatase TiO2 Decahedral Plates Directly Derived from Titanium Oxalate Crystals via Topotactic Transition. AB - Changing the composition and/or structure of some metal oxides at the atomic level can significantly improve their performance in different applications. Although many strategies have been developed, the introduction of heteroatoms, particularly anions to the internal part of metal oxide particles, is still not adequate. Here, an effective strategy is demonstrated for directly preparing polycrystalline decahedral plates of substitutional carbon-doped anatase TiO2 from titanium (IV) oxalate by a thermally induced topotactic transition in an inert atmosphere. Because of the carbon concentration gradient introduced in side of the plates, the carbon-doped TiO2 (TiO2-x Cx ) shows an increased visible light absorption and a two orders of magnitude higher electrical conductivity than pure TiO2 . Consequently, it can be used as a photocatalyst and an active material for lithium storage and shows much superior activity in generating hydroxyl radicals under visible light and greatly increased electrical-specific capacity at high charge-discharge rates. The strategy developed could also be applicable to the atomic-scale modification of other metal oxides. PMID- 29603438 TI - Anti-Muellerian hormone concentration in bitches with histopathologically diagnosed ovarian tumours and cysts. AB - Increased concentrations of Anti-Muellerian hormone (AMH) can indicate a granulosa cell tumour as shown in women, mares and cows. To investigate AMH to differentiate canine granulosa cell tumour from other ovarian pathologies, we evaluated the ovaries of 63 bitches. Blood serum samples were collected before surgery for AMH analysis. Ovaries were submitted for histopathological examination. Fourteen bitches showed normal ovaries. These bitches had AMH values between 0.12 and 0.99 ng/ml. In 20 bitches ovarian cysts i.e., follicular cysts (n = 8), corpora lutea cysts (n = 7), subsurface cysts (n = 5) were diagnosed. These dogs had AMH values of 0.11-2.09 ng/ml. Bitches with small luteinized follicular cysts had slightly higher AMH values than those without ovarian alteration. In 29 cases ovarian neoplasms i.e., granulosa cell tumour (n = 9), epithelial tumours (n = 16), dysgerminomas (n = 3) and one sarcoma were identified. Anti-Muellerian hormone values of bitches with an ovarian neoplasm except granulosa cell tumour ranged from 0.18 to 1.18 ng/ml. The AMH values of bitches with granulosa cell tumour ranged from 1.12 to <=23 ng/ml and were significantly higher (p < .05) than in all of the other bitches. The cut-off of 0.99 ng/ml gave a sensitivity of 100% and a specificity of 94.44% to diagnose granulosa cell tumour. In conclusion, markedly elevated AMH concentrations in bitches are indicative for a granulosa cell tumour. However, negative testing does not rule out the existence of small one. Differentiation of GCT from luteinized follicular cysts may especially be difficult. PMID- 29603439 TI - Deciphering the Mechanism of Human Carbonic Anhydrases Inhibition with Sulfocoumarins: Computational and Experimental Studies. AB - The reaction mechanism of the carbonic anhydrase-mediated hydrolysis of sulfocoumarins to sulfonic acids has been investigated on an enzyme cluster model using the B3LYP hybrid density functional theory (DFT) and the QST procedure for the Transition State (TS) search. A multistep process was highlighted, with the rate-determining step identified in the initial dual nucleophilic/acidic attack of the zinc-bound hydroxide ion to the sulfocoumarin sulfur atom and to the C3=C4 double bond. The reported multi-step process, combined to SAR analysis on a new set of derivatives, highlighted unprecedented mechanistic aspects of the CA mediated prodrug activation, which in turn possess relevant consequences to the isoforms-selective inhibition profiles reported by such a class of compounds. PMID- 29603440 TI - Role of oxytocin in parental behaviour. AB - Both animal and human studies have provided conclusive evidence that oxytocin (OXT) acts in the brain (eg, medial preoptic area, ventral tegmental area, nucleus accumbens) to promote parental behaviour under different reproductive and physiological conditions. OXT appears to accelerate and strengthen the neural process that makes newborns attractive or rewarding. Furthermore, OXT reduces stress/anxiety and might improve mood and well being, resulting in indirect benefits for parents. However, OXT also plays a role in the development of species reproductive and social strategies, making some species or individuals more prone to display caring activities in nonreproductive contexts. There are important differences in the development of the OXT system and its regulation by gonadal hormones that can make individuals or species very different. Those intra and interspecific differences in the OXT system have been associated with differences in parental behaviour. For example, differences in OXT levels in body fluids and genetic variants for the OXT and OXT receptor genes have been associated with variability in parental mood and behaviour in humans. Thus, OXT has received much attention as a potential therapeutic agent for affective, emotional and behavioural problems. Despite many preliminary studies indicating promising findings, several unknown aspects of the OXT system remain to be addressed before we can achieve a complete understanding of its function in the brain. The enormous interest that this area of study has attracted in the last decade will likely continually contribute to advancing our understanding of the role of OXT in parental behaviour and other behavioural and physiological functions. PMID- 29603441 TI - Cell-Penetrating Peptides Containing Fluorescent d-Cysteines. AB - A series of fluorescent d-cysteines (Cys) has been synthesized and their optical properties were studied. The key synthetic step is the highly diastereoselective 1,4-conjugate addition of aryl thiols to a chiral bicyclic dehydroalanine recently developed by our group. This reaction is fast at room temperature and proceeds with total chemo- and stereoselectivity. The Michael adducts were easily transformed into the corresponding amino acids to study their optical properties and, in some selected cases, into the corresponding N-Fmoc-d-cysteine derivatives to be used in solid-phase peptide synthesis (SPPS). To further demonstrate the utility of these non-natural Cys-derived fluorescent amino acids, the coumaryl and dansyl derivatives were incorporated into cell-penetrating peptide sequences through standard SPPS and their optical properties were studied in different cell lines. The internalization of these fluorescent peptides was monitored by fluorescence microscopy. PMID- 29603442 TI - Co-evolution with recombination affects the stability of mobile genetic element insertions within gene families of Salmonella. AB - Bacteria can have multiple copies of a gene at separate locations on the same chromosome. Some of these gene families, including tuf (translation elongation factor EF-Tu) and rrl (ribosomal RNA), encode functions critically important for bacterial fitness. Genes within these families are known to evolve in concert using homologous recombination to transfer genetic information from one gene to another. This mechanism can counteract the detrimental effects of nucleotide sequence divergence over time. Whether such mechanisms can also protect against the potentially lethal effects of mobile genetic element insertion is not well understood. To address this we constructed two different length insertion cassettes to mimic mobile genetic elements and inserted these into various positions of the tuf and rrl genes. We measured rates of recombinational repair that removed the inserted cassette and studied the underlying mechanism. Our results indicate that homologous recombination can protect the tuf and rrl genes from inactivation by mobile genetic elements, but for insertions within shorter gene sequences the efficiency of repair is very low. Intriguingly, we found that physical distance separating genes on the chromosome directly affects the rate of recombinational repair suggesting that relative location will influence the ability of homologous recombination to maintain homogeneity. PMID- 29603443 TI - A Versatile Colorimetric Probe based on Thiosemicarbazide-Amine Proton Transfer. AB - There is significant interest in the rapid and efficient detection of amines, which are widely used in different industries and also serve as markers in many biological processes. This work reports that the coupling of a thiosemicarbazide binding motif and a naphthalimide-based chromophore affords highly sensitive sensor molecules, which can indicate the presence of amines with a pronounced and readily visible color change. It was demonstrated that the binding mechanism involves a proton transfer from the thiosemicarbazide to the analyte. This process renders the mechanism highly sensitive and broadly exploitable. The potential usefulness of the sensor is demonstrated by fabricating an indicator paper, which allows for the detection of volatile amines at concentrations as low as ca. 10 ppm. PMID- 29603444 TI - Femoral vascular conductance and peroneal muscle sympathetic nerve activity responses to acute epidural spinal cord stimulation in humans. AB - NEW FINDINGS: What is the central question of this research? Does acute spinal cord stimulation increase vascular conductance and decrease muscle sympathetic nerve activity in the lower limbs of humans? What is the main finding and its importance? Acute spinal cord stimulation led to a rapid rise in femoral vascular conductance, and peroneal muscle sympathetic nerve activity demonstrated a delayed reduction that was not associated with the initial increase in femoral vascular conductance. These findings suggest that neural mechanisms in addition to attenuated muscle sympathetic nerve activity might be involved in the initial increase in femoral vascular conductance during acute spinal cord stimulation. ABSTRACT: Clinical cases have indicated an increase in peripheral blood flow after continuous epidural spinal cord stimulation (SCS) and that reduced muscle sympathetic nerve activity (MSNA) might be a potential mechanism. However, no studies in humans have directly examined the effects of acute SCS (<60 min) on vascular conductance and MSNA. In study 1, we tested the hypothesis that acute SCS (<60 min) of the thoracic spine would lead to increased common femoral vascular conductance, but not brachial vascular conductance, in 11 patients who previously underwent surgical SCS implantation for management of neuropathic pain. Throughout 60 min of SCS, common femoral artery conductance was elevated and significantly different from brachial artery conductance [in millilitres per minute: 15 min, change (Delta) 26 +/- 37 versus Delta-2 +/- 19%; 30 min, Delta28 +/- 45 versus Delta0 +/- 26%; 45 min, Delta48 +/- 43 versus Delta2 +/- 21%; 60 min, Delta36 +/- 61 versus Delta1 +/- 24%; and 15 min post-SCS, Delta51 +/- 64 versus Delta6 +/- 33%; P = 0.013]. A similar examination in a patient with cervical SCS revealed minimal changes in vascular conductance. In study 2, we examined whether acute SCS reduces peroneal MSNA in a subset of SCS patients (n = 5). The MSNA burst incidence in response to acute SCS gradually declined and was significantly reduced at 45 and 60 min of SCS (in bursts per 100 heart beats: 15 min, Delta-1 +/- 12%; 30 min, Delta-14 +/- 12%; 45 min, Delta-19 +/- 16%; 60 min, Delta-24 +/- 18%; and 15 min post-SCS: Delta-11 +/- 7%; P = 0.015). These data demonstrate that acute SCS rapidly increases femoral vascular conductance and reduces peroneal MSNA. The gradual reduction in peroneal MSNA observed during acute SCS suggests that neural mechanisms in addition to attenuated MSNA might be involved in the acute increase in femoral vascular conductance. PMID- 29603445 TI - Pb-Sn-Cu Ternary Organometallic Halide Perovskite Solar Cells. AB - Exploiting organic/inorganic hybrid perovskite solar cells (PSCs) with reduced Pb content is very important for developing environment-friendly photovoltaics. Utilizing of Pb-Sn alloying perovskite is considered as an efficient route to reduce the risk of ecosystem pollution. However, the trade-off between device performance and Sn substitution ratio due to the instability of Sn2+ is a current dilemma. Here, for the first time, the highly efficient Pb-Sn-Cu ternary PSCs are reported by partial replacing of PbI2 with SnI2 and CuBr2 . Sn2+ substitution results in a redshift of the absorption onset, whereas worsens the film quality. Interestingly, Cu2+ introduction can passivate the trap sites at the crystal boundaries of Pb-Sn perovskites effectively. Consequently, a power conversion efficiency as high as 21.08% in inverted planar Pb-Sn-Cu ternary PSCs is approached. The finding opens a new route toward the fabrication of high efficiency Pb-Sn alloying perovskite solar cells by Cu2+ passivation. PMID- 29603446 TI - Understanding the mode of binding mechanism of doripenem to human serum albumin: Spectroscopic and molecular docking approaches. AB - The infections caused by multidrug resistant bacteria are widely treated with carabapenem antibiotics as a drug of choice, and human serum albumin (HSA) plays a vital role in binding with drugs and affecting its rate of delivery and efficacy. So, we have initiated this study to characterize the mechanism of doripenem binding and to locate its site of binding on HSA by using spectroscopic and docking approaches. The binding of doripenem leads to alteration of the environment surrounding Trp-214 residue of HSA as observed by UV spectroscopic study. Fluorescence spectroscopic study revealed considerable interaction and complex formation of doripenem and HSA as indicated by Ksv and Kq values of the order of 104 M-1 and 1012 M-1 s-1 , respectively. Furthermore, doripenem quenches the fluorescence of HSA spontaneously on a single binding site with binding constant of the order of 103 M-1 , through an exothermic process. Van der Waals forces and hydrogen bonding are the major forces operating to stabilize HSA-doripenem complex. Circular dichroism spectroscopic study showed changes in the structure of HSA upon doripenem binding. Drug displacement and molecular docking studies revealed that the binding site of doripenem on HSA is located on subdomain IB and III A. This study concludes that, due to significant interaction of doripenem on either subdomain IB or IIIA of HSA, the availability of doripenem on the target site may be compromised. Hence, there is a possibility of unavailability of threshold amount of drug to be reached to the target; consequently, resistance may develop in the bacterial population. PMID- 29603447 TI - Chemically Tunable Formation of Different Discrete, Oligomeric, and Polymeric Self-Assembled Structures from Digold Metallotweezers. AB - Digold metallotweezers whose complex supramolecular landscape is controlled by adding a series of metal cations are described. The metallotweezers have a strong tendency to form interesting supramolecular structures on addition of Tl+ , Ag+ , and Cu+ . The choice of the cation can be used to direct the formation of a designated molecular architecture. The addition of thallium facilitates the formation of a self-aggregated duplex structure in which the cation occupies the cavity of the dimer. The same type of structure is formed when Cu+ is added, and the resulting duplex inclusion complex shows interesting vapochromic properties. This copper-encapsulating system evolves in solution to a 1D helical supramolecular polymer showing multiple aurophilic and Au???Cu interactions, in which the copper cation is bound to several alkynyl ligands of the tweezer. The addition of a small amount of silver cations to the digold tweezer yields a similar type of inclusion dimer complex, but adding an excess of the cation produces new discrete molecules presumably exhibiting multiple Au???Au, Au???Ag, and Ag???Ag metallophilic interactions. The differences in the supramolecular structures formed are ascribed to the different tendencies of the metal cations to exhibit interactions with the gold atoms and to coordinate to the alkynyl ligands of the tweezer. PMID- 29603448 TI - Stimuli-Driven Control of the Helical Axis of Self-Organized Soft Helical Superstructures. AB - Supramolecular and macromolecular functional helical superstructures are ubiquitous in nature and display an impressive catalog of intriguing and elegant properties and performances. In materials science, self-organized soft helical superstructures, i.e., cholesteric liquid crystals (CLCs), serve as model systems toward the understanding of morphology- and orientation-dependent properties of supramolecular dynamic helical architectures and their potential for technological applications. Moreover, most of the fascinating device applications of CLCs are primarily determined by different orientations of the helical axis. Here, the control of the helical axis orientation of CLCs and its dynamic switching in two and three dimensions using different external stimuli are summarized. Electric-field-, magnetic-field-, and light-irradiation-driven orientation control and reorientation of the helical axis of CLCs are described and highlighted. Different techniques and strategies developed to achieve a uniform lying helix structure are explored. Helical axis control in recently developed heliconical cholesteric systems is examined. The control of the helical axis orientation in spherical geometries such as microdroplets and microshells fabricated from these enticing photonic fluids is also explored. Future challenges and opportunities in this exciting area involving anisotropic chiral liquids are then discussed. PMID- 29603449 TI - Qualitative and quantitative analysis of lipo-alkaloids and fatty acids in Aconitum carmichaelii using LC-MS and GC-MS. AB - INTRODUCTION: Lipo-alkaloid (LA) is a kind of C19 -norditerpenoid alkaloid in Aconitum species, which usually contains an aconitane skeleton and one or two fatty acid residues. OBJECTIVE: To qualify and quantify the fatty acids and lipo alkaloids in Aconitum carmichaelii. METHODOLOGY: An ultra-high performance liquid chromatography-triple quadrupole-mass spectrometry (UHPLC-QQQ-MS) method was established to quantify LAs, while the free fatty acids were identified by gas chromatography-mass spectrometry (GC-MS) and ultra-high performance liquid chromatography-quadrupole-time-of-flight-mass spectrometry (UHPLC-Q-TOF-MS). RESULTS: Six major LAs (1-6) containing linoleic, palmitic, and oleic acid residues as side chains were quantified. Eighteen fatty acids were determined by GC-MS, and 15 were detected as the side chains of LAs. The LAs containing these 15 fatty acid residues accounted for about a third of the total identified LAs. Moreover, the contents of linoleic, palmitic, and oleic acids were highest. In addition, 12 oxygenated fatty acids were also identified by UHPLC-Q-TOF-MS for the first time. CONCLUSION: The positive correlation between free fatty acids and LAs in A. carmichaelii indicated that the types and contents of LAs were influenced by free fatty acids. PMID- 29603450 TI - Nerve growth factor-dependent hyperexcitability of capsaicin-sensitive bladder afferent neurones in mice with spinal cord injury. AB - NEW FINDINGS: What is the central question of this study? Nerve growth factor (NGF) is reportedly a mediator inducing urinary bladder dysfunction. Is NGF directly involved in hyperexcitability of capsaicin-sensitive C-fibre bladder afferent pathways after spinal cord injury (SCI)? What is the main finding and its importance? Neutralization of NGF by anti-NGF antibody treatment reversed the SCI-induced increase in the number of action potentials and the reduction in spike thresholds and A-type K+ current density in mouse capsaicin-sensitive bladder afferent neurones. Thus, NGF plays an important and direct role in hyperexcitability of capsaicin-sensitive C-fibre bladder afferent neurones attributable to the reduction in A-type K+ channel activity in SCI. ABSTRACT: Nerve growth factor (NGF) has been implicated as an important mediator in the induction of C-fibre bladder afferent hyperexcitability, which contributes to the emergence of neurogenic lower urinary tract dysfunction after spinal cord injury (SCI). In this study, we determined whether NGF immunoneutralization using an anti-NGF antibody (NGF-Ab) normalizes the SCI-induced changes in electrophysiological properties of capsaicin-sensitive C-fibre bladder afferent neurones in female C57BL/6 mice. The spinal cord was transected at the Th8/Th9 level. Two weeks later, continuous administration of NGF-Ab (10 MUg kg-1 h-1 , s.c. for 2 weeks) was started. Bladder afferent neurones were labelled with Fast Blue (FB), a fluorescent retrograde tracer, injected into the bladder wall 3 weeks after SCI. Four weeks after SCI, freshly dissociated L6-S1 dorsal root ganglion neurones were prepared. Whole-cell patch-clamp recordings were then performed in FB-labelled neurones. After recording action potentials or voltage gated K+ currents, the sensitivity of each neurone to capsaicin was evaluated. In capsaicin-sensitive FB-labelled neurones, SCI significantly reduced the spike threshold and increased the number of action potentials during membrane depolarization for 800 ms. These SCI-induced changes were reversed by NGF-Ab. Densities of slow-decaying A-type K+ (KA ) and sustained delayed rectifier-type K+ currents were significantly reduced by SCI. The NGF-Ab treatment reversed the SCI-induced reduction in the KA current density. These results indicate that NGF plays an important role in hyperexcitability of mouse capsaicin-sensitive C-fibre bladder afferent neurones attributable to a reduction in KA channel activity. Thus, NGF-targeting therapies could be effective for treatment of afferent hyperexcitability and neurogenic lower urinary tract dysfunction after SCI. PMID- 29603451 TI - Exploring the role of post-translational modifications in regulating alpha synuclein interactions by studying the effects of phosphorylation on nanobody binding. AB - Intracellular deposits of alpha-synuclein in the form of Lewy bodies are major hallmarks of Parkinson's disease (PD) and a range of related neurodegenerative disorders. Post-translational modifications (PTMs) of alpha-synuclein are increasingly thought to be major modulators of its structure, function, degradation and toxicity. Among these PTMs, phosphorylation near the C-terminus at S129 has emerged as a dominant pathogenic modification as it is consistently observed to occur within the brain and cerebrospinal fluid (CSF) of post-mortem PD patients, and its level appears to correlate with disease progression. Phosphorylation at the neighboring tyrosine residue Y125 has also been shown to protect against alpha-synuclein toxicity in a Drosophila model of PD. In the present study we address the potential roles of C-terminal phosphorylation in modulating the interaction of alpha-synuclein with other protein partners, using a single domain antibody fragment (NbSyn87) that binds to the C-terminal region of alpha-synuclein with nanomolar affinity. The results reveal that phosphorylation at S129 has negligible effect on the binding affinity of NbSyn87 to alpha-synuclein while phosphorylation at Y125, only four residues away, decreases the binding affinity by a factor of 400. These findings show that, despite the fact that alpha-synuclein is intrinsically disordered in solution, selective phosphorylation can modulate significantly its interactions with other molecules and suggest how this particular form of modification could play a key role in regulating the normal and aberrant function of alpha-synuclein. PMID- 29603452 TI - Pancreas preservation fluid microbial contamination is associated with poor islet isolation outcomes - a multi-centre cohort study. AB - The microbiological safety of islet preparations is paramount. Preservation medium contamination is frequent, and its impact on islet yield and function remains unclear. Microbiological samples collected during islet isolations from 2006 to 2016 were analyzed and correlated to isolation and allo- and autotransplantation outcomes. Microbial contamination of preservation medium was found in 64.4% of processed donor pancreases (291/452). We identified 464 microorganisms including Staphylococcus (253/464, 54.5%), Streptococcus (31/464, 6.7%), and Candida species (25/464, 5.4%). Microbial contamination was associated with longer warm and cold ischemia times and lower numbers of postpurification islet equivalents, purity, transplant rate, and stimulation index (all P < 0.05). Six percent of the preparations accepted for transplantation showed microbial contamination after isolation (12/200); 9 of 12 were Candida species. Six patients were transplanted with a sample with late microbial growth discovered after the infusion. Insulin independence rate was not affected. This risk of transplanting a contaminated islets preparation was reduced by half following the implementation of an additional sampling after 24 h of islet culture. Pancreas preservation fluid microbial contamination is associated with lower transplant rate and poorer in vitro function, but not with changes in graft survival. Culture medium testing 1 day after isolation reduces the risk of incidental transplantation with contaminated islets. PMID- 29603453 TI - Prognosis of primary sclerosing cholangitis - time to look at the population as a whole, not only from the center's or waiting list perspective. PMID- 29603454 TI - An Ultrastable Ionic Chemiresistor Skin with an Intrinsically Stretchable Polymer Electrolyte. AB - Ultrastable sensing characteristics of the ionic chemiresistor skin (ICS) that is designed by using an intrinsically stretchable thermoplastic polyurethane electrolyte as a volatile organic compound (VOC) sensing channel are described. The hierarchically assembled polymer electrolyte film is observed to be very uniform, transparent, and intrinsically stretchable. Systematic experimental and theoretical studies also reveal that artificial ions are evenly distributed in polyurethane matrix without microscale phase separation, which is essential for implementing high reliability of the ICS devices. The ICS displays highly sensitive and stable sensing of representative VOCs (including toluene, hexane, propanal, ethanol, and acetone) that are found in the exhaled breath of lung cancer patients. In particular, the sensor is found to be fully operational even after being subjected to long-term storage or harsh environmental conditions (relative humidity of 85% or temperature of 100 degrees C) or severe mechanical deformation (bending to a radius of curvature of 1 mm, or stretching strain of 100%), which can be an effective method to realize a human-adaptive and skin attachable biosensor platform for daily use and early diagnosis. PMID- 29603455 TI - Efficient Sodium Storage in Rolled-Up Amorphous Si Nanomembranes. AB - Alloying-type materials are promising anodes for high-performance sodium-ion batteries (SIBs) because of their high capacities and low Na-ion insertion potentials. However, the typical candidates, such as P, Sn, Sb, and Pb, suffer from severe volume changes (~293-487%) during the electrochemical reactions, leading to inferior cycling performances. Here, a high-rate and ultrastable alloying-type anode based on the rolled-up amorphous Si nanomembranes is demonstrated. The rolled-up amorphous Si nanomembranes show a very small volume change during the sodiation/desodiation processes and deliver an excellent rate capability and ultralong cycle life up to 2000 cycles with 85% capacity retention. The structural evolution and pseudocapacitance contribution are investigated by using the ex situ characterization techniques combined with kinetics analysis. Furthermore, the mechanism of efficient sodium-ion storage in amorphous Si is kinetically analyzed through an illustrative atomic structure with dangling bonds, offering a new perspective on understanding the sodium storage behavior. These results suggest that nanostructured amorphous Si is a promising anode material for high-performance SIBs. PMID- 29603456 TI - Light-Controlled Simultaneous "On Demand" Release of Cytotoxic Combinations for Bimodal Killing of Cancer Cells. AB - In this contribution, we report a novel entirely photocontrolled nanoplatform comprising a binary mixture of pluronic copolymers capable of self-assembling into core-shell micelles and co-entrapping two photoactivatable components: a benzoporphyrin photosensitizer for photodynamic therapy (PDT) and coumarin photocaged chemotherapeutic agent Chlorambucil (CAB). The resulting supramolecular micellar assembly is about 30 nm in diameter with a polydispersity index <0.1, stable for more than 72 h, and exhibits excellent preservation of the photochemical properties of the two photoresponsive components, even though they are confined within the same host nanocarrier. Appropriate regulation of the relative concentrations of these components makes them capable of absorbing visible light in comparable amounts, leading to effective simultaneous photogeneration of singlet oxygen and photo-triggered release of CAB. This "on demand" release of cytotoxic combinations results in amplified anticancer activity against MCF-7 human breast adenocarcinoma cells. PMID- 29603457 TI - Long Electron-Hole Diffusion Length in High-Quality Lead-Free Double Perovskite Films. AB - Developing environmentally friendly perovskites has become important in solving the toxicity issue of lead-based perovskite solar cells. Here, the first double perovskite (Cs2 AgBiBr6 ) solar cells using the planar structure are demonstrated. The prepared Cs2 AgBiBr6 films are composed of high-crystal-quality grains with diameters equal to the film thickness, thus minimizing the grain boundary length and the carrier recombination. These high-quality double perovskite films show long electron-hole diffusion lengths greater than 100 nm, enabling the fabrication of planar structure double perovskite solar cells. The resulting solar cells based on planar TiO2 exhibit an average power conversion efficiency over 1%. This work represents an important step forward toward the realization of environmentally friendly solar cells and also has important implications for the applications of double perovskites in other optoelectronic devices. PMID- 29603458 TI - Automated calibration of laser spectrometer measurements of delta18 O and delta2 H values in water vapour using a Dew Point Generator. AB - RATIONALE: Continuous measurement of stable O and H isotope compositions in water vapour requires automated calibration for remote field deployments. We developed a new low-cost device for calibration of both water vapour mole fraction and isotope composition. METHODS: We coupled a commercially available dew point generator (DPG) to a laser spectrometer and developed hardware for water and air handling along with software for automated operation and data processing. We characterised isotopic fractionation in the DPG, conducted a field test and assessed the influence of critical parameters on the performance of the device. RESULTS: An analysis time of 1 hour was sufficient to achieve memory-free analysis of two water vapour standards and the delta18 O and delta2 H values were found to be independent of water vapour concentration over a range of ~20,000 33,000 ppm. The reproducibility of the standard vapours over a 10-day period was better than 0.14 0/00 and 0.75 0/00 for delta18 O and delta2 H values, respectively (1 sigma, n = 11) prior to drift correction and calibration. The analytical accuracy was confirmed by the analysis of a third independent vapour standard. The DPG distillation process requires that isotope calibration takes account of DPG temperature, analysis time, injected water volume and air flow rate. CONCLUSIONS: The automated calibration system provides high accuracy and precision and is a robust, cost-effective option for long-term field measurements of water vapour isotopes. The necessary modifications to the DPG are minor and easily reversible. PMID- 29603459 TI - Trans-Metal-Trapping: Concealed Crossover Complexes En Route to Transmetallation? AB - Defined as the transfer of ligands from one metal to another, transmetallation is a common reaction in organometallic chemistry. Its chemical celebrity stems from its role in important catalytic cycles of cross-coupling reactions such as those of Negishi, Sonogashira, Stille, or Suzuki. This article focuses on trans-metal trapping (TMT), which could be construed as partially complete transmetallations. On mixing two distinct organometallic compounds, of for example lithium with aluminium or gallium, the two metals meet in a crossover co-complex, but the reaction ceases at that point and full transmetallation is not reached. Though in its infancy, trans-metal-trapping shows promise in transforming failed lithiations into successful lithiations and in stabilising sensitive carbanions through cooperative bimetallic effects making them more amenable to onward reactivity. PMID- 29603460 TI - Gene editing and gene regulation with CRISPR. PMID- 29603462 TI - Structural basis for the flexible recognition of alpha-glucan substrates by Bacteroides thetaiotaomicron SusG. AB - Bacteria that reside in the mammalian intestinal tract efficiently hydrolyze dietary carbohydrates, including starch, that escape digestion in the small intestine. Starch is an abundant dietary carbohydrate comprised of alpha1,4 and alpha1,6 linked glucose, yet mammalian intestinal glucoamylases cannot effectively hydrolyze starch that has frequent alpha1,6 branching as these structures hinder recognition and processing by alpha1,4-specific amylases. Here we present the structure of the cell surface amylase SusG from Bacteroides thetaiotaomicron complexed with a mixed linkage amylosaccharide generated from transglycosylation during crystallization. Although SusG is specific for alpha1,4 glucosidic bonds, binding of this new oligosaccharide at the active site demonstrates that SusG can accommodate alpha1,6 branch points at subsite -3 to 2, and also at subsite+1 adjacent to the site of hydrolysis, explaining how this enzyme may be able to process a wide range of limit dextrins in the intestinal environment. These data suggest that B. thetaiotaomicron and related organisms may have a selective advantage for amylosaccharide scavenging in the gut. PMID- 29603463 TI - Genetic costructure in a meta-community under threat of habitat fragmentation. AB - Habitat fragmentation increasingly threatens the services provided by natural communities and ecosystem worldwide. An understanding of the eco-evolutionary processes underlying fragmentation-compromised communities in natural settings is lacking, yet critical to realistic and sustainable conservation. Through integrating the multivariate genetic, biotic and abiotic facets of a natural community module experiencing various degrees of habitat fragmentation, we provide unique insights into the processes underlying community functioning in real, natural conditions. The focal community module comprises a parasitic butterfly of conservation concern and its two obligatory host species, a plant and an ant. We show that both historical dispersal and ongoing habitat fragmentation shape population genetic diversity of the butterfly Phengaris alcon and its most limited host species (the plant Gentiana pneumonanthe). Genetic structure of each species was strongly driven by geographical structure, altitude and landscape connectivity. Strikingly, however, was the strong degree of genetic costructure among the three species that could not be explained by the spatial variables under study. This finding suggests that factors other than spatial configuration, including co-evolutionary dynamics and shared dispersal pathways, cause parallel genetic structure among interacting species. While the exact contribution of co-evolution and shared dispersal routes on the genetic variation within and among communities deserves further attention, our findings demonstrate a considerable degree of genetic parallelism in natural meta-communities. The significant effect of landscape connectivity on the genetic diversity and structure of the butterfly also suggests that habitat fragmentation may threaten the functioning of the community module on the long run. PMID- 29603461 TI - Metaboreceptor activation in heart failure with reduced ejection fraction: Linking cardiac and peripheral vascular haemodynamics. AB - NEW FINDINGS: What is the central question of this research? Do patients with heart failure with reduced ejection fraction (HFrEF) exhibit a greater dependence on cardiac or peripheral vascular haemodynamics across multiple levels of muscle metaboreflex activation provoked by postexercise circulatory occlusion? What is the main finding and its importance? The metaboreflex-induced pressor response in HFrEF patients is governed almost entirely by the peripheral circulation, which places a substantial haemodynamic load on the failing heart. This maladaptive response exacerbates the disease-related impairment of systolic function that is a hallmark feature of HFrEF and may therefore contribute to exercise intolerance in this patient group. ABSTRACT: We sought to evaluate the muscle metaboreflex in heart failure with reduced ejection fraction (HFrEF) patients, with an emphasis on the interaction between cardiac and peripheral vascular haemodynamics across multiple levels of metaboreceptor activation. In 23 HFrEF patients (63 +/- 2 years of age) and 15 healthy control subjects (64 +/- 3 years of age), we examined changes in mean arterial pressure, cardiac output, systemic vascular conductance, effective arterial elastance, stroke work and forearm deoxyhaemoglobin concentration during metaboreceptor activation elicited by postexercise circulatory occlusion (PECO) after three levels of static intermittent handgrip exercise (15, 30 and 45% maximal voluntary contraction). Across workloads, the metaboreflex-induced increase in deoxyhaemoglobin and mean arterial pressure were similar between groups. However, in control subjects, the pressor response was driven by changes (Delta) in cardiac output (Delta495 +/- 155, Delta564 +/- 156 and Delta666 +/- 217 ml min-1 ), whereas this change was accomplished by intensity-dependent reductions in systemic vascular conductance in patients with HFrEF (Delta-4.9 +/- 1.5, Delta-9.1 +/- 1.9 and Delta-12.7 +/- 1.8 ml min mmHg-1 ). This differential response contributed to the exaggerated increases in effective arterial elastance in HFrEF patients compared with control subjects, coupled with a blunted response in stroke work in the HFrEF patients. Together, these findings indicate a preserved role of the metaboreflex-induced pressor response in HFrEF but suggest that this response is governed by changes in the peripheral circulation. The net effect of this response appears to be maladaptive, as it places a substantial haemodynamic load on the left ventricle that may exacerbate left ventricular systolic dysfunction and contribute to exercise intolerance in this patient population. PMID- 29603464 TI - Systematic review evaluating randomized controlled trials of smoking and alcohol cessation interventions in people with head and neck cancer and oral dysplasia. AB - BACKGROUND: Smoking and alcohol increase the risk of head and neck cancer and affect treatment outcomes. Interventions modifying these behaviors may improve posttreatment outcomes and survival. We systematically reviewed evidence of the effectiveness of smoking/alcohol interventions in head and neck cancer and oral dysplasia. METHODS: The AMED, CINAHL, Embase, MEDLINE, and Web of Science databases were searched for randomized controlled trials (RCTs) of smoking/alcohol interventions in people with head and neck cancer. A qualitative synthesis of the studies was conducted. RESULTS: Three RCTs were identified: 2 smoking interventions and 1 smoking and alcohol intervention. One intervention, which was comprised of a smoking intervention based on Cognitive Behavioral Therapy and pharmacologic management compared to usual care, reduced smoking prevalence. CONCLUSION: Further research is required into the underlying mechanisms that lead to cessation and interventions that include both pharmacological and behavioral therapy. Future RCTs should include suitable control conditions and sufficient power to assess clinical outcomes. PMID- 29603465 TI - Silica Metal Oxide Vesicles Catalyze Comprehensive Prebiotic Chemistry. AB - It has recently been demonstrated that mineral self-assembled structures catalyzing prebiotic chemical reactions may form in natural waters derived from serpentinization, a geological process widespread in the early stages of Earth like planets. We have synthesized self-assembled membranes by mixing microdrops of metal solutions with alkaline silicate solutions in the presence of formamide (NH2 CHO), a single-carbon molecule, at 80 degrees C. We found that these bilayer membranes, made of amorphous silica and metal oxide/hydroxide nanocrystals, catalyze the condensation of formamide, yielding the four nucleobases of RNA, three amino acids and, several carboxylic acids in a single pot experiment. Besides manganese, iron and magnesium, two abundant elements in the earliest Earth crust that are key in serpentinization reactions, are enough to produce all these biochemical compounds. These results suggest that the transition from inorganic geochemistry to prebiotic organic chemistry is common on a universal scale and, most probably, occurred earlier than ever thought for our planet. PMID- 29603466 TI - Oestrogen-related receptor reduces vitellogenin expression by crosstalk with the ecdysone receptor pathway in female silkworm, Bombyx mori. AB - Oestrogen-related receptor (ERR) is involved in oestrogen receptor (ER) signalling pathways owing to its similarity to ER in terms of domain structure and co-activator and response elements. Although insects lack ER, they harbour an ERR gene that is thought to modulate metabolism and energy conversion via an unknown mechanism. The present study investigated the function of ERR in insects using female silkworm (Bombyx mori, Bm). We found that the expression of B. mori vitellogenin (BmVg) and B. mori ERR (BmERR) in the fat bodies of female silkworms at different stages of development exhibited alternating patterns, and RNA interference of BmERR in females induced BmVg transcription, resulting in an increase in egg weight relative to the control. Furthermore, BmERR was found to be involved in regulating the transcription of BmVg through an oestrogen-related receptor response element (ERRE) in the promoter of the BmVg gene, as demonstrated by electrophoretic mobility shift assay, cell transfection assay and chromatin immunoprecipitation. In summary, our results indicate that BmERR bound to the ERRE motif in the BmVg promoter reducing the expression of BmVg in the fat body of the female silkworm. To our surprise, the ERRE also showed the ability to bind the ecdysone receptor (BmEcR) and ultraspiracle complex. Thus, we surmise that ERR participates in steroid hormone signalling by engaging in crosstalk with the ER pathway in vertebrates and with the EcR pathway in insects. PMID- 29603467 TI - Comparisons of behavioural and TRPA1 heat sensitivities in three sympatric Cuban Anolis lizards. AB - Thermal tolerances of organisms play a role in defining geographic ranges and occurrence of species. In Cuba, three sympatric species of Anolis lizards (Anolis allogus, Anolis homolechis and Anolis sagrei) inhabit different thermal microhabitats. A previous study found that these species showed distinct gene expression patterns in response to temperature stimuli, suggesting the genetically distinct thermal physiology among species. To investigate whether the Anolis species inhabiting locally distinct thermal habitats diverge their thermal tolerances, we first conducted behavioural experiments to analyse the temperatures at which the three Anolis species escape from heat source. Then, for each of the three species, we isolated cDNA encoding a putative molecular heat sensor, transient receptor potential ion channel ankyrin 1 (TRPA1), which has been suggested to play a role on eliciting behavioural responses to heat stimuli. We performed electrophysiological analysis to quantify activation temperature of Anolis TRPA1 to see whether the pattern of divergence in TRPA1 responses is congruent with that of divergence in behavioural responses. We found that temperatures triggering behavioural and TRPA1 responses were significantly lower for shade-dwelling species (A. allogus) than for sun-dwelling species (A. homolechis and A. sagrei). The ambient temperature of shade habitats where A. allogus occurs stays relatively cool compared to that of open habitats where A. homolechis and A. sagrei occur and bask. The high temperature thresholds of A. homolechis and A. sagrei may reflect their heat tolerances that would benefit these species to inhabit the open habitats. PMID- 29603468 TI - Diversification of African tree frogs (genus Leptopelis) in the highlands of Ethiopia. AB - The frog genus Leptopelis is composed of ~50 species that occur across sub Saharan Africa. The majority of these frogs are typically arboreal; however, a few species have evolved a fossorial lifestyle. Most species inhabit lowland forests, but a few species have adapted to high elevations. Five species of Leptopelis occupy the Ethiopian highlands and provide a good opportunity to study the evolutionary transition from an arboreal to a fossorial lifestyle, as well as the diversification in this biodiversity hot spot. We sequenced 14 nuclear and three mitochondrial genes, and generated thousands of SNPs from ddRAD sequencing to study the evolutionary relationships of Ethiopian Leptopelis. The five species of highland Leptopelis form a monophyletic group, which diversified during the late Miocene and Pliocene. We found strong population structure in the fossorial species L. gramineus, with levels of genetic differentiation between populations similar to those found between arboreal species. This could indicate that L. gramineus is a complex of cryptic species. We propose that after the original colonization of the Ethiopian highlands by the ancestor of the L. gramineus group, episodes of vicariance fragmented the ancestral populations of this group. We also report the re-evolution of arboreality in L. susanae, which evolved from a fossorial ancestor, a rare ecological switch in frogs that had previously been reported only once. PMID- 29603469 TI - Biodiversity matters in feedbacks between climate change and air quality: a study using an individual-based model. AB - Air quality is closely associated with climate change via the biosphere because plants release large quantities of volatile organic compounds (VOC) that mediate both gaseous pollutants and aerosol dynamics. Earlier studies, which considered only leaf physiology and simply scale up from leaf-level enhancements of emissions, suggest that climate warming enhances whole forest VOC emissions, and these increased VOC emissions aggravate ozone pollution and secondary organic aerosol formation. Using an individual-based forest VOC emissions model, UVAFME VOC, that simulates system-level emissions by explicitly simulating forest community dynamics to the individual tree level, ecological competition among the individuals of differing size and age, and radiative transfer and leaf function through the canopy, we find that climate warming only sometimes stimulates isoprene emissions (the single largest source of non-methane hydrocarbon) in a southeastern U.S. forest. These complex patterns result from the combination of higher temperatures' stimulating emissions at the leaf level but decreasing the abundance of isoprene-emitting taxa at the community level by causing a decline in the abundance of isoprene-emitting species (Quercus spp.). This ecological effect eventually outweighs the physiological one, thus reducing overall emissions. Such reduced emissions have far-reaching implications for the climate air-quality relationships that have been established on the paradigm of warming enhancement VOC emissions from vegetation. This local scale modeling study suggests that community ecology rather than only individual physiology should be integrated into future studies of biosphere-climate-chemistry interactions. PMID- 29603470 TI - A silent eligibility trace enables dopamine-dependent synaptic plasticity for reinforcement learning in the mouse striatum. AB - Dopamine-dependent synaptic plasticity is a candidate mechanism for reinforcement learning. A silent eligibility trace - initiated by synaptic activity and transformed into synaptic strengthening by later action of dopamine - has been hypothesized to explain the retroactive effect of dopamine in reinforcing past behaviour. We tested this hypothesis by measuring time-dependent modulation of synaptic plasticity by dopamine in adult mouse striatum, using whole-cell recordings. Presynaptic activity followed by postsynaptic action potentials (pre post) caused spike-timing-dependent long-term depression in D1-expressing neurons, but not in D2 neurons, and not if postsynaptic activity followed presynaptic activity. Subsequent experiments focused on D1 neurons. Applying a dopamine D1 receptor agonist during induction of pre-post plasticity caused long term potentiation. This long-term potentiation was hidden by long-term depression occurring concurrently and was unmasked when long-term depression blocked an L type calcium channel antagonist. Long-term potentiation was blocked by a Ca2+ permeable AMPA receptor antagonist but not by an NMDA antagonist or an L-type calcium channel antagonist. Pre-post stimulation caused transient elevation of rectification - a marker for expression of Ca2+ -permeable AMPA receptors - for 2 4-s after stimulation. To test for an eligibility trace, dopamine was uncaged at specific time points before and after pre- and postsynaptic conjunction of activity. Dopamine caused potentiation selectively at synapses that were active 2 s before dopamine release, but not at earlier or later times. Our results provide direct evidence for a silent eligibility trace in the synapses of striatal neurons. This dopamine-timing-dependent plasticity may play a central role in reinforcement learning. PMID- 29603471 TI - Interspecific competition promotes habitat and morphological divergence in a secondary contact zone between two hybridizing songbirds. AB - Interspecific competition is assumed to play an important role in the ecological differentiation of species and speciation. However, empirical evidence for competition's role in speciation remains surprisingly scarce. Here, we studied the role of interspecific competition in the ecological differentiation and speciation of two closely related songbird species, the Common Nightingale (Luscinia megarhynchos) and the Thrush Nightingale (Luscinia luscinia). Both species are insectivorous and ecologically very similar. They hybridize in a secondary contact zone, which is a mosaic of sites where both species co-occur (syntopy) and sites where only one species is present (allotopy). We analysed fine-scale habitat data for both species in both syntopic and allotopic sites and looked for associations between habitat use and bill morphology, which have been previously shown to be more divergent in sympatry than in allopatry. We found that the two nightingale species differ in habitat use in allotopic sites, where L. megarhynchos occurred in drier habitats and at slightly higher elevations, but not in syntopic sites. Birds from allotopic sites also showed higher interspecific divergence in relative bill size compared to birds from syntopic sites. Finally, we found an association between bill morphology and elevation. Our results are consistent with the view that interspecific competition in nightingales has resulted in partial habitat segregation in sympatry and that the habitat-specific food supply has in turn very likely led to bill size divergence. Such ecological divergence may enhance prezygotic as well as extrinsic postzygotic isolation and thus accelerate the completion of the speciation process. PMID- 29603472 TI - Flexible Versus Rigid G-Quadruplex DNA Ligands: Synthesis of Two Series of Bis indole Derivatives and Comparison of Their Interactions with G-Quadruplex DNA. AB - Small molecules that target G-quadruplex (G4) DNA structures are not only valuable to study G4 biology but also for their potential as therapeutics. This work centers around how different design features of small molecules can affect the interactions with G4 DNA structures, exemplified by the development of synthetic methods to bis-indole scaffolds. Our synthesized series of bis-indole scaffolds are structurally very similar but differ greatly in the flexibility of their core structures. The flexibility of the molecules proved to be an advantage compared to locking the compounds in the presumed bioactive G4 conformation. The flexible derivatives demonstrated similar or even improved G4 binding and stabilization in several orthogonal assays even though their entropic penalty of binding is higher. In addition, molecular dynamics simulations with the c-MYC G4 structure showed that the flexible compounds adapt better to the surrounding. This was reflected by an increased number of both stacking and polar interactions with both the residues in the G4 DNA structure and the DNA residues just upstream of the G4 structure. PMID- 29603473 TI - Selection outweighs drift at a fine scale: Lack of MHC differentiation within a family living lizard across geographically close but disconnected rocky outcrops. AB - The highly polymorphic genes of the major histocompatibility complex (MHC) are involved in disease resistance, mate choice and kin recognition. Therefore, they are widely used markers for investigating adaptive variation. Although selection is the key driver, gene flow and genetic drift also influence adaptive genetic variation, sometimes in opposing ways and with consequences for adaptive potential. To further understand the processes that generate MHC variation, it is helpful to compare variation at the MHC with that at neutral genetic loci. Differences in MHC and neutral genetic variation are useful for inferring the relative influence of selection, gene flow and drift on MHC variation. To date, such investigations have usually been undertaken at a broad spatial scale. Yet, evolutionary and ecological processes can occur at a fine spatial scale, particularly in small or fragmented populations. We investigated spatial patterns of MHC variation among three geographically close, naturally discrete, sampling sites of Egernia stokesii, an Australian lizard. The MHC of E. stokesii has recently been characterized, and there is evidence for historical selection on the MHC. We found E. stokesii MHC weakly differentiated among sites compared to microsatellites, suggesting selection, acting similarly at each site, has outweighed any effects of low gene flow or of genetic drift on E. stokesii MHC variation. Our findings demonstrate the strength of selection in shaping patterns of MHC variation or consistency at a fine spatial scale. PMID- 29603475 TI - Transoral endoscopic thyroid surgery via the tri-vestibular approach with a hybrid space-maintaining method: A preliminary report. AB - BACKGROUND: Transoral endoscopic thyroid surgery has been introduced in a few institutions. The purpose of this study was to present an innovative hybrid space maintaining method for the tri-vestibular approach. METHODS: Eighteen consecutive patients underwent transoral endoscopic thyroidectomy. Three incisions were made in the vestibule. The surgical space was maintained with CO2 insufflation along with a suspension device. Thyroidectomy and central neck dissection (CND) were performed safely and effectively. RESULTS: The mean operation time was 124 minutes for a simple lobectomy, subtotal thyroidectomy, and isthmectomy in 8 patients, 172 minutes for hemithyroidectomy with ipsilateral CND in 8 patients, and 205 minutes for total thyroidectomy with ipsilateral CND in 7 patients. Transient superior laryngeal nerve (SLN) injury occurred in 3 patients and transient mental nerve injury was found in 1 patient. No evidence of recurrence or metastasis was found at follow-up. CONCLUSION: This approach brings satisfactory cosmetic effect along with minimal invasion. Further study is needed to verify its validity. PMID- 29603474 TI - A novel transgenic zebrafish line for red opsin expression in outer segments of photoreceptor cells. AB - BACKGROUND: Opsins are a group of light-sensitive proteins present in photoreceptor cells, which convert the energy of photons into electrochemical signals, thus allowing vision. Given their relevance, we aimed to visualize the two red opsins at subcellular scale in photoreceptor cells. RESULTS: We generated a novel Zebrafish BAC transgenic line, which express fluorescently tagged, full length Opsin 1 long-wave-sensitive 1 (Opn1lw1) and full-length Opsin 1 long-wave sensitive 2 (Opn1lw2) under the control of their endogenous promoters. Both fusion proteins are localized in the outer segments of photoreceptor cells. During development, Opn1lw2-mKate2 is detected from the initial formation of outer segments onward. In contrast, Opn1lw1-mNeonGreen is first detected in juvenile Zebrafish at about 2 weeks postfertilization, and both opsins continue to be expressed throughout adulthood. It is important to note that the presence of the transgene did not significantly alter the size of outer segments. CONCLUSIONS: We have generated a transgenic line that mimics the endogenous expression pattern of Opn1lw1 and Opn1lw2 in the developing and adult retina. In contrast to existing lines, our transgene design allows to follow protein localization. Hence, we expect that these lines could act as useful real-time reporters to directly measure phenomena in retinal development and disease models. Developmental Dynamics 247:951-959, 2018. (c) 2018 The Authors Developmental Dynamics published by Wiley Periodicals, Inc. on behalf of American Association of Anatomists. PMID- 29603476 TI - Direct Electrochemistry of Bilirubin Oxidase from Magnaporthe orizae on Covalently-Functionalized MWCNT for the Design of High-Performance Oxygen Reducing Biocathodes. AB - Herein, the direct electrochemistry of bilirubin oxidase from Magnaporthe orizae (MoBOD) was studied on CNTs functionalized by electrografting several types of diazonium salts. The functionalization induces favorable or unfavorable orientation of MoBOD, the latter being compared to the well-known BOD from Myrothecium verrucaria (MvBOD). On the same nanostructured electrodes, MoBOD can surpass MvBOD in terms of both current densities and minimal overpotentials. Added to the fact that MoBOD is also highly active at the gas-diffusion electrode (GDE), these findings make MoBOD one of the MCOs with the highest catalytic activity towards the oxygen reduction reaction (ORR). PMID- 29603477 TI - Challenges and limitations in the diagnosis of atrioesophageal fistula. AB - INTRODUCTION: Atrioesophageal fistula (AEF) is a dire complication of atrial fibrillation ablation. The diagnostic yield of computed tomography (CT) chest, the role and timing of repeat testing, and the value of other investigations in the diagnosis of AEF is uncertain. METHODS: We systematically reviewed published AEF cases to evaluate radiological, bedside, and biochemical investigations for AEF (registered on PROSPERO [CRD42017077493]). RESULTS: Eighty-seven articles with 126 patients (median age, 59 years; male, 71%) were included in the analysis. CT chest was performed in 88% (111/126) and was abnormal in 87%. A clear diagnosis of AEF (fistula/perforation) was only detected in 35% (34/97). Other major findings included free air in mediastinum (26%), left atrium (LA), or LA wall (24%). In 11 patients with normal/nonspecific initial CT chest, major abnormalities were detected in 91% (10/11) of repeat CT chest performed 6 days (median; range, 4-22) after initial scan. Initial CT head was normal in 51%; diffuse air emboli was identified in 79% (22/28). Initial transthoracic echocardiography was normal in 61% of cases. The spectrum of radiological abnormalities included Air (mediastinum/LA), Effusion (pleural/pericardial), Fistula/Perforation, and Thickening (esophagus/LA) - "AEF-Tests." Esophagram demonstrated contrast extravasation in 87% (13/15). Blood culture was consistently positive (100%; 28/28), particularly for streptococcus species (93%; 26/28). CONCLUSION: The diagnosis of AEF remains challenging. Clinicians should be aware of the limitations in the yield of CT chest, the variety of major abnormalities reported, the need for repeat testing, unique brain imaging findings, and the importance of positive blood cultures and raised inflammatory markers. PMID- 29603478 TI - Synthesis of alpha-Chlorolactams by Cyanoborohydride-Mediated Radical Cyclization of Trichloroacetamides. AB - A cyanoborohydride-promoted radical cyclization methodology has been developed to access alpha-chlorolactams in a simple and efficient way using NaBH3 CN and trichloroacetamides easily available from allylic and homoallylic secondary amines. This methodology allowed the synthesis of a library of alpha chlorolactams (mono- and bicyclic), which were tested for herbicidal activity, trans-3-chloro-4-methyl-1-(3-trifluoromethyl)phenyl-2-pyrrolidinone being the most active. PMID- 29603479 TI - Large Oblate Hemispheroidal Ruthenium Particles Supported on Calcium Amide as Efficient Catalysts for Ammonia Decomposition. AB - Ammonia decomposition is an important technology for extracting hydrogen from ammonia toward the realization of a hydrogen economy. Herein, it is reported that large oblate hemispheroidal Ru particles on Ca(NH2 )2 function as efficient catalysts for ammonia decomposition. The turnover frequency of Ru/Ca(NH2 )2 increased by two orders of magnitude when the Ru particle size was increased from 1.5 to 8.4 nm. More than 90 % ammonia decomposition was achieved over Ru/Ca(NH2 )2 with large oblate hemispheroidal Ru particles at 360 degrees C, which is comparable to that of alkali-promoted Ru catalysts with small Ru particle sizes. XAFS analyses revealed that Ru particles are immobilized on Ca(NH2 )2 by Ru-N bonds formed at the metal/support interface, which lead to oblate hemispheroidal Ru particles. Such a strong metal-support interaction in Ru/Ca(NH2 )2 is also substantiated by DFT calculations. The high activity of Ru/Ca(NH2 )2 with large Ru particles primarily originates from the shape and appropriate size of the Ru particles with a high density of active sites rather than the electron-donating ability of Ca(NH2 )2 . PMID- 29603480 TI - Chemoenzymatic Synthesis of Asymmetrical Multi-Antennary N-Glycans to Dissect Glycan-Mediated Interactions between Human Sperm and Oocytes. AB - Complex N-glycans of glycoproteins of the zona pellucida (ZP) of human oocytes have been implicated in the binding of spermatozoa. The termini of these unusual bi-, tri-, and tetra-antennary N-glycans consist of the tetrasaccharide sialyl Lewisx (SLex ), which was previously identified as the minimal epitope for sperm binding. We describe here the chemoenzymatic synthesis of highly complex triantennary N-glycans derived from ZP carrying SLex moieties at the C-2 and C-2' arm and a sialyl-Lewisx -Lewisx (SLex -Lex ) residue at the C-6 antenna and two closely related analogues. The compounds were examined for their ability to inhibit the interaction of human sperm to ZP. It was found that the SLex -Lex moiety is critical for inhibitory activity, whereas the other SLex moieties exerted minimal effect. Further studies with SLex -Lex and SLex showed that the extended structure is the more potent inhibitor. In addition, trivalent SLex -Lex and SLex were prepared which showed greater inhibitory activity compared to their monovalent counterparts. Our studies show that although SLex can inhibit the binding of spermatozoa, presenting this epitope in the context of a complex N glycan results in a loss of inhibitory potential, and in this context only SLex Lex can make productive interactions. It is not the multivalent display of SLex on a multi-antennary glycan but the presentation of multiple SLex -Lex on the various glycosylation sites of ZP that accounts for high avidity binding. PMID- 29603481 TI - Phenoxyaluminum(salophen) Scaffolds: Synthesis, Electrochemical Properties, and Self-Assembly at Surfaces of Multifunctional Systems. AB - Salophens and Salens are Schiff bases generated through the condensation of two equivalents of salicylaldehyde with either 1,2-phenylenediamines or aliphatic diamines, respectively. Both ligands have been extensively exploited as key building blocks in coordination chemistry and catalysis. In particular, their metal complexes have been widely used for various catalytical transformations with high yield and selectivity. Through the modification of the phenol unit it is possible to tune the steric hindrance and electronic properties of Salophen and Salen. The introduction of long aliphatic chains in salicylaldehydes can be used to promote their self-assembly into ordered supramolecular structures on solid surfaces. Herein, we report a novel method towards the facile synthesis of robust and air-stable [Al(Salophen)] derivatives capable of undergoing spontaneous self-assembly at the graphite/solution interface forming highly ordered nanopatterns. The new synthetic approach relies on the use of [MeAlIII (Salophen)] as a building unit to introduce, via a simple acid/base reaction with functionalized acidic phenol derivatives, selected frameworks integrating multiple functions for efficient surface decoration. STM imaging at the solid/liquid interface made it possible to monitor the formation of ordered supramolecular structures. In addition, the redox properties of the Salophen derivatives functionalized with ferrocene units in solution and on surface were unraveled by cyclic voltammetry. The use of a five-coordinate aluminum alkyl Salophen precursor enables the tailoring of new Salophen molecules capable of undergoing controlled self-assembly on HOPG, and thereby it can be exploited to introduce multiple functionalities with subnanometer precision at surfaces, ultimately forming ordered functional patterns. PMID- 29603482 TI - 3D image fusion of whole-heart dynamic cardiac MR perfusion and late gadolinium enhancement: Intuitive delineation of myocardial hypoperfusion and scar. AB - BACKGROUND: Since patients with myocardial hypoperfusion due to coronary artery disease (CAD) with preserved viability are known to benefit from revascularization, accurate differentiation of hypoperfusion from scar is desirable. PURPOSE: To develop a framework for 3D fusion of whole-heart dynamic cardiac MR perfusion and late gadolinium enhancement (LGE) to delineate stress induced myocardial hypoperfusion and scar. STUDY TYPE: Prospective feasibility study. SUBJECTS: Sixteen patients (61 +/- 14 years, two females) with known/suspected CAD. FIELD STRENGTH/SEQUENCE: 1.5T (nine patients); 3.0T (seven patients); whole-heart dynamic 3D cardiac MR perfusion (3D-PERF, under adenosine stress); 3D LGE inversion recovery sequences (3D-SCAR). ASSESSMENT: A software framework was developed for 3D fusion of 3D-PERF and 3D-SCAR. Computation steps included: 1) segmentation of the left ventricle in 3D-PERF and 3D-SCAR; 2) semiautomatic thresholding of perfusion/scar data; 3) automatic calculation of ischemic/scar burden (ie, pathologic relative to total myocardium); 4) projection of perfusion/scar values onto artificial template of the left ventricle; 5) semiautomatic coregistration to an exemplary heart contour easing 3D orientation; and 6) 3D rendering of the combined datasets using automatically defined color tables. All tasks were performed by two independent, blinded readers (J.S. and R.M.). STATISTICAL TESTS: Intraclass correlation coefficients (ICC) for determining interreader agreement. RESULTS: Image acquisition, postprocessing, and 3D fusion were feasible in all cases. In all, 10/16 patients showed stress induced hypoperfusion in 3D-PERF; 8/16 patients showed LGE in 3D-SCAR. For 3D PERF, semiautomatic thresholding was possible in all patients. For 3D-SCAR, automatic thresholding was feasible where applicable. Average ischemic burden was 11 +/- 7% (J.S.) and 12 +/- 7% (R.M.). Average scar burden was 8 +/- 5% (J.S.) and 7 +/- 4% (R.M.). Interreader agreement was excellent (ICC for 3D-PERF = 0.993, for 3D-SCAR = 0.99). DATA CONCLUSION: 3D fusion of 3D-PERF and 3D-SCAR facilitates intuitive delineation of stress-induced myocardial hypoperfusion and scar. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;48:1129-1138. PMID- 29603483 TI - Regioisomeric Tandem Triblock Shape Amphiphiles Based on Polyhedral Oligomeric Silsesquioxanes. AB - We report the design, synthesis and self-assembly of a series of tandem triblock shape amphiphile regioisomers composed of one rod-like fluorinated polyhedral oligomeric silsesquioxane (FPOSS) cage tethered with two spherical tert-butyl POSS (tBPOSS) cages in para-, meta-, and ortho-configurations. Precision syntheses are achieved through sequential "click" reactions and the compounds are thoroughly characterized by combined techniques of NMR, FT-IR and MALDI-TOF MS spectroscopy. Only the ortho-isomer forms an ordered lamellae structure induced by the crystallization of perfluoroalkyl-chains and the other two remain amorphous due to frustrated packing by unfavorable regio-configuration. The distinct assembly behaviors of these three regioisomers reflect the delicate influence of a minute structural difference on precision macromolecular assembly. PMID- 29603484 TI - Genetic footprints of adaptive divergence in the bracovirus of Cotesia sesamiae identified by targeted resequencing. AB - The African parasitoid wasp Cotesia sesamiae is a generalist species structured in locally adapted populations showing differences in host range. The recent discovery of Cotesia typhae, a specialist, sister species to C. sesamiae, provides a good framework to study the genetic determinants of parasitoid host range. To investigate the genomic bases of divergence between these populations and species, we used a targeted sequencing approach on 24 samples. We targeted the bracovirus genomic region encoding virulence genes involved in the interaction with the lepidopteran hosts of the wasps. High sequencing coverage was obtained for all samples, allowing the study of genetic variation between wasp populations and species. By combining population genetic estimations, such as nucleotide diversity (pi), relative differentiation (FST ) and absolute divergence (dxy ), with branch-site dN/dS measures, we identified six of 98 bracovirus genes showing significant divergence and evidence of positive selection. These genes, belonging to different gene families, are potentially involved in host adaptation and in the specialization process. Fine-scale analyses of genetic variation also revealed mutations and large deletions in certain genes inducing pseudogenization and loss of function. The image emerging from these results is that adaptation mediated by bracovirus genes happens through selection of particularly adaptive alleles and loss of nonadaptive genes. These results highlight the central role of the bracovirus in the molecular interactions between the wasps and their hosts and in the evolutionary processes of specialization. PMID- 29603486 TI - Neonicotinoid insecticides negatively affect performance measures of non-target terrestrial arthropods: a meta-analysis. AB - Neonicotinoid insecticides are currently the fastest-growing and most widely used insecticide class worldwide. Valued for their versatility in application, these insecticides may cause deleterious effects in a range of non-target (beneficial) arthropods. However, it remains unclear whether strong patterns exist in terms of their major effects, if broad measures of arthropod performance are negatively affected, or whether different functional groups are equally vulnerable. Here, we present a meta-analysis of 372 observations from 44 field and laboratory studies that describe neonicotinoid effects on 14 arthropod orders across five broad performance measures: abundance, behavior, condition, reproductive success, and survival. Across studies, neonicotinoids negatively affected all performance metrics evaluated; however, magnitude of the effects varied. Arthropod behavior and survival were the most negatively affected and abundance was the least negatively affected. Effects on arthropod functional groups were inconsistent. Pollinator condition, reproductive success, and survival were significantly lower in neonicotinoid treatments compared to untreated controls; whereas, neonicotinoid effects on detritivores were not significant. Although magnitude of arthropod response to neonicotinoids varied among performance measures and functional groups, we documented a consistent negative relationship between exposure to neonicotinoid insecticides in published studies and beneficial arthropod performance. PMID- 29603485 TI - Anion Recognition by a Bioactive Diureidodecalin Anionophore: Solid-State, Solution, and Computational Studies. AB - Recent work has identified a bis-(p-nitrophenyl)ureidodecalin anion carrier as a promising candidate for biomedical applications, showing good activity for chloride transport in cells yet almost no cytotoxicity. To underpin further development of this and related compounds, a detailed structural and binding investigation is reported. Crystal structures of the transporter as five solvates confirm the diaxial positioning of urea groups while revealing a degree of conformational flexibility. Structures of complexes with Cl- , Br- , NO3- , SO42- and AcO- , supported by computational studies, show how the binding site can adapt to accommodate these anions. 1 H NMR binding studies revealed exceptionally high affinities for anions in DMSO, decreasing in the order SO42- >H2 PO4- ~HCO3- ~AcO- ?HSO4- >Cl- >Br- >NO3- >I- . Analysis of the binding results suggests that selectivity is determined mainly by the H-bond acceptor strength of different anions, but is also modulated by receptor geometry. PMID- 29603487 TI - Comparison between 3D isotropic and 2D conventional MR arthrography for diagnosing rotator cuff tear and labral lesions: A meta-analysis. AB - BACKGROUND: Although 3D-isotropic MR arthrography has been characterized as a substitute imaging tool for rotator cuff tear (RCT) and labral lesions, it has not been commonly used in clinical practice because of controversy related to image blurring and indistinctness of structural edges. PURPOSE: To perform a comparison of the diagnostic performance of 3D-isotropic MR arthrography and 2D conventional MR arthrography for diagnosis of RCT (solely RCT, full/partial thickness supraspinatus [SST]-infraspinatus [IST] tear, or subscapularis [SSc] tear) and labral lesions. STUDY TYPE: Meta-analysis. POPULATION: Patients with shoulder pain. FIELD STRENGTH/SEQUENCE: 3D-isotropic and 2D-conventional MR arthrography at 3.0T or 1.5T. ASSESSMENT: PubMed and EMBASE were searched following the PRISMA guidelines. STATISTICAL TESTS: Bivariate modeling and hierarchical summary receiver operating characteristic modeling were performed to compare the overall diagnostic performance of 3D-isotropic and 2D-conventional MR arthrography. Multiple-subgroup analyses were performed for diagnosing RCT, full/partial-thickness SST-IST tear, SSc tear, and labral lesions. Meta regression analyses were performed according to subject, study, and MR arthrography characteristics including 3D-isotropic sequences (turbo spine echo [TSE] vs. gradient echo [GRE]). RESULTS: Eleven studies (825 patients) were included. Overall, 3D-isotropic MR arthrography had similar pooled sensitivity (0.90 [95% CI, 0.87-0.93]) (P = 0.95) and specificity (0.92 [95% CI, 0.87-0.95]) (P = 0.99), relative to 2D-conventional MR arthrography (sensitivity, 0.91 [95% CI, 0.86-0.94]); specificity, 0.92 [95% CI, 0.87-0.95]). Multiple-subgroup analyses showed that sensitivities (P = 0.13-0.91) and specificities (P = 0.26 0.99) on 3D-isotropic MR arthrography for diagnosing RCT, full/partial-thickness SST-IST tear, SSC tear, and labral lesions were not significantly different from 2D-conventional MR arthrography. On meta-regression analysis, 3D-TSE sequence demonstrated higher sensitivity (P < 0.01) than 3D-GRE for RCT and labral lesions. DATA CONCLUSION: 3D-isotropic MR arthrography can replace 2D conventional MR arthrography. 3D-isotropic MR arthrography using TSE sequence is recommended for more accurate diagnosis, as it demonstrates increased sensitivity. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;48:1034-1045. PMID- 29603488 TI - AF news. PMID- 29603489 TI - $100 million to get Australia's health on track. PMID- 29603490 TI - Socioeconomic status and quality of life among Chinese American breast cancer survivors: The mediating roles of social support and social constraints. AB - OBJECTIVE: Literature has well noted ethnic/racial disparities in cancer survival and cancer care. However, socioeconomic disparities in psychosocial adjustment to breast cancer have garnered little attention. This study addresses the research gap by investigating the associations between socioeconomic indicators (ie, education, annual personal, and household income) and quality of life (QOL) and the mediating roles of social support and social constraints (objective and subjective conditions that constrain individuals from disclosing cancer concerns) in these associations among Chinese American breast cancer survivors (CABCS). METHODS: Ninety-six CABCS completed questionnaires assessing these variables. RESULTS: After controlling for stage of cancer, annual personal and household income had indirect effects on QOL through social support, and education showed indirect effect on QOL through social support and social constraints. Subscale analyses indicated that controlling for years of immigration, annual personal and household income showed indirect effect on functional well-being through social support. When controlling for stage of cancer and income, education showed indirect effects on physical well-being through social support and social constraints and showed both direct and indirect effects on breast cancer concerns through social constraints. CONCLUSION: This study suggested that socioeconomic indicators, education, and income could be associated with different aspects of QOL through unique interpersonal mechanisms among CABCS. Our findings implied that increasing social support and reducing social constraints when implementing psychosocial interventions for CABCS may help to address the SES-related health disparities. PMID- 29603491 TI - Assessment of epicardial fat and carotid intima media thickness in gestational hypertension. AB - AIM: Gestational hypertension (GHT) is a common disorder of pregnancy characterized by new onset hypertension without the presence of detectable proteinuria after 20 weeks of gestation. Epicardial fat thickness (EFT) and carotid intima media thickness (CIMT) are suggested as new predictors of subclinical atherosclerosis. Although the relationship between these parameters and essential hypertension has been demonstrated, this association in patients with GHT is still unknown. We aimed to investigate CIMT and EFT in patients with GHT. METHODS: A total of 90 patients (44 GHT and 46 controls) were enrolled. Patients with diabetes mellitus, chronic hypertension and cardiovascular disease (CVD) were excluded. In the third trimester, the mean CIMT at the far wall of both left and right common carotid arteries was measured on B-mode duplex ultrasound. EFT was measured on the free wall of the right ventricle at the end systole in the parasternal long-axis view by standard transthorasic 2D echocardiography. RESULTS: Unlike the mean CIMT (0.52 +/- 0.13 mm vs 0.47 +/- 0.11 mm; P = 0.078), the mean EFT was significantly higher in the GHT group compared to the controls (5.31 +/- 1.68 mm vs 4.17 +/- 1.16 mm; P = 0.002). In multivariate logistic regression analysis, among the most pertinent clinical variables, only EFT is an independent determinant of GHT (OR: 2.903; 95% confidence interval [CI]: 1.454-5.796; P = 0.003). In receiver operating characteristic (ROC) analysis, EFT >5.5 mm had 82.6% specificity and 52.3% sensitivity in predicting a diagnosis of GHT (ROC area under curve: 0.689, 95% CI: 0.577-0.802, P = 0.002). CONCLUSION: Maternal EFT may be higher in pregnant women with GHT in comparison with those of controls. PMID- 29603492 TI - Demand for neurological services in Central Eastern Europe: a 10-year national survey in Hungary. AB - BACKGROUND AND PURPOSE: In order to plan neurological capacities at a national level for the next decade, the current use of neurological services should be evaluated. We analyzed the utilization of neurological services in Hungary, a country with a single-payer health insurance system covering the whole population. METHODS: We created a database from medical reports submitted to the National Health Insurance Fund from all hospitals and outpatient services between 2004 and 2013. The number of subjects presenting to the neurological healthcare system and their major diagnoses by 10th International Classification of Diseases categories were analyzed. The overall healthcare service utilization of these patients was also estimated. RESULTS: Of the 10 million inhabitants, 2.9 million people used an inpatient or outpatient neurological service at least once over the 10-year period. Annually, 1% of the population was admitted to neurological inpatient wards and 6% of the population used some neurological outpatient service. Major reasons for using neurological services were: cerebrovascular diseases (I60-I69; 1.2 million patients), episodic and paroxysmal disorders (G40 G47; 1.3 million patients) and general symptoms and signs (R50-R56; 1.3 million patients). The 2.9 million people had 12.7 million hospital admissions to any ward and 365.7 million outpatient visits to any specialist during the 10 years. CONCLUSIONS: The demand for neurological services is high in Hungary; close to 30% of the population used an inpatient or outpatient neurological service at least once during this 10-year period. Results from this project provide data for international comparisons and help to ensure better informed and more focused resource allocation. PMID- 29603493 TI - Long non-coding RNA-CTD-2108O9.1 represses breast cancer metastasis by influencing leukemia inhibitory factor receptor. AB - Breast cancer (BC) is an aggressive malignant disease in women worldwide with a high tendency to metastasize. However, important biomarkers for BC metastasis remain largely undefined. In the present study, we identified that long non coding RNA-CTD-2108O9.1 is downregulated in BC tissues and cells and acts as a metastatic inhibitor of BC. Mechanistic investigation determined that lncRNA-CTD 2108O9.1 represses metastasis by targeting leukemia inhibitory factor receptor (LIFR), which is designated as a metastasis suppressor in BC. Our study characterizes a significant tumor suppressor active in BC metastasis repression through the known metastasis inhibitor LIFR. PMID- 29603494 TI - Clarifying the Relationships between Microsporidia and Cryptomycota. AB - Some protists with microsporidian-like cell biological characters, including Mitosporidium, Paramicrosporidium, and Nucleophaga, have SSU rRNA gene sequences that are much less divergent than canonical Microsporidia. We analysed the phylogenetic placement and environmental diversity of microsporidian-like lineages that group near the base of the fungal radiation and show that they group in a clade with metchnikovellids and canonical microsporidians, to the exclusion of the clade including Rozella, in line with what is currently known of their morphology and cell biology. These results show that the phylogenetic scope of Microsporidia has been greatly underestimated. We propose that much of the lineage diversity previously thought to be cryptomycotan/rozellid is actually microsporidian, offering new insights into the evolution of the highly specialized parasitism of canonical Microsporidia. This insight has important implications for our understanding of opisthokont evolution and ecology, and is important for accurate interpretation of environmental diversity. Our analyses also demonstrate that many opisthosporidian (aphelid+rozellid+microsporidian) SSU V4 OTUs from Neotropical forest soils group with the short-branching Microsporidia, consistent with the abundance of their protist and arthropod hosts in soils. This novel diversity of Microsporidia provides a unique opportunity to investigate the evolutionary origins of a highly specialized clade of major animal parasites. PMID- 29603495 TI - Trade-offs between carbon stocks and timber recovery in tropical forests are mediated by logging intensity. AB - Forest degradation accounts for ~70% of total carbon losses from tropical forests. Substantial emissions are from selective logging, a land-use activity that decreases forest carbon density. To maintain carbon values in selectively logged forests, climate change mitigation policies and government agencies promote the adoption of reduced-impact logging (RIL) practices. However, whether RIL will maintain both carbon and timber values in managed tropical forests over time remains uncertain. In this study, we quantify the recovery of timber stocks and aboveground carbon at an experimental site where forests were subjected to different intensities of RIL (4, 8, and 16 trees/ha). Our census data span 20 years postlogging and 17 years after the liberation of future crop trees from competition in a tropical forest on the Guiana Shield, a globally important forest carbon reservoir. We model recovery of timber and carbon with a breakpoint regression that allowed us to capture elevated tree mortality immediately after logging. Recovery rates of timber and carbon were governed by the presence of residual trees (i.e., trees that persisted through the first harvest). The liberation treatment stimulated faster recovery of timber albeit at a carbon cost. Model results suggest a threshold logging intensity beyond which forests managed for timber and carbon derive few benefits from RIL, with recruitment and residual growth not sufficient to offset losses. Inclusion of the breakpoint at which carbon and timber gains outpaced postlogging mortality led to high predictive accuracy, including out-of-sample R2 values >90%, and enabled inference on demographic changes postlogging. Our modeling framework is broadly applicable to studies that aim to quantify impacts of logging on forest recovery. Overall, we demonstrate that initial mortality drives variation in recovery rates, that the second harvest depends on old growth wood, and that timber intensification lowers carbon stocks. PMID- 29603496 TI - Novel application of additive manufacturing techniques for paediatric choledochal malformations. PMID- 29603497 TI - Hypertension and the acute phase of intracerebral haemorrhage: more evidence of the 'silent killer'. PMID- 29603498 TI - Effects of the butyric acid-producing strain Clostridium butyricum MIYAIRI 588 on broiler and piglet zootechnical performance and prevention of necrotic enteritis. AB - The objective of this study was to assess the effects of a probiotic strain Clostridium butyricumMIYAIRI 588 (CBM588) on broiler and weaned piglet health and zootechnical performance. Five field studies were carried out in broilers and five in weaned piglets under European feed additive guidelines. Each study followed a randomized blocked design with two treatments: Control (basal diet) and CBM588 supplemented groups. The zootechnical performance parameters selected were body weight, daily gain, feed intake and feed efficiency (feed:gain). Broilers fed diets with CBM588 gained significantly more weight (+2%, p < .001) and exhibited significantly better feed efficiency (-1.6%, p < .001) in comparison with Controls. Similarly, analysis of pooled data of weaned piglet trials showed that CBM588-fed piglets were significantly heavier than Controls (+2.6%, p = .014), exhibited significantly higher mean daily gain (+4.7%; p = .004), and significantly improved feed efficiency (-4.2%, p = .001). In addition to the zootechnical efficacy studies, the preventive effect of CBM588 on necrotic enteritis (NE) was assessed in a natural challenge model in broilers where CBM588 reduced the incidence and severity of NE lesions. These data indicate the potential of CBM588 to improve broiler and weaned piglet zootechnical performance, and to make a positive contribution to animal health. PMID- 29603499 TI - High diversity and variability in the bacterial microbiota of the coffee berry borer (Coleoptera: Curculionidae), with emphasis on Wolbachia. AB - AIMS: Variation in microbiota of the coffee berry borer (CBB) Hypothenemus hampei was studied. Diversity, structure and function of bacterial communities were compared between eggs vs adults, CBBs from shade coffee vs sun coffee, CBBs from the field vs raised in the laboratory, and CBBs with and without the antibiotic tetracycline. METHODS AND RESULTS: We sequenced the region V4 of the gene 16 S rRNA. Pseudomonadaceae and Enterobacteriaceae, particularly Pseudomonas and Pantoea, dominated microbiotas of the CBB. Comparative functional inferences with PICRUSt suggested that samples from the field were enriched for genes involved in carbohydrate and protein digestion and absorption, while laboratory-reared samples were higher in genes for melanization and caffeine metabolism. CONCLUSIONS: Microbiotas of the CBB were diverse and dominated by the genus Pseudomonas, several species of which have been previously associated with caffeine degradation in this insect. Wolbachia was the only endosymbiont detected with known ability to manipulate host reproduction. SIGNIFICANCE AND IMPACT OF THE STUDY: This study demonstrates that stage of development and origin of samples affected the structure and function of the CBB's bacterial communities. This is the first attempt to predict functional significance of the CBB microbiota in nutrition, reproduction and defence. PMID- 29603500 TI - Bombyx mori epidermal growth factor receptor is required for nucleopolyhedrovirus replication. AB - Baculovirus-host interactions are important models for studying the biological control of lepidopteran pests. Research on baculovirus-host interactions has focussed on baculovirus manipulation of cellular signalling pathways, including the extracellular signal-regulated kinase (ERK) and phosphatidylinositol-3 kinases/protein kinase B (PI3K/Akt) signalling pathways. However, the mechanism underlying ERK and PI3K/Akt activation and function in response to baculovirus infection remains poorly understood. Here, we demonstrated that baculovirus activated the Bombyx mori ERK and PI3K/Akt signalling pathways via the B. mori epidermal growth factor receptor (BmEGFR). To further characterize the function of the BmEGFR/ERK signalling pathway in baculovirus replication, we calculated genome-wide changes in kinase-chromatin interactions for ERK after baculovirus infection using chromatin immunoprecipitation followed by high-throughput sequencing. A Gene Ontology analysis showed that virus infection had effects on the biological regulation, cellular process and metabolic process pathways. Moreover, ERK was shown to regulate the transcription of late viral genes. Taken together, our results suggest that baculoviruses manipulate components of the host cell machinery for replication via modulation of the BmEGFR signalling pathway. PMID- 29603501 TI - Association of serum Cystatin C with neuromyelitis optica spectrum disorders. AB - BACKGROUND AND PURPOSE: The relationship between Cystatin C (CysC) and neuromyelitis optica spectrum disorders (NMOSD) is unknown. METHODS: Serum CysC levels were measured in 105 Chinese patients with NMOSD (53 in relapse, 52 in remission) and 109 healthy controls (HCs). The association of CysC with NMOSD and its clinical and magnetic resonance imaging parameters were evaluated. RESULTS: Cystatin C levels were significantly lower in patients with relapsing NMOSD than in those in remission (P < 0.001) or HCs (P < 0.05). CysC levels in NMOSD remission were higher than in HCs (P = 0.002). CysC levels were positively associated with age and negatively associated with brain lesion numbers in relapsing NMOSD (r = -0.252, P = 0.069). CONCLUSION: Our results indicate a reduced serum level of CysC in patients with relapsing NMOSD and an increased level in remission. Further studies on the role of CysC in NMOSD are warranted. PMID- 29603502 TI - Microbial mechanisms of carbon priming effects revealed during the interaction of crop residue and nutrient inputs in contrasting soils. AB - Agronomic practices such as crop residue return and additional nutrient supply are recommended to increase soil organic carbon (SOC) in arable farmlands. However, changes in the priming effect (PE) on native SOC mineralization in response to integrated inputs of residue and nutrients are not fully known. This knowledge gap along with a lack of understanding of microbial mechanisms hinders the ability to constrain models and to reduce the uncertainty to predict carbon (C) sequestration potential. Using a 13 C-labeled wheat residue, this 126-day incubation study examined the dominant microbial mechanisms that underpin the PE response to inputs of wheat residue and nutrients (nitrogen, phosphorus and sulfur) in two contrasting soils. The residue input caused positive PE through "co-metabolism," supported by increased microbial biomass, C and nitrogen (N) extracellular enzyme activities (EEAs), and gene abundance of certain microbial taxa (Eubacteria, beta-Proteobacteria, Acidobacteria, and Fungi). The residue input could have induced nutrient limitation, causing an increase in the PE via "microbial nutrient mining" of native soil organic matter, as suggested by the low C-to-nutrient stoichiometry of EEAs. At the high residue, exogenous nutrient supply (cf. no-nutrient) initially decreased positive PE by alleviating nutrient mining, which was supported by the low gene abundance of Eubacteria and Fungi. However, after an initial decrease in PE at the high residue with nutrients, the PE increased to the same magnitude as without nutrients over time. This suggests the dominance of "microbial stoichiometry decomposition," supported by higher microbial biomass and EEAs, while Eubacteria and Fungi increased over time, at the high residue with nutrients cf. no-nutrient in both soils. Our study provides novel evidence that different microbial mechanisms operate simultaneously depending on organic C and nutrient availability in a residue-amended soil. Our results have consequences for SOC modeling and integrated nutrient management employed to increase SOC in arable farmlands. PMID- 29603503 TI - Flawed statistics and science confirming existing paradigms. AB - BACKGROUND: Part of the scientific community states that implausible methods cannot have a true effect and that epidemiological proof can only lead to false positives. DISCUSSION: Homeopathy is regarded as an example of an implausible method with false positive evidence. However, epidemiological proof is necessary to falsify the placebo hypothesis. Implausibility is now supposed to rectify selection of a part of all trials, but the applied selection criteria are diverse and not common in conventional medicine. Applying Bayes' theorem only once to demonstrate that a low prior chance does not lead to reasonable probability is flawed application of this theorem. CONCLUSION: Demanding scientific evidence and then rejecting the same with post-hoc selection of trials and flawed statistics shows unwillingness to falsify the completeness of existing paradigms. PMID- 29603504 TI - A high-quality pedigree and genetic markers both reveal inbreeding depression for quality but not survival in a cooperative mammal. AB - Inbreeding depression, the reduced fitness of offspring of closely related parents, is commonplace in both captive and wild populations and has important consequences for conservation and mating system evolution. However, because of the difficulty of collecting pedigree and life-history data from wild populations, relatively few studies have been able to compare inbreeding depression for traits at different points in the life cycle. Moreover, pedigrees give the expected proportion of the genome that is identical by descent (IBDg ) whereas in theory with enough molecular markers realized IBDg can be quantified directly. We therefore investigated inbreeding depression for multiple life history traits in a wild population of banded mongooses using pedigree-based inbreeding coefficients (fped ) and standardized multilocus heterozygosity (sMLH) measured at 35-43 microsatellites. Within an information theoretic framework, we evaluated support for either fped or sMLH as inbreeding terms and used sequential regression to determine whether the residuals of sMLH on fped explain fitness variation above and beyond fped . We found no evidence of inbreeding depression for survival, either before or after nutritional independence. By contrast, inbreeding was negatively associated with two quality-related traits, yearling body mass and annual male reproductive success. Yearling body mass was associated with fped but not sMLH, while male annual reproductive success was best explained by both fped and residual sMLH. Thus, our study not only uncovers variation in the extent to which different traits show inbreeding depression, but also reveals trait-specific differences in the ability of pedigrees and molecular markers to explain fitness variation and suggests that for certain traits, genetic markers may capture variation in realized IBDg above and beyond the pedigree expectation. PMID- 29603505 TI - Precising definitions as a way to combat overdiagnosis. AB - Roughly, overdiagnosis (ODx) occurs when people are harmed by receiving diagnoses (often accompanied by interventions) that do not benefit them, usually because the diagnosed conditions do not pose a threat to their health. ODx is a theoretical as well as a practical problem as it relates to definitions of disease. Elsewhere, it has been argued that disease is a vague concept and that this vagueness may contribute to ODx. In response, we develop a stipulative or precising definition of disease, for the specific purpose of decreasing or preventing ODx. We call this diseaseODx , aimed at distinguishing cases where it would be beneficial to identify (and treat the condition) from those where diagnosis is more likely to harm than benefit. A preliminary definition of diseaseODx is that X is a diseaseODx iff there is dysfunction that has a significant risk of causing severe harm. This paper examines the 3 concepts in this definition, using a naturalistic account of function, a Feinbergian account of comparative harm, and a probabilistic understanding of risk. We then test the utility of this approach using examples of clinical conditions that are currently overdiagnosed. PMID- 29603506 TI - Association between iron-deficiency anemia and depression: A web-based Japanese investigation. AB - AIM: This web-based survey aimed to examine the relation between iron-deficiency anemia and depression in 11 876 Japanese participants. METHODS: Participants consisted of 1000 individuals with self-reported history of depression (mean age, 41.4 +/- 12.3 years; 499 women) and 10 876 population-based controls (mean age, 45.1 +/- 13.6 years; 5185 women). The 6-item Kessler Scale (K6) score was used as a psychological distress scale. The design of the study was cross-sectional. RESULTS: The rate of self-reported lifetime history of iron-deficiency anemia was higher in the depression group in both men (depression, 7.2%; control, 4.0%; P < 0.001; odds ratio [OR], 1.86; 95% confidence interval [CI], 1.30-2.68) and women (depression, 33.4%; control, 25.8%; P < 0.001; OR, 1.45; 95%CI, 1.19-1.76). The K6 score in participants with self-reported history of iron-deficiency anemia was higher in both the depression (P = 0.004) and control (P < 0.001) groups. In addition, in all participants, the rate of individuals who showed a K6 cut-off score of 13 or more was higher in those with a self-reported history of iron deficiency anemia (P < 0.001; OR, 1.47; 95%CI, 1.31-1.65). Logistic regression analyses revealed that self-reported history of depression and the K6 score were positively associated with self-reported history of iron-deficiency anemia (all P < 0.01). CONCLUSION: Self-reported history of iron-deficiency anemia was associated with self-reported history of depression. Furthermore, self-reported history of iron-deficiency anemia was associated with higher psychological distress. PMID- 29603508 TI - Steroidal hormone and morphological responses in the prostate anterior lobe in different cancer grades after Celecoxib and Goniothalamin treatments in TRAMP mice. AB - Prostate cancer is the second most diagnosed cancer in the world, and alternative methods to prevent and treat different lesion grades need to be evaluated. The objective was to evaluate the morphological, hormonal, and inflammatory responses in the prostate anterior lobe in transgenic adenocarcinoma of the mouse prostate (TRAMP), following Celecoxib and Goniothalamin (GTN) treatments. All animals were treated for 4 weeks, from 8 weeks of age and euthanized either immediately after treatment (12-week-old mice: immediate response) or later (22-week-old mice: late response). The results showed a significant increase of high-grade prostatic intraepithelial neoplasia (HGPIN) and well-differentiated adenocarcinoma (WDA), according to the age in the control groups. Celecoxib treatment decreased the WDA incidence in the late response group. GTN led to a significant healthy tissue increase, and an LGPIN and HGPIN decrease in the immediate response group. In the late response group, GTN led to healthy area increase and there was no occurrence of WDA. AR and ERalpha immunoexpressions were reduced by both treatments in the immediate response groups. However, only GTN was able to decrease the ERalpha level in the late response group. Regarding COX-2 immunoreactivity, both treatments reduced the frequency of this enzyme. We can conclude that the prostate anterior lobe is a good model to study prostate cancer, considering its slow progression. Both treatments led to cancer delay in the prostate anterior lobe. However, GTN pointed towards a better treatment spectrum in the signaling pathways in the prostate microenvironment, particularly in ERalpha. PMID- 29603509 TI - Translational neuroscience and psychiatry: A conceptual analysis. AB - As rapidly developing research disciplines and enterprises, the translational sciences have made significant impact on research direction in medicine. Psychiatry has likewise been affected, and in this regard, the translational neurosciences have been the major drivers. This paper explores the conceptual underpinnings of this enterprise in relation to psychiatry. It shows that translation is used in a metaphorical sense in this context but that this can be misleading because of the resultant connotation that there is equivalence between neurobiological states and mental states. Furthermore, this equivalence is reinforced by the unidirectional flow or bottom up approach of the translational process. Given that the epistemological basis to psychiatry is fundamentally different to that underlying medicine, questions are raised concerning the application of the translational neurosciences approach to mental symptoms and mental disorders. The hybrid structure of mental symptoms and mental disorders demands that attention is paid to the "semantic" as well as the neurobiological constituents. Neglect of the former would carry implications for the validity of research findings as well as have ethical consequences for treating patients. Translational neurosciences may have greater validity in those mental disorders and mental symptoms whose constitution and sense are carried by the neurobiological elements. PMID- 29603507 TI - Model-based detection and analysis of introgressed Neanderthal ancestry in modern humans. AB - Genetic evidence has revealed that the ancestors of modern human populations outside Africa and their hominin sister groups, notably Neanderthals, exchanged genetic material in the past. The distribution of these introgressed sequence tracts along modern-day human genomes provides insight into the selective forces acting on them and the role of introgression in the evolutionary history of hominins. Studying introgression patterns on the X-chromosome is of particular interest, as sex chromosomes are thought to play a special role in speciation. Recent studies have developed methods to localize introgressed ancestries, reporting long regions that are depleted of Neanderthal introgression and enriched in genes, suggesting negative selection against the Neanderthal variants. On the other hand, enriched Neanderthal ancestry in hair- and skin related genes suggests that some introgressed variants facilitated adaptation to new environments. Here, we present a model-based introgression detection method called dical-admix. We demonstrate its efficiency and accuracy through extensive simulations and apply it to detect tracts of Neanderthal introgression in modern human individuals from the 1000 Genomes Project. Our findings are largely concordant with previous studies, consistent with weak selection against Neanderthal ancestry. We find evidence that selection against Neanderthal ancestry was due to higher genetic load in Neanderthals resulting from small effective population size, rather than widespread Dobzhansky-Muller incompatibilities (DMIs) that could contribute to reproductive isolation. Moreover, we confirm the previously reported low level of introgression on the X chromosome, but find little evidence that DMIs contributed to this pattern. PMID- 29603510 TI - Esophageal provocation tests: Are they useful to improve diagnostic yield of high resolution manometry? AB - High resolution manometry (HRM) is the gold standard to diagnose esophageal motility disorders but has some limitations. The inclusion of provocative tests might enhance the diagnostic yield of HRM. These tests are easy to perform and to add to the regular manometry protocol. Multiple rapid swallows (MRS; 5 2-mL swallows) is useful to assess the contractile reserve and deglutitive inhibition. The optimal number of MRS to perform might be 3 as suggested by Mauro et al. in this issue of Neurogastroenterology & Motility. The absence of contractile reserve might be associated with gastro-esophageal reflux disease and with an increased risk of post fundoplication dysphagia. Single viscous and solid swallows might enhance the detection of esophageal motility disorders but are not significantly associated with symptom occurrence. Test meal has the advantage to represent a real-life scenario and is promising to depict significant motility findings responsible for esophageal symptoms. Post-prandial recording might also be of interest to diagnose rumination and belching disorders. The best indication of rapid drink challenge test (free drinking of 200 mL) is currently the diagnosis of esophago-gastric junction obstruction. Finally, abdominal compression might be an option to evaluate response of esophageal peristalsis in a context of outflow resistance as proposed by Brink et al. in this issue. These provocative maneuvers appear to provide a complementary role in the evaluation of esophageal motility but require prospective studies to determine the validity of the findings and whether they will lead to changes in clinical practice. PMID- 29603512 TI - Response: The coagulation laboratory monitoring of AFSTYLA single-chain FVIII concentrate. PMID- 29603511 TI - Objective quantification of psychomotor disturbances in patients with a major depressive episode. PMID- 29603513 TI - Risk score prediction model for dementia in patients with type 2 diabetes. AB - BACKGROUND AND PURPOSE: No study has established a prediction dementia model in the Asian populations. This study aimed to develop a prediction model for dementia in Chinese type 2 diabetes patients. METHODS: The retrospective cohort study included 27 540 Chinese type 2 diabetes patients (aged 50-94 years) enrolled in the Taiwan National Diabetes Care Management Program. Participants were randomly allocated into derivation and validation sets at a 2:1 ratio. Cox proportional hazards regression models were used to identify risk factors for dementia in the derivation set. Steps proposed by the Framingham Heart Study were used to establish a prediction model with a scoring system. RESULTS: The average follow-up was 8.09 years, with a total of 853 incident dementia cases in the derivation set. The dementia risk score summed up the individual scores (from 0 to 20). The areas under the curve of 3-, 5- and 10-year dementia risks were 0.82, 0.79 and 0.76 in the derivation set and 0.84, 0.80 and 0.75 in the validation set, respectively. CONCLUSIONS: The proposed score system is the first dementia risk prediction model for Chinese type 2 diabetes patients in Taiwan. PMID- 29603514 TI - Sexual acquisition of HIV infection after solid organ transplantation: Late presentation and potentially fatal complications. AB - INTRODUCTION: While the growing knowledge on HIV among solid organ transplant recipients (SOT) is limited to either pretransplant infection or allograft transmission, there are only sparse reports describing HIV-infection after transplantation through sexual route, the primary mode of transmission in the general population. METHODS: From two different centers, we report nine new cases of HIV infection in SOT recipients attributed to sexual acquisition: eight cases of kidney-transplant recipients and one heart-transplant recipient. FINDINGS: There were nine cases of post-transplant HIV-infection detected among 14 526 transplants performed 1998 to 2015. In 6/9 cases, infection was contracted 5 years after SOT. All but one patient had stable allograft function under immunosuppressive therapy. The main trigger to diagnosis was late CMV disease and sexually transmitted diseases; five patients had CDC-stage 3 HIV infection. In 7/9 patients, virologic response and CD4 recovery were achieved within 3 months after starting antiretroviral therapy (ART). After an average of 3.6 years post diagnosis, 5/9 patients remained alive with well-controlled infection and functioning allograft. CONCLUSION: Sexual acquisition of HIV infection after SOT represents a difficult challenge, as it may occur in any kind of transplant and at any time. The course of infection resembles that of the general population, with life-threatening infectious complications, but good response to ART. Assessment of lifestyle and risk behavior is paramount, as indications may be not disclosed without direct questioning. PMID- 29603515 TI - Cerebral microbleeds predict infectious intracranial aneurysm in infective endocarditis. AB - BACKGROUND AND PURPOSE: Magnetic resonance imaging (MRI) features such as cerebral microbleeds and sulcal susceptibility-weighted imaging (SWI) or gradient echo T2* lesions in infective endocarditis (IE) have been associated with the presence of infectious intracranial aneurysm (IIA). Our aim was to validate these MRI predictors for IIA in order to better assist in assessing the appropriate indications for digital subtraction angiography (DSA). METHODS: The derivation cohort comprised IE patients with neurological evaluation, MRI and DSA at a single tertiary referral center from January 2015 to July 2016. Validation was performed in a cohort of IE patients who underwent MRI and DSA at the same center from 2010 to 2014. RESULTS: Of 62 patients in the derivation cohort, 10 (16%) had IIAs. Of 129 in the validation cohort, 19 (15%) IIAs were identified. The MRI predictors for IIA consist of (i) contrast enhancement with microbleeds, (ii) cerebral microbleeds >5 mm or sulcal SWI lesions and (iii) any MRI hemorrhages. The sensitivity for the presence of IIA in each group of the derivation cohort was 90%, 80% and 100%, respectively. The sensitivity in the validation cohort was 47%, 68% and 94% respectively. The specificity in the derivation cohort was 87%, 85% and 18%. In the validation cohort, the specificity was similar at 87%, 75% and 27%. CONCLUSIONS: The absence of MRI hemorrhages may not necessitate the need for DSA. PMID- 29603517 TI - Israel Chemical Society Prizes: Y. Apeloig, S. Shaik, J. M. L. Martin, D. Meyerstein, S. Ruthstein, and M. E. van der Boom / NAS Award in Chemical Sciences: J. A. Doudna / Remsen Award and Ralph N. Adams Award: C. A. Mirkin. PMID- 29603516 TI - A PIGH mutation leading to GPI deficiency is associated with developmental delay and autism. AB - We identified an individual with a homozygous missense variant (p.Ser103Pro) in a conserved residue of the glycosylphosphatidylinositol (GPI) biosynthesis gene PIGH. This gene encodes an essential component of the phosphatidylinositol N acetylglucosaminyltransferase complex, in the first step of the biosynthesis of GPI, a glycolipid anchor added to more than one hundred human proteins, several being critical for embryogenesis and neurological functions. The affected individual had hypotonia, moderate developmental delay, and autism. Unlike other reported individuals with GPI deficiency, the proband did not have epilepsy; however, he did have two episodes of febrile seizures. He had normal alkaline phosphatase and no brachytelephalangy. Upon analysis of the surface expression of GPI-anchored proteins on granulocytes, he was demonstrated to have GPI deficiency. This suggests that PIGH mutations may cause a syndrome with developmental delay and autism, but without an epileptic encephalopathy, and should increase the awareness of the potentially deleterious nature of biallelic variants in this gene. PMID- 29603518 TI - Wound swab and wound biopsy yield similar culture results. AB - The question remains whether wound swabs yield similar culture results to the traditional gold standard, biopsies. Swabs are not invasive and easy to perform. However, they are believed to capture microorganisms from the surface rather than microorganisms that have invaded tissue. Several studies compared swabs and biopsies using different populations and sampling methods, complicating the ability to draw conclusions for clinical practice. This study aimed to compare swab and biopsy in clinical practice, by including a variety of wounds and using standard sampling and culture procedures. Swabs (Levine technique) and biopsies were taken for microbiological culture in a standardized manner from the same location of one wound for each patient. Statistical analyses were performed to determine overall agreement, and observed agreement and kappa for specific microorganisms. A variety of wounds of 180 patients from different healthcare facilities in The Netherlands were included. Skin flora was more frequently cultured from swabs, resulting in similar recovery rates when excluding skin flora (1.34 vs 1.35). Swabs were able to identify all microorganisms cultured from biopsies in 131 wounds (72.8%) wounds. Most frequently identified organisms were Staphylococcus aureus, Pseudomonas aeruginosa, and beta-haemolytic streptococci species. Observed agreement and kappa for these organisms varied between 87.2 and 97.8% and 0.73 and 0.85, respectively. This study demonstrates that swabs and biopsies tend to yield the same culture results when taken from the same location. For frequently occurring microorganisms, agreement between the two methods was even higher. Therefore, there seems to be no direct need for invasive biopsy in clinical practice. PMID- 29603519 TI - Comparison of two different culture conditions for derivation of early hiPSC. AB - Different culture-systems for derivation of induced pluripotent stem cells (iPSC) in vitro from human fibroblasts have been established. Here, we compared the efficacy of two different feeder-free culture-systems; Matrigel-coated surfaces in combination with mTeSR1 medium versus Vitronectin-coated surfaces in combination with Essential 8 (E8) medium. The comparison was performed by counting the number of emerging iPSC-looking colonies of re-programmed fibroblasts. The fibroblasts were re-programmed using episomal plasmids expressing OCT3/4, SOX2, KLF4, L-MYC, LIN28, and a p53 knock down shP53. Three different fibroblast lines, K40 and K48 from healthy controls and BBS1 from a patient with Bardet-Biedl syndrome, were used in two independent setups. The BBS1 line was used in both setups in combination with K40 and K48 respectively. In all four re-programming experiments, we observed a significantly higher number of emerging colonies with the combination Matrigel/mTeSR1 as compared to the combination Vitronectin/E8. The presence of iPSC was verified by alkaline phosphatase and Tra-1-60 staining. Furthermore, a higher expression of the pluripotency-associated markers NANOG and SOX2 in cells under Matrigel/mTeSR1 conditions compared with Vitronectin/E8 supported the higher proportion of iPSC on Matrigel/mTeSR1 plates. In conclusion, the combination Matrigel/mTeSR1 is more efficient for derivation of iPSC compared to the Vitronectin/E8 combination. PMID- 29603520 TI - Effect of pomegranate extract on vagina, skeleton, metabolic and endocrine profiles in an ovariectomized rat model. AB - AIM: Many women need estrogen therapy because of menopausal complaints. It is suggested that pomegranate plant has estrogenic effect. Aim of the study was to examine the effects of pomegranate seed extract on menopausal changes. METHODS: This study was conducted in an experimental environment with 23 Wistar Albino genus female rats. Sixteen rats were divided into two groups after ovariectomy. One group (SG) was fed with standard food and the pomegranate extract was added to drinking water of the other group (PG). Seven rats were identified as the sham group for the detection of basal values. At the end of 90 days, follicle stimulating hormone (FSH), estradiol, total cholesterol, high-density lipoprotein cholesterol (HDL)-cholesterol, low-density lipoprotein cholesterol (LDL) cholesterol, triglyceride, tibial bone cortex thickness and vaginal epithelium thickness of the groups were compared. RESULTS: FSH, total-cholesterol and HDL cholesterol levels were similar among the three groups (P > 0.05), while others were different (P < 0.05). In binary comparisons (PG vs SG), estradiol level (average +/- standard deviation [SD]: 252 +/- 43 vs 154 +/- 26 pg/mL), tibial bone cortex thickness (58 +/- 7 vs 40 +/- 2 MUm) and vaginal epithelium thickness (21 +/- 7 vs 10 +/- 4 MUm) were significantly higher in PG. In PG, triglyceride levels (103 +/- 26 vs 87 +/- 41 mg/dL) were higher and LDL-cholesterol levels were lower (20 +/- 8 vs 27 +/- 8 mg/dL), but these differences were not significant. CONCLUSION: In rats fed with pomegranate extract, estradiol levels increased and tibial bone cortex thickness and vaginal epithelium thickness also increased. Pomegranate itself or its formulation extracts may be a support or an alternative to the main treatment modalities in the preservation of bone density and the treatment of vaginal epithelial atrophy. PMID- 29603521 TI - Paliperidone palmitate treatment in a patient with monosomy X karyotype Turner syndrome who later developed schizophrenia. PMID- 29603522 TI - Re-infection of Toxoplasma gondii after HSCT presenting lymphadenopathy resembling recurrence of lymphoma. AB - Toxoplasma gondii (T. gondii) reactivation is one of the fatal complications after hematopoietic stem cell transplantation (HSCT); however, re-infection has not been reported. Here, we report a case of mycosis fungoides in which cervical lymphadenopathy developed after HSCT. Initially, recurrent lymphoma was suspected. However, biopsy of the lymph node showed typical histology of toxoplasmosis and serology showed re-infection of T. gondii. Toxoplasmosis needs to be differentiated for cases with lymphoadenopthy after HSCT. PMID- 29603523 TI - Evaluating the use of parental reports to estimate health care resource utilization in children with suspected genetic disorders. AB - OBJECTIVE: A key step in evaluating the cost-effectiveness of diagnostic genome wide sequencing (GWS) services is to measure the cost of prior and subsequent diagnosis-related health care resource utilization by patients. The majority of patients using diagnostic GWS services are children, and parental surveys are often used to complement utilization data abstracted from medical records. The objective of this study was to evaluate the validity of parental reports for children with very high levels of resource utilization. METHOD: Primary caregivers of children enrolled in the CAUSES Research Clinic, a diagnostic GWS programme at B.C. Children's Hospital, completed an online survey. Parent reported health care encounters for the 6-month period prior to survey completion were compared to utilization data abstracted from electronic medical records (EMR). The association between demographic characteristics and the probability of survey completion was tested using logistic regression. Agreement between parent reported and EMR data was evaluated using Cohen's kappa, prevalence- and bias adjusted kappa (PABAK), and the intraclass correlation coefficient (ICC). RESULTS: There were no major differences in demographic characteristics or resource utilization levels between families that completed the survey and those who did not. Agreement between parental reports and EMR data was high for hospitalizations (kappa = 0.71; PABAK = 0.89; ICC = 0.77) but lower for outpatient physician visits (kappa = 0.21; PABAK = 0.48; ICC = 0.27). CONCLUSIONS: Parental surveys are a valuable tool for estimating health care resource utilization during a 6-month recall period for children with suspected genetic disorders but are best used to complement utilization data collected from other sources. PMID- 29603524 TI - Valency-Controlled Framework Nucleic Acid Signal Amplifiers. AB - Weak ligand-receptor recognition events are often amplified by recruiting multiple regulatory biomolecules to the action site in biological systems. However, signal amplification in in vitro biomimetic systems generally lack the spatiotemporal regulation in vivo. Herein we report a framework nucleic acid (FNA)-programmed strategy to develop valence-controlled signal amplifiers with high modularity for ultrasensitive biosensing. We demonstrated that the FNA programmed signal amplifiers could recruit nucleic acids, proteins, and inorganic nanoparticles in a stoichiometric manner. The valence-controlled signal amplifier enhanced the quantification ability of electrochemical biosensors, and enabled ultrasensitive detection of tumor-relevant circulating free DNA (cfDNA) with sensitivity enhancement of 3-5 orders of magnitude and improved dynamic range. PMID- 29603525 TI - The Engineering of Chemical Synthesis: Humans and Machines Working in Harmony. AB - "Chemical synthesis has previously tended to rely heavily on robust labour intensive processes. We have been advocating a machine-assisted approach to synthesis for many years. To replace a bench chemist with a machine is not only unrealistic but impossible. What is realistic is to use this rapidly developing array of equipment and novel concepts to take us way beyond where we are today ...". Read more in the Guest Editorial by Steven V. Ley. PMID- 29603526 TI - Multiloci identification of Diaporthe fungi isolated from the medicinal plant Costus spiralis (Jacq.) Roscoe (Costaceae). AB - AIMS: The purpose of this study is to identify species from genus Diaporthe associated with a medicinal plant Costus spiralis by ITS, EF 1-alpha, TUB and CAL gens. METHODS AND RESULTS: The 30 isolates from the genus Diaporthe associated with the medicinal plant Costus spiralis were characterized based on morphological characters and the microculture technique and grouped by DNA fingerprinting with the ISSP gene. Afterwards, a total of 12 isolates were selected for the identification of the species based on the comparative research on the blast through the sequences of the ITS gene. Phylogenetic Tree of Maximum Likelihood were generated with the ITS gene individually and with the genes ITS, TUB, CAL and EF1-alpha combined with the Diaporthe species recognized and with the additional sequences obtained from GenBank for these species. CONCLUSIONS: It was not possible to characterize the 30 isolates microscopically and macromorphologically through the microculture technique and the macromorphological characteristics. The 12 isolates selected based on the DNA fingerprinting profile identified phylogenetically, revealed five distinct species of Diaporthe which are present in C. spiralis. SIGNIFICANCE AND IMPACT OF THE STUDY: The molecular analyses used in this study are excellent alternatives for species-level identification of Diaporthe associated with medicinal plants. PMID- 29603527 TI - De novo Biosynthesis of "Non-Natural" Thaxtomin Phytotoxins. AB - Thaxtomins are diketopiperazine phytotoxins produced by Streptomyces scabies and other actinobacterial plant pathogens that inhibit cellulose biosynthesis in plants. Due to their potent bioactivity and novel mode of action there has been considerable interest in developing thaxtomins as herbicides for crop protection. To address the need for more stable derivatives, we have developed a new approach for structural diversification of thaxtomins. Genes encoding the thaxtomin NRPS from S. scabies, along with genes encoding a promiscuous tryptophan synthase (TrpS) from Salmonella typhimurium, were assembled in a heterologous host Streptomyces albus. Upon feeding indole derivatives to the engineered S. albus strain, tryptophan intermediates with alternative substituents are biosynthesized and incorporated by the NRPS to deliver a series of thaxtomins with different functionalities in place of the nitro group. The approach described herein, demonstrates how genes from different pathways and different bacterial origins can be combined in a heterologous host to create a de novo biosynthetic pathway to "non-natural" product target compounds. PMID- 29603528 TI - Directed Evolution of Hyaluronic Acid Synthase from Pasteurella multocida towards High-Molecular-Weight Hyaluronic Acid. AB - Hyaluronic acid (HA), with diverse cosmetic and medical applications, is the natural glycosaminoglycan product of HA synthases. Although process and/or metabolic engineering are used for industrial HA production, the potential of protein engineering has barely been realised. Herein, knowledge-gaining directed evolution (KnowVolution) was employed to generate an HA synthase variant from Pasteurella multocida (pmHAS) with improved chain-length specificity and a twofold increase in mass-based turnover number. Seven improved pmHAS variants out of 1392 generated by error-prone PCR were identified; eight prospective positions were saturated and the most beneficial amino acid substitutions were recombined. After one round of KnowVolution, the longest HA polymer (<4.7 MDa), through an engineered pmHAS variant in a cell-free system, was synthesised. Computational studies showed that substitutions from the best variant (T40L, V59M and T104A) are distant from the glycosyltransferase sites and increase the flexibility of the N-terminal region of pmHAS. Taken together, these findings suggest that the N terminus may be involved in HA synthesis and demonstrate the potential of protein engineering towards improved HA synthase activity. PMID- 29603529 TI - Functional anatomy reveals secretory activity in papillose anthers of a buzz pollinated Solanum species (Cyphomandra clade - Solanaceae). AB - Pollination in Solanum (Solanaceae) species is commonly performed by female bees, which vibrate anthers to extract pollen. Another pollen removal type is by male euglossine bees, milking the anthers when searching for floral scents produced by secretory tissues (osmophorous) at the swollen connective of the anthers of species in the Cyphomandra clade. Some species of this clade, however, are buzz pollinated and present papillate anthers that should also have secretory activity, a hypothesis here tested. The anthers of Solanum luridifuscescens were fixed at different stages of development and analysed under light microscopy, SEM and TEM. Histochemical tests for the detection of starch and lipids were done. Epidermal cells of the abaxial surface of the anthers were visibly papillose, had large nuclei and dense cytoplasm rich in organelles such as mitochondria and plastids, typical features of secretory tissues. In this site, lipid droplets were detected, concomitantly with starch consumption, compatible with the secretory process in osmophores. No exudate or accumulation of substances was seen on the surface; in agreement with a previous pollination study performed in field conditions, where no pollinators were observed collecting floral scents, only pollen. The histochemical and structural analyses have evidenced the lipidic composition of the secretion, strongly pointing to terpenes as the secreted compounds. Ours findings show that papillae of the anthers have secretory activities that produce lipophilic compounds. This does not result in resources for bees, but could be an evolutionary step to the development of more specialised anthers in the Cyphomandra clade. PMID- 29603530 TI - Role of income in intergenerational co-residence: Evidence from selected African and Asian countries. AB - OBJECTIVE: The study investigates the macroeconomic determinants of co-residing arrangement between generations in selected developing countries with a focus on examining the effect of changing income level of the working generation. METHODS: A reduced form model is specified for co-residence between the older generation and altruistic working generation. The fixed- and random-effects models are applied in two waves of data for 22 countries. RESULTS: Estimated results indicate that the income of the altruistic working generation has a negative effect on co-residence, suggesting that if the income of the working generation increases, co-residence decreases. This decrease is greater for older men compared with their female counterparts. Life expectancy, literacy and culture also have significant influences on co-residence. CONCLUSION: Co-residence is expected to fall in developing countries with economic growth over time. Consequently, a higher proportion of older citizens will be vulnerable in the future. Hence, governments of developing countries will face increasing pressure from their older people to provide appropriate planning and strategy to face this challenge. PMID- 29603531 TI - A new multiplex real-time TaqMan(r) PCR for quantification of Mycoplasma hyopneumoniae, M. hyorhinis and M. flocculare: exploratory epidemiological investigations to research mycoplasmal association in enzootic pneumonia-like lesions in slaughtered pigs. AB - AIMS: A new multiplex qPCR, targeting Mycoplasma (M.) hyopneumoniae, M. hyorhinis and M. flocculare, was developed and the relationship between detection of those mycoplasma species and the extent of gross pneumonia-like lesions in slaughtered pigs lungs were investigated. METHODS AND RESULTS: The multiplex qPCR method targets the p102, p37 and fruA genes and has detection limits of 14, 146 and 16 genome equivalents MUl-1 for M. hyopneumoniae, M. hyorhinis and M. flocculare, respectively. In all, 671 lungs were collected and analysed, among them 666 were scored for macroscopic pneumonia and categorized according to the extent of the lesions (no or minor lesions, moderate lesions and extensive lesions). According to results of multiplex qPCR, 59.5% were positive for M. hyopneumoniae, 3.4% for M. hyorhinis and 34.7% for M. flocculare, with on average, 3.1 * 107 , 9.7 * 106 and 5.7 * 106 genome equivalents of mycoplasma ml-1 , respectively. More results showed that no or minor lesions were associated with multiplex qPCR-negative results or qPCR-positive results for M. flocculare. Moderate to extensive lesions were positively correlated with qPCR-positive results for M. hyopneumoniae. Extensive lesions were associated with qPCR-positive results for at least two mycoplasma species (M. hyopneumoniae and M. hyorhinis). CONCLUSION: The findings also indicated that M. hyopneumoniae and M. hyorhinis significantly increased the odds for a lung to have macroscopic pneumonia. No relationship was found between the extent of lesions and the mycoplasma genome load. SIGNIFICANCE AND IMPACT OF THE STUDY: This new multiplex qPCR appears to be specific, sufficiently sensitive and repeatable. The validation of this method with field samples guarantees its use for field epidemiological investigations, particularly to gain more insight into the aetiology of the porcine respiratory disease complex. PMID- 29603532 TI - Mapping the Relationship between Glycosyl Acceptor Reactivity and Glycosylation Stereoselectivity. AB - The reactivity of both coupling partners-the glycosyl donor and acceptor-is decisive for the outcome of a glycosylation reaction, in terms of both yield and stereoselectivity. Where the reactivity of glycosyl donors is well understood and can be controlled through manipulation of the functional/protecting-group pattern, the reactivity of glycosyl acceptor alcohols is poorly understood. We here present an operationally simple system to gauge glycosyl acceptor reactivity, which employs two conformationally locked donors with stereoselectivity that critically depends on the reactivity of the nucleophile. A wide array of acceptors was screened and their structure reactivity/stereoselectivity relationships established. By systematically varying the protecting groups, the reactivity of glycosyl acceptors can be adjusted to attain stereoselective cis-glucosylations. PMID- 29603533 TI - Aspergillus flavus native valve endocarditis following combined liver and renal transplantation: Case report and review of the literature. AB - Aspergillus endocarditis is a rare infection that occurs most commonly in patients with prior cardiac surgery but cases in post-transplant recipients without prior cardiac surgery have been reported. Diagnosis is often delayed and requires high index of suspicion. We here report a case of Aspergillus endocarditis in solid organ transplant recipient. PMID- 29603535 TI - Protein Crystallography and Site-Direct Mutagenesis Analysis of the Poly(ethylene terephthalate) Hydrolase PETase from Ideonella sakaiensis. AB - Unlike traditional recycling strategies, biodegradation is a sustainable solution for disposing of poly(ethylene terephthalate) (PET) waste. PETase, a newly identified enzyme from Ideonella sakaiensis, has high efficiency and specificity towards PET and is, thus, a prominent candidate for PET degradation. On the basis of biochemical analysis, we propose that a wide substrate-binding pocket is critical for its excellent ability to hydrolyze crystallized PET. Structure guided site-directed mutagenesis revealed an improvement in PETase catalytic efficiency, providing valuable insight into how the molecular engineering of PETase can optimize its application in biocatalysis. PMID- 29603534 TI - Low-intensity extracorporeal shockwave therapy ameliorates diabetic underactive bladder in streptozotocin-induced diabetic rats. AB - OBJECTIVES: To evaluate the therapeutic effect of once-weekly low-intensity extracorporeal shock wave therapy (Li-ESWT) on underactive bladder (UAB) in the streptozotocin (STZ)-induced diabetic rat model. MATERIALS AND METHODS: In all, 36 female Sprague-Dawley rats were divided into three groups: normal control (NC), diabetes mellitus control (DMC), and DM with Li-ESWT (DM Li-ESWT). The two DM groups received an intraperitoneal 60 mg/kg STZ injection to induce DM. The Li ESWT was applied toward the pelvis of the rats starting 4 weeks after STZ administration and lasting for 4 weeks. The Li-ESWT was given once weekly, with an energy flux density of 0.02 mJ/mm2 at 3 Hz for 400 pulses. All rats underwent conscious cystometry, leak-point pressure (LPP) assessment, ex vivo organ-bath study, histology, immunofluorescence, and Western Blot analysis. RESULTS: Conscious cystometry revealed voiding dysfunction in the DMC group, whereas the DM Li-ESWT group showed significantly improved voiding function, reflected in a reduced post-void residual urine volume and increased LPP compared to the DMC group. Ex vivo organ-bath studies showed that Li-ESWT enhanced muscle contractile activity of the bladder and urethra during electrical-field stimulation and drug stimulation. Histologically, Li-ESWT significantly restored bladder morphology, reflected by a reduction in the intravesical lumen area and increased muscle proportion of the bladder wall. Western Blot analysis showed higher smooth muscle actin expression in the bladder wall in the DM Li-ESWT group compared to the DMC group. Immunofluorescence showed decreased nerve-ending distribution, and destroyed and shortened nerve fibres in the DMC group, and recovery of neuronal integrity and innervation in the DM Li-ESWT group. CONCLUSIONS: In conclusion, Li ESWT ameliorated UAB and urinary incontinence in the diabetic UAB rat model. The improvement appears to be the result of restoration of bladder and urethral structure and function by Li-ESWT. Li-ESWT is non-invasive and may become a better alternative therapy for UAB. Further investigations are warranted. PMID- 29603536 TI - Elucidating the Polymeric Binder Distribution within Lithium-Ion Battery Electrodes Using SAICAS. AB - Polymeric binder distribution within electrodes is crucial to guarantee the electrochemical performance of lithium-ion batteries (LIBs) for their long-term use in applications such as electric vehicles and energy-storage systems. However, due to limited analytical tools, such analyses have not been conducted so far. Herein, the adhesion properties of LIB electrodes at different depths are measured using a surface and interfacial cutting analysis system (SAICAS). Moreover, two LiCoO2 electrodes, dried at 130 and 230 degrees C, are carefully prepared and used to obtain the adhesion properties at every 10 MUm of depth as well as the interface between the electrode composite and the current collector. At high drying temperatures, more of the polymeric binder material and conductive agent appears adjacent to the electrode surface, resulting in different adhesion properties as a function of depth. When the electrochemical properties are evaluated at different temperatures, the LiCoO2 electrode dried at 130 degrees C shows a much better high-temperature cycling performance than does the electrode dried at 230 degrees C due to the uniform adhesion properties and the higher interfacial adhesion strength. PMID- 29603537 TI - Use of the waist-to-height ratio to predict cardiovascular risk in patients with diabetes: Results from the ADVANCE-ON study. AB - AIMS: Patients with type 2 diabetes have a high risk of cardiovascular disease (CVD). Central obesity has been particularly associated with this risk relationship. We aimed to evaluate waist to height ratio (WHtR) as a predictor of risk in such patients. METHODS: WHtR was evaluated as a predictor of the risk of CVD and mortality amongst 11 125 participants with type 2 diabetes in the ADVANCE and ADVANCE-ON studies, and was compared with body mass index (BMI), waist circumference and waist hip ratio (WHR). Primary outcome was a composite of death from CVD, non-fatal myocardial infarction or non-fatal stroke. Secondary outcomes were myocardial infarction, stroke, cardiovascular death and death from any cause. Cox models were used, with bootstrapping to compare associations between anthropometric measures for the primary outcome. RESULTS: Median follow-up time was 9.0 years. There was a positive association between WHtR and adverse outcomes. The hazard ratio (HR) (confidence interval), per SD higher WHtR, was 1.16 (1.11-1.22) for the primary endpoint, with no heterogeneity by sex or region, but a stronger effect in individuals aged 66 years or older. The other 3 anthropometric measurements showed similar associations, although there was evidence that WHtR marginally outperformed BMI and WHR. Based on commonly used BMI cut-points, the equivalent WHtR cut-points were estimated to be 0.55 and 0.6, with no evidence of a difference across subgroups. CONCLUSIONS: In patients with diabetes, WHtR is a useful indicator of future adverse risk, with similar effects in different population subgroups. PMID- 29603538 TI - Overexpression of O-polysaccharide chain length regulators in Gram-negative bacteria using the Wzx-/Wzy-dependent pathway enhances production of defined modal length O-polysaccharide polymers for use as haptens in glycoconjugate vaccines. AB - AIMS: O-polysaccharide (OPS) molecules are protective antigens for several bacterial pathogens, and have broad utility as components of glycoconjugate vaccines. Variability in the OPS chain length is one obstacle towards further development of these vaccines. Introduction of sizing steps during purification of OPS molecules of suboptimal or of mixed lengths introduces additional costs and complexity while decreasing the final yield. The overall goal of this study was to demonstrate the utility of engineering Gram-negative bacteria to produce homogenous O-polysaccharide populations that can be used as the basis of carbohydrate vaccines by overexpressing O-polysaccharide chain length regulators of the Wzx-/Wzy-dependent pathway. METHOD AND RESULTS: The O-polysaccharide chain length regulators wzzB and fepE from Salmonella Typhimurium I77 and wzz2 from Pseudomonas aeruginosa PAO1 were cloned and expressed in the homologous organism or in other Gram-negative bacteria. Overexpression of these Wzz proteins in the homologous organism significantly increased the proportion of long or very long chain O-polysaccharides. The same observation was made when wzzB was overexpressed in Salmonella Paratyphi A and Shigella flexneri, and wzz2 was overexpressed in two other strains of P. aeruginosa. CONCLUSIONS: Overexpression of Wzz proteins in Gram-negative bacteria using the Wzx/Wzy-dependant pathway for lipopolysaccharide synthesis provides a genetic method to increase the production of an O-polysaccharide population of a defined size. SIGNIFICANCE AND IMPACT OF THE STUDY: The methods presented herein represent a cost-effective and improved strategy for isolating preferred OPS vaccine haptens, and could facilitate the further use of O-polysaccharides in glycoconjugate vaccine development. PMID- 29603539 TI - Asymptomatic bacteriuria in kidney transplant recipients: The challenge in the first 8 weeks. PMID- 29603540 TI - Awareness of atrial fibrillation in Japan: A large-scale, nationwide Internet survey of 50 000 Japanese adults. AB - AIM: Atrial fibrillation (AF) is the most common underlying cause of cardiogenic cerebral embolism. To prevent cardiogenic cerebral embolism, it is important to determine the level of awareness of AF in Japan. METHODS: We used survey monitor attribute data to sample 172 824 Japanese adults aged >=50 years from all 47 Japanese prefectures. Next, we carried out an Internet survey to determine these individuals' level of awareness of AF. RESULTS: We obtained valid responses from 53 128 respondents. There were 13 119 respondents (27.5%) spanning all age groups who had never heard the term AF (no prior knowledge), just 1791 respondents (3.8%) who knew AF well and 27 351 respondents (57.3%) who knew the name of the condition, but did not understand the disease or its treatment. No prior knowledge was highest in Kochi Prefecture (36.0%) and lowest in Yamanashi Prefecture. Knowing AF well was highest in Kyoto Prefecture (5.1%) and lowest in Tottori Prefecture, and knowing only the name was highest in Aomori Prefecture (63.0%). Factors contributing significantly to having "no prior knowledge" of AF included younger age, male sex and smaller population size (rural region), but not the numbers of arrhythmia or stroke specialists. CONCLUSIONS: Currently, 3.8% of Japanese adults had high awareness of AF, and we find this value very low. We also noted age-, sex- and region-related differences in awareness level. We believe that awareness initiatives that take into account age- and sex-related differences and prioritize prefectures with lower awareness of AF will be important for preventing cardiogenic cerebral embolism in the future. Geriatr Gerontol Int 2018; 18: 1100-1107. PMID- 29603541 TI - Augmentation of glucagon-like peptide-1 receptor signalling by neprilysin inhibition: potential implications for patients with heart failure. AB - Augmentation of glucagon-like peptide-1 (GLP-1) receptor signalling is an established approach to the treatment of type 2 diabetes. However, endogenous GLP 1 and long-acting GLP-1 receptor analogues are degraded not only by dipeptidyl peptidase-4, but also by neprilysin. This observation raises the possibilities that endogenous GLP-1 contributes to the clinical effects of neprilysin inhibition and that patients concurrently treated with sacubitril/valsartan and incretin-based drugs may experience important drug-drug interactions. Specifically, potentiation of GLP-1 receptor signalling may underlie the antihyperglycaemic actions of sacubitril/valsartan. Neprilysin inhibitors may also be able to augment the effects of long-acting GLP-1 analogues to increase heart rate and myocardial cyclic AMP, and thus, potentiate these deleterious actions; if so, concomitant treatment with GLP-1 receptor agonists may limit the efficacy of neprilysin inhibitors in patients with both heart failure and diabetes. For patients not concurrently treated with GLP-1 analogues, the action of neprilysin to enhance the effects of GLP-1 may be particularly relevant in the brain, where augmentation of GLP-1 and other endogenous peptides may act to inhibit amyloid-induced neuroinflammation and cytotoxicity and improve memory formation and executive functioning. Experimentally, neprilysin inhibitors may also potentiate the effects of endogenous GLP-1 and GLP-1 receptor agonists on blood vessels and the kidney. The role of neprilysin in the metabolism of endogenous GLP-1 and long-acting GLP-1 analogues points to a range of potential pathophysiological effects that may be clinically relevant to patients with heart failure, with or without diabetes. PMID- 29603542 TI - Accessing Frustrated Lewis Pair Chemistry from a Spectroscopically Stable and Classical Lewis Acid-Base Adduct. AB - B(C6 F5 )3 and P(MeNCH2 CH2 )3 N form a classical Lewis adduct, (C6 F5 )3 BP(MeNCH2 CH2 )3 N. Although (C6 F5 )3 BP(MeNCH2 CH2 )3 N does not exhibit spectroscopic evidence of dissociation into its constituent acid and base, products of frustrated Lewis pair (FLP) addition reactions are seen with PhNCO, PhCH2 N3 , PhNSO, and CO2 . Computational studies show that thermal access to the dissociated acid and base permits FLP reactivity to proceed. These results demonstrate that FLP reactivity extends across the entire continuum of equilibria governing Lewis acid-base adducts. PMID- 29603543 TI - Clinical significance of post-prophylaxis cytomegalovirus infection in lung transplant recipients. AB - Cytomegalovirus (CMV) disease has been associated with the development of chronic lung allograft dysfunction (CLAD) after transplantation. However, the relevance of CMV replication occurring after the discontinuation of antiviral prophylaxis on the development of CLAD has not been fully established. Patients who underwent lung transplantation during 2004-2014 were included. All patients received antiviral prophylaxis for 3-6 months, followed by monitoring of CMV replication during the first year post-transplantation (preemptive therapy). Risk factors for the development of CLAD were assessed by Cox models. A linear regression model with an interaction coefficient between time and CMV infection was used to evaluate the influence of CMV infection on the evolution of FEV1 . Overall, 69 patients were included, 30/69 (43%) patients developed at least 1 episode of significant CMV infection, and 8/69 (11.5%) patients developed CMV disease. After a median follow-up of 3.67 years, 25/69 (36%) patients developed CLAD and 14/69 (20%) patients died. In the univariate Cox analysis, significant CMV infection (HR 1.177, P = .698), CMV disease (HR 1.001, P = .998), and duration of CMV replication (HR 1.004, P = .758) were not associated with CLAD. Only bacterial pneumonia tended to be associated with CLAD in the multivariate model (HR 2.579, P = .062). We did not observe a significant interaction between CMV replication and evolution FEV1 (interaction coefficient 0.006, CI 95% [-0.084 to 0.096], P = .890). In this cohort of lung transplant recipients receiving antiviral prophylaxis and monitored by preemptive therapy post-prophylaxis, CMV infection did not have impact on long-term allograft lung function. PMID- 29603544 TI - Evolution and characterisation of the AhRAF4 NB-ARC gene family induced by Aspergillus flavus inoculation and abiotic stresses in peanut. AB - Aflatoxin contamination in peanut is a serious food safety issue to human health around the world. Finding disease resistance genes is a key strategy for genetic improvement in breeding to deal with this issue. We identified an Aspergillus flavus-induced NBS-LRR gene, AhRAF4, using a microarray-based approach. By comparison of 23 sequences from three species using phytogenetics, protein secondary structure and three-dimensional structural analyses, AhRAF4 was revealed to be derived from Arachis duranensis by recombination, and has newly evolved into a family of several members, characterised by duplications and point mutations. However, the members of the family descended from A. ipaensis were lost following tetraploidisation. AhRAF4 was slightly up-regulated by low temperature, drought, salicylic acid and ethylene, but down-regulated by methyl jasmonate. The distinct responses upon As. flavus inoculation and the differential reactions between resistant and susceptible varieties indicate that AhRAF4 might play a role in defence responses. Temporal and spatial expression and the phenotype of transformed protoplasts suggest that AhRAF4 may also be associated with pericarp development. Because tetraploid cultivated peanuts are vulnerable to many pathogens, an exploration of R-genes may provide an effective method for genetic improvement of peanut cultivars. PMID- 29603545 TI - Tunable Pentapeptide Self-Assembled beta-Sheet Hydrogels. AB - Oligopeptide-based supramolecular hydrogels hold promise in a range of applications. The gelation of these systems is hard to control, with minor alterations in the peptide sequence significantly influencing the self-assembly process. We explored three pentapeptide sequences with different charge distributions and discovered that they formed robust, pH-responsive hydrogels. By altering the concentration and charge distribution of the peptide sequence, the stiffness of the hydrogels could be tuned across two orders of magnitude (2-200 kPa). Also, through reassembly of the beta-sheet interactions the hydrogels could self-heal and they demonstrated shear-thin behavior. Using spectroscopic and cryo imaging techniques, we investigated the relationship between peptide sequence and molecular structure, and how these influence the mechanical properties of the hydrogel. These pentapeptide hydrogels with tunable morphology and mechanical properties have promise in tissue engineering, injectable delivery vectors, and 3D printing applications. PMID- 29603546 TI - Effects of empagliflozin on cardiorespiratory fitness and significant interaction of loop diuretics. AB - The effects of empagliflozin on cardiorespiratory fitness in patients with type 2 diabetes mellitus (T2DM) and heart failure with reduced ejection fraction (HFrEF) are unknown. In this pilot study we determined the effects of empagliflozin 10 mg/d for 4 weeks on peak oxygen consumption (VO2 ) in 15 patients with T2DM and HFrEF. As an exploratory analysis, we assessed whether there was an interaction of the effects of empagliflozin on peak VO2 of loop diuretics. Empagliflozin reduced body weight (-1.7 kg; P = .031), but did not change peak VO2 (from 14.5 mL kg-1 min-1 [12.6-17.8] to 15.8 [12.5-17.4] mL kg-1 min-1 ; P = .95). However, patients using loop diuretics (N = 9) demonstrated an improvement, whereas those without loop diuretics (N = 6) experienced a decrease in peak VO2 (+0.9 [0.1-1.4] vs -0.9 [-2.1 to -0.3] mL kg-1 min-1 ; P = .001), and peak VO2 changes correlated with the baseline daily dose of diuretics (R = +0.83; P < .001). Empagliflozin did not improve peak VO2 in patients with T2DM and HFrEF. However, as a result of exploratory analysis, patients concomitantly treated with loop diuretics experienced a significant improvement in peak VO2 . PMID- 29603547 TI - Continuous glucose monitoring during diabetic pregnancy (GlucoMOMS): A multicentre randomized controlled trial. AB - AIM: Diabetes is associated with a high risk of adverse pregnancy outcomes. Optimal glycaemic control is fundamental and is traditionally monitored with self measured glucose profiles and periodic HbA1c measurements. We investigated the effectiveness of additional use of retrospective continuous glucose monitoring (CGM) in diabetic pregnancies. MATERIAL AND METHODS: We performed a nationwide multicentre, open label, randomized, controlled trial to study pregnant women with type 1 or type 2 diabetes who were undergoing insulin therapy at gestational age < 16 weeks, or women who were undergoing insulin treatment for gestational diabetes at gestational age < 30 weeks. Women were randomly allocated (1:1) to intermittent use of retrospective CGM or to standard treatment. Glycaemic control was assessed by CGM for 5-7 days every 6 weeks in the CGM group, while self monitoring of blood glucose and HbA1c measurements were applied in both groups. Primary outcome was macrosomia, defined as birth weight above the 90th percentile. Secondary outcomes were glycaemic control and maternal and neonatal complications. RESULTS: Between July 2011 and September 2015, we randomized 300 pregnant women with type 1 (n = 109), type 2 (n = 82) or with gestational (n = 109) diabetes to either CGM (n = 147) or standard treatment (n = 153). The incidence of macrosomia was 31.0% in the CGM group and 28.4% in the standard treatment group (relative risk [RR], 1.06; 95% CI, 0.83-1.37). HbA1c levels were similar between treatment groups. CONCLUSIONS: In diabetic pregnancy, use of intermittent retrospective CGM did not reduce the risk of macrosomia. CGM provides detailed information concerning glycaemic fluctuations but, as a treatment strategy, does not translate into improved pregnancy outcome. PMID- 29603548 TI - Biochemical Characterization of beta-Amino Acid Incorporation in Fluvirucin B2 Biosynthesis. AB - Naturally occurring lactams, such as the polyketide-derived macrolactams, provide a diverse class of natural products that could enhance existing chemically produced lactams. Although beta-amino acid loading in the fluvirucin B2 polyketide pathway was proposed by a previously identified putative biosynthetic gene cluster, biochemical characterization of the complete loading enzymes has not been described. Here we elucidate the complete biosynthetic pathway of the beta-amino acid loading pathway in fluvirucin B2 biosynthesis. We demonstrate the promiscuity of the loading pathway to utilize a range of amino acids and further illustrate the ability to introduce non-native acyl transferases to selectively transfer beta-amino acids onto a polyketide synthase (PKS) loading platform. The results presented here provide a detailed biochemical description of beta-amino acid selection and will further aid in future efforts to develop engineered lactam-producing PKS platforms. PMID- 29603549 TI - Reference genes for RT-qPCR normalisation in different tissues, developmental stages and stress conditions of amaranth. AB - Studies of gene expression are very important for the identification of genes that participate in different biological processes. Currently, reverse transcription quantitative real-time PCR (RT-qPCR) is a high-throughput, sensitive and widely used method for gene expression analysis. Nevertheless, RT qPCR requires precise normalisation of data to avoid the misinterpretation of experimental data. In this sense, the selection of reference genes is critical for gene expression analysis. At this time, several studies focus on the selection of reference genes in several species. However, the identification and validation of reference genes for the normalisation of RT-qPCR have not been described in amaranth. A set of seven housekeeping genes were analysed using RT qPCR, to determine the most stable reference genes in amaranth for normalisation of gene expression analysis. Transcript stability and gene expression level of candidate reference genes were analysed in different tissues, at different developmental stages and under different types of stress. The data were compared using the geNorm, NormFinder and Bestkeeper statistical methods. The reference genes optimum for normalisation of data varied with respect to treatment. The results indicate that AhyMDH, AhyGAPDH, AhyEF-1alpha and AhyACT would be optimum for accurate normalisation of experimental data, when all treatment are analysed in the same experiment. This study presents the most stable reference genes for normalisation of gene expression analysis in amaranth, which will contribute significantly to future gene studies of this species. PMID- 29603550 TI - The links between adult attachment and post-traumatic stress: A systematic review. AB - PURPOSE: The theory of attachment has informed our understanding of survival and well-being throughout the lifespan. There is a growing interest in the relationship between attachment and symptoms of post-traumatic stress (PTS). Emerging evidence points to important links between attachment and PTS, yet current theoretical and clinical understandings of PTS symptoms and attachment remain relatively disparate. The current systematic review aimed to synthesize, describe, and critique evidence demonstrating the links between attachment and PTS in adults. It also aimed to explore whether the relationship between attachment and PTS differs according to the nature of the traumatic event. METHODS: Searches were conducted using PsycINFO, the Cochrane Library, Medline, and Google Scholar to identify empirical studies focusing on PTS in adults. RESULTS: Twenty-one papers were identified. Attachment was shown to have moderating and mediating influences on the relationship between trauma and PTS. This varied according to the type of trauma, and how symptoms of PTS were reported across the different attachment styles. Methodological rigour varied across studies. Clinical and research implications are discussed, including the consideration of attachment security in assessment and formulation. CONCLUSIONS: Although findings were mixed, this review suggests that there is an important link between attachment and PTS. It supports the current emerging evidence demanding the development of a more unified theoretical framework for attachment, types of trauma, and symptoms of PTS. PRACTITIONER POINTS: The findings discussed in this review have important implications for the treatment of PTS symptoms. Consideration of attachment styles in formulations is likely to inform treatment plans. There is increasing evidence to suggest that assessing and accounting for attachment style in therapy may improve the chances of successful treatment. PMID- 29603551 TI - Expanding the Chemistry of the Class C Radical SAM Methyltransferase NosN by Using an Allyl Analogue of SAM. AB - The radical S-adenosylmethionine (SAM) superfamily enzymes cleave SAM reductively to generate a highly reactive 5'-deoxyadenosyl (dAdo) radical, which initiates remarkably diverse reactions. Unlike most radical SAM enzymes, the class C radical SAM methyltransferase NosN binds two SAMs in the active site, using one SAM to produce a dAdo radical and the second as a methyl donor. Here, we report a mechanistic investigation of NosN in which an allyl analogue of SAM (allyl-SAM) was used. We show that NosN cleaves allyl-SAM efficiently and the resulting dAdo radical can be captured by the olefin moieties of allyl-SAM or 5' allylthioadenosine (ATA), the latter being a derivative of allyl-SAM. Remarkably, we found that NosN produced two distinct sets of products in the presence and absence of the methyl acceptor substrate, thus suggesting substrate-triggered production of ATA from allyl-SAM. We also show that NosN produces S adenosylhomocysteine from 5'-thioadenosine and homoserine lactone. These results support the idea that 5'-methylthioadenosine is the direct methyl donor in NosN reactions, and demonstrate great potential to modulate radical SAM enzymes for novel catalytic activities. PMID- 29603552 TI - Plant and animal PR1 family members inhibit programmed cell death and suppress bacterial pathogens in plant tissues. AB - A role for programmed cell death (PCD) has been established as the basis for plant-microbe interactions. A functional plant-based cDNA library screen identified possible anti-PCD genes, including one member of the PR1 family, designated P14a, from tomato. Members of the PR1 family have been subject to extensive research in view of their possible role in resistance against pathogens. The PR1 family is represented in every plant species studied to date and homologues have been found in animals, fungi and insects. However, the biological function of the PR1 protein from plants has remained elusive in spite of extensive research regarding a role in the response of plants to disease. Constitutive expression of P14a in transgenic tomato roots protected the roots against PCD triggered by Fumonisin B1, as did the human orthologue GLIPR1, indicating a kingdom crossing function for PR1. Tobacco plants transformed with a P14a-GFP fusion construct and inoculated with Pseudomonas syringae pv. tabaci revealed that the mRNA was abundant throughout the leaves, but the fusion protein was restricted to the lesion margins, where cell death and bacterial spread were arrested. Vitus vinifera grapes expressing the PR1 homologue P14a as a transgene were protected against the cell death symptoms of Pierce's disease. A pull-down assay identified putative PR1-interacting proteins, including members of the Rac1 immune complex, known to function in innate immunity in rice and animal systems. The findings herein are consistent with a role of PR1 in the suppression of cell death-dependent disease symptoms and a possible mode of action. PMID- 29603553 TI - Health-related quality of life in active surveillance and radical prostatectomy for low-risk prostate cancer: a prospective observational study (HAROW - Hormonal therapy, Active Surveillance, Radiation, Operation, Watchful Waiting). AB - OBJECTIVES: To compare health-related quality of life (HRQOL) between patients with localised prostate cancer in an active surveillance (AS) group and a radical prostatectomy (RP) group, as evidence shows that both groups have similar oncological outcomes. Thus, comparative findings on the patients' HRQOL are becoming even more important to allow for informed treatment decision-making. PATIENTS AND METHODS: The Hormonal therapy, Active Surveillance, Radiation, Operation, Watchful Waiting (HAROW) study is a prospective, observational study designed to collect data for different treatment options for newly diagnosed patients with localised prostate cancer under real-life conditions. At 6-month intervals, clinical data (D'Amico risk categories, Charlson Comorbidity Index) and HRQOL (European Organisation for Research and Treatment of Cancer quality of life questionnaire 30-item core questionnaire) were collected. Data were analysed by longitudinal multilevel analysis for patients with localised prostate cancer under AS and RP. RESULTS: Data from 961 patients (556 RP, 405 AS) were considered. The follow-up was 3.5 years (median 2 years). The results reveal significant, but not clinically relevant advantages for patients with low-risk prostate cancer managed with AS in contrast to RP concerning global HRQOL as well as role, emotional and social functioning over time, after controlling for age, comorbidities, and partnership status. In some, but not all HRQOL scales, RP patients start with a slightly lower HRQOL and recover up to the level of AS patients within 1-2 years after diagnosis. CONCLUSION: HRQOL is an important aspect in the decision-making and advising process for patients with prostate cancer. In many aspects of HRQOL, AS is associated with more favourable outcomes than RP within the first 1-2 years after diagnosis in our observational design, although the differences were not clinically significant. The result that HRQOL in AS patients is at least as high as in RP patients should be considered when advising patients about the different treatment options for low-risk localised prostate cancer. PMID- 29603554 TI - PURE is not so pure when it comes to dietary sodium and cardiovascular events! PMID- 29603555 TI - A new approach for safe planning transfer using semi-automatically adjustable instrument guides. AB - Accurate planning transfer is a prerequisite for successful operative care. For different applications, diverse computer-assisted systems have been developed and clinically evaluated. This paper presents the implementation and evaluation of a new modular concept. The approach is based on passive application specific kinematics that are semi-automatically adjusted using a universal hand-held computer controlled Smart Screw Driver. The system was realized for pedicle screw instrumentation and evaluated according to IEC 60601-1-6 (usability engineering). The accuracies of the drill holes achieved were comparable with robotic approaches, while operation time and radiation were reduced compared with conventional operation techniques. The adjustment procedure has proven high learnability and user satisfaction. The next step will be optimization of the kinematic structure and fixation to the patient in order to increase accuracies of planning transfer as well as evaluation of the overall system by medical staff in preclinical and clinical studies. PMID- 29603556 TI - Caffeic acid phenethyl ester guards against benign prostate hypertrophy in rats: Role of IGF-1R/protein kinase-B (Akt)/beta-catenin signaling. AB - Benign prostate hypertrophy (BPH) is among the most common diseases with a huge impact on the quality of life of elderly men. There is a current need for the development of well-tolerated and effective preventive strategies to improve the clinical outcome. Caffeic acid phenethyl ester (CAPE) is an important active ingredient isolated from honey-bee propolis with potent anti-proliferative, anti inflammatory and antioxidant effects. These properties promote CAPE as a promising candidate to be tested as an alternative therapy for BPH, which is still uninvestigated. Herein, we tested the ability of CAPE to guard against testosterone-induced BPH and investigated the involvement of IGF1-R/Akt/beta catenin signaling as a protective mechanism in testosterone-induced BPH rat model. Treatment with CAPE reduced testosterone-induced increase in the prostate index and histopathological alterations. In addition, co-treatment with CAPE significantly suppressed insulin-like growth factor-1 receptor (IGF-1R)/Akt/beta catenin/cyclinD1 axis as well as tumor necrosis factor-alpha level and nuclear factor (NF)-kB activity. Furthermore, the treatment with CAPE replenished the antioxidant defense systems, superoxide dismutase (SOD) and reduced glutathione (GSH) with subsequent reduction in prostate tissue lipid peroxides. This study highlights the potential merit of CAPE-enriched propolis formulations to protect elderly men against the development of BPH. (c) 2018 IUBMB Life, 70(6):519-528, 2018. PMID- 29603557 TI - Coadsorbate-Induced Reversal of Solid-Liquid Interface Dynamics. AB - Coadsorbed anions are well-known to influence surface reactivity and dynamics at solid-liquid interfaces. Here we demonstrate that the chemical nature of these spectator species can entirely determine the microscopic dynamic behavior. Quantitative in situ video-STM data on the surface diffusion of adsorbed sulfur atoms on Cu(100) electrodes in aqueous solution covered by bromide and chloride spectators, respectively, reveal in both cases a strong exponential potential dependence, but with opposite sign. This reversal is highly surprising in view of the isostructural adsorbate arrangement in the two systems. Detailed DFT studies suggest an anion-induced difference in the sulfur diffusion mechanism, specifically an exchange diffusion on the Br-covered surface. Experimental evidence for the latter is provided by the observation of Cu vacancy formation in the Br system, which can be rationalized by a side reaction of the sulfur exchange diffusion. PMID- 29603558 TI - Flip-avoiding interpolating surface registration for skull reconstruction. AB - Skull reconstruction is an important and challenging task in craniofacial surgery planning, forensic investigation and anthropological studies. Existing methods typically reconstruct approximating surfaces that regard corresponding points on the target skull as soft constraints, thus incurring non-zero error even for non defective parts and high overall reconstruction error. This paper proposes a novel geometric reconstruction method that non-rigidly registers an interpolating reference surface that regards corresponding target points as hard constraints, thus achieving low reconstruction error. To overcome the shortcoming of interpolating a surface, a flip-avoiding method is used to detect and exclude conflicting hard constraints that would otherwise cause surface patches to flip and self-intersect. Comprehensive test results show that our method is more accurate and robust than existing skull reconstruction methods. By incorporating symmetry constraints, it can produce more symmetric and normal results than other methods in reconstructing defective skulls with a large number of defects. It is robust against severe outliers such as radiation artifacts in computed tomography due to dental implants. In addition, test results also show that our method outperforms thin-plate spline for model resampling, which enables the active shape model to yield more accurate reconstruction results. As the reconstruction accuracy of defective parts varies with the use of different reference models, we also study the implication of reference model selection for skull reconstruction. PMID- 29603559 TI - Enzymatic Formation of a Skipped Methyl-Substituted Octaprenyl Side Chain of Longestin (KS-505a): Involvement of Homo-IPP as a Common Extender Unit. AB - Longestin (KS-505a), a specific inhibitor of phosphodiesterase, is a meroterpenoid that consists of a unique octacyclic terpene skeleton with branched methyl groups at unusual positions (C1 and C12). Biochemical analysis of Lon23, a methyltransferase involved in the biosynthesis of longestin, demonstrated that it methylates homoisopentenyl diphosphate (homo-IPP) to afford (3Z)-3-methyl IPP. This compound, along with IPP, is selectively accepted as extender units by Lon22, a geranylgeranyl diphosphate (GGPP) synthase homologue, to yield dimethylated GGPP (dmGGPP). The absolute configuration of dmGGPP was determined to be (4R,12R) by degradation and chiral GC analysis. These findings allowed us to propose an enzymatic sequence for key steps of the biosynthetic pathway of the unusual homoterpenoid longestin. PMID- 29603561 TI - Two-Dimensional Fullerene Assembly from an Exfoliated van der Waals Template. AB - Two-dimensional (2D) materials are commonly prepared by exfoliating bulk layered van der Waals crystals. The creation of synthetic 2D materials from bottom-up methods is an important challenge as their structural flexibility will enable chemists to tune the materials properties. A 2D material was assembled using C60 as a polymerizable monomer. The C60 building blocks are first assembled into a layered solid using a molecular cluster as structure director. The resulting hierarchical crystal is used as a template to polymerize its C60 monolayers, which can be exfoliated down to 2D crystalline nanosheets. Derived from the parent template, the 2D structure is composed of a layer of inorganic cluster, sandwiched between two monolayers of polymerized C60 . The nanosheets can be transferred onto solid substrates and depolymerized by heating. Electronic absorption spectroscopy reveals an optical gap of 0.25 eV, narrower than that of the bulk parent crystalline solid. PMID- 29603560 TI - Implications of sequence and timing of exposure for synergy between the pyrethroid insecticide alpha-cypermethrin and the entomopathogenic fungus Beauveria bassiana. AB - BACKGROUND: Combining low doses of chemical insecticides with entomopathogens constitutes a sustainable pest control method, but the significance of the timing and sequence of exposures needs clarification. We studied lethal effects of combinations of the entomopathogenic fungus Beauveria bassiana (KVL03-122) and the pyrethroid alpha-cypermethrin on the beetle Tenebrio molitor under varying timing and sequence of exposure. Synergy over time was evaluated in relation to the model of independent action (IA). We expected that increased progression of disease caused by B. bassiana would make beetles more susceptible to the insecticide, leading to enhanced synergy. RESULTS: Synergistic effects between B. bassiana and alpha-cypermethrin were observed when B. bassiana was applied first, but only when the interval between applications was >48 h. With 72 h between exposures, mortality had increased to 100% after 8 days, in contrast to the 60% mortality expected. No synergy was observed when the insecticide was applied prior to fungal exposure within 24 h. CONCLUSION: The sequence and timing of exposure do matter to achieve synergistic mortality by combining B. bassiana and alpha-cypermethrin, and the IA model proved to be a strong tool with which to evaluate the interactions of the two stressors over time. Pest control strategies could include B. bassiana followed by low-dose exposures to alpha-cypermethrin after 2-3 days. (c) 2018 Society of Chemical Industry. PMID- 29603562 TI - Coronary artery disease in decompensated patients undergoing liver transplantation evaluation. PMID- 29603563 TI - Palaeoproteomic Profiling of Conservation Layers on a 14th Century Italian Wall Painting. AB - Ahead of display, a non-original layer was observed on the surface of a fragment of a wall painting by Ambrogio Lorenzetti (active 1319, died 1348/9). FTIR analysis suggested proteinaceous content. Mass spectrometry was used to better characterise this layer and revealed two protein components: sheep and cow glue and chicken and duck egg white. Analysis of post-translational modifications detected several photo-oxidation products, which suggest that the egg experienced prolonged exposure to UV light and was likely applied long before the glue layer. Additionally, glycation products detected may indicate naturally occurring glycoprotein degradation or reaction with a carbohydrate material such as starch, identified by ATR-FTIR in a cross-section of a sample taken from the painting. Palaeoproteomics is shown to provide detailed characterisation of organic layers associated with mural paintings and therefore aids reconstruction of the conservation history of these objects. PMID- 29603565 TI - Electrooxidative Ruthenium-Catalyzed C-H/O-H Annulation by Weak O-Coordination. AB - Electrocatalysis has been identified as a powerful strategy for organometallic catalysis, and yet electrocatalytic C-H activation is restricted to strongly N coordinating directing groups. The first example of electrocatalytic C-H activation by weak O-coordination is presented, in which a versatile ruthenium(II) carboxylate catalyst enables electrooxidative C-H/O-H functionalization for alkyne annulations in the absence of metal oxidants; thereby exploiting sustainable electricity as the sole oxidant. Mechanistic insights provide strong support for a facile organometallic C-H ruthenation and an effective electrochemical reoxidation of the key ruthenium(0) intermediate. PMID- 29603564 TI - Film-based dose validation of Monte Carlo algorithm for Cyberknife system with a CIRS thorax phantom. AB - Monte Carlo (MC) simulation, as the most accurate dose calculation algorithm, is available in the MultiPlan treatment planning system for Cyberknife. The main purpose of this work was to perform experiments to thoroughly investigate the accuracy of the MC dose calculation algorithm. Besides the basic MC beam commissioning, two test scenarios were designed. First, single beam tests were performed with a solid water phantom to verify the MC source model in simple geometry. Then, a lung treatment plan on a CIRS thorax phantom was created to mimic the clinical patient treatment. The plan was optimized and calculated using ray tracing (RT) algorithm and then recalculated using MC algorithm. Measurements were performed in both a homogeneous phantom and a heterogeneous phantom (CIRS). Ion-chamber and radiochromic film were used to obtain absolute point dose and dose distributions. Ion-chamber results showed that the differences between measured and MC calculated dose were within 3% for all tests. On the film measurements, MC calculation results showed good agreements with the measured dose for all single beam tests. As for the lung case, the gamma passing rate between measured and MC calculated dose was 98.31% and 97.28% for homogeneous and heterogeneous situation, respectively, using 3%/2 mm criteria. However, RT algorithm failed with the passing rate of 79.25% (3%/2 mm) for heterogeneous situation. These results demonstrated that MC dose calculation algorithm in the Multiplan system is accurate enough for patient dose calculation. It is strongly recommended to use MC algorithm in heterogeneous media. PMID- 29603566 TI - Generation and Rearrangement of N,O-Dialkenylhydroxylamines for the Synthesis of 2-Aminotetrahydrofurans. AB - A new diastereoselective route to 2-aminotetrahydrofurans has been developed from N,O-dialkenylhydroxylamines. These intermediates undergo a spontaneous C-C bond forming [3,3]-sigmatropic rearrangement followed by a C-O bond-forming cyclization. A copper-catalyzed N-alkenylation of an N-Boc-hydroxylamine with alkenyl iodides, and a base-promoted addition of the resulting N-hydroxyenamines to an electron-deficient allene, provide modular access to these novel rearrangement precursors. The scope of this de novo synthesis of simple nucleoside analogues has been explored to reveal trends in diastereoselectivity and reactivity. In addition, a base-promoted ring-opening and Mannich reaction has been discovered to covert 2-aminotetrahydrofurans to cyclopentyl beta aminoacid derivatives or cyclopentenones. PMID- 29603567 TI - Involvement of serum-derived exosomes of elderly patients with bone loss in failure of bone remodeling via alteration of exosomal bone-related proteins. AB - Exosomes are secreted into the blood by various types of cells. These extracellular vesicles are involved in the contribution of exosomal proteins to osteoblastic or osteoclastic regulatory networks during the failure of bone remodeling, which results in age-related bone loss. However, the molecular changes in serum-derived exosomes (SDEs) from aged patients with low bone density and their functions in bone remodeling remain to be fully elucidated. We present a quantitative proteomics analysis of exosomes purified from the serum of the elderly patients with osteoporosis/osteopenia and normal volunteers; these data are available via Proteome Xchange with the identifier PXD006463. Overall, 1,371 proteins were identified with an overlap of 1,160 Gene IDs among the ExoCarta proteins. Bioinformatics analysis and in vitro studies suggested that protein changes in SDEs of osteoporosis patients are not only involved in suppressing the integrin-mediated mechanosensation and activation of osteoblastic cells, but also trigger the differentiation and resorption of osteoclasts. In contrast, the main changes in SDEs of osteopenia patients facilitated both activation of osteoclasts and formation of new bone mass, which could result in a compensatory elevation in bone remodeling. While the SDEs from aged normal volunteers might play a protective role in bone health through facilitating adhesion of bone cells and suppressing aging-associated oxidative stress. This information will be helpful in elucidating the pathophysiological functions of SDEs and aid in the development of senile osteoporosis diagnostics and therapeutics. PMID- 29603568 TI - Community activities predict disability and mortality in community-dwelling older adults. AB - AIM: With aging, it is important to maintain older community dwellers' regular engagement with familiar community activities (CA) engaged in close to home to protect them from frailty. Thus, the present study aimed to examine whether CA items or CA score were associated with mortality or the need for care under the new long-term care insurance service requirements over 3 years among community dwelling older Japanese adults. METHODS: We analyzed cohort data for older adults from a prospective cohort study in Kami town, Japan. The response rate to the self-reported questionnaire was 94.3% (n = 5094), and we followed these participants for 3 years. Our final sample comprised 5076 older adults. Missing data were filled in using multiple imputation. We used seven items to assess CA: (i) volunteer activity; (ii) regional activity related to the neighborhood; (iii) visiting friends; (iv) hobbies or favorite lessons; (v) earning an income; (vi) farm work and growing vegetables; and (vii) shopping daily by oneself. The Kihon Checklist and new long-term care insurance service certifications were used as the frailty screening and disability indices, respectively. RESULTS: During the follow-up survey, 705 participants obtained new long-term care insurance service certifications and 262 died. Using the receiver operating characteristic curve, the desirable cut-off of the CA score to predict disability and mortality was at least two items for all elderly age groups in rural areas. CONCLUSIONS: CA items and CA score could predict disability and mortality in community-dwelling older adults in Japanese rural areas. Therefore, it is recommended that older adults from all age groups participate in CA. Geriatr Gerontol Int 2018; 18: 1114-1124. PMID- 29603569 TI - Iron-Catalyzed Ring-Closing C-O/C-O Metathesis of Aliphatic Ethers. AB - Among all metathesis reactions known to date in organic chemistry, the metathesis of multiple bonds such as alkenes and alkynes has evolved into one of the most powerful methods to construct molecular complexity. In contrast, metathesis reactions involving single bonds are scarce and far less developed, particularly in the context of synthetically valuable ring-closing reactions. Herein, we report an iron-catalyzed ring-closing metathesis of aliphatic ethers for the synthesis of substituted tetrahydropyrans and tetrahydrofurans, as well as morpholines and polycyclic ethers. This transformation is enabled by a simple iron catalyst and likely proceeds via cyclic oxonium intermediates. PMID- 29603570 TI - Dissipative Synthetic DNA-Based Receptors for the Transient Loading and Release of Molecular Cargo. AB - Supramolecular chemistry is moving into a direction in which the composition of a chemical equilibrium is no longer determined by thermodynamics but by the efficiency with which kinetic states can be populated by energy consuming processes. Herein, we show that DNA is ideally suited for programming chemically fueled dissipative self-assembly processes. Advantages of the DNA-based systems presented in this study include a perfect control over the activation site for the chemical fuel in terms of selectivity and affinity, highly selective fuel consumption that occurs exclusively in the activated complex, and a high tolerance for the presence of waste products. Finally, it is shown that chemical fuels can be used to selectively activate different functions in a system of higher complexity embedded with multiple response pathways. PMID- 29603571 TI - Perioperative loss of psoas muscle is associated with patient survival in living donor liver transplantation. PMID- 29603572 TI - Analysis and optimization of bone machining for robotic orthopedic surgeries. AB - BACKGROUND: Robot-assisted joint replacement surgery is becoming increasingly more common worldwide, therefore it is important to characterize and improve the bone-cutting mechanics of surgical tools. METHODS: Linear coefficients relating cutting force and chip thickness were derived for a surgical spindle. The cutting coefficients were integrated into an analytical simulation which calculated cutting forces, torque, and power consumption. An optimization experiment was performed. High speed video was taken at various tool parameter settings. RESULTS: Varying machining parameters resulted in lower cutting forces. The surgical spindle stalled at the current spindle speed used in surgery, but did not for the new, optimized conditions. Multiple anomalies were identified in the videos that confirmed observations from the cutting force data. CONCLUSIONS: Improved surgical performance and accuracy were achieved using slower spindle speeds, decreased cutting depth, and increased feed rates, as well as improving motor torque to ensure a smooth cutting process. PMID- 29603573 TI - Sitting at mother's knee: global hypertension lessons learned. PMID- 29603574 TI - Event-free survival of infants and toddlers enrolled in the HR-NBL-1/SIOPEN trial is associated with the level of neuroblastoma mRNAs at diagnosis. AB - BACKGROUND: The purpose of this study was to evaluate whether levels of neuroblastoma mRNAs in bone marrow and peripheral blood from stage M infants (<=12 months of age at diagnosis, MYCN amplified) and toddlers (between 12 and 18 months, any MYCN status) predict event-free survival (EFS). METHODS: Bone marrow aspirates and peripheral blood samples from 97 infants/toddlers enrolled in the European High-Risk Neuroblastoma trial were collected at diagnosis in PAXgeneTM blood RNA tubes. Samples were analyzed by reverse transcription quantitative polymerase chain reaction according to standardized procedures. RESULTS: Bone marrow tyrosine hydroxylase (TH) or paired-like homeobox 2b (PHOX2B) levels in the highest tertile were associated with worse EFS; hazard ratios, adjusted for age and MYCN status, were 1.5 and 1.8 respectively. Expression of both TH and PHOX2B in the highest tertile predicted worse outcome (p = 0.015), and identified 20 (23%) infants/toddlers with 5-year EFS of 20% (95%CI: 4%-44%). Prognostic significance was maintained after adjusting for over-fitting bias (p = 0.038), age and MYCN status. In peripheral blood, PHOX2B levels in the highest tertile predicted a two-fold increased risk of an event (p = 0.032), and identified 23 (34%) infants/toddlers with 5-year EFS of 29% (95%CI: 12%-48%). Time-dependent receiver operating characteristic analysis confirmed the prognostic value of combined TH and PHOX2B in bone marrow and of PHOX2B in peripheral blood during the first year of follow-up. CONCLUSIONS: High levels of bone marrow TH and PHOX2B and of peripheral blood PHOX2B at diagnosis allow early identification of a group of high-risk infant and toddlers with neuroblastoma who may be candidates for alternative treatments. Integration with additional biomarkers, as well as validation in additional international trials is warranted. PMID- 29603575 TI - Time trends in service provision and survival outcomes for patients with renal cancer treated by nephrectomy in England 2000-2010. AB - OBJECTIVE: To describe the temporal trends in nephrectomy practice and outcomes for English patients with renal cell carcinoma (RCC). PATIENTS AND METHODS: Adult RCC nephrectomy patients treated between 2000 and 2010 were identified in the National Cancer Data Repository and Hospital Episode Statistics, and followed-up until date of death or 31 December 2015 (n = 30 763). We estimated the annual frequency for each nephrectomy type, the hospital and surgeon numbers and their case volumes. We analysed short-term surgical outcomes, as well as 1- and 5-year relative survivals. RESULTS: Annual RCC nephrectomy number increased by 66% during the study period. Hospital number decreased by 24%, whilst the median annual hospital volume increased from 10 to 23 (P < 0.01). Surgeon number increased by 27% (P < 0.01), doubling the median consultant number per hospital. The proportion of minimally invasive surgery (MIS) nephrectomies rose from 1% to 46%, whilst the proportion of nephron-sparing surgeries (NSS) increased from 5% to 16%, with 29% of all T1 disease treated with partial nephrectomy in 2010 (P < 0.01). The 30-day mortality rate halved from 2.4% to 1.1% and 90-day mortality decreased from 4.9% to 2.6% (P < 0.01). The 1-year relative survival rate increased from 86.9% to 93.4%, whilst the 5-year relative survival rate rose from 68.2% to 81.2% (P < 0.01). Improvements were most notable in patients aged >=65 years and those with T3 and T4 disease. CONCLUSIONS: Surgical RCC management has changed considerably with nephrectomy centralisation and increased NSS and MIS. In parallel, we observed significant improvements in short- and long-term survival particularly for elderly patients and those with locally advanced disease. PMID- 29603576 TI - Incidence of head and neck cancer in children: A Danish nationwide study from 1978 to 2014. AB - BACKGROUND: Pediatric head and neck malignancies are rare and only a few descriptive epidemiological studies have been published. Using unique nationwide registries, we report age-specific incidence rates of head and neck cancer (HNC) among children during four decades. METHODS: Data were obtained from the Danish Cancer Registry. We included children aged 0-14 years diagnosed between January 1, 1978 and December 31, 2014 with extra-orbital, nonskin and nonbone HNC. Patients were divided into nine groups in regard to tumor location: oral cavity, oropharynx, nasopharynx, hypopharynx, thyroid, major salivary glands, larynx, and middle ear. Based on the World Health Organization standard population and Danish age-specific population counts, age-adjusted incidence rates (AAIR) and average annual percentage change (AAPC) were calculated and examined for trends. RESULTS: In total, 169 children (55.6% females) were registered with a malignant tumor in the head and neck region. The AAIR increased with an AAPC of 2.2% (95% CI, 0.8 3.7%). Females showed an AAIR of 0.54 per 100,000 person years compared to that of males, with 0.41 per 100,000 person years (P < 0.01). The AAIR was higher among children aged 10-14 years compared to 0-9-year-old children (P < 0.01). Based on morphology, a significant increase in AAIR was observed for sarcomas, with an increase of 0.16-0.27 per 100,000 person years (P < 0.05). CONCLUSIONS: The incidence rate of pediatric HNC was higher among females and evidence of increasing rates was observed during 1978-2014, explained by an increase mainly in sarcomas. PMID- 29603577 TI - Standard methods for the assessment of structural and functional diversity of soil organisms: A review. AB - The lack of standardized methods to study soil organisms prevents comparisons across data sets and the development of new global and regional experiments and assessments. Moreover, standardized methods are needed to evaluate the impact of anthropogenic stressors, such as chemicals, on soil organism communities in the regulatory context. The goal of this contribution is to summarize current methodological approaches to measure structural and functional diversity of soil organisms, and to identify gaps and methodological improvements so as to cross data sets generated worldwide. This is urgently needed because several currently ongoing regional and global soil biodiversity studies are not coordinated with one another in terms of methodology, including database development. Therefore, we evaluated the standard methods to sample, identify, determine, and assess soil organisms currently applied or proposed, using well-accepted criteria such as ecological relevance; practicability of usage in terms of resources, time, and costs; and the level of standardization. Methods addressing both the structure and the functions of soil organisms (populations or communities) are included, with a special focus on new molecular methods based on nucleic acid extraction and further analyses by polymerase chain reaction (PCR)-based approaches for microorganisms and invertebrates. We particularly highlight the activities of the Technical Committee (TC) 190 of the International Organization for Standardization (ISO) because ISO guidelines are legally accredited by many national or international authorities when they put conservation laws and regulations into practice. Finally, we propose detailed recommendations regarding gaps in the available set of standards, in order to identify a list of new methods to be standardized. We propose to organize this whole process under the Global Soil Biodiversity Initiative (GSBI) in order to ensure a truly global approach for the assessment of soil biodiversity. Integr Environ Assess Manag 2018;14:463-479. (c) 2018 SETAC. PMID- 29603578 TI - Funerals. PMID- 29603579 TI - Association between daily salt intake of 3-year-old children and that of their mothers: A cross-sectional study. AB - This study investigated the association between the daily salt intake of 3-year old children and that of their mothers. A total of 641 children were studied. The daily salt intake of the children and their mothers was estimated by morning and spot urine methods, respectively. In the multivariable analysis, a 1 g higher maternal daily salt intake was associated with a 0.14 g (95% confidence interval [CI], 0.07-0.22, P < .001) higher salt intake of her children. In the secondary analysis, the odds ratios for excess salt intake of children were 1.61 (95% CI, 1.01-2.55, P = .045) and 1.81 (95% CI, 1.12-2.91, P = .015) for 9.7-11.5 g and 11.5 g or more of maternal daily salt intake, respectively. Our findings could help to convince mothers of the importance of appropriate salt intake, not only for themselves but also for their children. PMID- 29603580 TI - Exploring pathways towards improving patient experience of robot-assisted radical prostatectomy (RARP): assessing patient satisfaction and attitudes. AB - OBJECTIVE: To determine patient satisfaction and experience after robot-assisted radical prostatectomy (RARP) for prostate cancer, using a convergent mixed-method qualitative analysis approach. PATIENTS AND METHODS: 412 patients who underwent RARP between January 2014 and June 2016 were mailed questionnaires and invited to participate in focus groups. Qualitative data was thematically analysed using NVivo. Descriptive statistics were obtained from the questionnaire using SPSS. RESULTS: 214 patients responded (52% of sample size) of whom 97.6% were satisfied and 91.1% would likely recommend RARP. Key themes from the qualitative data highlighted the psychosocial impacts of the diagnosis and RARP process. The importance of early recovery, the benefits of pelvic floor exercises and educational resources were emphasised. CONCLUSION: Patients were overwhelmingly satisfied with RARP, largely due to relevance and timeliness of the information and support provided both before and after surgery. With an increased understanding of the factors and outcomes that are most important to patients regarding all aspects of hospital care, we can create more targeted care pathways. Key themes will help inform the implementation of an enhanced recovery after surgery (ERAS) protocol to further improve recovery and early return to function. PMID- 29603581 TI - Good clinical response to alectinib, a second generation ALK inhibitor, in refractory neuroblastoma. PMID- 29603582 TI - miRNA-mediated 'tug-of-war' model reveals ceRNA propensity of genes in cancers. AB - Competing endogenous RNA (ceRNA) are transcripts that cross-regulate each other at the post-transcriptional level by competing for shared microRNA response elements (MREs). These have been implicated in various biological processes impacting cell-fate decisions and diseases including cancer. There are several studies that predict possible ceRNA pairs by adopting various machine-learning and mathematical approaches; however, there is no method that enables us to gauge as well as compare the propensity of the ceRNA of a gene and precisely envisages which among a pair exerts a stronger pull on the shared miRNA pool. In this study, we developed a method that uses the 'tug of war of genes' concept to predict and quantify ceRNA potential of a gene for the shared miRNA pool in cancers based on a score represented by SoCeR (score of competing endogenous RNA). The method was executed on the RNA-Seq transcriptional profiles of genes and miRNA available at TCGA along with CLIP-supported miRNA-target sites to predict ceRNA in 32 cancer types which were validated with already reported cases. The proposed method can be used to determine the sequestering capability of the gene of interest as well as in ranking the probable ceRNA candidates of a gene. Finally, we developed standalone applications (SoCeR tool) to aid researchers in easier implementation of the method in analysing different data sets or diseases. PMID- 29603583 TI - Sustaining obesity prevention in communities: a systematic narrative synthesis review. AB - Obesity is a global problem for which sustainable solutions are yet to be realized. Community-based interventions have improved obesity-related behaviours and obesity in the short term. Few papers have explored how to make the interventions and their intended outcomes sustainable. The aim of this paper is to identify factors that contribute to the sustainability of community-based obesity prevention interventions and their intended outcomes. A systematic narrative synthesis review was conducted of published community-based obesity prevention interventions to identify factors contributing to intervention sustainability. Data extracted were included study authors' perspectives of intervention success and sustainability. Eighty-one papers met the inclusion criteria, and from these we identified ten factors that contribute to sustainability: resourcing, leadership, workforce development, community engagement, partnerships, policy, communications, adaptability, evaluation and governance. This review of community-based obesity prevention interventions gives rise to optimism that sustainable change is possible. We propose a framework to help practitioners build sustainability into their interventions and report on them so that others can also benefit. PMID- 29603585 TI - Localised prostate cancer in elderly men aged 80-89 years, findings from a population-based registry. AB - OBJECTIVES: To investigate the rate of prostate cancer-specific mortality (PCSM) and disease characteristics in patients diagnosed with localised prostate cancer at age 80-89 years in comparison with men diagnosed at age 70-79 years. PATIENTS AND METHODS: This is a retrospective study of data from the South Australian Prostate Cancer Clinical Outcomes Collaborative (SA-PCCOC). Included were men diagnosed between 2005 and 2014, aged >=70 years with no evidence of metastatic disease at presentation. Propensity score matching and competing risk Fine and Grey regression were used to assess the chance of treatment (curative vs non curative) and treatment effect on PCSM. RESULTS: Of the 1 951 eligible patients, 1 428 (76%) were aged 70-79 years and 460 (24%) were aged 80-89 years at diagnosis, with a median (interquartile range) age of 74 (72-76) and 83 (81-85) years, respectively. The 80-89 years group had higher Gleason scores and Prostate Specific Antigen (PSA) values (all P < 0.001) in comparison with the younger group. The 80-89 years group were less likely to be treated with curative treatment (odds ratio 0.12, 95% confidence interval 0.09-0.16; P < 0.001). The proportion of deaths attributable to prostate cancer was similar in both groups: 73 of 263 deaths (28%) in the 80-89 years group vs 97 of 310 deaths (31%) in the 70-79 years group. The risk of PCSM in individuals treated with curative intent was reduced in both groups. CONCLUSIONS: The proportion of prostate cancer deaths was similar in both groups. These findings support carefully selected individualised management of elderly patients diagnosed with localised prostate cancer. PMID- 29603584 TI - Simultaneous targeting of EGFR, HER2, and HER4 by afatinib overcomes intrinsic and acquired cetuximab resistance in head and neck squamous cell carcinoma cell lines. AB - The epidermal growth factor receptor (EGFR, HER1) is a therapeutic target in head and neck squamous cell carcinoma (HNSCC). After initial promising results with EGFR-targeted therapies such as cetuximab, therapeutic resistance has become a major clinical problem, and new treatment options are therefore necessary. Moreover, the relationship between HER receptors, anti-EGFR therapies, and the human papillomavirus (HPV) status in HNSCC is not fully understood. In contrast to first-generation EGFR inhibitors, afatinib irreversibly inhibits multiple HER receptors simultaneously. Therefore, treatment with afatinib might result in a more pronounced therapeutic benefit, even in patients experiencing cetuximab resistance. In this study, the cytotoxic effect of afatinib as single agent and in combination with cisplatin was investigated in cetuximab-sensitive, intrinsically cetuximab-resistant, and acquired cetuximab-resistant HNSCC cell lines with different HPV status under normoxia and hypoxia. Furthermore, the influence of cetuximab resistance, HPV, and hypoxia on the expression of HER receptors was investigated. Our results demonstrated that afatinib was able to establish cytotoxicity in cetuximab-sensitive, intrinsically cetuximab-resistant, and acquired cetuximab-resistant HNSCC cell lines, independent of the HPV status. However, cross-resistance between cetuximab and afatinib might be possible. Treatment with afatinib caused a G0 /G1 cell cycle arrest as well as induction of apoptotic cell death. Additive to antagonistic interactions between afatinib and cisplatin could be observed. Neither cetuximab resistance nor HPV status significantly influenced the expression of HER receptors in HNSCC cell lines. In contrast, the expression of EGFR, HER2, and HER3 was significantly altered under hypoxia. Oxygen deficiency is a common characteristic of HNSCC tumors, and these hypoxic tumor regions often contain cells that are more resistant to treatment. However, we observed that afatinib maintained its cytotoxic effect under hypoxia. In conclusion, our preclinical data support the hypothesis that afatinib might be a promising therapeutic strategy to treat patients with HNSCC experiencing intrinsic or acquired cetuximab resistance. PMID- 29603586 TI - Modeling of the metallic port in breast tissue expanders for photon radiotherapy. AB - The purpose of this study was to model the metallic port in breast tissue expanders and to improve the accuracy of dose calculations in a commercial photon treatment planning system (TPS). The density of the model was determined by comparing TPS calculations and ion chamber (IC) measurements. The model was further validated and compared with two widely used clinical models by using a simplified anthropomorphic phantom and thermoluminescent dosimeters (TLD) measurements. Dose perturbations and target coverage for a single postmastectomy radiotherapy (PMRT) patient were also evaluated. The dimensions of the metallic port model were determined to be 1.75 cm in diameter and 5 mm in thickness. The density of the port was adjusted to be 7.5 g/cm3 which minimized the differences between IC measurements and TPS calculations. Using the simplified anthropomorphic phantom, we found the TPS calculated point doses based on the new model were in agreement with TLD measurements within 5.0% and were more accurate than doses calculated based on the clinical models. Based on the photon treatment plans for a real patient, we found that the metallic port has a negligible dosimetric impact on chest wall, while the port introduced significant dose shadow in skin area. The current clinical port models either overestimate or underestimate the attenuation from the metallic port, and the dose perturbation depends on the plan and the model in a complex way. TPS calculations based on our model of the metallic port showed good agreement with measurements for all cases. This new model could improve the accuracy of dose calculations for PMRT patients who have temporary tissue expanders implanted during radiotherapy and could potentially reduce the risk of complications after the treatment. PMID- 29603588 TI - Renal failure in pediatric Castleman disease: Four French cases with thrombotic microangiopathy. AB - Pediatric Castleman disease (CD) is an uncommon and poorly understood disorder of the lymph nodes. Renal failure has not been described in pediatric multicentric CD (MCD). We report four cases, who presented with polyadenopathy, organomegaly, edema and fluid accumulations, high blood pressure, and acute renal failure. In all cases, renal biopsy confirmed diffuse thrombotic microangiopathy. Definitive diagnosis of MCD was made by a biopsy of an affected lymph node located by computer tomography before initiation of corticosteroid therapy. Treatment of CD with corticosteroid therapy and rituximab was rapidly effective without relapse to date. PMID- 29603587 TI - Influence of the quality of intraoperative fluoroscopic images on the spatial positioning accuracy of a CAOS system. AB - BACKGROUND: Spatial positioning accuracy is a key issue in a computer-assisted orthopaedic surgery (CAOS) system. Since intraoperative fluoroscopic images are one of the most important input data to the CAOS system, the quality of these images should have a significant influence on the accuracy of the CAOS system. But the regularities and mechanism of the influence of the quality of intraoperative images on the accuracy of a CAOS system have yet to be studied. METHODS: Two typical spatial positioning methods - a C-arm calibration-based method and a bi-planar positioning method - are used to study the influence of different image quality parameters, such as resolution, distortion, contrast and signal-to-noise ratio, on positioning accuracy. The error propagation rules of image error in different spatial positioning methods are analyzed by the Monte Carlo method. RESULTS: Correlation analysis showed that resolution and distortion had a significant influence on spatial positioning accuracy. In addition the C arm calibration-based method was more sensitive to image distortion, while the bi planar positioning method was more susceptible to image resolution. The image contrast and signal-to-noise ratio have no significant influence on the spatial positioning accuracy. The result of Monte Carlo analysis proved that generally the bi-planar positioning method was more sensitive to image quality than the C arm calibration-based method. CONCLUSIONS: The quality of intraoperative fluoroscopic images is a key issue in the spatial positioning accuracy of a CAOS system. Although the 2 typical positioning methods have very similar mathematical principles, they showed different sensitivities to different image quality parameters. The result of this research may help to create a realistic standard for intraoperative fluoroscopic images for CAOS systems. PMID- 29603589 TI - MARCKS phosphorylation by PKC strongly impairs cell polarity in the chick neural plate. AB - Neurulation involves a complex coordination of cellular movements that are in great part based on the modulation of the actin cytoskeleton. MARCKS, an F-actin binding protein and the major substrate for PKC, is necessary for gastrulation and neurulation morphogenetic movements in mice, frogs, and fish. We previously showed that this protein accumulates at the apical region of the closing neural plate in chick embryos, and here further explore its role in this process and how it is regulated by PKC phosphorylation. PKC activation by PMA caused extensive neural tube closure defects in cultured chick embryos, together with MARCKS phosphorylation and redistribution to the cytoplasm. This was concomitant with an evident disruption of neural plate cell polarity and extensive apical cell extrusion. This effect was not due to actomyosin hypercontractility, but it was reproduced upon MARCKS knockdown. Interestingly, the overexpression of a nonphosphorylatable form of MARCKS was able to revert the cellular defects observed in the neural plate after PKC activation. Altogether, these results suggest that MARCKS function during neurulation would be to maintain neuroepithelial polarity through the stabilization of subapical F-actin, a function that appears to be counteracted by PKC activation. PMID- 29603590 TI - Potential effects of multimodal psychosomatic inpatient treatment for patients with functional vertigo and dizziness symptoms - A pilot trial. AB - OBJECTIVES: Functional vertigo and dizziness (VD) are frequent and severely distressing complaints that are often described as hard to treat. Our aim was to provide preliminary data on potential effects of multimodal psychosomatic inpatient therapy for patients with functional VD symptoms in reducing vertigo related handicap and related psychopathology, and to evaluate the role of symptom burden and body-related locus of control in predicting vertigo-related handicap at follow-up. DESIGN: We conducted an uncontrolled clinical pilot trial. METHODS: We included data of n = 72 inpatients with functional VD as a primary symptom and various psychopathological and/or physical comorbidities admitted for multimodal psychosomatic inpatient treatment. Patients completed self-report questionnaires assessing vertigo-related handicap (VHQ), somatization (PHQ-15), depression (BDI II), anxiety (BAI), health-related quality of life (HRQOL; SF-36), and body related locus of control (KLC) at admission (T0), discharge (T1), and 6 months after discharge (T2). RESULTS: We observed medium effects for the change of vertigo-related handicap (T0-T1: g = -0.60, T0-T2: g = -0.67) and small effects for the change of somatization (T0-T1: g = -0.29, T0-T2: g = -0.24), mental HRQOL (T0-T1: g = 0.43, T0-T2: g = 0.49), and depression (T0-T1: g = -0.41, T0-T2: g = 0.28) from admission to discharge and admission to follow-up. Body-related locus of control did not predict vertigo-related handicap at follow-up. CONCLUSIONS: Findings provide preliminary evidence for the beneficial role of psychosomatic inpatient treatment for patients with functional VD symptoms. Potentially relevant predictors of outcome at follow-up are discussed. PRACTITIONER POINTS: The change of vertigo-related handicap and related variables through multimodal psychosomatic inpatient treatment was evaluated in a clinical pilot trial in patients with functional vertigo and dizziness. We observed medium effects for the change of vertigo-related handicap and small effects for the change of somatization, mental health-related quality of life, and depression. Internal body-related locus of control at admission did not predict vertigo-related handicap at follow-up. PMID- 29603592 TI - The pepper Bs4C proteins are localized to the endoplasmic reticulum (ER) membrane and confer disease resistance to bacterial blight in transgenic rice. AB - Transcription activator-like effector (TALE)-dependent dominant disease resistance (R) genes in plants, also referred to as executor R genes, are induced on infection by phytopathogenic bacteria of the genus Xanthomonas harbouring the corresponding TALE genes. Unlike the traditional R proteins, the executor R proteins do not determine the resistance specificity and may function broadly in different plant species. The executor R gene Bs4C-R in the resistant genotype PI 235047 of the pepper species Capsicum pubescens (CpBs4C-R) confers disease resistance to Xanthomonas campestris pv. vesicatoria (Xcv) harbouring the TALE genes avrBsP/avrBs4. In this study, the synthetic genes of CpBs4C-R and two other Bs4C-like genes, the susceptible allele in the genotype PI585270 of C. pubescens (CpBs4C-S) and the CaBs4C-R homologue gene in the cultivar 'CM334' of Capsicum annum (CaBs4C), were characterized in tobacco (Nicotiana benthamiana) and rice (Oryza sativa). The Bs4C genes induced cell death in N. benthamiana. The functional Bs4C-eCFP fusion proteins were localized to the endoplasmic reticulum (ER) membrane in the leaf epidermal cells of N. benthamiana. The Xa10 promoter Bs4C fusion genes in transgenic rice conferred strain-specific disease resistance to Xanthomonas oryzae pv. oryzae (Xoo), the causal agent of bacterial blight in rice, and were specifically induced by the Xa10-incompatible Xoo strain PXO99A (pHM1avrXa10). The results indicate that the Bs4C proteins from pepper species function broadly in rice and the Bs4C protein-mediated cell death from the ER is conserved between dicotyledonous and monocotyledonous plants, which can be utilized to engineer novel and enhanced disease resistance in heterologous plants. PMID- 29603591 TI - Phase I study of vorinostat in combination with isotretinoin in patients with refractory/recurrent neuroblastoma: A new approaches to Neuroblastoma Therapy (NANT) trial. AB - BACKGROUND: Vorinostat combined with retinoids produces additive antitumor effects in preclinical studies of neuroblastoma. Higher systemic exposures of vorinostat than achieved in pediatric phase I trials with continuous daily dosing are necessary for in vivo increased histone acetylation and cytotoxic activity. We conducted a phase I trial in children with relapsed/refractory neuroblastoma to determine the maximum tolerated dose (MTD) of vorinostat on an interrupted schedule, escalating beyond the previously identified pediatric MTD. METHODS: Isotretinoin (cis-13-retinoic acid) 80 mg/m2 /dose was administered by mouth twice daily on days 1-14 in combination with escalating doses of daily vorinostat up to 430 mg/m2 /dose (days 1-4; 8-11) in each 28-day cycle using the standard 3 + 3 design. Vorinostat pharmacokinetic testing and histone acetylation assays were performed. RESULTS: Twenty-nine patients with refractory or relapsed neuroblastoma were enrolled and 28 were evaluable for dose escalation decisions. Median number of cycles completed was two (range 1-15); 11 patients received four or more cycles. Three patients experienced cycle 1 dose-limiting toxicities. A total of 18 patients experienced grade 3/4 toxicities related to study therapy. The maximum intended dose of vorinostat (430 mg/m2 /day, days 1-4; 8-11) was tolerable and led to increased histone acetylation in surrogate tissues when compared to lower doses of vorinostat (P = 0.009). No objective responses were seen. CONCLUSIONS: Increased dose vorinostat (430 mg/m2 /day) on an interrupted schedule is tolerable in combination with isotretinoin. This dose led to increased vorinostat exposures and demonstrated increased histone acetylation. Prolonged stable disease in patients with minimal residual disease warrants further investigation. PMID- 29603593 TI - Phase I trial of the mTOR inhibitor everolimus in combination with multi-agent chemotherapy in relapsed childhood acute lymphoblastic leukemia. AB - BACKGROUND: We sought to determine the feasibility of co-administering everolimus with a four-drug reinduction in children and adolescents with acute lymphoblastic leukemia (ALL) experiencing a first marrow relapse. PROCEDURE: This phase I study tested everolimus with vincristine, prednisone, pegaspargase and doxorubicin in patients with marrow relapse occurring >18 months after first complete remission (CR). The primary aim was to identify the maximum tolerated dose of everolimus. Three dose levels (DLs) were tested during dose escalation (2, 3, and 5 mg/m2 /day). Additional patients were enrolled at the 3- and 5 mg/m2 /day DLs to further evaluate toxicity (dose expansion). RESULTS: Thirteen patients enrolled during dose escalation and nine during dose expansion. During dose escalation, one dose-limiting toxicity occurred (grade 4 hyperbilirubinemia) in six evaluable patients at DL3 (5 mg/m2 /day). The most common grade >=3 adverse events were febrile neutropenia, infections, transaminitis, hyperbilirubinemia, and hypophosphatemia. Two of the 12 patients treated at DL3 developed Rothia mucilaginosa meningitis. Nineteen patients (86%) achieved a second CR (CR2). Of those, 13 (68%) had a low end-reinduction minimal residual disease (MRD) level (<=10-3 by polymerase chain reaction-based assay). The CR2 rate for patients with B-cell ALL treated at DL3 (n = 12) was 92%; 82% of these patients had low MRD. CONCLUSIONS: Everolimus combined with four-drug reinduction chemotherapy was generally well tolerated and associated with favorable rates of CR2 and low end reinduction MRD. The recommended phase 2 dose of everolimus given in combination with a four-drug reinduction is 5 mg/m2 /day. This promising combination should be further evaluated in a larger patient cohort. PMID- 29603595 TI - Integrated technological and management solutions for wastewater treatment and efficient agricultural reuse in Egypt, Morocco, and Tunisia. AB - Mediterranean-African countries (MACs) face a major water crisis. The annual renewable water resources are close to the 500 m3 /capita threshold of absolute water scarcity, and water withdrawals exceed total renewable water resources by 30%. Such a low water availability curbs economic development in agriculture, which accounts for 86% of freshwater consumption. The analysis of the current situation of wastewater treatment, irrigation, and water management in MACs and of the research projects targeted to these countries indicates the need for 1) an enhanced capacity to analyze water stress, 2) the development of water management strategies capable of including wastewater reuse, and 3) development of locally adapted water treatment and irrigation technologies. This analysis shaped the MADFORWATER project (www.madforwater.eu), whose goal is to develop a set of integrated technological and management solutions to enhance wastewater treatment, wastewater reuse for irrigation, and water efficiency in agriculture in Egypt, Morocco, and Tunisia. MADFORWATER develops and adapts technologies for the production of irrigation-quality water from drainage canals and municipal, agro-industrial, and industrial wastewaters and technologies for water efficiency and reuse in agriculture, initially validated at laboratory scale, to 3 hydrological basins in the selected MACs. Selected technologies will be further adapted and validated in 4 demonstration plants of integrated wastewater treatment and reuse. Integrated strategies for wastewater treatment and reuse targeted to the selected basins are developed, and guidelines for the development of integrated water management strategies in other basins of the 3 target MACs will be produced. The social and technical suitability of the developed technologies and nontechnological tools in relation to the local context is evaluated with the participation of MAC stakeholders and partners. Guidelines on economic instruments and policies for the effective implementation of the proposed water management solutions in the target MACs will be developed. Integr Environ Assess Manag 2018;14:447-462. (c) 2018 The Authors. Integrated Environmental Assessment and Management published by Wiley Periodicals, Inc. on behalf of Society of Environmental Toxicology & Chemistry (SETAC). PMID- 29603594 TI - Serum amyloid A1 in combination with integrin alphaVbeta3 increases glioblastoma cells mobility and progression. AB - Glioblastoma multiforme (GBM) is a highly malignant type of brain tumor found in humans. GBM cells reproduce quickly, and the median survival time for patients after therapy is approximately 1 year with a high relapse rate. Current therapies and diagnostic tools for GBM are limited; therefore, we searched for a more favorable therapeutic target or marker protein for both therapy and diagnosis. We used mass spectrometry (MS) analysis to identify GBM-associated marker proteins from human plasma and GBM cell cultures. Additional plasma and 52 brain tissues obtained from patients with gliomas were used to validate the association rate of serum amyloid A1 (SAA1) in different grades of gliomas and its distribution in tumors. Microarray database analysis further validated the coefficient of SAA1 levels in gliomas. The cellular mechanisms of SAA1 in GBM proliferation and infiltration were investigated in vitro. We analyzed the correlation between SAA1 and patients' medication requirement to demonstrate the clinical effects of SAA1 in GBM. SAA1 was identified from MS analysis, and its level was revealed to be correlated with the disease grade, clinical severity, and survival rate of patients with gliomas. In vitro cultures, including GBM cells and normal astrocytes, revealed that SAA1 promotes cell migration and invasion through integrin alphaVbeta3 to activate the Erk signaling pathway. Magnetic resonance imaging and tumor region-specific microarray analysis identified a correlation between SAA1 and GBM cell infiltration in patients. In summary, our results demonstrate that SAA1 in combination with integrin alphaV and beta3 can serve as an indicator of high glioblastoma risk. We also identified the cellular mechanisms of SAA1 contributing to GBM progression, which can serve as the basis for future GBM therapy. PMID- 29603596 TI - Sirolimus exposure and the occurrence of cytomegalovirus DNAemia after allogeneic hematopoietic stem cell transplantation. AB - Sirolimus appears to protect against cytomegalovirus (CMV) in organ transplant recipients. The effect of this drug in allogeneic hematopoietic stem cell transplantation recipients remains unexplored. By means of multivariate continuous-time Markov model analyses, we identified 3 independent covariates that significantly impacted the risk of CMV DNAemia: recipient/donor CMV serostatus, tacrolimus exposure, and sirolimus exposure. CMV-seropositive recipients with CMV-seronegative donors had a significantly higher probability of having detectable CMV DNAemia. Increasing the tacrolimus trough concentration from 0 to 16 ng/mL increased the probability of patients having detectable CMV DNAemia by 40% (from 40% to 80%), whereas this probability decreased by 25% (from 40% to 15%) when trough concentrations of sirolimus increased from 0 to 16 ng/mL. Sensitivity analysis showed that sirolimus exposure between 0 and 6 ng/mL has no or negligible effect on CMV DNAemia, but levels >8 ng/mL significantly decreased the number of detectable CMV DNAemia cases (the risk ratios decreased from 0.68 to 0.21 when whole blood sirolimus concentrations changed from 8 to 18 ng/mL, P < .01). In conclusion, we used a pharmacometric statistical tool to provide the first clinical evidence that fewer CMV DNAemia events become detectable as sirolimus exposure increases. PMID- 29603597 TI - Health Care Provider Perceptions of the Safety of IUDs for Women with HIV. AB - CONTEXT: Women who are living with HIV use IUDs at a lower rate than the general population, and it is unclear whether health care providers' misconceptions about IUD safety contribute to this disparity. METHODS: A 2013-2014 nationwide survey of 1,998 U.S. family planning providers assessed perceptions of IUD safety for women with HIV or other medical conditions. Multivariable logistic regression was used to examine associations between provider characteristics and whether individuals believed IUDs were safe for HIV-positive women. Data from public sector providers and office-based physicians were analyzed separately. RESULTS: Seven in 10 providers considered IUDs safe for women with HIV, and there were no differences by provider type. Among public-sector providers, some of the characteristics associated with believing that IUDs were unsafe for seropositive women were working at a clinic without Title X funding (odds ratio, 1.5), not being trained in IUD insertion (2.1) and not using the U.S. Medical Eligibility Criteria for Contraceptive Use (U.S. MEC) for clinical guidance (1.8). Office based physicians who did not use the guidelines also had an increased likelihood of believing that IUDs were unsafe for women with HIV (2.9), and physicians who had completed training 25 or more years ago were more likely than those who had done so less than five years ago to consider IUDs unsafe (3.3). CONCLUSIONS: Greater use of evidence-based contraceptive guidance such as the U.S. MEC may help inform provider perceptions of IUD safety and hence contribute to increased contraceptive choice for women with HIV. PMID- 29603598 TI - Zika virus in Germany: case report and possible routes of transmission. PMID- 29603599 TI - Occupational subacute cutaneous lupus erythematosus caused by outdoor work. PMID- 29603601 TI - Disseminated Mycobacterium marinum skin infection due to chronic lymphedema in an immunocompetent patient. PMID- 29603600 TI - Histone/protein deacetylase inhibitor therapy for enhancement of Foxp3+ T regulatory cell function posttransplantation. AB - T-regulatory (Treg) cells are like other cells present throughout the body in being subject to biochemical modifications in response to extracellular signals. An important component of these responses involves changes in posttranslational modifications (PTMs) of histones and many nonhistone proteins, including phosphorylation/dephosphorylation, ubiquitination/deubiquitination, and acetylation/deacetylation. Foxp3, the key transcription factor of Tregs, is constantly being rapidly turned over, and a number of these PTMs determine its level of expression and activity. Of interest in the transplant setting, modulation of the acetylation or deacetylation of key lysine residues in Foxp3 can promote the stability and function, leading to increased Treg production and increased Treg suppressive activity. This mini-review focuses on recent data concerning the roles that histone/protein deacetylases (HDACs) play in control of Treg function, and how small molecule HDAC inhibitors can be used to promote Treg dependent allograft survival in experimental models. These data are discussed in the light of increasing interest in the identification and clinical evaluation of isoform-selective HDAC inhibitors, and their potential application as tools to modulate Foxp3+ Treg cell numbers and function in transplant recipients. PMID- 29603602 TI - Comment on: Effectiveness of antibacterial prophylaxis during induction chemotherapy in children with acute lymphoblastic leukemia. PMID- 29603603 TI - The retroauricular subcutaneously pedicled island flap for reconstruction of auricular conchal defects. PMID- 29603604 TI - Sweet T Cell Dysfunction. PMID- 29603605 TI - Stepping Up to Reduce Racial Disparities in Transplantation. PMID- 29603606 TI - Interim estimates of 2017-18 seasonal influenza vaccine effectiveness - United States, February 2018. PMID- 29603607 TI - An unusual case of cardiac failure following orthotopic liver transplantation. PMID- 29603608 TI - Triterpenes and Meroterpenes with Neuroprotective Effects from Ganoderma leucocontextum. AB - Ganoderma leucocontextum is a well-known medicinal mushroom cultivated in the Tibet Plateau of China. Chemistry investigation on the fruiting bodies of this mushroom resulted in the isolation of sixteen secondary metabolites including three new lanostane triterpenes, ganoleucoins Q - S (1 - 3), as well as thirteen known compounds (4 - 16). The structures of compounds 1 - 3 were determined by NMR, MS, CD spectral analysis, and chemical derivation method. The neuroprotective effects of compounds 1 - 16 were tested on PC12 cells. Compounds 1 and 2 showed protective effects against the H2 O2 induced damage with the survival rate of 83.19 +/- 0.92%, 73.37 +/- 1.25% at the concentration of 200 MUm, respectively. Meanwhile, compounds 1 and 2 induced neurite outgrowth at 50 - 200 MUm. The results from this study suggested that G. leucocontextum and its metabolites may be potential functional food ingredients for the prevention of neurodegenerative diseases. PMID- 29603609 TI - A General Strategy of Aerolysin Nanopore Detection for Oligonucleotides with the Secondary Structure. AB - An aerolysin nanopore is employed as a sensitive tool for single-molecule analysis of short oligonucleotides (<=10 nucleotides), poly(ethylene glycol) (PEGs), peptides, and proteins. However, the direct analysis of long oligonucleotides with the secondary structure (e.g., G-quadruplex topology) remains a challenge, which impedes the further practical applications of the aerolysin nanopore. Here, a simple and applicable method of aerolysin nanopore is presented to achieve a direct analysis of structured oligonucleotides that are extended to 30 nucleotides long by a cation-regulation mechanism. By regulating the cation type in electrolyte solution, the structured oligonucleotides are unfolded into linear form which ensures the successive translocation. The results show that each model oligonucleotide of 5'-(TTAGGG)n -3' can produce a well resolved current blockade in its unfolded solution of MgCl2 . The length between 6 and 30 nucleotides long of model oligonucleotides is proportional to the duration time, showing a translocation velocity as low as 0.70-0.13 ms nt-1 at +140 mV. This method exhibits an excellent sensitivity and a sufficient temporal resolution, provides insight into the aerolysin nanopore methodology for genetic and epigenetic biosensing, making aerolysin applicable in practical diagnosing with long and structured nucleic acids. PMID- 29603611 TI - A systematic review of pediatric self-report symptom measures: Congruence with the theory of unpleasant symptoms. AB - PURPOSE: Many children and adolescents experience unpleasant symptoms due to acute and chronic illnesses. Several symptom measures specific to children and adolescents are available to assess unpleasant symptoms. What is unclear is how well these measures assess all dimensions of the symptom experience. Using the Theory of Unpleasant Symptoms (TOUS) as a guide, the purpose of this systematic review of self-report symptom measures was to examine the comprehensiveness of current symptom measures designed to assess children's and adolescents' symptom experiences. CONCLUSIONS: The TOUS did not guide the development of any of the measures studied; hence, exact parallels were not expected. Currently, no pediatric self-report symptom measures were found that assessed all dimensions of the symptom experience. Four measures captured three dimensions: intensity, timing, and distress. Only two measures assessed quality. PRACTICE IMPLICATIONS: Practitioners need to be aware of the dimensions reflected in commonly used symptom measures. Augmentation of these measures is needed in order to assess the entire symptom experience in children and adolescents. PMID- 29603610 TI - Parent understanding of the risk of future limitations secondary to pediatric cancer treatment. AB - BACKGROUND: Parents and physicians may have different understandings of a child's risk of future limitations due to cancer or cancer treatment. We evaluated alignment between parent- and physician-estimated risk of late effects. METHODS: We surveyed 352 parents of children with cancer within 12 weeks of diagnosis, and the children's oncologists, at Dana-Farber/Boston Children's Cancer and Blood Disorders Center and Children's Hospital of Philadelphia. We assessed parent and physician estimations of the child's risk of future limitations in physical abilities, intelligence, or quality of life (QOL) due to cancer treatment. Physician-estimated risk of limitations >=50% was considered high risk. RESULTS: Physicians considered 22% of children at high risk of physical impairments, 9% at high risk for impaired intelligence, and 6% at high risk for impaired QOL. Among high-risk children, 38% of parents recognized this risk in physical abilities, 21% in intelligence, and 5% in QOL. In multivariable analysis, parental understanding of risk, defined as concordant parent and physician estimates, was greater among parents of children at lower risk of future limitations (odds ratio 2.59; 95% confidence interval 1.35-4.96). Regardless of risk, 92% of parents considered it very/extremely important to receive information about potential health implications of cancer treatment. CONCLUSIONS: Although most parents want information about life after cancer, most parents of children at high risk of future impairment do not recognize this risk. Strategies to improve communication about late effects throughout pediatric cancer treatment should prioritize meeting information needs and improving parent understanding of the risk of impairment. PMID- 29603612 TI - Hereditary dehydrated stomatocytosis with splicing site mutation of PIEZO1 mimicking myelodysplastic syndrome diagnosed by targeted next-generation sequencing. PMID- 29603614 TI - Better decision making in drug development through adoption of formal prior elicitation. AB - With the continued increase in the use of Bayesian methods in drug development, there is a need for statisticians to have tools to develop robust and defensible informative prior distributions. Whilst relevant empirical data should, where possible, provide the basis for such priors, it is often the case that limitations in data and/or our understanding may preclude direct construction of a data-based prior. Formal expert elicitation methods are a key technique that can be used to determine priors in these situations. Within GlaxoSmithKline, we have adopted a structured approach to prior elicitation on the basis of the SHELF elicitation framework and routinely use this in conjunction with calculation of probability of success (assurance) of the next study(s) to inform internal decision making at key project milestones. The aim of this paper is to share our experiences of embedding the use of prior elicitation within a large pharmaceutical company, highlighting both the benefits and challenges of prior elicitation through a series of case studies. We have found that putting team beliefs into the shape of a quantitative probability distribution provides a firm anchor for all internal decision making, enabling teams to provide investment boards with formally appropriate estimates of the probability of trial success as well as robust plans for interim decision rules where appropriate. As an added benefit, the elicitation process provides transparency about the beliefs and risks of the potential medicine, ultimately enabling better portfolio and company wide decision making. PMID- 29603613 TI - Sensitization in Transplantation: Assessment of Risk (STAR) 2017 Working Group Meeting Report. AB - The presence of preexisting (memory) or de novo donor-specific HLA antibodies (DSAs) is a known barrier to successful long-term organ transplantation. Yet, despite the fact that laboratory tools and our understanding of histocompatibility have advanced significantly in recent years, the criteria to define presence of a DSA and assign a level of risk for a given DSA vary markedly between centers. A collaborative effort between the American Society for Histocompatibility and Immunogenetics and the American Society of Transplantation provided the logistical support for generating a dedicated multidisciplinary working group, which included experts in histocompatibility as well as kidney, liver, heart, and lung transplantation. The goals were to perform a critical review of biologically driven, state-of-the-art, clinical diagnostics literature and to provide clinical practice recommendations based on expert assessment of quality and strength of evidence. The results of the Sensitization in Transplantation: Assessment of Risk (STAR) meeting are summarized here, providing recommendations on the definition and utilization of HLA diagnostic testing, and a framework for clinical assessment of risk for a memory or a primary alloimmune response. The definitions, recommendations, risk framework, and highlighted gaps in knowledge are intended to spur research that will inform the next STAR Working Group meeting in 2019. PMID- 29603615 TI - Reply to: Comment on: Adolescent patient involvement in discussions about relapsed or refractory cancer with oncology clinicians. PMID- 29603616 TI - A long history of widespread asymptomatic giant plaques. PMID- 29603617 TI - Engineering therapeutic T cells to suppress alloimmune responses using TCRs, CARs, or BARs. AB - Adoptive cell therapy with therapeutic T cells has become one of the most promising strategies to stimulate or suppress immune responses. Using virus mediated genetic manipulation, the antigen specificity of T cells can now be precisely redirected. Tailored specificity has not only overcome technical limitations and safety concerns but also considerably broadened the spectrum of therapeutic applications. Different T cell-engineering strategies have now become available to suppress alloimmune responses. We first provide an overview of the allorecognition pathways and effector mechanisms that are responsible for alloimmune injuries in the setting of vascularized organ transplantation. We then discuss the potential to use different T cell-engineering approaches to suppress alloimmune responses. Specifically, expression of allospecific T cell receptors, single-chain chimeric antigen receptors, or antigen domains recognized by B cell receptors (B cell antibody receptors) in regulatory or cytotoxic T cells are considered. The ability of these strategies to control the direct or indirect pathways of allorecognition and the cellular or humoral alloimmune responses is discussed. An intimate understanding of the complex interplay that occurs between the engineered T cells and the alloimmune players is a necessary prerequisite for the design of safe and successful strategies for precise immunomodulation in transplantation. PMID- 29603619 TI - A New Strategy for Maximizing the Storage Capacity of Lithium in Carbon Materials. AB - A novel strategy for maximizing the lithium storage capacity of carbon materials is reported. To redesign the interior structure, a large amount of Li, 4 wt%, is doped into the carbon during its synthesis. The Li-doped carbon is subsequently annealed, during which the diffusion of Li induces a disordered structure, thereby generating many nanocavities. The diffused Li atoms aggregate into a superdense state within the carbon structure; when the Li agglomerates escape from the carbon during the delithiation process, new void spaces are created at their location. Thus, the interior of carbon is evacuated to form a new structure capable of storing a large amount of Li, realizing a high reversible capacity during charging. At a rate of 1 C, the average reversible capacity of the material is three times higher than that of commercial graphite, with a stable cycling performance over 300 cycles. This is a remarkably improved Li storage performance for pure carbon, without the need for the silicon, tin, or transition metal oxide, that are becoming popular as next-generation materials. Therefore, this novel strategy can potentially aid in the design of high-performance materials via better carbon material design and combinations with other types of materials. PMID- 29603620 TI - Erythematous non-ulcerated nodule of the scapular region. PMID- 29603618 TI - Adolescent and young adult Hodgkin lymphoma: Raising the bar through collaborative science and multidisciplinary care. AB - Hodgkin lymphoma (HL) is one of the most common cancers in the adolescent and young adult (AYA) population (15-39 years). Despite continued improvements in HL outcomes, AYAs have not exhibited survival gains to the same extent as other age groups. At present, details about tumor biology, optimal therapeutic approaches, supportive care needs, and long-term toxicities in AYAs with HL remain understudied. Herein, we summarize the current state of the AYA population with HL, specifically focusing on how collaborations across the pediatric and medical oncology divide, coupled with multidisciplinary patient care, can further optimize outcomes for this group of patients. PMID- 29603621 TI - Uncommon ulcers in a patient with diabetes. PMID- 29603622 TI - Metabolic reprogramming of host cells upon bacterial infection: Why shift to a Warburg-like metabolism? AB - The finding that the Warburg effect observed in proliferating cancer cells is also observed during immune responses renewed the interest in the study of metabolic reprogramming of immune cells, a field of investigation called immunometabolism. However, the specific mechanisms and processes underlying metabolic changes of host cells upon bacterial infection remain poorly understood. Several recent reports have reported that mammalian cells infected with intracellular bacteria have an altered metabolism that resembles the Warburg effect seen in cancer cells. In this Review, we will summarize current knowledge on metabolic reprogramming and discuss putative causes underlying the preferential remodelling of host cells to Warburg-like metabolic programs during infection by intracellular bacteria. PMID- 29603623 TI - Vibsane-Type Diterpenoids from Viburnum odoratissimum and Their Cytotoxic and HSP90 Inhibitory Activities. AB - Four new vibsane-type diterpenoids, vibsanol I (1), 15-hydroperoxyvibsanol A (2), 14-hydroperoxyvibsanol B (3), 15-O-methylvibsanin U (4), and a new natural product, 5,6-dihydrovibsanin B (5), as well as six known analogues, were isolated from the twigs and leaves of Viburnum odoratissimum. Their structures were elucidated by spectroscopic analyses and chemical derivatization method. All compounds showed different levels of cytotoxicity against five cell lines (HL-60, A-549, SMMC-7721, MCF-7, and SW480). Remarkably, 14,18-O-diacetyl-15-O methylvibsanin U (4a) showed significant cytotoxicity against HL-60, A-549, SMMC 7721, MCF-7, and SW480, with IC50 values of 0.15 +/- 0.01, 0.69 +/- 0.01, 0.41 +/ 0.02, 0.75 +/- 0.03, and 0.48 +/- 0.03 MUm, respectively. In addition, vibsanin K (10) was identified as a HSP90 inhibitor with an IC50 value of 19.16 MUm. PMID- 29603624 TI - Design and Realization of 3D Printed AFM Probes. AB - Atomic force microscope (AFM) probes and AFM imaging by extension are the product of exceptionally refined silicon micromachining, but are also restricted by the limitations of these fabrication techniques. Here, the nanoscale additive manufacturing technique direct laser writing is explored as a method to print monolithic cantilevered probes for AFM. Not only are 3D printed probes found to function effectively for AFM, but they also confer several advantages, most notably the ability to image in intermittent contact mode with a bandwidth approximately ten times larger than analogous silicon probes. In addition, the arbitrary structural control afforded by 3D printing is found to enable programming the modal structure of the probe, a capability that can be useful in the context of resonantly amplifying nonlinear tip-sample interactions. Collectively, these results show that 3D printed probes complement those produced using conventional silicon micromachining and open the door to new imaging techniques. PMID- 29603625 TI - Psychopathology, cognition and outcome in Dutch and immigrant first-episode psychosis patients. AB - AIM: The primary aim was to examine differences in baseline symptom expression, neurocognition, social cognition and psychosocial functioning between Dutch, first-generation immigrants and second-generation immigrants with a first-episode psychosis (FEP). The secondary aim was to examine functional and symptomatic change and between-group differences at 12-months follow-up. Associations between migration, baseline characteristics and outcome were explored. METHODS: Forty-six Dutch, 56 second-generation- and 60 first-generation immigrant patients completed baseline measures for 6 symptom dimensions (positive symptoms, negative symptoms, neurocognitive functioning, social cognitive functioning, excitement and emotional distress) and 5 domains of psychosocial functioning (general functioning, work and study, relationships, self-care and disturbing behaviour). Functioning and psychotic symptoms were assessed at baseline and 12-months follow up. ANCOVA and t tests were used to assess between-group differences. General linear models were used to explore within-group differences. Backward-regression was used to explore predictors of outcome. RESULTS: Levels of positive symptoms, excitement and emotional distress did not differ between groups at baseline or follow-up. Dutch patients had lower levels of negative symptoms than both immigrant groups at follow-up. On neurocognition and social cognition, Dutch performed better than second-generation immigrants, who in turn performed better than first-generation immigrants. Psychosocial functioning across all domains at baseline and at 12-months follow-up was similar across groups. Baseline levels of general psychosocial functioning and income were the strongest predictors of outcome at follow-up. CONCLUSIONS: Psychosocial functioning and symptom profiles are comparable between Dutch, first-generation immigrant and second-generation immigrant FEP patients, excluding neurocognitive and social cognitive deficits. A range of baseline characteristics predicted outcome. PMID- 29603626 TI - Pulmonary hypertension: Barrier or just a bump in the road in transplanting adults with congenital heart disease. AB - BACKGROUND: Heart failure (HF) is the leading cause of death in adults with congenital heart disease (ACHD). Identification of disease progression and timing of referral for advanced therapies is often delayed. However, increased awareness and understanding of ACHD and improvements in the approach to treatment have led to improved outcomes. Pulmonary hypertension (PH) is a common barrier to HT. In ACHD, the approach to PH and HT is quite complicated, given the anatomic heterogeneity and lower prevalence and experience. However, in some cases, PH is a result of elevated systemic filling pressures and low output. METHODS: We describe the approach used to successfully transplant an ACHD patient with severe pre-HT PH performing HT alone. We review the literature and describe the one patient's journey from primarily palliative, to a combined heart-lung transplant candidate, to successful HT patient. RESULTS: We discuss the methodology used to successfully transplant a patient, with significantly elevated pulmonary pressures and an initial pulmonary vascular resistance (PVR) > 13 Wood units. CONCLUSIONS: There are a number of complexities associated with the ACHD population and it is of utmost importance to carefully identify the underlying hemodynamic milieu and inform the appropriate treatment course in order to have successful transplant outcomes. PMID- 29603627 TI - Equity in kidney transplantation: Policy change is only the first step. PMID- 29603628 TI - Pubogenital tinea after intimate shaving with isolation of Trichophyton benhamiae. PMID- 29603630 TI - Frailty after liver transplantation: The strong survive but may not prosper. PMID- 29603629 TI - CYP3A5*3 and ABCB1 61A>G Significantly Influence Dose-adjusted Trough Blood Tacrolimus Concentrations in the First Three Months Post-Kidney Transplantation. AB - Tacrolimus (TAC) is a first-line immunosuppressant used to prevent organ rejection after kidney transplantation. There is large inter-individual variability in its pharmacokinetics. Single nucleotide polymorphisms (SNPs) in genes encoding TAC metabolizing enzymes cytochromes P450 3A4/5 (CYP3A4/5), P glycoprotein efflux transporter (ABCB1), their expression regulator pregnane X receptor (NR1I2) and CYP3A co-factor cytochrome P450 reductase (POR) have been studied for their effects on tacrolimus disposition. However, except for CYP3A5*3, controversies remain about their roles in predicting dose-adjusted trough blood TAC concentrations (C0 /D). This study aimed to investigate the effects of ABCB1 (61A>G, 1199G>A, 1236C>T, 2677G>T and 3435C>T), CYP3A4*22, CYP3A5*3, NR1I2 (8055C>T, 63396C>T and -25385C>T) and POR*28 SNPs on TAC C0 /D. In total, 165 kidney transplant recipients were included in this study. SNPs were genotyped by probe-based real-time polymerase chain reaction. Associations between log-transformed whole blood TAC C0 /D (measured at 1 and 3 months post transplant) and genotypes/haplotypes were assessed by linear mixed effects analysis, controlling for age, sex and haematocrit. It was observed that CYP3A5 expressors (*1/*1 + *1/*3) (p = 5.5 * 10-16 ) and ABCB1 61G allele carriers (p = 0.001) had lower log-transformed TAC C0 /D (56% and 26% lower geometric mean TAC C0 /D, respectively) and accounted for approximately 30% and 4%, respectively, of log-transformed TAC C0 /D variability in the first 3 months post-transplant. In conclusion, CYP3A5*3 is a major, and ABCB1 61A>G is a novel, although minor, genetic factor affecting TAC C0 /D in kidney transplant recipients. PMID- 29603631 TI - dinoref: A curated dinoflagellate (Dinophyceae) reference database for the 18S rRNA gene. AB - Dinoflagellates are a heterogeneous group of protists present in all aquatic ecosystems where they occupy various ecological niches. They play a major role as primary producers, but many species are mixotrophic or heterotrophic. Environmental metabarcoding based on high-throughput sequencing is increasingly applied to assess diversity and abundance of planktonic organisms, and reference databases are definitely needed to taxonomically assign the huge number of sequences. We provide an updated 18S rRNA reference database of dinoflagellates: dinoref. Sequences were downloaded from genbank and filtered based on stringent quality criteria. All sequences were taxonomically curated, classified taking into account classical morphotaxonomic studies and molecular phylogenies, and linked to a series of metadata. dinoref includes 1,671 sequences representing 149 genera and 422 species. The taxonomic assignation of 468 sequences was revised. The largest number of sequences belongs to Gonyaulacales and Suessiales that include toxic and symbiotic species. dinoref provides an opportunity to test the level of taxonomic resolution of different 18S barcode markers based on a large number of sequences and species. As an example, when only the V4 region is considered, 374 of the 422 species included in dinoref can still be unambiguously identified. Clustering the V4 sequences at 98% similarity, a threshold that is commonly applied in metabarcoding studies, resulted in a considerable underestimation of species diversity. PMID- 29603632 TI - Metabolic Regulation of Methionine Restriction in Diabetes. AB - Although the effects of dietary methionine restriction have been investigated in the physiology of aging and diseases related to oxidative stress, the relationship between methionine restriction (MR) and the development of metabolic disorders has not been explored extensively. This review summarizes studies of the possible involvement of dietary methionine restriction in improving insulin resistance, glucose homeostasis, oxidative stress, lipid metabolism, the pentose phosphate pathway (PPP), and inflammation, with an emphasis on the fibroblast growth factor 21 and protein phosphatase 2A signals and autophagy in diabetes. Diets deficient in methionine may be a useful nutritional strategy in patients with diabetes. PMID- 29603634 TI - The Current Status of O-Heterocycles: A Synthetic and Medicinal Overview. AB - O-Heterocycles have been explored in the field of medicinal chemistry for a long time, but their significance has not been duly recognised and they are often shunned in favour of N-heterocycles. The design of bioactive molecules for nearly every pathophysiological condition is primarily focused on novel N-heterocycles. The main reasons for such bias include the ease of synthesis and possible mimicking of physiological molecules by N-heterocycles. But considering only this criterion rarely provides breakthrough molecules for a given disease condition, and instead the risks of toxicity or side effects are increased with such molecules. On the other hand, owing to improved synthetic feasibility, O heterocycles have established themselves as equally potent lead molecules for a wide range of pathophysiological conditions. In the last decade there have been hundreds of reports validating the fact that equally potent molecules can be designed and developed by using O-heterocycles, and these are also expected to have comparably low toxicity. Even so, researchers tend to remain biased toward the use of N-heterocycles over O-heterocycles. Thus, this review provides a critical analysis of the synthesis and medicinal attributes of O-heterocycles, such as pyrones, oxazolones, furanones, oxetanes, oxazolidinones, and dioxolonones, and others, reported in the last five years, underlining the need for and the advantages guiding researchers toward them. PMID- 29603635 TI - The impact of crown fracture in the permanent dentition on children's quality of life. AB - BACKGROUND/AIM: Among the diseases related to oral health, traumatic dental injuries (TDI) can lead to pain, loss of function and aesthetic problems, with physical, emotional and social consequences for children and their families. The aim of this study was to investigate the relationship between enamel fracture and enamel-dentin fracture with oral health-related quality of life (OHRQoL). MATERIAL AND METHODS: This cross-sectional study had a representative sample of 1589 children between 8-10 years of age from public schools. The OHRQoL was obtained through the Child Perceptions Questionnaire (CPQ8-10 ), which is a questionnaire validated for Brazilian children. Clinical data were collected by 4 calibrated examiners (Kappa > 0.7) using the Decay, Missing, Filled Teeth (DMFT) Index, Dental Aesthetic Index (DAI) and TDI. A socio-economic questionnaire was sent to the caregivers to be answered at home. Descriptive statistics and Poisson regression with prevalence ratio (PR) and 95% confidence interval (CI) were used for statistical analysis. RESULTS: The prevalence of TDI was 10.6%, and among these 10.3% who had an impact on the OHRQoL, it was due to enamel-dentin fracture. Children with enamel-dentin fracture had (PR 1.35; 95% CI 1.07-1.70) higher prevalence of impact on the OHRQoL. Children with enamel fracture had no impact on the OHRQoL (P = .254). CONCLUSION: Enamel fracture had no significant impact on children's quality of life, while enamel-dentin fracture did have an impact on quality of life. PMID- 29603636 TI - Publication rates of abstracts presented at the Royal Australian and New Zealand College of Radiologists annual scientific meetings: Any change since 2004? AB - INTRODUCTION: The aim of this study was to determine the publication rate of abstracts presented at annual Royal Australian and New Zealand College of Radiologists (RANZCR) conferences. METHODS: The College's Annual Scientific Meetings (ASMs) from 2010 to 2013 were examined, with the goal of comparing these results to the findings of an earlier identical study that examined RANZCR ASMs from 1996 to 1999. RESULTS: Of the 1152 research abstracts presented, 468 (41%) had been published as full articles. The overall abstract to publication ratio (APR) for radiology was 34% and for radiation oncology was 57%. For oral presentations, these were 44% for radiology and 55% for radiation oncology. Papers were published in a wide variety of journals but 23% of articles appeared in the College's journal, the Journal of Medical Imaging and Radiation Oncology. The mean time between presentation and publication was 16.5 months (median 17 months). CONCLUSION: Publication rates are comparable with international reports. The APR has increased since the previous study for both disciplines, but more so for Radiation Oncology. PMID- 29603633 TI - A Translational Model of Incomplete Catch-Up Growth: Early-Life Hypoxia and the Effect of Physical Activity. AB - Advances in therapies have led to prolonged survival from many previously lethal health threats in children, notably among prematurely born babies and those with congenital heart disease. Evidence for catch-up growth is common in these children, but in many cases the adult phenotype is never achieved. A translational animal model is required in which specific tissues can be studied over a reasonable time interval. We investigated the impact of postnatal hypoxia (HY) (12%O2 (HY12) or 10% O2 (HY10)) on growth in rats relative to animals raised in room air. Subgroups had access to running wheels following the HY period. Growth was fully compensated in adult HY12 rats but not HY10 rats. The results of this study indicate that neonatal hypoxia can be a useful model for the elucidation of mechanisms that mediate successful catch-up growth following neonatal insults and identify the critical factors that prevent successful catch up growth. PMID- 29603637 TI - Carpe diem-Time to transition from empiric to precision medicine in kidney transplantation. AB - The current immunosuppressive pipeline in kidney transplantation is limited. In part, this is due to excellent one-year allograft outcomes with the current standard of care (ie, calcineurin inhibitor in combination with anti proliferative agents). Despite this success, a recent Federal government sponsored systematic review has identified gaps/limits in the evidence of what constitutes optimal calcineurin inhibitor use in the short- and long-term. Moreover, recent empiric approaches to minimize/withdraw/convert from calcineurin inhibitors have come with the price of increased alloreactivity. As the time horizon to replace calcineurin inhibitors on a global scale may be distant, the transplant community should seize the opportunity to develop ways to personalize calcineurin inhibitor immunosuppression to the individual-transitioning from empiricism to precision. The authors argue in this viewpoint that the path to precision will require measures capable of detecting subclinical alloreactivity to define adequacy of immunosuppression, as well as novel genetic analytics to accurately define alloimmune risk at the individual level-both approaches will require validation in clinical trials. PMID- 29603638 TI - Near visual acuity of dental hygienists with and without magnification. AB - OBJECTIVES: The aim of this study was (i) to evaluate the visual performance of dental hygienists in their clinical environment and (ii) to analyse the relationship between self-assessed and objectively measured visual acuity. METHODS: The near visual acuity of 191 dental hygienists and dental hygiene students was self-assessed with a visual analogue scale and objectively measured with miniaturized visual tests in a simulated clinical setting. The visual acuity was also measured with magnification aids if they were part of the individual clinical equipment. The influence of age and magnification on the near visual acuity was analysed. RESULTS: The visual performance with respect to dental working distance showed a variability of 300% in the dimension of the smallest recognized structure. A weak positive correlation between the self-assessed and objectively measured visual performance (Spearman's rank correlation = 0.27) and a highly significant impact of the test person's age and the use of loupes (both P < .0001) were found. Test subjects >=40 years exhibited a similar visual acuity when using loupes compared to the visual acuity of test subjects <40 years without loupes. CONCLUSIONS: The visual performance with respect to dental working distance cannot be self-assessed and varies individually. Dental hygienists and students of dental hygiene with a weak near visual acuity were not aware of their deficiencies. Optical aids should be used to compensate for individual visual deficiencies and are mandatory above an age of 40 years due to the effects of presbyopia. PMID- 29603639 TI - Flexible Film Bulk Acoustic Wave Filters toward Radiofrequency Wireless Communication. AB - This paper presents a flexible radiofrequency filter with a central frequency of 2.4 GHz based on film bulk acoustic wave resonators (FBARs). The flexible filter consists of five air-gap type FBARs, each comprised of an aluminum nitride piezoelectric thin film sandwiched between two thin-film electrodes. By transfer printing the inorganic film structure from a silicon wafer to an ultrathin polyimide substrate, high electrical performance and mechanical flexibility are achieved. The filter has a peak insertion loss of -1.14 dB, a 3 dB bandwidth of 107 MHz, and a temperature coefficient of frequency of -27 ppm degrees C-1 . The passband and roll-off characteristics of the flexible filter are comparable with silicon-based commercial products. No electrical performance degradation and mechanical failure occur under bending tests with a bending radius of 2.5 mm or after 100 bending cycles. The flexible FBAR filters are believed to be promising candidates for future flexible wireless communication systems. PMID- 29603640 TI - The first 9 years of kidney paired donation through the National Kidney Registry: Characteristics of donors and recipients compared with National Live Donor Transplant Registries. AB - The practice of kidney paired donation (KPD) is expanding annually, offering the opportunity for live donor kidney transplant to more patients. We sought to identify if voluntary KPD networks such as the National Kidney Registry (NKR) were selecting or attracting a narrower group of donors or recipients compared with national registries. For this purpose, we merged data from the NKR database with the Scientific Registry of Transplant Recipients (SRTR) database, from February 14, 2008, to February 14, 2017, encompassing the first 9 years of the NKR. Compared with all United Network for Organ Sharing (UNOS) live donor transplant patients (49 610), all UNOS living unrelated transplant patients (23 319), and all other KPD transplant patients (4236), the demographic and clinical characteristics of NKR transplant patients (2037) appear similar to contemporary national trends. In particular, among the NKR patients, there were a significantly (P < .001) greater number of retransplants (25.6% vs 11.5%), hyperimmunized recipients (22.7% vs 4.3% were cPRA >80%), female recipients (45.9% vs 37.6%), black recipients (18.2% vs 13%), and those on public insurance (49.7% vs 41.8%) compared with controls. These results support the need for greater sharing and larger pool sizes, perhaps enhanced by the entry of compatible pairs and even chains initiated by deceased donors, to unlock more opportunities for those harder-to-match pairs. PMID- 29603641 TI - Donor kidney injury molecule-1 promotes graft recovery by regulating systemic necroinflammation. AB - Ischemia-reperfusion injury during kidney transplantation predisposes to delayed graft function, rejection, and premature graft failure. Exacerbation of tissue damage and alloimmune responses may be explained by necroinflammation: an autoamplification loop of cell death and inflammation, which is mediated by the release of damage-associated molecular patterns (eg, high-mobility group box-1; HMGB1) from necrotic cells that activate both innate and adaptive immune pathways. Kidney injury molecule-1 (KIM-1) is a phosphatidylserine receptor that is upregulated on injured proximal tubular epithelial cells and enables them to clear apoptotic and necrotic cells. Here we show a pivotal role for clearance of dying cells in regulating necroinflammation in a syngeneic murine kidney transplant model. We found persistent KIM-1 expression in KIM-1+/+ kidney grafts posttransplantation. Compared to recipients of KIM-1+/+ kidneys, recipients of KIM-1-/- kidneys exhibited significantly more renal dysfunction, apoptosis and necrosis, tubular obstruction, and graft failure. KIM-1-/- grafts also had more inflammatory cytokines, infiltrating neutrophils, and macrophages compared to KIM 1+/+ grafts. Most significantly, passive release of HMGB1 from apoptotic and necrotic cells led to dramatically higher serum HMGB1 levels and increased proinflammatory macrophages in recipients of KIM-1-/- grafts. Our data identify an endogenous protective mechanism against necroinflammation in kidney grafts that may be of therapeutic relevance in transplantation. PMID- 29603642 TI - Xenoreactive antibodies and latent fibrin formation in VAD and cardiac transplant recipients can confound the detection and measurement of anti-AT1R antibodies. AB - Autoantibodies to the angiotensin II type 1 receptor (AT1R) are thought to be important in antibody-mediated rejection (AMR), especially in the absence of anti HLA antibodies. We used a variety of methods to examine the specificity of a commercially available kit designed to quantitate anti-AT1R antibodies. We found that fibrin formation in serum samples from patients awaiting cardiac transplantation with ventricular assist devices (VADs) can produce falsely elevated anti-AT1R values. In addition, absorption studies with a variety of cell lines with or without expression of human AT1R, and those that express xenoantigens, suggest that many of the antibodies detected in the AT1R test system are heterophilic and have reactivity to xenoantigens. Furthermore, we provide data that show that reactivity to the sialic acid Neu5Gc is a common finding among samples that are highest in anti-AT1R levels. We conclude that a common laboratory method for quantitation of anti-AT1R antibodies is nonspecific and overestimates the frequency of true positives. A reevaluation of the role that anti-AT1R antibodies play in allograft function and patient outcomes is warranted. PMID- 29603643 TI - Skeletal Optimization of Cytotoxic Lipidic Dialkynylcarbinols. AB - In line with a recent study of the pharmacological potential of bioinspired synthetic acetylenic lipids, after identification of the terminal dialkynylcarbinol (DAC) and butadiynyl alkynylcarbinol (BAC) moieties as functional antitumor pharmacophoric units, this work specifically addresses the issue of carbon backbone length. A systematic variation of the aliphatic chain length was thus carried out in both the DAC and BAC series. The critical impact of the length of the lipidic skeleton was first confirmed in the racemic series, with the highest cytotoxic activity observed for C17 to C18 backbones. Enantiomerically enriched samples were prepared by asymmetric synthesis of the optimal C18 DAC and C17 BAC derivatives. Samples with upgraded enantiomeric purity were alternatively produced by enzymatic kinetic resolution. Eutomers possessing the S configuration displayed cytotoxicity IC50 values as low as 15 nm against HCT116 cancer cells, the highest level of activity reached to date in this series. PMID- 29603645 TI - The usefulness integrity testing in children: A single institution experience of 86 tests over a period of 20 years. PMID- 29603644 TI - Racial/ethnic disparities in waitlisting for deceased donor kidney transplantation 1 year after implementation of the new national kidney allocation system. AB - The impact of a new national kidney allocation system (KAS) on access to the national deceased-donor waiting list (waitlisting) and racial/ethnic disparities in waitlisting among US end-stage renal disease (ESRD) patients is unknown. We examined waitlisting pre- and post-KAS among incident (N = 1 253 100) and prevalent (N = 1 556 954) ESRD patients from the United States Renal Data System database (2005-2015) using multivariable time-dependent Cox and interrupted time series models. The adjusted waitlisting rate among incident patients was 9% lower post-KAS (hazard ratio [HR]: 0.91; 95% confidence interval [CI], 0.90-0.93), although preemptive waitlisting increased from 30.2% to 35.1% (P < .0001). The waitlisting decrease is largely due to a decline in inactively waitlisted patients. Pre-KAS, blacks had a 19% lower waitlisting rate vs whites (HR: 0.81; 95% CI, 0.80-0.82); following KAS, disparity declined to 12% (HR: 0.88; 95% CI, 0.85-0.90). In adjusted time-series analyses of prevalent patients, waitlisting rates declined by 3.45/10 000 per month post-KAS (P < .001), resulting in ~146 fewer waitlisting events/month. Shorter dialysis vintage was associated with greater decreases in waitlisting post-KAS (P < .001). Racial disparity reduction was due in part to a steeper decline in inactive waitlisting among minorities and a greater proportion of actively waitlisted minority patients. Waitlisting and racial disparity in waitlisting declined post-KAS; however, disparity remains. PMID- 29603646 TI - Can Graphics Tell Lies? A Tutorial on How To Visualize Your Data. AB - Visualizations are a powerful tool for telling a story about a data set or analysis. If done correctly, visualizations not only display data but also help the audience digest key information. However, if done haphazardly, visualization has the potential to confuse the audience and, in the most extreme circumstances, deceive. In this tutorial, we provide a set of general principles for creating informative visualizations that tell a complete and accurate story of the data. PMID- 29603647 TI - Boron Tribromide-Assisted Chiral Phosphoric Acid Catalysts for Enantioselective [2+2] Cycloaddition. AB - BBr3 -assisted chiral phosphoric acid catalysts for enantioselective [2+2] cycloaddition were developed. The reactions of phenyl vinyl sulfide with alpha substituted acroleins proceeded, and the corresponding [2+2] cycloadducts were obtained with high enantioselectivity. In particular, the [2+2] cycloadduct obtained from methacrolein is a synthetically useful optically active cyclobutane, which could be transformed to a key intermediate for (+)-frontalin, a pheromone of Asian elephants. PMID- 29603648 TI - Cationic and Neutral N-Heterocyclic Carbene Gold(I) Complexes: Cytotoxicity, NCI 60 Screening, Cellular Uptake, Inhibition of Mammalian Thioredoxin Reductase, and Reactive Oxygen Species Formation. AB - A structurally diverse library of 14 gold(I) cationic bis(NHC) and neutral mono(NHC) complexes (NHC: N-heterocyclic carbene) was synthesized and characterized in this work. Four of them were new cationic gold(I) complexes containing functionalized NHCs, and their X-ray crystal structures are presented herein. All of the complexes were investigated for their anticancer activities in four cancer cell lines, including a cisplatin-resistant variant, and a noncancerous cell line. Seven of the cationic gold(I) complexes were found to display high and specific cytotoxic activities toward cancer cells. Two of them were even able to overcome cisplatin resistance. Two highly potent cationic complexes (11 and 15) were also submitted to the NCI-60 cancer panel for further cytotoxicity evaluation. Complex 15 showed a surprisingly high potency toward leukemia among the nine examined cancer subtypes, particularly toward the CCRF CEM leukemia cell line with a concentration for 50 % inhibition of growth down to 79.4 nm. In addition, cationic complex 13, which demonstrated a remarkable cytotoxicity against hepatocellular carcinoma, was selected to obtain insight into the mechanistic aspects in HepG2 cells. Cellular uptake measurements were indicative of good bioavailability. By various biochemical assays, this complex was found to effectively inhibit thioredoxin reductase and its cytotoxicity toward HepG2 cells was found to be reactive oxygen species dependent. PMID- 29603649 TI - Ex and in vivo characterization of the wavelength-dependent 3-photon action cross sections of red fluorescent proteins covering the 1700-nm window. AB - Multiphoton action cross-sections are the prerequisite for excitation light selection. At the 1700-nm window suitable for deep-tissue imaging, wavelength dependent 3-photon action cross-sections etasigma3 for RFPs are unknown, preventing wavelength selection. Here we demonstrate: (1) ex vivo measurement of wavelength-dependent etasigma3 for purified RFPs; (2) a multiphoton imaging guided measurement system for in vivo measurement; and (3) in vivo measurement of wavelength-dependent etasigma3 in RFP labeled cells. These fundamental results will provide guidelines for excitation wavelength selection for 3-photon fluorescence imaging of RFPs at the 1700-nm window, and augment the existing database of multiphoton action cross-sections for fluorophores. PMID- 29603650 TI - Analysis of tetracyclines from milk powder by molecularly imprinted solid-phase dispersion based on a metal-organic framework followed by ultra high performance liquid chromatography with tandem mass spectrometry. AB - A novel molecularly imprinted polymer that could selectively recognize tetracyclines in milk powder was synthesized using a metal-organic framework as a support material, tetracycline as template molecule, and 3-aminophenylboronic acid as a functional monomer and a cross-linking agent. The novel molecularly imprinted polymer was characterized by Fourier transform infrared spectrometry, transmission electron microscopy, X-ray diffractometry, thermogravimetric analysis, and N2 adsorption/desorption measurements. The adsorption isotherms, adsorption kinetics, adsorption thermodynamics, and selective adsorption experiments of the novel molecularly imprinted polymer to tetracycline were also studied. The novel molecularly imprinted polymer was used as dispersant of matrix solid-phase dispersion to extraction tetracyclines. After that, the tetracyclines extracted from milk powder were determined by ultra high performance liquid chromatography with tandem mass spectrometry. Under the optimal conditions, the detection limits of tetracyclines were 0.217-0.318 ng/g. The relative standard deviations of intra- and interday precision ranged from 3.8 to 6.9% and from 2.8 to 7.4%, respectively. In all three concentration levels (1.0, 10, 50 ng/g), the recoveries of tetracyclines ranged from 84.7 to 93.9%. The method was successfully applied to the determination of tetracyclines in milk powder. PMID- 29603651 TI - Becoming a guest in your own home: Home care in Sweden from the perspective of older people with multimorbidities. AB - AIM AND OBJECTIVE: To describe the meaning of the phenomenon home care from the perspective of older persons who live alone with multimorbidity. BACKGROUND: In line with worldwide changing demographics, conditions for older people in need of home care are changing. In Sweden there is a stay-in-place policy and older people are expected to live and be cared for in their own home as long as possible. Home care, instituted by different laws, is a challenge affecting the older person when the private home becomes a workplace. DESIGN: This study uses a qualitative design with a lifeworld approach. METHODS: The study having been conducted in Sweden in 2016, the researchers interviewed 12 older persons that live alone and receive home care. Data were analysed using qualitative content analysis. RESULTS: The findings illustrate four sub-themes: adapting to a caring culture, feeling exposed, unable to influence care and forced relations. The overall theme reveals that older people experience a life-changing situation when receiving home care and they become a guest in their own home. CONCLUSIONS: Becoming older with increased needs means to disrupt one's life when one's private home becomes a public arena. The gap between an older person's rights by law and the older person's experiences of receiving home care needs to be highlighted to meet the oncoming challenges in providing a home care that includes participation of the older themselves. Only then can care be offered that enables older people to have a sense of control and experience their home as their own. IMPLICATIONS FOR PRACTICE: The findings emphasise the need to view older people as being self-determinant and independent. Older people receiving home care need to be seen as individuals, and their entire life situation should be considered by also acknowledging the important role played by relatives and caregivers. PMID- 29603652 TI - Chylomicrons against light scattering: The battle for characterization. AB - Chylomicrons (CMs) are lipoprotein particles circulating in blood and transporting dietary lipids. Optically speaking, CMs are small compared to the wavelength of visible light and widely distributed by the size and refractive index (RI). Consequently, intensity of light scattered by the CMs scales with up to the sixth power of their size, hampering simultaneous analysis of 60 and 600 nm CMs. We present an accurate method for quantitative characterization of large size CM subpopulation by the distributions over size and RI. For the first time the CM characteristics have been determined at a single particle level based on angle-resolved light-scattering measurements. We applied the developed method to 2 key processes relating to CM metabolism, namely in vivo dynamics of CMs in blood plasma after a meal and in vitro lipolysis of CMs by the lipoprotein lipase in postheparin plasma. We have observed the substantial variations in CM concentration, size and RI distributions. This opens the way for a multitude of medical applications involving screening of CM metabolism, which we exemplified by revealing large differences in CM characteristics after a 12-hour fast between a healthy volunteer and a patient with atherosclerosis. PMID- 29603653 TI - An Analytical Method for Assessing Optimal Storage Conditions of Gingival Crevicular Fluid and Disclosing a Peptide Biomarker Signature of Gingivitis by MALDI-TOF MS. AB - PURPOSE: Gingival crevicular fluid (GCF) is an important diagnostic source of biomarkers for both periodontitis and gingivitis. However, GCF peptide signature may change depending on factors such as handling and storage. Here we propose a standardized methodology for GCF analysis by MALDI-TOF/TOF-MS in order to distinguish a characteristic peptide signature of gingivitis. EXPERIMENTAL DESIGN: The best storage/handling conditions which may ensure the stability of the endogenous peptidome in GCF is determined and then MALDI-TOF MS comparative analysis is performed. Reproducible GCF MALDI-TOF signatures between two groups of gingivitis (n = 10) and healthy (n = 10) subjects are compared. RESULTS: A pattern of five peptides resulted differentially expressed between gingivitis and healthy groups. Interestingly, among these biomarkers the C-terminal fragment of alpha-1-antitrypsin (AAT) namely C-36 peptide and two different PTMs of the full length S100A9 protein are found. CONCLUSIONS AND CLINICAL RELEVANCE: The method described provides a rapid comparative analysis of GCF signatures between periodontally healthy and gingivitis subjects. A pattern based on the expression of endogenous peptides and their PTMs is identified in GCF as putative biomarkers of gingivitis. These findings improve the knowledge of the inflammatory, immune, and structural substrates which might have a key role in the pathogenesis of gingivitis. PMID- 29603655 TI - Kinetics-Controlled Degradation Reactions at Crystalline LiPON/Lix CoO2 and Crystalline LiPON/Li-Metal Interfaces. AB - Detailed understanding of solid-solid interface structure-function relationships is critical for the improvement and wide deployment of all-solid-state batteries. The interfaces between lithium phosphorous oxynitride (LiPON) solid electrolyte material and lithium metal anode, and between LiPON and Lix CoO2 cathode, have been reported to generate solid-electrolyte interphase (SEI)-like products and/or disordered regions. Using electronic structure calculations and crystalline LiPON models, we predict that LiPON models with purely P-N-P backbones are kinetically inert towards lithium at room temperature. In contrast, transfer of oxygen atoms from low-energy Lix CoO2 (104) surfaces to LiPON is much faster under ambient conditions. The mechanisms of the primary reaction steps, LiPON structural motifs that readily reacts with lithium metal, experimental results on amorphous LiPON to partially corroborate these predictions, and possible mitigation strategies to reduce degradations are discussed. LiPON interfaces are found to be useful case studies for highlighting the importance of kinetics-controlled processes during battery assembly at moderate processing temperatures. PMID- 29603654 TI - Click-evoked auditory brainstem responses and autism spectrum disorder: A meta analytic review. AB - : Behavior does not differentiate ASD risk prior to 12 months of age, but biomarkers may inform risk before symptoms emerge. Click-evoked auditory brainstem responses (ABRs) may be worth consideration due to their measurement properties (noninvasiveness; reliability) and conceptual features (well characterized neural generators), but participant characteristics and assessment protocols vary considerably across studies. Our goal is to perform a meta analysis of the association between ABRs and ASD. Following an electronic database search (PubMed, Medline, PsycInfo, PsycArticles), we included papers that were written in English, included ASD and typically-developing (TD) groups, and reported the information needed to calculate standardized mean differences (Hedges's g) for at least one ABR latency component (I, III, V, I-III, III-V, I V). We weighted and averaged effect sizes across conditions and subsets of participants to yield one estimate per component per study. We then performed random-effects regressions to generate component-specific estimates. ASD was associated with longer ABR latencies for Waves III (g = 0.5, 95% CI 0.1, 0.9), V (g = 0.7, 95% CI 0.3, 1.1), I-III (g = 0.7, 95% CI 0.2, 1.2), and I-V (g = 0.6, 95% CI 0.2, 1.0). All components showed significant heterogeneity. Associations were strongest among participants <=8 years of age and those without middle ear abnormalities or elevated auditory thresholds. In sum, associations between ABRs and ASD are medium-to-large in size, but exhibit heterogeneity. Identifying sources of heterogeneity is challenging, however, due to power limitations and co occurrence of sample/design characteristics across studies. Research addressing the above limitations is crucial to determining the etiologic and/or prognostic value of ABRs for ASD. Autism Res 2018, 11: 916-927. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Auditory brainstem responses (ABR) may be associated with ASD, but participant characteristics and assessment protocols vary considerably across individual studies. Our goal is to combine the results across these studies to facilitate clarity on the topic. Doing so represents a first step in evaluating whether ABRs yield potential for informing the etiology of ASD risk and/or ASD symptom profiles. PMID- 29603656 TI - Guiding low spatial ability individuals through visual cueing: The dual importance of where and when to look. AB - Research suggests that spatial ability may predict success in complex disciplines including anatomy, where mastery requires a firm understanding of the intricate relationships occurring along the course of veins, arteries, and nerves, as they traverse through and around bones, muscles, and organs. Debate exists on the malleability of spatial ability, and some suggest that spatial ability can be enhanced through training. It is hypothesized that spatial ability can be trained in low-performing individuals through visual guidance. To address this, training was completed through a visual guidance protocol. This protocol was based on eye movement patterns of high-performing individuals, collected via eye-tracking as they completed an Electronic Mental Rotations Test (EMRT). The effects of guidance were evaluated using 33 individuals with low mental rotation ability, in a counterbalanced crossover design. Individuals were placed in one of two treatment groups (late or early guidance) and completed both a guided, and an unguided EMRT. A third group (no guidance/control) completed two unguided EMRTs. All groups demonstrated an increase in EMRT scores on their second test (P < 0.001); however, an interaction was observed between treatment and test iteration (P = 0.024). The effect of guidance on scores was contingent on when the guidance was applied. When guidance was applied early, scores were significantly greater than expected (P = 0.028). These findings suggest that by guiding individuals with low mental rotation ability "where" to look early in training, better search approaches may be adopted, yielding improvements in spatial reasoning scores. It is proposed that visual guidance may be applied in spatial fields, such as STEMM (science, technology, engineering, mathematics and medicine), surgery, and anatomy to improve student's interpretation of visual content. Anat Sci Educ. (c) 2018 American Association of Anatomists. PMID- 29603657 TI - Changes in Plasma Metabolite Concentrations after a Low-Glycemic Index Diet Intervention. AB - SCOPE: To examine whether a low-glycemic index (LGI) diet improves a set of plasma metabolites related to different metabolic diseases, and comparison to a high-glycemic index (HGI) diet and a low-fat (LF) diet. METHODS AND RESULTS: A parallel, randomized trial with three intervention diets: an LGI diet, an HGI diet, and an LF diet. A total of 122 adult overweight and obese subjects were enrolled in the study for 6 months. Blood samples were collected at baseline and at the end of the intervention. The plasma metabolomic profile of 102 subjects was analyzed using three different approaches: GC/quadrupole-TOF, LC/quadrupole TOF, and nuclear magnetic resonance. Both univariate and multivariate analysis were performed. Serine levels were significantly higher following the LGI diet compared to both the HGI and LF diets (q = 0.002), whereas leucine (q = 0.015) and valine (q = 0.024) were lower in the LGI diet compared to the LF diet. A set of two sphingomyelins, two lysophosphatidylcholines, and six phosphatidylcholines were significantly modulated after the LGI diet compared to the HGI and LF diets (q < 0.05). Significant correlations between changes in plasma amino acids and lipid species with changes in body weight, glucose, insulin, and some inflammatory markers are also reported. CONCLUSION: These results suggest that an LGI diet modulates certain circulating amino acids and lipid levels. These findings may explain the health benefits attributed to LGI diets in metabolic diseases such as type 2 diabetes. PMID- 29603658 TI - Reductive Cleavage Method for Quantitation of Monolignols and Low-Abundance Monolignol Conjugates. AB - As interest in biomass utilization has grown, the manipulation of lignin biosynthesis has received significant attention, such that recent work has demanded more robust lignin analytical methods. As the derivatization followed by reductive cleavage (DFRC) method is particularly effective for structurally characterizing natively acylated lignins, we used an array of synthetic beta ether gamma-acylated model compounds to determine theoretical yields for all monolignol conjugates currently known to exist in lignin, and we synthesized a new set of deuterated analogs as internal standards for quantification using GC MS/MS. Yields of the saturated ester conjugates ranged from 40 to 90 %, and NMR analysis revealed the presence of residual unsaturated conjugates in yields of 20 to 35 %. In contrast to traditional selected-ion-monitoring, we demonstrated the superior sensitivity and accuracy of multiple-reaction-monitoring detection methods, and further highlighted the inadequacy of traditional standards relative to isotopically labeled analogs. PMID- 29603659 TI - Carboxylate Analogues of Aryl-Urea-Substituted Fatty Acids That Target the Mitochondria in MDA-MB-231 Breast Cancer Cells to Promote Cell Death. AB - Selective targeting of the tumor cell mitochondrion is a viable approach for the development of anticancer agents because the organelle is functionally different from the mitochondria of normal cells. We recently developed a novel aryl-urea fatty acid, 16({[4-chloro-3-(trifluoromethyl)phenyl]carbamoyl}amino)hexadecanoic acid (1) that was found to disrupt mitochondria and to activate apoptosis in MDA MB-231 breast cancer cells. However, there is currently little information on the structural requirements for the activity of compound 1 analogues. The present study evaluated the role of the carboxylic acid group on the anticancer activity of 1. Bioisosteric replacement of the carboxylate in 1 maintained activity. Thus, like 1, the sulfonic acid analogue 1-SA and the oxo-thiadiazole analogue 1-OT were also found to target the mitochondrion and to activate cell killing capacity. The hydroxamic acid analogue 1-HA also killed MDA-MB-231 cells, but its onset of action was slower than that of 1-SA and 1-OT. In contrast, replacement of the carboxylate with non-bioisosteric amido and methylamido groups produced analogues that minimally altered mitochondrial function and showed little capacity to decrease tumor cell viability. These findings suggest that the carboxylate moiety in the novel mitochondrially targeted agent 1 is an important determinant of the kinetics and efficacy of anticancer cell activities of compound 1 analogues. Further development of carboxylate-modified analogues of aryl-urea fatty acids as potential anticancer agents could now be warranted. PMID- 29603660 TI - Magnetic solid-phase extraction or dispersive liquid-liquid microextraction for pyrethroid determination in environmental samples. AB - The determination of 15 pyrethroids in soil and water samples was carried out by gas chromatography with mass spectrometry. Compounds were extracted from the soil samples (4 g) using solid-liquid extraction and then salting-out assisted liquid liquid extraction. The acetonitrile phase obtained (0.8 mL) was used as a dispersant solvent, to which 75 MUL of chloroform was added as an extractant solvent, submitting the mixture to dispersive liquid-liquid microextraction. For the analysis of water samples (40 mL), magnetic solid-phase extraction was performed using nanocomposites of magnetic nanoparticles and multiwalled carbon nanotubes as sorbent material (10 mg). The mixture was shaken for 45 min at room temperature before separation with a magnet and desorption with 3 mL of acetone using ultrasounds for 5 min. The solvent was evaporated and reconstituted with 100 MUL acetonitrile before injection. Matrix-matched calibration is recommended for quantification of soil samples, while water samples can be quantified by standards calibration. The limits of detection were in the range of 0.03-0.5 ng/g (soil) and 0.09-0.24 ng/mL (water), depending on the analyte. The analyzed environmental samples did not contain the studied pyrethroids, at least above the corresponding limits of detection. PMID- 29603661 TI - Mechanism of Evolution of Koneramine Complexes from One-Pot Reactions: Snapshots of Intermediates Offer Facile Routes to New Dipicolylamines. AB - Koneramines (LR OR', R=Ph or Ts; R'=Me, iPr) and their complexes were found to emerge from the system of pyridine-2-carboxaldehyde and N phenyl/tosylethylenediamine when a primary or secondary alcohol was used as solvent. Imidazolidinylpyridines (LR , R=Ph or Ts) became major emergents whereas hemi-aminals (LR OH, R=Ph or Ts) are minor emergents of the system when tertiary butanol was used as the solvent; the bulky tertiary butyl group prevented the addition of alcohol to the iminium ion that diverted the equilibrium towards imidazolidinylpyridines. By playing with the components of the reaction mixture, crystals of the metastable intermediates bound to copper(II) and/or zinc(II) were obtained and the structures were determined by X-ray diffraction analysis. The reported results shed light on how to control the emergents of the multicomponent reaction mixture that forms koneramines. Reactivity studies of the intermediates pave the way for a new type of koneramine complexes that are new dipicolylamines where the two pyridine moieties of the resulting koneramine are not the same. PMID- 29603662 TI - Arf1 regulates the ER-mitochondria encounter structure (ERMES) in a reactive oxygen species-dependent manner. AB - The Arf family of small GTP-binding and -hydrolyzing proteins are some of the most important intracellular regulators of membrane dynamics. In this study, we identified the Golgi-localized Arf family G protein Arf1 in Candida albicans and confirmed its conserved function in regulating the secretory pathway. Interestingly, deletion of ARF1 resulted in intracellular reactive oxygen species (ROS) accumulation, and induced formation of the endoplasmic reticulum (ER) mitochondria encounter structure (ERMES). Moreover, N-acetylcysteine-mediated ROS scavenging in the arf1Delta/Delta strain attenuated ERMES formation, indicating that intracellular ROS accumulation resulting from ARF1 deletion facilitated ERMES formation. In addition, Arf1 regulated many key physiological processes in C. albicans, including cell cycle progression, morphogenesis and virulence. This study uncovers a role for Arf family G proteins in regulating ERMES formation and sheds new light on the crucial contribution of ROS to membrane dynamics. PMID- 29603663 TI - Separation and determination of the enantiomers of lactic acid and 2 hydroxyglutaric acid by chiral derivatization combined with gas chromatography and mass spectrometry. AB - Lactic acid and 2-hydroxyglutaric acid are chiral metabolites that have two distinct d- and l-enantiomers with distinct biochemical properties. Perturbations of a single enantiomeric form have been found to be closely related to certain diseases. Therefore, the ability to differentiate the d and l enantiomers is important for these disease studies. Herein, we describe a method for the separation and determination of lactic acid and 2-hydroxyglutaric acid enantiomers by chiral derivatization (with l-menthol and acetyl chloride) combined with gas chromatography and mass spectrometry. The two pairs of above mentioned enantiomers exhibited linear calibration curves with a correlation coefficient (R2 ) exceeding 0.99. The measured data were accurate in the acceptable recovery range of 88.17-102.30% with inter- and intraday precisions (relative standard deviations) in the range of 4.23-17.26%. The limits of detection for d-lactic acid, l-lactic acid, d-2-hydroxyglutaric acid, and l-2 hydroxyglutaric acid were 0.13, 0.11, 1.12, and 1.16 MUM, respectively. This method was successfully applied to analyze mouse plasma. The d-lactic acid levels in type 2 diabetes mellitus mouse plasma were observed to be significantly higher (P < 0.05, t-test) than those of normal mice, suggesting that d-lactic acid may serve as an indicator for type 2 diabetes mellitus. PMID- 29603664 TI - Exploring electrophysiological correlates of social cognition in subclinical schizotypy. AB - Impairments in social cognition and associated abnormalities in brain function are well documented in psychotic disorders. They may represent neurodevelopmental vulnerabilities and may therefore be present in less severe or even subclinical conditions of the schizophrenia spectrum, such as schizotypy. Schizotypy has features highly suggestive of social cognitive impairments, but little is known about possible related abnormalities of brain function. This exploratory pilot study examines electrophysiological event-related potentials (ERPs) implicated in schizophrenia, in 23 undergraduates with a range of subclinical schizotypal characteristics. ERPs were recorded in response to emotional face stimuli in an experimental paradigm designed to assess very early stages of social stimulus processing. Three ERPs were assessed, P100, N170 and P300. P100 and P300 were found to be related to multiple schizotypal features, but N170 was not. The results support occurrence of social cognitive impairments linked to abnormal brain function across the schizophrenia spectrum. Copyright (c) 2018 John Wiley & Sons, Ltd. PMID- 29603665 TI - Ultraviolet radiation oxidative stress affects eye health. AB - In the eye, ultraviolet radiation (UVR) is not known to contribute to visual perception but to mainly damage multiple structures. UVR carries higher energy than visible light and high dose exposure to UVR causes direct cellular damage, which has an important role in the development of cancer. This review provides an overview on the most recent knowledge on the role of UVR in oxidative stress (OS) in relation to noncancer ocular pathologies: various corneal pathologies, cataract, glaucoma and age-related macular degeneration. Possible OS signaling streams and mechanisms in the aging eye are discussed. Excessive exposure to UVR through live may seriously contribute to increase in OS of various eye tissues and thus lead to the advancement of serious ocular pathologies. Children are especially vulnerable to UVR because of their larger pupils and more transparent ocular media: up to 80% of a person's lifetime exposure to UVR is reached before the age of 18. Therefore, efficient everyday protection of the sensitive tissues of the eye by wearing of sunglasses, clear UVR-blocking spectacles or contact lenses should be considered from early age on. Many initiatives are taken worldwide to inform and raise the population's awareness about these possible UVR hazards to the eye. PMID- 29603666 TI - Opto-electro-thermal optimization of photonic probes for optogenetic neural stimulation. AB - Implantable photonic probes are of increasing interest to the field of biophotonics and in particular, optogenetic neural stimulation. Active probes with onboard light emissive elements allow for electronic multiplexing and can be manufactured through existing microelectronics methods. However, as the optogenetics field moves towards clinical practice, an important question arises as to whether such probes will cause excessive thermal heating of the surrounding tissue. Light emitting diodes typically produce more heat than light. The resultant temperature rise of the probe surface therefore needs to be maintained under the regulatory limit of 2 degrees C. This work combines optical and thermal modelling, which have been experimental verified. Analysis has been performed on the effect of probe/emitter geometries, emitter, and radiance requirements. Finally, the effective illumination volume has been calculated within thermal limits for different probe emitter types and required thresholds. PMID- 29603668 TI - Cerebral capillary flow imaging by wavelength-division-multiplexing swept-source optical Doppler tomography. AB - Swept-source-based optical coherence tomography (SS-OCT) has demonstrated the unique advantages for fast imaging rate and long imaging distance; however, limited axial resolution and complex phase noises restrict swept-source optical Doppler tomography (SS-ODT) for quantitative capillary blood flow imaging in the deep cortices. Here, the wavelength-dividing-multiplexing optical Doppler tomography (WDM-ODT) method that divides a single interferogram into multiple phase-correlated interferograms is proposed to effectively enhance the sensitivity for cerebral capillary flow imaging. Both flow phantom and in vivo mouse brain imaging studies show that WDM-ODT is able to significantly suppress background phase noise and image cerebral capillary flow down to the vessel size of 5.6 MUm. Comparison between the wavelength-division-multiplexing SS-ODT and the spectral-domain ultrahigh-resolution ODT (uODT) reveals that SS-ODT outpaces uODT by extending the capillary flow imaging depth to 1.6 mm in mouse cortex. Thus, for the first time, quantitative capillary flow imaging is demonstrated using SS-ODT in the deep cortex. PMID- 29603667 TI - A Targeted LC-MS Strategy for Low-Abundant HLA Class-I-Presented Peptide Detection Identifies Novel Human Papillomavirus T-Cell Epitopes. AB - For rational design of therapeutic vaccines, detailed knowledge about target epitopes that are endogenously processed and truly presented on infected or transformed cells is essential. Many potential target epitopes (viral or mutation derived), are presented at low abundance. Therefore, direct detection of these peptides remains a challenge. This study presents a method for the isolation and LC-MS3 -based targeted detection of low-abundant human leukocyte antigen (HLA) class-I-presented peptides from transformed cells. Human papillomavirus (HPV) was used as a model system, as the HPV oncoproteins E6 and E7 are attractive therapeutic vaccination targets and expressed in all transformed cells, but present at low abundance due to viral immune evasion mechanisms. The presented approach included preselection of target antigen-derived peptides by in silico predictions and in vitro binding assays. The peptide purification process was tailored to minimize contaminants after immunoprecipitation of HLA-peptide complexes, while keeping high isolation yields of low-abundant target peptides. The subsequent targeted LC-MS3 detection allowed for increased sensitivity, which resulted in successful detection of the known HLA-A2-restricted epitope E711-19 and ten additional E7-derived peptides on the surface of HPV16-transformed cells. T-cell reactivity was shown for all the 11 detected peptides in ELISpot assays, which shows that detection by our approach has high predictive value for immunogenicity. The presented strategy is suitable for validating even low abundant candidate epitopes to be true immunotherapy targets. PMID- 29603670 TI - Diamine-Functionalization of a Metal-Organic Framework Adsorbent for Superb Carbon Dioxide Adsorption and Desorption Properties. AB - For real-world postcombustion applications in the mitigation of CO2 emissions using dry sorbents, adsorption and desorption behaviors should be controlled to design and fabricate prospective materials with optimal CO2 performances. Herein, we prepared diamine-functionalized Mg2 (dobpdc) (H4 dobpdc=4,4'-dihydroxy-(1,1' biphenyl)-3,3'-dicarboxylic acid). (1-diamine) with ethylenediamine (en), primary secondary (N-ethylethylenediamine-een and N-isopropylethylenediamine-ipen), primary-tertiary, and secondary-secondary diamines. A slight alteration of the number of alkyl substituents on the diamines and their alkyl chain length dictates the desorption temperature (Tdes ) at 100 % CO2 , desorption characteristics, and DeltaT systematically to result in the tuning of the working capacity. The existence of bulky substituents on the diamines improves the framework stability upon exposure to O2 , SO2 , and water vapor, relevant to real flue-gas conditions. Bulky substituents are also responsible for an interesting two-step behavior observed for the ipen case, as revealed by DFT calculations. Among the diamine-appended metal-organic frameworks, 1-een, which has the required adsorption and desorption properties, is a promising material for sorbent-based CO2 capture processes. Hence, CO2 performance and framework durability can be tailored by the judicial selection of the diamine structure, which enables property design at will and facilitates the development of desirable CO2 -capture materials. PMID- 29603671 TI - Penguin colony attendance under artificial lights for ecotourism. AB - Wildlife watching is an emerging ecotourism activity around the world. In Australia and New Zealand, night viewing of little penguins attracts hundreds of thousands of visitors per year. As penguins start coming ashore after sunset, artificial lighting is essential to allow visitors to view them in the dark. This alteration of the nightscape warrants investigation for any potential effects of artificial lighting on penguin behavior. We experimentally tested how penguins respond to different light wavelengths (colors) and intensities to examine effects on the colony attendance behavior at two sites on Phillip Island, Australia. At one site, nocturnal artificial illumination has been used for penguin viewing for decades, whereas at the other site, the only light is from the natural night sky. Light intensity did not affect colony attendance behaviors of penguins at the artificially lit site, probably due to penguin habituation to lights. At the not previously lit site, penguins preferred lit paths over dark paths to reach their nests. Thus, artificial light might enhance penguin vision at night and consequently it might reduce predation risk and energetic costs of locomotion through obstacle and path detection. Although penguins are faithful to their path, they can be drawn to artificial lights at small spatial scale, so light pollution could attract penguins to undesirable lit areas. When artificial lighting is required, we recommend keeping lighting as dim and time-restricted as possible to mitigate any negative effects on the behavior of penguins and their natural habitat. PMID- 29603669 TI - Practice patterns and outcomes of chemoradiotherapy versus radiotherapy alone for older patients with nasopharyngeal cancer. AB - Older patients are at increased risk of toxicities from aggressive oncologic therapy and of nononcologic death. A meta-analysis of non-nasopharyngeal head and neck cancers showed no statistical benefit in adding chemotherapy to radiotherapy (RT) in older patients; another meta-analysis of RT versus chemoradiotherapy (CRT) in NPC found advantages to CRT, but vastly under-represented patients >=70 years old. This is the largest study to date evaluating outcomes of CRT versus RT alone in this population. The National Cancer Data Base (NCDB) was queried for primary nasopharyngeal cancer cases (2004-2013) in patients >=70 years old receiving RT alone or CRT. Patients with unknown RT/chemotherapy and T1N0 or M1 disease were excluded. Logistic regression analysis ascertained factors associated with CRT delivery. Kaplan-Meier analysis evaluated overall survival (OS) between both cohorts. Cox proportional hazards modeling determined variables associated with OS. In total, 930 patients were analyzed (n = 713 (77%) CRT, n = 217 (23%) RT). Groups were relatively balanced; CRT was less frequently delivered in patients with advancing age, lower nodal burden, and females (P < 0.05 for all). Median OS in the CRT and RT groups were 35.3 versus 20.0 months, respectively (P = 0.002). On multivariate analysis, independent predictors of OS included age, comorbidities, income and insurance status, tumor grade, and stage (P < 0.05 for all). Notably, receipt of chemotherapy independently predicted for improved OS (P = 0.036). CRT, compared to RT alone, was independently associated with improved survival in NPC patients >=70 years old. CRT appears to be a promising approach in this population, but treatment-related toxicity risks should continue to be weighed against potential oncologic benefits. PMID- 29603673 TI - Numerical investigation of the effect of bone cement porosity on osteoporotic femoral augmentation. AB - Femoroplasty is the injection of bone cement into the proximal femur, enhances the bone load capacity, and is typically applied to osteoporotic femora. To minimize the required injected volume of bone cement and maximize the load capacity enhancement, an optimization problem must be solved, where the modulus of elasticity of the augmented bone is a key element. This paper, through the numerical investigation of a fall on the greater trochanter of an osteoporotic femur, compares different ways to calculate this modulus and introduces an approach, based on the concept of bone cement porosity, which provides results statistically similar to those obtained with other considerations. Based on this approach, the present paper quantifies the correlation between degree of osteoporosis and optimum volume of bone cement. It concludes with an exhaustive search that reveals the effect of the bone cement porosity on the optimum volume of PMMA, for various combinations of the frontal and transverse angles of the fall on the greater trochanter. PMID- 29603674 TI - An ultra-low-cost smartphone octochannel spectrometer for mobile health diagnostics. AB - With the rapid development and proliferation of mobile devices with powerful computing power and the ability of integrating sensors into mobile devices, the potential impact of mobile health (mHealth) diagnostics on the public health is drawing researchers' attention. We developed a Smartphone Octo-channel Spectrometer (SOS) as a mHealth diagnostic tool. The SOS has nanoscale wavelength resolution, is self-illuminated from the smartphone itself, and is ultra-low cost (less than $20). A user interface controls the optical sensing parameters and precise alignment. After calibrating and testing the SOS by quantifying protein concentrations, we clinically validated the SOS by comparing the diagnostic performance of our device with that of a clinical spectrophotometer. About 180 serum samples from de-identified patients with 4 types of autoantibodies were blindly read the ELISA results. The accuracy of the SOS achieved 100% across the clinical reportable range compared with the FDA-approved instrument. Furthermore, the self-illuminated SOS only requires about half of the light intensity of the FDA-approved instrument to achieve clinical-level sensitivity. The low-energy consumption and low-cost SOS enables point-of-care spectrophotometric sensing in low-resource areas, and can be integrated into point-of-care diagnostic systems for rapid multiplex readout and analysis at patient bedside or at home. PMID- 29603672 TI - Early and prolonged opportunities to practice suturing increases medical student comfort with suturing during clerkships: Suturing during cadaver dissection. AB - Medical students are expected to perform common procedures such as suturing on patients during their third-year clerkships. However, these experiences are often viewed by medical students as stressors rather than opportunities for learning. The source of this stress is the lack of instruction on common procedures prior to being asked to observe or perform the procedure on a patient. First-time exposures to procedures in stressful environments may result in decreased confidence in medical students and decrease the frequency with which they perform these procedures in the future. The authors sought to change this paradigm by: (1) introducing a suturing module to first-year medical students in the context of the anatomy dissection laboratory and (2) measuring its effects on student attitudes and behavior over the course of their third-year clerkships when they encounter patients. The authors found that early and prolonged introduction to suturing was associated with increased student confidence relative to suturing a patient. Participation in the suturing module was associated with increased student confidence in identifying suturing instruments (P < 0.001) and suturing patients (P = 0.013). Further it positively affected their behavior as demonstrated by increased performance of suturing events from students exposed to the suturing module. (P < 0.001) This study demonstrates that early and prolonged opportunities to practice a procedural skill in a low-stress environment increases student confidence during patient interactions and alters student behavior. PMID- 29603675 TI - Automated screening of Papanicolaou tests: A review of the literature. AB - Automated Papanicolaou test screening systems have now been available for over 25 years. Currently two automated screening systems are in widespread clinical use. These are the ThinPrep Imaging System and the FocalPoint GS Imaging System. In their current configurations, both facilitate faster screening by showing a limited number of fields of view (FOV) to cytotechnologists. The FOV are based on the use of proprietary algorithms applied to computerized images of the slide that determine the cells and cell groups with the highest likelihood of abnormality. If all of the FOV are deemed to be negative, the case can be signed out with no additional review; if one or more fields appear possibly abnormal, the entire slide must be manually screened. The United States Food and Drug Administration has ruled that for workload calculation purposes, looking at only the FOV review counts as one-half slide, potentially greatly increasing the number of slides that can be screened. However, follow-up studies of this technology have shown that screening accuracy declines when very large numbers of cases are reviewed per day. Recommendations designed to limit screening volumes to levels that do not jeopardize patient care have therefore been created. The development of fully automated screening that does not rely on human judgment remains an unrealized aspiration. This review covers the history of the development and clinical implementation of automated screening technology with descriptions of the various automated screening systems and their performance as reported in published literature. PMID- 29603676 TI - Direct C-H Arylation Meets Perovskite Solar Cells: Tin-Free Synthesis Shortcut to High-Performance Hole-Transporting Materials. AB - In contrast to the traditional multistep synthesis, we demonstrate herein a two step synthesis shortcut to triphenylamine-based hole-transporting materials (HTMs) through sequential direct C-H arylations. These hole-transporting molecules are fabricated in perovskite-based solar cells (PSCs) that exhibit promising efficiencies up to 17.69 %, which is comparable to PSCs utilizing commercially available 2,2',7,7'-tetrakis[N,N-di(4-methoxyphenyl)amino]-9,9' spirobifluorene (spiro-OMeTAD) as the HTM. This is the first report describing the use of step-saving C-H activations/arylations in the facile synthesis of small-molecule HTMs for perovskite solar cells. PMID- 29603677 TI - CapsidMesh: Atomic-detail structured mesh representation of icosahedral viral capsids and the study of their mechanical properties. AB - Viruses are the most abundant pathogens affecting all forms of life. A major component of a virus is a protein shell, known as the viral capsid, that encapsulates the genomic material. The fundamental functions of the capsid are to protect and transport the viral genome and recognize the host cell. Descriptions of this macromolecular complex have been proposed at different scales of approximation. Here, we introduce a methodology to generate a structured volumetric mesh of icosahedral viral capsids (CapsidMesh) based on the atomic positions of their constituents. Material properties of the capsid proteins can be set on every mesh element individually. Hence, we have control over all levels of protein structure (atoms, amino acids, subunits, oligomers, and capsid). The CapsidMesh models are suitable for numerical simulations and analysis of a physical process using a third-party package. In particular, we used our methodology to generate a CapsidMesh of several capsids previously characterized by atomic force microscopy experiments and then simulated the mechanical nanoindentation through the finite element method. By fitting to the experimental linear elastic response, we estimated the elastic modulus and mechanical stresses produced on the capsids. Our results show that the atomic detail of the CapsidMesh is sufficient to reproduce anisotropic properties of the particle. PMID- 29603678 TI - Synthetic Applications of Transition-Metal-Catalyzed C-P Bond Cleavage. AB - The wide occurrence of carbon-phosphorus bond activation in modern organic synthesis, catalyst deactivation, and biological process has attracted interest for synthetic applications. Over the past few decades, transition-metal-mediated transformations have become extremely powerful tools in organic synthesis. In this review, considerable progress that has been made in catalytic activations and transformations of carbon-phosphorus bonds within the coordination sphere of transition metals is described. Mechanistic information is also presented, and it is hoped that this review not only provides an account of the state of the art in the field, but also highlights the future potential of these reactions in organic synthesis. PMID- 29603679 TI - Mechanical Considerations for Electrospun Nanofibers in Tendon and Ligament Repair. AB - Electrospun nanofibers possess unique qualities such as nanodiameter, high surface area to volume ratio, biomimetic architecture, and tunable chemical and electrical properties. Numerous studies have demonstrated the potential of nanofibrous architecture to direct cell morphology, migration, and more complex biological processes such as differentiation and extracellular matrix (ECM) deposition through topographical guidance cues. These advantages have created great interest in electrospun fibers for biomedical applications, including tendon and ligament repair. Electrospun nanofibers, despite their nanoscale size, generally exhibit poor mechanical properties compared to larger conventionally manufactured polymer fiber materials. This invites the question of what role electrospun polymer nanofibers can play in tendon and ligament repair applications that have both biological and mechanical requirements. At first glance, the strength and stiffness of electrospun nanofiber grafts appear to be too low to fill the rigorous loading conditions of these tissues. However, there are a number of strategies to enhance and tune the mechanical properties of electrospun nanofiber grafts. As researchers design the next-generation electrospun tendon and ligament grafts, it is critical to consider numerous physiologically relevant mechanical criteria and to evaluate graft mechanical performance in conditions and loading environments that reflect in vivo conditions and surgical fixation methods. PMID- 29603681 TI - A comparative CFD study of four inferior vena cava filters. AB - Computational fluid dynamics was used to simulate the flow of blood within an inferior vena cava (IVC) geometry model that was reconstructed from computed tomography images obtained from a real patient. The main novelty of the present work is that we simulated the implantation of 4 different filter models in this realistic IVC geometry. We considered different blood flow rates in the range between Vin =20 and Vin =80 cm3 /s, and all simulations were performed with both the Newtonian and a non-Newtonian model for the blood viscosity. We compared the hemodynamics performance of the different filter models, and we paid a special attention to the total drag force, Fd , exerted by the blood flow on the filter surface. This force is the sum of 2 contributions: the viscous skin friction force, which was found to be roughly proportional to the filter surface area, and the pressure force, which depended on the particular filter geometry design. The Fd force is relevant because it must be balanced by the total force exerted by the filter hooks/struts on the IVC wall at the attachment locations. For the highest Vin value investigated, the variation in Fd among filters was from 116 to 308 dyne. We also showed how the present results can be extrapolated to obtain good estimates of the drag forces if the blood viscosity levels change, ie, if the patient with a filter implanted is treated with anticoagulant therapy. PMID- 29603680 TI - Chinese children with autism: A multiple chemical elements profile in erythrocytes. AB - : Several lines of evidence suggested that abnormal levels of certain chemical elements may contribute to the development of autism spectrum disorders (ASD). The present work aimed to investigate the multiple chemical elements profile in the erythrocytes of autistic versus typically developing children (TDC) of China. Analyses were carried out to explore the possible association between levels of elements and the risk as well as the severity of ASD. Erythrocyte levels of 11 elements (32%) among 34 detected elements in autistic group were significantly different from those in the TDC group. To our knowledge, this is the first study which compared the levels of rare earth elements in erythrocytes between children with or without ASD. Five elements including Pb, Na, Ca, Sb, and La are associated with the Childhood Autism Rating Scale (CARS) total score. Also, a series of tendencies were found in this research which was believed to affect auditory response, taste, smell, and touch, as well as fear or nervousness. It can be concluded that Chinese autistic children suffer from multi-chemical element imbalances which involves a complex combination of genetic and environmental factors. The results showed a significant correlation between abnormal levels of several chemical elements and the severity of the autistic syndrome. LAY SUMMARY: It is suggested that abnormal levels of some chemical elements may contribute to the development of autism spectrum disorders (ASD). In this work, the impact of element imbalances on the risk and severity of ASD was investigated, focusing on the analysis of abnormal levels of the multi-chemical elements profile in erythrocytes compared with typically developing children. Furthermore, the results showed a significant correlation between abnormal levels of several chemical elements and the severity of the autistic syndrome. Autism Res 2018, 11: 834-845. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. PMID- 29603682 TI - Adipose-derived stem cells improve erectile function partially through the secretion of IGF-1, bFGF, and VEGF in aged rats. AB - Adipose-derived stem cells (ADSCs) have recently been considered as a promising therapy for erectile dysfunction (ED). However, the mechanism of ADSC-based therapy is unclear. Insulin-like growth factor-1 (IGF-1), basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) secreted by ADSCs were assessed in vitro. Sixteen 24-month-old male Sprague-Dawley rats were used for comparative analysis of 2-week treatment with labeled ADSCs or PBS. Eight additional 5-month-old rats were used as a young rat group. At 2 weeks post transplantation, all rats were analyzed for erectile function, cavernous IGF-1, bFGF and VEGF levels, and penile histology. Conditioned medium and co-culture systems were used in cell experiments to detect how growth factors act on corpus cavernosum smooth muscle cells (CCSMCs) under oxidative stress conditions via crystal violet staining and immunofluorescence staining. We found that ADSCs secreted significantly higher IGF-1, bFGF, and VEGF levels in culture medium compared with basal medium. Compared with young rats, untreated aged rats had significantly lower Max ICP/MAP and ADSC treatment significantly increased the ratio. Immunofluorescence staining demonstrated a small number of labeled ADSCs in the corpus cavernosum. The untreated aged rats showed significantly decreased cavernous IGF-1, bFGF, and VEGF levels and significantly decreased contents of cavernous smooth muscle and endothelium compared with young rats. ADSC treatment partially normalized these alterations. In cell experiments, the groups receiving growth factor neutralizing antibody separately or combined had significantly decreased numbers of CCSMCs compared with control groups. These results indicated that ADSC treatment may improve aging-related ED partially through the secretion of IGF-1, bFGF, and VEGF. PMID- 29603683 TI - Oral Candida colonization and plaque type psoriasis: Is there any relationship? AB - AIM: The potential role of superantigens derived from microbial agents could be considered in the pathogenesis of psoriasis, but the association between Candida albicans and psoriasis severity is still controversial. The present study was designed to compare the prevalence of oral candidiasis in a group of psoriatic patients and healthy patients, and its correlation with psoriasis severity. METHODS: Seventy psoriatic patients with no history of systemic treatment and 70 closely-matched control patients underwent oral examination. Scraping of oral mucosa to detect Candida species was done using a sterile cytobrush. RESULTS: Candida was detected in the oral cavity of 20% of patients with psoriasis and 2.8% of control cases (P = .002), but none had clinical features of oral candidiasis. Candida albicans was the only species isolated from the oral cavity of both groups. No correlation was found between sex, age, phototherapy, and presence of oral candidiasis. There was a positive correlation between psoriasis severity and colony count (P < .001). CONCLUSIONS: The prevalence of oral candidiasis is higher in psoriatic patients and is associated with disease severity. It is not exactly clear whether oral candidiasis can aggravate psoriasis or if psoriasis can predispose patients to oral candidiasis. PMID- 29603685 TI - Newsletter Spring 2018: Clinician Investigator Trainee Association of Canada (CITAC). AB - A decade of CITAC Annual General Meetings: 2007-2017 In 2007, the Clinician Investigator Trainee Association of Canada (CITAC) launched its inaugural Annual General Meeting (AGM). The AGM has since become a major annual event, jointly organized by CITAC and leaders from the Canadian Society for Clinical Investigation (CSCI), and continues to provide a forum for clinician investigator (CI) trainees to exchange ideas, advance career prospects and engage with the broader community. Indeed, since its inception, all Canadian institutions with medical doctor and clinician investigator (MD+CI) training programs have participated in the AGM, while more than 1,000 trainees have registered as CITAC members. The 10th CITAC-CSCI AGM was recently held in Toronto (November 20-22, 2017). There were nearly 200 attendees, including CI trainees, faculty member and physician leaders from across Canada (Figure 1A, 1B). Trainees spanning diverse career stages had opportunities to participate in interactive poster sessions, workshops and lectures by leading physician-scientists. These exercises were designed to encourage and enhance networking, career development and mentorship for prospective physician-scientists. PMID- 29603684 TI - Effects of a novel selective peroxisome proliferator-activated receptor-alpha modulator, pemafibrate, on hepatic and peripheral glucose uptake in patients with hypertriglyceridemia and insulin resistance. AB - AIMS/INTRODUCTION: Pemafibrate is a novel selective peroxisome proliferator activated receptor-alpha modulator with potent triglyceride-lowering and high density lipoprotein cholesterol-raising effects. We showed that pemafibrate decreased the homeostatic model assessment for insulin resistance in patients with dyslipidemia. To investigate how pemafibrate improves insulin sensitivity, we used a hyperinsulinemic-euglycemic clamp technique to determine the splanchnic and peripheral glucose uptake in patients with hypertriglyceridemia and insulin resistance. MATERIALS AND METHODS: A total of 27 patients with hypertriglyceridemia and insulin resistance were randomly assigned to receive pemafibrate (0.4 mg/day, b.i.d.) or placebo treatment for 12 weeks. The hyperinsulinemic-euglycemic clamp test combined with oral glucose loading was carried out at weeks 0 and 12 to evaluate the splanchnic and peripheral glucose uptake. RESULTS: Pemafibrate, but not the placebo, significantly increased the splanchnic glucose uptake rate from baseline (19.6 +/- 5.9% with P = 0.005 and 2.1 +/- 7.4% with P = 0.78, respectively), although no significant difference between the groups was observed (P = 0.084). Conversely, peripheral glucose uptake rate was not significantly altered. Pemafibrate, compared with the placebo, significantly decreased plasma triglycerides (-61.4 +/- 16.4% vs -2.5 +/ 41.4%, P = 0.001), free fatty acids (-24.8 +/- 23.2% vs 2.0 +/- 26.8%, P = 0.016) and gamma-glutamyl transpeptidase (-30 +/- 46 vs 10 +/- 19 U/L, P = 0.009) levels, and significantly increased fibroblast growth factor 21 (457.7 +/- 402.1 vs -41.7 +/- 37.4 pg/mL, P = 0.007) levels. CONCLUSIONS: Pemafibrate increased splanchnic glucose uptake from baseline in patients with hypertriglyceridemia. PMID- 29603686 TI - Dose adjustment of immunosuppressants during co-administration of posaconazole: a systematic review. AB - PURPOSE: The purpose of this retrospective study was to analyze the dose adjustment of immunosuppressants (cyclosporine, tacrolimus and sirolimus) for the patients with allogeneic hematopoietic stem cell and solid-organ (heart/lung) transplantation during co-administration of posaconazole. METHODS: MEDLINE, EMBASE and Cochrane Library were searched from January 1, 2000 to June 30, 2017 for clinical reports of patients who received allogeneic hematopoietic stem cell and organ transplantation and were co-administered posaconazole and immunosuppressants (cyclosporine, tacrolimus or sirolimus). RESULTS: Seven studies were included in the systematic review with a total of 215 patients. Five studies involved hematopoietic stem cell transplant, one heart transplant and one lung transplant. In general, the co-administration of posaconazole with sirolimus, tacrolimus or cyclosporine necessitated immunosuppressant dose reductions to maintain the levels of the drug in the optimal therapeutic range. Reported dose reductions were 50%-68% for sirolimus, 75% for tacrolimus and 14% 49% for cyclosporine. The findings were similar for hematopoietic stem cell, heart or lung transplantation studies. CONCLUSION: Our findings indicate that, when posaconazole is co-administered, the dosage of sirolimus and tacrolimus should be reduced by 60%-70% and for cyclosporine and by 30%-40% following allogeneic hematopoietic stem cell and solid-organ transplantation. PMID- 29603687 TI - MiR-7, miR-9 and miR-375 contribute to effect of Exendin-4 on pancreatic beta cells in high-fat-diet-fed mice. AB - PURPOSE: The purpose of this study was to test whether glucagon-like peptide-1 (GLP-1) receptor activation preserved pancreatic beta-cells via the regulation of microRNAs and target genes in high-fat-diet-fed mice. METHODS: C57BL/6 male mice were simultaneously treated with high-fat-diet (HFD) and GLP-1 analogue, Exendin 4 (Ex-4) (3 MUg/kg/day or 30 MUg/kg/day), i.p. or vehicle, for consecutive 13 weeks. Fasting blood glucose, postprandial blood glucose, DeltaI30/DeltaG30, HOMA IR and HOMA-% beta were measured in each group. Pancreatic beta-cell mass was assessed by immunohistochemistry. The expression of miRNAs and related downstream genes were investigated using quantitative real-time PCR. RESULTS: Thirteen weeks of Ex-4 treatment significantly reduced body weight and food intake in HFD-fed mice (P. PMID- 29603688 TI - Serum level of fetuin B is associated with osteoporosis: a 4-year prospective study in China. AB - PURPOSE: As a novel hepatokine, fetuin B involves in various functions of energy metabolism. Recent advance reveals a complex interaction between bone and liver via the secretion of hepatokines. The association between serum fetuin B and osteoporosis was evaluated in a 4-year hospital-based prospective study of 1,370 Chinese postmenopausal women. METHODS: Bone mineral densities (BMDs) were obtained on femoral neck and lumbar spines by dual energy X-ray absorptiometry. Serum fetuin B level was tested by enzyme-linked immunosorbent assay. RESULTS: Of the 1,370 participants in the baseline study (2012), 650 subjects were included in the 4-year follow-up study (2016). Serum fetuin B level presented higher in subjects with osteoporosis (106.7 +/- 17.6 MUg/ml) than it in controls (86.3 +/- 17.5 MUg/ml) (P < 0.001). Meanwhile, fetuin B positively correlated with triglycerides (r = 0.227, P = 0.001), femoral BMD (r = -0.426, P < 0.001) and lumbar BMD (r = -0.332, P < 0.001). At the 4-year follow-up, 116 subjects had developed osteoporosis. Serum fetuin B concentration was significantly higher in subjects who developed (P < 0.001). The osteoporosis incidence increased from Q1 9.9%, Q2 14.7%, and Q3 17.8% to Q4 30.2% (P for trend < 0.001), among the quartiles of baseline fetuin B. A higher fetuin B baseline level was linked to the incidence of osteoporosis (adjusted OR = 1.179, 95% CI [1.119 - 1.243], P = 0.009). CONCLUSION: Serum fetuin B levels increased with the development of osteoporosis. PMID- 29603689 TI - CIM Journal Club: Gene therapy for spinal muscular atrophy Comment on Mendell et al. N Engl J Med 2017;377:1713-22. AB - In their landmark paper, Mendell et al. show that infants with spinal muscular atrophy (SMA) reached important motor milestones and survived longer when treated with AVXS-101 (AveXis), a viral vector containing DNA encoding the survival of motor neuron protein (SMN). Patients not only crawled, stood and walked independently, but learned to speak. These results are very encouraging for patients with SMA and offer hope for pediatric and adult patients with other types of motor neuron diseases. PMID- 29603690 TI - The 2nd Annual Clinical Scientist Trainee Symposium, August 22, 2017, London, Canada. AB - Clinician scientists play a critical role in bridging research and clinical practice. Unfortunately, the neglect of research training in medical schools has created clinicians who are unable to translate evidence from literature to practice. Furthermore, the erosion of research training in medical education has resulted in clinicians who lack the skills required for successful scientific investigation. To counteract this, the Schulich School of Medicine & Dentistry has made an effort to engage trainees, at all levels, in the research process. The 2nd Annual Clinician Scientist Trainee Symposium was held in London, Ontario, Canada on August 22, 2017. Organized each year since 2016 by the Schulich Research Office, the symposium features research being conducted by trainees in Schulich's Clinical Research Training Program. The focus this year was on the current state of clinician-scientist training in Canada and visions for the path ahead. PMID- 29603691 TI - Aligners: the Invisible Corrector-A Boon or Bane. AB - The trend of clinical orthodontics has shown a palpable shift from conventional braces to innovative technologies like invisible aligners. Aligners are sequences of clear trays worn by patients to straighten their teeth. They were envisaged for the main purpose of esthetics, mainly directed toward self-conscious teenagers who otherwise would shy away from essential correction of malocclusion. PMID- 29603692 TI - Effect of At-home and In-office Bleaching on Marginal Microleakage in Composite Resin Restorations using Two Adhesive Systems. AB - AIM: The aim of this study is to assess marginal microleakage of cervical cavities restored with composite resins and two different adhesive techniques subjected to at-home and in-office bleaching. MATERIALS AND METHODS: In this randomized, blind laboratory experiment, 60 bovine teeth recently extracted were collected and divided into six groups (n = 10 each group). The teeth received cervical cavity preparations (2 mm * 3 mm * 1 mm) with enamel margins. Two different adhesive systems were used (Single Bond 2 and Clearfil SE Bond), in addition to composite resin (Z250). Restored teeth received two different bleaching gels (Opalescence PF and Opalescence Boost). Teeth were thermo-cycled and analyzed under confocal laser scanning microscopy. RESULTS: No significant differences were observed (p > 0.05) in microleakage scores between the two groups not subjected to bleaching nor between the four groups that received bleaching treatment (p > 0.05), regardless of the gel and adhesive system employed. However, when comparing nonbleached with bleached teeth, those not subjected to bleaching showed statistically lower marginal microleakage scores (p < 0.05). Data were statistically analyzed using the Kruskal-Wallis test followed by Student-Newman-Keuls post hoc test, with significance set at 5%. CONCLUSION: Marginal microleakage in composite resin restorations is influenced by the action of bleaching agents used both at-home and in-office, regardless of the adhesive system employed (total-etch or self-etch). CLINICAL SIGNIFICANCE: Both at-home and in-office bleaching agents have an influence on the adhesive interface of resin restorations, producing changes and inducing marginal leakage. PMID- 29603693 TI - Assessment of Salivary Catalase, a-Amylase, and Cotinine Levels in Chronic Smokers: A Comparative Study. AB - INTRODUCTION: One of the common practices observed in many parts of the world is smoking, of which tobacco forms an important constituent which is burned and inhaled. Smoking is known to have potential effect on body's immune system, antioxidants level, and salivary cotinine levels. Hence, we planned the present study to evaluate the impact of cigarette smoke on salivary anti-oxidant levels and cotinine levels in smokers and nonsmokers. MATERIALS AND METHODS: The present study included assessment of salivary parameters of smokers and nonsmokers. A total of 400 subjects were analyzed, of which 200 were active smokers and 200 were nonsmokers. Unstimulated salivary samples were taken and assessment of a amylase levels was done using biochemical kit and spectrophotometer. Assessment of salivary catalase (CAT) activity was done using Luck method. For the determination of cotinine levels, Bioassay Technology Laboratory kit was used using enzyme-linked immunosorbent assay (ELISA) technique. After the assessment of levels of all the salivary parameters, all the data were recorded, compiled, and analyzed. RESULTS: a-Amylase in smokers and nonsmokers group was found to be 206.25 and 169.85 U/mL respectively. Nonsignificant results were obtained while comparing the salivary a-amylase levels among the two study groups. Nonsignificant results were obtained while comparing the salivary CAT levels among the smokers and nonsmokers group. We observed statistically significant results while comparing mean cotinine levels among smokers group and nonsmokers group. CONCLUSION: Alteration in cotinine levels occurs in smokers in comparison to nonsmokers. CLINICAL SIGNIFICANCE: Smoking can cause harmful effect on the oral mucous membrane by altering salivary defense components. PMID- 29603694 TI - Arab Societal Awareness of Dental Veneers. AB - AIM: The aim of this study is to assess the Arab society's knowledge, awareness, and attitudes toward dental veneers. MATERIALS AND METHODS: A cross-sectional study was performed by collecting data through an online questionnaire created using the Survey Monkey website and distributed among Middle Eastern societies through social media to ascertain participants' knowledge and awareness regarding dental veneers. The sample included Arab laypeople who were over 18 years old, to represent the awareness of the majority regarding dental veneers. RESULTS: The sample of this study included 1,332 subjects from different Middle Eastern nationalities, mainly Saudis, Kuwaitis, and Emiratis (15.6% of males and 84.4% of females). The results of this study showed that the total knowledge of dental veneers is 50.12%. The respondents with the highest level of knowledge acquired their information mainly from newspapers and magazines, followed by the Internet, then dentists, then social media, and, finally, friends and relatives. Cost was the only factor limiting 38.4% of subjects from receiving veneers, and 56% of the subjects would receive veneers if they were free of cost. In total, 72.6% of the respondents believed that veneers are currently overused. CONCLUSION: The knowledge and awareness of dental veneers were below a satisfactory level. Participants who relied on social media as a source of information had lower knowledge levels. CLINICAL SIGNIFICANCE: This study emphasized the need for continual societal education regarding dental veneers. PMID- 29603695 TI - Evaluation of Flexural Strength of Polymethyl Methacrylate modified with Silver Colloidal Nanoparticles subjected to Two Different Curing Cycles: An in vitro Study. AB - AIM: Silver colloidal nanoparticles have been incorporated into acrylic resins to induce antimicrobial properties. However, as additives, they can influence the mechanical properties of the final product. Mechanical properties are also dependent on different curing cycles. The aim of this study was to evaluate flexural strength of a denture base resin incorporated with different concentrations of silver colloidal nanoparticles subjected to two different curing cycles. MATERIALS AND METHODS: Lucitone 199 denture base resin was used into which silver colloidal nanoparticles were incorporated at 0.5 and 5% by polymer mass. Specimens devoid of nanoparticles were used as controls. A total of 60 specimens were fabricated and divided into two groups. Each group was divided into three subgroups consisting of 10 specimens each. The specimens were fabricated according to American Dental Association (ADA) specification No. 12 and tested for flexural strength using universal testing machine. RESULTS: Silver colloidal nanoparticle incorporation at 0.5% concentration increased the mean flexural strength in both curing cycles by 7.5 and 4.4%, respectively, when compared with the control group. CONCLUSION: The study suggested that the mean flexural strength value of 0.5% silver colloidal nanoparticles in denture base resin was above the value of the control group both in short and long curing cycles, which makes it clinically suitable as a denture base material. However, at 5% concentration, the statistically significant amount of decrease in flexural strength compared with the value of control group both in short and long curing cycles gives it a questionable prognosis. CLINICAL SIGNIFICANCE: The specimens incorporated with the antimicrobial agent 0.5% silver colloidal nanoparticles and processed by long curing cycles showed significant increase in its flexural strength compared with the control group, which makes it clinically suitable as a denture base material. PMID- 29603696 TI - Dentition Status and Treatment Needs among Women involved in Sex Work as a Profession in the Red Light District of Pune, Maharashtra, India: A Cross sectional Study. AB - INTRODUCTION: The overall rehabilitation of women in sex work is unfortunately limited most of the time only to moving them to another profession, but it should be focused on including health as an important factor. Factors that restrict regular dental care include misconceptions, dental fear and expense of dental care, unpleasant dental experiences, and socioeconomic factors, but such a direct correlation cannot be made in the case of such women. Until now, no study has been conducted related to the complete dentition status and treatment needs of women in sex work. AIM: The aim of our survey was to evaluate the dentition status and treatment needs among the brothel-based women engaged in sex work. MATERIALS AND METHODS: A pilot study was conducted on 30 women and the final sample size was estimated to be 350. All the women were above 18 years old. Systematic random sampling method was followed after line listing of the brothels. The dentition status and treatment needs were recorded using the World Health Organization assessment form, 1997. The data collected were tabulated and analyzed using Statistical Package for the Social Sciences (SPSS), version 16.0. The Chi-squared test was carried out to check the association, and all p-values below 0.05 were considered to be statistically significant. RESULTS: The mean number of decayed teeth per person was 5.05 (+/-4.81), missing teeth per person was 0.96 +/- 2.71, filled teeth per person was 0.04 (+/-0.34), and the mean of decayed missing filled permanent teeth per person was 6.05 (+/-5.84). There was a significant association between dental caries and age, using finger to clean the teeth, and not visiting the dentist. CLINICAL SIGNIFICANCE: Due to different risk factors, such as diet, improper oral hygiene maintenance, and substance abuse, the overall dental health was found to be compromised in this population. Economic burden is an important factor that influences their attitude toward oral health and is likely to be inherited by their next generation also. PMID- 29603697 TI - Awareness of Biomedical Waste Management among Dentists associated with Institutions and Private Practitioners of North India: A Comparative Study. AB - AIM: The present study aimed to obtain information about knowledge, execution, and attitude toward biomedical waste (BMW) and its management. MATERIALS AND METHODS: In the present study, a self-administered closed-ended questionnaire was designed to conduct a cross-sectional survey. It was distributed among 614 dentists (institution associated or private practitioners) in the cities of North India. The questionnaire comprised 36 questions regarding knowledge, execution, and attitude toward BMW and its management. Frequency distribution and chi-square test along with paired t-test were used to compare the data obtained between the private practitioners and institution-associated dentists. RESULTS: The study showed that 80% private practitioners were aware of the categories of BMW as compared with 100% of institution-associated dentists. However, 41% dentists associated with institution were disposing the chemical waste directly into sewer and a surprising high number of private practitioners were discarding directly without any treatment. Furthermore, regarding the mandatory maintenance of BMW records, 100% institution-associated respondents were aware, whereas only 6.5% private practitioners knew about it. Regarding BMW management not frequently being followed, 78% of private practitioners believed extra burden as the reason. CONCLUSION: Most of the dentists had adequate knowledge regarding BMW policies and its management. Although it was being practiced in mostly all the institutes on a regular basis, the majority of private practitioners were not practicing it due to various reasons, such as financial burden, lack of availability of service, and poor attitude toward its management. CLINICAL SIGNIFICANCE: There is a need to make it compulsory and organize training sessions to educate the dental personnel and to establish the importance of proper management. PMID- 29603698 TI - Does ErbiumiYttrium-Aluminum-Garnet Laser to Enamel improve the Performance of Etch-and-rinse and Universal Adhesives? AB - AIM: This study aims to evaluate the effect of erbium: Yttrium-aluminum-garnet (Er:YAG) laser irradiation on the enamel microshear bond strength (MUSBS), followed by the utilization of etch-and-rinse and universal adhesive systems. MATERIALS AND METHODS: A total of 32 molars were sectioned in the mesiodistal direction producing 64 samples that were randomized into two groups (n = 32): single bond 2 (SB2) (etch-and-rinse system; 3M), SB universal (SBU) (universal etching system; The SB2 and SBU groups were then divided into two subgroups (n = 16): (i) enamel was irradiated with an Er:YAG laser (lambda = 2.94 MUm, 60 mJ, 10 Hz), and (ii) enamel served as a control. The samples were restored with TPH3 (Dentsply), stored in artificial saliva for 24 hours, and subjected to a micro shear test. RESULTS: Kruskal-Wallis (p < 0.05) and Mann-Whitney U tests indicated no significant differences in uSBS between the groups, and the fractures were predominately at the resin-enamel interface. CONCLUSION: The previous irradiation of enamel with Er:YAG laser does not interfere with the performance of simplified two-step etch-and-rinse and universal adhesive systems. CLINICAL SIGNIFICANCE: The increasing use of Er:YAG laser is important to evaluate the influence of this irradiation on the adhesion of restorative materials. Thus, to obtain the longevity of the restorative procedures, it is necessary to know the result of the association of the present adhesive systems to the irradiated substrate. PMID- 29603699 TI - Evaluation of the Effects of Fluoride Prophylactic Agents on Mechanical Properties of Nickel Titanium Wires using Scanning Electron Microscope. AB - INTRODUCTION: Orthodontic treatment these days is increasing in demand, and therefore, it is relatively imperative for the orthodontist to prescribe the use of fluoride-containing products, such as mouthwashes and gels, to help prevent dental caries and maintain healthy oral health. The aim of the study was to assess and evaluate the effects of fluoride prophylactic agents on mechanical properties of nickel titanium (NiTi) wires during orthodontic treatment using scanning electron microscope (SEM). MATERIALS AND METHODS: We used the commercially available round preformed NiTi orthodontic archwire (3M company) and three different mouthwash solutions, i.e., Phos-Flur gel (1.1% sodium acidulated phosphate fluoride, APF, 0.5% w/v fluoride, pH = 5.1; Colgate Oral Pharmaceuticals) and Prevident 5000 (1.1% sodium fluoride neutral agent, 0.5% w/v fluoride, pH = 7; Colgate Oral Pharmaceuticals). All the specimens were subjected to a three-point bending test on a universal testing machine. To observe the surface morphological changes, one wire from each group was randomly selected and observed under a SEM. RESULTS: It was observed that there was not much difference in the values of both modulus of elasticity and yield strength obtained after loading of stress on the wires in all the three experimental conditions. A significant difference in both modulus of elasticity and yield strength was observed during unloading of stress. Further, when the surface characteristics were observed for all the specimens using SEM images, it was observed that NiTi wires treated with Phos-Flur showed large surface defects which appeared as round, pitted areas depicting corrosion, numerous white inclusions, and overall damaged surface structure of the wire as compared with the control. CONCLUSION: Thus, fluoridated mouthwashes are essential to maintain good oral hygiene and decrease instance of caries in patients undergoing orthodontic treatment. The prophylactic usage of topical fluoride agents on NiTi wire seems to diminish the mechanical properties of the orthodontic wire that could significantly affect future treatment outcomes. CLINICAL SIGNIFICANCE: It has been proved that fluoride mouthwashes/gels do affect the structural surface qualities and strength of wires used during the orthodontic treatment irrespective of the composition of the wires. Therefore, it is the responsibility of the clinician to prescribe these prophylactic agents carefully while keeping in mind their pH so that the overall result of the treatment may not be hampered and delayed due to change in properties of the wires used. PMID- 29603700 TI - Assessment of Lipid Peroxidation Levels and Total Antioxidant Status in Chronic and Aggressive Periodontitis Patients: An in vivo Study. AB - INTRODUCTION: Periodontitis is a common problem affecting a significant population of the world. For the assessment of oxidative stress of an individual, total oxidation status (TOS) and total antioxidant capacity (TAOC) are the significant biomarkers. Hence, we planned the present study to assess malondialde hyde (MDA), TOS, TAOC levels, and oxidative stress index (OSI) in generalized aggressive periodontitis (GP) and chronic periodontitis (CP) patients. MATERIALS AND METHODS: The present study included assessment of 40 CP patients, 40 GP patients, and 40 healthy controls. Clinical assessment of all the subjects was done by measuring the probing depth (PD), clinical attachment (CL), gingival index (GI), gingival bleeding index (GBI), and plaque index (PI). Salivary and serum samples were taken and assessed by standard procedures as described previously in the literature. All the values were assessed and compared. RESULTS: Significant results were obtained while comparing all the periodontal parameters in between various study groups. Mean serum MDA levels in the CP, GP, and control group were found to be 0.68, 0.65, and 0.61 MUM respectively. Statistically nonsignificant results were obtained while comparing the serum MDA levels in between the three study groups. Significant results were obtained while comparing the mean serum and salivary TOS values, TAOC values, and OSI in between various study groups. CONCLUSION: In periodontitis patients, oxidative stress was significantly higher in comparison with healthy subjects. CLINICAL SIGNIFICANCE: Oxidative parameters do play a significant role in the pathologic profile of periodontitis. PMID- 29603701 TI - Evaluation of Mineral Trioxide Aggregate, Resin-modified Glass lonomer Cements, and Composite as a Coronal Barrier: An in vitro Microbiological Study. AB - AIM: The purpose of the study is to evaluate the bacterial micro-leakage of three different materials, mineral trioxide aggregate (MTA), resin-modified glass ionomer cement (RMGIC), and flowable composite, as a coronal barrier against Enterococcus faecalis. MATERIALS AND METHODS: A total of 100 human extracted single-rooted teeth were selected. Access opening done, working length determined, and canals were cleaned and shaped with ProTaper F3 and obturated with AH26 and gutta-percha (GP) using lateral condensation technique. Samples were divided into three experimental and two control groups. Approximately 3 mm GP was removed from the coronal orifice and restored with one of the test materials. Teeth were suspended in glass tubes containing brain heart infusion (BHI) broth and equipped with microcaps, which were used to check bacterial leakage. A 24-hour broth of E. faecalis was placed in the pulp chamber. Tubes were incubated and checked for turbidity for 90 days. Data were analyzed using chi-squared test between the test and control groups and Fisher test between the test groups. RESULTS: Significantly lesser number of samples turned turbid in the RMGIC group followed by MTA group and the maximum number of samples turned turbid in the flowable composite group. CONCLUSION: The RMGIC is a better coronal sealer, followed by MTA and flowable composite. CLINICAL SIGNIFICANCE: Coronal sealing ability of RMGIC is more promising in comparison with the other agents. PMID- 29603702 TI - Evaluation of the Efficacy of Different Mixing Techniques and Disinfection on Microbial Colonization of Polyether Impression Materials: A Comparative Study. AB - AIM: This study aims to determine the role of mixing techniques of polyether impression materials and efficacy of disinfection on microbial colonization of these impression materials. MATERIALS AND METHODS: Polyether impression material was mixed using two methods: First by hand mixing (group I) and second using an automixer (group II) with a total of 100 samples. Four microbial strains were studied, which included Escherichia coli, Staphylococcus aureus, Pseudomonas aeruginosa, and Candida albicans. After incubation, the bacterial colonies were counted, and then, disinfectant solution was applied. The effect of disinfection solution was evaluated for each specimen. RESULTS: The surface of polyether impression materials mixed with an automixer has less number of voids and overall a smoother surface as compared with the hand-mixed ones. On comparing the disinfection procedures, i.e., specimens without any disinfection and specimens after disinfection, statistically highly significant difference was seen between all the groups. CONCLUSION: We can conclude that impression mixing procedures are important in determining the surface characteristics of the impression and ultimately the colonization of bacteria and also determine the importance of disinfection on microbial colonization. CLINICAL SIGNIFICANCE: This study emphasises the deleterious role of nosocomial infections and specific measures that should be taken regarding the prevention of such diseases. Dental impressions are proved to be a source of such infections and may lead to transmission of such diseases. Thus, proper measures should be taken right from the first step of impression taking to minimizing and preventing such kind of contaminations in clinical practice. PMID- 29603703 TI - Radiographic Assessment of Anatomy of Nasopalatine Canal for Dental Implant Placement: A Cone Beam Computed Tomographic Study. AB - AIM: The aim of this study is to assess the morphology of nasopalatine canal (NPC) with cone beam computed tomography (CBCT). MATERIALS AND METHODS: A total of 460 subjects of both genders were subjected to CBCT with NewTom machine, and sagittal and coronal sections were used for evaluation of the shape of NPC and width of buccal cortical plate. Types of NPC were also assessed. RESULTS: Of 460 subjects, males were 210 and females were 250. The difference was nonsignificant (p = 0.1). Type III canals were mostly seen in both males and females, followed by types I and II. The mean length of NPC in males and females showed statistical significant difference (p < 0.05). Males showed significantly higher diameter of nasal opening, oral opening, and width of the buccal bone plate over the oral opening as compared with females. CONCLUSION: The exact location, morphology, and dimensions of NPC can be well visualized with CBCT. All findings were higher in males as compared with females. CLINICAL SIGNIFICANCE: The success of dental implant in maxillary anterior region may be affected by the approximation with NPC. The exact location and morphology play an important role for the correct placement of implant. Cone beam computed tomography is a useful tool providing three-dimensional images in all sections. PMID- 29603704 TI - Comparison between Fluoride and Nano-hydroxyapatite in Remineralizing Initial Enamel Lesion: An in vitro Study. AB - AIM: The aim of this study was to compare the effectiveness of nano hydroxyapatite (nano-HAP) paste and fluoride varnish in remineralizing initial enamel lesion in young permanent teeth and their ability to resist secondary caries under dynamic pH cycling quantitatively and qualitatively. MATERIALS AND METHODS: Initial caries-like lesions were artificially developed on 45 specimens. Specimens were divided into three groups: (1) Control (without treatment), (2) fluoride varnish (3M ESPE), and (3) nano-HAP paste (Desensibilize Nano P). The nano-HAP paste was applied twice separated by one pH cycle, and the varnish was applied only once followed by 7 days of pH cycling. All specimens were examined using DIAGNOdent(r) pen (KaVo, Germany), and a representative specimen was randomly selected from each group for qualitative evaluation using scanning electron microscope (SEM) at four stages: Baseline, after lesion formation, immediately after remineralization, and after pH cycling. Data were statistically analyzed with Statistical Package for the Social Sciences (SPSS), version 20. RESULTS: The degree of demineralization was significantly elevated in control group; however, no significant difference was found between fluoride varnish group and nano-HAP paste group (p < 0.001). CONCLUSION: Nano-HAP paste showed promising long-term protective effect in terms of surface depositions and maintaining a smooth surface compared with fluoride varnish. CLINICAL SIGNIFICANCE: Based on the findings of this study, nano-HAP paste might be recommended as alternative remineralizing agent with lower fluoride concentration than fluoride varnish that could be beneficial for children, pregnant females, and those who are at high risk of dental fluorosis. PMID- 29603705 TI - Comparison of Visual Analog Scale Scores in Pain Assessment during Pulpotomy using Different Injection Materials in Children Aged 6 to 8 and 8 to 10 Years. AB - AIM: Proper anesthesia and pain management during treatment are most important concerns in dentistry for people of all ages, especially children. This study compared the success rate of lidocaine block with articaine buccal infiltration during anesthesia of the primary mandibular second molars in children aged 6 to 8 and 8 to 10 years. MATERIALS AND METHODS: The present clinical trial was conducted on 40 children aged 6 to 8 and 8 to 10 years who were referred to the Department of Pediatrics of the Faculty of Dentistry at Shahid Sadoughi University of Medical Sciences in Yazd (Islamic Republic of Iran) and needed to be treated with pulpotomy on both primary mandibular second molars. The patients were randomly divided into two groups. At the first session, a group received articaine buccal infiltration and the other group experienced inferior alveolar nerve (IAN) block. At the next visit, this trend was reversed. Visual analog scale (VAS) was used to evaluate the pain during pulpotomy. RESULTS: Data were analyzed by Statistical Package for the Social Sciences (version 17) software using Mann-Whitney test. According to the results of this test, the pain during pulpotomy was significantly lower in the articaine group (p < 0.001). CONCLUSION: Articaine buccal infiltration can be employed for pulpotomy treatment in primary mandibular second molars. CLINICAL SIGNIFICANCE: This research will eliminate block injection of lidocaine in children and utilize infiltration of articaine for pulpotomy treatment of mandibular teeth, hence preventing lingual nerve damage and prolonging paresthesia of IAN, lip, and cheek bite due to IAN block anesthesia. PMID- 29603706 TI - Effect of Different Surface Treatments on Biaxial Flexural Strength of Yttria stabilized Tetragonal Zirconia Polycrystal. AB - INTRODUCTION: Ceramics are widely applied in dentistry owing to their excellent mechanical and physical attributes. The most popular ceramics are LavaTM, KaVo Everest, and Cercon. However, it is unclear whether or not a different surface treatment along with low-temperature aging and mechanical loading (ML) affects the physical properties of computer-aided design (CAD)/computer-aided manufacturing (CAM)-machined yttria-stabilized tetragonal zirconia polycrystal (Y TZP) ceramic. AIM: The objective of this research was to assess the impact of various surface treatments as air-particle abrasion, ML, low-temperature degradation (LTD), and their cumulative effects on biaxial flexural properties of Y-TZP. MATERIALS AND METHODS: Totally, 50 specimens were fabricated by CAD-CAM machining from Cercon(r) and divided into five groups following different surface treatments as control (C), air-particle abrasion (Si), ML, LTD, and cumulative treatment (CT) group. Results were investigated by two-way analysis of variance (ANOVA) and Tukey honest significant difference (HSD) test. RESULTS: The highest biaxial flexural strength was observed in the Si group (950.2 +/- 126.7 MPa), followed by the LTD group (861.3 +/- 166.8 MPa), CT group (851.2 +/- 126.5 MPa), and the least with ML (820 +/- 110 MPa). A significant difference was observed in the two-way ANOVA test. X-ray diffraction (XRD) analysis showed that the control group consists of 100% tetragonal zirconia and the maximum amount of monoclinic phase was obtained after LTD. CONCLUSION: No negative effect on biaxial flexural strength was observed; indeed, it increases the biaxial strength. Hence, these surface treatments can be done in routine clinical practice to improve the performance of ceramic restoration. PMID- 29603707 TI - Comparative Evaluation of Periodontal Status of Chronic Renal Failure Patients and Systemically Healthy Individuals. AB - AIM: Periodontitis, a chronic infectious disease, affects most of the population at one time or the other and its expression is a combination of hosts, microbial agents, and environmental factors. Extensive literature exists for the relationship between periodontal disease and diabetes mellitus, cardiovascular diseases, and adverse pregnancy outcomes. Only a few studies performed in a limited number of patients have reported peri-odontal health status in chronic renal failure patients. Hence, the aim of the present study is to assess and compare the periodontal status of patients with chronic renal failure undergoing dialysis, predialysis with systemically healthy individuals. MATERIALS AND METHODS: A total of 90 patients were divided into three groups. Group I: 30 renal dialysis patients. Group II: 30 predialysis patients. Control group comprised 30 systemically healthy patients who formed group III. Periodontal examination was carried out using oral hygiene index-simplified (OHI-S), plaque index (PI), gingival index (GI), probing depth, and clinical attachment loss. RESULTS: The results of the study showed that the periodontal status of patients with chronic renal failure undergoing dialysis (dialysis group) and patients with chronic renal failure not undergoing renal dialysis (predialysis) when compared with systemically healthy subjects showed significantly higher mean scores of OHI-S, PI, and clinical attachment loss. CONCLUSION: Thus, patients with chronic renal failure showed poor oral hygiene and higher prevalence of periodontal disease. CLINICAL SIGNIFICANCE: The dental community's awareness of implications of poor health within chronic renal failure patients should be elevated. PMID- 29603708 TI - Quality of Life-related "Patient-reported Outcome Measures" in Oral Submucous Fibrosis Patients. AB - AIM: The aim of this study was to explore the patients' perspectives about the impact of oral submucous fibrosis (OSF) on life quality. MATERIALS AND METHODS: Thirty clinically diagnosed OSF patients with a wide degree of disease severity and diverse range of sociodemographic profile were included in this study. Fourteen participants were interviewed and four focus group discussions were conducted in nonclinical settings. The audio recordings were anonymized, transcribed, and translated in English from Marathi language. Data were analyzed using an in-depth narrative thematic analysis method. RESULTS: Four main themes evolved from the interviews: (1) discomfort and functional impairment; (2) psychological wellness; (3) physical wellness, and (4) social wellness. Majority of the participants discussed about discomfort and functional impairment. Participants also reported greater impact of OSF on psychological and social wellness. CONCLUSION: This study demonstrated the impact of OSF on different aspects of participant's life. "Discomfort and functional impairment" was noticed to be the most recognized theme by our participants. However, OSF also has impacts on other important domains, namely psychological, social, and physical wellness. CLINICAL SIGNIFICANCE: The patient-reported outcome (PRO) measure (PROM) reflects an integral aspect of general health and well-being and thus can be used to elucidate the impact of OSF on the quality of life (QoL) of affected individuals. These patients' perspectives should be taken into consideration along with thorough clinical examination to decide and effectively manage the overall health care needs of the OSF patients. PMID- 29603709 TI - Comparative Evaluation of Flexural Strength of Nano-zirconia-integrated Pressable Feldspathic and Lithium Disilicate Ceramics. AB - AIM: The purpose of the study was to evaluate and compare the flexural strength of nano-reinforced zirconia feldspathic porcelain, lithium disilicate ceramics, and zirconia. MATERIALS AND METHODS: Ten bar-shaped specimens of computer-aided design (CAD)/computer-aided manufacturing (CAM) zirconia, reinforced feldspathic porcelain, and reinforced lithium disilicate were fabricated in accordance to International Organization for Standardization (ISO 6872; n = 10). Feldspathic porcelain and lithium disilicate ceramic specimens were reinforced with 5, 10, 15, and 20% of zirconia nanoparticles through a customized technique. The specimens were subjected to three-point flexural strength test using universal testing machine (UTM) and examined for crack propagation using a scanning electron microscope (SEM). Oneway analysis of variance (ANOVA) and Tukey test were used to analyze the data (p < 0.05). RESULTS: The flexural strength of feldsphatic porcelain increased with the increase in the concentration of zirconia particles. The mean flexural strength of 5, 10, 15, and 20% nano zirconia-incorporated lithium disilicate was 93.8, 97.1, 100.6, and 100.8 MPa respectively, and was lower than the control group (221.7 MPa). A significant difference in the flexural strength was found with the incorporation of nano zirconia particles. CONCLUSION: The flexural strength of zirconia-integrated feld spathic porcelain increased and lithium disilicate ceramics decreased with the nano-zirconia reinforcement. CLINICAL SIGNIFICANCE: The simplified approach of reinforcing feldspathic porcelain with zirconia nanoparticles can be adapted in clinical situations of higher masticatory forces. PMID- 29603710 TI - Utilizing the GentleWave(r) System for Debridement of Undetected Apical Anatomy. AB - AIM AND BACKGROUND: Debriding and disinfecting complex anatomies within the root canal system pose a major challenge during root canal therapy. Even with current chemomechanical techniques, debris and bacterial remnants are commonly left behind, which are generally believed to increase the risk of endodontic failure. This case details the use of a new technique to debride complex apical anatomy in a maxillary molar. CASE REPORT: A 48-year-old female presented to the clinic with a chief complaint of increasing pain in her tooth. Clinical examination of the right first maxillary molar (#3) revealed moderate sensitivity to percussion and mild sensitivity to palpation. A pulpal diagnosis of symptomatic irreversible pulpitis and a periapi-cal diagnosis of symptomatic apical periodontitis were made. Mechanical instrumentation was performed using rotary file size #25/.04 for the mesiobuccal and distobuccal canals and size #25/.06 for the palatal canal to create a fluid path and enable obturation of the root canal system following the GentleWave(r) Procedure. The GentleWave Procedure was completed using Multisonic UltracleaningTM for complete debridement and disinfection of the root canal system. The tooth was obturated using a warm vertical continuous wave obturation technique. Postoperative radiographs revealed complex anatomy within the apical third that was undetected both during pre-operative radiography and mechanical instrumentation. The palatal canal exhibited a complex apical delta with multiple points of exit, and the mesiobuccal canal revealed an undetected lateral canal within the apical third that had a separate and distinct egress. Conclusion and clinical significance: It is important for the clinician to debride and disinfect complex anatomy within the root canal system to reduce the risk of endodontic failure. This case report highlights the clinical significance of utilizing the GentleWave Procedure for detecting complex apical anatomy during endodontic therapy. PMID- 29603711 TI - Management of a Severe Cervicofacial Odontogenic Infection. AB - INTRODUCTION: Odontogenic infections originate from a tooth or from its supporting structures, generally secondary to a pulp necrosis, periodontal disease, pericoronitis, apical lesions, or complications of dental procedures, which can be restricted to the alveolus or can reach the jaws and face through maxillofacial spaces. These are the most common conditions which affect the head and neck regions. AIM: The aim of this study is to report a severe case of a cervicofacial odontogenic infection while discussing the most relevant aspects. CASE REPORT: A 47-year-old female patient with a background of diabetes mellitus (DM) had a cervicofacial infection presenting edema and erythema in the left hemiface extending from the frontoparietal to cervical region and was submitted to extensive surgical treatment combined with antibiotic therapy. CONCLUSION: Although the prevalence and complication rates of odontogenic infections had decreased with the advancement of diagnostic techniques, availability of effective antibiotics, and improvement in oral hygiene, still there are conditions that require attention and accurate treatment to prevent the progression of the pathology to deeper fascial spaces. CLINICAL SIGNIFICANCE: Odontogenic infections can be treated with fewer complications if approached earlier when diagnosed while their premature clinical manifestations. However, if the treatment is postponed and the infection spreads into deeper fascial spaces, it can damage vital structures, and, consequently, threaten the patient's life. In these cases, extensive and aggressive therapy should be performed. PMID- 29603713 TI - Researching research. PMID- 29603712 TI - A Retrospective Study to Compare the Use of the Mean Apnea-Hypopnea Duration and the Apnea-Hypopnea Index with Blood Oxygenation and Sleep Patterns in Patients with Obstructive Sleep Apnea Diagnosed by Polysomnography. AB - BACKGROUND The apnea-hypopnea index (AHI) and the mean apnea-hypopnea duration (MAD) are used to measure the severity of the symptoms of obstructive sleep apnea (OSA). The aim of this study was to compare the use of the MAD with the AHI as indicators of clinical and demographic parameters, blood oxygenation, and sleep parameters in patients diagnosed with OSA by polysomnography (PSG). MATERIAL AND METHODS A retrospective study included 511 patients with OSA diagnosed by PSG and who had the AHI and the MAD measured according to the guidelines from the American Academy of Sleep Medicine (AASM). The patients were divided into two groups: patients with a short MAD and with a long MAD, according to median duration, and using the inter-quartile range (IQR), as the data were not normally distributed. Clinical and demographic parameters were recorded. Pulse oximetry was used to measure blood oxygen saturation during sleep, sleep structure was recorded, and the Epworth Sleepiness Scale (ESS) questionnaire was used to measure daytime sleepiness. RESULTS In all 511 patients with OSA, the MAD was significantly, but weakly, correlated with the AHI (r=0.17, P<0.01), but showed no significant associations with patient age (r=0.08, P=0.06), body weight (r=0.014, P=0.75), and height (r=0.06, P=0.16). Patients with a long MAD or severe OSA (n=260) had significantly worse blood oxygen levels and sleep parameters. CONCLUSIONS For patients with severe OSA, this study showed that the MAD was a useful indicator of blood oxygenation and sleep parameters. PMID- 29603714 TI - Sensitivity analysis and power for instrumental variable studies. AB - In observational studies to estimate treatment effects, unmeasured confounding is often a concern. The instrumental variable (IV) method can control for unmeasured confounding when there is a valid IV. To be a valid IV, a variable needs to be independent of unmeasured confounders and only affect the outcome through affecting the treatment. When applying the IV method, there is often concern that a putative IV is invalid to some degree. We present an approach to sensitivity analysis for the IV method which examines the sensitivity of inferences to violations of IV validity. Specifically, we consider sensitivity when the magnitude of association between the putative IV and the unmeasured confounders and the direct effect of the IV on the outcome are limited in magnitude by a sensitivity parameter. Our approach is based on extending the Anderson-Rubin test and is valid regardless of the strength of the instrument. A power formula for this sensitivity analysis is presented. We illustrate its usage via examples about Mendelian randomization studies and its implications via a comparison of using rare versus common genetic variants as instruments. PMID- 29603715 TI - Minimising 'research waste' in academic anaesthesia funding and outputs. PMID- 29603716 TI - Digest: Plants adapt under attack: genotypic selection and phenotypic plasticity under herbivore pressure. AB - Plant species adapt to changing environmental conditions through phenotypic plasticity and natural selection. Agrawal et al. (2018) found that dandelions responded to the presence of insect pests by producing higher levels of defensive compounds. This defensive response resulted both from phenotypic plasticity, with individual plants' defenses triggered by insect attack, and from evolution by natural selection acting on genetic variation in the plant population. PMID- 29603717 TI - Bilateral striatal necrosis and dyschromatosis symmetrica hereditaria: A-I editing efficiency of ADAR1 mutants and phenotype expression. PMID- 29603718 TI - Nonparametric estimation of transition probabilities for a general progressive multi-state model under cross-sectional sampling. AB - Nonparametric estimation of the transition probability matrix of a progressive multi-state model is considered under cross-sectional sampling. Two different estimators adapted to possibly right-censored and left-truncated data are proposed. The estimators require full retrospective information before the truncation time, which, when exploited, increases efficiency. They are obtained as differences between two survival functions constructed for sub-samples of subjects occupying specific states at a certain time point. Both estimators correct the oversampling of relatively large survival times by using the left truncation times associated with the cross-sectional observation. Asymptotic results are established, and finite sample performance is investigated through simulations. One of the proposed estimators performs better when there is no censoring, while the second one is strongly recommended with censored data. The new estimators are applied to data on patients in intensive care units (ICUs). PMID- 29603719 TI - Towards more accurate prognostication after preterm birth. PMID- 29603720 TI - Chronic pain: a source of disability in its own right? PMID- 29603721 TI - Should school-based physical therapists be more targeted in their interventions for children with disabilities? PMID- 29603722 TI - Effective anti-programmed death-1 therapy in a SUFU-mutated patient with Gorlin Goltz syndrome. AB - We present the case of a 77-year-old male patient with more than 50 basal cell carcinomas on the head and upper trunk. The patient did not respond to several lines of treatment, including surgery, imiquimod, retinoids, itraconazole and therapy with the hedgehog inhibitor vismodegib. The patient responded well to off label therapy with the anti-programmed death-1 antibody pembrolizumab after four infusions. PMID- 29603723 TI - Training of parental scaffolding in high-socio-economic status families: How do parents of full- and preterm-born toddlers benefit? AB - BACKGROUND: Preterm children have an increased risk regarding self-regulation development. Given the strong link between parenting behaviour (i.e., scaffolding and sensitivity) and children's self-regulation, parental training presents a promising way to counteract the negative consequences of preterm birth. AIMS: We explored the effectiveness of parental training by comparing a basic scaffolding training and a combined scaffolding/sensitivity training to an active treatment control group (stress management). Basic and combined treatments should increase parents' domain-specific self-efficacy (DSSE) and beliefs on parental co regulation and the promotion of learning (BCL) more than the control treatment should. No such differences were expected for parents' domain-general self efficacy (DGSE). We examined whether parents of preterm and full-term children benefitted equally from training conditions. SAMPLE(S): A total of 87 parents of full-term and 35 parents of preterm toddlers (24-36 months of age, corrected for prematurity) participated. METHODS: Based on a quasi-experimental pre-test-post test follow-up design, parents were randomly assigned to treatments. A multimethod approach was applied, including self-report, parent-child interactions, and standardized behavioural tasks. The presented study is limited to questionnaire data on parents' DGSE, DSSE, and BCL. RESULTS: An overall increase resulted from pre- to post-test and/or follow-up. Parents' BCL changed significantly stronger in the combined training than in the control group. Parents of preterm and full-term children benefitted equally from basic and combined training. CONCLUSIONS: The combined training enhanced BCL among parents of full-term and preterm children the most. If such training also yields improvement on the behavioural level, this finding will advance preterm aftercare. PMID- 29603724 TI - Multimorbidity and Functional Limitation in Individuals with Heart Failure: A Prospective Community Study. AB - OBJECTIVES: To characterize the individual and combined effects of multimorbidity and functional limitation on healthcare use and mortality in a large, community cohort of individuals with heart failure (HF). DESIGN: Prospective cohort study. SETTING: Eleven southeastern Minnesota counties. PARTICIPANTS: Individuals (mean age 74, 54% male) with a first-ever HF code (International Classification of Diseases, Ninth Revision code 428 or Tenth Revision code I50) between January 1, 2013 and March 31, 2016 (N=2,692). MEASUREMENTS: Eight activities of daily living measured using a survey on a Likert scale (1=without any difficulty, 5=unable to do; median=8). Participants with a score greater than 8 were categorized as having functional limitation. Multimorbidity was defined as having 2 or more noncardiac comorbidities. RESULTS: Twenty-five percent of participants had neither multimorbidity nor functional limitation, 35% had multimorbidity, 9% had functional limitation, and 31% had both. After adjustment, participants with multimorbidity and functional limitation had greater risks of all outcomes (death: hazard ratio (HR)=4.92, 95% confidence interval (CI)=3.03-8.00; emergency department (ED) visit: HR=3.67, 95% CI=2.94-4.59; hospitalization: HR=3.66, 95% CI=2.85-4.70; outpatient visit: HR=1.73, 95% CI=1.52-1.96) than those with neither. Participants with functional limitation alone had greater risks of death (HR=4.84, 95% CI=2.78-8.43), ED visits (HR=2.35, 95% CI=1.75-3.16), and hospitalizations (HR=2.10, 95% CI=1.52-2.88) but not outpatient visits. Those with multimorbidity alone had similar risks of ED visits and hospitalizations as those with functional limitation alone but were more likely to have outpatient visits (HR=1.50, 95% CI=1.34-1.67). CONCLUSION: Individuals with both multimorbidity and functional limitation have the highest risk of death and healthcare use. Individuals with only functional limitation have similar rates of hospitalizations and ED visits as those with only multimorbidity, underscoring the need to consider both when managing individuals with HF. PMID- 29603725 TI - Digest: Life history evolution in Darwin's dream ponds. AB - Can variation in sex-specific parental investment lead to sexual dimorphism in immune response? Keller et al. (2018) measured immune cell parameters, expression of candidate genes, and composition of buccal microbiota in mouthbrooding cichlid species from Lake Tanganyika that show either maternal or biparental care. They found that maternal mouthbrooding species have increased sexual dimorphism in immune parameters, while biparental mouthbrooders exhibit an upregulated adaptive immune response, suggesting resource allocation shifts between parental investment and the immune system. PMID- 29603726 TI - Mechanisms driving the lactate switch in Chinese hamster ovary cells. AB - The metabolism of Chinese Hamster Ovary (CHO) cells in a production environment has been extensively investigated. However, a key metabolic transition, the switch from lactate production to lactate consumption, remains enigmatic. Though commonly observed in CHO cultures, the mechanism(s) by which this metabolic shift is triggered is unknown. Despite this, efforts to control the switch have emerged due to the association of lactate consumption with improved cell growth and productivity. This review aims to consolidate current theories surrounding the lactate switch. The influence of pH, NAD+ /NADH, pyruvate availability and mitochondrial function on lactate consumption are explored. A hypothesis based on the cellular redox state is put forward to explain the onset of lactate consumption. Various techniques implemented to control the lactate switch, including manipulation of the culture environment, genetic engineering, and cell line selection are also discussed. PMID- 29603727 TI - Novel Pompe disease phenotype: a treatment-related modified phenotype neglecting the brain. PMID- 29603728 TI - Distinct profiles of TERT promoter mutations and telomerase expression in head and neck cancer and cervical carcinoma. AB - Two recurrent mutations (-124 G > A and -146 G > A) in the core promoter region of the human telomerase reverse transcriptase (TERT) gene create consensus binding sites for ETS transcription factors and cause increased TERT expression in several tumour types. We analyzed TERT promoter mutations and TERT mRNA levels in head and neck cancer, cervical carcinoma and cervical intraepithelial neoplasia (CIN) as well as in C-4I, CaSki, HeLa and SiHa cervical cell lines. Nucleotide sequence analysis of TERT promoter region showed that 33.3% of oral squamous cell carcinoma (SCC) and 16.8% of cervical SCC harboured mutually exclusive G to A transitions at nucleotide position -124 or -146. TERT promoter was mutated at nucleotide -146 (G > A) in SiHa cell line. Other nucleotide changes creating in some cases putative ETS binding sites were more frequent in oral SCC (26.7%) than in cervical carcinoma (4.8%). The frequency of mutations was independent of human papillomavirus (HPV) tumour status in both cervical and oral cancer. Expression of TERT gene was significantly higher in TERT promoter mutated (-124G > A or -146G > A) cervical SCC compared to not mutated SCC irrespective of HPV16 E6 and E7 levels. Such hot spot changes were not detected in oropharyngeal SCC, cervical adenocarcinoma and CIN lesions. Our results suggest that TERT promoter mutations play a relevant role in oral SCC as well as in cervical SCC, besides the already known effect of HPV16 E6 protein on TERT expression. PMID- 29603729 TI - Analysis of the distribution and scholarly output from National Institute of Academic Anaesthesia (NIAA) research grants. AB - The National Institute of Academic Anaesthesia (NIAA) was founded in 2008 to lead a UK strategy for developing academic anaesthesia. We aimed to assess the distribution of applications and quantify the academic returns of NIAA-supported research grants, as this has hitherto not been analysed. We sought data on the baseline characteristics of all grant applicants and recipients. Every grant recipient from 2008 to 2015 was contacted to ascertain the status of their supported research projects. We also examined Google Scholar, Scopus(r) database and InCites Journal Citation Reports for citation, author and journal metrics, respectively. In total, 495 research project applications were made, with 150 grants being awarded. Data on 121 out of 150 (80.7%) grant awards, accounting for L3.5 million, were collected, of which 91 completed studies resulted in 140 publications and 2759 citations. The median (IQR [range]) time to first or only publication was 3 (2-4 [0-9]) years. The overall cost per publication was L14,970 (L7457-L24,998 [L2212-L73,755]) and the cost per citation was L1515 (L323-L3785 [L70-L36,182]), with 1 (0-2 [0-8]) publication and 4 (0-25 [0-265]) citations resulting per grant. The impact factor of journals in which publications arose was 4.7 (2.5-6.2 [0-47.8]), with the highest impact arising from clinical and basic science studies, particularly in the fields of pain and peri-operative medicine. Grants were most frequently awarded to clinical and basic science categories of study, but in terms of specialty, critical care medicine and peri operative medicine received the greatest number of grants. Superficially, there seemed a geographical disparity, with 123 (82%) grants being awarded to researchers in England, London receiving 48 (32%) of these. However, this was in proportion to the number of grant applications received by country or city of application, such that there was no significant difference in overall success rates. There was no significant difference in productivity in terms of publications and citations from grants awarded to each city. The 150 grants were awarded to 107 recipients (identified as the most senior applicant for each grant), 27 of whom received >= two grants. Recipients had a median career total of 21 (8-76 [0-254]) publications and 302 (44-1320 [0-8167]) citations, with an h index of 8 (3-22 [0-54]). We conclude that a key determinant of grant success is simply applying. This is the first study to report the distribution and scholarly output of individual anaesthesia research grants, particularly from a collaborative body such as the NIAA, and can be used as a benchmark to further develop academic anaesthesia in the UK and beyond. PMID- 29603730 TI - ForC: a global database of forest carbon stocks and fluxes. AB - Forests play an influential role in the global carbon (C) cycle, storing roughly half of terrestrial C and annually exchanging with the atmosphere more than five times the carbon dioxide (CO2 ) emitted by anthropogenic activities. Yet, scaling up from field-based measurements of forest C stocks and fluxes to understand global scale C cycling and its climate sensitivity remains an important challenge. Tens of thousands of forest C measurements have been made, but these data have yet to be integrated into a single database that makes them accessible for integrated analyses. Here we present an open-access global Forest Carbon database (ForC) containing previously published records of field-based measurements of ecosystem-level C stocks and annual fluxes, along with disturbance history and methodological information. ForC expands upon the previously published tropical portion of this database, TropForC (https://doi.org/10.5061/dryad.t516f), now including 17,367 records (previously 3,568) representing 2,731 plots (previously 845) in 826 geographically distinct areas. The database covers all forested biogeographic and climate zones, represents forest stands of all ages, and currently includes data collected between 1934 and 2015. We expect that ForC will prove useful for macroecological analyses of forest C cycling, for evaluation of model predictions or remote sensing products, for quantifying the contribution of forests to the global C cycle, and for supporting international efforts to inventory forest carbon and greenhouse gas exchange. A dynamic version of ForC is maintained at on GitHub (https://GitHub.com/forc-db), and we encourage the research community to collaborate in updating, correcting, expanding, and utilizing this database. ForC is an open access database, and we encourage use of the data for scientific research and education purposes. Data may not be used for commercial purposes without written permission of the database PI. Any publications using ForC data should cite this publication and Anderson-Teixeira et al. (2016a) (see Metadata S1). No other copyright or cost restrictions are associated with the use of this data set. PMID- 29603731 TI - Differential adaptation to a harsh granite outcrop habitat between sympatric Mimulus species. AB - Understanding which environmental variables and traits underlie adaptation to harsh environments is difficult because many traits evolve simultaneously as populations or species diverge. Here, we investigate the ecological variables and traits that underlie Mimulus laciniatus' adaptation to granite outcrops compared to its sympatric, mesic-adapted progenitor, Mimulus guttatus. We use fine-scale measurements of soil moisture and herbivory to examine differences in selective forces between the species' habitats, and measure selection on flowering time, flower size, plant height, and leaf shape in a reciprocal transplant using M. laciniatus * M. guttatus F4 hybrids. We find that differences in drought and herbivory drive survival differences between habitats, that M. laciniatus and M. guttatus are each better adapted to their native habitat, and differential habitat selection on flowering time, plant stature, and leaf shape. Although early flowering time, small stature, and lobed leaf shape underlie plant fitness in M. laciniatus' seasonally dry environment, increased plant size is advantageous in a competitive mesic environment replete with herbivores like M. guttatus'. Given that we observed divergent selection between habitats in the direction of species differences, we conclude that adaptation to different microhabitats is an important component of reproductive isolation in this sympatric species pair. PMID- 29603732 TI - FREEWAT, a Free and Open Source, GIS-Integrated, Hydrological Modeling Platform. PMID- 29603733 TI - Herbivory and eutrophication mediate grassland plant nutrient responses across a global climatic gradient. AB - Plant stoichiometry, the relative concentration of elements, is a key regulator of ecosystem functioning and is also being altered by human activities. In this paper we sought to understand the global drivers of plant stoichiometry and compare the relative contribution of climatic vs. anthropogenic effects. We addressed this goal by measuring plant elemental (C, N, P and K) responses to eutrophication and vertebrate herbivore exclusion at eighteen sites on six continents. Across sites, climate and atmospheric N deposition emerged as strong predictors of plot-level tissue nutrients, mediated by biomass and plant chemistry. Within sites, fertilization increased total plant nutrient pools, but results were contingent on soil fertility and the proportion of grass biomass relative to other functional types. Total plant nutrient pools diverged strongly in response to herbivore exclusion when fertilized; responses were largest in ungrazed plots at low rainfall, whereas herbivore grazing dampened the plant community nutrient responses to fertilization. Our study highlights (1) the importance of climate in determining plant nutrient concentrations mediated through effects on plant biomass, (2) that eutrophication affects grassland nutrient pools via both soil and atmospheric pathways and (3) that interactions among soils, herbivores and eutrophication drive plant nutrient responses at small scales, especially at water-limited sites. PMID- 29603734 TI - School-based physical therapy services and student functional performance at school. AB - AIM: We explored relationships of school-based physical therapy to standardized outcomes of students receiving physical therapy. METHOD: Using a practice-based evidence research design, School Function Assessment (SFA) outcomes of 296 students with disabilities (mean age 7y 4mo [standard deviation 2y]; 166 males, 130 females), served by 109 physical therapists, were explored. After training, therapists completed 10 SFA scales on students at the beginning and end of the school year. Therapists collected detailed weekly data on services (activities, interventions, types, student participation) using the School-Physical Therapy Interventions for Pediatrics (S-PTIP) system. Stepwise linear regressions were used to investigate S-PTIP predictors of SFA outcomes. RESULTS: Predictors of SFA section outcomes varied in strength, with the coefficient of determination (R2 ) for each outcome ranging from 0.107 to 0.326. Services that correlated positively with the SFA outcomes included mobility, sensory, motor learning, aerobic/conditioning, functional strengthening, playground access interventions, and higher student participation during therapy (standardized beta=0.11-0.26). Services that correlated negatively with the SFA outcomes included providing services within student groups, within school activity, with students not in special education, during recreation activities, and with positioning, hands-on facilitation, sensory integration, orthoses, and equipment interventions (standardized beta=-0.14 to -0.22). INTERPRETATION: Consideration of outcomes is prudent to focus services. Overall results suggest we should emphasize active mobility practice by using motor learning interventions and engaging students within therapy sessions. WHAT THIS PAPER ADDS: No specific interventions predicted positively on all School Function Assessment (SFA) outcomes. Active movement practice seems related to overall better SFA outcomes. Active mobility practice improved SFA participation, mobility, recreation, and activities of daily living. Engaging students in therapy activities and interventions improved outcomes. PMID- 29603735 TI - Unexpected instabilities explain batch-to-batch variability in cell-free protein expression systems. AB - Cell-free methods of protein synthesis offer rapid access to expressed proteins. Though the amounts produced are generally only at a small scale, these are sufficient to perform protein-protein interaction assays and tests of enzymatic activity. As such they are valuable tools for the biochemistry and bioengineering community. However the most complex, eukaryotic cell-free systems are difficult to manufacture in house and can be prohibitively expensive to obtain from commercial sources. The Leishmania tarentolae system offers a relatively cheap alternative which is capable of producing difficult to express proteins, but which is simpler to produce in large scale. However, this system suffers from batch-to-batch variability, which has been accepted as a consequence of the complexity of the extracts. Here we show an unexpected origin for the variability observed and demonstrate that small variations in a single parameter can dramatically affect expression, such that minor pipetting errors can have major effects on yields. L. tarentolae cell-free lysate activity is shown to be more stable to changes in Mg2+ concentration at a lower ratio of feed solution to lysate in the reaction than typically used, and a higher Mg2+ optimum. These changes essentially eliminate batch-to-batch variability of L. tarentolae lysate activity and permit their full potential to be realized. PMID- 29603736 TI - Time from breast cancer diagnosis to therapeutic surgery and breast cancer prognosis: A population-based cohort study. AB - Theoretically, time from breast cancer diagnosis to therapeutic surgery should affect survival. However, it is unclear whether this holds true in a modern healthcare setting in which breast cancer surgery is carried out within weeks to months of diagnosis. This is a population- and register-based study of all women diagnosed with invasive breast cancer in the Stockholm-Gotland healthcare region in Sweden, 2001-2008, and who were initially operated. Follow-up of vital status ended 2014. 7,017 women were included in analysis. Our main outcome was overall survival. Main analyses were carried out using Cox proportional hazards models. We adjusted for likely confounders and stratified on mode of detection, tumor size and lymph node metastasis. We found that a longer interval between date of morphological diagnosis and therapeutic surgery was associated with a poorer prognosis. Assuming a linear association, the hazard rate of death from all causes increased by 1.011 (95% CI 1.006-1.017) per day. Comparing, for example, surgery 6 weeks after diagnosis to surgery 3 weeks after diagnosis, thereby confers a 1.26-fold increased hazard rate. The increase in hazard rate associated with surgical delay was strongest in women with largest tumors. Whilst there was a clear association between delays and survival in women without lymph node metastasis, the association may be attenuated in subgroups with increasing number of lymph node metastases. We found no evidence of an interaction between time to surgery and mode of detection. In conclusion, unwarranted delays to primary treatment of breast cancer should be avoided. PMID- 29603737 TI - Clinical presentation and magnetic resonance imaging findings in 11 dogs with eosinophilic meningoencephalitis of unknown aetiology. AB - OBJECTIVES: To describe the clinical presentation, MRI findings and outcome in dogs with eosinophilic meningoencephalitis of unknown origin. MATERIALS AND METHODS: Dogs were included in this retrospective study if they had complete medical records, complete neurological examination, MR imaging, cerebellomedullary cerebrospinal fluid sample consistent with eosinophilic pleocytosis and negative infectious disease testing. RESULTS: Eleven dogs were included with a median age of 22.0 months (range 7.6 to 92.0 months). Nine breeds were represented. Neurological abnormalities included obtundation (n=10), menace response deficits (n=9), proprioceptive deficits (n=7), ataxia (n=7) and seizures (n=2). Neuroanatomical localisation was multi-focal (n=4), central vestibular system (n=4), diffuse forebrain (n=2) or left trigeminal/facial nerves (n=1). Seven dogs had peripheral eosinophilia. Ten dogs had bilateral symmetrical lesions affecting the cortical grey matter, which was hyperintense on T2-weighted and fluid-attenuating inversion recovery images and iso- to hypointense on T1 weighted images with associated meningeal contrast enhancement. MRI findings were consistent with diffuse meningitis and atrophy or necrosis of cortical grey matter. One dog had increased contrast uptake in the left trigeminal nerve. Ten dogs receiving corticosteroids survived to discharge, with seven also receiving cytarabine arabinoside. Median survival time was 762 days. CLINICAL SIGNIFICANCE: Eosinophilic meningoencephalitis of unknown origin affects younger larger-breed dogs, with the majority having suspected diffuse cerebrocortical meningitis and cortical (polio)encephalitis, which can be identified on MRI. Response to immunosuppressive treatment is good in the medium to long term, although further studies are required in this area. PMID- 29603738 TI - Increased systemic levels of inflammatory mediators following one-stage full mouth scaling and root planing. AB - BACKGROUND AND OBJECTIVE: Full-mouth scaling and root planing (FM-SRP) acts as a potent inflammatory stimulus immediately after treatment; however, systemic inflammation typically improves in the long term. The contribution of FM-SRP to systemic biological and acute-phase responses is largely unknown. The purpose of this prospective intervention study was to assess the systemic and local biological responses after FM-SRP. MATERIAL AND METHODS: Thirty-one patients with generalized moderate-to-severe chronic periodontitis received 1-stage FM-SRP. Measurement of clinical parameters and body temperature as well as collection of subgingival plaque, peripheral blood and gingival crevicular fluid was performed before and after treatment 2 or 3 times. Quantification of periodontopathic bacteria in the sulcus and measurement of corresponding serum IgG titers were performed. Systemic and local inflammatory markers such as endotoxin, high sensitive C-reactive protein (hs-CRP) and 6 inflammatory cytokines were assessed using high-sensitivity assays. RESULTS: Compared to baseline values, FM-SRP resulted in a substantial improvement in clinical parameters (P < .05), lower bacterial counts (P < .01) and a significant decrease of IgG titers against Porphyromonas gingivalis (P < .001) 6 weeks after treatment. Comparing baseline parameters to those at 1 day post-treatment, there was a statistically significant elevation in body temperature (P = .007). In addition, a 5-fold increase in hs-CRP (P < .001), a remarkable increase in interferon-gamma (P < .001) and a slight increase in interleukin (IL)-12p70 (P = .001) were detected in serum samples. In the gingival crevicular fluid, marked increases in hs-CRP (P < .001), IL-5 (P = .001), IL-6, IL-12p70 and tumor necrosis factor-alpha (P < .001 for the latter 3 markers) were noted 1 day after treatment. Endotoxin levels were below measurable limits for most time points. CONCLUSION: FM-SRP resulted in clinical and microbiological improvement 6 weeks post-treatment, but produced a moderate systemic acute-phase response including elevated inflammatory mediators 1 day post-treatment. PMID- 29603739 TI - Vascular targeting of LIGHT normalizes blood vessels in primary brain cancer and induces intratumoural high endothelial venules. AB - High-grade brain cancer such as glioblastoma (GBM) remains an incurable disease. A common feature of GBM is the angiogenic vasculature, which can be targeted with selected peptides for payload delivery. We assessed the ability of micelle tagged, vascular homing peptides RGR, CGKRK and NGR to specifically bind to blood vessels in syngeneic orthotopic GBM models. By using the peptide CGKRK to deliver the tumour necrosis factor (TNF) superfamily member LIGHT (also known as TNF superfamily member 14; TNFSF14) to angiogenic tumour vessels, we have generated a reagent that normalizes the brain cancer vasculature by inducing pericyte contractility and re-establishing endothelial barrier integrity. LIGHT-mediated vascular remodelling also activates endothelia and induces intratumoural high endothelial venules (HEVs), which are specialized blood vessels for lymphocyte infiltration. Combining CGKRK-LIGHT with anti-vascular endothelial growth factor and checkpoint blockade amplified HEV frequency and T-cell accumulation in GBM, which is often sparsely infiltrated by immune effector cells, and reduced tumour burden. Furthermore, CGKRK and RGR peptides strongly bound to blood vessels in freshly resected human GBM, demonstrating shared peptide-binding activities in mouse and human primary brain tumour vessels. Thus, peptide-mediated LIGHT targeting is a highly translatable approach in primary brain cancer to reduce vascular leakiness and enhance immunotherapy. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29603741 TI - Where do satellite cells orbit? An endomysium space odyssey. PMID- 29603740 TI - Nicotine inhibits osteogenic differentiation of human periodontal ligament cells under cyclic tensile stress through canonical Wnt pathway and alpha7 nicotinic acetylcholine receptor. AB - BACKGROUND AND OBJECTIVES: Nicotine, the main psychoactive component of tobacco, affects cell metabolism, proliferation, adhesion and, importantly, the osteogenic differentiation of fibroblasts. Approximately 15% of all orthodontic patients are adults among who one-fifth are smokers. Hence, it is necessary to have insight into the effects of nicotine on the osteogenic differentiation of hPDLCs during orthodontic tooth movement. This study aimed to investigate the effects and mechanisms of nicotine on the osteogenic differentiation of human periodontal ligament cells (hPDLCs) under the application of cyclic tensile stress. MATERIAL AND METHODS: hPDLCs were obtained from donor third molars. The hPDLCs were treated with nicotine and/or cyclic tensile stress that was applied with a cell stress plus unit. The effect of nicotine on cell viability was analyzed using the MTT assay. The osteogenic differentiation of hPDLCs was detected by alkaline phosphatase staining, Alizarin Red S staining, quantitative real-time polymerase chain reaction and western blotting. RESULTS: In combination with cyclic tensile stress, nicotine prevented the tensile stress-induced increase in alkaline phosphatase activity, formation of mineralization nodules and the upregulation of mRNA and protein expression of Runt-related transcription factor 2, transcription factor Sp7 and collagen type I; however, canonical Wnt pathway was activated. Furthermore, the addition of Dickkopf-related protein 1 and alpha-bungarotoxin counteracted the negative effect of nicotine and rescued the osteogenic differentiation of hPDLCs, respectively. CONCLUSION: These results indicate that nicotine prevents the increased osteogenic potential of hPDLCs induced by cyclic tensile stress by binding to an alpha7 nicotinic acetylcholine receptor and activating the canonical Wnt pathway. PMID- 29603742 TI - Prognostic factors for the use of intrauterine balloon tamponade in the management of severe postpartum hemorrhage. AB - OBJECTIVE: To identify prognostic factors associated with successful management of severe postpartum hemorrhage (PPH) using intrauterine balloon tamponade (IUBT). METHODS: Retrospective review of all cases of severe PPH with blood loss greater than 1 L in a tertiary unit in Hong Kong from July 1, 2012, to June 30, 2017. Records of patients who had undergone IUBT insertion were reviewed. Univariate analysis and logistic regression models were used to identify prognostic factors for successful management with IUBT. RESULTS: Of 22 860 deliveries during the study period, severe PPH occurred in 1.4% (n=311), and IUBT was attempted in 26.0% (n=81) of these patients. IUBT alone was successful in arresting hemorrhage in 72.8% (n=59), and the overall rate for avoiding hysterectomy was 86.4% (n=70). Presence of coagulopathy (P=0.048) and placenta accreta (P=0.048) were the adverse prognostic factors associated with higher failure rates. Less blood loss (<=1400 mL) at the time of insertion of IUBT and a positive tamponade test (<=50 mL of blood drained from the uterus within the first 30 minutes after insertion of IUBT) were good predictors for success of IUBT. CONCLUSION: The presence of adverse prognostic factors should prompt early resort to other treatment modalities or hysterectomy as a salvage procedure. PMID- 29603744 TI - Genetic predisposition to obesity is associated with asthma in US Hispanics/Latinos: Results from the Hispanic Community Health Study/Study of Latinos. PMID- 29603743 TI - Inhibition of Na+ /K+ -ATPase and KIR channels abolishes hypoxic hyperaemia in resting but not contracting skeletal muscle of humans. AB - KEY POINTS: Increasing blood flow (hyperaemia) to exercising muscle helps match oxygen delivery and metabolic demand. During exercise in hypoxia, there is a compensatory increase in muscle hyperaemia that maintains oxygen delivery and tissue oxygen consumption. Nitric oxide (NO) and prostaglandins (PGs) contribute to around half of the augmented hyperaemia during hypoxic exercise, although the contributors to the remaining response are unknown. In the present study, inhibiting NO, PGs, Na+ /K+ -ATPase and inwardly rectifying potassium (KIR ) channels did not blunt augmented hyperaemia during hypoxic exercise beyond previous observations with NO/PG block alone. Furthermore, although inhibition of only Na+ /K+ -ATPase and KIR channels abolished hyperaemia during hypoxia at rest, it had no effect on augmented hyperaemia during hypoxic exercise. This is the first study in humans to demonstrate that Na+ /K+ -ATPase and KIR channel activation is required for augmented muscle hyperaemia during hypoxia at rest but not during hypoxic exercise, thus providing new insight into vascular control. ABSTRACT: Exercise hyperaemia in hypoxia is augmented relative to the same exercise intensity in normoxia. During moderate-intensity handgrip exercise, endothelium-derived nitric oxide (NO) and vasodilating prostaglandins (PGs) contribute to ~50% of the augmented forearm blood flow (FBF) response to hypoxic exercise (HypEx), although the mechanism(s) underlying the remaining response are unclear. We hypothesized that combined inhibition of NO, PGs, Na+ /K+ -ATPase and inwardly rectifying potassium (KIR ) channels would abolish the augmented hyperaemic response in HypEx. In healthy young adults, FBF responses were measured (Doppler ultrasound) and forearm vascular conductance was calculated during 5 min of rhythmic handgrip exercise at 20% maximum voluntary contraction under regional sympathoadrenal inhibition in normoxia and isocapnic HypEx (O2 saturation ~80%). Compared to control, combined inhibition of NO, PGs, Na+ /K+ ATPase and KIR channels (l-NMMA + ketorolac + ouabain + BaCl2; Protocol 1; n = 10) blunted the compensatory increase in FBF during HypEx by ~50% (29 +/- 6 mL min-1 vs. 62 +/- 8 mL min-1 , respectively, P < 0.05). By contrast, ouabain + BaCl2 alone (Protocol 2; n = 10) did not affect this augmented hyperaemic response (50 +/- 11 mL min-1 vs. 60 +/- 13 mL min-1 , respectively, P > 0.05). However, the blocked condition in both protocols abolished the hyperaemic response to hypoxia at rest (P < 0.05). We conclude that activation of Na+ /K+ ATPase and KIR channels is involved in the hyperaemic response to hypoxia at rest, although it does not contribute to the augmented exercise hyperaemia during hypoxia in humans. PMID- 29603745 TI - Effect of postharvest application of ethylene on the profile of phenolic acids and anthocyanins in three blueberry cultivars (Vaccinium corymbosum). AB - BACKGROUND: The blueberry is a fruit that has been studied extensively for its health benefits, mainly due to its high antioxidant activity. There is a strong correlation between antioxidant activity and total anthocyanin and phenolic compound content. Postharvest treatment using ethylene may be a factor affecting the anthocyanin content. The objective of this work was to analyze postharvest treatment using ethylene on the anthocyanin profile during the storage of blueberries and phytochemical composition of 'Bluecrop', 'Goldtraube,' and 'Ozarkblue.' Fruits were harvested at commercial maturity; the treatment was carried out with 1000 uL L-1 of ethylene for 24 h followed by storage at 4 degrees C under normal atmosphere for 56 days. RESULTS: One day after treatment with ethylene, this increased the proportion of seven (more than 45%) and four (more than 65%) of the nine anthocyanins identified in the Bluecrop and Goldtraube cultivars respectively, and decreased five of the seven anthocyanins identified in 'Ozarkblue'. For 'Bluecrop,' however, this increase reduced until the end of storage but in 'Goldtraube' seven anthocyanins had increased. CONCLUSION: The effect of ethylene on anthocyanin composition of blueberries appeared to depend on the cultivar. 'Bluecrop' and 'Goldtraube' responded positively with an increase in total anthocyanins. (c) 2018 Society of Chemical Industry. PMID- 29603747 TI - Immune-mediated antitumor effect of a transplanted lymph node. AB - Lymph node (LN) transplantation is a recognized method for reconstruction of the lymphatic system and is used in the clinical setting to treat lymphedema. However, it is unclear whether transplanted LNs contribute to immune surveillance. In our study, we investigated whether a single transplanted non vascularized LN, defined as a tumor-draining transplanted lymph node (TDTLN), could exert an immune-mediated antitumor effect. LN and lung metastases and primary tumor enlargement were evaluated in mice that were inoculated with B16 F10-luc2 melanoma cells in a hind limb footpad without (group 1) and with (group 2) popliteal lymph node (PLN) resection and in mice that underwent LN transplantation after PLN resection (group 3). The function of a TDTLN (group 3) and a tumor-draining popliteal lymph node (TDPLN; group 1) was evaluated in the context of cancer. LN and lung metastases were significantly aggravated by PLN resection but were significantly decreased by LN transplantation. Immunohistochemistry showed that the TDTLNs retained T-cells and B-cells and fluorescence-activated cell sorting analysis confirmed expansion of lymphocytes in these nodes; however, the degree of expansion in TDTLNs was different from that in TDPLNs. Expression of cytokines associated with immunostimulation was confirmed in the TDTLNs as well as in the TDPLNs. One of the differences in the immune-mediated antitumor effect of the TDPLNs and TDTLNs was ascribed to a difference in the site of lymphocyte homing to peripheral LNs through high endothelial venules. Non-vascularized LN transplantation had an immune-mediated antitumor effect. PMID- 29603746 TI - Mbd2 enables tumourigenesis within the intestine while preventing tumour promoting inflammation. AB - Epigenetic regulation plays a key role in the link between inflammation and cancer. Here we examine Mbd2, which mediates epigenetic transcriptional silencing by binding to methylated DNA. In separate studies the Mbd2-/- mouse has been shown (1) to be resistant to intestinal tumourigenesis and (2) to have an enhanced inflammatory/immune response, observations that are inconsistent with the links between inflammation and cancer. To clarify its role in tumourigenesis and inflammation, we used constitutive and conditional models of Mbd2 deletion to explore its epithelial and non-epithelial roles in the intestine. Using a conditional model, we found that suppression of intestinal tumourigenesis is due primarily to the absence of Mbd2 within the epithelia. Next, we demonstrated, using the DSS colitis model, that non-epithelial roles of Mbd2 are key in preventing the transition from acute to tumour-promoting chronic inflammation. Combining models revealed that prior to inflammation the altered Mbd2-/- immune response plays a role in intestinal tumour suppression. However, following inflammation the intestine converts from tumour suppressive to tumour promoting. To summarise, in the intestine the normal function of Mbd2 is exploited by cancer cells to enable tumourigenesis, while in the immune system it plays a key role in preventing tumour-enabling inflammation. Which role is dominant depends on the inflammation status of the intestine. As environmental interactions within the intestine can alter DNA methylation patterns, we propose that Mbd2 plays a key role in determining whether these interactions are anti- or pro-tumourigenic and this makes it a useful new epigenetic model for inflammation-associated carcinogenesis. (c) 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID- 29603748 TI - Adventitious lateral rooting: the plasticity of root system architecture. AB - Root formation under natural conditions is plastic in response to multiple signals. Recent studies suggested that the WUSCHEL-RELATED HOMEOBOX11 (WOX11) mediated adventitious root formation pathway can occur in the primary root (PR) in Arabidopsis thaliana, resulting in the production of a specific type of lateral roots (LRs) in response to wounding or environmental signals. This process differs from the previously characterized process for LR development, which does not require WOX11. The WOX11-mediated PR-derived roots can be considered like LRs that exhibit an 'adventitious' feature. Therefore, we consider these roots to be adventitious lateral roots (adLRs). The identification of WOX11-mediated adLRs implies that studying the formation of roots in response to wounding and environmental signals is important for characterizing the plasticity of the root system architecture. PMID- 29603749 TI - The gene PbTMT4 from pear (Pyrus bretschneideri) mediates vacuolar sugar transport and strongly affects sugar accumulation in fruit. AB - Tonoplast monosaccharide transporters (TMTs) play important roles in vacuolar sugar accumulation in plants. In this study, six TMT genes (PbTMT1-6) were identified in the Pyrus bretschneideri genome database, and their expression profiles were correlated with soluble sugar contents during the pear (P. bretschneideri cv. Ya Li) fruit development process. Subsequently, PbTMT4 was identified as a strong contributor to fructose, glucose and sucrose accumulation in fructescence of pears. Heterologous expression of PbTMT4, in the hexose transporter-deficient yeast strain EBY.VW4000, facilitated growth in media containing low levels of glucose, fructose, sucrose or sorbitol. In addition, PbTMT4-transformed tomato plants flowered and bore fruit significantly earlier than wild-type (WT) plants, and glucose and fructose levels in mature tomatoes were increased by about 32 and 21% compared with those in WT plants. However, no obvious alterations in sucrose content, plant height and weight per fruit were observed. Finally, subcellular localization experiments in transformed Arabidopsis plants showed that PbTMT4 is localized to tonoplast vesicles of protoplasts. These preliminary results suggest that PbTMT4 participates in vacuolar accumulation of sugars, and thus affects plant growth and development. PMID- 29603750 TI - RNA-Seq analysis unveils gene regulation of fruit size cooperatively determined by velocity and duration of fruit swelling in peach. AB - Fruit swelling determines fruit size and usually occurs in two distinct time periods in peach. However, little is known about the gene regulation of fruit swelling. In this study, measurements of longitudinal and transverse diameters in developing and ripening peach fruits unveiled two periods of fruit swelling: the first swelling ends at approximately 65 days after flower blooming (DAFB) and the second swelling starts at approximately 75 DAFB. Comparisons of diameters sizes and development periods among cultivars and accessions revealed a cooperative regulation of swelling velocity and swelling duration, which leads to final determination of fruit size. Furthermore, RNA-sequencing was conducted for fruits at the initial swelling, non-swelling interval between the two swellings (hereafter, 'the interval'), second swelling and ripening stages. A total of 110 and 128 differentially expressed genes were screened from fruits in the first and second swelling, respectively. Besides, the nine most differentially expressed genes located within the reported quantitative trait locations (QTLs) of fruit size in peach were detected in both the first and second swelling stages. Those genes have been reported to be involved in mediating cell size, which indicates the occurrence of both cell proliferation and cell expansion in each of the two major periods of fruit swelling. In addition, a potential gene regulation network is proposed herein and could be used to elucidate the molecular mechanism of peach fruit swellings mediated by multiple key genes. PMID- 29603752 TI - Acute cardiovascular exercise does not enhance locomotor learning in people with stroke. PMID- 29603751 TI - Behavioral Self-Regulation, Early Academic Achievement, and the Effectiveness of Urban Schools for Low-Income Ethnic Minority Children. AB - The independent and joint associations between child behavioral self-regulation ability and school effectiveness in relation to academic achievement were examined in a sample of low-income African American (n = 132) and Latino (n = 198) children attending kindergarten and first grade across a large metropolitan area. Child behavioral self-regulation and school effectiveness were positively associated with both reading and mathematics performance. School effectiveness moderated the effect of behavioral self-regulation on reading but not math achievement. Lower child behavioral self-regulation during early elementary school was associated with lower reading achievement the following year but only among children attending less effective schools. Behavioral self-regulation was not related to reading achievement among children attending more effective schools. Implications of these findings for policies addressing disparities in early academic achievement are discussed. PMID- 29603753 TI - Technical Note: An approach to building a Monte Carlo simulation model for a double scattering proton beam system. AB - PURPOSE: The purpose of this study was to demonstrate and develop a Monte Carlo (MC) simulation model for a passive double scattering compact proton therapy system based on limited information of the mechanical components. METHOD: We built a virtual machine source model (VMSM) which included a detailed definition of each beam-modifying component in the nozzle. Conceptually, it is similar to the conventional virtual analytical source model (VASM), except that the numerical machine nozzle or beamline is constructed in the VMSM, whereas in the VASM analytical parameters characterizing the energy spectrum and source fluence distribution are sought. All major beam shaping components were included in the VMSM and the model simulates interactions of the beam with a rotating range modulation wheel (RMW) combined with the beam current modulation. The RMWs, the first and second scatterer in the system were generated and tuned to reproduce measurement data as closely as possible. To validate the model, we compared the percent depth dose curves, spread out Bragg peaks (SOBPs) and lateral profiles against measured commissioning beam data. RESULTS: The agreement of beam range between the MC calculation and measurement was within 1 mm for all beam options. The distal-falloff length was in good agreement as well (<1 mm for the large and deep groups, <1.5 mm for the small group). Agreement to within 2.5 mm of measured SOBP widths was obtained for all MC calculations. For lateral profiles, differences were found to be less than 2 mm. CONCLUSIONS: We demonstrated that with limited geometrical information it is possible to build an acceptable source model for MC simulations of a passive double scattering compact proton therapy system. The agreement between the measurements and the MC model provides validation for use of the model for further studies of the dosimetric effects in patient treatments. PMID- 29603754 TI - Extraction approaches used for the determination of biologically active compounds (cyclitols, polyphenols and saponins) isolated from plant material. AB - Based on the bioactive properties of certain compounds, such as antioxidant and anti-inflammatory activities, an interesting subject of research are natural substances present in various parts of plants. The choice of the most appropriate method for separation and quantification of biologically active compounds from plants and natural products is a crucial step of any analytical procedure. The aim of this review article is to present an overview of a comprehensive literature study from the last 10 years (2007-2017), where relevant articles exposed the latest trends and the most appropriate methods applicable for separation and quantification of biologically active compounds from plant material and natural products. Consequently, various extraction methods have been discussed, together with the available procedures for purification and pre concentration and dedicated methods used for analysis. PMID- 29603755 TI - Impact of left atrial size on isolation area in the acute phase of pulmonary vein isolation using 28 mm cryoballoon. AB - BACKGROUND: The impact of left atrial (LA) size on isolation area (ISA) using a 28-mm second-generation cryoballoon (CB) in the acute phase after pulmonary vein isolation (PVI) and the differences of CB from contact force-guided radiofrequency (RF) ablation have not been fully investigated. METHODS: We examined 85 consecutive patients (CB group, 35; RF group, 50) with drug refractory paroxysmal atrial fibrillation who underwent their first PVI procedure at two institutions. We evaluated ISA after PVI using 3D-Merge computed tomography images (GE Healthcare, Little Chalfont, UK) and high-resolution electroanatomical mapping. RESULTS: Total ISA was significantly smaller in the CB group (20.6 +/- 6.0 cm2 ) than in the RF group (29.0 +/- 7.1 cm2 ; P < 0.0001). In the CB group, ISA of the left pulmonary vein (LPV), right pulmonary vein (RPV), and total ISA were not correlated with the left atrial surface area (LASA). The ratios of ISA to LASA (%ISA) of LPV and total ISA negatively correlated with LASA in the CB group (LPV: r = -0.4001, P = 0.0173; total ISA: r = -0.4733, P = 0.0041). In contrast, in the RF group, ISA of LPV, RPV, and total ISA positively correlated with LASA; (LPV: r = 0.5155, P = 0.001; RPV: r = 0.6398, P < 0.0001; total ISA: r = 0.7299, P < 0.0001). CONCLUSION: ISA created using CB was significantly smaller than that using RF and did not change regardless of LASA increment. Differences in ISA between the two groups became more prominent in the large atrium. PMID- 29603756 TI - Case of photosensitivity after the administration of olmesartan medoxomil. PMID- 29603757 TI - Extracellular matrix scaffolds for treatment of large volume muscle injuries: A review. AB - OBJECTIVE: Large muscular or musculotendinous defects present a dilemma because of the inadequacies of current treatment strategies. Extracellular matrices (ECM) are potential clinically applicable regenerative biomaterials. This review summarizes information from the preclinical literature evaluating the use of ECM for muscle regeneration in animal models of volumetric muscle loss (VML). STUDY DESIGN: Literature review. SAMPLE POPULATION: Animal models of VML in which surgical repair was performed with an ECM product, with or without added cell populations. METHODS: PubMed, Google Scholar, CAB abstracts, and Scopus were searched for preclinical studies using ECM in animal models of VML. The search terms "extracellular matrix," "VML," "muscle regeneration," "cell seeded," and "scaffold" identified 40 articles that met inclusion criteria of an animal model of VML in which surgical repair was performed with an ECM product, with or without added cell populations. Key skeletal muscle repair mechanisms and experimental findings on scaffold type, VML location, and experimental animal species were summarized. CONCLUSIONS: Satellite cells and basal lamina are key endogenous contributors to skeletal muscle regeneration. ECM as a dynamic tissue component may provide structural integrity, signaling molecules, and a 3 dimensional topography conducive to muscle regeneration. Preclinical models of muscle repair most commonly used mice and rats (88%). Most experimental lesions were created in abdominal wall (33%), anterior tibialis (33%), latissimus dorsi (10%), or quadriceps (10%) muscles. Matrices varied markedly in source and preparation. Experimental outcomes of ECM and cell-seeded ECM implantation for muscle regeneration in VML were highly variable and dependent on matrix tissue source, preparation method, and anatomic site of injury. Scar tissue formation likely contributes to load transfer. Nonappendicular lesions had better regenerative results compared with appendicular VML. CLINICAL SIGNIFICANCE: The preponderance of current evidence supports the use of ECM for muscle defect repair only in specific instances, such as nonappendicular and/or partial thickness defects. Consequently, clinical use of ECM in veterinary patients requires careful consideration of the specific ECM product, lesion size and location, and loading circumstances. PMID- 29603758 TI - Evaluation of 5 methods for diagnosing failure of passive transfer in 160 Holstein calves. AB - BACKGROUND: Inadequate absorption of colostral IgG1 is termed failure of transfer of passive immunity (FTPI). Dairy calves with FTPI have increased mortality and morbidity in their first 6 months of life. OBJECTIVES: This study compared the clinical performance of 5 methods for diagnosing FTPI in Holstein calves. METHODS: An observational study was performed using 160 Holstein heifer calves. Serum was harvested at 48 hours of age, and FTPI was assessed using a digital Brix refractometer for total solids measurements, and digital refractometry and the biuret method to measure serum total protein (STP) concentrations. Serum gamma-glutamyltransferase activity was measured with an automated analyzer, and serum IgG was measured with the zinc sulfate turbidity test and an enzyme-linked immunosorbent assay. Diagnostic test performance was compared with that of the reference method (FTPI defined as a serum total IgG concentration <10 g/L). Test performance was evaluated using the area under the receiver operating characteristic curve, the sensitivity, the specificity, and the positive likelihood ratio at the optimal test cut point, and by calculating the kappa coefficient. RESULTS: A serum digital Brix percentage of <7.8% and an STP concentration of <52 g/L measured using digital refractometry were the best methods to identify calves with FTPI. The STP concentration measured with digital refractometry was 0.1 g/L lower than that measured with the biuret method. CONCLUSIONS: The digital Brix refractometer and the digital refractometer provide accurate and clinically useful methods for identifying dairy calves with FTPI. In this study, the excellent performance of the Brix refractometer was likely due to the use of a fixed sample volume (200 MUL) and a uniform sample temperature at the time of measurement. PMID- 29603759 TI - Hepatic granulomas: a 17-year single tertiary centre experience. AB - AIMS: Hepatic granulomas have an estimated prevalence of 5% in liver biopsies, with a wide range of aetiologies globally. Our aim was to assess the clinical relevance, presenting features and underlying aetiology in a non-transplant, tertiary referral centre from a western country. METHODS AND RESULTS: This was a retrospective, single-centre review of clinical, laboratory and histological data including all adult patients for whom a liver biopsy was performed from January 1998 to December 2014. A total of 297 cases with hepatic granulomas were found in 9374 biopsies, but 57 were excluded from analysis either because they were lipogranulomas or the biopsy/aetiological work-up had not been performed at our institution. Overall, the most common aetiology was tuberculosis (35.8%), followed by primary biliary cholangitis (PBC) - 15.0%. In 30 patients (12.5%) granulomas were classified as idiopathic. From 1998 to June 2006 there were 147 granulomas in 5304 biopsies (2.8%), a frequency that did not change significantly compared to the period from July 2006 to December 2014 (93 granulomas in 4070 biopsies, 2.3%, P > 0.05). However, for the majority of cases (61.9%) there was a shift in granuloma aetiology during the former time-period that infectious diseases were responsible, whereas in the latter, autoimmune liver diseases (43%) were the main aetiology. In addition, while three cases of drug-induced granulomas were found from 1998 to June 2006, we report two cases in the second time-period. CONCLUSIONS: Hepatic granulomas can result from various infectious and non-infectious diseases. During recent years, an epidemiological shift regarding granuloma aetiology was observed, from systemic infectious diseases to non-infectious, mainly immune-mediated primary liver disorders. With an appropriate work-up the aetiology can be identified in the vast majority of cases (~90%), rendering its histological identification and characterisation essential, as disease-specific therapies are becoming available. PMID- 29603760 TI - Comparison of flexible ureteroscopy damage rates for lower pole renal stones by laser fiber type. AB - OBJECTIVES: Laser lithotripsy, often used during ureteronephroscopy (URNS), requires the Ho:YAG optical fiber transmit energy via total internal reflection (TIR). In critical lower pole deflections, energy may refract into the cladding causing fiber failure and scope damage. New optical fiber technology aims to have increased tolerance for high degrees of flexion. We compared two brands of laser fibers with sub-300 micron cores (Sureflex, Boston Flexiva) to determine failure rates and scope repair costs. METHODS: A retrospective cohort study comparing these two fibers for patients at a single academic institution who underwent flexible URNS with laser lithotripsy was performed from September 2013 to October 2015. Preoperative imaging was evaluated for stone burden and location. Intraoperative variables were collected, including energy use, lower pole lasering, laser fiber malfunction, and scope damage. The primary outcome was scope damage caused by laser fiber malfunction. Secondary outcome was scope repair costs. Fisher's exact test and two tailed t-tests were used. RESULTS: Of 223 subjects, 143 met inclusion criteria, and 8 had laser fiber failure. All failures occurred with the Sureflex fiber (8 of 63, 13%) vs the Boston Flexiva fiber (0 of 80, 0%) (P < 0.01). Malfunctions occurred in 8 of 79 lower pole stone applications versus 0 of 64 non-lower pole stone laser applications (P < 0.01). No other risk factor was different between fiber cohorts, except energy setting. Scope repair cost averaged $9155 CDN, yielding an average repair cost per case of $1144 CDN for the Sureflex versus $0 for the Boston fiber (P < 0.01). CONCLUSIONS: Both optical fibers perform well in non-lower pole locations. However, the challenge for laser fibers in lower pole URNS is to maintain TIR. Fiber failure reflects an inability to maintain reflection and is not based on energy used or stone burden. The Boston Flexiva laser fiber has fewer failures, resulting in $0 repair cost per case, compared to the Sureflex fiber in URNS with an average repair cost of $1144 CDN per case. Lasers Surg. Med. 50:798-801, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29603762 TI - Adaptation and evaluation of the Family Involvement and Alienation Questionnaire for use in the care of older people, psychiatric care, palliative care and diabetes care. AB - AIM: To adapt the Family Involvement and Alienation Questionnaire (FIAQ) for use in the care of older people, psychiatric care, palliative care and diabetes care and to evaluate its validity and reliability. BACKGROUND: Involvement in the professional care has proven to be important for family members. However, they have described feelings of alienation in relation to how they experienced the professionals' approach. To explore this issue, a broad instrument that can be used in different care contexts is needed. DESIGN: A psychometric evaluation study, with a cross-sectional design. METHOD: The content validity of the FIAQ was evaluated during 2014 by cognitive interviews with 15 family members to adults in different care contexts. Psychometric evaluation was then conducted (2015-2016). A sample of 325 family members participated, 103 of whom in a test retest evaluation. Both parametric and non-parametric methods were used. RESULTS: The content validity revealed that the questionnaire was generally understood and considered to be relevant and retrievable by family members in the contexts of the care of older people, psychiatric care, palliative care and diabetes care. Furthermore, the FIAQ (Revised), demonstrated satisfactory psychometric properties in terms of data quality, homogeneity, unidimensionality (factor structure), internal consistency and test-retest reliability. CONCLUSION: The study provides evidence that the FIAQ (Revised) is reliable and valid for use in further research and in quality assessment in the contexts of the care of older people, psychiatric care, palliative care and diabetes care. PMID- 29603761 TI - An experimental investigation of a novel iron chelating protoporphyrin IX prodrug for the enhancement of photodynamic therapy. AB - OBJECTIVES: Non-melanoma skin cancers are the most frequently occurring type of cancer worldwide. They can be effectively treated using topical dermatological photodynamic therapy (PDT) employing protoporphyrin IX (PpIX) as the active photosensitising agent as long as the disease remains superficial. Novel iron chelating agents are being investigated to enhance the effectiveness and extend the applications of this treatment modality, as limiting free iron increases the accumulation of PpIX available for light activation and thus cell kill. METHODS: Human lung fibroblasts (MRC-5) and epithelial squamous carcinoma (A431) cells were treated with PpIX precursors (aminolaevulinic acid [ALA] or methyl aminolevulinate [MAL]) with or without the separate hydroxypyridinone iron chelating agent (CP94) or alternatively, the new combined iron chelator and PpIX producing agent, AP2-18. PpIX fluorescence was monitored hourly for 6 hours prior to irradiation. PDT effectiveness was then assessed the following day using the lactate dehydrogenase and neutral red assays. RESULTS: Generally, iron chelation achieved via CP94 or AP2-18 administration significantly increased PpIX fluorescence. ALA was more effective as a PpIX-prodrug than MAL in A431 cells, corresponding with the lower PpIX accumulation observed with the latter congener in this cell type. Addition of either iron chelating agent consistently increased PpIX accumulation but did not always convey an extra beneficial effect on PpIX PDT cell kill when using the already highly effective higher dose of ALA. However, these adjuvants were highly beneficial in the skin cancer cells when compared with MAL administration alone. AP2-18 was also at least as effective as CP94 + ALA/MAL co-administration throughout and significantly better than CP94 supplementation at increasing PpIX fluorescence in MRC5 cells as well as at lower doses where PpIX accumulation was observed to be more limited. CONCLUSIONS: PpIX fluorescence levels, as well as PDT cell kill effects on irradiation can be significantly increased by pyridinone iron chelation, either via the addition of CP94 to the administration of a PpIX precursor or alternatively via the newly synthesized combined PpIX prodrug and siderophore, AP2-18. The effect of the latter compound appears to be at least equivalent to, if not better than, the separate administration of its constituent parts, particularly when employing MAL to destroy skin cancer cells. AP2-18 therefore warrants further detailed analysis, as it may have the potential to improve dermatological PDT outcomes in applications currently requiring enhancement. Lasers Surg. Med. 50:552-565, 2018. (c) 2018 The Authors. Lasers in Surgery and Medicine Published by Wiley Periodicals, Inc. PMID- 29603763 TI - Generation and use of tritiated borane in situ for formamide tritiation to an N methyl-3 H group. AB - The synthesis of [N-methyl-3 H](+/-)-mecamylamine is described as an example of a convenient and mild method to reduce formamide groups using tritiated borane generated in situ. The product was characterized by thin layer chromatography, high performance liquid chromatography, mass spectrometry, and tritium NMR. PMID- 29603764 TI - A prospective phase II study of low dose lenalidomide plus dexamethasone in patients with newly diagnosed polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome. AB - Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome is a rare plasma dyscrasia without standard treatment. This phase II prospective trial evaluates the safety and response of 12 cycles of low dose lenalidomide (10 mg) plus dexamethasone (Rdex) in patients with newly diagnosed POEMS syndrome. Forty-one patients (28 men) were enrolled and the median age at diagnosis was 49 years (range, 21-70 years). Twenty-one patients (46%) achieved complete hematologic response and the neurologic response rate was 95%. The median serum vascular endothelial growth factor (VEGF) declined from 5155 pg/mL (range, 534-14 328 pg/mL) to 832 pg/mL (95-6254 pg/mL) after therapy. The overall VEGF response rate was 83%, and the median time to response was 2 months, with a mean VEGF reduction of 43% at the first month. In terms of clinical response, Rdex substantially relieved extravascular volume overload, organomegaly, and pulmonary hypertension. No treatment-related deaths occurred and no patients suffered from lenalidomide-related grade 3 or above adverse events. After a median follow-up of 34 months, median overall survival (OS) and progression-free survival (PFS) were not reached, with an estimated 3-year OS and PFS of 90% and 75%, respectively. In conclusion, Rdex was active with high hematologic, VEGF and organ response rate and well tolerated for patients with newly diagnosed POEMS syndrome. This trial was registered at www.clinicaltrials.gov as #NCT01816620. PMID- 29603766 TI - Authorship grids: Practical tools to facilitate collaboration and ethical publication. AB - Publication of new findings and approaches in peer-reviewed journals is fundamental to advancing science. As interprofessional, team-based scientific publication becomes more common, authors need tools to guide collaboration and ethical authorship. We present three forms of authorship grids that are based on national and international author recommendations, including guidelines from the International Committee of Medical Journal Editors, the Committee on Publication Ethics, National Institutes of Health data sharing policies, common reporting guidelines, and Good Clinical Practice standards from the International Conference on Harmonization. The author grids are tailored to quantitative research, qualitative research, and literature synthesis. These customizable grids can be used while planning and executing projects to define each author's role, responsibilities, and contributions as well as to guide conversations among authors and help avoid misconduct and disputes. The grids also can be submitted to journal editors and published to provide public attribution of author contributions. PMID- 29603769 TI - Looking back, looking forward at RINAH. PMID- 29603768 TI - Psychometric properties of the postpartum depression screening scale beyond the postpartum period. AB - Accurate postpartum depression screening measures are needed to identify mothers with depressive symptoms both in the postpartum period and beyond. Because it had not been tested beyond the immediate postpartum period, the reliability and validity of the Postpartum Depression Screening Scale (PDSS) and its sensitivity, specificity, and predictive value for diagnoses of major depressive disorder (MDD) were assessed in a diverse community sample of 238 mothers of 4- to 15 month-old infants. Mothers (N = 238; M age = 30.2, SD = 5.3) attended a lab session and completed the PDSS, the Beck Depression Inventory-II (BDI-II), and a structured clinical interview (SCID) to diagnose MDD. The reliability, validity, specificity, sensitivity, and predictive value of the PDSS to identify maternal depression were assessed. Confirmatory factor analysis supported the construct validity of five but not seven content subscales. The PDSS total and subscale scores demonstrated acceptable to high reliability (alpha = 0.68-0.95). Discriminant function analysis showed the scale correctly provided diagnostic classification at a rate higher than chance alone. Sensitivity and specificity for major depressive disorder (MDD) diagnosis were good and comparable to those of the BDI-II. Even in mothers who were somewhat more diverse and had older infants than those in the original normative study, the PDSS appears to be a psychometrically sound screener for identifying depressed mothers in the 15 months after childbirth. PMID- 29603770 TI - Angiolymphoid hyperplasia with eosinophilia: A case of spontaneous partial regression post-biopsy. PMID- 29603771 TI - Differences in leaf thermoregulation and water use strategies between three co occurring Atlantic forest tree species. AB - Given anticipated climate changes, it is crucial to understand controls on leaf temperatures including variation between species in diverse ecosystems. In the first study of leaf energy balance in tropical montane forests, we observed current leaf temperature patterns on 3 tree species in the Atlantic forest, Brazil, over a 10-day period and assessed whether and why patterns may vary among species. We found large leaf-to-air temperature differences (maximum 18.3 degrees C) and high leaf temperatures (over 35 degrees C) despite much lower air temperatures (maximum 22 degrees C). Leaf-to-air temperature differences were influenced strongly by radiation, whereas leaf temperatures were also influenced by air temperature. Leaf energy balance modelling informed by our measurements showed that observed differences in leaf temperature between 2 species were due to variation in leaf width and stomatal conductance. The results suggest a trade off between water use and leaf thermoregulation; Miconia cabussu has more conservative water use compared with Alchornea triplinervia due to lower transpiration under high vapour pressure deficit, with the consequence of higher leaf temperatures under thermal stress conditions. We highlight the importance of leaf functional traits for leaf thermoregulation and also note that the high radiation levels that occur in montane forests may exacerbate the threat from increasing air temperatures. PMID- 29603772 TI - Occupational mobility among individuals in entry-level healthcare jobs in the USA. AB - AIMS: The aim of this study was to explore career transitions among individuals in select entry-level healthcare occupations. BACKGROUND: Entry-level healthcare occupations are among the fastest growing occupations in the USA. Public perception is that the healthcare industry provides an opportunity for upward career mobility given the low education requirements to enter many healthcare occupations. The assumption that entry-level healthcare occupations, such as nursing assistant, lead to higher-skilled occupations, such as Registered Nurse, is under-explored. DESIGN: We analysed data from the Panel Study of Income Dynamics, which is a nationally representative and publicly available longitudinal survey of US households. METHODS: Using longitudinal survey data, we examined the job transitions and associated characteristics among individuals in five entry-level occupations at the aide/assistant level over 10 years timeline (2003-2013) to determine whether they stayed in health care and/or moved up in occupational level over time. RESULTS/FINDINGS: This study found limited evidence of career progression in health care in that only a few of the individuals in entry-level healthcare occupations moved into occupations such as nursing that required higher education. While many individuals remained in their occupations throughout the study period, we found that 28% of our sample moved out of these entry-level occupations and into another occupation. The most common "other" occupation categories were "office/administrative" and "personal care/services occupations." Whether these moves helped individuals advance their careers remains unclear. CONCLUSION: Employers and educational institutions should consider efforts to help clarify pathways to advance the careers of individuals in entry-level healthcare occupations. PMID- 29603773 TI - Treatment patterns and clinical outcomes in high-risk newly diagnosed multiple myeloma patients carrying the 17p deletion: An observational multi-center retrospective study. AB - Del17p is a genomic imbalance occurring in ~7%-10% of myeloma at diagnosis newly diagnosed myeloma patients (NDMM) and comprises a poor prognostic factor. The goal of this study is to analyze real world data and outcomes among NDMM patients carrying 17p deletion. We report an observational, retrospective, multicenter study. Sixty consecutive patients diagnosed with multiple myeloma in the 8 participating centers diagnosed between 1/2008 and 1/2016 proven to carry 17p deletion by means of fluorescence in situ hybridization (FISH) were identified. Most received a bortezomib-based induction, over half underwent autologous hematopoietic cell transplantation (HCT); 30% of the patients gained early access to new novel agents via clinical trials, access programs or private insurance. Overall response rate (ORR) after induction was 85%; 94% for transplant eligible (TE); and 75% for transplant ineligible (NTE), and declined in subsequent treatment lines, 64% achieved >= VGPR. Median overall survival (OS) was 43 months; median progression free survival (PFS) was 11 months, 19 months for TE and 7 for NTE. In multivariate analysis: higher M-Spike, presence of extramedullary disease, and >50% of cells baring del17p were associated with adverse PFS; Autologous HCT and higher hemoglobin were associated with longer PFS; OS was 59 months for patients with early access to newer agents. Older age and higher M-Spike levels were associated with adverse OS, Autologous HCT was associated with favorable OS, 59.7 vs 28.7 months for NTE patients. Despite the improvement achieved with autologous HCT and new novel agents, the prognosis of patients with 17p deletion is still inferior, emphasizing the need for novel approaches. PMID- 29603774 TI - Thirty-two Japanese cases of infantile hemangiomas treated with oral propranolol. AB - Infantile hemangiomas undergo rapid growth during early infancy followed by gradual involution. Infantile hemangiomas sometimes impair vital functions or cause disfigurement. Thirty-two Japanese patients between the ages of 1 and 4 months with proliferating infantile hemangiomas received oral propranolol on an outpatient basis. The success rate (complete or nearly complete resolution) at week 25 was 56% (18/32). Two patients dropped out because of a personal reason and moving out. Recurrence after termination of treatment was seen in six patients. Adverse events occurred in 16 patients. There were no adverse events on day 1 (initiation of treatment at a dose of 1 mg/kg per day) and day 8 (dose increase to 2 mg/kg per day). One patient was hospitalized due to pneumonia, and suspended propranolol for 26 days. Oral propranolol at 2 mg/kg per day is effective and safe in Japanese patients with infantile hemangiomas. PMID- 29603775 TI - Adapting legume crops to climate change using genomic approaches. AB - Our agricultural system and hence food security is threatened by combination of events, such as increasing population, the impacts of climate change, and the need to a more sustainable development. Evolutionary adaptation may help some species to overcome environmental changes through new selection pressures driven by climate change. However, success of evolutionary adaptation is dependent on various factors, one of which is the extent of genetic variation available within species. Genomic approaches provide an exceptional opportunity to identify genetic variation that can be employed in crop improvement programs. In this review, we illustrate some of the routinely used genomics-based methods as well as recent breakthroughs, which facilitate assessment of genetic variation and discovery of adaptive genes in legumes. Although additional information is needed, the current utility of selection tools indicate a robust ability to utilize existing variation among legumes to address the challenges of climate uncertainty. PMID- 29603776 TI - Selective bladder denervation for overactive bladder (OAB) syndrome: From concept to healing outcomes using the ovine model. AB - AIMS: We evaluated a Selective Bladder Denervation (SBD) device, which uses radiofrequency ablation, for the treatment of overactive bladder syndrome in terms of its nerve denervation, ablation characteristics, and post-treatment healing. METHODS: Using the SBD device, eight fresh extirpated ovine bladder trigones were treated (90 degrees C set point for 60 s) and nitroblue tetrazolium viability stained to characterize the ablation. In addition, 12 trigones were treated in vivo with three adjacent ablations and divided into survival cohorts: Day 7, Day 30, and Day 90 to assess the ablations and their associated healing. RESULTS: The ex vivo single trigone ablations had a 7.9 +/- 0.9 mm width and 5.7 +/- 1.0 mm thickness that involved the submucosa, detrusor muscle, adventitia, and vagina. Microscopic viability staining confirmed complete nerve necrosis within the targeted tissue. The in vivo Day 7 trigones supported the ex vivo ablation characteristics and showed up to minimal inflammation, granulation tissue, and collagen fibrosis. Day 30 trigones had essentially absent inflammation and granulation tissue with evolving collagen fibrosis at the ablation's periphery. Day 90 trigones had essentially absent acute inflammation, minimal chronic inflammation, essentially absent granulation tissue, and up to mild collagen fibrosis. No ureteral/urethral alterations, vesico-vaginal fistulas, or other complications were identified. CONCLUSIONS: The SBD device provided a targeted trigone ablation with resultant denervation. The tissue healing timeline followed that expected for a hyperthermic ablation and was characterized by a fibroproliferative healing response with limited inflammation and granulation tissue. The ablations did not impact the overlying bladder mucosal surface. PMID- 29603777 TI - Postoperative survival and early complications after intracranial surgery in dogs. AB - OBJECTIVE: To describe survival and early postoperative outcome after intracranial surgery in dogs. STUDY DESIGN: Retrospective case series. ANIMALS: Fifty client-owned dogs that underwent intracranial surgery. METHODS: Records were searched and analyzed for dogs that underwent intracranial surgery between 2005 and 2015. Signalment, clinical presentation, neurological deficits, concurrent medical conditions, laboratory data, diagnosis, administration of perioperative glucocorticoids or antiepileptic drugs, and specific imaging, surgical, and anesthetic variables were recorded. Risk factors for survival, occurrence of postoperative complications, and hospitalization times were identified with univariate linear and logistic regression, followed by multivariable regression models. RESULTS: All dogs were recovered with a specific protocol in an intensive care unit. Forty-nine of 50 (98%) dogs survived the immediate postoperative period, and 46 of 50 (92%) survived to discharge. Early postoperative neurological deterioration was seen in 45% (22/49) of dogs, and a postoperative complication was diagnosed in 23 of 49 (47%). Nonneurological postoperative complications were seen in 9 of 49 (18%) dogs; the most common consisted of aspiration pneumonia (6/49, 12%). Among variables associated with outcomes, higher postoperative natremia (P = .023) and prolonged hospitalization (P = .024) were associated with the occurrence of postoperative, nonneurological complications. CONCLUSION: The short-term survival rate of this population was excellent. About half of the dogs experienced neurologic deterioration and postoperative complications, and most resolved with treatment. CLINICAL SIGNIFICANCE: In our clinical setting, intracranial surgery in dogs was associated with a high rate of survival and a low rate of severe postoperative complications. PMID- 29603778 TI - Does longer roster lead-time reduce temporary staff usage? A regression analysis of e-rostering data from 77 hospital units. AB - AIMS: Use of temporary nursing staff is contentious and expensive. Using e rostering data from 77 hospital units, this research investigates whether longer roster lead-times reduce temporary staff usage. BACKGROUND: It is commonly assumed that longer roster approval lead-times, the time from when a roster is approved, to when it is worked, result in better, more cost-effective rosters. Consequently, many hospitals target lead-times of 6 weeks, a figure recommended for the UK National Health Service in a recent governmental review. This contrasts with the minimum lead-time advocated by New South Wales Ministry of Health, which advises a shorter lead-time of 2 weeks. Using data from 77 hospital units, this paper explores this assumed relationship. DESIGN: Using data extracted from the e-rostering system of an NHS Acute Foundation Trust, this study uses linear regression analysis to explore the relationship between roster approval lead-time and temporary staff usage. The data were captured over a period of 9 months from 15 February 2016-23 October 2016, a total of 693 rosters. RESULTS/FINDINGS: This research suggests that late roster approval may contribute to as much as 37% of temporary staff usage, while approval 4-6 weeks prior to the roster being worked reduces this to approximately 15%. However, this is only relevant under specific conditions. Importantly, this should be considered before mandating lead-times across all units. CONCLUSIONS: This research implies that the optimum approval lead-time lies between 4-6 weeks; however, given other challenges, achieving this in practice may prove difficult. PMID- 29603779 TI - Characterizing the behavior, uptake, and toxicity of NM300K silver nanoparticles in Caenorhabditis elegans. AB - Using Caenorhabditis elegans as a model organism, we addressed the potential linkage among toxicity of NM300K Ag nanoparticles (AgNPs), their particle size distribution, and the presence of dissolved Ag in the test media. Of the 3 endpoints assessed (growth, fertility, and reproduction), reproduction was the most sensitive, with the 50% effect concentration (EC50) ranging from 0.26 to 0.84 mg Ag L-1 and 0.08 to 0.11 mg Ag L-1 for NM300K and AgNO3 , respectively. Silver uptake by C. elegans was similar for both forms of Ag, whereas bioaccumulation was higher in AgNO3 exposure. The observed differences in toxicity between NM300K and AgNO3 did not correlate with bioaccumulated Ag, which suggests that toxicity is a function of the type of exposing agent (AgNPs vs AgNO3 ) and its mode of action. Before addition of the food source (Escherichia coli), size fractionation revealed that dissolved Ag comprised 13 to 90% and 4 to 8% of total Ag in the AgNO3 and NM300K treatments, respectively. No dissolved Ag was detectable in the actual test media due to immediate Ag adsorption to bacteria. The results of the present study indicate that information on behavior and characterization of exposure conditions is essential for nanotoxicity studies. Environ Toxicol Chem 2018;37:1799-1810. (c) 2018 SETAC. PMID- 29603780 TI - Effect of severity of urinary incontinence on quality of life in women. AB - AIMS: While the effect of different types of incontinence on the quality of life (QoL) has been clearly documented, the information about the impact of incontinence severity on QoL in women is lacking. Therefore, we investigated whether increasingly severe degrees of incontinence were linearly correlated with poorer QoL. METHODS: We included 391 incontinent women and 81 continent volunteers in the study and assessed them in accordance with routine clinical practice. A 24 h pad-weight test was used to objectively quantify the incontinence severity. We then stratified participants according to incontinence type and severity and assessed correlations between incontinence severity and Patient Perception of Bladder Condition (PPBC), International Consultation on Incontinence short-form questionnaire (ICIQ-SF), and King's Health Questionnaire (KHQ) quality of life scores in the entire study population and in individual groups according to incontinence type. RESULTS: Minimal incontinence was associated with significant negative impact on QoL, as measured by all quality of life assement tools. There were nonlinear correlations between scores on individual questionnaires and daily leakage volumes. Stress urinary incontinence had a weaker impact on quality of life than urge or mixed incontinence, as measured by PPBC (P < 0.0001), KHQ part 1 (P < 0.0001), and KHQ part 2 (P < 0.001). Stress urinary incontinence also had a weaker impact on QoL than mixed incontinence as measured by ICI-Q (P = 0.007). CONCLUSIONS: This study demonstrated that even mild urinary leakage significantly reduces the QoL, while subsequent increase in the degree of incontinence has only minimal additional effect. There was no linear correlation between incontinence severity and QoL. PMID- 29603781 TI - Efficacy and safety of mirabegron for the treatment of neurogenic detrusor overactivity-Prospective, randomized, double-blind, placebo-controlled study. AB - AIMS: To assess the efficacy and safety of mirabegron in the treatment of neurogenic detrusor overactivity. METHODS: This prospective, multicenter, randomized, double-blind, placebo-controlled study was conducted in three tertiary centers, and included 78 patients suffering from spinal cord injury or multiple sclerosis. Patients were randomized for Mirabegron 50 mg (Group A) or placebo (Group B). Urodynamic parameters, the 24 h pad-weight test, and patient reported outcomes were assessed. Safety assessments included monitoring the incidence and severity of adverse events. Changes in time and differences between groups were assessed with nonparametric Kruskal-Wallis one-way analysis of variance; P <= 0.05 was considered statistically significant. RESULTS: In total, 66 patients were eligible for inclusion in the final analysis. There was a significant increase of volume at the first detrusor contraction (P = 0.00047) and an improvement in bladder compliance (P = 0.0041) in the mirabegron group compared with the placebo-treated group, whereas the increase in cystometric capacity did not reach statistical significance (P = 0.061). There was a clear tendency to reduced urine leakage (P = 0.056) in Group A. There were significant changes in all the patient-reported outcomes, favoring the mirabegron group. The incidence of drug-related adverse events was 3.13%. CONCLUSIONS: Mirabegron (50 mg) improved both urodynamic variables and patient-reported outcomes in patients with NDO. The treatment was tolerated well. PMID- 29603782 TI - Observation of untoward 3 Jcc correlations in 1,1-ADEQUATE spectra of pyrimidine analogs: Avoiding potential interpretation pitfalls. AB - Recently, it has been reported that large n JCC correlations can sometimes be observed in 1,1-ADEQUATE spectra with significant intensity, which opens the possibility of structural misassignment. In this work, we have focused on pyrimidine-based compounds, which exhibit multiple bond correlations in the 1,1 ADEQUATE experiment as a consequence of 3 JCC coupling constants greater than 10 Hz. Results are supported by both the experimental measurement of 3 JCC coupling constants in question using J-modulated-ADEQUATE and density functional theory calculations. PMID- 29603783 TI - Successful treatment of cutaneous phaeohyphomycosis caused by Exophiala lecanii corni with voriconazole. PMID- 29603784 TI - A novel Tc-99m and fluorescence-labeled arginine-arginine-leucine-containing peptide as a multimodal tumor imaging agent in a murine tumor model. AB - We developed a Tc-99m and TAMRA-labeled peptide, Tc-99m arginine-arginine-leucine (RRL) peptide (TAMRA-GHEG-ECG-RRL), to target tumor cells and evaluated the diagnostic performance of Tc-99m TAMRA-GHEG-ECG-RRL as a dual-modality imaging agent for tumor in a murine model. TAMRA-GHEG-ECG-RRL was synthesized using Fmoc solid-phase peptide synthesis. Binding affinity and in vitro cellular uptake studies were performed. Gamma camera imaging, biodistribution, and ex vivo imaging studies were performed in murine models with PC-3 tumors. Tumor tissue slides were prepared and analyzed with immunohistochemistry using confocal microscopy. After radiolabeling procedures with Tc-99m, Tc-99m TAMRA-GHEG-ECG-RRL complexes were prepared in high yield (>96%). The Kd of Tc-99m TAMRA-GHEG-ECG-RRL determined by saturation binding was 41.7 +/- 7.8 nM. Confocal microscopy images of PC-3 cells incubated with TAMRA-GHEG-ECG-RRL showed strong fluorescence in the cytoplasm. Gamma camera imaging revealed substantial uptake of Tc-99m TAMRA-GHEG ECG-RRL in tumors. Tumor uptake was effectively blocked by the coinjection of an excess concentration of RRL. Specific uptake of Tc-99m TAMRA-GHEG-ECG-RRL was confirmed by biodistribution, ex vivo imaging, and immunohistochemistry stain studies. In conclusion, in vivo and in vitro studies revealed substantial uptake of Tc-99m TAMRA-GHEG-ECG-RRL in tumors. Tc-99m TAMRA-GHEG-ECG-RRL has potential as a dual-modality tumor imaging agent. PMID- 29603785 TI - Alpha-1 adrenergic antagonists, 5-alpha reductase inhibitors, phosphodiesterase type 5 inhibitors, and phytotherapic compounds in men with lower urinary tract symptoms suggestive of benign prostatic obstruction: A systematic review and meta analysis of urodynamic studies. AB - AIMS: To perform a systematic review and meta-analysis of studies evaluating the urodynamic outcomes of alpha-1 adrenergic antagonists (ABs), 5-alpha reductase inhibitors (5-ARIs), phosphodiesterase type 5 inhibitors (PDE5is), and phytotherapic compounds in patients with lower urinary tract symptoms related to benign prostatic obstruction (LUTS/BPO). METHODS: A systematic review of PubMed/Medline, ISI Web of Knowledge, and Scopus databases was performed in June 2017. We included full papers that met the following criteria: original research; English language; human studies; enrolling LUTS/BPO patients; reporting maximum urinary flow (Qmax), and detrusor pressure at maximum urinary flow (PdetQmax). The primary endpoint was variation in bladder outlet obstruction index (BOOI). Secondary endpoints were variations in Qmax and PdetQmax. RESULTS: Twenty-three studies involving 1044 patients were included in the final analysis. Eighteen, three, two, and one study evaluated the urodynamic outcomes of ABs, 5-ARIs, PDE5is, and phytotherapic compounds, respectively. BOOI, PdetQmax, and Qmax improved in a statistically significant manner in patients receiving ABs and in those receiving 5-ARIs. The overall pooled data showed a mean BOOI change of 15.40 (P < 0.00001) and of -10.55 (P = 0,004) for ABs and 5-ARIs, respectively. Mean PdetQmax and Qmax changes were:12.30 cm H2 O (P < 0.00001) and +2.27 ml/s (P < 0.00001) for ABs and -9.63 cm H2 O (P = 0.05), and +1.18 mL/s (P = 0.04) for 5 ARIs. PDE5is and phytotherapic compounds had no significant effects on urodynamic parameters. CONCLUSIONS: ABs and 5-ARIs efficiently improve BOOI in men with LUTS/BPO. Both treatments are associated with a clinically significant decrease in PdetQmax but only marginal improvements in Qmax. PMID- 29603786 TI - Cutaneous hydrophilic polymer embolism accompanied by acute renal failure. PMID- 29603787 TI - Intraoperative use of indocyanine green angiography for selecting the more reliable perforator of the anterolateral thigh flap: A comparison study. AB - INTRODUCTION: Anatomical variability of anterolateral thigh flap (ALT) perforators has been reported. The aim of this study is to assess if the use of intraoperative indocyanine green angiography (iICGA) can help surgeons to choose the ALT flap best perforator to be preserved. PATIENTS AND METHODS: A retrospective study was conducted in 28 patients with open tibial fracture, following a road traffic crash, who had undergone ALT flap. Patients were classified into two groups: ICGA group (iICGA was used to select the more reliable perforator) and control group. The mean tissue loss size of the ICGA group (n = 13, 11 men and 2 women, mean age: 52 +/- 6 years) was of 16.6 cm * 12.2 cm. The mean defect size of the control group (n = 15, 14 men and 1 women, mean age: 50 +/- 5.52 years) was of 15.3 cm * 11.1 cm. Statistical analysis was performed to analyze and compare the results. RESULTS: ICGA allowed preserving only the most functional perforator, that provided the best ALT flap perfusion in 10 out of the 13 cases (77%). ICGA allowed a significant operative time reduction (160 +/- 23 vs. 202 +/- 48 minutes; P < .001). One case of distal necrosis was observed in the ICGA group (mean follow-up 12.3 months), while partial skin necrosis occurred in three cases of the control group (mean follow-up 13.1 months); P = .35. No additional coverage was required and a successful bone healing was observed in both groups. CONCLUSIONS: These findings suggest that iICGA is an effective method that allows to select the most reliable ALT flap perforators and to reduce operative time. PMID- 29603788 TI - Perspectives on periviability counselling and decision-making differed between neonatologists in the United States and the Netherlands. AB - AIM: American guidelines suggest that neonatal resuscitation be considered at 23 weeks of gestation, one week earlier than in the Netherlands, but how counselling practices differ at the threshold of viability is unknown. This pilot study compared prenatal periviability counselling in the two countries. METHODS: In 2013, a cross-sectional survey was sent to 121 Dutch neonatologists as part of a nationwide evaluation of prenatal counselling. In this pilot study, the same survey was sent to a convenience sample of 31 American neonatologists in 2014. The results were used to compare the organisation, content and decision-making processes in prenatal counselling at 24 weeks of gestation between the two countries. RESULTS: The survey was completed by 17 (55%) American and 77 (64%) Dutch neonatologists. American neonatologists preferred to meet with parents more frequently, for longer periods of time, and to discuss more intensive care topics, including long-term complications, than Dutch neonatologists. Neonatologists from both countries preferred shared decision-making when deciding whether to initiate intensive care. CONCLUSION: Neonatologists in the United States and the Netherlands differed in their approach to prenatal counselling at 24 weeks of gestation. Cross-cultural differences may play a role. PMID- 29603789 TI - Relationship between serum quantitative HBsAg and HBV DNA levels in chronic hepatitis B patients. AB - Serum hepatitis B surface antigen (HBsAg) level has been developed as an important marker to predict treatment outcome recent years. The authors aimed to identify the correlation between quantitative HBsAg and hepatitis B virus (HBV) DNA level in chronic hepatitis B (CHB) patients and explore whether quantitative HBsAg can be used as a surrogate marker of serum HBV DNA for CHB patients. One hundred seventy-three patients were included in this study. Patients were divided into two groups: Hepatitis B e antigen (HBeAg) positive and negative patients. There was a positive correlation between quantitative HBsAg and HBV DNA level in HBeAg positive patients (r = 0.509, P < 0.001) and poor correlation in HBeAg negative patients (r = 0.176, P = 0.096). Interestingly, completely no correlation (r = -0.01, P = 0.994) was found in younger HBeAg negative patients (<40 years old), whereas in older HBeAg negative patients (>40 years old) there is a positive correlation (r = 0.448, P = 0.003). Mean HBsAg titer and Alanine aminotransferase (ALT) level were significantly higher in HBeAg positive group (3.81 log10 IU/mL; 105 IU/mL) than in negative group (2.85 log10 IU/mL; 32 IU/mL) (P < 0.001). We concluded that quantitative HBsAg could reflect HBV DNA level in HBeAg positive patients, but could not surrogate for HBV DNA level in HBeAg negative patients. Our study improves understanding of the relationship between HBsAg titers and HBV DNA levels in CHB patient and may have implications for future treatment algorithms evaluating the HBsAg titers in both HBeAg positive and negative patients. PMID- 29603790 TI - Arthroscopic removal of osteochondral fragments in the dorsal pouch of the proximal intertarsal joint in 29 horses. AB - OBJECTIVE: To describe the radiographic and surgical findings of horses with osteochondral fragments (OCF) in the proximal intertarsal joint (PIJ) and to detail the technique for arthroscopic fragment retrieval and report outcomes. STUDY DESIGN: Retrospective case series. ANIMALS: Twenty-nine horses (32 tarsi) with OCF in the PIJ. METHODS: Medical records of horses with radiographic evidence of OCF in the PIJ were reviewed. Clinical features, number of fragments, location, arthroscopic appearance, and outcome were recorded. Technical modifications with visual aids specific to this arthroscopic technique are described. RESULTS: Twenty-seven horses (93%) had radiographic evidence of osteochondritis dissecans lesions in the tarsocrural joint (TCJ). OCF were most commonly located distal to the medial trochlear ridge of the talus. In all cases, fragments were successfully retrieved with a technique based on exposing the fragments after resection of the proximal intertarsal joint capsule (PIJC). Fragments were visible from the TCJ prior resection of the PIJC in 4 of 32 tarsi. A third portal was created to access fragments located distal to the lateral trochlear ridge in 3 of 32 tarsi. Moderate intra-articular bleeding occurred when the PIJC was resected in 3 of 32 tarsi. One horse had postoperative swelling that resolved with conservative medical management. All horses with long-term follow up available (16/29) started training or returned to their athletic career. CONCLUSION AND CLINICAL SIGNIFICANCE: The arthroscopic technique based on resection of PIJC was effective in retrieving OCF in the PIJ and was associated with minor complications. The clinical relevance of these fragments in the PIJ remains unknown. PMID- 29603791 TI - Observation study showed that the continuity of skin-to-skin contact with low birthweight infants in Uganda was suboptimal. AB - AIM: Kangaroo mother care (KMC) is a safe and effective method of reducing neonatal mortality in resource-limited settings, but there has been a lack of data on the duration of skin-to-skin contact (SSC) in busy, low-resource newborn units. Previous studies of intermittent KMC suggest the duration of SSC ranged from 10 minutes to 17 hours per day. METHODS: This was an observational study of newborn infants born weighing less than 2000 g, which collected quantitative data on SSC over the first week after birth. The study took place in July 2016 in the newborn unit of a low-resource facility in Uganda. RESULTS: The mean daily duration of SSC over the first week after birth was three hours. This differed significantly from the World Health Organization recommendation of at least 20 hours of SSC per day. SSC was provided by mothers most of the time (73.5%), but other family members also took part, especially on the day of birth. CONCLUSION: Our study found a disappointingly low daily duration of SSC in this Ugandan newborn unit. However, advocacy and community education of SSC may help to decrease the stigma of KMC, improve overall acceptance and reduce the age at SSC initiation. PMID- 29603792 TI - Mid-regional pro-adrenomedullin could be a biomarker of severity in bronchiolitis. PMID- 29603793 TI - Head-up tilt test provokes dynamic alterations in total peripheral resistance and cardiac output in children with vasovagal syncope. AB - AIM: This study examined the total peripheral vascular resistance (TPVR) and cardiac output changes due to the head-up tilt test (HUTT) in children with vasovagal syncope (VVS). METHODS: From December 2013 to January 2016, we recruited 77 children diagnosed with VVS group at Peking University First Hospital, China, and 28 children without VVS provided the control group. Heart rate, blood pressure, TPVR, cardiac output and baroreflex sensitivity were monitored during the HUTT. RESULTS: In the supine position, TPVR and baroreflex sensitivity were higher in the patients with VVS than the controls, but cardiac output did not differ between the two groups. There were obvious increases in the VVS patients from TPVR in the supine position to the prepositive response period (p < 0.05), then the positive response period (p < 0.01). However, we noted the opposite trend in cardiac output, from the supine position to the prepositive response period (p < 0.01) then the positive response period (p < 0.01). CONCLUSION: During HUTT, children with VVS demonstrated increases in TPVR but decreases in cardiac output, during the transition from the supine position to the positive response. This response might be involved in the pathogenesis of VVS. PMID- 29603794 TI - Identification of metabolites in plasma for predicting survival in glioblastoma. AB - Circulating metabolomics profiling holds prognostic potential. However, such efforts have not been extensively carried out in glioblastoma. In this study, two step (training and testing) metabolomics profiling was conducted from the plasma samples of 159 glioblastoma patients. Metabolomics profiling was tested for correlation with 2-year overall and disease-free survivals. Arginine, methionine, and kynurenate levels were significantly associated with 2-year overall survival in both the training and testing sets. In the combined sets, elevated levels of arginine and methionine were associated with a 34% and 37% increased probability whereas kynurenate was associated with a 55% decreased probability of 2-year overall survival. These three metabolites were also significantly associated with 2-year disease-free survival. Risk scores were generated using the linear combination of levels of these significant metabolites. Glioblastoma patients with a high-risk score exhibited a 2.41-fold decreased probability of 2-year overall survival (hazard ratio (HR) = 2.41; 95% Confidence Interval (CI) = 1.20 4.93) and a 3.17-fold decreased probability of 2-year disease free survival (HR = 3.17, 95%CI = 1.42-7.54) relative to those with a low-risk score. In conclusion, we identified a unique plasma metabolite profile that is predictive of glioblastoma prognosis. PMID- 29603795 TI - Optia(r) continuous mononuclear collection (CMNC) system is a safe and efficient system for hematopoietic progenitor cells-apheresis (HPC-a) collection and yields a lower product hematocrit (HCT%) than the COBE(r) spectra system: A retrospective study. AB - PURPOSE: We evaluated the Optia(r) continuous mononuclear collection (CMNC) system for hematopoietic progenitor cell-apheresis (HPC-A) collection (Terumo BCT, Lakewood, CO) compared to the COBE(r) Spectra (Terumo BCT, Lakewood, CO), including both large volume leukapheresis (LVL) and non-LVL collections. METHODS: We performed a retrospective data analysis of all autologous HPC-A collections with the Optia(r) CMNC system (n = 93; LVL = 59, non-LVL = 34) since implementation at our institution and compared it with a similar number of concurrent collections utilizing the COBE(r) Spectra (n = 96; LVL = 68, non-LVL = 28). The population studied included multiple myeloma (62 patients/171 collections) and lymphoma (5 patients/18 collections). Mobilization was achieved using chemotherapy + G-CSF (n = 108), chemotherapy + G-CSF + plerixafor (n = 67), G-CSF alone (n = 10), or G-CSF + plerixafor (n = 4). Based on our minimum predicted collection formula and the collection goal, 7-30 L of whole blood was processed. Per protocol, a minimum of 2 days of collection was performed. RESULTS: HPC-A collected on Optia(r) CMNC had lower %HCT than those collected on COBE(r) Spectra (3.7 versus 4.3%, P = .029). There were no statistically significant differences between the two devices for other variables examined, including preapheresis WBC count and CD34+ cell count, procedure time, whole blood volume processed, collection efficiency (CE2), % platelet loss and throughput. CE2 for both devices was higher when <30 L of whole blood volume was processed. A linear correlation was noted between the preapheresis CD34+ cell count and CD34+ cells collected. No adverse events or bleeding episodes were noted, even when acetyl salicyclic acid (ASA) was given. CONCLUSIONS: Optia(r) CMNC system is equivalent to the COBE(r) Spectra, with significantly lower product HCT%. PMID- 29603796 TI - A comprehensive protocol for chemical analysis of flame combustion emissions by secondary ion mass spectrometry. AB - RATIONALE: Time-of-flight secondary ion mass spectrometry (TOF-SIMS) is used to provide detailed information on the surface chemical composition of soot. An analytical protocol is proposed and tested on a laboratory flame, and the results are compared with our previous measurements provided by two-step laser mass spectrometry (L2MS). METHODS: This work details: (1) the development of a dedicated apparatus to sample combustion products from atmospheric flames and deposit them on substrates suitable for TOF-SIMS analysis; (2) the choice of the deposition substrate and the material of the sampling line, and their effect on the mass spectra; (3) a method to separate the contributions of soot and condensable gas based on impact deposition; and finally (4) post-acquisition data processing. RESULTS: Compounds produced during flame combustion are detected on the surface of different deposition substrates and attributed a molecular formula based on mass defect analysis. Silicon and titanium wafers perform similarly, while the surface roughness of glass microfiber filters results in a reduced mass resolution. The mass spectra obtained from the analysis of different locations of the deposits obtained by impaction show characteristic patterns that are attributed to soot/condensable gas. CONCLUSIONS: A working method for the analysis of soot samples and the extraction of useful data from mass spectra is proposed. This protocol should help to avoid common experimental issues like sample contamination, while optimizing the setup performance by maximizing the achievable mass resolution. PMID- 29603797 TI - Reductions in otitis and other respiratory tract infections following childhood pneumococcal vaccination. AB - AIM: Streptococcus pneumoniae commonly causes respiratory tract infections including acute otitis media and pneumonia. In this study, we evaluated the impact of general infant pneumococcal vaccination, introduced in Sweden in 2009, on respiratory tract infections. METHODS: We studied the incidence of respiratory tract infections and antibiotic consumption in Vasterbotten County, Sweden, during 2005-2014 using the County Council's diagnosis register. RESULTS: Comparing the prevaccination period of 2005-2008 to 2014, the incidences of all cause acute otitis media decreased significantly in children aged 0-4 and five years to 17 years, by 41.5% and 20.9%, respectively. In addition, we also noted significant reductions in sinusitis and other upper respiratory tract infections, and some reductions in adults. Antibiotic consumption for upper respiratory tract infections decreased by 37.1%, with the largest decrease occurring in children aged 0-4 years. For pneumonia, the incidence significantly decreased by 28.6% for children aged 0-4 years, with no significant changes in older children or adults. CONCLUSION: Pneumococcal vaccination was followed by reduced incidence of upper respiratory tract infections and antibiotic consumption in vaccinated children, with some indications of possible herd immunity. For pneumonia, a major reduction was noted limited to the youngest children. PMID- 29603798 TI - The start of a new wave: Developments in proteasome inhibition in multiple myeloma. AB - Multiple myeloma (MM) accounts for 10% of hematological cancers. Stem cell transplantation remains the cornerstone of first-line treatment for eligible patients, but historically, pharmaceutical treatment options for MM have been limited. The proteasome was identified as a target for MM therapy in the early 2000s and, in 2004, the boronic acid proteasome inhibitor bortezomib gained European approval. Bortezomib now plays a major role in MM treatment, but the duration of its use can be limited by toxicities such as peripheral neuropathy and the development of resistance. A new generation of proteasome inhibitors has since entered the treatment landscape: carfilzomib, an epoxyketone-based agent with a distinct mode of action, high clinical efficacy, and lower levels of peripheral neuropathy compared with bortezomib, received approval in 2015 for use in patients with relapsed and/or refractory MM (RRMM). Ixazomib, a second generation, orally administered, boronic acid proteasome inhibitor, has also been approved for use in patients with RRMM. In just over a decade, proteasome inhibitor-based regimens have become an integral component of MM treatment; with more proteasome inhibitors in development, this remains a vibrant research area with potential to improve the lives of patients with MM in the years to come. PMID- 29603799 TI - Impact of white blood cells on thrombotic risk in patients with optimized platelet count in essential thrombocythemia. AB - OBJECTIVES: Risk of thrombosis is significantly enhanced by both elevated platelet (PLT) and white blood cell (WBC) counts according to a retrospective analysis of a large anagrelide registry in thrombocythemic MPN patients. We were interested in the impact of elevated WBC counts on thrombosis risk in patients where PLT counts were reduced below the calculated cutoff of 574.5 G/L by treatment with anagrelide. METHODS: Cox regression analysis and Kaplan-Meier plot were applied on all patients in the registry with optimized PLT counts. RESULTS: Using the calculated cutoff of 9.66 G/L for WBC, Cox regression analysis revealed a clear influence of elevated WBC counts on the occurrence of a major thrombotic event (P = .012). A Kaplan-Meier plot revealed a markedly shorter time to a major thrombotic event for patients with WBC counts above the cutoff (P = .001). CONCLUSIONS: These data suggest that additional correction of elevated WBC counts is mandatory in patients with optimally managed PLT counts to reduce thrombotic risk. This study is the first investigation in a prospectively observed large patient cohort which was treated homogenously allowing for evaluation of single parameters for an effect on thrombophilia. PMID- 29603801 TI - Bladder overdistension with polyuria in a hypertensive rat model. AB - AIMS: Polyuria can lead to progressive chronic bladder overdistension. The impact of polyuria on the bladder has been extensively studied in settings of either diabetes or sucrose diuresis in animals. The goal of this study was to investigate the outcomes of polyuria in a hypertension setting. MATERIALS AND METHODS: Male Dahl/SS rats, a hypertension model, received a high-salt or normal diet for 6 weeks. Twenty-four-hour water intake, micturition patterns, and blood pressures were recorded biweekly. Conscious cystometry was carried out at the end of this period. Bladders were collected to measure contractile force and for histological analysis. Paired t-tests were used to compare changes between Week 0 and Week 6 within each group. Unpaired t-tests were used for comparisons between groups for all parameters at Week 6. RESULTS: Six weeks of high-salt diet significantly increased water intake and total urine. Blood pressures and volume of urine per micturition was higher in rats on high-salt diet. Bladder overdistension in the high-salt diet group was confirmed by cystometry, shown by a significantly higher bladder capacity, and compliance. No difference in detrusor contractility was observed between both groups. Collagen content was significantly higher in the lamina propria of the high-salt group compared to the normal group, while the opposite was observed in the muscularis. CONCLUSIONS: Polyuria, in a hypertension context, leads to changes in bladder morphology and function. These findings help clarify the deleterious clinical impact of polyuria on voiding function, highlighting the variable consequences of bladder overdistension according to the underlying pathology. PMID- 29603800 TI - Remodelling and inflammation in preschoolers with severe recurrent wheeze and asthma outcome at school age. AB - BACKGROUND: The influence of airway remodelling and inflammation in preschoolers with severe recurrent wheeze on asthma outcomes is poorly understood. OBJECTIVE: To assess their association with asthma symptoms and lung function at school age. METHODS: Preschoolers (38.4 months) initially investigated with bronchial biopsies were re-assessed for asthma symptoms and lung function at school age. RESULTS: Thirty-six of 49 preschoolers (73.5%) were assessed at 10.9 years. Twenty-six (72.2%) had persistent asthma. Submucosal eosinophil counts were higher in children with severe exacerbations at school age than in those without (16/0.1 mm2 [11.2-30.4] vs 8/0.1 mm2 [2.4-17.6], P = .02), and correlated with the number of severe exacerbations (P = .04, r = .35). Submucosal neutrophil counts correlated with FEV1/FVC (P < .01, r = .47) and FEF25-75% predicted (P = .02, r = .43). Airway smooth muscle (ASM) area correlated with FEV1/FVC (P < .01, r = .51). Vessel numbers negatively correlated with FEV1% predicted and FEV1/FVC (P = .03, r = -.42; P = .04, r = -.41; respectively) and FEF25-75% predicted (P = .02, r = -.46). CONCLUSION: Eosinophilic inflammation in preschoolers with severe recurrent wheeze might be predictive of future severe exacerbations, neutrophilia might be associated with better lung function. Changes in ASM and vascularity might affect lung function at school age. PMID- 29603802 TI - Paediatric antiepileptic polytherapy: systematic review of efficacy and neurobehavioural effects and a tertiary centre experience. AB - AIM: This paper presents the prevalence of antiepileptic polytherapy at a single tertiary institution and systematically reviews the evidence base for its efficacy and neurobehavioural safety in children. METHOD: Prevalence of antiepileptic polypharmacy was determined from pharmacy dispensing records at a paediatric tertiary hospital and neurobehavioural comorbidities quantified through casenote review; comparison is made with studies evaluating the neurobehavioural safety of antiepileptic polytherapy, identified via systematic literature review. RESULTS: Amongst 262 patients at the hospital, 117 (44.7%) were prescribed polytherapy; with patients having an intellectual disability statistically more likely to be prescribed polytherapy than those without (70.5% vs 40.6%; p < 0.0001). Systematic review identified no trials addressing the efficacy or neurobehavioural outcomes of polytherapy as a primary outcome. Several observational studies identified associations between polytherapy and neurobehavioural adverse outcomes such as anxiety and behavioural disturbance. Observational studies also suggest that a reduction in polytherapy load is generally not associated with worsening seizure control. CONCLUSION: Whilst antiepileptic polytherapy is common practice within paediatric epilepsy cohorts attending tertiary care institutions, evidence is lacking to support its efficacy. There are significant practical difficulties to undertaking randomised controlled trials within this population. Nonetheless, clinicians must consider that adverse neurobehavioural consequences of polytherapy might outweigh benefits to seizure control. PMID- 29603803 TI - Estimating N2 O processes during grassland renewal and grassland conversion to maize cropping using N2 O isotopocules. AB - RATIONALE: Enhanced nitrous oxide (N2 O) emissions can occur following grassland break-up for renewal or conversion to maize cropping, but knowledge about N2 O production pathways and N2 O reduction to N2 is very limited. A promising tool to address this is the combination of mass spectrometric analysis of N2 O isotopocules and an enhanced approach for data interpretation. METHODS: The isotopocule mapping approach was applied to field data using a delta15 NspN2O and delta18 ON2O map to simultaneously determine N2 O production pathways contribution and N2 O reduction for the first time. Based on the isotopic composition of N2 O produced and literature values for specific N2 O pathways, it was possible to distinguish: (i) heterotrophic bacterial denitrification and/or nitrifier denitrification and (ii) nitrification and/or fungal denitrification and the contribution of N2 O reduction. RESULTS: The isotopic composition of soil emitted N2 O largely resembled the known end-member values for bacterial denitrification. The isotopocule mapping approach indicated different effects of N2 O reduction on the isotopic composition of soil-emitted N2 O for the two soils under study. Differing N2 O production pathways in different seasons were not observed, but management events and soil conditions had a significant impact on pathway contribution and N2 O reduction. N2 O reduction data were compared with a parallel 15 N-labelling experiment. CONCLUSIONS: The field application of the isotopocule mapping approach opens up new prospects for studying N2 O production and consumption of N2 O in soil simultaneously based on mass spectrometric analysis of natural abundance N2 O. However, further studies are needed in order to properly validate the isotopocule mapping approach. PMID- 29603804 TI - Optimism, proactive coping and quality of life among nurses: A cross-sectional study. AB - AIMS AND OBJECTIVES: To assess the optimism and proactive coping use of nurses and examined their influence on quality of life. BACKGROUND: Nurses are often exposed to challenging situations in the clinical area, which may negatively impact the quality of life of nurses. Hence, being optimistic and proactive may assist nurses to develop a positive outlook towards life, improve overall health, achieve high longevity and low stress levels, and acquire effective coping skills. DESIGN: A descriptive, cross-sectional design. METHODS: A convenience sample of 227 nurses working in the two hospitals in the northern Philippines was surveyed in this study using the Revised Life Orientation Test, Proactive Coping Subscale and World Health Organization Quality of Life-BREF. A multivariate multiple regression analysis was performed to examine the multivariate effect of the demographic characteristics, optimism and proactive coping of respondents on the four dimensions of quality of life. RESULTS: The findings indicate that the nurses had an above-average level of optimism and use of proactive coping. Associations between some of the nurses' demographic and work-related variables and their optimism and proactive coping were established. The nurses reported that their highest quality of life was in the social relationship domain while physical domain was rated the poorest dimension. Optimism and proactive coping along with gender, marital status and type of hospital showed a statistically significant multivariate effect on the four domains of quality of life. CONCLUSIONS: Optimism and proactive coping when dealing with work-related stresses have a positive impact on the quality of life of nurses. RELEVANCE TO CLINICAL PRACTICE: This study highlights the importance of optimism and proactive coping in ensuring high levels of quality of life among nurses. The findings can inform the creation of policies and interventions to ensure the highest level of well-being among nurses, thereby allowing them to better perform their duty of providing quality nursing care. PMID- 29603805 TI - Resistance band training or general exercise in multidisciplinary rehabilitation of low back pain? A randomized trial. AB - Multidisciplinary biopsychosocial rehabilitation has been recommended for chronic low back pain (LBP), including physical exercise. However, which exercise modality that is most advantageous in multidisciplinary biopsychosocial rehabilitation is unclear. In this study, we investigated whether multidisciplinary biopsychosocial rehabilitation could be more effective in reducing pain-related disability when general physical exercise was replaced by strength training in the form of progressive resistance training using elastic resistance bands. In this single-blinded (researchers), randomized controlled trial, 99 consenting adults with moderate-to-severe non-specific LBP were randomized to three weeks of multidisciplinary biopsychosocial rehabilitation with either general physical exercise or progressive resistance band training and were then instructed to continue with their respective home-based programs for nine additional weeks, in which three booster sessions were offered. The primary outcome was between-group difference in change on the Oswestry Disability Index (ODI) at 12 weeks. Due to early dropouts, data from 74 participants (mean age: 45 years, 57% women, mean ODI: 30.4) were obtained at baseline, 61 participants were followed-up at 3 weeks, and 46 at 12 weeks. There was no difference in the change in ODI score between groups at 12 weeks (mean difference 1.9, 95% CI: -3.6, 7.4, P = .49). Likewise, the change in secondary outcomes did not differ between groups, except for the patient-specific functional scale (0-10), which favored general physical exercise (mean difference 1.4, 95% CI: 0.1, 2.7, P = .033). In conclusion, this study does not support that progressive resistance band training compared to general physical exercise improve outcomes in multidisciplinary biopsychosocial rehabilitation for patients with non-specific LBP. PMID- 29603806 TI - Glucose concentrations after insulin-induced hypoglycemia and glycemic variability in healthy and diabetic cats. AB - BACKGROUND: Little information is available about posthypoglycemic hyperglycemia (PHH) in diabetic cats, and a causal link between hypoglycemia and subsequent hyperglycemia is not clear. Fluctuations in blood glucose concentrations might only represent high glycemic variability. HYPOTHESIS: Insulin induces PHH in healthy cats, and PHH is associated with poorly regulated diabetes and increased glycemic variability in diabetic cats. ANIMALS: Six healthy cats, 133 diabetic cats. METHODS: Insulin (protamine-zinc and degludec; 0.1-0.3 IU/kg) administered to healthy cats. Blood glucose curves were generated with portable glucose meter to determine the percentage of curves with PHH. Data from insulin-treated diabetic cats with blood glucose curves showing hypoglycemia included data of cats with and without PHH. Post-hypoglycemic hyperglycemia was defined as blood glucose concentrations <4 mmol/L followed by blood glucose concentrations >15 mmol/L within 12 hours. Glycemic variability was calculated as the standard deviation of the blood glucose concentrations. RESULTS: In healthy cats, all insulin doses caused hypoglycemia but PHH was not observed; glycemic variability did not differ between insulin preparations. Among diabetic cats with hypoglycemia, 33 (25%) had PHH. Compared with cats without PHH, their daily insulin dose was higher (1.09 +/- 0.55 versus 0.65 +/- 0.56 IU/kg; P < .001), serum fructosamine concentration was higher (565 +/- 113 versus 430 +/- 112 umol/L; P < .001), remission was less frequent (10% versus 56%; P < .001), and glycemic variability was larger (8.1 +/- 2.4 mmol/L versus 2.9 +/- 2.2 mmol/L; P < .001). CONCLUSIONS AND CLINICAL IMPORTANCE: Insulin-induced hypoglycemia did not cause PHH in healthy cats but it occurred in 25% of diabetic cats with hypoglycemia, particularly when diabetes was poorly controlled. Glycemic variability was increased in cats with PHH. PMID- 29603807 TI - Factors associated with undiagnosed obstructive sleep apnoea among hypertensive patients: A multisite cross-sectional survey study in Taiwan. AB - AIMS AND OBJECTIVES: To investigate the distribution and risk factors associated with undiagnosed obstructive sleep apnoea among hypertensive patients. BACKGROUND: Obstructive sleep Apnoea has been deemed a cardinal risk factor affecting cardiovascular event, and the condition is still frequently overlooked clinically. The lack of advanced diagnosis often causes hypertensive patients with obstructive sleep apnoea to miss opportunities for preventing chronic diseases. DESIGN: A cross-sectional design. METHODS: A total of 215 hypertensive participants were recruited from the cardiovascular outpatients of medical centre in northern and middle Taiwan. The Chinese version of Pittsburgh Sleep Quality Index, the Chinese version of the Epworth Sleep Scale and a portable sleep monitoring device were used for data collection. Logistic regression analysis was conducted to identify the factors affecting hypertensive patients with obstructive sleep apnoea, and a multinomial logistic regression analysis was used to examine the major influence factors for each obstructive sleep apnoea severity level. RESULTS: 81.9% of the hypertensive participants were found having obstructive sleep apnoea. Concerning to the obstructive sleep apnoea severity, 50.0% of participants had mild obstructive sleep apnoea. After controlling the confounding variables, the supine position (odds ratio, 1.04; 95% CI, 1.01-1.07), SO2 (odds ratio, 0.58; 95% CI, 0.38-0.89) and oxygen desaturation index (odds ratio, 2.70; 95% CI, 1.18-6.18) were significantly associated with obstructive sleep apnoea. Furthermore, severe obstructive sleep apnoea was significantly correlated with gender (odds ratio, 0.04; 95% CI, 0.00-0.66), excessive daytime sleepiness (odds ratio, 20.27; 95% CI, 1.58-26.97) and oxygen desaturation index (odds ratio, 4.05; 95% CI, 1.86-8.81). CONCLUSIONS: Nearly 82% of the hypertensive participants were found having undiagnosed obstructive sleep apnoea, and 80% of them were mild or moderate severity. Oxygen desaturation index, SO2 and the supine position were found to be major predictors for obstructive sleep apnoea. Remarkably, oxygen desaturation index was the most significant predictor for mild, moderate and severe obstructive sleep apnoea. RELEVANCE TO CLINICAL PRACTICE: Healthcare providers should enhance their sensitivities to hypertensive patients at a high risk for obstructive sleep apnoea by actively assessing common obstructive sleep apnoea symptoms and providing strategies to alleviate obstructive sleep apnoea symptoms. PMID- 29603808 TI - Impact of timing on soft tissue augmentation during implant treatment: A systematic review and meta-analysis. AB - BACKGROUND: To achieve a predictable esthetic and functional outcome, soft tissue augmentation has become popular in implant treatment. OBJECTIVES: The aim of this systematic review and meta-analysis was to assess the influence of different timing for soft tissue augmentation during implant treatment on soft tissue conditions and its stability. MATERIAL AND METHODS: Electronic and manual searches for articles written in English up to September 2017 were performed by two independent reviewers. Human clinical studies with the purpose of evaluating outcomes (at least 3-month follow-up) of autogenous soft tissue graft for augmentation during implant treatment, either simultaneous or after implant placement (staged), were included. Cumulative changes of keratinized tissue width (KTW), soft tissue thickness (STT), and mid-buccal mucosal recession (MR) data were analyzed with a random-effects model to compare the postoperative outcomes. RESULTS: Twenty-nine human studies (eight randomized clinical trials, six cohort studies, and 15 case series) that met the inclusion criteria were included. For the overall data, the weighted mean STT gain (1 year after surgery) was 1.03 mm (95% CI: 0.78-1.29 mm), among which the simultaneous group was 1.12 mm (95% CI: 0.75-1.49 mm) and staged group (3-6 months after implant placement) was 0.95 mm (95% CI: 0.58-1.31 mm). There was no statistically significant difference in KTW and MR between 3 months and more than 3 months after surgery. CONCLUSIONS: This review revealed that the stability of soft tissue, in terms of KTW and mid-buccal MR, can be obtained 3 months after surgery. There is no difference between simultaneous and staged soft tissue augmentation during implant treatment, and both procedures significantly enhance KTW and STT. PMID- 29603809 TI - Management of hypersensitivity reactions to Tocilizumab. PMID- 29603810 TI - Associations between patient symptoms and falls in an acute care hospital: A cross-sectional study. AB - AIM AND OBJECTIVES: To describe associations between patient fall risk and common symptoms among hospitalised inpatients. BACKGROUND: Predictors of falls have been identified in a variety of populations and settings, but the role of inpatients' symptom experience has not been adequately evaluated. DESIGN: Cross-sectional. METHODS: Participants included 614 medical and elective surgical patients in an acute hospital in Norway. Patient falls during hospitalisation were assessed by self-report and incident reports. Pain intensity and the occurrence and distress of 15 other symptoms were assessed by self-report. RESULTS: Patient falls were associated with male sex and having more comorbidities. Medical patients were more likely to fall than elective surgical patients. In logistic regression analyses, higher symptom counts were associated with increased risk of fall, with each additional symptom conferring a 15% increase in fall risk. Symptom distress related to concentration difficulties, lack of energy, sleep problems, nausea, vomiting and diarrhoea was associated with increased risk of fall, even after adjusting for the influence of age, sex and comorbidities (odds ratios ranged 2.3 4.8). Severe pain, as well as symptom distress related to drowsiness, itching, dizziness or swelling of arms/legs, was also associated with patient falls, although these associations were attenuated after accounting for age, sex and comorbidities. Overall, symptom distress was more strongly associated with fall risk than symptom occurrence. CONCLUSIONS: Symptom burden and distress may help identify hospital patients at risk for fall. Additional research is needed to determine whether symptoms are useful for assessing fall risk among hospital patients and other high-risk populations. If symptoms are useful indicators of fall risk, they should be considered for inclusion in standardised risk assessments. RELEVANCE TO CLINICAL PRACTICE: Clinicians ought to pay particular attention to increased fall risk among patients reporting many symptoms and those experiencing distress from concentration difficulties, fatigue, sleep problems, nausea, vomiting and diarrhoea. PMID- 29603811 TI - Utility of catheterized specimens in reducing overdiagnosis of urinary tract infections in women. AB - AIMS: To evaluate the utility of catheterized samples in reducing overdiagnosis of UTI based on voided specimens among patients presenting with a range of urinary symptoms. We also aimed to determine variables that may modify the predictive value of the voided midstream urine culture. METHODS: Patient charts were reviewed to identify female patients referred to our voiding dysfunction clinic with a range of complaints warranting urine studies (5/2014-8/2016). Patients with a positive voided urine culture who also had a catheterized urine culture in our system were included. Multiple logistic regression analysis was performed to identify patient characteristics associated with a negative catheterized specimen despite a positive voided specimen. RESULTS: One hundred and seven women were included in the study. Eighty percent of the cohort was post menopausal. Although all patients had positive voided specimens, only 53 (49.5%) had positive catheterized specimens. On multivariate analysis negative nitrites on clean catch UA was a significant predictor of a negative catheterized sample (adjusted OR 8.9, 95%CI 2.2-43.7, P = 0.003). WBC/HPF <10 on clean catch UA trended towards significance (adjusted OR 4.72, 95%CI 1.1-26.1, P = 0.05). CONCLUSIONS: Relying on clean catch urine samples may lead to significant over diagnosis of UTIs. Our study suggests that in female patients who have vague symptoms of UTI, obtaining catheterized specimens may be beneficial in avoiding the overdiagnosis of UTIs and the overuse of antibiotics. Larger, prospective studies testing our hypothesis are necessary, and would greatly assist in establishing clinical practices that reduce the amount of antibiotics inappropriately prescribed. PMID- 29603812 TI - Patients' experiences and care needs during the diagnostic phase of an integrated brain cancer pathway: A case study. AB - AIMS AND OBJECTIVES: To identify and describe patients' experiences and care needs throughout the diagnostic phase of an integrated brain cancer pathway. BACKGROUND: A malignant brain tumour is a devastating diagnosis, which may cause psychical symptoms and cognitive deficits. Studies have shown that the shock of the diagnosis, combined with the multiple symptoms, affects patients' ability to understand information and express needs of care and support. Unmet needs have been reported within this group of patients; however, the experiences and care needs of patients going through the diagnostic phase of a standardised integrated brain cancer pathway have not previously been explored. DESIGN: A case study design was used to provide detailed information of the complex needs of patients being diagnosed with a malignant brain tumour. METHODS: Research interviews and direct participant observation of four patients during hospital admission, brain surgery and discharge were conducted in a Danish university hospital. Systematic text condensation was used to analyse the data material. RESULTS: Four major themes were identified: information needs, balancing hope and reality while trying to perceive the unknown reality of brain cancer, not knowing what to expect and participants' perceptions of the relationship with the healthcare providers. The analysis revealed that participants were in risk of having unmet information needs and that contextual factors seemed to cause fragmented care that led to feelings of uncertainty and loss of control. CONCLUSIONS: Brain tumour patients have complex care needs and experience a particular state of vulnerability during the diagnostic phase. Through personal relationships based on trust with skilled healthcare providers, participants experienced an existential recognition and alleviation of emotional distress. RELEVANCE TO CLINICAL PRACTICE: Patients receiving a brain tumour diagnosis experience unmet care needs in several areas during their hospital stay. There is a need for interventions from healthcare providers. PMID- 29603813 TI - Enhanced self-monitoring blood glucose in non-insulin-requiring Type 2 diabetes: A qualitative study in primary care. AB - AIMS AND OBJECTIVES: To contribute to both theoretical and practical understanding of the role of self-monitoring blood glucose for self-management by describing the experience of people with non-insulin-requiring Type 2 diabetes in an enhanced structured self-monitoring blood glucose intervention. BACKGROUND: The complex context of self-monitoring blood glucose in Type 2 diabetes requires a deeper understanding of the clients' illness experience with structured self monitoring of blood glucose. Clients' numeracy skills contribute to their response to blood glucose readings. Nurses' use of motivational interviewing to increase clients' regulatory self-efficacy is important to the theoretical perspective of the study. DESIGN: A qualitative descriptive study. METHODS: A purposive sample of eleven adults recently (<2 years) diagnosed with non-insulin requiring Type 2 diabetes who had experienced a structured self-monitoring blood glucose intervention participated in this study. Audio recordings of semi structured interviews and photographs of logbooks were analysed for themes using constant comparison and member checking. RESULTS: The illness experience states of Type 2 diabetes include 'Diagnosis,' 'Behavior change,' and 'Routine checking.' People check blood glucose to confirm their Type 2 diabetes diagnosis, to console their diabetes-related fears, to create personal explanations of health behaviour's impact on blood glucose, to activate behaviour change and to congratulate their diabetes self-management efforts. CONCLUSIONS: These findings support the Transtheoretical model's stages of change and change processes. Blood glucose checking strengthens the relationships between theoretical concepts found in Diabetes Self-management Education-Support including the following: engagement, information sharing and behavioural support. RELEVANCE TO CLINICAL PRACTICE: Tailoring diabetes care specifically to clients' stage of their illness experience with use of self-monitoring blood glucose contributes to engagement in self-management. Motivational interviewing and collaborative decision-making using blood glucose checking increase regulatory self-efficacy for people living with non-insulin-requiring Type 2 diabetes. PMID- 29603814 TI - Prevalence and factors associated with polypharmacy in the older people: 2006 2014. AB - AIMS AND OBJECTIVES: To analyse the prevalence, risk factors and evolution over time of polypharmacy and self-medication in the older people in Spain from 2006 2014. BACKGROUND: Polypharmacy is a public health problem for older people worldwide which causes different negative effects on their health, increasing health costs and pharmaceutical spending. However, previous studies do not include nationally representative samples and none of them provide updated data. DESIGN: Cross-sectional study with community-dwelling older adults (N = 26,277) who participated in the National Health Survey in Spain in 2006 and 2011/2012 and the European Health Survey in Spain in 2009 and 2014. METHODS: Polypharmacy (defined as use of five or more medications in the last 2 weeks), excessive polypharmacy (defined as use of ten or more medications in the last 2 weeks) and self-medication (defined as use of medications without a prescription) were evaluated. A logistic regression was used for to know the association between polypharmacy and self-medication with the sociodemographic characteristic. RESULTS: The participants were 62% female and 38% male. The mean medication consumption was 2.96 (SD +/- 2.11). Prevalence of polypharmacy was present in 21.9%, prevalence of excessive polypharmacy was 0.6%, and prevalence of self medication was 10.7%. The most commonly used medications were for blood pressure (51.6%), pain (42.8%) and cholesterol (28.2%). Polypharmacy is associated with sex (females), age, being separated/divorced/widowed, lack of education, higher body mass index, being bedridden during the last 2 weeks and self-medication. CONCLUSIONS: The prevalence of polypharmacy and prevalence of self-medication are considerable, and they increased significantly from 2006-2014. RELEVANCE TO CLINICAL PRACTICE: To deal with polypharmacy is a big challenge for nurses. These data suggest to establish innovative clinical strategies in which the health professionals and the patients are involved to improve the personal behaviour with medicines and to reduce the risks and costs of polypharmacy and self medication. PMID- 29603815 TI - The relationship of delirium and risk factors for cardiology intensive care unit patients with the nursing workload. AB - AIMS AND OBJECTIVES: To evaluate the relationship of delirium and risk factors for cardiology intensive care unit (ICU) patients with the nursing workload. BACKGROUND: Delirium is a common syndrome in patients with cardiac problems. The risk factors causing delirium and the presence and type of delirium affect the nurse workload and patient care quality adversely. DESIGN: This cross-sectional study was conducted with 133 patients staying at the cardiology ICU of a university hospital between 5 January-31 March 2017. METHOD: The study data were collected using the Patient Information Form, Delirium Risk Factors' Form and Therapeutic Intervention Scoring System-28 (TISS-28) scale to identify the nurse workload. The statistical analysis of the data was performed using frequency, chi square, Mann-Whitney U, correlation and regression analyses. RESULTS: It was found that patients who developed delirium were 65 years or older, they had more nasogastric/total parenteral nutrition (NG/TPN), benzodiazepine and physical restraints in comparison with those with no delirium development, and that the prevalence of hypoxia and hypoalbuminemia were higher in these patients. The mean TISS-28 score was higher in patients with delirium, compared with those without delirium. There was a positive correlation between the mean Acute Physiology and Chronic Health Evaluation II (APACHE II) scores and the mean TISS-28 score of the patients. The mean TISS-28 score was found to significantly increase with being at the age of 65 and above and the administration of mechanical ventilation. The patients with delirium required a mean of 60-min additional care. CONCLUSIONS: Our study results suggest that the presence of delirium and the delirium risk factors, irrespective of delirium, increase the nurse workload. RELEVANCE TO CLINICAL PRACTICE: An effective management of delirium risk factors can improve the patient care quality by reducing delirium occurrence and nurse workload. PMID- 29603816 TI - Enantio- and Diastereoselective Synthesis of Latanoprost using an Organocatalyst. AB - An enantioselective total synthesis of latanoprost was achieved. Its chiral cyclopentane core structure was constructed through an organocatalyst-mediated [3+2]-cycloaddition reaction, and chirality in the omega-side chain was generated by prolinate-anion-mediated alpha-aminoxylation of an aldehyde. Highly diastereoselective domino acetalization and an oxy-Michael reaction were key steps for the generation of C9 chirality. PMID- 29603817 TI - Utilisation of hepatocellular carcinoma screening in Australians at risk of hepatitis B virus-related carcinoma and prescribed anti-viral therapy. AB - AIMS AND OBJECTIVES: To investigate hepatocellular carcinoma screening utilisation and factors associated with utilisation among patients prescribed hepatitis B virus anti-viral therapy and at risk of hepatocellular carcinoma. BACKGROUND: The incidence of hepatocellular carcinoma has increased in Australia over the past three decades with chronic hepatitis B virus infection a major contributor. hepatocellular carcinoma surveillance programs aim to detect cancers early enabling curative treatment options, longer survival and longer times to recurrence. DESIGN: Multi-site cross-sectional survey. METHODS: An online study questionnaire was administered to eligible participants attending three Sydney tertiary hospitals. Data were grouped into six mutually exclusive hepatocellular carcinoma risk factor categories as per American Association for the Study of Liver Diseases guidelines. All analyses were undertaken in STATA. Logistic regression was used to assess the associations between covariates and screening utilisation. Multivariate models described were assessed using the Hosmer Lemeshow goodness of fit. RESULTS: Of the 177 participants, 137 (77.4%) self reported that US had been performed in the last six months. Awareness that screening should be performed and knowing the correct frequency of US screening were independently associated with screening utilisation. Participants who knew that screening should be undertaken were three times more likely to have had pretreatment education or were prescribed hepatitis B virus anti-viral treatment for >4 years. Participants reporting a family history of hepatocellular carcinoma were less likely to know that screening should be undertaken every 6 months. CONCLUSION: While utilisation of hepatocellular carcinoma surveillance programs was higher in this study than in previous reports, strategies to further improve surveillance remain necessary. RELEVANCE TO CLINICAL PRACTICE: Findings from this research form the basis for proposing strategies to improve utilisation of hepatocellular carcinoma screening, inform hepatitis B virus-related clinical practice and for the delivery of care and nursing education to people receiving hepatitis B virus anti-viral therapy and at risk of developing hepatocellular carcinoma. PMID- 29603818 TI - Altruism, honesty and religiosity in nursing students. AB - AIMS AND OBJECTIVES: To identify, at different stages of nursing education, the extent to which nursing students appreciate altruism, honesty, religiosity and other, sometimes contrasting, values in practice. BACKGROUND: Nursing is informed by values that guide care ethos and activities. Embodiment of these core values has become a matter of concern. Reports outlining deficiencies in health care followed by polemics in nursing journals have called into question whether nursing students are sufficiently motivated by values and educated in their application. This study explores these values among undergraduate nursing students in the Republic of Ireland. Considering the strong religious tradition in health care in Ireland, religiosity was also included. DESIGN: A link to an online survey was distributed via email to all nursing students in the thirteen Schools of Nursing in the Republic of Ireland. METHOD: Quantitative data were collected using an adaptation of the Salford-Scott (Journal of Advanced Nursing, 57(8), 2007, 366) Nursing Values Questionnaire. RESULTS: Participants (n = 158) reported positively to statements related to honesty and altruism. Both altruism and religiosity received support, but the latter was to a lesser extent. Students considered their professionalism more important than altruism, and honesty varied according to the situation. CONCLUSIONS: This study adds new information by confirming that students exhibit support for two of the most essential values in nursing: altruism and honesty. The adapted Salford-Scott instrument has shown reliability and promise in further empirical study in nursing. RELEVANCE TO CLINICAL PRACTICE: Priority given to professionalism over altruism reflects concerns highlighted in the international literature around overly task-oriented care in which compassion gets lost. Also, when loyalty supersedes honesty, problems with accountability in health care may emerge. Uncertainty around religiosity in health care may reflect limitations in competence in nurses to relate to patients with religions or spirituality other than their own. PMID- 29603819 TI - Multicenter Evaluation of the YEARS Criteria in Emergency Department Patients Evaluated for Pulmonary Embolism. AB - BACKGROUND: It may be possible to safely rule out pulmonary embolism (PE) in patients with low pretest probability (PTP) using a higher than standard D-dimer threshold. The YEARS criteria, which include three questions from the Wells PE score to identify low-PTP patients and a variable D-dimer threshold, was recently shown to decrease the need for imaging to rule out PE by 14% in a multicenter study in the Netherlands. However, the YEARS approach has not been studied in the United States. METHODS: This study was a prospective, observational study of consecutive adult patients evaluated for PE in 17 U.S. emergency departments. Prior to diagnostic testing, we collected the YEARS criteria: "Does the patient have clinical signs or symptoms of DVT?" "Does the patient have hemoptysis?" "Are alternative diagnoses less likely than PE?" with YEARS (+) being any "yes" response. A negative D-dimer was <1000 mg/dL for YEARS (-) patients and <500 mg/dL for YEARS (+) patients. We calculated test characteristics and used Fisher's exact test to compare proportions of patients who would have been referred for imaging and patients who would have had PE "missed." RESULTS: Of 1,789 patients, 84 (4%) had PE, 1,134 (63%) were female, 1,038 (58%) were white, and mean (+/-SD) age was 48 (+/-16) years. Using the standard D-dimer threshold, 940 (53%) would not have had imaging, with two (0.2%, 95% confidence interval [CI] = 0.02%-0.60%) missed PE. Using YEARS adjustment, 1,204 (67%, 95% CI = 65% 69%) would not have been referred for imaging, with six (0.5%, 95% CI = 0.18% 1.1%) missed PE, and using "alternative diagnoses less likely than PE" adjustment, 1,237 (69%, 95% CI = 67%-71%) would not have had imaging with six (0.49%, 95% CI = 0.18%-1.05%) missed PE. Sensitivity was 97.6% (95% CI = 91.7% 99.7%) for the standard threshold and 92.9% (95% CI = 85%-97%) for both adjusted thresholds. Negative predictive value (NPV) was nearly 100% for all approaches. CONCLUSIONS: D-dimer adjustment based on PTP may result in a reduced need for imaging to evaluate possible PE, with some additional missed PE but no decrease in NPV. PMID- 29603820 TI - Intentional rounding in acute adult healthcare settings: A systematic mixed method review. AB - AIMS AND OBJECTIVES: To determine the impact of intentional rounding on patient and nursing outcomes and identify the barriers and facilitators surrounding implementation. BACKGROUND: Intentional rounding is an organised approach whereby health professionals' regularly check on patients to ensure their fundamental care needs are met. Despite wide scale adoption of intentional rounding, there is limited evidence to inform practice. METHODS: This systematic mixed-method review was conducted using the Joanna Briggs Institute methodology. Databases CINAHL, MEDLINE, EMBASE, COCHRANE, SCOPUS and WEB of SCIENCE were searched to identify research studies published in English between January 2006-January 2017 that reported on intentional rounding and patient and nursing staff outcomes. Studies were assessed for methodological quality. The findings were synthesised into themes using a narrative approach. RESULTS: Twenty-one studies were included in the review. Six studies reported a reduction in the number of falls, and a further five studies reported a reduction in call bell use following the introduction of intentional rounding. Nurses' satisfaction and attitudes towards intentional rounding were reported in seven studies with equivocal results. The quality of the studies was weak making comparisons difficult. CONCLUSIONS: While results suggest positive outcomes for falls and call bell use, conclusions on the available data are overshadowed by the quality of the studies. Well-designed studies are required to advance evidence in this field. RELEVANCE TO CLINICAL PRACTICE: The evidence on intentional rounding is mixed and suggests that the introduction of intentional rounding should be accompanied by a protocol for robust evaluation to measure the impact of this process change. This should be accompanied by standardised reporting measures to enable comparisons and contribute to the quality of available evidence on intentional rounding. PMID- 29603821 TI - Lymphocytes immunotherapy for preserving pregnancy: Mechanisms and Challenges. AB - Due to the expression of paternal antigens by the embryo, pregnancy is considered as a semi-allograft and so immunological dysregulation is considered as one of the important causes in repeated implantation failure (RIF) and recurrent pregnancy loss (RPL). It has been revealed that lymphocytes immunotherapy (LIT) could be an appropriate approach to prevent pregnancy loss in such patients. Various mechanisms have been suggested for effectiveness of LIT such as enhancing expression of anti-paternal cytotoxic antibodies (APCA), progesterone-induced blocking factor (PIBF), anti-idiotypic antibodies (Ab2), and mixed lymphocyte reaction blocking antibodies (MLR-Bf), as well as reduction in the T helper 1/T helper 2 ratio and deviation in the pattern of cytokines production. However, there are controversial results about the beneficial effect of LIT treatment in RIF and RPL patients. In the current study, we reviewed findings of LIT in RIF and RPL patients with a focus on possible mechanisms of alloimmunization in preserving pregnancy. Besides, we highlighted possible reasons for mixed results about the effectiveness of LIT and way of solving the problem. Also, we proposed potential laboratory and clinical criteria to recruit patients for LIT. PMID- 29603822 TI - Manganese-Based Nanozymes: Multienzyme Redox Activity and Effect on the Nitric Oxide Produced by Endothelial Nitric Oxide Synthase. AB - Nanomaterials having enzyme-like activity (nanozymes) make them suitable candidates for various biomedical applications. In this study, we demonstrate the morphology-dependent enzyme mimetic activity of Mn3 O4 nanoparticles. It is found that Mn3 O4 nanoparticles mimic the functions of all three cellular antioxidant enzymes: superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). Interestingly, the nanozyme activity of Mn3 O4 depends on various factors including size, morphology, surface area, and the redox properties of the metal ions. The Mn3 O4 nanoflowers exhibited remarkably high activity in all three enzyme systems and the order of multienzyme activity of different morphologies was: flowers ? flakes > hexagonal plates~polyhedrons~cubes. Interestingly, all five nanoforms are taken up by the mammalian cells and were found to be biocompatible, with very low cytotoxicity. The activity of the most active nanoflowers was studied in primary human umbilical vein endothelial cells (HUVEC) and human pulmonary microvascular endothelial cells (hPMEC) and it was found that Mn3 O4 does not reduce the level of nitric oxide (NO). This is in contrast to the effect of some of the Mn-porphyrin-based SOD mimetics, which are known to scavenge NO in endothelial cells. PMID- 29603823 TI - Effects of nurse-led lower extremity strength training on knee function recovery in patients who underwent total knee replacement. AB - AIMS AND OBJECTIVES: To examine the effects of lower extremity muscle strength training on knee function recovery and quality of life in patients who underwent total knee replacement. BACKGROUND: Patients with knee osteoarthritis after surgery experience decreased knee function that impacts their quality of life. However, patients typically lack a long-term, home-based and continuous leg exercise training method and rarely have studies explored the effects of exercise training on knee function recovery and quality of life. DESIGN: A experimental and longitudinal study design. METHODS: The simple randomised sampling (based on patients' admission priority order) was used to collect participant data. Outcome measurements included the Knee Injury and Osteoarthritis Outcome Score. Participants were randomised to receive and starting lower extremity muscle strength training before surgery (training group, n = 100) or to receive usual care (nontraining group, n = 100). Data were collected and followed up with the patients before surgery (T1) and at 2 weeks (T2), 1 month (T3), 2 months (T4) and 3 months (T5) after discharge. RESULTS: The Knee Injury and Osteoarthritis Outcome Score subscale scores showed that both groups of patients experienced knee function and quality of life decreases 2 weeks after total knee replacement, but all subscale scores gradually increased from the first month to the third month after total knee replacement. Both groups and times were significantly different, but the training group's knee function and quality of life recovered earlier and better than the nontraining group does. CONCLUSIONS: This study confirmed that lower extremity muscle strength training helps to improve quality of life and knee function in patients who undergo total knee replacement. Healthcare staff should include this training in presurgical nursing care and in patients' discharge plans as a continuous, daily rehabilitation activity at home. RELEVANCE TO CLINICAL PRACTICE: When patients are diagnosed with knee osteoarthritis and undergo surgery, a presurgical exercise education and discussion of knee function rehabilitation should be part of standard care. PMID- 29603824 TI - Expression of protein arginine methyltransferase-5 in oral squamous cell carcinoma and its significance in epithelial-to-mesenchymal transition. AB - Protein arginine methyltransferases (PRMT) 5, a member of type II arginine methyltransferases, catalyzes the symmetrical dimethylation of arginine residues on histone and non-histone substrates. Although the overexpression of PRMT5 has been reported in various cancers, its role in oral squamous cell carcinoma (OSCC) has not been elucidated. In the present study, we immunohistochemically examined the expression of PRMT5 in surgically resected oral epithelial dysplasia (OED, n = 8), oral intraepithelial neoplasia (OIN)/carcinoma in situ (CIS) (n = 11) and OSCC (n = 52) with or without contiguous OED lesions. In the normal epithelium, PRMT5 was weakly expressed in the cytoplasm of basal layer cells. In OED, OIN/CIS, and OSCC, its expression consistently and uniformly increased in the cytoplasm of dysplastic and cancer cells. Moreover, nuclear and cytoplasmic localization was detected in the invasive front of cancer cells, particularly in cases showing poor differentiation or aggressive invasion patterns. The concomitant nuclear and cytoplasmic expression of PRMT5 correlated with the loss of E-cadherin and cytokeratin 17, and the upregulation of vimentin, features that are both indicative of epithelial-to-mesenchymal transition. PRMT5 may play a role from early oncogenesis through to the progression of OSCC, particularly in the aggressive mode of stromal invasion. PMID- 29603825 TI - Processing of interaural phase differences in components of harmonic and mistuned complexes in the inferior colliculus of the Mongolian gerbil. AB - Harmonicity and spatial location provide eminent cues for the perceptual grouping of sounds. In general, harmonicity is a strong grouping cue. In contrast, spatial cues such as interaural phase or time difference provide for strong grouping of stimulus sequences but weak grouping for simultaneously presented sounds. By studying the neuronal basis underlying the interaction of these cues in processing simultaneous sounds using van Rossum spike train distance measures, we aim at explaining the interaction observed in psychophysical experiments. Responses to interaural phase differences imposed on single components of harmonic and mistuned complex tones as well as noise delay functions were recorded as multiunit responses from the inferior colliculus of Mongolian gerbils. Results revealed a better representation of interaural phase differences if imposed on a harmonic rather than a mistuned frequency component of a complex tone. The representation of interaural phase differences was better for long integration-time windows approximately reflecting firing rates rather than short integration-time windows reflecting the temporal pattern of the stimulus-driven response. We found only a weak impact of interaural phase differences if combined with mistuning of a component in a harmonic tone complex. PMID- 29603826 TI - Seed point discontinuity-based segmentation method for the substantia nigra and the red nucleus in quantitative susceptibility maps. AB - BACKGROUND: The automatic segmentation of cerebral nuclei in the quantitative susceptibility mapping (QSM) images can provide assistance for surgical treatment and pathological mechanism studies. However, as the most frequently used segmentation method, the atlas method provides unsatisfactory results when segmenting the substantia nigra (SN) and the red nucleus (RN). PURPOSE: To propose and evaluate an improved automatic method based on seed points discontinuity for segmentations of the SN and the RN in QSM images. STUDY TYPE: Prospective. SUBJECTS: In all, 22 subjects, 11 patients with Parkinson's disease (PD), and 11 healthy subjects (mean age of 68.0 +/- 6.9 years) underwent MR scans. FIELD STRENGTH/SEQUENCE: 3T system and a 3D multiecho gradient echo sequence with monopolar readout gradient. ASSESSMENT: Manual segmentations by two radiologists (both with over 10 years of experience in neuroimaging) were used to establish a baseline for assessment. The Dice coefficient and the center-of gravity distance was employed to evaluate the segmentation accuracy. STATISTICAL TESTS: The mean value and standard deviation of the Dice coefficient and center of-gravity distance were calculated separately to compare segmentation results from the proposed method, the level set method, the atlas method (including the single-atlas method and the multi-atlas majority voting method). RESULTS: The statistical results of Dice coefficient of the SN and the RN between the ground truth and the segmentation were 0.79 +/- 0.14 and 0.77 +/- 0.06 for the proposed method, 0.40 +/- 0.10 and 0.65 +/- 0.09 for the level set method, 0.68 +/- 0.09 and 0.64 +/- 0.07 for the single-atlas method, 0.70 +/- 0.06 and 0.68 +/- 0.05 for the multi-atlas majority voting method, respectively. The proposed method also provides the lowest center-of-gravity distance value (1.05 +/- 0.71 for the SN and 0.74 +/- 0.35 for the RN). DATA CONCLUSION: The segmentation results of the proposed method performed well on the in vivo data and were closer to the manual segmentation than the atlas method. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;48:1112-1119. PMID- 29603827 TI - Differences between acute-onset chronic inflammatory demyelinating polyneuropathy and acute inflammatory demyelinating polyneuropathy in adult patients. AB - Acute inflammatory demyelinating polyneuropathy (AIDP) and acute-onset chronic inflammatory demyelinating polyneuropathy (A-CIDP) are conditions presenting overlapping clinical features during early stages (first 4 weeks), although the latter may progress after 8 weeks. The aim of this study was to identify predictive factors contributing to their differential diagnosis. Clinical records of adult patients with AIDP or A-CIDP diagnosed at our institution between January 2006 and July 2017 were retrospectively reviewed. Demographic characteristics, clinical manifestations, cerebrospinal-fluid (CSF) findings, treatment and clinical evolution were analyzed. Nerve conduction studies were performed in all patients with at least 12 months follow-up. A total of 91 patients were included (AIDP, n = 77; A-CIDP, n = 14). The median age was 55.5 years in patients with A-CIDP vs 43 years in AIDP (P = .07). The history of diabetes mellitus was more frequent in A-CIDP (29% vs 8%, P = .04). No significant differences between groups were observed with respect to: human immunodeficiency virus (HIV) status, presence of auto-immune disorder or oncologic disease. Cranial, motor and autonomic nerve involvement rates were similar in both groups. Patients in the A-CIDP group showed higher frequency of proprioceptive disturbances (83% vs 28%; P < .001), sensory ataxia (46% vs 16%; P = .01), and the use of combined immunotherapy with corticoids (29% vs 3%; P = .005). There were no significant differences in CSF findings, intensive care unit (ICU) admission, or mortality rates. During the first 8 weeks both entities are practically indistinguishable. Alterations in proprioception could suggest A CIDP. Searching for markers that allow early differentiation could favor the onset of corticotherapy without delay. PMID- 29603828 TI - Does an interdisciplinary outpatient atrial fibrillation (AF) clinic affect the number of acute AF admissions? A retrospective cohort study. AB - AIMS AND OBJECTIVES: To investigate the impact of a multidisciplinary outpatient clinic for patients with atrial fibrillation-clinic on the number of acute hospitalisations for atrial fibrillation compared with usual outpatient care for this condition before the establishment of the atrial fibrillation-clinic. BACKGROUND: Guidelines recommend a structured outpatient clinic follow-up in multidisciplinary teams for patients with atrial fibrillation due to fewer hospitalisations and death. However, the evidence base is weak. DESIGN: The study is a retrospective cohort study including a total of 129 patients from the cardiac outpatient clinic at a large Danish University Hospital. The study population consisted of two groups: a usual care group before a dedicated atrial fibrillation-clinic was established (n = 73) and the atrial fibrillation-clinic group (n = 56). The primary endpoint was acute hospitalisation for atrial fibrillation. METHODS: Cox regression was used to assess the hazard ratio for acute hospitalisations for atrial fibrillation. RESULTS: When comparing the atrial fibrillation-clinic with the usual care group, adjusted for age and sex, this study showed a trend towards more frequent acute hospitalisations in the usual care group. CONCLUSION: The results of this study are hypothesis-generating and should lead to larger prospective trials to evaluate the impact of dedicated multidisciplinary atrial fibrillation-clinics on atrial fibrillation-related issues as acute hospitalisations for atrial fibrillation, symptoms and quality of life. RELEVANCE TO CLINICAL PRACTICE: Follow-up in a dedicated multidisciplinary AF-clinic might empower patients better to cope with acute arrhythmia symptoms. PMID- 29603829 TI - Variable impact of CSF flow suppression on quantitative 3.0T intracranial vessel wall measurements. AB - BACKGROUND: Flow suppression techniques have been developed for intracranial (IC) vessel wall imaging (VWI) and optimized using simulations; however, simulation results may not translate in vivo. PURPOSE: To evaluate experimentally how IC vessel wall and lumen measurements change in identical subjects when evaluated using the most commonly available blood and cerebrospinal fluid (CSF) flow suppression modules and VWI sequences. STUDY TYPE: Prospective. POPULATION/SUBJECTS: Healthy adults (n = 13; age = 37 +/- 15 years) were enrolled. FIELD STRENGTH/SEQUENCE: A 3.0T 3D T1 /proton density (PD)-weighted turbo-spin-echo (TSE) acquisition with post-readout anti-driven equilibrium module, with and without Delay-Alternating-with-Nutation-for-Tailored-Excitation (DANTE) was applied. DANTE flip angle (8-12 degrees ) and TSE refocusing angle (sweep = 40-120 degrees or 50-120 degrees ) were varied. ASSESSMENT: Basilar artery and internal carotid artery (ICA) wall thicknesses, CSF signal-to-noise ratio (SNR), contrast-to-noise ratio (CNR), and signal ratio (SR) were assessed. Measurements were made by two readers (radiology resident and board-certified neuroradiologist). STATISTICAL TESTS: A Wilcoxon signed-rank test was applied with corrected two-sided P < 0.05 required for significance (critical P = 0.008, 0.005, and 0.05 for SNR/CNR, SR, and wall thickness, respectively). RESULTS: A TSE pulse sweep = 40-120 degrees and sweep = 50-120 degrees provided similar (P = 0.55) CSF suppression. Addition of the DANTE preparation reduced CSF SNR from 17.4 to 6.7, thereby providing significant (P < 0.008) improvement in CSF suppression. The DANTE preparation also resulted in a significant (P < 0.008) reduction in vessel wall SNR, but variable vessel wall to CSF CNR improvement (P = 0.87). There was a trend for a difference in blood SNR with vs. without DANTE (P = 0.05). The outer vessel wall diameter and wall thickness values were lower (P < 0.05) with (basilar artery 4.45 mm, 0.81 mm, respectively) vs. without (basilar artery 4.88 mm, 0.97 mm, respectively) DANTE 8 degrees . DATA CONCLUSION: IC VWI with TSE sweep = 40-120 degrees and with DANTE flip angle = 8 degrees provides the best CSF suppression and CNR of the approaches evaluated. However, improvements are heterogeneous, likely owing to intersubject vessel pulsatility and CSF flow variations, which can lead to variable flow suppression efficacy in these velocity-dependent modules. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;48:1120-1128. PMID- 29603830 TI - PRMT9 promotes hepatocellular carcinoma invasion and metastasis via activating PI3K/Akt/GSK-3beta/Snail signaling. AB - Protein arginine methyltransferases (PRMT) catalyze protein arginine methylation and play an important role in many biological processes. Aberrant PRMT expression in tumor cells has been documented in several common cancer types; however, its precise contribution to hepatocellular carcinoma (HCC) cell invasion and metastasis is not fully understood. In this study, we identified a new oncogene, PRMT9, whose overexpression strongly promotes HCC invasion and metastasis. PRMT9 expression was detected more frequently in HCC tissues than in adjacent noncancerous tissues. PRMT9 overexpression was significantly correlated with hepatitis B virus antigen (HBsAg) status, vascular invasion, poor tumor differentiation and advanced TNM stage. Patients with higher PRMT9 expression had a shorter survival time and higher recurrence rate. PRMT9 expression was an independent and significant risk factor for survival after curative resection. Functional studies demonstrated that PRMT9 increased HCC cell invasion and lung metastasis. Knocking down PRMT9 with short hairpin RNA (shRNA) inhibited HCC cell invasion. Further investigations found that PRMT9 increased cell migration and invasion through epithelial-mesenchymal transition (EMT) by regulating Snail expression via activation of the PI3K/Akt/GSK-3beta/Snail signaling pathway. In clinical HCC samples, PRMT9 expression was positively associated with Snail expression and was negatively associated with E-cadherin expression. In conclusion, our study demonstrated that PRMT9 is an oncogene that plays an important role in HCC invasion and metastasis through EMT by regulating Snail expression via activation of the PI3K/Akt/GSK-3beta/Snail signaling pathway. Thus, PRMT9 may serve as a candidate prognostic biomarker and a potential therapeutic target. PMID- 29603831 TI - An autopsy case report: Differences in radiological images correlate with histology in Erdheim-Chester disease. AB - p16 activation caused by oncogenic mutations may represent oncogene-induced senescence (OIS), a protective mechanism against oncogenic events. However, OIS can contribute to tumor development via tissue remodeling in some tumors. Erdheim Chester disease (ECD), a rare non-Langerhans cell histiocytosis, is one such tumor. Its clinical and histological features vary, making it difficult to diagnose. Herein, we describe an autopsy of an ECD patient. The patient underwent radiological examinations, including 18 F-fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (PET/CT), bone scintigraphy and CT. A biopsy from the lesion with the highest FDG accumulation confirmed the presence of foamy macrophages, a diagnostic clue for ECD. Based on this finding and the clinical features, ECD was diagnosed. However, the patient died from heart dysfunction. After the autopsy, each radiologically different site showed various histological findings regarding the morphology of macrophages, fibrosis, inflammation, and p16 expression. OIS-induced histological progression can cause certain changes observed in radiological images. In addition, in order to evaluate the increase in glucose metabolism, which can affect FDG accumulation, the expression of glucose transporter 1 and hexokinase II was also analyzed. Summarizing the radio-histological correlation can help further both the understanding and diagnosis of ECD. PMID- 29603832 TI - Trends and risk factors of hepatitis A in Catalonia after the introduction of a hepatitis A+B vaccination programme. AB - At the end of 1998, universal hepatitis A+B vaccination of 12 year olds was introduced in Catalonia. The aim was to examine trends in hepatitis A during 2005 2015 and assess risk factors by age group. We carried out an observational epidemiological study of the incidence and risk factors of hepatitis A reported to the surveillance system. Information on exposure was recorded for each case for the 2-6 weeks before symptom onset. Spearman's coefficient was used to evaluate the trends of rates. The chi-square test was used to compare categorical. We studied 2621 hepatitis A cases; the age mean was 26.6 years (SD=18.2), and >50% of cases were in the 20-49 years age group. The incidence decreased from 3.28/100 000 in 2005 to 1.50/100 000 in 2015. The rate for women decreased over time (P = .008), but the reduction was not significant in men (P = .234). Men consistently had higher rates than women with the biggest difference being in the 20-34 years age group (rate 8.8 vs 2.8). The greatest risk factor was travel to an endemic country (42.1%) in the 0-19 years age group and male-to male sexual contact (18.6%) in the 20-49 years age group. The case fatality rate in adults aged >49 years was 0.4%. In conclusion, the vaccination programme of preadolescents resulted in a reduction in hepatitis A cases. However, a significant amount of cases still appear in immigrants and men who have sex with men. Hepatitis A in adults is an emerging health problem that will require new strategies. PMID- 29603834 TI - Carbon-Electrode-Tailored All-Inorganic Perovskite Solar Cells To Harvest Solar and Water-Vapor Energy. AB - Moisture is the worst enemy for state-of-the-art perovskite solar cells (PSCs). However, the flowing water vapor within nanoporous carbonaceous materials can create potentials. Therefore, it is a challenge to integrate water vapor and solar energies into a single PSC device. We demonstrate herein all-inorganic cesium lead bromide (CsPbBr3 ) solar cells tailored with carbon electrodes to simultaneously harvest solar and water-vapor energy. Upon interfacial modification and plasma treatment, the bifunctional PSCs yield a maximum power conversion efficiency up to 9.43 % under one sun irradiation according to photoelectric conversion principle and a power output of 0.158 MUW with voltage of 0.35 V and current of 0.45 MUA in 80 % relative humidity through the flowing potentials at the carbon/water interface. The initial efficiency is only reduced by 2 % on exposing the inorganic PSC with 80 % humidity over 40 days. The successful realization of physical proof-of-concept multi-energy integrated solar cells provides new opportunities of maximizing overall power output. PMID- 29603833 TI - Prospective comparison of PI-RADS version 2 and qualitative in-house categorization system in detection of prostate cancer. AB - BACKGROUND: Prostate Imaging-Reporting and Data System v. 2 (PI-RADSv2) provides standardized nomenclature for interpretation of prostate multiparametric MRI (mpMRI). Inclusion of additional features for categorization may provide benefit to stratification of disease. PURPOSE: To prospectively compare PI-RADSv2 to a qualitative in-house system for detecting prostate cancer on mpMRI. STUDY TYPE: Prospective. POPULATION: In all, 338 patients who underwent mpMRI May 2015-May 2016, with subsequent MRI/transrectal ultrasound fusion-guided biopsy. FIELD STRENGTH: 3T mpMRI (T2 W, diffusion-weighted [DW], apparent diffusion coefficient [ADC] map, b-2000 DWI acquisition, and dynamic contrast-enhanced [DCE] MRI). ASSESSMENT: One genitourinary radiologist prospectively read mpMRIs using both in house and PI-RADSv2 5-category systems. STATISTICAL TEST: In lesion-based analysis, overall and clinically significant (CS) tumor detection rates (TDR) were calculated for all PI-RADSv2 and in-house categories. The ability of each scoring system to detect cancer was assessed by area under receiver operator characteristic curve (AUC). Within each PI-RADSv2 category, lesions were further stratified by their in-house categories to determine if TDRs can be increased by combining features of both systems. RESULTS: In 338 patients (median prostate specific antigen [PSA] 6.5 [0.6-113.6] ng/mL; age 64 [44-84] years), 733 lesions were identified (47% tumor-positive). Predictive abilities of both systems were comparable for all (AUC 76-78%) and CS cancers (AUCs 79%). The in-house system had higher overall and CS TDRs than PI-RADSv2 for categories 3 and 4 (P < 0.01 for both), with the greatest difference between the scoring systems seen in lesions scored category 4 (CS TDRs: in-house 65%, PI-RADSv2 22.1%). For lesions categorized as PI-RADSv2 = 4, characterization of suspicious/indeterminate extraprostatic extension (EPE) and equivocal findings across all mpMRI sequences contributed to significantly different TDRs for both systems (TDR range 19-75%, P < 0.05). DATA CONCLUSION: PI-RADSv2 behaves similarly to an existing validated system that relies on the number of sequences on which a lesion is seen. This prospective evaluation suggests that sequence positivity and suspicion of EPE can enhance PI-RADSv2 category 4 cancer detection. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 3 J. Magn. Reson. Imaging 2018;47:1326-1335. PMID- 29603835 TI - Soil abiotic variables are more important than Salicaceae phylogeny or habitat specialization in determining soil microbial community structure. AB - Predicting the outcome of interspecific interactions is a central goal in ecology. The diverse soil microbes that interact with plants are shaped by different aspects of plant identity, such as phylogenetic history and functional group. Species interactions may also be strongly shaped by abiotic environment, but there is mixed evidence on the relative importance of environment, plant identity and their interactions in shaping soil microbial communities. Using a multifactor, split-plot field experiment, we tested how hydrologic context, and three facets of Salicaceae plant identity-habitat specialization, phylogenetic distance and species identity-influence soil microbial community structure. Analysis of microbial community sequencing data with generalized dissimilarity models showed that abiotic environment explained up to 25% of variation in community composition of soil bacteria, fungi and archaea, while Salicaceae identity influenced <1% of the variation in community composition of soil microbial taxa. Multivariate linear models indicated that the influence of Salicaceae identity was small, but did contribute to differentiation of soil microbes within treatments. Moreover, results from a microbial niche breadth analysis show that soil microbes in wetlands have more specialized host associations than soil microbes in drier environments-showing that abiotic environment changed how plant identity correlated with soil microbial communities. This study demonstrates the predominance of major abiotic factors in shaping soil microbial community structure; the significance of abiotic context to biotic influence on soil microbes; and the utility of field experiments to disentangling the abiotic and biotic factors that are thought to be most essential for soil microbial communities. PMID- 29603837 TI - Treatment with the GSK3-beta inhibitor Tideglusib improves hippocampal development and memory performance in juvenile, but not adult, Cdkl5 knockout mice. AB - Cyclin-dependent kinase-like 5 (CDKL5) disorder is a severe neurodevelopmental disorder characterized by early-onset epileptic seizures, severe developmental delay, and intellectual disability. To date, no effective pharmacological treatments are available to improve the neurological phenotype that is due to mutations in the CDKL5 gene. Murine models of CDKL5 disorder have recently been generated, making the preclinical testing of pharmacological interventions possible. Using a Cdkl5 knockout (KO) mouse model, we recently demonstrated that deficiency of Cdkl5 causes defects in postnatal hippocampal development and hippocampus-dependent learning and memory. These defects were accompanied by an increased activity of GSK3beta, an important inhibitory regulator of many neuronal functions. Pharmacological inhibition of GSK3beta activity was able to recover hippocampal defects and cognitive performance in juvenile Cdkl5 KO mice, suggesting that GSK3beta inhibitors might be a potential therapeutic option for CDKL5 disorder. As GSK3beta inhibitors have been shown to have differential medication responses in young people and adults, this study was designed to examine whether GSK3beta is a possible therapeutic target both in juvenile and in adult CDKL5 patients. We found that treatment with the GSK3beta inhibitor Tideglusib during the juvenile period improved hippocampal development and hippocampus-dependent behaviors in Cdkl5 KO mice, while treatment later on in adulthood had no positive effects. These results suggest that pharmacological interventions aimed at normalizing impaired GSK3beta activity might have different age-dependent outcomes in CDKL5 disorder. This is of utmost importance in the development of therapeutic approaches in CDKL5 patients and in the design of rational clinical trials. PMID- 29603836 TI - Regulons and protein-protein interactions of PRD-containing Bacillus anthracis virulence regulators reveal overlapping but distinct functions. AB - Bacillus anthracis produces three regulators, AtxA, AcpA and AcpB, which control virulence gene transcription and belong to an emerging class of regulators termed 'PCVRs' (Phosphoenolpyruvate-dependent phosphotransferase regulation Domain Containing Virulence Regulators). AtxA, named for its control of toxin gene expression, is the master virulence regulator and archetype PCVR. AcpA and AcpB are less well studied. Reports of PCVR activity suggest overlapping function. AcpA and AcpB independently positively control transcription of the capsule biosynthetic operon capBCADE, and culture conditions that enhance AtxA level or activity result in capBCADE transcription in strains lacking acpA and acpB. We used RNA-Seq to assess the regulons of the paralogous regulators in strains constructed to express individual PCVRs at native levels. Plasmid and chromosome borne genes were PCVR controlled, with AtxA, AcpA and AcpB having a >= 4-fold effect on transcript levels of 145, 130 and 49 genes respectively. Several genes were coregulated by two or three PCVRs. We determined that AcpA and AcpB form homomultimers, as shown previously for AtxA, and we detected AtxA-AcpA heteromultimers. In co-expression experiments, AcpA activity was reduced by increased levels of AtxA. Our data show that the PCVRs have specific and overlapping activity and that PCVR stoichiometry and potential heteromultimerization can influence target gene expression. PMID- 29603838 TI - Stem Cell Defect in Ubiquitin-Green Fluorescent Protein Mice Facilitates Engraftment of Lymphoid-Primed Hematopoietic Stem Cells. AB - Transgenic mice expressing green fluorescent protein (GFP) are useful in transplantation experiments. When we used ubiquitin-GFP (UBC-GFP) transgenic mice to study the availability of niches for transplanted hematopoietic stem and progenitor cells, the results were strikingly different from the corresponding experiments that used congenic mice polymorphic in the CD45 antigen. Analysis of these unexpected results revealed that the hematopoiesis of UBC-GFP mice was outcompeted by the hematopoiesis of wild-type (WT) mice. Importantly, UBC-GFP mice engrafted the transplanted bone marrow of WT mice without conditioning. There was a significant bias toward lymphopoiesis in the WT branch of chimeric UBC-GFP/WT hematopoiesis. A fraction of immature Sca-1+ cells in the spleen of UBC-GFP mice expressed GFP at a very high level. The chimeric hematopoiesis was stable in the long term and also after transplantation to secondary recipient mice. The article thus identifies a specific defect in the hematopoiesis of UBC GFP transgenic mice that compromises the lymphoid-primed hematopoietic stem cells in the bone marrow and spleen. Stem Cells 2018;36:1237-1248. PMID- 29603839 TI - Humoral immunity response to human endogenous retroviruses K/W differentiates between amyotrophic lateral sclerosis and other neurological diseases. AB - BACKGROUND AND PURPOSE: Human endogenous retroviruses (HERV) K/W seem to play a role in fostering and exacerbation of some neurological diseases, including amyotrophic lateral sclerosis (ALS). Given these findings, the immunity response against HERV-K and HERV-W envelope surface (env-su) glycoprotein antigens in serum and cerebrospinal fluid (CSF) was investigated for ALS, multiple sclerosis (MS) and Alzheimer's disease patients and in healthy controls. METHODS: Four antigenic peptides derived respectively from HERV-K and HERV-W env-su proteins were studied in 21 definite or probable ALS patients, 26 possible or definite relapsing-remitting MS patients, 18 patients with Alzheimer's disease and 39 healthy controls. An indirect enzyme-linked immunosorbent assay was set up to detect specific antibodies (Abs) against env-su peptides. RESULTS: Amongst the measured levels of Abs against the four different HERV-K peptide fragments, only HERV-K env-su19-37 was significantly elevated in ALS compared to other groups, both in serum and CSF. Instead, amongst the Abs levels directed against the four different HERV-W peptide fragments, only HERV-W env-su93-108 and HERV-W env-su248 262 were significantly elevated, in the serum and CSF of the MS group compared to other groups. In ALS patients, the HERV-K env-su19-37 Abs levels were significantly correlated with clinical measures of disease severity, both in serum and CSF. CONCLUSIONS: Increased circulating levels of Abs directed against the HERV-W env-su93-108 and HERV-W env-su248-262 peptide fragments could serve as possible biomarkers in patients with MS. Similarly, increased circulating levels of Abs directed against the HERV-K env-su19-37 peptide fragment could serve as a possible early novel biomarker in patients with ALS. PMID- 29603840 TI - Dental participation in geriatric interprofessional education courses: A systematic review. AB - INTRODUCTION: Although the interdisciplinary management of the ageing individual is highly stressed, there is limited information on the outcomes of interprofessional education (IPE) activities of dental students in geriatrics. This systematic review aimed to identify studies with dentists participating in formal IPE courses in geriatrics and assess the outcomes reported. MATERIAL AND METHODS: Electronic databases (PubMed, EMBASE, CINAHL and Scopus), reference lists from relevant studies and cited papers were investigated. The inclusion criteria were as follows: about formal interactive learning; learners from at least 2 disciplines; including dentists; related to geriatrics; any study design; reporting any outcome; only full papers; published in peer-reviewed journals; English language. RESULTS: Of the 1259 records retrieved, 26 were assessed for eligibility based on defined inclusion criteria and 7 studies were included in the final analysis. Two studies reported specific outcomes for dentists with lower, or even negative, post-training scores for interprofessional collaborative practice competences compared to other disciplines, but only one of them used a previously validated scale. There were no reports on the effect of IPE courses on dental trainees' gerodontology skill improvements or on their attitudes towards the older persons. CONCLUSION: The existing evidence is insufficient to determine any outcomes of formal interprofessional training of dentists in geriatrics. More studies with better experimental design should be developed. Among the strengths of IPE in geriatrics are the interdisciplinary nature of geriatric care, the sharing of common geriatric competences among participating disciplines and the opportunity to use nursing homes as a training site. PMID- 29603842 TI - A randomised, multi-centre phase III study of 3 different doses of intravenous immunoglobulin 10% in patients with chronic inflammatory demyelinating polyradiculoneuropathy (ProCID trial): Study design and protocol. AB - Patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) show varying degrees of response to intravenous immunoglobulin (IVIg) therapy. This randomised phase III study in patients with CIDP (ProCID trial) will compare the efficacy and safety of 3 different doses (0.5, 1.0, and 2.0 g/kg) of IVIg 10% (panzyga) administered every 3 weeks for 24 weeks. The primary efficacy endpoint is the rate of treatment response, defined as a decrease in adjusted inflammatory neuropathy cause and treatment disability score of >=1 point, in the IVIg 1.0 g/kg arm at week 24. Patients with definite or probable CIDP according to European Federation of Neurological Sciences/Peripheral Nerve Society criteria with IVIg or corticosteroid dependency and active disease are eligible. All potentially eligible patients will undergo IVIg or corticosteroid dose reduction (washout phase) over <=12 weeks or until deterioration of CIDP (active disease). Patients with deterioration during the washout phase will be randomised to receive study treatment during a dose-evaluation phase starting with a loading dose of IVIg 2.0 g/kg followed by maintenance treatment with IVIg 0.5, 1.0, or 2.0 g/kg every 3 weeks. Rescue medication (2 doses of IVIg 2.0 g/kg given 3 weeks apart) will be administered to patients in the IVIg 0.5 and 1.0 g/kg groups who deteriorate after week 3 and before week 18 or who do not improve at week 6. Safety, tolerability and quality of life will be assessed. The ProCID study will provide new information on the best maintenance dose of IVIg for patients with CIDP. PMID- 29603841 TI - Regulation of early endosomes across eukaryotes: Evolution and functional homology of Vps9 proteins. AB - Endocytosis is a crucial process in eukaryotic cells. The GTPases Rab 5, 21 and 22 that mediate endocytosis are ancient eukaryotic features and all available evidence suggests retained conserved function. In animals and fungi, these GTPases are regulated in part by proteins possessing Vps9 domains. However, the diversity, evolution and functions of Vps9 proteins beyond animals or fungi are poorly explored. Here we report a comprehensive analysis of the Vps9 family of GTPase regulators, combining molecular evolutionary data with functional characterization in the non-opisthokont model organism Trypanosoma brucei. At least 3 subfamilies, Alsin, Varp and Rabex5 + GAPVD1, are found across eukaryotes, suggesting that all are ancient features of regulation of endocytic Rab protein function. There are examples of lineage-specific Vps9 subfamily member expansions and novel domain combinations, suggesting diversity in precise regulatory mechanisms between individual lineages. Characterization of the Rabex5 + GAPVD1 and Alsin orthologues in T. brucei demonstrates that both proteins are involved in endocytosis, and that simultaneous knockdown prevents membrane recruitment of Rab5 and Rab21, indicating conservation of function. These data demonstrate that, for the Vps9-domain family at least, modulation of Rab function is mediated by evolutionarily conserved protein-protein interactions. PMID- 29603843 TI - Umpolung of Imines Enables Catalytic Asymmetric Regio-reversed [3+2] Cycloadditions of Iminoesters with Nitroolefins. AB - A copper-catalyzed regio-reversed asymmetric [3+2] cycloaddition of iminoesters with nitroolefins is disclosed for the first time. This method enables the facile synthesis of polysubstituted chiral pyrrolidines bearing at least one chiral quaternary center in high yields with excellent regio-, diastereo-, and enantioselectivity. The application of chiral P,S ligands and the unique effect of alpha-aryl groups on the iminoesters are key to the success of this method. The practicality and versatility of the reaction are also demonstrated. PMID- 29603844 TI - How Changing the Bridgehead Can Affect the Properties of Tripodal Ligands. AB - Although a multitude of studies have explored the coordination chemistry of classical tripodal ligands containing a range of main-group bridgehead atoms or groups, it is not clear how periodic trends affect ligand character and reactivity within a single ligand family. A case in point is the extensive family of neutral tris-2-pyridyl ligands E(2-py)3 (E=C-R, N, P), which are closely related to archetypal tris-pyrazolyl borates. With the 6-methyl substituted ligands E(6-Me-2-py)3 (E=As, Sb, Bi) in hand, the effects of bridgehead modification alone on descending a single group in the periodic table were assessed. The primary influence on coordination behaviour is the increasing Lewis acidity (electropositivity) of the bridgehead atom as Group 15 is descended, which not only modulates the electron density on the pyridyl donor groups but also introduces the potential for anion selective coordination behaviour. PMID- 29603845 TI - Vulvodynia drug research: heterogeneity in, uncertainty out. PMID- 29603846 TI - Network-based decoupling of local gyrification in obsessive-compulsive disorder. AB - Gyrification is associated with cortical maturation and closely linked to neurodevelopmental processes. Obsessive-compulsive disorder has previously been associated with neurodevelopmental risk factors. Using graph theoretical modeling we examined structural covariance patterns to assess potential disruptions in processes associated with neurodevelopment in OCD. In total 97 patients and 92 healthy controls underwent magnetic resonance imaging. Structural covariance networks based on local gyrification indices were constructed using an atlas based parcellation scheme. Network properties were assessed using the network based statistic as well as global and local graph theoretical measures. Correlations between gyrification and symptom severity as well as age of disease onset were examined. Network-based statistic analysis revealed one cluster with significantly decreased structural covariance in patients comprising mainly ventral brain regions (p = .041). Normalized characteristic path length was found to be impaired in patients (p = .051). On a nodal level, left middle frontal sulcus displayed a significantly decreased local clustering coefficient (p < .001). Finally, gyrification in several inferior frontal nodes significantly correlated with age of onset but not symptom severity. The decrease in a gyrification-based covariance network in OCD appears to be mostly confined to ventral areas in which gyrification starts the latest during development. This pattern may indicate that alterations taking place during development are potentially time locked to specific periods. Correlations between gyrification in inferio-frontal nodes and age of onset potentially indicate a structural trait rather than state marker for OCD. Finally, a trend in impaired global integration capabilities may point towards potentially widespread global alterations during neurodevelopment in patients. PMID- 29603847 TI - Inclusion of non-English-speaking patients in research: A single institution experience. AB - BACKGROUND: Considering the recent increase in medical care provided to patients from foreign countries and the diversity of languages spoken by families living within the United States, it is important to determine whether non-English speaking patients have access to participate in clinical research from which they may benefit. AIMS: We aimed to determine the number of non-English-speaking patients presenting to Boston Children's Hospital for medical care between 2011 and 2016, the number of clinical research protocols active within the Department of Anesthesiology, Critical Care and Pain Medicine approved to enroll non-English speaking patients, as well as the number of both non-English- and English speaking patients approached and enrolled in these studies. Furthermore, we attempted to determine barriers that may have prevented non-English-speaking patients from inclusion in clinical research. METHODS: We conducted a retrospective review of various data sources during a 5-year period. Data included the number of non-English-speaking patients presenting to Boston Children's Hospital for care as well as the number of English- and non-English speaking patients approached for studies at the Department of Anesthesiology each year. Additionally, we reviewed data from the IRB which included the justification that research teams provided when opting to exclude non-English speaking participants. In addition, we attempted to determine the barriers that may have prevented these patients from inclusion in research protocols. RESULTS: We found that the number of non-English-speaking patients presenting to Boston Children's Hospital increased over time. However, the number of studies approved to enroll non-English-speaking patients within the Department of Anesthesiology and the rate of enrollment of these patients did not increase at the same rate. CONCLUSION: In order to increase the number of non-English-speaking patients approached to participate in research, we must improve cultural awareness and provide investigators with resources for interpreter and translation services. PMID- 29603848 TI - The integral theory and its tethered vagina syndrome revisited: vaginal scarring may cause massive urinary incontinence. PMID- 29603849 TI - Density Functional Theory Calculations of the Quantum Capacitance of Graphene Oxide as a Supercapacitor Electrode. AB - Graphene oxide has become an attractive electrode-material candidate for supercapacitors thanks to its higher specific capacitance compared to graphene. The quantum capacitance makes relative contributions to the specific capacitance, which is considered as the major limitation of graphene electrodes, while the quantum capacitance of graphene oxide is rarely concerned. This study explores the quantum capacitance of graphene oxide, which bears epoxy and hydroxyl groups on its basal plane, by employing density functional theory (DFT) calculations. The results demonstrate that the total density of states near the Fermi level is significantly enhanced by introducing oxygen-containing groups, which is beneficial for the improvement of the quantum capacitance. Moreover, the quantum capacitances of the graphene oxide with different concentrations of these two oxygen-containing groups are compared, revealing that more epoxy and hydroxyl groups result in a higher quantum capacitance. Notably, the hydroxyl concentration has a considerable effect on the capacitive behavior. PMID- 29603850 TI - The development of search filters for adverse effects of surgical interventions in medline and Embase. AB - BACKGROUND: Search filter development for adverse effects has tended to focus on retrieving studies of drug interventions. However, a different approach is required for surgical interventions. OBJECTIVE: To develop and validate search filters for medline and Embase for the adverse effects of surgical interventions. METHODS: Systematic reviews of surgical interventions where the primary focus was to evaluate adverse effect(s) were sought. The included studies within these reviews were divided randomly into a development set, evaluation set and validation set. Using word frequency analysis we constructed a sensitivity maximising search strategy and this was tested in the evaluation and validation set. RESULTS: Three hundred and fifty eight papers were included from 19 surgical intervention reviews. Three hundred and fifty two papers were available on medline and 348 were available on Embase. Generic adverse effects search strategies in medline and Embase could achieve approximately 90% relative recall. Recall could be further improved with the addition of specific adverse effects terms to the search strategies. CONCLUSION: We have derived and validated a novel search filter that has reasonable performance for identifying adverse effects of surgical interventions in medline and Embase. However, we appreciate the limitations of our methods, and recommend further research on larger sample sizes and prospective systematic reviews. PMID- 29603851 TI - Determining the optimal dose of atrasentan by evaluating the exposure-response relationships of albuminuria and bodyweight. AB - This study aimed to identify the optimal dose of the endothelin-1 receptor antagonist atrasentan with maximal albuminuria reduction and minimal signs of sodium retention, as manifested by increase in bodyweight. Data from the RADAR JAPAN studies were used, evaluating the effect of 0.75 or 1.25 mg/d of atrasentan in 161 patients with type 2 diabetes and kidney disease. Individual pharmacokinetic parameters were estimated using a population pharmacokinetic approach. Subsequently, changes in the urinary albumin-to-creatinine ratio (UACR) and bodyweight from baseline after 2 weeks' exposure were modelled as a function of the pharmacokinetic parameters. The 0.75 and 1.25 mg doses showed a mean UACR reduction of 34.0% and 40.1%, whereas mean bodyweight increased by 0.9 and 1.1 kg, respectively. A large variation between individuals was observed in the UACR and bodyweight responses. Individual pharmacokinetic parameters correlated significantly with both individual UACR and bodyweight responses (P < .01). The individual response curves for UACR and bodyweight crossed at approximately the mean trough concentration of 0.75 mg atrasentan, indicating that 0.75 mg/d of atrasentan is the optimal dose for kidney protection with maximal efficacy (albuminuria reduction) and safety (minimal sodium retention). PMID- 29603852 TI - Proposed information outreach programme in primary and secondary health care of Punjab, Pakistan. AB - The study reported is part of Dr. Naeem's doctoral research, supervised by Professor Bhatti, with the objective to propose an information outreach programme for health care professionals working in rural areas of the Punjab province, Pakistan. A cross-sectional survey was conducted involving 517 practitioners from across different health care facilities in the area. The goals of the outreach programme are identified on the basis of the findings regarding practitioners' current usage and awareness of, as well as attitude and self-efficacy towards using health information resources. The identification of these goals and their related activities, including logistical, promotional and educational, results in a model of the required inputs and investments to achieve both the short term, intermediate and long term results of the programme. F.J. PMID- 29603853 TI - A comprehensive review of guidelines on prevention of preterm birth, albeit lacking in consensus in clinical recommendations. PMID- 29603854 TI - Copper-Mediated Reversible Deactivation Radical Polymerization in Aqueous Media. AB - Key advances within the past 10 years have transformed copper-mediated radical polymerization from a technique which was not very tolerant of protic media into a range of closely related processes capable of controlling the polymerization of a wide range of monomers in pure water at ppm catalyst loadings. This approach has afforded water-soluble macromolecules of desired molecular weight, architecture, and chemical functionality, with applications ranging from drug delivery to oil processing. In this Review we highlight and critically evaluate the synthetic methods that have been developed to control radical polymerization in water by using copper complexes as well as identify future areas of interest and challenges still to be overcome. PMID- 29603855 TI - Five-year refractive changes in a rural Chinese adult population and its related factors: the Handan Eye Study. AB - IMPORTANCE: Provision of refractive changes is important to predict eye care needs for aging population. BACKGROUND: To provide 5-year refractive changes in a rural Chinese adult population. DESIGN: Population-based longitudinal study. PARTICIPANTS: At baseline, 6830 subjects aged 30+ years took part in the Handan Eye Study. A total of 5394 of the 6323 survivors (85.3%) participated in the 5 year follow-up. METHODS: Ocular examinations including standardized refraction were performed according to the same protocol at both baseline and follow-up. MAIN OUTCOME MEASURES: Change in spherical equivalent (SE; sphere + 1/2 cylinder) and astigmatism. RESULTS: A total of 3970 right eyes were available for refraction analysis. The 5-year change in SE for all subjects was +0.17 diopters (D), and was -0.21D, +0.14D, +0.40D and +0.08D for subjects aged 30-39, 40-49, 50 59, and 60-69 years, respectively. By binary regression analysis, myopic shift was associated with severe nuclear opacity, longer axil length, diabetes and large change of lens power, while hyperopic shift was associated with older age and ocular hypertension at baseline. There was a mean change of 0.18D in the against-the-rule astigmatism. CONCLUSIONS AND RELEVANCE: There was a myopic shift for those 30-39 years old and a hyperopic shift from 40 to 69 years old in a rural Chinese adult population. Those with severe nuclear opacity, longer axil length, diabetes and large change of lens power tended to have a myopic shift, while those being older and having ocular hypertension at baseline were prone to have a hyperopic shift. There was also an increase in against-the-rule astigmatism in this population. PMID- 29603856 TI - Hepatotoxicity of immune checkpoint inhibitors: An evolving picture of risk associated with a vital class of immunotherapy agents. AB - Immune checkpoint inhibitors (ICIs) block CTLA-4, PD-1 and PD-L1, or other molecules that control antitumour activities of lymphocytes. These products are associated with a broad array of immune-related toxicities affecting a variety of organs, including the liver. ICI-associated immune-mediated hepatitis (IMH) ranges in severity between mild and life-threatening and is marked by findings that bear both similarities as well as differences with idiopathic autoimmune hepatitis. Hepatotoxic events are often detected in clinical trials of ICIs that are powered for efficacy. Risk levels for ICI-induced liver injury may be impacted by the specific checkpoint molecule targeted for treatment, the ICI dose levels, and the presence of a pre-existing autoimmune diathesis, chronic infection or tumour cells which infiltrate the liver parenchyma. When patients develop liver injury during ICI treatment, a prompt assessment of the cause of injury, in conjunction with the application of measures to optimally manage the adverse event, should be made. Strategies to manage the risk of IMH include the performance of pretreatment liver tests with regular monitoring during and after ICI treatment and patient education. Using Common Terminology Criteria for Adverse Events developed at the National Cancer Institute to measure the severity level of liver injury, recommended actions may include continued ICI treatment with close patient monitoring, ICI treatment suspension or discontinuation and/or administration of corticosteroids or, when necessary, a non-steroidal immunosuppressive agent. The elucidation of reliable predictors of tumour specific ICI treatment responses, as well as an increased susceptibility for clinically serious immune-related adverse events, would help optimize treatment decisions for individual patients. PMID- 29603857 TI - Approaches based on passive and active antibacterial coating on titanium to achieve antibacterial activity. AB - Titanium (Ti) and its alloys are widely applied as orthopedic implants for hip and knee prosthesis, fixation, and dental implants. However, Ti and its alloys are bioinert and susceptible to bacteria and biofilm formation. Strategies for improving the antibacterial properties of Ti can be divided into two approaches, namely, passive coating and active coating on the Ti surface. Passive coating on Ti mainly kills the bacteria in contact but does not kill plankton or bacteria dwell in the bone tissue around the Ti implant. Active coating mainly involves the release of antibacterial agents to kill the bacteria, but this may result in the development of bacterial resistance. Both strategies include advantages and disadvantages. This article reviews the current and potential future approaches for improving antibacterial activity on Ti. We mainly focus on current approaches for fabricating antibacterial Ti and its limitations and countermeasures, and provide direction for further studies of biofunctionalization of Ti with antibacterial properties. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A:2531-2539, 2018. PMID- 29603858 TI - Double Bonds? Studies on the Barrier to Rotation about the Cumulenic C=C Bonds of Tetraaryl[n]cumulenes (n=3, 5, 7, 9). AB - Bonding is a fundamental aspect of organic chemistry, yet the magnitude of C=C bonding in [n]cumulenes as a function of increasing chain length has yet to be experimentally verified for derivatives longer than n=5. The synthesis of a series of apolar and unsymmetrically substituted tetraaryl[n]cumulenes (n=3, 5, 7, 9) was developed and rotational barriers for Z/E isomerization were measured using dynamic VTNMR spectroscopy. Both experiment and theory confirm a dramatic reduction in the rotational barrier (through estimation of DeltaG?rot for the isomerization) across the series, from >24 to 19 to 15 to 11 kcal-1 in [n]cumulenes with n=3, 5, 7, 9, respectively. The reduction in cumulenic bonding in longer cumulenes thus affords bond rotational barriers that are more characteristic of a sterically hindered single bond than that of a double bond. PMID- 29603859 TI - Correlations between skin hydration parameters and corneocyte-derived parameters to characterize skin conditions. AB - BACKGROUND: Skin hydration is generally assessed using the parameters of skin surface water content (SWC) and trans-epidermal water loss (TEWL). To date, few studies have characterized skin conditions using correlations between skin hydration parameters and corneocyte parameters. AIMS: The parameters SWC and TEWL allow the classification of skin conditions into four distinct Groups. The purpose of this study was to assess the characteristics of skin conditions classified by SWC and TEWL for correlations with parameters from corneocytes. METHODS: A human volunteer test was conducted that measured SWC and TEWL. As corneocyte-derived parameters, the size and thick abrasion ratios, the ratio of sulfhydryl groups and disulfide bonds (SH/SS) and CP levels were analyzed. RESULTS: Volunteers were classified by their median SWC and TEWL values into 4 Groups: Group I (high SWC/low TEWL), Group II (high SWC/high TEWL), Group III (low SWC/low TEWL), and Group IV (low SWC/high TEWL). Group IV showed a significantly smaller size of corneocytes. Groups III and IV had significantly higher thick abrasion ratios and CP levels. Group I had a significantly lower SH/SS value. The SWC/TEWL value showed a decline in order from Group I to Group IV. CONCLUSION: Groups classified by their SWC and TEWL values showed characteristic skin conditions. We propose that the SWC and TEWL ratio is a comprehensive parameter to assess skin conditions. PMID- 29603860 TI - Measuring rootworm refuge function: Diabrotica virgifera virgifera emergence and mating in seed blend and strip refuges for Bacillus thuringiensis (Bt) maize. AB - BACKGROUND: Current insect resistance management plans rely on refuges of plants without Bacillus thuringiensis (Bt) toxins to provide a gene pool of unexposed insects. Insects from refuges must mate with insects from Bt maize to slow resistance evolution. We used stable isotope labeling to observe Diabrotica virgifera virgifera emergence, dispersal, physical characteristics, and mating in Bt and refuge maize planted in different refuge configurations. Our objective was to assess how refuge type facilitates mating between insects from Bt and refuge plants. RESULTS: Mating between D. v. virgifera beetles from different plant types was more likely in seed blends compared with strip refuges. Adult D. v. virgifera from refuge plants emerged before those from Bt plants. In strip refuges, D. v. virgifera from refuge plants did not disperse far from refuge boundaries. Larval host plant type did not affect adult size. Larger males and females were more likely to mate. Low proportions of D. v. virgifera from refuge plants were found in 5% seed blend refuges. CONCLUSION: Seed blend refuges can help to facilitate gene flow between D. v. virgifera beetles from Bt and refuge maize, but current approaches do not meaningfully contribute to delaying resistance because numbers of refuge beetles produced are insufficient. (c) 2018 Society of Chemical Industry. PMID- 29603861 TI - Concise Review: Crosstalk of Mesenchymal Stroma/Stem-Like Cells with Cancer Cells Provides Therapeutic Potential. AB - Various direct and indirect cellular interactions between multi-functional mesenchymal stroma/stem-like cells (MSCs) and cancer cells contribute to increasing plasticity within the tumor tissue and its microenvironment. Direct and tight communication between MSC and cancer cells is based on membrane protein interactions and the exchange of large plasma membrane fragments also known as trogocytosis. An ultimate but rare direct interaction resumes in fusion of these two cellular partners resulting in the formation of new cancer hybrid cell populations. Alternatively, indirect interactions are displayed by the release of membranous vesicle-encapsulated microRNAs and proteins or soluble components such as molecular growth factors, hormones, chemo-/cytokines, and metabolites. Released single molecules as well as multivesicular bodies including exosomes and microvesicles can form local concentration gradients within the tumor microenvironment and are incorporated not only by adjacent neighboring cells but also affect distant target cells. The present Review will focus on vesicle mediated indirect communication and on cancer cell fusion with direct contact between MSC and cancer cells. These different types of interaction are accompanied by functional interference and mutual acquisition of new cellular properties. Consequently, alterations in cancer cell functionalities paralleled by the capability to reorganize the tumor stroma can trigger changes in metastatic behavior and promote retrodifferentiation to develop new cancer stem like cells. However, exosomes and microvesicles acting over long distances may also provide a tool with therapeutic potential when loaded with anti-tumor cargo. Stem Cells 2018;36:951-968. PMID- 29603862 TI - Intraoperative hypoxia secondary to pneumothorax: The role of lung ultrasound. AB - Intraoperative pneumothorax during general anesthesia is a dangerous event. It is a possible cause of sudden intraoperative hypoxia, which can be critical especially in high-risk patients such as those with end-stage heart failure. Early diagnosis and effective treatment are essential. We describe the case of a pneumothorax during cardiac transplantation, diagnosed by ultrasound and immediately treated. A good skill in lung ultrasound is advantageous in the management of intraoperative hypoxia, particularly for prompt diagnosis of pneumothorax. PMID- 29603863 TI - Restorative surgery after colectomy for ulcerative colitis in England and Sweden: observations from a comparison of nationwide cohorts. AB - AIM: A longstanding disparity exists between the approaches to restorative surgery after colectomy for patients with ulcerative colitis (UC) in England and Sweden. This study aims to compare rates of colectomy and restorative surgery in comparable national cohorts. METHOD: The English Hospital Episode Statistics (HES) and Swedish National Patient Register (NPR) were interrogated between 2002 and April 2012. Patients with two diagnostic episodes for UC (age >= 15 years) were included. Patients were excluded if they had an episode of inflammatory bowel disease or colectomy before 2002. The cumulative incidences of colectomy and restorative surgery were calculated using the Kaplan-Meier method. RESULTS: A total of 98 691 patients were included in the study, 76 129 in England and 22 562 in Sweden. The 5-year cumulative incidence of all restorative surgery after colectomy in England was 33% vs 46% in Sweden (P-value < 0.001). Of the patients undergoing restorative surgery, 92.3% of English patients had a pouch vs 38.8% in Sweden and 7.7% vs 59.1% respectively had an ileorectal anastomosis (IRA). The 5 year cumulative incidence of colectomy in this study cohort was 13% in England and 6% in Sweden (P-value < 0.001). CONCLUSION: Following colectomy for UC only one-third of English patients and half of Swedish patients underwent restorative surgery. In England nearly all these patients underwent pouches, in Sweden a less significant majority underwent IRAs. It is surprising to demonstrate this discrepancy in a comparable cohort of patients from similar healthcare systems. The causes and consequences of this international variation in management are not fully understood and require further investigation. PMID- 29603864 TI - Vascular smooth muscle cells direct extracellular dysregulation in aortic stiffening of hypertensive rats. AB - Aortic stiffening is an independent risk factor that underlies cardiovascular morbidity in the elderly. We have previously shown that intrinsic mechanical properties of vascular smooth muscle cells (VSMCs) play a key role in aortic stiffening in both aging and hypertension. Here, we test the hypothesis that VSMCs also contribute to aortic stiffening through their extracellular effects. Aortic stiffening was confirmed in spontaneously hypertensive rats (SHRs) vs. Wistar-Kyoto (WKY) rats in vivo by echocardiography and ex vivo by isometric force measurements in isolated de-endothelized aortic vessel segments. Vascular smooth muscle cells were isolated from thoracic aorta and embedded in a collagen I matrix in an in vitro 3D model to form reconstituted vessels. Reconstituted vessel segments made with SHR VSMCs were significantly stiffer than vessels made with WKY VSMCs. SHR VSMCs in the reconstituted vessels exhibited different morphologies and diminished adaptability to stretch compared to WKY VSMCs, implying dual effects on both static and dynamic stiffness. SHR VSMCs increased the synthesis of collagen and induced collagen fibril disorganization in reconstituted vessels. Mechanistically, compared to WKY VSMCs, SHR VSMCs exhibited an increase in the levels of active integrin beta1- and bone morphogenetic protein 1 (BMP1)-mediated proteolytic cleavage of lysyl oxidase (LOX). These VSMC-induced alterations in the SHR were attenuated by an inhibitor of serum response factor (SRF)/myocardin. Therefore, SHR VSMCs exhibit extracellular dysregulation through modulating integrin beta1 and BMP1/LOX via SRF/myocardin signaling in aortic stiffening. PMID- 29603865 TI - Randomized clinical study of alterations in the color and surface roughness of dental enamel brushed with whitening toothpaste. AB - OBJECTIVES: This clinical study evaluated the influence of whitening toothpaste on color and surface roughness of dental enamel. MATERIALS AND METHODS: Initially, the abrasiveness of the toothpastes used (Sorriso Dentes Brancos [SDB]; Colgate Luminous White and Close up White Now) was tested on 30 (n = 10) plexiglass acrylic plates that were submitted to mechanical tooth brushing totalizing 29,200 cycles. Subsequently, 30 participants were selected, and received a toothbrush and nonwhitening toothpaste (SDB). The participants used these products for 7 days and initial color readouts (Spectrophotometer) and surface roughness of one maxillary central incisors was performed after this period of time. For surface roughness readouts, one replica of the maxillary central incisor was obtained by a polyvinyl siloxane impression material (Express) and polyurethane resin. After baseline measurements, participants were separated into three groups (n = 10), according to the toothpaste used. The participants returned after 7, 30, and 90 days when new color readouts and surface roughness were recorded. The measured values were statistically analyzed (2-way-ANOVA, repeated measures, Tukey, P < .05). RESULTS: Whitening toothpastes did not promote significant (P > .05) color alteration and nor increased the surface roughness of the dental enamel in brushing time of the study. CONCLUSIONS: The abrasiveness of whitening toothpaste and the brushing trial period did not affect the surface roughness of dental enamel. However, color changes observed on enamel were above the perceptibility and acceptability thresholds reported in the literature. CLINICAL SIGNIFICANCE: The over-the counter toothpastes tested had an effect on dental enamel color above the perceptibility and acceptability thresholds but did not change the surface roughness of the teeth. PMID- 29603866 TI - Genome-wide analysis of adolescent psychotic-like experiences shows genetic overlap with psychiatric disorders. AB - This study aimed to test for overlap in genetic influences between psychotic-like experience traits shown by adolescents in the community, and clinically recognized psychiatric disorders in adulthood, specifically schizophrenia, bipolar disorder, and major depression. The full spectra of psychotic-like experience domains, both in terms of their severity and type (positive, cognitive, and negative), were assessed using self- and parent-ratings in three European community samples aged 15-19 years (Final N incl. siblings = 6,297 10,098). A mega-genome-wide association study (mega-GWAS) for each psychotic-like experience domain was performed. Single nucleotide polymorphism (SNP) heritability of each psychotic-like experience domain was estimated using genomic relatedness-based restricted maximum-likelihood (GREML) and linkage disequilibrium- (LD-) score regression. Genetic overlap between specific psychotic-like experience domains and schizophrenia, bipolar disorder, and major depression was assessed using polygenic risk score (PRS) and LD-score regression. GREML returned SNP-heritability estimates of 3-9% for psychotic-like experience trait domains, with higher estimates for less skewed traits (Anhedonia, Cognitive Disorganization) than for more skewed traits (Paranoia and Hallucinations, Parent rated Negative Symptoms). Mega-GWAS analysis identified one genome-wide significant association for Anhedonia within IDO2 but which did not replicate in an independent sample. PRS analysis revealed that the schizophrenia PRS significantly predicted all adolescent psychotic-like experience trait domains (Paranoia and Hallucinations only in non-zero scorers). The major depression PRS significantly predicted Anhedonia and Parent-rated Negative Symptoms in adolescence. Psychotic-like experiences during adolescence in the community show additive genetic effects and partly share genetic influences with clinically recognized psychiatric disorders, specifically schizophrenia and major depression. PMID- 29603868 TI - American Society of Pediatric Hematology/Oncology (ASPHO), David L. Lawrence Convention Center, Pittsburgh, PA, May 2-5, 2018. PMID- 29603869 TI - Implementing assessments of robot-assisted technical skill in urological education: a systematic review and synthesis of the validity evidence. AB - OBJECTIVES: To systematically review and synthesise the validity evidence supporting intraoperative and simulation-based assessments of technical skill in urological robot-assisted surgery (RAS), and make evidence-based recommendations for the implementation of these assessments in urological training. MATERIALS AND METHODS: A literature search of the Medline, PsycINFO and Embase databases was performed. Articles using technical skill and simulation-based assessments in RAS were abstracted. Only studies involving urology trainees or faculty were included in the final analysis. RESULTS: Multiple tools for the assessment of technical robotic skill have been published, with mixed sources of validity evidence to support their use. These evaluations have been used in both the ex vivo and in vivo settings. Performance evaluations range from global rating scales to psychometrics, and assessments are carried out through automation, expert analysts, and crowdsourcing. CONCLUSION: There have been rapid expansions in approaches to RAS technical skills assessment, both in simulated and clinical settings. Alternative approaches to assessment in RAS, such as crowdsourcing and psychometrics, remain under investigation. Evidence to support the use of these metrics in high-stakes decisions is likely insufficient at present. PMID- 29603867 TI - Delineating the psychiatric and behavioral phenotype of recurrent 2q13 deletions and duplications. AB - Recurrent deletions and duplications at the 2q13 locus have been associated with developmental delay (DD) and dysmorphisms. We aimed to undertake detailed clinical characterization of individuals with 2q13 copy number variations (CNVs), with a focus on behavioral and psychiatric phenotypes. Participants were recruited via the Unique chromosomal disorder support group, U.K. National Health Service Regional Genetics Centres, and the DatabasE of genomiC varIation and Phenotype in Humans using Ensembl Resources (DECIPHER) database. A review of published 2q13 patient case reports was undertaken to enable combined phenotypic analysis. We present a new case series of 2q13 CNV carriers (21 deletion, 4 duplication) and the largest ever combined analysis with data from published studies, making a total of 54 deletion and 23 duplication carriers. DD/intellectual disabilities was identified in the majority of carriers (79% deletion, 70% duplication), although in the new cases 52% had an IQ in the borderline or normal range. Despite the median age of the new cases being only 9 years, 64% had a clinical psychiatric diagnosis. Combined analysis found attention deficit hyperactivity disorder (ADHD) to be the most frequent diagnosis (48% deletion, 60% duplication), followed by autism spectrum disorders (33% deletion, 17% duplication). Aggressive (33%) and self-injurious behaviors (33%) were also identified in the new cases. CNVs at 2q13 are typically associated with DD with mildly impaired intelligence, and a high rate of childhood psychiatric diagnoses-particularly ADHD. We have further characterized the clinical phenotype related to imbalances of the 2q13 region and identified it as a region of interest for the neurobiological investigation of ADHD. PMID- 29603870 TI - Development of a systematic strategy for the global identification and classification of the chemical constituents and metabolites of Kai-Xin-San based on liquid chromatography with quadrupole time-of-flight mass spectrometry combined with multiple data-processing approaches. AB - To rapidly identify and classify complicated components and metabolites for traditional Chinese medicines, a liquid chromatography with quadrupole time-of flight mass spectrometry method combined with multiple data-processing approaches was established. In this process, Kai-Xin-San, a widely used classic traditional Chinese medicine preparation, was chosen as a model prescription. Initially, the fragmentation patterns, diagnostic product ions and neutral loss of each category of compounds were summarized by collision-induced dissociation analysis of representative standards. In vitro, the multiple product ions filtering technique was utilized to identify the chemical constituents for globally covering trace components. With this strategy, 108 constituents were identified, and compounds database was successfully established. In vivo, the prototype compounds were extracted based on the established database, and the neutral loss filtering technique combined with the drug metabolism reaction rules was employed to identify metabolites. Overall, 69 constituents including prototype and metabolites were characterized in rat plasma and nine constituents were firstly characterized in rat brain, which may be the potential active constituents resulting in curative effects by synergistic interaction. In conclusion, this study provides a generally applicable strategy to global metabolite identification for the complicated components in complex matrix and a chemical basis for further pharmacological research of Kai-Xin-San. PMID- 29603871 TI - Modelling cost-effectiveness of a biomarker-based approach to neoadjuvant chemotherapy for muscle-invasive bladder cancer. AB - OBJECTIVES: To model the cost-effectiveness of a biomarker-based approach to select patients for neoadjuvant chemotherapy (NAC) before radical cystectomy (RC) in muscle-invasive bladder cancer (MIBC). PATIENTS AND METHODS: We obtained data from the most recent clinical studies on patients with locally advanced MIBC treated by RC, including stage distributions, overall survival (OS) estimates, associated costs, and utilisation/response to NAC. Additionally, we estimated the putative efficacy of three biomarkers to select patients for NAC: DNA-repair gene panel [ataxia telangiectasia mutated (ATM), retinoblastoma 1 (RB1), and Fanconi anaemia complementation group C (FANCC)], excision repair cross-complementation group 2 (ERCC2), and ribonucleic acid (RNA) subtypes. A decision analysis model was developed to evaluate the cost-effectiveness of biomarker-based approaches to select patients with MIBC for NAC. Comparison of cost-effectiveness included RC alone, unselected NAC plus RC, and NAC based on the three aforementioned biomarkers. RESULTS: The DNA-repair gene panel-based approach to NAC was the most cost-effective strategy (mean OS of 3.14 years, $31 482/life year). Under this approach, 38% would undergo NAC, about twice the number of patients who are currently receiving NAC for MIBC. Such an approach would improve mean OS by 5.2, 1.6, and 4.4 months compared to RC alone, a hypothetical scenario where all patients received NAC, and compared to current estimates of NAC utilisation, respectively. CONCLUSIONS: A biomarker-based strategy to identify patients with MIBC who should undergo NAC was more cost-effective than unselected use of NAC or RC alone. As further data becomes available, such a model may serve as a basis for incorporating biomarkers into clinical decision making. PMID- 29603872 TI - Effect of once weekly dulaglutide by baseline beta-cell function in people with type 2 diabetes in the AWARD programme. AB - Glucagon-like peptide-1 receptor agonists lower blood glucose in type 2 diabetes (T2D) partially through glucose-dependent stimulation of insulin secretion. The aim of this study was to investigate whether beta-cell function (as measured by HOMA2-%B) at baseline affects the glycaemic response to dulaglutide. Dulaglutide treated patients from AWARD-1, AWARD-3 and AWARD-6 clinical studies were categorised based on their homeostatic model assessment of beta-cell function (HOMA2-%B) tertiles. Changes in glycaemic measures in response to treatment with once-weekly dulaglutide were evaluated in each HOMA2-%B tertile. Patients with low HOMA2-%B had higher baseline glycated haemoglobin (HbA1c), fasting and postprandial blood glucose, and longer duration of diabetes (P < .001, all) (mean low, middle and high tertiles with dulaglutide 1.5 mg: HOMAB-2%B, 31%, 58%, 109%; HbA1c, 8.7%, 7.7%, 7.3%, respectively). At 26 weeks, the low tertile experienced larger reductions in HbA1c compared to the high tertile with dulaglutide 1.5 mg (mean; -1.55% vs. -0.98% [-16.94 vs. -10.71 mmol/mol]). Differences between low and high tertiles disappeared when adjusted for baseline HbA1c (LSM; -1.00 vs. 1.18% [-10.93 vs. -12.90 mmol/mol]). Greater decreases in fasting blood glucose and greater increases in fasting C-peptide were observed in the low tertile. Similar increases in HOMA2-%B were observed in all tertiles. Dulaglutide demonstrated clinically relevant HbA1c reduction irrespective of estimated baseline beta-cell function. PMID- 29603873 TI - In vitro assessment of electrospun polyamide-6 scaffolds for esophageal tissue engineering. AB - Artificial tissue-engineered grafts offer a potential alternative to autologous tissue grafts for patients, which can be traumatic. After decellularizing Papio hamadryas esophagus and studying the morphology and physical properties of the extracellular matrix (ECM), we generated electrospun polyamide-6 based scaffolds to mimic it. The scaffolds supported a greater mechanical load than the native ECM and demonstrated similar 3D microstructure, with randomly aligned fibers, 90% porosity, 29 MUm maximal pore size, and average fiber diameter of 2.87 +/- 0.95 um. Biocompatibility studies showed that human adipose- and bone marrow-derived mesenchymal stromal cells (AD-MSC and BMD-MSC) adhered to the scaffold surface and showed some proliferation: scaffold cell coverage was 25% after 72 h of incubation when seeded with 1000 cells/mm2 ; cells elongated processes along the polyamide-6, although they flattened 1.67-4 times less than on cell culture plastic. Human umbilical vein endothelial cells, however, showed poor adherence and proliferation. We thus provide in vitro evidence that polyamide-6 scaffolds approximating the esophageal biomechanics and 3D topography of nonhuman primates may provide a biocompatible substrate for both AD-MSC and BMD-MSCs, supporting their adhesion and survival to some degree. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2018. PMID- 29603874 TI - Comparison of measured electron energy spectra for six matched, radiotherapy accelerators. AB - : This study compares energy spectra of the multiple electron beams of individual radiotherapy machines, as well as the sets of spectra across multiple matched machines. Also, energy spectrum metrics are compared with central-axis percent depth-dose (PDD) metrics. METHODS: A lightweight, permanent magnet spectrometer was used to measure energy spectra for seven electron beams (7-20 MeV) on six matched Elekta Infinity accelerators with the MLCi2 treatment head. PDD measurements in the distal falloff region provided R50 and R80-20 metrics in Plastic Water(r) , which correlated with energy spectrum metrics, peak mean energy (PME) and full-width at half maximum (FWHM). RESULTS: Visual inspection of energy spectra and their metrics showed whether beams on single machines were properly tuned, i.e., FWHM is expected to increase and peak height decrease monotonically with increased PME. Also, PME spacings are expected to be approximately equal for 7-13 MeV beams (0.5-cm R90 spacing) and for 13-16 MeV beams (1.0-cm R90 spacing). Most machines failed these expectations, presumably due to tolerances for initial beam matching (0.05 cm in R90 ; 0.10 cm in R80-20 ) and ongoing quality assurance (0.2 cm in R50 ). Also, comparison of energy spectra or metrics for a single beam energy (six machines) showed outlying spectra. These variations in energy spectra provided ample data spread for correlating PME and FWHM with PDD metrics. Least-squares fits showed that R50 and R80-20 varied linearly and supralinearly with PME, respectively; however, both suggested a secondary dependence on FWHM. Hence, PME and FWHM could serve as surrogates for R50 and R80-20 for beam tuning by the accelerator engineer, possibly being more sensitive (e.g., 0.1 cm in R80-20 corresponded to 2.0 MeV in FWHM). CONCLUSIONS: Results of this study suggest a lightweight, permanent magnet spectrometer could be a useful beam-tuning instrument for the accelerator engineer to (a) match electron beams prior to beam commissioning, (b) tune electron beams for the duration of their clinical use, and (c) provide estimates of PDD metrics following machine maintenance. However, a real-time version of the spectrometer is needed to be practical. PMID- 29603875 TI - Toll-like receptors 2 and 3 enhance melanogenesis and melanosome transport in human melanocytes. AB - Because little is known about how the innate immune response influences skin pigmentation, we examined whether Toll-like receptor (TLR) agonists participate in melanogenesis and melanosome transportation. We observed that TLR2/2 agonist HKLM and TLR3 agonist Poly(I:C) increased the amount of extracellular melanin from primary human epidermal melanocytes. HKLM, but not Poly(I:C), increased the melanogenic genes such as tyrosinase and dopachrome tautomerase. Poly(I:C) increased the expression of Rab27A, a molecule that facilitates melanosome transport to perimembranous actin filament. UVB irradiation induced Rab27A and melanosome transportation in a similar manner of Poly(I:C). SiRNA for TLR3 or Rab27A suppressed the perimembranous accumulation of Gp100-positive vesicles in melanocytes and decreased melanin transfer to neighboring keratinocytes induced by both Poly(I:C) and UVB. These results suggest that the microenvironment in the epidermis and innate immune stimuli, such as microbiome and ultraviolet represented here by TLR2 and TLR3 agonists, could affect the melanogenesis in human melanocytes. PMID- 29603876 TI - Development of asymmetric resorbable membranes for guided bone and surrounding tissue regeneration. AB - Membranes design for guided tissue engineering have been studied to aid in cell viability and function as tissue barriers. Two asymmetric resorbable membranes for guided bone regeneration (GBR) were produced: chitosan/pectin/poly caprolactone (PECm) and poly(vinyl alcohol)/polyethylenimine/poly(ethylene glycol) (PVAm). Both membranes were characterized by physical, chemical, mechanical, degradation rate, and in vitro biological assessment. Scanning electron microscopy (SEM) confirmed the membranes asymmetry, in which PECm asymmetry is given by roughness and chemical composition, while PVAm's only by differences in porosity. Fourier transform infrared spectroscopy (FTIR) identified chemical groups and bonds between polymers. Both sides of PVAm revealed to be hydrophobic, whereas the PECm presented one side with higher hydrophobicity than the other. In vitro biological assessment disclosed that PECm presented a higher cell adhesion growth pattern than PVAm, where it seemed to occur a delay in proliferation due to initial low cell adhesion. Both developed membranes are suitable for GBR, since both membranes fulfil the requirements to be used as a tissue barrier. The PECm has an additional role in cell viability that was not observed in the PVAm. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2141-2150, 2018. PMID- 29603877 TI - Concordance of somatic mutational profile in multiple primary melanomas. AB - This study aimed to determine the frequency and concordance of BRAF and NRAS mutation in tumours arising in patients with multiple primary melanoma (MPM). Patients with MPM managed at one of three tertiary referral centres in Melbourne, Australia, from 2010 to 2015 were included. Incident and subsequent melanomas underwent mutation testing. Cohen's kappa (kappa) coefficient assessed agreement between incident and subsequent primary melanomas for both BRAF and NRAS mutation status (mutant versus wild-type). Mutation testing of at least two primary tumours from 64 patients was conducted. There was poor agreement for both BRAF and NRAS mutation status between incident and subsequent melanomas (kappa = 0.10, 95% CI -0.10 to 0.42; kappa = 0.06, 95% CI -0.10 to 0.57, respectively). In view of the low concordance in BRAF mutation status between incident and subsequent melanomas, mutational analysis of metastatic tissue, rather than of a primary melanoma, in patients with MPM should be used to guide targeted therapy. PMID- 29603878 TI - Bone morphogenetic protein-2 release profile modulates bone formation in phosphorylated hydrogel. AB - The optimal release profile of locally delivered bone morphogenetic protein-2 (BMP-2) for safe and effective clinical application is unknown. In this work, the effect of differential BMP-2 release on bone formation was investigated using a novel biomaterial oligo[(polyethylene glycol) fumarate] bis[2-(methacryloyloxy) ethyl] phosphate hydrogel (OPF-BP) containing poly(lactic-co-glycolic acid) microspheres. Three composite implants with the same biomaterial chemistry and structure but different BMP-loading methods were created: BMP-2 encapsulated in microspheres (OPF-BP-Msp), BMP-2 encapsulated in microspheres and adsorbed on the phosphorylated hydrogel (OPF-BP-Cmb), and BMP-2 adsorbed on the phosphorylated hydrogel (OPF-BP-Ads). These composites were compared with the clinically used BMP-2 carrier, Infuse(r) absorbable collagen sponge (ACS). Differential release profiles of bioactive BMP-2 were achieved by these composites. In a rat subcutaneous implantation model, OPF-BP-Ads and ACS generated a large BMP-2 burst release (>75%), whereas a more sustained release was seen for OPF-BP-Msp and OPF BP-Cmb (~25% and 50% burst, respectively). OPF-BP-Ads generated significantly more bone than did all other composites, and the bone formation was 12-fold higher than that of the clinically used ACS. Overall, this study clearly shows that BMP-2 burst release generates more subcutaneous bone than do sustained release in OPF-BP-microsphere composites. Furthermore, composites should not only function as a delivery vehicle but also provide a proper framework to achieve appropriate bone formation. PMID- 29603879 TI - Revealing geographical and population heterogeneity in HIV incidence, undiagnosed HIV prevalence and time to diagnosis to improve prevention and care: estimates for France. AB - INTRODUCTION: To close gaps in HIV prevention and care, knowledge about locations and populations most affected by HIV is essential. Here, we provide subnational and sub-population estimates of three key HIV epidemiological indicators, which have been unavailable for most settings. METHODS: We used surveillance data on newly diagnosed HIV cases from 2004 to 2014 and back-calculation modelling to estimate in France, at national and subnational levels, by exposure group and country of birth: the numbers of new HIV infections, the times to diagnosis, the numbers of undiagnosed HIV infections. The denominators used for rate calculations at national and subnational levels were based on population size (aged 18 to 64) estimates produced by the French National Institute of Statistics and Economic Studies and the latest national surveys on sexual behaviour and drug use. RESULTS: We estimated that, in 2014, national HIV incidence was 0.170/00 (95% confidence intervals (CI): 0.16 to 0.18) or 6607 (95% CI: 6057 to 7196) adults, undiagnosed HIV prevalence was 0.640/00 (95% CI: 0.57 to 0.70) or 24,197 (95% CI: 22,296 to 25,944) adults and median time to diagnosis over the 2011 to 2014 period was 3.3 years (interquartile range: 1.2 to 5.7). Three mainland regions, including the Paris region, out of the 27 French regions accounted for 56% of the total number of new and undiagnosed infections. Incidence and undiagnosed prevalence rates were 2- to 10-fold higher than the national rates in three overseas regions and in the Paris region (p-values < 0.001). Rates of incidence and undiagnosed prevalence were higher than the national rates for the following populations (p-values < 0.001): born-abroad men who have sex with men (MSM) (respectively, 108- and 78-fold), French-born MSM (62- and 44-fold), born abroad persons who inject drugs (14- and 18-fold), sub-Saharan African-born heterosexuals (women 15- and 15-fold, men 11- and 13-fold). Importantly, affected populations varied from one region to another, and in regions apparently less impacted by HIV, some populations could be as impacted as those living in most impacted regions. CONCLUSIONS: In France, some regions and populations have been most impacted by HIV. Subnational and sub-population estimates of key indicators are not only essential to adapt, design implement and evaluate tailored HIV interventions in France, but also elsewhere where similar heterogeneity is likely to exist. PMID- 29603880 TI - FMR1 premutation frequency in a large, ethnically diverse population referred for carrier testing. AB - Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and is caused by an expansion of cytosine-guanine-guanine (CGG) repeats in the FMR1 gene. Female premutation allele carriers (55-200 CGG repeats) are at risk to have an affected child. Currently, specific population-based carrier screening for FXS is not recommended. Previous studies exploring female premutation carrier frequency have been limited by size or ethnicity. This retrospective study provides a pan-ethnic estimate of the Fragile X premutation carrier frequency in a large, ethnically diverse population of women referred for routine carrier screening during a specified time period at Progenity, Inc. Patient ethnicity was self-reported and categorized as: African American, Ashkenazi Jewish, Asian, Caucasian, Hispanic, Native American, Other/Mixed/Unknown, or Sephardic Jewish. FXS test results were stratified by ethnicity and repeat allele category. Total premutation carrier frequency was calculated and compared against each ethnic group. A total of 134,933 samples were included. The pan-ethnic premutation carrier frequency was 1 in 201. Only the Asian group differed significantly from this frequency. Using the carrier frequency of 1 in 201, a conservative pan-ethnic risk estimate for a male fetus to have FXS can be calculated as 1 in 2,412. This risk is similar to the highest ethnic-based fetal risks for cystic fibrosis and spinal muscular atrophy, for which population-wide screening is currently recommended. This study adds to the literature and supports further evaluation into specific population-wide screening recommendations for FXS. PMID- 29603881 TI - Decreased risk for microscopic colitis and inflammatory bowel disease among patients with reflux disease. AB - AIM: Previous studies have found an increased risk for microscopic colitis (MC) associated with proton pump inhibitors. In patients with ulcerative colitis (UC) or Crohn's disease (CD), proton pump inhibitors have been associated with an increased risk for IBD flares and impaired outcomes. The aim of this study was to test the epidemiological associations between gastro-oesophageal reflux disease (GERD) and MC, UC or CD in a large database. METHOD: The Miraca Life Sciences Database is a national electronic repository of histopathological records of patients distributed throughout the entire USA. A case-control study evaluated whether the presence of Barrett's metaplasia, erosive oesophagitis on endoscopy or histological signs of reflux oesophagitis, clinical diagnosis of GERD or any GERD type affected the occurrence of MC, UC or CD among 228 506 subjects undergoing bidirectional endoscopy. Multivariate logistic regression analyses were used to calculate ORs and their 95% CI for the risk of MC, UC or CD associated with various types of GERD and were adjusted for age, sex and presence of Helicobacter pylori. RESULTS: The analysis revealed an inverse relationship between GERD and different types of inflammatory bowel disease. The inverse relationships applied similarly to MC (mean = 0.62, 95% CI: 0.58-0.66), UC (mean = 0.89, 95% CI: 0.81-0.97) and CD (mean = 0.76, 95% CI: 0.69-0.85). It also applied to different forms of GERD, with a trend towards more pronounced inverse relationships associated with Barrett's metaplasia or erosive oesophagitis than clinical diagnosis of GERD. CONCLUSION: Gastro-oesophageal reflux disease is inversely associated with all forms of inflammatory bowel disease, such as MC, UC, or CD. PMID- 29603882 TI - The cost-effectiveness and budgetary impact of a dolutegravir-based regimen as first-line treatment of HIV infection in India. AB - INTRODUCTION: Dolutegravir (DTG)-based antiretroviral therapy (ART) is recommended for first-line HIV treatment in the US and Europe. Efavirenz (EFV) based regimens remain the standard of care (SOC) in India. We examined the clinical and economic impact of DTG-based first-line ART in the setting of India's recent guidelines change to treating all patients with HIV infection regardless of CD4 count. METHODS: We used a microsimulation of HIV disease, the Cost-Effectiveness of Preventing AIDS Complications (CEPAC)-International model, to project outcomes in ART-naive patients under two strategies: (1) SOC: EFV/tenofovir disoproxil fumarate (TDF)/lamivudine (3TC); and (2) DTG: DTG + TDF/3TC. Regimen-specific inputs, including virologic suppression at 48 weeks (SOC: 82% vs. DTG: 90%) and annual costs ($98 vs. $102), were informed by clinical trial data and other sources and varied widely in sensitivity analysis. We compared incremental cost-effectiveness ratios (ICERs), measured in $/year of life saved (YLS), to India's per capita gross domestic product ($1600 in 2015). We compared the budget impact and HIV transmission effects of the two strategies for the estimated 444,000 and 916,000 patients likely to initiate ART in India over the next 2 and 5 years. RESULTS: Compared to SOC, DTG improved 5-year survival from 76.7% to 83.0%, increased life expectancy from 22.0 to 24.8 years (14.0 to 15.5 years, discounted), averted 13,000 transmitted HIV infections over 5 years, increased discounted lifetime care costs from $3040 to $3240, and resulted in a lifetime ICER of $130/YLS, less than 10% of India's per capita GDP in 2015. DTG maintained an ICER below 50% of India's per capita GDP as long as the annual three-drug regimen cost was <=$180/year. Over a 2- or 5-year horizon, total undiscounted outlays for HIV-related care were virtually the same for both strategies. CONCLUSIONS: A generic DTG-based regimen is likely to be cost effective and should be recommended for initial therapy of HIV infection in India. PMID- 29603883 TI - Monitoring of blood oxygenation in brain by resonance Raman spectroscopy. AB - Blood oxygenation in cerebral vessels is an essential parameter to evaluate brain function and to investigate the coupling between local blood flow and neuronal activity. We apply resonance Raman spectroscopy in vivo to study hemoglobin oxygenation in cortex vessels of anesthetized ventilated mice. We demonstrate that the pairs of Raman peaks at 1355 and1375 cm-1 (symmetric vibrations of pyrrol half-rings in the heme molecule), 1552 and 1585 cm-1 and 1602 and 1638 cm 1 (vibrations of methine bridges in heme molecule) are reliable markers for quantitative estimation of the relative amount of oxyhemoglobin in venules, arterioles, and capillaries. in vivo measurements of blood oxygenation in the cortex of mice ventilated with inspiratory gas mixtures containing different amounts of oxygen-normoxia, hyperoxia and hypoxia-validate the proposed approach. Our method allows to visualize blood saturation with O2 in different microvascular networks. PMID- 29603884 TI - Molecular cross-talk of IL-6 in tumors and new progress in combined therapy. AB - IL-6, a cytokine activated by type I interferons (IFNs), is encoded by the IL-6 gene, and secreted by T cells and macrophages. It serves many purposes in the human body and is significant to pathological and physiological activities, such as acute inflammatory responses, autoimmune diseases, and tumor formation. The wide range of IL-6 actions on tumors rely on more than one specific pathway. Advances in modern research have determined that to fulfill its complex physiological functions, IL-6 must be involved in cross-talk with a number of other molecular pathways. Therefore, it is important to clarify the comprehensive pathway network associated with IL-6 activity and to explore the mechanisms to inhibit its pathological activity in order to develop corresponding treatment plans. This study is a simple review of the pathological and physiological actions of IL-6 on the human body. It explains in detail the molecular pathways involved in cross-talk between IL-6 and tumors, summarizing and discussing the latest progress made in IL-6-related internal medicine treatments in recent years, including chemotherapies, targeted therapies, and immunotherapies. Our results provide new insight into the treatment of tumors. PMID- 29603885 TI - Synchronous nephron-sparing approaches for bilateral renal masses: peri-operative and renal functional outcomes. AB - OBJECTIVES: To evaluate the peri-operative and renal functional outcomes of patients undergoing synchronous bilateral partial nephrectomy (PN) or percutaneous cryoablation (PCA). PATIENTS AND METHODS: We retrospectively reviewed our institutional nephrectomy and renal mass ablation registries to identify all patients with synchronous bilateral renal masses who underwent simultaneous bilateral PN (n = 76) or PCA (n = 13) between 1974 and 2013. Changes in estimated glomerular filtration rate (eGFR) as well as peri-operative complications are descriptively reported for each procedure. RESULTS: The number of treated renal masses in the 76 patients in the PN group and the 13 patients in the PCA group was 249 and 28, respectively. The median (interquartile range [IQR]) age at treatment was 62 (50, 71) years for the PN group and 67 (56, 72) for the PCA group. The median (IQR) maximum tumour sizes were 4.6 (3.4, 6.5) cm and 2.6 (2.4, 3.2) cm for the PN and PCA groups, respectively. The median (IQR) length of hospital stay was 7 (5, 8) days for the PN group and 1 (1, 10) days for the PCA group. The median (IQR) change in eGFR from baseline to discharge was -32 (-46, -15)% for the PN group and -17% (-33, -3) for the PCA group. By 3 months, median (IQR) renal function improved, with changes of -9 (-19, 0)% and -8 (-11, 15)%, respectively, compared with baseline. No patient in either group required renal replacement therapy in the peri-operative period. Early postoperative complications (within 30 days) occurred in 16 patients (21.6%) in the PN and four patients in the PCA group. In particular, angioembolization for bleeding was required in the postoperative period in two patients (2.7%) in the PN and one patient in the PCA group. CONCLUSIONS: Our experience suggests that synchronous bilateral PN or PCA are feasible treatment options for select patients presenting with bilateral renal masses. In select cases, both approaches appear to have reasonable rates of peri-operative complications and effects on renal function. PMID- 29603886 TI - Raccoon roundworm (Baylisascaris procyonis) as an occupational hazard: 2. Use of personal protective equipment and infection control practices among raccoon rehabilitators. AB - Baylisascaris procyonis, the raccoon roundworm, is a zoonotic ascarid of importance to human and animal health. Wildlife rehabilitators who care for raccoons may be at an increased risk for exposure to the parasite, especially if proper precautions are not taken. In a wider effort to evaluate awareness regarding B. procyonis in the wildlife rehabilitation community, an online survey (38-39 questions) including questions about B. procyonis knowledge and attitudes was developed and administered to wildlife rehabilitators. To assess precautions taken among raccoon rehabilitators, participants who rehabilitated raccoons (n = 447) answered additional questions about use of personal protective equipment (PPE) and infection control practices (ICPs). Reported use of gloves was variable, but hand hygiene was generally consistent. Masks and gowns were seldom used. Part-time or infrequent volunteers and rehabilitators located in the Central, Midwest and Southeast were significantly less likely to report consistent use of PPE. A total knowledge score from the survey was used to predict the likelihood of reporting the use of particular ICPs/PPE. Knowledge score had a highly significant but small effect on the likelihood of prophylactic use of anthelmintics, anthelmintics use for B. procyonis specifically, cleaning appropriately, and using species-dedicated housing. Risk factor analysis was performed on data from a prior serologic survey to evaluate factors associated with exposure to B. procyonis and inconsistent handwashing after contact with live raccoons and their faeces; practising rehabilitation in B. procyonis hyperendemic regions and practising rehabilitation in the western region were significant risk factors for being seropositive. These data further demonstrate that correct PPE/ICPs are critical in mitigating the risk of B. procyonis exposure among raccoon rehabilitators and among other captive species. PMID- 29603887 TI - Screening and management of mental health and substance use disorders in HIV treatment settings in low- and middle-income countries within the global IeDEA consortium. AB - INTRODUCTION: Integration of services to screen and manage mental health and substance use disorders (MSDs) into HIV care settings has been identified as a promising strategy to improve mental health and HIV treatment outcomes among people living with HIV/AIDS (PLWHA) in low- and middle-income countries (LMICs). Data on the extent to which HIV treatment sites in LMICs screen and manage MSDs are limited. The objective of this study was to assess practices for screening and treatment of MSDs at HIV clinics in LMICs participating in the International epidemiology Databases to Evaluate AIDS (IeDEA) consortium. METHODS: We surveyed a stratified random sample of 95 HIV clinics in 29 LMICs in the Caribbean, Central and South America, Asia-Pacific and sub-Saharan Africa. The survey captured information onsite characteristics and screening and treatment practices for depression, post-traumatic stress disorder (PTSD), substance use disorders (SUDs) and other mental health disorders. RESULTS: Most sites (n = 76, 80%) were in urban areas. Mental health screening varied by disorder: 57% of sites surveyed screened for depression, 19% for PTSD, 55% for SUDs and 29% for other mental health disorders. Depression, PTSD, SUDs and other mental health disorders were reported as managed on site (having services provided at the HIV clinic or same health facility) at 70%, 51%, 41% and 47% of sites respectively. Combined availability of screening and on-site management of depression, PTSD, and SUDs, and other mental health disorders was reported by 42%, 14%, 26% and 19% of sites, respectively. On-site management of depression and PTSD was reported significantly less often in rural as compared to urban settings (depression: 33% and 78% respectively; PTSD: 24% and 58% respectively). Screening for depression and SUDs was least commonly reported by HIV programmes that treated only children as compared to HIV programmes that treated only adults or treated both adults and children. CONCLUSIONS: Significant gaps exist in the management of MSDs in HIV care settings in LMICs, particularly in rural settings. Identification and evaluation of optimal implementation strategies to scale and sustain integrated MSDs and HIV care is needed. PMID- 29603889 TI - Apically extruded debris during the removal of canal filling material from root canals using three techniques. AB - AIM: In the present study, we evaluated the effect of the single-cone technique (SCT), cold lateral compaction (CLC), and wave vertical compaction (WVC) technique performed using two different sealers on the amount of apically extruded debris (AED) produced during the removal of canal filling material. METHODS: Ninety extracted mandibular premolars were prepared with ProTaper instruments. The teeth were then randomly assigned to six groups (N = 15) for root canal filling: (a) group 1, CLC+AH Plus; (b) group 2, SCT+AH Plus; (c) group 3, WVC+AH Plus; (d) group 4, CLC+MTA Fillapex; (e) group 5, SCT+MTA Fillapex; and (f) group 6, WVC+MTA Fillapex. In all groups, the removal of canal filling material was performed with ProTaper retreatment instruments. The mean weight of the AED was assessed with an analytical balance. RESULTS: The amount of AED was lowest in groups 2 and 5 (P < .05), with no difference between these groups (P > .05). Groups 3 and 6 produced the greatest amount of extruded debris (P < .05); there was no difference between these groups (P > .05). Additionally, there was no difference between groups 1 and 4 (P > .05). There was no significant difference among the groups regarding sealer type (P > .05). CONCLUSIONS: The canal filling technique used affected the amount of AED produced during the removal of canal filling material, but not sealer type. PMID- 29603888 TI - The cost-effectiveness of HIV pre-exposure prophylaxis in men who have sex with men and transgender women at high risk of HIV infection in Brazil. AB - INTRODUCTION: Men who have sex with men (MSM) and transgender women (TGW) in Brazil experience high rates of HIV infection. We examined the clinical and economic outcomes of implementing a pre-exposure prophylaxis (PrEP) programme in these populations. METHODS: We used the Cost-Effectiveness of Preventing AIDS Complications (CEPAC)-International model of HIV prevention and treatment to evaluate two strategies: the current standard of care (SOC) in Brazil, including universal ART access (No PrEP strategy); and the current SOC plus daily tenofovir/emtracitabine PrEP (PrEP strategy) until age 50. Mean age (31 years, SD 8.4 years), age-stratified annual HIV incidence (age <= 40 years: 4.3/100 PY; age > 40 years: 1.0/100 PY), PrEP effectiveness (43% HIV incidence reduction) and PrEP drug costs ($23/month) were from Brazil-based sources. The analysis focused on direct medical costs of HIV care. We measured the comparative value of PrEP in 2015 United States dollars (USD) per year of life saved (YLS). Willingness-to-pay threshold was based on Brazil's annual per capita gross domestic product (GDP; 2015: $8540 USD). RESULTS: Lifetime HIV infection risk among high-risk MSM and TGW was 50.5% with No PrEP and decreased to 40.1% with PrEP. PrEP increased per person undiscounted (discounted) life expectancy from 36.8 (20.7) years to 41.0 (22.4) years and lifetime discounted HIV-related medical costs from $4100 to $8420, which led to an incremental cost-effectiveness ratio (ICER) of $2530/YLS. PrEP remained cost-effective (<1x GDP) under plausible variation in key parameters, including PrEP effectiveness and cost, initial cohort age and HIV testing frequency on/off PrEP. CONCLUSION: Daily tenofovir/emtracitabine PrEP among MSM and TGW at high risk of HIV infection in Brazil would increase life expectancy and be highly cost-effective. PMID- 29603890 TI - Papillomaviruses in ruminants: An update. AB - Papillomaviruses (PVs) are complex viruses which infect the skin or mucosae of a broad range of amniotes worldwide. They cause benign or malignant lesions depending on environmental factors, virus oncogenicity and the location of infection. Bovine papillomaviruses (BPVs) are the second most studied PVs beyond human PVs. In the past few years, genetic characterization of animal PVs has increased due to the availability of new techniques, which simplified the sequencing of entire genomes. Therefore, this review aims to provide an update of the current epidemiology, classification and genome features of ruminant PVs (mainly BPVs) affecting animals worldwide. The review also aimed to clarify the key differences between the high-risk Delta papillomaviruses and the seemingly low-risk Xi, Epsilon, Dyoxi and Dyokappapillomavirus as well as the recently described PVs BPV18, 19, 21 and PpuPV1 that belongs to an unclassified genus. PMID- 29603891 TI - Change of salivary fluoride level with intake of fluoride releasing lozenges: A pilot study. AB - AIM: Long-term, low-level fluoride concentrations in saliva are highly effective in caries prevention and remineralization. The aim of the present two-phased study was to test whether fluoride-releasing lozenges compared to placebo significantly raise salivary fluoride levels above baseline achieved by 1100 ppm fluoride toothpaste in a double-blind, crossover pilot study. METHODS: In phase 1, a four-arm crossover basic study, four participants used one dissolvable lozenge with .25, 0.5, 1 or 1.5 mg fluoride for 1 hour. In phase 2, the three-arm crossover main study, 11 participants used three lozenges per day for 1 hour for 1 week, establishing long-term salivary fluoride levels dissolving 0 (control), 0.5 and 1.5 mg fluoride lozenges. Saliva was collected at baseline; during lozenge use; 5, 15, 30, and 60 minutes later; and early the next morning. Salivary fluoride levels were determined by laboratory diffusion analysis. RESULTS: In phase 1, 5 minutes after using one lozenge, salivary fluoride levels were above baseline (0.03 ppm), reaching 0.13 +/- 0.19 ppm for the 0.25 mg and 0.73 +/- 0.75 ppm for the 1.5 mg fluoride lozenge, dropping to baseline after 60 minutes. In phase 2, after 1 week use of 0.5 and 1.5 mg lozenges, respectively, for the 0.5 mg lozenge for 15 minutes and the 1.5 mg lozenge 30 minutes after use, the salivary levels were significantly higher than baseline/control (0.02 ppm). During 1-hour lozenge use, fluoride levels >0.1 ppm were consistently achieved. CONCLUSIONS: Fluoride lozenges achieved elevated salivary fluoride levels during use, but only for short periods after use. PMID- 29603892 TI - Niclosamide, a Drug with Many (Re)purposes. AB - Niclosamide is an anthelmintic drug that has been used for over 50 years mainly to treat tapeworm infections. However, with the increase in drug repurposing initiatives, niclosamide has emerged as a true hit in many screens against various diseases. Indeed, from being an anthelmintic drug, it has now shown potential in treating Parkinson's disease, diabetes, viral and microbial infections, as well as various cancers. Such diverse pharmacological activities are a result of niclosamide's ability to uncouple mitochondrial phosphorylation and modulate a selection of signaling pathways, such as Wnt/beta-catenin, mTOR and JAK/STAT3, which are implicated in many diseases. In this highlight, we discuss the plethora of diseases that niclosamide has shown promise in treating. PMID- 29603893 TI - Development of generic raman models for a GS-KOTM CHO platform process. AB - The monitoring and control of bioprocesses is of the utmost importance in order to provide a consistent, safe, and high-quality product for consumers. Current monitoring and control schemes rely on infrequent and time consuming offline sampling methods, which inherently leads to some variability in the process which may impact the product quality profile. As part of Lonza's dedication to process analytical technology (PAT) initiatives this study evaluated the ability to generate generic calibration models, which are independent of the cell line, using Raman probes to monitor changes in glucose, lactate, glutamate, ammonium, viable cell concentration (VCC), total cell concentration (TCC) and product concentration. Calibration models were developed from cell culture using two different CHOK1SV GS-KOTM cell lines producing different monoclonal antibodies (mAbs). Developed predictive models, measured changes in glucose, lactate, ammonium, VCC, and TCC with average prediction errors of 0.44, 0.23, 0.03 g L-1 , 1.90 * 106 cells mL-1 , and 1.85 * 106 cells mL-1 , respectively over the course of cell culture with minimal cell line dependence. The development of these generic models allows the application of spectroscopic PAT techniques in clinical and commercial manufacturing environments, where processes are typically run once or twice in GMP manufacturing based on a common platform process. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:730-737, 2018. PMID- 29603894 TI - Prostate cancer prevention: proof is elusive. PMID- 29603895 TI - Sexual function in patients undergoing combination treatment with alpha1 adrenoceptor antagonists and 5alpha-reductase inhibitors: a step forward in a still-open debate. PMID- 29603896 TI - Well-being beyond the bladder. How do we improve the overall health of patients with bladder cancer? PMID- 29603897 TI - Low rates of bone density testing in prostate cancer survivors on androgen deprivation therapy: where do we go from here? PMID- 29603898 TI - Sepsis: recognition, diagnosis and early management: (c) NICE (2017) Sepsis: recognition, diagnosis and early management. PMID- 29603899 TI - The adoption of generic immunosuppressant medications in kidney, liver, and heart transplantation among recipients in Colorado or nationally with Medicare part D. AB - The transplant community is divided regarding whether substitution with generic immunosuppressants is appropriate for organ transplant recipients. We estimated the rate of uptake over time of generic immunosuppressants using US Medicare Part D Prescription Drug Event (PDE) and Colorado pharmacy claims (including both Part D and non-Part D) data from 2008 to 2013. Data from 26 070 kidney, 15 548 liver, and 6685 heart recipients from Part D, and 1138 kidney and 389 liver recipients from Colorado were analyzed. The proportions of patients with PDEs or claims for generic and brand-name tacrolimus or mycophenolate mofetil were calculated over time by transplanted organ and drug. Among Part D kidney, liver, and heart beneficiaries, the proportion dispensed generic tacrolimus reached 50%-56% at 1 year after first generic approval and 78%-81% by December 2013. The proportion dispensed generic mycophenolate mofetil reached 70%-73% at 1 year after generic market entry and 88%-90% by December 2013. There was wide interstate variability in generic uptake, with faster uptake in Colorado compared with most other states. Overall, generic substitution for tacrolimus and mycophenolate mofetil for organ transplant recipients increased rapidly following first availability, and utilization of generic immunosuppressants exceeded that of brand-name products within a year of market entry. PMID- 29603900 TI - Men who have sex with men more often chose daily than event-driven use of pre exposure prophylaxis: baseline analysis of a demonstration study in Amsterdam. AB - INTRODUCTION: The Amsterdam PrEP project is a prospective, open-label demonstration study at a large sexually transmitted infection (STI) clinic. We examined the uptake of PrEP; the baseline characteristics of men who have sex with men (MSM) and transgender persons initiating PrEP; their choices of daily versus event-driven PrEP and the determinants of these choices. METHODS: From August 2015 through May 2016, enrolment took place at the STI clinic of the Public Health Service of Amsterdam, the Netherlands. MSM or transgender persons were eligible if they had at least one risk factor for HIV infection within the preceding six months. Participants were offered a choice between daily or event driven use of tenofovir/emtricitabine. Baseline data were analysed using descriptive statistics and multivariable analysis was employed to determine variables associated with daily versus event-driven PrEP. RESULTS: Online applications were submitted by 870 persons, of whom 587 were invited for a screening visit. Of them, 415 were screened for eligibility and 376 initiated PrEP. One quarter (103/376, 27%) chose event-driven PrEP. Prevalence of bacterial STI was 19.0% and mean condomless anal sex (CAS) episodes in the preceding three months were 11. In multivariable analysis, older age (>=45 vs. <=34, aOR 2.1, 95% CI 1.2 to 3.9), being involved in a steady relationship (aOR 1.7, 95% CI 1.0 to 2.7), no other daily medication use (aOR 0.6, 95% CI 0.3 to 0.9), and fewer episodes of CAS (per log increase aOR 0.7, 95% CI 0.6 to 0.9) were determinants for choosing event-driven PrEP. DISCUSSION: PrEP programmes are becoming one of the more important intervention strategies with the goal of reducing incident HIV infection and we were unable to accommodate many of the persons applying for this study. Offering a choice of dosing regimen to PrEP users may enable further personalization of HIV prevention strategies and enhance up-take, adherence and cost-effectiveness. CONCLUSIONS: The majority of participants preferred daily versus event-driven use. Within this majority, a high number of CAS episodes before PrEP initiation was reported and we observed a high prevalence of STI. Determinants of choosing event-driven PrEP were older age, fewer CAS episodes, no other daily medication use, and involved in a steady relationship. PMID- 29603901 TI - Behavior of several pseudomonas putida strains growth under different agitation and oxygen supply conditions. AB - The growth rate of four strains of Pseudomonas putida, KT2440, KT2442, KTH2, and KTH2 (pESOX3), under different fluid dynamic conditions has been studied. The cultures were conducted in a stirred tank bioreactor by changing the stirrer speed. Several process variables, such as biomass concentration, dissolved oxygen concentration, oxygen mass transfer rate and oxygen uptake rate, have been measured or calculated. Also cell viability was determined by viable colony counting in Petri dishes and culture samples were subjected into a transmission electron microscopy analysis, in order to describe the integrity of the individual cells. The experimental results show that the genetically modified organisms, the strains KTH2 and KTH2 (pESOX3), present a different growth under low agitation conditions, and low oxygen supply level, while the growth of the wild type strains, KT2440 and KT2442, followed the typical sigmoidal evolution that could be described by the logistic equation. The presence of outer membrane vesicles has been observed in the GMO strains. When the cultures were conducted at low stirrer speed, and so at low oxygen transfer rate, these vesicles were detected, indicating the bacterial response to oxidative stress, caused by the catalytic activity of the HpaC enzyme. For all of the strains tested, no hydrodynamic stress has been detected, even at very high agitation levels. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:900-909, 2018. PMID- 29603902 TI - Intravital molecular tagging velocimetry of cerebral blood flow using Evans Blue. AB - The effects of light-driven enhancement of Evans Blue dye complexes with blood plasma proteins were observed for the first time, both in vitro and in vivo. The possible background of the effect concerns the photochemical cis-trans isomerization of the azo dye molecules. The effect was induced in the solution with a red laser with a wavelength of 638 nm, which corresponds to the peak of the dye absorption. The lifetime of the enhanced fluorescence is approximately 1 second and enables its use as an optically tagged molecular flow tracer for blood flow velocity measurements. Utilizing the effect, we performed for the first time the intravital molecular tagging velocimetry of the blood velocity in blood vessels in a living animal. The results of the measurements of the blood flow velocities in the cerebral veins of a group of healthy mice are presented. PMID- 29603903 TI - Photobiomodulation of freshly isolated human adipose tissue-derived stromal vascular fraction cells by pulsed light-emitting diodes for direct clinical application. AB - A highly interesting source for adult stem cells is adipose tissue, from which the stromal vascular fraction (SVF)-a heterogeneous cell population including the adipose-derived stromal/stem cells-can be obtained. To enhance the regenerative potential of freshly isolated SVF cells, low-level light therapy (LLLT) was used. The effects of pulsed blue (475 nm), green (516 nm), and red (635 nm) light from light-emitting diodes applied on freshly isolated SVF were analysed regarding cell phenotype, cell number, viability, adenosine triphosphate content, cytotoxicity, and proliferation but also osteogenic, adipogenic, and proangiogenic differentiation potential. The colony-forming unit fibroblast assay revealed a significantly increased colony size after LLLT with red light compared with untreated cells, whereas the frequency of colony-forming cells was not affected. LLLT with green and red light resulted in a stronger capacity to form vascular tubes by SVF when cultured within 3D fibrin matrices compared with untreated cells, which was corroborated by increased number and length of the single tubes and a significantly higher concentration of vascular endothelial growth factor. Our study showed beneficial effects after LLLT on the vascularization potential and proliferation capacity of SVF cells. Therefore, LLLT using pulsed light-emitting diode light might represent a new approach for activation of freshly isolated SVF cells for direct clinical application. PMID- 29603904 TI - The Chromosome 18 Clinical Resource Center. AB - BACKGROUND: The Chromosome 18 Clinical Research Center has created a pediatrician friendly virtual resource center for managing patients with chromosome 18 abnormalities. To date, children with rare chromosome abnormalities have been cared for either symptomatically or palliatively as a reaction to the presenting medical problems. As we enter an era of genomic-informed medicine, we can provide children, even those with individually unique chromosome abnormalities, with proactive medical care and management based on the most contemporary data on their specific genomic change. It is problematic for practicing physicians to obtain and use the emerging data on specific genes because this information is derived from diverse sources (e.g., animal studies, case reports, in vitro explorations) and is often published in sources that are not easily accessible in the clinical setting. METHODS: The Chromosome 18 Clinical Resource Center remedies this challenging problem by curating and synthesizing the data with clinical implications. The data are collected from our database of over 26 years of natural history and medical data from over 650 individuals with chromosome 18 abnormalities. RESULTS: The resulting management guides and video presentations are a first edition of this collated data specifically oriented to guide clinicians toward the optimization of care for each child. CONCLUSION: The chromosome 18 data and guides also serve as models for an approach to the management of any individual with a rare chromosome abnormality of which there are over 1,300 born every year in the US alone. PMID- 29603905 TI - Variation in Phenolic Content, Profile, and Antioxidant Activity of Seeds among Different Paeonia ostii Cultivated Populations in China. AB - The purpose of this study was to analyze the phenolic profiles of seeds from fifteen Paeonia ostii cultivated populations in China and identify their relationship with antioxidant activities and associated environmental factors. Thirteen individual phenolic compounds were quantitatively determined by HPLC, and (+)-catechin was the most abundant phenolic compound in the seeds. Correlation analysis showed that phenolics were the most effective antioxidant compound class by evaluating DPPH, ABTS, and hydroxyl radical scavenging activities as well as ferric reducing antioxidant power. Latitude and annual rainfall had significant effects on the contents of many phenolic compounds, and elevation was only significantly correlated with gallic acid content. Within fifteen P. ostii cultivated populations, the seeds of Tongling population exhibited the highest phenolic contents and strongest antioxidant activities. These results suggest that Tongling population has a relatively high utilization value and a potential for sources of natural antioxidants. PMID- 29603906 TI - Antibacterial activity and in vivo wound healing potential of phenolic extracts from jaboticaba skin. AB - In this study, different phenolic extracts were obtained from the jaboticaba skin meal (JSM), whose phenolic compounds were characterized and their antibacterial activities were assessed. Moreover, the activity of lyophilized ethanolic extract of jaboticaba skin (EEJS) on wound healing was analyzed in rats. The JSM phenolic extracts were obtained in four ways: aqueous, methanolic, ethanolic, and acetone extracts. The phenolic compounds were characterized in these extracts by high performance liquid chromatography, and their antibacterial activities were evaluated. The in vivo experiment was divided into four groups and received the following treatments: G1-silver sulfadiazine (positive control); G2-EEJS at 10%; G3-EEJS at 5%, and G4-EEJS at 2.5%. The aqueous extract did not inhibit the growing of any bacterium. The ethanolic, acetone, and methanolic extracts inhibited the growing of all bacteria tested at the concentrations of 1.25%, 2.50%, and 5.00%, respectively. The ethanolic extract was the one that showed the highest bacterial inhibition potential and the highest contents of phenolic compounds, especially of catechin, epicatechin gallate, and epicatechin. The G3 and G4 treatments presented faster wound healing compared to the G1 one, as it promoted a less intense inflammatory reaction and full closure of the wounds at an accelerated rate. PMID- 29603907 TI - Monitoring mAb cultivations with in-situ raman spectroscopy: The influence of spectral selectivity on calibration models and industrial use as reliable PAT tool. AB - Raman spectroscopy is a suitable monitoring technique for CHO cultivations. However, a thorough discussion of peaks, bands, and region assignments to key metabolites and culture attributes, and the interpretability of produced calibrations is scarce. That understanding is vital for the long-term predictive ability of monitoring models, and to facilitate lifecycle management that comply with regulatory guidelines. Several fed-batch lab-scale mAb mammalian cultivations were carried out, with in situ Raman spectroscopy used for process state estimation and attribute monitoring. The goal was to evaluate its use as a process analytical technology (PAT) tool to detect residual glucose and lactate levels, understand their dynamics and interconversion, and eventually estimate key performance culture and product quality attributes. Glucose and lactate models were optimized up to 0.31 g L-1 with 3 Latent Variables (LVs) and 0.19 g L 1 (2 LVs) accuracy, respectively. Glutamine and product titer models, were not specific and accurate enough, even though indirect calibrations were obtained with a RMSEP of 0.12 g L-1 (4 LVs) and 0.29 g L-1 (5 LVs), respectively. A critical discussion and details about the extensive work done in calibration development and optimization are provided. Namely, considering a risk-based selection of variability sources impacting sample spectra, executing designed experiments with spiked cultivations, and using advanced chemometric procedures for variable selection and model cross validation. A strategy is presented to evaluation Raman spectroscopy as a reliable PAT technology fit-for industrial use. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:659 670, 2018. PMID- 29603908 TI - Poly(ethylene glycol) diacrylate based monolithic capillary columns for the analysis of polar small solutes by capillary electrochromatography. AB - Monolithic stationary phases based on poly(ethylene glycol) diacrylates for capillary electrochromatography were developed. Several poly(ethylene glycol) diacrylates (Mn 250, 575, and 700) were used as single monomers and the resulting columns were carefully compared. Methanol and ethyl ether were selected as porogenic solvents, and in all cases ultraviolet radiation was selected as initiation method to prepare polymeric monoliths. The influence of the monomer chain length and ratio monomer/porogen on the morphological and electrochromatographic properties of the resulting monoliths was investigated. Several families of compounds with different polarity (alkyl benzenes, organophosphorous pesticides, benzoic acid derivatives, and sulfonamides) were selected to evaluate the performance of the fabricated monolithic columns. The best results were obtained for poly(ethylene glycol) diacrylate 700 monoliths affording efficiencies of 144 000 plates/m for retained polar aromatic small molecules and excellent reproducibility in column preparation (RSD values below 2.5%). PMID- 29603909 TI - In vitro studies on the degradation of poly(cis-1,4-isoprene). AB - Cleavage of the backbone of poly(cis-1,4-isoprene) (IR) in solid rubber material was accomplished by the addition of partially purified latex clearing protein (Lcp1VH2 ) using a 200-mL enzyme reactor. Two strategies for the addition of Lcp1VH2 were studied revealing that the daily addition of 50 ug mL-1 of Lcp1VH2 for 5 days was clearly a more efficient regime in comparison to a one-time addition of 250 ug of Lcp1VH2 at the beginning. Soluble oligo(cis-1,4-isoprene) molecules occurred as degradation products and were identified by ESI-MS and GPC. Oxygenase activity of Lcp1VH2 with solid IR particles as substrate was shown for the first time by measuring the oxygen consumption in the reaction medium. A strong decrease of the dissolved oxygen concentration was detected at the end of the assay, which indicates an increase in the number of cleavage reactions. The oligo(cis-1,4-isoprene) molecules comprised 1 to 11 isoprene units and exhibited an average molecular weight (Mn ) of 885 g mol-1 . Isolation of the oligo(cis-1,4 isoprene) molecules was achieved by using silica gel column chromatography. The relative quantification of the isolated products was performed by HPLC-MS after derivatization with 2,4-dinitrophenilhydrazyne yielding a concentration of total degradation products of 1.62 g L-1 . Analysis of the polymer surface in samples incubated for 3 days with Lcp1VH2 via ATR-FTIR indicated the presence of carbonyl groups, which occurred upon the cleavage reaction. This study presents a cell free bioprocess as an alternative rubber treatment that can be applied for the partial degradation of the polymer. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:890-899, 2018. PMID- 29603910 TI - Insulin secretion kinetics from single islets reveals distinct subpopulations. AB - Type II diabetes progresses with inadequate insulin secretion and prolonged elevated circulating glucose levels. Also, pancreatic islets isolated for transplantation or tissue engineering can be exposed to glucose over extended timeframe. We hypothesized that isolated pancreatic islets can secrete insulin over a prolonged period of time when incubated in glucose solution and that not all islets release insulin in unison. Insulin secretion kinetics was examined and modeled from single mouse islets in response to chronic glucose exposure (2.8-20 mM). Results with single islets were compared to those from pools of islets. Kinetic analysis of 58 single islets over 72 h in response to elevated glucose revealed distinct insulin secretion profiles: slow-, fast-, and constant-rate secretors, with slow-secretors being most prominent (ca., 50%). Variations in the temporal response to glucose therefore exist. During short-term (<4 h) exposure to elevated glucose few islets are responding with sustained insulin release. The model allowed studying the influence of islet size, revealing no clear effect. At high-glucose concentrations, when secretion is normalized to islet volume, the tendency is that smaller islets secrete more insulin. At high-glucose concentrations, insulin secretion from single islets is representative of islet populations, while under low-glucose conditions pooled islets did not behave as single ones. The characterization of insulin secretion over prolonged periods complements studies on insulin secretion performed over short timeframe. Further investigation of these differences in secretion profiles may resolve open-ended questions on pre-diabetic conditions and transplanted islets performance. This study deliberates the importance of size of islets in insulin secretion. (c) 2018 American Institute of Chemical Engineers Biotechnol. Prog., 34:1059-1068, 2018. PMID- 29603911 TI - Treatment trends and Medicare reimbursements for localized prostate cancer in elderly patients. AB - INTRODUCTION: The absolute and proportional numbers of elderly patients diagnosed with localized prostate cancer (PCa) are on the rise. We examined treatment trends and reimbursement figures in localized PCa patients aged >=80 years. METHODS: Between 2000 and 2008, we identified 30 217 localized PCa patients aged >=80 years in Surveillance, Epidemiology, and End Results (SEER)-Medicare-linked database. Alternative treatment modalities consisted of conservative management (CM), radiation therapy (RT), radical prostatectomy (RP), and primary androgen deprivation therapy (PADT). For all four modalities, utilization and reimbursements were examined. RESULTS: PADT was the most frequently used treatment modality between 2000 and 2005. CM became the dominant treatment modality from 2006-2008. RP rates were marginal. RT ranked third, and its annual rate increased from 20.77% in 2000 to 29.13% in 2008. Median individual reimbursement of RT was highest and ranged from $29 343 in 2000 to $31 090 in 2008, followed by RP (from $20 560 in 2000 to $19 580 in 2008), PADT (from $18 901 in 2000 to $8000 in 2008), and CM (from $1824 in 2000 to $1938 in 2008). RT contributed to most of the cumulative annual reimbursements from 2003 (49.24%) to 2008 (72.97%). PADT ranked first from 2000 (54.56%) to 2002 (50.49%), but decreased by 19.40% in 2008. CM's contribution increased from 4.42% in 2000 to 6.96% in 2008. RP's share of reimbursements was stable during the study period. CONCLUSIONS: Our results, focusing on localized PCa treatment in patients aged >=80 years, showed an important increase in rates, median cost, and proportion of cumulative cost related to RT. PMID- 29603913 TI - Techniques - Temporary suprapubic diversion in a septic male infant using double J stent: Indications and surgical technique. PMID- 29603912 TI - Photoselective vaporization of the prostate with the 180-W XPS-Greenlight laser: Five-year experience of safety, efficiency, and functional outcomes. AB - INTRODUCTION: Transurethral resection of the prostate (TURP) is still considered the gold standard surgical treatment for symptomatic benign prostatic hyperplasia (BPH). However, photoselective vaporization of the prostate (PVP) has gained widespread global acceptance in national guidelines as a safe and effective alternative option. Nevertheless, further evidence is required to assess the durability of Greenlight PVP. Herein, we report our five years of PVP experience with the Greenlight 180W XPS laser system. METHODS: A retrospective analysis was conducted on a prospectively gathered database of 370 consecutively included patients who underwent PVP using Greenlight XPS-180 W laser system (Boston Scientific, Boston, MA, U.S.) performed by a single experienced laser surgeon between 2011 and 2016. Preoperative characteristics, intervention parameters, postoperative functional, uroflowmetry outcomes, and complications were collected. Outcomes are reported over a period of five years. RESULTS: Mean age was 68 years, with a mean prostate volume of 78.8 cc (95% confidence interval [CI] 70.9-78.7]). The mean followup was 59.4 months (55.4-63.5). Mean energy, operative time, and energy/cc were 270.2 kJ (255.2-285.2), 62.7 minutes (59.6 65.7), and 3.7 kJ/cc (3.6-3.9), respectively. Compared to preoperative values, International Prostate Symptom Score (IPSS), maximum flow rate (Qmax), and post void residual (PVR) parameters were significantly improved and sustained over the five postoperative years. Of note, only 66 patients (out of 370) had a complete five-year followup. Prostate-specific antigen (PSA) reached nadir at one year, with a drop of 67% from the mean preoperative value of 6.2 ng/mL. Mean IPSS nadir was reached at three years, with a drop of 80.4% (-21.1 points). Similarly, mean quality of life (QoL) score dropped by 82.8% after three years (preoperative mean of 4.7). With respect to mean Qmax, there was an increase by 72.7% (+14.7 mL/s) at one year, reaching the value of 19.9 mL/s. Moreover, mean PVR was 32.8 mL at four years compared to 345 mL preoperatively. At five years followup, PSA, IPSS, QoL, and PVR dropped by 59.7% (3.7 ng/mL), 75.2% (19.7 points), 78.72% (3.7 points), and 84.4% (291.3 mL), respectively. Qmax increased by 12.9 mL/s. Clavien complication rates were low, with bladder neck stenosis observed in seven (1.6%) men. During the five-year followup, only four patients (1%) required BPH surgical re-intervention. CONCLUSIONS: This is the first long-term reporting of Greenlight XPS-180W laser system. In experienced hands, the observed outcomes appear to demonstrate that Greenlight XPS-180 W laser system is safe, efficacious, and durable for the treatment of bladder outlet obstruction (BOO) secondary to BPH. PMID- 29603914 TI - A new wave of urologists? Graduating urology residents' practices of and attitudes toward social media. AB - INTRODUCTION: Social media (SoMe) have revolutionized healthcare, but physicians remain hesitant to adopt SoMe in their practices. We sought to assess graduating urology residents' practices of and attitudes toward SoMe. METHODS: A close-ended questionnaire, employing five-point Likert scales, was distributed to all final year residents (n=100) in Canadian urology training programs in 2012, 2014, and 2016 to assess SoMe usage and perceived usefulness. RESULTS: All (100%) questionnaires were completed. Respondents frequently used online services for personal (100%) and professional (96%) purposes. Most (92%) used SoMe. Many (73%) frequently used SoMe for personal purposes, but few (12%) frequently used SoMe for professional purposes. While a majority (59%) opposed direct patient interaction online, most supported using SoMe to provide patients with static information (76%) and collaborate with colleagues (65%). Many (70-73%) were optimistic that novel solutions to privacy issues in online communications will arise, making SoMe and email contact with patients conceivable. Few (2-8%) were aware and had read guidelines and legislations regarding physician online practices; however, awareness of medical associations' and institutional SoMe policies significantly increased over time (p<0.05). CONCLUSIONS: Despite their active online use, graduating urology residents rarely used SoMe in professional settings and were wary of using it in patient care. Nevertheless, they were optimistic toward its integration in urology and supported its use in physician physician communication. Considering SoMe's increased influence on urology and graduating residents' limited awareness of guidelines and legislations, postgraduate medical educators should encourage residents to become more familiar with current online communication recommendations. PMID- 29603915 TI - Examining the association between adiposity and biochemical recurrence after radical prostatectomy. AB - INTRODUCTION: Herein, we examined the association between adiposity, as measured by computed tomography (CT), and biochemical recurrence (BCR) after radical prostatectomy (RP). METHODS: Using axial CT images, preoperative fat mass index (FMI) was calculated for 698 men who underwent RP from 2007-2010 by using measurements of total surface area of adipose tissue at the L3 level. Obesity was classified according to National Health and Nutrition Examination Survey (NHANES) standards for obesity (FMI >9 kg/m2). The associations between obesity and the distribution of adiposity (visceral vs. subcutaneous) with BCR were examined using the Kaplan-Meier method and Cox proportional hazards regression analyses. RESULTS: Obese men were older than non-obese men (63.0 vs. 60.7 years; p<0.001), but were similar with regards to all other clinical and pathological characteristics. With a median followup of six years, 152 patients were diagnosed with BCR. Five-year BCR-free survival was similar between obese and non-obese patients (80.6% vs. 82.1%; p=0.27). Furthermore, in multivariable analyses, obesity was not independently associated with the risk of BCR (hazard ratio [HR] 1.02; 95% confidence interval [CI] 0.73-1.43). Similar results were obtained when analyzing FMI as a continuous variable (HR 1.02; 95% CI 0.94-1.09 for each 1 kg/m2 increase in FMI). Additionally, neither visceral adiposity, subcutaneous adiposity, or visceral-to-subcutaneous adiposity ratio were associated with BCR (all p>0.05) in multivariable analyses. CONCLUSIONS: Neither total abdominal adiposity nor the distribution of adiposity were independently associated with BCR after RP in this study. As such, the presence of obesity may not be a marker of increased oncological risk after RP. PMID- 29603916 TI - Phase 1 pharmacokinetics and phase 3 efficacy of testosterone nasal gel in subjects with seasonal allergies. AB - INTRODUCTION: NATESTO(r) testosterone nasal gel (TNG) is a liquid gel that is applied in the nose for the treatment of male hypogonadism. There is a reasonable concern that administration of TNG to patients with active rhinitis could modify absorption. Results from two clinical studies are reported wherein subjects with allergic rhinitis (AR) subjects are treated with TNG. METHODS: The 24-hour pharmacokinetics (PK) and relative bioavailability of serum total testosterone (sTT) from TNG (11 mg tid ) were determined using a phase 1 Latin-square design with 18 eugonadal AR subjects crossed over between asymptomatic, symptomatic untreated, and symptomatic-treated (oxymetazoline) conditions. Allergy symptoms, assessed using Total Nasal Symptom Score (TNSS), were induced using grass pollen in an allergy challenge chamber (ACC) prior to administration of TNG. The data are discussed in relation to results from a phase 3 study in 306 hypogonadal patients which compare clinical outcomes of AR and non-AR patients treated with TNG. RESULTS: PK analysis (Tmax, maximum observed concentration [Cmax], area under the curve [AUC]) of sTT showed no difference in the rate or extent of absorption of exogenous testosterone from TNG as a function of allergy symptoms. The relative bioavailability also showed all three conditions to be equivalent. However, pre-dose mean sTT in AR patients was 21-25% lower when symptomatic vs. asymptomatic, which is attributed to the allergic reaction. A large phase 3 study, based predominantly on PK measures of sTT, showed that clinical outcomes for AR and non-AR patients treated with TNG were identical, including the percentage of patients in the eugonadal range, hormone profiles, and adverse events. CONCLUSIONS: AR does not affect absorption of TNG. Patient outcomes for long-term treatment with TNG for up to one year are not dependent on AR history. PMID- 29603917 TI - A population-based study examining the influence of a specialized rapid-access cancer clinic on initial treatment choice in localized prostate cancer. AB - INTRODUCTION: Treatment decisions in localized prostate cancer are complicated by the available choices. A rapid-access cancer clinic (RAC) has been unique to Calgary, AB, since 2007. This RAC offers multidisciplinary prostate cancer education by a urologist, medical oncologist, and radiation oncologist. It is hypothesized that treatment utilization data from decisions taken at RAC may serve to benchmark the appropriateness of treatment decisions on a population level. METHODS: Records of patients with clinically localized prostate cancer in Alberta between October 1, 2007 and September 30, 2009 were reviewed with ethics approval. Records were linked to the Alberta Cancer Registry database. Clinical, treatment, and health services characteristics pertaining to patients attending RAC were compared to the general population. The primary endpoint was utilization rates of each initial treatment. RESULTS: During this two-year period, 2838 patients were diagnosed with localized prostate cancer; 375 attended RAC. The utilization rates among RAC patients vs. the whole Alberta population were: prostatectomy 60.3% (95% confidence interval [CI] 55.3-65.2) vs. 48.0% (95% CI 47.1-50.7; chi2 p<0.001); active surveillance 16.0% (95% CI 12.3-19.7%) vs. 13.5% (95% CI 12.2-15.8; chi2 p=0.214); radiotherapy 11.7% (95% CI 8.5-15.0) vs. 18.0% (95% CI 16.9-20.5; chi2 p=0.002); and hormone therapy 8.0% (95% CI 5.2-10.8) vs. 17.4% (95% CI 16.1-18.9; chi2 p<0.001). CONCLUSIONS: A specialized clinic for localized prostate cancer may be associated with a higher likelihood of receiving surgery or active surveillance as initial treatment compared to the prostate cancer population in Alberta. PMID- 29603918 TI - The effect of age on cancer-specific mortality in patients with small renal masses: A population-based analysis. AB - INTRODUCTION: Contemporary data regarding the effect of age, especially in elderly patients, on cancer-specific mortality (CSM) for pT1a renal cell carcinoma (RCC) are lacking. The objective of the current study is to evaluate CSM in a large population-based cohort of surgically treated pT1a RCC patients according to age groups. METHODS: Within the Surveillance Epidemiology and End Results database (2000-2013), we identified 37 121 pT1a RCC patients who underwent either partial or radical nephrectomy. The population was stratified into five groups according to decades: <50, 50-59, 60-69, 70-79, and >=80 years. The effect of age on CSM was evaluated using competing risks regression models according to Fuhrman grade (FG). Analyses were repeated in clear-cell RCC (ccRCC). RESULTS: Patients aged 50-59 (9615), 60-69 (10 762), 70-79 (7096), and >=80 (1789) years demonstrated higher rate of CSM compared to patients aged <50 (7856) years (hazard ratios [HR] 2.11, 3.04, 4.47, and 7.56, respectively; all p<0.001). The effect of age on CSM in FG 1-2 patients resulted in HRs ranging from 2.01-8.23 for the same age decades (all p< 0.001). Similarly, the effect of age on CSM in FG 3-4 patients resulted in HRs ranging from 2.38-5.92, respectively (all p<0.001). Virtually the same results were recorded in ccRCC patients. CONCLUSIONS: Older age is associated with higher CSM in surgically treated patients with pT1a RCC. This effect seems to be more pronounced in patient with FG 1-2 disease. This observation should be considered when making treatment decisions in elderly patients. PMID- 29603919 TI - Images - Ureteral fibroepithelial polyps: A modern approach to management. PMID- 29603920 TI - The role of neutrophil-lymphocyte ratio as a prognostic indicator in patients undergoing nephrectomy for renal cell carcinoma. AB - INTRODUCTION: Prognosis in patients with cancer is influenced by underlying tumour biology and also the host inflammatory response to the disease. There is limited evidence to suggest that an elevated neutrophil-lymphocyte ratio (NLR) predicts a poorer prognosis in patients undergoing nephrectomy for renal cell carcinoma (RCC). The aim of this paper is to investigate if patients undergoing nephrectomy for RCC with NLR <=4 have a better overall and recurrence-free survival than patients with NLR >4. METHODS: All patients who underwent nephrectomy at a single centre between January 1, 2011 and December 31, 2014 were identified. Patients were included if postoperative histology demonstrated RCC and if preoperative NLR was available. Patients were excluded if nephrectomy was not curative intent (i.e., cytoreductive nephrectomy), if primary tumour was graded to be T3b-4 disease, if there was presence of nodal or metastatic disease on preoperative staging, or if adequate followup notes were not available. Primary and secondary outcomes were overall survival and recurrence-free survival, respectively. RESULTS: A total of 154 patients were included in analysis of overall survival; 146 patients were included in analysis of recurrence-free survival. Patients with NLR <=4 had a much better overall survival than patients with NLR >4 (95% vs. 78%; p=0.0219). Patients with NLR >4 also had higher rates of recurrence (p=0.0218). CONCLUSIONS: NLR may be a useful tool in identifying patients who may benefit from more frequent surveillance in the early postoperative period and may allow clinicians to offer surveillance schemes tailored to the individual patient. PMID- 29603922 TI - Case - Utility of magnetic resonance urography in pediatric urinary incontinence: Radiological considerations. PMID- 29603921 TI - Improving patient journey and quality of care: Summary from the second Bladder Cancer Canada-Canadian Urological Association-Canadian Urologic Oncology Group (BCC-CUA-CUOG) bladder cancer quality of care consensus meeting. PMID- 29603923 TI - Semantic word impressions expressed by hue. AB - We investigated the possibility of whether impressions of semantic words showing complex concepts could be stably expressed by hues. Using a paired comparison method, we asked ten subjects to select from a pair of hues the one that more suitably matched a word impression. We employed nine Japanese semantic words and used twelve hues from vivid tones in the practical color coordinate system. As examples of the results, for the word "vigorous" the most frequently selected color was yellow and the least selected was blue to purple; for "tranquil" the most selected was yellow to green and the least selected was red. Principal component analysis of the selection data indicated that the cumulative contribution rate of the first two components was 94.6%, and in the two dimensional space of the components, all hues were distributed as a hue-circle shape. In addition, comparison with additional data of color impressions measured by a semantic differential method suggested that most semantic word impressions can be stably expressed by hue, but the impression of some words, such as "magnificent" cannot. These results suggest that semantic word impression can be expressed reasonably well by color, and that hues are treated as impressions from the hue circle, not from color categories. PMID- 29603924 TI - Paradoxical pupil responses to isolated M-cone increments. AB - M-cone onsets appear dimmer than the background and elicit electroretinograms (ERGs) resembling the light offset response. We sought a corresponding anomalous pupillary light reflex (PLR) using a 4-primary ganzfeld as stimulator and pupillometer. Increments and decrements of white light were compared with M- and L-cone onsets and offsets using silent substitution. Luminance bias (LB) could be added to or subtracted from the cone-isolating stimuli. There was a normal PLR to L-cone increments, but the pupil constricted mainly to M-cone decrements. Changing LB produced a neutral point where on and off responses were balanced. The results reflect ERG and psychophysical studies. This observation may be linked to the antagonistic nature of the M-cone input to cone opponent mechanisms. PMID- 29603925 TI - Extrinsic cone-mediated post-receptoral noise inhibits the rod temporal impulse response function. AB - We determined how extrinsic white noise correlating with cone inputs to the three primary visual pathways affects both rod-pathway temporal contrast sensitivity and the impulse response function. A four-primary photostimulator provided independent control of rod and cone photoreceptor excitations under mesopic illumination (20 photopic Td). We show that rod-pathway temporal contrast sensitivity uniformly decreases across all temporal frequencies in the presence of cone noise correlating with the inferred magnocellular, parvocellular, or koniocellular pathways. The rod-pathway temporal impulse response functions derived using the Stork-Falk procedure (with a minimum phase assumption) had lower amplitudes in the pathway-specific cone noise. Therefore, cone noise impairs rod-pathway temporal contrast sensitivity without delaying rod-pathway signal transmission. PMID- 29603926 TI - Correlated cone noise decreases rod signal contributions to the post-receptoral pathways. AB - This study investigated how invisible extrinsic temporal white noise that correlates with the activity of one of the three [magnocellular (MC), parvocellular (PC), or koniocellular (KC)] post-receptoral pathways alters mesopic rod signaling. A four-primary photostimulator provided independent control of the rod and three cone photoreceptor excitations. The rod contributions to the three post-receptoral pathways were estimated by perceptually matching a 20% contrast rod pulse by independently varying the LMS (MC pathway), +L-M (PC pathway), and S-cone (KC pathway) excitations. We show that extrinsic cone noise caused a predominant decrease in the overall magnitude and ratio of the rod contributions to each pathway. Thus, the relative cone activity in the post-receptoral pathways determines the relative mesopic rod inputs to each pathway. PMID- 29603927 TI - Chips in the sunshine: color constancy with real versus simulated Munsell chips under illuminants adjacent to the daylight locus. AB - Accurate color judgments rely on a powerful cognitive component. Here we compare the performance of color constancy under real and simulated conditions. Shifts in the u'v' color plane induced by illuminant A (2750 K) and illuminant S (>20,000 K) were measured using asymmetric color matching. A general linear model was used to predict performance from the following dependent variables: chroma ("4" and "6"), illuminant ("A" and "S"), presentation mode ("Real" and "Monitor"), and hue zone ("blue," "green," "yellow," "red," and "purple"). There was a strong overall effect [F(7,264)=78.65, p<0.001]. Post hoc analysis showed that performance was substantially superior under real [chromatic constancy index (cCI)=0.76] compared with simulated cCI=0.55) conditions. PMID- 29603928 TI - Photoreceptor-specific light adaptation of critical flicker frequency in trichromat and dichromat observers. AB - The silent substitution paradigm offers possibilities to investigate and compare the temporal properties of mechanisms driven by single photoreceptor types, including the critical flicker frequency (CFF), in which the state of adaptation can be kept as invariant. We have (1) measured CFFs using triple silent substitutions to isolate L-, M-, and S-cone as well as rod-driven pathways under identical mean luminances and chromaticities; (2) repeated the CFF measurements at different mean luminances in order to validate the Ferry-Porter law (stating that the relationship between CFF and the log retinal illuminance-log I-is linear); and (3) compared these CFF versus log I functions for L-, M-, S-cone-, and rod-isolating stimuli for five trichromats and four X-linked dichromats (two protanopes, two deuteranopes). We show that the effects of luminance on the CFFs with silent substitution are comparable to those measured previously with chromatic stimuli. We found that M-cone-driven CFFs are smaller in trichromats than in protanopes. Furthermore, the slopes of the M-cone-driven CFF versus log I functions are smaller in trichromats. Possibly, the lacking L-cones are replaced by M-cones in these two protanopes and the CFF depends on cone density. Furthermore, we found that in trichromats, the slopes of the CFF-log I functions are smaller for M-cone- than for L-cone-isolating stimuli. This contradicts the current interpretation of the CFF-log I functions for chromatic stimuli, which states that CFF is mediated by the most strongly modulated photoreceptor type. Thus, the larger slopes that were previously found with medium-wavelength chromatic stimuli compared with long-wavelength chromatic stimuli seem to be the result of an addition of signals from different photoreceptors and do not necessarily result from M-cones being inherently faster. PMID- 29603929 TI - Perceptual resolution of color for multiple chromatically ambiguous objects. AB - In a classic study, Kovacs et al. [Proc. Natl. Acad. Sci. USA93, 15508 (1996)PNASA60027-842410.1073/pnas.93.26.15508] used an array of many disks presented dichoptically with half of the disks in one eye "red" and the other half "green;" disk chromaticities in the fellow eye were reversed, resulting in binocular color rivalry for every disk, thus creating color ambiguity. Surprisingly, the binocularly fused percept sometimes was all disks of the same color (red or green), which showed that perceptual resolution of the many ambiguous neural representations did not rely completely on monocular dominance or on independent resolution for each disk. The present study replicates and expands on the original with the aim to isolate binocularly driven neural mechanisms of perceptual resolution without contamination from monocular dominance. Observers viewed a color-rivalrous array with 16 disks presented either steadily to each eye, as in Kovacs et al., or with chromatic interocular switch rivalry (CISR), which swaps the two images between the eyes every 133 ms. The total proportion of viewing time when the 16 disks were perceived to be all red or all green was measured. For three observers, the disks all appeared the same color more often with CISR than with steady rivalrous presentation, suggesting that monocular dominance interferes with grouped perceptual resolution of ambiguous stimuli in the Kovacs paradigm. This conclusion was supported by an additional condition using CISR, but with every disk the same color in one eye at each instant (e.g., all "red" disks in one eye and all "green" in the other). This condition was never significantly different from the original CISR condition, as expected if CISR reveals only binocularly mediated perceptual resolution of the disks' color, irrespective of monocular neural representations. In conclusion, chromatically tuned binocularly driven neurons account for perceptual resolution of CISR. PMID- 29603930 TI - Electroretinographical determination of human color vision type. AB - It has been previously demonstrated that electroretinography (ERG) elicited by heterochromatically modulated stimuli can be used for objective determination of color vision type. Color vision of trichromatic, deuteranopic, and protanopic participants was psychophysically assessed by the Cambridge Color Test and confirmed genetically. ERG responses to red and green lights modulating in counterphase at 12 and 36 Hz were recorded, while the fraction of red modulation was varied. At 36 Hz (and second harmonics at 12 Hz), the responses were minimal at red fractions that differed significantly in protanopes. At 12 Hz (fundamental component), the responses of the trichromats differed significantly compared to those of the dichromats. An improved protocol shows that the three subject groups can be separated with no overlap. PMID- 29603931 TI - Contrast-dependent red-green balance shifts depend on S-cone activity. AB - Previous research from our lab has established that red-green-balanced yellow targets become greenish-brown as surround luminance increases, while red-green balanced brown targets become reddish-yellow as surround luminance decreases. To help assess the generality and underlying processes of this contrast-dependent red-green hue shift, we investigated red-green hue shifts for target stimuli that appeared achromatic or blue as well as yellow/brown. Results confirmed that the red-green hue shift was largest for yellow/brown targets and was progressively reduced for achromatic and blue targets as target excitation of S cones increased. The magnitude of the hue shift could be predicted by the S/(L+M) excitation of the target when bright white surrounds are used. The hue shift also requires that the target and surround are presented to the same eye, consistent with processing in monocular pathways. Increased S-cone excitation by the surround was associated with red-green hue shifts for all targets equally. Thus, S-cone signals from bright white surrounds might play a role in the contrast dependent red-green hue shift, but the source of the variation of the magnitude of the hue shift with variations in target S-cone excitation when presented on those surrounds is unknown. PMID- 29603932 TI - Age and gender effects on perceptual color scaling using triadic comparisons. AB - We examined age and gender as possible determinants of individual differences in triadic judgments of color dissimilarity. Seventy triads were constructed from 21 equal-lightness Munsell samples, at equal hue steps, forming a rough ellipse in the CIE-LAB plane, and presented to 51 males and 53 females (half young, half elderly adults) who indicated each triad's "odd one out." Principal component analysis followed by multidimensional scaling (MDS) revealed group differences in judgment reliability, with better performance for female and younger groups. Gender differences in color similarity were more pronounced with age, and specific to sectors of the color circle, arguably involving the use of conventional knowledge of color relationships. Maximum-likelihood MDS and inspection of specific triads allowed a more detailed description of these differences. PMID- 29603933 TI - Human S-cone electroretinograms obtained by silent substitution stimulation. AB - We used triple silent substitution stimuli to characterize human S-cone electroretinograms (ERGs) in normal trichromats. Short-wavelength-cone (S-cone) ERGs were found to have different morphological features and temporal frequency response characteristics compared to ERGs derived from L-cones, M-cones, and rod photoreceptors in normal participants. Furthermore, in two cases of retinal pathology, blue cone monochromatism (BCM) and enhanced S-cone syndrome (ESCS), S cone ERGs elicited by our stimuli were preserved and enhanced, respectively. The results from both normal and pathological retinae demonstrate that triple silent substitution stimuli can be used to generate ERGs that provide an assay of human S-cone function. PMID- 29603934 TI - Cone and melanopsin contributions to human brightness estimation. AB - We determined the contributions of cone and melanopsin luminance signaling to human brightness perception. The absolute brightness of four narrowband primary lights presented in a full-field Ganzfeld was estimated in two conditions, either cone luminance-equated (186.7-1,867.0 cd.m-2) or melanopsin luminance-equated (31.6-316.3 melanopsin cd.m-2). We show that brightness estimations for each primary light follow an approximately linear increase with increasing cone or melanopsin luminance (in log units), but are not equivalent for primary lights equated with either cone or melanopsin luminance. Instead, brightness estimations result from a combined interaction between cone and melanopsin signaling. Analytical modeling with wavelength-dependent coefficients signifies that melanopsin luminance positively correlates with brightness magnitudes, and the cone luminance has two contribution components, one that is additive to melanopsin luminance and a second that is negative, implying an adaptation process. These results provide a new framework for evaluating the physiological basis of brightness perception and have direct practical applications for the development of energy-efficient light sources. PMID- 29603935 TI - Age-related changes in ON and OFF responses to luminance increments and decrements. AB - Impulse response functions for an incremental luminous pulse (ON flash) or a decremental luminous pulse (OFF flash) were derived for twelve young (19-24 years old) and ten old (65-84 years old) observers. Thresholds were measured for two pulses separated by stimulus-onset-asynchronies from 13.3 to 186.7 ms. The pulses had a spatial Gaussian shape and were presented as increments or decrements on a 15 cd/m2 equal-energy white background, having the same chromaticity as the pulse. A spatial four-alternative forced-choice method was combined with a staircase procedure. Retinal illuminance was equated individually by heterochromatic flicker photometry and using a 2.3-mm exit pupil in a Maxwellian view optical system to reduce the effects of age-related changes and individual variations in lens density and pupil size. Luminance ON- and OFF-impulse response functions calculated from the threshold data revealed significant age-related changes in the response amplitude of both first excitatory and first inhibitory phases. However, there were no significant changes in the time to the first peak or the second peak. These age-related changes in luminance varying ON- and OFF impulse response functions (IRFs), reflecting putative properties of the magnocellular pathway, are discussed in relation to motion detection and the balance of ON and OFF pathways across the life span. PMID- 29603936 TI - Development of color vision discrimination during childhood: differences between Blue-Yellow, Red-Green, and achromatic thresholds. AB - Nonvisual demands of tests affect vision test results in children. 150 children (79 females and 71 males, 5.3-12.7 years of age) were examined. Isoluminant Blue, Yellow, Red, Green, and Black and White thresholds were established with a four alternative forced-choice and pseudo-10-bit system with adaptive staircase and gaming elements. Where Threshold=b0+b1*age-1, b1 for RG=6.26+/-1.90 (95% confidence limits), Achr=3.96+/-1.07 and BY=12.48+/-2.76 were significantly different. The noncolor demands of the test are the same for RG, BY, and Achr, so the later development of BY discrimination is not an artifact of the test. PMID- 29603937 TI - Influence of permittivity on gradient force exerted on Mie spheres. AB - In optical trapping, whether a particle could be stably trapped into the focus region greatly depends on the strength of the gradient force. Individual theoretical study on gradient force exerted on a Mie particle is rare because the mathematical separation of the gradient force and the scattering force in the Mie regime is difficult. Based on the recent forces separation work by Du et al. [Sci. Rep.7, 18042 (2017)SRCEC32045-232210.1038/s41598-017-17874-1], we investigate the influence of permittivity (an important macroscopic physical quantity) on the gradient force exerted on a Mie particle by cooperating numerical calculation using fast Fourier transform and analytical analysis using multipole expansion. It is revealed that gradient forces exerted on small spheres are mainly determined by the electric dipole moment except for certain permittivity with which the real part of polarizability of the electric dipole approaches zero, and gradient forces exerted on larger spheres are complex because of the superposition of the multipole moments. The classification of permittivity corresponding to different varying tendencies of gradient forces exerted on small spheres or larger Mie particles are illustrated. Absorption of particles favors the trapping of small spheres by gradient force, while it is bad for the trapping of larger particles. Moreover, the absolute values of the maximal gradient forces exerted on larger Mie particles decline greatly versus the varied imaginary part of permittivity. This work provides elaborate investigation on the different varying tendencies of gradient forces versus permittivity, which favors more accurate and free optical trapping. PMID- 29603938 TI - Impact of intraocular lens displacement on the fixation axis. AB - To investigate the impact of intraocular lens (IOL) decentration <=+/-1 mm and IOL tilt <=+/-10 degrees on the fixation axis and spherical equivalent refraction (SE), 50 pseudo-phakic eyes were simulated using numerical ray tracing. We computed the position of the object point whose image ends up at the virtual fovea for each scenario and estimated the corresponding change of fixation axis and SE. The eye turned opposite to the direction of IOL decentration or tilt to compensate for the associated prismatic effect (angle <1.2 degrees ). Decentration of the aspheric IOL resulted in a hyperopic shift (<0.57 D), and tilt in a myopic shift (<0.77 D). PMID- 29603939 TI - Linear solutions to metamaterial volume hologram design using a variational approach. AB - Multiplex volume holograms are conventionally constructed by the repeated exposure of a photosensitive medium to a sequence of external fields, each field typically being the superposition of a reference wave that reconstructs the hologram and the other being a desired signal wave. Because there are no sources of radiation internal to the hologram, the pattern of material modulation is limited to the solutions to Helmholtz's equation in the medium. If the three dimensional structure of the medium could be engineered at each point rather than limited to the patterns produced by standing waves, more versatile structures may result that can overcome the typical limitations to hologram dynamic range imposed by sequentially superimposing holograms. Metamaterial structures and other synthetic electromagnetic materials offer the possibility of achieving high medium contrast engineered at the subwavelength scale. By posing the multiplex volume holography problem as a linear medium design problem, we explore the potential improvements that such engineered synthetic media may provide over conventional multiplex volume holograms. PMID- 29603940 TI - Assessment of the orthogonal and non-orthogonal coupled-mode theory for parallel optical waveguide couplers. AB - The coupled-mode theory (CMT) is a powerful approach routinely used to calculate the effects of spatial mode interactions in perturbed structures, such as optical waveguides. One of its basic hypotheses requires that perturbations are weak. This is usually not the case for devices fabricated with modern semiconductor based technologies. In this paper, the CMT is studied in these critical cases to assess its validity. Attention will be focused on the quite common case of parallel coupled waveguides. For these structures, results can in fact be compared to the exact ones, obtained using super-modes. The study will show that not all the possible expressions of the coupling coefficients are equivalent, and which one can be pragmatically used to obtain results with minimum errors with respect to exact solutions. PMID- 29603941 TI - Hyperspectral database of fruits and vegetables. AB - We have built a hyperspectral database of 42 fruits and vegetables. Both the outside (skin) and inside of the objects were imaged. We used a Specim VNIR HS-CL 30-V8E-OEM mirror-scanning hyperspectral camera and took pictures at a spatial resolution of ~57 px/deg by 800 pixels at a wavelength resolution of ~1.12 nm. A stable, broadband illuminant was used. Images and software are freely available on our webserver (http://www.allpsych.uni-giessen.de/GHIFVD; pronounced "gift"). We performed two kinds of analyses on these images. First, when comparing the insides and outsides of the objects, we observed that the insides were lighter than the skins, and that the hues of the insides and skins were significantly correlated (circular correlation=0.638). Second, we compared the color distribution within each object to corresponding human color discrimination thresholds. We found a significant correlation (0.75) between the orientation of ellipses fit to the chromaticity distributions of our fruits and vegetables with the orientations of interpolated MacAdam discrimination ellipses. This indicates a close relationship between sensory processing and the characteristics of environmental objects. PMID- 29603942 TI - Hue opponency: chromatic valence functions, individual differences, cortical winner-take-all opponent modeling, and the relationship between spikes and sensitivity. AB - Neural spike rate data are more restricted in range than related psychophysical data. For example, several studies suggest a compressive (roughly cube root) nonlinear relationship between wavelength-opponent spike rates in primate midbrain and color appearance in humans, two rather widely separated domains. This presents an opportunity to partially bridge a chasm between these two domains and to probe the putative nonlinearity with other psychophysical data. Here neural wavelength-opponent data are used to create cortical competition models for hue opponency. This effort led to creation of useful models of spiking neuron winner-take-all (WTA) competition and MAX selection. When fed with actual primate data, the spiking WTA models generate reasonable wavelength-opponent spike rate behaviors. An average psychophysical observer for red-green and blue yellow opponency is curated from eight applicable studies in the refereed and dissertation literatures, with cancellation data roughly every 10 nm in 18 subjects for yellow-blue opponency and 15 subjects for red-green opponency. A direct mapping between spiking neurons with broadband wavelength sensitivity and human psychophysical luminance yields a power law exponent of 0.27, similar to the cube root nonlinearity. Similarly, direct mapping between the WTA model opponent spike rates and psychophysical opponent data suggests power law relationships with exponents between 0.24 and 0.41. PMID- 29603943 TI - Factorization of the coherency matrix of polarization optics. AB - We show that the coherency matrix associated with a general depolarizing Mueller matrix can be factorized into the product of a matrix, the coherency matrix factor, and its conjugate transpose. The coherency matrix factor contains all the information in the Mueller matrix, and directly shows useful properties in an illustrative fashion. Propagation through a nondeterministic uniform medium is analyzed. Some examples for simple systems are shown, and an experimental Mueller matrix is considered. The coherency matrix and the coherency matrix factor can be diagonalized, even if the Mueller matrix cannot. PMID- 29603944 TI - Computerized simulation of color appearance for anomalous trichromats using the multispectral image. AB - Most color simulators for color deficiencies are based on the tristimulus values and are intended to simulate the appearance of an image for dichromats. Statistics show that there are more anomalous trichromats than dichromats. Furthermore, the spectral sensitivities of anomalous cones are different from those of normal cones. Clinically, the types of color defects are characterized through Rayleigh color matching, where the observer matches a spectral yellow to a mixture of spectral red and green. The midpoints of the red/green ratios deviate from a normal trichromat. This means that any simulation based on the tristimulus values defined by a normal trichromat cannot predict the color appearance of anomalous Rayleigh matches. We propose a computerized simulation of the color appearance for anomalous trichromats using multispectral images. First, we assume that anomalous trichromats possess a protanomalous (green shifted) or deuteranomalous (red shifted) pigment instead of a normal (L or M) one. Second, we assume that the luminance will be given by L+M, and red/green and yellow/blue opponent color stimulus values are defined through L-M and (L+M)-S, respectively. Third, equal-energy white will look white for all observers. The spectral sensitivities of the luminance and the two opponent color channels are multiplied by the spectral radiance of each pixel of a multispectral image to give the luminance and opponent color stimulus values of the entire image. In the next stage of color reproduction for normal observers, the luminance and two opponent color channels are transformed into XYZ tristimulus values and then transformed into sRGB to reproduce a final image for anomalous trichromats. The proposed simulation can be used to predict the Rayleigh color matches for anomalous trichromats. We also conducted experiments to evaluate the appearance of simulated images by color deficient observers and verified the reliability of the simulation. PMID- 29603945 TI - Comparison of different theories for focusing through a plane interface: comment. AB - In light focusing through a dielectric interface, Wiersma et al. [J. Opt. Soc. Am. A14, 1482 (1997)JOAOD60740-323210.1364/JOSAA.14.001482] claim that the Debye Wolf diffraction theory and the m-theory predict axial focal fields with "little difference." We found a possible mistake of using an inaccurate apodization factor in the m-theory integral. Here we correct the apodization factor, which then leads to better agreement on axial intensity distributions between the two theories than reported. PMID- 29603946 TI - Comparison of different theories for focusing through a plane interface: reply. AB - The correction pointed out by Kim et al. [J. Opt. Soc. Am. A35, 591 (2018)JOAOD60740-323210.1364/JOSAA.35.000591] to our paper [J. Opt. Soc. Am. A14, 1482 (1997)JOAOD60740-323210.1364/JOSAA.14.001482] is welcome. A few additional remarks are included in this reply. PMID- 29603947 TI - Color Vision 2018: Introduction by the feature editors. AB - This feature issue of the Journal of the Optical Society of America A (JOSA A) reflects the basic and applied research interests of members of the color vision community. Most of the articles stem from presentations at the 24th Biennial Symposium of the International Colour Vision Society (ICVS). PMID- 29603948 TI - Efficient, nonlinear phase estimation with the nonmodulated pyramid wavefront sensor. AB - The sensitivity of the pyramid wavefront sensor (PyWFS) has made it a popular choice for astronomical adaptive optics (AAO) systems. The PyWFS is at its most sensitive when it is used without modulation of the input beam. In nonmodulated mode, the device is highly nonlinear. Hence, all PyWFS implementations on current AAO systems employ modulation to make the device more linear. The upcoming era of 30-m class telescopes and the demand for ultra-precise wavefront control stemming from science objectives that include direct imaging of exoplanets make using the PyWFS without modulation desirable. This article argues that nonlinear estimation based on Newton's method for nonlinear optimization can be useful for mitigating the effects of nonlinearity in the nonmodulated PyWFS. The proposed approach requires all optical modeling to be pre-computed, which has the advantage of avoiding real-time simulations of beam propagation. Further, the required real time calculations are amenable to massively parallel computation. Numerical experiments simulate a PyWFS with faces sloped 3.7 degrees to the horizontal, operating at a wavelength of 0.85 MUm, and with an index of refraction of 1.45. A singular value analysis shows that the common practice of calculating two "slope" images from the four PyWFS pupil images discards critical information and is unsuitable for the nonmodulated PyWFS simulated here. Instead, this article advocates estimators that use the raw pixel values not only from the four geometrical images of the pupil, but from surrounding pixels as well. The simulations indicate that nonlinear estimation can be effective when the Strehl ratio of the input beam is greater than 0.3, and the improvement relative to linear estimation tends to increase at larger Strehl ratios. At Strehl ratios less than about 0.5, the performances of both the nonlinear and linear estimators are relatively insensitive to noise since they are dominated by nonlinearity error. PMID- 29603949 TI - Matched coordinates in the framework of polynomial modal methods for complex metasurface modeling. AB - The polynomial modal method (PMM) is one of the most powerful methods for modeling diffraction from lamellar gratings. In the present work, we show that applying it to the so-called matched coordinates leads to important improvement of convergence for crossed lamellar gratings with patterns that are not parallel to the coordinates' axes. After giving the new formulation of the PMM under matched coordinates in the general framework of biperiodic structures, we provide numerical examples to demonstrate the effectiveness of the proposed approach. PMID- 29603950 TI - Improved photon-pair generation from transition-metal dichalcogenide monolayers embedded in one-dimensional photonic crystals. AB - We have theoretically investigated photon-pair generation from transition-metal dichalcogenide (TMDC) monolayers embedded in photonic crystals (PCs) by a rigorous quantum model of spontaneous parametric downconversion. The mean number of output photon pairs and the signal-field energy spectrum have been elaborated. Two different structures are studied: one is a monolayer WS2 embedded in the defective PC, and the other is a stack of WS2 layers in the dielectric multilayer structure. It is clearly shown that an obvious improvement of the generation rate of the correlated photon pairs from the monolayer WS2 can be realized in these two structures, and the enhancement can reach as much as 14 orders of magnitude. Such an effective improvement utilizes the improved field localization at the defect state or the band-edge state, the propagation of photons in the PCs, and coherent superposition; similar phenomena can occur for other TMDC monolayers. These phenomena are very beneficial for the design of optical devices. PMID- 29603951 TI - Which tone-mapping operator is the best? A comparative study of perceptual quality. AB - Tone-mapping operators (TMOs) are designed to generate perceptually similar low dynamic-range images from high-dynamic-range ones. We studied the performance of 15 TMOs in two psychophysical experiments where observers compared the digitally generated tone-mapped images to their corresponding physical scenes. All experiments were performed in a controlled environment, and the setups were designed to emphasize different image properties: in the first experiment we evaluated the local relationships among intensity levels, and in the second one we evaluated global visual appearance among physical scenes and tone-mapped images, which were presented side by side. We ranked the TMOs according to how well they reproduced the results obtained in the physical scene. Our results show that ranking position clearly depends on the adopted evaluation criteria, which implies that, in general, these tone-mapping algorithms consider either local or global image attributes but rarely both. Regarding the question of which TMO is the best, KimKautz ["Consistent tone reproduction," in Proceedings of Computer Graphics and Imaging (2008)] and Krawczyk ["Lightness perception in tone reproduction for high dynamic range images," in Proceedings of Eurographics (2005), p. 3] obtained the better results across the different experiments. We conclude that more thorough and standardized evaluation criteria are needed to study all the characteristics of TMOs, as there is ample room for improvement in future developments. PMID- 29603952 TI - Joint camera blur and pose estimation from aliased data. AB - A joint-estimation algorithm is presented that enables simultaneous camera blur and pose estimation from a known calibration target in the presence of aliasing. Specifically, a parametric maximum-likelihood (ML) point-spread function estimate is derived for characterizing a camera's optical imperfections through the use of a calibration target in an otherwise loosely controlled environment. The imaging perspective, ambient-light levels, target reflectance, detector gain and offset, quantum efficiency, and read-noise levels are all treated as nuisance parameters. The Cramer-Rao bound is derived, and simulations demonstrate that the proposed estimator achieves near optimal mean squared error performance. The proposed method is applied to experimental data to validate the fidelity of the forward models as well as to establish the utility of the resulting ML estimates for both system identification and subsequent image restoration. PMID- 29603953 TI - Iterative optimization in tomographic deconvolution phase microscopy. AB - Tomographic deconvolution phase microscopy (TDPM) is a three-dimensional (3D) quantitative phase imaging (QPI) method using partially coherent light that can be implemented on a commercial microscope platform. However, the measurement procedure is relatively time-consuming because it requires many illumination angles. In the present work, an edge-preserving iterative optimization algorithm is presented and applied to TDPM, so that the required number of illumination angles is reduced from 15 to 3, while the measurement accuracy remains high. In addition, the iterative algorithm does not require matrix representation of operators, so the memory requirement is correspondingly reduced. PMID- 29603954 TI - Evidence for an impact of melanopsin activation on unique white perception. AB - Current models of human color vision only consider cone inputs at photopic light levels, yet it is unclear whether the recently discovered melanopsin-expressing intrinsically photosensitive retinal ganglion cells (ipRGCs) contribute to color perception. Using a lab-made five-primary photostimulator that can independently control the stimulations of rods, cones, and ipRGCs in human retina, we determined the observer's unique white perception, an equilibrium point for signals arising from the opponent mechanisms of color vision, under different levels of melanopsin activation. We found changing melanopsin activation levels shifts the equilibrium point in the chromatic pathways. Our results suggest potential evidence for an impact of melanopsin activation on unique white perception and the existing color vision model for the periphery may need to be revised by incorporating melanopsin signaling. PMID- 29603955 TI - Computational color prediction versus least-dissimilar matching. AB - The performance of color prediction methods CIECAM02, KSM2, Waypoint, Best Linear, Metamer Mismatch Volume Center, and Relit color signal are compared in terms of how well they explain Logvinenko and Tokunaga's asymmetric color matching results [Seeing Perceiving24, 407 (2011)]. In their experiment, four observers were asked to determine (three repeats) for a given Munsell paper under a test illuminant which of 22 other Munsell papers was the least-dissimilar under a match illuminant. Their use of "least-dissimilar" as opposed to "matching" is an important aspect of their experiment. Their results raise several questions. Question 1: Are observers choosing the original Munsell paper under the match illuminant? If they are, then the average (over 12 matches) color signal (i.e., cone LMS or CIE XYZ) made under a given illuminant condition should correspond to that of the test paper's color signal under the match illuminant. Computation shows that the mean color signal of the matched papers is close to the color signal of the physically identical paper under the match illuminant. Question 2: Which color prediction method most closely predicts the observers' average least dissimilar match? Question 3: Given the variability between observers, how do individual observers compare to the computational methods in predicting the average observer matches? A leave-one-observer-out comparison shows that individual observers, somewhat surprisingly, predict the average matches of the remaining observers better than any of the above color prediction methods. PMID- 29603956 TI - Fast propagation of electromagnetic fields through graded-index media. AB - Graded-index (GRIN) media are widely used for modeling different situations: some components are designed considering GRIN modulation, e.g., multi-mode fibers, optical lenses, or acousto-optical modulators; on the other hand, there are other components where the refractive-index variation is undesired due to, e.g., stress or heating; and finally, some effects in nature are characterized by a GRIN variation, like turbulence in air or biological tissues. Modeling electromagnetic fields propagating in GRIN media is then of high importance for optical simulation and design. Though ray tracing can be used to evaluate some basic effects in GRIN media, the field properties are not considered and evaluated. The general physical optics techniques, like finite element method or finite difference time domain, can be used to calculate fields in GRIN media, but they need great numerical effort or may even be impractical for large-scale components. Therefore, there still exists a demand for a fast physical optics model of field propagation through GRIN media on a large scale, which will be explored in this paper. PMID- 29603957 TI - Phase function of a spherical particle when scattering an inhomogeneous electromagnetic plane wave. AB - In absorbing media, electromagnetic plane waves are most often inhomogeneous. Existing solutions for the scattering of an inhomogeneous plane wave by a spherical particle provide no explicit expressions for the scattering components. In addition, current analytical solutions require evaluation of the complex hypergeometric function F12 for every term of a series expansion. In this work, I develop a simpler solution based on associated Legendre functions with argument zero. It is similar to the solution for homogeneous plane waves but with new explicit expressions for the angular dependency of the far-field scattering components, that is, the phase function. I include recurrence formulas for practical evaluation and provide numerical examples to evaluate how well the new expressions match previous work in some limiting cases. The predicted difference in the scattering phase function due to inhomogeneity is not negligible for light entering an absorbing medium at an oblique angle. The presented theory could thus be useful for predicting scattering behavior in dye-based random lasing and in solar cell absorption enhancement. PMID- 29603958 TI - Decay of correlations between cross-polarized electromagnetic waves in a two dimensional random medium. AB - The problem of multiple scattering of polarized light in a two-dimensional medium composed of fiberlike inhomogeneities is studied. The attenuation lengths for the density matrix elements are calculated. For a highly absorbing medium it is found that, as the sample thickness increases, the intensity of waves polarized along the fibers decays faster than the other density matrix elements. With further increase in the sample thickness, the off-diagonal elements which are responsible for correlations between the cross-polarized waves disappear. In the asymptotic limit of very thick samples the scattered light proves to be polarized perpendicular to the fibers. The difference in the attenuation lengths between the density matrix elements results in a nonmonotonic depth dependence of the degree of polarization. In the opposite case of a weakly absorbing medium, the off-diagonal element of the density matrix and, correspondingly, the correlations between the cross-polarized fields are shown to decay faster than the intensity of waves polarized along and perpendicular to the fibers. PMID- 29603959 TI - Denoising imaging polarimetry by adapted BM3D method. AB - In addition to the visual information contained in intensity and color, imaging polarimetry allows visual information to be extracted from the polarization of light. However, a major challenge of imaging polarimetry is image degradation due to noise. This paper investigates the mitigation of noise through denoising algorithms and compares existing denoising algorithms with a new method, based on BM3D (Block Matching 3D). This algorithm, Polarization-BM3D (PBM3D), gives visual quality superior to the state of the art across all images and noise standard deviations tested. We show that denoising polarization images using PBM3D allows the degree of polarization to be more accurately calculated by comparing it with spectral polarimetry measurements. PMID- 29603960 TI - Possible influences on color constancy by motion of color targets and by attention-controlled gaze. AB - We investigated the influence of motion on color constancy using a chromatic stimulus presented in various conditions (static, motion, and rotation). Attention to the stimulus and background was also controlled in different gaze modes, constant fixation of the stimulus, and random viewing of the stimulus. Color constancy was examined in six young observers using a haploscopic view of a computer monitor. The target and background were illuminated in simulation by red, green, blue, and yellow, shifted from daylight (D65) by specific color differences along L - M or S - (L + M) axes on the equiluminance plane. The standard pattern (under D65) and test pattern (under the color illuminant) of a 5 deg square were presented side by side, consisting of 1.2-deg square targets with one of 12 colors at each center, surrounded by 230 background ellipses consisting of eight other colors. The central color targets in both patterns flipped between top and bottom locations at the rate of 3 deg/s in the motion condition. The results indicated an average reduction of color constancy over the 12 test colors by motion. The random viewing parameter indicated better color constancy by more attention to the background, although the difference was not significant. Color constancy of the four color illuminations was better to worse in green, red, yellow, and blue, respectively. The reduction of color constancy by motion could be explained by less contribution of the illumination estimation effect on color constancy. In the motion with constant fixation condition, the retina strongly adapted to the mean chromaticity of the background. However, motion resulted in less attention to the color of the background, causing a weaker effect of the illumination estimation. Conversely, in the static state with a random viewing condition, more attention to the background colors caused a stronger illumination estimation effect, and color constancy was improved overall. PMID- 29603961 TI - Color constancy of color reproductions in art paintings. AB - Popular color reproductions of art paintings such as postcards are intended to remind viewers of the original works. It is, however, unclear how well the quality of the reproductions is preserved under various illuminations. Color constancy of the reproductions in relation to colors in the original paintings was estimated computationally with hyperspectral images of 15th-century Flemish paintings, 20th-century modern abstract paintings, and their corresponding postcards with a series of illuminants: the CIE daylight D65 with correlated color temperature (CCT) 6500 K, daylight D40, fluorescent lamps F2 and F11, and a LED lamp designed for museums with CCT approximately 3500-4000 K. Despite large colorimetric differences between the types of art paintings and between the illuminants simulated, local areas showed good color constancy: skin areas in the Flemish paintings ranged from 0.76 to 0.81, whereas nonskin areas ranged from 0.19 to 0.68. This result suggests that viewers may be able to achieve color constancy with the reproduction postcards by disregarding inconsistent colors representations from the original paintings caused by changes in illumination conditions. PMID- 29603962 TI - Processing of chromatic information in a deep convolutional neural network. AB - Deep convolutional neural networks are a class of machine-learning algorithms capable of solving non-trivial tasks, such as object recognition, with human-like performance. Little is known about the exact computations that deep neural networks learn, and to what extent these computations are similar to the ones performed by the primate brain. Here, we investigate how color information is processed in the different layers of the AlexNet deep neural network, originally trained on object classification of over 1.2M images of objects in their natural contexts. We found that the color-responsive units in the first layer of AlexNet learned linear features and were broadly tuned to two directions in color space, analogously to what is known of color responsive cells in the primate thalamus. Moreover, these directions are decorrelated and lead to statistically efficient representations, similar to the cardinal directions of the second-stage color mechanisms in primates. We also found, in analogy to the early stages of the primate visual system, that chromatic and achromatic information were segregated in the early layers of the network. Units in the higher layers of AlexNet exhibit on average a lower responsivity for color than units at earlier stages. PMID- 29603963 TI - Age, pupil size differences, and color choices for the "dress" and the "jacket". AB - The color identification responses to photographs of #thedress (white/gold and blue/black) and a jacket (white/blue and green/black, and teal) reveal obvious individual differences in color perception. To explore possible association between pupil size/retinal illuminance and color perception, we recorded the pupil diameters of participants shown 22 uniformly colored (generated from the RGB values using a laptop LCD display) screens followed by photographs of #thedress and jacket. We analyzed (a) pupil size difference in the color groups and (b) age-related pupil size and/or reflex change and its influence on color perception. The data confirms that the average pupil size of the white/gold group was significantly less than the blue/black group for the dress. The pupil size difference between the color groups is slightly higher in the 21-30-year and 31 55-year age groups but not in the 18-20-year age group, while a similar variance was not observed for the jacket color groups. Interestingly, the average pupil size of both color groups was smaller for the dress compared to the baseline (collected with a gray hue displayed on the screen), whereas an opposite effect was observed for the jacket. The contrasting results for the two photographs do not allow for a strong inference of only pupil size change principal for differences in color perception. But, a probable explanation of the pupil size difference could be the subjective variation in the perceptual interpretation of illumination cues in the photographs. PMID- 29603964 TI - Are hue and saturation carried in different neural channels? AB - Chromatic discrimination data show that a smaller physical stimulus change is required to detect a change in hue than to detect a change in saturation [Palette30, 21 (1968); Proc. R. Soc. London Ser. B283, 20160164 (2016)PRLBA40080 464910.1098/rspb.2016.0164], and, on this basis, it has been suggested that hue and saturation are carried in different neural channels [Color Space and Its Divisions: Color Order from Antiquity to the Present (Wiley, 2003), p. 311]. We used an adaptation paradigm to test explicitly for separate mechanisms, measuring hue and saturation detection thresholds before and after adaptation to hue and saturation stimuli. Within-condition adaptation did not elevate detection thresholds significantly more than between-condition adaptation. We therefore did not find psychophysical evidence for a neural channel that extracts hue thresholds more effectively than the neural channel or channels that determine saturation thresholds. PMID- 29603965 TI - Effects of eccentricity on color contrast. AB - Using near-threshold stimuli, human color sensitivity has been shown to decrease across the visual field, likely due in part to physiological differences between the fovea and periphery. It remains unclear to what extent this holds true for suprathreshold stimuli. The current study used suprathreshold contrast matching to examine how perceived contrast varies with eccentricity along the cardinal axes in a cone-opponent space. Our data show that, despite increasing stimulus size in the periphery, the LM axis stimuli were still perceived as reduced in contrast, whereas the S axis perceived contrast was observed to increase with eccentricity. PMID- 29603966 TI - Correlation between perception of color, shadows, and surface textures and the realism of a scene in virtual reality. AB - Head-mounted displays allow us to go through immersive experiences in virtual reality and are expected to be present in more and more applications in both recreational and professional fields. In this context, recent years have witnessed significant advances in rendering techniques following physical models of lighting and shading. The aim of this paper is to check the fidelity of the visual appearance of real objects captured through a 3D scanner, rendered in a personal computer and displayed in a virtual reality device. We have compared forward versus deferred rendering in real-time computing using two different illuminations and five artwork replicas. The survey contains seven items for each artwork (color, shading, texture, definition, geometry, chromatic aberration, and pixelation) and an extra item related to the global realism. The results confirm recent advances in virtual reality, showing considerable visual fidelity of generated to real-world images, with a rate close to 4 in a 5-step perceptive scale. They also show a high correlation of the realism sensation with the fidelity of color reproduction, material texture, and definition of the artwork replicas. Moreover, statistically significant differences between two rendering modes are found, with a higher value of realism sensation in the deferred rendering mode. PMID- 29603967 TI - Contrast-dependent red-green hue shift. AB - On bright surrounds, red-green-balanced yellow targets become greenish brown with decreased target luminance, and red-green-balanced brown targets become reddish yellow with increased target luminance. These effects imply luminance- and/or contrast-dependent weighting of M- and L-cone signals in post-receptoral pathways. We show psychophysically that luminance contrast between the surround and the target is the primary determinant of the magnitude of red-green hue shift, requiring surround luminance at least twice the target luminance and increasing with further increases of surround/target contrast. There is a much smaller effect of absolute stimulus luminance, with dimmer stimuli showing slightly larger hue shifts. To evaluate a possible retinal origin of the changes in cone-signal weightings underlying the hue shift, we recorded spike responses from both ON- and OFF-center midget ganglion cells in peripheral primate retina. We found no evidence that the relative strength of L- and M-cone post-receptoral responses changed systematically with change of surround irradiance. Nor was there any systematic difference between ON- and OFF-subtypes. This suggests that the change in cone signal weighting occurs later in the visual system. PMID- 29603968 TI - Effect of eccentricity and light level on the timing of light adaptation mechanisms. AB - We explored the complexity of the light adaptation process, assessing adaptation recovery (Ar) at different eccentricities and light levels. Luminance thresholds were obtained with transient background fields at mesopic and photopic light levels for temporal retinal eccentricities (0 degrees -15 degrees ) with test/background stimulus size of 0.5 degrees /1 degrees using a staircase procedure in a two-channel Maxwellian view optical system. Ar was obtained in comparison with steady data [Vis. Res.125, 12 (2016)VISRAM0042 698910.1016/j.visres.2016.04.008]. Light level proportionally affects Ar only at fovea. Photopic extrafoveal thresholds were one log unit higher for transient conditions. Adaptation was equally fast at low light levels for different retinal locations with variations mainly affected by noise. These results evidence different timing in the mechanisms of adaptation involved. PMID- 29603969 TI - Remote controls illusion: strange interactions across space cannot be explained by simple contrast filters. AB - The visual system has separable visual encoding for luminance and for contrast modulation [J. Vis.8(1), B152 (2008)1534-736210.1167/8.6.1]; the two dimensions can be represented with a luminance contrast versus luminance plane. Here we use a contrast asynchrony paradigm to explore contextual effects on luminance contrast modulation: two identical rectangular bars (0.5 degrees *2.5 degrees ) have luminance levels that modulate at 2 Hz; when one bar is placed on a bright field and the other bar on a dark field, observers perceive the bars modulating in antiphase with each other and yet becoming light and dark at the same time. The antiphase perception corresponds to the change in contrast between the bars and their surrounds (a change along the contrast axis of the plane); the in-phase perception corresponds to the luminance modulation (a change along the luminance axis of the plane). We examine spatial interaction by adding bright rectangular (0.5 degrees *2.5 degrees ) flankers on both sides of the dark-field bar and dark flankers on both sides of the bright-field bar. Remarkably, flankers produce an in-phase appearance when separated from the bars by between 2' and 4' of visual angle, and produce antiphase appearance when they directly adjoin the bars or are separated by more than 8'. To estimate the dimensions of the spatial interaction, we parametrically adjust the size of the gap between bars and flankers and the length of the flankers. We attempt to account for the results with models based on rectified difference of Gaussian filters and with rectified oriented difference of Gaussian filters. The models can account for the results when the flankers are the same height as bars, but are unable to account for the effects of increasing the flanker length. The models therefore suggest that the spatial interaction across distances requires more complex interactions of contrast filters. PMID- 29603970 TI - Quantitative study of color category boundaries. AB - We use World Color Survey (WCS) data to design quantitative methods to study color categorization, with the focus on the "geometric" properties of categories, in particular, on studying their shape, and creating a consistent methodology to identify category boundaries. We introduce the notion of "No Man's Land" and "Some Man's Land" to distinguish color chips that belong to no color category and those that belong to some color category. We introduce a "color-stimulus strength" function that characterizes color boundaries. While categories may come in a variety of shapes, and their boundaries are nonuniform and can vary in thickness, there are universal patterns that emerge. For example, the boundary-to category-mass ratio is a decreasing function of category strength (i.e., stronger categories have relatively thinner boundaries), and boundary mass obeys a "square root"-like law as a function of category mass (i.e., roughly speaking, color categories behave like 2D circles). We further identify a relationship between color boundaries and Shannon's entropy, which can be calculated by using the field data of the WCS. We find that depending on the informational content of a given chip, it can belong to three distinct types: (I) strongly belonging to a color category; (II) belonging to a boundary between two or more categories; (III) not belonging to a category or a boundary. The last two cases can be interpreted in terms of evolution and temporal dynamics of color categories. PMID- 29603971 TI - Individual variations in color-concept space replicate across languages. AB - The cross-cultural nature of color categories and concepts is central to the Berlin-Kay tradition of color-language universalism. In an extension, we examine the cognitive organization of color concepts, the pattern of associations among them, where cross-cultural regularities may also exist. We focus here on individual variations in that pattern. Listing data provide a convenient probe of "associational space" and are amenable to factor analysis using a correlational index of between-list similarity. The rotated factors are "points-of-view": alternative prototypal ways of organizing the concepts and extremes of a spectrum of listing-sequence variation. Points-of-view proved to be comparable for three languages (Hungarian, Italian, Estonian) when visualized with multidimensional scaling. This allowed a similar interpretation of the spectrum of variation in each language, as individual differences in the weight of a conceptual distinction between chromatic and "achromatic" terms, supporting the case for cross-language convergence. PMID- 29603972 TI - The Verriest Lecture: Color vision in an uncertain world. AB - The natural world is optically unconstrained. Surface properties may vary from one point to another, and reflected light may vary from one instant to the next. The aim of this work is to quantify some of the physical failures of color vision performance that result from uncertainty. In computational simulations with images of vegetated and nonvegetated outdoor scenes, it is shown that color provides an unreliable guide to surface identity. It is also shown that changes in illuminant may cause colors to no longer match and the relations between individual colors to vary. These failures are generally well described by a measure of the randomness of the colors in scenes, the Shannon entropy. Although uncertainty is intrinsic to the environment, its consequences for color vision can be predicted. PMID- 29603973 TI - Rough surface reconstruction at grazing angles by an iterated marching method. AB - An iterated marching method is presented for the reconstruction of rough perfectly reflecting one-dimensional (1D) surfaces from scattered data arising from a scalar wave at grazing incidence. This is based on coupled integral equations adapted from an earlier approach using the parabolic equation, relating the scattered field at a plane to the unknown surface. Taking the flat surface as an initial guess, these are solved here using at most three iterations. The method is applied to scattered field data generated from the full Helmholtz equations. This approach improves stability and self-consistency. The reconstructed surface profiles are found to be in good agreement with the exact forms. The sensitivity with respect to random noise is also investigated, and the algorithm is found to exhibit a type of self-regularization. PMID- 29603974 TI - Toward omnidirectional and automated imaging system for measuring oceanic whitecap coverage: retraction. AB - The referenced paper [J. Opt. Soc. Am. A33, 1589 (2016)JOAOD61084 752910.1364/JOSAA.33.001589] has been retracted and replaced with a revised version. PMID- 29603975 TI - Toward omnidirectional and automated imaging system for measuring oceanic whitecap coverage. AB - Accurate measurements of the oceanic whitecap coverage from whitecap images are required for better understanding the air-gas transfer and aerosol production processes. However, this is a challenging task because the whitecap patches are formed immediately after the wave breaks and are spread over a wide area. The main challenges in designing a whitecap-imaging instrument are the small field of view of the camera lens, processing large numbers of images, recording data over long time periods, and deployment difficulties in stormy conditions. This paper describes the design of a novel high-resolution optical instrument for imaging oceanic whitecaps and the automated algorithm processing the collected images. The instrument was successfully deployed in 2013 as part of the HiWINGS campaign in the North Atlantic Ocean. The instrument uses a fish-eye camera lens to image the whitecaps in wide angle of view (180 degrees ). PMID- 29603976 TI - CIE 2017 color fidelity index Rf: a better index to predict perceived color difference? AB - The CIE General Color Rendering Index Ra is currently widely and internationally used to assess the ability of white light sources to render colors. But over the past decades, there has been increasing evidence of its limitations. As a result of several years of scientific work, the Commission Internationale de l'Eclairage (CIE) published in April 2017 an updated calculation method. To reduce misinterpretation by users and make a clear distinction with the other aspects of color quality, the color rendering index was renamed color fidelity index (CIE Rf). Before proposing this index as a new international standard for color fidelity prediction, there is a need for validation. This paper presents a psychophysical experiment designed to address this aim. Twelve observers evaluated color differences of 16 color samples under eight pairs of light sources. 3000K and 4000K light-emitting diodes and fluorescent sources with CIE Rf values ranging from 64 to 94 were investigated. Results show that the prediction of color differences is significantly better in CAM02-UCS color space than in CIE U*V*W* or CIELAB, whatever the color matching functions. A high correlation was found between perceived color differences and CIE-Rf. This psychophysical experiment did not make it possible to detect significant differences with the other tested color fidelity indices (CIE-Ra, CQS-Qf, CRI2012, CRI-CAM02UCS, and IES-Rf). However, there are some signs of an improvement of the prediction by CIE-Rf in comparison to CIE-Ra. To increase, in further works, the chance to detect potential significant differences between color fidelity indices, some modifications of the experimental protocols are suggested. PMID- 29603977 TI - Quantization noise as a determinant for color thresholds in machine vision. AB - Color discrimination simulation is applied to study a uniformity of the color space of machine vision devices whose operation is based on a three-component color model and which involve analog-to-digital conversion of signals with a resolution of 8 bits per channel. Algorithms for finding the intervals of the dominant wavelength and color saturation of a specimen are developed. The spectral dependence of intervals of color parameters calculated using the digital images is found. It is shown that machine vision possesses the color discrimination thresholds, which can be drawn in the CIE1931 xy chromaticity diagram in the form of equal-contrast ellipses similar to the MacAdam ellipses. At resolution of 6 bits, the size of a reference MacAdam's ellipse is a little less than that of the machine vision ellipse's sizes, and at resolution of 7 bits, it is a little more than that of the machine vision ellipse's sizes. A hypothesis is proposed that implies that the process of an encoding of the visual neural signals may include procedures similar to an analog-to-digital conversion. PMID- 29603978 TI - Chromatic induction in space and time. AB - : The color appearance of a light depends on variation in the complete visual field over both space and time. In the spatial domain, a chromatic stimulus within a patterned chromatic surround can appear a different hue than the same stimulus within a uniform surround. In the temporal domain, a stimulus presented as an element of a continuously changing chromaticity can appear a different color compared to the identical stimulus, presented simultaneously but viewed alone. This is the flash-lag effect for color, which has an analog in the domain of motion: a pulsed object seen alone can appear to lag behind an identical pulsed object that is an element of a motion sequence. Studies of the flash-lag effect for motion have considered whether it is mediated by a neural representation for the moving physical stimulus or, alternatively, for the perceived motion. The current study addresses this question for the flash-lag effect for color by testing whether the color flash lag depends on a representation of only the changing chromatic stimulus or, alternatively, its color percept, which can be altered by chromatic induction. METHODS: baseline measurements for spatial chromatic induction determined the chromaticity of a flashed ring within a uniform surround that matched a flashed ring within a patterned surround. Baseline measurements for the color flash-lag effect determined the chromaticity of a pulsed ring presented alone (within a uniform surround) that matched a pulsed ring presented in a sequence of changing chromaticity over time (also within a uniform surround). Finally, the main experiments combined chromatic induction from a patterned surround and the flash lag effect, in three conditions: (1) both the changing and pulsed rings were within a patterned chromatic surround; (2) the changing ring was within a patterned surround and the pulsed ring within a uniform surround; and (3) the changing ring was within a uniform surround and the pulsed ring within a patterned surround. RESULTS: the flash-lag measurements for a changing chromaticity were affected by perceptual changes induced by the surrounding chromatic pattern. Thus, the color shifts induced by a chromatic surround are incorporated in the neural representation mediating the flash-lag effect for color. PMID- 29603979 TI - Broadband wide-angle polarization-insensitive metasurface solar absorber. AB - In this paper, a new ultra-thin and broadband wide-angle polarization-insensitive metasurface solar absorber is designed and optimized. The proposed metasurface absorber topology is optimized by using a genetic algorithm to enhance the bandwidth and decrease the unit cell area. The proposed unit cell is designed with fourfolded symmetric subunit cells rotated in the clockwise direction to achieve a polarization-independent response. The unit cell with 320*320 nm2 area and 50 nm thickness has a broadband (>=90%) absorption response in the visible frequency region of the solar spectrum and infrared from 350 THz to 700 THz for normal incident angles and higher than 70% for incident angles up to 40 degrees at both polarizations. PMID- 29603980 TI - Color metamerism and the structure of illuminant space. AB - The colors of two surfaces might appear exactly alike under one illuminant while varying under others. This is due to the metamerism phenomenon in which physically distinct reflectance spectra result in identical cone photoreceptor excitations. The existence of such metameric pairs can potentially cause great ambiguities for our visual perception by challenging phenomena such as color constancy. We investigated frequency and magnitude of metamerism in a wide range of scenarios by studying a large set of surface reflectance spectra illuminated under numerous natural and artificial sources of light. Our results extend previous studies in the literature by demonstrating that metamers are indeed relatively infrequent. Potentially troublesome cases in which two surfaces with an identical color under one illuminant appear very differently under a second illuminant are exceedingly rare. We used the frequency of metameric pairs in combination with non-metric multidimensional scaling to establish a new representation of illuminants based on metamerism. This approach imposes a systematic structure onto the representation of illuminants and allows to better prognosticate the likelihood of metamers under new illuminants. PMID- 29603981 TI - Calculation of vectorial diffraction in optical systems. AB - A vectorial diffraction theory that considers light polarization is essential to predict the performance of optical systems that have a high numerical aperture or use engineered polarization or phase. Vectorial diffraction integrals to describe light diffraction typically require boundary fields on aperture surfaces. Estimating such boundary fields can be challenging in complex systems that induce multiple depolarizations, unless vectorial ray tracing using 3*3 Jones matrices is employed. The tracing method, however, has not been sufficiently detailed to cover complex systems and, more importantly, seems influenced by system geometry (transmission versus reflection). Here, we provide a full tutorial on vectorial diffraction calculation in optical systems. We revisit vectorial diffraction integrals and present our approach of consistent vectorial ray tracing irrespective of the system geometry, where both electromagnetic field vectors and ray vectors are traced. Our method is demonstrated in simple optical systems to better deliver our idea, and then in a complex system where point spread function broadening by a conjugate reflector is studied. PMID- 29603982 TI - Three-dimensional localized Airy-Cartesian and Airy-helical-Cartesian wave packets in free space. AB - We have analytically investigated three-dimensional (3D) Airy-Cartesian (AiC) and Airy-helical-Cartesian (AiHC) wave packets by solving the (3+1)-dimensional free space Schrodinger equation. The complex amplitude of the AiC and AiHC wave packets is described by the product of the Hermite polynomials, the Gaussian functions, and the Airy functions. We find that the AiC and AiHC wave packets will gradually spread along the propagation distances, but attenuate along the time domain. The distributions of the radiation force depend on the distribution factor. In addition, the chirp factor has the effect of the energy concentration of the wave packets. The different 3D spatiotemporal profiles, the photoelasticity, and vortex rings can be obtained by choosing different values of the mode number, the distribution factor, the chirp factor, the initial velocity, and the propagation distances. PMID- 29603983 TI - Accuracy enhanced and synthetic wavelength adjustable optical metrology via spectrally resolved digital holography. AB - This paper demonstrates the usefulness of spectrally resolved digital holography for dual-wavelength optical metrology. Based on the large degree of phase information available, multiple de-correlated dual-wavelength phase maps can be generated, which, when averaged, result in a signal-to-noise-ratio improvement. Compared with single-wavelength averaging, no further post-processing of the reconstructed dual-wavelength phase map is required. Moreover, the constraint imposed on the wavelength stability, as experienced in the conventional dual wavelength method, can be relaxed, and the corresponding synthetic wavelength is adapted to the object under investigation. In addition, the possibility of optical sectioning based on the narrow-width coherence envelope is also demonstrated in transmission mode. PMID- 29603984 TI - A mathematical approach to best luminance maps. AB - An algorithm to calculate the best global mapping from color to grayscale is presented. We assert that the best mapping minimizes the difference between the multi-channel local tensor and the tensor of the resultant mono-chromatic image. To minimize the objective function, we represent the grayscale image as a weighted sum of the RGB channels, three channels and their second-order polynomial and three channels and their root polynomial. The optimization searches for the best weights to combine the linear, polynomial, and root polynomial functions. Our results show that the optimal weights can half the root mean square difference between the color gradients and those achieved by the conventional luminance transformation. Further improvement is achieved by adding the squared and root squared channels to the solution. The improvements are also visually evident. PMID- 29603986 TI - Averaging colors of multicolor mosaics. AB - The present study investigated how color information was summarized in multicolor mosaics. The mosaics were composed of small elements of 17 colors that roughly belonged to a single color category. We manipulated the degree of color variation around the mean by varying the proportion of different color elements. Observers matched the mean color of the multicolor mosaic by adjusting the color of a spatially uniform matching stimulus. Results showed that when the color variation was large, the matched color deviated from the colorimetric mean toward the most saturated color, although the hue of the matched color was almost the same as that of the colorimetric mean. These findings together suggested differential processing of hue and saturation. The deviation of the matched color decreased, but did not disappear, when the color variation was reduced. The analysis of color metric underlying color averaging revealed differential color scaling in nearly orthogonal blue-orange and green-purple directions, implying that the visual system does not solely rely on linear cone-opponent codes when summarizing color signals. The deviation itself was consistently found regardless of different color metrics tested. The robustness of the deviation indicated an inherent bias of mean color judgments favoring highly saturated colors. PMID- 29603985 TI - Discrimination of spectral reflectance under environmental illumination. AB - Color constancy is the ability to recover a stable perceptual estimate of surface reflectance, regardless of the lighting environment. However, we know little about how observers make judgments of the surface color of glossy objects, particularly in complex lighting environments that introduce complex spatial patterns of chromatic variation across an object's surface. To address this question, we measured thresholds for reflectance discrimination using computer rendered stimuli under environmental illumination. In Experiment 1, we found that glossiness and shape had small effects on discrimination thresholds. Importantly, discrimination ellipses extended along the direction in which the chromaticities in the environmental illumination spread. In Experiment 2, we also found that the observers' abilities to judge surface colors were worse in lighting environments with an atypical chromatic distribution. PMID- 29603987 TI - Physical optics-based diffraction coefficient for a wedge with different face impedances. AB - A new diffraction field expression is introduced with the aid of the modified theory of physical optics for a wedge with different face impedances. First, the scattered geometrical optics fields are determined when both faces of the wedge are illuminated by the incident wave. The geometrical optics waves are then expressed in terms of the sum of two different fields that occur for different impedance wedges. The diffracted fields are determined for the two cases separately, and the total diffracted field is obtained as a sum of these waves. Lastly, the uniform field expressions are obtained, and the resultant fields are numerically compared with the solution of Maliuzhinets. PMID- 29603988 TI - Passively Q-switched solid-state Tm:YAG laser using topological insulator Bi2Te3 as a saturable absorber. AB - We demonstrated a passively Q-switched solid-state Tm:YAG laser using topological insulator (TI) Bi2Te3 as the saturable absorber (SA) for the first time, to the best of our knowledge. The Q-switched laser pulses were obtained with the minimum pulse width of 382 ns, the maximum pulse energy of 4.8 MUJ, the maximum average output power of 272 mW, and a pulse repetition rate of 57.67 kHz. The results indicate that Bi2Te3 can be a promising kind of saturable absorber in the 2 MUm wavelength region. PMID- 29603989 TI - Effect of temperature on surface error and laser damage threshold for self healing BK7 glass. AB - Cracks caused during the lapping and polishing process can decrease the laser induced damage threshold (LIDT) of the BK7 glass optical elements, which would shorten the lifetime and limit the output power of the high-energy laser system. When BK7 glass is heated under appropriate conditions, the surface cracks can exhibit a self-healing phenomenon. In this paper, based on thermodynamics and viscous fluid mechanics theory, the mechanisms of crack self-healing are explained. The heat-healing experiment was carried out, and the effect of water was analyzed. The multi-spatial-frequency analysis was used to investigate the effect of temperature on surface error for self-healing BK7 glass, and the lapped BK7 glass specimens before and after heat healing were detected by an interferometer and atomic force microscopy. The low-spatial-frequency error was analyzed by peak to valley and root mean square, the mid-spatial-frequency error was analyzed by power spectral density, and the high-spatial-frequency error was analyzed by surface roughness. The results showed that the optimal heating temperature for BK7 was 450 degrees C, and when the heating temperature was higher than the glass transition temperature (555 degrees C), the surface quality decreased a lot. The laser damage test was performed, and the specimen heated at 450 degrees C showed an improvement in LIDT. PMID- 29603990 TI - Fiber birefringence measurement by an external applied strain method and a polarimetric fiber laser sensor. AB - In this work, a high-sensitivity and low-cost sensing scheme for measuring intrinsic and induced fiber birefringence change is reported based on a polarimetric fiber laser sensor interrogated by the beat frequency technique. The fiber birefringence measurement is achieved by an external applied strain method. A detailed theoretical analysis of the principle for fiber birefringence measurement is carried out. Two alternative equations are given for determining the change of fiber birefringence, which make it very convenient for users to choose different order beat signals. To verify the performance of the sensing system, the external applied strain-induced fiber birefringence change is measured experimentally. The experiment result shows that the fiber birefringence experiences a linear increase with the increase of applied strain. A strain response coefficient of 4.646*10-11/MUepsilon is obtained. Furthermore, the repeatability and stability performances of the polarimetric fiber laser sensor are also investigated. PMID- 29603991 TI - Performance analysis of triple asymmetrical optical multiple ring resonator with a 1 * 3 input-output waveguide for application as an optical filter. AB - Modelling of a triple asymmetrical optical multiple ring resonator (TAOMRR) with a 1*3 input-output waveguide has been carried out in the present paper, and its performance as an optical filter is analyzed. The mathematical modelling of the proposed configuration is carried out in the z domain using a delay line signal processing technique. Free spectral range (FSR), group delay, and dispersion characteristics of the proposed TAOMRR are evaluated from the frequency response plot obtained in MATLAB from all the possible input-output port configurations. The field analysis of the proposed configuration is realized using the finite difference time domain (FDTD) method. The optimal coupling coefficient obtained from the MATLAB simulation is used to design the various optical couplers in FDTD analysis. The proposed configuration offers three outputs with different FSRs for a single input port, which greatly enhances the data handling capabilities in communication networks. PMID- 29603992 TI - Mach-Zehnder interferometric magnetic field sensor based on a photonic crystal fiber and magnetic fluid. AB - A Mach-Zehnder interferometric magnetic field sensor based on a photonic crystal fiber (PCF) and magnetic fluid (MF) was designed and experimentally demonstrated. The sensing probe consists of a single-mode-(SM)-multimode-PCF-SM fiber structure through arc fusion splicing. It was then laser engrave notched with the femtosecond laser so that the PCF cladding was selectively infilled MF. A well defined interference pattern was obtained on account of the tunable refractive index of the MF infilled PCF cladding. The transmission spectra of the proposed sensor under different magnetic field intensities have been measured and theoretically analyzed. The results show that the sensitivity of the proposed sensor can reach -0.13 dB/mT and 0.07334 nm/mT in the magnetic field intensity from 1 mT to 20 mT and 2 mT to 20 mT, respectively. PMID- 29603993 TI - Performance of heterodyne differential phase-shift-keying underwater wireless optical communication systems in gamma-gamma-distributed turbulence. AB - The analytical expressions for the average bit error rate and the outage probability of a heterodyne differential phase-shift-keying underwater wireless optical communication (UWOC) system are derived with proper consideration of all of the channel-degrading effects, including absorption, scattering, and turbulence-induced fading. The scintillation index of a spherical wave is evaluated in order to quantify the underwater system performance in a strong turbulence regime. The spherical wave propagating through the strong underwater turbulence environment is modeled as gamma-gamma distribution. Then, the system performance is simulated for various variations of the underwater turbulence, i.e., the rate of dissipation of kinetic energy per unit mass of fluid, the ratio of temperature to salinity contributions to the refractive index spectrum, and the UWOC system link length. The results show that the analytical expressions for describing the system performance are valid. PMID- 29603994 TI - Manipulation of group-velocity-locked vector dissipative solitons and properties of the generated high-order vector soliton structure. AB - Details of various composites of the projections originated from a fundamental group-velocity-locked vector dissipative soliton (GVLVDS) are both experimentally and numerically explored. By combining the projections from the orthogonal polarization components of the GVLVDS, a high-order vector soliton structure with a double-humped pulse profile along one polarization and a single-humped pulse profile along the orthogonal polarization can be observed. Moreover, by de chirping the composite double-humped pulse, the time separation between the two humps is reduced from 15.36 ps to 1.28 ps, indicating that the frequency chirp of the GVLVDS contributes significantly to the shaping of the double-humped pulse profile. PMID- 29603995 TI - Ultra-long magnetization needle induced by focusing azimuthally polarized beams with a spherical mirror. AB - Based on extended Richards-Wolf theory for axisymmetric surfaces and the inverse Faraday effect, we propose the generation of a purely longitudinal magnetization needle by focusing Gaussian annular azimuthally polarized beams with a spherical mirror. The needle obtained has a longitudinal length varying hundreds to thousands of wavelengths while keeping the lateral size under 0.4lambda, and the corresponding aspect ratio can easily reach more than 2000. It may be the first time that a magnetization needle whose aspect ratio is over 500 has been achieved. The approximate analytical expressions of the magnetization needle are given, and the longitudinal length is tunable by changing the value of the angular thickness and the position of the annular beams. PMID- 29603996 TI - GaN microring waveguide resonators bonded to silicon substrate by a two-step polymer process. AB - Using a polymer bonding technique, GaN microring waveguide resonators were fabricated on a Si substrate for future hybrid integration of GaN and Si photonic devices. The designed GaN microring consisted of a rib waveguide having a core of 510 nm in thickness, 1000 nm in width, and a clad of 240 nm in thickness. A GaN crystalline layer of 1000 nm in thickness was grown on a Si(111) substrate by metal organic chemical vapor deposition using a buffer layer of 300 nm in thickness for the compensation of lattice constant mismatch between GaN and Si crystals. The GaN/Si wafer was bonded to a Si(100) wafer by a two-step polymer process to prevent it from trapping air bubbles. The bonded GaN layer was thinned from the backside by a fast atom beam etching to remove the buffer layer and to generate the rib waveguides. The transmission characteristics of the GaN microring waveguide resonators were measured. The losses of the straight waveguides were measured to be 4.0+/-1.7 dB/mm around a wavelength of 1.55 MUm. The microring radii ranged from 30 to 60 MUm, where the measured free-spectral ranges varied from 2.58 to 5.30 nm. The quality factors of the microring waveguide resonators were from 1710 to 2820. PMID- 29603997 TI - Investigation of impact and spreading of molten nanosized gold droplets on solid surfaces. AB - Understanding the impact dynamics and spreading of molten nanosized droplets on a solid surface is a crucial step towards the design and control of nano fabrication in many novel applications of nanotechnology. In this context, molecular dynamic (MD) simulations have been conducted to compute temperature and dynamic contact angles of nano-droplets during impact. The evolution of the morphology of a molten metallic nano-droplet impacting on a substrate has been studied using a combination of experimental and simulation techniques. Femtosecond lasers have been used to transfer nanosized gold droplets. Droplet morphology calculated in MD simulations is found to be in good agreement with that seen in scanning electron microscopy (SEM) images. It is found that the spreading of nanoscale molten gold droplets upon impact is enhanced by increasing the droplet impact energy. As observed in experimental data, MD simulation results show that a high droplet-substrate heat transfer rate together with increased wettability of the substrate facilitates spreading and results in a thinner metal deposit after solidification. PMID- 29603998 TI - One lens optical correlation: application to face recognition. AB - Despite its extensive use, the traditional 4f Vander Lugt Correlator optical setup can be further simplified. We propose a lightweight correlation scheme where the decision is taken in the Fourier plane. For this purpose, the Fourier plane is adapted and used as a decision plane. Then, the offline phase and the decision metric are re-examined in order to keep a reasonable recognition rate. The benefits of the proposed approach are numerous: (1) it overcomes the constraints related to the use of a second lens; (2) the optical correlation setup is simplified; (3) the multiplication with the correlation filter can be done digitally, which offers a higher adaptability according to the application. Moreover, the digital counterpart of the correlation scheme is lightened since with the proposed scheme we get rid of the inverse Fourier transform (IFT) calculation (i.e., decision directly in the Fourier domain without resorting to IFT). To assess the performance of the proposed approach, an insight into digital hardware resources saving is provided. The proposed method involves nearly 100 times fewer arithmetic operators. Moreover, from experimental results in the context of face verification-based correlation, we demonstrate that the proposed scheme provides comparable or better accuracy than the traditional method. One interesting feature of the proposed scheme is that it could greatly outperform the traditional scheme for face identification application in terms of sensitivity to face orientation. The proposed method is found to be digital/optical implementation-friendly, which facilitates its integration on a very broad range of scenarios. PMID- 29603999 TI - Absolute frequency measurement of molecular iodine hyperfine transitions at 647 nm. AB - We report absolute frequency measurements of molecular iodine P(46) 5-4 a1, a10, and a15 hyperfine transitions at 647 nm with a fiber-based frequency comb. The light source is based on a Littrow-type external-cavity diode laser. A frequency stability of 5*10-12 at a 200 s integration time is achieved when the light source is stabilized to the P(46) 5-4 a15 line. The pressure shift is determined to be -8.3(7) kHz/Pa. Our determination of the line centers reached a precision of 21 kHz. The light source can serve as a reference laser for lithium spectroscopy (2S->3P). PMID- 29604000 TI - Cost-effective way to improve the optical properties of poly(methyl methacrylate)/poly(ethylene terephthalate) light scattering materials: drop coalescence. AB - Herein, the dependence of the dispersed phase diameter on the shear history during melt processing is verified experimentally. We fabricated different kinds of poly(methyl methacrylate) (PMMA)/poly(ethylene terephthalate) (PET) blends by modifying the shear rate and shear time in a torque rheometer. Light-scattering sheets (LSSs) were then prepared by compression molding with the above blends. The total transmittance of the LSS with a shear history of 8 min at 30 rpm and then 20 min at 5 rpm achieves 84.8% due to the drop coalescence and larger diameters of the PET scatterers in the PMMA matrix, while the total transmittance of a sheet with a shear history at only 30 rpm is just 70.8%. In addition to high total transmittance, the sheet also features high haze (beyond 92.5%) and tiny direct transmittance (less than 5%), which is vital for uniform illumination and glare protection from lasers and light-emitting diodes. PMID- 29604001 TI - Improving the performance of underwater wireless optical communication links by channel coding. AB - We investigate the efficacy of error correcting codes in improving the performance of underwater wireless optical communication systems. For this purpose, the effectiveness of several coding schemes, i.e., the classical Reed Solomon and a recent family of low-density parity check codes, is studied in the physical (PHY) and the upper layers assuming negligible water turbulence. The presented numerical results testify to the interest of using efficient codes both at the PHY and upper protocol layers, although we are concerned by a non-fading channel. Furthermore, we discuss the choice of coding schemes and the appropriate degree of data protection in the PHY and upper layers. PMID- 29604002 TI - Optical characterization of porcine articular cartilage using a polarimetry technique with differential Mueller matrix formulism. AB - A method is proposed for characterizing the optical properties of articular cartilage sliced from a pig's thighbone using a Stokes-Mueller polarimetry technique. The principal axis angle, phase retardance, optical rotation angle, circular diattenuation, diattenuation axis angle, linear diattenuation, and depolarization index properties of the cartilage sample are all decoupled in the proposed analytical model. Consequently, the accuracy and robustness of the extracted results are improved. The glucose concentration, collagen distribution, and scattering properties of samples from various depths of the articular cartilage are systematically explored via an inspection of the related parameters. The results show that the glucose concentration and scattering effect are both enhanced in the superficial region of the cartilage. By contrast, the collagen density increases with an increasing sample depth. PMID- 29604003 TI - Study on vibration sensing performance of an equal strength cantilever beam based on an excessively tilted fiber grating. AB - An equal strength cantilever beam vibration sensor based on an excessively tilted fiber grating (Ex-TFG) with light intensity demodulation is proposed. The basic principles and sensing characteristics of vibration sensing of an equal strength cantilever beam and Ex-TFG, the combination of which is applied into vibration sensing, are analyzed. An Ex-TFG is attached to the middle axis of an equal strength cantilever beam. As the vibration of a piezoelectric ceramic causes the equal strength cantilever beam to deform, the same and uniform deformation also occurs on the Ex-TFG. Experimental results show that when the thickness of the equal strength cantilever beam is 0.3 mm and the Ex-TFG is at transverse electric (TE) polarization state, the sensing performance is the best, with the maximum acceleration sensitivity reaching 81.065 mv.m-1.s2, and the fast Fourier transform (FFT) main frequency components of the sensing signal accounting for more than 80%. In addition, this sensor is stable in sensing performance, easy in demodulation, simple in structure, high in sensitivity, and easy in manufacture, applicable for the sensing and on-line monitoring of low-frequency vibration signals. PMID- 29604004 TI - Green's function for a sharpened and metal-coated dielectric probe. AB - In apertureless scanning-probe optical microscopy and in the case of more traditional scanned optical probes coated with a metal that is thin near the probe tip (in lieu of an aperture), samples are probed via interaction between the probe and surface. In the nanometer-scale region between the tip and the sample, the field can be approximated by quasi-electrostatic analytics. Hence, the coated probe can be modeled as in the present case as a hyperboloid of revolution without the need for hyperboloidal wave functions in the near zone. The solutions to Laplace's equation and in general Green's function with the application of the boundary conditions, therefore, yield an appropriate approximation and allow a completely analytical solution for the resonance effects upon the probe tip to be obtained. The large field enhancements due to the sharpness of the tip and to surface plasmon fields may thus be analytically examined. PMID- 29604005 TI - Methods based on 1D homography for camera calibration with 1D objects. AB - This paper focuses on camera calibration with one-dimensional (1D) objects, and novel methods are proposed in this paper. Different from the known 1D object based camera calibration algorithms, which define the camera coordinate system as the world coordinate system, we assume that the 1D calibration object is located along the X axis of the world coordinate system. Based on this new model, a 3*2 1D homography is defined to relate the points in the 1D objects to the perspective image points thereof. Then, the basic constraint for camera calibration using 1D objects from a single image is derived. Subsequently, two existing motions, namely, rotating around a fixed point and moving on a plane, are discussed, and new algorithms are proposed. In our methods, if the number of points in the 1D objects is more than three, more compact constraints can be obtained when the 1D objects rotate around a fixed point. In the case of planar motion, the estimation of vanishing points is not needed, and the calibration accuracy is significantly improved. Finally, both computer simulations and experiments are performed to validate the effectiveness and robustness of our algorithms. PMID- 29604006 TI - Analysis of composite/difference field scattering properties between a slightly rough optical surface and multi-body defects. AB - The effective extraction of optical surface roughness and defect characteristic provide important realistic values to improve optical system efficiency. Based on finite difference time domain/multi-resolution time domain (FDTD/MRTD) mixed approach, composite scattering between a slightly rough optical surface and multi body defect particles with different positions is investigated. The scattering contribution of defect particles or the slightly rough optical surface is presented. Our study provides a theoretical and technological basis for the nondestructive examination and optical performance design of nanometer structures. PMID- 29604007 TI - Tunable Bragg defect mode in one-dimensional photonic crystal containing a graphene-embedded defect layer. AB - Using the transfer matrix method, the transmission properties of defective one dimensional photonic crystal are analyzed in the terahertz region. The defect layer is composed of a graphene-embedded dielectric layer. We investigate the variation of the defect mode's frequency as a function of graphene chemical potential for different values of incident angles. The numerical results show that the frequency of the defect mode can be tuned effectively as the chemical potential of graphene nanolayers changes using an applied gate voltage. The present results can be useful in designing tunable graphene-based photonic devices such as filters and sensors in terahertz regions. PMID- 29604008 TI - Three-dimensional facial digitization using advanced digital image correlation. AB - Presented in this paper is an effective technique to acquire the three dimensional (3D) digital images of the human face without the use of active lighting and artificial patterns. The technique is based on binocular stereo imaging and digital image correlation, and it includes two key steps: camera calibration and image matching. The camera calibration involves a pinhole model and a bundle-adjustment approach, and the governing equations of the 3D digitization process are described. For reliable pixel-to-pixel image matching, the skin pores and freckles or lentigines on the human face serve as the required pattern features to facilitate the process. It employs feature-matching-based initial guess, multiple subsets, iterative optimization algorithm, and reliability-guided computation path to achieve fast and accurate image matching. Experiments have been conducted to demonstrate the validity of the proposed technique. The simplicity of the approach and the affordable cost of the implementation show its practicability in scientific and engineering applications. PMID- 29604009 TI - Multiresonance response in hyperbolic metamaterials. AB - In this paper we demonstrate a new class of anisotropic 1D hyperbolic metamaterials (HMMs) possessing multiresonant dispersion characteristics. With the help of an EMT-based model, we analyze HMMs with unit cells composed of layers characterized by various plasma frequencies, revealing multiple resonance transitions corresponding to the critical absorptions points. In particular, we show that relative locations of plasma frequencies of constituent materials and the unit cell's geometry determine the type of dispersion characteristics as well as spectral locations of critical absorption points. It is shown that a multispectral low-loss highly dispersive medium is achieved in a structure comprising layers of closely located plasma resonances. Moreover, we present that pure metallic multilayer structure can exhibit hyperbolic dispersion. The obtained results possess a significant potential in applications where a multispectral character is required, including phase matching, multiple-point perfect absorption, as well as diffractionless imaging and focusing. PMID- 29604010 TI - Phaseless computational ghost imaging at microwave frequencies using a dynamic metasurface aperture. AB - We demonstrate a dynamic metasurface aperture as a unique tool for computational ghost imaging at microwave frequencies. The aperture consists of a microstrip waveguide loaded with an array of metamaterial elements, each of which couples energy from the waveguide mode to the radiation field. With a tuning mechanism introduced into each independently addressable metamaterial element, the aperture can produce diverse radiation patterns that vary as a function of tuning state. Here, we show that fields from such an aperture approximately obey speckle statistics in the radiative near field. Inspired by the analogy with optical correlation imaging, we use the dynamic aperture as a means of illuminating a scene with structured microwave radiation, receiving the backscattered intensity with a simple waveguide probe. By correlating the magnitude of the received signal with the structured intensity patterns, we demonstrate high-fidelity, phaseless imaging of sparse targets. The dynamic metasurface aperture as a novel ghost imaging structure can find application in security screening, through-wall imaging, as well as biomedical diagnostics. PMID- 29604011 TI - Using turbulence scintillation to assist object ranging from a single camera viewpoint. AB - Image distortions caused by atmospheric turbulence are often treated as unwanted noise or errors in many image processing studies. Our study, however, shows that in certain scenarios the turbulence distortion can be very helpful in enhancing image processing results. This paper describes a novel approach that uses the scintillation traits recorded on a video clip to perform object ranging with reasonable accuracy from a single camera viewpoint. Conventionally, a single camera would be confused by the perspective viewing problem, where a large object far away looks the same as a small object close by. When the atmospheric turbulence phenomenon is considered, the edge or texture pixels of an object tend to scintillate and vary more with increased distance. This turbulence induced signature can be quantitatively analyzed to achieve object ranging with reasonable accuracy. Despite the inevitable fact that turbulence will cause random blurring and deformation of imaging results, it also offers convenient solutions to some remote sensing and machine vision problems, which would otherwise be difficult. PMID- 29604012 TI - Quantitative discrimination of pearls using polarization-sensitive optical coherence tomography. AB - We propose a robust method that can quantitatively discriminate genuine pearls from imitation ones by introducing the concept of entropy in the polarization sensitive optical coherence tomography (PS-OCT). Qualitatively, by examining the birefringence properties of the nacre region of pearls with PS-OCT, the genuine pearls can be easily discriminated. To quantify the amount of birefringence formation, however, the concept of phase retardation entropy is introduced, which is expected to have a higher value when a PS-OCT tomogram has more diverse phase retardation values in its histogram. Experimental confirmation demonstrated that the phase retardation entropy of a genuine pearl was always higher than an imitated pearl. By experimenting with various genuine and imitation pearls, we can say that the phase retardation entropy is effective as a quantitative criterion for discriminating and evaluating pearls. PMID- 29604013 TI - Anti-reflective coating with a conductive indium tin oxide layer on flexible glass substrates. AB - Flexible glass has many applications including photovoltaics, organic light emitting device (OLED) lighting, and displays. Its ability to be processed in a roll-to-roll facility enables high-throughput continuous manufacturing compared to conventional glass processing. For photovoltaic, OLED lighting, and display applications, transparent conductors are required with minimal optical reflection losses. Here, we demonstrate an anti-reflective coating (ARC) that incorporates a useful transparent conductor that is realizable on flexible substrates. This reduces the average reflectivity to less than 6% over the visible band from normal incidence to incident angles up to 60 degrees . This ARC is designed by the average uniform algorithm method. The coating materials consist of a multilayer stack of an electrically functional conductive indium tin oxide with conductivity 2.95*105 Siemens/m (31 Omega/?), and AlSiO2. The coatings showed modest changes in reflectivity and no delamination after 10,000 bending cycles. This demonstrates that effective conductive layers can be integrated into ARCs and can be realized on flexible glass substrates with proper design and process control. PMID- 29604014 TI - Switchable phase/intensity sensor made with ring-shaped and hexagonal ferroelectric domains. AB - We present a device, similar to a Shack-Hartmann sensor, that can detect both the intensity distribution and wavefront of an incident wave. Its operation is based on the use of an array of electrically controllable Fresnel zone plates made in a ferroelectric crystal, lithium niobate. This sensor, which requires only one camera, can be quickly switched between intensity- and phase-detecting modes. Two kinds of arrays are shown: Fresnel zone plates with a few ring-shaped ferroelectric domains and plates made with nested hexagonal domains. Both arrays are suitable for use in a Shack-Hartmann wavefront sensor. However, since in lithium niobate domains naturally tend to form hexagons, it is easier to make hexagonal, rather than ring-shaped, domains and, consequently, smaller zone plates can be produced. This allows an increase in the number of zone plates and a reduction in their focal length, which improves the fidelity of the reconstructed wavefront. PMID- 29604015 TI - Design of discrete and continuous super-resolving Toraldo pupils in the microwave range. AB - The concept of super-resolution refers to various methods for improving the angular resolution of an optical imaging system beyond the classical diffraction limit. In optical microscopy, several techniques have been successfully developed with the aim of narrowing the central lobe of the illumination point spread function. In astronomy, however, no similar techniques can be used. A feasible method to design antennas and telescopes with angular resolution better than the diffraction limit consists of using variable transmittance pupils. In particular, discrete binary phase masks (0 or pi) with finite phase-jump positions, known as Toraldo pupils (TPs), have the advantage of being easy to fabricate but offer relatively little flexibility in terms of achieving specific trade-offs between design parameters, such as the angular width of the main lobe and the intensity of sidelobes. In this paper, we show that a complex transmittance filter (equivalent to a continuous TP, i.e., consisting of infinitely narrow concentric rings) can achieve more easily the desired trade-off between design parameters. We also show how the super-resolution effect can be generated with both amplitude and phase-only masks and confirm the expected performance with electromagnetic numerical simulations in the microwave range. PMID- 29604016 TI - Laser investigation of Yb:YLF crystals fabricated with the micro-pulling-down technique. AB - Fiber rods of 10% doped Yb:YLF were fabricated with the micro-pulling-down technique and characterized. The crystal a axis was oriented along the rod length, allowing polarized emission with the largest cross section available in the c direction. Laser experiments showed that these fiber samples perform similarly to crystals grown by the standard Czochralski method. Intrinsic slope efficiency of ~50% was measured in both cases, with small comparable intracavity losses, proving the good quality of the fiber material. PMID- 29604017 TI - Improvement of the fringe analysis algorithm for wavelength scanning interferometry based on filter parameter optimization. AB - The phase slope method which estimates height through fringe pattern frequency and the algorithm which estimates height through the fringe phase are the fringe analysis algorithms widely used in interferometry. Generally they both extract the phase information by filtering the signal in frequency domain after Fourier transform. Among the numerous papers in the literature about these algorithms, it is found that the design of the filter, which plays an important role, has never been discussed in detail. This paper focuses on the filter design in these algorithms for wavelength scanning interferometry (WSI), trying to optimize the parameters to acquire the optimal results. The spectral characteristics of the interference signal are analyzed first. The effective signal is found to be narrow-band (near single frequency), and the central frequency is calculated theoretically. Therefore, the position of the filter pass-band is determined. The width of the filter window is optimized with the simulation to balance the elimination of the noise and the ringing of the filter. Experimental validation of the approach is provided, and the results agree very well with the simulation. The experiment shows that accuracy can be improved by optimizing the filter design, especially when the signal quality, i.e., the signal noise ratio (SNR), is low. The proposed method also shows the potential of improving the immunity to the environmental noise by adapting the signal to acquire the optimal results through designing an adaptive filter once the signal SNR can be estimated accurately. PMID- 29604018 TI - Airlight-imposed errors for space-object polarimetric observations from the ground. AB - We discuss and characterize how polarimetric sensing is contaminated by various "airlight" phenomena, as well as unpolarized light from the target, when space objects are observed with a ground-based telescope. Estimates of the polarization state are limited by unpolarized target light regardless of sensor technology or estimator algorithm, and increased target brightness actually degrades estimation of the S1, S2, and S3 Stokes parameters if the added light is unpolarized. Unpolarized airlight in the field of view has an identical degrading effect. Atmospheric scattering can significantly polarize airlight, so airlight polarization must be calibrated and subtracted from the estimated target polarization. We derive an expression for the mean-square Stokes estimation error when noisy, biased estimates for the airlight polarization state are subtracted from noisy, biased estimates of the target polarization state; this expression shows that target and airlight Stokes estimation noise and bias generally sum in the ms estimation error for airlight-calibrated target Stokes. While SNR for the estimate of a given Stokes parameter increases with the magnitude of that parameter, estimation bias also appears to be correlated with magnitude. We note that when the linear Stokes reference is not arbitrary, requiring a rotational transformation of the estimated Stokes vector, the SNRs of the S1 and S2 estimates vary with the rotation angle. Finally, we show that measured data can be used in numerical calculations described here to approximate the errors associated with Stokes estimation, with or without airlight calibration. PMID- 29604019 TI - Beam quality improvement by controlling thermal lens spherical aberration in an end-pumped Nd:YVO4 laser. AB - We present for the first time, to the best of our knowledge, the influence of spherical aberration on the beam quality of a single-stage laser amplifier. We set up an amplifier with a special structure to measure the spherical aberration distribution in the cavity. The output power of the oscillator was controlled, and the pump power of the amplifier was adjusted to improve the beam quality. The results show that there is an optimal amplifier pump power, which maximizes the output laser beam quality. In the presented experiment, an optimal laser beam was achieved with an output power of 10.54 W and beam quality of Mx2=1.54, My2=1.39 for a pump power of 9.33 W, oscillator output power of 9.2 W, and a beam quality of Mx2=2.10, My2=2.03. PMID- 29604020 TI - Ultra-fast all-optical decoder based on nonlinear photonic crystal ring resonators. AB - In this paper, a 2-to-4 all-optical decoder based on photonic crystal ring resonators is introduced. The photonic crystal structure has a 2D square chalcogenide rod lattice whose maximum response time is 2 ps. Three ring resonators including nonlinear rods with 9*10-17 m2/W for a Kerr coefficient carry out a switching operation at 1550 nm wavelength. The switching speed of the device is 500 GHz, which is more than that in previously presented works. Also, the small size of the structure is sufficient for optical integrated circuits. PMID- 29604021 TI - Effect of anisotropy on bit error rate for an asymmetrical Gaussian beam in a turbulent ocean. AB - Effect of anisotropy on the average bit error rate (BER) is investigated when an asymmetrical Gaussian beam is propagated in an anisotropic turbulent ocean. BER is found to decrease in response to an increase in anisotropy levels in the x and y directions. Higher average signal-to-noise ratio, wavelength, and microscale length yield smaller BER values. BER starts to rise with an increase in the asymmetrical beam source size in the x and y directions, source size ratio in the x and y directions, salinity and temperature contribution factor, the dissipation of the mean squared temperature, and the propagation distance. At the fixed source size ratio in the x and y directions of the asymmetrical beam source size, larger source sizes increase BER. An anisotropic turbulent ocean seems to exhibit better BER values as compared with an isotropic turbulent ocean. PMID- 29604022 TI - 12-W continuous-wave green output from a 200-MUm fiber-coupled diode laser based on TO-Can packaged emitters. AB - A 12-W green laser diode module with fiber-coupled output is developed. The high power fiber-coupled output of a green diode laser is realized by using the technologies of beam collimation, spatial beam combining, beam shaping, and fiber coupling based on TO-Can packaged emitters. According to the optical fiber parameters, the detailed beam combination method is described and the maximum quantity of a single emitter in beam combination is calculated theoretically. In the experiment, as many as 16 green laser diode emitters with output power of 1 W each were combined and coupled into a fiber with core diameter of 200 MUm and a numerical aperture of 0.22. A total of 12.2 W continuous-wave output at the wavelength of 520 nm was achieved with a coupling efficiency of 86.5% and an electro-optical efficiency of 10.6%. PMID- 29604023 TI - Optical configuration with fixed transverse magnification for self-interference incoherent digital holography. AB - The optical configuration proposed in this paper consists of a 4-f optical setup with the wavefront modulation device on the Fourier plane, such as a concave mirror and a spatial light modulator. The transverse magnification of reconstructed images with the proposed configuration is independent of locations of an object and an image sensor; therefore, reconstructed images of object(s) at different distances can be scaled with a fixed transverse magnification. It is yielded based on Fourier optics and mathematically verified with the optical matrix method. Numerical simulation results and experimental results are also given to confirm the fixity of the reconstructed images. PMID- 29604024 TI - Optimizing laser crater enhanced Raman spectroscopy. AB - Raman signal enhancement by laser crater production was systematically studied for 785 nm continuous wave laser pumping. Laser craters were produced in L aspartic acid powder by a nanosecond pulsed solid state neodymium-doped yttrium aluminum garnet laser (532 nm, 8 ns, 1 mJ/pulse), while Raman spectra were then acquired by using a commercial spectrometer with 785 nm laser beam pumping. The Raman signal enhancement effect was studied in terms of the number of ablating pulses used, the lens-to-sample distance, and the crater-center-laser-spot offset. The influence of the experiment parameters on Raman signal enhancement was studied for different powder materials. Maximum Raman signal enhancement reached 11 fold for loose powders but decreased twice for pressed tablets. Raman signal enhancement was demonstrated for several diverse powder materials like gypsum or ammonium nitrate with better results achieved for the samples tending to give narrow and deep craters upon the laser ablation stage. Alternative ways of cavity production (steel needle tapping and hole drilling) were compared with the laser cratering technique in terms of Raman signal enhancement. Drilling was found to give the poorest enhancement of the Raman signal, while both laser ablation and steel needle tapping provided comparable results. Here, we have demonstrated for the first time, to the best of our knowledge, that a Raman signal can be enhanced 10 fold with the aid of simple cavity production by steel needle tapping in rough highly reflective materials. Though laser crater enhancement Raman spectroscopy requires an additional pulsed laser, this technique is more appropriate for automatization compared to the needle tapping approach. PMID- 29604025 TI - Photonic bandpass filter characteristics of multimode SOI waveguides integrated with submicron gratings. AB - It has been shown that a fundamental mode adiabatically launched into a multimode SOI waveguide with submicron grating offers well-defined flat-top bandpass filter characteristics in transmission. The transmitted spectral bandwidth is controlled by adjusting both waveguide and grating design parameters. The bandwidth is further narrowed down by cascading two gratings with detuned parameters. A semi analytical model is used to analyze the filter characteristics (1500 nm<=lambda<=1650 nm) of the device operating in transverse-electric polarization. The proposed devices were fabricated with an optimized set of design parameters in a SOI substrate with a device layer thickness of 250 nm. The pass bandwidth of waveguide devices integrated with single-stage gratings are measured to be ~24 nm, whereas the device with two cascaded gratings with slightly detuned periods (DeltaLambda=2 nm) exhibits a pass bandwidth down to ~10 nm. PMID- 29604026 TI - Partially coherent noise-like pulse generation in amplified spontaneous Raman emission. AB - Amplified spontaneous Raman emission under picosecond pulse pumping is studied in detail both experimentally and numerically. It is found that the Raman output pulses are noise-like with partial coherence, which has important implications for various applications. Numerical simulation reproduces the finding well, along with the temporal and spectral dependence of the Raman pulse on the pump pulse energy. The numerical simulations of the temporal, spectral, and energy evolution of the Raman and pump pulse along the fiber gives insight on how to design such sources. PMID- 29604027 TI - 14 GHz broadband and continuously frequency-tuned Nd:YVO4 laser with an RTP etalon. AB - A laser-diode-pumped broadband and continuously frequency-tuned all-solid-state Nd:YVO4 laser at 1064 nm with an output power of 200 mW is demonstrated. A RbTiOPO4 (RTP) etalon and a piezoelectric-transducer (PZT) are utilized for coarse and fine frequency tuning, respectively. Dependence of the frequency excursion on the applied voltage to the RTP etalon and the displacement of the PZT is theoretically and experimentally investigated. A continuous frequency tuning of 14 GHz is conducted by synchronous adjustment of the RTP etalon and the PZT. The tuning covers more than 6 times the longitudinal mode spacing of a laser resonator without any mode hops. PMID- 29604028 TI - Highly directive switchable nanoantenna array based on dielectric omega particles at terahertz frequencies. AB - A high-refractive-index dielectric particle with the ability of supporting both electric and magnetic resonances, operating at 1-2 terahertz, is proposed. It is shown that the suggested omega-shaped nanoparticle is able to control the resonance frequencies independently by changing geometrical dimension. It is also demonstrated numerically that an asymmetric omega particle shows a tunable radiation pattern, depending on the incident frequency. The radiation beam can steer in the range of +/-30 degrees . The omega particle shows a directive radiation pattern with small back radiation, due to the constructive interference of the induced electric and magnetic moments. Therefore, the application of the proposed antenna in directivity enhancement is considered. Then, in order to achieve high directivity, omega particles are arranged in an array. Their employment for directivity enhancement has led to the maximum directivity of 11.8 dB. Side-lobe level has the minimum amount of -18.3 dB, and total size of the structure is 400 MUm*400 MUm?2.6lambda*2.6lambda in the x-y plane, while it does not exceed a quarter of a wavelength in height. PMID- 29604029 TI - Extraction of interference phase in frequency-scanning interferometry based on empirical mode decomposition and Hilbert transform. AB - Nonlinear optical frequency scanning is inevitable in frequency scanning interferometry with tunable lasers and seriously reduces the accuracy of interference signal phase extraction. To address this, we propose a phase extraction algorithm based on empirical mode decomposition and Hilbert transformation. The method can effectively eliminate the influence of the optical frequency scanning nonlinearity. The validity and stability of the method have been verified through simulations and experiments. Moreover, the single-cycle relative error of the phase between adjacent peaks and the standard deviation of the measurement system improved to 0.6% and 0.7 MUm, respectively, with a 5 MHz sampling rate. PMID- 29604030 TI - Transparent surface orientation from polarization imaging using vector operation. AB - The existing methods for shape measurement using polarization of transparent objects are based on two assumptions: (1) the paraxial assumption, assuming that the reflected ray is parallel to the optical axis of the imaging system; and (2) the s-component approximation assumption, which assumes that the s-component of the reflected light is predominant and the p-component is neglected. To overcome limitations posed by these two assumptions, this paper proposes a method based on the polarization characteristics of reflection from a transparent surface and vector operation. To overcome the paraxial assumption, the normal vector of the transparent surface is deduced by vector operation, analyzing the relationships between the direction vector of reflection, the normal vector of the reflection plane, the intersection line of the reflection plane and imaging plane, and the normal vector of the transparent surface. To overcome the limitations of the s component approximation assumption, the angle between the s-component and the polarization direction of the reflected light is analyzed, which yields improved measurement precision. An experiment was performed with transparent targets (flat glass positioned at different angles), and the results show that the measurement error with this method is significantly less than those of existing methods. Thus, we believe this method overcomes the abovementioned limitations while also improving measurement precision. PMID- 29604031 TI - Three-mirror anastigmat for cosmic microwave background observations. AB - An off-axis three-mirror anastigmat is proposed for future cosmic microwave background observations. The telescope has a 5 m diameter primary, giving 1.5' angular resolution at lambda=2 mm, which is sufficient for measurements of gravitational lensing and for galaxy cluster surveys. The design includes several key features, not previously combined in a large telescope, that are important for sensitive measurements, especially on large angular scales: (1) high throughput (8 degrees diameter diffraction-limited field of view at lambda=1 mm, and 12*8 degrees at lambda=3 mm, so a single telescope could support all the detectors for an optimistic, future experiment); (2) low scattering (all the mirrors are small enough to be monolithic, so there are no segment gaps); (3) full boresight rotation, over the full elevation range, for measuring polarization errors; and (4) a comoving shield or baffle around the entire telescope to control pickup. PMID- 29604032 TI - Optimal bandwidth and systematic error of full-Stokes micropolarizer arrays. AB - In this paper, we present the first in-depth analysis of the bandwidth tradeoffs, error performance, and noise resiliency of full-Stokes micropolarizer array (MPA) designs. By applying our Fourier domain tools that provide a systematic way for arranging information carriers and allocating bandwidth, we develop a number of new full-Stokes MPA layouts and compare them to the existing full-Stokes MPAs in the literature, all of which use 2*2 pixel unit cells to build the MPA. We compare the reconstruction accuracy afforded by these traditional designs with the generalized 2*L family of MPAs, a 3*3 tiling, as well as a 2*2*3 layout that uses multiple snapshots and trades off temporal resolution for spatial resolution. Of those systems, the hybrid spatiotemporally modulated 2*2*3 MPA provisions the most bandwidth and provides the highest reconstruction accuracy, while the modified 2*L family remains the best performing single-snapshot MPA. Additionally, we study the degradation of reconstruction accuracy under the presence of systematic error in MPA fabrication. We find that reducing the amount of correlated error is by far the largest factor in ensuring robust performance. PMID- 29604033 TI - Phase and amplitude beam shaping with two deformable mirrors implementing input plane and Fourier plane phase modifications. AB - We find that ideas in optical image encryption can be very useful for adaptive optics in achieving simultaneous phase and amplitude shaping of a laser beam. An adaptive optics system with simultaneous phase and amplitude shaping ability is very desirable for atmospheric turbulence compensation. Atmospheric turbulence induced beam distortions can jeopardize the effectiveness of optical power delivery for directed-energy systems and optical information delivery for free space optical communication systems. In this paper, a prototype adaptive optics system is proposed based on a famous image encryption structure. The major change is to replace the two random phase plates at the input plane and Fourier plane of the encryption system, respectively, with two deformable mirrors that perform on demand phase modulations. A Gaussian beam is used as an input to replace the conventional image input. We show through theory, simulation, and experiments that the slightly modified image encryption system can be used to achieve arbitrary phase and amplitude beam shaping within the limits of stroke range and influence function of the deformable mirrors. In application, the proposed technique can be used to perform mode conversion between optical beams, generate structured light signals for imaging and scanning, and compensate atmospheric turbulence-induced phase and amplitude beam distortions. PMID- 29604034 TI - Intensity, phase, and polarization of a vector Bessel vortex beam through multilayered isotropic media. AB - This paper investigates the characteristics of reflected and transmitted fields of a vector Bessel vortex beam through multilayered isotropic media on the basis of the vector angular spectrum expansion and presents the effects of media on intensity, phase, and polarization. The method is verified by studying the reflection and transmission on a single interface at vertical incidence. For both paraxial and nonparaxial incident beam cases, numerical simulations of the field components and the time-averaged Poynting vector power density of the reflected and transmitted beams for the three-layered media are presented and discussed in detail. It is shown that as the incident angle increases, the magnitude distribution of the reflected beams illustrates significant distortions and no longer represents similar patterns to that of the incident beam, whereas the magnitude distribution of the transmitted beams can maintain similar profiles to the incident beam, apart from the notable distortion of the central ring. For the same incident angle, the effects of media on the magnitude distribution for the nonparaxial case are more evident than those for the paraxial case. The results of phase distribution and polarization of the reflected and transmitted fields show that as the incident angle increases, the distortion of the phase distribution and polarization for the reflected fields are more significant and the topological charge cannot be preserved. PMID- 29604035 TI - Detection with polychromatic x-ray pencil beam illumination: information theoretic bounds. AB - Non-destructive testing (NDT) by x-ray imaging is commonly used for finding manufacturing defects, cargo inspection, or security screening. These tasks can be regarded as examples of a detection problem where a target is either present or not. Task-specific information (TSI) [J. Opt. Soc. Am. A24, B25 (2007)JOAOD60740-323210.1364/JOSAA.24.000B25; Appl. Opt.47, 4457 (2008)APOPAI0003 693510.1364/AO.47.004457] bounds, an information-theoretic based metric, are presented for a threat detection task. A system using polychromatic x-ray pencil beam object illumination and energy-resolving detectors for both absorption and diffraction measurements is employed for this task. Water and diesel are two liquids chosen as non-threat and threat materials, respectively, for this study. Three different threat class configurations are examined: a homogeneous object with fixed thickness, a homogeneous object with stochastic thickness, and a dual material object (i.e., representing a target and clutter) with stochastic thickness, where the threat material has a fixed thickness. We find for the threat class composed of a dual-material object that a minimum threat thickness of 4.5 cm is needed to achieve a desired TSI>=0.7 using a joint absorption and diffraction measurement. PMID- 29604036 TI - Multiplanar imaging properties of Theon sieves. AB - Greek ladders with diffraction-limited array foci provide a probability to realize array imaging with equal intensity. Here, taking the ancient Theon sequence as an example, we design the optical structure and have measured the focusing properties by digital holography. Then, we verify the multiplanar imaging with different magnifications by experiment. The experimental results agree well with the theoretical analysis. In addition, bi-Fourier planes filtering technology is proposed to solve the problem of crosstalk between different imaging planes to further improve the imaging resolution. Therefore, we can freely design the focal length of the bifocal lens to achieve high-quality imaging at different resolutions. As a kind of amplitude-only diffractive lens, multifocal imaging provides a possibility of application in array biological imaging, ophthalmology, and an optical zoom system. PMID- 29604037 TI - Analysis of freeform mirror systems based on the decomposition of the total wave aberration into Zernike surface contributions. AB - The application of freeform elements in optical systems increases the number of variables available for correction. This creates the potential to design compact systems with excellent imaging performance. However, it is non-trivial to determine which configuration of the system to choose and where to place the freeform element to obtain the best design. The knowledge of aberration distribution in the system is very helpful in answering these questions. In the following paper, we analyze Zernike surface contributions to the total wave aberration in non-symmetric freeform mirror systems using the method introduced in [J. Opt. Soc. Am. A34, 1856 (2017)JOAOD60740-323210.1364/JOSAA.34.001856]. We demonstrate the benefits of the proposed method in determining effective location of the freeform element and in finding critical differences between possible configurations. By analyzing surface contributions to the total wave aberration characterized by Zernike fringe coefficients, it is possible to find solutions corrected for aberrations of orders higher than the order of coefficients used for freeform sag contribution described with the same Zernike polynomial set. PMID- 29604038 TI - Holographic waveguide heads-up display for longitudinal image magnification and pupil expansion. AB - The field of view of traditional heads-up display systems is limited by the size of the projection optics. Our research is focused on overcoming this limitation by coupling image-bearing light into a waveguide using holographic elements, propagating the light through that waveguide, and extracting the light several times with additional holographic optical elements. With this configuration, we demonstrated both longitudinal magnification and pupil expansion of the heads-up display. We created a ray-trace model of the optical system to optimize the component parameters and implemented the solution in a prototype that demonstrates the merit of our approach. Longitudinal magnification is achieved by encoding optical power into the hologram injecting the light into the waveguide, while pupil expansion is obtained by expanding the size of the hologram extracting the light from the waveguide element. To ensure uniform intensity of the image, the diffraction efficiency of the extracting hologram is modulated according to the position. Our design has a 12 degrees *8 degrees field of view at a viewing distance of 10 in. (250 mm), with infinite longitudinal magnification and a 1.7* lateral pupil expansion. PMID- 29604039 TI - Demystifying Fisher Information: What Observation Data Reveal about Our Models. AB - Information theory is the basis for understanding how information is transmitted as observations. Observation data can be used to compare uncertainty on parameter estimates and predictions between models. Jacobian Information (JI) is quantified as the determinant of the weighted Jacobian (sensitivity) matrix. Fisher Information (FI) is quantified as the determinant of the weighted FI matrix. FI measures the relative disorder of a model (entropy) in a set of models. One dimensional models are used to demonstrate the relationship between JI and FI, and the resulting uncertainty on estimated parameter values and model predictions for increasing model complexity, different model structures, different boundary conditions, and over-fitted models. Greater model complexity results in increased JI accompanied by an increase in parameter and prediction uncertainty. FI generally increases with increasing model complexity unless model error is large. Models with lower FI have a higher level of disorder (increase in entropy) which results in greater uncertainty of parameter estimates and model predictions. A constant-head boundary constrains the heads in the area near the boundary, reducing sensitivity of simulated equivalents to estimated parameters. JI and FI are lower for this boundary condition as compared to a constant-outflow boundary in which the heads in the area of the boundary can adjust freely. Complex, over fitted models, in which the structure of the model is not supported by the observation dataset, result in lower JI and FI because there is insufficient information to estimate all parameters in the model. PMID- 29604040 TI - Clinical and dermoscopic response predictors in psoriatic patients undergoing narrowband ultraviolet B phototherapy: results from a prospective study. AB - BACKGROUND: Although disease severity, gender, body weight, and previous treatments have all been reported to affect clinical response of psoriasis vulgaris to narrowband ultraviolet B (NB-UVB) therapy, little information about possible local (lesional) influencing factors is available. OBJECTIVE: To assess correlations between clinical/dermoscopic findings of psoriatic plaques and therapeutic response to NB-UVB phototherapy in order to find positive and/or negative response predictor factors to such a treatment. METHODS: For each target lesion, we calculated local psoriasis severity index and assessed dermoscopic findings at the baseline. After 8 weeks of treatment, we evaluated clinical improvement of each lesion, correlating the therapeutic outcome with initial clinical and dermoscopic features. RESULTS: Ninety-eight target lesions from 27 patients were included in the study. After 8 weeks of therapy, 31 lesions experienced no/limited improvement, while partial response was observed in 40 plaques and optimal response in 27 lesions. Regarding clinical variables, we found an association between poor therapeutic outcomes and both legs localization and more marked lesion scaling/infiltration. Similarly, globular vessels on dermoscopy were more commonly associated with no/limited response as well as lesions localized on the legs, particularly those showing treatment resistance. Conversely, the presence of dotted vessels carried a higher probability for getting improvement. CONCLUSION: Therapeutic response of psoriasis vulgaris to NB UVB treatment may be negatively affected by local clinical factors, that is, significant scaling/infiltration and legs localization, and dermoscopy may be useful in highlighting possible response predictors, with globular and dotted vessels associated with bad and good outcomes, respectively. PMID- 29604041 TI - GxG epistasis in growth and condition and the maintenance of genetic polymorphism in Gambusia holbrooki. AB - Theory on indirect genetic effects (IGEs) indicates that variation in the genetic composition of social groups can generate GxG epistasis that may promote the evolution of stable polymorphisms. Using a livebearing fish with a genetic polymorphism in coloration and associated behavioral differences, we tested whether genotypes of social partners interacted with focal individual genotypes to influence growth and condition over 16 weeks of development. We found that IGEs had a significant influence on patterns of feeding, regardless of focal fish genotype. There was no influence of social environment on juvenile length, but there was significant GxG epistasis for body condition. Each focal juvenile was in better condition when its own genotype was not present in adult social partners. These data are consistent with negative frequency-dependent selection in which each morph performs better when it is rare. Neither variation in feeding nor activity-related behaviors explained variation in body condition, suggesting that GxG epistasis for condition was caused by physiological differences between the two genotypes. These findings indicate that GxG epistasis in a given polymorphism can generate fitness landscapes that contribute to the maintenance of that polymorphism and to maintenance of genetic variation for additional fitness-related traits. PMID- 29604042 TI - Higher carbohydrate intake is associated with increased risk of all-cause and disease-specific mortality in head and neck cancer patients: results from a prospective cohort study. AB - No studies have evaluated associations between carbohydrate intake and head and neck squamous cell carcinoma (HNSCC) prognosis. We prospectively examined associations between pre- and post-treatment carbohydrate intake and recurrence, all-cause mortality, and HNSCC-specific mortality in a cohort of 414 newly diagnosed HNSCC patients. All participants completed pre- and post-treatment Food Frequency Questionnaires (FFQs) and epidemiologic surveys. Recurrence and mortality events were collected annually. Multivariable Cox Proportional Hazards models tested associations between carbohydrate intake (categorized into low, medium and high intake) and time to recurrence and mortality, adjusting for relevant covariates. During the study period, there were 70 deaths and 72 recurrences. In pretreatment analyses, high intakes of total carbohydrate (HR: 2.29; 95% CI: 1.23-4.25), total sugar (HR: 3.03; 95% CI: 1.12-3.68), glycemic load (HR: 2.10; 95% CI: 1.15-3.83) and simple carbohydrates (HR 2.26; 95% CI 1.19 4.32) were associated with significantly increased risk of all-cause mortality compared to low intake. High intakes of carbohydrate (HR 2.45; 95% CI: 1.23-4.25) and total sugar (HR 3.03; 95% CI 1.12-3.68) were associated with increased risk of HNSCC-specific mortality. In post-treatment analyses, medium fat intake was significantly associated with reduced risk of recurrence (HR 0.08; 95% CI 0.01 0.69) and all-cause mortality (HR 0.27; 95% CI 0.07-0.96). Stratification by tumor site and cancer stage in pretreatment analyses suggested effect modification by these factors. Our data suggest high pretreatment carbohydrate intake may be associated with adverse prognosis in HNSCC patients. Clinical intervention trials to further examine this hypothesis are warranted. PMID- 29604043 TI - Optimizing Digital Integrated Care via Micro-Randomized Trials. AB - Mobile health (mHealth) interventions are a promising tool in providing digitally mediated integrative care. They can extend care outside of the clinic by providing reminders to take medications, assisting in managing symptoms, and supporting healthy behaviors including physical activity, healthy eating, and stress management. mHealth interventions can adapt the delivery of care across time in order to optimize treatment effectiveness. Yet there exists limited empirical evidence useful to the development of adaptive mHealth interventions. This article describes a new randomized trial design, the Micro-Randomized Trial (MRT), for informing the development of mHealth interventions. We provide examples of scientific questions important to the development of an mHealth intervention, and describe how these questions can be answered using an MRT. PMID- 29604044 TI - A retrospective study of the characteristics of patients with early-onset compared to adult-onset hidradenitis suppurativa. AB - BACKGROUND: The mean age of onset of hidradenitis suppurativa (HS) is between 20 and 24 years. Very few data about patients with early-onset HS exist. OBJECTIVE: To investigate the association of early-onset HS with the clinical characteristics: age, gender, body mass index (BMI), smoking, family history of HS, Hurley stage, and number of areas affected. METHODS: This was a retrospective study of the reported early age at HS onset (<=17 years old) with clinical characteristics and with the severity of HS at first consultation visit. RESULTS: In 166 patients, 42 patients (25.3%) reported early-onset HS. Compared to adult onset HS, patients with early-onset HS were younger (mean age: 37 years vs. 27 years, P < 0.0001), had a significantly younger mean age of onset (28.2 years old vs. 14.5 years old, respectively, P < 0.0001), longer mean disease duration (8.8 years vs. 12.6 years, respectively, P = 0.011) and were less frequently smokers (P < 0.001), whereas there was no association with gender (P = 0.177) or BMI (0.086). Patients with a family history had increased risk for early-onset HS (OR: 2.45, 95% CI: 1.08-5.56). Early-onset HS was not associated with Hurley stage (OR: 1.12, 95% CI: 0.33-3.74) or with the number of body areas affected (OR: 1.54, 95% CI: 0.49-4.83). CONCLUSION: Early-onset HS was frequent and associated with a family history of HS. There was no difference in the severity of HS in adult life for patients with an onset of HS at <=17 years, compared to patients with adult-onset, which may be reassuring information for these younger patients. PMID- 29604045 TI - Understanding Hematological Toxicities Using Mathematical Modeling. AB - Balancing antitumor efficacy with toxicity is a significant challenge, and drug induced myelosuppression is a common dose-limiting toxicity of cancer treatments. Mathematical modeling has proven to be a powerful ally in this field, scaling results from animal models to humans, and designing optimized treatment regimens. Here we outline existing mathematical approaches for studying bone marrow toxicity, identify gaps in current understanding, and make future recommendations to advance this vital field of safety research further. PMID- 29604047 TI - Digest: Context matters: The effects of light environment and female presence on the structure of wolf spider courtship displays. AB - Does variation in the environment in which a signal is presented affect the components of a complex, ritualized animal display? Using a signal phenotype network, Rosenthal et al. (2018) found that light and female presence alter the structure of wolf spider courtship displays, providing evidence that complex signaling behaviors may be modified depending on the social and environmental context. PMID- 29604046 TI - Initiation and slow propagation of epileptiform activity from ventral to dorsal medial entorhinal cortex is constrained by an inhibitory gradient. AB - KEY POINTS: The medial entorhinal cortex (mEC) has an important role in initiation and propagation of seizure activity. Several anatomical relationships exist in neurophysiological properties of mEC neurons; however, in the context of hyperexcitability, previous studies often considered it as a homogeneous structure. Using multi-site extracellular recording techniques, ictal-like activity was observed along the dorso-ventral axis of the mEC in vitro in response to various ictogenic stimuli. This originated predominantly from ventral areas, spreading to dorsal mEC with a surprisingly slow velocity. Modulation of inhibitory tone was capable of changing the slope of ictal initiation, suggesting seizure propagation behaviours are highly dependent on levels of GABAergic function in this region. A distinct disinhibition model also showed, in the absence of inhibition, a prevalence for interictal-like initiation in ventral mEC, reflecting the intrinsic differences in mEC neurons. These findings suggest the ventral mEC is more prone to hyperexcitable discharge than the dorsal mEC, which may be relevant under pathological conditions. ABSTRACT: The medial entorhinal cortex (mEC) has an important role in the generation and propagation of seizure activity. The organization of the mEC is such that a number of dorso ventral relationships exist in neurophysiological properties of neurons. These range from intrinsic and synaptic properties to density of inhibitory connectivity. We examined the influence of these gradients on generation and propagation of epileptiform activity in the mEC. Using a 16-shank silicon probe array to record along the dorso-ventral axis of the mEC in vitro, we found 4 aminopyridine application produces ictal-like activity originating predominantly in ventral areas. This activity spreads to dorsal mEC at a surprisingly slow velocity (138 MUm s-1 ), while cross-site interictal-like activity appeared relatively synchronous. We propose that ictal propagation is constrained by differential levels of GABAergic control since increasing (diazepam) or decreasing (Ro19-4603) GABAA receptor activation, respectively, reduced or increased the slope of ictal initiation. The observation that ictal activity is predominately generated in ventral mEC was replicated using a separate 0-Mg2+ model of epileptiform activity in vitro. By using a distinct disinhibition model (co-application of kainate and picrotoxin) we show that additional physiological features (for example intrinsic properties of mEC neurons) still produce a prevalence for interictal-like initiation in ventral mEC. These findings suggest that the ventral mEC is more likely to initiate hyperexcitable discharges than the dorsal mEC, and that seizure propagation is highly dependent on levels of GABAergic expression across the mEC. PMID- 29604048 TI - Peripherally induced regulatory T cells contribute to the control of autoimmune diabetes in the NOD mouse model. AB - Type 1 diabetes (T1D) results from the autoimmune destruction of pancreatic beta cells and is partly caused by deficiencies in the Foxp3+ regulatory T-cell (Treg) compartment. Conversely, therapies that increase Treg function can prevent autoimmune diabetes in animal models. The majority of Tregs develop in the thymus (tTregs), but a proportion of Foxp3+ Tregs is generated in the periphery (pTregs) from Foxp3- CD4+ T-cell precursors. Whether pTregs play a distinct role in T1D has not yet been explored. We report here that pTregs are a key modifier of disease in the nonobese diabetic (NOD) mouse model for T1D. We generated NOD mice deficient for the Foxp3 enhancer CNS1 involved in pTreg induction. We show that CNS1 knockout decreased the frequency of pTregs and increased the risk of diabetes. Our results show that pTregs fulfill an important non-redundant function in the prevention of beta cell autoimmunity that causes T1D. PMID- 29604049 TI - Aberrant cell signalling in PBMCs upon IFN-alpha stimulation in primary Sjogren's syndrome patients associates with type I interferon signature. AB - Primary Sjogren's syndrome (pSS) is a complex systemic autoimmune disease with heterogeneous disease manifestations. Genetic predisposition, hormonal and environmental factors are all thought to contribute to disease etiology and pathogenesis. A better understanding of the disease pathogenesis is required in order to establish new targeted therapies. We analysed MAPK/ERK and JAK/STAT signalling networks in peripheral blood mononuclear cells (PBMCs) upon stimulation with interferon alpha 2b (IFN-alpha2b) by flow cytometry to define potentially dysfunctional intracellular signalling pathways involved in disease pathogenesis. Cells derived from pSS patients displayed small but significant increases in basal phosphorylation levels of numerous signalling proteins compared to cells from healthy donors. The phosphorylation profiles following stimulation with IFNalpha2b differed significantly between pSS patients and healthy donors, especially regarding STAT1 Y701. PCA further grouped patients according to clinical characteristics. Type I IFN induced gene expression was found to negatively correlate with the IFN-alpha2b induced phosphorylation of STAT3 S727 in T cells and positively with pSTAT1 Y701 in B cells. Increases in pSTAT1 Y701 were associated with the presence of autoantibodies. Our results indicate involvement of both STAT3 S727 and STAT1 Y701 pathways in pSS patients. Therapies targeting these pathways might therefore be beneficial for certain subgroups of patients. PMID- 29604051 TI - Clinical implication of FMR1 intermediate alleles in a Spanish population. AB - FMR1 premutation carriers (55-200 CGGs) are at risk of developing Fragile X associated primary ovarian insufficiency as well as Fragile X-associated tremor/ataxia syndrome. FMR1 premutation alleles are also associated with a variety of disorders, including psychiatric, developmental, and neurological problems. However, there is a major concern regarding clinical implications of smaller CGG expansions known as intermediate alleles (IA) or gray zone alleles (45-54 CGG). Although several studies have hypothesized that IA may be involved in the etiology of FMR1 premutation associated phenotypes, this association still remains unclear. The aim of this study was to provide new data on the clinical implications of IA. We reviewed a total of 17 011 individuals: 1142 with primary ovarian insufficiency, 478 with movement disorders, 14 006 with neurodevelopmental disorders and 1385 controls. Similar IA frequencies were detected in all the cases and controls (cases 1.20% vs controls 1.39%, P = .427). When comparing the allelic frequencies of IA >= 50CGGs, a greater, albeit not statistically significant, number of alleles were detected in all the cohorts of patients. Therefore, IA below 50 CGGs should not be considered as risk factors for FMR1 premutation-associated phenotypes, at least in our population. However, the clinical implication of IA >= 50CGGs remains to be further elucidated. PMID- 29604050 TI - Common data elements for epilepsy mobile health systems. AB - OBJECTIVE: Common data elements (CDEs) are currently unavailable for mobile health (mHealth) in epilepsy devices and related applications. As a result, despite expansive growth of new digital services for people with epilepsy, information collected is often not interoperable or directly comparable. We aim to correct this problem through development of industry-wide standards for mHealth epilepsy data. METHODS: Using a group of stakeholders from industry, academia, and patient advocacy organizations, we offer a consensus statement for the elements that may facilitate communication among different systems. RESULTS: A consensus statement is presented for epilepsy mHealth CDEs. SIGNIFICANCE: Although it is not exclusive, we believe that the use of a minimal common information denominator, specifically these CDEs, will promote innovation, accelerate scientific discovery, and enhance clinical usage across applications and devices in the epilepsy mHealth space. As a consequence, people with epilepsy will have greater flexibility and ultimately more powerful tools to improve their lives. PMID- 29604052 TI - Filling the gap between chemical carcinogenesis and the hallmarks of cancer: A temporal perspective. AB - BACKGROUND: Cancer is believed to arise through the perturbation of pathways and the order of pathway perturbation events can enhance understanding and evaluation of carcinogenicity. This order has not been examined so far, and this study aimed to fill this gap by attempting to gather evidence on the potential temporal sequence of events in carcinogenesis. DESIGN: The methodology followed was to discuss first the temporal sequence of hallmarks of cancer from the point of view of pathological specimens of cancer (essentially branched mutations) and then to consider the hallmarks of cancer that one well-known carcinogen, benzo(a)pyrene, can modify. RESULTS: Even though the sequential order of driving genetic alterations can vary between and within tumours, the main cancer pathways affected are almost ubiquitous and follow a generally common sequence: resisting cell death, insensitivity to antigrowth signals, sustained proliferation, deregulated energetics, replicative immortality and activation of invasion and metastasis. The first 3 hallmarks can be regarded as almost simultaneous while angiogenesis and avoiding immune destruction are perhaps the only hallmarks with a varying position in the above sequence. CONCLUSIONS: Our review of hallmarks of cancer and their temporal sequence, based on mutational spectra in biopsies from different cancer sites, allowed us to propose a hypothetical temporal sequence of the hallmarks. This sequence can add molecular support to the evaluation of an agent as a carcinogen as it can be used as a conceptual framework for organising and evaluating the strength of existing evidence. PMID- 29604053 TI - History-dependence of muscle slack length following contraction and stretch in the human vastus lateralis. AB - KEY POINTS: In reduced muscle preparations, the slack length and passive stiffness of muscle fibres have been shown to be influenced by previous muscle contraction or stretch. In human muscles, such behaviours have been inferred from measures of muscle force, joint stiffness and reflex magnitudes and latencies. Using ultrasound imaging, we directly observed that isometric contraction of the vastus lateralis muscle at short lengths reduces the slack lengths of the muscle tendon unit and muscle fascicles. The effect is apparent 60 s after the contraction. These observations imply that muscle contraction at short lengths causes the formation of bonds which reduce the effective length of structures that generate passive tension in muscles. ABSTRACT: In reduced muscle preparations, stretch and muscle contraction change the properties of relaxed muscle fibres. In humans, effects of stretch and contraction on properties of relaxed muscles have been inferred from measurements of time taken to develop force, joint stiffness and reflex latencies. The current study used ultrasound imaging to directly observe the effects of stretch and contraction on muscle tendon slack length and fascicle slack length of the human vastus lateralis muscle in vivo. The muscle was conditioned by (a) strong isometric contractions at long muscle-tendon lengths, (b) strong isometric contractions at short muscle tendon lengths, (c) weak isometric contractions at long muscle-tendon lengths and (d) slow stretches. One minute after conditioning, ultrasound images were acquired from the relaxed muscle as it was slowly lengthened through its physiological range. The ultrasound image sequences were used to identify muscle tendon slack angles and fascicle slack lengths. Contraction at short muscle tendon lengths caused a mean 13.5 degree (95% CI 11.8-15.0 degree) shift in the muscle-tendon slack angle towards shorter muscle-tendon lengths, and a mean 5 mm (95% CI 2-8 mm) reduction in fascicle slack length, compared to the other conditions. A supplementary experiment showed the effect could be demonstrated if the muscle was conditioned by contraction at short lengths but not if the relaxed muscle was held at short lengths, confirming the role of muscle contraction. These observations imply that muscle contraction at short lengths causes the formation of bonds which reduce the effective length of structures that generate passive tension in muscles. PMID- 29604054 TI - Site conditions determine a key native plant's contribution to invasion resistance in grasslands. AB - Many plant invasion studies in grasslands suggest that resident plants that share functional traits with invaders can reduce invasion by competing for limiting resources. However, since invasion studies often occur in highly controlled plots or microcosms, it is unclear how heterogeneous site conditions alter competitive interactions under realistic scenarios. To explore how landscape heterogeneity affects biotic resistance provided by competitive resident plants, we conducted a field-based experiment across four sites in California grasslands. Plots contained naturally occurring populations of native Hemizonia congesta, but differed in other characteristics, including litter cover, annual grass cover, soil moisture, and species richness. We invaded plots with the functionally similar nonnative Centaurea solstitalis (yellow starthistle) and, at one site, supplemented one-half of the established plots with water to test the effects of increasing a limiting resource. As in simplified plots and microcosms, increasing H. congesta abundance reduced starthistle biomass by competing for limited soil moisture, but only in plots with high starthistle germination. We conclude that higher abundances of native H. congesta can reduce starthistle invasion in heterogeneous grasslands, but competition is also affected by both abiotic (soil moisture) and biotic (starthistle germination number) conditions that vary across sites. PMID- 29604055 TI - Rates of molecular evolution in tree ferns are associated with body size, environmental temperature, and biological productivity. AB - Variation in rates of molecular evolution (heterotachy) is a common phenomenon among plants. Although multiple theoretical models have been proposed, fundamental questions remain regarding the combined effects of ecological and morphological traits on rate heterogeneity. Here, we used tree ferns to explore the correlation between rates of molecular evolution in chloroplast DNA sequences and several morphological and environmental factors within a Bayesian framework. We revealed direct and indirect effects of body size, biological productivity, and temperature on substitution rates, where smaller tree ferns living in warmer and less productive environments tend to have faster rates of molecular evolution. In addition, we found that variation in the ratio of nonsynonymous to synonymous substitution rates (dN/dS) in the chloroplast rbcL gene was significantly correlated with ecological and morphological variables. Heterotachy in tree ferns may be influenced by effective population size associated with variation in body size and productivity. Macroevolutionary hypotheses should go beyond explaining heterotachy in terms of mutation rates and instead, should integrate population-level factors to better understand the processes affecting the tempo of evolution at the molecular level. PMID- 29604056 TI - CRIPTO promotes an aggressive tumour phenotype and resistance to treatment in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Despite increasing treatment options for this disease, prognosis remains poor. CRIPTO (TDGF1) protein is expressed at high levels in several human tumours and promotes oncogenic phenotype. Its expression has been correlated to poor prognosis in HCC. In this study, we aimed to elucidate the basis for the effects of CRIPTO in HCC. We investigated CRIPTO expression levels in three cohorts of clinical cirrhotic and HCC specimens. We addressed the role of CRIPTO in hepatic tumourigenesis using Cre-loxP-controlled lentiviral vectors expressing CRIPTO in cell line-derived xenografts. Responses to standard treatments (sorafenib, doxorubicin) were assessed directly on xenograft-derived ex vivo tumour slices. CRIPTO-overexpressing patient-derived xenografts were established and used for ex vivo drug response assays. The effects of sorafenib and doxorubicin treatment in combination with a CRIPTO pathway inhibitor were tested in ex vivo cultures of xenograft models and 3D cultures. CRIPTO protein was found highly expressed in human cirrhosis and hepatocellular carcinoma specimens but not in those of healthy participants. Stable overexpression of CRIPTO in human HepG2 cells caused epithelial-to-mesenchymal transition, increased expression of cancer stem cell markers, and enhanced cell proliferation and migration. HepG2 CRIPTO cells formed tumours when injected into immune-compromised mice, whereas HepG2 cells lacking stable CRIPTO overexpression did not. High-level CRIPTO expression in xenograft models was associated with resistance to sorafenib, which could be modulated using a CRIPTO pathway inhibitor in ex vivo tumour slices. Our data suggest that a subgroup of CRIPTO-expressing HCC patients may benefit from a combinatorial treatment scheme and that sorafenib resistance may be circumvented by inhibition of the CRIPTO pathway. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29604057 TI - Independent development of endometrial epithelium and stroma within the same endometriosis. AB - The pathogenesis of endometriosis, a common benign but debilitating disease in women, remains elusive. The currently held stem cell theory posits that circulating progenitor/stem cells are deposited outside the uterus, where they differentiate into endometrial stroma and glandular tissue to establish endometriosis. Fundamental to testing this hypothesis is to elucidate the evolution of both tissue types. Here, we applied droplet digital PCR to analyze synonymous and missense somatic passenger mutations, which are neutral with respect to clonal selection, among six non-superficial endometriotic lesions. We found that among 19 mutations sequenced, all were significantly enriched in epithelial but not in stromal components of every lesion examined. Our data indicate that the evolution of non-superficial endometriosis is complex, in that epithelium is clonal and its development is independent of stroma, providing new insight into the genesis of endometriosis. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. PMID- 29604058 TI - Mutations in the voltage-sensing domain affect the alternative ion permeation pathway in the TRPM3 channel. AB - KEY POINTS: Mutagenesis at positively charged amino acids (arginines and lysines) (R1-R4) in the voltage-sensor domain (transmembrane segment (S) 4) of voltage gated Na+ , K+ and Ca2+ channels can lead to an alternative ion permeation pathway distinct from the central pore. Recently, a non-canonical ion permeation pathway was described in TRPM3, a member of the transient receptor potential (TRP) superfamily. The non-canonical pore exists in the native TRPM3 channel and can be activated by co-stimulation of the endogenous agonist pregnenolone sulphate and the antifungal drug clotrimazole or by stimulation of the synthetic agonist CIM0216. Alignment of the voltage sensor of Shaker K+ channels with the entire TRPM3 sequence revealed the highest degree of similarity in the putative S4 region of TRPM3, and suggested that only one single gating charge arginine (R2) in the putative S4 region is conserved. Mutagenesis studies in the voltage sensing domain of TRPM3 revealed several residues in the voltage sensor (S4) as well as in S1 and S3 that are crucial for the occurrence of the non-canonical inward currents. In conclusion, this study provides evidence for the involvement of the voltage-sensing domain of TRPM3 in the formation of an alternative ion permeation pathway. ABSTRACT: Transient receptor potential (TRP) channels are cationic channels involved in a broad array of functions, including homeostasis, motility and sensory functions. TRP channel subunits consist of six transmembrane segments (S1-S6), and form tetrameric channels with a central pore formed by the region encompassing S5 and S6. Recently, evidence was provided for the existence of an alternative ion permeation pathway in TRPM3, which allows large inward currents upon hyperpolarization independently of the central pore. However, very little knowledge is available concerning the localization of this alternative pathway in the native TRPM3 channel protein. Guided by sequence homology with Shaker K+ channels, in which mutations in S4 can create an analogous 'omega' pore, we performed site-directed mutagenesis studies and patch clamp experiments to identify amino acid residues involved in the formation of the non-canonical pore in TRPM3. Based on our results, we pinpoint four residues in S4 (W982, R985, D988 and G991) as crucial determinants of the properties of the alternative ion permeation pathway. PMID- 29604059 TI - Transition probabilities help identify putative drivers of community change in complex systems. AB - Understanding the role of larger-scale processes in modulating the assembly, structure, and dynamics of communities is critical for forecasting the effects of climate-change and managing ecosystems. Developing this comprehensive perspective is difficult though, because species interactions are complex, interdependent, and dynamic through space and time. Typically, experiments focus on tractable subsets of interactions that will be most critical to investigate and explain shifts in communities, but qualitatively base these choices on experience, natural history, and theory. One quantitative approach to identify the putative forces regulating communities, without reducing system complexity, is estimating transition probabilities among species occupying space (i.e., multispecies Markov chain models). Although not mechanistic, these models estimate the relative frequency and importance of ecological pathways in community assembly and dynamics, and can serve as a framework to identify how pathways change across large scales and which are most important to investigate further. Here, we demonstrate this method in the Gulf of Maine (GOM) intertidal zone, where research has largely focused on the local-scale processes that influence communities, while the mechanisms responsible for more regional shifts in communities are less clear. Transition probabilities of faunal elements were quantified bimonthly for ~2.5 yr in local intertidal communities at three replicate sites in the southern, mid-coast, and northern GOM. Transitions related to mortality, colonization, and replacement by mussels, barnacles, red algae, and encrusting corallines differed regionally, suggesting specific pathways related to consumer pressure and recruitment vary across the GOM with shifting intertidal community structure. Combined with species abundance data and insights from previous research, we develop and evaluate the pathways by which communities likely change in the GOM. Species interactions in local communities can be complex, and this complexity should be incorporated into hypothesis building, experiments, theory, interpretations, and forecasts in ecology. Such a comprehensive approach will be critical to understand how regional shifts in local interactions can drive large-scale community change. PMID- 29604060 TI - River food webs: an integrative approach to bottom-up flow webs, top-down impact webs, and trophic position. AB - The majority of food web studies are based on connectivity, top-down impacts, bottom-up flows, or trophic position (TP), and ecologists have argued for decades which is best. Rarely have any two been considered simultaneously. The present study uses a procedure that integrates the last three approaches based on taxon specific secondary production and gut analyses. Ingestion flows are quantified to create a flow web and the same data are used to quantify TP for all taxa. An individual predator's impacts also are estimated using the ratio of its ingestion (I) of each prey to prey production (P) to create an I/P web. This procedure was applied to 41 invertebrate taxa inhabiting submerged woody habitat in a southeastern U.S. river. A complex flow web starting with five basal food resources had 462 flows >1 mg.m-2 .yr-1 , providing far more information than a connectivity web. Total flows from basal resources to primary consumers/omnivores were dominated by allochthonous amorphous detritus and ranged from 1 to >50,000 mg.m-2 .yr-1 . Most predator-prey flows were much lower (<50 mg.m-2 .yr-1 ), but some were >1,000 mg.m-2 .yr-1 . The I/P web showed that 83% of individual predator impacts were weak (<10%), whereas total predator impacts were often strong (e.g., 35% of prey sustained an impact >90%). Quantitative estimates of TP ranged from 2 to 3.7, contrasting sharply with seven integer-based trophic levels based on longest feeding chain. Traditional omnivores (TP = 2.4-2.9) played an important role by consuming more prey and exerting higher impacts on primary consumers than strict predators (TP >= 3). This study illustrates how simultaneous quantification of flow pathways, predator impacts, and TP together provide an integrated characterization of natural food webs. PMID- 29604061 TI - Stress-testing the brain to understand its breaking points. PMID- 29604062 TI - Saving the brain one heartbeat at a time. PMID- 29604063 TI - Somatic POLE exonuclease domain mutations are early events in sporadic endometrial and colorectal carcinogenesis, determining driver mutational landscape, clonal neoantigen burden and immune response. AB - Genomic instability, which is a hallmark of cancer, is generally thought to occur in the middle to late stages of tumourigenesis, following the acquisition of permissive molecular aberrations such as TP53 mutation or whole genome doubling. Tumours with somatic POLE exonuclease domain mutations are notable for their extreme genomic instability (their mutation burden is among the highest in human cancer), distinct mutational signature, lymphocytic infiltrate, and excellent prognosis. To what extent these characteristics are determined by the timing of POLE mutations in oncogenesis is unknown. Here, we have shown that pathogenic POLE mutations are detectable in non-malignant precursors of endometrial and colorectal cancer. Using genome and exome sequencing, we found that multiple driver mutations in POLE-mutant cancers show the characteristic POLE mutational signature, including those in genes conventionally regarded as initiators of tumourigenesis. In POLE-mutant cancers, the proportion of monoclonal predicted neoantigens was similar to that in other cancers, but the absolute number was much greater. We also found that the prominent CD8+ T-cell infiltrate present in POLE-mutant cancers was evident in their precursor lesions. Collectively, these data indicate that somatic POLE mutations are early, quite possibly initiating, events in the endometrial and colorectal cancers in which they occur. The resulting early onset of genomic instability may account for the striking immune response and excellent prognosis of these tumours, as well as their early presentation. (c) 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland. PMID- 29604064 TI - Altered autonomic control of heart rate variability in the chronically hypoxic fetus. AB - KEY POINTS: Fetal heart rate variability (FHRV) has long been recognised as a powerful predictor of fetal wellbeing, and a decrease in FHRV is associated with fetal compromise. However, the mechanisms by which FHRV is reduced in the chronically hypoxic fetus have yet to be established. The sympathetic and parasympathetic influences on heart rate mature at different rates throughout fetal life, and can be assessed by time domain and power spectral analysis of FHRV. In this study of chronically instrumented fetal sheep in late gestation, we analysed FHRV daily over a 16 day period towards term, and compared changes between fetuses of control and chronically hypoxic pregnancy. We show that FHRV in sheep is reduced by chronic hypoxia, predominantly due to dysregulation of the sympathetic control of the fetal heart rate. This presents a potential mechanism by which a reduction in indices of FHRV predicts fetuses at increased risk of neonatal morbidity and mortality in humans. Reduction in overall FHRV may therefore provide a biomarker that autonomic dysregulation of fetal heart rate control has taken place in a fetus where uteroplacental dysfunction is suspected. ABSTRACT: Although fetal heart rate variability (FHRV) has long been recognised as a powerful predictor of fetal wellbeing, the mechanisms by which it is reduced in the chronically hypoxic fetus have yet to be established. In particular, the physiological mechanism underlying the reduction of short term variation (STV) in fetal compromise remains unclear. In this study, we present a longitudinal study of the development of autonomic control of FHRV, assessed by indirect indices, time domain and power spectral analysis, in normoxic and chronically hypoxic, chronically catheterised, singleton fetal sheep over the last third of gestation. We used isobaric chambers able to maintain pregnant sheep for prolonged periods in hypoxic conditions (stable fetal femoral arterial PMID- 29604065 TI - Enterocyte K+ ion permeability and fluid secretion: missing the correct channel or missing the point? PMID- 29604066 TI - Response: Comparing the dosages of lacosamide, eslicarbazepine acetate, and controlled-release carbamazepine in noninferiority epilepsy monotherapy trials: How much "fair" is "fair". PMID- 29604067 TI - International conference and workshop "Hallmarks of Epileptic Brain Activity" in Tbilisi, Georgia, October 24-27, 2017. PMID- 29604068 TI - Comparing the dosages of lacosamide, eslicarbazepine acetate, and controlled release carbamazepine in noninferiority epilepsy monotherapy trials: How much "fair" is "fair"? PMID- 29604069 TI - Moderate and severe hypoxia elicit divergent effects on cardiovascular function and physiological rhythms. AB - KEY POINTS: In the present study, we provide evidence for divergent physiological responses to moderate compared to severe hypoxia, addressing an important knowledge gap related to severity, duration and after-effects of hypoxia encountered in cardiopulmonary situations. The physiological responses to moderate and severe hypoxia were not proportional, linear or concurrent with the time-of-day. Hypoxia elicited severity-dependent physiological responses that either persisted or fluctuated throughout normoxic recovery. The physiological basis for these distinct cardiovascular responses implicates a shift in the sympathovagal set point and probably not molecular changes at the artery resulting from hypoxic stress. ABSTRACT: Hypoxia is both a consequence and cause of many acute and chronic diseases. Severe hypoxia causes hypertension with cardiovascular sequelae; however, the rare studies using moderate severities of hypoxia indicate that it can be beneficial, suggesting that hypoxia may not always be detrimental. Comparisons between studies are difficult because of the varied classifications of hypoxic severities, methods of delivery and use of anaesthetics. Thus, to investigate the long-term effects of moderate hypoxia on cardiovascular health, radiotelemetry was used to obtain in vivo physiological measurements in unanaesthetized mice during 24 h of either moderate PMID- 29604070 TI - Sheet beam x-ray fluorescence computed tomography (XFCT) imaging of gold nanoparticles. AB - PURPOSE: X-ray fluorescence computed tomography (XFCT) experiments have typically used pencil beams for data acquisition, which yielded good quality images of gold nanoparticles (AuNP) but prolonged the imaging time. Here we propose three novel collimator geometries for use with faster sheet beam XFCT data acquisition. The feasibility of a multipinhole, parallel, and converging collimator was investigated in a Monte Carlo study. METHODS: A cylindrical water phantom with 2 cm in diameter and 3 cm in height containing 0.5-2 mm diameter vials with 0.4% 1.6% AuNP concentrations was modelled by FLUKA. A 15 and 81 keV monoenergetic x ray sheet beam of 0.4 mm in width was used to image the phantom with L-shell and K-shell XFCT, respectively, with a dose of 30 mGy. The collimator thickness for L shell and K-shell data acquisition was 3.3 and 5.1 mm, respectively. The XFCT images resulting from three collimator geometries were generated using the maximum likelihood expectation maximization (MLEM) iterative reconstruction method. With a resolution of 0.4 mm they were corrected for x-ray attenuation. The sheet beam XFCT images were compared against pencil beam geometry images that were generated using 55 translations. To assess image quality, the contrast-to noise ratio (CNR) was evaluated for each vial. The Rose criterion was used to determine the lowest AuNP concentration detectable for each image. RESULTS: Among the three collimator geometry types, the sheet beam L-shell and K-shell parallel collimator XFCT images yielded AuNP sensitivity limits at 0.09% and 0.08%, respectively, for a 2 mm diameter vial. The AuNP sensitivity limits of the pencil beam XFCT images were 0.07% and 0.01% for L-shell and K-shell XFCT, respectively. The L-shell parallel collimator AuNP imaging sensitivity approached that of the pencil beam geometry with a 55-fold reduction in imaging time. The AuNP sensitivity limits for the 1 mm diameter vial for the L-shell and K-shell parallel collimator XFCT images were 0.19% and 0.16%, respectively, and those of the pencil beam XFCT images were 0.08% and 0.01% for L-shell and K-shell XFCT, respectively. The remaining two collimator geometries resulted in a lower CNR and poorer image quality. For a 2 mm diameter vial, the AuNP sensitivity limits for the L-shell and K-shell multipinhole collimator XFCT images were 0.23% and 0.52%, respectively, while for the L-shell and K-shell converging collimator XFCT images the AuNP sensitivity limits were 0.38% and 0.13%, respectively. CONCLUSION: This work demonstrates the feasibility of sheet beam L-shell XFCT imaging for small animal studies using parallel-oriented lead collimators which can detect AuNP concentrations approaching the level of pencil beam images with reduced imaging time. PMID- 29604071 TI - Novel amoxicillin nanoparticles formulated as sustained release delivery system for poultry use. AB - Amoxicillin is used in the treatment and prevention of a wide range of diseases in poultry breeding. However, its short half-life and low bioavailability restrict its clinical application in these species. Entrapment of drugs into polymeric nanoparticles (nps) presents a means to improve gastrointestinal absorption and oral bioavailability of drugs. This study was aimed to overcome limitation of amoxicillin use in poultry breeding. Amoxicillin was loaded into sodium alginate-polyvinyl alcohol (NaAlg-PVA) blend nps, and characterization of the prepared nps was performed. For pharmacokinetic study, commercial male broilers were used and comparative pharmacokinetics of free and nanoparticle form of amoxicillin were investigated. Twenty-one broilers were divided into three groups. All groups received 10 mg/kg drug. Blood samples were collected, and drug plasma concentrations were determined by HPLC. The results demonstrated that the particle size, zeta potential, encapsulation efficiency, and loading capacity of the nps were 513.96 +/- 19.46 nm, -45.36 +/- 1.35 mV, 43.66 +/- 3.30, and 12.06 +/- 0.83%, respectively. In vitro drug release exhibited a biphasic pattern with an initial burst release of 18% within 2 hr followed by a sustained release over 22 hr. The pharmacokinetic results showed that amoxicillin nps have higher bioavailability and longer plasma half-life (p < .01) than free amoxicillin. These results indicate that amoxicillin nano formulation is suitable for oral administration in broilers. PMID- 29604072 TI - Endogenous microbial contamination of melons (Cucumis melo) from international trade: an underestimated risk for the consumer? AB - BACKGROUND: Fruits and vegetables have increasingly been related to foodborne outbreaks. Besides surface contamination, a possible internalization of microorganisms into edible parts of plants during growth has already been observed. To examine an actual risk for the consumer, microbial contamination of the rind and pulp of 147 muskmelons from international trade was assessed using cultural and biochemical methods, polymerase chain reaction and matrix-assisted laser desorption/ionization-time of flight mass spectrometry. RESULTS: One hundred percent of the rind samples [3.69-8.92 log colony forming units (CFU) g-1 ] and 89.8% of the pulp samples (maximum load 3.66 log CFU g-1 ) were microbiologically contaminated. Among the 432 pulp isolates, opportunistic and potentially pathogenic bacteria were identified, mainly Staphylococcus spp. (48.9%), Clostridium spp. (42.9%) and Enterobacteriaceae (27.9%). Salmonella spp., Escherichia coli and isolates of the Bacillus cereus group were found on the rind (1.4%, 0.7% and 42.9%, respectively) and in the pulp (0.7%, 1.4% and 4.7%). Clostridium perfringens was isolated from the rind of seven melons. CONCLUSION: The present study revealed a regularly occurring internal contamination of melons. Possible health risks for consumers because of an occurrence of microorganisms in melon pulp should be considered in future food safety assessments. (c) 2018 Society of Chemical Industry. PMID- 29604073 TI - Changes in the content of immunostimulating components of colostrum obtained from dairy cows at different levels of production. AB - BACKGROUND: Recent data indicate that almost 60% of colostrum samples do not have enough antibodies to provide adequate protection for the calf. Thus, the aim of this study was to determine the influence of the level of production of cows on the content of immunostimulating components of protein fraction of colostrum. The observations were conducted on two farms that keep dairy cows. One of the farms was selected to represent a typical performance level for the mass population of dairy cows in Poland, about 5500 kg of milk per cow per year (LI) and the second one was characterized by a higher level of production, about 8000 kg (HI). RESULTS: Based on the data obtained, 100% of the samples collected from LI had an immunoglobulin G (IgG) content >50 gL-1 , in the first collection. In the case of HI, 63% of the samples had an IgG content >50 gL-1 , with a distribution in the range of 10.7 to 72.7 gL-1 . The colostrum of LI cows was characterized by a higher content of lactoferrin, lysozyme, alpha-lactalbumin, and beta lactoglobulin compared to the milk of HI cows. CONCLUSIONS: The immunostimulating components of colostrum declined rapidly in subsequent milkings or with the increased productivity of the cows. The concentration of IgG was negatively correlated with the performance level of cows, which means that high-producing cows had colostrum with a low concentration of IgG. (c) 2018 Society of Chemical Industry. PMID- 29604074 TI - Effect of four rounds of annual school-wide mass praziquantel treatment for schistosoma mansoni control on schistosome-specific immune responses. AB - This study evaluated potential changes in antischistosome immune responses in children from schools that received 4 rounds of annual mass drug administration (MDA) of praziquantel (PZQ). In a repeated cross-sectional study design, 210 schistosome egg-positive children were recruited at baseline from schools in western Kenya (baseline group). Another 251 children of the same age range were recruited from the same schools and diagnosed with schistosome infection by microscopy (post-MDA group). In-vitro schistosome-specific cytokines and plasma antibody levels were measured by ELISA and compared between the 2 groups of children. Schistosome soluble egg antigen (SEA) and soluble worm antigen preparation (SWAP) stimulated higher IL-5 production by egg-negative children in the post-MDA group compared to the baseline group. Similarly, anti-SEA IgE levels were higher in egg-negative children in the post-MDA group compared to the baseline group. Anti-SEA and anti-SWAP IgG4 levels were lower in egg-negative children in the post-MDA group compared to baseline. This resulted in higher anti SEA IgE/IgG4 ratios for children in the post-MDA group compared to baseline. These post-MDA immunological changes are compatible with the current paradigm that treatment shifts immune responses to higher antischistosome IgE:IgG4 ratios in parallel with a potential increase in resistance to reinfection. PMID- 29604075 TI - New methods for high-accuracy insect chitin measurement. AB - BACKGROUND: There is a growing interest in the use of insects in poultry, swine and aquaculture feed, as well as pet food applications. All insects produce chitin-based exoskeletons. With regard to chitin content, a precise determination in agricultural applications is crucial because it has favorable functional properties, although it is also difficult to digest for some species of livestock. Three measurement methods were compared to determine the most reliable method of chitin content determination in different insects and selected Hermetia illucens products: acid detergent fiber (ADF) provides the fiber content and the acid detergent lignin (ADL) additionally considers the catecholic compounds. Acetyl group measurement relates the acetate content to the chitin content. RESULTS: Comparing different insect species, the highest chitin value via ADF measurement was determined for the Tenebrio molitor larvae (155 g kg-1 ). Chitin values higher than 200 g kg-1 revealed that H. illucens residues are a much better valuable source of chitin. For the larval exoskeletons, a chitin content for all measurement methods of more than 350 g kg-1 was determined. In general, the ADF measurement is approximately 5% higher than the ADF-ADL and acetyl measurements. ADF-ADL and acetyl group determinations are approximately equivalent measurement methods. CONCLUSION: According to statistical analysis, ADF-ADL represents a compromise between accuracy and equipment demand and is a suitable method for determining the chitin content of both insects and their residues. (c) 2018 Society of Chemical Industry. PMID- 29604076 TI - Reactive oxygen species metabolism and phenylpropanoid pathway involved in disease resistance against Penicillium expansum in apple fruit induced by epsilon poly-l-lysine. AB - BACKGROUND: Blue mould caused by Penicillium expansum comprises a notable disease of apple fruit during storage. epsilon-Poly-l-lysine (PL) consists of epsilon amino and alpha-hydroxyl and has been used in food preservation. In the present study, apple fruits (cv. Fuji) were used to investigate the effects of PL dipping treatment, at different concentrations of PL, on the lesion diameter of fruit inoculated with P. expansum, aiming to screen the optimal concentration for controlling blue mould. The effects of PL at the optimal concentration on reactive oxygen species (ROS) metabolism and the phenylpropanoid pathway were also investigated. RESULTS: The results indicated that 25, 50, 100 and 200 uL L-1 PL treatment significantly decreased the lesion diameter in apple fruit inoculated with P. expansum and the smallest lesion diameter was determined for 50 uL L-1 PL-treated fruits. The results also indicated that 50 uL L-1 PL treatment increased the hydrogen peroxide content and the activities of enzymes involved in ROS metabolism, including superoxide dismutase, catalase, ascorbate peroxidase, glutathione reductase and peroxidase in apple fruit. The activity of phenylalanine ammonia-lyase and the contents of lignin, total phenolic compounds and flavonoids were also enhanced by PL treatment. CONCLUSION: The disease resistance to P. expansum in apple fruits enhanced by PL treatment is related to activating ROS metabolism and the phenylpropanoid pathway and the accumulation of antifungal compounds. (c) 2018 Society of Chemical Industry. PMID- 29604077 TI - Association between B-type natriuretic peptide and within-visit blood pressure variability. AB - BACKGROUND: Blood pressure variability (BPV) has been shown to predict cardiovascular events. Within-visit BPV is the simplest and easiest measure of BPV, but previous studies have shown conflicts as to whether within-visit BPV correlates with target organ damage. We aimed to evaluate whether within-visit BPV correlates with B-type natriuretic peptide (BNP) in a general population. HYPOTHESIS: Within-visit BPV correlates with BNP in a general population. METHODS: This was a cross-sectional study that included 633 individuals, randomly selected, age 45 to 99 years, registered in the primary care program from an urban medium-sized town. Patients were scheduled for a single-day visit that consisted of clinical evaluation and laboratory tests. Three blood pressure (BP) readings, 1 minute apart, were done, and within-visit BPV was determined as the coefficient of variation (CV) of the 3 BP measures. Our main outcome was to correlate BNP and within-visit BPV. A multivariable model was estimated using a generalized linear model to evaluate the independent effects of different variables on BNP levels. RESULTS: The median age was 57 years. Median BNP was 16 pg/mL, and the median systolic and diastolic BP-CV were, respectively, 3.9% and 3.5%. There was a weak but positive correlation between BNP and both systolic BP CV and diastolic BP-CV (r = 0.107 and P = 0.007 and r = 0.092 and P = 0.019, respectively). In multiple regression equation, systolic BP, diastolic BP-CV, body mass index, and estimated glomerular filtration rate were associated with BNP. CONCLUSIONS: In the present study, there was a positive, albeit weak, correlation between within-visit BPV and BNP. In addition, diastolic BPV was associated with BNP even after adjustment for multiple confounders. PMID- 29604078 TI - Maternal undernutrition in late gestation increases IGF2 signalling molecules and collagen deposition in the right ventricle of the fetal sheep heart. AB - KEY POINTS: This study investigates the impact of decreased fetal plasma glucose concentrations on the developing heart in late gestation, by subjecting pregnant ewes to a 50% global nutrient restriction. Late gestation undernutrition (LGUN) decreased fetal plasma glucose concentrations whilst maintaining a normoxemic blood gas status. LGUN increased the mRNA expression of IGF2 and IGF2R. Fetal plasma glucose concentrations, but not fetal blood pressure, were significantly correlated with IGF2 expression and the activation of CAMKII in the fetal right ventricle. LGUN increased interstitial collagen deposition and altered the protein abundance of phospho-PLB and phospho-troponin I, regulators of cardiac contractility and relaxation. This study shows that a decrease in fetal plasma glucose concentrations may play a role in the development of detrimental changes in the right ventricle in early life, highlighting CAMKII as a potential target for the development of intervention strategies. ABSTRACT: Exposure of the fetus to a range of environmental stressors, including maternal undernutrition, is associated with an increased risk of death from cardiovascular disease in adult life. This study aimed to determine the effect of maternal nutrient restriction in late gestation on the molecular mechanisms that regulate cardiac growth and development of the fetal heart. Maternal undernutrition resulted in a decrease in fetal glucose concentrations across late gestation, whilst fetal arterial PO2 remained unchanged between the control and late gestation undernutrition (LGUN) groups. There was evidence of an up-regulation of IGF2/IGF2R signalling through the CAMKII pathway in the fetal right ventricle in the LGUN group, suggesting an increase in hypertrophic signalling. LGUN also resulted in an increased mRNA expression of COL1A, TIMP1 and TIMP3 in the right ventricle of the fetal heart. In addition, there was an inverse relationship between fetal glucose concentrations and COL1A expression. The presence of interstitial fibrosis in the heart of the LGUN group was confirmed through the quantification of picrosirius red-stained sections of the right ventricle. We have therefore shown that maternal undernutrition in late gestation may drive the onset of myocardial remodelling in the fetal right ventricle and thus has negative implications for right ventricle function and cardiac health in later life. PMID- 29604080 TI - Out of balance: how a binaural coincidence detection circuit responds to unilateral deafferentation. PMID- 29604079 TI - Genomic epidemiology of multidrug-resistant Gram-negative organisms. AB - The emergence and spread of antibiotic-resistant Gram-negative bacteria (rGNB) across global healthcare networks presents a significant threat to public health. As the number of effective antibiotics available to treat these resistant organisms dwindles, it is essential that we devise more effective strategies for controlling their proliferation. Recently, whole-genome sequencing has emerged as a disruptive technology that has transformed our understanding of the evolution and epidemiology of diverse rGNB species, and it has the potential to guide strategies for controlling the evolution and spread of resistance. Here, we review specific areas in which genomics has already made a significant impact, including outbreak investigations, regional epidemiology, clinical diagnostics, resistance evolution, and the study of epidemic lineages. While highlighting early successes, we also point to the next steps needed to translate this technology into strategies to improve public health and clinical medicine. PMID- 29604082 TI - Causal inference and temporal predictions in audiovisual perception of speech and music. AB - To form a coherent percept of the environment, the brain must integrate sensory signals emanating from a common source but segregate those from different sources. Temporal regularities are prominent cues for multisensory integration, particularly for speech and music perception. In line with models of predictive coding, we suggest that the brain adapts an internal model to the statistical regularities in its environment. This internal model enables cross-sensory and sensorimotor temporal predictions as a mechanism to arbitrate between integration and segregation of signals from different senses. PMID- 29604081 TI - The peripheral chemoreflex: indefatigable guardian of fetal physiological adaptation to labour. AB - The fetus is consistently exposed to repeated periods of impaired oxygen (hypoxaemia) and nutrient supply in labour. This is balanced by the healthy fetus's remarkable anaerobic tolerance and impressive ability to mount protective adaptations to hypoxaemia. The most important mediator of fetal adaptations to brief repeated hypoxaemia is the peripheral chemoreflex, a rapid reflex response to acute falls in arterial oxygen tension. The overwhelming majority of fetuses are able to respond to repeated uterine contractions without developing hypotension or hypoxic-ischaemic injury. In contrast, fetuses who are either exposed to severe hypoxaemia, for example during uterine hyperstimulation, or enter labour with reduced anaerobic reserve (e.g. as shown by severe fetal growth restriction) are at increased risk of developing intermittent hypotension and cerebral hypoperfusion. It is remarkable to note that when fetuses develop hypotension during such repeated severe hypoxaemia, it is not mediated by impaired reflex adaptation, but by failure to maintain combined ventricular output, likely due to a combination of exhaustion of myocardial glycogen and evolving myocardial injury. The chemoreflex is suppressed by relatively long periods of severe hypoxaemia of 1.5-2 min, longer than the typical contraction. Even in this setting, the peripheral chemoreflex is consistently reactivated between contractions. These findings demonstrate that the peripheral chemoreflex is an indefatigable guardian of fetal adaptation to labour. PMID- 29604083 TI - The neural basis of visual symmetry and its role in mid- and high-level visual processing. AB - Symmetry is an important and prominent feature of the visual world. It has been studied as a basis for image segmentation and perceptual organization, but it also plays a role in higher level processes, such as face and object perception. Over the past decade, there has been progress in the study of the neural mechanisms of symmetry perception in humans and other animals. There is extended activity in the ventral stream, including the lateral occipital complex (LOC) and VO1; this activity starts in V3 and it occurs independently of the task (automatic response). Additionally, when the task requires processing of symmetry, the activation may emerge for objects that are symmetrical, even though they do not project a symmetrical image. There is also some evidence of hemispheric lateralization, especially for the LOC. We review the studies on the cortical basis of visual symmetry processing and its links to encoding of other aspects of the visual world, such as faces and objects. PMID- 29604084 TI - Behavioral decoding of working memory items inside and outside the focus of attention. AB - How we attend to our thoughts affects how we attend to our environment. Holding information in working memory can automatically bias visual attention toward matching information. By observing attentional biases on reaction times to visual search during a memory delay, it is possible to reconstruct the source of that bias using machine learning techniques and thereby behaviorally decode the content of working memory. Can this be done when more than one item is held in working memory? There is some evidence that multiple items can simultaneously bias attention, but the effects have been inconsistent. One explanation may be that items are stored in different states depending on the current task demands. Recent models propose functionally distinct states of representation for items inside versus outside the focus of attention. Here, we use behavioral decoding to evaluate whether multiple memory items-including temporarily irrelevant items outside the focus of attention-exert biases on visual attention. Only the single item in the focus of attention was decodable. The other item showed a brief attentional bias that dissipated until it returned to the focus of attention. These results support the idea of dynamic, flexible states of working memory across time and priority. PMID- 29604085 TI - Identification and characterization of a novel carboxylesterase from Phaseolus vulgaris for detection of organophosphate and carbamates pesticides. AB - BACKGROUND: Organophosphate and carbamate pesticide residues in food and the environment pose a great threat to human health and have made the easy and rapid detection of these pesticide residues an important task. Discovering new enzyme sources from plants can help reduce the cost of large-scale applications of rapid pesticide detection via enzyme inhibition. RESULTS: Plant esterase from kidney beans was purified. Kidney bean esterase is identified as a carboxylesterase by substrate and inhibitor specificity tests and mass spectrometry identification. The kidney bean esterase demonstrates optimal catalytic activity at 40 degrees C, pH 6.5 and an enzyme concentration of 0.30 ug mL-1 . The kidney bean esterase can be inhibited by organophosphate and carbamate pesticides, which can be substituted for acetylcholinesterase. The limit of detection of the purified kidney bean esterase was two- to 20-fold higher than that of the crude one. The method detection limit meets the detection requirement for the maximum residue limits (MRL) in actual samples. CONCLUSION: The findings of the present study provide a new source of enzymes for pesticides detection by enzyme inhibition. (c) 2018 Society of Chemical Industry. PMID- 29604086 TI - EM-enhanced US-based seed detection for prostate brachytherapy. AB - PURPOSE: Intraoperative dosimetry in low-dose-rate (LDR) permanent prostate brachytherapy requires accurate localization of the implanted seeds with respect to the prostate anatomy. Transrectal Ultrasound (TRUS) imaging, which is the main imaging modality used during the procedure, is not sufficiently robust for accurate seed localization. We present a method for integration of electromagnetic (EM) tracking into LDR prostate brachytherapy procedure by fusing it with TRUS imaging for seed localization. METHOD: Experiments were conducted on five tissue mimicking phantoms in a controlled environment. The seeds were implanted into each phantom using an EM-tracked needle, which allowed recording of seed drop locations. After each needle, we reconstructed a 3D ultrasound (US) volume by compounding a series of 2D US images acquired during retraction of an EM-tracked TRUS probe. Then, a difference image was generated by nonrigid registration and subtraction of two consecutive US volumes. A US-only seed detection method was used to detect seed candidates in the difference volume, based on the signature of the seeds. Finally, the EM-based positions of the seeds were used to detect the false positives of the US-based seed detection method and also to estimate the positions of the missing seeds. After the conclusion of the seed implant process, we acquired a CT image. The ground truth for seed locations was obtained by localizing the seeds in the CT image and registering them to the US coordinate system. RESULTS: Compared to the ground truth, the US-only detection algorithm achieved a localization error mean of 1.7 mm with a detection rate of 85%. By contrast, the EM-only seed localization method achieved a localization error mean of 3.7 mm with a detection rate of 100%. By fusing EM tracking information with US imaging, we achieved a localization error mean of 1.8 mm while maintaining a 100% detection rate without any false positives. CONCLUSIONS: Fusion of EM-tracking and US imaging for prostate brachytherapy can combine high localization accuracy of US-based seed detection with the robustness and high detection rate of EM-based seed localization. Our phantom experiments serve as a proof of concept to demonstrate the potential value of integrating EM tracking into LDR prostate brachytherapy. PMID- 29604088 TI - Impact of Mono-Fluorination on the Photophysics of the Flavin Chromophore. AB - Three mono-fluorinated derivatives of the flavin core system 10-methyl isoalloxazine (MIA) were synthesized. Aqueous solutions of these compounds were characterized by steady-state and time-resolved spectroscopy. The positions for the fluorination (6, 7 and 8) were motivated by the nodal structure of the frontier orbitals of MIA. In comparison with MIA, the fluorination results in bathochromic (6F- and 7F-MIA) and hypsochromic (8F-MIA) shifts of the adiabatic excitation energy of the lowest allowed transition. Shifts of up to ~500 cm-1 were observed. These spectroscopic shifts go along with changes in fluorescence quantum yields and lifetimes. In addition, triplet yields are affected. For 7F MIA, a 50% increase in the fluorescence quantum yield as well as a 50% decrease in triplet yield is observed rendering the compound interesting for fluorescence applications. The measured effects are discussed in terms of qualitative perturbation theory. PMID- 29604087 TI - Uteroplacental insufficiency temporally exacerbates salt-induced hypertension associated with a reduced natriuretic response in male rat offspring. AB - KEY POINTS: Low weight at birth increases the risk of developing chronic diseases in adulthood A diet that is high in salt is known to elevate blood pressure, which is a major risk factor for cardiovascular and kidney diseases The present study demonstrates that growth restricted male rats have a heightened sensitivity to high dietary salt, in the context of raised systolic blood pressure, reduced urinary sodium excretion and stiffer mesenteric resistance vessels Other salt induced effects, such as kidney hyperfiltration, albuminuria and glomerular damage, were not exacerbated by being born small The present study demonstrates that male offspring born small have an increased cardiovascular susceptibility to high dietary salt, such that that minimizing salt intake is probably of particular benefit to this at-risk population ABSTRACT: Intrauterine growth restriction increases the risk of developing chronic diseases in adulthood. Lifestyle factors, such as poor dietary choices, may elevate this risk. We determined whether being born small increases the sensitivity to a dietary salt challenge, in the context of hypertension, kidney disease and arterial stiffness. Bilateral uterine vessel ligation or sham surgery (offspring termed Restricted and Control, respectively) was performed on 18-day pregnant Wistar Kyoto rats. Male offspring were allocated to receive a diet high in salt (8% sodium chloride) or remain on standard rat chow (0.52% sodium chloride) from 20 to 26 weeks of age for 6 weeks. Systolic blood pressure (tail-cuff), renal function (24 h urine excretions) and vascular stiffness (pressure myography) were assessed. Restricted males were born 15% lighter than Controls and remained smaller throughout the study. Salt-induced hypertension was exacerbated in Restricted offspring, reaching a peak systolic pressure of ~175 mmHg earlier than normal weight counterparts. The natriuretic response to high dietary salt in Restricted animals was less than in Controls and may explain the early rise in arterial pressure. Growth restricted males allocated to a high salt diet also had increased passive arterial stiffness of mesenteric resistance arteries. Other aspects of renal function, including salt-induced hyperfiltration, albuminuria and glomerular damage, were not exacerbated by uteroplacental insufficiency. The present study demonstrates that male offspring exposed to uteroplacental insufficiency and born small have an increased sensitivity to salt-induced hypertension and arterial remodelling. PMID- 29604089 TI - Electrocardiographic left ventricular hypertrophy predicts recurrence of atrial arrhythmias after catheter ablation of paroxysmal atrial fibrillation. AB - BACKGROUND: Left ventricular hypertrophy (LVH) is an independent predictor of new onset atrial fibrillation. Whether LVH can predict the recurrence of arrhythmia after radiofrequency catheter ablation (RFCA) in patients with paroxysmal atrial fibrillation (PAF) remains unclear. HYPOTHESIS: PAF patients with baseline electrocardiographic LVH has a higher recurrence rate after RFCA procedure compared with those without LVH. METHODS: A total of 436 patients with PAF undergoing first RFCA were consecutively enrolled and clustered into 2 groups based on electrocardiogram (ECG) findings: non-ECG LVH (218 patients) and ECG LVH (218 patients). LVH was characterized by the Romhilt-Estes point score system; the score >=5points were defined as LVH. RESULTS: At 42 months' (interquartile range, 18.0-60.0 months) follow-up after RFCA, 151 (69.3%) patients in the non ECG LVH group and 108 (49.5%) patients in the ECG LVH group maintained sinus rhythm without using antiarrhythmic drugs (P < 0.001). Patients with ECG LVH tended to experience a much higher prevalence of stroke and recurrence of atrial arrhythmia episodes compared with those without ECG LVH (log-rank P < 0.001). Multivariate analysis found the presence of ECG LVH and left atrial diameter to be independent risk factors for recurrence after adjusting for confounding factors. CONCLUSIONS: The presence of ECG LVH was a strong and independent predictor of recurrence in patients with PAF following RFCA. PMID- 29604090 TI - The effect of exogenous phytase supplementation on nutrient digestibility, ruminal fermentation and phosphorous bioavailability in Rambouillet sheep. AB - BACKGROUND: The effect of phytase supplementation with respect to a high sorghum grain diet on sheep voluntary feed intake, apparent nutrient digestibility, ruminal fermentation, phosphorus (P) excretion and blood serum P concentration was evaluated. RESULTS: Phytase supplementation significantly decreased fecal P excretion (P = 0.003), resulting in a 26% decrease in relation to the phytase free diet. Dry matter intake, nutrient digestibility, ruminal butyrate and serum P were not (P > 0.10) affected by the phytase level. Neutral detergent digestibility showed a tendency to increase linearly (P = 0.10) with increasing phytase levels. Ruminal pH was lower for phytase supplemented sheep, with a significant decrease (P = 0.007) at 9 h post feeding, whereas ruminal ammonia-N at 3 h post feeding was lower (P = 0.004) for the phytase treatment groups, resulting in a decreasing linear response (P = 0.001) with an increasing phytase dose. Duodenal pH was significantly reduced at 6 h post feeding. Propionate tended (P = 0.051) to be increased linearly as the phytase supplementation level increased. CONCLUSION: Exogenous phytase supplementation of high sorghum grain diets significantly decreased fecal P excretion in Rambouillet rams. Phytase supplementation appears to affect neutral detergent fiber digestibility, duodenal and ruminal pH, ammonia and propionate. (c) 2018 Society of Chemical Industry. PMID- 29604091 TI - Achievement of multiple therapeutic targets for cardiovascular disease prevention: Retrospective analysis of real practice in Italy. AB - BACKGROUND: Pharmacological therapy in patients at high cardiovascular (CV) risk should be tailored to achieve recommended therapeutic targets. HYPOTHESIS: To evaluate individual global CV risk profile and to estimate the control rates of multiple therapeutic targets for in adult outpatients followed in real practice in Italy. METHODS: Data extracted from a cross-sectional, national medical database of adult outpatients in real practice in Italy were analyzed for global CV risk assessment and rates of control of major CV risk factors, including hypertension, dyslipidemia, diabetes, and obesity. CV risk characterization was based on the European SCORE equation and the study population stratified into 3 groups: low risk (<2%), intermediate risk (>=2%-<5%), and high to very high risk (>=5%). RESULTS: We analyzed data from 7158 adult outpatients (mean age, 57.7 +/ 5.3 years; BMI, 28.3 +/-5.0 kg/m2 , BP, 136.0 +/-14.3/82.2 +/-8.3 mm Hg; total cholesterol, 212.7 +/-40.7 mg/dL), among whom 2029 (45.2%) had low, 1730 (24.2%) intermediate, and 731 (16.3%) high to very high risk. Increased SCORE risk was an independent predictor of poor achievement of diastolic BP <90 mm Hg (OR: 0.852, 95% CI: 0.822-0.882), LDL-C < 130 mg/dL (OR: 0.892, 95% CI: 0.861-0.924), HDL-C > 40 (males)/>50 (females) mg/dL (OR: 0.926, 95% CI: 0.895-0.958), triglycerides <160 mg/dL (OR: 0.925, 95% CI: 0.895-0.957), and BMI <25 kg/m2 (OR: 0.888, 95% CI: 0.851-0.926), even after correction for diabetes, renal function, pharmacological therapy, and referring physicians (P < 0.001). CONCLUSIONS: Despite low prevalence and optimal medical therapy, individuals with high to very high SCORE risk did not achieve recommended therapeutic targets in a real-world practice. PMID- 29604092 TI - Prognostic relevance of subclinical coronary and carotid atherosclerosis in a diabetic and nondiabetic asymptomatic population. AB - BACKGROUND: We sought to evaluate the incremental prognostic benefit of carotid artery disease and subclinical coronary artery disease (CAD) features in addition to clinical evaluation in an asymptomatic population. METHODS: Over a 6-year period, 10-year Framingham risk score together with carotid ultrasound and coronary computed tomography angiography were evaluated for prediction of major adverse cardiac events (MACE). RESULTS: We enrolled 517 consecutive asymptomatic patients (63% male, mean age 64 +/-10 years; 17.6% with diabetes). Median (interquartile range) coronary artery calcium score (CACS) was 34 (0-100). Over a median follow-up of 4.4 (3.4-5.1) years, there were 53 MACE (10%). Patients experiencing MACE had higher CACS, incidence of carotid disease, presence of CAD >=50%, and remodeled plaque as compared with patients without MACE. At multivariable analyses, presence of CAD >=50% (HR: 5.14, 95% CI: 2.1-12.4) and percentage of segments with remodeled plaque (HR: 1.04, 95% CI: 1.03-1.06) independently predicted MACE (P < 0.001). Models adding CAD >=50% or percentage of segments with remodeled plaque resulted in higher discrimination and reclassification ability compared with a model based on 10-year FRS, carotid disease, and CACS. Specifically, the C-statistic improved to 0.75 with addition of CAD and 0.84 when adding percentage of segments with remodeled plaque, whereas net reclassification improvement indices were 0.86 and 0.92, respectively. CONCLUSIONS: In an asymptomatic population, CAD and plaque positive remodeling increase MACE prediction compared with a model based on 10-year FRS, carotid disease, and CACS estimation. In the diabetes subgroup, percentage of segments with remodeled plaque was the only predictor of MACE. PMID- 29604093 TI - Serum albumin concentration as an independent prognostic indicator in patients with pulmonary arterial hypertension. AB - BACKGROUND: Serum albumin is a strong prognostic indicator for many disease processes, yet limited data exist regarding its prognostic relationship in pulmonary arterial hypertension (PAH). Our study aims to assess the relationship of hypoalbuminemia with disease severity and mortality in this population. HYPOTHESIS: Serum albumin concentrations are a predictor of outcomes in PAH. METHODS: A retrospective review of all patients with World Health Organization group 1 PAH evaluated between March 2001 and August 2008 was performed. Patients were stratified into groups based on serum albumin concentration <=3.3 g/dL (hypoalbuminemia) vs >3.3 g/dL. Clinical, hemodynamic, and survival comparisons were compared between groups using Student t test and chi2 test, followed by univariate analysis and multivariate logistic regression. RESULTS: A total of 163/273 (59.7%) patients had a documented serum albumin concentration. Hypoalbuminemia was present in 41 (25.2%) patients and serum albumin <=3.3 g/dL represented the lowest quartile of serum albumin. Patients with hypoalbuminemia had higher rates of renal dysfunction (26.8% vs 9.8%, P =0.0069) and hepatic dysfunction (29.3% vs 6.6%, P <0.001), and lower hemoglobin levels (11.6 vs 13.4 g/dL, P < 0.001). Hemodynamic and functional capacity assessments were comparable between groups. Independent predictors of mortality included low albumin levels (hazard ratio [HR]: 0.485, P = 0.008), high right atrial systolic area (HR: 1.062, P = 0.003), low Fick-derived cardiac index (HR: 1.465, P = 0.016), and high New York Heart Association functional class (HR: 1.767, P = 0.042). Patients with hypoalbuminemia demonstrated a significantly lower survival rate at latest follow-up (P = 0.01). CONCLUSIONS: Lower serum albumin concentrations in patients with PAH are associated with higher mortality and can serve as a marker of disease severity in this patient population. PMID- 29604094 TI - Cardiac resynchronization therapy is associated with a reduction in ICD therapies as it improves ventricular function. AB - BACKGROUND: Repeated implantable cardioverter-defibrillator (ICD) therapies cause myocardial damage and, thus, an increased risk of arrhythmias and mortality. HYPOTHESIS: Cardiac resynchronization therapy-defibrillator (CRT-D) reduces the number of appropriate therapies in patients with left ventricular dysfunction (left ventricular ejection fraction [LVEF] <50%). METHODS: The retrospective study involved 175 consecutive patients (mean age, 64.6 +/-10.4 years; 86.9% males) with reduced LVEF of 27.9% +/-7.6% treated with an ICD (56.6%) or CRT-D (43.4%), according to standard indications, between January 2009 and July 2014. Devices were placed for either primary (54.3%) or secondary prevention (45.7%). Mean follow-up was 2.5 +/-1.5 years. Predictors of first appropriate therapy were assessed using Cox regression analysis. RESULTS: Forty-four (25.1%) patients received >=1 appropriate therapy. Although patients treated with CRT-D had lower LVEF and poorer New York Heart Association class, CRT-D patients with LVEF improvement >35% at the end of follow-up had a significantly lower risk of receiving a first appropriate therapy relative to those with an ICD (adjusted hazard ratio: 0.24, 95% confidence interval: 0.07-0.83, P = 0.025), independently of ischemic cardiomyopathy, baseline LVEF, and secondary prevention. There were no differences in mortality between the ICD and the CRT-D groups. CONCLUSIONS: Although patients receiving CRT-D had a worse clinical profile, they received fewer device therapies in comparison with those receiving an ICD. This reduction is associated with a significant improvement in LVEF. PMID- 29604095 TI - Performance evaluation of a chemiluminescence microparticle immunoassay for CK MB. AB - BACKGROUND: To verify and evaluate the performance characteristics of a creatine kinase phosphokinase isoenzymes MB (CK-MB) assay kit, which produced by Xiamen Innodx Biotech Co. Ltd. METHODS: Evaluation was carried out according to "Guidelines for principle of analysis performance evaluation of in vitro diagnostic reagent." The performance parameters included detection limit, linearity range, reportable range, recovery test, precision verification, interference test, cross-reactivity, matrix effect, and method comparison. RESULTS: The detection limit was 0.1 ng/mL. The assay had clinical linearity over range of 0.1 ng/mL-500 ng/mL. Reportable range was from 0.1 ng/mL to 1000 ng/mL. The average percent of recovery was 99.66%. The coefficient of variation (CV) for within-run and between-run of low CK-MB sample was 5.55% and 6.16%, respectively. As for high-level sample, it was 7.88% and 7.80%. In medical decision level, the relative deviation (Bias) of all interference tests was lower than 15%. When the sample had mild-hemolysis; hemoglobin <=15 g/L; triglyceride <=17 mmol/L; bilirubin <=427.5 MUmol/L; rheumatoid factor <=206U/mL, there was no significant interference to be found. Moreover, assay kit had no cross-reaction with CK-MM and CK-BB. At last, total diagnostic accuracy of kit was 93.24%, when compared with refer kit. CONCLUSION: Overall the results of the verification study indicated the performance of kit is met the requirements of the clinical test. PMID- 29604097 TI - Time-dependent pair distribution functions based on Smoluchowski equation and application to an electrolyte solution. AB - Time-dependent pair distribution function characterizes the diffusion of pairs of molecules in liquids. In the diffusion regime, the function is described with three-dimensional Smoluchowski equation. We propose a scheme to numerically calculate the function between polyatomic and monoatomic species based on the Smoluchowski equation. The present scheme is successfully applied to the diffusion of Ar-Ar pair in liquid Ar and ethylene carbonate (EC)-Li+ pair in 1 M LiPF6 /EC electrolyte solution. (c) 2018 Wiley Periodicals, Inc. PMID- 29604096 TI - PROTON GRADIENT REGULATION 5 supports linear electron flow to oxidize photosystem I. AB - In higher plants, light drives the linear photosynthetic electron transport reaction from H2 O to electron sinks, which is called the linear electron flow (LEF). LEF activity should be regulated depending on electron sinks; otherwise excess electrons accumulate in the thylakoid membranes and stimulate reactive oxygen species (ROS) production in photosystem I (PSI), which causes oxidative damage to PSI. To prevent ROS production in PSI, PSI should be oxidized during photosynthesis, and PROTON GRADIENT REGULATION 5 (PGR5) and PGR like 1 (PGRL1) are important for this oxidation. PGR5 and PGRL1 are recognized as a component of ferredoxin-dependent cyclic electron flow around PSI (Fd-CEF-PSI), however there is no direct evidence for the significant operation of Fd-CEF-PSI during photosynthesis in wild-type (WT) plants. Thus, electron distribution by PGR5 and PGRL1 between Fd-CEF-PSI and LEF is still elusive. Here, we show direct evidence that Fd-CEF-PSI activity is minor during steady-state photosynthesis by measuring the Fd redox state in vivo in Arabidopsis thaliana. We found that Fd oxidation rate is determined by LEF activity during steady-state photosynthesis in WT. On the other hand, pgr5 and pgrl1 showed lower electron transport efficiency from PSI to electron sinks through Fd during steady-state photosynthesis. These results demonstrate that electrons are exclusively consumed in electron sinks through Fd, and the phenotypes of pgr5 and pgrl1 are likely caused by the disturbance of the LEF between PSI and electron sinks. We suggest that PGR5 and PGRL1 modulate the LEF according to electron sink activities around PSI. PMID- 29604098 TI - Immunological effects of placental extracellular vesicles. AB - Extracellular vesicles (EVs) extruded by the human placenta are increasingly being recognized as an essential mode of feto-maternal communication. In the past two decades, there has been an explosion of research into the roles that placental EVs play in modulating the maternal immune and cardiovascular systems during healthy pregnancies, as well as how this communication is altered in obstetric diseases. This review aims to introduce readers to the processes of placental EV formation and the cargos they carry, and also to collate and summarize the published literature that investigates the immunological effects of placental EVs throughout human pregnancy. PMID- 29604099 TI - Evaluation of complete blood count parameters to predict endometrial cancer. AB - BACKGROUND: Complete blood count parameters have been introduced to be diagnostic biomarkers for many cancer-related diseases associated with inflammatory process. The aim of our study was to detect whether there is any relationship between benign or malignant endometrial pathologies and complete blood count parameters. METHODS: Four hundred and sixteen patients with a complaint of abnormal uterine bleeding who admitted to Zeynep Kamil Women and Children's Health Training and Research hospital between 2013 and 2016 and undergoing endometrial biopsy were included in the study. The patients were evaluated in three groups as follows: endometrial carcinoma (n: 97), endometrial hyperplasia (n: 135), and healthy control (n: 184) groups. All patients had a complete blood count on the day of biopsy or within the week of the biopsy, and the presence of a relationship between complete blood count parameters and benign or malignant endometrial disease was investigated. RESULTS: Mean corpuscular volume measurements were found to be significantly higher in endometrial carcinoma (P = .018) and endometrial hyperplasia (P = .001) groups compared to the control group. While red cell distribution width measurements were found to be significantly lower in patients with endometrial carcinoma group compared to other groups (P < .01); the area under curve obtained for MPV is 58.7% to determine endometrial carcinoma. CONCLUSION: Mean corpuscular volume and red cell distribution width are bio markers that we can use as the predictive marker in patients with endometrial carcinoma and which are cheap, repeatable, and readily obtainable from complete blood count panels and promising. PMID- 29604100 TI - Absence of KRAS hotspot mutations in endometriosis of Korean patients. PMID- 29604101 TI - Computer tomographic imaging in 4 dogs with primary nasal canine transmissible venereal tumor and differing cellular phenotype. AB - Primary nasal canine transmissible venereal tumor (CTVT) without genital affection is uncommon. The aim of this report was to describe the primary nasal CTVT findings and CT staging in 4 dogs with different cytological phenotypes. Three male dogs and 1 bitch were evaluated for their chronic histories of sneezing, snoring, mucopurulent nasal discharge and nasal deformation. Cytological examination of nasal secretions suggested CTVT, confirmed by histopathological examination and LINE-1/c-myc. Males had the plasmacytoid phenotype of CTVT, and the bitch had the lymphocytoid phenotype. CTVT were staged based on the CT findings using modified Adams staging system. The bitch was classified as stage 1, 2 males were classified as stage 3 and 1 male as stage 4. All dogs had a complete tumoral remission after chemotherapy. Plasmacytoid phenotype was identified in cases with most important damage of the nasal cavity. However, the cytological type did not affect the response to chemotherapy. PMID- 29604102 TI - Systematic Review and Meta-Analysis of Real-World Studies Evaluating Rivaroxaban for Cancer-Associated Venous Thrombosis. AB - INTRODUCTION: While not designated as guideline-recommended first-line anticoagulation therapy, about one in five patients in the United States receive rivaroxaban for the treatment of cancer-associated venous thrombosis (CAT). METHODS: A systematic review and meta-analysis were performed to evaluate the incidences of recurrent venous thromboembolism (VTE), major bleeding, and all cause mortality in rivaroxaban patients treated for CAT in routine practice. Literature searches of MEDLINE and SCOPUS were performed through September 2017 to identify real-world studies of >= 20 patients evaluating the incidence of recurrent VTE, major bleeding, or all-cause mortality in CAT patients anticoagulated with rivaroxaban. Using a Hartung-Knapp random-effects model, the pooled incidence estimates and 95% confidence intervals (CIs) were calculated for each end point. RESULTS: Six studies evaluating rivaroxaban for CAT were identified. Of these, three were prospective and three were retrospective. Study sample sizes ranged from 41 to 949 patients, and duration of follow-up ranged from 164 to 496 days. The most frequent active cancer sites reported in studies were gastrointestinal (range: 12.0-56.0%), genitourinary (range: 8.6-26.0%), and breast (range: 9.3-25.5%). The weighted average incidences of recurrent VTE, major bleeding, and all-cause mortality were 4.2% (95% CI = 2.6-6.6%; I2 = 31%), 2.9% (95% CI = 1.6-5.0%; I2 = 59%), and 16.1% (95% CI = 6.0-36.6%; I2 = 96%). CONCLUSIONS: This meta-analysis suggests that incidences of recurrent VTE and major bleeding among rivaroxaban-managed patients are not dissimilar to those seen in recent randomized trials of anticoagulation in CAT. The pooled incidence for mortality was lower than reported in many anticoagulation CAT trials. This may suggest that rivaroxaban is being used in CAT patients who have less severe cancer. PMID- 29604103 TI - Recalcitrant psoriasiform dermatosis of the face: Is it related to pityriasis rubra pilaris? AB - BACKGROUND: There are patients with recalcitrant psoriasiform plaques that do not fit into conventional categories of facial dermatoses. Our study aims to describe the clinicopathological characteristics of several patients with a unique presentation of persistent psoriasiform facial rashes. METHODS: This retrospective cross-sectional study analyzed clinical and histological data of known cases of recalcitrant psoriasiform dermatosis of the face diagnosed at National Skin Centre, Singapore, over 10 years. RESULTS: There were 8 Chinese patients with mean age at onset of 29 years. Majority had pink to pink-orange well-defined plaques with dry scale (n = 6, 75%), distributed mostly on the cheeks (100%) and chin (n = 7, 88%). Hyperkeratosis, parakeratosis, preserved granular layer and psoriasiform hyperplasia were showed in all biopsies. Other common findings included subtle subcorneal acantholysis, "checkerboard" alternating ortho-/parakeratosis, vacuolated keratinocytes and follicular plugging. All patients showed little treatment response. One patient eventually developed features of type II pityriasis rubra pilaris (PRP). Our study was limited by its small sample size and lack of a pre-existing diagnostic code. CONCLUSIONS: This recalcitrant psoriasiform facial dermatosis seems to be a distinct entity, with consistent and reproducible clinical features and a PRP like histology, bearing some resemblance to the recently described condition facial discoid dermatosis. PMID- 29604104 TI - Serum thyroid-stimulating hormone levels and smoking status: Data from the Korean National Health and Nutrition Examination Survey VI. AB - OBJECTIVE: We aimed to evaluate differences in serum thyroid-stimulating hormone (TSH) levels according to smoking status and urine iodine concentration (UIC) in a healthy Korean population using data from the Sixth Korean National Health and Nutrition Examination Survey (KNHANES VI). STUDY DESIGN: Sixth Korean National Health and Nutrition Examination Survey (2013-2015) is a nationwide, cross sectional survey of the Korean population. PATIENTS: Research subjects were selected by two-stage stratified cluster sampling of the population and housing census data. A total of 5639 subjects aged >18 years, who were not pregnant, and had undergone thyroid function testing during the survey period, were included. MEASUREMENT: The level of serum TSH according to smoking status, iodine intake and presence of TPOAb were evaluated. RESULTS: In the reference population, mean serum TSH level in current smokers (1.87 mIU/L, 95% CI, 0.52-5.37 mIU/L) was significantly lower than that in nonsmokers (2.33 mIU/L, 95% CI, 0.79-6.69 mIU/L, P < .001). The rate of thyroperoxidase antibody (TPOAb) positivity was higher in never smoker (7.7%) than past smokers (5.1%) and current smokers (4.7%), but sex specific rate of TPOAb was not different according to smoking status. The lower serum TSH levels in current smokers were more apparent in iodine-deficient subjects (UIC < 100 MUg/L), and this change was diminished in subjects with UICs between 100 and 299 MUg/L. The difference in serum TSH levels in current smokers disappeared in subjects with UICs >= 300 MUg/L. CONCLUSIONS: Smoking is associated with a left-shift in serum TSH level that is more apparent in iodine deficient subjects. Smoking status is not associated with the presence of TPOAb or iodine intake. The results suggest that smoking has a direct effect on thyroid function that is not mediated by autoimmune processes in the thyroid gland. PMID- 29604105 TI - Xenopus laevis macrophage-like cells produce XCL-1, an intelectin family serum lectin that recognizes bacteria. AB - Xenopus laevis Ca2+ -dependent lectin-1 (XCL-1) is an intelectin family serum lectin that selectively recognizes carbohydrate chains on the bacterial cell surface. Immunofluorescence examination of control spleen tissues from normal X. laevis revealed cells producing XCL-1 (XCL-1+ cells) exclusively in red pulps. Intraperitoneal injection of Escherichia coli lipopolysaccharide (LPS) caused a marked increase in the number of XCL-1+ cells in red pulps on day 3, followed by a rapid decrease to near control levels by day 7. XCL-1+ cells were also detected in peripheral blood leukocytes (PBLs) and peritoneal exudate cells (PECs), and their numbers increased upon LPS injection until day 7. The XCL-1+ cells exhibited the morphological characteristics of macrophages, with a large oval or lobulated nucleus and abundant cytoplasm with vacuoles and dendritic projections. Western blot analyses revealed concurrent increases in XCL-1 levels in the spleen, PBLs, and PECs. When LPS-stimulated frogs were intraperitoneally injected with paraformaldehyde-fixed, green fluorescent protein-labeled E. coli cells (GFP Eco), these were phagocytosed by XCL-1+ PECs. The purified XCL-1 protein agglutinated GFP-Eco in a Ca2+ -dependent manner, which was blocked effectively by xylose and partly by LPS and Staphylococcus aureus peptidoglycan, but not by sucrose. These results indicate that X. laevis macrophage-like cells produce XCL 1 and suggest that XCL-1 promotes the clearance of invaded bacteria by facilitating phagocytosis. PMID- 29604106 TI - Longitudinal associations between younger children's humour styles and psychosocial adjustment. AB - Whilst a multitude of studies have examined links between different styles of humour and aspects of adjustment, longitudinal research is noticeably lacking. Following a study which identified bidirectional associations between humour styles and psychosocial adjustment in older children, the current research aimed to investigate these associations in younger children. In total, 413 children aged 8-11 years completed the humour styles questionnaire for younger children (HSQ-Y) alongside measures of psychosocial adjustment in both the autumn and the summer over the course of a school year. Findings across the school year suggested that children's adjustment may impact significantly on their use of different styles of humour. Further longitudinal research over a longer time period would now be beneficial to further increase our understanding of the associations between humour styles and adjustment throughout development. Statement of contribution What is already known on this subject? Research has identified associations between children's humour styles and psychosocial adjustment. Research with older children has also identified longitudinal associations. What does this study add? This is the first study to identify longitudinal associations between humour styles and adjustment in younger children. This allows for stronger statements to be made about causal relationships. PMID- 29604107 TI - The 1918 Spanish flu outbreak that devastated a Greek island underlines past lessons that must never be forgotten. PMID- 29604108 TI - Lower Apgar scores and Caesarean sections are related to attention deficit/hyperactivity disorder. AB - AIM: We examined the associations between prenatal, birth-related and newborn risk factors and attention-deficit/hyperactivity disorder (ADHD). METHODS: In this population-based study, 10 409 subjects diagnosed with ADHD by 31 December 2011 and 39 124 controls, born between 1 January 1991 and 31 December 2005, were identified from Finnish nationwide registers. Perinatal data were obtained from the Birth Register. Conditional logistic regression was used to examine the associations after controlling for confounders. RESULTS: Lower Apgar scores were associated with a higher risk of ADHD, with odds ratios of 1.12 (95% confidence intervals 1.06-1.19) for one-minute Apgar scores of 7-8, 1.17 (95% CI 1.02-1.35) for scores of 5-6 and 1.41 (95% CI 1.18-1.68) for scores of 0-4, compared to Apgar scores of 9-10. Elective Caesarean sections were associated with an increased risk of ADHD with an adjusted odds ratio of 1.15 (95% CI 1.05-1.26). Other identified risk factors were breech presentation, induced labour and admission to a neonatal intensive care unit. Low umbilical artery pH did not increase the risk of ADHD. CONCLUSION: Elective Caesareans and perinatal adversities leading to lower Apgar scores increased the risk of ADHD. Future research to identify the mechanisms behind these findings is warranted. PMID- 29604109 TI - Procalcitonin Monitoring as a Guide for Antimicrobial Therapy: A Review of Current Literature. AB - Effective antimicrobial stewardship practices are increasingly essential to best utilize the current arsenal of antimicrobials for the shortest necessary duration to minimize the development of antimicrobial resistance, secondary infections, and health care costs. Monitoring of serum procalcitonin (PCT) levels represents an effective antimicrobial stewardship strategy to differentiate bacterial infections from viral infections and noninfectious inflammatory conditions. Current literature illustrates the merits of PCT monitoring in reducing duration of antibiotic therapy without detrimental effects on mortality or infection relapses. However, the interpretation of PCT levels can be challenging, especially in light of comorbid disease states that can elevate PCT levels. This review sheds light on the utility of PCT monitoring, as well as providing insight into the practical interpretation of PCT levels. Much of the current literature surrounding PCT monitoring consists of use among patients with lower respiratory tract infections or in the critically ill. Overall, studies have demonstrated shorter antibiotic therapy durations when PCT monitoring is utilized. No studies to date have found increased rates of mortality or infection relapses, suggesting that PCT monitoring is not only effective, but also safe when used as a guide for antimicrobial therapy. Nonetheless, many conditions were shown to elevate PCT serum concentrations, even in the absence of bacterial infections, which can make interpretation of PCT concentrations challenging. Two common conditions that affect the accurate interpretation of PCT levels are renal dysfunction and congestive heart failure. Limited studies have been performed in these populations, but current available data propose the need for higher PCT thresholds in those with renal dysfunction or congestive heart failure and support utilizing PCT trends to monitor clinical improvement from bacterial infections. Evidence also suggests that PCT monitoring is cost-effective, as long as the test is ordered judiciously. In summary, PCT monitoring represents a promising antimicrobial stewardship strategy to limit exposure to unnecessary antimicrobial therapy. PMID- 29604110 TI - Preschoolers' conformity (and its motivation) is linked to own and parents' personalities. AB - Previous studies on conformity have primarily focused on factors that moderate conformity rates overall and paid little attention to explaining the individual differences. In this study, we investigate five-factor model personality traits of both parents and children and experimentally elicited conformity in 3.5-year olds (N = 59) using an Asch-like paradigm with which we measure both overt conformity (public responses) and covert opinions (private beliefs after conformist responses): A correct covert opinion after an incorrect conformist response results from a socially normative motivation, whereas an incorrect covert opinion results from an informational motivation. Our data show (1) low parental extroversion is associated with participants' overall rate of conformity, (2) and low participant extroversion and high openness are associated with an informational instead of a normative motivation to conform. This suggests that sensitivity to the social context or social engagement level, as manifested through extroversion, could be an important factor in conformist behaviour. Statement of contribution What is already known on this subject? We all conform, from early in life - and even when we should know better We can conform for normative and informational motivations Some are more prone to conform than others What does this study add? This is the first study to take an individual differences approach to developmental conformity Social engagement (extroversion) is an important factor in conformity. PMID- 29604112 TI - CYP2E1 and GSTM1 gene polymorphisms, environmental factors, and the susceptibility to lung cancer. AB - OBJECTIVE: To investigate the relationships between the CYP2E1 RsaI polymorphism, GSTM1 polymorphism, and the susceptibility to lung cancer, along with the interactions between environmental factors and these genes. METHODS: A case control study was carried out to explore the independent effect of gene polymorphisms on risk of lung cancer, and the combined effects of gene loci. The stratification analysis of age, sex, smoking, and drinking combined with positive loci was also analyzed, and any interaction was identified. RESULTS: The logistic regression analysis showed that there were statistical relationships between the CYP2E1 RsaI TT genotype and lung cancer, GSTM1 (-) and lung cancer. The combined effect's analysis of these 2 loci showed that, with an increase in the number of risk alleles, the risk of lung cancer also increased (supposing 0 risk allele as the reference group). Subjects carrying 3 risk alleles had the highest risk of developing lung cancer with an adjusted OR = 10.38 (95% CI 2.10-51.35). Stratified analysis showed that, in women, nonsmoking subjects, or nondrinking subjects, the combined effects could increase the risk of lung cancer; no heterogeneity was found between these layers except sex. The interaction analysis showed that, supposing the male, GSTM1 (+) genotype as the reference, the female, GSTM1 (-) genotype had a significantly increased risk of lung cancer (OR = 2.17 [1.01-4.70]); when the non-smoking, GSTM1 (+) genotype subjects was the reference group, smoking, GSTM1 (+) genotype subjects and smoking, GSTM1 (-) genotype subjects had significantly higher risk of lung cancer (OR = 2.00 [1.01-3.96], OR = 2.89 [1.28-6.54]). CONCLUSION: CYP2E1 RsaI TT genotype was a protective factor against the development of lung cancer, while GSTM1 (-) genotype was a risk factor for lung cancer. Increases in the number of the risk alleles also increased lung cancer risk. GSTM1 (-) genotype, sex, and smoking status might interact in the incidence of lung cancer. PMID- 29604111 TI - A retrospective analysis of 237 Chinese families with Duchenne muscular dystrophy history and strategies of prenatal diagnosis. AB - BACKGROUND: To offer 4-year clinical prenatal diagnosis experience of Duchenne muscular dystrophy (DMD). METHODS: Denaturing high-performance liquid chromatography (DHPLC) and Sanger sequencing were used for molecular diagnosis of 237 DMD families. RESULTS: In the study, deletions, duplications, complex rearrangement and small mutations accounted for 47.3%, 8.4%, 1.7% and 42.6% of 237 families, respectively. Sixty-six different deletion patterns were identified in 112 families. Fourteen different duplication patterns were identified in 20 families and 4 complex rearrangements were identified. About 87.1% different small mutation patterns were identified, including 37.6% different nonsense mutation patterns, 24.8% different frameshift mutation patterns, 7.9% different missense mutation patterns, and 16.8% different splice site mutation patterns. There was no significant difference in the age of onset and mutation patterns (P > .05). The follow-up examinations revealed that the pregnancies of 14 cases were interrupted. Two cases were preterm births, 151 cases were delivered at term, 63 cases continued to pregnancy, and 7 cases were lost to follow-up. CONCLUSION: DHPLC and Sanger sequencing technique are efficient, sensitive, and specific in screening for DMD gene mutations. And pre-pregnancy DMD gene examination is an important step to assess mutation type of family with suspected DMD and guides exactly prenatal diagnosis in high-risk families. PMID- 29604113 TI - Minority Stress and Relational Mechanisms of Suicide among Sexual Minorities: Subgroup Differences in the Associations Between Heterosexist Victimization, Shame, Rejection Sensitivity, and Suicide Risk. AB - Despite sexual orientation disparities in suicide, there is limited research examining factors associated with suicide risk among sexual minorities while considering subgroup differences within this group. This study identified differences between sexual minorities at risk for suicide and those not at risk. The study also examined heterosexist victimization, as one form of minority stress, and two relational mechanisms (i.e., shame and rejection sensitivity) as risk factors for suicidality. We examined a moderated-mediation model, in which we tested gender and sexual orientation differences in the mediating effects of the relational mechanisms on the association between heterosexist victimization and suicide risk. Participants were recruited online and completed an online survey. The sample included 719 sexual minority adults. Of the sample, 27.7% were at risk for suicide. Suicide risk varied by age, gender, sexual orientation, income, education, and relationship status. Heterosexist victimization, shame, and rejection sensitivity were significant risk factors for suicide. Shame and rejection sensitivity were mediators of the association between heterosexist victimization and suicide risk for subgroups of sexual minorities, mostly lesbian and gay individuals and to some extent bisexual individuals. The findings underscore minority stress, shame, and rejection sensitivity as key intervention points. PMID- 29604114 TI - Alterations in serum amino acid concentrations in dogs with protein-losing enteropathy. AB - BACKGROUND: Certain amino acids are decreased in humans with inflammatory bowel disease (IBD) and supplementation with the same amino acids has shown beneficial effects in animal models of IBD. Currently, the amino acid status of dogs with protein-losing enteropathy (PLE) is unknown. HYPOTHESIS/OBJECTIVE: To determine if serum amino acid concentrations are abnormal in dogs with PLE and correlated with clinical and laboratory variables and outcome. ANIMALS: Thirty client-owned dogs diagnosed with PLE and 12 apparently healthy dogs seen at Bristol Veterinary School. METHODS: Retrospective study using stored residual serum from fasted dogs with PLE, collected at the time of diagnostic investigation and from apparently healthy dogs. Serum was analyzed for 30 amino acids using an automated high performance liquid chromatography amino acid analyzer. RESULTS: Serum tryptophan concentrations were significantly decreased in dogs with PLE (median, 22 nmol/mL; range, 1-80 nmol/mL) compared with apparently healthy control dogs (median, 77.5 nmol/mL; range, 42-135 nmol/mL, P < .001). There were no significant differences in the remaining 29 serum amino acids between dogs with PLE and apparently healthy. Serum tryptophan concentrations were also significantly correlated with serum albumin concentrations in dogs with PLE (P = .001, R2 = 0.506). CONCLUSIONS AND CLINICAL IMPORTANCE: Decreased serum tryptophan concentration might play a role in the pathogenesis of canine PLE or be a consequence of the disease. PMID- 29604115 TI - Accurate and fast neonatal heart rate assessment with a smartphone-based application - a manikin study. AB - AIM: This study determined the accuracy and speed of the NeoTapLifeSupport (NeoTapLS), a free smartphone application that aims to assess a neonate's heart rate. METHODS: We asked 30 participants with a variety of backgrounds to test the NeoTapLS, which was developed by our own nonprofit organisation Tap4Life, to determine a randomly selected heart rate by auscultation or palpation. The study was carried out in 2014 at Sachs' Children and Youth Hospital, Sweden, using a Laerdal SimNewB manikin that simulates true values. The NeoTapLS calculates the heart rate based on the user's last three taps on the smartphone screen. RESULTS: A total of 1200 measurements were carried out. A high correlation was found between measured and true values by auscultation (correlation coefficient 0.993) as well as by palpation (correlation coefficient 0.986) with 93.5% of the auscultations and 86.3% of the palpations differing from the true value by five beats or fewer. The mean time to the first estimated heart rate was 14.9 seconds for auscultation and 16.3 seconds for palpation. CONCLUSION: Heart rates could be accurately and rapidly assessed using the NeoTapLS on a manikin. A globally accessible mobile health system could offer a low-cost alternative to expensive medical equipment. PMID- 29604116 TI - Revisiting the promise of conservation psychology. PMID- 29604117 TI - Recognition of protein allosteric states and residues: Machine learning approaches. AB - Allostery is a process by which proteins transmit the effect of perturbation at one site to a distal functional site upon certain perturbation. As an intrinsically global effect of protein dynamics, it is difficult to associate protein allostery with individual residues, hindering effective selection of key residues for mutagenesis studies. The machine learning models including decision tree (DT) and artificial neural network (ANN) models were applied to develop classification model for a cell signaling allosteric protein with two states showing extremely similar tertiary structures in both crystallographic structures and molecular dynamics simulations. Both DT and ANN models were developed with 75% and 80% of predicting accuracy, respectively. Good agreement between machine learning models and previous experimental as well as computational studies of the same protein validates this approach as an alternative way to analyze protein dynamics simulations and allostery. In addition, the difference of distributions of key features in two allosteric states also underlies the population shift hypothesis of dynamics-driven allostery model. (c) 2018 Wiley Periodicals, Inc. PMID- 29604118 TI - What does lung function tell us about respiratory multimorbidity in childhood and early adulthood? Results from the MAS birth cohort study. AB - BACKGROUND: Interaction between respiratory multimorbidity and lung function has not been examined in longitudinal population studies. We aimed to assess the association of multimorbidity of asthma and rhinitis with lung function and bronchial hyperresponsiveness in comparison with single and no allergies from early school age to young adulthood. METHODS: In 1990, the Multicenter Allergy Study birth cohort recruited 1314 newborns from 5 German cities. At 7, 13, and 20 years, we performed lung function and bronchial challenge tests. We assessed symptoms, medications, and doctor's diagnoses for asthma and rhinitis for 3 outcomes: current multimorbidity (both coexisting), asthma only, and rhinitis only. RESULTS: From 7 to 20 years, multimorbidity prevalence more than doubled from 3.5% to 7.7%, current asthma only (without rhinitis co-occurring) decreased by half from 2.8% to 1.3%, and current rhinitis only (without asthma co occurring) increased from 14.3% to 41.6%. Resting lung function parameters differed between allergic and asymptomatic participants but showed no considerable differences between the allergic phenotypes. Frequency and severity of bronchial hyperresponsiveness were particularly associated with multimorbidity. At the age of 20 years, participants with multimorbidity showed a clearly higher severity in hyperresponsiveness compared to participants who suffered only asthma (P = .049) or rhinitis (P = .008) or were asymptomatic (P < .001). CONCLUSION: Single lung function measurements from childhood ongoing do not seem to discriminate between subjects with multimorbidity, single allergies, and no allergy. Our results show that multimorbidity is associated with more severe symptoms compared to those suffering only a single allergic disease. PMID- 29604119 TI - Suicidality Disclosed Online: Using a Simulated Facebook Task to Identify Predictors of Support Giving to Friends at Risk of Self-harm. AB - Although peer support in response to online disclosures of suicidality may be imperative for suicide prevention efforts, little is known as to how often support is provided or what predicts giving support. This study addresses this issue by investigating the odds of providing peer support in response to simulated online disclosures of suicidality. While interacting with a simulated Facebook newsfeed, participants (N = 690, Mage = 20.24, 527 female) were given the opportunity to leave comments on two posts disclosing low, moderate, or severe risk for suicide. Participants also completed questionnaires on their symptoms of depression and anxiety, experience with a loved one's suicidality, and Facebook use strategies. Only 33.6% of participants left a positive, supportive comment on at least one of the two suicide posts. Content severity, experience with a loved one's suicide attempts, and use of Facebook to meet people were predictive of providing positive comments. These findings suggest that young adults vary in their propensity to provide support after encountering a suicide disclosure online and that giving support is driven by a combination of contextual and intrapersonal factors. PMID- 29604120 TI - An Empirical Test of the Three-Step Theory of Suicide in U.K. University Students. AB - The purpose of this study was to further our understanding of how individuals move down the pathway from first thinking about suicide to ultimately attempting to take their own lives by empirically testing the Three-Step Theory (3ST) in a sample of university students (n = 665). Results largely support the theory's central propositions. First, an interactive model of pain and hopelessness accounted for substantial variance in suicidal desire. This result replicated in both men and women, and across age groups (i.e., below 35 and at or above 35). Also, as predicted, connectedness was protective against ideation in those high on both pain and hopelessness. However, contrary to our prediction, connectedness was similarly protective among everyone else. Finally, suicide capacity predicted suicide attempt history over and above current and lifetime suicide ideation. These findings provide further support to the 3ST. PMID- 29604121 TI - Equine idiopathic hemorrhagic cystitis: Clinical features and comparison with bladder neoplasia. AB - BACKGROUND: A new syndrome of hematuria in horses has been documented. HYPOTHESIS/OBJECTIVES: Hemorrhagic cystitis is a novel cause of stranguria and hematuria in horses. This syndrome may be difficult to differentiate from bladder neoplasia because they share several clinical features. ANIMALS: Eleven horses with idiopathic hemorrhagic cystitis and 7 horses with bladder neoplasia. METHODS: Retrospective cohort study. RESULTS: Hemorrhagic cystitis was detected on cystoscopy of affected horses, with hemorrhagic and thickened apical bladder mucosa. Clinical signs and endoscopic appearance of the bladder resolved within 3 8 weeks. Histopathology of bladder mucosal biopsy specimens featured neutrophilic and hemorrhagic cystitis. Histopathology was suggestive of dysplasia or neoplasia in 3 horses with hemorrhagic cystitis, yet the horses experienced complete resolution, suggesting that small biopsy specimens obtained by endoscopy can be difficult to interpret. Horses with bladder neoplasia had lower hematocrits, were older, more likely to be female, and more likely to have a mass detected on ultrasonographic examination of the bladder than horses with hemorrhagic cystitis syndrome. CONCLUSIONS AND CLINICAL IMPORTANCE: Hemorrhagic cystitis represents a novel differential diagnosis for horses with hematuria, and is associated with a favorable prognosis. Although histopathology may suggest a neoplastic process, affected horses should be monitored cystoscopically, because complete resolution of hemorrhagic cystitis occurs. The cause of this disease is unknown, and warrants investigation. PMID- 29604122 TI - Salivary flow and xerostomia in patients with type 2 diabetes. AB - BACKGROUND: Saliva is secreted by the major and minor salivary glands. There are a number of physiological factors that can reduce this secretion such as age, sex, body weight, number of teeth present in the mouth or time of day. This decrease may also be caused by the use of certain drugs, radiotherapy for head and neck cancer, chronic rheumatic diseases such as Sjogren's syndrome and other systemic disorders such as diabetes mellitus (DM). Objective of this study was to investigate the effect of type 2 DM on salivary secretion and its relation to the sensation of xerostomia. METHODS: Forty-seven patients with type 2 DM and 46 healthy individuals, aged 40-80, participated in the study. Samples of saliva were collected, at rest and after stimulation, at baseline and after the administration of a meal. A questionnaire of 10 items was used to define the patients' sensations of xerostomia. For statistical analysis, the Mann-Whitney test was used to assess the difference in salivary flow between the two groups and the relationship between the response to each of the questions and salivary flow levels. The degree of the patients' sensation of xerostomia was analysed by the Fisher test. RESULTS AND CONCLUSIONS: There was a significant decrease in total saliva levels at rest in patients with type 2 DM compared to the control group. The study group also experienced higher levels of dryness at night and on waking as well as a greater sensation of lingual burning compared to the control group. PMID- 29604123 TI - Well-Being and Posttraumatic Growth Among Syrian Refugees in Jordan. AB - The Syrian War has created a mass exodus of Syrian citizens to neighboring countries and exposed them to many atrocities. We explored factors affecting well being and posttraumatic growth (PTG) of refugees residing in Jordan. Participants (N = 250) were surveyed via nongovernmental organizations (NGOs). Outcome criteria included a global well-being rating and the Posttraumatic Growth Inventory. Trauma exposure assessment included The Harvard Trauma Questionnaire (HTQ) and The War Events Questionnaire. Ordinary least squares regression examined associations between potential contributors to refugee well-being and PTG, including work, age, sex, income, education, posttraumatic stress disorder (PTSD) severity, physical pain, health, NGO assistance, psychotic/affective mental disorder, and length of residence in Jordan. Mean participant score on the PTSD-HTQ scale was 2.37 (SD = 0.63; range: 1 [no symptoms] to 3.88 [extremely severe symptoms]). Additionally, 74.6% of participants received NGO assistance and 92.7% experienced war events. Univariate and multivariate results indicated enhancement of well-being was associated with income, r = .34, beta = .26, p < .001; health, r = .35, beta = .26, p = .001; and absence of affective disorder, r = -.31, beta = -.18, p = .012; and that PTG increased in association with income, r = .28, beta = .20, p = .007; NGO assistance, r = .07, beta = .14, p = .045; and absence of psychosis, r = -.12, beta = -.17, p = .013, and affective disorder, r = -.26; beta = -.16, p = .033. Findings suggest sufficient income and humanitarian assistance can contribute to Syrian refugees' mental health. PMID- 29604124 TI - Risk factors and mortality rate in premature babies with acute kidney injury. AB - BACKGROUND: Acute kidney injury (AKI) is a common morbidity in neonatal intensive care units and associated with poor outcome. This study aimed to determine the prevalence of AKI and provide a demographic data and risk factors associated with the mortality and morbidity. METHODS: This is a retrospective study included 105 premature babies. Diagnosis of AKI was based on neonatal KDIGO classification criteria. The babies were stratified into two groups according to AKI status during the hospitalization. Clinical and laboratory characteristics of the AKI group were compared to non-AKI group. RESULTS: AKI occurred in 21 (20.0%) of 105 premature babies, and mortality rate in these babies was 61.9%. Lower gestational weeks, lower Apgar scores at 5 minutes, lower systolic blood pressures, and inotropic supports were independent risk factors for the development of AKI in preterm babies (P < .05, for each). Oliguria, preeclampsia/eclampsia, resuscitation at birth, lower diastolic blood pressure, patent ductus arteriosus (PDA), inotropic support, and furosemide treatment were associated with the mortality (P < .05, for each). CONCLUSIONS: Prenatal risk factors and medical interventions are associated with AKI, and AKI is associated with increased morbidity and mortality. Therefore, identification of AKI is very important in this vulnerable population and it should be performed as quickly as possible in all babies who are at high risk for developing of AKI. PMID- 29604125 TI - Prenatal and early-life antibiotic use and risk of childhood asthma: A retrospective cohort study. AB - BACKGROUND: Although associations between antibiotic exposure in infants and asthma development are reported, few studies have examined the effects of prenatal exposure to antibiotics. We evaluated this association considering the antibiotic types using a large-scale claim database in Japan. METHODS: This retrospective study using health insurance administrative claim data in Japan included children born between January 2005 and September 2014. We constructed 2 cohorts: initial cohort, with information on children's mothers, and sibling cohort, with at least one sibling. Cox proportional hazard regression and sibling matched cohort analyses were performed to determine the association between exposure to antibiotics in utero or the first year of life and asthma development until age 6. RESULTS: In the initial cohort, antibiotic exposure during the foetal period was associated with early asthma development (until age 3; HR: 1.18, 95% CI: 1.08-1.30). However, this association disappeared after 3 years. The association between antibiotic exposure in the first year of life and asthma was stronger in early (HR: 2.43, 95% CI: 2.20-2.69) than later (HR: 1.23, 95% CI: 1.11-1.36) life. In the sibling cohort, we observed positive associations between foetal exposure and asthma by adjusting for familial factors (HR: 1.34, 95% CI: 1.05-1.72), which remained during the first year of life (HR: 1.62, 95% CI: 1.27 2.07). CONCLUSIONS: Exposure to antibiotics during the first year of life was associated with childhood asthma even after adjusting for familial factors. However, a weak association was observed between prenatal antibiotic exposure and asthma development. PMID- 29604126 TI - SAM syndrome is characterized by extensive phenotypic heterogeneity. AB - Severe skin dermatitis, multiple allergies and metabolic wasting (SAM) syndrome is a rare life-threatening inherited condition caused by bi-allelic mutations in DSG1 encoding desmoglein 1. The disease was initially reported to manifest with severe erythroderma, failure to thrive, atopic manifestations, recurrent infections, hypotrichosis and palmoplantar keratoderma. We present 3 new cases of SAM syndrome in 2 families and review the cases published so far. Whole exome and direct sequencing were used to identify SAM syndrome-causing mutations. Consistent with previous data, SAM syndrome was found in all 3 patients to result from homozygous mutations in DSG1 predicted to result in premature termination of translation. In contrast, as compared with patients previously reported, the present cases were found to display a wide range of clinical presentations of variable degrees of severity. The present data emphasize the fact that SAM syndrome is characterized by extensive phenotypic heterogeneity, suggesting the existence of potent modifier traits. PMID- 29604127 TI - Interactions between different media and follicle-stimulating hormone supplementation on in vitro culture of preantral follicles enclosed in ovarian tissue derived from collared peccaries (Pecari tajacu Linneaus, 1758). AB - The aim was to verify the effect of follicle-stimulating hormone (FSH) supplementation to alpha-MEM+ or TCM199+ media on the in vitro development of ovarian preantral follicles (PFs) derived from collared peccaries. Ovaries (n = 5 pairs) were collected and divided into fragments destined to control group (non cultured) or treatments that were cultured for 7 days. The PFs morphology, growth and activation were evaluated by classical histology. The immunohistochemistry markers Ag-NOR and PCNA were used for nuclear proliferation analysis, and the picrosirius red labelling was used for ovarian extracellular matrix (ECM) evaluation. After 7-day culture, only the TCM199+ treatment maintained the proportion of intact PFs similar to day 1 (63.2%), but no differences were found among treatments (p > .05). In addition, a significant increase in the growing follicles proportion was verified for all the treatments, indicating follicular activation (p > .05). By the Ag-NOR analysis, only the TCM199+/FSH maintained the nuclear proliferation similar to the first day (p > .05). The picrosirius red staining revealed that the ECM remained intact in all the treatments (p > .05). We suggest the use of TCM199+ medium supplemented of FSH for the in vitro development of peccaries PFs under 7-day culturing conditions. PMID- 29604128 TI - Multiple functional gastrointestinal disorders are frequent in formula-fed infants and decrease their quality of life. AB - AIM: This prospective study evaluated the incidence of functional gastrointestinal disorders (FGIDs) during infancy, on their own or combined with other symptoms. METHODS: We asked 273 French paediatricians with a specific interest in FGIDs to provide feedback on 2757 infants aged zero to six months from March 2013 to January 2014. Gastrointestinal health status was assessed by two questionnaires at inclusion and at a four-week follow-up visit. FGIDs were assessed according to the Rome III criteria and quality of life (QoL) was monitored. RESULTS: Combined FGIDs were diagnosed in 2145 (78%) infants: 63% with two disorders and 15% with three or more disorders. The most frequently combined FGIDs were gas/bloating and colic (28%), colic and regurgitation (17.0%) and gas/bloating and regurgitation (8%). Compared to infants with a single FGID, combined FGID were associated with lower body weight (4.63 vs 4.79 kg, p = 0.009), shorter breastfeeding duration (33 vs 43 days, p < 0.001), a decreased QoL score (5.9 vs 6.5, p < 0.001), more frequent drug prescriptions (25% vs 13%, p < 0.001) and significantly greater improvements in QoL scores after four weeks (p = 0.003). CONCLUSION: Combined FGIDs were extremely common in infants up to six months of age and had a negative impact on breastfeeding, weight gain and QoL. PMID- 29604129 TI - Bicelle size modulates the rate of bacteriorhodopsin folding. AB - The conformational equilibria of integral membrane proteins have proven extremely difficult to characterize within native lipid bilayers. To circumvent technical issues, investigations of the structure and stability of alpha-helical membrane proteins are often carried out in mixed micelle or bicelle solvents that mimic the membrane and facilitate measurements of reversible folding. Under these conditions, the energetics of membrane protein folding are typically proportional to the mole fraction of an anionic detergent in the micelle. However, investigations of the folding and unfolding of bacteriorhodopsin (bR) surprisingly revealed that the folding rate is also highly sensitive to the bulk molar concentration of lipids and detergents. We show here that this rate enhancement coincides with changes in bicelle size and suggest this effect arises through restriction of the conformational search space during folding. In conjunction with previous mutagenic studies, these results provide additional evidence that a topological search limits the rate of bR folding. Furthermore, this finding provides insights into the manner by which micellar and bicellar environments influence the conformational stability of polytopic membrane proteins. PMID- 29604130 TI - Structural basis for tankyrase-RNF146 interaction reveals noncanonical tankyrase binding motifs. AB - Poly(ADP-ribosyl)ation (PARylation) catalyzed by the tankyrase enzymes (Tankyrase 1 and -2; a.k.a. PARP-5a and -5b) is involved in mitosis, telomere length regulation, GLUT-4 vesicle transport, and cell growth and differentiation. Together with the E3 ubiquitin ligase RNF146 (a.k.a. Iduna), tankyrases regulate the cellular levels of several important proteins including Axin, 3BP2, and angiomotins, which are key regulators of Wnt, Src and Hippo signaling, respectively. These tankyrase substrates are first PARylated and then ubiquitylated by RNF146, which is allosterically activated by binding to PAR polymer. Each tankyrase substrate is recognized by a tankyrase-binding motif (TBM). Here we show that RNF146 binds directly to tankyrases via motifs in its C terminal region. Four of these RNF146 motifs represent novel, extended TBMs, that have one or two additional amino acids between the most conserved Arg and Gly residues. The individual RNF146 motifs display weak binding, but together mediate a strong multivalent interaction with the substrate-binding region of TNKS, forming a robust one-to-one complex. A crystal structure of the first RNF146 noncanonical TBM in complex with the second ankyrin repeat domain of TNKS shows how an extended motif can be accommodated in a peptide-binding groove on tankyrases. Overall, our work demonstrates the existence of a new class of extended TBMs that exist in previously uncharacterized tankyrase-binding proteins including those of IF4A1 and NELFE. PMID- 29604131 TI - Changes in the regulation and activity of glutathione redox system, and lipid peroxidation processes in short-term aflatoxin B1 exposure in liver of laying hens. AB - The purpose of this study was to investigate the short-term (48 hr) effects of feeding aflatoxin contaminated diet (170.3 MUg/kg AFB1) in 49-week-old laying hens. Liver samples were taken at 12-hr intervals. Feed intake, body weight, absolute and relative liver weight were the same in groups. However, there was no feed intake during both dark periods (between 12nd to 24th and 36th to 48th hours of the experiment); therefore, aflatoxin intake was also negligible. Markers of initial phase of lipid peroxidation, conjugated dienes and trienes did not change as effect of aflatoxin, but terminal marker, malondialdehyde content was significantly higher at 12 hr as effect of aflatoxin. No significant difference was found in reduced glutathione concentration and glutathione peroxidase activity between the groups. Expression of glutathione peroxidase 4 gene (GPX4) was significantly reduced due to aflatoxin treatment at 12 and 24 hr, but induced later, while glutathione reductase gene (GSR) expression was significantly lower at 24 hr and glutathione synthetase gene (GSS) in aflatoxin-treated group at 12 hr. The results suggest that aflatoxin induced oxygen-free radical formation, but it did not reach critical level during this short period of time to cause activation of the expression of glutathione system. PMID- 29604132 TI - Secondary sexual traits and semen characteristic of chicken germline chimeras. AB - Birds obtained by embryo engineering are used to study embryo development and to produce transgenic birds. As this method of producing birds still generate strong emotions of the public opinion head ornaments, testes and semen characteristics of sex chimera roosters were examined to check whether they differ from chickens obtained by non-manipulated methods. Measurements of head ornaments, testes and semen were correlated with each other. Semen quality factor (SQF) was calculated, as well as the level of fluctuating asymmetry (FA) of bilateral traits (wattles and testes). Positive correlation was found for comb width and wattle length and comb thickness and sperm concentration. Semen characteristics and FA did not exceed the level encounter in other chicken lines. Results obtained indicate that germline chimeras are similar in appearance of secondary sexual traits, and semen and testes characteristics to chickens produced in non-manipulated way. PMID- 29604133 TI - The effect of farrowing duration and parity on preovulatory follicular size and oxytocin release of sows at subsequent oestrus. AB - This study examined the extent to which prolonged farrowing and parity are associated with plasma oxytocin concentrations and follicular development of oestrous sows during subsequent insemination. A total of 30 sows were allocated to two groups based on farrowing duration: (i) SHORT (n = 14): 159 +/- 29 min, (ii) LONG (n = 16): 533 +/- 190 min. The sows were also divided into two parity classes: (i) YOUNG (n = 14): parity 2.5 +/- 0.8, (ii) OLD (n = 16): parity 6.4 +/ 2.3. After weaning, the ovaries were examined daily with transrectal ultrasound. On the second day of oestrus, blood samples were collected for oxytocin (OT) assay at -15, -10, -5, 0, +1, +2, +3, +4, +6, +8, +10, +15, +20, +25, +30, +40, +50 and +60 min with a boar contact between 0 and +10 min. Boar presence stimulated an increase in OT concentrations (p < .05). During boar presence, OT in the LONG group was higher than in the SHORT group (p < .01). The sows in the OLD group had a longer farrowing duration than in the YOUNG group (p < .05). OT levels and diameters of follicles were more relevant for parity than was the duration of farrowing. We therefore conclude that the OT levels and follicular development of oestrous sows are associated due to parity but difficult to be predicted from the duration of previous farrowing. PMID- 29604135 TI - Cleavage of Two Hydrogen Molecules by Boryldisilenes. AB - Activation of H2 by compounds of main-group elements has received considerable attention. Herein, we report synthesis of novel monoboryl- and monoamino substituted disilenes and their characterization by a combination of NMR spectroscopy and single-crystal X-ray diffraction analysis. The monoboryldisilene reacts with two molecules of H2 to provide the corresponding trihydridodisilane and hydroborane, whereas the aminodisilene does not react with H2 under the same conditions. The present results together with our previous results indicate that the presence of the boryl-substituent on the Si=Si double bond is essential to activate the H2 molecule. The low lying empty 2p orbital on the boron atom that interacts effectively with the pi*(Si=Si) orbital could be responsible for the activation of H2 . PMID- 29604136 TI - Discontinued stimulation of cardiomyocytes provides protection against hypothermia-rewarming-induced disruption of excitation-contraction coupling. AB - NEW FINDINGS: What is the central question of this study? Will discontinued stimulation of isolated cardiomyocytes (asystole) during hypothermia mitigate hypothermia-rewarming-induced cytosolic Ca2+ overload? What is the main finding and its importance? Mimicking asystole or hypothermic cardiac arrest by discontinued stimulation of cardiomyocytes during hypothermia resulted in normal contractile function after rewarming. This result suggests that asystole during severe hypothermia provides protection from hypothermia-rewarming-induced contractile dysfunction in cardiomyocytes. ABSTRACT: After exposure of spontaneously beating hearts or electrically stimulated isolated cardiomyocytes to hypothermia-rewarming (H/R), cardiac dysfunction or alteration in excitation contraction coupling, respectively, is a consequence. In contrast, hypothermic cardiac arrest, as routinely applied during cardiac surgery, will not impose any hazard to cardiac function after rewarming. We hypothesize that by maintaining asystole during H/R, cardiomyocytes will avoid Ca2+ overload attributable to the transient stimulation-evoked elevation of [Ca2+ ]i and thus, H/R-induced elevation of phosphorylated cardiac troponin I and reduced Ca2+ sensitivity after rewarming. To test this hypothesis, the aim of the study was to determine whether discontinued electrical stimulation (to imitate hypothermic cardiac arrest) versus stimulation during 3 h of H/R prevents disruption of excitation contraction coupling in our established cardiomyocyte H/R model. Cytosolic Ca2+ and the contractile response (sarcomere length shortening) were measured using an IonOptix system, and the dynamic assessment of Ca2+ sensitivity of contraction was conducted using a phase-loop plot. Cardiomyocytes were divided into three groups. Group 1 (time-matched control) was continuously stimulated at 0.5 Hz for 3 h at 35 degrees C. Group 2 was continuously stimulated during H/R at 0.5 Hz, whereas in group 3 stimulation was discontinued during H/R and thus the cells remained quiescent until the resumption of stimulation after rewarming. The results demonstrate that discontinued stimulation of cardiomyocytes during H/R, imitating hypothermic cardiac arrest during cardiac surgery, provides protection against H/R-induced disruption of excitation-contraction coupling. We suggest that protective effects are caused by preventing the protein kinase A-induced elevation of phosphorylated cardiac troponin I, which is a key mechanism to reduce myofilament Ca2+ sensitivity of contraction. PMID- 29604134 TI - B4GALNT2 and xenotransplantation: A newly appreciated xenogeneic antigen. AB - Analysis of non-Gal antibody induced after pig-to-baboon cardiac xenotransplantation identified the glycan produced by porcine beta-1,4-N-acetyl galactosaminyltransferase 2 (B4GALNT2) as an immunogenic xenotransplantation antigen. The porcine B4GALNT2 enzyme is homologous to the human enzyme, which synthesizes the human SDa blood group antigen. Most humans produce low levels of anti-SDa IgM which polyagglutinates red blood cells from rare individuals with high levels of SDa expression. The SDa glycan is also present on GM2 gangliosides. Clinical GM2 vaccination studies for melanoma patients suggest that a human antibody response to SDa can be induced. Expression of porcine B4GALNT2 in human HEK293 cells results in increased binding of anti-SDa antibody and increased binding of Dolichos biflorus agglutinin (DBA), a lectin commonly used to detect SDa. In pigs, B4GALNT2 is expressed by vascular endothelial cells and endothelial cells from a wide variety of pig backgrounds stain with DBA, suggesting that porcine vascular expression of B4GALNT2 is not polymorphic. Mutations in B4GALNT2 have been engineered in mice and pigs. In both species, the B4GALNT2-KO animals are apparently normal and no longer show evidence of SDa antigen expression. Pig tissues with a mutation in B4GALNT2, added to a background of alpha-1,3-galactosyltransferase deficient (GGTA1-KO) and cytidine monophosphate-N-acetylneuraminic acid hydroxylase deficient (CMAH-KO), show reduced antibody binding, confirming the presence of B4GALNT2-dependent antibodies in both humans and non-human primates. Preclinical xenotransplantation using B4GALNT2-deficient donors has recently been reported. Elimination of this source of immunogenic pig antigen should minimize acute injury by preformed anti pig antibody and eliminate an induced clinical immune response to this newly appreciated xenotransplantation antigen. PMID- 29604137 TI - Immunomodulatory effect of Artemisia argyi polysaccharide on peripheral blood leucocyte of broiler chickens. AB - This study was conducted to investigate the immunomodulatory effect of a water soluble polysaccharide extracted from Artemisia argyi (AAP) in vitro. The effect was assessed in peripheral blood leucocytes (PBLs) of broilers, which were incubated with different AAP concentrations (0, 25, 50, 100, and 200 MUg/ml) for 24 hr at 37 degrees C in a 5% CO2 incubator. The results showed that, compared with the control group, immunoglobulin M (IgM) concentration was increased in the supernatant of the 100 MUg/ml AAP-treated group (p < .05), and immunoglobulin G (IgG) concentration was increased in the supernatant of the 200 MUg/ml of AAP group (p < .05). In terms of cytokine production, production of interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) in the supernatant was enhanced in the AAP group in a dose-dependent function, as well as enhanced mRNA expressions were showed in the cells (p < .05). The highest concentration of these three cytokines was observed in different AAP groups (IL 1beta for 25 MUg/ml of AAP, IL-6 for 100, and 200 MUg/ml of AAP, and TNF-alpha for 100 MUg/ml of AAP respectively). The concentration of nitric oxide (NO) was increased when using AAP at the concentration of 100 MUg/ml (p < .05) as compared to the control group. No significant effects on inducible nitric oxide synthase, Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 and nuclear factor Kappa B (NF-kappaB) mRNA level were observed at each concentration of AAP. In conclusion, we found that AAP can specifically promote the production of immunoglobulins (IgM and IgG), cytokines (IL-1beta, IL-6 and TNF-alpha), as well as the NO concentration in vitro, but not through the activation of the TLR4/NF kappaB signalling pathway. PMID- 29604138 TI - Glucocorticoid withdrawal affects stress-induced changes of urocortin 2 gene expression in rat adrenal medulla and brain. AB - Corticotropin-releasing factor is well known activator of the hypothalamic pituitary-adrenocortical axis, that represents crucial system participating on stress response of the organism. Urocortins are members of the corticotropin releasing factor family of peptides with proposed effects on neuroendocrine and behavioral stress response mechanisms. Urocortin 2, one of three known urocortins, is present in central and peripheral stress response system and its expression can be augmented by glucocorticoids. In the present study we have examined how glucocorticoid withdrawal affects urocortin 2 gene expression after acute immobilization in the adrenal medulla and selected brain areas in rats. We used pharmacological adrenalectomy to block synthesis of corticosterone. Our results show that the immobilization-induced rise in urocortin 2 mRNA levels in rat adrenal medulla was not inhibited by glucocorticoid withdrawal. On the other hand, observed changes in the brain indicate that the effect of stress and pharmacological adrenalectomy on urocortin 2 gene expression is site-specific. While in the paraventricular nucleus and locus coeruleus the immobilization induced rise of urocortin 2 was not inhibited by pharmacological adrenalectomy in the arcuate nucleus and central amygdala it was. Moreover, we have seen a significant depletion of urocortin 2 plasma levels after immobilization. The immobilization induced rise of urocortin 2 gene expression in rat adrenal medulla and brain areas regulating stress response pathways and preservation of its induction after adrenalectomy suggests a role of urocortin 2 in the neuroendocrine stress response of an organism. This article is protected by copyright. All rights reserved. PMID- 29604139 TI - Preliminary observations of a new approach to tissue repair: Peripheral blood mononuclear cells in platelet-rich plasma injected into skin graft area. AB - Our purpose was accelerating the physiologic wound healing, stimulating tissue regeneration and the reparative tissue processes in resistant skin ulcers as in a case of an erosive lichen planus of the soles and after a surgical treatment as for severe Darier disease. The challenge was to establish an effective therapy to enhance tissue healing by the injection of a mixture of peripheral blood mononuclear cells (PB-MNCs) and platelet-rich plasma (PRP) into a skin autograft area. This new perioperative biotechnological approach enriches PRP with the effects of PB-MNCs. It offers a novel advanced strategy that could become an ideal biologic blood-derived therapy, whose components are entirely autologous and produced by a protocol independent by the operator. PMID- 29604140 TI - Cytidinediphosphate-diacylglycerol synthase 5 is required for phospholipid homeostasis and is negatively involved in hyperosmotic stress tolerance. AB - Cytidinediphosphate diacylglycerol synthase (CDS) uses phosphatidic acid (PA) and cytidinetriphosphate to produce cytidinediphosphate-diacylglycerol, an intermediate for phosphatidylglycerol (PG) and phosphatidylinositol (PI) synthesis. This study shows that CDS5, one of the five CDSs of the Oryza sativa (rice) genome, has multifaceted effects on plant growth and stress responses. The loss of CDS5 resulted in a decrease in PG and PI levels, defective thylakoid membranes, pale leaves in seedlings and growth retardation. In addition, the loss of CDS5 led to an elevated PA level and enhanced hyperosmotic tolerance. The inhibition of phospholipase D (PLD)-derived PA formation in cds5 restored the hyperosmotic stress tolerance of the mutant phenotype to that of the wild type, suggesting that CDS5 functions as a suppressor in PLD-derived PA signaling and negatively affects hyperosmotic stress tolerance. PMID- 29604141 TI - PGD2/PTGDR2 Signaling Restricts the Self-Renewal and Tumorigenesis of Gastric Cancer. AB - The antitumor effect of prostaglandin D2 (PGD2) on gastric cancer (GC) has been known for decades. However, the mechanism of PGD2's control of GC growth is unclear. Cancer stem cells (CSCs) are implicated in tumor neovascularization, invasiveness, and therapeutic resistance. Herein, we discovered that signaling between PGD2 and its receptor (PTGDR2) has the ability to restrict the self renewal of GC cells in vitro and suppress tumor growth and metastasis in vivo. To obtain these findings, we first determined that PGD2 synthase (L-PTGDS) and PTGDR2 expression were lower in GC tissues than adjacent tissues and was associated with the patients' prognosis. Moreover, the expression of L-PTGDS and PTGDR2 was negatively correlated with the GC-CSC markers Sall4 and Lgr5 in GC tissues. Second, L-PTGDS and PTGDR2 expression were knocked down in CSC-like cells, resulting in enhanced expression of CSC markers and self-renewal ability. Direct PGD2 stimulation and L-PTGDS overexpression produced the opposite effect. Thirdly, PGD2 inhibited tumor growth and incidence rate in a subcutaneous tumor model and suppressed liver and mesenteric metastasis in a peritoneal metastasis model. Interfering with the expression of PTGDR2 reversed these effects in vivo. Last, a mechanistic study found that PGD2 inhibited STAT3 phosphorylation and nuclear expression. Further experiments revealed that the inhibitory effect of PGD2 on the expression of CSC markers disappeared after mutations were introduced into STAT3 phosphorylation (Thr705) site. In short, this study reveals a novel function of PGD2/PTGDR2 signaling on CSC regulation and provides a new way to control the development of GC. Stem Cells 2018;36:990-1003. PMID- 29604142 TI - Irradiation of semen doses with LED-based red light in a photo chamber does not improve in vitro quality of thermically stressed boar spermatozoa. AB - Recent reports indicate that stimulation of liquid-stored boar semen with red LED based light improves sperm quality and reproductive performance in sow herds. So far, in vitro data after LED stimulation of whole semen doses are lacking. In this study, the effect of LED light exposure on the in vitro quality of boar spermatozoa after storage and thermic incubation was examined. Boar semen doses were stored at 17 degrees C (n = 10) or 5 degrees C (n = 6) in Beltsville Thawing Solution extender and then exposed to red LED light using a commercial photo chamber. During a subsequent long-term incubation at 38 degrees C, neither sperm kinematic parameters nor mitochondria function or membrane integrity differed between control and treated samples (p > .05). It is concluded that stimulation of semen doses in the LED-photo chamber does not improve quality of thermically stressed boar sperm in vitro. Other than the sperm traits tested here might be involved in the previously reported improvement of in vivo fertility. PMID- 29604143 TI - Cotard's syndrome in anti-N-methyl-d-aspartate receptor encephalitis. PMID- 29604144 TI - Changes in plasma concentrations of S100A7 and S100A8 in dairy cows during pregnancy. AB - This study was carried out to examine the changes in plasma concentrations of the Ca-binding antimicrobial proteins S100A7 and S100A8 during pregnancy in dairy cows. Holstein Friesian cows (n = 19) were inseminated with Holstein Friesian semen. Blood was collected at days 30, 60, 90, 120, 150, 180, 210, 240 and 270 after insemination. Plasma was used for measuring the concentrations of S100A7 and S100A8. Both S100A7 and S100A8 concentrations showed similar patterns during gestation; they increased during the midgestation, between days 90 and 180, and then declined before calving. The findings indicated that plasma concentrations of S100A7 and S100A8 did not change significantly during pregnancy in cows. Further studies are required to determine the roles of S100A7 and S100A8 in physiological function during pregnancy in dairy cows. PMID- 29604145 TI - 34 S: A New Opportunity for the Efficient Synthesis of Stable Isotope Labeled Compounds. AB - The synthesis of stable isotope labeled (SIL) complex drug molecules with a >=3 mass unit increase from the parent compound is essential for drug discovery and development. Typical approaches that rely on 2 H, 13 C, and 15 N isotopes can be very challenging or even intractable, and can delay the drug development process. This work introduces a new concept for the synthesis of labeled compounds that relies on the use of 34 S. The synthetic utility of 34 S was demonstrated with the efficient synthesis of [34 S]phosphorothioates [34 S2 ]-PS-ODNs-TTT and [13 C, 15 N, 34 S]-ceftolozane. In addition, a procedure for the direct oxidation of phosphites to [34 S]phosphorothioates using elemental 34 S without isotope dilution was developed. PMID- 29604146 TI - Life before and beyond blistering: The role of collagen XVII in epidermal physiology. AB - Type XVII collagen (COL17) is a transmembranous protein that is mainly expressed in the epidermal basal keratinocytes. Epidermal-dermal attachment requires COL17 expression at the hemidesmosomes of the epidermal basement membrane zone because congenital COL17 deficiency leads to junctional epidermolysis bullosa and acquired autoimmunity to COL17 induces bullous pemphigoid. Recently, in addition to facilitating epidermal-dermal attachment, COL17 has been reported to serve as a niche for hair follicle stem cells, to regulate proliferation in the interfollicular epidermis and to be present along the non-hemidesmosomal plasma membrane of epidermal basal keratinocytes. This review focuses on the physiological properties of COL17 in the epidermis, its role in maintaining stem cells and its association with signalling pathways. We propose possible solutions to unanswered questions in this field. PMID- 29604147 TI - Implementation of a patient safety program at a tertiary health system: A longitudinal analysis of interventions and serious safety events. AB - BACKGROUND: We hypothesize that implementation of a safety program based on high reliability organization principles will reduce serious safety events (SSE). METHODS: The safety program focused on 7 essential elements: (a) safety rounding, (b) safety oversight teams, (c) safety huddles, (d) safety coaches, (e) good catches/safety heroes, (f) safety education, and (g) red rule. An educational curriculum was implemented focusing on changing high-risk behaviors and implementing critical safety policies. All unusual occurrences were captured in the Midas system and investigated by risk specialists, the safety officer, and the chief medical officer. A multidepartmental committee evaluated these events, and a root cause analysis (RCA) was performed. Events were tabulated and serious safety event (SSE) recorded and plotted over time. Safety success stories (SSSs) were also evaluated over time. RESULTS: A steady drop in SSEs was seen over 9 years. Also a rise in SSSs was evident, reflecting on staff engagement in the program. The parallel change in SSEs, SSSs, and the implementation of various safety interventions highly suggest that the program was successful in achieving its goals. CONCLUSION: A safety program based on high-reliability organization principles and made a core value of the institution can have a significant positive impact on reducing SSEs. PMID- 29604148 TI - Differential promoter methylation of DAZL gene in bulls with varying seminal parameters. AB - In India, cross-breeding of indigenous cattle with exotic cattle such as Holstein Friesian and Jersey has been going on since last four decades to improve milk production. Although it has led to increased milk yield, the subfertility in male cross-bred progeny has remained a significant problem. Epigenetic modifications (DNA methylation, histone modifications and chromatin remodelling) are regarded as key players influencing gene expression. DAZL gene plays an important role in germline development and gametogenesis. The methylation and mRNA expression level of this gene have been significantly negatively correlated in the testes of cattle-yak hybrids and their parents. This study analysed the methylation profile of DAZL gene promoter in bull spermatozoa in an attempt to speculate its role in cross-bred cattle subfertility. Semen samples from Sahiwal, Holstein Friesian and Frieswal bulls (Sahiwal X Holstein Friesian) with varying semen motility parameters were collected, and DNA was isolated. Methylation-specific primers were used to amplify part of promoter and exon 1 of DAZL gene using bisulphite converted DNA. The amplified products were sequenced after cloning in pTZ57R/T vector. Sequence analysis revealed significantly higher DNA methylation of DAZL gene in Frieswal bulls with poor motility (28.26%) as compared to medium (15.21%) and high motility phenotype (6.52%). In pure-bred counterparts, Sahiwal and Holstein Friesian, epigenetic marks were more in the former (15.21%) than the latter (4.34%), but in both cases, the values were lower as compared to the poor motility Frieswal bulls. This suggests that differential hypermethylation of the CpG islands could possibly influence reproductive parameters in bovines. PMID- 29604149 TI - Functional classification of protein structures by local structure matching in graph representation. AB - As a result of high-throughput protein structure initiatives, over 14,400 protein structures have been solved by Structural Genomics (SG) centers and participating research groups. While the totality of SG data represents a tremendous contribution to genomics and structural biology, reliable functional information for these proteins is generally lacking. Better functional predictions for SG proteins will add substantial value to the structural information already obtained. Our method described herein, Graph Representation of Active Sites for Prediction of Function (GRASP-Func), predicts quickly and accurately the biochemical function of proteins by representing residues at the predicted local active site as graphs rather than in Cartesian coordinates. We compare the GRASP Func method to our previously reported method, Structurally Aligned Local Sites of Activity (SALSA), using the Ribulose Phosphate Binding Barrel (RPBB), 6 Hairpin Glycosidase (6-HG), and Concanavalin A-like Lectins/Glucanase (CAL/G) superfamilies as test cases. In each of the superfamilies, SALSA and the much faster method GRASP-Func yield similar correct classification of previously characterized proteins, providing a validated benchmark for the new method. In addition, we analyzed SG proteins using our SALSA and GRASP-Func methods to predict function. Forty-one SG proteins in the RPBB superfamily, nine SG proteins in the 6-HG superfamily, and one SG protein in the CAL/G superfamily were successfully classified into one of the functional families in their respective superfamily by both methods. This improved, faster, validated computational method can yield more reliable predictions of function that can be used for a wide variety of applications by the community. PMID- 29604150 TI - Neurophysiological study of critical illness polyneuropathy and myopathy in mechanically ventilated children; additional aspects in paediatric critical illness comorbidities. AB - BACKGROUND AND PURPOSE: Critical illness polyneuropathy and myopathy (CIP/CIM) is being increasingly recognized as a significant clinical problem in critically ill children especially if they have spent long periods in the intensive care unit. So the aim was to determine the frequency of CIP/CIM amongst mechanically ventilated children and to analyse the associated risk factors and drawbacks frequently encountered in this cohort. METHODS: The study included 105 patients admitted to the paediatric intensive care unit who underwent mechanical ventilation for >=7 days. These patients were screened daily for awakening. Patients with severe muscle weakness on day 7 post-awakening underwent nerve conduction studies and electromyography. Accordingly, the patients were classified as CIP/CIM patients if they had abnormal neurophysiology studies or control patients if normal neurophysiology studies were obtained. Their clinical and laboratory profiles had been recorded as well. RESULTS: Overall, of 105 patients who achieved satisfactory awakening, 34 patients (32.4%) developed CIP/CIM mostly of the axonal polyneuropathy pattern (27.6%) whilst 71 control patients (67.6%) showed normal electrophysiological studies. The mean duration of mechanical ventilation was significantly longer in patients with CIP/CIM compared to control patients (P = 0.001). The study also revealed that 62.1% of our CIP/CIM patients failed weaning trials and finally died. CIP/CIM was significantly associated with decreased platelets, elevated liver enzymes and prolonged prothrombin time. Acidosis, low serum calcium and albumin levels and higher blood glucose were also found to be more significant in CIP/CIM patients compared to control patients. CONCLUSION: Critically ill children frequently develop CIP/CIM, mostly of axonal polyneuropathy pattern, which compromises rehabilitation and recovery and is associated with a number of comorbidities. PMID- 29604151 TI - Pathway Diversity Leads to 2D-Nanostructure in Photo-triggered Supramolecular Assembly. AB - This Communication reports photo-triggered supramolecular assembly of a naphthalene-diimide (NDI) derivative, appended with a photo-labile ortho nitrobenzyl (ONB)-ester protected carboxylic acid. Photo-irradiation produces the free COOH group which facilitates H-bonding-driven face-to-face stacking of the NDI chromophores producing an ultra-thin (height <2.0 nm) two-dimensional (2D) nanosheet. In contrast, spontaneous supramolecular assembly of the same active monomer exhibits entirely different features such as uncontrolled growth, J aggregation and fibrillar morphology. A completely different pathway for photo triggered assembly is attributed to the dual function of the photo-caged pro monomer in i) producing the carboxylic acid in controlled manner and ii) simultaneously inhibiting the spontaneous J-aggregation of the photo-generated monomers by ester-carboxylic acid H-bonding and in turn directing a distinct growth mechanism. PMID- 29604153 TI - Agricultural diversification as an important strategy for achieving food security in Africa. AB - Farmers in Africa have long adapted to climatic and other risks by diversifying their farming activities. Using a multi-scale approach, we explore the relationship between farming diversity and food security and the diversification potential of African agriculture and its limits on the household and continental scale. On the household scale, we use agricultural surveys from more than 28,000 households located in 18 African countries. In a next step, we use the relationship between rainfall, rainfall variability, and farming diversity to determine the available diversification options for farmers on the continental scale. On the household scale, we show that households with greater farming diversity are more successful in meeting their consumption needs, but only up to a certain level of diversity per ha cropland and more often if food can be purchased from off-farm income or income from farm sales. More diverse farming systems can contribute to household food security; however, the relationship is influenced by other factors, for example, the market orientation of a household, livestock ownership, nonagricultural employment opportunities, and available land resources. On the continental scale, the greatest opportunities for diversification of food crops, cash crops, and livestock are located in areas with 500-1,000 mm annual rainfall and 17%-22% rainfall variability. Forty-three percent of the African cropland lacks these opportunities at present which may hamper the ability of agricultural systems to respond to climate change. While sustainable intensification practices that increase yields have received most attention to date, our study suggests that a shift in the research and policy paradigm toward agricultural diversification options may be necessary. PMID- 29604152 TI - Hepatocellular carcinoma over three decades in Victoria, Australia: epidemiology, diagnosis and trends, 1984-2013. AB - BACKGROUND: Liver cancer continues to be a health priority in Australia, with the majority attributable to preventable causes, and certain populations at higher risk. AIMS: Epidemiological assessment of incidence, trends and distribution to inform prevention, and reassessment of data in light of recent changes to registry case definitions. METHODS: Reported cases of hepatocellular carcinoma (HCC) in Victoria, Australia, 1984-2013, were obtained from the Victorian Cancer Registry. Demographic characteristics were examined, incidence and survival assessed using Poisson and Cox regression, and geographic distribution mapped. Incidence was compared before and after inclusion of non-histologically confirmed cases in Registry data to assess impacts on incidence trends. RESULTS: Diagnoses of HCC rose substantially between 1984 and 2013, increasing sixfold from 0.9 to 5.9 per 100 000. The rate of increase per year accelerated from 5.3% between 1984 and 2003 to 9.5% between 2004 and 2013. Cases were disproportionately male (80%), median age at diagnosis was 66 years and 53% were born overseas. Even during 2004 2013, 5-year survival was only 16%, although higher among younger people, metropolitan residents and people born overseas. Incidence showed strong geographic clustering. The proportion of cases diagnosed clinically increased from 1% during 1984-2004 to 43% in 2009-2013. The revised case definition added 993 cases (27.3% of total). CONCLUSION: Cases of HCC are becoming increasingly common, and revised incidence estimates highlight the impact of case definitions in the context of changing diagnostic approaches. The ongoing burden, disproportionate population distribution and low survival emphasise the importance of prevention and early detection as a public health imperative. PMID- 29604154 TI - Redox-Divergent Synthesis of Fluoroalkylated Pyridines and 2-Pyridones through Cu Catalyzed N-O Cleavage of Oxime Acetates. AB - Cu-catalyzed redox-divergent [3+3] coupling of oxime esters with beta-CF3 enones and acrylates is described. This redox-neutral coupling with enones and acrylates affords trifluoromethylated pyridines and pyridones, respectively. Under reductive conditions, difluoromethylated pyridines, difluoromethlated pyridones, and trifluoromethylated dihydropyridones are obtained. The reactions occur under mild conditions with broad substrate scope and regio/redox selectivity. PMID- 29604155 TI - Association of endothelial dysfunction with cardiovascular risk factors and new onset diabetes mellitus in patients with hypertension. AB - Asymmetric dimethylarginine (ADMA), which is the main endogenous inhibitor of nitric oxide synthase, plays a critical role in the process of endothelial dysfunction. The authors evaluated the association between high plasma ADMA levels in patients with hypertension and the presence of cardiovascular risk factors and the development of type 2 diabetes mellitus (DM) and cardiovascular outcomes, including death. The authors evaluated 191 patients with hypertension who were stratified into two groups according to the median value of basal ADMA: those with high levels of plasma ADMA (>0.55 MUmol/L) and low levels of plasma ADMA (<=0.55 MUmol/L) who were prospectively evaluated over 5.8 years. High ADMA levels were seen in patients with higher weight, body mass index, waist circumference, triglycerides, uric acid, and high-sensitivity C-reactive protein, and lower levels of high-density lipoprotein cholesterol and in patients with type 2 DM. There was an association between high plasma ADMA levels and the occurrence of cardiovascular death. In a subgroup of patients with hypertension free from metabolic syndrome and DM at baseline, there was an association between high ADMA levels and the development of type 2 DM. This study confirms the association of high plasma ADMA levels and the presence of cardiovascular risk factors in patients with hypertension and suggests a positive predictive value of high plasma ADMA levels for cardiovascular death in patients with hypertension and also for the development of type 2 DM in a subgroup of patients with hypertension free from metabolic abnormalities. PMID- 29604156 TI - Assessment and management of bipolar disorder: Principal summary of updated Chinese guidelines. PMID- 29604157 TI - The response of soil solution chemistry in European forests to decreasing acid deposition. AB - Acid deposition arising from sulphur (S) and nitrogen (N) emissions from fossil fuel combustion and agriculture has contributed to the acidification of terrestrial ecosystems in many regions globally. However, in Europe and North America, S deposition has greatly decreased in recent decades due to emissions controls. In this study, we assessed the response of soil solution chemistry in mineral horizons of European forests to these changes. Trends in pH, acid neutralizing capacity (ANC), major ions, total aluminium (Altot ) and dissolved organic carbon were determined for the period 1995-2012. Plots with at least 10 years of observations from the ICP Forests monitoring network were used. Trends were assessed for the upper mineral soil (10-20 cm, 104 plots) and subsoil (40-80 cm, 162 plots). There was a large decrease in the concentration of sulphate (SO42 ) in soil solution; over a 10-year period (2000-2010), SO42- decreased by 52% at 10-20 cm and 40% at 40-80 cm. Nitrate was unchanged at 10-20 cm but decreased at 40-80 cm. The decrease in acid anions was accompanied by a large and significant decrease in the concentration of the nutrient base cations: calcium, magnesium and potassium (Bc = Ca2+ + Mg2+ + K+ ) and Altot over the entire dataset. The response of soil solution acidity was nonuniform. At 10-20 cm, ANC increased in acid-sensitive soils (base saturation <=10%) indicating a recovery, but ANC decreased in soils with base saturation >10%. At 40-80 cm, ANC remained unchanged in acid-sensitive soils (base saturation <=20%, pHCaCl2 <= 4.5) and decreased in better-buffered soils (base saturation >20%, pHCaCl2 > 4.5). In addition, the molar ratio of Bc to Altot either did not change or decreased. The results suggest a long-time lag between emission abatement and changes in soil solution acidity and underline the importance of long-term monitoring in evaluating ecosystem response to decreases in deposition. PMID- 29604158 TI - Ozone pollution will compromise efforts to increase global wheat production. AB - Introduction of high-performing crop cultivars and crop/soil water management practices that increase the stomatal uptake of carbon dioxide and photosynthesis will be instrumental in realizing the United Nations Sustainable Development Goal (SDG) of achieving food security. To date, however, global assessments of how to increase crop yield have failed to consider the negative effects of tropospheric ozone, a gaseous pollutant that enters the leaf stomatal pores of plants along with carbon dioxide, and is increasing in concentration globally, particularly in rapidly developing countries. Earlier studies have simply estimated that the largest effects are in the areas with the highest ozone concentrations. Using a modelling method that accounts for the effects of soil moisture deficit and meteorological factors on the stomatal uptake of ozone, we show for the first time that ozone impacts on wheat yield are particularly large in humid rain-fed and irrigated areas of major wheat-producing countries (e.g. United States, France, India, China and Russia). Averaged over 2010-2012, we estimate that ozone reduces wheat yields by a mean 9.9% in the northern hemisphere and 6.2% in the southern hemisphere, corresponding to some 85 Tg (million tonnes) of lost grain. Total production losses in developing countries receiving Official Development Assistance are 50% higher than those in developed countries, potentially reducing the possibility of achieving UN SDG2. Crucially, our analysis shows that ozone could reduce the potential yield benefits of increasing irrigation usage in response to climate change because added irrigation increases the uptake and subsequent negative effects of the pollutant. We show that mitigation of air pollution in a changing climate could play a vital role in achieving the above mentioned UN SDG, while also contributing to other SDGs related to human health and well-being, ecosystems and climate change. PMID- 29604159 TI - Novel alleles of rice eIF4G generated by CRISPR/Cas9-targeted mutagenesis confer resistance to Rice tungro spherical virus. AB - Rice tungro disease (RTD) is a serious constraint in rice production across tropical Asia. RTD is caused by the interaction between Rice tungro spherical virus (RTSV) and Rice tungro bacilliform virus. RTSV resistance found in traditional cultivars has contributed to a reduction in the incidence of RTD in the field. Natural RTSV resistance is a recessive trait controlled by the translation initiation factor 4 gamma gene (eIF4G). The Y1059 V1060 V1061 residues of eIF4G are known to be associated with the reactions to RTSV. To develop new sources of resistance to RTD, mutations in eIF4G were generated using the CRISPR/Cas9 system in the RTSV-susceptible variety IR64, widely grown across tropical Asia. The mutation rates ranged from 36.0% to 86.6%, depending on the target site, and the mutations were successfully transmitted to the next generations. Among various mutated eIF4G alleles examined, only those resulting in in-frame mutations in SVLFPNLAGKS residues (mainly NL), adjacent to the YVV residues, conferred resistance. Furthermore, our data suggest that eIF4G is essential for normal development, as alleles resulting in truncated eIF4G could not be maintained in homozygous state. The final products with RTSV resistance and enhanced yield under glasshouse conditions were found to no longer contain the Cas9 sequence. Hence, the RTSV-resistant plants with the novel eIF4G alleles represent a valuable material to develop more diverse RTSV-resistant varieties. PMID- 29604160 TI - Baseline characteristics and enrichment results from the SONAR trial. AB - AIM: The SONAR trial uses an enrichment design based on the individual response to the selective endothelin receptor antagonist atrasentan on efficacy (the degree of the individual response in the urinary albumin-to-creatinine ratio [UACR]) and safety/tolerability (signs of sodium retention and acute increases in serum creatinine) to assess the effects of this agent on major renal outcomes. The patient population and enrichment results are described here. METHODS: Patients with type 2 diabetes with an estimated glomerular filtration rate (eGFR) within 25 to 75 mL/min/1.73 m2 and UACR between 300 and 5000 mg/g were enrolled. After a run-in period, eligible patients received 0.75 mg/d of atrasentan for 6 weeks. A total of 2648 responder patients in whom UACR decreased by >=30% compared to baseline were enrolled, as were 1020 non-responders with a UACR decrease of <30%. Patients who experienced a weight gain of >3 kg and in whom brain natriuretic peptide exceeded >=300 pg/mL, or who experienced an increase in serum creatinine >20% (0.5 mg/dL), were not randomized. RESULTS: Baseline characteristics were similar for atrasentan responders and non-responders. Upon entry to the study, median UACR was 802 mg/g in responders and 920 mg/g in non responders. After 6 weeks of treatment with atrasentan, the UACR change in responders was -48.8% (95% CI, -49.8% to -47.9%) and in non-responders was -1.2% (95% CI, -6.4% to 3.9%). Changes in other renal risk markers were similar between responders and non-responders except for a marginally greater reduction in systolic blood pressure and eGFR in responders. CONCLUSIONS: The enrichment period has successfully identified a population with a profound UACR reduction without clinical signs of sodium retention in whom a large atrasentan effect on clinically important renal outcomes is possible. The SONAR trial aims to establish whether atrasentan confers renal protection. PMID- 29604161 TI - Automated blood pressure measurement may not improve efficiency if manual technique was suboptimal. PMID- 29604162 TI - Utility of the Hospital Admission Risk Programme diabetes risk calculator in identifying patients with type 2 diabetes at risk of unplanned hospital presentations. AB - BACKGROUND: Prevention of hospitalisation is an important aspect of type 2 diabetes (T2D) management. AIMS: We retrospectively determined the utility of the Hospital Admission Risk Programme (HARP) diabetes risk calculator (HARP tool) in identifying patients with T2D more likely to have unplanned hospital presentations. METHODS: The HARP tool includes a clinical assessment score (Part A) and a psychosocial and self-management impact score (Part B), and categorises patients into low, medium, high or urgent risk of acute hospitalisation. It was completed for T2D patients attending Royal North Shore Hospital, Sydney, in 2013. RESULTS: Within the cohort of 278 patients (age 65.3 +/- 10.5 years; 62.9% male; diabetes duration 10.7 +/- 6.6 years), 67.3% were classified as low risk, 32.7% as medium risk and none as high or urgent risk. Following adjustment for confounders, a medium HARP score was associated with a 3.1-fold increased risk of unplanned hospital presentations in the subsequent 12 months (95% confidence interval: 1.35-7.31; P = 0.008). Part A scores were significantly higher for patients that presented to hospital compared to those that did not (14.2 +/- 6.8 vs 11.4 +/- 5.5; P = 0.034), whereas there was no difference in Part B scores (P = 0.860). CONCLUSIONS: In patients with low and medium HARP scores, clinical features were more predictive of hospital presentations than certain psychosocial or self-management factors in the present cohort. Further studies are required to characterise unplanned hospitalisation in patients with higher HARP scores, or whether additional psychosocial assessments could improve the tool's predictability. PMID- 29604163 TI - Multicenter in vitro thromboelastography and thromboelastometry standardization. AB - OBJECTIVE: To establish and compare the repeatability and reproducibility of activated thromboelastography (TEG) and thromboelastometry (ROTEM) assays. DESIGN: Multicenter in vitro test standardization. SETTING: Veterinary academic centers. ANIMALS: Test samples were obtained from normal, healthy dogs. Sixty identical 5 mL aliquots of canine platelet-rich plasma collected by apheresis, frozen in 6% dimethyl sulfoxide, were tested initially. Sixty identical 6 mL aliquots of canine fresh frozen plasma with admixed cryoprecipitate were subsequently evaluated. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Frozen study samples, quality controls, reagents, and consumables were distributed to participating centers (7 TEG and 3 ROTEM). TEG centers analyzed study samples with kaolin and tissue factor activated assays; ROTEM centers ran proprietary ellagic acid activated and tissue factor activated assays. All machines underwent quality control prior to sample analysis. Within- and between center coefficients of variation (CVs) were calculated and compared using Mann Whitney tests and calculation of intraclass correlation coefficients. Within and between centers, individual parameters for both TEG and ROTEM assays were comparable. Both within-center and between-center CVs varied markedly (0.7-120.5% and 1.4-116.5%, respectively) with assay type, instrument, and parameter. CVs for equivalent parameters were not significantly different between the 2 platforms. Intraclass correlation coefficients suggested moderate agreement between centers. In general, individual parameter CVs for platelet-rich plasma samples were lower in TEG centers, while CVs for canine fresh frozen plasma with admixed cryoprecipitate samples were lower in ROTEM centers. CONCLUSIONS: More variation within and between centers was identified than anticipated, but some parameters such as alpha angle were repeatable and reproducible. Sample types for future multicenter standardization efforts will require further optimization and may need to be adapted separately to each platform. Individual centers using viscoelastic tests for evaluation and management of clinical patients should take steps to minimize preanalytical and analytical sources of variation. PMID- 29604164 TI - Genotype-specific fitness cost of resistance to Bt toxin Cry1Ac in pink bollworm. AB - BACKGROUND: To improve resistance management strategies for Bacillus thuringiensis (Bt) crops, a better understanding of the relative fitness of pest genotypes with resistance alleles in the absence of Bt toxins is needed. Here, we evaluated the impact of costs of resistance to Bt toxin Cry1Ac on the relative fitness of specific pink bollworm (Pectinophora gossypiella) genotypes. We created two heterogeneous strains with an intermediate frequency of mutant cadherin alleles linked with resistance to Cry1Ac, reared the strains on diet without Bt and tracked the decline in frequency of resistant genotypes for 15-30 generations using polymerase chain reaction amplification. We used a population genetics model and sensitivity analyses to estimate the relative fitness of resistant genotypes. RESULTS: Costs were completely recessive in one strain and almost completely recessive in the other. Estimates of the decline in relative fitness of the resistant homozygotes fed on a diet without Bt were 14-22% in one strain and 21-36% in the other. CONCLUSION: Our genotype-specific cost estimates and the results of studies discussed herein indicate that costs associated with resistance to Bt are often large enough to significantly delay the evolution of resistance to pyramided Bt crops in pests with recessive inheritance of resistance. (c) 2018 Society of Chemical Industry. PMID- 29604165 TI - Mating disruption of Homalodisca vitripennis (Germar) (Hemiptera: Cicadellidae) by playback of vibrational signals in vineyard trellis. AB - BACKGROUND: Glassy-winged sharpshooter (GWSS), Homalodisca vitripennis (Germar) (Hemiptera: Cicadellidae) is an important vector of the bacterium Xylella fastidiosa, the causal agent of Pierce's disease of grapevine. Area-wide insecticide applications have suppressed GWSS populations for ~ 25 years, but reduced levels of insecticide susceptibility have been reported. Therefore, alternative methods of control are needed. Objectives of this study were to evaluate the efficacy of playback of vibrational mating communication signals for disrupting mating of GWSS in a natural vineyard setting and to evaluate spectral properties of signal transmission through vineyard trellis. RESULTS: Playback reduced mating of GWSS on grapevines. A total of 28 (of 134) male-female pairs mated in the control treatment (silence) and only one (of 134) pair mated when treated with the vibrational signal playback. Playback of vibrational signals through vineyard trellis was affected by distance from the signal source, with frequency composition being the highest at the source and lowest on vines positioned away from the source. Frequency composition in canes housing test insects decreased exponentially as distance from the source increased, whereas the relative amplitude of analyzed frequencies decreased linearly. CONCLUSION: Although further studies are needed prior to method implementation, data from this study continue to support integration of vibrational mating disruption with current methods to suppress GWSS populations. Published 2018. This article is a U.S. Government work and is in the public domain in the USA. PMID- 29604167 TI - Prevalence and risk factors of hypertension: A nationwide cross-sectional study in Lebanon. AB - There is limited epidemiologic data on hypertension (HTN) in Lebanon. This study aimed to determine the prevalence and associated risk factors of HTN in the adult Lebanese population and evaluate the association between dietary and psychological factors on systolic blood pressure (SBP). Cross-sectional analyses were conducted using a multistage cluster sample across Lebanon. A total of 2014 participants were included. The prevalence and control rates of HTN were 31.2% and 28.7%, respectively. In women, educational level and physical activity were negatively associated with HTN (P < .05 for both) and adherence to the Lebanese Mediterranean diet was associated with a lower SBP. Other factors were associated with HTN in men. There was no relationship with SBP and psychological distress. Of the modifiable risk factors, body mass index persisted as the only contributory factor in both sexes (P < .01). Accordingly, prevention of HTN at the population level should focus mainly on overweight prevention. PMID- 29604166 TI - RAVL1, an upstream component of brassinosteroid signalling and biosynthesis, regulates ethylene signalling via activation of EIL1 in rice. PMID- 29604168 TI - Regulation of C. elegans L4 cuticle collagen genes by the heterochronic protein LIN-29. AB - The cuticle, the outer covering of the nematode C. elegans, is synthesized five times during the worm's life by the underlying hypodermis. Cuticle collagens, the major cuticle component, are encoded by a large family of col genes and, interestingly, many of these genes express predominantly at a single developmental stage. This temporal preference motivated us to investigate the mechanisms underlying col gene expression and here we focus on a subset of col genes expressed in the L4 stage. We identified minimal promoter regions of <300 bp for col-38, col-49, and col-63. In these regions, we predicted cis-regulatory sequences and evaluated their function in vivo via mutagenesis of a col-38p::yfp reporter. We used RNAi to study the requirement for candidate transcription regulators ELT-1 and ELT-3, LIN-29, and the LIN-29 co-factor MAB-10, and found LIN-29 to be necessary for the expression of four L4-specific genes (col-38, col 49, col-63, and col-138). Temporal misexpression of LIN-29 was also sufficient to activate these genes at a different developmental stage. The LIN-29 DNA-binding domain bound the col-38, col-49, and col-63 minimal promoters in vitro. For col 38 we showed that the LIN-29 sites necessary for reporter expression in vivo are also bound in vitro: this is the first identification of specific binding sites for LIN-29 necessary for in vivo target gene expression. PMID- 29604170 TI - Developing and validating a new precise risk-prediction model for new-onset hypertension: The Jichi Genki hypertension prediction model (JG model). AB - No integrated risk assessment tools that include lifestyle factors and uric acid have been developed. In accordance with the Industrial Safety and Health Law in Japan, a follow-up examination of 63 495 normotensive individuals (mean age 42.8 years) who underwent a health checkup in 2010 was conducted every year for 5 years. The primary endpoint was new-onset hypertension (systolic blood pressure [SBP]/diastolic blood pressure [DBP] >= 140/90 mm Hg and/or the initiation of antihypertensive medications with self-reported hypertension). During the mean 3.4 years of follow-up, 7402 participants (11.7%) developed hypertension. The prediction model included age, sex, body mass index (BMI), SBP, DBP, low-density lipoprotein cholesterol, uric acid, proteinuria, current smoking, alcohol intake, eating rate, DBP by age, and BMI by age at baseline and was created by using Cox proportional hazards models to calculate 3-year absolute risks. The derivation analysis confirmed that the model performed well both with respect to discrimination and calibration (n = 63 495; C-statistic = 0.885, 95% confidence interval [CI], 0.865-0.903; chi2 statistic = 13.6, degree of freedom [df] = 7). In the external validation analysis, moreover, the model performed well both in its discrimination and calibration characteristics (n = 14 168; C-statistic = 0.846; 95%CI, 0.775-0.905; chi2 statistic = 8.7, df = 7). Adding LDL cholesterol, uric acid, proteinuria, alcohol intake, eating rate, and BMI by age to the base model yielded a significantly higher C-statistic, net reclassification improvement (NRI), and integrated discrimination improvement, especially NRInon event (NRI = 0.127, 95%CI = 0.100-0.152; NRInon-event = 0.108, 95%CI = 0.102 0.117). In conclusion, a highly precise model with good performance was developed for predicting incident hypertension using the new parameters of eating rate, uric acid, proteinuria, and BMI by age. PMID- 29604171 TI - Identification of the novel HLA-B*51:230 allele in a Saudi individual. AB - One nucleotide replacement at codon 349 of HLA-B*51:01:01:01 results in a new allele, HLA-B*51:230. PMID- 29604169 TI - Genome and evolution of the shade-requiring medicinal herb Panax ginseng. AB - Panax ginseng C. A. Meyer, reputed as the king of medicinal herbs, has slow growth, long generation time, low seed production and complicated genome structure that hamper its study. Here, we unveil the genomic architecture of tetraploid P. ginseng by de novo genome assembly, representing 2.98 Gbp with 59 352 annotated genes. Resequencing data indicated that diploid Panax species diverged in association with global warming in Southern Asia, and two North American species evolved via two intercontinental migrations. Two whole genome duplications (WGD) occurred in the family Araliaceae (including Panax) after divergence with the Apiaceae, the more recent one contributing to the ability of P. ginseng to overwinter, enabling it to spread broadly through the Northern Hemisphere. Functional and evolutionary analyses suggest that production of pharmacologically important dammarane-type ginsenosides originated in Panax and are produced largely in shoot tissues and transported to roots; that newly evolved P. ginseng fatty acid desaturases increase freezing tolerance; and that unprecedented retention of chlorophyll a/b binding protein genes enables efficient photosynthesis under low light. A genome-scale metabolic network provides a holistic view of Panax ginsenoside biosynthesis. This study provides valuable resources for improving medicinal values of ginseng either through genomics-assisted breeding or metabolic engineering. PMID- 29604172 TI - Prevalence, distribution and amplitude of the complement interference phenomenon in single antigen flow beads assays. AB - HLA antibody detection with single antigen flow beads (SAFB) assays is impaired by complement interference whose frequency, predictability and distribution among HLA antigens have not been analyzed in large cohorts. We compared in two patients' cohorts the routine follow-up SAFB profiles obtained in class I (n = 129) and class II (n = 85) with and without ethylenediaminetetraacetic acid (EDTA)-treatment. The presence of complement interference was defined according to the reproducibility of the SAFB assays evaluated with our class I and II routine positive control sera. Interference occurred in 29.5% and 45.9% of patients in class I and II, respectively. In the untreated condition, at serum level, neither the number of positive beads, the highest bead mean fluorescence intensity (MFI) nor MFI at bead level, satisfactorily predicted interference. HLA C were the least affected among class I beads. HLA-DQ beads were the most affected in class II. At least one antibody specificity was falsely negative without EDTA for about 3% of sera in class I and 9% in class II. EDTA-treatment did not significantly modify the low-MFI strengths (500-3000 range). This study emphasizes the high frequency of complement interference and the importance and advantages of systematically pretreating sera with EDTA before performing SAFB assays. PMID- 29604173 TI - Cerebral amyloid angiopathy: Review of clinico-radiological features and mimics. AB - Cerebral amyloid angiopathy (CAA) is an important cause of lobar intracerebral haemorrhage (ICH) in the elderly, but has other clinico-radiological manifestations. In the last two decades, certain magnetic resonance imaging (MRI) sequences, namely gradient-recalled echo imaging and the newer and more sensitive susceptibility-weighted imaging, have been utilised to detect susceptibility sensitive lesions such as cerebral microbleeds and cortical superficial siderosis. These can be utilised sensitively and specifically by the Modified Boston Criteria to make a diagnosis of CAA without the need for 'gold-standard' histopathology from biopsy. However, recently, other promising MRI biomarkers of CAA have been described which may further increase precision of radiological diagnosis, namely chronic white matter ischaemia, cerebral microinfarcts and lobar lacunes, cortical atrophy, and increased dilated perivascular spaces in the centrum semiovale. However, the radiological manifestations of CAA, as well as their clinical correlates, may have other aetiologies and mimics. It is important for the radiologist to be aware of these clinico-radiological features and mimics to accurately diagnose CAA. This is increasingly important in a patient demographic that has a high prevalence for use of antiplatelet and antithrombotic medications for other comorbidities which inherently carries an increased risk of ICH in patients with CAA. PMID- 29604174 TI - Using an injection port helps improve metabolic control and compliance to a strict basal-bolus regimen in children and adolescents with type 1 diabetes. PMID- 29604175 TI - A spidroin-derived solubility tag enables controlled aggregation of a designed amyloid protein. AB - Amyloidogenesis is associated with more than 30 diseases, but the molecular mechanisms involved in cell toxicity and fibril formation remain largely unknown. The inherent tendency of amyloid-forming proteins to aggregate renders expression, purification, and experimental studies challenging. NT* is a solubility tag derived from a spider silk protein that was recently introduced for the production of several aggregation-prone peptides and proteins at high yields. Herein, we investigate whether fusion to NT* can prevent amyloid fibril formation and enable controlled aggregation for experimental studies. As an example of an amyloidogenic protein, we chose the de novo-designed polypeptide beta17. The fusion protein NT*-beta17 was recombinantly expressed in Escherichia coli to produce high amounts of soluble and mostly monomeric protein. Structural analysis showed that beta17 is kept in a largely unstructured conformation in fusion with NT*. After proteolytic release, beta17 adopts a beta-sheet conformation in a pH- and salt-dependent manner and assembles into amyloid-like fibrils. The ability of NT* to prevent premature aggregation and to enable structural studies of prefibrillar states may facilitate investigation of proteins involved in amyloid diseases. PMID- 29604176 TI - Deficits in prospective memory following damage to the medial subdivision of the mediodorsal thalamic nucleus. AB - Identifying the neurocognitive mechanisms that lead individuals remembering to execute an intention at the right moment (prospective memory, PM) and how such mechanisms are influenced by the features of that intention is a fundamental theoretical challenge. In particular, the functional contribution of subcortical regions to PM is still unknown. This study was aimed at investigating the role of the medial subdivision of the mediodorsal thalamic nucleus (mMDT) in PM, with particular focus on the processes that are mediated by the projections from/to this structure. We analysed the performance of a patient (OG) with a right-sided lesion involving the mMDT in a series of PM tasks that varied for focality (i.e., overlapping of processes for the PM and ongoing tasks) and emotional valence of the stimuli, comparing the patient's performance with that of a control group. We found that the mMDT damage led to deficits in PM that were modulated by focality and emotional valence. OG indeed showed: a greater cost in the ongoing performance when a non-focal PM task was added; a slowing down in retrieving the intentions, in particular when these were associated with focal PM cues; an abnormal performance in the task with positive PM cues. Our findings provide evidence of a contribution of mMDT to PM and suggest a modulation of prefrontal dependent strategic monitoring and a possible interaction with the limbic structures in the integration of emotion and PM processes. They also give support to the still controversial idea that connections with the perirhinal cortex mediate familiarity-based recognition. PMID- 29604177 TI - Systematic review and meta-analysis of double-blind, placebo-controlled, randomized clinical trials using probiotics in chronic periodontitis. AB - AIM: The aim of the present study was to evaluate the efficacy of probiotics as an adjunct to scaling and root planning (SRP) in the treatment of chronic periodontitis (CP). METHODS: The focused question of the study was: Does adjunctive use of probiotics yield better clinical periodontal outcomes compared to placebo/no treatment group in the treatment of CP? Electronic and manual literature searches were conducted up to December 2017 using the following databases: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, and Cochrane Oral Health Group Trials Register. Forest plots were computed reporting weighted mean difference (WMD) of outcomes and 95% confidence intervals (CI). RESULTS: Seven clinical studies were included. Four studies showed additional benefits in reducing periodontal probing depth (PPD) and gaining clinical attachment level (CAL), whereas, three studies showed comparable clinical periodontal outcomes between probiotics and SRP/placebo. Significant heterogeneity was observed for PPD reduction and CAL gain. The overall mean difference for CAL gain between probiotics and placebo/SRP was significant (WMD = 1.41, 95% CI = 0.15-2.67, P = .028) at follow up. CONCLUSION: Adjunctive probiotics could result in additional benefits in CAL gain in CP. Nevertheless, further high-quality randomized clinical trials with microbiological outcomes are warranted to obtain strong conclusions in this regard. PMID- 29604179 TI - Ace1 prevents intracellular copper accumulation by regulating Fet3 expression and thereby restricting Aft1 activity. AB - In the yeast Saccharomyces cerevisiae Aft1, the low iron-sensing transcription factor is known to regulate the expression of the FET3 gene. However, we found that a strain-lacking FET3 is more sensitive to copper excess than a strain lacking AFT1, and accordingly, FET3 expression is not fully compromised in the latter. These findings suggest that, under such conditions, another regulator comes into play and controls FET3 expression. In this work, we identify Ace1, the regulator of copper detoxification genes, as a regulator of FET3. We suggest that the activation of FET3 by Ace1 prevents the hyper activation of Aft1, possibly by assuring the adequate functioning of mitochondrial iron-sulfur cluster biogenesis. While reinforcing the link between iron and copper homeostasis, this work unveils a novel protection mechanism against copper toxicity mediated by Ace1, which relies in the activation of FET3 and results in the restriction of Aft1 activity as a means to prevent excessive copper accumulation. PMID- 29604178 TI - Cysteine dioxygenase is essential for mouse sperm osmoadaptation and male fertility. AB - Sperm entering the epididymis are immotile and cannot respond to stimuli that will enable them to fertilize. The epididymis is a highly complex organ, with multiple histological zones and cell types that together change the composition and functional abilities of sperm through poorly understood mechanisms. Sperm take up taurine during epididymal transit, which may play antioxidant or osmoregulatory roles. Cysteine dioxygenase (CDO) is a critical enzyme for taurine synthesis. A previous study reported that male CDO-/- mice exhibit idiopathic infertility, prompting us to investigate the functions of CDO in male fertility. Immunoblotting and quantitative reverse transcription-polymerase chain reaction analysis of epididymal segments showed that androgen-dependent CDO expression was highest in the caput epididymidis. CDO-/- mouse sperm demonstrated a severe lack of in vitro fertilization ability. Acrosome exocytosis and tyrosine phosphorylation profiles in response to stimuli were normal, suggesting normal functioning of pathways associated with capacitation. CDO-/- sperm had a slight increase in head abnormalities. Taurine and hypotaurine concentrations in CDO-/- sperm decreased in the epididymal intraluminal fluid and sperm cytosol. We found no evidence of antioxidant protection against lipid peroxidation. However, CDO-/- sperm exhibited severe defects in volume regulation, swelling in response to the relatively hypo-osmotic conditions found in the female reproductive tract. Our findings suggest that epididymal CDO plays a key role in post-testicular sperm maturation, enabling sperm to osmoregulate as they transition from the male to the female reproductive tract, and provide new understanding of the compartmentalized functions of the epididymis. PMID- 29604180 TI - Glycosylated amyloid-like proteins in the structural extracellular polymers of aerobic granular sludge enriched with ammonium-oxidizing bacteria. AB - A new type of structural extracellular polymers (EPS) was extracted from aerobic granular sludge dominated by ammonium-oxidizing bacteria. It was analyzed by Raman and FTIR spectroscopy to characterize specific amino acids and protein secondary structure, and by SDS-PAGE with different stains to identify different glycoconjugates. Its intrinsic fluorescence was captured to visualize the location of the extracted EPS in the nitrifying granules, and its hydrogel forming property was studied by rheometry. The extracted EPS is abundant with cross beta-sheet secondary structure, contains glycosylated proteins/polypeptides, and rich in tryptophan. It forms hydrogel with high mechanical strength. The extraction and discovery of glycosylated proteins and/or amyloids further shows that conventionally used extraction and characterization techniques are not adequate for the study of structural extracellular polymers in biofilms and/or granular sludge. Confirming amyloids secondary structure in such a complex sample is challengeable due to the possibility of amyloids glycosylation and self-assembly. A new definition of extracellular polymers components which includes glycosylated proteins and a better approach to studying them is required to stimulate biofilm research. PMID- 29604181 TI - A Default Option to Enhance Nutrition Within Financial Constraints: A Randomized, Controlled Proof-of-Principle Trial. AB - OBJECTIVE: This study aimed to examine the feasibility and initial efficacy of a novel default option intervention targeting nutritional quality of online grocery purchases within the financial constraints of food insecurity. METHODS: Female undergraduates (n = 59) without eating disorder symptoms or dietary restrictions selected foods online with a budget corresponding to maximum Supplemental Nutrition Assistance Program benefits. Before completing the task again, participants were randomly assigned to receive a $10 incentive for selecting nutritious groceries (n = 17), education about nutrition (n = 24), or a default online shopping cart containing a nutritionally balanced selection of groceries (n = 18) to which they could make changes. Nutritional quality was quantified by using the Thrifty Food Plan Calculator. RESULTS: Compared with the education condition, participants in the default condition selected significantly more whole grains and fruits and foods lower in cholesterol, saturated fats, sodium, and overall calories. There were no statistically significant differences in nutritional outcomes between the incentive condition and the other two groups. CONCLUSIONS: Findings provide initial support for the efficacy of a default option in facilitating healthier food choice behaviors within financial constraints. PMID- 29604182 TI - Prevalence of temporomandibular disorders among a cohort of university undergraduates in Australia. AB - AIM: The aim of the present study was to determine the prevalence of temporomandibular disorder (TMD) symptoms among dentistry students at James Cook University in Australia, and to determine the associations of TMD symptoms with demographic parameters and compare the prevalence to that of the Australian general population. METHODS: The study was conducted at the School of Dentistry, James Cook University. Axis I symptom questionnaire of diagnostic criteria for TMD was used to assess the prevalence of TMD symptoms. Additional questions were included to gather demographic information on the participants. Data were collected anonymously via the online survey tool, SurveyMonkey. RESULTS: The overall prevalence of TMD symptoms in this cohort was 77.2%. The most common TMD symptoms were pain (48.5%) and joint noises (48.5%). Females reported a significantly higher prevalence of TMD symptoms than males, with 73 of 88 female respondents (83%) and 32 of 48 male respondents (66.7%) reporting at least one symptom of TMD (P = .030). CONCLUSIONS: The overall prevalence of TMD symptoms in the population studied was 77.2%, with female preponderance of TMD symptoms (83%). This is higher than the estimated prevalence (23%) in the Australian general population. PMID- 29604183 TI - The Nem1/Spo7-Pah1/lipin axis is required for autophagy induction after TORC1 inactivation. AB - Autophagy is a process that requires intense membrane remodeling and consumption. The nutrient-responsive TORC1 (target of rapamycin complex 1) kinase regulates autophagy. However, how TORC1 controls autophagy via lipid/membrane biogenesis is unknown. TORC1 regulates the function of yeast phosphatidate phosphatase lipin Pah1 via the Nem1/Spo7 phosphatase complex. Here, we show that the Nem1/Spo7-Pah1 axis is required for autophagy induction after TORC1 inactivation and survival during starvation. Furthermore, this axis was critical for nucleophagy (both micronucleophagy and macronucleophagy) and was required for proper localization of micronucleophagy factor Nvj1 and macronucleophagy receptor Atg39. This study indicated that the Nem1/Spo7-Pah1 axis controlled by TORC1 is a critical branch for autophagy induction in nutrient starvation conditions. PMID- 29604184 TI - Modulator Dynamics Shape the Design Space for Stepwise-Elution Simulated Moving Bed Chromatographic Separations. AB - For proteins and other biological macromolecules, SMB chromatography is best operated non-isocratically. However, traditional modes of non-isocratic SMB operation generate significant mobile-phase modulator dynamics. The mechanisms by which these modulator dynamics affect a separation's success, and thus frame the design space, have yet to be explained quantitatively. Here, the dynamics of the modulator (e.g., salts in ion exchange and hydrophobic interaction chromatography) are explicitly accounted for. This leads to the elucidation of two new design constraints, presented as dimensionless numbers, which quantify the effects of the modulator phenomena and thus predict the success of a non isocratic SMB separation. Consequently, these two new design constraints re define the SMB design space. Computational and experimental studies at the boundaries of this design space corroborate the theoretical predictions. The design of efficient and robust operating conditions through use of the new design space is also demonstrated. PMID- 29604185 TI - Prevalence, clinical correlates, and outcomes of anaemia in multi-ethnic Asian patients with heart failure with reduced ejection fraction. AB - AIMS: Recent international heart failure (HF) guidelines recognize anaemia as an important comorbidity contributing to poor outcomes in HF, based on data mainly from Western populations. We sought to determine the prevalence, clinical correlates, and prognostic impact of anaemia in patients with HF with reduced ejection fraction across Asia. METHODS AND RESULTS: We prospectively studied 3886 Asian patients (60 +/- 13 years, 21% women) with HF (ejection fraction <=40%) from 11 regions in the Asian Sudden Cardiac Death in Heart Failure study. Anaemia was defined as haemoglobin <13 g/dL (men) and <12 g/dL (women). Ethnic groups included Chinese (33.0%), Indian (26.2%), Malay (15.1%), Japanese/Korean (20.2%), and others (5.6%). Overall, anaemia was present in 41%, with a wide range across ethnicities (33-54%). Indian ethnicity, older age, diabetes, and chronic kidney disease were independently associated with higher odds of anaemia (all P < 0.001). Ethnicity modified the association of chronic kidney disease with anaemia (Pinteraction = 0.045), with the highest adjusted odds among Japanese/Koreans [2.86; 95% confidence interval (CI) 1.96-4.20]. Anaemic patients had lower Kansas City Cardiomyopathy Questionnaire scores (P < 0.001) and higher risk of all-cause mortality and HF hospitalization at 1 year (hazard ratio = 1.28, 95% CI 1.08 1.50) compared with non-anaemic patients. The prognostic impact of anaemia was modified by ethnicity (Pinteraction = 0.02), with the greatest hazard ratio in Japanese/Koreans (1.82; 95% CI 1.14-2.91). CONCLUSIONS: Anaemia is present in a third to more than half of Asian patients with HF and adversely impacts quality of life and survival. Ethnic differences exist wherein prevalence is highest among Indians, and survival is most severely impacted by anaemia in Japanese/Koreans. PMID- 29604186 TI - Clinical Efficacy and Safety of Baminercept, a Lymphotoxin beta Receptor Fusion Protein, in Primary Sjogren's Syndrome: Results From a Phase II Randomized, Double-Blind, Placebo-Controlled Trial. AB - OBJECTIVE: To evaluate the clinical efficacy and safety of baminercept, a lymphotoxin beta receptor IgG fusion protein (LTbetaR-Ig), for the treatment of primary Sjogren's syndrome (SS), and to explore the possible mechanisms of action of this treatment. METHODS: In this multicenter trial, 52 patients with primary SS were randomized in a 2:1 ratio to receive subcutaneous injections of 100 mg of baminercept every week for 24 weeks or matching placebo. The primary end point was the change between screening and week 24 in the stimulated whole salivary flow (SWSF) rate. Secondary end points included the European League Against Rheumatism Sjogren's Syndrome Disease Activity Index (ESSDAI), as well as measurements of select chemokines and cytokines and enumeration of peripheral blood B and T cell subsets. RESULTS: The change from baseline to week 24 in the SWSF rate was not significantly different between the baminercept and placebo treatment groups (baseline-adjusted mean change -0.01 versus 0.07 ml/minute; P = 0.332). The change in the ESSDAI during treatment was also not significantly different between the treatment groups (baseline-adjusted mean change -1.23 versus -0.15; P = 0.104). Although the incidence of adverse events was similar between the treatment groups, baminercept therapy was associated with a higher incidence of liver toxicity, including 2 serious adverse events. Baminercept also produced a significant decrease in plasma levels of CXCL13 and significant changes in the number of circulating B and T cells, consistent with its known inhibitory effects on LTbetaR signaling. CONCLUSION: In this trial, treatment with baminercept failed to significantly improve glandular and extraglandular disease in patients with primary SS, despite evidence from mechanistic studies showing that it blocks LTbetaR signaling. PMID- 29604187 TI - Investigating the possible mechanisms involved in adenosine preconditioning induced cardioprotection in rats. AB - BACKGROUND: Adenosine is a breakdown product of adenosine triphosphate and plays an important role in pharmacological preconditioning. The cardioprotective effects of adenosine preconditioning are well established. However, the possible mechanisms need to be explored. AIM: This study was aimed to investigate the possible mechanisms involved in adenosine preconditioning-induced cardioprotection in rats. METHODS: Rat heart was isolated and perfused on Langendorff apparatus. Global ischemia for 30 minutes followed by reperfusion for 120 minutes was employed to produce myocardial injury. Myocardial injury was assessed by measuring myocardial infarct size, release of lactate dehydrogenase (LDH) and creatine kinase (CK) in the coronary effluent and hemodynamic parameters including left ventricular developed pressure (LVDP), dp/dtmax, and dp/dtmin . Serum nitrite levels were measured as an index of nitric oxide release in blood. RESULTS: Adenosine (4 mg/kg) preconditioning significantly decreased ischemia-reperfusion-induced increase in LDH, CK release, infarct size, improved LVDP, dp/dtmax and dp/dtmin, and increased serum nitrite levels. Pretreatment with L-NAME, a specific NOS inhibitor, (5 mg/kg) and montelukast, leukotriene receptor antagonist, (10 mg/kg) significantly abrogated the cardioprotective effect of adenosine preconditioning. However, seratrodast, thromboxane A2 antagonist, (15 mg/kg) had no effect on adenosine-induced cardioprotection. Sodium nitroprusside (SNP) preconditioning also produced cardioprotective effects. However, caffeine (20 mg/kg) (adenosine receptor blocker) and seratrodast (15 mg/kg) had no effect on SNP-induced cardioprotection. Administration of montelukast abrogated the cardioprotective effects of SNP preconditioning-induced cardioprotection. CONCLUSION: Adenosine preconditioning may increase the release of nitric oxide, which in turn may increase the release of cysteinyl leukotrienes to confer cardioprotection. PMID- 29604188 TI - Maternal care exerts disease-modifying effects on genetic absence epilepsy and comorbid depression. AB - WAG/Rij rats, a genetic animal model of absence epilepsy with comorbidity of depression, exhibit behavioral depression-like symptoms and spontaneous generalized spike-wave discharges (SWDs) in the EEG at the age of 6 to 8 months. The aim of the present study was to test the hypothesis that maternal care is an environmental factor which, along with genetic predisposition, may contribute to the expression of absence seizures and depression-like comorbidity later in life. To achieve this, a cross-fostering procedure was used. EEG and behavior in the forced swimming test were analyzed in WAG/Rij and Wistar offspring reared by their own mothers (non-cross-fostered), foster mothers of the same strain (in fostered) or another strain (cross-fostered) at the age of 7 to 8 months. Maternal care and forced swimming test behavior were assessed in the dams. WAG/Rij mothers showed depression-like behavior and reduced maternal care irrespective of litter size and litter composition (own or foster pups) compared with Wistar dams. WAG/Rij offspring reared by Wistar dams with a high level of maternal care exhibited less and shorter SWDs and reduced depression-like comorbidity in adulthood compared with age-matched WAG/Rij offspring reared by their own or foster WAG/Rij mothers with a low level of maternal care. Moreover, rearing by Wistar mothers delayed the onset of absence epilepsy in WAG/Rij rats. Adoption by WAG/Rij dams did not change EEG and behavior in Wistar rats. Our study demonstrates that improvement of early care-giving environment can be used as a disease-modifying treatment to counteract epileptogenesis and behavioral comorbidities in genetic absence epilepsy. PMID- 29604190 TI - Seroprevalence of Bluetongue Virus in small ruminants in Balochistan province, Pakistan. AB - Bluetongue (BT), caused by bluetongue virus (BTV), is a vector-borne disease of small ruminants that has the potential to spread across international borders. Despite large populations of susceptible animals and borders with BTV endemic countries, little is known of the disease burden and prevalent serotypes in the province of Balochistan in Pakistan. We conducted a cross-sectional study to determine seroconversion and prevalent serotypes in selected districts of the province using a competitive enzyme-linked immunosorbent assay (cELISA) and real time polymerase chain reaction (RT-PCR). Sera (n = 876) were collected from clinically healthy sheep and goats originating from the districts of Quetta (n = 300), Mastung (n = 201), Killa Saifullah (n = 75) and Kech (n = 300). None of the study herds (n = 97) were seronegative for BTV, and at the individual level, the overall prevalence of BTV seroconversion was 47.26% (n = 414/876, 95% CI = 43.92% 50.63%). A higher percentage of goats (50.87%, 95% CI = 45.99%-55.73%) were seropositive for anti-VP7 immunoglobulins (IgG) than sheep (44.21%, 95% CI = 39.81%-48.70%). Odds ratios of seroconversion for goats were associated with breed type (chi2 = 16.84, p = .01), parity (chi2 = 23.66, p = .00) and presence of vector (chi2 = 2.63, p = .10), whereas for sheep, it was associated with breed type (chi2 = 13.80, p = .01) and parity (chi2 = 53.40, p = .00). Serotype 8 was the most prevalent (26.82%, 95% CI = 14.75%-43.21%) followed by an equal prevalence of serotypes 2 and 9 (7.31%, 95% CI = 1.91%-21.01%). To the best of our knowledge, this is the first study conducted in Balochistan province and the results indicate that there is a necessity to initiate intervention strategies to control BT disease burden not only in this region of Pakistan but also in adjacent areas of the neighbouring countries, Iran and Afghanistan. PMID- 29604191 TI - Alleviation of Murine Osteoarthritis by Cartilage-Specific Deletion of IkappaBzeta. AB - OBJECTIVE: IkappaBzeta, an atypical IkappaB family member, regulates gene expression in the nucleus as a transcriptional cofactor. Although IkappaBzeta has been extensively studied in the immune system, its specific roles in osteoarthritis (OA) are currently unknown. The objective of this study was to investigate the potential role of IkappaBzeta in chondrocyte catabolism and OA pathogenesis. We also determined the molecular mechanism underlying its relationship to the transcription factor NF-kappaB. METHODS: We determined expression levels of IkappaBzeta in mouse chondrocytes treated with interleukin 1beta (IL-1beta), in human OA cartilage, and in mouse experimental OA cartilage. Adenovirus-mediated overexpression and small interfering RNA knockdown of IkappaBzeta were performed to determine the impact of IkappaBzeta on catabolic gene expression in vitro. Cartilage-specific IkappaBzeta-transgenic and -knockout mice were generated and used for in vivo studies. Experimental and spontaneous OA were induced by surgical destabilization of the medial meniscus and by aging, respectively. Coimmunoprecipitation assay was used to examine the association between IkappaBzeta and NF-kappaB subunits. RESULTS: IkappaBzeta was highly up regulated in chondrocytes in response to IL-1beta and in OA cartilage of human and mouse knee joints. Overexpression of IkappaBzeta in chondrocytes promoted spontaneous OA development by activating chondrocyte catabolism. Genetic ablation of IkappaBzeta in chondrocytes abolished catabolic gene induction by IL-1beta and protected against the development of experimental OA. IkappaBzeta formed complexes with NF-kappaB members to regulate catabolic factor expression. CONCLUSION: These findings demonstrate a critical role for IkappaBzeta in OA pathogenesis. Inhibition of IkappaBzeta function might be an effective therapeutic approach for OA treatment. PMID- 29604189 TI - Risk, Timing, and Predictors of Disease Flare After Discontinuation of Anti-Tumor Necrosis Factor Therapy in Children With Polyarticular Forms of Juvenile Idiopathic Arthritis With Clinically Inactive Disease. AB - OBJECTIVE: To determine the frequency, time to flare, and predictors of disease flare upon withdrawal of anti-tumor necrosis factor (anti-TNF) therapy in children with polyarticular forms of juvenile idiopathic arthritis (JIA) who demonstrated >=6 months of continuous clinically inactive disease. METHODS: In 16 centers 137 patients with clinically inactive JIA who were receiving anti-TNF therapy (42% of whom were also receiving methotrexate [MTX]) were prospectively followed up. If the disease remained clinically inactive for the initial 6 months of the study, anti-TNF was stopped and patients were assessed for flare at 1, 2, 3, 4, 6, and 8 months. Life-table analysis, t-tests, chi-square test, and Cox regression analysis were used to identify independent variables that could significantly predict flare by 8 months or time to flare. RESULTS: Of 137 patients, 106 (77%) maintained clinically inactive disease while receiving anti TNF therapy for the initial 6 months and were included in the phase of the study in which anti-TNF therapy was stopped. Stopping anti-TNF resulted in disease flare in 39 (37%) of 106 patients by 8 months. The mean/median +/- SEM time to flare was 212/250 +/- 9.77 days. Patients with shorter disease duration at enrollment, older age at onset and diagnosis, shorter disease duration prior to experiencing clinically inactive disease, and shorter time from onset of clinically inactive disease to enrollment were found to have significantly lower hazard ratios for likelihood of flare by 8 months (P < 0.05). CONCLUSION: Over one-third of patients with polyarticular JIA with sustained clinically inactive disease will experience a flare by 8 months after discontinuation of anti-TNF therapy. Several predictors of lower likelihood of flare were identified. PMID- 29604192 TI - A Preview of Selected Articles. PMID- 29604193 TI - Resting Metabolic Rate, Total Daily Energy Expenditure, and Metabolic Adaptation 6 Months and 24 Months After Bariatric Surgery. AB - OBJECTIVE: Little is known about long-term metabolic (energy expenditure) adaptation after bariatric surgery. METHODS: Resting metabolic rate under basal conditions (RMR), total daily energy expenditure (TDEE), and body composition were measured in 25 participants in the Longitudinal Assessment of Bariatric Surgery-2. RESULTS: Six months after surgery, BMI (+/-SD) decreased (47 +/- 6 kg/m2 to 37 +/- 5 kg/m2 ), body fat went from 48% +/- 6% to 40% +/- 6% fat, and fat-free mass went from 67 +/- 9 kg to 60 +/- 9 kg. In absolute terms, RMR and TDEE both decreased significantly (1,730 +/- 278 kcal/d vs. 1,430 +/- 200 kcal/d and 2,879 +/- 544 kcal/d vs. 2,369 +/- 304 kcal/d), and the achieved energy balance was -1,293 +/- 355 kcal/d. Sixteen of these participants underwent repeated measures at ~24 months; TDEE decreased 6 months postoperatively (2,957 +/- 540 kcal/d to 2,423 +/- 324 kcal/d; P = 0.0003), but at ~24 months, TDEE (2,602 +/- 471 kcal/d) was not significantly different compared with month 6. The average negative energy balance from baseline to month 24 was -379 +/- 131 kcal/d. CONCLUSIONS: RMR and TDEE fall precipitously in the first 6 months after bariatric surgery, but these adaptive changes were no longer significant after 2 years. PMID- 29604194 TI - Canned sea fish marketed in Serbia: their zinc, copper, and iron levels and contribution to the dietary intake. AB - The aim of this study was to determine the levels of Zn, Cu, and Fe in three canned fish species marketed Serbia to see if they meet recommended daily intake requirements or exceed safety limits. We collected a total of 207 samples of canned tuna, sardine, and mackerel, in oil or tomato sauce and analysed them with inductively coupled plasma mass spectrometry (ICP-MS) after acid digestion. The highest levels were obtained for Zn (15.1 mg kg-1) and Cu (1.37 mg kg-1) in sardine in oil and tomato sauce, respectively, and for Fe (18.98 mg kg-1) in mackerel in tomato sauce. Our results keep within the ranges reported by several national food databases and available literature data, with a few exceptions. Our findings also single out canned sardines as the richest source of the three essential elements combined. The estimated daily intake (EDI) of the three essential elements, however, was subpar, and ranged between 0.14 % and 0.72 % of the recommended dietary allowance (RDA) for Zn, Cu, and Fe. PMID- 29604195 TI - Role of gene polymorphisms in vitamin D metabolism and in multiple sclerosis. AB - Multiple sclerosis (MS) is a complex inflammatory disease of the central nervous system (CNS) resulting in neurological impairment and disability. There is evidence that adequate vitamin D levels may lower the risk of MS development. The aetiology of MS is complex and involves both genetic and environmental factors. In fact, not one but several genes are believed to lead to the disease. As for environmental factors, one of the most important risk factors is vitamin D deficiency, which, in turn, is closely related to gene polymorphisms that play a role in vitamin D metabolism and regulation. However, information about these gene polymorphisms is quite contradictory. The aim of this review is to discuss the association between some of the vitamin D-related gene variants and MS. PMID- 29604196 TI - Occupational exposure to blood and bodily fluids among healthcare workers in Serbian general hospitals. AB - The risk of occupational bloodborne infections (HBV, HCV, and HIV) among healthcare workers remains a serious issue in developing countries. The aim of this study was to estimate occupational exposure to bloodborne infections among general hospital workers in Serbia. This cross-sectional study was conducted in the spring of 2013 and included 5,247 healthcare workers from 17 general hospitals. The questionnaire was anonymous, self-completed, and included sociodemographic information with details of blood and bodily fluid exposure over the career and in the previous year (2012). Significant predictors of sharps injuries were determined with multiple logistic regressions. The distribution of accidents in 2012 was equal between the genders (39 %), but in entire career it was more prevalent in women (67 %). The most vulnerable group were nurses. Most medical doctors, nurses, and laboratory technicians reported stabs or skin contact with patients' blood/other bodily fluid/tissue as their last accident. Healthcare workers from the north/west part of the country reported a significantly lower number of accidents over the entire career than the rest of the country (p<0.001). The south of Serbia stood out as the most accident-prone in 2012 (p=0.042). PMID- 29604197 TI - Glutathionylation: a regulatory role of glutathione in physiological processes. AB - Glutathione (gamma-glutamyl-cysteinyl-glycine) is an intracellular thiol molecule and a potent antioxidant that participates in the toxic metabolism phase II biotransformation of xenobiotics. It can bind to a variety of proteins in a process known as glutathionylation. Protein glutathionylation is now recognised as one of important posttranslational regulatory mechanisms in cell and tissue physiology. Direct and indirect regulatory roles in physiological processes include glutathionylation of major transcriptional factors, eicosanoids, cytokines, and nitric oxide (NO). This review looks into these regulatory mechanisms through examples of glutathione regulation in apoptosis, vascularisation, metabolic processes, mitochondrial integrity, immune system, and neural physiology. The focus is on the physiological roles of glutathione beyond biotransformational metabolism. PMID- 29604198 TI - Evaluation of breath alcohol analysers by comparison of breath and blood alcohol concentrations. AB - The main goal of this study was to determine the reliability of hand-held breath alcohol analysers currently approved for roadside screening of traffic offenders. The first part of the study included a retrospective data analysis of 714 offence records collected in 2011. Blood alcohol concentrations (BAC) obtained from the offenders 0-303 min after the police had screened them for breath alcohol concentration (BrAC) were back-calculated (cBAC) to assess the accuracy of breathalyser screening. All participants were in the alcohol elimination phase, and our analyses did not reveal any significant differences between cBAC and BrAC. To verify our findings, we performed a controlled drinking study that involved 63 healthy volunteers who consumed alcoholic beverages to simulate real drinking conditions. Immediately after alcohol consumption, BrAC was determined with a Drager breath alcohol analyser model 6810, and 29 participants gave blood and urine sample for concomitant BAC analysis one hour later. BAC and urine alcohol concentrations were determined with headspace gas chromatography. Again, we found no significant differences between BrAC and BAC. These results confirmed the high reliability of breath alcohol analysers for measuring BrAC as long as police officers perform the measurements according to the manufacturer's instructions. PMID- 29604199 TI - Antimycobacterial potential of the juniper berry essential oil in tap water. AB - Mycobacterium avium complex-related diseases are often associated with poorly maintained hot water systems. This calls for the development of new control strategies. The aim of this study was to investigate the activity of essential oils (EOs) from the Mediterranean plants, common juniper, immortelle, sage, lavandin, laurel, and white cedar against Mycobacterium avium ssp. avium, Mycobacterium intracellulare, and Mycobacterium gordonae in culturing broth and freshwater as their most common habitat. To do that, we developed a new method of water microdilution to determine their minimal effective concentrations (MEC). The most active EO was the one from the common juniper with the MEC of 1.6 mg mL 1. Gas chromatography / mass spectrometry the juniper EO identified monoterpenes (70.54 %) and sesquiterpenes (25.9 %) as dominant component groups. The main monoterpene hydrocarbons were alpha-pinene, sabinene, and beta-pinene. The juniper EO significantly reduced the cell viability of M. intracellulare and M. gordonae at MEC, and of M. avium at 2xMEC. Microscopic analysis confirmed its inhibitory effect by revealing significant morphological changes in the cell membrane and cytoplasm of all three bacteria. The mode of action of the juniper EO on the cell membrane was confirmed by a marked leakage of intracellular material. Juniper EO has a great practical potential as a complementary or alternative water disinfectant in hot water systems such as baths, swimming pools, spa pools, hot tubs, or even foot baths/whirlpools. PMID- 29604200 TI - The efficiency of lactic acid bacteria against pathogenic fungi and mycotoxins. AB - Mycotoxins are produced by some fungal species of the genera Aspergillus, Penicillium, and Fusarium and are common contaminants of a wide range of food commodities. Numerous strategies are used to minimise fungal growth and mycotoxin contamination throughout the food chain. This review addresses the use of lactic acid bacteria, which can inhibit fungal growth and participate in mycotoxin degradation and/or removal from contaminated food. Being beneficial for human and animal health, lactic acid bacteria have established themselves as an excellent solution to the problem of mycotoxin contamination, yet in practice their application in removing mycotoxins remains a challenge to be addressed by future research. PMID- 29604201 TI - Discrepancies in the evaluation of incapacity for work in a patient with epidermolysis bullosa acquisita between public pension fund and occupational medicine expert raise the issue of competencies. AB - Abstrat A 50-year-old female patient suffering from a severe form of epidermolysis bullosa acquisita (EBA) took legal action against the Croatian Pension Insurance Institute (CPII) in an attempt to overturn their assessment that she was no longer capable of working as a seamstress but still capable of doing administrative jobs. Her claim was that she was not capable of doing any job at all. She was first diagnosed EBA in 2000, and the disease progressed slowly with intermittent remissions. In 2012, skin erosions appeared on her feet, followed by the loss of all toenails and lesions and infiltrations on the tongue and oral mucosa. Her whole body was covered in oozing wounds, she was in pain, and parts of her skin would stick to fabric while changing clothes or bandages. The most recent findings showed oesophageal stricture. She can consume only liquid food and is on the waiting list for receiving a feeding tube. The occupational health expert witness confirmed that the patient was generally incapable of work and was fighting her life. The judge and CPII lawyers fully accepted this report and the earlier assessment was overturned. To avoid incompetent assessments of working (in)capacity in the future, CPII and similar institutions should engage occupational medicine specialists to work in their assessment teams. PMID- 29604202 TI - Synthetic DNA filaments: from design to applications. AB - Natural filaments, such as microtubules and actin filaments, are fundamental components of the cell. Despite their relatively simple linear structure, filaments play a number of crucial roles in living organisms, from scaffolding to cellular adhesion and motility. The mechanical properties of natural filaments mostly rely on the structural features of the component units and on the way they are connected together, thus providing an ideal molecular model for emulation purposes. In this review, we describe the progresses done in this field using DNA for the rational design of synthetic filamentous-like materials with tailored structural and physical characteristics. We firstly survey the strategies that have been adopted until now for the construction of individual DNA building components and their programmable self-assembly into linear oligomeric structures. We then describe the theoretical models of polymer elasticity applied to calculate the bending strength of DNA filaments, expressed in terms of persistence length. Finally, we report some of the most exciting examples of truly biomimetic DNA filaments, which are capable of mimicking not only the sophisticated structural features of their natural counterparts but also their responsiveness to external stimuli, thus resulting in active motion and growing networks between distant loci. PMID- 29604203 TI - The miRNA-kallikrein interaction: a mosaic of epigenetic regulation in cancer. AB - The kallikrein-related peptidases (KLKs) constitute a family of 15 highly conserved serine proteases with trypsin- and chymotrypsin-like activities. Dysregulated expression and/or aberrant activation of KLKs has been linked to various pathophysiological processes, including cancer. Many KLKs have been identified as potential cancer biomarkers. microRNAs (miRNAs) are a class of small non-coding RNAs that regulate gene expression by pairing to the 3' untranslated region (UTR) of complimentary mRNA targets. miRNAs are dysregulated in many cancers, including prostate, kidney and ovarian cancers. Several studies have shown that miRNAs are involved in the post-transcriptional regulation of KLKs. However, recent evidence suggests that miRNAs can also act as downstream effectors of KLKs. In this review, we provide an update on the epigenetic regulation of KLKs by miRNAs. We also present recent experimental evidence that supports the regulatory role of KLKs on miRNA networks. The potential diagnostic and therapeutic applications of miRNA-kallikrein interactions are also discussed. PMID- 29604204 TI - Kallikrein-related peptidases in lung diseases. AB - Human tissue kallikreins (KLKs) are 15 members of the serine protease family and are present in various healthy human tissues including airway tissues. Multiple studies have revealed their crucial role in the pathophysiology of a number of chronic, infectious and tumour lung diseases. KLK1, 3 and 14 are involved in asthma pathogenesis, and KLK1 could be also associated with the exacerbation of this inflammatory disease caused by rhinovirus. KLK5 was demonstrated as an influenza virus activating protease in humans, and KLK1 and 12 could also be involved in the activation and spread of these viruses. KLKs are associated with lung cancer, with up- or downregulation of expression depending on the KLK, cancer subtype, stage of tumour and also the microenvironment. Functional studies showed that KLK12 is a potent pro-angiogenic factor. Moreover, KLK6 promotes malignant-cell proliferation and KLK13 invasiveness. In contrast, KLK8 and KLK10 reduce proliferation and invasion of malignant cells. Considering the involvement of KLKs in various physiological and pathological processes, KLKs appear to be potential biomarkers and therapeutic targets for lung diseases. PMID- 29604206 TI - From molecules to patients: exploring the therapeutic role of soluble guanylate cyclase stimulators. AB - Nitric oxide (NO) signaling represents one of the major regulatory pathways for cardiovascular function. After the discovery of NO, awarded with the Nobel Prize in 1998, this signaling cascade was stepwise clarified. We now have a good understanding of NO production and NO downstream targets such as the soluble guanylyl cyclases (sGCs) which catalyze cGMP production. Based on the important role of NO-signaling in the cardiovascular system, intense research and development efforts are currently ongoing to fully exploit the therapeutic potential of cGMP increase. Recently, NO-independent stimulators of sGC (sGC stimulators) were discovered and characterized. This new compound class has a unique mode of action, directly binding to sGC and triggering cGMP production. The first sGC stimulator made available to patients is riociguat, which was approved in 2013 for the treatment of different forms of pulmonary hypertension (PH). Besides riociguat, other sGC stimulators are in clinical development, with vericiguat in phase 3 clinical development for the treatment of chronic heart failure (HF). Based on the broad impact of NO/cGMP signaling, sGC stimulators could have an even broader therapeutic potential beyond PH and HF. Within this review, the NO/sGC/cGMP/PKG/PDE-signaling cascade and the major pharmacological intervention sites are described. In addition, the discovery and mode of action of sGC stimulators and the clinical development in PH and HF is covered. Finally, the preclinical and clinical evidence and treatment approaches for sGC stimulators beyond these indications and the cardiovascular disease space, like in fibrotic diseases as in systemic sclerosis (SSc), are reviewed. PMID- 29604205 TI - Kallikrein-related peptidase 6 orchestrates astrocyte form and function through proteinase activated receptor-dependent mechanisms. AB - Kallikrein-related peptidase 6 (Klk6) is the most abundant serine proteinase in the adult central nervous system (CNS), yet we know little regarding its physiological roles or mechanisms of action. Levels of Klk6 in the extracellular environment are dynamically regulated in CNS injury and disease positioning this secreted enzyme to affect cell behavior by potential receptor dependent and independent mechanisms. Here we show that recombinant Klk6 evokes increases in intracellular Ca2+ in primary astrocyte monolayer cultures through activation of proteinase activated receptor 1 (PAR1). In addition, Klk6 promoted a condensation of astrocyte cortical actin leading to an elongated stellate shape and multicellular aggregation in a manner that was dependent on the presence of either PAR1 or PAR2. Klk6-evoked changes in astrocyte shape were accompanied by translocation of beta-catenin from the plasma membrane to the cytoplasm. These data are exciting because they demonstrate that Klk6 can influence astrocyte plasticity through receptor-dependent mechanisms. Furthermore, this study expands our understanding of the mechanisms by which kallikreins can contribute to neural homeostasis and remodeling and point to both PAR1 and PAR2 as new therapeutic targets to modulate astrocyte form and function. PMID- 29604207 TI - Hepatitis B virus X protein promotes proliferation of hepatocellular carcinoma cells by upregulating miR-181b by targeting ING5. AB - Hepatitis B virus X protein (HBx) played a key role in the development of hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC). Emerging evidence has demonstrated that miR-181b and the inhibitor of growth protein 5 (ING5) participated in the pathophysiological process. However, the regulatory mechanism of HBx remained unknown. The expression of miR-181b and ING5 in HCC tissues and cell lines were examined using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting. Cell viability was determined using the MTT method following HCC cell lines transfection. The interaction between miR-181b and ING5 was assessed by luciferase reporter assay. The nude mice tumor model was well established to evaluate the role and biological functions of HBx on the progression of HBV-related HCC in vivo. MiR-181b was upregulated and ING5 was downregulated in HCC tissues and cell lines. As suggested by the results from in vitro and in vivo experiments, HBx downregulates the expression of the miR-181b target gene ING5, resulting in the promotion of HCC cell proliferation. HBx accelerates proliferation activity of HCC cells by increasing miR-181b expression via targeting ING5, thereby influencing the progression of HBV-related HCC. PMID- 29604208 TI - The Role of the Innate Immune System on Pulmonary Infections. AB - Inhalation is required for respiration and life in all vertebrates. This process is not without risk, as it potentially exposes the host to environmental pathogens with every breath. This makes the upper respiratory tract is one of the most common routes of infection and one of the leading cause of morbidity and mortality in the world. To combat this, the lung relies on the innate immune defenses. In contrast to the adaptive immune system, the innate immune system does not require sensitization, previous exposure or priming to attack foreign particles. In the lung, the innate immune response starts with the epithelial barrier and mucus production, and is reinforced by phagocytic cells and T cells. These cells are vital for the production of cytokines, chemokines and anti microbial peptides that are critical or clearance of infectious agents. In this review, we discuss all aspects of the innate immune response, with a special emphasis on ways to target aspects of the immune response to combat antibiotic resistant bacteria. PMID- 29604209 TI - How different priming stimulations affect the corticospinal excitability induced by noninvasive brain stimulation techniques: a systematic review and meta analysis. AB - Noninvasive brain stimulation (NIBS) techniques could induce changes in corticospinal excitability (CSE) and neuroplasticity. These changes could be affected by different factors, including having a session of stimulation called the 'priming' protocol before the main stimulation session called the 'test' protocol. Literature indicates that a priming protocol could affect the activity of postsynaptic neurons, form a neuronal history, and then modify the expected effects of the test protocol on CSE indicated by the amplitude of transcranial magnetic stimulation-induced motor-evoked potentials. This prior history affects a threshold to activate the necessary mechanism stabilizing the neuronal activity within a useful dynamic range. For studying the effects of this history and related metaplasticity mechanisms in the human primary motor cortex (M1), priming test protocols are successfully employed. Thirty-two studies were included in this review to investigate how different priming protocols could affect the induced effects of a test protocol on CSE in healthy individuals. The results showed that if the history of synaptic activity were high or low enough to displace the threshold, the expected effects of the test protocol would be the reverse. This effect reversal is regulated by homeostatic mechanisms. On the contrary, the effects of the test protocol would not be the reverse, and at most we experience a prolongation of the lasting effects if the aforementioned history is not enough to displace the threshold. This effect prolongation is mediated by nonhomeostatic mechanisms. Therefore, based on the characteristics of priming test protocols and the interval between them, the expected results of priming test protocols would be different. Moreover, these findings could shed light on the different mechanisms of metaplasticity involved in NIBS. It helps us understand how we can improve the expected outcomes of these techniques in clinical approaches. PMID- 29604210 TI - A New Triage Method for Burn Disasters: Fast Triage in Burns (FTB). AB - BACKGROUND There are few triage methods based on patient age and extent of burn. However, in case of mass casualties, age might be hard to define. Burn segregation in mass-casualty accidents requires an easy, fast, and effective method. Triage in burns should also segregate casualties requiring treatment in burn centers. The aim of this study was to create a proprietary segregation algorithm dedicated to mass-casualty incidents. MATERIAL AND METHODS A retrospective analysis of 939 burned patients admitted to the Clinical Department of Burns, Plastic and Reconstructive Surgery, Military Institute of Medicine (MIM) in Warsaw and to the Center for the Treatment of Burns (CTB) in Siemianowice Slaskie in 2012 and 2013 was performed. The aim was to reveal which early factors could be used during segregation of burn victims in mass-casualty incidents on the battlefield and in civilian circumstances. Only easy and quick to-evaluate factors that can be examined without medical equipment and laboratory tests were used in creating the proprietary triage algorithm. RESULTS As a result of our study, we created an algorithm for fast triage in mass-casualty situations. The algorithm is based on parameters that can be easily evaluated without additional equipment. To create the algorithm, we used factors that had the strongest impact on mortality prediction in severely burned patients, in multifactor analysis: advanced age (p<0.001. OR=1.04), extent of the deep burn (p<0.001. OR=1.1), and low systolic arterial pressure (p<0.001. OR=0.96). CONCLUSIONS The FTB (Fast Triage in Burns) algorithm is a new triage method dedicated for massive burn events in civilian circumstances. The FTB algorithm is a simple, quick, and credible means of segregating burn victims. The algorithm is dedicated to use in pre-hospital care, during mass-casualty events both in civilian and battlefield circumstances. The aim is to be able to evaluate burn victims immediately, without access to medical equipment or additional tests and to evaluate indications for burn center care. It is a unique method designed to be used during segregation in isolated burn mass-casualty incidents. PMID- 29604212 TI - Shyness and sociability among extremely low birth weight survivors in the third and fourth decades of life: Associations with relationship status. AB - OBJECTIVE: We examined differences between the oldest known longitudinally followed cohort of extremely low birth weight survivors (ELBW; < 1,000 grams) and normal birth weight (NBW; > 2,500 grams) control participants on shyness and sociability, as well as conflicted shyness in adulthood across nearly a decade from their 20s to 30s. METHOD: 100 ELBW survivors and 88 NBW control participants self-reported on shyness and sociability using the Cheek and Buss (1981; Cheek, 1983) shyness and sociability scale. Participants also self-reported on their relationship status. A composite measure of conflicted shyness was also computed (i.e., the product of shyness and sociability). RESULTS: We found that, in their 30s, ELBW survivors reported higher shyness, but similar levels of sociability and conflicted shyness compared to controls. However, the ELBW group exhibited a greater decrease in conflicted shyness than NBW controls from their 20s to their 30s. Greater decreases in conflicted shyness in both groups were associated with being male, as well as with changes in relationship status such as finding a partner or getting married. CONCLUSIONS: Relatively higher shyness among ELBW survivors in adulthood suggests that stressful pre- and early postnatal environments may have lasting effects on personality development. However, later social influences such as relationship status may attenuate some types of shyness in adulthood. PMID- 29604211 TI - Terrestrial and marine Antarctic fungi extracts active against Xanthomonas citri subsp. citri. AB - : This study aims to obtain secondary metabolites extracts from filamentous fungi isolated from soil and marine sediments from Antarctica and assess its potential antibacterial activity on Xanthomonas citri subsp. citri, the agent of citrus canker. Metabolites production was conducted in Malt 2% broth at 15 degrees C for 20 days after which intracellular and extracellular extracts were obtained. The extracts were evaluated by cell viability assays through Resazurin Microtitre Assay. From 158 fungal extracts, 33 hampered bacterial growth in vitro. The average inhibition of the extracts obtained from terrestrial (soil) and marine (sediments) fungi was 94 and 97% respectively. These inhibition values were close to the average of 90% cell death for the positive control. MIC90 and MBC for the bioactive extracts were established. Isolates that produced active metabolites against the phytopathogen were identified using molecular taxonomy (ITS-rRNA sequencing) as: Pseudogymnoascus, Penicillium, Cadophora, Paraconiothyrium and Toxicocladosporium. Antarctic fungal strains isolated from terrestrial and marine sediments were able to produce secondary metabolites with antimicrobial activity against X. citri subsp. citri, highlighting the importance of these microbial genetic resources. These metabolites have potential to be used as alternatives for the control of this plant pathogen. SIGNIFICANCE AND IMPACT OF THE STUDY: This manuscript makes an impact on the study of micro-organisms from extreme habitats and their possible contribution in discovering new active molecules against pathogens of agricultural interest. Studies on the Antarctic continent and its communities have attracted the scientific community due to the long period of isolation and low levels of disturbance that surrounds the region. Knowing the potential of fungi in this region to produce active secondary metabolites, we aim to contribute to the discovery of compounds with antibacterial action in Xanthomonas citri subsp. citri, a plant pathogen present in several regions around the globe. PMID- 29604213 TI - Steal the light: shade vs fire adapted vegetation in forest-savanna mosaics. AB - Shade cast by trees, which suppresses grass growth, and fire fuelled by grass biomass, which prevents tree sapling establishment, are mutually exclusive and self-reinforcing drivers of biome distribution in savanna-forest mosaics. We investigated how shade depth, represented by canopy leaf area index (LAI), is generated by adult trees across savanna-forest boundaries and how a shade gradient filters tree functioning, and grass composition and biomass. Forest trees exerted greater shading through increased stem density and greater light interception per unit biomass. A critical transition at LAI c. 1.5 was linked to tree shifts from savanna to forest species, functional shifts from fire-tolerant to light-competitive species, and grass composition shifts from C4 to C3 pathways. A second transition to grass fuel loads too low to support fires, occurred at a lower canopy density (LAI > 0.5), accompanied by shifts in C4 subtype dominance. This pattern suggests that shade suppression of grass biomass is an essential first step for the maintenance of alternative stable states. PMID- 29604214 TI - Novelty seeking is linked to openness and extraversion, and can lead to greater creative performance. AB - OBJECTIVE: Novelty seeking (the tendency to explore things novel and unfamiliar) has been extensively researched in the clinical and health domains, but its effects on creative performance are largely unknown. We examined whether creativity-related personality traits (openness to experience and extraversion) are associated with novelty seeking, and whether novelty seeking is linked to, and facilitates, creativity. METHOD: In Study 1a (N = 230; Mage = 20; 64% females) and Study 1b (N = 421; Mage = 19; 65% females), we measured extraversion, openness to experience, novelty seeking, and divergent thinking. To provide causal evidence for the relation between novelty seeking and creativity, in Study 2 (N = 147; Mage = 27; 75% females), we manipulated people's motivation to seek novelty and then measured subsequent divergent thinking. RESULTS: In Studies 1a and 1b, we demonstrated that trait novelty seeking is associated with openness and extraversion, on the one hand, and divergent thinking on the other. In Study 2, the novelty seeking manipulation led to greater divergent thinking. CONCLUSIONS: We conclude that novelty seeking is linked to openness to experience and extraversion, and that it can lead to greater divergent thinking. PMID- 29604215 TI - Qualitative and quantitative screening of the beta-glucosidase activity in Saccharomyces cerevisiae and Saccharomyces uvarum strains isolated from refrigerated must. AB - : The aim of the present work was to screen a pool of 75 yeasts belonging to the species Saccharomyces cerevisiae and Saccharomyces uvarum in order to select the strains endowed with beta-glucosidase activity. The first screening was a qualitative assay based on chromogenic substrates (arbutin and esculin). The second screening was the quantitative evaluation of the beta-glucosidase activity via a p-nitrophenyl-beta-d-glucopyranoside assay. The measurement was performed on three different cell preparations, including the extracellular compartment, the cell lysates and the whole cells. This study pointed out the high frequency of beta-glucosidase activity in S. uvarum strains. In particular, we retrieved three promising S. uvarum strains, CRY14, VA42 and GRAS14, featuring a high enzymatic activity, exploitable for winemaking. SIGNIFICANCE AND IMPACT OF THE STUDY: In yeasts, beta-glucosidase activity has been extensively described, especially in non-Saccharomyces species, while there is only little evidence of this activity in strains belonging to the Saccharomyces species. In winemaking, beta-glucosidase plays essential roles in the hydrolysis of glyco-conjugated precursors and the release of active aromatic compounds. This study provides new insights into the beta-glucosidase activity in strains belonging to Saccharomyces cerevisiae and Saccharomyces uvarum species, which are the most important strains in wine industry. Our results point out a marked enzymatic activity for the tested S. uvarum strains. These strains could be exploited for their potential ability to enhance the aroma profiles of wine. In addition, they could be potential sources for the commercial production of enzymes to be applied in winemaking. PMID- 29604216 TI - Role of Sarcopenia in Nonalcoholic Fatty Liver Disease: Definition Is Crucially Important. PMID- 29604217 TI - Receipt of a pediatric liver offer as the first offer reduces waitlist mortality for adult women. AB - : In liver transplantation, adults with small stature have a greater susceptibility to waitlist mortality. This may explain the persistent waitlist mortality disparity that exists for women. We hypothesized that women who receive early offers of pediatric donor livers have improved waitlist survival, and that preferentially offering these organs to women mitigates this sex-based disparity. We analyzed donor liver offers from 2010 to 2014. Adult candidates who received a first offer that ranked within the first three match run positions from the donors' perspective were classified based on gender and whether they received a pediatric versus adult offer. We used competing risks regression to associate first offer type and waitlist mortality. A total of 8,101 waitlist candidates received a first offer that was ranked within the first three match run positions: 5.6% (293/5,202) men and 6.2% (179/2,899) women received a pediatric donor liver as their first offer. In multivariable analyses, compared with adult first men, adult-first women (subhazard ratio [sHR] 1.33, 95% confidence interval 1.17-1.51, P < 0.01) had an increased pretransplant mortality risk while pediatric-first men and pediatric-first women had noninferior risks of morality. Pediatric-to-adult and adult-to-adult recipients had similar risks of graft failure and posttransplant mortality. CONCLUSION: Our study examines allograft selection by donor age, recipient sex, and in effect size as a means to address disparities in waitlist mortality. We found that women who received a pediatric donor liver as the first offer had a lower risk of waitlist mortality compared with those who receive adult offers. Our data provides a simple approach to mitigating the increased waitlist mortality experienced by women by incorporating donor and recipient size as variables into organ allocation. (Hepatology 2018). PMID- 29604218 TI - Triarchic psychopathy and deficits in facial affect recognition. AB - OBJECTIVE: Impaired socialization due to amygdala dysfunction has been proposed as a factor underlying psychopathy. Supporting this hypothesis, some research indicates that psychopathy is associated with deficits in facial affect recognition, but other studies have failed to find such a relationship. This study investigated whether healthy young adults elevated in psychopathic traits displayed deficits in identifying facial affective displays overall as well as deficits specific to fear recognition. METHOD: Facial affect recognition was measured in a sample of 110 undergraduate men (n = 36) and women (n = 74). Participants completed the Triarchic Psychopathy Measure, and participants' eye gaze was measured using ASL Eye Trac 6. The facial affect recognition task was created using the NimStim facial expression stimuli. RESULTS: Individuals elevated in psychopathic traits did not display deficits in recognition of emotional faces overall or for fearful faces compared to individuals lower in psychopathic traits. However, meanness was negatively correlated with fear identification. CONCLUSIONS: We conclude that deficient emotion processing in psychopathic individuals may be specific to ambiguous affective expressions. We discuss implications for the study of psychopathy and emotion processing. PMID- 29604219 TI - Plasma Bile Acid Concentrations in Humans: Suggestions for Presentation in Tabular Form. PMID- 29604220 TI - Liver Angiopoietin-2 Is a Key Predictor of De Novo or Recurrent Hepatocellular Cancer After Hepatitis C Virus Direct-Acting Antivirals. AB - : Recent reports suggested that direct acting antivirals (DAAs) might favor hepatocellular carcinoma (HCC). In study 1, we studied the proangiogenic liver microenvironment in 242 DAA-treated chronic hepatitis C patients with advanced fibrosis. Angiopoietin-2 (ANGPT2) expression was studied in tissue (cirrhotic and/or neoplastic) from recurrent, de novo, nonrecurrent HCC, or patients never developing HCC. Circulating ANGPT2,vascular endothelial growth factor (VEGF), and C-reactive protein (CRP) were also measured. In study 2, we searched for factors associated with de novo HCC in 257 patients with cirrhosis of different etiologies enrolled in a dedicated prospective study. Thorough biochemical, clinical, hemodynamic, endoscopic, elastographic, and echo-Doppler work-up was performed in both studies. In study 1, no patients without cirrhosis developed HCC. Of 183 patients with cirrhosis, 14 of 28 (50.0%) with previous HCC recurred whereas 21 of 155 (13.5%) developed de novo HCC. Patients with recurrent and de novo HCCs had significantly higher liver fibrosis (LF) scores, portal pressure, and systemic inflammation than nonrecurrent HCC or patients never developing HCC. In recurrent/de novo HCC patients, tumor and nontumor ANGPT2 showed an inverse relationship with portal vein velocity (PVv; r = -0.412, P = 0.037 and r = 0.409, P = 0.047 respectively) and a positive relationship with liver stiffness (r = 0.526, P = 0.007; r = 0.525, P = 0.003 respectively). Baseline circulating VEGF and cirrhotic liver ANGPT2 were significantly related (r = 0.414, P = 0.044). VEGF increased during DAAs, remaining stably elevated at 3-month follow up, when it significantly related with serum ANGPT2 (r = 0.531, P = 0.005). ANGPT2 expression in the primary tumor or in cirrhotic tissue before DAAs was independently related with risk of HCC recurrence (odds ratio [OR], 1.137; 95% confidence interval [CI], 1.044-1.137; P = 0.003) or occurrence (OR, 1.604; 95% CI, 1.080-2.382; P = 0.019). In study 2, DAA treatment (OR, 4.770; 95% CI, 1.395 16.316; P = 0.013) and large varices (OR, 3.857; 95% CI, 1.127-13.203; P = 0.032) were independent predictors of de novo HCC. CONCLUSION: Our study indicates that DAA-mediated increase of VEGF favors HCC recurrence/occurrence in susceptible patients, that is, those with more severe fibrosis and splanchnic collateralization, who already have abnormal activation in liver tissues of neo angiogenetic pathways, as shown by increased ANGPT2. (Hepatology 2018; 00:000 000). PMID- 29604221 TI - Quantifying soil moisture impacts on light use efficiency across biomes. AB - Terrestrial primary productivity and carbon cycle impacts of droughts are commonly quantified using vapour pressure deficit (VPD) data and remotely sensed greenness, without accounting for soil moisture. However, soil moisture limitation is known to strongly affect plant physiology. Here, we investigate light use efficiency, the ratio of gross primary productivity (GPP) to absorbed light. We derive its fractional reduction due to soil moisture (fLUE), separated from VPD and greenness changes, using artificial neural networks trained on eddy covariance data, multiple soil moisture datasets and remotely sensed greenness. This reveals substantial impacts of soil moisture alone that reduce GPP by up to 40% at sites located in sub-humid, semi-arid or arid regions. For sites in relatively moist climates, we find, paradoxically, a muted fLUE response to drying soil, but reduced fLUE under wet conditions. fLUE identifies substantial drought impacts that are not captured when relying solely on VPD and greenness changes and, when seasonally recurring, are missed by traditional, anomaly-based drought indices. Counter to common assumptions, fLUE reductions are largest in drought-deciduous vegetation, including grasslands. Our results highlight the necessity to account for soil moisture limitation in terrestrial primary productivity data products, especially for drought-related assessments. PMID- 29604223 TI - Reply. PMID- 29604222 TI - BILIARY ATRESIA: Clinical and Research Challenges for the 21st Century. AB - Biliary atresia (BA) is a fibroinflammatory disease of the intra- and extrahepatic biliary tree. Without medical treatment, surgical hepatic portoenterosmy (HPE) may restore bile drainage, but progression of the intrahepatic disease results in complications of portal hypertension and advanced cirrhosis in most children. Recognizing that further progress in the field is unlikely without a better understanding of the underlying cause(s) and pathogenesis of the disease, the National Institutes of Diabetes and Digestive and Kidney Diseases sponsored a research workshop focused on innovative and promising approaches and on identifying future areas of research. Investigators discussed recent advances using gestational ultrasound and results of newborn BA screening with serum direct (conjugated) bilirubin that support a pre-natal onset of biliary injury. Experimental and human studies implicate the toxic properties of environmental toxins (e.g. biliatresone) and of viruses (e.g. CMV) to the biliary system. Among host factors, sequence variants in genes related to biliary development and ciliopathies, a notable lack of a cholangiocyte glycocalyx and of submucosal collagen bundles in the neonatal extrahepatic bile ducts, and an innate pro-inflammatory bias of the neonatal immune system contribute to an increased susceptibility to damage and obstruction following an epithelial injury. These advances form the foundation for a future research agenda focused on identifying the environmental and host factor(s) that cause BA, the potential use of population screening, studies of the mechanisms of prominent fibrosis in young infants, determinations of clinical surrogates of disease progression, and the design of clinical trials that target subgroups of patients with initial drainage following HPE. This article is protected by copyright. All rights reserved. PMID- 29604225 TI - Bedside reasoning on causes and mechanisms of diseases in the era of precision medicine: a timeless story? AB - This is a short reflection about bedside reasoning in clinical medicine, emphasizing the importance of distinguishing between causes and mechanisms of diseases. All complex/sporadic diseases result from interactions between a genetic predisposition and environmental factors. The main disease mechanisms resulting in clinical signs involve inflammation, insult of vessels or nerves, pharmacological or hormonal dysfunction, altered metabolism and overload, tumoral proliferations, intrinsic dysfunction, malformation and traumatism. Different mechanisms can occur during the same disease process. The practical consequences of identifying causes and mechanisms of diseases are illustrated. As a unifying concept, a very simple diagnostic flow chart that puts the patient, and not the disease, into centre of reflection and that bridges the gap between basic knowledge and patient care is provided. This diagnostic flow chart helps both the experienced physician and the medical student to perform a complete diagnostic process, addressing the specificities of the clinical findings, the pathogenesis and the causative factors, an aim that has become possible in the era of precision medicine. Two examples of patients with a dermatologic presentation highlight this diagnostic process, which paves the way to rational therapy and to translational research. PMID- 29604224 TI - Mutations in VPS13D lead to a new recessive ataxia with spasticity and mitochondrial defects. AB - OBJECTIVE: To identify novel causes of recessive ataxias, including spinocerebellar ataxia with saccadic intrusions, spastic ataxias, and spastic paraplegia. METHODS: In an international collaboration, we independently performed exome sequencing in 7 families with recessive ataxia and/or spastic paraplegia. To evaluate the role of VPS13D mutations, we evaluated a Drosophila knockout model and investigated mitochondrial function in patient-derived fibroblast cultures. RESULTS: Exome sequencing identified compound heterozygous mutations in VPS13D on chromosome 1p36 in all 7 families. This included a large family with 5 affected siblings with spinocerebellar ataxia with saccadic intrusions (SCASI), or spinocerebellar ataxia, recessive, type 4 (SCAR4). Linkage to chromosome 1p36 was found in this family with a logarithm of odds score of 3.1. The phenotypic spectrum in our 12 patients was broad. Although most presented with ataxia, additional or predominant spasticity was present in 5 patients. Disease onset ranged from infancy to 39 years, and symptoms were slowly progressive and included loss of independent ambulation in 5. All but 2 patients carried a loss-of-function (nonsense or splice site) mutation on one and a missense mutation on the other allele. Knockdown or removal of Vps13D in Drosophila neurons led to changes in mitochondrial morphology and impairment in mitochondrial distribution along axons. Patient fibroblasts showed altered morphology and functionality including reduced energy production. INTERPRETATION: Our study demonstrates that compound heterozygous mutations in VPS13D cause movement disorders along the ataxia-spasticity spectrum, making VPS13D the fourth VPS13 paralog involved in neurological disorders. Ann Neurol 2018. PMID- 29604227 TI - Synthesis of Highly Substituted 1,2-Diazetidin-3-ones, Small-Ring Scaffolds for Drug Discovery. AB - 1,2-Diazetidin-3-ones are readily accessible, small ring scaffolds that upon functionalization have the potential to produce diverse 3-dimensional structures for drug discovery. Thus, treatment of diazo hydrazides, obtained from simple hydrazides and malonyl half ester derivatives, followed by diazo transfer, with catalytic amounts of rhodium(II) acetate dimer results in intramolecular carbenoid N-H insertion to give 1,2-diazetidin-3-ones. Although subsequent functionalization reactions could be hampered by the lability of the 4-membered ring, a wide range of new derivatives was available by deprotection at N-1, and subsequent amide or urea formation. The structures of four four-membered rings was confirmed by X-ray crystallography; the compounds showed modest growth inhibitory activity in mammary carcinoma cells. PMID- 29604226 TI - Stem cell modeling of mitochondrial parkinsonism reveals key functions of OPA1. AB - OBJECTIVE: Defective mitochondrial function attributed to optic atrophy 1 (OPA1) mutations causes primarily optic atrophy and, less commonly, neurodegenerative syndromes. The pathomechanism by which OPA1 mutations trigger diffuse loss of neurons in some, but not all, patients is unknown. Here, we used a tractable induced pluripotent stem cell (iPSC)-based model to capture the biology of OPA1 haploinsufficiency in cases presenting with classic eye disease versus syndromic parkinsonism. METHODS: iPSCs were generated from 2 patients with OPA1 haploinsufficiency and 2 controls and differentiated into dopaminergic neurons. Metabolic profile was determined by extracellular flux analysis, respiratory complex levels using immunoblotting, and complex I activity by a colorimetric assay. Mitochondria were examined by transmission electron microscopy. Mitochondrial DNA copy number and deletions were assayed using long-range PCR. Mitochondrial membrane potential was measured by tetramethylrhodamine methyl ester uptake, and mitochondrial fragmentation was assessed by confocal microscopy. Exome sequencing was used to screen for pathogenic variants. RESULTS: OPA1 haploinsufficient iPSCs differentiated into dopaminergic neurons and exhibited marked reduction in OPA1 protein levels. Loss of OPA1 caused a late defect in oxidative phosphorylation, reduced complex I levels, and activity without a significant change in the ultrastructure of mitochondria. Loss of neurons in culture recapitulated dopaminergic degeneration in syndromic disease and correlated with mitochondrial fragmentation. INTERPRETATION: OPA1 levels maintain oxidative phosphorylation in iPSC-derived neurons, at least in part, by regulating the stability of complex I. Severity of OPA1 disease associates primarily with the extent of OPA1-mediated fusion, suggesting that activation of this mechanism or identification of its genetic modifiers may have therapeutic or prognostic value. Ann Neurol 2018;83:915-925. PMID- 29604229 TI - Reply. PMID- 29604228 TI - A study into the association between local recurrence rates and surgical resection margins in organ-sparing surgery for penile squamous cell cancer. AB - OBJECTIVE: To evaluate the significance of close surgical margins in organ sparing surgery (OSS) in the treatment of penile squamous cell carcinoma (pSCC) and clinicopathological factors that may influence local recurrence. PATIENTS AND METHODS: At our tertiary referral centre, between March 2001 and September 2012, 332 patients treated with OSS for pSCC had clear surgical margins. As the focus was the impact of close clear margins on local recurrence, patients with positive margins were excluded for the purpose of this study. Our overall positive margin rate for OSS in penile cancer is 7.6% (42 patients). Analysis was carried out on an on-going prospective database, including prospective accurate pathological recording of surgical margins. Patients underwent OSS after multidisciplinary team (MDT) discussion. Local recurrence was the primary outcome measured and Fisher's exact test and time-to-recurrence curves were used in the analysis. All local recurrences were scrutinised by the MDT and were categorised into: true recurrences or metachronous new occurrences (i.e. tumours arising from a background of penile intraepithelial neoplasia and forming on an epithelial surface not related to the site of initial resection). A multivariate analysis was also conducted to elucidate other factors influencing local recurrence. RESULTS: In all, 64% of the patients had a <5 mm clear deep surgical margin, with 16% clear by <1 mm. Overall, 4% of patients had a true local recurrence, with a median time to recurrence of 6 months. In all, 53% were due to embolic spread, with residual occult local disease accounting for 47%. There was a statistically significant relationship between cavernosal involvement (P = 0.014) and lymphovascular invasion (LVI; P = 0.001) and local recurrence. Although multivariate analysis revealed that the extent of clear margin was not a predictor of disease (P = 0.405), we found an increased risk of local recurrence in the clear margin cohort of <1 mm compared to those of >1 mm (P < 0.001). Those patients considered to have metachronous tumours were scrutinised by our MDT, and eight patients (2.4%) were found to have new occurrences. Our overall proportion of patients therefore needing further treatment for either new occurrences or recurrent disease after OSS stands at 6.4%. CONCLUSIONS: Overall the presence of local recurrent disease in OSS in our experience is low (4%). We report an embolic mechanism of local recurrence, strongly suggested by the presence of cavernosal involvement and LVI. We conclude that a deep clear margin of >1 mm has a very low risk of local recurrence in penile OSS. PMID- 29604230 TI - Prostaglandin F2alpha Receptor Modulation Affects Eye Development in Guinea Pigs. AB - Retinal arachidonic acid (ARA) levels in form-deprived eyes decline in guinea pigs. As prostaglandin F2alpha (PGF2alpha) is an ARA metabolite and endogenous agonist of prostaglandin F receptor (FP), we have been suggested that down regulation of PGF2alpha-FP receptor signalling pathway contributes to myopia onset. To test this hypothesis, this study determines whether: (i) retinal PGF2alpha levels decline during the development of form deprivation myopia (FDM) in guinea pigs; (ii) FP receptor agonism and antagonism alter emmetropization and myopia development. Pigmented guinea pigs were randomly assigned to normal vision and form-deprived groups. Ultraperformance liquid chromatography coupled with a mass spectrometer (UPLC-MS) measured retinal PGF2alpha levels 2 weeks after form deprivation (FD). The selective FP agonist, latanoprost acid (LAT) and its corresponding antagonist, AL8810, were peribulbarly injected into each group. An eccentric infrared photorefractor (EIR) monitored refraction. A-scan ultrasonography measured axial elongation (AL) and vitreous chamber depth (VCD). Tonometry measured the intraocular pressure (IOP). Retinal PGF2alpha levels declined in form-deprived eyes compared to those in normal eyes. Neither LAT nor AL8810 affected IOP with or without FD. On the other hand, after 4 weeks of daily 0.5 MUg AL8810 treatment, a myopia of -1.99 +/- 0.34 dioptre (D) developed, but LAT had no effect on emmetropization in a normal visual environment. Nevertheless, daily 30 MUg LAT treatment for 4 weeks inhibited FDM development by 41% (vehicle control: -8.39 +/- 0.45 D; LAT: -4.95 +/- 0.39 D; two-way anova with repeated measures, p < 0.05). Down-regulation of PGF2alpha-FP receptor signalling pathway may contribute to myopia onset as retinal PGF2alpha declined in myopic eyes and antagonism of FP receptor by AL8810 induced a myopic shift in normal vision environment. Meanwhile, up-regulation of this pathway by LAT inhibited FDM development. However, the mechanism underlying LAT-induced FDM inhibition needs further clarification. This uncertainty exists because its inhibition of FDM suggests that LAT strengthens the scleral framework which reduces axial elongation. On the other hand, its IOP-lowering effect is attributed to thinning and weakening the scleral framework in glaucoma treatment. PMID- 29604231 TI - Reframing the approach to patients with hepatocellular carcinoma: Longitudinal assessment with hazard associated with liver transplantation for HCC (HALTHCC) improves ablate and wait strategy. AB - : Patients with hepatocellular carcinoma (HCC) are screened at presentation for appropriateness of liver transplantation (LT) using morphometric criteria, which poorly specifies risk. Morphology is the crux of measuring tumor response to locoregional therapy (LRT) using modified Response Evaluation Criteria in Solid Tumors (mRECIST). This study investigated the utility of following a continuous risk score (hazard associated with liver transplantation in hepatocellular carcinoma; HALTHCC) to longitudinally assess risk. This multicenter, retrospective study from 2002 to 2014 enrolled 419 patients listed for LT for HCC. One cohort had LRT while waiting (n = 351), compared to the control group (n = 68) without LRT. Imaging studies (n = 2,085) were collated to laboratory data to calculate HALTHCC, MORAL, Metroticket 2.0, and alpha fetoprotein (AFP) score longitudinally. Cox proportional hazards evaluated associations of HALTHCC and peri-LRT changes with intention-to-treat (ITT) survival (considering dropout or post-LT mortality), and utility was assessed with Harrell's C-index. HALTHCC better predicted ITT outcome (LT = 309; dropout = 110) when assessed closer to delisting (P < 0.0001), maximally just before delisting (C-index, 0.742 [0.643 0.790]). Delta-HALTHCC post-LRT was more sensitive to changes in risk than mRECIST. HALTHCC score and peri-LRT percentage change were independently associated with ITT mortality (hazard ratio = 1.105 [1.045-1.169] per point and 1.014 [1.004-1.024] per percent, respectively). CONCLUSIONS: HALTHCC is superior in assessing tumor risk in candidates awaiting LT, and its utility increases over time. Peri-LRT relative change in HALTHCC outperforms mRECIST in stratifying risk of dropout, mortality, and recurrence post-LT. With improving estimates of post LT outcomes, it is reasonable to consider allocation using HALTHCC and not just waiting time. Furthermore, this study supports a shift in perspective, from listing to allocation, to better utilize precious donor organs. (Hepatology 2018). PMID- 29604232 TI - Clinical Course of Hepatic Artery Thrombosis After Living Donor Liver Transplantation Using the Right Lobe. AB - Hepatic artery thrombosis (HAT) can result in biliary tree necrosis and graft loss, necessitating retransplantation. The most effective treatment approach is still controversial. This study was performed to review the outcomes of HAT after living donor liver transplantation (LDLT) and to clarify the feasibility of different strategies. From May 1996 to August 2017, LDLT using the right lobe was performed in 827 adult patients in our center. Our technique of hepatic artery (HA) reconstruction is end-to-end anastomosis under a microscope (10*). Diagnosis of HAT was performed using Doppler sonography and computed tomography (CT) angiography. HAT was initially treated with surgical or endovascular procedure, and retransplantation was considered according to the graft condition. Among the 827 cases of LDLT using the right lobe, HAT occurred in 16 (1.9%) cases within 1 month after transplantation. Within the first week, 7 of these HAT cases (43.8%) occurred (early HAT), while the remaining 9 cases (56.2%) occurred between the first week and 1 month (late HAT). The incidence of graft failure was high in early HAT (42.9%), and the frequency of biliary complications was high in late HAT (77.8%). The success rate of HA recanalization was 62.5% (10/16): 100% (5/5) after reoperation and 45.5% (5/11) after the endovascular procedure. Of the patients in whom treatment failed in late HAT (n = 5), 4 underwent neovascularization during observation. A total of 5 patients underwent graft failure, and 3 of these patients underwent repeat liver transplantation (LT). Mortality occurred in 3 patients, including 1 in the surgical group and 2 in the endovascular group. In conclusion, early diagnosis and aggressive treatment of HAT are necessary to avoid graft failure, and the choice of treatment depends on various factors. Although further studies are required, early HAT requires preparation for graft failure, while late HAT requires treatment for biliary complications. PMID- 29604233 TI - Permeability of the blood-brain barrier predicts no evidence of disease activity at 2 years after natalizumab or fingolimod treatment in relapsing-remitting multiple sclerosis. AB - OBJECTIVE: To investigate whether blood-brain barrier (BBB) permeability, as measured by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), can provide early detection of suboptimal treatment response in relapsing-remitting multiple sclerosis (RRMS). METHODS: Thirty-five RRMS patients starting on fingolimod or natalizumab, drugs with a common effect of decreasing lymphocyte influx into the central nervous system, were scanned with DCE-MRI at 3T prior to treatment and at 3 and 6 months posttreatment. We calculated the influx constant Ki , a measure of BBB permeability, using the Patlak model. Suboptimal treatment response was defined as loss of no evidence of disease activity (NEDA) status after 2 years of treatment. RESULTS: Subjects with loss of NEDA status at 2 years had a 51% higher mean Ki in normal-appearing white matter (NAWM) measured after 6 months of treatment, compared to subjects with maintained NEDA status (mean difference = 0.06ml/100g/min, 95% confidence interval [CI] = 0.02-0.09, p = 0.002). Ki in NAWM at 6 months was a good predictor of loss of NEDA status at 2 years (area under the curve = 0.84, 95% CI = 0.70-0.99, p = 0.003), and a value above 0.136ml/100/g/min yielded an odds ratio of 12.4 for suboptimal treatment response at 2 years, with a sensitivity of 73% and a specificity of 82%. INTERPRETATION: Our results suggest that BBB permeability as measured by DCE-MRI reliably predicts suboptimal treatment response and is a surrogate marker of the state of health of the BBB. We find a predictive threshold for disease activity, which is remarkably identical in clinically isolated syndrome as previously reported and established RRMS as investigated here. Ann Neurol 2018;83:902-914. PMID- 29604234 TI - Increased skeletal muscle mitochondrial free radical production in peripheral arterial disease despite preserved mitochondrial respiratory capacity. AB - NEW FINDINGS: What is the central question of this study? What is the degree to which skeletal muscle mitochondria-derived reactive oxygen species (ROS) production is linked to impaired skeletal muscle function in patients with early stage peripheral arterial disease (PAD) and what is the impact on mitochondrial respiratory capacity? What is the main finding and its importance? This is the first study to document increased mitochondria-derived reactive oxygen species production associated with elevated intramuscular oxidative stress, despite preserved mitochondrial respiratory function, in patients with PAD. Furthermore, systemic inflammation, mitochondria-derived ROS production and skeletal muscle oxidative stress were strongly correlated to disease severity, as indicated by ankle-brachial index, in patients with PAD. ABSTRACT: Skeletal muscle mitochondrial dysfunction, which is not fully explained by disease-related arterial occlusion, has been implicated in the pathophysiology of peripheral arterial disease (PAD). Therefore, this study comprehensively assessed mitochondrial respiratory function in biopsies from the gastrocnemius of 10 patients with PAD (Fontaine Stage II) and 12 healthy controls (HC). Intramuscular and systemic inflammation, mitochondria-derived reactive oxygen species (ROS) production, and oxidative stress were also assessed to better understand the mechanisms responsible for the proposed PAD-induced mitochondrial dysfunction. Interestingly, mitochondrial respiratory capacity, assessed as complex I (CI) and complex II (CII)-driven State 3 respiration, measured separately and in combination (State 3 CI+II), revealed no difference between the patients with PAD and the HC. However, mitochondria-derived ROS production was significantly elevated in PAD (HC: 1.0 +/- 0.9; PAD: 4.3 +/- 1.0 AU (mg tissue)-1 ). Furthermore, patients with PAD exhibited significantly greater concentrations of the pro-inflammatory markers tumour necrosis factor alpha in plasma (HC: 0.9 +/- 0.4; PAD: 2.0 +/- 0.3 pg ml-1 ) and interleukin 6 in both plasma (HC: 2.3 +/- 0.4; PAD: 4.3 +/- 0.5 pg ml-1 ) and muscle (~75% greater). Intramuscular oxidative stress, assessed by protein carbonyls and 4-hydroxynonenal, was significantly greater in PAD compared to HC. Ankle brachial index was significantly correlated with intramuscular inflammation, oxidative stress and mitochondria-derived ROS production. Thus, elevated intramuscular inflammation, oxidative stress and mitochondria-derived ROS production are likely to contribute to the pathophysiology of the skeletal muscle dysfunction associated with PAD, even in the presence of preserved mitochondrial respiratory function in this population. PMID- 29604235 TI - Phylogenomic analyses reveal a deep history of hybridization and polyploidy in the Neotropical genus Lachemilla (Rosaceae). AB - Hybridization, incomplete lineage sorting, and phylogenetic error produce similar incongruence patterns, representing a great challenge for phylogenetic reconstruction. Here, we use sequence capture data and multiple species tree and species network approaches to resolve the backbone phylogeny of the Neotropical genus Lachemilla, while distinguishing among sources of incongruence. We used 396 nuclear loci and nearly complete plastome sequences from 27 species to clarify the relationships among the major groups of Lachemilla, and explored multiple sources of conflict between gene trees and species trees inferred with a plurality of approaches. All phylogenetic methods recovered the four major groups previously proposed for Lachemilla, but species tree methods recovered different topologies for relationships between these four clades. Species network analyses revealed that one major clade, Orbiculate, is likely of ancient hybrid origin, representing one of the main sources of incongruence among the species trees. Additionally, we found evidence for a potential whole genome duplication event shared by Lachemilla and allied genera. Lachemilla shows clear evidence of ancient and recent hybridization throughout the evolutionary history of the group. Also, we show the necessity to use phylogenetic network approaches that can simultaneously accommodate incomplete lineage sorting and gene flow when studying groups that show patterns of reticulation. PMID- 29604236 TI - RNA-based analyses reveal fungal communities structured by a senescence gradient in the moss Dicranum scoparium and the presence of putative multi-trophic fungi. AB - Diverse plant-associated fungi are thought to have symbiotrophic and saprotrophic states because they can be isolated from both dead and living plant tissues. However, such tissues often are separated in time and space, and fungal activity at various stages of plant senescence is rarely assessed directly in fungal community studies. We used fungal ribosomal RNA metatranscriptomics to detect active fungal communities across a natural senescence gradient within wild collected gametophytes of Dicranum scoparium (Bryophyta) to understand the distribution of active fungal communities in adjacent living, senescing and dead tissues. Ascomycota were active in all tissues across the senescence gradient. By contrast, Basidiomycota were prevalent and active in senescing and dead tissues. Several fungi were detected as active in living and dead tissues, suggesting their capacity for multi-trophy. Differences in community assembly detected by metatranscriptomics were echoed by amplicon sequencing of cDNA and compared to culture-based inferences and observation of fungal fruit bodies in the field. The combination of amplicon sequencing of cDNA and metatranscriptomics is promising for studying symbiotic systems with complex microbial diversity, allowing for the simultaneous detection of their presence and activity. PMID- 29604238 TI - Integrated Approaches to Testing and Assessment. AB - The concept of Integrated Approaches to Testing and Assessment (IATA) has been advanced by the Organisation for Economic Cooperation and Development (OECD) member countries to enable a progressive shift from traditional chemical assessments largely based on the observation of the adverse effect in animal models, using individual methods or predefined batteries of standard toxicity tests, to assessment strategies integrating diverse lines of evidence. The flexible nature of IATA allows the inclusion of mechanistic data generated with non-animal methods and with new technologies (e.g. high-throughput and high content methods). The assessment process within IATA is typically conducted through weight-of-evidence which inevitably includes the elements of subjective expert judgement. For these reasons, IATA cannot be fully harmonized across sectors and countries. Nevertheless, some of the IATA components, such as defined approaches, which consist of a fixed data interpretation procedure (DIP) applied to data generated with a defined set of information sources, can be harmonized. The focus of this MiniReview is to provide an illustration of the differences between the IATA developed so far in the areas of regulatory toxicology, and ongoing activities related to the international harmonization of defined approaches that rely on multiple non-animal information sources. PMID- 29604237 TI - Expanding the donor pool: Donation after circulatory death and living liver donation do not compromise the results of liver transplantation. AB - Because of the shortfall between the number of patients listed for liver transplantation (LT) and the available grafts, strategies to expand the donor pool have been developed. Donation after circulatory death (DCD) and living donor (LD) grafts are not universally used because of the concerns of graft failure, biliary complications, and donor risks. In order to overcome the barriers for the implementation of using all 3 types of grafts, we compared outcomes after LT of DCD, LD, and donation after brain death (DBD) grafts. Patients who received a LD, DCD, or DBD liver graft at the University of Toronto were included. Between January 2009 through April 2017, 1054 patients received a LT at our center. Of these, 77 patients received a DCD graft (DCD group); 271 received a LD graft (LD group); and 706 received a DBD graft (DBD group). Overall biliary complications were higher in the LD group (11.8%) compared with the DCD group (5.2%) and the DBD group (4.8%; P < 0.001). The 1-, 3-, and 5-year graft survival rates were similar between the groups with 88.3%, 83.2%, and 69.2% in the DCD group versus 92.6%, 85.4%, and 84.7% in the LD group versus 90.2%, 84.2%, and 79.9% in the DBD group (P = 0.24). Furthermore, the 1-, 3-, and 5-year patient survival was comparable, with 92.2%, 85.4%, and 71.6% in the DCD group versus 95.2%, 88.8%, and 88.8% in the LD group versus 93.1%, 87.5%, and 83% in the DBD group (P = 0.14). Multivariate Cox regression analysis revealed that the type of graft did not impact graft survival. In conclusion, DCD, LD, and DBD grafts have similar longterm graft survival rates. Increasing the use of LD and DCD grafts may improve access to LT without affecting graft survival rates. Liver Transplantation 24 779-789 2018 AASLD. PMID- 29604239 TI - Personal Infant Feeding Experiences of Postpartum Nurses Affect How They Provide Breastfeeding Support. AB - OBJECTIVE: To describe the experiences of postpartum nurses when feeding their own infants and explore how these experiences influence the breastfeeding support they provide to new mothers. DESIGN: Qualitative research with interviews using dialogic data generation and analysis. SETTING: Large academic women and children's hospital in the Southern United States. PARTICIPANTS: Nine postpartum nurses who gave birth and breastfed or mixed-fed infants at any time in the past. METHODS: Individual, semistructured, face-to-face interviews. RESULTS: Participants described breastfeeding experiences similar to those of other women: some were positive, some negative. Most participants reported that they received less breastfeeding support than they needed during the maternity hospitalization. They attributed this to the fact that they were nurses. The infant feeding experiences of participants led them to promote breastfeeding in a more personal way and establish deeper connections with the mothers in their care. The practice of all participants changed because of their desire to prevent other mothers from experiencing the physical or psychological pain they experienced with breastfeeding. CONCLUSION: Personal infant feeding experiences shaped the breastfeeding practice of participants in unique and unpredictable ways. Nurses may benefit from increased breastfeeding education and support during their own maternity hospitalizations. Additionally, the inclusion of reflective narrative processes in breastfeeding education could encourage nurses to explore their personal, empirical, and clinical knowledge and construct an approach to breastfeeding practice that integrates these sources of information. PMID- 29604240 TI - Editorial Comment. PMID- 29604241 TI - Editorial Comment. PMID- 29604242 TI - Reply by Authors. PMID- 29604243 TI - How to Incorporate Quality Improvement and Patient Safety Projects in Your Training. PMID- 29604244 TI - Skills Acquired During My 1-Year AGA Editorial Fellowship. PMID- 29604245 TI - Curcumin protects rabbit articular chondrocytes against sodium nitroprusside induced apoptosis in vitro. AB - The preventive and therapeutic effects of curcumin on degeneration of articular (joint) cartilage diseases have rarely been investigated. In the present study, the protective effects of curcumin against sodium nitroprusside (SNP)-induced chondrocyte apoptosis were evaluated and the underlying molecular mechanisms were elucidated. Curcumin was used to as a co-treatment with SNP in chondrocytes, and changes occurring in the cells were observed and evaluated. It was shown using a cell counting kit-8 (CCK-8) assay that curcumin protected the viability of chondrocytes against SNP damage. NO (nitric oxide) from SNP could be scavenged by curcumin. Flow cytometry and Hoechst 33342 staining showed that curcumin not only inhibited the cell apoptosis in a concentration-dependent pattern but also ameliorated the SNP-induced nuclear chromatin damage and reduction of the mitochondrial membrane potential in chondrocytes. In SNP-treated chondrocytes, curcumin downregulated the expression of Bax and cleaved caspase-3 but upregulated the expression of Bcl-2, as shown by western blot. Meanwhile, curcumin administration also protected extracellular matrix (ECM) synthesis and prevented its degradation. Taken together, these results support the hypothesis that curcumin exerts its protective effect on chondrocytes against SNP-induced apoptosis, at least partly, via blocking the mitochondrial-dependent apoptotic pathway and maintaining the metabolic balance of ECM. Thus, curcumin may be a potential candidate to be used as a unique biological agent for the prevent and treatment of osteoarthritis (OA). PMID- 29604246 TI - In vitro 4-Aryloxy-7-chloroquinoline derivatives are effective in mono- and combined therapy against Leishmania donovani and induce mitocondrial membrane potential disruption. AB - The present study evaluates in vitro the effect of two synthetic compounds of the 7-chloro-4-aryloxyquinoline series, QI (C17H12ClNO3) and QII (C18H15ClN4O2S), on Leishmania donovani parasites. The results obtained demonstrate that these compounds are able to inhibit the proliferation of L. donovani promastigotes in a dose-dependent way (QI IC50 = 13.03 +/- 3.4 and QII IC50 = 7.90 +/- 0.6 MUM). Likewise, these compounds significantly reduced the percentage of macrophage infection by amastigotesand the number of amastigotes within macrophage phagolysosomes, the clinical relevant phase of these parasites. Compound QI showed an IC50 value of 0.66 +/- 0.2 MUM, while for derivative QII, the corresponding IC50 was 1.02 +/- 0.17 MUM. Interestingly, the amastigotes were more susceptible to the drug treatment when compared to promastigotes. Furthermore, no cytotoxic effect of these compounds was observed on the macrophage cell line at the concentrations tested. The combination of these compounds with miltefosine and amphotericin B on both parasite morphotypes was evaluated. The isobolograms showed a synergistic effect for both combinations; with a Fractional Inhibitory Concentration (FIC) Index lower than 1 for promastigotes and less than 0.3 for intracellular amastigotes. The effect of QI and QII on mitochondrial membrane potential was also studied. The combination of quinolone derivatives compounds with miltefosine and amphotericin B showed 5-8 fold stronger depolarization of membrane mitochondrial potential when compared to drugs alone. The present work validates the combination of drugs as an effective alternative to potentiate the action of anti-Leishmania agents and points to the quinoline compounds studied here as possible leishmanicidal drugs. PMID- 29604247 TI - Involvement of microRNAs-MMPs-E-cadherin in the migration and invasion of gastric cancer cells infected with Helicobacter pylori. AB - It has been found that Helicobacter pylori (H. pylori)is not only the main cause of gastric cancer, but also closely related to its metastasis. E-cadherin cleavage induced by matrix metalloproteinases (MMPs) plays an important role in the tumor metastasis. In the present study, we investigated the role of microRNAs MMPs-E-cadherin in migration and invasion of gastric cancer cells treated with H. pylori. The results showed that H. pylori induced migration and invasion of SGC 7901 cells with a down-regulation of E-cadherin expression, which were abolished by MMPs knock down, E-cadherin overexpression, mimics of miR128 and miR148a. MiR128/miR148a inhibitors restored MMP-3/MMP-7 expression, down-regulated E cadherin level, and accelerated cellular migration and invasion. This study suggests that H. pylori induces migration and invasion of gastric cancer cells through reduction of E-cadherin function by activation of MMP-3, - 7. The present results also suggest that the activated MMPs/E-cadherin pathway is related with down-regulation of miR128/miR148a in the human gastric cancer cells infected with H. pylori. PMID- 29604248 TI - miR-675 promotes odontogenic differentiation of human dental pulp cells by epigenetic regulation of DLX3. AB - In a previous study, we showed that microRNA-675 (miR-675) was significantly down regulated in patients with tricho-dento-osseous (TDO) syndrome. One of the main features of TDO syndrome is dentin hypoplasia. Thus, we hypothesize that miR-675 plays a role in dentin development. In this study, we determined the role of miR 675 in the odontogenic differentiation of human dental pulp cells (hDPCs). Stable overexpression and knockdown of miR-675 in hDPCs were performed using recombinant lentiviruses containing U6 promoter-driven miR-675 and short hairpin-miR675 expression cassettes, respectively. Alkaline phosphatase (ALP) assay, Alizarin red staining assay, quantitative polymerase chain reaction (qPCR), Western blot analysis, and immunofluorescent staining revealed the promotive effects of miR 675 on the odontogenic differentiation of hDPCs. Further, we found that miR-675 facilitates the odontogenic differentiation process of hDPCs by epigenetic regulation of distal-less homeobox (DLX3). Thus, for the first time, we determined that miR-675 regulates the odontogenic differentiation of hDPCs by inhibiting the DNA methyltransferase 3 beta (DNMT3B)-mediated methylation of DLX3. Our findings uncover an unanticipated regulatory role for miR-675 in the odontogenic differentiation of hDPCs by epigenetic changes in DLX3 and provide novel insight into dentin hypoplasia feature in TDO patients. PMID- 29604250 TI - Cord blood attached-segments are not homogeneous in post-thaw CD34+ cell viability and clonogenicity. PMID- 29604249 TI - Requirement of zebrafish pcdh10a and pcdh10b in melanocyte precursor migration. AB - Melanocytes derive from neural crest cells, which are a highly migratory population of cells that play an important role in pigmentation of the skin and epidermal appendages. In most vertebrates, melanocyte precursor cells migrate solely along the dorsolateral pathway to populate the skin. However, zebrafish melanocyte precursors also migrate along the ventromedial pathway, in route to the yolk, where they interact with other neural crest derivative populations. Here, we demonstrate the requirement for zebrafish paralogs pcdh10a and pcdh10b in zebrafish melanocyte precursor migration. pcdh10a and pcdh10b are expressed in a subset of melanocyte precursor and somatic cells respectively, and knockdown and TALEN mediated gene disruption of pcdh10a results in aberrant migration of melanocyte precursors resulting in fully melanized melanocytes that differentiate precociously in the ventromedial pathway. Live cell imaging analysis demonstrates that loss of pchd10a results in a reduction of directed cell migration of melanocyte precursors, caused by both increased adhesion and a loss of cell-cell contact with other migratory neural crest cells. Also, we determined that the paralog pcdh10b is upregulated and can compensate for the genetic loss of pcdh10a. Disruption of pcdh10b alone by CRISPR mutagenesis results in somite defects, while the loss of both paralogs results in enhanced migratory melanocyte precursor phenotype and embryonic lethality. These results reveal a novel role for pcdh10a and pcdh10b in zebrafish melanocyte precursor migration and suggest that pcdh10 paralogs potentially interact for proper transient migration along the ventromedial pathway. PMID- 29604252 TI - From the Price equation to the selection gradient in class-structured populations: a quasi-equilibrium route. AB - Recent studies in theoretical evolutionary ecology have emphasised two approaches to modelling evolution. On the one hand, models based on a separation of time scales rely on the concept of invasion fitness. On the other hand, models based on the Price equation track the dynamics of a trait average, coupled with a description of ecological dynamics. The aim of this article is to show that, in class-structured populations, both approaches yield the same expression for the selection gradient under weak selection. Although the result is not new, I propose an alternative route to its derivation using the dynamics of scaled measures of between-class phenotypic differentiation. Under weak selection, these measures of phenotypic differentiation can be treated as fast variables compared to the trait mean, which allows for a quasi-equilibrium approximation. This suggests a different approach to calculating weak selection approximations of evolutionary dynamics, and clarifies the links between short- and long-term perspectives on evolution in structured populations. PMID- 29604251 TI - Patients with Atopic Dermatitis Colonized with Staphylococcus aureus Have a Distinct Phenotype and Endotype. AB - Patients with atopic dermatitis (AD) are commonly colonized with Staphylococcus aureus (AD S. aureus+), but what differentiates this group from noncolonized AD patients (AD S. aureus-) has not been well studied. To evaluate whether these two groups have unique phenotypic or endotypic features, we performed a multicenter, cross-sectional study enrolling AD S. aureus+ (n = 51) and AD S. aureus- (n = 45) participants defined by the presence or absence of S. aureus by routine culture techniques and nonatopic, noncolonized control individuals (NA S. aureus-) (n = 46). Filaggrin (FLG) genotypes were determined, and disease severity (Eczema Area and Severity Index, Rajka-Langeland Severity Score, Investigator's Global Assessment score, Numerical Rating Scale, and Dermatology Life Quality Index) was captured. Skin physiology was assessed (transepidermal water loss [TEWL], stratum corneum integrity, hydration, and pH), and serum biomarkers were also measured. We found that AD S. aureus+ patients had more severe disease based on all scoring systems except itch (Numerical Rating Scale), and they had higher levels of type 2 biomarkers (eosinophil count, tIgE, CCL17, and periostin). Additionally, AD S. aureus+ patients had significantly greater allergen sensitization (Phadiatop and tIgE), barrier dysfunction (TEWL and stratum corneum integrity), and serum lactate dehydrogenase (LDH) than both the AD S. aureus- and NA S. aureus- groups. FLG mutations did not associate with S. aureus+ colonization. In conclusion, adult patients with AD who are colonized on their skin with S. aureus have more severe disease, greater type 2 immune deviation, allergen sensitization, barrier disruption, and LDH level elevation than noncolonized patients with AD. PMID- 29604253 TI - Erratum. PMID- 29604254 TI - Erratum. PMID- 29604256 TI - Undesirable impact on structure and stability of insulin on addition of (+) catechin hydrate with sugar. AB - Insulin (In) based formulation has been used over decades for the cure of In dependent diabetic patients, however, more attempts are still required to improve the remedial use of In. In this regard, the use of green tea has become widespread nowadays. However, it is unknown that (+)-catechin hydrate (CAT), a major component of green tea which enhances anti-diabetic activity of In, will or will not enhance the structure and stability of In if ingested with sugars. Interestingly, by using biophysical techniques, present study reveals the fact that the use of sugar during the intake of green tea extract may produce unwanted effects on In which may further lead to some disorders associated with In stability and also create obstacle in successful implications of In formulations. PMID- 29604257 TI - Leaf-age dependent response of carotenoid accumulation to elevated CO2 in Arabidopsis. AB - Carotenoids contribute to photosynthesis, photoprotection, phytohormone and apocarotenoid biosynthesis in plants. Carotenoid-derived metabolites control plant growth, development and signalling processes and their accumulation can depend upon changes in the environment. Elevated carbon dioxide (eCO2) often enhances carbon assimilation, early growth patterns and overall plant biomass, and may increase carotenoid accumulation due to higher levels of precursors from isoprenoid biosynthesis. Variable effects of eCO2 on carotenoid accumulation in leaves have been observed for different plant species. Here, we determined whether the variable response of carotenoids to eCO2 was potentially a function of leaf age and the impact of eCO2 on leaf development by growing Arabidopsis in ambient CO2 (400 ppm) and eCO2 (800 ppm). eCO2 increased plant leaf number, rosette area, biomass, seed yield and net photosynthesis. In addition, eCO2 increased carotenoid content by 10-20% in younger emerging leaves, but not in older mature leaves. Older leaves contained approximately 60% less total carotenoids compared to younger leaves. The age-dependent effect on carotenoid content was observed for cotyledon, juvenile and adult phase leaves. We conclude that younger leaves utilize additional carbon from enhanced photosynthesis in eCO2 to increase carotenoid content, yet older leaves have less capacity to store additional carbon into carotenoids. PMID- 29604255 TI - Genetic Ancestry for Sleep Research: Leveraging Health Inequalities to Identify Causal Genetic Variants. AB - Recent evidence has highlighted the health inequalities in sleep behaviors and sleep disorders that adversely affect outcomes in select populations, including African-American and Hispanic-American subjects. Race-related sleep health inequalities are ascribed to differences in multilevel and interlinked health determinants, such as sociodemographic factors, health behaviors, and biology. African-American and Hispanic-American subjects are admixed populations whose genetic inheritance combines two or more ancestral populations originating from different continents. Racial inequalities in admixed populations can be parsed into relevant groups of mediating factors (environmental vs genetic) with the use of measures of genetic ancestry, including the proportion of an individual's genetic makeup that comes from each of the major ancestral continental populations. This review describes sleep health inequalities in African-American and Hispanic-American subjects and considers the potential utility of ancestry studies to exploit these differences to gain insight into the genetic underpinnings of these phenotypes. The inclusion of genetic approaches in future studies of admixed populations will allow greater understanding of the potential biological basis of race-related sleep health inequalities. PMID- 29604258 TI - Novel Drosophila model for mitochondrial diseases by targeting of a solute carrier protein SLC25A46. AB - Mutations in SLC25A46 gene have been identified in mitochondrial diseases that are sometimes classified as Charcot-Marie-Tooth disease type 2, optic atrophy and Leigh syndrome. Human SLC25A46 functions as a transporter across the outer mitochondrial membrane. However, it is still unknown how the neurodegeneration occurring in these diseases relates to the loss of SLC25A46 function. Drosophila has CG5755 (dSLC25A46) as a single human SLC25A46 homolog. Here we established pan-neuron specific dSLC25A46 knockdown flies, and examined their phenotypes. Neuron specific knockdown of dSLC25A46 resulted in an impaired motility in both larvae and adults. Defects at neuromuscular junctions (NMJs), such as reduced synaptic branch length, decreased number and size of bouton, reduced density and size of active zone were also observed with the dSLC25A46 knockdown flies. Mitochondrial hyperfusion in synapse at NMJ, accumulation of reactive oxygen species and reduction of ATP were also observed in the dSLC25A46 knockdown flies. These results indicate that depletion of SLC25A46 induces mitochondrial defects accompanied with aberrant morphology of motoneuron and reduction of active zone that results in defect in locomotive ability. In addition, it is known that SLC25A46 mutations in human cause optic atrophy and knockdown of dSLC25A46 induces aberrant morphology of optic stalk of photoreceptor neurons in third instar larvae. Morphology and development of optic stalk of photoreceptor neurons in Drosophila are precisely regulated via cell proliferation and migration. Immunocytochemical analyses of subcellular localization of dSLC25A46 revealed that dSLC25A46 localizes not only in mitochondria, but also in plasma membrane. These observations suggest that in addition to the role in mitochondrial function, plasma membrane-localized dSLC25A46 plays a role in cell proliferation and/or migration to control optic stalk formation. The dSLC25A46 knockdown fly thus recapitulates most of the phenotypes in mitochondrial disease patients, providing a useful tool to study these diseases. PMID- 29604259 TI - Lectin-induced renal local complement activation is involved in tubular interstitial injury in diabetic nephropathy. AB - BACKGROUND: Complement has been suggested to be involved in diabetic nephropathy (DN), but the exact significance and underlying mechanisms remain unclear. Data about renal local complement activation in DN patients is scarce. The purpose of the study was to clarify the significance and mechanism of renal local complement activation in DN. METHODS: Sixty-two biopsy-proven DN patients were recruited. Renal expression of C1Q, factor B, C5b-9, MBL and MBL-associated serine protease 1 (MASP1) were detected and associated with the kidney damage. RESULTS: C5b-9, MBL and MASP1 was found to increase with the progression of DN. Especially, the level of C5b-9, MBL and MASP1 in tubular interstitium was closely associated with the damage degree of tubular interstitium. In addition, MBL and MASP1 co localized and their levels in tubular interstitium correlated with the levels of C5b-9 in tubules and tubular interstitium. CONCLUSION: Increased renal local complement activation was present in DN patients and might contribute to the kidney damage, especially tubular interstitial damage. MBL pathway might play an important role in renal tubular interstitial complement activation. Methods against complement activation or MBL pathway might be effective in reducing renal tubular interstitial damage in DN patients. PMID- 29604260 TI - Immune state correlates with histopathological level and reveals molluscan health in populations of Modiolus kurilensis by integral health index (IHI). AB - Quantitative analysis of the histopathological and immune parameters of bivalve Modiolus kurilensis collected from water areas with different level of ecotoxicological stress was performed. Significant differences between samples from polluted and non-polluted sites were revealed for total haemocyte count; percentage of agranulocytes; size and internal complexity of agranulocytes and granulocytes; phagocytic activity; percentage of NBT-positive cells; hemolytic activity and plasma protein concentration; percentage of the optical density of haemolymph major polypeptide bands at 55 kDa, 78 kDa, and 124 kDa; concretion coverage area in the kidney tubules; thickness of the tubular basement membrane; nephrocyte shape; and karyopyknosis of the kidneys; and hypervacuolisation; necrosis; karyopyknosis; haemocyte infiltration; fibrosis; and invasion of the digestive gland. Analysis of the global histopathological condition index based on the weighted indices also revealed that both the digestive gland and kidneys showed significantly greater histopathological changes in the bivalves collected from polluted water. Bivalve histopathology is an established tool in aquatic toxicology. However, it reflects a morphological picture of change, which, as a rule, can be clearly recorded only at the later stages of pathology, and in some cases, indicates an adaptation to stressors within the physiological norm. In this respect, a promising and highly sensitive biomarker of the functional state of bivalves, in terms of norm and pathology as well as their habitat, is the evaluation of immune status in combination with morphological changes. However, the use of different methods and scales of assessment and the diagnosis of biomarkers, characterised by different profiles of the stress response, makes it difficult to compare the results of different studies. We propose a reliable and powerful system for assessing the physiological state of bivalve molluscs, expressed in the integral health index (IHI) and based on the standardisation of the numerical values for all parameters that have significant differences between animals collected from impacted and non-impacted water areas. In our study, IHI calculated in three variants (for histopathological parameters, for immunological parameters, and in combination) showed the most significant differences in each of the cases, but the strongest difference (-4.07) was in calculating the total IHI, which included both the immune and histopathological parameters (p = 0.00005). PMID- 29604262 TI - An improved approach to estimate the avidity index of immunoglobulins: Evaluation of the method using IgG anti-Toxoplasma gondii. PMID- 29604261 TI - Afterload promotes maturation of human induced pluripotent stem cell derived cardiomyocytes in engineered heart tissues. AB - Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) grown in engineered heart tissue (EHT) can be used for drug screening, disease modeling, and heart repair. However, the immaturity of hiPSC-CMs currently limits their use. Because mechanical loading increases during development and facilitates cardiac maturation, we hypothesized that afterload would promote maturation of EHTs. To test this we developed a system in which EHTs are suspended between a rigid post and a flexible one, whose resistance to contraction can be modulated by applying braces of varying length. These braces allow us to adjust afterload conditions over two orders of magnitude by increasing the flexible post resistance from 0.09 up to 9.2 MUN/MUm. After three weeks in culture, optical tracking of post deflections revealed that auxotonic twitch forces increased in correlation with the degree of afterload, whereas twitch velocities decreased with afterload. Consequently, the power and work of the EHTs were maximal under intermediate afterloads. When studied isometrically, the inotropy of EHTs increased with afterload up to an intermediate resistance (0.45 MUN/MUm) and then plateaued. Applied afterload increased sarcomere length, cardiomyocyte area and elongation, which are hallmarks of maturation. Furthermore, progressively increasing the level of afterload led to improved calcium handling, increased expression of several key markers of cardiac maturation, including a shift from fetal to adult ventricular myosin heavy chain isoforms. However, at the highest afterload condition, markers of pathological hypertrophy and fibrosis were also upregulated, although the bulk tissue stiffness remained the same for all levels of applied afterload tested. Together, our results indicate that application of moderate afterloads can substantially improve the maturation of hiPSC-CMs in EHTs, while high afterload conditions may mimic certain aspects of human cardiac pathology resulting from elevated mechanical overload. PMID- 29604263 TI - Cerebrospinal fluid alpha-synuclein contributes to the differential diagnosis of Alzheimer's disease. AB - INTRODUCTION: The ability of Alzheimer's disease (AD) cerebrospinal fluid (CSF) biomarkers (amyloid beta peptide 1-42, total tau, and phosphorylated tau) to discriminate AD from related disorders is limited. Biomarkers for other concomitant pathologies (e.g., CSF alpha-synuclein [alpha-syn] for Lewy body pathology) may be needed to further improve the differential diagnosis. METHODS: CSF total alpha-syn, phosphorylated alpha-syn at Ser129, and AD CSF biomarkers were evaluated with Luminex immunoassays in 367 participants, followed by validation in 74 different neuropathologically confirmed cases. RESULTS: CSF total alpha-syn, when combined with amyloid beta peptide 1-42 and either total tau or phosphorylated tau, improved the differential diagnosis of AD versus frontotemporal dementia, Lewy body disorders, or other neurological disorders. The diagnostic accuracy of the combined models attained clinical relevance (area under curve ~0.9) and was largely validated in neuropathologically confirmed cases. DISCUSSION: Combining CSF biomarkers representing AD and Lewy body pathologies may have clinical value in the differential diagnosis of AD. PMID- 29604264 TI - European Prevention of Alzheimer's Dementia Registry: Recruitment and prescreening approach for a longitudinal cohort and prevention trials. AB - INTRODUCTION: It is a challenge to find participants for Alzheimer's disease (AD) prevention trials within a short period of time. The European Prevention of Alzheimer's Dementia Registry (EPAD) aims to facilitate recruitment by preselecting subjects from ongoing cohort studies. This article introduces this novel approach. METHODS: A virtual registry, with access to risk factors and biomarkers for AD through minimal data sets of ongoing cohort studies, was set up. RESULTS: To date, ten cohorts have been included in the EPAD. Around 2500 participants have been selected, using variables associated with the risk for AD. Of these, 15% were already recruited in the EPAD longitudinal cohort study, which serves as a trial readiness cohort. DISCUSSION: This study demonstrates that a virtual registry can be used for the preselection of participants for AD studies. PMID- 29604265 TI - Prediction of DNase I hypersensitive sites in plant genome using multiple modes of pseudo components. AB - DNase I hypersensitive sites (DHSs) are accessible chromatin zones hypersensitive to DNase I endonucleases in plant genome. DHSs have been used as markers for the presence of transcriptional regulatory elements. It is an important complement to develop computational methods to identify DHSs for discovering potential regulatory elements. To the best of our knowledge, several machine learning approaches have been proposed for the DHSs prediction, but there is still room for improvements. In this work, a new predictor called pDHS-WE was proposed for prediction of DHSs in plant genome by using weighted ensemble learning framework. Here, five classes of heterogeneous features were used to represent the sequences. Five random forest (RF) operators were constructed based on these five classes of features. The proposed pDHS-WE was formed by fusing the five individual RF classifiers into an ensemble predictor. Genetic algorithm was employed to obtain the weights of different classes of features. In the experiments, pDHS-WE obtained accuracy of 88.5%, sensitivity of 89.1%, specificity of 88.0%, and AUC of 0.958, which was more than 2.7%, 2%, 3.5% and 2.6% higher than state-of-the-art methods, respectively. The results suggested that pDHS-WE may become a useful tool for transcriptional regulatory elements analysis in plant genome. PMID- 29604266 TI - Patulin induced ROS-dependent autophagic cell death in Human Hepatoma G2 cells. AB - Patulin (PAT) is a secondary metabolite produced by certain species of Penicillium, Byssochlamys and Aspergillus. It has been shown to induce liver toxicity, but the possible molecular mechanisms are not completely elucidated. In our study, we treated Human Hepatoma G2 (HepG2) cells by 3-methyladenine (3-MA), an autophagosome formation inhibitor, and rapamycin, an autophagosome formation stimulator. The results showed that 3-MA protected the HepG2 cells against PAT cytotoxicity, while rapamycin decreased the cell viability. Thus, autophagy may play an important role in PAT-induced toxicity. To uncover the mechanism by which cells decrease proliferation and activation of autophagy, we found that collapses of mitochondrial membrane potential (DeltaPsim) and reactive oxygen species (ROS) level were increased under treatment with PAT. Further, we elucidated that the expression of p-Akt1 and p-MTOR was inhibited during this process. N-acetyl-l cysteine (NAC), a ROS inhibitor, protected against PAT-induced cytotoxicity, decreased the protein expression of LC3-II, and up-regulated the level of p-Akt1 and p-MTOR. These findings suggested that PAT-induced autophagic cell death was ROS-dependent in HepG2 cells. In conclusion, it is possible that PAT elicited autophagy through ROS-Akt1-MTOR pathway in the HepG2 cells. PMID- 29604267 TI - SERCA plays a crucial role in the toxicity of a betulinic acid derivative with potential antimalarial activity. AB - Malaria is one of the most significant infectious diseases that affect poor populations in tropical areas throughout the world. Plants have been shown to be a good source for the development of new antimalarial chemotherapeutic agents, as shown for the discovery of quinine and artemisinin derivatives. Our research group has been working with semisynthetic triterpene derivatives that show potential antimalarial activity toward different strains of Plasmodium falciparum by specifically modulating calcium pathways in the parasite. Promising results were obtained for nanomolar concentrations of the semisynthetic betulinic acid derivative LAFIS13 against the P. falciparum 3D7 strain in vitro, with a selectivity index of 18 compared to a mammalian cell line. Continuing these studies, we present here in vitro and in vivo toxicological evaluations of this compound, followed by docking studies with PfATP6, a sarco/endoplasmic reticulum Ca+2-ATPase (SERCA) protein. LAFIS13 showed an LD50 between 300 and 50 mg/kg, and the acute administration of 50 mg/kg (i.p.) had no negative effects on hematological, biochemical and histopathological parameters. Based on the results of the in vitro assays, LAFIS13 not exerted significant effects on coagulation parameters of human peripheral blood, but a hemolytic activity was verified at higher concentrations. According to the molecular docking study, the PfATP6 protein may be a target for LAFIS13, which corroborates its previously reported modulatory effects on calcium homeostasis in the parasite. Notably, LAFIS13 showed a higher selectivity for the mammalian SERCA protein than for PfATP6, thus impairing the selectivity between parasite and host. In summary, the direct interaction with calcium pumps and the hemolytic potential of the compound proved to be plausible mechanism of LAFIS13 toxicity. PMID- 29604268 TI - Mild aerobic training with blood flow restriction increases the hypertrophy index and MuSK in both slow and fast muscles of old rats: Role of PGC-1alpha. AB - AIMS: Existing evidence emphasize the role of mitochondrial dysfunction in sarcopenia which is revealed as loss of skeletal muscle mass and neuromuscular junction remodeling. We assessed the effect of low-intensity aerobic training along with blood flow restriction on muscle hypertrophy index, muscle-specific kinase (MuSK), a pivotal protein of the neuromuscular junction and Peroxisome proliferator-activated receptor gamma co-activator 1-alpha (PGC-1alpha) in aged male rats. MAIN METHODS: Animals groups were control (CTL), sham (Sh), leg blood flow restriction (BFR), exercise (Ex), sham + exercise (Sh + Ex), and BFR plus exercise (BFR + Ex) groups. The exercise groups were trained with low intensity exercise for 10 weeks. 48 h after the last training session, animals were sacrificed under anesthesia. Soleus and EDL muscles were isolated, hypertrophy index was estimated and MuSK and PGC-1alpha were measured by western blot method. KEY FINDINGS: Hypertrophy index enhanced in soleus and Extensor digitorum longus (EDL) muscles of BFR + Ex group (P < 0.01 versus CTL and Sh groups, and P < 0.001 versus other groups). The MuSK protein of soleus and EDL muscles increased in BFR + Ex group (P < 0.01 and P < 0.001, respectively) in comparison with CTL and Sh groups. In BFR + Ex group, the PGC-1alpha protein increased in both soleus and EDL (P < 0.001 compared to other groups). Also the PGC-1alpha of soleus muscle was higher in Ex and Sh + Ex groups versus CTL and Sh groups (P < 0.05). SIGNIFICANCE: Findings suggest that low endurance exercise plus BFR improves the MuSK and hypertrophy index of both slow and fast muscles of elderly rats probably through the rise of PGC-1alpha expression. PMID- 29604269 TI - Fisetin inhibits IL-31 production in stimulated human mast cells: Possibilities of fisetin being exploited to treat histamine-independent pruritus. AB - : Interleukin-31 (IL-31) is a recently discovered cytokine that is tightly linked to the pathogenesis of pruritus seen in atopic dermatitis. Flavonoids, like fisetin, are naturally occurring molecules with antioxidant, cytoprotective, and anti-inflammatory actions. AIM: the present study sought to investigate whether fisetin modulates IL-31 and histamine release in human mast cells (HMC-1). MAIN METHODS: HMC-1 cells were pretreated with fisetin at various doses and stimulated with phorbol-12-myristate 13-acetate and calcium ionophore A23187 (PI) for different time intervals. We evaluated IL-31 production and histamine release and signaling mechanism of the action of fisetin on IL-31 production. We also investigated the effects of fisetin on scratching behaviors in mice. KEY FINDINGS: Fisetin decreased PI-stimulated mRNA expression and production of IL-31 in HMC-1 cells. Fisetin inhibited PI-induced phosphorylation of mitogen-activated protein kinases that further suppressed nuclear factor (NF-kappaB) activation and translocation to the nucleus through the inhibition of IkappaB-alpha phosphorylation. Fisetin also prevented mast cell release of histamine in HMC-1 cells. Mice in-vivo studies show that fisetin reduced scratching behaviors in mice. SIGNIFICANCE: These pharmacological actions of fisetin provide new suggestions that fisetin can be of potential use for the treatment of pruritus that cannot be treated with histamine receptor blockers alone. PMID- 29604270 TI - Hesperidin suppresses the migration and invasion of non-small cell lung cancer cells by inhibiting the SDF-1/CXCR-4 pathway. AB - OBJECTIVE: The present study aimed to investigate the ability of hesperidin to suppress the migration and invasion of A549 cells, and to investigate the role of the SDF-1/CXCR-4 cascade in this suppression. METHODS: We performed a Transwell migration assay to measure the migratory capability of A549 cells treated with 0.5% DMSO, SDF-1alpha, AMD3100 or hesperidin. The SDF-1 level in the culture medium was determined by an enzyme-linked immunosorbent assay (ELISA) to detect whether different concentrations of hesperidin affected SDF-1 secretion. A wound healing assay was performed to determine the effects of different concentrations of hesperidin on the migration inhibition of A549, H460 and H1975 cells. Additionally, the effect of various hesperidin concentrations on the rate of A549 cell invasion and migration was examined with and without Matrigel in Transwell assays, respectively. Western blot analysis was used to evaluate the protein levels of CXCR-4, MMP-9, CK-19, Vimentin, p65, p-p65, p-IkappaB, IkappaB, p-Akt and Akt. RT-qPCR was used to detect the mRNA levels of CXCR-4, MMP-9, CK-19, Vimentin, p65, IkappaB, SDF-1 and Akt. RESULTS: The Transwell migration assay indicated that SDF-1alpha promoted A549 cell migration, while AMD3100 and hesperidin significantly inhibited the migratory capability. The wound-healing assay demonstrated that hesperidin treatment significantly reduced the rate of wound closure compared with the control group in a dose-dependent manner. Similarly, the migration and invasive abilities of A549 cells, H460 and H1975 cells treated with hesperidin were significantly decreased compared with the control group. The ELISA data suggested that hesperidin attenuated the secretion of SDF-1 from A549 cells in a dose-dependent manner. Furthermore, western blot analysis indicated that SDF-1alpha treatment significantly increased the levels of CXCR-4, p-p65, p-IkappaB and p-Akt in A549 cells. In contrast, AMD3100 or hesperidin reversed the effect induced by SDF-1alpha through decreasing the expression of CXCR-4. Subsequent RT-qPCR and western blot analyses also confirmed that hesperidin had a significant effect on the expression of EMT-related proteins, including MMP-9, CK-19 and Vimentin, in A549 cells. CONCLUSION: In summary, we demonstrated that hesperidin inhibited the migratory and invasive capabilities of A549 human non-small cell lung cancer cells by the mediation of the SDF-1/CXCR-4 signaling cascade, thus providing the foundation for the development of hesperidin as a safer and more effective anticancer drug for non small cell lung cancer. PMID- 29604271 TI - Endothelial modulation of a nitric oxide donor complex-induced relaxation in normotensive and spontaneously hypertensive rats. AB - We hypothesized that endothelium modulates relaxation induced by a nitric oxide (NO) donor ruthenium complex (TERPY, [Ru(terpy)(bdq)NO]3+) in mesenteric arteries of normotensive and spontaneously hypertensive (SHR) rats in different ways. We analyzed the mechanism involved in TERPY-induced relaxation in the second and third branches of mesenteric arteries and investigated how endothelium contributes to the TERPY vasodilator effect on SHR blood vessels. TERPY induced concentration-dependent relaxation in endothelium-denuded (E-) and endothelium intact (E+) mesenteric arteries of normotensive rats and SHR. Pretreatment with ODQ (which inhibits soluble guanylyl cyclase) or TEA (tetraethylammonium, which blocks potassium channels) significantly reduced the TERPY vasodilator effect on E- mesenteric arteries of normotensive rats and SHR. The presence of endothelium shifted the concentration-effect curves for TERPY in E+ mesenteric arteries of normotensive rats to the right. Conversely, the presence of endothelium shifted the concentration-effect curves for TERPY in the case of SHR E+ mesenteric arteries to the left, which suggested increased potency. L-NNA, a more selective endothelial NO synthase (eNOS) inhibitor, reduced TERPY potency in SHR. The presence of endothelium and notably of NOS contributed to the TERPY vasodilator action in SHR: TERPY promoted eNOS Ser1177 phosphorylation with consequent NO production and increased soluble guanylyl cyclase activity, which may have directly activated potassium channels. PMID- 29604272 TI - Resistin upregulates MUC5AC/B mucin gene expression in human airway epithelial cells. AB - Adipokines, a group of proteins including leptin, visfatin, resistin, and adiponectin, are produced by adipocytes. Among adipokines, resistin is implicated in insulin resistance and inflammatory response modulation. Mucus hypersecretion has been greatly linked to airway diseases, such as asthma, chronic obstructive pulmonary disease, and rhinosinusitis. Increasing evidence has indicated that adipokines, such as leptin and visfatin, play important regulatory roles in various biological processes involved in mucus secretion. However, the effects of resistin on mucin expression in human airway epithelial cells, as well as the underlying mechanisms, have not been investigated yet. We showed that resistin affected mucin expression in human airway epithelial cells via the mitogen activated protein kinase/nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB) pathway. Resistin increased MUC5AC and MUC5B expression in NCI H292 and primary human nasal epithelial cells. Additionally, it significantly increased the phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2), p38, and NF-kappaB. ERK1/2 and p38 specific inhibitors significantly attenuated resistin-induced MUC5AC/5B expression; however, NF-kappaB inhibitor reduced resistin-induced MUC5AC, but not MUC5B, expression. Knockdown of ERK1, ERK2, and p38 by ERK1, ERK2, and p38 small interfering RNA (siRNA), respectively, significantly blocked resistin-induced MUC5AC and MUC5B mRNA expression. In addition, NF-kappaB siRNA attenuated resistin-induced MUC5AC, but not MUC5B, expression. These results suggested that resistin induced MUC5AC and MUC5B expression via activation of different signaling pathways in human airway epithelial cells. PMID- 29604273 TI - Ubiquitin-specific protease 8 deubiquitinates Sec31A and decreases large COPII carriers and collagen IV secretion. AB - Nascent cargo proteins in the endoplasmic reticulum are transported to the Golgi by COPII carriers. Typical COPII vesicles are 60-70 nm in diameter, and much larger macromolecules, such as procollagen, are transported by atypical large COPII carriers in mammalian cells. The formation of large COPII carriers is enhanced by Cul3 ubiquitin ligase, which mono-ubiquitinates Sec31A, a COPII coat protein. However, the deubiquitinating enzyme for Sec31A was unclear. Here, we show that the deubiquitinating enzyme USP8 interacts with and deubiquitinates Sec31A. The interaction was mediated by the adaptor protein STAM1. USP8 overexpression inhibited the formation of large COPII carriers. By contrast, USP8 knockdown caused the accumulation of COPII coat proteins around the cis-Golgi, promoted the intracellular trafficking of procollagen IV from the endoplasmic reticulum to the Golgi, and increased collagen IV secretion. We concluded that USP8 deubiquitinates Sec31A and inhibits the formation of large COPII carriers, thereby suppressing collagen IV secretion. PMID- 29604274 TI - Suppression of tau propagation using an inhibitor that targets the DK-switch of nSMase2. AB - Targeting of molecular pathways involved in the cell-to-cell propagation of pathological tau species is a novel approach for development of disease-modifying therapies that could block tau pathology and attenuate cognitive decline in patients with Alzheimer's disease and other tauopathies. We discovered cambinol through a screening effort and show that it is an inhibitor of cell-to-cell tau propagation. Our in vitro data demonstrate that cambinol inhibits neutral sphingomyelinase 2 (nSMase2) enzyme activity in dose response fashion, and suppresses extracellular vesicle (EV) production while reducing tau seed propagation. Our in vivo testing with cambinol shows that it can reduce the nSMase2 activity in the brain after oral administration. Our molecular docking and simulation analysis reveals that cambinol can target the DK-switch in the nSMase2 active site. PMID- 29604275 TI - Oleuropein attenuates hydrogen peroxide-induced autophagic cell death in human adipose-derived stem cells. AB - Mesenchymal stem cells (MSCs) are multipotent progenitor cells with self-renewing properties; thus, transplanting functionally enhanced MSCs might be a promising strategy for cell therapy against ischemic diseases. However, extensive oxidative damage in ischemic tissue affects the cell fate of transplanted MSCs, eventually resulting in cell damage and autophagic cell death. Oleuropein (OLP) is a bioactive compound isolated from olives and olive oil that harbors antioxidant properties. This study aimed to investigate the potential cytoprotective effects of OLP against oxidative stress and autophagic cell death in MSCs. We found that short-term priming with OLP attenuated H2O2-induced apoptosis by regulating the pro-apoptotic marker Bax and the anti-apoptotic markers Bcl-2 and Mcl-1. Notably, OLP inhibits H2O2 -induced autophagic cell death by modulating autophagy-related death signals, including mTOR (mammalian target of rapamycin), ULK1 (unc-51 like autophagy activating kinase 1), Beclin-1, AMPK (AMP-activated protein kinase), and LC3 (microtubule-associated protein 1a/1b-light chain 3). Our data suggest that OLP might reduce H2O2-induced autophagy and cell apoptosis in MSCs by regulating both the AMPK-ULK axis and the Bcl-2-Mcl-1 axis. Consequently, short term cell priming with OLP might enhance the therapeutic effect of MSCs against ischemic vascular diseases, which provides an important potential improvement for emerging therapeutic strategies. PMID- 29604276 TI - A new vaccine targeting RANKL, prepared by incorporation of an unnatural Amino acid into RANKL, prevents OVX-induced bone loss in mice. AB - Bone homeostasis is maintained by a dynamic balance between osteoblastic bone formation and osteoclastic bone resorption. The receptor activator of nuclear kappaB ligand (RANKL) is essential for the function of the bone-resorbing osteoclasts, and targeting RANKL has been proved highly successful in osteoporosis patients. This study aimed to design a novel vaccine targeting RANKL and evaluate its therapeutic effects in OVX-induced bone loss model. Anti-RANKL vaccine was generated by incorporating the unnatural amino acid p nitrophenylalanine (pNO2Phe) into selected sites in the murine RANKL (mRANKL) molecule. Specifically, mutation of a single tyrosine residue Tyr234 (Y234) or Tyr240 (Y240) of mRANKL to pNO2Phe (thereafter named as Y234pNO2Phe or Y240pNO2Phe) induced a high titer antibody response in mice, whereas no significant antibody response was observed for the wild type mRANKL (WT mRANKL). The antiserum induced by Y234pNO2Phe or Y240pNO2Phe could efficiently prevent osteoclastogenesis in vitro. Moreover, immunization with Y234pNO2Phe or Y240pNO2Phe could also prevent OVX-induced bone loss in mice, suggesting that selected pNO2Phe-substituted mRANKL may pave the way for creating a novel vaccine to treat osteoporosis. PMID- 29604277 TI - JIP3 deficiency attenuates cardiac hypertrophy by suppression of JNK pathway. AB - Pathological cardiac hypertrophy is a leading cause of morbidity and mortality worldwide; however, our understanding of the molecular mechanisms revealing the disease is still unclear. In the present study, we suggested that c-Jun N terminal kinase (JNK)-interacting protein 3 (JIP3), involved in various cellular processes, played an essential role in regulating pathological cardiac hypertrophy through in vivo and in vitro studies. JIP3 was highly expressed in human hearts with hypertrophic cardiomyopathy (HCM), and in mouse hypertrophic hearts. Following, the wild type (WT) and JIP3-knockout (KO) mice subjected to aortic banding (AB) challenge were used as animal models with cardiac hypertrophy. The results showed that JIP3-KO mice after AB operation exhibited attenuated cardiac function, reduced fibrosis levels and decreased hypertrophic marker proteins, including atrial natriuretic peptides (Anp) and brain/B-type natriuretic peptides (Bnp) and beta-myosin heavy chain (beta-Mhc). Loss of JIP3 also ameliorated oxidative stress, inflammatory response, apoptosis and endoplasmic reticulum (ER) stress in hearts of mice after AB surgery. Consistently, the expressions of ER stress-related molecules, such as phosphorylated-alpha-subunit of the eukaryotic initiation factor-2 (eIF2alpha), glucose-regulated protein (GRP) 78 and C/-EBP homologous protein (CHOP), were markedly decreased by JIP3-deficiency in hearts of AB-operated mice. JNK and its down-streaming signal of p90rsk was highly activated by AB operation in WT mice, while being significantly reversed by JIP3-ablation. Intriguingly, the in vitro results showed that promoting JNK activation by using its activator of anisomycin enhanced AngII-stimulated ER stress, oxidative stress, apoptosis and inflammatory response in cardiomyocytes isolated from WT mice. However, JIP3-KO-attenuated these pathologies was rescued by anisomycin treatment in AngII-incubated cardiomyocytes. Together, the findings indicated that blockage of JIP3 could alleviate cardiac hypertrophy via inactivating JNK pathway, and thus might be a promising strategy to prevent pathological cardiac hypertrophy. PMID- 29604278 TI - Genetic overexpression of COMP-Ang1 impairs BM microenvironment and induces senescence of BM HSCs. AB - Supplemental Angiopoietin 1 (Ang1) exerts its therapeutic potential on microvascular regression-associated diseases, and this potential is linked with the function of hematopoietic stem cells (HSCs). However, the underlying mechanisms of the effect of enhanced angiogenesis on the modulation of HSCs are not yet defined. Here, we generated transgenic mice expressing Cartilage Oligomeric Matrix Protein (COMP)-Ang1 in keratin 14-expressing cells. The mutant animals expressed excessive angiogenic characteristics in the skin and bone marrow (BM) along with redder skin with more numerous and branched vessels compared with their wild-type (WT) littermates. The mutants displayed reduced long bone formation and osteoclast activity than did WT littermates and had fewer CD150+CD48-Lineage-Sca-1+c-Kit+ (LSK) cells in the BM. The mutants also exhibited greater senescence-associated (SA) beta-gal activity, p16INK4a protein expression, and superoxide anion levels in CD150+CD48-LSK cells in the BM. Furthermore, transplantation assay revealed that the mutant-derived LSK cells were inferior to the cells derived from WT littermate in inducing competitive repopulating capacity in the recipients. Collectively, our results demonstrate that persistent and prolonged administration of COMP-Ang1 by inducible transgenic expression mediates excessive angiogenesis in the body and impairs BM microenvironment, eventually leading to senescence of BM HSCs. PMID- 29604279 TI - Resveratrol protects HaCaT cells from ultraviolet B-induced photoaging via upregulation of HSP27 and modulation of mitochondrial caspase-dependent apoptotic pathway. AB - The skin is the outermost protective barrier between the internal and external environment in humans. Chronic exposure to ultraviolet (UV) radiation is a major cause of photoaging. Evidence suggests that resveratrol suppresses UVB-induced photoaging. In this study, we aimed to investigate the protective effects of resveratrol against UVB-induced photoaging in HaCaT cells and to determine the underlying mechanisms. Apoptosis of normal or HSP27-overexpressing HaCaT cells in the presence of UVB was analyzed by flow cytometry. The mRNA and protein expression levels were measured by quantitative real-time polymerase chain reaction (qRT-PCR) and western blotting. Resveratrol inhibited UVB-induced apoptosis by upregulating the expression of HSP27, reducing the production of proapoptotic proteins such as p65, Bax, and cleaved caspase-3, and promoting the expression of anti-apoptotic protein Bcl-2. However, UVB irradiation on HaCaT cells pretreated with resveratrol led to the upregulation of Bax, downregulation of Bcl-2, and promotion of p65 and caspase-3 activation after silencing of HSP27 gene. These findings suggest that the inhibition of HSP27 expression can partially reverse the anti-apoptotic effect of resveratrol and confirm that resveratrol can regulate HSP27 and thus control p65 and caspase-3 activation. In summary, resveratrol plays a role in photoprotection by upregulating HSP27 expression, increasing Bcl-2/Bax ratio, and inhibiting caspase-3 activity and p65 expression. PMID- 29604280 TI - Effect of a contact lens on mouse retinal in vivo imaging: Effective focal length changes and monochromatic aberrations. AB - For in vivo mouse retinal imaging, especially with Adaptive Optics instruments, application of a contact lens is desirable, as it allows maintenance of cornea hydration and helps to prevent cataract formation during lengthy imaging sessions. However, since the refractive elements of the eye (cornea and lens) serve as the objective for most in vivo retinal imaging systems, the use of a contact lens, even with 0 Dpt. refractive power, can alter the system's optical properties. In this investigation we examined the effective focal length change and the aberrations that arise from use of a contact lens. First, focal length changes were simulated with a Zemax mouse eye model. Then ocular aberrations with and without a 0 Dpt. contact lens were measured with a Shack-Hartmann wavefront sensor (SHWS) in a customized AO-SLO system. Total RMS wavefront errors were measured for two groups of mice (14-month, and 2.5-month-old), decomposed into 66 Zernike aberration terms, and compared. These data revealed that vertical coma and spherical aberrations were increased with use of a contact lens in our system. Based on the ocular wavefront data we evaluated the effect of the contact lens on the imaging system performance as a function of the pupil size. Both RMS error and Strehl ratios were quantified for the two groups of mice, with and without contact lenses, and for different input beam sizes. These results provide information for determining optimum pupil size for retinal imaging without adaptive optics, and raise critical issues for design of mouse optical imaging systems that incorporate contact lenses. PMID- 29604281 TI - Deletion of GLUT1 in mouse lens epithelium leads to cataract formation. AB - The primary energy substrate of the lens is glucose and uptake of glucose from the aqueous humor is dependent on glucose transporters. GLUT1, the facilitated glucose transporter encoded by Slc2a1 is expressed in the epithelium of bovine, human and rat lenses. In the current study, we examined the expression of GLUT1 in the mouse lens and determined its role in maintaining lens transparency by studying effects of postnatal deletion of Slc2a1. In situ hybridization and immunofluorescence labeling were used to determine the expression and subcellular distribution of GLUT1 in the lens. Slc2a1 was knocked out of the lens epithelium by crossing transgenic mice expressing Cre recombinase under control of the GFAP promoter with Slc2a1loxP/loxP mice to generate Slc2a1loxP/loxP;GFAP-Cre+/0 (LensDeltaGlut1) mice. LensDeltaGlut1 mice developed visible lens opacities by around 3 months of age, which corresponded temporally with the total loss of detectable GLUT1 expression in the lens. Spectral domain optical coherence tomography (SD-OCT) imaging was used to monitor the formation of cataracts over time. SD-OCT imaging revealed that small nuclear cataracts were first apparent in the lenses of LensDeltaGlut1 mice beginning at about 2.7 months of age. Longitudinal SD-OCT imaging of LensDeltaGlut1 mice revealed disruption of mature secondary fiber cells after 3 months of age. Histological sections of eyes from LensDeltaGlut1 mice confirmed the disruption of the secondary fiber cells. The structural changes were most pronounced in fiber cells that had lost their organelles. In contrast, the histology of the lens epithelium in these mice appeared normal. Lactate and ATP were measured in lenses from LensDeltaGlut1 and control mice at 2 and 3 months of age. At 2 months of age, when GLUT1 was still detectable in the lens epithelium, albeit at low levels, the amount of lactate and ATP were not significantly different from controls. However, in lenses isolated from 3-month-old LensDeltaGlut1 mice, when GLUT1 was no longer detectable, levels of lactate and ATP were 50% lower than controls. Our findings demonstrate that in vivo, the transparency of mature lens fiber cells was dependent on glycolysis for ATP and the loss of GLUT1 transporters led to cataract formation. In contrast, lens epithelium and cortical fiber cells have mitochondria and could utilize other substrates to support their anabolic and catabolic needs. PMID- 29604282 TI - Integration of a Physician Assistant Into an Ophthalmology Consult Service in an Academic Setting. AB - PURPOSE: To describe the impact of a physician assistant (PA) in an academic ophthalmology consult service. DESIGN: Evaluation research. METHODS: A PA was integrated into our ophthalmology consult service to enhance resident education. First-year resident annual surgical logs before and after the introduction of the PA were reviewed. Residents were anonymously surveyed for their perceptions regarding the impact of the PA integration on their residency experience. Consult wait time was compared for residents and the PA. Internal financial metrics for the PA were reviewed for a cost scenario analysis using 2016 national salary data for PAs. RESULTS: The PA made approximately 28 days per year for each first-year resident available for alternative clinical assignments, which resulted in a 75% increase in total first-year resident annual surgical volume. The majority of residents (93%) strongly agreed that having a PA improved both their ophthalmic education (by enabling them to spend time on other clinical assignments) and their service-to-education balance on the consult rotation. Adjusted median consult wait time for residents was 28 minutes longer (P < .001) than for the PA. A PA would likely need to see an average of 8-12 patients per day to be cost neutral to a consult service. CONCLUSIONS: Integrating a PA into an ophthalmology consult service can optimize the resident clinical service-to-education balance, reduce consult wait time, and be financially feasible. PAs trained in ophthalmology present a unique opportunity for all institutions that require clinical ophthalmology expertise. PMID- 29604283 TI - Challenging Management of Double Vision After Functional Endoscopic Sinus Surgery A Series of 6 Cases. AB - PURPOSE: To present 6 cases of orbital trauma, diplopia and strabismus after functional endoscopic sinus surgery (FESS). DESIGN: Retrospective observational case series. METHODS: The medical charts of suitable patients were reviewed for information on medical examination, imaging studies, the type of corrective surgery, and surgical outcomes. STUDY POPULATION: All patients with diplopia and strabismus after undergoing FESS who were treated or consulted at our institution between 2008 and 2017 were included. MAIN OUTCOME MEASURES: The presence and extent of strabismus and double vision at the end of follow-up. RESULTS: Six patients complained of diplopia after FESS; all of them had proven orbital trauma. In Cases 1-5, patients suffered medial rectus (MR) muscle transection and subsequent exotropia. Their prognosis was guarded despite prompt surgical intervention, and ranged from large exotropia when direct recovery of the MR was attempted, to primary gaze orthotropia but with minimal adduction capacity, during which vertical recti transposition was attempted. Patient 6 sustained transient diplopia, although all of his extraocular muscles appeared intact on imaging. His eye position and movement were completely resolved with conservative measures only. CONCLUSIONS: Our experience was that immediate recovery procedures to reattach the muscle in cases with proven transection of the MR muscle are futile, and that definitive corrective strabismus surgery (ie, vertical muscle transposition) has a better chance to achieve favorable results. PMID- 29604284 TI - Effect of Antituberculous Therapy on Uveitis Associated With Latent Tuberculosis. AB - PURPOSE: To describe the clinical features of patients with uveitis associated with latent tuberculosis (TB) and examine the effect of anti-TB treatment (ATT) on uveitis outcome. DESIGN: Retrospective cohort study. METHODS: One hundred ninety-nine eyes of 129 patients diagnosed with uveitis associated with latent TB were evaluated for recurrence of disease following treatment. Eighty-nine of the patients (69%) received ATT and information was gathered retrospectively regarding clinical outcome, vision, and treatment. Outcome measures included best corrected visual acuity (BCVA) and rate of disease recurrence. RESULTS: This study included 89 patients (69%) who received ATT and 40 patients who did not. The uveitis was treated with local and systemic anti-inflammatory and immunosuppressive therapy in all patients. The mean change in BCVA following treatment was 4.5 +/- 1.4 letters over the follow-up period, with no difference between eyes of patients receiving ATT and those who did not. Sixty-eight eyes (34.9%) had a recurrence of uveitis (0.64 +/- 0.08 recurrences per year), with eyes of patients receiving ATT less likely to develop a recurrence compared to those not receiving ATT (29.5% vs 48.2%, odds ratio 0.47, 95% confidence interval 0.29-0.77, P = .003). Eyes treated with ATT recurred at an estimated median of 120 months, compared with 51 months in eyes with no treatment (P = .005). CONCLUSIONS: Treatment with ATT halved the risk of uveitis recurrence and delayed the onset of the first recurrence in eyes with uveitis associated with latent TB. PMID- 29604285 TI - Reply. PMID- 29604286 TI - Labial swelling; anterior perineal herniation of urinary bladder diverticulum. PMID- 29604287 TI - Reply. PMID- 29604288 TI - The preterm labor associated ADAMTS2 gene is induced by glucocorticoids. PMID- 29604289 TI - Effect of Spironolactone on Myocardial Fibrosis and Other Clinical Variables in Patients with Hypertrophic Cardiomyopathy. AB - BACKGROUND: Myocardial fibrosis has proved to be an important marker and determinant in the pathogenesis of hypertrophic cardiomyopathy. In particular, scar formation, if substantial, can promote ventricular tachyarrhythmias or progressive heart failure in the absence of left ventricular outflow obstruction. Therefore, an intervention to mitigate myocardial fibrosis would be potentially advantageous to hypertrophic cardiomyopathy patients. METHODS: Eligible hypertrophic cardiomyopathy patients were randomized 1:1 in a prospective double blind fashion to spironolactone 50 mg or placebo to be taken over a 12-month period. The primary endpoint was the effect of mineralocorticoid receptor blockade on serum markers of collagen synthesis and degradation. A number of other functional and morphologic variables and biomarkers comprised secondary exploratory measures. RESULTS: Fifty-three hypertrophic cardiomyopathypatients (41 +/- 13 years old; 72% men) were randomized; demographic and clinical variable were well matched at baseline. Absolute change between baseline and 12 months did not differ between hypertrophic cardiomyopathy patients treated with spironolactone and those receiving placebo with respect to serum markers of collagen synthesis or degradation, fibrosis by late gadolinium enhancement on cardiac magnetic resonance imaging, or other clinical variables, including objective measure of functional capacity (peak VO2), New York Heart Association functional class, left ventricular wall thickness, mass and volume, and left atrial size, as well as assessment of diastolic function (P = .4-1.0). CONCLUSIONS: These findings do not support the use of spironolactone in hypertrophic cardiomyopathy to improve left ventricular remodeling by mitigating myocardial fibrosis or altering clinical course. PMID- 29604290 TI - Intestinal Failure and Aberrant Lipid Metabolism in Patients With DGAT1 Deficiency. AB - BACKGROUND & AIMS: Congenital diarrheal disorders are rare inherited intestinal disorders characterized by intractable, sometimes life-threatening, diarrhea and nutrient malabsorption; some have been associated with mutations in diacylglycerol-acyltransferase 1 (DGAT1), which catalyzes formation of triacylglycerol from diacylglycerol and acyl-CoA. We investigated the mechanisms by which DGAT1 deficiency contributes to intestinal failure using patient-derived organoids. METHODS: We collected blood samples from 10 patients, from 6 unrelated pedigrees, who presented with early-onset severe diarrhea and/or vomiting, hypoalbuminemia, and/or (fatal) protein-losing enteropathy with intestinal failure; we performed next-generation sequencing analysis of DNA from 8 patients. Organoids were generated from duodenal biopsies from 3 patients and 3 healthy individuals (controls). Caco-2 cells and patient-derived dermal fibroblasts were transfected or transduced with vectors that express full-length or mutant forms of DGAT1 or full-length DGAT2. We performed CRISPR/Cas9-guided disruption of DGAT1 in control intestinal organoids. Cells and organoids were analyzed by immunoblot, immunofluorescence, flow cytometry, chromatography, quantitative real time polymerase chain reaction, and for the activity of caspases 3 and 7. RESULTS: In the 10 patients, we identified 5 bi-allelic loss-of-function mutations in DGAT1. In patient-derived fibroblasts and organoids, the mutations reduced expression of DGAT1 protein and altered triacylglycerol metabolism, resulting in decreased lipid droplet formation after oleic acid addition. Expression of full-length DGAT2 in patient-derived fibroblasts restored formation of lipid droplets. Organoids derived from patients with DGAT1 mutations were more susceptible to lipid-induced cell death than control organoids. CONCLUSIONS: We identified a large cohort of patients with congenital diarrheal disorders with mutations in DGAT1 that reduced expression of its product; dermal fibroblasts and intestinal organoids derived from these patients had altered lipid metabolism and were susceptible to lipid-induced cell death. Expression of full-length wildtype DGAT1 or DGAT2 restored normal lipid metabolism in these cells. These findings indicate the importance of DGAT1 in fat metabolism and lipotoxicity in the intestinal epithelium. A fat-free diet might serve as the first line of therapy for patients with reduced DGAT1 expression. It is important to identify genetic variants associated with congenital diarrheal disorders for proper diagnosis and selection of treatment strategies. PMID- 29604291 TI - ARID1A Maintains Differentiation of Pancreatic Ductal Cells and Inhibits Development of Pancreatic Ductal Adenocarcinoma in Mice. AB - BACKGROUND & AIMS: The ARID1A gene encodes a protein that is part of the large adenosine triphosphate (ATP)-dependent chromatin remodeling complex SWI/SNF and is frequently mutated in human pancreatic ductal adenocarcinomas (PDACs). We investigated the functions of ARID1A during formation of PDACs in mice. METHODS: We performed studies with Ptf1a-Cre;KrasG12D mice, which express activated Kras in the pancreas and develop pancreatic intraepithelial neoplasias (PanINs), as well as those with disruption of Aird1a (Ptf1a-Cre;KrasG12D;Arid1af/f mice) or disruption of Brg1 (encodes a catalytic ATPase of the SWI/SNF complex) (Ptf1a Cre;KrasG12D; Brg1f/fmice). Pancreatic ductal cells (PDCs) were isolated from Arid1af/f mice and from Arid1af/f;SOX9OE mice, which overexpress human SOX9 upon infection with an adenovirus-expressing Cre recombinase. Pancreatic tissues were collected from all mice and analyzed by histology and immunohistochemistry; cells were isolated and grown in 2-dimensional and 3-dimensional cultures. We performed microarray analyses to compare gene expression patterns in intraductal papillary mucinous neoplasms (IPMNs) from the different strains of mice. We obtained 58 samples of IPMNs and 44 samples of PDACs from patients who underwent pancreatectomy in Japan and analyzed them by immunohistochemistry. RESULTS: Ptf1a Cre;KrasG12D mice developed PanINs, whereas Ptf1a-Cre;KrasG12D;Arid1af/f mice developed IPMNs and PDACs; IPMNs originated from PDCs. ARID1A-deficient IPMNs did not express SOX9. ARID1A-deficient PDCs had reduced expression of SOX9 and dedifferentiated in culture. Overexpression of SOX9 in these cells allowed them to differentiate and prevented dilation of ducts. Among mice with pancreatic expression of activated Kras, those with disruption of Arid1a developed fewer PDACs from IPMNs than mice with disruption of Brg1. ARID1A-deficient IPMNs had reduced activity of the mTOR pathway. Human IPMN and PDAC specimens had reduced levels of ARID1A, SOX9, and phosphorylated S6 (a marker of mTOR pathway activation). Levels of ARID1A correlated with levels of SOX9 and phosphorylated S6. CONCLUSIONS: ARID1A regulates expression of SOX9, activation of the mTOR pathway, and differentiation of PDCs. ARID1A inhibits formation of PDACs from IPMNs in mice with pancreatic expression of activated KRAS and is down-regulated in IPMN and PDAC tissues from patients. PMID- 29604292 TI - Improved Diet Quality Associates With Reduction in Liver Fat, Particularly in Individuals With High Genetic Risk Scores for Nonalcoholic Fatty Liver Disease. AB - BACKGROUND & AIMS: Dietary modification has been recommended for treatment of nonalcoholic fatty liver disease (NAFLD), although it is not clear whether improving diet quality can prevent its development. We performed a prospective study to examine the association between diet quality change and change in liver fat. We also examined the association between genetic risk score and liver fat change in individuals with different levels of diet quality change. METHODS: Our study included 1521 participants who attended the seventh and eighth examinations (1998-2001 and 2005-2008) of the second-generation cohort or attended the first and second examinations (2002-2005 and 2008-2011) of the third-generation cohort in the Framingham Heart Study. The self-administered semiquantitative 126-item Harvard food frequency questionnaire was used to determine dietary intake in the year leading up to an examination. We assessed levels of liver fat using liver phantom ratio (LPR) on computed tomography images from 2002 through 2005 and again from 2008 through 2011. LPR values are inversely related to liver fat: increased LPR indicates decreased liver fat. We examined associations of changes in 2 diet scores, the Mediterranean-style diet score (MDS) and Alternative Healthy Eating Index (AHEI), with changes in liver fat and new-onset fatty liver. We evaluated interactions between diet score change and a weighted genetic risk score for NAFLD, determined based on multiple single-nucleotide polymorphisms identified in genome-wide association studies of NAFLD. The primary outcome was change in LPR between baseline and follow-up measurement. RESULTS: For each 1 standard deviation increase in MDS, the LPR increased (meaning liver fat decreased) by 0.57 (95% confidence interval [CI] 0.27-0.86; P < .001) and the odds for incident fatty liver decreased by 26% (95% CI 10%-39%; P = .002). For each 1 standard deviation increase in AHEI, LPR increased by 0.56 (95% CI 0.29 0.84; P < .001) and the odds for incident fatty liver decreased by 21% (95% CI 5% 35%; P = .02). Increased diet scores were also associated with reduced odds of developing more-advanced fatty liver. Higher genetic risk scores were associated with increased liver fat accumulation in participants who had decreased MDS (P < .001) or AHEI scores (P = .001), but not in those with stable or improved diet scores (P for gene-diet interaction <.001). CONCLUSIONS: In an analysis of participants in the Framingham Heart Study, increasing diet quality, determined based on MDS and AHEI scores, is associated with less liver fat accumulation and reduced risk for new-onset fatty liver. An improved diet is particularly important for individuals with a high genetic risk for NAFLD. PMID- 29604293 TI - Immune Cell Production of Interleukin 17 Induces Stem Cell Features of Pancreatic Intraepithelial Neoplasia Cells. AB - BACKGROUND & AIMS: Little is known about how the immune system affects stem cell features of pancreatic cancer cells. Immune cells that produce interleukin 17A (IL17A) in the chronically inflamed pancreas (chronic pancreatitis) contribute to pancreatic interepithelial neoplasia (PanIN) initiation and progression. We investigated the effects that IL17A signaling exerts on pancreatic cancer progenitor cells and the clinical relevance of this phenomena. METHODS: We performed studies with Mist1Cre;LSLKras;Rosa26mTmG (KCiMist;G) and Kras(G12D);Trp53(R172H);Pdx1-Cre (KPC) mice (which upon tamoxifen induction spontaneously develop PanINs) and control littermates. Some mice were injected with neutralizing antibodies against IL17A or control antibody. Pancreata were collected, PanIN epithelial cells were isolated by flow cytometry based on lineage tracing, and gene expression profiles were compared. We collected cells from pancreatic tumors of KPC mice, incubated them with IL17 or control media, measured expression of genes regulated by IL17 signaling, injected the cancer cells into immune competent mice, and measured tumor growth. IL17A was overexpressed in pancreata of KCiMist mice from an adenoviral vector. Pancreata were collected from all mice and analyzed by histology and immunohistochemistry. Levels of DCLK1 and other proteins were knocked down in KPC pancreatic cancer cells using small interfering or short hairpin RNAs; cells were analyzed by immunoblotting. We obtained 65 pancreatic tumor specimens from patients, analyzed protein levels by immunohistochemistry, and compared results with patient survival times. We also analyzed gene expression levels and patient outcome using The Cancer Genome Atlas database. RESULTS: PanIN cells from KCiMist;G mice had a gene expression pattern associated with embryonic stem cells. Mice given injections of IL17-neutralizing antibodies, or with immune cells that did not secrete IL17, lost this expression pattern and had significantly decreased expression of DCLK1 and POU2F3, which regulate tuft cell development. KCiMist mice that overexpressed IL17 formed more PanINs, with more DCLK1-positive cells, than control mice. Pancreatic tumor cells from KPC mice and human Capan-2 cells exposed to IL17A had increased activation of NF-kappaB and mitogen-activated protein kinase signaling and increased expression of DCLK1 and ALDH1A1 (a marker of embryonic stem cells) compared with cells in control media. These cells also formed tumors faster that cells not exposed to IL17 when they were injected into immunocompetent mice. KPC cells with knockdown of DCLK1 expressed lower levels of ALDH1A1 after incubation with IL17 than cells without knockdown. Expression of the IL17 receptor C was higher in DCLK1-positive PanIN cells from mice compared with DCLK1-negative PanIN cells. In human pancreatic tumor tissues, high levels of DCLK1 associated with a shorter median survival time of patients (17.7 months, compared with 26.6 months of patients whose tumors had low levels of DCLK1). Tumor levels of POU2F3 and LAMC2 were also associated with patient survival time. CONCLUSIONS: In studies of mouse and human pancreatic tumors and precursors, we found that immune cell-derived IL17 regulated development of tuft cells and stem cell features of pancreatic cancer cells via increased expression of DCLK1, POU2F3, ALDH1A1, and IL17RC. Strategies to disrupt this pathway might be developed to prevent pancreatic tumor growth and progression. PMID- 29604294 TI - The effect of N-acetylcysteine or bupropion on methamphetamine self administration and methamphetamine-triggered reinstatement of female rats. AB - N-acetylcysteine and bupropion are two promising candidate medications for treatment of substance use disorder. The effects of N-acetylcysteine or bupropion on methamphetamine self-administration of female rats are not well understood. To fill this gap, this study assessed the effects of N-acetylcysteine (0, 30, 60, or 120 mg/kg) and bupropion (0, 10, 30, and 60 mg/kg) on methamphetamine self administration of female rats across the natural estrous cycle. Following a completed dose-response curve, responding for methamphetamine self-administration was extinguished and the effects of N-acetylcysteine or bupropion on methamphetamine-triggered reinstatement was evaluated in separate experiments. N acetylcysteine did not decrease responding maintained by methamphetamine or methamphetamine-triggered reinstatement. Bupropion significantly decreased methamphetamine self-administration and methamphetamine-triggered reinstatement in female rats with highest dose (60 mg/kg) also significantly decreasing general chamber activity. In a companion experiment, testing the effect of bupropion on responding maintained by sucrose, we confirmed non-specificity of bupropion's effects as bupropion also decreased responding for sucrose. Considered together, our findings suggest that while N-acetylcysteine has considerable promise for treatment of cocaine dependence it may not generalize to other stimulants like methamphetamine. Furthermore, although bupropion has been shown to effectively decrease methamphetamine self-administration, and presently methamphetamine triggered reinstatement, its locomotor and reward suppressing effects warrant further investigation including both sexes. PMID- 29604296 TI - Circulating CD34+ and CD34+VEGFR2+ progenitor cells are associated with KLOTHO KL VS polymorphism. AB - BACKGROUND: KLOTHO is a regulator of endothelial cells activity and integrity. It has been described for the first time because of its anti-aging properties. KLOTHO encoding gene is present in many functional variants in humans, including "KL-VS" variant that has been connected with longevity and cardiovascular disease development. Few mechanisms have been proposed to explain these associations, but none of them focused on cells from CD34+ population. The aim of our study was to investigate influence of KLOTHO KL-VS polymorphism on populations of CD34+ and CD34+VEGFR2+ cells. METHODS AND RESULTS: We examined 167 Polish subjects from Pomeranian region. The analysis concerned KL-VS polymorphism, flow cytometry evaluation of whole blood cells and determination of endothelium-associated serum/plasma factors. Our results indicate that individuals possessing at least one KL-VS allele are characterized by greater number of CD34+ and CD34+VEGFR2+ and their various subpopulations (CD34+CD133+, CD34+c-Kit+, CD34+CXCR4+ and CD34+VEGFR2+c-Kit+) than wild-type volunteers. This group also exhibited more favorable lipid profile and statistically insignificant decrease of vWF and angiotensin II in their blood, whereas VEGF levels were elevated. CONCLUSION: One of the mechanisms that are responsible for previously described KL-VS heterozygote advantage may be connected with maintaining greater size of hematopoietic and endothelial progenitor cells population. PMID- 29604295 TI - Cannabinoid receptor-mediated disruption of sensory gating and neural oscillations: A translational study in rats and humans. AB - Cannabis use has been associated with altered sensory gating and neural oscillations. However, it is unclear which constituent in cannabis is responsible for these effects, or whether these are cannabinoid receptor 1 (CB1R) mediated. Therefore, the present study in humans and rats examined whether cannabinoid administration would disrupt sensory gating and evoked oscillations utilizing electroencephalography (EEG) and local field potentials (LFPs), respectively. Human subjects (n = 15) completed four test days during which they received intravenous delta-9-tetrahydrocannabinol (Delta9-THC), cannabidiol (CBD), Delta9 THC + CBD, or placebo. Subjects engaged in a dual-click paradigm, and outcome measures included P50 gating ratio (S2/S1) and evoked power to S1 and S2. In order to examine CB1R specificity, rats (n = 6) were administered the CB1R agonist CP-55940, CP-55940+AM-251 (a CB1R antagonist), or vehicle using the same paradigm. LFPs were recorded from CA3 and entorhinal cortex. Both Delta9-THC (p < 0.007) and Delta9-THC + CBD (p < 0.004) disrupted P50 gating ratio compared to placebo, while CBD alone had no effect. Delta9-THC (p < 0.048) and Delta9-THC + CBD (p < 0.035) decreased S1 evoked theta power, and in the Delta9-THC condition, S1 theta negatively correlated with gating ratios (r = -0.629, p < 0.012 (p < 0.048 adjusted)). In rats, CP-55940 disrupted gating in both brain regions (p < 0.0001), and this was reversed by AM-251. Further, CP-55940 decreased evoked theta (p < 0.0077) and gamma (p < 0.011) power to S1, which was partially blocked by AM-251. These convergent human/animal data suggest that CB1R agonists disrupt sensory gating by altering neural oscillations in the theta-band. Moreover, this suggests that the endocannabinoid system mediates theta oscillations relevant to perception and cognition. PMID- 29604297 TI - Reducing adult cardiac surgical site infections and the economic impact of using multidisciplinary collaboration. AB - BACKGROUND: Cardiac surgical site infections (SSIs) have devastating consequences and present several challenges for patients and healthcare providers. Adult cardiac SSI surveillance commenced in 2009 at our hospitals, Guy's & St Thomas' NHS Foundation Trust, London, as a patient safety initiative amid reported increased incidence of SSIs. Before this time, infection incidence was unclear because data collection was not standardized. AIM: To standardize SSI data collection and establish baseline SSI rates to facilitate deployment of evidence based targeted interventions within clinical governance structures to improve quality, safety, and efficiency in line with our organizational targets. METHODS: We standardized local data collection protocols in line with Public Health England recommendations and identified local champions. We undertook prospective SSI surveillance collaboratively to enable us to identify potential practice concerns and address them more effectively through a series of initiatives. Clinical staff completed dedicated surveillance forms intraoperatively and postoperatively. FINDINGS: Overall adult cardiac SSI rates fell from 5.4% in 2009 to 1.2% in 2016 and coronary artery bypass graft rates from 6.5% in 2009 to 1.7% in 2016 (P < 0.001). Gram-negative bacteria were recognized as important SSI causative organisms and were better controlled after introducing stringent infection control measures. CONCLUSION: Comprehensive, evidence-based infection control practices were successfully implemented through a multidisciplinary collaborative approach, which may have great potential to reduce Gram-negative, Staphylococcus aureus, polymicrobial and overall SSI burden and/or associated costs. We now investigate all SSIs using an established SSI detailed investigation protocol to promote continual quality improvement that aligns us perfectly with global efforts to fight antimicrobial resistance. PMID- 29604298 TI - Molecular epidemiology and antimicrobial resistance of Clostridium difficile in a national geriatric hospital in Costa Rica. AB - BACKGROUND: The epidemiology of Clostridium difficile infections (CDI) is changing rapidly worldwide; knowledge on the genotypes of C. difficile circulating in specialized geriatric hospitals and their resistance to antibiotics is scarce or non-existent. METHODS: Prospective study of the molecular epidemiology of CDI, conducted in a national geriatric hospital in Costa Rica for a period of 11 months. RESULTS: The study patients exhibited a diverse range of comorbidities, but none were associated with CDI. Polyclonality, including three new ribotypes, and a high level of resistance to antibiotics were determined by analysing the 32 isolates obtained in these cases. Despite the diversity in strains observed, the most frequent types were NAP6/RT002 and NAP2/RT001. NAP9/RT017 was associated with community acquisition. Nineteen types of antimicrobials were used before the onset of diarrhoea in the patients; no particular genotype was associated with the onset of infection or severity. CONCLUSION: Based on the abundance of strain types observed and their resistance to antibiotics in this geriatric hospital, these results contribute to a better overall understanding of the epidemiology of CDI worldwide, and to surveillance programmes targeting geriatric populations. PMID- 29604299 TI - Evaluating the newly developed dye, DyeTox13 Green C-2 Azide, and comparing it with existing EMA and PMA for the differentiation of viable and nonviable bacteria. AB - PCR-based methods for enumerating bacteria cells could lead to an overestimation of viable cells due to the amplification of DNA from dead cells. To overcome this disadvantage, DNA intercalating dyes such as Ethidium monoazide (EMA) or Propidium monoazide (PMA) combined with qPCR have been considered promising alternative methods to discriminate between viable and nonviable cells. The drawback of those DNA intercalating dyes, however, could not assess the physiological states of cells. Thus, the objective of this study was to develop a novel molecular viability assay to selectively detect only the cells that exhibit metabolic activity. This study's results showed that DyeTox13 Green C-2 Azide dye coupled with qPCR can be used effectively to distinguish between active and nonactive gram-negative bacteria (P. aeruginosa PAO1) and gram-positive bacteria (E. faecalis v583). In this study, we evaluated the usefulness of the DyeTox13 Green C-2 Azide-qPCR assay for selectively amplifying nucleic acids of microorganisms that have metabolic activities. We conclude that the use of DyeTox13 Green C-2 Azide-qPCR is a promising alternative for discriminating active cells from nonactive cells but the dye's performance might be dependent on the kind of bacterial species. PMID- 29604300 TI - Face memory and face recognition in children and adolescents with attention deficit hyperactivity disorder: A systematic review. AB - This review focuses on facial recognition abilities in children and adolescents with attention deficit hyperactivity disorder (ADHD). A systematic review, using PRISMA guidelines, was conducted to identify original articles published prior to May 2017 pertaining to memory, face recognition, affect recognition, facial expression recognition and recall of faces in children and adolescents with ADHD. The qualitative synthesis based on different studies shows a particular focus of the research on facial affect recognition without paying similar attention to the structural encoding of facial recognition. In this review, we further investigate facial recognition abilities in children and adolescents with ADHD, providing synthesis of the results observed in the literature, while detecting face recognition tasks used on face processing abilities in ADHD and identifying aspects not yet explored. PMID- 29604301 TI - Learning context and the other-race effect: Strategies for improving face recognition. AB - People recognize faces of their own race more accurately than faces of other races-a phenomenon known as the "Other-Race Effect" (ORE). Previous studies show that training with multiple variable images improves face recognition. Building on multi-image training, we take a novel approach to improving own- and other race face recognition by testing the role of learning context on accuracy. Learning context was either contiguous, with multiple images of each identity seen in sequence, or distributed, with multiple images of an identity randomly interspersed among different identities. In two experiments, East Asian and Caucasian participants learned own- and other-races faces either in a contiguous or distributed order. In Experiment 1, people learned each identity from four highly variable face images. In Experiment 2, identities were learned from one image, repeated four times. In both experiments we found a robust other-race effect. The effect of learning context, however, differed depending on the variability of the learned images. The distributed presentation yielded better recognition when people learned from single repeated images (Exp. 1), but not when they learned from multiple variable images (Exp. 2). Overall, performance was better with multiple-image training than repeated single image training. We conclude that multiple-image training and distributed learning can both improve recognition accuracy, but via distinct processes. The former broadens perceptual tolerance for image variation from a face, when there are diverse images available to learn. The latter effectively strengthens the representation of differences among similar faces, when there is only a single learning image. PMID- 29604302 TI - Inference on admixture fractions in a mechanistic model of recurrent admixture. AB - Signatures of recent historical admixture are ubiquitous in human populations. We present a mechanistic model of admixture with two source populations, encompassing recurrent admixture periods and study the distribution of admixture fractions for finite but arbitrary genome size. We provide simulation-based methods to estimate the introgression parameters and discuss the implications of reaching stationarity on estimability of parameters when there are recurrent admixture events with different rates. PMID- 29604303 TI - Final size of a multi-group SIR epidemic model: Irreducible and non-irreducible modes of transmission. AB - A model of an epidemic outbreak incorporating multiple subgroups of susceptible and infected individuals is investigated. The asymptotic behavior of the model is analyzed and it is proved that the infected classes all converge to 0. A computational algorithm is developed for the cumulative final size of infected individuals over the course of the epidemic. The results are applied to the SARS epidemic in Singapore in 2003, where it is shown that the two-peak evolution of the infected population can be attributed to a two-group formulation of transmission. PMID- 29604304 TI - A mathematical model for malaria transmission with asymptomatic carriers and two age groups in the human population. AB - In this paper a conceptual mathematical model of malaria transmission proposed in a previous paper has been analyzed in a deeper detail. Among its key epidemiological features of this model, two-age-classes (child and adult) and asymptomatic carriers have been included. The extra mortality of mosquitoes due to the use of long-lasting treated mosquito nets (LLINs) and Indoor Residual Spraying (IRS) has been included too. By taking advantage of the natural double time scale of the parasite and the human populations, it has been possible to provide interesting threshold results. In particular it has been shown that key parameters can be identified such that below a threshold level, built on these parameters, the epidemic tends to extinction, while above another threshold level it tends to a nontrivial endemic state, for which an interval estimate has been provided. Numerical simulations confirm the analytical results. PMID- 29604306 TI - Exploring the maximum duration of the contingent negative variation. AB - While the contingent negative variation (CNV) has been the subject of extensive research over the last fifty years, the maximum duration during which such cortical negativity can be maintained has, to the best of our knowledge, never been systematically explored. Participants were presented with the classic S1-S2 paradigm task, where a warning stimulus (S1) acts as a cue for the appearance of an imperative stimulus (S2). A fast motor response was required upon S2 arrival. Inter-stimulus intervals (ISIs) of 2.5, 5, 7.5 and 10 s duration were presented in blocked fashion. Data was analysed using both EEG referenced to linked mastoids and the current source density (CSD) technique, which maximizes the cortical origin of the measured voltage. Mean late CNV (lCNV) amplitude was found to be significantly higher for fast reaction time (RT) trials when CSD data was split according to the median into 'fast' and 'slow' RT halves. Post-hoc comparisons showed that this RT effect was particularly strong for the 10 s condition. This may be explained by the lack of an lCNV component and thus of cortical negativity prior to S2 in the 10 s condition. Our results suggest that intervals of a duration between 7.5 and 10 s represent the upper boundary during which the lCNV component can be elicited. PMID- 29604305 TI - Oral exposure to silver nanoparticles increases oxidative stress markers in the liver of male rats and deregulates the insulin signalling pathway and p53 and cleaved caspase 3 protein expression. AB - The present study was aimed at assessing the impact of AgNPs on the liver of male rats orally exposed to 0, 50, 100 and 200 mg/kg/day of polyvinyl pyrrolidone coated AgNPs (PVP-AgNPs) for 90 days. The induction of apoptotic cell death -by measuring the protein levels of the active form of caspase 3- and the levels of the microtubule-associated protein 1A/1B-light chain (LC3) protein were measured as a marker of the induction of autophagy. PVP-AgNPs caused an increase of the activity of superoxide dismutase (SOD) and catalase (CAT) in the liver of male rats. However, the activity decreased after exposure to high amounts of PVP AgNPs. Increased protein levels of IRS-1, AKT, GSK3beta and mTOR proteins were observed in a dose-dependent manner. However, these proteins showed a decrease at 200 mg/kg/day. The same pattern was observed for the p53, p21 and cleaved caspase 3 protein levels. The current results suggest that the increase of ROS production by PVP-AgNPs stimulated SOD and CAT activity, as well as IRS-1, AKT, mTOR, p53, p21 and caspase 3 as protective mechanisms of cell survival and preserve DNA fidelity. However, cellular damage by excessive ROS production might induce the depletion of these survival mechanisms at 200 mg/kg/day. PMID- 29604307 TI - Laughter as a social rejection cue: Influence of prior explicit experience of social rejection on cardiac signs of "freezing". AB - The study aimed at investigating the immediate cardiac effect of the sudden perception of other people's laughter after experimentally manipulating healthy participants' proneness to experience laughter as a cue of social threat. We expected that participants would show cardiac signs of freezing (i.e., sustained heart rate deceleration immediately after perception of the laughter) after prior social rejection but not or less so after prior acceptance, due to an increased bias to perceive the ambiguous social signal as a cue of social threat and rejection after rejection had been primed. Contrary to expectations, the perception of other people's laughter elicited a decelerative (freezing) response regardless of whether it was preceded by the experience of social rejection or acceptance. The response was prolonged in participants who had been accepted beforehand compared to those who had been rejected. The findings indicate that, given a relevant social context, other people's laughter can be a powerful cue of social threat and rejection also in healthy individuals. Prolonged heart rate deceleration after an ambiguous social signal may facilitate the processing of significant social information in the socially threatening situation. The study adds to the literature rendering the course of the immediate transient heart rate response a useful tool in social rejection research. Additionally, the findings suggested that in some cases the further progress of transient heart rate changes in more extended time-windows (about 30 s) may provide additional relevant information about the processing of social cues. PMID- 29604308 TI - TRIM50 regulates Beclin 1 proautophagic activity. AB - Autophagy is a catabolic process needed for maintaining cell viability and homeostasis in response to numerous stress conditions. Emerging evidence indicates that the ubiquitin system has a major role in this process. TRIMs, an E3 ligase protein family, contribute to selective autophagy acting as receptors and regulators of the autophagy proteins recognizing endogenous or exogenous targets through intermediary autophagic tags, such as ubiquitin. Here we report that TRIM50 fosters the initiation phase of starvation-induced autophagy and associates with Beclin1, a central component of autophagy initiation complex. We show that TRIM50, via the RING domain, ubiquitinates Beclin 1 in a K63-dependent manner enhancing its binding with ULK1 and autophagy activity. Finally, we found that the Lys-372 residue of TRIM50, critical for its own acetylation, is necessary for its E3 ligase activity that governs Beclin1 ubiquitination. Our study expands the roles of TRIMs in regulating selective autophagy, revealing an acetylation-ubiquitination dependent control for autophagy modulation. PMID- 29604310 TI - The novelty bubble. PMID- 29604309 TI - A damaged DNA binding protein 2 mutation disrupting interaction with proliferating-cell nuclear antigen affects DNA repair and confers proliferation advantage. AB - In mammalian cells, Nucleotide Excision Repair (NER) plays a role in removing DNA damage induced by UV radiation. In Global Genome-NER subpathway, DDB2 protein forms a complex with DDB1 (UV-DDB), recognizing photolesions. During DNA repair, DDB2 interacts directly with PCNA through a conserved region in N-terminal tail and this interaction is important for DDB2 degradation. In this work, we sought to investigate the role of DDB2-PCNA association in DNA repair and cell proliferation after UV-induced DNA damage. To this end, stable clones expressing DDB2Wt and DDB2PCNA- were used. We have found that cells expressing a mutant DDB2 show inefficient photolesions removal, and a concomitant lack of binding to damaged DNA in vitro. Unexpected cellular behaviour after DNA damage, such as UV resistance, increased cell growth and motility were found in DDB2PCNA- stable cell clones, in which the most significant defects in cell cycle checkpoint were observed, suggesting a role in the new cellular phenotype. Based on these findings, we propose that DDB2-PCNA interaction may contribute to a correct DNA damage response for maintaining genome integrity. PMID- 29604311 TI - Encapsulation and controlled release of retinol from silicone particles for topical delivery. AB - Retinol, a derivative of vitamin A, is a ubiquitous compound used to treat acne, reduce wrinkles and protect against conditions like psoriasis and ichthyosis. While retinol is used as the primary active ingredient (AI) in many skin care formulations, its efficacy is often limited by an extreme sensitivity to degrade and toxicity at high concentrations. While microencapsulation is an appealing method to help overcome these issues, few microencapsulation strategies have made a major translational impact due to challenges with complexity, cost, limited protection of the AI and poor control of the release of the AI. We have developed a class of silicone particles that addresses these challenges for the encapsulation, protection and controlled release of retinol and other hydrophobic compounds. The particles are prepared by the sol-gel polymerization of silane monomers, which enables their rapid and facile synthesis at scale while maintaining a narrow size distribution (i.e., CV < 20%). We show that our particles can: (i) encapsulate retinol with high efficiency (>85%), (ii) protect retinol from degradation (yielding a half-life 9* greater than unencapsulated retinol) and (iii) slowly release retinol over several hours (at rates from 0.14 to 0.67 MUg cm-2 s-1/2). To demonstrate that the controlled release of retinol from the particles can reduce irritation, we performed a double blind study on human subjects and found that formulations containing our particles were 12-23% less irritating than identical formulations containing Microsponge(r) particles (an industry standard by Amcol, Inc.). To show that the silicone particles can elicit a favorable biological response, similar to the Microsponge(r) particles, we applied both formulations to reconstructed human epidermal tissues and found an upregulation of keratin 19 (K19) and a downregulation of K10, indicating that the reduced irritation observed in the human study was not caused by reduced activity. We also found a decrease in the production of interleukin-1alpha (IL 1alpha) compared to formulations containing the Microsponge particles, suggesting lower irritation levels and supporting the findings from the human study. Finally, we show that the silicone particles can encapsulate other AIs, including betamethasone, N, N-diethyl-meta-toluamide (DEET), homosalate and ingenol mebutate, establishing these particles as a true platform technology. PMID- 29604312 TI - Anticancer activity of novel steroidal 6-substituted 4-en-3-one D-seco dinitriles. AB - Steroidal 16,17-seco-16,17a-dinitriles possessing 4-ene-3,6-dione (3), 6 methylene-4-en-3-one (5), (6E)-hydroxyimino-4-en-3beta-ol (9) or (6E) hydroxyimino-4-en-3-one (10) moiety were synthesized starting from 3beta-acetoxy 16,17-secoandrost-4-ene-16,17a-dinitrile (1). Antiproliferative activity of the newly synthesized compounds, as well as previously synthesized 3-oxo-16,17 secoandrosta-1,4-diene-16,17a-dinitrile (VII), was tested in vitro. Compound 9 displayed submicromolar antiproliferative activity against human cervical carcinoma (HeLa) cells (IC50 0.48 MUM), and compounds 3 and 10 expressed strong inhibitory potential against HeLa cells (IC50 4.31 MUM and 2.64 MUM, respectively). Also, compound 10 was effective in inhibiting estrogen hormone independent (MDA-MB-231) cells (IC50 2.78 MUM). All tested compounds had no influence on the proliferation of healthy cells (MRC-5). Since MDA-MB-231 breast cancer cells and HeLa cervical cancer cells were most sensitive to treatment by 16,17-seco-16,17a-dinitriles, apoptosis induction after treatment by compounds 3, VII, 9 and 10 was studied in these cells, to reveal the mechanism underlying cell growth inhibition. All tested compounds significantly induced apoptosis in both treated cell lines, which was evident from results obtained by a double AO-EB staining test and quantified by counting cells with apoptotic morphology after staining with Giemsa dye. Among all tested substances, (6E)-hydroxyimino-4-en-3 one derivative 10 expressed the most proapoptotic activity. PMID- 29604313 TI - Protective effects of pituitary adenylate cyclase activating polypeptide against neurotoxic agents. AB - Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuropeptide highly expressed in the central and peripheral nervous system, where it exerts several neuromodulatory functions and is an important trophic and protective factor. PACAP has been shown to activate several protective pathways, mainly through its specific PAC1 receptor and protein kinase A, C and MAP kinases downstream. It has been shown to have very potent neuroprotective actions against different neurotoxic agents both in vitro and in vivo. The aim of the present review is to provide an overview on the neurotoxic injuries against which PACAP exerts protection, and to give an insight into its protective mechanism. We give a summary of the neuroprotective effects against the most commonly used neurotoxic agents, such as 6-OHDA, MPTP, glutamate and some less well-known neurotoxic compounds. Also endogenous PACAP has neuroprotective effects, known from studies in PACAP knockout mice or from blocking endogenous effects by antagonists. Altogether, the vast amount of data for the neuroprotective effects of PACAP give a firm background for its endogenous role as part of the neuroprotective machinery and its possible future therapeutic use as a neuroprotective factor. PMID- 29604314 TI - Zebrafish models relevant to studying central opioid and endocannabinoid systems. AB - The endocannabinoid and opioid systems are two interplaying neurotransmitter systems that modulate drug abuse, anxiety, pain, cognition, neurogenesis and immune activity. Although they are involved in such critical functions, our understanding of endocannabinoid and opioid physiology remains limited, necessitating further studies, novel models and new model organisms in this field. Zebrafish (Danio rerio) is rapidly emerging as one of the most effective translational models in neuroscience and biological psychiatry. Due to their high physiological and genetic homology to humans, zebrafish may be effectively used to study the endocannabinoid and opioid systems. Here, we discuss current models used to target the endocannabinoid and opioid systems in zebrafish, and their potential use in future translational research and high-throughput drug screening. Emphasizing the high degree of conservation of the endocannabinoid and opioid systems in zebrafish and mammals, we suggest zebrafish as an excellent model organism to study these systems and to search for the new drugs and therapies targeting their evolutionarily conserved mechanisms. PMID- 29604315 TI - Physical Examination for Men and Women With Urologic Chronic Pelvic Pain Syndrome: A MAPP (Multidisciplinary Approach to the Study of Chronic Pelvic Pain) Network Study. AB - OBJECTIVE: To examine the feasibility of implementing a standardized, clinically relevant genitourinary examination for both men and women, and to identify physical examination findings characteristic of urologic chronic pelvic pain syndrome (UCPPS). MATERIALS AND METHODS: This study analyzed 2 samples: men and women with UCPPS who participated in the Multidisciplinary Approach to the Study of Chronic Pelvic Pain (MAPP) Research Network Epidemiology and Phenotyping (EP) Study, and age-matched controls who were either positive for chronic fatigue syndrome or healthy (pain-free). We compared physical examination findings in both positive and healthy controls with UCPPS cases: findings from both the EP examinations and from an extended genitourinary examination. RESULTS: EP and extended examinations were performed on 143 participants: 62 UCPPS cases (30 women, 32 men), 42 positive controls (15 women, 27 men), and 39 healthy controls (22 women, 17 men). EP examinations showed that pelvic floor tenderness was more prevalent in cases (55.0%) than in positive (14.6%) or healthy controls (10.5%). Extended examinations revealed specific areas of tenderness in the pelvic floor musculature. Cases were also more likely than healthy controls to report tenderness in multiple areas, including suprapubic, symphysis pubis, and posterior superior iliac spine, and on bimanual examination. No comparative findings were specific to biological sex, and no evidence of pudendal neuropathy was observed on extended examination of cases or controls. CONCLUSION: The extended genitourinary examination is an easily administered addition to the assessment of men and women during evaluation for UCPPS. Physical findings may help to better categorize patients with UCPPS into clinically relevant subgroups for optimal treatment. PMID- 29604316 TI - Effect of phytate and zinc ions on fluoride toothpaste efficacy using an in situ caries model. AB - OBJECTIVES: To compare and explore the dose-response of phytate-containing 1150 ppm fluoride toothpastes on model caries lesions and to determine the impact of zinc ions. METHODS: This was a single-centre, randomised, blinded (examiner/laboratory analyst), six-treatment, four-period crossover, in situ study in adults with a removable bilateral maxillary partial denture. Study treatments were toothpastes containing: 0.425% phytate/F; 0.85% phytate/F; 0.85% phytate/Zn/F; F-only; Zn/F and a 0% F placebo. Where present, F was 1150 ppm as NaF; Zn was 0.3% as ZnCl2. Human enamel specimens containing early-stage, surface softened (A-lesions) or more advanced, subsurface (B-lesions) caries lesions were placed into the buccal flanges of participants' modified partial denture (one of each lesion type per side). A-lesions were removed after 14 days of twice-daily treatment use; B-lesions were removed after a further 14 days. A-lesions were analysed for surface microhardness recovery. Both lesion types were analysed by transverse microradiography and for enamel fluoride uptake, with B-lesions additionally analysed by quantitative light-induced fluorescence. Comparison was carried out using an analysis of covariance model. RESULTS: Statistically significant differences between 1150 ppm F and the placebo toothpastes (p < 0.05) were shown for all measures, validating the model. No differences between fluoride toothpastes were observed for any measure with little evidence of a dose response for phytate. Study treatments were generally well-tolerated. CONCLUSIONS: Results suggest phytate has little impact on fluoride's ability to promote early-stage lesion remineralisation or prevent more advanced lesion demineralisation in this in situ caries model. Similarly, results suggest zinc ions do not impair fluoride efficacy. CLINICAL SIGNIFICANCE: Toothpastes may contain therapeutic or cosmetic agents that could interfere with fluoride's caries prevention efficacy. The present in situ caries study has demonstrated that phytate, added to provide enhanced extrinsic stain removal/prevention, and zinc, added to inhibit malodour, do not impair fluoride efficacy. PMID- 29604317 TI - Therapeutic time window of anti-high mobility group box-1 antibody administration in mouse model of spinal cord injury. AB - Spinal cord injury (SCI) is a devastating neurologic disorder that often leads to permanent disability, and there is no effective treatment for it. High mobility group box-1 (HMGB1) is a damage-associated molecular protein that triggers sterile inflammation upon injuries. We have previously shown that two administrations of neutralizing monoclonal antibody (mAb) against HMGB1 (immediately after (0 h) and 6 h after) SCI dramatically improves functional recovery after SCI in mice. However, when considering clinical application, 0 h after SCI is not practical. Therefore, in this study, we examined the therapeutic time window of the mAb administration. Injection at 3 h after SCI significantly improved the functional recovery comparably to injection immediately after SCI, while injection at 6 h was less effective, and injection at 9 or 12 h had no therapeutic effect. We also found beneficial effects of injection at 3 h after injury on blood-spinal cord barrier maintenance, inflammatory-related gene expression and preservation of the damaged spinal cord tissue. Taken together, our results suggest that a single administration of anti-HMGB1 mAb within a proper time window could be a novel and potential therapeutic strategy for SCI. PMID- 29604318 TI - Gender comparisons of young adults' eating behavior regulation: Re-examination of the Regulation of Eating Behavior Scale (REBS). AB - The aim of this study was to evaluate the psychometric properties of the Regulation of Eating Behavior Scale (REBS) in mixed-gender, American samples and to evaluate how responses differed across male and female respondents. Responses were examined in a sample of 535 undergraduate students in the Southeastern United States. A confirmatory factor analysis was used to confirm the predicted factor structure; male and female participants were analyzed in a multi-group, unconstrained configural model, with male and female participants analyzed simultaneously to allow for multi-group comparisons within the same model. Additional analyses evaluated measurement invariance, reliability of the measure in the new sample, gender differences in subscale scores, and correlations across factors. Results of confirmatory factor analysis, multi-group by gender comparisons suggested that the factor structure did not vary across genders. In addition, factor structure was consistent with the findings of the original studies examining the psychometric property of the REBS, with the exception of the 'introjected regulation' subscale, which measures regulation of eating behaviors to avoid self-enforced consequences. Consistent with expectations, female participants' ratings were higher, on average, on more autonomous forms of eating regulation; however, contrary to expectations, scores did not differ significantly between males and females on more external forms of eating regulation. Conclusions, limitations, and implications are discussed. PMID- 29604320 TI - Examining consumer luxury brand-related behavior intentions in a social media context: The moderating role of hedonic and utilitarian motivations. AB - Luxury brand marketers have recently turned their attention to customer-driven social media devoted to their brands. The key concepts of involvement, interaction and behavioral intention provide the theoretical foundation to investigate luxury brands. The purpose of this study is to test a model that analyzes the relationship among brand involvement, consumer-brand interaction and behavioral intention in the context of luxury brand-related activities on social media. Based on content value theory, the present research identifies the moderating role of utilitarian/hedonic motivations on the relationships proposed. Data were collected from 326 social media users who look for information on internet about luxury brands before purchasing a specific brand. We provide evidence indicating positive relationships between brand involvement, consumer brand interaction and behavioral intention. The results also confirm the moderating role of the utilitarian/hedonic motivations. This study provides recommendations to luxury brands to understand the nature of consumer involvement and brand-customer relationship in order to forecast the behavioral intention of their consumers more accurately. PMID- 29604319 TI - What matters most - what parents model or what parents eat? AB - PURPOSE: Parents have a strong influence on their children's eating habits; however, researchers struggle to identify which food parenting practices to recommend. This study examined the influence of parents modeling of healthy eating ("parent role modeling") and parents' actual food intake ("parent dietary intake") on child diet quality, and explored whether these practices work together to influence children's diets. METHODS: Baseline data from a larger intervention trial were used for this analysis. The sample included parents of preschool-age children from households with at least one overweight parent. The Comprehensive Feeding Practices Questionnaire was used to assess parent modeling of healthy eating ("healthy modeling"). Three days of dietary recalls were used to collect parents' report of their own intake and their children's intake (excluding food at child care). Associations between parent healthy modeling and parent intake of healthy and unhealthy foods were explored using Pearson correlations. Associations between parent healthy modeling and parent Healthy Eating Index (HEI) score on child HEI score were examined with linear regression. Additionally, the interaction between parent healthy modeling and HEI score on child HEI score was tested. RESULTS: Parent healthy modeling was significantly correlated with parent intake of healthy foodsLinear regression showed a significant association between parent modeling and child HEI score, even after controlling for parent diet (beta = 3.08, SE = 0.87, p < 0.001). Children whose parents had high parent healthy modeling scores had higher HEI scores (mean = 61.5 +/- 10.4) regardless of parent HEI score. We did not find evidence that parent healthy modeling and diet quality interact to influence child diet quality. CONCLUSIONS: Parents' healthy modeling is an important practice in influencing children's diet quality, possibly more so than the quality of parents' diets. PMID- 29604321 TI - Action blindsight and antipointing in a hemianopic patient. AB - Blindsight refers to the observation of residual visual abilities in the hemianopic field of patients without a functional V1. Given the within- and between-subject variability in the preserved abilities and the phenomenal experience of blindsight patients, the fine-grained description of the phenomenon is still debated. Here we tested a patient with established "perceptual" and "attentional" blindsight (c.f. Danckert and Rossetti, 2005). Using a pointing paradigm patient MS, who suffers from a complete left homonymous hemianopia, showed clear above chance manual localisation of 'unseen' targets. In addition, target presentations in his blind field led MS, on occasion, to spontaneous responses towards his sighted field. Structural and functional magnetic resonance imaging was conducted to evaluate the magnitude of V1 damage. Results revealed the presence of a calcarine sulcus in both hemispheres, yet his right V1 is reduced, structurally disconnected and shows no fMRI response to visual stimuli. Thus, visual stimulation of his blind field can lead to "action blindsight" and spontaneous antipointing, in absence of a functional right V1. With respect to the antipointing, we suggest that MS may have registered the stimulation and subsequently presumes it must have been in his intact half field. PMID- 29604322 TI - State or trait? Auditory event-related potentials in adolescents with current and remitted major depression. AB - OBJECTIVE: Event-related potential (ERP) studies have revealed abnormal neurophysiological patterns underlying selective attention in patients with Major Depression (MD). Only few included both patients in acute and remitted state to address the question whether these abnormalities are state- or trait- dependent and none focused on adolescent MD. Thus, the aim of our study was to address this question in an adolescent sample. METHODS: 22 adolescents with acute MD, 20 adolescents with remitted MD (rMD) and 32 healthy controls (HC) performed a standard two-tone auditory oddball task while ERPs (N100, P200, N200, P300) were collected. RESULTS: Adolescents with rMD showed a reduced N200 amplitude to target tones across frontal, central and parietal recording sites. Adolescents with MD exhibited a reduced N200 amplitude to targets in the frontal region compared to HC. No differences emerged between rMD and the MD group. CONCLUSIONS: The reduced N200 amplitude in adolescents with rMD and MD presumably reflects difficulties in stimulus classification and response selection. Our results indicate that this neurophysiological characteristic is a trait marker of adolescent depression. PMID- 29604324 TI - Effect of blood T1 estimation strategy on arterial spin labeled cerebral blood flow quantification in children and young adults with kidney disease. AB - PURPOSE: To compare blood T1 estimation approaches used for quantifying cerebral blood flow (CBF) with arterial spin labeled (ASL) perfusion MRI in a developmental cohort of chronic kidney disease (CKD) patients with anemia and a control group. METHODS: 61 patients with CKD and 47 age-matched control subjects were studied. Blood T1 approaches included: (1) a fixed value, (2) estimation based on measured hematocrit (Hct), and (3) estimation based on Age+Sex using a published formula. Resulting T1 and CBF values were compared along with group, age and sex effects. RESULTS: Highly significant group differences in CBF using fixed blood T1 were reduced when Hct-corrected blood T1 was used, and were eliminated entirely when using the Age+Sex estimated approach. In the control cohort, fixed T1 method showed the strongest correlations of CBF with age and sex. Hct-corrected T1 preserved a significant correlation between CBF and age and sex, while Age+Sex estimated T1 produced a poor fit of CBF with age and sex. CONCLUSIONS: Blood T1 estimation method can confound the interpretation of CBF changes measured using ASL MRI in patients with CKD. Blood T1 should ideally be corrected for hematocrit effects in clinical populations with anemia. PMID- 29604323 TI - The impact of oxidative DNA damage and stress on telomere homeostasis. AB - Telomeres are dynamic nucleoprotein-DNA structures that cap and protect linear chromosome ends. Because telomeres shorten progressively with each replication, they impose a functional limit on the number of times a cell can divide. Critically short telomeres trigger cellular senescence in normal cells, or genomic instability in pre-malignant cells, which contribute to numerous degenerative and aging-related diseases including cancer. Therefore, a detailed understanding of the mechanisms of telomere loss and preservation is important for human health. Numerous studies have shown that oxidative stress is associated with accelerated telomere shortening and dysfunction. Oxidative stress caused by inflammation, intrinsic cell factors or environmental exposures, contributes to the pathogenesis of many degenerative diseases and cancer. Here we review the studies demonstrating associations between oxidative stress and accelerated telomere attrition in human tissue, mice and cell culture, and discuss possible mechanisms and cellular pathways that protect telomeres from oxidative damage. PMID- 29604325 TI - Characteristic phase distribution in the white matter of infants on phase difference enhanced imaging. AB - BACKGROUND AND PURPOSE: The infantile brain is continuously undergoing development. Non-invasive methods to assess the neurological development of infants are important for the early detection of abnormalities. Some microstructures in the brain have been demonstrated via phase difference-enhanced imaging (PADRE), which may reflect myelin-related microstructures. We aimed to assess the white matter (WM) signal distribution in infants using PADRE and compared it with that using T1-weighted images (T1WI) and diffusion tensor imaging (DTI) on magnetic resonance imaging (MRI). MATERIALS AND METHOD: This study included 18 infants (postmenstrual age at MRI, 37-40 weeks) without abnormal findings on MRI. Signal distribution using T1WI, a fractional anisotropy (FA) map and PADRE was assessed regarding the following intraparenchymal structures: the optic radiation (OR), internal capsule (IC), corpus callosum, corticospinal tract (CST), semiovale center and subcortical regions. RESULTS: We found that the signal distribution was significantly different (P<0.001) with a relatively large signal change found at the IC and CST across the three imaging methods. Signal changes were also greater at the OR and rolandic subcortical WM on PADRE, whereas these were smaller on T1WI and FA. CONCLUSION: PADRE demonstrated a characteristic phase shift distribution in infantile WM, which was different from that observed on T1WI and FA maps, and may demonstrate the developing myelin-related structures. PADRE can be a unique indicator of infantile brain development. PMID- 29604328 TI - Temporal Resolution Pattern of Myocardial Edema in Patients With Takotsubo Syndrome. PMID- 29604326 TI - Whether to push or pull? Nicotine reduction and non-combusted alternatives - Two strategies for reducing smoking and improving public health. AB - Combustible cigarettes remain the most harmful and addictive tobacco product, and reducing the prevalence of smoking continues to be a critical public health goal. While nicotine is the constituent primarily responsible for addiction to cigarettes, most of the harm associated with smoking comes from byproducts of tobacco combustion. Recently, two different approaches for reducing the harms of smoking have emerged, both of which focus on breaking the link between the addiction to nicotine and the harms caused by smoking. First, the addictive potential of cigarettes could be minimized by requiring a large reduction in the nicotine content of cigarettes. Evidence for a nicotine reduction policy thus far shows that the use of very low nicotine content cigarettes results in a reduction in the number of cigarettes people smoke per day and a reduction in cigarette dependence. Second, emerging alternative nicotine delivery systems (ANDS) like electronic cigarettes may provide sufficient nicotine to act as substitutes for cigarettes while delivering much lower levels of toxicants. Evidence suggests that the emergence of ANDS has increased the percentage of smokers who are able to quit. The present paper will briefly review the evidence for each of these approaches, and consider what contemporary reinforcement and addiction theories can tell us about their likely success. We argue that the most effective endgame approach is one that pursues both nicotine reduction and alternative nicotine delivery systems as complementary. PMID- 29604327 TI - Changes in the mode of travel to work and the severity of depressive symptoms: a longitudinal analysis of UK Biobank. AB - Although commuting provides an opportunity for incorporating physical activity into daily routines, little is known about the effect of active commuting upon depressive symptoms. This study aimed to determine whether changes in commute mode are associated with differences in the severity of depressive symptoms in working adults. Commuters were selected from the UK Biobank cohort if they completed >=2 assessment centre visits between 2006 and 2016. Modes of travel to work were self-reported at each visit. Participants were categorised as 'inactive' (car only) or 'active' commuters (any other mode(s), including walking, cycling and public transport). Transitions between categories were defined between pairs of visits. The severity of depressive symptoms was defined using the two-item Patient Health Questionnaire (PHQ-2). Scores were derived between zero and six. Higher values indicate more severe symptoms. Separate analyses were conducted in commuters who were asymptomatic (zero score) and symptomatic (non-zero score) at baseline. The analytical sample comprised 5474 participants aged 40-75 at baseline with a mean follow-up of 4.65 years. Asymptomatic commuters who transitioned from inactive to active commuting reported less severe symptoms at follow-up than those who remained inactive (beta -0.10, 95% CI [-0.20, 0.00]; N = 3145). A similar but non-significant relationship is evident among commuters with pre-existing symptoms (beta -0.60, 95% CI [-1.27, 0.08]; N = 1078). After adjusting for transition category, longer commutes at baseline were associated with worse depressive symptoms at follow-up among symptomatic participants. Shifting from exclusive car use towards more active commuting may help prevent and attenuate depressive symptoms in working adults. PMID- 29604329 TI - MiR-451a attenuates free fatty acids-mediated hepatocyte steatosis by targeting the thyroid hormone responsive spot 14 gene. AB - The thyroid hormone responsive spot 14 (THRSP) gene is a de novo lipogenesis related gene that plays a significant role in the initiation and development of nonalcoholic fatty liver disease (NAFLD). Several previous studies had shown that endogenous and environmental factors could regulate the expression of THRSP. The role of microRNAs (miRNAs), however, in controlling THRSP expression has not been investigated. In this study, we first constructed the hepatic steatosis cell model by using a mixture of free fatty acids (FFAs; oleate/palmitate, 2:1 ratio) to treat and demonstrate the promotive role of THRSP in lipid accumulation in hepatic cells. By analyzing the photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP) database and performing a luciferase reporter assay, we confirmed that microRNA-451a specifically binds to mouse and human THRSP 3'UTR and inhibits its activity. Overexpression of miR-451a efficiently reduced THRSP mRNA and protein expression as well as triglyceride (TG) accumulation in cultured hepatic cells (AML12 and HepG2). Moreover, overexpression of miR-451a significantly decreases TG accumulation in the livers of mice injected with an miR-451a agomir. All these results demonstrated that miR 451a might participate in the FFA-induced hepatic steatosis by regulating the expression of the THRSP gene which represents a new potential target for NAFLD therapy. PMID- 29604331 TI - Choosing the right delay-discounting task: Completion times and rates of nonsystematic data. AB - A variety of delay discounting tasks are widely used in human studies designed to quantify the degree to which individuals discount the value of delayed rewards. It is currently unknown which task(s) yields the largest proportion of valid and systematic data using standard criteria (Johnson & Bickel, 2008). The goal of this study was to compare three delay-discounting tasks on task duration and amount of valid and systematic data produced. In Experiment 1, 180 college students completed one of three tasks online (fixed alternatives, titrating, or visual analogue scale [VAS]). Invalid and nonsystematic data, identified using standard criteria, were most prevalent with the VAS (47.3% of participants). The other tasks produced more (and similar amounts of) valid and systematic data, but required more time to complete than the VAS. Viewing systematic data as more important than completion times, Experiment 2 (n = 153 college students) sought to reduce the amount of invalid datasets in the fixed-alternatives task, and compare amounts of nonsystematic data with the titrating task. Completion times were superior in the titrating task, which produced modestly more systematic data than the fixed-alternatives task. Causes of invalid and nonsystematic data are discussed, as are methods for reducing data exclusion. PMID- 29604332 TI - Effects of hydrochlorothiazide and amlodipine on single oral dose pharmacokinetics of valsartan in healthy Korean subjects: Population model-based approach. AB - Fixed dose combination (FDC) of valsartan (VAL) and hydrochlorothiazide (HCT) or VAL and amlodipine (AML) has been available in many countries for the treatment of hypertension. Due to drug-drug interaction potentials, in the current study we aimed to evaluate potent effects of HCT and AML on pharmacokinetics (PKs) of VAL when they are orally co-administered as FDC (VAL/HCT at 80/12.5 mg or 160/12.5 mg; and VAL/AML at 160/5 mg or 160/10 mg) products in healthy Korean subjects. Population pharmacokinetic (PK) modeling and analysis were performed by the nonlinear mixed-effects modeling software. PKs of VAL was described by two compartment disposition model, first-order elimination, four-sequential first order absorption model, correlation between apparent clearances and volumes of distribution, and lag time. For all FDCs, there were no statistically significant differences in both maximum concentration and areas under the concentration-time curves (AUCs) of VAL in comparison to those when administered VAL alone, except the combination of VAL/AML at 160/10 mg, where AUC0-infinity increased by 11.8% in mean and 6.86% in median. In addition, there was an increasing trend in time to reach peak (Tmax) of VAL in FDCs, where it was increased by 0.22-0.34 h in mean and 0.40-0.44 h in median, except the combination of VAL/HCT at 160/12.5 mg. However, these differences in AUC0-infinity and Tmax might not be considered as clinically important. In conclusion, HCT or AML has no potent effect on PKs of VAL when they are co-administered as FDC products. No dose adjustment for VAL is recommended when co-administered with HCT or AML. PMID- 29604333 TI - Biophysical and in silico interaction studies of aporphine alkaloids with Malonyl CoA: ACP transacylase (FabD) from drug resistant Moraxella catarrhalis. AB - Malonyl-CoA:acyl carrier protein transacylase (FabD), being an essential enzyme of the FAS II pathway, is an attractive target for developing broad-spectrum antibiotics. It performs initiation reaction to form malonyl-ACP, which is a key building block in fatty acid biosynthesis. In this study, we have characterized the FabD from drug-resistant pathogen Moraxella catarrhalis (McFabD). More importantly, we have shown the binding of McFabD with three new compounds from the class of aporphine alkaloids. ITC based binding studies have shown that apomorphine is binding to McFabD with a stronger affinity (KD = 4.87 MUM) as compared to boldine (KD = 7.19 MUM) and magnoflorine (KD = 11.7 MUM). The possible mechanism of fluorescence quenching is found to be static with Kq values higher than 1010, which was associated with the ground state complex formation of aporphine alkaloids with McFabD. Conformational changes observed in the secondary and tertiary structure marked by the loss of helical content during the course of interactions. Molecular docking based studies have predicted the binding mode of aporphine alkaloids and it is found that these compounds are interacting in a similar fashion as known inhibitor corytuberine is interacting with McFabD. The analysis of docking poses have revealed that His 210, Leu102, Gln19, Ser101 and Arg 126 are critical residues, which may play important role in binding. The growth inhibition assay has shown that apomorphine has better MIC value (4-8 MUg/ml) against Moraxella catarrhalis as compared to boldine and magnoflorine. Therefore, the current study suggests that aporphine alkaloids can act as antibacterial agents and possible target of these compounds could be FabD enzyme from the FAS II pathway, and apomorphine scaffold will be more suitable among these compounds for potential development of antibacterial agents. PMID- 29604334 TI - Alternative translation initiation of Caveolin-2 desensitizes insulin signaling through dephosphorylation of insulin receptor by PTP1B and causes insulin resistance. AB - Insulin resistance, defined as attenuated sensitivity responding to insulin, impairs insulin action. Direct causes and molecular mechanisms of insulin resistance have thus far remained elusive. Here we show that alternative translation initiation (ATI) of Caveolin-2 (Cav-2) regulates insulin sensitivity. Cav-2beta isoform yielded by ATI desensitizes insulin receptor (IR) via dephosphorylation by protein-tyrosine phosphatase 1B (PTP1B), and subsequent endocytosis and lysosomal degradation of IR, causing insulin resistance. Blockage of Cav-2 ATI protects against insulin resistance by preventing Cav-2beta-PTP1B directed IR desensitization, thereby normalizing insulin sensitivity and glucose uptake. Our findings show that Cav-2beta is a negative regulator of IR signaling, and identify a mechanism causing insulin resistance through control of insulin sensitivity via Cav-2 ATI. PMID- 29604330 TI - Metabotropic glutamate receptor trafficking. AB - The metabotropic glutamate receptors (mGlu receptors) are G protein-coupled receptors that bind to the excitatory neurotransmitter glutamate and are important in the modulation of neuronal excitability, synaptic transmission, and plasticity in the central nervous system. Trafficking of mGlu receptors in and out of the synaptic plasma membrane is a fundamental mechanism modulating excitatory synaptic function through regulation of receptor abundance, desensitization, and signaling profiles. In this review, we cover the regulatory mechanisms determining surface expression and endocytosis of mGlu receptors, with particular focus on post-translational modifications and receptor-protein interactions. The literature we review broadens our insight into the precise events defining the expression of functional mGlu receptors at synapses, and will likely contribute to the successful development of novel therapeutic targets for a variety of developmental, neurological, and psychiatric disorders. PMID- 29604335 TI - Identification of prion protein-derived peptides of potential use in Alzheimer's disease therapy. AB - Soluble form of the prion protein (PrP) has been previously shown to interact with amyloid-beta (Abeta) peptides, suppressing their fibrillization as well as toxicity, which indicates that this protein may play a protective role in Alzheimer's disease (AD). The shortest known PrP fragment retaining all of these properties corresponds to physiologically generated proteolytic polypeptide PrP23 110/111, called N1. Here we have identified two N1-derived synthetic peptides, encompassing residues 23-50 (PrP23-50) and 90-112 (PrP90-112), which bind to Abeta1-42 protofibrillar oligomers as well as amyloid fibrils. We found that, akin to N1, the abovementioned synthetic peptides not only reduce the initial rate of Abeta fibrillization, but also alter the aggregation pathway of Abeta, inhibiting formation of protofibrillar oligomers and facilitating amorphous aggregation. Furthermore, our data show that N1, PrP23-50 and PrP90-112 protect cultured hippocampal neurons from neurotoxic effects of Abeta oligomers, preventing oligomers-induced retraction of neurites and loss of cell membrane integrity. The above PrP fragments can also attenuate neuronal intake of Abeta. Our results strongly suggest that synthetic peptides such as PrP23-50 and PrP90 112 can be useful in designing a novel class of therapeutics in AD. PMID- 29604336 TI - Mast cell disorders: Protean manifestations and treatment responses. PMID- 29604337 TI - Sexually dimorphic tibia shape is linked to natural osteoarthritis in STR/Ort mice. AB - OBJECTIVES: Human osteoarthritis (OA) is detected only at late stages. Male STR/Ort mice develop knee OA spontaneously with known longitudinal trajectory, offering scope to identify OA predisposing factors. We exploit the lack of overt OA in female STR/Ort and in both sexes of parental, control CBA mice to explore whether early divergence in tibial bone mass or shape are linked to emergent OA. METHOD: We undertook detailed micro-CT comparisons of trabecular and cortical bone, multiple structural/architectural parameters and finite element modelling (FEM) of the tibia from male and female STR/Ort and CBA mice at 8-10 (pre-OA), 18 20 (OA onset) and 40 + weeks (advanced OA) of age. RESULTS: We found higher trabecular bone mass in female STR/Ort than in either OA-prone male STR/Ort or non-prone CBA mice. Cortical bone, as expected, showed greater cross-sectional area in male than female CBA, which surprisingly was reversed in STR/Ort mice. STR/Ort also exhibited higher cortical bone mass than CBA mice. Our analyses revealed similar tibial ellipticity, yet greater predicted resistance to torsion in male than female CBA mice. In contrast, male STR/Ort exhibited greater ellipticity than both female STR/Ort and CBA mice at specific cortical sites. Longitudinal analysis revealed greater tibia curvature and shape deviations in male STR/Ort mice that coincided with onset and were more pronounced in late OA. CONCLUSION: Generalised higher bone mass in STR/Ort mice is more marked in non OA prone females, but pre-OA divergence in bone shape is restricted to male STR/Ort mice in which OA develops spontaneously. PMID- 29604338 TI - High prevalence of Clostridium difficile PCR ribotype 078 in pigs in Korea. AB - Clostridium difficile can cause neonatal enteritis, but has been isolated from both diseased and healthy pigs. C. difficile shedding by pigs is a potential source of zoonotic transmission to humans. The objectives of this study were to characterize the prevalence and genotype of C. difficile with respect to age and health status in the pig industry for the first time in Korea. Fecal samples of 910 pigs were analyzed for the presence of C. difficile. In total, 176 (19.3%) C. difficile strains were isolated. The prevalence was significantly higher (p < 0.01) in diarrheic samples (30.4%) than in non-diarrheic samples (13.3%). The prevalence was highest in diarrheic suckling piglets (53.6%), followed by diarrheic sows (40.0%) and non-diarrheic suckling piglets (34.0%). The toxin genes tcdA, tcdB, cdtA, and cdtB were all detected in 153 isolates (A+B+CDT+, 86.9%). Furthermore, the majority of toxigenic strains (86.5%) were identified as PCR ribotype 078, which is an important pathogen in both pigs and humans. These results indicated that C. difficile is a leading causative pathogen of neonatal diarrhea in piglets in Korea. PMID- 29604339 TI - Expression of the long non-coding RNA H19 and MALAT-1 in growth hormone-secreting pituitary adenomas and its relationship to tumor behavior. AB - Aggressive growth hormone-secreting pituitary adenomas (GHPAs) represent an important clinical problem in patients with acromegaly. Surgical therapy, although often the mainstay of treatment for GHPAs, is less effective in aggressive GHPAs due to their invasive and destructive growth patterns, and their proclivity for infrasellar invasion. LncRNAs are important players in cancer development and emerging in various fundamental biological processes. In the present study, qRT-PCR was performed to examine the expression of lncRNA H19 and MALAT-1 in invasive and non-invasive GHPAs. Our results revealed that the expression of lncRNA H19 was remarkably higher in invasive GHPAs, however, there was no significant differences between the expression of lncRNA MALAT-1 in invasive GHPAs and non-invasive GHPAs, suggesting that lncRNA H19 may play an important role in GHPA invasion. LncRNA H19 might be a target for the study of GHPAs invasion, and a potential index for the diagnosis or prognosis of GHPAs. PMID- 29604340 TI - A case of Pitt-hopkins Syndrome with de novo mutation in TCF4: Clinical features and treatment for epilepsy. AB - Pitt-Hopkins syndrome (PTHS), belonging to the group of 18q-syndromes, is a rare genetic disorder caused by mutations in TCF4. PTHS is characterized by distinctive facial appearance, intermittent hyperventilation, intellectual disability and developmental delay. Although patients with PTHS generally have various systemic symptoms, most of them with a TCF4 mutation manifest the central nervous system (CNS) disorders. We described the first Chinese case with Pitt Hopkins syndrome based on clinical presentations and genetic findings. In addition to the typical features of PTHS, the girl also had paroxysms of tachypnea followed by cyanosis and recurrent seizures. Comprehensive medical examinations were performed including metabolic screening, hepatic and renal function evaluation, abdominal and cardiac ultrasounds. The presence of epileptic discharges in electroencephalography and abnormal brain magnetic resonance imaging were found. High-throughput sequencing was used to detect genetic mutations associated with CNS disorders. Sanger sequencing was used to confirm the mutations in the patient. The c.2182C>T (p.Arg728Ter) mutation was a de novo nonsense mutation at exon 18 in the TCF4 gene of the patient. In conclusion, we have identified a de novo nonsense mutation of TCF4 carried by a Chinese girl with PTHS. The patient underwent anti-epileptic therapy (sodium valproate, levetiracetam, clonazepam), resulting in a reduction of the seizures. PMID- 29604341 TI - Maternal smoking during pregnancy and the risk of pediatric cardiovascular diseases of the offspring: A population-based cohort study with up to 18-years of follow up. AB - BACKGROUND: Cigarette smoke is a well-known reproductive toxicant. We aimed to study the long-term effect of cigarette smoking during pregnancy on the risk for childhood cardiovascular morbidity of the offspring. METHODS: A population-based cohort analysis was performed comparing total and subtypes of cardiovascular related pediatric hospitalizations among offspring of smoking mothers versus offspring of non-smoking mothers. The analysis included all singletons born between the years 1999-2014.A Kaplan-Meier survival curve was used to compare the cumulative cardiovascular morbidity, and a Cox proportional hazards model was constructed to adjust for confounders. RESULTS: The study population included 242,342 newborns which met inclusion criteria; among them 2861 were born to smoking mothers. Offspring of smoking mothers had higher rates of cardiovascular related hospitalizations (1.3% vs. 0.6%, OR 2.1, 95% CI 1.5-2.9; p < 0.001; Kaplan-Meier log-rank test p < 0.001). CONCLUSION: Smoking exposure during pregnancy is associated with an increased risk for long-term pediatric cardiovascular morbidity of the offspring. PMID- 29604342 TI - GPS: Identification of disease genes by rank aggregation of multi-genomic scoring schemes. AB - In solving the gene prioritization problem, ranking candidate genes from most to least promising is attempted before further experimental validation. Integrating the results of various data sources and methods tends to result in a better performance when solving the gene prioritization problem. Therefore, a wide range of datasets and algorithms was investigated; these included topological features of protein networks, physicochemical characteristics and blast similarity scores of protein sequences, gene ontology, biological pathways, and tissue-based data sources. The novelty of this study lies in how the best-performing methods and reliable multi-genomic data sources were applied in an efficient two-step approach. In the first step, various multi-genomic data sources and algorithms were evaluated and seven best-performing rankers were then applied to prioritize candidate genes in different ways. In the second step, global prioritization was obtained by aggregating several scoring schemes. The results showed that protein networks, functional linkage networks, gene ontology, and biological pathway data sources have a significant impact on the quality of the gene prioritization approach. The findings also demonstrated a direct relationship between the degree of genes and the ranking quality of the evaluated tools. This approach outperformed previously published algorithms (e.g., DIR, GPEC, GeneDistiller, and Endeavour) in all evaluation metrices and led to the development of GPS software. Its user-friendly interface and accuracy makes GPS a powerful tool for the identification of human disease genes. GPS is available at http://gpsranker.com and http://LBB.ut.ac.ir. PMID- 29604343 TI - Use of polymerase chain reaction (PCR) in the diagnosis of congenital toxoplasmosis. AB - Congenital toxoplasmosis (CT) is a parasitic disease that causes serious fetal and neonatal harm or death. In countries that do not have antenatal screening programs, the initiation of CT treatment relies on a postnatal diagnosis. Until recently, diagnosis was based on clinical signs and immunoglobulin seropositivity, which is fraught with difficulty. In these cases, diagnosis was often delayed or treatment, which carries risk, started empirically. We highlight the use of polymerase chain reaction to diagnose a case of congenital toxoplasmosis, allowing early treatment and justifying the treatment burden. PMID- 29604344 TI - An avirulent Micropterus salmoides rhabdovirus vaccine candidate protects Chinese perch against rhabdovirus infection. AB - In order to develop live vaccine against Siniperca chuatsi rhabdovirus (SCRV) disease, an avirulent virus strain, designed as Micropterus salmoides rhabdovirus Sanshui (MSRV-SS), was selected from six fish rhabdovirus isolates (SCRV-QY,SCRV SS,SCRV-GM,CMRV-FS,OMBRV-JM,MSRV-SS) by fish challenge assay. When Chinese perch (Siniperca chuatsi) were intraperitoneally injected live virus strain MSRV-SS, they were completely protected from virulent SCRV-GM challenge with a relative percent survival (RPS) of 100% on 18th day post vaccination. Then, the wild type MSRV-SS was purified by plaque clone assays, and the biological characteristics of the clonal strain designed as MSRV-SS-7 were investigated. The MSRV-SS-7 was avirulent to Chinese perch and its growth characteristic was similar to the MSRV SS. The immune protection effects of clonal MSRV-SS-7 against virulent SCRV-GM were evaluated by intraperitoneal injection (IP) vaccination and immersion (IM) vaccination, their RPSs were all 100%. Altogether, these results indicate that MSRV-SS-7 is a potential live vaccine candidate against SCRV disease. PMID- 29604345 TI - Inflammation, insulin signaling and cognitive function in aged APP/PS1 mice. AB - Cognitive dysfunction and neuroinflammation are typical in Alzheimer's disease (AD), but are also associated with normal aging, albeit less severely. Insulin resistance in the brain has been demonstrated in AD patients and is thought to be involved in AD pathophysiology. Using 15-18 month-old APP/PS1 mice, this study measured peripheral and central insulin signaling and sensitivity, inflammatory markers in brain and plasma and oxidative stress and synapse density in the brain. Novel object recognition, Morris water maze and reversal water maze tasks were performed to assess cognitive function in aged APP/PS1 mice and wild type littermates. Glucose tolerance and insulin sensitivity were similar in APP/PS1 mice and wild type controls, however IRS-1 pSer616 was increased in cortex and dentate gyrus of APP/PS1 mice. Recognition and spatial memory was impaired in both APP/PS1 and wild type mice, however learning impairments were apparent in APP/PS1 mice. Expression of GLP-1 receptor, ERK2, IKKbeta, mTOR, PKCtheta, NF kappaB1 and TLR4 was similar between aged APP/PS1 mice and age-matched wild types. Compared to age-matched wild type mice, IFNgamma and IL-4 were increased in brains of APP/PS1 mice. These results suggest that normal aging may be associated with enhanced neuroinflammation, oxidative stress, and cognitive decline, however distinctions are apparent in the brain of APP/PS1 mice in terms of inflammation and insulin signaling and in certain cognitive domains. Demarcation of pathological events that distinguish AD from normal aging will allow for improvements in diagnostic tools and the development of more effective therapeutics. PMID- 29604346 TI - Dithiolethione ACDT suppresses neuroinflammation and ameliorates disease severity in experimental autoimmune encephalomyelitis. AB - Multiple sclerosis (MS) is an autoimmune disorder characterized by the central nervous system (CNS) infiltration of myelin-specific pathogenic T cells followed by brain inflammation in association with demyelination. Similarly, experimental autoimmune encephalomyelitis (EAE), the animal model of MS, also exhibits increased CNS infiltration of pathogenic T cells, including Th1 and Th17, leading to detrimental effects of neuroinflammation and demyelination. We previously reported that 3H-1,2-dithiole-3-thione (D3T), the structurally-simplest of the sulfur-containing dithiolethiones, exerted a promising therapeutic effect in EAE. In the current study we report that 5-Amino-3-thioxo-3H-(1,2)dithiole-4 carboxylic acid ethyl ester (ACDT), a substituted derivative of D3T, exhibits anti-inflammatory properties in EAE. ACDT, administered post immunization, delayed disease onset and reduced disease severity in chronic C57BL/6 EAE, and ACDT, administered during disease remission, suppressed disease relapse in relapsing-remitting SJL/J EAE. Further analysis of the cellular and molecular mechanisms underlying the protective effects of ACDT in EAE revealed that ACDT inhibited pathogenic T cell infiltration, suppressed microglia activation, repressed neurotoxic A1 astrocyte generation, lessened blood-brain barrier disruption, and diminished MMP3/9 production in the CNS of EAE. In summary, we demonstrate that ACDT suppresses neuroinflammation and ameliorates disease severity in EAE through multiple cellular mechanisms. Our findings suggest the potential of developing ACDT as a novel therapeutic agent for the treatment of MS/EAE. PMID- 29604347 TI - Thirty years of Brain, Behavior, and Immunity and counting: How is the journal preparing for the future? PMID- 29604348 TI - Leukocyte-endothelial cell interaction is enhanced in podocalyxin-deficient mice. AB - The highly sialoglycosylated extracellular domain of podocalyxin (Podxl) is a constituent of the endothelial glycocalyx of most blood vessels but it is unknown if Podxl plays a prominent role in the function of the glycocalyx as a regulator of leukocyte-endothelial adhesion. We have recently found that mice lacking Podxl in the vascular endothelium develop histological lesions compatible with severe vasculitis resulting in organ failure and premature death. In this work, we show that these mice have an increased quantity of resident leukocytes within the peritoneal cavity in both basal and inflammatory conditions. Adhesion of macrophagic cells to lung endothelial cells from Podxl-deficient mice was increased under inflammatory stimuli. Both, chemokine binding and chemokine mediated adhesion of immune cells were significantly higher in Podxl-deficient endothelial cells. Moreover, glycocalyx function assessed by measuring the anticoagulant capacity of endothelial cell monolayers to inactivate thrombin was significantly altered in the absence of Podxl. Overall, the results suggest that Podxl is an essential component of the glycocalyx and has an important so far unknown role in preventing leukocyte-endothelial cell adhesion under resting and inflammatory conditions. PMID- 29604349 TI - High sensitive and multiple detection of acute myocardial infarction biomarkers based on a dual-readout immunochromatography test strip. AB - Immunochromatography test strip (ICTS) displayed high advantages in screening acute myocardial infarction (AMI) biomarkers. However, the low sensitivity and nonquantitative results seriously limited its clinical application. Herein, we designed a highly sensitive, quantitative and dual-readout ICTS for assaying multiple AMI biomarkers based on magnetic nanoparticles (MNPs) quenching the fluorescence of Cy5, which was labeled on capture antibodies on test (T) lines. The changes of fluorescent intensity caused by MNPs nanoprobes enabled us to sensitively quantify cTnI and CK-MB for early diagnosis of AMI in 15 min with a corresponding detection limit of 0.049 ng/mL and 0.085 ng/mL, respectively. Meanwhile, the aggregations of MNPs on T lines allowed colorimetric readout in 2 min for rapid diagnosis of emergent and severe AMI patients. Furthermore, the detection results of 30 clinical serum samples were coincident with those by electrochemiluminescence immunoassay. So this approach is promising a new avenue for clinical diagnosis and prognosis of AMI. PMID- 29604351 TI - Decrease in post-stroke spasticity and shoulder pain prevalence over the last 15 years. AB - OBJECTIVES: The usual complications after recent stroke such as disabling spasticity and shoulder pain seemed less frequent in recent years. This study examined the frequency of spasticity and shoulder pain in recent post-stroke patients over time in our physical and rehabilitation medicine department. METHODS: This was a retrospective study of post-stroke inpatients over the last 15 years. Spasticity and shoulder pain prevalence were analyzed, as were demographic, clinical and stroke characteristics. RESULTS: We reviewed medical records for 786 patients (506 men); mean age 58.1 years (SD 13.2); 530 (68%) with ischemic stroke and 256 (32.36%) hemorrhagic stroke. After a first increase from 2000 to 2006, the prevalence of disabling spasticity decreased from 2006 to 2015 (31%-10%; P<0.001). Shoulder pain at admission and during hospitalization also decreased (13% of patients in 2000 to 8% in 2015, P<0.001). Disabling spasticity was associated with shoulder pain (26% of patients with disabling spasticity presented shoulder pain at admission vs 7% with hyperreflexia of the deep tendon reflexes, P<0.05). Characteristics of stroke, time of admission after stroke and length of stay did not change over the years. We observed an increase in number of walking patients at admission and number with a functional paretic arm at admission and discharge (P<0.05), which may explain the increase in functional independence measure scores at admission and discharge (both P<0.05). Prevalence of cognitive disorders increased over the same period (24% in 2000 vs 63% in 2015, P<0.05). CONCLUSIONS: Disabling spasticity and shoulder pain frequency in recent post-stroke patients decreased over the last 15 years, and functional abilities both at admission and discharge improved. Confirmation of these results in a multicentric study may be important evidence of an improvement in stroke healthcare both in stroke and physical and rehabilitation medicine units in the last 10 years in France and could affect future estimations of the need for rehabilitation care after stroke. PMID- 29604350 TI - Exercise prevents high fat diet-induced bone loss, marrow adiposity and dysbiosis in male mice. AB - High fat diets can have detrimental effects on the skeleton as well as cause intestinal dysbiosis. Exercise prevents high fat (HF) diet-induced obesity and also improves bone density and prevents the intestinal dysbiosis that promotes energy storage. Previous studies indicate a link between intestinal microbial balance and bone health. Therefore, we examined whether exercise could prevent HF induced bone pathology in male mice and determined whether benefits correlate to changes in host intestinal microbiota. Male C57Bl/6 mice were fed either a low fat diet (LF; 10 kcal% fat) or a HF diet (60 kcal% fat) and put under sedentary or voluntary exercise conditions for 14 weeks. Our results indicated that HF diet reduced trabecular bone volume, when corrected for differences in body weight, of both the tibia (40% reduction) and vertebrae (25% reduction) as well and increased marrow adiposity (44% increase). More importantly, these effects were prevented by exercise. Exercise also had a significant effect on several cortical bone parameters and enhanced bone mechanical properties in LF but not HF fed mice. Microbiome analyses indicated that exercise altered the HF induced changes in microbial composition by reducing the Firmicutes/Bacteriodetes ratio. This ratio negatively correlated with bone volume as did levels of Clostridia and Lachnospiraceae. In contrast, the abundance of several Actinobacteria phylum members (i.e., Bifidobacteriaceae) were positively correlated with bone volume. Taken together, exercise can prevent many of the negative effects of a high fat diet on male skeletal health. Exercise induced changes in microbiota composition could represent a novel mechanism that contributes to exercise induced benefits to bone health. PMID- 29604352 TI - Pancreaticoduodenectomy is justified in a subset of elderly patients with pancreatic ductal adenocarcinoma: A population-based retrospective cohort study of 4,283 patients. AB - BACKGROUND: The survival benefit of pancreaticoduodenectomy (PD) in elderly patients with pancreatic ductal adenocarcinoma (PDAC) is still unclear. METHODS: Data pertaining to elderly (age >=75 years) and younger (age <75 years) patients with potentially curable PDAC who underwent pancreaticoduodenectomy in the period 2004-2013 were extracted from the Surveillance, Epidemiology, and End Results database. The Cox proportional hazards model and stratified Kaplan-Meier survival analyses were performed. RESULTS: A total of 4283 patients (3256 younger patients and 1027 elderly patients) were included. On multivariate analysis, advanced age (age >=75 years) was not found to be an independent risk factor for diseases specific survival (DSS). Survival analysis disaggregated by gender, tumor size, American Joint Committee on Cancer stage, and tumor differentiation showed comparable DSS in younger and elderly patients (log-rank test). Among patients with poorly-differentiated or undifferentiated tumors, those in the elderly age group experienced shorter DSS as compared to that of younger patients (poorly differentiated: elderly vs. younger, 32.779 months vs. 42.198 months, P = 0.043; undifferentiated: elderly vs. younger, 17.500 months vs. 43.028 months, P = 0.210). However, PD was still warranted for elderly patients with poorly differentiated tumors (surgery vs. without surgery, 32.779 months vs. 11.490 months, P < 0.001). Patients with undifferentiated tumors experienced a non significant survival benefit after PD (surgery vs. without surgery, 17.500 months vs. 11.699 months, P = 0.330). CONCLUSIONS: Advanced age (age >=75 years) is not an independent risk factor for DSS. PD is justified in a subset of elderly PDAC patients; however, it should be performed in a high-volume center to minimize the risk of post operative complications. Future studies should explore individualized treatment strategies for elderly patients with undifferentiated tumors. PMID- 29604353 TI - Genome engineering of Clostridium difficile using the CRISPR-Cas9 system. AB - OBJECTIVES: Clostridium difficile is a notorious pathogenic species that can cause severe gastrointestinal infections in humans and animals. C. difficile infection (CDI) results in thousands of deaths worldwide every year. The elucidation of related mechanisms of CDI and exploration of potential therapeutic strategies are largely delayed due to the lack of efficient genetic engineering tools for C. difficile strains. METHODS: Plasmids carrying the CRISPR-Cas9 system were constructed and transformed into C. difficile through conjugation. Mutants were identified using colony PCR with primers annealing to the regions flanking the target gene deletion/integration locus. Heat-survival assay was used to compare the sporulation frequency between the mutant with spo0A deletion and the wild type strain. The fluorescence in the mutant with the insertion of the green fluorescent protein (GFP) gene was inspected under a fluorescent microscope. RESULTS: An efficient genome editing tool was developed for C. difficile based on the CRISPR-Cas9 system. With this tool, spo0A was deleted with a 100% mutation efficiency. Conversely, an anaerobic GFP gene was successfully inserted into the C. difficile chromosome (with a mutation efficiency of 80%). CONCLUSIONS: The developed CRISPR-Cas9-based genome engineering tool will facilitate functional genomic studies in C. difficile as well as the elucidation of mechanisms related to host-bacteria interaction and pathogenesis of CDI. This will be highly beneficial for the development of innovative strategies for CDI diagnostics and therapies. PMID- 29604354 TI - Thrombin-like enzymes from snake venom: Structural characterization and mechanism of action. AB - Snake venom thrombin-like enzymes (SVTLEs) constitute the major portion (10-24%) of snake venom and these are the second most abundant enzymes present in the crude venom. During envenomation, these enzymes had shown prominently the various pathological effects, such as disturbance in hemostatic system, fibrinogenolysis, fibrinolysis, platelet aggregation, thrombosis, neurologic disorders, activation of coagulation factors, coagulant, procoagulant etc. These enzymes also been used as a therapeutic agent for the treatment of various diseases such as congestive heart failure, ischemic stroke, thrombotic disorders etc. Although the crystal structures of five SVTLEs are available in the Protein Data Bank (PDB), there is no single article present in the literature that has described all of them. The current work describes the structural aspects, structure-based mechanism of action, processing and inhibition of these enzymes. The sequence analysis indicates that these enzymes show a high sequence identity (57-85%) with each other and low sequence identity with trypsin (36-43%), human alpha-thrombin (29 36%) and other snake venom serine proteinases (57-85%). Three-dimensional structural analysis indicates that the loops surrounding the active site are variable both in amino acids composition and length that may convey variable substrate specificity to these enzymes. The surface charge distributions also vary in these enzymes. Docking analysis with suramin shows that this inhibitor preferably binds to the C-terminal region of these enzymes and causes the destabilization of their three-dimensional structure. PMID- 29604355 TI - Gintonin, a ginseng-derived exogenous lysophosphatidic acid receptor ligand, enhances blood-brain barrier permeability and brain delivery. AB - Gintonin is a ginseng-derived G-protein-coupled lysophosphatidic acid (LPA) receptor ligand. Gintonin induces [Ca2+]i transient and biological effects through LPA receptor and increases the permeability of the blood-brain barrier (BBB). However, little is known about its mechanisms on the BBB. We examined the in vitro effects of gintonin using primary human brain microvascular endothelial cells (HBMECs) and the in vivo effects of gintonin on brain delivery. Fluorescent labeled gintonin bound to HBMECs and co-localized with the LPA1 receptor. Gintonin caused morphological changes, increased junctional spaces, and induced differential effects on junctional protein levels such as vascular endothelial cadherin, occludin, zonula occludens 1, and claudin-5, in HBMECs. Gintonin led to the opening of gap junctions between HBMECs, and allowed Texas red-dextran to enter the cells, which was blocked by Ki16425, an LPA1/3 receptor antagonist, and Y27632, a Rho-associated kinase inhibitor. Intravenous administration of gintonin in rodents also increased the delivery of fluorescein isothiocyanate-dextran or erythropoietin to the brain. Furthermore, fluorescent-labeled gintonin bound to endothelial cells, neurons, and glia in the brain following its entry. Our findings show that gintonin facilitates entry to the brain through the paracellular pathway. Thus, gintonin may be an herbal medicine-derived candidate to overcome the BBB in drug delivery. PMID- 29604356 TI - Effect of metal ions on the enzymatic hydrolysis of hemp seed oil by lipase Candida sp. 99-125. AB - In order to study the effect of metal ions on the enzymatic hydrolysis of hemp seed oil by Candida sp. 99-125, the spectroscopy, stability and hydrolytic activity of the biocatalyst were investigated in presence of Ca2+, Mg2+, Fe2+, Fe3+, Cu2+, Sn2+, Pb2+, Zn2+ and Ba2+ metal ions, respectively. The UV spectroscopy showed that all the metal ions enhanced the absorbance but the decrease of fluorescence intensity was observed. All the metal ions could improve the lipase thermal stability except Cu2+ and Ba2+. Hydrolysis of hemp seed oil proved that Ca2+, Fe3+, Pb2+ and Ba2+ could significantly improve the hydrolytic rate, and metal ions could influence lipase selectivity. The study revealed that metal ions could improve lipase stability, hydrolysis activity in the hydrolytic process of hemp seed oil by Candida sp. 99-125. PMID- 29604357 TI - Defining Innovation in Neurosurgery: Results from an International Survey. AB - BACKGROUND: Innovation is a part of the daily practice of neurosurgery. However, a clear definition of what constitutes innovation is lacking and opinions vary from continent to continent, from hospital to hospital, and from surgeon to surgeon. METHODS: In this study, we distributed an online survey to neurosurgeons from multiple countries to investigate what neurosurgeons consider innovative, by gathering opinions on several hypothetical cases. The anonymous survey consisted of 52 questions and took approximately 10 minutes to complete. RESULTS: A total of 355 neurosurgeons across all continents excluding Antarctica completed the survey. Neurosurgeons achieved consensus (>75%) in considering specific cases to be innovative, including laser resection of meningioma, focused ultrasonography for tumor, oncolytic virus, deep brain stimulation for addiction, and photodynamic therapy for tumor. Although the new dura substitute case was not considered innovative, there was consensus among neurosurgeons indicating that institutional review board approval was still necessary to maintain ethical standards. Furthermore, although 90% of neurosurgeons considered an oncolytic virus for glioblastoma multiforme to be innovative, only 78% believed that institutional review board approval was necessary before treatment. CONCLUSIONS: Our results indicate that innovation is a heterogeneous concept among neurosurgeons that necessitates standardization to ensure appropriate patient safety without stifling progress. We discuss both the ethical drawbacks of not having a clear definition of innovation and the challenges in achieving a unified understanding of innovation in neurosurgery and offer suggestions for uniting the field. PMID- 29604358 TI - Trepanation Procedures/Outcomes: Comparison of Prehistoric Peru with Other Ancient, Medieval, and American Civil War Cranial Surgery. AB - More prehistoric trepanned crania have been found in Peru than any other location worldwide. We examine trepanation practices and outcomes in Peru over nearly 2000 years from 400 BC to provide a perspective on the procedure with comparison with procedures/outcomes of other ancient, medieval, and American Civil War cranial surgery. Data on trepanation demographics, techniques, and survival rates were collected through the scientific analysis of more than 800 trepanned crania discovered in Peru, through field studies and the courtesy of museums and private collections in the United States and Peru, over nearly 3 decades. Data on procedures and outcomes of cranial surgery ancient, medieval, and during 19th century through the American Civil war were obtained via a literature review. Successful trepanations from prehistoric times through the American Civil War likely involved shallow surgeries that did not pierce the dura mater. Although there are regional and temporal variations in ancient Peru, overall long-term survival rates for the study series were about 40% in the earliest period (400 200 BC), with improvement to a high of 91% in samples from AD 1000-1400, to an average of 75%-83% during the Inca Period (AD 1400s-1500). In comparison, the average cranial surgery mortality rate during the American Civil war was 46%-56%, and short- and long-term survival rates are unknown. The contrast in outcomes highlights the astonishing success of ancient cranial surgery in Peru in the treatment of living patients. PMID- 29604359 TI - Herpes simplex virus virucidal activity of MST-312 and epigallocatechin gallate. AB - Herpes Simplex Virus (HSV) is the cause of cold sores, blindness and encephalitis and often leads to recurrent infections. Use of current anti-viral therapies can be limited when drug resistant HSV mutants arise. Thus, novel drugs for the treatment of HSV are needed. Previous research in our laboratory has determined that the telomerase inhibitor, MST-312, interferes with multiple steps of the HSV life cycle. The structure of MST-312 contains moieties related to a natural compound found in green tea, epigallocatechin gallate (EGCG). EGCG has been reported to possess direct virucidal activities toward HSV-1. Here, we tested the virucidal activity of MST-312 and compared it to that of EGCG. Specifically, HSV 1 was exposed to various concentrations of MST-312 or EGCG for time periods between 1 and 60 min and then the ability of the treated virions to form plaques on Vero cells was assessed. When treated for 60 min, 40 MUM MST-312 and 0.5-1.0 MUM EGCG significantly reduced the number of HSV-1 plaque forming units. The temperature at which treatment occurred impacted the ability of the compounds to limit viral replication. Both compounds were effective when treatment occurred at 37 degrees C and room temperature (RT). However, no inhibition was seen when virions were treated with MST-312 at 4 degrees C. 1 min treatment with 2 MUM EGCG at RT was sufficient to significantly reduce HSV titers. Higher concentrations of MST-312 were required to inactivate HSV-1 virions compared to EGCG. These data indicate that both EGCG and MST-312 possess direct virucidal properties on HSV-1. PMID- 29604360 TI - Temporal evolutionary analysis of re-emerging recombinant GII.P16_GII.2 norovirus with acute gastroenteritis in patients from Hubei Province of China, 2017. AB - Norovirus (NoV) is a major pathogenic agent of human acute viral gastroenteritis that occurs worldwide. In March 2017, a series of acute NoV-associated gastroenteritis outbreaks occurred in Hubei Province in central China. Here, we sought to better understand the main genotypes and potential evolutionary advantages of circulating NoV strains underlying these outbreaks. During the outbreak, 111 fecal swabs and stool samples were collected from outpatients with acute NoV-associated gastroenteritis in Hubei Province. RNA was extracted from the samples and used as a template for real-time RT-PCR. Sequencing of a portion of the capsid gene and the ORF1/ORF2 overlap was used to assess DNA sequence homology, phylogeny, and recombination using pairwise alignments, MEGA, and Simplot, respectively. Bayesian evolutionary inference analysis was performed using the BEAST software platform to assess the genetic relationships, evolution rate, and evolutionary history of norovirus. GII NoV was determined to be the major pathogen of the acute gastroenteritis outbreaks in Hubei Province, with a 57.7% positive rate. Homology and phylogenic analysis of a portion of the capsid region for GII NoV isolates collected during outbreaks in Hubei showed that the isolates had a very high sequence identity and belonged to GII.2 genotype. Phylogenetic analysis of recombination using the ORF1/ORF2 overlap region revealed a recombinant strain, GII.P16_GII.2, in samples isolated from Hubei Province. The partial polymerase region and capsid gene of the recombinant strain had very high identity (98.7-98.8%) with the NoV strains isolated in Germany in 2016. The evolutionary rate of VP1 gene of GII.2 was distinctly higher than that of the partial polymerase region of GII.16. A phylogenetic tree generated using MCMC showed that the recombinant NoV GII.16_GII.2 was significantly divergent from other GII.16_GII.2 strains observed in China and Japan. Continued circulation of this GII.16_GII.2 recombinant could overtake the predominant GII.4 NoV strain with geographic expansion. Further analysis of the evolutionary dynamics of norovirus is necessary to develop more effective prevention and control strategies. PMID- 29604361 TI - The vitamin D receptor regulates miR-140-5p and targets the MAPK pathway in bone development. AB - BACKGROUND: Skeletal development is a complicated process. The status of vitamin D (VD) is closely related to fetal bone development in the embryonic period. Recently, miRNAs have been found to participate in the regulation of skeletal growth and development in several species. However, the mechanisms underlying the interactions among vitamin D, its receptor (VDR), and miRNAs during the process of bone development remain unclear. The aim of this study was to identify miRNAs that are regulated by 1,25(OH)2D3 in murine osteoblasts and to analyze the relationship and the effects of VD/VDR and miRNAs in vitro and in vivo. METHODS: We performed miRNA sequencing in murine primary osteoblasts and in an osteoblast cell line treated with 1,25(OH)2D3 to identify miRNAs in these cells. After qRT PCR validation, miR-140-5p was selected for further analysis. We assessed the pathways comprising predicted target genes for several expressed miRNAs, including miR-140-5p, validated predicted target genes in the MAPK pathway by qRT PCR, and explored the correlation between VD/VDR and miR-140-5p in vitro and in vivo. RESULTS: 88 miRNAs in murine primary osteoblasts and 49 miRNAs in osteoblast cell line were found to be differentially expressed. MiR-140-5p was upregulated in these 2 types of murine osteoblasts. The expression of miR-140-5p was promoted by 1,25(OH)2D3 through transcriptional activation by VDR, with targeted inhibition of MAPK signaling in osteoblasts. A positive correlation between vitamin D/VDR and miR-140-5p was observed in VDR-knockout mice and in 165 human serum specimens. These data show for the first time that VDR transcriptionally activates miR-140-5p. Therefore, the VD/VDR/miR-140-5p/MAPK signaling axis plays an important role in transmitting the effects of 1,25(OH)2D3. CONCLUSION: Our results demonstrate a novel regulatory mechanism by which miR-140-5p targets the MAPK pathway by means of VD/VDR in vitro and in vivo. These findings provide a new reference for mechanistic research and therapeutic approaches for vitamin D-related bone diseases. PMID- 29604362 TI - Lacking ketohexokinase-A exacerbates renal injury in streptozotocin-induced diabetic mice. AB - OBJECTIVE: Ketohexokinase (KHK), a primary enzyme in fructose metabolism, has two isoforms, namely, KHK-A and KHK-C. Previously, we reported that renal injury was reduced in streptozotocin-induced diabetic mice which lacked both isoforms. Although both isoforms express in kidney, it has not been elucidated whether each isoform plays distinct roles in the development of diabetic kidney disease (DKD). The aim of the study is to elucidate the role of KHK-A for DKD progression. MATERIALS AND METHODS: Diabetes was induced by five consecutive daily intraperitoneal injections of streptozotocin (50 mg/kg) in C57BL/6J wild-type mice, mice lacking KHK-A alone (KHK-A KO), and mice lacking both KHK-A and KHK-C (KHK-A/C KO). At 35 weeks, renal injury, inflammation, hypoxia, and oxidative stress were examined. Metabolomic analysis including polyol pathway, fructose metabolism, glycolysis, TCA (tricarboxylic acid) cycle, and NAD (nicotinamide adenine dinucleotide) metabolism in kidney and urine was done. RESULTS: Diabetic KHK-A KO mice developed severe renal injury compared to diabetic wild-type mice, and this was associated with further increases of intrarenal fructose, dihydroxyacetone phosphate (DHAP), TCA cycle intermediate levels, and severe inflammation. In contrast, renal injury was prevented in diabetic KHK-A/C KO mice compared to both wild-type and KHK-A KO diabetic mice. Further, diabetic KHK-A KO mice contained decreased renal NAD+ level with the increase of renal hypoxia inducible factor 1-alpha expression despite having increased renal nicotinamide (NAM) level. CONCLUSION: These results suggest that KHK-C might play a deleterious role in DKD progression through endogenous fructose metabolism, and that KHK-A plays a unique protective role against the development of DKD. PMID- 29604363 TI - In vitro fertilization/intracytoplasmic insemination and thyroid function: reviewing the evidence. AB - Recent findings, that specific G protein-coupled TSH receptors (TSHR) and the nuclear thyroid hormone receptors (THRs) are widely expressed in reproductive tissues, reveal the close links between hypothalamus-pituitary-thyroid and hypothalamus-pituitary-gonadal axes. It has been suggested that thyroid function as well as thyroid autoimmunity (TAI) have an impact on Assisted Reproduction Technology (ART) reproductive outcome. Lately, it became evident that ovarian stimulation (OS) may also have an impact on thyroid function. This narrative review describes the mutual interaction between thyroid function and OS, by reviewing the current evidence, assessing the pathophysiological links and arriving at practical recommendations. PMID- 29604364 TI - The p75 neurotrophin receptor might mediate sepsis-induced synaptic and cognitive impairments. AB - Systemic inflammation induces cognitive impairment, yet the mechanism involved in this process is unclear. Neurotrophin receptor p75 (p75NTR) signaling is a key pathological factor contributing to neurobehavioral abnormalities in many neurodegenerative diseases. However, the role of p75NTR signaling in the regulation of sepsis-induced cognitive impairment remains largely to be elucidated. In this study, systemic inflammation was induced by cecal ligation and puncture (CLP). Neurobehavioral performances were evaluated by open field, novel object recognition, and fear conditioning tests. The expressions of proinflammatory cytokines (tumor necrosis factor (TNF-alpha), interleukin-1beta (IL-1beta), IL-6, IL-10), apoptosis marker cleaved caspase-3, ionized calcium binding adaptor molecule 1 (IBA1), proBDNF, p75NTR, c-Jun N-terminal kinase (JNK), and pJNK in the hippocampus were determined by enzyme-linked immunosorbent assay, western blot analysis, and immunofluorescence. The synaptic marker in the CA1 region of the hippocampus was assessed by Golgi staining. In the present study, we showed that systemic inflammation induced cognitive impairment, which was accompanied by increased expressions of hippocampcal proBDNF and p75NTR. Of note, we found that LM11A-31, an orally available, blood-brain barrier-permeant small-molecule p75NTR signaling modulator significantly reversed the sepsis induced cognitive impairment and restored most of the abnormal biochemical parameters. Taken together, our study suggests that proBDNF/p75NTR signaling pathway might play a key role in the development of sepsis-induced cognitive impairment, whereas specific p75NTR inhibitor may provide a novel therapeutic approach for this disorder and possible other neurodegenerative diseases. PMID- 29604366 TI - Differential recruitment of theory of mind brain network across three tasks: An independent component analysis. AB - Social neuroscience research has focused on an identified network of brain regions primarily associated with processing Theory of Mind (ToM). However, ToM is a broad cognitive process, which encompasses several sub-processes, such as mental state detection and intentional attribution, and the connectivity of brain regions underlying the broader ToM network in response to paradigms assessing these sub-processes requires further characterization. Standard fMRI analyses which focus only on brain activity cannot capture information about ToM processing at a network level. An alternative method, independent component analysis (ICA), is a data-driven technique used to isolate intrinsic connectivity networks, and this approach provides insight into network-level regional recruitment. In this fMRI study, three complementary, but distinct ToM tasks assessing mental state detection (e.g. RMIE: Reading the Mind in the Eyes; RMIV: Reading the Mind in the Voice) and intentional attribution (Causality task) were each analyzed using ICA in order to separately characterize the recruitment and functional connectivity of core nodes in the ToM network in response to the sub processes of ToM. Based on visual comparison of the derived networks for each task, the spatiotemporal network patterns were similar between the RMIE and RMIV tasks, which elicited mentalizing about the mental states of others, and these networks differed from the network derived for the Causality task, which elicited mentalizing about goal-directed actions. The medial prefrontal cortex, precuneus, and right inferior frontal gyrus were seen in the components with the highest correlation with the task condition for each of the tasks highlighting the role of these regions in general ToM processing. Using a data-driven approach, the current study captured the differences in task-related brain response to ToM in three distinct ToM paradigms. The findings of this study further elucidate the neural mechanisms associated with mental state detection and causal attribution, which represent possible sub-processes of the complex construct of ToM processing. PMID- 29604367 TI - Effects of N-methyl-d-aspartate receptor (NMDAr) uncompetitive antagonists in a delay discounting paradigm using a concurrent-chains procedure. AB - Impulsive choice is often assessed in rodents using a delay discounting (DD) paradigm in which the delay to a large reinforcer (LR) increases across the session. This procedure allows one to test the effects of pharmacological manipulations within a single session. Because discounting is influenced by sensitivity to reinforcer magnitude (SRM) and sensitivity to delayed reinforcement (SDR), applying quantitative analyses (e.g., fitting hyperbolic function) is important for determining the precise behavioral mechanisms being altered following drug administration. One caveat to this approach is that observing increases in SMR/SDR can be difficult (e.g., most rats choose the LR when its delivery is immediate, whereas some rats may show exclusive preference for the small reinforcer [SR] when a delay on the LR is imposed). We utilized a variant of a concurrent-chains procedure in which rats (n = 8) could not show exclusive preference for either reinforcer, thus allowing one to observe increases/decreases in responding at each delay. The NMDAr antagonists MK-801 (0, 0.003, 0.01, 0.03 mg/kg), ketamine (0, 1.0, 5.0, 10.0 mg/kg), and memantine (0, 2.5, 5.0, 7.5 mg/kg) were administered following baseline training because this receptor has recently been implicated in DD. MK-801 (0.03 mg/kg) decreased SRM and SDR. Memantine (7.5 mg/kg) decreased SRM only. These results show that this variant of the concurrent-chains procedure can be used to study the effects of pharmacological manipulations on distinct aspects of DD. PMID- 29604368 TI - Osmolality predictive models of different polymers as tools in parenteral and ophthalmic formulation development. AB - During the development of parenteral dosage forms, different physicochemical studies are required to ensure stable, effective and safe formulations. The osmolality of this kind of dosage forms should bear a close similarity to the body fluids to prevent local irritation, pain or even more significant side effects like endothelial damage. The osmotic studies performed in Polyethylene glycol 400 (PEG 400), Polyethylene glycol 4000 (PEG 4000), Poloxamer 407 (P407), Sodium Hyaluronate (SH), Chondroitin Sulphate Sodium (CS), Cremophor RH 40 (CRE40) and Polyvinyl alcohol (PVA) aqueous solutions, showed that the theoretical determination of the osmolality based on their molecular weight as the only determinant factor did not agree with the values obtained by the measurement of colligative properties such as the freezing point depression. The data obtained from this study and its analysis, provided predictive equations that can be used as tools in the primary development to estimate formulation's osmolality at different concentrations; and its evolution over a period at the hypothetical worst-case scenario of storage temperature. PMID- 29604365 TI - Effects of ceftriaxone on hydrocodone seeking behavior and glial glutamate transporters in P rats. AB - Hydrocodone (HYD) is one of the most widely prescribed opioid analgesic drugs. Several neurotransmitters are involved in opioids relapse. Among these neurotransmitters, glutamate is suggested to be involved in opioid dependence and relapse. Glutamate is regulated by several glutamate transporters, including glutamate transporter 1 (GLT-1) and cystine/glutamate transporter (xCT). In this study, we investigated the effects of ceftriaxone (CEF) (200 mg/kg, i.p.), known to upregulate GLT-1 and xCT, on reinstatement to HYD (5 mg/kg, i.p.) using the conditioned place preference (CPP) paradigm in alcohol-preferring (P) rats. Animals were divided into three groups: 1) saline-saline group (SAL-SAL); 2) HYD SAL group; and 3) HYD-CEF group. The CPP was conducted as follows: habituation phase, conditioning phase with HYD (i.p.) injections every other day for four sessions, extinction phase with CEF (i.p.) injections every other day for four sessions, and reinstatement phase with one priming dose of HYD. Time spent in the HYD-paired chamber after conditioning training was increased as compared to pre conditioning. There was an increase in time spent in the HYD-paired chamber with one priming dose of HYD in the reinstatement test. HYD exposure downregulated xCT expression in the nucleus accumbens and hippocampus, but no effects were observed in the dorsomedial prefrontal cortex and amygdala. Importantly, CEF treatment attenuated the reinstatement effect of HYD and normalized xCT expression in the affected brain regions. These findings demonstrate that the attenuating effect of HYD reinstatement with CEF might be mediated through xCT. PMID- 29604369 TI - Star-shaped poly(oligoethylene glycol) copolymer-based gels: Thermo-responsive behaviour and bioapplicability for risedronate intranasal delivery. AB - The aim of this work was to obtain an intranasal delivery system with improved mechanical and mucoadhesive properties that could provide prolonged retention time for the delivery of risedronate (RS). For this, novel in situ forming gels comprising thermo-responsive star-shaped polymers, utilizing either polyethylene glycol methyl ether (PEGMA-ME 188, Mn 188) or polyethylene glycol ethyl ether (PEGMA-EE 246, Mn 246), with polyethylene glycol methyl ether (PEGMA-ME 475, Mn 475), were synthesized and characterized. RS was trapped in the selected gel forming solutions at a concentration of 0.2% w/v. The pH, rheological properties, in vitro drug release, ex vivo permeation as well as mucoadhesion were also examined. MTT assays were conducted to verify nasal tolerability of the developed formulations. Initial in vivo studies were carried out to evaluate anti osteoporotic activity in a glucocorticoid induced osteoporosis model in rats. The results showed successful development of thermo-sensitive formulations with favorable mechanical properties at 37 degrees C, which formed non-irritant, mucoadhesive porous networks, facilitating nasal RS delivery. Moreover, sustained release of RS, augmented permeability and marked anti-osteoporotic efficacy as compared to intranasal (IN) and intravenous (IV) RS solutions were realized. The combined results show that the in situ gels should have promising application as nasal drug delivery systems. PMID- 29604370 TI - The application of STEP-technology(r) for particle and protein dispersion detection studies in biopharmaceutical research. AB - Particle detection and analysis techniques are essential in biopharmaceutical industries to evaluate the quality of various parenteral formulations regarding product safety, product quality and to meet the regulations set by the authority agencies. Several particle analysis systems are available on the market, but for the operator, it is quite challenging to identify the suitable method to analyze the sample. At the same time these techniques are the basis to gain a better understanding in biophysical processes, e.g. protein interaction and aggregation processes. The STEP-Technology(r) (Space and Time resolved Extinction Profiles), as used in the analytical photocentrifuge LUMiSizer(r), has been shown to be an effective and promising technique to investigate particle suspensions and emulsions in various fields. In this study, we evaluated the potentials and limitations of this technique for biopharmaceutical model samples. For a first experimental approach, we measured silica and polystyrene (PS) particle standard suspensions with given particle density and refractive index (RI). The concluding evaluation was performed using a variety of relevant data sets to demonstrate the significant influences of the particle density for the final particle size distribution (PSD). The most challenging property required for successful detection, turbidity, was stated and limits have been set based on the depicted absorbance value at 320 nm (A320 values). Furthermore, we produced chemically cross-linked protein particle suspensions to model physically "stable" protein aggregates. These results of LUMiSizer(r) analysis have been compared to the orthogonal methods of nanoparticle tracking analysis (NTA), dynamic light scattering (DLS) and micro-flow imaging (MFI). Sedimentation velocity distributions showed similar tendencies, but the PSDs and absolute size values could not be obtained. In conclusion, we could demonstrate some applications as well as limitations of this technique for biopharmaceutical samples. In comparison to orthogonal methods this technique is a great complementary approach if particle data e.g. density or refractive index can be determined. PMID- 29604371 TI - In situ monitoring of nanoparticle formation: Antisolvent precipitation of azole anti-fungal drugs. AB - In this work we report the effect of stabilizer choice and concentration on nanoparticle (NP) stability over time. Three different BCS class II active pharmaceutical ingredient (APIs): itraconazole (ITR), ketoconazole (KETO) and posaconazole (POS) were chosen due to their poor aqueous solubility and closely related chemical structures. Polyethylene glycol, polyethylene glycol methyl ether and polyethylene glycol dimethyl ether (DMPEG) with a molecular weight of 2000 Da were included as stabilisers. NPs were formed in situ using an anti solvent addition, bottom up method at 25 degrees C. Colloidal stability was monitored using dynamic light scattering (DLS), accompanied by morphological examination of the NPs using scanning electron microscopy. Kinetic modelling indicates nanoparticle growth is driven by Ostwald ripening (OR). The presence of DMPEG causes OR growth to become an interface controlled process following a parabola trend. DMPEG encourages OR for POS NPs whilst driving the crystallisation process. The rate of OR appears to be inherent of the crystallisation pathway by which these APIs proceed. Crystallisation mechanisms are API, stabilizer type and concentration dependent. DLS is suitable as an initial systematic screening method for stabilizer selection, aiding the pharmaceutical scientist in the optimisation of nano-formulations. PMID- 29604372 TI - Pegylated nanoparticles for the oral delivery of nimodipine: Pharmacokinetics and effect on the anxiety and cognition in mice. AB - Nimodipine may be of interest to treat behavioral alterations and memory deficits. However, its oral administration is hampered by a low bioavailability. The aim of this work was to develop pegylated nanoparticles as oral carriers of nimodipine and test their capability to both reverse the anxiety and protect against cognitive impairment of in stressed mice. Pegylated nanoparticles (NMD NP/PEG), with a size of 190 nm and a payload of 68 ug/mg, significantly improve the oral bioavailability of nimodipine; about 7-times higher than for the control drug solution (62% vs 9%). The effect of oral nimodipine on the anxiety and cognitive capabilities in a model of stressed mice was also evaluated. NMD-NP/PEG displayed a poor effect on the anxiety-like behavior of animals. Nevertheless, only the treatment with NMD-NP/PEG exerted a protective effect against the memory impairments induced by chronic corticosterone administration, improving the cognitive capabilities of animals when compared with controls. These pegylated nanocarriers may represent a useful strategy to develop new oral treatments for preventing from cognitive impairments. PMID- 29604373 TI - Transdermal immunomodulation: Principles, advances and perspectives. AB - Immunomodulation, manipulation of the immune responses towards an antigen, is a promising strategy to treat cancer, infectious diseases, allergies, and autoimmune diseases, among others. Unique features of the skin including the presence of tissue-resident immune cells, ease of access and connectivity to other organs makes it a unique target organ for immunomodulation. In this review, we summarize advances in transdermal delivery of agents for modulating the immune responses for vaccination as well as tolerization. The biological foundation of skin-based immunomodulation and challenges in its implementation are described. Technological approaches aimed at enhancing the delivery of immunomodulatory therapeutics into skin are also discussed in this review. Progress made in the treatment of several specific diseases including cancer, infections and allergy are discussed. Finally, this review discusses some practical considerations and offers some recommendations for future studies in the field of transdermal immunomodulation. PMID- 29604374 TI - Insulin delivery systems combined with microneedle technology. AB - Diabetes, a metabolic disorder of glucose, is a serious chronic disease and an important public health problem. Insulin is one of the hormones for modulating blood glucose level and the products of which is indispensable for most diabetes patients. Introducing microneedles (MNs) to insulin delivery is promising to pave the way for modulating glucose level noninvasively of diabetes patients, as which born to be painless, easy to handle and no need of any power supply. In this work, we review the process of insulin delivery systems (IDSs) based on MN technology in terms of two categories: drug free MNs and drug loaded MNs. Drug free MNs include solid MNs ("poke and patch"), hollow MNs ("poke and flow") and reservoir-based swelling MNs ("poke and swell R-type"), and drug loaded MNs include coated MNs ("coat and poke"), dissolving MNs ("poke and release") and insulin incorporated swelling MNs ("poke and swell I-type"). Majority researches of MN-based IDSs have been conducted by using hollow MNs or dissolving MNs, and almost all clinical trials for MN-based IDSs have employed hollow MNs. "Poke and patch" approach dramatically increase skin permeability compared to traditional transdermal patch, but MNs fabricated from silicon or metal may leave sharp waste in the skin and cause a safety issue. "Poke and flow" approach, similar to transitional subcutaneous (SC) injection, is capable of producing faster insulin absorption and action than SC injection but may associate with blockage, leakage and low flow rate. Coated MNs are able of retaining the activity of drug, which loaded in a solid phase, for a long time, however have been relatively less studied for insulin application as the low drug dosing. "Poke and release" approach leaves no biohazardous sharp medical waste and is capable of rapid drug release. "Poke and swell R-type" can be seen as a combination of "poke and flow" and "poke and patch" approach, while "poke and swell I-type" is an approach between "coat and poke" and "poke and release" approach. Insulin MNs are promising for painless diabetes therapeutics, and additional efforts for addressing fundamental issues including the drug loading, the PK/PD profile, the storage and the safety of insulin MNs will accelerate the clinical transformation. PMID- 29604375 TI - Drug delivery to the lens for the management of cataracts. AB - Cataracts are one of the most prevalent diseases of the lens, affecting its transparency and are the leading cause of reversible blindness in the world. The clarity of the lens is essential for its normal physiological function of refracting light onto the retina. Currently there is no pharmaceutical treatment for prevention or cure of cataracts and surgery to replace the affected lens remains the gold standard in the management of cataracts. Pharmacological treatment for prevention of cataracts is hindered by many physiological barriers that must be overcome by a therapeutic agent to reach the avascular lens. Various therapeutic agents and formulation strategies are currently being investigated to prevent cataract formation as access to surgery is limited. This review provides a summary of recent research in the field of drug delivery to the lens for the management of cataracts including models used to study cataract treatments and discusses the future perspectives in the field. PMID- 29604376 TI - Identification and characterization of potential bioactive compounds from the leaves of Leucosidea sericea. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Leucosidea sericea is a southern African tree used for treating different diseases including microbial infections and inflammatory-related conditions. AIM OF THE STUDY: To isolate and identify the chemicals in Leucosidea sericea which possibly account for the diverse therapeutic effects of the species. MATERIALS AND METHODS: Leaf material was extracted using 20% methanol and subsequently partitioned with different solvents (hexane, dichloromethane, ethyl acetate and butanol). Resultant fractions were subjected to bioactive (antimicrobial)-guided isolation and the structural elucidation was conducted using NMR (1D and 2D) spectroscopic methods. Given the broad uses of Leucosidea sericea in traditional medicine, the extract, fractions and isolated compounds were evaluated in five (5) biological assays in vitro (antimicrobial, antioxidant, acetylcholinesterase (AChE) and anti-inflammatory inhibition as well as cytotoxicity effect). RESULTS: As the most active fractions, from ethyl acetate yielded 5,7-dihydroxychromone (1); 1-hydroxy-2 oxopomolic acid (2); 3,5,7,3',4'-pentahydroxyflavone (3) and Tiliroside (4). For the first time, these four (4) compounds were isolated from leaves of Leucosidea sericea. These aforementioned compounds demonstrated broad-spectrum antibacterial activity (1.95-125 ug/mL) and noteworthy antifungal (3.9-250 ug/mL) potential. In addition to its noteworthy antimicrobial activity, compound 3 also demonstrated significant antioxidant (EC50 = 14 ug/mL in DPPH assay) and anti-inflammatory (inhibited the level of ELAM by approximately 36% and decreased also the viability of endothelial cells) activities in vitro. Overall, AChE inhibition activity and cytotoxic response was generally weak for the extracts, fractions and isolated compounds. CONCLUSION: The pool of chemicals in Leucosidea sericea were enriched with the isolation and identification of four (4) compounds obtained from the leaf extract. Among these compounds, the significant antimicrobial activity of compound 3 provides strong evidence that support the use of Leucosidea sericea for microbial-related infections in folk medicine. PMID- 29604377 TI - Pomegranate polyphenols and urolithin A inhibit alpha-glucosidase, dipeptidyl peptidase-4, lipase, triglyceride accumulation and adipogenesis related genes in 3T3-L1 adipocyte-like cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Pomegranate fruit is considered an antidiabetic medicine in certain systems of traditional medicine. In addition, pomegranate polyphenols are known as powerful antioxidants with beneficial effects such as the reduction of oxidative / inflammatory stress and the increase of protective signalling such as antioxidant enzymes, neurotrophic factors and cytoprotective proteins. AIM OF THE STUDY: This work evaluates the effects of pomegranate juice, its main polyphenols known as ellagic acid and punicalagin, as well as its main metabolite urolithin A, on physiological and pharmacological targets of metabolic diseases such as obesity and diabetes. MATERIALS AND METHODS: For this purpose, enzyme inhibition bioassays of lipase, alpha-glucosidase and dipeptidyl peptidase 4 were carried out in cell-free systems. Similarly, adipocytes derived from 3T3 L1 cells were employed to study the effects of ellagic acid, punicalagin and urolithin A on adipocyte differentiation and triglyceride (TG) accumulation. RESULTS: Pomegranate juice, ellagic acid, punicalagin and urolithin A were able to inhibit lipase, alpha-glucosidase and dipeptidyl peptidase-4. Furthermore, all tested compounds but significantly the metabolite urolithin A displayed anti adipogenic properties in a dose-dependent manner as they significantly reduced TG accumulation and gene expression related to adipocyte formation such as adiponectin, PPARgamma, GLUT4, and FABP4 in 3T3-L1 adipocytes. CONCLUSION: These results may explain from a molecular perspective the beneficial effects and traditional use of pomegranate in the prevention of metabolic-associated disorders such as obesity, diabetes and related complications. PMID- 29604378 TI - Taste of phytocompounds: A better predictor for ethnopharmacological activities of medicinal plants than the phytochemical class? AB - ETHNOPHARMACOLOGICAL RELEVANCE: Understanding the patterns that shape traditional medical knowledge is essential for accelerating ethnopharmacological progress. According to Ayurveda, medicinal plants that belong to different taxa, but which have similar taste, may display similar (ethno)pharmacological activities (EPAs) (Bhishagratna, 1998; Sharma and Dash, 2006). AIM OF THE STUDY: To understand the patterns that govern the distribution of herbal EPAs in Ayurveda and to evaluate the potential concordance between chemical class or taste of the constituent phytocompounds and EPAs. MATERIAL AND METHODS: A mixed database (PhytoMolecularTasteDB) was constructed for Ayurvedic medicinal plants by integrating modern data (medicinal plant composition, phytochemical taste) with traditional data (ethnopharmacological activities of plant). PhytoMolecularTasteDB contains 431 Ayurvedic medicinal plants, 94 EPAs, 223 chemical classes of phytocompounds and 438 herbal tastants. Potential global or individual associations between chemical classes/taste of the phytoconstituents and EPAs were statistically analyzed. RESULTS: There was no global statistical correlation between the various chemical classes of phytocompounds and EPAs, although there were several individual correlations. The results suggest the existence of a global statistical correlation (besides several individual correlations) between the plant "molecular taste" (various taste-based classes of phytocompounds) and EPAs. CONCLUSIONS: These results suggest that phytochemical taste may be more relevant than chemical class for EPAs prediction. PMID- 29604379 TI - Ethnopharmacological properties of Artemisia asiatica: A comprehensive review. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia asiatica Nakai (Compositae) has a long history as a traditional remedy. Preparation from various parts of the plant (aerial parts and leaves) are used to treat a wide range of diseases including gastric trouble, liver dysfunction, and skin inflammation. AIMS OF THIS REVIEW: The aims of this review were: 1) to provide an overview of recent studies and progress on A. asiatica-derived ethnopharmacological compounds and their pharmacological activities; and 2) to summarize existing evidence and provide insight for future studies. MATERIALS AND METHODS: This investigation was carried out by analyzing published books and research papers via scientific databases, namely Science Direct, PubMed ACS Publication, Wiley Online Library, CNKI and information obtained online. The keywords "Artemisia asiatica traditional uses," "Compounds isolated and studied in Artemisia asiatica," and "Pharmacological advances in Artemisia asiatica" were used and articles published between 1995 and 2017 were considered. In total, 500 works related to biological activities of A. asiatica were identified, and only materials published in English were included in the review. RESULTS: Comparative analysis of literature searched through sources available confirmed that the ethnopharmacological use of A. asiatica was recorded in Korea, China, and Japan. Phytochemical studies revealed the presence of flavonoids, sesquiterpene lactones, monoterpenes, and steroids in A. asiatica. Of these, flavonoids have been shown to exhibit significant pharmacological effects such as gastroprotective, anti-inflammatory, anti-tumor, and anti microbial actions. CONCLUSIONS: Phytochemical and pharmacological studies of Artemisia asiatica have proven that this plant is one of valuable medicinal sources with neuroprotective, gastroprotective, anti-oxidative, anti inflammatory, and anti-cancer effects. Although ethanol extract of this plant is now being prescribed as gastroprotective and anti-ulcerative medicine, it is now time to expand its application to other human inflammatory diseases such as pancreatitis and hepatitis and further extensive study on toxicity in human. Therefore, the present review will encourage further studies of A. asiatica in the pursuit of wide range of therapeutic remedy. PMID- 29604380 TI - Informal Caregiver Challenges for Advanced Cancer Patients During End-of-Life Care in Johannesburg, South Africa and Distinctions Based on Place of Death. AB - CONTEXT: In sub-Saharan Africa, late diagnosis with cancer is common. Many dying patients rely on family members for care; little is known about the challenges African informal caregivers face. OBJECTIVES: To better understand the challenges of informal caregivers at the end of life in South Africa, both at home and in inpatient facilities. METHODS: We included advanced cancer patients and caregivers from a public hospital in Johannesburg, South Africa. Study nurses interviewed patients and caregivers about their experiences. Using univariate and multivariate analyses, we determined the factors associated with greater caregiver difficulty, focusing on patients dying at home vs. in inpatient facilities. RESULTS: Among 174 informal caregivers, 62 (36%) reported "a lot" of challenges. These caregivers struggled most with keeping the patient clean (16%) and with patient interactions (34%). Symptoms associated with greater difficulty included pain (odds ratio [OR] 2.4 [95% CI 1.2-4.7]), urinary incontinence (OR 2.3 [95% CI 1.1-4.9]), fecal incontinence (OR 2.4 [95% CI 1.0-5.7]), insomnia (OR 2.9 [95% CI 1.3-6.9]), fatigue (OR 6.3 [95% CI 1.8-21.6]), extremity weakness (OR 2.9 [95% CI 1.3-6.9]), shame (OR 4.2 [95% CI 1.5-12.0]), and sadness (OR 2.3 [95% CI 1.1-4.8]). Caregivers of patients dying at home reported the greatest difficulty with patients' physical symptoms; caregivers of those dying in facilities reported the greatest difficulty with emotional symptoms. CONCLUSION: Informal caregivers of patients dying at home reported challenges with practical functional care; this effect was reduced in the inpatient setting. Skills training for these caregivers could relieve some of this burden. PMID- 29604381 TI - Sex Differences and Estrous Cycle Changes in Synaptic Plasticity-related microRNA in the Rat Medial Amygdala. AB - The posterodorsal medial amygdala (MePD) is a sex steroid-sensitive and sexually dimorphic subcortical area that dynamically modulates social behaviors in rats. As different microRNA (miRNA) can act as post-transcriptional regulators of synaptic processing, we addressed changes that occur in miRNA expression in the MePD of males and females along the estrous cycle. The expression of miR25-3p, miR132-3p, miR138-5p, miR181a-5p, miR195-5p, and miR199a-5p, involved in neuronal cytoskeleton remodeling and synaptic plasticity, were evaluated by RT-qPCR. We found that the expression of miR138-5p was higher in males than in females along the different phases of the estrous cycle. Males also showed higher levels of miR 181a when compared to females in diestrus and estrus. On the other hand, when compared to females in proestrus, males presented lower levels of miR132-3p and miR199a-5p. The expression of miR25-3p was higher in diestrus females than in proestrus females. In addition, diestrus females showed higher values of miR25 3p, miR181a-5p, and miR195-5p when compared to estrus females. These miRNA expression profiles indicate a variable and fine-tuned protein regulation in the adult MePD. It is likely that these miRNA can be involved in structural and functional synaptic features and plasticity characteristic of males and cycling females and for the MePD regulation of mammalian reproduction. PMID- 29604382 TI - The Role of Depressive Subtypes within the Neuroinflammation Hypothesis of Major Depressive Disorder. AB - Major depressive disorder (MDD) is a very common disease that affects more than 350 million people worldwide, representing an enormous socioeconomic burden. From a clinical perspective, MDD can be divided into different subtypes, such as melancholic or atypical MDD. Interestingly, increasing evidence points toward an involvement of the immune system in MDD pathogenesis. However, inflammation does not seem to have the same impact on every MDD type. Here, we describe how inflammation can affect monoaminergic and glutamatergic neurotransmission, which provides a possible mechanism for MDD onset. Next, we examine the regional specificity of neuroinflammation, which shows striking overlaps with neural patterns activated in atypical MDD. Furthermore, we outline how inflammation may translate to subtype-specific clinical features and we suggest how this could be used for diagnostic and treatment purposes. By providing a link back to a dysregulated immune system as a contributing factor to MDD subtypes, we explain how brain regions particularly affected by certain subtypes may regulate the cortisol circuitry. PMID- 29604383 TI - Inactivation of the Ventrolateral Orbitofrontal Cortex Impairs Flexible Use of Safety Signals. AB - Survival depends on adaptation to shifting environmental risks and opportunities. Regarding risks, the mechanisms which permit acquisition, recall, and flexible use of aversive associations is poorly understood. Drawing on the evidence that the orbital frontal cortex is critical to integrating outcome expectancies with flexible appetitive behavioral responses, we hypothesized that OFC would contribute to behavioral flexibility within an aversive learning domain. We introduce a fear conditioning procedure in which adult male rats were presented with shock-paired conditioned stimulus (CS+) or a safety cue (CS-). In a recall test, rats exhibit greater freezing to the CS+ than the CS-. Temporary inactivation of the ventrolateral OFC with muscimol prior to conditioning did not affect later discrimination, but inactivation after learning and prior to recall impaired discrimination between safety and danger cues. This result complements prior research in the appetitive domain and suggests that the OFC plays a general role in behavioral flexibility regardless of the valence of the CS. PMID- 29604384 TI - Allopregnanolone Effects on Transmission in the Brain Stem Solitary Tract Nucleus (NTS). AB - During pregnancy, the progesterone metabolite, allopregnanolone (ALLO), becomes elevated and has been associated with altered levels within the CNS and resulting changes in GABAA receptor function. Pregnant animals poorly compensate reflexes for a decrease in blood pressure during hemorrhage. Previous works suggested that ALLO decreases baroreflex responses by central actions, however, the underlying mechanisms are poorly understood. In this study, we tested ALLO actions on visceral afferent synaptic transmission at second-order neurons within medial portions of the nucleus tractus solitarius (NTS) using hindbrain slices from non pregnant female rats. Solitary tract (ST) stimulation-evoked excitatory postsynaptic currents (ST-eEPSCs) in NTS neurons directly connected to vagal afferents within the ST. ST-eEPSCs were functionally identified as monosynaptic by the latency characteristics (low jitter = standard deviation of latency, <=200 MUs) to ST stimulation. Such second-order neurons all displayed spontaneous inhibitory postsynaptic currents (sIPSCs), and low micromolar concentrations of ALLO increased frequency and decay time. At submicromolar concentrations, ALLO induced a tonic, GABAergic inhibitory current and suppressed ST-eEPSCs' amplitude. While GABAA receptor antagonist, bicuculline, blocked all ALLO effects, gabazine only blocked sIPSC actions. In current-clamp mode, ALLO perfusion increased failure of ST stimulation to trigger action potentials in most neurons. Thus, our results indicate that ALLO acts to suppress visceral afferent ST synaptic transmission at first synapses by activating pharmacologically distinct GABAA subtypes at different concentration ranges. This ALLO-mediated attenuated visceral afferent signal integration in NTS may underlie reflex changes in blood pressure during gestation. PMID- 29604385 TI - Cardiac telocytes. From basic science to cardiac diseases. II. Acute myocardial infarction. AB - INTRODUCTION: The purpose of this study was to evaluate the scientific evidence regarding a potential role of telocytes in myocardial infarction. MATERIALS AND METHODS: To this purpose, we performed a systematic review of relevant scientific literature, indexed in PubMed, Web of Science, and Scopus. RESULTS AND DISCUSSIONS: We found six articles containing relevant studies aimed at liking myocardial infarction and telocytes. The studies that were analysed in this review failed to show, beyond a reasonable doubt, that telocytes do actually have significant roles in myocardial regeneration after myocardial infarction. The main issues to be addressed in future studies are a correct characterization of telocytes, and a differentiation from other cell types that either have similar morphologies (using electron microscopy) or similar immunophenotypes, with emphasis on endothelial progenitors, which were previously shown to have similar morphology, and functions in cardiac regeneration after myocardial infarction. PMID- 29604386 TI - Applications of inflammation-derived gingival stem cells for testing the biocompatibility of dental restorative biomaterials. AB - BACKGROUND: Normal or inflamed gingival tissues are regarded as a source of mesenchymal stem cells (MSCs) abundant and easily accessible through minimally invasive dental procedures. Due to the proximity of dental resin composites to gingival tissues and to the possible local cytotoxic effect of the eluted components, gingiva-derived MSCs could be used to investigate the biocompatibility of dental biomaterials. PURPOSE: The present research aimed to isolate (MSCs) from inflamed and normal gingiva, to fully characterize them and to observe their behavior in relation with some commercial resin composite materials and one experimental material. MATERIAL AND METHODS: Following their isolation, putative MSCs from both gingival sources were grown under the same culture conditions and characterized by immunophenotyping of cell surface antigens by flow-cytometry and transcription factors by immunocytochemical staining. Moreover, stemness gene expression was evaluated by RT-PCR analysis. Multipotent mesenchymal differentiation potential was investigated. Osteogenic and neurogenic differentiated cells were highlighted by immunocytochemical staining, chondrogenic cells by cytochemical staining, and adipocytes by cytochemical staining and spectrophotometry, respectively. Resin composite cytotoxicity was evaluated by cell membrane fluorescent labeling with PKH 26 and MTT assay. The results of PKH labeling were statistically analysed using two-way RM ANOVA with Bonferroni post-tests. For MTT assay, two-way RM ANOVA with Bonferroni post-tests and unpaired t test with Welch's correction were used. RESULTS: A similar expression pattern of surface markers was observed. The cells were positive for CD105, CD73, CD90, CD49e, CD29, CD44 and CD166 and negative for CD45, CD34, CD14, CD79, HLA-DR and CD117 indicating a mesenchymal stem cell phenotype. The qRT-PCR analysis revealed a low gene expression for NOG, BMP4 and Oct3/4 and an increased expression for Nanog in both cells lines. Immunocytochemical analysis highlighted a more intense protein expression for Nanog, Oct3/4 and Sox-2 in MSCs derived from normal gingiva than from inflamed gingiva. Multipotent differentiation capacity of MSCs isolated from both sources was highlighted. The tested materials had no hazardous effect on MSCs as the two cell lines developed well onto resin composite substrates. Cell counting revealed some significant differences in the number of PKH-labeled MSCs at some experimental moments. Also, some differences in cell viability were recorded indicating better developmental conditions offered by some of the tested biomaterials. CONCLUSIONS: The experimental resin composite behaved like the most biocompatible commercial material. Inflamed gingiva-derived MSCs retain their stem cell properties and could be used as a valuable cell line for testing dental biomaterials. PMID- 29604387 TI - Structural differences in enamel and dentin in human, bovine, porcine, and ovine teeth. AB - BACKGROUND: The aim was to study differences between crystalline nanostructures from the enamel and dentin of human, bovine, porcine, and ovine species. METHODS: Dentine and enamel fragments extracted from sound human, bovine, porcine and ovine incisors and molars were mechanically ground up to a final particle size of <100MUm. Samples were analyzed using X-ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), and differential scanning calorimetry (DSC). RESULTS: Human enamel (HE) and dentin (HD) showed a-axis and c-axis lengths of the carbonate apatite (CAP) crystal lattice nearer to synthetic hydroxyapatite (SHA), which had the smallest size. Enamel crystal sizes were always higher than those of dentin for all species. HE and HD had the largest crystal, followed by bovine samples. Hydroxyapatites (HAs) in enamel had a higher crystallinity index (CI), CIRietveld and CIFTIR, than the corresponding dentin of the same species. HE and HD had the highest CIs, followed by ovine enamel (OE). The changes in heat capacity that were nearest to values in human teeth during the glass transition (DeltaCp) were in porcine specimens. There was a significant direct correlation between the size of the a-axis and the substitution by both type A and B carbonates. The size of the nanocrystals and the crystallinity (CIRietveld y CIFTIR) were significantly and negatively correlated with the proteic phase of all the substrates. There was a strongly positive correlation between the caloric capacity, the CIs and the crystal size and a strongly negative correlation between carbonates type A and B and proteins. CONCLUSIONS: There are differences in the organic and inorganic content of human, bovine, porcine and ovine enamels and dentins which should be taken into account when interpreting the results of studies using animal substrates as substitutes for human material. PMID- 29604388 TI - Craniofacial structure alterations of foetuses from folic acid deficient pregnant mice. AB - INTRODUCTION: Craniofacial development in mammals is a complex process that involves a coordinated series of molecular and morphogenetic events. Folic acid (FA) deficiency has historically been associated with congenital spinal cord malformations, but the effect that a maternal diet deficient in FA has on the development of other structures has been poorly explored. In the present study, the objective was to describe and quantify the alterations of craniofacial structures presented in mouse foetuses from dams fed a FA deficient (FAD) diet compared with controls that were given a regular maternal diet. MATERIAL AND METHODS: E17 mouse foetuses were removed from dams that were fed with a control diet or with a FAD diet for several weeks. Foetuses with maternal FAD diets were selected for the study when they showed an altered tongue or mandible. Histological sections were used to quantify the dimensions of the head, tongue, mandibular bone and masseter muscle areas using ImageJ software. The muscles of the tongue, suprahyoid muscles, lingual septum, submandibular ducts, and lingual arteries were also analysed. RESULTS: The heads of malformed foetuses were smaller than the heads of the controls, and they showed different types of malformations: microglossia with micrognathia (some of which were combined with cleft palate) and aglossia with either micrognathia or agnathia. Lingual and suprahyoid muscles were affected in different forms and degrees. We also found alterations in the lingual arteries and in the ducts of the submandibular glands. Summarised we can state that pharyngeal arches-derived structures were affected, and the main malformations observed corroborate the vulnerability of cranial neural crest cells to FA deficiency. CONCLUSION: The present study reveals alterations in the development of craniofacial structures in FAD foetuses. This study provides a new focus for the role of FA during embryological development. PMID- 29604389 TI - Effects of sodium-glucose cotransporter-2 inhibitors on cardiovascular disease, death and safety outcomes in type 2 diabetes - A systematic review. AB - AIM: Sodium glucose co-transporter 2 (SGLT2) inhibitors appear to protect against increased risks of cardiovascular and kidney disease in patients with type 2 diabetes but also cause some harms. Whether effects are comparable across drug class or specific to individual compounds is unclear. This meta-analysis assessed the class and individual compound effects of SGLT2 inhibition versus control on cardiovascular events, death, kidney disease and safety outcomes in patients with type 2 diabetes. METHODS: MEDLINE, EMBASE, the Cochrane Library and regulatory databases were systematically searched for data from randomized clinical trials that included reporting of cardiovascular events, deaths or safety outcomes. We used fixed effects models and inverse variance weighting to calculate relative risks with the 95% confidence intervals. RESULTS: The analyses included data from 82 trials, four overviews and six regulatory reports and there were 1,968 major cardiovascular events identified for analysis. Patients randomly assigned to SGLT2 had lower risks of major cardiovascular events (RR 0.85, 95%CI 0.77-0.93), heart failure (RR 0.67, 95%CI 0.55-0.80), all-cause death (RR 0.79, 95%CI 0.70 0.88) and serious decline in kidney function (RR 0.59, 0.49-0.71). Significant adverse effects were observed for genital infections (RR 3.06, 95%CI 2.73-4.43), volume depletion events (RR 1.24, 95%CI 1.07-1.43) and amputation (RR 1.44 95%CI 1.13-1.83). There was a high likelihood of differences in the associations of the individual compounds with cardiovascular death, hypoglycaemia and amputation (all I2 > 80%) and a moderate likelihood of differences in the associations with non fatal stroke, all-cause death, urinary tract infection and fracture (all I2 > 30%). CONCLUSION: There are strong overall associations of SGLT2 inhibition with protection against major cardiovascular events, heart failure, serious decline in kidney function and all-cause death. SGLT2 inhibitors were also associated with infections, volume depletion effects and amputation. Some associations appear to differ between compounds. PMID- 29604390 TI - A call for inclusion of work-related diabetes distress in the spectrum of diabetes management: Results from a cross-sectional survey among working people with type 1 diabetes. AB - AIM: Diabetes distress captures a range of emotional responses and reactions to life with diabetes and is considered a part of the experience of managing diabetes and its treatment. Given the importance of the social context of work life for people of working age we set out to explore whether work-related diabetes distress is a distinct and important dimension of diabetes-related emotional distress in working people with type 1 diabetes. METHODS: A questionnaire with self-reported measures of psychosocial health and well-being at work was completed by 1126 working people with type 1 diabetes from a specialist diabetes clinic in Denmark. Work-related diabetes distress was assessed with two questions about worry and exhaustion related to reconciling work life and diabetes. Diabetes-related emotional distress was assessed with the Problem Areas in Diabetes scale (PAID-5), a short form version of the full PAID scale. We performed inter-item correlation analyses, exploratory factor analysis, and hierarchical multiple regression analyses. RESULTS: Inter-item correlations and exploratory factor analysis indicated that work-related diabetes distress was distinct from diabetes-related emotional distress. Further, work-related diabetes distress was found to be a unique contributor to work ability, quality of life, intentional hyperglycaemia at work, and absenteeism, after adjusting for covariates and diabetes-related emotional distress. CONCLUSIONS: The findings suggest that work-related diabetes distress captures an aspect of distress so far unaccounted for in workers with type 1 diabetes. Further studies are needed to strengthen the conceptual basis of work-related diabetes distress, explore its clinical usefulness and clarify its risk factors. PMID- 29604391 TI - Macular corneal dystrophy: A review. AB - Macular corneal dystrophy is a corneal stromal dystrophy which leads to progressive vision loss. Macular corneal dystrophy is an autosomal recessive condition in which there is abnormality of proteoglycan synthesis. Mutations in the carbohydrate sulfotransferase gene prevent normal sulfation of corneal keratan. Different immunophenotypes have been described depending on the presence of keratan sulfate in cornea and/or serum. The deposition of abnormal proteoglycans leads to loss of corneal transparency and decreased vision. Imaging techniques such as in vivo confocal microscopy and anterior segment ocular coherence tomography have helped enhance our understanding of the corneal ultrastructural changes in this condition. These imaging modalities provide additional information without the need for a tissue biopsy or excision. Traditionally, full-thickness penetrating keratoplasty to replace the opacified cornea has remained the standard of treatment to improve vision. However, newer surgical interventions such as deep anterior lamellar keratoplasty and phototherapeutic keratectomy have also been shown to play a role in the treatment. Disease recurrence remains a challenge and the reason for poor visual prognosis. Newer techniques such as gene-targeting therapies and enzyme replacement therapies are being studied for a potential permanent solution in macular corneal dystrophy. Recent research is directed toward development of genetically modified products to integrate into host corneal DNA and block the mutant genes and hence overcome the underlying pathophysiology. Enzyme replacement therapy is another intervention with potential to treat macular corneal dystrophy. Animal studies show clearance of accumulated keratan sulfate from the body tissues in the treatment of systemic mucopolysaccharidosis by long term enzyme replacement therapy. Future research should be directed toward elucidation of the relationship between the mutated carbohydrate sulfotransferase gene, the mechanism of deposit formation, and the development of pharmaceutical agents based on gene therapy. PMID- 29604392 TI - IGF2 induces CD133 expression in esophageal cancer cells to promote cancer stemness. AB - Failure to eradicate cancer stem cells (CSC) during primary therapy may lead to cancer recurrence. We recently reported that CD133 is a functional biomarker for CSCs in esophageal squamous cell carcinoma (ESCC) but the molecular pathways critical for maintenance of CD133-positive CSCs are largely unknown. Here, we revealed that knockdown of IGF2 or treatment with PI3K/AKT inhibitors markedly inhibited the abilities of CD133-positive ESCC cells to self-renew, resist chemotherapeutic drugs, and form tumors. Further functional analysis identified miR-377 as a downstream regulator of PI3K/AKT signaling, and a mediator of the effects of IGF2 on CD133 expression and CSC properties. We found that the expression levels of IGF2 and CD133 were positively correlated with each other in primary ESCC, and that concurrent elevation of IGF2 and CD133 expression was significantly associated with poor patient survival. Furthermore, in vivo experiments demonstrated that IGF2-neutralizing antibody enhanced the sensitivity of tumor xenografts in nude mice to 5-fluorouracil treatment. This study underpins the importance of the IGF2-PI3K/AKT-miR-377-CD133 signaling axis in the maintenance of cancer stemness and in the development of novel therapeutic strategy for treatment of esophageal cancer. PMID- 29604393 TI - MicroRNAs in type 2 immunity. AB - Type 2 immunity drives the pathology of allergic diseases and is necessary for expulsion of parasitic worms as well as having important implications in tumor progression. Over the last decade, a new research field has emerged describing a significant link between type 2 immunity and cancer development, called AllergoOncology. Thus, type 2 immune responses must be carefully regulated to mediate effective protection against damaging environmental factors, yet avoid excessive activation and immunopathology. Regulation of gene expression by microRNAs is required for normal behavior of most mammalian cells and has been studied extensively in the context of cancer. Although microRNA regulation of the immune system in cancer is well established and includes type 2 immune reactions in the tumor microenvironment, the involvement of microRNAs in these responses initiated by allergens, parasites or other environmental factors is just emerging. In this review, we focus on recent advances which increase the understanding of microRNA-mediated regulation of key mechanisms of type 2 immunity. PMID- 29604394 TI - Long non-coding RNA SNHG15 interacts with and stabilizes transcription factor Slug and promotes colon cancer progression. AB - Slug is a fast-turnover transcription factor critical for controlling cell fate and cancer cell invasion and metastasis. The stability of Slug is important and maintained by diverse mechanisms. In this study, we presented a paradigm of this activity by identifying long noncoding RNA (lncRNA) small nucleolar RNA host gene 15 (SNHG15) that binds to and stabilizes Slug in colon cancer cells. LncRNA SNHG15 transcription is upregulated in a variety of human cancers according to The Cancer Genome Atlas. Here, ectopic expression of SNHG15 promoted colon cancer cell migration in vitro, accelerated xenografted tumor growth in vivo, and elevated levels of SNHG15 were associated with poor prognosis for colon cancer patients. Mechanistically, SNHG15 maintains Slug stability in living cells by impeding its ubiquitination and degradation through interaction with the zinc finger domain of Slug. These findings revealed a novel mechanism underlying the control of Slug stability by demonstrating that oncogenic lncRNA SNHG15 interacts with and blocks Slug degradation via the ubiquitin-proteasome system. PMID- 29604395 TI - Chest compressions during ventilation in out-of-hospital cardiac arrest cause reversed airflow. AB - AIM: During cardiopulmonary resuscitation, once the patient is intubated, compressions and ventilations are performed simultaneously. Chest compressions during the inspiratory phase of ventilation may force air out of the lungs, causing so-called "reversed airflow", which may lead to ineffective ventilation. The purpose of this study is to determine the occurrence of this phenomenon and to quantify the volume of reversed airflow. METHODS: Observational study. During manual ventilation of intubated patients receiving chest compressions, the pressure gradient over the endotracheal tube was measured using two air-filled catheters connected to a custom-made portable device. Chest compression data were measured using an accelerometer on a Zoll E- series defibrillator. All data are reported as mean (standard deviation; range). RESULTS: Twenty-five patients and a total of 368 ventilations were studied, on average 15 (6; 10-30) per patient. The mean tidal volume, minute volume and ventilation rate were respectively 690 ml (160; 240-1260), 10.5 l/min (4.8; 4.4-22.1) and 18/min (6; 6-35). Reversed airflow was observed in 21/25 patients (84%) and in 65% of all ventilations, with on average two episodes per ventilation. Fifty-five percent of the chest compressions during the inspiratory phase of the ventilation generated reversed airflow. The mean volume of the reversed airflow was 96 ml per episode (52; 12 364). CONCLUSION: Chest compressions during ventilation in intubated patients generated reversed airflow in most patients. There was wide variation in the number of episodes and volume of the reversed airflow between patients. The effect of this phenomenon on the efficacy of ventilation during resuscitation and on outcome needs further investigation. PMID- 29604396 TI - A discrete role for alternative oxidase under hypoxia to increase nitric oxide and drive energy production. AB - Alternative oxidase (AOX) is an integral part of the mitochondrial electron transport and can prevent reactive oxygen species (ROS) and nitric oxide (NO) production under non-stressed, normoxic conditions. Here we assessed the roles of AOX by imposing stress under normoxia in comparison to hypoxic conditions using AOX over expressing (AOX OE) and anti-sense (AOX AS) transgenic Arabidopsis seedlings and roots. Under normoxic conditions stress was induced with the defence elicitor flagellin (flg22). AOX OE reduced NO production whilst this was increased in AOX AS. Moreover AOX AS also exhibited an increase in superoxide and therefore peroxynitrite, tyrosine nitration suggesting that scavenging of NO by AOX can prevent toxic peroxynitrite formation under normoxia. In contrast, during hypoxia interestingly we found that AOX is a generator of NO. Thus, the NO produced during hypoxia, was enhanced in AOX OE and suppressed in AOX AS. Additionally, treatment of WT or AOX OE with the AOX inhibitor SHAM inhibited hypoxic NO production. The enhanced levels of NO correlated with expression of non-symbiotic haemoglobin, increased NR activity and ATP production. The ATP generation was suppressed in nia1,2 mutant and non symbiotic haemoglobin antisense line treated with SHAM. Taken together these results suggest that hypoxic NO generation mediated by AOX has a discrete role by feeding into the haemoglobin-NO cycle to drive energy efficiency under conditions of low oxygen tension. PMID- 29604397 TI - Oxidative post-translational modification of betaeta 2-glycoprotein I in the pathophysiology of the anti-phospholipid syndrome. AB - The anti-phospholipid syndrome (APS) is a prothrombotic autoimmune disorder characterized by either thrombosis or pregnancy complications in the setting of persistent anti-phospholipid antibodies (aPL). betaeta 2-glycoprotein I (beta2 GPI) is the major autoantigen in APS that binds anionic phospholipids as well as specific receptors on platelets and endothelial cells resulting in activation of prothrombotic pathways. beta2-GPI consists of 5 Domains that exist in a circular or linear form, with the latter occurring after binding to anionic phospholipids. beta2-GPI also undergoes dynamic posttranslational modification between oxidized and free thiol forms. The relationship between posttranslational modification and structural conformation is yet to be definitively clarified. Compared with controls, patients with the APS have higher levels of total beta2-GPI and lower levels of free thiol beta2-GPI. This raises the possibility of using quantification of beta2-GPI posttranslational modification as a redox biomarker in the management and diagnosis of the APS. PMID- 29604398 TI - Introduction to special issue: Circadian regulation of metabolism, redox signaling and function in health and disease. PMID- 29604399 TI - Recurrently Mutated Genes Differ between Leptomeningeal and Solid Lung Cancer Brain Metastases. AB - When compared with solid brain metastases from NSCLC, leptomeningeal disease (LMD) has unique growth patterns and is rapidly fatal. Patients with LMD do not undergo surgical resection, limiting the tissue available for scientific research. In this study we performed whole exome sequencing on eight samples of LMD to identify somatic mutations and compared the results with those for 26 solid brain metastases. We found that taste 2 receptor member 31 gene (TAS2R31) and phosphodiesterase 4D interacting protein gene (PDE4DIP) were recurrently mutated among LMD samples, suggesting involvement in LMD progression. Together with a retrospective review of the charts of an additional 44 patients with NSCLC LMD, we discovered a surprisingly low number of KRAS mutations (n = 4 [7.7%]) but a high number of EGFR mutations (n = 33 [63.5%]). The median interval for development of LMD from NSCLC was shorter in patients with mutant EGFR (16.3 months) than in patients with wild-type EGFR (23.9 months) (p = 0.017). Targeted analysis of recurrent mutations thus presents a useful complement to the existing diagnostic tool kit, and correlations of EGFR in LMD and KRAS in solid metastases suggest that molecular distinctions or systemic treatment pressure underpin the differences in growth patterns within the brain. PMID- 29604401 TI - Limb muscle quality and quantity in elderly adults with dynapenia but not sarcopenia: An ultrasound imaging study. AB - BACKGROUND: Dynapenia is prevalent in people with reduced skeletal muscle mass, i.e. sarcopenia, but a certain population develops muscle strength loss despite having normal skeletal muscle volume. To date, studies investigating muscle quality and quantity in groups with dynapenia but not sarcopenia are limited. METHODS: Echogenicity and thickness of the biceps brachii, triceps brachii, rectus femoris, and medial gastrocnemius muscles were measured using high resolution ultrasonography in 140 community-dwelling elderly adults. Participants with decreased handgrip strength but normal muscular volume were diagnosed as having dynapenia without sarcopenia. A multivariate regression model was used to analyze the association between dynapenia and ultrasound indicators of the sampled muscle expressed as odds ratio (OR) and 95% confidence interval (CI). RESULTS: A total of 140 participants were recruited for the study, 12.6% (n = 18) of whom had dynapenia. The dynapenia group had a higher mean age, higher proportion of women, slower fast gait speed, reduced handgrip strength, and decreased thicknesses of the biceps brachii, rectus femoris, and medial gastrocnemius muscles. On multivariate logistic regression analysis, dynapenia was associated with older age (OR, 1.18; 95% CI, 1.05 to 1.33), higher body mass index (OR, 1.28; 95% CI, 1.05 to 1.64), and decreased thicknesses of the rectus femoris (OR, 0.01; 95% CI, <0.01 to 0.24) and medial gastrocnemius muscles (OR, 0.03; 95% CI, <0.01 to 0.61). CONCLUSION: Dynapenia without sarcopenia is associated with decreased thicknesses of the rectus femoris and medial gastrocnemius muscles, an association that remains significant after adjustment for demographics, body composition, and physical performance. Ultrasound measurements of lower-limb muscle thickness can be considered an auxiliary criterion for evaluating dynapenia. PMID- 29604400 TI - Arabidopsis SWC4 Binds DNA and Recruits the SWR1 Complex to Modulate Histone H2A.Z Deposition at Key Regulatory Genes. AB - Deposition of the H2A.Z histone variant by the SWR1 complex (SWR1-C) in regulatory regions of specific loci modulates transcription. Characterization of mutations in Arabidopsis thaliana homologs of yeast SWR1-C has revealed a role for H2A.Z exchange in a variety of developmental processes. Nevertheless, the exact composition of plant SWR1-C and how it is recruited to target genes remains to be established. Here we show that SWC4, the Arabidopsis homolog of yeast SANT domain protein Swc4/Eaf2, is a DNA-binding protein that interacts with SWR1-C subunits. We demonstrate that the swc4-1 knockout mutant is embryo-lethal, while SWC4 RNAi knockdown lines display pleiotropic phenotypic alterations in vegetative and reproductive traits, including acceleration of flowering time, indicating that SWC4 controls post-embryonic processes. Transcriptomic analyses and genome-wide profiling of H2A.Z indicate that SWC4 represses transcription of a number of genes, including the floral integrator FT and key transcription factors, mainly by modulating H2A.Z deposition. Interestingly, SWC4 silencing does not affect H2A.Z deposition at the FLC locus nor expression of this gene, a master regulator of flowering previously shown to be controlled by SWR1-C. Importantly, we find that SWC4 recognizes specific AT-rich DNA elements in the chromatin regions of target genes and that SWC4 silencing impairs SWR1-C binding at FT. Collectively, our data suggest that SWC4 regulates plant growth and development by aiding SWR1-C recruitment and modulating H2A.Z deposition. PMID- 29604402 TI - Effects of aquatic and land-based exercises on amyloid beta, heat shock protein 27, and pulse wave velocity in elderly women. AB - BACKGROUND: Alzheimer's disease is a neurodegenerative brain disease resulting from the deterioration of neuronal cells and vascular dementia, the latter of which results from cerebrovascular disorders. Exercise is effective in preventing and treating degenerative brain diseases as it activates blood flow to the brain, increases nerve production in the hippocampus, and promotes the expression of synaptic plasticity-related proteins. Therefore, this study investigated the effects of 16-week aquatic and land-based exercise programs on amyloid beta (Abeta), heat shock protein (HSP) 27 levels, and pulse wave velocity (PWV). MATERIALS AND METHODS: Forty elderly women, aged 60-70 years, voluntarily participated in the study. They were divided into control (n = 12), aquatic exercise (n = 14), and land-based exercise groups (n = 14). The variables of amyloid beta, heat shock protein 27, and pulse wave velocity were measured in all the participants before and after the 16-week study. RESULTS: Significantly higher levels of serum HSP27 (p < 0.05) and significantly lower levels of vascular elasticity (p < 0.05) were found in the aquatic exercise group after 16 weeks of exercise compared with the control group. Abeta did not significantly differ between groups. Thirty minutes after the first exercise, Abeta in the aquatic exercise group (p < 0.01) and HSP27 in the land-based exercise group (p < 0.05) were significantly higher than the corresponding levels in the resting condition before exercise. 30 min after the last exercise, Abeta (p < 0.01) and HSP27 (p < 0.05) were significantly higher. CONCLUSIONS: Aquatic and land-based exercises increased serum Abeta and HSP27 and decreased pulse wave velocity. Thus, they may play a positive role in the prevention of degenerative brain diseases and improvement of brain function in elderly people. PMID- 29604403 TI - Slow loaded breathing training improves blood pressure, lung capacity and arm exercise endurance for older people with treated and stable isolated systolic hypertension. AB - BACKGROUND: Hypertension and reduced lung function are important features of aging. Slow loaded breathing training reduces resting blood pressure and the question is whether this can also improve lung function. METHODS: Thirty-two people (67 +/- 5 years, 16 male) with controlled isolated systolic hypertension undertook an eight weeks randomised controlled training trial with an inspiratory load of 25% maximum inspiratory pressure (MIP) at 6 breaths per minute (slow loaded breathing; SLB) or deep breathing control (CON). Outcome measures were resting blood pressure (BP) and heart rate; MIP; lung capacity; chest and abdominal expansion; arm cranking exercise endurance at 50% heart rate reserve. RESULTS: Home based measurement of resting systolic BP decreased by 20 mm Hg (15 to 25) (Mean and 95%CI) for SLB and by 5 mm Hg (1 to 7) for CON. Heart rate and diastolic BP also decreased significantly for SLB but not CON. MIP increased by 15.8 cm H2O (11.8 to 19.8) and slow vital capacity by 0.21 L (0.15 to 0.27) for SLB but not for CON. Chest and abdominal expansion increased by 2.3 cm (2.05 to 2.55) and 2.5 cm (2.15 to 2.85), respectively for SLB and by 0.5 cm (0.26 to 0.74) and 1.7 cm (1.32 to 2.08) for CON. Arm exercise time increased by 4.9 min (3.65 to 5.15) for SLB with no significant change for CON. CONCLUSION: Slow inspiratory muscle training is not only effective in reducing resting BP, even in older people with well controlled isolated systolic hypertension but also increases inspiratory muscle strength, lung capacity and arm exercise duration. PMID- 29604404 TI - Cardiovascular tissue engineering: From basic science to clinical application. AB - Valvular heart disease is an increasing population health problem and, especially in the elderly, a significant cause of morbidity and mortality. The current treatment options, such as mechanical and bioprosthetic heart valve replacements, have significant restrictions and limitations. Considering the increased life expectancy of our aging population, there is an urgent need for novel heart valve concepts that remain functional throughout life to prevent the need for reoperation. Heart valve tissue engineering aims to overcome these constraints by creating regenerative, self-repairing valve substitutes with life-long durability. In this review, we give an overview of advances in the development of tissue engineered heart valves, and describe the steps required to design and validate a novel valve prosthesis before reaching first-in-men clinical trials. In-silico and in-vitro models are proposed as tools for the assessment of valve design, functionality and compatibility, while in-vivo preclinical models are required to confirm the remodeling and growth potential of the tissue engineered heart valves. An overview of the tissue engineered heart valve studies that have reached clinical translation is also presented. Final remarks highlight the possibilities as well as the obstacles to overcome in translating heart valve prostheses into clinical application. PMID- 29604405 TI - Color-motion feature binding occurs unconsciously. AB - The relationship between consciousness and feature binding has long been a topic of debate. Although they may be associated, there is growing evidence supporting the notion that feature binding and visual consciousness can be separated to some degree. In our study, we manipulated the visibility of priming stimuli, which consisted of color-motion features, and then measured the effects of those manipulations on reporting of cued targets' direction of rotation. A priming effect was observed even when the priming stimuli were invisible, implying that the color-motion features of the prime could bind unconsciously. These findings support the notion that, at least under certain conditions, feature binding and visual consciousness are separable psychological processes wherein feature binding is not sufficient to establish visual awareness. PMID- 29604406 TI - Interaction of dynamin I with NAP-22, a neuronal protein enriched in the presynaptic region. AB - Neurons have well-developed membrane microdomains called "rafts" that are recovered as a detergent-resistant low-density membrane microdomain fraction (DRM). NAP-22 is one of the major protein components of neuronal DRM and localizes in the presynaptic region. In order to know the role of NAP-22 in the synaptic transmission, NAP-22 binding proteins in the cytosol were searched with an affinity screening with NAP-22 as a bait and several protein bands were detected. Using mass-analysis and western blotting, one of the main band of ~90 kDa was identified as dynamin I. The GTPase activity of dynamin I was partly inhibited by NAP-22 expressed in bacteria and this inhibition was recovered by the addition of calmodulin, a NAP-22 binding protein. The GTPase activity of dynamin was known to be activated with acidic membrane lipids such as phosphatidylserine and the addition of NAP-22, a phosphatidylserine binding protein, inhibited the activation of the GTPase by this lipid. Since NAP-22 localizes on the presynaptic plasma membrane and on synaptic vesicles, these results suggest the participation of NAP-22 in the membrane cycling through binding to dynamin and acidic membrane lipids at the presynaptic region. PMID- 29604407 TI - The effect of movement and load on the dynamic coupling of abdominal electromyography. AB - This study investigated the degree of neural coupling in abdominal muscle activity and whether the task constraints of movement and load altered the coupling within three muscle pairings. Nineteen young, physically-active individuals performed sit-up and reverse crunch movements in bodyweight (BW) and loaded (+4.54 kg) conditions. Surface electromyography (sEMG) was recorded from the rectus abdominus (RA), external oblique (EO), and transverse abdominus (TA) muscles. Linear (correlation coefficient) and non-linear (Cross-Approximate Entropy) measurements evaluated the degree of couplings across three muscle pairings. Compared to a resting coupling state, most conditions showed evidence of coupling. The linear coupling showed greater coupling compared to the resting state. Dynamic coupling showed lower degrees of coupling for the RA-EO and RA-TA pairings but stronger coupling for the EO-TA pairing with the sit-up movement exhibiting lower Cross-ApEn (higher dynamic coupling) than the reverse crunch. The results provide preliminary evidence of coupling in abdominal muscle activity that was influenced by movement, but not load. The functional roles of the RA (prime mover), EO and TA (stabilizers) muscles may have influenced the degree of coupling and future investigations are needed to better understand the coupling of abdominal muscle activity. PMID- 29604408 TI - Evaluation of FGF 20 variants for susceptibility to Parkinson's disease in Eastern Indians. AB - BACKGROUND: Parkinson's disease (PD) is the second most common neurodegenerative disease and has a complex etiology. Single nucleotide polymorphisms in the 3' untranslated region of Fibroblast growth factor 20 (FGF 20) have been reported to be associated with PD; however, the results are controversial. Although FGF20 enhances the survival of dopaminergic neurons, it may also result in PD susceptibility by altering alpha-synuclein expression. MATERIALS AND METHODS: To identify and characterize genetic risk variants in FGF 20 in Eastern Indian PD patients, 2 SNPs of FGF 20 (rs1721100 and rs2720208) were genotyped in 336 PD cases and 313 ethnically matched controls by PCR-RFLP. RESULTS: We observed statistically significant differences in genotypic and allelic frequencies of rs1721100 between PD cases and controls but not for rs12720208. Haplotype G-C showed a significant protective effect against PD. A functional assay revealed that the risk allele C at rs1721100 has little or no effect on relative luciferase activity from a reporter construct in the presence of miR-3189-3p, whereas allele G results in significant dose-dependent reduction. CONCLUSION: Our results suggest that FGF 20 is a susceptibility gene for PD in Eastern Indians. PMID- 29604409 TI - Hippocampal gene expression profiling in a rat model of functional constipation reveals abnormal expression genes associated with cognitive function. AB - Disease progress and pathological proceeding of functional gastrointestinal disorder (FGID) are considered to be closely related to disordered brain-gut interaction, but only a few researches reported the relationship of functional constipation (FC) and disordered brain-gut interaction. It has been found that FC has a great correlation with emotional problems in clinical patients, but its related mechanisms have not been clearly clarified. In order to explore the molecular pathogenesis of FC related to emotional problem, BGI-500 sequencing technology was used for the first time to study the transcriptomics changes of hippocampus in a rat model. The results showed that the differential expressed genes (DEGs) were mainly involved in the modulation of hemoglobin binding and oxidative stress. These changes could result in changes of hemoglobin content and quality, which could further induce the decreased oxygen-carrying function of erythrocytes. In biological pathway, the disorder of cholinergic system could be speculated through related DEGs. And then, those enriched DEGs were verified by qRTPCR methods As far as the mRNA expressions of Chrna4, Camk2d and Gng13, there were significant difference between the control rats and model rats. These results show that FC could result in side effects on cognitive function, suggesting a new thought for understanding emotional disorder related to cognitive function. PMID- 29604410 TI - The use of random forests in modelling short-term air pollution effects based on traffic and meteorological conditions: A case study in Wroclaw. AB - Random forests, an advanced data mining method, are used here to model the regression relationships between concentrations of the pollutants NO2, NOx and PM2.5, and nine variables describing meteorological conditions, temporal conditions and traffic flow. The study was based on hourly values of wind speed, wind direction, temperature, air pressure and relative humidity, temporal variables, and finally traffic flow, in the two years 2015 and 2016. An air quality measurement station was selected on a main road, located a short distance (40 m) from a large intersection equipped with a traffic flow measurement system. Nine different time subsets were defined, based among other things on the climatic conditions in Wroclaw. An analysis was made of the fit of models created for those subsets, and of the importance of the predictors. Both the fit and the importance of particular predictors were found to be dependent on season. The best fit was obtained for models created for the six-month warm season (April September) and for the summer season (June-August). The most important explanatory variable in the models of concentrations of nitrogen oxides was traffic flow, while in the case of PM2.5 the most important were meteorological conditions, in particular temperature, wind speed and wind direction. Temporal variables (except for month in the case of PM2.5) were found to have no significant effect on the concentrations of the studied pollutants. PMID- 29604411 TI - An investigation of the biochar-based visible-light photocatalyst via a self assembly strategy. AB - In order to reduce the cost of commercial visible-light photocatalyst, a self assembly strategy was deployed in producing a Ti-coupled N-embedded chicken feather biochar based catalyst (TINCs). The TINCs were manufactured by blending Ti-contained cross-link agent with hydrolyzed N-embedded chicken feather. These synthesis materials were well characterized with X-ray diffraction, Fourier transform infrared, Scanning electron microscopy, Transmission electron microscope, Energy dispersive X-ray spectroscopy, X-ray photoelectron spectroscopy, Raman spectroscopy, Surface area analysis and UV-vis absorption spectra. There were multilayered graphene oxide-like structures observed on TINCs, which were similar to the TiO2-graphene oxide material. Correspondingly, the TINCs had presented a 90.91% degradation rate of Rhodamine B under visible light after 240 min. The corresponding TOC of the solution had dropped by 56.26%. Every slice of TINCs was constituted by multilayered graphene oxide-like framework, interspersing with TiO2 nanoparticles uniformly. Some mechanisms were also analyzed. The cost analysis investigated that TINCs was promising in industrialization. PMID- 29604412 TI - Effect of pre-treatment of bentonite with sodium and calcium ions on phosphate adsorption onto zirconium-modified bentonite. AB - To understand the influence of the pre-treatment of bentonite with Na+ and Ca2+ on the adsorption of phosphate on zirconium-modified bentonite, three kinds of adsorbent materials including zirconium-modified raw, Na+-pretreated and Ca2+ pretreated bentonites were synthesized and characterized firstly, and afterward their adsorption performance and mechanism for phosphate were studied comparatively. The phosphate adsorption ability for zirconium-modified bentonite decreased after the pre-treatment of bentonite with Na+, but it increased after the pre-treatment of bentonite with Ca2+. The maximum phosphate adsorption capacity calculated from the Langmuir isotherm model for zirconium-modified Ca2+ pretreated bentonites (13.4 mg P/g) was much higher than that for the zirconium modified raw bentonite (9.06 mg P/g). The pre-treatment of bentonite with Na+ and Ca2+ did not change the interaction type between zirconium-modified bentonite and phosphate, i.e., the coordination of phosphate to zirconium. The decreased phosphate adsorption capacity for zirconium-modified bentonite induced by the Na+ pre-treatment could be mainly attributed to the decrease of the specific surface area and the content of exchangeable Ca. The increased phosphate adsorption capacity for zirconium-modified bentonite induced by the Ca2+ pre-treatment could be mainly due to the increase in the amount of exchangeable Ca. Results of this work suggest that the zirconium-modified Ca2+-pretreated bentonite is more suitably used as an adsorbent for the removal of phosphate from wastewater than the zirconium-modified raw and Na+-pretreated bentonites. PMID- 29604413 TI - Towards an energy-friendly and cleaner solvent-extraction of vegetable oil. AB - The extraction of vegetable oils is an energy-intensive process. It has moreover a significant environmental impact through hexane emissions and through the production of organic-loaded wastewater. A rice bran oil process was selected as the basis, since full data were available. By using Aspen Plus v8.2 simulation, with additional scripts, several improvements were examined, such as using heat exchanger networks, integrating a Vapor Recompression Heat Pump after the evaporation and stripping, and examining a nitrogen stripping of hexane in the rice bran meal desolventizing unit followed by a gas membrane to recover hexane. Energy savings by the different individual and combined improvements are calculated, and result in a 94.2% gain in steam consumption and a 73.8% overall energy saving. The power consumption of the membrane unit reduces the overall energy savings by about 5%. Hexane separation and enrichment by gas membranes facilitates its condensation and re-use, while achieving a reduction of hexane emissions by over 50%. Through the considerable reduction of required steam flow rates, 61% of waste water is eliminated, mostly as organic-loaded steam condensate. Through overall energy savings, 52% of related CO2 emissions are eliminated. PMID- 29604414 TI - Demonstration of acid and water recovery systems: Applicability and operational challenges in Indian metal finishing SMEs. AB - Diffusion dialysis, acid retardation and nanofiltration plants were acquired from Europe and demonstrated in several Indian metal finishing companies over a three year period. These companies are primarily small and medium enterprises (SMEs). Free acid recovery rate from spent pickling baths using diffusion dialysis and retardation was in the range of 78-86% and 30-70% respectively. With nanofiltration, 80% recovery rate of rinse water was obtained. The demonstrations created awareness among the metal finishing companies to reuse resources (acid/water) from the effluent streams. However, lack of efficient oil separators, reliable chemical analysis and trained personnel as well as high investment cost limit the application of these technologies. Local manufacturing, plant customization and centralized treatment are likely to encourage the uptake of such technologies in the Indian metal finishing sector. PMID- 29604415 TI - Sustainability partnerships and viticulture management in California. AB - Agricultural regions in the United States are experimenting with sustainability partnerships that, among other goals, seek to improve growers' ability to manage their vineyards sustainably. In this paper, we analyze the association between winegrape grower participation in sustainability partnership activities and practice adoption in three winegrowing regions of California. Using data gathered from a survey of 822 winegrape growers, we find a positive association between participation and adoption of sustainable practices, which holds most strongly for practices in which the perceived private benefits outweigh the costs, and for growers with relatively dense social networks. We highlight the mechanisms by which partnerships may catalyze sustainable farm management, and discuss the implications of these findings for improving sustainability partnerships. Taken together, we provide one of the most comprehensive quantitative analyses to date regarding the effectiveness of agricultural sustainability partnerships for improving farm management. PMID- 29604416 TI - The effect of food, light intensity and tank volume on resting eggs production in Daphnia carinata. AB - Sexual reproduction is an important stage of cyclical parthenogenesis Daphnia, these cyclic parthenogens need to time their shift from asexual to sexual reproduction correctly, based on environmental cues. We investigated the effect of food quality and quantity, light intensity, and culture tank volume on the resting eggs production of a tropical Daphnia carinata clone of Vietnam. The results showed that sexual ephippia production of the D. carinata was strongly induced when fed with green algae Scenedesmus sp., under moderate light intensity condition. The experiments also showed that food limitation is not an obligate requirement of shifting from parthenogenetic reproduction to sexual ephippia reproduction in D. carinata. Beside of that, culture volume seemed to be an important determinant of successfully forming of embryos inside ephippium. These findings here were from cultures in contaminant free condition, thus they are important basics for further studies of additional effects of environment toxicants on D. carinata species of Vietnam. PMID- 29604417 TI - Evaluating how variants of floristic quality assessment indicate wetland condition. AB - Biological indicators are useful tools for the assessment of ecosystem condition. Multi-metric and multi-taxa indicators may respond to a broader range of disturbances than simpler indicators, but their complexity can make them difficult to interpret, which is critical to indicator utility for ecosystem management. Floristic Quality Assessment (FQA) is an example of a biological assessment approach that has been widely tested for indicating freshwater wetland condition, but less attention has been given to clarifying the factors controlling its response. FQA quantifies the aggregate of vascular plant species tolerance to habitat degradation (conservatism), and model variants have incorporated species richness, abundance, and indigenity (native or non-native). To assess bias, we tested FQA variants in open-canopy freshwater wetlands against three independent reference measures, using practical vegetation sampling methods. FQA variants incorporating species richness did not correlate with our reference measures and were influenced by wetland size and hydrogeomorphic class. In contrast, FQA variants lacking measures of species richness responded linearly to reference measures quantifying individual and aggregate stresses, suggesting a broad response to cumulative degradation. FQA variants incorporating non-native species, and a variant additionally incorporating relative species abundance, improved performance over using only native species. We relate our empirical findings to ecological theory to clarify the functional properties and implications of the FQA variants. Our analysis indicates that (1) aggregate conservatism reliably declines with increased disturbance; (2) species richness has varying relationships with disturbance and increases with site area, confounding FQA response; and (3) non-native species signal human disturbance. We propose that incorporating species abundance can improve FQA site-level relevance with little extra sampling effort. Using our practical sampling methods, an FQA variant ignoring species richness and incorporating non-native species and relative species abundance can be logistically efficient, easily understood, and effective for wetland assessment. PMID- 29604418 TI - Biodegradation of typical pharmaceutical compounds by a novel strain Acinetobacter sp. AB - A novel sulfamethoxazole (SMX)-degrading strain, Acinetobacter sp., was used to degrade other pharmaceutical compounds, including sulfadiazine (SD), sulfamethazine (SMT), trimethoprim (THM), triclosan (TCS), diclofenac (DFC) and carbamazepine (CBZ). The experimental results showed that Acinetobacter sp. can completely degrade SMX, SD and SMT, but with different mineralization efficiency. Acinetobacter sp. can mineralize 98.8% of SMX, while only 17.5% and 20.5% for SD and SMT, respectively. The intermediate products of SMX, SD and SMT degradation were tentatively identified. Based on the intermediates, it is inferred that the initial step for degrading sulfonamides by Acinetobacter sp. was the amidation of the amino groups in the benzene ring. The presence of methyl in the heterocyclic ring could induce the formation of methylase. By comparing the intermediates of SMX, SD and SMT degradation, it is concluded that Acinetobacter sp. preferred attacking the oxazole ring. However, Acinetobacter sp. cannot degrade THM, TCS, DFC and CBZ, while Acinetobacter sp. can still degrade SMX in the respective presence of THM, DFC and CBZ, although the degradation rate decreased. Moreover, the presence of TCS could completely inhibit the degradation of SMX by Acinetobacter sp. PMID- 29604419 TI - Role of NT-proANP and NT-proBNP in patients with atrial fibrillation: Association with atrial fibrillation progression phenotypes. AB - BACKGROUND: Electroanatomic remodeling in atrial fibrillation (AF) leads to disease initiation and perpetuation. Although atrial natriuretic peptide (ANP) is specifically expressed in the atria and is involved in atrial remodeling, B-type natriuretic peptide (BNP) is associated with mortality and cardiovascular events in AF. OBJECTIVE: The purpose of this study was to investigate the association between N-terminal (NT)-proBNP and NT-proANP levels with 3 AF progression phenotypes: persistent AF, left atrial diameter (LAD) dilation, and left atrial low-voltage areas (LVAs). METHODS: We studied NT-proBNP and NT-proANP in a discovery cohort (n = 51) and replicated the findings in a validation cohort (n = 241) undergoing first AF catheter ablation. Blood plasma samples from femoral vein were collected before catheter ablation. LVAs were determined using high density maps and defined as <0.5 mV. RESULTS: In our pilot cohort (age 62 +/- 10 years; 63% male; 59% persistent AF; 22% LVA), NT-proANP-but not NT-proBNP-levels were significantly higher in LVA patients (14.1 vs 8.6 ng/mL; P = .009) and correlated with LAD (r2 = 0.362; P = .011). These results were replicated in the validation cohort (age 64 +/- 11 years; 59% male; 59% persistent AF; 27% LVA) (12.7 vs 8.8 ng/mL; P = .016) and correlated with LAD (r2 = 0.180; P = .019). NT proANP levels increased according to 4 disease progression groups: paroxysmal AF without LVA, persistent AF without LVA, paroxysmal AF with LVA, and persistent AF with LVA (mean 15, 20, 19, and 27 ng/mL, respectively; P = .004). CONCLUSION: Natriuretic peptides show different sensitivity for phenotypes of AF progression. The clinical impact of NT-proANP in refining individualized therapy and disease prevention should be addressed in larger studies. PMID- 29604420 TI - Prognostic value of global longitudinal strain in heart failure patients treated with cardiac resynchronization therapy. AB - BACKGROUND: Myocardial fibrosis (macroscopic scar or diffuse reactive fibrosis) is one of the determinants of impaired left ventricular (LV) global longitudinal strain (GLS) in heart failure (HF) patients. OBJECTIVE: The purpose of this study was to evaluate the prognostic value of LV GLS in HF patients treated with cardiac resynchronization therapy (CRT). METHODS: The study included 829 HF patients (mean age 64.6 +/- 10.4 years; 72% men) treated with CRT. Before CRT implantation, LV GLS was assessed using 2-dimensional speckle tracking echocardiography. The primary endpoint was the combination of all-cause mortality, heart transplantation, and LV assist device implantation. The secondary endpoint was the occurrence of ventricular arrhythmias or appropriate implantable defibrillator device therapies. RESULTS: During follow-up, 332 patients reached the primary endpoint, and 233 presented with the secondary endpoint. Patients were divided according to LV GLS quartiles. Patients with the most impaired LV GLS quartile had a 2-fold higher risk of reaching the combined endpoint compared with patients in the best LV GLS quartile (hazard ratio [HR] 2.088; 95% confidence interval [CI] 1.555-2.804; P <.001). LV GLS was significantly associated with the combined endpoint (HR 1.075; 95% CI 1.020 1.133; P = .007) after adjusting for clinical, electrocardiographic, and echocardiographic characteristics. Although patients in the most impaired LV GLS quartile showed higher event rates for the secondary endpoint compared with the other groups, LV GLS was not independently associated with the secondary endpoint (HR 1.047; 95% CI 0.989-1.107; P = .115). CONCLUSION: In this large cohort of CRT patients, baseline LV GLS was independently associated with the combined endpoint. PMID- 29604421 TI - Study on antiviral activities, drug-likeness and molecular docking of bioactive compounds of Punica granatum L. to Herpes simplex virus - 2 (HSV-2). AB - Herpes simplex virus - 2 (HSV-2) causes lifelong persisting infection in the immunocompromised host and intermittent in healthy individuals with high morbidity in neonatals and also increase the transmission of HIV. Acyclovir is widely used drug to treat HSV-2 infection but it unable to control viral latency and recurrent infection and prolonged usage lead to drug resistance. Plant-based bioactive compounds are the lead structural bio-molecules play an inevitable role as a potential antiviral agent with reduced toxicity. Therefore, there is an urgent need to develop anti-HSV-2 bioactive molecules to prevent viral resistance and control of latent infection. Punica granatum fruit is rich in major bioactive compounds with potential antimicrobial properties. Hence, we evaluated the anti HSV-2 efficacy of lyophilized extracts and bioactive compounds isolated from fruit peel of P. granatum. As a result, ethanolic peel extract showed significant inhibition at 62.5 MUg/ml. Hence, the fruit peel ethanolic extract was subjected for the isolation of bioactive compounds isolation by bioactivity-guided fractionation. Among isolated bioactive compounds, punicalagin showed 100% anti HSV-2 activity at 31.25 MUg/ml with supportive evidence of desirable in silico ADMET properties and strong interactions to selected protein targets of HSV-2 by docking analysis. PMID- 29604422 TI - Isovitexin alleviates liver injury induced by lipopolysaccharide/d-galactosamine by activating Nrf2 and inhibiting NF-kappaB activation. AB - The aim of this study was to investigate the protective effects and mechanism of isovitexin, a glycosylflavonoid isolated from rice hulls of Oryza sativa, on Lipopolysaccharide (LPS)/d-galactosamine (D-Gal)-induced acute liver injury. The mice were randomly divided into five groups: control group, LPS/D-Gal group, and LPS/D-Gal + isovitexin groups. The mice of LPS/D-Gal group were received of LPS (50 MUg/kg) and D-gal (800 mg/kg) intraperitoneal. The mice of LPS/D-Gal + isovitexin groups were received isovitexin (25, 50, 100 mg/kg) 1 h before LPS/D Gal treatment. The results showed that the severity of liver injury was attenuated by treatment of isovitexin, as confirmed by the decreased liver histopathologic changes, as well as serum AST and ALT levels. Furthermore, the levels of TNF-alpha in serum and liver tissues, MPO activity and MDA content were significantly inhibited by isovitexin. In addition, isovitexin significantly attenuated NF-kappaB phosphorylation induced by LPS/D-Gal. The expression of Nrf2 and HO-1 were significantly up-regulated by isovitexin. In conclusion, isovitexin could protect against LPS/D-Gal-induced liver injury by inhibiting inflammatory and oxidative responses. Isovitexin also had protective effects against carbon tetrachloride (CCl4)-induced liver injury. Isovitexin may used as a potential agent for the treatment of liver injury. PMID- 29604423 TI - Occurrence of virulence-associated genes among Staphylococcus saprophyticus isolated from different sources. AB - Staphylococcus saprophyticus is an important pathogen responsible for community urinary tract infections (UTI). Besides composing the human microbiota, this species is widely distributed in the environment and the origins of this organism for human infection is not fully characterized. Although some virulence determinants are known, such as d-serine deaminase (DsdA), urease and cell-wall associated proteins, few studies investigated the distribution of virulence associated genes and analyzed the pathogenic potential of S. saprophyticus strains from different sources. The aim of the present study was to detect the presence of S. saprophyticus genes encoding surface proteins UafA, Aas, Ssp, SdrI, SssF as well as the DsdA and urease enzymes. A total of 142 S. saprophyticus strains were obtained from four sources: UTI, colonization, water and food. It was found, in every tested strain, the presence of genes encoding the surface proteins UafA, Aas, Ssp and SssF and the DsdA and urease enzymes. In contrast, the gene encoding SdrI surface protein was not detected in any of the strains of S. saprophyticus. These results provide a better understanding of the characteristics of S. saprophyticus strains and suggest that isolates from non human sources have a potential to colonize the urinary tract. PMID- 29604424 TI - Photocatalytically-assisted electrooxidation of herbicide fenuron using a new bifunctional electrode PbO2/SnO2-Sb2O3/Ti//Ti/TiO2. AB - The degradation of the herbicide fenuron was investigated using a new porous bifunctional electrode where the electrooxidation takes place on one side and the photocatalysis on the other side. The characterization of the synthetized bifunctional electrode (PbO2/SnO2-Sb2O3/Ti//Ti/TiO2) was performed by scanning electron microscopy, energy dispersive X-ray spectrometry and X-ray diffraction analysis and showed that the anodic side (Ti/SnO2-Sb2O3/PbO2) is covered with a tetragonal beta-PbO2 film and that the photocatalytic side (Ti/TiO2) consists of an anatase phase of TiO2. The single application of electrooxidation achieved 87.8% fenuron degradation and 84.1% chemical oxygen demand (COD) removal while heterogeneous photocatalysis resulted in only 59.2% and 39.7% fenuron concentration decay and COD removal, respectively. On the other hand, the photocatalytically-assisted electrooxidation (photo-electrooxidation) performed on the bifunctional electrode provided higher performances of fenuron degradation (97.5%) and mineralization (97.4%). Investigation of operating parameters highlighted the positive effect of increase in current density. Conversely, an increase in fenuron concentration led to a decrease in degradation rate and COD removal. It was also found that the COD removal and mineralization efficiency are higher in a neutral medium. PMID- 29604425 TI - Relationship between urbanisation and pollutant emissions in transboundary river basins under the strategy of the Belt and Road Initiative. AB - Urbanisation has increased the discharge of pollutants, altered water flow regimes, and modified the morphology of transboundary river basins. All these actions have resulted in multiple pressures on aquatic ecosystems of transboundary river basins, undermining the healthy development of their aquatic ecosystems as well as impairing the sustainable economic and social development associated therewith. Quantifying the relationship between socio-economic factors, and water environment systems, and understanding the multiple pressures in their combined impact on environmental fairness of transboundary river basins is challenging, and it is crucial to the strategic planning of the Belt and Road strategy. Here, the Songhua River basin, which is the largest branch of the China Russia boundary river is taken as the study area. The Environmental Kuznets Curve (EKC) model, which is coupled with the integrated model (pollutant emissions intensity, pollutant discharge efficiency, and pollutant emissions per capita), are used to reveal the spatio-temporal variations in regional pollutant emissions in the SRB. The results show that the features of the EKC are present in the pollutant emissions during economic development of the SRB. It also demonstrates that the turning point value of the EKC appeared when the GDP per capita is around Y40,000 (CNY) in the SRB, which means that the pollutant emissions show an increasing trend, when the GDP per capita is less than Y40,000. Our findings could contribute to a better understanding of the coupling relationship between pollutant emissions in transboundary river basins and urbanisation process in water stress to help address water allocation problems. PMID- 29604426 TI - A novel microbial fuel cell sensor with a gas diffusion biocathode sensing element for water and air quality monitoring. AB - Toxicity monitoring is essential for the protection of public health and ecological safety. Microbial fuel cell (MFC) sensors demonstrated good potential in toxicity monitoring, but current MFC sensors can only be used for anaerobic water monitoring. In this study, a novel gas diffusion (GD)-biocathode sensing element was fabricated using a simple method. The GD-biocathode MFC sensor can directly be used for formaldehyde detection (from 0.0005% to 0.005%) in both aerobic and anaerobic water bodies. Electrochemical analysis indicated that the response by the sensor was caused by the toxic inhibition to the microbial activity for the oxygen reduction reaction (ORR). This study for the first time demonstrated that the GD-biocathode MFC sensor has a detection limit of 20 ppm for formaldehyde and can be used to monitor air pollution. Selective sensitivity to formaldehyde was not achieved as the result of using a mixed-culture, which confirms that it can serve as a generic biosensor for monitoring gaseous pollutants. This study expands the realm of knowledge for MFC sensor applications. PMID- 29604428 TI - Lack of evidence of mimivirus replication in human PBMCs. AB - The Acanthamoeba polyphaga mimivirus (APMV) was first isolated during a pneumonia outbreak in Bradford, England, and since its discovery many research groups devoted efforts to understand whether this virus could be associated to human diseases, in particular clinical signs and symptoms of pneumonia. In 2013, we observed cytopathic effect in amoebas (rounding and lysis) inoculated with APMV inoculated PBMCs (peripheral blood mononuclear cell) extracts, and at that point we interpreted those results as mimivirus replication in human PBMCs. Based on these results we decided to further investigate APMV replication in human PBMCs, by transmission electron microscopy (TEM) and qPCR. No viral factory was observed in APMV inoculated PBMCs, at any analyzed time and M.O.I.s (multiplicity of infection), by checking 550 cells per condition tested. We also measured the variation of viral DNA by qPCR targeting helicase gene during the course of the TEM experiment in PBMCs, but the DNA levels stayed the same as the first time point post infection. In summary, our newest qPCR and TEM results do not support previous statements (including ours) that mimivirus is able to replicate in humans PBMCs. PMID- 29604427 TI - The potential role of malonic acid in the atmospheric sulfuric acid - Ammonia clusters formation. AB - Malonic acid (MOA), one of the major dicarboxylic acids (DCAs) in aerosols, has been identified experimentally and computationally to be a strong acid. However, its potential role in the atmospheric clusters formation is still ambiguous. Hence, the participant mechanism of MOA on the formation of atmospheric sulfuric acid (SA)- ammonia (A) clusters was investigated by combining computational methods with atmospheric cluster dynamics code (ACDC). The most stable molecular structures obtained at the M06-2X/6-311++G(3df,3pd) level of theory shows that the added MOA molecule in the SA-A-based clusters presents a promotion on the interactions between SA and A molecules. ACDC simulations indicate directly an obvious enhancement strength RMOA on the clusters formation rates at 218 K and the concentration of MOA ([MOA]) larger than 108 molecules cm-3, up to five orders of magnitude. Meanwhile, enhancement strength of MOA is compared with that of glycolic acid, and as expected, MOA presents a superior enhancement strength. Both RMOA and the compared enhancement strength (rcom) present a positive dependency on [MOA] and a negative dependency on [SA]. With the increase of [A], both RMOA and rcom (except at [SA] = 104 molecules cm-3) first increase, reaching the maximum value and then decrease. Finally, a catalytic participant mechanism of MOA where MOA acts as a mediate bridge for the formation of pure SA-A-based clusters has been identified by tracing the main growth pathways of the system. PMID- 29604429 TI - Familiarization of undergraduate medical students with the two-dimensional vision of laparoscopic surgery: Preliminary results of a prospective follow-up study. AB - BACKGROUND: To date, the feasibility of pre-graduate training in 2D vision has not been studied thoroughly. The purpose of this pilot study is to present the preliminary results of a pre-graduate laparoscopic training program. MATERIALS AND METHODS: We invited pre-graduate medical students to participate in an experimental training program which strengthened their essential skills in 2D vision. An easy-to-use, cost-effective, hand-made laparoscopic training box was constructed and used. RESULTS: Twenty-four pre-graduate students participated in our study. The ability of medical students to co-ordinate their movements on the 2D-space was strengthened from the first to the fourth time of performing the easiest tasks (bead transfer and rope cutting) (P<.001). This was not observed in the case of the two harder tasks (necklace formation and intracorporeal knot), despite the fact that time to fulfillment differed (P=.058 & P=.082) respectively. The overall assessment of the simulator in terms of portability, imaging, light, camera convenience to use and significance ranked from high to very high. CONCLUSION: Familiarization with the 2D environment of laparoscopic surgery is extremely important for medical students. The results of our study seem to be promising, as they show that basic tasks are easy to learn with the use of relatively inexpensive equipment. PMID- 29604430 TI - Prevalence and risk factors for Extended-Spectrum Beta-Lactamase-producing- Enterobacteriaceae in French military and civilian travelers: A cross-sectional analysis. AB - BACKGROUND: International travel is a risk factor for colonization with Extended Spectrum Beta-Lactamase-producing- Enterobacteriaceae (ESBL-E). We describe the prevalence of and risk-factors for ESBL-E colonization in civilian and military travelers. METHODS: Patients hospitalized in the infectious diseases department of Begin Military Hospital (France) from May 2012 to November 2015, who had traveled abroad over the past two months, were screened for intestinal colonization with ESBL-E. RESULTS: Forty-one out of 166 travelers (24.7%) had ESBL-E colonization, predominantly Escherichia coli. The risk factors for ESBL-E colonization in the univariate analysis were a treatment with any antibiotic in the last two months (OR 4.19, 95% CI 1.91-9.16) or with a beta-lactam in the same period (OR 3.35, 95% CI 1.44-7.82), and an hospitalization in the last two months (OR 3.96, 95% CI 1.91-9.16). The military status, military mission or military accommodation were not associated with an increased risk of ESBL-E colonization. In the multivariate analysis, a treatment with any antibiotic in the last two months was significantly associated with ESBL-E colonization (OR 6.71, 95% CI 3.36-19.08). CONCLUSION: Antibiotic treatment in the two previous months is strongly predictive of ESBL-E colonization in international travelers, while the military status and its specific living conditions are not. PMID- 29604431 TI - Prevalence of mutations in genes associated with isoniazid resistance in Mycobacterium tuberculosis isolates from re-treated smear-positive pulmonary tuberculosis patients: A meta-analysis. AB - OBJECTIVES: The prevalence of isoniazid (INH) monoresistance is high in India. In this study, molecular epidemiological characteristics associated with INH resistance mutations in Mycobacterium tuberculosis in codon katG315 and in the promoter region of the inhA gene were investigated. METHODS: Sputum specimens of smear-positive tuberculosis (TB) patients were subjected to GenoType MTBDRplus assay to identify katG and inhA mutations in M. tuberculosis. In addition to the current study, 17 publications assessed 14100 genotypically resistant M. tuberculosis isolates for mutations in katG inclusive of codon 315. RESULTS: In total, 1821 (11.8%) of 15438 INH-resistant strains had detectable mutations: 71.0% in katG315 and 29.0% in the inhA promoter region. The prevalence of IHN monoresistance was 89.1% in the economically-active age group, 0.4% in the paediatric age group and 10.5% in those aged >60years; the rate in males and females was 12.0% and 10.8%, respectively. Meta-analysis derived a pooled katGS315T resistant TB prevalence of 67.3% (95% CI 59.3-75.4%) with Q=732.19, I2=98.35% and P=0.000 for treated TB cases. CONCLUSION: INH resistance was spread widely and transmission of INH-resistant isolates, especially with katG315T mutation, was confirmed. Therefore, it is important to diagnose katG315T mutants among INH-resistant strains as it may be a risk factor for subsequent development of multidrug-resistant TB (MDR-TB). Prompt detection of patients with INH resistant strains would expedite modification of treatment regimens, and appropriate infection control measures could be taken in time to diminish the risk of further development and transmission of MDR-TB. PMID- 29604432 TI - Prevalence of antibiotic-resistant coliform bacteria, Enterococcus spp. and Staphylococcus spp. in wastewater sewerage biofilm. AB - OBJECTIVES: Urban wastewater contains various micropollutants and a high number of different micro-organisms. Some bacteria in wastewater can attach to surfaces and form biofilm, which gives bacteria an advantage in the fight against environmental stresses. This work focused on analysis of bacterial communities in biofilms isolated from influent and effluent sewerage of a wastewater treatment plant (WWTP) in Bratislava, Slovakia. METHODS: Detection of biofilm microbiota was performed by culture-independent and -dependent approaches. The composition of bacterial strains was detected by denaturing gradient gel electrophoresis fingerprinting coupled with construction of 16S rRNA clone libraries. Analysis of the concentration of antibiotics and the prevalence of antibiotic-resistant coliforms, Enterococcus spp. and Staphylococcus spp. in sewerage was also studied. RESULTS: Biofilm collected at the inlet point was characterised primarily by the presence of Pseudomonas spp., Acinetobacter spp. and Janthinobacterium spp. clones, whilst members of the genus Pseudomonas were largely detected in biofilm isolated in outflow of the WWTP. Predominant antibiotics such as azithromycin, clarithromycin and ciprofloxacin were found in influent wastewater. The removal efficiency of these antibiotics, notably azithromycin and clarithromycin, was 30% in most cases. CONCLUSION: The highest number of antibiotic-resistant bacteria, with a predominance of coliforms, was detected in samples of effluent biofilm. Multidrug-resistant strains in effluent biofilm showed very good biofilm-forming ability. PMID- 29604433 TI - Identification of a novel nonsense mutation leading to congenital factor XIII deficiency. PMID- 29604434 TI - Fasting plasma glucose, oral glucose tolerance test, and the risk of first-time venous thromboembolism. A report from the VEINS cohort study. AB - INTRODUCTION: It remains unclear whether high plasma glucose levels are associated with venous thromboembolism (VTE). This study investigated the association between fasting plasma glucose (FPG), oral glucose tolerance test (two-hour post-load plasma glucose (2HPG)), diabetes, and VTE. MATERIALS AND METHODS: The population-based, prospective Venous thromboEmbolism In Northern Sweden (VEINS) cohort study included 108,025 residents of Vasterbotten County in northern Sweden. The participants were aged 30 to 60 years and had no previous VTE events. They were included from 1985 onwards and were followed until a VTE event, death, emigration, or the study end on September 5, 2014. All underwent a health examination that measured weight, height, FPG, and 2HPG and included a questionnaire regarding smoking, education level, and history of diabetes. Potential VTE events were identified by an extensive diagnosis registry search and were validated by reviewing medical records and radiology reports. RESULTS: An objectively verified first-time VTE event was experienced by 2054 participants during 1,496,669 person-years of follow-up. In univariable analysis, there were associations between FPG, 2HPG, diabetes, and the risk of VTE. These associations disappeared after adjustment for potential confounders (age, sex, body mass index, cancer at inclusion, education level, smoking, and hypertension). The adjusted hazard ratios were 1.01 (95% confidence interval 0.83-1.23) for diabetes, 1.01 for each standard deviation of FPG (95% confidence interval 0.97 1.05), and 0.96 for each standard deviation of 2HPG (95% confidence interval 0.91 1.00). CONCLUSIONS: There were no independent associations between FPG, 2HPG, diabetes, and future risk of VTE. PMID- 29604435 TI - In vitro effects of Crotalus atrox snake venom on chick and mouse neuromuscular preparations. AB - The neuromuscular effect of venoms is not a major clinical manifestation shared between rattlesnakes native to the Americas, which showed two different venom phenotypes. Taking into account this dichotomy, nerve muscle preparations from mice and chicks were used to investigate the ability of Crotalus atrox venom to induce in vitro neurotoxicity and myotoxicity. Unlike crotalic venoms of South America, low concentrations of C. atrox venom did not result in significant effects on mouse neuromuscular preparations. The venom was more active on avian nerve-muscle, showing reduction of twitch heights after 120 min of incubation with 10, 30 and 100 MUg/mL of venom with diminished responses to agonists and KCl. Histological analysis highlighted that C. atrox was myotoxic in both species of experimental animals; as evidenced by degenerative events, including edematous cells, delta lesions, hypercontracted fibers and muscle necrosis, which can lead to neurotoxic action. These results provide key insights into the myotoxicity and low neurotoxicity of C. atrox in two animal models, corroborating with previous genomic and proteomic findings and would be useful for a deeper understanding of venom evolution in snakes belonging to the genus Crotalus. PMID- 29604437 TI - Thymidine phosphorylase in cancer aggressiveness and chemoresistance. AB - Thymidine phosphorylase (TP) is a rate-limiting enzyme in thymidine catabolism. TP has several important roles in biological and pharmacological mechanisms; importantly TP acts as an angiogenic factor and one of metabolic enzymes of fluoro-pyrimidine anticancer agents and modifies inflammation. Improving our understanding of the characteristics and functions of TP has led to the development of novel TP-based anticancer therapies. We recently reported that TP dependent thymidine catabolism contributes to tumour survival in low nutrient conditions and the pathway from thymidine to the glycolysis cascade is affected in the context of physiological and metabolic conditions. In this review, we describe recent advancement in our understanding of TP, with a focus on cancer cell biology and the pharmacology of pyrimidine analogue anticancer agents. This review provides comprehensive understanding of the molecular mechanism of TP function in cancer. PMID- 29604438 TI - Porous calcium phosphate glass microspheres for orthobiologic applications. AB - : Orthobiologics is a rapidly advancing field utilising cell-based therapies and biomaterials to enable the body to repair and regenerate musculoskeletal tissues. This paper reports on a cost-effective flame spheroidisation process for production of novel porous glass microspheres from calcium phosphate-based glasses to encapsulate and deliver stem cells. Careful selection of the glass and pore-forming agent, along with a manufacturing method with the required processing window enabled the production of porous glass microspheres via a single-stage manufacturing process. The morphological and physical characterisation revealed porous microspheres with tailored surface and interconnected porosity (up to 76 +/- 5%) with average pore size of 55 +/- 8 um and surface areas ranging from 0.34 to 0.9 m2 g-1. Furthermore, simple alteration of the processing parameters produced microspheres with alternate unique morphologies, such as with solid cores and surface porosity only. The tuneable porosity enabled control over their surface area, degradation profiles and hence ion release rates. Furthermore, cytocompatibility of the microspheres was assessed using human mesenchymal stem cells via direct cell culture experiments and analysis confirmed that they had migrated to within the centre of the microspheres. The novel microspheres developed have huge potential for tissue engineering and regenerative medicine applications. STATEMENT OF SIGNIFICANCE: This manuscript highlights a simple cost-effective one-step process for manufacturing porous calcium phosphate-based glass microspheres with varying control over surface pores and fully interconnected porosity via a flame spheroidisation process. Moreover, a simple alteration of the processing parameters can produce microspheres which have a solid core with surface pores only. The tuneable porosity enabled control over their surface area, degradation profiles and hence ion release rates. The paper also shows that stem cells not only attach and proliferate but more importantly migrate to within the core of the porous microspheres, highlighting applications for bone tissue engineering and regenerative medicine. PMID- 29604439 TI - Reprint of: Quantitative proteomic analysis reveals that chemotaxis is involved in chlortetracycline resistance of Aeromonas hydrophila. AB - : In recent years, Aeromonas hydrophila, which has been classified as a food borne pathogen, has presented with increased levels of antibiotic resistance, with the mechanisms of this resistance being poorly understood. In this study, iTRAQ coupled mass spectrometry was employed to compare differentially expressed proteins in chlortetracycline (CTC) resistant A. hydrophila relative to a control strain. Result showed that a total of 234 differential proteins including 151 down-regulated and 83 up-regulated were identified in chlortetracycline resistance strain. Bioinformatics analysis showed that chemotaxis related proteins, such as CheA-2, CheR-3, CheW-2, EnvZ, PolA, FliS and FliG were down regulated in addition to previously reported tricarboxylic acid cycle (TCA) related proteins also being down-regulated. A subset of identified differentially expressed proteins was then further validated via Western blotting. Exogenous metabolite combined with CTC further enhanced the bacterial susceptibilities to CTC in A. hydrophila. Furthermore, a bacterial survival capability assay showed that several chemotaxis related mutants, such as DeltacheR-3 and DeltaAHA_0305, may affect the antimicrobial susceptibility of A. hydrophila. Overall, these findings contribute to a further understanding of the mechanism of CTC resistance in A. hydrophila and may contribute to the development of more effective future treatments. BIOLOGICAL SIGNIFICANCE: A. hydrophila is a well-known fish pathogenic bacterium and has presented with increasing levels of antibiotic resistance, with the mechanisms of this resistance being poorly understood. Our current study compared the differentially expression proteins between chlortetracycline (CTC) resistant and control stains via an iTARQ-based quantitative proteomics method. Chemotaxis related proteins were down-regulated in CTC resistant strain but exogenous metabolite addition increased bacterial susceptibility in A.hydrophila. Significantly, chemotaxis related genes depletion affected antimicrobial susceptibilities of A.hydrophila indicating the role of chemotaxis process in antibiotics resistance. PMID- 29604440 TI - Nanoaggregates of iron poly-oxo-clusters obtained by laser ablation in aqueous solution of phosphonates. AB - Laser ablation in liquid (LAL) emerged as a versatile technique for the synthesis of nanoparticles with various structures and compositions, although the control over products remains challenging in most cases. For instance, it is still difficult to drive the size of metal oxide crystalline domains down to the level of few atom clusters with LAL. Here we demonstrate that laser ablation of a bulk iron target in aqueous solution of phosphonates gives phosphonate-grafted iron oxo-clusters polymerized into nanoaggregates with Fe:ligand ratio of 2:1, instead of the usual nanocrystalline iron oxides. We attribute this result to the strong ability of phosphonate groups to bind iron oxide clusters and prevent their further growth into crystalline iron oxide. These laser generated poly-oxo clusters are biocompatible and trackable by magnetic resonance imaging, providing interesting features for use in biological environments, such as nano-vehicles for iron administration. Besides, this method is promising for the generation of atom-scale metal-oxide clusters, which are ubiquitary in chemistry and of interest in biochemistry, catalysis, molecular magnetism and materials science. PMID- 29604441 TI - Ultrasonically facilitated adsorption of an azo dye onto nanostructures obtained from cellulosic wastes of broom and cooler straw. AB - In the present work, ultrasonically facilitated adsorption (UFA) of a cationic dye [Basic Red 46 (BR46)] was examined using cellulosic nanostructures obtained from broom and cooler straw. Although the exclusive application of the nanostructured broom resulted in the 43.51% adsorption of BR46, the UFA process gave rise to the substantial removal efficiency of about 93%. In the case of the nanostructured straw, the efficiency was increased from 36.9% to 55.7%. The UFA process for both adsorbents reached the equilibrium within 60 min which was shorter than the time for the only adsorption. According to the values of the mean free energy (E), the decolorization via the UFA process applying broom (15.81 kJ/mol) and straw (11.18 kJ/mol) nanostructures was occurred chemically. An insignificant loss in the adsorption capacity of both adsorbents was observed after three regeneration tests by means of 0.05 M hydrochloric acid, indicating the good reusability potential of the as-synthesized cellulosic nanostructures. PMID- 29604436 TI - Investigational chemotherapy and novel pharmacokinetic mechanisms for the treatment of breast cancer brain metastases. AB - In women, breast cancer is the most common cancer diagnosis and second most common cause of cancer death. More than half of breast cancer patients will develop metastases to the bone, liver, lung, or brain. Breast cancer brain metastases (BCBM) confers a poor prognosis, as current therapeutic options of surgery, radiation, and chemotherapy rarely significantly extend life and are considered palliative. Within the realm of chemotherapy, the last decade has seen an explosion of novel chemotherapeutics involving targeting agents and unique dosage forms. We provide a historical overview of BCBM chemotherapy, review the mechanisms of new agents such as poly-ADP ribose polymerase inhibitors, cyclin dependent kinase 4/6 inhibitors, phosphatidyl inositol 3-kinaseinhibitors, estrogen pathway antagonists for hormone-receptor positive BCBM; tyrosine kinase inhibitors, antibodies, and conjugates for HER2+ BCBM; repurposed cytotoxic chemotherapy for triple negative BCBM; and the utilization of these new agents and formulations in ongoing clinical trials. The mechanisms of novel dosage formulations such as nanoparticles, liposomes, pegylation, the concepts of enhanced permeation and retention, and drugs utilizing these concepts involved in clinical trials are also discussed. These new treatments provide a promising outlook in the treatment of BCBM. PMID- 29604442 TI - Palladium - silicon nanocomposites as a stable electrocatalyst for hydrogen evolution reaction. AB - Pd nanoparticles grown in-situ on the surface of silicon nanowires (Pd-SiNW nanocomposites) were employed as electrocatalysts in hydrogen evolution reaction and exhibited satisfactory catalytic performance. Here, SiNWs served as the carrier with vast surface area. It is interesting to note that Pd-SiNW nanocomposites were more stable for hydrogen evolution reaction than the commercial Pt/C catalysts, which might be attributed to the three-dimensional crisscrossing structure of the composites and the strong interaction between Pd and Si. The strong interaction is due to the low lattice mismatch in the epitaxial growth of Pd particles on the surface of Si. Such special structure and interaction help to tightly hold Pd nanoparticles, which could avoid the loss of catalysts and keep the catalyst from being agglomerated and growing large. PMID- 29604443 TI - Near wall void growth leads to disintegration of colloidal bacterial streamer. AB - We investigated the failure of thick bacterial floc-mediated streamers in a microfluidic device with micropillars. It was found that streamers could fail due to the growth of voids in the biomass that originate near the pillar walls. The quantification of void growth was made possible by the use of 200 nm fluorescent polystyrene beads. The beads get trapped in the extracellular matrix of the streamer biomass and acted as tracers. Void growth time-scales could be characterized into short-time scales and long time-scales and the crack/void propagation showed several instances of fracture-arrest ultimately leading to a catastrophic failure of the entire streamer structure. This mode of fracture stands in strong contrast to necking-type instability observed before in streamers. PMID- 29604444 TI - Adsorption mechanisms of metal ions on the potassium dihydrogen phosphate (1 0 0) surface: A density functional theory-based investigation. AB - The adsorption of metal ions (K+, Na+, Ca2+, Cu2+, Al3+, Cr3+) on the (1 0 0) surface of potassium dihydrogen phosphate (KDP) has been studied using density functional theory (DFT). Calculation results show that all the investigated metal ions can be spontaneously adsorbed on the surface with negative adsorption energies. The adsorption stability increases in the order of Na+ < K+ < Cu2+ < Ca2+ < Al3+ < Cr3+, and shows a consistent trend as the adsorbed metal ion valence (monovalent < divalent < trivalent). Three types of stable adsorption configurations are observed, corresponding to three different bonding mechanisms. Na+, K+ and Ca2+ ions with a large radius can form two ionic bonds and one weak covalent bond with the O and H atoms respectively. In addition, the medium-sized ion of Cu2+ forms two covalent bonds with the O and H atoms. Furthermore, Al3+ and Cr3+ ions with the smallest radius form two metal-oxygen and one metal hydrogen covalent bonds with the surface, making one H-O bond broken. Compared with other metal ions, Al3+ and Cr3+ have the strongest interactions with the surface, which can be explained by the significant electron transfer and more stable covalent bond formations between these two ions and the surface. PMID- 29604445 TI - Hollow PdCo alloy nanospheres with mesoporous shells as high-performance catalysts for methanol oxidation. AB - Monodisperse hollow mesoporous PdCo alloy nanospheres are prepared via a simple galvanic replacement reaction. The as-prepared PdCo hollow nanospheres have small diameter, such as Pd78Co22 nanospheres of diameter about 25 nm and mesoporous shells about 4-5 nm. The Pd78Co22 hollow mesoporous nanospheres possess the largest electrochemical active surface areas (ECSA, 53.91 m2 g-1), mass activity (1488 mA mg-1) and specific activity (2.76 mA cm-2) towards to methanol oxidation relative to the Pd68Co32, Pd92Co8 hollow mesoporous nanospheres and commercial Pd/C catalysts. Moreover, the activity of Pd78Co22 after long-term stability tests is still the best and even better than those of fresh Pd68Co32 and commercial Pd/C catalysts. The PdCo catalysts not only effectively reduce the Pd usage by forming hollow structure, but also fully realize the Pd-Co alloying effects for enhancing the methanol oxidation catalytic performance. PMID- 29604446 TI - Fabricating highly catalytically active block copolymer/metal nanoparticle microstructures at the liquid/liquid interface. AB - HYPOTHESIS: Our previous studies have shown that the metal nanoparticle/polymer composite structures fabricated at the liquid/liquid interface have good reusability but lower catalytic activity for heterogeneous reactions in aqueous solutions. This should be attributed to the poor water wettability and more compact structure of the polymer matrices. Therefore, it should be possible to improve the catalytic activity through designing and fabricating a porous composite structure with good water wettability. EXPERIMENTS: A modified liquid/liquid interface adsorption and fabrication method was used. An aqueous solution of copper acetate and a chloroform/DMF mixed solution of PS-b-PAA acted as the two phases. Through spontaneous emulsification, self-assembly of the polymer molecules with Cu2+ ions in the droplets, and adsorption of the formed spherical micelles and nanofibers to the planar liquid/liquid interface, a porous composite microstructure was formed. FINDINGS: This structure consisted of nanofiber-connected nanospheres which have a PS core and a PAA corona. Tiny and well-dispersed Cu nanoparticles were embedded in the hydrophilic corona and were adsorbed on the nanofibers surface as well. After physical cross-linking with 1,6 diaminohexane, the composite material exhibited high catalytic activity and good reusability for the reactions in aqueous solutions. For example, the rate constant for the reduction of p-nitroaniline reached 1965 s-1 g-1. PMID- 29604447 TI - MOG-derived porous FeCo/C nanocomposites as a potential platform for enhanced catalytic activity and lithium-ion batteries performance. AB - The transition metal alloy nanoparticles (NPs) have received significant attention because of their unique physicochemical properties as well as low cost. Herein, we report a facile and clean synthetic route to prepare porous FeCo/C bimetallic alloy nanocomposites by using metal-organic gels (MOGs) as precursors. The bimetallic MOGs based on iron and cobalt bridged by tri-carboxylate organic ligands were first synthesized by a general and fast solvothermal method. The desired FeCo/C nanocomposites were then obtained by a one-step annealing process in which MOGs served as both the precursor and the self-sacrificing template. Significantly, the as-synthesized FeCo/C nanocomposites exhibit excellent catalytic activity and lithium-ion batteries performance. This fast and clean synthetic strategy is extended to synthesis diversity and range of potential applications of porous carbon-coated transition-metal alloy nanocomposites. PMID- 29604448 TI - Binary gas mixture adsorption-induced deformation of microporous carbons by Monte Carlo simulation. AB - Considering the thermodynamic grand potential for more than one adsorbate in an isothermal system, we generalize the model of adsorption-induced deformation of microporous carbons developed by Kowalczyk et al. [1]. We report a comprehensive study of the effects of adsorption-induced deformation of carbonaceous amorphous porous materials due to adsorption of carbon dioxide, methane and their mixtures. The adsorption process is simulated by using the Grand Canonical Monte Carlo (GCMC) method and the calculations are then used to analyze experimental isotherms for the pure gases and mixtures with different molar fraction in the gas phase. The pore size distribution determined from an experimental isotherm is used for predicting the adsorption-induced deformation of both pure gases and their mixtures. The volumetric strain (epsilon) predictions from the GCMC method are compared against relevant experiments with good agreement found in the cases of pure gases. PMID- 29604449 TI - The mechanisms of Ag85A DNA vaccine activates RNA sensors through new signal transduction. AB - Low immunogenicity is one of the major problems limiting the clinical use for DNA vaccines, which makes it impossible to obtain a strong protective immune response after vaccination. In order to explore whether Ag85A DNA vaccine could mount more efficiently protective immune response through new RNA sensor and its signal transduction pathway of antigen presentation we designed and synthesized Ag85A gene fragment containing multiple points mutations and transfected the gene fragment into the dendritic cell line (DC2.4) by CRISPR/Cas9. Subsequently, we focused on the changes of RNA sensors RIG-I, Mda-5, and the downstream adaptors MAVS, IRF3, IRF7 and IFN-beta. The results indicated the significant increases in the mRNA and protein expression of RNA sensors RIG-I, Mda-5 and related adaptors MAVS, IRF3, IRF7, and IFN-beta in the mutant DC 2.4 cells. The flow cytometry results demonstrated that the expression of MHC II on the surface of DC 2.4 significantly increased when compared with that in control. Therefore, it is suggested that Ag85A mutant DNA could release immunogenic message through RNA sensors and related adaptors via non protein pathway. There is at least one RNA signal transduction pathway of Ag85A DNA in DC2.4 cell. The work provides a new mode of action for nucleic acid vaccine to improve immunogenicity and meaningful data for the better understanding of the mechanisms of DNA vaccine. PMID- 29604450 TI - Changes in methylation within the STK32B promoter are associated with an increased risk for generalized anxiety disorder in adolescents. AB - Generalized anxiety disorder (GAD) is highly prevalent among adolescents. An early detection of individuals at risk may prevent later psychiatric condition. Genome-wide studies investigating single nucleotide polymorphisms (SNPs) concluded that a focus on epigenetic mechanisms, which mediate the impact of environmental factors, could more efficiently help the understanding of GAD pathogenesis. We investigated the relationship between epigenetic shifts in blood and the risk to develop GAD, evaluated by the Development and Well-Being Assessment (DAWBA) score, in 221 otherwise healthy adolescents. Our analysis focused specifically on methylation sites showing high inter-individual variation but low tissue-specific variation, in order to infer a potential correlation between results obtained in blood and brain. Two statistical methods were applied, 1) a linear model with limma and 2) a likelihood test followed by Bonferroni correction. Methylation findings were validated in a cohort of 160 adults applying logistic models against the outcome variable "anxiety treatment obtained in the past" and studied in a third cohort with regards to associated expression changes measured in monocytes. One CpG site showed 1% increased methylation in adolescents at high risk of GAD (cg16333992, padj. = 0.028, estimate = 3.22), as confirmed in the second cohort (p = 0.031, estimate = 1.32). The identified and validated CpG site is located within the STK32B promoter region and its methylation level was positively associated with gene expression. Gene ontology analysis revealed that STK32B is involved in stress response and defense response. Our results provide evidence that shifts in DNA methylation are associated with a modulated risk profile for GAD in adolescence. PMID- 29604451 TI - Amyloid structure of high-order assembly of Leucine-rich amelogenin revealed by solid-state NMR. AB - High-order assemblies of amelogenin, the major protein in enamel protein matrix, are believed to act as the template for enamel mineral formation. The Leucine rich amelogenin (LRAP) is a natural splice-variant of amelogenin, a functional protein in vivo, containing conserved domains of amelogenin. In this work, we showed LRAP aggregates hierarchically into assemblies with various sizes including scattered beads, beads-on-a-string and gel-like precipitations in the presence of both calcium and phosphate ions. Solid-state NMR combined with X-ray diffraction and microscopic techniques, was applied to give a picture of LRAP self-assemblies at the atomic level. Our results, for the first time, confirmed LRAP assemblies with different sizes all contained a consistent rigid segment with beta-sheet secondary structure (residues 12-27) and the beta-sheet segment would further assemble into amyloid-like structures. PMID- 29604453 TI - Bayesian uncertainty quantification in linear models for diffusion MRI. AB - Diffusion MRI (dMRI) is a valuable tool in the assessment of tissue microstructure. By fitting a model to the dMRI signal it is possible to derive various quantitative features. Several of the most popular dMRI signal models are expansions in an appropriately chosen basis, where the coefficients are determined using some variation of least-squares. However, such approaches lack any notion of uncertainty, which could be valuable in e.g. group analyses. In this work, we use a probabilistic interpretation of linear least-squares methods to recast popular dMRI models as Bayesian ones. This makes it possible to quantify the uncertainty of any derived quantity. In particular, for quantities that are affine functions of the coefficients, the posterior distribution can be expressed in closed-form. We simulated measurements from single- and double tensor models where the correct values of several quantities are known, to validate that the theoretically derived quantiles agree with those observed empirically. We included results from residual bootstrap for comparison and found good agreement. The validation employed several different models: Diffusion Tensor Imaging (DTI), Mean Apparent Propagator MRI (MAP-MRI) and Constrained Spherical Deconvolution (CSD). We also used in vivo data to visualize maps of quantitative features and corresponding uncertainties, and to show how our approach can be used in a group analysis to downweight subjects with high uncertainty. In summary, we convert successful linear models for dMRI signal estimation to probabilistic models, capable of accurate uncertainty quantification. PMID- 29604452 TI - MRI gradient-echo phase contrast of the brain at ultra-short TE with off resonance saturation. AB - Larmor-frequency shift or image phase measured by gradient-echo sequences has provided a new source of MRI contrast. This contrast is being used to study both the structure and function of the brain. So far, phase images of the brain have been largely obtained at long echo times as maximum phase signal-to-noise ratio (SNR) is achieved at TE = T2* (~40 ms at 3T). The structures of the brain, however, are compartmentalized and complex with a wide range of signal relaxation times. At such long TE, the short-T2 components are largely attenuated and contribute minimally to phase contrast. The purpose of this study was to determine whether proton gradient-echo images of the brain exhibit phase contrast at ultra-short TE (UTE). Our data showed that UTE images acquired at 7 T without off-resonance saturation do not contain significant phase contrast between gray and white matter. However, UTE images of the brain can attain strong phase contrast even at a nominal TE of 106 MUs by using off-resonance RF saturation pulses, which provide direct saturation of ultra-short-T2 components and indirect saturation of longer-T2 components via magnetization transfer. In addition, phase contrast between gray and white matter acquired at UTE with off-resonance saturation is reversed compared to that of the long-T2 signals acquired at long TEs. This finding opens up a potential new way to manipulate image phase contrast of the brain. By accessing short and ultra-short-T2 species, MRI phase images may further improve the characterization of tissue microstructure in the brain. PMID- 29604455 TI - Human fronto-parietal response scattering subserves vigilance at night. AB - Lack of sleep has a considerable impact on vigilance: we perform worse, we make more errors, particularly at night, when we should be sleeping. Measures of brain functional connectivity suggest that decrease in vigilance during sleep loss is associated with an impaired cross-talk within the fronto-parietal cortex. However, fronto-parietal effective connectivity, which is more closely related to the causal cross-talk between brain regions, remains unexplored during prolonged wakefulness. In addition, no study has simultaneously investigated brain effective connectivity and wake-related changes in vigilance, preventing the concurrent incorporation of the two aspects. Here, we used electroencephalography (EEG) to record responses evoked by Transcranial Magnetic Stimulation (TMS) applied over the frontal lobe in 23 healthy young men (18-30 yr.), while they simultaneously performed a vigilance task, during 8 sessions spread over 29 h of sustained wakefulness. We assessed Response Scattering (ReSc), an estimate of effective connectivity, as the propagation of TMS-evoked EEG responses over the fronto-parietal cortex. Results disclose a significant change in fronto-parietal ReSc with time spent awake. When focusing on the night-time period, when one should be sleeping, participants with lower fronto-parietal ReSc performed worse on the vigilance task. Conversely, no association was detected during the well rested, daytime period. Night-time fronto-parietal ReSc also correlated with objective EEG measures of sleepiness and alertness. These changes were not accompanied by variations in fronto-parietal response complexity. These results suggest that decreased brain response propagation within the fronto-parietal cortex is associated to increased vigilance failure during night-time prolonged wakefulness. This study reveals a novel facet of the detrimental effect on brain function of extended night-time waking hours, which is increasingly common in our societies. PMID- 29604454 TI - Bayesian convolutional neural network based MRI brain extraction on nonhuman primates. AB - Brain extraction or skull stripping of magnetic resonance images (MRI) is an essential step in neuroimaging studies, the accuracy of which can severely affect subsequent image processing procedures. Current automatic brain extraction methods demonstrate good results on human brains, but are often far from satisfactory on nonhuman primates, which are a necessary part of neuroscience research. To overcome the challenges of brain extraction in nonhuman primates, we propose a fully-automated brain extraction pipeline combining deep Bayesian convolutional neural network (CNN) and fully connected three-dimensional (3D) conditional random field (CRF). The deep Bayesian CNN, Bayesian SegNet, is used as the core segmentation engine. As a probabilistic network, it is not only able to perform accurate high-resolution pixel-wise brain segmentation, but also capable of measuring the model uncertainty by Monte Carlo sampling with dropout in the testing stage. Then, fully connected 3D CRF is used to refine the probability result from Bayesian SegNet in the whole 3D context of the brain volume. The proposed method was evaluated with a manually brain-extracted dataset comprising T1w images of 100 nonhuman primates. Our method outperforms six popular publicly available brain extraction packages and three well-established deep learning based methods with a mean Dice coefficient of 0.985 and a mean average symmetric surface distance of 0.220 mm. A better performance against all the compared methods was verified by statistical tests (all p-values < 10-4, two sided, Bonferroni corrected). The maximum uncertainty of the model on nonhuman primate brain extraction has a mean value of 0.116 across all the 100 subjects. The behavior of the uncertainty was also studied, which shows the uncertainty increases as the training set size decreases, the number of inconsistent labels in the training set increases, or the inconsistency between the training set and the testing set increases. PMID- 29604456 TI - A preference for mathematical processing outweighs the selectivity for Arabic numbers in the inferior temporal gyrus. AB - A region in the posterior inferior temporal gyrus (ITG), referred to as the number form area (NFA, here ITG-numbers) has been implicated in the visual processing of Arabic numbers. However, it is unknown if this region is specifically involved in the visual encoding of Arabic numbers per se or in mathematical processing more broadly. Using functional magnetic resonance imaging (fMRI) during experiments that systematically vary tasks and stimuli, we find that mathematical processing, not preference to Arabic numbers, consistently drives both mean and distributed responses in the posterior ITG. While we replicated findings of higher responses in ITG-numbers to numbers than other visual stimuli during a 1-back task, this preference to numbers was abolished when participants engaged in mathematical processing. In contrast, an ITG region (ITG-math) that showed higher responses during an adding task vs. other tasks maintained this preference for mathematical processing across a wide range of stimuli including numbers, number/letter morphs, hands, and dice. Analysis of distributed responses across an anatomically-defined posterior ITG expanse further revealed that mathematical task but not Arabic number form can be successfully and consistently decoded from these distributed responses. Together, our findings suggest that the function of neuronal regions in the posterior ITG goes beyond the specific visual processing of Arabic numbers. We hypothesize that they ascribe numerical content to the visual input, irrespective of the format of the stimulus. PMID- 29604458 TI - Modelfree global tractography. AB - Tractography based on diffusion-weighted MRI investigates the large scale arrangement of the neurite fibers in brain white matter. It is usually assumed that the signal is a convolution of a fiber specific response function (FRF) with a fiber orientation distribution (FOD). The FOD is the focus of tractography. While in the past the FRF was estimated beforehand and was usually assumed to be fix, more recent approaches estimate the response function during tractography. This work proposes a novel objective function independent of the FRF, just aiming for FOD reconstruction. The objective is integrated into global tractography showing promising results. PMID- 29604457 TI - Lateral prefrontal cortex lesion impairs regulation of internally and externally directed attention. AB - Our capacity to flexibly shift between internally and externally directed attention is crucial for successful performance of activities in our daily lives. Neuroimaging studies have implicated the lateral prefrontal cortex (LPFC) in both internally directed processes, including autobiographical memory retrieval and future planning, and externally directed processes, including cognitive control and selective attention. However, the causal involvement of the LPFC in regulating internally directed attention states is unknown. The current study recorded scalp EEG from patients with LPFC lesions and healthy controls as they performed an attention task that instructed them to direct their attention either to the external environment or their internal milieu. We compared frontocentral midline theta and posterior alpha between externally and internally directed attention states. While healthy controls showed increased theta power during externally directed attention and increased alpha power during internally directed attention, LPFC patients revealed no differences between the two attention states in either electrophysiological measure in the analyzed time windows. These findings provide evidence that damage to the LPFC leads to dysregulation of both types of attention, establishing the important role of LPFC in supporting sustained periods of internally and externally directed attention. PMID- 29604459 TI - Subcortical sources dominate the neuroelectric auditory frequency-following response to speech. AB - Frequency-following responses (FFRs) are neurophonic potentials that provide a window into the encoding of complex sounds (e.g., speech/music), auditory disorders, and neuroplasticity. While the neural origins of the FFR remain debated, renewed controversy has reemerged after demonstration that FFRs recorded via magnetoencephalography (MEG) are dominated by cortical rather than brainstem structures as previously assumed. Here, we recorded high-density (64 ch) FFRs via EEG and applied state-of-the art source imaging techniques to multichannel data (discrete dipole modeling, distributed imaging, independent component analysis, computational simulations). Our data confirm a mixture of generators localized to bilateral auditory nerve (AN), brainstem inferior colliculus (BS), and bilateral primary auditory cortex (PAC). However, frequency-specific scrutiny of source waveforms showed the relative contribution of these nuclei to the aggregate FFR varied across stimulus frequencies. Whereas AN and BS sources produced robust FFRs up to ~700 Hz, PAC showed weak phase-locking with little FFR energy above the speech fundamental (100 Hz). Notably, CLARA imaging further showed PAC activation was eradicated for FFRs >150 Hz, above which only subcortical sources remained active. Our results show (i) the site of FFR generation varies critically with stimulus frequency; and (ii) opposite the pattern observed in MEG, subcortical structures make the largest contribution to electrically recorded FFRs (AN >= BS > PAC). We infer that cortical dominance observed in previous neuromagnetic data is likely due to the bias of MEG to superficial brain tissue, underestimating subcortical structures that drive most of the speech-FFR. Cleanly separating subcortical from cortical FFRs can be achieved by ensuring stimulus frequencies are >150-200 Hz, above the phase-locking limit of cortical neurons. PMID- 29604460 TI - Landscape Analysis of Global Health Tracks in United States Pediatric Residencies: Moving Toward Standards. AB - OBJECTIVE: The number of pediatric Global Health (GH) tracks has more than doubled in less than 10 years. The goal of this study was to describe the characteristics of the pediatric GH tracks to identify commonalities and differences in track structure, funding, and education. In addition, we also identified demographic, institutional, and residency-related factors that were significantly associated with educational offerings and logistical challenges. METHODS: A cross-sectional survey was electronically administered to pediatric residency programs with GH tracks. Statistical analyses included frequencies to describe GH track characteristics. Fisher's exact tests were used to identify bivariate associations between track structure and funding with educational offerings and logistical challenges. RESULTS: Leaders of 32 pediatric GH tracks (67%) completed the survey. The majority of GH tracks were completed within the 3 years of residency (94%) and identified a GH track director (100%); however, tracks varied in size, enrollment methods, domestic and international partnerships, funding, and evaluations. Dedicated faculty time and GH track budget amounts were associated with more robust infrastructure pertaining to resident international electives, including funding and mentorship. Many tracks did not meet American Academy of Pediatrics recommended standards for clinical international rotations. CONCLUSIONS: Despite the presence of multiple similarities among pediatric GH tracks, there are large variations in track structure, education, and funding. The results from this study support the proposal of a formal definition and minimum standards for a GH track, which may provide a framework for quality, consistency, and comparison of GH tracks. PMID- 29604461 TI - Assessing Potential Confounding and Misclassification Bias When Studying the Safety of the Childhood Immunization Schedule. AB - OBJECTIVES: Some parents are concerned the childhood immunization schedule could increase risk for allergic disorders, including asthma. To inform future safety studies of this speculated association, a parent survey was conducted to examine the risk of misclassification of vaccination status in electronic health record data, and to assess the potential for confounding if asthma risk factors varied by vaccination status. METHODS: A survey was conducted among parents of children 19 to 35 months old at 6 medical organizations within the Vaccine Safety Datalink. Parents of children in 4 vaccination groups were surveyed: 1) no vaccines by 12 months of age and a diagnosis of parental vaccine refusal; 2) consistent vaccine limiting (<=2 vaccines per visit); 3) not consistently vaccine limiting but otherwise undervaccinated with a vaccine refusal diagnosis; and 4) fully vaccinated with no delays and no vaccine refusal. Parents were surveyed about their child's vaccination status and whether asthma risk factors existed. RESULTS: Among a survey sample of 2043 parents, 1209 responded (59.2%). For receiving no vaccines, the observed agreement between parent report and electronic health record data was 94.0% (kappa = 0.79); for receiving all vaccines with no delays, the observed agreement was 87.3% (kappa = 0.73). Although most asthma risk factors (allergic rhinitis, eczema, food allergies, family asthma history) reported by parents did not differ significantly between children in the vaccination groups studied, several factors (aeroallergen sensitivity, breastfeeding) differed significantly between groups. CONCLUSIONS: Measurement and control of disease risk factors should be carefully considered in observational studies of the safety of the immunization schedule. PMID- 29604462 TI - Physiological and transcriptomic analysis revealed the involvement of crucial factors in heat stress response of Rhododendron hainanense. AB - Molecular regulatory mechanism of heat stress response (HSR) in Ericaceae remains unknown. Here, we sought to identify HSR mechanisms in Rhododendron hainanense, a Ericaceae species, through a combination of physiological and transcriptomic studies. The levels of MDA, H2O2, Pro, SOD, CAT and APX in leaves of R. hainanense were analyzed to characterize a dramatic difference in varied temperature treatment. Also, three sequencing libraries, including one control and two heat stress (HS)-treated samples, were constructed for comparative transcriptomic analysis. By Illumina sequencing and Trinity strategy, 350 million clean reads (average length = 149 bp) was assembled into 183,486 unigenes. According to analysis of differential expression genes (DEGs), a total of 2658 DEGs were obtained. Moreover, a complex interaction network of 982 DEGs was established, of which master portions were comprised of 109 transcription factors (TFs). Importantly, integrated differential expression profiling, qRT-PCR and functional analysis, several TFs of R. hainanense (ABR1, IAA26, OBF1, LUX, SCL3, DIV, NAC29, NAC72 and TCP3) and their potential regulations for the crosstalk between hormonal signal and HSR were identified. These findings will contribute to our understanding of the regulatory mechanisms of HSR in R. hainanense, breeding cultivars with improved thermotolerance. PMID- 29604463 TI - Identification of differentially expressed microRNAs during preadipocyte differentiation in Chinese crested duck. AB - MicroRNAs (miRNAs) are considered key players in the regulation of a broad range of biological processes. Specifically, miRNAs have been reported to play an important role in the process of adipogenesis. In this study, we constructed a model of adipogenesis by isolating preadipocytes (WCC) derived from adipose tissue and preadipocytes after 72 h differentiation (WCT) in vitro. Deep sequencing of miRNAs expressed in WCT and WCC cells was conducted; we identified 105 differentially expressed miRNA candidates (fifty up-regulated and fifty-five down-regulated). Among them, twelve were novel miRNAs, and ninety-three were previously known miRNAs. Furthermore, seven miRNAs were selected for expression confirmation by reverse transcription quantitative PCR (RT-qPCR); the results showed that the differential expression of miRNAs between the two groups was consistent with our sequencing results. Of them, miR-223, miR-184-3p, and miR-10b 5 showed a strong correlation to adipogenesis. Using target prediction, we predicted that the 105 differentially expressed miRNAs targeted 4155 unique mRNAs. The prediction of targets of differentially expressed miRNAs revealed that the miRNAs participated in the regulation of multiple adipogenesis-related signalling pathways, including the peroxisome proliferator-activated receptor (PPAR) signalling pathway, insulin signalling pathway, fatty acid biosynthesis, and fatty acid degradation. Overall, our findings provide a background for further research into miRNAs and lay a foundation for the prediction and analysis of miRNAs related to adipogenesis. PMID- 29604464 TI - Integrative analysis of mRNA and lncRNA profiles identified pathogenetic lncRNAs in esophageal squamous cell carcinoma. AB - Systems biology approaches can help understand pathogenesis of complex human diseases like cancers for identification of potential new therapeutic targets. Here in this study, we performed genome-wide screening for mRNA and lncRNA profiles in esophageal cancer to identify the novel cancer-related mRNA and lncRNA in esophageal squamous cell carcinoma (ESCC). We identified 1260 up regulated/1445 down-regulated mRNAs and 402 up-regulated/741 down-regulated lncRNAs. Further functional analysis revealed differentially expressed genes (DEGs) of mRNA and lncRNA are related to different pathways. mRNA pathways are mainly involved in cell cycles while lncRNA pathways are for regulation and metabolic procession. Differentially expressed mRNAs/lncRNAs were validated with qPCR. At last, mRNA and lncRNA co-expression network were built and highly connected networks were identified, which may provide a mechanism of mRNA expression regulation by lncRNA. In together, we used next generation sequencing data to explore the co-expression networks of lncRNA and mRNA, which may elucidate the functions and mechanisms of lncRNA in ESCC. PMID- 29604465 TI - A transcriptomic investigation of digestive processes in orange-spotted grouper, Epinephelus coioides, before, during, and after metamorphic development. AB - The orange-spotted grouper (OG), Epinephelus coioides, is an ecologically and economically important species with strong market demand. However, larval rearing for this species is especially difficult, with mass mortality occurring at multiple stages including the period coinciding with metamorphic development. The aim of the present study was to characterise the molecular ontogenesis of genes that influence appetite, feeding, and digestion in OG larvae head and body tissue at 12, 18, and 50 days post hatch (dph), which coincides with the beginning and end of metamorphic development. The sequences of many transcripts involved in the regulation of appetite, feeding and digestive processes were detected from 12 dph in OG larvae, including those that were differentially expressed in body tissue in fish at different stages of development such as cholecystokinin, peptide Y, and meprin A. Of the transcripts encoding digestive enzymes, only the expression level of bile salt-activated lipase decreased as development progressed. In contrast, a dramatic increase in expression for other body-expressed transcripts encoding digestive enzymes and a proton pump subunit was observed at 50 dph, which is indicative of an increase in digestive capacity. In addition, we have provided evidence suggesting that various trypsinogen isoforms are present, and have differing expression patterns throughout larval development in whole body tissue. We also report on the presence of a prey-specific transcript encoding alpha-amylase that was present in the body-transcriptome. Taken together, these results give insight into the processes underpinning attainment of digestive capacity, and form the basis of a new transcriptomic database that will aid further study into the digestive development and dietary requirements of orange spotted grouper larvae. PMID- 29604466 TI - PON1 promoter polymorphisms contribute to PCOS susceptibility and phenotypic outcomes in Indian women. AB - Polycystic ovary syndrome is a common endocrinopathy characterized by anovulatory infertility, hyperandrogenism, insulin resistance and oxidative stress, which predisposes affected women to reproductive and cardiometabolic complications in later life. We have investigated the association of PON1 promoter polymorphisms with PCOS susceptibility, PON1 activity and its related traits in Indian women. The genotypic and allelic frequency distribution of only -907G/C polymorphism in PON1 promoter showed significant difference between non-hyperandrogenic control and PCOS women, and was significantly associated with reduced susceptibility to PCOS, considering the recessive model. PON1 lactonase and arylesterase activities were also significantly decreased in women with PCOS compared to controls. Further, PON1 promoter polymorphisms were linked to altered insulin and testosterone levels in hyperandrogenic and non-hyperandrogenic women with PCOS. This study highlights PON1 as an important candidate gene influencing genetic pathophysiology of PCOS. PMID- 29604467 TI - Decreased expression of serum- and glucocorticoid-inducible kinase 1 (SGK1) promotes alpha-synuclein increase related with down-regulation of dopaminergic cell in the Substantia Nigra of chronic MPTP-induced Parkinsonism mice and in SH SY5Y cells. AB - Parkinson's disease (PD) is a chronically progressive neurodegenerative disease, with its main pathological hallmarks being a dramatic loss of dopaminergic neurons predominantly in the Substantia Nigra (SN), and the formations of intracytoplasmic Lewy bodies and dystrophic neurites. Alpha-synuclein (alpha syn), widely recognized as the most prominent element of the Lewy body, is one of the representative hallmarks in PD. However, the mechanisms behind the increased alpha-syn expression and aggregation have not yet been clarified. To examine what causes alpha-syn expression to increase, we analyzed the pattern of gene expression in the SN of mice intoxicated with 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP), where down-regulation of dopaminergic cells occurred. We identified serum- and glucocorticoid-dependent kinase 1 (SGK1) as one of the genes that is evidently downregulated in chronic MPTP-intoxication. The results of Western blot analyses showed that, together with the down-regulation of dopaminergic cells, the decrease in SGK1 expression increased alpha-syn expression in the SN in a chronic MPTP-induced Parkinsonism mouse. For an examination of the expression correlation between SGK1 and alpha-syn, SH-5YSY cells were knocked down with SGK1 siRNA then, the downregulation of dopaminergic cells and the increase in the expression of alpha-syn were observed. These results suggest that decreased expression of SGK1 may play a critical role in increasing the expression of alpha-syn, which is related with dopaminergic cell death in the SN of chronic MPTP-induced Parkinsonism mice and in SH-SY5Y cells. PMID- 29604468 TI - Learning to recognize unfamiliar talkers: Listeners rapidly form representations of facial dynamic signatures. AB - Seeing the motion of a talking face can be sufficient to recognize personally highly familiar speakers, suggesting that dynamic facial information is stored in long-term representations for familiar speakers. In the present study, we tested whether talking-related facial dynamic information can guide the learning of unfamiliar speakers. Participants were asked to identify speakers from configuration-normalized point-light displays showing only the biological motion that speakers produced while saying short sentences. During an initial learning phase, feedback was given. During test, listeners identified speakers from point light displays of the training sentences and of new sentences. Listeners learned to identify two speakers, and four speakers in another experiment, from visual dynamic information alone. Learning was evident already after very little exposure. Furthermore, listeners formed abstract representations of visual dynamic signatures that allowed them to recognize speakers at test even from new linguistic materials. Control experiments showed that any potentially remaining static information in the point-light displays was not sufficient to guide learning and that listeners learned to recognize the identity, rather than the sex, of the speakers, as learning was also found when speakers were of the same sex. Overall, these results demonstrate that listeners can learn to identify unfamiliar speakers from the motion they produce during talking. Listeners thus establish abstract representations of the talking-related dynamic facial motion signatures of unfamiliar speakers already from limited exposure. PMID- 29604469 TI - Looking into the future: An inward bias in aesthetic experience driven only by gaze cues. AB - The inward bias is an especially powerful principle of aesthetic experience: In framed images (e.g. photographs), we prefer peripheral figures that face inward (vs. outward). Why does this bias exist? Since agents tend to act in the direction in which they are facing, one intriguing possibility is that the inward bias reflects a preference to view scenes from a perspective that will allow us to witness those predicted future actions. This account has been difficult to test with previous displays, in which facing direction is often confounded with either global shape profiles or the relative locations of salient features (since e.g. someone's face is generally more visually interesting than the back of their head). But here we demonstrate a robust inward bias in aesthetic judgment driven by a cue that is socially powerful but visually subtle: averted gaze. Subjects adjusted the positions of people in images to maximize the images' aesthetic appeal. People with direct gaze were not placed preferentially in particular regions, but people with averted gaze were reliably placed so that they appeared to be looking inward. This demonstrates that the inward bias can arise from visually subtle features, when those features signal how future events may unfold. PMID- 29604470 TI - Individual differences in nonverbal prediction and vocabulary size in infancy. AB - Children who generate and update verbal predictions have larger vocabularies, suggesting that prediction may be a mechanism that supports language learning. We hypothesize that this relation is not confined to the domain of language, but instead signals a broader individual difference in information processing. To investigate this possibility, we tested infants (n = 50) in the early stages of vocabulary development (12-24 months) on their ability to generate and update nonverbal, visual predictions. In an eye-tracking task, a central fixation reliably preceded a peripheral target. Then, halfway through the experiment, the peripheral target began appearing on the opposite side. We assessed infants' proficiency in initiating anticipatory eye movements before and after the switch, and found that infants with larger vocabularies did not generate more predictions overall, but were more efficient in updating predictions to the new target side. These findings establish a link between nonverbal prediction and vocabulary in infancy, and suggest a promising means of addressing whether or not prediction abilities are causally related to language learning. PMID- 29604471 TI - Application of modern autoradiography to nuclear forensic analysis. AB - Modern autoradiography techniques based on phosphorimaging technology using image plates (IPs) and digital scanning can identify heterogeneities in activity distributions and reveal material properties, serving to inform subsequent analyses. Here, we have adopted these advantages for applications in nuclear forensics, the technical analysis of radioactive or nuclear materials found outside of legal control to provide data related to provenance, production history, and trafficking route for the materials. IP autoradiography is a relatively simple, non-destructive method for sample characterization that records an image reflecting the relative intensity of alpha and beta emissions from a two-dimensional surface. Such data are complementary to information gathered from radiochemical characterization via bulk counting techniques, and can guide the application of other spatially resolved techniques such as scanning electron microscopy (SEM) and secondary ion mass spectrometry (SIMS). IP autoradiography can image large 2-dimenstional areas (up to 20*40cm), with relatively low detection limits for actinides and other radioactive nuclides, and sensitivity to a wide dynamic range (105) of activity density in a single image. Distributions of radioactivity in nuclear materials can be generated with a spatial resolution of approximately 50MUm using IP autoradiography and digital scanning. While the finest grain silver halide films still provide the best possible resolution (down to ~10MUm), IP autoradiography has distinct practical advantages such as shorter exposure times, no chemical post-processing, reusability, rapid plate scanning, and automated image digitization. Sample preparation requirements are minimal, and the analytical method does not consume or alter the sample. These advantages make IP autoradiography ideal for routine screening of nuclear materials, and for the identification of areas of interest for subsequent micro-characterization methods. In this paper we present a summary of our setup, as modified for nuclear forensic sample analysis and related research, and provide examples of data from select samples from the nuclear fuel cycle and historical nuclear test debris. PMID- 29604472 TI - Microbial diversity changes with rhizosphere and hydrocarbons in contrasting soils. AB - In the ecotoxicological assessment of petroleum hydrocarbon-contaminated soil, microbial community profile is important aspect due to their involvement in soil functions. However, soil physicochemical properties and the inhabiting plants could dictate the microbial composition. A question remains unanswered is, how an integrated approach may be utilized to account for various contrasting soil properties, plant types (reference vs. native) and the nature of the hydrocarbon contamination. In this study, we utilized bacterial DNA profiling techniques to investigate the relationship between soil properties, contaminant and plant species. Results identified that Proteobacteria and Actinobacteria were the most abundant bacteria of the 45 phyla identified in the hydrocarbon-contaminated soil. The bulk and rhizosphere microbiome showed that the contaminated soil originally had quite distinct bacterial communities compared to the artificially contaminated soil (mine soil = 95 genera vs. other soils = 2-29 genera). In these cases, not significantly but the native plant slightly increased bacterial diversity and relative abundance in the same soils. Also, within each site, the bacterial community was significantly altered with the hydrocarbon concentration. In this instance, the influence of the contaminant was strong and also with the soil pH and organic matter. These results would significantly contribute to the novel insights on the molecular technique-based hydrocarbon toxicity assessment and the development of the further integrative approach with other microbial community and their metabolic profile in the contaminated sites. PMID- 29604473 TI - Structure of surface polysaccharides from Aeromonas sp. AMG272, a plant-growth promoting rhizobacterium isolated from rice rhizosphere. AB - Aeromonas sp. AMG272 is a Gram-negative bacterium that has been isolated from agricultural soil and studied for its plant growth-promoting activities. Structures of the O-specific polysaccharide chain of the AMG272 lipopolysaccharide and its capsular polysaccharide were elucidated using GLC-MS and NMR spectroscopy. The structure of the O-specific polysaccharide, ->4)-alpha l-Rhap-(1 -> 3)-beta-d-GlcpNAc-(1->, has been found in other Aeromonas strains and related bacteria, whereas the structure of the capsular polysaccharide has not been reported before: ->6)[beta-d-Fucp3NAc4Ac-(1 -> 3)]-alpha-d-GlcpNAc-(1 -> 4)-alpha-d-Galp-(1 -> 3)-alpha-d-GalpNAc-(1 -> 4)-alpha-d-Galp-(1 -> . PMID- 29604474 TI - Varenicline for smoking reduction in smokers not yet ready to quit: A double blind, proof-of-concept randomized clinical trial. AB - BACKGROUND: Varenicline has demonstrated efficacy for quitting smoking. Its agonist and antagonist effects suggest that it would be efficacious for reducing cigarettes per day in smokers not yet ready to quit. OBJECTIVES: To conduct a proof-of-concept placebo-controlled randomized clinical trial of varenicline for smokers willing to reduce, but not quit smoking. METHODS: Smokers (N = 53) were randomized to receive 28-days of varenicline plus brief counseling or 28-days of placebo plus brief counseling. They were instructed to reduce their cigarettes per day with the goal of reducing by 50% from baseline to end-of-treatment. RESULTS: Most (82.7%) participants attended all four counseling sessions and more than half took their medication as prescribed on at least 80% of days. Approximately half of our participants reported at least one adverse event, but no serious adverse events were reported or discovered. Although twice as many smokers receiving varenicline made a quit attempt as compared to those receiving placebo, the data did not support the hypothesis that taking varenicline would have a benefit over placebo in meeting a 50% smoking reduction goal. Those who reduced their cigarettes per day by at least 50% and those who reduced their CO intake by at least 50% from baseline to end-of-treatment showed higher self efficacy for quitting at end-of-treatment, however. CONCLUSIONS: These data support the proof-of-concept that smokers not ready to quit are willing to use varenicline while reducing the number of cigarettes smoked per day, and that successful reduction is associated with increased self-efficacy for later quitting. PMID- 29604475 TI - Robotic-Assisted Laparoscopic Cervicovaginal Myomectomy. AB - STUDY OBJECTIVE: To illustrate a robotic-assisted laparoscopic resection for cervicovaginal myomectomy. DESIGN: Step-wise instruction using video and case report (Canadian Task Force classification III). SETTING: A tertiary referral center. PATIENT: A 39-year-old woman. INTERVENTION: Robotic-assisted laparoscopy resection of leiomyoma. MEASUREMENTS AND MAIN RESULTS: A 39-year-old woman, gravida 0, body mass index of 23.0 kg/m2, with a known cervicovaginal myoma that in the past underwent uterine artery embolization, presented with recurrence of her severe abnormal vaginal bleeding. She was referred for surgical resection of the mass. Magnetic resonance imaging revealed a 5-cm posterior cervicovaginal leiomyoma. The patient wanted to preserve her reproductive organs. A total robotic procedure lasted 123 minutes, with an estimated blood loss of 100 mL. She was discharged uneventfully on the day 0 postoperatively. Pathology results showed a 37-g leiomyoma of the uterus. The patient presented at her 2-weeks postoperative visit with no more complaint of vaginal bleeding. CONCLUSION: Robot assisted laparoscopic surgery is a feasible approach for cervicovaginal myoma with minimal complications. PMID- 29604476 TI - Transcriptional Analysis of the Guinea Pig Mucosal Immune Response to Intravaginal Infection with Herpes Simplex Virus Type 2. AB - Genital herpes infection in guinea pigs closely models human infection but tools for immune characterization are limited. Immunity to HSV infection at the vaginal epithelial surface was characterized in guinea pigs using PCR-based array analysis of vaginal swab samples. IFNgamma was one of the most significantly upregulated genes throughout the infection and over 40% of genes with significantly altered expression were linked to IFNgamma based on INTERFEROME analysis. IFNgamma transcripts and biologically active IFNgamma at the genital mucosa were confirmed by RTPCR and IFNgamma reporter cells. Gene ontology analysis revealed activation of many biological processes related to genital immunity shared by humans and mice demonstrating the similarities of the local immune response to primary genital HSV-2 infection in guinea pigs and other established models. This transcription-based array will be useful for dissection of immunity during reactivation from latency, an infection outcome that is not well recapitulated by other animal models. PMID- 29604477 TI - Impact of immune escape mutations and N-linked glycosylation on the secretion of hepatitis B virus virions and subviral particles: Role of the small envelope protein. AB - Hepatitis B virus (HBV) expresses three co-terminal envelope proteins: large (L), middle (M), and small (S), with the S protein driving the secretion of both virions and subviral particles. Virion secretion requires N-linked glycosylation at N146 in the S domain but can be impaired by immune escape mutations. An M133T mutation creating a novel glycosylation site at N131could rescue virion secretion of N146Q mutant (loss of original glycosylation site) and immune escape mutants such as G145R. Here we demonstrate that other novel N-linked glycosylation sites could rescue virion secretion of the G145R and N146Q mutants to variable extents. Both G145R and N146Q mutations impaired virion secretion through the S protein. The M133T mutation restored virion secretion through the S protein, and could work in trans. Impaired virion secretion was not necessarily associated with a similar block in the secretion of subviral particles. PMID- 29604478 TI - AAV6 K531 serves a dual function in selective receptor and antibody ADK6 recognition. AB - Adeno-associated viruses (AAVs) are being developed as vectors for the treatment of genetic disorders. However, pre-existing antibodies present a significant limitation to achieving optimal efficacy for the AAV gene delivery system. Efforts aimed at engineering vectors with the ability to evade the immune response include identification of residues on the virus capsid important for these interactions and changing them. Here K531 is identified as the determinant of monoclonal antibody ADK6 recognition by AAV6, and not the closely related AAV1. The AAV6-ADK6 complex structure was determined by cryo-electron microscopy and the footprint confirmed by cell-based assays. The ADK6 footprint overlaps previously identified AAV antigenic regions and neutralizes by blocking essential cell surface glycan attachment sites. This study thus expands the available repertoire of AAV-antibody information that can guide the design of host immune escaping AAV vectors able to maintain capsid functionality. PMID- 29604479 TI - Anemia and iron deficiency in rural Bangladeshi pregnant women living in areas of high and low iron in groundwater. AB - BACKGROUND: Recent studies found a low rate of iron deficiency in Bangladeshi non pregnant and non-lactating women. This was attributed to high iron concentrations in drinking water. However, there are limited data on iron deficiency among pregnant women in Bangladesh. OBJECTIVES: Our aim was to investigate the prevalence of anemia, iron deficiency, and iron deficiency anemia (IDA) among rural pregnant women and explore the association of groundwater iron concentration with anemia and iron deficiency in this group. METHODS: This study used data from a baseline assessment of an intervention study on rural pregnant women (n = 522), gestational age <=20 wk, living in areas of low and high iron in groundwater. RESULTS: Overall, 34.7% of the pregnant women had anemia, 27% had iron deficiency, and 13.4% had IDA. Prevalence of anemia, iron deficiency, and IDA among the pregnant women living in low-groundwater-iron areas was significantly higher than among the pregnant women from high-groundwater-iron areas. The odds of iron deficiency were significantly lower among pregnant women in the higher quartiles of daily iron intake from drinking water. CONCLUSIONS: This study found a differential prevalence of anemia and iron deficiency among pregnant women living in areas of high and low groundwater iron. Iron status was independently associated with daily iron intake from drinking water. However, a significant proportion of the anemia could not be attributed to iron deficiency. Further research to identify other nutritional and non-nutritional contributors to anemia in Bangladesh is needed to formulate effective prevention and control programs for anemia. PMID- 29604480 TI - Nonalcoholic fatty liver disease and advanced fibrosis are associated with left ventricular diastolic dysfunction. AB - BACKGROUND AND AIMS: Nonalcoholic fatty liver disease (NAFLD) may be associated with a wide spectrum of cardiac abnormalities, which share many metabolic risk factors. This study aimed to evaluate whether NAFLD is associated with left ventricular (LV) diastolic dysfunction independent of other classical risk factors. METHODS: A total of 3300 subjects (mean age, 54.1 years; 62.9% men), who underwent echocardiography and hepatic ultrasonography, were enrolled. LV diastolic dysfunction was diagnosed and graded using conventional and Doppler echocardiographic assessments. NAFLD was diagnosed by ultrasonographic findings without any evidence of significant alcohol consumption or viral hepatitis, other liver diseases, or medication provoking fatty liver. Advanced fibrosis was defined as having intermediate-high probability for advanced fibrosis using the NAFLD fibrosis score. RESULTS: The prevalence of LV diastolic dysfunction was 35.1%. NAFLD had a higher prevalence and severity of LV diastolic dysfunction. The prevalence rates of LV diastolic dysfunction were significantly increased according to the NAFLD fibrosis grade (30.4% for no-NAFLD, 35.2% for NAFLD without advanced fibrosis and 57.4% for NAFLD with advanced fibrosis, p < 0.001). Multivariable analysis showed that NAFLD was associated with a 29% increase in the risk of diastolic dysfunction compared with controls (odds ratio [OR] 1.29; 95% confidence interval [CI] 1.07-1.60). There was significant interaction between obesity (BMI < 25 kg/m2vs. >= 25 kg/m2) and advanced fibrosis for LV diastolic dysfunction. A significant, incrementally increased risk of diastolic dysfunction according to the fibrosis grade was more pronounced in the non-obese population [adjusted OR (95% CI), 1.40 (1.06-1.84) for NAFLD without advanced fibrosis, 1.44 (0.95-2.17) for NAFLD with advanced fibrosis vs. no NAFLD, P for trend = 0.022] compared with the obese population (p for trend = 0.081), independent of other well-defined risk factors. CONCLUSIONS: NAFLD was associated with increased risk for LV diastolic dysfunction. In addition, an incrementally increased risk for LV diastolic dysfunction according to fibrosis grade was prominent in the non-obese population. PMID- 29604481 TI - Treatment patterns in hyperlipidaemia patients based on administrative claim databases in Japan. AB - BACKGROUND AND AIMS: Real-world evidence on treatment of hyperlipidaemia (HLD) in Japan is limited. We aimed to describe treatment patterns, persistence with, and adherence to treatment in Japanese patients with HLD. METHODS: Retrospective analyses of adult HLD patients receiving drug therapy in 2014-2015 were conducted using the Japan Medical Data Center (JMDC) and Medical Data Vision (MDV) databases. Depending on their HLD treatment history, individuals were categorised as untreated (UT) or previously treated (PT), and were followed for at least 12 months. Outcomes of interest included prescribing patterns of HLD drug classes, persistence with treatment at 12 months, and adherence to treatment. RESULTS: Data for 49,582 and 53,865 patients from the JMDC and MDV databases, respectively, were analysed. First-line HLD prescriptions for UT patients were predominantly for moderate statins (JMDC: 75.9%, MDV: 77.0%). PT patients most commonly received combination therapy (JMDC: 43.9%, MDV: 52.6%). Approximately half of the UT patients discontinued treatment during observation. Within each cohort, persistence rates were lower in UT patients than in PT patients (JMDC: 45.0% vs. 77.5%; MDV: 51.9% vs. 85.3%). Adherence was >=80% across almost all HLD drug classes, and was slightly lower in the JMDC cohort than MDV cohort. CONCLUSIONS: Most common prescriptions were moderate statins in UT patients and combination therapy in PT patients. The high discontinuation rate of HLD therapy in UT patients warrants further investigation and identification of methods to encourage and support long-term persistence. PMID- 29604482 TI - Diagnostic value of Status Epilepticus Severity Score for survival conditions of patients with status epilepticus: A PRISMA-compliant systematic review and meta analysis. AB - OBJECTIVE: In recent years, the Status Epilepticus Severity Score (STESS) has been widely used to predict survival conditions of patients with status epilepticus (SE). However, the diagnostic value of STESS has not yet been evaluated. We therefore performed this meta-analysis to assess the overall diagnostic accuracy of STESS for predicting survival condition of patients with SE. METHODS: Systemic searches for relevant published studies were conducted in EMBASE, PubMed, Web of Science, and Cochrange databases up to July 2, 2017. Quality Assessment of Diagnostic Accuracy Studies (QUADAS) was used to evaluate the quality of included studies. All statistical analyses were performed using Stata12.0 and Meta-DiSc software. RESULTS: A total of 11 studies including 12 observations with 1356 patients were included in this meta-analysis. Summary estimates of the diagnostic value of STESS for survival condition of patients with SE were listed as follows: sensitivity, 0.81 (95% confidence intervals (CI): 0.76-0.85); specificity, 0.53 (95% CI: 0.50-0.56); positive likelihood ratio (PLR), 1.86 (95% CI: 1.57-2.21); negative likelihood ratio (NLR), 0.38 (95% CI: 0.30-0.48); diagnostic odds ratio (DOR), 5.24 (95% CI: 3.49-7.87); and area under the curve (AUC), 0.81. Metaregression analysis showed that ethnicity, study design, publish year, and sample size did not significantly influence the diagnostic performance statistically (all P>0.05). CONCLUSIONS: The STESS is a promising candidate for predicting survival condition of patients with SE. However, the potential tool should be validated in well-designed studies with larger sample sizes. PMID- 29604483 TI - Development and psychometric evaluation of the youth and parent versions of the Epilepsy Disclosure Scale (EDS). AB - OBJECTIVES: The aim of this paper was to describe the development and psychometric evaluation of new Epilepsy Disclosure Scales (EDSs) for youths with epilepsy (YWE) and their parents. METHODS: Developing the EDSs for youths and parents comprised a number of stages, including questionnaire construction and item development for the new EDSs (consisting of a pilot and review of the newly developed EDSs) and psychometric evaluation of the measures to assess their appropriateness, factor structure, reliability, and validity. Psychometric properties were determined using a cross-sectional survey of 47 YWE and 72 parents. RESULTS: Two scales were developed to assess the epilepsy disclosure behaviors of YWE and their parents; that is, the extent to which they tell and talk to others about the child's epilepsy. The youth version of the EDS comprised six items and had a unidimensional factor structure that explained 55% of the variance. The parent version of the EDS also consisted of six items, with a single factor explaining 47% of the variance. The suitability, validity, and reliability of the youth and parent versions of EDSs were supported by positive indicators, such as a high Cronbach's alpha (representative of good internal consistency) and the confirmation of a number of hypothesized relationships between epilepsy disclosure and psychosocial and illness attitude variables (demonstrative of their convergent validity). CONCLUSION: Prior to the development of these instruments, no valid and reliable measures existed that could suitably capture disclosure amongst populations living with epilepsy. The youth and parent versions of the EDS are valid, reliable, brief, and easily administered and thus could prove useful in research as well as in the clinical setting. These scales will enable researchers and clinicians to profile the epilepsy disclosure behaviors of YWE and their parents, which play an important role and have implications both for the psychosocial wellbeing of families living with epilepsy and for epilepsy-related stigma. PMID- 29604484 TI - Psychiatric and cognitive adverse events: A pooled analysis of three phase III trials of adjunctive eslicarbazepine acetate for partial-onset seizures. AB - OBJECTIVE: To evaluate the nature and incidence of psychiatric and cognitive adverse events (AEs) reported with eslicarbazepine acetate (ESL) used as adjunctive treatment for refractory partial-onset seizures (POS) in adults. METHODS: This was a post-hoc analysis of data pooled from three randomized double blind, placebo-controlled trials (BIA-2093-301, -302, -304). After an 8-week baseline period, patients received placebo or adjunctive ESL 400mg (studies 301 and 302 only), 800mg, or 1200mg once daily (QD) for 14weeks (2-week titration period, 12-week maintenance period). Psychiatric and cognitive AEs were identified from individual patient data. Suicidality was also evaluated using the Columbia-Classification Algorithm of Suicide Assessment (C-CASA), or the Columbia Suicide Severity Rating Scale (C-SSRS). P-values were obtained using the chi square test of independence or Fisher's exact test, without correcting for multiplicity. RESULTS: The analysis population included 1447 patients (ESL, n=1021; placebo, n = 426). Psychiatric treatment-emergent AEs (TEAEs) occurred in 10.8% of patients receiving ESL, and in a comparable proportion (10.3%) of patients receiving placebo (p=0.802). The incidence of depression and suicidality related TEAEs was higher for ESL (7.4%) vs. placebo (3.8%) (p=0.009). The occurrence of these TEAEs differed between treatment groups (p = 0.010), but there was no notable trend between increasing ESL dose and increasing incidence of depression and suicidality-related TEAEs. Aggression/hostility-related TEAEs occurred in <0.1% of patients taking ESL vs. 0.9% taking placebo. The incidence of cognitive TEAEs was higher for ESL (7.1%) vs. placebo (4.0%) (p=0.023); incidences of memory impairment, attention disturbance, apathy, and aphasia were higher for ESL 1200mg than for other treatment groups. Incidences of psychiatric and cognitive serious AEs (SAEs) were 0.6% and 0.2% with ESL, and 0.5% and 0% with placebo, respectively. Psychiatric and cognitive TEAEs leading to discontinuation occurred in 1.9% and 1.4% of patients taking ESL, and 0.7% and 0.5% taking placebo, respectively. CONCLUSIONS: In phase III clinical trials of adjunctive ESL for treatment-refractory POS, psychiatric and cognitive TEAEs were reported infrequently with ESL and placebo. The incidences of depression and suicidality-related TEAEs and of cognitive TEAEs were higher for patients taking ESL vs. placebo. Incidences of psychiatric and cognitive SAEs, and TEAEs leading to discontinuation, were low with ESL and placebo. PMID- 29604485 TI - Sensory-motor performance in seven-year-old children born extremely preterm. AB - BACKGROUND: Children born preterm are prone to motor problems. Research on their motor performance has, however, rarely been integrated with sensory processing. AIM: To examine sensory-motor performance in children born extremely preterm (EPT). METHOD: In a longitudinal prospective cohort study, 49 EPT (born <28 gestational weeks; 32 boys and 17 girls) and 33 term-born (16 boys and 17 girls) children were assessed with six individual subtests from the Sensory Integration and Praxis Tests at the age of 7.0 to 7.3 years. RESULTS: The rate of test z scores indicating dysfunction [from -2 standard deviations (SD) to < -1 SD for mild and < -2 SD for moderate-to-severe] was significantly higher in EPT children than in term-born children in all the subtests. When comparing mean performance adjusted for gender and mother's education, EPT children performed worse than term-born children in Design Copying (z-score difference - 0.83; 95% confidence interval -1.32 to -0.34), Motor Accuracy (-0.82; -1.26 to -0.38), Postural Praxis (-0.95; -1.45 to -0.45), Manual Form Perception (-0.59; -1.12 to -0.06), and Finger Identification (-0.88; -1.45 to -0.31). Additional adjustment for Full Scale Intelligence Quotient rendered difference in Manual Form Perception non significant. CONCLUSION: Seven-year-old EPT children perform worse than their term-born peers in tests for visual-motor, somatosensory, and motor planning performance. PMID- 29604486 TI - Effects of caffeine on the preterm brain: An observational study. AB - BACKGROUND AND AIM: Caffeine improves neurodevelopmental outcome of preterm infants. This study analyses the effects of caffeine on the neonatal brain. We hypothesized that caffeine has a neuroprotective effect through an increase in oxygen metabolism; reflected by increased cerebral oxygen extraction, electrical function, and perfusion. METHODS: Preterm infants <32 weeks gestation (GA) receiving their primary dose caffeine-base (10 mg/kg) were included. Ten minutes of stable monitoring were selected before, during, and every hour up to 6 h after caffeine. Near-infrared spectroscopy monitored regional cerebral oxygenation (rScO2) and extraction (FTOE). Amplitude-integrated electroencephalogram (aEEG) monitored minimum, mean and maximum amplitudes. Spontaneous activity transients (SAT) rate and the interval between SATs (ISI) were calculated. Mean arterial blood pressure (MABP), heart rate (HR) and arterial oxygen saturation (SaO2) were monitored. Arterial pCO2's were collected before and 4 h after caffeine. Brain perfusion was assessed 1 h before and 3 h after caffeine by Doppler-measured resistance-index (RI), peak systolic velocity (PSV) and end-diastolic velocity (EDV), in the anterior cerebral artery (ACA) and internal carotid artery (ICA). Results were presented in mean +/- SD. RESULTS: 34 infants, mean GA 28.8 +/- 2.1 wk, were included. rScO2 significantly decreased from 69 +/- 11 to 63 +/- 12 1 h after caffeine, and recovered at 6 h (66 +/- 10). FTOE increased correspondingly. MABP and HR increased significantly. PSV in the ACA decreased slightly. Other Doppler variables, aEEG parameters, and SaO2 were unaffected. CONCLUSION: Caffeine increases oxygen extraction, suggesting a (transient) stimulating effect on brain metabolism. However, no substantial changes were found in brain perfusion and in electrical brain activity. PMID- 29604487 TI - Clinical rounds with parental involvement in a neonatal unit. PMID- 29604489 TI - Attenuation of TNF-induced neutrophil adhesion by simvastatin is associated with the inhibition of Rho-GTPase activity, p50 activity and morphological changes. AB - Neutrophil adhesion to the vasculature in response to potent inflammatory stimuli, such as TNF-alpha (TNF), can contribute to atheroprogression amongst other pathophysiological mechanisms. Previous studies have shown that simvastatin, a statin with known pleiotropic anti-inflammatory properties, can partially abrogate the effects of TNF-induced neutrophil adhesion, in association with the modulation of beta2-integrin expression. We aimed to further characterize the effects of this statin on neutrophil and leukocyte adhesive mechanisms in vitro and in vivo. A microfluidic assay confirmed the ability of simvastatin to inhibit TNF-induced human neutrophil adhesion to fibronectin ligand under conditions of shear stress, while intravital imaging microscopy demonstrated an abrogation of leukocyte recruitment by simvastatin in the microvasculature of mice that had received a TNF stimulus. This inhibition of neutrophil adhesion was accompanied by the inhibition of TNF-induced RhoA activity in human neutrophils, and alterations in cell morphology and beta2 integrin activity. Additionally, TNF augmented the activity of the p50 NFkappaB subunit in human neutrophils and TNF-induced neutrophil adhesion and beta2 integrin activity could be abolished using pharmacological inhibitors of NFkappaB translocation, BAY11-7082 and SC514. Accordingly, the TNF-induced elevation of neutrophil p50 activity was abolished by simvastatin. In conclusion, our data provide further evidence of the ability of simvastatin to inhibit neutrophil adhesive interactions in response to inflammatory stimuli, both in vivo and in vitro. Simvastatin appears to inhibit neutrophil adhesion by interfering in TNF induced cytoskeletal rearrangements, in association with the inhibition of Rho A activity, NFkappaB translocation and, consequently, beta2-integrin activity. PMID- 29604488 TI - Prefrontal over-activation during walking in people with mobility deficits: Interpretation and functional implications. AB - BACKGROUND: Control of walking by the central nervous system includes contributions from executive control mechanisms, such as attention and motor planning resources. Executive control of walking can be estimated objectively by recording prefrontal cortical activity using functional near infrared spectroscopy (fNIRS). OBJECTIVE: The primary objective of this study was to investigate group differences in prefrontal/executive control of walking among young adults, older adults, and adults post-stroke. Also assessed was the extent to which walking-related prefrontal activity fits existing cognitive frameworks of prefrontal over-activation. METHODS: Participants included 24 adults post stroke with moderate to severe walking deficits, 15 older adults with mild gait deficits, and 9 young healthy adults. Executive control of walking was quantified as oxygenated hemoglobin concentration in the prefrontal cortex measured by fNIRS. Three walking tasks were assessed: typical walking, walking over obstacles, and walking while performing a verbal fluency task. Walking performance was assessed by walking speed. RESULTS: There was a significant effect of group for prefrontal activity (p < 0.001) during typical and obstacles walking tasks, with young adults exhibiting the lowest level of prefrontal activity, followed by older adults, and then adults post-stroke. In young adults the prefrontal activity during typical walking was much lower than for the verbal fluency dual-task, suggesting substantial remaining prefrontal resources during typical walking. However, in older and post-stroke adults these remaining resources were significantly less (p < 0.01). Cumulatively, these results are consistent with prefrontal over-activation in the older and stroke groups, which was accompanied by a steeper drop in walking speed as task complexity increased to include obstacles (p < 0.05). CONCLUSIONS: There is a heightened use of prefrontal/executive control resources in older adults and post-stroke adults during walking. The level of prefrontal resource utilization, particularly during complex walking tasks like obstacle crossing, may approach the ceiling of available resources for people who have walking deficits. Prior cognitive research has revealed that prefrontal over-activation combined with limited prefrontal resources can lead to poor cognitive performance. The present study suggests a similar situation influences walking performance. Future research should further investigate the extent to which prefrontal over-activation during walking is linked to adverse mobility outcomes. PMID- 29604490 TI - Detection of changes in mould cell wall stress-related gene expression by a novel reverse transcription real-time PCR method. AB - The cell wall integrity (CWI) pathway is activated in response to cell wall stresses due to different food-related environments. Rho1 is one of the main regulators within such pathway. The objective of this work was to design an easy to-use RT-qPCR technique for the evaluation of the Rho1 gene expression useful to measure responses to the presence of cell wall stressors such as the antifungal protein PgAFP. Two primer pairs were designed from published conserved regions. Their specificity initially was determined by in silico analysis for several fungal species. After optimising the qPCR, the primer pair Rho1-F1/R2 was selected due to the lowest Cq values obtained and its specificity. The qPCR method showed efficiencies between 97.5% and 100.5%. Applicability of the designed qPCR method was evaluated in the presence of the stressor PgAFP. The PgAFP-resistant Penicillium polonicum and the PgAFP-sensitive Aspergillus flavus showed Rho1 gene over- and under- expression, respectively, indicating that the CWI pathway is activated in the former species but not activated in the latter one in response to the stress caused by PgAFP. This novel qPCR methodology able to detect changes in CWI-related gene expression in filamentous fungi will be useful in future studies to evaluate physiological mould responses to different food environmental challenges. PMID- 29604491 TI - UV-C inactivation of foodborne bacterial and viral pathogens and surrogates on fresh and frozen berries. AB - Outbreaks of foodborne illness associated with berries often involve contamination with hepatitis A virus (HAV) and norovirus but also bacteria such as Escherichia coli O157:H7 and parasites such as Cyclospora caytanensis. We evaluated the applicability of UV-C to the inactivation of pathogens on strawberries, raspberries and blueberries. Our three-step approach consisted of assessing the chemical safety of UV-C-irradiated berries, evaluating the sensory quality after UV-C treatment and finally studying the inactivation of the target microorganisms. Treatments lasting up to 9 min (4000 mJ cm-2) did not produce detectable levels of furan (<5 MUg/kg), a known photolysis product of fructose with genotoxic activity and thus were assessed to be toxicologically safe. No effect on taste or appearance was observed, unless treatment was excessively long. 20 s of treatment (an average fluence of ~ 212 mJ cm-2) reduced active HAV titer by >1 log10 unit in 95% of cases except on frozen raspberries, while 120 s were required to inactivate murine norovirus to this extent on fresh blueberries. The mean inactivation of HAV and MNV was greater on blueberries (2-3 log10) than on strawberries and raspberries (<2 log10). MNV was more sensitive on fresh than on frozen berries, unlike HAV. Inactivation of Salmonella, E. coli O157:H7 and Listeria monocytogenes was poor on all three berries, no treatment reducing viable counts by >1 log10 unit. In most matrices, prolonging the treatment did not improve the result to any significant degree. The effect was near its plateau after 20 s of treatment. These results provide insight into the effectiveness of UV-C irradiation for inactivating bacterial and viral pathogens and surrogates on fresh and frozen berries having different surface types, under different physical conditions and at different levels of contamination. Overall they show that UV-C as single processing step is unsuitable to inactivate significant numbers of foodborne pathogens on berries. PMID- 29604492 TI - 3D FEM simulation of tool wear in ultrasonic assisted rotary turning. AB - In this study, a model is developed to predict tool wear and heat distribution on tool faces in conventional, rotary, and ultrasonic assisted rotary tuning methods. To model the flank wear rate, a modified Usui wear rate model which includes tool clearance angle, is proposed. As well as the simulation, a series of experiments is conducted to validate the model, by comparison of the predicted and measured flank wear rates, which are shown to be in good agreement. According to the results of the simulation, localized heat in the tool-chip contact zone during conventional turning is distributed in the circumference of the tool cutting edge in rotary turning. Due to the existence of disengagement periods in ultrasonic-assisted rotary turning, the total time for thermal conduction in the contact zone decreases, resulting in a significant reduction in tool wear. PMID- 29604493 TI - Increasing the field-of-view of row-column-addressed ultrasound transducers: implementation of a diverging compound lens. AB - The purpose of this work is to investigate compound lenses for row-column addressed (RCA) ultrasound transducers for increasing the field-of-view (FOV) to a curvilinear volume region, while retaining a flat sole to avoid trapping air between the transducer sole and the patient, which would otherwise lead to unwanted reflections. The primary motivation behind this research is to develop a RCA ultrasound transducer for abdominal or cardiac imaging, where a curvilinear volume region is a necessity. RCA transducers provide 3-D ultrasound imaging with fewer channels than fully-addressed 2-D arrays (2N instead of N2), but they have inherently limited FOV. By increasing the RCA FOV, these transducers can be used for the same applications as fully-addressed transducers while retaining the same price range as conventional 2-D imaging due to the lower channel count. Analytical and finite element method (FEM) models were employed to evaluate design options. Composite materials were developed by loading polymers with inorganic powders to satisfy the corresponding speed of sound and specific acoustical impedance requirements. A Bi2O3 powder with a density of 8.9g/cm3 was used to decrease the speed of sound of a room temperature vulcanizing (RTV) silicone, RTV615, from 1.03mm/MUs to 0.792mm/MUs. Using micro-balloons in RTV615 and a urethane, Hapflex 541, their speeds of sound were increased from 1.03mm/MUs to 1.50mm/MUs and from 1.52mm/MUs to 1.93mm/MUs, respectively. A diverging add-on lens was fabricated of a Bi2O3 loaded RTV615 and an unloaded Hapflex 541. The lens was tested using a RCA probe, and a FOV of 32.2 degrees was measured from water tank tests, while the FEM model yielded 33.4 degrees . A wire phantom with 0.15mm diameter wires was imaged at 3MHz down to a depth of 14cm using a synthetic aperture imaging sequence with single element transmissions. The beamformed image showed that wires outside the array footprint were visible, demonstrating the increased FOV. PMID- 29604494 TI - Dissolution of studtite [UO2(O2)(H2O)4] in various geochemical conditions. AB - This study determined the dissolution rate of studtite, (UO2)O2(H2O)4, which can be formed by reaction between H2O2 and UO22+ that leaks from spent nuclear fuel (SNF) in deep geological repositories. The batch dissolution experiments were conducted using synthesized studtite under different solution conditions with varying pHs and concentrations of HCO3- and [H2O2] in synthetic groundwater. The experimental results suggested that carbonate ligand and H2O2 in groundwater accelerated the dissolution of studtite and uranium (U) release. Above 10-5 M of H2O2 initial concentration, the released uranium concentration in solution decreased, possibly as a result of reprecipitation of studtite due to reaction between uranium and H2O2. The results will be useful to assess the comprehensive transport of uranium from both nuclear waste and SNF stored in deep geological repositories. PMID- 29604495 TI - Is alpha-fetoprotein decline a prognostic factor of childhood non-seminomatous germ cell tumours? Results of the French TGM95 study. AB - PURPOSE: In adults' non-seminomatous germ cell tumours (NS-GCT), alpha fetoprotein (AFP) decline was identified as an important prognostic factor. We investigated its prognostic value in the French TGM95 study for childhood NS-GCT. PATIENTS AND METHODS: Three risk groups were defined: low risk (LR: localised and completely resected pS1, AFP<15000 ng/ml), with a 'wait-and-see' strategy; intermediate-risk (IR: localised incompletely resected, AFP<15000 ng/ml) with 3-5 vinblastine-bleomycine-cisplatin courses; high risk (HiR: AFP>=15000 ng/ml and/or metastatic) with 4-6 etoposide-ifosfamide-cisplatin courses. The multivariable prognostic analysis for progression-free survival (PFS) included age (+/-10 years), primary tumour site (1-testis, 2-ovary, 3-extragonadal), extent of disease (1-pS1, 2-loco-regional dissemination, 3-metastasis) and AFP (+/-10,000 ng/ml). AFP decline prognostic value was investigated in IR + HiR groups using predicted time to normalisation (TTN), AFP change, and difference between observed and expected (based on AFP half-life) area under the curve (O-E AUC). RESULTS: From January 1995 to December 2005, 239 patients (median age = 3years, 60 LR, 65 IR, 114 HiR) were included. Main sites were testis (n = 66), ovary (n = 77) and sacrococcygeal (n = 57). Five-year PFS and OS were 85% (95% confidence interval [CI] = 80-89%) and 93% (89-95%), respectively. Age >= 10 years (hazard ratio [HR] = 4.6, 95% CI = 2.1-10.1, p = 0.0001) and extragonadal primary (HR = 6.3, 95% CI = 2.0-19.9, p = 0.005) were significant prognostic factors. In AFP decline analysis (n = 151, 17 events), TTN (p = 0.61) and AFP change (p = 0.10) were not prognostic, whereas we showed a significant effect of O-E AUC (HR = 2.1, 95% CI = 1.0-4.2, p = 0.05). CONCLUSION: Age >= 10 years and extragonadal tumours remain as poor prognostic factors. Contrary to adults, TTN is not reliable in paediatric NS-GCT. The prognostic value of O-E AUC should be investigated in larger studies. PMID- 29604496 TI - Side chain removal from corticosteroids by unspecific peroxygenase. AB - Two unspecific peroxygenases (UPO, EC 1.11.2.1) from the basidiomycetous fungi Marasmius rotula and Marasmius wettsteinii oxidized steroids with hydroxyacetyl and hydroxyl functionalities at C17 - such as cortisone, Reichstein's substance S and prednisone - via stepwise oxygenation and final fission of the side chain. The sequential oxidation started with the hydroxylation of the terminal carbon (C21) leading to a stable geminal alcohol (e.g. cortisone 21-gem-diol) and proceeded via a second oxygenation resulting in the corresponding alpha ketocarboxylic acid (e.g. cortisone 21-oic acid). The latter decomposed under formation of adrenosterone (4-androstene-3,11,17-trione) as well as formic acid and carbonic acid (that is in equilibrium with carbon dioxide); fission products comprising two carbon atoms such as glycolic acid or glyoxylic acid were not detected. Protein models based on the crystal structure data of MroUPO (Marasmius rotula unspecific peroxygenase) revealed that the bulky cortisone molecule suitably fits into the enzyme's access channel, which enables the heme iron to come in close contact to the carbons (C21, C20) of the steroidal side chain. ICP MS analysis of purified MroUPO confirmed the presence of magnesium supposedly stabilizing the porphyrin ring system. PMID- 29604497 TI - Photo-antimicrobial efficacy of zinc complexes of porphyrin and phthalocyanine activated by inexpensive consumer LED lamp. AB - The properties and antimicrobial efficacies of zinc complexes of tetrakis(N methylpyridinium-4-yl) tetraiodide porphyrin and tetrakis(N-methylpyridinium-4 yl) tetraiodide phthalocyanine impregnated to paper were evaluated. Photo inactivation of microbes using inexpensive consumer light-emitting diode lamp was assessed on surface of dyed papers. Antimicrobial experiments of phthalocyanine dyed paper by live cell assessment through colony forming units counting demonstrated 3.72 and 4.01 log reduction against Escherichia coli (E. coli) and Acinetobacter baylyi (A. baylyi) respectively after 1 h of illumination with 35 mW/cm2 light. The porphyrin-dyed paper exhibited 1.66 and 2.01 log reduction in colony forming units against E. coli and A. baylyi respectively after 1 h exposure with 4 mW/cm2 light. Both dyed papers were photo-stable after 64 h of continuous exposure with 42 mW/cm2 light, while phthalocyanine-dyed paper exhibited superior leaching stability in phosphate-buffered saline. PMID- 29604498 TI - Oxidative stress and mitochondrial dysfunction mediated Cd-induced hepatic lipid accumulation in zebrafish Danio rerio. AB - The present study was performed to determine the effect of waterborne CdCl2 exposure influencing lipid deposition and metabolism, oxidative stress and mitochondrial dysfunction, and explore the underlying molecular mechanism of cadmium (Cd)-induced disorder of hepatic lipid metabolism in fish. To this end, adult zebrafish were exposed to three waterborne CdCl2 concentrations (0(control), 5 and 25 MUg Cd/l, respectively) for 30 days. Lipid accumulation, the activities of enzymes related to lipid metabolism and oxidative stress, as well as the expression level of genes involved in lipid metabolism and mitophagy were determined in the liver of zebrafish. Waterborne CdCl2 exposure increased hepatic triglyceride (TG) and Cd accumulation, the activities of fatty acid synthase (FAS), 6-phosphogluconate dehydrogenase (6PGD), glucose 6-phosphate dehydrogenase (G6PD) and malic enzyme (ME), and the mRNA level of fatty acid synthase (fas), acetyl-CoA carboxylase alpha (acaca), glucose 6-phosphate dehydrogenase (g6pd) and malic enzyme (me), but reduced the mRNA level of carnitine palmitoyl transferase 1 (cpt1), hormone-sensitive lipase alpha (hsla), and adipose triacylglyceride lipase (atgl). The activities of superoxide dismutase (SOD), glutathoinine peroxidase (GPx) and cytochrome c oxidase (COX) and the ATP level were significantly reduced after CdCl2 exposure. CdCl2 exposure significantly increased the mRNA level of genes (microtubule-associated protein light chain 3 alpha (lc3a), PTEN-induced putative kinase 1 (pink1), NIP3-like protein X (nix) and PARKIN (parkin)) related to mitophagy. To elucidate the mechanism, reactive oxygen species (ROS) scavenger N-acetylcysteine (NAC) and the mitochondrial permeability transition (MPT) inhibitor cyclosporine A (CsA) were used to verify the role of ROS and mitochondrial dysfunction in Cd-induced disorder of lipid metabolism. NAC pretreatment reversed the Cd-induced up regulation of TG accumulation and activities of lipogenic enzymes, and the Cd induced down-regulation of mRNA levels of lipolytic genes. Meanwhile, NAC pretreatment also blocked the mitochondrial membrane potential (MMP) collapse and decreased the ATP level, suggesting that ROS played a crucial role in regulating the Cd-induced mitochondrial dysfunction. Taken together, our findings, for the first time, highlight the importance of the oxidative stress and mitochondrial dysfunction in Cd-induced disorder of hepatic lipid metabolism, which proposed a novel mechanism for elucidating metal element exposure inducing the disorder of lipid metabolism in vertebrates. PMID- 29604499 TI - Effects of bisphenol A and its analogs bisphenol F and S on life parameters, antioxidant system, and response of defensome in the marine rotifer Brachionus koreanus. AB - To understand the adverse outcome in response to bisphenol A and its analogs bisphenol F and S (BPA, BPF, and BPS), we examined acute toxicity, life parameter, and defensome in the marine rotifer Brachionus koreanus. Among the bisphenol analogs, BPA showed the highest acute toxicity and then BPF and BPS, accordingly in the view of descending magnitude of toxicity. In life parameters including life span and reproduction, BPA, BPF, and BPS were found to cause adverse effect. Both intracellular ROS level and GST activity were significantly increased (P < 0.05) in response to each dosage of bisphenol analogs exposures. In response to bisphenol analogs, defensomes of phase I, II, and III detoxification mechanism demonstrated inverse relationship between the lipophilicity of bisphenol analogs and the expression patterns of defensomes. BPA and BPF were found to have significant modulation (P < 0.05) in the expression of cytochrome P450 (CYP) and GST genes. In phase III, BPS with comparatively lower lipophilicity demonstrated highly diversified expressional pattern, suggesting that BPS is likely caused less toxicity compared to BPA and BPF. In this study, via phase I, II, and III detoxification mechanism, bisphenol A and its analogs F and S demonstrated specific detoxification mechanism in rotifer. PMID- 29604500 TI - Physiological impacts and bioaccumulation of dietary Cu and Cd in a model teleost: The Amazonian tambaqui (Colossoma macropomum). AB - Increasing anthropogenic activities in the Amazon have led to elevated metals in the aquatic environment. Since fish are the main source of animal protein for the Amazonian population, understanding metal bioaccumulation patterns and physiological impacts is of critical importance. Juvenile tambaqui, a local model species, were exposed to chronic dietary Cu (essential, 500 MUg Cu/g food) and Cd (non-essential, 500 MUg Cd/g food). Fish were sampled at 10-14, 18-20 and 33-36 days of exposure and the following parameters were analyzed: growth, voluntary food consumption, conversion efficiency, tissue-specific metal bioaccumulation, ammonia and urea-N excretion, O2 consumption, Pcrit, hypoxia tolerance, nitrogen quotient, major blood plasma ions and metabolites, gill and gut enzyme activities, and in vitro gut fluid transport. The results indicate no ionoregulatory impacts of either of the metal-contaminated diets at gill, gut, or plasma levels, and no differences in plasma cortisol or lactate. The Cd diet appeared to have suppressed feeding, though overall tank growth was not affected. Bioaccumulation of both metals was observed. Distinct tissue-specific and time specific patterns were seen. Metal burdens in the edible white muscle remained low. Overall, physiological impacts of the Cu diet were minimal. However dietary Cd increased hypoxia tolerance, as evidenced by decreased Pcrit, increased time to loss of equilibrium, a lack of plasma glucose elevation, decreased plasma ethanol, and decreased NQ during hypoxia. Blood O2 transport characteristics (P50, Bohr coefficient, hemoglobin, hematocrit) were unaffected, suggesting that tissue level changes in metabolism accounted for the greater hypoxia tolerance in tambaqui fed with a Cd-contaminated diet. PMID- 29604501 TI - Oxide-free aC/Zr0.65Al0.075Cu0.275/aC phase plates for transmission electron microscopy. AB - Thin-film phase plates (PP) have become a valuable tool for the imaging of organic objects in transmission electron microscopy (TEM). The thin film usually consists of amorphous carbon (aC), which undergoes rapid aging under intense illumination with high-energy electrons. The limited lifetime of aC film PPs calls for alternative PP materials with improved material stability. This work presents thin-film PPs fabricated from the metallic glass alloy Zr0.65Al0.075Cu0.275 (ZAC), which was identified as a promising PP material with beneficial properties, such as a large inelastic mean free path. An adverse effect of the ZAC alloy is the formation of a surface oxide layer in ambient air, which reduces the electrical conductivity and causes electrostatic charging in the electron beam. To avoid surface oxidation, the ZAC alloy is enclosed by thin aC layers. The resulting aC/ZAC/aC layer system is used to fabricate Zernike and Hilbert PPs. Phase-contrast TEM imaging is demonstrated for a sample of carbon nanotubes, which show strong contrast enhancement in PP TEM images. PMID- 29604503 TI - Do adverse childhood experiences predict adult interpersonal difficulties? The role of emotion dysregulation. AB - Adverse childhood experiences (ACEs) are risk factors for interpersonal difficulties in adulthood, however the mechanism that underlies this association is unknown. The current study investigated the association of a wide range of ACEs with interpersonal difficulties in adulthood, and tested whether emotion dysregulation mediated the relationship between ACEs and interpersonal difficulties. Patients over the age of 18 were recruited from primary care clinics (N = 4006). Participants completed self-report questionnaires that assessed ACEs, emotion dysregulation, and interpersonal difficulties. Results indicated that, after controlling for a range of demographic variables, each type of ACE significantly predicted increased interpersonal difficulties and that cumulative ACEs predicted increased interpersonal difficulties, F(8, 3137) = 39.68, p < .001, R2 = 0.09. Further, emotion dysregulation mediated the association between ACEs and interpersonal difficulties, B = 0.79, SE = 0.09, 95% CI [0.64, 0.97]. These findings emphasize the role of childhood adversity on interpersonal functioning in adulthood, and highlight emotion dysregulation as a mechanism by which this association occurs. Results have the potential to inform preventative and treatment efforts to improve adaptive outcomes among individuals with a history of childhood adversity. PMID- 29604502 TI - The effects of implicit encouragement and the putative confession on children's memory reports. AB - The current study tested the effects of two interview techniques on children's report productivity and accuracy following exposure to suggestion: implicit encouragement (backchanneling, use of children's names) and the putative confession (telling children that a suspect "told me everything that happened and wants you to tell the truth"). One hundred and forty-three, 3-8-year-old children participated in a classroom event. One week later, they took part in a highly suggestive conversation about the event and then a mock forensic interview in which the two techniques were experimentally manipulated. Greater use of implicit encouragement led to increases, with age, in children's narrative productivity. Neither technique improved or reduced children's accuracy. No increases in errors about previously suggested information were evident when children received either technique. Implications for the use of these techniques in child forensic interviews are discussed. PMID- 29604504 TI - Consequences of parental burnout: Its specific effect on child neglect and violence. AB - Parental burnout is a specific syndrome resulting from enduring exposure to chronic parenting stress. It encompasses three dimensions: an overwhelming exhaustion related to one's parental role, an emotional distancing from one's children and a sense of ineffectiveness in one's parental role. This study aims to facilitate further identification of the consequences of parental burnout for the parents themselves, their spouses and their child(ren). In a sample of 1551 parents, we examined the relationship between parental burnout and seven possible consequences: escapism and suicidal thoughts, addictions, sleep disorders, marital conflicts, a partner estrangement mindset, and neglect and violence towards one's child(ren). We examined (1) to what extent parental and job burnout related to each of these possible consequences and (2) whether parental burnout is specifically related to neglectful and violent behaviour towards one's child(ren). The results suggest that parental burnout has a statistically similar effect to job burnout on addictions and sleep problems, a stronger effect on couples' conflicts and partner estrangement mindset and a specific effect on child-related outcomes (neglect and violence) and escape and suicidal ideation. These results emphasize the importance of accurately diagnosing this syndrome. PMID- 29604505 TI - Children's attention to task-relevant information accounts for relations between language and spatial cognition. AB - Children's spatial language reliably predicts their spatial skills, but the nature of this relation is a source of debate. This investigation examined whether the mechanisms accounting for such relations are specific to language use or reflect a domain-general mechanism of selective attention. Experiment 1 examined whether 4-year-olds' spatial skills were predicted by their selective attention or their adaptive language use. Children completed (a) an attention task assessing attention to task-relevant color, size, and location cues; (b) a description task assessing adaptive language use to describe scenes varying in color, size, and location; and (c) three spatial tasks. There was correspondence between the cue types that children attended to and produced across description and attention tasks. Adaptive language use was predicted by both children's attention and task-related language production, suggesting that selective attention underlies skills in using language adaptively. After controlling for age, gender, receptive vocabulary, and adaptive language use, spatial skills were predicted by children's selective attention. The attention score predicted variance in spatial performance previously accounted for by adaptive language use. Experiment 2 followed up on the attention task (Experiment 2a) and description task (Experiment 2b) from Experiment 1 to assess whether performance in the tasks related to selective attention or task-specific demands. Performance in Experiments 2a and 2b paralleled that in Experiment 1, suggesting that the effects in Experiment 1 reflected children's selective attention skills. These findings show that selective attention is a central factor supporting spatial skill development that could account for many effects previously attributed to children's language use. PMID- 29604506 TI - Association between serum uric acid level and multiple system atrophy: A meta analysis. AB - OBJECTIVES: Lower serum uric acid (UA) levels are considered to be related to the risk to develop many neurodegenerative disorders. However, the association between serum UA level and multiple system atrophy (MSA) remains controversial. The aim of this meta-analysis was to evaluate the relationship between serum UA level and MSA. PATIENTS AND METHODS: PubMed, Web of Science, Embase, Cochrane Library and China National Knowledge Infrastructure (CNKI) were searched for eligible studies. Standardized mean difference (SMD) and 95% confidence intervals (95% CI) were calculated in a fixed-effects model or a random-effects model when appropriate. Subgroup analyses were carried out based on gender. A total of 6 eligible studies involving 547 MSA patients and 637 healthy individuals were identified. RESULTS: Meta-analysis results revealed that individuals with MSA had lower sera levels of UA as compared with healthy controls (pooled SMD is -0.51, 95%CI: -0.88 to -0.14; p = 0.006). The subgroup analysis to detect sex differences showed that the pooled SMD was -0.61 (95% CI: -0.82 to -0.40; p < 0.0001) for males and -0.22 (95% CI: -0.55 to 0.10; p = 0.18) for females compared with healthy controls. CONCLUSION: Our meta-analysis revealed that lower serum level of UA is associated with an increased risk of MSA and the relationship is significant in men but not in women. PMID- 29604507 TI - Confocal scanning microscopy provides rapid, detailed intraoperative histological assessment of brain neoplasms: Experience with 106 cases. AB - OBJECTIVES: Frozen section histological analysis is currently the mainstay for intraprocedural tissue diagnosis during the resection of intracranial neoplasms and for evaluating tumor margins. However, frozen sections are time-consuming and often do not reveal the histological features needed for final diagnosis when compared with permanent sections. Confocal scanning microscopy (CSM) with certain stains may be a valuable technology that can add rapid and detailed histological assessment advantage for the neurosurgical operating room. This study describes potential advantages of CSM imaging of fresh human brain tumor tissues labeled with acriflavine (AF), acridine orange (AO), cresyl violet (CV), methylene blue (MB), and indocyanine green (ICG) within the neurosurgical operating room facility. PATIENTS AND METHODS: Acute slices from orthotopic human intracranial neoplasms were incubated with AF/AO and CV solutions for 10 s and 1 min respectively. Staining was also attempted with MB and ICG. Samples were imaged using a bench-top CSM system. Histopathologic features of corresponding CSM and permanent hematoxylin and eosin images were reviewed for each case. RESULTS: Of 106 cases, 30 were meningiomas, 19 gliomas, 13 pituitary adenomas, 9 metastases, 6 schwannomas, 4 ependymomas, and 25 other pathologies. CSM using rapid fluorophores (AF, AO, CV) revealed striking microvascular, cellular and subcellular structures that correlated with conventional histology. By rapidly staining and optically sectioning freshly resected tissue, images were generated for intraoperative consultations in less than one minute. With this technique, an entire resected tissue sample was imaged and digitally stored for tele-pathology and archiving. CONCLUSION: CSM of fresh human brain tumor tissue provides clinically meaningful and rapid histopathological assessment much faster than frozen section. With appropriate stains, including specific cellular structure or antibody staining, CSM could improve the timeliness of intraoperative decision making, and the neurosurgical-pathology workflow during resection of human brain tumors, ultimately improving patient care. PMID- 29604508 TI - Conventional digital subtractional vs non-invasive MR angiography in the assessment of brain arteriovenous malformation. AB - OBJECTIVES: Digital subtractional angiography (DSA) is the standard method for diagnosis, assessment and management of arteriovenous malformation in the brain. Conventional DSA (cDSA) is an invasive imaging modality that is often indicated before interventional treatments (embolization, open surgery, gamma knife). Here, we aimed to compare this technique with a non-invasive MR angiography (MRI DSA) for brain arteriovenous malformation (bAVM). PATIENTS AND METHODS: Fourteen patients with ruptured brain AVM underwent embolization treatment pre-operation. Imaging was performed for all patients using MRI (1.5 T). After injecting contrast Gadolinium, dynamic MRI was performed with 40 phases, each phase of a duration of 1.2 s and having 70 images. The MRI results were independently assessed by experienced radiologist blinded to the cDSA. RESULTS: The AVM nidus was depicted in all patients using cDSA and MRI DSA; there was an excellent correlation between these techniques in terms of the maximum diameter and Spetzler Martin grading. Of the fourteen patients, the drainage vein was depicted in 13 by both cDSA and MRI DSA showing excellent correlation between the techniques used. CONCLUSION: MRI DSA is a non-invasive imaging modality that can give the images in dynamic view. It can be considered as an adjunctive method with cDSA to plan the strategy treatment for bAVM. PMID- 29604509 TI - The Role of the Size and Location of the Tumors and of the Vertebral Anatomy in Determining the Structural Stability of the Metastatically Involved Spine: a Finite Element Study. AB - Vertebral fractures associated with the loss of structural integrity of neoplastic vertebrae are common, and determined to the deterioration of the bone quality in the lesion area. The prediction of the fracture risk in metastatically involved spines can guide in deciding if preventive solutions, such as medical prophylaxis, bracing, or surgery are indicated for the patient. In this study, finite element models of 22 thoracolumbar vertebrae were built based on CT scans of three spines, covering a wide spectrum of possible clinical scenarios in terms of age, bone quality and degenerative features, taking into account the local material properties of bone tissue. Simulations were performed in order to investigate the effect of the size and location of the tumoral lesion, the bone quality and the vertebral level in determining the structural stability of the neoplastic vertebrae. Tumors with random size and positions were added to the models, for a total of 660 simulations in which a compressive load was simulated. Results highlighted the fundamental role of the tumor size, whereas the other parameters had a lower, but non-negligible impact on the axial collapse of the vertebra, the vertebral bulge in the transverse plane and the canal narrowing under the application of the load. All the considered parameters are radiologically measurable, and can therefore be translated in a straightforward way to the clinical practice to support decisions about preventive treatment of metastatic fractures. PMID- 29604510 TI - Combined Selection System to Lower the Cutoff for Plasma Cell Enrichment Applied to iFISH Analysis in Multiple Myeloma. AB - Multiple myeloma (MM) is a very heterogeneous disease, characterized by multiple cytogenetic aberrations on plasma cells (PC) that have been traditionally used to predict the outcome of the disease. A mayor issue on the analysis of PC is the sometimes low infiltration of these cells in the bone marrow that hampers cytogenetic studies. To solve this problem we have optimized a selection strategy based on PC immunomagnetic isolation that has allowed us to lower to 1% the minimal PC infiltration requirement without loss of purity, enabling to perform genetic analysis. In this study, we have analyzed 153 bone marrow samples of patients suspected of MM, collected from February 2015 to May 2017 by the Genetics service of the Complejo Hospitalario de Navarra. Clinical characteristics of the patients and PC immunophenotyping, conventional cytogenetics and interphase fluorescence in situ hybridization (iFISH) analyses have been assessed on these samples. In our cohort 90% of the samples had cytogenetic abnormalities, among them 50% presented immunoglobulin rearrangements, 41.9% showed 1q gains, 29.7% showed 1p deletions and 33% presented TP53 deletion. PMID- 29604511 TI - A bacterium-based contact assay for evaluating the quality of solid samples Results from an international ring-test. AB - The contact assay measuring the inhibition of Arthrobacter globiformis dehydrogenase activity as an endpoint to evaluate the toxicity of solid samples was tested in an international ring-test to validate its performance for ISO standardization (ISO/CD 18187). This work reports the results of the ring-test involving 9 laboratories from six countries. At least 8 valid data sets were obtained for each sample and more than three quarters of the participants attained the validity criteria defined in the standard. The coefficient of variation within (CVr) and between (CVR) laboratories was generally on average <15% and <30% for negative and positive controls, respectively. Regarding solid samples, the laboratories provided a similar ranking of the samples based on their toxicity, despite some variation in the LOEC values. The logarithmic within lab standard deviation <0.50 for soils and <0.25 for wastes evidenced a good repeatability. The between-lab variability assessed by a CVR <30%, minimum maximum factor <4 and a reproducibility standard deviation (SDR) <0.13 for a great part of the solid samples, confirmed the test reproducibility. Overall, this assay proved to be robust, sensitive and feasible for routine use towards the quality assessment of soils and wastes. PMID- 29604512 TI - Cobalt nanoparticles encapsulated in nitrogen-rich carbon nanotubes as efficient catalysts for organic pollutants degradation via sulfite activation. AB - The activation of sulfite by heterogeneous catalysts displays a great potential in the development of new sulfate radials based technologies for wastewater treatment. Herein, cobalt nanoparticles embedded in N-doped carbon nanotubes (Co@NC) were prepared by a simple pyrolysis method. Due to the synergistic effects of the cobalt nanoparticles and N-doped carbon nanotubes, the Co@NC catalyst intrinsically shows an outstanding efficiency, excellent reusability and high stability in the catalytic oxidation of methyl orange (MO) in the presence of sulfite and dioxygen. The structure and efficiency of the catalyst was significantly affected by the content of cobalt and pyrolysis temperature. Several quenching experiments and electron paramagnetic resonance were carried out to investigate the catalytic mechanism. It is found that hydroxyl and sulfate radicals worked together to degrade MO in the system. The formation and decomposition of peroxymonosulfate may be an important route of these reactive radicals production. The effect of different anions, bicarbonate concentration, initial solution pH and dye types on the performance of the catalyst was also studied. This study can open a new approach for design and preparation of encapsulated cobalt in carbon materials as effective catalysts for pollutants degradation via sulfite activation. PMID- 29604513 TI - In-plane and out-of-plane rotational motion of individual chain molecules in steady shear flow of polymer melts and solutions. AB - Recent nonequilibrium molecular dynamics (NEMD) simulations of mildly entangled C400H802 and moderately entangled C700H1402 linear polyethylene melts undergoing steady shear flow have revealed that several inconsistencies between theory and experiment could be rectified by consideration of the rotational motion of individual polymer chains that occurs at moderate to high flow strengths. In this study, we investigated the configurational dynamics of the individual molecular chains that allow these once-entangled, long-chain molecules to execute retraction/extension semi-periodic cycles in response to the imposed shear via NEMD simulations. Brownian dynamics simulations were also performed to extract dynamical and configurational information about the similar cycles of polymer chain behavior that occur in dilute solutions of macromolecular chain liquids dissolved in low molecular weight solvents. Results revealed that the configurational motions of the individual chains in both melt and solution were essentially the same and governed by a single timescale that scaled exponentially with the magnitude of the shear rate. This configurational motion contained both in-plane and out-of-plane components with respect to the flow-gradient plane, with the out-of-plane component playing a much larger role during the retraction phase of the cycle than during the extension phase. This was determined to be caused by the enhancement of the retraction motion by the out-of-plane entropic Brownian forces; however, these entropic forces were detrimental to the in-plane hydrodynamic diffusive forces during the extension phase of the cycle and were thus suppressed. Consequently, the configuration of a rotating chain was significantly more compact during the retraction stage than during the extension stage, wherein the latter phase most molecules were more preferentially distributed in the flow-gradient plane. PMID- 29604514 TI - Renal involvement in fatal cases of chikungunya virus infection. AB - BACKGROUND: Information regarding physiopathology and complications in fatal cases of chikungunya virus (CHIKV) is scarce. OBJECTIVES: The aim of this study was to describe the frequency and severity of renal complications in fatal cases associated with CHIKV infection based on the clinical and histopathological features from post-mortem tissue biopsies. STUDY DESIGN: This retrospective study included fatal cases associated with CHIKV infection occurring from September 2014 through October 2015, reported to National System for Public Health Surveillance (SIVIGILA) and laboratory-confirmed by the National Institute of Health of Colombia. Medical records from 13 patients were available. Information was collected on history, physical examination, and haematological, biochemical, radiological, and virologic investigation reports. RESULTS: Diagnosis of CHIKV infection was performed by positive CHIKV-PCR on post-mortem tissue in 10 cases, positive CHIKV-PCR in serum in 6 cases and anti-CHIKV virus IgM in 2 cases. Only 3 cases were children (<=5 years old). Four cases had underlying diseases, mainly systemic arterial hypertension. The median value of creatinine at admission was 2.8 mg/dL (interquartile range 1.52-4.51). During hospitalization, 9 cases required ICU admission, 8 vasopressor support and 6 mechanical ventilation. Kidney histopathological findings were mainly acute interstitial nephritis (11 cases), congestion/oedema glomerular (10 cases) and acute tubular necrosis (5 cases). CONCLUSIONS: Renal impairment in fatal cases of CHIKV infection is frequent and related mainly to acute interstitial nephritis. These data demonstrate evidence of acquired kidney injuries during CHIKV infection. PMID- 29604515 TI - Effects of mobile phone distraction on pedestrians' crossing behavior and visual attention allocation at a signalized intersection: An outdoor experimental study. AB - With the rapid growth in mobile phone use worldwide, traffic safety experts have begun to consider the impact of mobile phone distractions on pedestrian crossing safety. This study sought to investigate how mobile phone distractions (music distraction, phone conversation distraction and text distraction) affect the behavior of pedestrians while they are crossing the street. An outdoor environment experiment was conducted among 28 college student pedestrians. Two HD videos and an eye tracker were employed to record and analyze crossing behavior and visual attention allocation. The results of the research showed that the three mobile phone distractions cause different levels of impairment to pedestrians' crossing performance, with the greatest effect from text distraction, followed by phone conversation distraction and music distraction. Pedestrians distracted by music initiate crossing later, have increased pupil diameter, and reduce their scanning frequency, fixation points and fixation times toward traffic signal area priorities. In addition to the above effects, pedestrians distracted by phone conversation cross the street more slowly, direct fewer fixation points to the right traffic area, and spend less fixation time and lower average fixation duration on the left traffic area. Moreover, pedestrians distracted by texting look left and right less often and switch, distribute and maintain less visual attention on the traffic environment. These findings may inform researchers, policy makers, and pedestrians. PMID- 29604516 TI - Market penetration of intersection AEB: Characterizing avoided and residual straight crossing path accidents. AB - Car occupants account for one third of all junction fatalities in the European Union. Driver warning can reduce intersection accidents by up to 50 percent; adding Autonomous Emergency Braking (AEB) delivers a reduction of up to 70 percent. However, these findings are based on an assumed 100 percent equipment rate, which may take decades to achieve. Our study investigates the relationship between intersection AEB market penetration rates and avoidance of accidents and injuries in order to guide implementation strategies. Additionally, residual accident characteristics (impact configurations and severity) are analyzed to provide a basis for future in-crash protection requirements. We determined which accidents would have been avoided through the use of an Intersection AEB system with different sensor field-of-views (180 degrees and 120 degrees ) by means of re-simulating the pre-crash phase of 792 straight crossing path (SCP) car-to-car accidents recorded in the German In-Depth Accident Study (GIDAS) and the associated Pre-Crash Matrix (PCM). Intersection AEB was activated when neither of the conflict opponents could avoid the crash through reasonable braking or steering reactions. For not-avoided accidents, we used the Kudlich-Slibar rigid body impulse model to calculate the change of velocity during the impact as a measure of impact severity and the principal direction of force. Accident avoidance over market penetration is not linear but exponential, with higher gains at low penetration rates and lower gains at higher rates. A wide field-of view sensor (180 degrees ) substantially increased accident avoidance and injury mitigation rates compared to a 120 degrees field-of-view sensor. For a 180 degrees field-of-view sensor at 100 percent market penetration, about 80 percent of the accidents and 90 percent of the MAIS2 + F injuries could be avoided. For the remaining accidents, AEB intervention rarely affected side of impact. The median change of velocity (delta-V) of the remaining crashes reduces only marginally at low penetration rates but this reduction increases with higher penetration rates. With 100 percent market penetration, one quarter of the vehicles still involved in straight crossing path accidents will sustain a delta V higher than 17 km/h. Intersection AEB is very effective. Enabling a fast initial implementation of systems with wide field-of-view sensor(s) and ensuring a high market penetration over the longer term is essential to achieve high crash avoidance and injury mitigation rates over time. The standards for in-crash protection must be high to mitigate injury in the unavoidable, residual accidents. PMID- 29604517 TI - A 210Pb chronological study in sediments from pocos de caldas alkaline massif (PCAM), Brazil. AB - The Constant Flux and Constant Sedimentation (CF:CS) of supported/excess 210Pb model was successfully used to study sediment profiles from Antas stream, located in the region of Pocos de Caldas city, Minas Gerais State, Brazil. Historical changes in the region were tracked from evaluating the sedimentation rate by the 210Pb method. In that site, Osamu Utsumi mine was the first mining-industrial complex for the production of concentrated uranium in Brazil. Four sediment testimonies were sampled along Antas stream in order to determine sedimentation rates using 210Pb as geochronometer. 210Pb and 238U activity concentrations were determined in sediment samples by alpha spectrometry, allowing to find the excess 210Pb present in the sediments. Additionally, the main oxides, organic matter, particles size and water composition were determined in order to assist the results interpretation from radionuclides data. The results allowed find one (profile PKS-4) or two (profiles PKS-1, PKS-2 and PKS-3) sedimentation rates, probably due to changes in the sediments input regime in the region. The sedimentation rates were in the range between 0.26 and 0.94 g/cm2.year, corresponding to the interval of linear sedimentation rate of 0.21 - 0.92 cm/year. The deposition year in the bottom of PKS-4 profile as estimated from the sedimentation rate coincided with the construction year of Bortolan dam (1956). Large touristic interventions carried out at Pocos de Caldas city from 1920s coupled to unbridled urbanization, industrialization and demographic growth there in the second half of the twentieth century possibly caused the changes found in the sedimentation rates. PMID- 29604518 TI - A chiral sensor based on weak measurement for the determination of Proline enantiomers in diverse measuring circumstances. AB - A new chiral sensor based on weak measurement to accurately measure the optical rotation (OR) has been developed for the estimation of a trace amount of chiral molecule. With the principle of optical weak measurement in frequency domain, the central wavelength shift of output spectra is quantitatively relative to the angle of preselected polarization. Hence, a chiral molecule (e.g., L-amino acid, or D-amino acid) can be enantioselectively determined by modifying the preselection angle with the OR, which will cause the rotation of a polarization plane. The concentration of the chiral sample, corresponding to its optical activity, is quantitatively analyzed with the central wavelength shift of output spectra, which can be collected in real time. Immune to the refractive index change, the proposed chiral sensor is valid in complicated measuring circumstance. The detections of Proline enantiomer concentration in different solvents were implemented. The results demonstrated that weak measurement acted as a reliable method to chiral recognition of Proline enantiomers in diverse circumstance with the merits of high precision and good robustness. In addition, this real-time monitoring approach plays a crucial part in asymmetric synthesis and biological systems. PMID- 29604519 TI - Planar intercalated copper (II) complex molecule as small molecule enzyme mimic combined with Fe3O4 nanozyme for bienzyme synergistic catalysis applied to the microRNA biosensor. AB - Enzyme mimics have been developed for bioassay of nucleic acids, with some of them involving complicated labeling. Herein, we report a label-free bioassay for ultrasensitive electronic determination of microRNA at an ultralow concentration based on target-triggered long-range self-assembly DNA-based hybridization chain reaction (HCR) protocol coupled with bienzyme mimics synergistic catalysis strategy. In this work, a planar intercalation molecule, copper (II) complex, is applied for the first time as a small molecule enzyme mimic as well as intercalation molecule in microRNA biosensor for signal amplification. Fe3O4 nanozyme were used as a separate and enriched target under magnetic field, and also in combination with HCR protocol detected in 3,3',5,5' tetramethylbenzidine+hydrogen peroxide (TMB+H2O2) system to improve the sensitivity of the biosensor. Under optimal conditions, these strategies present good electrochemical behaviors for the detection of microRNA with a wide range from 100 aM to 100 nM and at relatively low detection limit of 33 aM This remarkable sensitivity can make this proposed approach a promising scheme for development of next-generation microRNA sensors without the need of enzyme labeling or fluorophore labeling. PMID- 29604520 TI - Nanomaterials and phase sensitive based signal enhancment in surface plasmon resonance. AB - Measurement of small molecules in extremely dilute concentrations of analyte play an important role in different issues ranging from food industry to biological, pharmaceutical and therapeutical applications. Surface plasmon resonance (SPR) sensors can be a suitable choice for detection of small molecules based on interactions with biomolecules. However, sensitivity of the system for detection of these molecules is very low. Improving sensitivity has been a challenge for years. Therefore, different methods have been used to enhance SPR signals. The SPR signal enhancement using numerous nanomaterials has provided exciting results. Among various nanomaterials, metal nanoparticles (for instance gold, silver and magnetic nanoparticles), quantum dots, nanorads, and carbon-based nanostructures have got much attention due to ease in fabrication, appropriate size and shape. In addition to the advantages provided by using nanomaterials, signal enhancement provided by the appropriate use of phase information of the reflected light could be also important to improve SPR sensitivity. Phase sensitive SPR sensors are able to detect infinitesimal changes in external properties of target while traditional type of SPR cannot demonstrate these changes. This article provides an overview on signal enhancment in SPR using nanomaterials and properties of light. We also discuss on recent progresses of the field, describing basic concepts concerning nanostructures as well as phase sensitive sensors as platform for enhancement of signal in SPR. PMID- 29604521 TI - Application of antibody-nanogold-ionic liquid-carbon paste electrode for sensitive electrochemical immunoassay of thyroid-stimulating hormone. AB - A novel electrochemical immunosensor based on carbon paste electrode (CPE) composed of ionic liquid (IL) and graphite was constructed. It demonstrated good efficiency for quick (each test in 30 s) determination of thyroid stimulating hormone (TSH). Electrode surface was modified by gold nanoparticles in order to immobilize of the thyroid stimulating hormone antibody (anti-TSH) on the CPE. The immunoassay structure was established by sandwiching the antigen (TSH) between the thyroid stimulating hormone antibody on the CPE surface modified with gold nanoparticles and the secondary antibody, polyclonal anti-human-TSH labeled with horseradish peroxidase (HRP-labeled anti-TSH). The signal of differential pulse voltammetry (DPV) was used as a basis for the determination of TSH concentration. This signal is generated by the reaction between O-aminophenol (OAP) and H2O2 catalyzed by HRP. The proposed immunosensor is able to measure the concentration of TSH in a linear range between 0.2 and 90.0 ng/mL with a detection limit 0.1 +/ 0.02 ng/mL. In addition, high sensitivity and acceptable stability were achieved by this immunosensor which is promising in the clinical assay of TSH. PMID- 29604522 TI - Comparative adventitious root development in pre-etiolated and flooded Arabidopsis hypocotyls exposed to different auxins. AB - Adventitious roots (ARs) emerge from stems, leaves or hypocotyls, being strategic for clonal propagation. ARs may develop spontaneously, upon environmental stress or hormonal treatment. Auxins strongly influence AR development (ARD), depending on concentration and kind. However, the role of different types of auxin is rarely compared at the molecular level. Rooting triggered by light exposure and flooding was examined in intact etiolated Arabidopsis thaliana hypocotyls treated with distinct auxin types. Morphological aspects, rooting-related gene expression profiles, and IAA immunolocalization were recorded. NAA and 2,4-D effects were highly dose-dependent; at higher concentrations NAA inhibited root growth and 2,4 D promoted callus formation. NAA yielded the highest number of roots, but inhibited elongation. IAA increased the number of roots with less interference in elongation, yielding the best overall rooting response. IAA was localized close to the tissues of root origin. Auxin stimulated ARD was marked by increased expression of PIN1 and GH3.3. NAA treatment induced expression of CYCB1, GH3.6 and ARF8. These NAA-specific responses may be associated with the development of numerous shorter roots. In contrast, expression of the auxin action inhibitor IAA28 was induced by IAA. Increased PIN1 expression indicated the relevance of auxin efflux transport for focusing in target cells, whereas GH3.3 suggested tight control of auxin homeostasis. IAA28 increased expression during IAA-induced ARD differs from what was previously reported for lateral root development, pointing to yet another possible difference in the molecular programs of these two developmental processes. PMID- 29604523 TI - Genome-wide analysis of the MADS-box gene family in polyploid cotton (Gossypium hirsutum) and in its diploid parental species (Gossypium arboreum and Gossypium raimondii). AB - The MADS-box gene family encodes transcription factors that share a highly conserved domain known to bind to DNA. Members of this family control various processes of development in plants, from root formation to fruit ripening. In this work, a survey of diploid (Gossypium raimondii and Gossypium arboreum) and tetraploid (Gossypium hirsutum) cotton genomes found a total of 147, 133 and 207 MADS-box genes, respectively, distributed in the MIKC, Malpha, Mbeta, Mgamma, and Mdelta subclades. A comparative phylogenetic analysis among cotton species, Arabidopsis, poplar and grapevine MADS-box homologous genes allowed us to evaluate the evolution of each MADS-box lineage in cotton plants and identify sequences within well-established subfamilies. Chromosomal localization and phylogenetic analysis revealed that G. raimondii and G. arboreum showed a conserved evolution of the MIKC subclade and a distinct pattern of duplication events in the Malpha, Mgamma and Mdelta subclades. Additionally, G. hirsutum showed a combination of its parental subgenomes followed by a distinct evolutionary history including gene gain and loss in each subclade. qPCR analysis revealed the expression patterns of putative homologs in the AP1, AP3, AGL6, SEP4, AGL15, AG, AGL17, TM8, SVP, SOC and TT16 subfamilies of G. hirsutum. The identification of putative cotton orthologs is discussed in the light of evolution and gene expression data from other plants. This analysis of the MADS box genes in Gossypium species opens an avenue to understanding the origin and evolution of each gene subfamily within diploid and polyploid species and paves the way for functional studies in cotton species. PMID- 29604524 TI - Prevalence and clinical correlates of intermittent explosive disorder in Turkish psychiatric outpatients. AB - OBJECTIVE: Intermittent explosive disorder (IED) is defined as the failure to resist aggressive impulses resulting in repeated acts of verbal and/or physical aggression. Although it is frequently encountered in clinical psychiatric practice, there is a paucity of data concerning IED in the scientific literature both internationally and in Turkey. The aim of this study was to evaluate the prevalence of IED and associated sociodemographic and clinical features in a clinical setting. METHODS: A total of 406 patients who were referred to our psychiatry outpatient clinic for the first time in a six-month period were included in the study. The diagnosis of IED was made using both Diagnostic and Statistical Manual of Mental Disorders 4th edition (DSM-IV) and DSM-5 criteria. Axis I disorder and personality disorder diagnoses were made according to DSM-5 criteria. Diagnoses were based on information from the Structured Clinical Interview for DSM-IV (SCID I) and the Structured Clinical Interview for DSM-IV personality disorders (SCID II), Symptom Checklist-90 (SCL-90), Wender Utah Rating Scale, Adult Attention Deficit Hyperactivity Disorder (ADHD) DSM-IV Based Diagnostic Screening and Rating Scale, a clinical interview conducted by the researcher, and a sociodemographic data form. In addition, participants were administered the Buss-Perry Aggression Scale and Barratt Impulsiveness Scale Version 11 (BIS-11) to assess aggression and impulsivity. RESULTS: Lifetime and 12-month prevalence of IED according to DSM-5 were 16.7% and 11.3%, respectively. Mean age at onset was 16.4 years. The prevalence of lifetime IED was 3.8 times higher in males than females (95% CI = 1.9-7.5); twice as high in individuals living in rural areas compared to those living in urban centers (95% CI = 1.1 3.7); 2.7 times higher among those with lifetime suicide attempt versus those without (95% CI = 1.3-5.6); 4.5 times higher in those with lifetime self injurious behavior compared to those without (95% CI = 2.3-8.7); and 3 times higher in individuals reporting aggression/anger problems in the family compared to those without (95% CI = 1.5-5.9). The prevalences of childhood ADHD, conduct disorder, and oppositional defiant disorder were significantly higher in the IED group. CONCLUSION: The result of the current study has revealed that approximately one-sixth of respondents experienced lifetime IED according to DSM 5 diagnostic criteria. Statistically significant sociodemographic correlates of IED include gender, urbanicity, history of suicide attempt, history of self injurious behavior, and family history of aggression/anger problems. PMID- 29604526 TI - Alcohol use and change over time in firearm safety among families with young children. AB - BACKGROUND: Improperly stored firearms pose a clear health risk to children. Previous research concurrently links alcohol use with lower levels of firearm safety. The objectives of this study were to assess (1) how families move from unsafe to safer firearm storage practices and (2) how parental drinking was associated with moving away from unsafe firearm storage practices. METHODS: This study used data from the Early Childhood Longitudinal Study-Birth Cohort, 2003 when children were two years old and again when they were four years old. Parents were asked about firearm storage practices, alcohol consumption, and information to measure other confounding variables. Their responses were used to identify families who engaged in unsafe firearm storage practices (n = 650) during the initial testing period and to assess how alcohol consumption and other variables were associated with moving to safer firearm storage practices at the second testing period. RESULTS: Families grew more likely to adopt safer firearm storage practices as their children aged, compared with continuing unsafe practices. Multivariate logistic regressions indicated that parental drinking, however, reduced the likelihood that parents moved to safer storage practices, controlling for covariates. Other families- and community-level variables, in particular, family structure, were also associated with the likelihood of moving to safer firearm storage behaviors. CONCLUSIONS: Families with higher levels of alcohol use may need additional assistance in addressing firearm safety. The findings call for future research to better understand how physicians can counsel at-risk families to help them store firearms more securely. PMID- 29604527 TI - Sensation seeking moderates television's cultivation of alcohol and tobacco beliefs: Evidence from a national study of French adolescents. AB - BACKGROUND: Television (TV) is a key socialization agent, especially amongst youth. According to cultivation theory, youth heavily exposed to TV content, where positive images of smoking and drinking abound, should hold more positive beliefs concerning drinking and smoking outcomes. This research investigates the role of the sensation-seeking personality trait in moderating this TV cultivation effect. METHODS: A French national research company contacted its panel members with children aged 13-17. Parents completed a short survey and were asked for consent for their child to participate in a study. The children were then contacted, informed, and asked for assent. Assenters completed a survey that included measures of TV exposure, personality traits, drinking and smoking behaviors, and beliefs about the outcomes associated with drinking and smoking (expectancies). Parental drinking, smoking, and strictness were included as controls. RESULTS: Survey data from 1040 adolescents (54.2% males) and their parents reveal that the relationship between cumulative TV exposure and drinking and smoking behavior, mediated through expectancies, is strongest amongst high sensation seeking adolescents. The moderated mediation analysis shows that sensation seeking trait moderates the relationship between TV exposure and the beliefs adolescents hold about the consequences of alcohol and tobacco use, which themselves are related to greater likelihood to engage in substance use. CONCLUSION: Key personality traits and TV exposure levels must be accounted for to identify youth at risk of using substances at a time when many lifelong maladaptive behaviors and beliefs form. PMID- 29604525 TI - Factors associated with discontinuation of methadone maintenance therapy (MMT) among persons who use alcohol in Vancouver, Canada. AB - BACKGROUND: We sought to examine the factors associated with discontinuation of MMT among persons on methadone who use alcohol. METHODS: We evaluated the impact of drug-related and other factors on discontinuation of MMT among persons enrolled in MMT and who reported any use of alcohol versus those who were enrolled in two community-recruited prospective cohorts of people who use illicit drugs (PWUD). Extended Cox models with time-dependent variables identified factors independently associated with time to first MMT discontinuation. RESULTS: Between December 2005 and 2015, 823 individuals on MMT who also reported using alcohol at least once were included in these analyses. During the study period, 391 (47.5%) discontinued methadone. Daily heroin injection (Adjusted Hazard Ratio [AHR] = 2.67, 95% Confidence Interval [CI]: 2.10-3.40) and homelessness (AHR = 1.42, 95% CI: 1.10-1.83) were positively associated with MMT discontinuation, whereas receiving other concurrent addiction treatment in addition to MMT (AHR = 0.07, 95% CI: 0.05-0.08), as well as >60 mg methadone dose (AHR = 0.48, 95% CI: 0.39-0.60), Hepatitis C virus seropositivity (AHR = 0.65, 95% CI: 0.47-0.90), and HIV seropositivity (AHR = 0.72, 95% CI: 0.57-0.91) were negatively associated with MMT discontinuation. Any/heavy alcohol use was not independently associated with MMT discontinuation. CONCLUSIONS: This study reinforces the known risks of continued heroin injection and homelessness for MMT discontinuation among individuals who also consume alcohol and highlights the protective effect of both MMT dose and receipt of concurrent addiction treatment. PMID- 29604528 TI - Intraabdominal actinomycosis resulting in a difficult to diagnose intraperitoneal mass: A case report. AB - INTRODUCTION: Actinomycosis is a chronic suppurative granulomatous disease caused by Actinomyces israelii. Preoperative confirmed diagnosis is very difficult, so most cases are diagnosed preoperatively as malignant tumors. We report a case of intraabdominal actinomycosis which was difficult to diagnose preoperatively. PRESENTATION OF THE CASE: A woman, 60 years old, experienced discomfort in her lower right abdomen. She complained of nausea and anorexia and visited our hospital. Laboratory blood tests, abdominal CT, and abdominal MRI led to a diagnosis of a uterine sarcoma or primary intestinal mass, and she underwent surgery. Her histopathological diagnosis was intraabdominal actinomycosis. DISCUSSION: Actinomycosis is a chronic purulent granulomatous inflammation caused by Actinomyces israelii. No clinical symptoms or laboratory findings are characteristic of abdominal actinomycosis, so this disorder is very difficult to diagnose preoperatively. Therefore, many cases are diagnosed as malignant tumors and undergo surgery. After surgery, long-term antibiotic treatment (penicillin) is usually administered. CONCLUSIONS: We reported a case of intraabdominal actinomycosis that resulted in a difficult to diagnose intraperitoneal mass. When a large intraperitoneal mass is found, actinomycosis needs to be included as one of differential diagnoses. PMID- 29604529 TI - Renal cell metastasis to the thyroid gland: An emerging phenomenon. AB - INTRODUCTION: Suspected thyroid malignancies are usually assumed to be primary in origin. Rarely, in 1-3% of cases, the tumour arises from a secondary source such as a melanoma or breast carcinoma. There is a growing body of research concerning metastatic spread of renal cell carcinoma to the thyroid gland. PRESENTATION OF CASE: This case report describes the presentation and diagnostic work-up of an 84yr male presenting with a goitre and hoarse voice. Histopathological examination of the excised 95 * 65 * 55 mm tissue mass revealed metastatic clear cell renal cell carcinoma. DISCUSSION: This disease pattern has become increasingly apparent in recent literature. A literature review of 150 documented cases worldwide showed that the mean interval for this spread to occur is 9 years. CONCLUSION: There is a need for further investigation into the underlying pathophysiology of this phenomenon and increased awareness from clinicians of its existence. PMID- 29604530 TI - Double cross finger flaps from the middle to the index or ring finger: A case series of 4 patients with an emphasis on donor finger morbidity. AB - INTRODUCTION: The use of two cross finger flaps from one digit has not been previously reported and the technique raises concerns regarding donor finger morbidity. In this paper, the authors report on a case series of double cross fingers flaps harvested from the middle finger to reconstruct large defects in the adjacent index or ring finger; with an emphasis on documenting morbidity in the donor middle finger. METHODS: A total of four cases of double cross finger flaps were retrospectively reviewed. Demographic data, surgery, and postoperative complications were documented. Donor middle finger morbidity (stiffness, painful neuromas, skin graft instability, cold intolerance and cosmetic concerns) were also documented. RESULTS: All patients were young male industrial workers. Two patients underwent reconstruction with de-epithelialized cross finger flaps and the other two patients had classic cross finger flaps. No postoperative complications were noted. Mild stiffness at the distal interphalangeal joints were noted in all patients. There were no painful neuromas and one donor site had occasional blistering at the site of the skin graft. Mild cold intolerance was seen in the two patients with electric burns. Hyperpigmentation of the skin grafts was noted in all patients. CONCLUSIONS: Our paper introduces to the literature the technique of utilizing two cross finger flaps from the middle finger to reconstruct large dorsal or volar defects of the adjacent index or ring finger. The study shows that the technique is feasible and is easily executed. The results document an acceptable donor finger morbidity. PMID- 29604531 TI - The successful salvage of a thrombosed pancreatic graft at the early postoperative period of a simultaneous pancreas and kidney transplantation. AB - INTRODUCTION: Simultaneous kidney and pancreas transplant is the preferred treatment option for end-stage renal disease due to type 1 diabetic nephropathy. Vascular complications are detrimental to graft survival and can lead to graft loss in the early postoperative phase of transplantation. Generally, duplex Doppler ultrasound is used for vascular patency monitoring and pancreatectomy followed by re-transplantation is required in the majority of cases. Recently, pancreatic graft salvage with non-operative management, including medical anticoagulation and endovascular thrombectomy, in the early postoperative period has been described with success. PRESENTATION OF CASE: We report a case of early detection of pancreas venous graft thrombosis via clinical suspicion and radiological methods, and early intervention with endovascular thrombolysis. As a result, the pancreatic graft was successfully salvaged. DISCUSSION: A limited number of studies had showed successful graft salvage in only 30-45% of thrombosed pancreatic graft with surgical thrombectomy. Our patient also had bleeding from the vascular access site and ultimately required blood transfusion, however she recovered well after procedure. CONCLUSION: Given the complexity and significance of PVGT, urgent and prompt treatment is necessary. Interpreting outcomes from our case and other small studies, it appears that endovascular pharmacomechanical thrombectomy can be a vital tool to salvage graft organs in those receiving SPK. PMID- 29604532 TI - Preoperative radiologic patent blue localization for intracorporeal laparoscopic resection of a terminal ileal submucosal lipoma: A case report. AB - BACKGROUND: Ileal submucosal lipomas are rare cases and surgical intervention was necessary in case of abdominal pain and intussusception. Laparoscopic resection may be difficult for the intraluminal submucosal lesion. Herein, we report a case of terminal ileal submucosal lipoma resected by radiologic-assisted laparoscopic surgery. CASE PRESENTATION: The 31-year-old female was admitted for intermittent abdominal pain. The colonoscopy showed a 1.5 cm diameter subepithelial lesion in terminal ileum and computed tomography showed a hypodense lesion in distal ileum. The diagnosis of terminal ileal submucosal lipoma without obstruction was impressed and surgical strategy of minimal invasive surgery was taken. Preoperative CT-guided patent blue dye injection near the terminal ileal submucosal lipoma for localization was performed by Radiologist. Then laparoscopic resection with intracorporeal suture was done smoothly without complications. The pathology proved lipoma and she had good recovery within one week. CONCLUSIONS: There are many kinds of intervention methods to treat the small bowel lipoma. Our experience supports that laparoscopic surgery with radiologic localization assistance is feasible for terminal ileal nonintussusceptive submucosal lipoma resection. PMID- 29604533 TI - Midwifery students' experiences of learning through the use of written reflections - An interview study. AB - In an effort to strengthen midwifery students' learning process, written reflections during the students' clinical practice at birth units have been applied. The aim of this study was to examine how students of midwifery experienced the writing of daily reflections on their practice at birthing units. An interview study was carried out using an inductive method with descriptive design. During 2013 (n = 12) and 2014 (n = 7), respondents were recruited from two cohorts of midwifery students (n = 19) at a university in southern Sweden. Narrative interviews were carried out. The interviews were analysed with thematic content analysis. One theme including four categories emerged from the analysis. The theme was "An educational strategy for the present and the future". The four categories were "Towards personal and professional development", "Reflection requires effort", "Supervisors' commitment" and "Clarification of the rationale". Daily written reflections are useful for students' personal and professional development during clinical practice/placement. In order for the reflections to be used optimally, students must be given clear instructions on the purpose of their use and be given enough time to write them. Furthermore, supervisors must provide constructive feedback on the students' written reflections. PMID- 29604534 TI - The lived experiences of flemish midwifery students undertaking an internship in Suriname: A phenomenological study. AB - OBJECTIVE: The aim of this study is to explore the lived experience of Flemish midwifery students undertaking an internship in Suriname. DESIGN: Hermeneutic phenomenological method as described by van Manen. METHODS: Seven midwifery students from one University College were selected purposefully for an in-depth interview during their internship abroad within the period October-November 2014. All interviews were audio-taped, transcribed verbatim and analysed thematically. FINDINGS: The study revealed five overarching themes: (1) A time to reconsider the time, (2) a time of connection and disconnection, (3) spatiality for thought and rethinking, (4) a body to undergo or a body to respond and (5) the other(s) among the others. CONCLUSION: The experience of an internship in Suriname presents itself in each individual as: 'A process of awareness from the self with a main focus on the professional'. Meaning that it was a process of 'disconnection' from their own culture towards 'connection' with another culture. Both, the 'rethinking' of their role as a midwife, as well as, balancing between guarding one's own authenticity by 'responding' or being the friendly stranger through 'undergoing', was noticeably striking. PMID- 29604536 TI - Comment on Y.D. Fragoso et al.: "Lymphocyte count in peripheral blood is not associated with the level of clinical response to treatment with fingolimod" Multiple Sclerosis and Related Disorders 2017. PMID- 29604535 TI - L-NAME decreases the amount of nitric oxide and enhances the toxicity of cadmium via superoxide generation in barley root tip. AB - Exposure of barley roots to mM concentrations of L-NAME for 30 min caused a considerable root growth inhibition in a dose-dependent manner. The inhibition of root growth was higher in seedlings co-treated with Cd and L-NAME, compared with roots treated with Cd alone, despite the fact that L-NAME markedly reduced the uptake of Cd by roots. Treatment of roots with L-NAME evoked a decrease in NO level in both control and Cd-treated root tips only after a relatively long lag period, which overlaps with an increase in superoxide and H2O2 levels and peroxynitrite generation. L-NAME-induced root growth inhibition is alleviated not only by the application of the NO donor SNP but also by the ROS and peroxynitrite scavengers. Our results indicate that L-NAME, a NOS inhibitor in the animal kingdom, indeed evokes NO depletion also in the plant tissues; however, it does not occur due to the action of L-NAME as an inhibitor of NOS or NOS-like activity, but as a consequence of L-NAME-induced enhanced superoxide generation, leading to increased peroxynitrite level in the root tips due to the reaction between superoxide and NO. PMID- 29604537 TI - Chronic exposure to low environmental concentrations and legal aquaculture doses of antibiotics cause systemic adverse effects in Nile tilapia and provoke differential human health risk. AB - BACKGROUND: Antibiotics used globally to treat human and animal diseases exist ubiquitously in the environment at low doses because of misuse, overdose and poor absorption after ingestion, coupled with their high-water solubility and degradation resistance. However, the systemic chronic effects of exposure to low environmental concentrations of antibiotics (LECAs) and legal aquaculture doses of antibiotics (LADAs) in fish and their human health risk are currently unknown. OBJECTIVE: To investigate the in vivo chronic effects of exposure to LECAs and LADAs using oxytetracycline (OTC) and sulfamethoxazole (SMZ) in Nile tilapia (Oreochromis niloticus) and their human health risk. METHODS: Twenty O. niloticus weighing 27.73 +/- 0.81 g were exposed to water containing LECAs (OTC at 420 ng/L and SMZ at 260 ng/L) and diets supplemented with LADAs (OTC 80 mg/kg/day and SMZ 100 mg/kg/day) for twelve weeks. General physiological functions, metabolic activities, intestinal and hepatic health were systemically evaluated. The possible human health risks of the consumption of the experimental Nile tilapia fillets in adults and children were assessed by using risk quotient. RESULTS: After exposure, we observed retarded growth performance accompanied by reduced nutrients digestibility, feed efficiency, organ indices, and lipid body composition in treated fish. Antibiotics distorted intestinal morphological features subsequently induced microbiota dysbiosis and suppressed intestinal tight junction proteins. Exposure of fish to LECAs and LADAs induced oxidative stress, suppressed innate immunity, stimulated inflammatory and detoxification responses, concomitantly inhibited antioxidant capacity and caused lipid peroxidation in intestine and liver organs. Both LECAs and LADAs enhanced gluconeogenesis, inhibited lipogenesis and fatty acid beta oxidation in intestine and liver organs. The exposure of fish to LECAs and LADAs induced anaerobic glycolytic pathway and affected intestinal fat catabolism in intestine while halted aerobic glycolysis, increased hepatic fat catabolism, and induced DNA damage in liver. The hazard risk quotient in children for fish treated with OTCD was >1 indicating human health risk. CONCLUSION: Overall, both LECAs and LADAs impair general physiological functions, nutritional metabolism, and compromise fish immune system. Consumption of fish fed with legal OTC provokes health risk in children. Global stringent prohibition policy for use of antibiotics in aquaculture production and strategies to limit their release into the environment are urgently required to protect human health. PMID- 29604538 TI - Economic impacts from PM2.5 pollution-related health effects in China's road transport sector: A provincial-level analysis. AB - Economic impact assessments of air pollution-related health effects from a sectoral perspective in China is still deficient. This study evaluates the PM2.5 pollution-related health impacts of the road transport sector on China's economy at both national and provincial levels in 2030 under various air mitigation technologies scenarios. Health impacts are estimated using an integrated approach that combines the Greenhouse Gas and Air Pollution Interactions and Synergies (GAINS) model, a computable general equilibrium (CGE) model and a health model. Results show that at a national level, the road transport sector leads to 163.64 thousand deaths per year, increases the per capita risk of morbidity by 0.37% and accounts for 1.43 billion Yuan in health care expenditures. We estimate 442.90 billion Yuan of the value of statistical life loss and 2.09 h/capita of work time loss in 2015. Without additional control measures, air pollution related to the transport sector will cause 177.50 thousand deaths in 2030, a 0.40% per capita increase in the risk of morbidity, accounting for 4.12 billion Yuan in health care expenditures, 737.15 billion Yuan of statistical life loss and 2.23 h/capita of work time loss. Based on our model, implementing the most strict control strategy scenario would decrease mortality by 42.14%, morbidity risk by 42.14%, health care expenditures by 41.94%, statistical life loss by 26.22% and hours of work time loss by 42.65%, comparing with the no control measure scenario. In addition, PM2.5 pollution from the road transport sector will cause 0.68% GDP loss in 2030. At a provincial level, GDP losses in 14 out of 30 provinces far exceed the national rate. Henan (1.20%), Sichuan (1.07%), Chongqing (0.99%), Hubei (0.94%), and Shandong (0.90%) would experience the highest GDP loss in 2030. Implementing control strategies to reduce PM2.5 pollution in the road transport sector could bring positive benefits in half of the Chinese provinces especially in provinces that suffer greater health impacts from the road transport sector (such as Henan and Sichuan). PMID- 29604539 TI - Corrigendum to "Changes in patellofemoral pain resulting from repetitive impact landings are associated with the magnitude and rate of patellofemoral joint loading" [Clin. Biomech. 53 (2018) 31-36]. PMID- 29604540 TI - Effects of Co-occurring marijuana use and anxiety on brain structure and functioning: A systematic review of adolescent studies. AB - The prevalence of marijuana use among adolescents with anxiety disorders in the USA is markedly high and well documented; however, the literature on this co occurrence's effect on adolescent brain development and functioning is limited. This systematic review searched six databases to 1) explore the literature concerning marijuana use among adolescents with anxiety and 2) examine the effects of marijuana on brain structure and functioning. Overall, 27 studies from six countries were included in this review. Out of these studies, several disparate designs were utilized. The majority of studies revealed an association between marijuana use and anxiety, but the strength of the association and the variability among the studies' designs limited the comparison and warrants additional investigation. Only five studies met criteria that used brain-imaging techniques, and findings were non-conclusive. Future evaluations should further investigate the effects of co-occurring marijuana use and anxiety disorders on brain structure and functioning among adolescents. PMID- 29604542 TI - Design, synthesis and bioevaluation of 1,2,3,9-tetrahydropyrrolo[2,1 b]quinazoline-1-carboxylic acid derivatives as potent neuroprotective agents. AB - Diverse of 1,2,3,9-tetrahydropyrrolo[2,1-b]quinazoline-1-carboxylic acid derivatives were designed, synthesized and evaluated for their neuroprotective activity against NMDA-induced cytotoxicity in vitro, and 5q exhibited excellent neuroprotective activity. The compound 5q was selected for further investigation. We found that 5q could attenuate Ca2+ influx induced by NMDA, meanwhile, 5q could suppress the NR2B up-regulation and increase p-ERK1/2 expression. The molecular docking results showed that 5q might fit well in the binding pocket of 4 and interact with some key residues in the binding pocket of 1 simultaneously. Besides, 5q exhibited acceptable metabolic stability. These results suggested that 5q was a promising lead for further development of new potent and orally bioavailable NR2B-selective NMDAR antagonists. PMID- 29604541 TI - Optimization of the pharmacokinetic properties of potent anti-trypanosomal triazine derivatives. AB - Human African trypanosomiasis is causing thousands of deaths every year in the rural areas of sub-saharan Africa. There is a high unmet medical need since the approved drugs are poorly efficacious, show considerable toxicity and are not easy to administer. This work describes the optimization of the pharmacokinetic properties of a previously published family of triazine lead compounds. One compound (35 (UAMC-03011)) with potent anti-trypanosomal activity and no cytotoxicity was selected for further study because of its good microsomal stability and high selectivity for Trypanosoma brucei over a panel including Trypanosoma cruzi, L.eishmania infantum, and Plasmodium falciparum. In vivo pharmacokinetic parameters were determined and the compound was studied in an acute in vivo mouse disease model. One of the important learnings of this study was that the rate of trypanocidal activity is an important parameter during the lead optimization process. PMID- 29604543 TI - Design, synthesis and activity of BBI608 derivatives targeting on stem cells. AB - STAT3 plays a vital role in maintaining the self-renewal of tumor stem cells. BBI608, a small molecule identified by its ability to inhibit gene transcription driven by STAT3 and cancer stemness properties, can inhibit stemness gene expression and kill stemness-high cancer cells isolated from a variety of cancer types. In order to improve the pharmacokinetic properties of BBI608 and the antitumor activity, a series of BBI608 derivatives were designed and synthesized here. Most of these compounds were more potent than BBI608 on HepG2 cells, compound LD-8 had the most potent inhibitory activity among them and was 5.4-fold more potent than BBI608 (IC50 = 11.2 MUM), but had considerable activity on normal liver cells L-02. Compounds LD-17 (IC50 = 3.5 MUM) and LD-19 (IC50 = 2.9 MUM) were found to possess significant inhibitory activities and good selectivity. The results showed that compound LD-19 was worthy to investigate further as a lead compound according to its potent inhibitory activity, ideal ClogP value and better water solubility. PMID- 29604544 TI - Reduced heart rate variability and increased saliva cortisol in patients with TMD. AB - Temporomandibular disorders (TMD) are the most common source of non-dental pain. The pathogenesis of TMD is multifactorial, involving biological, psychological and behavioral factors. Those factors are involved with alterations of the autonomic nervous system (ANS) and stressful conditions. Heart rate variability (HRV) has been used as a marker of ANS function. Increased cortisol level (a stress indicator), has been found in chronic pain. Therefore, the present study aimed to compare pain intensity, HRV, psychological factors, and salivary cortisol level between TMD patients and a control group. Twenty-one TMD patients and twenty-three healthy control subjects participated in the study. All participants underwent 24-h-Holter monitoring to record HRV. Morning unstimulated saliva samples were collected from each participant for cortisol analysis. The pain intensity was assessed using a visual analog scale. The participants were evaluated for anxiety and depression via the Hospital Anxiety and Depression Scales. We found that pain intensity and psychological distress in the TMD group were significantly greater than those of the control (p < 0.01). Pain intensity showed a positive correlation with psychological distress (p < 0.01). HRV parameters in the TMD group were significantly lower than those in the control, suggesting reduced HRV in TMD patients. Pain intensity was negatively associated with HRV. Salivary cortisol level of the TMD group was greater than that of control. Our findings indicate that reduced HRV with higher psychological distress and increased salivary cortisol levels were observed in the TMD group. Therefore, TMD patients may benefit from interventions that can restore ANS function and stress balance. PMID- 29604545 TI - Effectiveness of a newly reconstructed floodplain oxbow to reduce NO3-N loads from a spring flood. AB - Enhancing NO3-N processing in floodplains offers opportunities to achieve water quality improvements in agricultural watersheds but few studies have quantified the effectiveness of newly reconstructed oxbows to reduce loads delivered from floods. In this study, we evaluated NO3-N retention during a spring storm water runoff event in a newly reconstructed oxbow (<1 year old) located along Morgan Creek in eastern Iowa. A 30-h flood connected the oxbow to the creek for approximately nine hours and delivered 14.7 kg of NO3-N into the oxbow. Using a NO3-N sensor, oxbow NO3-N concentrations were observed to increase from 0.7 to 5.3 mg/l after the flood event, but decreased to background conditions over the next 21 days. We estimated NO3-N retention to be 0.30 g N m-2 d-1 and the NO3-N retention efficiency to be 74.2% for the single flood event. The NO3-N mass reduction in the oxbow intersected with predicted mass reduction from a first order denitrification decay model after 21 days which suggests that denitrification was largely responsible for the observed NO3-N decrease. However, the effectiveness of the oxbow for reducing watershed-scale N loads appears to be limited, since the oxbow is located in a low-nutrient floodplain and would only retain NO3-N loads when delivered to the oxbow via flooding. Study results suggest that oxbows provides valuable ecosystem services during non-flooding periods and are activated for NO3-N load reduction during floods. PMID- 29604546 TI - Does spending time outdoors reduce stress? A review of real-time stress response to outdoor environments. AB - Everyday environmental conditions impact human health. One mechanism underlying this relationship is the experience of stress. Through systematic review of published literature, we explore how stress has been measured in real-time non laboratory studies of stress responses to deliberate exposure to outdoor environments. The types of exposures evaluated in this review include: nature viewing, outdoor walks, outdoor exercise and gardening. We characterize study design, modalities of stress measurements, and statistical estimates of effect and significance. Heart rate, blood pressure, and self-report measures provide the most convincing evidence that spending time in outdoor environments, particularly those with green space, may reduce the experience of stress, and ultimately improve health. More work is needed to understand effects of in situ modifications to outdoor environments on residents' stress response. PMID- 29604547 TI - Major obstetric hemorrhage: Patients' perspective on the quality of care. AB - OBJECTIVES: Major obstetric hemorrhage (MOH) is the leading cause of severe maternal morbidity and mortality, and can have a significant impact on a woman's life. This study aims to gain insight into the patients reported experiences (PREs) and outcomes (PROs) after a major obstetric hemorrhage, and to investigate which patients are most at risk for negative experiences. MATERIAL AND METHODS: A Consumer Assessment of Healthcare Providers and Systems (CAHPS) based questionnaire was developed covering items on the PREs and PROs, and send to all patients with blood loss exceeding 2500 ml in six hospitals over the period of 2008-2012. A regression analysis was performed to find determinants for negative experiences. RESULTS: In total 372 of the 570 questionnaires were returned. Women scored the overall care before, during and after the MOH with a mean of 7.67, 7.62 and 7.28, respectively. However, most PRE items individually were scored suboptimal, with items regarding information supply scoring the lowest. Our results on the PROs showed 81% of the women (362) sustaining extreme fatigue, whereas problems with concentration (53% of 373 women), memory (49% of 353), or reliving (49% of 356) and irritability (51% of 355) were also frequently endured. Negative long term effects were observed in 28% of the women (106 of 372). We found 'year of the MOH longer ago', 'a lower total blood loss' and 'a large location of birth' to be determinants for negative experiences. CONCLUSIONS: Women frequently reported negative experiences and outcomes following a MOH. Information supply after an MOH concerning both physical and psychological complaints is essential for the improvement of care. PMID- 29604548 TI - Non-ablative Er:YAG laser therapy effect on stress urinary incontinence related to quality of life and sexual function: A randomized controlled trial. AB - OBJECTIVE: Stress urinary incontinence (SUI) is a common complaint in women after childbirth. It affects their quality of life and sexual satisfaction and is one of the major reasons for gynaecological surgery. There is a need for effective non-invasive treatment alternatives. The aim of this study was to evaluate the efficacy and safety of non-ablative Er:YAG laser therapy in the treatment of SUI and improvement of sexual gratification in parous women. STUDY DESIGN: 114 premenopausal parous women with SUI were randomized in two groups of 57 women; a laser intervention group and sham group. Both groups were treated according to the IncontiLase(r) clinical treatment protocol for SUI with non-ablative thermal only Er:YAG laser, except that there was no energy output when treating the sham group. Patients were blinded to the allocation. At baseline and 3 months after treatment patients were clinically examined, answered questionnaires for SUI severity and sexual function assessment and their pelvic floor muscle (PFM) function was assessed with perineometry. Validated International Consultation on Incontinence Questionnaire - Urinary Incontinence Short Form (ICIQ-UI SF) was used as the primary outcome measure. The Pelvic Organ Prolapse Urinary Incontinence Sexual Questionnaire short form (PISQ-12) and The Female Sexual Function Index (FSFI) were used to assess the sexual function. Patients were monitored for discomfort and side-effects during treatment and follow-up period. RESULTS: 3 months after treatment the ICIQ-UI SF (p < 0.001), PISQ-12 (p = 0.014) and FSFI (p = 0.025) scores were significantly more improved in the laser group than in the sham control group. All perineometry variables improved in the laser group after treatment; duration and maximum pressure had statistically significantly better improvement than the sham group, whereas average pressure did not. 21% of laser treated patients were dry (ICIQ-UI SF = 0) at follow up compared to only 4% of the sham control patients. No serious adverse effects were observed or reported. The treatment was well tolerated by patients. CONCLUSIONS: The non-ablative Er:YAG laser therapy improves the impact of SUI symptoms on quality of life and sexual function in premenopausal parous women significantly better than placebo. It provides a promising minimally-invasive safe treatment alternative for SUI. PMID- 29604549 TI - Challenges in TEM sample preparation of solvothermally grown CuInS2 films. AB - Transmission electron microscopy (TEM) is a widely used tool to characterize materials. The required samples need to be electron transparent which should be achieved without changing the microstructure. This work describes different TEM sample preparation techniques of nanostructured CuInS2 thin films on fluorine doped tin oxide substrates, synthesized solvothermally using l-cysteine as sulfur source. Focused ion beam lamellae, conventional cross section samples and scratch samples have been prepared and investigated. It was possible to prepare appropriate samples with each technique, however, each technique brings with it certain advantages and disadvantages. FIB preparation of solvothermally synthesized CuInS2 suffers from two main drawbacks. First, the whole CuInS2 layer displays a strongly increased Cu content caused by Cu migration and preferential removal of In. Further, electron diffraction shows the formation of an additional CuS phase after Ga+ bombardment. Second, diffraction analysis is complicated by a strong contribution of crystalline Pt introduced during the FIB preparation and penetrating into the porous film surface. The conventional cross sectional CuInS2 sample also shows a Cu signal enhancement which is caused by contribution of the brass tube material used for embedding. Additionally, Cu particles have been observed inside the CuInS2 which have been sputtered on the film during preparation. Only the scratch samples allow an almost artefact-free and reliable elemental quantification using energy-dispersive X-ray spectroscopy. However, scratch samples suffer from the drawback that it is not possible to determine the layer thickness, which is possible for both cross sectional preparation techniques. Consequently, it is concluded that the type of sample preparation should be chosen dependent on the required information. A full characterization can only be achieved when the different techniques are combined. PMID- 29604550 TI - Trajectories of maternal stress and anxiety from pregnancy to three years and child development at 3 years of age: Findings from the All Our Families (AOF) pregnancy cohort. AB - BACKGROUND: Existing literature on maternal distress has focused on stress and anxiety during the pregnancy or postnatally and their relationship with child development. However, few studies have investigated the association between maternal stress and anxiety symptoms over time and child development in preschool children. The aim of this study was to examine the association between trajectories of maternal stress and anxiety symptoms from mid-pregnancy to three years postpartum and child development at age three years. METHODS: Data were analyzed from 1983 mother-child dyads who participated in the three year follow up of the All Our Families (AOF) study. Latent class analysis (LCA) was conducted to identify trajectories of women's stress and anxiety across from mid-pregnancy to three years postpartum. Multivariate logistic regression was used to explore the relationship between the stress and anxiety trajectories and child developmental delays while adjusting for the covariates. RESULTS: LCA identified three distinct trajectories of maternal stress and anxiety symptoms over time. Multivariate analysis showed mothers assigned to the high anxiety symptoms class had an increased risk (adjusted OR 2.80, 95% CI 2.80 (1.42 ? 5.51), p = 0.003) of having a child with developmental delays at 3 years. LIMITATIONS: The use of self reported maternal mental health symptoms and no data on fathers' mental health are our study's limitations. CONCLUSIONS: The findings from a population-based Canadian sample provide empirical support for a relationship between maternal anxiety overtime and risk of child developmental delays. Identifying and supporting mothers experiencing high anxiety symptoms in the perinatal period may mitigate the risk of these delays in children. PMID- 29604552 TI - Biologically synthesized titanium oxide nanostructures combined with morphogenetic protein as wound healing agent in the femoral fracture after surgery. AB - The aim of the present study is to develop novel approach for the green synthesis of titanium oxide nanoparticles (TiO2 NPs) using Eichhornia crassipes extract and calcined at different temperatures for evaluate the wound healing activity in the femoral fracture. The synthesized TiO2 are formed different (plate and rod-like) nanostructures at various calcination temperatures. These samples were characterized by X-ray diffraction (XRD), Fourier transform-infrared spectroscopy (FTIR), Field emission scanning electron microscope (FE-SEM) and transmission electron microscope (TEM). Microscopic studies of TiO2 NPs revealed that the synthesized TiO2 NPs are formed well-defined rod-like structures at 400 degrees C with size ranged from 200 nm to 500 nm. The characterized plate and rod-like TiO2 NPs are combined with human morphogenetic protein (HbMP) to improving its wound healing activity and osteoblast properties on femoral fractures. The biocompatibility was tested by using human bone marrow mesenchymal stem cells (BMSC) cells and antibacterial efficacy analyzed using human pathogenica bacteria Staphylococcus aureus and Escherichia coli through agar well diffusion assay. The green synthesized rod-like TiO2 NPs combined with HbMP has been exhibited effective bone fusion behaviors with biomechanical properties and also improved antibacterial activity against pathogenic bacteria. From this study results, it is suggested that green synthesized TiO2NPs could be used effectively in biomedical application. PMID- 29604553 TI - Stereological and molecular studies on the combined effects of photobiomodulation and human bone marrow mesenchymal stem cell conditioned medium on wound healing in diabetic rats. AB - We investigated the effects of conditioned medium (CM) from human bone marrow mesenchymal stem cells (h BMMSC)s and pulse wave photobiomodulation (PW PBM), applied alone or in combination, on the stereological parameters and gene expression of some growth factors, during wound healing in a streptozotocin (STZ) induced rat model of type one diabetes mellitus (T1DM). T1DM was induced in 72 rats and two incisions were made in each animal. The rats were assigned to one of four groups: a control (placebo) group, a Laser group (890 nm, 80 Hz, 0.2 J/cm2); a CM group, and a combined CM + Laser group. On post-surgical days 4, 7, and 15, skin samples were extracted for stereology and reverse transcription PCR (RT-PCR) analyses of gene expression of basic fibroblast growth factor (bFGF), hypoxia inducible factor (HIF-1alpha), and stromal cell-derived factor-1alpha (SDF 1alpha). The stereological examinations of the proximal and distal wounds revealed significantly enhanced healing in all the treated groups, compared to the control group. The extent of healing was significantly greater in the CM + Laser group than in the other treatment groups. The RT-PCR results also indicated greater gene expression in the CM + Laser and Laser groups than in the CM and control groups. Application of CM and PW PBM, alone or in combination accelerated the process of wound healing in T1DM rats. The results of combined application of CM and PW PBM, indicated a synergistic effect, and the combination treatment was statistically more effective than single applications of CM or PW PBM. PMID- 29604554 TI - Green synthesis of silver nanoparticles using leaf extract of Acalypha hispida and its application in blood compatibility. AB - The blood compatibility of AgNPs is of great relevance as it has good antifungal, antibacterial and anti-inflammatory properties and the toxicological information of their effects on cells need to be analyzed before using it as drug carriers in the biomedical field. The present study deals with the synthesis of AgNPs from an aqueous solution of silver nitrate using Acalypha hispida leaf extract as the reducing and capping agent. The presence of AgNPs in the reaction mixture was confirmed by visual observation of color change and subsequently identified using UV-Visible Spectroscopy. XRD results revealed the crystalline nature of synthesized AgNPs. The shape and size of particles were characterized by TEM. These results revealed the elemental status of nanopowder. The components present in leaf extract were identified by GC-MS and functional groups present in the sample when treated with silver nitrate were obtained from FT-IR results. The surface of synthesized AgNPs was modified using four different compounds such as CTAB, PEG, PEI, and APTMS to evaluate the blood compatibility. The results showed that 50 MUg/mL CTAB coated AgNPs and 50 and 100 MUg/mL PEG coated AgNPs had non hemolytic property and considered as more blood compatible surface modified AgNPs. This investigation gives an idea of using surface modified AgNPs in the field of biomedicine and therapeutic applications. PMID- 29604551 TI - The use of humanized mice for studies of viral pathogenesis and immunity. AB - Humanized mice, that is, animals engrafted with human tissues and/or expressing human genes, have been instrumental in improving our understanding of the pathogenesis and immunological processes that define some of the most challenging human-tropic viruses. In particular, mice engrafted with components of a human immune system (HIS) offer unprecedented opportunities for mechanistic studies of human immune responses to infection. Here, we provide a brief overview of the current panel of HIS mouse models available and cite recent examples of how such humanized animals have been used to study immune responses and pathogenesis elicited by human-tropic viruses. Finally, we will outline some of the challenges that lay ahead and strategies to improve and refine humanized mice with the goal of more accurately recapitulating human immune responses to viral infection. PMID- 29604555 TI - Nickel oxide decorated zinc oxide composite nanorods: Excellent catalyst for photoreduction of hexavalent chromium. AB - In light of the growing interest and ability to search for new materials, we have synthesized Nickel oxide (NiO) nanoparticles decorated Zinc (ZnO) nanorods composite (NiO/ZnO) nanostructure. The NiO/ZnO heterostructure formation was confirmed by X-ray powder diffraction and high-resolution transmission electron microscopy (HRTEM). The fabricated environmental friendly NiO/ZnO composite nanostructure shows a well-defined photoreduction characteristic of hexavalent Chromium (Cr) (VI) to tri-valent Chromium (Cr) (III) under UV-light. Such an enhanced photoreduction property is attributed due to the decreased electron-hole recombination process which was proved by photoluminescence (PL) spectroscopy, photocurrent study, and electrochemical impedance spectroscopy. Furthermore, the photocatalytic activity rate of the NiO decorated ZnO nanorods was much higher than that of bare ZnO nanorods for the reduction of chromium (VI) and the rate is found to be 0.306 min-1. These results have demonstrates that suitable surface engineering may open up new opportunities in the development of high-performance photocatalyst. PMID- 29604556 TI - Confinement effects and mechanistic aspects for montmorillonite nanopores. AB - Owing to the ubiquity, critical importance and special properties, confined microenvironments have recently triggered overwhelming interest. In this work, all-atom molecular dynamics simulations have been conducted to address the confinement effects and ion-specific effects for electrolyte solutions within montmorillonite nanopores, where the pore widths vary with a wide range. The adsorption number, structure, dynamics and stability of inner- and outer-sphere metal ions are affected by the change of pore widths (confinement effects), while the extents are significantly dependent on the type of adsorbed species. The type of adsorbed species is, however, not altered by the magnitude of confinement effects, and confinement effects are similar for different electrolyte concentrations. Ion-specific effects are pronounced for all magnitudes of confinement effects (from non- to strong confined conditions), and Hofmeister sequences of outer-sphere species are closely associated with the magnitude of confinement effects while those of inner-sphere species remain consistent. In addition, mechanistic aspects of confinement have been posed using the electrical double layer theories, and the results can be generalized to other confined systems that are ubiquitous in biology, chemistry, geology and nanotechnology. PMID- 29604557 TI - Headless compression screw for horizontal medial malleolus fractures. AB - BACKGROUND: Horizontal medial malleolus fractures are caused by the application of rotational force through the ankle joint in several orientations. Multiple techniques are available for the fixation of medial malleolar fractures. METHODS: Horizontal medial malleolus osteotomies were performed in eighteen synthetic distal tibiae and randomized into two fixation groups: 1) two parallel unicortical cancellous screws or 2) two Acutrak 2 headless compression screws. Specimens were subjected to offset axial tension loading. Frontal plane interfragmentary motion was monitored. FINDINGS: The headless compression group (1699 (SD 947) N/mm) had significantly greater proximal-distal stiffness than the unicortical group (668 (SD 298) N/mm), (P = 0.012). Similarly, the headless compression group (604 (SD 148) N/mm) had significantly greater medial-lateral stiffness than the unicortical group (281 (SD 152) N/mm), (P < 0.001). The force at 2 mm of lateral displacement was significantly greater in the headless compression group (955 (SD 79) N) compared to the unicortical group (679 (SD 198) N), (P = 0.003). At 2 mm of distal displacement, the mean force was higher in the headless compression group (1037 (SD 122) N) compared to the unicortical group (729 (SD 229) N), but the difference was not significant (P = 0.131). INTERPRETATION: A headless compression screw construct was significantly stiffer in both the proximal-distal and medial-lateral directions, indicating greater resistance to both axial and shear loading. Additionally, they had significantly greater load at clinical failure based on lateral displacement. The low-profile design of the headless compression screw minimizes soft tissue irritation and reduces need for implant removal. PMID- 29604558 TI - Isotherm and kinetic studies on adsorption of oil sands process-affected water organic compounds using granular activated carbon. AB - The production of oil from oil sands in northern Alberta has led to the generation of large volumes of oil sands process-affected water (OSPW) that was reported to be toxic to aquatic and other living organisms. The toxicity of OSPW has been attributed to the complex nature of OSPW matrix including the inorganic and organic compounds primarily naphthenic acids (NAs: CnH2n+ZOx). In the present study, granular activated carbon (GAC) adsorption was investigated for its potential use to treat raw and ozonated OSPW. The results indicated that NA species removal increased with carbon number (n) for a fixed Z number; however, the NA species removal decreased with Z number for a fixed carbon number. The maximum adsorption capacities obtained from Langmuir adsorption isotherm based on acid-extractable fraction (AEF) and NAs were 98.5 mg and 60.9 mg AEF/g GAC and 60 mg and 37 mg NA/g GAC for raw and ozonated OSPW, respectively. It was found that the Freundlich isotherm model best fits the AEF and NA equilibrium data (r2 >= 0.88). The adsorption kinetics showed that the pseudo-second order and intraparticle diffusion models were both appropriate in modeling the adsorption kinetics of AEF and NAs to GAC (r2 >= 0.97). Although pore diffusion was the rate limiting step, film diffusion was still significant for assessing the rate of diffusion of NAs. This study could be helpful to model, design and optimize the adsorption treatment technologies of OSPW and to assess the performance of other adsorbents. PMID- 29604559 TI - Phthalates in PM2.5 from Shenzhen, China and human exposure assessment factored their bioaccessibility in lung. AB - Temporal variability of phthalates (PAEs) in PM2.5 from Shenzhen during 2015-2016 was measured and the associated human exposure via inhalation was assessed. The PM2.5 concentrations ranged from 30.7 to 115 MUg m-3, greater than the air quality guidelines of interim target-3 (10-15 MUg m-3) and interim target-2 (15 25 MUg m-3) set by World Health Organization. PAEs were detected in 94.7% samples and the 95th percentile concentrations of total PAEs (?6PAEs) in Longgang and Nanshan districts were 324 and 44.7 ng m-3, respectively. Di-2-ethylhexyl phthalate was the dominant species, accounting for an average of 81.9% of ?6PAEs. The mean and 95th percentile concentrations of ?6PAEs in PM2.5 were used to calculate a "typical" and "high" total daily intake and uptake, respectively. The estimated total daily intakes of PAEs varied and depended on body weight in each age group. Infants had the highest "typical" and "high" daily intake of 43.4 and 179 ng kg-body weight (bw) -1 day-1 for boys, and 42.0 and 173 ng kg-bw-1 day-1 for girls, respectively. However, after taking the bioaccessibility of PAEs in PM2.5 into account, the total daily "typical" and "high" uptakes dropped to 27.3 and 113 ng kg-bw-1 day-1 for male infants, and 29.0 and 120 ng kg-bw-1 day-1 for female infants, respectively. Both of the data on the daily "high" intake and uptake were much lower than the tolerable daily intake set by the European Food Safety Agency. It merits attention that infants were subject to greater PAE exposure than adults. PMID- 29604560 TI - Formation of Fe nanoparticles on water-washed coal fly ash for enhanced reduction of p-nitrophenol. AB - The catalytic reduction of p-nitrophenol (p-NP) by coal fly ash (FA) washed with water was investigated in this study. A significant increase in pH (from 7.0 to 10.1) was observed in the suspension of raw fly ash (RFA), while water-washed fly ash (WFA) showed a relatively lower increase in pH (7.2), which was caused by the dissolution of Ca species during the water-washing process. Almost 33.4% of p-NP reduction was observed in the RFA suspension with NaBH4 in 1 h, while the enhanced reduction of p-NP (87.2%) was observed in the WFA suspension. The catalytic reduction of p-NP was inhibited by addition of CaO and Ca(OH)2, indicating that higher amount of CaO dissolved from RFA resulted in the inhibition effect. Similar experiments using different oxides (i.e., Al2O3, SiO2, CaO and MgO) revealed no significant reduction of p-NP, which was comparable with Fe2O3 (75.8%). Results from various surface analyses revealed that iron oxides on the surface of WFA can be reduced to elemental Fe nanoparticles, which can effectively reduce p-NP with NaBH4. No significant leaching of heavy metals such as Cr, Pb, and As was observed during the catalytic reduction of p-NP and in the suspension of WFA after reaction at pH 3, 5, 7, and 9 for 24 h, which can solve the toxic effect when the FA is used for environmental applications. We also observed a good reusability of WFA during the recycling test, indicating the potential use of WFA for the treatment of wastewater containing reductively degradable pollutants. PMID- 29604561 TI - Effect of phospholipid coating on the migration of plasticizers from PVC tubes. AB - Plasticizers in polyvinyl chloride (PVC) are not covalently bound to the polymer and can thus migrate into the contact medium. The presented study investigated the potential effects of phospholipid-lining as anti-coagulation coating (ACC) on the migration rate of plasticizers from PVC tubing into blood. For the in-vitro study, five different groups of tubing sets in six replicates were perfused with sheep blood (Group A: PVC plasticized with di-(2-ethylhexyl) phthalate (DEHP) without ACC, Group B: DEHP-plasticized PVC with ACC, Group C: PVC plasticized with tri-(2-ethylhexyl) trimellitate (TOTM) without ACC, Group D: TOTM plasticized PVC with ACC, Group E (control group): polyolefin material with ACC but without plasticizers). Both the levels of the unchanged plasticizers in blood and the concentration levels of their primary degradation products were assessed. For DEHP, the primary metabolite MEHP (mono-(2-ethylhexyl) phthalate) was determined. The isomers of MEHTM (mono-(2-ethylhexyl) trimellitate) and DEHTM (di (2-ethylhexyl) trimellitate), respectively, were investigated as primary metabolites of TOTM. The calculated DEHP equivalents (sum of determined levels of DEHP and MEHP) after 24 h of perfusion displayed a tendency towards lower levels in the tubing sets without ACC (Group A (201 +/- 56.4 MUmol/L)) compared to the tubing sets with ACC (Group B (253 +/- 369 MUmol/L)). Significantly different DEHP equivalents between Group A and Group B were found after a perfusion time of 6 h and 10 h, respectively. A similar effect was observed for the TOTM-containing tubing sets. However, the absolute plasticizer migration rate of TOTM (TOTM equivalents) after 24 h of perfusion was found to be significantly lower compared to that of DEHP (with a factor of over 200). The results indicate that phospholipid coating (ACC) rather enhances the migration of plasticizers and of their primary degradation products from PVC tubing into streaming blood. The enhancement effect was found to be slightly greater for TOTM, but as TOTM migrates in significantly lower levels than DEHP in all experimental settings, TOTM is confirmed to be a recommendable alternative plasticizer to DEHP in medical devices. PMID- 29604562 TI - Characterization of volatile organic compounds and the impacts on the regional ozone at an international airport. AB - In this study, the measurement of volatile organic compounds (VOCs) was conducted at Beijing Capital International Airport (ZBAA) and a background reference site in four seasons of 2015. Total concentrations of VOCs were 72.6 +/- 9.7, 65.5 +/- 8.7, 95.8 +/- 11.0, and 79.2 +/- 10.8 MUg/m3 in winter, spring, summer, and autumn, respectively. The most abundant specie was toluene (10.1%-17.4%), followed by benzene, ethane, isopentane, ethane, acetylene, and n-butane. Seasonal variations of VOCs were analyzed, and it was found that the highest concentration occurring in summer, while the lowest in spring. For the diurnal variation, the concentration of VOCs in the daytime (9:00-15:00) was less than that at night (15:00-21:00) obviously. Ozone Formation Potential (OFP) was calculated by using Maximum Incremental Reactivity (MIR) method. The greatest contribution to OFP from alkenes and aromatics, which accounted for 27.3%-51.2% and 36.6%-58.6% of the total OFP. The WRF-CMAQ model was used to simulate the impact of airport emissions on the surrounding area. The results indicated that the maximum impact of VOCs emissions and all sources emissions at the airport on O3 was 0.035 and -23.8 MUg/m3, respectively. Meanwhile, within 1 km from the airport, the concentration of O3 around the airport was greatly affected by airport emitted. PMID- 29604563 TI - Responses of soil organic carbon turnover to nitrogen deposition are associated with nitrogen input rates: Derived from soil 14C evidences. AB - Elevated atmospheric nitrogen (N) deposition has exerted profound influences on ecosystems. Understanding the effects of N deposition on the dynamics of soil organic carbon (SOC) is important in the studies of global carbon cycle. Although many studies have examined the effects of N deposition on SOC turnover using N addition experiments, the effects were reported to be different across studies. Thus, we lack a predictive understanding of how SOC turnover respond to atmospheric N deposition. The inconsistent results could be associated with ecosystem types and N addition rates. This study mainly wants to confirm the argument that the response of SOC turnover to N deposition is related with N input rates. We conducted a field experiment with multiple N addition levels (0, 3, 6, 12, and 24 g N m-2.yr-1) in Inner Mongolia Grassland, China. To better reveal the responses of SOC turnover to N enrichment, this study measured the soil 14C contents, because it can indicate SOC turnover directly. Compared with the control treatment (0 g N m-2.yr-1), N addition inhibits SOC turnover at the addition rate of 3 g N m-2.yr-1, whereas SOC turnover is not affected when N addition rate was 6, 12, and 24 g N m-2.yr-1. Our results suggest that N input rates affect the responses of SOC turnover to N enrichment. Thus, this study can confirm the argument mentioned above. Based on this study, it should be considered in the climate prediction model that varied atmospheric N deposition levels across regions may have different impacts on local SOC turnover. In addition, we also carried out a soil incubation to compare between the results obtained in incubation and that in 14C measurements. Two results are found to be inconsistent with each other. This indicates that soil respiration from incubation experiments could not comprehensively assess the effects of N deposition on SOC turnover. PMID- 29604564 TI - Cultivation of microalgal biomass using swine manure for biohydrogen production: Impact of dilution ratio and pretreatment. AB - This study assessed the impact of swine manure (SM) dilution ratio on the microalgal biomass cultivation and further tested for biohydrogen production efficiency from the mixed microalgal biomass. At first, various solid/liquid (S/L) ratio of the SM ranged from 2.5 to 10 g/L was prepared as a nutrient medium for the algal biomass cultivation without addition of the external nutrient sources over a period of 18 d. The peak biomass concentration of 2.57 +/- 0.03 g/L was obtained under the initial S/L loading rates of 5 g/L. Further, the cultivated biomass was subjected to two-step (ultrasonication + enzymatic) pretreatment and evaluated for biohydrogen production potential. Results showed that the variable amount of hydrogen production was observed with different S/L ratio of the SM. The peak hydrogen yield of 116 +/- 6 mL/g TSadded was observed at the 5 g/L grown SM mixed algal biomass. PMID- 29604565 TI - Improving alpha, omega-dodecanedioic acid productivity from n-dodecane and hydrolysate of Candida cells by membrane integrated repeated batch fermentation. AB - The aim of the present study is to develop an effective production process for alpha, omega-dodecanedioic acid (DC12) biosynthesis using n-dodecane and hydrolysate of Candida cells as substrates by membrane integrated repeated batch fermentation. Cells and n-dodecane were simultaneously recycled during the filtration of fermentation broth (FB) with a 150 kDa ceramic membrane under a cross-flow velocity of 4 m/s and a trans-membrane pressure of 0.2 MPa, and it was also revealed that the cells in the broth could alleviate the membrane fouling during the FB filtration. Moreover, the hydrolysate of the collected cells could be successfully used as a nitrogen source to replace 50% yeast extract for decreasing the DC12 production cost. With repeated-batch culture in a membrane bioreactor, the maximal DC12 productivity could be enhanced by 57.8% compared with the batch culture, meanwhile n-dodecane and cells could be recovered and used for the next fermentation cycle. PMID- 29604566 TI - Cirrhotic patients admitted to the ICU for medical reasons: Analysis of 5506 patients admitted to 286 ICUs in 8years. AB - PURPOSE: To describe characteristics and prognostic factors of cirrhotic patients admitted to a representative sample of Italian intensive care units (ICUs). MATERIALS AND METHODS: All patients admitted to 286 ICUs for medical reasons between 2002 and 2010 (excluding 2007) were considered. A logistic regression model was developed on cirrhotics to predict hospital mortality. The prediction was applied to different subgroups defined by both the level of unit expertise with cirrhotics and the overall unit performance, and compared to the actual mortality. RESULTS: 5506 cirrhotic patients (32.1% admitted to the ICU for non cirrhotic-related reasons) were compared to 130,477 controls. Hospital mortality was higher in cirrhotics (57.2% vs. 35.0%, p<0.001). ICU volume of cirrhotic patients did not influence mortality, while the overall performance of the unit did. The standardized mortality ratio for overall lower-performing units was 1.09 (95%CI: 1.05-1.14), for the average-performing units it was 1.01 (95%CI: 0.98 1.04), for the higher-performing units it was 0.92 (95%CI: 0.89-0.96). CONCLUSIONS: The outcome of critically ill cirrhotic patients is quite poor, but not to limit their admission to the ICU. When cirrhosis accompanies other acute conditions, the general level of intensive care medicine is more important than the specific liver-oriented expertise in treating these patients. PMID- 29604567 TI - Dimeric camptothecin derived phospholipid assembled liposomes with high drug loading for cancer therapy. AB - In this study, a newly liposomal formulation of camptothecin (CPT) based on the dimeric camptothecin glycerophosphorylcholine (di-CPT-GPC) prodrug was developed. The di-CPT-GPC prodrug was synthesized through the heterogeneous conjugation of camptothecin-20 succinate with glycerophosphorylcholine. It undergoes assembly to form liposomes without any excipient through the thin film hydration method, which, confirmed by dynamic light scattering (DLS), have an average diameter of approximately 165 +/- 5 nm. Observations on cryogenic transmission electron microscopy (cryo-TEM) demonstrated that the liposomes possess a typical multilamellar vesicle structure with a bilayer thickness of approximately 4 nm. The liposomes with a CPT loading up to 62 wt% maintained good stability in simulated physiological fluid. This can be attributed to the protection of the liposomes having CPT groups sequestered within the bilayer interior. Moreover, the in vitro release behavior of di-CPT-GPC liposomes was monitored using different media. The results showed that the liposomes could dissociate and sustainably release free active form CPT in a weak acidic environment. In vitro anticancer activity tests indicated that di-CPT-GPC liposomes had comparable cytotoxicity to the parent drug against MCF-7, HeLa and HepG-2 cells. Finally, a preliminary in vivo antitumor evaluation revealed that the liposomes inhibited tumor growth. Taken together, the di-CPT-GPC assembled liposomes with high drug loading could be a promising nanoformulation of CPT. PMID- 29604568 TI - Adsorption characteristics of various proteins on a metal surface in the presence of an external electric potential. AB - The effect of the properties of a protein on its adsorption to a metal surface in the presence of external electric potential was investigated. Protein adsorption processes at different surface potentials were measured for fifteen types of proteins using an in-situ ellipsometry. The tested proteins were classified into three groups, based on the amount of protein that was adsorbed as a function of the surface potential: In First group of proteins, an increasing trend for the amount adsorbed with a more positive surface potential was found; The amount adsorbed of alpha-chymotrypsinogen A and ribonuclease A (Second group) were roughly constant and independent of the applied surface electric potentials; In Third group, the amount adsorbed decreased with increasing surface potential. This protein classification was correlated with the isoelectric points of the proteins (First group: <=9.3; Second group: 9.3-10; Third group: >10). Increasing the pH positively and negatively shifted the surface potentials, allowing beta lactoglobulin (First group) and lysozyme (Third) to become adsorbed, respectively. The surface potential range for protein adsorption was also markedly shifted depending on the metal substrate type. These findings were interpreted based on the electrostatic interactions among the protein, surface hydroxyl groups, and the applied external electric field. PMID- 29604569 TI - Macrophage polarization, inflammatory signaling, and NF-kappaB activation in response to chemically modified titanium surfaces. AB - Functionalization of titanium devices with various bioactive molecules enhances many of their properties as implants, including biocompatibility, which is typically assessed by macrophage activation and inflammation. However, functionalization requires prior introduction of reactive groups, to which bioactive agents can then be grafted. Thus, we investigated the inflammatory properties of titanium pretreated with NaOH, titanium pretreated with NaOH and then with 3-aminopropyl triethoxysilane, and titanium pretreated with dopamine. Inflammation, macrophage polarization, and activation of NF-kappaB signaling were assessed by real-time PCR and western blotting. The data demonstrate that silanized titanium is the least inflammatory, and promotes macrophage M2 polarization with modest engagement of the NF-kappaB signaling pathway. Importantly, silanization introduces a reactive amino group, providing more opportunities for further functionalization. PMID- 29604570 TI - Electrospun epoxy-based nanofibrous membrane containing biocompatible feather polypeptide for highly stable and active covalent immobilization of lipase. AB - In this study, a novel poly (glycidyl methacrylate-co-methylacrylate)/feather polypeptide (P(GMA-co-MA)/FP) nanofibrous membrane containing reactive epoxy groups and biocompatible feather polypeptide (FP) was fabricated by electrospinning which was the first time used for the covalent immobilization of lipase. The results of FTIR spectra and SEM images of nanofibrous membrane before and after immobilization demonstrated that lipase has been successfully covalently immobilized on the nanofibrous membrane. FP was beneficial for the stabilization of the enzyme conformation which would promote the improvement of enzyme activity and stability. The P(GMA-co-MA)/FP-Lipase possesses a wide pH tolerance and high thermal stability, good reuse and organic solvent stability. The residual relative activity of immobilized lipase was about 38% which was treated under 70 degrees C for 3 h. The residual relative activity of immobilized lipase was 62% after 7 reuses and nearly 75% after being treated in methanol for 12 h. This study revealed that the biocompatible FP could be used as an additive to improve the enzyme activity and stability of immobilized enzyme on nanofibrous membranes. PMID- 29604571 TI - Cyclosporin A distribution in cholesterol-sphingomyelin artificial membranes modeled as Langmuir monolayers. AB - Cyclosporin A (CsA), a hydrophobic peptide, mainly known for its immunosuppressant properties, has shown a broad range of biological activities, including antimalarial action. Since CsA was found to be active on membrane level, it was subjected for investigations involving membrane models. Our former studies on interactions between CsA and different membrane lipids using Langmuir monolayer technique indicated its affinity for sphingomyelin (SM). Inspired by this finding we have extended our experiments on multicomponent systems and performed systematic investigations of CsA behavior towards artificial membranes containing different mutual proportion of sphingomyelin and cholesterol (Chol). Langmuir monolayer results have been complemented with in-situ films structure visualization applying Brewster angle microscopy (BAM) and, after films transfer onto solid support, atomic force microscopy (AFM). Our results show that cyclosporin A introduced to SM:Chol mixed monolayers distributes differently, depending on SM-to-Chol proportion. In raft-mimicking (2:1) stoichiometry, even distribution of the drug within SM:Chol matrix was observed. However, in SM:Chol model membranes of different proportion (3:1; 1:1; 1:2), containing either the excess of unbound sphingomyelin or cholesterol in addition to model lipid raft domains, introduction of CsA induced a phase separation. PMID- 29604572 TI - Poly(l-glutamic acid)-g-poly(ethylene glycol) external layer in polyelectrolyte multilayer films: Characterization and resistance to serum protein adsorption. AB - Formation of protein-resistant surfaces is a major challenge in the design of novel biomaterials and an important strategy to prevent protein adsorption is the formation of protein-resistant coatings. It can be achieved by proper modification of surfaces, e.g., by immobilization of hydrophilic polymers such as poly(ethylene glycol) (PEG). An appropriate method to immobilize PEG at charged surfaces is the adsorption of copolymers with PEG chains grafted onto polyelectrolyte backbone. The growing interest in the use of polyelectrolyte multilayer coatings in biomedical applications to improve biocompatibility and/or to prepare coating with antiadhesive properties has been the main reason for these studies. Therefore the aim was to produce protein resistant polyelectrolyte multilayer films. They were formed via the layer-by-layer approach, while their pegylation by the deposition of pegylated polyanion, PGA-g-PEG, as an external layer. The influence of PEG chain length and grafting density of PGA-g-PEG copolymers on the protein antiadhesive properties of pegylated polyelectrolyte multilayer films was investigated. To monitor the formation of pegylated and non pegylated multilayer films, adsorption of the following proteins: HSA, Fibrinogen, and FBS were measured by quartz crystal microbalance (QCM - D). We found that protein adsorption onto all pegylated polyelectrolyte multilayers was significantly reduced in comparison to non-pegylated ones. Long-term performance tests confirmed the stability and the durability of the protein resistant properties of the pegylated multilayers. Antiadhesive properties of tested surfaces pegylated by PGA-g-PEG were compared to the available data for pegylated polycation PLL-g-PEG. PMID- 29604573 TI - Design of polymer particle dispersions (latexes) in the course of radical heterophase polymerization for biomedical applications. AB - Dispersions of polymer particle (DPPs) are increasingly being exploited both as biomolecule carriers, and as markers in various DPP biomedical applications related to cell and molecular biology, enzymology, immunology, diagnostics, in vitro and in vivo visualization, bioseparation, etc. Their potential to reduce reaction scales, lower costs, improve the rate, sensitivity, selectivity, stability and reproducibility of assays governs the diversity of their bioapplications. This review focuses on the design of DPPs with innovative special properties in the course of free radical heterophase polymerization that provides careful control of both macromolecular and colloidal properties. We demonstrate approaches that, according to the polymerization technique, regulate the particle size, shape, particle size distribution, morphology, surface chemistry and functionality, as well as the formation of organic-inorganic hybrid DPPs. The production of bioreagents based on DPPs and their use in bioassay are also reviewed. PMID- 29604574 TI - Phylogeny and Morphology of New Diplonemids from Japan. AB - Diplonemids were recently found to be the most species-rich group of marine planktonic protists. Based on phylogenetic analysis of 18S rRNA gene sequences and morphological observations, we report the description of new members of the genus Rhynchopus - R. humris sp. n. and R. serpens sp. n., and the establishment of two new genera - Lacrimia gen. n. and Sulcionema gen. n., represented by L. lanifica sp. n. and S. specki sp. n., respectively. In addition, we describe the organism formerly designated as Diplonema sp. 2 (ATCC 50224) as Flectonema neradi gen. n., sp. n. The newly described diplonemids share a common set of traits. Cells are sac-like but variable in shape and size, highly metabolic, and surrounded by a naked cell membrane, which is supported by a tightly packed corset of microtubules. They carry a single highly reticulated peripheral mitochondrion containing a large amount of mitochondrial DNA, with lamellar cristae. The cytopharyngeal complex and flagellar pocket are contiguous and have separate openings. Two parallel flagella are inserted sub-apically into a pronounced flagellar pocket. Rhynchopus species have their flagella concealed in trophic stages and fully developed in swimming stages, while they permanently protrude in all other known diplonemid species. PMID- 29604575 TI - Rapid detection and quantification of the potentially toxic cyanobacterium Planktothrix rubescens by in-vivo fluorometry and flow cytometry. AB - We combined profiling of the bloom-forming and potentially toxigenic cyanobacterium Planktothrix rubescens using a multiparameter probe equipped with a phycoerythrin sensor (in vivo fluorometry, IVL) in Lake Mondsee, Austria, with flow cytometric live analyses of discrete samples taken from several depths in the upper 20 m of the water column. Results obtained by IVL and acoustic flow cytometry (AFC) were compared to microscopic analyses of integrated (0-21 m) water samples using fixed material. This comparison was made because the integrated samples are used for the Austrian monitoring programme according to the EU Water Framework Directive. We demonstrate that AFC provides quantitative analyses of the filaments of P. rubescens that are significantly correlated to IVF and microscopic analyses, allowing rapid (within hours) and more precise calculation of P. rubescens biomass than estimates derived from IVL. Our analysis shows that vertically integrated water samples provide unreliable information on the concentration of P. rubescens in the upper surface waters and on the peak concentration of P. rubescens within the water column. We conclude that the protocol that we developed is superior to the current monitoring practice. PMID- 29604576 TI - Sulfide inhibition of nitrite oxidation in activated sludge depends on microbial community composition. AB - Increasingly, technologies that use sulfide as an electron donor are being considered for nitrogen removal; however, our understanding of how sulfide affects microbial communities in nitrifying treatment processes is limited. In this study, we used batch experiments to quantify sulfide inhibition of both ammonium oxidizing bacteria (AOB) and nitrite oxidizing bacteria (NOB) using activated sludge from two full-scale treatment plants with distinct treatment processes. The batch experiments showed that NOB were more vulnerable to sulfide inhibition than AOB, and that inhibition constants (KI) for NOB were distinct between the two treatment plants, which also had distinct nitrite oxidizing microbial communities. A Nitrospira-rich, less diverse NOB community was inhibited more by sulfide than a more diverse community rich in Nitrotoga and Nitrobacter. Therefore, sulfide-induced nitritation may be more successful in less diverse, Nitrospira-rich communities. Additionally, sulfide significantly influenced the activity of non-nitrifying microbial community members, as measured by 16S rRNA cDNA sequencing. Overall, these results indicate that sulfide has a strong impact on both nitrification and the activity of the underlying microbial communities, and that the response is community-specific. PMID- 29604577 TI - Low levels of microplastics (MP) in wild mussels indicate that MP ingestion by humans is minimal compared to exposure via household fibres fallout during a meal. AB - Microplastics (MPs) are the most numerous debris reported in marine environments and assessment of the amounts of MPs that accumulate in wild organisms is necessary for risk assessment. Our objective was to assess MP contamination in mussels collected around the coast of Scotland (UK) to identify characteristics of MPs and to evaluate risk of human exposure to MPs via ingestion of mussels. We deployed caged mussels (Mytilus edulis) in an urbanised estuary (Edinburgh, UK) to assess seasonal changes in plastic pollution, and collected mussels (Mytilus spp and subtidal Modiolus modiolus) from eight sampling stations around Scotland to enumerate MP types at different locations. We determined the potential exposure of humans to household dust fibres during a meal to compare with amounts of MPs present in edible mussels. The mean number of MPs in M. modiolus was 0.086 +/- 0.031 (SE, n = 6)/g ww (3.5 +/- 1.29 (SE) per mussel). In Mytilus spp, the mean number of MPs/g ww was 3.0 +/- 0.9 (SE, n = 36) (3.2 +/- 0.52 (SE) per mussel), but weight dependent. The visual accuracy of plastic fibres identification was estimated to be between 48 and 50%, using Nile Red staining and FT-IR methodologies, respectively, halving the observed amounts of MPs in wild mussels. We observed an allometric relationship between the number of MPs and the mussels wet weight. Our predictions of MPs ingestion by humans via consumption of mussels is 123 MP particles/y/capita in the UK and can go up to 4620 particles/y/capita in countries with a higher shellfish consumption. By comparison, the risk of plastic ingestion via mussel consumption is minimal when compared to fibre exposure during a meal via dust fallout in a household (13,731 68,415 particles/Y/capita). PMID- 29604578 TI - Metabolites of organophosphate ester flame retardants in urine from Shanghai, China. AB - The metabolites of nine organophosphate ester (OPE) flame retardants were measured in 180 urine samples collected from a population (including adults and children) in western Shanghai, China, using liquid chromatography-tandem spectrometry (LC-MS/MS). The total urinary concentrations of nine OPE metabolites ranged 100-23800 pg/mL, with a geometric mean (GM) value of 1450 pg/mL. The concentrations of alkyl-OPE metabolites (879 pg/mL) were approximately an order of magnitude higher than those of aryl-OPE (53.7 pg/mL) and chlorinated-OPE metabolites (52.7 pg/mL). Diphenyl phosphate (DPHP), diethyl phosphate (DEP), di n-butyl phosphate (DNBP), bis(2-ethylhexyl) phosphate (BEHP), and bis(2 butoxyethyl) phosphate (BBOEP) were the dominant OPE metabolites found in urine. The results showed that an increase in age was associated with a significant decrease in urinary DPHP (r = -0.278, p < 0.01) and DNBP (r = -0.314, p < 0.01) concentrations. The highest concentrations of DPHP (GM = 80.7 pg/mL) and DNBP (GM = 16.9 pg/mL) were found in urine from people living in homes that were less than 10 years old. The urinary DNBP concentration was significantly associated with self-reported symptoms of allergy. Our result establishes baseline value for OPE exposure in a population in China for comparison in future studies. PMID- 29604579 TI - Road traffic noise abatement scenarios in Gothenburg 2015 - 2035. AB - Exposure to high levels of road traffic noise at the most exposed building facade is increasing, both due to urbanization and due to overall traffic increase. This study investigated how different noise reduction measures would influence the noise exposure on a city-wide scale in Gothenburg, a city in Sweden with approximately 550,000 inhabitants. Noise exposure was estimated under several different scenarios for the period 2015-2035, using the standardized Nordic noise prediction method together with traffic flow measurements and population statistics. The scenarios were based on reducing speed limits, reducing traffic flows, introducing more electrically powered vehicles and introducing low-noise tires and pavements. The most effective measures were introducing low-noise tires or pavements, which in comparison to business as usual produced between 13% and 29% reduction in the number of inhabitants exposed above 55 dB equivalent level. PMID- 29604580 TI - Filters from taxis air conditioning system: A tool to characterize driver's occupational exposure to bioburden? AB - Bioburden proliferation in filters from air conditioning systems of taxis represents a possible source of occupational exposure. The aim of this study was to determine the occurrence of fungi and bacteria in filters from the air conditioning system of taxis used for patient transportation and to assess the exposure of drivers to bioburden. Filters from the air conditioning systems of 19 taxis and 28 personal vehicles (used as controls) operating in three Portuguese cities including the capital Lisbon, were collected during the winter season. The occurrence and significance of bioburden detected in the different vehicles are reported and discussed in terms of colony-forming units (CFU) per 1 m2 of filter area and by the identification of the most frequently detected fungal isolates based on morphology. Azole-resistant mycobiota, fungal biomass, and molecular detection of Aspergillus species/strains were also determined. Bacterial growth was more prevalent in taxis (63.2%) than in personal vehicles (26.3%), whereas fungal growth was more prevalent in personal vehicles (53.6%) than in taxis (21.1 31.6%). Seven different azole-resistant species were identified in this study in 42.1% taxi filters. Levels of fungal biomass were above the detection limit in 63% taxi filters and in 75% personal vehicle filters. No toxigenic species were detected by molecular analysis in the assessed filters. The results obtained show that bioburden proliferation occurs widely in filters from the air conditioning systems of taxis, including the proliferation of azole-resistant fungal species, suggesting that filters should be replaced more frequently. The use of culture based-methods and molecular tools combined enabled an improved risk characterization in this setting. PMID- 29604581 TI - Synthesis and structure-activity relationship of novel bisindole amidines active against MDR Gram-positive and Gram-negative bacteria. AB - A series of novel diamidines with N-substituents on an amidine N-atom were synthesized and evaluated for their cytotoxicity and in vitro antibacterial activity against a range of Gram-positive and Gram-negative bacterial strains. Based on structure-activity relationship, N-substituents with a branched chain and a shorter carbon chain on the amidine N-atom exhibited more promising activity against Gram-negative and MDR-Gram-positive bacteria; compounds 5c and 5i were the most powerful candidate compounds. Compound 5c showed greater efficacy than levofloxacin against most drug-resistant Gram-positive bacteria and exhibited broad-spectrum antibacterial activity against Gram-negative bacteria, with MIC values in the range of 2-16 MUg/mL. Slightly more potent antibacterial activity against Klebsiella pneumoniae, Acinetobacter calcoaceticus, Enterobacter cloacae, and Proteus mirabilis was observed for 5i in comparison with 5c. Compound 5i also showed remarkable antibacterial activity against NDM-1-producing Gram-negative bacteria, with MIC values in the range of 2-4 MUg/mL, and was superior to the reference drugs meropenem and levofloxacin. Effective antibacterial activity of 5i was also shown in vivo in a mouse model of Staphylococcus aureus MRSA strain, with an ED50values of 2.62 mg/kg. PMID- 29604582 TI - Syntheses and in vitro evaluation of new S1PR1 compounds and initial evaluation of a lead F-18 radiotracer in rodents. AB - Thirteen new sphingosine-1-phosphate receptor 1 (S1PR1) ligands were designed and synthesized by replacing azetidine-3-carboxylic acid moiety of compound 4 with new polar groups. The in vitro binding potency of these new analogs toward S1PR1 was determined. Out of 13 new compounds, four compounds 9a, 10c, 12b, and 16b displayed high S1PR1 binding potency with IC50 values of 13.2 +/- 3.2, 14.7 +/- 1.7, 9.7 +/- 1.6, and 6.3 +/- 1.3 nM, respectively; further binding studies of these four ligands toward S1PR2-5 suggested they are highly selective for S1PR1 over other S1PRs. The radiosynthesis of the lead radiotracer [18F]12b was achieved with good radiochemical yield (~14.1%), high radiochemical purity (>98%), and good specific activity (~54.1 GBq/MUmol, decay corrected to the end of synthesis, EOS). Ex vivo autoradiography and initial biodistribution studies in rodents were performed, suggesting that [18F]12b was able to penetrate the blood-brain barrier (BBB) with high brain uptake (0.71% ID/g at 60 min post injection) and no defluorination was observed. In vitro autoradiography study in brain slices of lipopolysaccharides (LPS)-induced neuroinflammation mice indicated that SEW2871, a specific S1PR1 ligand was able to reduce the uptake of [18F]12b, suggesting [18F]12b has S1PR1 specific binding. These initial results suggested that [18F]12b has potential to be an F-18 labeled radiotracer for imaging S1PR1 in the brain of the animal in vivo. PMID- 29604583 TI - Arylureas derived from colchicine: Enhancement of colchicine oncogene downregulation activity. AB - Our efforts to get therapeutically useful colchicine derivatives for the treatment of cancer have led us to synthetize and biologically evaluate twenty seven N,N'-disubstituted ureas containing a colchicine moiety and an aryl fragment. The cytotoxicity of the compounds, their ability to inhibit the expression of oncogenes related to telomerase activation and to the VEGF/VEGFR-2 autocrine process, such as c-MYC, hTERT and VEGF and their capability to downregulate c-MYC and VEGFR-2 proteins and the secretion of VEGF have been measured. In these biological evaluations, we have found that the change of the acetyl group in colchicines for an N-arylurea unit causes a great improvement in anticancer properties. The most promising derivatives were compounds 6 (o-Cl) and 14 (o,o-di-F) as they were able to downregulate all the tested targets at a concentration below their IC50 values. Thus, the arylurea unit enhances the potential of colchicine as an anticancer agent. PMID- 29604584 TI - New cytokinin derivatives possess UVA and UVB photoprotective effect on human skin cells and prevent oxidative stress. AB - Eleven 6-furfurylaminopurine (kinetin, Kin) derivatives were synthesized to obtain biologically active compounds. The prepared compounds were characterized using 1H NMR, mass spectrometry combined with HPLC purity determination and elemental C, H, N analyses. The biological activity of new derivatives was tested on plant cells and tissues in cytokinin bioassays, such as tobacco callus, detached wheat leaf chlorophyll retention bioassay and Amaranthus bioassay. The selected compounds were subsequently tested on normal human dermal fibroblasts (NHDF) and keratinocyte cell lines (HaCaT) to exclude possible phototoxic effects and, on the other hand, to reveal possible UVA and UVB photoprotective activity. The protective antioxidant activity of the prepared cytokinin derivatives was further studied and compared to previously prepared antisenescent compound 6 furfurylamino-9-(tetrahydrofuran-2-yl)purine (Kin-THF) using induced oxidative stress (OS) on nematode Caenorhabditis elegans damaged by 5-hydroxy-1,4 naphthoquinone (juglone), a generator of reactive oxygen species. The observed biological activity was interpreted in relation to the structure of the prepared derivatives. The most potent oxidative stress protection of all the prepared compounds was shown by 6-(thiophen-2-ylmethylamino)-9-(tetrahydrofuran-2 yl)purine (6) and 2-chloro-6-furfurylamino-9-(tetrahydrofuran-2-yl)purine (9) derivatives and the results were comparable to Kin-THF. Compounds 6 and 9 were able to significantly protect human skin cells against UV radiation in vitro. Both the derivatives 6 and 9 showed higher protective activity in comparison to previously known structurally similar compounds Kin and Kin-THF. The obtained results are surprising due to the fact that the prepared compounds showed to be inactive in the ORAC assay which proved that the compounds did not act as direct antioxidants as they were unable to directly scavenge oxygen radicals. PMID- 29604585 TI - Oncogenic long noncoding RNA MALAT1 and HCV-related hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related mortality worldwide. The oncogenic function of the long non-coding RNA; metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) in HCC remains unclear. We aimed to evaluate MALAT1 serum expression profile in HCC and explore its relation to the clinicopathological features. Quantitative Real Time Polymerase Chain Reaction was applied in 70 cohorts (30 HCC, 20 HCV, 20 controls). Further meta-analysis of clinical studies and in vitro validated experiments was employed. Serum MALAT1 showed area under the curve of 0.79 and 0.70 to distinguish patients with cancer from normal and cirrhotic individuals at fold change of 1.0 and 1.26, respectively. Expression level was significantly higher in males (P <0.001) and patients with massive ascites (P = 0.005). Correlation analysis showed positive correlation of MALAT1 with total bilirubin (r = 0.456, P <0.001) and AST (r = 0.280, P = 0.019), and negative correlation with the hemoglobin level (r = 0.312, P = 0.009). Meta-analysis showed that the over-expressed MALAT1 was linked to tumor number [Cohen's d = 0.450, 95% CI (0.21 to 0.68)], clinical stage [Cohen's d = 0.048, 95% CI (-0.83 to 0.74)], and AFP level [Cohen's d = 0.354, 95% CI (0.1 to 0.57)]. In silico data analysis and systematic review confirmed MALAT1 oncogenic function in cancer development and progression. In conclusion, circulatory MALAT1 might represent a putative non invasive prognostic biomarker indicating worse liver failure score in HCV-related HCC patients with traditional markers. Large-scale verification is warranted in future studies. PMID- 29604586 TI - Inhibitory effect of sinigrin on adipocyte differentiation in 3T3-L1 cells: Involvement of AMPK and MAPK pathways. AB - Adipocyte differentiation is a critical adaptive response to nutritional overload and affects the metabolic outcome of obesity. Sinigrin (2-propenyl glucosinolate) is a glucosinolate belong to the glucoside contained in broccoli, brussels sprouts, and black mustard seeds. We investigated the effects of sinigrin on adipogenesis in 3T3-L1 preadipocytes and its underlying mechanisms. Sinigrin remarkably inhibited the accumulation of lipid droplets and adipogenesis by downregulating the expression of CCAAT-enhancer-binding protein alpha (C/EBPalpha), peroxisome proliferator-activated receptor gamma (PPARgamma), leptin and aP2. Sinigrin arrested cells in the G0/G1 phase of the cell cycle and increased the expression of p21 and p27. CDK2 expression was suppressed by sinigirn in MDI-induced adipocytes. Sinigrin increased the phosphorylation of adenosine monophosphate-activated protein kinase (AMPK), mitogen-activated protein kinase (MAPK) and acetyl-CoA carboxylase (ACC) in the early stage of adipocyte differentiation, suggesting that sinigrin has anti-adipogenic effects through AMPK, MAPK and ACC activation. Sinigrin also inhibited the production of pro-inflammatory cytokines including tumor necrosis factor -alpha (TNF-alpha) and interleukin (IL)-6, IL-1beta and IL-18. Taken together, these data suggest that sinigrin inhibits early-stage adipogenesis of 3T3-L1 adipocytes through the AMPK and MAPK signaling pathways. PMID- 29604587 TI - Apigenin enhances the antitumor effects of cetuximab in nasopharyngeal carcinoma by inhibiting EGFR signaling. AB - Nasopharyngeal carcinoma (NPC) is a type of head and neck cancers with poor prognosis. Despite that platinum-based chemotherapy concurrent with radiotherapy have made great achievements for the treatment of NPC, the therapeutic reaction and toxicity varies dramatically among individuals. Apigenin (API), a naturally occurring plant flavone, is considered to have anti-cancer effect. Cetuximab (CET), a well known epidermal growth factor receptor (EGFR) inhibitor, is widely used in various cancers, especially head and neck cancers. The aim of our study was to measure the combination of API and CET for the treatment of NPC in vitro and in vivo. Results demonstrated that combining API and CET could better suppress the viability of the human nasopharyngeal carcinoma cell lines (HONE1 and CNE2) and inhibit the growth of NPC than API or CET used alone. Besides, the combination of API with CET produced greater pro-apoptosis effect. Moreover, the increased G2/M phase arrest caused by CET could be remarkably enhanced by adding API in HONE1 and CNE2 cells. Although, both API and CET could decrease the expressions of p-EGFR, p-Akt, p-STAT3 and Cyclin D1. Combining them produced greater inhibition effect. These results suggested that the combination of API and CET may be a promising therapeutic approach for the treatment of NPC. PMID- 29604588 TI - Antioxidant effects and mechanism of silymarin in oxidative stress induced cardiovascular diseases. AB - Cardiovascular diseases (CVDs) are considered as the major reason for mortality and morbidity worldwide. Substantial evidence suggests that increased oxidative stress plays a significant role in the pathogenesis of CVDs, including atherosclerosis, hypertension, vascular endothelial dysfunction and ischemic heart disease. Cellular oxidative stress results in the release of toxic free radicals by endothelial cells and vascular smooth muscle cells that interact with cell components such as protein, DNA or lipid resulting in cardiovascular pathology. Silymarin has antioxidant activities against CVDs and offers protection against oxidative stress-induced hypertension, atherosclerosis and cardiac toxicity. We present a comprehensive review regarding the oxidative stress and protective effects of silymarin in CVDs management. We also aim to provide mechanistic insight of the mechanisms of silymarin action in oxidative stress-induced CVDs. PMID- 29604589 TI - Oncosis-like cell death is induced by berberine through ERK1/2-mediated impairment of mitochondrial aerobic respiration in gliomas. AB - Gliomas, the most common primary malignant brain tumor, exhibit high metabolic activity. The targeting of metabolism alterations, particularly in mitochondria, is emerging as an efficient approach for curing cancers. Here, we showed that berberine, a natural compound that is used as an antibacterial agent, could reduce cellular viability and induce oncosis-like death, characterized by cell swelling, cytoplasmic vacuoles and plasma membrane blebbing, in gliomas, and that these effects were correlated with intracellular adenosine triphosphate (ATP) depletion. We also found that berberine induced autophagy as a protective effect and decreased the oxygen consumption rate (OCR), which could inhibit mitochondrial aerobic respiration by repressing phosphorylated extracellular regulated protein kinases (p-ERK1/2). Furthermore, the down-regulation of mitochondrial p-ERK1/2 by berberine inhibited aerobic respiration and led to glycolysis, an inefficient energy production pathway. In addition, berberine reduced tumor growth and inhibited Ki-67 and p-ERK1/2 expression in vivo. The results demonstrate that berberine, which represses aerobic oxidation in mitochondria and decreases their energy production efficiency, decreases metabolic activity by reducing ERK1/2 activity. PMID- 29604590 TI - Nesfatin-1 promotes VSMC migration and neointimal hyperplasia by upregulating matrix metalloproteinases and downregulating PPARgamma. AB - The dedifferentiation, proliferation and migration of vascular smooth muscle cells (VSMCs) are essential in the progression of hypertension, atherosclerosis and intimal hyperplasia. Nesfatin-1 is a potential modulator in cardiovascular functions. However, the role of nesfatin-1 in VSMC biology has not been explored. The present study was designed to determine the regulatory role of nesfatin-1 in VSMC proliferation, migration and intimal hyperplasia after vascular injury. Herein, we demonstrated that nesfatin-1 promoted VSMC phenotype switch from a contractile to a synthetic state, stimulated VSMC proliferation and migration in vitro. At the molecular level, nesfatin-1 upregulated the protein and mRNA levels, as well as the promoter activities of matrix metalloproteinase 2 (MMP-2) and MMP-9, but downregulated peroxisome proliferator-activated receptor gamma (PPARgamma) levels and promoter activity in VSMCs. Blockade of MMP-2/9 or activation of PPARgamma prevented the nesfatin-1-induced VSMC proliferation and migration. In vivo, knockdown of nesfatin-1 ameliorated neointima formation following rat carotid injury. Taken together, our results indicated that nesfatin 1 stimulated VSMC proliferation, migration and neointimal hyperplasia by elevating MMP2/MMP-9 levels and inhibiting PPARgamma gene expression. PMID- 29604591 TI - miR-566 functions as an oncogene and a potential biomarker for prognosis in renal cell carcinoma. AB - BACKGROUND: Renal cell carcinoma (RCC), a heterogeneous type of cancer originating from the nephron, occupies approximately 3.9% of new carcinomas, with an increasing incidence in the past two decades. The most common subtype of renal cell carcinoma is clear cell RCC (ccRCC). Though surgery and other treatments are applied to RCC, it has the highest recurrence rate and mortality rate among the genitourinary cancers. As the study progressed, miRNAs are found to be the biomarkers for tumor diagnosis, prognosis and the targets for tumor management. METHODS: In present study, RT-qPCR, wound scratch assay, cell proliferation assay, transwell assay and flow cytometry assay were performed to ascertain miR 566 expression level and its proliferation, migration and apoptosis in RCC. Moreover, we analyzed the relation between miR-566 expression and clinicopathological variables or overall survival from the 42 formalin-fixed paraffin-embedded (FFPE) renal cancer samples. We further evaluate prognostic values of miR-566 expression. RESULTS: miR-566 is up-regulated in RCC tissue samples and renal carcinoma cell lines. miR-566 promotes cell proliferation, mobility and inhibits cell apoptosis in 786-O and ACHN cell lines. Cox proportional hazard regression analysis indicates that low expression of miR-566 patients have a remarkable longer overall survival in the univariate and multivariate analysis. The Kaplan-Meier survival curves show that the low expression of miR-566 patients have a remarkable longer overall survival. CONCLUSIONS: The results of the current study demonstrate that oncogene miR-566 is a potential biomarker not only for diagnosis but also for prognosis for RCC. PMID- 29604592 TI - Quercus dilatata Lindl. ex Royle ameliorates BPA induced hepatotoxicity in Sprague Dawley rats. AB - Quercus dilatata Lindl. ex Royle was evaluated for in vitro polyphenol content and antioxidant potential as well as in vivo protective role against bisphenol A (BPA) induced hepatotoxicity. The distilled water-acetone (QDDAE) and methanol ethyl acetate (QDMEtE) extracts were standardized and administered in high (300 mg/kg body weight (BW) and low (150 mg/kg BW) doses to Sprague Dawley rats, injected with BPA (25 mg/kg BW). Silymarin (50 mg/kg BW) was used as positive control. Subsequently, blood and liver homogenates were collected after four weeks of treatment, and the defensive effects of both extracts against oxidative damage and genotoxicity were assessed via hematological and biochemical investigations, determination of endogenous expression of enzymes as well as levels of free radicals and comet assay. Between the two extracts, maximum phenolics (213 +/- 0.15 MUg gallic acid equivalent/mg dry extract (DE) and flavonoids (55.6 +/- 0.16 MUg quercetin equivalent/mg DE) content, DPPH scavenging activity (IC50: 8.1 +/- 0.5 MUg/ml), antioxidant capacity (53.7 +/- 0.98 MUg ascorbic acid equivalent (AAE)/mg DE) and reducing potential (228.4 +/- 2.4 MUg AAE/mg DE) were observed in QDMEtE. In in vivo analysis, a dose dependent hepatoprotective activity was exhibited by both the extracts. QDDAE demonstrated maximum reduction in levels of alanine transaminase (49.77 +/- 3.83 U/l), thiobarbituric acid reactant substances (33.46 +/- 0.70 nM/min/mg protein), hydrogen peroxide (18.08 +/- 0.01 ng/mg tissue) and nitrite (55.64 +/- 1.79 MUM/ml), along with decline in erythrocyte sedimentation rate (4.13 +/- 0.072 mm/h), histopathological injuries and DNA damage in BPA intoxicated rats as compared with QDMEtE. Likewise, QDDAE also significantly restored activity levels of endogenous antioxidants, including superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (POD) and GSH with values of 6.46 +/- 0.15 U/mg protein, 6.87 +/- 0.1 U/min, 11.94 +/- 0.17 U/min and 16.86 +/- 1.56 nM/min/mg protein, respectively. Comparative results were obtained for QDMEtE. In conclusion, the present study endorses the significant hepatoprotective potential of standardized extracts of Q. dilatata with known polyphenolics content and validates the traditional use of this plant in natural medicine to manage disorders like hepatotoxicity. PMID- 29604593 TI - Ebselen can Protect Male Reproductive Organs and Male Fertility from Manganese Toxicity: Structural and Bioanalytical Approach in a Rat Model. AB - Ebselen (EBS) is a versatile compound that can protect the cellular components from oxidative and free radical-mediated damage. In the present study, we investigated the protective effect of EBS against manganese (Mn) toxicity on male reproductive organs. Thirty-two male rats were assigned into four groups, namely, negative control, EBS (15 mg/kg body weight (bw), as a single protective IP injection), MnCl2 (50 mg/kg bw, orally for 30 consecutive days), and EBS + MnCl2 (as mentioned before). The results showed that EBS ameliorated the alterations caused by MnCl2 in the testicular, epididymal, and seminal vesicle tissues. MnCl2 increased the sperm abnormalities, decreased gonadosomatic index (GSI), sperm motility, and sperm count. Further, it reduced the serum levels of testosterone (T) and luteinizing hormone (LH). The elevated levels of malondialdehyde (MDA), nitric oxide (NO), and 8-OH-2'-deoxyguanosine (8-OHdG) and decreased the levels of superoxide dismutase (SOD), glutathione (GSH), and catalase (CAT) upon exposure to MnCl2 indicated a disturbance in the activities of the testicular antioxidant enzymes and indices. Histologically, MnCl2 decreased the diameter of seminiferous tubules (ST), the height of germinal epithelium, number of spermatogonia/ST, spermatocytes/ST, spermatids/ST, and Leydig cells/intertubular area (IA). Chemoprotection with EBS successfully mitigated most of the above mentioned parameters concluding that EBS could be used as a useful prophylactic therapy whenever Mn toxicity is involved. PMID- 29604594 TI - LncRNA SNHG20 promotes cell proliferation and invasion via miR-140-5p-ADAM10 axis in cervical cancer. AB - BACKGROUND: Recent studies highlight the crucial regulatory roles of long non coding RNAs (lncRNAs) in carcinogenesis. However, involvement of the lncRNA SNHG20 in cervical cancer progression remains unclear. METHODS: The expression of SNHG20 and miR-140-5p was determined in cervical cancer. Gain or loss of function assays were used to explore the roles of SNHG20 and miR-140-5p in cervical cancer cells. Luciferase assay and Western blot were used to explore the underlying mechanisms of SNHG20 and miR-140-5p in cervical cancer progression. RESULTS: QRT PCR showed that SNHG20 expression was significantly increased in cervical cancer. MiR-140-5p acted as a downstream target of SNHG20. SNHG20 inhibition or miR-140 5p overexpression reduced cervical cancer cells proliferation and invasion ability. Furthermore, we identified that ADAM10 could act as a potential target of miR-140-5p. MEK/ERK signaling could be inhibited by miR-140-5p mimics in cervical cancer cells. In addition, ADAM10 overexpression abrogated the effect of miR-140-5p mimics on cervical cancer cells proliferation and invasion. CONCLUSIONS: Our study demonstrated that SNHG20 could function as an oncogenic lncRNA by regulating miR-140-5p-ADAM10 axis and MEK/ERK signaling pathway in cervical cancer. PMID- 29604595 TI - Ameliorating effects of tempol on methotrexate-induced liver injury in rats. AB - Methotrexate (MTX) is used in the treatment of certain types of cancers and chronic inflammatory illnesses, although the clinical use of MTX is limited due to its adverse effects, the most common of which are hepatotoxicity and nephrotoxicity. In the present study, we demonstrate the protecting influence of tempol related to oxidative stress in MTX-induced liver toxicity in rats using histopathological and biochemical parameters. The rats were divided into four groups: control group (group 1), tempol group (group 2), MTX group (group 3) and MTX + tempol group (group 4). The control group (group 1) received physiological saline for 10 days; the tempol group (group 2) received 30 mg/kg i.p. for 10 days, the MTX group (group 3) received a single dose of 20 mg/kg intraperitoneal (i.p.) on the fourth day of the study, and the MTX + tempol group (group 4) received a single dose of 20 mg/kg i.p. on the fourth day, followed by tempol 30 mg/kg i.p. for 10 days. Malondialdehyde (MDA), myeloperoxidase (MPO), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were found to be significantly lower in the MTX + tempol group then in the MTX group; while superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) levels were found to be higher in the MTX + tempol group than in the MTX group. Tempol ameliorates vacuolic degeneration, inflammation and necrosis in MTX treated rats. Our study demonstrates that tempol treatment after MTX administration ameliorates oxidative damage in liver tissue in rats. PMID- 29604596 TI - Submicron emulsion of cinnamaldehyde ameliorates bleomycin-induced idiopathic pulmonary fibrosis via inhibition of inflammation, oxidative stress and epithelial-mesenchymal transition. AB - AIMS: Idiopathic pulmonary fibrosis (IPF) is the most frequent and severe form of idiopathic interstitial pneumonias. The pathogenesis is associated with inflammation and oxidative stress and epithelial-mesenchymal transition (EMT). Cinnamaldehyde exhibits antiinflammatory and antioxidant properties, but its effect on IPF is unknown. The present study is to investigate the anti-fibrotic effect and action mechanism of cinnamaldehyde on IPF. MATERIALS AND METHODS: IPF was induced by intratracheal bleomycin in mice. Submicron emulsion of cinnamaldehyde was given by intraperitoneal injection once everyday for 7 or 21 continuous days after bleomycin administration. Lung histological and injury indexes were analyzed. The protein expressions of inflammation and oxidative stress as well as EMT markers alpha-smooth muscle actin (alpha-SMA) and E cadherin in mice and cultured A549 cells were measured. RESULTS: Cinnamaldehyde attenuated the bleomycin-induced histological injury, reduced hydroxyproline level and improved pulmonary function by the inhibiting inflammatory cytokines and reactive oxygen species production as well as enhancing total superoxide dismutase activity in bleomycin-induced mice. Cinnamaldehyde also inhibited EMT in both bleomycin-induced mice and TGF-beta1-stimulated A549 cells. CONCLUSIONS: Cinnamaldehyde ameliorated bleomycin-induced IPF via inhibition of inflammation and oxidative stress and EMT. PMID- 29604597 TI - The natural phenolic peperobtusin A induces apoptosis of lymphoma U937 cells via the Caspase dependent and p38 MAPK signaling pathways. AB - Our previous research found the ethyl acetate extract of Peperomia tetraphylla (EAEPT) inhibited the growth of U937 cells by blocking the cell cycle and prompted apoptosis via the reactive oxygen species (ROS)-medicated mitochondria pathway. While the compounds in EAEPT which possessed the anti-tumor activity were unclear. Peperobtusin A is a phenolic compound, which was isolated from the whole plant of Peperomia tetraphylla. In this work, we found that peperobtusin A had the anti-proliferative effects against human lymphoma U937 cells and induced apoptosis in a dose dependent manner. Peperobtusin A significantly enhanced the formation of intracellular ROS and induced the loss of mitochondrial membrane potential (Deltapsim). And peperobtusin A could increase the ratio of Bax/Bcl-2, induce the cleavage of Bid, Caspase-3, Caspase-8 and Caspase-9 and enhance the level of P-P38. Moreover, peperobtusin A induced the accumulation of cells at S phase. Through using of inhibitors such as antioxidant NAC, pan-caspase inhibitor Z-VAD-FMK, p38 MAPK specific inhibitor SB203580, we found that intracellular ROS generation, activation of Caspases and p38 MAPK played very important roles in the apoptosis induced by peperobtusin A in U937 cells. Our results indicated that intracellular ROS generation, the Caspase-dependent and p38 MAPK signaling pathways involved in apoptosis induced by peperobtusin A in U937 cells. PMID- 29604598 TI - Concentration-dependent dual effects of silibinin on kanamycin-induced cells death in Staphylococcus aureus. AB - Silibinin has dual effects on bacteria, depending on the concentrations or living contexts. The mechanism of either action has not yet been elucidated. Present study suggests that silibinin has yinyang impacts on the growth of Staphylococcus aureus depending on doses. S. aureus treated with low concentration of silibinin (L, 6.2 MUM) showed enhanced resistance to kanamycin through increased level of hydrogen peroxide (H2O2). However, S. aureus treated with medium concentration of silibinin (M, 50 MUM) showed increased susceptibility to kanamycin through reduced level of H2O2. These findings suggested that dual effects of silibinin were concentration-dependent and apparently related to the levels of H2O2 that assist bacterial survival at higher concentrations. Interestingly, treatment with high concentration of silibinin (H, 400 MUM) alone without kanamycin exhibited cytotoxicity to S. aureus regardless of H2O2 levels. Based on the findings in vitro, we moved to examine the influence of silibinin on S. aureus-induced mouse peritonitis model. Silibinin at high concentration was shown to enhance the survival of peritonitis mice and protected them from S. aureus-induced tissue injury presumably by antibacterial effect of high concentration of silibinin. When the infected mice were co-treated with kanamycin, bacterial burden and H2O2 levels in lung, liver and spleen were all increased by treatment with a low dose of silibinin, while decreased with a medium dose of silibinin. Thus, the findings highlighted the potential of silibinin to be as a modifying agent in case of antibiotic resistance. PMID- 29604599 TI - Garlic extract favorably modifies markers of endothelial function in obese patients -randomized double blind placebo-controlled nutritional intervention. AB - OBJECTIVE: Garlic exerts a range of effects relevant to human health. However, its influence on the endothelium in obese individuals remains unknown. We aimed to determine the effects of garlic extract (GE) on arterial stiffness and markers of endothelial function. METHODS: Ninety-two subjects were enrolled in this study. The participants were randomly assigned to receive 400 mg of GE or placebo daily for 3 months. The arterial stiffness index (SI) and markers of endothelial function such as high-sensitivity C-reactive protein (hsCRP), cholesterol (total, LDL, HDL), triglycerides, and plasminogen activator inhibitor 1 (PAI-1), as well as total antioxidant status (TAS) were quantified at baseline and the end of study. RESULTS: At the end of study SI (p = 0.01), hsCRP (p < 0.001, PAI-1 (p < 0.001), LDL cholesterol (p < 0.001), and TAS (p < 0.01) were reduced in the GE supplemented group, but not in the placebo group. CONCLUSION: This randomized, double-blind, placebo-controlled trial demonstrates that supplementation with GE favorably modifies endothelial biomarkers associated with cardiovascular risk and suggests that GE can be used to suppress chronic inflammation in obese individuals. PMID- 29604600 TI - Toward universal influenza virus vaccines: from natural infection to vaccination strategy. AB - Conceptually, a universal influenza vaccine should elicit broadly protective antibody responses targeting highly conserved epitope(s) shared by various virus strains. Strategically directing antibody immunity to the conserved hemagglutinin stalk has recently emerged as a promising approach that is substantiated by the identification of naturally occurring, stalk-reactive human antibodies capable of conferring broad protection against influenza virus challenge in animal models. Despite all the advancements, future realization of this strategy still faces many challenges, particularly whether it is able to induce enough of cross reactive antibody response to protect against pandemic viruses. In this respect, recent in-depth dissections of human immune responses to H7N9 virus and vaccination provide much-needed new insights. PMID- 29604601 TI - The increasing burden of cancer attributable to high body mass index in Brazil. AB - BACKGROUND: Body mass index (BMI) has been constantly increasing over the last decades in most parts of the world, most notably in transitioning nations such as Brazil. High BMI (>22 kg/m2) is associated with an increased risk of 14 types of cancer. We estimated the extent to which reducing high BMI could lower cancer incidence in Brazil, nationally as well as at regional and state levels. METHODS: We calculated fractions of cancer incidence in 2012 attributable to high BMI as well as projections for attributable cases in 2025 using BMI data from representative national surveys and relative risks published in meta-analyses. Estimates of cancer incidence were retrieved from GLOBOCAN and the Brazilian National Cancer Institute. RESULTS: We found that 15,465 (3.8%) of all new cancer cases diagnosed in Brazil in 2012 were attributable to high BMI, with a higher burden in women (5.2%) than in men (2.6%). The cancer sites contributing most to the number of attributable cases were breast (n = 4777), corpus uteri (n = 1729), and colon (n = 681) in women, and colon (n = 1062), prostate (n = 926), and liver (n = 651) in men. The highest population attributable fractions (PAFs) for all cancers were found in the richer states of the country, located in the south (1.5% men/3.4% women) and the southeast (1.5% men/3.3% women). CONCLUSIONS: Cancer cases attributable to high BMI will reach 29,490, which will be 4.6% of all cancers in Brazil in 2025; the extent will be greater in women (6.2% or 18,837) than in men (3.2% or 10,653). This information is a tool to support policy makers for future cancer prevention strategies in Brazil. PMID- 29604602 TI - (18F)-FDG-PET/MRI of unicentric retroperitoneal Castleman disease in a pediatric patient. AB - Castleman disease (CD) is a rare lymphoproliferative disorder of unknown etiology that may occur anywhere in the lymphatic system. Imaging plays an important role in detecting and staging this disease. Positron Emission Tomography/Magnetic Resonance Imaging (PET/MRI) combines the metabolic information derived from nuclear medical imaging with the high soft tissue resolution from MRI. We review the features of CD in standard diagnostic imaging, analyze the specific imaging findings of CD in FDG-PET/MRI and discuss a potential benefit of PET/MRI based on the case of a 15-year-old female patient with retroperitoneal CD. PMID- 29604603 TI - Vaginal spindle cell epithelioma: A first complete MRI and histopathologic description. AB - Spindle cell epithelioma of the vagina is a benign entity with fewer than sixty cases described in the literature, and only two with limited imaging findings, since the early 1950s. Early pathology literature suggested the lesions were mixed tumors of myoepithelial origin, but subsequent studies have found relatively few immunohistochemical characteristics in common with other mixed cell tumors. More recently, Mullerian, urogenital sinus epithelial, and pluripotential cell origins have been proposed. Given lesion rarity and a typical lack of imaging before excision, the imaging appearance of vaginal spindle cell epitheliomas has not been fully described in the radiology literature, and without comprehensive pathology correlation. The authors describe a case of spindle cell epithelioma in a 54-year-old woman which was incidentally discovered on MRI performed for uterine fibroid embolization planning. Pathology and immunohistochemistry confirmed the diagnosis. PMID- 29604604 TI - An exploration of peer-assisted learning in undergraduate nursing students in paediatric clinical settings: An ethnographic study. AB - BACKGROUND: Peer-assisted leaning relates to the acquisition of knowledge and skills through shared learning of matched equals. The concept has been explored within the field of nurse education across a range of learning environments, but its impact in practice is still relatively unknown. This paper reports on findings when observing paediatric undergraduate nursing students who engage in PAL within the clinical practice setting. OBJECTIVES: The aim of this paper is to report the findings of a study undertaken to explore peer-assisted learning in undergraduate nursing students, studying children's health, in the clinical practice setting. DESIGN: A qualitative ethnographic study using non-participant observations. SETTINGS: A range of inpatient paediatric clinical settings across two teaching hospitals. PARTICIPANTS: First, second and third year paediatric student nurses enrolled on a Bachelor of Nursing Programme. METHODS: Non participant observations were used to observe a range of interactions between the participants when engaging in peer-assisted learning within the same clinical area. A total of 67 h of raw data collected across all observations was analysed using framework analysis to draw together key themes. RESULTS: Of the 20 identified students across two hospitals, 17 agreed to take part in the study. Findings were aggregated into three key themes; 1. Peers as facilitators to develop learning when engaging in peer-assisted learning, 2. Working together to develop clinical practice and deliver care, 3. Positive support and interaction from peers to enhance networking and develop working structure. CONCLUSIONS: Peer assisted learning in undergraduate children's nursing students stimulates students in becoming engaged in their learning experiences in clinical practice and enhance collaborative support within the working environment. The benefits of peer-assisted learning in current clinical practice settings can be challenging. Therefore, education and practice need to be aware of the benefits and their contribution towards future strategies and models of learning. PMID- 29604605 TI - An evaluation of the effectiveness of nursing students' hand hygiene compliance: A cross-sectional study. PMID- 29604606 TI - Exploring student nurses' attitudes towards those who are obese and whether these attitudes change following a simulated activity. AB - BACKGROUND: As the prevalence of obesity increases worldwide the field of bariatric medicine has emerged, focussing on the causes, prevention and treatment of obesity. People who are obese regularly face bias from healthcare professionals, which can negativity impact on care delivery and patient outcomes. The introduction of bariatric empathy suits into simulated practice may enable student nurses to appreciate the needs of, and influence their attitudes towards, obese people. OBJECTIVES: The aim of this study was to explore student nurses' attitudes towards those who are obese and whether these attitudes change following a simulated activity. DESIGN: A mixed methods study incorporating a pre post design. SETTING: A UK university which provides pre-registration nursing education. PARTICIPANTS: Nursing students in part 1 (n = 39) and part 2 (n = 29) in adult and mental health fields. METHODS: Part 1 and 2 nursing students completed the "Nurses' attitudes towards obesity and obese patients scale" (NATOOPS) questionnaire. Part 2 students also took part in a simulation activity while wearing a bariatric empathy suit and completed the NATOOPS questionnaire again immediately after the simulation activity. Students who wore the empathy suits were invited to a focus group. RESULTS: Part 1 students reported poorer attitudes on the NATOOPS scale than Part 2 students. After wearing the bariatric empathy suits students reported changed attitudes on the NATOOPS in three areas: response to obese patients, characteristics of obese patients and supportive roles in caring for obese patients. Five themes emerged from the focus groups related to physical and psychological impact of the suits; thinking differently; simulation as a learning experience and challenges and recommendations. CONCLUSIONS: Following a structured educational experience student nurses' attitudes were more positive towards obese patients. The characteristics of the educational activity that appeared to influence student nurses' attitudes was related to the "lived experience" of wearing bariatric empathy suits. PMID- 29604607 TI - Inducing tunable host luminescence in Zn2GeO4 tetrahedral materials via doping Cr3. AB - Zn2GeO4 consisting of tetrahedron, and it is a self-luminescent material due to the presence of the native defects and shows a bluish white emission excited by ultraviolet. Although Cr3+ doped in a tetrahedron generally cannot show luminescence, in this research, new defects are formed as Cr3+ doped in Zn2GeO4, hence a green emission band can be obtained. Meanwhile, the intensity of host emission is also decreased. Therefore, Zn2GeO4:Cr3+ are synthesized using a high temperature solid-phase method. Thermoluminescence (TL) and luminescence decay curves are used to investigate the variation of native defects. The emission colour can be tuned from bluish white to green when Cr3+ doped in Zn2GeO4. This result has guidance for controlling the native emission of self-luminescent material. PMID- 29604608 TI - A benzothiazole-based fluorescent probe for hypochlorous acid detection and imaging in living cells. AB - A benzothiazole-based turn-on fluorescent probe with a large Stokes shift (190nm) has been developed for hypochlorous acid detection. The probe displays prompt fluorescence response for HClO with excellent selectivity over other reactive oxygen species as well as a low detection limit of 0.08MUM. The sensing mechanism involves the HClO-induced specific oxidation of oxime moiety of the probe to nitrile oxide, which was confirmed by HPLC-MS technique. Furthermore, imaging studies demonstrated that the probe is cell permeable and can be applied to detect HClO in living cells. PMID- 29604609 TI - The coming of age of EvoMPMI: evolutionary molecular plant-microbe interactions across multiple timescales. AB - Plant-microbe interactions are great model systems to study co-evolutionary dynamics across multiple timescales. However, mechanistic research on plant microbe interactions has often been conducted with little consideration of evolutionary concepts and methods. Conversely, evolutionary research has rarely integrated the range of mechanisms and models from the molecular plant-microbe interactions field. In recent years, the incipient field of evolutionary molecular plant-microbe interactions (EvoMPMI) has emerged to bridge this gap. Here, we report on some of the recent advances in EvoMPMI. In particular, we highlight new systems to study microbe interactions with early diverging land plants, and new findings from studies of adaptive evolution in pathogens and plants. By linking mechanistic and evolutionary research, EvoMPMI promises to expand our understanding of plant-microbe interactions. PMID- 29604610 TI - Long-term outcome after epilepsy surgery in older adults. AB - PURPOSE: The incidence of epilepsy in older adults is growing, as does the incidence of comorbidities. Therefore, when it comes to epilepsy surgery in medically intractable epilepsy, age is often seen as a limiting factor. To investigate the outcome after epilepsy surgery in a population of older adults, we compared the benefit for patients aged 50-59 years with those aged 60 years and older in respect of efficacy and safety. METHOD: Patients aged >=50 years with medically intractable epilepsy who underwent epilepsy surgery from 1990 to 2013 were selected from the database of a German epilepsy center. All of them received a standardised and detailed presurgical diagnostic evaluation. Follow-up included at least four scheduled visits with EEG, MRI and neuropsychological testing. Outcome was assessed using the Engel outcome scale. RESULTS: 79 patients aged between 50 and 67 years were followed-up for a median of 4.7 years (2-16 years). 68% of patients were free of disabling seizures (Engel class I, >=60 years: 75%) and 58% were seizure-free (Engel class IA, >=60 years: 70%). 90% of our patients suffered from temporal lobe epilepsy (TLE), 9% from frontal lobe epilepsy (FLE) and one occipital lobe epilepsy (OLE). After surgery, 9% discontinued or tapered their medication. Permanent surgical complications occurred in 10% of cases and transient neurological deficits were seen in 11%. Older patients had a higher risk for postoperative hygroma (>=60 years 15%; <60 years 8%) and were more prone to postoperative memory deficits (>=60 years 45%), especially after resection of the dominant temporal lobe. Verbal and figural memory testing did not differ significantly between the groups. CONCLUSIONS: The results support the view that in selected older patients, epilepsy surgery shows equal or even higher success rates as compared to younger patients. However, patients of older age may be at greater risk for postoperative hygroma and memory deficits, especially after dominant temporal lobe resections. PMID- 29604611 TI - Controlled semantic cognition relies upon dynamic and flexible interactions between the executive 'semantic control' and hub-and-spoke 'semantic representation' systems. AB - Built upon a wealth of neuroimaging, neurostimulation, and neuropsychology data, a recent proposal set forth a framework termed controlled semantic cognition (CSC) to account for how the brain underpins the ability to flexibly use semantic knowledge (Lambon Ralph et al., 2017; Nature Reviews Neuroscience). In CSC, the 'semantic control' system, underpinned predominantly by the prefrontal cortex, dynamically monitors and modulates the 'semantic representation' system that consists of a 'hub' (anterior temporal lobe, ATL) and multiple 'spokes' (modality specific areas). CSC predicts that unfamiliar and exacting semantic tasks should intensify communication between the 'control' and 'representation' systems, relative to familiar and less taxing tasks. In the present study, we used functional magnetic resonance imaging (fMRI) to test this hypothesis. Participants paired unrelated concepts by canonical colours (a less accustomed task - e.g., pairing ketchup with fire-extinguishers due to both being red) or paired well-related concepts by semantic relationship (a typical task - e.g., ketchup is related to mustard). We found the 'control' system was more engaged by atypical than typical pairing. While both tasks activated the ATL 'hub', colour pairing additionally involved occipitotemporal 'spoke' regions abutting areas of hue perception. Furthermore, we uncovered a gradient along the ventral temporal cortex, transitioning from the caudal 'spoke' zones preferring canonical colour processing to the rostral 'hub' zones preferring semantic relationship. Functional connectivity also differed between the tasks: Compared with semantic pairing, colour pairing relied more upon the inferior frontal gyrus, a key node of the control system, driving enhanced connectivity with occipitotemporal 'spoke'. Together, our findings characterise the interaction within the neural architecture of semantic cognition - the control system dynamically heightens its connectivity with relevant components of the representation system, in response to different semantic contents and difficulty levels. PMID- 29604612 TI - Multivariate assessment of azo dyes' biological activity parameters. AB - Lipophilicity as key molecular descriptor of potential biological activity for selected derivatives of azo dyes was determined mathematically, by using relevant software packages and by reversed-phase thin-layer chromatography (RPTLC) on C18 and cyano modified carriers in mixtures of water/n-propanol and water/acetone. The obtained chromatographic parameters, RM0 and m, of the examined azo dyes were correlated with the standard measure of lipophilicity, log P, important pharmacokinetic predictors and selected toxicity parameters applying linear regression analysis. Thereby, good correlations for each applied system were obtained (average correlation coefficient, r, 0.944, 0.885 and 0.919). Also, the correlations between the studied parameters of azo dyes were examined applying two multivariate methods (Cluster Analysis and Principal Component Analysis). It was shown that the polarity of the substituent, and to a lesser extent its electronic effects has the greatest influence on the studied parameters of the azo dyes derivatives. Multivariate methods pointed out the similarity of the chromatographic retention constant, RM0, with the parameters of lipophilicity, unlike the chromatographic parameter m, which exhibits better agreement with the toxicity parameters. PMID- 29604613 TI - Complementation of UPLC-Q-TOF-MS and CESI-Q-TOF-MS on identification and determination of peptides from bovine lactoferrin. AB - Digested peptides of bovine lactoferrin as the functional hydrolysates were identified by the Q-TOF tandem mass spectrometry (Q-TOF-MS) coupled with ultra performance liquid chromatograph (UPLC) and capillary electrophoresis (CE). The former (UPLC-Q-TOF-MS) identified 106 peptides while the latter (CE-Q-TOF-MS) characterized 102 peptides after comparison of peptides in terms of their molecular weight (MW), mass-to-charge ratio (m/z), and isoelectric point (pI). In addition, the hydrophilic value, net charge (q), and molecular radius (r) of the peptides were calculated, and a correlation analysis of the two methods was conducted between the retention time (RT) and r/q ratio of the peptides in order to elucidate the different separation principles of the unique peptides. It was shown that the peptides with larger hydrophilic value were beneficial to be separated by UPLC, while the peptides with larger r/q ratio were beneficial to be separated by CE. Combination of the above mentioned two complementary techniques have confidently improved the sequence coverage of lactoferrin and enhanced the identification of peptides, which makes it up to 65.8% in this study. PMID- 29604614 TI - Determination of 18 veterinary antibiotics in environmental water using high performance liquid chromatography-q-orbitrap combined with on-line solid-phase extraction. AB - The use of antibiotics and their occurrence in the environment have received significant attention in recent years owing to the generation of antibiotic resistant bacteria. Antibiotic residues in water near livestock farming areas should be monitored to establish effective strategies for reducing the use of veterinary antibiotics. However, environmental water contamination resulting from veterinary antibiotics has not been studied extensively. In this work, we developed an analytical method for the simultaneous determination of multiple classes of veterinary antibiotic residues in environmental water using on-line solid-phase extraction (SPE)-high performance liquid chromatography (HPLC)-high resolution mass spectrometry (HRMS). Eighteen popular antibiotics (eight classes) were selected as target analytes based on veterinary antibiotics sales in South Korea in 2015. The developed method was validated by calibration-curve linearities, precisions, relative recoveries, and method detection limits (MDLs)/limits of quantification (LOQs) of the selected antibiotics, and applied to the analysis of environmental water samples (groundwater, river water, and wastewater-treatment-plant effluent). All calibration curves exhibited r2 > 0.995 with MDLs ranging from 0.2 to 11.9 ng/L. Relative recoveries were between 50 and 150% with coefficients of variation below 20% for all analytes (spiked at 500 ng/L) in groundwater and river water samples. Relative standard deviations (RSDs) of standard-spiked samples were lower than 7% for all antibiotics. The on-line SPE system eliminates human-based SPE errors and affords excellent method reproducibility. Amoxicillin, ampicillin, clopidol, fenbendazole, flumequine, lincomycin, sulfadiazine, and trimethoprim were detected in environmental water samples in concentrations ranging from 1.26 to 127.49 ng/L. The developed method is a reliable analytical technique for the potential routine monitoring of veterinary antibiotics. PMID- 29604615 TI - An innovative method for synthesis of imprinted polymer nanomaterial holding thiamine (vitamin B1) selective sites and its application for thiamine determination in food samples. AB - Thiamine is a highly hydrophilic vitamin which is insoluble in common organic solvents, utilized traditionally for synthesis of molecularly imprinted polymer. In this work a simple strategy is introduced to overcome the insolubility problem of thiamine and prepare an efficient MIP in chloroform. Thiamine, as a cationic agent, involved in an ion-pair complex with anionic species of trimethylsilyl propane sulfonate (TPS). The ion-pair was then transferred effectively to apolar solvent of chloroform where the polymerization reaction was conducted to produce nano-sized thiamine imprinted polymer. The experimental conditions such as pH, ionic strength and carrier agent/thiamine mole ratio were optimized to maximize the thiamine amount, transported to chloroform. The characteristics of the polymer were investigated by FT-IR, SEM and Zeta potential analysis techniques. The experimental adsorption isotherms of thiamine onto MIP and non-imprinted polymer (NIP) were determined and well fitted by Langmuir-Freundlich model. Maximum binding capacities of the MIP and NIP materials were obtained as 106.1 and 35.7 MUmol g-1, respectively. After investigation and fixing of the experimental conditions on thiamine extraction by the MIP, it was successfully utilized for thiamine extraction from food samples and its determination by fluorimetric method. PMID- 29604616 TI - A porous graphitized carbon LC-ESI/MS method for the quantitation of metronidazole and fluconazole in breast milk and human plasma. AB - Information on drug transfer into the breast milk is essential to protect the infant from undesirable adverse effects of maternal consumption of drugs and to allow effective pharmacological treatment of breastfeeding mothers. Metronidazole and fluconazole are two drugs frequently used in nursing women to treat various infections, thus questioning infant's safety due to drug exposure through breast milk. In this article a porous graphitized carbon LC/ESI-MS assay was developed for the quantitation of metronidazole and fluconazole in breast milk and human plasma. The assay was based on the use of 150 MUL of biological samples, following acetonitrile precipitation of proteins and filtration that enabled injection into the LC/ESI-MS system. All analytes and the internal standard, ropinirole, were separated by using a porous graphitized carbon analytical column (150 * 2.1 mm i.d., particle size 5 MUm) with isocratic elution. The mobile phase consists of 55% acetonitrile in water acidified with 0.1% concentrated formic acid and pumped at a flow rate of 0.25 mL min-1. The assay was linear over a concentration range of 0.1 to 15 MUg mL-1 for all analytes in both biological samples. Intermediate precision was found to be <8.4% over the tested concentration ranges. A run time of <5 min for each sample made it possible to analyze a large number of biological samples per day. The method is the first reported application for the analysis of metronidazole and fluconazole in both breast milk and human plasma and it can be used to support a wide range of clinical studies. PMID- 29604617 TI - Foot posture development in children aged 5 to11 years: A three-year prospective study. AB - BACKGROUND: The paediatric flatfoot is a common presentation but it is unclear whether the condition will resolve on its own as the child gets older or whether treatment is required. Therefore, the study objective was to evaluate paediatric foot posture, and anthropometry, in children at two time points, three years apart. MATERIAL AND METHODS: A sample of 1032 healthy children (505 boys, 527 girls; aged 5-11 years) was recruited for foot posture index (FPI) and anthropometry assessment (weight, height and body mass index, BMI). Assessment was repeated when the children were aged 8 years to 14 years. Paired t-tests, Anova, frequency tables and a multiple regressions were conducted. RESULTS: Initially, approximately 70% had a neutral FPI range, 20% pronated, 3% highly pronated, and 4% supinated. Initial mean FPI was 3.6 +/- 2.8, being higher in boys 3.7 +/- 2.8 than in girls 3.4 +/- 2.7 (p = 0.034). All FPI categories changed over time, with supinated and neutral FPI increased by 19.5% and 4.7% respectively. In contrast, pronated and highly pronated FPI reduced by 10.6% and 55.6% respectively. Regression showed only 1% FPI change was explained by increased height. FPI scores were significantly reduced after three years (3.57 to 3.33; p < 0.001). CONCLUSION: Children's foot posture shifts toward neutral as age increases. There is minimal relationship with weight, height or BMI. Appreciation of developing foot posture could reduce over diagnosis and unnecessary treatment of paediatric flatfeet. PMID- 29604618 TI - An open prospective pilot study of a herbal combination "Relief" as a supportive dietetic measure during alcohol withdrawal. AB - OBJECTIVE: A herbal combination (saffron extract, passion flower herb extract, cocoa seed extract, radish extract and black cumin extract) called "Relief" was designed as a supportive therapy of alcohol withdrawal syndrome (AWS). This combination was based on the scientific evidence of each constituent effect on AWS-like symptoms. In addition, our preclinical studies have shown the effectiveness of Relief on AWS detoxification. The rationale of the study was to document whether the oral intake of the designed content of Relief could have a positive effect on the course of alcohol detoxification by reducing some of the AWS in hospitalized patients. METHODS: This pilot study was performed as non interventional, open, single-armed, prospective on 32 hospitalized patients entered for detoxification of alcohol withdrawal syndrome. Each patient received daily three capsules of Relief for 15 days, and AWS parameters were monitored, in addition to serum liver enzymes and quality of life which was evaluated using the Befindlichkeits-Skala (Bf-SR) scaling system. RESULTS: Relief administration significantly reduced the percentage of patients with hyperhidrosis (r=0.815, p<0.001), reduced serum liver enzymes by ~50-80% (p<0.05), and increased normalization of appetite (r=0.777, p<0.001). Besides, before the treatment began the Bf-SR scale was 28.3+/-4.3, which was typical for neurological syndromes such as depression or insomnia, and during Relief administration the Bf-SR scale significantly dropped to 15.6+/-2.4 (p<0.001). As for the safety, four, but not serious, adverse events were observed; two of them may be product related. Finally, 84.4% of patients' assessed Relief treatment as good to excellent and 87.5% of the patients declared an interest in reusing Relief for the next detoxification period. CONCLUSIONS: Despite the limitations of the present study, the findings showed the potential of Relief for the improvement of the clinical situation of patients with symptoms of alcohol withdrawal and therefore, justify a full-scale well-controlled study design to be implemented. PMID- 29604619 TI - Positive and negative symptoms in schizophrenia and their relation to depression, anxiety, hope, self-stigma and personality traits - a cross-sectional study. AB - OBJECTIVE: The purpose of the investigation was to explore the relationship between positive or negative symptoms, social anxiety, hope, personality, and self-stigma in patients with schizophrenia spectrum disorders. METHOD: 57 outpatients took part in this cross-sectional study. The structured interview M.I.N.I. International Neuropsychiatric Interview was used to confirm the diagnosis. All patients completed the Liebowitz Social Anxiety Scale, Internalized Stigma of Mental Illness Scale, Beck Depression Inventory-II, Beck Anxiety Inventory, Adult Dispositional Hope Scale, and Temperament and Character Inventory - Revised. The disorder severity was evaluated by Clinical Global Impression - Severity scale, and Positive and Negative Syndrome Scale. The patients were in a stabilized state that did not require hospitalization or modifications in the treatment. RESULTS: Both positive and negative symptoms of schizophrenia positively correlated with the length of the disorder, global severity of the disorder, the severity of the general and social anxiety symptoms, the severity of self-stigma, and negatively with personality traits Self-directedness and Cooperativeness. Only negative symptoms significantly positively correlated with the severity of depressive symptoms and personality trait Harm-avoidance and negatively with the hope and personality trait Persistence. Comorbidity with social phobia is associated with statistically significantly higher mean scores on the total score of schizophrenic symptomatology, negative subscale average rating, and general psychopathological items measured by PANSS. Patient with comorbid depression would experience a higher level of negative symptomatology than patients without such comorbidity. PMID- 29604620 TI - Supplementation of Caricol(r)-Gastro reduces chronic gastritis disease associated pain. AB - OBJECTIVE: Papaya and oats are natural food and used in traditional medicine in many parts of the world. Papaya has a high content of enzymes supporting digestive function. Oats are a source of minerals, beta-glucan fibres, immunmodulatory and antiinflammatory probiotic substances. Caricol(r)-Gastro combines both constituents, it was designed as vegan organic preparation for intestinal inflammatory diseases. We performed a randomized, double blind placebo controlled clinical trial to investigate the potential of Caricol(r)-Gastro as add on therapy in patients with diagnosed chronic gastritis. METHODS: 60 Patients with endoscopically confirmed mild chronic disease were recruited. A structured interview documented the baseline data. Then the patients were allocated to the verum or placebo group by handing out a numbered study package with the study substance for the daily intake at home. A single dose was 20 g, taken twice per day. After 30 days the participants were interviewed again. RESULTS: After the intake phase the disease related symptoms were found improved in both groups, indicating a strong placebo effect. However, the pain load reduction in the Caricol(r)-Gastro group was significantly larger (p=0.048). DISCUSSION: Due to the inherent biological activities of ingredients of papaya and of oats and their known effects (anti-inflammatory, epithelial integrity), the observed beneficial effects may be owed to the constituents synergisms to reduce chronic inflammation. We conclude, that the regular intake is a safe add on therapeutic option for patients with chronic gastritis to support standard medical care. PMID- 29604621 TI - ECDC Vibrio Map Viewer: Tracking the Whereabouts of Pathogenic Species. PMID- 29604622 TI - Rate-induced tipping from periodic attractors: Partial tipping and connecting orbits. AB - We consider how breakdown of the quasistatic approximation for attractors can lead to rate-induced tipping, where a qualitative change in tracking/tipping behaviour of trajectories can be characterised in terms of a critical rate. Associated with rate-induced tipping (where tracking of a branch of quasistatic attractors breaks down), we find a new phenomenon for attractors that are not simply equilibria: partial tipping of the pullback attractor where certain phases of the periodic attractor tip and others track the quasistatic attractor. For a specific model system with a parameter shift between two asymptotically autonomous systems with periodic attractors, we characterise thresholds of rate induced tipping to partial and total tipping. We show these thresholds can be found in terms of certain periodic-to-periodic and periodic-to-equilibrium connections that we determine using Lin's method for an augmented system. PMID- 29604623 TI - Complex contagions with timers. AB - There has been a great deal of effort to try to model social influence-including the spread of behavior, norms, and ideas-on networks. Most models of social influence tend to assume that individuals react to changes in the states of their neighbors without any time delay, but this is often not true in social contexts, where (for various reasons) different agents can have different response times. To examine such situations, we introduce the idea of a timer into threshold models of social influence. The presence of timers on nodes delays adoptions i.e., changes of state-by the agents, which in turn delays the adoptions of their neighbors. With a homogeneously-distributed timer, in which all nodes have the same amount of delay, the adoption order of nodes remains the same. However, heterogeneously-distributed timers can change the adoption order of nodes and hence the "adoption paths" through which state changes spread in a network. Using a threshold model of social contagions, we illustrate that heterogeneous timers can either accelerate or decelerate the spread of adoptions compared to an analogous situation with homogeneous timers, and we investigate the relationship of such acceleration or deceleration with respect to the timer distribution and network structure. We derive an analytical approximation for the temporal evolution of the fraction of adopters by modifying a pair approximation for the Watts threshold model, and we find good agreement with numerical simulations. We also examine our new timer model on networks constructed from empirical data. PMID- 29604624 TI - Supply network science: Emergence of a new perspective on a classical field. AB - Supply networks emerge as companies procure goods from one another to produce their own products. Due to a chronic lack of data, studies on these emergent structures have long focussed on local neighbourhoods, assuming simple, chain like structures. However, studies conducted since 2001 have shown that supply chains are indeed complex networks that exhibit similar organisational patterns to other network types. In this paper, we present a critical review of theoretical and model based studies which conceptualise supply chains from a network science perspective, showing that empirical data do not always support theoretical models that were developed, and argue that different industrial settings may present different characteristics. Consequently, a need that arises is the development and reconciliation of interpretation across different supply network layers such as contractual relations, material flow, financial links, and co-patenting, as these different projections tend to remain in disciplinary siloes. Other gaps include a lack of null models that show whether the observed properties are meaningful, a lack of dynamical models that can inform how layers evolve and adopt to changes, and a lack of studies that investigate how local decisions enable emergent outcomes. We conclude by asking the network science community to help bridge these gaps by engaging with this important area of research. PMID- 29604625 TI - Geometric k-nearest neighbor estimation of entropy and mutual information. AB - Nonparametric estimation of mutual information is used in a wide range of scientific problems to quantify dependence between variables. The k-nearest neighbor (knn) methods are consistent, and therefore expected to work well for a large sample size. These methods use geometrically regular local volume elements. This practice allows maximum localization of the volume elements, but can also induce a bias due to a poor description of the local geometry of the underlying probability measure. We introduce a new class of knn estimators that we call geometric knn estimators (g-knn), which use more complex local volume elements to better model the local geometry of the probability measures. As an example of this class of estimators, we develop a g-knn estimator of entropy and mutual information based on elliptical volume elements, capturing the local stretching and compression common to a wide range of dynamical system attractors. A series of numerical examples in which the thickness of the underlying distribution and the sample sizes are varied suggest that local geometry is a source of problems for knn methods such as the Kraskov-Stogbauer-Grassberger estimator when local geometric effects cannot be removed by global preprocessing of the data. The g knn method performs well despite the manipulation of the local geometry. In addition, the examples suggest that the g-knn estimators can be of particular relevance to applications in which the system is large, but the data size is limited. PMID- 29604626 TI - Multistability and tipping: From mathematics and physics to climate and brain Minireview and preface to the focus issue. AB - Multistability refers to the coexistence of different stable states in nonlinear dynamical systems. This phenomenon has been observed in laboratory experiments and in nature. In this introduction, we briefly introduce the classes of dynamical systems in which this phenomenon has been found and discuss the extension to new system classes. Furthermore, we introduce the concept of critical transitions and discuss approaches to distinguish them according to their characteristics. Finally, we present some specific applications in physics, neuroscience, biology, ecology, and climate science. PMID- 29604627 TI - A model of spreading of sudden events on social networks. AB - Information spreading has been studied for decades, but its underlying mechanism is still under debate, especially for those ones spreading extremely fast through the Internet. By focusing on the information spreading data of six typical events on Sina Weibo, we surprisingly find that the spreading of modern information shows some new features, i.e., either extremely fast or slow, depending on the individual events. To understand its mechanism, we present a susceptible-accepted recovered model with both information sensitivity and social reinforcement. Numerical simulations show that the model can reproduce the main spreading patterns of the six typical events. By this model, we further reveal that the spreading can be speeded up by increasing either the strength of information sensitivity or social reinforcement. Depending on the transmission probability and information sensitivity, the final accepted size can change from continuous to discontinuous transition when the strength of the social reinforcement is large. Moreover, an edge-based compartmental theory is presented to explain the numerical results. These findings may be of significance on the control of information spreading in modern society. PMID- 29604628 TI - Rotor-angle versus voltage instability in the third-order model for synchronous generators. AB - We investigate the interplay of rotor-angle and voltage stability in electric power systems. To this end, we carry out a local stability analysis of the third order model which entails the classical power-swing equations and the voltage dynamics. We provide necessary and sufficient stability conditions and investigate different routes to instability. For the special case of a two-bus system, we analytically derive a global stability map. PMID- 29604629 TI - Emergence, evolution, and control of multistability in a hybrid topological quantum/classical system. AB - We present a novel class of nonlinear dynamical systems-a hybrid of relativistic quantum and classical systems and demonstrate that multistability is ubiquitous. A representative setting is coupled systems of a topological insulator and an insulating ferromagnet, where the former possesses an insulating bulk with topologically protected, dissipationless, and conducting surface electronic states governed by the relativistic quantum Dirac Hamiltonian and the latter is described by the nonlinear classical evolution of its magnetization vector. The interactions between the two are essentially the spin transfer torque from the topological insulator to the ferromagnet and the local proximity induced exchange coupling in the opposite direction. The hybrid system exhibits a rich variety of nonlinear dynamical phenomena besides multistability such as bifurcations, chaos, and phase synchronization. The degree of multistability can be controlled by an external voltage. In the case of two coexisting states, the system is effectively binary, opening a door to exploitation for developing spintronic memory devices. Because of the dissipationless and spin-momentum locking nature of the surface currents of the topological insulator, little power is needed for generating a significant current, making the system appealing for potential applications in next generation of low power memory devices. PMID- 29604630 TI - Dynamic behavior of combustion instability in a cylindrical combustor with an off center installed coaxial injector. AB - We have intensively studied the dynamic behavior of combustion instability in a cylindrical combustor with an off-center installed coaxial injector. The most interesting discovery in this study is the appearance of a deterministic chaos in a transition from a dynamically stable state to well-developed high-frequency thermoacoustic combustion oscillations with increasing the volume flow rate of nitrogen with which oxygen is diluted. The presence of deterministic chaos is reasonably identified by considering an extended version of the Sugihara-May algorithm [G. Sugihara and R. May, Nature 344, 734 (1990)] as a local predictor and the multiscale complexity-entropy causality plane based on statistical complexity. PMID- 29604632 TI - Information geometric methods for complexity. AB - Research on the use of information geometry (IG) in modern physics has witnessed significant advances recently. In this review article, we report on the utilization of IG methods to define measures of complexity in both classical and, whenever available, quantum physical settings. A paradigmatic example of a dramatic change in complexity is given by phase transitions (PTs). Hence, we review both global and local aspects of PTs described in terms of the scalar curvature of the parameter manifold and the components of the metric tensor, respectively. We also report on the behavior of geodesic paths on the parameter manifold used to gain insight into the dynamics of PTs. Going further, we survey measures of complexity arising in the geometric framework. In particular, we quantify complexity of networks in terms of the Riemannian volume of the parameter space of a statistical manifold associated with a given network. We are also concerned with complexity measures that account for the interactions of a given number of parts of a system that cannot be described in terms of a smaller number of parts of the system. Finally, we investigate complexity measures of entropic motion on curved statistical manifolds that arise from a probabilistic description of physical systems in the presence of limited information. The Kullback-Leibler divergence, the distance to an exponential family and volumes of curved parameter manifolds, are examples of essential IG notions exploited in our discussion of complexity. We conclude by discussing strengths, limits, and possible future applications of IG methods to the physics of complexity. PMID- 29604631 TI - Artificial neural network detects human uncertainty. AB - Artificial neural networks (ANNs) are known to be a powerful tool for data analysis. They are used in social science, robotics, and neurophysiology for solving tasks of classification, forecasting, pattern recognition, etc. In neuroscience, ANNs allow the recognition of specific forms of brain activity from multichannel EEG or MEG data. This makes the ANN an efficient computational core for brain-machine systems. However, despite significant achievements of artificial intelligence in recognition and classification of well-reproducible patterns of neural activity, the use of ANNs for recognition and classification of patterns in neural networks still requires additional attention, especially in ambiguous situations. According to this, in this research, we demonstrate the efficiency of application of the ANN for classification of human MEG trials corresponding to the perception of bistable visual stimuli with different degrees of ambiguity. We show that along with classification of brain states associated with multistable image interpretations, in the case of significant ambiguity, the ANN can detect an uncertain state when the observer doubts about the image interpretation. With the obtained results, we describe the possible application of ANNs for detection of bistable brain activity associated with difficulties in the decision-making process. PMID- 29604633 TI - Leaking in history space: A way to analyze systems subjected to arbitrary driving. AB - Our aim is to unfold phase space structures underlying systems with a drift in their parameters. Such systems are non-autonomous and belong to the class of non periodically driven systems where the traditional theory of chaos (based e.g., on periodic orbits) does not hold. We demonstrate that even such systems possess an underlying topological horseshoe-like structure at least for a finite period of time. This result is based on a specifically developed method which allows to compute the corresponding time-dependent stable and unstable foliations. These structures can be made visible by prescribing a certain type of history for an ensemble of trajectories in phase space and by analyzing the trajectories fulfilling this constraint. The process can be considered as a leaking in history space-a generalization of traditional leaking, a method that has become widespread in traditional chaotic systems, to leaks depending on time. PMID- 29604634 TI - Crises, noise, and tipping in the Hassell population model. AB - We consider a problem of the analysis of the noise-induced tipping in population systems. To study this phenomenon, we use Hassell-type system with Allee effect as a conceptual model. A mathematical investigation of the tipping is connected with the analysis of the crisis bifurcations, both boundary and interior. In the parametric study of the abrupt changes in dynamics related to the noise-induced extinction and transition from order to chaos, the stochastic sensitivity function technique and confidence domains are used. The effectiveness of the suggested approach to detect early warnings of critical stochastic transitions is demonstrated. PMID- 29604635 TI - Asymmetry in electrical coupling between neurons alters multistable firing behavior. AB - The role of asymmetry in electrical synaptic connection between two neuronal oscillators is studied in the Hindmarsh-Rose model. We demonstrate that the asymmetry induces multistability in spiking dynamics of the coupled neuronal oscillators. The coexistence of at least three attractors, one chaotic and two periodic orbits, for certain coupling strengths is demonstrated with time series, phase portraits, bifurcation diagrams, basins of attraction of the coexisting states, Lyapunov exponents, and standard deviations of peak amplitudes and interspike intervals. The experimental results with analog electronic circuits are in good agreement with the results of numerical simulations. PMID- 29604636 TI - Scaling tunable network model to reproduce the density-driven superlinear relation. AB - Previous works have shown the universality of allometric scaling under total and density values at the city level, but our understanding of the size effects of regions on the universality of allometric scaling remains inadequate. Here, we revisit the scaling relations between the gross domestic production (GDP) and the population based on the total and density values and first reveal that the allometric scaling under density values for different regions is universal. The scaling exponent beta under the density value is in the range of (1.0, 2.0], which unexpectedly exceeds the range observed by Pan et al. [Nat. Commun. 4, 1961 (2013)]. For the wider range, we propose a network model based on a 2D lattice space with the spatial correlation factor alpha as a parameter. Numerical experiments prove that the generated scaling exponent beta in our model is fully tunable by the spatial correlation factor alpha. Our model will furnish a general platform for extensive urban and regional studies. PMID- 29604637 TI - Riddled basins of attraction in systems exhibiting extreme events. AB - Using a system of two FitzHugh-Nagumo units, we demonstrate the occurrence of riddled basins of attraction in delay-coupled systems as the coupling between the units is increased. We characterize riddled basins using the uncertainty exponent which is a measure of the dimensions of the basin boundary. Additionally, we show that the phase space can be partitioned into pure and mixed regions, where initial conditions in the pure regions certainly avoid the generation of extreme events, while initial conditions in the mixed region may or may not exhibit such events. This implies that any tiny perturbation of initial conditions in the mixed region could yield the emergence of extreme events because the latter state possesses a riddled basin of attraction. PMID- 29604638 TI - Fast and unbiased estimator of the time-dependent Hurst exponent. AB - We combine two existing estimators of the local Hurst exponent to improve both the goodness of fit and the computational speed of the algorithm. An application with simulated time series is implemented, and a Monte Carlo simulation is performed to provide evidence of the improvement. PMID- 29604639 TI - Dynamic modes in a network of five oscillators with inhibitory all-to-all pulse coupling. AB - The dynamic modes of five almost identical oscillators with pulsatile inhibitory coupling with time delay have been studied theoretically. The models of the Belousov-Zhabotinsky reaction and phase oscillators with all-to-all coupling have been considered. In the parametric plane Cinh-tau, where Cinh is the coupling strength and tau is the time delay between a spike in one oscillator and pulsed perturbations of all other oscillators, three main regimes have been found: regular modes, when each oscillator gives only one spike during the global period T, C (complex) modes, when the number of pulses of different oscillators is different, and OS (oscillations-suppression) modes, when at least one oscillator is suppressed. The regular modes consist of several cluster modes and are found at relatively small Cinh. The C and OS modes observed at larger Cinh intertwine in the Cinh-tau plane. In a relatively narrow range of Cinh, the dynamics of the C modes are very sensitive to small changes in Cinh and tau, as well as to the initial conditions, which are the characteristic features of the chaos. On the other hand, the dynamics of the C modes are periodic (but with different periods) and well reproducible. The number of different C modes is enormously large. At still larger Cinh, the C modes lose sensitivity to small changes in the parameters and finally vanish, while the OS modes survive. PMID- 29604640 TI - Sensitivity analysis of the noise-induced oscillatory multistability in Higgins model of glycolysis. AB - A phenomenon of the noise-induced oscillatory multistability in glycolysis is studied. As a basic deterministic skeleton, we consider the two-dimensional Higgins model. The noise-induced generation of mixed-mode stochastic oscillations is studied in various parametric zones. Probabilistic mechanisms of the stochastic excitability of equilibria and noise-induced splitting of randomly forced cycles are analysed by the stochastic sensitivity function technique. A parametric zone of supersensitive Canard-type cycles is localized and studied in detail. It is shown that the generation of mixed-mode stochastic oscillations is accompanied by the noise-induced transitions from order to chaos. PMID- 29604641 TI - Long-range fluctuations and multifractality in connectivity density time series of a wind speed monitoring network. AB - This paper studies the daily connectivity time series of a wind speed-monitoring network using multifractal detrended fluctuation analysis. It investigates the long-range fluctuation and multifractality in the residuals of the connectivity time series. Our findings reveal that the daily connectivity of the correlation based network is persistent for any correlation threshold. Further, the multifractality degree is higher for larger absolute values of the correlation threshold. PMID- 29604642 TI - Quenching oscillating behaviors in fractional coupled Stuart-Landau oscillators. AB - Oscillation quenching has been widely studied during the past several decades in fields ranging from natural sciences to engineering, but investigations have so far been restricted to oscillators with an integer-order derivative. Here, we report the first study of amplitude death (AD) in fractional coupled Stuart Landau oscillators with partial and/or complete conjugate couplings to explore oscillation quenching patterns and dynamics. It has been found that the fractional-order derivative impacts the AD state crucially. The area of the AD state increases along with the decrease of the fractional-order derivative. Furthermore, by introducing and adjusting a limiting feedback factor in coupling links, the AD state can be well tamed in fractional coupled oscillators. Hence, it provides one an effective approach to analyze and control the oscillating behaviors in fractional coupled oscillators. PMID- 29604643 TI - On multistability behavior of unstable dissipative systems. AB - We present dissipative systems with unstable dynamics called the unstable dissipative systems which are capable of generating a multi-stable behavior, i.e., depending on its initial condition, the trajectory of the system converges to a specific attractor. Piecewise linear (PWL) systems are generated based on unstable dissipative systems, whose main attribute when they are switched is the generation of chaotic trajectories with multiple wings or scrolls. For this PWL system, a structure is proposed where both the linear part and the switching function depend on two parameters. We show the range of values of such parameters where the PWL system presents a multistable behavior and trajectories with multiscrolls. PMID- 29604644 TI - Adiabatic decay of internal solitons due to Earth's rotation within the framework of the Gardner-Ostrovsky equation. AB - The adiabatic decay of different types of internal wave solitons caused by the Earth's rotation is studied within the framework of the Gardner-Ostrovsky equation. The governing equation describing such processes includes quadratic and cubic nonlinear terms, as well as the Boussinesq and Coriolis dispersions: (ut + c ux + alpha u ux + alpha1 u2 ux + beta uxxx)x = gamma u. It is shown that at the early stage of evolution solitons gradually decay under the influence of weak Earth's rotation described by the parameter gamma. The characteristic decay time is derived for different types of solitons for positive and negative coefficients of cubic nonlinearity alpha1 (both signs of that parameter may occur in the oceans). The coefficient of quadratic nonlinearity alpha determines only a polarity of solitary wave when alpha1 < 0 or the asymmetry of solitary waves of opposite polarity when alpha1 > 0. It is found that the adiabatic theory describes well the decay of solitons having bell-shaped profiles. In contrast to that, large amplitude table-top solitons, which can exist when alpha1 is negative, are structurally unstable. Under the influence of Earth's rotation, they transfer first to the bell-shaped solitons, which decay then adiabatically. Estimates of the characteristic decay time of internal solitons are presented for the real oceanographic conditions. PMID- 29604645 TI - Entropy-based generating Markov partitions for complex systems. AB - Finding the correct encoding for a generic dynamical system's trajectory is a complicated task: the symbolic sequence needs to preserve the invariant properties from the system's trajectory. In theory, the solution to this problem is found when a Generating Markov Partition (GMP) is obtained, which is only defined once the unstable and stable manifolds are known with infinite precision and for all times. However, these manifolds usually form highly convoluted Euclidean sets, are a priori unknown, and, as it happens in any real-world experiment, measurements are made with finite resolution and over a finite time span. The task gets even more complicated if the system is a network composed of interacting dynamical units, namely, a high-dimensional complex system. Here, we tackle this task and solve it by defining a method to approximately construct GMPs for any complex system's finite-resolution and finite-time trajectory. We critically test our method on networks of coupled maps, encoding their trajectories into symbolic sequences. We show that these sequences are optimal because they minimise the information loss and also any spurious information added. Consequently, our method allows us to approximately calculate the invariant probability measures of complex systems from the observed data. Thus, we can efficiently define complexity measures that are applicable to a wide range of complex phenomena, such as the characterisation of brain activity from electroencephalogram signals measured at different brain regions or the characterisation of climate variability from temperature anomalies measured at different Earth regions. PMID- 29604646 TI - Effect of time-delay and dissipative coupling on amplitude death in coupled thermoacoustic oscillators. AB - We here systematically investigate amplitude death (AD) phenomenon in a thermoacoustic system using a mathematical model of coupled prototypical thermoacoustic oscillators, the horizontal Rijke tubes. AD has recently been identified as a relatively simple phenomenon, which can be exploited to stop the unwanted high amplitude pressure oscillations resulting from the occurrence of thermoacoustic instability. We examine the effect of time-delay and dissipative couplings on a system of two Rijke tubes when they are symmetrically and asymmetrically coupled. The regions where appropriate combinations of delay time, detuning, and the strengths of time-delay and dissipative coupling lead to AD are identified. The relative ease of attaining AD when both the couplings are applied simultaneously is inferred from the model. In the presence of strong enough coupling, AD is observed even when the oscillators of dissimilar amplitudes are coupled, while a significant reduction in the amplitudes of both the oscillators is observed when the coupling strength is not enough to attain AD. PMID- 29604647 TI - Reconstructing latent dynamical noise for better forecasting observables. AB - I propose a method for reconstructing multi-dimensional dynamical noise inspired by the embedding theorem of Muldoon et al. [Dyn. Stab. Syst. 13, 175 (1998)] by regarding multiple predictions as different observables. Then, applying the embedding theorem by Stark et al. [J. Nonlinear Sci. 13, 519 (2003)] for a forced system, I produce time series forecast by supplying the reconstructed past dynamical noise as auxiliary information. I demonstrate the proposed method on toy models driven by auto-regressive models or independent Gaussian noise. PMID- 29604648 TI - Implications of tristability in pattern-forming ecosystems. AB - Many ecosystems show both self-organized spatial patterns and multistability of possible states. The combination of these two phenomena in different forms has a significant impact on the behavior of ecosystems in changing environments. One notable case is connected to tristability of two distinct uniform states together with patterned states, which has recently been found in model studies of dryland ecosystems. Using a simple model, we determine the extent of tristability in parameter space, explore its effects on the system dynamics, and consider its implications for state transitions or regime shifts. We analyze the bifurcation structure of model solutions that describe uniform states, periodic patterns, and hybrid states between the former two. We map out the parameter space where these states exist, and note how the different states interact with each other. We further focus on two special implications with ecological significance, breakdown of the snaking range and complex fronts. We find that the organization of the hybrid states within a homoclinic snaking structure breaks down as it meets a Maxwell point where simple fronts are stationary. We also discover a new series of complex fronts between the uniform states, each with its own velocity. We conclude with a brief discussion of the significance of these findings for the dynamics of regime shifts and their potential control. PMID- 29604649 TI - Detecting, anticipating, and predicting critical transitions in spatially extended systems. AB - A data-driven linear framework for detecting, anticipating, and predicting incipient bifurcations in spatially extended systems based on principal oscillation pattern (POP) analysis is discussed. The dynamics are assumed to be governed by a system of linear stochastic differential equations which is estimated from the data. The principal modes of the system together with corresponding decay or growth rates and oscillation frequencies are extracted as the eigenvectors and eigenvalues of the system matrix. The method can be applied to stationary datasets to identify the least stable modes and assess the proximity to instability; it can also be applied to nonstationary datasets using a sliding window approach to track the changing eigenvalues and eigenvectors of the system. As a further step, a genuinely nonstationary POP analysis is introduced. Here, the system matrix of the linear stochastic model is time dependent, allowing for extrapolation and prediction of instabilities beyond the learning data window. The methods are demonstrated and explored using the one dimensional Swift-Hohenberg equation as an example, focusing on the dynamics of stochastic fluctuations around the homogeneous stable state prior to the first bifurcation. The POP-based techniques are able to extract and track the least stable eigenvalues and eigenvectors of the system; the nonstationary POP analysis successfully predicts the timing of the first instability and the unstable mode well beyond the learning data window. PMID- 29604650 TI - Detection of generalized synchronization using echo state networks. AB - Generalized synchronization between coupled dynamical systems is a phenomenon of relevance in applications that range from secure communications to physiological modelling. Here, we test the capabilities of reservoir computing and, in particular, echo state networks for the detection of generalized synchronization. A nonlinear dynamical system consisting of two coupled Rossler chaotic attractors is used to generate temporal series consisting of time-locked generalized synchronized sequences interleaved with unsynchronized ones. Correctly tuned, echo state networks are able to efficiently discriminate between unsynchronized and synchronized sequences even in the presence of relatively high levels of noise. Compared to other state-of-the-art techniques of synchronization detection, the online capabilities of the proposed Echo State Network based methodology make it a promising choice for real-time applications aiming to monitor dynamical synchronization changes in continuous signals. PMID- 29604651 TI - The influence of environmental forcing on biodiversity and extinction in a resource competition model. AB - In this paper, we study a model of many species that compete, directly or indirectly, for a pool of common resources under the influence of periodic, stochastic, and/or chaotic environmental forcing. Using numerical simulations, we find the number and sequence of species going extinct when the community is initially packed with a large number of species of random initial densities. Thereby, any species with a density below a given threshold is regarded to be extinct. PMID- 29604652 TI - Describing chaotic attractors: Regular and perpetual points. AB - We study the concepts of regular and perpetual points for describing the behavior of chaotic attractors in dynamical systems. The idea of these points, which have been recently introduced to theoretical investigations, is thoroughly discussed and extended into new types of models. We analyze the correlation between regular and perpetual points, as well as their relation with phase space, showing the potential usefulness of both types of points in the qualitative description of co existing states. The ability of perpetual points in finding attractors is indicated, along with its potential cause. The location of chaotic trajectories and sets of considered points is investigated and the study on the stability of systems is shown. The statistical analysis of the observing desired states is performed. We focus on various types of dynamical systems, i.e., chaotic flows with self-excited and hidden attractors, forced mechanical models, and semiconductor superlattices, exhibiting the universality of appearance of the observed patterns and relations. PMID- 29604653 TI - Weight of fitness deviation governs strict physical chaos in replicator dynamics. AB - Replicator equation-a paradigm equation in evolutionary game dynamics mathematizes the frequency dependent selection of competing strategies vying to enhance their fitness (quantified by the average payoffs) with respect to the average fitnesses of the evolving population under consideration. In this paper, we deal with two discrete versions of the replicator equation employed to study evolution in a population where any two players' interaction is modelled by a two strategy symmetric normal-form game. There are twelve distinct classes of such games, each typified by a particular ordinal relationship among the elements of the corresponding payoff matrix. Here, we find the sufficient conditions for the existence of asymptotic solutions of the replicator equations such that the solutions-fixed points, periodic orbits, and chaotic trajectories-are all strictly physical, meaning that the frequency of any strategy lies inside the closed interval zero to one at all times. Thus, we elaborate on which of the twelve types of games are capable of showing meaningful physical solutions and for which of the two types of replicator equation. Subsequently, we introduce the concept of the weight of fitness deviation that is the scaling factor in a positive affine transformation connecting two payoff matrices such that the corresponding one-shot games have exactly same Nash equilibria and evolutionary stable states. The weight also quantifies how much the excess of fitness of a strategy over the average fitness of the population affects the per capita change in the frequency of the strategy. Intriguingly, the weight's variation is capable of making the Nash equilibria and the evolutionary stable states, useless by introducing strict physical chaos in the replicator dynamics based on the normal form game. PMID- 29604654 TI - Stochastic mixed-mode oscillations in a three-species predator-prey model. AB - The effect of demographic stochasticity, in the form of Gaussian white noise, in a predator-prey model with one fast and two slow variables is studied. We derive the stochastic differential equations (SDEs) from a discrete model. For suitable parameter values, the deterministic drift part of the model admits a folded node singularity and exhibits a singular Hopf bifurcation. We focus on the parameter regime near the Hopf bifurcation, where small amplitude oscillations exist as stable dynamics in the absence of noise. In this regime, the stochastic model admits noise-driven mixed-mode oscillations (MMOs), which capture the intermediate dynamics between two cycles of population outbreaks. We perform numerical simulations to calculate the distribution of the random number of small oscillations between successive spikes for varying noise intensities and distance to the Hopf bifurcation. We also study the effect of noise on a suitable Poincare map. Finally, we prove that the stochastic model can be transformed into a normal form near the folded node, which can be linked to recent results on the interplay between deterministic and stochastic small amplitude oscillations. The normal form can also be used to study the parameter influence on the noise level near folded singularities. PMID- 29604655 TI - Supply network configuration-A benchmarking problem. AB - Managing supply networks is a highly relevant task that strongly influences the competitiveness of firms from various industries. Designing supply networks is a strategic process that considerably affects the structure of the whole network. In contrast, supply networks for new products are configured without major adaptations of the existing structure, but the network has to be configured before the new product is actually launched in the marketplace. Due to dynamics and uncertainties, the resulting planning problem is highly complex. However, formal models and solution approaches that support supply network configuration decisions for new products are scant. The paper at hand aims at stimulating related model-based research. To formulate mathematical models and solution procedures, a benchmarking problem is introduced which is derived from a case study of a cosmetics manufacturer. Tasks, objectives, and constraints of the problem are described in great detail and numerical values and ranges of all problem parameters are given. In addition, several directions for future research are suggested. PMID- 29604656 TI - Spectral simplicity of apparent complexity. I. The nondiagonalizable metadynamics of prediction. AB - Virtually all questions that one can ask about the behavioral and structural complexity of a stochastic process reduce to a linear algebraic framing of a time evolution governed by an appropriate hidden-Markov process generator. Each type of question-correlation, predictability, predictive cost, observer synchronization, and the like-induces a distinct generator class. Answers are then functions of the class-appropriate transition dynamic. Unfortunately, these dynamics are generically nonnormal, nondiagonalizable, singular, and so on. Tractably analyzing these dynamics relies on adapting the recently introduced meromorphic functional calculus, which specifies the spectral decomposition of functions of nondiagonalizable linear operators, even when the function poles and zeros coincide with the operator's spectrum. Along the way, we establish special properties of the spectral projection operators that demonstrate how they capture the organization of subprocesses within a complex system. Circumventing the spurious infinities of alternative calculi, this leads in the sequel, Part II [P. M. Riechers and J. P. Crutchfield, Chaos 28, 033116 (2018)], to the first closed form expressions for complexity measures, couched either in terms of the Drazin inverse (negative-one power of a singular operator) or the eigenvalues and projection operators of the appropriate transition dynamic. PMID- 29604657 TI - Dynamics of a parametrically excited simple pendulum. AB - The dynamics of a parametric simple pendulum submitted to an arbitrary angle of excitation phi was investigated experimentally by simulations and analytically. Analytical calculations for the loci of saddle-node bifurcations corresponding to the creation of resonant orbits were performed by applying Melnikov's method. However, this powerful perturbative method cannot be used to predict the existence of odd resonances for a vertical excitation within first order corrections. Yet, we showed that period-3 resonances indeed exist in such a configuration. Two degenerate attractors of different phases, associated with the same loci of saddle-node bifurcations in parameter space, are reported. For tilted excitation, the degeneracy is broken due to an extra torque, which was confirmed by the calculation of two distinct loci of saddle-node bifurcations for each attractor. This behavior persists up to phi~7pi/180, and for inclinations larger than this, only one attractor is observed. Bifurcation diagrams were constructed experimentally for phi=pi/8 to demonstrate the existence of self excited resonances (periods smaller than three) and hidden oscillations (for periods greater than three). PMID- 29604658 TI - The role of community structure on the nature of explosive synchronization. AB - In this paper, we analyze explosive synchronization in networks with a community structure. The results of our study indicate that the mesoscopic structure of the networks could affect the synchronization of coupled oscillators. With the variation of three parameters, the degree probability distribution exponent, the community size probability distribution exponent, and the mixing parameter, we could have a fast or slow phase transition. Besides, in some cases, we could have communities which are synchronized inside but not with other communities and vice versa. We also show that there is a limit in these mesoscopic structures which suppresses the transition from the second-order phase transition and results in explosive synchronization. This could be considered as a tuning parameter changing the transition of the system from the second order to the first order. PMID- 29604659 TI - Transient chaos in the Lorenz-type map with periodic forcing. AB - We consider a case study of perturbing a system with a boundary crisis of a chaotic attractor by periodic forcing. In the static case, the system exhibits persistent chaos below the critical value of the control parameter but transient chaos above the critical value. We discuss what happens to the system and particularly to the transient chaotic dynamics if the control parameter periodically oscillates. We find a non-exponential decaying behavior of the survival probability function, study the impact of the forcing frequency and amplitude on the escape rate, analyze the phase-space image of the observed dynamics, and investigate the influence of initial conditions. PMID- 29604660 TI - Stable amplitude chimera states in a network of locally coupled Stuart-Landau oscillators. AB - We investigate the occurrence of collective dynamical states such as transient amplitude chimera, stable amplitude chimera, and imperfect breathing chimera states in a locally coupled network of Stuart-Landau oscillators. In an imperfect breathing chimera state, the synchronized group of oscillators exhibits oscillations with large amplitudes, while the desynchronized group of oscillators oscillates with small amplitudes, and this behavior of coexistence of synchronized and desynchronized oscillations fluctuates with time. Then, we analyze the stability of the amplitude chimera states under various circumstances, including variations in system parameters and coupling strength, and perturbations in the initial states of the oscillators. For an increase in the value of the system parameter, namely, the nonisochronicity parameter, the transient chimera state becomes a stable chimera state for a sufficiently large value of coupling strength. In addition, we also analyze the stability of these states by perturbing the initial states of the oscillators. We find that while a small perturbation allows one to perturb a large number of oscillators resulting in a stable amplitude chimera state, a large perturbation allows one to perturb a small number of oscillators to get a stable amplitude chimera state. We also find the stability of the transient and stable amplitude chimera states and traveling wave states for an appropriate number of oscillators using Floquet theory. In addition, we also find the stability of the incoherent oscillation death states. PMID- 29604661 TI - Spectral simplicity of apparent complexity. II. Exact complexities and complexity spectra. AB - The meromorphic functional calculus developed in Part I overcomes the nondiagonalizability of linear operators that arises often in the temporal evolution of complex systems and is generic to the metadynamics of predicting their behavior. Using the resulting spectral decomposition, we derive closed-form expressions for correlation functions, finite-length Shannon entropy-rate approximates, asymptotic entropy rate, excess entropy, transient information, transient and asymptotic state uncertainties, and synchronization information of stochastic processes generated by finite-state hidden Markov models. This introduces analytical tractability to investigating information processing in discrete-event stochastic processes, symbolic dynamics, and chaotic dynamical systems. Comparisons reveal mathematical similarities between complexity measures originally thought to capture distinct informational and computational properties. We also introduce a new kind of spectral analysis via coronal spectrograms and the frequency-dependent spectra of past-future mutual information. We analyze a number of examples to illustrate the methods, emphasizing processes with multivariate dependencies beyond pairwise correlation. This includes spectral decomposition calculations for one representative example in full detail. PMID- 29604662 TI - Array invariant-based calibration of array tilt using a source of opportunity. AB - The array invariant, a robust approach to source-range estimation in shallow water, is based on the dispersion characteristics of broadband signals in ideal waveguides. It involves time-domain plane-wave beamforming using a vertical line array (VLA) to separate multiple coherent arrivals in beam angle and travel time. Typically, a probe signal (i.e., a cooperating source) is required to estimate the Green's function, but the array invariant has been recently extended to a ship of opportunity radiating random signals using a ray-based blind deconvolution [Byun, Kim, Cho, Song, and Byun, J. Acoust. Soc. Am. 142, EL286 EL291 (2017)]. Still, one major drawback is its sensitivity to the array tilt, shifting the beam angles and adversely affecting the array invariant parameter that determines the source range. In this paper, a simple optimization algorithm for simultaneous estimation of the array tilt and the source range is presented. The method is applied to a ship of opportunity (200-900 Hz) circling around a 56 m long VLA at a speed of 3 knots (1.5 m/s) at ranges of 1.8-3.6 km in approximately 100-m deep shallow water. It is found that the standard deviation of the relative range error significantly reduces to about 4%, from 14% with no compensation of the array tilt. The estimated tilt angle displayed as a function of the ship's azimuth angle reveals that the VLA is tilted about 3 degrees towards the northwest, suggesting that the array invariant can serve as a remote sensing technique for calibration of the array tilt using a source of opportunity. PMID- 29604663 TI - Environmental inversion using dispersion tracking in a shallow water environment. AB - It has been previously shown using synthetic data that dispersion tracking with particle filtering can be used for sediment sound speed inversion. Here, dispersion tracking is performed with data collected in the Gulf of Mexico for sediment sound speed and thickness and water column depth estimation. In this experiment, sound that propagates a long distance from the source allows the identification of dispersion curves reflecting the different group velocities of modal frequencies within and across modes. Although the data are noisy, dispersion curves are tracked with sequential filtering and used for inversion. Probability density functions of the three unknown parameters are obtained. Water column depth is estimated with little uncertainty. The estimated sound speed is representative of sandy sediment and the sediment thickness matches to a large extent prior knowledge. PMID- 29604664 TI - The effect of resonance on transient microbubble acoustic response: Experimental observations and numerical simulations. AB - A large number of acoustic signals from single lipid-shelled Definity(r) (Lantheus Medical Imaging, N. Billerica, MA) microbubbles have been measured using a calibrated microacoustic system, and a unique transient characteristic of resonance has been identified in the onset of scatter. Comparison of the numerically obtained response of microbubbles with acoustic measurements provides good agreement for a soft shell that is characterized by small area dilatation modulus and strain softening behavior, and identifies time to maximum radial excursion and scatter as a robust marker of resonance during transient response. As the sound amplitude increases a two-population pattern emerges in the time delay vs the fundamental acoustic scatter plots, consisting of an initial part pertaining to microbubbles with less than resonant rest radii, which corresponds to the weaker second harmonic resonance, and the dominant resonant envelope pertaining to microbubbles with resonant and greater than resonant rest radii, which corresponds to the primary and subharmonic resonances. Consequently, a wider resonant spectrum is observed. It is a result of the strain softening nature of soft lipid shells, based on which the microbubble sizes corresponding to the above resonances decrease as the sound amplitude increases. This bares an impact on the selection of an optimal microbubble size pertaining to subharmonic imaging. PMID- 29604665 TI - Replacement of sensor cables for reducing effects on articulation in the Northern Digital Incorporated's Wave electromagnetic articulography system. AB - This study attempted to improve the five-degrees-of-freedom sensors of the Northern Digital Incorporated's Wave electromagnetic articulography system by replacing their cables with thinner and more flexible cables to reduce interference in articulation. Measurement errors and data loss rates were compared between the original and the proposed sensors. The proposed sensors showed twofold tracking accuracy and data loss rates compared to the original sensors in an experiment using a crank-rocker mechanism. Data loss rates of the proposed sensors increased in articulatory data collection from four speakers. The proposed sensors have been made available commercially. PMID- 29604666 TI - Experimental characterization of the propagation of guided acoustic waves in pipe strings. AB - This paper experimentally characterizes the propagation of guided acoustic waves in pipe strings. It verifies through experiments the dispersion phenomenon in cylindrical waveguides and shows how it matches the expected theoretical results that were previously derived in the literature and also experimentally confirms that pipe strings have certain passbands and stopbands that will allow signals with certain frequencies to propagate and will inhibit others. The theoretical dispersion relation was computed for frequencies between 0 and 5 kHz. Then, an experimental testbed was used to produce measured results which were found to agree nicely with the theoretical results. PMID- 29604667 TI - Extrapolation of rotating sound fields. AB - A method is presented for the computation of the acoustic field around a tonal circular source, such as a rotor or propeller, based on an exact formulation which is valid in the near and far fields. The only input data required are the pressure field sampled on a cylindrical surface surrounding the source, with no requirement for acoustic velocity or pressure gradient information. The formulation is approximated with exponentially small errors and appears to require input data at a theoretically minimal number of points. The approach is tested numerically, with and without added noise, and demonstrates excellent performance, especially when compared to extrapolation using a far-field assumption. PMID- 29604668 TI - Active room compensation for sound reinforcement using sound field separation techniques. AB - This work investigates how the sound field created by a sound reinforcement system can be controlled at low frequencies. An indoor control method is proposed which actively absorbs the sound incident on a reflecting boundary using an array of secondary sources. The sound field is separated into incident and reflected components by a microphone array close to the secondary sources, enabling the minimization of reflected components by means of optimal signals for the secondary sources. The method is purely feed-forward and assumes constant room conditions. Three different sound field separation techniques for the modeling of the reflections are investigated based on plane wave decomposition, equivalent sources, and the Spatial Fourier transform. Simulations and an experimental validation are presented, showing that the control method performs similarly well at enhancing low frequency responses with the three sound separation techniques. Resonances in the entire room are reduced, although the microphone array and secondary sources are confined to a small region close to the reflecting wall. Unlike previous control methods based on the creation of a plane wave sound field, the investigated method works in arbitrary room geometries and primary source positions. PMID- 29604669 TI - Investigating the status of a rare cross-linguistic contrast: The case of Romanian palatalized postalveolars. AB - This study examines a rare cross-linguistic contrast, that between plain and secondarily palatalized postalveolar fricatives, through (i) an acoustic analysis of the production of 31 Romanian speakers, and (ii) a perception experiment with a different group of 31 native speakers. Evidence of acoustic separation between plain and palatalized forms was found for 27 of the subjects, suggesting that the contrast is produced by the majority. This is consistent with previous reports of native speakers collected in 1961. These findings were supported by the results of the perceptual experiment, which showed that native speakers exhibit moderate sensitivity to this contrast. An examination of each of the two genders' production separately suggests that a process of neutralization may be in progress, more strongly realized by males compared to females. Aside from documenting this phenomenon in Romanian, an explanation is sought for its longevity, and it is proposed that grammatical restructuring offers the best account for the observed facts. PMID- 29604670 TI - Continuously steerable second-order differential microphone arrays. AB - This paper proposes a second-order differential microphone array (DMA) that can continuously steer in the main lobe direction. First, a general response of the second-order DMA is derived as a linear combination of a monopole and dipoles. Nine- and seven-microphone systems are proposed to realize continuous steering of the second-order DMA. The proposed system synthesizes the steered beam pattern without requiring the phase shifter by using back-to-back cardioids. Simulation results show that the nine-microphone configuration yields a nearly constant and high white noise gain, but the seven-microphone configuration has the practical advantage that it requires fewer microphones. PMID- 29604671 TI - Effects of reverberation and noise on speech intelligibility in normal-hearing and aided hearing-impaired listeners. AB - Many hearing-aid wearers have difficulties understanding speech in reverberant noisy environments. This study evaluated the effects of reverberation and noise on speech recognition in normal-hearing listeners and hearing-impaired listeners wearing hearing aids. Sixteen typical acoustic scenes with different amounts of reverberation and various types of noise maskers were simulated using a loudspeaker array in an anechoic chamber. Results showed that, across all listening conditions, speech intelligibility of aided hearing-impaired listeners was poorer than normal-hearing counterparts. Once corrected for ceiling effects, the differences in the effects of reverberation on speech intelligibility between the two groups were much smaller. This suggests that, at least, part of the difference in susceptibility to reverberation between normal-hearing and hearing impaired listeners was due to ceiling effects. Across both groups, a complex interaction between the noise characteristics and reverberation was observed on the speech intelligibility scores. Further fine-grained analyses of the perception of consonants showed that, for both listener groups, final consonants were more susceptible to reverberation than initial consonants. However, differences in the perception of specific consonant features were observed between the groups. PMID- 29604672 TI - Forced sound transmission through a finite-sized single leaf panel subject to a point source excitation. AB - In the case of a point source in front of a panel, the wavefront of the incident wave is spherical. This paper discusses spherical sound waves transmitting through a finite sized panel. The forced sound transmission performance that predominates in the frequency range below the coincidence frequency is the focus. Given the point source located along the centerline of the panel, forced sound transmission coefficient is derived through introducing the sound radiation impedance for spherical incident waves. It is found that in addition to the panel mass, forced sound transmission loss also depends on the distance from the source to the panel as determined by the radiation impedance. Unlike the case of plane incident waves, sound transmission performance of a finite sized panel does not necessarily converge to that of an infinite panel, especially when the source is away from the panel. For practical applications, the normal incidence sound transmission loss expression of plane incident waves can be used if the distance between the source and panel d and the panel surface area S satisfy d/S>0.5. When d/S ~0.1, the diffuse field sound transmission loss expression may be a good approximation. An empirical expression for d/S=0 is also given. PMID- 29604674 TI - The effect of sentential context on phonetic categorization is modulated by talker accent and exposure. AB - Higher-level factors, including the contextual plausibility of competing word candidates, interact with lower-level phonetic cues to influence how listeners interpret the speech signal. This work shows that listeners' phonetic categorization (e.g., coat versus goat) is more heavily influenced by sentential context when listening to a non-native versus native talker. Further, the effect of context on phonetic categorization decreases as the listener becomes familiar with the talker's phonetic characteristics, for both native and non-native talkers. Overall, results suggest that listeners adjust their perceptual strategies to optimize accurate perception of a talker's message. PMID- 29604673 TI - Accuracy of the quantities measured by four vocal dosimeters and its uncertainty. AB - Although vocal dosimeters are often used for long-term voice monitoring, the uncertainty of the quantities measured by these devices is not always stated. In this study, two common vocal dosimetry quantities, mean vocal sound pressure level and mean vocal fundamental frequency, were measured by four vocal dosimeters (VocaLog2, VoxLog, Voice Care, and APM3200). The expanded uncertainty of the mean error in the estimation of these two quantities as measured by the four dosimeters was performed by simultaneously comparing signals acquired through a reference microphone and the devices themselves. Dosimeters, assigned in random order, were worn by the participants (22 vocally healthy adults), along with a head-mounted microphone, which acted as a reference. For each device, participants produced a sustained /a/ vowel four times and then read a text with three different vocal efforts (relaxed, normal, and raised). The measurement uncertainty was obtained by comparing data from the microphone and the dosimeters. The mean vocal sound pressure level was captured the most accurately by the Voice Care and the VoxLog while the APM3200 was the least accurate. The most accurate mean vocal fundamental frequency was estimated by the Voice Care and the APM3200, while the VoxLog was the least accurate. PMID- 29604675 TI - Effects of nonlinear frequency compression on the acoustic properties and recognition of speech sounds in Mandarin Chinese. AB - The present study examined the change in spectral properties of Mandarin vowels and fricatives caused by nonlinear frequency compression (NLFC) used in hearing instruments and how these changes affect the perception of speech sounds in normal-hearing listeners. Speech materials, including a list of Mandarin monosyllables in the form of /dV/ (12 vowels) and /Ca/ (five fricatives), were recorded from 20 normal-hearing, native Mandarin-speaking adults (ten males and ten females). NLFC was based on Phonak SoundRecover algorithms. The speech materials were processed with six different NLFC parameter settings. Detailed acoustic analysis revealed that the high front vowel /i/ and certain compound vowels containing /i/ demonstrated positional deviation in certain processed conditions in comparison to the unprocessed condition. All five fricatives showed acoustic changes in spectral features in all processed conditions. Fourteen Mandarin-speaking, normal-hearing adult listeners performed phoneme recognition with the six NLFC processing conditions. When the cut-off frequency was set relatively low, recognition of /s/ was detrimentally affected, whereas none of the NLFC processing configurations affected the other phonemes. The discrepancy between the considerable acoustic changes and the negligible adverse effects on perceptual outcomes is partially accounted for by the phonology system and phonotactic constraints in Mandarin. PMID- 29604676 TI - Stability analysis of inverse time domain boundary element method for near-field acoustic holography. AB - Stability of the inverse time domain boundary element method (ITBEM) for near field acoustic holography is investigated. An eigenvalue system is built by reformulating the ITBEM to an iterative format. Through the analysis of the eigenvalue system, a stabilization criterion is derived. Then the stabilization criterion is utilized to reveal the stabilization mechanism of the TSVD method which plays an important role in the ITBEM. Furthermore, a method for properly choosing the ratio of truncated singular values to ensure the stability is provided. Although stability can be managed by using the TSVD method, the accuracy of the results cannot always be guaranteed. To overwhelm this difficulty, an averaging technique is further introduced, and its stabilization mechanism is investigated by incorporating it into the ITBEM formulations. Numerical simulations are carried out to validate the stabilization criterion, and the stabilization mechanisms of TSVD and averaging are shown specifically with extensive eigenvalue analyses. PMID- 29604677 TI - Active nonreciprocal acoustic metamaterials using a switching controller. AB - A class of active acoustic diodes and metamaterials is developed to control the flow and distribution of acoustic energy in acoustic cavities and systems. Such development departs radically from the currently available approaches where the non-reciprocities are generated by hard-wired designs, favoring one transmission direction which is dictated by the arrangement of the hardware and hence it cannot be reversed, or without the presentation of rigorous control theory analysis. The proposed active nonreciprocal acoustic metamaterial (ANAM) cell consists of a one-dimensional acoustic cavity provided with active flexible boundaries. These boundaries are made from piezoelectric bimorphs interacting with the cavity to monitor the pressures of the propagating acoustic waves. The outer layers of the bimorphs provide the necessary control actions by direct application of the appropriate control voltage on each layer or by proper connection of nonlinearly activated shunted networks of switching resistors. The control of the switching is carried out using a Switching Mode Control (SMC) strategy. In this strategy, a lumped-parameter model of the ANAM cell is developed to predict the nonreciprocal characteristics of the cell by proper selection of the slope of the switching surfaces. Numerical examples are presented to demonstrate the merits of the proposed SMC. PMID- 29604678 TI - ACOUSTICAL NEWS. AB - Editor's Note: Readers of this journal are encouraged to submit news items on awards, appointments, and other activities about themselves or their colleagues. Deadline dates for news and notices are 2 months prior to publication. PMID- 29604679 TI - Direction of arrival estimation using nonsingular spherical ESPRIT. AB - The eigenbeam-ESPRIT (EB-ESPRIT) is a parametric method that estimates the direction of arrival of source signals using a recurrence relation of spherical harmonics. In EB-ESPRIT, the sound-source elevation angle is estimated from an arctangent function, which diverges near the equator in the spherical coordinate system and inevitably induces an ill-conditioning problem. Here, a nonsingular spherical ESPRIT technique based on sine-based recurrence relations is proposed, in which the elevation angles are estimated from an arcsine function. It is shown that the proposed technique can estimate more sources than the conventional EB ESPRIT technique while also avoiding ill-conditioning problems. PMID- 29604680 TI - Generation of extremely nonlinear standing-wave field using loudspeaker-driven dissonant tube. AB - A method of generating nonlinear, pure standing-wave fields is proposed using a commercially available ordinary loudspeaker to drive easily manufactured dissonant standing-wave tubes at the first peak resonance frequencies, instead of traditional valley ones. With the transfer matrix, the dissonant properties of such standing-wave tubes with uniform cross-section (STUS), with tapered cross section (STTS), and with abrupt cross-section (STAS) were analyzed, and extremely nonlinear pure standing-wave fields were obtained experimentally, whose sound pressure level reached 185 dB at the individual first resonance frequencies. The evolution properties of the nonlinear pure standing-wave fields in the STUS, STAS, and STTS were also investigated experimentally. The results show that the STAS provides a good approach to creating extremely nonlinear pure standing-wave field. PMID- 29604681 TI - Measuring vocal difference in bird population pairs. AB - Over time, a bird population's acoustic and morphological features can diverge from the parent species. A quantitative measure of difference between two populations of species/subspecies is extremely useful to zoologists. Work in this paper takes a dialect difference system first developed for speech and refines it to automatically measure vocalisation difference between bird populations by extracting pitch contours. The pitch contours are transposed into pitch codes. A variety of codebook schemes are proposed to represent the contour structure, including a vector quantization approach. The measure, called Bird Vocalisation Difference, is applied to bird populations with calls that are considered very similar, very different, and between these two extremes. Initial results are very promising, with the behaviour of the metric consistent with accepted levels of similarity for the populations tested to date. The influence of data size on the measure is investigated by using reduced datasets. Results of species pair classification using Gaussian mixture models with Mel-frequency cepstral coefficients is also given as a baseline indicator of class confusability. PMID- 29604682 TI - Cognitive disruption by noise-vocoded speech stimuli: Effects of spectral variation. AB - The effect of irrelevant sounds on short-term memory was investigated in two experiments using noise-vocoded speech stimuli (NVSS). Speech samples were systematically modified by a noise-vocoder and a set of stimuli varying from amplitude-modulated white noise to intelligible speech was created. Eight NVSS conditions, composed of 1-, 2-, 4-, 6-, 9-, 12-, 15-, and 18-bands, were used as the distracting stimuli in a digit-recall task next to the speech and silence conditions. The results showed that performance decreased with the number of frequency bands up to the 6-bands condition, but there was no influence of number of bands on performance beyond six bands. The results were analyzed using four acoustic metrics proposed in the literature: the frequency domain correlation coefficient (FDCC), the fluctuation strength, the speech transmission index (STI), and the normalized covariance measure (NCM). None of the metrics successfully predicted the results. However, the parameter values of the FDCC, the STI, and the NCM indicated that a prediction model for irrelevant sound effect should account for both temporal and spectral features of the irrelevant sounds. PMID- 29604683 TI - Sound scattering and transmission through a circular cylindrical aperture revisited using the radial polynomials. AB - The problem of sound scattering and transmission through a circular cylindrical aperture in a flat thick rigid wall has been revisited rigorously using the radial polynomials. The acoustic power transmission and back scattering coefficients have been presented in the form of highly convergent hypergeometric series described earlier in the literature for vibrating circular pistons and plates based on the crucial property of the polynomials in terms of the Hankel transform. The problem is solved by using the continuity conditions at both aperture outlets. The complex integrals necessary to satisfy the continuity conditions are expressed as the exact formulas, which makes the final results for the acoustic power coefficients much more accurate than in the case of numerical integration. A significant improvement has also been reached in numerical efficiency. On average, the calculations are 500 times more efficient compared to numerical integration with no accuracy loss. Additionally, the acoustic pressure on the aperture outlets has been presented exactly in the form of a highly convergent hypergeometric series as well as using the modal impedance coefficients. PMID- 29604684 TI - The joint influence of vowel duration and creak on the perception of internal phrase boundaries. AB - Lengthening and creaky voice are associated with prosodic finality in English. Listeners can use lengthening to identify both utterance-internal and final prosodic phrase boundaries and can use creak to locate utterance endings. Less is known about listeners' use of creak to locate internal prosodic boundaries and the relative importance assigned to duration and creak when both are present. Participants in two experiments segmented structurally ambiguous sentences in which duration and creak were manipulated to signal prosodic boundaries. When duration- and creak-based cues provided redundant information, their effects were additive. When these cues conflicted, the effect of creak was subtractive. PMID- 29604685 TI - Localization of adventitious respiratory sounds. AB - In a recent publication by Henry and Royston [J. Acoust. Soc. Am. 142, 1774-1783 (2017)], an algorithm was introduced to calculate the acoustic response to externally introduced and endogenous respiratory sounds within a realistic, patient-specific subglottal airway tree. This work is extended using an efficient numerical boundary element (BE) approach to calculate the resulting radiated sound field from the airway tree into the lung parenchyma taking into account the surrounding chest wall. Within the BE model of the left lung parenchyma, comprised of more than 6000 triangular surface elements, more than 30 000 monopoles are used to approximate complex airway-originated acoustic sources. The chest wall is modeled as a boundary condition on the parenchymal surface. Several cases were simulated, including a bronchoconstricted lung that had an internal acoustic source introduced in a bronchiole, approximating a wheeze. An acoustic source localization algorithm coupled to the BE model estimated the wheeze source location to within a few millimeters based solely on the acoustic field at the surface. Improved noninvasive means of locating adventitious respiratory sounds may enhance an understanding of acoustic changes correlated to pathology, and potentially provide improved noninvasive tools for the diagnosis of pulmonary diseases that uniquely alter acoustics. PMID- 29604687 TI - The role of gesture delay in coda /r/ weakening: An articulatory, auditory and acoustic study. AB - The cross-linguistic tendency of coda consonants to weaken, vocalize, or be deleted is shown to have a phonetic basis, resulting from gesture reduction, or variation in gesture timing. This study investigates the effects of the timing of the anterior tongue gesture for coda /r/ on acoustics and perceived strength of rhoticity, making use of two sociolects of Central Scotland (working- and middle class) where coda /r/ is weakening and strengthening, respectively. Previous articulatory analysis revealed a strong tendency for these sociolects to use different coda /r/ tongue configurations-working- and middle-class speakers tend to use tip/front raised and bunched variants, respectively; however, this finding does not explain working-class /r/ weakening. A correlational analysis in the current study showed a robust relationship between anterior lingual gesture timing, F3, and percept of rhoticity. A linear mixed effects regression analysis showed that both speaker social class and linguistic factors (word structure and the checked/unchecked status of the prerhotic vowel) had significant effects on tongue gesture timing and formant values. This study provides further evidence that gesture delay can be a phonetic mechanism for coda rhotic weakening and apparent loss, but social class emerges as the dominant factor driving lingual gesture timing variation. PMID- 29604686 TI - Relationship between speech-evoked neural responses and perception of speech in noise in older adults. AB - Speech-in-noise (SPIN) perception involves neural encoding of temporal acoustic cues. Cues include temporal fine structure (TFS) and envelopes that modulate at syllable (Slow-rate ENV) and fundamental frequency (F0-rate ENV) rates. Here the relationship between speech-evoked neural responses to these cues and SPIN perception was investigated in older adults. Theta-band phase-locking values (PLVs) that reflect cortical sensitivity to Slow-rate ENV and peripheral/brainstem frequency-following responses phase-locked to F0-rate ENV (FFRENV_F0) and TFS (FFRTFS) were measured from scalp-electroencephalography responses to a repeated speech syllable in steady-state speech-shaped noise (SpN) and 16-speaker babble noise (BbN). The results showed that (1) SPIN performance and PLVs were significantly higher under SpN than BbN, implying differential cortical encoding may serve as the neural mechanism of SPIN performance that varies as a function of noise types; (2) PLVs and FFRTFS at resolved harmonics were significantly related to good SPIN performance, supporting the importance of phase-locked neural encoding of Slow-rate ENV and TFS of resolved harmonics during SPIN perception; (3) FFRENV_F0 was not associated to SPIN performance until audiometric threshold was controlled for, indicating that hearing loss should be carefully controlled when studying the role of neural encoding of F0 rate ENV. Implications are drawn with respect to fitting auditory prostheses. PMID- 29604688 TI - The Airy phase of explosive sounds in shallow water. AB - The Airy phase is identified in the received signals from explosive charges deployed in a shallow water acoustic experiment conducted in the New England Mudpatch region during the spring of 2017. Measured and modeled time-frequency dispersion curves are compared and a geoacoustic sensitivity study utilizing marginal probability distributions for the sound speed in five sediment layers is performed. The analysis suggests that inclusion of the Airy phase frequency and arrival time in a geoacoustic-inversion method could lower the uncertainty of sound speed parameter estimation in a multi-layer sediment as compared to methods that do not include the Airy phase structure. PMID- 29604689 TI - Time domain nearfield acoustical holography with three-dimensional linear deconvolution. AB - In this paper, a formulation is proposed to improve the time domain reconstruction of non-stationary acoustic fields with nearfield acoustical holography. The formulation involves applying three-dimensional (3D) linear deconvolution using a Green's function sampled in the time and spatial domains. Because linear deconvolution does not assume periodic signals, it more appropriately describes the decaying behavior of sources that begin and end at null amplitude and that radiate over a finite amount of time. The proposed method outperforms standard circular convolution-based nearfield acoustical holography by up to a factor three in relative root-mean-square error, when compared using a transient baffled piston model, and its reconstructions remain accurate over large back-propagation distances. Furthermore, it is shown that truncation errors in linear deconvolution can be reduced by applying a 3D patch extrapolation algorithm; however, convergence depends on the choice of an adequate Tikhonov's regularization parameter. Three methods for predicting the optimal parameter are compared: the L-curve, the generalized cross-validation, and the empirical Bayesian method. It is shown that with the proposed formulation applied to reconstructing the field radiated by a transient baffled piston, the generalized cross-validation gives the overall best prediction for the noise levels and back propagation distances studied. PMID- 29604690 TI - Evaluation of radiation loading on finite cylindrical shells using the fast Fourier transform: A comparison with direct numerical integration. AB - The radiation loading on a vibratory finite cylindrical shell is conventionally evaluated through the direct numerical integration (DNI) method. An alternative strategy via the fast Fourier transform algorithm is put forward in this work based on the general expression of radiation impedance. To check the feasibility and efficiency of the proposed method, a comparison with DNI is presented through numerical cases. The results obtained using the present method agree well with those calculated by DNI. More importantly, the proposed calculating strategy can significantly save the time cost compared with the conventional approach of straightforward numerical integration. PMID- 29604691 TI - Upwelling regime off the Cabo Frio region in Brazil and impact on acoustic propagation. AB - This work introduces a description of the complex upwelling regime off the Cabo Frio region in Brazil and shows that ocean modeling, based on the feature oriented regional modeling system (FORMS) technique, can produce reliable predictions of sound speed fields for the corresponding shallow water environment. This work also shows, through the development of simulations, that the upwelling regime can be responsible for the creation of shadow coastal zones, in which the detection probability is too low for an acoustic source to be detected. The development of the FORMS technique and its validation with real data, for the particular region of coastal upwelling off Cabo Frio, reveals the possibility of a sustainable and reliable forecast system for the corresponding (variable in space and time) underwater acoustic environment. PMID- 29604692 TI - Understanding low-pass-filtered Mandarin sentences: Effects of fundamental frequency contour and single-channel noise suppression. AB - The present work assessed the effects of flattening the fundamental frequency (F0) contour and processing by single-channel noise suppression on the intelligibility of low-pass (LP)-filtered (LPF) sentences. The original F0 contour was replaced by an average flat F0 contour or treated by single-channel noise suppression, followed by application of LP filtering to Mandarin sentences. Processed stimuli were presented to normal-hearing listeners to recognize. Flattening the F0 contour significantly affected the understanding of LPF sentences. Noise suppression by existing single-channel algorithms did not improve the intelligibility of LPF sentences. PMID- 29604694 TI - Use of the kurtosis statistic in an evaluation of the effects of noise and solvent exposures on the hearing thresholds of workers: An exploratory study. AB - The aim of this exploratory study was to examine whether the kurtosis metric can contribute to investigations of the effects of combined exposure to noise and solvents on human hearing thresholds. Twenty factory workers exposed to noise and solvents along with 20 workers of similar age exposed only to noise in eastern China were investigated using pure-tone audiometry (1000-8000 Hz). Exposure histories and shift-long noise recording files were obtained for each participant. The data were used in the calculation of the cumulative noise exposure (CNE) and CNE adjusted by the kurtosis metric for each participant. Passive samplers were used to measure solvent concentrations for each worker exposed to solvents over the full work shift. Results showed an interaction between noise exposure and solvents for the hearing threshold at 6000 Hz. This effect was observed only when the CNE level was adjusted by the kurtosis metric. PMID- 29604693 TI - Speech recognition for school-age children and adults tested in multi-tone vs multi-noise-band maskers. AB - The present study set out to test whether greater susceptibility to modulation masking could be responsible for immature recognition of speech in noise for school-age children. Listeners were normal-hearing four- to ten-year-olds and adults. Target sentences were filtered into 28 adjacent narrow bands (100-7800 Hz), and the masker was either spectrally matched noise bands or tones centered on each of the speech bands. In experiment 1, odd- and even-numbered bands of target-plus-masker were presented to opposite ears. Performance improved with child age in all conditions, but this improvement was larger for the multi-tone than the multi-noise-band masker. This outcome is contrary to the expectation that children are more susceptible than adults to masking produced by inherent modulation of the noise masker. In experiment 2, odd-numbered bands were presented to both ears, with the masker diotic and the target either diotic or binaurally out of phase. The binaural difference cue was particularly beneficial for young children tested in the multi-tone masker, suggesting that development of auditory stream segregation may play a role in the child-adult difference for this condition. Overall, results provide no evidence of greater susceptibility to modulation masking in children than adults. PMID- 29604695 TI - Active feedforward noise control and signal tracking of headsets: Electroacoustic analysis and system implementation. AB - Active noise control (ANC) of headsets is revisited in this paper. An in-depth electroacoustic analysis of the combined loudspeaker-cavity headset system is conducted on the basis of electro-mechano-acoustical analogous circuits. Model matching of the primary path and the secondary path leads to a feedforward control architecture. The ideal controller sheds some light on the key parameters that affect the noise reduction performance. Filtered-X least-mean-squares algorithm is employed to implement the feedforward controller on a digital signal processor. Since the relative delay of the primary path and the secondary path is crucial to the noise reduction performance, multirate signal processing with polyphase implementation is utilized to minimize the effective analog-digital conversion delay in the secondary path. Ad hoc decimation and interpolation filters are designed in order not to introduce excessive phase delays at the cutoff. Real-time experiments are undertaken to validate the implemented ANC system. Listening tests are also conducted to compare the fixed controller and the adaptive controller in terms of noise reduction and signal tracking performance for three noise types. The results have demonstrated that the fixed feedforward controller achieved satisfactory noise reduction performance and signal tracking quality. PMID- 29604697 TI - Characterizing acoustic shocks in high-performance jet aircraft flyover noise. AB - Acoustic shocks have been previously documented in high-amplitude jet noise, including both the near and far fields of military jet aircraft. However, previous investigations into the nature and formation of shocks have historically concentrated on stationary, ground run-up measurements, and previous attempts to connect full-scale ground run-up and flyover measurements have omitted the effect of nonlinear propagation. This paper shows evidence for nonlinear propagation and the presence of acoustic shocks in acoustical measurements of F-35 flyover operations. Pressure waveforms, derivatives, and statistics indicate nonlinear propagation, and the resulting shock formation is significant at high engine powers. Variations due to microphone size, microphone height, and sampling rate are considered, and recommendations for future measurements are made. Metrics indicating nonlinear propagation are shown to be influenced by changes in sampling rate and microphone size, and exhibit less variation due to microphone height. PMID- 29604696 TI - Effects of age on sensitivity to interaural time differences in envelope and fine structure, individually and in combination. AB - Sensitivity to interaural time differences (ITDs) in envelope and temporal fine structure (TFS) of amplitude-modulated (AM) tones was assessed for young and older subjects, all with clinically normal hearing at the carrier frequencies of 250 and 500 Hz. Some subjects had hearing loss at higher frequencies. In experiment 1, thresholds for detecting changes in ITD were measured when the ITD was present in the TFS alone (ITDTFS), the envelope alone (ITDENV), or both (ITDTFS/ENV). Thresholds tended to be higher for the older than for the young subjects. ITDENV thresholds were much higher than ITDTFS thresholds, while ITDTFS/ENV thresholds were similar to ITDTFS thresholds. ITDTFS thresholds were lower than ITD thresholds obtained with an unmodulated pure tone, indicating that uninformative AM can improve ITDTFS discrimination. In experiment 2, equally detectable values of ITDTFS and ITDENV were combined so as to give consistent or inconsistent lateralization. There were large individual differences, but several subjects gave scores that were much higher than would be expected from the optimal combination of independent sources of information, even for the inconsistent condition. It is suggested that ITDTFS and ITDENV cues are processed partly independently, but that both cues influence lateralization judgments, even when one cue is uninformative. PMID- 29604698 TI - Testing and refining a loudness model for time-varying sounds incorporating binaural inhibition. AB - This paper describes some experimental tests and modifications to a model of loudness for time-varying sounds incorporating the concept of binaural inhibition. Experiment 1 examined the loudness of a 100% sinusoidally amplitude modulated 1000-Hz sinusoidal carrier as a function of the interaural modulation phase difference (IMPD). The IMPD of the test sound was 90 degrees or 180 degrees and that of the comparison sound was 0 degrees . The level difference between the test and the comparison sounds at the point of equal loudness (the LDEL) was estimated for baseline levels of 30 and 70 dB sound pressure level and modulation rates of 1, 2, 4, 8, 16, and 32 Hz. The LDELs were negative (mean = 1.1 and -1.5 dB for IMPDs of 90 degrees and 180 degrees ), indicating that non zero IMPDs led to increased loudness. The original version of the model predicted the general form of the results, but there were some systematic errors. Modifications to the time constants of the model gave a better fit to the data. Experiment 2 assessed the loudness of unintelligible speech-like signals, generated using a noise vocoder, whose spectra and time pattern differed at the two ears. Both the original and modified models gave good fits to the data. PMID- 29604699 TI - Higher-order frequency locking of an organ pipe: A measurement study based on synchronization theory. AB - Higher-order frequency locking of an organ pipe was investigated in terms of relationships between the locking phenomena and the harmonics of the pipe sound and an external force acting onto the pipe. The authors first assumed the pipe as a phase oscillator that is used in synchronization theory and predicted frequency ratios that can cause frequency locking. The authors then forced an actual pipe using a pure tone with frequency ratios of 1 : 1, 1 : 2, 2 : 1, 1 : 3, and 2 : 3. In addition, experiments were conducted using complex tones to investigate effects of higher harmonics of the external force on frequency locking. As a result, frequency locking occurred only at frequency ratios of 1 : 1, 1 : 2, and 1 : 3 in the case of the pure tone in agreement with the prediction of synchronization theory. For the complex tone, the authors succeeded in inducing 2 : 1 locking. The results show that the frequency of a harmonic component of the external force was close to that of the pipe sound when frequency locking occurred. Frequency locking of an organ pipe was therefore enhanced through the proximity of the harmonics of the pipe sound and the external force. PMID- 29604700 TI - Broadband multizone sound rendering by jointly optimizing the sound pressure and particle velocity. AB - In this paper, a recently proposed approach to multizone sound field synthesis, referred to as joint pressure and velocity matching (JPVM), is investigated analytically using a spherical harmonics representation of the sound field. The approach is motivated by the Kirchhoff-Helmholtz integral equation and aims at controlling the sound field inside the local listening zones by evoking the sound pressure and particle velocity on surrounding contours. Based on the findings of the modal analysis, an improved version of JPVM is proposed, which provides both better performance and lower complexity. In particular, it is shown analytically that the optimization of the tangential component of the particle velocity vector, as is done in the original JPVM approach, is very susceptible to errors and thus not pursued anymore. Furthermore, the analysis provides fundamental insights as to how the spherical harmonics used to describe three-dimensional sound fields translate into two-dimensional basis functions as observed on the contours surrounding the zones. By means of simulations, it is verified that discarding the tangential component of the particle velocity vector ultimately leads to an improved performance. Finally, the impact of sensor noise on the reproduction performance is assessed. PMID- 29604702 TI - Tensorial dynamic time warping with articulation index representation for efficient audio-template learning. AB - Audio classification techniques often depend on the availability of a large labeled training dataset for successful performance. However, in many application domains of audio classification (e.g., wildlife monitoring), obtaining labeled data is still a costly and laborious process. Motivated by this observation, a technique is proposed to efficiently learn a clean template from a few labeled, but likely corrupted (by noise and interferences), data samples. This learning can be done efficiently via tensorial dynamic time warping on the articulation index-based time-frequency representations of audio data. The learned template can then be used in audio classification following the standard template-based approach. Experimental results show that the proposed approach outperforms both (1) the recurrent neural network approach and (2) the state-of-the-art in the template-based approach on a wildlife detection application with few training samples. PMID- 29604701 TI - Mixed stimulation rates to improve sensitivity of interaural timing differences in bilateral cochlear implant listeners. AB - Normal hearing listeners extract small interaural time differences (ITDs) and interaural level differences (ILDs) to locate sounds and segregate targets from noise. Bilateral cochlear implant listeners show poor sensitivity to ITDs when using clinical processors. This is because common clinical stimulation approaches use high rates [~1000 pulses per-second (pps)] for each electrode in order to provide good speech representation, but sensitivity to ITDs is best at low rates of stimulation (~100-300 pps). Mixing rates of stimulation across the array is a potential solution. Here, ITD sensitivity for a number of mixed-rate configurations that were designed to preserve speech envelope cues using high rate stimulation and spatial hearing using low rate stimulation was examined. Results showed that ITD sensitivity in mixed-rate configurations when only one low rate electrode was included generally yielded ITD thresholds comparable to a configuration with low rates only. Low rate stimulation at basal or middle regions on the electrode array yielded the best sensitivity to ITDs. This work provides critical evidence that supports the use of mixed-rate strategies for improving ITD sensitivity in bilateral cochlear implant users. PMID- 29604703 TI - A numerical hybrid model for outdoor sound propagation in complex urban environments. AB - Noise mapping in large and dense urban areas is computationally challenging, if not impossible, with the use of conventional numerical techniques. Recently, promising results have shown the potential of energy-based models to compete with conventional numerical techniques. In this paper, a hybrid full-wave/diffusion propagation model is proposed to address some of the flaws of the traditional diffusion model. The full-wave model is used for predicting sound propagation (i) near the source, where interactions between waves are important, and (ii) outside the cluttered environment, where free-field-like conditions apply. The diffusion model is used in regions where diffusion conditions are met. PMID- 29604705 TI - The fractal derivative wave equation: Application to clinical amplitude/velocity reconstruction imaging. AB - This paper proposes a dissipative acoustic wave equation in which the fractal derivative is employed to represent dissipation. The proposed model is derived from the viscoelastic constitutive relationship via the fractal derivative. It is noted that the fractal derivative is a local operator and avoids the expensive computational costs of non-local fractional derivative, which is popular in recent decades to describe frequency-dependent dissipation in acoustic wave propagation in soft materials. The proposed model is tested to simulate the clinical amplitude/velocity reconstruction imaging of breast tumors, where the reflecting plate is imaged as an elevated line in correspondence to tumor. Numerical experiments show that the present model is capable of indicating the size, position and quantity of tumors. The comparative study confirms that the fractal derivative acoustic wave equation has an advantage over the fractional derivative model regarding computational costs. PMID- 29604706 TI - Auditory distraction by speech: Sound masking with speech-shaped stationary noise outperforms -5 dB per octave shaped noise. AB - Sound masking can reduce the distraction due to ambient sounds in open-plan offices. This paper compares a typical masking sound with a slope of -5 dB per octave to a steady-state signal with the spectrum of the disturbing speech signal. Subjects had to complete a number recall task and a questionnaire in a laboratory experiment. The sound conditions with the spectrally-matched noise resulted in similar error rates at 3 dB higher speech-to-noise ratios as compared to the standard noise. Using a speech-shaped steady-state noise as masking sound could reduce the effect of distracting speech in the work place more efficiently. PMID- 29604707 TI - Acoustically sticky topographic metasurfaces for underwater sound absorption. AB - A class of metasurfaces for underwater sound absorption, based on a design principle that maximizes thermoviscous loss, is presented. When a sound meets a solid surface, it leaves a footprint in the form of thermoviscous boundary layers in which energy loss takes place. Considered to be a nuisance, this acoustic to vorticity/entropy mode conversion and the subsequent loss are often ignored in the existing designs of acoustic metamaterials and metasurfaces. The metasurface created is made of a series of topographic meta-atoms, i.e., intaglios and reliefs engraved directly on the solid object to be concealed. The metasurface is acoustically sticky in that it rather facilitates the conversion of the incident sound to vorticity and entropy modes, hence the thermoviscous loss, leading to the desired anechoic property. A prototype metasurface machined on a brass object is tested for its anechoicity, and shows a multitude of absorption peaks as large as unity in the 2-5 MHz range. Computations also indicate that a topographic metasurface is robust to hydrostatic pressure variation, a quality much sought after in underwater applications. PMID- 29604708 TI - Low-frequency band gap of locally resonant phononic crystals with a dual-base plate. AB - To achieve a wider band gap and a lower cut-on frequency, a locally resonant phononic crystal (LRPC) with a dual-base plate is investigated in this paper. Compared with the LRPC with a single plate, the band structure of the LRPC with a dual-base plate is calculated using the method of plane wave expansion and verified by the finite element method. According to the analysis of the band curves of the LRPC with a dual-base plate, the mechanisms are explained. Next, the influences of the thickness of the plates, the stiffness of the springs, the mass of resonators, and the lattice constant are also investigated. The results show that the structural asymmetry between the upper and the lower plate is conducive to reducing the cut-on frequency and broadening the band gap effectively. The results indicate a different approach for the application of LRPC in vibration and noise control. PMID- 29604709 TI - Quantifying undesired parallel components in Thevenin-equivalent acoustic source parameters. AB - The calibration of an ear probe to determine its Thevenin-equivalent acoustic source parameters facilitates the measurement of ear-canal impedance and reflectance. Existing calibration error metrics, used to evaluate the quality of a calibration, are unable to reveal undesired parallel components in the source parameters. Such parallel components can result from, e.g., a leak in the ear tip or improperly accounting for evanescent modes, and introduce errors into subsequent measurements of impedance and reflectance. This paper proposes a set of additional error metrics that are capable of detecting such parallel components by examining the causality of the source admittance in the frequency domain and estimating the source pressure in the time domain. The proposed and existing error metrics are applied to four different calibrations using two existing calibration methods, representing typical use cases and introducing deliberate parallel components. The results demonstrate the capability of the proposed error metrics in identifying various undesired components in the source parameters that might otherwise go undetected. PMID- 29604710 TI - The role of phase synchronisation between low frequency amplitude modulations in child phonology and morphology speech tasks. AB - Recent models of the neural encoding of speech suggest a core role for amplitude modulation (AM) structure, particularly regarding AM phase alignment. Accordingly, speech tasks that measure linguistic development in children may exhibit systematic properties regarding AM structure. Here, the acoustic structure of spoken items in child phonological and morphological tasks, phoneme deletion and plural elicitation, was investigated. The phase synchronisation index (PSI), reflecting the degree of phase alignment between pairs of AMs, was computed for 3 AM bands (delta, theta, beta/low gamma; 0.9-2.5 Hz, 2.5-12 Hz, 12 40 Hz, respectively), for five spectral bands covering 100-7250 Hz. For phoneme deletion, data from 94 child participants with and without dyslexia was used to relate AM structure to behavioural performance. Results revealed that a significant change in magnitude of the phase synchronisation index (DeltaPSI) of slower AMs (delta-theta) systematically accompanied both phoneme deletion and plural elicitation. Further, children with dyslexia made more linguistic errors as the delta-theta DeltaPSI increased. Accordingly, DeltaPSI between slower temporal modulations in the speech signal systematically distinguished test items from accurate responses and predicted task performance. This may suggest that sensitivity to slower AM information in speech is a core aspect of phonological and morphological development. PMID- 29604711 TI - Long-range reverberation in an Arctic environment: Effects of ice thickness and elasticity. AB - A full-field perturbation approach is modified for an ice-covered ocean and applied to estimating narrowband long-range reverberation caused by roughness of the ice-water interface. First-order approximation of the approach is used which requires the roughness amplitudes be small compared to the acoustic wavelength. To obtain the zeroth-order Green's function and transmission loss field used in the reverberation model, elastic parabolic equation solutions are generated in range-independent environments. Ice is represented by an isospeed layer on top of a linear transition layer. Effects of ice properties are discussed and demonstrated by comparing reverberation calculated for different ice layer thicknesses and wave speeds for typical ice values. PMID- 29604712 TI - The ocean noise coherence matrix and its rank. AB - An expression for the cross-spectral density matrix of ocean noise naturally separates into a Toeplitz part and a Hankel part [Harrison (2017). J. Acoust. Soc. Am. 141, 2812-2820]. The Toeplitz part is shown to be substantially rank deficient for all practical acoustic cases, which has implications for adaptive beam forming. The influence of the Hankel part on passive fathometry is investigated, and its effect on adaptive beam forming is shown to be weak or negligible. Numerical demonstrations of these findings including beam patterns and eigenvalue spectra derived via circulant matrices are given based on a simple half-space with a Rayleigh reflection coefficient. Two sets of experimental data are revisited in this context, deriving eigenvalue spectra, beam patterns, and passive fathometry impulse responses with conventional and adaptive processing and differing amounts of averaging. The solution to a long-standing puzzle of processing inconsistency is suggested. PMID- 29604713 TI - Effect of mouth-opening levels on sound field gain in the ear canal. AB - The human external auditory canal can become deformed when the mandible moves, and this changes the sound field in the external auditory canal. This study measured the sound field gain in the external auditory canal while varying mouth opening in three levels. The mandible was fixed at the 1/3, the 2/3, and the maximal mouth-opening levels. Seven 65-dB tones of 200, 500, 1000, 2000, 4000, 6000, and 8000 Hz, which are the sound pressure level and frequency range when people are talking at a normal level, were adopted as the sound stimulus to measure sound field gains at 5, 10, 15, and 20 mm to the interior of the external auditory canal. The results show that, with the exception of the 1.25 dB decrease from 12.96 to 11.71 dB at a depth of 5 mm with a stimulus at 8000 Hz, the differences in the sound field gain at the other depths and stimulus frequencies were within 1 dB and were not statistically significant. These results suggest that mouth-opening level has no effect on the measurement of the sound field in the external auditory canal. PMID- 29604714 TI - Geometry and topology of the space of sonar target echos. AB - Successful synthetic aperture sonar target classification depends on the "shape" of the scatterers within a target signature. This article presents a workflow that computes a target-to-target distance from persistence diagrams, since the "shape" of a signature informs its persistence diagram in a structure-preserving way. The target-to-target distances derived from persistence diagrams compare favorably against those derived from spectral features and have the advantage of being substantially more compact. While spectral features produce clusters associated to each target type that are reasonably dense and well formed, the clusters are not well-separated from one another. In rather dramatic contrast, a distance derived from persistence diagrams results in highly separated clusters at the expense of some misclassification of outliers. PMID- 29604715 TI - Selection of a sound propagation model for noise annoyance prediction: A perceptual approach. AB - Sound propagation effects need to be considered in studies dealing with the perception of annoying auditory sensations evoked by transportation noise. Thus, in a listening test requiring participants to make dissimilarity ratings, the effects of several feasible propagation models are compared to actual recordings of vehicle noises made at a given distance. As a result, a model taking into account first order reflections without any phase term is found to be the most appropriate model for simulating road traffic noise propagation in an urban environment from a perceptual point of view. PMID- 29604716 TI - Erratum: A multiscale analytical model of bronchial airway acoustics [J. Acoust. Soc. Am. 142, 1774-1783 (2017)]. PMID- 29604717 TI - ACOUSTICAL STANDARDS NEWS. AB - American National Standards (ANSI Standards) developed by Accredited Standards Committees S1, S2, S3, S3/SC 1, and S12 in the areas of acoustics, mechanical vibration and shock, bioacoustics, animal bioacoustics, and noise, respectively, are published by the Acoustical Society of America (ASA). In addition to these standards, ASA publishes a catalog of Acoustical American National Standards. To receive a copy of the latest Standards catalog, please contact asastds@acousticalsociety.org.Comments are welcomed on all material in Acoustical Standards News.This Acoustical Standards News section in JASA, as well as the National Catalog of Acoustical Standards and other information on the Standards Program of the Acoustical Society of America, are available via the ASA home page: http://acousticalsociety.org. PMID- 29604718 TI - The dynamic gammawarp auditory filterbank. AB - Auditory filterbanks are an integral part of many metrics designed to predict speech intelligibility and speech quality. Considerations in these applications include accurate reproduction of auditory filter shapes, the ability to reproduce the impact of hearing loss as well as normal hearing, and computational efficiency. This paper presents an alternative method for implementing a dynamic compressive gammachirp (dcGC) auditory filterbank [Irino and Patterson (2006). IEEE Trans. Audio Speech Lang. Proc. 14, 2222-2232]. Instead of using a cascade of second-order sections, this approach uses digital frequency warping to give the gammawarp filterbank. The set of warped finite impulse response filter coefficients is constrained to be symmetrical, which results in the same phase response for all filters in the filterbank. The identical phase responses allow the dynamic variation in the gammachirp filter magnitude response to be realized as a sum, using time-varying weights, of three filters that provide the responses for high-, mid-, and low-intensity input signals, respectively. The gammawarp filterbank offers a substantial improvement in execution speed compared to previous dcGC implementations; for a dcGC filterbank, the gammawarp implementation is 24 to 38 times faster than the dcGC Matlab code of Irino. PMID- 29604719 TI - Speech-material and talker effects in speech band importance. AB - Band-importance functions created using the compound method [Apoux and Healy (2012). J. Acoust. Soc. Am. 132, 1078-1087] provide more detail than those generated using the ANSI technique, necessitating and allowing a re-examination of the influences of speech material and talker on the shape of the band importance function. More specifically, the detailed functions may reflect, to a larger extent, acoustic idiosyncrasies of the individual talker's voice. Twenty one band functions were created using standard speech materials and recordings by different talkers. The band-importance functions representing the same speech material type produced by different talkers were found to be more similar to one another than functions representing the same talker producing different speech material types. Thus, the primary finding was the relative strength of a speech material effect and weakness of a talker effect. This speech-material effect extended to other materials in the same broad class (different sentence corpora) despite considerable differences in the specific materials. Characteristics of individual talkers' voices were not readily apparent in the functions, and the talker effect was restricted to more global aspects of talker (i.e., gender). Finally, the use of multiple talkers diminished any residual effect of the talker. PMID- 29604720 TI - Numerical investigation of shear layer effect on sound generation in jet diffusion flame. AB - Shear layer effect was pointed out to be associated with the vortex-flame interaction and leads to the difference in combustion noise. In this work, numerical simulation combining with an acoustic analogy equation was performed to investigate the shear layer effect on the sound generation by jet diffusion flames. To easily identify the cause and effect, the approach that varies the thickness of shear layer by changing the Prandtl number is adopted, which provides deeper physical insight into the characteristics of the acoustic near field. The formation and evolution mechanisms of sound sources in jet diffusion flames are interpreted. It is observed that the sound sources are concentrated in vortex centers and appear as either the sources or the drains for the sound waves. The spectral analysis shows that the low frequency sound is emitted from the flame base, while the high frequency sound is radiated from the downstream region. Moreover, the theoretical analysis based on vortical dynamics shows that the low frequency sound is primarily affected by the combustion-induced buoyancy effect, whereas the high frequency sound is determined by the baroclinic torque. PMID- 29604721 TI - Low-frequency outdoor-indoor noise level difference for wind turbine assessment. AB - To increase the understanding of wind turbine noise on sleep, human physiological reactions need to be studied in a controlled laboratory setting. The paper presents an outdoor-indoor noise level difference as a function of frequency, applicable to creating wind turbine indoor sounds with the outdoor sounds as input. For this, a combination of measurement data and modeling results has been used. The suggested data are provided in a table. PMID- 29604722 TI - Near-field head-related transfer-function measurement and database of human subjects. AB - Near-field head-related transfer functions (HRTFs) of human subjects are essential to those researching spatial hearing. By using a carefully designed measurement system, near-field HRTFs of human subjects were measured and a database was constructed. The database includes 56 Chinese human subjects, seven source distances from 0.2 to 1.0 m, and 685 directions at each distance for each subject. In the present work, the technique of near-field HRTF measurement is outlined, the performance of the measurement system is assessed and validated, and the resultant database is reported. The database can provide fundamental data for future research. PMID- 29604723 TI - Calibration and energy measurement of optically levitated nanoparticle sensors. AB - Optically levitated nanoparticles offer enormous potential for precision sensing. However, as for any other metrology device, the absolute measurement performance of a levitated-particle sensor is limited by the accuracy of the calibration relating the measured signal to an absolute displacement of the particle. Here, we suggest and demonstrate calibration protocols for levitated-nanoparticle sensors. Our calibration procedures include the treatment of anharmonicities in the trapping potential, as well as a protocol using a harmonic driving force, which is applicable if the sensor is coupled to a heat bath of unknown temperature. Finally, using the calibration, we determine the center-of-mass temperature of an optically levitated particle in thermal equilibrium from its motion and discuss the optimal measurement time required to determine the said temperature. PMID- 29604724 TI - Contributed Review: Camera-limits for wide-field magnetic resonance imaging with a nitrogen-vacancy spin sensor. AB - Sensitive, real-time optical magnetometry with nitrogen-vacancy centers in diamond relies on accurate imaging of small (?10-2), fractional fluorescence changes across the diamond sample. We discuss the limitations on magnetic field sensitivity resulting from the limited number of photoelectrons that a camera can record in a given time. Several types of camera sensors are analyzed, and the smallest measurable magnetic field change is estimated for each type. We show that most common sensors are of a limited use in such applications, while certain highly specific cameras allow achieving nanotesla-level sensitivity in 1 s of a combined exposure. Finally, we demonstrate the results obtained with a lock-in camera that paves the way for real-time, wide-field magnetometry at the nanotesla level and with a micrometer resolution. PMID- 29604725 TI - Simple and portable low frequency lock-in amplifier designed for photoacoustic measurements and its application to thermal effusivity determination in liquids. AB - The lock-in amplifier is a very useful instrument for observing very small signals under adverse signal-to-noise conditions. In this work, we describe a simple and portable lock-in amplifier designed to be used in photoacoustic measurements. The device was used to measure the thermal effusivity of eight different liquid samples (distilled water, glycerol, acetone, ethanol, 2 propanol, chloroform, hexane, and methanol), as well as the effusivity of acetone in aqueous solution at distinct concentrations, giving good results. The instrument has a bandwidth of 10 Hz-10 kHz and a sensitivity of 1 MUV. PMID- 29604726 TI - A new device for high-temperature in situ GISAXS measurements. AB - A heating stage originally designed for diffraction experiments is implemented into a Bruker NANOSTAR instrument for in situ grazing incidence small-angle x-ray scattering experiments. A controlled atmosphere is provided by a dome separating the sample environment from the evacuated scattering instrument. This dome is double shelled in order to enable cooling water to flow through it. A mesoporous silica film templated by a self-assembled block copolymer system is investigated in situ during step-wise heating in air. The GISAXS pattern shows the structural development of the ordered lattice of parallel cylindrical pores. The deformation of the elliptical pore-cross section perpendicular to the film surface was studied with increasing temperature. Moreover, the performance of the setup was tested by controlled in situ heating of a copper surface under controlled oxygen containing atmosphere. PMID- 29604727 TI - Contact angle measurement with a smartphone. AB - In this study, a smartphone-based contact angle measurement instrument was developed. Compared with the traditional measurement instruments, this instrument has the advantage of simplicity, compact size, and portability. An automatic contact point detection algorithm was developed to allow the instrument to correctly detect the drop contact points. Two different contact angle calculation methods, Young-Laplace and polynomial fitting methods, were implemented in this instrument. The performance of this instrument was tested first with ideal synthetic drop profiles. It was shown that the accuracy of the new system with ideal synthetic drop profiles can reach 0.01% with both Young-Laplace and polynomial fitting methods. Conducting experiments to measure both static and dynamic (advancing and receding) contact angles with the developed instrument, we found that the smartphone-based instrument can provide accurate and practical measurement results as the traditional commercial instruments. The successful demonstration of use of a smartphone (mobile phone) to conduct contact angle measurement is a significant advancement in the field as it breaks the dominate mold of use of a computer and a bench bound setup for such systems since their appearance in 1980s. PMID- 29604728 TI - Development of an electron momentum spectrometer for time-resolved experiments employing nanosecond pulsed electron beam. AB - The low count rate of (e, 2e) electron momentum spectroscopy (EMS) has long been a major limitation of its application to the investigation of molecular dynamics. Here we report a new EMS apparatus developed for time-resolved experiments in the nanosecond time scale, in which a double toroidal energy analyzer is utilized to improve the sensitivity of the spectrometer and a nanosecond pulsed electron gun with a repetition rate of 10 kHz is used to obtain an average beam current up to nA. Meanwhile, a picosecond ultraviolet laser with a repetition rate of 5 kHz is introduced to pump the sample target. The time zero is determined by photoionizing the target using a pump laser and monitoring the change of the electron beam current with time delay between the laser pulse and electron pulse, which is influenced by the plasma induced by the photoionization. The performance of the spectrometer is demonstrated by the EMS measurement on argon using a pulsed electron beam, illustrating the potential abilities of the apparatus for investigating the molecular dynamics in excited states when employing the pump probe scheme. PMID- 29604729 TI - Validating data analysis of broadband laser ranging. AB - Broadband laser ranging combines spectral interferometry and a dispersive Fourier transform to achieve high-repetition-rate measurements of the position of a moving surface. Telecommunications fiber is a convenient tool for generating the large linear dispersions required for a dispersive Fourier transform, but standard fiber also has higher-order dispersion that distorts the Fourier transform. Imperfections in the dispersive Fourier transform significantly complicate the ranging signal and must be dealt with to make high-precision measurements. We describe in detail an analysis process for interpreting ranging data when standard telecommunications fiber is used to perform an imperfect dispersive Fourier transform. This analysis process is experimentally validated over a 27-cm scan of static positions, showing an accuracy of 50 MUm and a root mean-square precision of 4.7 MUm. PMID- 29604730 TI - Design and development of a novel strain gauge automatic pasting device for mini split Hopkinson pressure bar. AB - In a split Hopkinson pressure bar (SHPB) experiment, the pasting quality of strain gauges will directly affect the accuracy of the measurement results. The traditional method of pasting the strain gauges is done manually by the experimenter. In the process of pasting, it is easy to shift or twist the strain gauge, and the experimental results are greatly affected by human factors. In this paper, a novel type automatic pasting device for strain gauges is designed and developed, which can be used to accurately and rapidly paste the strain gauges. The paste quality is reliable, and it can guarantee the consistency of SHPB experimental measurement. We found that a clamping force of 74 N achieved a success rate of 97%, whilst ensuring good adhesion. PMID- 29604731 TI - Measurement of nanoscale molten polymer droplet spreading using atomic force microscopy. AB - We present a technique for measuring molten polymer spreading dynamics with nanometer scale spatial resolution at elevated temperatures using atomic force microscopy (AFM). The experimental setup is used to measure the spreading dynamics of polystyrene droplets with 2 MUm diameters at 115-175 degrees C on sapphire, silicon oxide, and mica. Custom image processing algorithms determine the droplet height, radius, volume, and contact angle of each AFM image over time to calculate the droplet spreading dynamics. The contact angle evolution follows a power law with time with experimentally determined values of -0.29 +/- 0.01, 0.08 +/- 0.02, and -0.21 +/- 0.01 for sapphire, silicon oxide, and mica, respectively. The non-zero steady state contact angles result in a slower evolution of contact angle with time consistent with theories combining molecular kinetic and hydrodynamic models. Monitoring the cantilever phase provides additional information about the local mechanics of the droplet surface. We observe local crystallinity on the molten droplet surface, where crystalline structures appear to nucleate at the contact line and migrate toward the top of the droplet. Increasing the temperature from 115 degrees C to 175 degrees C reduced surface crystallinity from 35% to 12%, consistent with increasingly energetically favorable amorphous phase as the temperature approaches the melting temperature. This platform provides a way to measure spreading dynamics of extremely small volumes of heterogeneously complex fluids not possible through other means. PMID- 29604732 TI - Laser frequency stabilization using a transfer interferometer. AB - We present a laser frequency stabilization system that uses a transfer interferometer to stabilize slave lasers to a reference laser. Our implementation uses off-the-shelf optical components along with microcontroller-based digital feedback, and offers a simple, flexible, and robust way to stabilize multiple laser frequencies to better than 1 MHz. PMID- 29604733 TI - Stress distribution and pressure-bearing capacity of a high-pressure split cylinder die with prism cavity. AB - A novel high-pressure belt-type die with a split-type cylinder is investigated with respect to extending its lifetime and improving its pressure bearing capacity. Specifically, a tungsten carbide cylinder is split into several parts along the radial direction with a prism-type cavity. In this paper, the cylinders with different split numbers are chosen to study the stress distribution and compare them with the traditional belt-type die. The simulation results indicate that the split cylinder has much smaller stress than those in the belt-type cylinder, and the statistical analysis reveals that the split-pressure cylinder is able to bear higher pressure. Experimental tests also show that the high pressure die with a split cylinder and prism cavity has a stronger pressure bearing capacity than a belt-type die. The split cylinder has advantages of easy manufacturing, high pressure bearing capacity, and replaceable performance. PMID- 29604734 TI - A Fabry-Perot interferometer with wire-grid polarizers as beamsplitters at terahertz frequencies. AB - The design of a compact Fabry-Perot interferometer (FPi) and results of the experimental studies carried out using the device are presented. Our FPi uses freestanding wire-grid polarizers (WGPs) as beamsplitters and is suitable for use at terahertz (THz) frequencies. The FPi was studied at the LUCX facility, KEK, Japan, and an 8 MeV linear electron accelerator was used to generate coherent Smith-Purcell radiation. The FPi was designed to be easy to align and reposition for experiments at linear accelerator facilities. All of the components used were required to have a flat or well understood frequency response in the THz range. The performance of the FPi with WGPs was compared to that of a Michelson interferometer and the FPi is seen to perform well. The effectiveness of the beamsplitters used in the FPi is also investigated. Measurements made with the FPi using WGPs, the preferred beamsplitters, are compared to measurements made with the FPi using silicon wafers as alternative beamsplitters. The FPi performs well with both types of beamsplitter in the frequency range used (0.3-0.5 THz). The successful measurements taken with the FPi demonstrate a compact and adaptable interferometer that is capable of analyzing THz radiation over a broad frequency range. The scheme is particularly well suited for polarization studies of THz radiation produced in an accelerator environment. PMID- 29604735 TI - Feasibility evaluation of a neutron grating interferometer with an analyzer grating based on a structured scintillator. AB - We introduce an analyzer grating based on a structured scintillator fabricated by a gadolinium oxysulfide powder filling method for a symmetric Talbot-Lau neutron grating interferometer. This is an alternative way to analyze the Talbot self image of a grating interferometer without using an absorption grating to block neutrons. Since the structured scintillator analyzer grating itself generates the signal for neutron detection, we do not need an additional scintillator screen as an absorption analyzer grating. We have developed and tested an analyzer grating based on a structured scintillator in our symmetric Talbot-Lau neutron grating interferometer to produce high fidelity absorption, differential phase, and dark field contrast images. The acquired images have been compared to results of a grating interferometer utilizing a typical absorption analyzer grating with two commercial scintillation screens. The analyzer grating based on the structured scintillator enhances interference fringe visibility and shows a great potential for economical fabrication, compact system design, and so on. We report the performance of the analyzer grating based on a structured scintillator and evaluate its feasibility for the neutron grating interferometer. PMID- 29604736 TI - Collimation testing using slit Fresnel diffraction. AB - A simple collimation testing method based on slit Fresnel diffraction is proposed. The method needs only a CMOS and a slit with no requirement in dimensional accuracy. The light beam to be tested diffracts across the slit and forms a Fresnel diffraction pattern received by CMOS. After analysis, the defocusing amount and the distance between the primary peak point and secondary peak point of diffraction pattern fulfill an expression relationship and then the defocusing amount can be deduced from the expression. The method is applied to both the coherent beam and partially coherent beam, and these two beams are emitted from a laser and light-emitting diode (LED) with a spectrum width of about 50 nm in this paper. Simulations show that the wide spectrum of LED has the effect of smooth filtering to provide higher accuracy. Experiments show that the LED with a spectrum width of about 50 nm has a lower limitation error than the laser and can achieve up to 58.1601 MUm with focal length 200 mm and slit width 15 mm. PMID- 29604737 TI - Experimental platform for investigations of high-intensity laser plasma interactions in the magnetic field of a pulsed power generator. AB - An experimental platform for the studying of high-intensity laser plasma interactions in strong magnetic fields has been developed based on the 1 MA Zebra pulsed power generator coupled with the 50-TW Leopard laser. The Zebra generator produces 100-300 T longitudinal and transverse magnetic fields with different types of loads. The Leopard laser creates plasma at an intensity of 1019 W/cm2 in the magnetic field of coil loads. Focusing and targeting systems are integrated in the vacuum chamber of the pulsed power generator and protected from the plasma debris and strong mechanical shock. The first experiments with plasma at laser intensity >2 * 1018 W/cm2 demonstrated collimation of the laser produced plasma in the axial magnetic field strength >100 T. PMID- 29604738 TI - New design for inertial piezoelectric motors. AB - We have designed, implemented, and tested a novel inertial piezoelectric motor (IPM) that is the first IPM to have controllable total friction force, which means that it sticks with large total friction forces and slips with severely reduced total friction forces. This allows the IPM to work with greater robustness and produce a larger output force at a lower threshold voltage while also providing higher rigidity. This is a new IPM design that means that the total friction force can be dramatically reduced or even canceled where necessary by pushing the clamping points at the ends of a piezoelectric tube that contains the sliding shaft inside it in the opposite directions during piezoelectric deformation. Therefore, when the shaft is propelled forward by another exterior piezoelectric tube, the inner piezoelectric tube can deform to reduce the total friction force acting on the shaft instantly and cause more effective stepping movement of the shaft. While our new IPM requires the addition of another piezoelectric tube, which leads to an increase in volume of 120% when compared with traditional IPMs, the average step size has increased by more than 400% and the threshold voltage has decreased by more than 50 V. The improvement in performance is far more significant than the increase in volume. This enhanced performance will allow the proposed IPM to work under large load conditions where a simple and powerful piezoelectric motor is needed. PMID- 29604739 TI - Exploring microwave resonant multi-point ignition using high-speed schlieren imaging. AB - Microwave plasma offers a potential method to achieve rapid combustion in a high speed combustor. In this paper, microwave resonant multi-point ignition and its control method have been studied via high-speed schlieren imaging. The experiment was conducted with the microwave resonant ignition system and the schlieren optical system. The microwave pulse in 2.45 GHz with 2 ms width and 3 kW peak power was employed as an ignition energy source to produce initial flame kernels in the combustion chamber. A reflective schlieren method was designed to illustrate the flame development process with a high-speed camera. The bottom of the combustion chamber was made of a quartz glass coated with indium tin oxide, which ensures sufficient microwave reflection and light penetration. Ignition experiments were conducted at 2 bars of stoichiometric methane-air mixtures. Schlieren images show that flame kernels were generated at more than one location simultaneously and flame propagated with different speeds in different flame kernels. Ignition kernels were discussed in three types according to their appearances. Pressure curves and combustion duration also show that multi-point ignition plays a significant role in accelerating combustion. PMID- 29604740 TI - A multiple-fan active control wind tunnel for outdoor wind speed and direction simulation. AB - This article presents a new type of active controlled multiple-fan wind tunnel. The wind tunnel consists of swivel plates and arrays of direct current fans, and the rotation speed of each fan and the shaft angle of each swivel plate can be controlled independently for simulating different kinds of outdoor wind fields. To measure the similarity between the simulated wind field and the outdoor wind field, wind speed and direction time series of two kinds of wind fields are recorded by nine two-dimensional ultrasonic anemometers, and then statistical properties of the wind signals in different time scales are analyzed based on the empirical mode decomposition. In addition, the complexity of wind speed and direction time series is also investigated using multiscale entropy and multivariate multiscale entropy. Results suggest that the simulated wind field in the multiple-fan wind tunnel has a high degree of similarity with the outdoor wind field. PMID- 29604741 TI - Calibrating an ultra-low expansion cavity for high precision spectroscopy from 630 THz to 685 THz using molecular tellurium lines. AB - We report on the calibration of a temperature stabilized ultra-low expansion (ULE) cavity using previously measured molecular tellurium and atomic cesium lines. By means of a dual frequency modulation technique, the frequency dependence of the free spectral range of the ULE cavity is measured and was found to vary by less than 60 Hz over the ~55 THz range of the calibration. This method of calibration enables the ULE cavity to measure absolute frequencies to better than 1.5 MHz. PMID- 29604742 TI - Note: Tandem Kirkpatrick-Baez microscope with sixteen channels for high resolution laser-plasma diagnostics. AB - Multi-channel Kirkpatrick-Baez (KB) microscopes, which have better resolution and collection efficiency than pinhole cameras, have been widely used in laser inertial confinement fusion to diagnose time evolution of the target implosion. In this study, a tandem multi-channel KB microscope was developed to have sixteen imaging channels with the precise control of spatial resolution and image intervals. This precise control was created using a coarse assembly of mirror pairs with high-accuracy optical prisms, followed by precise adjustment in real time x-ray imaging experiments. The multilayers coated on the KB mirrors were designed to have substantially the same reflectivity to obtain a uniform brightness of different images for laser-plasma temperature analysis. The study provides a practicable method to achieve the optimum performance of the microscope for future high-resolution applications in inertial confinement fusion experiments. PMID- 29604743 TI - Increasing the magnetic-field capability of the magneto-inertial fusion electrical discharge system using an inductively coupled coil. AB - Magnetized high energy density physics (HEDP) is a very active and relatively unexplored field that has applications in inertial confinement fusion, astrophysical plasma science, and basic plasma physics. A self-contained device, the Magneto-Inertial Fusion Electrical Discharge System, MIFEDS [G. Fiksel et al., Rev. Sci. Instrum. 86, 016105 (2015)], was developed at the Laboratory for Laser Energetics to conduct magnetized HEDP experiments on both the OMEGA [T. R. Boehly et al., Opt. Commun. 133, 495-506 (1997)] and OMEGA EP [J. H. Kelly et al., J. Phys. IV France 133, 75 (2006) and L. J. Waxer et al., Opt. Photonics News 16, 30 (2005)] laser systems. Extremely high magnetic fields are a necessity for magnetized HEDP, and the need for stronger magnetic fields continues to drive the redevelopment of the MIFEDS device. It is proposed in this paper that a magnetic coil that is inductively coupled rather than directly connecting to the MIFEDS device can increase the overall strength of the magnetic field for HEDP experiments by increasing the efficiency of energy transfer while decreasing the effective magnetized volume. A brief explanation of the energy delivery of the MIFEDS device illustrates the benefit of inductive coupling and is compared to that of direct connection for varying coil size and geometry. A prototype was then constructed to demonstrate a 7-fold increase in energy delivery using inductive coupling. PMID- 29604744 TI - Quasi-adiabatic calorimeter for direct electrocaloric measurements. AB - The electrocaloric effect (ECE) in ferroelectric materials is a promising candidate for small, effective, low cost, and environmentally friendly solid state cooling applications. Instead of the commonly used indirect estimates based on Maxwell's relations, direct measurements of the ECE are required to obtain reliable values. In this work, we report on a custom-made quasi-adiabatic calorimeter for direct ECE measurements. The ECE is measured for two promising lead-free materials: Ba(Zr0.12Ti0.88)O3 and Ba(Zr0.2Ti0.8)O3 bulk ceramics. Adiabatic temperature changes of DeltaTEC = 0.5 K at 355 K and DeltaTEC = 0.3 K at 314 K were achieved under the application of an electric field of 2 kV/mm for the Ba(Zr0.12Ti0.88)O3 and Ba(Zr0.2Ti0.8)O3 samples, respectively. The quasi adiabatic ECE measurements reliably match other direct EC measurements using a differential scanning calorimeter or an infrared camera. The data are compared to indirect EC estimations based on Maxwell's relations and show that the indirect measurements typically underestimate the effect to a certain degree. PMID- 29604745 TI - A monolithic microsphere-fiber probe for spatially resolved Raman spectroscopy: Application to head and neck squamous cell carcinomas. AB - The ability to identify precise cancer margins in vivo during a surgical excision is critical to the well-being of the patient. Decreased operative time has been linked to shorter patient recovery time, and there are risks associated with removing either too much or too little tissue from the surgical site. The more rapidly and accurately a surgeon can identify and excise diseased tissue, the better the prognosis for the patient. To this end, we investigate both malignant and healthy oral cavity tissue using the Raman spectroscopy, with a monolithic microsphere-fiber probe. Our results indicate that this probe has decreased the size of the analyzed area by more than an order of magnitude, as compared to a conventional fiber reflection probe. Scanning the probe across the tissues reveals variations in the Raman spectra that enable us to differentiate between malignant and healthy tissues. Consequently, we anticipate that the high spatial resolution afforded by the probe will permit us to identify tumor margins in detail, thereby optimizing tissue removal and improving patient outcomes. PMID- 29604746 TI - Relaxation calorimetry at very low temperatures for systems with internal relaxation. AB - We present the detailed introduction of our relaxation calorimetry designed for tiny samples down to very low temperatures of 0.03 K. In particular, we discuss how to analyze the data that are modified by an internal thermal relaxation in the sample or in the sample stage of the specific heat cell. We demonstrate that the correct heat capacity is obtained even when the relaxation curve has a triple exponential decay, rather than a double exponential decay which has usually been discussed. As an example, we discuss the measurements performed for alpha-YbAlB4 in a magnetic field of 5 T, where we found the triple exponential decay due to a thermal relaxation between electron and nuclear contributions at relatively high temperature well above 0.1 K. Our modified analysis provides the best solution in such a case. PMID- 29604747 TI - Transmission in situ and operando high temperature X-ray powder diffraction in variable gaseous environments. AB - This work describes a device for time-resolved synchrotron-based in situ and operando X-ray powder diffraction measurements at elevated temperatures under controllable gaseous environments. The respective gaseous sample environment is realized via a gas-tight capillary-in-capillary design, where the gas flow is achieved through an open-end 0.5 mm capillary located inside a 0.7 mm capillary filled with a sample powder. Thermal mass flow controllers provide appropriate gas flows and computer-controlled on-the-fly gas mixing capabilities. The capillary system is centered inside an infrared heated, proportional integral differential-controlled capillary furnace allowing access to temperatures up to 1000 degrees C. PMID- 29604749 TI - Universal sensor based on the spectroscopy of glow discharge for the detection of traces of atoms or molecules in air. AB - A sensitive and versatile sensor for the detection of traces of atoms or molecules in air based on the emission spectroscopy of glow discharge in air has been developed and studied. The advantages of this sensor compared to other well known methods are that it renders the use of ultrahigh vacuum or cryogenic temperatures superfluous. The sensor is insensitive to the presence of water vapor (for example, in exhaled air) because of the absence of strong water lines in the visible spectral range. It has a high spectral selectivity limited only by Doppler broadening of the emission lines. The high selectivity of the sensor combined with a wide spectral range allows the detection of many toxic impurities, which can be present in air. Moreover, the spectral range used covers almost all biomarkers in exhaled air, making the proposed sensor extremely interesting for medical applications. To our knowledge, the proposed method is the first based on a glow discharge in air. PMID- 29604748 TI - Real-time synchronous measurement of curing characteristics and polymerization stress in bone cements with a cantilever-beam based instrument. AB - An instrumentation capable of simultaneously determining degree of conversion (DC), polymerization stress (PS), and polymerization exotherm (PE) in real time was introduced to self-curing bone cements. This comprises the combination of an in situ high-speed near-infrared spectrometer, a cantilever-beam instrument with compliance-variable feature, and a microprobe thermocouple. Two polymethylmethacrylate-based commercial bone cements, containing essentially the same raw materials but differ in their viscosity for orthopedic applications, were used to demonstrate the applicability of the instrumentation. The results show that for both the cements studied the final DC was marginally different, the final PS was different at the low compliance, the peak of the PE was similar, and their polymerization rates were significantly different. Systematic variation of instrumental compliance for testing reveals differences in the characteristics of PS profiles of both the cements. This emphasizes the importance of instrumental compliance in obtaining an accurate understanding of PS evaluation. Finally, the key advantage for the simultaneous measurements is that these polymerization properties can be correlated directly, thus providing higher measurement confidence and enables a more in-depth understanding of the network formation process. PMID- 29604750 TI - PDV-based estimation of ejecta particles' mass-velocity function from shock loaded tin experiment. AB - A metallic tin plate with a given surface finish of wavelength lambda ? 60 MUm and amplitude h ? 8 MUm is explosively driven by an electro-detonator with a shock-induced breakout pressure PSB = 28 GPa (unsupported). The resulting dynamic fragmentation process, the so-called "micro-jetting," is the creation of high speed jets of matter moving faster than the bulk metallic surface. Hydrodynamic instabilities result in the fragmentation of these jets into micron-sized metallic particles constituting a self-expanding cloud of droplets, whose areal mass, velocity, and particle size distributions are unknown. Lithium-niobate piezoelectric sensor measured areal mass and Photonic Doppler Velocimetry (PDV) was used to get a time-velocity spectrogram of the cloud. In this article, we present both experimental mass and velocity results and we relate the integrated areal mass of the cloud to the PDV power spectral density with the assumption of a power law particle size distribution. Two models of PDV spectrograms are described. The first one accounts for the speckle statistics of the spectrum and the second one describes an average spectrum for which speckle fluctuations are removed. Finally, the second model is used for a maximum likelihood estimation of the cloud's parameters from PDV data. The estimated integrated areal mass from PDV data is found to agree well with piezoelectric results. We highlight the relevance of analyzing PDV data and correlating different diagnostics to retrieve the physical properties of ejecta particles. PMID- 29604751 TI - Development of a helicon ion source: Simulations and preliminary experiments. AB - In the present context, the extraction system of a helicon ion source has been simulated and constructed. Results of the ion source commissioning at up to 20 kV are presented as well as simulations of an ion beam extraction system. Argon current of more than 200 MUA at up to 20 kV is extracted and is characterized with a Faraday cup and beam profile monitoring grid. By changing different ion source parameters such as RF power, extraction voltage, and working pressure, an ion beam with current distribution exhibiting a central core has been detected. Jump transition of ion beam current emerges at the RF power near to 700 W, which reveals that the helicon mode excitation has reached this power. Furthermore, measuring the emission line intensity of Ar ii at 434.8 nm is the other way we have used for demonstrating the mode transition from inductively coupled plasma to helicon. Due to asymmetrical longitudinal power absorption of a half-helix helicon antenna, it is used for the ion source development. The modeling of the plasma part of the ion source has been carried out using a code, HELIC. Simulations are carried out by taking into account a Gaussian radial plasma density profile and for plasma densities in range of 1018-1019 m-3. Power absorption spectrum and the excited helicon mode number are obtained. Longitudinal RF power absorption for two different antenna positions is compared. Our results indicate that positioning the antenna near to the plasma electrode is desirable for the ion beam extraction. The simulation of the extraction system was performed with the ion optical code IBSimu, making it the first helicon ion source extraction designed with the code. Ion beam emittance and Twiss parameters of the ellipse emittance are calculated at different iterations and mesh sizes, and the best values of the mesh size and iteration number have been obtained for the calculations. The simulated ion beam extraction system has been evaluated using optimized parameters such as the gap distance between electrodes, electrodes aperture, and extraction voltage. The gap distance, ground electrode aperture, and extraction voltage have been changed between 3 and 9 mm, 2-6.5 mm, and 10-35 kV in the simulations, respectively. PMID- 29604752 TI - Note: Eliminating stripe artifacts in light-sheet fluorescence imaging. AB - We report two techniques to mitigate stripe artifacts in light-sheet fluorescence imaging. The first uses an image processing algorithm called the multidirectional stripe remover method to filter stripes from an existing image. The second uses an elliptical holographic diffuser with strong scattering anisotropy to prevent stripe formation during image acquisition. These techniques facilitate accurate interpretation of image data, especially in denser samples. They are also facile and cost-effective. PMID- 29604753 TI - Dianion diagnostics in DESIREE: High-sensitivity detection of Cn2- from a sputter ion source. AB - A sputter ion source with a solid graphite target has been used to produce dianions with a focus on carbon cluster dianions, Cn2-, with n = 7-24. Singly and doubly charged anions from the source were accelerated together to kinetic energies of 10 keV per atomic unit of charge and injected into one of the cryogenic (13 K) ion-beam storage rings of the Double ElectroStatic Ion Ring Experiment facility at Stockholm University. Spontaneous decay of internally hot Cn2- dianions injected into the ring yielded Cn- anions with kinetic energies of 20 keV, which were counted with a microchannel plate detector. Mass spectra produced by scanning the magnetic field of a 90 degrees analyzing magnet on the ion injection line reflect the production of internally hot C72- - C242- dianions with lifetimes in the range of tens of microseconds to milliseconds. In spite of the high sensitivity of this method, no conclusive evidence of C62- was found while there was a clear C72- signal with the expected isotopic distribution. This is consistent with earlier experimental studies and with theoretical predictions. An upper limit is deduced for a C62- signal that is two orders-of-magnitude smaller than that for C72-. In addition, CnO2- and CnCu2- dianions were detected. PMID- 29604754 TI - Blind system identification of two-thermocouple sensor based on cross-relation method. AB - In dynamic temperature measurement, the dynamic characteristics of the sensor affect the accuracy of the measurement results. Thermocouples are widely used for temperature measurement in harsh conditions due to their low cost, robustness, and reliability, but because of the presence of the thermal inertia, there is a dynamic error in the dynamic temperature measurement. In order to eliminate the dynamic error, two-thermocouple sensor was used to measure dynamic gas temperature in constant velocity flow environments in this paper. Blind system identification of two-thermocouple sensor based on a cross-relation method was carried out. Particle swarm optimization algorithm was used to estimate time constants of two thermocouples and compared with the grid based search method. The method was validated on the experimental equipment built by using high temperature furnace, and the input dynamic temperature was reconstructed by using the output data of the thermocouple with small time constant. PMID- 29604755 TI - Development of an air flow calorimeter prototype for the measurement of thermal power released by large radioactive waste packages. AB - The estimation and control of the thermal power released by the radioactive waste packages are a key parameter in the management of radioactive waste geological repository sites. In the framework of the European project "Metrology for decommissioning nuclear facilities," the French National Agency of Radioactive Waste Management (ANDRA) collaborates with Laboratoire National de Metrologie et D'essais in order to measure the thermal power up to 500 W of typical real size radioactive waste packages (of at least 0.175 m3) with an uncertainty better than 5% by using a measurement method traceable to the international system of units. One of the selected metrological approaches is based on the principles of air flow calorimetry. This paper describes in detail the development of the air flow calorimeter prototype as well as the design of a radioactive waste package simulator used for its calibration. Results obtained from the calibration of the calorimeter and from the determination of thermal powers are presented here with an investigation of the measurement uncertainties. PMID- 29604756 TI - Full path compensation laser feedback interferometry for remote sensing with recovered nanometer resolutions. AB - The accuracy of the existing laser feedback interferometry for measuring the remote target is limited to several microns due to environmental disturbances. A novel approach is presented in this paper based on the double-beam frequency shift feedback of the laser, which can completely eliminate the dead path errors and measure the displacement or vibration with accuracy at nanometer scale even at a far measurement distance. The two beams emitted from one Nd:YVO4 crystal are incident on the measurement target and its adjacent reference surface, respectively. The reference surface could be taken from the nearby stationary object, without the need to put a reference mirror. The feedback paths and shift frequencies of the two beams are the same, so the air disturbances and the thermal effects in the way could be fully compensated. Under common room conditions, the displacement of a steel block at a distance of 10 m is measured, which proved that the system's stability is +/-12 nm in 100 s and +/-50 nm in 1000 s, the short-term resolution is better than 3 nm, and the linearity within the 300 mm range is 5 * 10-6 and within the 100 MUm range is 1 * 10-4. PMID- 29604757 TI - Study on data acquisition system based on reconfigurable cache technology. AB - Waveform capture rate is one of the key features of digital acquisition systems, which represents the waveform processing capability of the system in a unit time. The higher the waveform capture rate is, the larger the chance to capture elusive events is and the more reliable the test result is. First, this paper analyzes the impact of several factors on the waveform capture rate of the system, then the novel technology based on reconfigurable cache is further proposed to optimize system architecture, and the simulation results show that the signal-to noise ratio of signal, capacity, and structure of cache have significant effects on the waveform capture rate. Finally, the technology is demonstrated by the engineering practice, and the results show that the waveform capture rate of the system is improved substantially without significant increase of system's cost, and the technology proposed has a broad application prospect. PMID- 29604758 TI - Phase noise cancellation in polarisation-maintaining fibre links. AB - The distribution of ultra-narrow linewidth laser radiation is an integral part of many challenging metrological applications. Changes in the optical pathlength induced by environmental disturbances compromise the stability and accuracy of optical fibre networks distributing the laser light and call for active phase noise cancellation. Here we present a laboratory scale optical (at 578 nm) fibre network featuring all polarisation maintaining fibres in a setup with low optical powers available and tracking voltage-controlled oscillators implemented. The stability and accuracy of this system reach performance levels below 1 * 10-19 after 10 000 s of averaging. PMID- 29604759 TI - Design and development of a low cost, high current density power supply for streamer free atmospheric pressure DBD plasma generation in air. AB - This paper presents a new power supply architecture for generating a uniform dielectric barrier discharge (DBD) plasma in air medium at atmospheric pressure. It is quite a challenge to generate atmospheric pressure uniform glow discharge plasma, especially in air. This is because air plasma needs very high voltage for initiation of discharge. If the high voltage is used along with high current density, it leads to the formation of streamers, which is undesirable for most applications like textile treatment, etc. Researchers have tried to generate high density plasma using a RF source, nanosecond pulsed DC source, and medium frequency AC source. However, these solutions suffer from low current discharge and low efficiency due to the addition of an external resistor to control the discharge current. Moreover, they are relatively costly and bulky. This paper presents a new power supply configuration which is very compact and generates high average density (~0.28 W/cm2) uniform glow DBD plasma in air at atmospheric pressure. The efficiency is also higher as no external resistor is required to control the discharge current. An inherent feature of this topology is that it can drive higher current oscillations (~50 A peak and 2-3 MHz frequency) into the plasma that damp out due to the plasma dissipation only. A newly proposed model has been used with experimental validation in this paper. Simulations and experimental validation of the proposed topology are included. Also, the application of the generated plasma for polymer film treatment is demonstrated. PMID- 29604761 TI - A high bandwidth three-axis out-of-plane motion measurement system based on optical beam deflection. AB - Multi-axis measurement of motion is indispensable for characterization of dynamic systems and control of motion stages. This paper presents an optical beam deflection-based measurement system to simultaneously measure three-axis out-of plane motion of both micro- and macro-scale targets. Novel strategies are proposed to calibrate the sensitivities of the measurement system. Subsequently the measurement system is experimentally realized and calibrated. The system is employed to characterize coupled linear and angular motion of a piezo-actuated stage. The measured motion is shown to be in agreement with theoretical expectation. Next, the high bandwidth of the measurement system has been showcased by utilizing it to measure coupled two-axis transient motion of a Radio Frequency Micro-Electro-Mechanical System switch with a rise time of about 60 MUs. Finally, the ability of the system to measure out-of-plane angular motion about the second axis has been demonstrated by measuring the deformation of a micro-cantilever beam. PMID- 29604762 TI - A compact nanosecond pulse generator for DBD tube characterization. AB - High voltage pulses of very short duration and fast rise time are required for generating uniform and diffuse plasma under various operating conditions. Dielectric Barrier Discharge (DBD) has been generated by high voltage pulses of short duration and fast rise time to produce diffuse plasma in the discharge gap. The high voltage pulse power generators have been chosen according to the requirement for the DBD applications. In this paper, a compact solid-state unipolar pulse generator has been constructed for characterization of DBD plasma. This pulsar is designed to provide repetitive pulses of 315 ns pulse width, pulse amplitude up to 5 kV, and frequency variation up to 10 kHz. The amplitude of the output pulse depends on the dc input voltage. The output frequency has been varied by changing the trigger pulse frequency. The pulsar is capable of generating pulses of positive or negative polarity by changing the polarity of pulse transformer's secondary. Uniform and stable homogeneous dielectric barrier discharge plasma has been produced successfully in a xenon DBD tube at 400-mbar pressure using the developed high voltage pulse generator. PMID- 29604763 TI - HEKATE-A novel grazing incidence neutron scattering concept for the European Spallation Source. AB - Structure and magnetism at surfaces and buried interfaces on the nanoscale can only be accessed by few techniques, one of which is grazing incidence neutron scattering. While the technique has its strongest limitation in a low signal and large background, due to the low scattering probability and need for high resolution, it can be expected that the high intensity of the European Spallation Source in Lund, Sweden, will make many more such studies possible, warranting a dedicated beamline for this technique. We present an instrument concept, Highly Extended K range And Tunable Experiment (HEKATE), for surface scattering that combines the advantages of two Selene neutron guides with unique capabilities of spatially separated distinct wavelength frames. With this combination, it is not only possible to measure large specular reflectometry ranges, even on free liquid surfaces, but also to use two independent incident beams with tunable sizes and resolutions that can be optimized for the specifics of the investigated samples. Further the instrument guide geometry is tuned for reduction of high energy particle background and only uses low to moderate supermirror coatings for high reliability and affordable cost. PMID- 29604764 TI - An effective temperature compensation approach for ultrasonic hydrogen sensors. AB - Hydrogen is a kind of promising clean energy resource with a wide application prospect, which will, however, cause a serious security issue upon the leakage of hydrogen gas. The measurement of its concentration is of great significance. In a traditional approach of ultrasonic hydrogen sensing, a temperature drift of 0.1 degrees C results in a concentration error of about 250 ppm, which is intolerable for trace amount of gas sensing. In order to eliminate the influence brought by temperature drift, we propose a feasible approach named as linear compensation algorithm, which utilizes the linear relationship between the pulse count and temperature to compensate for the pulse count error (DeltaN) caused by temperature drift. Experimental results demonstrate that our proposed approach is capable of improving the measurement accuracy and can easily detect sub-100 ppm of hydrogen concentration under variable temperature conditions. PMID- 29604765 TI - A hydrogen leak-tight, transparent cryogenic sample container for ultracold neutron transmission measurements. AB - The improvement of the number of extractable ultracold neutrons (UCNs) from converters based on solid deuterium (sD2) crystals requires a good understanding of the UCN transport and how the crystal's morphology influences its transparency to the UCNs. Measurements of the UCN transmission through cryogenic liquids and solids of interest, such as hydrogen (H2) and deuterium (D2), require sample containers with thin, highly polished and optically transparent windows and a well defined sample thickness. One of the most difficult sealing problems is that of light gases like hydrogen and helium at low temperatures against high vacuum. Here we report on the design of a sample container with two 1 mm thin amorphous silica windows cold-welded to aluminum clamps using indium wire gaskets, in order to form a simple, reusable, and hydrogen-tight cryogenic seal. The container meets the above-mentioned requirements and withstands up to 2 bar hydrogen gas pressure against isolation vacuum in the range of 10-5 to 10-7 mbar at temperatures down to 4.5 K. Additionally, photographs of the crystallization process are shown and discussed. PMID- 29604766 TI - Calculation of density of states of transition metals: From bulk sample to nanocluster. AB - A technique is presented of restoring the electronic density of states of the valence band from data of X-ray photoelectron spectroscopy (XPS). The originality of the technique consists in using a stochastic procedure to solve an integral equation relating the density of states and the experimental X-ray photoelectron spectra via the broadening function. To obtain the broadening function, only the XPS spectra of the core levels are needed. The results are presented for bulk sample of gold and tungsten and nanoclusters of tantalum; the possibility of using the results to determine the density of states of low-dimensional structures, including ensembles of metal nanoclusters, is demonstrated. PMID- 29604767 TI - Compressing the fluctuation of the magnetic field by dynamic compensation. AB - We present a dynamic compensation method to compress the spatial fluctuation of the static magnetic field (C-field) that provides a quantization axis in the atomic fountain clock. The coil current of the C-field is point-by-point modulated in accordance with the atoms probing the magnetic field along the flight trajectory. A homogeneous field with a 0.2 nT inhomogeneity is produced compared to a 5 nT under the static magnetic field with a constant current during the Ramsey interrogation. The corresponding uncertainty associated with the second-order Zeeman shift that we calculate is improved by one order of magnitude. The technique provides an alternative method to improve the uniformity of the magnetic field, particularly for large-scale equipment that is difficult to construct with an effective magnetic shielding. Our method is simple, robust, and essentially important in frequency evaluations concerning the dominant uncertainty contribution due to the quadratic Zeeman shift. PMID- 29604768 TI - Development of a hybrid molecular beam epitaxy deposition system for in situ surface x-ray studies. AB - A portable metalorganic gas delivery system designed and constructed to interface with an existing molecular beam epitaxy chamber at beamline 33-ID-E of the Advanced Photon Source is described. This system offers the ability to perform in situ X-ray measurements of complex oxide growth via hybrid molecular beam epitaxy. The performance of the hybrid molecular beam epitaxy system while delivering metalorganic source materials is described. The high-energy X-ray scattering capabilities of the hybrid molecular beam epitaxy system are demonstrated both on oxide films grown solely from the metalorganic source and ABO3 oxide perovskites containing elements from both the metalorganic source and a traditional effusion cell. PMID- 29604769 TI - Note: Additionally refined new possibilities of plasma probe diagnostics. AB - In two previous Notes published in this journal, a method of measuring probe sheath thickness and ion mass was described using Langmuir probe diagnostics in low pressure xenon plasma close to Maxwellian substance. According to the first Note, this method includes two stages: (i) in a special experiment with known ion mass, the Bohm and Child-Langmuir-Boguslavsky (CLB) equations for cylindrical Langmuir probes used in this xenon plasma were solved jointly to determine the probe sheath thicknesses and Bohm coefficient CBCyl ~ 1.13; and (ii) in a general experiment, with known CBCyl, the same equations could be solved to obtain the probe sheath thicknesses and the mean ion mass. In the second Note, the (i) stage of this method was refined: the results of the CLB probe sheath model application, which were termed "evaluations," were corrected using the step-front probe sheath model, which was closer to reality in the special experiment with the xenon plasma. This process resulted in a Bohm coefficient of CBCyl ~ 1.23 for the cylindrical probe. In the present Note, corrected xenon plasma parameters without the influence of the bare probe protective shield were used for the (i) stage of this diagnostic method. This action also refined the Bohm coefficient, lowering it to CBCyl ~ 0.745 for cylindrical probes. This advance makes the new diagnostics method more objective and reliable. PMID- 29604770 TI - Free microparticles-An inducing mechanism of pre-firing in high pressure gas switches for fast linear transformer drivers. AB - Microparticle initiated pre-firing of high pressure gas switches for fast linear transformer drivers (FLTDs) is experimentally and theoretically verified. First, a dual-electrode gas switch equipped with poly-methyl methacrylate baffles is used to capture and collect the microparticles. By analyzing the electrode surfaces and the collecting baffles by a laser scanning confocal microscope, microparticles ranging in size from tens of micrometers to over 100 MUm are observed under the typical working conditions of FLTDs. The charging and movement of free microparticles in switch cavity are studied, and the strong DC electric field drives the microparticles to bounce off the electrode. Three different modes of free microparticle motion appear to be responsible for switch pre firing. (i) Microparticles adhere to the electrode surface and act as a fixed protrusion which distorts the local electric field and initiates the breakdown in the gap. (ii) One particle escapes toward the opposite electrode and causes a near-electrode microdischarge, inducing the breakdown of the residual gap. (iii) Multiple moving microparticles are occasionally in cascade, leading to pre firing. Finally, as experimental verification, repetitive discharges at +/-90 kV are conducted in a three-electrode field-distortion gas switch, with two 8 mm gaps and pressurized with nitrogen. An ultrasonic probe is employed to monitor the bounce signals. In pre-firing incidents, the bounce is detected shortly before the collapse of the voltage waveform, which demonstrates that free microparticles contribute significantly to the mechanism that induces pre-firing in FLTD gas switches. PMID- 29604771 TI - Near shot-noise limited time-resolved circular dichroism pump-probe spectrometer. AB - We describe an optical near shot-noise limited time-resolved circular dichroism (TRCD) pump-probe spectrometer capable of reliably measuring circular dichroism signals in the order of MUdeg with nanosecond time resolution. Such sensitivity is achieved through a modification of existing TRCD designs and introduction of a new data processing protocol that eliminates approximations that have caused substantial nonlinearities in past measurements and allows the measurement of absorption and circular dichroism transients simultaneously with a single pump pulse. The exceptional signal-to-noise ratio of the described setup makes the TRCD technique applicable to a large range of non-biological and biological systems. The spectrometer was used to record, for the first time, weak TRCD kinetics associated with the triplet state energy transfer in the photosynthetic Fenna-Matthews-Olson antenna pigment-protein complex. PMID- 29604772 TI - A new high temperature reactor for operando XAS: Application for the dry reforming of methane over Ni/ZrO2 catalyst. AB - The construction of a high-temperature reaction cell for operando X-ray absorption spectroscopy characterization is reported. A dedicated cell was designed to operate as a plug-flow reactor using powder samples requiring gas flow and thermal treatment at high temperatures. The cell was successfully used in the reaction of dry reforming of methane (DRM). We present X-ray absorption results in the fluorescence detection mode on a 0.4 wt. % Ni/ZrO2 catalyst under realistic conditions at 750 degrees C, reproducing the conditions used for a conventional dynamic microreactor for the DRM reaction. The setup includes a gas distribution system that can be fully remotely operated. The reaction cell offers the possibility of transmission and fluorescence detection modes. The complete setup dedicated to the study of catalysts is permanently installed on the Collaborating Research Groups French Absorption spectroscopy beamline in Material and Environmental sciences (CRG-FAME) and French Absorption spectroscopy beamline in Material and Environmental sciences at Ultra-High Dilution (FAME-UHD) beamlines (BM30B and BM16) at the European Synchrotron Radiation Facility in Grenoble, France. PMID- 29604773 TI - Note: A unibody NIR transmission probe for in situ liquid detection. AB - The transmission probe is widely used for in situ spectroscopic detection in various fields. Conventional transmission probes are always assembled from parts, which require accurate assembly and good sealing. In this paper, a universal and reliable near-infrared (NIR) transmission probe is proposed, which is simply made up of a unibody fused silica rod. The proposed NIR transmission probe has been successfully used to measure the alcohol by volume of the Chinese spirit for quality control. This unibody NIR transmission probe has great potential for the detection of corrosive substances, owing to the good chemical resistance. PMID- 29604774 TI - Improvements to the ion Doppler spectrometer diagnostic on the HIT-SI experiments. AB - An ion Doppler spectrometer diagnostic system measuring impurity ion temperature and velocity on the HIT-SI and HIT-SI3 spheromak devices has been improved with higher spatiotemporal resolution and lower error than previously described devices. Hardware and software improvements to the established technique have resulted in a record of 6.9 MUs temporal and <=2.8 cm spatial resolution in the midplane of each device. These allow Ciii and Oii flow, displacement, and temperature profiles to be observed simultaneously. With 72 fused-silica fiber channels in two independent bundles, and an f/8.5 Czerny-Turner spectrometer coupled to a video camera, frame rates of up to ten times the imposed magnetic perturbation frequency of 14.5 kHz were achieved in HIT-SI, viewing the upper half of the midplane. In HIT-SI3, frame rates of up to eight times the perturbation frequency were achieved viewing both halves of the midplane. Biorthogonal decomposition is used as a novel filtering tool, reducing uncertainty in ion temperature from ?13 to ?5 eV (with an instrument temperature of 8-16 eV) and uncertainty in velocity from ?2 to ?1 km/s. Doppler shift and broadening are calculated via the Levenberg-Marquardt algorithm, after which the errors in velocity and temperature are uniquely specified. Axisymmetric temperature profiles on HIT-SI3 for Ciii peaked near the inboard current separatrix at ~40 eV are observed. Axisymmetric plasma displacement profiles have been measured on HIT-SI3, peaking at ~6 cm at the outboard separatrix. Both profiles agree with the upper half of the midplane observable by HIT-SI. With its complete midplane view, HIT-SI3 has unambiguously extracted axisymmetric, toroidal current dependent rotation of up to 3 km/s. Analysis of the temporal phase of the displacement uncovers a coherent structure, locked to the applied perturbation. Previously described diagnostic systems could not achieve such results. PMID- 29604776 TI - Hypersonic force measurements using internal balance based on optical micromachined Fabry-Perot interferometry. AB - Force measurements using wind tunnel balance are necessary for determining a variety of aerodynamic performance parameters, while the harsh environment in hypersonic flows requires that the measurement instrument should be reliable and robust, in against strong electromagnetic interference, high vacuum, or metal (oxide) dusts. In this paper, we demonstrated a three-component internal balance for hypersonic aerodynamic force measurements, using novel optical micromachined Fabry-Perot interferometric (FPI) strain gauges as sensing elements. The FPI gauges were fabricated using Micro-Opto-Electro-Mechanical Systems (MOEMS) surface and bulk fabrication techniques. High-reflectivity coatings are used to form a high-finesse Fabry-Perot cavity, which benefits a high resolution. Antireflective and passivation coatings are used to reduce unwanted interferences. The FPI strain gauge based balance has been calibrated and evaluated in a Mach 5 hypersonic flow. The results are compared with the traditional technique using the foil resistive strain gauge balance, indicating that the proposed balance based on the MOEMS FPI strain gauge is reliable and robust and is potentially suitable for the hypersonic wind tunnel harsh environment. PMID- 29604777 TI - The LAMP instrument at the Linac Coherent Light Source free-electron laser. AB - The Laser Applications in Materials Processing (LAMP) instrument is a new end station for soft X-ray imaging, high-field physics, and ultrafast X-ray science experiments that is available to users at the Linac Coherent Light Source (LCLS) free-electron laser. While the instrument resides in the Atomic, Molecular and Optical science hutch, its components can be used at any LCLS beamline. The end station has a modular design that provides high flexibility in order to meet user defined experimental requirements and specifications. The ultra-high-vacuum environment supports different sample delivery systems, including pulsed and continuous atomic, molecular, and cluster jets; liquid and aerosols jets; and effusive metal vapor beams. It also houses movable, large-format, high-speed pnCCD X-ray detectors for detecting scattered and fluorescent photons. Multiple charged-particle spectrometer options are compatible with the LAMP chamber, including a double-sided spectrometer for simultaneous and even coincident measurements of electrons, ions, and photons produced by the interaction of the high-intensity X-ray beam with the various samples. Here we describe the design and capabilities of the spectrometers along with some general aspects of the LAMP chamber and show some results from the initial instrument commissioning. PMID- 29604778 TI - Direct measurement of fast transients by using boot-strapped waveform averaging. AB - An approximation to coherent sampling, also known as boot-strapped waveform averaging, is presented. The method uses digital cavities to determine the condition for coherent sampling. It can be used to increase the effective sampling rate of a repetitive signal and the signal to noise ratio simultaneously. The method is demonstrated by using it to directly measure the fluorescence lifetime from Rhodamine 6G by digitizing the signal from a fast avalanche photodiode. The obtained lifetime of 4.0 ns is in agreement with the known values. PMID- 29604779 TI - Note: A new method for directly reducing the sampling jitter noise of the digital phasemeter. AB - The sampling jitter noise is one non-negligible noise source of the digital phasemeter used for space gravitational wave detection missions. This note provides a new method for directly reducing the sampling jitter noise of the digital phasemeter, by adding a dedicated signal of which the frequency, amplitude, and initial phase should be pre-set. In contrast to the phase correction using the pilot-tone in the work of Burnett, Gerberding et al., Liang et al., Ales et al., Gerberding et al., and Ware et al. [M.Sc. thesis, Lulea University of Technology, 2010; Classical Quantum Gravity 30, 235029 (2013); Rev. Sci. Instrum. 86, 016106 (2015); Rev. Sci. Instrum. 86, 084502 (2015); Rev. Sci. Instrum. 86, 074501 (2015); and Proceedings of the Earth Science Technology Conference (NASA, USA, 2006)], the new method is intrinsically additive noise suppression. The experiment results validate that the new method directly reduces the sampling jitter noise without data post-processing and provides the same phase measurement noise level (10-6 rad/Hz1/2 at 0.1 Hz) as the pilot-tone correction. PMID- 29604780 TI - A simple vibrating sample magnetometer for macroscopic samples. AB - We here present a simple model of a vibrating sample magnetometer (VSM). The system allows recording magnetization curves at room temperature with a resolution of the order of 0.01 emu and is appropriated for macroscopic samples. The setup can be mounted with different configurations depending on the requirements of the sample to be measured (mass, saturation magnetization, saturation field, etc.). We also include here examples of curves obtained with our setup and comparison curves measured with a standard commercial VSM that confirms the reliability of our device. PMID- 29604781 TI - Scalable gamma-ray camera for wide-area search based on silicon photomultipliers array. AB - Portable coded-aperture imaging systems based on scintillators and semiconductors have found use in a variety of radiological applications. For stand-off detection of weakly emitting materials, large volume detectors can facilitate the rapid localization of emitting materials. We describe a scalable coded-aperture imaging system based on 5.02 * 5.02 cm2 CsI(Tl) scintillator modules, each partitioned into 4 * 4 * 20 mm3 pixels that are optically coupled to 12 * 12 pixel silicon photo-multiplier (SiPM) arrays. The 144 pixels per module are read-out with a resistor-based charge-division circuit that reduces the readout outputs from 144 to four signals per module, from which the interaction position and total deposited energy can be extracted. All 144 CsI(Tl) pixels are readily distinguishable with an average energy resolution, at 662 keV, of 13.7% FWHM, a peak-to-valley ratio of 8.2, and a peak-to-Compton ratio of 2.9. The detector module is composed of a SiPM array coupled with a 2 cm thick scintillator and modified uniformly redundant array mask. For the image reconstruction, cross correlation and maximum likelihood expectation maximization methods are used. The system shows a field of view of 45 degrees and an angular resolution of 4.7 degrees FWHM. PMID- 29604782 TI - An alternative way to increase the power gain of resonant rings. AB - Resonant rings which can amplify RF power through the coupling of waves are used for high power breakdown tests, unidirectional filters, or pulse-shaping techniques. Usually, the RF output terminal of a resonant ring is connected to a matched load. For the resonant ring at Peking University, the matched load has been replaced by a waveguide shorting plate to obtain higher conditioning power for the 1.3 GHz capacitive type power couplers. The power gain is increased significantly with this short termination with the same input RF power. Working mechanism analysis, experiments, and results of this modified resonant ring will be presented. PMID- 29604783 TI - Optical differential reflectance spectroscopy for photochromic molecules on solid surfaces. AB - Optical reflectance of thin adsorbates on solid surfaces is able to reveal fundamental changes of molecular properties compared to bulk systems. The detection of very small changes in the optical reflectance required several technical improvements in the past decades. We present an experimental setup that is capable of high-quality measurements of submonolayers and ultrathin layers of photochromic molecules on surfaces as well as quantifying their isomerization kinetics. By using photomultipliers as detectors, an enhancement of the signal-to noise ratio by a factor of three with a total reduction of light exposure on the sample by at least four orders of magnitude is achieved. The potential of the experimental setup is demonstrated by a characterization of the photoswitching and thermal switching of a spirooxazine derivate on a bismuth surface. PMID- 29604784 TI - An ionization pressure gauge with LaB6 emitter for long-term operation in strong magnetic fields. AB - We report here on a potentially significant improvement in the design of neutral pressure gauges of the so-called ASDEX-type which were first used in the Axially Symmetric Divertor EXperiment (ASDEX). Such gauges are considered state-of-the art and are in wide use in fusion experiments, but they nonetheless suffer from a relatively high failure rate when operated at high magnetic field strengths for long times. This is therefore a significant concern for long-pulse, high-field experiments such as Wendelstein 7-X (W7-X) and ITER. The new design is much more robust. The improvement is to use a LaB6 crystal instead of a tungsten wire as the thermionic emitter of electrons in the gauge. Such a LaB6 prototype gauge was successfully operated for a total of 60 h in B = 3.1 T, confirming the significantly improved robustness of the new design and qualifying it for near term operation in W7-X. With the LaB6 crystal, an order of magnitude reduction in heating current is achieved, relative to the tungsten filament based gauges, from 15-20 A to 1-2 A. This reduces the Lorenz forces and the heating power by an order of magnitude also and is presumably the reason for the much improved robustness. The new gauge design, test environment setup at the superconducting magnet, and results from test operation are described. PMID- 29604785 TI - Erratum: Note: Experimental setup for measuring the barocaloric effect in polymers: Application to natural rubber [Rev. Sci. Instrum. 88, 046103 (2017)]. PMID- 29604786 TI - Note: Making tens of centimeter long uniform microfluidic channels using commercial glass pipette. AB - Producing microchannels with diameters between 10 and 20 MUm and with lengths in the tens of centimeters is reported. The method can be modified to obtain diameters as narrow as 350 nm. Length-to-diameter aspect ratios that surpass 104 can be produced for a fraction of current production costs. The controllable channel is produced by applying a flame to the narrow end of a commercial pipette that is made from a soda-lime silicate. In combination with a pulling mechanism, applying heat to the composite material lengthens the pipette in a highly uniform way. Given that the materials and methods in this research are cost-effective when compared to femtosecond laser micromachining on 2D silicon-based surfaces, further research into producing microchannels from soda-lime silicates may revolutionize access to 3D controllable microchannels. PMID- 29604787 TI - Super-low-frequency wireless power transfer with lightweight coils for passing through a stainless steel plate. AB - To achieve wireless power transfer (WPT) through a stainless-steel plate, a super low frequency (SLF) was used as a resonance frequency. In our previous study of SLF-WPT, heavy coils were prepared. In this study, we designed lightweight coils using a WPT simulator that we developed previously. As a result, the weight was reduced to 1.69 kg from 11.9 kg, the previous coil weight. At a resonance frequency of 400 Hz, the transmission efficiency and output power of advanced SLF WPT reached 91% and 426 W, respectively, over a transmission distance of 30 mm. Furthermore, 80% efficiency and 317 W output were achieved when transmitting power through a 1 mm-thick stainless-steel plate. This performance is much better than that in previous reports. We show using both calculations and experimental results that a power-to-weight ratio of 252 W/kg is possible even when using a 400 Hz power supply frequency. PMID- 29604788 TI - Error analysis and new dual-cosine window for estimating the sensor frequency response function from the step response data. AB - Aiming at reducing the estimation error of the sensor frequency response function (FRF) estimated by the commonly used window-based spectral estimation method, the error models of interpolation and transient errors are derived in the form of non parameter models. Accordingly, window effects on the errors are analyzed and reveal that the commonly used hanning window leads to smaller interpolation error which can also be significantly eliminated by the cubic spline interpolation method when estimating the FRF from the step response data, and window with smaller front-end value can restrain more transient error. Thus, a new dual cosine window with its non-zero discrete Fourier transform bins at -3, -1, 0, 1, and 3 is constructed for FRF estimation. Compared with the hanning window, the new dual-cosine window has the equivalent interpolation error suppression capability and better transient error suppression capability when estimating the FRF from the step response; specifically, it reduces the asymptotic property of the transient error from O(N-2) of the hanning window method to O(N-4) while only increases the uncertainty slightly (about 0.4 dB). Then, one direction of a wind tunnel strain gauge balance which is a high order, small damping, and non-minimum phase system is employed as the example for verifying the new dual-cosine window based spectral estimation method. The model simulation result shows that the new dual-cosine window method is better than the hanning window method for FRF estimation, and compared with the Gans method and LPM method, it has the advantages of simple computation, less time consumption, and short data requirement; the actual data calculation result of the balance FRF is consistent to the simulation result. Thus, the new dual-cosine window is effective and practical for FRF estimation. PMID- 29604789 TI - Note: Soft X-ray transmission polarizer based on ferromagnetic thin films. AB - A transmission polarizer for producing elliptically polarized soft X-ray radiation from linearly polarized light is presented. The setup is intended for use at synchrotron and free-electron laser beamlines that do not directly offer circularly polarized light for, e.g., X-ray magnetic circular dichroism (XMCD) measurements or holographic imaging. Here, we investigate the degree of ellipticity upon transmission of linearly polarized radiation through a cobalt thin film. The experiment was performed at a photon energy resonant to the Co L3 edge, i.e., 778 eV, and the polarization of the transmitted radiation was determined using a polarization analyzer that measures the directional dependence of photo electrons emitted from a gas target. Elliptically polarized radiation can be created at any absorption edge showing the XMCD effect by using the respective magnetic element. PMID- 29604790 TI - A fully automated temperature-dependent resistance measurement setup using van der Pauw method. AB - The van der Pauw (VDP) method is widely used to identify the resistance of planar homogeneous samples with four contacts placed on its periphery. We have developed a fully automated thin film resistance measurement setup using the VDP method with the capability of precisely measuring a wide range of thin film resistances from few mOmega up to 10 GOmega under controlled temperatures from room temperature up to 600 degrees C. The setup utilizes a robust, custom-designed switching network board (SNB) for measuring current-voltage characteristics automatically at four different source-measure configurations based on the VDP method. Moreover, SNB is connected with low noise shielded coaxial cables that reduce the effect of leakage current as well as the capacitance in the circuit thereby enhancing the accuracy of measurement. In order to enable precise and accurate resistance measurement of the sample, wide range of sourcing currents/voltages are pre-determined with the capability of auto-tuning for ~12 orders of variation in the resistances. Furthermore, the setup has been calibrated with standard samples and also employed to investigate temperature dependent resistance (few Omega-10 GOmega) measurements for various chalcogenide based phase change thin films (Ge2Sb2Te5, Ag5In5Sb60Te30, and In3SbTe2). This setup would be highly helpful for measurement of temperature-dependent resistance of wide range of materials, i.e., metals, semiconductors, and insulators illuminating information about structural change upon temperature as reflected by change in resistances, which are useful for numerous applications. PMID- 29604791 TI - A postprocessing method in the HMC framework for predicting gene function based on biological instrumental data. AB - Predicting gene function based on biological instrumental data is a complicated and challenging hierarchical multi-label classification (HMC) problem. When using local approach methods to solve this problem, a preliminary results processing method is usually needed. This paper proposed a novel preliminary results processing method called the nodes interaction method. The nodes interaction method revises the preliminary results and guarantees that the predictions are consistent with the hierarchy constraint. This method exploits the label dependency and considers the hierarchical interaction between nodes when making decisions based on the Bayesian network in its first phase. In the second phase, this method further adjusts the results according to the hierarchy constraint. Implementing the nodes interaction method in the HMC framework also enhances the HMC performance for solving the gene function prediction problem based on the Gene Ontology (GO), the hierarchy of which is a directed acyclic graph that is more difficult to tackle. The experimental results validate the promising performance of the proposed method compared to state-of-the-art methods on eight benchmark yeast data sets annotated by the GO. PMID- 29604792 TI - Note: Force- and torque-detection of high frequency electron spin resonance using a membrane-type surface-stress sensor. AB - We developed a practical useful method for force- and torque-detected electron spin resonance (FDESR/TDESR) spectroscopy in the millimeter wave frequency region. This method uses a commercially available membrane-type surface-stress (MSS) sensor. The MSS is composed of a silicon membrane supported by four beams in which piezoresistive paths are integrated for detecting the deformation of the membrane. Although this device has a lower spin sensitivity than a microcantilever, it offers several distinct advantages, including mechanical strength, ease of use, and versatility. These advantages make this device suitable for practical applications that require FDESR/TDESR. PMID- 29604793 TI - Compact and tunable focusing device for plasma wakefield acceleration. AB - Plasma wakefield acceleration, either driven by ultra-short laser pulses or electron bunches, represents one of the most promising techniques able to overcome the limits of conventional RF technology and allows the development of compact accelerators. In the particle beam-driven scenario, ultra-short bunches with tiny spot sizes are required to enhance the accelerating gradient and preserve the emittance and energy spread of the accelerated bunch. To achieve such tight transverse beam sizes, a focusing system with short focal length is mandatory. Here we discuss the development of a compact and tunable system consisting of three small-bore permanent-magnet quadrupoles with 520 T/m field gradient. The device has been designed in view of the plasma acceleration experiments planned at the SPARC_LAB test-facility. Being the field gradient fixed, the focusing is adjusted by tuning the relative position of the three magnets with nanometer resolution. Details about its magnetic design, beam dynamics simulations, and preliminary results are examined in the paper. PMID- 29604794 TI - Design and performance of an ultra-high vacuum spin-polarized scanning tunneling microscope operating at 30 mK and in a vector magnetic field. AB - We describe the design and performance of a scanning tunneling microscope (STM) that operates at a base temperature of 30 mK in a vector magnetic field. The cryogenics is based on an ultra-high vacuum (UHV) top-loading wet dilution refrigerator that contains a vector magnet allowing for fields up to 9 T perpendicular and 4 T parallel to the sample. The STM is placed in a multi chamber UHV system, which allows in situ preparation and exchange of samples and tips. The entire system rests on a 150-ton concrete block suspended by pneumatic isolators, which is housed in an acoustically isolated and electromagnetically shielded laboratory optimized for extremely low noise scanning probe measurements. We demonstrate the overall performance by illustrating atomic resolution and quasiparticle interference imaging and detail the vibrational noise of both the laboratory and microscope. We also determine the electron temperature via measurement of the superconducting gap of Re(0001) and illustrate magnetic field-dependent measurements of the spin excitations of individual Fe atoms on Pt(111). Finally, we demonstrate spin resolution by imaging the magnetic structure of the Fe double layer on W(110). PMID- 29604795 TI - Novel high-frequency energy-efficient pulsed-dc generator for capacitively coupled plasma discharge. AB - The circuit design, assembly, and operating tests of a high-frequency and high voltage (HV) pulsed dc generator (PDG) for capacitively coupled plasma (CCP) discharge inside a vacuum chamber are reported. For capacitive loads, it is challenging to obtain sharp rectangular pulses with fast rising and falling edges, requiring intense current for quick charging and discharging. The requirement of intense current generally limits the pulse operation frequency. In this study, we present a new type of PDG consisting of a pair of half-resonant converters and a constant current-controller circuit connected with HV solid state power switches that can deliver almost rectangular high voltage pulses with fast rising and falling edges for CCP discharge. A prototype of the PDG is assembled to modulate from a high-voltage direct current (HVdc) input into a pulsed HVdc output, while following an input pulse signal and a set current level. The pulse rise time and fall time are less than 500 ns and 800 ns, respectively, and the minimum pulse width is 1 us. The maximum voltage for a negative pulse is 1000 V, and the maximum repetition frequency is 500 kHz. During the pulse on time, the plasma discharge current is controlled steadily at the set value. The half-resonant converters in the PDG perform recovery of the remaining energy from the capacitive load at every termination of pulse discharge. The PDG performed with a high energy efficiency of 85% from the HVdc input to the pulsed dc output at a repetition rate of 1 kHz and with stable plasma operation in various discharge conditions. The results suggest that the developed PDG can be considered to be more efficient for plasma processing by CCP. PMID- 29604796 TI - A multifunctional energy-saving magnetic field generator. AB - To improve the energy utilization of magnetic field generators for biological applications, a multifunctional energy-saving magnetic field generator (ESMFG) is presented. It is capable of producing both an alternating magnetic field (AMF) and a bipolar pulse magnetic field (BPMF) with high energy-saving and energy reuse rates. Based on a theoretical analysis of an RLC second-order circuit, the energy-saving and energy-reuse rates of both types of magnetic fields can be calculated and are found to have acceptable values. The results of an experimental study using the proposed generator show that for the BPMF, the peak current reaches 130 A and the intensity reaches 70.3 mT. For the AMF, the intensity is 11.0 mT and the RMS current is 20 A. The energy-saving and energy reuse rates for the AMF generator are 61.3% and 63.5%, respectively, while for the BPMF generator, the energy-saving rate is 33.6%. Thus, the proposed ESMFG has excellent potential for use in biomedical applications. PMID- 29604797 TI - Automated translating beam profiler for in situ laser beam spot-size and focal position measurements. AB - We present a simple and convenient, high-resolution solution for automated laser beam profiling with axial translation. The device is based on a Raspberry Pi computer, Pi Noir CMOS camera, stepper motor, and commercial translation stage. We also provide software to run the device. The CMOS sensor is sensitive over a large wavelength range between 300 and 1100 nm and can be translated over 25 mm along the beam axis. The sensor head can be reversed without changing its axial position, allowing for a quantitative estimate of beam overlap with counter propagating laser beams. Although not limited to this application, the intended use for this device is the automated measurement of the focal position and spot size of a Gaussian laser beam. We present example data of one such measurement to illustrate device performance. PMID- 29604798 TI - Experiments of a 100 kV-level pulse generator based on metal-oxide varistor. AB - This paper introduces the development and experiments of a 100 kV-level pulse generator based on a metal-oxide varistor (MOV). MOV has a high energy handling capacity and nonlinear voltage-current (V-I) characteristics, which makes it useful for high voltage pulse shaping. Circuit simulations based on the measured voltage-current characteristics of MOV verified the shaping concept and showed that a circuit containing a two-section pulse forming network (PFN) will result in better defined square pulse than a simple L-C discharging circuit. A reduced scale experiment was carried out and the result agreed well with simulation prediction. Then a 100 kV-level pulse generator with multiple MOVs in a stack and a two-section pulse forming network (PFN) was experimented. A pulse with a voltage amplitude of 90 kV, rise time of about 50 ns, pulse width of 500 ns, and flat top of about 400 ns was obtained with a water dummy load of 50 Omega. The results reveal that the combination of PFN and MOV is a practical way to generate high voltage pulses with better flat top waveforms, and the load voltage is stable even if the load's impedance varies. Such pulse generator can be applied in many fields such as surface treatment, corona plasma generation, industrial dedusting, and medical disinfection. PMID- 29604799 TI - A portable liquid crystal-based polarized light system for the detection of organophosphorus nerve gas. AB - Liquid crystal (LC)-based sensors have the advantageous properties of being fast, sensitive, and label-free, the results of which can be accessed directly only through the naked eye. However, the inherent disadvantages possessed by LC sensors, such as relying heavily on polarizing microscopes and the difficulty to quantify, have limited the possibility of field applications. Herein, we have addressed these issues by constructing a portable polarized detection system with constant temperature control. This system is mainly composed of four parts: the LC cell, the optics unit, the automatic temperature control unit, and the image processing unit. The LC cell was based on the ordering transitions of LCs in the presence of analytes. The optics unit based on the imaging principle of LCs was designed to substitute the polarizing microscope for the real-time observation. The image processing unit is expected to quantify the concentration of analytes. The results have shown that the presented system can detect dimethyl methyl phosphonate (a stimulant for organophosphorus nerve gas) within 25 s, and the limit of detection is about 10 ppb. In all, our portable system has potential in field applications. PMID- 29604800 TI - Modulation infrared thermometry of caloric effects at up to kHz frequencies. AB - We present a novel non-contact method for the direct measurement of caloric effects in low volume samples. The adiabatic temperature change DeltaT of a magnetocaloric sample is very sensitively determined from thermal radiation. Rapid modulation of DeltaT is induced by an oscillating external magnetic field. Detection of thermal radiation with a mercury-cadmium-telluride detector allows for measurements at field frequencies exceeding 1 kHz. In contrast to thermoacoustic methods, our method can be employed in vacuum which enhances adiabatic conditions especially in the case of small volume samples. Systematic measurements of the magnetocaloric effect as a function of temperature, magnetic field amplitude, and modulation frequency give a detailed picture of the thermal behavior of the sample. Highly sensitive measurements of the magnetocaloric effect are demonstrated on a 2 mm thick sample of gadolinium and a 60 MUm thick Fe80B12Nb8 ribbon. PMID- 29604801 TI - Infrared nanoscopy down to liquid helium temperatures. AB - We introduce a scattering-type scanning near-field infrared microscope (s-SNIM) for the local scale near-field sample analysis and spectroscopy from room temperature down to liquid helium (LHe) temperature. The extension of s-SNIM down to T = 5 K is in particular crucial for low-temperature phase transitions, e.g., for the examination of superconductors, as well as low energy excitations. The low temperature (LT) s-SNIM performance is tested with CO2-IR excitation at T = 7 K using a bare Au reference and a structured Si/SiO2-sample. Furthermore, we quantify the impact of local laser heating under the s-SNIM tip apex by monitoring the light-induced ferroelectric-to-paraelectric phase transition of the skyrmion-hosting multiferroic material GaV4S8 at Tc = 42 K. We apply LT s SNIM to study the spectral response of GaV4S8 and its lateral domain structure in the ferroelectric phase by the mid-IR to THz free-electron laser-light source FELBE at the Helmholtz-Zentrum Dresden-Rossendorf, Germany. Notably, our s-SNIM is based on a non-contact atomic force microscope (AFM) and thus can be complemented in situ by various other AFM techniques, such as topography profiling, piezo-response force microscopy (PFM), and/or Kelvin-probe force microscopy (KPFM). The combination of these methods supports the comprehensive study of the mutual interplay in the topographic, electronic, and optical properties of surfaces from room temperature down to 5 K. PMID- 29604802 TI - Computational model of gamma irradiation room at ININ. AB - In this paper, we present a model of the gamma irradiation room at the National Institute of Nuclear Research (ININ is its acronym in Spanish) in Mexico to improve the use of physics in dosimetry for human protection. We deal with air filled ionization chambers and scientific computing made in house and framed in both the GEANT4 scheme and our analytical approach to characterize the irradiation room. This room is the only secondary dosimetry facility in Mexico. Our aim is to optimize its experimental designs, facilities, and industrial applications of physical radiation. The computational results provided by our model are supported by all the known experimental data regarding the performance of the ININ gamma irradiation room and allow us to predict the values of the main variables related to this fully enclosed space to within an acceptable margin of error. PMID- 29604803 TI - High-performance 16-way Ku-band radial power combiner based on the TE01-circular waveguide mode. AB - This work presents a 16-way Ku-band radial power combiner for high power and high frequency applications, using the very low loss TE01 circular waveguide mode. The accomplished design shows an excellent performance: the experimental prototype has a return loss better than 30 dB, with a balance for the amplitudes of (+/ 0.15 dB) and (+/-2.5 degrees ) for the phases, in a 16.7% fractional bandwidth (2 GHz centered at 12 GHz). For obtaining these outstanding specifications, required, for instance, in high-frequency amplification or on plasma systems, a rigorous step-by-step procedure is presented. First, a high-purity mode transducer has been designed, from the TE10 mode in the rectangular waveguide to the TE01 mode in the circular waveguide, with very high attenuation (>50 dB) for the other propagating and evanescent modes in the circular waveguide. This transducer has been manufactured and measured in a back-to-back configuration, validating the design process. Second, an E-plane 16-way radial power divider has been designed, where the power is coupled from the 16 non-reduced-height radial standard waveguides into the TE01 circular waveguide mode, improving the insertion loss response and removing the usual tapered transformers of previous designs limiting the power handling. Finally, both the transducer and the divider have been assembled to make the final radial combiner. The prototype has been carefully manufactured, showing very good agreement between the measurements and the full-wave simulations. PMID- 29604804 TI - Path integral molecular dynamic simulation of flexible molecular systems in their ground state: Application to the water dimer. AB - We extend the Langevin equation Path Integral Ground State (LePIGS), a ground state quantum molecular dynamics method, to simulate flexible molecular systems and calculate both energetic and structural properties. We test the approach with the H2O and D2O monomers and dimers. We systematically optimize all simulation parameters and use a unity trial wavefunction. We report ground state energies, dissociation energies, and structural properties using three different water models, two of which are empirically based, q-TIP4P/F and q-SPC/Fw, and one which is ab initio, MB-pol. We demonstrate that our energies calculated from LePIGS can be merged seamlessly with low temperature path integral molecular dynamics calculations and note the similarities between the two methods. We also benchmark our energies against previous diffusion Monte Carlo calculations using the same potentials and compare to experimental results. We further demonstrate that accurate vibrational energies of the H2O and D2O monomer can be calculated from imaginary time correlation functions generated from the LePIGS simulations using solely the unity trial wavefunction. PMID- 29604805 TI - A polarized view on DNA under tension. AB - In the past decades, sensitive fluorescence microscopy techniques have contributed significantly to our understanding of the dynamics of DNA. The specific labeling of DNA using intercalating dyes has allowed for quantitative measurement of the thermal fluctuations the polymers undergo. On the other hand, recent advances in single-molecule manipulation techniques have unraveled the mechanical and elastic properties of this intricate polymer. Here, we have combined these two approaches to study the conformational dynamics of DNA under a wide range of tensions. Using polarized fluorescence microscopy in conjunction with optical-tweezers-based manipulation of YOYO-intercalated DNA, we controllably align the YOYO dyes using DNA tension, enabling us to disentangle the rapid dynamics of the dyes from that of the DNA itself. With unprecedented control of the DNA alignment, we resolve an inconsistency in reports about the tilted orientation of intercalated dyes. We find that intercalated dyes are on average oriented perpendicular to the long axis of the DNA, yet undergo fast dynamics on the time scale of absorption and fluorescence emission. In the overstretching transition of double-stranded DNA, we do not observe changes in orientation or orientational dynamics of the dyes. Only beyond the overstretching transition, a considerable depolarization is observed, presumably caused by an average tilting of the DNA base pairs. Our combined approach thus contributes to the elucidation of unique features of the molecular dynamics of DNA. PMID- 29604806 TI - An investigation of the sites occupied by atomic barium in solid xenon-A 2D-EE luminescence spectroscopy and molecular dynamics study. AB - A detailed characterisation of the luminescence recorded for the 6p 1P1-6s 1S0 transition of atomic barium isolated in annealed solid xenon has been undertaken using two-dimensional excitation-emission (2D-EE) spectroscopy. In the excitation spectra extracted from the 2D-EE scans, two dominant thermally stable sites were identified, consisting of a classic, three-fold split Jahn-Teller band, labeled the blue site, and an unusual asymmetric 2 + 1 split band, the violet site. A much weaker band has also been identified, whose emission is strongly overlapped by the violet site. The temperature dependence of the luminescence for these sites was monitored revealing that the blue site has a non-radiative channel competing effectively with the fluorescence even at 9.8 K. By contrast, the fluorescence decay time of the violet site was recorded to be 4.3 ns and independent of temperature up to 24 K. The nature of the dominant thermally stable trapping sites was investigated theoretically with Diatomics-in-Molecule (DIM) molecular dynamics simulations. The DIM model was parameterized with ab initio multi-reference configuration interaction calculations for the lowest energy excited states of the Ba?Xe pair. The simulated absorption spectra are compared with the experimental results obtained from site-resolved excitation spectroscopy. The simulations allow us to assign the experimental blue feature spectrum to a tetra-vacancy trapping site in the bulk xenon fcc crystal-a site often observed when trapping other metal atoms in rare gas matrices. By contrast, the violet site is assigned to a specific 5-atom vacancy trapping site located at a grain boundary. PMID- 29604807 TI - Comparison and combination of "direct" and fragment based local correlation methods: Cluster in molecules and domain based local pair natural orbital perturbation and coupled cluster theories. AB - Local correlation theories have been developed in two main flavors: (1) "direct" local correlation methods apply local approximation to the canonical equations and (2) fragment based methods reconstruct the correlation energy from a series of smaller calculations on subsystems. The present work serves two purposes. First, we investigate the relative efficiencies of the two approaches using the domain-based local pair natural orbital (DLPNO) approach as the "direct" method and the cluster in molecule (CIM) approach as the fragment based approach. Both approaches are applied in conjunction with second-order many-body perturbation theory (MP2) as well as coupled-cluster theory with single-, double- and perturbative triple excitations [CCSD(T)]. Second, we have investigated the possible merits of combining the two approaches by performing CIM calculations with DLPNO methods serving as the method of choice for performing the subsystem calculations. Our cluster-in-molecule approach is closely related to but slightly deviates from approaches in the literature since we have avoided real space cutoffs. Moreover, the neglected distant pair correlations in the previous CIM approach are considered approximately. Six very large molecules (503-2380 atoms) were studied. At both MP2 and CCSD(T) levels of theory, the CIM and DLPNO methods show similar efficiency. However, DLPNO methods are more accurate for 3 dimensional systems. While we have found only little incentive for the combination of CIM with DLPNO-MP2, the situation is different for CIM-DLPNO CCSD(T). This combination is attractive because (1) the better parallelization opportunities offered by CIM; (2) the methodology is less memory intensive than the genuine DLPNO-CCSD(T) method and, hence, allows for large calculations on more modest hardware; and (3) the methodology is applicable and efficient in the frequently met cases, where the largest subsystem calculation is too large for the canonical CCSD(T) method. PMID- 29604808 TI - Reinforced dynamics for enhanced sampling in large atomic and molecular systems. AB - A new approach for efficiently exploring the configuration space and computing the free energy of large atomic and molecular systems is proposed, motivated by an analogy with reinforcement learning. There are two major components in this new approach. Like metadynamics, it allows for an efficient exploration of the configuration space by adding an adaptively computed biasing potential to the original dynamics. Like deep reinforcement learning, this biasing potential is trained on the fly using deep neural networks, with data collected judiciously from the exploration and an uncertainty indicator from the neural network model playing the role of the reward function. Parameterization using neural networks makes it feasible to handle cases with a large set of collective variables. This has the potential advantage that selecting precisely the right set of collective variables has now become less critical for capturing the structural transformations of the system. The method is illustrated by studying the full atom explicit solvent models of alanine dipeptide and tripeptide, as well as the system of a polyalanine-10 molecule with 20 collective variables. PMID- 29604809 TI - RichMol: A general variational approach for rovibrational molecular dynamics in external electric fields. AB - In this paper, a general variational approach for computing the rovibrational dynamics of polyatomic molecules in the presence of external electric fields is presented. Highly accurate, full-dimensional variational calculations provide a basis of field-free rovibrational states for evaluating the rovibrational matrix elements of high-rank Cartesian tensor operators and for solving the time dependent Schrodinger equation. The effect of the external electric field is treated as a multipole moment expansion truncated at the second hyperpolarizability interaction term. Our fully numerical and computationally efficient method has been implemented in a new program, RichMol, which can simulate the effects of multiple external fields of arbitrary strength, polarization, pulse shape, and duration. Illustrative calculations of two-color orientation and rotational excitation with an optical centrifuge of NH3 are discussed. PMID- 29604811 TI - Communication: Density functional theory model for multi-reference systems based on the exact-exchange hole normalization. AB - The correct description of multi-reference electronic ground states within Kohn Sham density functional theory (DFT) requires an ensemble-state representation, employing fractionally occupied orbitals. However, the use of fractional orbital occupation leads to non-normalized exact-exchange holes, resulting in large fractional-spin errors for conventional approximative density functionals. In this communication, we present a simple approach to directly include the exact exchange-hole normalization into DFT. Compared to conventional functionals, our model strongly improves the description for multi-reference systems, while preserving the accuracy in the single-reference case. We analyze the performance of our proposed method at the example of spin-averaged atoms and spin-restricted bond dissociation energy surfaces. PMID- 29604810 TI - 48-spot single-molecule FRET setup with periodic acceptor excitation. AB - Single-molecule Forster resonance energy transfer (smFRET) allows measuring distances between donor and acceptor fluorophores on the 3-10 nm range. Solution based smFRET allows measurement of binding-unbinding events or conformational changes of dye-labeled biomolecules without ensemble averaging and free from surface perturbations. When employing dual (or multi) laser excitation, smFRET allows resolving the number of fluorescent labels on each molecule, greatly enhancing the ability to study heterogeneous samples. A major drawback to solution-based smFRET is the low throughput, which renders repetitive measurements expensive and hinders the ability to study kinetic phenomena in real time. Here we demonstrate a high-throughput smFRET system that multiplexes acquisition by using 48 excitation spots and two 48-pixel single-photon avalanche diode array detectors. The system employs two excitation lasers allowing separation of species with one or two active fluorophores. The performance of the system is demonstrated on a set of doubly labeled double-stranded DNA oligonucleotides with different distances between donor and acceptor dyes along the DNA duplex. We show that the acquisition time for accurate subpopulation identification is reduced from several minutes to seconds, opening the way to high-throughput screening applications and real-time kinetics studies of enzymatic reactions such as DNA transcription by bacterial RNA polymerase. PMID- 29604812 TI - Signatures of Wigner localization in one-dimensional systems. AB - We propose a simple and efficient approach to study Wigner localization in one dimensional systems using ab initio theory. In particular, we propose a suitable basis for the study of localization which consists of equally spaced overlapping gaussians. We illustrate our approach with full-configuration interaction which yields exact results for a given basis set. With our approach, we were able to study up to 8 electrons with full-configuration interaction. Finally, we propose the total-position spread tensor and the total electron entropy as convenient quantities to obtain signatures of Wigner localization. PMID- 29604813 TI - Novel strategy to implement active-space coupled-cluster methods. AB - A new approach is presented for the efficient implementation of coupled-cluster (CC) methods including higher excitations based on a molecular orbital space partitioned into active and inactive orbitals. In the new framework, the string representation of amplitudes and intermediates is used as long as it is beneficial, but the contractions are evaluated as matrix products. Using a new diagrammatic technique, the CC equations are represented in a compact form due to the string notations we introduced. As an application of these ideas, a new automated implementation of the single-reference-based multi-reference CC equations is presented for arbitrary excitation levels. The new program can be considered as an improvement over the previous implementations in many respects; e.g., diagram contributions are evaluated by efficient vectorized subroutines. Timings for test calculations for various complete active-space problems are presented. As an application of the new code, the weak interactions in the Be dimer were studied. PMID- 29604814 TI - On regularizing the MCTDH equations of motion. AB - The Multiconfiguration Time-Dependent Hartree (MCTDH) approach leads to equations of motion (EOM) which become singular when there are unoccupied so-called single particle functions (SPFs). Starting from a Hartree product, all SPFs, except the first one, are unoccupied initially. To solve the MCTDH-EOMs numerically, one therefore has to remove the singularity by a regularization procedure. Usually the inverse of a density matrix is regularized. Here we argue and show that regularizing the coefficient tensor, which in turn regularizes the density matrix as well, leads to an improved performance of the EOMs. The initially unoccupied SPFs are rotated faster into their "correct direction" in Hilbert space and the final results are less sensitive to the choice of the value of the regularization parameter. For a particular example (a spin-boson system studied with a transformed Hamiltonian), we could even show that only with the new regularization scheme could one obtain correct results. Finally, in Appendix A, a new integration scheme for the MCTDH-EOMs developed by Lubich and co-workers is discussed. It is argued that this scheme does not solve the problem of the unoccupied natural orbitals because this scheme ignores the latter and does not propagate them at all. PMID- 29604815 TI - Dynamics of Nafion membrane swelling in H2O/D2O mixtures as studied using FTIR technique. AB - Experiments with Fourier transform spectrometry of Nafion, a water-swollen polymeric membrane, are described. The transmittance spectra of liquid samples and Nafion, soaked in these samples, were studied, depending on the deuterium content in water in the spectral range 1.8-2.15 MUm. The experiments were carried out using two protocols: in the first protocol we studied the dynamics of Nafion swelling in H2O + D2O mixtures for the deuterium concentrations 3 < C < 104 ppm, and in the second protocol we studied the dynamics of swelling in pure heavy water (C = 106 ppm). For liquid mixtures in the concentration range 3 < C < 104 ppm, the transmittance spectra are the same, but for Nafion soaked in these fluids, the corresponding spectra are different. It is shown that, in the range of deuterium contents C = 90-500 ppm, the behavior of transmittance of the polymer membrane is non-monotonic. In experiments using the second protocol, the dynamics of diffusion replacement of residual water, which is always present in the bulk of the polymer membrane inside closed cavities (i.e., without access to atmospheric air), were studied. The experimentally estimated diffusion coefficient for this process is ~6.10-11 cm2/s. PMID- 29604816 TI - Single molecule force spectroscopy at high data acquisition: A Bayesian nonparametric analysis. AB - Bayesian nonparametrics (BNPs) are poised to have a deep impact in the analysis of single molecule data as they provide posterior probabilities over entire models consistent with the supplied data, not just model parameters of one preferred model. Thus they provide an elegant and rigorous solution to the difficult problem encountered when selecting an appropriate candidate model. Nevertheless, BNPs' flexibility to learn models and their associated parameters from experimental data is a double-edged sword. Most importantly, BNPs are prone to increasing the complexity of the estimated models due to artifactual features present in time traces. Thus, because of experimental challenges unique to single molecule methods, naive application of available BNP tools is not possible. Here we consider traces with time correlations and, as a specific example, we deal with force spectroscopy traces collected at high acquisition rates. While high acquisition rates are required in order to capture dwells in short-lived molecular states, in this setup, a slow response of the optical trap instrumentation (i.e., trapped beads, ambient fluid, and tethering handles) distorts the molecular signals introducing time correlations into the data that may be misinterpreted as true states by naive BNPs. Our adaptation of BNP tools explicitly takes into consideration these response dynamics, in addition to drift and noise, and makes unsupervised time series analysis of correlated single molecule force spectroscopy measurements possible, even at acquisition rates similar to or below the trap's response times. PMID- 29604817 TI - Rotational and fine structure of open-shell molecules in nearly degenerate electronic states. AB - An effective Hamiltonian without symmetry restriction has been developed to model the rotational and fine structure of two nearly degenerate electronic states of an open-shell molecule. In addition to the rotational Hamiltonian for an asymmetric top, this spectroscopic model includes the energy separation between the two states due to difference potential and zero-point energy difference, as well as the spin-orbit (SO), Coriolis, and electron spin-molecular rotation (SR) interactions. Hamiltonian matrices are computed using orbitally and fully symmetrized case (a) and case (b) basis sets. Intensity formulae and selection rules for rotational transitions between a pair of nearly degenerate states and a nondegenerate state have also been derived using all four basis sets. It is demonstrated using real examples of free radicals that the fine structure of a single electronic state can be simulated with either a SR tensor or a combination of SO and Coriolis constants. The related molecular constants can be determined precisely only when all interacting levels are simulated simultaneously. The present study suggests that analysis of rotational and fine structure can provide quantitative insights into vibronic interactions and related effects. PMID- 29604818 TI - Anionic water pentamer and hexamer clusters: An extensive study of structures and energetics. AB - An extensive study of structures and energetics for anionic pentamer and hexamer clusters is performed employing high level ab initio quantum chemical methods, such as the density-fitted orbital-optimized linearized coupled-cluster doubles (DF-OLCCD), coupled-cluster singles and doubles (CCSD), and coupled-cluster singles and doubles with perturbative triples [CCSD(T)] methods. In this study, sixteen anionic pentamer clusters and eighteen anionic hexamer clusters are reported. Relative, binding, and vertical detachment energies (VDE) are presented at the complete basis set limit (CBS), extrapolating energies of aug4-cc-pVTZ and aug4-cc-pVQZ custom basis sets. The largest VDE values obtained at the CCSD(T)/CBS level are 9.9 and 11.2 kcal mol-1 for pentamers and hexamers, respectively, which are in very good agreement with the experimental values of 9.5 and 11.1 kcal mol-1. Our binding energy results, at the CCSD(T)/CBS level, indicate strong bindings in anionic clusters due to hydrogen bond interactions. The average binding energy per water molecules is -5.0 and -5.3 kcal mol-1 for pentamers and hexamers, respectively. Furthermore, our results demonstrate that the DF-OLCCD method approaches to the CCSD(T) quality for anionic clusters. The inexpensive analytic gradients of DF-OLCCD compared to CCSD or CCSD(T) make it very attractive for high-accuracy studies. PMID- 29604819 TI - History, rare, and multiple events of mechanical unfolding of repeat proteins. AB - Mechanical unfolding of proteins consisting of repeat domains is an excellent tool to obtain large statistics. Force spectroscopy experiments using atomic force microscopy on proteins presenting multiple domains have revealed that unfolding forces depend on the number of folded domains (history) and have reported intermediate states and rare events. However, the common use of unspecific attachment approaches to pull the protein of interest holds important limitations to study unfolding history and may lead to discarding rare and multiple probing events due to the presence of unspecific adhesion and uncertainty on the pulling site. Site-specific methods that have recently emerged minimize this uncertainty and would be excellent tools to probe unfolding history and rare events. However, detailed characterization of these approaches is required to identify their advantages and limitations. Here, we characterize a site-specific binding approach based on the ultrastable complex dockerin/cohesin III revealing its advantages and limitations to assess the unfolding history and to investigate rare and multiple events during the unfolding of repeated domains. We show that this approach is more robust, reproducible, and provides larger statistics than conventional unspecific methods. We show that the method is optimal to reveal the history of unfolding from the very first domain and to detect rare events, while being more limited to assess intermediate states. Finally, we quantify the forces required to unfold two molecules pulled in parallel, difficult when using unspecific approaches. The proposed method represents a step forward toward more reproducible measurements to probe protein unfolding history and opens the door to systematic probing of rare and multiple molecule unfolding mechanisms. PMID- 29604820 TI - Simplified calculation approaches designed to reproduce the geometry of hydrogen bonds in molecular complexes in aprotic solvents. AB - The impact of the environment onto the geometry of hydrogen bonds can be critically important for the properties of the questioned molecular system. The paper reports on the design of calculation approaches capable to simulate the effect of aprotic polar solvents on the geometric and NMR parameters of intermolecular hydrogen bonds. A hydrogen fluoride and pyridine complex has been used as the main model system because the experimental estimates of these parameters are available for it. Specifically, F-H, F?N, and H-N distances, the values of 15N NMR shift, and spin-spin coupling constants 1J(19F1H), 1hJ(1H15N), and 2hJ(19F15N) have been analyzed. Calculation approaches based on the gas-phase and the Polarizable Continuum Model (PCM) approximations and their combinations with geometric constraints and additional noncovalent interactions have been probed. The main result of this work is that the effect of an aprotic polar solvent on the geometry of a proton-donor?H?proton-acceptor complex cannot be reproduced under the PCM approximation if no correction for solvent-solute interactions is made. These interactions can be implicitly accounted for using a simple computational protocol. PMID- 29604821 TI - Efficient use of single molecule time traces to resolve kinetic rates, models and uncertainties. AB - Single molecule time traces reveal the time evolution of unsynchronized kinetic systems. Especially single molecule Forster resonance energy transfer (smFRET) provides access to enzymatically important time scales, combined with molecular distance resolution and minimal interference with the sample. Yet the kinetic analysis of smFRET time traces is complicated by experimental shortcomings-such as photo-bleaching and noise. Here we recapitulate the fundamental limits of single molecule fluorescence that render the classic, dwell-time based kinetic analysis unsuitable. In contrast, our Single Molecule Analysis of Complex Kinetic Sequences (SMACKS) considers every data point and combines the information of many short traces in one global kinetic rate model. We demonstrate the potential of SMACKS by resolving the small kinetic effects caused by different ionic strengths in the chaperone protein Hsp90. These results show an unexpected interrelation between conformational dynamics and ATPase activity in Hsp90. PMID- 29604822 TI - Surface-induced effects in fluctuation-based measurements of single-polymer elasticity: A direct probe of the radius of gyration. AB - Single-molecule measurements of polymer elasticity are powerful, direct probes of both biomolecular structure and principles of polymer physics. Recent work has revealed low-force regimes in which biopolymer elasticity is understood through blob-based scaling models. However, the small tensions required to observe these regimes have the potential to create measurement biases, particularly due to the increased interactions of the polymer chain with tethering surfaces. Here, we examine one experimentally observed bias, in which fluctuation-based estimates of elasticity report an unexpectedly low chain compliance. We show that the effect is in good agreement with predictions based on quantifying the exclusion effect of the surface through an image-method calculation of available polymer configurations. The analysis indicates that the effect occurs at an external tension inversely proportional to the polymer's zero-tension radius of gyration. We exploit this to demonstrate a self-consistent scheme for estimating the radius of gyration of the tethered polymer. This is shown in measurements of both hyaluronic acid and poly(ethylene glycol) chains. PMID- 29604823 TI - Force feedback effects on single molecule hopping and pulling experiments. AB - Single-molecule experiments with optical tweezers have become an important tool to study the properties and mechanisms of biological systems, such as cells and nucleic acids. In particular, force unzipping experiments have been used to extract the thermodynamics and kinetics of folding and unfolding reactions. In hopping experiments, a molecule executes transitions between the unfolded and folded states at a preset value of the force [constant force mode (CFM) under force feedback] or trap position [passive mode (PM) without feedback] and the force-dependent kinetic rates extracted from the lifetime of each state (CFM) and the rupture force distributions (PM) using the Bell-Evans model. However, hopping experiments in the CFM are known to overestimate molecular distances and folding free energies for fast transitions compared to the response time of the feedback. In contrast, kinetic rate measurements from pulling experiments have been mostly done in the PM while the CFM is seldom implemented in pulling protocols. Here, we carry out hopping and pulling experiments in a short DNA hairpin in the PM and CFM at three different temperatures (6 degrees C, 25 degrees C, and 45 degrees C) exhibiting largely varying kinetic rates. As expected, we find that equilibrium hopping experiments in the CFM and PM perform well at 6 degrees C (where kinetics are slow), whereas the CFM overestimates molecular parameters at 45 degrees C (where kinetics are fast). In contrast, nonequilibrium pulling experiments perform well in both modes at all temperatures. This demonstrates that the same kind of feedback algorithm in the CFM leads to more reliable determination of the folding reaction parameters in irreversible pulling experiments. PMID- 29604824 TI - Experimental and theoretical investigation of the temperature dependent electronic quenching of O(1D) atoms in collisions with Kr. AB - The kinetics and dynamics of the collisional electronic quenching of O(1D) atoms by Kr have been investigated in a joint experimental and theoretical study. The kinetics of quenching were measured over the temperature range 50-296 K using the Laval nozzle method. O(1D) atoms were prepared by 266 nm photolysis of ozone, and the decay of the O(1D) concentration was monitored through vacuum ultraviolet fluorescence at 115.215 nm, from which the rate constant was determined. To interpret the experiments, a quantum close-coupling treatment of the quenching transition from the 1D state to the 3Pj fine-structure levels in collisions with Kr, and also Ar and Xe, was carried out. The relevant potential energy curves and spin-orbit coupling matrix elements were obtained in electronic structure calculations. We find reasonable agreement between computed temperature-dependent O(1D)-Rg (Rg = Ar, Kr, Xe) quenching rate constants and the present measurements for Kr and earlier measurements. In particular, the temperature dependence is well described. PMID- 29604825 TI - Publisher's Note: "An improved coupled-states approximation including the nearest neighbor Coriolis couplings for diatom-diatom inelastic collision" [J. Chem. Phys. 148, 084101 (2018)]. PMID- 29604827 TI - Sequence charge decoration dictates coil-globule transition in intrinsically disordered proteins. AB - We present an analytical theory to compute conformations of heteropolymers applicable to describe disordered proteins-as a function of temperature and charge sequence. The theory describes coil-globule transition for a given protein sequence when temperature is varied and has been benchmarked against the all-atom Monte Carlo simulation (using CAMPARI) of intrinsically disordered proteins (IDPs). In addition, the model quantitatively shows how subtle alterations of charge placement in the primary sequence-while maintaining the same charge composition-can lead to significant changes in conformation, even as drastic as a coil (swelled above a purely random coil) to globule (collapsed below a random coil) and vice versa. The theory provides insights on how to control (enhance or suppress) these changes by tuning the temperature (or solution condition) and charge decoration. As an application, we predict the distribution of conformations (at room temperature) of all naturally occurring IDPs in the DisProt database and notice significant size variation even among IDPs with a similar composition of positive and negative charges. Based on this, we provide a new diagram-of-states delineating the sequence-conformation relation for proteins in the DisProt database. Next, we study the effect of post-translational modification, e.g., phosphorylation, on IDP conformations. Modifications as little as two-site phosphorylation can significantly alter the size of an IDP with everything else being constant (temperature, salt concentration, etc.). However, not all possible modification sites have the same effect on protein conformations; there are certain "hot spots" that can cause maximal change in conformation. The location of these "hot spots" in the parent sequence can readily be identified by using a sequence charge decoration metric originally introduced by Sawle and Ghosh. The ability of our model to predict conformations (both expanded and collapsed states) of IDPs at a high-throughput level can provide valuable insights into the different mechanisms by which phosphorylation/charge mutation controls IDP function. PMID- 29604826 TI - Two states or not two states: Single-molecule folding studies of protein L. AB - Experimental tools of increasing sophistication have been employed in recent years to study protein folding and misfolding. Folding is considered a complex process, and one way to address it is by studying small proteins, which seemingly possess a simple energy landscape with essentially only two stable states, either folded or unfolded. The B1-IgG binding domain of protein L (PL) is considered a model two-state folder, based on measurements using a wide range of experimental techniques. We applied single-molecule fluorescence resonance energy transfer (FRET) spectroscopy in conjunction with a hidden Markov model analysis to fully characterize the energy landscape of PL and to extract the kinetic properties of individual molecules of the protein. Surprisingly, our studies revealed the existence of a third state, hidden under the two-state behavior of PL due to its small population, ~7%. We propose that this minority intermediate involves partial unfolding of the two C-terminal beta strands of PL. Our work demonstrates that single-molecule FRET spectroscopy can be a powerful tool for a comprehensive description of the folding dynamics of proteins, capable of detecting and characterizing relatively rare metastable states that are difficult to observe in ensemble studies. PMID- 29604828 TI - Density functional theory for hard uniaxial particles: Complex ordering of pear shaped and spheroidal particles near a substrate. AB - We develop a density functional for hard particles with a smooth uniaxial shape (including non-inversion-symmetric particles) within the framework of fundamental measure theory. By applying it to a system of tapered, aspherical liquid-crystal formers, reminiscent of pears, we analyse their behaviour near a hard substrate. The theory predicts a complex orientational ordering close to the substrate, which can be directly related to the particle shape, in good agreement with our simulation results. Furthermore, the lack of particle inversion-symmetry implies the possibility of alternating orientations in subsequent layers as found in a smectic/lamellar phase of such particles. Both theory and Monte Carlo simulations confirm that such ordering occurs in our system. Our results are relevant for adsorption processes of asymmetric colloidal particles and molecules at hard interfaces and show once again that tapering strongly affects the properties of orientationally ordered phases. PMID- 29604829 TI - Single molecule FRET investigation of pressure-driven unfolding of cold shock protein A. AB - We demonstrate that fused silica capillaries are suitable for single molecule fluorescence resonance energy transfer (smFRET) measurements at high pressure with an optical quality comparable to the measurement on microscope coverslips. Therefore, we optimized the imaging conditions in a standard square fused silica capillary with an adapted arrangement and evaluated the performance by imaging the focal volume, fluorescence correlation spectroscopy benchmarks, and FRET measurements. We demonstrate single molecule FRET measurements of cold shock protein A unfolding at a pressure up to 2000 bars and show that the unfolded state exhibits an expansion almost independent of pressure. PMID- 29604830 TI - Modeling antigen-antibody nanoparticle bioconjugates and their polymorphs. AB - The integration of nanomaterials with biomolecules has recently led to the development of new ways of designing biosensors, and through their assembly, to new hybrid structures for novel and exciting applications. In this work, we develop a coarse-grained model for nanoparticles grafted with antibody molecules and their binding with antigens. In particular, we isolate two possible states for antigen-antibody pairs during the binding process, termed as recognition and anchoring states. Using molecular simulation, we calculate the thermodynamic and structural features of three possible crystal structures or polymorphs, the body centered cubic, simple cubic, and face-centered cubic phases, and of the melt. This leads us to determine the domain of stability of the three solid phases. In particular, the role played by the switching process between anchoring and recognition states during melting is identified, shedding light on the complex microscopic mechanisms in these systems. PMID- 29604831 TI - Simulation of FRET dyes allows quantitative comparison against experimental data. AB - Fully understanding biomolecular function requires detailed insight into the systems' structural dynamics. Powerful experimental techniques such as single molecule Forster Resonance Energy Transfer (FRET) provide access to such dynamic information yet have to be carefully interpreted. Molecular simulations can complement these experiments but typically face limits in accessing slow time scales and large or unstructured systems. Here, we introduce a coarse-grained simulation technique that tackles these challenges. While requiring only few parameters, we maintain full protein flexibility and include all heavy atoms of proteins, linkers, and dyes. We are able to sufficiently reduce computational demands to simulate large or heterogeneous structural dynamics and ensembles on slow time scales found in, e.g., protein folding. The simulations allow for calculating FRET efficiencies which quantitatively agree with experimentally determined values. By providing atomically resolved trajectories, this work supports the planning and microscopic interpretation of experiments. Overall, these results highlight how simulations and experiments can complement each other leading to new insights into biomolecular dynamics and function. PMID- 29604832 TI - Thermodynamically stable diatomic dications: The cases of SrO2+ and SrH2. AB - A high level theoretical investigation of the low-lying electronic states of the diatomic dications SrO2+ and SrH2+ is presented for the first time along with experimental results of their mass spectra where they were detected. A global and reliable picture of the potential energy curves of the electronic states and the associated spectroscopic parameters provide quantitative results attesting to the thermodynamic stability of both species. Inclusion of spin-orbit interactions does not significantly change the energetic characterization. For SrO2+, the ground (X 3Sigma-) and first excited (A 3Pi, Te = 3971 cm-1) states are bound (De) by 15.94 kcal mol-1 and 4.71 kcal mol-1, respectively. Transition probabilities (Av'v") have been evaluated and radiative lifetimes estimated for the vibrational states of A 3Pi (v'), and transition probabilities are expected to be diagonally dominant and fall in the far-IR region of the spectrum. For the singlet states a 1Delta, b 1Pi, c 1Sigma+, and d 1Sigma+, transition probabilities have also been calculated for all symmetry allowed transitions and the radiative lifetimes evaluated for selected vibrational states of the upper levels. The transitions associated with the band systems d 1Sigma+-b 1Pi and d 1Sigma+-c 1Sigma+, although falling in the yellow region of the spectrum, with overlapping bands, are expected to show quite distinct intensities since the transition moment associated with d 1Sigma+-c 1Sigma+ is much larger. For singlet transitions, the prediction of relative intensities using the Franck-Condon approximation fails in most of the cases. For SrH2+, only the ground state is bound (De = 6.54 kcal mol-1); with an equilibrium distance of 5.117 a0, the associated spectroscopic parameters (omegae, omegaexe, Be) turned out to be (518.9, 32.77, 2.3227) in cm-1. For both species, dipole moment functions illustrate the variation of the molecular polarity with the internuclear distance. PMID- 29604833 TI - The role of Herzberg-Teller effects on the resonance Raman spectrum of trans porphycene investigated by time dependent density functional theory. AB - The S1 excited state properties as well as the associated absorption and resonance Raman (RR) spectra of trans-porphycene are investigated by means of time dependent density functional theory calculations. The relative magnitude of the Franck-Condon (FC) contribution and of the Herzberg-Teller (HT) effects is evaluated for both the absorption and RR intensities. The accuracy of the calculated spectra is assessed by employing different theoretical approximations and by comparing with experimental data. The obtained results show that Duschinsky effects lead to noticeable modifications in the absorption intensities but are nearly negligible in the RR spectrum. By contrast, the HT effects are stronger for the RR intensities compared to the absorption intensities, and these effects significantly improve the agreement with the experimental RR spectrum. Moreover, the HT effects produce different values of the RR depolarization ratios, which can be used to quantify the relative importance of the FC and HT contributions. Generally, it is found that the HT effects have a significant role on the RR spectrum of trans-porphycene and that their inclusion in the computational scheme is mandatory to accurately predict the RR intensities. PMID- 29604834 TI - Photodissociation dynamics of H2O at 111.5 nm by a vacuum ultraviolet free electron laser. AB - Photodissociation dynamics of H2O via the F state at 111.5 nm were investigated using the high resolution H-atom Rydberg "tagging" time-of-flight (TOF) technique, in combination with the tunable vacuum ultraviolet free electron laser at the Dalian Coherent Light Source. The product translational energy distributions and angular distributions in both parallel and perpendicular directions were derived from the recorded TOF spectra. Based on these distributions, the quantum state distributions and angular anisotropy parameters of OH (X) and OH (A) products have been determined. For the OH (A) + H channel, highly rotationally excited OH (A) products have been observed. These products are ascribed to a fast direct dissociation on the B1A1 state surface after multi step internal conversions from the initial excited F state to the B state. While for the OH (X) + H channel, very highly rotationally excited OH (X) products with moderate vibrational excitation are revealed and attributed to the dissociation via a nonadiabatic pathway through the well-known two conical intersections between the B-state and the X-state surfaces. PMID- 29604835 TI - Interstate vibronic coupling constants between electronic excited states for complex molecules. AB - In the construction of diabatic vibronic Hamiltonians for quantum dynamics in the excited-state manifold of molecules, the coupling constants are often extracted solely from information on the excited-state energies. Here, a new protocol is applied to get access to the interstate vibronic coupling constants at the time dependent density functional theory level through the overlap integrals between excited-state adiabatic auxiliary wavefunctions. We discuss the advantages of such method and its potential for future applications to address complex systems, in particular, those where multiple electronic states are energetically closely lying and interact. We apply the protocol to the study of prototype rhenium carbonyl complexes [Re(CO)3(N,N)(L)]n+ for which non-adiabatic quantum dynamics within the linear vibronic coupling model and including spin-orbit coupling have been reported recently. PMID- 29604836 TI - USAXS analysis of concentration-dependent self-assembling of polymer-brush modified nanoparticles in ionic liquid: [I] concentrated-brush regime. AB - Using ultra-small angle X-ray scattering (USAXS), we analyzed the higher-order structures of nanoparticles with a concentrated brush of an ionic liquid (IL) type polymer (concentrated-polymer-brush-modified silica particle; PSiP) in an IL and the structure of the swollen shell layer of PSiP. Homogeneous mixtures of PSiP and IL were successfully prepared by the solvent-casting method involving the slow evaporation of a volatile solvent, which enabled a systematic study over an exceptionally wide range of compositions. Different diffraction patterns as a function of PSiP concentration were observed in the USAXS images of the mixtures. At suitably low PSiP concentrations, the USAXS intensity profile was analyzed using the Percus-Yevick model by matching the contrast between the shell layer and IL, and the swollen structure of the shell and "effective diameter" of the PSiP were evaluated. This result confirms that under sufficiently low pressures below and near the liquid/crystal-threshold concentration, the studied PSiP can be well described using the "hard sphere" model in colloidal science. Above the threshold concentration, the PSiP forms higher-order structures. The analysis of diffraction patterns revealed structural changes from disorder to random hexagonal-closed-packing and then face-centered-cubic as the PSiP concentration increased. These results are discussed in terms of thermodynamically stable "hard" and/or "semi-soft" colloidal crystals, wherein the swollen layer of the concentrated polymer brush and its structure play an important role. PMID- 29604837 TI - Interaction of von Willebrand factor domains with collagen investigated by single molecule force spectroscopy. AB - von Willebrand factor (VWF) is a huge multimeric protein that plays a key role in primary hemostasis. Sites for collagen binding, an initial event of hemostasis, are located in the VWF-domains A1 and A3. In this study, we investigated single molecule interactions between collagen surfaces and wild type VWF A1A2A3 domain constructs, as well as clinically relevant VWF A3 domain point mutations, such as p.Ser1731Thr, p.Gln1734His, and p.His1786Arg. For this, we utilized atomic force microscopy based single molecular force spectroscopy. The p.Ser1731Thr mutant had no impact on the VWF-collagen type III and VI interactions, while the p.Gln1734His and p.His1786Arg mutants showed a slight increase in bond stability to collagen type III. This effect probably arises from additional hydrogen bonds that come along with the introduction of these mutations. Using the same mutants, but collagen type VI as a binding partner, resulted in a significant increase in bond stability. VWF domain A1 was reported to be essential for the interaction with collagen type VI and thus our findings strengthen the hypothesis that the VWF A1 domain can compensate for mutations in the VWF A3 domain. Additionally, our data suggest that the mutations could even stabilize the interaction between VWF and collagen without shear. VWF-collagen interactions seem to be an important system in which defective interactions between one VWF domain and one type of collagen can be compensated by alternative binding events. PMID- 29604838 TI - Study of homogeneous bubble nucleation in liquid carbon dioxide by a hybrid approach combining molecular dynamics simulation and density gradient theory. AB - A new method for predicting homogeneous bubble nucleation rates of pure compounds from vapor-liquid equilibrium (VLE) data is presented. It combines molecular dynamics simulation on the one side with density gradient theory using an equation of state (EOS) on the other. The new method is applied here to predict bubble nucleation rates in metastable liquid carbon dioxide (CO2). The molecular model of CO2 is taken from previous work of our group. PC-SAFT is used as an EOS. The consistency between the molecular model and the EOS is achieved by adjusting the PC-SAFT parameters to VLE data obtained from the molecular model. The influence parameter of density gradient theory is fitted to the surface tension of the molecular model. Massively parallel molecular dynamics simulations are performed close to the spinodal to compute bubble nucleation rates. From these simulations, the kinetic prefactor of the hybrid nucleation theory is estimated, whereas the nucleation barrier is calculated from density gradient theory. This enables the extrapolation of molecular simulation data to the whole metastable range including technically relevant densities. The results are tested against available experimental data and found to be in good agreement. The new method does not suffer from typical deficiencies of classical nucleation theory concerning the thermodynamic barrier at the spinodal and the bubble size dependence of surface tension, which is typically neglected in classical nucleation theory. In addition, the density in the center of critical bubbles and their surface tension is determined as a function of their radius. The usual linear Tolman correction to the capillarity approximation is found to be invalid. PMID- 29604839 TI - Analytic Morse/long-range potential energy surfaces and "adiabatic-hindered rotor" treatment for a symmetric top-linear molecule dimer: A case study of CH3F H2. AB - A first effective six-dimensional ab initio potential energy surface (PES) for CH3F-H2 which explicitly includes the intramolecular Q3 stretching normal mode of the CH3F monomer is presented. The electronic structure computations have been carried out at the explicitly correlated coupled cluster level of theory [CCSD(T) F12a] with an augmented correlation-consistent triple zeta basis set. Five dimensional analytical intermolecular PESs for nu3(CH3F) = 0 and 1 are then obtained by fitting the vibrationally averaged potentials to the Morse/Long-Range (MLR) potential function form. The MLR function form is applied to the nonlinear molecule-linear molecule case for the first time. These fits to 25 015 points have root-mean-square deviations of 0.74 cm-1 and 0.082 cm-1 for interaction energies less than 0.0 cm-1. Using the adiabatic hindered-rotor approximation, three-dimensional PESs for CH3F-paraH2 are generated from the 5D PESs over all possible orientations of the hydrogen monomer. The infrared and microwave spectra for CH3F-paraH2 dimer are predicted for the first time. These analytic PESs can be used for modeling the dynamical behavior in CH3F-(H2)N clusters, including the possible appearance of microscopic superfluidity. PMID- 29604840 TI - Detection of kinetic change points in piece-wise linear single molecule motion. AB - Single-molecule approaches present a powerful way to obtain detailed kinetic information at the molecular level. However, the identification of small rate changes is often hindered by the considerable noise present in such single molecule kinetic data. We present a general method to detect such kinetic change points in trajectories of motion of processive single molecules having Gaussian noise, with a minimum number of parameters and without the need of an assumed kinetic model beyond piece-wise linearity of motion. Kinetic change points are detected using a likelihood ratio test in which the probability of no change is compared to the probability of a change occurring, given the experimental noise. A predetermined confidence interval minimizes the occurrence of false detections. Applying the method recursively to all sub-regions of a single molecule trajectory ensures that all kinetic change points are located. The algorithm presented allows rigorous and quantitative determination of kinetic change points in noisy single molecule observations without the need for filtering or binning, which reduce temporal resolution and obscure dynamics. The statistical framework for the approach and implementation details are discussed. The detection power of the algorithm is assessed using simulations with both single kinetic changes and multiple kinetic changes that typically arise in observations of single-molecule DNA-replication reactions. Implementations of the algorithm are provided in ImageJ plugin format written in Java and in the Julia language for numeric computing, with accompanying Jupyter Notebooks to allow reproduction of the analysis presented here. PMID- 29604841 TI - Quantifying fluorescence enhancement for slowly diffusing single molecules in plasmonic near fields. AB - Gold nanorods are extensively used for single-molecule fluorescence enhancement as they are easy to synthesize, bio-compatible, and provide high light confinement at their nanometer-sized tips. The current way to estimate fluorescence enhancement relies on binned time traces or on fluorescence correlation spectroscopy. We report on novel ways to extract the enhancement factor in a single-molecule enhancement experiment, avoiding the arbitrary selection of one or a few high-intensity burst(s). These new estimates for the enhancement factor make use of the whole distribution of intensity bursts or of the interphoton delay distribution, which avoids the arbitrary binning of the fluorescence intensity time traces. We present experimental results on the bi dimensional case, experimentally achieved using a lipid bilayer to support the diffusion of fluorophores. We support our findings with histograms of fluorescence bursts and with an analytical derivation of the interphoton delay distribution of (nearly) immobilized emitters from the fluorescence intensity profile. PMID- 29604843 TI - CO oxidation on Ru-Pt bimetallic nanoclusters supported on TiO2(101): The effect of charge polarization. AB - Pt-based catalyst is widely used in CO oxidation, while its catalytic activity is often undermined because of the CO poisoning effect. Here, using density functional theory, we propose the use of a Ru-Pt bimetallic cluster supported on TiO2 for CO oxidation, to achieve both high activity and low CO poisoning effect. Excellent catalytic activity is obtained in a Ru1Pt7/TiO2(101) system, which is ascribed to strong electric fields induced by charge polarization between one Ru atom and its neighboring Pt atoms. Because of its lower electronegativity, the Ru atom donates electrons to neighboring Pt. This induces strong electric fields around the top-layered Ru, substantially promoting the adsorption of O2/CO + O2 and eliminating the CO poisoning effect. In addition, the charge polarization also drives the d-band center of the Ru1Pt7 cluster to up-shift to the Fermi level. For surface O2 activation/CO oxidation, the strong electric field and d band center close to the Fermi level can promote the adsorption of O2 and CO as well as reduce the reaction barrier of the rate-determining step. Meanwhile, since O2 easily dissociates on Ru1Pt7/TiO2(101) resulting in unwanted oxidation of Ru and Pt, a CO-rich condition is necessary to protect the catalyst at high temperature. PMID- 29604842 TI - Characterizing highly dynamic conformational states: The transcription bubble in RNAP-promoter open complex as an example. AB - Bio-macromolecules carry out complicated functions through structural changes. To understand their mechanism of action, the structure of each step has to be characterized. While classical structural biology techniques allow the characterization of a few "structural snapshots" along the enzymatic cycle (usually of stable conformations), they do not cover all (and often fast interconverting) structures in the ensemble, where each may play an important functional role. Recently, several groups have demonstrated that structures of different conformations in solution could be solved by measuring multiple distances between different pairs of residues using single-molecule Forster resonance energy transfer (smFRET) and using them as constrains for hybrid/integrative structural modeling. However, this approach is limited in cases where the conformational dynamics is faster than the technique's temporal resolution. In this study, we combine existing tools that elucidate sub millisecond conformational dynamics together with hybrid/integrative structural modeling to study the conformational states of the transcription bubble in the bacterial RNA polymerase-promoter open complex (RPo). We measured microsecond alternating laser excitation-smFRET of differently labeled lacCONS promoter dsDNA constructs. We used a combination of burst variance analysis, photon-by-photon hidden Markov modeling, and the FRET-restrained positioning and screening approach to identify two conformational states for RPo. The experimentally derived distances of one conformational state match the known crystal structure of bacterial RPo. The experimentally derived distances of the other conformational state have characteristics of a scrunched RPo. These findings support the hypothesis that sub-millisecond dynamics in the transcription bubble are responsible for transcription start site selection. PMID- 29604844 TI - Precision and accuracy in smFRET based structural studies-A benchmark study of the Fast-Nano-Positioning System. AB - Modern hybrid structural analysis methods have opened new possibilities to analyze and resolve flexible protein complexes where conventional crystallographic methods have reached their limits. Here, the Fast-Nano Positioning System (Fast-NPS), a Bayesian parameter estimation-based analysis method and software, is an interesting method since it allows for the localization of unknown fluorescent dye molecules attached to macromolecular complexes based on single-molecule Forster resonance energy transfer (smFRET) measurements. However, the precision, accuracy, and reliability of structural models derived from results based on such complex calculation schemes are oftentimes difficult to evaluate. Therefore, we present two proof-of-principle benchmark studies where we use smFRET data to localize supposedly unknown positions on a DNA as well as on a protein-nucleic acid complex. Since we use complexes where structural information is available, we can compare Fast-NPS localization to the existing structural data. In particular, we compare different dye models and discuss how both accuracy and precision can be optimized. PMID- 29604845 TI - Crystal growth kinetics of triblock Janus colloids. AB - We measure the kinetics of crystal growth from a melt of triblock Janus colloids using non-equilibrium molecular dynamics simulations. We assess the impact of interaction anisotropy by systematically varying the size of the attractive patches from 40% to 100% coverage, finding substantially different growth behaviors in the two limits. With isotropic particles, the interface velocity is directly proportional to the subcooling, in agreement with previous studies. With highly anisotropic particles, the growth curves are well approximated by using a power law with exponent and prefactor that depend strongly on the particular surface geometry and patch fraction. This nonlinear growth appears correlated to the roughness of the solid-liquid interface, with the strongest growth inhibition occurring for the smoothest crystal faces. We conclude that crystal growth for patchy particles does not conform to the typical collision-limited mechanism, but is instead an activated process in which the rate-limiting step is the collective rotation of particles into the proper orientation. Finally, we show how differences in the growth kinetics could be leveraged to achieve kinetic control over polymorph growth, either enhancing or suppressing metastable phases near solid-solid coexistence lines. PMID- 29604846 TI - In situ temperature monitoring in single-molecule FRET experiments. AB - Thermodynamic properties of single molecules including enthalpic and entropic contributions are often determined from experiments by a direct control and precise measurement of the local temperature. However, common temperature monitoring techniques using, for example, ultrafine temperature probes can lead to uncertainties as the probe cannot be placed in the vicinity of the molecule of interest. Here, we devised an approach to measure the local temperature in freely diffusing confocal single-molecule Forster Resonance Energy Transfer (smFRET) experiments in situ by directly adding the temperature-sensitive fluorescent dye Rhodamine B, whose fluorescence lifetime serves as a probe of the local temperature in the confocal volume. We demonstrate that the temperature and FRET efficiencies of static and dynamic molecules can be extracted within one measurement simultaneously, without the need of a reference chamber. We anticipate this technique to be particularly useful in the physicochemical analyses of temperature-dependent biomolecular processes from single-molecule measurements. PMID- 29604847 TI - Non-equilibrium stationary coherences in photosynthetic energy transfer under weak-field incoherent illumination. AB - We present a theoretical study of the quantum dynamics of energy transfer in a model photosynthetic dimer excited by incoherent light and show that the interplay between incoherent pumping and phonon-induced relaxation, dephasing, and trapping leads to the emergence of non-equilibrium stationary states characterized by substantial stationary coherences in the energy basis. We obtain analytic expressions for these coherences in the limits of rapid dephasing of electronic excitations and of small excitonic coupling between the chromophores. The stationary coherences are maximized in the regime where the excitonic coupling is small compared to the trapping rate. We further show that the non equilibrium coherences anti-correlate with the energy transfer efficiency in the regime of localized coupling to the reaction center and that no correlation exists under delocalized (Forster) trapping conditions. PMID- 29604848 TI - Rotation and diffusion of naphthalene on Pt(111). AB - The behavior of naphthalene on Pt(111) surfaces is studied by combining insight from scanning tunneling microscopy (STM) and van der Waals enabled density functional theory. Adsorption, diffusion, and rotation are investigated by a series of variable temperature STM experiments revealing naphthalene ability to rotate on-site with ease with a rotational barrier of 0.69 eV. Diffusion to neighbouring sites is found to be more difficult. The experimental results are in good agreement with the theoretical investigations which confirm that the barrier for diffusion is slightly higher than the one for rotation. The theoretical barriers for rotation and translation are found to be 0.75 and 0.78 eV, respectively. An automatic mapping of the possible diffusion pathways reveals very detailed diffusion paths with many small local minima that would have been practically impossible to find manually. This automated procedure provides detailed insight into the preferred diffusion pathways that are important for our understanding of molecule-substrate interactions. PMID- 29604849 TI - New insights onto dissociation of state-selected O2+ ions investigated by double imaging photoelectron photoion coincidence: The superimposed 32Piu and c4Sigmau- inner-valence states. AB - The double imaging photoelectron photoion coincidence technique has been applied to investigate the dissociation of state-selected O2+(32Piu, c4Sigmau-) ions at hv = 25.4 eV. It is shown that the O2+ ions prepared in the 32Piu inner-valence state can dissociate toward two channels where a distinct changeover from the third dissociation limit O(3P) + O+(2D) to the fifth limit O(3P) + O+(2P) is observed at a binding energy of ~23.8 eV. Up to four dissociation limits have been identified in the dissociation of the v = 0 vibrational level of the c4Sigmau- electronic state, and in particular, the products toward the third limit with a very weak intensity are definitely identified and assigned. In addition, the individual contributions of the two superimposed 32Piu and c4Sigmau states to the fifth dissociation limit are clearly separated and determined for the first time. The anisotropy parameters of the O+ fragment ion toward different dissociation limits have also been measured and exhibit specific state-selected characteristics. The dissociation mechanisms of the 32Piu and c4Sigmau- states including predissociation and tunneling motion are proposed based on the present experimental results and the existing theoretical potential energy curves. PMID- 29604850 TI - Improving estimation of kinetic parameters in dynamic force spectroscopy using cluster analysis. AB - Dynamic Force Spectroscopy (DFS) is a widely used technique to characterize the dissociation kinetics and interaction energy landscape of receptor-ligand complexes with single-molecule resolution. In an Atomic Force Microscope (AFM) based DFS experiment, receptor-ligand complexes, sandwiched between an AFM tip and substrate, are ruptured at different stress rates by varying the speed at which the AFM-tip and substrate are pulled away from each other. The rupture events are grouped according to their pulling speeds, and the mean force and loading rate of each group are calculated. These data are subsequently fit to established models, and energy landscape parameters such as the intrinsic off rate (koff) and the width of the potential energy barrier (xbeta) are extracted. However, due to large uncertainties in determining mean forces and loading rates of the groups, errors in the estimated koff and xbeta can be substantial. Here, we demonstrate that the accuracy of fitted parameters in a DFS experiment can be dramatically improved by sorting rupture events into groups using cluster analysis instead of sorting them according to their pulling speeds. We test different clustering algorithms including Gaussian mixture, logistic regression, and K-means clustering, under conditions that closely mimic DFS experiments. Using Monte Carlo simulations, we benchmark the performance of these clustering algorithms over a wide range of koff and xbeta, under different levels of thermal noise, and as a function of both the number of unbinding events and the number of pulling speeds. Our results demonstrate that cluster analysis, particularly K means clustering, is very effective in improving the accuracy of parameter estimation, particularly when the number of unbinding events are limited and not well separated into distinct groups. Cluster analysis is easy to implement, and our performance benchmarks serve as a guide in choosing an appropriate method for DFS data analysis. PMID- 29604851 TI - Interplay of intermolecular interactions and flexibility to mediate glass forming ability and fragility: A study of chemical analogs. AB - We have investigated the enthalpic and dielectric relaxations of four groups of quinoline analogs having similar structural properties (i.e., rigidity, stiffness, and bulkiness) but a different steric character and the nature of intermolecular interactions and flexibility. The dielectric fragility index (md) and the enthalpic one (mH), determined by the Tool-Narayanaswamy-Moynihan-Hodge formalism, are comparable. Generally, for the four sets of molecules of similar structures, both the interactions and flexibility are found to be critical in making the large span of fragility (i.e., from 59 to 131) and glass forming ability. By contrast, individual impacts of the interaction and flexibility can only explain fragility partly among each group of isomers. We found that the molecules with high fragility are of relatively low liquid density, reflecting the joint impact of the interactions and flexibility. An interesting result is observed among the isomers that the molecules which are fragile have enhanced glass forming ability. The results are unveiling the joint impacts of molecular structure (flexibility) and intermolecular interaction on the molecular dynamics. PMID- 29604852 TI - Single-molecule diffusometry reveals the nucleotide-dependent oligomerization pathways of Nicotiana tabacum Rubisco activase. AB - Oligomerization plays an important role in the function of many proteins, but a quantitative picture of the oligomer distribution has been difficult to obtain using existing techniques. Here we describe a method that combines sub stoichiometric labeling and recently developed single-molecule diffusometry to measure the size distribution of oligomers under equilibrium conditions in solution, one molecule at a time. We use this technique to characterize the oligomerization behavior of Nicotiana tabacum (Nt) Rubisco activase (Nt-Rca), a chaperone-like AAA-plus ATPase essential in regulating carbon fixation during photosynthesis. We directly observed monomers, dimers, and a tetramer/hexamer mixture and extracted their fractional abundance as a function of protein concentration. We show that the oligomerization pathway of Nt-Rca is nucleotide dependent: ATPgammaS binding strongly promotes tetramer/hexamer formation from dimers and results in a preferred tetramer/hexamer population for concentrations in the 1-10 MUM range. Furthermore, we directly observed dynamic assembly and disassembly processes of single complexes in real time and from there estimated the rate of subunit exchange to be ~0.1 s-1 with ATPgammaS. On the other hand, ADP binding destabilizes Rca complexes by enhancing the rate of subunit exchange by >2 fold. These observations provide a quantitative starting point to elucidate the structure-function relations of Nt-Rca complexes. We envision the method to fill a critical gap in defining and quantifying protein assembly pathways in the small-oligomer regime. PMID- 29604853 TI - Experimental study of the polyamorphism of water. I. The isobaric transitions from amorphous ices to LDA at 4 MPa. AB - The existence of more than one solid amorphous state of water is an extraordinary feature. Since polyamorphism might be connected to the liquid-liquid critical point hypothesis, it is particularly important to study the relations amongst the different amorphous ices. Here we study the polyamorphic transformations of several high pressure amorphous ices to low-density amorphous ice (LDA) at 4 MPa by isobaric heating utilising in situ volumetry and ex situ X-ray diffraction. We find that very-high density amorphous ice (VHDA) and unannealed high density amorphous ice (HDA) show significant relaxation before transforming to LDA, whereby VHDA is seen to relax toward HDA. By contrast, expanded HDA shows almost no relaxation prior to the transformation. The transition to LDA itself obeys criteria for a first-order-like transition in all cases. In the case of VHDA, even macroscopic phase separation is observed. These findings suggest that HDA and LDA are two clearly distinct polyamorphs. We further present evidence that HDA reaches the metastable equilibrium at 140 K and 0.1 GPa but only comes close to that at 140 K and 0.2 GPa. The most important is the path independence of the amorphous phase reached at 140 K and 0.1 GPa. PMID- 29604854 TI - Multiconfiguration pair-density functional theory investigation of the electronic spectrum of MnO4. AB - The electronic spectrum of permanganate ions contains various highly multiconfigurational ligand-to-metal charge transfer states and is notorious for being one of the most challenging systems to be treated by quantum-chemical methods. Here we studied the lowest nine vertical excitation energies using restricted active space second-order perturbation theory (RASPT2) and multiconfiguration pair-density functional theory (MC-PDFT) to test and compare these two theories in computing such a challenging spectrum. The results are compared to literature data, including time-dependent density functional theory, completely renormalized equation-of-motion couple-cluster theory with single and double excitations, symmetry-adapted-cluster configuration interaction, and experimental spectra in the gas phase and solution. Our results show that MC-PDFT accurately predicts the spectrum at a significantly reduced cost as compared to RASPT2. PMID- 29604855 TI - Oxygen and sulfur adsorption on vicinal surfaces of copper and silver: Preferred adsorption sites. AB - We present an extensive density functional theory (DFT) study of adsorption site energetics for oxygen and sulfur adsorbed on two vicinal surfaces of Cu and Ag, with the goal of identifying the most stable adsorption site(s), identifying trends and common themes, and comparing with experimental work in the literature where possible. We also present benchmark calculations for adsorption on the flat (111) and (100) surfaces. The first vicinal surface is the (211), and results are similar for both metals. We find that the step-doubling reconstruction is favored with both adsorbates and is driven by the creation of a special stable fourfold hollow (4fh) site at the reconstructed step. Zig-zag chain structures consisting of X-M-X units (X = chalcogen, M = metal) at the step edge are considered, in which the special 4fh site is partially occupied. The zig-zag configuration is energetically competitive for oxygen but not sulfur. DFT results for oxygen agree with experiment in terms of the stability of the reconstruction, but contradict the original site assignment. The second vicinal surface is the (410), where again results are similar for both metals. For oxygen, DFT predicts that step sites are filled preferentially even at lowest coverage, followed by terrace sites, consistent with the experiment. For sulfur, in contrast, DFT predicts that terrace sites fill first. Oxygen forms O-M-O rows on the top edge of the step, where it occupies incomplete 4fh sites. This resolves an experimental ambiguity in the site assignment. For both the (211) and (410) surfaces, the interaction energy that stabilizes the X-M-X chain or row correlates with the linearity of the X-M-X unit, which may explain key differences between oxygen and sulfur. PMID- 29604856 TI - Precision saturated absorption spectroscopy of H3. AB - In our previous work on the Lamb-dips of the nu2 fundamental band transitions of H3+, the saturated absorption spectrum was obtained by third-derivative spectroscopy using frequency modulation with an optical parametric oscillator (OPO). However, frequency modulation also caused errors in the absolute frequency determination. To solve this problem, we built a tunable offset locking system to lock the pump frequency of the OPO to an iodine-stabilized Nd:YAG laser. With this improvement, we were able to scan the OPO idler frequency precisely and obtain the saturated absorption profile using intensity modulation. Furthermore, ion concentration modulation was employed to subtract the background noise and increase the signal-to-noise ratio. To determine the absolute frequency of the idler wave, the OPO signal frequency was locked to an optical frequency comb. The absolute frequency accuracy of our spectrometer was better than 7 kHz, demonstrated by measuring the wavelength standard transition of methane at 3.39 MUm. Finally, we measured 16 transitions of H3+ and our results agree very well with other precision measurements. This work successfully resolved the discrepancies between our previous measurements and other precision measurements. PMID- 29604857 TI - Kinetic analysis of single molecule FRET transitions without trajectories. AB - Single molecule Forster resonance energy transfer (smFRET) is a popular tool to study biological systems that undergo topological transitions on the nanometer scale. smFRET experiments typically require recording of long smFRET trajectories and subsequent statistical analysis to extract parameters such as the states' lifetimes. Alternatively, analysis of probability distributions exploits the shapes of smFRET distributions at well chosen exposure times and hence works without the acquisition of time traces. Here, we describe a variant that utilizes statistical tests to compare experimental datasets with Monte Carlo simulations. For a given model, parameters are varied to cover the full realistic parameter space. As output, the method yields p-values which quantify the likelihood for each parameter setting to be consistent with the experimental data. The method provides suitable results even if the actual lifetimes differ by an order of magnitude. We also demonstrated the robustness of the method to inaccurately determine input parameters. As proof of concept, the new method was applied to the determination of transition rate constants for Holliday junctions. PMID- 29604858 TI - NH3 adsorption on anatase-TiO2(101). AB - The adsorption of ammonia on anatase TiO2 is of fundamental importance for several catalytic applications of TiO2 and for probing acid-base interactions. Utilizing high-resolution scanning tunneling microscopy (STM), synchrotron X-ray photoelectron spectroscopy, temperature-programmed desorption (TPD), and density functional theory (DFT), we identify the adsorption mode and quantify the adsorption strength on the anatase TiO2(101) surface. It was found that ammonia adsorbs non-dissociatively as NH3 on regular five-fold coordinated titanium surface sites (5f-Ti) with an estimated exothermic adsorption energy of 1.2 eV for an isolated ammonia molecule. For higher adsorbate coverages, the adsorption energy progressively shifts to smaller values, due to repulsive intermolecular interactions. The repulsive adsorbate-adsorbate interactions are quantified using DFT and autocorrelation analysis of STM images, which both showed a repulsive energy of ~50 meV for nearest neighbor sites and a lowering in binding energy for an ammonia molecule in a full monolayer of 0.28 eV, which is in agreement with TPD spectra. PMID- 29604859 TI - Sn2+-Stabilization in MASnI3 perovskites by superhalide incorporation. AB - Sn-based hybrid halide perovskites are a potential solution to replace Pb and thereby reduce Pb toxicity in MAPbI3 perovskite-based solar cells. However, the instability of Sn2+ in air atmosphere causes a poor reproducibility of MASnI3, hindering steps towards this goal. In this paper, we propose a new type of organic metal-superhalide perovskite of MASnI2BH4 and MASnI2AlH4. Through first principles calculations, our results reveal that the incorporation of BH4 and AlH4 superhalides can realize an impressive enhancement of oxidation resistance of Sn2+ in MASnI3 perovskites because of the large electron transfer between Sn2+ and [BH4]-/[AlH4]-. Meanwhile, the high carrier mobility is preserved in these superhalide perovskites and only a slight decrease is observed in the optical absorption strength. Our studies provide a new path to attain highly stable performance and reproducibility of Sn-based perovskite solar cells. PMID- 29604860 TI - Experimental study of the polyamorphism of water. II. The isobaric transitions between HDA and VHDA at intermediate and high pressures. AB - Since the first report of very-high density amorphous ice (VHDA) in 2001 [T. Loerting et al., Phys. Chem. Chem. Phys. 3, 5355-5357 (2001)], the status of VHDA as a distinct amorphous ice has been debated. We here study VHDA and its relation to expanded high density amorphous ice (eHDA) on the basis of isobaric heating experiments. VHDA was heated at 0.1 <= p <= 0.7 GPa, and eHDA was heated at 1.1 <= p <= 1.6 GPa to achieve interconversion. The behavior upon heating is monitored using in situ volumetry as well as ex situ X-ray diffraction and differential scanning calorimetry. We do not observe a sharp transition for any of the isobaric experiments. Instead, a continuous expansion (VHDA) or densification (eHDA) marks the interconversion. This suggests that a continuum of states exists between VHDA and HDA, at least in the temperature range studied here. This further suggests that VHDA is the most relaxed amorphous ice at high pressures and eHDA is the most relaxed amorphous ice at intermediate pressures. It remains unclear whether or not HDA and VHDA experience a sharp transition upon isothermal compression/decompression at low temperature. PMID- 29604861 TI - Dynamical simulation of electron transfer processes in self-assembled monolayers at metal surfaces using a density matrix approach. AB - A single-particle density matrix approach is introduced to simulate the dynamics of heterogeneous electron transfer (ET) processes at interfaces. The characterization of the systems is based on a model Hamiltonian parametrized by electronic structure calculations and a partitioning method. The method is applied to investigate ET in a series of nitrile-substituted (poly)(p phenylene)thiolate self-assembled monolayers adsorbed at the Au(111) surface. The results show a significant dependence of the ET on the orbital symmetry of the donor state and on the molecular and electronic structure of the spacer. PMID- 29604862 TI - A versatile optical microscope for time-dependent single-molecule and single particle spectroscopy. AB - This work reports the design and implementation of a multi-function optical microscope for time-dependent spectroscopy on single molecules and single nanoparticles. It integrates the now-routine single-object measurements into one standalone platform so that no reconfiguration is needed when switching between different types of sample or spectroscopy modes. The illumination modes include evanescent field through total internal reflection, dark-field illumination, and epi-excitation onto a diffraction-limited spot suitable for confocal detection. The detection modes include spectrally resolved line imaging, wide-field imaging with dual-color capability, and two-color single-element photon-counting detection. The switch between different spectroscopy and data acquisition modes is fully automated and executed through computer programming. The capability of this microscope is demonstrated through selected proof-of-principle experiments. PMID- 29604863 TI - Modification of the histone tetramer at the H3-H3 interface impacts tetrasome conformations and dynamics. AB - Nucleosomes consisting of a short piece of deoxyribonucleic acid (DNA) wrapped around an octamer of histone proteins form the fundamental unit of chromatin in eukaryotes. Their role in DNA compaction comes with regulatory functions that impact essential genomic processes such as replication, transcription, and repair. The assembly of nucleosomes obeys a precise pathway in which tetramers of histones H3 and H4 bind to the DNA first to form tetrasomes, and two dimers of histones H2A and H2B are subsequently incorporated to complete the complex. As viable intermediates, we previously showed that tetrasomes can spontaneously flip between a left-handed and right-handed conformation of DNA-wrapping. To pinpoint the underlying mechanism, here we investigated the role of the H3-H3 interface for tetramer flexibility in the flipping process at the single-molecule level. Using freely orbiting magnetic tweezers, we studied the assembly and structural dynamics of individual tetrasomes modified at the cysteines close to this interaction interface by iodoacetamide (IA) in real time. While such modification did not affect the structural properties of the tetrasomes, it caused a 3-fold change in their flipping kinetics. The results indicate that the IA-modification enhances the conformational plasticity of tetrasomes. Our findings suggest that subnucleosomal dynamics may be employed by chromatin as an intrinsic and adjustable mechanism to regulate DNA supercoiling. PMID- 29604864 TI - Stick boundary condition at large hard sphere arising from effective attraction in binary hard-sphere mixtures. AB - We have studied the diffusion of a large hard-sphere solute immersed in binary hard-sphere mixtures. We reveal how the boundary condition at the solute surface is affected by the solvent density around the solute. Solving equations for a binary compressible mixture by perturbation expansions, we obtain the boundary condition depending on the size ratio of binary solvent spheres. When the size ratio is 1:2, the boundary condition lies close to the slip boundary condition. By contrast, when the size ratio becomes large, the boundary condition approaches the stick boundary condition with the addition of larger solvent spheres. We find that the transition to the stick boundary condition is caused by the increase in the solvent density around the solute due to an entropic effect. PMID- 29604865 TI - Deciphering hierarchical features in the energy landscape of adenylate kinase folding/unfolding. AB - Hierarchical features of the energy landscape of the folding/unfolding behavior of adenylate kinase, including its dependence on denaturant concentration, are elucidated in terms of single-molecule fluorescence resonance energy transfer (smFRET) measurements in which the proteins are encapsulated in a lipid vesicle. The core in constructing the energy landscape from single-molecule time-series across different denaturant concentrations is the application of rate-distortion theory (RDT), which naturally considers the effects of measurement noise and sampling error, in combination with change-point detection and the quantification of the FRET efficiency-dependent photobleaching behavior. Energy landscapes are constructed as a function of observation time scale, revealing multiple partially folded conformations at small time scales that are situated in a superbasin. As the time scale increases, these denatured states merge into a single basin, demonstrating the coarse-graining of the energy landscape as observation time increases. Because the photobleaching time scale is dependent on the conformational state of the protein, possible nonequilibrium features are discussed, and a statistical test for violation of the detailed balance condition is developed based on the state sequences arising from the RDT framework. PMID- 29604866 TI - Theoretical study of ultrafast x-ray photoelectron diffraction from molecules undergoing photodissociation. AB - We present a new theoretical work for the ultrafast x-ray photoelectron diffraction (UXPD) method to track photodissociation of molecules over the long range in femtosecond time scale. Our theory combines the accurate multicenter description of XPD at short to medium distances and the multiple-scattering XPD approach at larger internuclear separations. Then, the theoretical framework is applied to a demonstration of the UXPD profiles from halogen diatomics undergoing photodissociation. The computational results indicate that such a combination of the two theoretical approaches sufficiently works to seamlessly track the conformational evolution during photodissociation. The present study provides information on dissociation kinetics of neutral diatomic molecules available with the UXPD method and is a step towards an approach applied to general photoelimination processes. PMID- 29604867 TI - Driven similarity renormalization group for excited states: A state-averaged perturbation theory. AB - The multireference driven similarity renormalization group (MRDSRG) approach [C. Li and F. A. Evangelista, J. Chem. Theory Comput. 11, 2097 (2015)] is generalized to treat quasi-degenerate electronic excited states. The new scheme, termed state averaged (SA) MRDSRG, is a state-universal approach that considers an ensemble of quasi-degenerate states on an equal footing. Using the SA-MRDSRG framework, we implement second- (SA-DSRG-PT2) and third-order (SA-DSRG-PT3) perturbation theories. These perturbation theories can treat a manifold of near-degenerate states at the cost of a single state-specific computation. At the same time, they have several desirable properties: (1) they are intruder-free and size-extensive, (2) their energy expressions can be evaluated non-iteratively and require at most the three-body density cumulant of the reference states, and (3) the reference states are allowed to relax in the presence of dynamical correlation effects. Numerical benchmarks on the potential energy surfaces of lithium fluoride, ammonia, and the penta-2,4-dieniminium cation reveal that the SA-DSRG-PT2 method yields results with accuracy similar to that of other second-order quasi degenerate perturbation theories. The SA-DSRG-PT3 results are instead consistent with those from multireference configuration interaction with singles and doubles (MRCISD). Finally, we compute the vertical excitation energies of (E,E)-1,3,5,7 octatetraene. The ordering of the lowest three states is predicted to be 2 1Ag-<1 1Bu+<1 1Bu- by both SA-DSRG-PT2 and SA-DSRG-PT3, in accordance with MRCISD plus Davidson correction. PMID- 29604868 TI - Crystallization of hard spheres revisited. I. Extracting kinetics and free energy landscape from forward flux sampling. AB - We investigate the kinetics and the free energy landscape of the crystallization of hard spheres from a supersaturated metastable liquid though direct simulations and forward flux sampling. In this first paper, we describe and test two different ways to reconstruct the free energy barriers from the sampled steady state probability distribution of cluster sizes without sampling the equilibrium distribution. The first method is based on mean first passage times, and the second method is based on splitting probabilities. We verify both methods for a single particle moving in a double-well potential. For the nucleation of hard spheres, these methods allow us to probe a wide range of supersaturations and to reconstruct the kinetics and the free energy landscape from the same simulation. Results are consistent with the scaling predicted by classical nucleation theory although a quantitative fit requires a rather large effective interfacial tension. PMID- 29604869 TI - Preface: Special Topic on Single-Molecule Biophysics. AB - Single-molecule measurements are now almost routinely used to study biological systems and processes. The scope of this special topic emphasizes the physics side of single-molecule observations, with the goal of highlighting new developments in physical techniques as well as conceptual insights that single molecule measurements bring to biophysics. This issue also comprises recent advances in theoretical physical models of single-molecule phenomena, interpretation of single-molecule signals, and fundamental areas of statistical mechanics that are related to single-molecule observations. A particular goal is to illustrate the increasing synergy between theory, simulation, and experiment in single-molecule biophysics. PMID- 29604870 TI - Short-range density functional correlation within the restricted active space CI method. AB - In the present work, I introduce a hybrid wave function-density functional theory electronic structure method based on the range separation of the electron electron Coulomb operator in order to recover dynamic electron correlations missed in the restricted active space configuration interaction (RASCI) methodology. The working equations and the computational algorithm for the implementation of the new approach, i.e., RAS-srDFT, are presented, and the method is tested in the calculation of excitation energies of organic molecules. The good performance of the RASCI wave function in combination with different short-range exchange-correlation functionals in the computation of relative energies represents a quantitative improvement with respect to the RASCI results and paves the path for the development of RAS-srDFT as a promising scheme in the computation of the ground and excited states where nondynamic and dynamic electron correlations are important. PMID- 29604871 TI - Physical-chemical mechanisms of pattern formation during gastrulation. AB - Gastrulation is a fundamental phase during the biological development of most animals when a single layer of identical embryo cells is transformed into a three layer structure, from which the organs start to develop. Despite a remarkable progress in quantifying the gastrulation processes, molecular mechanisms of these processes remain not well understood. Here we theoretically investigate early spatial patterning in a geometrically confined colony of embryonic stem cells. Using a reaction-diffusion model, a role of Bone-Morphogenetic Protein 4 (BMP4) signaling pathway in gastrulation is specifically analyzed. Our results show that for slow diffusion rates of BMP4 molecules, a new length scale appears, which is independent of the size of the system. This length scale separates the central region of the colony with uniform low concentrations of BMP molecules from the region near the colony edge where the concentration of signaling molecules is elevated. The roles of different components of the signaling pathway are also explained. Theoretical results are consistent with recent in vitro experiments, providing microscopic explanations for some features of early embryonic spatial patterning. Physical-chemical mechanisms of these processes are discussed. PMID- 29604872 TI - Electron-impact electronic-state excitation of para-benzoquinone. AB - Angle resolved electron energy loss spectra (EELS) for para-benzoquinone (C6H4O2) have been recorded for incident electron energies of 20, 30, and 40 eV. Measured differential cross sections (DCSs) for electronic band features, composed of a combination of energetically unresolved electronic states, are subsequently derived from those EELS. Where possible, the obtained DCSs are compared with those calculated using the Schwinger multichannel method with pseudopotentials. These calculations were performed using a minimum orbital basis single configuration interaction framework at the static exchange plus polarisation level. Here, quite reasonable agreement between the experimental cross sections and the theoretical cross sections for the summation of unresolved states was observed. PMID- 29604873 TI - A fluid membrane enhances the velocity of cargo transport by small teams of kinesin-1. AB - Kinesin-1 (hereafter referred to as kinesin) is a major microtubule-based motor protein for plus-end-directed intracellular transport in live cells. While the single-molecule functions of kinesin are well characterized, the physiologically relevant transport of membranous cargos by small teams of kinesins remains poorly understood. A key experimental challenge remains in the quantitative control of the number of motors driving transport. Here we utilized "motile fraction" to overcome this challenge and experimentally accessed transport by a single kinesin through the physiologically relevant transport by a small team of kinesins. We used a fluid lipid bilayer to model the cellular membrane in vitro and employed optical trapping to quantify the transport of membrane-enclosed cargos versus traditional membrane-free cargos under identical conditions. We found that coupling motors via a fluid membrane significantly enhances the velocity of cargo transport by small teams of kinesins. Importantly, enclosing a cargo in a fluid lipid membrane did not impact single-kinesin transport, indicating that membrane dependent velocity enhancement for team-based transport arises from altered interactions between kinesins. Our study demonstrates that membrane-based coupling between motors is a key determinant of kinesin-based transport. Enhanced velocity may be critical for fast delivery of cargos in live cells. PMID- 29604874 TI - Phasor based single-molecule localization microscopy in 3D (pSMLM-3D): An algorithm for MHz localization rates using standard CPUs. AB - We present a fast and model-free 2D and 3D single-molecule localization algorithm that allows more than 3 * 106 localizations per second to be calculated on a standard multi-core central processing unit with localization accuracies in line with the most accurate algorithms currently available. Our algorithm converts the region of interest around a point spread function to two phase vectors (phasors) by calculating the first Fourier coefficients in both the x- and y-direction. The angles of these phasors are used to localize the center of the single fluorescent emitter, and the ratio of the magnitudes of the two phasors is a measure for astigmatism, which can be used to obtain depth information (z-direction). Our approach can be used both as a stand-alone algorithm for maximizing localization speed and as a first estimator for more time consuming iterative algorithms. PMID- 29604875 TI - Solvent effect on FRET spectroscopic ruler. AB - A discrepancy has emerged in recent years between single-molecule Forster resonance energy transfer (smFRET) measurements and small angle X-ray scattering (SAXS) or small angle neutron scattering experiments in the study of unfolded or intrinsically disordered proteins in denaturing solutions. Despite significant advances that have been made in identifying various factors which may have contributed to the manifestation of the so-called smFRET-SAXS discrepancy, no consensus has been reached so far on its original source or eventual resolution. In this study, we investigate this problem from the perspective of the solvent effect on FRET spectroscopic ruler (SEFSR), a generic term we use to describe various solvent-dependent factors affecting the accuracy of the FRET experimental method that is known as a "spectroscopic ruler." Some factors belonging to SEFSR, such as direct dye-solvent interaction and labeling configuration, seem to have not received due attention regarding their significance in contributing to the discrepancy. We identify SEFSR by measuring a rigid segment of a double-stranded DNA in various solutions using the smFRET method and evaluate its relative importance in smFRET experiments by measuring segments of a single-stranded DNA and polyethylene glycol (PEG) in solutions. We find that SEFSR can produce non negligible FRET-inferred interdye distance changes in various solutions, with an intensity following the Hofmeister series in ionic solutions and dependent on labeling configurations. SEFSR is found to be significant in GuHCl and urea solutions, which can fully cover the apparent expansion signal of dye-labeled PEG. Our findings suggest that SEFSR may have played an important role in contributing to the smFRET-SAXS discrepancy. PMID- 29604876 TI - Equilibration and analysis of first-principles molecular dynamics simulations of water. AB - First-principles molecular dynamics (FPMD) simulations based on density functional theory are becoming increasingly popular for the description of liquids. In view of the high computational cost of these simulations, the choice of an appropriate equilibration protocol is critical. We assess two methods of estimation of equilibration times using a large dataset of first-principles molecular dynamics simulations of water. The Gelman-Rubin potential scale reduction factor [A. Gelman and D. B. Rubin, Stat. Sci. 7, 457 (1992)] and the marginal standard error rule heuristic proposed by White [Simulation 69, 323 (1997)] are evaluated on a set of 32 independent 64-molecule simulations of 58 ps each, amounting to a combined cumulative time of 1.85 ns. The availability of multiple independent simulations also allows for an estimation of the variance of averaged quantities, both within MD runs and between runs. We analyze atomic trajectories, focusing on correlations of the Kohn-Sham energy, pair correlation functions, number of hydrogen bonds, and diffusion coefficient. The observed variability across samples provides a measure of the uncertainty associated with these quantities, thus facilitating meaningful comparisons of different approximations used in the simulations. We find that the computed diffusion coefficient and average number of hydrogen bonds are affected by a significant uncertainty in spite of the large size of the dataset used. A comparison with classical simulations using the TIP4P/2005 model confirms that the variability of the diffusivity is also observed after long equilibration times. Complete atomic trajectories and simulation output files are available online for further analysis. PMID- 29604878 TI - Spectrally resolved single-molecule electrometry. AB - Escape-time electrometry is a recently developed experimental technique that offers the ability to measure the effective electrical charge of a single biomolecule in solution with sub-elementary charge precision. The approach relies on measuring the average escape-time of a single charged macromolecule or molecular species transiently confined in an electrostatic fluidic trap. Comparing the experiments with the predictions of a mean-field model of molecular electrostatics, we have found that the measured effective charge even reports on molecular conformation, e.g., folded or disordered state, and non-uniform charge distribution in disordered proteins or polyelectrolytes. Here we demonstrate the ability to use the spectral dimension to distinguish minute differences in electrical charge between individual molecules or molecular species in a single simultaneous measurement, under identical experimental conditions. Using one spectral channel for referenced measurement, this kind of photophysical distinguishability essentially eliminates the need for accurate knowledge of key experimental parameters, otherwise obtained through intensive characterization of the experimental setup. As examples, we demonstrate the ability to detect small differences (~5%) in the length of double-stranded DNA fragments as well as single amino acid exchange in an intrinsically disordered protein, prothymosin alpha. PMID- 29604877 TI - Internal friction in an intrinsically disordered protein-Comparing Rouse-like models with experiments. AB - Internal friction is frequently found in protein dynamics. Its molecular origin however is difficult to conceptualize. Even unfolded and intrinsically disordered polypeptide chains exhibit signs of internal friction despite their enormous solvent accessibility. Here, we compare four polymer theories of internal friction with experimental results on the intrinsically disordered protein ACTR (activator of thyroid hormone receptor). Using nanosecond fluorescence correlation spectroscopy combined with single-molecule Forster resonance energy transfer (smFRET), we determine the time scales of the diffusive chain dynamics of ACTR at different solvent viscosities and varying degrees of compaction. Despite pronounced differences between the theories, we find that all models can capture the experimental viscosity-dependence of the chain relaxation time. In contrast, the observed slowdown upon chain collapse of ACTR is not captured by any of the theories and a mechanistic link between chain dimension and internal friction is still missing, implying that the current theories are incomplete. In addition, a discrepancy between early results on homopolymer solutions and recent single-molecule experiments on unfolded and disordered proteins suggests that internal friction is likely to be a composite phenomenon caused by a variety of processes. PMID- 29604879 TI - Dissipation dynamics of field-free molecular alignment for symmetric-top molecules: Ethane (C2H6). AB - The field-free molecular alignment of symmetric-top molecules, ethane, induced by intense non-resonant linearly polarized femtosecond laser pulses is investigated experimentally in the presence of collisional relaxation. The dissipation dynamics of field-free molecular alignment are measured by the balanced detection of ultrafast molecular birefringence of ethane gas samples at high pressures. By separating the molecular alignment into the permanent alignment and the transient alignment, the decay time-constants of both components are quantified at the same pressure. It is observed that the permanent alignment always decays slower compared to the transient alignment within the measured pressure range. This demonstrates that the propensity of molecules to conserve the orientation of angular momentum during collisions, previously observed for linear species, is also applicable to symmetric-top molecules. The results of this work provide valuable information for further theoretical understanding of collisional relaxation within nonlinear polyatomic molecules, which are expected to present interesting and nontrivial features due to an extra rotational degree of freedom. PMID- 29604880 TI - The barrier to ice nucleation in monatomic water. AB - Crystallization from a supercooled liquid initially proceeds via the formation of a small solid embryo (nucleus), which requires surmounting an activation barrier. This phenomenon is most easily studied by numerical simulation, using specialized biased-sampling techniques to overcome the limitations imposed by the rarity of nucleation events. Here, I focus on the barrier to homogeneous ice nucleation in supercooled water, as represented by the monatomic-water model, which in the bulk exhibits a complex interplay between different ice structures. I consider various protocols to identify solidlike particles on a computer, which perform well enough for the Lennard-Jones model, and compare their respective impact on the shape and height of the nucleation barrier. It turns out that the effect is stronger on the nucleus size than on the barrier height. As a by-product of the analysis, I determine the structure of the nucleation cluster, finding that the relative amount of ice phases in the cluster heavily depends on the method used for classifying solidlike particles. Moreover, the phase which is most favored during the earlier stages of crystallization may happen, depending on the nucleation coordinate adopted, to be different from the stable polymorph. Therefore, the quality of a reaction coordinate cannot be assessed simply on the basis of the barrier height obtained. I explain how this outcome is possible and why it just points out the shortcoming of collective variables appropriate to simple fluids in providing a robust method of particle classification for monatomic water. PMID- 29604881 TI - Molecular simulation of capillary phase transitions in flexible porous materials. AB - We used flat-histogram sampling Monte Carlo to study capillary phase transitions in deformable adsorbent materials. Specifically, we considered a pure adsorbate fluid below its bulk critical temperature within a slit pore of variable pore width. The instantaneous pore width is dictated by a number of factors, such as adsorbate loading, reservoir pressure, fluid-wall interaction, and bare adsorbent properties. In the slit pores studied here, the bare adsorbent free energy was assumed to be biparabolic, consisting of two preferential pore configurations, namely, the narrow pore and the large pore configurations. Four distinct phases could be found in the adsorption isotherms. We found a low-pressure phase transition, driven primarily by capillary condensation/evaporation and accompanied by adsorbent deformation in response. The deformation can be a relatively small contraction/expansion as seen in elastic materials, or a large scale structural transformation of the adsorbent. We also found a high-pressure transition driven by excluded volume effects, which tends to expand the material and thus results in a large-scale structural transformation of the adsorbent. The adsorption isotherms and osmotic free energies can be rationalized by considering the relative free energy differences between the basins of the bare adsorbent free energy. PMID- 29604883 TI - Microscopic structural descriptor of liquid water. AB - The microscopic structure of liquid water has been believed to be the key to the understanding of the unique properties of this extremely important substance. Many structural descriptors have been developed for revealing local structural order in water, but their properties are still not well understood. The essential difficulty comes from structural fluctuations due to thermal noise, which are intrinsic to the liquid state. The most popular and widely used descriptors are the local structure index (LSI) and d5. Recently, Russo and Tanaka [Nat. Commun. 3, 3556 (2014)] introduced a new descriptor zeta which measures the translational order between the first and second shells considering hydrogen bonding (H bonding) in the first shell. In this work, we compare the performance of these three structural descriptors for a popular water model known as TIP5P water. We show that local structural ordering can be properly captured only by the structural descriptor zeta, but not by the other two descriptors particularly at a high temperature, where thermal noise effects are severe. The key difference of zeta from LSI and d5 is that only zeta considers H-bonding which is crucial to detect high translational and tetrahedral order of not only oxygen but also hydrogen atoms. The importance of H-bonding is very natural, considering the fact that the locally favored structures are stabilized by energy gain due to the formation of four hydrogen bonds between the central water molecule and its neighboring ones in the first shell. Our analysis of the water structure by using zeta strongly supports the two-state model of water: water is a dynamic mixture of locally favored (ordered) and normal-liquid (disordered) structures. This work demonstrates the importance of H-bonding in the characterization of water's structures and provides a useful structural descriptor for water-type tetrahedral liquids to study their structure and dynamics. PMID- 29604882 TI - Inferring properties of disordered chains from FRET transfer efficiencies. AB - Forster resonance energy transfer (FRET) is a powerful tool for elucidating both structural and dynamic properties of unfolded or disordered biomolecules, especially in single-molecule experiments. However, the key observables, namely, the mean transfer efficiency and fluorescence lifetimes of the donor and acceptor chromophores, are averaged over a broad distribution of donor-acceptor distances. The inferred average properties of the ensemble therefore depend on the form of the model distribution chosen to describe the distance, as has been widely recognized. In addition, while the distribution for one type of polymer model may be appropriate for a chain under a given set of physico-chemical conditions, it may not be suitable for the same chain in a different environment so that even an apparently consistent application of the same model over all conditions may distort the apparent changes in chain dimensions with variation of temperature or solution composition. Here, we present an alternative and straightforward approach to determining ensemble properties from FRET data, in which the polymer scaling exponent is allowed to vary with solution conditions. In its simplest form, it requires either the mean FRET efficiency or fluorescence lifetime information. In order to test the accuracy of the method, we have utilized both synthetic FRET data from implicit and explicit solvent simulations for 30 different protein sequences, and experimental single-molecule FRET data for an intrinsically disordered and a denatured protein. In all cases, we find that the inferred radii of gyration are within 10% of the true values, thus providing higher accuracy than simpler polymer models. In addition, the scaling exponents obtained by our procedure are in good agreement with those determined directly from the molecular ensemble. Our approach can in principle be generalized to treating other ensemble-averaged functions of intramolecular distances from experimental data. PMID- 29604884 TI - Transition paths in single-molecule force spectroscopy. AB - In a typical single-molecule force spectroscopy experiment, the ends of the molecule of interest are connected by long polymer linkers to a pair of mesoscopic beads trapped in the focus of two laser beams. At constant force load, the total extension, i.e., the end-to-end distance of the molecule plus linkers, is measured as a function of time. In the simplest systems, the measured extension fluctuates about two values characteristic of folded and unfolded states, with occasional transitions between them. We have recently shown that molecular (un)folding rates can be recovered from such trajectories, with a small linker correction, as long as the characteristic time of the bead fluctuations is shorter than the residence time in the unfolded (folded) state. Here, we show that accurate measurements of the molecular transition path times require an even faster apparatus response. Transition paths, the trajectory segments in which the molecule (un)folds, are properly resolved only if the beads fluctuate more rapidly than the end-to-end distance of the molecule. Therefore, over a wide regime, the measured rates may be meaningful but not the transition path times. Analytic expressions for the measured mean transition path times are obtained for systems diffusing anisotropically on a two-dimensional free energy surface. The transition path times depend on the properties both of the molecule and of the pulling device. PMID- 29604885 TI - Improved free-energy landscape reconstruction of bacteriorhodopsin highlights local variations in unfolding energy. AB - Precisely quantifying the energetics that drive the folding of membrane proteins into a lipid bilayer remains challenging. More than 15 years ago, atomic force microscopy (AFM) emerged as a powerful tool to mechanically extract individual membrane proteins from a lipid bilayer. Concurrently, fluctuation theorems, such as the Jarzynski equality, were applied to deduce equilibrium free energies (DeltaG0) from non-equilibrium single-molecule force spectroscopy records. The combination of these two advances in single-molecule studies deduced the free energy of the model membrane protein bacteriorhodopsin in its native lipid bilayer. To elucidate this free-energy landscape at a higher resolution, we applied two recent developments. First, as an input to the reconstruction, we used force-extension curves acquired with a 100-fold higher time resolution and 10-fold higher force precision than traditional AFM studies of membrane proteins. Next, by using an inverse Weierstrass transform and the Jarzynski equality, we removed the free energy associated with the force probe and determined the molecular free-energy landscape of the molecule under study, bacteriorhodopsin. The resulting landscape yielded an average unfolding free energy per amino acid (aa) of 1.0 +/- 0.1 kcal/mol, in agreement with past single-molecule studies. Moreover, on a smaller spatial scale, this high-resolution landscape also agreed with an equilibrium measurement of a particular three-aa transition in bacteriorhodopsin that yielded 2.7 kcal/mol/aa, an unexpectedly high value. Hence, while average unfolding DeltaG0 per aa is a useful metric, the derived high-resolution landscape details significant local variation from the mean. More generally, we demonstrated that, as anticipated, the inverse Weierstrass transform is an efficient means to reconstruct free-energy landscapes from AFM data. PMID- 29604886 TI - Importance sampling large deviations in nonequilibrium steady states. I. AB - Large deviation functions contain information on the stability and response of systems driven into nonequilibrium steady states and in such a way are similar to free energies for systems at equilibrium. As with equilibrium free energies, evaluating large deviation functions numerically for all but the simplest systems is difficult because by construction they depend on exponentially rare events. In this first paper of a series, we evaluate different trajectory-based sampling methods capable of computing large deviation functions of time integrated observables within nonequilibrium steady states. We illustrate some convergence criteria and best practices using a number of different models, including a biased Brownian walker, a driven lattice gas, and a model of self-assembly. We show how two popular methods for sampling trajectory ensembles, transition path sampling and diffusion Monte Carlo, suffer from exponentially diverging correlations in trajectory space as a function of the bias parameter when estimating large deviation functions. Improving the efficiencies of these algorithms requires introducing guiding functions for the trajectories. PMID- 29604887 TI - Rate constants for proteins binding to substrates with multiple binding sites using a generalized forward flux sampling expression. AB - To predict the response of a biochemical system, knowledge of the intrinsic and effective rate constants of proteins is crucial. The experimentally accessible effective rate constant for association can be decomposed in a diffusion-limited rate at which proteins come into contact and an intrinsic association rate at which the proteins in contact truly bind. Reversely, when dissociating, bound proteins first separate into a contact pair with an intrinsic dissociation rate, before moving away by diffusion. While microscopic expressions exist that enable the calculation of the intrinsic and effective rate constants by conducting a single rare event simulation of the protein dissociation reaction, these expressions are only valid when the substrate has just one binding site. If the substrate has multiple binding sites, a bound enzyme can, besides dissociating into the bulk, also hop to another binding site. Calculating transition rate constants between multiple states with forward flux sampling requires a generalized rate expression. We present this expression here and use it to derive explicit expressions for all intrinsic and effective rate constants involving binding to multiple states, including rebinding. We illustrate our approach by computing the intrinsic and effective association, dissociation, and hopping rate constants for a system in which a patchy particle model enzyme binds to a substrate with two binding sites. We find that these rate constants increase as a function of the rotational diffusion constant of the particles. The hopping rate constant decreases as a function of the distance between the binding sites. Finally, we find that blocking one of the binding sites enhances both association and dissociation rate constants. Our approach and results are important for understanding and modeling association reactions in enzyme-substrate systems and other patchy particle systems and open the way for large multiscale simulations of such systems. PMID- 29604888 TI - Conformational effects on the torsional barriers in m-methylanisole studied by microwave spectroscopy. AB - The microwave spectrum of m-methylanisole (also known as 3-methylanisole, or 3 methoxytoluene) was measured using a pulsed molecular jet Fourier transform microwave spectrometer operating in the frequency range of 2-26.5 GHz. Quantum chemical calculations predicted two conformers with the methoxy group in trans or cis position related to the ring methyl group, both of which were assigned in the experimental spectrum. Due to the internal rotation of the ring methyl group, all rotational transitions introduced large A-E splittings up to several GHz, which were analyzed with a newly developed program, called aixPAM, working in the principal axis system. There are significant differences in the V3 potential barriers of 55.7693(90) cm-1 and 36.6342(84) cm-1 determined by fitting 223 and 320 torsional components of the cis and the trans conformer, respectively. These values were compared with those found in other m-substituted toluenes as well as in o- and p-methylanisole. A comparison between the aixPAM and the XIAM code (using a combined axis system) was also performed. PMID- 29604889 TI - Electronic structure of ZrX2 (X = Se, Te). AB - The electronic structure of the ZrX2 (X = Se, Te) compounds has been studied using photoelectron, resonant photoelectron and X-ray absorption spectroscopy, theoretical calculations of the X-ray absorption spectra, and density of electronic states. It was found that the absorption spectra and valence band spectra are influenced by the chalcogen type. The results of the multiplet calculation of the Zr4+ atom show that the change in the splitting in the crystal field, which is described by the 10Dq parameter, is due to the change in the ratio of covalent and ionic contributions to the chemical bond. The resonance band near the Fermi level in the valence band spectra is observed for ZrTe2 in the Zr 3p-4d resonant excitation mode. The extent of photon energy indicates the charge localization on the Zr atom. Similar resonance band for ZrSe2 is absent; it indicates the presence of a gap at the Fermi level. PMID- 29604890 TI - Computational analysis for selectivity of histone deacetylase inhibitor by replica-exchange umbrella sampling molecular dynamics simulations. AB - We performed protein-ligand docking simulations with a ligand T247, which has been reported as a selective inhibitor of a histone deacetylase HDAC3, by the replica-exchange umbrella sampling method in order to estimate the free energy profiles along ligand docking pathways of HDAC3-T247 and HDAC2-T247 systems. The simulation results showed that the docked state of the HDAC3-T247 system is more stable than that of the HDAC2-T247 system although the amino-acid sequences and structures of HDAC3 and HDAC2 are very similar. By comparing structures obtained from the simulations of both systems, we found the difference between structures of hydrophobic residues at the entrance of the catalytic site. Moreover, we performed conventional molecular dynamics simulations of HDAC3 and HDAC2 systems without T247, and the results also showed the same difference of the hydrophobic structures. Therefore, we consider that this hydrophobic structure contributes to the stabilization of the docked state of the HDAC3-T247 system. Furthermore, we show that Tyr209, which is one of the hydrophobic residues in HDAC2, plays a key role in the instability from the simulation results of a mutated-HDAC2 system. PMID- 29604891 TI - Probabilistic analysis for identifying the driving force of protein folding. AB - Toward identifying the driving force of protein folding, energetics was analyzed in water for Trp-cage (20 residues), protein G (56 residues), and ubiquitin (76 residues) at their native (folded) and heat-denatured (unfolded) states. All-atom molecular dynamics simulation was conducted, and the hydration effect was quantified by the solvation free energy. The free-energy calculation was done by employing the solution theory in the energy representation, and it was seen that the sum of the protein intramolecular (structural) energy and the solvation free energy is more favorable for a folded structure than for an unfolded one generated by heat. Probabilistic arguments were then developed to determine which of the electrostatic, van der Waals, and excluded-volume components of the interactions in the protein-water system governs the relative stabilities between the folded and unfolded structures. It was found that the electrostatic interaction does not correspond to the preference order of the two structures. The van der Waals and excluded-volume components were shown, on the other hand, to provide the right order of preference at probabilities of almost unity, and it is argued that a useful modeling of protein folding is possible on the basis of the excluded-volume effect. PMID- 29604892 TI - High-speed atomic force microscopy reveals structural dynamics of alpha-synuclein monomers and dimers. AB - alpha-Synuclein (alpha-syn) is the major component of the intraneuronal inclusions called Lewy bodies, which are the pathological hallmark of Parkinson's disease. alpha-Syn is capable of self-assembly into many different species, such as soluble oligomers and fibrils. Even though attempts to resolve the structures of the protein have been made, detailed understanding about the structures and their relationship with the different aggregation steps is lacking, which is of interest to provide insights into the pathogenic mechanism of Parkinson's disease. Here we report the structural flexibility of alpha-syn monomers and dimers in an aqueous solution environment as probed by single-molecule time-lapse high-speed AFM. In addition, we present the molecular basis for the structural transitions using discrete molecular dynamics (DMD) simulations. alpha-Syn monomers assume a globular conformation, which is capable of forming tail-like protrusions over dozens of seconds. Importantly, a globular monomer can adopt fully extended conformations. Dimers, on the other hand, are less dynamic and show a dumbbell conformation that experiences morphological changes over time. DMD simulations revealed that the alpha-syn monomer consists of several tightly packed small helices. The tail-like protrusions are also helical with a small beta-sheet, acting as a "hinge". Monomers within dimers have a large interfacial interaction area and are stabilized by interactions in the non-amyloid central (NAC) regions. Furthermore, the dimer NAC-region of each alpha-syn monomer forms a beta-rich segment. Moreover, NAC-regions are located in the hydrophobic core of the dimer. PMID- 29604894 TI - Potential energy surface of triplet O4. AB - We present a global ground-state potential energy surface (PES) for the triplet spin state of O4 that is suitable for treating high-energy vibrational-rotational energy transfer and collision-induced dissociation in electronically adiabatic spin-conserving O2-O2 collisions. The surface is based on MS-CASPT2/maug-cc-pVTZ electronic structure calculations with scaled external correlation; the active space has 16 electrons in 12 orbitals. The global ground-state potential energy surface was fitted by a many-body approach with an accurate O-O pairwise interaction and a fit of the many-body interaction potential to 10 180 electronic structure data points. The many-body fit is based on permutationally invariant polynomials in terms of bond-order functions of the six interatomic distances; the bond-order functions are mixed exponential-Gaussian functions. The geometries calculated and used for the fit include geometry scans corresponding to dissociative and vibrationally excited diatom-diatom collisions of O2, scans corresponding to O3 interacting with O, additional geometries identified by running trajectories, and geometries along linear synchronous transit paths connecting randomly selected points. The global O4 PES includes subsurfaces describing the interaction of diatomic molecules with other diatomic molecules or interactions of triatomic molecules and an atom. The interaction of ozone with a ground-state oxygen atom occurs on the triplet O4 surface, and our surface includes high-energy points with O3-O geometries as well as O2-O2 geometries and O2-O-O geometries. PMID- 29604893 TI - Forced-rupture of cell-adhesion complexes reveals abrupt switch between two brittle states. AB - Cell adhesion complexes (CACs), which are activated by ligand binding, play key roles in many cellular functions ranging from cell cycle regulation to mediation of cell extracellular matrix adhesion. Inspired by single molecule pulling experiments using atomic force spectroscopy on leukocyte function-associated antigen-1 (LFA-1), expressed in T-cells, bound to intercellular adhesion molecules (ICAM), we performed constant loading rate (rf) and constant force (F) simulations using the self-organized polymer model to describe the mechanism of ligand rupture from CACs. The simulations reproduce the major experimental finding on the kinetics of the rupture process, namely, the dependence of the most probable rupture forces (f*s) on ln rf (rf is the loading rate) exhibits two distinct linear regimes. The first, at low rf, has a shallow slope, whereas the slope at high rf is much larger, especially for a LFA-1/ICAM-1 complex with the transition between the two occurring over a narrow rf range. Locations of the two transition states (TSs) extracted from the simulations show an abrupt change from a high value at low rf or constant force, F, to a low value at high rf or F. This unusual behavior in which the CACs switch from one brittle (TS position is a constant over a range of forces) state to another brittle state is not found in forced-rupture in other protein complexes. We explain this novel behavior by constructing the free energy profiles, F(Lambda)s, as a function of a collective reaction coordinate (Lambda), involving many key charged residues and a critical metal ion (Mg2+). The TS positions in F(Lambda), which quantitatively agree with the parameters extracted using the Bell-Evans model, change abruptly at a critical force, demonstrating that it, rather than the molecular extension, is a good reaction coordinate. Our combined analyses using simulations performed in both the pulling modes (constant rf and F) reveal a new mechanism for the two loading regimes observed in the rupture kinetics in CACs. PMID- 29604895 TI - Lipid diffusion in the distal and proximal leaflets of supported lipid bilayer membranes studied by single particle tracking. AB - Supported lipid bilayers (SLBs) have been studied extensively as simple but powerful models for cellular membranes. Yet, potential differences in the dynamics of the two leaflets of a SLB remain poorly understood. Here, using single particle tracking, we obtain a detailed picture of bilayer dynamics. We observe two clearly separate diffusing populations, fast and slow, that we associate with motion in the distal and proximal leaflets of the SLB, respectively, based on fluorescence quenching experiments. We estimate diffusion coefficients using standard techniques as well as a new method based on the blur of images due to motion. Fitting the observed diffusion coefficients to a two leaflet membrane hydrodynamic model allows for the simultaneous determination of the intermonolayer friction coefficient and the substrate-membrane friction coefficient, without any prior assumptions on the strengths of the relevant interactions. Remarkably, our calculations suggest that the viscosity of the interfacial water confined between the membrane and the substrate is elevated by ~104 as compared to bulk water. Using hidden Markov model analysis, we then obtain insight into the transbilayer movement of lipids. We find that lipid flip flop dynamics are very fast, with half times in the range of seconds. Importantly, we find little evidence for membrane defect mediated lipid flip-flop for SLBs at temperatures well above the solid-to-liquid transition, though defects seem to be involved when the SLBs are cooled down. Our work thus shows that the combination of single particle tracking and advanced hydrodynamic modeling provides a powerful means to obtain insight into membrane dynamics. PMID- 29604896 TI - The multi-state energy landscape of the SAM-I riboswitch: A single-molecule Forster resonance energy transfer spectroscopy study. AB - RNA (ribonucleic acid) molecules are highly flexible biopolymers fluctuating at physiological temperatures among many different conformations that are represented by minima in a hierarchical conformational free energy landscape. Here we have employed single-molecule FRET (smFRET) to explore the energy landscape of the B. subtilis yitJ SAM-I riboswitch (RS). In this small RNA molecule, specific binding of an S-adenosyl-L-methionine (SAM) ligand in the aptamer domain regulates gene expression by inducing structural changes in another domain, the expression platform, causing transcription termination by the RNA polymerase. We have measured smFRET histograms over wide ranges of Mg2+ concentration for three RS variants that were specifically labeled with fluorescent dyes on different sites. In the analysis, different conformations are associated with discrete Gaussian model distributions, which are typically fairly broad on the FRET efficiency scale and thus can be extremely challenging to unravel due to their mutual overlap. Our earlier work on two SAM-I RS variants revealed four major conformations. By introducing a global fitting procedure which models both the Mg2+ concentration dependencies of the fractional populations and the average FRET efficiencies of the individual FRET distributions according to Mg2+ binding isotherms, we were able to consistently describe the histogram data of both variants at all studied Mg2+ concentrations. With the third FRET-labeled variant, however, we found significant deviations when applying the four-state model to the data. This can arise because the different FRET labeling of the new variant allows two states to be distinguished that were previously not separable due to overlap. Indeed, the resulting five state model presented here consistently describes the smFRET histograms of all three variants as well as their variations with Mg2+ concentration. We also performed a triangulation of the donor position for two of the constructs to explore how the expression platform is oriented with respect to the aptamer. PMID- 29604897 TI - Homeobox Gene Involvement in Normal Hematopoiesis and in the Pathogenesis of Childhood Leukemias. AB - Homeobox (HOX) genes are a superfamily of highly conserved genes with essential functions in many aspects of mammalian development. Their expression is tightly regulated throughout the duration of definitive hematopoiesis, so the pathogenetic mechanism that leads to leukemia suggests that malignant transformation is directly intertwined with the deregulation of HOX gene expression. Even though HOX gene involvement has been reviewed extensively in adult leukemias, childhood leukemias have received much less attention and mainly in the context of leukemias harboring MLL (mixed-lineage leukemia) gene translocations. In recent years, scientific evidence has highlighted HOX gene involvement in the development of other subtypes of childhood leukemias and added HOX gene family members that were previously unrelated to the pathogenesis of childhood leukemia. This has significant implications when considering both the risk stratification of pediatric patients and potential targets for successful therapy. Through the identification of HOX target genes, their resulting interactions, and the cognate signaling pathways, we hope to gain a better understanding of the molecular mechanism(s) underlying the ectopic activation of these genes in childhood leukemias and subsequently to reveal new molecular targets for successful therapy in cases of poor prognosis or resistant disease. PMID- 29604898 TI - Animal Models of Uveal Melanoma for Localized Interventions. AB - Uveal melanoma is the most common primary intraocular malignancy in adults, carrying a significant risk for death from metastatic disease. Treatment efforts aim toward local tumor control and early detection and management of metastases. Animal models are a valuable tool in the study of the molecular, genetic, and cellular events associated with the development of uveal melanoma and the evaluation of the therapeutic potential for various treatment methods. So far, several spontaneous, transgenetic, or induced animal models have been used, each presenting distinct advantages and disadvantages. This review article systematically presents an analysis of these animal models aimed at localized interventions; We aim to assist researchers with the selection of the optimal animal model based on their particular research targets. PMID- 29604899 TI - Histone Acetyltransferases in Cancer: Guardians or Hazards? AB - Histone acetyltransferases (HATs) catalyzing N-epsilon-lysine or N-alpha-terminal acetylation on histone and non-histone substrates are important epigenetic regulators controlling gene expression and chromatin structure. Deregulation of these enzymes by genetic or epigenetic alterations accompanied by defects in gene transcription have been implicated in oncogenesis. Therefore, these enzymes are considered promising therapeutic targets, offering new horizons for epigenetic cancer therapy. However, recent observations suggest that these enzymes function as both oncogenes and tumor suppressors. In this review, we present the current evidence demonstrating that individual HATs can either prevent cancer cell proliferation or drive malignant transformation depending on the molecular context and cancer type. We therefore advocate that future therapeutic interventions targeted toward these enzymes should carefully consider the fact that HATs commonly have a two-sided role in carcinogenesis. PMID- 29604900 TI - The Role of Tissue Factor in Cancer-Related Hypercoagulability, Tumor Growth, Angiogenesis and Metastasis and Future Therapeutic Strategies. AB - It is widely recognized that a strong correlation exists between cancer and aberrant hemostasis. Patients with various types of cancers often develop thrombosis, a phenomenon commonly referred to as Trousseau syndrome. Tissue factor (TF) is expressed by tumor cells and contributes to a variety of pathologic processes, such as thrombosis, tumor growth, tumor angiogenesis, and metastasis. Tissue factor is expressed in two naturally occurring protein isoforms: membrane-bound full-length TF (flTF) and soluble alternatively spliced TF (asTF). Tissue factor is the primary initiator of blood coagulation, and it triggers intracellular signaling through protease-activated receptors (PARs). PARs are activated either by TF/FVIIa complexes or by thrombin generated following coagulation activation. Furthermore, the noncoagulant asTF retains an integrin-binding site and stimulates angiogenesis by ligating endothelial integrins alphavbeta3 and alpha6beta1. Lastly, the increased TF expression in tumors is associated with the release in blood of TF-positive procoagulant microparticles that favor thromboembolic complications. Therefore, the interruption of asTF and flTF signaling represents a potential antiangiogenic strategy. In this review, we summarize the current knowledge on the role of TF in cancer, and we explore therapeutic perspectives based on TF targeting. PMID- 29604901 TI - Ras Suppressor-1 (RSU-1) in Cancer Cell Metastasis: Friend or Foe? AB - Metastasis to distant organs and not the primary tumor itself is usually the cause of death for cancer patients. Hence, studying the key molecules and molecular pathways involved in metastasis are essential. Metastasis is a complex process in which cancer cells detach from the original tumor, migrate, and invade through surrounding tissues and metastasize to other sites of the body through the circulation. The cell-extracellular matrix (ECM) adhesion proteins play a fundamental role in this process as cancer cells need to weaken their adhesions to dissociate from the ECM as well as the neighboring cells within the tumor and finally form new adhesions and invade surrounding tissues. Ras suppressor-1 (RSU 1) was originally identified as a suppressor of Ras-dependent oncogenic transformation and found to be localized to cell-ECM adhesions where it binds to PINCH-1, a focal adhesion involved in cell survival. Although RSU-1 was connected to cancer early on, little is known about its expression in various cancer types or its role in metastasis. In this article, we review the recent literature regarding the expression of RSU-1 in various cancer types and its potential role in metastasis, discussing interesting findings and issues that still need to be addressed. PMID- 29604902 TI - Serum Levels of Soluble FLT3 Ligand in Patients with Active Multiple Myeloma Constitute Marker of Bone Marrow Plasma Cell Proliferative Activity. AB - The FLT3-ligand is a molecule implicated in hematopoiesis. The aim of the present study was to detect any possible connections between serum levels of FLT3-L and multiple myeloma (MM) proliferation markers, such as serum levels of interleukin 6 (IL-6), B-cell activating factor (BAFF), beta-2 microglobulin (B2M), CRP and LDH, as well the percentage of bone marrow infiltration and the plasma cells' proliferation marker Ki-67 PI. We measured the above parameters in 58 patients with active MM. All circulating markers were significantly higher in MM patients compared to controls (p < 0.001 for all cases), and all values were increasing in parallel with disease stage (p < 0.001 for all cases). Positive correlations between FLT3-L were noted with serum levels of BAFF (p < 0.003), IL-6 (p < 0.002), CRP (p < 0.0001), LDH (p < 0.001), and BM Ki-67 PI (p = 0.012), whereas only trends of correlation were noted with the B2M value and the percentage of infiltration. It seems that the increased serum levels of circulating FLT3-L, in parallel with MM activity, reflect their increased presence in the bone marrow microenvironment, probably as an effect of increased angiogenesis and myelosuppression. Consequently, they are potential markers of disease activity. PMID- 29604903 TI - Tumor-Suppressing Properties of Crocus sativus L.: Nature as an Anti-Cancer Agent. AB - Cancer is a growing problem because it is a chronic disease that affects, not only patient health, but also its daily living. Concurrent cancer therapies have ameliorated cancer prevalence, but the severity and frequency of toxicity and side effects during therapy have led the scientific community to rediscover the possible therapeutic effectiveness of herbs and spices. Crocus sativus L., commonly known as saffron, has been used in folk medicine for centuries. Today, data from numerous in vivo and in vitro studies support its anti-cancer activity, making it a promising anti-cancer agent for study. In the present review, we focus on the anti-cancer activity of C. sativus and its derivates. Medications that are currently used as chemotherapeutic or anti-cancer agents are associated with side effects whether used at effective doses or at levels that exceed the therapeutic dose. Therefore, many cancer survivors suffer from serious and even life-threatening long- or short-term sequelae, so the development of alternative/coadjutant drugs is imperative. PMID- 29604904 TI - Epithelial-to-Mesenchymal Transition: Liaison between Cancer Metastasis and Drug Resistance. AB - Metastasis and drug resistance are two of the leading causes of death in cancer patients. Poor responses to antitumor drugs can lead to tumor cell dissemination and metastasis. On the other hand, cells that metastasize to lymph nodes and distant organs are liable to drug resistance. Recently, the epithelial mesenchymal transition (EMT) has been found to play a critical role in cancer metastasis and drug resistance; however, the underlying and intrinsic links between them remain unclear. In this review, we summarize recent advances in tumor metastasis and drug resistance, and we focus especially on the association between EMT, metastasis, and drug resistance. We discuss the molecular mechanisms and potential pathways involved in the regulation of EMT, focusing simultaneously on the roles of EMT in modulating metastasis and drug resistance, especially the nature of their intrinsic links across different types of cancer. PMID- 29604905 TI - Oncogenic RAS: From Its Activation to Its Direct Targeting. AB - The RAS oncogenes are the most commonly mutated genes across human cancers. This review is a look back at the discovery of the RAS genes, how we came to understand their function, and how these oncogenes are aberrantly activated, driving cancer development and growth. It also highlights the comprehensive efforts made during the last 30 years to develop therapeutic strategies against the oncogenic mutant RAS. Although there have been many lost battles in the war against mutant RAS-bearing cancer cells, and we have yet to determine which is the "best" path for inhibition of the mutated RAS, a better understanding of the protein's structure combined with technological advances in the field has allowed the development of new strategies to make anti-RAS therapies a reality. The state of-the-art for each strategy is discussed, focusing on the promises and potential pitfalls of each of them. PMID- 29604906 TI - The Ideological Frame of the Genetic Basis of Cancer: The Important Role of miRNAs. AB - The elucidation of the genetic basis of cancer is the result of the research conducted since the beginning of the previous century, which peaked during the decades of 1960s and 1970s. It has been achieved through two different but convergent routes: the first includes the study of oncogenic viruses in rodents and birds and the second includes the use of chemical carcinogens in cells or in animal model systems (mice). Within this framework, the identification of genes that present mutations, alterations in expression levels, and epigenetic modifications has been facilitated through the development of animal carcinogenesis models. One of these models is the well-characterized mouse multistage skin cancer system discussed in this review. In addition, recent evidence shows the great significance that cancer stem cells seem to have in the emergence and progression of carcinogenesis. Finally, herein we discuss the critical role that miRNAs have emerged to play in cancer progression. miRNAs emerged as molecules with an impact on most cancer-related cellular processes, involving cell proliferation, cell death (apoptosis), angiogenesis, migration/motility, and rearrangement of the cytoskeleton. Their discovery has given rise to studies with a focus on miRNAs as key players in crucial oncogenesis-related processes and thus as potential targets in cancer therapeutics. PMID- 29604907 TI - Complex Interplay Between Aging and Cancer: Role of TGF-beta Signaling. AB - Although cancer is known to be predominantly a disease of the elderly, it is also thought that aging and cancer may occur either via similar or opposing cellular mechanisms. Studies during the past decades were focused on understanding the molecular events underlying both processes, aiming to ultimately improve the quality of life and lifespan. However, these efforts were traditionally performed or viewed independently without considering the interplay between aging and cancer-promoting mechanisms. Transforming growth factor-beta (TGF-beta) signaling is essential for embryonic development and physiological tissue homeostasis. Although the fundamental roles of TGF-beta in cancer progression have been investigated extensively, recent reports also provide evidence for its direct or indirect links to aging-related processes such as cell proliferation, senescence, stem cell renewal, DNA damage, inflammation, and telomere length. In this review, we present the latest findings regarding the TGF-beta-regulated convergent and divergent mechanisms controlling the balance between aging and cancer. Finally, the implications of these processes in developing strategies to prolong the cancer-free human lifespan are discussed. PMID- 29604908 TI - The Long Evolutionary Journey of Cancer from Ancestor to Modern Humans. AB - In this article, we review various key issues in cancer development and progression that have important implications for both cancer prevention and treatment: (1) evolutionary aspects of cancer appearance; (2) evidence of organ specific adult stem cells as cancer-initiating cells; (3) the immortality of cancer-initiating cells; (4) cancer cell loss of growth control, contact inhibition, terminal differentiation, and apoptosis; (5) stem-cell versus de differentiation theory of carcinogenesis; (6) mutations in cancer; (7) oncogenes and tumor suppressor genes; (8) epigenetics as the rate-limiting step in carcinogenesis; (9) the potential role of cultural, lifestyle, and nutritional behaviors in oncology; and (10) changes of commensal microbial community and its metagenome in carcinogenesis and tumor progression. Relevant, combined evidence is discussed from a standpoint whereby cancer is considered a multifaceted disease requiring integrated biomolecular and clinico-pathological information to design and implement strategies for either primary prevention or therapy. PMID- 29604909 TI - Antiproliferative Activity and Cytotoxicity of Some Medicinal Wood-Destroying Mushrooms from Russia. AB - We analyzed the antiproliferative activity of 6 medicinal wood-destroying mushrooms (Fomes fomentarius, Fomitopsis pinicola, Trametes versicolor, Trichaptum biforme, Inonotus obliquus, and Coniophora puteana) that are common in deciduous and mixed coniferous forests in Central Russia. Morphological identification of strains collected from the wild was confirmed based on ribosomal DNA internal transcribed spacer phylogenetic analysis. We observed cytotoxic and cell growth-inhibitory effects of hot water extracts from mycelial biomass of 5 species-T. versicolor, C. puteana, F. fomentarius, F. pinicola, and I. obliquus-on leukemia cell lines (Jukart, K562, and THP-1); the effective extract concentrations were mostly less than 50 MUg . mL-1. However, we observed no antiproliferative activity of dry biomass from methanol-chloroform (1:1) extracts of C. puteana and F. fomentarius. A chemosensitivity assay showed that the most effective polypore mushroom extract was the methanol extract of T. versicolor (strain It-1), which inhibited the growth of 6 various solid tumors (A 549 and SWi573 [lung], HBL-100 and T-47D [breast], HeLa [cervix], and WiDr [colon]) at concentrations below 45 MUg . mL-1, with a concentration as low as 0.7-3.6 MUg . mL-1 causing 50% reduction in the proliferation of cancer cells in lung and cervix tumors. Methanol extracts of F. pinicola and I. obliquus were less effective, with proliferation-inhibiting capacities at concentrations below 70 and 200 MUg . mL-1, respectively. Thus, T. versicolor is a prospective candidate in the search for and production of new antiproliferative chemical compounds. PMID- 29604910 TI - Antiproliferative and Antioxidant Activities of Wild Boletales Mushrooms from France. AB - We selected edible and inedible mushrooms growing in the Mediterranean area of France to screen their biological activity: Caloboletus calopus, Rubroboletus lupinus, R. pulchrotinctus, R. satanas, Gyroporus castaneus, Suillus luteus, and Omphalotus olearius. Mushrooms were sequentially extracted using cyclohexane, chloroform, ethanol, and water. The antiproliferative activity against the HCT116 colon adenocarcinoma cell line and the antioxidant properties (DPPH radical scavenging assay, Folin-Ciocalteu assay, and oxygen radical absorbance capacity) of the Boletales extracts were evaluated and compared. Among the 28 mushroom extracts evaluated, 11 presented antiproliferative activity against HCT116 cells. These activities were not linked to antioxidant capacity. Among the antioxidant extracts, most were aqueous extracts in the oxygen radical absorbance capacity assay, whereas the highest values on the Folin-Ciocalteu and DPPH assays were noted for chloroform, ethanol, or aqueous extracts, depending on the mushroom species. Further studies are necessary to identify bioactive compounds and to valorize the mushrooms-for edible species, directly as health foods, or, for inedible mushrooms, as ingredients in the pharmaceutical and food industries. PMID- 29604911 TI - Extrinsic and Intrinsic Apoptotic Responses Induced by Shiitake Culinary Medicinal Mushroom Lentinus edodes (Agaricomycetes) Aqueous Extract against a Larynx Carcinoma Cell Line. AB - Cumulative evidence from research studies has shown that the shiitake culinary medicinal mushroom, Lentinus edodes, is an excellent source of natural antitumor agents and is capable of inhibiting cancer cell growth. However, the cell signaling pathway that leads tumor cells to apoptosis is not well understood because many chemical compounds may be acting. This study investigated the chemopreventive effects of an L. edodes aqueous extract on human HEp-2 epithelial larynx carcinoma cells and normal human MRC-5 lung fibroblasts by identifying proliferative and apoptotic pathways. The chemical characterization of the dry powder was assessed by high-performance liquid chromatography. Antiproliferative and proapoptotic effects induced by the extract were evaluated by assessing proliferative markers, cell sorting through flow cytometry, and expression levels of apoptotic proteins with Western blotting. The results suggest that inhibition of cell proliferation was more prominent in HEp-2 than in MRC-5 cells. Cell death analysis showed the appearance of cell populations in the sub-G1 phase, with late apoptotic signal increased in a dose-dependent manner. In addition, the aqueous extract induced depolarization of mitochondria, activating the generation of intracellular reactive oxygen species in HEp-2 cells. These observations suggest that L. edodes extract may exert a chemopreventive effect, regulating mitotic induction of apoptogenic signals. These findings highlight the mushroom's pharmacological potential in cancer treatment. PMID- 29604912 TI - Purification and Antithrombotic Potential of a Fibrinolytic Enzyme from Shiitake Culinary- Medicinal Mushroom, Lentinus edodes GNA01 (Agaricomycetes). AB - We purified Lentinus edodes GNA01 fibrinolytic enzyme (LEFE) and identified it as a novel metalloprotease. LEFE was purified to homogeneity through a 2-step procedure, with an 8.28-fold increase in specific activity and 5.3% recovery. The molecular mass of LEFE was approximately 38 kDa, based on sodium dodecyl sulfate polyacrylamide gel electrophoresis. Its optimal pH, optimal temperature, pH stability, and thermal stability were 5, 30 degrees C, 6-7, and 40 degrees C, respectively. LEFE was inhibited by zinc and magnesium ions, and by EDTA and EGTA, indicating that LEFE is a metalloprotease. The protease exhibited fibrinolytic activity and a degradative effect on clot formation and blood clots. The protease prolonged activated partial thromboplastin time, prothrombin time, and coagulation time as induced by platelet aggregators (collagen and epinephrine). Taken together, our results indicate that L. edodes GNA01 produces a metalloprotease/fibrinolytic enzyme and that this enzyme might be applied as a new thrombolytic and antithrombotic agent for thrombosis-related cardiovascular disorders. PMID- 29604913 TI - Antioxidant Activity of Water Extract from Fermented Mycelia of Cordyceps sobolifera (Ascomycetes) in Caenorhabditis elegans. AB - This research aimed to evaluate the potential of Cordyceps sobolifera in mycelial biomass production via liquid culture and to assay the safety and determine the antioxidative and antiaging activities of Caenorhabditis elegans. A C. sobolifera isolate was cultured using the one-factor-at-a-time method to illustrate its carbon and nitrogen requirements. To assess safety, we determined the lethality, locomotion behavior, and reproduction of C. elegans cultured on a mycelial water extract (MWE) containing nematode growth medium (NGM). To investigate antiaging activity, C. elegans treated with MWE was incubated on NGM plates. The lethality was recorded throughout the whole life cycle. To identify antioxidant activity, C. elegans treated with MWE was exposed to paraquat, causing superoxide conditions. The results showed that C. sobolifera was favored by glucose and peptone as carbon and nitrogen sources, respectively. MWE was considered to be safe, as no abnormal behaviors were observed in C. elegans. Compared with nematodes pretreated with no MWE but with water instead, MWE at 1.0 mg/mL significantly prolonged the mean lifespan of C. elegans by 24%. We observed an obvious dose-effect relation between concentration and mean lifespan. The effective antioxidant activity was recorded at the high concentration of MWE. These findings demonstrate the potential antiaging and antioxidant properties of C. sobolifera as functional food and dietary supplement. PMID- 29604914 TI - In Vitro Antileishmanial Activity of a Black Morel, Morchella importuna (Ascomycetes). AB - We studied the anti-Leishmania activity of a fractionated extract from the mushroom Morchella importuna in an in vitro system. Leishmaniasis is an important infectious disease caused by a range of Leishmania species, which are multihost protozoa parasites transmitted to humans by the sand fly and infecting macrophages. Leishmaniasis is an increasing worldwide health problem, including in the Mediterranean basin. Current chemotherapy treatments are limited by their toxic effects, the need for long-term treatment, and the increasing development of resistance by the parasite cells. Thus, alternative therapies are being considered, including herbal and mushroom products. We studied the effect of extracts from M. importuna on L. tropica promastigote cell proliferation and survival, and on their toxicity against human macrophages. The aqueous mushroom extract was compared with 3 successive extracted fractions: an 80% ethanol fraction, a water-soluble polysaccharide fraction, and a polyphenolic fraction. All 4 extracts showed anti-Leishmania activity; the aqueous extract was most active. The inhibition activity was dose dependent in killing Leishmania. No cell recovery was recorded after exposure to the mushroom extract. Microscopic observation showed morphological changes and the loss of flagella on the parasites. No cytotoxic activity was recorded against human macrophages at the same extract concentrations. The findings suggest the potential use of extracts of an edible Morchella mushroom against the Leishmania parasite in humans. PMID- 29604915 TI - Aphrodisiac Activity of an Aqueous Extract of Wood Ear Mushroom, Auricularia polytricha (Heterobasidiomycetes), in Male Rats. AB - Auricularia polytricha is a popular mushroom found all over the world. In this study we considered the effect of an aqueous extract of A. polytricha (AEAP) on restoring sexual performance parameters to normal, evaluated by considering observations of sexual behavior. At 0, 6, 12, 18, and 24 days, the following parameters of sexual performance were identified before and throughout the observations: mount latency, intromission latency, ejaculation latency, mounting frequency, intromission frequency, ejaculation frequency, and postejaculatory interval. Treatment of rats under stress with AEAP showed promising effects on overcoming stress-induced sexual dysfunction, on sexual performance, and on accessory sexual organs and body weight. Mounting latency, intromission latency, ejaculation latency, and postejaculatory interval parameters were significantly decreased by AEAP, whereas mounting frequency, intromission frequency, and ejaculation frequency were significantly increased by AEAP. These properties were identified in sexually dynamic and indolent male rats. We conclude that AEAP has a potent aphrodisiac activity. PMID- 29604916 TI - Determination of the Biological Efficiency and Antioxidant Potential of Lingzhi or Reishi Medicinal Mushroom, Ganoderma lucidum (Agaricomycetes), Cultivated Using Different Agro-Wastes in Malaysia. AB - This study investigates the cultivation of Ganoderma lucidum using different agricultural biomasses from Malaysia. Five different combinations of rubber wood sawdust, empty fruit bunch fiber, and mesocarp fiber from oil palm, alone and in combination, were used to cultivate G. lucidum. Although all the substrate combinations worked well to grow the mushroom, the highest biological efficiency was obtained from the combination of empty fruit bunch fiber with sawdust. A total yield of 27% was obtained from empty fruit bunch fiber with sawdust, followed by sawdust (26%), empty fruit bunch fiber (19%), mesocarp fiber with sawdust (19%), and mesocarp fiber (16%). The quality of mushrooms was proved by proximate analysis and detection of phenolic compounds and flavonoids. The antioxidant activity verified by DPPH, ferric-reducing ability of plasma, and ABTS analyses revealed that the empty fruit bunch fiber with sawdust had higher activity than the other substrates. PMID- 29604917 TI - Prostate Cancer Biomarkers: Current Status. AB - Prostate cancer (PCa) is the second most frequently diagnosed cancer among men worldwide. Given the biological heterogeneity in localized PCa and its variable clinical course, a personalized approach to patient risk stratification and management is needed. A variety of high-throughput technologies, such as next generation sequencing, transcriptomic, epigenetic, and metabolomic modalities have led to an improved understanding of the genomic basis of PCa and the identification of PCa biomarkers. Novel genomic approaches offer additional information to improve clinical decision making. The goal of this report is to review the use of currently available molecular biomarkers in the diagnosis and prognostication of PCa outcome. PMID- 29604918 TI - Emerging Concepts and Methodologies in Cancer Biomarker Discovery. AB - Cancer biomarker discovery is a critical part of cancer prevention and treatment. Despite the decades of effort, only a small number of cancer biomarkers have been identified for and validated in clinical settings. Conceptual and methodological breakthroughs may help accelerate the discovery of additional cancer biomarkers, particularly their use for diagnostics. In this review, we have attempted to review the emerging concepts in cancer biomarker discovery, including real-world evidence, open access data, and data paucity in rare or uncommon cancers. We have also summarized the recent methodological progress in cancer biomarker discovery, such as high-throughput sequencing, liquid biopsy, big data, artificial intelligence (AI), and deep learning and neural networks. Much attention has been given to the methodological details and comparison of the methodologies. Notably, these concepts and methodologies interact with each other and will likely lead to synergistic effects when carefully combined. Newer, more innovative concepts and methodologies are emerging as the current emerging ones became mainstream and widely applied to the field. Some future challenges are also discussed. This review contributes to the development of future theoretical frameworks and technologies in cancer biomarker discovery and will contribute to the discovery of more useful cancer biomarkers. PMID- 29604919 TI - Liquid Biopsies in the Management of Bladder Cancer: Next-Generation Biomarkers for Diagnosis, Surveillance, and Treatment-Response Prediction. AB - In this review, we discuss the types of liquid biopsies currently available, and their recent and potential clinical applications, especially as they relate to the detection of molecular biomarkers of bladder cancer. The advances in research using high-throughput next-generation genomic techniques have identified a number of promising molecular biomarkers of bladder urothelial carcinoma. Liquid biopsy has recently received enormous attention as a potential tool for real-time monitoring of disease status in cancer patients, and genomic profiles are reported to closely match those of corresponding tumors. It is noninvasive and easily repeated, and allows monitoring during treatment and detection of different genomic alterations that are potentially accessible to targeted therapy or are associated with treatment resistance in bladder cancer patients. Moreover, liquid biopsy is a tool that allows rapid access to biomarker assessment in patients for whom solid biopsies are not available. Liquid biopsy will be widely applied to daily clinical practice and serve as an important tool for the screening, surveillance, prediction of outcomes, and selection of effective targeted therapies in bladder carcinoma. PMID- 29604920 TI - Gene Fusions in Human Cancers: A Review Focused on Diagnostic Biomarkers, Method Selections, and Treatments. AB - Recurrent gene fusions in cancers have been successfully applied in clinical diagnoses and treatments. Specific gene rearrangements or other specific cytogenetic translocations may be helpful in separating cancers from benign lesions. Also, the detection of gene fusions has brought great benefits to distinguish molecular subclassifications of cancers. Numerous approaches have been used to identify cancer-specific abnormalities, including FISH, RT-PCR, next generation sequencing, etc. In addition to diagnostic and genetic values, molecular testing has been becoming a valuable tool in the therapeutic research. Recent clinical trials involving gene fusions in cancers have also been developing under a rapid speed. Generally, we review gene fusions in cancers, emphasizing on relevant diagnostic biomarkers, method selections, and treatments. PMID- 29604921 TI - Genomic Pathology and Biomarkers in Breast Cancer. AB - Breast cancer is a highly heterogeneous disease. There are significant differences in morphology, immunophenotype, clinical behavior, and treatment response in breast cancer, which pose the greatest challenge for managing breast cancer patients. Great advances in breast cancer have been made at the molecular and genomic levels, which not only help us greatly in better understanding the heterogeneity and the carcinogenesis for breast cancer, but also help us in identifying new prognostic markers and therapeutic targets. In this review, we discuss these new findings in detail: (1) the two main pathways of the pathogenesis for breast cancer; (2) the traditional biomarkers including ER, PR, HER2, and some controversial biomarkers - Ki67, p53, AR, FRA for breast cancer; (3) the molecular classification of breast cancer, its IHC surrogates and its application in clinical management; (4) the multigene tests and their applications for breast cancer management; (5) next-generation sequencing and its clinical application for breast cancer; and (6) TIL and PD1/PD-L1 and their application in breast cancer. PMID- 29604922 TI - Biomarkers of DNA Repair and Related Pathways: Significance of Treatment in Triple-Negative Breast Cancer. AB - Triple-negative breast cancer (TNBC) is a complex heterogeneous disease that lacks the expressions of hormone receptors (HR) and human epidermal growth factor receptor 2 (HER2). Although TNBC make up less than 20% of breast cancer, it accounts for a large number of metastatic cases and deaths. Currently, extensive efforts have been made to look for potentially biomolecular targets for TNBC treatment. Based on the differences of molecular events identified by gene profiling analysis, the TNBC may be divided into some broad categories: basal like (BL), mesenchymal-like (ML), immune-associated, HER2-enriched and luminal/apocrine breast cancers. Most of these are in the BL-TNBC category. BL TNBC carries a representative molecular event of DNA-repair deficiency that increases the effectiveness of DNA destabilizers (represented by platinum agents) and DNA-damage response inhibitors (represented by PARP inhibitors). However, the results from clinical and preclinical studies have been inconsistent. Herein, we simply outline the progress of breast cancer classification and the significance of DNA repair deficiency in the clinic treatment for TNBCs. Previous studies have shown that the neoadjuvant therapies with platinum agents are effective for early stage and metastatic TNBC patients with DNA repair defects. The results indicate that proper biomarkers (such as homologous recombination repair defects, HRD) are necessary for predicting the response to chemotherapy and often sufficient to select patients in early-phase treatment. Furthermore, the combination of chemotherapy drugs and inhibitors of DNA damage response represents a potential therapeutic strategy for TNBCs. PMID- 29604923 TI - Epigenetic Modifications and Modulators in Prostate Cancer. AB - Prostate cancer (PCa) is one of the most common malignancies in men. Its clinical behavior ranges from indolent to aggressive. The clinical and morphological methods and features currently adopted show a low predictive value concerning the definition of its level of aggressiveness. Investigations have been led to understand its complex genomic landscape to improve diagnosis and prognosis as well as to define the potential role of new therapeutic targets. Epigenetic changes, including modifications in DNA methylation and histone acetylation, can contribute to the clinical behavior of PCa. MicroRNAs (miRNAs) can be used as potential biomarkers in the definition of PCa. The reversibility of epigenetic modifications opens the door to a potential perspective in the development of epigenetics modulators. The scope of this contribution is to review the main epigenetic modifications identified in PCa, including research on epigenetic modifiers and modulators. PMID- 29604924 TI - Precision in Diagnostic Molecular Pathology based on Immunohistochemistry. AB - Immunohistochemistry (IHC) is an indispensable tool for molecular pathological diagnosis. It has been applied in the differential diagnosis of benign and malignant tumors, the determination of tumor origin, cell differentiation, and the detection of microorganisms. By enabling the detection of proteins, IHC offers a platform for the assessment of genetic information from tumor genes and molecular pathological changes. Compared with other molecular pathology detection tools, IHC is cheaper, less time-consuming, and less labor-intensive and can be applied in routine pathological diagnosis efficiently. This review summarizes the IHC biomarkers that can be used to reflect molecular pathology or even to replace molecular pathology, and it highlights the shortcomings and precautions to be observed during their applications. PMID- 29604925 TI - The Roles of Chromatin Remodeling Genes in Pancreatic-Biliary Malignancies. AB - Recent studies have definitively established that chromatin remodeling is a crucial epigenetic mechanism not only in physiological conditions but also in influencing cancer biology. It is a dynamic process in which the chromatin, the functional entity of DNA, can undergo specific modifications by obtaining transcriptional activation or transcriptional silencing. One of the most important recent discoveries in cancer genetics and genomics is that the genes involved in the establishment of chromatin structure, the so called chromatin remodelers, are frequently mutated in different types of human cancer. This review aims to summarize the main novelties related to this topic, describing also the contribution of such genes during oncogenesis. Particularly, we focus on the switch/sucrose non-fermentable complexes and on three of the most important chromatin remodeling genes in biliary and pancreatic cancer: ARID1A, PBRM1, and BAP1. PMID- 29604926 TI - Xp11 Translocation Renal Cell Carcinoma and the Mesenchymal Counterparts: An Evolving Concept with Novel Insights on Clinicopathologic Features, Prognosis, Treatment, and Classification. AB - The TFE3 gene is one of four members of the micropathalima-associated transcription factor family, along with TFEB, TFEC, and MiTF, located on chromosome Xp11.2. The site is notable for its involvement in translocation in Xp11 translocation renal cell carcinoma (RCC) and the mesenchymal counterparts, including Xp11 neoplasm with melanocytic differentiation/TFE3 rearrangement associated perivascular epithelioid cell tumor (PEComa)/ melanotic Xp11 translocation renal cancer/melanotic Xp11 neoplasm, and alveolar soft-part sarcoma. By morphologic, immunohistochemical, genetic, and prognostic similarities, alveolar soft-part sarcoma with the ASPSCR1-TFE3 gene fusion has a closer relationship with Xp11 neoplasm with melanocytic differentiation/TFE3 rearrangement-associated PEComa/melanotic Xp11 translocation renal cancer/melanotic Xp11 neoplasm. These Xp11 translocation mesenchymal neoplasms may represent a distinct entity, which overlaps with Xp11 translocation RCC and broadens the spectrum of Xp11 translocation-associated neoplasms. The impact of individual fusion variants on specific clinicopathologic features of Xp11 translocation RCC has only recently been described. This review provides insight into the clinicopathologic features, prognosis, treatment, and classification of Xp11 translocation RCC and its mesenchymal counterparts, emphasizing the impact of individual fusion variants on specific clinicopathologic features of Xp11 translocation RCC and the relationships among these Xp11 translocation-associated neoplasms. PMID- 29604927 TI - Eph Receptors: Actors in Tumor Microenvironment. AB - Eph/ephrin signaling plays important roles both in embryonic development and human disease. The Eph receptors are involved in tumor development, progression, metastasis, and prognosis. The tumor microenvironment plays a critical role in tumor initiation, progression, metastasis, and resistance to therapy. Increasing data show that Ephs and ephrins mediate cell-cell interactions both in tumor cells and in tumor microenvironment. This review focuses on recent advances in dissecting the role of Eph and ephrin in tumor cells, tumor angiogenesis, epithelial-mesenchymal transition, hypoxia, and inflammation. PMID- 29604928 TI - Precise Diagnosis and Treatment of Thymic Epithelial Tumors Based on Molecular Biomarkers. AB - Thymic epithelial tumors (TETs), including thymoma and thymic carcinoma, are rare malignant tumors. The mainstay of treatment patients with TET is surgical resection, and chemotherapy is necessary for patients with tumor invasion or metastasis who are unable to undergo complete radical excision. However, for those patients who are resistant to chemotherapy, targeted therapy has become the most popular tumor treatment program, as well as for thymic tumors. Many genes implicated in tumorigenesis and metastasis have also been reported to be therapeutic targets in thymic malignancies. A significant advance in TET treatment may derive from the identification of novel molecular biomarkers that can improve the diagnosis, prognosis, and treatment of tumors. We review a number of case reports and small clinical trials reporting that a few inhibitors, such as sorafenib and sunitinib, are effective in the treatment of thymoma. In this review, we describe the current potential drug targets and their roles in the development of thymic malignancy. PMID- 29604929 TI - Genomic Pathology and Cancer Biomarkers: Prostate Cancer. AB - Our understanding of genomic pathology and biomarkers for prostate cancer is continually growing. Some promising and useful tissue markers are GSTP1, HOXD3, cell cycle proteins, chromatin remodeling proteins, androgen receptor, Stat5a/b, ERG, and PTEN. Serum and urine markers are mostly either prostate-specific antigen or newer tests using one or more other kallikreins or sarcosine. The data and evidence for all of these markers and the commercial tests using them are reviewed here. PMID- 29604931 TI - Next-Generation Sequencing for Minimal Residual Disease Surveillance in Acute Lymphoblastic Leukemia: An Update. AB - Monitoring minimal residual disease (MRD) is an important predictor of outcome in acute lymphoblastic leukemia (ALL) and is used in risk stratification, prognosis determination, and therapy guidance. Several laboratory techniques have proven utility for characterizing leukemic cells and following MRD through diagnosis, remission and possible recurrence. Methods for determining MRD are based on the detection of leukemia-specific aberrant immunophenotypes by mulitparameter flow cytometry or the evaluation of leukemia-specific rearranged immunoglobulin or T cell receptor sequences by quantitative real-time PCR. Next-generation sequencing (NGS) is emerging as a new flexible and sensitive tool to detect MRD, which allows identification of clonal composition and scalable sensitivity depending on sequence coverage. As NGS becomes more accessible and affordable, guidelines should be established for its application to MRD surveillance. PMID- 29604932 TI - YY1 Is an Inducer of Cancer Metastasis. AB - Yin Yang 1 (YY1) is a member of the GLI-Kruppel family of zinc finger proteins that plays vital roles in many biological processes, especially tumorigenesis. To date, ample evidence suggests a critical regulatory role of YY1 in tumor cell metastasis. The potential of YY1 as a valuable biomarker for cancer metastasis has been increasingly known. Here, we review the studies related to the expression, regulatory network, and clinical application of YY1 in cancer metastasis. We first summarize YY1 expression patterns in metastatic tumors. We then elaborate YY1-regulated mechanisms on five aspects, including epithelial mesenchymal transition, cell migration and invasion, stemness, polyploidy, and genomic stability. Finally, we discuss the correlation between YY1 expression and clinical outcomes and therapeutic potential of YY1 in cancer treatment. Based on this review, we conclude that YY1 is a bona fide inducer of cancer metastasis and can serve as a clinical biomarker and therapeutic target for cancer treatment. PMID- 29604930 TI - Oncogenic Signaling Pathways and Pathway-Based Therapeutic Biomarkers in Lymphoid Malignancies. AB - Lymphoma is characterized by heterogeneous biology, pathologic features, and clinical outcome. This has been proven by accumulating pathologic and molecular evidence attributed to underlying aberrant alterations at genetic, epigenetic, transcriptional, protein, microenvironmental levels, and dysregulated oncogenic signaling pathways. In the era of precision medicine, targeting oncogenic pathways to design drugs and to optimize treatment regimens for the lymphoma patients is feasible and clinically significant. As such, further understanding of the biology and the mechanisms behind lymphoma development and identification of oncogenic pathway activation and pathway-based biomarkers to better design precise therapies are challenging but hopeful. Furthermore, pathway-based targeted therapies in combination with traditional chemotherapy, single specific targeted antibody therapy, and immunotherapy might raise the hope for the patients with lymphoma, especially for relapsed and refractory lymphoma patients. PMID- 29604933 TI - The Role of Transcription Factor YY1 in the Biology of Cancer. AB - The transcription factor Yin Yang 1 (YY1) is a ubiquitously expressed protein involved in several biological functions, including embryogenesis, differentiation, replication, and cellular proliferation. YY1 can both activate and repress transcription depending on its interactions with other transcription factors and co-factors. It affects the transcription of a large number of mammalian and viral genes. In this review, we focus on the role of YY1 in cancer biology, including its expression, function, regulation by other upstream factors, and some of its more significant downstream effectors. We also discuss its context-dependent and tumor-specific role in human cancer progression, roles as a prognostic marker, and how its interactions with other cancer-associated factors can be exploited to develop novel targeted therapies. PMID- 29604935 TI - Therapeutic YY1 Inhibitors in Cancer: ALL in ONE. AB - Various targeted therapies for cancer have resulted in a significant prolongation of survival and a better quality of life. However, unfortunately, a small subset of cancer patients responds to such therapies initially and then develops resistance after the initial therapies. Based on resistant mechanisms, it should be possible to develop new and specific targeted therapies effective against unresponsive patients. Our investigations and those of others have identified a gene product, Yin Yang 1 (YY1), a transcription factor that is overexpressed in many cancers and that was shown to be involved in the regulation of cell survival, cell proliferation, cell invasion, metastasis, and resistance. Several studies showed that the inhibition of YY1 resulted in significant inhibition of the tumor phenotype and reversal of resistance. Examples of such YY1 inhibitors include siRNA YY1, nitric oxide donors, proteasome inhibitors, and inhibitors of activated survival pathways such as inhibitors of nuclear factor-kappa beta. However, there is still a need to develop specific and targeted inhibitors of YY1. In this review, a general discussion is provided on the role of YY1 overexpression in cancer and the application of various inhibitors of YY1 activities and their potential as therapeutics. PMID- 29604934 TI - Yin Yang 1 (YY1): Regulation of Survivin and Its Role In Invasion and Metastasis. AB - Despite significant clinical and basic science advancements, cancer remains a devastating disease that affects people of all ages, races, and backgrounds. The pathogenesis of cancer has recently been described to result from eight biological capabilities or hallmarks and two enabling characteristics. These eight hallmarks are: deregulation of cellular energetics, avoiding immune destruction, enabling replicative immortality, inducing angiogenesis, sustaining proliferative signaling, evading growth suppressors, resisting cell death, and activating invasion and metastasis. The enabling characteristics are: genome instability and mutation and tumor-promoting inflammation. Survivin, the fourth most common transcript found in cancer cells, is a protein that is thought to be involved in the enhanced proliferation, survival, and metastasis and possibly other key hallmarks of cancer cells. Understanding how this gene is turned on and off is vitally important for attempt improving cancer management and therapy. Our work has identified a novel transcriptional regulator of survivin called Yin Yang 1 (YY1), which has been observed to activate some gene promoters and repress others and is gaining increasing interest as a target of cancer therapy. Our work shows for the first time that YY1 represses survivin transcription by physically interacting with the survivin promoter. Furthermore, YY1 appears to contribute to basal survivin transcriptional activity, indicating that disruption of its binding may in part contribute to survivin overexpression after cellular stress events including chemotherapy and radiotherapy. PMID- 29604937 TI - The Forgotten YY2 in Reported YY1 Expression Levels in Human Cancers. AB - The transcription factor Yin Yang 1 (YY1) has been reported to be overexpressed in the majority of human cancers and that overexpression has prognostic significance. YY1 regulates several properties associated with cancer cells, including cell survival, cell proliferation, endothelial-mesenchymal transition, metastases, and resistance to both chemotherapeutics and immunotherapeutics. Although the majority of published reports focus on YY1 levels, little has been reported on the expression and activity of YY1 family member Yin Yang 2 (YY2). YY1 and YY2 share more than 50% homologies in DNA and amino acid sequences and share the same C-terminal zinc finger domains involved in DNA binding. This survey of the reported literature revealed that the antibodies used in published immunohistochemistry analyses were not uniquely specific for YY1. Most were likely cross-reactive with YY2. Furthermore, data from the Human Protein Atlas regarding YY1 and YY2 expression in various cancers were generated using antibodies that did not discriminate between YY1 and YY2. This review analyzed the commercially available antibodies listed against YY1 and YY2 and determined their cross-reactivities. A summary is of the published studies on the expression levels of YY1 in human cancers and their potential cross-reactivities with YY2 is also provided. Well-documented monospecific antibodies to both YY1 and YY2 have to be developed and used when examining the expression levels of YY1 and YY2 in human cancers to elucidate the accurate relationship between them and clinical significance of each. PMID- 29604936 TI - Targeting the Overexpressed YY1 in Cancer Inhibits EMT and Metastasis. AB - There have been recent developments in the treatment of various cancers, in particular non-metastatic cancers. However, many of the responding patients often relapse initially through the development of spread micro and macro-metastases. Unfortunately, there are very few therapeutic modalities for the treatment of metastatic cancers. The development of cancer metastasis has been proposed to involve the epithelial-mesenchymal transition (EMT), in which the tumor cells with the EMT phenotype exhibit various phenotypic markers and molecular modifications that are manifested to resist most conventional therapies. YY1 is a target of the hyperactivated nuclear factor-kappa beta pathway in cancer and it was reported that YY1 also regulates cell survival and cell proliferation in addition to its role in EMT and resistance. The overexpression of YY1 in the majority of cancers has been correlated with poor prognosis. It is hypothesized that targeting YY1 may result in several anti-tumor activities, including inhibition of cell survival and cell proliferation, inhibition of EMT, and reversal of resistance. This review discusses the potential therapeutic targeting of an overexpressed transcription factor, Yin Yang 1 (YY1), which has been implicated in the development of EMT and drug resistance. Several examples targeting YY1 in experimental models are presented. PMID- 29604938 TI - Physical Interaction of Human Yin Yang 1 Protein with DNA. AB - Yin Yang 1 (YY1)'s interaction with DNA can result in various, even contradicting, effects on transcription in the form of initiation, activation, or repression. This surprising activity can be explained in the context of the YY1 DNA's complex structure. YY1's DNA-binding domain is formed by four zinc finger motifs. However, the sequence of both the zinc fingers and the linkers is non canonical, which impairs their docking to the DNA duplex. Short linkers between the zinc fingers impose a concerted binding mechanism. Analysis of the sequences known to be recognized by YY1 suggests different contributions of particular zinc fingers in specific recognition of activated versus repressed promoters. Thermodynamic and kinetic studies show that, although the YY1's N-terminal fragment does not itself bind to DNA, it might regulate the interaction because its presence influences the binding parameters. Meta-analysis of YY1-DNA binding allowed us to observe that YY1's avidity to multiple binding sites is crucial in providing high-affinity specific sequence recognition. Alternatively, other trans acting factors can modulate the YY1-DNA interaction and influence its outcome. This complex mechanism causes great sensitivity for individual point mutations, an increasing number of which are found in YY1 in cancer tissues. PMID- 29604939 TI - Yin Yang I as an Epimodulator of miRNAs in the Metastatic Cascade. AB - Yin Yang 1 (YY1) belongs to the polycomb group (PcG) of proteins that modify chromatin epigenetically during dynamic regulation of their target genes. The predominant feature of YY1 is the zinc finger, an ancient structural motif that mediates protein-protein interactions and is capable of interacting with both DNA and RNA. Evidence reveals that YY1 acts predominantly as an epigenetic modulator, influencing the activity and/or localization of epigenetic modifiers molecules such as DNA methylation transferases, histone deacetylases, or non-coding RNAs. Deregulation of the epigenome is observed frequently in a variety of cancer types and is often correlated directly with advanced metastatic stages and poor prognosis. In this review, we address the current understanding of YY1 as a recruiter of epi-modifier molecules in the mechanism of aberrant regulation of target genes as a part of the metastatic cascade. PMID- 29604940 TI - The Multilayered Regulation of the Oncogenic Protein YY1. AB - The multifunctional protein Yin Yang 1 (YY1) plays critical roles in tumorigenesis. YY1 has been shown to be involved in the development, progression, resistance, and invasiveness of many types of cancers. Today, the value of YY1 as a prognostic marker and as a potential target in cancer therapy is being explored by multiple research groups around the world. Over the past 25 years, we have accumulated a wealth of information about the wide-ranging biological functions of YY1 at the molecular, cellular, and organismal levels. However, our knowledge of how YY1 is regulated and what regulates it has lagged behind. In the past few years, there has been a significant increase in the research addressing this issue. In this review, we summarize and analyze recent findings about the regulation of YY1 at multiple levels. We emphasize the necessity for deeper insights into these regulatory mechanisms if YY1 is to find its way to the clinical setting. PMID- 29604941 TI - YY1 in Cell Differentiation and Tissue Development. AB - Yin Yang1 (YY1) is a ubiquitous expressed transcription factor that modulates a variety of biologic processes with prominent roles in cellular differentiation and tissue development. Recent advances in molecular biology, mouse genetics, and particularly high-throughput sequencing have greatly enhanced our understanding of YY1 functions and underlying mechanisms in regulating transcription and epigenetics. In this review, we summarize findings on the roles of YY1 in cell differentiation and tissue development, in particular in muscle, nerve, and immune cells/tissues. PMID- 29604942 TI - Two Opposing Effects (Yin and Yang) Determine Cancer Progression. AB - In this review, we introduce a new vision of cancer describing opposing effects that control progression. Cancer is a paradigm of opposing of "Yin" and "Yang," with Yin being the effect to promote cancer and Yang that to maintain the normal state. This Yin Yang hypothesis has been used to select Yin and Yang genes to develop multigene signatures for determining prognosis in lung and breast cancer. Most of the Yin genes are involved in cell survival, growth, and proliferation, whereas most Yang genes are involved in cell apoptosis. Furthermore, Yin and Yang pathways have been identified in breast cancer and compounds that can inhibit the Yin pathways or activate the Yang pathways have been examined, suggesting a new promising targeting therapy for cancer. We are building a Yin Yang model to represent the dynamic change of Yin and Yang genes and pathways. PMID- 29604943 TI - Nerve Injuries around the Shoulder. AB - Nerve injuries around the shoulder are common. They usually occur as a result of motor vehicle accidents, gunshot or athletic injuries, or overuse and chronic repetitive stress often observed in sports involving repetitive overhead or throwing activities. The mechanisms of nerve injury include direct pressure, repetitive microtrauma, and compression- or stretch-induced ischemia. The severity and extent of compression is related to the degree of the nerve injury. Several nerve injury grading systems have been developed, allowing for the correlation between microscopic changes occurring after the injury and the patient's symptoms; recovery and prognosis is related to the type and severity of the injury. Distinct clinical syndromes involving the shoulder joint area can develop after injuries to the axillary, musculocutaneous, suprascapular, long thoracic, and spinal accessory nerves, as well as the proximal brachial plexus trunks and the lower cervical nerve roots. When a patient complains of pain, weakness, or paresthesia in the absence of known bone, soft tissue, or vascular injury, nerve injury must be suspected. This article summarizes the most common nerve injuries around the shoulder and discusses the classification, mechanism, treatment, and prognosis for these injuries. PMID- 29604944 TI - Stress and Strain Distribution Patterns in Bone around Splinted Standard and Short Implants Placed at the Crestal Level and Subcrestally using Three- Dimensional Finite Element Analysis. AB - Short implants can be used as alternatives to standard implants to prevent invasive surgical procedures. However, due to concerns about complications caused by less bone-implant contact area, researchers have focused on biomechanical properties of short implants and methods to promote them. Splinting has been suggested to decrease the limitation of short implants. This study compared the pattern of stress and strain distribution in bone supporting splinted standard and short implants positioned at crestal and subcrestal levels. An edentulous posterior mandible was made using computer-aided design. Five models of different combinations of splinted short (4 * 6 mm) and standard (4 * 10 mm) implants placed at the level of crestal bone or subcrestally mesial and distal to the edentulous region with a pontic between them were designed using the CATIA software program. ANSYS software was used for finite element analysis (FEA). In each model, 100 and 300 N loads at zero (parallel to the long axis of implants) and 30 degrees angles were applied to implants. Maximum stress and strain for each of the five models, including equivalent stress, shear stress, and strain in peri-implant cortical and cancellous bone, were calculated and stress distribution pattern in different models were recorded. The highest stress was caused by the 300 N load applied at a 30 degrees angle, followed by the 300 N load applied axially and the 100 N load applied at 30 degrees . This order changed in model 1, where the highest stress was noted under the 300 N load at 30 degrees , followed by the 100 N load at 30 degrees . Maximum stress in peri implant bone occurred under oblique (30 degrees ) load. Maximum stress was noted when two splinted short implants were placed subcrestally. In addition, stress in bone around crestal-level splinted short implants was lower than that around standard implants. Combination of short and standard implants had no biomechanical advantage. Application of load parallel to the long axis can significantly decrease stress in peri-implant bone. Although the combination of short and standard implants has no biomechanical advantage, crestal-level placement of splinted short implants is a suitable treatment plan. PMID- 29604945 TI - PMMA Cement Allergy Misleading Total Knee Arthroplasty Infection. AB - Arthroscopic and prosthetic hip and knee joint infection are uncommon; however, devastating complications in adult reconstruction surgery. An acute onset of pain combined with effusion, erythema, warmth and fever are the typical signs of early infection. Hypersensitivity or allergic reactions to arthroplasty components, concerning mainly metal-to-metal bearings and metal-on-plastic total knee arthroplasties have also been reported. Inflammation associated with allergic reaction to any of these materials (metallic and/or acrylic bone cement) can plausibly cause a number of similar manifestations to infection such as loosening, instability, stiffness, arthrofibrosis, swelling, warmth, and pain. This article presents a patient without known polymethylmethacrylate (PMMA) bone cement allergy who experienced a prosthetic joint infection after a cemented total knee arthroplasty. The diagnosis of infection was misled by the wrong timing of cultures with respect to antibiotics cessation, and the documentation of PMMA cement allergy with allergiologic examination and patch testing. PMID- 29604946 TI - Therapeutic Hypothermia in the ICU: The Nursing Aspect. AB - Clinical studies and experimental research have described therapeutic hypothermia for patients suffering from traumatic brain injury (TBI), cardiac arrest, and neonatal hypoxic ischemic encephalopathy. This procedure is implemented by intensive care unit (ICU)-trained nurses. The aim of the present study was to compare cold compresses/ ice packs, cooling blankets, and heat-exchange systems via intravascular catheters used in the ICU for therapeutic hypothermia from a nursing perspective with respect to ease of application, additional workload, ease of temperature monitoring, and effectiveness. A questionnaire was completed by ICU nurses to evaluate these techniques for therapeutic hypothermia. The results were calculated and a score of 1 to 5 was obtained, where 1 = very bad, 2 = bad, 3 = moderate, 4 = good, and 5 = very good. Overall, heat exchange via intravascular catheters had the best score for implementation of therapeutic hypothermia. Regarding ease of the application, cold compresses/ice packs had the best score. Regarding additional workload, cold compresses/ice packs had the worst score, whereas the heat-exchange system via intravascular catheters scored the best. Regarding ease of temperature monitoring, the heat-exchange system via intravascular catheters had the best score and, regarding effectiveness, cold compresses/ice packs scored the best. PMID- 29604947 TI - Finite Element Analysis of Dental Implants with and without Microthreads under Static and Dynamic Loading. AB - The aim of this study was to assess stress and strain patterns in cortical and cancellous bones surrounding newly designed dental implants with different thread patterns. Static loading of dental implants has been well studied, but studies on dynamic loading and fatigue analysis of dental implants are scarce. This study analyzed the static, dynamic, and fatigue behaviors of dental implants using finite element analysis (FEA). Two models of dental implants were analyzed in this study. Model A was a tapered implant with V-shaped threads and model B was a tapered implant with microthreads in the uppermost region and V-shaped threads in the rest of the body. Two types of loading conditions were simulated in an FEA model and stress and strain patterns in the surrounding bone were analyzed. Dynamic loading increased the level of stress by 5-10% compared with static loading. Both implants showed acceptable results under static and dynamic loadings, but the second implant with microthreads caused lower stress and strain in cortical and cancellous bones. Dynamic and fatigue analyses can provide a more realistic understanding of the function of dental implants. Replacing the uppermost threads with microthreads can lead to more desirable stress patterns in bone, as well as a higher safety factor and longevity. PMID- 29604948 TI - Deep Brain Stimulation as a Treatment for Refractory Epilepsy: Review of the Current State-of-the-Art. AB - Epilepsy affects ~ 1% of the global population, and 33% of patients are nonresponsive to medication and must seek alternative treatment options. Alternative options such as surgery and ablation exist but are not appropriate treatment plans for some patients. Neurostimulation methods such as vagal nerve stimulation, responsive neural stimulation, and deep brain stimulation (DBS) are viable alternatives for medically refractory patients. DBS stimulation has been used in the treatment of Parkinson's disease, dystonia, and pain management. For the treatment of epilepsy, DBS has been found to be an effective treatment plan, with promising results of reduced seizure frequency and intensity. In this review, we discuss DBS surgery and equipment, mechanisms of DBS for epilepsy, and efficacy, technological specifications, and suggestions for future research. We also review a historical summary of experiments involving DBS for epilepsy. Our literature review suggests that further studies are warranted for medically refractory epilepsy using DBS. PMID- 29604949 TI - Reuse of Single-Use HemaClear Exsanguination Tourniquets: A Technique Note. AB - Surgical tourniquets have an important role in limiting blood loss and improving surgical visualization. The HemaClear(r) tourniquet is a sterile silicone-ring tourniquet designed to exsanguinate as it is applied. HemaClear tourniquets may be rolled all the way up to the groin or the axilla and thus provide a larger operating field than standard wide pneumatic tourniquets. Although designed for single use, we propose here a technique permitting the reapplication of a HemaClear tourniquet on the contralateral limb in the setting of bilateral extremity sequential surgical procedures. Such one time reuse decreases health care costs. PMID- 29604950 TI - Long-Term Outcomes of Thompson's Hip Hemiarthroplasties: Literature Review. AB - The procedure of Thompson's hip hemiarthroplasty has been well established since the 1950s and is still widely used for neck of femur fractures. Symptomatic acetabular erosion is a concern, shown to be particularly present after long-term follow-up of active patients. We review the literature and present a unique 47 year follow-up of neck of femur fracture treated with Thompson's hemiarthroplasty. PMID- 29604951 TI - Patient Clinical Outcome after Reverse Shoulder Replacement: Implementing the Oxford Shoulder Score as a Cost-Effective Tool for Outpatient Assessment. AB - The aim of this study was to assess and calculate the number of follow-ups (FUs), relative cost, demographics, and overall patient satisfaction (as expressed in pain and function) after shoulder replacement surgery. Subjects included 54 patients (34 female, 20 male) who underwent reverse shoulder arthroplasty between 2011 and 2013 at East Surrey Hospital, United Kingdom. Patients were examined during a period of 3 yr and then 6-12 mo after final discharge. The mean FU period was 2 mo for 11 patients (4-13 mo for nine patients). Thirty-one patients were discharged after completing three FUs, seven needed more than three, and nine needed less than three. Two patients needed revision, and five did not come for review. After discharge, patients were assessed with the Oxford Shoulder Score (OSS), which showed that the majority of the 44 patients out of the 54 who answered (ten did not respond) were doing fine (42), and only two were unhappy. The frequent evaluation of postoperative patients provided the surgical team with the feedback necessary to study the clinical outcomes in relation to the above mentioned procedure. The use of the OSS as an FU tool was easy and successful and illustrated that it has potential to reduce the number of FUs in the near future. PMID- 29604952 TI - Nontraumatic Fracture of a Custom-Made Wagner Cone Prosthesis Hip Stem: A Case Report. AB - Fractures of modern cementless stems are almost extinct. However, extra small stems used for cases of developmental dysplasia of the hip (DDH) are still at risk for this complication. We review the fracture of a small size 11, custom made Wagner cone prosthesis in a 70 year old female patient. The patient had a body-mass index (BMI) of 22.2, 7 yrs after undergoing a total hip arthroplasty. The procedure was undertaken to correct extreme high-riding congenital hip dysplasia. She presented with sudden pain due to a non-traumatic fracture of the stem, just below the proximal third region. At revision, it was apparent that the stem had a concrete distal fixation, whereas the proximal part was loose and probably failed due to cantilever bending fatigue, although the patient had small stature and a low BMI. We trephined out the distal portion, and the patient was successfully revised with a cemented DDH Co-Cr stem. It is our belief that care should be taken when choosing extra small, cementless implants with distal fixation. Cemented prostheses may offer a safe alternative in such cases. PMID- 29604953 TI - Histological Findings in Six Failed Metal-on-Metal Implants. AB - Although joint replacement surgery to relieve pain due to osteoarthritis is generally a successful operation, adverse local tissue reactions can occur in hip arthroplasty in patients who receive metal-on-metal (MoM) implants and lead to early failure. This has led to revisions, lawsuits, and manufacturing recalls. An understanding of the pathological process initiated by metal wear debris is essential in clinical surveillance of cases. We retrospectively reviewed six cases of patients who underwent MoM hip arthroplasties and required early revision. Tissue removed at revision surgery was analyzed histologically by two independent reviewers. All six patients (four males, two females) underwent revision hip arthroplasty after early failure. Revision occurred between 18 and 56 months after the index procedure. Four patients received MoM implants from Depuy, one from Stryker, and one from Wright Medical. A consistent array of pathological findings was associated with these failed MoM implants. Beginning with the development of metal debris, a histiocytic response and proliferation occurred with subsequent corrosion product formation. Membranes were formed, many with cellular infiltrates and pseudosynovial linings and often with ulceration and bleeding. The tissue also demonstrated lymphocytosis and perivascular infiltrates with atypical changes of the endothelial lining cells. Our findings document a predictable cascade of harmful local tissue changes initiated by metal debris in failed MoM hip arthroplasties. PMID- 29604954 TI - An intramural uterine fibroid became submucosal in the puerperium - proposed probable mechanism: a case report. AB - BACKGROUND: Vaginal prolapse of a large uterine fibroid is a rare phenomenon in a woman who delivered vaginally recently, given that this fibroid might have obstructed labor. The author presents a case report of a vaginally prolapsed large pedunculated submucosal uterine myoma in a woman with a recent uncomplicated vaginal delivery. CASE PRESENTATION: A 25-year-old black African woman had four intramural uterine fibroids of diameters 62 to 94 mm diagnosed in April 2013 with standard ultrasound scan. She got pregnant in July 2014. An ultrasound scan done on 31 August 2014 at 10 weeks' gestation identified four intramural uterine fibroids, with sizes varying from 70 to 150 mm. Her pregnancy was well followed up, without any complications. She had an uneventful vaginal delivery on 10 April 2015. During uterine exploration, indicated for retention of parts of fetal membranes, no pedunculated submucosal fibroid was found. On 15 May 2015, she consulted for difficult micturition and partial urinary retention that occurred 2 days ago. A vaginally prolapsed 10 cm uterine fibroid was diagnosed. Forty-eight hours after administration of intravenously administered broad spectrum antibiotics, the myoma was successfully twisted off by means of vaginal route under general anesthesia, which relieved her symptoms. CONCLUSIONS: To the best of our knowledge, this is the first case of vaginally prolapsed large submucosal uterine fibroid in a woman who delivered vaginally recently. The author recommends that women with known large low situated uterine fibroid should be well observed during the postpartum period to diagnose a vaginally prolapsed uterine fibroid early, so as to prevent fibroid superinfection and obstructive complications. PMID- 29604955 TI - Multivariate analysis of covariates of adherence among HIV-positive mothers with low viral suppression. AB - BACKGROUND: As part of efforts to improve the prevention of mother-to-child transmission in Northern Uganda, we explored reasons for poor viral suppression among 122 pregnant and lactating women who were in care, received viral load tests, but had not achieved viral suppression and had more than 1000 copies/mL. Understanding the patient factors associated with low viral suppression was of interest to the Ministry of Health to guide the development of tools and interventions to achieve viral suppression for pregnant and lactating women newly initiating on ART as well as those on ART with unsuppressed viral load. METHODS: A facility-based cross-sectional and mixed methods study design was used, with retrospective medical record review. We assessed 122 HIV-positive mothers with known low viral suppression across 31 health facilities in Northern Uganda. Adjusted odds ratios were used to determine the covariates of adherence among HIV positive mothers using logistic regression. A study among health care providers shed further light on predictors of low viral suppression and a history of low early retention. This study was part of a larger national evaluation of the performance of integrated care services for mothers. RESULTS: Adherence defined as taking antiretroviral medications correctly everyday was low at 67.2%. The covariates of low adherence are: taking other medications in addition to ART, missed appointments in the past 6 months, experienced violence in the past 6 months, and faces obstacles to treatment. Mothers who were experiencing each of these covariates were less likely to adhere to treatment. These covariates were triangulated with perspectives of health providers as covariates of low adherence and included: long distances to health facility, missed appointments, running out of pills, sharing antiretroviral drugs, violence, and social lifestyles such as multiple sexual partners coupled with non-disclosure to partners. Inadequate counseling, stigma, and lack of client identity are the frontline factors accounting for the early loss of mothers from care. CONCLUSIONS: Adherence of 67% was low for reliable viral suppression and accounts for the low viral suppression among HIV-positive mothers studied, in absence of any other factors. This study provided insights into the covariates for low adherence to ART and low viral load suppression; these covariates included taking other medications in addition to ART, missed appointments in the past 6 months, feels like giving up, doesn't have someone with whom to share private concerns, experienced violence in the past 6 months, and faces obstacles to treatment and confirmed by health providers. To improve adherence, we recommend use of a screening tool to identify mothers with any of these covariates so that more intensive adherence support can be provided to these mothers. PMID- 29604957 TI - Behavior as Illness Indicator. PMID- 29604958 TI - MCE - Special issue on updates on steroid signalling in breast cancer. PMID- 29604956 TI - Berberine ameliorates diabetic nephropathy by inhibiting TLR4/NF-kappaB pathway. AB - BACKGROUND: Diabetic nephropathy (DN) is the leading cause of end-stage renal failure, contributing to severe morbidity and mortality in diabetic patients. Berberine (BBR) has been well characterized to exert renoprotective effects in DN progression. However, the action mechanism of BBR in DN remains to be fully understood. METHODS: The DN rat model was generated by intraperitoneal injection of streptozotocin (STZ, 65 mg/kg body weight) while 30 mM high glucose (HG) treated podocytes were used as an in vitro DN model. The fasting blood glucose level and ratio of kidney weight to body weight were measured after BBR treatment (50, 100, or 200 mg/kg) in STZ-induced DN rats. The renal injury parameters including 24-h urinary protein, blood urea nitrogen and serum creatinine were assessed. qRT-PCR was performed to detect the transcript amounts of inflammatory factors. The concentrations of inflammatory factors were evaluated by ELISA kits. Western blot analysis was conducted to measure the amounts of TLR4/NF-kappaB related proteins. The apoptotic rate of podocytes was analyzed by flow cytometry using Annexin V/propidium iodide. RESULTS: Berberine reduced renal injury in STZ induced DN rat model, as evidenced by the decrease in fasting blood glucose, ratio of kidney weight to body weight, 24-h urinary protein, serum creatinine, and blood urine nitrogen. BBR attenuated the systemic and renal cortex inflammatory response and inhibited TLR4/NF-kappaB pathway in STZ-induced DN rats and HG-induced podocytes. Also, HG-induced apoptosis of podocytes was lowered by BBR administration. Furthermore, blockade of TLR4/NF-kappaB pathway by resatorvid (TAK-242) or pyrrolidine dithiocarbamate aggravated the inhibitory effect of BBR on HG-induced inflammatory response and apoptosis in podocytes. CONCLUSIONS: Berberine ameliorated DN through relieving STZ-induced renal injury, inflammatory response, and podocyte HG-induced apoptosis via inactivating TLR4/NF-kappaB pathway. PMID- 29604959 TI - Coupling of P2Y receptors to Ca2+ mobilization in mesenchymal stromal cells from the human adipose tissue. AB - The purinergic transduction was examined in mesenchymal stromal cells (MSCs) from the human adipose tissue, and several nucleotides, including ATP, UTP, and ADP, were found to mobilize cytosolic Ca2+. Transcripts for multiple purinoreceptors were detected in MSC preparations, including A1, A2A, A2B, P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y13, P2Y14, P2X2, P2X4, and P2X7. Cellular responses to nucleotides were insignificantly sensitive to bath Ca2+, pointing at a minor contribution of Ca2+ entry, and were suppressed by U73122 and 2-APB, implicating the phosphoinositide cascade in coupling P2Y receptors to Ca2+ release. While individual cells were sensitive to several P2Y agonists, responsiveness to a given nucleotide varied from cell to cell, suggesting that particular MSCs could employ different sets of purinoreceptors. Caged Ca2+ stimulated Ca2+-induced Ca2+ release (CICR) that was mediated largely by IP3 receptors, and resultant Ca2+ transients were similar to nucleotide responses by magnitude and kinetics. A variety of findings hinted at CICR to be a universal mechanism that finalizes Ca2+ signaling initiated by agonists in MSCs. Individual MSCs responded to nucleotides in an all-or-nothing manner. Presumably just CICR provided invariant Ca2+ responses observed in MSCs at different nucleotide concentrations. The effects of isoform specific agonists and antagonists suggested that both P2Y1 and P2Y13 were obligatory for ADP responses, while P2Y4 and P2Y11 served as primary UTP and ATP receptors, respectively. Extracellular NAD+ stimulated Ca2+ signaling in each ATP-responsive MSC by involving P2Y11. The overall data indicate that extracellular nucleotides and NAD+ can serve as autocrine/paracrine factors regulating MSC functions. PMID- 29604960 TI - The changes of intracellular calcium concentration and distribution in the hard end pear (Pyrus pyrifolia cv. 'Whangkeumbae') fruit. AB - Hard end is a physiological disorder of pear fruit that is frequently observed in the 'Whangkeumbae' (Pyrus pyrifolia) variety, however, the mechanisms that are involved in its development are poorly understood. In this study, we explored the causes of hard end disorder in pear fruit in relation to calcium deficiency. During fruit development, the ratio of Ca/N, Ca/K, Ca/Mg and the content of B were significantly lower in the hard end fruit as compared to normal fruit. However, no calcium deficiency was detected in the soil and leaves of the orchard where the hard end fruit were located. Additionally, the Ca2+ influx in the calyx of hard end fruit was lower than that of normal fruit at 90 d after anthesis. The free Ca2+ and storage Ca2+ in the flesh cells of hard end fruit were less than that of normal fruit during fruit development, while an opposite tendency was observed at 120 d after anthesis (harvest day). In hard end fruit, the Ca2+ transport-related gene, PpCNGC1 (Cyclic nucleotide-gated ion channel 1), was up regulated; whereas the Ca2+ sensor-related genes of PpCIPKs, PpCDPK28 and PpCML41 were all down-regulated. Spraying with a 2% calcium chloride (CaCl2) solution inhibited the incidence rate of hard end disorder and decreased fruit firmness and lignin content during storage. Additionally, the ratio of Ca/N, Ca/K, Ca/Mg and the content of B all increased on harvest day. Our study suggests that low Ca2+ influx leads to less Ca2+ into the pear fruit, which results in an intracellular imbalance of Ca2+ and consequently triggers the development of hard end disorder. PMID- 29604961 TI - Deletion of Orai2 augments endogenous CRAC currents and degranulation in mast cells leading to enhanced anaphylaxis. AB - All three members of the Orai family of cation channels-Orai1, Orai2 and Orai3 are integral membrane proteins that can form store-operated Ca2+ channels resembling endogenous calcium release-activated channels (CRAC) in many aspects. Loss of function studies in human and murine models revealed many functions of Orai1 proteins not only for Ca2+ homeostasis, but also for cellular and systemic functions in many cell types. By contrast, the knowledge regarding the contribution of Orai2 and Orai3 proteins in these processes is sparse. In this study, we report the generation of mouse models with targeted inactivation of the Orai2 gene to study Orai2 function in peritoneal mast cells (PMC), a classical cell model for CRAC channels and Ca2+-dependent exocytosis of inflammatory mediators. We show that the Ca2+ rise triggered by agonists acting on high affinity Fc receptors for IgE or on MAS-related G protein-coupled receptors is significantly increased in Orai2-deficient mast cells. Ca2+ entry triggered by depletion of intracellular stores (SOCE) is also increased in Orai2-/- PMCs at high (2mM) extracellular Ca2+ concentration, whereas SOCE is largely reduced upon re-addtion of lower (0.1mM) Ca2+ concentration. Likewise, the density of CRAC currents, Ca2+-dependent mast cell degranulation, and mast cell-mediated anaphylaxis are intensified in Orai2-deficient mice. These results show that the presence of Orai2 proteins limits receptor-evoked Ca2+ transients, store-operated Ca2+ entry (SOCE) as well as degranulation of murine peritoneal mast cells but also raise the idea that Orai2 proteins contribute to Ca2+ entry in connective tissue type mast cells in discrete operation modes depending on the availability of calcium ions in the extracellular space. PMID- 29604962 TI - Dynamic Ca2+ imaging with a simplified lattice light-sheet microscope: A sideways view of subcellular Ca2+ puffs. AB - We describe the construction of a simplified, inexpensive lattice light-sheet microscope, and illustrate its use for imaging subcellular Ca2+ puffs evoked by photoreleased i-IP3 in cultured SH-SY5Y neuroblastoma cells loaded with the Ca2+ probe Cal520. The microscope provides sub-micron spatial resolution and enables recording of local Ca2+ transients in single-slice mode with a signal-to-noise ratio and temporal resolution (2ms) at least as good as confocal or total internal reflection microscopy. Signals arising from openings of individual IP3R channels are clearly resolved, as are stepwise changes in fluorescence reflecting openings and closings of individual channels during puffs. Moreover, by stepping the specimen through the light-sheet, the entire volume of a cell can be scanned within a few hundred ms. The ability to directly visualize a sideways (axial) section through cells directly reveals that IP3-evoked Ca2+ puffs originate at sites in very close (<=a few hundred nm) to the plasma membrane, suggesting they play a specific role in signaling to the membrane. PMID- 29604963 TI - STIM1 and TRPV4 regulate fluid flow-induced calcium oscillation at early and late stages of osteoclast differentiation. AB - Bone resorption is mainly mediated by osteoclasts (OCs), whose formation and function are regulated by intracellular Ca2+ oscillation. Our previous studies demonstrated that fluid shear stress (FSS) lead to Ca2+ oscillation through mechanosensitive cation-selective channels. However, the specific channels responsible for this FSS-induced Ca2+ oscillation remain unknown. In the present study, we examined the expression of several Ca2+ channels in OCs, including STIM1, ORAI1, TRPV1, TRPV4, TRPV5, and TRPV6, by western blotting and reverse transcription-polymerase chain reaction. The results showed that STIM1 was highly expressed in early stage OCs, while TRPV4 was highly expressed in late stage OCs. We observed intracellular Ca2+ responses in OCs that were mechanically stimulated by FSS. When we blocked STIM1-dependent store-operated Ca2+ entry or inhibited TRPV4 using siRNA or drug inhibition, FSS-induced Ca2+ oscillations were almost undetectable in early and late stage OCs, respectively. These results indicate that STIM1 and TRPV4 act as mechanical transduction channels for OCs during the early and late differentiation stages, respectively, suggesting that these calcium channel could serve as markers of osteoclastogenesis or bone resorption. PMID- 29604964 TI - Selective inhibition of histamine-evoked Ca2+ signals by compartmentalized cAMP in human bronchial airway smooth muscle cells. AB - Intracellular Ca2+ and cAMP typically cause opposing effects on airway smooth muscle contraction. Receptors that stimulate these pathways are therapeutic targets in asthma and chronic obstructive pulmonary disease. However, the interactions between different G protein-coupled receptors (GPCRs) that evoke cAMP and Ca2+ signals in human bronchial airway smooth muscle cells (hBASMCs) are poorly understood. We measured Ca2+ signals in cultures of fluo-4-loaded hBASMCs alongside measurements of intracellular cAMP using mass spectrometry or [3H] adenine labeling. Interactions between the signaling pathways were examined using selective ligands of GPCRs, and inhibitors of Ca2+ and cAMP signaling pathways. Histamine stimulated Ca2+ release through inositol 1,4,5-trisphosphate (IP3) receptors in hBASMCs. beta2-adrenoceptors, through cAMP and protein kinase A (PKA), substantially inhibited histamine-evoked Ca2+ signals. Responses to other Ca2+-mobilizing stimuli were unaffected by cAMP (carbachol and bradykinin) or minimally affected (lysophosphatidic acid). Prostaglandin E2 (PGE2), through EP2 and EP4 receptors, stimulated formation of cAMP and inhibited histamine-evoked Ca2+ signals. There was no consistent relationship between the inhibition of Ca2+ signals and the amounts of intracellular cAMP produced by different stimuli. We conclude that beta-adrenoceptors, EP2 and EP4 receptors, through cAMP and PKA, selectively inhibit Ca2+ signals evoked by histamine in hBASMCs, suggesting that PKA inhibits an early step in H1 receptor signaling. Local delivery of cAMP within hyperactive signaling junctions mediates the inhibition. PMID- 29604966 TI - Anoctamin 9/TMEM16J is a cation channel activated by cAMP/PKA signal. AB - Anoctamins (ANOs) are multifunctional membrane proteins that consist of 10 homologs. ANO1 (TMEM16A) and ANO2 (TMEM16B) are anion channels activated by intracellular calcium that meditate numerous physiological functions. ANO6 is a scramblase that redistributes phospholipids across the cell membrane. The other homologs are not well characterized. We found ANO9/TMEM16J is a cation channel activated by a cAMP-dependent protein kinase A (PKA). Intracellular cAMP activated robust currents in whole cells expressing ANO9, which were inhibited by a PKA blocker. A cholera toxin that persistently stimulated adenylate cyclase activated ANO9 as did the application of PKA. The cAMP-induced ANO9 currents were permeable to cations. The cAMP-dependent ANO9 currents were augmented by intracellular Ca2+. Ano9 transcripts were predominant in the intestines. Human intestinal SW480 cells expressed high levels of Ano9 transcripts and showed PKA inhibitor-reversible cAMP-dependent currents. We conclude that ANO9 is a cation channel activated by a cAMP/PKA pathway and could play a role in intestine function. PMID- 29604967 TI - An improved measurement of the Ca2+-binding affinity of fluorescent Ca2+ indicators. AB - Fluorescent Ca2+ indicators are widely used to measure the intracellular Ca2+ concentration ([Ca2+]i) in living cells, including neurons. By calibrating an indicator in solutions that mimic the main ionic constituents of the actual cytoplasm, [Ca2+]i can be determined from the measured fluorescence intensity. However, different studies have reported considerably different Ca2+-binding affinities (Kd) for the same indicator, even though they used calibrating solutions with similar compositions. In this paper, we present a method to accurately determine the Kd values of non-ratiometric Ca2+ indicators in solutions that mimicked a standard patch-clamp internal solution. The free Ca2+ concentration ([Ca2+]) in these solutions, which was set by either EGTA or HEDTA, was measured with a Ca2+-selective macroelectrode. We found that such a measurement was critical for an accurate calibration of the Ca2+ indicators. The Kd values of OGB-1, OGB-6F, fluo-5F, and fluo-4FF were 0.26 +/- 0.01, 8.7 +/- 0.4, 1.00 +/- 0.05, and 23.0 +/- 0.7 MUM, respectively. Calculating [Ca2+] with Maxchelator, a widely used computer program, led to a significant underestimation of the Kd values of OGB-6F, fluo-5F, and fluo-4FF. This is because the purity of EGTA was considerably less than that advertised by the manufacturer. In addition, the Kd value of HEDTA was overestimated by Maxchelator. Therefore, besides batch to-batch variations, the fact that [Ca2+] in the calibrating solutions of many studies was estimated with Maxchelator is very likely a reason for the different published values of Kd of Ca2+ indicators. Using a reaction-diffusion model to reproduce Ca2+ rises in a nerve terminal, we further showed that incorrect calibration of fluorescent Ca2+ indicators can underlie the large variation of the endogenous Ca2+ binding ratio between different types of excitatory synapses. PMID- 29604968 TI - A critical appraisal of the role of intracellular Ca2+-signaling pathways in Kawasaki disease. AB - Kawasaki disease is a multi-systemic vasculitis that generally occurs in children and that can lead to coronary artery lesions. Recent studies showed that Kawasaki disease has an important genetic component. In this review, we discuss the single nucleotide polymorphisms in the genes encoding proteins with a role in intracellular Ca2+ signaling: inositol 1,4,5-trisphosphate 3-kinase C, caspase-3, the store-operated Ca2+-entry channel ORAI1, the type-3 inositol 1,4,5 trisphosphate receptor, the Na+/Ca2+ exchanger 1, and phospholipase Cbeta4 and Cbeta1. An increase of the free cytosolic Ca2+ concentration is proposed to be a major factor in susceptibility to Kawasaki disease and disease outcome, but only for polymorphisms in the genes encoding the inositol 1,4,5-trisphosphate 3-kinase C and the Na+/Ca2+ exchanger 1, the free cytosolic Ca2+ concentration was actually measured and shown to be increased. Excessive cytosolic Ca2+ signaling can result in hyperactive calcineurin in T cells with an overstimulated nuclear factor of activated T cells pathway, in hypersecretion of interleukin-1beta and tumor necrosis factor-alpha by monocytes/macrophages, in increased urotensin-2 signaling, and in an overactivation of vascular endothelial cells. PMID- 29604965 TI - Computational modeling of amylin-induced calcium dysregulation in rat ventricular cardiomyocytes. AB - Hyperamylinemia is a condition that accompanies obesity and precedes type II diabetes, and it is characterized by above-normal blood levels of amylin, the pancreas-derived peptide. Human amylin oligomerizes easily and can deposit in the pancreas [1], brain [2], and heart [3], where they have been associated with calcium dysregulation. In the heart, accumulating evidence suggests that human amylin oligomers form moderately cation-selective [4,5] channels that embed in the cell sarcolemma (SL). The oligomers increase membrane conductance in a concentration-dependent manner [5], which is correlated with elevated cytosolic Ca2+. These findings motivate our core hypothesis that non-selective inward Ca2+ conduction afforded by human amylin oligomers increase cytosolic and sarcoplasmic reticulum (SR) Ca2+ load, which thereby magnifies intracellular Ca2+ transients. Questions remain however regarding the mechanism of amylin-induced Ca2+ dysregulation, including whether enhanced SL Ca2+ influx is sufficient to elevate cytosolic Ca2+ load [6], and if so, how might amplified Ca2+ transients perturb Ca2+-dependent cardiac pathways. To investigate these questions, we modified a computational model of cardiomyocytes Ca2+ signaling to reflect experimentally measured changes in SL membrane permeation and decreased sarcoplasmic/endoplasmic reticulum calcium ATPase (SERCA) function stemming from acute and transgenic human amylin peptide exposure. With this model, we confirmed the hypothesis that increasing SL permeation alone was sufficient to enhance Ca2+ transient amplitudes. Our model indicated that amplified cytosolic transients are driven by increased Ca2+ loading of the SR and that greater fractional release may contribute to the Ca2+-dependent activation of calmodulin, which could prime the activation of myocyte remodeling pathways. Importantly, elevated Ca2+ in the SR and dyadic space collectively drive greater fractional SR Ca2+ release for human amylin expressing rats (HIP) and acute amylin-exposed rats (+Amylin) mice, which contributes to the inotropic rise in cytosolic Ca2+ transients. These findings suggest that increased membrane permeation induced by oligomeratization of amylin peptide in cell sarcolemma contributes to Ca2+ dysregulation in pre-diabetes. PMID- 29604969 TI - Introduction to HIV infection and HIV neurology. AB - In this introductory chapter the impact of combination antiretriviral therapy is discussed. Three different "types" of HIV infection are described according to medication adherence and efficacy. Next, general principles of HIV related neurologic complications are defined. Last, a clinical approach to the HIV infected patient with a neurologic complication is then detailed. PMID- 29604970 TI - Central nervous system infection with Toxoplasma gondii. AB - Central nervous system infection by Toxoplasma gondii, or Toxoplasma encephalitis, is the most common cause of brain mass lesions in human immunodeficiency virus (HIV)-infected patients. It usually presents as one or more brain abscesses, but it can also cause a diffuse encephalitis or ventriculitis. Individuals who are Toxoplasma immunoglobulin G-seropositive, who have peripheral blood CD4+ T-cell concentrations below 200/MUL, are not on antiretroviral therapy, and are not taking trimethoprim-sulfamethoxazole to prevent Pneumocystis pneumonia, are at particular risk for Toxoplasma encephalitis. Neuroimaging typically shows round, isodense or hyperdense lesions in the hemispheric gray-white junction, deep white matter, or basal ganglia that enhance with contrast in a ring, nodular, or homogeneous pattern. In appropriate patients, response to an empiric treatment trial can establish the diagnosis. Immune reconstitution inflammatory syndrome is uncommon in HIV-infected patients treated for Toxoplasma encephalitis and combination antiretroviral therapy is an integral part of toxoplasmosis treatment. PMID- 29604971 TI - Progressive multifocal leukoencephalopathy. AB - Progressive multifocal leukoencephalopathy (PML) is a relatively common complication of HIV disease. In this chapter changes to the epidemiology are discussed along with an update in its pathogenesis and treatment. Immune reconstitution inflammatory syndrome is increasingly frequent in PML; accordingly management strategies and prognosis are detailed. PMID- 29604972 TI - Cryptococcal meningitis in AIDS. AB - Cryptococcal meningitis remains a significant cause of morbidity and mortality amongst patients living with human immunodeficiency virus (HIV). The prevalence in the developed world has decreased as HIV is being diagnosed earlier, but is still significant, and the prevalence in resource-limited settings is exceedingly high. The presenting symptoms usually include a headache, fever, and, less often, cranial nerve abnormalities. Space-occupying lesions do occur, but are rare. Once diagnosed, patients should be treated with a combination of amphotericin and flucytosine, with step-down therapy to fluconazole for a minimum of a year, or until the CD4 count is above 100 cells/MUL, whichever is longer. In the acute phase of treatment increased opening pressure is common, which should be managed aggressively with frequent lumbar punctures, or through neurosurgical interventions (lumbar drains, ventriculoperitoneal shunts) if those fail. Antiretrovirals should be delayed at least 2 weeks, but maybe as many as 10 weeks, after initiation of antifungal therapy in order to prevent clinical or subclinical immune reconstitution inflammatory syndrome (IRIS), which may lead to increased mortality. However, if IRIS does develop, there is no role for antiretroviral interruption, and the condition should be managed supportively by use of anti-inflammatories and aggressive management of elevated opening pressure, if present. Steroids should be administered for specific indications only (IRIS or cryptococcoma with cerebral edema and risk of herniation) as routine use of steroids increases mortality in cryptococcal meningitis. PMID- 29604973 TI - Other central nervous system infections: cytomegalovirus, Mycobacterium tuberculosis, and Treponema pallidum. AB - Human immunodeficiency virus (HIV)-infected individuals are particularly susceptible to several central nervous system infections: human cytomegalovirus, which may cause encephalitis, ventriculitis, polyradiculitis, or polyradiculomyelitis; Mycobacterium tuberculosis, which can cause meningitis or space-occupying lesions; and Treponema pallidum subspecies pallidum (T. pallidum), which affects the meninges, cerebrospinal fluid, cranial nerves, and vasculature in early neurosyphilis, and additionally the brain and spinal cord parenchyma in late neurosyphilis. Central nervous system cytomegalovirus infection is seen in HIV-infected individuals with very advanced immunosuppression. Its prognosis is poor and optimal therapy has not been determined. Tuberculous meningitis has a high mortality in those also infected with HIV, especially in the developing world, and better therapies are urgently needed. As the rates of syphilis increase in the developed world, neurosyphilis and in particular ocular syphilis are increasingly reported. The likelihood of all three of these central nervous system infections is decreased in individuals who receive potent antiretroviral therapy. PMID- 29604974 TI - CNS immune reconstitution inflammatory syndrome. AB - Immune reconstitution inflammatory syndrome (IRIS) describes a syndrome of aberrant reconstituted immunity, often in association with HIV infection, beginning with a normalization of CD4+ T-cell counts resulting in a dysregulated immune response against an infecting opportunistic pathogen and the host. In this chapter, we discuss the unique nature of IRIS when present in the central nervous system (CNS IRIS) and the changes experienced with each host pathogen and its unique influence on the immune system. Consensus on the mechanism of action of the immune system in IRIS pathology is less clear and multiple theories have been proposed. Here we explore the early history of the term IRIS, proposed mechanisms and animal models, as well as common CNS pathogens associated with IRIS, and management strategies. PMID- 29604975 TI - Primary CNS lymphoma in HIV infection. AB - Primary CNS lymphoma (PCNSL) has been designated an acquired immune deficiency syndrome (AIDS)-defining disease since 1983 and accounts for up to 15% of non Hodgkin lymphomas in human immunodeficiency virus (HIV) patients. The majority of HIV patients are Epstein-Barr virus (EBV)-related. The most likely etiology is ineffective immunoregulation of EBV, inducing oncogenic protein expression, and subsequent loss of apoptosis and increased proliferation of lymphocytes. PCNSL generally presents with supratentorial, single or multiple, contrast-enhancing lesions. Neurologic symptoms can be headache, cognitive function disorders, focal neurologic, deficit and epilepsy. Differential diagnosis includes other oncologic or infectious causes, with cerebral toxoplasmosis being the most important. Magnetic resonance imaging characteristics, activity on 201thallium single-photon emission computed tomography, presence of EBV DNA in the cerebrospinal fluid, and toxoplasmosis serology can make either PCNSL or cerebral toxoplasmosis more or less likely. However, definitive diagnosis of PCNSL relies on histopathologic confirmation. First-choice treatment is combination antiretroviral therapy in combination with high-dose methotrexate(-based) chemotherapy in patients in whom this is feasible. Combination antiretroviral therapy combined with whole-brain radiotherapy may be an alternative. Treatment of EBV with antiviral agents such as ganciclovir or zidovudine may be beneficial, but this needs further study. Prognosis of HIV-related PCNSL is poor, with median survival varying from 2 to 4 months, but patients treated with chemotherapy do better (median survival 1.5 years). PMID- 29604976 TI - HIV infection and stroke. AB - The landscape of human immunodeficiency virus (HIV) infection is changing with the increasing coverage of antiretroviral therapy (ART). Patients are living longer but continually exposed to a virologically suppressed HIV infection. This has resulted in a decrease in acquired immune deficiency syndrome (AIDS)-related complications such as opportunistic infections, and an increase in non-AIDS complications such as stroke. In this era, stroke is perhaps the most important neurologic complication of HIV infection. Furthermore, stroke is more of a heterogeneous disease in people living with HIV infection and therefore needs to be approached systematically. Many of the etiologies are treatable. HIV associated vasculopathy is perhaps the most common etiology in this population and our understanding of this is still evolving. Moreover, the treatment of HIV infection may contribute to an excess risk of stroke and interact with stroke therapies. PMID- 29604977 TI - Neuromuscular complications of HIV infection. AB - With the introduction of combination antiretroviral therapy, human immunodeficiency virus (HIV)-infected individuals are living longer, and are commonly confronted with chronic neuromuscular complications. The spectrum of neuromuscular disorders in patients living with HIV infection is wide, and is caused by HIV per se and its products, particular antiretroviral drugs, or a combination of both. The purpose of this chapter is to review peripheral nervous system disorders in the setting of HIV infection, and to provide a general approach to diagnosis and management of these disorders. The early identification of these conditions may help with early intervention and management, allow prevention of morbidities associated with these disorders, and contribute to future research efforts in the field of HIV. PMID- 29604978 TI - Neuropathogenesis of human immunodeficiency virus infection. AB - Human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) remain a common end-organ manifestation of viral infection. Subclinical and mild symptoms lead to neurocognitive and behavioral abnormalities. These are associated, in part, with viral penetrance and persistence in the central nervous system. Infections of peripheral blood monocytes, macrophages, and microglia are the primary drivers of neuroinflammation and neuronal impairments. While current antiretroviral therapy (ART) has reduced the incidence of HIV-associated dementia, milder forms of HAND continue. Depression, comorbid conditions such as infectious liver disease, drugs of abuse, antiretroviral drugs themselves, age related neurodegenerative diseases, gastrointestinal maladies, and concurrent social and economic issues can make accurate diagnosis of HAND challenging. Increased life expectancy as a result of ART clearly creates this variety of comorbid conditions that often blur the link between the virus and disease. With the discovery of novel biomarkers, neuropsychologic testing, and imaging techniques to better diagnose HAND, the emergence of brain-penetrant ART, adjunctive therapies, longer life expectancy, and better understanding of disease pathogenesis, disease elimination is perhaps a realistic possibility. This review focuses on HIV-associated disease pathobiology with an eye towards changing trends in the face of widespread availability of ART. PMID- 29604979 TI - HIV and spinal cord disease. AB - The epidemiology of spinal cord disease in human immunodeficiency virus (HIV) infection is largely unknown due to a paucity of data since combination antiretroviral therapy (cART). HIV mediates spinal cord injury indirectly, by immune modulation, degeneration, or associated infections and neoplasms. The pathologies vary and range from cytotoxic necrosis to demyelination and vasculitis. Control of HIV determines the differential for all neurologic presentations in infected individuals. Primary HIV-associated acute transverse myelitis, an acute inflammatory condition with pathologic similarities to HIV encephalitis, arises in early infection and at seroconversion. In contrast, HIV vacuolar myelopathy and opportunistic infections predominate in uncontrolled disease. There is systemic immune dysregulation as early as primary infection due to initial depletion of gut-associated lymphoid tissue CD4 cells and allowance of microbial translocation across the gut that never fully recovers throughout the course of HIV infection, regardless of how well controlled. The subsequent proinflammatory state may contribute to spinal cord diseases observed even after cART initiation. This chapter will highlight an array of spinal cord pathologies classified by stage of HIV infection and immune status. PMID- 29604980 TI - Imaging studies of the HIV-infected brain. AB - Human immunodeficiency virus (HIV) enters the brain early after infecting humans and may remain in the central nervous system despite successful antiretroviral treatment. Many neuroimaging techniques were used to study HIV+ patients with or without opportunistic infections. These techniques assessed abnormalities in brain structures (using computed tomography, structural magnetic resonance imaging (MRI), diffusion MRI) and function (using functional MRI at rest or during a task, and perfusion MRI with or without a contrast agent). In addition, single-photon emission computed tomography with various tracers (e.g., thallium 201, Tc99-HMPAO) and positron emission tomography with various agents (e.g., [18F]-dexoyglucose, [11C]-PiB, and [11C]-TSPO tracers), were applied to study opportunistic infections or HIV-associated neurocognitive disorders. Neuroimaging provides diagnoses and biomarkers to quantitate the severity of brain injury or to monitor treatment effects, and may yield insights into the pathophysiology of HIV infection. As the majority of antiretroviral-stable HIV+ patients are living longer, age-related comorbid disorders (e.g., additional neuroinflammation, cerebrovascular disorders, or other dementias) will need to be considered. Other highly prevalent conditions, such as substance use disorders, psychiatric illnesses, and the long-term effects of combined antiretroviral therapy, all may lead to additional brain injury. Neuroimaging studies could provide knowledge regarding how these comorbid conditions impact the HIV-infected brain. Lastly, specific molecular imaging agents may be needed to assess the central nervous system viral reservoir. PMID- 29604981 TI - Global developments in HIV neurology. AB - Neurologic conditions associated with HIV remain major contributors to morbidity and mortality, and are increasingly recognized in the aging population on long standing combination antiretroviral therapy (cART). Importantly, growing evidence suggests that the central nervous system (CNS) serves as a reservoir for viral replication with major implications for human immunodeficiency virus (HIV) eradication strategies. Though there has been major progress in the last decade in our understanding of the pathogenesis, burden, and impact of HIV-associated neurologic conditions, significant scientific gaps remain. In many low-income settings, second- and third-line cART regimens that carry substantial neurotoxicity remain treatment mainstays. Further, patients continue to present severely immunosuppressed with CNS opportunistic infections. Public health efforts should emphasize improvements in access and optimizing treatment of HIV positive patients, specifically in resource-limited settings, to reduce the risk of neurologic sequelae. PMID- 29604982 TI - HIV neuropathology. AB - Primary human immunodeficiency virus (HIV) neuropathologies can affect all levels of the neuraxis and occur in all stages of natural history disease. Some, like HIV encephalitis, HIV myelitis, and diffuse infiltrative lymphocytosis of peripheral nerve, reflect productive infection of the nervous system; others, like vacuolar myelopathy, distal symmetric polyneuropathy, and central and peripheral nervous system demyelination, are not clearly related to regional viral replication, and reflect more complex cascades of dysregulated host immunity and metabolic dysfunction. In pediatric patients, the spectrum of neuropathology is altered by the impacts of HIV on a developing nervous system, with microcephaly, abundant brain mineralization, and corticospinal tract degeneration as examples of this unique interaction. With efficacious therapies, CD8 T-cell encephalitis is emerging as a significant entity; often this is clinically recognized as immune reconstitution inflammatory syndrome, but has also been described in the context of viral escape and treatment interruption. The relationship of HIV neuropathology to clinical symptoms is sometimes straightforward, and sometimes mysterious, as individuals can manifest significant deficits in the absence of discrete lesions. However, at all stages of the natural history disease, neuroinflammation is abundant, and critical to the generation of clinical abnormality. Neuropathologic and neurobiologic investigations will be central to understanding HIV nervous system disorders in the era of efficacious therapies. PMID- 29604983 TI - Animal models of HIV-associated disease of the central nervous system. AB - It is difficult to study the pathogenesis of human immunodeficiency virus (HIV) associated neurocognitive disorder (HAND) in living patients because central nervous system (CNS) tissues are only available post mortem. Rodent and nonhuman primate (NHP) models of HAND allow for longitudinal analysis of HIV-associated CNS pathology and efficacy studies of novel therapeutics. Rodent models of HAND allow for studies with large sample sizes, short duration, and relatively low cost. These models include humanized mice used to study HIV-associated neuropathogenesis and transgenic mice used to study neurotoxic effects of viral proteins without infection. Simian immunodeficiency virus (SIV)-infected NHP are the premier model of neuroAIDS; SIV-associated CNS pathology is similar to HIV associated CNS pathology with HAND. Additionally, the size, lifespan of NHP, and time to acquired immune deficiency syndrome (AIDS) progression make SIV-infected NHP models optimal for studies of viral latency and reservoirs, and assessing novel therapeutics for neuroAIDS. NHP models of neuroAIDS generally include conventional progressors (AIDS within 2-3 years) and those that have rapid disease (AIDS within 150 days). Rapid AIDS models are achieved by immune modulation and/or infection with neurovirulent and neurosuppressive viral strains and result in a high incidence of SIV-associated encephalitis. In this chapter, we briefly review rodent and NHP models of neuroAIDS, including contributions made using these models to our understanding of HIV-associated CNS disease. PMID- 29604984 TI - Neuropharmacology. AB - With virologically suppressive antiretroviral therapy, immune system recovery is now achievable for persons living with HIV (PLWH). This immune recovery is associated with dramatic reductions in acquired immune deficiency syndrome (AIDS) defining illnesses including HIV dementia. However, milder form of cognitive disturbances are widely reported in PLWH despite effective antiretroviral therapy. The underlying pathogenic mechanisms of these cognitive disturbances remain elusive, with many potential pathogenic mechanisms including residual brain damage prior to the initiation of antiretroviral therapy and neuroinflammation and ongoing immune system disturbances despite antiretroviral therapy. Lifestyle factors and concomitant infections and medical problems are also likely to be major contributing factors. The penetration of antiretroviral agents into the central nervous system compartment resulting in a lack of suppression of HIV viremia in the brain has generated much interest as well as potential neuro-toxicities from antiretroviral agents themselves. This chapter reviews the clinical pharmacology, both the pharmacokinetic and pharmacodynamic effects, of antiretroviral therapy in the central nervous system compartment. PMID- 29604985 TI - Neurologic sequelae of primary HIV infection. AB - Primary human immunodeficiency virus type 1 (HIV-1) infection is defined as the period from initial infection with HIV to complete seroconversion. Neurologic sequelae of primary HIV-1 infection are not uncommon, potentially affecting all parts of the nervous system. It is important for the neurologist to be aware of symptomatic primary HIV infection, as it may afford an early and accurate diagnosis of HIV infection and the opportunity for consideration of early antiretroviral therapy. This chapter introduces the clinical manifestations of primary HIV infection, including the laboratory and diagnostic approach, before detailing the various neurologic sequelae. Finally the treatment of primary HIV infection and neurologic sequelae are discussed, in the context of recent advances in the field of HIV reservoirs and longer-term neurologic complications. PMID- 29604986 TI - HIV-associated neurocognitive disorder. AB - Human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) affects roughly half the HIV-positive population. The symptoms of cognitive slowing, poor concentration, and memory problems can impact on everyday life. Its diagnosis is validated where possible by identifying deficits in two cognitive domains on neuropsychologic testing in patients either with or without symptoms. Corroborating evidence may be found on imaging, blood tests, and cerebrospinal fluid analysis, though sensitive and specific biomarkers are currently lacking. The introduction of combined antiretroviral therapy in the 1990s has generated a therapeutic paradox whereby the number of severe cases of HAND has fallen, yet milder forms continue to rise in prevalence. New emphasis has been placed on identifying the cause of apparent ongoing HIV infection and inflammation of the central nervous system (CNS) in the face of durable systemic viral suppression, and how this equates to the neuronal dysfunction underlying HAND. The interaction with aging and comorbidities is becoming increasingly common as the HIV-positive population enters older adulthood, with neurodegenerative, metabolic, and vascular causes of cognitive impairment combining and probably accelerating in the context of chronic HIV infection. Therapies targeted to the CNS, but without neurotoxic side-effects, are being investigated to attempt to reduce the likelihood of developing, and improving, HAND. PMID- 29604987 TI - NeuroAIDS in children. AB - The human immunodeficiency virus-1 (HIV-1) enters the central nervous system compartment within the first few weeks of systemic HIV infection and may cause a spectrum of neurologic complications. Without combination antiretroviral therapy (cART), 50-90% of all HIV-infected infants and children develop some form of neuroAIDS. Of the estimated 2.3 million children less than 15 years of age who were living in sub-Saharan Africa at the end of 2014, only 30% were receiving cART, suggesting that there is a large burden of neuroAIDS among HIV-infected children in sub-Saharan Africa. There is complex interplay between the disease process itself, the child's immune reaction to the disease, the secondary complications, the side-effects of antiretroviral drugs, and inadequate antiretroviral drug uptake into the central nervous system. In addition there is the layering effect from the multiple socioeconomic challenges for children living in low- and middle-income countries. Adolescents may manifest with a range of neurocognitive sequelae from mild neurocognitive disorder through to severe neurocognitive impairment. Neuroimaging studies on white-matter tracts have identified dysfunction, especially in the frontostriatal networks needed for executive function. Psychiatric symptoms of depression, attention deficit hyperactivity disorder, and behavioral problems are also commonly reported in this age group. Antiretroviral drugs may cause treatment-limiting neurologic and neuropsychiatric adverse reactions. The following chapter addresses the neurologic complications known to be, and suspected of being, associated with HIV infection in children and adolescents. PMID- 29604988 TI - Foreword. PMID- 29604989 TI - Preface. PMID- 29604991 TI - Heat stress incidents, and match play at the Australian Open. PMID- 29604992 TI - First description of the pathogenicity of Babesia vogeli in experimentally infected dogs. AB - Babesiosis is a tick-borne disease that occurs worldwide with the most recognized Babesia species that infect dogs being Babesia canis, B. vogeli, B. rossi and B. gibsoni. While B. vogeli is reported in dogs worldwide, clinical and laboratory data on infections is based on reports of naturally infected dogs. To provide reliable data on the clinical and laboratory abnormalities associated with acute and more chronic infections in healthy dogs free of other tick-borne diseases, we experimentally infected dogs with a Chinese strain of B. vogeli. All of the six infected Beagles, three of which were splenectomized, became infected with B. vogeli detected in blood smears taken the day following infection and the organism detected by FRET-qPCRs in most blood samples (77/86; 90%) collected about every 4 days until the end of the experiment on day 95. All the infected dogs showed fever, partial anorexia and malaise that was more severe in the splenectomized dogs that did not gain weight for three weeks in the period after initial infection. Regenerative anemia, thrombocytopenia and decreased white blood cell counts were seen in all dogs but were more severe in the splenectomized dogs, of which two had life threatening infections and had to be removed from the study for treatment. Following re-infection on day 66, none of the dogs showed clinical signs and copy numbers did not change significantly although all the dogs were negative by FRET-qPCR on at least some of the subsequent sampling days. Laboratory values in the non-splenectomized dogs were relatively unchanged while in the splenectomized dog there was a temporary small increase in the platelet and white blood cell counts and a temporary slight worsening of the anemia. In summary, our study shows dogs experimentally infected with a B. vogeli strain from China develop only mild clinical signs that are followed by asymptomatic infections that can last for least 95 days. In splenectomized dogs, however, severe life threatening signs may develop. PMID- 29604994 TI - A new method for laboratory rearing of Galba truncatula, the intermediate host of Fasciola hepatica. AB - In this study a relatively large and open top aquarium was designed, constructed and introduced as a suitable habitat for nutrition, growth and development as well as for egg laying and breeding of Galba truncatula under laboratory conditions. The soil and water used in the aquarium were collected from the locality in which the snails were collected. The aquarium was placed in a laboratory with temperature of 18-32 oC and relative humidity of 22-37% respectively, according to the season. The artificial light was controlled by a light timer, giving 12 h of light and 12 h of darkness. The snails were fed with dried lettuce leaves, Cyperus alternifolius (aquatic plant), Spirulina (algae), Orthotrichum rupestre (moss) and cuttlebone (a supplementary source of calcium). Approximately five weeks after the start of study, there was evidence of reproduction and success in rearing of G. truncatula by the appearance of eggs and small snails (0.1-0.5 mm) in the aquarium. In conclusion, large scale laboratory rearing of G. truncatula is a feasible task. The method may be improved by balancing the temperature and relative humidity as well as by optimizing the soil type, the water quality and the type of food. PMID- 29604993 TI - W A A V P guideline for evaluating the efficacy of anticoccidials in mammals (pigs, dogs, cattle, sheep). AB - This guideline is intended as an aid in the design, implementation and interpretation of studies for the assessment of drug efficacy against Eimeria in cattle and sheep, Cystoisospora in pigs and dogs, and Cryptosporidium in cattle. It deals with the most important aspects of how to conduct both experimental and field studies for dose determination, dose confirmation and assessment of field effectiveness. Also, guidance on the selection of animals, diagnostic techniques, statistical evaluation and methods for the preparation, maintenance and use of parasites is provided. The specific management conditions that may influence the course of natural infections and consequently determine treatment schemes are mentioned and suggestions for best practice in sampling and evaluation of data prior to conducting of efficacy studies are given. The guideline is also intended to assist investigators in carrying out specific studies, provide relevant information for registration authorities involved in the decision-making process, assist in the approval of anticoccidial drugs in the target species, and facilitate the world-wide adoption of standard procedures. Although currently not implemented, issues of drug resistance testing and alternative methods for drug testing are also discussed as future issues in drug testing against mammalian coccidia. PMID- 29604996 TI - Anthelmintic efficacy of cranberry vine extracts on ovine Haemonchus contortus. AB - The discovery that plant secondary compounds, including proanthocyanidins (PAC), suppress gastrointestinal nematode (GIN) infection has provided promise for alternative methods of GIN control in small ruminants. This investigation is the first to examine the anthelmintic potential of cranberry vine (CV) against the GIN Haemonchus contortus. The purpose of this study was to explore the anti parasitic activity of CV in the form of a specific organic proanthocyanidin extract (CV-PAC) and an aqueous extract (CV-AqE) containing PAC and other compounds. In vitro egg hatching, first (L1) and third (L3) stage larval and adult worm motility and L3 exsheathment were evaluated after a 24-h incubation with CV products. In addition, CV treated worms were observed via scanning electron microscopy, and a preliminary investigation of the efficacy of CV powder against an experimental infection of H. contortus was conducted. The in vivo effect on an experimental infection was determined by administering 21.1 g CV powder to lambs (n = 9 per group) for three consecutive days, and collecting fecal egg count data for four weeks post-treatment. The effect of CV-PAC on egg hatching, L3 motility and exsheathment was limited. However, a substantial effect was observed on motility of post-hatch L1 (EC50 0.3 mg PAC/mL) and adults (EC50 0.2 mg PAC/mL). The CV-AqE showed more effect on egg hatching (EC50 5.3 mg/mL containing 0.6 mg PAC/mL) as well as impacting motility of L1 (EC50 1.5 mg/mL with 0.2 mg PAC/mL) and adults (EC50 3.4 mg/mL with 0.4 mg PAC/mL), but like CV PAC, did not substantially effect L3 motility or exsheathment. Scanning electron microscopy revealed an accumulation of aggregate on the cuticle around the buccal area of adult worms incubated in CV-AqE and CV-PAC. In the preliminary in vivo study, there was a significant effect of treatment over time (p = .04), although differences in individual weeks were not significant. In summary, both extracts inhibited motility of L1 and adult worms. The higher efficacy of CV-AqE than CV PAC at levels that contained the same concentrations of PAC tested alone, suggest that other secondary compounds in the CV-AqE contributed to the observed effects on the parasites. This first study of the in vitro and in vivo effects of CV suggest that this readily available plant product may have utility in integrated control of H. contortus and support the need for additional testing to provide further information. PMID- 29604997 TI - Clinical characteristics of Spirocerca lupi migration in the spinal cord. AB - Spirocerca lupi is a nematode infecting dogs mostly in tropical and subtropical areas. Although its typical target is the esophageal wall, aberrant migration is not uncommon, including migration of unknown incidence into the spinal cord. While successful treatment of intraspinal S. lupi (ISSL) infection depends on early diagnosis, tools for definitive ante-mortem diagnosis are unavailable. We therefore aimed at characterizing clinical signs and clinical pathology findings of ISSL in dogs. For that, we analyzed medical records of dogs hospitalized in 2005-2016 presenting with neurological signs consistent with ISSL, which were diagnosed definitively post-mortem. Retrieved information included signalment, medical history, chief complaint, physical and neurological evaluation, neuroanatomical localization at presentation, clinical pathology, imaging findings, treatment, outcome and post-mortem findings. Ten midsize to large breed dogs were included, 7 of which had received prophylactic treatment. In all 10 dogs, onset was acute and neurological deterioration until presentation (2 h-6 d) was fast. Neurological examination localized the lesions within the spinal cord and paresis or paralysis was asymmetric in all dogs. Spinal pain was documented in 9/10 dogs. Cerebrospinal fluid (CSF) analysis was abnormal in all dogs and was characterized by pleocytosis in 8/10, whereas cytology revealed the presence of eosinophils in all dogs. Advanced imaging excluded spinal cord compression in all dogs tested. Post-mortem examination detected spinal cord migration tract in all cases. Nematodes were found in the spinal cord parenchyma (8/10) or adjacent to it (2/10) in all dogs. A larva was found in the subarachnoid space of one dog and an adult nematode in the thoracic intervertebral artery of another. Esophageal nodules were found in 5/10 dogs. These findings suggest that the combination of sudden onset of acute asymmetric paresis accompanied by pain, presence of eosinophils in the CSF and lack of compressive lesion may serve as sufficient evidence for tentative diagnosis of ISSL in endemic areas. PMID- 29604998 TI - Evaluation of an antiparasitic compound extracted from Polygonum cuspidatum against Ichthyophthirius multifiliis in grass carp. AB - Ichthyophthirius multifiliis is a ciliated parasite that infests almost all freshwater fish species and causes great economic losses to the aquaculture industry. In this study, a compound with anti-I. multifiliis activity was isolated from Polygonum cuspidatum and identified as emodin. In vitro anti-I. multifiliis results showed that emodin at 1 mg/L killed all I. multifiliis theronts for 96.0 min, and at 0.5 mg/L or lower concentrations could not kill all I. multifiliis theronts, but could significantly reduce the infectivity of theronts after pretreatment with emodin at the low concentrations mentioned above for 2 h. Additionally, emodin at 1 mg/L and 2 mg/L completely terminated the reproduction of nonencysted and encysted tomonts, respectively. In vivo tests, emodin at 0.5 mg/L could cure infected grass carp and protect naive fish from I. multifiliis infection by continuous adding emodin for 10 days. The 96 h median lethal concentration (LC50) of emodin to grass carp was 3.15 mg/L, which were approximately 18 and 7 times the median effective concentration (EC50) of emodin for killing theronts (0.18 mg/L) and nonencysted tomonts (0.45 mg/L), respectively. On the basis of these results, emodin is an effective compound for the development of a new drug against I. multifiliis. PMID- 29604999 TI - Questionnaire-based survey on distribution of canine ocular thelaziosis in southwestern France. AB - The distribution of Thelazia callipaeda, commonly known as "oriental eyeworm'', has been considered for a long time to be confined to the former soviet Republics and Asia where the nematode causes infections in domestic and wild carnivores, rabbits and sometimes humans. However, since 2000, thelaziosis has been diagnosed in dogs and sometimes in cats from a growing number of European countries, including France. In 2006, a survey demonstrated that many autochthonous cases of canine thelaziosis were present in the department of Dordogne (southwestern France) in three hyperenzootic counties where strawberry production was predominant. The objective of the present study was to obtain an updated evaluation of the enzootic occurrence of T. callipaeda in France. In April 2016, an electronic questionnaire was sent to 1670 veterinary clinics from 24 French departments of southwestern France. Among 279 responses, 97 veterinary clinics reported cases of canine thelaziosis during the last 12 months. Most of them (72/97, 74.2%) reported a limited number of cases. Two veterinary clinics in previously-identified hyperenzootic counties of Dordogne reported the higher incidence (50 and 68 new cases annually). Noteworthly, two clinics located in another department (Landes) also reported many autochthonous cases (30 cases annually) demonstrating the existence of new enzootic foci. The present investigation confirmed that Dordogne is still an enzootic area of ocular thelaziosis and that the disease is spreading in new areas of southwestern France since a decade. PMID- 29605000 TI - Toll-like receptors and cytokines in the brain and in spleen of dogs with visceral leishmaniosis. AB - Visceral leishmaniosis (VL) is a multisystem disease that affects domestic dogs and can have several clinical manifestations, including some rare reports of neurological clinical signs, or it may remain asymptomatic, depending on the individual immune response against the Leishmania parasite. VL involves immune system sensors, such as the Toll-like receptors (TLRs), that are related to innate immunity and inflammation. Previously, we have reported the presence of brain inflammation in infected dogs. Here, we investigated the gene expression profile of TLRs 1-10 in the brain and the spleen of infected dogs, along with the production of proinflammatory cytokines (TNF-alpha, IFN-gamma, IL-1beta and IL-6) with the aim of explaining the origin of brain inflammation. The gene expression of TLRs has varied according to the tissue evaluated. In the brain, TLR-4 was only up-regulated in a small subpopulation of infected dogs, while in the spleen, we detected an increase in TLR-5 and TLR-9 transcripts, as well as a reduction in TLRs 2-4 and TLR-10. All cytokines except IL-6 were detected in infected dogs. Moreover, we detected Leishmania DNA in all infected dogs in both tissues evaluated. In the histopathological analysis, we observed a predominance of lymphoplasmacytic infiltrate, mainly in leptomeninges and choroid plexuses, ranging from mild to intense. This study provides the first insight into the TLRs profile in the brain and the spleen during canine VL and provides support to confirm the involvement of sensors of the innate immune system sensors against L. infantum parasites. PMID- 29605001 TI - Detection of Leishmania infantum DNA in phlebotomine sand flies from an area where canine leishmaniosis is endemic in southern Italy. AB - Phlebotomine sand flies (Diptera, Psychodidae) are vectors of Leishmania spp., among which Leishmania infantum is recognized as the main agent of human and canine leishmaniosis (CanL) in the Mediterranean area. In this study, females of Phlebotomus spp. (P. perniciosus, P. neglectus and P. papatasi) and Sergentomyia minuta were collected in a dog shelter of southern Italy, where CanL is endemic, and examined for Leishmania DNA. In total, 32 out of 56 of Phlebotomus spp. insects (57.1%) were found positive for L. infantum DNA by quantitative PCR (qPCR), with a mean parasite load of 1.9 * 103 promastigotes/ml among 23 positive P. perniciosus and 2.1 * 103 promastigotes/ml among five positive P. neglectus. Four P. papatasi, a species known to be refractory to L. infantum development, were also found positive. Among 216 S. minuta specimens examined, 25 (11.6%) scored positive for Leishmania tarentolae by conventional nested PCR; two (16.7%) of them were also positive for lizard blood, which is in agreement with the feeding preference of this phlebotomine species. Nine S. minuta (4.2%) were positive for L. infantum by qPCR, with a mean parasite load of 1.62 * 102 promastigotes/ml. The detection of L. infantum DNA in S. minuta may suggest that this species could acquire the protozoan, occasionally feeding on infected dogs. Further investigations need to clarify the potential role that S. minuta may have in the transmission of L. infantum to receptive mammal hosts. PMID- 29605002 TI - Circulating genotypes of Toxoplasma gondii in Northwestern Italy. AB - Toxoplasma gondii is an apicomplexan parasite that in Europe is genetically characterized by three main clonal genotypes, with a lesser prevalence of atypical patterns. Data on the genotypes of T. gondii circulating both in wildlife and livestock in Northern Italy are scarce. In the present study skeletal muscle samples of cattle (Bos taurus), swine (Sus scrofa domesticus), fox (Vulpes vulpes), roe deer (Capreolus capreolus) and wild boar (Sus scrofa) were genotyped by using a nested PCR of 6 loci (alt.SAG2, GRA6, 5'SAG2, BTUB, C22 8 and SAG1) and in silico RFLP. High prevalence of genotype I and non-canonical genotypes were observed in this study, with some differences in the population structure of the parasite between livestock and wildlife. Genetic variability of T. gondii in Europe could be more variable than previously thought, with possible implication for public health. PMID- 29605003 TI - Field evaluation of Duddingtonia flagrans IAH 1297 for the reduction of worm burden in grazing animals: Tracer studies in sheep. AB - The aim of these studies was to determine the reduction in pasture infectivity likely to be achieved by the supplementation of grazing sheep with BioWorma(r), a product containing the chlamydospores of the nematophagous fungus Duddingtonia flagrans strain IAH 1297. Four placebo-controlled trials were conducted between 2009 and 2013 in sheep in different climatic regions of New South Wales and Queensland, Australia and across several seasons. The effectiveness of BioWorma was assessed by total worm counts in tracer sheep placed in paddocks grazed by parasitised sheep which were fed a daily supplement with and without BioWorma under group-feeding conditions. Further proof of concept was obtained by assessing the worm burdens and weight gains of the parasitised sheep, as well as the number of anthelmintic ("salvage") treatments required when faecal egg counts exceeded a threshold level. Significant reductions ranging from 57 to 84% (P < 0.05) in worm burdens of the tracer sheep placed in the paddock grazed by BioWorma treated sheep were obtained in all four trials, compared to the Control group. In two of the studies the treatment effect was greater at the end of the trial, indicating that pasture infectivity in the Control paddocks had risen considerably. The main nematodes encountered were Haemonchus spp., Trichostrongylus spp., and Teladorsagia spp. (including multi-resistant strains) and significant reductions were demonstrated for each of these species. Given the results of the four trials it can be concluded that supplementation of pastured sheep with BioWorma was effective in reducing the numbers of parasitic nematode larvae ingested by tracer sheep. It is considered that these levels of reduced pasture larvae would result in productivity increases in grazing sheep and reduce the requirement for intervention with anthelmintic chemicals. Therefore, use of BioWorma will provide an alternative means for control of gastrointestinal nematode (GIN) parasites on pasture. PMID- 29605004 TI - An observational study of ewe treatments at lambing on early infection in lambs on UK sheep farms. AB - Anthelmintic treatments to ewes around lambing time, often with long acting products, have become common practice on UK sheep farms, but these treatments have also been shown to be highly selective for anthelmintic resistance in New Zealand and Australia, with field data supported by modelling results. The purpose of this study was to determine (1) the effect of treating or withholding anthelmintic treatments and (2) the effect of treatment of ewes with a persistent or non-persistent anthelmintic, on early infection in lambs in the UK. Faecal egg count data for 10-16 weeks old lambs collected over a three year period (2012 2014) was analysed. Samples were grouped according to whether the ewes on the farm had or had not been treated with an anthelmintic at lambing. For both analyses, data for early infection were analysed by generalised linear mixed model. There was no effect of withholding or treating ewes on subsequent early infection in lambs. In addition, there was no effect of region, farm type or management type on the faecal egg counts. There was, however an effect of year, with lambs having lower counts in 2014 than in 2012 and an interaction between year and ewe treatment, with data suggesting lower infection levels over time for those farms withholding anthelmintic treatments altogether. There was no effect of drug type on early infection in lambs nor region, farm type or treatment on the lamb faecal egg counts. However, there was an effect of year and an interaction between year and drug type with lower egg count over time with the short acting drugs. Our study supports data generated by other researchers suggesting that the practice of treating ewes at lambing to reduce contamination on pasture and minimise subsequent disease may not in fact always result in lower levels of infection in lambs. The study also demonstrated no significant benefit in early infection in lambs when ewes were treated with long acting compared to short acting anthelmintics. This provides further evidence to support the potential benefits of a more targeted approach to anthelmintic treatment on sheep farms. PMID- 29605005 TI - Comparison of infectivity and virulence of clones of Trypanosoma evansi and Ttrypanosoma equiperdum Venezuelan strains in mice. AB - Livestock trypanosomoses, caused by three species of the Trypanozoon subgenus, Trypanosoma brucei brucei, T. evansi and T. equiperdum are widely distributed and limit animal production throughout the world. The infectivity and virulence of clones derived from Trypanosoma evansi and Trypanosoma equiperdum Venezuelan strains were compared in an in vivo mouse model. Primary infectivity and virulence determinants such as survival rates, parasitemia levels, PCV, and changes in body weight and survival rates were monitored for up to 32 days. The T. equiperdum strain was the most virulent, with 100% mortality in mice, with the highest parasitemia levels (7.0 * 107 Tryps/ml) and loss of physical condition. The T. evansi strains induced 100% and 20% fatality in mice. Our results show that the homogeneous parasite populations maintain the virulent phenotype of the original T. equiperdum and T. evansi stocks. This is the first comparative study of infectivity and virulence determinants among clonal populations of T. equiperdum and T. evansi. PMID- 29605006 TI - Development of a multiplex quantitative PCR assay for eyeworm (Oxyspirura petrowi) and caecal worm (Aulonocephalus pennula) detection in Northern bobwhite quail (Colinus virginianus) of the Rolling Plains Ecoregion, Texas. AB - The Northern bobwhite quail (Colinus virginianus) is an economically significant gamebird that has experienced a decline throughout the Rolling Plains ecoregion of Texas. Recent surveys of this area have revealed a high prevalence in eyeworm (Oxyspirura petrowi) and caecal worm (Aulonocephalus pennula) infection that may contribute to this decline. In order to further understand these parasites role in bobwhite populations, a time-, and cost-effective multiplex quantitative PCR (qPCR) assay was developed in this study to detect eyeworm and caecal worm infection through egg detection using the ITS2 and COX1 gene region, respectively. Method validation for the qPCR involved bobwhite fecal samples from the Rolling Plains as well as samples spiked with eyeworm, caecal worm, and bobwhite DNA. Results showed an observed increasing qPCR parasite egg detection with increasing worm burdens. Future uses with this assay can also provide insight to seasonal parasite infection and the life cycles of eyeworm and caecal worm. PMID- 29605007 TI - How to improve the standardization and the diagnostic performance of the fecal egg count reduction test? AB - Although various studies have provided novel insights into how to best design, analyze and interpret a fecal egg count reduction test (FECRT), it is still not straightforward to provide guidance that allows improving both the standardization and the analytical performance of the FECRT across a variety of both animal and nematode species. For example, it has been suggested to recommend a minimum number of eggs to be counted under the microscope (not eggs per gram of feces), but we lack the evidence to recommend any number of eggs that would allow a reliable assessment of drug efficacy. Other aspects that need further research are the methodology of calculating uncertainty intervals (UIs; confidence intervals in case of frequentist methods and credible intervals in case of Bayesian methods) and the criteria of classifying drug efficacy into 'normal', 'suspected' and 'reduced'. The aim of this study is to provide complementary insights into the current knowledge, and to ultimately provide guidance in the development of new standardized guidelines for the FECRT. First, data were generated using a simulation in which the 'true' drug efficacy (TDE) was evaluated by the FECRT under varying scenarios of sample size, analytic sensitivity of the diagnostic technique, and level of both intensity and aggregation of egg excretion. Second, the obtained data were analyzed with the aim (i) to verify which classification criteria allow for reliable detection of reduced drug efficacy, (ii) to identify the UI methodology that yields the most reliable assessment of drug efficacy (coverage of TDE) and detection of reduced drug efficacy, and (iii) to determine the required sample size and number of eggs counted under the microscope that optimizes the detection of reduced efficacy. Our results confirm that the currently recommended criteria for classifying drug efficacy are the most appropriate. Additionally, the UI methodologies we tested varied in coverage and ability to detect reduced drug efficacy, thus a combination of UI methodologies is recommended to assess the uncertainty across all scenarios of drug efficacy estimates. Finally, based on our model estimates we were able to determine the required number of eggs to count for each sample size, enabling investigators to optimize the probability of correctly classifying a theoretical TDE while minimizing both financial and technical resources. PMID- 29605008 TI - Protective immunity against Eimeria maxima induced by vaccines of Em14-3-3 antigen. AB - Eimeria maxima 14-3-3 (Em14-3-3) open reading frame (ORF) which consisted of 861 bp encoding a protein of 286 amino acids was successfully amplified and sequenced. Subsequently, the Em14-3-3 ORF was subcloned into pET-32a (+) and pVAX1, respectively. RT-PCR and immunoblot analyses confirmed that the target gene was successfully transcribed and expressed in vivo. Immunofluorescence analysis showed that Em14-3-3 was expressed in both the sporozoites and merozoites. The animal experiments demonstrated that both rEm14-3-3 and pVAX1-14 3-3 could clearly alleviate jejunum lesions and body weight loss. The Em14-3-3 vaccines could increase oocyst decrease ratio, as well as produce an anticoccidial index of more than 165. The percentages of CD4+ in both the Em14-3 3 immunized groups were much higher, when compared with those of PBS, pET32a (+), and pVAX1 controls (P < 0.05). Similarly, the anti-Em14-3-3 antibody titers of both rEm14-3-3 and pVAX1-14-3-3 immunized groups showed higher levels compared with those of PBS, pET32a (+), and pVAX1 controls (P < 0.05). The IFN-gamma and tumor growth factor-beta (TGF-beta) levels showed significant increments in the rEm14-3-3 and pVAX1-14-3-3 immunized groups, when compared with those in the negative controls (P < 0.05). These results demonstrated that Em14-3-3 could be used as a promising antigen candidate for developing vaccines against E. maxima. PMID- 29605009 TI - Troglostrongylus brevior: a feline lungworm of paediatric concern. AB - The immature immune system of cats in their paediatric age (i.e., first six months of life) favours the establishment of infectious respiratory tract diseases mainly caused by well recognized viruses and bacteria species. Conversely, lungworm infections are less investigated during respiratory disorders in kittens. In the last decade, Troglostrongylus brevior has been found affecting the respiratory tract of cats, along with the better-known Aelurostrongylus abstrusus. Given the scant data available on the epidemiology of feline troglostrongylosis, faecal samples from 575 domestic animals living in three Italian municipalities (i.e., Bari, Messina and Siena) were screened for lungworm infection by Baermann and molecular tecniques. Animals were grouped according to their age as <=6 months (i.e., paediatric patients), 6-24 months, or >24 months. Paediatric cats were further sub-divided in infant (2-6 weeks), weanling (6-12 weeks) and juvenile (3-6 months). Of the 575 animals tested, 241 (42.0%) were younger than 6 months, 188 (33%) were 6-24-month-old and 146 (25%) were older than 24 months. Lungworm infection was diagnosed in 84 (14.6%) of the examined cats. Of the 49 (20.3%) paediatric animals positive for lungworms, T. brevior was the nematode species most frequently diagnosed (n = 44; 89.8%), followed by A. abstrusus (n = 2; 4.1%), and three cats (6.1%) were co-infected by both species. The diagnosis of T. brevior infection was significantly associated with animals aging <=6 months (18.2%; P < 0.01) than elder cats. Indeed, the prevalence of infection by T. brevior decreased in animals aging 6-24 months (3.2%) being not detected in cats older than two years. Results of this study indicate that paediatric cats are at higher risk of T. brevior infection compared to adults (P < 0.01). PMID- 29605010 TI - Awareness and control of canine leishmaniosis: A survey among Spanish and French veterinarians. AB - Zoonotic visceral leishmaniasis (ZVL) is a parasitic disease affecting dogs and humans, which is transmitted by female sandflies. Over the last decade, disease prevalence has increased fivefold in parts of southern Europe, where an estimated 2.5 million dogs are infected. This increase is mainly due to an expansion in sandfly distribution due to climate change and to the greater numbers of dogs travelling among European countries. To combat the spread of ZVL in Europe, international guidelines have been drawn up that describe strategies to prevent, control and monitor the disease. To investigate whether these strategies are being implemented in the field, we conducted an online survey among veterinarians in Spain (endemic for ZVL) and France (south: emerging; north: non-endemic). Of the 889 respondents, 459 veterinarians completed all questions. Although 60% of all veterinarians were aware of the current ZVL increase in Europe, 70% were not familiar with any guidelines for controlling the disease. Most of their preventive and treatment actions were, however, in line with intervention strategies recommended by the guidelines. From the veterinarians in this survey, 76% had received no reports regarding confirmed cases of canine leishmaniosis (CanL) or human visceral leishmaniasis in their region or country. The fact that 88% of confirmed cases of clinical CanL were not reported suggests inadequate disease monitoring and evaluation. We therefore recommend that an easy-to-use and accessible international online network be developed, where both veterinarians and physicians can report confirmed cases of leishmaniosis in dogs and humans. This is crucial for monitoring, controlling and preventing the further spread of ZVL in Europe at regional, national and international level. PMID- 29605011 TI - Tongue has higher larval burden of Trichinella spp. than diaphragm in wolverines (Gulo gulo). AB - Trichinella is an important zoonotic parasite found in a range of wildlife species harvested for food and fur in Canada. We compared larval intensity from tongue and diaphragm, the best predilection sites in other animal species, from naturally infected, wild wolverines (Gulo gulo) (n = 95). Muscle larvae of Trichinella spp. were recovered by the pepsin/HCl artificial digestion method (gold standard) using double separatory funnels, and species were identified using multiplex PCR. Prevalence was 83% (79/95). Of those positive for Trichinella spp. (n = 79), 76 (96.2%) were detected in both tissues, 2 (2.5%) were positive only on diaphragm, and 1 (1.3%) only on tongue. A total of 62 of 79 wolverines (78.5%) had higher larval burden in tongue than in diaphragm, whereas 17 wolverines (21.5%) had higher larval burden in diaphragm. The predilection site (higher larval burden) of Trichinella spp. larvae did not vary significantly between juvenile and adult wolverines (P = 0.2), between male and female wolverines (P = 0.9), and among wolverines classified as having low and high larval intensities overall (P = 0.2). Trichinella T6 was the predominant genotype (63 of 79; 80%), followed by T. nativa (T2) (6 of 79; 8%). Mixed infections of T2 and T6 were observed in 9 of 79 (12%) wolverines. Larval intensity of Trichinella T6 was higher in tongues than diaphragms. No statement can be made for T2 due to insufficient T2 positive samples. In conclusion, tongues are a better site for sampling than diaphragms in future surveys of Trichinella larval intensity in wolverines; however, either tissue is suitable for prevalence studies. PMID- 29605012 TI - Teaching Veterinary Parasitology in Portugal in the 21st century - Changes, challenges and opportunities after the Bologna process. AB - Veterinary education in Portugal began in 1830, but individualised teaching of parasitology started in 1911 at the Faculty of Veterinary Medicine, University of Lisbon (FMV-ULisboa). Parasitology and Parasitic Diseases were taught in the 3rd and 4th years of the veterinary course, respectively. In 2007/2008, a new curriculum was implemented as a consequence of the Bologna Process (BP), with Parasitology converted into "Parasitology I" (General Parasitology, Arthropods and Protozoology) and "Parasitology II" (Helminthology), being taught in the 1st and 2nd semesters of the 2nd year of the course, respectively. "Parasitic Diseases" became a one-semester subject in the 4th year. BP was intended to harmonise university courses, foster mobility and cooperation among European Universities, but instead there have been major challenges in reducing student contact and an erosion of Parasitology I and II as basic subjects, which were moved to 2nd year. In spite of these changes, the way subjects have been taught since then shows that veterinary students are satisfied with Parasitology; academic success ranges from 70% to 90%; the number of Master and PhD theses in Parasitology has increased; and students share their research results in classes and at conferences in our faculty and abroad. This shows how research and teaching of Veterinary Parasitology are tightly inter-linked and critical, presenting an opportunity to motivate future students to study Parasitology and Parasitic Diseases in such a challenging tertiary education environment in Portugal. PMID- 29605013 TI - Dofetilide dose reductions and discontinuations in women compared with men. AB - BACKGROUND: Compared with men, women have longer corrected QT (QTc) intervals, lower clearance of dofetilide, and higher rates of drug-induced torsades de pointes, but the dofetilide dosing algorithm is the same for men and women. OBJECTIVE: The purpose of this study was to evaluate the tolerability of the 500 MUg twice daily dose of dofetilide for men and women. METHODS: Men and women admitted to Duke University Medical Center (January 1, 2006, to October 19, 2012) for the initiation of dofetilide 500 MUg twice daily were matched 1:1 on age and estimated creatinine clearance. Electrocardiograms throughout dosing were analyzed, and rates of dofetilide discontinuations and dose reductions were compared in unadjusted and adjusted analyses. RESULTS: For 220 matched men and women, the median age was 62.5 years (interquartile range 55-69 years) and the median eCrCl was 98.1 mL/min (interquartile range 77.6-126.2 mL/min). Women were less likely than men to have hypertension and interventricular conduction delay but were otherwise similar. During dofetilide initiation, women were more likely than men to have their dofetilide dose discontinued or reduced (55% vs 32%; P < .001). In most women (82%) and men (69%), the reason for dose adjustment was significant QTc prolongation. In the adjusted analysis, female sex was associated with higher rates of dofetilide dose discontinuations or reductions (odds ratio 3.01; 95% confidence interval 1.58-5.71; P < .01). CONCLUSION: More than half of women who initiated on 500 MUg twice daily of dofetilide required medication discontinuations or dose reductions, mostly because of QTc prolongation. Additional studies are needed to evaluate the optimal dosing algorithm of dofetilide in women. PMID- 29605014 TI - Sex, drugs, and funky rhythms. PMID- 29605015 TI - Left atrial thrombus and dense spontaneous echocardiographic contrast in patients on continuous direct oral anticoagulant therapy undergoing catheter ablation of atrial fibrillation: Comparison of dabigatran, rivaroxaban, and apixaban. AB - BACKGROUND: Left atrial thrombus (LAT) and dense spontaneous echocardiographic contrast (SEC) detected by transesophageal echocardiography (TEE) in patients on continuous direct oral anticoagulants (DOAC) therapy before catheter ablation of atrial fibrillation (AF) or atrial flutter (AFL) have been described. OBJECTIVE: We sought to compare rates of TEE-detected LAT and dense SEC among patients taking different DOACs. METHODS: We evaluated 609 consecutive patients from 3 tertiary hospitals (median age 65 years; interquartile range 58-71 years; 436 (72%) men) who were on >=4 weeks of continuous DOAC therapy (dabigatran, n = 166 [27%]; rivaroxaban, n = 257 [42%]; or apixaban, n = 186 [31%]) undergoing TEE before catheter ablation of AF/AFL. Demographic, clinical, and TEE data were collected for each patient. RESULTS: Despite >=4 weeks of continuous DOAC therapy, 17 patients (2.8%) had LAT and 15 patients (2.5%) had dense SEC detected by TEE. The rates of LAT were 3.0%, 3.5%, and 1.6% for patients on dabigatran, rivaroxaban, and apixaban, respectively (P = .482). The rates of dense SEC were 1.2%, 3.5%, and 2.2% for patients on dabigatran, rivaroxaban, and apixaban, respectively (P = .299). Congestive heart failure (odds ratio 4.4; 95% confidence interval 1.6-12; P = .003) and moderate/severe left atrial enlargement (odds ratio 3.1; 95% confidence interval 1.1-8.6; P = .026) were independent predictors of LAT. CONCLUSION: In this study, ~3% of patients on continuous DOAC therapy had LAT detected before catheter ablation of AF/AFL. Specific DOAC therapy did not significantly affect the rates of LAT detection. PMID- 29605016 TI - Giant T-wave changes after termination of atrial fibrillation. PMID- 29605018 TI - Thrombin stimulates increased plasminogen activator inhibitor-1 release from liver compared to lung endothelium. AB - BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1) is a major regulator of the fibrinolytic system, covalently binding to tissue plasminogen activator and blocking its activity. Fibrinolysis shutdown is evident in the majority of severely injured patients in the first 24 h and is thought to be due to PAI-1. The source of this PAI-1 is thought to be predominantly endothelial cells, but there are known organ-specific differences, with higher levels thought to be in the liver. Thrombin generation is also elevated in injured patients and is a potent stimulus for PAI-1 release in human umbilical endothelial cells. We hypothesize that thrombin induces liver endothelial cells to release increased amounts of PAI-1, versus pulmonary endothelium, consisting of both stored PAI-1 and a larger contribution from de novo PAI-1 synthesis. METHODS: Human liver sinusoidal endothelial cells (LSECs) and human microvascular lung endothelial cells (HMVECs) were stimulated in vitro +/- thrombin (1 and 5 IU/mL) for 15-240 min, the supernatants were collected, and PAI-1 was measured by enzyme-linked immunosorbent assays. To elucidate the PAI-1 contribution from storage versus de novo synthesis, cycloheximide (10 MUg/mL) was added before thrombin in separate experiments. RESULTS: While both LSECs and HMVECs rapidly stimulated PAI-1 release, LSECs released more PAI-1 than HMVECs in response to high-dose thrombin, whereas low-dose thrombin did not provoke immediate release. LSECs continued to release PAI-1 over the ensuing 240 min, whereas HMVECs did not. Cycloheximide did not inhibit early PAI-1 release from LSECs but did at the later time points (30 240 min). CONCLUSIONS: Thrombin elicits increased amounts of PAI-1 release from liver endothelium compared with lung, with a small presynthesized stored contribution and a later, larger increase in PAI-1 release via de novo synthesis. This study suggests that the liver may be an important therapeutic target for inhibition of the hypercoagulable surgical patient and the associated complications that result. PMID- 29605019 TI - Severity classification of the quality of recovery-15 score-An observational study. AB - BACKGROUND: The quality of recovery-15 (QoR-15) is a patient-reported outcome measurement measuring QoR after surgery and anesthesia. The scale is arbitrary and ranges from 0 to 150. We aimed to classify the QoR-15 score into four severity classes; excellent, good, moderate, and poor recovery. MATERIALS AND METHODS: Data from one prospective observational cohort study and two randomized clinical trials were merged and comprised 276 adult patients with an American Society of Anesthesiologists class of I-III undergoing acute laparoscopic surgery for suspected appendicitis. Merged data were split into a "training" set and a "validation" set. Optimal cutoff points for classifying the QoR-15 into excellent, good, moderate, and poor recovery were identified in the "training" set. The four severity classes according to the QoR-15 score were validated in the "validation" set using prespecified hypotheses. RESULTS: The QoR-15 scores for excellent, good, moderate, and poor recovery were 136-150, 122-135, 90-121, and 0-89, respectively. A better severity class of recovery based on the QoR-15 score measured repeatedly six times over 30 d was associated with an increased chance of resuming recreational and occupational activities (P < 0.001). Patients with a better severity class of recovery on the first postoperative day had a lower incidence of postoperative complications within 30 d of surgery (P = 0.001). CONCLUSIONS: After surgery and anesthesia, patients can be classified as being in poor, moderate, good, or excellent recovery based on the QoR-15 score. PMID- 29605020 TI - Targeting intestinal epithelial cell-programmed necrosis alleviates tissue injury after intestinal ischemia/reperfusion in rats. AB - BACKGROUND: Intestinal dysfunction, especially acute pathologies linked to intestinal ischemia/reperfusion (I/R) injury, is profoundly affected by inflammation and improper execution of cell death. Few studies have examined the efficacy of combined strategies in regulated intestinal epithelial necrosis after intestinal I/R. Here, we evaluated the functional interaction between poly (adenosine diphosphate-ribose) polymerase 1 (PARP-1)-induced parthanatos and receptor-interacting protein 1/3 (RIP1/3) kinase-induced necroptosis in the pathophysiological course of acute ischemic intestinal injury. METHODS: Anesthetized adult male Sprague-Dawley rats were subjected to superior mesenteric artery occlusion consisting of 1.5 h of ischemia and 6 h of reperfusion. The PARP 1-specific inhibitor PJ34 (10 mg/kg) and the RIP1-specific inhibitor Necrostatin 1 (1 mg/kg) were intraperitoneally administered 30 min before the induction of ischemia. RESULTS: Intestinal I/R was found to result in PARP-1 activation and RIP1/3-mediated necrosome formation. PJ34 or Necrostatin-1 treatment significantly improved the mucosal injury, while the combined inhibition of PARP 1 and RIP1/3 conferred optimal protection of the intestine. Meanwhile, results from terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end labeling assay showed a decrease in intestinal epithelial cell death. Interestingly, we further showed that PARP-1 might act as a downstream signaling molecule of RIP1 in the process of I/R-induced intestinal injury and that the RIP1/PARP-1-dependent cell death signaling pathway functioned independently of caspase 3 inhibition. CONCLUSIONS: The results of our study provide a molecular basis for combination therapy that targets both pathways of regulated necrosis (parthanatos and necroptosis), to treat acute intestinal I/R induced intestinal epithelial barrier disruption. PMID- 29605021 TI - Diazoxide reduces local and remote organ damage in a rat model of intestinal ischemia reperfusion. AB - BACKGROUND: Intestinal ischemia reperfusion is a common clinical condition that causes functional impairment. Once tight junctions are damaged, barrier function is compromised, and the intestines become a source for entry of bacterial and inflammatory mediators into the circulation, leading to systemic inflammatory response syndrome, multiple organ failure, and death. It is possible that diazoxide could protect the intestines against ischemia reperfusion. The aim of this study is to determine whether diazoxide can provide protection in a rat model of intestinal ischemia reperfusion. METHODS: A total of 32 adult male specific pathogen-free Wistar rats were randomized into three groups: a control group, n = 6; a saline group, n = 13; and a diazoxide group, n = 13. The saline and diazoxide groups underwent clamping of the superior mesenteric artery for 1 h, with samples in all the groups being collected 12 h later. RESULTS: Intestinal histology showed greater damage in the intestinal ischemia reperfusion groups. mRNA expression of zonula occludens-1 and occludin (tight junction proteins) and interleukin-6 and cyclooxygenase-2 was the highest in the Saline group. The Diazoxide group showed a reduction in aspartate aminotransferase serum levels compared with the other groups. CONCLUSIONS: Increased expression of zonula occludens-1, occludin, and cyclooxygenase-2 suggested a greater regenerative effort because of more severe lesions in the saline group. In addition, increased expression of interleukin-6 in the saline group was suggestive of inflammation, indicating that diazoxide had protective effects in the diazoxide group. Reduced aspartate aminotransferase in the diazoxide group suggested liver protection. Diazoxide protects the intestines and liver from intestinal ischemia reperfusion lesions in rats. PMID- 29605022 TI - Posttransplant complications in adult recipients of intestine grafts without bowel decontamination. AB - BACKGROUND: Selective digestive decontamination is commonly used to decrease lumenal bacterial flora. Preoperative bowel decontamination may be associated with a lower wound infection rate but has not been shown to decrease risk of intra-abdominal abscess or lower leak rate for enteric anastomoses. Alternatively, the decontamination disrupts the normal flora of the gastrointestinal tract and may affect normal physiology, including immunologic function. This study reports complication rates of an intestine transplant program that has never used bowel decontamination. METHODS: All adult patients who underwent intestine transplant from 2003 to 2015 at a single center were reviewed. Posttransplant complications included intra-abdominal abscess, enteric fistula, and leak from the enteric anastomosis. Viral, fungal, and bacterial infections in the first year after transplant are reported. RESULTS: There were 184 adult patients who underwent deceased donor intestine transplant during the study period. Among these patients, 30% developed an infected postoperative fluid collection, 4 developed an enteric fistula (2%), and 16 had an enteric or anastomotic leak (8%). The rate of any bacterial infection was 91% in the first year, with a wound infection rate of 25%. Fungal infection occurred in 47% of patients. Rejection rates were 55% at 1 y for isolated intestine patients and 17% for multivisceral (liver inclusive) patients. CONCLUSIONS: Among this population of intestine transplant patients in which no bowel decontamination was used, rates of surgical complications, infections, and rejection were similar to those reported by other centers. Bowel decontamination provides no identifiable benefit in intestine transplantation. PMID- 29605023 TI - A subgroup analysis of penetrating injuries to the pancreas: 777 patients from the National Trauma Data Bank, 2010-2014. AB - BACKGROUND: This study is the first to analyze penetrating injuries to the pancreas within subgroups of severe traumatic brain injury (TBI), early deaths, and potential survivors. Our objectives were to identify national patterns of injury, predictors of mortality, and to validate the American Association for Surgery of Trauma Organ Injury Scale (AAST-OIS) pancreas injury grades by mortality. Secondary outcomes included hospital and intensive care unit length of stay and days on mechanical ventilation. METHODS: Using the Abbreviated Injury Scale 2005 and ICD-9-CM E-codes, we identified 777 penetrating pancreatic trauma patients from the National Trauma Data Bank that occurred between 2010 and 2014. Severe TBI was identified by ICD-9-CM diagnosis codes and Glasgow Coma Score (GCS; n = 7), early deaths were those that occurred within 24 h of admission (n = 82), and potential survivors included patients without severe TBI who survived longer than 24 h following admission (n = 690). We estimated multivariable generalized linear mixed models to predict mortality to account for the nesting of potential survivors within trauma centers. RESULTS: Our results indicated that overall mortality decreased from 16.9% to 6.8% after excluding severe TBI and early deaths. Approximately, 11% of patients died within 24 h of admission, of whom 78% died in the first 6 h. Associated injuries to the stomach, liver, and major vasculature occurred in approximately 50% of patients; rates of associated injuries were highest in patients who died within 6 h of admission. In potential survivors, mortality increased by AAST-OIS grade: 3.5% I/II; 8.3% III; 9.6% IV; and 13.8% V. Predictors of mortality with significantly increased odds of death were patients with increasing age, lower admission GCS, higher admission pulse rate, and more severe injuries as indicated by Organ Injury Scale grade. CONCLUSIONS: From 777 patients, we identified national patterns of injury, predictors of outcome, and mortality by AAST-OIS grade within the subgroups of severe TBI, early deaths, and potential survivors. Because AAST-OIS is not a reported element in the National Trauma Data Bank, we correlated Abbreviated Injury Scale 2005 codes to injury grade and identified an increase in mortality. After controlling for covariance, we found that greater age, lower GCS in stab wounds, higher pulse, and presence of a grade V pancreatic injury independently predicted the likelihood of death in patients surviving beyond 24 h following penetrating injuries to the pancreas. PMID- 29605024 TI - Benchmarking rectal cancer care: institutional compliance with a longitudinal checklist. AB - BACKGROUND: In 2012, the American Society of Colon and Rectal Surgeons published the Rectal Cancer Surgery Checklist, a consensus document listing 25 essential elements of care for all patients undergoing radical surgery for rectal cancer. The authors herein examine checklist adherence in a mature, multisurgeon specialty academic practice. MATERIALS AND METHODS: A retrospective medical record review of patients undergoing elective radical resection for rectal adenocarcinoma over a 23-mo period was conducted. Checklists were completed post hoc for each patient, and these results were tabulated to determine levels of compliance. Subgroup analyses by compliance and experience levels of the treating surgeon were performed. RESULTS: A total of 161 patients underwent resection, demonstrating a median completion rate of 84% per patient. Poor compliance was noted consistently in documenting baseline sexual function (0%), multidisciplinary discussion of treatment plans (16.8%), pelvic nerve identification (8.7%) and leak testing (52.9%), and radial margin status reporting (57.5%). Junior surgeons achieved higher rates of compliance and were more likely to restage after neoadjuvant therapy (67.9% versus 29.4%, P < 0.001), discuss patients at tumor board (31.3% versus 13.2%, P = 0.014), and document leak testing (86.7% versus 47.2%, P = 0.005) compared with senior surgeons. CONCLUSIONS: Checklist compliance within a high-volume, specialty academic practice remains varied. Only surgeon experience level was significantly associated with high checklist compliance. Junior surgeons achieved greater compliance with certain items, particularly those that reinforce decision-making. Further efforts to standardize rectal cancer care should focus on checklist implementation, targeted surgeon outreach, and assessment of checklist compliance correlation to clinical outcomes. PMID- 29605025 TI - Fewer thromboembolic events after implementation of a venous thromboembolism risk stratification tool. AB - BACKGROUND: Deep venous thrombosis and pulmonary embolus are leading preventable causes of death after surgery. Venous thromboembolism (VTE) prophylaxis management guidelines, with evidenced-based recommendations, are available in the literature. However, over 40% of "at-risk" surgical patients fail to receive appropriate VTE prophylaxis. Decision support-based interventions to reduce venous thromboembolic events were explored. METHODS: A venous thromboembolic risk stratification tool embedded in the electronic medical record, Epic, linking risk category to venous thromboembolic prophylaxis order sets was created, implemented, and analyzed for general surgery patients. Logistic regression analysis was used to compare rates of venous thromboembolic events before and after the intervention, controlling for age, gender, race, body mass index, inpatient status, transfer status, elective/emergent case status, American Society of Anesthesiologists classification, and wound classification. RESULTS: Venous thromboembolic events in the preintervention and postintervention periods were 55 (1.25%) and 12 (0.64%), respectively (P = 0.033). All-cause mortality events decreased after intervention from 49 (1.12%) to 14 (0.75%; P = 0.187). Multivariable analyses show that the risk of a venous thromboembolic event after intervention was half (odds ratio = 0.532; 95% confidence interval, 0.284-0.997; P = 0.049) as likely compared to that in the preintervention period. From 2012 to 2015, our institution moved from the ninth decile (poor) to the first decile (best) for the incidence of venous thromboembolic events among 760 National Surgical Quality Improvement Program hospitals across the nation. CONCLUSIONS: Postoperative thromboembolic events decreased after implementation of a VTE risk stratification tool, linking risk category to venous thromboembolic prophylaxis order sets, embedded in the electronic medical record, Epic. PMID- 29605026 TI - Visceral adiposity but not subcutaneous fat associated with improved outcome of patients with acute cholecystitis. AB - BACKGROUND: The aim of this study to study the effect of visceral and subcutaneous fat tissue mass on short- and long-term prognosis of patients with acute calculus cholecystitis (ACC). METHODS: Retrospective analysis of medical records. Included were all patients admitted because of ACC. Computed tomography images at the level of L3 were analyzed for body composition using designated software (Slice-O-matic; TomoVision, Montreal, Quebec, Canada). General linear model was used to analyze the effect of body composition on length of hospital stay, and Cox regression analysis was used to ascertain the effect of the different parameters on 1-y survival. RESULTS: Included were 159 patients (mean age: 71.7 +/- 15.8 y, 54.7% males). Fat was the most abundant tissue (401 +/- 175 cm2 of the computed tomography slices surface area), and visceral fat was 45.8 +/ 14.1% of the fat area measured. Using the general linear model, we found that American Society of Anesthesiologists score, disease severity index, and age were positively associated with higher length of stay, whereas high visceral fat was associated with lower length of stay (estimated marginal means at 7.4 +/- 1.4 d compared to 12.7 +/- 1.4 d among patients with lower visceral fat surface area, P = 0.010). The Cox regression model showed that 1-y survival risk was significantly reduced by age, the Charlson Comorbidity Index and high muscle mass. High visceral adiposity was associated with improved survival (odds ratio: 0.216, 95% confidence interval: 0.064-0.724, P = 0.013). Subcutaneous adiposity did not affect prognosis. CONCLUSIONS: Visceral adiposity is associated with shorter length of stay and improved 1-y survival among patients hospitalized with ACC. PMID- 29605027 TI - Determining the educational value of a technical and nontechnical skills medical student curriculum. AB - BACKGROUND: Residency application rates to general surgery remain low. The purpose of this study is to describe the educational value of a curriculum designed to increase preclinical medical student interest in surgical careers to better understand the process by which medical students decide to pursue a career in surgery. MATERIALS AND METHODS: We used qualitative methodology to describe the educational value of a technical and nontechnical skills curriculum offered to preclinical medical students at our institution. We conducted semistructured interviews of students and instructors who completed the curriculum in 2016. The interviews were recorded, transcribed, and inductively coded. The data were analyzed for emergent themes. RESULTS: A total of eight students and five instructors were interviewed. After analysis of 13 transcripts, four themes emerged: (1) The course provides a safe environment for learning, (2) acquisition and synthesis of basic technical skills increases preclinical student comfort in the operating room, (3) developing relationships with surgeons creates opportunities for extracurricular learning and scholarship, and (4) operative experiences can inspire students to explore a future career in surgery. CONCLUSIONS: These factors can help inform the design of future interventions to increase student interest, with the ultimate goal of increasing the number of students who apply to surgical residency programs. PMID- 29605028 TI - Pyruvate as a novel carrier of hydroxyethyl starch 130/0.4 may protect kidney in rats subjected to severe burns. AB - BACKGROUND: The carrier of hydroxyethyl starch (HES) may play a critical role in kidney injury in fluid resuscitation. This study aimed mainly to compare effects of pyruvate-enriched saline with normal saline (NS) and acetate Ringer's (AR) solution as a carrier in HES130/0.4 on kidney function in rats subjected to severe burns. METHODS: Using a lethal burn model, 140 rats were randomly allocated in seven groups (n = 20): sham group (group S); no fluid after burn (group N); burn resuscitated with NS (group NS); burn resuscitated with pyruvate saline (group PS); burn resuscitated with AR plus pyruvate-HES (group SP); burn resuscitated with AR plus acetate-HES (group SA), and burn resuscitated with AR plus NS-HES (group SN). A low volume (18.75 mL.kg-1 during 12 h) of HES130/0.4 was infused with the ratio of 1:1 to crystalloids. Renal surface blood flow, blood creatinine and blood urea nitrogen, early sensitive indicators of kidney function: alpha-1 microglobulin, cystatin-C, and neutrophil gelatinase-associated lipocalin in blood and urine, and kidney tissue water contents were determined. Renal histopathological alterations with Paller scores were also measured at 8 h and 24 h after burn (n = 10), respectively. RESULTS: The results showed in a comparable manner that group SP was the best in three HES groups and group PS was superior to group NS in renal preservation; group SP appeared significantly beneficial compared with group PS in renal surface blood flow, cystatin-C, neutrophil gelatinase-associated lipocalin, water contents, and Paller scores at 8-h or both time points after burn, respectively (all P < 0.05). CONCLUSIONS: The carrier of HES130/0.4 played a crucial role in kidney injury in fluid resuscitation of rats subjected to severe burns. Pyruvate-enriched HES130/0.4 was superior and HES130/0.4, per se, might be not renocytotoxic, but renoprotective. Further studies are warranted. PMID- 29605029 TI - Prediction of pathological response to neoadjuvant chemotherapy in breast cancer patients by imaging. AB - BACKGROUND: Diagnostic imaging is important for predicting the pathological response to chemotherapy during neoadjuvant chemotherapy (NAC) and for considering the surgical management with appropriate resection after NAC. This study was performed to examine the accuracy of the present radiological imaging for predicting the pathological complete response (pCR). METHODS: From 188 patients in our previous JONIE1 Study, a randomized controlled trial comparing chemotherapy with and without zoledronic acid for patients with human epidermal growth factor receptor 2-negative breast cancer, we evaluated 122 patients whose tumor size was examined by magnetic resonance imaging or ultrasound at three points: before NAC; after administering fluorouracil, epirubicin, and cyclophosphamide; and after NAC. The maximum tumor diameter was evaluated by magnetic resonance imaging or ultrasound. Tumor reduction ratios were calculated at the same three points. The association between the radiological clinical response and the pCR was examined. RESULTS: Among the 122 patients evaluated, there were 98 and 24 patients with luminal (Lum) and triple-negative (TN) subtypes, respectively. There were no patients who showed tumor progression after treatment. The radiological size of the tumors was finally reduced by an average of 58.4%. Clinical complete response and pCR were achieved in 22 (18.0%) and 15 (12.3%) patients, respectively. In the overall population (n = 122), the accuracy, sensitivity, and specificity for predicting pCR were 86.1%, 88.8%, and 66.7%, respectively. The negative predictive value and false-negative rate were 45.5% and 11.2%, respectively. According to subtypes, the accuracies were 83.7% and 95.8% in Lum and TN, respectively. Negative predictive value and false negative rate were markedly different between the Lum (29.4% and 13.5%) and TN subtypes (100% and 0%), respectively. CONCLUSIONS: This randomized clinical trial demonstrated that NAC was safe for operable breast cancer patients with appropriate radiological monitoring. Radiological evaluation after NAC may be a reliable method for predicting pathological response in the TN subtype, but not in the Lum subtype. PMID- 29605030 TI - Effect of hypertonic saline in the pretreatment of lung donors with hemorrhagic shock. AB - BACKGROUND: Hemorrhagic shock-induced lung edema and inflammation are two of the main reasons for the rejection of lungs donated for transplantation. Hypertonic saline (HS) induces intravascular volume expansion and has considerable immunomodulating effects that might minimize edema. Our hypothesis is based on the use of a hypertonic solution for treatment of donors who are in shock in an attempt to increase the supply of lungs for transplantation. METHODS: A total of 80 rats were allocated to four groups: one group was given an infusion of normal saline (NS; n = 20), one group received HS; n = 20, a sham group (n = 20), and a Shock group (n = 20). Half of the lungs from each group were evaluated in an ex vivo perfusion system, and the other half was used for measurements of cytokine levels and neutrophil counts. RESULTS: In the ex vivo perfusion assessment, the pulmonary artery pressures of the animals in the NS and HS groups did not exhibit significant differences compared with those in the sham group (P > 0.05) but were lower than those in the Shock group (P < 0.01). Furthermore, the tumor necrosis factor-alpha levels and neutrophil counts were lower in the HS group than those in the Shock group (P < 0.01) and did not exhibit significant differences compared with those in either the NS and Sham groups (P > 0.05). CONCLUSIONS: We showed that HS was equivalent to isotonic saline and contributed to the treatment of lungs subjected to hemorrhagic shock. PMID- 29605031 TI - Endovascular creation and validation of acute in vivo animal model for type A aortic dissection. AB - BACKGROUND: Animal modeling is a prerequisite for clinical transfer of new therapies. This study targets an acute in vivo animal model of type A dissection using endovascular approach with a view to test future stent grafts dedicated to this aortic segment. METHODS: Experiments were conducted on 13 swine. Two arterial accesses, femoral and percutaneous transapical, were required. Entry tear was created by endovascular instrumental means inserted through transapical access with either Outback catheter (group 1, n = 3) or EchoTip Endoscopic Ultrasound Needle (group 2, n = 10). Afterward, dissection extension was obtained in antegrade direction by looped guidewire technique, and, as often as possible, re-entry tear was created with either looped guidewire or Outback catheter. Finally, entry tear, dissected space, and re-entry tear when existing were dilated with 8-mm balloon. In our acute model, animals were euthanized at the end of the experiment day, and aortas were explanted for macroscopic and histologic examination. RESULTS: The model was successfully created in 10 out of 13 animals. In group 1, dissection was limited to arch with 23 mm average length and no possibility of achieving re-entry tear. One aortic perforation was observed. In group 2, dissection was extended up to descending thoracic or thoracoabdominal aorta, with 110 mm average length (range 40-165 mm), and re-entry tear was created in seven cases. Histologic examination confirmed the presence of intimo medial flap. CONCLUSIONS: The present experiment validates a new type A dissection animal model, which morphologically reproduces human aortic dissection features. As such, it provides an advantageous basis for testing future stent grafts. PMID- 29605032 TI - GYY4137 protects against myocardial ischemia/reperfusion injury via activation of the PHLPP-1/Akt/Nrf2 signaling pathway in diabetic mice. AB - BACKGROUND: This study explores the protective effects of a hydrogen sulfide donor, morpholin-4-ium 4-methoxyphenyl-morpholino-phosphinodithioate (GYY4137), in the hearts of diabetic mice that had been subjected to myocardial ischemia/reperfusion injury. Diabetes impairs the Akt pathway, in which the Akt protein is dephosphorylated and inactivated by PH domain leucine-rich repeat protein phosphatase-1 (PHLPP-1). However, the function of PHLPP-1 and molecular mechanism that underlies the cardiac protection exerted by GYY4137 remains unknown. METHODS: Diabetic or nondiabetic mice were subjected to 45 min of coronary artery occlusion followed by 2 h of reperfusion. H9c2 cells were cultured with normal or high glucose and then subjected to 3 h of hypoxia followed by 6 h of reoxygenation. Pretreatment with GYY4137 was performed in a randomized manner before ischemia/reperfusion or hypoxia/reoxygenation. The infarct size, cardiomyocyte apoptosis, and oxidative stress were measured. Western blotting was conducted to elucidate the protective mechanism. RESULTS: Diabetic mice or H9c2 cells exposed to high glucose displayed a larger infarct size, more severe cardiomyocyte apoptosis, lower cell viability, and increased oxidative stress, which were associated with increased levels of PHLPP-1 and reduced levels of p-Akt and nuclear factor-erythroid-2-related factor 2 (Nrf2) protein expression. These changes were prevented/reversed by GYYG4137 pretreatment. At the cellular level, PHLPP-1 siRNA attenuated cellular injury, and this was associated with increased p-Akt and nuclear Nrf2 protein, whereas the decrement of Akt phosphorylation induced by LY294002 augmented cellular injury and decreased nuclear Nrf2. CONCLUSIONS: GYY4137 activates the PHLPP 1/Akt/Nrf2 pathway to protect against diabetic myocardial ischemia/reperfusion injury. PMID- 29605033 TI - Relationship between duration of preoperative symptoms and postoperative ileus for small bowel obstruction. AB - BACKGROUND: Factors associated with postoperative ileus and increased resource utilization for patients who undergo operative intervention for small-bowel obstruction are not extensively studied. We evaluated the association between total duration of preoperative symptoms and postoperative outcomes in this population. MATERIALS AND METHODS: We performed a retrospective review of patients who underwent surgery for small-bowel obstruction (2013-2016). Clinical data were recorded. Total duration of preoperative symptoms included all symptoms before operation, including those before presentation. Primary endpoint was time to tolerance of diet. Secondary endpoints included length of stay, total parenteral nutrition use, and intensive care unit admission. Association between variables and outcomes was analyzed using univariable analysis, multivariable Poisson modeling, and t-test to compare groups. RESULTS: Sixty-seven patients were included. On presentation, the median duration of symptoms before hospitalization was 2 d (range 0-18 d). Total duration of preoperative symptoms was associated with time to tolerance of diet on univariable analysis (Pearson's moment correlation: 0.28, 95% confidence interval: 0.028-0.5, P = 0.03). On multivariable analysis, ascites was correlated with time to tolerance of diet (P < 0.01), but total duration of preoperative symptoms (P = 0.07) was not. Length of stay (Pearson's correlation: 0.24, 95% confidence interval: -0.02 to 0.47, P = 0.07) was not statistically different in patients with longer preoperative symptoms. Symptom duration was not statistically associated with intensive care unit (P = 0.18) or total parenteral nutrition (P = 0.3) utilization. CONCLUSIONS: Our findings demonstrate that preoperative ascites correlated with increased time to tolerance of diet, and duration of preoperative symptoms may be related to postoperative ileus. PMID- 29605034 TI - Impact of aortic root annuloplasty on 3D aortic root geometry. AB - BACKGROUND: The aim was to evaluate the impact of aortic root (AoR) annuloplasty on 3D AoR deformation. METHODS: In experimental setup, Yacoub procedure and Yacoub with annuloplasty were performed. Results were compared to native AoR. In each AoR modality, six microsonometric (2 mm, 200 Hz) crystals were implanted at the sinotubular junction (STJ) and at the AoR base (AoB). 3D deformation of the AoR was determined by AoR tilt (alpha) and rotation (beta) angle changes. RESULTS: Tilt angle in Yacoub AoR with annuloplasty and in Yacoub AoR was maximal at ejection, 26.71 +/- 0.18 degrees and 24.91 +/- 0.13 degrees , respectively, and minimal at diastole, 25.34 +/- 0.15 degrees and 21.90 +/- 0.15 degrees , respectively. Rotation angle in Yacoub AoR with and without annuloplasty was maximal at ejection, 27.04 +/- 0.25 degrees and 23.53 +/- 0.54 degrees , respectively, and minimal at diastole, 24.84 +/- 0.14 degrees and 21.62 +/- 0.16 degrees , respectively. In native AoR, tilt angle and rotation were minimal at ejection, 14.34 +/- 0.81 degrees and 18.1 +/- 3.20 degrees , respectively, and maximal at diastole, 18.78 +/- 0.84 degrees and 21.23 +/- 021 degrees , respectively. AoB and STJ had maximal expansion at ejection; 2.59 +/- 2.40% and 6.05 +/- 0.66 for Yacoub and 3.75 +/- 0.66% and 3.08 +/- 0.24% for Yacoub with annuloplasty. In native AoR, the expansion at ejection for AoB was 7.13 +/- 2.68% and for STJ was 16.42 +/- 0.63%. CONCLUSIONS: AoB annuloplasty reduces AoB deformation and has an impact on STJ dynamics. In both the Yacoub AoR modalities, during ejection, the AoR takes on more of a cone-like geometry, whereas in native AoR, it is of a cylinder-like shape. PMID- 29605035 TI - The efficacy of chemotherapy and operation in patients with colorectal neuroendocrine carcinoma. AB - BACKGROUND: Colorectal neuroendocrine carcinoma (CRNEC) is a rare type of malignancy and is quite aggressive with dismal prognosis. Neither large-scale retrospective studies nor prospective studies have been performed to evaluate the prognostic value of adjuvant chemotherapy in patients with CRNEC. METHODS: Using the Surveillance, Epidemiology, and End Results-Medicare database, 318 elderly patients who were diagnosed with high-grade colorectal neuroendocrine tumors were included. The survival benefit was evaluated using a Cox proportional hazards model and propensity score-matched techniques. RESULTS: Among patients with stage I-III CRNEC, there was also no significant difference in cancer-specific survival (CSS) (P = 0.898) or overall survival (OS) (P = 0.539) between the 5-fluorouracil (5-FU) and the no chemotherapy groups. Meanwhile, the etoposide + platinum (EP) regimen showed no improved survival in patients with stage I-III CRNEC compared with the no chemotherapy group. For stage IV CRNEC, there was no significant difference between operation group and no operation group in CSS (P = 0.317) or OS (P = 0.385). Both 5-FU and EP regimens improved the CSS (for 5-FU, hazard ratio [HR] = 0.257, 95% confidence interval [CI] = 0.134-0.491, P < 0.001; for EP, HR = 0.348, 95% CI = 0.192-0.631, P = 0.001) and OS (for 5-FU, HR = 0.274, 95% CI = 0.149-0.502, P < 0.001; for EP, HR = 0.345, 95% CI = 0.194-0.612, P < 0.001) of patients in stage IV CRNEC. CONCLUSIONS: Our findings demonstrated that neither the 5-FU based nor EP chemotherapy regimens improved the CSS or OS for patients with stage I-III CRNEC. And for stage IV CRNEC, chemotherapy is an independent prognostic factor for CSS and OS, while operation could not improve the CSS or OS for patients with stage IV CRNEC. PMID- 29605036 TI - Ketamine versus hydromorphone patient-controlled analgesia for acute pain in trauma patients. AB - BACKGROUND: It is unknown whether ketamine administered via patient-controlled analgesia (PCA) provides adequate analgesia while reducing opioid consumption in the traumatically injured patient. Differences in opioid consumption, pain scores, and adverse effects between ketamine and hydromorphone PCA were studied. MATERIALS AND METHODS: This is an investigator-initiated, single-center, double blinded, randomized, pilot trial conducted from 2014 to 2016 at a level 1 trauma center. Nonintubated trauma patients in intensive care, who were receiving PCA, were randomized to ketamine or hydromorphone PCA plus opioid analgesics for breakthrough pain. RESULTS: Twenty subjects were randomized. There was no difference in median daily breakthrough opioid use (10 [0.63-19.38] mg versus 10 [4.38-22.5] mg, P = 0.55). Subjects in the ketamine group had lower median cumulative opioid use on therapy day 1 than the hydromorphone group (4.6 [2.5-15] mg versus 41.8 [31.8-50] mg, P < 0.001), as well as in the first 48 h (10 [3.3 15] mg versus 48.5 [32.1-67.5] mg, P < 0.001) and first 72 h (10 [4.2-15] mg versus 42.5 [31.7-65.2] mg, P < 0.001) of therapy. Daily oxygen supplementation requirements were lower in the ketamine group (0.5 [0-1.5] L/min versus 2 [0.5-3] L/min, P = 0.020). Hallucinations occurred more frequently in the ketamine group (40% versus 0%, P = 0.090). CONCLUSIONS: Ketamine PCA led to lower cumulative opioid consumption and lower oxygen supplementation requirements, though hallucinations occurred more frequently with use of ketamine. Additional studies are needed to investigate the tolerability of ketamine as an alternative to traditional opioid-based PCA. PMID- 29605037 TI - Age- and gender-related hemorheological alterations in intestinal ischemia reperfusion in the rat. AB - BACKGROUND: Intestinal ischemia-reperfusion (I/R) is a life-threatening clinical disorder. During I/R, the microrheological parameters of blood (red blood cell deformability and aggregation) worsen, which may contribute to microcirculatory deterioration. Age and gender also have a great influence on hemorheological parameters. We aimed to investigate the gender and age-related microrheological alterations during intestinal I/R. MATERIALS AND METHODS: After the cannulation of the left femoral artery, median laparotomy was performed in Crl:WI rats under general anesthesia. In the young control animals there were no other interventions (female n = 7; male n = 7). In the young (female n = 7; male n = 7) and older I/R groups (female n = 6; male n = 6), the superior mesenteric artery was clipped for 30 min, and a 120-min reperfusion period was observed afterward. Blood samples were taken before and at the 30-min ischemia, in the 30th, 60th, and 120th min of the reperfusion. Hematological parameters, erythrocyte deformability, and aggregation were determined. RESULTS: Hematocrit increased significantly in the younger female I/R group. Red blood cell count was higher in male and older animals. In case of white blood cell count, male animals had higher values compared with females. Platelet count elevated in the younger male and older female I/R animals. Red blood cell deformability worsened, mainly in the male and older I/R groups. Enhanced erythrocyte aggregation was seen in all groups, being more expressed in the female I/R groups. CONCLUSIONS: Microrheological parameters show gender and age-related differences during intestinal I/R. These observations have importance in the planning and evaluation of experimental data. PMID- 29605038 TI - Biliary reconstruction with a pedicled gallbladder flap in patients during pancreaticoduodenectomy. AB - BACKGROUND: Stricture formation at the biliary-enteric anastomosis can cause serious complications after pancreaticoduodenectomy while the anastomotic size is reported to significantly affect stricture formation. In this study, we aimed to determine the effect of a pedicled gallbladder flap used as an alternative to biliary reconstruction during pancreaticoduodenectomy in patients with a nondilated extrahepatic bile duct. METHODS: Data of patients with a nondilated extrahepatic bile duct, who underwent pancreaticoduodenectomy between October 2012 and July 2015 at the Department of Hepatobiliary and Pancreaticosplenic Surgery at Beijing Chaoyang Hospital, were collected. A pedicled gallbladder flap for biliary reconstruction was consecutively performed in patients with morphologically normal gallbladder, whereas patients with abnormal gallbladder morphology accept conventional biliary reconstruction. RESULTS: A total of 29 patients were enrolled in this study with 17 patients using a pedicled gallbladder flap and 12 patients using the conventional technique. Patients of the two groups had similar preoperative and operative parameters as well as similar early complication rates. No patients in the former group experienced biliary stricture or transient episodes of cholangitis over the follow-up period. While in the latter group, one patient had biliary stricture in the 14th month which was cured by intervene treatment. Another two patients had intermittently mild-to-moderate elevations in liver enzymes level from the 11th month and the 18th month, respectively, and were treated with medication. CONCLUSIONS: Biliary reconstruction with a pedicled gallbladder graft can be used as an alternative in patients with a nondilated extrahepatic bile duct during pancreaticoduodenectomy. PMID- 29605039 TI - Activation of mammalian target of rapamycin induces lipid accumulation in the diaphragm of ventilated rats and hypoxia-treated C2C12 cells. AB - BACKGROUND: Our previous study demonstrated that ventilators increase diaphragmatic lipid accumulation in rabbits, but their cellular mechanism is poorly understood. Mammalian target of rapamycin (mTOR) plays an important role in atherosclerosis in rat vascular smooth muscle cells. The present study investigated the role of mTOR pathway activation in the diaphragmatic muscle of ventilated rats and hypoxia-induced C2C12 cells. MATERIALS AND METHODS: Male Sprague-Dawly rats were randomized into a control group (n = 8), controlled mechanical ventilation (CMV) group (n = 8), and CMV + Rapa group (n = 8). We evaluated the diaphragmatic contractility, lipid accumulation, and protein expression of the mTOR pathways. To explore the mechanism underlying ventilator induced lipid accumulation, we observed protein expression of the mTOR and low density lipoprotein receptor (LDLr) pathways in C2C12 cells under hypoxic and mTOR pathway inhibitor treatments. RESULTS: Compared with the control group, there was a significant decrease in the peak twitch and peak tetanic forces in the CMV group (384.24 +/- 70.39 versus 496.33 +/- 78.64 g/cm2, P < 0.05, and 869.24 +/- 76.67 versus 1090.72 +/- 118.91 g/cm2, P < 0.05, respectively). There was a significant increase in peak twitch and peak tetanic forces in the CMV + Rapa group compared with that in the CMV group (501.81 +/- 23.15 versus 384.24 +/ 70.39 g/cm2, P < 0.05, and 992.91 +/- 88.99 versus 869.24 +/- 76.67 g/cm2, P < 0.05, respectively). In the CMV group, there were significant increases in lipid accumulation (0.086 +/- 0.009 versus 0.005 +/- 0.002, P < 0.05) and expression of mTOR in diaphragmatic fibers compared with those in the control group (P < 0.05). Rapamycin prevented lipid accumulation in rats of the CMV + Rapa group compared with that in the CMV group rats (0.024 +/- 0.004 versus 0.086 +/- 0.009, P < 0.05). Compared with the CMV group, there was a significant decrease in the phosphorylated protein expression levels of mTOR in rats of the CMV + Rapa group (P < 0.05). Hypoxic conditions activated the mTOR and LDLr pathways in C2C12 cells, which were correlated with an increase in expression of the mTOR and LDLr pathways compared with the control group (P < 0.05). In C2C12 cells treated with hypoxia + rapamycin, activation of the mTOR and LDLr pathways was blocked compared with C2C12 cells treated with hypoxia (P < 0.05). CONCLUSIONS: These data suggest that CMV and hypoxia-induced activation of the mTOR pathway, resulting in lipid accumulation, and impaired the diaphragmatic contractile function. Therefore, pharmacologic agents that inhibit the mTOR pathway could potentially be useful for mitigating the diaphragmatic contractile dysfunction induced by mechanical ventilation. PMID- 29605040 TI - Outcomes of interval appendectomy in comparison with appendectomy for acute appendicitis. AB - BACKGROUND: Traditionally, patients treated conservatively for periappendiceal abscess or phlegmon would subsequently undergo interval appendectomy (IA); however, recent evidence has shed doubt on the necessity of this procedure. This study aimed to assess the outcomes of patients who underwent IA, in comparison with those operated acutely for appendicitis. MATERIALS AND METHODS: A retrospective analysis identified patients who underwent IA between 2000 and 2016. Their course and outcomes were compared with those of our previously published cohort of patients who underwent appendectomy for acute appendicitis. RESULTS: During the study period, 106 patients underwent IA. Their mean age was 39.7 +/- 16.2 y, and 60.4% were females. In their index admission, 75.5% presented with abscesses. IA was performed successfully in all patients, and no patient required colectomy. Pathology demonstrated neoplastic lesions in 6/106, but only one was malignant. IA patients were compared with a cohort of 1649 acute appendectomy patients. This group was significantly younger (33.7 +/- 13.3 y). Operation time was comparable between the groups (46.0 +/- 26.2 versus 42.7 +/- 20.9 min, respectively, P = 0.33). In the IA group, significantly more laparoscopic operations were performed (100% versus 93.9%), but with a higher conversion rate to open (1.9% versus 0.13%, P < 0.001). Although the overall complication rate was comparable, more intraoperative complications (2.8% versus 0.3%, P < 0.001) and deep/organ-space surgical site infections (surgical site infection; 4.7% versus 1.2%, P = 0.003) were reported in the IA group. CONCLUSIONS: IA can be a challenging procedure and should not be performed on a routine basis. However, neoplasia must be actively ruled out, particularly in the older age group. PMID- 29605041 TI - Surgeons overestimate postoperative complications and death when compared with the National Surgical Quality Improvement Project risk calculator. AB - BACKGROUND: The assessment of postoperative morbidity and mortality is difficult particularly for complex patients. We hypothesize that surgeons overestimate the risk for complications and death after surgery in complex surgical patients. MATERIALS AND METHODS: General surgery residents and attending surgeons estimated the likelihood of any morbidity, mortality, surgical site infection, pneumonia, and cardiac complications for seven complex scenarios. Responses were compared with the American College of Surgeons National Surgical Quality Improvement Project Surgical Risk Calculator. RESULTS: From 101 residents and 48 attending surgeons, overall response rate was 61.7%. For all seven clinical scenarios, there was no difference between resident and attending predictions of morbidity or mortality, with significant variation in estimates among participants. Mean percentages of the estimates were 25.8%-30% over the National Surgical Quality Improvement Project estimates for morbidity and mortality. CONCLUSIONS: General surgery residents and attending surgeons overestimated risks in complex surgical patients. These results demonstrate broad variance in and near universal overestimation of predicted surgical risk when compared with national, risk adjusted models. PMID- 29605042 TI - Towards the elimination of health care disparities in gynecologic oncology: Call to action. PMID- 29605043 TI - An educational intervention to improve human papilloma virus (HPV) and cervical cancer knowledge among African American college students. AB - OBJECTIVES: Misinformation and lack of formal education about cervical cancer may contribute to disparities. The objective of this study was to assess the role of an educational intervention in improving knowledge about Human papilloma virus (HPV) and cervical cancer among African American female college students. METHODS: We completed a total of 5 lectures at 4 different historically Black Colleges in North Carolina, Virginia, and West Virginia. Each 60min lecture reviewed basic female anatomy, HPV pathogenesis, cervical dysplasia, cervical cancer, HPV vaccination and cervical cancer screening. Participants completed pre and post-lecture surveys assessing knowledge, attitudes and beliefs related to cervical cancer screening, HPV, and the HPV vaccine. RESULTS: A total of 72 students attended the lectures and 57 students completed the surveys. 96% of students reported knowledge of the HPV vaccine, however only 52% reported receiving the vaccine, and 42% completed the 3-shot series. About 77% of students over 21years of age reported having a Pap smear. Of the 16 knowledge-based questions, correct response rates significantly increased (74% v. 91%, p=0.005) with the intervention. At the completion of the intervention, 94% affirmed plans to get regular Pap smears and 87% affirmed plans to get the HPV vaccine. CONCLUSIONS: Primary prevention and early detection are key interventions for reducing disparities in cervical cancer incidence and treatment. Community outreach efforts play an important role in reducing inequities in cancer among high-risk groups. The educational intervention utilized in this study was successful in improving knowledge about HPV and cervical cancer. PMID- 29605044 TI - Racial disparities in molecular subtypes of endometrial cancer. AB - OBJECTIVES: Racial differences in the molecular subtypes of endometrial cancer and associations with progression-free survival (PFS) were evaluated. METHODS: Molecular, clinical and PFS data were acquired from the Cancer Genome Atlas (TCGA) including classification into the integrative, somatic copy number alteration and transcript-based subtypes. The prevalence and prognostic value of the aggressive molecular subtypes (copy number variant [CNV]-high, cluster 4 or mitotic) were evaluated in Black and White patients. RESULTS: There were 337 patients including 14% self-designated as Black, 27% with advanced stage, and 82% with endometrioid histology. The CNV-high subtype was more common in Black than White patients (61.9% vs. 23.5%, P=0.0005) and suggested worse PFS in Black patients (hazard ratio [HR]=3.4, P=0.189). The cluster 4 subtype was more prevalent in Black patients (56.8% vs. 20.9%, P<0.0001) and associated with worse PFS in Black patients (HR=3.4, P=0.049). The mitotic subtype was more abundant in Black patients (64.1% vs. 33.7%, P=0.002), indicated worse PFS in Black patients (HR=4.1, P=0.044) including the endometrioid histology (HR=6.1, P=0.024) and exhibited race-associated enrichment in cell cycle signaling and pathways in cancer including PLK1 and BIRC7. All of these aggressive molecular subtypes also indicated worse PFS in White patients, with unique enrichments in mitotic signaling different from Black patients. CONCLUSIONS: The aggressive molecular subtypes from TCGA were more common in Black endometrial cancer patients and indicated worse PFS in both Black and White patients. The mitotic subtypes also indicated worse PFS in Black patients with endometrioid histology. Enrichment patterns in mitotic signaling may represent therapeutic opportunities. PMID- 29605045 TI - Laparoscopy decreases the disparity in postoperative complications between black and white women after hysterectomy for endometrial cancer. AB - OBJECTIVES: Black race has been associated with increased 30-day morbidity and mortality following surgery for endometrial cancer. Black women are also less likely to undergo laparoscopy when compared to white women. With the development of improved laparoscopic techniques and equipment, including the robotic platform, we sought to evaluate whether there has been a change in surgical approach for black women, and in turn, improvement in perioperative outcomes. METHODS: Using the American College of Surgeons' National Surgical Quality Improvement Project's database, patients who underwent hysterectomy for endometrial cancer from 2010 to 2015 were identified. Comparative analyses stratified by race and hysterectomy approach were performed to assess the relationship between race and perioperative outcomes. RESULTS: A total of 17,692 patients were identified: of these, 13,720 (77.5%) were white and 1553 (8.8%) were black. Black women were less likely to undergo laparoscopic hysterectomy compared to white women (49.3% vs 71.3%, p<0.0001). Rates of laparoscopy in both races increased over the 6-year period; however these consistently remained lower in black women each year. Black women had higher 30-day postoperative complication rates compared to white women (22.5% vs 13.6%, p<0.0001). When laparoscopic hysterectomies were isolated, there was no difference in postoperative complication rates between black and white women (9.2% vs 7.5%, p=0.1). CONCLUSIONS: Overall black women incur more postoperative complications compared to white women undergoing hysterectomy for endometrial cancer. However, laparoscopy may mitigate this disparity. Efforts should be made to maximize the utilization of minimally invasive surgery for the surgical management of endometrial cancer. PMID- 29605046 TI - Consideration of older patients for enrollment in phase 1 clinical trials: Exploring treatment related toxicities and outcomes. AB - OBJECTIVES: Age imposes a disparity in the treatment of and outcomes with gynecologic cancer. Older patients are underrepresented in primary treatment trials, but little is known about their ability to withstand trial-based treatment for recurrent or refractory disease. This study sought to examine treatment-related toxicities and outcomes of older versus younger patients participating in phase 1 clinical trials. METHODS: A retrospective analysis of patients enrolled in phase 1 clinical trials for gynecologic malignancies from 2010 to 2016 was performed. Demographic and clinic-pathologic data was abstracted. Toxicities were defined as either grade III or IV by CTCAE criteria. Best response was calculated using RECIST criteria. Associations between categorical variables were determined using Fisher's exact test and continuous variables using Wilcoxon rank sum test. Survival was estimated using the Kaplan Meier method. RESULTS: 237 patients were included with 22% (n=51) comprising the older cohort (>=70years). The vast majority (98%) were treated for recurrent disease. Older patients incurred similar grade III/IV hematologic (21% vs 16%, p=0.38) and non-hematologic toxicities (26% vs 29%, p=0.64). Older patients discontinued treatment due to toxicity only 8% of the time. Median survival was 13.0 and 10.3months in the <70 and >=70 groups, respectively (p=0.35). 63% of patients >=70 achieved clinical benefit. CONCLUSIONS: Although historically older patients have not been routinely considered for enrollment in phase 1 trials, our data demonstrates similar toxicity profiles to that of younger patients and 63% clinical benefit rate. Thus, with careful selection, patients >=70 should be considered when facing recurrent or refractory gynecologic cancer. PMID- 29605047 TI - Biological origins of sexual orientation and gender identity: Impact on health. AB - Gynecologic Oncologists are sometimes consulted to care for patients who present with diverse gender identities or sexual orientations. Clinicians can create more helpful relationships with their patients if they understand the etiologies of these diverse expressions of sexual humanity. Multidisciplinary evidence reveals that a sexually dimorphic spectrum of somatic and neurologic anatomy, traits and abilities, including sexual orientation and gender identity, are conferred together during the first half of pregnancy due to genetics, epigenetics and the diversity of timing and function of sex chromosomes, sex-determining protein secretion, gonadal hormone secretion, receptor levels, adrenal function, maternally ingested dietary hormones, fetal health, and many other factors. Multiple layers of evidence confirm that sexual orientation and gender identity are as biological, innate and immutable as the other traits conferred during that critical time in gestation. Negative social responses to diverse orientations or gender identities have caused marginalization of these individuals with resultant alienation from medical care, reduced self-care and reduced access to medical care. The increased risks for many diseases, including gynecologic cancers are reviewed. Gynecologic Oncologists can potentially create more effective healthcare relationships with their patients if they have this information. PMID- 29605048 TI - Racial and ethnic disparities over time in the treatment and mortality of women with gynecological malignancies. AB - OBJECTIVE: To examine temporal trends in treatment and survival among black, Asian, Hispanic, and white women diagnosed with endometrial, ovarian, cervical, and vulvar cancer. METHODS: Using the National Cancer Database (2004-2014), we identified women diagnosed with endometrial, ovarian, cervical, and vulvar cancer. For each disease site, we analyzed race/ethnicity-specific trends in receipt of evidence-based practices. Professional societies' recommendations were used to define these practices. Using data from the Surveillance, Epidemiology, and End Results Program (2000-2009) we analyzed trends in 5-year survival. RESULTS: Throughout the study period black (64.8%) and Hispanic (68.3%) women were less likely to undergo lymphadenectomy for stage I ovarian cancer compared to Asian (79.5%) and white patients (74.6%). Black women were the least likely group to undergo lymphadenectomy in all periods. Among patients with stage II-IV ovarian cancer, 76.6% of white and Asian women received both surgery and chemotherapy, compared to 70.8% of black and 73.9% Hispanic women. Hispanic women with deeply invasive or high-grade stage I endometrial cancer underwent lymphadenectomy less frequently (74.5%) than all other groups (80.7%). Black women were less likely to have chemo-radiotherapy for stage IIB-IVA cervical cancer (75.6% versus 80.4% of all others). Black women were also less likely to have a surgical lymph node evaluation for vulvar cancer (58.8% versus 63.5% of all others). Among women diagnosed with ovarian, endometrial, and cervical cancer, black women had lower five-year survival than other groups. CONCLUSION: Significant racial disparities persist in the delivery of evidence-based care. Black women with ovarian, endometrial, and cervical cancer continue to experience higher cancer-specific mortality than other groups. PMID- 29605049 TI - Exploring the impact of income and race on survival for women with advanced ovarian cancer undergoing primary debulking surgery at a high-volume center. AB - OBJECTIVE: To evaluate patients with advanced ovarian cancer (OC) undergoing primary debulking surgery (PDS) at a high-volume center (HVC), to determine whether socio-demographic disparities in PDS outcome and overall survival (OS) were present. METHODS: All patients with stages IIIB-IV high-grade OC undergoing PDS at our institution from 1/2001-12/2013 were identified. Patients self identified race/ethnicity as non-Hispanic White (NHW), non-Hispanic Black (NHB), Asian (A), or Hispanic (H). Income level for the entire cohort was estimated using the census-reported income level for each patient's zip code as a proxy for SES. Main outcome measures were PDS outcome and median OS. Cox proportional hazards model was used to examine differences in OS by racial/ethnic and income category, controlling for selected clinical factors. RESULTS: 963 patients were identified for analysis: 855 NHW; 43 A, 34H, 28 NHB, and 3 unknown. PDS outcome was not significantly different among NHB and H as compared to NHW. Compared to NHW, Asians were more likely to have >1cm residual (AOR 2.32, 95%CI 1.1-4.9, p=0.03). Median income for the entire cohort was $85,814 (range $10,926 $231,667). After adjusting for significant prognostic factors, there were no significant differences in PDS outcome between income groups (p=0.7281). Median OS was 55.1mos (95%CI 51.8-58.5) with no significant differences in OS between the income (p=0.628) or racial/ethnic (p=0.615) groups. CONCLUSION: Statistically significant socio-demographic disparities in PDS and survival outcomes were not observed among women with advanced OC treated at this HVC. Increased efforts are needed to centralize care to and increase the diversity of pts treated at HVCs. PMID- 29605050 TI - Do differences in medical comorbidities and treatment impact racial disparities in epithelial ovarian cancer? AB - BACKGROUND: Population-based studies of women with epithelial ovarian cancer suggest that black women have worse survival compared to white women. The primary objective of this study was to determine if, at a National Cancer Institute (NCI) Designated Comprehensive Cancer Center (CCC) serving a diverse racial and socioeconomic population, race is independently associated with differences in survival. METHODS: A retrospective review of women with EOC diagnosed between 2004-2009 undergoing treatment with follow-up at our institution was performed. Records were reviewed for demographics, comorbidities (as defined by the Charlson Comorbidity Index (CCI)), tumor characteristics, treatment, progression-free (PFS), and overall survival (OS). Survival was calculated using the Kaplan-Meier method and compared with the log-rank test. Multivariate survival analysis was performed with Cox (proportional hazards) model. RESULTS: 367 patients met inclusion criteria. 54 (15%) were black and 308 (84%) were white. Compared to white women, black women had higher BMI, lower rates of optimal surgical cytoreduction, lower rates of intraperitoneal chemotherapy, and higher CCI scores. The median PFS for black and white women were 9.7 and 14.6months, respectively (p=0.033). The median overall survival was 21.7months for black women and 42.6months for white women (p<0.001). On multivariate analysis, black race independently correlated with a worse overall survival (HR 1.61, 95% CI 1.06 2.43). CONCLUSION: In this cohort, racial disparities may be due to higher medical comorbidities and lower rates of optimal surgical cytoreduction. After accounting for these differences, race remained an independent predictor of worse overall survival. PMID- 29605051 TI - Delays in definitive cervical cancer treatment: An analysis of disparities and overall survival impact. AB - OBJECTIVE: Delays in time to treatment initiation (TTI) with definitive radiation therapy (RT) or chemotherapy and RT (CRT) for cervical cancer could lead to poorer outcomes. This study investigates disparities in TTI and the impact of TTI on overall survival (OS). METHODS: Adult women with non-metastatic cervical squamous cell carcinoma diagnosed between 2004 and 2014, treated with definitive RT or CRT, and reported to the National Cancer Database were included. TTI was defined as days from diagnosis to start of RT or CRT. The impact of TTI on OS in patients treated with concurrent CRT which included brachytherapy was then assessed. RESULTS: Overall, 14,924 patients were included (84.7% CRT, 15.3% RT). TTI was significantly longer for Non-Hispanic Black (NHB) (RR, 1.14; 95% CI, 1.11 to 1.18) and Hispanic women (RR, 1.19; 95% CI, 1.15 to 1.24) compared to Non Hispanic White (NHW) women. Expected TTI (eTTI) for NHW, NHB, and Hispanic women were 38.1, 45.2, and 49.4days. eTTI rose from 36.2days in 2004 to 44.3days by 2014. Intensity-modulated radiation therapy (IMRT) was associated with increased eTTI of 46.5days versus 40.0days for non-IMRT. Longer TTI was not associated with inferior OS in patients treated with concurrent CRT. CONCLUSIONS: Delays in starting RT/CRT for cervical cancer increased from 2004 to 2014. Delays disproportionately affect NHB and Hispanic women. However, increased TTI was not associated with increased mortality for women receiving CRT. Further study of TTI's impact on other endpoints is warranted to determine if TTI represents an important quality indicator. PMID- 29605052 TI - The impact of nativity on cervical cancer survival in the public hospital system of Queens, New York. AB - OBJECTIVE: We studied cervical cancer patients who presented to the Public Hospital System in ethnically-diverse Queens, New York from 2000 to 2010 with the purpose of examining the relationship between nativity (birthplace) and survival. METHODS: A retrospective review of tumor registries was used to identify patients diagnosed with cervical cancer between January 1, 2000 and December 31, 2010. Using electronic medical records, data from 317 patients were available for this analysis. RESULTS: The majority of patients were born outside the United States (US) (85.5% versus 14.5%). One hundred patients (31.5%) were born in Latin America, 105 in the Caribbean Islands (33.1%), 48 in Asia (15.1%), 8 in the South Asia (2.5%), 10 in Russia/Eastern Europe (3.2%) and 46 (14.5%) in the United States. Patients presented at varying stages of disease: 51.4% at stage I, 19.6% at stage II, 19.6% at stage III, and 8.5% at stage IV. Kaplan-Meier estimated survival curves stratified by birthplace demonstrated significant differences in survival distributions among the groups using the log-rank test (P<0.0001). The most favorable survival curves were observed among patients born in Latin America and Asia whereas the least favorable was demonstrated in US-born patients. Time to death was analyzed using the Cox proportional hazards model. Adjusting for age at diagnosis, insurance status, stage and treatment modality, nodal metastases and hydronephrosis, birthplace was significantly associated with survival time (P<0.0001). CONCLUSION: An immigrant health paradox was defined for foreign-born Latino and Asian patients presenting with cervical cancer to the Public Hospital System of Queens, New York as patients born in Latin America and Asia were less likely to die at any given time compared to those born in the United States. PMID- 29605053 TI - A contemporary framework of health equity applied to gynecologic cancer care: A Society of Gynecologic Oncology evidenced-based review. AB - Health disparities are defined as the preventable difference in the burden of disease, injury, and violence, or opportunity to achieve optimal health that socially disadvantaged populations experience compared to the population as a whole. Disparities in incidence and cancer outcomes for women with gynecologic malignancies have been well described particularly for American women of Black race. The etiology of these disparities has been tied to socio-economics, cultural, educational and genetic factors. While access to high quality treatment has been primarily linked to survival from cervical and ovarian cancer, innate biologic distinctions have been principally cited as reasons for differences in incidence and mortality in cancers of the uterine corpus. This article will update the framework of disparities to incorporate a broader understanding of the social determinants of health and how they affect health equity by addressing the root causes of disparities within the health care system. Special populations are identified who are at risk for health inequities which include but are not limited to Black race, underserved racial and ethnic minorities (e.g. indigenous peoples, low English fluency), trans/gender nonconforming people and rural populations. Each of these populations at risk have unique structural barriers within the healthcare system impacting gynecologic cancer outcomes. The authors provide practical recommendations for practitioners aimed at eliminating cancer related outcome disparities. PMID- 29605054 TI - Investigating Black-White disparities in gynecologic oncology: Theories, conceptual models, and applications. AB - Within gynecologic oncology are two of the top five widest Black-White mortality gaps among all cancer diagnoses in the United States. A rich body of work from the social sciences, including anthropology, sociology and social epidemiology, have broadened the understanding of and research approaches to the study of health and healthcare inequity experienced by Black Americans. Yet, these intellectual advancements in understanding are virtually absent from the gynecologic oncology literature. The goal of this analytic essay will be to introduce three current frameworks of studying racial inequity: The Ecosocial Theory of Disease Distribution, The Fundamental Cause Theory, and The Public Health Critical Race Praxis. Applications of each conceptual model to gynecologic oncology are illustrated. The Ecosocial Theory, in particular the concept of embodiment, can be used to design and interpret racial differences in molecular and genetic studies. The Fundamental Cause Theory explains the relationship of socioeconomic position with the evolving treatability of a given disease over time, and provides understanding to the contrast in racial disparities within ovarian, endometrial, and cervical cancers. The Public Health Critical Race Praxis is an iterative methodology that helps frame how to study the impact of racism on healthcare delivery. Different analytic approaches that account for the interaction of race and socioeconomic factors are reviewed. Finally, considerations for racial equity research in gynecologic oncology are proposed. PMID- 29605055 TI - Disparities in genetics assessment for women with ovarian cancer: Can we do better? AB - OBJECTIVE: We sought to characterize referral patterns for genetic counseling for women with ovarian cancer and hypothesized that differences in referral and testing rates are shaped by socioeconomic factors. METHODS: Patients were identified by pathology reports from August 2012 to January 2016 containing the words "serous" or "ovarian." Patient information was obtained via electronic medical record. Primary outcomes were placement of a genetics referral and completion of counseling. A secondary outcome was completion of genetic testing. RESULTS: We identified 246 women with a diagnosis of ovarian cancer. Ten were previously counseled and excluded. 53% of patients were referred for counseling with mean time from diagnosis to counseling of 4.6months. Age and family history were not associated with referral, however rates differed by race with 61% of Caucasian and 40%, 38% and 33% of Asian, Latina and Black women, respectively, referred (p=0.035). Overall, 36% of patients diagnosed underwent counseling, and 33% were tested. English language (p<0.0001), high-grade serous histology (p=<0.0001) and private or Medicare insurance (p<0.0001) were significantly associated with referral. CONCLUSION: We have not yet reached the Society of Gynecologic Oncology recommendation for referral to genetics. Women of color and those with public insurance have lower referral rates. This disparity in care impacts cancer treatment options and prevents appropriate screening for other hereditary malignancies. To provide comprehensive oncology care, including genetic assessment, we recommend focusing on these barriers including improving outreach and interpreter services. PMID- 29605056 TI - Improving cancer care for American Indians with cervical cancer in the Indian Health Service (IHS) system - Navigation may not be enough. AB - OBJECTIVES: Patient navigation programs have been shown to positively impact cancer outcomes for minority populations. Little is known regarding the effects of these programs on American Indian (AI) populations. The purpose of this study is to characterize the impact of a patient navigation program on AI cervical cancer patients at a tertiary care center. METHODS: A retrospective review of all AI cervical cancer patients receiving navigation services and a cohort of AI patients treated prior to navigation services was performed. Additional comparisons were made between those with and without Indian Health Service (IHS) funding. Summary statistics were used to describe demographic, clinical characteristics, treatment, and survivorship across groups. RESULTS: Of 55 patients identified, 34 received navigation and 21 did not. In navigated patients, median age was 46years (27-80years) compared with 42years (17-68years) in pre-navigation patients (p=0.53). There was no difference between stage at diagnosis (p=0.73). No difference was noted in treatment received between groups (p=0.48). Distance traveled for treatment between groups did not differ (p=0.46). Median time to initiation of treatment was not different between groups, 30.5days vs. 27.5days (p=0.18). Among patients with IHS funding, navigation services did not alter time to initiation of treatment (p=0.57), and there was no difference in completion of prescribed therapy between groups (92% navigated vs 100% pre navigation). CONCLUSIONS: Navigation services for AI cervical cancer patients did not alter initiation or completion of treatment. Navigation programs may provide less tangible benefits to AI cervical cancer patients and further study is warranted. PMID- 29605058 TI - Preface to Diagnosis of venous thromboembolism. PMID- 29605057 TI - First nations people's perspectives on barriers and supports for enhancing HPV vaccination: Foundations for sustainable, community-driven strategies. AB - OBJECTIVE: In Canada, Indigenous people have higher human papillomavirus (HPV) infection rates, lower screening rates for cervical cancer, and higher rates of invasive cancer, leading to worse cervical cancer-related outcomes than observed in non-Indigenous Canadian women. Lingering harms from European colonization drive these health inequities and create public health challenges. Policy guidance is needed to optimize HPV vaccination rates and, thereby, decrease the burden of HPV-related illness, including high-morbidity surgical procedures and chemo-radiotherapy. The Enhancing HPV Vaccination In First Nations Populations in Alberta (EHVINA) project focuses on First Nations, a diverse subset of recognized Indigenous people in Canada, and seeks to increase HPV vaccination among girls and boys living in First Nation communities. METHODS: Developing an effective strategy requires partnership with affected communities to better understand knowledge and perceptions about cancer, healthcare, and the HPV vaccine. A 2017 community gathering was convened to engage First Nations community members, health directors, and health services researchers in dialogue around unique barriers and supports to HPV vaccination in Alberta. Voices of community Elders, parents, health directors, and cancer survivors (n=24) are presented as qualitative evidence to help inform intervention design. RESULTS: Key findings from discussions indicate barriers to HPV vaccination include resource constraints and service infrastructure gaps, historical mistrust in healthcare systems, impacts of changing modes of communication, and community sensitivities regarding sexual health promotion. Supports were identified as strengthened inter generational relationships in communities. CONCLUSIONS AND FUTURE DIRECTION: Ongoing dialogue and co-development of community-based strategies to increase HPV vaccine uptake are required. The identification of possible barriers to HPV vaccination in a Canadian Indigenous population contributes to limited global literature on this subject and may inform researchers and policy makers who work with Indigenous populations in other regions. PMID- 29605059 TI - Four Decades of Change in Sexual Medicine. PMID- 29605060 TI - Response Regarding Existential Issues in Sexual Medicine: The Relation Between Death Anxiety and Hypersexuality. PMID- 29605061 TI - Response and Rebuttal to "Existential Issues in Sexual Medicine: The Relation Between Death Anxiety and Hypersexuality". PMID- 29605063 TI - Classification and Epidemiologic Aspects of Acute Liver Failure. AB - Acute liver failure is a rare condition with high short-term morbidity and mortality. The most widely accepted definition is an abnormality in coagulation with any degree of encephalopathy in a patient without cirrhosis and an illness duration of less than 26 weeks. Multiple classifications systems are currently in use to help categorize the condition. This article reviews the most commonly used systems. The epidemiologic aspects of the disease are also reviewed, including incidence, prevalence, demographics, geographic distribution, and racial and cultural factors and are discussed for the various subtypes of acute liver failure. PMID- 29605062 TI - Genetic Vulnerability of GPCRs: A Call to Action. AB - G-protein-coupled receptors (GPCRs) are the targets for many drugs, but the response shows interindividual variability. The 'one-drug-fits-all' approach has been challenged by evidence showing multiple human genetic variants of GPCRs. Identification and characterization of GPCR variants must be undertaken for rational, personalized, and economically sound prescribing practices. PMID- 29605064 TI - Acute Liver Failure: Mechanisms of Disease and Multisystemic Involvement. AB - Acute liver failure is accompanied by a pathologic syndrome common to numerous different etiologies of liver injury. This acute liver failure syndrome leads to potentially widespread devastating end-organ consequences. Systemic dysregulation and dysfunction is likely propagated via inflammation as well as underlying hepatic failure itself. Decoding the mechanisms of the disease process and multisystemic involvement of acute liver failure offers potential for targeted treatment opportunities and improved clinical outcomes in this sick population. PMID- 29605065 TI - The Pathology of Acute Liver Failure. AB - Varied injuries may manifest clinically as acute liver failure. The pathologic features include variable amounts of necrosis and regeneration. This article reviews pathologic classification of patterns of necrosis and associated inflammatory and regenerative responses in specimens from patients with acute liver failure. Detailed pathologic examination of these specimens with clinical pathologic correlation can give the multidisciplinary team vital information regarding etiology and timing as well as extent of injury, and regenerative response. Pathologists are a vital component of the health care team for patients with acute liver failure. PMID- 29605066 TI - Liver Regeneration in the Acute Liver Failure Patient. AB - Liver regeneration after simple resection represents a unique process in which the organ returns to its original size and histologic structure. Over the past 30 years, there has been significant progress in elucidating the mechanisms associated with regeneration after loss of hepatic mass. Liver regeneration after acute liver failure shares several of these classical pathways. It differs, however, in key processes, including the role of both differentiated and stemlike cells. This article outlines these differences in addition to new molecular mechanisms, including immunomodulation, microRNAs, and the gut-liver axis. In addition, applications to the patient population, including prognostication and stem cell therapies, are explored. PMID- 29605067 TI - Viral Hepatitis and Acute Liver Failure: Still a Problem. AB - Although the overall prevalence is on the decline, viral hepatitis still plays a major role in the development of acute liver failure (ALF) worldwide. Hepatitis A, B, D, and E contribute to most fulminant viral courses. These viruses have not gained much attention in recent years yet remain relevant from a clinical perspective as the incidence in certain populations is on the increase. Other viral therapies and immunotherapies are currently being examined as treatments for hepatitis D and hepatitis E. Clinicians should still maintain a high index of suspicion for viral causes in approaching patients with ALF. PMID- 29605068 TI - Nonacetaminophen Drug-Induced Acute Liver Failure. AB - Acute liver failure of all causes is diagnosed in between 2000 and 2500 patients annually in the United States. Drug-induced acute liver failure is the leading cause of acute liver failure, accounting for more than 50% of cases. Nonacetaminophen drug injury represents 11% of all cases in the latest registry from the US Acute Liver Failure Study Group. Although rare, acute liver failure is clinically dramatic when it occurs, and requires a multidisciplinary approach to management. In contrast with acetaminophen-induced acute liver failure, non acetaminophen-induced acute liver failure has a more ominous prognosis with a lower liver transplant-free survival. PMID- 29605069 TI - Acetaminophen (APAP or N-Acetyl-p-Aminophenol) and Acute Liver Failure. AB - Acetaminophen (APAP) is the leading cause of acute liver failure (ALF), although the worldwide frequency is variable. APAP hepatotoxicity develops either following intentional overdose or unintentional ingestion (therapeutic misadventure) in the background of several factors, such as concomitant use of alcohol and certain medications that facilitate the formation of reactive and toxic metabolites. Spontaneous survival is more common in APAP-induced ALF compared with non-APAP etiologies. N-acetylcysteine is recommended for all patients with APAP-induced ALF and it reduces mortality. Liver transplantation should be offered early to those who are unlikely to survive based on described prognostic criteria. PMID- 29605070 TI - Nonviral or Drug-Induced Etiologies of Acute Liver Failure. AB - Acute liver failure (ALF) is a rare but highly fatal condition. The most common causes include drug-induced and viral hepatitis, but other less common etiologies, especially autoimmune hepatitis, Budd-Chiari syndrome, and Wilson disease, need to be considered. Because diagnosis is frequently tied to potential for reversibility of ALF and prognosis, early identification in a timely manner is crucial. Other causes of ALF are more easily recognizable based on specific circumstances, such as ALF in pregnancy or ischemic hepatitis. Ultimately, maintaining a wide differential diagnosis in patients with ALF is essential to identifying the proper treatment and prognosis. PMID- 29605071 TI - The Clinical Spectrum and Manifestations of Acute Liver Failure. AB - Acute liver failure (ALF) is a rare life-threatening condition characterized by rapid progression and death. Causes vary according to geographic region, with acetaminophen and drug-induced ALF being the most common causes in the United States. Determining the cause aids in predicting the prognosis and the presentation of manifestations and guides providers to perform cause-specific management. At initial presentation, nonspecific symptoms are present but may progress to complications, including cerebral edema, infection, coagulopathy, renal failure, cardiopulmonary failure, and acid-base and/or metabolic disturbances. Although some cases of ALF resolve with conservative measures, liver transplantation is the ultimate treatment in many cases. PMID- 29605072 TI - Prognostic Models in Acute Liver Failure. AB - There is a strong imperative to develop valid and accurate prognostic modeling for acute liver failure (ALF). Despite the numerous clinical models that have been proposed thus far and the use of some such models, that is, King's College Criteria and Model for End-Stage Liver Disease, in clinical practice to aid decision-making, there is a significant need for improvement for determining patients' clinical course, survival, and requirement for liver transplantation. Future prognostic models shall need a stronger statistical foundation and accountability for time and variability in the clinical course of ALF and be applied for pretransplant and posttransplant outcomes. PMID- 29605073 TI - Non-Intensive Care Unit Management of Acute Liver Failure. AB - Acute liver failure (ALF) is an uncommon syndrome with a highly variable and unpredictable clinical course. The initial diagnostic evaluation is typically performed in a non-intensive care unit (ICU) setting, like the emergency department or general hospital ward. Prompt restoration of intravascular volume with intravenous fluids and correction of electrolyte, metabolic, and acid-base disturbances are important initial interventions in the management of ALF and can be safely accomplished in non-ICU settings in many patients. Similarly, therapies such as administration of N-acetylcysteine for acetaminophen-induced ALF and other cause-specific interventions can also be administered in non-ICU settings, thus minimizing delay. PMID- 29605074 TI - Management of Acute Liver Failure in the Intensive Care Unit Setting. AB - This article discusses the intensive care unit management of patients with acute liver failure. It focuses on the clinical presentation, identification, and management of the myriad of complications seen in patients with acute liver failure. PMID- 29605075 TI - Liver Transplantation for Acute Liver Failure. AB - With the advent of liver transplant for acute liver failure (ALF), survival rate has improved drastically. Liver transplant for ALF accounts for 8% of all transplant cases. The 1-year survival rates are 79% in Europe and 84% in the United States. Some patients with ALF may recover spontaneously, and approximately half will undergo liver transplant. It is imperative to identify patients with ALF as soon as possible to transfer them to a liver transplant center for a thorough evaluation. Emergent liver transplant in a patient with ALF may place the patient at risk for severe complications in the postoperative period. PMID- 29605077 TI - Acute Liver Failure. PMID- 29605076 TI - Future Approaches and Therapeutic Modalities for Acute Liver Failure. AB - The current gold standard for the management of acute liver failure is liver transplantation. However, because of organ shortages, other modalities of therapy are necessary as a possible bridge. This article discusses the current modalities as well as the future management of acute liver failure. Liver assist devices, hepatocyte transplantation, stem cell transplant, organogenesis, and repopulation of decellularized organs are discussed. PMID- 29605078 TI - Pre-surgical chemotherapy for breast cancer may be associated with improved outcomes. AB - BACKGROUND: Historical studies suggest no difference in disease outcome between neoadjuvant and adjuvant approaches in breast cancer. We hypothesize neoadjuvant chemotherapy (NCT) may offer several benefits, possibly improving quality of life outcomes. METHODS: Retrospective review of Tumor Registry data of breast cancer patients from 2011 to 2015. Pathologists reviewed cases from 2012 to 2013 to provide additional RCB (residual cancer burden) scores. RESULTS: From 2011 to 2015 there were 2707 breast cancer cases and 455 patients received NCT. RCB score was documented in 348 with excellent outcome in 41% (pCR in 115 patients, 28 RCB I). There were 137 RCB II and 68 RCB III. Clinically positive nodes were present in 202 of 455 and 77 (38%) had clearance of nodal disease. Of these 45 had axillary dissections. DISCUSSION: Neoadjuvant therapy was associated with excellent response rates. Thirty eight percent of patients with positive nodes converted to node negative although over 50% underwent axillary dissection. Higher utilization of NCT could decrease need for axillary dissection thereby lowering incidence of lymphedema and improving quality of life for survivors. PMID- 29605079 TI - Characteristics and Outcomes of Out-of-Hospital Cardiac Arrest Occurring While in a Motor Vehicle. AB - This study aimed to investigate the incidence, patient characteristics, and outcomes of out-of-hospital cardiac arrest (OHCA) occurring while in a motor vehicle in Osaka City, Japan (with a population of 2.6 million), from 2009 to 2015. The OHCA data used in this study were obtained from the population-based Utstein-style registry in Osaka City. Patients who had OHCA occurring while in a motor vehicle were included. The primary end point was 1-month survival with favorable neurologic outcome after OHCA. During the study period, 18,458 OHCAs were observed, and 264 of them (1.4%) occurred while on or in a motor vehicle (drivers, n = 179; nondrivers, n = 85). The overall incidence rate of OHCAs occurring while in a motor vehicle was 14.0 per million population per year (drivers, 9.5; nondrivers, 4.5). In the drivers with OHCAs, 78 (43.6%) and 101 (56.4%) cases were of medical origin and traffic injuries, respectively. Approximately half of OHCAs with a medical origin in drivers presumably occurred while driving (46.2%, 36 of 78). The overall proportion of 1-month survival with favorable neurologic outcome after OHCA was 6.4% (17 of 264). In the drivers, the proportion of OHCAs with a medical origin and because of traffic injuries were 11.5% (9 of 78) and 2.0% (2 of 101) (p = 0.008), respectively. In conclusion, although OHCAs occurring while in a motor vehicle represented a small subset of the overall OHCA burden, a relatively large number of cardiac arrests with a medical origin occurred in drivers. PMID- 29605080 TI - Statin Eligibility in Primary Prevention: From a Risk-Based Strategy to a Personalized Approach Based on the Predicted Benefit. AB - Guidelines have recommended statin initiation based on the absolute cardiovascular risk. We tested the hypothesis that a strategy based on the predicted cardiovascular benefit, compared with the risk-based approach, modifies statin eligibility and the estimated benefit in a population in primary cardiovascular prevention. The study included 16,008 subjects (48 +/- 6 years, 73% men) with low-density lipoprotein cholesterol levels of 70 to <190 mg/dl, not on lipid-lowering drugs, who underwent a routine health screening in a single center. For the risk-based strategy, criterion for statin eligibility was defined as a 10-year atherosclerotic cardiovascular disease (ASCVD) risk of >=7.5%. In the benefit-based strategy, subjects were considered for statin according to the predicted absolute cardiovascular risk reduction, so that the number of statin candidates would be the same as in the risk-based strategy. The benefit-based strategy would replace 11% of statin candidates allocated in the risk-based approach with younger, lower risk subjects with higher low-density lipoprotein cholesterol. Using the benefit-based strategy, 13% of subjects with 5.0% to < 7.5% ASCVD risk would shift from a statin-ineligible to a statin-eligible status, whereas 24% of those with 7.5% to <10.0% ASCVD risk would become statin ineligible. These effects would transfer the benefit from higher to lower risk subjects. In the entire population, no clinically meaningful change in the benefit would be expected. In conclusion, switching from a risk-based strategy to a benefit-based approach, while keeping the same rate of statin use in the population, is expected to promote substantial changes in statin eligibility in subjects at intermediate cardiovascular risk, modifying the subpopulation to be benefited by the treatment. PMID- 29605081 TI - FCS Analysis of Protein Mobility on Lipid Monolayers. AB - In vitro membrane model systems are used to dissect complex biological phenomena under controlled unadulterated conditions. In this context, lipid monolayers are a powerful tool to particularly study the influence of lipid packing on the behavior of membrane proteins. Here, monolayers deposited in miniaturized fixed area-chambers, which require only minute amounts of protein, were used and shown to faithfully reproduce the characteristics of Langmuir monolayers. This assay is ideally suited to be combined with single-molecule sensitive fluorescence correlation spectroscopy (FCS) to characterize diffusion dynamics. Our results confirm the influence of lipid packing on lipid mobility and validate the use of FCS as an alternative to conventional surface pressure measurements for characterizing the monolayer. Furthermore, we demonstrate the effect of lipid density on the diffusional behavior of membrane-bound components. We exploit the sensitivity of FCS to characterize protein interactions with the lipid monolayer in a regime in which the monolayer physical properties are not altered. To demonstrate the potential of our approach, we analyzed the diffusion behavior of objects of different nature, ranging from a small peptide to a large DNA-based nanostructure. Moreover, in this work we quantify the surface viscosity of lipid monolayers. We present a detailed strategy for the conduction of point FCS experiments on lipid monolayers, which is the first step toward extensive studies of protein-monolayer interactions. PMID- 29605082 TI - Can non-clinical community placements enhance medical students' understanding of the social determinants of ill health? AB - OBJECTIVES: Teaching the social determinants of health using classroom methods and medical settings is not effectual, yet few institutions require students to undertake placements in non-clinical settings. We sought to understand through qualitative investigation how non-clinical community placements contributed to students' understanding of health disparities. STUDY DESIGN: Qualitative methods. METHODS: Semistructured interviews with eight purposively selected students and a focus group were conducted by an independent, non-medical and non-religiously affiliated researcher. A thematic analysis elicited key themes and findings. RESULTS: On analysis, students valued the placements, reporting a greater understanding of and empathy for the needs of people from marginalised socio economic, cultural and ethnic groups. Some believed this was better gained in non clinical settings where doctor-patient barriers were absent. CONCLUSIONS: Non clinical community placements may provide a special opportunity to teach health determinants and cultural competence to medical students. PMID- 29605083 TI - Hydraulic permeability of meniscus fibrocartilage measured via direct permeation: Effects of tissue anisotropy, water volume content, and compressive strain. AB - Hydraulic permeability is an important material property of cartilaginous tissues, governing the rate of fluid flow, which is crucial to tissue biomechanics and cellular nutrition. The effects of strain, anisotropy, and region on the hydraulic permeability in meniscus tissue have not been fully elucidated. Using a one-dimensional direct permeation test, we measured the hydraulic permeability within statically compressed porcine meniscus specimens, prepared such that the explants were in either the axial or circumferential direction of either the central or horn (axial direction only) region of the medial and lateral menisci. A constant flow was applied and the pressure difference was measured using pressure transducers. Specimens were tested under 10-20% compressive strain. Permeability values were in the range of 1.53-1.87 * 10-15 m4/Ns, which is comparable to values found in the literature. Permeability was significantly anisotropic, being higher in the circumferential direction than in the axial direction. Additionally, there was a significant negative correlation between strain level and permeability for all groups. Lastly, no statistically significant difference was found between permeability coefficients from different regional locations. This study provides important information regarding structure-function relationships in meniscal tissues that helps to elucidate biomechanics and transport in the tissue, and can aid in the understanding of the tissue's role in the function of the knee joint and onset of osteoarthritis. PMID- 29605084 TI - Evaluation of bone resection margins of segmental mandibulectomy for oral squamous cell carcinoma. AB - Resection margins are frequently studied in patients with oral squamous cell carcinoma and are accepted as a constant prognostic factor. While most evidence is based on soft tissue margins, reported data for bone resection margins are scarce. The aim of this retrospective study was to evaluate and determine the utility of surgical margins in bone resections for oral cavity squamous cell carcinoma (OCSCC). The status of bone resection margins and their impact on survival was investigated in patients who had undergone segmental mandibulectomy for OCSCC. Medical records were retrieved for the years 2000-2012; 127 patients were identified and included in the study. Tumour-positive bone resection margins were found in 21% of the patients. The 5-year overall survival was significantly lower in this group (P<0.005). Therefore, there is a need for intraoperative feedback on the status of bone resection margins to enable immediate additional resection where necessary. Although the lack of intraoperative methods for the evaluation of bone tissue has been addressed by many authors, there is still no reliable method for widespread use. Future research should focus on an objective, accurate, and rapid method of intraoperative assessment for the entire bone resection margin to optimize patient outcomes. PMID- 29605085 TI - Community Assembly Theory as a Framework for Biological Invasions. AB - Biological invasions present a global problem underlain by an ecological paradox that thwarts explanation: how do some exotic species, evolutionarily naive to their new environments, outperform locally adapted natives? We propose that community assembly theory provides a framework for addressing this question. Local community assembly rules can be defined by evaluating how native species' traits interact with community filters to affect species abundance. Evaluation of exotic species against this benchmark indicates that exotics that follow assembly rules behave like natives, while those exhibiting novel interactions with community filters can greatly underperform or outperform natives. Additionally, advantages gained by exotics over natives following disturbance can be explained by accounting for extrinsic assembly processes that bias exotic traits toward ruderal strategies. PMID- 29605086 TI - Why Functional Traits Do Not Predict Tree Demographic Rates. AB - Foundational to trait-based community ecology is the expectation that functional traits determine demographic outcomes. However, trait-demographic rate relationships are frequently weak, particularly in tree communities. The foundation of trait-based tree community ecology may, therefore, appear to be unstable. Here we argue that there are three core reasons why trait-demographic relationships are generally weak in tree communities. Specifically, important contextual information is frequently ignored, there is too much focus on species relative to individuals, and there are dimensions of tree function that are critical for determining tree demographic rates that are not captured by easily measured functional traits. Rather than being evidence that trait-based community ecology is fundamentally flawed, these issues elucidate a pathway towards a more robust research program. PMID- 29605087 TI - Cryptic Species - Conceptual or Terminological Chaos? A Response to Struck et al. PMID- 29605088 TI - Corrigendum to "Surface chemical functionalization of cellulose nanocrystals by 3 aminopropyltriethoxysilane"[Int. J. Biol. Macromol. 106 (2018) 1288-1296]. PMID- 29605089 TI - Nurses' decision making in heart failure management based on heart failure certification status. AB - BACKGROUND: Research findings on the value of nurse certification were based on subjective perceptions or biased by correlations of certification status and global clinical factors. In heart failure, the value of certification is unknown. OBJECTIVES: Examine the value of certification based nurses' decision-making. METHODS: Cross-sectional study of nurses who completed heart failure clinical vignettes that reflected decision-making in clinical heart failure scenarios. Statistical tests included multivariable linear, logistic and proportional odds logistic regression models. RESULTS: Of nurses (N = 605), 29.1% were heart failure certified, 35.0% were certified in another specialty/job role and 35.9% were not certified. In multivariable modeling, nurses certified in heart failure (versus not heart failure certified) had higher clinical vignette scores (p = 0.002), reflecting higher evidence-based decision making; nurses with another specialty/role certification (versus no certification) did not (p = 0.62). CONCLUSIONS: Heart failure certification, but not in other specialty/job roles was associated with decisions that reflected delivery of high-quality care. PMID- 29605090 TI - Extracellular Vesicles: Multimodal Envoys in Neural Maintenance and Repair. AB - The physiology of the central nervous system (CNS) is built on a foundation of connection, integration, and the exchange of complex information among brain cells. Emerging evidence indicates that extracellular vesicles (EVs) are key players in the intercellular communication that underlies physiological processes such as synaptic plasticity and the maintenance of myelination. Furthermore, upon injury to the CNS, EVs may propagate inflammation across the blood-brain barrier and beyond, and also appear to mediate neuroprotection and modulate regenerative processes. In neurodegenerative diseases, EVs may play roles in the formation, spreading, and clearance of toxic protein aggregates. Here, we discuss the physiological roles of EVs in the healthy and the diseased CNS, with a focus on recent findings and emerging concepts. PMID- 29605091 TI - Ten-hour asymptomatic bronchoaspiration of a capsule endoscopy camera. PMID- 29605092 TI - Evaluation of a vaccination regimen and care in relation to follow-up and treatment of patients with inflammatory bowel disease. AB - INTRODUCTION AND AIMS: During the clinical course of inflammatory bowel disease, different causes can compromise kidney, liver, and bone marrow function and increase the risk for osteoporosis, infections, and neoplasias. The aim of the present study was to describe the follow-up of Mexican patients with inflammatory bowel disease in relation to their vaccination regimen, treatment-associated risks, and cancer screening. MATERIALS AND METHODS: A retrospective cross sectional study was conducted within the time frame of February and June 2017. One hundred patients that had a histopathologic diagnosis of inflammatory bowel disease were surveyed about their follow-up vaccination regimen, treatment associated risks, and cancer screening. SPSS v24 software was employed for the statistical analysis. RESULTS: One hundred patients with inflammatory bowel disease were studied (90% with ulcerative colitis and 10% with Crohn's disease; 60% women, 40% men): 75% stated that they had no vaccination regimen. A total of 71.4% of the women had at least one Pap smear in their lives and 28.6% did not have them done annually. Twenty-four percent of the patients wore sun block daily. A total of 18.2% of the patients with more than a 10-year progression of ulcerative colitis had an annual colonoscopy. Yearly kidney function was registered in 57.1% of the patients, 92.9% had a yearly complete blood count, and 78.6% had yearly liver function tests. A total of 34.8% of patients had no bone densitometry in their case records. CONCLUSIONS: These results are a red flag suggesting the need to reinforce the role of the primary healthcare providers in relation to vaccination follow-up and the need to improve the education of the patient in relation to inflammatory bowel disease. PMID- 29605093 TI - Mortality from chronic kidney disease in the elderly Peruvians, 2009-2013. PMID- 29605096 TI - Reporting identification of Acinetobacter spp genomic species: A nationwide proficiency study in Spain. AB - Acinetobacter baumannii is the most important genomic species of Acinetobacter from a clinical and epidemiological point of view. Nevertheless, genomic species other than A. baumannii are increasingly recognized as nosocomial pathogens. Molecular methods of identification (genotypic and proteomic assays) are more accurate and reliable and have greater discriminatory power than phenotypic methods. Eleven genomic species of Acinetobacter spp. (8 A. baumannii, 1 A. pittii, 1 A. nosocomialis and 1 A. lwoffii) with different antimicrobial resistance phenotypes and mechanisms of resistance to antimicrobial agents were sent to 48 participating Spanish centers to evaluate their ability for correct identification at the genomic species level. Identification of the genomic species was performed at the two Clinical Microbiology reference laboratories (Hospital Universitario Virgen Macarena, Seville, Spain; and Complejo Hospitalario Universitario de A Coruna, A Coruna, Spain) by partial DNA sequencing of the rpoB gene and MALDI-TOF. The mean percentage of agreement was 76.1%. Fifty percent of CC-01 (A. pittii) and 50% of CC-02 (A. nosocomialis) identification results were reported as A. baumannii. Discrepancies by type of systems used for identification were: MicroScan WA (51.1%), Vitek 2 (19.5%), MALDI-TOF (18.0%), Phoenix (4.5%), Wider (3.8%) and API 20 NE (3.0%). In conclusion, clinical microbiology laboratories must improve their ability to correctly identify the most prevalent non A. baumannii genomic species. PMID- 29605094 TI - Predicting timing of clinical outcomes in patients with chronic kidney disease and severely decreased glomerular filtration rate. AB - Patients with chronic kidney disease and severely decreased glomerular filtration rate (GFR) are at high risk for kidney failure, cardiovascular disease (CVD) and death. Accurate estimates of risk and timing of these clinical outcomes could guide patient counseling and therapy. Therefore, we developed models using data of 264,296 individuals in 30 countries participating in the international Chronic Kidney Disease Prognosis Consortium with estimated GFR (eGFR)s under 30 ml/min/1.73m2. Median participant eGFR and urine albumin-to-creatinine ratio were 24 ml/min/1.73m2 and 168 mg/g, respectively. Using competing-risk regression, random-effect meta-analysis, and Markov processes with Monte Carlo simulations, we developed two- and four-year models of the probability and timing of kidney failure requiring kidney replacement therapy (KRT), a non-fatal CVD event, and death according to age, sex, race, eGFR, albumin-to-creatinine ratio, systolic blood pressure, smoking status, diabetes mellitus, and history of CVD. Hypothetically applied to a 60-year-old white male with a history of CVD, a systolic blood pressure of 140 mmHg, an eGFR of 25 ml/min/1.73m2 and a urine albumin-to-creatinine ratio of 1000 mg/g, the four-year model predicted a 17% chance of survival after KRT, a 17% chance of survival after a CVD event, a 4% chance of survival after both, and a 28% chance of death (9% as a first event, and 19% after another CVD event or KRT). Risk predictions for KRT showed good overall agreement with the published kidney failure risk equation, and both models were well calibrated with observed risk. Thus, commonly-measured clinical characteristics can predict the timing and occurrence of clinical outcomes in patients with severely decreased GFR. PMID- 29605095 TI - Activated renal tubular Wnt/beta-catenin signaling triggers renal inflammation during overload proteinuria. AB - Imbalance of Wnt/beta-catenin signaling in renal cells is associated with renal dysfunction, yet the precise mechanism is poorly understood. Previously we observed activated Wnt/beta-catenin signaling in renal tubules during proteinuric nephropathy with an unknown net effect. Therefore, to identify the definitive role of tubular Wnt/beta-catenin, we generated a novel transgenic "Tubcat" mouse conditionally expressing stabilized beta-catenin specifically in renal tubules following tamoxifen administration. Four weeks after tamoxifen injection, uninephrectomized Tubcat mice displayed proteinuria and elevated blood urea nitrogen levels compared to non-transgenic mice, implying a detrimental effect of the activated signaling. This was associated with infiltration of the tubulointerstitium predominantly by M1 macrophages and overexpression of the inflammatory chemocytokines CCL-2 and RANTES. Induction of overload proteinuria by intraperitoneal injection of low-endotoxin bovine serum albumin following uninephrectomy for four weeks aggravated proteinuria and increased blood urea nitrogen levels to a significantly greater extent in Tubcat mice. Renal dysfunction correlated with the degree of M1 macrophage infiltration in the tubulointerstitium and renal cortical up-regulation of CCL-2, IL-17A, IL-1beta, CXCL1, and ICAM-1. There was overexpression of cortical TLR-4 and NLRP-3 in Tubcat mice, independent of bovine serum albumin injection. Finally, there was no fibrosis, activation of epithelial-mesenchymal transition or non-canonical Wnt pathways observed in the kidneys of Tubcat mice. Thus, conditional activation of renal tubular Wnt/beta-catenin signaling in a novel transgenic mouse model demonstrates that this pathway enhances intrarenal inflammation via the TLR 4/NLRP-3 inflammasome axis in overload proteinuria. PMID- 29605097 TI - 22nd World Muscle Society Congress Saint Malo 2017: Gulls on Guard through Ebb and Flow of Science Manifesting Extra Muscle. PMID- 29605098 TI - Possible involvement of acetylcholine-mediated inflammation in airway diseases. AB - Inhaled bronchodilator treatment with a long acting muscarinic antagonist (LAMA) reduces symptoms and the risk of exacerbations in COPD and asthma. However, increasing evidence from cell culture and animal studies suggests that anti muscarinic drugs could also possess anti-inflammatory effects. Recent studies have revealed that acetylcholine (ACh) can be synthesized and released from both neuronal and non-neuronal cells, and the released ACh can potentiate airway inflammation and remodeling in airway diseases. However, these anti-inflammatory effects of anti-muscarinic drugs have not yet been confirmed in COPD and asthma patients. This review will focus on recent findings about the possible involvement of ACh in airway inflammation and remodeling, and the anti inflammatory effect of anti-muscarinic drugs in airway diseases. Clarifying the acetylcholine-mediated inflammation could provide insights into the mechanisms of airway diseases, which could lead to future therapeutic strategies for inhibiting the disease progression and exacerbations. PMID- 29605099 TI - CRISPR/Cas13 as a Tool for RNA Interference. AB - Almost all biological processes involve RNA, making it crucial to develop tools for manipulation of the transcriptome. The bacterial CRISPR/Cas13 system was recently rewired to facilitate RNA manipulation in eukaryotes, including plants. We discuss here the opportunities and limitations of using CRISPR/Cas13 in plants for various types of RNA manipulation. PMID- 29605100 TI - How Does pH Fit in with Oscillating Polar Growth? AB - Polar growth in root hairs and pollen tubes is an excellent model for investigating plant cell size regulation. While linear plant growth is historically explained by the acid growth theory, which considers that auxin triggers apoplastic acidification by activating plasma membrane P-type H+-ATPases (AHAs) along with cell wall relaxation over long periods, the apoplastic pH (apopH) regulatory mechanisms are unknown for polar growth. Polar growth is a fast process mediated by rapid oscillations that repeat every ~20-40s. In this review, we explore a reactive oxygen species (ROS)-dependent mechanism that could generate oscillating apopH gradients in a coordinated manner with growth and Ca2+ oscillations. We propose possible mechanisms by which apopH oscillations are coordinated with polar growth together with ROS and Ca2+ waves. PMID- 29605101 TI - The latent trait of ICD-11 nicotine dependence criteria: Dimensional and categorical phenotypes. AB - We aimed to identify phenotypes of DSM-ICD nicotine dependence among a representative sample of lifetime weekly smokers in the largest metropolitan area in South America. Data came from 1,387 lifetime weekly smokers in the Sao Paulo Megacity Mental Health Survey. We used exploratory factor analysis (EFA) and latent class analysis (LCA) on ICD-11 nicotine dependence proposed criteria to explore dimensionality and phenotypes profiles, followed by logistic regression models to examine the association between latent classes and socio-demographic, psychiatric and chronic medical conditions. Analyses were performed using Mplus taking into account the complex survey design features. An unidimensional model had the best EFA fit with high loadings on all criteria. Response patterns detected by LCA indicated class differences based on severity continuum: a "non symptomatic class" (32.0%), a "low-moderate symptomatic class" (34.9%)-with high probability of the criterion "use in larger amounts", and a "high-moderate symptomatic class" (33.1%). We found an association between high-income and the intermediate class that differs from findings in high-income countries, and high likelihood of psychiatric comorbidity among the most symptomatic smokers. The best dimensional model that pulled together nicotine dependence criteria supported a single factor, in concordance with the changes proposed for ICD-11. PMID- 29605102 TI - Malignant Self-Regard in clinical outpatient samples. AB - While the malignant self-regard construct and a corresponding questionnaire, the Malignant Self-Regard Questionnaire (MSRQ; Huprich, 2011) have been empirically evaluated in several non-clinical samples, it has yet to be evaluated in a clinical population. In this study, 139 outpatients in the Departments of Psychiatry and Behavioral Sciences (n = 83) and Internal Medicine (n = 57) were administered the MSRQ and a number other measures to assess its construct and incremental validity. The MSRQ was internally consistent in both samples, and was positively correlated with four dimensions of levels of personality functioning, DSM-5 personality trait domains, overdependence, detachment, insecure attachment, and general perceptions of physical and mental well-being. Furthermore, the MSRQ incrementally predicated variance in levels of personality functioning, interpersonal dependency, and general perceptions of physical and mental well being above and beyond DSM-5 traits and (where appropriate) levels of personality functioning. These findings converge with studies of the MSRQ in nonclinical samples and support the clinical utility and validity of the MSRQ for further use. PMID- 29605103 TI - Effects of adjunctive N-acetylcysteine on depressive symptoms: Modulation by baseline high-sensitivity C-reactive protein. AB - : Outcomes in a RCTs of 12 weeks of theclinical efficacy of N-acetylcysteine (NAC) as an adjunctive treatment on depression and anxiety symptoms and its effects on high-sensitivity C-reactive protein (hs-CRP) levels. A wide array of measures were made. The 17-item version of the Hamilton Depression Rating Scale (HDRS17); the Hamilton Anxiety Rating Scale (HAM-A); Sheehan Disability Scale; Quality of Life; Clinical Global Impression (CGI); anthropometrics measures; and vital signs and biochemical laboratory. There were no significant differences among the groups regarding demographic, clinical features, use of medication, metabolic syndrome and comorbidities. From baseline to week 12, individuals receiving NAC, versus placebo, had a statistically significant reduction in depressive symptoms on HDRS17 (p < 0.01) and anxiety symptoms on HAM-A (p = 0.04), but only for individuals with levels of hs-CRP > 3 mg/L at baseline. Individuals receiving NAC with baseline levels of hs-CRP > 3 mg/L, had more significant reduction in uric acid levels compared to individuals with baseline levels of hs-CRP <= 3 mg/L on week 12. Participants receiving placebogained significantly more weight during the 12 weeks for baseline levels of hs-CRP <= 3 mg/L and hs-CRP > 3 mg/L, and individuals receiving NAC in both groups did not have significant weight change during the 12 weeks. No individuals were withdrawn from the study because of adverse event. NAC group exhibited significantly greater reduction on hs-CRP levels than placebo group from baseline to week 12. TRIAL REGISTRATION: clinicaltrials.gov Identifier; NCT02252341. PMID- 29605104 TI - The use of latent class analysis for identifying subtypes of depression: A systematic review. AB - Depression is a significant public health problem but symptom remission is difficult to predict. This may be due to substantial heterogeneity underlying the disorder. Latent class analysis (LCA) is often used to elucidate clinically relevant depression subtypes but whether or not consistent subtypes emerge is unclear. We sought to critically examine the implementation and reporting of LCA in this context by performing a systematic review to identify articles detailing the use of LCA to explore subtypes of depression among samples of adults endorsing depression symptoms. PubMed, PsycINFO, CINAHL, Scopus, and Google Scholar were searched to identify eligible articles indexed prior to January 2016. Twenty-four articles reporting 28 LCA models were eligible for inclusion. Sample characteristics varied widely. The majority of articles used depression symptoms as the observed indicators of the latent depression subtypes. Details regarding model fit and selection were often lacking. No consistent set of depression subtypes was identified across studies. Differences in how models were constructed might partially explain the conflicting results. Standards for using, interpreting, and reporting LCA models could improve our understanding of the LCA results. Incorporating dimensions of depression other than symptoms, such as functioning, may be helpful in determining depression subtypes. PMID- 29605105 TI - Optimisation of radiation dose and image quality in mobile neonatal chest radiography. AB - PURPOSE: To optimise the radiation dose and image quality for chest radiography in the neonatal intensive care unit (NICU) by increasing the mean beam energy. METHODS: Two techniques for the acquisition of NICU AP chest X-ray images were compared for image quality and radiation dose. 73 images were acquired using a standard technique (56 kV, 3.2 mAs and no additional filtration) and 90 images with a new technique (62 kV, 2 mAs and 2 mm Al filtration). The entrance surface air kerma (ESAK) was measured using a phantom and compared between the techniques and against established diagnostic reference levels (DRL). Images were evaluated using seven image quality criteria independently by three radiologists. Images quality and radiation dose were compared statistically between the standard and new techniques. RESULTS: The maximum ESAK for the new technique was 40.20 MUGy, 43.7% of the ESAK of the standard technique. Statistical evaluation demonstrated no significant differences in image quality between the two acquisition techniques. CONCLUSIONS: Based on the techniques and acquisition factors investigated within this study, it is possible to lower the radiation dose without any significant effects on image quality by adding filtration (2 mm Al) and increasing the tube potential. Such steps are relatively simple to undertake and as such, other departments should consider testing and implementing this dose reduction strategy within clinical practice where appropriate. PMID- 29605106 TI - Perspectives on the development of professionalism as experienced by radiography students. AB - INTRODUCTION: This study explores the perspectives of radiography students concerning the concept of professionalism and influence on its development. METHODS: This was a descriptive case study using interpretative phenomenological analysis methodology. Data were gathered from 31 students who participated in a questionnaire consisting of three sections. RESULTS: The results indicate that the students had an innate understanding of what professionalism is and they also described the main attributes, as highlighted by literature. The results further also indicated that there is a clear differentiation between the influence of the formal and hidden curricula. CONCLUSION: This study brings to light the experiences of student radiographers and what they expect would influence their professional development through the course of their training. Since their innate opinions align with international literature there is a need to have this included in formal dialogue. PMID- 29605107 TI - The introduction of mandatory CPD for newly state registered diagnostic radiographers: An Irish perspective. AB - INTRODUCTION: Irish diagnostic radiography has undergone significant change with the dual introduction of state registration and mandatory Continuing Professional Development (CPD) in October 2015. We aimed to investigate motivators and barriers around CPD participation, mechanisms of CPD delivery and confidence of radiographers in using e-learning. METHODS: A questionnaire distributed nationally during this period captured Radiographer opinion through the use of closed and open questions. The questionnaire was distributed in hard copy and online formats depending on site preference. RESULTS: 71% of centres participated, rendering 453 responses in total from a possible 1222 respondents employed in those sites at the time of the survey. A varied range of ages and post qualification experience were represented. Respondents indicated use of several CPD options with the majority considering CPD to be important, very important or critical. Social media as a mechanism of CPD delivery was considered acceptable by 48%, while online learning elicited responses ranging from not confident to absolutely confident. Top motivators for CPD activity included interest, developing new knowledge and competency. Principal barriers included funding, time allocation and location issues. CONCLUSION: This study identified Radiographer desire to undertake CPD and the need for developing online CPD offerings. An overall positive perception towards CPD was noted however barriers were identified which require specific redress strategies. PMID- 29605108 TI - Alleviating anxiety in patients prior to MRI: A pilot single-centre single blinded randomised controlled trial to compare video demonstration or telephone conversation with a radiographer versus routine intervention. AB - INTRODUCTION: Patients undergoing MRI often experience anxiety prior and during scanning. The aim of this study was to explore two simple, cost-effective and easily implemented interventions to reduce anxiety pre MRI scanning. METHODS: Seventy four patients attending first time for a MRI head, spine or cardiac scan were randomised into one of three interventions: video demonstration; telephone conversation with a radiographer; or routine MRI preparation (appointment letter). The State-Trait Anxiety Inventory (STAI) questionnaire was used to measure anxiety levels both pre and post intervention. Motion artefacts were visually assessed by 2 observers and a post scan survey was used to capture patient's satisfaction. RESULTS: ANCOVA revealed a significant reduction of anxiety in the video group (F = 13.664, p = 0.001), and also in the telephone group (F = 6.443, p = 0.015) compared to control patients. No significant difference was found between the two interventions (F = 0.665, p = 0.419). No difference was seen in motion artefacts between all three groups (Chi2 = 2.363 (p = 0.359) for observer 1 and Chi2 = 1.280 (p = 0.865) for observer 2). Fifty one percent (51.4%) of patients admitted to being anxious, with the possible outcome of the MRI results being the most common (18.9%) reason given for anxiety. CONCLUSION: This study has demonstrated that either of the interventions used can significantly reduce pre-MRI anxiety, with the video performing slightly better than the phone call intervention. Importantly, the routine appointment letter did not contain enough information to satisfy most patients, which argues strongly for a change in current practice. PMID- 29605109 TI - The experience of patients participating in a small randomised control trial that explored two different interventions to reduce anxiety prior to an MRI scan. AB - INTRODUCTION: This paper reports qualitative findings from within a larger randomised control trial where a video clip or telephone conversation with a radiographer was compared to routine appointment letter and information sheet to help alleviate anxiety prior to their MRI scan. METHODS: Questionnaires consisting of three free-text response questions were administered to all of the 74 patients recruited to the MRI anxiety clinical trial. The questionnaire was designed to establish patients' experiences of the intervention they had received. These questionnaires were administered post-scan. Two participants from each trial arm were also interviewed. A thematic approach was utilised for identifying recurrent categories emerging from the qualitative data which are supported by direct quotations. RESULTS: Participants in the interventional groups commented positively about the provision of pre-MRI scan information they received and this was contrastable with the relatively indifferent responses observed among those who received the standard information letter. Many important themes were identified including the patients needs for clear and simplified information, the experience of anticipation when waiting for the scan, and also the informally acquired information about having an MRI scan i.e. the shared experiences of friends and family. All themes highlighted the need for an inclusive and individually tailored approach to pre-scan information provision. CONCLUSION: Qualitative data collected throughout the trial is supportive of the statistical findings, where it is asserted that the use of a short video clip or a radiographer having a short conversation with patients before their scan reduces pre-scan anxiety. PMID- 29605110 TI - Digital imaging and radiographic practise in diagnostic radiography: An overview of current knowledge and practice in Europe. AB - INTRODUCTION: Recent research has identified the issue of 'dose creep' in diagnostic radiography and claims it is due to the introduction of CR and DR technology. More recently radiographers have reported that they do not regularly manipulate exposure factors for different sized patients and rely on pre-set exposures. The aim of the study was to identify any variation in knowledge and radiographic practice across Europe when imaging the chest, abdomen and pelvis using digital imaging. METHODS: A random selection of 50% of educational institutes (n = 17) which were affiliated members of the European Federation of Radiographer Societies (EFRS) were contacted via their contact details supplied on the EFRS website. Each of these institutes identified appropriate radiographic staff in their clinical network to complete an online survey via SurveyMonkey. Data was collected on exposures used for 3 common x-ray examinations using CR/DR, range of equipment in use, staff educational training and awareness of DRL. Descriptive statistics were performed with the aid of Excel and SPSS version 21. RESULTS: A response rate of 70% was achieved from the affiliated educational members of EFRS and a rate of 55% from the individual hospitals in 12 countries across Europe. Variation was identified in practice when imaging the chest, abdomen and pelvis using both CR and DR digital systems. There is wide variation in radiographer training/education across countries. CONCLUSION: There is a need for standardisation of education and training including protocols and exposure parameters to ensure that there is continued adherence to the ALARA principle. PMID- 29605112 TI - Ionising radiation risk disclosure: When should radiographers assume a duty to inform? AB - INTRODUCTION: Autonomy is a fundamental patient right for ethical practice, and informed consent is the mechanism by which health care professionals ensure this right has been respected. The ethical notion of informed consent has evolved alongside legal developments. Under Australian law, a provider who fails to disclose risk may be found to be in breach of a duty of disclosure, potentially facing legal consequences if the patient experiences harm that is attributable to an undisclosed risk. These consequences may include the common law tort of negligence. Ionising radiation, in the form of a medical imaging examination, has the potential to cause harm. However, stochastic effects cannot be attributable to a specific ionising radiation event. What then is the role of the Australian medical imaging service provider in disclosing ionising radiation risk? METHODS: The ethical and legal principles of informed consent, and the duty of information provision to the patient are investigated. These general principles are then applied to the specific and unusual case of ionising radiation, and what responsibilities apply to the medical imaging provider. Finally, the legal, professional and ethical duties of the radiographer to disclose information to their patients are investigated. RESULTS: Australian law is unclear as to whether a radiographer has a common law responsibility to disclose radiation risk. There is ambiguity as to whether stochastic ionising radiation risk could be considered a legal disclosure responsibility. CONCLUSION: While it is unlikely that not disclosing risk will have medicolegal consequences, doing so represents sound ethical practice. PMID- 29605111 TI - A service evaluation of on-line image-guided radiotherapy to lower extremity sarcoma: Investigating the workload implications of a 3 mm action level for image assessment and correction prior to delivery. AB - INTRODUCTION: Although all systematic and random positional setup errors can be corrected for in entirety during on-line image-guided radiotherapy, the use of a specified action level, below which no correction occurs, is also an option. The following service evaluation aimed to investigate the use of this 3 mm action level for on-line image assessment and correction (online, systematic set-up error and weekly evaluation) for lower extremity sarcoma, and understand the impact on imaging frequency and patient positioning error within one cancer centre. METHODS: All patients were immobilised using a thermoplastic shell attached to a plastic base and an individual moulded footrest. A retrospective analysis of 30 patients was performed. Patient setup and correctional data derived from cone beam CT analysis was retrieved. The timing, frequency and magnitude of corrections were evaluated. The population systematic and random error was derived. RESULTS: 20% of patients had no systematic corrections over the duration of treatment, and 47% had one. The maximum number of systematic corrections per course of radiotherapy was 4, which occurred for 2 patients. 34% of episodes occurred within the first 5 fractions. All patients had at least one observed translational error during their treatment greater than 0.3 cm, and 80% of patients had at least one observed translational error during their treatment greater than 0.5 cm. The population systematic error was 0.14 cm, 0.10 cm, 0.14 cm and random error was 0.27 cm, 0.22 cm, 0.23 cm in the lateral, caudocranial and anteroposterial directions. The required Planning Target Volume margin for the study population was 0.55 cm, 0.41 cm and 0.50 cm in the lateral, caudocranial and anteroposterial directions. CONCLUSION: The 3 mm action level for image assessment and correction prior to delivery reduced the imaging burden and focussed intervention on patients that exhibited greater positional variability. This strategy could be an efficient deployment of departmental resources if full daily correction of positional setup error is not possible. PMID- 29605113 TI - Disuse osteopenia following leg fracture in postmenopausal women: Implications for HIP fracture risk and fracture liaison services. AB - INTRODUCTION: Disuse osteopenia is a known consequence of reduced weight-bearing and has been demonstrated at the hip following leg injury but has not been specifically studied in postmenopausal women. METHOD: Bilateral DXA (GE Lunar Prodigy) bone mineral density (BMD) measurements were taken at the neck of femur (NOF), total hip region (TH) and lumbar spine in postmenopausal female groups comprising controls (N = 43), new leg fractures (#<3wks) (N = 9), and participants who had sustained a leg fracture more than one year previously (#>1yr) (N = 24). #>1yr were assessed at a single visit and the remaining groups at intervals over twelve months. Weight-bearing, function, 3-day pedometer readings, and pain levels were also recorded. RESULTS: The #<3wks demonstrated significant (p < 0.05) losses in ipsilateral TH BMD at 6 weeks from baseline 0.927 +/- 0.137 g/cm2, to 0.916 +/- 0.151 g/cm2 improving to 0.946 +/- 0.135 g/cm2 (n.s) at 12 months following gradual return to normal function and weight bearing activity. The #>1yr scored significantly below controls in almost all key physical and functional outcomes demonstrating a long-term deficit in hip bone density on the ipsilateral side. CONCLUSION: The clinical significance of post fracture reduction in hip BMD is a potential increased risk of hip fracture for a variable period that may be mitigated after return to normal function and weight bearing. Improvement at 12 months in #<3wks is not consistent with #>1yr results indicating that long-term impairment in function and bone health may persist for some leg fracture patients. Unilateral bone loss could have implications for Fracture Liaison Services when assessing the requirement for medication post fracture. PMID- 29605114 TI - Digital training platform for interpreting radiographic images of the chest. AB - INTRODUCTION: Time delays and errors exist which lead to delays in patient care and misdiagnosis. Reporting clinicians follow guidance to form their own search strategy. However, little research has tested these training guides. With the use of eye tracking technology and expert input we developed a digital training platform to be used in chest image interpretation learning. METHODS: Two sections of a digital training platform were planned and developed; A) a search strategy training tool to assist reporters during their interpretation of images, and B) an educational tool to communicate the search strategies of expert viewers to trainees by using eye tracking technology. RESULTS: A digital training platform for use in chest image interpretation was created based on evidence within the literature, expert input and two search strategies previously used in clinical practice. Images and diagrams, aiding translation of the platform content, were incorporated where possible. The platform is structured to allow the chest image interpretation process to be clear, concise and methodical. CONCLUSION: A search strategy was incorporated within the tool to investigate its use, with the possibility that it could be recommended as an evidence based approach for use by reporting clinicians. Eye tracking, a checklist and voice recordings have been combined to form a multi-dimensional learning tool, which has never been used in chest image interpretation learning before. The training platform for use in chest image interpretation learning has been designed, created and digitised. Future work will establish the efficacy of the developed approaches. PMID- 29605115 TI - Computer-aided detection in musculoskeletal projection radiography: A systematic review. AB - OBJECTIVES: To investigated the accuracy of computer-aided detection (CAD) software in musculoskeletal projection radiography via a systematic review. KEY FINDINGS: Following selection screening, eligible studies were assessed for bias, and had their study characteristics extracted resulting in 22 studies being included. Of these 22 three studies had tested their CAD software in a clinical setting; the first study investigated vertebral fractures, reporting a sensitivity score of 69.3% with CAD, compared to 59.8% sensitivity without CAD. The second study tested dental caries diagnosis producing a sensitivity score of 68.8% and specificity of 94.1% with CAD, compared to sensitivity of 39.3% and specificity of 96.7% without CAD. The third indicated osteoporotic cases based on CAD, resulting in 100% sensitivity and 81.3% specificity. CONCLUSION: The current evidence reported shows a lack of development into the clinical testing phase; however the research does show future promise in the variation of different CAD systems. PMID- 29605116 TI - Support needs of adolescents' post-cancer treatment: A systematic review. AB - INTRODUCTION: The study aimed to investigate the support needs for adolescents' post-cancer treatment. MATERIALS AND METHODS: A systematic literature review was conducted, articles were obtained from the following databases, Science Direct, PubMed and SCOPUS. Additional studies were identified from the reference lists of articles included in the review. RESULTS: 119 articles were identified as potentially relevant, of these, a total of 16 articles were nominated to be included in the review for analysis. CONCLUSION: The role of relationships and key workers were important to enabling survivors to self-manage. Studies have commended the role of friendships during the cancer treatment process but also as a means to coping with issues relating to survivorship. Using a coping mechanism thought to be beneficial by the survivor often improves their overall wellbeing. The eagerness to continue a normal successful life post-cancer treatment seems to be over-shadowed by the fear of not being able to conceive offspring. This, in turn, can impact the psychological wellbeing of survivors, thus signifying the need to develop ways in supporting these individuals. With research into quality of life (QoL) and survivorship issues continuing to progress and reach new heights, there is still much to be done. PMID- 29605118 TI - Editors' choice paper (Volume 23, 2017). PMID- 29605117 TI - Response to letter: Can placing lead-rubber inferolateral to the light beam diaphragm limit ionising radiation to multiple radiosensitive organs? PMID- 29605119 TI - Social media and radiography research: Ethical considerations. PMID- 29605120 TI - Assessment of deep inspiration breath hold (DIBH) amplitude and reduction in cardiac dose in left breast cancer patients. AB - INTRODUCTION: The primary aim of this study was to examine the impact of deep inspiration breath-hold (DIBH) amplitude on subsequent mean heart dose and V30 during radiotherapy. The secondary aim was to investigate if patient age influenced DIBH amplitude. METHOD: A retrospective study of 30 patients with left sided breast cancer was completed. Patients were randomly selected from the total number of patients dual scanned in free breathing (FB) and DIBH over a 2-year period. Plans were retrospectively virtually simulated and statistical analysis performed. RESULTS: All patients achieved decreased V30 and mean cardiac dose using DIBH. A positive correlation was found between DIBH amplitude and cardiac V30 dose reduction (p = 0.007, R = 0.48). Ratio of amplitude increase from FB to DIBH and cardiac V30 reduction was positively correlated and statistically significant (p = 0.04, R = 0.38); Ratio of amplitude increase of at least 15 times FB achieved 100% V30 dose reduction, however this was also achieved with ratio increase as low as 6.25 times FB. A statistically significant positive correlation was identified between DIBH amplitude and mean cardiac dose reduction (p = 0.003, R = 0.523). No correlation was found between patient age and amplitude ratio increase (p = 0.602, R = -0.099). CONCLUSION: A 100% reduction in cardiac V30 can be achieved with a DIBH amplitude increase of 15 times FB. A full reduction can also be achieved at much lower levels (6.25 times FB in current study); however there appears to be no pre-determining patient factors to identify this. DIBH amplitudes of 1 cm-4 cm reduce cardiac mean dose by at least 50%. PMID- 29605121 TI - An audit of clinical practice, referral patterns, and appropriateness of clinical indications for brain MRI examinations: A single-centre study in Ghana. AB - INTRODUCTION: The aim of this study was to investigate current brain MRI practice, pattern of brain MRI requests, and their appropriateness using the American College of Radiology (ACR) Appropriateness Criteria. MATERIAL AND METHODS: We used direct observation and questionnaires to obtain data concerning routine brain MRI practice. We then retrospectively analyzed (i) demographic characteristics, (ii) clinical history, and (iii) appropriateness of brain MRI requests against published criteria. RESULTS: All patients were administered the screening questionnaire; however, no reviews were undertaken directly with patients, and no signature of the radiographer was recorded. Apart from routine brain protocol, there were dedicated protocols for epilepsy and stroke. Brain MRI images from 161 patients (85 Males; 76 Females) were analyzed. The age group with most brain MRI requests were from 26 to 45 year olds. The commonest four clinical indications for imaging were brain tumour, headache, seizure, and stroke. Using the ACR Appropriateness Criteria, almost 43% of the brain MRI scans analyzed were found to be "usually appropriate", 38% were "maybe appropriate" and 19% were categorized as "usually not appropriate". CONCLUSION: There was knowledge gap with regards to MRI safety in local practice, thus there is the utmost need for MRI safety training. Data on the commonest indications for performing brain MRI in this study should be used to inform local neuroradiological practice. Dedicated stroke and epilepsy MRI protocols require additional sequences i.e. MRA and 3D T1 volume acquisition, respectively. The ACR Appropriateness Criteria is recommended for use by the referring practitioners to improve appropriateness of brain MRI requests. PMID- 29605122 TI - The effect of personalized versus standard patient protocols for radiostereometric analysis (RSA). AB - INTRODUCTION: Increasing pressure in the clinic requires a more standardized approach to radiostereometric analysis (RSA) imaging. The aim of this study was to investigate whether implementation of personalized RSA patient protocols could increase image quality and decrease examination time and the number of exposure repetitions. METHODS: Forty patients undergoing primary total hip arthroplasty were equally randomized to either a case or a control group. Radiographers in the case group were assisted by personalized patient protocols containing information about each patient's post-operative RSA imaging. Radiographers in the control group used a standard RSA protocol. RESULTS: At three months, radiographers in the case group significantly reduced (p < 0.001) the number of exposures by 1.6, examination time with 19.2 min, and distance between centrum of prosthesis and centrum of calibration field with 34.1 mm when compared to post-operative (baseline) results. At twelve months, the case group significantly reduced (p < 0.001) number of exposures by two, examination time with 22.5 min, and centrum of prosthesis to centrum of calibration field distance with 43.1 mm when compared to baseline results. No significant improvements were found in the control group at any time point. CONCLUSION: There is strong evidence that personalized RSA patient protocols have a positive effect on image quality and radiation dose savings. Implementation of personal patient protocols as a RSA standard will contribute to the reduction of examination time, thus ensuring a cost benefit for department and patient safety. PMID- 29605123 TI - A pilot study to determine the effect of radiographer training on radiostereometric analysis imaging technique. AB - INTRODUCTION: Producing x-ray images for radiostereometric analysis (RSA) is a demanding technique. Suboptimal examinations result in a high percentage of exposure repetition. The aim of this pilot study was to use an experiential training approach to sharpen the skills of radiographers in acquiring images of an optimal quality. METHODS: A controlled trial using action research strategy was used. The study entailed a two phased approach. Radiographers were purposefully recruited and trained to perform the required investigations. Each phase included 12 examinations of a total knee arthroplasty phantom followed by 10 patient examinations. The quality of all x-ray images performed during the two phases was characterized by measuring the number of visible beads, the center position of the prosthesis (CP) compared to the center of calibration field (CCF). The number of re-exposures used to obtain a usable image during patient examinations was also recorded. RESULTS: The radiographers undergoing the training resulted in a significant improvement in the quality of images produced and visualization of the beads. That is, the ability to move the CP on average 36.1 mm closer to the CCF (p < 0.001), the number of visible beads increased by 3.1 (p < 0.001) and radiographers needed 2.1-2.9 exposures less to obtain RSA images of sufficient qualities during patient examinations in phase 2 (p < 0.001). CONCLUSION: This study illustrates the value of experiential method of teaching and learning with minimal compromise on patient safety but a significant contribution in terms of establishing quality of RSA images. PMID- 29605124 TI - Application of newly developed Fluoro-QC software for image quality evaluation in cardiac X-ray systems. AB - INTRODUCTION: A quality assurance (QA) program is a valuable tool for the continuous production of optimal quality images. The aim of this paper is to assess a newly developed automatic computer software for image quality (IR) evaluation in fluoroscopy X-ray systems. METHODS: Test object images were acquired using one fluoroscopy system, Siemens Axiom Artis model (Siemens AG, Medical Solutions Erlangen, Germany). The software was developed as an ImageJ plugin. Two image quality parameters were assessed: high-contrast spatial resolution (HCSR) and signal-to-noise ratio (SNR). The time between manual and automatic image quality assessment procedures were compared. The paired t-test was used to assess the data. p Values of less than 0.05 were considered significant. RESULTS: The Fluoro-QC software generated faster IQ evaluation results (mean = 0.31 +/- 0.08 min) than manual procedure (mean = 4.68 +/- 0.09 min). The mean difference between techniques was 4.36 min. Discrepancies were identified in the region of interest (ROI) areas drawn manually with evidence of user dependence. The new software presented the results of two tests (HCSR = 3.06, SNR = 5.17) and also collected information from the DICOM header. Significant differences were not identified between manual and automatic measures of SNR (p value = 0.22) and HCRS (p value = 0.46). CONCLUSION: The Fluoro-QC software is a feasible, fast and free to use method for evaluating imaging quality parameters on fluoroscopy systems. PMID- 29605125 TI - MRI artefact in the rectum caused by ingested orthodontic brackets. AB - Magnetic susceptibility artefacts, caused by metallic objects, present a challenge in magnetic resonance imaging (MRI). In this case, MRI showed metal induced artefact in the rectum of a 14-year-old girl who presented with pain in the coccyx after a snowboarding accident. Previous radiographs showed no evidence of metal in the area. After the identification of the artefact and upon discussion with the patient, she disclosed that two orthodontic brackets had been swallowed two days prior to the MRI examination, likely the source of artefact. Following the passage of the brackets, subsequent MRI was artefact-free. A similar artefact was recreated by scanning a potato with and without an orthodontic bracket, highlighting the impact of the resulting artefact on MRI. PMID- 29605126 TI - Visualizing and studying frictional heating effects in reversed-phase liquid chromatography using infrared thermal imaging. AB - Column temperature control is a fundamental component of liquid chromatography experiments. However, it is typically monitored indirectly by tracking the temperature of an adjacent heating element that exchanges heat with the column in a controlled environment. The practice of not directly measuring the column temperature means that uncontrolled contributions of heat, such as frictional heating inside the column, can be overlooked. The present work describes the use of a high-resolution infrared thermal imaging camera to directly measure the column heat map during mobile phase flow. The approach was used to measure the longitudinal temperature gradient formed with three common mobile phases: water, methanol, and acetonitrile, in two 50 mm reversed-phase columns, a 1.7 MUm particle-packed column and a polystyrene divinylbenzene monolith. In a close approximation to an adiabatic environment, the temperature gradients (DeltaT) observed with the 1.7 MUm particle column at a linear velocity of 5.8 mm/s were up to +16.6 and + 12.8 degrees C above an ambient temperature of 23 degrees C for water and acetonitrile, respectively. In the case of water, the measured temperature gradient values (DeltaT) were within 1% difference of theoretically calculated values and on average within 10% for acetonitrile. By contrast, the DeltaT observed in the monolith was negligible. The elevated temperatures that are generated through friction in sub-2 MUm particle columns may be particularly important to consider for the design of experiments that measure structural features of temperature-sensitive analytes, such as biomolecules. While frictional heating is one important application of the thermal imaging approach described, the technique can be used to provide a data-rich profile of heat exchange in numerous experimental configurations, chromatographic or otherwise. PMID- 29605127 TI - Reaction-based SERS nanosensor for monitoring and imaging the endogenous hypochlorous acid in living cells. AB - Hypochlorous acid (HOCl), as an important reactive oxygen species (ROS), is involved with many pathological and physiological pathways, whereas many aspects of its roles remain unclear due to the lack of robust analytical methods. In this work, we report a novel kind of special reaction-based nanosensors, gold nanoparticles modified with newly synthesized 2-mercapto-4-methoxy-phenol molecules (AuNPs/MMP), to detect the endogenous HOCl in living cells according to the changes in the SERS spectrum of AuNPs/MMP resulting from the reaction of HOCl with MMP on AuNPs. These nanosensors can rapidly respond to HOCl within 1 min with the detection limit at 10-7 M level. Furthermore, the nanosensors exhibit high selectivity for HOCl because of the specificity of the reaction combined with the fingerprinting capability of SERS. Consequently, the proposed SERS nanosensors are capable of monitoring and imaging the endogenous HOCl generated in a living macrophage under stimulation, showing great promise to be used for in situ studies of the pathophysiological processes that involve HOCl. PMID- 29605128 TI - Solid phase microextraction with poly(deep eutectic solvent) monolithic column online coupled to HPLC for determination of non-steroidal anti-inflammatory drugs. AB - Polymer monolithic column based on a green deep eutectic solvent (DES) was prepared for in-tube solid phase microextraction of non-steroidal anti inflammatory drugs (NSAIDs) in aqueous samples. DES composed of choline chloride and itaconic acid was adopted as functional monomer to synthesize a polymeric monolith inside polydopamine-functionalized poly(ether ether ketone) (PEEK) tube. The obtained monolithic column was characterized with fourier transform infrared spectrometry, X-ray photoelectron spectrometer and field emission scanning electron microscope. An online SPME-HPLC method was developed by connecting the PEEK tube to the HPLC system. Parameters including sampling rate, desorption time, sample pH value and sample volume that can affect the performance of this method were investigated. Under the optimized conditions, the proposed SPME-HPLC method showed high extraction efficiency (enrichment factors about 100), good linearity (R >= 0.9997) and good reproducibility (relative standard deviation < 4.32%) for determination of three NSAIDs in aqueous solution. The limits of quantification were found to be in a range of 0.05-0.25 ng mL-1. The SPME-HPLC method was also successfully applied to detect NSAIDs in lake water and human plasma samples. PMID- 29605129 TI - Stop-flow reversed phase liquid chromatography * size-exclusion chromatography for separation of peptides. AB - Size-exclusion chromatography (SEC) with wide application in peptide analysis presents challenges in determination of molecular weight distribution due to the relatively low resolution. In this study, a stop-flow reversed phase liquid chromatography (RPLC) * SEC system was constructed, aiming at improving the peptide separation in SEC. As the chromatographic dispersion during stop-flow operation might contribute to the band broadening in the first dimension (1st D) RPLC, the effects of different stop-flow operational parameters on the additional band broadening were quantitatively evaluated. Unlike analytes of large molecular size or long retention time with low effective diffusion coefficient (Deff), additional band broadening was evidently observed for analytes of small molecular size and short retention time (high Deff). Therefore, optimal flow rate, low column temperature and short stop-flow time were suggested for analyzing small molecules of short retention time. The established stop-flow two-dimensional liquid chromatography (2D-LC) was further tested on protein hydrolysates. The resolution was evidently improved for both heart-cutting and comprehensive 2D-LC analysis (despite additional band broadening in RPLC). Compared with heart cutting analysis with higher 1st D resolution for selective fractions, comprehensive analysis could provide more complete information about the molecular weight distribution of the eluting solutes along RPLC. PMID- 29605131 TI - Nanofiber polymers as novel sorbents for on-line solid phase extraction in chromatographic system: A comparison with monolithic reversed phase C18 sorbent. AB - A novel application of nanofiber polymers in the wide area of a sample preparation techniques known as solid phase extraction has been studied. We demonstrated application of nanofibers as sorbents for use in a system including on-line extraction coupled with column-switching high performance liquid chromatography. Four types of nanofibers including polyamide 6 with two different surface densities, poly(epsilon-caprolactone), and polystyrene were tested. We found that three of them were very efficient extraction sorbents sufficiently stable for application in the on-line system. Our results confirmed that the extraction efficiency of the nanofibers depended on the type and chemistry of the spun polymer as well as on the fabrication process of the nanofibrous mats that affected their density, structure, surface density, and mechanical functionality. We also compared performance of all four nanofibers with a conventional monolithic reversed-phase C18 sorbent in terms of extraction efficiency using on line solid-phase extraction-HPLC system. Polyamide 6 was found to be the best sorbent for lipophilic analytes with a retention and extraction efficiency for the target analytes comparable with that of the C18 monolith. PMID- 29605130 TI - Ultrasound assisted enzymatic hydrolysis for isolating titanium dioxide nanoparticles from bivalve mollusk before sp-ICP-MS. AB - Applicability of single-particle inductively coupled plasma mass spectrometry (sp ICP-MS) using dwell times equal to or shorter than 100 MUs has been tested for assessing titanium dioxide nanoparticles (TiO2 NPs) in bivalve mollusks. TiO2 NPs isolation from fresh mollusk tissues was achieved by ultrasound assisted enzymatic hydrolysis procedure using a pancreatin/lipase mixture. Optimum extraction conditions imply ultrasonication (60% amplitude) for 10 min, and 7.5 mL of a solution containing 3.0 g L-1of pancreatin and lipase (pH 7.4). The developed method was found to be repeatable (repeatability of 17% for the over all procedure, TiO2 NPs concentration of 5.33 * 107 +/- 8.89 * 106, n = 11), showing a limit of detection of 5.28 * 106 NPs g-1, and a limit of detection in size of 24.4-30.4 nm, based on the 3sigma criteria, and on the 3sigma/5 sigma criteria, respectively. The analytical recovery within the 90-99% range (use of TiO2 NPs standards of 50 nm at 7 and 14 MUg L-1 as Ti). Several bivalve mollusks (clams, cockles, mussels, razor clams, oysters and variegated scallops) were analyzed for total titanium (ICP-MS after microwave assisted acid digestion), and for TiO2 NPs by the proposed method. TiO2 NPs concentrations were within the 2.36 * 107-1.25 * 108 NPs g-1 range, and the most frequent sizes were from 50 to 70 nm. PMID- 29605132 TI - Synthesis and application of molecularly imprinted silica for the selective extraction of some polar organophosphorus pesticides from almond oil. AB - The aim of this work was to prepare and evaluate molecularly imprinted polymers obtained by a sol-gel approach for the selective solid-phase extraction (SPE) of organophosphorus pesticides (OPs) from almond oil. The performances of molecularly imprinted silicas (MISs), prepared using different conditions of synthesis, were studied by applying different extraction procedures in order to determine the ability of the MISs to selectively extract ten target OPs. For this, the retention of OPs on MISs in pure media was compared with the retention on a non-imprinted silicas (NISs), used as control sorbent, to prove the presence of specific cavities. The most promising MIS allowed the selective extraction of the 3 most polar OPs among the 10 studied. The capacity was studied and the repeatability of the extraction recovery yield was demonstrated both in pure and real media. This MIS was able to selectively extract fenthion sulfoxide and dimethoate contained in almond oil extract after applying the optimized extraction procedure with recovery yields between 100 and 114%. The estimated limit of quantification (LOQ, S/N = 10), thanks to LC/MS analysis in MRM mode, between 1.2 and 4.6 MUg/kg for those OPs in the almond fruits, was more than 10 times lower than the Maximum Residue Levels (MRLs) established by the European Commission. This MIS therefore shows a high potential for the analysis of those two polar OPs at trace levels from almond oils. PMID- 29605133 TI - The influence of pH on sampler uptake for an improved configuration of the organic-diffusive gradients in thin films passive sampler. AB - Recent literature has demonstrated the utility of the organic-diffusive gradients in thin films (o-DGT) device as an effective passive sampler for polar organics in aquatic environments. Here, a new configuration comprising a polyacrylamide diffusive gel and SepraTM ZT sorbent was developed and calibrated under multiple pH conditions. Linear uptake (r2 > 0.9) was observed at pH ~ 5 for a suite of 31 pharmaceuticals and pesticides over 25 days, suitable for typical passive sampler deployments. At pH ~ 8.5, linear uptake (r2 > 0.9) was observed for many of the same compounds. Comparisons of the uptake rates between the two pH experiments generally agreed (14% average relative error), with only 6 compounds exhibiting marked reduction with pH (e.g. sulfonamide antibiotics). These discrepancies may be explained by changes in analyte-sorbent interaction (H-bonding) due to speciation changes at varying pH. Samplers performed well in field evaluations conducted in an impacted river system, showing close agreement with the previously validated agarose/HLB o-DGT configuration deployed simultaneously. This work illustrates that polyacrylamide diffusive gels are a more robust and resistant outer-membrane material compared to agarose used in earlier o-DGT configurations. SepraTM ZT binding gels served as an effective binding resin, offering a cost effective and commercially available sorbent. PMID- 29605134 TI - Highly-sensitive open-cell LA-ICPMS approaches for the quantification of rare earth elements in natural carbonates at parts-per-billion levels. AB - This work presents a high-sensitivity approach to quantify ultra-trace concentrations of rare earth elements (REEs) in speleothem carbonates using open cell laser ablation-sector field-inductively coupled plasma mass spectrometry (open-cell LA-SF-ICPMS). Specifically, open-cell LA in combination with a gas exchange device enabled sampling of large-scale carbonate specimens in an ambient environment. The use of a "jet" vacuum interface and the addition of small amounts of N2 gas allowed for a 20-40 fold sensitivity enhancement compared to the conventional interface configuration. Mass load effects, quantification capabilities and detection power were investigated in analyses of reference materials using various combinations of spot sizes and laser repetition rates. From a 160 MUm diameter circular laser spot and 10 Hz ablation frequency, limits of detection were in the low or sub-ng g-1 range for REEs. Little dependence of Ca normalized sensitivity factors on the amount of material introduced into the plasma was observed. Relative deviations of quantified concentrations from USGS MACS-3 preferred values were smaller than 12%. The analytical approach enabled the determination of REE concentration profiles at the single digit ng g-1 level. Application to a 15-cm piece stalagmite collected from East Timor revealed at least two abrupt elevations in light rare earth elements (LREEs) within a scanning distance of 8 mm. These anomaly regions extended over a distance of ~200 MUm and showed LREE abundances elevated by at least one order of magnitude. This high-resolution open-cell LA-SF-ICPMS method has the potential to be applied in micro-domain analyses of other natural carbonates, such as travertine, tufa, and flowstones. This is promising for a better understanding of earth and environmental sciences. PMID- 29605135 TI - Mass spectrometry profiling reveals altered plasma levels of monohydroxy fatty acids and related lipids in healthy humans after controlled exposure to biodiesel exhaust. AB - Experimental human exposure studies are an effective tool to study adverse health effects from acute inhalation of particulate matter and other constituents of air pollution. In this randomized and double-blinded crossover study, we investigated the systemic effect on bioactive lipid metabolite levels after controlled biodiesel exhaust exposure of healthy humans and compared it to filtered air at a separate exposure occasion. Eicosanoids and other oxylipins, as well as endocannabinoids and related lipids, were quantified in plasma from 14 healthy volunteers at baseline and at three subsequent time points (2, 6, and 24 h) after 1 h exposure sessions. Protocols based on liquid chromatography (LC) coupled to tandem mass spectrometry (MS/MS) methods were developed to detect temporal changes in circulating levels after biodiesel exhaust exposure. The exhaust was generated by a diesel engine fed with an undiluted rapeseed methyl ester fuel. Among the 51 analyzed lipid metabolites, PGF2alpha, 9,10-DiHOME, 9-HODE, 5-HETE, 11-HETE, 12-HETE, and DEA displayed significant responsiveness to the biodiesel exhaust exposure as opposed to filtered air. Of these, 9-HODE and 5-HETE at 24 h survived the 10% false discovery rate cutoff (p < 0.003). Hence, the majority of the responsive lipid metabolites were monohydroxy fatty acids. We conclude that it is possible to detect alterations in circulating bioactive lipid metabolites in response to biodiesel exhaust exposure using LC-MS/MS, with emphasis on metabolites with inflammation related properties and implications on cardiovascular health and disease. These observations aid future investigations on air pollution effects, especially with regard to cardiovascular outcomes. PMID- 29605136 TI - Lanthanide polymer labels for multiplexed determination of biomarkers in human serum samples by means of size exclusion chromatography-inductively coupled plasma mass spectrometry. AB - Lanthanide polymer-labelled antibodies were investigated to improve the analytical figures of merit of homogeneous immunoassays with inductively coupled plasma mass spectrometry (ICP-MS) detection for multiplexed biomarker analysis in human serum samples. Specific monoclonal antibodies against four cancer biomarkers (CEA, sErbB2, CA 15.3 and CA 125) were labelled with different polymer based lanthanide group to increase the number of metal labels per binding site. After the immunoreaction of the biomarkers with the specific antibodies, antigen antibody complexes were separated by size-exclusion chromatography followed by ICP-MS detection. The polymer label could be loaded with 30-times more atoms of the lanthanide that the lanthanide-DOTA complex traditionally used for this purpose elsewhere [1] which resulted in a 10-fold improvement in both sensitivity and detection limits. Analytical figures of merit obtained with the lanthanide polymer labelling strategy make the detection of the biomarkers feasible below the threshold reference values used in clinical analysis. This labelling method was successfully validated by analyzing a control human serum spiked with the four biomarkers at three different concentration levels. For all the biomarkers studied, the recovery values ranged from 95% to 110% whereas inter-assay and intra-assay precision were lower than 8%. Results obtained with this approach were equivalent to those obtained by heterogenous-based immunoassays based on the detection by electro-chemiluminescence or ELISA. However, the method developed offers better analytical figures of merit using a smaller amount of sample. PMID- 29605137 TI - Plasma-assisted alignment in the fabrication of microchannel-array-based in-tube solid-phase microextraction microchips packed with TiO2 nanoparticles for phosphopeptide analysis. AB - Phosphorylated peptides are important for understanding the processes of biological regulation. However, the detection of phosphopeptides remains a challenge because of their low abundance and the suppression by non phosphopeptides. Here, we report a strategy for the facile and rapid fabrication of TiO2-nanoparticle-packed microchannel-array glass microchips (TMA-microchips) for in-tube solid-phase microextraction (IT-SPME) using a plasma-assisted method for the precise alignment of the microstructure. This proposed strategy was applied to the selective enrichment of phosphopeptides from a protein digestion mixture, demonstrating the high capacity and selectivity of the SPME microchips. An important feature of this array design is that it fully exploits the advantage of nanoparticles for improving extraction capacity and simultaneously provides an effective way to reduce the pressure for driving solutions; thus, it paves the way for future methods that simultaneously take advantage of nanomaterials and microchips. PMID- 29605138 TI - Equipment-free nucleic acid extraction and amplification on a simple paper disc for point-of-care diagnosis of rotavirus A. AB - The use of paper-based methods for clinical diagnostics is a rapidly expanding research topic attracting a great deal of interest. Some groups have attempted to realize an integrated nucleic acid test on a single microfluidic paper chip, including extraction, amplification, and readout functions. However, these studies were not able to overcome complex modification and fabrication requirements, long turn-around times, or the need for sophisticated equipment like pumps, thermal cyclers, or centrifuges. Here, we report an extremely simple paper-based test for the point-of-care diagnosis of rotavirus A, one of the most common pathogens that causes pediatric gastroenteritis. This paper-based test could perform nucleic acid extraction within 5 min, then took 25 min to amplify the target sequence, and the result was visible to the naked eye immediately afterward or quantitative by the UV-Vis absorbance. This low-cost method does not require extra equipment and is easy to use either in a lab or at the point-of care. The detection limit for rotavirus A was found to be 1 * 103 copies/mL. In addition, 100% sensitivity and specificity were achieved when testing 48 clinical stool samples. In conclusion, the present paper-based test fulfills the main requirements for a point-of-care diagnostic tool, and has the potential to be applied to disease prevention, control, and precision diagnosis. PMID- 29605139 TI - A sensitive colorimetric aptasensor based on trivalent peroxidase-mimic DNAzyme and magnetic nanoparticles. AB - In this study, a novel colorimetric aptasensor was prepared by coupling trivalent peroxidase-mimic DNAzyme and magnetic nanoparticles for highly sensitive and selective detection of target proteins. A three G-quadruplex (G4) DNA-hemin complex was employed as the trivalent peroxidase-mimic DNAzyme, in which hemin assisted the G4-DNA to fold into a catalytic conformation and act as an enzyme. The design of the aptasensor includes magnetic nanoparticles (MNPs), complementary DNA (cDNA) modified with biotin, and a label-free single strand DNA (ssDNA) including the aptamer and trivalent peroxidase-mimic DNAzyme. The trivalent DNAzyme, which has the highest catalytic activity among multivalent DNAzymes, catalyzed the H2O2-mediated oxidation of ABTS. The colorless ABTS was oxidized to produce a blue-green product that can be clearly distinguished by the naked eye. The aptamer and trivalent peroxidase-mimic DNAzyme promote the specificity and sensitivity of this detection method, which can be generalized for other targets by simply replacing the corresponding aptamers. To demonstrate the feasible use of the aptasensor for target detection, a well-known tumor biomarker MUC1 was evaluated as the model target. The limits of detection were determined to be 5.08 and 5.60 nM in a linear range of 50-1000 nM in a buffer solution and 10% serum system, respectively. This colorimetric and label-free aptasensor with excellent sensitivity and strong anti-interference ability has potential application in disease diagnoses, prognosis tracking, and therapeutic evaluation. PMID- 29605140 TI - AuNS@Ag core-shell nanocubes grafted with rhodamine for concurrent metal-enhanced fluorescence and surfaced enhanced Raman determination of mercury ions. AB - Mercury ion (Hg2+) is a highly hazardous and widespread pollutant with bio accumulative properties. Although the existing Hg2+ detection methods have high sensitivity and reliability, whereas there have few reports concerning bimodal detection for Hg2+ with one sensor. Toward this goal, a novel sensor based on rhodamine derivatives (RhD) grafted AuNS@Ag core-shell nanocubes (CSN) has been synthesized and shown the bimodal detection capabilities with metal enhanced fluorescence (MEF) and surface enhanced Raman scattering (SERS) for Hg2+. Herein, resultant CSN acts as the signal enhancing material; RhD was modified on the outside of the shell to ensure the signal sensitive of the CSN-RhD hybrids. In this work, we investigate the size- and shape-dependent SERS activity of plasmonic CSN comprised of AuNS as cores and Ag cuboids as shells. The SERS activity of CSN with spherical core was found to increase with the increasing thickness of the Ag cubic shell. Sequel, under an optimized condition, a display of strong MEF and SERS signals of the resulting mixtures with increasing of Hg2+ concentrations was observed. The proposed bimodal sensor showed excellent performances for Hg2+ along with wide linear range of 0.001-1000 ppm and 0.01 1000 ppm as well as the relatively low detection limit of 0.94 and 5.16 ppb for MEF and SERS assays, respectively. Furthermore, the ability of the sensor to detect Hg2+was also confirmed in adulterated milk samples. PMID- 29605142 TI - Short- and Long-Term Outcomes of Patients With Hypertrophic Cardiomyopathy After Noncardiac Surgery: A Single-Center Retrospective Study. AB - OBJECTIVE: Although several studies have demonstrated that noncardiac surgery in patients with hypertrophic cardiomyopathy (HCM) is safe, the long-term outcomes remain unclear. Therefore, the authors investigated the postoperative long-term outcomes of patients with HCM who underwent noncardiac surgery at their hospital. DESIGN: Retrospective review. SETTING: Single university hospital. PARTICIPANTS: Seventy-two consecutive patients with HCM who underwent noncardiac surgery. INTERVENTION: No intervention. MEASUREMENTS AND MAIN RESULTS: The incidence of HCM-related events during the patient's hospital stay were evaluated as the short term outcomes, and HCM-related events after discharge were evaluated as the long term outcomes. HCM-related events were defined as sudden death, implantable cardioverter-defibrillator discharge with successful recovery from cardiopulmonary arrest, death due to heart failure, hospitalization for heart failure, myocardial infarction, and thrombosis caused by atrial fibrillation. The median postoperative follow-up was 1,382 days (3.8 years). Short-term mortality and morbidity rates were both 1.3%, whereas long-term mortality and morbidity rates were 4.2% and 15%, respectively. The 5-year event-free rate was 76%, whereas the postoperative HCM-related mortality rate was 4.2%. CONCLUSIONS: This study suggests that noncardiac surgery in patients with HCM is safe in terms of both short- and long-term outcomes. To confirm the findings, additional studies, such as prospective, multicenter, observational studies, should be conducted. PMID- 29605143 TI - Refusal of recommended maternity care: Time to make a pact with women? AB - BACKGROUND: The right to refuse medical treatment can be contentious in maternity care. Professional guidance for midwives and obstetricians emphasises informed consent and respect for patient autonomy, but there is little guidance available to clinicians about the appropriate clinical responses when women decline recommended care. OBJECTIVES: We propose a comprehensive, woman-centred, systems level framework for documentation and communication with the goal of supporting women, clinicians and health services in situations of maternal refusal. We term this the Personalised Alternative Care and Treatment framework. DISCUSSION: The Personalised Alternative Care and Treatment framework addresses Australian policy, practice, education and professional issues to underpin woman-centred care in the context of maternal refusal. It embeds Respectful Maternity Care in system-level maternity care policy; highlights the woman's role as decision maker about her maternity care; documents information exchanged with women; creates a 'living' plan that respects the woman's birth intentions and can be reviewed as circumstances change; enables communication between clinicians; permits flexible initiation pathways; provides for professional education for clinicians, and incorporates a mediation role to act as a failsafe. CONCLUSION: The Personalised Alternative Care and Treatment framework has the potential to meet the needs of women, clinicians and health services when pregnant women decline recommended maternity care. PMID- 29605141 TI - Dietary sources of cumulative phthalates exposure among the U.S. general population in NHANES 2005-2014. AB - BACKGROUND: Anti-androgenic phthalates are reproductive toxicants that may have additive effects on male development. Diet is the primary exposure source for most phthalates, which contaminate the food supply through food contact materials and industrialized production. OBJECTIVE: To compare dietary sources of cumulative phthalates exposure between "food at home" (e.g. food consumed from a grocery store) and "food away from home" (e.g. food consumed from fast food/restaurants and cafeterias) in the U.S. general population. METHODS: We estimated cumulative phthalates exposure by calculating daily intake from metabolite concentrations in urinary spot samples for 10,253 participants (>=6 years old) using National Health and Nutrition Examination Survey (NHANES, 2005 2014) data. We constructed a biologically relevant metric of phthalates daily intake (?androgen-disruptor, MUg/kg/day) by converting phthalates into anti androgen equivalent terms prior to their summation. Particular foods and the percent of total energy intake (TEI) consumed from multiple dining out sources were ascertained from 24-h recall surveys. Associations with ?androgen-disruptor levels were estimated for children, adolescents, and adults using multivariable linear regression. RESULTS: We observed a consistent positive association between dining out and Sigmaandrogen-disruptor levels across the study population (p trend <0.0001). Among adolescents, high consumers of foods outside the home had 55% (95% CI: 35%, 78%) higher Sigmaandrogen-disruptor levels compared to those who only consumed food at home. The contribution of specific dining out sources to Sigmaandrogen-disruptor levels varied by age group. For example, cafeteria food was associated with 15% (95% CI: 4.0%, 28%) and 64% (95% CI: 40%, 92%) higher Sigmaandrogen-disruptor levels in children and adults, respectively. Particular foods, especially sandwiches (i.e. cheeseburgers), were associated with increased Sigmaandrogen-disruptor levels only if they were purchased away from home (p < 0.01). CONCLUSION: Dining out may be an important source of biologically relevant cumulative phthalates exposure among the U.S. POPULATION: Future studies should evaluate modifiable production practices that remove phthalates from the food supply in addition to the efficacy of interventions that promote eating fresh foods prepared at home. PMID- 29605144 TI - Efficacy of metformin on glycemic control and weight in drug-naive type 2 diabetes mellitus patients: A systematic review and meta-analysis of placebo controlled randomized trials. AB - AIM OF THE STUDY: Metformin is recommended as the first-line treatment of type 2 diabetes mellitus. Despite its common use, few studies have been conducted to precisely measure the efficacy of metformin versus placebo as a first-line treatment. This study aims to assess the precise effects of metformin monotherapy on glycemic control and weight in drug-naive patients with type 2 diabetes mellitus. METHODS: Medline(r) and Cochrane databases were searched until March 19, 2016 to perform a systematic review and meta-analysis of placebo-controlled randomized trials evaluating metformin monotherapy in drug-naive patients with type 2 diabetes mellitus. Assessed outcomes include glycemic control (fasting plasma glucose, glycosated hemoglobin) and weight. RESULTS: Overall, 16 studies (1140 patients) were selected. Compared to placebo, metformin monotherapy was associated with decreased glycosated hemoglobin by 0.95% at 3 months (95% CI: 0.50 to 1.39, I2=87%) and 1.32% at 6 months (95% CI: 1.01 to 1.62, I2=71%), and decreased fasting plasma glucose by 1.92mmol/L at 1 month (95% CI: 0.11 to 3.74, I2=88%), 1.79mmol/L at 3 months (95% CI: 0.92 to 2.66, I2=88%) and 2.14mmol/L at 6 months (95% CI: 1.17 to 3.12, I2=82%). No significant difference was demonstrated for the comparisons of weight due to relatively small number of studies retrieved from the literature resulting in insufficient statistical power. CONCLUSION: This study provides the precise effects of metformin monotherapy regarding the decreases in fasting plasma glucose and glycosated hemoglobin that physician can expected in drug-naive patients with type 2 diabetes mellitus. No evidence was found for the effects on weight. PMID- 29605145 TI - Use of available clinical evidence to extrapolate drug effects from adults to children. AB - The extrapolation of the benefit risk ratio from adults to children is performed during drug development and often implicitly used by many paediatricians when prescribing off-label drugs in children. This is due to the specific constraints of paediatric clinical research leading to a lack of safety and efficacy data in children. Extrapolation frameworks for drug development have been proposed by several regulatory agencies. Using a meta-epidemiological approach, we explored the similarities and differences of the benefit, the benefit risk ratio and the perceived placebo effect between adults and children from meta-analyses including randomized double-blinded placebo-controlled trials evaluating a drug intervention in an indication in adults and children with separate data for both populations. We also explored the use of the effect model using adult data to predict the treatment effect in children and to calibrate future paediatric clinical trials. Our research highlights the importance of using all available evidence and quantitative methods before extrapolating the benefit risk ratio from adults to children and carrying out new studies in the context of the existing evidence. More generally, this should be applied to any research to avoid a waste of time and resources invested. PMID- 29605146 TI - Principles and applications of pharmacometrics in drug evaluation in children. AB - Drug evaluation in children is difficult for many well-identified reasons and many drugs are still used off-label. Innovative approaches are particularly adapted to the paediatric and neonatal populations, as clinical trials are difficult to conduct, need adapted designs in order to define the optimal dosage regimen in many diseases and therapeutic areas. Population approaches to define pharmacokinetics and pharmacokinetic/pharmacodynamics are now more currently used to define dosing regimens, adapted to the different paediatric and neonatal age groups, that allow to increase efficacy and reduce toxicity, by taking into account factors explaining variability in drug response. Such approaches are presented and the evaluation of vancomycin in neonates is detailed as different steps allowed validation of the optimal strategy to administer vancomycin in neonates. PMID- 29605147 TI - How We Create and Value New Codes. PMID- 29605148 TI - Time Trends in Characteristics of Patients Undergoing Primary Total Hip and Knee Arthroplasty in California, 2007-2010. AB - BACKGROUND: As the number of total hip and knee arthroplasty cases increases, it is important to understand the burden of factors that impact patient outcomes of these procedures. This article examined the time trends in key demographics, clinical characteristics, comorbidity burden (Deyo-Charlson Comorbidity Index [CCI]), and presence of depression in patients undergoing primary total hip arthroplasty and total knee arthroplasty using population-based, all-payer inpatient database, California Healthcare Cost and Utilization Project, from 2007 to 2010. METHODS: Chi-square tests and analysis of variance were used. Multivariate logistic regression analyses were also performed to compare the prevalence of depression in 2007 to later years. RESULTS: In the primary total hip arthroplasty cohort, the prevalence of depression significantly increased by 20%, mean age decreased by 0.4 years, mean length of stay (LOS) decreased by 0.5 days, and having a CCI score of >=3 increased by 30% (P value < .001 for all) over the study period. Similarly, in the primary total knee arthroplasty cohort, the prevalence of depression increased by 23%, the mean age decreased by 0.4 years, mean LOS decreased by 0.4 days, and the prevalence of CCI score of >=3 increased by 35% (P value < .001 for all). CONCLUSION: Despite the younger age of the joint arthroplasty population over time, we found increased prevalence of depression and comorbidity scores but shorter LOS. Further study is needed to determine the impact of the changing demographics of the total joint population and the best strategies to optimize their outcome with these procedures. PMID- 29605149 TI - Inadequate Glycemic Control Is Associated With Increased Surgical Site Infection in Total Joint Arthroplasty: A Systematic Review and Meta-Analysis. AB - BACKGROUND: The association between inadequate glycemic control and surgical site infection (SSI) following total joint arthroplasty (TJA) remains unclear. The aim of this study is to assess the relationship between perioperative glycemic control and the risk for SSI, mainly periprosthetic joint infection. METHODS: We searched OVID-MEDLINE, Embase, and Web of Science from inception up to June 2017. The main independent variable was glycemic control as defined by glycated hemoglobin (HbA1C) or perioperative glucose values. The main outcome was SSI. Publication year, location, study design, sample population (size, age, gender), procedure, glycemic control assessment, infection outcome, results, confounders, and limitations were assessed. Studies included in the meta-analysis had stratified glycemic control using a distinct HbA1C cut-off. RESULTS: Seventeen studies were included in this study. Meta-analysis of 10 studies suggested that elevated HbA1C levels were associated with a higher risk of SSI after TJA (pooled odds ratio 1.49, 95% confidence interval 0.94-2.37, P = .09) with significant heterogeneity between studies (I2 = 81.32%, P < .0001). In a subgroup analysis of studies considering HbA1C with a cut-off of 7% as uncontrolled, this association was no longer noticed (P = .50). All 5 studies that specifically assessed for SSI and perioperative hyperglycemia showed a significant association, which was usually attenuated after adjusting for covariates. CONCLUSION: Inadequate glycemic control was associated with increased risk for SSI after TJA. However, the optimal HbA1C threshold remains contentious. Pooled data does not support the conventional 7% cut-off for risk stratification. Future studies should examine new markers for determining adequate glycemic control. PMID- 29605150 TI - Inferomedial Hip Center Decreases Failure Rates in Cementless Total Hip Arthroplasty for Crowe II and III Hip Dysplasia. AB - BACKGROUND: We sought to evaluate the outcomes of cementless acetabular components used in patients with Crowe II and III dysplasia, and to compare outcomes between cups placed within vs outside of an "anatomic" zone. Our specific aims were to (1) plot hip centers in these patients at our institution to characterize "anatomic" vs "nonanatomic" positions, (2) evaluate the association between hip center and radiographic loosening, (3) determine whether hip center was associated with acetabular component revision, and (4) compare patient-reported outcome scores between groups. METHODS: We retrospectively reviewed 88 primary cementless total hip arthroplasties at a mean follow-up of 10 years (range 2-26 years). Patients were 85% female, with a mean age of 44 years (range 28-61 years) and a body mass index of 27 kg/m2 (range 19-42 kg/m2). Medical records and radiographs were reviewed, and a survey was conducted for all patients. Anatomic hip center was defined using the 4-zone system, wherein centers are "anatomic" if they are <1 cm superior and <1 cm lateral to the approximate femoral head center. Cox proportional analyses were used to compare outcomes between groups. RESULTS: Seventy hips (80%) had an anatomic hip center. Anatomic hips had a lower incidence of radiographic acetabular loosening (0% vs 17%, P = .007) and cup revision (0% vs 28%, P = .0002). There were no differences in Hip Disability and Osteoarthritis Outcome and Joint Replacement Scores (96.2 +/- 5 vs 91.9 +/- 12, P = .7). CONCLUSION: The incidence of aseptic loosening and cup revision were lower when hip center was <1 cm superior and 1 cm lateral to the approximate femoral head center. PMID- 29605151 TI - Robotics in Orthopedics: A Brave New World. AB - Future health-care projection projects a significant growth in population by 2020. Health care has seen an exponential growth in technology to address the growing population with the decreasing number of physicians and health-care workers. Robotics in health care has been introduced to address this growing need. Early adoption of robotics was limited because of the limited application of the technology, the cumbersome nature of the equipment, and technical complications. A continued improvement in efficacy, adaptability, and cost reduction has stimulated increased interest in robotic-assisted surgery. The evolution in orthopedic surgery has allowed for advanced surgical planning, precision robotic machining of bone, improved implant-bone contact, optimization of implant placement, and optimization of the mechanical alignment. The potential benefits of robotic surgery include improved surgical work flow, improvements in efficacy and reduction in surgical time. Robotic-assisted surgery will continue to evolve in the orthopedic field. PMID- 29605152 TI - Pharmacologic Hemostatic Agents in Total Joint Arthroplasty-A Cost-Effectiveness Analysis. AB - BACKGROUND: Total knee and hip arthroplasties can be associated with substantial blood loss, affecting morbidity and even mortality. Two pharmacological antifibrinolytics, epsilon-aminocaproic acid (EACA) and tranexamic acid (TXA) have been used to minimize perioperative blood loss, but both have associated morbidity. Given the added cost of these medications and the risks associated with then, a cost-effectiveness analysis was undertaken to ascertain the best strategy. METHODS: A cost-effectiveness model was constructed using the payoffs of cost (in United States dollars) and effectiveness (quality-adjusted life expectancy, in days). The medical literature was used to ascertain various complications, their probabilities, utility values, and direct medical costs associated with various health states. A time horizon of 10 years and a willingness to pay threshold of $100,000 was used. RESULTS: The total cost and effectiveness (quality-adjusted life expectancy, in days) was $459.77, $951.22, and $1174.87 and 3411.19, 3248.02, and 3342.69 for TXA, no pharmacologic hemostatic agent, and EACA, respectively. Because TXA is less expensive and more effective than the competing alternatives, it was the favored strategy. One-way sensitivity analyses for probability of transfusion and myocardial infarction for all 3 strategies revealed that TXA remains the dominant strategy across all clinically plausible values. CONCLUSION: TXA, when compared with no pharmacologic hemostatic agent and with EACA, is the most cost-effective strategy to minimize intraoperative blood loss in hip and knee total joint arthroplasties. These findings are robust to sensitivity analyses using clinically plausible probabilities. PMID- 29605153 TI - Time to Reimplantation: Waiting Longer Confers No Added Benefit. AB - BACKGROUND: While the preferred surgical treatment for chronic periprosthetic joint infection (PJI) in North America is a 2-stage exchange arthroplasty, the optimal time between first-stage and reimplantation surgery remains unknown. This study was conceived to examine the association between time to reimplantation and treatment failure. METHODS: Using an institutional database, we identified PJI cases treated with 2-stage exchange arthroplasty between 2000 and 2016. Musculoskeletal Infection Society criteria were used to define PJI, and treatment failure was defined using Delphi criteria. The interstage interval between first stage and reimplantation surgery for each case was collected, alongside demographics, patient-related and organism-specific data. Multivariate logistic regression analyses were used to examine association with treatment failure. RESULTS: Our final analysis consisted of 282 patients with an average time to reimplantation of 100.2 days (range, 20-648). Sixty-three patients (22.3%) failed at 1 year based on Delphi criteria. Time to reimplantation was not significantly associated with failure in both univariate (P = .598) and multivariate (P = .397) models. However, patients reimplanted at >26 weeks were twice as likely to fail in comparison to those reimplanted within <26 weeks (43.8% vs 21.1%), and this finding reached marginal significance (P = .057). Patients who failed had significantly more comorbidities (P = .008). Charlson comorbidity index was the only variable significantly associated with treatment failure in regression analysis (odds ratio, 1.40; 95% confidence interval, 1.06-1.86; P = .019). CONCLUSION: The length of the interstage interval was not a statistically significant predictor of failure in patients undergoing 2-stage exchange arthroplasty for PJI. PMID- 29605154 TI - Prognostication of diffuse large B-cell lymphoma in the molecular era: moving beyond the IPI. AB - Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease with variable outcomes. Despite the majority of patients being cured with combination chemoimmunotherapy, up to 30% eventually succumb to the disease. Until recently, baseline prognostic assessment has centred on the International Prognostic Index (IPI), although this index is yet to impact strongly on treatment choice. Molecular features such as cell of origin, MYC and BCL-2 genetic alterations and protein overexpression were identified over a decade ago, yet their prognostic value is still not fully elucidated. Adding complexity are the plethora of new clinical, biological and molecular prognostic markers described in the recent literature, most of which lack independent validation, likely act as surrogate markers for those already in common use and have yet to substantially impact on therapeutic decision making. This review comprehensively assesses the value of individual prognostic markers in the clinical setting and their potential to predict response to novel agents, and ways to optimise their use in future research. PMID- 29605155 TI - ALS Genes in the Genomic Era and their Implications for FTD. AB - Amyotrophic lateral sclerosis (ALS) is a complex neurodegenerative disease, characterized genetically by a disproportionately large contribution of rare genetic variation. Driven by advances in massive parallel sequencing and applied on large patient-control cohorts, systematic identification of these rare variants that make up the genetic architecture of ALS became feasible. In this review paper, we present a comprehensive overview of recently proposed ALS genes that were identified based on rare genetic variants (TBK1, CHCHD10, TUBA4A, CCNF, MATR3, NEK1, C21orf2, ANXA11, TIA1) and their potential relevance to frontotemporal dementia genetic etiology. As more causal and risk genes are identified, it has become apparent that affected individuals can carry multiple disease-associated variants. In light of this observation, we discuss the oligogenic architecture of ALS. To end, we highlight emerging key molecular processes and opportunities for therapy. PMID- 29605156 TI - A perspective for improving the sensitivity of detection: The application of multi-epitope recombinant antigen in serological analysis of buffalo schistosomiasis. AB - The sensitivity and specificity are two crucial aspects of addressing the efficacy of diagnostic antigens. Achilles' heel of low sensitivity rate exists in current diagnostic recombinant antigens for schistosomiasis detection. This study focused on the diagnosis of water buffalo schistosomiasis japonica and a perspective of improving recombinant antigens' sensitivity was assessed using archived 220 water buffalo sera (114 positive sera, 92 negative sera and 14 Paramphistomum-infected sera) and the method of enzyme-linked immunosorbent assay (ELISA). The subjects included two trivalent recombinant proteins, one bivalent antigen and two single-molecular antigens. The crude antigen SEA (soluble egg antigen) was employed as reference antigen. The highest sensitivity rate in the five recombinant antigens assigned to the trivalent multi-epitope antigen PA4 (95.61%, 109/114), no significant difference with SEA (100%, 114/114, p = .836), and showing remarkable differences with the two single-molecular antigens (p < 0.01). In term of specificity, two trivalent multi-epitope antigens PA4 (97.83%, 90/92), PA5 (100%, 92/92) and the bivalent antigen PA3 (98.91%, 91/92) had few differences with one monovalent antigens PA1 (97.83%, 90/92, p = .304/0.103/0.640), significant differences with another monovalent antigens PA2 (92.39%, 85/92, p < 0.01) and SEA (82.61%, 76/92, p < 0.01). Additional, all the recombinant antigens had low cross-reactivity (7.14%, 1/14, 0% for PA5) with serum samples of paramphistomiasis, contrast with that of SEA (50%, 7/14, p < 0.01). The results indicated that multi-epitope antigens have the possibility to improve diagnostic sensitivity and the trivalent multi-epitope antigen PA4 possesses greater likelihood to be a diagnostic antigen for water buffalo schistosomiasis. PMID- 29605157 TI - Fetal biometry to assess the size and growth of the fetus. AB - Ultrasound assessment of fetal size is central to modern practice of prenatal care. It facilitates accurate pregnancy dating and screening for fetal growth disorders. This article discusses evidence-based recommended methods for pregnancy dating and biometric measurements. We address some confusing terms such as fetal growth "standards" and fetal growth "references" along with explaining the differences between prescriptive and descriptive charts and between growth charts based on estimated fetal weight vs those based on birth weight. Opinions remain divided on which charts are best to use; however, since the publication of the Intergrowth 21st study, we are now in a position to be able to assess growth and development in an internationally standardized fashion, from fetal life up to 5 years of age. A universal quality control policy can help maintain the high standard of ultrasonography required to achieve an acceptable level of diagnostic accuracy for fetal growth disorders. PMID- 29605158 TI - Three-dimensional modeling of nitrate-N transport in vadose zone: Roles of soil heterogeneity and groundwater flux. AB - Contamination of groundwater from nitrogen fertilizers in agricultural lands is an important environmental and water quality management issue. It is well recognized that in agriculturally intensive areas, fertilizers and pesticides may leach through the vadose zone and eventually reach groundwater. While numerical models are commonly used to simulate fate and transport of agricultural contaminants, few models have considered a controlled field work to investigate the influence of soil heterogeneity and groundwater flow on nitrate-N distribution in both root zone and deep vadose zone. In this work, a numerical model was developed to simulate nitrate-N transport and transformation beneath a center pivot-irrigated corn field on Nebraska Management System Evaluation area over a three-year period. The model was based on a realistic three-dimensional sediment lithology, as well as carefully controlled irrigation and fertilizer application plans. In parallel, a homogeneous soil domain, containing the major sediment type of the site (i.e. sandy loam), was developed to conduct the same water flow and nitrate-N leaching simulations. Simulated nitrate-N concentrations were compared with the monitored nitrate-N concentrations in 10 multi-level sampling wells over a three-year period. Although soil heterogeneity was mainly observed from top soil to 3 m below the surface, heterogeneity controlled the spatial distribution of nitrate-N concentration. Soil heterogeneity, however, has minimal impact on the total mass of nitrate-N in the domain. In the deeper saturated zone, short-term variations of nitrate-N concentration correlated with the groundwater level fluctuations. PMID- 29605159 TI - Application of new point measurement device to quantify groundwater-surface water interactions. AB - The streambed point velocity probe (SBPVP) measures in situ groundwater velocities at the groundwater-surface water interface without reliance on hydraulic conductivity, porosity, or hydraulic gradient information. The tool operates on the basis of a mini-tracer test that occurs on the probe surface. The SBPVP was used in a meander of the Grindsted A (stream), Denmark, to determine the distribution of flow through the streambed. These data were used to calculate the contaminant mass discharge of chlorinated ethenes into the stream. SBPVP data were compared with velocities estimated from hydraulic head and temperature gradient data collected at similar scales. Spatial relationships of water flow through the streambed were found to be similar by all three methods, and indicated a heterogeneous pattern of groundwater-surface water exchange. The magnitudes of estimated flow varied to a greater degree. It was found that pollutants enter the stream in localized regions of high flow which do not always correspond to the locations of highest pollutant concentration. The results show the combined influence of flow and concentration on contaminant discharge and illustrate the advantages of adopting a flux-based approach to risk assessment at the groundwater-surface water interface. Chlorinated ethene mass discharges, expressed in PCE equivalents, were determined to be up to 444 kg/yr (with SBPVP data) which compared well with independent estimates of mass discharge up to 438 kg/yr (with mini-piezometer data from the streambed) and up to 372 kg/yr crossing a control plane on the streambank (as determined in a previous, independent study). PMID- 29605160 TI - Sexually dimorphic subcortical brain volumes in emerging psychosis. AB - BACKGROUND: In schizophrenic psychoses, the normal sexual dimorphism of the brain has been shown to be disrupted or even reversed. Little is known, however, at what time point in emerging psychosis this occurs. We have therefore examined, if these alterations are already present in the at-risk mental state (ARMS) for psychosis and in first episode psychosis (FEP) patients. METHODS: Data from 65 ARMS (48 (73.8%) male; age=25.1+/-6.32) and 50 FEP (37 (74%) male; age=27+/-6.56) patients were compared to those of 70 healthy controls (HC; 27 (38.6%) male; age=26+/-4.97). Structural T1-weighted images were acquired using a 3 Tesla magnetic resonance imaging (MRI) scanner. Linear mixed effects models were used to investigate whether subcortical brain volumes are dependent on sex. RESULTS: We found men to have larger total brain volumes (p<0.001), and smaller bilateral caudate (p=0.008) and hippocampus volume (p<0.001) than women across all three groups. Older subjects had more GM and WM volume than younger subjects. No significant sex*group interaction was found. CONCLUSIONS: In emerging psychosis there still seem to exist patterns of normal sexual dimorphism in total brain and caudate volume. The only structure affected by reversed sexual dimorphism was the hippocampus, with women showing larger volumes than men even in HC. Thus, we conclude that subcortical volumes may not be primarily affected by disrupted sexual dimorphism in emerging psychosis. PMID- 29605161 TI - Laryngeal Manifestations of Inflammatory Bowel Disease. AB - BACKGROUND: Laryngeal involvement in inflammatory bowel disease is rare. Only 12 cases of laryngeal involvement in Crohn disease have been reported until now. Moreover, only one case of laryngeal manifestations in ulcerative colitis has been reported so far. MATERIALS AND METHODS: In this article, we present a patient with ulcerative colitis, who consulted our ear, nose, and throat (ENT) clinic with laryngeal complaints. Furthermore, a review of current literature was performed. RESULTS: A concise overview of this rare extraintestinal manifestation and other ENT manifestations of inflammatory bowel diseases is provided. CONCLUSIONS: Laryngeal manifestations in inflammatory bowel disease are very rare, but these manifestations should be known by the otorhinolaryngologist. PMID- 29605162 TI - Corrigendum to "Clinical impact of circulating tumor cells and therapy response in pancreatic cancer" [43 (6) (2017) 1050-1055]. PMID- 29605163 TI - Response to commentary to "Prospective multicenter study on robot-assisted laparoscopic extravesical ureteral reimplantation (RALUR-EV): Outcomes and complications". PMID- 29605164 TI - Renal function outcomes in pediatric patients with symptomatic reflux into the transplanted kidney treated with redo ureteroneocystostomy. AB - INTRODUCTION: Asymptomatic post-renal transplant reflux is common but only 5-10% patients are diagnosed with vesico-ureteral reflux in the setting of post transplant febrile urinary tract infections, requiring redo ureteroneocystostomy (redo-UNC). Here we report the renal function outcomes of 37 such patients, stratified by lower urinary tract (LUT) status. OBJECTIVE: We hypothesized that those with pre-transplant LUT dysfunction would have lower glomerular filtration rate (GFR) on follow-up. STUDY DESIGN: Using procedure codes, 37 patients who underwent renal transplant followed by redo-UNC for transplant reflux at our institution between 1991 and 2014 were identified. Patient characteristics and GFR levels from four different time points were recorded. Comparisons were made between those with and without LUT dysfunction, using Fisher's exact, Wilcoxon rank sum, or signed-rank tests. Generalized estimating equations were constructed to account for the clustered nature of GFR within each LUT group and to assess their change over time. RESULTS: Twelve patients (32%) had pre-transplant LUT dysfunction. The proportion of males in this group was significantly higher (75% vs. 32%, p = 0.032), and there was no statistical difference towards presenting earlier with post-transplant reflux (1.4 vs. 2.3 years, p = 0.087). After an average of 4.9 years, the median GFRs were similar between the two groups (53 mg/dL vs. 58 mg/dL, p = 0.936). There was no significant difference in GFR at this last follow-up time point in patients with and without LUT dysfunction. DISCUSSION: Vesicoureteral reflux in the setting of renal transplantation is common and doesn't often require repair. In our series, we found that those with LUT dysfunction did not present statistically sooner with symptomatic transplant reflux. Longer-term follow-up did show a decline in GFR but did not reveal a difference in GFR in patients' with and without LUT dysfunction. CONCLUSIONS: Pediatric post-transplant GFR after open redo ureteral reimplant decreases over time in similar fashion in patients with symptomatic reflux regardless of whether they have LUT dysfunction or normal anatomy. Vigilance should apply to the recognition, treatment, and follow-up of all symptomatic transplant reflux regardless of LUT status. PMID- 29605165 TI - Cultivating the Desire to Mentor in Dietetic Interns. PMID- 29605166 TI - Identification of Generalist Registered Dietitian Nutritionist Knowledge Gaps in Diabetes Medical Nutrition Therapy Compared to Diabetes-Credentialed Registered Dietitian Nutritionists: Results of a Survey to Inform Educational Opportunities. PMID- 29605167 TI - The sperm mitochondrion: Organelle of many functions. AB - This review summarizes current research in sperm mitochondrial function with specific emphasis on mitochondrial metabolism, reactive oxygen species production and mitochondrial genomics. This organelle is key in many crucial sperm functions including motility, hyperactivation, capacitation, acrosome reaction, and fertilization, thus its role in male fertility cannot be ignored. Recent studies have further elucidated sperm metabolism, placing greater emphasis on the importance of mitochondrial energy production for some species. Additionally, the dogma of mitochondrial reactive oxygen species production is changing and is being described by some as an indicator of increased mitochondrial function, potentially representing the most fertile sperm. Further, the mitochondrial genome, specifically mitochondrial DNA copy number, has been indicated as a potential biomarker for sperm quality and fertility in several species. Methods to study the sperm mitochondria are also evolving, allowing for researchers to learn more about the bioenergetics and status of this important organelle. Because of the importance of mitochondrial function for sperm function in most species, it is crucial to better understand the mechanisms involved in order to improve our knowledge of sperm physiology as well as improve handling and storage techniques for the industry. PMID- 29605168 TI - No effect of prolonged pulsed high frequency ultrasound imaging of the basilar membrane on cochlear function or hair cell survival found in an initial study. AB - Miniature high frequency ultrasound devices show promise as tools for clinical middle ear and basal cochlea imaging and vibrometry. However, before clinical use it is important to verify that the ultrasound exposure does not damage the cochlea. In this initial study, electrophysiological responses of the cochlea were measured for a range of stimulus frequencies in both ears of anesthetized chinchillas, before and after exposing the organ of Corti region of one ear to pulsed focused ultrasound for 30 min. Measurements were again taken after an 11 day survival period. Cochlear tissue was examined with a confocal microscope for signs of damage to the cochlear hair cells. No significant change in response thresholds due to exposure was found, and no signs of ultrasound-induced tissue damage were observed, although one animal (out of ten) did have a region of extensive tissue damage in the exposed cochlea. However, after further analysis this was concluded to be not likely a result of the ultrasound exposure. PMID- 29605169 TI - Burnout and posttraumatic stress in paediatric critical care personnel: Prediction from resilience and coping styles. AB - INTRODUCTION: Our aims were (1) to explore the prevalence of burnout syndrome (BOS) and posttraumatic stress disorder (PTSD) in a sample of Spanish staff working in the paediatric intensive care unit (PICU) and compare these rates with a sample of general paediatric staff and (2) to explore how resilience, coping strategies, and professional and demographic variables influence BOS and PTSD. MATERIALS AND METHODS: This is a multicentre, cross-sectional study. Data were collected in the PICU and in other paediatric wards of nine hospitals. Participants consisted of 298 PICU staff members (57 physicians, 177 nurses, and 64 nursing assistants) and 189 professionals working in non-critical paediatric units (53 physicians, 104 nurses, and 32 nursing assistants). They completed the Brief Resilience Scale, the Coping Strategies Questionnaire for healthcare providers, the Maslach Burnout Inventory, and the Trauma Screening Questionnaire. RESULTS: Fifty-six percent of PICU working staff reported burnout in at least one dimension (36.20% scored over the cut-off for emotional exhaustion, 27.20% for depersonalisation, and 20.10% for low personal accomplishment), and 20.1% reported PTSD. There were no differences in burnout and PTSD scores between PICU and non-PICU staff members, either among physicians, nurses, or nursing assistants. Higher burnout and PTSD rates emerged after the death of a child and/or conflicts with patients/families or colleagues. Around 30% of the variance in BOS and PTSD is predicted by a frequent usage of the emotion-focused coping style and an infrequent usage of the problem-focused coping style. DISCUSSION AND CONCLUSIONS: Interventions to prevent and treat distress among paediatric staff members are needed and should be focused on: (i) promoting active emotional processing of traumatic events and encouraging positive thinking; (ii) developing a sense of detached concern; (iii) improving the ability to solve interpersonal conflicts, and (iv) providing adequate training in end-of-life care. PMID- 29605170 TI - Long-term photoreceptor rescue in two rodent models of retinitis pigmentosa by adeno-associated virus delivery of Stanniocalcin-1: Correct statistical methods? PMID- 29605171 TI - Our New President-David A. Lieberman, MD, AGAF, FACG. PMID- 29605174 TI - Significant Association Between Low Baseline Neutrophil-to-Lymphocyte Ratio and Improved Progression-free Survival of Patients With Locally Advanced or Metastatic Breast Cancer Treated With Eribulin But Not With Nab-Paclitaxel. AB - INTRODUCTION: Although eribulin and nab-paclitaxel are chemotherapy agents widely used for locally advanced or metastatic breast cancer (MBC), their predictive factors remain unknown. Because the absolute neutrophil-to-lymphocyte ratio (NLR) is a significant prognostic factor for early-stage breast cancer, we investigated its usefulness in terms of the eribulin or nab-paclitaxel treatment efficacy for MBC. PATIENTS AND METHODS: A total of 85 patients with MBC treated with eribulin (n = 59) or nab-paclitaxel (n = 26) were recruited. NLR values were collected at baseline, after 1 cycle, after 2 cycles, and at the end of treatment. The NLR cutoff value was set at 3. RESULTS: The progression-free survival (PFS) of patients with an NLR < 3 at baseline (median, 242 days; n = 24) was significantly better than that of patients with an NLR of >= 3 (median, 98 days; n = 35; hazard ratio, 0.37, 95% confidence interval, 0.18-0.71; P = .0032). Similarly, the overall survival was marginally significantly better in patients with an NLR < 3 who were treated with eribulin (P = .058). However, the NLR was not significantly associated with PFS or overall survival for patients treated with nab-paclitaxel. No significant association was found between the NLR during treatment and PFS in the eribulin group. The significance of the NLR for the efficacy of eribulin was consistent, irrespective of estrogen receptor status, previous anthracycline or endocrine use, and the number of previous chemotherapy regimens. CONCLUSION: A low NLR at baseline was significantly associated with improved PFS in patients treated with eribulin but not in those treated with nab-paclitaxel. Therefore, the baseline NLR might be clinically useful for selecting patients who would benefit from eribulin. PMID- 29605175 TI - Positive emotions-An interesting topic in clinical communication research. PMID- 29605176 TI - Preventing Mitochondrial Diseases: Embryo-Sparing Donor-Independent Options. AB - Mutant mitochondrial DNA gives rise to a broad range of incurable inborn maladies. Prevention may now be possible by replacing the mutation-carrying mitochondria of zygotes or oocytes at risk with donated unaffected counterparts. However, mitochondrial replacement therapy is being held back by theological, ethical, and safety concerns over the loss of human zygotes and the involvement of a donor. These concerns make it plain that the identification, validation, and regulatory adjudication of novel embryo-sparing donor-independent technologies remains a pressing imperative. This Opinion highlights three emerging embryo sparing donor-independent options that stand to markedly allay theological, ethical, and safety concerns raised by mitochondrial replacement therapy. PMID- 29605177 TI - Distinct Proteomic, Transcriptomic, and Epigenetic Stress Responses in Dorsal and Ventral Hippocampus. AB - BACKGROUND: Acutely stressful experiences can trigger neuropsychiatric disorders and impair cognitive processes by altering hippocampal function. Although the intrinsic organization of the hippocampus is highly conserved throughout its long dorsal-ventral axis, the dorsal (anterior) hippocampus mediates spatial navigation and memory formation, whereas the ventral (posterior) hippocampus is involved in emotion regulation. To understand the molecular consequences of stress, detailed genome-wide screens are necessary and need to distinguish between dorsal and ventral hippocampal regions. While transcriptomic screens have become a mainstay in basic and clinical research, proteomic methods are rapidly evolving and hold even greater promise to reveal biologically and clinically relevant biomarkers. METHODS: Here, we provide the first combined transcriptomic (RNA sequencing) and proteomic (sequential window acquisition of all theoretical mass spectra [SWATH-MS]) profiling of dorsal and ventral hippocampus in mice. We used three different acute stressors (novelty, swim, and restraint) to assess the impact of stress on both regions. RESULTS: We demonstrated that both hippocampal regions display radically distinct molecular responses and that the ventral hippocampus is particularly sensitive to the effects of stress. Separately analyzing these structures greatly increased the sensitivity to detect stress induced changes. For example, protein interaction cluster analyses revealed a stress-responsive epigenetic network around histone demethylase Kdm6b restricted to the ventral hippocampus, and acute stress reduced methylation of its enzymatic target H3K27me3. Selective Kdm6b knockdown in the ventral hippocampus led to behavioral hyperactivity/hyperresponsiveness. CONCLUSIONS: These findings underscore the importance of considering dorsal and ventral hippocampus separately when conducting high-throughput molecular analyses, which has important implications for fundamental research as well as clinical studies. PMID- 29605178 TI - Bio-Based Products from Microalgae Cultivated in Digestates. AB - In recent years the increasing demand for food, energy, and valuable chemicals has necessitated research and development on renewable, novel, and sustainable sources. Microalgae represent a promising option to produce various products with environmentally friendly applications. However, several challenges must be overcome to reduce production cost. To this end, using effluents from biogas production units, called digestates, in cultivation systems can help to optimize bioprocesses, and several bioproducts including biofuels, biofertilizers, proteins and valuable chemicals can be obtained. Nevertheless, several parameters, including the productivity and quality of biomass and specific target products, downstream processes, and cost-effectiveness, must be improved. Further investigations will be necessary to take full advantage of the produced biomass and effectively upscale the process. PMID- 29605179 TI - Development of a micro-solid-phase extraction molecularly imprinted polymer technique for synthetic cannabinoids assessment in urine followed by liquid chromatography-tandem mass spectrometry. AB - Several molecularly imprinted polymers (MIPs) have been synthesized for the first time using various synthetic cannabinoids (JWH007, JWH015 and JWH098) as template molecules. Ethylene dimethacrylate (EDMA) was used as a functional monomer for all cases. Similarly, divinylbenzene (DVB) and 2,2'-azobisisobutyronitrile (AIBN) were used as cross-linker and initiator, respectively. The prepared MIPs have been fully characterized and evaluated as new selective adsorbents for micro solid phase extraction (MU-SPE) of synthetic cannabinoids in urine. The developed MIP-MU-SPE devices consisted of a polypropylene (PP) porous membrane containing the adsorbent (novel porous membrane protected micro-solid phase extraction based on a cone-shaped device) for operating in batch mode, which allowed a fast and integrated extraction-cleanup procedure. High performance liquid chromatography tandem mass spectrometry (HPLC-MS/MS) was used for quantifying the analytes after MIP-MU-SPE. The best performances were obtained for MIPs prepared from JWH015 as a template. Optimum loading conditions were found to be urine pH of 5.0 and adsorption time of 8.0 min under mechanical (orbital-horizontal) stirring at 100 rpm. The composition of the eluting solution consisted of 75:20:5 heptane/2 propanol/ammonium hydroxide. The elution was assisted by ultrasounds (37 kHz, 325 W) for 8.0 min. In addition, studies regarding selectivity have also been addressed for several drugs of abuse under optimized loading/adsorption conditions. Validation of the method showed good precision and analytical recovery by intra-day and inter-day assays (RSD values lower than 7 and 10% for intra-day and inter-day precision, and within the 83-100% range for intra-day and inter-day analytical recovery). PMID- 29605180 TI - QSRR modeling for the chromatographic retention behavior of some beta-lactam antibiotics using forward and firefly variable selection algorithms coupled with multiple linear regression. AB - The justified continuous emerging of new beta-lactam antibiotics provokes the need for developing suitable analytical methods that accelerate and facilitate their analysis. A face central composite experimental design was adopted using different levels of phosphate buffer pH, acetonitrile percentage at zero time and after 15 min in a gradient program to obtain the optimum chromatographic conditions for the elution of 31 beta-lactam antibiotics. Retention factors were used as the target property to build two QSRR models utilizing the conventional forward selection and the advanced nature-inspired firefly algorithm for descriptor selection, coupled with multiple linear regression. The obtained models showed high performance in both internal and external validation indicating their robustness and predictive ability. Williams-Hotelling test and student's t-test showed that there is no statistical significant difference between the models' results. Y-randomization validation showed that the obtained models are due to significant correlation between the selected molecular descriptors and the analytes' chromatographic retention. These results indicate that the generated FS-MLR and FFA-MLR models are showing comparable quality on both the training and validation levels. They also gave comparable information about the molecular features that influence the retention behavior of beta lactams under the current chromatographic conditions. We can conclude that in some cases simple conventional feature selection algorithm can be used to generate robust and predictive models comparable to that are generated using advanced ones. PMID- 29605181 TI - Characterization of new polymer-grafted protein cation exchangers developed by partial neutralization of carboxyl groups derivatized by modification of poly(ethylenimine)-Sepharose with succinic anhydride. AB - Previously, we have studied protein adsorption and chromatographic behaviors on poly(ethylenimine) (PEI)-grafted Sepharose FF anion-exchange resins, and found that protein uptake rates increased greatly when PEI grafting density reached over a critical ionic capacity (cIC) due to the occurrence of the "chain delivery" effect. Moreover, by partial charge neutralization of starting resin FF PEI-L740 (IC = 740 mmol/L, larger than the cIC) with sodium acetate to FF-PEI R440, it exhibited a three-fold increase in uptake rate over FF-PEI-L740. In this work, to take the advantages of PEI and extend the applications of the PEI grafted resins in cation-exchange chromatography, a series of cation exchangers of five different ICs were developed. First, the charged of FF-PEI-L740 was reversed from positive to negative by reaction with excess succinic anhydride, which created a cation-exchanger with an IC of 970 mmol/L (FF-FEI-C970). FF-PEI C970 was further modified with ethanolamine for partial charge neutralizations, leading to the preparation of four charge-reduced cation exchangers with IC values (in mmol/L) of 780, 630, 560 and 430, which were denoted as FF-PEI-CR780, CR630 -CR560 and -CR430, respectively. Protein adsorption and chromatographic behaviors were investigated using lysozyme (Lys) as the model protein. It was found that, the resins of high and moderate IC values (IC >= 560 mmol/L) afforded adsorption capacities up to over 230 mg/mL. Besides, the uptake rate, represented by the effective pore diffusivity (De/D0), exhibited significant increase from 0.067 (FF-PEI-C970 and FF-PEI-CR780) to 0.343 (FF-PEI-CR630 and FF-PEI-CR560) and then to 1.035 (FF-PEI-CR430) with decreasing IC. It was considered that decreasing IC led to the decreased protein binding sites (binding strength), which encouraged the occurrence of the "chain delivery" effect. Moreover, the resins of high and moderate IC values, particularly, the resins of moderate IC values (FF-PEI-CR630 and FF-PEI-CR560), presented both high adsorption capacities and uptake kinetics at 0-100 mmol/L NaCl. Besides, dynamic binding capacity achieved 150 mg/mL for the resins of moderate IC values at 0 mmol/L NaCl concentration, and afforded >110 mg/mL for the resin of high IC values at 0-100 mmol/L NaCl concentration. The results proved the excellent IEC performance of the PEI-derived cation exchangers. PMID- 29605182 TI - Divergence in DNA Specificity among Paralogous Transcription Factors Contributes to Their Differential In Vivo Binding. AB - Paralogous transcription factors (TFs) are oftentimes reported to have identical DNA-binding motifs, despite the fact that they perform distinct regulatory functions. Differential genomic targeting by paralogous TFs is generally assumed to be due to interactions with protein co-factors or the chromatin environment. Using a computational-experimental framework called iMADS (integrative modeling and analysis of differential specificity), we show that, contrary to previous assumptions, paralogous TFs bind differently to genomic target sites even in vitro. We used iMADS to quantify, model, and analyze specificity differences between 11 TFs from 4 protein families. We found that paralogous TFs have diverged mainly at medium- and low-affinity sites, which are poorly captured by current motif models. We identify sequence and shape features differentially preferred by paralogous TFs, and we show that the intrinsic differences in specificity among paralogous TFs contribute to their differential in vivo binding. Thus, our study represents a step forward in deciphering the molecular mechanisms of differential specificity in TF families. PMID- 29605184 TI - Compensation of Signal Spillover in Suspension and Imaging Mass Cytometry. AB - The advent of mass cytometry increased the number of parameters measured at the single-cell level while decreasing the extent of crosstalk between channels relative to dye-based flow cytometry. Although reduced, spillover still exists in mass cytometry data, and minimizing its effect requires considerable expert knowledge and substantial experimental effort. Here, we describe a novel bead based compensation workflow and R-based software that estimates and corrects for interference between channels. We performed an in-depth characterization of the spillover properties in mass cytometry, including limitations defined by the linear range of the mass cytometer and the reproducibility of the spillover over time and across machines. We demonstrated the utility of our method in suspension and imaging mass cytometry. To conclude, our approach greatly simplifies the development of new antibody panels, increases flexibility for antibody-metal pairing, opens the way to using less pure isotopes, and improves overall data quality, thereby reducing the risk of reporting cell phenotype artifacts. PMID- 29605185 TI - Anti-inflammatory polymersomes of redox-responsive polyprodrug amphiphiles with inflammation-triggered indomethacin release characteristics. AB - Inflammation serves as a natural defense mechanism to protect living organisms from infectious diseases. Nonsteroidal anti-inflammatory drugs (NSAIDs) can help relieve inflammatory reactions and are clinically used to treat pain, fever, and inflammation, whereas long-term use of NSAIDs may lead to severe side effects including gastrointestinal damage and cardiovascular toxicity. Therefore, it is of increasing importance to configure new dosing strategies and alleviate the side effects of NSAIDs. Towards this goal, glutathione (GSH)-responsive disulfide bonds and hydrogen peroxide (H2O2)-reactive phenylboronic ester linkages were utilized as triggering moieties in this work to design redox-responsive prodrug monomers and polyprodrug amphiphiles based on indomethacin (IND) drug. Note that IND is a widely prescribed NSAID in the clinic. Starting from three types of redox-reactive IND prodrug monomers, redox-responsive polyprodrug amphiphiles were synthesized through reversible addition-fragmentation chain transfer (RAFT) polymerizations of prodrug monomers using poly(ethylene oxide) (PEO)-based macroRAFT agent. The resultant polyprodrug amphiphiles with high IND loading contents (>33 wt%) could self-assemble into polymersomes with PEO shielding coronas and redox-responsive bilayer membranes composed of IND prodrugs. Upon incubation with GSH or H2O2, controlled release of intact IND in the active form from polyprodrug polymersomes was actuated by GSH-mediated disulfide cleavage reaction and H2O2-mediated oxidation of phenylboronic ester moieties, respectively, followed by self-immolative degradation events. Furthermore, in vitro studies at the cellular level revealed that redox-responsive polymersomes could efficiently relieve inflammatory responses induced by lipopolysaccharide (LPS) in RAW264.7 macrophage cells. PMID- 29605183 TI - Systematic Evaluation of Molecular Networks for Discovery of Disease Genes. AB - Gene networks are rapidly growing in size and number, raising the question of which networks are most appropriate for particular applications. Here, we evaluate 21 human genome-wide interaction networks for their ability to recover 446 disease gene sets identified through literature curation, gene expression profiling, or genome-wide association studies. While all networks have some ability to recover disease genes, we observe a wide range of performance with STRING, ConsensusPathDB, and GIANT networks having the best performance overall. A general tendency is that performance scales with network size, suggesting that new interaction discovery currently outweighs the detrimental effects of false positives. Correcting for size, we find that the DIP network provides the highest efficiency (value per interaction). Based on these results, we create a parsimonious composite network with both high efficiency and performance. This work provides a benchmark for selection of molecular networks in human disease research. PMID- 29605186 TI - Cognitive behavioural therapy-a valid alternative to antipsychotics for psychosis? PMID- 29605188 TI - Utility of MALDI-TOF mass spectrometry in an outbreak investigation of acute endophthalmitis following intravitreal injection. AB - Bevacizumab, a recombinant humanized monoclonal antibody to inhibit tumour angiogenesis, is available for off-label use for treating choroidal neovascularization. Outbreaks have been reported after use of this drug, either because of contamination during manufacturing or the practice of multiple doses being administered from a single vial to different patients. In our institute we investigated one endophthalmitis outbreak following intravitreal injection of bevacizumab, rapidly identified the Stenotrophomonas maltophilia as the causative agent, and established the contaminated bevacizumab vial as the source using matrix-assisted laser desorption/ionization mass spectrometry (MALDI-TOF-MS) typing. The study emphasizes the need for early diagnosis of the source and pathogen for appropriate control measures. PMID- 29605187 TI - Antipsychotic drugs versus cognitive behavioural therapy versus a combination of both in people with psychosis: a randomised controlled pilot and feasibility study. AB - BACKGROUND: Little evidence is available for head-to-head comparisons of psychosocial interventions and pharmacological interventions in psychosis. We aimed to establish whether a randomised controlled trial of cognitive behavioural therapy (CBT) versus antipsychotic drugs versus a combination of both would be feasible in people with psychosis. METHODS: We did a single-site, single-blind pilot randomised controlled trial in people with psychosis who used services in National Health Service trusts across Greater Manchester, UK. Eligible participants were aged 16 years or older; met ICD-10 criteria for schizophrenia, schizoaffective disorder, or delusional disorder, or met the entry criteria for an early intervention for psychosis service; were in contact with mental health services, under the care of a consultant psychiatrist; scored at least 4 on delusions or hallucinations items, or at least 5 on suspiciousness, persecution, or grandiosity items on the Positive and Negative Syndrome Scale (PANSS); had capacity to consent; and were help-seeking. Participants were assigned (1:1:1) to antipsychotics, CBT, or antipsychotics plus CBT. Randomisation was done via a secure web-based randomisation system (Sealed Envelope), with randomised permuted blocks of 4 and 6, stratified by gender and first episode status. CBT incorporated up to 26 sessions over 6 months plus up to four booster sessions. Choice and dose of antipsychotic were at the discretion of the treating consultant. Participants were followed up for 1 year. The primary outcome was feasibility (ie, data about recruitment, retention, and acceptability), and the primary efficacy outcome was the PANSS total score (assessed at baseline, 6, 12, 24, and 52 weeks). Non-neurological side-effects were assessed systemically with the Antipsychotic Non-neurological Side Effects Rating Scale. Primary analyses were done by intention to treat; safety analyses were done on an as-treated basis. The study was prospectively registered with ISRCTN, number ISRCTN06022197. FINDINGS: Of 138 patients referred to the study, 75 were recruited and randomly assigned-26 to CBT, 24 to antipsychotics, and 25 to antipsychotics plus CBT. Attrition was low, and retention high, with only four withdrawals across all groups. 40 (78%) of 51 participants allocated to CBT attended six or more sessions. Of the 49 participants randomised to antipsychotics, 11 (22%) were not prescribed a regular antipsychotic. Median duration of total antipsychotic treatment was 44.5 weeks (IQR 26-51). PANSS total score was significantly reduced in the combined intervention group compared with the CBT group (-5.65 [95% CI 10.37 to -0.93]; p=0.019). PANSS total scores did not differ significantly between the combined group and the antipsychotics group (-4.52 [95% CI -9.30 to 0.26]; p=0.064) or between the antipsychotics and CBT groups (-1.13 [95% CI -5.81 to 3.55]; p=0.637). Significantly fewer side-effects, as measured with the Antipsychotic Non-neurological Side Effects Rating Scale, were noted in the CBT group than in the antipsychotics (3.22 [95% CI 0.58 to 5.87]; p=0.017) or antipsychotics plus CBT (3.99 [95% CI 1.36 to 6.64]; p=0.003) groups. Only one serious adverse event was thought to be related to the trial (an overdose of three paracetamol tablets in the CBT group). INTERPRETATION: A head-to-head clinical trial of CBT versus antipsychotics versus the combination of the two is feasible and safe in people with first-episode psychosis. FUNDING: National Institute for Health Research. PMID- 29605189 TI - Outbreak of invasive group A streptococcus: investigations using agar settle plates detect perineal shedding from a healthcare worker. AB - BACKGROUND: Outbreaks of group A streptococcus (GAS) infections may occur in healthcare settings. Transmission to patients is sometimes linked to colonized healthcare workers (HCWs) and/or a contaminated environment. AIM: To describe the investigation and control of an outbreak of healthcare-associated GAS on an elderly care medical ward, over six months. METHODS: Four patients developed septicaemia due to GAS infection without a clinically obvious site of infection. The outbreak team undertook an investigation involving a retrospective review of GAS cases, prospective case finding, HCW screening and environmental sampling using both swabs and settle plates. Immediate control measures included source isolation and additional cleaning of the ward environment with a chlorine disinfectant and hydrogen peroxide. FINDINGS: Prospective patient screening identified one additional patient with throat GAS carriage. Settle plate positivity for GAS was strongly associated with the presence of one individual HCW on the ward, who was subsequently found to have GAS perineal carriage. Contamination of a fabric-upholstered chair in an office adjacent to the ward, used by the HCW, was also detected. In total, three asymptomatic HCWs had throat GAS carriage and one HCW had both perineal and throat carriage. All isolates were typed as emm 28. CONCLUSION: This is the first outbreak report demonstrating the use of settle plates in a GAS outbreak investigation on a medical ward, to identify the likely source of the outbreak. Based on this report we recommend that both throat and perineal sites should be sampled if HCW screening is undertaken during an outbreak of GAS. Fabric, soft furnishings should be excluded from clinical areas as well as any adjacent offices because pathogenic bacteria such as GAS may contaminate this environment. PMID- 29605190 TI - Fracture strength testing of crowns made of CAD/CAM composite resins. AB - PURPOSE: The purpose of this study was to ascertain whether computer aided design/computer aided manufacturing (CAD/CAM) composite resin crowns have sufficient strength to withstand the bite force of the molar teeth. The null hypothesis was that the fracture strength of CAD/CAM composite resin crowns is lower than the average maximum bite force of the molar tooth. METHODS: The crowns, which shape is the right maxillary first molar, were fabricated using four CAD/CAM blanks made of composite resins (Block HC: HC, KZR-CAD HR: HR, KZR CAD HR2: HR2, Avencia Block: AVE) and one CAD/CAM blank made of lithium disilicate glass-ceramic (IPS e.max CAD: IPS), which was used as a control. Fracture strength of fabricated crowns bonded to metal abutment and biaxial flexural strength of the materials were evaluated. RESULTS: The results of fracture strength test and biaxial flexural strength test showed different tendencies. The fracture strength of CAD/CAM composite resin crowns except HC ranged from 3.3kN to 3.9kN, and was similar to that of IPS (3.3kN). In contrast, biaxial flexural strength of CAD/CAM composite resins ranged from 175MPa to 247MPa, and was significantly lower than that of IPS (360MPa). CONCLUSIONS: All CAD/CAM composite resin crowns studied presented about 3-4 times higher fracture strength than the average maximum bite force of the molar tooth (700-900N), which result leads to the conclusion that CAD/CAM composite resin crowns would have sufficient strength to withstand the bite force of the molar teeth. PMID- 29605191 TI - A quality improvement intervention to reduce emergency department radiography for bronchiolitis. AB - INTRODUCTION: Bronchiolitis is one of the most common infectious diseases in children and the most frequent cause of hospitalization in infants. Clinical practice guidelines recommend that a chest X-ray (CXR) should not be routinely obtained in the diagnosis of bronchiolitis, as studies have shown that they do not affect clinical outcomes, but rather lead to overuse of pharmacological agents and a longer length of hospital stay. OBJECTIVE: To determine whether active institution of bronchiolitis practice guidelines as part of a quality improvement project decreased the use of CXRs in the Pediatric Emergency Department (ED). Secondary outcomes included a decrease in the use of unnecessary medical interventions and a shorter mean hospital length of stay. METHODS: The study was conducted at two Hadassah Medical Center Pediatric EDs. Guidelines were reviewed with the ED staff during departmental seminars by a senior pediatric pulmonologist, and posted at the physician computer stations in the ED. Prospective, post-intervention, data obtained during the study period was compared to retrospective, pre-intervention, data from the year prior to implementation of the intervention. RESULTS: Post-intervention, 37% of patients vs. 58% in the retrospective cohort had a CXR via ED referral (p < 0.001). The use of hypertonic saline and bronchodilators decreased, while there was no significant change in antibiotic or corticosteroid use. There was a decrease in hospitalizations post-intervention (70% vs. 77%, p = 0.05). CONCLUSION: This key intervention was successful in reinforcing the AAP guidelines, promoting greater cost-effectiveness, reducing radiation exposure, and saving valuable time and resources for the ED staff and the hospital. PMID- 29605192 TI - Rate of, and barriers and enablers to, pulmonary rehabilitation referral in COPD: A systematic scoping review. AB - BACKGROUND: Despite pulmonary rehabilitation (PR) being an evidence-based treatment recommended for people with chronic obstructive pulmonary disease (COPD), referral to PR seems to be low. Collating the evidence on referral rates and perceived barriers and enablers may help provide knowledge needed to increase referral. OBJECTIVES: The purpose of this scoping review was to determine 1) the rate of referral of patients with COPD to PR by healthcare professionals (HCPs) and 2) the barriers and enablers to referral perceived by HCPs. METHODS: The JBI scoping review manual was used. Ovid Medline, CINAHL, EMBASE, and ProQuest Dissertations and Theses were searched from inception until July 28, 2017. 245 non-duplicate articles were screened. Included articles reported referral rates and/or HCP perceived barriers and/or enablers to PR referral. RESULTS: Forty-two studies were included. Twenty-eight observational studies reported referral rates ranging from 0% to 85%. Seven studies looking at the effects of different interventions to improve COPD care reported a range of 2%-56% referral pre intervention, and 8%-71% post-intervention. Nine studies reported HCP perceived barriers to referral. The two most common barriers were low knowledge of what PR is and its benefits and low knowledge of the referral process. Six studies reported HCP perceived enablers to referral. The most common enabler was training/experience in PR. CONCLUSION: The rate of referral to PR is suboptimal, but there are commonly reported barriers and enablers that may help with the creation of actionable changes. HCPs need more knowledge of PR and the benefits it provides. PMID- 29605193 TI - The contribution of thoracic vertebral deformity and arthropathy to trunk pain in patients with chronic obstructive pulmonary disease (COPD). AB - BACKGROUND: Pain, commonly localized to the trunk in individuals with COPD, may be due to osteoporosis-related vertebral deformity and chest wall hyper-expansion causing misalignment of joints between the ribs and vertebrae. The purpose of this study was to determine if thoracic vertebral deformity and arthropathy were independent contributors to trunk pain in COPD patients compared to people with a significant smoking history. METHOD: Participants completed the Brief Pain Inventory (BPI) on the same day as chest CT scans and spirometry. Current and ex smokers were separated into COPD (n = 91) or non-COPD (n = 80) groups based on spirometry. Subsequently, CT images were assessed for thoracic vertebral deformity, bone attenuation values, and arthropathy of thoracic vertebral joints. RESULTS: The trunk area was the most common pain location in both COPD and non COPD groups. Thoracic vertebral deformity and costotransverse joint arthropathy were independent contributors to trunk pain in COPD patients (adjusted OR = 3.55 and 1.30, respectively) whereas alcohol consumption contributed to trunk pain in the non-COPD group (adjusted OR = 0.35 in occasional alcohol drinkers; 0.08 in non-alcohol drinkers). The spinal deformity index and the number of narrowed disc spaces were significantly positively related to the BPI intensity, interference, and total scores significantly in COPD patients. CONCLUSION: Trunk pain, at least in part, is caused by thoracic vertebral deformity, and costotransverse and intervertebral arthropathy in patients living with COPD. The results of this study provided the foundation for the management of pain, which requires further exploration. PMID- 29605194 TI - Acute eosinophilic pneumonia in the deployed military setting. AB - RATIONALE: Acute eosinophilic pneumonia (AEP) is a rare but important cause of severe respiratory failure most typically caused by cigarette smoking, but can also be caused by medications, illicit drugs, infections and environmental exposures. There is growing evidence that disease severity varies and not all patients require mechanical ventilation or even supplemental oxygen. OBJECTIVES: To compare patients with AEP treated at Landstuhl Regional Medical Center (LRMC) to those in other published series, and to provide recommendations regarding diagnosis and treatment of AEP. METHODS: A retrospective chart review was completed on forty-three cases of AEP which were identified from March 2003 through March 2010 at LRMC, Germany. RESULTS: Tobacco smoking was reported by 91% of our patients. Only 33% of patients in our series had a fever (temperature > 100.4 degrees F) at presentation. Peripheral eosinophilia (>5%) was present in 35% on initial CBC, but was seen in 72% of patients during their hospital course. Hypoxemia, as measured by PaO2/FiO2 ratio, seemed to be less severe in patients with higher levels of bronchoalveolar (BAL) eosinophilia percentage. CONCLUSIONS: Based on our experience and literature review, we recommend adjustments to the diagnostic criteria which may increase consideration of this etiology for acute respiratory illnesses as well as provide clinical clues we have found particularly helpful. Similar to recent reports of initial peripheral eosinophilia correlating with less severe presentation we found that higher BAL eosinophilia correlated with less severe hypoxemia. PMID- 29605195 TI - Systemic and airway oxidative stress in competitive swimmers. AB - BACKGROUND: The environment in swimming pools, which contain chlorine, might interact with the airway epithelium, resulting in oxidative stress and/or inflammation during high intensity training periods. METHODS: We evaluated pulmonary functional (metacholine challenge test, FEV1 and VC), cellular (eosinophils and neutrophils), inflammatory (FeNo, IL-5, IL-6, IL-8 and TNF alpha), oxidative (8-isoprostanes) and angiogenesis factors (VEGF) in induced sputum and peripheral blood of 41 healthy non-asthmatic elite swimmers (median 16 years) during the period of high intensity training before a national championship. The second paired sampling was performed seven months later after training had been stopped for one month. RESULTS: There was a ten-fold increase (median 82-924 pg/ml; P < 0.001) in 8-isoprostanes in induced sputum and five fold increase (median 82-924 pg/ml; P < 0.001) in sera during training in comparison to the period of rest. However, there was no difference in FEV1 (113 vs 116%), VC (119 vs 118%), FeNo (median 34 vs 38 ppb), eosinophils (2.7 vs 2.9% in sputum; 180 vs 165 cells/MUl in blood), neutrophils, different cytokines or VEGF in induced sputum or sera. The only exception was TNF-alpha, which was moderately increased in sera (median 23 vs 40 pg/ml; P = 0.02) during the peak training period. Almost half (18 of 41) of swimmers showed bronchial hyperresponsiveness during the peak training period (PC20 cutoff was 4 mg/ml). There was no correlation between hyperresponsiveness and the markers of oxidative stress or inflammation. CONCLUSIONS: High intensity training in healthy, non asthmatic competitive swimmers results in marked oxidative stress at the airway and systemic levels, but does not lead to airway inflammation. However, we could not confirm that oxidative stress is associated with bronchial hyperresponsiveness (AHR), which is often observed during the peak exercise training period. PMID- 29605196 TI - Exhaled breath NOx levels in a middle-aged adults population-based study: reference values and association with the smoking status. AB - BACKGROUND: Biomarkers in exhaled breath condensate (EBC) are potentially sensitive indicators of early biochemical changes in airways following exposure to pneumotoxic substances, particularly in susceptible subjects. NOx are the stable end products of the nitrite-nitrate-NO oxidative stress pathway and can be used to monitor airway inflammatory diseases, especially in asthma. Nevertheless, population-based surveys are needed to better interpret EBC NOx levels in clinical studies. The aim of this study was to establish reference values of EBC NOx in a large group of middle-aged, healthy adults of a sample of the general population with particular focus on the smoking status. METHODS: The EBC NOx levels were analysed from 2872 subjects among the ELISABET population-based cross sectional study including a representative sample of men and women aged from 40 to 66 years olds conducted in northern France, which included comprehensive questionnaires by interview and spirometry data. Healthy participants were defined as participants with no self-reported respiratory disease. RESULTS: For the healthy subjects (n = 1251), the median NOx concentration (IQR) was equal to 7.2 MUM (3.12) and concentrations of NOx in EBC did not differ significantly according to smoking status. The upper fifth percentile (95%) (ULN) of NOx concentrations among healthy subjects was equal to 13.6 MUM, ranging from 12.7 MUM (smokers) to 14.4 MUM (ex smokers). Among subjects with EBC NOx values higher than the ULN and compared with subjects that had EBC NOx values lower than the ULN, we found a significant higher proportion of subjects with current asthma (10.5% vs 6.5%) or with chronic bronchitis symptoms (7.6% vs 3.3%). CONCLUSION: This population-based study has provided the distribution and the upper limit reference value of a nitrosative stress biomarker (NOx) in EBC of middle aged, healthy adults. EBC NOx levels were not associated with smoking status. PMID- 29605197 TI - Airway obstruction and lung hyperinflation in COPD are linked to an impaired left ventricular diastolic filling. AB - AIMS: Chronic obstructive pulmonary disease (COPD) and cardiovascular diseases are thought to be linked through various factors. We aimed to assess the relationship between airway obstruction, lung hyperinflation and diastolic filling in COPD. METHODS: The study population was a subset of the COPD cohort COSYCONET. Echocardiographic parameters included the left atrial diameter (LA), early (E) and late (A) transmitral flow, mitral annulus velocity (e'), E wave deceleration time (E[dt]), and isovolumic relaxation time (IVRT). We quantified the effect of various predictors including forced expiratory volume in 1 s (FEV1) and intrathoracic gas volume (ITGV) on the echocardiographic parameters by multiple linear regression and integrated the relationships into a path analysis model. RESULTS: A total of 615 COPD patients were included (mean FEV1 52.6% predicted). In addition to influences of age, BMI and blood pressure, ITGV was positively related to e'-septal and negatively to LA, FEV1 positively to E(dt) (p < 0.05 each). The effect of predictors was most pronounced for LA, e'-septal and E(dt), and less for E/A, IVRT and E/e'. Path analysis was used to take into account the additional relationships between the echocardiographic parameters themselves, demonstrating that their associations with the predictors were maintained and robust. CONCLUSIONS: Airway obstruction and lung hyperinflation were significantly associated with cardiac diastolic filling in patients with COPD, suggesting a decreased preload rather than an inherently impaired myocardial relaxation itself. This suggests that a reduction in obstruction and hyperinflation could help to improve cardiac filling. PMID- 29605198 TI - Gas exchange and breathing pattern in women with postmenopausal bone fragility. AB - BACKGROUND: Little is known about the relationship between bone fragility and respiratory function. We hypothesized that women with osteoporosis or osteopenia, without cardio-pulmonary disease, have perturbations in the pattern of breathing and gas exchange. METHODS: In 44 women with bone fragility (BF, T score: < -1), and 20 anthropomorphically-matched control women (T score > -1) we compared pulmonary function tests, central respiratory drive (mouth occlusion pressure or P 0.1), pattern of breathing using optoelectronic plethysmograph and arterial blood gases at rest. RESULTS: Static pulmonary function was similar in BF subjects and controls. However, the arterial blood gas measurements differed significantly. The arterial pH was significantly higher in BF subjects than in controls (P < 0.001). The partial pressure of carbon dioxide (PaCO2) and oxygen (PaO2) in arterial blood were significantly lower in BF subjects than controls (P < 0.001 and P = 0.009, respectively). The BF subjects had a shorter inspiratory fraction compared with controls (P = 0.036). Moreover, T-scores were significantly inversely correlated with the alveolar-arterial gradient of oxygen (r = -0.5; P = 0.0003) and the arterial pH (r = -0.4; P = 0.002), and positively correlated with arterial PaO2 (r = 0.3; P = 0.01) and PaCO2 (r = 0.4; P = 0.002) among all subjects. CONCLUSION: In the absence of known cardio-pulmonary disease, BF is associated with statistically significant perturbations in gas exchange and alterations in the pattern of breathing including shortening of the inspiratory time. PMID- 29605199 TI - The acute effects of bronchial thermoplasty on FEV1. AB - BACKGROUND: The most common adverse effect of bronchial thermoplasty (BT) is short-term aggravation of asthma immediately following the procedure. However, the magnitude and duration of this deterioration, and its predisposing factors are yet to be quantitated. This information will be particularly important as BT is extended to include more severely obstructed patients. METHODS: In this prospective, observational study of 20 consecutive patients with very severe asthma undergoing BT, post bronchodilator FEV1 was measured in the 30 min prior to surgery, and then 24 h following the 60 procedures. In half the patients, further spirometry was conducted on day 3 and day 7 post procedure. RESULTS: This study enrolled 12 males and 8 females, mean age 59.7 +/- 12.8 years, with mean prebronchodilator FEV1 of 52.3 +/- 15.2% predicted, mean forced expiratory ratio of 51.4 +/- 12.6%, and mean improvement in FEV1 post salbutamol of 19.5 +/- 15.3%. All patients were taking inhaled corticosteroids, mean beclomethasone equivalent dose 1950 +/- 857 mcg, and 7 patients required maintenance oral corticosteroids for control of their asthma. Twenty four hours after BT, the mean deterioration in post bronchodilator FEV1 was 166 +/- 237 mls (CI 102-224, p < 0.001) or 9.1 +/- 15.2% of baseline. This deterioration was significantly greater after upper lobe procedures (p < 0.01, ANOVA repeated measures), where a mean fall in FEV1 of 17.1 +/- 12.6% was observed. The change in FEV1 post procedure was significantly correlated with the number of radiofrequency activations applied, r = -0.376, p < 0.005. By multivariate analysis, the only factor other than activations predictive of the change in FEV1 was age, which was protective. When the lower lobes were treated, the postbronchodilator FEV1 had returned to baseline values by day 3, but patients took 7 days to recover after upper lobe treatments. Despite the severity of asthma in these patients, and the measured deterioration post treatment, there was only one instance of readmission in the 60 procedures. CONCLUSIONS: The deterioration in lung function after BT is transient and well tolerated, but is greatest after upper lobe treatment, and is significantly related to the number of radiofrequency activations applied. PMID- 29605200 TI - Efficacy of treatments in primary spontaneous pneumothorax: A systematic review and network meta-analysis of randomized clinical trials. AB - BACKGROUND: Primary spontaneous pneumothorax (PSP) remains a significant global health problem. Despite general agreement, an official algorithm for the management of PSP still does not exist. OBJECTIVES: Evaluating the efficacy of all available treatments in PSP. METHODS: A systematic search of 12 electronic databases was performed to identify all randomized controlled trials (RCTs) of any treatments in PSP. The primary endpoint was recurrence incidence; secondary were an immediate success, complication and hospitalization days. All available outcomes were included in frequentist network meta-analysis. RESULTS: 4262 patients of 29 RCTs were included. In patients with first episode of PSP, video assisted thoracoscopic surgery (VATS), tube drainage and aspiration had no significant difference regarding recurrence. Chemical pleurodesis significantly reduced the recurrent incidence of 46% compared with aspiration and 54% compared with tube drainage. VATS and aspiration significantly decreased hospitalization days compared with tube drainage. In patients with recurrent or persistent PSP, thoracotomy with mechanical pleurodesis has a higher rank than VATS with or without pleurodesis in preventing recurrence, with no significant difference. VATS alone significantly reduced complications compared with all others treatments, except thoracotomy with abrasion. CONCLUSIONS: Aspiration and tube drainage have no significant difference in treating patients with first episode of PSP regarding recurrence. Aspiration reduced hospitalization days when compared with tube drainage. Thoracotomy with mechanical pleurodesis and VATS with or without pleurodesis are not significantly different in preventing recurrence in patients with recurrent or persistent PSP. VATS alone reduced complications compared with others treatments except for thoracotomy with abrasion. PMID- 29605201 TI - Distinctive characteristics and prognostic significance of interstitial pneumonia with autoimmune features in patients with chronic fibrosing interstitial pneumonia. AB - BACKGROUND: Interstitial lung diseases are heterogeneous, and patients with chronic fibrosing interstitial pneumonia (CFIP) often have clinical, serologic, and morphologic features suggestive but not diagnostic of connective tissue disease. Recently, the concept of interstitial pneumonia with autoimmune features (IPAF) has been proposed as a platform for such patients. However, the prognostic role of IPAF, including the cumulative incidence of acute exacerbations (AEs), is not fully clear. The aim of this study was to elucidate the clinical features and prognostic significance of IPAF. METHODS: The clinical characteristics and prognostic relevance of a diagnosis of IPAF were retrospectively explored in 194 patients with CFIP, including 163 with idiopathic pulmonary fibrosis (IPF) and 31 with nonspecific interstitial pneumonia (NSIP), in our interstitial lung disease database. RESULTS: Sixteen percent of patients with CFIP (8% of IPF, 61% of NSIP) met the criteria for IPAF. Patients with IPAF were significantly younger and included a higher proportion of women, never-smokers, and patients with NSIP than those without IPAF. The morphologic domain was the most common in patients with IPAF (97%), followed by the serologic domain (72%) and clinical domain (53%). CFIP patients with IPAF had a more favorable prognosis with regard to overall survival (OS; P < 0.001, log-rank test) and incidence of AEs (P = 0.029, Gray's test) than those without IPAF. In the subgroup analysis, NSIP patients with IPAF had significantly better survival than those without IPAF (P = 0.031, log-rank test), and IPF patients with IPAF tended to have better OS than those without IPAF (P = 0.092, log-rank test). However, there were no significant differences in the incidence of AEs between patients with IPAF and those without IPAF in the IPF and NSIP subgroups. Furthermore, fulfilment of the IPAF criteria was an independent predictor of OS (hazard ratio (HR) 0.127; 95% confidence interval (CI) 0.017-0.952; P = 0.045) and incidence of AEs (HR 0.225: 95% CI 0.054-0.937; P = 0.040). CONCLUSIONS: A diagnosis of IPAF might predict a favorable prognosis and less risk of AEs in patients with CFIP. PMID- 29605202 TI - Can the ceramic industry be a new and hazardous sector for work-related asthma? AB - BACKGROUND: Work-related asthma (WRA) constitutes a significant proportion of all asthma cases and continues to be reported from different industries. The aim of the study was to identify the occupations that can be related to WRA and diagnostic steps used in suspected WRA patients. METHODS: We retrospectively reviewed the clinical records of WRA suspected patients who were referred to Ankara Occupational and Environmental Diseases Hospital, Turkey from January 2015 to January 2017. Detailed occupational history, the diagnostic steps such as pulmonary function testing (PFT), peak expiratory flow (PEF) monitoring and nonspecific bronchial provocation tests (NSBPT) were recorded. RESULTS: Among 160 patients, 148 were male and 12 were female. Only 2 of them were diagnosed as work exacerbated asthma (WEA). Diagnosis of asthma was based on using reversible airflow limitation 28.8% (n = 46) or NSBPT 31.9% (n = 51). Toxicological analysis showed that 28 patients had heavy metal poisoning, 9 patients had solvent poisoning, 4 patients had both. According to occupations, 32 of them were ceramic workers (20.0%) and 27 of them were metal workers (16.9%). Plastic workers (4 +/- 2.8 years), cleaners (6.2 +/- 5.7 years), metal workers (7.4 +/- 5.4 years), painters (10 +/- 5.2 years), ceramic workers (10.8 +/- 5.9 years) had the shortest exposure durations for development of occupational asthma (OA). An analysis of variance showed that the effect of heavy metal and solvent poisoning on mean time for onset of OA was not significant. CONCLUSIONS: The results demonstrate that besides the sectors known to cause WRA, ceramic and metal industries can be related to important exposures related to WRA. Medical surveillance of employees in this sector is important in early detection. PMID- 29605203 TI - In vitro and clinical characterization of the valved holding chamber AeroChamber Plus(r) Flow-Vu(r) for administrating tiotropium Respimat(r) in 1-5-year-old children with persistent asthmatic symptoms. AB - BACKGROUND: When characterizing inhalation products, a comprehensive assessment including in vitro, pharmacokinetic (PK), and clinical data is required. We conducted a characterization of tiotropium Respimat(r) when administered with AeroChamber Plus(r) Flow-Vu(r) anti-static valved holding chamber (test VHC) with face mask in 1-5-year-olds with persistent asthmatic symptoms. METHODS: In vitro tiotropium dose and particle size distribution delivered into a cascade impactor were evaluated under fixed paediatric and adult flow rates between actuation and samplings. The tiotropium mass likely to reach children's lungs was assessed by tidal breathing simulations and an ADAM-III Child Model. PK exposure to tiotropium in preschool children with persistent asthmatic symptoms (using test VHC) was compared with pooled data from nine Phase 2/3 trials in older children, adolescents, and adults with symptomatic persistent asthma not using test VHC. RESULTS: At fixed inspiratory flow rates, emitted mass and fine particle dose decreased under lower flow conditions; dose reduction was observed when Respimat(r) was administered by test VHC at paediatric flow rates. In <5-year-old children, such a dose reduction is appropriate. In terms of dose per kg/body weight, in vitro-delivered dosing in children was comparable with adults. Transmission and aerosol holding properties of Respimat(r) when administered with test VHC were fully sufficient for aerosol delivery to patients. At zero delay, particles <5 MUm (most relevant fraction) exhibited a transfer efficacy of >=60%. The half-time was>10 s, allowing multiple breaths. Standardized tidal inhalation resulted in an emitted mass from the test VHC of approximately one-third of labelled dose, independent of coordination and face mask use, indicating predictable tiotropium administration by test VHC with Respimat(r). Tiotropium exposure in 1-5-year-old patients using the test VHC, when adjusted by height or body surface, was comparable with that in older age groups without VHCs; no overexposure was observed. Adverse events were less frequent with tiotropium (2.5 MUg, n = 20 [55.6%]; 5 MUg, n = 18 [58.1%]) than placebo (n = 25 [73.5%]). CONCLUSIONS: Our findings provide good initial evidence to suggest that tiotropium Respimat(r) may be administered with AeroChamber Plus(r) Flow-Vu(r) VHC in 1-5-year-old patients with persistent asthmatic symptoms. To confirm the clinical efficacy and safety in these patients, additional trials are required. CLINICAL TRIALS REGISTRY NUMBER: The trial was registered under NCT01634113 at http://www.clinicaltrials.gov. PMID- 29605204 TI - Pulmonary hypertension in chronic hemolytic anemias: Pathophysiology and treatment. AB - Pulmonary hypertension has emerged as a major cause of morbidity and mortality in patients with hemoglobinopathies and chronic hemolytic anemias. These hematological diseases include - but are not limited to - sickle cell disease (SCD), thalassemia, paroxysmal nocturnal hematuria, and hereditary spherocytosis. Although most studies have been based on the use of echocardiography as a screening tool for pulmonary hypertension as opposed to the gold standard of right heart catheterization for definitive diagnosis, the association between chronic hemolytic anemia and pulmonary hypertension is evident. Studies have shown that patients with SCD and a tricuspid regurgitant velocity (TRV) >= 2.5 m/sec are at increased risk of pulmonary hypertension and are at increased mortality risk. Additional markers of risk of pulmonary hypertension and increased mortality include a pro-BNP >160 pg/mL combined with a 6-min walk distance of <333 m. There is currently a lack of concrete data to support the use of targeted oral pulmonary arterial hypertension therapy in chronic hemolytic anemia. As a result, management is generally targeted towards medical optimization of the underlying anemia. This literature review aims to discuss the pathophysiology, diagnostic and prognostic tools, recent studies and current protocols that are essential in guiding management of pulmonary hypertension in chronic hemolytic anemias. PMID- 29605206 TI - The 100 most influential publications in asthma from 1960 to 2017: A bibliometric analysis. AB - BACKGROUND: The area of asthma medicine has produced a large volume of important clinical and scientific papers that can be found in those most influential journals. The purpose of our study was to identify the 100 most cited papers in asthma research and to analyze their characteristics. METHODS: We used the Institute for Scientific Information Web of Knowledge Database to identify the most frequently cited articles published from 1960 to December 2017. Original articles and reviews were included in the study. The 100 top-cited articles were then analyzed with regard to number of citations, publication year, journals, institution, research type and field, authors and countries of authors of publications. RESULTS: The 100 top-cited articles in asthma were published between 1960 and 2011 with a median of 933 citations per article (range, 701 2947). The number of citations per article was greatest for articles published in the 1990s. The United States of America contributed most of the classic articles, followed by England. The leading institutions were Imperial College London, McMaster University, Erasmus University Rotterdam. The 100 top-cited articles were published in twenty-five journals, led by The New England Journal of Medicine (21 articles), followed by American Journal of Respiratory and Critical Care Medicine (19 articles), Lancet (11 articles), respectively. Among the 100 classics, 50% articles were clinical research articles. CONCLUSIONS: Our study provides a historical perspective on the progress of research on asthma. Studies conducted in well-developed European countries and North America, published in high-impact journals had the highest citations. PMID- 29605205 TI - Caregiver and pediatric provider perspectives on symptom-based inhaled corticosteroid therapy in asthma. AB - OBJECTIVES: Guidelines recommend that healthcare providers adjust the dose of inhaled corticosteroids (ICS) in asthma patients based on the degree of symptom severity and control. Symptom-based, intermittent ICS therapy (use of ICS together with short acting bronchodilators- symptom-based adjustment: SBA) has been demonstrated to be comparable to guideline-based management by providers in controlled clinical trials. We sought input from African American caregivers and pediatricians on the acceptability and barriers for this alternative management strategy. METHODS: Focus group interviews of caregivers and individual interviews with community providers of African-American children ages 6-17 years with mild moderate persistent asthma were conducted by trained facilitators to assess perceptions of how asthma affects children and their caregivers, and of SBA as a management strategy. Interview data were transcribed and analyzed using inductive thematic based coding. RESULTS: Twenty-six parents participated in six focus groups. Fourteen pediatricians were interviewed. Caregivers reported facing financial burden and difficulty with tracking medications. Caregivers and pediatricians were favorable about SBA, citing its potential for decreased use of medications and cost and similarity to actual care provided. Some caregivers voiced concern that SBA would not be as effective as daily ICS. Caregivers suggested that education on symptom recognition and close communication between physician and patient would facilitate the implementation of SBA. CONCLUSIONS: SBA was generally viewed favorably by caregivers and providers of African American children. However, concerns regarding effectiveness of SBA were voiced by both caregivers and providers. Patient education and provider-patient communication is important in implementing this alternative asthma management strategy. PMID- 29605207 TI - Persistent air leak - review. AB - A persistent air leak (PAL) can be caused by either an alveolar-pleural fistula (APF) or bronchopleural fistula (BPF). Complications from PAL lead to an increase in morbidity and mortality, prolonged hospital stay, and higher resource utilization. Pulmonary physicians and thoracic surgeons are often tasked with the difficult and often times frustrating diagnosis and management of PALs. While most patients will improve with chest tube thoracostomy, many will fail requiring alternative bronchoscopic or surgical strategies. Herein, we review the bronchoscopic and surgical diagnostic and treatment options for PAL as it pertains to the field of interventional pulmonology and thoracic surgery. PMID- 29605208 TI - Characteristics and mortality risk of children with life-threatening influenza infection admitted to paediatric intensive care in England 2003-2015. AB - BACKGROUND: Information is lacking about the severity of complications in children with influenza admitted to paediatric intensive care units (PICU) in the UK. In this study, we report risk factors for mortality, invasive ventilation and use of vasoactive drugs for children admitted to PICU with influenza. METHODS: We evaluated all admissions to PICUs in England for resident children with a recorded influenza diagnosis between September 2003 and March 2015. We used the Paediatric Intensive Care Audit Network (PICANet) database linked to hospital admission records to identify influenza cases, and high-risk comorbidities among admitted children. We used mixed effects logistic regression models to determine risk factors for mortality, use of invasive ventilation and vasoactive drugs. RESULTS: We identified 1961 influenza-related PICU admissions in 1778 children. Children with high-risk conditions accounted for 1540 admissions (78.5%). The odds of mortality were significantly higher for girls than boys (adjusted odds ratio 1.91; 95% confidence interval 1.31, 2.79), children from Asian/Asian British (2.70; 1.74, 4.20) or other minority ethnic groups (3.95; 1.65, 9.42) compared to white British children, and significantly increased before and during the A(H1N1)pdm 2009 pandemic compared to the post-pandemic period. Children required invasive ventilation in 1588 admissions (81.0%), and received vasoactive drugs in 586 admissions (29.9%). CONCLUSIONS: Nearly four fifths of influenza related PICU admissions occurred in children with high-risk conditions, highlighting the burden of severe influenza in this vulnerable population Further research is required to explain sex and ethnic group differences in PICU mortality among children admitted with influenza. PMID- 29605209 TI - The potential impact of paternal age on risk of asthma in childhood: a study within the Danish National Birth Cohort. AB - BACKGROUND: Advanced paternal age has been associated with offspring morbidity and mortality, possibly due to de novo mutations and epigenetic changes in male germ cells. Epigenetic changes in the cord blood cells have been linked to asthma symptoms in offspring, but the role of paternal age has been less studied. METHODS: From the Danish National Birth Cohort, 48,785 children who completed the 7-year follow-up were included. Parental reports of physician-diagnosed asthma had been obtained by a posted or web-based questionnaire. Paternal age at delivery was obtained through linkage with maternal civil registration number in the Danish Civil Registration System and classified into four groups: <=24, 25-34 (reference), 35-39, and >40 years. We calculated the prevalence proportion of asthma and prevalence ratios (PRs) with 95% confidence intervals (CIs) using log binomial regression, adjusting for paternal smoking, paternal asthma, and paternal socioeconomic status. RESULTS: At the 7-year follow-up, 5875 children (12%) had physician-diagnosed asthma. The prevalence of asthma in 7-year old children was higher with paternal age of <=24 (adjusted PR 1.40; 95% CI: 1.26; 1.55) and lower with the paternal age of >=35 years (adjusted PR 0.84; 95% CI: 0.78; 0.89) compared to the reference group. CONCLUSIONS: Paternal age of >=35 years was associated with a lower prevalence of asthma in childhood, and paternal age of <=24 years with higher prevalence compared with paternal age of 25-34 years. The potential causes of higher asthma prevalence among offspring of young fathers warrant further investigation. PMID- 29605210 TI - A review of the etiology and clinical presentation of non-cystic fibrosis bronchiectasis: A tertiary care experience. AB - INTRODUCTION: Non-cystic fibrosis(CF) bronchiectasis has been recognized in children for the past 200 years. Early childhood pneumonia and underlying conditions such as immunodeficiency, primary ciliary dyskinesia(PCD), and congenital lung pathology should be considered in the etiology. The aim of our study was to describe the clinical characteristics, laboratory, and radiological findings of a large population of patients with non-CF bronchiectasis at a tertiary center. METHODS: We analyzed the clinical findings of 187 patients diagnosed with non-CF bronchiectasis over a period of 10 years (January 2005 December 2015) at the Hacettepe University Faculty of Medicine Department of Pediatric Pulmonology. RESULTS: The median age at the time of diagnosis of non-CF bronchiectasis was 8 years (1-18 years). Consanguinity was positive in 59.4% (n = 111) of patients and 19.8% (n = 37) of patients had a positive family history for non-CF bronchiectasis. Common causes were PCD in 51.3% (n = 96), immunodeficiency in 15% (n = 28), history of tuberculosis in 5.9% (n = 11), post-infectious complication in 3.2% (n = 6) and other anomalies in 2.1% (n = 4) of patients. The frequency of pulmonary lobe involvement was as follows: 71.1% left-lower lobe, 59.4% right lower lobe, 54% right-middle lobe, 26.8% left lingula, 13.9% right upper lobe, and 9.6% left upper lobe. CONCLUSIONS: Diagnosis of non-CF bronchiectasis is often delayed because of a failure to recognize the significance of symptoms. Through clinical investigation, including a HRCT scan of the chest, sweat test, studies of immune function, and ciliary function in a child with a prolonged suppurative cough, remains important. In Turkey, the most common causes of non-CF bronchiectasis are PCD and immunodeficiency, related to a high frequency of consanguinity. PMID- 29605211 TI - Spirometric impairments, cardiovascular outcomes, and noncardiovascular death in older persons. AB - BACKGROUND: In prior work involving older persons, the reported associations of spirometric impairments with cardiovascular outcomes may have been confounded by age-related changes in lung function. Hence, using more age-appropriate spirometric criteria from the Global Lung Function Initiative (GLI), we have evaluated the associations of spirometric impairments, specifically restrictive pattern and airflow-obstruction, with cardiovascular death (CV-death) and hospitalization (CV-hospitalization). In these analyses, we also evaluated the competing outcome of noncardiovascular death (nonCV-death) and calculated measures of relative and absolute risk. METHODS: Our study sample was drawn from the Cardiovascular Health Study (CHS), including 4232 community-dwelling white persons aged >=65 years. Multivariable regression models included the following baseline predictors: GLI-defined restrictive-pattern and airflow-obstruction, age, male gender, obesity, waist circumference, current smoker status, >=10 pack years of smoking, hypertension, dyslipidemia, diabetes, and cardiovascular and cerebrovascular disease. Outcomes included adjudicated CV-death, CV hospitalization, and nonCV-death, ascertained over 10 years of follow-up. Measures of association included hazard ratios (HRs), rate ratios (RRs), and average attributable fraction (AAF), each with 95% confidence intervals. RESULTS: Restrictive-pattern and airflow-obstruction were associated with CV-death (adjusted HRs: 1.57 [1.18, 2.09] and 1.29 [1.04, 1.60]) and with nonCV-death (adjusted HRs: 2.10 [1.63, 2.69] and 1.79 [1.51, 2.12]), respectively. Airflow obstruction, but not restrictive-pattern, was also associated with CV hospitalization (adjusted RRs: 1.18 [1.02, 1.36] and 1.20 [0.96, 1.50], respectively). The adjusted AAFs of restrictive-pattern and airflow-obstruction were 1.68% (0.46, 3.06) and 2.35% (0.22, 4.72) for CV-death, and 3.44% (1.97, 5.08) and 7.77% (5.15, 10.60) for nonCV-death, respectively. CONCLUSION: Assessment of GLI-defined spirometric impairments contributes to broad geriatric risk stratifications for both cardiovascular and non-cardiovascular outcomes. PMID- 29605212 TI - Prevalence and risk factors of asthma in mainland China: The CARE study. AB - BACKGROUND: There are limited population based data on the prevalence of asthma in China. The China Asthma and Risk factors Epidemiologic (CARE) survey was designed to understand the prevalence and risk factors for asthma in mainland China. OBJECTIVES: The CARE survey aims to demonstrate the prevalence and risk factors of asthma in mainland China among adolescents (age >14 years) and adults. METHODS: The survey was performed between February 2010 and August 2012 in eight provinces/cities of seven areas in mainland China. The inhabitants (age, >14 years) recruited in this survey were through multi-stage cluster random sampling. Asthma diagnosis was based on medical history and lung function tests. Multivariable logistic regression was used to analyzed the risk factors for asthma. RESULTS: The study included 164 215 subjects (men, 79 692 [48.53%]; women, 84 523 [51.47%]). 2034 (1.24%) were asthmatic patients. Among all asthmatic patients, 521 (25.61%) were newly diagnosed. Univariable regression analysis showed that risk factors for asthma included smoking, first-degree relatives with asthma, allergic rhinitis, chronic bronchitis, COPD, pollinosis, allergic pneumonia, concomitant allergic diseases, BMI and raising pets. Multivariable logistic regression indicated that asthma risk factors included women, age stratification, smoking, first-degree relatives suffering from asthma or pollinosis, combined with allergic rhinitis, eczema or GERD. CONCLUSIONS: We speculated that the prevalence of asthma is increasing in mainland China among individuals aged >14 years in the past 10 years. A number of risk factors were identified. The risk factors of asthma would be further elucidated in our future work. CLINICAL IMPLICATIONS: Our CARE study highlights that asthma epidemic in mainland China should be paid more attention. PMID- 29605213 TI - Interstitial lung abnormality is prevalent and associated with worse outcome in patients undergoing transcatheter aortic valve replacement. AB - BACKGROUND: Interstitial lung abnormality (ILA) is found in 5-10% of the general population and is associated with increased mortality risk. Risk factors for ILA, including advanced age and smoking history also increase the risk for aortic stenosis (AS). Transcatheter aortic valve replacement (TAVR) has become an increasingly utilized intervention for patients with severe AS, and requires a high-resolution computed tomography (HRCT) of the chest to assess aortic valve dimensions. OBJECTIVES: To determine the prevalence and clinical significance of ILA on HRCT performed in patients referred for TAVR. METHODS: Consecutive pre TAVR HRCTs performed over a 5-year period were reviewed. ILA was defined as bilateral, nondependent reticular opacities. All-cause mortality among TAVR recipients was compared between ILA cases and non-ILA controls matched 2:1 by age and gender using Cox proportional hazards regression and the Kaplan Meier estimator. RESULTS: Of 623 HRCTs screened, ILA was detected in 92 (14.7%), including 62 patients that underwent TAVR. Among ILA cases, 17 (27.4%) had a typical or probable usual interstitial pneumonia pattern, suggesting a diagnosis of idiopathic pulmonary fibrosis. Survival was worse in ILA cases compared to non ILA controls (p = 0.008) and ILA was an independent predictor of mortality after multivariable adjustment (HR 3.29, 95% CI 1.34-8.08; p = 0.009). CONCLUSIONS: ILA is a common finding among patients with severe AS and is associated with increased mortality in those undergoing TAVR. Further research is needed to elucidate the biology underpinning this observation and determine whether ILA evaluation and risk stratification modulates this mortality risk. PMID- 29605214 TI - Burden of pneumococcal community-acquired pneumonia in adults across Europe: A literature review. AB - BACKGROUND: The burden of community-acquired pneumonia (CAP) caused by Streptococcus pneumoniae (pneumococcus) among adults in Europe is poorly defined. METHODS: Structured searches of PubMed were conducted to identify the incidence of pneumococcal CAP among adults across Europe. RESULTS: The overall incidence rates for CAP was 68-7000 per 100,000 and the incidence in hospitalised CAP cases of all causes was 16-3581 per 100,000. In general the incidence of CAP increased consistently with age. Available data indicated higher burdens of pneumococcal CAP caused in groups with more comorbidities. Most cases of pneumococcal CAP (30% 78%) were caused by serotypes covered by PCV13 vaccine; the incidence of PCV13 related pneumonia decreased after the introduction of childhood vaccination. CONCLUSIONS: We observed a high burden adult pneumococcal CAP in Europe despite use of the 23-valent pneumococcal polysaccharide vaccine, particularly in elderly patients with comorbidities. CAP surveillance presented wide variations across Europe. Pneumococcal CAP has to be monitored very carefully due to the possible effect of current vaccination strategies. PMID- 29605215 TI - Direct and indirect effects of Growth Hormone Deficiency (GHD) on lung function in children: A mediation analysis. AB - BACKGROUND: Studies on pulmonary function tests (PFTs) in Growth Hormone Deficiency (GHD) children are lacking. The aims of this study were: (i) to investigate PFTs in GHD pre-pubertal children with respect to Controls, before starting Growth Hormone Therapy (GHT) (T0); (ii) to evaluate changes of PFTs in GHD vs Controls, after 1-year GHT (T1). For both aims the mediation analysis (MA) was applied to evaluate the extent to which the relationship between GHD and PFTs could be ascribed to a height-mediated (indirect) or a GH direct effect. METHODS: 47 pre-pubertal GHD children (aged 5-14 years) underwent PFTs at T0 and T1. At T0, 47 healthy children matched for age and sex were enrolled as Controls. A MA was performed to assess the relationship between GHD and PFTs and height. Statistical analyses were performed using the statistical software R (https://cran.r-project.org/mirrors.html). A p-value <0.05 was considered significant. MEASUREMENTS AND MAIN RESULTS: At T0, PFTs indices were significantly lower in GHD than in Controls. From T0 to T1 a significant improvement was found in PFTs. The percentages of the mediated effect on FVC, FEV1, FEF25-75% and TLC were <50% at T0, suggesting that the direct effect was prevalent. At T1, the percentages of the mediated effect for spirometry indices were >=50%, indicating that the indirect (height-mediated) effect was the most relevant. CONCLUSIONS: The study shows that pre-pubertal children with GHD have an impairment of lung function not exclusively attributable to the indirect (height-mediated) effect, but also to the direct GH action which is mitigated after 1-year of GHT. PMID- 29605216 TI - Inhaled corticosteroids and asthma control in adult-onset asthma: 12-year follow up study. AB - BACKGROUND: Prescribed inhaled corticosteroid (ICS) doses in asthma have been studied in cross-sectional settings whereas long-term follow-up studies have not been carried out. OBJECTIVE: To evaluate prescribed medication longitudinally by calculating cumulative ICS doses and dose changes in a cohort of new-onset adult asthma during 12 years and in different groups of asthma control. METHODS: A total of 203 patients were followed for 12 years as part of Seinajoki Adult Asthma Study (SAAS). All asthma-related visits and prescribed medication over the study period were collected from medical records. RESULTS: Total cumulative ICS dose for the 12-year follow-up period was 3.4g (+/-SEM 0.1) per patient. Both respiratory specialists and GPs prescribed step-ups and step-downs in ICS treatment and in total 649 dose changes were noted during the follow-up (median 3(1-5) per patient). Patients with uncontrolled asthma received higher ICS doses throughout the follow-up period, and therefore, cumulative 12-year ICS dose (3.8g +/- SEM 0.2) in this group was higher than that in those with partially controlled (3.4g +/- SEM 0.2) or controlled disease (2.9g +/- SEM 0.2) (p = 0.0001). Patients with uncontrolled asthma were also prescribed a higher number of ICS dose changes than patients with controlled disease. CONCLUSION: Despite frequent dose changes and high ICS doses during the 12-year follow-up, the level of asthma control remained poor in patients with uncontrolled asthma. This suggests that high ICS doses may not be effective enough for management of disease in patients with uncontrolled adult-onset asthma and novel targeted treatments are required. PMID- 29605217 TI - Long term survival after admission for COPD exacerbation: A comparison with the general population. AB - BACKGROUND AND OBJECTIVE: Life expectancy data of COPD patients in comparison to the general population are primarily based upon long-term population cohort studies. These studies are limited by a poor definition of clinically significant COPD. The key element in the course of COPD is a clinical exacerbation. Therefore, this study investigated 15-year survival following hospitalization for an exacerbation of COPD in comparison to the general population. METHODS: A number of 4229 subjects was studied, including 845 hospitalized COPD patients and 3384 age and sex matched controls. Mortality risks were assessed using Kaplan Meier survival curves, and hazard rate ratios for death were estimated using Cox proportional hazards regression models, for each Gold Class separately. RESULTS: Overall 15-year survival was 7.3% in the COPD group and 40.6% in the general population. Survival was 24%, 11.1%, 5.3% and 0% for COPD GOLD I-IV. The mean life expectancy following hospitalization was 9.7, 7.1, 6.1 and 3.4 years for stage GOLD I-IV and 10.2 years for the general population. Overall, negative prognostic factors were age, male gender, low FEV1, low TLCO, respiratory insufficiency, Charlson comorbidity class, ICU-admission and exacerbation frequency. Factors differed among GOLD stages. CONCLUSIONS: The 15-year survival for hospitalized COPD patients is reduced by 82% in comparison to the general population. This indicates a more deleterious course of clinically significant COPD in comparison to population cohorts. As such, every possible effort should be taken to reduce exacerbations in a personalized way. PMID- 29605218 TI - Six-minute walk test as a determinant of the functional capacity of children and adolescents with cystic fibrosis: A systematic review. AB - Cystic Fibrosis (CF) is a multisystem disorder. The involvement of the respiratory system is frequent and culminates in dyspnea and exercise intolerance. Functional capacity is an important diagnostic tool, because it reflects the cardiorespiratory status, quality of life and prognosis. This systematic review aims to assess the reproducibility and validity of the six minute walk test (6MWT) to reflect the functional capacity of children and adolescents with cystic fibrosis, and also the correlation between 6MWT and lung function. Searches for articles were performed in eight databases using MeSH/DeCS keywords. A total of 695 articles were found and, after verifying all eligibility criteria, six articles were included for analysis and scoring regarding the methodological quality according to the QUADAS scale (Quality Assessment of Diagnostic Accuracy Studies). All articles had good methodology (QUADAS between 9 and 11 points). The 6MWT is not correlated with lung function. There is a strong indication that the 6MWT is a reproducible test to assess the functional capacity of children and adolescents with CF. The validity assessment could not be reached because the studies included in this systematic review did not use adequate statistical tools to carry out such an evaluation. PMID- 29605219 TI - Bacterial pneumonia in kidney transplant recipients. AB - Bacterial pathogens are the most frequent cause of pneumonia after transplantation. Early after transplantation, recipients are at higher risk for nosocomial infections. The most commonly encountered pathogens during this period are gram-negative bacilli (Klebsiella pneumoniae, Escherichia coli, Pseudomonas aeruginosa ...), but gram-positive coccus such as Staphylococcus aureus or Streptococcus pneumoniae and anaerobic bacteria can also be found. Empirical antibiotic therapy should be guided by previous colonisation of the recipient and bacterial resistance pattern in the hospital. Six months after transplantation, pneumonias are mostly due to community-acquired bacteria (S. pneumonia, H. influenza, Mycoplasma, Chlamydia and others). Opportunistic pathogens take advantage of the state of immunosuppression which is usually highest from one to six months after transplantation. During this period, but also occurring many years later in the setting of a chronically depressed immune system, bacterial pathogens with low intrinsic virulence can cause pneumonia. The diagnosis of pneumonia caused by opportunistic pathogens can be challenging. The delay in diagnosis preventing the early instauration of adequate treatment in kidney transplant recipients with a depressed immune system, frequently coupled with co morbid conditions and a state of frailty, will affect prognosis and outcome, increasing morbidity and mortality. This review will focus on the most common opportunistic bacterial pathogens causing pneumonia in kidney transplant recipients: Legionella, Nocardia, Mycobacterium tuberculosis/nontuberculous, and Rhodococcus. Recognition of their specificities in the setting of immunosuppression will allow early diagnosis, crucial for initiation of effective therapy and successful outcome. Interactions with immunosuppressive therapy should be considered as well as reducing immunosuppression if necessary. PMID- 29605221 TI - Inflammatory markers and the risk of dementia and Alzheimer's disease: A meta analysis. AB - INTRODUCTION: Inflammatory markers are often elevated in patients with dementia, including Alzheimer's disease (AD). However, it remains unclear whether inflammatory markers are associated with the risk of developing dementia. METHODS: We searched PubMed, Embase, and Cochrane library for prospective population-based studies reporting associations between inflammatory markers and all-cause dementia or AD. We used random effects meta-analyses to obtain pooled hazard ratios (HRs) and 95% confidence intervals of inflammatory markers (highest vs. lowest quantile) for all-cause dementia and AD. RESULTS: Fifteen articles from 13 studies in six countries reported data that could be meta-analyzed. C reactive protein (HR = 1.37 [1.05; 1.78]), interleukin-6 (HR = 1.40 [1.13; 1.73]), alpha1-antichymotrypsin (HR = 1.54 [1.14; 2.80]), lipoprotein-associated phospholipase A2 activity (HR = 1.40 [1.03; 1.90]), and fibrinogen were each associated with all-cause dementia, but neither was significantly associated with AD. DISCUSSION: Several inflammatory markers are associated with an increased risk of all-cause dementia; however, these markers are not specific for AD. Whether inflammatory markers closely involved in AD pathology are associated with the risk of AD remains to be elucidated. PMID- 29605220 TI - Lymphocytic focus score is positively related to airway and interstitial lung diseases in primary Sjogren's syndrome. AB - OBJECTIVE: Although high-resolution computed tomography (HRCT) is useful for the characterization of minute morphological changes in the lungs, no study has investigated risk factors for lung involvement detected by HRCT in patients with Sjogren's syndrome with or without respiratory symptoms. The aim of the current study was to investigate risk factors for lung involvement in patients with primary Sjogren's syndrome detected by HRCT, with a particular focus on airway and interstitial lung diseases. METHODS: We performed a retrospective cohort study of patients with primary Sjogren's syndrome and investigated risk factors for lung involvement detected by HRCT. A total of 101 patients with primary Sjogren's syndrome with initial HRCT examinations were enrolled. RESULTS: Higher age, dry mouth, and higher labial gland biopsy focus scores (>=4) were risk factors for airway diseases (odds ratio [OR] 1.064 confidence interval [CI] 1.026 1.102, OR 8.795 CI 2.317-33.378 and OR 3.261 CI 1.100-9.675, respectively) in the multivariable analysis. Higher age, male sex, and higher labial gland biopsy focus scores (>=4) were risk factors for interstitial lung diseases (OR 1.078 CI 1.032-1.127, OR 12.178 CI 1.121-132.307 and OR 3.954 CI 1.423-10.987, respectively) in the multivariable analysis. The presence of anti-T-lymphotropic virus type 1 antibodies was significantly more common in patients with airway diseases. CONCLUSIONS: This study showed significant associations of labial gland biopsy focus scores and dry mouth with pulmonary manifestations in patients with primary Sjogren's syndrome. Focus scores as well as dry mouth may reflect lymphoproliferative activity in the lungs in patients with primary Sjogren's syndrome. PMID- 29605222 TI - Imaging correlations of tau, amyloid, metabolism, and atrophy in typical and atypical Alzheimer's disease. AB - INTRODUCTION: Neuroimaging modalities can measure different aspects of the disease process in Alzheimer's disease, although the relationship between these modalities is unclear. METHODS: We assessed subject-level regional correlations between tau on [18F]AV-1451 positron emission tomography (PET), beta amyloid on Pittsburgh compound B PET, hypometabolism on [18F] fluorodeoxyglucose PET, and cortical thickness on magnetic resonance imaging in 96 participants with typical and atypical Alzheimer's disease presentations. We also assessed how correlations between modalities varied according to age, presenting syndrome, tau-PET severity, and asymmetry. RESULTS: [18F]AV-1451 uptake showed the strongest regional correlation with hypometabolism. Correlations between [18F]AV-1451 uptake and both hypometabolism and cortical thickness were stronger in participants with greater cortical tau severity. In addition, age, tau asymmetry, and clinical diagnosis influenced the strength of the correlation between [18F]AV 1451 uptake and cortical thickness. DISCUSSION: These findings support a close relationship between tau and hypometabolism in Alzheimer's disease but show that correlations between neuroimaging modalities vary across participants. PMID- 29605224 TI - Pediatric burns in Israeli natives versus asylum seekers living in Israel: Lessons learned. AB - BACKGROUND: Burn injuries are one of the leading causes of morbidity and mortality in the pediatric population. In early childhood, burns have a wide range of adverse long-term consequences ranging from functional impairment to psychological implications. Children from low-income and middle-income countries are at a higher risk of suffering from burn injuries. In the last 10 years the population of asylum seekers from low-income countries in Israel has increased dramatically. About 25,000 or 60% of asylum seekers are living in the Tel Aviv area, making up roughly 6% of the city's total population (about 405,000). AIM: A retrospective study aimed to profile the pediatric burn injuries treated at the Tel Aviv Sourasky Medical Center over the last 9 years in an effort to examine the distinct characteristics of African asylum seekers who suffer burn injuries in comparison with Israeli nationals. PATIENTS & METHODS: Medical records of 876 patients under the age of 18 years presenting between 2007-2015 were retrospectively reviewed. The parameters collected included gender, causality, total body surface area (TBSA), burn depth and patient outcome. CONCLUSIONS: There was no significant difference regarding: age; male-female ratio; scald types burns; limb involvement. However, hospitalization and length of hospital stay were significantly higher among asylum seekers, as was family burden. Questions may be raised regarding prevention, education & social support. Our research provides a small glimpse into the world of asylum seekers in Israel. We hope it will serve as a window into the much grander problems that this population faces on a daily basis. PMID- 29605223 TI - Olfactory function and neurocognitive outcomes in old age: The Atherosclerosis Risk in Communities Neurocognitive Study. AB - INTRODUCTION: We tested the hypothesis that poor sense of smell is associated with lower cognitive function and higher mild cognitive impairment (MCI) prevalence. METHODS: Olfaction, measured by the Sniffin' Sticks test, was categorized as olfactory impairment (OI) (score <=6) or no OI (score >6). MCI was adjudicated based on review of a neuropsychological examination. Linear regression estimated the mean difference in cognitive factor scores, and log binomial regression quantified MCI prevalence among participants with versus without OI. RESULTS: Participants with OI had lower mean factor scores (memory: 0.27 standard deviation [SD], 95% confidence interval [CI]: -0.35 to -0.19; language: -0.24 SD, 95% CI: -0.30 to -0.17; executive function/processing speed: 0.09 SD, 95% CI: -0.12 to -0.06; and general cognitive performance: -0.25 SD, 95% CI: -0.30 to -0.20). OI was also associated with MCI (n = 204; prevalence ratio = 1.56, 95% CI: 1.37, 1.78). DISCUSSION: An impaired sense of smell may serve as a readily accessible early marker of neurodegeneration and improve upon the prevailing delayed diagnoses and underascertainment of MCI/dementia. PMID- 29605225 TI - Histomorphological changes in the pancreas and kidney and histopathological changes in the liver in male Wistar rats on antiretroviral therapy and melatonin treatment. AB - Combination antiretroviral therapy (cART) has shown to cause inflammation, cellular injury and oxidative stress, whereas melatonin has been successful in reducing these effects. The aim of the study was to determine potential morphometric changes caused by cART in combination with melatonin supplementation in human immunodeficiency virus (HIV)-free rats. Tissue samples (N = 40) of the pancreas, liver and kidney from a control (C/ART-/M-), cART group (C/ART + ), melatonin (C/M + ) and experimental group (ART+/M + ) were collected and stained with haematoxylin and eosin (H&E) and evaluated for histopathology. The pancreata were labelled with anti-insulin and anti-glucagon to determine alpha- and beta cell regions. Kidneys were stained with periodic acid Schiff (PAS) to measure the area, perimeter, diameter and radius of renal corpuscles, glomeruli and proximal convoluted tubules (PCTs). Blood tests were conducted to determine hepatotoxicity. No significant changes in histopathology were seen. Melatonin stimulated pancreatic islet abundance, as the number of islets per mm2 was significantly higher in the C/M+ than in the C/ART-/M- and ART+/M+. Parameters of the renal corpuscle, glomeruli, renal space and PCTs were significantly lower in the C/ART+ compared to the other groups, thus cART may have caused tubular dysfunction or cellular damage. A significant increase in serum haemoglobin was observed in the C/ART+ compared to the C/ART-, which showed cART increases serum haemoglobin in the absence of immune deficiency. Serum lipids were significantly decreased in the C/M+ compared to the C/ART-, possibly due to the effect of melatonin on the decrease of lipolysis, decreasing effect on cholesterol absorption and stimulation of lipoprotein lipase (LPL) activity. In conclusion, we have demonstrated that melatonin stimulated alpha-cell production, increased the number of pancreatic islets and caused a decrease in total lipids, whereas cART increased serum haemoglobin and decreased various parameters of the nephron in an HIV-free rat model, suggestive of tubular dysfunction. PMID- 29605226 TI - Emergence delirium and intranasal dexmedetomidine: The importance of method, dosing, and timing of administration. PMID- 29605228 TI - P_UNSAT approach of attractor calculation for Boolean gene regulatory networks. AB - Boolean network models provide an efficient way for studying gene regulatory networks. The main dynamics of a Boolean network is determined by its attractors. Attractor calculation plays a key role for analyzing Boolean gene regulatory networks. An approach of attractor calculation was proposed in this study, which combined the predecessor approach and the logic unsatisfiability approach to accelerate attractor calculation. The proposed algorithm is effective to calculate all attractors for large-scale Boolean gene regulatory networks even the networks with a relatively large average degree. PMID- 29605227 TI - Effect of cellular de-differentiation on the dynamics and evolution of tissue and tumor cells in mathematical models with feedback regulation. AB - Tissues are maintained by adult stem cells that self-renew and also differentiate into functioning tissue cells. Homeostasis is achieved by a set of complex mechanisms that involve regulatory feedback loops. Similarly, tumors are believed to be maintained by a minority population of cancer stem cells, while the bulk of the tumor is made up of more differentiated cells, and there is indication that some of the feedback loops that operate in tissues continue to be functional in tumors. Mathematical models of such tissue hierarchies, including feedback loops, have been analyzed in a variety of different contexts. Apart from stem cells giving rise to differentiated cells, it has also been observed that more differentiated cells can de-differentiate into stem cells, both in healthy tissue and tumors, aspects of which have also been investigated mathematically. This paper analyses the effect of de-differentiation on the basic and evolutionary dynamics of cells in the context of tissue hierarchy models that include negative feedback regulation of the cell populations. The models predict that in the presence of de-differentiation, the fixation probability of a neutral mutant is lower than in its absence. Therefore, if de-differentiation occurs, a mutant with identical parameters compared to the wild-type cell population behaves like a disadvantageous mutant. Similarly, the process of de-differentiation is found to lower the fixation probability of an advantageous mutant. These results indicate that the presence of de-differentiation can lower the rates of tumor initiation and progression in the context of the models considered here. PMID- 29605229 TI - When soothing succeeds: Simulating a risk for repeated shaking in abusive head trauma in infants. AB - PURPOSE: To investigate the observation that perpetrators of abusive head trauma engage in repeated shakings because shaking "works" to quiet the infant. METHODS: Sixty first-time parent couples individually cared for a programmable model infant in two consecutive 7-min trials. After six minutes of consolable followed by inconsolable crying, parents selected one of three soothing techniques. For trial one, parents were randomized to a "Successful" or "Failed" Soothing Condition. Whether the soothing technique was repeated after trial two was determined by the study investigators. Parents rated their frustration after each trial. RESULTS: As hypothesized, parents were more likely to repeat a soothing technique that "worked" in trial one. Compared to fathers, mothers reported more frustration when soothing failed. CONCLUSIONS: That caregivers were more likely to repeat a successful soothing technique converges with perpetrator confessions that crying cessation after shaking may be a reason why shaking is used repeatedly in response to crying. PMID- 29605230 TI - An efficient protocol for in vivo labeling of proliferating epithelial cells. AB - The study of organogenesis, tissue-homeostasis and regeneration requires the precise assessment of in vivo cell proliferation. To this end a host of methods have been developed to detect and quantify DNA synthesis in proliferating cells. These include cell labeling with various nucleotide analogues and fluorescence reporter-based animal models with each method presenting its idiosyncratic shortcomings. Quantitative assessment of epithelial cell turnover has been partly hampered due to their variable and limited in vivo accessibility and the requirement for harsher isolation procedures to procure single cells for FACS analysis. Here, we report a reliable protocol to study in vivo cell proliferation of epithelial cells in mice by repeatedly injecting EdU intravenously for an extended 12-day period. EdU incorporation was quantitated ex vivo by FACS after tissue dissociation in order to obtain single epithelial cell suspensions. As a lead population, we analyzed thymic epithelial cells (TECs), where we were able to label compartmentalized TEC subsets to saturation without apparent toxic effects on the thymus architecture or stress-sensitive TEC lineage differentiation. The data is in concordance with the prevailing model of medullary TEC terminal differentiation that includes the post-Aire stage. The same protocol was successfully applied to epithelial cells of various other organs - skin, lymph node, kidney and small intestine - tissues with widely varying frequencies and rates of proliferating epithelial cells. PMID- 29605231 TI - Neutrophils mediate HIV-specific antibody-dependent phagocytosis and ADCC. AB - There is growing evidence to support the role of Fc-mediated effector functions, such as Antibody-Dependent Cellular cytotoxicity (ADCC) and Antibody-Dependent Phagocytosis (ADP) in the protection and control of HIV. The RV144 trial and other recent HIV vaccine studies have highlighted the importance of ADCC responses in protection against HIV. The role of neutrophils, the most abundant leukocyte in the blood, has not been thoroughly evaluated for Fc-mediated effector functions to HIV. We optimized HIV-specific neutrophil ADCC and Antibody Dependent Neutrophil Phagocytosis (ADNP) assays using freshly isolated primary human neutrophils from blood. We also developed methods to study ADP using the neutrophil-like HL-60 cell line. We found that neutrophils mediate both HIV specific ADP and ADCC responses. In vitro, neutrophil-mediated ADCC responses peaked at 4 h, much faster than primary NK cell or monocyte-mediated responses. We detected a wide range of responses in the ADNP, HL-60 mediated ADP and ADCC across a cohort of 41 viremic antiretroviral therapy naive HIV positive subjects. HL-60 and Neutrophil-mediated ADP and ADCC responses correlated well with each other, suggesting that they measure overlapping functions. The ADNP and HL-60 ADP inversely correlated with HIV viral load, suggesting that these antibody-mediated neutrophil-based assays should prove useful in dissecting HIV-specific immunity. PMID- 29605232 TI - Chronic treatment with the new anticonvulsant drug lacosamide impairs learning and memory processes in rats: A possible role of BDNF/TrkB ligand receptor system. AB - Cognitive impairment is considered a frequent side effect in the drug treatment of epilepsy. The objective of the present study was to investigate the effects of lacosamide (LCM) on learning and memory processes in rats, on the serum level of brain-derived neurotrophic factor (BDNF) and BDNF/TrkB ligand receptor system expression in the hippocampal formation. Male Wistar rats underwent long-term treatment with three different doses of lacosamide - 3 mg/kg (LCM 3), 10 mg/kg (LCM 10) and 30 mg/kg (LCM 30). All rats were subjected to one active and one passive avoidance tests. The BDNF/TrkB immunohistochemical expression in the hippocampus was measured and serum BDNF was determined. The LCM-treated rats made fewer avoidance responses than controls during acquisition training and in the memory retention test. The number of escapes in the LCM 10 and LCM 30 groups decreased throughout the test, while the rats in the LCM 3 group showed fewer escapes only in the memory test in the active avoidance task. In the step-down test, the latency time of the LCM-30 treated rats was reduced as compared with the controls during the learning session and the short- and long-term memory retention tests. Lacosamide induced a dose-dependent reduction of the hippocampal expression of BDNF and its receptor TrkB. We found no significant difference between BDNF serum levels in the test animals and controls. The results of the study suggest that LCM suppresses the learning and memory processes in rats, with the inhibition of hippocampal BDNF/TrkB ligand receptor system being one of the possible mechanisms causing this effect. PMID- 29605233 TI - [Usefulness and reliability of abdominal clinical ultrasound in family medicine (1): Liver, biliary tract and pancreas]. AB - Ultrasound is a safe and reliable way to increase diagnosis capabilities, as well as an improving and speed up method for taking decisions for healthcare professionals of every medical specialty. Family doctor, who must be ready to address all kind of health problems for his patients, is the key person to incorporate this tool to his daily activity, acquiring the best managing skill, unknown nowadays, being quite large the clinical situations in the day by day practice, in which he can obtain benefit in a reliable and effective way. Due to this practice is explorer dependent, it's needed to assure the best competence of the professional who practice it, and define the benefits and potential risks its use can create, as well as its application scenarios, in order to avoid unnecessary explorations and minimize opportunity costs that this activity can add to a currently saturated agenda. This work pretends to summarize the current state of abdominal point of care ultrasound, and its utility for the family doctor, in those scenarios that can be potentially reliable and effective. PMID- 29605234 TI - [Biological and biosimilar drugs: Clarifying concepts]. PMID- 29605236 TI - YouTube as a source of information for obstructive sleep apnea. AB - PURPOSE: Assess the quality of information on obstructive sleep apnea (OSA) presented on YouTube for patients. MATERIALS AND METHODS: "Obstructive sleep apnea" was entered into the YouTube search. Two independent reviewers categorized and analyzed videos utilizing a customized scoring-system along with search position, likes, and views. RESULTS: Forty-eight videos were analyzed. Most were educational (52.1%). Educational and news videos had significantly higher scores, but had no significant differences in search position, likes/day, or views/day. Most videos mentioned positive airway pressure (65%), and nearly half (44%) mentioned mandibular devices in the management of OSA. Few videos discussed surgery (13%) or otolaryngology (15%). CONCLUSION: YouTube is a promising source of information for OSA patients. Educational and news videos are of highest quality. General quality measures like search position, views, and likes are not correlated with formally scored value. Sleep surgery and otolaryngologists are minimally mentioned, representing an opportunity for improvement. PMID- 29605237 TI - Development, validation and application of a ventilator-associated pneumonia prevention checklist in a single cardiac surgery centre. AB - OBJECTIVES: The purpose of this study was to develop, validate and apply a ventilator-associated pneumonia prevention checklist in a single cardiac surgery centre. METHODS: An initial checklist was designed based on the published care bundles for prevention of ventilator-associated pneumonia; the Delphi method used for validation. A total of 20 experts were invited to score the items and give suggestions for the checklist. The final checklist was then applied to patients receiving cardiac surgery. Non-compliance with the protocol and outcome indicators were observed. RESULTS: Two rounds of Delphi were conducted. The final one-page checklist consisted of three main parts: (1) demographic data of the patient receiving cardiac surgery; (2) general assessment of the patient (3) checklist of prevention measures. The average time to complete the checklist was between two and four minutes. After the application of the checklist, the incidence of ventilator-associated pneumonia decreased from 14.48 to 5.47 episodes per thousand ventilator hours. In patients requiring >48 hours mechanical ventilation, the ventilator-associated pneumonia rate and duration of ventilation was significantly decreased. CONCLUSION: A checklist was developed for ventilator associated pneumonia based on care bundles and validated using the Delphi method. The checklist appeared to be a useful tool in preventing ventilator associated pneumonia and shortening the ventilation time. PMID- 29605235 TI - Application of a short term air quality action plan in Madrid (Spain) under a high-pollution episode - Part I: Diagnostic and analysis from observations. AB - Exceedances of NO2 hourly limit value (200 MUg.m-3) imply the need to implement short term action plans to avoid adverse effects on human health in urban areas. The Madrid City Council applied the stage 3 of the NO2 protocol during a high pollution episode under stable meteorological conditions on December 2016 for the first time. This included road traffic access restrictions to the city centre (50% of conventional private vehicles based on plate numbers). In this contribution we analyse different meteorological and air quality observations, including non-standard parameters (such as number of ultrafine particles and remote sensing techniques MAXDOAS) for a better understanding of the effectivity of short-term emission abatement measures under real conditions and to identify options to improve the NO2 protocol in the future. According to our results, the inversion base height computed from vertical temperature soundings is a meaningful index to anticipate very unfavourable conditions and trigger the actions included in the protocol. The analysis of the concentration levels of the main pollutants from the Madrid air quality monitoring network indicate that only stage 3 of the protocol had a significant effect on NO2 maximum concentrations. The restrictions applied may have prevented NO2 concentrations to further increase in the city centre (up to 15%) although pollution levels in the city outskirts, outside the area directly affected by the traffic restrictions, remained unchanged or may have been slightly increased. Nonetheless, further studies are needed to estimate more precisely the effect of the measures taken and to assess potential trade-offs. Our results suggest that emissions play an important role also under very strong stability conditions although drastic measures are needed to achieve a significant impact. This highlights the importance of an appropriate timing for short-term actions and the need of permanent abatement measures related to air quality plans and policies. PMID- 29605238 TI - Group meetings after critical illness-Giving and receiving strength. AB - INTRODUCTION: An increasing number of intensive care patients are surviving critical illness, but many develop mental, cognitive and physical impairments after discharge. Adapting to a new life situation, often with major challenges, implies the need of support. Therefore, it is important to develop interventions aimed at promoting recovery. OBJECTIVE: The aim was to describe former intensive care patients' feelings of sharing their experience of critical illness with other former patients. METHOD: Former intensive care patients (n = 17) participated in group meetings and wrote about their thoughts in a notebook after each group meeting. To deepen the understanding of the former patients' experience 11 of the former patients were interviewed. The notes in the notebooks and the interviews were analysed using qualitative content analysis. FINDINGS: Meeting others revealed to the former patients new dimensions of being critically ill, and they both gave and received strength from each other. The meetings were meaningful as they gained insight into other patients' lives, and realised what it meant to survive intensive care. CONCLUSIONS: The group meetings meant sharing experiences and understanding the process of survival after critical illness. Giving and receiving strength from others helped the participants to go further. PMID- 29605240 TI - Fractional Flow Reserve in Nonculprit Vessel During ST-Segment Elevation Myocardial Infarction: Reliable or Prone to Error? PMID- 29605241 TI - Coronary Flow Measurements in Clinical Practice: The Waves Are There, The Wind Is Calling. PMID- 29605239 TI - Looking for light in the din: An examination of the circadian-disrupting properties of a medical intensive care unit. AB - OBJECTIVE: Critically ill patients exhibit profound disturbances of circadian rhythmicity, most commonly in the form of a phase delay. We investigated the specific zeitgeber properties of a medical intensive care unit to develop a model that explained these abnormalities. RESEARCH METHODOLOGY: Prospective, observational study conducted during 2013-2014. Twenty-four-hour ambient light (lux, 672 hours) and sound pressure levels (dBA, 504 hours) were measured in patient rooms. Patients and families were surveyed regarding their perceptions of the environment. SETTING: University-based adult medical intensive care unit. MAIN OUTCOME MEASURES: The timing and intensity of the ambient light-dark cycle and sound environment and the relationship of these measurements to patient/family perceptions. RESULTS: Twenty-four-hour light-dark cycles were extremely weak and phase delayed relative to the solar cycle. Morning light averaged 12.1 (4.8, 37.2) lux, when only 24.9% +/- 10.9% of available light was utilised; yet patients and families did not identify low daytime light levels as problematic. Median noise levels were invariably excessive (nighttime 47.9 [45.0, 51.3] dBA) with minimal variation, consistent with the absence of a defined rest period. CONCLUSION: The intensive care unit functions as a near-constant routine protocol disconnected from solar time. Behavioural interventions to promote entrainment should be supported by objective measurements of light and sound. PMID- 29605242 TI - Hybrid Closure of Apical Post-Infarct Septal Defect: Externalizing an Occluder and Excluding the Right Ventricle. PMID- 29605243 TI - Diagnostic and Prognostic Efficacy of Coronary Flow Capacity Obtained Using Pressure-Temperature Sensor-Tipped Wire-Derived Physiological Indices. AB - OBJECTIVES: This study aimed to evaluate the feasibility and efficacy of pressure temperature sensor-tipped wire-derived coronary flow capacity (PTW-CFC) for assessing flow impairment and prognosis. BACKGROUND: CFC provides an integrated coronary physiological assessment in which coronary flow reserve and coronary flow during hyperemia are organized. METHODS: A total of 643 native de novo lesions for which physiological assessments were performed using a PressureWire (St. Jude Medical, St. Paul, Minnesota) in patients with stable coronary artery disease were identified. The entire cohort was stratified by PTW-CFC according to the well-validated thresholds of coronary flow reserve and the corresponding inverse of thermodilution-derived mean transit time under hyperemia. Coronary physiological indices and the prevalence of major adverse cardiac events (MACE) were assessed according to PTW-CFC categories. Furthermore, in patients who underwent percutaneous coronary intervention (PCI), post-PCI PTW-CFC categorization was performed and clinical outcomes were evaluated. RESULTS: PTW CFC categorization efficiently discriminated previously validated coronary physiological parameters for functional stenosis severity and microvascular dysfunction. MACE rates during follow-up (2.4 years) were significantly associated with advanced impairment of PTW-CFC except for severely reduced PTW CFC. In the subgroup analysis of patients with severely reduced pre-PCI PTW-CFC who underwent successful PCI, MACE incidence was significantly frequent in patients with post-PCI non-normal PTW-CFC compared with those with post-PCI normal PTW-CFC. CONCLUSIONS: PTW-CFC mapping was feasible, provided accurate stratifications of coronary flow impairment, and may predict MACE. Combined analysis involving PTW-CFC and fractional flow reserve may enrich the clinical implication of integrated coronary physiology and may help predict prognosis. PMID- 29605245 TI - Successful Catheter Treatment Using Pre-Operative 3D Organ Model Simulation for Atrial Septal Defect With Dextrocardia and Interrupted Inferior Vena Cava to the Superior Vena Cava. PMID- 29605244 TI - Transcatheter Mitral Valve Replacement After Transcatheter Electrosurgical Laceration of Alfieri STItCh (ELASTIC): First-in-Human Report. PMID- 29605246 TI - Influence of Local Myocardial Damage on Index of Microcirculatory Resistance and Fractional Flow Reserve in Target and Nontarget Vascular Territories in a Porcine Microvascular Injury Model. AB - OBJECTIVES: The aim of this study was to investigate the influence of microvascular damage in one vessel territory on invasively measured physiological parameters in the other vessel, using a porcine microvascular damage model. BACKGROUND: Although fractional flow reserve (FFR)-guided decision-making for the nonculprit stenosis in patients with acute myocardial infarction has been reported to be better than angiography-guided revascularization, there have been debates regarding the influence of microvascular dysfunction on measured FFR in nonculprit vessels. METHODS: In Yorkshire swine, microvascular damage was induced with selective intracoronary injection of microspheres (100 MUm * 105 each) into the left anterior descending artery (LAD). Coronary stenosis was created in both the LAD and the left circumflex artery (LCx) using balloon catheters. Coronary physiological changes were assessed with index of microcirculatory resistance (IMR) and FFR at baseline and at each subsequent injection of microsphere up to a fifth dose in both the LAD and LCx. Measurements were repeated 5 times at each stage, and a total of 424 measurements were made in 12 Yorkshire swine models. RESULTS: The median area stenosis in LAD and LCx was 48.1% (interquartile range: 40.8% to 50.4%) and 47.9% (interquartile range: 31.1% to 62.9%), respectively. At baseline, FFR in the LAD was lower than that in the LCx (0.89 +/- 0.01 and 0.94 +/- 0.01; p < 0.001). There was no difference in the IMR (18.4 +/- 5.8 U and 17.9 +/- 1.2 U; p = 0.847). With repeated injections of microspheres, IMR in LAD was significantly increased, up to 77.7 +/- 15.7 U (p < 0.001). Given the same stenosis, FFR in the LAD was also significantly increased, up to 0.98 +/- 0.01 along with IMR increase (p < 0.001). Conversely, IMR and FFR were not changed in the LCx throughout repeated injury to the LAD territory (p = 0.105 and p = 0.286 for IMR and FFR, respectively). The increase in LAD IMR was mainly driven by the increase in hyperemic mean transit time (p < 0.001). CONCLUSIONS: In Yorkshire swine models, local microvascular damage increased both FFR and IMR in a vessel supplying target myocardial territory. However, IMR and FFR were maintained in the other vessel. These physiological results in swine support the concept that FFR measurement might provide useful information for evaluating nonculprit lesions in clinical settings involving significant acute myocardial injury. PMID- 29605247 TI - Breast reconstruction after breast conservation therapy for breast cancer. AB - Conservative breast surgery followed by irradiation, often referred to as Breast conserving therapy (BCT), has replaced modified radical mastectomy for the treatment of early stage invasive breast cancer and ductal carcinoma in situ (DCIS). About 10% to 40% of the patients treated with BCT have poor cosmetic outcome results. Small tumours in large breasts can be successfully treated by lumpectomy and radiotherapy, with good cosmetic outcome. However when the tumour breast ratio is higher, the cosmetic outcome can be very disappointing. A surgical conflict arises between optimal oncologic resection and the desire to spare as much tissue as possible to minimize the risk of deformities. In case of a small defect lipofilling can be performed. This technique transplants fat grafts from a donor site to the defect in the breast. In case of larger defects there is the option of oncoplastic surgery. Oncoplastic techniques combine the optimal oncological resection with an adequate reconstruction for optimal cosmetic outcome. Oncoplastic techniques allow the breast surgeon to perform a tumour resection with adequate margins and the plastic surgeon will reconstruct the defect during the same procedure for optimal cosmetic outcome. The use of oncoplastic techniques to reconstruct defects of partial mastectomies (BCT) can be immediate, delayed or immediate delayed. Current breast cancer treatment leads to long-term surivival. It it there for important not only to survive but also life. Therefore the quality of life and good cosmetic outcome is mandatory after breast cancer treatment. Oncoplastic surgery is based on two techniques: volume displacement and volume replacement. The volume displacement techniques use (dermo)glandular flaps of the breast to fill the resection defect. Volume displacement techniques ideally work when the tumour resection can be incorporated in a breast reduction pattern. A similar technique is used on the contralateral breast to match size and shape. The volume replacement techniques use autologous non-breast tissues to compensate the volume loss after tumour resection. Volume replacement techniques are used when a large resection volume is needed in a small breast. Depending on the location and size of the defect many different flaps can be used for partial breast reconstruction. PMID- 29605248 TI - Metabolism is the tie: The Bertalanffy-type cancer growth model as common denominator of various modelling approaches. AB - Cancer or tumour growth has been addressed from a variety of mathematical modelling perspectives in the past. Examples are single variable growth models, reaction diffusion models, compartment models, individual cell-based models, clonal competition models, to name only a few. In this paper, we show that the so called Bertalanffy-type growth model is a macroscopic model variant that can be conceived as an optimal condensed modelling approach that to a high degree preserves complexity with respect to the aforementioned more complex modelling variants. The derivation of the Bertalanffy-type model is crucially based on features of metabolism. Therefore, this model contains a shape parameter that can be interpreted as a resource utilisation efficiency. This shape parameter reflects features that are usually captured in much more complex models. To be specific, the shape parameter is related to morphological structures of tumours, which in turn depend on metabolic conditions. We, furthermore, show that a single variable variant of the Bertalanffy-type model can straightforwardly be extended to a multiclonal competition model. Since competition is crucially based on available shared or clone-specific resources, the metabolism-based approach is an obvious candidate to capture clonal competition. Depending on the specific context, metabolic reprogramming or other oncogene driven changes either lead to a suppression of cancer cells or to an improved competition resulting in outgrowth of tumours. The parametrisation of the Bertalanffy-type growth model allows to account for this observed variety of cancer characteristics. The shape parameter, conceived as a classifier for healthy and oncogenic phenotypes, supplies a link to survival and evolutionary stability concepts discussed in demographic studies, such as opportunistic versus equilibrium strategies. PMID- 29605249 TI - Purification, biochemical, and molecular characterization of novel protease from Bacillus licheniformis strain K7A. AB - A novel extracellular alkaline protease, called SAPHM, from Bacillus licheniformis strain K7A was purified by four steps procedure involving heat treatment (30 min at 70 degrees C) followed by ammonium sulfate precipitation (40-70%)-dialysis, UNO Q-12 FPLC, and ZORBAX PSM 300 HPLC, and submitted to biochemical characterization assays. The purified enzyme is a monomer of molecular mass of 30,325.12 Da. It was completely inhibited by phenylmethanesulfonyl fluoride (PMSF)and diiodopropyl fluorophosphates (DFP), which strongly suggested its belonging to the serine protease family. Its sequence of the 26 NH2-terminal residues showed high homology with those of Bacillus proteases. The purified enzyme was optimally active at pH 10 and temperature 70 degrees C. Its catalytic efficiency was higher than those of Alcalase and Thermolysin. SAPHM exhibited excellent stability to detergents and wash performance analysis revealed that it could remove blood-stains effectively. Data suggest also that SAPHM may be considered as potential candidate for future applications in non-aqueous peptide biocatalysis because it possesses an elevated organic solvent resistance. The sapHM gene encoding SAPHM was cloned, sequenced, and expressed in Escherichia coli strain BL21(DE3)pLysS. The biochemical properties of the extracellular purified recombinant enzyme (rSAPHM) were similar to those of native one. The deduced amino acid sequence showed strong homology with other Bacillus proteases. The highest sequence identity value (97%) was obtained with APRMP1 protease from Bacillus licheniformis strain MP1, with only 9 aa of difference. PMID- 29605250 TI - Binding behaviors and kinetics studies on the interaction of silver nanoparticles with trypsin. AB - The interaction of nanoparticles (NPs) with proteins is a topic of high relevance for the medical application of nanomaterials. In this study, a comprehensive investigation was performed to clarify the binding mechanism, adsorption isotherms and kinetics of the interaction between silver nanoparticles (AgNPs) and trypsin. The experimental results indicate that the binding of AgNPs to trypsin seems to be a static quenching mechanism. Thermodynamic analysis reveals that AgNPs binding to trypsin is synergistically driven by enthalpy and entropy, and the major driving forces are hydrophobic and electrostatic interactions. The adsorption of trypsin on AgNPs was analyzed by Langmuir and Freundlich models, suggesting that the equilibrium adsorption data fit well with Freundlich model. The kinetics of adsorption data were modeled using the pseudo-first-order and pseudo-second-order kinetic equations. The results indicate that a pseudo-second order kinetic equation describes better. The conformational change at the secondary structural level of trypsin induced by AgNPs was investigated with the circular dichroism (CD) measurements and no obvious changes in trypsin secondary structural elements are observed. These fundamental works will provide some new insights into the safe and effective application of AgNPs in biological and medical areas. PMID- 29605251 TI - Protein engineering: Regulatory perspectives of stearoyl CoA desaturase. AB - Stearoyl Co A desaturase (SCD) is a rate-limiting lipogenic enzyme that plays an integral role in catalyzing the synthesis of monounsaturated fatty acids, chiefly oleate and palmitoleate. Both contribute a major part of the biological membrane. Numerous SCD isoforms exist in mouse and humans, i.e., SCD-1 to SCD-4 and SCD-1 and SCD-5, respectively. From the biological viewpoint, hyperexpression of SCD1 cause many metabolic disorders including obesity, insulin resistance, hypertension, and hypertriglyceridemia, etc. Herein, an effort has been made to highlight the value of protein engineering in controlling the SCD-1 expression with the involvement of different inhibitors as therapeutic agents. The first part of the review describes Stearoyl CoA desaturase index and different SCD isoforms. Various regulatory aspects of SCD are reviewed in four subsections, i.e., (1) hormonal regulation, (2) regulation by dietary carbohydrates, (3) regulation by green tea, and (4) regulation via polyunsaturated fatty acids (PUFAs). Moreover, the regulation of Stearoyl CoA desaturase expression in the metabolism of fats and carbohydrates is discussed. The third part mainly focuses on natural and synthetic inhibitors. Towards the end, information is also given on potential future considerations of SCD-1 inhibitors as metabolic syndrome therapeutics, yet additional work is required. PMID- 29605252 TI - miR-181c-3p and -5p promotes high-glucose-induced dysfunction in human umbilical vein endothelial cells by regulating leukemia inhibitory factor. AB - Diabetes mellitus is a chronic metabolic disease with high blood glucose level and closely related to endothelial dysfunction, an important factor in the pathogenesis of vascular changes. Several miRNAs have been reported to be altered in a diabetic environment including miR-181c. In the article, we found that the expression of miR-181c-3p and miR-181c-5p was significantly downregulated under glucose treatment in a dose-dependent manner and in peripheral blood from diabetic patients compared with healthy participants. We explored the role of miR 181c-3p and miR-181c-5p in high glucose (HG)-induced dysfunction in human umbilical vein endothelial cells (HUVECs) by regulating leukemia inhibitory factor (LIF), their potential target with binding sites in 3-UTR region, that is also closely related to glucose metabolism. In addition, miR-181c-3p and miR-181c 5p significantly enhanced HG-induced oxidative stress injury by increasing malondialdehyde (MDA) and reactive oxygen species (ROS) production and promoted HG-induced HUVECs apoptosis, confirmed by TUNEL staining. LIF partially reduced those effects by decreasing oxidative stress and inhibiting cell apoptosis. Therefore, knocking down of LIF in HUVECs by LIF siRNA transfection, significantly increased HG-induced MDA and ROS production and induced more intense HUVECs apoptosis. Our results indicate that miR-181c-3p and miR-181c-5p promote HG-induced HUVECs injury through their target LIF. PMID- 29605253 TI - Acetonitrile as solvent for protein interaction analysis. AB - Dimethyl sulfoxide (DMSO) is routinely used to dissolve hydrophobic and aromatic substances in drug screening. The dissolved substances are then diluted, e.g., 100-fold, into aqueous media containing their target molecules. Such a practice may be suitable for biological evaluation of the drug substances. However, structural evaluation using spectroscopic techniques, in particular far UV measurements, may be hampered by strong absorbance of DMSO. Here, I have tested acetonitrile (ACN) that is almost exclusively used for reverse phase chromatography of proteins and small organic molecules. Using a small aromatic/hydrophobic molecule, dodecyl-gallate, and bovine serum albumin as a model system, a side-by-side comparison was made for DMSO and ACN with regard to dissolution capability and far UV circular dichroism (CD) performance. PMID- 29605254 TI - Low-fibrillated bacterial cellulose nanofibers as a sustainable additive to enhance recycled paper quality. AB - Bacterial cellulose is a biological macromolecule synthesized by bacteria of high purity and crystallinity. Bacterial cellulose nanofibers (BCNF) have been produced by soft homogenization and added to a recycled pulp to improve its quality. The benefits of BCNF on mechanical, physical and optical paper properties have been quantified and the retention mechanism of the BCNF in the paper network has been proposed. The use of BC to improve paper strength is usually limited by the decrease of tear index. The novelty of this work is that these two effects are decoupled by the addition of BCNF of low fibrillation (35.2%). In this way, some BCNF clusters are produced together with the individual nanofibers. Thus, with the addition of 3% BCNF, tensile and tear indexes as well as strain at break were improved by 11.1, 7.6, and 66.8%, respectively. Furthermore, the clusters were retained in the fiber network not only by hydrogen bonding, but also by physical retention within the gaps. Therefore, the addition of BCNF not only increases the mechanical properties of paper but also makes the handsheets more flexible and facilitates filler retention. PMID- 29605255 TI - Microencapsulation of docosahexaenoic acid (DHA) with four wall materials including pea protein-modified starch complex. AB - Omega-3 fatty acids, specifically docosahexaenoic acid (DHA, 22 carbons and 6 double bonds) are fundamental compounds for a healthy diet. However, due to their unsaturated nature, omega fatty acid-rich oils are chemically unstable and susceptible to oxidative deterioration. The oxidation results in production of free radicals and unpleasant tastes, negatively impacting the shelf-life, sensory properties, and acceptability of food products. This study was conducted to examine the effect of wall materials on protection of DHA in canola oil against oxidation. A total of 4 wall materials including pea protein isolate (PPI), pea protein isolate - modified starch complex (PPI-MS), Tween 20, and SDS were used for microemulsion preparation with canola oil containing DHA. The freeze-dried powders were analyzed with respect to physicochemical characteristics, oxidative stability, and release properties. The results showed that the PPI-MS as a natural polymeric wall material exhibited similar or better encapsulation efficiency and acceptable level of peroxide value compared to the synthetic surfactants (Tween 20 and SDS). The utilization of protein-polysaccharide complexes enabled the incorporation of specific properties of each biopolymer to further improve emulsion stability for the production of capsules with improved oxidative stability. PMID- 29605256 TI - Chloroacetaldehyde dehydrogenase from Ancylobacter aquaticus UV5: Cloning, expression, characterization and molecular modeling. AB - 1,2-Dichloroethane (1,2-DCE) is oxidatively converted to a carcinogenic intermediate compound, chloroacetaldehyde by chloroacetaldehyde dehydrogenase (CAldA) during its biodegradation by many bacterial strains, including Xanthobacter autotrophicus and Ancylobacter aquaticus. In this study, a 55kDa NAD dependent CAldA expressed by chromosomally encoded aldA gene, is reported in an indigenous Ancylobacter aquaticus UV5. A. aquaticus UV5 aldA gene was found to be 99% homologous to the plasmid (pXAU1) encoded aldA gene reported in X. autotrophicus GJ10. Pulse-field gel electrophoresis (PFGE) and PCR experiments revealed the absence of pXAU1 in A. aquaticus UV5 and that aldA was chromosomal encoded. A 6* His-tag fused CAldA cloned in pET15b, overexpressed and purified on Co-agarose affinity column using AKTA purification system showed Mr of 57,526. CAldA was active optimally at pH9 and 30 degrees C. The Km and vmax for the substrate, acetaldehyde were found to be 115MUM and 650mU/mg, respectively. CAldA substrate specificity was found to be low for chloroacetaldehyde, formaldehyde, propionaldehyde, butyraldehyde, benzaldehyde and glutaraldehyde as compared to acetaldehyde. Computational modeling revealed a predicted structure of CAldA consisting of five beta-sheets that comprise seven antiparallel beta-strands and 11 mix strands. The Molecular Dynamics and Docking studies showed that acetaldehyde bind to CaldA more tightly as compared to chloroacetaldehyde. PMID- 29605257 TI - Antimicrobial and anticancer potential of low molecular weight polypeptides extracted and characterized from leaves of Azadirachta indica. AB - Low molecular weight antimicrobial polypeptides were extracted and purified from the young fresh leaves of Azadirachta indica (neem). The total protein extracted was precipitated with 15% TCA-Acetone. The total purified proteins yielded from the two extraction methods were 122.33+/-2.21 and 115.09+/-1.88mg/g of the total fresh weight. The SDS-PAGE analysis identified the presence of eight low molecular weight polypeptide bands. The antimicrobial activity of the resolved bands was detected by Polyacrylamide gel-Agar overlay diffusion assay (PAG-ADA). Their broad-spectrum bactericidal activity was confirmed using the same technique and found three low molecular weight bands from 11 to 14kDa collectively exhibiting superior bactericidal activities against Staphylococcus aureus, methicillin-resistant Staphylococcus aureus (MRSA), Staphylococcus epidermis, Enterococcus faecalis, Pseudomonas aeruginosa and fungicidal activity against Candida tropicalis. The FTIR spectrum of the protein bands depicted the presence of hydroxyl and carbonyl groups in the protein bands. These polypeptides were characterized by MALDI-TOF/TOF analysis. Further, the purified protein extract was found to be active against HELA, BT-549 and Neuro-2a cell lines with IC50 value of 74.03+/-2.31, 64.82+/-1.64, 238.32+/-2.12 and 109.94+/-2.96, 59.61+/ 0.75 for 24h and 48h, respectively. The results of present study indicate that these polypeptides exhibit broad spectrum antimicrobial and anticancer activity and can therefore be explored for their therapeutic potential. PMID- 29605258 TI - Induced macrophage activation in live excised atherosclerotic plaque. AB - Atherosclerotic plaques are complex tissues containing many different cell types. Macrophages contribute to inflammation, formation of the necrotic core, and plaque rupture. We examined whether macrophages in plaque can be activated and compared this to monolayer cells. The volume of calcium in the plaque was compared to the level of macrophage activation measured by total neopterin output. Carotid plaque samples were cut into 3 mm sections and cultured for up to 96 h. Live sections were stimulated with interferon-gamma, phytohaemagglutinin or phorbol 12-myristate 13-acetate. Macrophage activation and oxidative stress were monitored by total neopterin (oxidized and non-oxidized 7,8-dihydroneopterin) and neopterin levels every 24 h for up to 4 d. The calcium content of two plaques was investigated by spectral imaging. Direct stimulation of macrophages in plaque sections with interferon-gamma caused a sustained increase in neopterin (p = .037) and total neopterin (p = .003). The addition of phorbol 12-myristate 13 acetate to plaque had no significant effect on total neopterin production (p = .073) but increased neopterin (p = .037) whereas phytohaemagglutinin caused a significant increase in both neopterin and total neopterin (p = .0279 and .0168). There was an inverse association (R2 = 0.91) between the volume of calcium and macrophage activation as measured by total neopterin production in stimulated plaque tissue. Resident macrophages within excised carotid plaque activated either directly or indirectly generate the biomarkers 7,8-dihydroneopterin and neopterin. Macrophage activation rather than the oxidative environment is associated with plaque calcification. PMID- 29605259 TI - Gene expression profiling coupled with Connectivity Map database mining reveals potential therapeutic drugs for Hirschsprung disease. AB - BACKGROUND: Hirschsprung disease (HD) is a congenital intestinal anomaly resulting from a failure to form enteric ganglia in the lower bowel. Surgery is the main therapeutic strategy, although neural stem cell transplantation has recently shown promise. However, HD remains a challenging disorder to treat. Our aim was to identify drugs that could counteract the dysregulated pathways in HD and could thus be potential novel therapies. METHODS: We used microarray analysis to identify genes differentially expressed in ganglionic and aganglionic bowel samples from eight children with HD. The signature of differentially expressed genes was then used as a search query to explore the Connectivity Map (cMAP), a transcriptional expression database that catalogs gene signatures elicited by chemical perturbagens. RESULTS: We uncovered several dysregulated signaling pathways, and in particular regulation of neuron development, in HD. The cMAP search identified some compounds with the potential to counteract the effects of the dysregulated molecular signature in this disease. One of these, pepstatin A, was recently shown to rescue the migration defects observed in a mouse model of HD, providing strong support for our findings. CONCLUSIONS: This study advances our understanding of the molecular changes in HD and identifies several potential pharmacological interventions. Further testing of the identified compounds is warranted. PMID- 29605260 TI - Pediatric phyllodes tumors: A review of the National Cancer Data Base and adherence to NCCN guidelines for phyllodes tumor treatment. AB - BACKGROUND: Phyllodes tumors are fibroepithelial breast lesions that are uncommon in women and rare among children. Due to scarcity, few large pediatric phyllodes tumor series exist. Current guidelines do not differentiate treatment recommendations between children and adults. We examined national guideline adherence for children and adults. METHODS: We queried the NCDB (2004-2014) for female patients with phyllodes tumor histology, excluding patients with missing age or survival data. Patients were stratified by age (pediatric <21, adult >=21), and compared based on patient characteristics, treatment patterns, and survival. RESULTS: We identified 2787 cases of phyllodes tumor (2725 adult, 62 pediatric). Median age was 17years in children and 52years in adults. Margin positivity rates and median tumor size were similar between adults and children. Treatment was discordant with NCCN guidelines in 28.6% of adults and 14.5% of children through use of axillary staging, chemotherapy, adjuvant endocrine therapy, and radiotherapy. Five-year and ten-year survival were comparable between both groups. CONCLUSION: Children and adults present with similarly sized phyllodes tumors. Trends reveal high margin positivity rates, and overtreatment with regional axillary staging and systemic adjuvant therapies. Particularly in children, treatment decisions must consider risks of adjuvant therapy including radiation-related second primary cancers, given uncertain benefit. TYPE OF STUDY: Retrospective Comparative Study. LEVEL OF EVIDENCE: Level III. PMID- 29605261 TI - Reality check: What happens when patients with anorectal malformations grow up? A pilot study of medical care transition from the adult patient perspective. AB - BACKGROUND: There has been an increased focus on transition of pediatric and adolescent patients to adult centered care. For patients with rare and complex conditions, such as anorectal malformations (ARM), difficulties are compounded by the absence of structured transition protocols and lack of adult provider expertise. We sought to explore the actual experiences of adult patients with ARM and distinguish if there are factors that influence the ability to achieve satisfactory transition to adult centered medical care. METHODS: Patients older than 18years with ARM were identified through a hospital database and social support networks, and invited to participate in an anonymous questionnaire. Patients were asked to describe their transition experience as well as report their demographics, and functional outcomes (bowel and bladder function). RESULTS: Twenty-six surveys were completed. Comparison of those respondents (53%) who had transitioned to adult providers to those that had not yet transferred care demonstrated no difference in satisfaction with bowel and bladder function, presence of ostomy, and education level. There was a slight trend for patients with more complex malformations to seek further medical care with adult providers. Of those who transitioned, 67% reported no discussion prior to their transition and 71% received no recommendations for follow-up providers. CONCLUSIONS: This pilot project suggests that a significant number of adult patients with ARM lack transition preparation and fail to find adult providers with expertise. Future studies will need to find optimal ways to address these issues. TYPE OF STUDY: Survey. Retrospective Study LEVELS OF EVIDENCE: Level II. PMID- 29605262 TI - A novel image-based system for risk stratification in patients with desmoplastic small round cell tumor. AB - BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is an aggressive soft tissue sarcoma affecting children and young adults with 5-year overall survival (OS) of approximately 20%. Despite generally poor prognosis, long-term survival does occur. However, no evidence-based system exists to risk-stratify patients at diagnosis. METHODS: We retrospectively reviewed all DSRCT cases diagnosed at our institution between January 2000 and September 2016. Demographics, diagnostic imaging, and clinical data were reviewed. Univariate and multivariate Cox proportional hazard modeling was used to evaluate associations between imaging characteristics and OS. RESULTS: There were 130 patients (85% male; median age at presentation: 21.2 years) with confirmed DSRCT and sufficient imaging and clinical information for analysis. Median 5-year OS was 28% (95% CI: 19%-37%). In univariate analysis, shorter OS was associated with presence of liver lesions (hazard ratio [HR] 2.1, 95% CI: 1.28-3.45), chest lesions (HR 1.86, 95% CI: 1.11 3.1), and ascites (HR 1.69, 95% CI: 1.06-2.7). In multivariate analysis, liver involvement and ascites were predictive and were used to stratify risk (intermediate=no liver involvement or ascites; high=either liver involvement or ascites; very high=both liver involvement and ascites). Intermediate-risk patients had a 5-year survival of 61% (95% CI: 40%-76%) versus 16% (95% CI: 6% 29%) among high-risk patients and 8% (95% CI: 1%-29%) among very high risk patients. CONCLUSION: Patients with DSRCT can be risk-stratified at diagnosis based on specific imaging characteristics. TYPE OF STUDY: Retrospective study with no comparison group. LEVEL OF EVIDENCE: Level IV. PMID- 29605264 TI - Congenital diaphragmatic hernia is associated with nonscrotal testes. AB - BACKGROUND: Congenital diaphragmatic hernia (CDH) is a rare birth defect with a high mortality and morbidity. Nonscrotal testes (NST) are the most reported genital anomaly in boys. Both defects have known associated anomalies, but little is known about the association between CDH and NST. This study evaluates this association and the location of the NST in a large cohort of male CDH survivors. Moreover, we analyzed possible associative factors for NST in CDH patients. METHODS: A cohort of CDH patients, born between January 2000 and March 2014 and treated in a high volume expertise center, was evaluated retrospectively. Boys with a minimum follow-up of 18months were included. The patients were evaluated for testes location, performed orchidopexy, and possible associative factors such as birth weight, gestational age, other congenital anomalies and CDH characteristics (surgical treatment, approach and ECMO). RESULTS: Seventy-five CDH patients were included. Twenty-seven (36%) were diagnosed with NST, of which 22 (29%) received orchidopexy. In 54 patients (72%) there were reports on testes location at birth and location was known for all patients at the age of 18months, although side of NST was unknown in four. The location of the NST was mostly ipsilateral to the CDH (n=20, 87%), of which eight (35%) had a bilateral NST with a unilateral CDH. There were no significant differences in birth weight, gestational age, and CDH specific characteristics in patients with or without NST. CONCLUSION: This study shows a strong association between CDH and NST, with a prevalence of 36%. However, no specific characteristics of the CDH were related to the NST. The testes of all male CDH patients should be thoroughly evaluated in the first year of their life, to ensure a proper and timely treatment. LEVEL OF EVIDENCE: Level IV; case series. PMID- 29605265 TI - Global experiences in fellowship training: A valuable opportunity to match competencies with contemporary priorities and needs. PMID- 29605263 TI - Regarding global pediatric surgery training opportunities. PMID- 29605266 TI - Gastrointestinal mucosal development and injury in premature lambs supported by the artificial placenta. AB - BACKGROUND: An Artificial Placenta (AP) utilizing extracorporeal life support (ECLS) could revolutionize care of extremely premature newborns, but its effects on gastrointestinal morphology and injury need investigation. METHODS: Lambs (116 121days GA, term=145; n=5) were delivered by C-section, cannulated for ECLS, had total parenteral nutrition (TPN) provided, and were supported for 7days before euthanasia. Early and Late Tissue Controls (ETC, n=5 and LTC, n=5) delivered at 115-121days and 125-131days, respectively, were immediately sacrificed. Standardized jejunal samples were formalin-fixed for histology. Crypt depth (CD), villus height (VH), and VH:CD ratios were measured. Measurements also included enterocyte proliferation (Ki-67), Paneth cell count (Lysozyme), and injury scores (H&E). ANOVA and Chi Square were used with p<0.05 considered significant. RESULTS: CD, VH, and VH:CD were similar between groups (p>0.05). AP demonstrated more enterocyte proliferation (95.7+/-21.8) than ETC (49.4+/-23.4; p=0.003) and LTC (66.1+11.8; p=0.04), and more Paneth cells (81.7+/-17.5) than ETC (41.6+/ 7.0; p=0.0005) and LTC (40.7+/-8.2, p=0.0004). Presence of epithelial injury and congestion in the bowel of all groups were not statistically different. No villus atrophy or inflammation was present in any group. CONCLUSIONS: This suggests preserved small bowel mucosal architecture, high cellular turnover, and minimal evidence of injury. STUDY TYPE: Research paper/therapeutic potential. LEVEL OF EVIDENCE: N/A. PMID- 29605267 TI - Effects of an artificial placenta on brain development and injury in premature lambs. AB - PURPOSE: We evaluated whether brain development continues and brain injury is prevented during Artificial Placenta (AP) support utilizing extracorporeal life support (ECLS). METHODS: Lambs at EGA 118days (term=145; n=4) were placed on AP support (venovenous ECLS with jugular drainage and umbilical vein reinfusion) for 7days and sacrificed. Early (EGA 118; n=4) and late (EGA 127; n=4) mechanical ventilation (MV) lambs underwent conventional MV for up to 48h and were sacrificed, and early (n=5) and late (n=5) tissue control (TC) lambs were sacrificed at delivery. Brains were harvested, formalin-fixed, rehydrated, and studied by magnetic resonance imaging (MRI). The gyrification index (GI), a measure of cerebral folding complexity, was calculated for each brain. Diffusion weighted imaging was used to determine fractional anisotropy (FA) and apparent diffusion coefficient (ADC) in multiple structures to assess white matter (WM) integrity. RESULTS: No intracranial hemorrhage was observed. GI was similar between AP and TC groups. ADC and FA did not differ between AP and late TC groups in any structure. Compared to late MV brains, AP brains demonstrated significantly higher ADC (0.45+/-0.08 vs. 0.27+/-0.11, p=0.02) and FA (0.61+/ 0.04 vs. 0.44+/-0.05; p=0.006) in the cerebral peduncles. CONCLUSIONS: After 7days of AP support, WM integrity is preserved relative to mechanical ventilation. TYPE OF STUDY: Research study. PMID- 29605268 TI - Improving the value of care for appendectomy through an individual surgeon specific approach. AB - PURPOSE: Standardized care via a unified surgeon preference card for pediatric appendectomy can result in significant cost reduction. The purpose of this study was to evaluate the impact of cost and outcome feedback to surgeons on value of care in an environment reluctant to adopt a standardized surgeon preference card. METHODS: Prospective observational study comparing operating room (OR) supply costs and patient outcomes for appendectomy in children with 6-month observation periods both before and after intervention. The intervention was real-time feedback of OR supply cost data to individual surgeons via automated dashboards and monthly reports. RESULTS: Two hundred sixteen children underwent laparoscopic appendectomy for non-perforated appendicitis (110 pre-intervention and 106 post intervention). Median supply cost significantly decreased after intervention: $884 (IQR $705-$1025) to $388 (IQR $182-$776), p<0.001. No significant change was detected in median OR duration (47min [IQR 36-63] to 50min [IQR 38-64], p=0.520) or adverse events (1 [0.9%] to 6 [4.7%], p=0.062). OR supply costs for individual surgeons significantly decreased during the intervention period for 6 of 8 surgeons (87.5%). CONCLUSION: Approaching value measurement with a surgeon specific (rather than group-wide) approach can reduce OR supply costs while maintaining excellent clinical outcomes. LEVEL OF EVIDENCE: Level II. PMID- 29605269 TI - Is isomerism a risk factor for intestinal volvulus? AB - INTRODUCTION: Isomerism, or heterotaxy syndrome, affects many organ systems anatomically and functionally. Intestinal malrotation is common in patients with isomerism. Despite a low reported risk of volvulus, some physicians perform routine screening and prophylactic Ladd procedures on asymptomatic patients with isomerism who are found to have intestinal malrotation. The primary aim of this study was to determine if isomerism is an independent risk factor for volvulus. METHODS: Kid's Inpatient Database data from 1997 to 2012 was utilized for this study. Characteristics of admissions with and without isomerism were compared with a particular focus on intestinal malrotation, volvulus, and Ladd procedure. A logistic regression was conducted to determine independent risk factors for volvulus with respect to isomerism. RESULTS: 15,962,403 inpatient admissions were included in the analysis, of which 7970 (0.05%) patients had isomerism, and 6 patients (0.1%) developed volvulus. Isomerism was associated with a 52-fold increase in the odds of intestinal malrotation by univariate analysis. Of 251 with isomerism and intestinal malrotation, only 2.4% experienced volvulus. Logistic regression demonstrated that isomerism was not an independent risk factor for volvulus. CONCLUSION: Isomerism is associated with an increased risk of intestinal malrotation but is not an independent risk factor for volvulus. TYPE OF STUDY: Prognosis study. LEVEL OF EVIDENCE: Level III. PMID- 29605270 TI - Pumpless arteriovenous extracorporeal membrane oxygenation: A novel mode of respiratory support in a lamb model of congenital diaphragmatic hernia. AB - BACKGROUND: Extracorporeal membrane oxygenation (ECMO) is commonly required in neonates with congenital diaphragmatic hernia (CDH) complicated by pulmonary hypertension (PH). ECMO carries significant risk, and is contraindicated in the setting of extreme prematurity or intracranial hemorrhage. Pumpless arteriovenous ECMO (P-ECMO) may represent an alternative for respiratory support. The present study summarizes our initial experience with P-ECMO in a lamb model of CDH. STUDY DESIGN: Surgical creation of CDH was performed at 65-75days' gestation. At term (135-145days), lambs were delivered into the P-ECMO circuit. Three animals were maintained on a low-heparin infusion protocol (target ACT 160-180) and three animals were maintained with no systemic heparinization. RESULTS: Animals were supported by the circuit for 380.7 +/- 145.6h (range, 102-504h). Circuit flow rates ranged from 97 to 208ml/kg/min, with adequacy of organ perfusion demonstrated by stable serum lactate levels (3.0 +/- 1.7) and pH (7.4 +/- 0.3). Necropsy demonstrated no evidence of thrombogenic complications. CONCLUSION: Pumpless extracorporeal membrane oxygenation achieved support of CDH model lambs for up to three weeks. This therapy has the potential to bridge neonates with decompensated respiratory failure to CDH repair with no requirement for systemic anticoagulation, and may be applicable to patients currently precluded from conventional ECMO support. PMID- 29605271 TI - Reply to Letter to the Editor. PMID- 29605272 TI - Impact of Ambiguous and Restrictive Regulations on Opioid-Prescribing Practice in Georgia. AB - CONTEXT: Chronic pain management with opioids in incurable patients remains a challenge of modern medicine regardless of the evidence-based effectiveness of opioids and recommendations of authorities such as the World Health Organization and International Narcotics Control Board. Many countries, including Georgia, maintain overly restrictive regulations that contribute to inadequate pain management. OBJECTIVE: To identify barriers to pain management in Georgia caused by legislation, administrative issues, and physicians' lack of knowledge and understanding of legislative aspects governing opioid use, and their impact on opioid-prescribing practice. METHODS: We conducted a survey among 550 primary health care physicians. In total, 302 physicians completed the questionnaire. Overall, 289 questionnaires were analyzed statistically with SPSS version 20 (Armonk, NY: IBM Corp.). RESULTS: We found that 38% of the physicians avoid prescribing opioids and only one-third of the physicians make an independent decision to treat the patients with opioids. About one-third of the physicians know the updated liberalized legislation and even fewer follow it. Those who apply more liberal legislation and have better medical practice are investigated three to five times more by legal authorities for prescribing morphine to incurable patients than those who do not. CONCLUSION: Ambiguous legislation negatively influences opioid-prescribing practice. Most of the physicians believe that the legislation is restrictive. Physicians who have better medical and legal knowledge and understanding are controlled and investigated more because of their opioid-prescribing practice. Physicians who are concerned that they might be investigated are less inclined to prescribe opioids or use liberalized regulations. PMID- 29605274 TI - Optimizing the dosing schedule of l-asparaginase improves its anti-tumor activity in breast tumor-bearing mice. AB - Proliferation of acute lymphoblastic leukemic cells is nutritionally dependent on the external supply of asparagine. l-asparaginase, an enzyme hydrolyzing l asparagine in blood, is used for treatment of acute lymphoblastic leukemic and other related blood cancers. Although previous studies demonstrated that l asparaginase suppresses the proliferation of cultured solid tumor cells, it remains unclear whether this enzyme prevents the growth of solid tumors in vivo. In this study, we demonstrated the importance of optimizing dosing schedules for the anti-tumor activity of l-asparaginase in 4T1 breast tumor-bearing mice. Cultures of several types of murine solid tumor cells were dependent on the external supply of asparagine. Among them, we selected murine 4T1 breast cancer cells and implanted them into BALB/c female mice kept under standardized light/dark cycle conditions. The growth of 4T1 tumor cells implanted in mice was significantly suppressed by intravenous administration of l-asparaginase during the light phase, whereas its administration during the dark phase failed to show significant anti-tumor activity. Decreases in plasma asparagine levels due to the administration of l-asparaginase were closely related to the dosing time dependency of its anti-tumor effects. These results suggest that the anti-tumor efficacy of l-asparaginase in breast tumor-bearing mice is improved by optimizing the dosing schedule. PMID- 29605275 TI - Magnetic resonance imaging and positron emission tomography in anti-NMDA receptor encephalitis: A systematic review. AB - Due to a variety of clinical manifestations anti-N-methyl-d-aspartate (NMDA) receptor encephalitis may be difficult to diagnose. Magnetic resonance imaging (MRI) may be used as a component of the workup for encephalopathy. However, the use of MRI in anti-NMDA encephalitis is complicated by wide-ranging reports regarding the frequency of normal MRI findings in this disease. Positron emission tomography (PET) is a modality of imaging that may assess functional rather than structural disturbances. Therefore, this review was conducted to summarise published studies regarding the use of MRI and PET in the diagnosis of anti-NMDA receptor encephalitis. The terms (MR OR magnetic resonance OR PET OR positron emission tomography) AND (NMDA encephalitis OR N-methyl-d-aspartate encephalitis) were used to search the databases PubMed, EMBASE and Scopus on 10/5/2017. These searches returned 1534 results. Sixty studies met the inclusion criteria. The results indicated that fewer than half of MRIs in anti-NMDA receptor encephalitis show abnormal findings. When abnormal findings are present they most commonly include T2/FLAIR medial temporal and frontal hyperintensity, and leptomeningeal contrast enhancement. Cortical grey matter changes were reported in the same number of patients as subcortical white matter changes. The only MRI finding with prognostic significance at this stage is progressive cerebellar atrophy. FDG-PET has been assessed in a few small studies and can demonstrate abnormalities in cases where MRI does not. Further research should aim for larger sample sizes and to report (and attempt to control for) the time between symptom onset and the scan being conducted, and pre-imaging treatments. PMID- 29605276 TI - 3-Dimensional printing guide template assisted percutaneous vertebroplasty: Technical note. AB - Percutaneous vertebroplasty (PVP) is currently considered as an effective treatment for pain caused by acute osteoporotic vertebral compression fracture. Recently, puncture-related complications are increasingly reported. It's important to find a precise technique to reduce the puncture-related complications. We report a case and discussed the novel surgical technique with step-by-step operating procedures, to introduce the precise PVP assisted by a 3 dimensional printing guide template. Based on the preoperative CT scan and infrared scan data, a well-designed individual guide template could be established in a 3-dimensional reconstruction software and printed out by a 3 dimensional printer. In real operation, by matching the guide template to patient's back skin, cement needles' insertion orientation and depth were easily established. Only 14 times C-arm fluoroscopy with HDF mode (total exposure dose was 4.5 mSv) were required during the procedure. The operation took only 17 min. Cement distribution in the vertebral body was very good without any puncture related complications. Pain was significantly relieved after surgery. In conclusion, the novel precise 3-dimensional printing guide template system may allow (1) comprehensive visualization of the fractured vertebral body and the individual surgical planning, (2) the perfect fitting between skin and guide template to ensure the puncture stability and accuracy, and (3) increased puncture precision and decreased puncture-related complications, surgical time and radiation exposure. PMID- 29605277 TI - Comparison between frontolateral approach and pterional approach in the surgical treatment of paraclinoid aneurysms. AB - OBJECTIVE: To compare the pterional and frontolateral approach to determine the most effective route for paraclinoid aneurysm surgery. METHODS: Between June 2010 and December 2015, a total of 176 patients with paraclinoid aneurysm underwent surgical clipping, 96 through the pterional and 80 through the frontolateral approach. We analyzed the two groups and compared demographic, radiologic, and clinical variables including age, sex, aneurysm type,intraoperative rupture rates, operative time,anatomical obstacles,outcome and postoperative complications. RESULTS: The 2 groups were comparable with respect to baseline characteristics. The mean operation time was also signifcantly shorter in frontolateral group than in the pterion group (204.3 min vs. 264.1 min, p < 0.05). Furthermore, the mean craniotomy area was much smaller in the frontolateral group (1255.4 mm2 vs. 2758.5 mm2, p < 0.05). No patient experienced rebleeding in either group. In the frontolateral group, the exploration allows enough room for intracranial manipulation with maximal protection of the brain and other intracranial structures. CONCLUSION: The frontolateral approach is a simple, reliable, and efficient procedure. The frontolateral approach could be a good alternative to the classic pterional approach for the treatment of paraclinoid aneurysms. PMID- 29605278 TI - Rare case of diffuse spinal arachnoiditis following a complicated vertebral artery dissection. AB - Spinal arachnoiditis (SA) is an extremely rare and delayed complication of subarachnoid hemorrhage (SAH). Little is known about its underlying pathogenesis and subsequent clinical course. A middle-aged patient presented with the worst headache of her life and a grade 3 SAH of the basal-cisterns and posterior fossa was identified on Computed Tomography scans (CT). Angiography revealed a ruptured dissecting aneurysm of the left vertebral artery (VA-V4), as well as an unruptured left Anterior Cerebral Artery (ACA-A1) aneurysm. The VA aneurysm was treated with flow diversion. The patient re-ruptured the stented aneurysm, another telescoping pipeline was placed. The patient developed polymicrobial ventriculitis, and returned several months later complaining of paraparesis and left sided weakness. Magnetic Resonance Imaging (MRI) revealed diffuse thecal dural thickening from the cervicomedullary junction to the sacrum. Loculations, diffuse edema and cord compression were noticed along the inferior surface of the cerebellum, and the cervico-thoracic spine with a T4-T6 syrinx. The patient underwent a posterior (T4-T8) spinal fusion and (T5-T7) decompression with arachnoid-cyst fenestration and placement of a subarachnoid-pleural shunt. On latest follow-up, the patient is weaning off the thoraco-lumbosacral orthosis and ambulating with a cane. SA is often a complicated two-staged disease in which a "free interval phase" separates the initial inflammatory reaction (IIR) from the late adhesive phase. Posterior fossa bleeding, warranting prolonged surveillance, additional bleeding and ventriculitis might augment the risk and the severity of arachnoiditis. PMID- 29605279 TI - Epstein-Barr virus-associated smooth muscle tumor involving the spine of an HIV infected patient: Case report and review of the literature. AB - Within the last two decades, there have been multiple reports of Epstein-Barr virus (EBV)-associated smooth muscle tumors in immunocompromised patients. This includes HIV-infected patients, post-transplant patients, and patients with congenital defects of their immune systems. Here we report the case of a 24-year old African American female with congenital HIV presenting with progressive lower extremity weakness, constipation, aching pain in her shoulders, and subcostal anesthesia. Magnetic resonance imaging (MRI) revealed a large circumferential lesion extending from T1-T3 and a smaller left paraspinal lesion at C6-C7. The T1 T3 mass was excised via a right-sided costotransversectomy with laminectomy and fusion from T1-T3. Highly active antiretroviral therapy (HAART) was started postoperatively, and adjuvant radiotherapy was initiated but patient was lost to follow-up. Surgical pathology demonstrated a smooth muscle tumor diffuse nuclear positivity for EBV-encoded small RNA 1 by in situ hybridization. Although eight studies have reported HIV patients with EBV-associated smooth muscle tumors of the spine, to the author's knowledge, this is the first review comprised solely of patients with spinal involvement with the addition of our patient case. PMID- 29605280 TI - Letter to the editor regarding "The trans-laminar terminalis approach reduces mortalities associated with chordoid glioma resections: A case report and a review of 20 years of literature". PMID- 29605281 TI - Simultaneous pupil expansion and displacement for femtosecond laser-assisted cataract surgery in patients with lens ectopia. AB - We describe a new approach for cataract surgery in ectopia lentis associated with an inadequately dilated pupil. A Malyugin ring 2.0 is first positioned in the eye to expand the pupil. One of the ring coils is then temporarily sutured to the limbal area with 10-0 polypropylene. With this maneuver, the pupillary expansion ring is placed in alignment with the center of the ectopic lens. Femtosecond laser anterior capsulotomy and lens fragmentation is then performed. Next, the temporary suture is released, a capsular hook(s) is placed to support the lens, and the lens is emulsified. A modified capsular tension ring is then inserted and sutured to the ciliary sulcus to center the capsular bag and the intraocular lens is implanted. This new technique for patients with insufficiently dilated pupils associated with ectopia lentis has the potential to improve surgical results and minimize complications in selected cases. PMID- 29605282 TI - Accuracy of 8 intraocular lens calculation formulas in relation to anterior chamber depth in patients with normal axial lengths. AB - PURPOSE: To determine the effect of anterior chamber depth (ACD) on the accuracy of 8 intraocular lens calculation formulas in patients with normal axial lengths (ALs). SETTING: Baylor College of Medicine, Alkek Eye center, Houston, Texas, USA. DESIGN: Retrospective case series. METHODS: Patients having cataract surgery with ALs between 22.0 mm and 25.0 mm were divided into 3 groups based on their preoperative ACD measurement. The mean prediction errors, mean absolute errors (MAEs), and median absolute errors for each group were calculated. RESULTS: For the ACD of 3.0 mm or less group and the ACD of 3.5 mm or more group, the Barrett Universal II, Holladay 2, Haigis, and Olsen ray-tracing formulas had mean prediction error values that were not significantly different from zero. For the ACD of 3.01 to 3.49 mm group, all formulas had mean prediction error values that were not significantly different from zero. For the ACD of 3.0 mm or less group, the Barrett Universal II formula had a smaller median absolute error than the Haigis, Hoffer Q, and Olsen optical low-coherence reflectometry (OLCR) (Lenstar) formulas and a smaller MAE than the Hoffer Q, Hill-RBF, and Olsen OLCR (P < .05). In the ACD of 3.5 mm or more group, the Barrett MAE was smaller than the Hoffer Q (P < .05); however, there were no significant differences between median absolute errors. CONCLUSION: In eyes with normal ALs, taking preoperative ACD values into consideration might improve refractive outcomes. PMID- 29605283 TI - Patient satisfaction with epithelium-off corneal crosslinking. AB - PURPOSE: To assess patient satisfaction with corneal crosslinking (CXL). SETTING: Price Vision Group, Indianapolis, Indiana, USA. DESIGN: Prospective case series. METHODS: Patients treated with the Dresden protocol or accelerated epithelium-off CXL during an 8-year period were invited to participate in an electronic survey. RESULTS: Of the 552 patients who were invited to participate, 448 (80% response rate) completed the electronic survey. The median time from CXL to survey completion was 3.5 years (range 1 to 9 years). The participants were 73% men; 78% had keratoconus, 22% had post-refractive surgical ectasia, and 44% had bilateral treatment. Comparable proportions of those treated with standard and accelerated CXL reported that it halted disease progression (88% versus 87%, respectively, P = .78). A younger treatment age was associated with higher perceived efficacy (P = .0003). The proportion who considered CXL effective was 93% among those with mild keratoconus, 86% with moderate to severe keratoconus, and 78% with post refractive surgical ectasia (P = .0004). Regarding vision, 41% reported improvement after CXL, 46% noted no change, and 14% perceived continued decline. The mean satisfaction score was 8.8 +/- 1.7 (SD) on a scale of 1 (would not recommend CXL) to 10 (definitely would recommend) among those treated for keratoconus and 7.6 +/- 2.5 among those treated for ectasia after keratorefractive surgery (P < .0001). Eleven (1.7%) of 644 treated eyes had subsequent keratoplasty. CONCLUSION: Most patients considered CXL effective. The perceived efficacy did not vary significantly as a function of follow-up time (P = .90), suggesting no discernible fading of effect over the 1- to 9-year follow up. PMID- 29605284 TI - Refractive outcomes of phacoemulsification cataract surgery in glaucoma patients. AB - PURPOSE: To evaluate refractive outcomes after phacoemulsification cataract surgery in patients with glaucoma. SETTING: University of Colorado Health Eye Center, Aurora, Colorado, USA. DESIGN: Retrospective case series. METHODS: The incidence of refractive surprise was evaluated in patients with and without glaucoma after phacoemulsification cataract surgery. Refractive surprise was defined as the difference in spherical equivalent of the refractive target and postoperative refraction in diopters (D). RESULTS: The study comprised 206 eyes in the glaucoma group and 1162 control eyes. The refractive surprise greater than +/-0.5 D and +/-1.0 D was 29.9% and 4.9% in the control group and 40.3% (P = .0061) and 11.2% (P = .0011) in the glaucoma group. Primary open-angle glaucoma (POAG) (n = 154 eyes), chronic angle-closure glaucoma (n = 18 eyes), and pseudoexfoliation glaucoma (n = 23 eyes) had odds ratios of 1.90 (P = .1760), 14.54 (P = .0006), and 7.27 (P = .0138), respectively, of refractive surprise greater than +/-1.0 D compared with patients without glaucoma. Refractive surprise was noted more often in POAG eyes with axial lengths longer than 25.0 mm (P = .0298). Glaucoma eyes had worse mean postoperative corrected distance visual acuity than control eyes (glaucoma: 0.1088 logarithm of the minimum angle of resolution [logMAR]; controls: 0.0358 logMAR; P = .01). CONCLUSION: Patients with a diagnosis of glaucoma were more likely to have a refractive surprise and/or worse visual outcome after phacoemulsification cataract surgery. PMID- 29605286 TI - Pulmonary hypertension in patients with interstitial lung disease. AB - Interstitial lung diseases (ILDs) comprise a broad and heterogeneous group of more than two hundred diseases with common functional characteristics. Their diagnosis and management require a multidisciplinary approach. This multidisciplinary approach involves the assessment of comorbid conditions including pulmonary hypertension (PH) that exerts a dramatic impact on survival. The current World Health Organization (WHO) classification of PH encompasses many of the interstitial lung diseases into WHO Group 3, while sarcoidosis, Pulmonary Langerhans Cell Histiocytosis and lymphangioleiomyomatosis are placed into WHO Group 5 as diseases with unclear or multifactorial mechanisms. Connective tissue diseases could span any of the 5 WHO groups based on the primary phenotype into which they manifest. Interestingly, several challenging phenotypes present with features that overlap between two or more WHO PH groups. Currently, PH-specific treatment is recommended only for patients classified into WHO Group 1 PH. The lack of specific treatment for other groups, including PH in the setting of ILD, reflects the poor outcomes of these patients. Thus, identification of the optimal strategy for ILD patients with PH remains an amenable need. This review article provides a brief overview of biomarkers indicative of vascular remodeling in interstitial lung disease, summarizes the current state of knowledge regarding patients with PH and ILD and highlights future perspectives that remain to be addressed. PMID- 29605287 TI - Sequential ethanol fermentation and anaerobic digestion increases bioenergy yields from duckweed. AB - The potential for improving bioenergy yields from duckweed, a fast-growing, simple, floating aquatic plant, was evaluated by subjecting the dried biomass directly to anaerobic digestion, or sequentially to ethanol fermentation and then anaerobic digestion, after evaporating ethanol from the fermentation broth. Bioethanol yields of 0.41 +/- 0.03 g/g and 0.50 +/- 0.01 g/g (glucose) were achieved for duckweed harvested from the Penn State Living-Filter (Lemna obscura) and Eco-MachineTM (Lemna minor/japonica and Wolffia columbiana), respectively. The highest biomethane yield, 390 +/- 0.1 ml CH4/g volatile solids added, was achieved in a reactor containing fermented duckweed from the Living-Filter at a substrate-to-inoculum (S/I) ratio (i.e., duckweed to microorganism ratio) of 1.0. This value was 51.2% higher than the biomethane yield of a replicate reactor with raw (non-fermented) duckweed. The combined bioethanol-biomethane process yielded 70.4% more bioenergy from duckweed, than if anaerobic digestion had been run alone. PMID- 29605288 TI - Identification and molecular characterization of two Cu/Zn-SODs and Mn-SOD in the marine ciliate Euplotes crassus: Modulation of enzyme activity and transcripts in response to copper and cadmium. AB - The superoxide dismutase (SOD) family is a first line antioxidant enzyme group involved in transformation of the superoxide anion (O2-) into hydrogen peroxide (H2O2) and O2. SOD gene expression patterns and enzyme activities therefore have a role as molecular biomarkers in evaluating the oxidative stress status of aquatic organisms. However, antioxidant enzyme systems are yet to be fully explored in the marine ciliates. In this study, we identified and characterized two types of Cu/Zn SODs (Ec-Cu/ZnSOD1 and Ec-Cu/ZnSOD2) and Ec-Mn SOD in the marine ciliate Euplotes crassus. Subsequently, SOD activity and transcriptional modulation of the relevant genes were investigated after the exposure to Cd and Cu for 8 h. All Ec-SODs showed conserved domains and metal binding sites on their active sites. Total SOD activity was induced at 1 h after exposure to Cd (125 and 1000 MUg/L), and showed a marginal increase at 1-h exposure to Cu (10 and 100 MUg/L). However, SOD activity was maintained at a steady level under Cd and decreased under Cu exposure conditions at 3 h and 8 h. mRNA expression of both the Ec-Cu/Zn-SODs and Mn-SOD were remarkably elevated after the exposure to Cd (250-1000 MUg/L, maximum 4-fold, p < 0.05) and, in particular, Cu (25-100 MUg/L, maximum > 20-fold, p < 0.05), in a concentration - dependent manner. These findings suggest that Ec-SODs may be actively involved in cellular protection against metal - mediated oxidative stress. This study is therefore helpful in understanding the molecular responses for metal toxicity in the ciliates. PMID- 29605289 TI - Magnetic Resonance Imaging Markers of Cerebral Small Vessel Disease in Hematoma Expansion of Intracerebral Hemorrhage. AB - BACKGROUND: Hematoma expansion is an independent risk factor of unfavorable outcome after intracerebral hemorrhage (ICH), which always occurs in the early phase after symptoms onset. The relationship between underlying small vessel disease (SVD) and hematoma expansion was inconsistent in patients with ICH. We aimed to investigate the relationship between magnetic resonance (MR) characteristics of SVD and hematoma expansion in patients with ICH within 72 hours after symptoms onset. METHODS: Data were derived from a cohort of biological sample collection from April 2014 to April 2016. We recruited patients aged 18 years or older with a baseline and follow-up computed tomography within 72 hours after symptom onset, as well as an MR imaging within 3 months before or after ICH. Hematoma expansion was defined as an increase in volume between baseline and final hematoma volume exceeding 6 mL or 33% of the baseline volume. Multivariate logistic regression was used to explore the association between clinical characteristics, imaging markers, total SVD score, and hematoma expansion in patients with ICH. RESULTS: A total of 103 patients experienced hematoma expansion among the 263 enrolled patients (mean age 53.4 +/- 14.0 years, 76.4% male). Electrocardiogram abnormal rhythm, fewer non-lobar microbleeds, lower plasma homocysteine concentration, and smaller baseline hematoma volume independently predicted the risk of hematoma expansion (P = .004, .021, .001, and .024, respectively). Odds ratios ranged from 1.02 to 3.72. CONCLUSIONS: Our study suggested that the use of MR markers revealing underlying SVD may help to identify patients with ICH with potential hematoma expansion. PMID- 29605290 TI - Responses in patients receiving sequential paclitaxel post progression on PD1 inhibitors. AB - This report describes highlights the dramatic responses seen in patients who were given paclitaxel post progression on immunotherapy. There are multiple mechanisms by which synergistic effects of immunotherapy and chemotherapy occur. Further prospective studies on chemotherapy and immunotherapy are eagerly awaited. PMID- 29605291 TI - Proteomic analysis revealed proteins induced upon Azotobacter vinelandii encystment. PMID- 29605292 TI - Parallel reaction monitoring on a Q Exactive mass spectrometer increases reproducibility of phosphopeptide detection in bacterial phosphoproteomics measurements. AB - Increasing number of studies report the relevance of protein Ser/Thr/Tyr phosphorylation in bacterial physiology, yet the analysis of this type of modification in bacteria still presents a considerable challenge. Unlike in eukaryotes, where tens of thousands of phosphorylation events likely occupy more than two thirds of the proteome, the abundance of protein phosphorylation is much lower in bacteria. Even the state-of-the-art phosphopeptide enrichment protocols fail to remove the high background of abundant unmodified peptides, leading to low signal intensity and undersampling of phosphopeptide precursor ions in consecutive data-dependent MS runs. Consequently, large-scale bacterial phosphoproteomic datasets often suffer from poor reproducibility and a high number of missing values. Here we explore the application of parallel reaction monitoring (PRM) on a Q Exactive mass spectrometer in bacterial phosphoproteome analysis, focusing especially on run-to-run sampling reproducibility. In multiple measurements of identical phosphopeptide-enriched samples, we show that PRM outperforms data-dependent acquisition (DDA) in terms of detection frequency, reaching almost complete sampling efficiency, compared to 20% in DDA. We observe a similar trend over multiple heterogeneous phosphopeptide-enriched samples and conclude that PRM shows a great promise in bacterial phosphoproteomics analyses where reproducible detection and quantification of a relatively small set of phosphopeptides is desired. SIGNIFICANCE: Bacterial phosphorylated peptides occur in low abundance compared to their unmodified counterparts, and are therefore rarely reproducibly detected in shotgun (DDA) proteomics measurements. Here we show that parallel reaction monitoring complements DDA analyses and makes detection of known, targeted phosphopeptides more reproducible. This will be of significance in replicated MS measurements that have a goal to reproducibly detect and quantify phosphopeptides of interest. PMID- 29605293 TI - Accuracy analysis of computer-assisted surgery for femoral trochanteric fracture using a fluoroscopic navigation system: Stryker ADAPT(r) system. AB - PURPOSE: ADAPT is a fluoroscopic computer-assisted surgery system which intraoperatively shows the distance from the tip of the screw to the surface of the femoral head, tip-to-head-surface distance (TSD), and the tip-apex distance (TAD) advocated by Baumgaertner et al. The study evaluated the accuracy of ADAPT. PATIENTS AND METHODS: A total of 55 patients operated with ADAPT between August 2016 and March 2017 were included as subjects. TSD and TAD were measured postoperatively using computed tomography (CT) and X-rays. The intraclass correlation coefficient (ICC) was checked in advance. The error was defined as the difference between postoperative and intraoperative measurement values of ADAPT. Summary statistics, root mean square errors (RMSEs), and correlations were evaluated. RESULTS: ICC was 0.94 [95% CI: 0.90-0.96] in TSD and 0.99 [95% CI: 0.98-0.99] in TAD. The error was -0.35 mm (-1.83 mm to 1.12 mm) in TSD and +0.63 mm (-5.65 mm to 4.59 mm) in TAD. RMSE was 0.63 mm in TSD and 1.53 mm in TAD. Pearson's correlation coefficient was 0.79 [95% CI: 0.66-0.87] in TSD and 0.83 [95% CI: 0.72-0.89] in TAD. There were no adverse events with ADAPT use. CONCLUSION: ADAPT is highly accurate and useful in guiding surgeons in properly positioning the screws. PMID- 29605294 TI - MiR-615 inhibits cell proliferation, migration and invasion by targeting EGFR in human glioblastoma. AB - MiR-615 and epidermal growth factor receptor (EGFR) are associated with a number of disease processes and pathogenesis. However, little is known about the mechanisms of miR-615 and EGFR in human glioblastoma multiforme (GBM). Here, we found that down-regulation of miR-615 expression occurred in GBM tissues and cells, and was inversely correlated with overall survival, relapse-free survival, WHO grade as well as EGFR expression. We further determined that miR-615 functions as a tumor suppressor by inhibiting GBM cell proliferation, cell cycle, migration and invasion, and promoting cell apoptosis. In-vivo assay validated the inhibition effect of miR-615 on tumor growth and EGFR expression. Luciferase reporter assays demonstrated that miR-615 targeted the 3'-untranslated region (3' UTR) of EGFR. Besides, over-expression of EGFR reversed the inhibition effects of miR-615, while silencing of EGFR aggravated these inhibition effects. In conclusions, we identified that miR-615 plays a tumor suppressor role in GBM cell proliferation, migration and invasion by targeting EGFR expression, and miR-615 may act as a novel biomarker for early diagnosis or therapeutic targets of GBM. PMID- 29605295 TI - Heparan sulfate in pancreatic beta-cells contributes to normal glucose homeostasis by regulating insulin secretion. AB - Heparan sulfate (HS), a linear polysaccharide, is involved in diverse biological functions of various tissues. HS is expressed in pancreatic beta-cells and may be involved in beta-cell functions. However, the importance of HS for beta-cell function remains unknown. Here, we generated mice with beta-cell-specific deletion of Ext1 (betaExt1CKO), which encodes an enzyme essential for HS synthesis, to investigate the detailed roles of HS in beta-cell function. betaExt1CKO mice decreased body weights compared with control mice, despite increased food intake. Additionally, betaExt1CKO mice showed impaired glucose tolerance associated with decreased insulin secretion upon glucose challenge. Glucose-induced insulin secretion (GIIS) from isolated betaExt1CKO islets was also significantly reduced, highlighting the contribution of HS to insulin secretion and glucose homeostasis. The gene expression essential for GIIS was decreased in betaExt1CKO islets. Pdx1 and MafA were downregulated in betaExt1CKO islets, indicating that HS promoted beta-cell development and maturation. BrdU- or Ki67-positive beta-cells were reduced in betaExt1CKO pancreatic sections, suggesting the involvement of HS in the proliferation of beta-cells. Moreover, insufficient vascularization in betaExt1CKO islets may contribute to central distribution of alpha-cells. These data demonstrate HS plays diverse roles in beta-cells, and that loss of HS leads to insufficient insulin secretion and dysregulation of glucose homeostasis. PMID- 29605296 TI - ATF3 mediates the inhibitory action of TNF-alpha on osteoblast differentiation through the JNK signaling pathway. AB - Tumor necrosis factor (TNF)-alpha, which is a proinflammatory cytokine, inhibits osteoblast differentiation under diverse inflammatory conditions. Activating transcription factor 3 (ATF3), which is a member of the ATF/cAMP response element binding protein family of transcription factors, has been implicated in the regulation of cell proliferation and differentiation. However, the precise interactions between ATF3 and the TNF-alpha signaling pathway in the regulation of osteoblast differentiation remain unclear. In this study, we examined the role of ATF3 in the TNF-alpha-mediated inhibition of osteoblast differentiation and investigated the signaling pathways involved. The treatment of cells with TNF alpha downregulated osteogenic markers, but significantly upregulated the expression of Atf3. The inhibition of Atf3 by small interfering RNAs rescued osteogenesis, which was inhibited by TNF-alpha. Conversely, the enforced expression of Atf3 enhanced the TNF-alpha-mediated inhibition of osteoblast differentiation, as revealed by the measurement of osteogenic markers and alkaline phosphatase staining. Mechanistically, TNF-alpha-induced Atf3 expression was significantly suppressed by the inhibition of the c-Jun N-terminal kinase (JNK) pathway. Furthermore, the overexpression of Atf3 did not affect the rescue effect that inhibiting TNF-alpha expression using a JNK inhibitor had on alkaline phosphatase activity and mineralization. Taken together, these results indicate that ATF3 mediates the inhibitory action of TNF-alpha on osteoblast differentiation and that the TNF-alpha-activated JNK pathway is responsible for the induction of Atf3 expression. PMID- 29605297 TI - Downregulation of circ_008018 protects against cerebral ischemia-reperfusion injury by targeting miR-99a. AB - Circular RNAs (circRNAs) are highly expressed in eukaryotic cells and regulate physiological and pathophysiological processes. However, the role of circRNAs in cerebral ischemia-reperfusion (I/R) injury remains largely unknown. In this study, we found that circ_008018 level was higher in the cortical tissue of mice with middle cerebral artery occlusion as compared to those in the sham group 24 h after reperfusion. Knockdown of circ_008018 attenuated cerebral I/R-induced brain tissue damage and neurological deficits in mice by inducing microRNA miR-99a overexpression. The decreased phosphorylation of Akt and glycogen synthase kinase 3beta caused by I/R was partly reversed by circ_008018 silencing or miR-99a overexpression. Taken together, these results provide new insight into the mechanisms of apoptosis resulting from cerebral I/R injury and suggest that targeted inhibition of circ_008018 can protect against subsequent neurological damage. PMID- 29605298 TI - Micro124-mediated AHR expression regulates the inflammatory response of chronic rhinosinusitis (CRS) with nasal polyps. AB - MicroRNAs represent a component of the innate immune responses that can restrain inflammatory signaling, miR124 is an important member of inflammation-associated miRNAs, and abnormal miR124 expression is observed in many inflammatory diseases and immune disorders. However, the role and signaling pathways of miR124 in chronic rhinosinusitis with nasal polyps (CRSwNPs) have not been studied in detail. The aryl hydrocarbon receptor (AHR) is a ligand-inducible transcription factor that is highly conserved in evolution and plays important roles in the inflammatory response process. In our study, we describe the role of miR124 in the inflammatory response of CRS with nasal polyps. We found that the expression of miR124 was decreased in nasal polyps, and negatively correlated with the expression of AHR. MiR124 can inhibit AHR expression by directly target 3' untranslated region (3'-UTR) of AHR. To further investigate the relationship between miR124, AHR and CRS inflammatory response, we transfect HNEpC cells with miR124 mimic, miR124 inhibitors or siRNA of AHR, then all the results showed that miR124 could regulates cellular inflammatory response through negatively regulating AHR expression. This study demonstrated that the regulation of AHR expression by miR124 is critical to the development of inflammatory response in CRSwNPs. PMID- 29605299 TI - Long noncoding RNA LNC473 inhibits the ubiquitination of survivin via association with USP9X and enhances cell proliferation and invasion in hepatocellular carcinoma cells. AB - Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related death worldwide. Recent studies reported that lncRNA LINC00473 (LNC473) was involved in cancer progression. However, the clinical significance and functional role of LNC473 in HCC progression is still unknown. In the present study, we found that the LNC473 expression was markedly elevated in HCC tissues and correlated with bigger tumor size, higher BCLC stage, vascular invasion and poor prognosis. Gain- and loss-of-function assay showed that LNC473 enhanced HCC cell proliferation and invasion and induced epithelial-mesenchymal transition (EMT) process. Mechanistically, LNC473 associated with oncoprotein survivin and regulates its stability. Moreover, LNC473 could recruit deubiquitinase USP9X to inhibit the ubiquitination level of survivin and then increase survivin expression. Therefore, our results suggest that LNC473 exerts its functions as an oncogene in HCC progression and may be a therapeutic target for HCC treatment. PMID- 29605300 TI - LncRNA-MALAT1 promotes CPC proliferation and migration in hypoxia by up regulation of JMJD6 via sponging miR-125. AB - The death of cardiomyocytes after myocardial infarction (MI) often leads to ventricular remodeling as well as heart failure (HF). The cardiac progenitor cells (CPCs) have the ability to regenerate functional heart muscle in patients after MI, which provides a promising method for MI-induced HF therapy. However, to date, CPCs can easily lose their proliferation ability in the infarcted myocardium. Therefore, exploring the mechanism for CPC proliferation is essential for CPC-based therapy in MI-induced HF. A previous study indicated that a hypoxic environment is essential for CPC proliferation, but the mechanism is not yet clear. In this work, we discovered that CoCl2-induced hypoxia can promote CPC proliferation and migration. Additionally, long non-coding RNA MALAT1 expression was significantly up-regulated in the CoCl2-induced hypoxia CPC model. MALAT1 suppression inhibited CPC proliferation and migration under hypoxic conditions. In addition, MALAT1 acted as a sponge for miR-125. The miR-125 inhibitor restored the proliferation and migration potentials of CPCs after a MALAT1 knockdown in hypoxia. A further study demonstrated that JMJD6 was a target of miR-125 whose expression was negatively regulated by miR-125. JMJD6 knockdown blocked miR-125 inhibitor's protective effect on CPC function in hypoxia. Ultimately, our finding demonstrated that MALAT1 can modulate CPC proliferation and migration potential through the miR-125/JMJD6 axis in hypoxia. Our finding provided a new regulatory mechanism for CPC proliferation in hypoxia, which provided a new target for MI induced HF therapy. PMID- 29605301 TI - Hsa_circ_0007534/miR-761/ZIC5 regulatory loop modulates the proliferation and migration of glioma cells. AB - Increasing evidences demonstrate the essential roles of circular RNAs (circRNAs) in human cancers. However, the study about the functions of circRNAs in glioma remains very limited. In the present study, we found that circRNA hsa_circ_0007534 was highly expressed in glioma tissues compared to normal brain tissues. Furthermore, we found that knockdown of hsa_circ_0007534 significantly inhibited the proliferation and migration of glioma cells. In mechanism, we showed that hsa_circ_0007534 could sponge miR-761 to repress its availability in glioma cells. We found that inhibition of miR-761 could rescue the suppressed proliferation and migration of glioma cells by hsa_circ_0007534 knockdown. Moreover, we explored the downstream mechanism and found that ZIC5 was a target of miR-761. We showed that hsa_circ_0007534 promoted the expression of ZIC5 by inhibiting miR-761 in glioma cells. And restoration of ZIC5 expression significantly reversed the effects of hsa_circ_0007534 knockdown on glioma cell proliferation and migration. In summary, our results demonstrated that hsa_circ_0007534 serves as an oncogene in glioma via promoting ZIC5 expression by repressing miR-761 availability. Our results suggested that hsa_circ_0007534/miR 761/ZIC5 regulatory loop might be a promising therapeutic target for glioma treatment. PMID- 29605302 TI - Higher dietary carotenoid intake associated with lower risk of hip fracture in middle-aged and elderly Chinese: A matched case-control study. AB - BACKGROUND: Mechanism studies have suggested that carotenoids may benefit bone health due to their antioxidant properties, but epidemiological data on their effects on risk of hip fracture are sparse. PURPOSE: To explore the relationships between dietary total and specific carotenoids and the risk of hip fracture in a middle-aged and elderly Chinese population. DESIGN: A case-control study of 1070 patients with hip fractures (diagnosed within 2 weeks) aged 55-80 years and 1070 age- (within 3 years) and gender-matched controls was conducted in Guangdong, China between 2009 and 2015. Information on dietary carotenoid intake was assessed using a 79-item food frequency questionnaire administered in face-to face interviews, and general information was collected using structured questionnaires. The univariate and multivariate conditional logistic regression models were applied to analyze the associations. MAIN RESULTS: Higher intakes of both total and some specific carotenoids (including beta-carotene, beta cryptoxanthin and lutein/zeaxanthin) were significantly associated with a lower risk of hip fracture (all p trends <0.01). Compared with the lowest quartile of carotenoids, the multivariate-adjusted odds ratios and 95% confidential intervals of the highest quartile were 0.44 (0.29, 0.68) (total carotenoids), 0.50 (0.29, 0.69) (beta-carotene), 0.55 (0.38, 0.80) (beta-cryptoxanthin) and 0.40 (0.27, 0.59) (lutein/zeaxanthin), respectively. There were no statistically significant associations between alpha-carotene and lycopene intakes and hip fracture risk after adjustment for various confounding variables. CONCLUSION: These results suggest that the consumption of carotenoids may be protective against hip fracture in middle-aged and elderly Chinese adults. PMID- 29605303 TI - Inverse association between sympathetic nervous system activity and bone mass in middle aged overweight individuals. AB - BACKGROUND/PURPOSE: Sympathetic nervous system activation in obesity is associated with impaired cardiovascular and metabolic function. Animal studies have shown a direct link between sympathetic nervous activation and bone health but little is known about this link in humans. This study examined whether sympathetic activation may impact bone health in overweight adults. METHODS: This cross sectional study included 96 overweight or obese middle-aged adults (51 males, mean body mass index: 32.8 kg/m2, mean age: 55.3 years). Multivariate linear regression models evaluated associations between whole body and leg bone mineral density (BMD) and bone mineral content (BMC) derived from dual-energy X ray absorptiometry and muscle sympathetic nervous system activity (MSNA) measured by microneurography. RESULTS: Older age, male sex and higher weight were associated with higher leg and body BMC and BMD. After adjustment for age, sex and weight, MSNA was significantly inversely associated with total BMC (p = 0.012) and with leg BMC (p < 0.01) but was not associated with either total or leg BMD (p = 0.159 and p = 0.063 respectively). When the analysis was sex specific, the relationships between MSNA and total and leg BMC were only significant in males. CONCLUSIONS: Our study indicates that in middle aged overweight or obese males, sympathetic activation may have a deleterious effect on bone mineral content. PMID- 29605304 TI - Antibody drug conjugates of cleavable amino-alkyl and aryl maytansinoids. AB - Natural products have been used for many medicinal purposes for centuries. Antibody drug conjugates (ADCs) have utilized this rich source of small molecule therapeutics to produce several clinically useful treatments. ADCs based on the natural product maytansine have been successful clinically. The authors further the utility of the anti-cancer natural product maytansine by developing efficacious payloads and linker-payloads for conjugating to antibodies. The success of our approach was realized in the EGFRvIII targeting ADC EGFRvIII-16. The ADC was able to regress tumors in 2 tumor models (U251/EGFRvIII and MMT/EGFRvIII). When compared to a positive control ADC, the efficacy observed was similar or improved while the isotype control ADCs had no effect. PMID- 29605305 TI - Direct and indirect effects of waste management policies on household waste behaviour: The case of Sweden. AB - Swedish legislation makes municipalities responsible for recycling or disposing of household waste. Municipalities therefore play an important role in achieving Sweden's increased levels of ambition in the waste management area and in achieving the goal of a more circular economy. This paper studies how two municipal policy instruments - weight-based waste tariffs and special systems for the collection of food waste - affect the collected volumes of different types of waste. We find that a system of collecting food waste separately is more effective overall than imposing weight-based waste tariffs in respect not only of reducing the amounts of waste destined for incineration, but also of increasing materials recycling and biological recovery, despite the fact that the direct incentive effects of these two systems should be similar. Separate food waste collection was associated with increased recycling not only of food waste but also of other waste. Introducing separate food waste collection indirectly signals to households that recycling is important and desirable, and our results suggest that this signalling effect may be as important as direct incentive effects. PMID- 29605306 TI - Measuring methane emissions from a UK landfill using the tracer dispersion method and the influence of operational and environmental factors. AB - The methane emissions from a landfill in south-east, UK were successfully quantified during a six-day measurement campaign using the tracer dispersion method. The fair weather conditions made it necessary to perform measurements in the late afternoon and in the evening when the lower solar flux resulted in a more stable troposphere with a lower inversion layer. This caused a slower mixing of the gasses, but allowed plume measurements up to 6700 m downwind from the landfill. The average methane emission varied between 217 +/- 14 and 410 +/- 18 kg h-1 within the individual measurement days, but the measured emission rates were higher on the first three days (333 +/- 27, 371 +/- 42 and 410 +/- 18 kg h 1) compared to the last three days (217 +/- 14, 249 +/- 20 and 263 +/- 22 kg h 1). It was not possible to completely isolate the extent to which these variations were a consequence of measuring artefacts, such as wind/measurement direction and measurement distance, or from an actual change in the fugitive emission. Such emission change is known to occur with changes in the atmospheric pressure. The higher emissions measured during the first three days of the campaign were measured during a period with an overall decrease in atmospheric pressure (from approximately 1014 mbar on day 1 to 987 mbar on day 6). The lower emissions measured during the last three days of the campaign were carried out during a period with an initial pressure increase followed by a period of slowly reducing pressure. The average daily methane recovery flow varied between 633 and 679 kg h-1 at STP (1 atm, 0 degrees C). The methane emitted to the atmosphere accounted for approximately 31% of the total methane generated, assuming that the methane generated is the sum of the methane recovered and the methane emitted to the atmosphere, thus not including a potential methane oxidation in the landfill cover soil. PMID- 29605307 TI - Distinct recovery of copper and aluminum from waste electric wires using a roll type electrostatic separator. AB - Electrostatic separators are commonly employed for the sorting of insulating and conducting fractions of granular mixtures. However, separation of the various metals that compose the conductive fraction still represents a major challenge for the recycling industry. The aim of this paper is to identify the conditions in which a roll-type electrostatic separator could be used for distinctly recover the copper and aluminum from waste electric wires. A numerical model of particle trajectories was employed to predefine these conditions and guide the experimental study. The electrostatic separation experiments were carried out using a reverse-S-type-plate high-voltage electrode. The visualization of particle trajectories using a high-speed camera paved the way to an original design. Thus, a metallic trap was attached to the high-voltage electrode, to facilitate the collection of the aluminum flake-like particles from a mixture that also contains copper strands. With a plastic trap replacing the metallic one, to avoid electric field modification, 68.6% of the copper was recovered with a purity attaining 99%. PMID- 29605308 TI - Effects of spray-dried plasma protein product on early-lactation dairy cows. AB - Spray-dried plasma protein (SDP) compared with blood meal (BM) may contain various functional and active components that may benefit animal health. The objective of this experiment was to investigate the effects of feeding SDP or BM on production and blood profile in dairy cows during the transition and early lactation periods. Seventy-two Holstein cows at 14 d before calving were used in a randomized block design. During the prepartum period, cows were fed a typical late-gestation diet containing BM (100 g/cow per day; 100BM, n = 24) or SDP (100 g/cow per day; 100SDP; n = 48). After calving, cows that were fed BM prepartum were fed a typical lactation diet formulated to provide 100 g/d of BM (100BM). Half the cows that were fed 100SDP prepartum were fed a lactation diet formulated to provide 100 g/d of SDP (100SDP; n = 24), and half were fed a diet formulated to provide 400 g/d of SDP (400SDP; n = 24) on a dry matter basis where SDP replaced BM (100SDP) or BM and soybean products (400SDP). All diets were balanced for crude protein concentration and metabolizable protein supply assuming BM and SDP were equal in rumen-degradable protein and rumen-undegradable protein. All data were analyzed using the MIXED procedure of SAS (SAS Institute Inc., Cary, NC) as a randomized block design where contrasts were made for 100BM versus 100SDP for prepartum variables and 100BM versus 100SDP and 100SDP versus 400SDP for postpartum variables. Prepartum supplementation of SDP had no effect on plasma fatty acids and beta-hydroxybutyrate (2 d before calving). Plasma fatty acids (255 +/- 29 uEq/mL) and beta-hydroxybutyrate (675 +/- 70 umol/L) at 8 and 14 d of lactation were not affected by SDP in the diet. Feeding SDP at 100 g/d compared with 100BM increased or tended to increase milk fat, protein, and lactose contents for 16 wk after parturition. Providing SDP at 400 g/d in the diet increased milk yield (42 vs. 39 kg/d), energy-corrected milk (44 vs. 41 kg/d), energy-corrected milk per kilogram of dry matter intake, and yields of milk fat (1.60 vs. 1.48 kg/d), protein (1.21 vs. 1.16 kg/d), and lactose compared with 100SDP. Body weight losses tended to be lower for 100SDP compared with 100BM without a difference between 100SDP and 400SDP. Plasma histidine concentration (d 14 of lactation) was lower for SDP compared with 100BM. In addition, plasma 1 methyl-l-histidine tended to be lower as inclusion rate of SDP increased. In conclusion, SDP at 400 g/d increased milk and milk component yields without an increase in feed intake. Studies evaluating effects of functional and active compounds in SDP on gut microbiome, gut health, and immune functions may be needed to determine mode of action. PMID- 29605309 TI - The effect of using cow genomic information on accuracy and bias of genomic breeding values in a simulated Holstein dairy cattle population. AB - Using cow data in the training population is attractive as a way to mitigate bias due to highly selected training bulls and to implement genomic selection for countries with no or limited proven bull data. However, one potential issue with cow data is a bias due to the preferential treatment. The objectives of this study were to (1) investigate the effect of including cow genotype and phenotype data into the training population on accuracy and bias of genomic predictions and (2) assess the effect of preferential treatment for different proportions of elite cows. First, a 4-pathway Holstein dairy cattle population was simulated for 2 traits with low (0.05) and moderate (0.3) heritability. Then different numbers of cows (0, 2,500, 5,000, 10,000, 15,000, or 20,000) were randomly selected and added to the training group composed of different numbers of top bulls (0, 2,500, 5,000, 10,000, or 15,000). Reliability levels of de-regressed estimated breeding values for training cows and bulls were 30 and 75% for traits with low heritability and were 60 and 90% for traits with moderate heritability, respectively. Preferential treatment was simulated by introducing upward bias equal to 35% of phenotypic variance to 5, 10, and 20% of elite bull dams in each scenario. Two different validation data sets were considered: (1) all animals in the last generation of both elite and commercial tiers (n = 42,000) and (2) only animals in the last generation of the elite tier (n = 12,000). Adding cow data into the training population led to an increase in accuracy (r) and decrease in bias of genomic predictions in all considered scenarios without preferential treatment. The gain in r was higher for the low heritable trait (from 0.004 to 0.166 r points) compared with the moderate heritable trait (from 0.004 to 0.116 r points). The gain in accuracy in scenarios with a lower number of training bulls was relatively higher (from 0.093 to 0.166 r points) than with a higher number of training bulls (from 0.004 to 0.09 r points). In this study, as expected, the bull-only reference population resulted in higher accuracy compared with the cow only reference population of the same size. However, the cow reference population might be an option for countries with a small-scale progeny testing scheme or for minor breeds in large counties, and for traits measured only on a small fraction of the population. The inclusion of preferential treatment to 5 to 20% of the elite cows led to an adverse effect on both accuracy and bias of predictions. When preferential treatment was present, random selection of cows did not reduce the effect of preferential treatment. PMID- 29605310 TI - Responses of dairy cows with divergent residual feed intake as calves to metabolic challenges during midlactation and the nonlactating period. AB - Residual feed intake (RFI) is defined as the difference between the actual and expected feed intake required to support animal maintenance and growth. Thus, a cow with a low RFI can obtain nutrients for maintenance and growth from a reduced amount of feed compared with a cow with a high RFI. Variation in RFI is underpinned by a combination of factors, including genetics, metabolism, thermoregulation and body composition; hypothalamic-pituitary-adrenal (HPA) axis responsiveness is also a possible contributor. Responses to 3 metabolic challenges were measured in lactating and nonlactating dairy cattle. Sixteen Holstein Friesian cows with phenotypic RFI measurements that were obtained during the growth period (188-220 d old) were grouped as either low-calfhood RFI (n = 8) or high-calfhood RFI (n = 8). An ACTH (2 ug/kg of body weight), insulin (0.12 U/kg), and epinephrine (a low dose of 0.1 ug/kg and a high dose of 1.6 ug/kg of epinephrine) challenge were each conducted during both midlactation (122 +/- 23.4 d in milk) and the nonlactating period (dry period; approximately 38 d after cessation of milking). Cows were housed in metabolism stalls for the challenges and were fed a diet of alfalfa cubes ad libitum for at least 10 d before the experiment (lactating cows also were offered a total of 6 kg of dry matter/d of crushed wheat grain plus minerals fed as 3 kg of dry matter at each milking) and were fasted for 12 h before the challenges. The efficiency of conversion of feed into milk (the ratio of feed consumed to milk produced over the 7 d before the experiment) during midlactation was better (lower) in low-calfhood RFI cows, although dry matter intake did not differ between RFI groups. Low-calfhood RFI cows exhibited a lower plasma cortisol response to the ACTH challenge than high calfhood RFI cows, particularly in midlactation (-15%). The low-calfhood RFI cows had a greater plasma insulin-like growth factor-1 response to the insulin challenge and plasma fatty acid response to epinephrine compared with the high calfhood RFI cows. These data suggest that high-calfhood RFI cows exhibit a more responsive HPA axis. As divergence in RFI measured during growth is retained (although reduced) during lactation, it is possible that energy is used to respond to HPA axis activation at the expense of production in high-calfhood RFI dairy cattle during lactation and contributes to a decrease in overall feed use efficiency. PMID- 29605311 TI - Nuclear factor erythroid 2-related factor 2-antioxidant activation through the action of ataxia telangiectasia-mutated serine/threonine kinase is essential to counteract oxidative stress in bovine mammary epithelial cells. AB - Nuclear factor (erythroid-derived 2)-like factor 2 (NFE2L2, formerly Nrf2) is a transcription factor that binds to the antioxidant response element (ARE) in the upstream promoter region of various antioxidant-responsive genes. Hence, at least in nonruminants, the NFE2L2-ARE signaling pathway plays an important role in the cellular antioxidant defense system. Whether oxidative stress in bovine mammary epithelial cells alters NFE2L2 or the NFE2L2-ARE pathway is unclear. Therefore, the objective of this study was to examine the response in NFE2L2- and NFE2L2-ARE related components in bovine mammary epithelial cells (BMEC) under oxidative stress. An in silico analysis to identify potential phosphorylation sites on NFE2L2 and the protein kinases was performed with Netphos 3.1 (http://www.cbs.dtu.dk/services/NetPhos/) and Scansite (http://scansite.mit.edu) software. Isolated BMEC were exposed to H2O2 (600 MUM) for 6 h to induce oxidative stress. In silico analysis revealed ataxia telangiectasia-mutated (ATM) serine/threonine kinase as a key kinase responsible for the phosphorylation of NFE2L2. Thus, after the 6 h incubation with H2O2, BMEC were transiently transfected with ATM-small interfering RNA (siRNA) 1, 2, or 3. Compared with the control, transfection with ATM-siRNA3 resulted in proliferation rates that were 60.7 and 36.2% lower with or without H2O2. In addition, production of reactive oxygen species and malondialdehyde increased markedly, but activities of superoxide dismutase, glutathione peroxidase, catalase, and glutathione-S transferase decreased markedly in transfected cells without or with H2O2 compared with the control. Transfected cells had markedly lower protein and mRNA expression of NFE2L2 without or with H2O2 compared with the control. In addition, fluorescent activity of the ARE in transfected BMEC indicated that NFE2L2-driven transcriptional activation decreased under oxidative stress. Overall, results indicate that ATM is a physiologically relevant NFE2L2 kinase. Furthermore, inhibition of ATM activity can cause marked alterations in oxidative stress leading to cell death as a result of diminished capacity of BMEC to cope with H2O2-induced cytotoxicity. The relevance of this kinase in vivo merits further study. PMID- 29605312 TI - Effect of human chorionic gonadotrophin administration 2 days after insemination on progesterone concentration and pregnancy per artificial insemination in lactating dairy cows. AB - The aim of this study was to examine the effect of a single administration of human chorionic gonadotrophin (hCG) during the establishment of the corpus luteum (CL) on progesterone (P4) concentration and pregnancy per artificial insemination (P/AI) in lactating dairy cows. Postpartum spring-calving lactating dairy cows (n = 800; mean +/- SD days in milk and parity were 78.5 +/- 16.7 and 2.3 +/- 0.8, respectively) on 3 farms were enrolled on the study. All cows underwent the same fixed-time AI (FTAI) protocol involving a 7-d progesterone-releasing intravaginal device with gonadotrophin-releasing hormone (GnRH) administration at device insertion, prostaglandin at device removal followed by GnRH 56 h later, and AI 16 h after the second GnRH injection. Cows were blocked on days postpartum, body condition score, and parity and randomly assigned to receive either 3,000 IU of hCG 2 d after FTAI or no further treatment (control). Blood samples were collected on d 7 and 14 postestrus by coccygeal venipuncture on a subset of 204 cows to measure serum P4 concentration, and pregnancy was diagnosed by ultrasonography approximately 30 and 70 d after FTAI. Administration of hCG caused an increase in circulating P4 concentrations compared with the control treatment on d 7 (+22.2%) and d 14 (+25.7%). The P/AI at 30 d after FTAI was affected by treatment, farm, body condition score, and calving to service interval. Overall, administration of hCG decreased P/AI (46.3% vs. 55.1% for the control). Among cows that did not become pregnant following AI, a greater proportion of control cows exhibited a short repeat interval (<=17 d) compared with cows treated with hCG (8.6% vs. 2.8%, respectively). In addition, the percentages of cows pregnant at d 21 (59.6% vs. 52.0%) and d 42 (78.3% vs. 71.9%) were greater in control than in hCG-treated cows. The overall incidence of embryo loss was 10.7% and was not affected by treatment. There was a tendency for an interaction between treatment and CL status at synchronization protocol initiation for both P4 concentration and P/AI. In conclusion, administration of hCG 2 d after FTAI increased circulating P4 concentrations. Unexpectedly, cows treated with hCG had lower fertility; however, this negative effect on fertility was manifested primarily in cows lacking a CL at the onset of the synchronization protocol. PMID- 29605313 TI - Behavior of Escherichia coli O157:H7 during the manufacture and ripening of Fontina Protected Designation of Origin cheese. AB - This study was conducted to describe the cheese-making procedure of Fontina Protected Designation of Origin (PDO) cheese and to evaluate the behavior of Escherichia coli O157:H7 during cheese manufacture and ripening. The study was divided into 2 phases: the production of Fontina PDO cheese was monitored at 3 different dairies in the Aosta Valley and an E. coli O157 challenge was conducted at a fourth dairy. The dairies employ different commercial starter cultures for cheese making. The growth of lactic acid bacilli (LAB) and the decrease in pH were slower in the first hours and the LAB concentrations were overall higher in dairy A than in the other 2 dairies. The pH remained substantially unchanged during ripening (range 5.2 to 5.4) in all dairies. Water activity remained constant at around 0.98 until d 21, when it decreased to around 0.97 until d 80 in dairies A and B and 0.95 in dairy E. Whole raw cow milk was used for making Fontina cheese according to the standard procedure. For the experimental production, the milk was inoculated with E. coli O157:H7 at a concentration of approximately 5 log10 cfu/mL and commercial starter cultures were used according to the Fontina PDO regulation. An increase of 2.0 log10 cfu/g in E. coli O157:H7 was observed during the first 9.5 h of cheese making, followed by a decrease at 46 h when pH decreased to 5.4 in all trials. Fresh cheeses were salted and held at 10 degrees C for ripening for 80 d. Water activity was decreased to 0.952 at the end of the ripening stage. The LAB concentrations declined gradually; this trend was more marked for the lactobacilli than either the thermophilic or the mesophilic lactococci. The increase in LAB count and the decrease in pH in the first hours did not seem to affect E. coli O157 growth. Ripening was found to inhibit pathogen survival, however, as seen in the reduction of 3 log10 from the maximum concentration measured during the earlier stages of production. PMID- 29605314 TI - Effects of methionine plus cysteine inclusion on performance and body composition of liquid-fed crossbred calves fed a commercial milk replacer and no starter feed. AB - This experiment aimed to evaluate the effects of supplying 4 different inclusion levels of Met + Cys to crossbred liquid-fed calves on animal performance and body composition. Thirty-six Holstein-Gyr male calves were separated into 2 age groups: 16 calves, slaughtered at an age of 30 d, representing the physiological phase from 8 to 30 d, and 20 calves, slaughtered at an age of 60 d, representing the physiological phase from 30 to 60 d. At 8 d of age, the animals were randomly distributed among the experimental treatments: 4 Met + Cys inclusion levels (Met + Cys: 8.0, 8.7, 9.4, and 10.2 g/d), provided by an AA supplement added to 1.0 kg (as fed) of commercial milk replacer containing soy protein concentrate and wheat protein isolate reconstituted at 13.8% (dry matter basis). The diet was supplied without allowing leftovers and no starter feed was provided. The experimental diets were supplied without allowing orts, so that the dry matter, crude protein, and ether extract intakes were the same for all animals, independent of Met + Cys level. Total weight gain, average daily gain, gain composition, and body composition were evaluated for both age groups separately. Digestibility of organic matter, crude protein, and ether extract was lower for 8 to 30 d than for 30 to 60 d. The effect of Met + Cys levels on the digestibility of nutrients was not observed; there also was no significant interaction between physiological phase and Met + Cys levels. For the 8 to 30 d group, no responses in performance were observed according to the different Met + Cys levels, which indicates that 8.0 g/d of Met + Cys met the requirements for this physiological phase. The 30 to 60 d group responded positively to higher Met + Cys inclusion in the diet. In conclusion, an optimal Met + Cys dietary level to ensure best performance and protein gain ranges from 8.41 to 9.81 g/d. PMID- 29605315 TI - Low colostrum yield in Jersey cattle and potential risk factors. AB - Consumption of an adequate volume of high-quality colostrum is vital to a dairy calf's ability to survive and become a productive herd member. However, some dairy herds have reported a deficiency of colostrum production, which ranges from a low volume to no colostrum produced, by cows during fall and winter. Little information regarding this phenomenon exists. The purpose of this study was to characterize the syndrome and identify potential risk factors for low colostrum yield. A 2,500-cow Jersey dairy farm was enrolled in a prospective cohort study in May 2016, to evaluate possible effects of photoperiod, temperature, and cow factors on colostrum production. Dairy personnel were trained to collect, weigh, and evaluate colostrum quality. Information on parity, previous lactation length, previous 305-d mature-equivalent milk production, and dry period length were collected through the farm's dairy management software. Weather and photoperiod data were also collected. Over the year of enrollment, 2,988 eligible cows calved and had colostrum weights recorded and 38% were primiparous (n = 1,143), 25% were in their second lactation (n = 752), and 37% were in their third or greater lactation (n = 1,093). The overall average colostrum yield was 6.6 kg/cow in June 2016, 2.5 kg/cow in December 2016, and 4.8 kg/cow in May 2017. Multiparous cows had a larger decline in colostrum production between June and December (6.6 to 1.3 kg/cow) compared with primiparous animals (6.5 to 4.2 kg/cow). Overall, average colostrum production decreased by 0.17 kg/cow per week during this time, 0.22 kg for multiparous cows and 0.08 kg for primiparous cows. A logistic regression model was constructed for all cows to evaluate effects of cow factors on low colostrum production (<2.7 kg at first milking). Dry period length, calf sex, singleton or twin, age at freshening, month of calving and previous lactation length were significantly associated with the probability of low colostrum yield (<2.7 kg at first milking). A cross-correlation function analysis between the time series for colostrum yield and photoperiod revealed a high correlation at the time of calving and 1 mo prior, particularly for multiparous cows. A pedigree analysis showed that extreme colostrum yield (low vs. high) followed some sire lines. Low colostrum production in this herd could have an economic effect on the dairy and calf health and appears to have a strong seasonal and, potentially, a genetic component. PMID- 29605316 TI - Changes in the expression of alpha-tocopherol-related genes in liver and mammary gland biopsy specimens of peripartum dairy cows. AB - Blood alpha-tocopherol (alpha-Toc) concentrations decline gradually throughout the prepartum period, reaching the nadir after calving in dairy cows. The 6 alpha Toc-related molecules [alpha-Toc transfer protein (TTPA); afamin; scavenger receptor class B, Type I; ATP-binding cassette transporter A1; tocopherol associated protein (SEC14L2); and cytochrome P450 family 4, subfamily F, polypeptide 2 (CYP4F2)] are expressed in liver and other peripheral tissues. These molecules could regulate alpha-Toc transport, blood concentrations, and metabolism of alpha-Toc. Therefore, the aim of this study was to evaluate the changes in the expression of alpha-Toc-related genes in liver and mammary gland tissues of dairy cows around calving, which have remained elusive until now. In experiment (Exp.) 1, 28 multiparous Holstein cows were used (from -5 to 6 wk relative to parturition) to monitor the changes in dietary alpha-Toc intake, blood concentrations of alpha-Toc, and lipoproteins; in Exp. 2, 7 peripartum Holstein cows were used (from -4 to 4 wk relative to parturition) for liver tissue biopsy; and in Exp. 3, 10 peripartum Holstein cows were used (from -8 to 6 wk relative to parturition) to carry out the mammary gland tissue biopsy and milk sampling. In Exp. 1, the serum alpha-Toc concentrations declined gradually with decreasing amount of alpha-Toc intake and plasma high-density lipoprotein concentrations toward calving time. However, in the early lactation period after calving, serum alpha-Toc concentrations remained at a lower concentration despite the recovery of alpha-Toc intake and plasma high-density lipoprotein concentrations. In Exp. 2, just after calving, the TTPA, SEC14L2, afamin, and albumin mRNA expression levels in the liver were temporarily downregulated, and the hepatic mRNA levels of endoplasmic reticulum stress-induced unfolded protein response markers and acute-phase response marker increased at calving. In Exp. 3, the concentrations of alpha-Toc in colostrum were greater than those in precolostrum (samples were collected at wk -1 relative to parturition) and mature milk. The expression of TTPA, SEC14L2, and CYP4F2 mRNA in bovine mammary gland tissue was detected. However, TTPA and SEC14L2 mRNA expressions showed the opposite trends: the expression levels of TTPA mRNA peaked whereas SEC14L2 mRNA reached a nadir at calving. These results indicate that the expression of alpha Toc-related genes involved in specific alpha-Toc transfer and metabolism in the liver and mammary gland are altered during calving. Moreover, these changes might be associated with the maintenance of lower serum alpha-Toc concentrations after calving. PMID- 29605317 TI - Milk mid-infrared spectral data as a tool to predict feed intake in lactating Norwegian Red dairy cows. AB - Mid-infrared (MIR) spectroscopy of milk was used to predict dry matter intake (DMI) and net energy intake (NEI) in 160 lactating Norwegian Red dairy cows. A total of 857 observations were used in leave-one-out cross-validation and external validation to develop and validate prediction equations using 5 different models. Predictions were performed using (multiple) linear regression, partial least squares (PLS) regression, or best linear unbiased prediction (BLUP) methods. Linear regression was implemented using just milk yield (MY) or fat, protein, and lactose concentration in milk (Mcont) or using MY together with body weight (BW) as predictors of intake. The PLS and BLUP methods were implemented using just the MIR spectral information or using the MIR together with Mcont, MY, BW, or NEI from concentrate (NEIconc). When using BLUP, the MIR spectral wavelengths were always treated as random effects, whereas Mcont, MY, BW, and NEIconc were considered to be fixed effects. Accuracy of prediction (R) was defined as the correlation between the predicted and observed feed intake test day records. When using the linear regression method, the greatest R of predicting DMI (0.54) and NEI (0.60) in the external validation was achieved when the model included both MY and BW. When using PLS, the greatest R of predicting DMI (0.54) and NEI (0.65) in the external validation data set was achieved when using both BW and MY as predictors in combination with the MIR spectra. When using BLUP, the greatest R of predicting DMI (0.54) in the external validation was when using MY together with the MIR spectra. The greatest R of predicting NEI (0.65) in the external validation using BLUP was achieved when the model included both BW and MY in combination with the MIR spectra or when the model included both NEIconc and MY in combination with MIR spectra. However, although the linear regression coefficients of actual on predicted values for DMI and NEI were not different from unity when using PLS, they were less than unity for some of the models developed using BLUP. This study shows that MIR spectral data can be used to predict NEI as a measure of feed intake in Norwegian Red dairy cattle and that the accuracy is augmented if additional, often available data are also included in the prediction model. PMID- 29605318 TI - Intravenous lipid infusion affects dry matter intake, methane yield, and rumen bacteria structure in late-lactating Holstein cows. AB - Increasing the dietary fat content of ruminant diets decreases methane (CH4) production. This effect is caused by the toxic properties of fatty acids on rumen microbial populations, coating of feed particles diminishing the accessibility for microbes, and a reduction in dry matter intake (DMI). The latter effect is caused by postabsorptive long-chain fatty acids eliciting anorexic signaling; however, whether circulating long-chain fatty acids affect rumen CH4 production alike is unknown. To approach this question, 5 rumen-cannulated Holstein cows in late lactation received 2 jugular catheters and were kept in respiration chambers to measure CH4 production and DMI for 48 h. In a crossover design, cows were intravenously infused with a 20% lipid emulsion (LIPO) or 0.9% NaCl (CON). The LIPO cows received 2.1 kg of triglycerides/d [0.152 +/- 0.007 g of triglycerides/(kg of BW * h)-1] consisting of 12.1% palmitic acid, 4.2% stearic acid, 31.1% oleic acid, and 52.7% linoleic acid. Blood and rumen fluid samples were taken hourly during the day. Results showed that LIPO compared with CON infusion increased plasma triglyceride as well as free fatty acid and serotonin concentrations but reduced the proportion of de novo synthesized milk fatty acids (sum of C6 to C16). Daily CH4 production and DMI were lower, whereas daily CH4 yield (CH4/DMI) was greater in LIPO than CON cows, although CH4 yield decreased from d 1 to d 2 by 2 to 14% in LIPO-infused cows only. This effect was associated with a higher (acetate + butyrate)/propionate ratio, tending lower propionate concentrations between 24 and 34 h of infusion, reduced relative abundances of genera belonging to Succinivibrio, Ruminococcaceae, and Ruminiclostridium, and greater relative Bacteroidetes genus abundances in the rumen. PMID- 29605319 TI - Interaction of 5-hydroxy-l-tryptophan and negative dietary cation-anion difference on calcium homeostasis in multiparous peripartum dairy cows. AB - Hypocalcemia affects almost 50% of all dairy cows. Our laboratory has previously demonstrated that infusions of the serotonin precursor 5-hydroxy-l-tryptophan (5 HTP) increase circulating calcium concentrations in the Holstein transition cow. It is unknown whether feeding a negative dietary cation-anion difference (DCAD) diet alters the relationship between 5-HTP and hypocalcemia. The main objective of this study was to determine whether feeding a negative DCAD (-DCAD) diet before calving in conjunction with 5-HTP treatment could further diminish the magnitude of hypocalcemia at the time of calving. We used a randomized complete block design with a 2 * 2 factorial arrangement. Thirty-one multiparous Holstein cows were fed either a positive (+13 mEq/100 g) or negative (-13 mEq/100 g) DCAD diet 21 d before parturition and were intravenously infused daily with saline or 5-HTP (1 mg/kg) starting 7 d before the estimated date of parturition. Cows were blocked by parity and were randomly assigned to 1 of 4 treatment groups: positive DCAD plus saline, positive DCAD plus 5-HTP, negative DCAD plus saline, and negative DCAD plus 5-HTP, resulting in n = 8 per group. Total calcium (tCa), ionized calcium (iCa), and feed intake were recorded. The iCa was elevated prepartum in the -DCAD/5-HTP group compared with the other treatment groups as well as on d 0 and 1 postpartum. Although differences in tCa were not significant across the pre- or postpartum periods, tCa was numerically higher on d 0 and significantly higher on d 1 in -DCAD/5-HTP cows compared with all other groups. Prepartum the -DCAD/5-HTP treatment group ate less than the other treatment groups; however, postpartum dry matter intake differences were not significant. These findings demonstrate that feeding a -DCAD diet in conjunction with 5-HTP prepartum can increase postpartum circulating iCa concentrations and therefore diminish the magnitude of hypocalcemia at the time of parturition. PMID- 29605320 TI - Symposium review: Amino acid uptake by the mammary glands: Where does the control lie? AB - Milk protein yield responses to changes in the profile of essential amino acids absorbed by the gastrointestinal tract or circulating in blood plasma do not follow the classic limiting amino acid response, in part because of an ability of the mammary glands to modify their blood flow rate and net clearance of amino acids out of plasma. The hypothesis that mammary blood flow is locally regulated to maintain ATP balance accounts for observed changes in flow due to postruminal glucose, insulin, and essential amino acid (EAA) infusions. An additional hypothesis that net mammary uptakes of metabolites from blood are affected by perturbations in their respective arterial concentrations and the rate of mammary blood flow also appears to hold for the energy metabolites glucose, acetate, beta hydroxybutyrate, and fatty acids. However, net EAA uptakes by the mammary glands are poorly predicted by models considering arterial concentrations and blood flow rates only. Evidence points to intramammary protein synthesis and secretion as the determinant of net EAA uptake. The intracellular signaling network anchored by the mechanistic target of rapamycin complex 1 stands as an excellent candidate to explain nutritional effects on milk protein synthesis because it integrates information on physiological and nutritional state to affect protein synthesis and cell metabolism, growth, proliferation, and differentiation in many cell types. In mammary cells in vitro and in vivo, the mechanistic target of rapamycin complex 1, integrated stress response, and glycogen synthase kinase-3 networks that contribute to regulation of initiation of mRNA translation are responsive to acute changes in nutrient supply and EAA profile. However, after several days of postruminal infusion of balanced and imbalanced EAA profiles, these signaling networks do not appear to continue to account for changes in milk protein yields. Gene expression evidence suggests that regulation of components of the unfolded protein response that control biogenesis of the endoplasmic reticulum and differentiation of a secretory phenotype may contribute to effects of nutrition on milk protein yield. Connections between early signaling events and their long term consequences should be sought. PMID- 29605321 TI - Short communication: Relationships among temperature-humidity index with rectal, udder surface, and vaginal temperatures in lactating dairy cows experiencing heat stress. AB - The objective of this study was to evaluate relationships between measurements of temperature-humidity index (THI) and rectal, vaginal, and udder surface temperatures in lactating cows exposed to heat stress (HS). In experiment 1, 12 multiparous and 8 primiparous Holstein cows experienced a THI ranging from 69 to 76 at 2000 to 1000 h and THI from 74 to 82 at 1000 to 2000 h (peaked at 82 from 1400 to 1800 h). Cows were exposed to HS 10 h daily for 21 d. Measurements of rectal temperature (RT) and udder surface temperature were collected at 1000 and 1500 h (+/-30 min). Vaginal temperature was monitored every 10 min using digital loggers, averaged over 1 h, and paired with corresponding rectal and udder surface temperature data. In experiment 2, 12 multiparous Holstein cows experienced a THI ranging from 60 to 76 at 2000 to 1000 h and THI from 69 to 83 at 1000 to 2000 h (peaked at 83 from 1600 and 1900 h), eliciting 10 h/d of HS for 7 d. Rectal and udder surface temperatures were analyzed at 0700 and 1500 h (+/ 30 min). Vaginal temperature was recorded and analyzed as indicated in experiment 1. Afternoon THI showed weak correlations with surface temperature (r = 0.19, n = 420 in experiment 1; r = 0.23, n = 84 in experiment 2), weak to moderate correlations with RT (r = 0.34, n = 366 in experiment 1; r = 0.26, n = 84 in experiment 2), and moderate correlations with vaginal temperature (r = 0.34, n = 175 in experiment 1; r = 0.35, n = 40 in experiment 2). Moreover, vaginal temperature increased 0.10 and 0.22 degrees C per unit of THI (R2 = 0.15 in experiment 1; R2 = 0.40 in experiment 2). Afternoon vaginal temperature strongly correlated with RT (r = 0.69, n = 131 in experiment 1; r = 0.63, n = 37 in experiment 2) and explained 57 (experiment 1) and 68% (experiment 2) of variation in RT. Surface temperature showed moderate to strong correlations with RT (r = 0.57, n = 84) and vaginal temperature (r = 0.74, n = 37) in experiment 2. In conclusion, THI showed a weak to moderate relationship with core body temperatures and explained the increase in rectal and vaginal temperatures experienced by HS cows. Compared with rectal temperature, vaginal temperature showed stronger relationships with THI and can be used to determine thermal load. Udder surface temperature showed a moderate to strong relationship with core body temperature, and this relationship may support the use of surface temperature data to manage thermal load in HS cows. PMID- 29605322 TI - Technical note: High-throughput method for antifungal activity screening in a cheese-mimicking model. AB - In this study, we developed a high-throughput antifungal activity screening method using a cheese-mimicking matrix distributed in 24-well plates. This method allowed rapid screening of a large variety of antifungal agent candidates: bacterial fermented ingredients, bacterial isolates, and preservatives. Using the proposed method, we characterized the antifungal activity of 44 lactic acid bacteria (LAB) fermented milk-based ingredients and 23 LAB isolates used as protective cultures against 4 fungal targets (Mucor racemosus, Penicillium commune, Galactomyces geotrichum, and Yarrowia lipolytica). We also used this method to determine the minimum inhibitory concentration of a preservative, natamycin, against 9 fungal targets. The results underlined the strain-dependency of LAB antifungal activity, the strong effect of fermentation substrate on this activity, and the effect of the screening medium on natamycin minimum inhibitory concentration. Our method could achieved a screening rate of 1,600 assays per week and can be implemented to evaluate antifungal activity of microorganisms, fermentation products, or purified compounds compatible with dairy technology. PMID- 29605323 TI - Effects of fat supplementation to diets high in nonforage fiber on production responses of midlactation dairy cows. AB - The effects of dietary nonforage fiber sources on production responses of lactating dairy cattle have been well described, but interactions with other components of the diet have been less thoroughly explored. We investigated the effects of adding 2 commonly fed fat sources to a ration featuring high levels of nonforage fiber supplied by a corn milling by-product. Midlactation Holstein cows were blocked by parity, stratified by days in milk, and randomly assigned to 1 of 6 pens (12 cows/pen). Pens were randomly assigned to treatment sequences in a 3 * 3 Latin square design, where the treatments consisted of prilled saturated fat (SAT; Energy Booster 100, Milk Specialties Co., Dundee, IL), calcium salts of long-chain fatty acids (UNS; Megalac, Church and Dwight Co. Inc., Princeton, NJ), or no added dietary fat (control), with fat sources included to provide 1.2% added fat (dry matter basis). Treatment periods were 21 d; milk and feed samples were collected and milk yield and feed intake were recorded for the last 4 d of each period. Results were analyzed with mixed models with pen as the experimental unit, and orthogonal contrasts were employed to evaluate the overall effect of added fat and the effect of fat source. Dry matter intake and milk yield tended to increase with added fat. Protein content decreased with fat supplementation, to a greater degree for UNS than for SAT, but protein yield was not affected. Fat content, fat yield, and energy-corrected milk yield were not affected by treatment. Conversion of feed to milk tended to increase for UNS compared with SAT. Fat supplementation to diets high in nonforage fiber had effects that were similar to those reported for more traditional lactation diets, except for the dry matter intake response. PMID- 29605325 TI - Veterinarians' attitudes toward antimicrobial use and selective dry cow treatment in the Netherlands. AB - In the Netherlands, regulations have been in place since 2008 to reduce the overall use of antimicrobials to mitigate antimicrobial resistance. As part of these regulations, a ban on the preventive use of antimicrobials, such as applying blanket dry cow treatment, was introduced and alternative measures such as selective dry cow treatment (SDCT) were implemented. Both farmers and veterinarians play an important role in implementing these measures and have a shared responsibility with respect to prudent antimicrobial use (AMU). The attitude of Dutch dairy veterinarians toward restricted AMU and toward SDCT is unknown, but a favorable attitude toward this approach seems crucial for successful implementation. In 2015, an online questionnaire was collected from 181 veterinarians that contained questions with regard to their attitude and behavior toward reduction of AMU and toward SDCT. Descriptive statistics were used to describe the data, and multivariable logistic regression models with a logit link function were applied to evaluate potential associations between veterinarians' attitudes toward AMU and SDCT and the rationale behind their mindset, based on positive and negative aspects of reduction in AMU. The veterinarians were divided into 3 groups based on their opinion on 4 statements with regard to AMU and SDCT: veterinarians with an unfavorable, a neutral, and a favorable attitude toward reduction of AMU and toward SDCT. For the multivariable logistic regression analysis, the first 2 groups were combined and compared with the veterinarians with a favorable attitude. The general attitude of Dutch dairy veterinarians toward reduction of AMU was positive, and most expressed the belief that they can still be a good veterinarian when they prescribe less antimicrobials. Veterinarians indicated they progressively promoted SDCT beginning in 2013. Most veterinarians see the advice they provide to farmers on SDCT as the best possible approach and are convinced that their farmers apply this SDCT approach. The results of the multivariable analyses showed that veterinarians with a favorable attitude mentioned positive aspects of SDCT, such as an increased consciousness of AMU among farmers, improving animal health, reducing antimicrobial resistance, and a chance to add value for the farmer, more often than other veterinarians. The latter group significantly more often indicated negative aspects of SDCT, such as a higher risk of sick cows and feeling pushed to follow the rules. In conclusion, the general attitude of Dutch dairy veterinarians toward reduction of AMU and SDCT was found to be positive. However, given the influence veterinarians potentially have on the attitude of farmers and the variability found in their attitude and behavior, veterinarians need specific attention if regional or national programs are organized trying to change behavior of farmers and encourage prudent AMU and SDCT. PMID- 29605324 TI - Invited review: Whey proteins as antioxidants and promoters of cellular antioxidant pathways. AB - Oxidative stress contributes to cell injury and aggravates several chronic diseases. Dietary antioxidants help the body to fight against free radicals and, therefore, avoid or reduce oxidative stress. Recently, proteins from milk whey liquid have been described as antioxidants. This review summarizes the evidence that whey products exhibit radical scavenging activity and reducing power. It examines the processing and treatment attempts to increase the antioxidant bioactivity and identifies 1 enzyme, subtilisin, which consistently produces the most potent whey fractions. The review compares whey from different milk sources and puts whey proteins in the context of other known food antioxidants. However, for efficacy, the antioxidant activity of whey proteins must not only survive processing, but also upper gut transit and arrival in the bloodstream, if whey products are to promote antioxidant levels in target organs. Studies reveal that direct cell exposure to whey samples increases intracellular antioxidants such as glutathione. However, the physiological relevance of these in vitro assays is questionable, and evidence is conflicting from dietary intervention trials, with both rats and humans, that whey products can boost cellular antioxidant biomarkers. PMID- 29605326 TI - Effect of re-ensiling on the quality of sorghum silage. AB - The commercialization of silage in many countries, including Brazil, has increased in recent years. Re-ensiling of previously ensiled forage occurs when silage is relocated from one farm to another, where it will be compacted and sealed again. During this process, silage is exposed to oxygen before being ensiled, which may affect its quality. We exposed sorghum silage to air during the anaerobic storage phase to simulate the transportation of silages between farms. Experimental treatments included silage exposed to air for 0 or 12 h, with or without the use of an inoculant containing a mixture of Lactobacillus plantarum and the propionic bacteria Propionibacterium acidipropionici (1 * 106 cfu/g of forage; Biomax corn, Lallemand, Saint-Simon, France), totaling 4 treatments: conventional silage, conventional silage with inoculant use, re ensilage after exposure to air, and re-ensilage after exposure to air with use of an inoculant. The sorghum was stored in experimental silos containing about 9.0 kg of fresh forage per replicate. Treatments were tested in a factorial 2 * 2 design with 5 replicates each. Chemical composition, in vitro dry matter digestibility, fermentative characteristics, losses (due to gas, effluents, and total dry matter), microorganism counts, and aerobic stability of sorghum silage were evaluated. Dry matter content of sorghum before ensiling was 273.12 g/kg. The 12-h re-ensiling process increased the effluent loss of the silage when compared with conventional silage (456.42 vs. 201.19 g/kg of FM, respectively). In addition, re-ensiled silages presented lower concentrations of lactic acid and higher concentrations of propionic acid than the silages that had not been opened during storage. The aerobic stability of silage was not affected by the re ensiling process and the use of inoculant. The use of inoculant increased the pH and loss of dry matter of the silages (4.23 vs. 3.98 and 14.05 vs. 7.82%, respectively) and therefore did not provide any benefits in this study. PMID- 29605327 TI - Comparison of adhesion characteristics of common dairy sporeformers and their spores on unmodified and modified stainless steel contact surfaces. AB - The attachment of aerobic spore-forming bacteria and their spores to the surfaces of dairy processing equipment leads to biofilm formation. Although sporeformers may differ in the degree of attachment, various surface modifications are being studied in order to develop a surface that is least vulnerable to attachment. This study was conducted to compare the extent of adhesion of spores and vegetative cells of the thermotolerant sporeformer Bacillus licheniformis and the high-heat-resistant sporeformers Geobacillus stearothermophilus and Bacillus sporothermodurans on both native and modified stainless steel surfaces. We studied the effect of contact surface and cell surface properties (including surface energy, surface hydrophobicity, cell surface hydrophobicity, and zeta potential) on the adhesion tendency of both types of sporeformers and their spores. Attachment to native and modified (Ni-P-polytetrafluoroethylene, Ni-P PTFE) stainless steel surfaces was determined by allowing interaction between the respective contact surface and vegetative cells or spores for 1 h at ambient temperature. The hydrophobicity of vegetative cells and spores of aerobic spore forming bacteria was determined using the hexadecane assay, and zeta potential was determined using the Zeta sizer Nano series instrument (Malvern Panalytical, Malvern, UK). The results indicated a higher adhesion tendency of spores over vegetative cells for both thermotolerant and high-heat-resistant sporeformers. On comparing the sporeformers, B. sporothermodurans demonstrated the highest adhesion tendency followed by G. stearothermophilus; B. licheniformis exhibited minimal attachment on both surfaces. The tendency to adhere varied with cell surface properties, decreasing with lower cell surface hydrophobicity and higher cell surface charge. On the other hand, modifying contact surface properties for higher surface hydrophobicity and lower surface energy decreased attachment. PMID- 29605328 TI - Short communication: Chemical-sensory and volatile compound characterization of ricotta forte, a traditional fermented whey cheese. AB - Ricotta forte is a traditional whey cheese, obtained through natural fermentation of fresh ricotta, that is getting increasing attention by food traders. In view of possible initiatives for its valorization, the chemical and sensory characteristics were investigated. Samples were obtained from 14 different manufacturer, and were subjected to chemical, biochemical, volatile organic compound, and sensory analyses. All samples presented low pH with high moisture (62-66%) and fat content (57-60% on dry matter). From a biochemical point of view, the electrophoretic patterns evidenced that beta-lactoglobulin was the main protein present at all sample ages. Only intermediate levels of proteolysis (20.69% ripening index) took place during aging, whereas the main biochemical event in this dairy product was lipolysis (2.10 mEq/g of acid degree value). Accordingly, free fatty acids dominated the volatile organic compound profile and strongly influenced the sensory characteristics with flavor described as rancid, pungent, acrid, and smelly feet: all associated with short-chain fatty acids such as acetic, propionic, butyric, and caproic. Finally, the sample age did not influence chemical composition, whereas it had significant effect on lipolysis and flavor intensity. PMID- 29605329 TI - Prediction accuracy of direct and indirect approaches, and their relationships with prediction ability of calibration models. AB - Milk infrared spectra are routinely used for phenotyping traits of interest through links developed between the traits and spectra. Predicted individual traits are then used in genetic analyses for estimated breeding value (EBV) or for phenotypic predictions using a single-trait mixed model; this approach is referred to as indirect prediction (IP). An alternative approach [direct prediction (DP)] is a direct genetic analysis of (a reduced dimension of) the spectra using a multitrait model to predict multivariate EBV of the spectral components and, ultimately, also to predict the univariate EBV or phenotype for the traits of interest. We simulated 3 traits under different genetic (low: 0.10 to high: 0.90) and residual (zero to high: +/-0.90) correlation scenarios between the 3 traits and assumed the first trait is a linear combination of the other 2 traits. The aim was to compare the IP and DP approaches for predictions of EBV and phenotypes under the different correlation scenarios. We also evaluated relationships between performances of the 2 approaches and the accuracy of calibration equations. Moreover, the effect of using different regression coefficients estimated from simulated phenotypes (betap), true breeding values (betag), and residuals (betar) on performance of the 2 approaches were evaluated. The simulated data contained 2,100 parents (100 sires and 2,000 cows) and 8,000 offspring (4 offspring per cow). Of the 8,000 observations, 2,000 were randomly selected and used to develop links between the first and the other 2 traits using partial least square (PLS) regression analysis. The different PLS regression coefficients, such as betap, betag, and betar, were used in subsequent predictions following the IP and DP approaches. We used BLUP analyses for the remaining 6,000 observations using the true (co)variance components that had been used for the simulation. Accuracy of prediction (of EBV and phenotype) was calculated as a correlation between predicted and true values from the simulations. The results showed that accuracies of EBV prediction were higher in the DP than in the IP approach. The reverse was true for accuracy of phenotypic prediction when using betap but not when using betag and betar, where accuracy of phenotypic prediction in the DP was slightly higher than in the IP approach. Within the DP approach, accuracies of EBV when using betag were higher than when using betap only at the low genetic correlation scenario. However, we found no differences in EBV prediction accuracy between the betap and betag in the IP approach. Accuracy of the calibration models increased with an increase in genetic and residual correlations between the traits. Performance of both approaches increased with an increase in accuracy of the calibration models. In conclusion, the DP approach is a good strategy for EBV prediction but not for phenotypic prediction, where the classical PLS regression-based equations or the IP approach provided better results. PMID- 29605330 TI - Effects of nutrition on the fertility of lactating dairy cattle. AB - This meta-analysis of 39 experiments containing 118 treatments explored the effects of diet interventions in early lactation on the proportion of dairy cows pregnant to artificial insemination (AI; pregnancy to AI) and on calving to pregnancy interval. It also identified factors that may explain variation in these responses. The objectives were to identify effects of diet on reproduction, rather than differences between specific dietary interventions. The examination of calving to pregnancy interval used the more traditional method of analyzing differences between a treatment and the reference treatment used for comparison within a given experiment. The systematic review identified fewer experiments (n = 39) than had been expected. Four different multivariable models including the random effect of experiment were used to examine the effects of CPM-Dairy (version 3.08) estimated diet and production variables on proportion pregnant to AI. These models examined (1) output of products, (2) balance or duodenal availability of nutrients, (3) intake of nutrients, or (4) percentage of nutrients in the diet. The multivariable models identified positive associations between estimated increased fatty acid intake [incidence rate ratio (IRR) = 1.0003 +/- 0.0001g/d; +/-standard error], starch intake (IRR = 1.061 +/- 0.029 kg/d), metabolizable energy balance (IRR = 1.004 +/- 0.002 MJ/d), and duodenal C14:0 (IRR = 1.008 +/- 0.004 g/d) availability with the proportion of cows pregnant to AI, whereas rapidly fermentable sugar intake (IRR = 0.813 +/- 0.054 kg/d), percentage of sugar in the diet (IRR = 0.960 +/- 0.015%), and milk protein yield (IRR 0.922 +/- 0.022 g/100 g per day) were associated with a reduced proportion of cows pregnant to AI. There was no multivariable model developed to assess variables associated with calving to pregnancy interval but, univariably, increased metabolizable energy balance was associated with a shorter calving to pregnancy interval whereas increased milk production was associated with longer time to pregnancy. Increased intake of some AA, particularly threonine and lysine, were associated with a longer calving to pregnancy interval. It is clear nutritional management around calving can influence reproductive success. The importance of dietary fats and increased energy and protein balances in early lactation for improved fertility outcomes is supported and suggests that starch and sugars may have different effects on the proportion of cows that are pregnant to AI. This work also highlighted a need for further focused field studies exploring the roles of specific fatty acids, AA, phosphorus, and carbohydrates on reproduction. PMID- 29605331 TI - Essential oil and monensin affect ruminal fermentation and the protozoal population in continuous culture. AB - The interaction of monensin and essential oil was hypothesized to suppress protozoa and methane production while maintaining normal rumen function. The objective of this study was to determine the effects of feeding monensin (MON) and CinnaGar (CIN, a commercial blend of cinnamaldehyde and garlic oil; Provimi North America, Brookville, OH) on ruminal fermentation characteristics. Continuous culture fermentors (n = 4) were maintained in 4 experimental periods in a 4 * 4 Latin square design. Four dietary treatments were arranged in a 2 * 2 factorial: (1) control diet, 37 g/d of dry matter (40 g/d at ~92.5% dry matter) of a 50:50 forage:concentrate diet containing no additive; (2) MON at 11 g/909 kg of dry matter; (3) CIN at 0.0043% of dry matter; and (4) a combination of MON and CIN at the levels in (2) and (3). Treatment had no effects on protozoal populations, concentration of NH3N, total N flow of effluent, production of total volatile fatty acids, or flows of conjugated linoleic acid and total C18 fatty acids. The MON decreased acetate:propionate ratio and biohydrogenation of both total C18 and 18:1 cis-9 but increased protozoal generation time, concentration of peptide, and flow of 18:1 trans-11. The MON tended to decrease protozoal counts in effluent and flow of 18:0 but tended to increase propionate production. The CIN decreased true organic matter digestibility and protozoal N flow of effluent but increased nonammonia, nonmicrobial N flow. The CIN tended to decrease protozoal counts, microbial N flow, and neutral detergent fiber digestibility but tended to increase biohydrogenation of total C18, 18:2, and 18:3. The CIN tended to increase isovalerate production. The MON and CIN tended to interact for increased methane production and bacterial N flow. A second experiment was conducted to determine the effects of MON and CIN on protozoal nitrogen and cell volume in vitro. Four treatments included (1) control (feed only), (2) feed + 0.0043% dry matter CIN, (3) feed + 2.82 MUM MON, and (4) feed + CIN + MON at the same levels as in (2) and (3). With no interactions, MON addition decreased percentage of protozoa that were motile and tended to decrease cell volume at 6 h. The CIN did not affect cell count or other indicators of motility or volume at either 3 or 6 h. Under the conditions of our study, we did not detect an additive response for MON and CIN to decrease protozoal counts or methane production. A 3-dimensional method is suggested to better estimate protozoal cell volume. PMID- 29605332 TI - Use of a culture-independent on-farm algorithm to guide the use of selective dry cow antibiotic therapy. AB - An algorithm using only computer-based records to guide selective dry-cow therapy was evaluated at a New York State dairy farm via a randomized field trial. DairyComp 305 (Valley Ag Software, Tulare, CA) and Dairy Herd Improvement Association test-day data were used to identify cows as low risk (cows that might not benefit from dry-cow antibiotics) or high risk (cows that will likely benefit). Low-risk cows were those that had all of the following: somatic cell count (SCC) <=200,000 cells/mL at last test, an average SCC <=200,000 cells/mL over the last 3 tests, no signs of clinical mastitis at dry-off, and no more than 1 clinical mastitis event in the current lactation. Low-risk cows were randomly assigned to receive intramammary antibiotics and external teat sealant (ABXTS) or external teat sealant only (TS) at dry-off. Using pre-dry-off and postcalving quarter-level culture results, low-risk quarters were assessed for microbiological cure risk and new infection risk. Groups were also assessed for differences in first-test milk yield and linear scores, individual milk weights for the first 30 d, and culling and mastitis events before 30 d in milk. A total of 304 cows and 1,040 quarters in the ABXTS group and 307 cows and 1,058 quarters in the TS group were enrolled. Among cows to be dried, the proportion of cows that met low-risk criteria was 64% (n = 611/953). Of cultures eligible for bacteriological cure analysis (n = 171), 93% of ABXTS cured, whereas 88% of TS cured. Of the non-cures, 95% were contributed by the minor pathogens coagulase negative staphylococci (n = 19/20). These organisms also accounted for 57.5% of new infections (n = 77/134). We found no statistical differences between treatment groups for new infection risk (TS = 7.3% quarters experiencing new infections; ABXTS = 5.5%), milk production (ABXTS = 40.5 kg; TS = 41.2 kg), linear scores (ABXTS = 2.5; TS = 2.7), culling events (ABXTS, n = 18; TS, n = 15), or clinical mastitis events (ABXTS, n = 9; TS, n = 5). Results suggest that the algorithm used decreased dry-cow antibiotic use by approximately 60% without adversely affecting production or health outcomes. PMID- 29605333 TI - Short communication: Pair housing dairy calves in modified calf hutches. AB - The objective of this study was to test if body weight (BW) and starter intake increased and reaction to novelty decreased for preweaning Holstein heifer calves pair housed in modified hutches (n = 8 pairs) versus individually housed in a single hutch (n = 14 calves). Calves were alternately assigned to housing treatment at d 5 of age. Cross sucking was recorded in 5-min scans for 30 min after milk feeding once per week over 14 wk. Calf health and BW were measured weekly from birth until approximately 88 d. When calves were 60 d old they underwent a food neophobia test where they were exposed to a novel feed for the first time. Cross sucking was observed only 5 times (in 4 different pairs) over the entire milk-feeding period. Pair-housed calves ate more starter than individually housed calves [0.89 (0.72-1.08) vs. 0.48 (0.42-0.56) kg/d; median and confidence interval], these calves also consumed 2.6 times more novel feed in the neophobia test (150 +/- 27 vs. 58 +/- 20 g/30 min). We observed no effect of treatment on BW. We concluded that social housing in modified hutches promotes solid feed intake and decreases fearfulness in dairy calves. PMID- 29605334 TI - Characteristics of quinolone-resistant Escherichia coli isolated from bovine mastitis in China. AB - Escherichia coli is the leading causative agent of bovine mastitis worldwide. Quinolone-resistant E. coli is becoming a potential threat to veterinary and public health. The aim of this study was to investigate the characteristics of quinolone-resistant E. coli isolated from bovine mastitis cases in China. Antimicrobial susceptibility of the isolates against 15 antimicrobial agents was determined by disc diffusion method. Phylogenetic grouping was detected by PCR. Extended-spectrum beta-lactamase-producing isolates were determined by double disc synergy test. In addition, the plasmid-mediated quinolone resistance (PMQR) and beta-lactamase-encoding genes, as well as mutations of quinolone resistance determining regions in GyrA, GyrB, ParC, and ParE, were measured by PCR and DNA sequencing. Overall, 75 (22.9%) out of 328 E. coli isolates were confirmed as ciprofloxacin-resistant from 2,954 mastitic milk samples. Phylogenetic group analysis showed that the majority of these strains belonged to phylogenetic group A (57.3%) and group B1 (24.0%). All the resistant isolates were identified as multidrug resistant, showing high resistance to cephalosporins and non-beta lactams. Forty-nine (65.3%) of the quinolone-resistant isolates were positive for PMQR genes; aac-(6')-Ib-cr was the most common PMQR determinant detected in 33 (44.0%) isolates. Eighteen (24.0%), 4 (5.3%), 3 (4.0%), and 1 (1.3%) of the quinolone-resistant isolates were harboring oqxA/B, qepA4, qnrS, and qnrB2, respectively. Additionally, 55 (73.3%) of the quinolone-resistant E. coli isolates were found to be extended-spectrum beta-lactamase producers. The preponderant beta-lactamase-encoding gene, blaTEM, was detected in 44 (58.7%) isolates; blaCTX-M, blaCMY, and blaSHV were found in 35 (46.7%), 22 (29.3%), and 2 (2.7%) isolates, respectively. Moreover, the most frequently identified substitutions were S83L/D87N or S83L in GyrA, detected in all of the quinolone resistant isolates. Meanwhile, 74 (98.7%), 33 (44.0%), and 6 (8.0%) of the isolates were carrying substitutions S80I in ParC, S458A in ParE, and S492N in GyrB, respectively. All 58 (77.3%) isolates with a high level of ciprofloxacin resistance (>32 ug/mL) carried single or double mutations in GyrA combined with single mutation in ParC. To the best of our knowledge, this is the first report on the high occurrence of PMQR determinants and quinolone-determining resistant regions mutations in quinolone-resistant E. coli isolated from bovine mastitis in China. PMID- 29605336 TI - Development and standardization of Arabic words in noise test in Egyptian children. AB - OBJECTIVES: To develop and establish norms of Arabic Words in Noise test in Egyptian children. METHOD: Total number of participants was 152 with normal hearing and ranging in age from 5 to 12 years. They are subdivided into two main groups (standardization group) which comprised 120 children with normal scholastic achievement and (application group) which comprised 32 children with different types of central auditory processing disorders. Arabic version of both Speech perception in noise (SPIN) and Words in Noise (WIN) tests were presented in each ear at zero signal to-noise ratio (SNR) using ipsilateral Cafeteria noise fixed at 50 dB sensation level (dBSL). RESULTS: The least performance in WIN test occurred between 5 and 7 years and highest scores from 9 to 12 years. However, no statistically significant difference was found among the three standardization age groups. Moreover, no statistically significant difference was found between the right and left ears scores or among the three lists. When the WIN test was compared to SPIN test in children with and without abnormal SPIN scores it showed highly consistent results except in children suffering from memory deficit reflecting that WIN test is more accurate than SPIN in this group of children. CONCLUSIONS: The Arabic WIN test can be used in children as young as 5 years. Also, it can be a good cross check test with SPIN test or used to follow up children after rehabilitation program in hearing impaired children or follow up after central auditory remediation of children with selective auditory attention deficit. PMID- 29605335 TI - Quantitative PCR coupled with sodium dodecyl sulfate and propidium monoazide for detection of viable Staphylococcus aureus in milk. AB - Conventional quantitative PCR (qPCR) are unable to differentiate DNA of viable Staphylococcus aureus cells from dead ones. The aim of this study was to use sodium dodecyl sulfate (SDS) and propidium monoazide (PMA) coupled with lysostaphin to detect viable Staph. aureus. The cell suspensions were treated with SDS and PMA before DNA extraction. The SDS is an anionic surfactant, which can increase the permeability of dead cells to PMA without compromising the viability of live cells. The lysostaphin was applied to improve the effectiveness of DNA extraction. The reliability and specificity of this method were further determined by the detection of Staph. aureus in spiked milk. The results showed that there were significant differences between the SDS-PMA-qPCR and qPCR when a final concentration of 200 MUg/mL of lysostaphin was added in DNA extraction. The viable Staph. aureus could be effectively detected when SDS and PMA concentrations were 100 ug/mL and 40 MUM, respectively. Compared with conventional qPCR, the SDS-PMA-qPCR assay coupled with lysostaphin was more specific and sensitive. Therefore, this method could accurately detect the number of viable Staph. aureus cells. PMID- 29605337 TI - Clinically recorded cortical auditory evoked potentials from paediatric cochlear implant users fitted with electrically elicited stapedius reflex thresholds. AB - OBJECTIVES: This study aimed to objectively evaluate access to soft sounds (55 dB SPL) in paediatric CI users, all wearing MED-EL (Innsbruck, Austria) devices who were fitted with the objective electrically elicited stapedius reflex threshold (eSRT) fitting method, to track their cortical auditory evoked potential (CAEP) presence and latency, and to compare their CAEPs to those of normal-hearing peers. METHODS: Forty-five unilaterally implanted, pre-lingually deafened MED-EL CI users, aged 12-48 months, underwent CAEP testing in the clinic at regular monthly intervals post switch-on. CAEPs were recorded in response to short speech tokens /m/, /g/ and /t/ presented in the free field at 55 dB SPL. Twenty children with normal hearing (NH), similarly aged, underwent CAEP testing once. RESULTS: The proportion of present CAEPs increased and CAEP P1 latencies reduced significantly with post-implantation duration. CAEPs were scored based on their presence and age-appropriate P1 latency. These CAEP scores increased significantly with post-implantation duration. CAEP scores were significantly worse for the /m/ speech token compared to the other two tokens. Compared to the NH group, CAEP scores were significantly smaller for all post-implantation test intervals. CONCLUSIONS: This study provides clinicians with a first step towards typical ranges of CAEP presence, latency, and derived CAEP score over the first months of MED-EL CI use. CAEPs within these typical ranges could validate intervention whereas less than optimum CAEPs could prompt clinicians to seek solutions in a timely manner. CAEPs could clinically validate whether a CI provides adequate access to soft sounds. This approach could form an alternative to behavioural soft sound access verification. PMID- 29605338 TI - A case-control study of Drug-Induced Sleep Endoscopy (DISE) in pediatric population: A proposal for indications. AB - OBJECTIVE: To evaluate whether and when Drug-Induced Sleep Endoscopy (DISE) changes diagnosis and treatment plan in pediatric Obstructive Sleep Apnoea Syndrome (OSAS) with the aim to identify specific subgroups of patients for whom DISE should be especially considered. METHODS: A case-control study of DISE in 150 children with OSAS. Pre-operative OSA were assessed through detailed history, Chervin questionnaire, physical examination and overnight polysomnography. The group of study was divided into three subgroups according to clinical and polysomnographyc criteria: conventional OSAS, disproportional OSAS and persistent OSAS. Endoscopic evaluation of the upper airway during DISE was scored using Chan classification. Surgical treatment was tailored individually upon the basis of sleep endoscopy findings: performance of any surgery other than tonsillectomy and adenoidectomy (T&A) was considered as a change of the treatment plan. Cases and controls were compared considering presence and absence of DISE-directed extra surgery, respectively. RESULTS: 150 patients with mean age (SD) 56.09 (23.94) months and mean apnoea-hypopnea index (AHI) of 5.79 (6.52) underwent DISE. The conventional subgroup represented the 58.67% of the sample (n = 88), while the disproportional one counted for the 26.67% (n = 40), and the persistent one for 14.66% (n = 22) of the population. Sleep endoscopy changed the surgical plan in 4.5% of conventional OSAS, 17.5% of disproportional OSAS and 72.7% of persistent OSAS (p < 0.005). Overall, a change of the treatment plan operated by DISE was associated with a non-conventional OSAS status (OR = 6; 95% CI = 1.6-26.4). CONCLUSIONS: DISE is a safe procedure in children suffering from OSAS, and, despite being unnecessary in conventional cases of OSA, DISE should be considered not only in syndromic children, as previously demonstrated, but also in the general non-syndromic pediatric population, in the case of non-conventional OSA patients, and in children with persistent OSAS. PMID- 29605339 TI - Cochlear implantation in children with auditory neuropathy spectrum disorder: A multicenter study on auditory performance and speech production outcomes. AB - OBJECTIVES: To evaluate the auditory performance and speech production outcome in children with auditory neuropathy spectrum disorder (ANSD). The effect of age on the outcomes of the surgery at the time of implantation was also evaluated. METHODS: Cochlear implantation was performed in 136 children with bilateral severe-to- profound hearing loss due to ANSD, at four tertiary academic centers. The patients were divided into two groups based on the age at the time of implantation; Group I: Children <=24 months, and Group II: subjects >24 months. The categories of auditory performance (CAP) and speech intelligibility rating (SIR) scores were evaluated after the first and second years of implantation. The differences between the CAP and SIR scores in the two groups were assessed. RESULTS: The median CAP scores improved significantly after the cochlear implantation in all the patients (p value < 0.001). The improvement in the CAP scores during the first year in Group II was greater than Group I (p value: 0.007), but the improvement in CAP scores tended to be significantly higher in patients who were implanted at <=24 months (p value < 0.001). There was no significant difference between two groups in SIR scores at first-year and second year follow-ups. The evaluation of the SIR improvement revealed significantly higher values for Group I during the second-year follow-up (p value: 0.003). CONCLUSION: The auditory performance and speech production skills of the children with ANSD improved significantly after cochlear implantation, and this improvement was affected by age at the time of implantation. PMID- 29605340 TI - Endoscopic percutaneous suture lateralization for neonatal bilateral vocal fold immobility. AB - OBJECTIVE: Bilateral vocal-fold immobility (BFVI) is a rare but significant cause of severe respiratory distress in neonates. The primary aim of treatment is to provide an adequate airway while minimizing adverse effects such as aspiration and dysphonia. Our objective here is to describe the outcomes of a series of neonates undergoing percutaneous endoscopic suture lateralization for BVFI using a novel technique. METHODS: In this retrospective case series, we present 6 neonates (mean age: 18 days) with BVFI from three tertiary academic medical centers. The etiologies included 4 idiopathic, 1 unspecified neurodegenerative disorder, and 1 acquired from cardiac surgery. All had stridor and respiratory distress with hypoxemia requiring respiratory support at diagnosis. Endoscopic vocal-fold lateralization was performed under spontaneous-breathing suspension laryngoscopy using a novel technique of percutaneous needle-directed placement of 4-0 prolene suture without use of specialized equipment. RESULTS: All patients had clinical improvement in stridor and respiratory support requirements and avoided tracheostomy. One patient had persistent aspiration after lateralization that resolved after suture removal. One patient required bilateral lateralization procedures. One patient expired of epilepsy due to neurodegenerative disease unrelated to airway pathology. At last follow-up (mean 12.6 months), 5/5 remaining patients were on room air without tracheostomy and feeding orally without aspiration; 4/5 had partial or complete return of vocal-fold function. CONCLUSION: Endoscopic percutaneous suture lateralization may be a safe and effective non-destructive primary treatment modality for neonatal BVFI. All neonates undergoing this procedure avoided tracheotomy. PMID- 29605341 TI - High-level heteroplasmy for the m.7445A>G mitochondrial DNA mutation can cause progressive sensorineural hearing loss in infancy. AB - OBJECTIVE: Hearing loss caused by mutation of mitochondrial DNA typically develops in late childhood or early adulthood, but rarely in infancy. We report the investigation of a patient to determine the cause of his early onset hearing loss. MATERIALS AND METHODS: The proband was a boy aged 1 year and 2 months at presentation. Newborn hearing screening test by automated auditory brainstem response generated "pass" results for both ears. His reaction to sound deteriorated by 9 months. Average pure tone threshold at 0.5, 1, and 2 kHz was 55 dB by conditioned orientation response audiometry. His father had congenital hearing loss, and his mother had progressive hearing loss since childhood. Invader assays and Sanger sequencing were performed to investigate genetic causes of the hearing loss in the proband, and heteroplasmy was assessed by PCR restriction fragment length polymorphism, Sanger sequencing, and pyrosequencing. Additionally, mitochondrial function was evaluated by measurement of the oxygen consumption rate of patient skin fibroblasts. RESULTS: An m.7445A > G mitochondrial DNA mutation and a heterozygous c.235delC (p.L79Cfs*3) mutation of GJB2 were detected in the proband. His mother carried the m.7445A > G mitochondrial DNA mutation, and his father was a compound heterozygote for GJB2 mutations (c.[235delC]; [134G > A; 408C > A]). Tissue samples from both the proband and his mother exhibited a high degree of heteroplasmy. Fibroblasts from the proband exhibited markedly reduced oxygen consumption rates. These data indicate that the proband had impaired mitochondrial function, resulting in hearing loss. CONCLUSION: This research demonstrates that hearing loss in a proband who presented in infancy and that of his mother resulted from a high level of heteroplasmy for the m.7445A > G mitochondrial DNA mutation, indicating that this alteration can cause hearing loss in infancy. PMID- 29605342 TI - Safety and postoperative adverse events in management of acute mastoiditis in children - 30 Day NSQIP outcomes. AB - OBJECTIVE: To examine preoperative risk factors, postoperative 30-day outcomes and adverse events of acute mastoiditis using a national pediatric surgical database. METHODS: We explored our objectives using a cross-sectional analysis of a hospital-based reporting system database. The American College of Surgeons National Surgical Quality Improvement Program (NSQIP) pediatric database was used to identify surgical encounters for the treatment of acute mastoiditis from 2012 to 2015. Patient demographics, co-morbidities, laboratory values, surgical details, complications, and outcomes were tabulated. Linear regression was used to determine predictors of prolonged hospital stay based on pre-operative, surgical and outcome variables. RESULTS: 113 patients with acute mastoiditis were identified from with mean age of 7.8 years. Mastoidectomy was the most common index procedure performed (44; 34%). Average hospital stay length was 5.2 days. No patients died within 30 days. 4 (3.1%) patients required readmission, and 9 (6.9%) required unplanned subsequent operative procedures. Pre-operative presence of sepsis or systemic inflammatory response syndrome (SIRS; p = 0.03), and unplanned additional procedures were associated with a prolonged hospital stay (p = 0.03), but age, gender, race, and pre-operative morbidities were not (p > 0.05). CONCLUSIONS: Contemporary surgical management of acute mastoiditis in children appears to be safe. Mortality is rare and has been potentially eliminated as a complication. Rates of pre-operative systemic infection were very high, despite current antibiotic utilization trends. Opportunities for quality improvement exist to investigate how to decrease rates of preoperative sepsis, limit readmissions, and unplanned re-operations. The role of mastoidectomy appears prominent, as it was used in about two-thirds of cases. LEVEL OF EVIDENCE: 4. PMID- 29605343 TI - Surgical treatment for chronic cervical lymphadenitis in children. Experience from a tertiary care paediatric centre on non-tuberculous mycobacterial infections. AB - OBJECTIVES: Non-tuberculous mycobacteria are the most frequent cause of chronic lymphadenitis in children. We reviewed treatment and outcomes of paediatric patients with chronic cervical lymphadenitis, to better understand their differential diagnosis, surgical indication, complication and recover. METHODS: A retrospective study was carried out on children who underwent surgery from 2013 to 2016 at Meyer Children's University Hospital, Florence, Italy. Time to cure, type of surgery, and complications rate were determined and etiologic agents were identified and correlated to their clinical presentation. RESULTS: 275 children were evaluated. Nearly 98% of the patients were cured regardless of which therapeutic option was used and surgery was necessary in 38.2% of children. Complete excisional biopsy ensured recover in 97.7% of patients compared with the non-excisional surgical group 88.2% (p = 0.06). Re-interventions were needed in the 2.3% of complete excision group and in two cases of the incision and drainage group; all of them developed fistula and were caused by Mycobacterium avium complex. Excision followed by adjunctive antibiotic therapy was favoured in the majority of the patients (80.1%, n = 71). CONCLUSION: In cases of non-tuberculous mycobacteria lymphadenitis, surgery is the treatment of choice and it is closely related to a favourable prognosis. PMID- 29605344 TI - Development and validation of a quality of life instrument for patients with laryngeal cleft. AB - OBJECTIVE: To develop and validate a novel pediatric health-related quality of life (HR-QoL) instrument for patients with laryngeal cleft and their families. METHODS: We surveyed primary caregivers of patients that underwent endoscopic repair of Type I or II laryngeal cleft. The proposed HR-QoL instrument consists of 40 items representing four domains, assessing the patient's physical symptoms, the patient's and family's social functioning, and the family's emotions regarding the patient's illness pre- and post-operatively. Confirmatory factor analysis was employed to assess construct validity, dimensionality, and optimal simple structure. RESULTS: Of 78 eligible participants reached by phone, 40 (51%) of them completed the questionnaire. Confirmatory factor analysis suggested that all four measured constructs were well supported by the measured items in comparison to a unidimensional model. All factor loadings and factor correlations were significant and factor correlations ranged between 0.723 and 0.879. Indices of test-retest reliability and internal consistency reliability were well above recommended standards. There was a significant correlation between current instrument and PedsQLTM score. The overall QoL score significantly improved from 112.3 (+/-28.1) before surgery to 158.0 (+/-28.5) after surgery (mean difference 45.7; 95% CI: 37.3, 54.1; p < 0.001). CONCLUSION: Our proposed pediatric HR-QoL instrument is a valid tool for measuring quality of life in patients with laryngeal cleft and their families. This instrument can provide insight into the effects of medical and surgical therapy and guide pre- and post-operative management of laryngeal cleft. PMID- 29605345 TI - Early experience with high-flow nasal oxygen therapy (HFNOT) in pediatric endoscopic airway surgery. AB - OBJECTIVE: Reporting our institutional experience with high-flow nasal oxygen therapy (HFNOT), a recently-introduced technique, for endoscopic airway approaches. METHODS: Prospective collection of data of children (<16 years) undergoing endoscopic between January 2016 and August 2017 at a tertiary referral university hospital. RESULTS: HFNOT was used in 6 children who underwent 14 procedures for different forms and causes of upper airway obstruction of various origins. No intraoperative complications; related to oxygenation were observed, and the surgical procedures could be carried out as; initially planned. CONCLUSIONS: We found that HFNOT is an effective and safe technique with a variety of potential applications in the field of endoscopic pediatric airway surgery. PMID- 29605346 TI - Nasal saline irrigation in pediatric rhinosinusitis: A systematic review. AB - OBJECTIVE: To determine the efficacy of nasal saline irrigation (NSI) in reducing symptoms and improving quality of life in pediatric patients with acute (ARS) or chronic (CRS) rhinosinusitis. DATA SOURCES: We searched the PubMed/MEDLINE and Embase electronic databases (indexed January, 1950 through April, 2017). REVIEW METHODS: Studies assessing the efficacy of NSI in pediatric patients with ARS or CRS were selected for analysis. Outcome measures, including symptom scores and parental surveys, were analyzed. Two independent reviewers evaluated each abstract and article. RESULTS: Of the 272 articles identified using our search strategy, only 1 study, focusing on the use of NSI in pediatric ARS, met all inclusion criteria. No studies investigating NSI in pediatric CRS were included for analysis. In general, studies demonstrated significant improvement of symptom scores with the use of NSI in pediatric rhinosinusitis; but, the use of varied outcome measures, control treatments, and NSI delivery made including studies and drawing conclusions difficult. No quantitative meta-analysis could be performed. CONCLUSION: NSI may provide benefit for ARS in children; however, additional high quality studies with defined outcome measures are needed to determine the quantitative efficacy of this therapy in the pediatric patients with rhinosinusitis-especially in pediatric CRS. PMID- 29605347 TI - Diagnosis and management of pediatric sinusitis: A survey of primary care, otolaryngology and urgent care providers. AB - OBJECTIVES: The aims of this project were two-fold: 1) To assess pediatric primary care (PCP), pediatric otolaryngology (ENT) and pediatric urgent care (UC) providers' perception of their adherence to the 2013 American Academy of Pediatrics (AAP) established guidelines for the diagnosis and management of acute bacterial rhinosinusitis (ABRS) in children 1-18 years old and 2) to assess the same providers' practice patterns in the diagnosis and management of pediatric chronic rhinosinusitis (PCRS). METHOD: A 21-item questionnaire (CVI .9) was designed by th investigators using Survey Monkey(r). The survey was emailed to pediatric providers (including physicians and advanced practice providers) in a Midwestern USA healthcare system (94 PCP, 25 UC, 19 ENT providers) from 20 pediatric primary care practices, 1 pediatric UC practice and 1 pediatric otolaryngology practice. RESULTS: Diagnosis: The following diagnostic criteria are utilized: persistent nasal congestion/cough lasting >10 days (95%), worsening of classic viral URI symptoms at days 5-7 (70%), severe onset and purulent nasal discharge for at least 3 consecutive days (45%). ENT will most commonly culture their patients. ENT providers (57%) approve of a nasal culture being obtained by PCPs. MANAGEMENT: Typically used antibiotics: amoxicillin (72%), Amoxicillin clavulanic acid (98%), cefdinir (73%), azithromycin (15%). ENT providers will also use clarithromycin and Bactrim more often compared to PCPs. For PCN allergy patients, most providers choose cefdinir. Typical length of antibiotic therapy for providers is 10 days (70%) and 14 days (17%); ENT (21%) prescribes 7 days past any symptom compared to PCP (6%) and UC (5%). Use of adjuvant therapy is variable among the groups. CONCLUSION: This quality initiative project demonstrates that providers' diagnosis of ABRS is consistent with the 2013 AAP guidelines while variation in clinical management exists for both ABRS and PCRS. This survey demonstrates the need to educate all providers on the current 2013 AAP guidelines and define practice across all settings. PMID- 29605348 TI - Systematic review/meta-analysis comparing successful outcomes after single vs. double-stage laryngotracheal reconstruction. AB - OBJECTIVE: To compare operation-specific decannulation rates between single-stage (SSLTR) and double-stage laryngotracheal reconstruction (DSLTR) when controlling for grade of airway stenosis. METHODS: A systematic review and meta-analysis were performed using PubMed, EMBASE and Cochrane databases from 1970 to 2015 to examine primary SSLTR and DSLTR for subglottic stenosis in patients 18 years or younger. Primary outcome was decannulation or extubation after LTR. Failures included patients not decannulated or requiring additional open airway procedures prior to decannulation. Only studies providing outcomes delineated by airway stenosis grade were included. Non-English language studies and case reports were excluded. RESULTS: There were 712 abstracts reviewed and 16 studies with 663 pooled patients included in the systematic review analysis. The metaanalysis included 5 studies. Overall, the operation-specific decannulation success was statistically significantly different between SSLTR [93.2% (N = 221)] and DSLTR [83.7% (N = 442)] (P<0.001). When controlling for stenosis severity, however, no difference was found in decannulation success between SS- or DSLTR except in the grade 3 group: Grade 1-100% (N = 6) vs. 100% (N = 6), (P = 1); Grade 2 - 84.9% (N = 106) vs. 83.3% (N = 138), (P = 0.72); Grade 3-80.2% (N = 101) vs. 69.7% (N = 238), (P = 0.03); Grade 4-33.3% (N = 6) vs. 50% (N = 58), (P = 0.67). CONCLUSION: No difference in decannulation rates was seen between SSLTR and DSLTR when comparing similar grades of stenosis except in grade 3 stenosis. With worsening stenosis, the success rate declines with both methods. Prospective studies with standardized enrollment criteria and reported outcomes are needed to better understand the advantages and disadvantages of each approach. PMID- 29605349 TI - Utility of whole exome sequencing in the diagnosis of Usher syndrome: Report of novel compound heterozygous MYO7A mutations. AB - Next generation sequencing (NGS), such as targeted panel sequencing, whole-exome sequencing and whole-genome sequencing has led to an exponential increase of elucidated genetic causes in both rare diseases, and common but heterogeneous disorders. NGS is applied in both research and clinical settings, and the clinical exome sequencing (CES), which provides not only the sequence variation data but also clinical interpretation, aids in reaching a final conclusion with regards to a genetic diagnosis. Usher syndrome is a group of disorders, characterized by bilateral sensorineural hearing loss, with or without vestibular dysfunction and retinitis pigmentosa. The index patient, a 2-year-old child was initially diagnosed with nonsyndromic hearing impairment. Homozygosity mapping followed by CES was utilized as a diagnostic tool to identify the genetic basis of his hearing loss. A paternally inherited novel insertion, c.198_199insA (p.Val67Serfs*73) and a maternally inherited novel deletion, c.1219_1226del (p.Phe407Aspfs*33) in gene MYO7A were found in compound heterozygous state in the index patient. The result expands the mutational spectrum of MYO7A. In addition it helped in early diagnosis of the syndrome, for planning and adjustments for the patient, and as well as for future family planning. This study highlights the clinical effectiveness of CES for Usher syndrome diagnosis in a child presented with congenital hearing loss. PMID- 29605350 TI - What parents are reading about laryngomalacia: Quality and readability of internet resources on laryngomalacia. AB - OBJECTIVE: The goal of this study is to measure the quality and readability of websites related to laryngomalacia, and to compare the quality and readability scores for the sites accessed through the most popular search engines. INTRODUCTION: Laryngomalacia is a common diagnosis in children but is often difficult for parents to comprehend. As information available on the internet is unregulated, the quality and readability of this information may vary. METHODS: An advanced search on Google, Yahoo, and Bing was conducted using the terms "laryngomalacia" OR "soft larynx" OR "floppy voice box." The first ten websites meeting inclusion and exclusion criteria were evaluated, for each search engine. Quality and readability were assessed using the DISCERN criteria and the Flesch reading ease scoring (FRES) and Flesch-Kincaid grade level (FKGL) tests, respectively. RESULTS: The top 10 hits on each search engine yielded 15 unique web pages. The median DISCERN score (out of a possible high-score of 80) was 48.5 (SD 12.6). The median USA grade-level estimated by the FKGL was 11.3 (SD 1.4). Only one website (6.7%), had a readability score in the optimal range of 6th to 8th grade reading level. DISCERN scores did not correlate with FKGL scores (r = 0.10). CONCLUSION: Online information discussing laryngomalacia often varies in quality and may not be easily comprehensible to the public. It is important for healthcare professionals to understand the quality of health information accessible to patients as it may influence medical decision-making by patient families. PMID- 29605351 TI - Evaluation of the outcome of CT and MR imaging in pediatric patients with bilateral sensorineural hearing loss. AB - OBJECTIVE: To evaluate the clinically relevant abnormalities as visualized on CT and MR imaging in children with symmetric and asymmetric bilateral sensorineural hearing loss (SNHL), in relation to age and the severity of hearing loss. STUDY DESIGN: Retrospective cohort study. SETTING: Tertiary referral otology and audiology center. PATIENTS AND DIAGNOSTIC INTERVENTIONS: From January 2006 until January 2016, a total of 207 children diagnosed with symmetric and asymmetric bilateral SNHL were included. They underwent CT and/or MR imaging for the evaluation of the etiology of their hearing loss. MAIN OUTCOME MEASURES: Radiologic abnormalities associated with SNHL. RESULTS: 302 scans were performed in 207 children (median age of 0.8 years old) with bilateral SNHL. The most frequently identified cause of bilateral SNHL was a malformation of the labyrinth. The combined diagnostic yield of CT and MR imaging was 32%. The diagnostic yield of MR (34%) was considerably higher than that of CT (20%). We found a higher rate of abnormalities in children with profound hearing loss (41%) compared to milder hearing loss (8-29%), and in asymmetric SNHL (52%) compared to symmetric SNHL (30%). CONCLUSION: Imaging is essential in the etiologic evaluation of children with bilateral SNHL. The highest diagnostic yield is found in children with bilateral asymmetric SNHL or profound SNHL. Based on our findings, MR is the primary imaging modality of choice in the etiological evaluation of children with bilateral SNHL because of its high diagnostic yield. PMID- 29605352 TI - Open resection and laryngotracheal reconstruction in a case of subglottic hemangioma in PHACE syndrome. AB - We describe a 1 month old infant with PHACE syndrome who underwent successful management of subglottic hemangioma by open resection and laryngotracheal reconstruction using a thyroid ala graft. Propranolol is typically the treatment of choice for subglottic hemangiomas however, recent reports have suggested adverse complications with the use of propranolol in children with PHACE syndrome. The child had cerebral and cervical vascular anomalies associated with her PHACE syndrome making her at an increased risk of stroke with the use of propranolol. PMID- 29605353 TI - Effect of early correction of nasal septal deformity in unilateral cleft lip and palate on inferior turbinate hypertrophy and nasal patency. AB - OBJECTIVES: A relatively neglected aspect of cleft lip nasal deformity is the effect of septal deviation and inferior turbinate hypertrophy (ITH) on the functional airway. In particular, ITH in the noncleft side can be especially problematic, because it reduces the healthy nasal area, creating bilateral nasal obstruction that might affect the growth of the maxillofacial skeleton. Although these anatomic and functional changes are documented, few recommendations have been developed regarding the proper approach to ITH. The aim of the present study was to asses the ITH severity and determine the degree of nasal airway patency in patients who have undergone primary correction of the nasal septum during lip repair compared to patients operated on without primary septal correction. METHODS: The study population included two groups. One group consisted of twenty unilateral cleft lip palate UCLP patients who have previously undergone primary rhinoseptoplasty as part of their treatment plan. The control group consisted of twenty UCLP patients operated on without rhinoseptal correction. The Nasal Obstructive Symptom Evaluation (NOSE) scale and nasal endoscopy were used to assess nasal obstruction. RESULTS: The overall untreated group reported severe symptoms across all NOSE scale dimensions more frequently than children who have undergone primary rhinoseptoplasty. The difference was statistically significant for each dimensions (p < 0.05). The mean NOSE score for group A and group B was 21.4 +/- 9.4 and 70.8 +/- 17.2 respectively (p < 0.0001). In group A turbinate size decreased significantly (p < 0.05) compared to pre-operative data. Comparing the two groups a statistically significant difference in turbinate size was observed (p < 0.0001). CONCLUSION: The results of the present study confirm that there is a significant degree of ITH and nasal airway dysfunction in patients with UCLP. Early septal repositioning during primary cleft lip repair results in a statistically significant reduction in IT size and improvement of nasal patency. PMID- 29605354 TI - Trends in the management of secondary post-tonsillectomy hemorrhage in children. AB - OBJECTIVE: To define current practices in management of secondary post tonsillectomy hemorrhage (PTH) in children by pediatric and general otolaryngologists. INTRODUCTION: Bleeding after tonsillectomy is common. Our goal was to describe management methods across the U.S. METHODS: Questions regarding perioperative management and treatment in response to three hypothetical cases featuring secondary post-tonsillectomy bleeding were posed via REDCap survey. Comparisons were made for pediatric otolaryngology fellowship training, regions of residency training and current practice, practice type, and number of years in practice. RESULTS: A total of 400 surveys were distributed with 104 responses. Fellowship-trained respondents were more likely to have been in practice for less than ten years (41.5% versus 17.8%) and to practice in an academic setting (67.3% versus 13.6%). They were less likely to prescribe antibiotics after tonsillectomy and more likely to prescribe acetaminophen (98.3% versus 80.4%), ibuprofen (79.3% versus 56.5%), and narcotics (74.1% versus 50.0%) compared to general otolaryngologists. When faced with a post-tonsillectomy patient with visible clot but no active bleeding, pediatric otolaryngologists were less likely to remove the clot (31.6% versus 54.3%) and more likely to proceed to the OR (75.9% versus 56.5%) and admit the patient (87.9% versus 68.9%). Few regional differences were encountered; however, factors influencing the decision to pursue operative intervention varied by region. CONCLUSION: Pediatric otolaryngologists are more likely to follow American Academy of Otolaryngology guidelines for tonsillectomy perioperative management. They also manage patients with secondary PTH differently than general otolaryngologists. Management trends are similar by region but salient factors considered in the decision-making process vary. PMID- 29605355 TI - A functional and anatomical comparison between two passive transcutaneous bone conduction implants in children. AB - OBJECTIVE: To compare anatomical and functional outcomes of two passive transcutaneous bone conduction implant systems: SophonoTM and BAHA AttractTM. MATERIALS AND METHODS: Twenty patients, affected by bilateral conductive hearing loss, underwent unilateral transcutaneous bone conduction implant surgery. Ten children received a SophonoTM implant (6 males, 4 females, mean age 11 years, mean unaided Pure Tone Average (PTA) 0.25-4kHz = 69.70dB HL) and 10 a BAHA AttractTM system (7 males, 3 females, mean age 19 years, mean unaided PTA0.25 4kHz = 66.40dB HL). The following outcomes were considered: incidence of local complications, hearing aid benefit, hearing aid gain and changes in quality of life (QOL), as measured by the Glasgow Children's Benefit Inventory (GCBI). RESULTS: One patient in the Sophono group experienced magnet-related skin decubitus, while two patients (one per group) had skin hyperemia in the area overlying the magnet. The mean BAHA-aided threshold was 23.70dB, whereas the mean Sophono-aided threshold was 31.60dB. The mean gain was significantly different for lower frequencies, the BAHA having better functional outcomes. All patients reported an improvement in their QOL. CONCLUSION: Given the lower thickness of the internal magnet, the SophonoTM system might be more suitable for younger children, whereas BAHA offered better functional results. Both systems can be considered valid and safe options for the functional rehabilitation of conductive hearing loss in children, provided that precautions are observed, such as a gradual use of the device and use of the least powerful magnets in the first months after the activation. PMID- 29605356 TI - Autosomal dominant stapes fixation, syndactyly, and symphalangism in a family with NOG mutation: Long term follow-up on surgical treatment. AB - OBJECTIVE: Evaluation of clinical findings and audiological outcome after surgery in a Danish family with autosomal dominant facio-audio-symphalangism syndrome with stapes fixation, syndactyly and symphalangism. METHODS: Retrospective report on eight affected family members in a Danish family. Clinical investigation included X-ray, audiology and in one case video-recorded surgery. Main outcome measure was audiologic results after stapedectomy. Sanger DNA sequencing of NOG was performed on peripheral blood. RESULTS: Audiologic analysis showed that seven of eight affected family members had bilateral conductive hearing loss. Three patients were treated with stapedectomy, on one or both ears, due to fixation of stapes. All the affected members had syndactyly and symphalangism. A not previously reported mutation in the NOG gene (c.688_699del, p.Cys230_Cys232delins11) was found to segregate with the stapes fixation, syndactyly, and symphalangism. p.Cys230_Cysdelins11 was classified as likely pathogenic according to guidelines from the American College of Medical Genetics and Genomics. CONCLUSION: The clinical presentation of the reported mutation corresponds with previous case reports of families with NOG mutation. In this family, surgery with stapedectomy had lasting effect without renewed fixation of the stapes in a follow up period of 18 months-38 years. PMID- 29605357 TI - Obstructive sleep apnea syndrome and growth failure. AB - Obstructive sleep apnea syndrome is a common problem among children and is recognized as a cause of significant medical morbidity. Since the 1980s, it has been suggested that obstructive sleep apnea syndrome is a risk factor for growth failure in children. In many cases, it has been shown that growth failure is reversible once the obstructive sleep apnea syndrome is resolved. The objectives of this study were to analyze and compare growth failure prevalence in a Mediterranean population of children with obstructive sleep apnea syndrome and healthy children matched in age and sex, and to assess the effectiveness of tonsillectomy and adenoidectomy in resolving growth retardation. We compared 172 children with obstructive sleep apnea syndrome (apnea-hypopnea index >= 3) who had undergone tonsillectomy and adenoidectomy with 172 healthy controls in terms of key anthropometric parameters. Most of the criteria used for growth failure were higher to a statistically significant degree in the study group vs the control group: height-for-age <= 3rd percentile (7.56% vs 2.91%; p = 0.044), weight-for-age <= 5th percentile (9.30% vs 2.33%; p = 0.005), weight-for-age <= 3rd percentile (8.14% vs 2.33%; p = 0.013) and height and/or weight for-age <= 5th percentile (13.95% vs 5.81%; p = 0.009). The height-for-age <= 5th percentile was almost at the limit of statistical significance (8.72% for the study group vs 4.65% for the control group; p = 0.097). At one-year post-surgery follow-up, 10 of 15 children with height-for-age <= 5th percentile had achieved catch-up growth (66.6%), and 14 of 24 children with height- and/or weight-for-age <= 5th percentile had normalized growth (58.33%). For children with failure to thrive or who have growth failure, physicians should consider the possibility of obstructive sleep apnea. A significant number of children with obstructive sleep apnea concurrent with growth failure could benefit from tonsillectomy and adenoidectomy to recover and normalize their growth rate. PMID- 29605359 TI - Caregivers' perception of speech and language status and related needs in children with cleft lip and palate. AB - BACKGROUND AND PURPOSE: Comprehensive management for communication disorders in individuals with CLP was provided in a community based program in two rural districts in Tamilnadu, India. This program provides services at the community to empower the families about CLP and treatment options. OBJECTIVE: To document the caregiver perceptions' of communication status and needs in children with repaired CLP. METHOD: Six Focus Group Discussions were conducted in Thiruvannamalai and Cuddalore districts in Tamil Nadu, India. Participants were 55 Caregivers of children (5-12 years of age) with repaired CLP. RESULTS: Most participants were concerned about their child's communication and few expressed concerns about specific errors in speech observed in their children. The caregivers recognized the need for and were willing to avail speech correction services. The focus group discussions highlighted some factors that need to be considered while planning a service delivery program for speech correction. The caregivers' expressed inability to independently carryout home training programs attributing it the lack of cooperation from their children. However they were open to receiving services if it was logistically convenient. CONCLUSION: This study provided the caregiver perceptions' of needs relating to communication in children with CLP. These need to be incorporated in the existing program to develop a model for speech intervention that would be feasible, sustainable and have good compliance. PMID- 29605358 TI - Surgical management of children presenting with surgical-needed tracheal stenosis. AB - OBJECTIVES: The purpose of this work was to assess epidemiological aspects, surgical approach, morbidity and mortality rates of patients presenting with tracheal stenosis requiring surgery, and the evolution of surgical techniques over the last years. METHODS: We performed a retrospective observational study from 1990 to 2017 in a pediatric tertiary-care center with needing surgery for tracheal stenosis. We analyzed clinical patients' characteristics, type of stenosis, type of surgery and follow-up. RESULTS: Twenty-eight children presented with tracheal stenosis, half of them with congenital stenosis (complete tracheal rings) and the other half with acquired stenosis (neoplasic or post intubation injury). 39.3% of these stenoses were associated with a vascular ring (61.5% in case of congenital stenosis). Depending on the extent of the stenosis and its origin, the surgery could be performed endoscopically or by an external approach. Enlargement tracheoplasty with an autograft (14.3%) was replaced by slide tracheoplasty with Cardio Pulmonary By-Pass (CPBP, 28.6%) with improved results for the treatment of long segment tracheal stenosis, involving more than 30% of the tracheal length (all were congenital in our study). Slide tracheoplasty has been performed since the late 90's in our institution. 25% of children have had a resection and anastomosis of the trachea because they had a stenosis involving less than 30% of tracheal length. Endoscopic surgery was performed for membranous stenoses, which were often seen after intubation or tracheotomy (32.1% of patients). CONCLUSION: Effective treatment of surgical tracheal stenosis was performed in 28 children between 1990 and 2015. Surgical techniques have evolved over time, leading to a better management of this rare and serious disease. PMID- 29605360 TI - Grommet and adenoid pain evaluation (GRAPE) study. AB - In the GRAPE study an analysis is made of postoperative pain sensation in children between 6 months and 6 years after adenotomy and placement of ear grommets. Intraoperative treatment with paracetamol versus placebo shows no statistically significant difference in pain between both groups indicating that this type of surgery causes little discomfort and does not require specific intraoperative analgesic treatment. PMID- 29605361 TI - Combined Nd:YAG laser and bleomycin sclerotherapy under the same anesthesia for cervicofacial venous malformations: A safe and effective treatment option. AB - INTRODUCTION: Extensive cervicofacial venous malformations (VM) pose significant challenges to a patient's quality of life (altered breathing, dysphagia, dysarthria). Treatment options include: 1) Surgical debulking; 2) Sclerotherapy; 3) laser therapy; or 4) Combined modalities. Recent studies have demonstrated the importance of multimodality and multidisciplinary management of these patients. However, no studies have described combined single anesthetic laser and sclerotherapy treatment. We sought to demonstrate the safety and efficacy of combined Nd:YAG laser and sclerotherapy under the same anesthetic administration. METHODS: Retrospective review of 8 patients (Age 6 mo -74 yrs, x 31) with extensive cervicofacial VM with significant airway involvement. Patients were treated with combined suspension laryngoscopy with Nd:YAG laser of airway VM followed by image guided direct puncture sclerotherapy using bleomycin in the airway VM and sodium tetradecyl sulfate (STS) foam in the cervicofacial VM during the same anesthetic encounter. RESULTS: All 8 patients had extensive cervicofacial VMs that were symptomatic with snoring or orthopnea. Four of the patients had previously been treated at outside institutions with residual disease or significant complications. All patients remained intubated post procedure (Avg. 1.07 days) and tolerated extubation without re-intubation or any major complications. The average length of hospital stay was 3.2 days, of which 1.9 days were spent in the ICU. Patients reported symptomatic improvement or had decreased VM disease on MRI follow up. CONCLUSION: Combined Nd:YAG laser therapy and sclerotherapy allows treatment of both superficial and deep components of VMs in a safe and efficient manner. In addition, suspension laryngoscopy provides improved visualization and access for the interventional radiologist in difficult to reach areas for sclerotherapy. PMID- 29605362 TI - Can the number of eosinophils in adenoid and tonsil tissue determine the allergy in children? AB - OBJECTIVE: Previous reports have indicated the association of allergy with Waldeyer's ring. The aim of this prospective study was to evaluate the correlation between the allergy and the number of eosinophils in the adenoid and tonsil tissue. METHODS: 101 children who were underwent adenoidectomy and/or tonsillectomy were prospectively enrolled in this study. 46 children who had positive skin-prick test for at least one of the allergen panel were sensitized and 55 children were nonsensitized as a result of skin-prick test. Hematoxylin eosin stained sections were examined under 400* magnification in a blinded fashion in 10 random sections for all samples and compared the groups. RESULTS: The number of eosinophils in adenoid and tonsil tissue was significantly higher in sensitized patients. The number of eosinophils in the adenoid and tonsil samples also were interrelated too (p < 0.001, kappa coefficient: 0.617). As a result of ROC analysis, patients with a cut-off of >=5 eosinophils was in the sensitized group for adenoid samples [Sensitivity value: 72.09 and specifity value: 91.84]. Patients with a cut-off of >=3 eosinophils are in the sensitized group for tonsil samples [Sensitivity value: 52.94 and specifity value: 92.11]. CONCLUSION: Presence of sensitization can be distinguished by looking at the number of eosinophils in the adenoid and tonsil tissue. It can be used to determine whether the patient is allergic or not. Examination of the routine hematoxylin-eosin stained adenotonsillary specimen for eosinophilia will guide us the diagnosis and treatment of allergic rhinitis and also reduce the cost considerably. PMID- 29605363 TI - Three-dimensional assessment of facial asymmetry in preschool patients with orofacial clefts after neonatal cheiloplasty. AB - OBJECTIVES: To evaluate facial asymmetry changes in pre-school patients with orofacial clefts after neonatal cheiloplasty and to compare facial asymmetry with age-matched healthy controls. METHODS AND MATERIALS: The sample consisted of patients with unilateral cleft lip (UCL), unilateral cleft lip and palate (UCLP), and bilateral cleft lip and palate (BCLP). The patients were divided in two age groups with a mean age of 3 years (n = 51) and 4.5 years (n = 45), respectively, and 78 age-matched individuals as controls. Three-dimensional (3D) facial scans were analyzed using geometric morphometry and multivariate statistics. RESULTS: Geometric morphometry showed positive deviations from perfect symmetry on the right side of the forehead in the intervention groups and the controls. The UCL groups showed the greatest asymmetric nasolabial area on the cleft-side labia and the contralateral nasal tip. The UCLP group showed, moreover, asymmetry in buccal region due to typical maxillar hypoplasia, which was accentuated in the older group. The BCLP groups showed slightly similar but greater asymmetry than the control groups, except for the philtrum region. CONCLUSIONS: Asymmetry of each of the cleft groups significantly differed from the controls. Except for the buccal region in the UCLP and BCLP groups, asymmetry did not significantly increase with age. PMID- 29605364 TI - Management of complex pediatric laryngotracheal stenosis with skin graft reconstruction. AB - OBJECTIVES: For pediatric patients with laryngotracheal stenosis, the ultimate goal is creation of a safe, functional airway. Unfortunately, wound healing in a hollow structure can complicate repair attempts, leading to restenosis. Herein, we present our experience using skin-grafting techniques in two complex pediatric laryngotracheal stenosis cases, leading to successful decannulation or speech production. METHODS: A chart review was performed examining the evaluation and management of two pediatric patients with laryngotracheal stenosis despite prior reconstructive attempts. Patient history, bronchoscopic evaluation, intra operative technique, post-operative management, treatment outcomes, and complications were noted. Harvesting and preparation of the split-thickness skin grafts (STSG) proceeded in a similar manner for each case. Stenting material varied based on the clinical scenario. RESULTS: Using this technique, our patient with a Type 3 glottic web achieved substantial improvement in exercise tolerance, as well as vocal strength and quality. In addition, our aphonic patient could vocalize for the first time since her laryngotracheal injury. CONCLUSIONS: Temporary endoluminal stenting with skin graft lining can reproduce epithelial continuity and provide "biological inhibition" to enhance the wound healing process. When previous reconstructive efforts have failed, use of STSG can be considered in the management of complex pediatric laryngotracheal stenosis. PMID- 29605365 TI - Genetic mutations in non-syndromic deafness patients in Hainan Province have a different mutational spectrum compared to patients from Mainland China. AB - OBJECTIVES: To provide appropriate genetic testing and counseling for non syndromic hearing impairment patients in Hainan Province, an island in the South China Sea. METHODS: 299 unrelated students with non-syndromic hearing loss who attended a special education school in Hainan Province were enrolled in this study. Three prominent deafness-related genes (GJB2, SLC26A4, and mtDNA 12S rRNA) were analyzed using Sanger sequencing. RESULTS: GJB2 mutations were detected in 32.78% (98/299) of the entire cohort; however, only 5.69% (17/299) had two confirmed pathogenic mutations. The most common mutation observed in this population was c.109G > A in the GJB2 gene, with an allelic frequency of 15.05% (90/598), which is significantly higher than that reported in previous cohorts. A total of 16 patients had two confirmed pathogenic SLC26A4 gene mutations, and 16 patients had one. The IVS7-2A > G mutation was the most commonly observed, with an allelic frequency of 3.51% (21/598). Three patients had a m.1555A > G mutation in the mtDNA 12S rRNA gene. CONCLUSIONS: These results reveal that genetic etiology occurred in 11.71% (35/299) of patients, suggesting that Hainan province have a different mutational spectrum compare to Mainland China in non-syndromic deafness patients, which provide useful information to genetic counseling in Hainan province. PMID- 29605366 TI - Population-based survey of inpatient pediatric tonsillectomy and postoperative hemorrhage in Taiwan, 1997-2012. AB - OBJECTIVE: Tonsil surgery in children is a common surgical procedure, and is mostly performed as an inpatient procedure in Taiwan. This study elucidates the epidemiology and postoperative hemorrhage of inpatient tonsillectomies in Taiwanese children. METHODS: This study used the Taiwan National Health Insurance Research Database for analysis. From 1997 to 2012, all in-hospital children (aged <18 years) who underwent tonsillectomies were identified through the International Codes of Diseases (9th Revision). Incidence rates and trends of inpatient pediatric tonsillectomies during the study period were identified. Major complications, including readmission, reoperation, and mortality were identified. The factors associated with major complications were analyzed. RESULTS: From 1997 to 2012, 17326 children received inpatient tonsillectomies (mean age, 8.6 +/- 3.8 y; 65% boys). The overall incidence rate was 20.6 per 100,000 children. The incidence rate was highest in children who were 6-8 years of age, and boys exhibited a higher rate than girls (P < 0.001). Longitudinal data indicated that the incidence rate increased from 1997 (15.7/100,000 children) to 2012 (19.2/100,000 children) (P trend < 0.001). The proportions of readmission for any reason, readmission for bleeding, and reoperation were 1.8%, 0.9%, and 0.3%, respectively. No mortality occurred within 30 days of the tonsillectomy. A multivariable logistic model indicated that toddlers were associated with an increased risk of readmission for any reason (OR, 2.70; 95% CI 1.60-4.56), and adolescents were at risk of bleeding-related readmission (OR, 2.81; 95% CI 1.91-4.14) and reoperation (OR, 2.86; 95% CI 1.47-5.55). Children with comorbidities (OR, 3.14; 95% CI 1.93-5.09) or a surgical indication of tumor (OR, 11.73; 95% CI 4.93-27.91) had a higher risk of readmission. The use of nonsteroidal anti-inflammatory drugs or steroids is associated with an increased risk of readmission or reoperation. Moreover, concurrent procedures (i.e., adenoidectomy, ear surgery, or nasal surgery) did not increase the risk of readmission or reoperation. CONCLUSIONS: The incidence rate and indications of obstructive sleep disorders for inpatient pediatric tonsillectomy increased during 1997-2012 in Taiwan. Postoperative readmission and reoperation were rare. Age, surgical indication, comorbidities, and drug administration were associated with readmission or reoperation in this study cohort. PMID- 29605367 TI - Clinical and sociodemographic characteristics associated with disease severity in juvenile recurrent respiratory papillomatosis: A study of 104 patients in a tertiary care pediatric hospital. AB - BACKGROUND: Juvenile recurrent respiratory papillomatosis (JRRP) is generally aggressive and with a high recurrence rate. Currently, there is no definite curative treatment for JRRP. Therefore, a greater understanding of the aspects that influence the severity and prognosis of the disease is required. OBJECTIVE: The aim of this study was to establish the clinical and socioeconomic characteristics of pediatric patients with JRRP and its relationship with the severity of the disease in a tertiary care pediatric hospital. RESULTS: A strong relationship was observed between the severity of the disease and the age at the time of diagnosis, and having a tracheostomy. A moderate association was found between the severity of the disease and the age at the time of the study, the area of origin and the recurrence rate. None of the socioeconomic statuses had a correlation with the severity of the JRRP. CONCLUSIONS: JRRP is associated with multiple surgeries due to the recurrence and aggressiveness of the disease. The socioeconomic status does not seem to influence the severity of the disease, whereas younger patients and users of tracheostomy should receive a more strict follow-up given the increased risk of severe disease. PMID- 29605368 TI - Differences and similarities in early vocabulary development between children with hearing aids and children with cochlear implant enrolled in 3-year auditory verbal intervention. AB - OBJECTIVE: The overall objective of this study was to evaluate the implementation of a Nordic Auditory Verbal (AV) intervention for children with all degrees and types of hearing impairment (HI) using all kinds of hearing technology. A first specific objective was to identify differences and similarities in early vocabulary development between children with cochlear implant (CI) compared with children with hearing aids (HAs)/Bone anchored hearing aids (Bahs) enrolled in a 3-year AVprogram, and to compare the group of children with HI to a control group of children with normal hearing (NH). A second specific objective was to study universal neonatal hearing screening (UNHS) using the 1-3-6 Early Hearing Detection and Intervention (EHDI) guidelines. INTRODUCTION: Effect of AV intervention for children with HI using different hearing technology is not thoroughly studied. It is relevant to question, whether children with mild to moderate HI encounter the same intensive need for AV intervention as children with congenital deafness. METHODS: A longitudinal and comparative study design was used involving two cohorts of children, i.e. 36 children with CI and 19 children with HA/Bahs. The children were the first in Denmark to receive a 3-year AV intervention by formally trained AV-practitioners. Children were tested annually with standardized speech and language tests, i.e. Peabody Picture Vocabulary test, Reynell test and a Danish test for active vocabulary, Viborgmaterialet. Categorical variables were compared using Fischer's exact test and continuous variables were compared using Wilcoxon-Mann-Whitney test, as data was not normally distributed. RESULTS: Median age of diagnosis was 6 months and median age at intervention was 13 and 12 months respectively. There was no statistically significant difference between the two groups in terms of scores according to age equivalency for the three tests. However, there was a significant difference between children with HI regardless of hearing technology and children with NH. CONCLUSION: Children with HI progressed over a three-year period, but they did not reach the same level as children with NH. The high completion rate of 98,2% of families over a three-year period indicates the relevance of AV practice in a Nordic country. Children were diagnosed later than 3 months and intervention also started later than recommended. A result that warrants further investigation. PMID- 29605369 TI - Frequency-specific auditory brainstem response testing with age-appropriate sedation. AB - OBJECTIVE: Auditory brainstem response (ABR) testing is the gold-standard procedure for hearing evaluation in pediatric patients who cannot complete a behavioral hearing test. The amount of audiological information obtained depends on the quality of the patient's sleep during the test. In this retrospective database review, we aimed to assess the amount and the characteristics of the audiological information obtained in ABR testing in pediatric patients with age appropriate sedation. METHODS: A retrospective chart review was conducted on 501 consecutive ABR sedation sessions performed between January 2014 and June 2016 at the Tel Aviv Medical Center. Oral triclofos was used for the sedation of younger patients (3-24 months) and intravenous propofol for older patients (>24 months). The dataset included 370 triclofos sessions (in 337 patients) and 131 propofol sessions (in 126 patients). RESULTS: None of the children developed complications, and all were discharged on the same day of the evaluation. Among the hearing-impaired children, a mean of 10 (1.8 SD) ABR threshold measurements was obtained from propofol-sedated patients and 9.4 (2.8 SD) measurements from those sedated with triclofos (P = 0.039). The major characteristics of the hearing loss, including its degree, type, and configuration, were obtained from all propofol-sedated patients and from 95% of those sedated with triclofos. CONCLUSIONS: A comprehensive evaluation of hearing status can be obtained in ABR testing with age-appropriate sedation. An average number of ~10 threshold measurements were obtained during ABR testing with age-appropriate sedation, thus allowing for the evaluation of the degree, type and configuration of the hearing loss. PMID- 29605370 TI - A novel missense mutation in GIPC3 causes sensorineural hearing loss in an Iranian family revealed by targeted next-generation sequencing. AB - BACKGROUND: Recent studies have confirmed the utility of targeted next-generation sequencing (NGS), providing a remarkable opportunity to find variants in known disease genes, especially in genetically heterogeneous disorders such as hearing loss (HL). METHODS: After excluding mutations in the most common autosomal recessive non-syndromic HL (ARNSHL) genes via Sanger sequencing and genetic linkage analysis, we performed NGS in the proband an Iranian family with ARNSHL. The NimbleGen sequence capture array captures codingsequences (CDSs) and 100 bp of the flanking sequence of 129 common deafness genes (cat# Oto-DA3). NGSwas performed on the IlluminaHiSeq2000. BWA, SAMtools, Picard, GATK, Variant Tools, ANNOVAR, and IGV were applied for Bioinformatics analyses. Data filtering with allele frequencies (<5% in the 1000 Genomes Project and 5400 NHLBI exomes) and PolyPhen2/SIFTscores (>0.95) prioritized 1indel (insertions/deletions) and 3 missense variants in this family. Eventually, Sanger sequencing, segregation pattern, the frequency in 50 healthy matched normal controls, and evolutionary conservation of amino acid residues revealed the pathogenic variant. RESULTS: We identified a novel missenseGIPC3 mutation, c.472G > A (p.Glu158 Lys). The pathogenicity of GIPC3c.472G > A was supported by its absence in the population databases and the healthy-matched controls.Sanger sequencing confirmed co segregation of the mutation with HL. CONCLUSIONS: This study is the first report of the contribution of theGIPC3 gene to HL in the Iranian population.Targeted NGS allows easier detection of mutations in relatively uncommon deafness genes in families with ARNSHL. PMID- 29605371 TI - An approach to successful slide tracheoplasty in the low birth weight neonate with single lung. AB - The advent of the slide tracheoplasty technique and a multi-disciplinary approach has improved outcomes of congenital tracheal stenosis. However, tracheal surgery in younger patients with pulmonary malformations, especially low birth-weight neonates, has been associated with increased mortality. Patients with very low birth-weight, pulmonary malformations and prematurity may be palliated prior to definitive tracheal surgery due to the poor prognosis. We report a successful and unique approach of delaying tracheal reconstruction to allow growth and development in the premature, very low birth-weight neonate (1046g) with left lung agenesis. PMID- 29605372 TI - Emberger syndrome: A rare association with hearing loss. AB - Emberger Syndrome (ES) is a rare genetic disorder characterized by lymphedema and myelodysplasia. It is also associated with hearing loss. The genetic mutations associated with ES are not part of the comprehensive 80 gene next generation sequencing (NGS) panel. As a result, the otolaryngologist should maintain an index of suspicion for ES in any child with SNHL who presents repeatedly with recurrent infections, lymphedema and/or cutaneous warts. This paper describes the clinical evolution and management of two children who were followed up for hearing loss and eventually were diagnosed with ES. PMID- 29605373 TI - Swallowing outcomes in children after slide tracheoplasty. AB - INTRODUCTION: Slide tracheoplasty is now considered gold standard treatment for long segment congenital tracheal stenosis. Outcomes are typically focused upon airway patency. Dysphagia is often reported in children undergoing cardiothoracic surgery, but not specifically after slide tracheoplasty. This study was carried out to describe the nature and prevalence of dysphagia following slide tracheoplasty for long segment congenital tracheal stenosis. METHODS: Retrospective case note review was conducted on a series of patients who underwent swallow evaluation following slide tracheoplasty between 2006 and 2014. A clinical swallow assessment was carried out by a Speech and Language Therapist with videofluoroscopic evaluation of swallowing where indicated. Logistic regression assessed the impact of gender, feeding history, weight, tracheal diameter, stenting and co-morbidities on the likelihood of having post-operative dysphagia. RESULTS: 43 out of 83 slide tracheoplasty patients underwent swallow evaluation. Dysphagia was identified in 30 (70%) of 43 patients. Videofluoroscopy was undertaken in 22 of these patients. All patients who had a videofluoroscopy presented with altered swallow physiology. Aspiration risk was confirmed in 15 patients with frank aspiration seen in 9. Pre-operative history of dysphagia was present in 9 patients. There were two cases of vocal fold palsy. The presence of a stent was the strongest predictor of post-operative dysphagia with an odds ratio of 10.6 (95% CI 1.2-92.8). CONCLUSIONS: This study documents a high prevalence of post-operative dysphagia in a pediatric population following slide tracheoplasty. In most cases there was no history suggestive of dysphagia pre operatively. Swallowing needs to be assessed after slide tracheoplasty and longitudinal studies are required. PMID- 29605374 TI - Primary augmentation pharyngoplasty with calcium hydroxylapatite for treatment of velopharyngeal insufficiency: Surgical and speech outcomes. AB - INTRODUCTION: Augmentation pharyngoplasty (AP) is a technique that may effectively treat velopharyngeal insufficiency (VPI), while avoiding typical short and long term surgical risks. This study seeks to determine if children with VPI treated by AP with calcium hydoxylapatite (CaHa) demonstrate clinically significant improvement in speech outcomes. METHODS: Retrospective review (2012 2016) of prospectively collected database of children with VPI, cared for at a single tertiary children's hospital. Preoperative speech assessment, nasometry, and video nasendoscopy were used to identify patients with VPI treated by AP with CaHa. Demographics, surgical/speech outcomes, complications, novel surgical technique and follow-up were recorded. Main outcome measures included pre and postoperative nasality and perceptual speech assessments, based on the Pittsburgh Weighted Values for Speech (PWS). RESULTS: 17 patients treated with AP with CaHa, as initial primary treatment for VPI, were identified. 8 patients had cleft palate, 9 patients had isolated VPI. Mean age at treatment was 6.6 years, with no operative complications. Mean nasality scores before and after surgery were 3.2 vs. 0.5 (p < 0.001). Mean PWS before and after surgery were 9.7 vs. 2.1 (p < 0.001). Based on the PWS scoring, 4/8 of cleft patients (50%) and 8/9 of isolated patients (89%) achieved a competent/borderline competent nasopharyngeal valve. 17/17 of patients (100%) had improvement in nasality. Mean length of follow-up was 32.8 months (range 10-64 months). CONCLUSION: In this largest series of patients to date, AP with CaHa is a safe, minimally invasive, enduring treatment for VPI in properly selected patients. Nasality and speech scores significantly improved, especially in patients with isolated VPI. PMID- 29605375 TI - Nasal erosion as an uncommon sign of child abuse. AB - While various forms of facial trauma, bruising, burns, and fractures are frequently seen in cases of child abuse, purposeful nasal erosion has rarely been identified as a form of abusive injury. Progressive destruction of nasal tissue in children provokes a wide differential diagnosis crossing multiple subspecialties: infectious, primary immunodeficiencies, inflammatory conditions, malignancy, and genetic disorders. Progressive nasal erosion also can be a manifestation of child abuse. The proposed mechanism is repetitive mechanical denudation of the soft tissue and cartilage resulting in chronic inflammation, bleeding, and ultimately destruction of the insulted tissue. We report 6 cases of child abuse manifesting as overt nasal destruction. PMID- 29605376 TI - In Reply to 'Thoracic Ultrasound Artifacts: Still a Matter of Discussion'. PMID- 29605377 TI - Thoracic Ultrasound Artifacts: Still a Matter of Discussion. PMID- 29605378 TI - De Novo Heart Failure After Kidney Transplantation: Trends in Incidence and Outcomes. AB - BACKGROUND: Heart failure is an important cause of morbidity and mortality following kidney transplantation. Some studies in the general population have shown that the incidence of heart failure has decreased during the past 20 years. However, it is not currently known whether such a trend exists in the kidney transplantation population. STUDY DESIGN: Retrospective observational cohort study. SETTING & PARTICIPANTS: Adult patients included in the US Renal Data System who underwent their first kidney transplantation in the United States between 1998 and 2010 with at least 6 months of continuous Medicare parts A and B coverage before transplantation and no prior evidence for a diagnosis of heart failure before kidney transplantation. PREDICTORS: Calendar year of transplantation and calendar year of posttransplantation heart failure diagnosis. OUTCOMES: De novo posttransplantation heart failure defined using International Classification of Diseases, Ninth Revision diagnosis codes and mortality following de novo posttransplantation heart failure diagnosis. Secular trends in de novo post-kidney transplantation heart failure were examined using Cox proportional hazards analysis. RESULTS: Within a study cohort of 48,771 patients, 7,269 developed de novo heart failure within 3 years of kidney transplantation, with a median time to heart failure of 0.76 years. The adjusted HR for heart failure with death as competing risk comparing patients who underwent transplantation in 2010 with those who underwent transplantation in 1998 was 0.69 (95% CI, 0.60-0.79). No temporal trend in mortality following a diagnosis of post kidney transplantation heart failure was observed. LIMITATIONS: Potential residual confounding from either incorrectly ascertained or unavailable confounders. The cohort was limited to Medicare beneficiaries. CONCLUSIONS: Adjusted for demographic and clinical characteristics, the risk for developing de novo post-kidney transplantation heart failure has declined significantly between 1998 and 2010, with no apparent change in subsequent mortality. PMID- 29605379 TI - Bacteriology of the Buttonhole Cannulation Tract in Hemodialysis Patients: A Prospective Cohort Study. AB - BACKGROUND: The buttonhole cannulation technique for arteriovenous fistulas is widely used, but has been associated with an increased rate of vascular access related infections. We describe the frequency and type of bacterial colonization of the buttonhole tract over time and associated clinical infections. STUDY DESIGN: A prospective observational cohort study with 9 months of follow-up. SETTING & PARTICIPANTS: 84 in-center hemodialysis patients using the buttonhole cannulation technique at 2 Danish dialysis centers. OUTCOMES: Bacterial growth from the buttonhole tract and dialysis cannula tip and clinically important infections during follow-up. MEASUREMENTS: On 3 occasions 1 month apart, cultures before dialysis (from the skin surrounding the buttonhole before disinfection and from the cannulation tract after disinfection and scab removal) and the cannula tip after dialysis. Patients with positive cultures from the buttonhole tract or cannula tip had repeat cultures within 1 week, along with blood cultures. RESULTS: Growth from the cannulation tract and/or cannula tip at each of the 3 monthly sets of cultures was found in 18%, 20%, and 17% of patients, respectively. 38% of patients had at least 1 positive culture from the buttonhole tract. Sustained growth was detected in 11% of patients, whereas asymptomatic bacteremia was seen in 30% of those with positive buttonhole cultures. Staphylococci species were the most common pathogens (Staphylococcus aureus, 25%; and Staphylococcus epidermidis, 41%). Colonization-positive buttonholes had more localized redness and slightly more tenderness. During follow-up, significantly more access-related infections were diagnosed among those with positive buttonhole cultures (P<0.001). LIMITATIONS: No comparison to area puncture cannulation technique. Blood cultures were obtained only from patients with positive buttonhole bacteriology. CONCLUSIONS: Transient or sustained colonization of the buttonhole tract by staphylococci and asymptomatic bacteremia is common in hemodialysis patients, implying a substantial risk for access related infections among patients using a buttonhole cannulation technique. These findings suggest the possible value of surveillance of buttonhole colonization. PMID- 29605380 TI - Cryptographic Protocols to Facilitate Decision Making in Kidney Paired Donation. PMID- 29605382 TI - Physical activity is associated with changes in knee cartilage microstructure. AB - OBJECTIVE: The purpose of this study was to determine if there is an association between objectively measured physical activity and longitudinal changes in knee cartilage microstructure. METHODS: We used accelerometry and T2-weighted magnetic resonance imaging (MRI) data from the Osteoarthritis Initiative, restricting the analysis to men aged 45-60 years, with a body mass index (BMI) of 25-27 kg/m2 and no radiographic evidence of knee osteoarthritis. After computing 4-year changes in mean T2 relaxation time for six femoral cartilage regions and mean daily times spent in the sedentary, light, moderate, and vigorous activity ranges, we performed canonical correlation analysis (CCA) to find a linear combination of times spent in different activity intensity ranges (Activity Index) that was maximally correlated with a linear combination of regional changes in cartilage microstructure (Cartilage Microstructure Index). We used leave-one-out pre validation to test the robustness of the model on new data. RESULTS: Nineteen subjects satisfied the inclusion criteria. CCA identified an Activity Index and a Cartilage Microstructure Index that were significantly correlated (r = .82, P < .0001 on test data). Higher levels of sedentary time and vigorous activity were associated with greater medial-lateral differences in longitudinal T2 changes, whereas light activity was associated with smaller differences. CONCLUSIONS: Physical activity is better associated with an index that contrasts microstructural changes in different cartilage regions than it is with univariate or cumulative changes, likely because this index separates the effect of activity, which is greater in the medial loadbearing region, from that of patient specific natural aging. PMID- 29605383 TI - Prognosis of Intracerebral Hemorrhage with Newly Diagnosed Diabetes Mellitus According to Hemoglobin A1c Criteria. AB - OBJECTIVES: Hemoglobin A1c (HbA1c) has been recommended for diagnosing diabetes mellitus (DM). We aimed to assess the prevalence of newly diagnosed diabetes mellitus (NDDM) in patients with intracerebral hemorrhage (ICH) using HbA1c criteria and to investigate the long-term prognosis of patients with ICH with NDDM. MATERIALS AND METHODS: Data of patients with ICH without a DM history were derived from the Abnormal Glucose Regulation in Patients with Acute Stroke across China. NDDM was defined as a fasting plasma glucose (FPG) level of 7.0 mmol/L or higher, a 2-hour oral glucose tolerance test (OGTT) result of 11.1 mmol/L or higher, or an HbA1c level of 6.5% or higher. The prevalence of NDDM with different screening methods was assessed. The association between NDDM and 1-year prognosis (mortality, stroke recurrence, and poor functional outcome [modified Rankin scale score of 3-6]) was estimated. RESULTS: There were 357 patients with ICH included in the analysis, and 131 (36.7%) were diagnosed as NDDM using the new criteria. NDDM was present in 31 (8.7%), 98 (27.5%), and 68 (19.0%) patients with ICH, based on FPG, 2-hour OGTT, and HbA1c criteria, respectively. NDDM was independently associated with 1-year poor functional outcome (odds ratio 1.93; 95% confidence interval, 1.10-3.38, P = .02). Nevertheless, NDDM showed no significant association with 1-year death and stroke recurrence (P > .05 for both). CONCLUSIONS: More than one third of patients with ICH without a history of DM were diagnosed NDDM using the new criteria. NDDM by the new criteria was an independent risk factor of poor functional outcome, but not of death and stroke recurrence at 1 year after ICH onset. PMID- 29605384 TI - The impact of TNF-alpha 308G>A gene polymorphism on children's overweight risk and an assessment of biochemical variables: A cross-sectional single-center experience. AB - INTRODUCTION: The aim of this study was to assess the role of TNF-alpha 308 G>A gene polymorphism in children's overweight risk so as to correlate this polymorphism with anthropometric and biochemical variables. MATERIALS AND METHOD: A cross-sectional study was carried out on 188 Romanian children ages 5-18 years, who were classified into controls (Group 1; n = 109) and overweight children (Group 2; n = 79). RESULTS: Higher values of MUAC and TST (p < 0.001) were obtained in the overweight group. A significant association was found between TNF alpha 308 G>A polymorphism and weight status in the studied population (p = 0.009). There was also a positive association between the variant genotypes (GA or AA) of TNF-alpha 308G>A gene polymorphism and weight status, which was more frequently found among normal weight than overweight children (74.5% versus 25.5%, respectively). The final logistic multivariable included five independent variables (TNF-alpha genotype, gender, cholesterol, ASAT, and ALAT), which were statistically significant predictors with negative/positive effects on children's overweight risk; this model explained 30% of the variance in the outcome variable. CONCLUSION: The variant genotype of TNF-alpha 308G>A gene polymorphism was more frequent among normal weight children. In the presence of other covariates, such as age, gender, cholesterol, LDL cholesterol, ALAT, and glycemia, the TNF-alpha 308 G>A gene polymorphism remained an independent protective factor for children's overweight status. PMID- 29605381 TI - Type 2 diabetes patients have accelerated cartilage matrix degeneration compared to diabetes free controls: data from the Osteoarthritis Initiative. AB - PURPOSE: Osteoarthritis (OA) and diabetes mellitus (DM) share common risk factors with a potential underlying relationship between both diseases. The purpose of this study was to investigate the longitudinal effects of DM on cartilage deterioration over 24-months with MR-based T2 relaxation time measurements. METHODS: From the Osteoarthritis Initiative (OAI) cohort 196 diabetics were matched in small sets for age, sex, BMI and Kellgren-Lawrence score with 196 non diabetic controls. Knee cartilage semi-automatic segmentation was performed on 2D multi-slice multi-echo spin-echo sequences. Texture of cartilage T2 maps was obtained via grey level co-occurrence matrix analysis. Linear regression analysis was used to compare cross-sectional and changes in T2 and texture parameters between the groups. RESULTS: Both study groups were similar in age (63.3 vs 63.0 years, P = 0.70), BMI (30.9 vs 31.2 kg/m2, P = 0.52), sex (female 53.6% vs 54.1%, P = 0.92) and KL score distribution (P = 0.97). In diabetics, except for the patella, all compartments showed a significantly higher increase in mean T2 values when compared to non-diabetic controls. Global T2 values increased almost twice as much; 1.77ms vs 0.98ms (0.79ms [CI: 0.39,1.19]) (P < 0.001). Additionally, global T2 values showed a significantly higher increase in the bone layer (P = 0.006), and in a separate analysis of the texture parameters, diabetics also showed consistently higher texture values (P < 0.05), indicating a more disordered cartilage composition. CONCLUSION: Cartilage T2 values in diabetics show a faster increase with a consistently more heterogeneous cartilage texture composition. DM seems to be a risk factor for developing early OA with an accelerated degeneration of the articular cartilage in the knee. PMID- 29605385 TI - Effects of APOE-epsilon4 allele load on brain morphology in a cohort of middle aged healthy individuals with enriched genetic risk for Alzheimer's disease. AB - INTRODUCTION: Apolipoprotein E (APOE)-epsilon4 is the major genetic risk factor for Alzheimer's disease. However, the dose-dependent impact of this allele on brain morphology of healthy individuals remains unclear. METHODS: We analyzed gray matter volumes (GMvs) in a sample of 533 healthy middle-aged individuals with a substantial representation of epsilon4-carriers (207 heterozygotes and 65 homozygotes). RESULTS: We found APOE-epsilon4 additive GMv reductions in the right hippocampus, caudate, precentral gyrus, and cerebellar crus. In these regions, the APOE genotype interacted with age, with homozygotes displaying lower GMv after the fifth decade of life. APOE-epsilon4 was also associated to greater GMv in the right thalamus, left occipital gyrus, and right frontal cortex. DISCUSSION: Our data indicate that APOE-epsilon4 exerts additive effects on GMv in regions relevant for Alzheimer's disease pathophysiology already in healthy individuals. These findings elucidate the mechanisms underlying the increased Alzheimer's disease risk in epsilon4-carriers, suggesting a dose-dependent disease vulnerability on the brain structure level. PMID- 29605386 TI - Resolving embarrassing medical conditions with online health information. AB - PURPOSE: Reliance on online health information is proliferating and the Internet has the potential to revolutionize the provision of public health information. The anonymity of online health information may be particularly appealing to people seeking advice on 'embarrassing' health problems. The purpose of this study was to investigate (1) whether data generated by the embarrassingproblems.com health information site showed any temporal patterns in problem resolution, and (2) whether successful resolution of a medical problem using online information varied with the type of medical problem. METHODS: We analyzed the responses of visitors to the embarrassingproblems.com website on the resolution of their problems. The dataset comprised 100,561 responses to information provided on 77 different embarrassing problems grouped into 9 classes of medical problem over an 82-month period. Data were analyzed with a Bernoulli Generalized Linear Model using Bayesian inference. RESULTS: We detected a statistically important interaction between embarrassing problem type and the time period in which data were collected, with an improvement in problem resolution over time for all of the classes of medical problem on the website but with a lower rate of increase in resolution for urinary health problems and medical problems associated with the mouth and face. As far as we are aware, this is the first analysis of data of this nature. CONCLUSIONS: Findings support the growing recognition that online health information can contribute to the resolution of embarrassing medical problems, but demonstrate that outcomes may vary with medical problem type. The results indicate that building data collection into online information provision can help to refine and focus health information for online users. PMID- 29605387 TI - The place of morphology in learning to read in English. AB - Morphology is a major organising principle of English and other alphabetic languages, but has been largely neglected in theories of reading acquisition. In this article, I develop the view that learning to appreciate morphological relationships may be a vital part of acquiring a direct mapping between printed words and their meanings, represented in the ventral brain pathway of the reading network. I show that morphology provides an important degree of regularity across this mapping in English, and suggest that this regularity is directly associated with irregularity in the mapping between spelling and sound. I further show that while children in primary school display explicit knowledge of morphological relationships, there is scant evidence they show the rapid morphological analysis of printed words that skilled readers exhibit. These findings suggest that the acquisition of long-term morphological knowledge may be associated with the ongoing development of reading expertise. Implications for reading instruction are discussed. PMID- 29605388 TI - Emerging Actors in Diabetic Cardiomyopathy: Heartbreaker Biomarkers or Therapeutic Targets? AB - The diabetic heart is characterized by metabolic disturbances that are often accompanied by local inflammation, oxidative stress, myocardial fibrosis, and cardiomyocyte apoptosis. Overall changes result in contractile dysfunction, concentric left ventricular (LV) hypertrophy, and dilated cardiomyopathy, that together affect cardiac output and eventually lead to heart failure, the foremost cause of death in diabetic patients. There are currently several validated biomarkers for the diagnosis and risk assessment of cardiac diseases, but none is capable of discriminating patients with diabetic cardiomyopathy (DCM). In this review we point to several novel candidate biomarkers from new activated molecular pathways (including microRNAs) with the potential to detect or prevent DCM in its early stages, or even to treat it once established. The prospective use of selected biomarkers that integrate inflammation, oxidative stress, fibrosis, and metabolic dysregulation is widely discussed. PMID- 29605390 TI - Acetaminophen in the Neonatal Intensive Care Unit: Shotgun Approach or Silver Bullet. PMID- 29605389 TI - Epidemiologic Impact of the New Guidelines for the Diagnosis of Acute Rheumatic Fever. AB - OBJECTIVES: To estimate the incidence of acute rheumatic fever (ARF) in a metropolitan area of Northern Italy and study how the introduction of the 2015 revised Jones criteria affects the epidemiology in a region with moderate to high incidence of ARF. STUDY DESIGN: The incidence of ARF in children 5-14 years old living in the Province of Turin was estimated using low-risk criteria in a 10 year period (group A patients). The proportion of patients fulfilling only high risk (HR) criteria (group B patients) was also calculated both prospectively (from July 2015 through December 2016) and retrospectively (from January 2007 through June 2015). RESULTS: One hundred thirty-five group A patients were identified for an annual incidence of 3.2-9.6 out of 100 000 children. The use of HR criteria identified an additional 28 patients (group B), resulting in a 20.7% increase in the incidence of ARF. Age, sex annual incidence, and seasonal distribution pattern were comparable between group A and group B patients. CONCLUSIONS: HR criteria should be used for the diagnosis ARF in our region. The application of these criteria led to a 20% increase in patients with the diagnosis of ARF. The characteristics of patients fulfilling only HR criteria are similar to the remaining patients, suggesting that these criteria are sensitive and specific. PMID- 29605391 TI - Valganciclovir Is Beneficial in Children with Congenital Cytomegalovirus and Isolated Hearing Loss. AB - OBJECTIVE: To evaluate the efficacy of antiviral treatment for infants with congenital cytomegalovirus (cCMV) with isolated sensorineural hearing loss (SNHL). STUDY DESIGN: Data were reviewed retrospectively for infants with isolated SNHL who received prolonged antiviral treatment between 2005 and 2017. Hearing status was evaluated for infants who had been followed for >1 year. RESULTS: Among 329 infants treated for cCMV, 59 (18%) were born with isolated SNHL. Hearing impairment was unilateral in 38 (64.4%) infants and bilateral in 21 (35.6%). Of the 80 affected ears at baseline, 55 (68.8%) improved, and only 2 (2.5%) deteriorated. Most of the improved ears (53/55 = 96.3%) returned to normal hearing with no deterioration observed in the ears that were unaffected at baseline. On best ear evaluation, of 21 infants who had bilateral hearing loss, 16 (76.1%) improved (93.7% regaining normal functional hearing); none deteriorated. CONCLUSION: Infants born with isolated SNHL due to cCMV were found to benefit from prolonged antiviral treatment. These children (and ears) showed significant improvement in hearing status and no deterioration of unaffected ears at baseline. Our data serve as observational evidence of the benefits of antiviral treatment in these children. Avoiding treatment of these children due to the lack of prospective data is debatable. PMID- 29605392 TI - Prediction of Neonatal Hyperthyroidism. AB - OBJECTIVES: To assess whether it is possible to identify the neonatal predictors of neonatal hyperthyroidism at the presymptomatic stage of the disease. STUDY DESIGN: This retrospective multicenter study in 10 maternity units was based on the medical records of all patients monitored for a pregnancy between January 1, 2007, and January 1, 2014. Among 280 000 births, 2288 medical records of women with thyroid dysfunction were selected and screened. Of these, 415 women had Graves disease and were positive for thyrotropin receptor antibody during pregnancy, and were included. RESULTS: A thyroid-stimulating hormone (TSH) level of less than 0.90 mIU/L between days 3 and 7 of life predicted neonatal hyperthyroidism with a sensitivity 78% (95% CI, 74%-82%) and a and specificity of 99% (95% CI, 98%-100%), a positive predictive value of 90% (95% CI, 87%-93%), a negative predictive value of 98% (95% CI, 97%-99%), and an area under the receiver operating characteristic curve of 0.99 (95% CI, 0.97-1.0). A thyrotropin receptor antibody (TRAb) elimination time was calculated using the equation: 7.28 + 2.88 * log() + 11.62 log(TRAb2). CONCLUSIONS: All newborns with a TSH level of less than 0.90 mIU/L should be examined by a pediatrician. Using TSH, it is possible to screen for neonatal hypothyroidism and for neonatal hyperthyroidism with a TSH cutoff of 0.90 mIU/L, and this shows the relevance of our study in terms of public health. PMID- 29605393 TI - Differentiating Tonsil Cancer from Benign Tonsillar Hypertrophy. PMID- 29605394 TI - Cannabis Use During the Perinatal Period in a State With Legalized Recreational and Medical Marijuana: The Association Between Maternal Characteristics, Breastfeeding Patterns, and Neonatal Outcomes. AB - OBJECTIVES: To evaluate state-level prevalence estimates of prenatal and early postnatal cannabis use in a state with legalized medical and recreational marijuana and the association with adverse neonatal outcomes. STUDY DESIGN: We conducted a cross-sectional study on 3,207 respondents from the 2014-2015 Colorado Pregnancy Risk Assessment Monitoring System with state-developed questions on cannabis use. Differences in perinatal cannabis use were evaluated according to maternal characteristics, breastfeeding patterns, and pregnancy intendedness. Multiple logistic regression models evaluated the relationship between prenatal cannabis use and adverse neonatal outcomes including low birth weight, small for gestational age, preterm birth, and admission to the neonatal intensive care unit. RESULTS: The self-reported prevalence of cannabis use at any time during pregnancy was 5.7 +/- 0.5% and the prevalence of early postnatal cannabis use among women who breastfed was 5.0% (95% CI, 4.1%-6.2%). Prenatal cannabis use was associated with a 50% increased likelihood of low birth weight, independent of maternal age, race/ethnicity, level of education, and tobacco use during pregnancy (OR, 1.5; 95% CI, 1.1-2.1; P = .02). Small for gestational age, preterm birth, and neonatal intensive care unit admission were not associated with prenatal cannabis use, independent of prenatal tobacco use. CONCLUSIONS: Our findings underscore the importance of screening for cannabis use during prenatal care and the need for provider counselling about the adverse health consequences of continued use during pregnancy and lactation. PMID- 29605395 TI - Prophylactic Dextrose Gel Does Not Prevent Neonatal Hypoglycemia: A Quasi Experimental Pilot Study. AB - OBJECTIVE: To test the hypothesis that prophylactic dextrose gel administered to newborn infants at risk for hypoglycemia will increase the initial blood glucose concentration after the first feeding and decrease neonatal intensive care unit (NICU) admissions for treatment of asymptomatic neonatal hypoglycemia compared with feedings alone. STUDY DESIGN: This quasi-experimental study allocated asymptomatic at-risk newborn infants (late preterm, birth weight <2500 or >4000 g, and infants of mothers with diabetes) to receive prophylactic dextrose gel (Insta-Glucose; Valeant Pharmaceuticals North America LLC, Bridgewater, New Jersey); other at-risk infants formed the control group. After the initial feeding, the prophylactic group received dextrose gel (0.5 mL/kg) rubbed into the buccal mucosa. The blood glucose concentration was checked 30 minutes later. Initial glucose concentrations and rate of NICU admissions were compared between the prophylactic group and controls using bivariate analyses. A multivariable linear regression compared first glucose concentrations between groups, adjusting for at-risk categories and age at first glucose concentration. RESULTS: There were 236 subjects (72 prophylactic, 164 controls). The first glucose concentration was not different between the prophylactic and control groups in bivariate analysis (52.1 +/- 17.1 vs 50.5 +/- 15.3 mg/dL, P = .69) and after adjusting for covariates (P = .18). Rates of NICU admission for treatment of transient neonatal hypoglycemia were 9.7% and 14.6%, respectively (P = .40). CONCLUSIONS: Prophylactic dextrose gel did not reduce transient neonatal hypoglycemia or NICU admissions for hypoglycemia. The carbohydrate concentration of Insta-Glucose (77%) may have caused a hyperinsulinemic response, or alternatively, exogenous enteral dextrose influences glucose homeostasis minimally during the first few hours when counter-regulatory mechanisms are especially active. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02523222. PMID- 29605396 TI - Bronchopulmonary Dysplasia: The Ongoing Search for One Definition to Rule Them All. PMID- 29605397 TI - Venous Thromboembolism in Children with Sickle Cell Disease: A Retrospective Cohort Study. AB - OBJECTIVES: To describe the cumulative incidence of venous thromboembolism (VTE) in children with sickle cell disease (SCD) followed at a single institution and report on the risk factors associated with VTE development. STUDY DESIGN: Charts for all patients with SCD, aged 0-21 years, followed at Nationwide Children's Hospital over a 6-year period (January 1, 2009, to January 31, 2015) were reviewed. Data on VTE diagnosis, sex, body mass index/weight-for-length, SCD genotype, SCD clinical complications, central venous catheter (CVC) placement, and thrombophilia testing were collected. RESULTS: Cumulative incidence of VTE in children with SCD followed at a single tertiary care institution was found to be 2.9% (12/414). Nine of the 12 VTE were CVC-associated. On univariate analysis, hemoglobin SS genotype (OR 10.7, 95% CI 1.4-83.5), CVC presence (OR 34.4, 95% CI 8.9-134.6), central nervous system vasculopathy (OR 19.4, 95% CI 5.6-63.4), chronic transfusion therapy (OR 30.6, 95% CI 8.9-122.2), and older age (P = .03) were associated with VTE. However, presence of CVC was the only independent risk factor identified on multivariable logistic regression analysis (OR 33.8, 95% CI 8.7-130.9). CONCLUSION: In our institution, nearly 3% of children with SCD had a history of VTE. CVC is an independent predictor of VTE in children with SCD. PMID- 29605398 TI - [A cross-sectional study of the impact of educational information on topical photoprotection habits in medical students]. AB - OBJECTIVES: Skin cancer (melanoma and non-melanoma) is the most common cancer in humans, with melanoma being the most aggressive. Due to the fact that ultraviolet (UV) radiation exposure is the only adjustable aetiological factor, UV protection is the essential preventive measure. Based on these grounds, a study was conducted in order to compare three population groups with different levels of knowledge about UV protection, as well as to determine any differences in sun exposure habits, and the level of awareness of the damaging effects of the sun on the skin. MATERIALS AND METHODS: An observational, cross-sectional study was conducted using a questionnaire survey of 317 Spanish university students aged 18 25years old, between October and December 2015. Descriptive statistics methods and Pearson's Chi-squared were used. RESULTS: Six questions were used to evaluate the sun exposure habits. Significant differences were detected in two of them: mole self-assessment (P<.001) and the use of an appropriate sun protection factor (P=.025). Five questions were asked concerning the level of knowledge about UV protection, with differences (P<.001) being found in all cases. CONCLUSIONS: Despite having more knowledge about the risks of sun exposure in the medical dermatology students group, only two of the six habits questioned were improved. Other factors that could be involved are the aesthetic or sociocultural factors. The early prevention of skin cancer is essential, with health promotion programs needing to be established that take into account all these conditions. PMID- 29605399 TI - The relationship between the menstrual cycle and cortisol secretion: Daily and stress-invoked cortisol patterns. AB - The menstrual cycle involves significant changes in hormone levels, causing physical and psychological changes in women that are further influenced by stress. The aim of this study was to understand the relationship between menstrual cycle phase and salivary cortisol patterns during the day as well as the salivary cortisol response to the Virtual Reality Version of the Trier Social Stress Test (TSST-VR). Forty two women not taking oral contraceptives (24 in follicular phase and 18 in luteal phase) participated in the study. Five samples of salivary cortisol collected during the day and another five samples of cortisol during the TSST-VR were analyzed. Psychological stress measures and psychopathological symptomatology were also evaluated. A 2 * 4 mixed ANCOVA showed an interaction between the two groups on the TSST-RV invoked cortisol response to the [F(3,42) = 3.681; p = 0.023) where women in luteal phase showed higher cortisol post exposure levels (5.96 +/- 3.76 nmol/L) than women in follicular phase (4.31 +/- 2.23 nmol/L). No other significant differences were found. Our findings provide evidence that menstrual cycle phase tended to influence cortisol response to laboratory-induced mental stress, with more reactivity observed in the luteal phase. PMID- 29605400 TI - Extracellular DNA promotes colorectal tumor cell survival after cytotoxic chemotherapy. AB - BACKGROUND: Inflammation promotes the growth and survival of malignant cells. Inflammation within the tumor microenvironment is a result of damage-associated molecular patterns released by dead or dying cells that provide survival signals to the surrounding cells. It has been proposed that extracellular DNA can act as a damage-associated molecular pattern given the association between circulating DNA and autoimmune diseases. Herein, we demonstrate a novel role for genomic extracellular DNA binding to the Toll-like receptor (TLR)-9 on tumor cells in response to cytotoxic insult. MATERIALS AND METHODS: The colorectal tumor cell line HCCT116 was used to study the role of DNA in tumor cell response to chemotherapy. Cell viability was assessed using CCK-8 assay. Cell death mechanisms were assessed by YOYO-1 and lactate dehydrogenase staining for necrosis and TUNEL staining for apoptosis. Autophagy was measured by LC3 punctate formation. TLR9-short hairpin RNA was used to knockdown TLR-9 and determine its role in tumor cell response to DNA. RESULTS: DNA is released from necrotic tumor cells after chemotherapy. Survival after cytotoxic insult is enhanced by the presence of extracellular DNA as a result of inhibition of apoptosis and enhanced autophagy. Knockdown of TLR-9 enhanced apoptosis, diminished autophagy, and decreased survival after cytotoxic insult in the presence or absence of extracellular DNA. CONCLUSIONS: DNA in the tumor microenvironment promotes survival through induction of autophagy via TLR-9 signaling. This work has important implications for targeting extracellular DNA, TLR-9, and autophagy during treatment with chemotherapy and enhances our understanding of the role of extracellular DNA in the tumor microenvironment. PMID- 29605401 TI - Current view on the nonoperative management of acute appendicitis in a county hospital in Guatemala. PMID- 29605402 TI - Prevalence of migraines in adolescents with endometriosis. AB - OBJECTIVE: To determine the prevalence and experience of migraines in adolescents with surgically confirmed endometriosis compared with those without endometriosis. DESIGN: Cross-sectional study conducted within The Women's Health Study: From Adolescence to Adulthood-an ongoing longitudinal cohort. SETTING: Boston Center for Endometriosis. PATIENT(S): Adolescent females enrolled November 2012 through November 2016. The case group included adolescents surgically diagnosed with endometriosis. The control group included adolescents without endometriosis, recruited from the local community and clinics. INTERVENTION(S): Not available. MAIN OUTCOME MEASURE(S): An extensive online health questionnaire regarding medical history, lifestyle, medication use, anthropometrics, and symptom experience and treatments. Migraine diagnosis was self-reported. Migraine pain and noncyclic pelvic pain severity were rated using an 11-point numerical rating scale. Cyclic pelvic pain was categorized. RESULT(S): Adolescents with endometriosis were more likely to experience migraines (69.3%) than those without endometriosis (30.7%) (multivariable odds ratio = 4.77, 95% confidence interval 2.53, 9.02). For each 1-point increase in the migraine numerical rating scale, the odds of endometriosis increased by 22% (multivariable odds ratio = 1.22, 95% confidence interval 1.03, 1.44; Ptrend = .02). Among those with endometriosis, age of menarche was associated inversely with the odds of migraines. Participants with endometriosis and migraines have more dysmenorrhea than those without migraines. CONCLUSION(S): Adolescents with endometriosis are more likely to experience migraines than adolescents without endometriosis. A linear relationship exists between migraine pain severity and the odds of endometriosis, suggesting heightened pain sensitivity for adolescents with endometriosis. Due to the strong correlation, patients who present with either condition should be screened for comorbidity to maximize the benefits of care. PMID- 29605403 TI - Cycle day, estrogen level, and lead follicle size: analysis of 27,790 in vitro fertilization cycles to determine optimal start criteria for gonadotropin releasing hormone antagonist. AB - OBJECTIVE: To determine the optimal criteria at which to start GnRH antagonists during controlled ovarian hyperstimulation (COH) for in vitro fertilization (IVF). DESIGN: Retrospective clinical cohort. SETTING: IVF clinics. PATIENT(S): Women undergoing fresh autologous IVF using GnRH antagonist for ovulation suppression during COH. INTERVENTION(S): Measurement of lead follicle size, E2 level, and cycle day of stimulation on day of antagonist initiation. MAIN OUTCOME MEASURE(S): Clinical pregnancy rate (PR). RESULT(S): The highest clinical PR was achieved when the antagonist was started when a lead follicle reached 14-15.9 mm in size (mean clinical PR 21.3; 95% confidence interval [CI] 19.3, 23.6) on cycle day 6 (mean clinical PR 22.2; 95% CI 17, 28.4), or when the E2 level was between 500 and 599 pg/mL (mean clinical PR 25.4; 95% CI 19.5, 32.4). Starting antagonists when the E2 level was <300 or >1,100 pg/mL reduced the odds of clinical pregnancy by 40% (odds ratio 0.60, 95% CI 0.5, 0.7). CONCLUSION(S): Cycle day, E2 level, and follicle size at time of antagonist start are all independent predictors of a clinical pregnancy after IVF. Initiating antagonists when the E2 level is extremely low (<300 pg/mL) or extremely high (>1,100 pg/mL) significantly reduces the odds of pregnancy. PMID- 29605404 TI - Informing offspring of their conception by gamete or embryo donation: an Ethics Committee opinion. AB - This document discusses the ethical implications of informing offspring about their conception using gamete or embryo donation. It replaces the 2013 ASRM Ethics Committee document of the same name (Fertil Steril 2013;100:45-9). PMID- 29605405 TI - Estrogen deprivation and cardiovascular disease risk in primary ovarian insufficiency. AB - OBJECTIVE: To evaluate the association between estrogen (E) exposure and deficiency and cardiovascular disease (CVD) risk among women with primary ovarian insufficiency (POI). DESIGN: Cross-sectional study conducted between 1996 and 2016. SETTING: Tertiary referral centers. PATIENT(S): A total of 385 women with POI, defined by amenorrhea and FSH levels >=40 IU/L before 40 years of age, were recruited. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Women underwent a standardized intake questionnaire including data on menstrual cyclicity. Lifetime E exposure and E-free period were assessed. Serum was analyzed for endocrine and CVD profiles. The Framingham 30-year risk of CVD was calculated. RESULT(S): Lifetime E exposure (mean +/- SD) was 19.3 +/- 7.0 years, E-free period was 3.1 +/- 4.1 years, and age at screening was 34.8 +/- 7.4 years. In multivariate models E-free interval associated positively with estimated risk of hard and general CVD events (beta 0.18 [95% confidence interval 0.08, 0.29]; 0.20 [0.05, 0.35], respectively), and lifetime E exposure associated negatively with estimated risk of hard and general CVD events (-0.15 [-0.24, -0.05]; -0.16 [ 0.29, -0.03], respectively), as well as low density lipoprotein cholesterol ( 0.03 [-0.06, 0.00]) and non-high density lipoprotein cholesterol (-0.04 [-0.07, 0.00]). CONCLUSION(S): Prolonged E deprivation is associated with an increased estimated risk of CVD, whereas prolonged E exposure is associated with a reduced estimated risk. These results support the policy of early and continued use of E replacement therapy in women with POI. CLINICAL TRIAL REGISTRATION NUMBER: NCT0230904. PMID- 29605406 TI - Micro-RNA profile and proteins in peritoneal fluid from women with endometriosis: their relationship with sterility. AB - OBJECTIVE: To define the microRNA (miRNA) profile and its relationship with cytokines content in peritoneal fluid (PF) from endometriosis patients. DESIGN: Case-control study. SETTING: University hospital, research institute. PATIENT(S): One hundred twenty-six women with endometriosis (EPF) and 45 control women (CPF). MAIN OUTCOMES MEASURE(S): MiRNA arrays were prepared from six EPF and six CPF. Quantitative reverse transcription-polymerase chain reaction validation of nine selected miRNAs (miR-29c-3p, -106b-3p, -130a-3p, -150-5p, -185-5p, -195-5p, 451a, -486-5p, and -1343-5p) was performed. Vascular endothelial growth factor-A (VEGF-A), thrombospondin-1 (TSP-1), urokinase plasminogen activator (uPA), plasminogen activator inhibitor-1 (PAI-1), matrix metalloproteinase-3 (MMP3), tissue inhibitor of metalloproteinases type 1 (TIMP-1), interleukin (IL)-6, IL-8, IL-17A, macrophage inflammatory protein 1beta (MIP1beta), platelet-derived growth factor alpha-polypeptide A, and regulated on activation, normal T cell expressed and secreted (RANTES) were quantified by ELISA and MILLIPLEX. RESULT(S): MiRNA arrays showed 126 miRNAs differentially expressed (fold change +/-1.2) (78 down regulated, 48 up-regulated) in EPF. Validation showed higher levels of miR-106b 3p, -451a, -486-5p, IL-6, IL-8, uPA, and TIMP-1 in EPF. In menstrual phase, EPF presented up-regulation of miR-106b-3p, -130a-3p, -150-5p, -185-5p, -451a, -486 5p, VEGF-A, IL-8, MIF 1beta, uPA, and PAI-1 compared with other phases; however, CPF did not. MiRNA-486-5p was up-regulated in sterile EPF compared with sterile controls, and VEGF-A, IL-8, and TIMP-1 were increased in sterile and fertile EPF compared with fertile CPF. CONCLUSION(S): MiRNAs seem to be involved in the peritoneal alterations in endometriosis, suggesting new mechanisms by which ectopic lesions could implant in endometriosis patients; and to serve as biomarkers for fertility outcome prediction. PMID- 29605407 TI - Next generation sequencing for preimplantation genetic screening improves pregnancy outcomes compared with array comparative genomic hybridization in single thawed euploid embryo transfer cycles. AB - OBJECTIVE: To evaluate whether the use of next generation sequencing (NGS) for preimplantation genetic screening (PGS) in single thawed euploid embryo transfer (STEET) cycles improves pregnancy outcomes compared with array comparative genomic hybridization (aCGH). DESIGN: Retrospective cohort study. SETTING: Single university-based fertility center. PATIENT(S): A total of 916 STEET cycles from January 2014 to December 2016 were identified. Cases included 548 STEET cycles using NGS for PGS and controls included 368 STEET cycles using aCGH for PGS. INTERVENTION(S): Patients having a STEET after undergoing IVF and PGS with either NGS or aCGH. MAIN OUTCOME MEASURE(S): Primary outcomes were implantation rate, ongoing pregnancy/live birth rate (OP/LBR), biochemical pregnancy rate (PR), and spontaneous abortion (SAB) rate. RESULT(S): The implantation rate was significantly higher in the NGS group compared with the aCGH group (71.6% vs. 64.6%). The OP/LBR was also significantly higher in the NGS group (62% vs. 54.4%), and there were significantly more biochemical pregnancies in the aCGH group compared with the NGS group (15.1% vs. 8.7%). After adjustment for confounding variables with a multiple logistic regression analysis, OP/LBR remained significantly higher in the NGS group. The SAB rate was not significantly different in the NGS group compared with the aCGH group (12.4% vs. 12.7%). CONCLUSION(S): Preimplantation genetic screening using NGS significantly improves pregnancy outcomes versus PGS using aCGH in STEET cycles. Next generation sequencing has the ability to identify and screen for embryos with reduced viability such as mosaic embryos and those with partial aneuploidies or triploidy. Pregnancy outcomes with NGS may be improved due to the exclusion of these abnormal embryos. PMID- 29605408 TI - Cumulus oophorus complexes favor physiologic selection of spermatozoa for intracytoplasmic sperm injection. AB - OBJECTIVE: To investigate the effectiveness of cumulus oophorus complexes (COCs) in the physiologic selection of spermatozoa for intracytoplasmic sperm injection (ICSI). DESIGN: A prospective sibling oocytes study. SETTING: Center of reproductive medicine. PATIENT(S): Couples undergoing ICSI during 2016, females aged <=38 years, and at least six metaphase II (MII) oocytes retrieved. Sixty patients were included in the study. Of 857 MII oocytes, 429 were allocated to the study group and were injected with the sperm selected via COCs; 428 MII oocytes were allocated as controls (C) and fertilized by conventional ICSI. INTERVENTION(S): In the study group, ICSI was performed with spermatozoa that traversed the COCs in vitro. MAIN OUTCOMES MEASURE(S): Blastocyst/top blastocyst formation rate, fertilization rate, and oocyte utilization rate. RESULT(S): Oocytes injected with COC-selected spermatozoa had a significantly higher fertilization rate than the conventional ICSI group (85.31% vs. 74.77%). There were no statistically differences in cleavage and top embryo rate on day 3 between the COC-ICSI and C-ICSI groups. However, with day 5 or 6 embryos, compared with conventional ICSI, COC-ICSI significantly improved blastocyst formation rate (64.90% vs. 53.50%), blastocyst formation rate at day 5 (46.52% vs. 38.85%), top blastocyst rate (38.72% vs. 24.20%), and the usable blastocysts formation rate (62.12% vs. 46.82%). The oocyte utilization rate was improved greatly in the COC-ICSI group compared with the C-ICSI group (51.98% vs. 34.35%). Furthermore, the fertilization rate, top embryo rate on day 3, usable blastocyst rate, top blastocyst rate, and day 5 usable blastocysts rate were similar between the conventional IVF and COC-ICSI groups. Single-blastocyst transfer was performed in 82 cycles, including 44 fresh cycles and 38 frozen-thawed cycles. The cumulative embryo implantation rate in the COC-ICSI group was 64.29%, slightly higher than in the C-ICSI group (53.85%), but there was no statistical difference. CONCLUSION(S): The use of COCs to select spermatozoa for ICSI appears to be effective and led to a statistically significant improvement in blastocyst development and quality. PMID- 29605409 TI - Effect of type 3 intramural fibroids on in vitro fertilization-intracytoplasmic sperm injection outcomes: a retrospective cohort study. AB - OBJECTIVE: To evaluate the influence of type 3 intramural fibroids on in vitro fertilization-intracytoplasmic sperm injection (IVF-ICSI) outcomes. DESIGN: Retrospective cohort study. SETTING: University-based reproductive medicine center. PATIENT(S): All women undergoing IVF-ICSI from January 1, 2009, to December 31, 2016, in our unit. INTERVENTION(S): Each woman was matched with three separate control subjects of the same age (+/-1 year), number of cycles, type of infertility (primary or secondary), type of protocol used for controlled ovarian hyperstimulation (COH), and no uterine fibroids identified by transvaginal ultrasound. MAIN OUTCOME MEASURE(S): Implantation, clinical pregnancy, clinical miscarriage, and live birth rates. RESULT(S): We included 151 patients with type 3 intramural fibroids and 453 matched control subjects who underwent IVF-ICSI. The rate of "other protocol" used in COH was significantly higher in women with type 3 fibroids than in the control subjects (P<.001). The experimental group had a significantly lower implantation rate. Type 3 fibroids also resulted in a lower frequency of live births and clinical pregnancy. There was no significant difference between the groups in the rate of clinical miscarriage. Compared with the corresponding control subjects, patients with type 3 fibroids with a single fibroid diameter (SD) or total reported fibroid diameter (TD) >2.0 cm also had significantly lower rates of live birth, clinical pregnancy, and implantation. Type 3 fibroids with SD or TD <=2.0 cm had no significant difference in IVF-ICSI outcomes compared with corresponding control subjects. CONCLUSION(S): Our results suggest that type 3 fibroids exert a negative impact on the rates of implantation, clinical pregnancy, and live birth in patients undergoing IVF-ICSI, but do not significantly increase the clinical miscarriage rate. The deleterious impact of type 3 fibroids was remarkable in women with type 3 fibroids with TD or SD >2.0 cm. PMID- 29605410 TI - Environmentally relevant levels of bisphenol A affect uterine decidualization and embryo implantation through the estrogen receptor/serum and glucocorticoid regulated kinase 1/epithelial sodium ion channel alpha-subunit pathway in a mouse model. AB - OBJECTIVE: To investigate whether bisphenol A (BPA) exposure is associated with uterine decidualization and embryo implantation failure in mice. DESIGN: Experimental animal study and in vitro study. SETTING: University-based infertility center. ANIMAL(S): ICR mice. INTERVENTION(S): Mice treated with different doses of BPA; Ishikawa cells cultured in medium of different concentrations of BPA. MAIN OUTCOME MEASURE(S): Embryo implantation sites, uterine weight, quantitative real-time reverse transcriptase-polymerase chain reaction, Western blot analysis, hematoxylin and eosin staining, and immunohistochemical, cell proliferation, and statistical analyses. RESULT(S): In the experiment of mouse model, administration of 1-100 MUg/kg/day of BPA by gavage led to reduction of the number of embryo implantation sites in a dose dependent manner; 100 MUg/kg/day of BPA statistically significantly reduced the number of implantation sites compared with the control group. The uterine weight change (the wet weight of the decidualized uterine horn divided by the wet weight of the undecidualized uterine horn of the mouse) in groups exposed to BPA (100 10,000 MUg/kg/day) were statistically significantly lower compared with the control group. Immunohistochemical analysis demonstrated that administration of 100, 1,000, or 10,000 MUg/kg/day of BPA by gavage statistically significantly down-regulated the expression of epithelial Na+ channel alpha-subunit (ENaCalpha) in the luminal epithelial cells and desmin in decidual cells of the oil-induced decidualized uterine horns. Administration of 100 MUg/kg/day BPA on embryo days 0.5-3.5 by gavage statistically significantly decreased the level of uterine serum and glucocorticoid-regulated kinase 1 (SGK1) protein expression on embryo days 4 and 6. After treatment with 0.001, 0.01, 0.1, or 1.0 MUg/mL of BPA for 48 hours, the SGK1, ENaCalpha, and phospho-SGK1 protein expression of Ishikawa cells was down-regulated, and the effect of BPA on SGK1 could be abrogated by fulvestrant. CONCLUSION(S): Our study provides the first indication that BPA exposure at levels as low as 100 MUg/kg/day can impair embryo implantation in mice and BPA can affect decidualization of the uterus in mouse model. Our results suggest that BPA can down-regulate SGK1 and ENaCalpha protein expression through estrogen receptors in Ishikawa cells. PMID- 29605411 TI - Efficacy and safety of pulsatile gonadotropin-releasing hormone therapy among patients with idiopathic and functional hypothalamic amenorrhea: a systematic review of the literature and a meta-analysis. AB - OBJECTIVE: To systematically review and appraise the existing evidence in relation to the efficacy and safety of pulsatile gonadotropin-releasing hormone (pGnRH) for the treatment of women with hypothalamic amenorrhea (HA). DESIGN: Systematic review and meta-analysis. SETTING: Not applicable. PATIENT(S): A total of 35 studies (three randomized and 32 observational) encompassing 1,002 women with HA. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Primary outcomes: ovulation rate (OvR), pregnancy per ovulatory cycle rate (POR), and live birth per ovulatory cycle rate (LBOR). SECONDARY OUTCOMES: multiple gestation (MG), ovarian hyperstimulation syndrome (OHSS), and superficial thrombophlebitis (ST) rates. The summary measures were expressed as proportions and 95% confidence intervals (CI). RESULT(S): Pulsatile GnRH treatment appears to achieve high OvRs. A trend toward high PORs and LBORs among women with HA is demonstrated. SC pGnRH achieves comparable OvR compared with IV pGnRH. The incidence of OHSS is low and of mild severity. Treatment with pGnRH is associated with low but slightly higher MG rates compared with the general population. IV administered pGnRH is rarely associated with ST. CONCLUSION(S): The high OvRs leading to a high rate of singleton pregnancies and the low likelihood of OHSS render the pGnRH treatment modality both effective and safe for the treatment of women with HA of either primary or secondary origin. PMID- 29605412 TI - Outside influence: The sense of agency takes into account what is in our surroundings. AB - We are quite capable of distinguishing those outcomes we cause from those we do not. This ability to sense self-agency is thought to be produced by a comparison between a predictive representation of an outcome and the actual outcome that occurs. It is unclear, though, specifically what types of information can be entered into agency computations. Here, we demonstrate that information from non target stimuli (stimuli that are not directly acted upon) incidentally present in our surroundings can influence predictions of outcomes, consequently modulating the sense of agency over clearly-defined target outcomes (those that occur to acted-upon stimuli). This provides the first evidence that our sense of agency is contextualized with respect to what is in our immediate visual environment. Furthermore, our data suggest that agency computations, instead of just a single comparison, may involve comparisons performed in stages, with different stages involving different types/classes of information. A model of such multi-stage comparisons is described. PMID- 29605413 TI - Distal Esophageal Spasm: A Review. AB - Distal esophageal spasm is a rare motility disorder presenting principally with nonobstructive dysphagia and noncardiac chest pain. In symptomatic patients, the manometric diagnosis is made when >10% of the wet swallows have simultaneous and/or premature contractions intermixed with normal peristalsis. We characterize manometry and barium as complementary diagnostic approaches, and given the intermittent nature of the disorder, one should be always aware that it is almost impossible to rule out spasm. Treatment is difficult; we propose an approach beginning with the least invasive intervention. PMID- 29605414 TI - Fecal Microbiota Transplantation in Inflammatory Bowel Disease: A Primer for Internists. AB - Inflammatory bowel disease consists of disorders characterized by chronic idiopathic bowel inflammation. The concept of host-gut-microbiome interaction in the pathogenesis of various complex immune-mediated chronic diseases, including inflammatory bowel disease, has recently generated immense interest. Mounting evidence confirms alteration of intestinal microflora in patients with inflammatory bowel disease. Thus, restoration of normal gut microbiota has become a focus of basic and clinical research in recent years. Fecal microbiota transplantation is being explored as one such therapeutic strategy and has shown encouraging results in the management of patients with inflammatory bowel disease. PMID- 29605415 TI - Spinal Cord Disorders: Myelopathy. AB - Myelopathy is a clinical diagnosis based on symptoms and physical examination findings. Laboratories and imaging, particularly with magnetic resonance imaging, can suggest a cause. Compressive myelopathy from degenerative disease of the vertebral column is the most common cause of myelopathy in older adults and should be screened for first in most cases. There are many other causes of myelopathy, including infectious, immune-mediated, nutritional, vascular, and neoplastic etiologies. PMID- 29605416 TI - Lyme Endocarditis. AB - BACKGROUND: Valvular involvement as a manifestation of Lyme carditis is rare. The first case describing a possible association between Lyme disease and cardiac valvular disease in the United States was published in 1993. Since that time there have been 2 cases of Lyme endocarditis confirmed by Borrelia-positive 16S ribosomal RNA polymerase chain reaction and sequencing from valvular tissue and reported from Europe. Here we describe a case of Lyme endocarditis that, to our knowledge, is the first reported case confirmed by molecular diagnostics in the United States. METHODS: We present the case of a 68-year-old man with progressive dyspnea who had mitral valve perforation with severe mitral valve insufficiency seen on transesophageal echocardiogram. RESULTS: Subsequently resected valve tissue had signs of acute inflammation without organisms seen. Although blood and valve tissue cultures were negative, 16S ribosomal RNA polymerase chain reaction and sequencing demonstrated Borrelia burgdorferi. CONCLUSION: Lyme endocarditis can be a challenging diagnosis to confirm, given the rarity of cases and the need for molecular tools of resected valve tissue. It should be included among diagnostic possibilities in patients with culture-negative endocarditis who have exposure to ticks in endemic and emerging areas of Lyme disease. PMID- 29605417 TI - Linagliptin attenuates chronic post-ischemia pain: Possible anti-inflammatory and anti-oxidant mechanisms. AB - Complex regional pain syndrome (CRPS) is a debilitating neurologic disorder with an interlinked and yet incompletely defined pathogenesis. Treatment options remain a therapeutic challenge. Linagliptin is one of the dipeptidyl peptidase-4 (DPP-4) inhibitors which are used for the treatment of diabetes mellitus. Apart from the improvement of glycemic control, accumulating evidence points to the beneficial effects of DPP-4 inhibitors in a wide array of conditions. Herein, the present study was outlined to investigate the antinociceptive effect of linagliptin in acute pain conditions, and in an animal model of CRPS. A prolonged hind paw ischemia reperfusion (I/R) injury to the left hind paw was done to induce chronic post-ischemia pain (CPIP) in rats. Allodynia and hyperalgesia were assessed in both ipsilateral and contralateral hind paws at different time points. At the end of the experiment, markers of oxidative stress and inflammatory cytokines were assayed in paw skin samples. The results showed that linagliptin had no effect on acute nociception. On the other hand, linagliptin treatment, for seven days, ameliorated hyperalgesia, mechanical and cold allodynia, and attenuated oxidative and inflammatory markers in CPIP rats. In conclusion, linagliptin was able to ameliorate aberrant pain behavior induced by prolonged hind paw ischemia. These effects can be attributed, at least partially, to the reduction of inflammatory cytokine levels and restore oxidant/antioxidant balance in the CPIP model. Hence, linagliptin pleiotropic effects open a new horizon to further investigate its role in the treatment of inflammatory and chronic painful conditions, especially in diabetic patients. PMID- 29605418 TI - Selective downregulation of vesicular glutamate transporter2 in ventral posterolateral nucleus of thalamus attenuates neuropathic mechanical allodynia in mice. AB - Vesicular glutamate transporters (VGLUTs) transport glutamate into synaptic vesicles prior to exocytotic release. The expression pattern of VGLUT2 and studies of genetically modified mice have revealed that VGLUT2 contributes to neuropathic pain. We previously showed that VGLUT2 is upregulated in supraspinal regions including the thalamus in mice following spared nerve injury (SNI), and blocking VGLUTs using the VGLUT inhibitor CSB6B attenuated mechanical allodynia. To further evaluate the role of VGLUT2 in neuropathic pain, in this study, we developed a lentiviral vector expressing small hairpin RNAs (shRNAs) against mouse VGLUT2, which was injected into the ventral posterolateral (VPL) nucleus of the thalamus in the presence or absence of SNI. The administration of VGLUT2 shRNAs result in downregulation of VGLUT2 mRNA and protein expression, and decreased extracellular glutamate release in primary cultured neurons. We also showed that VGLUT2 shRNAs attenuated SNI-induced mechanical allodynia, in accordance with knockdown of VGLUT2 in the VPL nucleus in mice. Accordingly, our study supports the essential role of supraspinal VGLUT2 in neuropathic pain in adult mice and, thereby, validates VGLUT2 as a potential target for neuropathic pain therapy. PMID- 29605419 TI - Long-term oral atazanavir attenuates myocardial infarction-induced cardiac fibrosis. AB - Atazanavir is an antiretroviral medication used to treat and prevent HIV/AIDS, but its effects on cardiac fibrosis are unknown. The aim of this study was to determine the effects of atazanavir on myocardial infarction (MI)-induced cardiac fibrosis in rats and used a TLR 9 antagonist, hydroxychloroquine (HCQ) to elucidate the potential mechanism in vitro. The results indicated that atazanavir significantly attenuated CoCl2-induced neonatal rat cardiac fibroblast (rCFs) proliferation in a concentration-dependent manner. Treatment of rCFs with atazanavir 1-10 uM blocked CoCl2-induced nuclear factor kappaB phosphorylation (p NF-kappaB), p-IkappaBalpha and high-mobility group box 1 (HMGB1) expression. Treatment of rCFs with atazanavir 3 uM blocked HMGB1 downstream, p-NF-kappaB by blocking HMGB1 binds to toll-like receptor 9 (TLR 9). Intragastric administration of atazanavir sulfate 30 mg/k ameliorated changes in the left ventricular systolic pressure (LVSP), + dp/dtmax, and - dp/dtmax after 4 weeks. This was associated with attenuation of alpha-SMA, HMGB1, p-NF-kappaB, TLR 9, collagen I, collagen III expression and hydroxyproline (Hyp) content in ischemic myocardial tissue. Additionally, continuous intragastric administration of atazanavir for 28 days attenuated cardiac remodeling. These data suggested that the protective effect of atazanavir is likely due to blocking of myocardial inflammatory cascades through an HMGB1/TLR 9 signaling pathway. PMID- 29605420 TI - [How I do... the Rouhier-modified colpocleisis technique (Lyons school of vaginal surgery)]. PMID- 29605421 TI - Change in physical activity and accumulation of cardiometabolic risk factors. AB - This study aims to examine the association between change in physical activity over time and accumulation of cardiometabolic risk factors. Four consecutive surveys (Time 1 to 4) were conducted with 4-year intervals in 1997-2013 (the Finnish Public Sector study). Physical activity of 15,634 cardio-metabolically healthy participants (mean age 43.3 (SD 8.7) years, 85% women) was assessed using four-item survey measure and was expressed as weekly metabolic equivalent (MET) hours in Time 1, 2, and 3. At each time point, participants were categorised into low (<14 MET-h/week), moderate (>=14 to <30 MET-h/week), or high (>=30 MET h/week) activity level and change in physical activity levels between Time 1 and 3 (over 8 years) was determined. The outcome was the number of incident cardiometabolic risk factors (hypertension, dyslipidemia, diabetes, and obesity) at Time 4. Cumulative logistic regression was used for data analysis. Compared to maintenance of low physical activity, increase in physical activity from low baseline activity level was associated with decreased accumulation of cardiometabolic risk factors in a dose-response manner (cumulative odds ratio [cOR] = 0.73, 95% CI 0.59-0.90 for low-to-moderate and cOR = 0.67, 95% CI 0.49 0.89 for low-to-high, P for trend 0.0007). Decrease in physical activity level from high to low was associated with increased accumulation of cardiometabolic risk factors (cOR = 1.60, 95% CI 1.27-2.01) compared to those who remained at high activity level. Thus even a modest long-term increase in physical activity was associated with reduction in cardiometabolic risk whereas decrease in physical activity was related to increased risk. PMID- 29605422 TI - Leukocytoclastic Vasculitis and Desensitization to High-dose Methotrexate in Primary Central Nervous System Lymphoma. PMID- 29605423 TI - Treating Adult Acute Lymphoblastic Leukemia in Brazil-Increased Early Mortality Using a German Multicenter Acute Lymphoblastic Leukemia-based regimen. AB - BACKGROUND: Acute lymphoblastic leukemia (ALL) in adults is an invariably aggressive and rare disease. Its treatment is based on the use of multidrug regimens, which have been improved since the 1970s. Few published data are available on the results of adult ALL treatment in Latin America. MATERIALS AND METHODS: We retrospectively analyzed the data from 59 patients with ALL treated from 2009 to 2015 at Hospital of Clinics of University of Sao Paulo, using an adapted German Multicenter ALL (GMALL) protocol (07/2003). RESULTS: The median patient age was 35 years (range, 16-71 years), with 76% of new cases of B-cell lineage. Central nervous system involvement was present in 29%. Most patients were in the high-risk group, using the original GMALL criteria (68%). The early death rate was 17%, preventing early evaluation of the response in these patients. Despite a reasonable complete remission rate (76%), most patients eventually died of sepsis, especially during the induction phase and salvage regimens. The median overall survival was 17 months. CONCLUSION: Intensified chemotherapy protocols for adult ALL have succeeded in achieving better survival rates in adults, especially younger adults. The low overall survival found with GMALL in Brazil's public hospital denotes the importance of optimizing the adaptations of international protocols for treatment of ALL in nondeveloped countries and, in parallel, improving supportive care in public services. PMID- 29605424 TI - Baseline levels of environmental genotoxicity and potential confounding factors using common sole (Solea solea) as sentinel organism. AB - Micronuclei (MN) and nuclear buds (NB) frequency was assessed monthly over a one year period in erythrocytes of common soles (Solea solea) from the Basque continental shelf, a minor disturbed area, in order to determine baseline levels and potential biotic and abiotic confounding factors within biomonitoring purposes. Both genotoxic parameters presented seasonal variations, although only NB frequency was positively correlated with environmental variables (i.e. water temperature and salinity). On the contrary, MN and NB were not affected by age and gender. Therefore, samples of combined age and gender can be used for biomonitoring genotoxic effects, although sampling period together with water temperature and salinity should be thoroughly considered for NB. Overall, these findings are the first attempt to establish baseline MN (0.10-0.780/00) and NB (0.13-0.820/00) frequencies in common sole from Basque marine waters, which are useful for upcoming data comparisons and integration within genotoxicity evaluation procedures of similar marine environments under biomonitoring scopes. PMID- 29605425 TI - Stepwise impairment of neural stem cell proliferation and neurogenesis concomitant with disruption of blood-brain barrier in recurrent ischemic stroke. AB - Stroke patients are at increased risk for recurrent stroke and development of post-stroke dementia. In this study, we investigated the effects of recurrent stroke on adult brain neurogenesis using a novel rat model of recurrent middle cerebral artery occlusion (MCAO) developed in our laboratory. Using BrdU incorporation, activation and depletion of stem cells in the subgranular zone (SGZ) and subventricular zone (SVZ) were assessed in control rats and rats after one or two strokes. In vitro neurosphere assay was used to assess the effects of plasma from normal and stroke rats. Also, EM and permeability studies were used to evaluate changes in the blood-brain-barrier (BBB) of the SGZ after recurrent stroke. We found that proliferation and neurogenesis was activated 14 days after MCAO. This was correlated with increased permeability in the BBB to factors which increase proliferation in a neurosphere assay. However, with each stroke, there was a stepwise decrease of proliferating stem cells and impaired neurogenesis on the ipsilateral side. On the contralateral side, this process stabilized after a first stroke. These studies indicate that stem cells are activated after MCAO, possibly after increased access to systemic stroke-related factors through a leaky BBB. However, the recruitment of stem cells for neurogenesis after stroke results in a stepwise ipsilateral decline with each ischemic event, which could contribute to post-stroke dementia. PMID- 29605426 TI - Translation-relevant EEG phenotypes in a mouse model of Fragile X Syndrome. AB - Identification of comparable biomarkers in humans and validated animal models will facilitate pre-clinical to clinical therapeutic pipelines to treat neurodevelopmental disorders. Fragile X Syndrome (FXS) is a leading known genetic cause of intellectual disability with symptoms that include increased anxiety, social and sensory processing deficits. Recent EEG studies in humans with FXS have identified neural oscillation deficits that include enhanced resting state gamma power and reduced inter-trial coherence of sound evoked gamma oscillations. To determine if analogous phenotypes are present in an animal model of FXS, we recorded EEGs in awake, freely moving Fmr1 knock out (KO) mice using similar stimuli as in the human studies. We report remarkably similar neural oscillation phenotypes in the Fmr1 KO mouse including enhanced resting state gamma power and reduced evoked gamma synchronization. The gamma band inter-trial coherence of neural response was reduced in both auditory and frontal cortex of Fmr1 KO mice stimulated with a sound whose envelope was modulated from 1 to 100 Hz, similar to that seen in humans with FXS. These deficits suggest a form of enhanced 'resting state noise' that interferes with the ability of the circuit to mount a synchronized response to sensory input, predicting specific sensory and cognitive deficits in FXS. The abnormal gamma oscillations are consistent with parvalbumin neuron and perineuronal net deficits seen in the Fmr1 KO mouse auditory cortex indicating that the EEG biomarkers are not only clinically relevant, but could also be used to probe cellular and circuit mechanisms of sensory hypersensitivity in FXS. PMID- 29605427 TI - On reducing the risk of vaccine-associated paralytic poliomyelitis in the global transition from oral to inactivated poliovirus vaccine. PMID- 29605428 TI - Skeletal muscle channelopathy: a new risk for sudden infant death syndrome. PMID- 29605430 TI - An unusual Monteggia equivalent type 1 lesion: Diaphyseal ulna and radius fractures with a posterior elbow dislocation in a child. AB - In this report, we describe an extremely unusual Monteggia equivalent type 1 lesion in a 10-year-old boy following a fall from a height of 1 m. On the plain radiographs, our patient had a particular Monteggia equivalent type 1 injury associating a posterior elbow dislocation with diaphyseal radius and ulna fractures. The patient was treated by closed reduction technique. At six months of follow-up, the fractures were consolidated and the elbow was stable. To our knowledge, only 8 adult cases and one paediatric observation with similar lesions had been reported through medical literature. Therefore, the aim of our case report is to remind this rare entity and also to provide a comprehensive review of the literature related to this uncommon lesion. PMID- 29605429 TI - Dysfunction of NaV1.4, a skeletal muscle voltage-gated sodium channel, in sudden infant death syndrome: a case-control study. AB - BACKGROUND: Sudden infant death syndrome (SIDS) is the leading cause of post neonatal infant death in high-income countries. Central respiratory system dysfunction seems to contribute to these deaths. Excitation that drives contraction of skeletal respiratory muscles is controlled by the sodium channel NaV1.4, which is encoded by the gene SCN4A. Variants in NaV1.4 that directly alter skeletal muscle excitability can cause myotonia, periodic paralysis, congenital myopathy, and myasthenic syndrome. SCN4A variants have also been found in infants with life-threatening apnoea and laryngospasm. We therefore hypothesised that rare, functionally disruptive SCN4A variants might be over represented in infants who died from SIDS. METHODS: We did a case-control study, including two consecutive cohorts that included 278 SIDS cases of European ancestry and 729 ethnically matched controls without a history of cardiovascular, respiratory, or neurological disease. We compared the frequency of rare variants in SCN4A between groups (minor allele frequency <0.00005 in the Exome Aggregation Consortium). We assessed biophysical characterisation of the variant channels using a heterologous expression system. FINDINGS: Four (1.4%) of the 278 infants in the SIDS cohort had a rare functionally disruptive SCN4A variant compared with none (0%) of 729 ethnically matched controls (p=0.0057). INTERPRETATION: Rare SCN4A variants that directly alter NaV1.4 function occur in infants who had died from SIDS. These variants are predicted to significantly alter muscle membrane excitability and compromise respiratory and laryngeal function. These findings indicate that dysfunction of muscle sodium channels is a potentially modifiable risk factor in a subset of infant sudden deaths. FUNDING: UK Medical Research Council, the Wellcome Trust, National Institute for Health Research, the British Heart Foundation, Biotronik, Cardiac Risk in the Young, Higher Education Funding Council for England, Dravet Syndrome UK, the Epilepsy Society, the Eunice Kennedy Shriver National Institute of Child Health & Human Development of the National Institutes of Health, and the Mayo Clinic Windland Smith Rice Comprehensive Sudden Cardiac Death Program. PMID- 29605431 TI - Combination of blood lactate level with assessment of blood consumption (ABC) scoring system: A more accurate predictor of massive transfusion requirement. AB - PURPOSE: Exsanguination is the most common leading cause of death in trauma patients. The massive transfusion (MT) protocol may influence therapeutic strategies and help provide blood components in timely manner. The assessment of blood consumption (ABC) score is a popular MT protocol but has low predictability. The lactate level is a good parameter to reflect poor tissue perfusion or shock states that can guide the management. This study aimed to modify the ABC scoring system by adding the lactate level for better prediction of MT. METHODS: The data were retrospectively collected from 165 trauma patients following the trauma activated criteria at Songklanagarind Hospital from January 2014 to December 2014. The ABC scoring system was applied in all patients. The patients who had an ABC score >=2 as the cut point for MT were defined as the ABC group. All patients who had a score >=2 with a lactate level >4 mmol/dL were defined as the ABC plus lactate level (ABC + L) group. The prediction for the requirement of massive blood transfusion was compared between the ABC and ABC + L groups. The ability of ABC and ABC + L groups to predict MT was estimated by the area under the receiver operating characteristic curve (AUROC). RESULTS: Among 165 patients, 15 patients (9%) required massive blood transfusion. There were no significant differences in age, gender, mechanism of injury or initial vital signs between the MT group and the non-MT group. The group that required MT had a higher Injury Severity Score and mortality. The sensitivity and specificity of the ABC scoring system in our institution were low (81%, 34%, AUC 0.573). The sensitivity and specificity were significantly better in the ABC + L group (92%, 42%, AUC = 0.745). CONCLUSION: The ABC scoring system plus lactate increased the sensitivity and specificity compared with the ABC scoring system alone. PMID- 29605432 TI - An overview of the American trauma system. AB - The American trauma system is designed to provide an organized response to injury. It draws its foundations from lessons learned from America's involvement in the wars of the 20th century as well as principles developed in urban community hospitals. Although run at the local and state government level, it is guided by national societies and has become a world class example. It also currently faces challenges with declining reimbursement and providing equal access to care for all Americans. Professional societies and legislative bodies are continuing to work together for fair and equitable solutions to these issues. PMID- 29605433 TI - Epidemiological profile of pediatric ocular trauma in a tertiary hospital of northern India. AB - PURPOSE: Ocular trauma is one of the most common causes of acquired blindness in children. It measures about 8%-14% of total childhood injuries. This study aims to determine the epidemiological profile of ocular trauma in the pediatric age group attending a tertiary hospital in northern India. METHODS: A retrospective study was conducted in our hospital between June 2014 to July 2015 and all the children aged 0-16 years presenting with ocular trauma in eye outpatient department and emergency were enrolled in the study. Various epidemiological parameters like age, sex distribution, duration of presentation, mode of injury, type of injury and final visual outcome were analyzed. RESULTS: Of total 357 patients, 271 (76%) were below the age of 12 years; 41.1% of children with ocular trauma belonged to age group 2-6 years. The male to female ratio was 2.9:1. Out of total patients, 242 (67.8%) presented with closed globe injury. Among the closed globe injury, the history of fall was present in about 35% of children, followed by trauma while playing with bat/ball (15.7%) and finger nail trauma (13.2%). Among open globe injury, trauma with needle, knife, glass and pen were common causes. Home was the most common place of injury (47.8%), followed by streets (17.9%) and playground (14.9%). CONCLUSION: Children are vulnerable to ocular trauma and need more supervision. Sharp objects like needles, knives, household chemicals like acids should be out of reach of children. PMID- 29605434 TI - ACSL5 genotype influence on fatty acid metabolism: a cellular, tissue, and whole body study. AB - BACKGROUND: Acyl-CoA Synthetase Long Chain 5 (ACSL5) gene's rs2419621 T/C polymorphism was associated with ACSL5 mRNA expression and response to lifestyle interventions. However, the mechanistic understanding of the increased response in T allele carriers is lacking. Study objectives were to investigate the effect of rs2419621 genotype and ACSL5 human protein isoforms on fatty acid oxidation and respiration. METHODS: Human ACSL5 overexpression in C2C12 mouse myoblasts was conducted to measure 14C palmitic acid oxidation and protein isoform localization in vitro. 14C palmitic acid oxidation studies and Western blot analysis of ACSL5 proteins were carried out in rectus abdominis primary myotubes from 5 rs2419621 T allele carriers and 4 non-carriers. In addition, mitochondrial high-resolution respirometry was conducted on vastus lateralis muscle biopsies from 4 rs2419621 T allele carriers and 4 non-carriers. Multiple linear regression analysis was conducted to test the association between rs2419621 genotype and respiratory quotient related pre- and post-lifestyle intervention measurements in postmenopausal women with overweight or obesity. RESULTS: In comparison to rs2419621 non-carriers, T allele carriers displayed higher levels of i) 683aa ACSL5 isoform, localized mainly in the mitochondria, playing a greater role in fatty acid oxidation in comparison to the 739aa protein isoform ii) in vitro CO2 production in rectus abdominis primary myotubes iii) in vivo fatty acid oxidation and lower carbohydrate oxidation post-intervention iv) ex vivo complex I and II tissue respiration in vastus lateralis muscle. CONCLUSIONS: These results support the conclusion that rs2419621 T allele carriers, are more responsive to lifestyle interventions partly due to an increase in the short ACSL5 protein isoform, increasing cellular, tissue and whole-body fatty acid utilization. With the increasing effort to develop personalized medicine to combat obesity, our findings provide additional insight into genotypes that can significantly affect whole body metabolism and response to lifestyle interventions. PMID- 29605435 TI - Endocrine disruptors and testicular function. AB - Despite concerns of the scientific community regarding the adverse effects of human exposure to exogenous man-made chemical substances or mixtures that interfere with normal hormonal balance, the so called "endocrine disruptors (EDs)", their production has been increased during the last few decades. EDs' extensive use has been implicated in the increasing incidence of male reproductive disorders including poor semen quality, testicular malignancies and congenital developmental defects such as hypospadias and cryptorchidism. Several animal studies have demonstrated that exposure to EDs during fetal, neonatal and adult life has deleterious consequences on male reproductive system; however, the evidence on humans remains ambiguous. The complexity of their mode of action, the differential effect according to the developmental stage that exposure occurs, the latency from exposure and the influence of the genetic background in the manifestation of their toxic effects are all responsible factors for the contradictory outcomes. Furthermore, the heterogeneity in the published human studies has hampered agreement in the field. Interventional studies to establish causality would be desirable, but unfortunately the nature of the field excludes this possibility. Therefore, future studies based on standardized guidelines are necessary, in order to estimate human health risks and implement policies to limit public exposure. PMID- 29605436 TI - The role of ZA channel water-mediated interactions in the design of bromodomain selective BET inhibitors. AB - The Bromodomain and Extra-Terminal domain (BET) family of proteins are involved in the regulation of gene transcription, and their dysregulation is implicated in several diseases including cancer. BET proteins contain two tandem bromodomains (BD1 and BD2) that independently recognize acetylated-lysine residues and appear to have distinct biological roles. We compared several published co-crystal structures and found five positions near the substrate binding pocket that vary between BET bromodomains. One position located in the ZA loop has unique properties. In BRD2-4, this residue is glutamine in BD1 and lysine in BD2; in BRDT, this residue is arginine in BD1 and asparagine in BD2. Using molecular modeling, we identified differences in the water-mediated network at this position between bromodomains. Molecular dynamics simulations helped rationalize the observed bromodomain selectivity for exemplar BET inhibitors and a congeneric series of tetrahydroquinolines (THQ) that differed by a single heteroatom near the ZA channel. The 2-furan SJ830599, the most BD2-selective THQ analog, did not disrupt the water-mediated networks in either domain, but was electrostatically repulsed by the specific arrangement of the W5 water dipole in BD1. Our work underscores the value of exploring water-mediated interactions to study ligand binding, and highlights the difficulty of optimizing polar interactions due to high desolvation penalties. Finally, we suggest further modifications to THQ based BET inhibitors that would increase BD2-selectivity in BRD2-4, while minimizing affinity for one or both bromodomains of BRDT. PMID- 29605437 TI - [Isolated nonsyndromic nail dysplasia: Homozygous mutation in SLC25A16]. PMID- 29605438 TI - [Apremilast withdrawals more frequent in standard practice than in clinical trials]. PMID- 29605440 TI - Discussion. PMID- 29605439 TI - The control of amplitude and direction in a bimanual coordination task. AB - Bimanual coordination requires task-specific control of the spatial and temporal characteristics of the movements of both hands. The present study focused on the spatial relationship between hand movements when their amplitude and direction were manipulated. In the experiment in question, participants were instructed to draw two lines simultaneously. These two lines were instructed to be drawn in mirror symmetric or perpendicular directions of each other while the length was instructed to be the same or different. The coordinative quality of amplitude control was compared when the task required symmetric and asymmetric bimanual spatial coordination patterns. Results showed that the amplitude accuracy decreased when different amplitudes and/or directions had to be generated simultaneously. The coordinative quality of direction was also compared when the task required symmetric and asymmetric bimanual spatial coordination patterns. Unlike amplitude, the direction accuracy was largely independent of coordination symmetry/asymmetry of direction or amplitude. The results suggest that the coordinative quality of amplitude control does not only interfere with amplitude asymmetry, but it also interferes with direction asymmetry. Moreover, in bimanual coordination amplitude control is more vulnerable to the influence of direction control demands than vice versa. PMID- 29605441 TI - Outcomes after endoscopic mucosal resection or esophagectomy for submucosal esophageal adenocarcinoma. AB - OBJECTIVES: Endoscopic mucosal resection (EMR) is a diagnostic and potentially therapeutic option for patients with submucosal esophageal adenocarcinoma. However, there are significant concerns regarding the risk of lymph node metastasis. Our purpose was to construct a comparative effectiveness analysis comparing recurrence patterns after therapeutic EMR or esophagectomy. METHODS: Patients who underwent therapeutic EMR or esophagectomy from 2007 to 2015 with pathologically staged submucosal adenocarcinoma were identified from a departmental database. Cancer-related outcomes were compared among an unmatched as well as a propensity matched cohort. Risk stratification was also used to compare results among those with a low, medium, or high risk of nodal metastasis. RESULTS: Seventy-two patients met criteria for analysis, among whom 23 underwent therapeutic EMR with esophageal preservation and 49 underwent esophagectomy. Median follow-up was 43 months. Patients who underwent esophagectomy had larger, deeper tumors. Esophageal preservation was associated with an increased risk of local recurrence (P = .01), but not distant recurrence (P = .44). After propensity matching, there continued to be no difference in distant recurrence rate (P = .66). In a risk-stratified analysis, low-risk patients showed no recurrences or cancer-related deaths, however, high-risk patients showed a trend toward increased distant recurrence after therapeutic EMR. CONCLUSIONS: Esophageal preservation after therapeutic EMR was associated with an increased risk of local recurrence. Among low-risk patients, either strategy resulted in excellent cancer control. However, among high-risk patients, esophageal preservation showed a trend toward increased distant failure. These findings should prompt further investigation to determine optimal treatment for patients with submucosal esophageal adenocarcinoma. PMID- 29605442 TI - Intranasal administration of sodium dimethyldithiocarbamate induces motor deficits and dopaminergic dysfunction in mice. AB - The primary etiology of Parkinson's disease (PD) remains unclear, but likely reflects a combination of genetic and environmental factors. Exposure to some pesticides, including ziram (zinc dimethyldithiocarbamate), is a relevant risk factor for PD. Like some other environmental neurotoxicants, we hypothesized that ziram can enter the central nervous system from the nasal mucosa via the olfactory nerves. To address this issue, we evaluated the effects of 1, 2 or 4 days of intranasal (i.n., 1 mg/nostril/day) infusions of sodium dimethyldithiocarbamate (NaDMDC), a dimethyldithiocarbamate more soluble than ziram, on locomotor activity in the open field, neurological severity score and rotarod performance. We also addressed the effects of four daily i.n. NaDMDC infusions on olfactory bulb (OB) and striatal measures of cell death, reactive oxygen species (ROS), tyrosine hydroxylase, and the levels of dopamine, noradrenaline, serotonin, and their metabolites. A single i.n. administration of NaDMDC did not significantly alter the behavioral measures. Two consecutive days of i.n. NaDMDC administrations led to a transient neurological deficit that spontaneously resolved within a week. However, the i.n. infusions of NaDMDC for 4 consecutive days induced motor and neurological deficits for up to 7 days after the last NaDMDC administration and increased striatal TH immunocontent and dopamine degradation within a day of the last infusion. Pharmacological treatment with the anti-parkinsonian drugs l-DOPA and apomorphine improved the NaDMDC induced locomotor deficits. NaDMDC increased serotonin levels and noradrenaline metabolism in the OB 24 h after the last NaDMDC infusion, ROS levels in the OB 2 h after the last infusion, and striatum 2 and 24 h after the last infusion. These results demonstrate, for the first time, that i.n. NaDMDC administration induces neurobehavioral and neurochemical impairments in mice. This accords with evidence that dimethyldithio-carbamate exposure increases the risk of PD and highlights the possibility that olfactory system could be a major route for NaDMDC entry to central nervous system. PMID- 29605443 TI - Are Electronic and Paper Questionnaires Equivalent to Assess Patients with Overactive Bladder? AB - PURPOSE: Overactive bladder syndrome is defined as urinary urgency, usually accompanied by frequency and nocturia, with or without urgency urinary incontinence in the absence of urinary tract infection or another obvious pathological condition. Electronic questionnaires have been used in a few specialties with the hope of improving treatment outcomes and patient satisfaction. However, they have not been widely used in the urological field. When treating overactive bladder, the main outcome is to improve patient quality of life. The primary objective of this study was to evaluate whether electronic questionnaires would be equally accepted as or preferred to paper questionnaires. The secondary objective was to look at the preference in relation to patient age, education and iPad(r) tablet familiarity. MATERIALS AND METHODS: We prospectively evaluated the iList(r) electronic questionnaire application using a friendly iPad tablet in patients with overactive bladder who presented to the urology clinic at our institution. Each of the 80 patients who were recruited randomly completed the validated OABSS (Overactive Bladder Symptom Score) and the PPBC (Patient Perception of Bladder Condition) questionnaires in paper and electronic format on the tablet. Variables potentially associated with the outcomes of interest included demographic data, questionnaire method preference, patient response rate and iPad familiarity. We used the 2-sided Z-test to determine whether the proportion of patients who considered the tablet to be the same, better or much better than paper was significantly greater than 50%. The 2-sided chi-square test was applied to assess whether the intervention effect significantly differed among the demographic subgroups. RESULTS: A total of 80 patients 21 to 87 years old were enrolled in the study from November 2015 to August 2016. Of the patients 53% were female and 49% were 65 years or younger. The incidence of those who considered the tablet to be the same or better than paper was 82.5% (95% CI 74.2 90.8, p <0.001). The incidence of patients who considered the tablet to be the same or better than paper ranged from 76% to 97% regardless of age, gender and education subgroup as well as in those with any familiarity with the tablet (each p <0.001). Of the 20 patients who were not familiar with the tablet 45% preferred the electronic questionnaire (p = 0.654). CONCLUSIONS: We found that the proportion of patients who considered electronic questionnaires to be equivalent to or better than paper versions was higher than those who preferred paper questionnaires regardless of age, gender or education level. PMID- 29605444 TI - Performance Characteristics of Transrectal Shear Wave Elastography Imaging in the Evaluation of Clinically Localized Prostate Cancer: A Prospective Study. AB - PURPOSE: We tested the diagnostic accuracy of shear wave elastography to detect and phenotypically characterize prostate cancer compared with whole mount radical prostatectomy histopathology. MATERIALS AND METHODS: In this prospective, protocol driven, diagnostic accuracy study 212 consecutive men undergoing laparoscopic radical prostatectomy for clinically localized prostate cancer were recruited. Quantitative stiffness data on the prostate gland were obtained in each patient using an endocavitary transrectal transducer before laparoscopic radical prostatectomy. Those data were compared with a detailed histopathological examination of the radical prostatectomy specimen using 3-dimensional printing mold based technology to ensure an improved image histology orientation. ROC curves were assessed between the groups. RESULTS: Quantitative stiffness data estimated in kPa were significantly higher in malignant compared with benign areas. At a cutoff of 82.6 kPa the sensitivity and specificity of shear wave elastography were 96.8% and 67.8%, respectively (p <0.01). Significant differences were observed for different cancer grades with the Young moduli, including 91.6, 102.3 and 131.8 kPa for low grade (Gleason score 6), intermediate grade (Gleason score 7) and high grade (Gleason score 8 or greater) prostate cancer, respectively (p <0.05). Shear wave elastography also detected capsular breaches with significant prediction of prostate cancer pathological staging. Potential limitations include selection bias and study being single center site. CONCLUSIONS: Quantitative shear wave elastography via the transrectal approach accurately detected cancer foci and revealed significant differences between cancerous and benign tissue. Moreover, this technique can be used to reliably phenotype prostate cancer aggressiveness. PMID- 29605445 TI - The diagnostic value of long non-coding RNA MIR31HG and its role in esophageal squamous cell carcinoma. AB - AIMS: This study aimed to assess plasma lncRNA microRNA-31 hist gene (MIR31HG) as a novel diagnostic and therapeutic biomarker for esophageal squamous cell carcinoma (ESCC) and to investigate its role in ESCC. MAIN METHODS: The expression of MIR31HG, Furin and MMP1 was examined via quantitative real-time polymerase chain reaction. MIR31HG expression between plasma and ESCC tissues was compared using Pearson correlation analysis; furthermore, the association between Furin/MMP1 levels and MIR31HG levels in ESCC tissues was analyzed. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic value of plasma MIR31HG. A WST-1 assay was performed to assess cell proliferation. The migratability and invasiveness of cells was determined via Transwell assays. KEY FINDINGS: MIR31HG was significantly upregulated in ESCC tissues and plasma (P < 0.01). A significant positive association was obtained between plasma and tissue MIR31HG expression in ESCC (r = 0.78, P < 0.01). Furthermore, MIR31HG displayed high diagnostic sensitivity and specificity for predicting ESCC occurance. Furthermore, knockdown of MIR31HG suppressed the capacity for proliferation, migration, and invasion of ESCC cells (P < 0.01). In addition, silencing of MIR31HG inhibited the expression of Furin and MMP1 in EC9706 and EC1 and the level of Furin/MMP1 in ESCC tissues displayed a significant positive correlation with MIR31HG (P < 0.01). SIGNIFICANCE: MIR31HG can be used as a novel potential diagnostic biomarker and a potential therapeutic target for ESCC. PMID- 29605446 TI - Characterizing the glymphatic influx by utilizing intracisternal infusion of fluorescently conjugated cadaverine. AB - AIMS: Accumulating evidence supports that cerebrospinal fluid (CSF) in the subarachnoid space (SAS) could reenter the brain parenchyma via the glymphatic influx. The present study was designed to characterize the detailed pathway of subarachnoid CSF influx by using a novel CSF tracer. MAIN METHODS: Fluorescently conjugated cadaverine (A488-ca), for the first time, was employed to investigate CSF movement in the brain. Following intracisternal infusion of CSF tracers, mice brain was sliced and prepared for fluorescence imaging. Some brain sections were immunostained in order to observe tracer distribution and cellular uptake. KEY FINDINGS: A488-ca moved into the brain parenchyma rapidly, and the influx was time and region dependent. A488-ca entered the mice brain more readily and spread more widely than another commonly used CSF tracer-fluorescently conjugated ovalbumin (OA-45). Furthermore, A488-ca could enter the brain parenchyma either along the paravascular space or across the pial surface. Suppression of glymphatic transport by administration with acetazolamide strikingly reduced the influx of A488-ca. More importantly, relative to OA-45 largely remained in the extracellular space, A488-ca exhibited obvious cellular uptake by astrocytes surrounding the blood vessels and neurons in the cerebral cortex. SIGNIFICANCE: Subarachnoid CSF could flow into the brain parenchyma via the glymphatic influx, in which the transcellular pathway was faithfully traced by intracisternal infusion with fluorescently conjugated cadaverine. These observations extend our comprehension on the glymphatic influx pathway. PMID- 29605448 TI - Neutrophils and redox stress in the pathogenesis of autoimmune disease. AB - Polymorphonuclear leukocytes, or neutrophils, are specialist phagocytic cells of the innate immune system. Their primary role is host defence against micro organisms, which they kill via phagocytosis, followed by release of reactive oxygen species (ROS) and proteolytic enzymes within the phagosome. ROS are generated via the action of the NADPH oxidase (also known as NOX2), in a process termed the 'Respiratory Burst'. This process consumes large amounts of oxygen, which is converted into the highly-reactive superoxide radical O2- and H2O2. Subsequent activation of myeloperoxidase (MPO) generates secondary oxidants and chloroamines that are highly microbiocidal in nature, which together with proteases such as elastase and gelatinase provide a toxic intra-phagosomal environment able to kill a broad range of micro-organisms. However, under certain circumstances such as during an auto-immune response, neutrophils can be triggered to release ROS and proteases extracellularly causing damage to host tissues, modification of host proteins, lipids and DNA and dysregulation of oxidative homeostasis. This review describes the range of ROS species produced by human neutrophils with a focus on the implications of neutrophil redox products in autoimmune inflammation. PMID- 29605447 TI - Redox regulation of cell proliferation: Bioinformatics and redox proteomics approaches to identify redox-sensitive cell cycle regulators. AB - Plant stem cells are the foundation of plant growth and development. The balance of quiescence and division is highly regulated, while ensuring that proliferating cells are protected from the adverse effects of environment fluctuations that may damage the genome. Redox regulation is important in both the activation of proliferation and arrest of the cell cycle upon perception of environmental stress. Within this context, reactive oxygen species serve as 'pro-life' signals with positive roles in the regulation of the cell cycle and survival. However, very little is known about the metabolic mechanisms and redox-sensitive proteins that influence cell cycle progression. We have identified cysteine residues on known cell cycle regulators in Arabidopsis that are potentially accessible, and could play a role in redox regulation, based on secondary structure and solvent accessibility likelihoods for each protein. We propose that redox regulation may function alongside other known posttranslational modifications to control the functions of core cell cycle regulators such as the retinoblastoma protein. Since our current understanding of how redox regulation is involved in cell cycle control is hindered by a lack of knowledge regarding both which residues are important and how modification of those residues alters protein function, we discuss how critical redox modifications can be mapped at the molecular level. PMID- 29605449 TI - A fluorometric assay for lysosomal phospholipase A2 activity using fluorescence labeled truncated oxidized phospholipid. AB - Lysosomal phospholipase A2 (LPLA2) is a key enzyme involved in the homeostasis of cellular phospholipids. Recently, LPLA2 was reported to preferentially degrade some truncated oxidized phospholipids at the sn-1 position. A commercially available, truncated oxidized phospholipid conjugated with a fluorescent dye, 1 palmitoyl-2-glutaroyl-sn-glycero-3-phosphoethanolamine-N-[4-(dipyrrometheneboron difluoride) butanoyl] (PGPE-BODIPY), was used to develop a specific assay for this enzyme. When recombinant mouse LPLA2 was incubated with liposomes consisting of 1,2-O-octadecyl-sn-glycero-3-phosphocholine/PGPE-BODIPY under acidic conditions, PGPE-BODIPY was converted to palmitic acid and a polar BODIPY product. After phase partitioning by chloroform/methanol, the polar BODIPY product was recovered in the aqueous phase and identified as 1-lyso-PGPE-BODIPY. The formation of 1-lyso-PGPE-BODIPY was quantitatively determined by fluorescent measurements. The Km and Vmax values of the recombinant LPLA2 for PGPE-BODIPY were 5.64 MUM and 20.7 MUmol/min/mg protein, respectively. Detectable activity against PGPE-BODIPY was present in LPLA2 deficient mouse sera, but the deacylase activity was completely suppressed by treatment with 4-(2 aminoethyl)benzenesulfonyl fluoride (AEBSF). AEBSF had no effect on LPLA2 activity. The LPLA2 activity of mouse serum pre-treated with AEBSF was specifically and quantitatively determined by this assay method. The PGPE-BODIPY and AEBSF based LPLA2 assay is convenient and can be used to measure LPLA2 activity in a variety of biological specimens. PMID- 29605450 TI - [Limitation of therapeutic effort in patients with bacteremia]. AB - INTRODUCTION: The limitation of therapeutic effort (LTE) depends on medical, ethical and individual factors. We describe the characteristics of patients with bacteremia in which it was decided to limit the therapeutic effort. METHOD: Prospective study of bacteremia in a community hospital in 2011. We collected information regarding patient variable (age, sex, Barthel index, comorbidities, Charlson Index and exogenous factors) as well as regarding the infectious episode (etiology, focus, place of adquisition, clinical expressivity, LTE and hospital mortality). The group in which LTE was performed was compared to the one that was not. RESULTS: We collected 233 episodes of bacteremia in 227 patients. We performed LTE in 19 patients (8.2%). Patients with LTE were older (80.7 vs. 72.6 years, p=.014), had more comorbidity (Charlson index 4.6 vs. 2.1, p<.001 and most frequently were severe dependents (57.9% vs. 18.8%, p<.001). We found no association with sex, place of adquisition or clinical expressivity. The commonest clinical focus in patients with LTE was the urinary (42.1%) and there was a predominance of gram positive bacteria (63.2%). The empirical treatment was started early in 73.7% of cases. All patients except one died. CONCLUSION: LTE is considered in an important number of patients with bacteremia. They usually are older, with more comorbidity and functional dependence, bad functional basal status and important comorbidity. Knowing their differential characteristics allow us to understand this decision. PMID- 29605451 TI - Unplanned emergency department consultations and readmissions within 30 and 90 days of bariatric surgery. AB - INTRODUCTION: Hospital readmission is used as a measure of quality healthcare. The aim of this study was to determine the incidence, causes, and risk factors related to emergency consultations and readmissions within 30 and 90 days in patients undergoing laparoscopic gastric bypass and laparoscopic sleeve gastrectomy. METHODS: Retrospective study of 429 patients operated on from January 2004 to July 2015 from a prospectively maintained database and electronic medical records. Demographic data, type of intervention, postoperative complications, length of hospital stay and records of emergency visits and readmissions were analyzed. RESULTS: Within the first 90 days postoperative, a total of 117 (27%) patients consulted the Emergency Department and 24 (6%) were readmitted. The most common reasons for emergency consultation were noninfectious problems related to the surgical wound (n=40, 34%) and abdominal pain (n=28, 24%), which was also the first cause of readmission (n=9, 37%). Postoperative complications, reintervention, associated surgery in the same operation and depression were risk factors for emergency consultation within the first 90 days of the postoperative period. CONCLUSIONS: Despite the high number of patients who visit the Emergency Department in the first 90 days of the postoperative period, few require readmission and none surgical reoperation. It is important to know the reasons for emergency consultation to establish preventive measures and improve the quality of care. PMID- 29605452 TI - Efficiency of the Bethesda System for Thyroid Cytopathology. AB - INTRODUCTION: Fine-needle aspiration biopsies are a key tool for preoperative assessment of thyroid nodules, and the Bethesda system is the preferred method to report cytological analysis. The purpose of this study is to assess the efficiency of the Bethesda system to identify the malignancy risk of thyroid nodules. METHODS: Patients who underwent thyroid surgery between June 2010 and June 2017 were included. Samples were classified into 6categories according to rates of malignancy associated with each diagnostic category. In order to investigate the correlation between categories, a statistical analysis compared the categories with pathology reports. Diagnostic indicators were calculated as a screening test (categories IV, V, VI as true-positive) and as a method to identify malignancy (V, VI as true-positive). RESULTS: In a series of 522 patients, we found 184 (35.2%) malignant tumours, papillary carcinoma being the most prevalent with 155 cases (84.2%). Malignant rates for diagnostic categories were: I, 0%; II, 1.5%; III, 6.4%; IV, 31%; V, 86.5%; VI, 100%. A robust correlation was identified between categories on statistical analysis. For the "screening test" analysis, sensitivity was 98.9%, specificity 84.4%, positive predictive value 69.6%, negative predictive value 99.5%, and diagnostic accuracy 88.2%. Analysing the accuracy to detect malignancy, values were: sensitivity 98.6%, specificity 97.6%, positive predictive value 93.5%, negative predictive value 99.5%, diagnostic accuracy 97.9%. CONCLUSION: The Bethesda system is a clear and reliable approach to report thyroid cytology and therefore is an effective tool to identify malignancy risk and guide clinical management. PMID- 29605453 TI - Role of altered immune cells in liver diseases: a review. AB - Immune cells play an important role in controlling liver tumorigenesis, viral hepatitis, liver fibrosis and contribute to pathogenesis of liver inflammation and injury. Accumulating evidence suggests the effectiveness of natural killer (NK) cells and Kupffer cells (KCs) against viral hepatitis, hepatocellular damage, liver fibrosis, and carcinogenesis. Activation of natural killer cells provides a novel therapeutic strategy to cure liver related diseases. This review discusses the emerging roles of immune cells in liver disorders and it will provide baseline data to scientists to design better therapies for treatment. PMID- 29605454 TI - How to integrate quantitative information into imaging reports for oncologic patients. AB - Nowadays, the images and information generated in imaging tests, as well as the reports that are issued, are digital and represent a reliable source of data. Reports can be classified according to their content and to the type of information they include into three main types: organized (free text in natural language), predefined (with templates and guidelines elaborated with previously determined natural language like that used in BI-RADS and PI-RADS), or structured (with drop-down menus displaying questions with various possible answers that have been agreed on with the rest of the multidisciplinary team, which use standardized lexicons and are structured in the form of a database with data that can be traced and exploited with statistical tools and data mining). The structured report, compatible with Management of Radiology Report Templates (MRRT), makes it possible to incorporate quantitative information related with the digital analysis of the data from the acquired images to accurately and precisely describe the properties and behavior of tissues by means of radiomics (characteristics and parameters). In conclusion, structured digital information (images, text, measurements, radiomic features, and imaging biomarkers) should be integrated into computerized reports so that they can be indexed in large repositories. Radiologic databanks are fundamental for exploiting health information, phenotyping lesions and diseases, and extracting conclusions in personalized medicine. PMID- 29605456 TI - Motivational Interviewing: A Tool to Open Dialogue With Teens With Type 1 Diabetes Mellitus. PMID- 29605455 TI - Integration of in vitro biorelevant dissolution and in silico PBPK model of carvedilol to predict bioequivalence of oral drug products. AB - Bioequivalence implementation in developing countries where a high proportion of similar drug products are being marketed has found several obstacles, impeding regulatory agencies to move forward with this policy. Biopharmaceutical quality of these products, several of which are massively prescribed, remains unknown. In this context, an in vitro-in silico-in vivo approach is proposed as a mean to screen product performance and target specific formulations for bioequivalence assessment. By coupling in vitro biorelevant dissolution testing in USP-4 Apparatus (flow-through cell) with physiologically-based pharmacokinetic (PBPK) modeling in PK-Sim(r) software (Bayer, Germany), the performance of seven similar products of carvedilol tablets containing 25 mg available in the Uruguayan market were compared with the brand-name drug Dilatrend(r). In silico simulations for Dilatrend(r) were compared with published results of bioequivalence studies performed in fasting conditions allowing model development through a learning and confirming process. Single-dose pharmacokinetic profiles were then simulated for the brand-name drug and two similar drug products selected according to in vitro observations, in a virtual Caucasian population of 1000 subjects (50% male, aged between 18 and 50 years with standard body-weights). Population bioequivalence ratios were estimated revealing that in vitro differences in drug release would have a major impact in carvedilol maximum plasma concentration, leading to a non bioequivalence outcome. Predictions support the need to perform in vivo bioequivalence for these products of extensive use. Application of the in vitro in silico-in vivo approach stands as an interesting alternative to tackle and reduce drug product variability in biopharmaceutical quality. PMID- 29605457 TI - Arthropod toxins and their antinociceptive properties: From venoms to painkillers. AB - The complex process of pain control commonly involves the use of systemic analgesics; however, in many cases, a more potent and effective polypharmacological approach is needed to promote clinically significant improvement. Additionally, considering side effects caused by current painkillers, drug discovery is once more turning to nature as a source of more efficient therapeutic alternatives. In this context, arthropod venoms contain a vast array of bioactive substances that have evolved to selectively bind to specific pharmacological targets involved in the pain signaling pathway, playing an important role as pain activators or modulators, the latter serving as promising analgesic agents. The current review explores how the pain pathway works and surveys neuroactive compounds obtained from arthropods' toxins, which function as pain modulators through their interaction with specific ion channels and membrane receptors, emerging as promising candidates for drug design and development. PMID- 29605458 TI - Monitoring the degradation capability of novel haloalkaliphilic tributyltin chloride (TBTCl) resistant bacteria from butyltin-polluted site. AB - Tributyltin (TBT) is recognized as a major environmental problem at a global scale. Haloalkaliphilic tributyltin (TBT)-degrading bacteria may be a key factor in the remediation of TBT polluted sites. In this work, three haloalkaliphilic bacteria strains were isolated from a TBT-contaminated site in the Mediterranean Sea. After analysis of the 16S rRNA gene sequences the isolates were identified as Sphingobium sp. HS1, Stenotrophomonas chelatiphaga HS2 and Rhizobium borbori HS5. The optimal growth conditions for biodegradation of TBT by the three strains were pH 9 and 7% (w/v) salt concentration. S. chelatiphaga HS2 was the most effective TBT degrader and has the ability to transform most TBT into dibutyltin and monobutyltin (DBT and MBT). A gene was amplified from strain HS2 and identified as TBTB-permease-like, that encodes an ArsB-permease. A reverse transcription polymerase chain reaction analysis in the HS2 strain confirmed that the TBTB-permease-like gene contributes to TBT resistance. The three novel haloalkaliphilic TBT degraders have never been reported previously. PMID- 29605459 TI - Postoperative analgesic efficacy of ultrasound-guided ilioinguinal iliohypogastric nerve block compared with medial transverse abdominis plane block in inguinal hernia repair: A prospective, randomised trial. AB - PURPOSE: Analgesic efficacy of ultrasound-guided transverse abdominis plane block, administered a little more medially, just close to the origin of the transverse abdominis muscle has not yet been investigated in patients undergoing unilateral inguinal hernia repair. We hypothesised that medial transverse abdominis plane block would provide comparable postoperative analgesia to ilioinguinal-iliohypogastric nerve block in inguinal hernia repair patients. METHODS: This prospective, randomised trial was conducted in 50 ASA I and II male patients>=18 years of age. Patients were randomised into two groups to receive either pre-incisional ipsilateral ultrasound-guided ilioinguinal-iliohypogastric nerve block or medial transverse abdominis plane block, with 0.3ml/kg of 0.25% bupivacaine. Our primary objective was postoperative 24-hour analgesic consumption and secondary outcomes included pain scores, time to first request for rescue analgesic and side effects, if any, in the postoperative period. RESULTS: There was no significant difference in the total postoperative analgesic consumption [group I: 66.04mg; group II: 68.33mg (P value 0.908)]. Time to first request for rescue analgesic was delayed, though statistically non-significant (P value 0.326), following medial transverse abdominis plane block, with excellent pain relief seen in 58.3% patients as opposed to 45.8% patients in ilioinguinal iliohypogastric nerve block group. CONCLUSION: Medial transverse abdominis plane block being a novel, simple and easily performed procedure can serve as an useful alternative to ilioinguinal-iliohypogastric nerve block for providing postoperative pain relief in inguinal hernia repair patients. PMID- 29605460 TI - Impairment of learning and memory performances induced by BPA: Evidences from the literature of a MoA mediated through an ED. AB - Many rodent studies and a few non-human primate data report impairments of spatial and non-spatial memory induced by exposure to bisphenol A (BPA), which are associated with neural modifications, particularly in processes involved in synaptic plasticity. BPA-induced alterations involve disruption of the estrogenic pathway as established by reversal of BPA-induced effects with estrogenic receptor antagonist or by interference of BPA with administered estradiol in ovariectomized animals. Sex differences in hormonal impregnation during critical periods of development and their influence on maturation of learning and memory processes may explain the sexual dimorphism observed in BPA-induced effects in some studies. Altogether, these data highly support the plausibility that alteration of learning and memory and synaptic plasticity by BPA is essentially mediated by disturbance of the estrogenic pathways. As memory function in humans involves similar signaling pathways, this mode of action of BPA has the potential to alter human cognitive abilities. PMID- 29605461 TI - Hockey Games and the Incidence of ST-Elevation Myocardial Infarction. AB - BACKGROUND: The association between diagnosed acute ST-elevation myocardial infarction (STEMI) and hockey games in the Canadian population is unknown. METHODS: We retrospectively analyzed the association between hockey games of the National Hockey League Montreal Canadiens and daily hospital admissions for acute STEMI at the Montreal Heart Institute, Canada. RESULTS: Between June 2010 and December 2014, a total of 2199 patients (25.9% women; mean age, 62.6 +/- 12.4 years) were admitted for acute STEMI. An increase in STEMI admissions was observed the day after a hockey game of the Montreal Canadiens in the overall population (from 1.3 +/- 1.2 to 1.5 +/- 1.3), however, this difference was not significant (P = 0.1). The number of STEMI admissions increased significantly from 0.9 +/- 1.0 to 1.2 +/- 1.0 per day in men (P = 0.04), but not in women (P = 0.7). The association between ice hockey matches and STEMI admission rates was strongest after a victory of the Montreal Canadiens. Accordingly, an increased risk for the occurrence of STEMI was observed in the overall population (hazard ratio [HR], 1.15; 95% confidence interval [CI], 1.0-1.3; P = 0.037) when the Montreal Canadiens won a match. This association was present in men (HR, 1.2; 95% CI, 1.03-1.4; P = 0.02) but not in women (P = 0.87), with a most pronounced effect seen in younger men (younger than 55 years; HR, 1.4; 95% CI, 1.1-1.8; P = 0.009). CONCLUSIONS: Although a weak association between hockey games and hospital admissions for STEMI was found in our overall population, the event of a hockey game significantly increased the risk for STEMI in younger men. Preventive measures targeting behavioural changes could positively affect this risk. PMID- 29605462 TI - High expression of long noncoding RNA NORAD indicates a poor prognosis and promotes clinical progression and metastasis in bladder cancer. AB - PURPOSE: To explore the function of NORAD in bladder cancer (BC), and to verify whether NORAD could be used as a biomarker to determine preoperative presence of progression and lymph node metastasis. To our knowledge, it is the first study investigating NORAD and its implications in BC. METHODS: BC specimens of 90 patients underwent bladder cystectomy or transurethral resection between January 2012 to December 2016 were tested by fluorescence in situ hybridization. The association between NORAD expression and clinicopathological features and prognosis of the patients was analyzed using Kaplan-Meier survival analysis and Cox regression analysis. Quantitative real-time polymerase chain reaction was performed in 4 BC cell lines and 10 fresh tumor sample together with adjacent tissues. MTT, colony formation assay, and Annexin-V apoptosis detection were performed after knockdown of NORAD using shRNA in TSSCUP cells. Western blot was performed to related proteins extracted from these cells. RESULTS: Fluorescence in situ hybridization indicated that high NORAD expression was associated with more advanced histological grade and clinical stage for patients with BC. Higher NORAD expression resulted in lower overall survival, and was an independent prognostic indicator. Real-time polymerase chain reaction showed that the expression of NORAD in BC tissues was higher than those measured in adjacent normal tissues. MTT and colony formation assay demonstrated that knockdown of NORAD results in lower proliferation in TSSCUP cells, whereas PUM2 expression was upregulated and E2F3 downregulated. CONCLUSIONS: High NORAD expression could serve as an independent prognostic factor for overall survival of patients with transitional BC. NORAD could be considered as a promising candidate for novel biomarker and therapeutic target for human BC. PMID- 29605463 TI - Implementation of thyroid function tests algorithms by clinical laboratories: A four-year experience of good clinical and diagnostic practice in a tertiary hospital in Greece. AB - INTRODUCTION: Thyroid Function Tests (TFTs) are among the most commontly ordered tests. Significant overuse of TFTs can occur when instead of using a single TSH test to screen for thyroid disease a full panel (TSH plus FT4 and FT3) is ordered. The aim of our study was to evaluate the effectiveness of the application of a scientifically-established laboratory-controlled algorithm for TFTs to physician's orders for inpatients and to address potential pitfalls of such an approach. MATERIALS AND METHODS: We collected and analyzed Laboratory Information System data of the TFTs performed between April 2009 and March 2016 in a 739-bed tertiary teaching hospital. Between April 2013 and March 2016, we applied a laboratory controlled algorithm for inpatient TFT assays after TSH and did not perform further tests, unless a justified bypass was requested by the treating physician. RESULTS: Algorithm application led to significant reductions of TFTs executed per TSH ordered. Compared to the four years preceding the intervention, executed FT4/TSH tests decreased from 93 to 18%, FT3/TSH from 92 to 18%, anti-TG/TSH from 18 to 4% and anti-TPO/TSH from 11 to 3%. Simultaneously, FT4, FT3, anti-TG, and anti-TPO tests ordered in outpatients also displayed a significant gradual decrease. CONCLUSIONS: Hospital-based laboratories can safely apply a generally accepted TFTs algorithm on physician's orders without any compromise in diagnostic/therapeutic accuracy, thus achieving significant direct cost-reduction and increased physician awareness on current TFT ordering practices. Such an approach, combined with collaboration with ordering physicians, can safeguard patients from the consequences of low-value care practices. PMID- 29605464 TI - Childhood emotional maltreatment, anxiety, attachment, and mindfulness: Associations with facial emotion recognition. AB - The current study investigated factors thought to contribute to facial emotion processing. Female university students (N = 126) completed self-report measures of childhood emotional maltreatment, anxiety symptoms, attachment anxiety and avoidance, and trait mindfulness before completing a facial emotion recognition task, where they viewed sequences of faces that incorporated progressively more emotional content until they were able to correctly identify the emotion. They completed the task under low and high cognitive load conditions to distinguish between relatively effortful versus automatic processing abilities. Regression analyses revealed that under low cognitive load, attachment avoidance and mindfulness predicted quicker identification of fear (i.e., with less perceptual information), whereas anxiety predicted slower identification of fear (i.e., with more perceptual information). In the high cognitive load condition, emotional maltreatment and mindfulness predicted quicker identification of fear, and anxiety and mindfulness predicted faster identification of emotions overall. Although current findings are correlational, most of these effects were specific to fearful faces, suggesting that experiences of childhood emotional maltreatment and associated socio-emotional sequelae are related to heightened processing of threat-related information. PMID- 29605466 TI - Molecular characterization of Cryptosporidium spp. in poultry from Brazil. AB - Cryptosporidiosis is an important zoonotic disease caused by Cryptosporidium. Infections in birds are mainly caused by C. meleagridis, C. baileyi, and C. galli. C. meleagridis is the third most common cause of cryptosporidiosis in humans and the only Cryptosporidium species known to infect both birds and mammals. One hundred and fifty-five fecal specimens from different poultry species (chicken, turkey, ostrich, helmeted guinea fowl, quail, pheasant, and emu) were collected at local markets in the state of Minas Gerais, Brazil. Twenty three (14.8%) birds (20 chickens, 2 quails, and 1 turkey) were found Cryptosporidium-positive. This constitutes the first report of Cryptosporidium in turkeys from Brazil. Nucleotide sequence analysis identified C. meleagridis in chickens (15), a turkey (1), and a quail (1), C. baileyi in chickens (4) and a quail (1), and a mixed infection C. meleagridis/C. baileyi in a chicken (1). This is the first report of C. meleagridis in turkeys and quails from Brazil. Using the gp60 gene, three subtype families were identified, IIIa, IIIb and IIIg. Within subtype family IIIg, four subtypes were identified in chickens, two novel (IIIgA25G3R1 and IIIgA21G3R1) and two previously reported (IIIgA22G3R1 and IIIgA24G2R1). Within subtype family IIIb two subtypes were identified, IIIbA24G1R1 in a chicken and IIIbA23G1R1 in a quail. A novel subtype in the family IIIa was identified (IIIaA22G3R1) in a turkey. The finding of C. meleagridis subtypes previously identified in humans (IIIgA22G3R1, IIIbA24G1R1 and IIIbA23G1R1) indicates that they can be potentially zoonotic. Further subtyping studies that clarify genetic diversity of C. meleagridis are required to better understand host specificity, source of infection, and transmission dynamics of C. meleagridis. PMID- 29605465 TI - Microwave-assisted co-pyrolysis of brown coal and corn stover for oil production. AB - The controversial synergistic effect between brown coal and biomass during co pyrolysis deserves further investigation. This study detailed the oil production from microwave-assisted co-pyrolysis of brown coal (BC) and corn stover (CS) at different CS/BC ratios (0, 0.33, 0.50, 0.67, and 1) and pyrolysis temperatures (500, 550, and 600 degrees C). The results showed that a higher CS/BC ratio resulted in higher oil yield, and a higher pyrolysis temperature increased oil yield for brown coal and coal/corn mixtures. Corn stover and brown coal showed different pyrolysis characteristics, and positive synergistic effect on oil yield was observed only at CS/BC ratio of 0.33 and pyrolysis temperature of 600 degrees C. Oils from brown coal mainly included hydrocarbons and phenols whereas oils from corn stover and coal/corn mixtures were dominated by ketones, phenols, and aldehydes. Positive synergistic effects were observed for ketones, aldehydes, acids, and esters whereas negative synergistic effects for hydrocarbons, phenols and alcohols. PMID- 29605467 TI - An insight of in vitro transport of PEGylated non-ionic surfactant vesicles (NSVs) across the intestinal polarized enterocyte monolayers. AB - PEGylated non-ionic surfactant-based vesicles (NSVs) are promising drug delivery systems for the local, oral and systemic administrations of therapeutics. The aim of this study was to test the cellular biocompatibility and transport of Nile Red loaded NSVs (NR-NSVs) across the Caco-2-cell monolayers, which represent an in vitro model of human intestinal epithelium. The NR-NSVs assumed a spherical shape with a mean size of 140 nm, and a narrow size distribution. The NR-NSVs did not modify Caco-2 cell viability, which remained unaltered in vitro up to a concentration of 1 mM. The transport studies demonstrated that the NR-NSVs moved across the Caco-2 monolayers without affecting the transepithelial electrical resistance. These results were supported by flow cytometry analysis, which demonstrated that NR-NSVs were internalized inside the Caco-2 cells. Nanoparticle tracking and Transmission Electron Microscopy (TEM) analysis showed the presence of NR-NSVs in the basolateral side of the Caco-2 monolayers. TEM images also showed that NSVs were transported intact across the Caco-2 monolayers, thus demonstrating a predominant transcytosis mechanism of transport through endocytosis. The NSVs did not affect the integrity of the membrane barrier in vitro, and can potentially be used in clinics to increase the oral bioavailability and delivery of therapeutics. PMID- 29605468 TI - Biopolymer nanogels improve antibacterial activity and safety profile of a novel lysine-based alpha-peptide/beta-peptoid peptidomimetic. AB - Infections caused by Pseudomonas aeruginosa are associated with high morbidity and mortality, especially in immunocompromised patients. These bacteria frequently grow within a biofilm matrix, rendering therapy with conventional antibiotics inefficient; a fact that emphasizes the need for new treatment strategies. Antimicrobial peptidomimetics constitute potential alternatives to traditional antimicrobial agents. However, their application remains limited due to the lack of efficient delivery to their target site in vivo and the risk of high systemic toxicity. Nanogels composed of cross-linked networks of amphiphilic polymers with a therapeutic drug molecule embedded constitute attractive drug delivery systems, as they have been shown to display unique properties such as biocompatibility and biodegrability, as well as confer improved drug stability and reduced drug-mediated cytotoxicity. Here, we report on the first formulation of biopolymer nanogels incorporating a potent antibacterial peptidomimetic. A lysine-based alpha-peptide/beta-peptoid hybrid with potent activity against P. aeruginosa was designed and formulated into a nanogel together with octenyl succinic anhydride-modified hyaluronic acid in order to improve its cell selectivity. Twelve nanogel formulations were prepared by using a design of experiments setup in order to identify the parameters yielding the highest drug loading and the smallest particle size. Encapsulation of the peptidomimetic into nanogels significantly decreased the cytotoxicity of the peptidomimetic to eukaryotes. The most promising formulation with high encapsulation efficiency (88%) of the peptidomimetic demonstrated a three-fold reduction in cytotoxicity towards hepatocytes along with improved bacterial killing kinetics. PMID- 29605469 TI - Type 1 and type 2 diabetes mellitus and incidence of seven cardiovascular diseases. AB - BACKGROUND: The association between type 1 diabetes mellitus (T1DM) and specific cardiovascular diseases (CVD) is uncertain. Furthermore, data on type 2 diabetes mellitus (T2DM) in relation to risk of aortic valve stenosis, atrial fibrillation, abdominal aortic aneurysm, and intracerebral hemorrhage are scarce and inconclusive. We examined the associations of T1DM and T2DM with incidence of seven CVD outcomes. METHODS: This study comprised 71,483 Swedish adults from two population-based prospective cohorts. T1DM and T2DM diagnosis and incident CVD cases were ascertained through linkage with the population-based registers. RESULTS: T1DM was associated with myocardial infarction (hazard ratio [HR] 3.26; 95% confidence interval [CI] 2.47-4.30), heart failure (HR 2.68; 95% CI 1.76 4.09), and ischemic stroke (HR 2.61; 95% CI 1.80-3.79). Increased risk of myocardial infarction, ischemic stroke, and heart failure was also observed in T2DM patients and the magnitude of the associations increased with longer T2DM duration. T2DM was also associated with an increased risk of aortic valve stenosis (HR 1.34; 95% CI 1.05-1.71) and with lower risk of abdominal aortic aneurysm (HR 0.57; 95% CI 0.40-0.82) and intracerebral hemorrhage (HR 0.51; 95% CI 0.30-0.88). Only long-term T2DM (>=20 years) was associated with an increased risk of atrial fibrillation (HR 1.44; 95% CI 1.02-2.04). CONCLUSION: T1DM and T2DM are associated with increased risk of major CVD outcomes. TRIAL REGISTRATION: The Cohort of Swedish Men and the Swedish Mammography Cohort are registered at clinicaltrials.gov as NCT01127711 and NCT01127698, respectively. PMID- 29605470 TI - Outcomes associated with mammalian target of rapamycin (mTOR) inhibitors in heart transplant recipients: A meta-analysis. AB - BACKGROUND: Data evaluating mTOR inhibitor use heart transplant (HT) patients comes from relatively small studies and controversy exists regarding their specific role. We performed a meta-analysis of randomized trials to evaluate the efficacy and safety of mTOR inhibitors in HT patients. METHODS: We performed a systematic literature search of Medline and Embase through July 2017 identifying studies evaluating mTOR inhibitors in HT patients reporting effects on coronary allograft vasculopathy (CAV), renal function, acute cellular rejection (ACR), cytomegalovirus (CMV) infection, and discontinuation due to adverse drug events (ADE). Data were pooled using a random-effects model producing a mean difference (MD; for continuous data) or odds ratio (OR; for dichotomous data) and 95% confidence interval (CI). RESULTS: 14 trials reported at least one outcome of interest. Change in mean maximal intimal thickness was significantly reduced with mTOR (-0.04 [-0.07 to -0.02]) compared to calcineurin inhibitor/mycophenolate mofetil (CNI/MMF). Rates of CMV infection were also significantly reduced (0.26; [0.2 to 0.32]) with mTOR regimens compared to CNI/MMF therapy. ACR was more frequent with CNI-sparing regimens 6.46 [1.55 to 26.95]). eGFR was significantly improved with CNI-sparing therapies (mean difference 12.09 mL/min [2.43 to 21.74]), but was similar between CNI/mTOR versus CNI/MMF regimens (p > 0.05). Rates of discontinuation due to ADE were higher in mTOR-containing regimens (OR 2.15 [1.28 to 3.60], p = 0.01), while mortality rates were similar (OR 0.91 [0.61 to 1.37], p = 0.62). CONCLUSIONS: mTOR-containing regimens can attenuate CAV and CMV risk in HT recipients. A mTOR/MMF combination preserves renal function but increases the risk of ACR. PMID- 29605471 TI - Thermal heterogeneity of carotid arteries as a novel biomarker in patients with diabetes mellitus assessed for coronary artery disease. AB - BACKGROUND: Vulnerable plaque plays crucial role in prognosis of diabetes mellitus (DM). Microwave radiometry (MWR) allows measurement of the temperature of tissues, thus indirectly reflecting inflammation, a characteristic of atherosclerotic plaque stability. Aim of the study was to evaluate the relation of carotid artery inflammation with glycemic control and presence of coronary artery disease (CAD). METHODS: We included 112 patients (65 +/- 9 years, 30 +/- 5 kg/m2, 74 DM and 38 non-DM, with a 2:1 ratio) that were referred for scheduled coronary angiography (CA) for evaluation of their clinical condition. We measured thermal heterogeneity, expressed as temperature difference (DeltaT) along each carotid artery, with MWR and maximum temperature difference between the 2 carotid arteries (DeltaTaumax). RESULTS: Patients with DM presented higher DeltaTmax comparing to patients without DM (0.91 +/- 0.29 vs 0.71 +/- 0.25 degrees C, p < 0.001). Glycaemia over time was associated with thermal heterogeneity of carotids (HbA1c: <6.5: 0.78 +/- 0.23, HbA1c: 6.5-7: 0.87 +/- 0.24, HbA1c: 7-8: 0.99 +/- 0.30, HbA1c: >8: 1.15 +/- 0.35 degrees C, p = 0.003). Patients with CAD presented higher DeltaTaumax comparing to patients with normal CA (0.93 +/- 0.24 vs 0.68 +/- 0.25 degrees C, p < 0.001) and patients that underwent coronary revascularization presented higher DeltaTmax (0.95 +/- 0.25 vs 0.76 +/- 0.26 degrees C, p < 0.001). A DeltaTmax >= 0.9 (received by ROC analysis) was an independent predictor for revascularization in DM patients (odds ratio 3.29, 95% CI: 1.07-10.16; p = 0.039) when adjusted for sex, age and the established risk factors of CAD. CONCLUSION: Local inflammatory activation of carotid arteries is more pronounced in patients with DM and is associated with the glycemic control. Carotids' thermal heterogeneity is associated with need for revascularization supporting its predictive value in DM patients assessed for CAD. PMID- 29605472 TI - Interactive effects of salinity and temperature acclimation on gill morphology and gene expression in threespine stickleback. AB - Colonization of freshwater habitats from marine environments exposes organisms to novel combinations of temperature and salinity, but little is known about physiological responses to the interactive effects of these stressors. Here, we examined the effects of temperature (14 versus 4 degrees C) and salinity (11 versus 0.3 ppt) on gill gene expression in marine, anadromous, and freshwater populations of threespine stickleback (Gasterosteus aculeatus). Expression of the epithelial calcium channel was not affected by temperature or salinity, but had significantly higher expression in the freshwater ecotype. The combination of low temperature and low salinity had non-additive effects on the expression of the Na+/H+ exchanger. Fish exposed to the combination of low temperature and low salinity had expression levels similar to fish exposed to either factor in isolation. Expression of Na+,K+-ATPase alpha-subunit was greater in fish exposed to low temperature and low salinity than in fish exposed to the factors separately, and this effect was the most pronounced in the marine ecotype. We also examined the interactive effects of salinity and temperature on gill morphology in the marine ecotype, and observed non-additive effects. Low temperature increased the size of the interlamellar cell mass in fish held at 11 ppt, but not at 0.3 ppt, and the effect of low salinity was in the opposite direction in fish at high and low temperatures. These data demonstrate interactive effects of temperature and salinity and highlight that overwintering in cold freshwater was likely a physiological challenge for marine stickleback as they colonized freshwater following the last glaciation. PMID- 29605473 TI - Real-Time Three-Dimensional Echocardiography of the Left Ventricle-Pediatric Percentiles and Head-to-Head Comparison of Different Contour-Finding Algorithms: A Multicenter Study. AB - BACKGROUND: Real-time three-dimensional echocardiography (RT3DE) is a promising method for accurate assessment of left ventricular (LV) volumes and function, however, pediatric reference values are scarce. The aim of the study was to establish pediatric percentiles in a large population and to compare the inherent influence of different evaluation software on the resulting measurements. METHODS: In a multicenter prospective-design study, 497 healthy children (ages 1 day to 219 months) underwent RT3DE imaging of the LV (ie33, Philips, Andover, MA). Volume analysis was performed using QLab 9.0 (Philips) and TomTec 4DLV2.7 (vendor-independent; testing high (TomTec75) and low (TomTec30) contour-finding activity). Reference percentiles were computed using Cole's LMS method. In 22 subjects, cardiovascular magnetic resonance imaging (CMR) was used as the reference. RESULTS: A total of 370/497 (74.4%) of the subjects provided adequate data sets. LV volumes had a significant association with age, body size, and gender; therefore, sex-specific percentiles were indexed to body surface area. Intra- and interobserver variability for both workstations was good (relative bias +/- SD for end-diastolic volume [EDV] in %: intraobserver: QLab = -0.8 +/- 2.4; TomTec30 = -0.7 +/- 7.2; TomTec75 = -1.9 +/- 6.7; interobserver: QLab = 2.4 +/- 7.5; TomTec30 = 1.2 +/- 5.1; TomTec75 = 1.3 +/- 4.5). Intervendor agreement between QLab and TomTec30 showed larger bias and wider limits of agreement (bias: QLab vs TomTec30: end-systolic volume [ESV] = 0.8% +/- 23.6%; EDV = -2.2% +/- 17.0%) with notable individual differences in small children. QLab and TomTec underestimated CMR values, with the highest agreement between CMR and QLab. CONCLUSIONS: RT3DE allows reproducible noninvasive assessment of LV volumes and function. However, intertechnique variability is relevant. Therefore, our software-specific percentiles, based on a large pediatric population, serve as a reference for both commonly used quantification programs. PMID- 29605474 TI - Hemodynamic Mechanisms of Exercise-Induced Pulmonary Hypertension in Patients with Lymphangioleiomyomatosis: The Role of Exercise Stress Echocardiography. AB - BACKGROUND: The pathogenesis of pulmonary hypertension (PH) in lymphangioleiomyomatosis (LAM) has not yet been completely clarified. The aim of this study was to conduct a noninvasive evaluation of the main hemodynamic mechanisms of exercise-induced PH in patients with LAM, assessed using exercise stress echocardiography. METHODS: Fifteen patients with LAM (mean age, 47 +/- 13 years; all women) without resting PH were enrolled in a prospective single-center study and compared with 15 healthy female control subjects (mean age, 45.2 +/- 8 years; P = .65). A complete echocardiographic study with Doppler tissue imaging was performed at baseline and during semisupine symptom-limited exercise testing to evaluate (1) left ventricular systolic and diastolic function, (2) right ventricular contractile function, (3) estimated pulmonary capillary wedge pressure, (4) estimated systolic and mean pulmonary artery pressure, and (5) estimated pulmonary vascular resistance. RESULTS: Compared with healthy control subjects, patients with LAM during exercise showed echocardiographic signs of right ventricular overload and right ventricular systolic dysfunction and significant increases in mean pulmonary artery pressure (14.4 +/- 6.5 vs 4.2 +/- 3.1 mm Hg, P < .0001), pulmonary vascular resistance (+68.3 +/- 42.1 vs -0.1 +/- 18.3 dyne-sec/cm5, P < .0001), and, unexpectedly, pulmonary capillary wedge pressure (+8.3 +/- 5.3 vs -0.5 +/- 1.3 mm Hg, P < .0001). CONCLUSIONS: Exercise induced PH in patients with LAM could be related not only to hypoxic pulmonary vascular vasoconstriction during exercise (precapillary PH) but also to a significant exercise-induced increase in estimated pulmonary capillary wedge pressure, probably secondary to diastolic dysfunction (postcapillary PH). PMID- 29605475 TI - Evaluation of reported contents in prescription and over-the-counter prenatal multivitamins. AB - OBJECTIVES: To evaluate the reported amount of 14 vitamins and 10 minerals in over-the-counter (OTC) and prescription (Rx) prenatal multivitamins and minerals (PMVMs) and compare them with the Health and Medicine Division (HMD) of the National Academies recommended dietary allowances (RDAs) and tolerable upper intake levels for intake. DESIGN: Observational convenience sample of supplemental facts labels on OTC and Rx PMVMs identified and evaluated from online retailers, grocery stores, and pharmacies. SETTING AND PARTICIPANTS: Not applicable. OUTCOME MEASURES: Reported vitamin and mineral amounts in PMVMs were compared with HMD RDAs to determine whether PMVMs could correct RDA deficiencies in the average pregnant woman's diet. Reported vitamin and mineral amounts were compared in OTC and Rx PMVMs and to HMD upper intake levels. RESULTS: One hundred sixty-three OTC and 88 Rx PMVMs were evaluated. The average pregnant woman in the United States is deficient in many vitamins and minerals from food intake alone. Over 80% of OTC and Rx PMVMs would correct the RDA deficit for vitamin B6, folic acid, vitamin C, vitamin E, and iron. Over 90% of OTC products would correct the deficit for vitamin A and zinc; however, 47% and 74% of Rx products would correct for those deficits, respectively. Approximately 73% of OTC and 60% of Rx PMVMs corrected calcium deficit, and 33% of OTC and 24% of Rx PMVMs corrected vitamin D deficit. A minority of PMVMs corrected deficits for magnesium and choline. OTC products have significantly more of each vitamin compared with Rx, with several exceptions including: iron, folic acid, copper, and vitamin B6. CONCLUSION: Most pregnant women take PMVMs. If pregnant women are not consuming enough essential micronutrients from diet, it is possible that PMVMs will provide adequate amounts; however, this depends on the specific vitamin or mineral. There is notable variation between Rx and OTC PMVM options. PMID- 29605476 TI - ESTRO ACROP guidelines for target volume definition in the treatment of locally advanced non-small cell lung cancer. AB - Radiotherapy (RT) plays a major role in the curative treatment of locally advanced non-small cell lung cancer (NSCLC). Therefore, the ACROP committee was asked by the ESTRO to provide recommendations on target volume delineation for standard clinical scenarios in definitive (chemo)radiotherapy (RT) and adjuvant RT for locally advanced NSCLC. The guidelines given here are a result of the evaluation of a structured questionnaire followed by a consensus discussion, voting and writing procedure within the committee. Hence, we provide advice for methods and time-points of diagnostics and imaging before the start of treatment planning and for the mandatory and optional imaging to be used for planning itself. Concerning target volumes, recommendations are given for GTV delineation of primary tumour and lymph nodes followed by issues related to the delineation of CTVs for definitive and adjuvant radiotherapy. In the context of PTV delineation, recommendations about the management of geometric uncertainties and target motion are given. We further provide our opinions on normal tissue delineation and organisational and responsibility questions in the process of target volume delineation. This guideline intends to contribute to the standardisation and optimisation of the process of RT treatment planning for clinical practice and prospective studies. PMID- 29605477 TI - Susceptibility-weighted magnetic resonance imaging of cerebrovascular sequelae after radiotherapy for pediatric brain tumors. AB - BACKGROUND AND PURPOSE: Due to sensitive neuroimaging techniques, cerebrovascular complications such as cerebral microbleeds (CMB) and cerebral cavernous malformations (CCM) are increasingly recognized as considerable late effects after treatment for pediatric brain tumor. The aim of this study was to analyze CMB in a cohort of patients after cranial irradiation therapy for medulloblastoma or other pediatric brain tumors using susceptibility-weighted magnetic resonance imaging (SWI). MATERIALS AND METHODS: Forty former pediatric brain tumor patients were enrolled in this prospective cross-sectional study and examined by cranial MRI including SWI sequences. Cerebral microbleeds, clinical symptoms and disability were evaluated. RESULTS: Thirty-six (90%) of the examined individuals (mean follow-up age 22.2 y; mean follow-up time 13.5 y) were affected by CMB. Longer follow-up time and higher craniospinal irradiation doses correlated with higher total lesion count (p < 0.01). Thirteen patients (32.5%) presented with clinical symptoms. Individuals with CMB were more severely disabled than patients without CMB (p < 0.05). CONCLUSIONS: Cerebrovascular sequelae occur frequently after treatment for pediatric brain tumor. In this study, a remarkable part of pediatric brain tumor patients presents with CMB. As a sign of vascular damage, they can cause clinical symptoms and may correspond to neurocognitive decline. Further studies are needed to standardize MRI protocols and to improve quality of long-term follow-up. PMID- 29605478 TI - Practice patterns of image guided particle therapy in Europe: A 2016 survey of the European Particle Therapy Network (EPTN). AB - BACKGROUND AND PURPOSE: Image guidance is critical in achieving accurate and precise radiation delivery in particle therapy, even more than in photon therapy. However, equipment, quality assurance procedures and clinical workflows for image guided particle therapy (IGPT) may vary substantially between centres due to a lack of standardization. A survey was conducted to evaluate the current practice of IGPT in European particle therapy centres. MATERIAL AND METHODS: In 2016, a questionnaire was distributed among 19 particle therapy centres in 12 European countries. The questionnaire consisted of 30 open and 37 closed questions related to image guidance in the general clinical workflow, for moving targets, current research activities and future perspectives of IGPT. RESULTS: All centres completed the questionnaire. The IGPT methods used by the 10 treating centres varied substantially. The 9 non-treating centres were in the process to introduce IGPT. Most centres have developed their own IGPT strategies, being tightly connected to their specific technical implementation and dose delivery methods. CONCLUSIONS: Insight into the current clinical practice of IGPT in European particle therapy centres was obtained. A variety in IGPT practices and procedures was confirmed, which underlines the need for harmonisation of practice parameters and consensus guidelines. PMID- 29605479 TI - Is accurate contouring of salivary and swallowing structures necessary to spare them in head and neck VMAT plans? AB - BACKGROUND AND PURPOSE: Current standards for organ-at-risk (OAR) contouring encourage anatomical accuracy which can be resource intensive. Certain OARs may be suitable for alternative delineation strategies. We investigated whether simplified salivary and swallowing structure contouring can still lead to good OAR sparing in automated head and neck cancer (HNC) plans. MATERIALS AND METHODS: For 15 HNC patients, knowledge-based plans (KBPs) using RapidPlanTM were created using: (1) standard clinical contours for all OARs (benchmark-plans), (2) automated knowledge-based contours for the salivary glands, with standard contours for the remaining OARs (SS-plans) and (3) simplified contours (SC-plans) consisting of quick-to-draw tubular structures to account for the oral cavity, salivary glands and swallowing muscles. Individual clinical OAR contours in a RapidPlanTM model were combined to create composite salivary/swallowing structures. These were matched to tube-contours to create SC-plans. All plans were compared based on dose to anatomically accurate clinical OAR contours. RESULTS: Salivary gland delineation in SS-plans required on average 2 min, compared with 7 min for manual delineation of all tubular-contours. Automated atlas-based contours overlapped with, on average, 71% of clinical salivary gland contours while tube-contours overlapped with 95%/75%/93% of salivary gland/oral cavity/swallowing structure contours. On average, SC-plans were comparable to benchmark-plans and SS-plans, with average differences in composite salivary and swallowing structure dose <=2 Gy and <1 Gy respectively. CONCLUSIONS: Simplified contours could be created quickly and resulted in clinically acceptable HNC VMAT plans. They can be combined with automated planning to facilitate the implementation of advanced radiotherapy, even when resources are limited. PMID- 29605480 TI - Emergency department boarding and adverse hospitalization outcomes among patients admitted to a general medical service. AB - OBJECTIVE: Overcrowding in the emergency department (ED) has been associated with patient harm, yet little is known about the association between ED boarding and adverse hospitalization outcomes. We sought to examine the association between ED boarding and three common adverse hospitalization outcomes: rapid response team activation (RRT), escalation in care, and mortality. METHOD: We conducted an observational analysis of consecutive patient encounters admitted from the ED to the general medical service between February 2013 and June 2015. This study was conducted in an urban, academic hospital with an annual adult ED census over 90,000. We defined boarding as patients with greater than 4h from ED bed order to ED departure to hospital ward. The primary outcome was a composite of adverse outcomes in the first 24h of admission, including RRT activation, care escalation to intensive care, or in-hospital mortality. RESULTS: A total of 31,426 patient encounters were included of which 3978 (12.7%) boarded in the ED for 4h or more. Adverse outcomes occurred in 1.92% of all encounters. Comparing boarded vs. non boarded patients, 41 (1.03%) vs. 244 (0.90%) patients experienced a RRT activation, 53 (1.33%) vs. 387 (1.42%) experienced a care escalation, and 1 (0.03%) vs.12 (0.04%) experienced unanticipated in-hospital death, within 24h of ED admission. In unadjusted analysis, there was no difference in the composite outcome between boarding and non-boarding patients (1.91% vs. 1.91%, p=0.994). Regression analysis adjusted for patient demographics, acuity, and comorbidities also showed no association between boarding and the primary outcome. A sensitivity analysis showed an association between ED boarding and the composite outcome inclusive of the entire inpatient hospital stay (5.8% vs. 4.7%, p=0.003). CONCLUSION: Within the first 24h of hospital admission to a general medicine service, adverse hospitalization outcomes are rare and not associated with ED boarding. PMID- 29605481 TI - Improving emergency department to hospital medicine transfer of care through electronic pass-off. PMID- 29605482 TI - Lithiasis-induced acute kidney injury: Is ultrasonography enough? PMID- 29605483 TI - Severe opioid withdrawal precipitated by Vivitrol(r). AB - The risk of severe precipitated opioid withdrawal (POW) is amplified when precipitated by a long-acting opioid antagonist. IM extended release naltrexone (XRNTX;Vivitrol(r)) is an FDA approved therapy to prevent relapse of opioid and alcohol abuse. Two cases of precipitated opioid withdrawal from XRNTX are presented that illustrate different patient reactions to POW. A 56-year-old woman developed a hypertensive emergency and required continuous intravenous vasodilator, clonidine, and intensive care monitoring after re-initiation of XRNTX following opioid relapse. A 25-year-old man developed agitation and altered mental status after receipt of XRNTX at the conclusion of a twelve-day detoxification program during which he continued surreptitious use of heroin. The patient received benzodiazepines and haloperidol without adequate affect, and required intubation with propofol, lorazepam, and dexmedetomidine infusions. Management of POW from XRNTX is a challenge to emergency providers and protocols to guide management do not exist. Recommended therapies include intravenous fluids, anti-emetics, clonidine, or benzodiazepines as well as therapy tailored to the organ system affected. To minimize risk of POW it is important for providers instituting XRNTX to adhere to the manufacturers warnings and clinic protocols including a naloxone challenge and ensure an adequate opioid free period prior to administration of XRNTX. PMID- 29605484 TI - AMN082-a metabotropic glutamate receptor type 7 allosteric agonist in the NAc facilitates extinction and inhibits the reinstatement of morphine-induced conditioned place preference in male rats. AB - Nucleus accumbens (NAc) plays a primary role in opioid reward. The actions of glutamate (which is the most extensive excitatory neurotransmitter in the mammalian central nervous system) are mediated through the activation of the ionotropic and metabotropic glutamate receptors (mGluRs). Previous studies have shown the extensive distributions of the different types of mGluRs, including mGluR7, in regions that are involved in opioid reward, such as NAc. In this study, CPP was used to investigate the effect of mGluR7 on the extinction period, and the reinstatement of morphine. The animals received bilaterally microinjections of AMN082, a selective mGluR7 allosteric agonist, into the NAc. In Experiment 1, the rats received AMN082 (1 and 5 MUg/0.5 MUl) during the extinction period. In Experiment 2, the CPP morphine-extinguished rats received AMN082 (1, 3 and 5 MUg/0.5 MUl) five minutes prior to the administration of an ineffective dosage of morphine (1 mg/kg) in order to reinstate the extinguished morphine. The results of the recorded conditioning scores in this study showed that the intra-accumbal administration of AMN08 reduced the extinction period of morphine. Moreover, the administration of AMN082 into the NAc dose-dependently inhibited the reinstatement of morphine. The findings suggested that the mGluR7 in the NAc facilitates the extinction and inhibits the reinstatement of the morphine-induced CPP that could have been mediated by an increase in the release of extracellular glutamate. PMID- 29605485 TI - A cAMP analog attenuates beta-amyloid (1-42)-induced mitochondrial dysfunction and spatial learning and memory deficits. AB - Alzheimer's disease (AD), a neurodegenerative disorder in elderly, is indicated with deposition of Amyloid beta (Abeta) in the brain and accompanied with cognitive impairment. Bucladesine, a phosphodiesterase inhibitor, may ameliorate AD's cognitive dysfunctions through mimicking the action of cAMP and raising its intracellular level. Here, we investigated the effects of bucladesine on Abeta induced memory and learning impairment in a Morris water maze (MWM) model. Rats were injected with bucladesine (1 MUl/side from a 100 MUM stock solution) and Abeta (1 MUl/side from a 100 MUM stock solution) intra-hippocampally and after 19 days were trained for 4 successive days. The oxidative stress was evaluated through measurement of thiobarbituric acid (TBARS), thiol groups, and ferric reducing antioxidant power (FRAP). Effect of Abeta and its combination with bucladesine on the mitochondrial function was assessed according to changes in the ROS generation, mitochondrial membrane potential (MMP), mitochondrial swelling, ATP/ADP ratio, mitochondrial outer membrane damage and cytochrome C release. Our results showed a significant elevation in TBARS level after administration of Abeta causing mitochondrial ROS generation, swelling, outer membrane damage, cytochrome C release and also lower thiol, FRAP, and MMP levels. Abeta-induced spatial memory impairment was prevented by pre-treatment with bucladesine and the changed mitochondrial and biochemical indices upon treatment dose were improved. Taken together, we have obtained satisfactory results suggesting protecting effects of bucladesine against the Abeta-mediated memory deficit and implying its plausible beneficial capacity as a therapeutic agent in oxidative stress-associated neurodegenerative diseases. PMID- 29605486 TI - Integration of 1H NMR- and UPLC-Q-TOF/MS-based plasma metabonomics study to identify diffuse axonal injury biomarkers in rat. AB - Diffuse axonal injury (DAI) is much common during traumatic brain injury (TBI) and is associated with high mortality and poor neurological outcome. Although many studies have been examined, there are still no reliable objective diagnostic modalities available for clinicians to make an early diagnosis of DAI. Therefore, we established a rat model of DAI, applying an integrated 1H NMR- and UPLC-Q TOF/MS-based metabonomics approach to identify differentially changed metabolites in plasma. A total of twenty-two metabolites in the injury group were identified as differentially changed. Among them, four metabolites, glutamine, pyruvate, glycerol and phosphocholine, were identified as candidate biomarkers based on their high fold-changes and biological functions, and may play important roles in axonal injury progression in DAI. Our study not only identified several novel biomarkers that improved our understanding of the metabolic events underlying DAI, but also may provide some potential novel therapeutic targets for preventing axonal injury in DAI. PMID- 29605487 TI - Association between ABCA1 gene polymorphisms and the therapeutic response to donepezil therapy in Han Chinese patients with Alzheimer's disease. AB - AIM: It is reported that ABCA1, which plays a key role in cholesterol transport and apolipoprotein E (APOE) metabolism in the brain, is related to Alzheimer's disease. However, few studies have focused on the relationship between the ABCA1 gene and the therapeutic response to donepezil (DNP), which has been shown to be related to reduced sAPP production.This study evaluated the association between the ABCA1 gene polymorphism and the clinical response to donepezil therapy in Han Chinese patients with Alzheimer's disease. METHODS: We examined ABCA1 gene polymorphisms in 88 Han Chinese patients with Alzheimer's disease who were receiving DNP therapy. The Mini-Mental State Examination was conducted before and after DNP treatment, and the ABCA1 rs 2230806 and rs 2230808, APOE E3 genotypes of each patient were identified. RESULTS: We found that patients with the ABCA1 rs2230806 GG genotype responded better to DNP treatment compared to those with the AA and AG genotypes (p = 0.001). Patients who were APOE E3 non-carriers and had the ABCA1 rs2230806 GG genotype tended to have a better clinical response to DNP therapy. CONCLUSIONS: The ABCA1 rs 2230806 polymorphism and its combination with the APOE E3 allele may provide clinically relevant information for predicting the therapeutic response to DNP therapy. PMID- 29605488 TI - The combined impact of IgLON family proteins Lsamp and Neurotrimin on developing neurons and behavioral profiles in mouse. AB - Cell surface neural adhesion proteins are critical components in the complex orchestration of cell proliferation, apoptosis, and neuritogenesis essential for proper brain construction and behavior. We focused on the impact of two plasticity-associated IgLON family neural adhesion molecules, Neurotrimin (Ntm) and Limbic system associated membrane protein (Lsamp), on mouse behavior and its underlying neural development. Phenotyping neurons derived from the hippocampi of Lsamp-/-, Ntm-/- and Lsamp-/-Ntm-/- mice was performed in parallel with behavioral testing. While the anatomy of mutant brains revealed no gross changes, the Ntm-/- hippocampal neurons exhibited premature sprouting of neurites and manifested accelerated neurite elongation and branching. We propose that Ntm exerts an inhibitory impact on neurite outgrowth, whereas Lsamp appears to be an enhancer of the said process as premature neuritogenesis in Ntm-/- neurons is apparent only in the presence of Lsamp. We also show interplay between Lsamp and Ntm in regulating tissue homeostasis: the impact of Ntm on cellular proliferation was dependent on Lsamp, and Lsamp appeared to be a positive regulator of apoptosis in the presence of Ntm. Behavioral phenotyping indicated test-specific interactions between Lsamp and Ntm. The phenotypes of single mutant lines, such as reduced swimming speed in Morris water maze and increased activity in the elevated plus maze, were magnified in Lsamp-/-Ntm-/- mice. Altogether, evidence both from behavioral experiments and cultured hippocampal cells show combined and differential interactions between Ntm and Lsamp in the formation of hippocampal circuits and behavioral profiles. We demonstrate that mutual interactions between IgLON molecules regulate the initiation of neurite sprouting at very early ages, and even cell-autonomously, independent of their regulation of cell-cell adhesion. PMID- 29605489 TI - Baseline levels of metabolites in different tissues of mussel Mytilus galloprovincialis (Bivalvia: Mytilidae). AB - The Mediterranean mussel Mytilus galloprovincialis (Lamarck 1819) is a popular shellfish commonly included in human diet and is routinely used as bioindicator in environmental monitoring programmes worldwide. Recently, metabolomics has emerged as a powerful tool both in food research and ecotoxicology for monitoring mussels' freshness and assessing the effects of environmental changes. However, there is still a paucity of data on complete metabolic baseline of mussel tissues. To mitigate this knowledge gap, similarities and differences in metabolite profile of digestive gland (DG), gills (G), and posterior adductor muscle (PAM) of aquaculture-farmed M. galloprovincialis were herein investigated by a proton nuclear magnetic resonance (1H NMR)-based metabolomic approach and discussed considering their physiological role. A total of 44 metabolites were identified in mussel tissues and grouped in amino acids, energy metabolites, osmolytes, neurotransmitters, nucleotides, alkaloids, and miscellaneous metabolites. A PCA showed that mussel tissues clustered separately from each other, suggesting a clear differentiation in their metabolic profiles. A Venn diagram revealed that mussel DG, G and PAM shared 27 (61.36%) common metabolites, though with different concentrations. Osmolytes were found to dominate the metabolome of all tissues. The DG exhibited higher level of glutathione and carbohydrates. The G showed greater level of osmolytes and the exclusive presence of neurotransmitters, namely acetylcholine and serotonin. In PAM higher levels of energetics-related metabolites were found. Overall, findings from this study are helpful for a better understanding of mussel tissue-specific physiological functions as well as for future NMR-based metabolomic investigations of marine mussel health and safety. PMID- 29605490 TI - Transcriptome-wide analysis of differential gene expression in response to light:dark cycles in a model cnidarian. AB - Animals respond to diurnal shifts in their environment with a combination of behavioral, physiological, and molecular changes to synchronize with regularly timed external cues. Reproduction, movement, and metabolism in cnidarians have all been shown to be regulated by diurnal lighting, but the molecular mechanisms that may be responsible for these phenotypes remain largely unknown. The starlet sea anemone, Nematostella vectensis, has oscillating patterns of locomotion and respiration, as well as the molecular components of a putative circadian clock that may provide a mechanism for these light-induced responses. Here, we compare transcriptomic responses of N. vectensis when cultured under a diurnal lighting condition (12 h light: 12 h dark) with sea anemones cultured under constant darkness for 20 days. More than 3,000 genes (~13% of transcripts) had significant differences in expression between light and dark, with most genes having higher expression in the photoperiod. Following removal of the light cue 678 genes lost differential expression, suggesting that light-entrained gene expression by the circadian clock has temporal limits. Grouping of genes differentially expressed in light:dark conditions showed that cell cycle and transcription maintained diel expression in the absence of light, while many of the genes related to metabolism, antioxidants, immunity, and signal transduction lost differential expression without a light cue. Our data highlight the importance of diel light cycles on circadian mechanisms in this species, prompting new hypotheses for the role of photoreception in major biological processes, e.g., metabolism, immunity. PMID- 29605491 TI - Comparative analysis of retinal ganglion cell damage in three glaucomatous rat models. AB - Progressive retinal ganglion cell (RGC) death is the major cause of retinal nerve fiber layer thinning and visual field defects in glaucoma. The purpose of this study was to compare RGC damage in three commonly used glaucomatous rat models. These models were generated by (i) injection of paramagnetic microbeads into the anterior chamber; (ii) cauterization of three episcleral veins of the eye (EVC); and (iii) intravitreal injection of N-Methyl-D-Aspartate (NMDA). Intraocular pressure (IOP) was measured with a rebound tonometer at 6, 12, and 18 h; 1, 3, and 5 days; and 1, 2, 3, 4, 6, and 8 weeks. We measured the RGC density of the three glaucomatous models in the flat-mounted retina by immunofluorescence. Subsequently, the thicknesses of both retinal ganglion cell layer (GCL) and inner retinal layer (IRL) were analyzed by hematoxylin and eosin staining of retinal sections. The visual functional deterioration was evaluated by measurement of the photopic negative response (PhNR) of different models. The IOP averages during three weeks were 22.35 +/- 1.23 mmHg (mean +/- SD), 20.91 +/- 1.97 mmHg, and 9.67 +/- 0.42 mmHg, with 50.2%, 44.00% and 66.76% RGC loss by 8 weeks, respectively, in the microbead group, EVC group and NMDA group. Decreased thickness in the GCL was observed in all three groups, while the thickness of IRL and ONL was decreased in the EVC and NMDA groups. Significant positive correlation of RGC loss rate with DeltaIOP integral were demonstrated in both microbead and EVC models. Moreover, we found that the PhNR amplitudes declined early by the first day in the NMDA group, 5 days later in the EVC group and by 7 days in the microbead group. Each glaucomatous rat model has its strength and weakness. Our study provides detailed data for choosing suitable animal models to advance glaucoma research. PMID- 29605492 TI - Comparative analysis on the dynamic of lacrimal gland damage and regeneration after Interleukin-1alpha or duct ligation induced dry eye disease in mice. AB - The loss of functional lacrimal gland (LG) tissue causes quantitative tear deficiency and is the most common reason for the development of severe dry eye disease (DED). The induction of LG regeneration in situ would be a promising approach to curatively treat DED, but underlying mechanisms are mainly unclear. Therefore, this study aims to comparatively evaluate the dynamic of LG damage and regeneration in two mouse models in order to study mechanisms of LG regeneration. Male C57BL/6 J mice were used to induce damage to the right extraorbital LG either by a single interleukin (IL) 1alpha injection or a ligation of the secretory duct for 7 days. Fluorescein staining (FL) and LG wet weight were assessed. In addition, the dynamic of damage and regeneration of acini structures as well as inflammation and the appearance of progenitor cells were (immuno-) histologically evaluated on day 1, 2, 3, 5, 7 after IL-1alpha injection and day 3, 7, 14, 21, 28 after duct ligation (DL). While LG weight was only slightly affected after IL-1alpha injection, DL led to a significant decrease at day 7 followed by an increase after re-opening. Additionally, DL resulted in a more pronounced inflammatory reaction than IL-1alpha injection. After DL the infiltration with CD3+ T cells, CD138 + plasma cells and CD68 + macrophages increased, while IL-1alpha injection only caused an infiltration with CD68 + macrophages. Furthermore, the damage of LG structures was significantly higher after DL than after IL-1alpha injection. Accordingly, regeneration of LG was prolonged and only partial at day 28 after DL, whilst 5 days after IL-1alpha injection a complete LG completely regeneration was achieved. We also found a significantly increased number of nestin + mesenchymal stem cells in both models during injury phase. Our results showed that both models induce LG damage followed by a spontaneous regeneration of acini structures. IL-1alpha injection caused an immediate inflammation with a transient period of slight tissue damage. However, DL caused a more distinct tissue damage followed by a prolonged period of regeneration, which might make it appear more attractive to study regenerative therapies and their effects on LG regeneration. PMID- 29605493 TI - Excited-state dynamics of 3,3'-dihydroxyisorenieratene and (3R,3'R)-zeaxanthin: Observation of vibrationally hot S0 species. AB - We report on an ultrafast transient absorption study of all-trans-3,3' dihydroxyisorenieratene ("DHIR") and all-trans-(3R,3'R)-zeaxanthin in organic solvents covering the wavelength range 350-770 nm. The lifetime of the S2 state in both carotenoids is 160-170 fs. Upon internal conversion (IC) non-equilibrated S1 molecules are formed which internally relax on a 300-400 fs time scale. The time constant for IC from S1 depends on the type of terminal substituent: Replacement of the two terminal beta-ionone rings of zeaxanthin by two aryl rings in DHIR results in an increase from 9.5 to 10.9 ps in THF. This suggests a mild decrease in the effective conjugation length of DHIR. IC to the ground electronic state prepares vibrationally hot S0* molecules which exhibit characteristic bleach and absorption bands. These are typically denoted as "S* features". Collisional cooling of S0* happens with a time constant of 15 ps. Based on our results and the findings from previous studies for other carotenoids, such as macro-beta-carotenes, beta-carotenes and long-chain apocarotenals, we conclude that S0* spectral features are ubiquitous in carotenoid photophysics: They are particularly easy to observe in systems with a very short S1 lifetime and a high quantum yield for IC to the ground electronic state. PMID- 29605494 TI - Plasma proteins associated with circulating carotenoids in Nepalese school-aged children. AB - Carotenoids are naturally occurring pigments that function as vitamin A precursors, antioxidants, anti-inflammatory agents or biomarkers of recent vegetable and fruit intake, and are thus important for population health and nutritional assessment. An assay approach that measures proteins could be more technologically feasible than chromatography, thus enabling more frequent carotenoid status assessment. We explored associations between proteomic biomarkers and concentrations of 6 common dietary carotenoids (alpha-carotene, beta-carotene, lutein/zeaxanthin, beta-cryptoxanthin, and lycopene) in plasma from 500 6-8 year old Nepalese children. Samples were depleted of 6 high abundance proteins. Plasma proteins were quantified using tandem mass spectrometry and expressed as relative abundance. Linear mixed effects models were used to determine the carotenoid:protein associations, accepting a false discovery rate of q < 0.10. We quantified 982 plasma proteins in >10% of all child samples. Among these, relative abundance of 4 were associated with beta carotene, 11 with lutein/zeaxanthin and 51 with beta-cryptoxanthin. Carotenoid associated proteins are notably involved in lipid and vitamin A transport, antioxidant function and anti-inflammatory processes. No protein biomarkers met criteria for association with alpha-carotene or lycopene. Plasma proteomics may offer an approach to assess functional biomarkers of carotenoid status, intake and biological function for public health application. Original maternal micronutrient trial from which data were derived as a follow-up activity was registered at ClinicalTrials.gov: NCT00115271. PMID- 29605495 TI - [Frequency of Candida in root canals of teeth with primary and persistent endodontic infections]. AB - BACKGROUND: Microbiological identification in endodontic infections has focused mainly on bacteria without giving much attention to yeasts, which, due to their virulence factors, can affect the outcomes of root canal treatment. AIMS: To determine the frequency of Candida in anaerobic conditions in root canals with primary and persistent endodontic infection, as well as to evaluate a microbiological sampling method using aspiration compared to the traditional absorption method with paper points. METHODS: Fifty microbiological samples were obtained from teeth of 47 patients requiring endodontic treatments, due to either primary or persistent infections. Two microbiological sampling methods were used: an aspiration method, and the traditional paper point absorption method. In each of these methods, two types of medium were used (M1-M4). Samples were cultured under anaerobic conditions until reaching 0.5 McFarland turbidity, and then inoculated on Sabouraud dextrose, as well as on anaerobic enriched blood agar plates. Macroscopic and microscopic observations of the colonies were performed. The germ-tube test, growth on CHROMagar, and biochemical identification were performed on the isolated yeasts. RESULTS: Fungal infection was found in 18 (36%) samples out of the 50 teeth evaluated. In the 18 samples positive for fungal infection, 15 out of 36 (41.6%) teeth were taken from a primary infection, and 3 out of 14 (21.4%) from a persistent infection. The aspiration method using Sabouraud dextrose medium recovered a greater diversity of species. CONCLUSIONS: Yeasts frequency was higher in teeth with primary infections compared to teeth with persistent infections. The predominant yeast species was Candida albicans. The aspirating sampling method was more efficient in the recovery of Candida isolates than the traditional absorption method. PMID- 29605497 TI - Surgery for Buruli ulcer in the antibiotic era. PMID- 29605496 TI - Cost-effectiveness of posaconazole in private and public Brazilian hospitals. AB - BACKGROUND: Posaconazole is used for the prophylaxis of invasive fungal disease (IFD). Previous studies have shown it to be cost-effective compared to fluconazole/itraconazole. However, posaconazole has never been economically evaluated in developing countries. AIMS: The aim of the present study was to perform a cost-effectiveness analysis of posaconazole compared to fluconazole in public (SUS) and private hospitals (PHS) in Brazil. METHODS: A cost-effectiveness simulation was conducted on the basis of a pivotal study on the use of posaconazole in acute myeloid leukemia (AML) patients, adjusting the costs to Brazilian data. RESULTS: A pharmacoeconomic analysis was performed on a hypothetical sample of 100 patients in each drug group. The total cost of posaconazole use alone was USD$ 220,656.31, whereas that for fluconazole was USD$ 83,875.00. Our results showed that patients with IFD remain hospitalized for an additional 12 days, at an average cost of USD$ 850.85 per patient per day. The total money spent by PHS for 100 patients for 100 days was USD$ 342,318.00 for the posaconazole group and USD$ 302,039.00 for the fluconazole group. An analysis of sensitivity (10%) revealed no intergroup difference. CONCLUSIONS: In Brazil posaconazole is cost-effective, and should be considered for the prophylaxis of patients with AMD/myelodysplasia (AML/MDS) undergoing chemotherapy. PMID- 29605498 TI - Delayed versus standard assessment for excision surgery in patients with Buruli ulcer in Benin: a randomised controlled trial. AB - BACKGROUND: Surgical intervention was once the mainstay of treatment for Buruli ulcer disease, a neglected tropical disease caused by Mycobacterium ulcerans. Since the introduction of streptomycin and rifampicin for 8 weeks as standard care, surgery has persisted as an adjunct therapy, but its role is uncertain. We investigated the effect of delaying the decision to operate to 14 weeks on rates of healing without surgery. METHODS: In this randomised controlled trial, we enrolled patients aged 3 years or older with confirmed disease at one hospital in Lalo, Benin. Patients were randomly assigned (1:1) to groups assessing the need for excision surgery 8 weeks (standard care) or 14 weeks after initiation of antimicrobial treatment. The primary endpoint was the number of patients healed without the need for surgery (not including skin grafting), assessed in all patients in follow-up at 50 weeks (or last observation for those healed for >10 weeks). A doctor masked to treatment assignment checked the indications for surgery according to predefined criteria. This study is registered with ClinicalTrials.gov, number NCT01432925. FINDINGS: Between July 1, 2011, and Jan 15, 2015, 119 patients were enrolled, with two patients per group lost to follow up. 55 (96%) of 57 participants in the delayed-decision group and 52 (90%) of 58 participants in the standard-care group had healed lesions 1 year after start of antimicrobial treatment (relative risk [RR] 1.08, 95% CI 0.97-1.19). 37 (67%) of 55 patients in the delayed-decision group had their lesions healed without surgical intervention, as did 25 (48%) of 52 in the standard-care group (RR 1.40, 95% CI 1.00-1.96). The time to heal and residual functional limitations did not differ between the two groups (median time to heal 21 weeks [IQR 10-27] in the delayed-decision group and 21 weeks [10-39] in the standard-care group; functional limitations in six [11%] of 57 and three [5%] of 58 patients; p=0.32). Postponing the decision to operate resulted in reduced median duration of hospitalisation (5 days [IQR 0-187] vs 131 days [0-224]; p=0.024) and wound care (153 days [IQR 56-224] vs 182 days [94-307]; p=0.036). INTERPRETATION: In our study, patients treated for Buruli ulcer benefited from delaying the decision to operate. Even large ulcers can heal with antibiotics alone, without delaying healing rate and without an increase in residual functional limitations. FUNDING: NWO-VENI grant 241500, BUG Foundation, and UBS OPTIMUS. PMID- 29605499 TI - Significance of abnormal peritoneal cytology on survival of women with stage I-II endometrioid endometrial cancer. AB - OBJECTIVE: To examine survival of women with stage I-II endometrioid endometrial cancer whose peritoneal cytology showed malignant or atypical cells (abnormal peritoneal cytology). METHODS: This is a multi-center retrospective study examining 1668 women with stage I-II endometrioid endometrial cancer who underwent primary hysterectomy with available peritoneal cytology results between 2000 and 2015. Abnormal peritoneal cytology was correlated to clinico pathological characteristics and oncological outcome. RESULTS: Malignant and atypical cells were seen in 125 (7.5%) and 58 (3.5%) cases, respectively. On multivariate analysis, non-obesity, non-diabetes mellitus, cigarette use, and lympho-vascular space invasion were independently associated with abnormal peritoneal cytology (all, P<0.05). Abnormal peritoneal cytology was independently associated with decreased disease-free survival (hazard ratio 3.07, P<0.001) and cause-specific survival (hazard ratio 3.42, P=0.008) on multivariate analysis. Abnormal peritoneal cytology was significantly associated with increased risks of distant-recurrence (5-year rates: 8.8% versus 3.6%, P=0.001) but not local recurrence (5.2% versus 3.0%, P=0.32) compared to negative cytology. Among women with stage I disease, abnormal peritoneal cytology was significantly associated with an increased risk of distant-recurrence in the low risk group (5-year rates: 5.5% versus 1.0%, P<0.001) but not in the high-intermediate risk group (13.3% versus 10.8% P=0.60). Among 183 women who had abnormal peritoneal cytology, postoperative chemotherapy significantly reduced the rate of peritoneal recurrence (5-year rates: 1.3% versus 9.2%, P=0.039) whereas postoperative radiotherapy did not (7.1% versus 5.5%, P=0.63). CONCLUSION: Our study suggests that abnormal peritoneal cytology may be a prognostic factor for decreased survival in women with stage I-II endometrioid endometrial cancer, particularly for low-risk group. PMID- 29605500 TI - Course of chemotherapy-induced peripheral neuropathy and its impact on health related quality of life among ovarian cancer patients: A longitudinal study. AB - OBJECTIVE: Chemotherapy-induced peripheral neuropathy (CIPN) presents itself as sensory peripheral neuropathy (SPN) or motor peripheral neuropathy (MPN). Our aim was to examine the course of SPN and MPN, and their impact on health-related quality of life (HRQoL) among ovarian cancer patients. METHODS: All newly diagnosed ovarian cancer patients from twelve hospitals in the South of the Netherlands were eligible for participation. Patients (N=174) completed questions on CIPN (EORTC QLQ-OV28) and HRQoL (EORTC QLQ-C30) after initial treatment and at 6, 12, and 24months (response rates were 70%, 71%, 58%, and 43% respectively). RESULTS: Generalized linear mixed models showed that among chemotherapy-treated patients (N=98), SPN levels were stable over time. For MPN, symptoms significantly improved at 12months. At 2years, 13% still reported high SPN. Also, 11% still reported high MPN. Regarding HRQoL, patients with high SPN reported a worse physical, role, emotional, social, and cognitive functioning compared to those with low SPN. Moreover, those who changed from low to high SPN over time worsened on physical functioning. For MPN, a worse global quality of life and a worse functioning was reported among patients with high MPN. Also, those who changed from low to high MPN over time worsened on global quality of life and on physical, role, social, and cognitive functioning. CONCLUSIONS: Among chemotherapy-treated ovarian cancer patients, SPN levels were stable over time. In contrast, MPN symptoms significantly improved at 12months. These symptoms seriously impacted HRQoL. Future studies should examine the impact of different treatment decisions and alterations on CIPN, so recommendations can be made to reduce CIPN (prevalence). PMID- 29605501 TI - Amyloid fibrillation of an intrinsically disordered plant phloem protein AtPP16-1 under acidic condition. AB - Arabidopsis thaliana Phloem Protein 16-1 (AtPP16-1) is a 156-residue intrinsically disordered nucleic acid binding protein which is putatively involved in long-distance systemic transport of RNA to budding regions in plants. Dimerization or oligomerization of the protein at pH higher than about 4.1 leaves no apolar surface exposed for interaction with the dye 8-Anilinonaphthalene-1 sulfonate (ANS). The most stable monomeric state is found near pH 4 where the structure of the protein is determined to have three short beta-strands and a single alpha-helix. By surveying the pH-dependent propensity of fibrillation we find the protein enters the amyloidogenic state at pH 2, 60 degrees C. The reaction product is not amorphous aggregate, but simple amyloid fibrils with sparse or no branching. The mean diameters of the fibril population scaled from AFM images are 13.2 and 21.2 nm for precursor aggregates (PA) and proto- or elongated fibrils, respectively. These values are somewhat larger than the fibril diameters generally cited, and the reason could be larger lateral association for both PA and protofibrils. The protein AtPP16-1 is strictly pH-selective in terms of its structure and stability, and the solution structure is known at pH 4. Under the conditions of pH 2 used here for fibrillation, the protein retains substantial secondary structure. Even if the pH and temperature conditions used for fibrillation are hardly physiological, there is a finite possibility that some aggregation of AtPP16-1 would occur in vivo, as the case of transglutaminase aggregates in the chloroplast of transplastomic plants, for example. The pH related problem has been discussed in detail, but the questions emanating are: do phloem proteins fibrillate in vivo, and if so what implication fibrillation has for plant physiology? PMID- 29605502 TI - Corrigendum to "Dopaminergic involvement in a drummer with focal dystonia: A case study" [Clin. Neurol. Neurosurg. (2018) 166 (March) 54-55]. PMID- 29605503 TI - The effect of the lectin from Cherax quadricarinatus on its granular hemocytes. AB - In crustaceans, lectins and hemocytes of the innate immune system provide the first line of defense. Although evidence points to the potential role of lectins in regulating hemocyte activity, the processes underlying the lectin activation have not been evaluated. In the present study, the receptor for CqL, a humoral lectin from Cherax quadricarinatus specific for galactose/sialic acid, was identified in a granular subset of hemocytes. The CqL receptor (CqLR) is a 490 kDa glycoprotein, composed of four identical 120-kDa subunits. As shown by immunohistochemistry, CqL at 7.5 MUg/mL as optimal dose, after 2 min, induced, specifically on granular hemocytes, increased phosphorylation of serine (152%), threonine (192%), and tyrosine (242%) as compared with non-treated hemocytes; moreover, CqL induced increased generation of reactive oxygen species (ROS). Specific kinase inhibitors showed inhibition (P < 0.001) of ROS production induced by CqL. These results strongly suggest that CqL actively participated in the generation of ROS through kinases induced by a CqLR in a subset of granular hemocytes of the crayfish C. quadricarinatus. The results provide strong evidence that CqL activates, through specific granular hemocytes, receptors that modulate cellular functions in C. quadricarinatus. PMID- 29605504 TI - Circadian genes period1b and period2 differentially regulate inflammatory responses in zebrafish. AB - The circadian clock has been shown to regulate various immune processes in different animals. Our previous report demonstrated that the innate immune responses in zebrafish show significant rhythmicity that could be regulated by melatonin. Here, we used diurnal zebrafish to determine the role of circadian genes in the inflammatory responses. Our results indicate that circadian genes exhibit rhythmic oscillations in zebrafish leukocytes, and mutations of the clock genes period1b (per1b) and period2 (per2) considerably affect these oscillations. Using a wounded zebrafish inflammation model, we found that under constant dark conditions (DD), the expression of pro-inflammatory cytokines is significantly downregulated in per1b gene mutant zebrafish and significantly upregulated in the per2 gene mutant zebrafish. Furthermore, using real-time imaging technology, we found that the per1b gene markedly disturbs the rhythmic recruitment of neutrophils toward the injury, whereas the per2 gene does not show a significant effect. Taken together, our results reveal differential functions of the circadian genes per1b and per2 in the inflammatory responses, serving as evidence that circadian rhythms play a vital role in immune processes. PMID- 29605505 TI - Comparison of the susceptibility and resistance of four marine perciform fishes to Cryptocaryon irritans infection. AB - Cryptocaryon irritans is a type of marine ectoparasitic ciliate that infects teleost fishes. To illustrate the susceptibility and innate immune mechanism of fishes to C. irritans, four species of marine perciform fishes were selected in Fujian Province, a high-prevalence area of cryptocaryoniasis in China. The survival, diameter/number of tomonts, and infection ratio among Larimichthys crocea, Lateolabrax japonicus, Pagrus major, and Nibea albiflora were compared after artificial infection. Meanwhile, the immobilization titers of four fish species with no C. irritans infection were detected. Results showed that survival and serum immobilization titer of N. albiflora were significantly higher than those of the other three fish species. A strong negative linear correlation was found between the survival/serum immobilization titer and the mean tomont diameter. In addition, the smallest C. irritans infection ratio was found in N. albiflora, implying that the serum of fishes especially that of N. albiflora, inhibited the development of parasitic C. irritans cells, and the smallest tomont size was directly related to the number of infective theronts corresponding to the highest survival of fish. Moreover, complement activity inhibition assays suggested that the alternative complement pathway might play a major role in C. irritans resistance. PMID- 29605506 TI - Molecular cloning and functional analysis of Growth arrest and DNA damage inducible 45 aa and ab (Gadd45aa and Gadd45 ab) in Ctenopharyngodon idella. AB - The Gadd45aa and Gadd45 ab genes are members of the Gadd45 family, which are critically involved in immunological and apoptosis functions. In this study, we isolated and characterized Gadd45aa and Gadd45 ab cDNA from grass carp (Ctenopharyngodon idella) (designated CiGadd45aa and CiGadd45 ab). The CiGadd45aa and CiGadd45 ab fragments spanned 1272 bp/1248 bp, which contained 474 bp/480 bp open reading frames encoding 157/159 amino acid proteins. BLAST analysis revealed that CiGadd45aa and CiGadd45 ab shared high similarity with known Gadd45a sequences. qRT-PCR analysis showed widespread and abundant expression of CiGadd45aa in gill, intestine, kidney, brain, blood, skin and fin, but low in liver, spleen, head kidney, heart, and muscle. CiGadd45 ab was expressed highly in liver, spleen and blood but at low levels in gill, intestine, kidney, head kidney, heart, brain, skin, muscle, and fin. Following challenge of grass carp with Aeromonas hydrophila, CiGadd45aa and CiGadd45 ab expression was upregulated. In immune-relevant tissues and MAPK family genes (p38, JNK and ERK) were upregulated by CiGadd45aa and CiGadd45 ab overexpression and partly downregulated by interfered in the CIK grass carp kidney cell line. In addition, transcription of the cytokine-encoding il-8 gene was upregulated/downregulated by CiGadd45aa and CiGadd45 ab overexpression and interference. These results suggest that CiGadd45aa and CiGadd45 ab play roles in innate immune responses against A. hydrophila in grass carp. PMID- 29605507 TI - Developmental dysgraphia is often associated with minor neurological dysfunction in children with developmental coordination disorder (DCD). AB - OBJECTIVES: Children with developmental coordination disorder (DCD) are particularly affected by handwriting disorders, which remain poorly understood and are not clearly defined. The aim of our study is to provide a better understanding of handwriting disorders, and specifically of dysgraphia in children with DCD. METHODS: Sixty-five children with DCD (5-15 years), enrolled according to DSM-5, were assessed with handwriting testing and standardized assessments of neuropsychological, neurovisual, MRI and neuropsychomotor functions, with special attention paid to muscular tone examination. RESULTS: While handwriting disorders were strongly represented in our sample of children with DCD (89%), dysgraphia appeared uncommon (17%) and was closely related to several specific dysfunctions of laterality establishment; mild pyramidal tract dysfunction with distal phasic stretch reflex (PSR) in lower limbs; digital praxis slowness (both P<0.05). DISCUSSION: In our sample, dysgraphia was closely related to minor neurological dysfunction (MND) suggesting a disturbance of motor control at the level of the corticospinal motor pathway. This highlights the uncommon character of dysgraphia in children with DCD for which diagnosis should be made through a particular attention to evaluation of MND with muscular tone examination. This consideration, both in the research setting and in clinical practice, appears necessary to avoid inaccurate clinical diagnosis and to optimize appropriate therapeutic management. PMID- 29605509 TI - The effects of lower CD34 yields after lowe dose G-CSF induction on long-term autologous stem cell transplantation outcome: A single center study. AB - Peripheral blood stem cell transplantation (PBSCT) is an effective treatment for hematological malignancies. Mobilization of peripheral blood stem cells performs in different ways among transplantation centers. Since the Effects of lower CD34+ cells dose after low dose G-CSF induction on autologous stem cell transplantation outcomes are not studied much, so this study was performed for this purpose. 735 autologous stem cell transplanted patients with diagnoses of multiple myeloma (n = 330), Hodgkin lymphoma (n = 200), non-Hodgkin lymphoma (n = 129), acute myeloid leukemia (n = 54) and solid tumors (n = 22) were retrospectively evaluated. G-CSF was administered at the dose of 5 MUg/kg/day during mobilization and all patients except acute myeloid leukemia received 10 MUg/kg/day on the last day. Peripheral blood stem cells were harvested in one session for all patients. The amount of injected CD34+ cells/kg for patients were divided and studied in four groups: <0.5 * 106 (n = 36), 0.5-1.0 * 106, (n = 132), 1.0-2.0 * 106 (n = 226) and >2.0 * 106 (n = 305). The median time of follow up was 26.9 months. The amount of CD34+ cells dose were a significant predictor of platelet engraftment, but overall survival, relapse-free survival and also relapse rate was not associated with cells yield. More platelet transfusion (P = 0.003) and antibiotics prescription (P = 0.001) in transplanted patients with lower CD34 cells dose should be balanced with risks of higher G-CSF doses administration and also its side effects. Our results declare that lower CD34 yields after lowe dose G-CSF induction are probably not a troublesome issue affecting transplantation outcomes. PMID- 29605510 TI - Immunotherapy for pancreatic cancer: A long and hopeful journey. AB - Multiple therapeutic strategies have been developed to treat pancreatic cancer. However, the outcomes of these approaches are disappointing. Due to deeper understandings of the pivotal roles of the immune system in pancreatic cancer tumorigenesis and progression, novel therapeutic strategies based on immune cells and the tumor microenvironment are being investigated. Some of these approaches, such as checkpoint inhibitors, chimeric antigen receptor T-cell therapy, and BiTE antibodies, have achieved exciting outcomes in preclinical and clinical trials. The current review describes the roles of immune cells and the immunosuppressive microenvironment in the development of pancreatic cancer, as well as the preclinical and clinical outcomes and benefits of recent immunotherapeutic approaches, which may help us further disclose the mechanisms of pancreatic cancer progression and the dialectical views of feasibility and effectiveness of immunotherapy in treatment of pancreatic cancer. PMID- 29605508 TI - Apoptosis-Inducing Factor (AIF) in Physiology and Disease: The Tale of a Repented Natural Born Killer. AB - Apoptosis-inducing factor (AIF) is a mitochondrial oxidoreductase that contributes to cell death programmes and participates in the assembly of the respiratory chain. Importantly, AIF deficiency leads to severe mitochondrial dysfunction, causing muscle atrophy and neurodegeneration in model organisms as well as in humans. The purpose of this review is to describe functions of AIF and AIF-interacting proteins as regulators of cell death and mitochondrial bioenergetics. We describe how AIF deficiency induces pathogenic processes that alter metabolism and ultimately compromise cellular homeostasis. We report the currently known AIFM1 mutations identified in humans and discuss the variability of AIFM1-related disorders in terms of onset, organ involvement and symptoms. Finally, we summarize how the study of AIFM1-linked pathologies may help to further expand our understanding of rare inherited forms of mitochondrial diseases. PMID- 29605511 TI - Tetrandrine inhibits deregulated cell cycle in pancreatic cancer cells: Differential regulation of p21Cip1/Waf1, p27Kip1 and cyclin D1. AB - Current therapies in Pancreatic Cancer (PaCa) are ineffective due to deregulated cell cycle driven by landscape mutations. In this study, we show for the first time that tetrandrine (TET) inhibits proliferation of the PaCa cells and inhibits PaCa tumor growth. TET inhibits cell cycle transition at G1/S boundary. TET increased levels of p21Cip1/Waf1 and p27Kip1, had no effect on the levels of CDK4/6 proteins and decreased the levels of cyclin D1 and pRb proteins. TET resulted in changes in mRNA levels of cyclin D1 and p21Cip1/Waf1 but had no effect on the mRNA of p27Kip1. We show, for the first time in any system, that TET treatment downregulated Skp2, E3 ligase specific for degradation of p27Kip1 during the cell cycle. Taken together our results show, that TET indirectly impairs the activities of CDK4/6 to halt deregulated cell cycle and inhibit PaCa tumor growth. These results suggest that TET may serve as a novel agent for treatment of PaCa, for which there is no effective cure to date. PMID- 29605513 TI - Pharmacovigilance in Crisis: Drug Safety at a Crossroads. AB - Pharmacovigilance (PV) is under unprecedented stress from fundamental changes in a booming pharmaceutical industry, from the challenges of creating and maintaining an increasingly complex PV system in a globally diverse regulatory environment, and from unpredicted consequences of historical PV cost-reduction strategies. At the same time, talent availability lags demand, and many PV professionals may no longer be finding personal fulfillment in their careers. The situation creates risks for companies. Advantages and disadvantages of potential strategies to address this increasing problem at a corporate and industry level and in collaboration with regulatory agencies are discussed, as well as opportunities to adopt new technologies, including artificial intelligence and machine-learning to automate pharmacovigilance operations. These approaches would address burdensome and wasteful effort assuring regulatory compliance and free up resources to support the original mission of PV as an important public health activity and to reinvest in the development of new drugs. PMID- 29605512 TI - A novel tropomyosin-related kinase A inhibitor, KK5101 to treat pancreatic cancer. AB - Tropomyosin-related kinase A (TrkA) plays important roles in tumor cell growth and survival signaling and contributes to chemo-resistance in pancreatic cancer. Therefore, we developed KK5101, a novel TrkA target inhibitor and assessed its anti-cancer effects and investigated underlying mechanism of action in pancreatic cancer. KK5101 was characterized to inhibit TrkA selectively and potently by protein binding assay. It effectively inhibited the growth and proliferation of pancreatic cancer cells. Also, KK5101 increased apoptosis with loss of mitochondrial membrane potential, as evidenced by increases of cytochrome c releases. It increased numbers of TUNEL-positive apoptotic cells, and cell death including early and late apoptosis by Annexin V assay. In addition, activation of the TrkA signaling cascades including p-AKT, p-MEK, and p-STAT3 were inhibited by KK5101 treatment in vitro, as well as ex vivo tumor spheroid models, resulting in potent induction of apoptosis. Importantly, KK5101 also significantly attenuated tumor growth of in vivo pancreatic cancer models. These findings indicate that KK5101 may exert antitumor effects by directly affecting cancer cell growth or survival via inhibition of TrkA signaling pathway. We therefore suggest that KK5101 is a novel therapeutic candidate for treating pancreatic cancer. PMID- 29605514 TI - Hepatitis B vaccination coverage among adults aged >= 18 years traveling to a country of high or intermediate endemicity, United States, 2015. AB - BACKGROUND: Persons from the United States who travel to developing countries are at substantial risk for hepatitis B virus (HBV) infection. Hepatitis B vaccine has been recommended for adults at increased risk for infection, including travelers to high or intermediate hepatitis B endemic countries. PURPOSE: To assess hepatitis B vaccination coverage among adults >= 18 years traveling to a country of high or intermediate endemicity from the United States. METHODS: Data from the 2015 National Health Interview Survey (NHIS) were analyzed to determine hepatitis B vaccination coverage (>=1 dose) and series completion (>=3 doses) among persons aged >= 18 years who reported traveling to a country of high or intermediate hepatitis B endemicity. Multivariable logistic regression and predictive marginal analyses were conducted to identify factors independently associated with hepatitis B vaccination. RESULTS: In 2015, hepatitis B vaccination coverage (>=1 dose) among adults aged >= 18 years who reported traveling to high or intermediate hepatitis B endemic countries was 38.6%, significantly higher compared with 25.9% among non-travelers. Series completion (>=3 doses) was 31.7% and 21.2%, respectively (P < 0.05). On multivariable analysis among all respondents, travel status was significantly associated with hepatitis B vaccination coverage and series completion. Other characteristics independently associated with vaccination (>=1 dose, and >= 3 doses) among travelers included age, race/ethnicity, educational level, duration of U.S. residence, number of physician contacts in the past year, status of ever being tested for HIV, and healthcare personnel status. CONCLUSIONS: Although travel to a country of high or intermediate hepatitis B endemicity was associated with higher likelihood of hepatitis B vaccination, hepatitis B vaccination coverage was low among adult travelers to these areas. Healthcare providers should ask their patients about travel plans and recommend and offer travel related vaccinations to their patients or refer them to alternate sites for vaccination. PMID- 29605515 TI - Motors of influenza vaccination uptake and vaccination advocacy in healthcare workers: A comparative study in six European countries. AB - BACKGROUND: Annual vaccination is the most effective way to prevent and control the health and economic burden caused by seasonal influenza. Healthcare workers (HCWs) play a crucial role in vaccine acceptance and advocacy for their patients. This study explored the drivers of HCWs' vaccine acceptance and advocacy in six European countries. METHODS: Healthcare workers (mainly general practitioners, specialist physicians, and nurses) voluntarily completed a questionnaire in Bulgaria (N = 485), Czech Republic (N = 518), Kosovo (N = 466), Poland (N = 772), Romania (N = 155), and the United Kingdom (N = 80). Twelve-item scales were used to analyse sentiment clusters for influenza vaccination acceptance and engagement with vaccination advocacy. Past vaccination behaviour and patient recommendation were also evaluated. All data were included in a single analysis. RESULTS: For vaccination acceptance, the main cluster (engaged sentiment: 68%) showed strong positive attitudes for influenza vaccination. A second cluster (hesitant sentiment: 32%) showed more neutral attitudes. Cluster membership was predicted by country of origin and age. The odds ratio for past vaccination in the engaged cluster was 39.6 (95% CI 12.21-128.56) although this varied between countries. For vaccination advocacy, the main cluster (confident sentiment: 73%) showed strong positive attitudes towards advocacy; a second cluster (diffident sentiment: 27%) showed neutral attitudes. Cluster membership was predicted by country of origin, age and profession, with specialist physicians being the least likely to belong to the confident sentiment cluster. HCWs characterised by confident advocacy sentiments were also more likely recommend flu vaccination. Again, this association was moderated by country of origin. CONCLUSIONS: These data show that there is room to improve both vaccination acceptance and advocacy rates in European HCWs, which would be expected to lead to higher rates of HCW vaccination. Benefits that could be expected from such an outcome are improved advocacy and better control of morbidity and mortality related to seasonal influenza infection. PMID- 29605516 TI - Vaccine hesitancy around the globe: Analysis of three years of WHO/UNICEF Joint Reporting Form data-2015-2017. AB - In order to gather a global picture of vaccine hesitancy and whether/how it is changing, an analysis was undertaken to review three years of data available as of June 2017 from the WHO/UNICEF Joint Report Form (JRF) to determine the reported rate of vaccine hesitancy across the globe, the cited reasons for hesitancy, if these varied by country income level and/or by WHO region and whether these reasons were based upon an assessment. The reported reasons were classified using the Strategic Advisory Group of Experts (SAGE) on Immunization matrix of hesitancy determinants (www.who.int/immunization/sage/meetings/2014/october/SAGE_working_group_revised_r port_vaccine_hesitancy.pdf). Hesitancy was common, reported by >90% of countries. The list of cited reasons was long and covered 22 of 23 WHO determinants matrix categories. Even the most frequently cited category, risk- benefit (scientific evidence e.g. vaccine safety concerns), accounted for less than one quarter of all reasons cited. The reasons varied by country income level, by WHO region and over time and within a country. Thus based upon this JRF data, across the globe countries appear to understand the SAGE vaccine hesitancy definition and use it to report reasons for hesitancy. However, the rigour of the cited reasons could be improved as only just over 1/3 of countries reported that their reasons were assessment based, the rest were opinion based. With respect to any assessment in the previous five years, upper middle income countries were the least likely to have done an assessment. These analyses provided some of the evidence for the 2017 Assessment Report of the Global Vaccine Action Plan recommendation that each country develop a strategy to increase acceptance and demand for vaccination, which should include ongoing community engagement and trust-building, active hesitancy prevention, regular national assessment of vaccine concerns, and crisis response planning (www.who.int/immunization/sage/meetings/2017/october/1_GVAP_Assessment_report_web version.pdf). PMID- 29605517 TI - Mary Poppins was right: Adding small amounts of sugar or salt reduces the bitterness of vegetables. AB - Only a quarter of adults and 7% of children consume recommended amounts of vegetables each day. Often vegetables are not initially palatable due to bitterness, which may lead children and adults to refuse to taste or eat them. The objective of this research was to determine if very small amounts of sugar or salt (common household ingredients) could lead to significant reductions in bitterness intensity and increased hedonic ratings of green vegetable purees. For Experiment 1, three different green vegetable purees (broccoli, spinach, and kale) were prepared with different levels of sugar (0%, 0.6%, 1.2%, and 1.8%) or salt (0 and 0.2%). Samples were evaluated using standard descriptive analysis techniques with nine adults who completed more than 20 h of green vegetable specific training as a group. For Experiment 2, each vegetable puree was prepared with either 0% or 2% sugar, and bitterness was assessed via a forced choice task with 84 adults. For Experiment 3, each vegetable puree was prepared with 0%, 1%, or 2% sugar and rated for liking on standard 9 point hedonic scales by 99 adults. Experiments 1 and 2 showed that addition of small amounts of sugar and salt each reduced the bitterness (and increased sweetness and saltiness) from all three vegetables without altering other sensory properties (e.g. texture or aroma). Experiment 3 showed that adding sugar to vegetable purees increased hedonic ratings for adult consumers. We also found parents had mixed attitudes about the idea of adding sugar to foods intended for infants and toddlers. Further research on the effects of bitterness masking especially for specific populations (e.g., infants and young children or adults who have higher sensitivity to bitter taste) is warranted. PMID- 29605518 TI - Shoulder Arthroplasty for Sequelae of Obstetrical Brachial Plexus Injury. AB - PURPOSE: Shoulder arthroplasty following obstetrical brachial plexus injury (OBPI) is technically challenging because glenoid morphology, muscle balance, and humeral version are substantially altered compared with the neurologically intact shoulder. The purpose of this study is to report the outcome of shoulder arthroplasty in a group of patients with end-stage arthritis secondary to OBPI. MATERIALS AND METHODS: Seven patients with OBPI and secondary glenohumeral arthritis were treated with shoulder arthroplasty between 1976 and 2014. Two underwent hemiarthroplasty (HA), 2 underwent total shoulder arthroplasty (TSA), and 3 underwent reverse shoulder arthroplasty (RSA). One HA was lost to follow-up and was excluded. The remaining 6 patients (mean age, 62.5 years old at the time of surgery) were followed for a minimum of 2 years (mean, 7.5 years; range, 2-13 years) Outcome measures included pain, range of motion, and postoperative modified Neer ratings. RESULTS: Pain improved in all shoulders. Mean forward flexion was unchanged. No shoulders treated with HA/TSA regained forward elevation above 90 degrees , compared with 1 out of the 3 RSAs. External rotation improved from a mean of -10 degrees to 20 degrees . Active internal rotation decreased from L1 to L5. Immediate postoperative radiographs showed either severe posterior or posterosuperior subluxation in all 3 patients treated with nonconstrained implants. CONCLUSIONS: Shoulder arthroplasty is an acceptable option to relieve pain in patients with symptomatic shoulder arthritis as a sequel of OBPI. However, range of motion improvements are not expected. TYPE OF STUDY /LEVEL OF EVIDENCE: Therapeutic V. PMID- 29605519 TI - A New, Direct Measure of Thumb Use in Children After Index Pollicization for Congenital Thumb Hypoplasia. AB - PURPOSE: After index pollicization for congenital thumb hypoplasia, time-based hand dexterity tests do not indicate whether the new thumb is being used by a child. The Thumb Grasp and Pinch assessment (T-GAP) is a new outcome measure that classifies grasp and pinch styles to quantify use of the new thumb. The goal of this study was to establish concurrent validity and construct validity in the T GAP. METHODS: Data from children treated with index finger pollicization for congenital thumb hypoplasia were retrospectively reviewed. Measures of strength, range of motion, and scores on the Box and Blocks Test (BBT), 9-Hole Peg Test (NHPT), Functional Dexterity Test (FDT), and Task 7 (Heavy Objects) from the Jebsen-Taylor Test (JTT7) were recorded. Patients also completed the T-GAP consisting of 9 age-appropriate tasks, during which grasp patterns were classified. Spearman correlation coefficients were calculated comparing the T-GAP score with scores on the BBT, NHPT, FDT, and JTT7. RESULTS: We evaluated 21 thumbs in 21 children an average of 71.7 months after pollicization surgery (range, 9-175 months). The T-GAP score was significantly correlated with BBT, NHPT, FDT, and JTT7 (R = 0.69, -0.60,-0.59, and -0.60, respectively). The T-GAP score was significantly correlated with tripod pinch, key pinch, and grip strength (R = 0.77, 0.75, and 0.71, respectively) and with opposition and grasp span (R = 0.50 and 0.52, respectively). The T-GAP was the only functional measure correlated with parent and patient satisfaction with thumb function. CONCLUSIONS: Concurrent validity was supported by significant correlations between T-GAP score for all 4 dexterity measures. Construct validity was supported by significant correlations between strength and range of motion of the thumb and T-GAP score. CLINICAL RELEVANCE: This evaluation may help surgeons and therapists better understand results after pollicization and determine whether the new thumb is being incorporated into daily activities. PMID- 29605520 TI - Chills, aesthetic experience, and new versus old knowledge - What do chills actually portend?: Comment on "Physics of mind: Experimental confirmations of theoretical predictions" by Schoeller et al. PMID- 29605521 TI - When is positive affective response to sad-sounding music paradoxical?: Comment on "An integrative review of the enjoyment of sadness associated with music" by Tuomas Eerola et al. PMID- 29605522 TI - Trial Protocol: Home-based exercise programs to prevent falls and upper limb dysfunction among community-dwelling older people: study protocol for the BEST (Balance Exercise Strength Training) at Home randomised, controlled trial. AB - INTRODUCTION: Falling when older is a major public health issue. There is compelling evidence to show that specific exercise programs can reduce the risk and rate of falls in community-dwelling older people. Another major health issue for older people living in the community is upper limb dysfunction, including shoulder pain. Home-based exercise programs appeal to some older people, due to their convenience. RESEARCH QUESTIONS: This trial aims to determine the effectiveness and cost-effectiveness of a home-based lower limb exercise program compared with a home-based upper limb exercise program to prevent falls and upper limb dysfunction among community-dwelling people aged 65+ years. DESIGN: Randomised, controlled trial. PARTICIPANTS AND SETTING: A total of 576 community dwelling people will be recruited from the Illawarra and Shoalhaven regions of New South Wales, Australia. INTERVENTION: Participants will be randomised to either a home-based lower limb exercise intervention or a home-based upper limb exercise intervention. The lower limb program is designed to improve balance and strength in the lower limbs. The upper limb program is designed to improve upper limb strength and mobility. Participants will attend three group-based instruction sessions to learn and progress the exercises, and will be instructed to perform the exercises three times per week at home for 12 months. OUTCOME MEASURES: The two primary outcomes will be fall rates, recorded with monthly calendars for a 12-month period, and upper limb dysfunction, measured with the Disability of the Arm, Shoulder and Hand questionnaire. Secondary outcomes will include: lower limb strength and balance; shoulder strength and mobility; physical activity; quality of life; attitudes to exercise; proportion of fallers; fear of falling; and health and community service use. The cost-effectiveness of both exercise programs from a health and community service provider perspective will be evaluated. ANALYSIS: Negative binomial regression models will be used to estimate the between-group difference in fall rates. Modified Poisson regression models will be used to compare groups on dichotomous outcome measures. Linear regression models will be used to assess the effect of group allocation on the continuously scored measures, after adjusting for baseline scores. Two economic evaluations will be conducted: the first will assess cost-effectiveness of the lower limb program compared with the upper limb program; and the second will assess cost-effectiveness of the upper limb program compared with the lower limb program. DISCUSSION: If effective, the trial will provide a model for both upper limb and lower limb exercise programs that can be performed at home and implemented at scale to community-dwelling older adults. PMID- 29605523 TI - Rapid identification of carbapenemase-type blaGES and ESBL-type blaGES using multiplex PCR. AB - Guiana extended-spectrum (GES) beta-lactamases are emerging in Japan. The GES family can be classified into 2 groups, one with extended-spectrum beta-lactamase (ESBL)-like activity, which hydrolyzes penicillins and cephalosporins, and the other with carbapenemase-like activity with an extended spectrum toward carbapenems. This difference is mediated by variations in a specific amino acid in the GES protein: G170 N or G170S substitutions. We developed an amplification refractory mutation system (ARMS) PCR assay that enabled rapid identification of these variant genes without sequencing. PMID- 29605524 TI - Lateral flow assay for brucellosis testing in multiple livestock species. AB - Lateral flow assay (LFA) for brucellosis was standardized and evaluated. The test showed high diagnostic sensitivity, specificity and accuracy for diagnosis of brucellosis in bovines, small ruminants and swine. The study emphasized the importance of LFA as a useful, rapid, and easy-to-perform tool for the testing of brucellosis. PMID- 29605525 TI - Strengthening the public health workforce: An estimation of the long-term requirements for public health specialists in Serbia. AB - At the beginning of the 21st century, planning the public health workforce requirements came into the focus of policy makers. The need for improved provision of essential public health services, driven by a challenging non communicable disease and causes of death and disability within Serbia, calls for a much needed estimation of the requirements of the public health professionals. Mid and long-term public health specialists' supply and demand estimations out to 2025were developed based on national staffing standards and regional distribution of the workforce in public health institutes of Serbia. By 2025, the supply of specialists, taking into account attrition rate of -1% reaches the staffing standard. However, a slight increase in attrition rates has the impact of revealing supply shortage risks. Demand side projections show that public health institutes require an annual input of 10 specialists or 2.1% annual growth rate in order for the four public health fields to achieve a headcount of 487 by 2025 as well as counteract workforce attrition rates. Shortage and poor distribution of public health specialists underline the urgent need for workforce recruitment and retention in public health institutes in order to ensure the coordination, management, surveillance and provision of essential public health services over the next decade. PMID- 29605526 TI - Decoding disclosure: Comparing conflict of interest policy among the United States, France, and Australia. AB - "Sunshine" policy, aimed at making financial ties between health professionals and industry publicly transparent, has recently gone global. Given that transparency is not the sole means of managing conflict of interest, and is unlikely to be effective on its own, it is important to understand why disclosure has emerged as a predominant public policy solution, and what the effects of this focus on transparency might be. We used Carol Bacchi's problem-questioning approach to policy analysis to compare the Sunshine policies in three different jurisdictions, the United States, France and Australia. We found that transparency had emerged as a solution to several different problems including misuse of tax dollars, patient safety and public trust. Despite these differences in the origins of disclosure policies, all were underpinned by the questionable assumption that informed consumers could address conflicts of interest. We conclude that, while transparency reports have provided an unprecedented opportunity to understand the reach of industry within healthcare, policymakers should build upon these insights and begin to develop policy solutions that address systemic commercial influence. PMID- 29605527 TI - Confirmatory versus explorative endpoint analysis: Decision-making on the basis of evidence available from market authorization and early benefit assessment for oncology drugs. AB - The early benefit assessment of pharmaceuticals in Germany and their preceding market authorization pursue different objectives. This is reflected by the inclusion of varying confirmatory endpoints within the evaluation of oncology drugs in early benefit assessment versus market authorization, with both relying on the same evidence. Data from assessments up to July 2015 are used to estimate the impact of explorative in comparison to confirmatory endpoints on market authorization and early benefit assessment by contrasting the benefit-risk ratio of EMA and the benefit-harm balance of the HTA jurisdiction. Agreement between market authorization and early benefit assessment is examined by Cohen's kappa (k). 21 of 41 assessments were considered in the analysis. Market authorization is more confirmatory than early benefit assessment because it includes a higher proportion of primary endpoints. The latter implies a primary endpoint to be relevant for the benefit-harm balance in only 67% of cases (0.078). Explorative mortality endpoints reached the highest agreement regarding the mutual consideration for the risk-benefit ratio and the benefit-harm balance (0.000). For explorative morbidity endpoints (-0.600), quality of life (-0.600) and side effects (-0.949) no agreement is ascertainable. To warrant a broader confirmatory basis for decisions supported by HTA, closer inter-institutional cooperation of approval authorities and HTA jurisdictions by means of reliable joint advice for manufacturers regarding endpoint definition would be favorable. PMID- 29605528 TI - Cyberknife stereotactic radiosurgery and radiation therapy treatment planning system. AB - CyberKnife is an image-guided stereotactical dose delivery system designed for both focal irradiation and radiation therapy (SRT). Focal irradiation refers the use of many small beams to deliver highly focus dose to a small target region in a few fractions. The system consists of a 6-MV linac mounted to a robotic arm, coupled with a digital x-ray imaging system. The radiation dose is delivered using many beams oriented at a number of defined or nodal positions around the patients. The CyberKnife can be used for both intracranial and extracranial treaments unlike the Gamma Knife which is limited to intracranial cases. Multiplan (Accuray Inc., Sunnyvale, CA) is the treatment planning system developed to cooperate with this accurate and versatile SRS and SRT system, and exploit the full function of Cyberknife in high-precision radiosurgery and therapy. Optimized inverse treatment plan can be achieved by fine-tuning contours and planning parameters. Precision is the newest version of Cyberknife treatment planning system (TPS) and an upgrade to Multiplan. It offers several new features such as Monte Carlo for multileaf collimator (MLC) and retreatment for other modalities that added more support for the Cyberknife system. The Cybeknife TPS is an easy-to-use and versatile inverse planning platform, suitable for stereotactic radiosurgery and radiation therapy. The knowledge and experience of the planner in this TPS is essential to improve the quality of patient care. PMID- 29605530 TI - Zinc improves mitochondrial respiratory function and prevents mitochondrial ROS generation at reperfusion by phosphorylating STAT3 at Ser727. AB - Serine 727 (Ser727) phosphorylation of STAT3 plays a role in the regulation of mitochondrial respiration. This study aimed to test if zinc could regulate mitochondrial respiration through phosphorylation of STAT3 at Ser727 in the setting of ischemia/reperfusion in the heart. Under normoxic conditions, treatment of isolated rat hearts with ZnCl2 increased cytosolic STAT3 phosphorylation at Ser727 followed by phospho-STAT3 translocation to mitochondria. In isolated rat hearts subjected to 30 min regional ischemia followed by 20 min of reperfusion, ZnCl2 given 5 min before the onset of reperfusion also increased mitochondrial phospho-STAT3. ZnCl2 enhanced ERK phosphorylation and PD98059 reversed the effect of ZnCl2 on STAT3 phosphorylation. ZnCl2 improved the mitochondrial oxidative phosphorylation at reperfusion. This effect was abolished by STAT3S727A, a mutant in which Ser727 is replaced with alanine, in H9c2 cells subjected to hypoxia/reoxygenation. In addition, ZnCl2 increased the mRNA level of the complex I subunit ND6, which was also reversed by STAT3S727A. Moreover, ZnCl2 attenuated mitochondrial ROS generation and dissipation of mitochondrial membrane potential (DeltaPsim) at reoxygenation through Ser727 phosphorylation. Finally, ZnCl2 suppression of succinate dehydrogenase (SDH) activity upon the onset of reperfusion was nullified by the Ser727 mutation. In conclusion, zinc improves cardiac oxidative phosphorylation and inhibits mitochondrial ROS generation at reperfusion by increasing mitochondrial STAT3 phosphorylation at Ser727 via ERK. The preservation of ND6 mtDNA and the inhibition of SDH activity may account for the role of STAT3 in the beneficial action of zinc on the mitochondrial oxidative phosphorylation and ROS generation at reperfusion. PMID- 29605529 TI - Bi-hemispheric repetitive transcranial magnetic stimulation for upper limb motor recovery in chronic stroke: A feasibility study. PMID- 29605531 TI - High prevalence of ceftriaxone resistance among invasive Salmonella enterica serotype Choleraesuis isolates in Thailand: The emergence and increase of CTX-M 55 in ciprofloxacin-resistant S. Choleraesuis isolates. AB - S. Choleraesuis is a highly invasive zoonotic pathogen that causes a serious systemic infection in humans. The emergence and increase of resistance to ceftriaxone and ciprofloxacin among S. Choleraesuis has become a serious therapeutic problem. The present study demonstrated high frequency of antimicrobial resistance in Salmonella Choleraesuis among 414 nontyphoidal Salmonella isolates from bacteremic patients in Thailand. High rates of ceftriaxone (58.3%) and ciprofloxacin (19.6%) resistances were observed in S. Choleraesuis isolates. The dissemination of the self-transferable blaCTX-M-14 carrying IncFIIs, IncFII, and IncI1 plasmids and blaCMY-2-carrying IncA/C plasmid along with the clonal spread of blaCMY-2-harbouring S. Choleraesuis isolates contributed to the high frequency of resistance to extended-spectrum cephalosporins (ESCs; third- and fourth-generation cephalosporins) during 2005 2007. We reported the first occurrence of ceftazidime-hydrolysing CTX-M-55 in S. Choleraesuis isolates which dramatically increased and became the most abundant CTX-M variant among ESC-resistant S. Choleraesuis isolates during 2012-2016. The spread of clone pulsotype B3 was due to the dissemination of IncA/C plasmids carrying both blaCTX-M-55 and qnrS1 among ciprofloxacin-resistant S. Choleraesuis isolates harbouring D87G in GyrA. These isolates were apparently responsible for the high rates of co-resistance to ESCs and ciprofloxacin (51.3%) during 2012 2016. This study emphasizes the importance to have an action plan to control the dissemination of antimicrobial resistance in S. Choleraesuis since this poses a threat to global health due to travel and trade in animal food products. PMID- 29605532 TI - Epidemiology and molecular characterization of Neisseria lactamica carried in 11 19 years old students in Salvador, Brazil. AB - Neisseria lactamica is a nonpathogenic commensal bacterium that is potentially associated with the development of natural immunity against N. meningitidis. However, the genetic variation present in natural populations of N. lactamica has not been fully investigated. To better understand its epidemiology and genetic variation, we studied N. lactamica carriage in 1200 students aged 11-19 years old in Salvador, Brazil. The carriage prevalence was 4.5% (54/1200), with no statistical difference among sex and age, although we observed a trend towards higher carriage prevalence among 11-year-old individuals. Whole genome sequence analysis revealed a high genetic diversity among the isolates, with the presence of 32 different STs, 28 (87.5%) of which were new. A total of 21/50 (42%) isolates belonged to three different clonal complexes. While none of the isolates contained nadA or fHpb alleles, we detected 21 FetA variants, 20 NhbA variants and two variants of PorB. The data provide detailed information on circulating N. lactamica isolates in adolescents in Brazil and are complementary to studies in other countries. PMID- 29605533 TI - A comparative analysis of corpora allata-corpora cardiaca microRNA repertoires revealed significant changes during mosquito metamorphosis. AB - The corpora allata (CA) are a pair of endocrine glands with neural connections to the brain and close association with another neuroendocrine organ, the corpora cardiaca (CC). The CA from adult female Aedes aegypti mosquitoes synthesize fluctuating levels of juvenile hormone (JH), which have been linked to the ovarian development and are influenced by nutritional signals. In this study, we investigated the potential involvement of microRNAs (miRNAs), a type of small non coding RNAs, in the regulation of gene expression in CA-CC complexes during mosquito reproductive development, at stages with distinct JH biosynthesis patterns. We analyzed the miRNA repertoires expressed in the CA-CC of pupae, sugar-fed and blood-fed female Ae. aegypti. In total, 156 mature miRNAs were detected in the CA-CC, with 84 displaying significant differences in expression among the three CA-CC developmental stages. There were more miRNAs that were expressed in pupae, and decreased or were absent after adult emergence, when compared with changes between CA-CC of sugar and blood-fed females. Analysis of the genes identified as potential targets for the CA-CC miRNA repertoires classified them into the broad categories of metabolism, information storage and processing, and cellular processes and signaling; with genes involved in cellular processes and signaling representing the largest portion. Among them, the signal transduction mechanisms and intracellular trafficking, secretion and vesicular transport contained almost 55% of the genes' targets. A substantial number of miRNAs were differentially abundant in the libraries of the three developmental stages, and those changes were much more notable when pupae and adult stages were compared. We detected putative binding sites for some of the most abundant miRNAs on genes encoding JH biosynthetic enzymes and CC neuropeptides. These studies should help us to gain a better understanding of the regulation of CA-CC activity mediated by miRNAs during major developmental stages in mosquitoes. PMID- 29605534 TI - Erratum to "Discovery of N-arylpyrroles as agonists of GPR120 for the treatment of type II diabetes" Bioorg. Med. Chem. Lett. 28 (2018) [841-846]. PMID- 29605535 TI - Evaluating the Effect of Resveratrol on the Healing of Extraction Sockets in Cyclosporine A-Treated Rats. AB - PURPOSE: The objective of this study was to investigate the effects of resveratrol on alveolar socket healing after tooth extraction in normal and cyclosporin A (CsA)-treated rats. MATERIALS AND METHODS: Seventy-two female Sprague-Dawley rats were separated into 4 groups of 18. Group 1 was injected with a placebo solution intraperitoneally. Group 2 was injected with resveratrol (10 MUmol/kg) intraperitoneally. Groups 3 and 4 were injected with CsA (10 mg/kg) subcutaneously for 8 days once daily before tooth extraction. Next, the teeth were extracted and CsA injection continued until the animals were sacrificed. Eight days after commencing the CsA injections, group 4 was injected with resveratrol while continuing with CsA injections. Nine rats from each group were sacrificed on days 14 and 28, and sections were examined to assess the degree of inflammation, formation of connective tissue, and new bone formation. Immunohistochemical analysis was used to evaluate the alveolar socket healing process using osteocalcin and osteopontin markers. A P value less than .05 was considered significant. RESULTS: There was more new bone formation in group 2 than in the other 3 groups on day 14 after tooth extraction (P < .05), and there was more new bone formation in group 2 than in groups 3 and 4 on day 28 after extraction (P < .05). Based on the immunohistochemical assessment, the amount of osteocalcin and osteopontin labeling was greater in group 2 compared with the other 3 groups on day 14 (P < .05); however, on day 28 after extraction, it was greater in group 4 compared with group 3 (P < .05). CONCLUSIONS: Resveratrol improves alveolar socket healing in normal and CsA-treated rats. Resveratrol also increases levels of osteocalcin and osteopontin in normal and CsA-treated rats. These results suggest that this natural compound is useful for alveolar socket healing after tooth extraction. PMID- 29605536 TI - Association of the Preoperative Body Mass Index With Postoperative Complications After Treatment of Oral Squamous Cell Carcinoma. AB - PURPOSE: Nutritional status is believed to influence surgical outcome. Because of a lack of actual reports in the literature, this study evaluated the surgical outcome of patients after treatment for oral squamous cell carcinoma (OSCC), with special focus on the preoperative body mass index (BMI). PATIENTS AND METHODS: This retrospective cohort study investigated the association between preoperative BMI and surgical outcome for patients with OSCC, focusing on local and medical complications. This research also analyzed common clinical and demographic parameters, such as age, gender, TNM stage, tumor differentiation, risk behavior, Karnofsky Index, duration of operation, and length of hospital stay. Statistics were performed using the chi2 test or Fisher exact test for categorical analysis and the t test or analysis of variance and Pearson correlation test for continuous variables. Multivariate analysis was computed for BMI with a multivariate linear regression model and for local and medical complications with multivariate Poisson regression. RESULTS: In the sample of 419 patients with OSCC, 8.6% were underweight, 54.7% were normal weight, and 36.8% were overweight (overall mean BMI, 24.28 kg/m2). BMI was significantly associated with age (P = .0017), consumption of nicotine (P = .0178) and alcohol (P = .0008), dental status (P = .0163), tumor differentiation (P = .0288), and tumor status (P = .0005). Underweight in particular was negatively correlated with local postoperative complications (P = .0047). Local complications were associated with the need for operative revisions (P < .0001) and an increase of hospital length of stay (P < .0001) using multivariable analysis. CONCLUSION: These results indicate that evaluation of preoperative morbidity and nutritional status, especially in underweight patients, is worthwhile to improve medical and economic postoperative outcomes after surgical therapy of OSCC. PMID- 29605537 TI - Furuncular myiasis due to Cordylobia anthropophaga in a Latin American resident. PMID- 29605539 TI - Integrated flow-mediated vasodilation response predicts cardiovascular events in elderly patients with cardiovascular risk factors: the Japan Morning Surge-Home Blood Pressure study. AB - The integrated flow-mediated vasodilation (FMD) response has been associated with cardiovascular (CV) risk factors, but the association between the integrated FMD response and subsequent CV events has been unclear. We enrolled 555 patients who had at least one CV risk factor (hypertension, dyslipidemia, diabetes, or smoking). We measured the peak percentage change in diameter (DeltaFMD), and integrated FMD response calculated as the area under the dilation curve over a 120-second dilation period (FMD-AUC120). Elderly patients (age >= 65 years, N = 270) in the lowest tertile of FMD-AUC120 (FMD-AUC120 < 5.6) had a higher rate of CV events compared with those in the two higher tertiles (FMD-AUC120 >= 5.6) (log rank 4.15, P = .041). The association remained significant after adjusting for covariates (hazard ratio 3.84, P = .007). In the 285 middle-aged patients (age < 65 years), the CV event rates were similar between patients in the lowest tertile and those in the two higher tertiles of FMD-AUC120 (log rank 0.39, P = .53). The CV event rates were similar between patients in the lowest tertile and those in the two higher tertiles of DeltaFMD in elderly and middle-aged patient groups. In conclusion, integrated flow-mediated vasodilation response, but not DeltaFMD, predicted CV events in elderly patients with CV risk factors. PMID- 29605538 TI - Cadmium body burden, hypertension, and changes in blood pressure over time: results from a prospective cohort study in American Indians. AB - American Indian communities are at greater risk of hypertension and cardiovascular disease than the general US population and are exposed to greater cadmium levels. However, cadmium's effect on blood pressure is unclear. This study assesses the association between baseline urinary cadmium and longitudinal changes in blood pressure in American Indian communities. Cadmium was measured in 3047 baseline urine samples from Strong Heart Study participants from three geographic areas. Longitudinal changes in blood pressure across three study visits (1989-1999) were modeled using linear mixed models by baseline log urinary cadmium to creatinine ratio. Hypertension risk was evaluated using interval censored survival analysis. Higher levels of urinary cadmium at baseline were associated with faster rates of increase in diastolic and systolic blood pressure (P [trend] = .001 and .02, respectively). The estimated change in diastolic and systolic blood pressures per year was 0.18 mm Hg (0.05-0.31) and 0.62 mm Hg (0.37 0.87) in the upper quintile of cadmium level compared with -0.11 mm Hg (-0.24 to 0.02) and 0.21 mm Hg (-0.04 to 0.46) in the lowest, respectively. A one-unit increase in log-transformed urinary cadmium was associated with 10% greater hypertension risk (95% confidence interval: 1.01-1.20). In conclusion, blood pressure of individuals with greater baseline levels of urinary cadmium increased at a faster rate relative to those with lower levels. PMID- 29605540 TI - The management of methamphetamine use in sexual settings among men who have sex with men in Malaysia. AB - BACKGROUND: The intentional use of illicit drugs for sexual purposes (also known as 'chemsex') is well known within the MSM communities in Malaysia although research in this population is scarce primarily because both drug use and homosexuality are illegal and stigmatised in Malaysia. METHODS: From April to December 2014, interviews were conducted with twenty men (age range 21-43) living in Greater Kuala Lumpur who had sexual intercourse with other men in the past 6 months and who used illicit drugs at least monthly in the past 3 months. Fourteen men were recruited via gay social networking smartphone applications or websites while six were referred by the participants. Data were analsed using thematic analytic approach. FINDINGS: The average duration of illicit drug use was 6.4 years (range 1-21) and all participants were using methamphetamine ("ice" or crystal meth) with frequency of use ranged from daily to once a month. Participants came from diverse ethnic, economic, and occupational backgrounds. Most participants used an inhalation apparatus ("bong") to consume methamphetamine and injection was rare in the sample. The primary motivation of methamphetamine use was to increase sexual capacity, heighten sexual pleasure and enhance sexual exploration and adventurism. Socializing with friends ("chilling"), and increased energy for work were secondary motivations. Participants emphasized the need to control the use of methamphetamine and some have established rules to control the amount and duration of use and a minority of men have maintained condom use during anal sex while under the influence of methamphetamine. Participants who professed to be in control of their drug use characterized themselves as functional users regardless of the health and social consequences from continuing use. Overall, participants perceived themselves differently from the traditional opioid users and reported limited access to sexual health and substance use treatment services. CONCLUSION: There is a need to increase access to HIV prevention services such as PrEP and PEP, professional support, and substance abuse treatment for drug-using MSM. A more open and friendly environment towards drug-using MSM may help them access and engage with the health services. PMID- 29605541 TI - Activation of the 12/15 lipoxygenase pathway accompanies metabolic decline in db/db pre-diabetic mice. AB - The 12-lipoxygenase (12LO) pathway is a promising target to reduce islet dysfunction, adipose tissue (AT) inflammation and insulin resistance. Optimal pre clinical models for the investigation of selective12LO inhibitors in this context have not yet been identified. The objective of this study was to characterize the time course of 12LO isoform expression and metabolite production in pancreatic islets and AT of C57BLKS/J-db/db obese diabetic mouse in a pre-diabetic state in order to establish a suitable therapeutic window for intervention with selective lipoxygenase inhibitors. Mice have 2 major 12LO isoforms -the leukocyte type (12/15LO) and the platelet type (p12LO) and both are expressed in islets and AT. We found a sharp increase in protein expression of 12/15LO in the pancreatic islets of 10-week old db-/- mice compared to 8- week old counterparts. Immunohistochemistry showed that the increase in islet 12/15LO parallels a decline in islet number. Analysis of 12- and 15-hydroperoxytetraeicosanoid acids (HETE)s showed a 2-3 fold increase especially in 12(S)-HETE that mirrored the increase in 12/15LO expression in islets. Analysis of AT and stromal vascular fraction (SVF) showed a significant increase of platelet 12LO gene expression along with 12- and 15- HETEs. The data demonstrate that the db/db mouse is a suitable model for investigation of 12/15LO inhibitors in the development of inflammatory mediated type 2 diabetes, with a narrow window of therapeutic intervention prior to 8 weeks of age. PMID- 29605542 TI - Non-culture based assays for the detection of fungal pathogens. AB - Traditional, culture based methods for the diagnosis of fungal infections are still considered as gold standard, but they are time consuming and low sensitive. Therefore, in order to overcome the limitations, many researchers have focused on the development of new immunological and molecular based rapid assays that could enable early diagnosis of infection and accurate identification of fungal pathogens causing superficial and invasive infection. In this brief review, we highlighted the advantages and disadvantages of conventional diagnostic methods and possibility of non-culture based assays in diagnosis of superficial fungal infections and presented the overview on currently available immunochromatographic assays as well as availability of biomarkers detection by immunodiagnostic procedures in prompt and accurate diagnosis of invasive fungal infections. In addition, we presented diagnostic efficiency of currently available molecular panels and researches in this area. PMID- 29605543 TI - Anti-candidal activity of selected analgesic drugs used alone and in combination with fluconazole, itraconazole, voriconazole, posaconazole and isavuconazole. AB - BACKGROUND: The antifungal activity of some popular analgesic drugs was postulated by several authors. OBJECTIVES: The aim of this study was to verify the antifungal effectiveness of acetylsalicylic acid, ibuprofen, metamizole, meloxicam and paracetamol against triazole-susceptible and triazole-resistant Candida spp isolates. METHODS: The minimal inhibitory concentration as well as fractional inhibitory concentration of selected analgesics and triazole on eighteen Candida spp isolates were determined by the standard microdilution method according to EUCAST. RESULTS: Among five tested compounds, only ibuprofen showed an antifungal effect against all tested isolates. In combination tests of analgesics with triazole, three types of interaction have been observed: indifference, synergism and antagonism. An azole-resistant strain of C. albicans demonstrated synergism with IBU and each of the 5 tested azole. Posaconazole also demonstrated synergism with IBU in two other cases, namely a C. albicans strain and with C. glabrata, which were both azole-resistant. Combination of FLU and IBU in two cases resulted in antagonism: in experiments with C. glabrata and C. tropicalis. This interaction was also observed when metamizole and fluconazole were used in combination on C. krusei. CONCLUSIONS: The results obtained by us confirmed antifungal activity of ibuprofen, what support purposefulness to continue the study on antimicrobial activity of this group of drugs. PMID- 29605544 TI - Role of X-linked inhibitor of apoptosis (XIAP) in frozen and thawed dormant and normal-hatched murine blastocysts. AB - Cryo-injury of mammalian blastocysts occurs during cryopreservation and induces apoptosis in trophoblast cells. This damage affects subsequent embryo development or may even cause death before implantation. X-linked inhibitor of apoptosis (XIAP) is an anti-apoptosis gene that has been widely studied in cancer research. However, only a few studies have investigated the activity of XIAP in cryopreservation. In this study, we investigate the role of XIAP in frozen and thawed murine blastocysts. A total of 1630 blastocysts were divided into fresh and freeze-thaw groups, and XIAP expression was investigated using qPCR, Western blot and confocal analyses. In addition, the effect of the embelin (a XIAP inhibitor) was also evaluated by co-culturing 390 dormant blastocysts. XIAP protein is primarily localized to the mitochondria of trophoblastic cells. Gene and protein expression is significantly down-regulated in blastocysts after cryopreservation, whereas embelin has negative effect on their survivals. These findings further broaden the understanding of mammalian embryonic cryopreservation. PMID- 29605546 TI - Trypanosomatids Are Much More than Just Trypanosomes: Clues from the Expanded Family Tree. AB - Trypanosomes and leishmanias are widely known parasites of humans. However, they are just two out of several phylogenetic lineages that constitute the family Trypanosomatidae. Although dixeny - the ability to infect two hosts - is a derived trait of vertebrate-infecting parasites, the majority of trypanosomatids are monoxenous. Like their common ancestor, the monoxenous Trypanosomatidae are mostly parasites or commensals of insects. This review covers recent advances in the study of insect trypanosomatids, highlighting their diversity as well as genetic, morphological and biochemical complexity, which, until recently, was underappreciated. The investigation of insect trypanosomatids is providing an important foundation for understanding the origin and evolution of parasitism, including colonization of vertebrates and the appearance of human pathogens. PMID- 29605547 TI - Coordination of Cell Polarity, Mechanics and Fate in Tissue Self-organization. AB - Self-organization guides robust, spatiotemporally ordered formation of complex tissues and ultimately whole organisms. While products of gene expression serve as building blocks of living matter, how these interact to give rise to tissues of distinct patterns and function remains a central question in biology. Tissue self-organization relies on dynamic interactions between constituents spanning a range of spatiotemporal scales with tuneable chemical and mechanical parameters. This review highlights recent studies dissecting mechanisms of these interactions. We propose that feedback interactions between cell polarity, mechanics, and fate are a key principle underlying tissue self-organization. We also provide a glimpse into how such processes can be studied in future endeavors. PMID- 29605545 TI - A comparison of intrauterine hemopoietic cell transplantation and lentiviral gene transfer for the correction of severe beta-thalassemia in a HbbTh3/+ murine model. AB - Major hemoglobinopathies place tremendous strain on global resources. Intrauterine hemopoietic cell transplantation (IUHCT) and gene transfer (IUGT) can potentially reduce perinatal morbidities with greater efficacy than postnatal therapy alone. We performed both procedures in the thalassemic HbbTh3/+ mouse. Intraperitoneal delivery of co-isogenic cells at embryonic days13-14 produced dose-dependent chimerism. High-dose adult bone marrow (BM) cells maintained 0.2 3.1% chimerism over ~24 weeks and treated heterozygotes (HET) demonstrated higher chimerism than wild-type (WT) pups (1.6% vs. 0.7%). Fetalliver (FL) cells produced higher chimerism than BM when transplanted at thesame doses, maintaining 1.8-2.4% chimerism over ~32 weeks. We boosted transplanted mice postnatally with BM cells after busulfan conditioning. Engraftment was maintained at >1% only in chimeras. IUHCT-treated nonchimeras and non-IUHCT mice showed microchimerism or no chimerism. Improved engraftment was observed with a higher initial chimerism, in HET mice and with the addition of fludarabine. Chimeric HET mice expressed 2.2 15.1% engraftment with eventual decline at 24 weeks (vs. <1% in nonchimeras) and demonstrated improved hematological indices and smaller spleens compared with untreated HETmice. Intravenous delivery of GLOBE lentiviral-vector expressing human beta-globin (HBB) resulted in a vector concentration of 0.001-0.6 copies/cell. Most hematological indices were higher in treated than untreated HET mice, including hemoglobin and mean corpuscular volume, but were still lower than in WT. Therefore, direct IUGT and IUHCT strategies can be used to achieve hematological improvement but require further dose optimization. IUHCT will be useful combined with postnatal transplantation to further enhance engraftment. PMID- 29605548 TI - SCN1A rs3812718 polymorphism is associated with epilepsy: An updated meta analysis. AB - To clarify the association between SCN1A rs3812718 polymorphism and epilepsy, we performed an updated meta-analysis. PubMed, Science Direct, Embase, Springer, Google Scholar, and Cochrane databases were searched before January 20, 2018. Odds ratios and 95% confidence intervals were used to assess the strength of associations. Finally, simply eight studies were included in this meta-analysis and all together recruited 7184 individuals, and they consisted of 3595 cases and 3589 controls. Based on the quality evaluation with the NOS, the overall quality of eight studies was scored from seven to eight which indicated good quality. A significant association between SCN1A rs3812718 polymorphism and the risk of epilepsy was detected in the homozygote comparison (OR = 1.64, 95% CI, 1.25-2.15, P = .001, P(BON) = 0.004), and dominant model (OR = 1.36, 95% CI, 1.08-1.72, P < .001, P(BON) < 0.001), but not in heterozygote comparison (OR = 1.22, 95% CI, 0.98-1.53, P = .003, P(BON) = 0.001), and recessive model (OR = 1.35, 95% CI, 1.22-1.49, P = .104, P(BON) = 0.104). In conclusion, our results suggest that SCN1A rs3812718 polymorphism is associated with the risk of epilepsy. PMID- 29605549 TI - Hepatozoon martis n. sp. (Adeleorina: Hepatozoidae): Morphological and pathological features of a Hepatozoon species infecting martens (family Mustelidae). AB - Species of the genus Hepatozoon (Adeleorina: Hepatozoidae) are arthropod transmitted protozoan parasites that infect a wide range of vertebrate hosts. In the present study, we describe a new species of Hepatozoon primarily infecting martens and propose the name Hepatozoon martis n. sp., based on its unique morphological, molecular and pathogenic features. The overall prevalence of infection with H. martis n. sp. assessed by PCR in European pine martens (Martes martes) from Bosnia and Herzegovina and stone martens (Martes foina) from Croatia was 100% and 64%, respectively. Gamonts were found in neutrophils and monocytes, and various developmental stages were described in tissue cross-sections. Hepatozoon martis n. sp. shows a high predilection for muscle tissue, and the heart was the most frequently affected organ among the tissues tested by histopathology. Microscopically, pyogranulomatous lesions associated with the presence of the parasitic forms were observed in the cardiac and skeletal muscles of all positive animals examined. Furthermore, the possible existence of alternative, non-vectorial routes of transmission is discussed. PMID- 29605550 TI - Purification and biochemical characterization of VesT1s, a novel phospholipase A1 isoform isolated from the venom of the greater banded wasp Vespa tropica. AB - Vespa tropica, a social wasp locally found in Thailand is responsible for many out off the record accidental stings due to close encounters with human activities and because of the animal's highly potent venom. Phospholipase (PLA) is one of the major proteins commonly found in insect venom. In this work, V. tropica phospholipase was successfully isolated, purified and characterized. Three isoforms PLAs have been purified using reversed phase HPLC, and are named VesT1s (VesT1.01a, VesT1.01b and VesT1.02). They are not glycoproteins. VesT1.01s has a molecular weight of 33.72 kDa while for VesT1.02 a mass of 34 kDa was found. The deduced sequence of the mature VesT1.02 protein is composed of 301 amino acid residues (1005 bp), including the catalytic triad (Ser-His-Asp), which is similar to other wasp venom PLAs. The 12 cysteine residues found are conserved among venom PLA1. They form six disulfide bonds, and therefore have no free sulfhydryl groups. Based on homology modelling, VesT1.02 belongs to the alpha/beta hydrolase fold family. Its structure is composed of 10 beta-sheets and 11 alpha-helixes, characterized by a beta-strand/epsilonSer/alpha-helix structural motif, which contains the Gly-X-Ser-X-Gly consensus sequence. The shortened lid and shortened beta9 loop, which play important roles in substrate selectivity, cause this enzyme to only exhibit PLA activity. Moreover, these PLAs have been shown to be highly thermally stable after heating at 100 degrees C for 5 min. We propose that an inserted Pro residue might be involved in this high thermo-stability. PMID- 29605551 TI - Deriving proper measurement uncertainty from Internal Quality Control data: An impossible mission? AB - Measurement uncertainty (MU) is a "non-negative parameter characterizing the dispersion of the quantity values being attributed to a measurand, based on the information used". In the clinical laboratory the most convenient way to calculate MU is the "top down" approach based on the use of Internal Quality Control data. As indicated in the definition, MU depends on the information used for its calculation and so different estimates of MU can be obtained. The most problematic aspect is how to deal with bias. In fact bias is difficult to detect and quantify and it should be corrected including only the uncertainty derived from this correction. Several approaches to calculate MU starting from Internal Quality Control data are presented. The minimum requirement is to use only the intermediate precision data, provided to include 6 months of results obtained with a commutable quality control material at a concentration close to the clinical decision limit. This approach is the minimal requirement and it is convenient for all those measurands that are especially used for monitoring or where a reference measurement system does not exist and so a reference for calculating the bias is lacking. Other formulas including the uncertainty of the value of the calibrator, including the bias from a commutable certified reference material or from a material specifically prepared for trueness verification, including the bias derived from External Quality Assessment schemes or from historical mean of the laboratory are presented and commented. MU is an important parameter, but a single, agreed upon way to calculate it in a clinical laboratory is not yet available. PMID- 29605552 TI - Automated structure and flow measurement - a promising tool in nailfold capillaroscopy. AB - OBJECTIVES: Despite increasing interest in nailfold capillaroscopy, objective measures of capillary structure and blood flow have been little studied. We aimed to test the hypothesis that structural measurements, capillary flow, and a combined measure have the predictive power to separate patients with systemic sclerosis (SSc) from those with primary Raynaud's phenomenon (PRP) and healthy controls (HC). METHODS: 50 patients with SSc, 12 with PRP, and 50 HC were imaged using a novel capillaroscopy system that generates high-quality nailfold images and provides fully-automated measurements of capillary structure and blood flow (capillary density, mean width, maximum width, shape score, derangement and mean flow velocity). Population statistics summarise the differences between the three groups. Areas under ROC curves (AZ) were used to measure classification accuracy when assigning individuals to SSc and HC/PRP groups. RESULTS: Statistically significant differences in group means were found between patients with SSc and both HC and patients with PRP, for all measurements, e.g. mean width (MUm) +/- SE: 15.0 +/- 0.71, 12.7 +/- 0.74 and 11.8 +/- 0.23 for SSc, PRP and HC respectively. Combining the five structural measurements gave better classification (AZ = 0.919 +/- 0.026) than the best single measurement (mean width, AZ = 0.874 +/- 0.043), whilst adding flow further improved classification (AZ = 0.930 +/- 0.024). CONCLUSIONS: Structural and blood flow measurements are both able to distinguish patients with SSc from those with PRP/HC. Importantly, these hold promise as clinical trial outcome measures for treatments aimed at improving finger blood flow or microvascular remodelling. PMID- 29605553 TI - Negative Pressure Wound Therapy Followed by Basic Fibroblast Growth Factor Spray as a Recovery Technique in Partial Necrosis of Distally Based Sural Flap for Calcaneal Osteomyelitis: A Case Report. AB - The distally based sural flap is regarded as the first choice for reconstruction in the distal part of the lower leg because the flap is easy to raise, reliable in its blood supply, and prone to only a few complications. Limited data have investigated the details of treatment in cases of failure of distally based sural flaps. We report a case of calcaneal osteomyelitis in which a successful outcome was finally obtained with a partially necrosed, distally based sural flap using negative pressure wound therapy with basic fibroblast growth factor spray. The 2 year follow-up examination was uneventful. Moreover, the patient was able to walk freely with an ankle-foot orthosis in her house. This technique can be considered as a useful and effective option to recover unfavorable results of distally based sural flaps. PMID- 29605554 TI - Ankle Arthritis Combined With Chronic Instability of the Syndesmosis After Ankle Fracture With Syndesmotic Injury: A Case Report. AB - Syndesmotic injuries associated with ankle fractures are commonly treated with reduction and fixation using a transfixing screw. On rare occasions, however, progression to chronic instability of the syndesmosis is observed. Several surgical techniques have been applied in such cases but usually without a report on the results. We report a case of chronic syndesmotic instability and ankle joint osteoarthritis after ankle fracture-dislocation in a 21-year-old male patient who underwent distal tibiofibular arthrodesis. During the relatively long 4-year, 1-month follow-up period, the pain and activity improved from the patient's preoperative condition. Radiographs demonstrated cessation of arthritic changes in the ankle that had initially displayed joint space narrowing. Our findings suggest distal tibiofibular arthrodesis as an option to consider for the treatment of young and active patients with arthritic changes in the ankle joint with concomitant chronic instability of the syndesmosis. PMID- 29605555 TI - Randomized controlled trial: PPI-based triple therapy containing metronidazole versus clarithromycin as first-line treatment for Helicobacter pylori in adolescents and young adults in Japan. AB - BACKGROUND/AIMS: Treating Helicobacter pylori infection in young people is effective for preventing gastric cancer. This study compares the efficacy of triple therapies in adolescents and young adults in Japan. METHODS: This multicenter, randomized trial was conducted between February 2012 and March 2015. Infected participants were stratified into adolescents (13-19 years) and young adults (20-39 years). They were randomly assigned to a clarithromycin based (PAC) or metronidazole based (PAM) triple therapy for 1 week. RESULTS: Overall, 137 and 169 participants received the PAC and PAM treatments, respectively. In adolescents, the H. pylori eradication rates were 60.5% and 63.4% for PAC, and 98.3% and 100% for PAM in the intention-to-treat (ITT) and per-protocol (PP) analyses, respectively. In young adults, the eradication rates were 67.0% and 66.7% for PAC, and 95.5% and 96.3% for PAM in ITT and PP analyses, respectively. The eradication rate of PAM was significantly higher than that of PAC in both strata. No severe adverse events were observed. CONCLUSION: In Japan, PAM may be selected as a first-line treatment for young people with H. pylori if antibiotic susceptibility tests cannot be performed. PMID- 29605556 TI - Re-evaluation of the etiology and clinical and radiological features of community acquired lobar pneumonia in adults. AB - OBJECTIVE: The aims of this study were to elucidate the frequency and etiology of community-acquired lobar pneumonia (CALP) and the clinical and radiological differences between CALP and tuberculous lobar pneumonia (TLP). PATIENTS AND METHODS: We retrospectively reviewed medical records of patients with community acquired pneumonia (CAP) (n = 1032) and tuberculosis (n = 1101) admitted to our hospital. RESULTS: Sixty-nine (6.7%) patients with CAP and 23 (2.1%) with pulmonary tuberculosis developed CALP. Legionella species were the most common pathogen (27 patients, 39.1%), followed by Streptococcus pneumoniae (19 patients, 27.5%) and Mycoplasma pneumoniae (18 patients, 26.1%). Symptom duration was longer in the patients with TLP than in those with CALP. On chest radiographs, cavitation in the area of lobar pneumonia and nodular shadows were radiological findings predictive of TLP. High-resolution computed tomography showed cavitation in the area of lobar pneumonia, well-defined centrilobular nodules, and tree-in bud sign to be the radiological findings predictive of TLP by multivariate logistic regression models. CONCLUSION: Common causes of CALP are Legionella species, S. pneumoniae, and M. pneumoniae. TLP should be considered in patients with lobar pneumonia, particularly in patients with long symptom duration, cavitation, and nodular shadows on chest radiographs, and cavitation, well defined centrilobular nodules, and tree-in-bud sign on CT. PMID- 29605558 TI - Navigated versus conventional total knee arthroplasty: A prospective study at three years follow-up. AB - OBJECTIVE: Computer-assisted surgery application in total knee arthroplasty (TKA) has shown more accurate implant alignment compared with conventional instrumentation and is associated with more homogeneous alignment results. Although longer implant survival and superior clinical outcomes should be expected from navigated TKA, currently available evidence does not support this hypothesis. The aim of this study was to compare navigated TKA with conventional TKA regarding clinical and radiological outcomes after a 3-year follow-up under the hypothesis that navigated TKA would provide better outcomes than conventional TKA. MATERIAL AND METHOD: In a prospective multicentre study, 119 patients underwent navigated TKA and 80 patients received conventional instrumentation. Patients were evaluated at the baseline and at postoperative months 3, 12, 24, and 36. Analysis included the American Knee Society Score (KSS), Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Short Form-12 (SF12) Health Survey, and radiographic assessment. RESULTS: All clinical scores improved significantly for all patients during the follow-up but were significantly better in the navigation group. The percentage of patients showing a mechanical axis between 3 degrees of varus and 3 degrees of valgus was significantly higher in the ATR group (93%) than in the conventional TKA group (71%) (P<.01). CONCLUSIONS: The use of computer-assisted surgery in TKA provides more accurate mechanical alignment and superior short-term functional outcomes compared to conventional TKA. PMID- 29605557 TI - Nitrolipids in kidney physiology and disease. AB - The kidneys are vital organs responsible for maintaining body fluid homeostasis within proper physiologic ranges. Kidney disease is an epidemic clinical problem causing significant morbidity and mortality, and current treatments are limited to renin-angiotensin system blockade or renal replacement therapy for the majority of affected individuals. There is a critical, unmet need for novel pharmacological agents to improve the outcome of patients with kidney disease. Nitro-oleic acid (NO2-OA) is an endogenously generated electrophilic compound with the capacity to modify thiols in proteins, altering their function. The most important targets appear to be the Keap1/Nrf2 and NF-kappaB pathways, which have widespread effects on antioxidant, detoxifying, and inflammatory responses in cells and tissues. Through these and potentially additional protective actions, NO2-OA may be capable of preserving or enhancing kidney function in acute and chronic kidney diseases. PMID- 29605559 TI - Technical aspects and complications in the surgical treatment of poliomyelitis affected lower limb fractures. AB - OBJECTIVE: Post-polio patients present problems such as small and deformed bones, with narrow intramedullary canal and osteoporosis, affecting surgical treatment. The aim of this article is to describe the main preoperative and intraoperative complications of the surgical treatment of fractures in this population. MATERIAL AND METHODS: A retrospective analysis was conducted between 1995 and 2014. Data obtained from the medical records included patient age, fracture pattern (AO/OTA), device used, technical aspects of the surgery that changed compared to a standard procedure, and the presence of intraoperative skeletal complications. RESULTS: Sixty-four patients with 78 fractures were included in the study. Forty seven percent of the fractures were at the proximal femur. The main complications of hip arthroplasty (14 patients) were absent hip abductors and intraoperative instability (3), bad cup fixation (3) and intraoperative periprosthetic fracture (2). The main problems of intramedullary nailing were due to a narrow canal and previous bone deformity. Main problems reported when plating included difficulty to fit a precontoured plate, and oversized hardware. CONCLUSION: Given the large number of intraoperative complications, in preoperative planning we must include nails of small diameter and length, locking plates and external fixators, and, in the case of hip arthroplasty, long and thin stems and restrictive or dual mobility acetabular systems. PMID- 29605560 TI - Initial group dietary education compared to individual education in gestational diabetes mellitus management: Do outcomes differ? AB - AIMS: To assess the effectiveness of Initial Group versus Initial Individual GDM dietary education in terms of insulin requirements and pregnancy outcomes. METHODS: A retrospective audit of clinical data was conducted where English speaking women who received initial education in a group setting (01-2-2012 to 01 2-2014) (Group), were compared to women who received initial individual education with a dietitian (1-2-2010 to 31-1-2012) (Individual), all followed by one individual dietitian appointment. The same dietary information was provided in both settings. Data collected included: attendance rates, insulin requirements, maternal weight gain, and rates of adverse birth outcomes. Data were compared by t-test or Chi-squared test. Multivariable logistic regression analysis was conducted to determine independent predictors of insulin therapy. RESULTS: Of 743 women; (362 Group and 381 Individual), Group women had a lower HbA1c at GDM diagnosis 5.3 +/- 0.6% versus 5.5 +/- 0.5% (34 +/- 6.6 mmol/mol versus 37 +/- 5.5 mmol/mol p < 0.0001). There were no other differences in baseline characteristics. More Group women required insulin (42.0% versus 34.6%, p = 0.048). Group education was found to be an independent predictor of insulin therapy (OR = 1.9 [1.29, 2.75] p < 0.001). CONCLUSIONS: Despite adjusting for all known potential confounders, unlike Individual education, Group education remained a significant predictor of insulin therapy (but resulted in similar therapeutic and pregnancy outcomes to Individual education). PMID- 29605561 TI - Comparison of Natural Language Processing Rules-based and Machine-learning Systems to Identify Lumbar Spine Imaging Findings Related to Low Back Pain. AB - RATIONALE AND OBJECTIVES: To evaluate a natural language processing (NLP) system built with open-source tools for identification of lumbar spine imaging findings related to low back pain on magnetic resonance and x-ray radiology reports from four health systems. MATERIALS AND METHODS: We used a limited data set (de identified except for dates) sampled from lumbar spine imaging reports of a prospectively assembled cohort of adults. From N = 178,333 reports, we randomly selected N = 871 to form a reference-standard dataset, consisting of N = 413 x ray reports and N = 458 MR reports. Using standardized criteria, four spine experts annotated the presence of 26 findings, where 71 reports were annotated by all four experts and 800 were each annotated by two experts. We calculated inter rater agreement and finding prevalence from annotated data. We randomly split the annotated data into development (80%) and testing (20%) sets. We developed an NLP system from both rule-based and machine-learned models. We validated the system using accuracy metrics such as sensitivity, specificity, and area under the receiver operating characteristic curve (AUC). RESULTS: The multirater annotated dataset achieved inter-rater agreement of Cohen's kappa > 0.60 (substantial agreement) for 25 of 26 findings, with finding prevalence ranging from 3% to 89%. In the testing sample, rule-based and machine-learned predictions both had comparable average specificity (0.97 and 0.95, respectively). The machine-learned approach had a higher average sensitivity (0.94, compared to 0.83 for rules based), and a higher overall AUC (0.98, compared to 0.90 for rules-based). CONCLUSIONS: Our NLP system performed well in identifying the 26 lumbar spine findings, as benchmarked by reference-standard annotation by medical experts. Machine-learned models provided substantial gains in model sensitivity with slight loss of specificity, and overall higher AUC. PMID- 29605562 TI - The Impact of Interruptions on Chest Radiograph Interpretation: Effects on Reading Time and Accuracy. AB - RATIONALE AND OBJECTIVES: The objective of this study was to experimentally test the effect of interruptions on image interpretation by comparing reading time and response accuracy of interrupted case reads to uninterrupted case reads in resident and attending radiologists. MATERIALS AND METHODS: Institutional review board approval was obtained before participant recruitment from an urban academic health-care system during January 2016-March 2016. Eleven resident and 12 attending radiologists examined 30 chest radiographs, rating their confidence regarding the presence or the absence of a pneumothorax. Ten cases were normal (ie, no pneumothorax present), 10 cases had an unsubtle pneumothorax (ie, readily perceivable by a nonexpert), and 10 cases had a subtle pneumothorax. During three reads of each case type, the participants were interrupted with 30 seconds of a secondary task. The total reading time and the accuracy of interrupted and uninterrupted cases were compared. A mixed-factors analysis of variance was run on reading time and accuracy with experience (resident vs attending) as a between subjects factor and case type (normal, unsubtle, or subtle) and interruption (interruption vs no interruption) as within-subjects factors. RESULTS: Interrupted tasks had significantly longer reading times than uninterrupted cases (P = .032). During subtle cases, interruptions reduced accuracy (P = .034), but during normal cases, interruptions increased accuracy (P = .038). CONCLUSIONS: Interruptions increased reading times and increased the tendency for a radiologist to conclude that a case is normal for both resident and attending radiologists, demonstrating that interruptions reduce efficiency and introduce patient safety concerns during reads of abnormal cases. PMID- 29605563 TI - Rapid phenotypic methods to improve the diagnosis of bacterial bloodstream infections: meeting the challenge to reduce the time to result. AB - BACKGROUND: Administration of appropriate antimicrobial therapy is one of the key factors in surviving bloodstream infections. Blood culture is currently the reference standard for diagnosis, but conventional practices have long turnaround times while diagnosis needs to be faster to improve patient care. Phenotypic methods offer an advantage over genotypic methods in that they can identify a wide range of taxa, detect the resistance currently expressed, and resist genetic variability in resistance detection. AIMS: We aimed to discuss the wide array of phenotypic methods that have recently been developed to substantially reduce the time to result from identification to antibiotic susceptibility testing. SOURCES: A literature review focusing on rapid phenotypic methods for improving the diagnosis of bloodstream infection was the source. CONTENT: Rapid phenotypic bacterial identification corresponds to Matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF), and rapid antimicrobial susceptibility testing methods comprised of numerous different approaches, are considered and critically assessed. Particular attention is also paid to emerging technologies knocking at the door of routine microbiology laboratories. Finally, workflow integration of these methods is considered. IMPLICATIONS: The broad panel of phenotypic methods currently available enables healthcare institutions to draw up their own individual approach to improve bloodstream infection diagnosis but requires a thorough evaluation of their workflow integration. Clinical microbiology will probably move towards faster methods while maintaining a complex multi-method approach as there is no all-in one method. PMID- 29605564 TI - New insights on antimicrobial efficacy of copper surfaces in the healthcare environment: a systematic review. AB - OBJECTIVES: Hospital-acquired infections (HAIs) are a major public health issue. The potential of antimicrobial copper surfaces in reducing HAIs' rates is of interest but remains unclear. We conducted a systematic review of studies assessing the activity of copper surfaces (colony-forming unit (CFU)/surface, both in vitro and in situ) as well as clinical studies. In vitro study protocols were analysed through a tailored checklist developed specifically for this review, in situ studies and non-randomized clinical studies were assessed using the ORION (Outbreak Reports and Intervention studies Of Nosocomial infection) checklist and randomized clinical studies using the CONSORT guidelines. METHODS: The search was conducted using PubMed database with the keywords 'copper' and 'surfaces' and 'healthcare associated infections' or 'antimicrobial'. References from relevant articles, including reviews, were assessed and added when appropriate. Articles were added until 30 August 2016. Overall, 20 articles were selected for review including 10 in vitro, eight in situ and two clinical studies. RESULTS: Copper surfaces were found to have variable antimicrobial activity both in vitro and in situ, although the heterogeneity in the designs and the reporting of the results prevented conclusions from being drawn regarding their spectrum and activity/time compared to controls. Copper effect on HAIs incidence remains unclear because of the limited published data and the lack of robust designs. Most studies have potential conflicts of interest with copper industries. CONCLUSIONS: Copper surfaces have demonstrated an antimicrobial activity but the implications of this activity in healthcare settings are still unclear. No clear effect on healthcare associated infections has been demonstrated yet. PMID- 29605565 TI - Accuracy of quick Sequential Organ Failure Assessment (qSOFA) score and systemic inflammatory response syndrome (SIRS) criteria for predicting mortality in hospitalized patients with suspected infection: a meta-analysis of observational studies. AB - OBJECTIVE: To identify sensitivity, specificity and predictive accuracy of quick sequential organ failure assessment (qSOFA) score and systemic inflammatory response syndrome (SIRS) criteria to predict in-hospital mortality in hospitalized patients with suspected infection. METHODS: This meta-analysis followed the Meta-analysis of Observational Studies in Epidemiology (MOOSE) group consensus statement for conducting and reporting the results of systematic review. PubMed and EMBASE were searched for the observational studies which reported predictive utility of qSOFA score for predicting mortality in patients with suspected or proven infection with the following search words: 'qSOFA', 'q SOFA', 'quick-SOFA', 'Quick Sequential Organ Failure Assessment', 'quick SOFA'. Sensitivity, specificity, area under receiver operating characteristic (ROC) curves with 95% confidence interval (CI) of qSOFA and SIRS criteria for predicting in-hospital mortality was collected for each study and a 2 * 2 table was created for each study. RESULTS: Data of 406 802 patients from 45 observational studies were included in this meta-analysis. Pooled sensitivity (95% CI) and specificity (95% CI) of qSOFA >=2 for predicting mortality in patients who were not in an intensive care unit (ICU) was 0.48 (0.41-0.55) and 0.83 (0.78-0.87), respectively. Pooled sensitivity (95% CI) of qSOFA >=2 for predicting mortality in patients (both ICU and non-ICU settings) with suspected infection was 0.56 (0.47-0.65) and pooled specificity (95% CI) was 0.78 (0.71 0.83). CONCLUSION: qSOFA has been found to be a poorly sensitive predictive marker for in-hospital mortality in hospitalized patients with suspected infection. It is reasonable to recommend developing another scoring system with higher sensitivity to identify high-risk patients with infection. PMID- 29605566 TI - Therapeutic effect of perinatal exogenous melatonin on behavioral and histopathological changes and antioxidative enzymes in neonate mouse model of cortical malformation. AB - BACKGROUND: Melatonin, which is an antioxidant and neuroprotective agent, can be an effective treatment for neurological disorders. We assessed the effect of melatonin administration on histological changes, antioxidant enzyme levels, and behavioral changes in a neonate mouse model of cortical malformation. MATERIALS AND METHODS: Cortical malformation was induced by two injections of 15 mg/kg methylazoxymethanol (MAM) on gestational day 15 (E15). Pregnant Balb/c mice were randomly divided into the following six groups: Control (CO), Melatonin (MEL), Luzindole (LUZ), MAM, MEL + MAM1 (co-treatment), and MEL + MAM2 (pretreatment). Melatonin was intraperitoneally injected at a dose of 10 mg/kg daily (from E15 until delivery of from E6 for 20 days after delivery). On postnatal day 31, the activity and anxiety of mice were assessed by open field and elevated plus maze tests, respectively. Histopathological changes in the neonate cortex were studied using hematoxylin and eosin staining and neurofilament immunohistochemistry. Enzyme-linked immunosorbent assays were used to measure the activity of nitric oxide (NO), malondialdehyde (MDA), and antioxidant enzymes, including catalase (CAT), super oxide dismutase (SOD), and glutathione peroxidase (GPX). RESULTS: In the behavioral assessment of neonate mice, a significant increase in the crossing activity and decrease in anxiety were recorded in groups treated with MAM plus melatonin. In histological examination, heterotopic, dysmorphic, and ectopic cells, as well as dyslamination, were seen in the MAM and LUZ groups. However, these defects were attenuated in the MAM plus melatonin groups. Significant reductions were recorded in the SOD and GPX levels in the MAM and LUZ groups compared to the control, while the NO level was increased in these groups. Groups that received MAM plus melatonin showed significant increases in the levels of SOD and GPX and a significant decrease in the level of NO, compared to the MAM group. CONCLUSION: Melatonin increased the crossing activity and decreased the anxiety in the treated mice of the neonate mouse model of cortical malformation. Histologically, the administration of exogenous melatonin in pregnant mice and their neonates had a protective effect on the cerebral cortex of neonates. Also, this effect is elicited by decreasing NO and increasing antioxidative enzymes. PMID- 29605567 TI - Electrosprayed mesoporous particles for improved aqueous solubility of a poorly water soluble anticancer agent: in vitro and ex vivo evaluation. AB - Encapsulation of poorly water-soluble drugs into mesoporous materials (e.g. silica) has evolved as a favorable strategy to improve drug solubility and bioavailability. Several techniques (e.g. spray drying, solvent evaporation, microwave irradiation) have been utilized for the encapsulation of active pharmaceutical ingredients (APIs) into inorganic porous matrices. In the present work, a novel chalcone (KAZ3) with anticancer properties was successfully synthesized by Claisen-Schmidt condensation. KAZ3 was loaded into mesoporous (SBA 15 and MCM-41) and non-porous (fumed silica, FS) materials via two techniques; electrohydrodynamic atomization (EHDA) and solvent impregnation. The effect of both loading methods on the physicochemical properties of the particles (e.g. size, charge, entrapment efficiency, crystallinity, dissolution and permeability) was investigated. Results indicated that EHDA technique can load the active in a complete amorphous form within the pores of the silica particles. In contrast, reduced crystallinity (~79%) was obtained for the solvent impregnated formulations. EHDA engineered formulations significantly improved drug dissolution up to 30-fold, compared to the crystalline drug. Ex vivo studies showed EHDA formulations to exhibit higher permeability across rat intestine than their solvent impregnated counterparts. Cytocompatibility studies on Caco-2 cells demonstrated moderate toxicity at high concentrations of the anticancer agent. The findings of the present study clearly show the immense potential of EHDA as a loading technique for mesoporous materials to produce poorly water-soluble API carriers of high payload at ambient conditions. Furthermore, the scale up potential in EHDA technologies indicate a viable route to enhance drug encapsulation and dissolution rate of loaded porous inorganic materials. PMID- 29605568 TI - [Mixed methods studies in the health sciences. A critical map]. AB - Mixed methods studies (MMS) play an increasingly important role in the health sciences. Its potential lies in the acquisition of causal conditions and in the intersubjective understanding of diverse and new phenomena. The holistic and multi-perspective analysis strategy of MMS also allows a subject-oriented and an evidence-based approach to clinical practice. The article reviews the use of MMS in the health sciences on the basis of various reviews, and it highlights current methodological developments and research gaps. PMID- 29605569 TI - Prevalence of drug use among students in mainland China: A systematic review and meta-analysis for 2003-2013. AB - BACKGROUND: In response to calls to reassess and reform international drug policy, we estimated the prevalence of drug use among students in China from 2004 to 2013 through a systematic review and meta-analysis. METHODS: We systemically identified and reviewed published studies on illicit drug use and abuse of sedative-hypnotics among students in China. We estimated the prevalence of drug use among students using a meta-regression model. The trends in drug use and any geographic differences were assessed using multilevel models, and the association between drug use and sedative-hypnotics abuse was also examined. RESULTS: The pooled prevalence of illicit drug use and sedative-hypnotics abuse in students was 2.10% (95% CI: 1.80-2.50) and 6.10% (95% CI: 5.10-7.20). A significant decrease in the prevalence of illicit drug use was observed in 2009-2013 (OR = 0.28, 95% CI: 0.25-0.32). Students in higher grades showed a higher prevalence of both illicit drug use and sedative-hypnotics abuse than those in lower grades. Provincial differences in illicit drug use (OR = 2.66, 95% CI: 1.24-5.73) and sedative-hypnotics abuse (OR = 1.37, 95% CI: 1.05-1.79) were identified. The geographical area of illicit drug use was observed to be expanding. CONCLUSION: Prevalence of drug use among students is twice as high as in the general population of adults in China, indicating that drug use is becoming an urgent public health issue among the younger population. Further investigation among school students is needed. PMID- 29605570 TI - A new HIV-1 Rev structure optimizes interaction with target RNA (RRE) for nuclear export. AB - HIV-1 Rev mediates the nuclear export of unspliced and partially-spliced viral transcripts for the production of progeny genomes and structural proteins. In this process, four (or more) copies of Rev assemble onto a highly-structured 351 nt region in such viral transcripts, the Rev response element (RRE). How this occurs is not known. The Rev assembly domain has a helical-hairpin structure which associates through three (A-A, B-B and C-C) interfaces. The RRE has the topology of an upper-case letter A, with the two known Rev binding sites mapping onto the legs of the A. We have determined a crystal structure for the Rev assembly domain at 2.25 A resolution, without resort to either mutations or chaperones. It shows that B-B dimers adopt an arrangement reversed relative to that previously reported, and join through a C-C interface to form tetramers. The new subunit arrangement shows how four Rev molecules can assemble on the two sites on the RRE to form the specificity checkpoint, and how further copies add through A-A interactions. Residues at the C-C interface, specifically the Pro31 Trp45 axis, are a potential target for intervention. PMID- 29605571 TI - Structural and functional analysis of Erwinia amylovora SrlD. The first crystal structure of a sorbitol-6-phosphate 2-dehydrogenase. AB - Sorbitol-6-phosphate 2-dehydrogenases (S6PDH) catalyze the interconversion of d sorbitol 6-phosphate to d-fructose 6-phosphate. In the plant pathogen Erwinia amylovora the S6PDH SrlD is used by the bacterium to utilize sorbitol, which is used for carbohydrate transport in the host plants belonging to the Amygdaloideae subfamily (e.g., apple, pear, and quince). We have determined the crystal structure of S6PDH SrlD at 1.84 A resolution, which is the first structure of an EC 1.1.1.140 enzyme. Kinetic data show that SrlD is much faster at oxidizing d sorbitol 6-phosphate than in reducing d-fructose 6-phosphate, however, equilibrium analysis revealed that only part of the d-sorbitol 6-phosphate present in the in vitro environment is converted into d-fructose 6-phosphate. The comparison of the structures of SrlD and Rhodobacter sphaeroides sorbitol dehydrogenase showed that the tetrameric quaternary structure, the catalytic residues and a conserved aspartate residue that confers specificity for NAD+ over NADP+ are preserved. Analysis of the SrlD cofactor and substrate binding sites identified residues important for the formation of the complex with cofactor and substrate and in particular the role of Lys42 in selectivity towards the phospho substrate. The comparison of SrlD backbone with the backbone of 302 short-chain dehydrogenases/reductases showed the conservation of the protein core and identified the variable parts. The SrlD sequence was compared with 500 S6PDH sequences selected by homology revealing that the C-terminal part is more conserved than the N-terminal, the consensus of the catalytic tetrad (Y[SN]AGXA) and a not previously described consensus for the NAD(H) binding. PMID- 29605572 TI - Decreased ghrelin and des-acyl ghrelin plasma levels in patients affected by pharmacoresistant epilepsy and maintained on the ketogenic diet. AB - BACKGROUND & AIMS: The gastric hormones ghrelin and des-acyl ghrelin have been found to be altered in patients treated with antiepileptic drugs. However, it is unknown if these hormones could be modified by other antiepileptic treatments, such as the ketogenic diet. Especially, a reduction in ghrelin levels could be relevant in view of the growth retardation observed under ketogenic diet treatment. For this reason we aimed to determine the changes in ghrelin and des acyl ghrelin plasma levels in children affected by refractory epilepsy and treated with the ketogenic diet up to 90 days. METHODS: Both peptides were measured by immunoassays in plasma obtained from 16 children. RESULTS: Ghrelin plasma levels were progressively reduced by the ketogenic diet, reaching a minimum corresponding to 42% of basal levels after 90 days of ketogenic diet (P < 0.05, Duncan's test). Des-acyl ghrelin plasma levels were similarly affected, reaching minimal levels at 30 days (65% of basal levels), and maintaining a significant reduction until 90 days after the onset of ketogenic diet (P < 0.01 for both time intervals). No significant changes in growth were observed during the monitored period of ketogenic diet administration. CONCLUSIONS: Ghrelin and des-acyl ghrelin are downregulated by the ketogenic diet in children affected by refractory epilepsy. Although no significant changes in growth were observed during the short time period of our investigation, the reduction in ghrelin availability may explain the reported growth retardation found in children treated with the ketogenic diet in the long-term. PMID- 29605573 TI - Multi-site implementation of nutrition screening and diagnosis in medical care units: Success of the More-2-Eat project. AB - BACKGROUND: Improving the detection and treatment of malnourished patients in hospital is needed to promote recovery. AIM: To describe the change in rates of detection and triaging of care for malnourished patients in 5 hospitals that were implementing an evidence-based nutrition care algorithm. To demonstrate that following this algorithm leads to increased detection of malnutrition and increased treatment to mitigate this condition. METHODS: Sites worked towards implementing the Integrated Nutrition Pathway for Acute Care (INPAC), including screening (Canadian Nutrition Screening Tool) and triage (Subjective Global Assessment; SGA) to detect and diagnose malnourished patients. Implementation occurred over a 24-month period, including developmental (Period 1), implementation (Periods 2-5), and sustainability (Period 6) phases. Audits (n = 36) of patient health records (n = 5030) were conducted to identify nutrition care practices implemented with a variety of strategies and behaviour change techniques. RESULTS: All sites increased nutrition screening from Period 1, with three achieving the goal of 75% of admitted patients being screened by Period 3, and the remainder achieving a rate of 70% by end of implementation. No sites were conducting SGA at Period 1, and sites reached the goal of a 75% completion rate or referral for those identified to be at nutrition risk, by Period 3 or 4. By Period 2, 100% of patients identified as SGA C (severely malnourished) were receiving a comprehensive nutritional assessment. In Period 1, the nutrition diagnosis and documentation by the dietitian of 'malnutrition' was a modest 0.37%, increasing to over 5% of all audited health records. The overall use of any Advanced Nutrition Care practices increased from 31% during Period 1 to 63% during Period 6. CONCLUSION: The success of this multi-site study demonstrated that implementation of nutrition screening and diagnosis is feasible and leads to appropriate care. INPAC promotes efficiency in nutrition care while minimizing the risk of missing malnourished patients. TRIAL REGISTRATION: Retrospectively registered ClinicalTrials.gov Identifier: NCT02800304, June 7, 2016. PMID- 29605574 TI - Efficacy of cinnamon in patients with type II diabetes mellitus: A randomized controlled clinical trial. AB - BACKGROUND & AIMS: Multiple studies have evaluated the hypoglycemic effect of cinnamon in patients with diabetes mellitus (DM) type II, with conflicting results. Differences in Baseline Body Mass Index (BMI) of patients may be able to explain the observed differences in the results. This study was designed to evaluate the effect of cinnamon supplementation on anthropometric, glycemic and lipid outcomes of patients with DM type II based on their baseline BMI. METHODS: The study was designed as a triple-blind placebo-controlled randomized clinical trial, using a parallel design. One hundred and forty patients referred to Diabetes Clinic of Yazd University of Medical Sciences with diagnosis of DM type II were randomly assigned in four groups: cinnamon (BMI >= 27, BMI < 27) and Placebo (BMI >= 27, BMI < 27). Patients received cinnamon bark powder or placebo in 500 mg capsules twice daily for 3 months. Anthropometric, glycemic and lipid outcomes were measured before and after the intervention. RESULT: Cinnamon supplementation led to improvement of all anthropometric (BMI, body fat, and visceral fat), glycemic (FPG, 2hpp, HbA1C, Fasting Insulin, and Insulin Resistance), and lipids (Cholesterol Total, LDL-c and HDL-c) outcomes (except for triglycerides level). All observed changes (except for Cholesterol Total and LDL c) were significantly more prominent in patients with higher baseline BMI (BMI >= 27). CONCLUSION: Based on the study findings, cinnamon may improve anthropometric parameters, glycemic indices and lipid profile of patients with type II diabetes. These benefits are significantly more prominent in patients with higher baseline BMI (BMI >= 27). The trial protocol was registered in Iranian Registry of Clinical Trials database (registration ID: IRCT2017031133015N1). PMID- 29605575 TI - Effects of benign prostatic hyperplasia and finasteride therapy on prostatic blood flow in dogs. AB - Benign prostatic hyperplasia (BPH) is characterized by an enlargement of the prostate accompanied by an increase in prostatic blood perfusion and vascularization. The most indicated treatment is to perform orchiectomy, however, medical treatment with finasteride can be an option for breeding dogs or elderly animals with a critical health status. In dogs, the influence of medical treatment on prostatic hemodynamics is still unknown. Therefore, this study aimed to evaluate the effects of benign prostatic hyperplasia and finasteride therapy on hemodynamic and vascular features of the canine prostate. For this purpose, twenty dogs of different breeds, body weights (10-30 kg) and ages (5-13 years) were used, assigned for: Healthy-non treated group (n = 5), BPH-non treated group (n = 5), Healthy-finasteride treated group (n = 5) and BPH-finasteride treated group (n = 5). Dogs that presented hematospermia and at least one general clinical sign (tenesmus, hematuria or dysuria) were presumptively diagnosed with BPH. Dogs were evaluated ultrasonographycally by B-mode and Doppler of the prostatic artery in a monthly interval (day 0, 30 and 60) in order to measure prostate volume (PV), expected prostate volume (EPV), prostate vascularization score (scored as minimum, intermediary and maximum) and prostatic artery blood flow parameters with the use of spectral and color Doppler ultrasound. It was possible to observe a decrease in prostate vascularization score between Day 0 (intermediary degree) and 60 (minimum degree) in finasteride treated dogs. Moreover, non-treated dogs had higher score of vascularization at Day 60 compared to animals treated with finasteride, regardless of BPH diagnosis. Healthy-non treated animals presented higher peak systolic:diastolic velocity (S/D) than BPH non treated dogs. Furthermore, BPH-non treated dogs had lower S/D than BPH finasteride treated dogs. In 30 and 60 days, no difference on PV was observed between BPH-finasteride treated group and Healthy-non treated group. At day 60, no difference between PV and EPV was observed for the BPH-finasteride treated group. In conclusion, finasteride treatment reduces simultaneously the volume, local vascularization and blood flow of the prostate, thus, being considered an effective and additional choice of therapy for BPH. Moreover, the course of therapy in dogs can be followed by analyzing changes in prostatic artery. PMID- 29605576 TI - Effects of maternal dietary selenium (Se-enriched yeast) on testis development, testosterone level and testicular steroidogenesis-related gene expression of their male kids in Taihang Black Goats. AB - To investigate the effects of maternal dietary selenium (Se-enriched yeast) on testis development, testosterone level and steroidogenesis-related gene expression in testis of their male kids, selected pregnant Taihang Black Goats were randomly allotted to four treatment groups. They were fed the basal gestation and lactation diets supplemented with 0 (control), 0.5, 2.0 and 4.0 mg of Se/kg DM. Thirty days after weaning, testes were collected from the kids. After the morphological development status of testis was examined, tissue samples were collected for analyzing testosterone concentration and histological parameters. Testosterone synthesis-related genes were detected using real-time PCR. Localization and quantification of androgen receptor (AR) in testis of goats were determined by immunohistochemical and western blot analysis. The results show that Se supplementation in the diet of dams led to higher (p < 0.05) testicular weight, volume, length, width, transverse and vertical grith of their male kids. Excessive Se (4.0 mg/kg) can inhibit the development of testis by decreasing testicular weight and volume. The density of spermatogenic cells and Leydig cells in the Se treatment groups was significantly (p < 0.05) higher than that in the control. Maternal dietary Se did not affect the thickness of testes, thickness of germinal epithelium and diameter of seminiferous tubule. Se supplemented in the diet of dams improved the testosterone level in testis tissue and serum, and promote the expression of testosterone-related genes. The mRNA expression of StAR, 3beta-HSD and CYP11A1 was decreased with the increasing dietary Se levels of dams. Maternal dietary Se can improve the AR protein abundance in testis of their offspring. AR immunopositive product was detected in Leydig cells, peritubular myoid cells, perivascular smooth muscle cells, primary spermatocytes and spermatids. The expression of AR in spermatogenetic cells is stage specific. This study suggests that maternal dietary Se can influence the testis development and spermatogenesis of their male kids by modulating testosterone synthesis in goats. More attention should be given to the potential role of maternal nutrition in improving reproductive performance of their offspring. PMID- 29605577 TI - Intraoperative cell cycle analysis for tumor margins evaluation: The future is now? PMID- 29605578 TI - Tracing the interplay between syntactic and lexical features: fMRI evidence from agreement comprehension. AB - The current fMRI study was designed to investigate whether the processing of different gender-related cues embedded in nouns affects the computation of agreement dependencies and, if so, where this possible interaction is mapped in the brain. We used the Spanish gender agreement system, which makes it possible to manipulate two different factors: the agreement between different sentence constituents (i.e., by contrasting congruent versus incongruent determiner-noun pairs) and the formal (i.e., orthographical/morphological) and/or lexical information embedded in the noun -i.e., by contrasting transparent (e.g., libromasc. [book]; lunafem. [moon]) and opaque nouns (e.g., lapizmasc. [pencil]; vejezfem. [old age]). Crucially, these data illustrated, for the first time, how the network underlying agreement is sensitive to different gender-to-ending cues: different sources of gender information associated with nouns affect the neural circuits involved in the computation of local agreement dependencies. When the gender marking is informative (as in the case of transparent nouns), both formal and lexical information is used to establish grammatical relations. In contrast, when no formal cues are available (as in the case of opaque nouns), gender information is retrieved from the lexicon. We demonstrated the involvement of the posterior MTG/STG, pars triangularis within the IFG, and parietal regions during gender agreement computation. Critically, in order to integrate the different available information sources, the dynamics of this fronto-temporal loop change and additional regions, such as the hippocampus, the angular and the supramarginal gyri are recruited. These results underpin previous neuroanatomical models proposed in the context of both gender processing and sentence comprehension. But, more importantly, they provide valuable information regarding how and where the brain's language system dynamically integrates all the available form-based and lexical cues during comprehension. PMID- 29605579 TI - Noninvasive stimulation of the ventromedial prefrontal cortex modulates emotional face processing. AB - The ventromedial prefrontal cortex (vmPFC) is associated with emotional states that can be characterized as positive affect. Moreover, a variety of psychiatric disorders that are associated with disturbed reactions toward reward- or safety signaling stimuli reveal functional or structural anomalies within this area. Thus, neuromodulation of this region via transcranial direct current stimulation (tDCS) offers an attractive opportunity to noninvasively influence pleasant emotional and reward processing. Recent experiments revealed hemodynamic and electrophysiological evidence for valence specific modulations of emotional scene processing after excitatory and inhibitory tDCS of the vmPFC. Here, we identified that tDCS modulation of vmPFC during emotional face processing results in effects convergent with scene processing, in that excitatory tDCS increased neural reactivity during happy compared to fearful face perception, whereas inhibitory stimulation led to a converse effect. In addition, behavioral data (affect identification of ambiguous expressive faces) revealed a bias toward preferential processing of happy compared to fearful faces after excitatory compared to after inhibitory stimulation. These results further support the vmPFC as an appropriate target for noninvasive neuromodulation of an appetitive processing network in patients suffering from disturbed cognition of reward- and safety-signaling stimuli. It should however be noted that electrophysiological pre-tDCS differences at earlier time intervals of emotional face and scene processing appeared amplified by tDCS, which remains to be investigated. PMID- 29605580 TI - Calibrated fMRI for mapping absolute CMRO2: Practicalities and prospects. AB - Functional magnetic resonance imaging (fMRI) is an essential workhorse of modern neuroscience, providing valuable insight into the functional organisation of the brain. The physiological mechanisms underlying the blood oxygenation level dependent (BOLD) effect are complex and preclude a straightforward interpretation of the signal. However, by employing appropriate calibration of the BOLD signal, quantitative measurements can be made of important physiological parameters including the absolute rate of cerebral metabolic oxygen consumption or oxygen metabolism (CMRO2) and oxygen extraction (OEF). The ability to map such fundamental parameters has the potential to greatly expand the utility of fMRI and to broaden its scope of application in clinical research and clinical practice. In this review article we discuss some of the practical issues related to the calibrated-fMRI approach to the measurement of CMRO2. We give an overview of the necessary precautions to ensure high quality data acquisition, and explore some of the pitfalls and challenges that must be considered as it is applied and interpreted in a widening array of diseases and research questions. PMID- 29605581 TI - Hematological complications in children subjected to extracorporeal membrane oxygenation. AB - OBJECTIVES: To analyze the hematological complications and need for transfusions in children receiving extracorporeal life support (ECLS). DESIGN: A retrospective study was carried out. SETTING: A pediatric intensive care unit. PATIENTS: Children under 18 years of age treated with ECLS between September 2006 and November 2015. INTERVENTIONS: None. VARIABLES OF INTEREST: Patient and ECLS characteristics, anticoagulation, hematological and coagulation parameters, transfusions and clinical course. RESULTS: A total of 100 patients (94 with heart disease) with a median age of 11 months were studied. Seventy-six patients presented bleeding. The most frequent bleeding point being the mediastinum and 39 patients required revision surgery. In the first 3days, 97% of the patients required blood transfusion (34.4ml/kg per day), 94% platelets (21.1ml/kg per day) and 90% plasma (26.6ml/kg per day). Patients who were in the postoperative period, those who were bleeding at the start of ECLS, those requiring revision surgery, those who could not suspend extracorporeal circulation, and those subjected to transthoracic cannulation required a greater volume of transfusions than the rest of the patients. Thromboembolism occurred in 14 patients and hemolysis in 33 patients. Mortality among the children who were bleeding at the start of ECLS (57.6%) was significantly higher than in the rest of the patients (37.5%) (P=0.048). CONCLUSIONS: Children treated with ECLS present high blood product needs. The main factors related to transfusions were postoperative period, bleeding at the start of ECLS, revision surgery, transthoracic cannulation, and the impossibility of suspending extracorporeal circulation. Children with bleeding suffered greater mortality than the rest of the patients. PMID- 29605583 TI - Rapid purification of bacteriophage endolysin TSPphg and its exogenous treatment could act as an alternative bacterial cell disruption method. AB - Bacteriophage endolysins have long been demonstrated to be effective enzybiotics, and have the potential value in the areas of food, agricultural, and industrial science. Traditionally, extraction of recombinant proteins from bacterium E. coli is achieved by chemical, biological or mechanical disruption methods. Here, we present heat treatment, a simple and highly effective method that differs from the conventional ones, for disruption of E. coli cells to extract recombinant TSPphg, an endolysin originated from thermophilic bacteriophage TSP4. In addition, we found that exogenous TSPphg treatment is able to disrupt E. coli cell and release its intracellular proteins, suggesting its great potentiality to be developed as an alternative bacterial cell disruption method. Moreover, the large scale purification of TSPphg by heat treatment can be carried out directly in fermentation broth in situ without complex downstream processing, which may make it a more applicable approach for commercial scale processes. Our findings shed light on recovery of recombinant thermostable proteins and strategy of bacterial cell disruption. PMID- 29605582 TI - Pharmacist Adscription To Intensive Care: Generating Synergies. AB - OBJECTIVE: To evaluate incorporation of the hospital pharmacist to the routine activity of an Intensive Care Unit (ICU). DESIGN: A prospective observational study was carried out to evaluate the impact of pharmacist interventions, made by a pharmacist temporarily assigned to the ICU, upon medical prescriptions. SETTING: A medical and surgical ICU with 21 beds. PATIENTS: Patients with at least one ICU stay were included, while patients with admission and discharge in periods when the pharmacist was not present were excluded. INTERVENTIONS: The interventions were made after daily review of the prescriptions, and were communicated verbally or in writing to the supervising physician. MAIN VARIABLES: Number of interventions, therapeutic group of the drugs involved, type of intervention and degree of acceptance. RESULTS: A total of 194 interventions were made in 62 patients. The majority were related to safety aspects (33%) and the optimization of therapy (32%). The most frequent interventions were the administration of drugs via the nasogastric tube (19%) and pharmacokinetic monitoring (14.4%). The most frequently involved groups of drugs were anti infectious agents (33%) and digestive system medications (27%). A total of 56.2% of the interventions were made verbally, and 80% were accepted. CONCLUSIONS: Pharmacist adscription to an ICU and the implementation of interventions on prescriptions have allowed improvement of safety and the optimization of pharmacotherapy in more than 50% of the patients. The high rate of acceptance of these interventions would support the implementation of such programs in critical care units. PMID- 29605584 TI - Enzymatic synthesis of methyl derivatives of L-tryptophan selectively labeled with hydrogen isotopes. AB - We report the enzymatic synthesis of the derivatives of L-tryptophan methylated in indole moiety and labeled with deuterium and tritium in the 2-position of side chain. For kinetic studies twelve isotopomers, i.e., 1'-methyl-[2-2H]-, 1'-methyl [2-3H]-, 1'-methyl-[2-2H/3H]-, 2'-methyl-[2-2H]-, 2'-methyl-[2-3H]-, 2'-methyl-[2 2H/3H]-, 5'-methyl-[2-2H]-, 5'-methyl-[2-3H]-, 5'-methyl-[2-2H/3H]-, 7'-methyl-[2 2H]-, 7'-methyl-[2-3H]-, and 7'-methyl-[2-2H/3H]-L-tryptophan are obtained by the enzymatic coupling of the appropriate methylated indole moiety with S-methyl-L cysteine catalyzed by the enzyme tryptophanase. PMID- 29605585 TI - Diet, gut microbiota composition and feeding behavior. AB - Advances in sequencing technologies have allowed for a more complete analysis of the microbiota composition and identification of differences among individuals and/or physiologies. Changes in microbiota composition and associated inflammation have been linked to both metabolic and behavioral disorders, and abnormality in microbiota composition, or dysbiosis, may play a causal role in the etiology and maintenance of these pathologies. There is accumulating evidence showing that the gut microbiota can communicate to the central nervous system to alter host behavior. Supplementation with L. rhamnosus in mice notably causes a decrease in anxiety. Interestingly, these effects are abolished by vagotomy, identifying the vagus nerve as a potential communication route for microbiota originating signals. Chronic high fat feeding notably leads to remodeling of the vagal afferent pathway and is associated with an increase in energy intake; these effects appear to be mediated by microbiota-induced inflammation. Therefore, preventing bacterial-driven inflammation, via dietary manipulation for example, may have potential therapeutic effects for both metabolic and behavioral disorders. PMID- 29605586 TI - A protective role of autophagy in TDCIPP-induced developmental neurotoxicity in zebrafish larvae. AB - Tris (1, 3-dichloro-2-propyl) phosphate (TDCIPP), an extensively used organophosphorus flame retardant, is frequently detected in various environmental media and biota, and has been demonstrated as neurotoxic. Autophagy has been proposed as a protective mechanism against toxicant-induced neurotoxicity. The purpose of the present study was to investigate the effect of TDCIPP exposure on autophagy, and its role in TDCIPP-induced developmental neurotoxicity. Zebrafish embryos (2-120 h post-fertilization [hpf]) were exposed to TDCIPP (0, 5, 50 and 500 MUg/l) and a model neurotoxic chemical, chlorpyrifos (CPF, 100 MUg/l). The developmental endpoints, locomotive behavior, cholinesterase activities, gene and protein expression related to neurodevelopment and autophagy were measured in the larvae. Our results demonstrate that exposure to TDCIPP (500 MUg/l) and CPF causes developmental toxicity, including reduced hatching and survival rates and increased malformation rate (e.g., spinal curvature), as well as altered locomotor behavior. The expression of selected neurodevelopmental gene and protein markers (e.g., mbp, syn2a, and alpha1-tubulin) was significantly down regulated in CPF and TDCIPP exposed zebrafish larvae. Treatment with CPF significantly inhibits AChE and BChE, while TDCIPP (0-500 MUg/l) exerts no effects on these enzymes. Furthermore, the conversion of microtubule-associated protein I (LC3 I) to LC3 II was significantly increased in TDCIPP exposed zebrafish larvae. In addition, exposure to TDCIPP also activates transcription of several critical genes in autophagy (e.g. Becn1, atg3, atg5, map1lc3b and sqstm1). To further investigate the role of autophagy in TDCIPP induced developmental neurotoxicity, an autophagy inducer (rapamycin, Rapa, 1 nM) and inhibitor (chloroquine, CQ, 1 MUM) were used. The results demonstrate that the hatching rate, survival rate, and the expression of mbp and a1-tubulin proteins were all significantly increased in larvae treated with TDCIPP (500 MUg/l) and Rapa compared to TDCIPP alone. In contrast, co-treatment with the autophagy inhibitor CQ results in exacerbated neurodevelopmental toxicity. Taken together, our results confirm that exposure to TDCIPP induces autophagy, which plays a protective role in TDCIPP-induced developmental neurotoxicity in zebrafish embryos and larvae. PMID- 29605587 TI - Disparities in Access and Regionalization of Care in Testicular Cancer. AB - INTRODUCTION: Timely mobilization of specialized resources are needed to achieve optimal outcomes in testicular cancer. We used the National Cancer Database to investigate the hospital and demographic features driving disparity. PATIENTS AND METHODS: We identified adult men with testicular tumors diagnosed from 2004 to 2013. We a priori examined the association among race/ethnicity, socioeconomic status (SES), travel burden, hospital characteristics, and indicators of delays in testicular cancer care. The outcomes included large primary tumor, stage III at diagnosis, orchiectomy delay, and mortality. The analyses included multivariable Cox proportional hazards regression for time-dependent outcomes and logistic regression for categorical outcomes. RESULTS: Of 31,964 men, 29% had a large primary tumor, 17% presented with stage III disease, 10% experienced an orchiectomy delay, and 6% died. Black race or Hispanic ethnicity, low SES, and underinsurance were associated with poorer outcomes (P < .001 for all). Higher hospital volume, cancer center status, and lower travel burden were associated with improved outcomes (P < .001 for all). CONCLUSION: Nonwhite race/ethnicity, low SES, and underinsurance were associated with diminished access to testicular cancer care. Insurance status, a marker of SES, had the most consistent association with poor outcomes. This finding highlights the oncologic imperative to improve access to adequate health insurance. Regionalization of subspecialty care might, paradoxically, improve outcomes but also create additional barriers in the form of an added travel burden. PMID- 29605588 TI - Genotoxic effect of Lippia alba (Mill.) N. E. Brown essential oil on fish (Oreochromis niloticus) and mammal (Mus musculus). AB - "Erva cidreira" (Lippia alba (Mill.) N. E. Brown) is popular for its therapeutic properties, especially its sedative properties. Such properties led to the discovery of the anesthetic action of Lippia alba essential oil in fish culture. The objective of this study was to evaluate the genotoxic effect of Lippia alba essential oil in fish and mammals. The oil was extracted by hydrodistillation with a Clevenger apparatus and analyzed by gas chromatography coupled to mass spectrometry (GC-MS), where the compounds linalool, eucalyptol, gamma-muurolene, and caryophyllene were identified as the most abundant compounds. Lippia alba essential oil showed inhibitory activity on LPS-stimulated Nitric Oxide (NO) production (77% at 20 MUg mL-1) in RAW 264.7 macrophages without influence cellular viability. Genotoxic action was observed by micronucleus and comet assay in the doses 100, 200 and 300 mg Kg-1, showing greater damage to fish than mammals. When we compared the treatment modes, greater damage was observed in the treatment by inhalation, but this was still not toxic. The oxidative stress measured by quantification of advanced oxidation protein products revealed low oxidation but significantly more harm than the control. These findings support the use of Lippia alba essential oil as an anesthetic for fish without harm to consumers. PMID- 29605589 TI - Patients' perceptions of sleep in a Critical Care Unit. AB - INTRODUCTION AND OBJECTIVES: Patients' sleep can be disturbed during their stay in an Intensive Care Unit. Many factors can explain this disturbance, both within the ICU environment and caused by patients' illnesses. There is evidence that patients' sleep can be improved within ICUs. The aim of this study is to describe patients perceptions of a night's sleep and develop a care plan that promotes a night's sleep. METHODOLOGY: A prospective descriptive study was performed in the ICU of a training hospital. The sleep of 125 patients was explored. Sociodemographic and clinical variables were collected from patients' medical records. The 5-item Richards-Campbell Sleep Questionnaire was utilised to assess patients' perception of a night's sleep. In addition, an ad-hoc 9-item questionnaire was developed which included factors that can affect sleep according to the literature. Patients had to grade the level of interference of those factors with their night's sleep. RESULTS: The sleep of patients in our Intensive Care Unit was moderately deep, with light arousals and ease in falling sleep again. The average value on the Richards-Campbell Sleep Questionnaire was 52.92mm. The factors that significantly interfered with sleep were: pain (P=0.009), worries/anxiety (P=.01), staff voices (P=0.033), alarm/medical devices sounds (P=0.047) and peripheral intravenous lines (P=.036). CONCLUSIONS: Our patients' perception of a night's sleep in the ICU was fair. Optimising pain management, answering questions or worries, minimizing background noise and voices have the potential to improve sleep quality. PMID- 29605590 TI - Measurement of fat fraction in the human thymus by localized NMR and three-point Dixon MRI techniques. AB - PURPOSE: To develop a protocol to non-invasively measure and map fat fraction, fat/(fat+water), as a function of age in the adult thymus for future studies monitoring the effects of interventions aimed at promoting thymic rejuvenation and preservation of immunity in older adults. MATERIALS AND METHODS: Three dimensional spoiled gradient echo 3T MRI with 3-point Dixon fat-water separation was performed at full inspiration for thymus conspicuity in 36 volunteers 19 to 56 years old. Reproducible breath-holding was facilitated by real-time pressure recording external to the console. The MRI method was validated against localized spectroscopy in vivo, with ECG triggering to compensate for stretching during the cardiac cycle. Fat fractions were corrected for T1 and T2 bias using relaxation times measured using inversion recovery-prepared PRESS with incremented echo time. RESULTS: In thymus at 3 T, T1water = 978 +/- 75 ms, T1fat = 323 +/- 37 ms, T2water = 43.4 +/- 9.7 ms and T2fat = 52.1 +/- 7.6 ms were measured. Mean T1 corrected MRI fat fractions varied from 0.2 to 0.8 and were positively correlated with age, weight and body mass index (BMI). In subjects with matching MRI and MRS fat fraction measurements, the difference between these measurements exhibited a mean of -0.008 with a 95% confidence interval of (0.123, -0.138). CONCLUSIONS: 3 point Dixon MRI of the thymus with T1 bias correction produces quantitative fat fraction maps that correlate with T2-corrected MRS measurements and show age trends consistent with thymic involution. PMID- 29605591 TI - Mutation and Methylation Analysis of Circulating Tumor DNA Can Be Used for Follow up of Metastatic Colorectal Cancer Patients. AB - BACKGROUND: Targeted therapies, although contributing to survival improvement in metastatic colorectal cancer (mCRC), are expensive and may cause adverse effects. Therefore, confirming that patients are responding to these therapies is extremely important. Currently, follow-up is performed using radiographic evaluation, which has its limitations. Liquid biopsies, reflecting real-time tumor characteristics, hold great potential in monitoring tumor disease. PATIENTS AND METHODS: Blood samples were collected at different time points during treatment of 24 mCRC patients. Mutation and NPY methylation picoliter droplet based digital PCR (ddPCR) assays were performed on circulating DNA to investigate whether these assays can be used for disease monitoring. RESULTS: The results of the mutation and methylation assays were correlated with each other and corresponded with the results of radiographic evaluation. There was a steep decrease in circulating tumor DNA levels immediately after treatment initiation. Furthermore, circulating tumor DNA levels were increased in progressive samples and were undetectable in patients undergoing curative surgery. CONCLUSION: This prospective study showed that tumor-specific mutation and NPY methylation ddPCR assays performed on circulating DNA can be used for the follow-up of mCRC patients during treatment and could complement current follow-up methods. The analysis of NPY methylation is promising, as it has the additional advantage that no prior knowledge of tumor mutations is needed. PMID- 29605592 TI - Aflibercept Plus FOLFIRI in the Real-life Setting: Safety and Quality of Life Data From the Italian Patient Cohort of the Aflibercept Safety and Quality-of Life Program Study. AB - BACKGROUND: Aflibercept combined with FOLFIRI (folinic acid, 5-fluorouracil, irinotecan) as second-line treatment of metastatic colorectal cancer (mCRC) significantly improved survival compared with FOLFIRI alone in the pivotal VELOUR (aflibercept vs. placebo in combination with irinotecan and 5-fluorouracil in the treatment of patients with metastatic colorectal cancer after failure of an oxaliplatin-based regimen) trial. No quality-of-life assessment was performed in VELOUR; therefore, the ASQoP (Aflibercept Safety and Quality-of-Life Program) trial was designed to capture the safety and health-related quality of life (HRQL). PATIENTS AND METHODS: ASQoP was an international, open-label, single-arm trial evaluating the safety and HRQL of aflibercept combined with FOLFIRI administered in a real-life setting to 781 patients with mCRC, pretreated with an oxaliplatin-based regimen with or without bevacizumab. The Italian subset of ASQoP enrolled 200 patients from 28 institutions. The primary endpoint was safety; HRQL was a secondary endpoint, assessed by validated questionnaires (European quality of life 5-dimension instrument 3-level; European Organization for Research and Treatment for Cancer Quality of Life Questionnaire Core 30, version 3; and EORTC-CR29) at baseline, during treatment, and at the end of treatment. RESULTS: The median age of the Italian ASQoP population was 63 years; the median number of aflibercept and FOLFIRI cycles was 7. Treatment-emergent adverse events were reported in 97.5% of patients. Hypertension (28.5%), neutropenia (27.5%; from laboratory data), asthenic conditions (20.0%), diarrhea (17.0%), and stomatitis (13.0%) were the most frequent (incidence, >= 5%) grade 3/4 toxicities. One toxic death occurred during the study period due to sepsis, without neutropenic complications. No significant worsening of HRQL was shown during treatment. CONCLUSION: Aflibercept combined with FOLFIRI was well tolerated when administered as second-line treatment for patients with mCRC in a real-life setting. It did not affect HRQL and showed similar rates of treatment emergent adverse events as those observed in the VELOUR trial. No new safety signals were identified. PMID- 29605593 TI - Lesion mapping in acute stroke aphasia and its implications for recovery. AB - Patients with stroke offer a unique window into understanding human brain function. Mapping stroke lesions poses several challenges due to the complexity of the lesion anatomy and the mechanisms causing local and remote disruption on brain networks. In this prospective longitudinal study, we compare standard and advanced approaches to white matter lesion mapping applied to acute stroke patients with aphasia. Eighteen patients with acute left hemisphere stroke were recruited and scanned within two weeks from symptom onset. Aphasia assessment was performed at baseline and six-month follow-up. Structural and diffusion MRI contrasts indicated an area of maximum overlap in the anterior external/extreme capsule with diffusion images showing a larger overlap extending into posterior perisylvian regions. Anatomical predictors of recovery included damage to ipsilesional tracts (as shown by both structural and diffusion images) and contralesional tracts (as shown by diffusion images only). These findings indicate converging results from structural and diffusion lesion mapping methods but also clear differences between the two approaches in their ability to identify predictors of recovery outside the lesioned regions. PMID- 29605594 TI - "Neural overlap of L1 and L2 semantic representations across visual and auditory modalities: a decoding approach". AB - This study investigated whether brain activity in Dutch-French bilinguals during semantic access to concepts from one language could be used to predict neural activation during access to the same concepts from another language, in different language modalities/tasks. This was tested using multi-voxel pattern analysis (MVPA), within and across language comprehension (word listening and word reading) and production (picture naming). It was possible to identify the picture or word named, read or heard in one language (e.g. maan, meaning moon) based on the brain activity in a distributed bilateral brain network while, respectively, naming, reading or listening to the picture or word in the other language (e.g. lune). The brain regions identified differed across tasks. During picture naming, brain activation in the occipital and temporal regions allowed concepts to be predicted across languages. During word listening and word reading, across language predictions were observed in the rolandic operculum and several motor related areas (pre- and postcentral, the cerebellum). In addition, across language predictions during reading were identified in regions typically associated with semantic processing (left inferior frontal, middle temporal cortex, right cerebellum and precuneus) and visual processing (inferior and middle occipital regions and calcarine sulcus). Furthermore, across modalities and languages, the left lingual gyrus showed semantic overlap across production and word reading. These findings support the idea of at least partially language- and modality-independent semantic neural representations. PMID- 29605595 TI - Delineating resetting and updating in visual working memory based on the object to-representation correspondence. AB - When an object we represent in visual working memory (VWM) changes, its representation is modified accordingly. VWM can either access and change the existing representation by an updating process, or it can reset, by encoding the object in its novel status as a new representation. Our goal was to show that the determining factor of updating versus resetting is the availability of a stable correspondence between the object and its VWM representation. Here, we demonstrate that updating relies on the object-to-representation mapping to access and modify the appropriate representation, while losing this mapping triggers a resetting process. We compared very similar situations of object separation that either allowed the mapping to hold, or caused it to be lost. When an object that was mapped to one representation separated, VWM reset, manifested by a sharp drop in the contralateral delay activity (CDA) amplitude (an electrophysiological marker of VWM contents; Experiment 1), and a behavioral cost to detect salient changes that co-occurred with the resetting-triggering event (Experiment 2). When each part was mapped to a different representation, the separation resulted in updating, with a gradual rise in CDA amplitude (Experiment 1), and a reduced behavioral cost (Experiment 2). Thus, while updating and resetting resulted in similar final representations (corresponding to the post change objects), their dynamics were different, depending on the availability of the mapping. Our results reveal the triggering conditions of resetting and updating, establish methods to study these online processes, and highlight the importance of the object-to-representation correspondence in VWM. PMID- 29605596 TI - Intraoperative Bypass Graft Flow Measurement With Transit Time Flowmetry: A Clinical Assessment. AB - BACKGROUND: Guidelines advocate transit time flowmetry (TTFM) for intraoperative graft patency verification during coronary artery bypass graft surgery (CABG), but studies on accuracy and precision of the TTFM technique are few. In an observational study of CABG patients, we analyzed covariation of left internal mammary artery (LIMA) blood flow with TTFM and free flow measurements. METHODS: Covariation of TTFM and free blood flows was evaluated in 60 patients undergoing CABG using the LIMA as one of the conduits. With LIMA flow measurements routinely performed before and after vasodilation, results are based on 120 paired intraoperative measurements. RESULTS: As demonstrated by a combined approach of regression and Bland-Altman analysis for the two flow situations, TTFM was higher than free flow in 64% of measurements, with an overestimation by TTFM of 7.1% +/- 16.3% in the overall cohort (prevasodilation), statistically carried by measurements with 4-mm probes (overestimation by 13.3% +/- 15.4%, both p < 0.01). In a multiregression analysis, oversizing of the TTFM probe (odds ratio 9.56, 95% confidence interval: 2.03 to 45.10, p = 0.004) and high flows (odds ratio 1.02, 95% confidence interval: 1.01 to 1.04, p < 0.001) were independent determinants of flow overestimation by TTFM, although in the Bland-Altman analysis no systematic overestimation was seen in the postvasodilation situation. In a receiver-operating characteristics analysis, optimal cutoff value as determined from Youden's index for assuming flow overestimation was 68 mL/min. CONCLUSIONS: Overall, with slight overall overestimation of 7.1%, TTFM is an accurate indicator of LIMA blood flow during CABG, with a clinically acceptable precision. Overestimation may be expected with flows greater than 68 mL/min, but most importantly, in situations with oversized TTFM probes. PMID- 29605597 TI - Hybrid Open Minimally Invasive Transcatheter Mitral Valve Replacement. AB - We describe a hybrid surgical interventional technique for minimally invasive implantation of a transcatheter aortic valve in the mitral position. This technique does not require circular mitral annular calcification and minimizes the risk of left ventricular outflow tract obstruction. We believe this technique represents a useful approach for surgeons and interventional cardiologists until specialized transcatheter mitral valve devices become available. PMID- 29605598 TI - Dominant Spinal Feeder Through Arterial "Basket" of Conus Medullaris. PMID- 29605599 TI - Do Repeated Operations for Recurrent Colorectal Lung Metastases Result in Improved Survival? AB - BACKGROUND: Lung metastases occur in 10% to 20% of patients with colorectal cancer (CRC). Lung metastatic pathways of CRC are poorly known, and the optimal management for recurrent lung metastases remains uncertain. METHODS: Long-term oncologic outcomes of 203 patients with CRC lung metastases who underwent metastasectomy were investigated in this multicenter retrospective study. Ninety two patients (45.3%) with tumor relapse underwent repeated metastasectomy and 11 (5.4%) received a third metastasectomy for a second relapse. Demographic and clinical data, including histologic grade of primary tumor, presence of CRC liver metastases, type of primary tumor resection, number, size, location, and resection type of pulmonary metastases, were evaluated. Overall survival (OS) and disease-free survival were analyzed. Cox regression model was performed to identify variables that influenced OS. RESULTS: One hundred seventy-three patients (85.2%) received a wedge resection, 21 (10.3%) underwent pulmonary lobectomy, and 9 (4.4%) underwent other procedures (pneumonectomy, bilobectomy). The mean follow-up was 39 months (range: 7 to 154 months). One-, 3-, and 5-year global OS from CRC diagnosis was 99%, 80%, and 60%, respectively, and 97%, 60%, and 34% from the first metastasectomy, respectively. Log-rank test between OS (one versus repeated metastasectomy) did not show significant differences (p = 0.659). Cox regression model showed that nodal status (hazard ratio [HR] 17.7, p = 0.008) and administration of adjuvant chemotherapy (HR 0.33, p = 0.026) are risk and protective factors, respectively, for OS. CONCLUSIONS: Repeated pulmonary metastasectomy should be offered to patients with metastatic CRC because there are no differences in terms of OS between patients undergoing single and repeated metastasectomy. Adjuvant chemotherapy should be suggested in case of metastatic CRC. PMID- 29605600 TI - Open Modified En Bloc Ivor Lewis Esophagectomy: How I Teach It. PMID- 29605601 TI - Identification of host cellular proteins LAGE3 and IGFBP6 that interact with orf virus protein ORFV024. AB - OBJECTIVE: Orf virus (ORFV) is the pathogen causing contagious pustular dermatitis in goats, sheep and herdsmen. Evidence has confirmed that ORFV can be used as a preventive and therapeutic immunomodulatory agent in several animal models. Our previous data demonstrated that ORFV024 is able to inhibit activation of the NF-kappaB signaling pathway and act as an important modulator for early immune responses against viral infection. However, the molecular mechanism by which ORFV024 exerting biological function remains unclear. In the present study, we explored and analyzed the function of host cellular proteins that interact with ORFV024. METHODS: The yeast two-hybrid (Y2H) assay was performed to screen proteins interacting with ORFV024 using a cDNA library derived from primary ovine fetal turbinate cells (OFTu). Two of the screened proteins were further confirmed by confocal microscopy, His-tag pull-down assay and CO-Immunoprecipitation (CO IP) assay. In addition, the ORFV024 interaction network was constructed using the STRING database. RESULTS: In this study, 11 ovine cellular proteins were found to interact with ORFV024. In view of the importance of LAGE3 and IGFBP6 in the ORFV024 functional analysis, we further constructed LAGE3 and IGFBP6 interaction networks. The interactions between ORFV024 and LAGE3 or IGFBP6 were confirmed by confocal microscopy, LAGE3 was further confirmed in the His-tag pull-down assay and CO-IP assay. CONCLUSIONS: Our findings indicate that ORFV024 can interact with ovine cellular proteins LAGE3 and IGFBP6. PMID- 29605602 TI - De novo transcriptome sequencing and comprehensive analysis of the heat stress response genes in the basidiomycetes fungus Ganoderma lucidum. AB - Ganoderma lucidum is a valuable basidiomycete with numerous pharmacological compounds, which is widely consumed throughout China. We previously found that the polysaccharide content of Ganoderma lucidum fruiting bodies could be significantly improved by 45.63% with treatment of 42 degrees C heat stress (HS) for 2 h. To further investigate genes involved in HS response and explore the mechanisms of HS regulating the carbohydrate metabolism in Ganoderma lucidum, high-throughput RNA-Seq was conducted to analyse the difference between control and heat-treated mycelia at transcriptome level. We sequenced six cDNA libraries with three from control group (mycelia cultivated at 28 degrees C) and three from heat-treated group (mycelia subjected to 42 degrees C for 2 h). A total of 99,899 transcripts were generated using Trinity method and 59,136 unigenes were annotated by seven public databases. Among them, 2790 genes were identified to be differential expressed genes (DEGs) under HS condition, which included 1991 up regulated and 799 down-regulated. 176 DEGs were then manually classified into five main responsive-related categories according to their putative functions and possible metabolic pathways. These groups include stress resistance-related factors; protein assembly, transportation and degradation; signal transduction; carbohydrate metabolism and energy provision-related process; other related functions, suggesting that a series of metabolic pathways in Ganoderma lucidum are activated by HS and the response mechanism involves a complex molecular network which needs further study. Remarkably, 48 DEGs were found to regulate carbohydrate metabolism, both in carbohydrate hydrolysis for energy provision and polysaccharide synthesis. In summary, this comprehensive transcriptome analysis will provide enlarged resource for further investigation into the molecular mechanisms of basidiomycete under HS condition. PMID- 29605603 TI - Downregulation of microRNA-370 in esophageal squamous-cell carcinoma is associated with cancer progression and promotes cancer cell proliferation via upregulating PIN1. AB - PIN1 is a peptidyl-prolyl cis/trans isomerase (PPIase) that controls cell fate by regulating multiple signal transduction pathways and is found to be overexpressed in a variety of malignant tumors. Herein, we found the expression of PIN1 is up regulated while miRNA-370 (miR-370) down-regulated in both esophageal squamous cell carcinoma (ESCC) tissues and cells. Transfection of miR-370 can significantly decrease PIN1 expression in targeting ESCC cells. Overexpression of miR-370 can induce decreased cell proliferation and cell cycle arrest, as well as increased apoptosis in ESCC cells, while this function can be significantly prevented by co-transfection of PIN1. Further experimental results demonstrated that beta-catenin, cyclin D1, and caspase activation might be involved in miR 370/PIN1 induced growth inhibition and apoptosis. Besides, low miR-370 and high PIN1 expression significantly correlated with tumor diameter, poor differentiation, tumor invasion and lymph node metastasis in patients diagnosed with ESCC. In conclusion, downregulation of miR-370 in ESCC is associated with cancer progression and promotes cancer cell proliferation via upregulating PIN1, which might be a potential therapeutic target and adverse prognostic factor in the clinic. PMID- 29605604 TI - Effects of Rosuvastatin on the expression of the genes involved in cholesterol metabolism in rats: adaptive responses by extrahepatic tissues. AB - BACKGROUND: Statins mostly target the liver; therefore, increase in the synthesis of cholesterol by extra-hepatic tissues and then transferring this cholesterol to the liver can be regarded as adaptive responses by these tissues. In addition to cholesterol, these adaptive responses can increase isoprenoid units as the byproducts of the cholesterol biosynthesis pathway; isoprenoids play a key role in regulating cell signaling pathways and cancer development. Thus, there is a primary need for in vivo investigation of the effects of statins on the cholesterol metabolism in the extra-hepatic tissues. MATERIALS: Eighteen male Sprague-Dawley rats were randomly divided into control (n = 9) and treatment (n = 9) groups. The treatment group was orally given 10 mg/kg/day of Rosuvastatin for 6 weeks. Then, serum lipid profile, expression levels of 3-hydroxy-3-methyl glutaryl-coenzyme A reductase (HMGCR), ABCA1, ABCG1 and ApoA1, and activity of HMGCR were measured in the liver, intestine and adipose tissues. RESULTS: Rosuvastatin significantly reduced total cholesterol and LDL-C. The expression levels of ABCA1, ABCG1, and ApoA1 in the liver and HMGCR in both liver and intestine were significantly increased in the Rosuvastatin treated-group. However, in the intestine, there were no significant differences in the expression levels of ABCA1 and ABCG1 between the study groups. Rosuvastatin had no effect on the adipose tissue. The HMGCR activity was significantly increased in the liver and intestine of the Rosuvastatin-treated group. CONCLUSIONS: In spite of the adipose tissue, the intestine efficiently responses to the reduced levels of cholesterol and increases its cholesterogenesis capacity. However, adipose tissue seems to play a small role in correcting cholesterol deficiency during the course of statin therapy. PMID- 29605605 TI - Epigenetics and testicular germ cell tumors. PMID- 29605606 TI - Inhibition of hsa-miR-6086 protects human umbilical vein endothelial cells against TNFalpha-induced proliferation inhibition and apoptosis via CDH5. AB - MiRNAs are considered as a novel class of biomarkers or treatment targets for cardiovascular diseases. Hsa-miR-6086, a novel mi-RNA, was reported to be downregulated during the differentiation of human embryonic stem cells into endothelial cells (ECs). Interestingly, CDH5 (cadherin 5), encoding a classical cadherin of the cadherin superfamily, is a cellular marker of ECs and has been reported to be a target of hsa-miR-6086. However, the role of hsa-miR-6086 in ECs is virtually unknown. Herein, we report that hsa-miR-6086 was markedly induced by TNFalpha stimulation in human umbilical vein endothelial cells (HUVECs), whereas CDH5 expression was greatly reduced. Importantly, TNFalpha-induced suppression of CDH5 expression was largely prevented by inhibiting hsa-miR-6086, and hsa-miR 6086 mimic greatly decrease CDH5 expression in HUVECs, suggesting that the induction of hsa-miR-6086 is responsible for CDH5 downregulation by TNFalpha. In addition, restoration of CDH5 expression level by either inhibiting hsa-miR-6086 or exogenously expressing CDH5 cDNA that is not affected by hsa-miR-6086 protected HUVECs against TNFalpha-induced apoptosis and cell growth inhibition. Taken together, our study reveals that hsa-miR-6086 is induced by TNFalpha and mediates TNFalpha-induced HUVEC growth inhibition through downregulating CDH5 expression. Hence, hsa-miR-6086 might be a new target for treating TNFalpha induced endothelial dysfunction. PMID- 29605607 TI - Identification of candidate genes for necrotizing enterocolitis based on microarray data. AB - Necrotizing enterocolitis (NEC) is one of the most serious diseases that could threaten the life of neonates. However the current opinions about the pathogenesis or how to prevent or treat the disease are still ambiguous. The purpose of the present study was to identify the key genes of this disease and provide new insights into the mechanism of NEC. The gene expression data of GSE46619, including 5 specimens from NEC patients and 4 samples from surgical control infants, were collected from Gene Expression Omnibus (GEO) database. The differentially expressed genes (DEGs) were screened with regard to NEC versus surgical-control group using Limma package in R software and Gene Ontology (GO) enrichment analysis and pathway enrichment analysis were conducted by means of Database for Annotation, Visualization and Integrated Discovery (DAVID) website subsequently. Furthermore the protein-protein interaction (PPI) network for DEGs was constructed using Cytoscape software and the most highly connected module was extracted using MCODE plugin from the PPI network. Moreover, the significantly enriched sub-pathways were identified using iSubpathwayMiner package in R software. A total of 2629 DEGs were screened out between NEC and control samples, including 367 up-regulated genes and 2262 down-regulated genes and they involved in different GO terms and pathways which may be associated with NEC onset and progression. PPI network and module analysis revealed that several genes were defined as hub genes including AGT, IL8 and KNG1. The sub-pathway analysis screened out 189 significantly enriched sub-pathways, including Tryptophan metabolism, Fatty acid metabolism, and Arachidonic acid metabolism. Genes in the corresponding sub-pathway, such as ACACB and CAT were regarded as critical genes in NEC. QRT-PCR was also conducted to identify the expression of the five key genes (AGT, IL8, KNG1, ACACB and CAT) in NEC samples. These findings have identified several hub genes (e.g., AGT, IL8, KNG1, ACACB and CAT) which were presumed to serve critical roles in NEC. PMID- 29605608 TI - Genetic variations in key inflammatory cytokines exacerbates the risk of diabetic nephropathy by influencing the gene expression. AB - BACKGROUND: Diabetic nephropathy is the single strongest predictor of mortality in patients with diabetes. The development of overt nephropathy involves important inter-individual variations, even after adjusting for potential confounding influences of modifiable and non-modifiable risk factors. Genome-wide transcriptome studies have reported the activation of inflammatory signaling pathways and there is mounting indication of the role of genetic factors. METHODS: We screened nine genetic variations in three cytokine genes (TNF-alpha, IL-6 and IL-beta) in 1326 unrelated subjects comprising of healthy controls (n = 464), type 2 diabetics with nephropathy (DN, n = 448) and type 2 diabetes without nephropathy (T2D, n = 414) by sequence-specific amplification. Functional implication of SNPs was elucidated by correlation studies and relative gene expression using Realtime-Quantitative PCR (RT-qPCR). RESULTS: Individual SNP analysis showed highest association of IL-1beta rs16944-TT genotype (OR = 3.51, 95%CI = 2.36-5.21, P = 0.001) and TNF-alpha rs1800629-AA genotype (OR = 2.75, 95% CI = 1.64-4.59, P = 0.001) with T2D and DN respectively. The haplotype frequency showed significant risk of seven combinations among T2D and four combinations among DN subjects. The highest risk of T2D and DN was associated with GGTGAGTTT (OR = 4.25, 95%CI = 3.3-14.20, P = 0.0016) and GACGACCTT (OR = 21.3, 95%CI = 15.1 28.33, P = 0.026) haplotypes respectively. Relative expression by RT-qPCR showed increased cytokine expression in cases as compared to controls. TNF-alpha expression was increased by more than four-folds (n-fold = 4.43 +/- 1.11) in DN. TNF-alpha, IL-6 and IL-1beta transcript levels were significantly modulated by promoter region SNPs. CONCLUSIONS: The present study implicates a strong association between cytokine TNF-alpha, IL-6 and IL-1beta gene promoter polymorphisms and modulation of transcript levels with susceptibility to nephropathy in diabetes subjects. PMID- 29605609 TI - Genome-wide identification, phylogenetic analysis, and expression profiling of polyamine synthesis gene family members in tomato. AB - Polyamines (PAs), including putrescine (Put), spermidine (Spd), spermine (Spm), and thermospermine (T-Spm), play key roles in plant development, including fruit setting and ripening, morphogenesis, and abiotic/biotic stress. Their functions appear to be intimately related to their synthesis, which occurs via arginine/ornithine decarboxylase (ADC/ODC), Spd synthase (SPDS), Spm synthase (SPMS), and Acaulis5 (ACL5), respectively. Unfortunately, the expression and function of these PA synthesis-relate genes during specific developmental process or under stress have not been fully elucidated. Here, we present the results of a genome-wide analysis of the PA synthesis genes (ADC, ODC, SPDS, SPMS, ACL5) in the tomato (Solanum lycopersicum). In total, 14 PA synthesis-related genes were identified. Further analysis of their structures, conserved domains, phylogenetic trees, predicted subcellular localization, and promoter cis-regulatory elements were analyzed. Furthermore, we also performed experiments to evaluate their tissue expression patterns and under hormone and various stress treatments. To our knowledge, this is the first study to elucidate the mechanisms underlying PA function in this variety of tomato. Taken together, these data provide valuable information for future functional characterization of specific genes in the PA synthesis pathway in this and other plant species. Although additional research is required, the insight gained by this and similar studies can be used to improve our understanding of PA metabolism ultimately leading to more effective and consistent plant cultivation. PMID- 29605610 TI - Temperature sensitivity of gaseous elemental mercury in the active layer of the Qinghai-Tibet Plateau permafrost. AB - Soils represent the single largest mercury (Hg) reservoir in the global environment, indicating that a tiny change of Hg behavior in soil ecosystem could greatly affect the global Hg cycle. Climate warming is strongly altering the structure and functions of permafrost and then would influence the Hg cycle in permafrost soils. However, Hg biogeochemistry in climate-sensitive permafrost is poorly investigated. Here we report a data set of soil Hg (0) concentrations in four different depths of the active layer in the Qinghai-Tibet Plateau permafrost. We find that soil Hg (0) concentrations exhibited a strongly positive and exponential relationship with temperature and showed different temperature sensitivity under the frozen and unfrozen condition. We conservatively estimate that temperature increases following latest temperature scenarios of the IPCC could result in up to a 54.9% increase in Hg (0) concentrations in surface permafrost soils by 2100. Combining the simultaneous measurement of air-soil Hg (0) exchange, we find that enhanced Hg (0) concentrations in upper soils could favor Hg (0) emissions from surface soil. Our findings indicate that Hg (0) emission could be stimulated by permafrost thawing in a warmer world. PMID- 29605611 TI - Effects of CeO2 nanoparticles on bacterial community and molecular ecological network in activated sludge system. AB - The increasing use of cerium oxide nanoparticles (CeO2 NPs) has caused concerns regarding their potential environmental risks. However, their effects on bacterial communities and network interactions in activated sludge process are still unclear. In this study, we carried out long-term exposure experiments (210 d) to investigate the influence of CeO2 NPs on wastewater treatment performance, bacterial community structure and network interactions in activated sludge systems. The results showed that long-term exposure to 1 mg/L CeO2 NPs induced the deterioration of denitrifying process, which was consistent with the inhibition of enzyme activities of nitrite oxidoreductase and nitrate reductase under CeO2 NPs. CeO2 NPs decreased the bacterial diversity and altered the overall bacterial community structure in activated sludge. Some dominant denitrifying bacteria, such as Flexibacter and Acinetobacter decreased significantly. Molecular ecological network analysis showed that CeO2 NPs decreased the network complexity of bacterial community, and probably promoted the competition in bacterial communities of activated sludge. These changes of denitrifying bacteria and the bacterial network may be relevant to the deterioration of denitrifying process. This study provides insights into how the bacteria community and their molecular ecological network respond to CeO2 NPs in activated sludge systems. PMID- 29605612 TI - Enhanced oxidation of arsenite to arsenate using tunable K+ concentration in the OMS-2 tunnel. AB - Cryptomelane-type octahedral molecular sieve manganese oxide (OMS-2) possesses high redox potential and has attracted much interest in its application for oxidation arsenite (As(III)) species of arsenic to arsenate (As(V)) to decrease arsenic toxicity and promote total arsenic removal. However, coexisting ions such as As(V) and phosphate are ubiquitous and readily bond to manganese oxide surface, consequently passivating surface active sites of manganese oxide and reducing As(III) oxidation. In this study, we present a novel strategy to significantly promote As(III) oxidation activity of OMS-2 by tuning K+ concentration in the tunnel. Batch experimental results reveal that increasing K+ concentration in the tunnel of OMS-2 not only considerably improved As(III) oxidation kinetics rate from 0.027 to 0.102 min-1, but also reduced adverse effect of competitive ion on As(III) oxidation. The origin of K+ concentration effect on As(III) oxidation was investigated through As(V) and phosphate adsorption kinetics, detection of Mn2+ release in solution, surface charge characteristics, and density functional theory (DFT) calculations. Experimental results and theoretical calculations confirm that by increasing K+ concentration in the OMS-2 tunnel not only does it improve arsenic adsorption on K+ doped OMS 2, but also accelerates two electrons transfers from As(III) to each bonded Mn atom on OMS-2 surface, thus considerably improving As(III) oxidation kinetics rate, which is responsible for counteracting the adverse adsorption effects by coexisting ions. PMID- 29605613 TI - Ambient PM2.5-bound polycyclic aromatic hydrocarbons (PAHs) in rural Beijing: Unabated with enhanced temporary emission control during the 2014 APEC summit and largely aggravated after the start of wintertime heating. AB - For human health benefits it is crucial to see if carcinogenic air pollutants like polycyclic aromatic hydrocarbons (PAHs) are reduced accordingly along with the control of the criteria pollutants including fine particles (PM2.5). A number of studies documented that enhanced temporary emission control during the 2014 Asia-Pacific Economic Cooperation summit (APEC) in Beijing resulted in substantial drops of observed ambient PM2.5, as well as PAHs, in urban areas of Beijing, yet it is not clear whether PM2.5-bound PAHs in the rural areas were also lowered during the APEC. Here filter-based PM2.5 samples were collected at a rural site in northeast of Beijing, and analyzed for 25 PAHs before (Oct. 27-Nov. 2, 2014), during (Nov. 3-12, 2014) and after (Nov. 13, 2014-Jan. 14, 2015) the APEC. Observed concentrations of PM2.5, OC and EC during the APEC dropped by about 30%, however, average PM2.5-bound PAHs and their incremental lifetime cancer risk (ILCR), 25.65 ng/m3 and 3.2 * 10-4, remained almost unchanged when compared to that of 25.48 ng/m3 and 3.5 * 10-4, respectively, before the APEC. After the APEC with the start of wintertime central heating in urban Beijing on Nov. 15, 2014, average total concentration of PAHs and their ILCR highly elevated and reached 118.25 ng/m3 and 1.5 * 10-3, respectively. Source apportioning by positive matrix factorization (PMF) revealed that coal combustion was the largest source that contributed 63.2% (16.1 ng/m3), 78.5% (20.1 ng/m3) and 56.1% (66.3 ng/m3) to the total PAHs before, during and after the APEC, respectively. Uncontrolled residential coal use during the APEC was found to be the reason for unabated levels of PAHs, and the largely aggravated PAHs after the APEC was resulted from increased coal consumption for wintertime residential heating. Our results suggested reducing emission from residential coal combustion is crucial to mitigate carcinogenic PAHs in ambient air, especially in rural areas. PMID- 29605614 TI - Particulate mercury in ambient air in Shanghai, China: Size-specific distribution, gas-particle partitioning, and association with carbonaceous composition. AB - Mercury (Hg) has a complex atmospheric transformation cycle and acts as a global pollutant. Size-specific particle bound mercury (PBM) was implemented in different functional (industrial, urban and suburban) areas in Shanghai, China. The total concentration of 13-staged PBM (rang of 0.01-18.0 MUm) varied of 99.0 611 pg/m3, with an average value of 318 +/- 144 pg/m3. The Gaoqiao petrochemical industry (GQPI) site showed the highest concentrations, whereas the suburban Shanghai Jiao Tong University (SJTU) displayed the lowest. The PBM in nucleation, accumulation and coarse modes were 7.63-96.7, 69.5-455, and 9.43-176 pg/m3, respectively, and the fractions of 0.56-1.00 and 0.32-0.56 MUm were the two most abundant. Both OC and EC displayed unimodal distribution patterns (peak of 0.56 1.00 MUm) at GQPI, while bimodal distributions were observed at urban and suburban sites. Statistically positive correlations between the overall PBM and the corresponding PM and carbonaceous compounds (r = 0.38-0.54, p < 0.01), indicating their similar origins and OC/EC enhanced gaseous mercury forming PBM. The gas-particle partition model predicted gaseous oxidized mercury (GOM) were 253 +/- 133, 237 +/- 122, and 257 +/- 144 pg/m3 for GQPI, SAES and SJTU, respectively. The particle proportions of divalent mercury in the fraction of 0.32-1.00 MUm were substantial (>80%), but smaller (<50%) for nucleation and coarse modes. The fraction of 9.90-18.00 MUm occupied nearly 50% of the overall dry deposition fluxes of mercury. These finding highlight the emissions from different mercury and OC/EC origins, caused different size-specific distributions of PBM, which further affect their gas-particle partitioning and dry deposition of mercury species. PMID- 29605615 TI - Bioaccessible trace metals in lip cosmetics and their health risks to female consumers. AB - Females can be exposed to toxic elements in lip cosmetics following ingestion. The bioaccessibility of Cr, Mn, Co, Ni, Cu, Cd, Sb and Pb in lip cosmetics (n = 32) were assessed via the dilute HCl extraction method, In Vitro Gastrointestinal protocol (IVG) and the United States Pharmacopeia Methodology (USPM), and then health risks were characterized. The total concentrations of trace metals (TMs) in lip cosmetics were in the range of 15.55-111.97 mg/kg (Mean: 60.99 mg/kg). Cu, Pb and Cr were the three major TMs and accounting for >75% of the total concentrations. Except Sb and Pb in 4/32 and 4/32 samples were higher than the US FDA (Food and Drug Administration of the United States) limits, the other TMs were lower than that limits. Only bioaccessible Pb in all samples significantly exceeded the FDA limit 0.1 mg/kg in candy. Using IVG or USPM might be preferable for evaluating the TMs exposure over HCl since they better represent gastrointestinal physiology. The estimated average daily intake (ADI) of bioaccessible ?TMs through lip cosmetics ingestion of career women and female college students were under safety level. The long-term exposure of bioaccessible TMs by lip cosmetics using would inevitably cause non-carcinogenic health risk. This is the first report on the in vitro tests used for evaluating bioaccessible TMs in lip cosmetics. PMID- 29605616 TI - Comparison of heterotrophic and autotrophic denitrification processes for nitrate removal from phosphorus-limited surface water. AB - Phosphorus (P) limitation has been demonstrated for micro-polluted surface water denitrification treatment in previous study. In this paper, a lab-scale comparative study of autotrophic denitrification (ADN) and heterotrophic denitrification (HDN) in phosphorus-limited surface water was investigated, aiming to find out the optimal nitrogen/phosphorus (N/P) ratio and the mechanism of the effect of P limitation on ADN and HDN. Furthermore, the optimal denitrification process was applied to the West Lake denitrification project, aiming to improve the water quality of the West Lake from worse than grade V to grade IV (GB3838-2006). The lab-scale study showed that the lack of P indeed inhibited HDN more greatly than ADN. The optimal N/P ratio for ADN and HDN was 25 and a 0.15 mg PO43--P L-1 of microbial available phosphorus (MAP) was observed. P additions could greatly enhance the resistance of ADN and HDN to hydraulic loading shock. Besides, The P addition could effectively stimulate the HDN performance via enriching the heterotrophic denitrifiers and the denitrifying phosphate-accumulating organisms (DNPAOs). Additionally, HDN was more effective and cost-effective than ADN for treating P-limited surface water. The study of the full-scale HDBF (heterotrophic denitrification biofilter) indicated that the denitrification performance was periodically impacted by P limitation, particularly at low water temperatures. PMID- 29605617 TI - Land-use-based sources and trends of dissolved PBDEs and PAHs in an urbanized watershed using passive polyethylene samplers. AB - Narragansett Bay is a temperate estuary on the Atlantic coast of Rhode Island in the north-eastern United States, which receives organic pollutants from urban and industrial activities in its watershed, though detailed knowledge on sources and fluxes is missing. Twenty-four polyethylene passive samplers were deployed in the surface water of the watershed around Narragansett Bay during June-July of 2014, to examine the spatial variability and possible sources of priority pollutants, namely dissolved polycyclic aromatic hydrocarbons (PAHs) and polybrominated diphenyl ethers (PBDEs). Dissolved ?22PAH concentrations ranged from 3.6 to 340 ng L-1, and from 2.9 to 220 pg L-1 for ?12PBDE. The spatial variability of the concentrations was correlated to land use pattern and population distribution, in particular with human activities within 2 km of sampling sites. River discharges derived from the concentrations of PAHs and PBDEs measured here were 10-20 times greater than their previously measured concentrations in the open waters of Narragansett Bay. These results imply that river waters are the main source of PAHs and PDBEs to the Bay and that major sink terms (e.g., sedimentation, degradation) affect their concentrations in the estuary. Predicted PAH and PBDE toxicity based on dissolved concentrations did not exceed 1 toxic unit, suggested that no toxicity occurred at the sampling sites. PMID- 29605618 TI - Progressive myoclonus epilepsy without renal failure in a Chinese family with a novel mutation in SCARB2 gene and literature review. AB - PURPOSE: To describe the clinical and genetic features of a Chinese progressive myoclonus epilepsy (PME) patient related with SCARB2 mutation without renal impairment and review 27 SCARB2-related PME patients from 11 countries. METHODS: The patient was a 27-year-old man with progressive action myoclonus, ataxia, epilepsy, dysarthria and absence of cognitive deterioration. Renal functional test was normal. Electroencephalography (EEG) showed progressively slowed background activity and sporadic generalized spike-and-wave discharges. Electromyography (EMG) showed slowed motor and sensory nerve conduction velocities and distal motor latency delay accompanied by normal compound motor action potential (CMAP) and amplitudes of sensory nerve action potential (SNAP). The amplitude of cortical components of brainstem auditory-evoked potential (BAEP) was normal with slightly prolonged latencies. Generalized atrophy, ventricle enlargement and white matter degeneration was observed in brain magnetic resonance imaging (MRI). Open muscle biopsy and genetic analysis were performed. Two hundred healthy individuals were set for control. Quantitative real time PCR (qPCR), western blotting and immunofluorescence were carried out to evaluate the fate of the SCARB2 mRNA and lysosomal-membrane type 2 (LIMP2) protein level. RESULTS: One homozygous mutation in SCARB2 gene (c.1187 + 5G > T) was identified in the patient. Each of his parents carried a heterozygous variant. This mutation was not detected among the healthy controls and predicted to be damaging or disease causing by prediction tools. qPCR revealed a significantly lower level of SCARB2 mRNA in peripheral blood cell of the proband compared with his parents and healthy control individuals. Muscle biopsy showed mild variation in fiber size. Western blotting and immunofluorescence detected an extremely weak signal of LIMP2 protein from skeletal muscle of the proband. CONCLUSION: In this study, we identified a SCARB2-related PME patient with normal renal function and a novel homozygous splicing mutation. SCARB2 gene should be analyzed in patients with progressive action myoclonus, epilepsy, peripheral neuropathy, without cognitive deterioration or renal failure. PMID- 29605619 TI - Evolution in the surgical management of chronic rhinosinusitis: Current indications and pitfalls. AB - Chronic rhinosinusitis (CRS) consists of a range of inflammatory conditions in the sinuses that can result in clinical symptoms. The underlying pathophysiology and its relationship to lower airway disease are complex. Current definitions of CRS can serve more as an indication for potential surgical intervention rather than a marker of disease state. CRS can be asymptomatic and may require medical management to avoid disease progression and minimize the risk of lower airway disease. Endoscopic surgery has undergone a significant evolution and refinement, but the most common surgical complication remains persistent inflammation and disease recurrence. It is important to recognize that surgery alone rarely cures CRS and patients require long-term medical therapy for continued asymptomatic inflammation. Careful postoperative care and endoscopic follow-up to ensure resolution of inflammation are key to ensuring optimal surgical outcomes and reduce the risk of revision surgery. Future work on CRS endotypes will allow discovery of new therapies to treat CRS, as well as refine indications for medical or surgical intervention and postoperative care. PMID- 29605620 TI - [Incidence and evolution of congenital heart disease in Spain from 2003 until 2012]. AB - INTRODUCTION AND OBJECTIVES: Congenital heart disease (CHD) represents the most common congenital malformation. The objective of this study was to analyse the incidence of CHD in Spain, and it is the first nationwide study so far. METHODS: A retrospective observational study was performed in order to evaluate the incidence of CHD in Spain. The administrative database (minimum basic data set) from 2003 to 2012 was analysed in children less than one year old admitted to hospital with codes of CHD (International Classification of Diseases, 9th Revision, clinical modification). Cumulative incidence, Incidence relative risk, and standardised incidence ratio were calculated to study geographic variations. RESULTS: There were 64,831 infants with CHD among the 4,766,325 births analysed during the period studied, with an incidence of 13.60/00. The incidence excluding atrial septal defect was 7.29 0/00.The most frequent CHD were atrial septal defect (6.310/00), ventricular septal defect (3.480/00), patent ductus arteriosus (2.710/00), coarctation of the aorta (0.550/00), pulmonary stenosis (0.500/00), transposition of the great arteries (0.490/00), atrioventricular septal defect (0.450/00), and tetralogy of Fallot (0.410/00). Castilla and Leon, together with Extremadura, showed the highest risks for severe and very severe CHD, while Madrid and Cantabria showed the lowest. CONCLUSIONS: An increase of mild CHD was observed during the period analysed. This could have been influenced by improvements in diagnostic techniques, extended use of echocardiography, and the International Classification of Diseases, 9th Revision, clinical modification coding system, and to a decrease in very severe CHD, which is less influenced by external factors. Significant geographical differences were found in the incidence of severe and very severe CHD. PMID- 29605621 TI - Is ICS-LAMA an alternative option to treat patients with COPD? PMID- 29605622 TI - E-cigarettes: from nicotine to cannabinoids, the French situation. PMID- 29605623 TI - COPD and rural health in the USA. PMID- 29605625 TI - Activation of soluble guanylyl cyclase with inhibition of multidrug resistance protein inhibitor-4 (MRP4) as a new antiplatelet therapy. AB - The intracellular levels of cyclic GMP are controlled by its rate of formation through nitric oxide-mediated stimulation of soluble guanylate cyclase (sGC) and its degradation by phosphodiesterases. Multidrug resistance protein 4 (MRP4) expressed in human platelets pumps cyclic nucleotides out of cells. In search for new antiplatelet strategies, we tested the hypothesis that sGC activation concomitant with MRP4 inhibition confers higher antiplatelet efficacy compared with monotherapy alone. This study was undertaken to investigate the pharmacological association of the sGC activator BAY 60-2770 with the MRP4 inhibitor MK571 on human washed platelets. Collagen- and thrombin-induced platelet aggregation and ATP-release reaction assays were performed. BAY 60-2770 (0.001-10 uM) produced significant inhibitions of agonist-induced platelet aggregation accompanied by reduced ATP-release. Pre-incubation with 10 uM MK571 alone had no significant effect on platelet aggregation and ATP release, but it produced a left displacement by about of 10-100-fold in the concentration response curves to BAY 60-2770. Pre-incubation with MK571increased and decreased, respectively, the intracellular and extracellular levels of cGMP to BAY 60-2770, whereas the cAMP levels remained unchanged. The increased VASP-serine 239 phosphorylation in BAY 60-2770-treated platelets was enhanced by MK571. In Fluo-4 loaded platelets, BAY 60-2770 reduced the intracellular Ca2+ levels, an effect significantly potentiated by MK571. Flow cytometry assays showed that BAY 60-2770 reduces the alphaIIbbeta3 integrin activation, which was further reduced by MK571 association. Blocking the MRP4-mediated efflux of cGMP may be a potential mechanism to enhance the antiplatelet efficacy of sGC activators. PMID- 29605624 TI - Tiotropium and olodaterol in the prevention of chronic obstructive pulmonary disease exacerbations (DYNAGITO): a double-blind, randomised, parallel-group, active-controlled trial. AB - BACKGROUND: Combinations of long-acting bronchodilators are recommended to reduce the rate of chronic obstructive pulmonary disease (COPD) exacerbations. It is unclear whether combining olodaterol, a long-acting beta-agonist, with tiotropium, a long-acting anti-muscarinic, reduces the rate of exacerbations compared with tiotropium alone. METHODS: This 52-week, double-blind, randomised, parallel-group, active-controlled trial randomly assigned (1:1) patients with COPD with a history of exacerbations using a randomised block design to receive tiotropium-olodaterol 5 MUg-5 MUg or tiotropium 5 MUg once daily. Patients using inhaled corticosteroids continued this therapy. Treatment was masked to patients, investigators, and those involved in analysing the data. The primary endpoint was the rate of moderate and severe COPD exacerbations from the first dose of medication until 1 day after last drug administration. The primary analysis included all randomly assigned patients who received any dose of study medication but were not from a site excluded due to on-site protocol violations. The trial is registered with ClinicalTrials.gov, number NCT02296138. FINDINGS: Overall, 9009 patients were screened from 818 centres in 51 countries. We recruited 7880 patients between Jan 22, 2015 and March 7, 2016 (mean age 66.4 years [SD 8.5], 5626 [71%] were men, mean FEV1 percent predicted 44.5% [SD 27.7]): 3939 received tiotropium-olodaterol and 3941 tiotropium. The rate of moderate and severe exacerbations was lower with tiotropium-olodaterol than tiotropium (rate ratio [RR] 0.93, 99% CI 0.85-1.02; p=0.0498), not meeting the targeted 0.01 significance level. The proportion of patients reporting adverse events was similar between treatments. INTERPRETATION: Combining tiotropium and olodaterol did not reduce exacerbation rate as much as expected compared with tiotropium alone. FUNDING: Boehringer Ingelheim International GmbH. PMID- 29605627 TI - Constitutive activity of the metabotropic glutamate receptor 2 explored with a whole-cell label-free biosensor. AB - Label-free cellular assays using a biosensor provide new opportunities for studying G protein-coupled receptor (GPCR) signaling. As opposed to conventional in vitro assays, integrated receptor-mediated cellular responses are determined in real-time rather than a single downstream signaling pathway. In this study, we examined the potential of a label-free whole cell impedance-based biosensor system (i.e. xCELLigence) to study the pharmacology of one GPCR in particular, the mGlu2 receptor. This receptor is a target for the treatment of several psychiatric diseases such as schizophrenia and depression. After optimization of assay conditions to prevent interference of endogenous glutamate in the culture medium, detailed pharmacological assessments were performed. Concentration response curves showed a concentration-dependent increase in impedance for agonists and positive allosteric modulators, whereas receptor inhibition by an antagonist or negative allosteric modulator resulted in a concentration-dependent decrease in cellular impedance. Interestingly, constitutive receptor activity was observed that was decreased by LY341495, which therefore behaved as an inverse agonist here, a property that was heretofore unappreciated. This was confirmed by concentration-dependent modulation of LY341495 potency and efficacy by a allosteric modulators. In summary, the use of the xCELLigence system to study mGlu2 receptor pharmacology was validated. This is the first class C GPCR to be characterized extensively by such method, opening new avenues to study receptor pharmacology including inverse agonism and demonstrating its value for future drug discovery efforts of mGlu receptors as well as other GPCRs. PMID- 29605626 TI - Novel regulations of the angiotensin II receptor type 1 by calmodulin. AB - The angiotensin II receptor type 1 (AT1R) mediates many Ca2+-dependent actions of angiotensin II (AngII). Calmodulin (CaM) is a key transducer of Ca2+ signals in cells. Two locations on the receptor's submembrane domains (SMD) 3 and 4 are known to interact with CaM. However, the binding sites for CaM, biochemical properties of the interactions, and their functional impact are not fully understood. Using a FRET-based screening method, we identified a new binding site for CaM on SMD2 (a.a. 125-141), in addition to SMD3 and the juxtamembranous region of SMD4 (SMD4JM, a.a., 309-327). Simultaneous measurements of CaM binding and free Ca2+ show that the interactions are Ca2+-dependent, with disparate Kd and EC50(Ca2+) values within the physiological range of cytoplasmic Ca2+. Full interaction between CaM and SMD3 requires the entire domain (a.a. 215-242) and has an EC50(Ca2+) value in the range of resting cytoplasmic Ca2+, suggesting AT1R CaM interaction can occur in resting conditions in cells. AngII induces robust ERK1/2 phosphorylation in primary vascular smooth muscle cells. This effect is suppressed by AT1R inhibitor losartan and virtually abolished by CaM antagonist W 7. AngII-induced ERK1/2 phosphorylation is suppressed in cells expressing mutant AT1R with reduced CaM binding at each identified binding domain. AngII triggers transient Ca2+ signals in cells expressing wild-type AT1R. These signals are reduced in cells expressing mutant AT1R with reduced CaM binding at SMD3 or SMD4JM, but are very slow-rising, low amplitude signal in cells expressing AT1R with reduced CaM binding at SMD2. The data indicate that CaM interactions with AT1R can occur at various domains, with different affinities, at different physiological Ca2+ levels, and are important for AT1R-mediated signaling. PMID- 29605628 TI - Exploring different photodynamic therapy parameters to optimize elimination of Enterococcus faecalis in planktonic form. AB - BACKGROUND: The failure of endodontic treatment is linked to the presence of Enterococcus faecalis in the root canals. The scope of this study was to evaluate the influence of the energy dose and frequency of photodynamic therapy (PDT cycles), as well as the volume of bacterial suspensions (BS) in the elimination of Enterococcus faecalis in planktonic form. METHODS: In four successive assays BS of Enterococcus faecalis ATCC 19433 were irradiated with a diode laser (40 mW) using the photosensitizer (PS) methylene blue (MB) (0.005 MUg/mL). Group 1 - Effect of energy dose: 100 MU L of BS and 100 MU L of PS were irradiated by 1, 2.5, 5, 7.5 and 10 minute s. Group 2 - Effect of PDT cycles: The BS received 1, 2, 3 or 4 PDT cycles (in each cycle 100 m L of PS was added and irradiated by 2.5 minutes). Group 3 - Effect of energy dose and bacterial suspension volume: 10 MU L of BS and 10 MU L of PS were irradiated similar to group 1. Group 4 - Effect of energy dose, bacterial suspension volume and PDT cycles: 10 MU L of BS and 10 MUL of PS were irradiated according to group 2. The laser source and MB isolated represented the controls. RESULTS: The mean log reduction after separate applying laser light and MB were 0.01 and 0.07, respectively. It was found that wells with 100 MU L of BS irradiated with 2.4 to 24 J of energy did not cause significant bacterial elimination (p > 0.05), on the other hand PDT cycles above 12 J increased significantly bacterial elimination (p < 0.05). In 10 MU L wells irradiation from 12 J of energy provided higher bacterial elimination (p < 0.05) which combined with PDT cycle resulted in the logarithmic elimination of E. faecalis (p < 0.05). CONCLUSIONS: The energy dose, the volume of the bacterial suspension and, especially, the PDT cycles optimized the bacterial elimination of Enterococcus faecalis in planktonic form. PMID- 29605629 TI - Tissue-muscle perfusion assessed by one day 99mTc-MIBI rest-dipyridamol scintigraphy in non-diabetic and diabetic patients. AB - AIM: To determine the perfusion reserve of the lower limbs using the method 99mTc MIBI (rest-dipyridamole) perfusion scintigraphy (one-day protocol) in the diagnostic evaluation of peripheral artery disease (PAD) in patients with and without diabetes mellitus (DM). MATERIAL AND METHODS: We performed tissue-muscle perfusion scintigraphy (TMPS) of the lower limbs, through one-day rest dipyridamole protocol with 99mTc-MIBI in 24 patients, divided in two groups according to the presence of diabetes - patients with DM (Dp) 13/24 (54%), 2 males and 9 female patients, age 63+/-13 years and patients without DM (NDp) 11/24 (46%), 3 males and 10 females, age 61+/-14 years. RESULTS: In the dynamic phase of the rest study, the time of maximum activity (Tmax), in the early arterial phase, of the calf region was significantly prolonged in Dp compared to NDp, with lower accumulation of the radiotracer in the 1st minute (85%/87% in Dp vs. 89%/90% in NDp, ns). 4/11 of NDp (36.4%) and 7/13 of Dp (53.8%) registered pathological value of the inter-extremity index of the calves in the stress study. Perfusion reserve (PR) of the thighs (LT, RT) and calves (LC, RC) calculated with the formula "(ROI stress-ROI rest)*100%/ROI rest", was significantly lower in Dp: LT: 28+/-19% vs. 43+/-24% in NDp, p<0.05; RT: 27+/-17% vs. 40+/-25% in NDp, p<0.05; LC: 22+/-15% vs. 36+/-15% in NDp, p<0.01; RC: 25+/ 15% vs. 38+/-14% in NDp, p<0.01. CONCLUSION: This one-day protocol (rest dipyridamole with 99mTc-MIBI) of perfusion scintigraphy of lower limbs is considered as a useful procedure in PAD assessment, especially the asymptomatic form. TMPS of the lower limbs in our study indicated that perfusion reserve in patients with DM was significantly lower, compared to the patients without diabetes. PMID- 29605630 TI - 99mTc-HMPAO brain SPECT in the monitoring of cerebral vasculitis therapy. AB - OBJECTIVE: The central nervous system (CNS) may be involved in a variety of inflammatory diseases of the blood vessels, generally known as vasculitis. The clinical diagnosis of such involvement in early stages is difficult, since a mild cognitive impairment can be the only symptom. It was hypothesized that brain perfusion SPECT would be able to reveal CNS involvement and to monitor the course of the disease. The purpose of this study was assess if and when an improvement of cerebral perfusion can be registered by SPECT during the follow-up of these diseases. MATERIAL AND METHODS: Eighteen patients affected by Systemic Lupus Erythematosus (SLE), 22 by undifferentiated vasculitis (UV), 5 by Behcet's disease (BD) and 5 by primary Sjogren's Syndrome (pSS) were enrolled in this prospective study. A 99mTc-HMPAO brain perfusion SPECT was performed before the treatment and was repeated during the follow-up at different time intervals. Image analysis was performed on 10 cerebral areas using a specific software. RESULTS: In the SLE patients, no significant improvement of brain perfusion was found. On the contrary, in the UV the cerebral uptake of the tracer significantly improved from the twenty-fourth month (18/22 patients). Patients with BD showed an improvement of scintigraphic findings (5/5 patients), while a similar result was obtained only in 2 of the patients with pSS. CONCLUSIONS: In conclusion, brain SPECT seems to be able to monitor the disease in UV, indicating the moment when an improvement of the cerebral perfusion is achieved. In SLE patients this scintigraphic technique did not show a significant improvement in CNS perfusion. PMID- 29605631 TI - Grammatical gender affects gender perception: Evidence for the structural feedback hypothesis. AB - Two experiments assessed the extent to which grammatical gender provides a predictive basis for bilinguals' judgments about perceptual gender. In both experiments, French-English bilinguals and native English monolinguals were consecutively presented with images of objects manipulated for their (i) conceptual gender association and (ii) grammatical gender category and were instructed to make a decision on a subsequent target face. The experiments differed in the implicitness of the association between the object primes and target faces. Results revealed that when prior knowledge sources such as conceptual gender can be strategically used to resolve the immediate task (Experiment 1), this information was readily extracted and employed. However, grammatical gender demonstrated a more robust and persisting effect on the bilinguals' judgments, indicating that the retrieval of obligatory grammatical information is automatic and modulates perceptual judgments (Experiment 2). These results suggest that grammar enables an effective and robust means to access prior knowledge which may be independent of task requirements. PMID- 29605632 TI - Long-term administration of pDC-Stimulative Lactococcus lactis strain decelerates senescence and prolongs the lifespan of mice. AB - The decline in immune function caused by aging increases the risk of infectious diseases, tumorigeneses and chronic inflammation, resulting in accelerating senescence. We previously reported a lactic acid bacteria, Lactococcus lactis strain Plasma (synonym of Lactococcus lactis subsp. lactis JCM 5805, Lc-Plasma), that stimulates plasmacytoid dendritic cells (pDCs), which play a crucial role in phylaxis from viral infection. In this study, we investigated the anti-aging effects of long-term oral administration of Lc-Plasma in a senescence-accelerated mouse strain, SAMP6. Mice given Lc-Plasma showed a significant improvement in survival rate at 82 weeks and a decreased senescence score as compared with control mice throughout this study. Anatomic analysis at 82 weeks revealed that the frequency of altered hepatocellular foci was significantly lower, and the incidence of other pathological findings in the liver and lungs tended to be lower in Lc-Plasma mice than in control mice. Transcription level of the IL-1beta gene in lungs also tended to be lower in Lc-Plasma mice. Furthermore, the thinning of skin and age-related decrease in muscle mass were also significantly suppressed in the Lc-Plasma group as compared with the control group. Consistent with these phenotypic features, pDCs activity was significantly higher in Lc Plasma mice than in control mice. In conclusion, long-term administration of Lc Plasma can decelerate senescence and prolong lifespan via maintenance of the immune system due to activation of pDCs. PMID- 29605633 TI - Peroxiredoxin 2 mediates insulin sensitivity of skeletal muscles through regulation of protein tyrosine phosphatase oxidation. AB - Insulin signaling is essential for regulating glucose homeostasis. Numerous studies have demonstrated that reactive oxygen species (ROS) affect insulin signaling, and low ROS levels can act as a signal to regulate cellular function. Peroxiredoxins (Prxs) are highly abundant and widely expressed antioxidant enzymes. However, it is unclear whether antioxidant enzymes, such as Prx2, mediate insulin signaling. The aim of our study was to investigate the influence of Prx2 deficiency on insulin signaling. Our western blot results showed that Prx2 deficiency enhanced insulin signaling and increased oxidation of protein tyrosine phosphatase 1B (PTP1B) and phosphatase and tensin homologue (PTEN) in mouse embryonic fibroblasts (MEFs) treated with insulin. In addition, we assessed ROS levels with a Cytosol-HyPer H2O2 sensor. As a result, increased ROS levels and Akt activation were decreased by N-acetyl-cysteine (Nac), which acted as an antioxidant in Prx2-deficient MEFs. Body weight measurements and glucose tolerance test (GTT) revealed significant body weight reduction and increase in glucose clearance in Prx2-/- mice fed a high-fat diet. Interestingly, glucose transporter type 4 (GLUT4) was significantly higher in Prx2-/- mice than in wild type mice according to western blotting results. Western blotting also revealed that Akt phosphorylation was higher in Prx2-/- MEFs and muscle tissue than in wild-type. Together, our findings indicate that increased ROS due to Prx2 deficiency promotes insulin sensitivity and glucose clearance in skeletal muscles by increasing protein tyrosine phosphatase (PTPs) oxidation. These results provide novel insights into the fundamental mechanisms of insulin signaling induced by Prx2 deficiency and suggest that ROS-based therapeutic strategies can be used to suppress insulin resistance. PMID- 29605634 TI - CRISPcut: A novel tool for designing optimal sgRNAs for CRISPR/Cas9 based experiments in human cells. AB - The ability to direct the CRISPR/Cas9 nuclease to a unique target site within a genome would have broad use in targeted genome engineering. However, CRISPR RNA is reported to bind to other genomic locations that differ from the intended target site by a few nucleotides, demonstrating significant off-target activity. We have developed the CRISPcut tool that screens the off-targets using various parameters and predicts the ideal genomic target for -guide RNAs in human cell lines. sgRNAs for four different types of Cas9 nucleases can be designed with an option for the user to work with different PAM sequences. Direct experimental measurement of genome-wide DNA accessibility is incorporated that effectively restricts the prediction of CRISPR targets to open chromatin. An option to predict target sites for paired CRISPR nickases is also provided. The tool has been validated using a dataset of experimentally used sgRNA and their identified off-targets. URL: http://web.iitd.ac.in/crispcut. PMID- 29605635 TI - Rapid changes in auditory processing in songbirds following acute aromatase inhibition as assessed by fMRI. AB - Contribution to Special Issue on Fast effects of steroids. This review introduces functional MRI (fMRI) as an outstanding tool to assess rapid effects of sex steroids on auditory processing in seasonal songbirds. We emphasize specific advantages of this method as compared to other more conventional and invasive methods used for this purpose and summarize an exemplary auditory fMRI study performed on male starlings exposed to different types of starling song before and immediately after the inhibition of aromatase activity by an i.p. injection of VorozoleTM. We describe how most challenges that relate to the necessity to anesthetize subjects and minimize image- and sound-artifacts can be overcome in order to obtain a voxel-based 3D-representation of changes in auditory brain activity to various sound stimuli before and immediately after a pharmacologically-induced depletion of endogenous estrogens. Analysis of the fMRI data by assumption-free statistical methods identified fast specific changes in activity in the auditory brain regions that were stimulus-specific, varying over different seasons, and in several instances lateralized to the left side of the brain. This set of results illustrates the unique features of fMRI that provides opportunities to localize and quantify the brain responses to rapid changes in hormonal status. fMRI offers a new image-guided research strategy in which the spatio-temporal profile of fast neuromodulations can be identified and linked to specific behavioral inputs or outputs. This approach can also be combined with more localized invasive methods to investigate the mechanisms underlying the observed neural changes. PMID- 29605636 TI - Rapid effects of 17beta-estradiol on aggressive behavior in songbirds: Environmental and genetic influences. AB - Contribution to Special Issue on Fast effects of steroids. 17beta-estradiol (E2) has numerous rapid effects on the brain and behavior. This review focuses on the rapid effects of E2 on aggression, an important social behavior, in songbirds. First, we highlight the contributions of studies on song sparrows, which reveal that seasonal changes in the environment profoundly influence the capacity of E2 to rapidly alter aggressive behavior. E2 administration to male song sparrows increases aggression within 20 min in the non-breeding season, but not in the breeding season. Furthermore, E2 rapidly modulates several phosphoproteins in the song sparrow brain. In particular, E2 rapidly affects pCREB in the medial preoptic nucleus, in the non-breeding season only. Second, we describe studies of the white-throated sparrow, which reveal how a genetic polymorphism may influence the rapid effects of E2 on aggression. In this species, a chromosomal rearrangement that includes ESR1, which encodes estrogen receptor alpha (ERalpha), affects ERalpha expression in the brain and the ability of E2 to rapidly promote aggression. Third, we summarize studies showing that aggressive interactions rapidly affect levels of E2 and other steroids, both in the blood and in specific brain regions, and the emerging potential for steroid profiling by liquid chromatography tandem mass spectrometry (LC-MS/MS). Such studies of songbirds demonstrate the value of an ethologically informed approach, in order to reveal how steroids act rapidly on the brain to alter naturally-occurring behavior. PMID- 29605637 TI - Genome sequence of two members of the chloroaromatic-degrading MT community: Pseudomonas reinekei MT1 and Achromobacter xylosoxidans MT3. AB - We describe the genome sequence of Pseudomonas reinekei MT1 and Achromobacter xylosoxidans MT3, the most abundant members of a bacterial community capable of degrading chloroaromatic compounds. The MT1 genome contains open reading frames encoding enzymes responsible for the catabolism of chlorosalicylate, methylsalicylate, chlorophenols, phenol, benzoate, p-coumarate, phenylalanine, and phenylacetate. On the other hand, the MT3 strain genome possesses no ORFs to metabolize chlorosalicylates; instead the bacterium is capable of metabolizing nitro-phenolic and phenolic compounds, which can be used as the only carbon and energy source by MT3. We also confirmed that MT3 displays the genetic machinery for the metabolism of chlorocathecols and chloromuconates, where the latter are toxic compounds secreted by MT1 when degrading chlorosalicylates. Altogether, this work will advance our fundamental understanding of bacterial interactions. PMID- 29605638 TI - B-factor-saturation mutagenesis as a strategy to increase the thermostability of alpha-L-rhamnosidase from Aspergillus terreus. AB - The alpha-L-Rhamnosidase is an important enzyme with applications in the food and pharmaceutical industries because it can release terminal L-rhamnose residues from various natural products. In this study, the B-factor-saturation mutagenesis strategy was used to increase the thermostability of alpha-L-rhamnosidase from Aspergillus terreus. The D594Q and G827K/D594Q mutant enzymes were obtained by screening a series of mutants; they prolonged the half-life of the enzyme at 70 degrees C by 2.1-fold and 2.3-fold, respectively. Analysis of the 3D structure showed that in the thermostable variants the number of hydrogen bonds and salt bridges was increased, explaining the enhanced thermostability. Kinetic studies showed that the KM values for the D594Q and G827K/D594Q mutant enzymes decreased by 4.0% and 3.8%, respectively. Additionally, the kcat/KM values for the D594Q and G827K/D594Q mutant enzymes increased by 15.5% and 9.2%, respectively. Moreover, the D594Q and G827K/D594Q mutant enzymes exhibited markedly improved isoquercitrin yield at 70 degrees C that increased by 13.5% and 11.0%, respectively. Therefore, the D594Q and G827K/D594Q mutant enzymes are more suitable for the industrial processes of isoquercitrin preparation. PMID- 29605639 TI - Multivessel analysis of progressive vascular aging in the rat: Asynchronous vulnerability among vascular territories. AB - Aging induces vascular dysfunction, representing the major risk factor for cardiovascular disease. Our aim was to ascertain specific vulnerability of vascular territories to aging by evaluating the progressive impact of aging on vascular function in four different vascular beds: aorta, mesenteric artery (MA), coronary artery (CA), and penile corpus cavernosum (CC) from 3, 6, 9, 12, 20 or 24 months-old male rats. Contractile/relaxant responses were evaluated in organ chambers (A/CC) and wire myographs (MA/CA). Relationships of systemic biomarkers with endothelial function impairment were also determined. Although all vessels manifested aging-related impairment in endothelial vasodilation, CA was the most impacted by aging considering the onset (at 6 months) and magnitude of endothelial dysfunction (reduction by 1.5 log units in the concentration required for 50% of maximal relaxation for acetylcholine). H2O2-induced vasodilations were progressively reduced by aging in aorta, CC and CA while NO-donor-induced vasodilation was impaired by aging only in CA. Serum asymmetric dimethylarginine significantly correlated to endothelial decline in aorta, MA, and CC, while HOMA IR was significantly associated with endothelial dysfunction in CA and MA. CA are especially vulnerable to aging-related vascular dysfunction. Correlations of vascular dysfunction with systemic biomarkers differ among vessels, further suggesting heterogeneity in aging-induced vascular impact. PMID- 29605640 TI - Metal concentrations and risk assessment in water, sediment and economic fish species with various habitat preferences and trophic guilds from Lake Caizi, Southeast China. AB - Despite the potential emissions of heavy metal pollution in Lake Caizi due to extensive agriculture, urban growth and fishing activities, the risk posed by metal concentrations to aquatic environments and human populations has not yet been studied. In this study we compared the concentrations of Hg, As, Pb, Cd, Cr, Cu and Zn in water, sediment, and economic fish species with different habitat preferences and trophic guilds across important fishery areas in Lake Caizi, located on the northern shore of the Yangtze River, Southeast China. The concentrations of Cr in water were found approximately 6 times higher than the safety thresholds established by international legislation. Cr, Zn, As and Cd concentrations in sediments surpassed the background values for Yangtze River basin in Anhui Province. However, all the studied fish species in Lake Caizi had metal concentrations lower than legislation thresholds established by China and international organizations. Heavy metal concentrations were found to be significantly higher in demersal (inhabiting near the sediments) and piscivorous (possessing higher trophic level) fishes than in pelagic/benthopelagic (inhabiting the upper and lower water column) and herbivorous/planktivorous (possessing lower trophic level) fishes. Our finding demonstrated that the metal concentrations in fishes are simultaneously influenced by the habitat and bio accumulation through the food chain. According to target hazard quotient (THQ) calculations for heavy metal contents in the muscles of fish species, all the determined heavy metals gave THQ values lower than 1, suggesting the inexistence of health risks from the intake of fishes from Lake Caizi. PMID- 29605641 TI - Biochemical mechanism of phytoremediation process of lead and cadmium pollution with Mucor circinelloides and Trichoderma asperellum. AB - This study focused on the bioremediation mechanisms of lead (0, 100, 500, 1000 mg kg-1) and cadmium (0,10,50,100 mg kg-1) contaminated soil using two indigenous fungi selected from mine tailings as the phytostimulation of Arabidopsis thaliana. The two fungal strains were characterized as Mucor circinelloides (MC) and Trichoderma asperellum (TA) by internal transcribed spacer sequencing at the genetic levels. Our research revealed that Cadmium was more toxic to plant growth than lead and meanwhile, MC and TA can strengthen A. thaliana tolerance to cadmium and lead with 40.19-117.50% higher root length and 58.31-154.14% shoot fresh weight of plant compared to non-inoculation. In this study, TA exhibited a higher potential to the inactivation of cadmium; however, MC was more effective in lead passivation. There was a direct correlation between the type of fungi, heavy metal content, heavy metal type and oxidative damage in plant. Both lead and cadmium induced oxidative damage as indicated by increased superoxide dismutase and catalase activities, while the antioxidant levels were significantly higher in fungal inoculated plants compared with those non inoculated. The analysis of soil enzyme activity and taxonomic richness uncovered that the dominant structures of soil microbial community were altered by exogenous microbial agents. MC enhanced higher microbial diversity and soil enzyme activity than TA. The two indigenous fungi lessened several limiting factors with respect to phytoremediation technology, such as soil chemistry, contamination level and transformation, and metal solubility. PMID- 29605642 TI - Using a mesocosm approach to evaluate marine benthic assemblage alteration associated with CO2 enrichment in coastal environments. AB - The effects of acidification related to the CO2 enrichment in the coastal environments on marine macrobenthic abundance, diversity and richness were analyzed in a medium- term (21 days) using mesocosm experiments. Two sampling sites located in the Bay of Cadiz - SW, Spain were selected and tested at pH values ranged from 7.9 to 6.0 (+/- 0.1). Moreover, variations in the concentrations of metals in the sediment samples were analyzed at the end of each experiment. The results showed low variation in the concentrations of metals in the sediment among the pH treatments. A significant decrease (p < 0.05) in the abundance, diversity and richness of assemblages were measured between the control and the lowest pH level in both sampling sites tested in this study (Rio San Pedro and El Trocadero). The majority of species were found in all samples except in pH 6.0 which only two species were found (Hydrobia ulvae and Scrobicularia plana,) in Rio San Pedro sediment fauna. In general, the results of cluster analysis showed 60% and 40% similarity in all replicated tests in El Trocadero and Rio San Pedro of sediment fauna, respectively. The results of the Principal Component Analysis (PCA) showed that both sediment parameters and pH reduction can interfere in the benthic assemblage indices. Although the assemblages' indices have shown decreases only in the lower pHs, the organisms also could be impacted by chronic effects. Therefore, the extension of this study is important in order to improve the knowledge about the risks associated with CO2 enrichment in on marine organisms. PMID- 29605643 TI - Intracellular toxicity exerted by PCBs and role of VBNC bacterial strains in biodegradation. AB - Polychlorinated biphenyls (PCBs) are xenobiotic compounds that persists in the environment for long-term, though its productivity is banned. Abatement of the pollutants have become laborious due to it's recalcitrant nature in the environment leading to toxic effects in humans and other living beings. Biphenyl degrading bacteria co-metabolically degrade low chlorinated PCBs using the active metabolic pathway. bph operon possess different genetic arrangements in gram positive and gram negative bacteria. The binding ability of the genes and the active sites were determined by PCB docking studies. The active site of bphA gene with conserved amino acid residues determines the substrate specificity and biodegradability. Accumulation of toxic intermediates alters cellular behaviour, biomass production and downturn the metabolic activity. Several bacteria in the environment attain unculturable state which is viable and metabolically active but not cultivable (VBNC). Resuscitation-promoting factor (Rpf) and Rpf homologous protein retrieve the culturability of the so far uncultured bacteria. Recovery of this adaptive mechanism against various physical and chemical stressors make a headway in understanding the functionality of both environmental and medically important unculturable bacteria. Thus, this paper review about the general aspects of PCBs, cellular toxicity exerted by PCBs, role of unculturable bacterial strains in biodegradation, genes involved and degradation pathways. It is suggested to extrapolate the research findings on extracellular organic matters produced in culture supernatant of VBNC thus transforming VBNC to culturable state. PMID- 29605644 TI - Antialgal compounds with antialgal activity against the common red tide microalgae from a green algae Ulva pertusa. AB - Nine antialgal active compounds, (i.e. trehalose (1), twenty-two methyl carbonate (2), (-)-dihydromenisdaurilide (3), 3,7,11,15-tetramethyl-2-hexadecen-1-ol (4), isophytol (5), 8-hexadecenol (6), 17-hydroxyheptadecanoic acid (7), trans-asarone (8) and 2-amino-3-mercaptopropanoic acid (9)) were isolated from Ulva pertusa for the first time by sephadex LH-20 column chromatography, silica gel column chromatography and repeated preparative TLC. Except for compound 4, all compounds represented novel isolated molecules from marine macroalgae. Further, antialgal activities of these compounds against Amphidinium carterae, Heterosigma akashiwo, Karenia mikimitoi, Phaeocystis globosa, Prorocentrum donghaiense and Skeletonema costatum were investigated for the first time. Results showed these nine compounds have selectivity antialgal effects on all test red tide microalgae, and antialgal activities against red tide microalgae obviously enhanced with the increase of concentration of antialgal compounds. Based on this, EC50-96 h values of these nine compounds for six red tide microalgae were obtained for the first time. By analyzing and comparing EC50-96 h values, it has been determined that seven compounds (1, 3, 4, 6, 7, 8 and 9) showed the superior application potential than potassium dichromate or gossonorol and other six compounds as a characteristic antialgal agent against Heterosigma akashiwo, Karenia mikimitoi and Prorocentrum donghaiense. Overall this study has suggested that green algae Ulva pertusa is a new source of bioactive compounds with antialgal activity. PMID- 29605645 TI - Iris lactea var. chinensis (Fisch.) cysteine-rich gene llCDT1 enhances cadmium tolerance in yeast cells and Arabidopsis thaliana. AB - : IlCDT1, a cysteine-rich protein, was isolated from Iris lactea var. chinensis (Fisch.) (I. lactea var. chinensis). Its transcription was up-regulated by the exogenous application of Cd. The truncated IlCDT1 (25-54) containing 14 Cys residues confers Cd tolerance to yeast as the intact IlCDT1, indicating that Cys residues are required for Cd tolerance presumably by chelating Cd. When the gene was constitutively expressed in A. thaliana, root length of transgenic lines was longer than that of wild-type under 100 MUM or 200 MUM Cd stress. However, Cd absorption in wild-type was more than in two trangenic lines under 100 MUM Cd exposure. IlCDT1 may directly bind Cd, through chelating Cd and avoiding the Cd uptake into the cells. Together, IlCDT1 may be a promising gene for the Cd tolerance improvement. SUMMARY: Cysteine-rich gene llCDT1 enhances cadmium tolerance in yeast cells and Arabidopsis thaliana. PMID- 29605646 TI - Responses of Labeo rohita fingerlings to N-acetyl-p-aminophenol toxicity. AB - The short term (96 h) toxicity of N-acetyl-p-aminophenol (0.58 mg/L - Treatment I and 0.29 mg/L - Treatment II) on certain health indicators (haematology, biochemical, and enzymology) of an Indian major carp Labeo rohita was studied. When compared to control, N-acetyl-p-aminophenol treated fish showed a significant (P < 0.05) decrease in haemoglobin (Hb), haematocrit (Hct), and erythrocyte (RBC) levels throughout the study period. Whereas, a significant (P < 0.05) increase were noted in leucocyte (WBC) counts (except 48 h in Treatment-I), mean corpuscular volume (MCV), and mean corpuscular haemoglobin (MCH) values (except 24 h in Treatment-I). Mean corpuscular haemoglobin concentration (MCHC) values were found to be decreased significantly (P < 0.05) in fish exposed to 0.58 mg/L of N-acetyl-p-aminophenol, whereas in 0.29 mg/L exposed fish the values were found to be increased significantly (P < 0.05) (except 72 h). A significant (P < 0.05) increase in plasma glucose levels was noticed in fish exposed to 0.58 mg/L of N-acetyl-p-aminophenol (except 96 h). However, a biphasic trend in plasma glucose level was observed at 0.29 mg/L of N-acetyl-p-aminophenol exposed fish. Protein levels were found to be increased in both the treatments except at the end of 48 and 96 h in 0.58 and 0.29 mg/L, respectively. In both the treatments fluctuations of enzyme (GOT, GPT, and LDH) activities in gill and liver were also noted. However, these enzyme activities found to be significantly (P < 0.05) decreased in kidney and plasma of fish. From the result we conclude that the drug N-acetyl-p-aminophenol upon short term exposure could pose a risk to fish and the alteration of these parameters can be used to ecological risk assessment of pharmaceuticals in aquatic organisms. PMID- 29605647 TI - Heavy metal induced oxidative damage and root morphology alterations of maize (Zea mays L.) plants and stress mitigation by metal tolerant nitrogen fixing Azotobacter chroococcum. AB - Heavy metals are one of the major abiotic stresses that adversely affect the quantity and nutritive value of maize. Microbial management involving the use of plant growth promoting rhizobacteria (PGPR) is a promising inexpensive strategy for metal clean up from polluted soils. Considering these, metal tolerant plant growth promoting nitrogen fixing rhizobacterial strain CAZ3 identified by 16SrRNA gene sequence analysis as Azotobacter chroococcum was recovered from metal polluted chilli rhizosphere. When exposed to varying levels of metals, A. chroococcum survived up to 1400 and 2000 ug mL-1 of Cu and Pb, respectively and expressed numerous plant growth promoting activities even under metal stress. Strain CAZ3 secreted 65.5 and 60.8 ug mL-1 IAA at 400 ug mL-1 each of Cu and Pb, respectively and produced siderophores, ammonia and ACC deaminase under metal pressure. The melanin extracted from A. chroococcum revealed metal chelating ability under EDX. Following application, strain CAZ3 enhanced growth and yield of maize grown both in the presence of Cu and Pb. The dry biomass of roots of inoculated plants grown with 2007 mg Cu kg-1 and 585 mg Pb kg-1 was increased by 28% and 20%, respectively. At 585 mg Pb kg-1, the bioinoculant also increased the kernel attributes. At 2007 mg Cu kg-1 strain CAZ3 enhanced the number, yield and protein of kernels by 10%, 45% and 6%, respectively. Interestingly, strain CAZ3 significantly reduced the levels of proline, malondialdehyde and antioxidant enzymes in foliage. The roots of inoculated plants accumulated greatest amounts of metals compared to other organs. In kernels, the concentration of Pb was more as compared to Cu. The metal concentrations in roots, shoots and kernels, however, declined following CAZ3 inoculation. Copper and lead had substantial distortive impact on root and leaf morphology while cell death were visible under CLSM and SEM. Conclusively, A. chroococcum CAZ3 could be a most suitable and promising option to increase maize production in metal polluted soils despite the soils being contaminated with heavy metals. PMID- 29605648 TI - Genome sequencing analysis of liver cancer for precision medicine. AB - Liver cancer is the third leading cause of cancer-related death worldwide. Some thousands of liver cancer genome have been sequenced globally so far and most of driver genes/mutations with high frequency are established in liver cancer, including Wnt/beta-catenin pathway, TP53/cell-cycle pathways, telomere maintenance, and chromatin regulators. HBV integration into cancer-related genes is also a driver event in hepatocarcinogenesis. These genes are affected by structural variants, copy-number alterations and virus integrations as well as point mutations. Etiological factors of liver cancer is most understood among common cancers, such as hepatitis, aflatoxin, alcohol, and metabolic diseases, and mutational signatures of liver cancer can provide evidence of the association between specific etiological factors and mutational signatures. Molecular classifications based on somatic mutations profiles, RNA expression profiles, and DNA methylation profiles are related with patient prognosis. For precision medicine, several actionable mutations with solid evidence such as targets of multi-kinase inhibitors is observed in liver cancer, but there is few molecular target therapy so far. It is possible that rare actionable mutations in liver cancer can guide other specific molecular therapy and immune therapy. PMID- 29605650 TI - Evaluating the anti-biofilm and antibacterial effects of Juglans regia L. extracts against clinical isolates of Pseudomonas aeruginosa. AB - OBJECTIVE: Pseudomonas aeruginosa, an opportunistic pathogen, can cause serious health problems and produces several virulence factors. The most important of these factors is biofilm. Many studies suggest administration of new generation of antibiotics, as P. aeruginosa biofilm has developed high resistance to antimicrobial drugs. Emergence of multidrug resistant (MDR) strains has resulted in screening biofilm inhibitors from natural products or modified from natural compounds. To test this hypothesis, we evaluated the inhibitory effects (antibacterial and antibiofilm) of Juglans regia L. extract on biofilm formation by clinical isolates of P. aeruginosa. METHODS: Samples collected from burn, tracheal and urine infections of hospitalized patients (Shahid Motahari Hospital, Tehran, Iran) were identified as P. aeruginosa using traditional biochemical tests. Antibiotic susceptibility testing of isolates was performed using disk diffusion method. The microtiter plate method was used to evaluate the ability of pathogenic strains in producing biofilm. Antibacterial and antibiofilm effects of aqueous and methanol Juglans regia L. leaf extracts were determined by microtiter plate method. RESULTS: 46.7% of P. aeruginosa isolates (n = 50) were resistant to gentamicin and 100% of them could form a biofilm. All isolates (100%) exhibited MDR phenotype. Various concentrations of Juglans regia L. extracts exhibited significant effects on the growth and biofilm inhibition of the isolates. In addition, aqueous Juglans regia L. leaf extract had better inhibition activity on planktonic growth, and methanol extract was more effective on inhibiting biofilm of P. aeruginosa. CONCLUSIONS: The results of this study indicate that antibiotic resistant strains were significantly associated with biofilm formation. The J. regia L. extract, at various concentrations, may provide an alternative to control biofilm-related infections caused by P. aeruginosa. Further analyses are needed to validate the antibiofilm activity of these medicinal plants. PMID- 29605649 TI - Mast cell heterogeneity and anti-inflammatory annexin A1 expression in leprosy skin lesions. AB - Mast cells (MCs) have important immunoregulatory roles in skin inflammation. Annexin A1 (ANXA1) is an endogenous anti-inflammatory protein that can be expressed by mast cells, neutrophils, eosinophils, monocytes, epithelial and T cells. This study investigated MCs heterogeneity and ANXA1 expression in human dermatoses with special emphasis in leprosy. Sixty one skin biopsies from 2 groups were investigated: 40 newly diagnosed untreated leprosy patients (18 reaction-free, 11 type 1 reaction/T1R, 11 type 2 reaction/T2R); 21 patients with other dermatoses. Tryptase/try+ and chymase/chy + phenotypic markers and toluidine blue stained intact/degranulated MC counts/mm2 were evaluated. Try+/chy+ MCs and ANXA1 were identified by streptavidin-biotin-peroxidase immunostaining and density was reported. In leprosy, degranulated MCs outnumbered intact ones regardless of the leprosy form (from tuberculoid/TT to lepromatous/LL), leprosy reactions (reactional/reaction-free) and type of reaction (T1R/T2R). Compared to other dermatoses, leprosy skin lesions showed lower numbers of degranulated and intact MCs. Try+ MCs outnumbered chy+ in leprosy lesions (reaction-free/reactional, particularly in T2R), but not in other dermatoses. Compared to other dermatoses, ANXA1 expression, which is also expressed in mast cells, was higher in the epidermis of leprosy skin lesions, independently of reactional episode. In leprosy, higher MC degranulation and differential expression of try+/chy+ subsets independent of leprosy type and reaction suggest that the Mycobacterium leprae infection itself dictates the inflammatory MCs activation in skin lesions. Higher expression of ANXA1 in leprosy suggests its potential anti-inflammatory role to maintain homeostasis preventing tissue and nerve damage. PMID- 29605651 TI - Designer drugs - A continuing chemical (R)evolution. PMID- 29605652 TI - Cerebral ischemia: Celebrating successes, confronting challenges. PMID- 29605653 TI - [Study of the feasibility of spirometry in general practice]. AB - COPD is common but is under-diagnosed by general practitioners (GP). GP have a major role in the early diagnosis of this disease. GP could have access to spirometry. The aim of this study was to evaluate the quality and interpretation of spirometry performed by primary care residents following a short education session. Three residents were trained in spirometry for half a day. They then performed spirometry on all smokers over the age of 35 visiting five general practices. The results were reviewed blindly by an independent specialist pulmonologist to assess their quality and interpretation. Among 184 eligible patients, 89% agreed to participate and 66% (n=107) came for the second appointment. The pulmonologist evaluated the quality of spirometry as good in 72% of cases, of suboptimal but acceptable quality in 20% and of poor quality in 8%. Interpretation was accurate in 91% of tests. The Kappa concordance coefficient between GPs and the expert was 0.93. Airflow obstruction was detected in 17.5% of the screened subjects. The average time for a consultation with spirometry was 19minutes. The consultation dedicated to spirometry was well accepted by patients. A short training has to be structured to allow GPs to perform and interpret spirometry properly. This work needs to be extended to better assess reproducibility in cases of abnormal spirometry. PMID- 29605654 TI - A closer look at children's metacognitive skills: The case of the distinctiveness heuristic. AB - The primary aim of this study was to document the developmental course of distinctiveness effects throughout childhood. Specifically, we examined whether the reduction in false recognition rates that is traditionally observed in children after distinctive encoding could be explained not only by enhanced discrimination between studied and new items but also by the implementation of a conservative response criterion resulting from the use of metacognitive expectations about the quality of memories (i.e., distinctiveness heuristic). Two experiments were conducted in which children in three age groups-4-5, 6-7, and 8 9 years-were asked to study a set of items presented in either pictorial (distinctive) or word (less distinctive) form. In Experiment 1, pictures and words were displayed in two separate lists, a design that is supposed to favor reliance on the distinctiveness heuristic. In Experiment 2, the two types of stimuli were presented within the same list, a design that is supposed to make using the metacognitive heuristic ineffective. Overall, Experiments 1 and 2 provide evidence that children as young as 4 years rely on the distinctiveness heuristic to guide their memory decisions, resulting in a reduction in the false recognition rate when items are presented using a pure-list design (Experiment 1) but not when they are presented using a mixed-list design (Experiment 2). The implications of these findings for our understanding of the development of metacognition and the involvement of metacognitive skills in children's memory performance are discussed. PMID- 29605655 TI - How do 3-month-old infants attribute preferences to a human agent? AB - The current study showed that 3-month-old infants attributed a preference to a human agent, with her face and upper body visible, when she consistently reached for and grasped one of two objects with her bare hand. In contrast, infants did not appear to interpret the agent's same actions of grasping the object as indicative of her preference when it was the only object present or when it hid the other object from her but not from the infants. These results suggest that even from an early age, infants interpret human agents' actions in terms of mental states such as goals and preferences. In light of the current results, mechanisms for early psychological understanding are discussed. PMID- 29605656 TI - Critical patch-size for two-sex populations. AB - As environments become increasingly degraded, mainly due to human activities, species are often subject to isolated habitats surrounded by unfavorable regions. Since the pioneering work by Skellam [25] mathematical models have provided useful insights into the population persistence in such cases. Most of these models, however, neglect the sex structure of populations and the differences between males and females. In this work we investigate, through a reaction diffusion system, the dynamics of a sex-structured population in a single semipermeable patch. The critical patch size for persistence is determined from implicit relationships between model parameters. The effects of the various growth and movement parameters are also investigated. PMID- 29605657 TI - Analysis of the interaction among rice, weeds, inorganic fertilizer, and a herbivore in a composite farming paddy ecosystem. AB - As one of the Globally Important Agricultural Heritage Systems (GIAHS), rice field composite farming is an ecological measure in rice production, which can reduce the amount of chemical fertilizers, pesticides and herbicides. This research studies the interaction among rice, weed, inorganic fertilizer and herbivore in a composite farming paddy ecosystem. We develop a differential equation model to analyze the relations and interactions among those components. Results show the existence of an equilibrium for paddy and weed extinction, one or two equilibria for rice extinction, an equilibrium for weed extinction, and an equilibrium for rice and weed coexistence. Based on the obtained stability conditions of these equilibria, measures are proposed to avoid the existence or the stability of equilibria for rice extinction. Other measures are proposed to lead to a stable equilibrium for weed extinction, which is the most desirable result in rice production. Conditions for maximizing the yield of rice are also obtained by taking the relative mortality of rice as variable. In addition, we discover the existence of Hopf bifurcation phenomenon in the system, and develop the critical value of Hopf bifurcation by taking the artificial fertilizer rate as the bifurcation parameter. Our findings provide effective guidance and insights for rice production in a composite farming paddy ecosystem. PMID- 29605658 TI - Novel mutations in the ciliopathy-associated gene CPLANE1 (C5orf42) cause OFD syndrome type VI rather than Joubert syndrome. AB - Mutations in CPLANE1 (previously known as C5orf42) cause Oral-Facial-Digital Syndrome type VI (OFD6) as well as milder Joubert syndrome (JS) phenotypes. Seven new cases from five unrelated families diagnosed with pure OFD6 were systematically examined. Based on the clinical manifestations of these patients and those described in the literature, we revised the diagnostic features of OFD6 and include the seven most common characteristics: 1) molar tooth sign, 2) tongue hamartoma and/or lobulated tongue, 3) additional frenula, 4) mesoaxial polydactyly of hands, 5) preaxial polydactyly of feet, 6) syndactyly and/or bifid toe, and 7) hypothalamic hamartoma. By whole or targeted exome sequencing, we identified seven novel germline recessive mutations in CPLANE1, including missense, nonsense, frameshift and canonical splice site variants, all causing OFD6 in these patients. Since CPLANE1 is also mutated in JS patients, we examined whether a genotype-phenotype correlation could be established. We gathered and compared 46 biallelic CPLANE1 mutations reported in 32 JS and 26 OFD6 patients. Since no clear correlation between paired genotypes and clinical outcomes could be determined, we concluded that patient's genetic background and gene modifiers may modify the penetrance and expressivity of CPLANE1 causal alleles. To conclude, our study provides a comprehensive view of the phenotypic range, the genetic basis and genotype-phenotype association in OFD6 and JS. The updated phenotype scoring system together with the identification of new CPLANE1 mutations will help clinicians and geneticists reach a more accurate diagnosis for JS-related disorders. PMID- 29605659 TI - Interscalene brachial plexus bolus block versus patient-controlled interscalene indwelling catheter analgesia for the first 48 hours after arthroscopic rotator cuff repair. AB - BACKGROUND: We sought to compare the efficacy of interscalene brachial plexus bolus blockade (IBPBB) and patient-controlled interscalene indwelling catheter analgesia (PCIA) for postoperative pain management within 48 hours postoperatively in patients undergoing arthroscopic rotator cuff repairs (ARCR). METHODS: Patients undergoing ARCR were randomized into 3 groups by postoperative analgesia method. The IBPBB group received a mixed solution of 16 mL of 0.75% ropivacaine and 4 mL of 2% lidocaine as a bolus postoperatively. The PCIA group received a 10-mL bolus solution of 0.75% ropivacaine (4 mL) and 5% dextrose water (6 mL) just after the operation and continuous infusion of this solution. The control received only meperidine as needed, 12.5 mg, intravenously. Visual analog scale (VAS) pain scores were evaluated for the first 48 hours postoperatively. RESULTS: For the first 2 hours postoperatively, VAS scores in the IBPBB group were significantly lower than in the PCIA group and control group, but at 12 and 24 hours postoperatively, VAS scores of the IBPBB group were significantly higher than the PCIA group (P < .05). At 48 hours postoperatively, there was no significant difference in VAS scores among the 3 groups (P = .169). The method of analgesia was the only factor affecting pain scores at 24 hours postoperatively (P < .05). CONCLUSIONS: IBPBB provided effective immediate postoperative analgesia until 6 hours postoperatively. Especially until postoperative 2 hours, the VAS pain score was less than 1 point in the IBPBB group; however, there was significant rebound pain at 12 hours after surgery. During the first 24 hours postoperatively, PCIA reduced postoperative pain without rebound pain. Surgeons should choose methods for control of postoperative pain considering the advantages and disadvantages of each analgesic method. PMID- 29605660 TI - Stressed Out: Mitohormesis Is Crossing Borders. AB - Labbadia et al. showed that low-dose mitochondrial stress promotes protein homeostasis in the cytosol to endure proteotoxic conditions, particularly during aging. This hormetic mitochondrial stress response is heat shock factor 1 (HSF1) dependent and, remarkably, does not affect physiological parameters that are usually associated with pathogenic disturbance of mitochondrial function. PMID- 29605661 TI - A Novel Mechanism to Drive Castration-Resistant Prostate Cancer. AB - Androgen receptor signaling is critical for prostate adenocarcinoma, even after androgen deprivation therapy. Persistence of intratumoral androgens has been found in castration-resistant prostate cancer and attributed to increased in situ synthesis. Recently, Sharifi and colleagues reported an additional mechanism that can enhance local androgenic exposure: downregulation of an androgen-inactivating enzyme. PMID- 29605662 TI - The mTOR cell signaling pathway is crucial to the long-term protective effects of ischemic postconditioning against stroke. AB - Ischemic postconditioning (IPostC) protects against stroke, but few have studied the pathophysiological mechanisms of its long-term protective effects. Here, we investigated whether the mTOR pathway is involved in the long-term protective effects of IPostC. Stroke was induced in rats by distal middle cerebral artery occlusion (dMCAo) combined with 30 min of bilateral common carotid artery (CCA) occlusion, and IPostC was induced after the CCA release. Injury size and behavioral tests were measured up to 3 weeks post stroke. We used rapamycin and mTOR shRNA lentiviral vectors to inhibit mTOR activities, while S6K1 viral vectors, a main downstream mTOR gene, were used to promote mTOR activities. We found that rapamycin administration abolished the long-term protective effects of IPostC. In addition, IPostC promoted the presynaptic growth associated protein 43 (GAP-43) and the postsynaptic protein 95 (PSD-95) levels at 1 week post-stroke, which were reduced by rapamycin. Furthermore, rapamycin reduced phosphorylated mTOR (p-mTOR) protein levels measured at 3 weeks after stroke. These results were confirmed by mTOR shRNA transfection. Moreover, we found that injection of S6K1 viral vectors promoted GAP-43 and PSD-95 protein levels. We conclude that mTOR may play a crucial, protective role in brain damage after stroke and contribute to the protective effects of IPostC. PMID- 29605663 TI - Assessment of the H-reflex using two synchronized magnetic stimulators in order to increase stimulus durations: A comparison with electrical stimulation. AB - Magnetic nerve stimulation (MNS) may be a less painful alternative to electrical nerve stimulation (ENS) for Hoffmann reflex (H-reflex) measurement, however standard MNS (sMNS) techniques utilize a short stimulus duration, thereby limiting its use for H-reflex assessment. This limitation may be partly overcome by coupling two magnetic stimulators to increase the pulse duration (coupled MNS: cMNS). The aim of this study was to test this assumption by comparing the H reflex characteristics evoked by ENS, sMNS and cMNS. Thirteen healthy volunteers were tested with ENS and both MNS in the prone position. Maximal soleus H-reflex (Hmax) and M-wave (Mmax) amplitudes were measured to compute the Hmax/Mmax ratio. Hmax was evoked at rest and during both isometric submaximal (10%MVC) and maximal plantar-flexions (MVC). At rest, MNS techniques underestimated Hmax (ENS: 8.32 +/ 2.73 mV; sMNS: 6.85 +/- 2.29 mV; cMNS: 7.48 +/- 2.23 mV; p < 0.05). In contrast, no difference was observed for Hmax/Mmax (ENS: 0.59 +/- 0.17; sMNS: 0.45 +/- 0.28; cMNS: 0.47 +/- 0.29; p = 0.11). sMNS, cMNS and ENS similarly detected Hmax facilitation during MVC (ENS: +120 +/- 248%; sMNS: +228 +/- 350%; cMNS: +162 +/- 180% of the rest value; p = 0.344). Owing to their shorter stimulus duration, both MNS techniques underestimated the Hmax compared to ENS. However, when the gold standard ENS technique cannot be used, coupled MNS may be recommended since it provides better H-reflex characteristic assessment than standard MNS due to its longer stimulus duration. PMID- 29605664 TI - Structural equation model of the relationship between metals in contaminated soil and in earthworm (Metaphire californica) in Hunan Province, subtropical China. AB - Earthworms have the ability to take up heavy metals in soil and partition them in different subcellular compartments. In this study, we used a structural equation model (SEM) to investigate the two-step causal relationship between environmental availability (EA) and environmental bioavailability (EB) of heavy metals (Cd, Cu, Zn, and Pb), as reflected by their levels in soil fractions and in earthworms from field-contaminated areas in Southern China. In the SEM, the correlation between EA and EB reflected the bioavailability of Cd, Zn, and Pb. For Cd, the causal relationship between the latent variables EA and EB was reflected by DTPA fractions in soil as well as by earthworm internal and subcellular cytosol fractions. The extractable and oxidizable fractions of Zn in soil influenced Zn concentrations in the cytosol and debris. The DTPA and reducible Pb fractions were bioavailable to earthworm internal Pb concentrations and those in cytosol fractions. These results implied that the DTPA, extractable, oxidizable, or reducible fractions of different metals could be the bioavailable sources to earthworm internal metals and partitioned in their subcellular compartments. PMID- 29605665 TI - Bioaccumulation of cadmium in soil organisms - With focus on wood ash application. AB - Harvesting whole-tree biomass for biofuel combustion intensifies removal of nutrients from the ecosystem. This can be partly amended by applying ash from the combustion back to the system and thus recycle the nutrients. However, besides being rich in inorganic nutrients, ash also contains trace amounts of heavy metals. Due to the risk of toxic effects and trophic transfer of heavy metals, especially cadmium, legislation usually restricts the use of ash as a soil amendment. In order to provide researchers and governmental agencies with a tool to assess the risk of cadmium bioaccumulation in specific soil systems after ash application, we review: 1) the properties of ash; 2) the chemical and toxic properties of cadmium; 3) the key factors affecting cadmium bioavailability, cadmium uptake-, storage- and elimination-abilities in soil organisms and the risk of cadmium accumulation and biomagnification in the soil food web; 4) how ash impact on soil can change the risk of cadmium bioaccumulation. We conclude that for assessing the risk of cadmium bioaccumulation for specific sites, it is necessary to consider both the type and composition of ash, the soil conditions and organism composition on the site. On a general basis, we conclude that granulated ashes low in cadmium content, applied to low pH soils with high organic matter content, in systems with low abundances of earthworms, isopods and gastropods, will have a low risk of cadmium accumulation. PMID- 29605666 TI - Estimation of population-level effect of the endocrine disruptor pyriproxyfen in Daphnia magna by using changes in sex ratio and reproductive output. AB - Here we developed an analytical means of estimating population-level effects of endocrine disruptors on Daphnia magna. Our approach was based on the fact that the endocrine-disrupting juvenile hormone analogs induce the production of male neonates if they are exposed to the analogs during a particular period in their prenatal development; the method also assumed that the abnormal production of male neonates in the sake of production of female neonates reduces population growth. We constructed a linear toxicodynamics model to elucidate the period in which D. magna neonates are sensitive to exposure to the analog and also the probability of an individual neonate changing sex under specific exposure concentrations. The proposed model was applied to D. magna reproduction test data obtained under time-varying exposure to pyriproxyfen to derive the maximum likelihood estimates and the posterior distributions of the model parameters. To quantitatively assess the ecological risk at the population level, we conducted a population dynamics simulation under two time-varying exposure scenarios (i.e., constant or pulsed exposure) by using an age-structured population model. When the change in sex ratio was based on the time-weighted average concentration during the period of sensitivity, change in sex ratio caused approximately equivalent population-level effects as did reproductive inhibition (i.e., reduction in the total number of neonates per female parent) regardless of the exposure scenario. In contrast, when change in sex ratio was based on maximum concentration during the sensitive period, change in sex ratio caused only half the population-level effects as did reproductive inhibition under constant exposure, whereas it caused a much larger population-level effect than did reproductive inhibition under pulsed exposure. PMID- 29605667 TI - EpiTools, A software suite for presurgical brain mapping in epilepsy: Intracerebral EEG. AB - BACKGROUND: In pharmacoresistant epilepsy, exploration with depth electrodes can be needed to precisely define the epileptogenic zone. Accurate location of these electrodes is thus essential for the interpretation of Stereotaxic EEG (SEEG) signals. As SEEG analysis increasingly relies on signal processing, it is crucial to make a link between these results and patient's anatomy. Our aims were thus to develop a suite of software tools, called "EpiTools", able to i) precisely and automatically localize the position of each SEEG contact and ii) display the results of signal analysis in each patient's anatomy. NEW METHOD: The first tool, GARDEL (GUI for Automatic Registration and Depth Electrode Localization), is able to automatically localize SEEG contacts and to label each contact according to a pre-specified nomenclature (for instance that of FreeSurfer or MarsAtlas). The second tool, 3Dviewer, enables to visualize in the 3D anatomy of the patient the origin of signal processing results such as rate of biomarkers, connectivity graphs or Epileptogenicity Index. RESULTS: GARDEL was validated in 30 patients by clinicians and proved to be highly reliable to determine within the patient's individual anatomy the actual location of contacts. COMPARISON WITH EXISTING METHODS: GARDEL is a fully automatic electrode localization tool needing limited user interaction (only for electrode naming or contact correction). The 3Dviewer is able to read signal processing results and to display them in link with patient's anatomy. CONCLUSION: EpiTools can help speeding up the interpretation of SEEG data and improving its precision. PMID- 29605668 TI - A low-cost solution for quantification of movement during DBS surgery. AB - BACKGROUND: During the deep brain stimulation (DBS) electrode implantation operation with microelectrode recordings (MER) in awake patients, somatotopic testing and test stimulation are performed to improve electrode placement and provide the most beneficial symptom reduction possible, while minimizing side effects. As this procedure is commonly used to alleviate abnormal movements associated with Parkinson's disease (PD) and Essential Tremor (ET), intraoperative assessment of a patient's movements is critical to optimizing surgical benefit. However, despite its importance, movement assessment is typically subjective and qualitative. NEW METHOD: Here, we present a detailed description of a low-cost, open-source system as a solution. RESULTS: The described system measures movements intraoperatively and in synchrony with neurophysiological recordings for both online visualization and offline analysis. COMPARISON WITH EXISTING METHOD(S): Few movement quantification systems are designed to interface with intraoperative neurophysiological recordings; the widespread application of such systems may be limited by their cost and proprietary, closed-source nature. The system presented provides a low-cost, open source alternative. CONCLUSIONS: The system outlined in this work may improve the DBS procedure by adding valuable objectivity in movement quantification. PMID- 29605669 TI - Is the association of deliberate self-harm with emotional relief stable or dependent on emotional context? AB - BACKGROUND AND OBJECTIVES: Despite strong support for the role of emotional relief in deliberate self-harm (DSH), no research has examined the impact of emotional distress on the strength of the DSH-relief association. Thus, it remains unclear whether the association of DSH with emotional relief is stable across emotional contexts or context-dependent. This study aimed to examine if the implicit DSH-relief association is stronger in the context of emotional distress (relative to a neutral emotional context). METHODS: Young adult women with (n = 60) and without (n = 60) a history of recent recurrent DSH were randomly assigned to complete a novel version of the Implicit Association Test (IAT) assessing the DSH-relief association at baseline (following an initial neutral emotion induction) and again following either a neutral or negative (i.e., social rejection) emotion induction. RESULTS: Consistent with hypotheses, the DSH-relief association was stronger among women with recent recurrent DSH (vs. those without DSH) at baseline. Contrary to hypotheses, however, whereas the DSH-relief association remained stable following both the neutral and negative emotion inductions among participants with DSH, it became stronger across both conditions for participants without DSH. LIMITATIONS: The use of a community sample of young adult women may limit generalizability to other relevant populations (e.g., clinical populations, young men, adolescents). Additionally, the negative emotion induction may not have been powerful enough to affect the strength of the learned DSH-relief association among individuals with a repeated history of DSH. CONCLUSIONS: Findings suggest that the repeated use of DSH to bring about emotional relief may engender associations of DSH with relief that are relatively insensitive to emotional context. PMID- 29605670 TI - Serum Soluble CD48 Levels as a Prognostic Marker in Mycosis Fungoides and Sezary Syndrome. PMID- 29605671 TI - Exacerbated Immune Complex-Mediated Vascular Injury in Mice with Heterozygous Deficiency of Aryl Hydrocarbon Receptor through Upregulation of Fcgamma Receptor III Expression on Macrophages. AB - Aryl hydrocarbon receptor (AhR), which was discovered as a receptor for environmental concomitants, plays an important role widely in the immune system. In this study, we assessed AhR involvement in immune-complex-mediated vascular injury by examining the reverse-passive Arthus reaction in AhR heterozygous knockout (AhR+/-) mice. In the cutaneous Arthus reaction, dermal edema was severer in AhR+/- mice than in wild-type mice. The number of infiltrating neutrophils and mRNA expression levels of CXC chemokine ligand 1 and IL-6 were also increased in AhR+/- mice. Similarly, in the peritoneal Arthus reaction, infiltration of neutrophils was increased in AhR+/- mice. Peritoneal macrophages from AhR+/- mice expressed higher levels of Fcgamma receptor III and produced higher levels of CXC chemokine ligand 1 and IL-6 after immune complex treatment. In addition, AhR occupied the promoter regions of Fcgamma receptor III gene in peritoneal macrophages in a ligand-dependent manner. Depletion of macrophages reduced the cutaneous Arthus reaction in AhR+/- mice, and adoptive transfer of AhR+/- mice macrophages into wild-type mice exacerbated the peritoneal Arthus reaction. Furthermore, AhR expression was decreased and Fcgamma receptor III expression was increased in CD14+ monocytes in peripheral blood from patients with immune-complex-mediated vasculitis compared with those from healthy controls. These results suggest that downregulation of AhR is associated with the exacerbation of immune-complex-mediated vascular injury. PMID- 29605673 TI - High-Fat Diet Exacerbates Early Psoriatic Skin Inflammation Independent of Obesity: Saturated Fatty Acids as Key Players. AB - In obesity, hypertrophic adipocytes secrete high amounts of adipocytokines, resulting in low-grade inflammation amplified by infiltrating proinflammatory macrophages, oxidative stress, hypoxia, and lipolysis. These chronic proinflammatory conditions support the development of type II diabetes and cardiovascular diseases, but the mechanisms of obesity-related exacerbation of inflammatory skin disorders like psoriasis are unclear. In this study, we uncovered dietary saturated fatty acids (SFAs) as major risk factors for the amplification of skin inflammation, independent of obesity-related parameters such as fat mass extension, adipocytokine levels, and glucose homeostasis. Correlation analyses in a cohort of psoriasis vulgaris patients showed that free fatty acid serum level was the only obesity-associated parameter affecting disease severity. Studies in mice with high-fat diet-induced obesity with psoriasiform inflammation confirmed this critical role of free fatty acids. An increase of free fatty acids in healthy, lean mice alone was sufficient to induce an exacerbation of psoriasiform inflammation. In particular, saturated fatty acids sensitize myeloid cells to an increased inflammatory response in answer to proinflammatory stimuli, which in turn augments the activation of keratinocytes. Consequently, reduction of nutritional saturated fatty acids alone diminished the psoriatic phenotype in obese mice. Thus, our findings may open new perspectives for adjuvant dietary measures accompanying anti-inflammatory psoriasis therapies in lean and obese patients. PMID- 29605672 TI - MiR-31 Mediates Inflammatory Signaling to Promote Re-Epithelialization during Skin Wound Healing. AB - Wound healing is essential for skin repair after injury, and it consists of hemostasis, inflammation, re-epithelialization, and remodeling phases. Successful re-epithelialization, which relies on proliferation and migration of epidermal keratinocytes, requires a reduction in tissue inflammation. Therefore, understanding the molecular mechanism underlying the transition from inflammation to re-epithelialization will help to better understand the principles of wound healing. Currently, the in vivo functions of specific microRNAs in wound healing are not fully understood. We observed that miR-31 expression is strongly induced in wound edge keratinocytes, and is directly regulated by the activity of NF kappaB and signal transducer and activator of transcription 3 signaling pathways during the inflammation phase. We used miR-31 loss-of-function mouse models to demonstrate that miR-31 promotes keratinocyte proliferation and migration. Mechanistically, miR-31 activates the Ras/mitogen-activated protein kinase signaling by directly targeting Rasa1, Spred1, Spred2, and Spry4, which are negative regulators of the Ras/mitogen-activated protein kinase pathway. Knockdown of these miR-31 targets at least partially rescues the delayed scratch wound re-epithelialization phenotype observed in vitro in miR-31 knockdown keratinocytes. Taken together, these findings identify miR-31 as an important cell-autonomous mediator during the transition from inflammation to re epithelialization phases of wound healing, suggesting a therapeutic potential for miR-31 in skin injury repair. PMID- 29605674 TI - Therapeutic potentials of Houttuynia cordata Thunb. against inflammation and oxidative stress: A review. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Houttuynia cordata Thunb. (Family: Saururaceae) is an herbaceous perennial plant that grows in moist and shady places. The plant is well known among the people of diverse cultures across Japan, Korea, China and North-East India for its medicinal properties. Traditionally the plant is used for its various beneficial properties against inflammation, pneumonia, severe acute respiratory syndrome, muscular sprain, stomach ulcer etc. Oxidative stress and inflammation were found to be linked with most of the diseases in recent times. Many ancient texts from Chinese Traditional Medicine, Ayurveda and Siddha, and Japanese Traditional medicine have documented the efficacy of H. cordata against oxidative stress and inflammation. AIM OF THE STUDY: This review aims to provide up-to-date and comprehensive information on the efficacy of H. cordata extracts as well as its bioactive compounds both in vitro and in vivo, against oxidative stress and inflammation MATERIALS AND METHODS: Relevant information on H. cordata against oxidative stress and inflammation were collected from the established scientific databases such as NCBI, Web of Science, ScienceDirect, Elsevier, and Springer. Additionally, a few books and magazines were also consulted to get the important information. RESULTS: Herbal medicines or plant products were traditionally being used for treating the oxidative stress and inflammation related diseases in diverse communities across the world. Scientifically, H. cordata has shown to target several signaling pathways and found to effectively reduce the oxidative stress and inflammation. Phyto constituents such as afzelin, hyperoside and quercitrin have shown to reduce inflammation both in vitro and in vivo models. These molecules were also shown to have strong antioxidant properties both in vivo and in vitro models. CONCLUSIONS: H. cordata extracts and its bioactive molecules were shown to have both anti inflammatory and anti-oxidative properties. As both in vitro and in vivo studies were shown that H. cordata did not have any toxicity on the various model systems used, future clinical studies will hopefully make an impact on the future direction of treating inflammation-related diseases. PMID- 29605675 TI - Implications of applying cumulative risk assessment to the workplace. AB - Multiple changes are influencing work, workplaces and workers in the US including shifts in the main types of work and the rise of the 'gig' economy. Work and workplace changes have coincided with a decline in unions and associated advocacy for improved safety and health conditions. Risk assessment has been the primary method to inform occupational and environmental health policy and management for many types of hazards. Although often focused on one hazard at a time, risk assessment frameworks and methods have advanced toward cumulative risk assessment recognizing that exposure to a single chemical or non-chemical stressor rarely occurs in isolation. We explore how applying cumulative risk approaches may change the roles of workers and employers as they pursue improved health and safety and elucidate some of the challenges and opportunities that might arise. Application of cumulative risk assessment should result in better understanding of complex exposures and health risks with the potential to inform more effective controls and improved safety and health risk management overall. Roles and responsibilities of both employers and workers are anticipated to change with potential for a greater burden of responsibility on workers to address risk factors both inside and outside the workplace that affect health at work. A range of policies, guidance and training have helped develop cumulative risk assessment for the environmental health field and similar approaches are available to foster the practice in occupational safety and health. PMID- 29605677 TI - Not only biocidal products: Washing and cleaning agents and personal care products can act as further sources of biocidal active substances in wastewater. AB - The emission sources of biocidal active substances in households have been under discussion since these substances have been detected frequently in municipal wastewater and receiving surface water bodies. Therefore, the goal of this study was to investigate the products responsible for the emission of these substances to wastewater. We analysed the wastewater of two streets for a set of biocidal active substances. Time-proportional sampling was conducted for one week of each season during one year in each street. The 14 substances analysed with liquid chromatography coupled with tandem mass spectrometry were 1,2-benzisothiazol 3(2H)-one (BIT), C12-benzalkonium chloride, carbendazim, 5-chloro-2-methyl-2H isothiazol-3-one (CMIT), dichlorooctylisothiazolinone (DCOIT), N,N-diethyl-meta toluamide (DEET), diuron, icaridine, 2-octyl-2H-isothiazol-3-one (OIT), piperonyl butoxide (PBO), triclosan, tebuconazole, terbutryn and tetramethrin. Using data available from household product inventories of the two streets, we searched the lists of ingredients for the products possibly being responsible for the emissions. Except for four substances, all substances have been detected in at least 10% of the samples. Highest concentrations were measured for C12 benzalkonium chloride with an average concentration in the daily samples of 7.7 MUg/L in one of the streets. Next to C12-benzalkonium chloride, BIT, DEET and icaridine were detected in all samples in average concentrations above 1 MUg/L in at least one street. The results show that washing and cleaning agents were important sources for preservatives such as BIT and OIT, while triclosan was apparently mainly emitted through personal care products. The mosquito repelling substances DEET and icaridine were found throughout the year, with highest emissions in summer and autumn. In conclusion, the results demonstrate that the sources of biocidal active substances in municipal wastewater are complex and that measures for the prevention of the emission of biocidal active substances into the aquatic environment have to be carried out under different legislations. This has to be taken into account discussing emission reduction at the source. PMID- 29605676 TI - Residential proximity to major roadways and traffic in relation to outcomes of in vitro fertilization. AB - BACKGROUND: Emerging data from animal and human studies suggest that traffic related air pollution adversely affects early pregnancy outcomes; however evidence is limited. OBJECTIVE: We examined whether residential proximity to major roadways and traffic, as proxies for traffic-related air pollution, are associated with in vitro fertilization (IVF) outcomes. METHODS: This analysis included 423 women enrolled in the Environment and Reproductive Health (EARTH) Study, a prospective cohort study, who underwent 726 IVF cycles (2004-2017). Using geocoded residential addresses collected at study entry, we calculated the distance to nearest major roadway and the traffic density within a 100 m radius. IVF outcomes were abstracted from electronic medical records. We used multivariable generalized linear mixed models to evaluate the associations between residential proximity to major roadways and traffic density and IVF outcomes adjusting for maternal age, body mass index, race, education level, smoking status, and census tract median income. RESULTS: Closer residential proximity to major roadways was statistically significantly associated with lower probability of implantation and live birth following IVF. The adjusted percentage of IVF cycles resulting in live birth for women living >=400 m from a major roadway was 46% (95% CI 36, 56%) compared to 33% (95% CI 26, 40%) for women living <50 m (p-for-comparison, 0.04). Of the intermediate outcomes, there were suggestive associations between living closer to major roadways and slightly higher estradiol trigger concentrations (p-trend = 0.16) and lower endometrial thickness (p-trend = 0.06). Near-residence traffic density was not associated with outcomes of IVF. CONCLUSION: Closer residential proximity to major roadways was related to reduced likelihood of live birth following IVF. PMID- 29605678 TI - Association between air pollution and rhinitis incidence in two European cohorts. AB - BACKGROUND: The association between air pollution and rhinitis is not well established. AIM: The aim of this longitudinal analysis was to study the association between modeled air pollution at the subjects' home addresses and self-reported incidence of rhinitis. METHODS: We used data from 1533 adults from two multicentre cohorts' studies (EGEA and ECRHS). Rhinitis incidence was defined as reporting rhinitis at the second follow-up (2011 to 2013) but not at the first follow-up (2000 to 2007). Annual exposure to NO2, PM10 and PM2.5 at the participants' home addresses was estimated using land-use regression models developed by the ESCAPE project for the 2009-2010 period. Incidence rate ratios (IRR) were computed using Poisson regression. Pooled analysis, analyses by city and meta-regression testing for heterogeneity were carried out. RESULTS: No association between long-term air pollution exposure and incidence of rhinitis was found (adjusted IRR (aIRR) for an increase of 10 MUg.m-3 of NO2: 1.00 [0.91 1.09], for an increase of 5 MUg.m-3 of PM2.5: 0.88 [0.73-1.04]). Similar results were found in the two-pollutant model (aIRR for an increase of 10 MUg.m-3 of NO2: 1.01 [0.87-1.17], for an increase of 5 MUg.m-3 of PM2.5: 0.87 [0.68-1.08]). Results differed depending on the city, but no regional pattern emerged for any of the pollutants. CONCLUSIONS: This study did not find any consistent evidence of an association between long-term air pollution and incident rhinitis. PMID- 29605679 TI - Prenatal exposure to endocrine disrupting chemicals and risk of being born small for gestational age: Pooled analysis of seven European birth cohorts. AB - BACKGROUND AND AIMS: There is evidence that endocrine disrupting chemicals (EDCs) have developmental effects at environmental concentrations. We investigated whether some EDCs are associated with the adverse birth outcome Small for Gestational Age (SGA). METHODS: We used PCB 153, p,p'-DDE, HCB, PFOS and PFOA measured in maternal, cord blood or breast milk samples of 5446 mother-child pairs (subset of 693 for the perfluorinated compounds) from seven European birth cohorts (1997-2012). SGA infants were those with birth weight below the 10th percentile for the norms defined by gestational age, country and infant's sex. We modelled the association between measured or estimated cord serum EDC concentrations and SGA using multiple logistic regression analyses. We explored effect modification by child's sex and maternal smoking during pregnancy. RESULTS: Among the 5446 newborns, 570 (10.5%) were SGA. An interquartile range (IQR) increase in PCB 153 was associated with a modestly increased risk of SGA (odds ratio (OR) of 1.05 [95% CI: 1.04-1.07]) that was stronger in girls (OR of 1.09 [95% CI: 1.04-1.14]) than in boys (OR of 1.03 [95% CI: 1.03-1.04]) (p interaction = 0.025). For HCB, we found a modestly increased odds of SGA in girls (OR of 1.04 [95% CI: 1.01-1.07] per IQR increase), and an inverse association in boys (OR of 0.90 [95% CI: 0.85-0.95]) (p-interaction = 0.0003). Assessment of the HCB-sex-smoking interaction suggested that the increased odds of SGA associated with HCB exposure was only in girls of smoking mothers (OR of 1.18 [95% CI: 1.11 1.25]) (p-interaction = 0.055). Higher concentrations of PFOA were associated with greater risk of SGA (OR of 1.64 [95% CI: 0.97-2.76]). Elevated PFOS levels were associated with increased odds of SGA in newborns of mothers who smoked during pregnancy (OR of 1.63 [95% CI: 1.02-2.59]), while an inverse association was found in those of non-smoking mothers (OR of 0.66 [95% CI: 0.61-0.72]) (p interaction = 0.0004). No significant associations were found for p,p'-DDE. CONCLUSIONS: Prenatal environmental exposure to organochlorine and perfluorinated compounds with endocrine disrupting properties may contribute to the prevalence of SGA. We found indication of effect modification by child's sex and smoking during pregnancy. The direction of the associations differed by chemical and these effect modifiers, suggesting diverse mechanisms of action and biological pathways. PMID- 29605680 TI - Low peripheral levels of insulin growth factor-1 are associated with high incidence of delirium among elderly patients: A systematic review and meta analysis. AB - INTRODUCTION: Delirium, a serious condition observed in critically ill patients, clinically presents with impaired cognition and consciousness. The relationship between delirium and peripheral levels of insulin growth factor-1 (IGF-1) is unclear. Thus we conducted a meta-analysis to address this issue. METHODS: Seven major electronic databases were searched from inception until October 2, 2017 to obtain relevant clinical variables to compare the difference in IGF-1 levels between delirious and non-delirious elderly in-patients. A random effects meta analysis was conducted. RESULTS: We studies 10 articles involving 294 delirious patients (mean age 73.0 years) and 604 non-delirious patients (mean age 76.9 years). We found that peripheral levels of IGF-1 in patients with delirium were significantly lower than in those without delirium (Hedges' g = -0.209, 95% confidence interval [CI] = -0.393 to -0.026, p = 0.025). Meta-regression analyses found that no variables such as percentage of cognitive impairment, mean age, and female proportion contribute to heterogeneity in terms of the entire population. CONCLUSIONS: Our data suggests that lower peripheral levels of IGF-1 could be associated with a higher incidence of delirium among elderly patients. Further prospective studies with larger sample sizes are needed to investigate the association between peripheral levels of IGF-1 and delirium. PMID- 29605681 TI - Evaluation of a community transition to professional practice program for graduate registered nurses in Australia. AB - Australia has an increasing demand for a sustainable primary health care registered nursing workforce. Targeting graduate registered nurses who typically begin their nursing career in acute-care hospital settings is a potential workforce development strategy. We evaluated a graduate registered nurse Community Transition to Professional Practice Program which was designed specifically to develop and foster skills required for primary health care. The aims of this study were to evaluate graduates' intention to remain in the primary health care nursing workforce, and graduate competency, confidence and experiences of program support; these were compared with graduates undertaking the conventional acute-care transition program. Preceptor ratings of graduate competence were also measured. All of the 25 graduates (n = 12 community, n = 13 acute-care) who completed the questionnaire at 6 and 12 months intended to remain in nursing, and 55% (n = 6) of graduates in the Community Transition Program intended to remain in the primary health care nursing workforce. There were no differences in graduate experiences, including level of competence, or preceptors' perceptions of graduate competence, between acute-care and Community Transition Programs. The Community Transition to Professional Practice program represents a substantial step towards developing the primary health care health workforce by facilitating graduate nurse employment in this area. PMID- 29605682 TI - Simultaneous qualitative and quantitative evaluation of Ilex kudingcha C. J. tseng by using UPLC and UHPLC-qTOF-MS/MS. AB - In this study, a systematic method was established for the holistic quality control of Ilex kudingcha C. J. Tseng, a popular functional drink for adjuvant treatment of diabetes, hypertension, obesity and hyperlipidemia. Both qualitative and quantitative analyses were conducted. For qualitative analysis, an ultra high performance liquid chromatography (UHPLC) coupled with an electrospray ionization quadrupole time-of-flight mass spectrometry (ESI-qTOF-MS) method was established for rapid separation and structural identification of the constituents in Ilex kudingcha. Samples were separated on an ACQUITY UPLC HSS T3C18 column (2.1 mm * 100 mm, 1.8 MUm) by gradient elution using 0.1% (v/v) formic acid (solvent A) and acetonitrile (solvent B) as mobile phases at a flow rate of 0.25 mL min-1. The chromatographic profiling of Ilex kudingcha by UHPLC-qTOF-MS/MS resulted in the characterization of 53 compounds, comprising 18 compounds that were unambiguously identified by comparison with reference standards. For quantitative analysis, 18 major compounds from 15 batches of Ilex kudingcha samples were simultaneously detected by UPLC-DAD at wavelengths of 210 nm, 260 nm, and 326 nm. The method was validated with respect to precision, linearity, repeatability, stability, accuracy, and so on. The contents of the 18 target compounds were applied for hierarchical clustering analysis (HCA) and principal component analysis (PCA) to differentiate between the samples. The results of HCA and PCA were consistent with each other. Sample No. 1 differed significantly based on HCA and PCA, and the differentiating components were confirmed to originate from different batches of samples. Phenolic acids and triterpenes were found to be the main ingredients in Ilex kudingcha. This strategy was effective and straightforward, and provided a potential approach for holistic quality control of Ilex kudingcha. PMID- 29605683 TI - Development and validation of a RP-HPLC method for the simultaneous detection and quantification of simvastatin's isoforms and coenzyme Q10 in lecithin/chitosan nanoparticles. AB - Hybrid nanocapsules constituted of phospholipids and polysaccharides have been proposed as colloidal systems for the delivery of drugs via non-parenteral administration routes, due their capacity of high drug loading, controlled drug release and targeted delivery to the specific organ. Moreover, nanoparticles systems offer the possibility of co-encapsulation of drugs in the same drug delivery system and, consequently, the simultaneous administration of compounds. Characterization of nanoparticles properties, specifically involves quantification of the active pharmaceutical ingredients and is pivotal in the development of innovative nanomedicines. Therefore, this study has proposed and validated a new RP-HPLC-UV method for the simultaneous determination of simvastatin and coenzyme Q10 in hybrid nanoparticles systems. A reversed phase (RP) C8 column and a gradient elution of water: methanol at flow rate of 1.5 ml/min was used. Simvastatin (SVT), simvastatin hydroxyacid isoform (SVA) and coenzyme Q10 were identified by dual wavelength-UV detection at 238 nm (statins) and 275 nm, respectively. The proposed method was selective and linear in the range of 0.5-25 MUg/ml (r2 > 0.999), precise, with values of relative standard deviation (RSD) lower than 2%, robust and accurate (recovery values of 100 +/- 5%), satisfying FDA guidelines. Furthermore, low detection (LOD <0.2 MUg/ml) and quantification limits (LOQ <0.4 MUg/ml) were suitable for the application of the method for the in vitro study of release kinetics of simvastatin and coenzyme Q10 co-encapsulated in lecithin/chitosan nanoparticles. The proposed method represents, to our knowledge, the only method for the simultaneous quantification of simvastatin, coenzyme Q10 and of the hydrolysed hydroxyacid isoform of the statin in nanoparticles. PMID- 29605684 TI - Mouse APOBEC3 expression in NIH 3T3 cells mediates hypermutation of AKV murine leukemia virus. AB - Mouse APOBEC3 (mA3) is a cytidine deaminase that can act on the single-stranded DNA reverse transcripts of retroviruses resulting in G->A hypermutation of proviral DNA. Many mA3 studies have used NIH 3T3 cells assuming that endogenous mA3 production was negligible. We developed a monoclonal antibody specific for mA3 that reveals detectable mA3 in NIH 3T3 cells and we demonstrate that AKV released from the cells undergoes G->A hypermutation. Inactivation of the mA3 gene abolished the deamination confirming that AKV hypermutation was mediated by mA3. The G->A mutations in AKV viral transcripts deviated from a normal distribution with all the mutations contained within only 20% of the transcripts. Single cell analyses revealed that the expression of mA3 in NIH 3T3 cells was limited to 20% of the cells, which likely accounted for the abnormal distribution of mutations. Endogenous NIH 3T3 mA3 was found to restrict AKV replication. PMID- 29605686 TI - Long-term clinical outcomes of optimal medical therapy vs. successful percutaneous coronary intervention for patients with coronary chronic total occlusions. AB - OBJECTIVES: There are little data on the long-term clinical outcomes of optimal medical therapy (OMT) compared with successful percutaneous coronary intervention (PCI) in patients with chronic total occlusions (CTOs). METHODS: A total of 388 patients with >=1 CTO were enrolled from January 2008 to December 2010. 62 patients were excluded, and 326 patients were divided into an OMT group (n = 125) and PCI group (n = 201) according to the initial treatment strategy. Propensity score matching was also done to adjust for baseline characteristics. The primary outcome was major adverse cardiac event (MACE), included cardiac death, recurrent myocardial infarction, and repeated revascularization. RESULTS: After a mean follow-up of 47.2 +/- 20.0 months, there was no significant difference between the two groups with respect to the prevalence of MACE (successful PCI vs. OMT: 29.6% vs. 21.9%, unadjusted hazard ratio [HR] 1.47, 95% confidence interval [CI] 0.95-2.28, p=0.085). After multivariate analyses, there were significant differences in the prevalence of MACE (adjusted HR 1.76, 95% CI 1.09-2.28, p=0.02) and repeated revascularization (2.14; 1.18-3.90, 0.01). In the propensity score-matched population (80 pairs), there were no significant differences in the prevalence of MACE (adjusted HR 1.89, 95% CI 0.96-3.71, p=0.06) and cardiac death (1.30, 0.44-3.80, 0.63) between groups. CONCLUSION: In the treatment of patients with CTOs, successful PCI did not reduce the long-term risk of MACE compared with OMT. PMID- 29605687 TI - Prosthetic mitral valve thrombosis during pregnancy treated successfully with thrombolysis. PMID- 29605685 TI - Genomic, Recombinational and Phylogenetic Characterization of Global Feline Herpesvirus 1 Isolates. AB - Feline herpes virus type 1 (FHV-1) is widely considered to be the leading cause of ocular disease in cats and has been implicated in upper respiratory tract infections. Little, however is known about interstrain phylogenetic relationships, and details of the genomic structure. For the present study, twenty-six FHV-1 isolates from different cats in animal shelters were collected from eight separate locations in the USA, and the genomes sequenced. Genomic characterization of these isolates includied short sequence repeat (SSR) detection, with fewer SSRs detected, compared to herpes simplex viruses type 1 and 2. For phylogenetic and recombination analysis, 27 previously sequenced isolates of FHV-1 were combined with the 26 strains sequenced for the present study. The overall genomic interstrain genetic distance between all available isolates was 0.093%. Phylogenetic analysis identified four main FHV-1 clades primarily corresponding to geographical collection site. Recombination analysis suggested that interclade recombination has occurred. PMID- 29605688 TI - HLA-inferred extended haplotype disparity level is more relevant than the level of HLA mismatch alone for the patients survival and GvHD in T cell-replate hematopoietic stem cell transplantation from unrelated donor. AB - Serious risks in unrelated hematopoietic stem cell transplantation (HSCT) including graft versus host disease (GvHD) and mortality are associated with HLA disparity between donor and recipient. The increased risks might be dependent on disparity in not-routinely-tested multiple polymorphisms in genetically dense MHC region, being organized in combinations of two extended MHC haplotypes (Ehp). We assessed the clinical role of donor-recipient Ehp disparity levels in N = 889 patients by the population-based detection of HLA allele phase mismatch. We found increased GvHD incidences and mortality rates with increasing Ehp mismatch level even with the same HLA mismatch level. In multivariate analysis HLA mismatch levels were excluded from models and Ehp disparity level remained independent prognostic factor for high grade acute GvHD (p = 0.000037, HR = 10.68, 95%CI 5.50 32.5) and extended chronic GvHD (p < 0.000001, HR = 15.51, CI95% 5.36-44.8). In group with single HLA mismatch, patients with double Ehp disparity had worse 5 year overall survival (45% vs. 56%, p = 0.00065, HR = 4.05, CI95% 1.69-9.71) and non-relapse mortality (40% vs. 31%, p = 0.00037, HR = 5.63, CI95% 2.04-15.5) than patients with single Ehp disparity. We conclude that Ehp-linked factors contribute to the high morbidity and mortality in recipients given HLA-mismatched unrelated transplant and Ehp matching should be considered in clinical HSCT. PMID- 29605689 TI - HLA-G mediated immune regulation is impaired by a single amino acid exchange in the alpha 2 domain. AB - The trade-off from HLA class I expression to HLA-G expression support the immune evasion of malignant cells. The essential role of the virtually invariant HLA-G in immune tolerance, tumor immunology and its expression frequency in immune privileged tissues is known; however the specific importance of allelic subtypes in immune responses is still not well understood. HLA-G*01:01, *01:03 and *01:04 are the most prevalent allelic variants differing at residues 31 and 110, respectively. In cytotoxicity assays applying K562 cells transduced with the HLA G variants as targets and NK cells as effectors the differential protective potential of HLA-G variants was analyzed. Their peptide profiles were determined utilizing soluble HLA technology. An increased protective potential of HLA G*01:04 could be observed. All variants exhibit a unique peptide repertoire with marginal overlap, while G*01:04 differs in its peptide anchor profile substantially. The functional differences between HLA-G subtypes could be explained by the constraint of the bound peptides, modifying the pHLA-G accessible surface. For the first time a contribution of amino acid alterations within the HLA-G heavy chain for peptide selection and NK cell recognition could be observed. These results will be a step towards understanding immune tolerance and will guide towards personalized immune therapeutic strategies. PMID- 29605690 TI - Lack of evidence of association between IFNG and IL28B polymorphisms and QuantiFERON-CMV test results in seropositive transplant patients. AB - The aim of this study was to analyze the relationship between the IFNG +874 T/A and IL28B (rs12979860) C/T polymorphisms and the secretion of IFNG by CD8+ T cells after stimulation with cytomegalovirus (CMV) peptides, measured using QuantiFERON-CMV (QF-CMV) assay. A total of 184 CMV-seropositive solid organ transplant patients (108 kidney, 68 liver and 8 lung) were recruited. Of them, 151 patients were QF-CMV Reactive (IFNG >= 0.2 UI/mL) and 33 were Non-reactive. Genotype frequencies in the study population were TT (26.6%), AT (50.0%) and AA (23.4%) for IFNG +874 and CC (52.7%), CT (39.1%) and TT (8.2%) for IL28B (rs12979860). These frequencies did not significantly differ between QF-CMV Reactive and Non-reactive patients. Nor were any significant differences observed in the quantitative IFNG level among the genotypes in either the IFNG or the IL28 genes. When we analyzed whether these polymorphisms had any impact on the risk of CMV replication after transplantation, the adjusted analysis showed no association. In summary, our results showed that IFNG +874 T/A and IL28B (rs12979860) C/T polymorphisms are not associated with the IFNG response to CMV measured by the QuantiFERON-CMV assay, although these results should be confirmed with a higher number of patients. PMID- 29605692 TI - Catastrophizing, Solicitous Responses From Significant Others, and Function in Individuals With Neuropathic Pain, Osteoarthritis, or Spinal Pain in the General Population. AB - : That certain psychological factors are negatively associated with function in patients with chronic pain is well established. However, few studies have evaluated these factors in individuals with chronic pain from the general population. The aims of this study were to: 1) evaluate the unique associations between catastrophizing and perceived solicitous responses and psychological function, physical function, and insomnia severity in individuals with neuropathic pain, osteoarthritis, or spinal pain in the general population; and 2) determine if diagnosis moderates the associations found. Five hundred fifty one individuals from the general population underwent examinations with a physician and physiotherapist, and a total of 334 individuals were diagnosed with either neuropathic pain (n = 34), osteoarthritis (n = 78), or spinal pain (n = 222). Results showed that catastrophizing was significantly associated with reduced psychological and physical function, explaining 24% and 2% of the variance respectively, whereas catastrophizing as well as perceived solicitous responding were significantly and uniquely associated with insomnia severity, explaining 8% of the variance. Perceived solicitous responding was significantly negatively associated with insomnia severity. Moderator analyses indicated that: 1) the association between catastrophizing and psychological function was greater among individuals with spinal pain and neuropathic pain than those with osteoarthritis, and 2) the association between catastrophizing and insomnia was greater among individuals with spinal pain and osteoarthritis than those with neuropathic pain. No statistically significant interactions including perceived solicitous responses were found. The findings support earlier findings of an association between catastrophizing and function among individuals with chronic pain in the general population, and suggest that diagnosis may serve a moderating role in some of these associations. PERSPECTIVE: When examining persons with pain in the general population, catastrophizing is associated with several aspects of function, and diagnosis serves as a moderator for these associations. The replication of these associations in the general population support their reliability and generalizability. PMID- 29605691 TI - A Controlled Pilot Trial of PainTracker Self-Manager, a Web-Based Platform Combined With Patient Coaching, to Support Patients' Self-Management of Chronic Pain. AB - : The objective of this study was to develop and pilot test a chronic pain empowerment and self-management platform, derived from acceptance and commitment therapy, in a pain specialty setting. A controlled, sequential, nonrandomized study design was used to accommodate intervention development and to test the efficacy of the PainTracker Self-Manager (PTSM) intervention (Web-based educational modules and outcome tracking combined with tailored patient coaching sessions and provider guidance). Generalized estimating equations evaluated changes over time (baseline, 3 months, 6 months) in pain self-efficacy (primary outcome), chronic pain acceptance (activity engagement and pain willingness), perceived efficacy in patient-provider interactions, pain intensity and interference, and overall satisfaction with pain treatment (secondary outcomes) between intervention (n = 48) and usual care control groups (n = 51). The full study sample (N = 99) showed greater improvements over time (significant Group * Time interactions) in pain self-efficacy and satisfaction with pain treatment. Among study completers (n = 82), greater improvement in activity engagement as well as pain intensity and interference were also observed. These preliminary findings support the efficacy of the PTSM intervention in a pain specialty setting. Further research is needed to refine and expand the PTSM intervention and to test it in a randomized trial in primary care settings. PERSPECTIVE: We developed a Web-based patient empowerment platform that combined acceptance and commitment therapy-based educational modules and tailored coaching sessions with longitudinal tracking of treatments and patient-reported outcomes, named PTSM. Pilot controlled trial results provide preliminary support for its efficacy in improving pain self-efficacy, activity engagement, pain intensity and interference, and satisfaction with pain treatment. PMID- 29605693 TI - Defined drug release from 3D-printed composite tablets consisting of drug-loaded polyvinylalcohol and a water-soluble or water-insoluble polymer filler. AB - 3D-printed tablets are a promising new approach for personalized medicine. In this study, we fabricated composite tablets consisting of two components, a drug and a filler, by using a fused deposition modeling-type 3D printer. Polyvinylalcohol (PVA) polymer containing calcein (a model drug) was used as the drug component and PVA or polylactic acid (PLA) polymer without drug was used as the water-soluble or water-insoluble filler, respectively. Various kinds of drug PVA/PVA and drug-PVA/PLA composite tablets were designed, and the 3D-printed tablets exhibited good formability. The surface area of the exposed drug component is highly correlated with the initial drug release rate. Composite tablets with an exposed top and a bottom covered with a PLA layer were fabricated. These tablets showed zero-order drug release by maintaining the surface area of the exposed drug component during drug dissolution. In contrast, the drug release profile varied for tablets whose exposed surface area changed. Composite tablets with different drug release lag times were prepared by changing the thickness of the PVA filler coating the drug component. These results which used PVA and PLA filler will provide useful information for preparing the tablets with multi-components and tailor-made tablets with defined drug release profiles using 3D printers. PMID- 29605694 TI - Pharmaceutical 3D printing: Design and qualification of a single step print and fill capsule. AB - Fused deposition modeling (FDM) 3D printing (3DP) has a potential to change how we envision manufacturing in the pharmaceutical industry. A more common utilization for FDM 3DP is to build upon existing hot melt extrusion (HME) technology where the drug is dispersed in the polymer matrix. However, reliable manufacturing of drug-containing filaments remains a challenge along with the limitation of active ingredients which can sustain the processing risks involved in the HME process. To circumvent this obstacle, a single step FDM 3DP process was developed to manufacture thin-walled drug-free capsules which can be filled with dry or liquid drug product formulations. Drug release from these systems is governed by the combined dissolution of the FDM capsule 'shell' and the dosage form encapsulated in these shells. To prepare the shells, the 3D printer files (extension '.gcode') were modified by creating discrete zones, so-called 'zoning process', with individual print parameters. Capsules printed without the zoning process resulted in macroscopic print defects and holes. X-ray computed tomography, finite element analysis and mechanical testing were used to guide the zoning process and printing parameters in order to manufacture consistent and robust capsule shell geometries. Additionally, dose consistencies of drug containing liquid formulations were investigated in this work. PMID- 29605695 TI - Kaempferol-loaded mucoadhesive nanoemulsion for intranasal administration reduces glioma growth in vitro. AB - In order to search for new approaches to treat glioma, intranasal administration has been proposed as an alternative route to deliver drugs into the brain. Among the drug alternatives, kaempferol (KPF) has been reported to induce glioma cell death. This study aimed to prepare nanoemulsions containing KPF with and without chitosan to investigate their potential for brain delivery following intranasal administration, and to evaluate their antitumor activity against glioma cells. KPF-loaded nanoemulsion (KPF-NE) and KPF-loaded mucoadhesive nanoemulsion (KPF MNE) were prepared by high-pressure homogenization technique and were characterized for their globule size, zeta potential, drug content, pH, viscosity, mucoadhesive strength and morphology. KPF from KPF-MNE showed significantly higher permeation across the mucosa in ex vivo diffusion studies. Histopathological examination suggests both nanoemulsions to be safe for the nasal mucosa and able to preserve KPF antioxidant capability. KPF-MNE enhanced significantly the amount of drug into rat's brain following intranasal administration (5- and 4.5-fold higher than free drug and KPF-NE, respectively). In addition, KPF-MNE reduced C6 glioma cell viability through induction of apoptosis to a greater extent than either free KPF or KPF-NE. The mucoadhesive nanoemulsion developed for intranasal administration may be a promising system for delivery to the brain, and KPF-MNE is a candidate for further antiglioma trials. PMID- 29605696 TI - The Role of Fast Imaging Employing Steady-State Acquisition (FIESTA) Magnetic Resonance Imaging for Assessment of Delayed Enhancement of Fat Graft Packing on Postoperative Imaging After Vestibular Schwannoma Surgery. AB - OBJECTIVE: To investigate the role and efficacy of fast imaging employing steady state acquisition (FIESTA) imaging in distinguishing fat graft enhancement from residual or recurrent tumor after vestibular schwannoma (VS) surgery. METHODS: A retrospective study of 33 patients who underwent VS resection via the retrosigmoid or translabyrinthine approach with fat graft reconstruction was performed. Magnetic resonance imaging (MRI) was collected at different time points: preoperative, immediate postoperative (24-48 hours), delayed postoperative (3-6 months after surgery), and yearly postoperative. The image sets contained T1, T2, fat-suppressed T1-weighted with gadolinium, and FIESTA. The radiographs were analyzed for tumor recurrence by the primary neurosurgeon and an independent blinded neuroradiologist. If fat-suppressed T1-weighted images demonstrated postoperative enhancement in the resection bed, a comparison was made with FIESTA imaging. RESULTS: At 3-6 months postoperatively and at 1 year and beyond, 28 (84.8%) and 33 (100%) of patients, respectively, displayed delayed enhancement of the fat graft on postgadolinium fat-suppressed T1-weighted MRI. The enhancement seen on postgadolinium, fat-suppressed, T1-weighted MRI consistently correlated with the characteristic fat graft signal on FIESTA imaging and not tumor recurrence. FIESTA imaging was able to distinguish residual tumor from enhancing fat graft compared with postgadolinium, fat-suppressed, T1 weighted MRI (P < 0.0001) due to distinctive signaling patterns. CONCLUSIONS: FIESTA is an effective tool in discerning fat graft enhancement from residual or recurrent tumor on delayed postoperative imaging after VS resection. Fat graft used in reconstruction consistently enhances on delayed postoperative postgadolinium, fat-suppressed, T1-weighted imaging, which correlates with the fat graft signal seen on FIESTA images. PMID- 29605697 TI - Validation of Grading Scores and Outcome Prognostic Factors in Intracranial Meningiomas in Elderly Patients. AB - OBJECTIVE: Meningiomas are the most frequent benign intracranial tumors and they are becoming more frequent because of the aging population and advances in diagnostics and neurosurgical treatment. Therefore, there will be an increase of this disease in the coming years. METHODS: We performed a retrospective analysis of patients older than 70 years who underwent surgery for intracranial meningiomas, and we established risk factors related to outcome, morbidity, and mortality. We compared 3 previously described scores (Geriatric Scoring System [GSS], Clinico-Radiological Grading System [CRGS], and Sex, Karnofsky, ASA, Location and Edema [SKALE] score). RESULTS: We identified 110 patients older than 70 years. In the univariate analysis, postoperative Karnofsky Performance Status (KPS) was related to the presence of edema (P = 0.036), tumor size (P = 0.043), previous neurologic impairment (P = 0.012), and preoperative American Society of Anesthesiologists (ASA) physical status classification (P = 0.029). In the multivariable logistic regression model, ASA classification (odds ratio, 0.324; P = 0.04) and preoperative KPS (odds ratio, 1.042; P = 0.05) were also statistically significant. In all cases, better survival curves in the Kaplan Meier survival test appear in patients with lower scores (CRGS, P = 0.015; GSS, P = 0.014; SKALE, P < 0.001). Also, morbidity measured as postoperative KPS correlated with these scores (CRGS, P < 0.001; SKALE, P < 0.001; GSS, P < 0.001). However, only SKALE correlated with perioperative morbidity, mortality, and 1 year mortality. CONCLUSIONS: Meningioma resection in patients older than 70 years is safe, with an acceptable rate of mortality and morbidity. Patients who should undergo surgery must be selected in relation to their comorbidities, such as ASA classification or preoperative KPS. However, SKALE could be a useful tool as an initial approach. PMID- 29605698 TI - Left Frontal Meningioangiomatosis Associated with Type IIIc Focal Cortical Dysplasia Causing Refractory Epilepsy and Literature Review. AB - BACKGROUND: We report the surgical management of a lesional drug-resistant epilepsy caused by a meningioangiomatosis associated with a type IIIc focal cortical dysplasia located in the left supplementary motor area in a young male patient. CASE DESCRIPTION: A first anatomically based partial surgical resection was performed on an 11-year-old under general anesthesia without intraoperative mapping, which allowed for postoperative seizure control (Engel IA) for 6 years. The patient then exhibited intractable right sensatory and aphasic focal onset seizures despite 2 appropriate antiepileptic drugs. A second functional-based surgical resection was performed using intraoperative corticosubcortical functional mapping with direct electrical stimulation under awake conditions. A complete surgical resection was performed, and a left partial supplementary motor area syndrome was observed. At 6 months postoperatively, the patient is seizure free (Engel IA) with an ongoing decrease in antiepileptic drug therapy. CONCLUSIONS: Intraoperative functional brain mapping can be applied to preserve the brain function and networks around a meningioangiomatosis to facilitate the resection of potentially epileptogenic perilesional dysplastic cortex and to tailor the extent of resection to functional boundaries. PMID- 29605699 TI - Tailored Strategies to Manage Cerebrospinal Fluid Leaks or Pseudomeningocele After Surgery for Tethered Cord Syndrome. AB - BACKGROUND: Cerebrospinal fluid (CSF) leaks are a dreaded complication after surgery for tethered cord and are associated with significant patient morbidity. Although many strategies for managing postoperative CSF leaks exist, this problem is still daunting, especially in very young patients. In this study, we compared different management techniques for CSF leaks or significant pseudomeningocele in patients with tethered cord syndrome (TCS). METHODS: We analyzed a cohort of children who underwent surgery for TCS from January 2011 to March 2016 (n = 260) and postoperatively experienced either a CSF leak or significant pseudomeningocele. A subset of patients presented with CSF leak (n = 25). We analyzed patient age, sex, presentation, leak appearance, management, and outcome. The different techniques of management were compared for efficacy and morbidity. RESULTS: The diseases associated with leak formation included lipomyelomeningocele (n = 16), myelocystocele (n = 4), and myelomeningocele (n = 5). Three children also had hydrocephalus. Management techniques included cystoperitoneal shunt (CPS) (n = 15), primary resuturing with local rotation flap of muscle (n = 3), external ventricular drain placement (n = 1), ventriculoperitoneal shunt (n = 3), external ventricular drainage (n = 1), and a combination of techniques (rotation flap with external drain; n = 1). Five patients who underwent primary wound revision experienced a leak and required a secondary intervention, but none of the patients who underwent CPS had any complications. CONCLUSIONS: In carefully selected cases, CPS performed early after CSF leakage is highly successful with low morbidity. The primary closure can be attempted for low-pressure leaks without an associated pseudomeningocele. PMID- 29605700 TI - Stereoelectroencephalography-Guided Radiofrequency Thermocoagulation for Hypothalamic Hamartomas: Preliminary Evidence. AB - BACKGROUND: The use of magnetic resonance imaging (MRI)-guided ablation methods, such as laser interstitial thermal therapy and MRI-guided radiofrequency thermocoagulation (RF-TC), poses a risk of mistreatment in patients with nonepileptic hypothalamic hamartoma (HH). Using stereoelectroencephalography (SEEG)-guided RF-TC could solve this problem; however, there are no reports on the efficacy of this technique. Thus, we examined the safety and efficacy of this method. METHODS: This retrospective study was conducted in 9 consecutive patients with HH treated between August 2015 and July 2017. All patients underwent a single round of SEEG-guided RF-TC treatment after comprehensive assessment. Outcomes were assessed using Engel's classification system. Spearman's correlation and receiver operating characteristic curves were analyzed to identify potential factors predictive of seizure outcome after an average follow up duration of 18.78 months. RESULTS: A total of 20 SEEG electrodes were implanted in 9 patients with HH, and 73 lesions were created within the tumors. No obvious symptoms were observed during coagulation. Five patients (55.56%) achieved Engel's class I recovery, and the other 4 (44.44%) achieved Engel's class II recovery; weight gain was observed in 1 patient. Correlation analysis revealed a trend of better seizure outcomes for larger-sized tumors. CONCLUSIONS: The SEEG signal can guide ablation of HH. SEEG-guided RF-TC is a safe procedure that shows promising efficacy. Special attention to the tumor attachment and multiple rounds of RF-TC might help improve seizure-free rates in the future. PMID- 29605701 TI - The Role of Posterior Screw Fixation in Single-Level Transforaminal Lumbar Interbody Fusion During Whole Body Vibration: A Finite Element Study. AB - OBJECTIVE: Few studies have evaluated the need for supplementary instrumentation after lumbar interbody fusion under the condition of whole body vibration (WBV) that is typically present in vehicles. This study aimed to determine the effect of posterior pedicle screw fixation on dynamic response of the whole lumbar spine to vertical WBV after transforaminal lumbar interbody fusion (TLIF). METHODS: A previously validated nonlinear, osteoligamentous finite element (FE) model of the intact L1-sacrum human lumbar spine was modified to simulate single-level (L4-L5) TLIF without and with bilateral pedicle screw fixation (BPSF). Transit dynamic analysis was performed on the 2 developed models under a sinusoidal vertical vibration load of +/-40 N and a compressive follower preload of 400 N. The resulting dynamic response results for the 2 models in terms of stresses and deformations were recorded and compared. RESULTS: When compared with no fixation, BPSF decreased dynamic responses of the spinal levels to the vertical vibration after TLIF. At the fused level (L4-L5), vibration amplitudes of the von-Mises stresses in L4 inferior endplate and L5 superior endplate decreased after BPSF by 48.0% and 46.4%, respectively. At other disc levels (L1-L2, L2-L3, L3-L4, and L5 S1), vibration amplitudes of the disc bulge, von-Mises stress in annulus ground substance and intradiscal pressure also produced 4.2%-9.0%, 2.3%-8.9%, and 3.4% 8.8% deceases, respectively, after BPSF. CONCLUSIONS: After TLIF, application of BPSF can be helpful in the prevention of spine injury during vertical WBV. PMID- 29605702 TI - Role of the Cortico-Subthalamic Hyperdirect Pathway in Deep Brain Stimulation for the Treatment of Parkinson Disease: A Diffusion Tensor Imaging Study. AB - OBJECTIVE: To evaluate the clinical effect of the position of stimulation contacts relative to the hyperdirect pathway (HDP) on the alleviation of motor symptoms in patients with Parkinson disease (PD). METHODS: A group of 11 patients diagnosed with idiopathic PD were included in this study, and all selected targets were in the subthalamic nucleus (STN). In 1 patient, a single side electrode was implanted because of unilateral symptoms; in all other patients, bilateral electrodes each containing 4 discrete contacts were implanted. Nine contacts were excluded due to adverse reactions caused by stimulation, and thus a total of 75 active contacts were evaluated using the same stimulus parameters. Fiber tractography results were individually processed using StealthViz software before all data were subjected to statistical analysis. RESULTS: Under the same stimulus parameters, the shortest distance of each contact to the HDP was smaller in group I (n = 45; >50% improvement rate) compared with group II (n = 30; <=50% improvement rate) (mean, 1.18 +/- 0.86 mm vs. 2.14 +/- 1.20 mm; t = 3.78; P < 0.05), and the shortest distance had a negative correlation with the improvement of motor symptoms (r = -0.48; P < 0.05). CONCLUSIONS: Stimulation of the HDP coincided with the improvement of motor symptoms in patients with PD. We propose an improvement of the direct visualization method based on diffusion tensor imaging fiber tractography of the HDP to select the motor part of the STN. Further rigorous clinical trials are needed to verify the value of this method for achieving precise target location and individualized treatment. PMID- 29605703 TI - Variability in the time to initiation of CPR in continuously monitored pediatric ICUs. AB - AIM: To study the influence of patient characteristics and unit ergonomics and human factors on the time to initiation of CPR. METHODS: A single center study of children, 0 to 21 years old, admitted to an ICU who experienced cardiopulmonary arrest (CPA) requiring >1 min of chest compressions. Time of CPA was determined by analysis of continuous ECG, plethysmography, arterial blood pressure, and end tidal CO2 (EtCO2) waveforms. Initiation of CPR was identified by the onset of cyclic artifact in the ECG waveform. Patient characteristics and unit ergonomics and human factors were examined including CPA cause, identification on the High Risk Checklist (HRC), existing monitoring, ICU type, time of day, nursing shift change, and outcome. RESULTS: The median time from CPA to initiation of CPR was 50.5 s (IQR 26.5 to 127.5) in 36 CPAs. Forty-seven percent of patients experienced time from CPA to initiation of CPR of >1 min. There was no difference in CPA cause, ICU type, time of day, or nursing shift change. CONCLUSION: Nearly half of pediatric patients who experienced CPA in an ICU setting did not meet AHA guidelines for early initiation of CPR. This is an opportunity to study the recognition phase of CPA using continuous monitoring data with the aim of improving the understanding of and factors contributing to delays in initiation of CPR. PMID- 29605704 TI - Spent coffee ground as a new bulking agent for accelerated biodrying of dewatered sludge. AB - The feasibility of using spent coffee ground (SCG) as a new bulking agent for biodrying of dewatered sludge (DS) was investigated in comparison with two other frequently-used bulking agents, air-dried sludge (AS) and sawdust (SD). Results showed that the moisture contents (MC) of 16-day DS biodrying with AS (Trial A), SCG (Trial B) and SD (Trial C) decreased from 70.14 wt%, 68.25 wt% and 71.63 wt% to 59.12 wt%, 41.35 wt% and 57.69 wt%, respectively. In case of Trial B, the MC rapidly decreased to 46.16 wt% with the highest water removal (70.87%) within 8 days because of the longest high-temperature period (5.8 days). Further studies indicated that the abundant biodegradable volatile solids (BVS) and high dissolved organic matter (DOM) contents in SCG were the main driving forces for water removal. According to pyrosequencing data, Firmicutes, most of which were recognized as thermophiles, was rapidly enriched on Day 8 and became the dominant phylum in Trial B. Four thermophilic genera, Bacillus, Ureibacillus, Geobacillus and Thermobifida, which can produce thermostable hydrolytic extracellular enzymes, were the most abundant in Trial B, indicating that these thermophilic bacteria evolved during the long high-temperature period enhanced the biodegradation of BVS in SCG. The 8-day biodried product of Trial B was demonstrated to be an excellent solid fuel with low heating value (LHV) of 9284 kJ kg-1, which was 2.1 and 1.8 times those of biodried products with AS and SD, respectively. Thus SCG was found to be an excellent bulking agent accelerating DS biodrying and producing a solid fuel with a high calorific value. PMID- 29605705 TI - NSQIP Analysis of Axillary Lymph Node Dissection Rates for Breast Cancer: Implications for Resident and Fellow Participation. AB - INTRODUCTION: Management of the axilla in invasive breast cancer (IBC) has shifted away from more radical surgery such as axillary lymph node dissection (ALND), towards less invasive procedures, such as sentinel lymph node biopsy. Because of this shift, we hypothesize that there has been a national downward trend in ALND procedures, subsequently impacting surgical trainee exposure to this procedure using the ACS-NSQIP database to evaluate this. METHODS: Women with IBC were identified in the ACS-NSQIP database from 2007 to 2014. Procedures including ALND were identified using CPT codes. This number was divided by total cases, given a varying number of participating institutions each year. Next, cases involving resident participation were identified and divided by training level: junior (post graduate year-[PGY] 1-2), senior (PGY 3-5) and fellow (PGY >= 6). Two tailed z tests were used to compare proportions, with significance determined when p < 0.05. RESULTS: A total of 128,372 women were identified with IBC with 36,844 ALND. ALND rates decreased by an average of 2.43% yearly from 2007 to 2014. Resident participation significantly drops in 2011, from 49.3% before to 29.4% after (p < 0.01). Junior residents experienced a significant decrease in participation rate (43.3%-32.2%, p < 0.05). Senior residents and fellows experienced an upward trend in their participation, although not significant (51.2%-56.3%, p = 0.35, and 5.6%-11.6%, p = 0.056, respectively). CONCLUSIONS: Using the ACS-NSQIP database, we demonstrate the downward trend in rate of ALND for IBC with subsequent decrease in resident participation. Junior residents experienced a significant decrease in their participation with no significant change for senior or fellow-level trainees. Awareness of this trend is important when creating future surgical curriculum changes for general surgery and fellowship training programs. PMID- 29605706 TI - Fatal and non-fatal overdose among opiate users in South Wales: A qualitative study of peer responses. AB - BACKGROUND: Overdose is a major cause of death among injecting drug users in Wales. Few studies, however, have explored the overdose responses of witnesses in this context. This study applies Rhodes' concept of the 'risk environment' to examine how witnesses respond to opiate overdose. METHOD: In depth, semi structured interviews were conducted with fifty-five participants recruited from statutory and third sector drug treatment providers operating across South Wales and from two Welsh prisons. Eligibility was based on whether the person was, or had recently been, an opiate user and whether they had personally experienced or witnessed an overdose event. RESULTS: Witnesses were amenable to assisting overdosed peers. However, a number of micro- and macro-level factors impeded the successful implementation of harm reduction techniques in response to an overdose. At micro level, the social setting of injecting drug use, peer group drug use norms and difficulties in identifying an overdose were linked to ineffective response. Macro-level factors including laws governing the possession of drugs and harm reduction discourse were also found to limit the uptake of overdose response techniques. CONCLUSION: Findings suggest a need to insert pragmatic solutions into overdose prevention programmes and training to counter the factors hindering effective responses to overdose. This includes simpler techniques and harnessing the support and knowledge of injecting drug users' social networks. Although these will go some way to addressing specific micro level barriers, we also emphasise the need for additional policy measures that can address the macro-environmental conditions that produce and maintain features of injecting drug users' risk environments. PMID- 29605707 TI - Epigenome-wide association studies for systemic autoimmune diseases: The road behind and the road ahead. AB - Epigenetics is known to be an important mechanism in the pathogenesis of autoimmune diseases. Epigenetic variations can act as integrators of environmental and genetic exposures and propagate activated states in immune cells. Studying epigenetic alterations by means of genome-wide approaches promises to unravel novel molecular mechanisms related to disease etiology, disease progression, clinical manifestations and treatment responses. This paper reviews what we have learned in the last five years from epigenome-wide studies for three systemic autoimmune diseases, namely systemic lupus erythematosus, primary Sjogren's syndrome, and rheumatoid arthritis. We examine the degree of epigenetic sharing between different diseases and the possible mediating role of epigenetic associations in genetic and environmental risks. Finally, we also shed light into the use of epigenetic markers towards a better precision medicine regarding disease prediction, prevention and personalized treatment in systemic autoimmunity. PMID- 29605709 TI - Intra-, peri- and postoperative complications in pelvic organ prolapse surgery in geriatric women. AB - OBJECTIVE: Pelvic organ prolapse is a common problem among geriatric women. Advanced age is associated with a high prevalence of comorbidities that can lead to restrictive use of surgical treatment. With rising life expectancy it is predicted that surgical treatment in these women will be seen more frequently. Inconsistently there is a lack of clinical trials giving attention to elderly women suffering from pelvic organ prolapse. The aim of this study was to quantify the rate of complications in elderly women undergoing surgery for pelvic organ prolapse. STUDY DESIGN: 72 women aged >=75 years who underwent surgical correction for pelvic organ prolapse were included in this study. Demographics, comorbidities, intra-, peri- and postoperative severe and non-severe complications were recorded. Additionally we compared the pre- and postoperative presence of symptoms linked to pelvic organ prolapse. Follow-up for the review of pelvic floor symptoms was six month. RESULTS: The mean age was 81.4 years. Four (5.6%) of the patients had a severe intra-, peri- or postoperative complication (two bowel injuries, one bleeding requiring blood transfusion, one resuscitation). All women with severe complications showed no persistent problem at the time of discharge or during the follow-up period. There was a significant postoperative decrease in pelvic organ prolapse connected symptoms, such as stress urinary incontinence (p = .013), voiding dysfunction (p < .001), recurrent urinary tract infection (p = .001) and rectal outlet obstruction (p = .006). CONCLUSION: Elderly women undergoing an operation for pelvic organ prolapse have a low risk of complication and benefit from surgery. Age alone should not be a contraindication to surgery. PMID- 29605710 TI - Serum AMH levels and insulin resistance in women with PCOS. AB - OBJECTIVE: To compare the serum AMH levels between women with and without insulin resistance (IR) in polycystic ovary syndrome (PCOS). STUDY DESIGN: 293 women with PCOS according to the Rotterdam criteria were enrolled into our study. Insulin resistance was diagnosed according to the Homeostatic model assessment insulin resistant (HOMA-IR) formula and the cut-off point was set to more than 2.5. Women were grouped according to the presence of insulin resistance (IR) (HOMA-IR >= 2.5). Serum AMH and other hormones were compared between the IR (+) and IR (-) groups. Additionally, AMH percentiles were (<25, 25-75, >75) constructed; HOMA-IR and BMI values in women with/without IR were compared in different percentiles. Further, HOMA-IR, BMI and AMH values were measured across different PCOS phenotypes. RESULTS: The prevalence of IR was 45%. The prevalence of IR was 57% in women with BMI >= 25. Serum AMH levels were not significantly different among women with and without IR. Also, HOMA-IR values were not significant among different AMH percentiles. However, in each AMH percentile BMI were found to be higher in women with IR than in women without IR. The median HOMA-IR values were the highest in women with BMI >= 25 in both IR (+) and IR (-) groups. No significant difference was found among PCOS phenotypes in terms of HOMA-IR and BMI. Positive correlations were found between BMI, free testosterone and HOMA-IR. However, no correlation was found between AMH and HOMA-IR. CONCLUSION: The serum AMH levels between women with IR and without IR in PCOS were not significantly different. Also, we did not reveal a correlation between serum AMH levels and IR in women with PCOS. IR was not correlated with different PCOS phenotypes either. We found a positive correlation between BMI and IR. IR should be investigated in women with PCOS having a BMI >= 25, independent of their phenotype or AMH levels. PMID- 29605708 TI - Long Terminal Repeat CRISPR-CAR-Coupled "Universal" T Cells Mediate Potent Anti leukemic Effects. AB - Gene editing can be used to overcome allo-recognition, which otherwise limits allogeneic T cell therapies. Initial proof-of-concept applications have included generation of such "universal" T cells expressing chimeric antigen receptors (CARs) against CD19 target antigens combined with transient expression of DNA targeting nucleases to disrupt the T cell receptor alpha constant chain (TRAC). Although relatively efficient, transgene expression and editing effects were unlinked, yields variable, and resulting T cell populations heterogeneous, complicating dosing strategies. We describe a self-inactivating lentiviral "terminal" vector platform coupling CAR expression with CRISPR/Cas9 effects through incorporation of an sgRNA element into the DeltaU3 3' long terminal repeat (LTR). Following reverse transcription and duplication of the hybrid DeltaU3-sgRNA, delivery of Cas9 mRNA resulted in targeted TRAC locus cleavage and allowed the enrichment of highly homogeneous (>96%) CAR+ (>99%) TCR- populations by automated magnetic separation. Molecular analyses, including NGS, WGS, and Digenome-seq, verified on-target specificity with no evidence of predicted off target events. Robust anti-leukemic effects were demonstrated in humanized immunodeficient mice and were sustained longer than by conventional CAR+TCR+ T cells. Terminal-TRAC (TT) CAR T cells offer the possibility of a pre manufactured, non-HLA-matched CAR cell therapy and will be evaluated in phase 1 trials against B cell malignancies shortly. PMID- 29605713 TI - Cost Effectiveness of a Community-Delivered Consultation to Improve Infant Sleep Problems and Maternal Well-Being. AB - OBJECTIVES: To evaluate the cost effectiveness of a community-delivered consultation aimed at improving infant sleep and maternal well-being. METHODS: A decision-analytic model was developed that compared the costs and benefits of an infant sleep consultation with usual care. The effectiveness of the consultation was based on clinical evidence, and improvements in maternal quality of life were estimated by mapping the Edinburgh Postnatal Depression Scale scores to published utility scores. Cost effectiveness was calculated as the incremental cost per quality-adjusted life-year gained (QALY). RESULTS: The statistically significant improvements in mean Edinburgh Postnatal Depression Scale scores at 4- and 16 month follow-ups were used to estimate the benefit in terms of QALYs. The modeled results demonstrated that the infant sleep consultation is low-cost (A$ 436), more effective in terms of QALYs gained (0.017), and cost-effective. The estimated incremental cost-effectiveness ratio was A$ 4031/QALY gained. The main drivers of the model were the use of early parenting centers and nurse training costs. CONCLUSIONS: Community-based nurse-delivered infant sleep consultations aid infant sleep, improve maternal quality of life, and are cost-effective compared with usual care and lead to improvements in quality of life through a reduction in postnatal depression. PMID- 29605714 TI - Direct carborane-peptide conjugates: Synthesis and evaluation as non-natural lipopeptide mimetics. AB - Herein, we report the synthesis and characterization of direct carborane-peptide conjugates. Carboranes are non-natural and extremely hydrophobic compounds and turned out to be suitable pharmacophores for diverse biological applications. In this work, we established an efficient procedure for the coupling of carboranes to peptides on solid support. We identified the coupling of carborane-1 carboxylic acids to amino groups to be superior to those with hydroxy- or sulfhydryl-groups. The carborane-peptide conjugates showed remarkably prolonged, and carborane isomer dependent chromatographic retention times. This effect can be used to generate non-natural lipopeptides with fine-tuned properties. PMID- 29605712 TI - Electrically-receptive and thermally-responsive paper-based sensor chip for rapid detection of bacterial cells. AB - Although significant technological advancements have been made in the development of analytical biosensor chips for detecting bacterial strains (E. coli, S. Mutans and B. Subtilis), critical requirements i.e. limit of detection (LOD), fast time of response, ultra-sensitivity with high reproducibility and good shelf-life with robust sensing capability have yet to be met within a single sensor chip. In order to achieve these criteria, we present an electrically-receptive thermally responsive (ER-TR) sensor chip comprised of simple filter paper used as substrate coated with composite of poly(N-isopropylacrylamide) polymer (PNIPAm) - graphene nanoplatelet (GR) followed by evaporation of Au electrodes for capturing both Gram-positive (S. mutans and B. subtilis) and Gram-negative (E. coli) bacterial cells in real-time. Autoclave water, tap water, lake water and milk samples were tested with ER-TR chip with and without bacterial strains at varying concentration range 101-105 cells/mL. The sensor was integrated with in-house built printed circuit board (PCB) to transmit/receive electrical signals. The interaction of E. coli, S. mutans and B. subtilis cells with fibers of PNIPAm-GR resulted in a change of electrical resistance and the readout was monitored wirelessly in real-time using MATLAB algorithm. Finally, prepared ER-TR chip exhibited the reproducibility of 85-97% with shelf-life of up to four weeks after testing with lake water sample. PMID- 29605711 TI - Fetal cell-free DNA fraction in maternal plasma for the prediction of hypertensive disorders of pregnancy. AB - OBJECTIVE: The purpose of this study is to compare the fetal fractions during non invasive prenatal testing (NIPT) in singleton pregnancies according to gestational age and maternal characteristics to evaluate the utility of this parameter for the prediction of pregnancy complications including gestational diabetes mellitus (GDM) and hypertensive disorders of pregnancy (HDP). STUDY DESIGN: This study was a multicenter prospective cohort study. The present data were collected from women whose NIPT results were negative. The relationships between the fetal fractions and the gestational age, maternal weight and height, and incidences of miscarriage, preterm delivery, and pregnancy complications including GDM, HDP and placental abruption were assessed. RESULTS: A total of 5582 pregnant women with verified NIPT negative results were registered in the study. The demographic characteristics of the study populations were statistically analyzed, and the women with HDP tended to have a low fetal fraction in samples taken during early gestation. The area under the curve (AUC) in a receiver operating characteristic curve (ROC) analysis was 0.608 for women with HDP. CONCLUSION: A low fetal fraction on NIPT might be correlated with future HDP. However, predicting HDP during early pregnancy in women with a low fetal fraction might be difficult. PMID- 29605716 TI - Autologous Stem Cell Transplantation for Patients with Early Progression of Follicular Lymphoma: A Follow-Up Study of 2 Randomized Trials from the German Low Grade Lymphoma Study Group. AB - Patients with follicular lymphoma (FL) and progression of disease (POD) within 24 months after frontline treatment (POD24) have poor overall survival (OS). The optimal salvage treatment for these patients is unknown. We assessed the role of high-dose therapy and autologous stem cell transplantation (ASCT) in transplant eligible patients. We analyzed 162 patients with advanced-stage FL who had received frontline treatment within the GLSG1996 or GLSG2000 trials. All patients had POD at age <= 65 years and had not received a prior transplant. Second-line treatment was not specified by study protocols. Survival was calculated from time of second-line treatment. Eighteen patients (11%) progressed (n = 16) or died (n = 2) during cytoreductive second-line treatment (considered "cytoreduction failure"); none received ASCT, and their median second-line OS was <1 year. A total of 113 patients had POD24 (70%), whereas 49 had POD after 24 months (30%). Sixty-three patients without cytoreduction failure received ASCT (39%), and 81 received no transplant (50%). In patients with POD24, a significant survival benefit was associated with ASCT with a 5-year second-line progression-free survival for ASCT versus no transplant of 51% versus 19% (hazard ratio, .38; 95% confidence interval, .24 to .62; P < .0001) and a 5-year second-line OS of 77% versus 59% (hazard ratio, .54, 95% confidence interval, .30 to .95; P= .031). Thus, ASCT is an effective treatment option for transplant-eligible patients with high-risk FL as identified by POD24 and should be evaluated in prospective clinical trials. PMID- 29605715 TI - A computational biology approach of a genome-wide screen connected miRNAs to obesity and type 2 diabetes. AB - OBJECTIVE: Obesity and type 2 diabetes (T2D) arise from the interplay between genetic, epigenetic, and environmental factors. The aim of this study was to combine bioinformatics and functional studies to identify miRNAs that contribute to obesity and T2D. METHODS: A computational framework (miR-QTL-Scan) was applied by combining QTL, miRNA prediction, and transcriptomics in order to enhance the power for the discovery of miRNAs as regulative elements. Expression of several miRNAs was analyzed in human adipose tissue and blood cells and miR-31 was manipulated in a human fat cell line. RESULTS: In 17 partially overlapping QTL for obesity and T2D 170 miRNAs were identified. Four miRNAs (miR-15b, miR-30b, miR-31, miR-744) were recognized in gWAT (gonadal white adipose tissue) and six (miR-491, miR-455, miR-423-5p, miR-132-3p, miR-365-3p, miR-30b) in BAT (brown adipose tissue). To provide direct functional evidence for the achievement of the miR-QTL-Scan, miR-31 located in the obesity QTL Nob6 was experimentally analyzed. Its expression was higher in gWAT of obese and diabetic mice and humans than of lean controls. Accordingly, 10 potential target genes involved in insulin signaling and adipogenesis were suppressed. Manipulation of miR-31 in human SGBS adipocytes affected the expression of GLUT4, PPARgamma, IRS1, and ACACA. In human peripheral blood mononuclear cells (PBMC) miR-15b levels were correlated to baseline blood glucose concentrations and might be an indicator for diabetes. CONCLUSION: Thus, miR-QTL-Scan allowed the identification of novel miRNAs relevant for obesity and T2D. PMID- 29605717 TI - Biomechanical and biomolecular characterization of extracellular matrix structures in human colon carcinomas. AB - The extracellular matrix (ECM) is extensively remodeled in tumor tissues. Overproduction of collagens, pathological collagen crosslinking and alignment of fibers are major processes that ultimately result in an increased tissue stiffness. Although it is known that glycosaminoglycans (GAGs) play an important role in tumor signaling, their contribution to the biomechanical properties of tumor ECM is unknown. In this study, ECM structures of human colon carcinoma and normal (control) colon tissues were histologically identified. Using atomic force microscopy (AFM) nanoindentation, we show that the collagen-rich regions within the ECM of colon carcinoma tissues were significantly stiffer than the submucosal collagen-rich layer of control tissues. Screening of these regions with Raman microspectroscopy revealed significantly different molecular fingerprints for collagen fibers in colon carcinoma tissues compared to control tissues. We further showed an increased alignment of collagen fibers and elevated levels of GAG immuno-reactivity within the collagen network of colon carcinoma tissues. GAGs such as heparan sulfate and chondroitin sulfate were detected in significantly elevated levels in collagen fibers of carcinoma tissues. Moreover, immunodetection of the collagen-associated proteoglycan decorin was significantly decreased in carcinomas tissues of individual patients when compared with the corresponding control tissues. Overall a strong patient-to-patient variability was evident in the ECM composition, structure and biomechanics of individual colon carcinoma tissues. Although, biomechanical characteristics of tumor ECM were not directly impacted by GAG content, GAGs might play an important role during the mechanical and structural remodeling of pathological tumor ECM. To manipulate GAG expression and deposition in tumor microenvironments could represent a novel potential therapeutic strategy. PMID- 29605718 TI - A novel mouse model of intervertebral disc degeneration shows altered cell fate and matrix homeostasis. AB - Intervertebral disc degeneration and associated low back and neck pain is a ubiquitous health condition that affects millions of people world-wide, and causes high incidence of disability and enormous medical/societal costs. However, lack of appropriate small animal models with spontaneous disease onset has impeded our ability to understand the pathogenetic mechanisms that characterize and drive the degenerative process. We report, for the first time, early onset spontaneous disc degeneration in SM/J mice known for their poor regenerative capacities compared to "super-healer" LG/J mice. In SM/J mice, degenerative process was marked by decreased nucleus pulposus (NP) cellularity and changes in matrix composition at P7, 4, and 8 weeks with increased severity by 17 weeks. Distinctions between NP and annulus fibrosus (AF) or endplate cartilage were lost, and NP and AF of SM/J mice showed higher histological grades. There was increased NP cell death in SM/J mice with decreased phenotypic marker expression. Polarized microscopy and FTIR spectroscopy demonstrated replacement of glycosaminoglycan-rich NP matrix with collagenous fibrous tissue. The levels of ARGxx were increased in, indicating higher aggrecan turnover. Furthermore, an aberrant expression of collagen X and MMP13 was observed in the NP of SM/J mice, along with elevated expression of Col10a1, Ctgf, and Runx2, markers of chondrocyte hypertrophy. Likewise, expression of Enpp1 as well as Alpl was higher, suggesting NP cells of SM/J mice promote dystrophic mineralization. There was also a decrease in several pathways necessary for NP cell survival and function including Wnt and VEGF signaling. Importantly, SM/J discs were stiffer, had decreased height, and poor vertebral bone quality, suggesting compromised motion segment mechanical functionality. Taken together, our results clearly demonstrate that SM/J mouse strain recapitulates many salient features of human disc degeneration, and serves as a novel small animal model. PMID- 29605719 TI - Oxygen management in mechanically ventilated patients: A multicenter prospective observational study. AB - PURPOSE: To observe arterial oxygen in relation to fraction of inspired oxygen (FIO2) during mechanical ventilation (MV). MATERIALS AND METHODS: In this multicenter prospective observational study, we included adult patients required MV for >48h during the period from March to May 2015. We obtained FIO2, PaO2 and SaO2 from commencement of MV until the 7th day of MV in the ICU. RESULTS: We included 454 patients from 28 ICUs in this study. The median APACHE II score was 22. Median values of FIO2, PaO2 and SaO2 were 0.40, 96mmHg and 98%. After day two, patients spent most of their time with a FIO2 between 0.3 and 0.49 with median PaO2 of approximately 90mmHg and SaO2 of 97%. PaO2 was >=100mmHg during 47.2% of the study period and was >=130mmHg during 18.4% of the study period. FIO2 was more likely decreased when PaO2 was >=130mmHg or SaO2 was >=99% with a FIO2 of 0.5 or greater. When FIO2 was <0.5, however, FIO2 was less likely decreased regardless of the value of PaO2 and SaO2. CONCLUSIONS: In our multicenter prospective study, we found that hyperoxemia was common and that hyperoxemia was not corrected. PMID- 29605720 TI - Concomitant BCORL1 and BRAF Mutations in Vemurafenib-Resistant Melanoma Cells. AB - BRAF is the most frequently mutated gene in melanoma. Constitutive activation of mutant BRAFV600E leads to aberrant Ras-independent MAPK signaling and cell transformation. Inhibition of mutant BRAF is a current frontline therapy for such cases, with improved survival compared with chemotherapy. Unfortunately, reactivation of MAPK signaling by several mechanisms has been shown to cause drug resistance and disease recurrence. In this work, we describe the co-occurrence of an in-frame deletion within an amplified BRAFV600E locus and a missense point mutation of the transcriptional repressor BCORL1 in vemurafenib-resistant A375 melanoma cells. Functional data confirmed that truncated p47BRAFV600E and mutant BCORL1Q1076H both contribute to resistance. Interestingly, either endogenous BCORL1 silencing or ectopic BCORL1Q1076H expression mimicked the effects of a CRISPR/Cas9-edited BCORL1Q1076H locus, suggesting a complex mixture of loss- and gain-of-function effects caused by the mutation. Transcriptomic data confirmed this hypothesis. Finally, we show that the pan-RAF inhibitor sorafenib is not affected by expression of BRAF deletion variant and effectively synergizes with vemurafenib to block resistant cells, suggesting a possible intervention for this class of mutants. PMID- 29605721 TI - Combined Inhibition of ATR and WEE1 as a Novel Therapeutic Strategy in Triple Negative Breast Cancer. AB - Triple negative breast cancer (TNBC) is a highly aggressive subtype of breast cancer that poses a clinical challenge. Thus, new therapy strategies are urgently needed. The selective WEE1 inhibitor, AZD1775, has shown strong anti proliferative effects on a variety of tumors. Here, we first demonstrate that inhibition of ATR by selective inhibitor AZD6738 can enhance AZD1775-caused growth inhibition in TNBC. Our results show that the enhanced cell death is attributed to repressed DNA damage repair and excessive replication stress, thereby causing increased DNA damage reflected by accumulation of the DNA double strand-break marker gammaH2AX. On the other hand, combined treatment with AZD6738 and AZD1775 forces mitotic entry of cells with DNA damages by activating CDK1 activity, inducing severely aberrant mitosis and mitotic catastrophe, ultimately resulting in cell death. Dual inhibition of WEE1 and ATR also inactivated RAD51 mediated homologous recombination, which sensitized TNBC cells to cisplatin and PARP inhibitor. Here, based on the preclinical results that ATR inhibition synergizes with WEE1 inhibition in TNBC, we propose that this combination therapy alone, or in parallel with chemotherapy, represents an innovative and potent targeted therapy in TNBC. PMID- 29605722 TI - Efficacy of EUS-guided and ERCP-guided biliary drainage for malignant biliary obstruction: prospective randomized controlled study. AB - BACKGROUND AND AIMS: ERCP-guided biliary drainage (ERCP-BD) is a criterion standard treatment for malignant biliary obstruction when curative surgery is not an option. Alternative methods such as percutaneous transhepatic biliary drainage would significantly lower the quality of life. EUS-guided biliary drainage (EUS BD) has been developed and performed by experienced endoscopists. Therefore, the aims of this study were to evaluate the efficacy and safety of EUS-BD compared with ERCP in malignant biliary obstruction. METHODS: The prospective randomized controlled study was conducted, and 30 patients were enrolled: 15 for each EUS-BD and ERCP-BD arms. The technical success, procedural time, clinical success, and adverse events were evaluated. RESULTS: Thirty patients had extrahepatic malignant biliary tract obstruction (19 men, 11 women). Twenty-seven patients had unresectable pancreatic ductal adenocarcinomas, 1 patient had distal common bile duct cancer, and 2 patients had metastatic malignant lymphadenopathy. There were no significant differences both in terms of technical success rate and clinical success rate (100% vs 93% and 93% vs 100% in ERCP-BD vs EUS-BD, respectively; P = 1.00, P = 1.00). Four patients (31%) had tumor ingrowth-caused stent dysfunction in the ERCP-BD group, whereas 2 patients had food impaction and 2 patients had stent migration in the EUS-BD group. No significant procedure-related adverse events occurred in either group. CONCLUSIONS: This prospective randomized controlled study suggests that EUS-BD has similar safety to ERCP-BD. EUS-BD was not superior to ERCP-BD in terms of relief of malignant biliary obstruction. EUS BD may have fewer cases of tumor ingrowth but may also have more cases of food impaction or stent migration. (Clinical trial registration number: NCT01421836.). PMID- 29605723 TI - Risk Factors for Gastrointestinal Leak after Bariatric Surgery: MBASQIP Analysis. AB - BACKGROUND: Gastrointestinal leak remains one of the most dreaded complications in bariatric surgery. We aimed to evaluate risk factors and the impact of common perioperative interventions on the development of leak in patients who underwent laparoscopic bariatric surgery. STUDY DESIGN: Using the 2015 database of accredited centers, data were analyzed for patients who underwent laparoscopic sleeve gastrectomy or Roux-en-Y gastric bypass (LRYGB). Emergent, revisional, and converted cases were excluded. Multivariate logistic regression was used to analyze risk factors for leak, including provocative testing of anastomosis, surgical drain placement, and use of postoperative swallow study. RESULTS: Data from 133,478 patients who underwent laparoscopic sleeve gastrectomy (n = 92,495 [69.3%]) and LRYGB (n = 40,983 [30.7%]) were analyzed. Overall leak rate was 0.7% (938 of 133,478). Factors associated with increased risk for leak were oxygen dependency (adjusted odds ratio [AOR] 1.97), hypoalbuminemia (AOR 1.66), sleep apnea (AOR 1.52), hypertension (AOR 1.36), and diabetes (AOR 1.18). Compared with LRYGB, laparoscopic sleeve gastrectomy was associated with a lower risk of leak (AOR 0.52; 95% CI 0.44 to 0.61; p < 0.01). Intraoperative provocative test was performed in 81.9% of cases and the leak rate was higher in patients with vs without a provocative test (0.8% vs 0.4%, respectively; p < 0.01). A surgical drain was placed in 24.5% of cases and the leak rate was higher in patients with vs without a surgical drain placed (1.6% vs 0.4%, respectively; p < 0.01). A swallow study was performed in 41% of cases and the leak rate was similar between patients with vs without swallow study (0.7% vs 0.7%; p = 0.50). CONCLUSIONS: The overall rate of gastrointestinal leak in bariatric surgery is low. Certain preoperative factors, procedural type (LRYGB), and interventions (intraoperative provocative test and surgical drain placement) were associated with a higher risk for leaks. PMID- 29605724 TI - Timing of Laparotomy and Closure in Burn Patients with Abdominal Compartment Syndrome: Effects on Survival. AB - BACKGROUND: Survival of burn patients with abdominal compartment syndrome (ACS) is uniformly reported to be poor, averaging just 16% after laparotomy. We hypothesize that better outcomes can be achieved with a strategy of immediate laparotomy and early fascial closure. STUDY DESIGN: Patients with burn injury who were diagnosed with ACS between 2005 and 2016 were identified through a search of databases. Data were gathered from electronic medical records. Timing of laparotomy and closure were calculated for each patient. Patients were stratified into predefined groups based on timing of laparotomy, cause of ACS, patient age, and timing of abdominal closure. Survival rates were calculated and compared. RESULTS: Forty-six patients with burn injury and ACS were identified. Abdominal compartment syndrome developed during initial resuscitation in 27 patients, during perioperative resuscitation in 5 patients, and during an episode of sepsis in 13 patients. Overall survival was 56%. Mean time to laparotomy from diagnosis of ACS was 1 hour 8 minutes (SD 59 minutes). When ACS developed in patients during initial resuscitation, the mean time to laparotomy from hospital admission was 13 hours (SD 7 hours). Survival rate in this group was 70%, and survival rate in patients treated for ACS later in their hospital course was 33% (p = 0.03). Survival among patients whose laparotomy was closed within 48 hours was 100%, and survival among patients whose laparotomy was not closed within 48 hours was 48% (p = 0.01). CONCLUSIONS: Immediate laparotomy resulted in much higher survival rates than previously reported in burn patients with ACS. Survival was higher when ACS was diagnosed during initial resuscitation. Fascial closure within 48 hours was associated with improved survival compared with later fascial closure. PMID- 29605725 TI - Utility of Viscoelastic Assays Beyond Coagulation: Can Preoperative Thrombelastography Indices Predict Tumor Histology, Nodal Disease, and Resectability in Patients Undergoing Pancreatectomy? AB - BACKGROUND: Hypercoagulability and malignancy have been linked since the 1860s. However, the impact of different neoplasms on multiple components of the coagulation system remains poorly understood. Thrombelastography (TEG) enables measurement of coagulation incorporating clotting through fibrinolysis. We hypothesize that specific TEG indices that are associated with hypercoagulability can be appreciated in patients with adenocarcinoma undergoing pancreatic resection. STUDY DESIGN: Blood samples were obtained from patients undergoing pancreatic resection before surgical incision and assayed with TEG. The 4 indices of coagulation measured by TEG included in the analysis were R time, angle, maximum amplitude, and lysis at 30 minutes. Patient tumor type, nodal disease, and mass resectability were contrasted with TEG indices. RESULTS: One hundred patients were enrolled over 18 months. The majority (63%) of patients had adenocarcinoma. Patients with adenocarcinoma had increased angle compared with other lesions (49 degrees [interquartile range {IQR} 37 to 59 degrees] vs 43 degrees [IQR 32 to 49 degrees]; p = 0.011). When excluding patients that underwent neoadjuvant therapy, patients with adenocarcinoma had shorter R times (13 minutes [IQR 9 to 16 minutes] vs 14 minutes [IQR 12 to 18 minutes]; p = 0.051), steeper angles (49 degrees [IQR 40 to 59 degrees] vs 43 degrees [IQR 32 to 49 degrees]; p = 0.010), and higher maximum amplitude (67 mm [IQR 61 to 69 mm] vs 62 mm [IQR 57 to 67 mm]; p = 0.017). Nodal disease was associated with a significantly increased angle (49 degrees [IQR 42 to 59 degrees] vs 40 degrees [IQR 32 to 50 degrees]; p = 0.002) and maximum amplitude (64 mm [IQR 61 to 69 mm] vs 62 mm [IQR 56 to 67 mm]; p = 0.017). Patients who underwent successful mass resection had longer R times (14 minutes [IQR 11 to 17 minutes] vs 10 minutes [IQR 9 to 15]; p = 0.033) and shorter angles (44 degrees [IQR 35 to 55 degrees] vs 58 degrees [IQR 45 to 66 degrees]; p = 0.025). CONCLUSIONS: Patients with adenocarcinoma undergoing pancreatic resection have multiple TEG abnormalities consistent with hypercoagulability. These TEG outputs are associated with tumor type, nodal disease, and probability of a successful resection. The use of preoperative TEG has the potential to aid surgeon and patient discussions on anticipated disease burden and prognosis before resection. PMID- 29605726 TI - Civilian Prehospital Tourniquet Use Is Associated with Improved Survival in Patients with Peripheral Vascular Injury. AB - BACKGROUND: Tourniquet use has been proven to reduce mortality on the battlefield. Although empirically transitioned to the civilian environment, data substantiating survival benefit attributable to civilian tourniquet use is lacking. We hypothesized that civilian prehospital tourniquet use is associated with reduced mortality in patients with peripheral vascular injuries. STUDY DESIGN: We conducted a multicenter retrospective review of all patients sustaining peripheral vascular injuries admitted to 11 Level I trauma centers (January 2011 through December 2016). The study population was divided into 2 groups based on prehospital tourniquet use. Baseline characteristics were compared and factors associated with mortality identified. Logistic regression, adjusting for demographic, physiologic and injury-related parameters, was used to evaluate the association between prehospital tourniquet use and mortality. Delayed amputation was the secondary end point. RESULTS: During 6 years, 1,026 patients with peripheral vascular injuries were admitted. Prehospital tourniquets were used in 181 (17.6%) patients. Tourniquet time averaged 77.3 +/- 63.3 minutes (interquartile range 39.0 to 92.3 minutes). Traumatic amputations occurred in 98 patients (35.7% had a tourniquet). Mortality was 5.2% in the non-tourniquet group compared with 3.9% in the tourniquet group (odds ratio 1.36; 95% CI 0.60 to 1.65; p = 0.452). After multivariable analysis, the use of tourniquets was found to be independently associated with survival (adjusted odds ratio 5.86; 95% CI 1.41 to 24.47; adjusted p = 0.015). Delayed amputation rates were not significantly different between the 2 groups (1.1% vs 1.1%; adjusted odds ratio 1.82; 95% CI 0.36 to 9.99; adjusted p = 0.473). CONCLUSIONS: Although still underused, civilian prehospital tourniquet application was independently associated with a 6 fold mortality reduction in patients with peripheral vascular injuries. More aggressive prehospital application of extremity tourniquets in civilian trauma patients with extremity hemorrhage and traumatic amputation is warranted. PMID- 29605727 TI - Abnormal High-Resolution Manometry Findings and Outcomes after Paraesophageal Hernia Repair. AB - BACKGROUND: Abnormal esophageal peristalsis diagnosed by high-resolution manometry is frequently found as part of the preoperative evaluation of patients with paraesophageal hernia (PEH). Currently, the clinical relevance of these findings is largely unknown. STUDY DESIGN: From 2013 to 2016, two hundred and twelve patients undergoing PEH repair were prospectively recorded in an IRB approved database. Preoperative high-resolution manometry was available for reanalysis according to the latest Chicago Classification (version 3.0) in 200 patients. Outcomes in patients with abnormal motility (AM) were compared with patients with normal motility (NM). RESULTS: Abnormal motility was documented in 106 (53%) patients. Abnormal motility was associated with older age (72 vs 69 years) and increased age-adjusted Charlson Comorbidity Index (both, p = 0.04). Compared with preoperative symptoms, postoperative retrosternal pain in AM vs NM patients went from 79% to 5% vs 75% to 2%, regurgitation from 52% to 2% vs 59% to 0%, and dysphagia from 56% to 7% vs 67% to 7%. An esophagogram was performed at a median of 4 months and 3.5 months postoperatively. Postoperative reflux in AM vs NM went from 54% to 21% vs 57% to 16%, and abnormal esophageal motility, visually assessed during the esophagogram, was stable (52% to 56% vs 41% to 48% for AM vs NM, respectively). CONCLUSIONS: Patients found to have AM according to the Chicago classification before surgical repair of PEH demonstrated similar symptomatic improvement compared with patients with NM. Selective motility disorders diagnosed by preoperative high-resolution manometry should not preclude surgical repair of giant PEHs. PMID- 29605728 TI - The L83L ORF of African swine fever virus strain Georgia encodes for a non essential gene that interacts with the host protein IL-1beta. AB - African swine fever virus (ASFV) causes a contagious and frequently lethal disease of pigs causing significant economic consequences to the swine industry. The ASFV genome encodes for more than 150 genes, but only a few of them have been studied in detail. Here we report the characterization of open reading frame L83L which encodes a highly conserved protein across all ASFV isolates. A recombinant ASFV harboring a HA tagged L83L protein was developed (ASFV-G-L83L-HA) and used to demonstrate that L83L is a transiently expressed early virus protein. A recombinant ASFV lacking the L83L gene (ASFV-G-DeltaL83L) was developed from the highly virulent field isolate Georgia2007 (ASFV-G) and was used to show that L83L is a non-essential gene. ASFV-G-DeltaL83L had similar replication in primary swine macrophage cells when compared to its parental virus ASFV-G. Analysis of host-protein interactions for L83L identified IL-1beta as its host ligand. Experimental infection of domestic pigs showed that ASFV-G-DeltaL83L is as virulent as the parental virus ASFV-G. PMID- 29605729 TI - Sogatella furcifera hepe-like virus: First member of a novel Hepeviridae clade identified in an insect. AB - A novel virus was identified in the white-backed planthopper (Sogatella furcifera, Hemiptera: Delphacidae) and tentatively named Sogatella furcifera hepe like virus (SfHeV). Its genome is a linear, single-stranded monopartite RNA, 7,312 nucleotides (nt) long with a 66-nt 5' UTR, 54-nt 3' UTR, and 28-nt polyA, showing typical genomic features of viruses in the family Hepeviridae, but highly divergent from known members in the family, with amino acid sequence identities of only 18.9-23% (ORF1), 13.1-18.8% (ORF2) and 1.9-11% (ORF3). Phylogenetic analysis revealed that SfHeV was closer to cutthroat trout virus (CTV), but did not cluster with any members of the family. SfHeV is the first hepe-like virus identified in a hemipteran insect and was detected in all developmental stages suggesting the presence of some level of vertical transmission. On the basis of these data, we propose that SfHeV represents a novel clade in the family Hepeviridae and tentatively name the genus Insecthepevirus. PMID- 29605730 TI - Metabotropic glutamate receptors: targets for neuroprotective therapies in Parkinson disease. AB - Metabotropic glutamate receptors (mGluRs) are heavily expressed throughout the basal ganglia (BG), where they modulate neuronal excitability, transmitter release and long term synaptic plasticity. Therefore, targeting specific mGluR subtypes by means of selective drugs could be a possible strategy for restoring normal synaptic function and neuronal activity of the BG in Parkinson disease (PD). Preclinical studies have revealed that specific mGluR subtypes mediate significant neuroprotective effects that reduce toxin-induced midbrain dopaminergic neuronal death in animal models of PD. Although the underlying mechanisms of these effects must be further studied, there is evidence that intracellular calcium regulation, anti-inflammatory effects, and glutamatergic network modulation contribute to some of these neuroprotective properties. It is noteworthy that these protective effects extend beyond midbrain dopaminergic neurons to include other monoaminergic cell groups for some mGluRs. In this review, we discuss evidence for mGluR-mediated neuroprotection in PD and highlight the challenges to translate these findings into human trials. PMID- 29605731 TI - Phylogenomic Analysis of Nassula variabilis n. sp., Furgasonia blochmanni, and Pseudomicrothorax dubius Confirms a Nassophorean Clade. AB - The class Nassophorea includes the microthoracids and nassulids, which share morphological similarities in their somatic kinetids and cytopharyngeal baskets. The monophyly of this clade has been challenged by small subunit rRNA gene sequences and multi-gene analyses that do not provide strong support. To provide a more robust test of the monophyly of the Nassophorea, phylogenomic analyses were based on 124 genes derived from the single-cell transcriptomes of the microthoracid Pseudomicrothorax dubius and the nassulid Furgasonia blochmanni. The nassulid Nassula sorex from the Culture Centre for Algae and Protozoa was also included, but this isolate was discovered to have been misidentified. We first redescribe, using light and scanning electron microscopical techniques, this "N. sorex" as a new species of Nassula, Nassula variabilis n. sp., characterized by its highly variable nassulid frange. We have sequenced the single-cell transcriptomes to obtain data for phylogenomic analyses. These gave robust support for the Nassophorea, which are sister to a clade of Colpodea species. If our topology truly represents the order of divergence of taxa, a cytopharyngeal basket with microtubular nematodesmata and with Y and Z microtubular ribbons was likely an ancestral feature, at least of the Phyllopharyngea, Colpodea, Nassophorea, and Oligohymenophorea. PMID- 29605732 TI - Bradykinin-potentiating PEPTIDE-10C, an argininosuccinate synthetase activator, protects against H2O2-induced oxidative stress in SH-SY5Y neuroblastoma cells. AB - Bradykinin-potentiating peptides (BPPs - 5a, 7a, 9a, 10c, 11e, and 12b) of Bothrops jararaca (Bj) were described as argininosuccinate synthase (AsS) activators, improving l-arginine availability. Agmatine and polyamines, which are l-arginine metabolism products, have neuroprotective properties. Here, we investigated the neuroprotective effects of low molecular mass fraction from Bj venom (LMMF) and two synthetic BPPs (BPP-10c, 500 Da) region. The EEM fluorescence spectra showed that aromatic compounds accounted for a large proportion of the sampled EfOM based on the fluorescence regional integration technique. The abovementioned analysis highlights the similarities in the characteristics of the EfOM originating from different coking WTPs, regardless of treatment plant design. Meanwhile, significant differences between the characteristics of the EfOM in coking wastewater and municipal wastewater were observed. PMID- 29605751 TI - Antioxidant and enzymatic responses to oxidative stress induced by cold temperature storage and ripening in mango (Mangifera indica L. cv. 'Cogshall') in relation to carotenoid content. AB - The effects of 15 days of storage at 12 degrees C and 7 degrees C followed by fruit ripening at 20 degrees C on oxidative status, antioxidant defense systems and carotenoid accumulation were studied for two successive years in mango fruits (Mangifera indica L.) cv. Cogshall. Changes in the non-enzymatic (ascorbate) and enzymatic (SOD, CAT, APX, MDHAR, DHAR and GR) antioxidant systems, as well as oxidative parameters (H2O2 and MDA) and the contents of the major carotenoids were measured for three maturity stages, at harvest and after ripening following cold temperature storage. In control conditions (20 degrees C), ripening induced an increase in oxidation resulting in ROS production and a decrease in ascorbate content. Fruit tissue protection was activated by means of antioxidant and ascorbate regeneration enzyme systems. Carotenoid accumulated exponentially during ripening. Storage at low temperatures increased respiration crisis intensity and therefore increased oxidation in the fruit pulp. Fruit response to this increase varied according to the maturity stage, i.e., enzymatic responses in younger fruits were very low in comparison to the control, whereas second harvest fruits had a significantly higher degree of enzymatic activity to cope with the oxidative stress. Carotenoid contents decreased with low temperatures and first harvest fruits showed significantly lower values than the control, in opposition to second harvest fruits that appeared not to be affected. We also suggest that, based on a review of the literature, a link can be made between antioxidant system defense and carotenoid metabolism since ROS seems to play a central role as a stress signal in plants. PMID- 29605752 TI - Incidence and risk factor of deep venous thrombosis in patients undergoing craniotomy for brain tumors: A Japanese single-center, retrospective study. AB - INTRODUCTION: It has been reported that brain tumor resection by craniotomy is a high risk for deep venous thrombosis (DVT), though few data is available in Japanese patients. The aim of this retrospective study was to evaluate the incidence and risk factors for DVT in Japanese adult patients with brain tumor surgery. MATERIALS AND METHODS: Medical records of Japanese adult patients with craniotomy for brain tumor were reviewed. In addition to clinical variables including patients' age, sex, body mass index, previous history of DVT, leg paresis, medications, tumor histology, surgical factors, adjuvant therapy, infection, and duration of post-operative immobilization and hospitalization, plasma D-dimer levels were measured at pre-surgery (baseline), on post-operative day (POD) one to 30 and during adjuvant therapy, and were compared between patients with and without DVT. RESULTS: Thirteen of 61 patients (21.3%) had DVT after surgery with mechanical prophylaxis. All DVTs were asymptomatic. Multivariate analyses found post-operative infection (odds ratio, 12.15; 95% confidence interval, 1.09-134.98; P = 0.03) to be a sole independent risk factor for DVT. D-dimer levels were not significantly different between patients with and without DVT at baseline and POD 1-30, but were significantly elevated during adjuvant therapy in patients with DVT (P = 0.03). CONCLUSIONS: Not a few Japanese patients developed DVT after brain tumor surgery with mechanical prophylaxis, and patients with infection should be carefully monitored for post-operative DVT. PMID- 29605753 TI - Evaluation of a midwifery initiated oral health-dental service program to improve oral health and birth outcomes for pregnant women: A multi-centre randomised controlled trial. AB - BACKGROUND: Oral health care during pregnancy is important for the health of the mother and child. However, pregnant women have limited knowledge about maternal oral health and seldom seek dental care. Further, due to limited training antenatal care providers like midwives rarely discuss oral health with pregnant women. The Midwifery-Initiated Oral Health Dental Service program was developed to address current gaps in oral promotional interventions during pregnancy. OBJECTIVES: To assess the effectiveness of a Midwifery-Initiated Oral Health Dental Service program in improving uptake of dental services, oral health knowledge, quality of oral health, oral health status and birth outcomes of pregnant women. DESIGN: Multi-centre randomised controlled trial. SETTING: Three large metropolitan public hospitals in Sydney, Australia. PARTICIPANTS: Pregnant women attending their first antenatal appointment who were at least 18 years old and had a single low risk pregnancy between 12 and 20 weeks gestation. METHODS: 638 pregnant women were allocated to three groups using block randomisation (n = 211) control group, intervention group 1 (n = 215), intervention group 2 (n = 212) and followed up till birth. Study investigators and data collectors were blinded to group allocation. Intervention group 1 received a midwifery intervention from trained midwives involving oral health education, screening and referrals to existing dental pathways. Intervention group 2 received the midwifery intervention and a dental intervention involving assessment/treatment from cost free local dental services. The control group received oral health information at recruitment. Primary outcome was uptake of dental services. Secondary outcomes included oral health knowledge, quality of oral health, oral health status and birth outcomes. RESULTS: Substantial improvements in the use of dental services (20.2% Control Group; 28.3% Intervention group 1; 87.2% Intervention group 2; Odds Ratio Intervention group 2 vs Control Group = 29.72, 95% CI 15.02-58.53, p < 0.001), women's oral health knowledge (p = 0.03); quality of oral health (p < 0.001) and oral health outcomes (sulcus bleeding, dental plaque, clinical attachment loss, decayed/filled teeth- p < 0.001) were found in Intervention group 2. No difference in the rate of preterm or low-birth weight was found. CONCLUSIONS: The Midwifery-Initiated Oral Health Dental Service program (Intervention group 2) improved the uptake of dental services and oral health of pregnant women and is recommended during antenatal care. A cause and effect relationship between this intervention and improved birth outcomes was not supported. PMID- 29605754 TI - Interventions to prevent and reduce the impact of musculoskeletal injuries among nurses: A systematic review. AB - BACKGROUND: Musculoskeletal injuries and musculoskeletal pain are prevalent among nurses compared to many other occupational groups. OBJECTIVE: To identify interventions that may be effective at reducing the prevalence and impact of musculoskeletal injuries and pain in registered nurses. DESIGN: Systematic review. DATA SOURCES: Seven databases were systematically searched, including MEDLINE, CINAHL, EMBASE, PsycInfo, Academic Search Complete, Health Source Nursing, and the Cochrane Database of Systematic Reviews. REVIEW METHODS: Peer reviewed journal articles reporting interventions designed to reduce the occurrence of musculoskeletal injuries and pain among registered nurses, published between January 2004 and June 2016, were eligible for inclusion. Randomised and non-randomised controlled trials, as well as studies implementing before-after designs were included. Studies investigating interventions in samples predominately comprised of nursing aides or non-nursing personnel were excluded. Relevant articles were collected and critically analysed using the Effective Public Health Practice Project methodology. Two reviewers independently extracted data and performed quality appraisals for each study. A narrative synthesis of study findings was performed. RESULTS: Twenty studies met criteria for inclusion in the review. Types of interventions reported included: patient lift systems (N = 8), patient handling training (N = 3), multi-component interventions (N = 7), cognitive behavioural therapy (N = 1), and unstable shoes (N = 1). Only two studies received a 'strong' quality rating according to quality assessment criteria. One of these found no evidence for the effectiveness of patient handling training; the other found preliminary support for unstable shoes reducing self-reported pain and disability among nurses. Overall, evidence for each intervention type was limited. CONCLUSIONS: There is an absence of high quality published studies investigating interventions to protect nurses from musculoskeletal injuries and pain. Further research (including randomised controlled trials) is needed to identify interventions that may reduce the high rates of injury and pain among nurses. PMID- 29605755 TI - Family ethnic socialization predicts better academic outcomes via proactive coping with discrimination and increased self-efficacy. AB - As the U.S. Latino youth population grows, understanding how family and individual resources may promote Latino adolescents' academic outcomes is important. The current investigation examined whether family ethnic socialization predicted adolescents' use of proactive strategies for coping with ethnic-racial discrimination and examined a potential pathway through which these contextual and individual resources may relate to educational outcomes. Drawing on data from a sample of Latino adolescents (n = 321; Mage = 15.31 years, SD = .76; 49.5% female), results of a cross-sectional structural equation model showed a double mediation of the relation between family ethnic socialization and GPA by proactive coping strategies and self-efficacy. Alternate models, limitations of the current investigation, and implications for future research are discussed. PMID- 29605756 TI - A modified technique for the application of ultrasound-guided costoclavicular brachial plexus block for elbow surgery leading to differential block. PMID- 29605758 TI - Electrophysiological activity is associated with vulnerability of Internet addiction in non-clinical population. AB - This study investigated the electrophysiological activity associated with vulnerability of problematic Internet use in non-clinical population. The resting EEG spectrum of alpha (8-13 Hz) rhythm was measured in 22 healthy subjects who have used the Internet for recreational purpose. The vulnerability of Internet addiction was assessed using Young's Internet Addiction Test (IAT) and Assessment for Computer and Internet Addiction-Screener (AICA-S) respectively. Depression and impulsivity were also measured with Beck Depression Inventory (BDI) and Barratt Impulsiveness Scale 11(BIS-11) respectively. The IAT was positively correlated with alpha power obtained during eyes closed (EC, r = 0.50, p = 0.02) but not during eyes open (EO). This was further supported by a negative correlation (r = -0.48, p = 0.02) between IAT scores and alpha desynchronization (EO-EC). These relationships remained significant following correction for multiple comparisons. Furthermore, The BDI score showed positive correlation with alpha asymmetry at mid-lateral (r = 0.54, p = 0.01) and mid-frontal (r = 0.46, p = 0.03) regions during EC, and at mid-frontal (r = 0.53, p = 0.01) region during EO. The current findings suggest that there are associations between neural activity and the vulnerability of problematic Internet use. Understanding of the neurobiological mechanisms underlying problematic Internet use would contribute to improved early intervention and treatment. PMID- 29605757 TI - Smoking-related health beliefs and smoking behavior in the National Lung Screening Trial. AB - Understanding the association between smoking-related health beliefs and smoking cessation in the context of lung screening is important for effective cessation treatment. The purpose of the current study is to explore how current smokers' self-reported smoking-related health cognitions (e.g., self-efficacy) and emotions (e.g., worry) are related to cessation. This study utilized longitudinal data from current smokers (age 55-74) in a sub-study of the National Lung Screening Trial (NLST; 2002-2006; N = 2738). Logistic regression analyses examined associations of cessation at last assessment with smoking-related health cognitions and emotions, demographics, and two-way interactions among smoking related health cognition and emotion variables, gender, and age. Over 37% (n = 1028) of smokers had quit at their last assessment of smoking status. Simple logistic regressions showed the likelihood of quitting was greater among participants reporting higher perceived severity of smoking-related diseases (OR = 1.17, p = .04), greater self-efficacy for quitting (OR = 1.32, p < .001), and fewer perceived barriers to quitting (OR = 0.82, p = .01). Likelihood of quitting was lower among non-Hispanic Black participants (versus non-Hispanic White participants) (OR = 0.68, p = .04) and higher among older participants (OR = 1.03, p = .002). Multiple logistic regression showed that participants reporting greater self-efficacy for quitting (B = 0.09, p = .05), fewer perceived barriers to quitting (B = -0.22, p = .01), and who were older (B = 0.03, p < .01) were more likely to quit smoking. These results suggest that, among heavy smokers undergoing lung screening, smoking-related health cognitions and emotions are associated with smoking cessation. These health beliefs must be considered an integral component of cessation in screening settings. PMID- 29605759 TI - Time cost of child rearing and its effect on women's uptake of free health checkups in Japan. AB - Women of child-rearing age have the lowest uptake rates for health checkups in several developed countries. The time cost incurred by conflicting child-rearing roles may contribute to this gap in access to health checkups. We estimated the time cost of child rearing empirically, and analyzed its potential impact on uptake of free health checkups based on a sample of 1606 women with a spouse/partner from the dataset of a population-based survey conducted in the greater Tokyo metropolitan area in 2010. We used a selection model to estimate the counterfactual wage of non-working mothers, and estimated the number of children using a simultaneous equation model to account for the endogeneity between job participation and child rearing. The time cost of child rearing was obtained based on the estimated effects of women's wages and number of children on job participation. We estimated the time cost to mothers of rearing a child aged 0-3 years as 16.9 USD per hour, and the cost for a child aged 4-5 years as 15.0 USD per hour. Based on this estimation, the predicted uptake rate of women who did not have a child was 61.7%, while the predicted uptake rates for women with a child aged 0-3 and 4-5 were 54.2% and 58.6%, respectively. These results suggest that, although Japanese central/local governments provide free health checkup services, this policy does not fully compensate for the time cost of child rearing. It is strongly recommended that policies should be developed to address the time cost of child rearing, with the aim of closing the gender gap and securing universal access to preventive healthcare services in Japan. PMID- 29605761 TI - Validation of the evaluation capacity in organizations questionnaire. AB - The purpose of this study was to test the construct validity of the Evaluation Capacity in Organizations Questionnaire (ECOQ). Conceptually, the ECOQ examines the role of evaluation in organizational development and, most notably in organizational learning. In this model, evaluation capacity building (ECB) initiatives are assumed to contribute to the development of a culture of systematic self-assessment and reflection, which, in turn, leads to increased organizational learning. Our sample consisted of internal evaluators within the federal, provincial or municipal government, not-for-profit organizations, private firms, and colleges or universities in Canada. Exploratory factor analysis (EFA) and latent path analysis (LPA) were conducted to better understand the underlying structural aspect of the organizational capacity to do and use evaluation construct as measured by the ECOQ. The results of our study indicate that the ECOQ effectively assesses an organization's capacity to do and use evaluation. Furthermore, evidence provided by the LPA statistical analysis suggests that an organization's capacity to learn is enhanced by the relationships among the various factors. Implications of using a validated model of an organization's capacity to do and use evaluations in both research and practice are discussed. PMID- 29605760 TI - Next generation natural killer cells for cancer immunotherapy: the promise of genetic engineering. AB - Recent advances in the field of cellular therapy have focused on autologous T cells engineered to express a chimeric antigen receptor (CAR) against tumor antigens. Remarkable responses have been observed in patients receiving autologous CD19-redirected T cells for the treatment of B-lymphoid malignancies. However, the generation of autologous products for each patient is logistically challenging and expensive. Extensive research efforts are ongoing to generate an off-the-shelf cellular product for the treatment of cancer patients. Natural killer (NK) cells are attractive contenders since they have potent anti-tumor activity, and their safety in the allogeneic setting expands the cell sources for NK cell therapy beyond an autologous one. In this review, we discuss advantages and limitations of NK cellular therapy, and novel genetic engineering strategies that may be applied to overcome some of the limitations. Next-generation engineered NK cells are showing great promise in the preclinical setting and it is likely that in the next few years CAR-engineered NK cells will be incorporated into the current armamentarium of cell-based cancer therapeutics. PMID- 29605762 TI - Is Participatory Action Research an innovative pedagogical alternative for training teachers as researchers? The training plan and evaluation for normal schools. AB - Normal schools in Mexico train teachers for basic level education. Classified as Higher Education Institutions, part of their mandate is to conduct scientific research to improve educational quality. Currently, normal school students can meet graduation requirements by either writing a thesis or reporting on professional practice using Participatory Action Research (PAR). Teachers at normal schools have only limited experience in conducting and supervising PAR projects. With the aim of analyzing the situation and addressing this paradox, we used PAR to develop a plan to train normal school teachers in application of PAR methodology. We present the training proposal and evaluate its results in a pilot phase. These suggest that PAR represents an innovative option for training teachers to conduct research and therefore fulfill part of their responsibilities at normal schools in Mexico. Changes in institutional culture and structure would be required for successful implementation of PAR in this context. PMID- 29605763 TI - Analogous corticosteroids, 9A and EK100, derived from solid-state-cultured mycelium of Antrodia camphorata inhibit proinflammatory cytokine expression in macrophages. AB - Antrodia camphorata mycelium is used in traditional Chinese medicine in Taiwan. The wild-type mycelium is rare and expensive, so a solid-state-cultured mycelium of A. camphorata (SCMAC) has been developed. Previous studies have found SCMAC to have anti-inflammatory effects. However, the immunomodulatory effects of SCMAC and of its active phytosterol compounds EK100 and 9A on asthma remain unknown. In this study, BALB/c mice were repeatedly exposed to Dermatogoides pteronyssinus (Der p) at 1-week intervals and were orally administered crude SCMAC extract before the Der p challenge. The mice were sacrificed 72 h after the last challenge to examine the airway remodeling, inflammation, and expression profiles of cytokines and various genes. Then, 30-ug/mL Der p-stimulated MH-S cells with 9A or EK100 were collected for real-time PCR analysis, and the effects of 9A and EK100 on macrophages were evaluated. The crude extract reduced Der p-induced airway hyperresponsiveness, total serum immunoglobulin E levels, and recruitment of inflammatory cells to the bronchoalveolar lavage fluid through cytokine downregulation and Th1/Th2/Th17 response modulation. Additionally, 9A and EK100 inhibited IL-1beta and IL-6 expression in alveolar macrophages. These results indicate that the pharmacologically active compounds in a crude SCMAC extract exert synergistic effects on multiple targets to relieve asthma symptoms. PMID- 29605764 TI - The potency of commercial blackcurrant juices to induce relaxation in porcine coronary artery rings is not correlated to their antioxidant capacity but to their anthocyanin content. AB - OBJECTIVE: Polyphenol-rich products such as fruit juices have been found to have strong antioxidant capacities and to induce potent endothelium-dependent relaxation. We evaluated whether the commercial blackcurrant juices induced endothelium-dependent relaxation of isolated coronary arteries can be related to their antioxidant capacity and/or phenolic content. METHODS: Six different commercial blackcurrant juices were selected. Their main phenolic compounds were measured by ultra-performance liquid chromatography and antioxidant capacity was evaluated by spectrometric methods. Vascular reactivity studies with these juices were done using isolated porcine coronary arteries. RESULTS: The six different commercial blackcurrant juices induced relaxation ranging from 21% to 100% at the concentration of 0.5% volume per volume (v/v). The relaxation induced at 0.5% v/v was not correlated to their antioxidant capacity measured by either oxygen radical antioxidant capacity or DPPH (2,2-diphenyl-1-picrylhydrazyl) assays and also not to the ascorbic acid, total polyphenols, total flavanols, and total phenolic acid contents. In contrast, the amplitude of the relaxation was correlated to the total anthocyanins content and the individual anthocyanin concentration. CONCLUSIONS: Correlations between relaxation amplitude and total anthocyanin or individual anthocyanin contents are of interest for the development of functional blackcurrant beverages with the potential to promote vascular protection. PMID- 29605765 TI - Resting energy expenditure and body composition in patients with head and neck cancer: An observational study leading to a new predictive equation. AB - OBJECTIVES: Patients with head and neck cancer have changes in body composition and resting energy expenditure (REE) related to significant inflammatory processes. We investigated REE and body composition in a population of patients with head and neck cancer, comparing the measured REE with predicted energy expenditure and deriving an equation of anthropometric values and body composition. METHODS: This retrospective, observational, descriptive study of a single center included patients with head and neck cancer. We evaluated nutritional status by body mass index (BMI) and Patient-Generated Subjective Global Assessment (PG-SGA), body composition by electric bioimpedance, and REE by indirect calorimetry (IC). RESULTS: We included 140 patients, most of whom were men (80.7%), 60 y or older (58.6%), and had advanced disease (77.9%). Most were malnourished by BMI standards (77.9%) and severely malnourished according to the PG-SGA (49.3%), with a fat-free mass below the ideal values (82.9%) associated with sarcopenia (92.1%). Hypermetabolism was 57%. When comparing REE with the Harris-Benedict formula, we found the agreement limits from -546 613 to 240 708, the mean difference was -152 953 (95% confidence interval [CI], -185 844 to -120 062) and Pitman's variance test was r = -0.294 (P = 0.001). When we included the activity factor and the thermogenesis factor in REE and compared with Harris Benedict, we found the agreement limits from -764.423 to 337.087, a mean difference of -213.668 (95% CI -259.684 to -167.652), and the Pitman's variance text at r = -0.292 (P = 0.001). CONCLUSION: Predictive equations, generally recommended by guidelines, are imprecise when compared with IC measures. Therefore, we suggest a new predictive equation. PMID- 29605766 TI - The benefits of soluble non-bacterial fraction of kefir on blood pressure and cardiac hypertrophy in hypertensive rats are mediated by an increase in baroreflex sensitivity and decrease in angiotensin-converting enzyme activity. AB - OBJECTIVES: We aimed to evaluate whether long-term treatment with the soluble non bacterial fraction of kefir affects mean arterial pressure (MAP) and cardiac hypertrophy through the modulation of baroreflex sensitivity, ACE activity, and the inflammatory-to-anti-inflammatory cytokine ratio in spontaneously hypertensive rats (SHRs). METHODS: SHRs were treated with the soluble non bacterial kefir fraction (SHR-kefir) or with kefir vehicle (SHR-soluble fraction of milk). Normotensive control Wistar Kyoto animals received the soluble fraction of milk. All treatments were administered by gavage (0.3 mL/100g/body weight), once daily for eight weeks. At the end, after basal MAP and Heart Rate (HT) measurement, barorreflex sensitivity was evaluated through in bolus administrations of sodium nitroprusside and phenylephrine (AP50 [arterial pressure 50%], the lower plateau, and HR range were measured). ACE activity and cytokines (TNF-alpha and IL-10) were evaluated by ELISA. Cardiac hypertrophy was analysed morphometrically. RESULTS: Compared to SHR control, SHR-kefir exhibited a significant decrease in both MAP (SHR: 184 +/- 5; SHR-Kefir: 142 +/- 8 mmHg), and HR (SHR: 360 +/- 10; SHR-kefir: 310 +/- 14 bpm). The non-bacterial fraction of kefir also reduced cardiac hypertrophy, TNF-alpha-to-IL10 ratio, and ACE activity in SHRs. SHR-kefir baroreflex sensitivity, resulted in a partial but significant recovery of baroreflex gain, as demonstrated by improvements in AP50, the lower plateau, and HR range. CONCLUSION: In summary, our results indicate that long-term administration of the non-bacterial fraction of kefir promotes a significant decrease in both MAP and HR, by improving baroreflex, and reduces cardiac hypertrophy in SHRs, likely via ACE inhibition, and reduction of the TNF alpha-to-IL10 ratio. PMID- 29605767 TI - The psoas muscle transversal diameter predicts mortality in patients with cirrhosis on a waiting list for liver transplantation: A retrospective cohort study. AB - OBJECTIVE: Malnutrition impairs prognosis in liver cirrhosis. Our aims were to determine (1) if transversal (TPTI) and axial (APTI) psoas thickness indices predict mortality in cirrhotic patients and (2) the feasibility and reproducibility of transversal (TDPM) and axial (ADPM) diameters of the psoas muscle measurements. METHODS: This was a retrospective study. Inclusion criteria included cirrhosis diagnosis, on liver transplantation waiting list, and abdominal computed tomography (CT) scan within the 3 mo preceding list inscription. TDPM and ADPM were measured on a single umbilicus-targeted CT image by non-expert and expert operators. TPTI or APTI (mm/m) were calculated as TDPM or ADPM/height (m). Area under the receiver operating characteristic curve (AUC) and Cox proportional hazard models were assessed. TPTI and APTI interobserver agreement: kappa correlation test. RESULTS: A total of 173 patients were included. Low TPTI was associated with increased mortality: AUC = 0.66 (95% confidence interval, 0.51-0.80). TPTI was the only factor associated with mortality (hazard ratio = 0.87, 95% confidence interval 0.76-0.99, P = 0.034). There was an almost perfect interobserver agreement between the two operators: TDPM, kappa = 0.97; ADPM, kappa = 0.94; P <0.0001. CONCLUSIONS: TPTI measured on umbilicus-targeted CT scan before inscription on the waiting list for liver transplantation predicts mortality of cirrhotic patients. TPTI measurement is easy and reliable, even by a non-trained operator, and this is highly feasible in daily clinical practice. PMID- 29605768 TI - Perinatal exposure to energy drink induces oxidative damage in the liver, kidney and brain, and behavioral alterations in mice offspring. AB - The worldwide consumption of energy drinks (EDs) has increased in recent years. EDs have several side effects and can be linked to liver injury, kidney damage and risk-seeking behavior. The impact of perinatal consumption of EDs on the newborns has not been previously investigated. In this study, we evaluated the effects of perinatal exposure to a caffeinated ED on the liver, kidney, brain, locomotor activity and anxiety in mice newborns. Pregnant mice received 2.5 or 5 ml ED by oral gavage from the first day of pregnancy until day 15 after birth. Perinatal exposure to the ED induced a significant increase in lipid peroxidation and declined antioxidant defenses in the liver, kidney, cerebrum, cerebellum and medulla oblongata of the newborns at days 21 and 35 after birth. ED induced several histological alterations, including vacuolations and lipid infiltration of hepatocytes, developing and degenerated glomeruli and dilated urinary spaces in the renal cortex, pyknosis and chromatolysis of the cerebral and medullary neurons, and degenerated and abnormal Purkinje cells in the cerebellum. In addition, ED increased the locomotion and induced anxiety-like behavior in mice newborns. In conclusion, perinatal exposure to EDs induces oxidative stress, tissue injury and behavioral alterations in the mice newborns. Therefore, the consumption of EDs during pregnancy and lactation has a negative impact on the newborns and should be treated as a significant health problem that warrants attention. PMID- 29605769 TI - Phytochemicals-induced hormesis protects Caenorhabditis elegans against alpha synuclein protein aggregation and stress through modulating HSF-1 and SKN-1/Nrf2 signaling pathways. AB - Mild stress activates the adaptive cellular response for the subsequent severe stress called hormesis. Hormetic stress plays a vital role to activate multiple stress-responsive genes for the benefit of an organism. In tropical regions of world, tubers of Dioscorea spp. has been extensively used in folk medicine and also consumed as food. In this study, we report that the phytochemicals of Dioscorea alata L., tubers extends the lifespan of nematode model Caenorhabditis elegans by hormetic mechanism. We showed that the low dose of tubers extract at 200 and 300 MUg/mL extends the mean lifespan of wild-type worms, whereas higher doses are found to be toxic. Supplementation of tubers extract slightly increased the intracellular ROS in second-day adult worms and it might activate the adaptive stress response, which protects the worms from oxidative and thermal stress. Transgenic reporter gene expression assay showed that extract treatment enhanced the expression of stress protective genes such as hsp-16.2, hsp-6, hsp 60 and gst-4. Further studies proved that the transcription factors HSF-1 and SKN 1/Nrf2 were implicated in hormetic stress response of the worms. Moreover, pretreatment of extract reduced the high glucose-mediated lipid accumulation by enhancing the expression of glyoxalase-1. It was also found that the aggregation of Parkinson's related protein alpha-synuclein reduced in the transgenic strain NL5901 and extended its lifespan. Finally, our results concluded that the presences of hormetic dietary phytochemicals in tubers might drive the stress response in C. elegans via HSF-1 and SKN-1/Nrf2 signaling pathways. PMID- 29605770 TI - p-Coumaric acid mediated protection of H9c2 cells from Doxorubicin-induced cardiotoxicity: Involvement of augmented Nrf2 and autophagy. AB - Doxorubicin (Dox) is a widely administered chemotherapeutic drug and incidences of cardiotoxicity associated with its administration have been of general concern. Extensive research proposes several mechanisms as a cause of Dox induced cardiotoxicity. However, none of these studies have been able to suggest a find one, cure all antidote for the same. To this end, several studies involving plant based compounds or natural products have gained acclaim for their ability to address at least one factor contributing to drug induced pathogenesis. We had previously reported that p-coumaric (pCA) has a protective effect on Dox induced oxidative stress in rat-derived cardiomyoblasts. In this study we investigated the effects of pCA on the regulation of Nrf-2, mitochondrial viability, autophagy and apoptosis in Doxorubicin treated H9c2 cardiomyocytes. ROS induced mitochondrial stress, changes in mitochondrial membrane potential, loss of membrane integrity; nuclear damage as single/double stranded breaks, autophagy and the effects of pre and co-treatment of pCA on Nrf-2 mediated signaling was evaluated by various approaches. The effect of pCA on drug uptake was evaluated through confocal Raman Spectroscopy. We find that nuclear translocation of Nrf-2 is prominently marked by protein-specific antibody conjugated fluorophore in Dox treated cells especially. Cell survival is mediated to a certain extent by the expression of the anti-apoptotic BCl2 in pCA treated cells. However, mRNA levels of autophagy related (Atg) genes suggest that autophagy plays a decisive role in deciding cellular fate. Caspase-3 activation is also observed in pCA treated cells which suggest an alternative function of caspase-3 in pCA mediated cell survival. Expression of antioxidant enzymes confirm the oxidative stress induced by Dox treatment in cells and the modulation of cell redox homeostasis through treatment with pCA. PMID- 29605771 TI - The dipeptidyl peptidase-4 (DPP-4) inhibitor sitagliptin ameliorates retinal endothelial cell dysfunction triggered by inflammation. AB - : Diabetic retinopathy is considered a low-grade chronic inflammatory disease and several inflammatory molecules, including tumor necrosis factor (TNF)-alpha, are known to play a major role in the degeneration of retinal capillaries. Previous studies have reported that sitagliptin, a DPP-4 inhibitor, prevents the increase in blood-retinal barrier (BRB) permeability and inhibits the tight junction disassembly induced by diabetes. AIM: Our goal was to investigate whether sitagliptin is able to prevent retinal endothelial cells (EC) dysfunction triggered by the pro-inflammatory cytokine TNF-alpha. MAIN METHODS: The effects of TNF-alpha and/or sitagliptin on primary cultures of bovine retinal EC were tested. The EC monolayer permeability was analyzed by using 70 kDa rhodamine isothiocyanate (RITC) dextran. The cellular distribution profile of claudin-5 was examined by immunofluorescence staining, and DPP-4 activity was evaluated by using a fluorogenic substrate. Cell viability was assessed by MTT assay, and cell proliferation by the BrdU incorporation assay. Retinal EC migration and angiogenesis were evaluated by a scratch assay and a capillary tube formation in matrigel assay, respectively. KEY FINDINGS: TNF-alpha increased the permeability of EC monolayer and induced the loss of claudin-5 immunostaining at the cell borders. This impairment was associated with decreased migration and capillary morphogenesis of retinal EC. Sitagliptin was unable to prevent the effect of TNF alpha on EC permeability. However, it decreased DPP-4 activity in bovine retinal EC exposed to TNF-alpha, without affecting cell viability. Moreover, sitagliptin enhanced the migration and capillary morphogenesis in bovine retinal EC challenged with TNF-alpha. SIGNIFICANCE: These results suggest that sitagliptin is able to positively modulate vascular EC function under conditions of retinal inflammation. PMID- 29605772 TI - NOS1 mediates AP1 nuclear translocation and inflammatory response. AB - A hallmark of the AP1 functioning is its nuclear translocation, which induces proinflammatory cytokine expression and hence the inflammatory response. After endotoxin shock AP1 transcription factor, which comprises Jun, ATF2, and Fos family of proteins, translocates into the nucleus and induces proinflammatory cytokine expression. In the current study, we found, NOS1 inhibition prevents nuclear translocation of the AP1 transcription factor subunits. Pharmacological inhibition of NOS1 impedes translocation of subunits into the nucleus, suppressing the transcription of inflammatory genes causing a diminished inflammatory response. In conclusion, the study shows the novel mechanism of NOS1 mediated AP1 nuclear translocation, which needs to be further explored. PMID- 29605773 TI - Peel flour of Passiflora edulis Var. Flavicarpa supplementation prevents the insulin resistance and hepatic steatosis induced by low-fructose-diet in young rats. AB - The increase in fructose consumption in the last decades has an important correlation with the growth of overweight population. Fructose is a monosaccharide found in fruits, vegetables and honey, however, it is widely used in processed food and beverages such as sweeteners. This monosaccharide is metabolized in the liver, so it can produce glucose, lactate, triglycerides, free fatty acids and uric acid, which are responsible for negative effects on the liver and extrahepatic tissues. One effect of the high consumption of fructose is the resistance to Insulin, which appears to be an important issue in the development of metabolic abnormalities observed in animals that were subjected to a high fructose diet. The population and, consequently, the market search for natural sources to manage metabolic abnormalities is increasing, but, adequate scientific proof still is necessary. The Passiflora edulis peel flour (PEPF) is a byproduct of the juice industry, and, represents an important source of fiber and bioactive compounds. The present study investigates the PEPF supplementation (30%) effects on insulin sensitivity, adiposity and metabolic parameters in young rats that were given beverages enriched with 10% of fructose for 8 weeks. Fructose intake induced insulin resistance, increased serum triglycerides levels, growth of fat deposits in the liver and widening of the diameter of adipocytes. In contrast, the group that received PEPF did not present such abnormalities, which could be related to the presence of fiber or bioactive compounds (phenolics compounds, e.g., caffeic acid and isoorientin) in its composition, as identified by analytical methods. Thus, for the first time, it has been demonstrated that PEPF supplementation prevents insulin resistance and hepatic steatosis induced by low-fructose-diet in young rats. PMID- 29605774 TI - Automatic frontal sinus recognition in computed tomography images for person identification. AB - In many cases of person identification the use of biometric features obtained from the hard tissues of the human body, such as teeth and bones, may be the only option. This paper presents a new method of person identification based on frontal sinus features, extracted from computed tomography (CT) images of the skull. In this method, the frontal sinus is automatically segmented in the CT image using an algorithm developed in this work. Next, shape features are extracted from both hemispheres of the segmented frontal sinus by using BAS (Beam Angle Statistics) method. Finally, L2 distance is used in order to recognize the frontal sinus and identify the person. The novel frontal sinus recognition method obtained 77.25% of identification accuracy when applied on a dataset composed of 310 CT images obtained from 31 people, and the automatic frontal sinus segmentation in CT images obtained a mean Cohen Kappa coefficient equal to 0.8852 when compared to the ground truth (manual segmentation). PMID- 29605775 TI - A thoracoabdominal approach for gastrobronchial fistula repair post complicated laparoscopic sleeve gastrectomy. AB - INTRODUCTION: There has been a recent surge in bariatric surgery. Consequently, identification of new complications is imminent. Gastrobronchial fistula is one of the newly identified severe complications. The medical community is yet to come up with a consensus on management, which is further complicated by the lack of literature on par with its rarity. Therefore, we aim to contribute to a better understanding and add to the managerial approach. PRESENTATION OF CASE: We report a case of a 36-year-old female. Post-operative stenting and esophageal dilation was performed. 15 months post LSG patient presented with productive cough with green sputum, food particle and left sided chest pain. Endoscopic clip placement was attempted with no avail. The surgical approach involved posterolateral thoracotomy for left lower lobe resection with debridement of eroded diaphragm. The abdominal cavity was accessed via a medial diaphragmatic incision. The situation necessitated a splenectomy. Singular repair, with omental patch was performed. The jejunum was brought to the site of the fistula and the opening was covered with clean serosa. DISCUSSION: The management of gastrobronchial fistulas involves a comprehensive clinical evaluation. In the absence of red flags, an initial conservative management should be undertaken. When all else fail, surgery is the only route towards a permanent and definitive treatment. CONCLUSION: The need for further research and consensus is of utmost importance to guide future surgeons and to increase awareness among the medical community, due to its presentation under the facade of common symptoms. PMID- 29605776 TI - Asymptomatic gastric diverticulum as incidental radiographic finding after surgery for strangulated inguinal hernia: Report of a case. AB - INTRODUCTION: Gastric diverticula consist a rare form of diverticula of the gastrointestinal tract. They can be described as an "out-pouching" protrusion from the gastric wall. They are usually found in patients aged between 20 and 60 years old. PRESENTATION OF CASE: We present herein a case of an 82 year- old male patient who was admitted to our hospital with a strangulated inguinal hernia and a gastric diverticulum was incidentally found, as a post- operative radiographic finding. DISCUSSION: For symptomatic gastric diverticula, a conservative treatment is usually preferred as first approach with PPIs and soft diet to alleviate the symptoms. Surgical treatment as first approach should be preserved for cases where a connection has been established between the patients' symptoms and the clinical presentation. CONCLUSION: Resection via laparoscopic surgery is nowadays the method of choice for the treatment of gastric diverticula. Open surgery is still performed through a median laparotomy or a subcostal incision. PMID- 29605777 TI - Jejuno-gastric intussusception: A case report of unusual cause of food intolerance after roux-En-Y gastric bypass. AB - INTRODUCTION: Morbid obesity is increasing worldwide as a result, weight loss procedures such as Roux- En-Y gastric bypass (RYGB) are increasing as well. RYGB has multiple complications including intussusception, most of the cases are jejuno-jejunal. Only one case reported to be Jejuno-gastric intussusception (JGI) but through the remnant and not the gastro-jejunostomy anastomosis (GJ). CASE REPORT: A 50-year-old female presented to the emergency department complaining of diffuse abdominal pain, nausea, and vomiting. Her surgical history is significant for an RYGB 17 years ago. Nausea and food intolerance were the most prominent symptoms. CT scan of the abdomen and upper GI series were normal. Only Esophagogastroduodenoscopy (EGD) showed JGI through GJ, with friable mucosa and a small gastro-gastric fistula. Patient underwent successful reconstruction of GJ and had no symptoms afterwards. CONCLUSION: JGI is a rare of cause of abdominal pain, nausea and vomiting after RYGB. Early diagnosis is crucial, a thorough work up is needed to make diagnosis of JGI including EGD. Revision of GJ anastomosis is necessary to address this phenomenon. PMID- 29605778 TI - Cirrhosis following single anastomosis duodeno-ileal switch: A case report. AB - INTRODUCTION: Single anastomosis duodeno-ileal switch (SADI-S) involves a single, loop duodeno-ileal anastomosis with omission of the traditional Roux-en-Y distal ileo-ileal anastomosis. Not much has been published on the complications of SADI S. PRESENTATION OF CASE: The patient is a 40 year-old male who underwent robot assisted SADI-S three years prior. At the time of surgery, his body mass index (BMI) was 69 kg/m2. His BMI was 31 kg/m2 at the time of presentation. Computed tomography of the abdomen and pelvis showed a liver with a nodular appearance and moderate ascites throughout the abdomen and above the liver. Liver function showed AST 73 U/L, ALT 63 U/L, alkaline phosphatase 128 U/L, bilirubin 1.0 mg/dL, and albumin 2.8 g/dL. He underwent diagnostic and therapeutic paracentesis with removal of 6L of fluid that was negative for infection or malignant cells. Esophagogastroduodenoscopy showed grade I esophageal varices and diffuse mild gastritis. DISCUSSION: Mild hepatic dysfunction is common after biliopancreatic diversion and usually manifests as a temporary rise in liver enzymes that peak several months after surgery and normalize by one year. Cirrhosis and liver failure are rare sequelae that may develop at any time after surgery. Potential mechanisms include the absorption of hepatotoxic compounds from the bypassed small intestine in the context of bacterial overgrowth, protein malnutrition, and excessive free fatty acid mobilization causing steatosis and oxidative damage to hepatocytes. CONCLUSION: Close laboratory monitoring is important after SADI-S in order to detect worsening hepatic dysfunction, which may occur many years after the surgery in the absence of other etiologies for liver failure. PMID- 29605779 TI - A systematic comparison of two empirical gas-liquid mass transfer determination methodologies to characterize methane biodegradation in stirred tank bioreactors. AB - This study aimed at systematically comparing the potential of two empirical methods for the estimation of the volumetric CH4 mass transfer coefficient (klaCH4), namely gassing-out and oxygen transfer rate (OTR), to describe CH4 biodegradation in a fermenter operated with a methanotrophic consortium at 400, 600 and 800 rpm. The klaCH4 estimated from the OTR methodology accurately predicted the CH4 elimination capacity (EC) under CH4 mass transfer limiting conditions regardless of the stirring rate (~9% of average error between empirical and estimated ECs). Thus, empirical CH4-ECs of 37.8 +/- 5.8, 42.5 +/- 5.4 and 62.3 +/- 5.2 g CH4 m-3 h-1vs predicted CH4-ECs of 35.6 +/- 2.2, 50.1 +/- 2.3 and 59.6 +/- 3.4 g CH4 m-3 h-1 were recorded at 400, 600 and 800 rpm, respectively. The rapid Co2+-catalyzed reaction of O2 with SO3-2 in the vicinity of the gas-liquid interphase during OTR determinations, mimicking microbial CH4 uptake in the biotic experiments, was central to accurately describe the klaCH4. PMID- 29605780 TI - Sustainability performance evaluation: Literature review and future directions. AB - Current global economic activities are increasingly being perceived as unsustainable. Despite the high number of publications, sustainability science remains highly dispersed over diverse approaches and topics. This article aims to provide a structured overview of sustainability performance evaluation related publications and to document the current state of literature, categorize publications, analyze and link trends, as well as highlight gaps and provide research recommendations. 128 articles between 2007 and 2018 are identified. The results suggest that sustainability performance evaluation models shall be more balanced, suitable criteria and their interrelations shall be well defined and subjectivity of qualitative criteria inherent to sustainability indicators shall be considered. To address this subjectivity, group decision-making techniques and other analytical methods that can deal with uncertainty, conflicting indicators, and linguistic evaluations can be used in future works. By presenting research gaps, this review stimulates researchers to establish practically applicable sustainability performance evaluation frameworks to help assess and compare the degree of sustainability, leading to more sustainable business practices. The review is unique in defining corporate sustainability performance evaluation for the first time, exploring the gap between sustainability accounting and sustainability assessment, and coming up with a structured overview of innovative research recommendations about integrating analytical assessment methods into conceptual sustainability frameworks. PMID- 29605781 TI - Discriminating activated sludge flocs from biofilm microbial communities in a novel pilot-scale reciprocation MBR using high-throughput 16S rRNA gene sequencing. AB - Membrane bioreactors (MBRs) are a well-established filtration technology that has become a popular solution for treating wastewater. One of the drawbacks of MBRs, however, is the formation of biofilm on the surface of membrane modules. The occurrence of biofilms leads to biofouling, which eventually compromises water quality and damages the membranes. To prevent this, it is vital to understand the mechanism of biofilm formation on membrane surfaces. In this pilot-scale study, a novel reciprocation membrane bioreactor was operated for a period of 8 months and fed with domestic wastewater from an aerobic tank of a local WWTP. Water quality parameters were monitored and the microbial composition of the attached biofilm and suspended aggregates was evaluated in this reciprocating MBR configuration. The abundance of nitrifiers and composition of microbial communities from biofilm and suspended solids samples were investigated using qPCR and high throughput 16S amplicon sequencing. Removal efficiencies of 29%, 16%, and 15% of chemical oxygen demand, total phosphorus and total nitrogen from the influent were observed after the MBR process with average effluent concentrations of 16 mg/L, 4.6 mg/L, and 5.8 mg/L respectively. This suggests that the energy-efficient MBR, apart from reducing the total energy consumption, was able to maintain effluent concentrations that are within regulatory standards for discharge. Molecular analysis showed the presence of amoA Bacteria and 16S Nitrospira genes with the occurrence of nitrification. Candidatus Accumulibacter, a genus with organisms that can accumulate phosphorus, was found to be present in both groups which explains why phosphorus removal was observed in the system. High-throughput 16S rRNA amplicon sequencing revealed the genus Saprospira to be the most abundant species from the total OTUs of both the membrane tank and biofilm samples. PMID- 29605782 TI - A study to investigate viscous coupling effects on the hydraulic conductance of fluid layers in two-phase flow at the pore level. AB - This paper examines the role of momentum transfer across fluid-fluid interfaces in two-phase flow. A volume-of-fluid finite-volume numerical method is used to solve the Navier-Stokes equations for two-phase flow at the micro-scale. The model is applied to investigate viscous coupling effects as a function of the viscosity ratio, the wetting phase saturation and the wettability, for different fluid configurations in simple pore geometries. It is shown that viscous coupling effects can be significant for certain pore geometries such as oil layers sandwiched between water in the corner of mixed wettability capillaries. A simple parametric model is then presented to estimate general mobility terms as a function of geometric properties and viscosity ratio. Finally, the model is validated by comparison with the mobilities computed using direct numerical simulation. PMID- 29605783 TI - Hydrogen bond strengthening between o-nitroaniline and formaldehyde in electronic excited states: A theoretical study. AB - To study the hydrogen bonds upon photoexcited, the time dependent density function method (TD DFT) was performed to investigate the excited state hydrogen bond properties of between o-nitroaniline (ONA) and formaldehyde (CH2O). The optimized structures of the complex and the monomers both in the ground state and the electronically excited states are calculated using DFT and TD DFT method respectively. Quantum chemical calculations of the electronic and vibrational absorption spectra are also carried out by TD DFT method at the different level. The complex ONA?CH2O forms the intramolecular hydrogen bond and intermolecular hydrogen bonds. Since the strength of hydrogen bonds can be measured by studying the vibrational absorption spectra of the characteristic groups on the hydrogen bonding acceptor and donor, it evidently confirms that the hydrogen bonds is strengthened in the S1/S2/T1 excited states upon photoexcitation. As a result, the hydrogen bonds cause that the CH stretch frequency of the proton donor CH2O has a blue shift, and the electron excitations leads to a frequency red shift of NO and NH stretch modes in the o-nitroaniline(ONA) and a small frequency blue shift of CH stretch mode in the formaldehyde(CH2O) in the S1 and S2 excited states. The excited states S1, S2 and T1 are locally excited states where only the ONA moiety is excited, but the CH2O moiety remains in its ground state. PMID- 29605784 TI - A novel biphenyl-derived salicylhydrazone Schiff base fluorescent probes for identification of Cu2+ and application in living cells. AB - A novel biphenyl-derived salicylhydrazone Schiff base (BSS) fluorescent probes for highly sensitive and selective identification of Cu2+ has been synthesized. In addition, the recognition has been proved experimentally. The results indicated that the complex forms a 1:1 complex with Cu2+ shows fluorescent quenching. Furthermore, the detection limit of 1.54*10-8M. More interesting, the probe BSS not only have a good biocompatibility in living cells, but also the sense behavior of Cu2+ in the cell nucleus. PMID- 29605785 TI - Turn on macrocyclic chemosensor for Al3+ ion with facile synthesis and application in live cell imaging. AB - An effort of a new Schiff base macrocyclic chemosensor, 14-methyl-2,6,8,12,14,18 hexaaza-1,7,13(1,2),4,10,16(1,4)-hexabenzenacyclooctadecaphane-2,5,8,11,14,17 hexaene (me1) and 14,74-dimethyl-2,6,8,12,14,18-hexaaza-1,7,13(1,2),4,10,16(1,4) hexabenzenacyclooctadecadecaphane-2,5,8,11,14,17-hexaene (dm2), which enables selective sensing of Al3+ in aqueous DMF were synthesized by a simplistic one step condensation reaction of macrocyclic compounds. The probe me1 and dm2 characterized by elemental analysis, FT-IR, 1H and 13C NMR, LC-MS spectral techniques. The compounds as mentioned above subjected to FE-SEM with EDS and elemental color mapping. On addition of Al3+, the fluorescent probe me1 and dm2 induces turn-on responses in both absorption and sensing spectra by a PET mechanism. The receptor me1 and dm2 serve highly selective, sensitive and turn-on detection of Al3+. Further, they did not interfere with other cations present in biological or environmental samples. The detection limit is found to be 3MUM and 5MUM. From the view of cytotoxic activity, the ability of these compounds me1 and dm2 to inhibit the growth of KB cell lines examined. The chelating functionality of compounds me1 and dm2 examined for their inhibitory properties of KB cell, live cell images. The compounds me1 and dm2 subjected to theoretical studies by DFT-B3LYP invoking the 6-31G level of theory. The energy of the HOMO and LUMO has been established. PMID- 29605786 TI - Firearm storage and shooting experience: Factors relevant to the practical capability for suicide. AB - The capability for suicide is posited to facilitate the relatively rare transition from suicidal ideation to suicidal behavior, although the operational definition of the construct continues to evolve. The Three Step Theory proposes that capability is multifaceted and includes practical capability for suicide, defined as comfort with and access to lethal means. Empirical examinations of this construct are thus far limited. Two previous studies have examined the association between firearm storage and shooting experience and common measures of capability for suicide. This study expands the generalizability of previous findings by investigating the relationship between capability for suicide, firearm storage practices, and experience shooting a firearm in a sample of 300 American firearm owners. We found that individuals who store their firearms unsafely (loaded, in a non-secure location, or without a locking device) and who have greater experience shooting firearms have significantly higher capability for suicide. These findings extend the evidence for the construct of practical capability as it relates to firearms and highlight the need for firearm-specific means safety measures to prevent suicide. PMID- 29605788 TI - Peer learning across the curriculum. PMID- 29605787 TI - Basic life support and external defibrillation competences after instruction and at 6 months comparing face-to-face and blended training. Randomised trial. AB - AIM OF THE STUDY: The objective of this study was to compare the immediate and 6 month efficacy of basic life support (BLS) and automatic external defibrillation (AED) training using standard or blended methods. METHODS: First-year students of medicine and nursing (n = 129) were randomly assigned to a control group (face-to face training based on the European Resuscitation Council [ERC] Guidelines) or to an experimental group that trained with a self-training video, a new website, a Moodle platform, an intelligent manikin, and 45 min of instructor presence. Both groups were homogeneous and were evaluated identically. Theoretical knowledge was evaluated using a multi-choice questionnaire (MCQ). Skill performance was evaluated by the instructor's rubric and on a high-fidelity Resusci Anne QCPR manikin. RESULTS: Immediately after the course, there were no statistically significant differences in knowledge between the two groups. The median score of practical evaluation assessed by the instructor was significantly better in the experimental group (8.15, SD 0.93 vs 7.7, SD 1.18; P = 0.02). No differences between groups were found when using a high-fidelity manikin to evaluate chest compressions and lung inflations. At six months, the scores in knowledge and skill performance were significantly lower compared to the evaluations at the end of the instruction, but they remained still higher compared to baseline. The experimental group had higher scores in practical skills evaluated by the instructor than the control group (7.44, SD 1.85 vs 6.10, SD 2.6; P = 0.01). CONCLUSIONS: The blended method provides the same or even higher levels of knowledge and skills than standard instruction both immediately after the course and six months later. PMID- 29605789 TI - The role of the lipidome in obesity-mediated colon cancer risk. AB - Obesity is a state of chronic inflammation influenced by lipids such as fatty acids and their secondary oxygenated metabolites deemed oxylipids. Many such lipid mediators serve as potent signaling molecules of inflammation, which can further alter lipid metabolism and lead to carcinogenesis. For example, sphingosine-1-phosphate activates cyclooxygenase-2 in endothelial cells resulting in the conversion of arachidonic acid (AA) to prostaglandin E2 (PGE2). PGE2 promotes colon cancer cell growth. In contrast, the less studied path of AA oxygenation via cytochrome p450 enzymes produces epoxyeicosatetraenoic acids (EETs), whose anti-inflammatory properties cause shrinking of enlarged adipocytes, a characteristic of obesity, through the liberation of fatty acids. It is now thought that EET depletion occurs in obesity and may contribute to colon cell carcinogenesis. Meanwhile, gangliosides, a type of sphingolipid, are cell surface signaling molecules that contribute to the apoptosis of colon tumor cells. Many of these discoveries have been made recently and the mechanisms are still not fully understood, leading to an exciting new chapter of lipidomic research. In this review, mechanisms behind obesity-associated colon cancer are discussed with a focus on the role of small lipid signaling molecules in the process. Specifically, changes in lipid metabolite levels during obesity and the development of colon cancer, as well as novel biomarkers and targets for therapy, are discussed. PMID- 29605790 TI - Fatal varicella in immigrants from tropical countries: Case reports and forensic perspectives. AB - The primary Varicella Zoster Virus (VZV) infection results in varicella, a generally benign, self-limiting disease in immunocompetent children. Despite the usual course a possible fatal evolution of the primary infection is observed predominantly in immunocompromised subjects and in adults, especially emigrating from tropical regions. Two cases of fatal varicella have been investigated and discussed. Death occurred in two patients over 40 years of age, coming from South Asia and receiving chronic immunosuppressive therapy. The forensic expert must be cautious and consider all clinical records in managing fatal varicella cases, bearing in mind risk factors and pre-existing conditions such as age, geographical provenance and pathological comorbidity, which may lead to a bad prognosis irrespective of therapies. Based on the severe and fatal course observed in the reported cases, an extension of the immunization program appears advisable for immigrants from tropical countries, especially before scheduled immunotherapy. PMID- 29605792 TI - Determination of benzodiazepines in beverages using green extraction methods and capillary HPLC-UV detection. AB - Dispersive liquid-liquid microextraction with and without ultrasound assistance (DLLME, UA-DLLME) and microextraction with packed sorbent (MEPS) methods for the extraction and determination of eight different benzodiazepines (BDZ) (chlordiazepoxide, flurazepam, bromazepam, oxazepam, lorazepam, clobazam, clonazepam, and flunitrazepam) in three commercial non-alcoholic and light alcoholic beverages were optimized and compared. Benzodiazepines are frequently used for their extensive diffusion and strong numbing effect in drug-facilitated crimes (DFC). The tiny small amount of sample required for DLLME and MEPS extraction makes them very suitable for specimens collected at the crime scene of DFCs. Microextraction techniques are of increasing interest thanks to their accordance to green analytical chemistry (GAC) guidelines providing good recovery values. Ultrasound assistance (UA-DLLME) was used to investigate whether this type of energy can improve the recoveries of the analytes. Analyses of the extracts were performed with reverse-phase capillary high-performance liquid chromatography with UV detection (HPLC - UV), thanks to low environmental impact, robustness, diffusion, and affordability. Recovery percentages at three different concentrations in the three beverages were between 14.30% and 103.28% with intraday and interday RSD lower than +/-2.78%. The same samples were extracted using a MEPS protocol, and the results were compared with those obtained with DLLME. MEPS gave recoveries between 20.90% and 101.88% for all matrices showing a better performance than DLLME at higher concentrations, though lower recoveries were observed with diluted samples. PMID- 29605791 TI - Use of postmortem computed tomography to retrieve small metal fragments derived from a weapon in the bodies of victims in two homicide cases. AB - Postmortem computed tomography (PMCT) is becoming a commonly used modality in routine forensic investigation. Mechanical injuries including lacerations, incisions, stab wounds and gunshot wounds frequently contain foreign bodies that may have significant value as clues in criminal investigations. CT is a sensitive modality for detection of metal foreign bodies that may be associated with injuries to the victim in cases of homicide or traffic accidents. Here we report two cases in which PMCT was able to act as a guide to forensic pathologists for retrieval of metal fragments in the corpses of the victims, the retrieved fragments then being used to validate the confessions of the assailants through comparison with the knife and the crowbar, respectively, that had been used in the crimes. In these cases, the small metal fragments retrieved from the corpses of the victims with the aid of PMCT were decisive pieces of evidence confirming the circumstances of the crimes. These cases illustrate how PMCT can be used to complement the findings of classical autopsy for integrative investigation of corpses with injury. PMID- 29605793 TI - The association between lifetime cannabis use and dysthymia across six birth decades. AB - BACKGROUND: Though high rates of co-occurring cannabis use and depression are well-documented, data regarding the association between cannabis use and dysthymia is scarce. The aim of this cross-sectional study was to explore clinical correlations of cannabis use among individuals with dysthymia, as well as the changes in the association between cannabis use and dysthymia across six decades of birth cohorts. METHODS: Data were drawn from the National Epidemiologic Survey on Alcohol and Related Conditions-III (NESARC-III; 2012 2013; N = 36,309). Participants were divided into six birth cohorts (1940s 1990s), based on their decade of birth, and individuals with dysthymia were further categorized by 3 levels of lifetime cannabis use: non-users, non-CUD users, and CUD-users. We compared rates of co-occurring psychiatric and substance use disorders among cannabis users vs non-users and conducted logistic regression analyses in order to determine the odds of dysthymia among cannabis users across six decades. RESULTS: Rates of several psychiatric disorders, such as personality disorders, and substance use disorders were higher among individuals with dysthymia who used cannabis compared to those who did not. The interaction between cannabis use (without a CUD) and birth cohort was associated with a decrease in the odds of dysthymia (OR=0.90, 95% CI 0.84-0.97) and remained significant after controlling for confounding variables. Similar changes over time were not demonstrated for CUD users. LIMITATIONS: Likelihood for recall bias and misclassification based on cross-sectional nature of the study and on respondents' self-reports of symptoms throughout their lifetime. CONCLUSIONS AND IMPLICATIONS: Our study's findings demonstrate that the association between cannabis use (but not CUDs) and dysthymia has weakened over time. These findings highlight the need for further research examining changes over time in the relationship between cannabis use and associated psychiatric disorders. PMID- 29605794 TI - Potentiality of Neopestalotiopsis clavispora ASU1 in biosorption of cadmium and zinc. AB - In this study, a fungal isolate was isolated from avocado fruit collected from a market in Makkah city, Saudi Arabia, and identified as Neopestalotiopsis clavispora ASU1. The biomass of Neopestalotiopsis clavispora ASU1 was used as a natural bio-sorbent for removal of Cd(II) and Zn(II) from aqueous solutions. Characterization of fungal biomass was performed using Fourier transform infrared spectroscopy, X-ray Diffractometer, and BET surface area. Different factors on Cd(II) and Zn(II) biosorption were studied to evaluate the maximum conditions for metals biosorption. The (qmax) for Cd(II) and Zn (II) by N. clavispora ASU1 calculated from the Langmuir adsorption isotherm was 185.3 +/- 0.25 and 153.8 +/- 0.21 mg/g, respectively. Based on r2, the equilibrium biosorption isotherms fitted well with Langmuir model than Freundlich isotherm. The adsorption kinetics was studied, and the biosorption followed to the pseudo-second-order model. Thus, the current study indicated that the biomass of N. clavispora ASU1 is an effective adsorbent for the removal of heavy metals from aqueous solutions. PMID- 29605795 TI - Acute and chronic toxicity assessment of benzylpenicillin G residue in heat treated animal food products. AB - The current level of penicillin use and its persisting residue in livestock is potentially concerning; the toxicity of penicillin residue in heat-treated animal food products (HAFP) is yet to be elucidated. In this study, the acute and chronic toxicity of benzylpenicillin G (BPG) residue in HAFP was investigated in a mouse model. The calculated LD50 of BPG heated to cooking temperature (BPHCT) was 933.04 mg kg-1 [b.w.] intraperitoneally corresponding to 3.75 times lower than its prototype. Mice fed on the experimental diet containing heat-treated beef with high BPG levels for 6 months displayed a reduction in body weight and altered serum values indicating for liver and renal function. Further, the organ ratios of intestinal and spleen were increased. Histopathological changes were observed in the liver, lung and parenchyma testis tissue. BPHCT residue induced sperm aberration and micronucleated polychromatic erythrocytes formation. Present results indicate that prolonged exposure of BPHCT at higher residue levels might have an impact on public health. Importantly the toxic concentrations of BPHCT are relatively high compared with levels that would result from the degradation of antibiotic residues in meat from animals that have received a therapeutic dose of BPG. PMID- 29605796 TI - Femoral anteversion assessment: Comparison of physical examination, gait analysis, and EOS biplanar radiography. AB - BACKGROUND: Multiple measurement methods are available to assess transverse plane alignment of the lower extremity. RESEARCH QUESTION: This study was performed to determine the extent of correlation between femoral anteversion assessment using simultaneous biplanar radiographs and three-dimensional modeling (EOS imaging), clinical hip rotation by physical examination, and dynamic hip rotation assessed by gait analysis. METHODS: Seventy-seven patients with cerebral palsy (GMFCS Level I and II) and 33 neurologically typical children with torsional abnormalities completed a comprehensive gait analysis with same day biplanar anterior-posterior and lateral radiographs and three-dimensional transverse plane assessment of femoral anteversion. Correlations were determined between physical exam of hip rotation, EOS imaging of femoral anteversion, and transverse plane hip kinematics for this retrospective review study. RESULTS: Linear regression analysis revealed a weak relationship between physical examination measures of hip rotation and biplanar radiographic assessment of femoral anteversion. Similarly, poor correlation was found between clinical evaluation of femoral anteversion and motion assessment of dynamic hip rotation. Correlations were better in neurologically typical children with torsional abnormalities compared to children with gait dysfunction secondary to cerebral palsy. SIGNIFICANCE: Dynamic hip rotation cannot be predicted by physical examination measures of hip range of motion or from three-dimensional assessment of femoral anteversion derived from biplanar radiographs. PMID- 29605797 TI - Self-reported sleep duration affects tandem gait, but not steady-state gait outcomes among healthy collegiate athletes. AB - BACKGROUND: Sleep deficits are associated with motor and cognitive function deficits, even in the absence of a recent concussion. RESEARCH QUESTION: Does the amount of self-reported sleep prior to pre-season concussion testing affect single-task and dual-task instrumented steady-state gait and timed tandem gait test performance? METHODS: One hundred and fourteen healthy collegiate athletes (mean age 18.8 +/- 0.7 years; 60% female) reported the amount of sleep they received during the prior night and completed a timed tandem gait test and an instrumented assessment of steady-state gait in both single-task and dual-task conditions. Outcome variables included spatio-temporal gait parameters during steady-state gait, best and mean tandem gait times, and cognitive test accuracy. RESULTS: Participants who reported sleeping <7 h of sleep during the night prior to testing (n = 62) had significantly longer tandem gait times in single-task and dual-task conditions (11.1 +/- 2.2 vs. 10.1 +/- 2.0 s and 14.5 +/- 4.3 vs. 12.3 +/- 2.6 s, respectively; p = .009) compared to those who reported sleeping >=7 h (n = 52). No significant differences between groups were observed for spatio temporal steady-state gait variables or for cognitive test accuracy. SIGNIFICANCE: Self-reported sleep duration may be associated with baseline testing tandem gait performance. Thus, as sleep can play a role in motor abilities, clinicians may consider interpreting tandem gait performance in light of sleep duration during the night prior to testing. PMID- 29605798 TI - Health Care Cost for Multiple Sclerosis: The Case of a Health Insurer in Colombia. AB - BACKGROUND: There have been many studies on the cost of multiple sclerosis in countries with high prevalence, whereas in Latin America such analyses are few. Taking into consideration the burden of this disease and the high financial impact of treatment on the health care system, it is necessary to know the behavior of cost of illness. OBJECTIVES: To describe the direct costs associated with health care in patients with multiple sclerosis affiliated with a health insurer in Colombia. METHODS: An analysis of direct costs of disease was performed from the perspective of the third-party payer. A direct measurement from the technical costing "top-down" approach was used. Data were adjusted for inflation and expressed in 2014 US dollars. RESULTS: The average annual cost per patient for the country was $29,339 (2010), $20,956 (2011), $23,892 (2012), $24,148 (2013), and $22,688 (2014). Drug therapy represented 86.1% of the total cost. Between 2010 and 2013, interferons accounted for the largest proportion of the costs of drug treatment (98.5% to 53%), whereas fingolimod showed an increase and accounted for 47% in 2014. CONCLUSIONS: Medications account for the largest proportion of disease costs, with few variations in the last 5 years; nevertheless, the increase in the use of new pharmaceuticals poses a challenge to maintain the financial balance of health insurance. PMID- 29605799 TI - Trends in testing algorithms used to diagnose HIV infection, 2011-2015, United States and 6 dependent areas. AB - BACKGROUND: In 2014 the Centers for Disease Control and Prevention (CDC) and the Association of Public Health Laboratories (APHL) issued updated laboratory testing recommendations for the diagnosis of HIV infection. OBJECTIVES: To examine trends in the use of HIV diagnostic testing algorithms, and determine whether the use of different algorithms is associated with selected patient characteristics and linkage to HIV medical care. STUDY DESIGN: Analysis of HIV infection diagnoses during 2011-2015 reported to the National HIV Surveillance System through December 2016. Algorithm classification: traditional = initial HIV antibody immunoassay followed by a Western blot or immunofluorescence antibody test; recommended = initial HIV antibody IA followed by HIV-1/2 type differentiating antibody test; rapid = two CLIA-waived rapid tests on same date. RESULTS: During 2011-2015, the percentage of HIV diagnoses made using the traditional algorithm decreased from 84% to 16%, the percentage using the recommended algorithm increased from 0.1% to 64%, and the percentage using the rapid testing algorithm increased from 0.1% to 2%. The percentage of persons linked to care within 30 days after HIV diagnosis in 2015 was higher for diagnoses using the recommended algorithm (59%) than for diagnoses using the traditional algorithm (55%) (p < 0.05). CONCLUSIONS: During 2011-2015, the percentage of HIV diagnoses reported using the recommended and rapid testing algorithms increased while the use of the traditional algorithm decreased. In 2015, persons with HIV diagnosed using the recommended algorithm were more promptly linked to care than those with diagnosis using the traditional algorithm. PMID- 29605800 TI - An Evidence Framework for Off-Patent Pharmaceutical Review (EFOR) for Health Technology Assessment in Emerging Markets. AB - OBJECTIVE: This article introduces an Evidence Framework for Off-Patent Pharmaceutical Review (EFOR), which establishes value-based criteria in a template that manufacturers use to provide evidence showing how their products meet those criteria. Health authorities in emerging markets can then use the evidence presented in the EFOR to evaluate off-patent pharmaceuticals (OPPs) in a consistent, transparent, and evidence-based manner to support policy decisions, including pricing, reimbursement, formulary listing, and drug procurement. METHODS: A literature search found no multi-criteria evidence framework for evaluating OPPs in emerging markets. An International Outcomes Research Board (IORB) of academia and industry experts conducted extensive research, meetings, and workshops to define high-priority criteria to incorporate into an evidence based health technology assessment (HTA) tool using the multi-criteria decision analysis (MCDA) technique. The resulting framework was further tailored for country-specific needs in workshops in three emerging countries (Kazakhstan, Vietnam, and Indonesia). RESULTS: The IORB defined nine criteria four categories (Product, Manufacturing, Service, and Value Assessment), which OPP manufacturers can use to provide evidence for reimbursement and health policy decision making. Then the IORB developed the EFOR as a base case document, which can be adapted and used as a template by health authorities in emerging countries. CONCLUSIONS: Emerging countries have a significant need for an HTA tool that balances affordability with accurate evidence showing the value differentiation of OPPs. The value attributes in this setting often are different from those in developed markets, which emphasize new products and have high regulation and manufacturing standards. The EFOR is an easy-to-use, adaptable framework that emerging countries can use to increase the consistency, transparency, and effectiveness of drug decision making. The open source EFOR is available as Supplemental Materials. PMID- 29605802 TI - Optical coherence tomography as a biomarker of neurodegeneration in multiple sclerosis: A review. AB - Neurodegeneration is one the most important pathological factors which contributes to permanent disability in multiple sclerosis (MS). Optical coherence tomography (OCT) measurements of macular ganglion cell layer (mGCL) and retinal nerve fiber layer (RNFL) have been proposed as biomarkers of axonal damage in MS. The aim of this review is to describe the most relevant findings regarding OCT and axonal damage in MS. We have selected studies that describe retina impairment in MS patients, and those which quantitatively assess the relationship between OCT and physical disability, cognitive impairment and relationship between OCT and magnetic resonance imaging (MRI). Results show that there is a relationship between the degree of retinal layers reduction and physical or cognitive disability and degenerative changes in MRI. PMID- 29605801 TI - Prevalence of and risk factors for cognitive impairment in patients with relapsing-remitting multiple sclerosis: Multi-center, controlled trial. AB - BACKGROUND: Cognitive impairment (CI) is a common problem in multiple sclerosis (MS), may occur either in early or late phase of the disease, and impairs quality of life. OBJECTIVES: This study aimed to determine the prevalence of CI and related risk factors in relapsing-remitting MS (RRMS) patients in Turkey. METHODS: The present cross-sectional, multi-center, and nationally representative study included RRMS patients. Sociodemographic characteristics, cognitive functions and additional outcomes were compared between patients with and without CI. RESULTS: The analyses included 487 RRMS patients. According to the BRB-N battery results, CI prevalence was 53.7%. There was a negative significant correlation of BRB-N subtests with age, disease duration, and EDSS and MSNQ patient rated scores. On the logistic regression analysis, increased age, living in village/rural area, high income level, and high EDSS score were significant increasing risk factors in the development of CI. CONCLUSIONS: This is the first national cognitive data obtained from MS in Turkey, which is a country between Europe and Asia and thus has characteristics of both continents. The similarity of the results of the present study obtained from Turkey to the Western-based data indicates that CI is universal in MS and the main factors affecting CI have not changed. PMID- 29605803 TI - Critical role of oxygen for rapid degradation of organic contaminants in permanganate/bisulfite process. AB - Organic contaminants can be oxidized rapidly in permanganate/bisulfite (PM/BS) process due to generation of Mn(III)aq. However, the influence of O2 and its role in contaminants degradation in PM/BS process are poorly understood. Thus, the influence of O2 concentration on phenol removal was quantified and isotopic oxygen tracers (18O-labeled water and 18O2) were employed to further unravel the mechanisms of PM/BS process. The introduction of O2 to PM/BS process appreciably improved phenol oxidation. Under oxic conditions the oxidation products of bisulfite included SO42- and HSO5- while SO42- was the single stable oxidation product under anaerobic conditions. The oxygen isotope labeling experiments confirmed that HSO5- originated from the oxidation of SO3- by O2 to SO5- and the following reduction of SO5- by HSO3-. Incorporation of oxygen isotope from H218O to MnO2 due to the disproportionation of Mn(III)aq was observed, which verified the generation of Mn(III)aq in PM/BS process. The critical influence of O2 on PM/BS process was mainly associated with rapid oxidation of SO3- by O2 to SO5-, which otherwise competed with target contaminants for Mn(III)aq. Oxygen from H2O and/or O2 can also be incorporated in the degradation products of organics in PM/BS process. PMID- 29605804 TI - Self-sustained photocatalytic power generation using eco-electrogenic engineered systems. AB - An eco-electrogenic engineered system (EES) was designed to mimic the functional role of natural aquatic ecosystems and evaluated their response to bio electrogenic activity by cascadically interlinking three tanks with functionally diverse biota viz., floating macrophytes (Tank 1), submerged plants (Tank 2) and filter feeders (fish and snails) (Tank 3). Tank 1 showed efficient power generation (voltage (series): 0.86 V; current density (parallel): 37 mA/m2) than Tank 2 (voltage (series): 0.76 V; current density (parallel): 34 mA/m2) and Tank 3 (voltage (series): 0.65 V; current density (parallel): 22 mA/m2). Integrating all three tanks enabled maximum power generation in parallel-series (P-S) connection (9.5 mW/m2) than individual series and parallel connections (6.5/5 mW/m2). Interaction of microbes and plants studied at the interface of electrochemical and engineering aspects illustrated the feasibility of EES as a self-sustainable system with innate diverse functional aquatic biota and rhizo microbiome to produce bioelectricity. PMID- 29605805 TI - Nitrifying aerobic granular sludge fermentation for releases of carbon source and phosphorus: The role of fermentation pH. AB - The effect of fermentation pH (uncontrolled, 4 and 10) on the releases of carbon source and phosphorus from nitrifying aerobic granular sludge (N-AGS) was investigated. Meanwhile, metal ion concentration and microbial community characterization were explored during N-AGS fermentation. The results indicated that N-AGS fermentation at pH 10 significantly promoted the releases of soluble chemical oxygen demand (SCOD) and total volatile fatty acids (TVFAs). However, SCOD and TVFA released from N-AGS were inhibited at pH 4. Moreover, acidic condition promoted phosphorus release (mainly apatite) from N-AGS during anaerobic fermentation. Nevertheless, alkaline condition failed to increase phosphorus concentration due to the formation of chemical-phosphate precipitates. Compared with the previously reported flocculent sludge fermentation, N-AGS fermentation released more SCOD and TVFAs, possibly due to the greater extracellular polymeric substances content and some hydrolytic-acidogenic bacteria in N-AGS. Therefore, N-AGS alkaline fermentation facilitated the carbon source recovery, while N-AGS acidic fermentation benefited the phosphorus recovery. PMID- 29605806 TI - Actin depolymerization enhances adipogenic differentiation in human stromal stem cells. AB - Human stromal stem cells (hMSCs) differentiate into adipocytes that play a role in skeletal tissue homeostasis and whole body energy metabolism. During adipocyte differentiation, hMSCs exhibit significant changes in cell morphology suggesting changes in cytoskeletal organization. Here, we examined the effect of direct modulation of actin microfilament dynamics on adipocyte differentiation. Stabilizing actin filaments in hMSCs by siRNA-mediated knock down of the two main actin depolymerizing factors (ADFs): Cofilin 1 (CFL1) and Destrin (DSTN) or treating the cells by Phalloidin reduced adipocyte differentiation as evidenced by decreased number of mature adipocytes and decreased adipocyte specific gene expression (ADIPOQ, LPL, PPARG, FABP4). In contrast, disruption of actin cytoskeleton by Cytochalasin D enhanced adipocyte differentiation. Follow up studies revealed that the effects of CFL1 on adipocyte differentiation depended on the activity of LIM domain kinase 1 (LIMK1) which is the major upstream kinase of CFL1. Inhibiting LIMK by its specific chemical inhibitor LIMKi inhibited the phosphorylation of CFL1 and actin polymerization, and enhanced the adipocyte differentiation. Moreover, treating hMSCs by Cytochalasin D inhibited ERK and Smad2 signaling and this was associated with enhanced adipocyte differentiation. On the other hand, Phalloidin enhanced ERK and Smad2 signaling, but inhibited adipocyte differentiation which was rescued by ERK specific chemical inhibitor U0126. Our data provide a link between restructuring of hMSCs cytoskeleton and hMSCs lineage commitment and differentiation. PMID- 29605807 TI - Phenylthiazoles with tert-Butyl side chain: Metabolically stable with anti biofilm activity. AB - A new series of phenylthiazoles with t-butyl lipophilic component was synthesized and their antibacterial activity against a panel of multidrug-resistant bacterial pathogens was evaluated. Five compounds demonstrated promising antibacterial activity against methicillin-resistant staphylococcal strains and several vancomycin-resistant staphylococcal and enterococcal species. Additionally, three derivatives 19, 23 and 26 exhibited rapid bactericidal activity, and remarkable ability to disrupt mature biofilm produced by MRSA USA300. More importantly, a resistant mutant to 19 couldn't be isolated after subjecting MRSA to sub-lethal doses for 14 days. Lastly, this new series of phenylthiazoles possesses an advantageous attribute over the first-generation compounds in their stability to hepatic metabolism, with a biological half-life of more than 9 h. PMID- 29605808 TI - Antiproliferative efficacy of curcumin mimics through microtubule destabilization. AB - Curcumin possesses an attractive chemical structure with highly conjugated diferuloylmethane core. Curcumin mimics have been designed and prepared with an additional bridged phenyl ring in conjugation. Fourteen diverse analogues were evaluated against a panel of human cancer cell lines. The best analogue of the series i.e. compound 6a exhibited potent cytotoxicity against A431, epidermoid carcinoma cell line (IC50 = 1.5 MUM) and DLD1, colorectal adenocarcinoma cell line (IC50 = 6.9 MUM). In tubulin kinetics experiment, compound 6a destabilized polymerisation process (IC50 = 4.68 MUM). In cell cycle analysis, compound 6a exerted G2/M phase arrest in A431 cells and induced apoptosis. In Ehrlich Ascites Carcinoma in Swiss-albino mice, compound 6a showed 78.6% tumour reduction at 80 mg/kg dose and 57% solid tumour reduction at 150 mg/kg dose. Further, in acute oral toxicity experiment in rodent model, compound 6a was given in three different oral doses to Swiss albino mice. There were non-significant changes in various biochemical parameters and major body organs studied, including their absolute and relative weights. It was tolerable up to 300 mg/kg dose in Swiss albino mice. The present study shows that the novel curcumin mimic 6a is a safe and efficacious anticancer compound. However, it needs to be optimized for better efficacy. PMID- 29605809 TI - Success stories of natural product-based hybrid molecules for multi-factorial diseases. AB - Complex diseases comprises of highly complicated etiology resulting in limited applicability of conventional targeted therapies. Consequently, conventional medicinal compounds suffer major failure when used for such disease conditions. Additionally, development of multidrug resistance (MDR), adverse drug reactions and clinical specificity of single targeted drug therapy has increased thrust for novel drug therapy. In this rapidly evolving era, natural product-based discovery of hybrid molecules or multi-targeted drug therapies have shown promising results and are trending now a days. Historically, nature has blessed human with different sources viz. plant, animal, microbial, marine and ethnopharmaceutical sources which has given a wide variety of medicinally active compounds. These compounds from natural origin are always choice of interest of medicinal chemists because of their minimum side effects. Hybrid molecules synthesized by fusing or conjugating different active molecules obtained from these sources are reported to synergistically block different pathways which contribute in the pathogenesis of complex diseases. This review strives to encompass all natural product-derived hybrid molecules which act as multi-targeting agents striking various targets involved in different pathways of complex diseased conditions reported in literature. PMID- 29605810 TI - Design, synthesis and biological evaluation of C(4) substituted monobactams as antibacterial agents against multidrug-resistant Gram-negative bacteria. AB - A series of novel pyridone conjugated monobactams with various substituents at the (4) position were synthesized and evaluated for their antibacterial activities against a panel of multidrug-resistant (MDR) Gram-negative bacteria in vitro. Compounds 46d, 54 and 75e displayed good to moderate activities against P. aeruginosa, among which the activity of 75e against P. aeruginosa was comparable to that of BAL30072 under iron limitation condition. Compounds 35, 46d, 54, 56a, 56c and 56d exhibited good to excellent antibacterial activities against E. coli and K. pneumoniae, which were comparable or superior to that of BAL30072. In vitro liver microsomal stability was further evaluated and the results manifested that Compounds 35, 46d and 54 were metabolically stable in human liver microsomes. PMID- 29605811 TI - Test method for mechanical properties of implantable catheters according to DIN 10555-3. AB - To enable causal analysis of port catheter failure, this study aimed to develop an experimental setup for uniaxial tensile tests that addresses the specific requirements of highly elastic medical catheters; and to quantify parameters of the catheters' mechanical competence with respect to effects of artificial aging. Segments of 6F-polyurethane catheters were tested in their native status, after chemical and after mechanical aging. Tension experiments were performed with a rate of 220 mm/min until catheter failure. Material behavior was analyzed based on load cell measurements of the universal test system and an additional optical distance registration. The Young's modulus, the ultimate stress and the ultimate strain were determined. Chemical aging significantly decreased Young's modulus (84%; p = 0.001) and ultimate stress (83%; p < 0.001), whereas mechanical aged samples demonstrated similar results for the Young's modulus (p = 0.772) and a non-significant rise of ultimate stress (13%; p = 0.128). Ultimate strain did not differ significantly regardless of the pretreatment. The results proof reliability, reproducibility and sensitivity to quantify artificial aging induced variations and also promise to detect deviations in material features caused by long-term clinical usage of catheters. PMID- 29605813 TI - Association between asthma and lung function in adolescents born very preterm: results of the EPIPAGE cohort study. AB - Prematurity and bronchopulmonary dysplasia (BPD) affect long-term lung function. We studied the respiratory outcome of adolescents born very preterm and controls from the Etude EPIdemiologique sur les Petits Ages Gestationnels cohort and analysed their current lung function in relation to asthma symptoms (categorised in three age groups) from birth. In models including BPD, asthma at each age and confounding factors in the preterm group, BPD and preschool wheeze were the only independent variables associated with FEV1 Preschool wheeze is an independent factor associated with FEV1 impairment in adolescents born very preterm. These results highlight the need for optimal management of early respiratory symptoms in preterm-born infants. TRIAL REGISTRATION NUMBER: Results, NCT01424553. PMID- 29605812 TI - Targeted mass spectrometry enables robust quantification of FANCD2 mono ubiquitination in response to DNA damage. AB - The Fanconi anemia pathway is an important coordinator of DNA repair pathways and is particularly relevant to repair of DNA inter-strand crosslinks. Central to the pathway is monoubiquitination of FANCD2, requiring the function of multiple proteins in an upstream Fanconi core complex. We present development and analytical characterization of a novel assay for quantification of unmodified and monoubiquitinated FANCD2 proteoforms, based on peptide immunoaffinity enrichment and targeted multiple reaction monitoring mass spectrometry (immuno-MRM). The immuno-MRM assay is analytically characterized using fit-for-purpose method validation. The assay linear range is >3 orders of magnitude with total repeatability <16% CV. In proof-of-principle experiments, we demonstrate application of the multiplex assay by quantifying the FANCD2 proteoforms following mitomycin-c treatment in an isogenic pair of FancA-corrected and uncorrected cell lines, as well as primary peripheral blood mononuclear cells from Fanconi Anemia patients. Additionally, we demonstrate detection of endogenous FANCD2 monoubiquitination in human breast cancer tissue. The immuno MRM assay provides a potential functional diagnostic for patients with Fanconi Anemia with defects in the upstream FA complex or FANCD2, and a potential test for predicting sensitivity to DNA cross-linking agents in human cancers. PMID- 29605814 TI - Evaluation of choroidal lesions with swept-source optical coherence tomography. AB - AIMS: The aim of our study was to image choroidal lesions with swept-source optical coherence tomography (SS-OCT) and to identify the morphological characteristics associated with optimal visualisation. METHODS: This was a prospective, cross-sectional study. Patients with choroidal melanocytic lesions <3 mm in thickness on B-scan ultrasonography were recruited. All participants underwent SS-OCT. On SS-OCT we evaluated qualitative (eg, lesion outline, detection of scleral-choroidal interface and quality of the image) and quantitative (measurement of maximum lesion thickness and the largest basal diameter) parameters. Probability of optimal image quality was examined using ordered logistic regression models. The main outcome measure was quality of the choroidal lesion images on SS-OCT, defined as: optimal, suboptimal or poor. RESULTS: We included 85 choroidal lesions of 82 patients. There were 24 choroidal lesions (29%) for which image quality was classified as optimal, 31 lesions (37%) as suboptimal and 30 lesions (36%) as poor. The factors associated with optimal image quality were distance closer to the fovea (OR 0.76, p<0.001), posterior pole location (OR 3.87, p=0.05), lower ultrasonography thickness (OR 0.44, p=0.04), lighter lesion pigmentation (OR 0.12, p=0.003) and smaller lesion diameter (OR 0.73, p<0.001). In the multivariable analysis, closer distance to the fovea (OR 0.81, p=0.005), lighter lesion pigmentation (OR 0.11, p=0.01) and smaller lesion diameter (OR 0.76, p=0.006) remained statistically significant. CONCLUSION: SS-OCT is useful in imaging most choroidal melanocytic lesions. Image quality is best when the choroidal lesion is closer to the fovea, has a smaller diameter and a lighter choroidal pigmentation. PMID- 29605815 TI - Predictability of formulae for intraocular lens power calculation according to the age of implantation in paediatric cataract. AB - AIMS: To analyse the predictability of diverse intraocular lens (IOL) power calculation formulae in paediatric patients with congenital cataract. METHODS: The medical records of patients who underwent cataract surgery and posterior chamber IOL implantation (in-the-bag) for congenital cataract before 17 years of age were reviewed retrospectively. Target refractions calculated by Sanders Retzlaff-Kraff (SRK)/II, SRK/T and Hoffer-Q formulae were compared with the actual refraction. Patients were subgroup according to the age at IOL implantation (age group 0-24 months, 25-60 months, 61-120 months, 121-203 months), and we compared mean prediction error (PE) and mean absolute error (AE) for each formula. Corrected AE was obtained by linear regression analysis. RESULTS: Totally 481 eyes were included in the final analysis. Both SRK/II and SRK/T yielded the lowest mean AE in the age group 0-24 months and SRK/II yielded the lowest mean AE in the age group 25-60 months. For every formula, the mean PE was positive during the first five years of age, which converged to zero according to age as IOL implantation increases. The tendency for immediate postoperative overcorrection in younger patients (<6 years) could be improved by corrected formulae based on the linear regression equation. CONCLUSIONS: Patients with congenital cataract who underwent IOL implantation within 5 years of age showed higher AE than the older ones did. Among the three formulae evaluated, SRK/II consistently provided the best predictive result in these patients. For patients aged >10 years, all three formulae showed favourable predictive abilities. PMID- 29605816 TI - Regulation of kynurenine metabolism by a ketogenic diet. AB - Ketogenic diets (KDs) are increasingly utilized as treatments for epilepsy, other neurological diseases, and cancer. Despite their long history in suppressing seizures, the distinct molecular mechanisms of action of KDs are still largely unknown. The goal of this study was to identify key metabolites and pathways altered in the hippocampus and plasma of rats fed a KD versus control diet (CD) either ad libitum or calorically restricted to 90% of the recommended intake. This was accomplished using a combination of targeted methods and untargeted MS based metabolomics analyses. Various metabolites of and related to the tryptophan (TRP) degradation pathway, such as kynurenine (KYN), kynurenic acid as well as enzyme cofactors, showed significant changes between groups fed different diets and/or calorie amounts in plasma and/or the hippocampus. KYN was significantly downregulated in both matrices in animals of the CD-calorically restricted, KD-ad libitum, and KD-calorically restricted groups compared with the CD-ad libitum group. Our data suggest that the TRP degradation pathway is a key target of the KD. PMID- 29605817 TI - Management of Left Main Coronary Artery Disease. PMID- 29605818 TI - Evolution of epilepsy prevalence and incidence in a Tanzanian area endemic for onchocerciasis and the potential impact of community-directed treatment with ivermectin: a cross-sectional study and comparison over 28 years. AB - INTRODUCTION: Worldwide, there are an estimated 50 million people affected by epilepsy. Its aetiology is manifold, and parasitic infections play an important role, specifically onchocerciasis. In onchocerciasis endemic areas, a distinctive form of epilepsy has been described as nodding syndrome, affecting children and causing nodding seizures, mental retardation and debilitating physical development. Onchocerciasis control programmes using community-directed treatment with ivermectin (CDTI) are implemented in endemic countries. This study is designed to contribute to a better understanding of the linkage between the onset of epilepsy, onchocerciasis and CDTI. Comparing the epidemiological data on epilepsy and onchocerciasis from pre-CDTI and 20 years after its introduction will allow identifying a potential impact of ivermectin on the onset of epilepsy. METHODS AND ANALYSIS: The study will be conducted in the Mahenge highlands in Tanzania. Study site selection is based on an in-depth study on epilepsy in that area dating from 1989. CDTI was introduced in 1997. By a door-to-door approach, the population will be screened for epilepsy using a validated questionnaire. Suspected cases will be invited for a neurological examination for case verification. Onchocerciasis prevalence will be assessed by a rapid epidemiological assessment. As an indicator for ongoing transmission, children younger than 10 years of age will be tested for Ov16 antibodies. Ivermectin use will be assessed at household level. Epilepsy data will be analysed in comparison with the 1989 data to reveal pre-CDTI and post-CDTI prevalence and incidence. ETHICS AND DISSEMINATION: The protocol has received ethical approval from the ethics committees of the University of Antwerp, Belgium, and of the National Institut of Medical Research, Dar es Salaam, Tanzania. The findings will be published in peer-reviewed journals, and presented to the health authorities in Tanzania, at national, regional and village level. PMID- 29605820 TI - Body size measures and risk of venous thromboembolism: protocol for a systematic review and meta-analysis. AB - INTRODUCTION: Obesity is significant risk factor for venous thromboembolism (VTE); however, the related mechanisms remain unclear. Previous studies have suggested that this might be related to physical factors including anthropometric measures. We intend to conduct a systematic review and meta-analysis of prospective studies to summarise the extant literature on the associations between a set of seven measures of body size and the risk of VTE. METHODS AND ANALYSIS: The current systematic review will include prospective cohort studies assessing the association between seven measures of body size (height, weight, body mass index, waist and hip circumferences, waist-to-hip ratio, waist-to height ratio) and the risk of VTE. We will conduct comprehensive searches of MEDLINE and Excerpta Medica Database (EMBASE) for articles published from inception through 31 August 2017, without any language restriction. Two investigators will independently screen, select studies and perform data extraction and risk of bias assessment, with discrepancies resolved by a third investigator. For each body size measure, study-specific relative risks will be pooled using random effects meta-analysis models. Statistical heterogeneity will be assessed using Cochran's Q statistic, H and the I2 statistics. Sources of heterogeneity will be investigated using subgroup and meta-regression analyses as deemed appropriate. Publication bias will be assessed with funnel plots supplemented by Egger's test. ETHICS AND DISSEMINATION: This systematic review will use data from published literature; therefore, ethical approval is not required. We expect our findings to supplement previous epidemiological studies by providing an updated and comprehensive synthesis of the available evidence on the association between body size measures and risk of VTE in the general population. Findings will be published in peer-reviewed journal and presented at scientific meetings. PROSPERO REGISTRATION NUMBER: CD CRD42017071996. PMID- 29605819 TI - Effect of personalised citizen assistance for social participation (APIC) on older adults' health and social participation: study protocol for a pragmatic multicentre randomised controlled trial (RCT). AB - INTRODUCTION: The challenges of global ageing and the growing burden of chronic diseases require innovative interventions acting on health determinants like social participation. Many older adults do not have equitable opportunities to achieve full social participation, and interventions might underempower their personal and environmental resources and only reach a minority. To optimise current practices, the Accompagnement-citoyen Personnalise d'Integration Communautaire (APIC), an intervention demonstrated as being feasible and having positive impacts, needs further evaluation. METHODS AND ANALYSIS: A pragmatic multicentre, prospective, two-armed, randomised controlled trial will evaluate: (1) the short-term and long-term effects of the APIC on older adults' health, social participation, life satisfaction and healthcare services utilisation and (2) its cost-effectiveness. A total of 376 participants restricted in at least one instrumental activity of daily living and living in three large cities in the province of Quebec, Canada, will be randomly assigned to the experimental or control group using a centralised computer-generated random number sequence procedure. The experimental group will receive weekly 3-hour personalised stimulation sessions given by a trained volunteer over the first 12 months. Sessions will encourage empowerment, gradual mobilisation of personal and environmental resources and community integration. The control group will receive the publicly funded universal healthcare services available to all Quebecers. Over 2 years (baseline and 12, 18 and 24 months later), self-administered questionnaires will assess physical and mental health (primary outcome; version 2 of the 36-item Short-Form Health Survey, converted to SF-6D utility scores for quality-adjusted life years), social participation (Social Participation Scale) and life satisfaction (Life Satisfaction Index-Z). Healthcare services utilisation will be recorded and costs of each intervention calculated. ETHICS AND DISSEMINATION: The Research Ethics Committee of the CIUSSS Estrie - CHUS has approved the study (MP-31-2018-2424). An informed consent form will be read and signed by all study participants. Findings will be published and presented at conferences. TRIAL REGISTRATION NUMBER: NCT03161860; Pre-results. PMID- 29605821 TI - Within-subject and between-subject biological variation estimates of 21 hematological parameters in 30 healthy subjects. AB - BACKGROUND: The complete blood count (CBC) is used to evaluate health status in the contexts of various clinical situations such as anemia, infection, inflammation, trauma, malignancies, etc. To ensure safe clinical application of the CBC, reliable biological variation (BV) data are required. The study aim was to define the BVs of CBC parameters employing a strict protocol. METHODS: Blood samples, drawn from 30 healthy subjects (17 females, 13 males) once weekly for 10 weeks, were analyzed using a Sysmex XN 3000 instrument. The data were assessed for normality, trends, outliers and variance homogeneity prior to coefficient of variation (CV)-analysis of variance (ANOVA). Sex-stratified within-subject (CVI) and between-subjects (CVG) BV estimates were determined for 21 CBC parameters. RESULTS: For leukocyte parameters, with the exception of lymphocytes and basophils, significant differences were found between female/male CVI estimates. The mean values of all erythrocyte-, reticulocyte- and platelet parameters differed significantly between the sexes, except for mean corpuscular hemoglobin concentration, mean corpuscular volume and platelet numbers. Most CVI and CVG estimates appear to be lower than those previously published. CONCLUSIONS: Our study, based on a rigorous protocol, provides updated and more stringent BV estimates for CBC parameters. Sex stratification of data is necessary when exploring the significance of changes in consecutive results and when setting analytical performance specifications. PMID- 29605822 TI - SBML Level 3 package: Render, Version 1, Release 1. AB - Many software tools provide facilities for depicting reaction network diagrams in a visual form. Two aspects of such a visual diagram can be distinguished: the layout (i.e.: the positioning and connections) of the elements in the diagram, and the graphical form of the elements (for example, the glyphs used for symbols, the properties of the lines connecting them, and so on). This document describes the SBML Level 3 Render package that complements the SBML Level 3 Layout package and provides a means of capturing the precise rendering of the elements in a diagram. The SBML Level 3 Render package provides a flexible approach to rendering that is independent of both the underlying SBML model and the Layout information. There can be one block of render information that applies to all layouts or an additional block for each layout. Many of the elements used in the current render specification are based on corresponding elements from the SVG specification. This allows us to easily convert a combination of layout information and render information into a SVG drawing. PMID- 29605823 TI - Synthetic Biology Open Language (SBOL) Version 2.2.0. AB - Synthetic biology builds upon the techniques and successes of genetics, molecular biology, and metabolic engineering by applying engineering principles to the design of biological systems. The field still faces substantial challenges, including long development times, high rates of failure, and poor reproducibility. One method to ameliorate these problems would be to improve the exchange of information about designed systems between laboratories. The synthetic biology open language (SBOL) has been developed as a standard to support the specification and exchange of biological design information in synthetic biology, filling a need not satisfied by other pre-existing standards. This document details version 2.2.0 of SBOL that builds upon version 2.1.0 published in last year's JIB special issue. In particular, SBOL 2.2.0 includes improved description and validation rules for genetic design provenance, an extension to support combinatorial genetic designs, a new class to add non-SBOL data as attachments, a new class for genetic design implementations, and a description of a methodology to describe the entire design-build-test-learn cycle within the SBOL data model. PMID- 29605824 TI - Utility of serum resistin in the diagnosis of neonatal sepsis and prediction of disease severity in term and late preterm infants. AB - Introduction Resistin is a proinflammatory hormone recently proposed as a sepsis biomarker. Our aim was to evaluate the diagnostic and prognostic values of this marker in neonatal sepsis. Methods This is a prospective observational study that includes 60 term and late preterm neonates with proven and possible sepsis besides 30 healthy controls. Resistin and other biomarkers, like C-reactive protein (CRP), were measured within 2 h of neonatal intensive care unit (NICU) admission. Infants were monitored and the primary outcome was 30-day mortality. Results Resistin was higher among septic neonates compared with controls (P<0.001). Resistin had an area under the receiver operating characteristic (ROC) curve of 0.994 for differentiating septic infants from controls. The area under the curve (AUC) for differentiating infants with culture-proven sepsis from controls was 0.999 compared with an AUC of 1 for CRP. The other markers, like platelet count, were inferior to resistin and CRP. Resistin was positively correlated with CRP [Spearman's correlation coefficient (rs)=0.55, P<0.001]. No significant differences in resistin levels were noted between survivors and non survivors but resistin was higher among infants with severe sepsis (P=0.015) and among those who needed mechanical ventilation (P<0.001). Conclusion Resistin is useful for the diagnosis of neonatal sepsis. Resistin failed to predict mortality but was associated with indicators of disease severity. PMID- 29605825 TI - Potassium Citrate is Better in Reducing Salt and Increasing Urine pH than Oral Intake of Lemonade: A Cross-Over Study. AB - BACKGROUND Urine solute supersaturation leads to the formation of urinary tract caliceal stones. Many parameters can be involved in the supersaturation of solutes in urine, such as pH. Uric acid has pKa <=5.5, and it is solubilized at pH >=5.5. The objective of the study was to evaluate the effects of potassium citrate and lemonade supplementation in pediatric patients with urolithiasis. MATERIAL AND METHODS A total of 126 children who had lower ureteral stones calculi and fragments with severe colic pain participated in this cross-over study. Children drank lemonade (2 mEq/kg/day citrate) in 3 divided doses for 5 days. After a 15-day washout period, children drank 2 mEq/kg/day of potassium citrate in 3 divided doses for 5 days. On the sixth of the day of individual intervention, a 24-h urine sample was collected and evaluated for pH, urine volume, citrate level, uric acid level, magnesium, phosphorus, potassium, and sodium. Urinary parameters for 1-day urine collection measurements after each supplementation were compared with baseline using the Mann-Whitney test following Tukey post hoc test at 95% confidence level. RESULTS Potassium citrate supplementation resulted in reduction of sodium concentration (p=0.0337; q=3.76) and increased pH of urine (p=0.0118; q=4.389). However, urine volume, citrate level, and uric acid level, as well as elemental magnesium, phosphorus, and potassium, remained unchanged after 5 days of supplementation with potassium citrate or lemonade. CONCLUSIONS Potassium citrate supplementation is an effective therapy for preventing pediatric urolithiasis, with acceptable adverse effects. PMID- 29605826 TI - Triple Negative Breast Cancer Depends on Sphingosine Kinase 1 (SphK1)/Sphingosine 1-Phosphate (S1P)/Sphingosine 1-Phosphate Receptor 3 (S1PR3)/Notch Signaling for Metastasis. AB - BACKGROUND Triple negative breast cancer (TNBC) has a more aggressive recurrence. Previous reports have demonstrated that sphingosine kinase 1 (SphK1) is a crucial regulator of breast cancer progression. However, the correlation of SphK1 with clinical prognosis has been poorly investigated. Thus, we aimed to elaborate the role of SphK1 in TNBC metastasis. MATERIAL AND METHODS We first determined the level of SphK1 in breast cancer tissue samples and breast cancer cells. Furthermore, the expression of HER2 and phosphor-SphK1 (pSphK1) in human breast cancer tissue samples was determined by immunohistochemical analysis. Associations between SphK1 and clinical parameters of tumors were analyzed. The activity of SphK1 was measured by fluorescence analysis. Extracellular sphingosine-1-phosphate (S1P) was detected using an ELISA kit. Associations between SphK1 and metastasis potential were analyzed by Transwell assay. RESULTS Levels of SphK1 in TNBC patients were significantly higher than levels in other patients with other breast tumors. The expression of SphK1 was positively correlated with poor overall survival (OS) and progression-free survival (PFS), as well as poor response to 5-FU and doxorubicin. The depression of SphK1 thus could repress the Notch signaling pathway, reduce migration, and invasion of TNBC cells in vivo and in vitro. Furthermore, silencing of SphK1 by Ad-SPHK1-siRNA or SphK1 inhibitor PF543 sensitized TNBCs to 5-FU and doxorubicin. Our results also indicated that SphK1 inhibition could effectively counteracts tumors metastasis via Notch signaling pathways, indicating a potentially anti-tumor strategy in TNBC. CONCLUSIONS We found that elevated levels of pSphK1 were positive correlation with high expression of S1P, which in turn promoted metastasis of TNBC through S1P/S1PR3/Notch signaling pathway. PMID- 29605827 TI - Prevalence of Self-Reported Food Allergy in Six Regions of Inner Mongolia, Northern China: A Population-Based Survey. AB - BACKGROUND The aim of this study was to determine the prevalence of self-reported food allergy in 6 regions of Inner Mongolia, northern China. MATERIAL AND METHODS A random cluster sampling population study using a field questionnaire was distributed to 4714 individuals in 6 regions within Inner Mongolia, northern China; the study included ethnic Mongol minorities and Chinese Han populations. The questionnaire obtained data on ethnicity, age, sex, level of education, income, socioeconomic status, rural versus urban location, medical and family history, and food allergy. RESULTS There were 4441 (73.5%) completed questionnaires. The prevalence of self-reported food allergy was 18.0% (15.2% men; 20.6% women) and was age-related, being significantly greater in children compared with adults (38.7% vs. 11.9%) (P<0.001). There was a significant difference in self-reported food allergy between rural and urban populations (14.6% vs. 21.4%) (P<0.001) and between Mongolian and Han populations (20.8% vs. 15.8%) (P<0.001). Socioeconomic status, higher education level, and increased family income were significantly correlated with the prevalence of food allergy (P<0.001). Participants with allergic diseases and atopic family history were at increased risk (OR>1, P<0.001). There were no significant associations between the prevalence of food allergy and birth history, infant feeding, and duration of breastfeeding. CONCLUSIONS An increase in the prevalence of self-reported food allergy was found in the Inner Mongolia region of northern China, which was greater in urban areas compared with rural areas. PMID- 29605828 TI - Current and future international patterns of care of neurogenic bladder after spinal cord injury. AB - PURPOSE: We aim to summarize the literature on international patterns of care for patients with neurogenic bladder (NGB) from spinal cord injury (SCI). METHODS: We performed a PubMed database search, hand review of references, communication with professional societies, and registry evaluations for pertinent data. RESULTS: Established patterns of care, including SCI registries and specialty centers, are available in high-resource countries such as the US and UK. As such, mortality rates from complications of NGB/SCI are lower. Access to intermittent catheterization supplies, among other resources, may be inadequate in many low income regions. Cultural and religious beliefs may also hinder integration of proper bladder management in SCI patients. While guidelines exist in many parts of the world, it is unclear how rigorously they are disseminated or followed. CONCLUSIONS: While there is a paucity of high-level evidence, the differences in patterns of care are closely related to socioeconomic status and resources of the geographic area. Future research efforts should focus on improving access to diagnostic modalities, supplies, and specialists in these areas. PMID- 29605829 TI - Home-Based Care and Perceived Quality of Life Among People Living with HIV in Ho Chi Minh City, Viet Nam. AB - We conducted a cross-sectional study to examine the perceptions of quality of life among people living with HIV who received home-based care services administered through outpatient clinics in Ho Chi Minh City, Viet Nam. Data were collected from a sample of 180 consecutively selected participants (86 cases, 94 controls) at four outpatient clinics, all of whom were on antiretroviral therapy. Quality of life was evaluated using the WHOQOL-BREF instrument. In adjusted analysis, those who received home-based care services had a quality of life score 4.08 points higher (on a scale of 100) than those who did not receive home-based care services (CI 95%, 2.32-5.85; p < 0.001). The findings suggest that home based care is associated with higher self-perceptions of quality of life among people living with HIV. PMID- 29605830 TI - Policy Coherence and Interplay between Climate Change Adaptation Policies and the Forestry Sector in Nepal. AB - Least Developed Countries are likely to be hit the hardest by climate change and need focused efforts towards adaptation. Nepal recognizes that it needs to integrate climate change adaptation into various policies, but limited understanding of how to make these policies coherent is among the factors that hinder effective adaptation action. This can lead to wasted resources and lost opportunities. This paper applies concepts from policy coherence for development frameworks and policy content analysis to examine coherence in Nepal's climate and forest policies-and discusses the factors hindering effective implementation. The policies are analyzed at the horizontal/external level at three layers motivation, measures, and planned implementation process. The paper finds that policies are more consistent on motivation level and adaptation measures, but are less coherent on implementation. The National Adaptation Programme of Action (NAPA) is more explicit in identifying institutions, organizations, roles and responsibilities, resource allocation (financial), and a monitoring and evaluation plan for climate change adaptation while other policies such as Climate Change Policy 2011, National Biodiversity Strategy and Action Plan 2014 2020, Forest Policy 2015, and Forest Sector Strategy 2016 have critical gaps in this area. This paper conclude that formulation of a policy, articulating targets, and mobilizing financial resources are in themselves not sufficient to effectively address climate change adaptation. Policy-based legislation is required, together with development of a supportive collaborative multi stakeholder approach at different levels of governance, backed up by effective, collaborative monitoring and enforcement. PMID- 29605832 TI - Foreword for the special issue on Neural Coding. PMID- 29605831 TI - Influence of sleep-disordered breathing assessed by pulse oximetry on long-term clinical outcomes in patients who underwent percutaneous coronary intervention. AB - BACKGROUND: Sleep-disordered breathing (SDB) has been recognized as an important risk factor for coronary artery disease (CAD). However, SDB was not fully examined, because sleep studies are limited. Nocturnal pulse oximetry has been suggested to be a useful tool for evaluating SDB. Therefore, the aim of this study was to investigate the influence of SDB assessed by nocturnal pulse oximetry on clinical outcomes in patients who underwent percutaneous coronary intervention (PCI). METHODS: We conducted a prospective, multicenter, observational cohort study, wherein SDB was assessed by finger pulse oximetry in patients who underwent PCI from January 2014 to December 2016. SDB was defined as 4% oxygen desaturation index of 5 and higher. The primary endpoint was major adverse cardiac or cerebrovascular event (MACCE), defined as a composite of all cause mortality, acute coronary syndrome, and/or stroke. RESULTS: Of 539 patients, 296 (54.9%) had SDB. MACCE occurred in 32 patients (5.8%) during a median follow-up of 1.9 years. The cumulative incidence of MACCE was significantly higher in patients with SDB (P = 0.0134). In the stepwise multivariable Cox proportional model, the presence of SDB was a significant predictor of MACCE (hazard ratio 2.26; 95% confidence interval 1.05-5.4, P = 0.036). CONCLUSIONS: SDB determined by nocturnal pulse oximetry was associated with worse clinical outcomes in patients who underwent PCI. Screening for SDB with nocturnal pulse oximetry was considered to be important for risk stratification in patients with CAD. PMID- 29605833 TI - Phylogenetic insights on Mediterranean and Afrotropical Rhipicephalus species (Acari: Ixodida) based on mitochondrial DNA. AB - A multigene phylogeny including 24 Rhipicephalus species from the Afrotropical and Mediterranean regions, based on mitochondrial DNA genes (COI, 12S and 16S), was constructed based on Bayesian inference and maximum likelihood estimations. The phylogenetic reconstruction revealed 31 Rhipicephalus clades, which include the first molecular records of Rhipicephalus duttoni (Neumann), and Rhipicephalus senegalensis (Koch). Our results support the R. pulchellus, R. evertsi and R. pravus complexes as more phylogenetically close to Rhipicephalus (Boophilus) than to the remaining Rhipicephalus clades, suggesting two main monophyletic groups within the genus. Additionally, the phenotypic resembling R. sanguineus s.l. and Rhipicephalus turanicus (Pomerantsev) are here represented by nine clades, of which none of the R. turanicus assemblages appeared as distributed in the Iberian Peninsula. These results not only indicate that both species include more cryptic diversity than the already reported, but also suggest that R. turanicus distribution is less extended than previously anticipated. This analysis allowed to improve species identification by exposing cryptic species and reinforced mtDNA markers suitability for intra/inter-species clarification analyses. Incorporating new species molecular records to improve phylogenetic clarification can significantly improve ticks' identification methods which will have epidemiologic implications on public health. PMID- 29605834 TI - Electromagnetic radiation and behavioural response of ticks: an experimental test. AB - Factors associated with the increased usage of electronic devices, wireless technologies and mobile phones nowadays are present in increasing amounts in our environment. All living organisms are constantly affected by electromagnetic radiation which causes serious environmental pollution. The distribution and density of ticks in natural habitats is influenced by a complex of abiotic and biotic factors. Exposure to radio-frequency electromagnetic field (RF-EMF) constitutes a potential cause altering the presence and distribution of ticks in the environment. Our main objective was to determine the affinity of Dermacentor reticulatus ticks towards RF-EMF exposure. Originally designed and constructed radiation-shielded tube (RST) test was used to test the affinity of ticks under controlled laboratory conditions. All test were performed in an electromagnetic compatibility laboratory in an anechoic chamber. Ticks were irradiated using a Double-Ridged Waveguide Horn Antenna to RF-EMF at 900 and 5000 MHz, 0 MHz was used as control. The RF-EMF exposure to 900 MHz induced a higher concentration of ticks on irradiated arm of RST as opposed to the RF-EMF at 5000 MHz, which caused an escape of ticks to the shielded arm. This study represents the first experimental evidence of RF-EMF preference in D. reticulatus. The projection of obtained results to the natural environment could help assess the risk of tick borne diseases and could be a tool of preventive medicine. PMID- 29605835 TI - Microwave-assisted green synthesis of 4,5-dihydro-1H-pyrazole-1-carbothioamides in water. AB - Rapid, efficient, simple and green procedure for the synthesis of 4,5-dihydro-1H pyrazole-1-carbothioamides via the multicomponent reaction of aryl aldehydes, acetophenones and thiosemicarbazide in water in the presence of tetrabutylammonium hydroxide under microwave irradiation is reported. PMID- 29605836 TI - Structure and function of anticoagulation clinics in the United States: an AC forum membership survey. AB - Many anticoagulation clinics have adapted their services to provide care for patients taking direct oral anticoagulants (DOAC) in addition to traditional warfarin management. Anticoagulation clinic scope of service and operations in this transitional environment have not been well described in the literature. A survey was conducted of United States-based Anticoagulation Forum members to inquire about anticoagulation clinic structure, function, and services provided. Survey responses are reported using summary or non-parametric statistics, when appropriate. Unique clinic survey responses were received from 159 anticoagulation clinics. Clinic structure and staffing are highly variable, with approximately half of clinics (52%) providing DOAC-focused care in addition to traditional warfarin-focused care. Of those clinics managing DOAC patients, this accounts for only 10% of their clinic volume. These clinics commonly have a DOAC follow up protocol (75%). Clinics assign a median of 190.5 (interquartile range 50-300) patients per staff full-time-equivalent, with more patients assigned in phone-based care clinics than in face-to-face based care clinics. Most clinics (68.5%) report receiving reimbursement, which occur either through a combination of patient and insurance provider billing (78.2%), insurance reimbursement only (19.5%) or patient reimbursement only (2.3%). There is wide heterogeneity in anticoagulation clinic structure, function, and services provided. Half of all survey-responding anticoagulation clinics provide care for DOAC-treated patients. Understanding how changes in healthcare policy and reimbursement have impacted these clinics remains to be explored. PMID- 29605837 TI - Pathophysiology of Noncardiac Syncope in Athletes. AB - The most frequent cause of syncope in young athletes is noncardiac etiology. The mechanism of noncardiac syncope (NCS) in young athletes is neurally-mediated (reflex). NCS in athletes usually occurs either as orthostasis-induced, due to a gravity-mediated reduced venous return to the heart, or in the context of exercise. Exercise-related NCS typically occurs after the cessation of an exercise bout, while syncope occurring during exercise is highly indicative of the existence of a cardiac disorder. Postexercise NCS appears to result from hypotension due to impaired postexercise vasoconstriction, as well as from hypocapnia. The mechanisms of postexercise hypotension can be divided into obligatory (which are always present and include sympathoinhibition, histaminergic vasodilation, and downregulation of cardiovagal baroreflex) and situational (which include dehydration, hyperthermia and gravitational stress). Regarding postexercise hypocapnia, both hyperventilation during recovery from exercise and orthostasis-induced hypocapnia when recovery occurs in an upright posture can produce postexercise cerebral vasoconstriction. Athletes have been shown to exhibit differential orthostatic responses compared with nonathletes, involving augmented stroke volume and increased peripheral vasodilation in the former, with possibly lower propensity to orthostatic intolerance. PMID- 29605838 TI - Assessment of Skeletal Muscle Contractile Properties by Radial Displacement: The Case for Tensiomyography. AB - Skeletal muscle operates as a near-constant volume system; as such muscle shortening during contraction is transversely linked to radial deformation. Therefore, to assess contractile properties of skeletal muscle, radial displacement can be evoked and measured. Mechanomyography measures muscle radial displacement and during the last 20 years, tensiomyography has become the most commonly used and widely reported technique among the various methodologies of mechanomyography. Tensiomyography has been demonstrated to reliably measure peak radial displacement during evoked muscle twitch, as well as muscle twitch speed. A number of parameters can be extracted from the tensiomyography displacement/time curve and the most commonly used and reliable appear to be peak radial displacement and contraction time. The latter has been described as a valid non-invasive means of characterising skeletal muscle, based on fibre-type composition. Over recent years, applications of tensiomyography measurement within sport and exercise have appeared, with applications relating to injury, recovery and performance. Within the present review, we evaluate the perceived strengths and weaknesses of tensiomyography with regard to its efficacy within applied sports medicine settings. We also highlight future tensiomyography areas that require further investigation. Therefore, the purpose of this review is to critically examine the existing evidence surrounding tensiomyography as a tool within the field of sports medicine. PMID- 29605839 TI - Genomic changes in an attenuated genotype I Japanese encephalitis virus and comparison with virulent parental strain. AB - Genotype I Japanese encephalitis virus (JEV) strain SCYA201201 was previously isolated from brain tissues of aborted piglets. In this study, we obtained an attenuated SCYA201201-0901 strain by serial passage of strain SCYA201201-1 in Syrian baby hamster kidney cells, combined with multiple plaque purifications and selection for virulence in mice. We investigated the genetic changes associated with attenuation by comparing the entire genomes of SCYA201201-0901 and SCYA201201-1. Sequence comparisons identified 14 common amino acid substitutions in the coding region, with two nucleotide point mutations in the 5'-untranslated region (UTR) and another three in the 3'-UTR, which differed between the attenuated and virulent strains. In addition, a total of 13 silent nucleotide mutations were found after attenuation. These substitutions, alone or in combination, may be responsible for the attenuated phenotype of the SCYA201201 0901 strain in mice. This information will contribute to our understanding of attenuation and of the molecular basis of virulence in genotype I strains such as SCYA201201-0901, as well as aiding the development of safer JEV vaccines. PMID- 29605840 TI - Targeted Gene Deletion in Cordyceps militaris Using the Split-Marker Approach. AB - The macrofungus Cordyceps militaris contains many kinds of bioactive ingredients that are regulated by functional genes, but the functions of many genes in C. militaris are still unknown. In this study, to improve the frequency of homologous integration, a genetic transformation system based on a split-marker approach was developed for the first time in C. militaris to knock out a gene encoding a terpenoid synthase (Tns). The linear and split-marker deletion cassettes were constructed and introduced into C. militaris protoplasts by PEG mediated transformation. The transformation of split-marker fragments resulted in a higher efficiency of targeted gene disruption than the transformation of linear deletion cassettes did. The color phenotype of the Tns gene deletion mutants was different from that of wild-type C. militaris. Moreover, a PEG-mediated protoplast transformation system was established, and stable genetic transformants were obtained. This method of targeted gene deletion represents an important tool for investigating the role of C. militaris genes. PMID- 29605842 TI - Sustainability in humanitarian surgery during medical short-term trips (MSTs): feasibility of inguinal hernia repair in rural Nigeria over 6 years and 13 missions. AB - PURPOSE: Surgical teaching missions are known to contribute significantly in reducing the local burden of disease. However, the value of short-term medical service trips (MSTs) remains under debate. Humanitarian surgery is highly dependent on funding, and consequently, data evaluation is needed to secure funding for future projects. The aim of this trial is to evaluate the results of 6-year MSTs to rural Nigeria with a specific emphasis on hernia repairs. METHODS: Retrospective series of consecutive operations performed between 2011 and 2016 in rural Nigeria during 13 MSTs. Operations were categorized into type and number of procedures and origin of the surgeon. In terms of inguinal hernia repairs additional data was evaluated such as frequency of local anaesthesia (LA) and the type of hernia. The total amount of disability-adjusted life years (DALYs) averted during each mission are presented and discussed with regard to sustainability of these missions. RESULTS: From 2011 to 2016, a total of 1674 patients were operated. Of these, 1302 patients were operated for 1481 hernias of which 36.7% accounting as inguinoscrotal hernias. The percentage of operations performed by Nigerian staff increased from 31 to 55%. Overall, eighteen percent of the operations was solely performed by Nigerians. Totally, we averted 8092.83 DALY's accounting for 5.46 DALY's per hernia. CONCLUSION: The presented missions contribute significantly to an improvement in local healthcare and decrease the burden of disease. We were able to show the sustainable character of these surgical missions. As a next step, we will analyse the cost-effectiveness of MSTs. PMID- 29605841 TI - Secukinumab Versus Adalimumab for Psoriatic Arthritis: Comparative Effectiveness up to 48 Weeks Using a Matching-Adjusted Indirect Comparison. AB - INTRODUCTION: Secukinumab and adalimumab are approved for adults with active psoriatic arthritis (PsA). In the absence of direct randomized controlled trial (RCT) data, matching-adjusted indirect comparison can estimate the comparative effectiveness in anti-tumor necrosis factor (TNF)-naive populations. METHODS: Individual patient data from the FUTURE 2 RCT (secukinumab vs. placebo; N = 299) were adjusted to match baseline characteristics of the ADEPT RCT (adalimumab vs. placebo; N = 313). Logistic regression determined adjustment weights for age, body weight, sex, race, methotrexate use, psoriasis affecting >= 3% of body surface area, Psoriasis Area and Severity Index score, Health Assessment Questionnaire Disability Index score, presence of dactylitis and enthesitis, and previous anti-TNF therapy. Recalculated secukinumab outcomes were compared with adalimumab outcomes at weeks 12 (placebo-adjusted), 16, 24, and 48 (nonplacebo adjusted). RESULTS: After matching, the effective sample size for FUTURE 2 was 101. Week 12 American College of Rheumatology (ACR) response rates were not significantly different between secukinumab and adalimumab. Week 16 ACR 20 and 50 response rates were higher for secukinumab 150 mg than for adalimumab (P = 0.017, P = 0.033), as was ACR 50 for secukinumab 300 mg (P = 0.030). Week 24 ACR 20 and 50 were higher for secukinumab 150 mg than for adalimumab (P = 0.001, P = 0.019), as was ACR 20 for secukinumab 300 mg (P = 0.048). Week 48 ACR 20 was higher for secukinumab 150 and 300 mg than for adalimumab (P = 0.002, P = 0.027), as was ACR 50 for secukinumab 300 mg (P = 0.032). CONCLUSIONS: In our analysis, patients with PsA receiving secukinumab were more likely to achieve higher ACR responses through 1 year (weeks 16-48) than those treated with adalimumab. Although informative, these observations rely on a subgroup of patients from FUTURE 2 and thus should be considered interim until the ongoing head-to-head RCT EXCEED can validate these findings. FUNDING: Novartis Pharma AG. PMID- 29605844 TI - CpG Islands: A Historical Perspective. AB - The discovery of CpG islands (CGIs) and the study of their structure and properties run parallel to the development of molecular biology in the last two decades of the twentieth century and to the development of high-throughput genomic technologies at the turn of the millennium. First identified as discrete G + C-rich regions of unmethylated DNA in several vertebrates, CGIs were soon found to display additional distinctive chromatin features from the rest of the genome in terms of accessibility and of the epigenetic modifications of their histones. These features, together with their colocalization with promoters and with origins of DNA replication in mammals, highlighted their relevance in the regulation of genomic processes. Recent approaches have shown with unprecedented detail the dynamics and diversity of the epigenetic landscape of CGIs during normal development and under pathological conditions. Also, comparative analyses across species have started revealing how CGIs evolve and contribute to the evolution of the vertebrate genome. PMID- 29605843 TI - Mesh migration into an inguinal hernia sac following a laparoscopic umbilical hernia repair. PMID- 29605845 TI - Biochemical Identification of Nonmethylated DNA by BioCAP-Seq. AB - CpG islands are regions of vertebrate genomes that often function as gene regulatory elements and are associated with most gene promoters. CpG island elements usually contain nonmethylated CpG dinucleotides, while the remainder of the genome is pervasively methylated. We developed a biochemical approach called biotinylated CxxC affinity purification (BioCAP) to unbiasedly isolate regions of the genome that contain nonmethylated CpG dinucleotides. The resulting highly pure nonmethylated DNA is easily analyzed by quantitative PCR to interrogate specific loci or via massively parallel sequencing to yield genome-wide profiles. PMID- 29605846 TI - Prediction of CpG Islands as an Intrinsic Clustering Property Found in Many Eukaryotic DNA Sequences and Its Relation to DNA Methylation. AB - The promoter region of around 70% of all genes in the human genome is overlapped by a CpG island (CGI). CGIs have known functions in the transcription initiation and outstanding compositional features like high G+C content and CpG ratios when compared to the bulk DNA. We have shown before that CGIs manifest as clusters of CpGs in mammalian genomes and can therefore be detected using clustering methods. These techniques have several advantages over sliding window approaches which apply compositional properties as thresholds. In this protocol we show how to determine local (CpG islands) and global (distance distribution) clustering properties of CG dinucleotides and how to generalize this analysis to any k-mer or combinations of it. In addition, we illustrate how to easily cross the output of a CpG island prediction algorithm with our methylation database to detect differentially methylated CGIs. The analysis is given in a step-by-step protocol and all necessary programs are implemented into a virtual machine or, alternatively, the software can be downloaded and easily installed. PMID- 29605847 TI - CpG Islands in Cancer: Heads, Tails, and Sides. AB - DNA methylation is a dynamic epigenetic mark that characterizes different cellular developmental stages, including tissue-specific profiles. This CpG dinucleotide modification cooperates in the regulation of the output of the cellular genetic content, in both healthy and pathological conditions. According to endogenous and exogenous stimuli, DNA methylation is involved in gene transcription, alternative splicing, imprinting, X-chromosome inactivation, and control of transposable elements. When these dinucleotides are organized in dense regions are called CpG islands (CGIs), being commonly known as transcriptional regulatory regions frequently associated with the promoter region of several genes. In cancer, promoter DNA hypermethylation events sustained the mechanistic hypothesis of epigenetic transcriptional silencing of an increasing number of tumor suppressor genes. CGI hypomethylation-mediated reactivation of oncogenes was also documented in several cancer types. In this chapter, we aim to summarize the functional consequences of the differential DNA methylation at CpG dinucleotides in cancer, focused in CGIs. Interestingly, cancer methylome is being recently explored, looking for biomarkers for diagnosis, prognosis, and predictors of drug response. PMID- 29605848 TI - Infinium DNA Methylation Microarrays on Formalin-Fixed, Paraffin-Embedded Samples. AB - Formalin-fixed, paraffin-embedded (FFPE) samples usually yield fragmented DNA, which is incompatible with traditional Infinium Methylation beadchips. In this chapter, we aim to explain in detail all the processes carried out in order to obtain high-quality methylation profiles from FFPE samples through an FFPE restoration procedure. High-throughput methylation profiling platforms such as the Infinium Methylation beadchips have been extensively used by the scientific community to elucidate many hypotheses in multiple scenarios, now with the incorporation of FFPE samples to these platforms, a myriad of new opportunities is being opened. PMID- 29605849 TI - The Use of Methylation-Sensitive Multiplex Ligation-Dependent Probe Amplification for Quantification of Imprinted Methylation. AB - Imprinting disorders are a group of congenital diseases that can result from multiple mechanisms affecting imprinted gene dosage including cytogenetic aberration and epigenetic anomalies. Quantification of CpG methylation and correct copy-number calling is required for molecular diagnosis. Methylation sensitive multiplex ligation-dependent probe amplification (MS-MLPA) is a multiplex method that accurately measures both parameters in a single assay. This technique relies upon the ligation of MLPA probe oligonucleotides and digestion of the genomic DNA-probe hybrid complexes with the Hha1 methylation-sensitive restriction endonuclease prior to fluorescent PCR amplification with a single primer pair. Since each targeted probe contains stuffer sequence of varying length, each interrogated position is visualized as an amplicon of different size upon capillary electrophoresis. PMID- 29605850 TI - The Pancancer DNA Methylation Trackhub: A Window to The Cancer Genome Atlas Epigenomics Data. AB - The Cancer Genome Atlas (TCGA) epigenome data includes the DNA methylation status of tumor and normal tissues of large cohorts for dozens of cancer types. Due to the moderately large data sizes, retrieving and analyzing them requires basic programming skills. Simple data browsing (e.g., candidate gene search) is hampered by the scarcity of easy-to-use data browsers addressed to the broad community of biomedical researchers. We propose a new visualization method depicting the overall DNA methylation status at each TCGA cohort while emphasizing its heterogeneity, thus facilitating the evaluation of the cohort variability and the normal versus tumor differences. Implemented as a trackhub integrated to the University of California Santa Cruz (UCSC) genome browser, it can be easily added to any genome-wide annotation layer.To exemplify the trackhub usage we evaluate local DNA methylation boundaries, the aberrant DNA methylation of a CpG island located at the estrogen receptor 1 (ESR1) in breast and colon cancer, and the hypermethylation of the Homeobox HOXA gene cluster and the EN1 gene in multiple cancer types. The DNA methylation pancancer trackhub is freely available at http://maplab.cat/tcga_450k_trackhub . PMID- 29605851 TI - Methylation-Sensitive Amplification Length Polymorphism (MS-AFLP) Microarrays for Epigenetic Analysis of Human Genomes. AB - Somatic, and in a minor scale also germ line, epigenetic aberrations are fundamental to carcinogenesis, cancer progression, and tumor phenotype. DNA methylation is the most extensively studied and arguably the best understood epigenetic mechanisms that become altered in cancer. Both somatic loss of methylation (hypomethylation) and gain of methylation (hypermethylation) are found in the genome of malignant cells. In general, the cancer cell epigenome is globally hypomethylated, while some regions-typically gene-associated CpG islands become hypermethylated. Given the profound impact that DNA methylation exerts on the transcriptional profile and genomic stability of cancer cells, its characterization is essential to fully understand the complexity of cancer biology, improve tumor classification, and ultimately advance cancer patient management and treatment. A plethora of methods have been devised to analyze and quantify DNA methylation alterations. Several of the early-developed methods relied on the use of methylation-sensitive restriction enzymes, whose activity depends on the methylation status of their recognition sequences. Among these techniques, methylation-sensitive amplification length polymorphism (MS-AFLP) was developed in the early 2000s, and successfully adapted from its original gel electrophoresis fingerprinting format to a microarray format that notably increased its throughput and allowed the quantification of the methylation changes. This array-based platform interrogates over 9500 independent loci putatively amplified by the MS-AFLP technique, corresponding to the NotI sites mapped throughout the human genome. PMID- 29605852 TI - Genome-Wide Profiling of DNA Methyltransferases in Mammalian Cells. AB - Chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) is currently the method of choice to determine binding sites of chromatin associated factors in a genome-wide manner. Here, we describe a method to investigate the binding preferences of mammalian DNA methyltransferases (DNMT) based on ChIP-seq using biotin-tagging. Stringent ChIP of DNMT proteins based on the strong interaction between biotin and avidin circumvents limitations arising from low antibody specificity and ensures reproducible enrichment. DNMT-bound DNA fragments are ligated to sequencing adaptors, amplified and sequenced on a high throughput sequencing instrument. Bioinformatic analysis gives valuable information about the binding preferences of DNMTs genome-wide and around promoter regions. This method is unconventional due to the use of genetically engineered cells; however, it allows specific and reliable determination of DNMT binding. PMID- 29605853 TI - Experimental Design and Bioinformatic Analysis of DNA Methylation Data. AB - DNA methylation is a crucial regulatory mechanism of gene expression, affected in many human pathologies. Therefore, it is not surprising that nowadays, in the era of high-throughput methods, a lot of data sets representing DNA methylation in various conditions are available and the amount of such data keeps growing. In this chapter, we discuss those aspects of experiment planning and data analysis, which we consider the most important for reliability and reproducibility of DNA methylation studies: usage of replicates, data quality control at various stages, selection of a statistical model, and incorporation of DNA methylation into the multi-omics analysis. PMID- 29605854 TI - Assay for Transposase Accessible Chromatin (ATAC-Seq) to Chart the Open Chromatin Landscape of Human Pancreatic Islets. AB - The regulatory mechanisms that ensure an accurate control of gene transcription are central to cellular function, development and disease. Such mechanisms rely largely on noncoding regulatory sequences that allow the establishment and maintenance of cell identity and tissue-specific cellular functions.The study of chromatin structure and nucleosome positioning allowed revealing transcription factor accessible genomic sites with regulatory potential, facilitating the comprehension of tissue-specific cis-regulatory networks. Recently a new technique coupled with high-throughput sequencing named Assay for Transposase Accessible Chromatin (ATAC-seq) emerged as an efficient method to chart open chromatin genome wide. The application of such technique to different cell types allowed unmasking tissue-specific regulatory elements and characterizing cis regulatory networks. Herein we describe the implementation of the ATAC-seq method to human pancreatic islets, a tissue playing a central role in the control of glucose metabolism. PMID- 29605855 TI - Defining Regulatory Elements in the Human Genome Using Nucleosome Occupancy and Methylome Sequencing (NOMe-Seq). AB - NOMe-seq (nucleosome occupancy and methylome sequencing) identifies nucleosome depleted regions that correspond to promoters, enhancers, and insulators. The NOMe-seq method is based on the treatment of chromatin with the M.CviPI methyltransferase, which methylates GpC dinucleotides that are not protected by nucleosomes or other proteins that are tightly bound to the chromatin (GpCm does not occur in the human genome and therefore there is no endogenous background of GpCm). Following bisulfite treatment of the M.CviPI-methylated chromatin (which converts unmethylated Cs to Ts and thus allows the distinction of GpC from GpCm) and subsequent genomic sequencing, nucleosome-depleted regions can be ascertained on a genome-wide scale. The bisulfite treatment also allows the distinction of CpG from CmpG (most endogenous methylation occurs at CpG dinucleotides) and thus the endogenous methylation status of the genome can also be obtained in the same sequencing reaction. Importantly, open chromatin is expected to have high levels of GpCm but low levels of CmpG; thus, each of the two separate methylation analyses serve as independent (but opposite) measures which provide matching chromatin designations for each regulatory element.NOMe-seq has advantages over ChIP-seq for identification of regulatory elements because it is not reliant upon knowing the exact modifications on the surrounding nucleosomes. Also, NOMe-seq has advantages over DHS (DNase hypersensitive site)-seq, FAIRE (Formaldehyde Assisted Isolation of Regulatory Elements)-seq, and ATAC (Assay for Transposase Accessible Chromatin)-seq because it also gives positioning information for several nucleosomes on either side of each open regulatory element. Here, we provide a detailed protocol for NOMe-seq that begins with the isolation of chromatin, followed by methylation of GpCs with M.CviPI and treatment with bisulfite, and ending with the creation of next generation sequencing libraries. We also include sequencing QC analysis metrics and bioinformatics steps that can be used to identify nucleosome-depleted regions throughout the genome. PMID- 29605856 TI - Genome-Wide Mapping of Protein-DNA Interactions on Nascent Chromatin. AB - Chromatin immunoprecipitation (ChIP) is the most widely used method to analyze protein-DNA interactions in vivo. Coupled with next generation sequencing, ChIP seq experiments map protein-DNA interactions in a genome-wide fashion. Here we describe a novel method called nasChIP-seq for mapping genome-wide occupancy of posttranslationally modified histones or transcription factors on newly replicated DNA. PMID- 29605857 TI - Analysis of Chromatin Interactions Mediated by Specific Architectural Proteins in Drosophila Cells. AB - Chromosome conformation capture assays have been established, modified, and enhanced for over a decade with the purpose of studying nuclear organization. A recently published method uses in situ Hi-C followed by chromatin immunoprecipitation (HiChIP) to enrich the overall yield of significant genome wide interactions mediated by a specific protein. Here we applied a modified version of the HiChIP protocol to retrieve the significant contacts mediated by architectural protein CP190 in D. melanogaster cells. PMID- 29605858 TI - High-Throughput Single-Cell RNA Sequencing and Data Analysis. AB - Understanding biological systems at a single cell resolution may reveal several novel insights which remain masked by the conventional population-based techniques providing an average readout of the behavior of cells. Single-cell transcriptome sequencing holds the potential to identify novel cell types and characterize the cellular composition of any organ or tissue in health and disease. Here, we describe a customized high-throughput protocol for single-cell RNA-sequencing (scRNA-seq) combining flow cytometry and a nanoliter-scale robotic system. Since scRNA-seq requires amplification of a low amount of endogenous cellular RNA, leading to substantial technical noise in the dataset, downstream data filtering and analysis require special care. Therefore, we also briefly describe in-house state-of-the-art data analysis algorithms developed to identify cellular subpopulations including rare cell types as well as to derive lineage trees by ordering the identified subpopulations of cells along the inferred differentiation trajectories. PMID- 29605859 TI - Functional Insulator Scanning of CpG Islands to Identify Regulatory Regions of Promoters Using CRISPR. AB - The ability to mutate a promoter in situ is potentially a very useful approach for gaining insights into endogenous gene regulation mechanisms. The advent of CRISPR/Cas systems has provided simple, efficient, and targeted genetic manipulation in eukaryotes, which can be applied to studying genome structure and function.The basic CRISPR toolkit comprises an endonuclease, Cas9, and a short DNA-targeting sequence, made up of a single guide RNA (sgRNA). The catalytic domains of Cas9 are rendered active upon dimerization of Cas9 with sgRNA, resulting in targeted double stranded DNA breaks. Among other applications, this method of DNA cleavage can be coupled to endogenous homology-directed repair (HDR) mechanisms for the generation of site-specific editing or knockin mutations, at both promoter regulatory and gene coding sequences.A well characterized regulatory feature of promoter regions is the high abundance of CpGs. These CpG islands tend to be unmethylated, ensuring a euchromatic environment that promotes gene transcription. Here, we demonstrate CRISPR mediated editing of two CpG islands located within the promoter region of the MDR1 gene (Multi Drug Resistance 1). Cas9 is used to generate double stranded breaks across multiple target sites, which are then repaired while inserting the beta globin (beta-globin) insulator, 5'HS5. Thus, we are screening through promoter regulatory sequences with a chromatin barrier element to identify functional regions via "insulator scanning." Transcriptional and functional assessment of MDR1 expression provides evidence of genome engineering. Overall, this method allows the scanning of CpG islands to identify their promoter functions. PMID- 29605860 TI - An Application-Directed, Versatile DNA FISH Platform for Research and Diagnostics. AB - DNA fluorescence in situ hybridization (DNA FISH) has emerged as a powerful microscopy technique that allows a unique view into the composition and arrangement of the genetic material in its natural context-be it the cell nucleus in interphase, or chromosomes in metaphase spreads. The core principle of DNA FISH is the ability of fluorescently labeled DNA probes (either double- or single stranded DNA fragments) to bind to their complementary sequences in situ in cells or tissues, revealing the location of their target as fluorescence signals detectable with a fluorescence microscope. Numerous variants and improvements of the original DNA FISH method as well as a vast repertoire of applications have been described since its inception more than 4 decades ago. In recent years, the development of many new fluorescent dyes together with drastic advancements in methods for probe generation (Boyle et al., Chromosome Res 19:901-909, 2011; Beliveau et al., Proc Natl Acad Sci U S A 109:21301-21306, 2012; Bienko et al., Nat Methods 10:122-124, 2012), as well as improvements in the resolution of microscopy technologies, have boosted the number of DNA FISH applications, particularly in the field of genome architecture (Markaki et al., Bioessays 34:412-426, 2012; Beliveau et al., Nat Commun 6:7147, 2015). However, despite these remarkable steps forward, choosing which type of DNA FISH sample preparation protocol, probe design, hybridization procedure, and detection method is best suited for a given application remains still challenging for many research labs, preventing a more widespread use of this powerful technology. Here, we present a comprehensive platform to help researchers choose which DNA FISH protocol is most suitable for their particular application. In addition, we describe computational pipelines that can be implemented for efficient DNA FISH probe design and for signal quantification. Our goal is to make DNA FISH a versatile and streamlined technique that can be easily implemented by both research and diagnostic labs. PMID- 29605862 TI - Correction to: Does increased femoral antetorsion predispose to cartilage lesions of the patellofemoral joint? AB - Unfortunately, the following reference was not included in the original publication of the article. PMID- 29605861 TI - Synergistic activity of platelet rich plasma and high volume image guided injection for patellar tendinopathy. AB - PURPOSE: Platelet rich plasma and high volume image guided injections of saline have been used in the treatment of patellar tendinopathy with positive results. As the different mechanisms of action do not interfere each other, it can be hypothesized that they can be used in combination. Aim of this study was twofold: first, to evaluate the efficacy of these two treatments in the management of patellar tendinopathy; second, to verify whether the combination of these therapies could provide further advantages. METHODS: Fifty-four patients suffering from patellar tendinopathy were enrolled. After clinical (VAS and VISA P) and sonographic evaluation, two ultrasound guided injections (2 weeks apart) of platelet rich plasma, high-volume image-guided injections of saline, or both in association were performed. The VAS and VISA-P scores obtained from the three treatments groups (18 patients in each group) were compared across the different follow-up times (3 and 6 months). RESULTS: In the short term both treatments showed comparable efficacy, whereas in the medium term the positive effects of high-volume image-guided injections gradually diminished and platelet rich plasma showed greater efficacy. Better results (reduced pain, improved function and increased number of subjects who exhibited optimal recovery [> 20 points in VISA P score]) were observed when both procedures were associated. CONCLUSIONS: The contemporaneous administration of platelet rich plasma and high volume image guided injections of saline treatments, which influence tendon repair by means of different mechanisms, grants a greater improvement for patellar tendinopathy. This finding has clinical relevance, given that this condition has a substantial impact on sports and work performance. LEVEL OF EVIDENCE: III. PMID- 29605863 TI - Increased tenascin C and DKK1 in vitiligo: possible role of fibroblasts in acral and non-acral disease. AB - Recently, multiple culprits-in addition to melanocytes-have been implicated in the pathogenesis of vitiligo. Among those factors are fibroblasts. However, their exact role has not been clearly elucidated. The aim of the study was to evaluate the possible role played by fibroblasts in vitiligo via studying the expression Tenascin C and DKK1 in acral versus non-acral vitiligo lesions. This case-control study included 19 non-segmental vitiligo patients and ten controls. All patients were subjected to thorough clinical evaluation. Both Tenascin C and DKK1 were measured in lesional and peri-lesional skin of acral and non-acral lesions using ELISA technique. The measured levels of Tenascin C and DKK1 were significantly higher in the vitiligo group when compared to controls in all assessed sites (P < 0.05). Tenascin C was found to be significantly higher in lesional areas compared to peri-lesional ones only in the acral sites. DKK1 was significantly higher in lesional areas in all assessed sites (P < 0.05). The current work suggests a malfunction of fibroblasts in vitiligo, through demonstrating significant up regulation of two melanogenesis inhibitory products (Tenascin C and DKK1) in patients compared to controls. Larger scale studies are warranted to detect the possible implications of such findings on vitiligo treatment. PMID- 29605864 TI - Robotic kidney autotransplantation in a porcine model: a procedure-specific training platform for the simulation of robotic intracorporeal vascular anastomosis. AB - Robotic-assisted kidney transplantation (RKT) with the Da Vinci (Intuitive, USA) platform has been recently developed to improve outcomes by decreasing surgical site complications and morbidity, especially in obese patients. This potential paradigm shift in the surgical technique of kidney transplantation is performed in only a few centers. For wider adoption of this high stake complex operation, we aimed to develop a procedure-specific simulation platform in a porcine model for the training of robotic intracorporeal vascular anastomosis and evaluating vascular anastomoses patency. This paper describes the requirements and steps developed for the above training purpose. Over a series of four animal ethics' approved experiments, the technique of robotic-assisted laparoscopic autotransplantation of the kidney was developed in Amsterdam live pigs (60-70 kg). The surgery was based around the vascular anastomosis technique described by Menon et al. This non-survival porcine training model is targeted at transplant surgeons with robotic surgery experience. Under general anesthesia, each pig was placed in lateral decubitus position with the placement of one robotic camera port, two robotic 8 mm ports and one assistant port. Robotic docking over the pig posteriorly was performed. The training platform involved the following procedural steps. First, ipsilateral iliac vessel dissection was performed. Second, robotic-assisted laparoscopic donor nephrectomy was performed with in situ perfusion of the kidney with cold Hartmann's solution prior to complete division of the hilar vessels, ureter and kidney mobilization. Thirdly, the kidney was either kept in situ for orthotopic autotransplantation or mobilized to the pelvis and orientated for the vascular anastomosis, which was performed end to end or end to side after vessel loop clamping of the iliac vessels, respectively, using 6/0 Gore-Tex sutures. Following autotransplantation and release of vessel loops, perfusion of the graft was assessed using intraoperative indocyanine green imaging and monitoring urine output after unclamping. This training platform demonstrates adequate face and content validity. With practice, arterial anastomotic time could be improved, showing its construct validity. This porcine training model can be useful in providing training for robotic intracorporeal vascular anastomosis and may facilitate confident translation into a transplant human recipient. PMID- 29605865 TI - Intratympanic steroid use for idiopathic sudden sensorineural hearing loss: current otolaryngology practice in Germany and Austria. AB - AIMS: The frequency of the use of intratympanic steroids (ITS) as a treatment for idiopathic sudden sensorineural hearing loss (ISSNHL) in Europe is still unknown and remains a contentious issue amongst otolaryngologists. We undertook a survey of otolaryngologists in Germany and Austria to establish if there is any professional consensus with which to form a protocol for its use. METHODS: A survey of 21 questions was distributed electronically to otolaryngologists in Germany and Austria and data on demographics, indications for intratympanic treatment, procedure, follow-up, and outcomes were analysed. RESULTS: We received 908 responses. 49.1% of otolaryngologists used ITS for ISSNHL. Of those otolaryngologists who use ITS, 73.7% do not use it as primary treatment. 20.6% use ITS in conjunction with oral steroids for primary treatment and only 5.8% use ITS as monotherapy for primary treatment. 90.5% use ITS as salvage therapy. 81.1% do not consider the use of ITS after 2 weeks from the onset of symptoms. 8.3% used a tympanostomy tube and while the most commonly used steroid was dexamethasone at a concentration of 4 mg/ml (61%), a wide variety or other steroids and concentrations were used. CONCLUSIONS: This survey illustrates wide variation of current practice of intratympanic corticosteroid injection for ISSHL in Germany and Austria. In the absence of high-level evidence, knowing what current practice is allows clinicians to assess what they do against what their colleagues are doing, and if they do something very different, make them question their practice. Moreover, the obtained data will help to direct future clinical trials with the aim to compare the outcomes of more commonly used protocols. PMID- 29605866 TI - Effects of gadolinium-based contrast agents on submandibular gland tissue in rats. AB - AIM: The aim of this prospective animal study is to investigate the influence of multiple administrations of macrocyclic ionic (gadoteric acid) and linear nonionic (gadodiamide) gadolinium-based contrast agents (GBCA) on submandibular gland tissue (SGT) of the rats. MATERIAL AND METHOD: Twenty-four Sprague Dawley female rats were included the study. Group 1 was determined as a control group (n = 6). Group 2 was determined as saline group (n = 6). Group 3 was determined as Omniscan group (n = 6) and received only intraperitoneal (IP) 0.1 mmol (0.2 mL/kg)/kg gadodiamide for 8 days. Group 4 was determined as Dotarem group (n = 6) and received only IP 0.1 mmol (0.2 mL/kg)/mg/kg gadoteric acid daily for 8 days. On the 9th day of the administration, the rats were sedated with ketamine and xylazine through IP injection. The right SGT was removed after sedation. Histopathological and immunohistochemical changes in SGT were evaluated. RESULTS: The SGT of the Omniscan and Dotarem groups decreased SGT acini surface area, and serous acinar cells number were observed. On the other hand, no pathology was observed. Mucous acinar cells' caspase-3 positivity for the same markers in Omniscan and Dotarem sections was similar to the control group. However, Omniscan and Dotarem groups serous acinar cells were caspase-3 (+) staining. The intensity of serous acinar cells' caspase-3 (+) for the same markers in Dotarem sections was similar to the Omniscan group. The results also revealed in the analysis of the mean area of the acinus area of the SGT; there were significantly decreased Dotarem group rats when compared to control rats (p < 0.05). CONCLUSION: We consider that numerical increased apoptosis results arise from repeated doses of GBCAs. Being aware of this effect of the contrast agent may have significance for the chronic sialo-adenitis patients group when used for recurrent contrasted MRI for diagnosis of diseases like MS which requires in follow-up. We should be aware about the frequently contrasted MRI in routine investigations. PMID- 29605868 TI - 6-Gingerol Ameliorates Behavioral Changes and Atherosclerotic Lesions in ApoE-/- Mice Exposed to Chronic Mild Stress. AB - Chronic mild stress (CMS) has been demonstrated to contribute to atherosclerosis. 6-gingerol (6-Gin), a phenolic component of ginger (Zingiber officinale), has been shown to exert numerous pharmacological properties, such as anti inflammatory and cardioprotective effects. Here we investigated the role of CMS in the development of atherosclerosis in high-fat diet (HFD)-fed ApoE-/- mice and evaluated the potential therapeutic effects of 6-Gin. Mice were exposed to CMS for 20 weeks, at week 5, they were fed with a high-fat diet (HFD), then received 6-Gin (20 mg/kg/day, intragastrically) treatment. Antiatherosclerotic simvastatin (Sim) and antidepressant lorazepam (Lor) were used for positive drugs. The behavioral and atherosclerotic changes, plasma lipid profiles as well as inflammatory cytokine levels were measured. Our results showed that CMS-exposed mice exhibited reduced body weight gain, sucrose preference and locomotor activity, which are representative of some of the core symptoms of depression. Furthermore, CMS challenge aggravated atherosclerotic lesions, as indicated by increased plaque formation, elevation of plasma total cholesterol, triglyceride, low-density lipoprotein cholesterin, and proinflammatory cytokines including TNF alpha, IL-1beta, and IL-6. In addition, the expression levels of phosphorylated adenosine monophosphate-activated protein kinase (p-AMPK), acetyl-CoA carboxylase (ACC), hHMG-CoA reductase (HMGCR), fatty acid synthase (FAS), sterol regulatory element binding protein (SREBP)-1 and SREBP-2 in the liver tissues were altered after CMS exposure. 6-Gin not only improved the behavioral changes, but also alleviated atherosclerotic lesions, and reversed the expression levels of lipid profiles and inflammatory cytokines in stressed mice. Moreover, the antiatherosclerotic effects of 6-Gin is mediated in part by the AMPK signaling pathway, which is closely associated with cholesterol synthesis and lipid accumulation. Together, these results suggest that 6-Gin attenuates arteriosclerosis in ApoE-/- mice exposed to CMS and HFD, and it may be a potential therapeutic agent for the treatment of atherosclerosis. PMID- 29605867 TI - A Graphene Oxide-Based Fluorescent Aptasensor for the Turn-on Detection of CCRF CEM. AB - A convenient, low-cost, and highly sensitive fluorescent aptasensor for detection of leukemia has been developed based on graphene oxide-aptamer complex (GO-apt). Graphene oxide (GO) can absorb carboxyfluorescein-labeled Sgc8 aptamer (FAM-apt) by pi-pi stacking and quench the fluorescence through fluorescence resonance energy transfer (FRET). In the absence of Sgc8 target cell CCRF-CEM, the fluorescence is almost all quenched. Conversely, when the CCRF-CEM cells are added, the quenched fluorescence can be recovered rapidly and significantly. Therefore, based on the change of fluorescence signals, we can detect the number of CCRF-CEM cells in a wide range from 1 * 102 to 1 * 107 cells/mL with a limit of detection (LOD) of 10 cells/mL. Therefore, this strategy of graphene oxide based fluorescent aptasensor may be promising for the detection of cancer. PMID- 29605869 TI - Intrauterine arterial pseudoaneurysm, a rare cause of per vaginal bleeding. AB - The current study evaluated two cases of pervaginal bleeding subsequent of intrauterine arterial pseudoaneurysm. Each case was complaining of intermittent attacks of heavy vaginal bleeding: one case with history of cesarean section and the other case after uterine curettage. Intrauterine arterial pseudoaneurysm can be caused by a traumatic injury to the vessel wall with subsequent formation of periarterial hematoma that liquefies forming periarterial bloody cyst, which communicates through the narrow neck with the arterial lumen. Transvaginal ultrasound aided with color duplex capability is an accurate tool for assessment. PMID- 29605870 TI - Rapid and stable production of 2,3-butanediol by an engineered Saccharomyces cerevisiae strain in a continuous airlift bioreactor. AB - Utilization of renewable feedstocks for the production of bio-based bulk chemicals, such as 2,3-butanediol (2,3-BDO), by engineered strains of the non pathogenic yeast, Saccharomyces cerevisiae, has recently become an attractive option. In this study, to realize rapid production of 2,3-BDO, a flocculent, 2,3 BDO-producing S. cerevisiae strain YPH499/dPdAdG/BDN6-10/FLO1 was constructed from a previously developed 2,3-BDO-producing strain. Continuous 2,3-BDO fermentation was carried out by the flocculent strain in an airlift bioreactor. The strain consumed more than 90 g/L of glucose, which corresponded to 90% of the input, and stably produced more than 30 g/L of 2,3-BDO over 380 h. The maximum 2,3-BDO productivity was 7.64 g/L/h at a dilution rate of 0.200/h, which was higher than the values achieved by continuous fermentation using pathogenic bacteria in the previous reports. These results demonstrate that continuous 2,3 BDO fermentation with flocculent 2,3-BDO-producing S. cerevisiae is a promising strategy for practical 2,3-BDO production. PMID- 29605871 TI - Movement of pulsed resource subsidies from kelp forests to deep fjords. AB - Resource subsidies in the form of allochthonous primary production drive secondary production in many ecosystems, often sustaining diversity and overall productivity. Despite their importance in structuring marine communities, there is little understanding of how subsidies move through juxtaposed habitats and into recipient communities. We investigated the transport of detritus from kelp forests to a deep Arctic fjord (northern Norway). We quantified the seasonal abundance and size structure of kelp detritus in shallow subtidal (0-12 m), deep subtidal (12-85 m), and deep fjord (400-450 m) habitats using a combination of camera surveys, dive observations, and detritus collections over 1 year. Detritus formed dense accumulations in habitats adjacent to kelp forests, and the timing of depositions coincided with the discrete loss of whole kelp blades during spring. We tracked these blades through the deep subtidal and into the deep fjord, and showed they act as a short-term resource pulse transported over several weeks. In deep subtidal regions, detritus consisted mostly of fragments and its depth distribution was similar across seasons (50% of total observations). Tagged pieces of detritus moved slowly out of kelp forests (displaced 4-50 m (mean 11.8 m +/- 8.5 SD) in 11-17 days, based on minimum estimates from recovered pieces), and most (75%) variability in the rate of export was related to wave exposure and substrate. Tight resource coupling between kelp forests and deep fjords indicate that changes in kelp abundance would propagate through to deep fjord ecosystems, with likely consequences for the ecosystem functioning and services they provide. PMID- 29605872 TI - Biological therapy downregulates the heterodimer S100A8/A9 (calprotectin) expression in psoriatic patients. AB - The pathophysiology of psoriasis is very complex and involves an interplay between immune cells and keratinocytes. The keratinocyte production of calprotectin (S100A8/A9), induced by the inflammatory psoriatic milieu, may be involved in initiating immune cell invasion, as well as in propagating inflammation. However, the exact role of calprotectin in psoriasis remains unclear. Therapeutic approaches utilizing adalimumab, etanercept and ustekinumab are widely used in psoriatic treatment, but their anti-inflammatory mechanisms are not fully understood. The aim of this study was to investigate, by immunohistochemical analysis, the expression of the heterocomplex S100A8/A9 in lesional skin from psoriatic patients undergoing biological therapy with adalimumab, etanercept or ustekinumab. Our results showed that S100A8/A9, absent or present at very low level in skin biopsies from healthy subjects, is dramatically upregulated in each epidermal layer from psoriatic patients. Interestingly, calprotectin was mainly localized in keratinocyte nuclei from psoriatic patients, suggesting a role of S100A8/A9 in keratinocyte nuclear function. Furthermore, we have shown that the biological treatment induced a drastic reduction of S100A8/A9 expression in skin biopsies from treated patients, correlating with PASI reduction. Our results suggest that calprotectin may play a crucial role as a significant marker of inflammation in psoriasis, and that its reduction of expression may be considered a favourable prognostic marker in psoriasis. PMID- 29605873 TI - Clinical characteristics and outcomes of diffuse large B-cell lymphoma in adolescents and young adults. AB - Clinical information regarding non-Hodgkin lymphoma (NHL) in adolescents and young adults (AYA) is lacking. We retrospectively analyzed 1426 consecutively registered patients with newly diagnosed NHL. Of 798 DLBCL patients, 42 (5.3%) were identified as AYA (16-39 years). The characteristics of AYA DLBCL patients showed no significant differences compared to older adult DLBCL patients (age >= 40 years). Progression-free survival (PFS) and overall survival (OS) in AYA were similar to those in patients aged 40-60 years. However, in older adult groups, PFS and OS were significantly different according to the age group (40-60, 61-79, and >= 80 years). In univariate analysis in AYA, performance status, clinical stage, International Prognostic Index (IPI), and age-adjusted IPI significantly affected both PFS and OS. In multivariate analysis, only clinical stage was identified as an independent predictor among AYA. In conclusion, disease characteristics and outcomes of DLBCL in AYA were nearly the same as those in older adults. PMID- 29605874 TI - The hematopoietic stem cell diet. AB - Hematopoietic stem cells (HSCs) are responsible for sustaining life-long blood formation or hematopoiesis and are also used clinically in a form of bone marrow transplantation, a curative cellular therapy for a range of hematological diseases. HSCs are maintained throughout adult life by a complex biological niche or microenvironment, which is thought to be composed of a range of cellular, molecular, and metabolic components. The metabolic components of the HSC niche have become of increasing interest over the past few years. It is now well recognized that metabolic activity is intimately linked to HSC function, and dysregulation of these metabolic pathways result in hematological pathologies such as leukemia. Here, we review the recent progress in this field including our current understanding of the "dietary" requirements of HSCs and how nutrition influences HSC activity. These recent findings have suggested promising new metabolic approaches to improve clinical HSC transplantation and leukemia therapies. PMID- 29605876 TI - Cdc20/p55 mediates the resistance to docetaxel in castration-resistant prostate cancer in a Bim-dependent manner. AB - PURPOSE: At least to date, no effective treatment for advanced castration resistant prostate cancer (CRPC) has been established. Recent studies indicated that cell division cycle 20 homolog (Cdc20) overexpression is associated with poor prognosis in patients with castration-resistant prostate cancer. However, the mechanism of Cdc20 in the development of docetaxel resistance in CRPC remains elusive. METHODS: In this study, the transcription of Cdc20 was confirmed in three independent CRPC cell lines derived from different tissues, including LNCaP, PC3, and DU145. Docetaxel resistant (DR) cell lines were generated within the background of DU145 and PC3. The protein levels of Cdc20 and the biological phenotype were detected in both wild-type and DR cell lines. To further explore the mechanism of Cdc20 overexpression, stable cell lines with Cdc20 or Bcl-2 interacting mediator of cell death (Bim) deprivation were generated and examined for biological parameters. In addition, a specific Cdc20 inhibitor was used in DR cell lines to explore the potential solution for docetaxel resistant CRPC. RESULTS: Here, we identified Cdc20 is overexpressed in docetaxel resistant CRPC cell lines, including LNCaP, PC3, and DU145. We also reported that DR cell lines, which mimic the recurrent prostate cancer cells after docetaxel treatment, have higher levels of Cdc20 protein compared with the CRPC cell lines. Interestingly, the protein levels of Bim, an E3 ligase substrate of Cdc20, were decreased in DR cell lines compared with the wild-type, while the mRNA levels were similar. More importantly, in DR cell lines, the biological phenotype induced by Cdc20 deletion could be significantly reversed by the additional knockdown of Bim. As a result, docetaxel resistant prostate cancer cells treated with the pharmacological Cdc20 inhibitor became sensitive to docetaxel treatment. CONCLUSIONS: In conclusion, our data collectively demonstrated that Cdc20 overexpression facilitates the docetaxel resistant of the CRPC cell lines in a Bim-dependent manner. Furthermore, additionally targeting Cdc20 might be a promising solution for the treatment of the CRPC with docetaxel resistance. PMID- 29605875 TI - The Relationship of Motivation and Neurocognition with Functionality in Schizophrenia: A Meta-analytic Review. AB - The role that neurocognition plays in functionality in schizophrenia has been widely examined, although in recent years increasing attention has been paid to the influence of motivation instead. This study provides a review of the relationship of neurocognition and motivation with functionality in schizophrenia, taking into account objective/subjective functionality assessment, demographic variables, and the different terms used when referring to motivation. A search of electronic databases identified 34 studies that met the inclusion criteria for review. Correlation coefficients between motivation and functionality and between neurocognition and functionality were extracted. For a better understanding, potential moderator variables were also extracted. Meta analysis showed that both motivation and neurocognition assessments were strongly associated with functioning, with correlations between motivation and functional outcomes being stronger. However, more than three-quarters of the variance in outcome remained unexplained by the moderating factors examined. The paper concludes with recommendations for clinical practice and future research. PMID- 29605879 TI - Parsing the Paradox: Hispanic Mortality in the US by Detailed Cause of Death. AB - US Hispanics are a disadvantaged population that paradoxically has lower mortality rates than non-Hispanic whites. We conducted a descriptive analysis of age-adjusted mortality rates for 113 causes of death for US Hispanics (USH) and US non-Hispanic whites (USNHW) during 1999-2015. All-cause, age-adjusted mortality rates per 100,000 were: 581.1 USH and 788.8 USNHW. Lower Hispanic mortality from cancer, heart disease, and respiratory disease accounted for almost all the all-cause mortality gap. USH rates were higher than USNHW rates for cancers of the stomach, liver, and cervix; diabetes mellitus; liver disease; and homicide. Behavioural factors such as less smoking among USH probably drive their lower rates for the major chronic diseases. Social disadvantages contribute to elevated risk for certain cancers, diabetes, and homicide. Efforts to improve Hispanic well-being in the US should remedy the social disadvantages while preserving the health advantages the population enjoys. PMID- 29605878 TI - Do people with intersecting identities report more high-risk alcohol use and lifetime substance use? AB - OBJECTIVES: We examined protective and non-protective effects of disadvantaged social identities and their intersections on lifetime substance use and risky alcohol consumption. METHODS: Data from 90,941 participants of the Global Drug Survey 2015 were analysed. Multivariable logistic regressions were used to calculate adjusted odds ratios for lifetime use of nine psychoactive substances, as well as high-risk/harmful alcohol use. Disadvantaged identities from three categories (ethnicity, sexual identity, gender), and interactions between these were compared. RESULTS: Findings indicate that participants with disadvantaged ethnic and sexual minority identities are more likely to use psychoactive substances compared to their counterparts. The intersecting identity 'disadvantaged ethnic identity and sexual minority' appears to be protective compared to those with just one of these identities. While female gender appears to be highly protective in general, it is not protective among females with disadvantaged social identities. CONCLUSIONS: Stark disparities in substance use between different social identities and their intersections emphasise the importance of intersectionality theories in public health research intervention design. Future research on health equity, particularly substance use, should target individuals with intersecting identities. PMID- 29605877 TI - How are growth hormone and insulin-like growth factor-1 reported as markers for drug effectiveness in clinical acromegaly research? A comprehensive methodologic review. AB - OBJECTIVE: In rare disease research, most randomized prospective clinical trials can only use limited number of patients and are comprised of highly heterogeneous populations. Therefore, it is crucial to report the results in such a manner that it allows for comparison of treatment effectiveness and biochemical control between studies. The aim of this review was to investigate the current methods that are being applied to measure and report growth hormone (GH) and insulin-like growth factor-1 (IGF-1) as markers for drug effectiveness in clinical acromegaly research. SEARCH STRATEGY: A systematic search of recent prospective and retrospective studies, published between 2012 and 2017, that studied the effects of somatostatin analogues or dopamine agonists in acromegaly patients was performed. The markers of interest were GH, IGF-1, and the suppression of GH after an oral glucose tolerance test (OGTT). Additionally, the use of pharmacokinetic (PK) measurements in these studies was analyzed. The sampling design, cut-off for biochemical control, reported units, and used summary statistics were summarized. RESULTS: A total of 49 articles were selected out of the 263 screened abstracts. IGF-1 concentrations were measured in all 49 studies, GH in 45 studies, and an OGTT was performed in 11 studies. A wide range of different cut-off values and sampling designs were used to determine biochemical control in acromegaly patients. The summary statistics were reported in various ways, with the percentage of biochemical control most frequently used. Nine studies sampled the PK at one or more time points. Non-compartmental analyses were commonly performed on the available PK data. CONCLUSIONS: The way GH and IGF 1 are measured and reported in acromegaly research varies considerably. A consensus on how to report study results would enable better comparisons between studies, thereby improving evidence based decision making to optimize treatment in acromegaly. PMID- 29605880 TI - Effect of a 24-h extended visiting policy on delirium in critically ill patients. PMID- 29605881 TI - Inter- and intraobserver repeatability and reproducibility of choroidal thickness measurements using two different methods. AB - PURPOSE: To measure the inter- and intraobserver repeatability and reproducibility of choroidal thickness measurements taken by the enhanced depth imaging of spectral-domain optical coherence tomography (EDI-OCT) in randomly selected subjects using two different protocols. METHODS: Twenty subjects of the Thessaloniki Eye Study database were randomly selected. The participants underwent EDI-OCT, and the choroidal thickness was measured on EDI images using two different protocols. All images were assessed by two examiners independently in two sessions in different days. RESULTS: The interobserver intraclass correlation coefficient (ICC) for average choroidal thickness was 0.944. The average ICC for central, Cmin, and Cmax choroidal thickness was 0.899, 0.863, and 0.955, respectively. The interobserver ICC for average choroidal volume was 0.932. Intraobserver repeatability ICC for grader 1 ranged between 0.925 and 0.9720 and for grader 2 between 0.913 and 0.994. CONCLUSION: Choroidal thickness measurements by EDI-OCT showed a high inter- and intraobserver reproducibility. PMID- 29605882 TI - Erratum to: Molecular Magnetic Resonance Imaging (mMRI). PMID- 29605885 TI - RETRACTED ARTICLE: What it means to care for a person with a chronic disease: integrating the patient's experience into the medical viewpoint. PMID- 29605883 TI - Induction of a central memory and stem cell memory phenotype in functionally active CD4+ and CD8+ CAR T cells produced in an automated good manufacturing practice system for the treatment of CD19+ acute lymphoblastic leukemia. AB - Relapsed/refractory B-precursor acute lymphoblastic leukemia (pre-B ALL) remains a major therapeutic challenge. Chimeric antigen receptor (CAR) T cells are promising treatment options. Central memory T cells (Tcm) and stem cell-like memory T cells (Tscm) are known to promote sustained proliferation and persistence after T-cell therapy, constituting essential preconditions for treatment efficacy. Therefore, we set up a protocol for anti-CD19 CAR T-cell generation aiming at high Tcm/Tscm numbers. 100 ml peripheral blood from pediatric pre-B ALL patients was processed including CD4+/CD8+-separation, T-cell activation with modified anti-CD3/-CD28 reagents and transduction with a 4-1BB based second generation CAR lentiviral vector. The process was performed on a closed, automated device requiring additional manual/open steps under clean room conditions. The clinical situation of these critically ill and refractory patients with leukemia leads to inconsistent cellular compositions at start of the procedure including high blast counts and low T-cell numbers with exhausted phenotype. Nevertheless, a robust T-cell product was achieved (mean CD4+ = 50%, CD8+ = 39%, transduction = 27%, Tcm = 50%, Tscm = 46%). Strong proliferative potential (up to > 100-fold), specific cytotoxicity and low expression of co inhibitory molecules were documented. CAR T cells significantly released TH1 cytokines IFN-gamma, TNF-alpha and IL-2 upon target-recognition. In conclusion, partly automated GMP-generation of CAR T cells from critically small blood samples was feasible with a new stimulation protocol that leads to high functionality and expansion potential, balanced CD4/CD8 ratios and a conversion to a Tcm/Tscm phenotype. PMID- 29605884 TI - Moss habitats distinctly affect their associated bacterial community structures as revealed by the high-throughput sequencing method. AB - To better understand the factors that influence the distribution of bacteria associated with mosses, the communities inhabiting in five moss species from two different habitats in Beijing Songshan National Nature Reserve were investigated using the high-throughput sequencing method. The sequencing was performed based on the bacterial 16S rRNA and 16S rDNA libraries. Results showed that there are abundant bacteria inhabiting in all the mosses sampled. The taxonomic analysis of these bacteria showed that they mainly consisted of those in the phyla Proteobacteria and Actinobacteria, and seldom were from phylum Armatimonadetes, Bacteroidetes and Firmicutes. The hierarchical cluster tree, based on the OTU level, divided the bacteria associated with all samples into two branches according to the habitat types of the host (terrestrial and aquatic). The PCoA diagram further divided the bacterial compositions into four groups according to both types of habitats and the data sources (DNA and RNA). There were larger differences in the bacterial community composition in the mosses collected from aquatic habitat than those of terrestrial one, whether at the DNA or RNA level. Thus, this survey supposed that the habitat where the host was growing was a relevant factor influencing bacterial community composition. In addition, the bacterial community detected at the RNA level was more sensitive to the habitat of the growing host, which could also be proved by the significantly differences in the predicted function by PICRUSt and the metabolically active dominant genera between different groups. This study expands the knowledge about the interactions between mosses and microbes. PMID- 29605886 TI - Reductive nitrosylation of ferric human hemoglobin bound to human haptoglobin 1-1 and 2-2. AB - Haptoglobin (Hp) sequesters hemoglobin (Hb) preventing the Hb-based damage occurring upon its physiological release into plasma. Here, reductive nitrosylation of ferric human hemoglobin [Hb(III)] bound to human haptoglobin (Hp) 1-1 and 2-2 [Hp1-1:Hb(III) and Hp2-2:Hb(III), respectively] has been investigated between pH 7.5 and 9.5, at T=20.0 degrees C. Over the whole pH range explored, only one process is detected reflecting NO binding to Hp1 1:Hb(III) and Hp2-2:Hb(III). Values of the pseudo-first-order rate constant for Hp1-1:Hb(III) and Hp2-2:Hb(III) nitrosylation (k) do not depend linearly on the ligand concentration but tend to level off. The conversion of Hp1-1:Hb(III)-NO to Hp1-1:Hb(II)-NO and of Hp2-2:Hb(III)-NO to Hp2-2:Hb(II)-NO is limited by the OH-- and H2O-based catalysis. In fact, bimolecular NO binding to Hp1-1:Hb(III), Hp2 2:Hb(III), Hp1-1:Hb(II), and Hp2-2:Hb(II) proceeds very rapidly. The analysis of data allowed to determine the values of the dissociation equilibrium constant for Hp1-1:Hb(III) and Hp2-2:Hb(III) nitrosylation [K = (1.2 +/- 0.1) * 10-4 M], which is pH-independent, and of the first-order rate constant for Hp1-1:Hb(III) and Hp2 2:Hb(III) conversion to Hp1-1:Hb(II)-NO and Hp2-2:Hb(II)-NO, respectively (k'). From the dependence of k' on [OH-], values of hOH- [(4.9 +/- 0.6) * 103 M-1 s-1 and (6.79 +/- 0.7) * 103 M-1 s-1, respectively] and of [Formula: see text] [(2.6 +/- 0.3) * 10-3 s-1] were determined. Values of kinetic and thermodynamic parameters for Hp1-1:Hb(III) and Hp2-2:Hb(III) reductive nitrosylation match well with those of the Hb R-state, which is typical of the alphabeta dimers of Hb bound to Hp. PMID- 29605887 TI - Delafloxacin: Place in Therapy and Review of Microbiologic, Clinical and Pharmacologic Properties. AB - Delafloxacin (formerly WQ-3034, ABT492, RX-3341) is a novel fluoroquinolone chemically distinct from currently marketed fluoroquinolones with the absence of a protonatable substituent conferring a weakly acidic character to the molecule. This property results in increased intracellular penetration and enhanced bactericidal activity under acidic conditions that characterize the infectious milieu at a number of sites. The enhanced potency and penetration in low pH environments contrast what has been observed for other zwitterionic fluoroquinolones, which tend to lose antibacterial potency under acidic conditions, and may be particularly advantageous against methicillin-resistant Staphylococcus aureus, for which the significance of the intracellular mode of survival is increasingly being recognized. Delafloxacin is also unique in its balanced target enzyme inhibition, a property that likely explains the very low frequencies of spontaneous mutations in vitro. Delafloxacin recently received US Food and Drug Administration approval for the treatment of acute bacterial skin and skin structure infections and is currently being evaluated in a phase 3 trial among patients with community-acquired pneumonia. In the current era of a heightened awareness pertaining to collateral ecologic damage, safety issues and antimicrobial stewardship principles, it is critical to describe the unique properties of delafloxacin and define its potential role in therapy. The purpose of this article is to review available data pertaining to delafloxacin's biochemistry, pharmacokinetic/pharmacodynamics characteristics, in vitro activity and potential for resistance selection as well as current progress in clinical trials to ultimately assist clinicians in selecting patients who will benefit most from the distinctive properties of this agent. PMID- 29605888 TI - Correction to: The quadriceps active ratio: a dynamic MRI-based assessment of patellar height. AB - In the online version of the original article, one of the white lines was not accurately drawn in Fig. 1. PMID- 29605889 TI - Cutoff values of major surgical complications rates after gastrectomy. AB - Gastric cancer is one of the most frequent cancers worldwide, and surgical resection remains the mainstay of the therapeutic pathway. Gastrectomy for cancer is still performed in many hospitals, and centralization remains limited to a small number of health systems. Morbidity and mortality after surgery for gastric cancer are surprisingly high. However, while mortality is obviously defined, major morbidity definitions still present some critical points. The aim of this study is to underline the need for universally accepted definitions of major complications and to describe the research agenda of a multicenter, European based, prospective project launched by the European Chapter of the International Gastric Cancer Association (IGCA), with the goal of providing a list of complications related to gastrectomy for cancer with their definitions. PMID- 29605890 TI - Hypothesis-free screening of large administrative databases for unsuspected drug outcome associations. AB - Active surveillance for unknown or unsuspected adverse drug effects may be carried out by applying epidemiological techniques to large administrative databases. Self-controlled designs, like the symmetry design, have the advantage over conventional design of adjusting for confounders that are stable over time. The aim of this paper was to describe the output of a comprehensive open-ended symmetry analysis of a large dataset. All drug dispensings and all secondary care contacts in Denmark during the period 1995-2012 for persons born before 1950 were analyzed by a symmetry design. We analyzed all drug-drug sequences and all drug disease sequences occurring during the study period. The identified associations were ranked according to the number of outcomes that potentially could be attributed to the exposure. In the main analysis, 29,891,212 incident drug therapies, and 21,300,000 incident diagnoses were included. Out of 186,758 associations tested in the main analysis, 43,575 (23.3%) showed meaningful effect size. For the top 200 drug-drug associations, 47% represented unknown associations, 24% represented known adverse drug reactions, 30% were explained by mutual indication or reverse causation. For the top 200 drug-disease associations the proportions were 31, 15, and 55%, respectively. Screening by symmetry analysis can be a useful starting point for systematic pharmacovigilance activities if coupled with a systematic post-hoc review of signals. PMID- 29605891 TI - Antenatal non-medical risk assessment and care pathways to improve pregnancy outcomes: a cluster randomised controlled trial. AB - Social deprivation negatively affects health outcomes but receives little attention in obstetric risk selection. We investigated whether a combination of (1) risk assessment focused on non-medical risk factors, lifestyle factors, and medical risk factors, with (2) subsequent institution of risk-specific care pathways, and (3) multidisciplinary consultation between care providers from the curative and the public health sector reduced adverse pregnancy outcomes among women in selected urban areas in the Netherlands. We conducted a cluster randomised controlled trial in 14 urban municipalities across the Netherlands. Prior to the randomisation, municipalities were ranked and paired according to their expected proportion of pregnant women at risk for adverse outcomes at birth. The primary outcome was delivery of a preterm and/or small for gestational age (SGA) baby, analysed with multilevel mixed-effects logistic regression analysis adjusting for clustering and individual baseline characteristics. A total of 33 community midwife practices and nine hospitals participated throughout the study. Data from 4302 participants was included in the Intention To Treat (ITT) analysis. The intervention had no demonstrable impact on the primary outcome: adjusted odds ratio (aOR) 1.17 (95% CI 0.84-1.63). Among the secondary outcomes, the intervention improved the detection of threatening preterm delivery and fetal growth restriction during pregnancy [aOR 1.27 (95% CI 1.01-1.61)]. Implementation of additional non-medical risk assessment and preventive strategies into general practices is feasible but did not decrease the incidence of preterm and/or SGA birth in the index pregnancy in deprived urban areas.Trial registration Netherlands National Trial Register (NTR-3367). PMID- 29605892 TI - Suggestion of reduced cancer risks following cardiac x-ray exposures is unconvincing. PMID- 29605893 TI - Does Real World Use of Liraglutide Match its Use in the LEADER Cardiovascular Outcome Trial? Study Protocol. AB - BACKGROUND: Liraglutide is an injectable therapy to treat type 2 diabetes (T2DM), belonging to the glucagon-like peptide-1 receptor agonist class of drugs. The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial established that liraglutide demonstrated glucose-lowering benefits and improved cardiovascular outcomes in those individuals with T2DM at high cardiovascular risk. AIMS: The aim of this study is to report the prevalence and characteristics of people treated with liraglutide compared with the LEADER trial. In addition, the remaining portion of the T2DM population will be examined to determine the prevalence of those who meet the inclusion criteria for the LEADER trial but who are not treated with this medication. STUDY DESIGN AND METHODS: This is a cross-sectional analysis of routinely collected primary care data on all people with T2DM included in the Royal College of General Practitioners (RCGP) Research and Surveillance Center (RSC) network database. People with T2DM will be identified from the dataset using a well-established ontological process. Read and other clinical codes will be used to identify people prescribed liraglutide and those at high cardiovascular risk. We will use descriptive statistics to report the characteristics of people with T2DM prescribed liraglutide compared with those of the LEADER trial and the proportion of the wider T2DM cohort that matches the LEADER inclusion criteria. In terms of ethical considerations, this study used pseudonymized data, and was classed as an "Audit of current practice". PLANNED OUTPUTS: The results of the study will be submitted for publication in a peer-reviewed journal to report the applicability of the results of the LEADER trial to real-world clinical practice. FUNDING: Novo Nordisk Limited. PMID- 29605894 TI - EPHX1 rs1051740 T>C (Tyr113His) is strongly associated with acute myeloid leukemia and KMT2A rearrangements in early age. AB - Experimental and epidemiological data have shown that acute myeloid leukemia in early-age (i-AML) originates prenatally. The risk association between transplacental exposure to benzene metabolites and i-AML might be influenced by genetic susceptibility. In this study, we investigated the relationship between genetic polymorphisms in CYP2E1, EPHX1, MPO, NQO1, GSTM1 and GSTT1 genes, and i AML risk. The study included 101 i-AMLs and 416 healthy controls. Genomic DNA from study subjects was purified from bone marrow or peripheral blood aspirates and genotyped for genetic polymorphisms by real-time PCR allelic discrimination, Sanger sequencing and multiplex PCR. Crude and adjusted odds ratios (OR, adjOR, respectively) with 95% confidence intervals (95% CI) were assessed using unconditional logistic regression to estimate the magnitude of risk associations. EPHX1 rs1051740 T>C was associated with i-AML risk under the co-dominant (adjOR 3.04, P = 0.003) and recessive (adjOR 2.99, P = 0.002) models. In stratified analysis, EPHX1 rs1051740 was associated with increased risk for i-AML with KMT2A rearrangement (adjOR 3.06, P = 0.045), i-AML with megakaryocytic differentiation (adjOR 5.10, P = 0.008), and i-AML with type I mutation (adjOR 2.02, P = 0.037). EPHX1 rs1051740-rs2234922 C-G haplotype was also associated with increased risk for i-AML (adjOR 2.55, P = 0.043), and for i-AML with KMT2A rearrangement (adjOR 3.23, P = 0.034). Since EPHX1 enzyme is essential in cellular defense against epoxides, the diminished enzymatic activity conferred by the variant allele C could explain the risk associations found for i-AML. In conclusion, EPHX1 rs1051740 plays an important role in i-AML's genetic susceptibility by modulating the carcinogenic effects of epoxide exposures in the bone marrow. PMID- 29605896 TI - Interplay between carbon, nitrogen and phosphate utilization in the control of secondary metabolite production in Streptomyces. AB - Streptomyces species are a wide and diverse source of many therapeutic agents (antimicrobials, antineoplastic and antioxidants, to name a few) and represent an important source of compounds with potential applications in medicine. The effect of nitrogen, phosphate and carbon on the production of secondary metabolites has long been observed, but it was not until recently that the molecular mechanisms on which these effects rely were ascertained. In addition to the specific macronutrient regulatory mechanisms, there is a complex network of interactions between these mechanisms influencing secondary metabolism. In this article, we review the recent advances in our understanding of the molecular mechanisms of regulation exerted by nitrogen, phosphate and carbon sources, as well as the effects of their interconnections, on the synthesis of secondary metabolites by members of the genus Streptomyces. PMID- 29605895 TI - Using a Modified Theory of Planned Behavior to Examine Adolescents' Workplace Safety and Health Knowledge, Perceptions, and Behavioral Intention: A Structural Equation Modeling Approach. AB - Work, a defining feature of adolescence in the United States, has many benefits. Work also has risks, as adolescents experience a higher rate of serious job related injuries compared to adults. Talking Safety, a free curriculum from the National Institute for Occupational Safety and Health, is one tool educators may adopt to provide teens with essential workplace safety and health education. Adolescents (N = 2503; female, 50.1%; Hispanic, 50.0%) in a large urban school district received Talking Safety from their eighth-grade science teachers. This study used a modified theory of planned behavior (which included a knowledge construct), to examine students' pre- and post-intervention scores on workplace safety and health knowledge, attitude, self-efficacy, and behavioral intention to enact job safety skills. The results from confirmatory factor analyses indicate three unique dimensions reflecting the theory, with a separate knowledge factor. Reliability estimates are omega >= .83. The findings from the structural equation models demonstrate that all paths, except pre- to posttest behavioral intention, are statistically significant. Self-efficacy is the largest contributor to the total effect of these associations. As hypothesized, knowledge has indirect effects on behavioral intention. Hispanic students scored lower at posttest on all but the behavioral intention measure, possibly suggesting the need for tailored materials to reach some teens. Overall the findings support the use of a modified theory of planned behavior to evaluate the effectiveness of a foundational workplace safety and health curriculum. This study may inform future efforts to ensure that safe and healthy work becomes integral to the adolescent experience. PMID- 29605897 TI - Ultraviolet radiation in the Atacama Desert. AB - The world's highest levels of surface ultraviolet (UV) irradiance have been measured in the Atacama Desert. This area is characterized by its high altitude, prevalent cloudless conditions, and a relatively low total ozone column. In this paper, we provide estimates of the surface UV (monthly UV index at noon and annual doses of UV-B and UV-A) for all sky conditions in the Atacama Desert. We found that the UV index at noon during the austral summer is expected to be greater than 11 in the whole desert. The annual UV-B (UV-A) doses were found to range from about 3.5 kWh/m2 (130 kWh/m2) in coastal areas to 5 kWh/m2 (160 kWh/m2) on the Andean plateau. Our results confirm significant interhemispherical differences. Typical annual UV-B doses in the Atacama Desert are about 40% greater than typical annual UV-B doses in northern Africa. Mostly due to seasonal changes in the ozone, the differences between the Atacama Desert and northern Africa are expected to be about 60% in the case of peak UV-B levels (i.e. the UV B irradiances at noon close to the summer solstice in each hemisphere). Interhemispherical differences in the UV-A are significantly lower since the effect of the ozone in this part of the spectrum is minor. PMID- 29605898 TI - Spondylolisthesis adjacent to a cervical disc arthroplasty does not increase the risk of adjacent level degeneration. AB - PURPOSE: To understand whether a spondylolisthesis in the sub-axial spine cranial to a cervical disc arthroplasty (CDA) construes a risk of adjacent level disease (ALD). METHODS: A retrospective review of 164 patients with a minimum 5-year follow-up of a cervical disc arthroplasty was performed. Multi-level surgeries, including hybrid procedures, were included. Multiple implant types were included. The two inter-vertebral discs (IVD) cranial of the CDA were monitored for evidence of radiologic degeneration using the Kettler criteria. RESULTS: The rate of ALD in CDA found in this series was 17.8%, with most affecting the immediately adjacent IVD (27.4 and 7.6%, respectively p = 0.000). Pre-operative mild spondylolisthesis adjacent to a planned CDA was not found to be a risk factor for ALD within 5 years. Those with a degenerative spondylolisthesis are at higher risk of ALD (33%) than those with a non-degenerative cause for their spondylolisthesis (11%). Post-operative CDA alignment, ROM or induced spondylolisthesis do not affect the rate of ALD in those with an adjacent spondylolisthesis. Patients with ALD experience significantly worse 5-year pain and functional outcomes than those unaffected by ALD. CONCLUSIONS: A pre operatively identified mild spondylolisthesis in the sub-axial spine cranially adjacent to a planned CDA is not a risk factor for ALD within 5 years. These slides can be retrieved under Electronic Supplementary Material. PMID- 29605899 TI - Reoperation and complications after anterior cervical discectomy and fusion and cervical disc arthroplasty: a study of 52,395 cases. AB - PURPOSE: The aim of this study was to analyze rates of perioperative complications and subsequent cervical surgeries in patients treated for cervical degenerative disc disease with anterior cervical discectomy and fusion (ACDF) and those treated with artificial cervical disc arthroplasty (ACDA) for up to 5-year follow-up. METHODS: California's Office of Statewide Health Planning and Development discharge database was analyzed for patients aged 18-65 years undergoing single-level ACDF or ACDA between 2003 and 2010. Medical comorbidities were identified with CMS-Condition Categories. Readmissions for short-term complications of the procedure were identified and rates of subsequent cervical surgeries were calculated at 90-day and 1-, 3-, and 5-year follow-up. Multivariate regression modeling was used to identify associations with complications and subsequent cervical surgeries correcting for patient and provider characteristics. RESULTS: A total of 52,395 eligible cases were identified: 50,926 ACDF and 1469 ACDA. Readmission was less common in the ACDA group (OR: 0.69, 95% CI: 0.48-1.0, p = 0.048). Subsequent cervical spine surgery was more common in the ACDF group in the immediate perioperative period (within 90 days of surgery) (ACDF 3.35% vs. ACDA 2.04%, OR: 0.63, 95% CI: 0.44-0.92, p = 0.015). At 1-, 3-, and 5-year postoperatively, rates of subsequent cervical surgeries were similar between the two cohorts. CONCLUSIONS: We found no protective benefit for ACDA versus ACDF for single-level disease at up to 5-year follow-up in the largest cohort of patients examined to date. Early complications were rare in both cohorts stressing the value of large cohort studies to study risk factors for rare events. These slides can be retrieved under Electronic Supplementary Material. PMID- 29605900 TI - Computed tomography showing formation of caseous calcification of the mitral annulus over time. AB - Caseous calcification of the mitral annulus (CCMA) is a rare variant of mitral annulus calcification. Herein, we present computed tomographic images of formation of CCMA over time. PMID- 29605901 TI - Right ventricular septomarginal trabeculation hypertrophy is associated with disease severity in patients with pulmonary arterial hypertension. AB - To characterize the morphological change in the right ventricle (RV) of patients with pulmonary artery hypertension (PAH) and further explore the correlation between septomarginal trabeculation (SMT) and right ventricular (RV) function, myocardial fibrosis, and exercise capacity in patients with PAH. Sixty untreated PAH patients were prospectively included from May 2016 to April 2017. All patients underwent comprehensive clinical evaluation and cardiac magnetic resonance (CMR). The area and diameter of the basal segment of SMT, and the mass of SMT were measured on cine SSFP images. Relationship between parameters of SMT and RV ejection fraction (RVEF), 6 min walking distance (6MWD), myocardial fibrosis and pulmonary vascular resistance (PVR) were evaluated by Pearson's correlation and logistic regression. Predictive performance of SMT parameters for reduced RVEF or impaired 6MWD was evaluated by receiver operating characteristics (ROC) analysis. Compared with SMT diameter index and mass index, SMT area index (SMT Ai) in basal segment was the best parameter to show correlation with RVEF (r = - 0.496, P < 0.001), 6MWD (r = - 0.619, P < 0.001), and inferior insertion point (I IP) extracelluar volume (ECV) (r = 0.365, P = 0.008). ROC showed that SMT Ai had the strongest predictive value for reduced RVEF (AUC = 0.756), and impaired 6MWD (AUC = 0.813). SMT parameters were closely correlated with RV systolic function and 6MWD in patients with PAH. SMT Ai is a simple imaging indicator for the severity of PAH. PMID- 29605902 TI - Three-dimensional full automated software in the evaluation of the left ventricle function: from theory to clinical practice. AB - Left ventricular systolic function evaluation is an essential part of all transthoracic echocardiographic (TTE) studies. 3D echocardiography (3DE) is superior to 2D and is recommended as the method of choice. However, since it is time consuming and requires training, it is rarely performed. Different automatic analysis software tries to overcome these limitations but they need to be accurate and reproducible before they can be used clinically. The aim of this study was to test the accuracy and reproducibility of new 3D automatic quantitative software in everyday clinical practice. 69 patients referred to our Echo Lab for a clinically indicated echocardiographic examination were included. All patients underwent a full TTE with 3D image acquisition. Left ventricular volumes and ejection fraction (LVEF) were obtained using Heart Model software, and compared with conventional 3D volumetric data. Automated analysis was performed using three different sliders setting, with or without regional editing if necessary. 20 patients underwent a cardiac magnetic resonance (CMR) study the same day of the echo and automated measurements were also compared with a CMR reference. Intra- and inter-technique comparisons including linear regression with Pearson correlation coefficients and Bland-Altman analyses were calculated. Mean age of the patients was 59 years, with 49.3% male. The automated 3DE model demonstrated excellent correlation with the conventional 3DE measurements of LVEF, using three different sliders settings (r = 0.906; r = 0.898 and r = 0.940). Correlations with CMR values were very good as well (r = 0.888; r = 0.869; r = 0.913). Similarly, no significant differences were noted between the values of EDV and ESV, measured with the automated model or CMR, with excellent correlation (EDV: r = 0.892, r = 0.842, 0.910; ESV: r = 0.925, r = 0.860, r = 0.907). Finally, volumes calculated with the automated software were significantly greater than those obtained manually, but they showed a very good correlation (EDV: r = 0.875, r = 0.856, r = 0.891; ESV: r = 0.929, r = 0.879, r = 949). 3D automatic software for LV quantification is feasible and shows excellent correlations with both CMR and 3D echocardiography, considered the gold standard. No clinically relevant differences were noted when applying different border settings. This technique holds promise to facilitate the integration of 3D TTE into clinical practice. PMID- 29605903 TI - More, better, faster. PMID- 29605905 TI - Experimental Characterization of Protein Complex Structure, Dynamics, and Assembly. AB - Experimental methods for the characterization of protein complexes have been instrumental in achieving our current understanding of the protein universe and continue to progress with each year that passes. In this chapter, we review some of the most important tools and techniques in the field, covering the important points in X-ray crystallography, cryo-electron microscopy, NMR spectroscopy, and mass spectrometry. Novel developments are making it possible to study large protein complexes at near-atomic resolutions, and we also now have the ability to study the dynamics and assembly pathways of protein complexes across a range of sizes. PMID- 29605904 TI - Three-dimensional computer-assisted dissection of pancreatic lymphatic anatomy on human fetuses: a step toward automatic image alignment. AB - PURPOSE: Pancreatic cancer is the fourth cause of death by cancer worldwide. Lymph node (LN) involvement is known to be the main prognostic factor. However, lymphatic anatomy is complex and only partially characterized. The aim of the study was to study the pancreatic lymphatic system using computer-assisted anatomic dissection (CAAD) technique and also to update CAAD technique by automatizing slice alignment. METHODS: We dissected three human fetuses aged from 18 to 34 WA. 5-um serial sections of duodeno-pancreas and spleen blocks were stained (hematoxylin-eosin, hematoxylin of Mayer and Masson trichrome), scanned, aligned and modeled in three dimensions. RESULTS: We observed a rich, diffuse but not systematized lymphatic network in the peri-pancreatic region. There was an equal distribution of LNs between the cephalic and body-tail portions. The lymphatic vascularization appeared in continuity from the celiac trunk to the distal ends of its hepatic and splenic arterial branches parallel to the nerve ramifications of the celiac plexus. We also observed a continuity between the drainage of the pancreatic head and the para-aortic region posteriorly. CONCLUSION: In view of the wealth of peri-pancreatic LNs, the number of LNs to harvest could be increased to improve nodal staging and prognostic evaluation. Pancreatic anatomy as described does not seem to be compatible with the sentinel LN procedure in pancreatic surgery. Finally, we are now able to offer an alternative to manual alignment with a semi-automated alignment. PMID- 29605906 TI - High-Throughput Electron Cryo-tomography of Protein Complexes and Their Assembly. AB - Electron cryo-tomography and subtomogram averaging enable visualization of protein complexes in situ, in three dimensions, in a near-native frozen-hydrated state to nanometer resolutions. To achieve this, intact cells are vitrified and imaged over a range of tilts within an electron microscope. These images can subsequently be reconstructed into a three-dimensional volume representation of the sample cell. Because complexes are visualized in situ, crucial insights into their mechanism, assembly process, and dynamic interactions with other proteins become possible. To illustrate the electron cryo-tomography workflow for visualizing protein complexes in situ, we describe our workflow of preparing samples, imaging, and image processing using Leginon for data collection, IMOD for image reconstruction, and PEET for subtomogram averaging. PMID- 29605907 TI - Preparation of Tunable Microchips to Visualize Native Protein Complexes for Single-Particle Electron Microscopy. AB - Recent advances in technology have enabled single-particle electron microscopy (EM) to rapidly progress as a preferred tool to study protein assemblies. Newly developed materials and methods present viable alternatives to traditional EM specimen preparation. Improved lipid monolayer purification reagents offer considerable flexibility, while ultrathin silicon nitride films provide superior imaging properties to the structural study of protein complexes. Here, we describe the steps for combining monolayer purification with silicon nitride microchips to create a tunable approach for the EM community. PMID- 29605908 TI - Time-Resolved Cryo-electron Microscopy Using a Microfluidic Chip. AB - With the advent of direct electron detectors, cryo-EM has become a popular choice for molecular structure determination. Among its advantages over X-ray crystallography are (1) no need for crystals, (2) much smaller sample volumes, and (3) the ability to determine multiple structures or conformations coexisting in one sample. In principle, kinetic experiments can be done using standard cryo EM, but mixing and freezing grids require several seconds. However, many biological processes are much faster than that time scale, and the ensuing short lived states of the molecules cannot be captured. Here, we lay out a detailed protocol for how to capture such intermediate states on the millisecond time scale with time-resolved cryo-EM. PMID- 29605909 TI - Characterizing Protein-Protein Interactions Using Solution NMR Spectroscopy. AB - In this chapter, we describe how NMR chemical shift titrations can be used to study the interaction between two proteins with emphasis on mapping the interface of the complex and determining the binding affinity from a quantitative analysis of the experimental data. In particular, we discuss the appearance of NMR spectra in different chemical exchange regimes (fast, intermediate, and slow) and how these regimes affect NMR data analysis. PMID- 29605910 TI - Reconstitution of Isotopically Labeled Ribosomal Protein L29 in the 50S Large Ribosomal Subunit for Solution-State and Solid-State NMR. AB - Solid-state nuclear magnetic resonance (NMR) has recently emerged as a method of choice to study structural and dynamic properties of large biomolecular complexes at atomic resolution. Indeed, recent technological and methodological developments have enabled the study of ever more complex systems in the solid state. However, to explore multicomponent protein complexes by NMR, specific labeling schemes need to be developed that are dependent on the biological question to be answered. We show here how to reconstitute an isotopically labeled protein within the unlabeled 50S or 70S ribosomal subunit. In particular, we focus on the 63-residue ribosomal protein L29 (~7 kDa), which is located at the exit of the tunnel of the large 50S ribosomal subunit (~1.5 MDa). The aim of this work is the preparation of a suitable sample to investigate allosteric conformational changes in a ribosomal protein that are induced by the nascent polypeptide chain and that trigger the interaction with different chaperones (e.g., trigger factor or SRP). PMID- 29605911 TI - Characterizing Protein-Protein Interactions Using Deep Sequencing Coupled to Yeast Surface Display. AB - In this chapter, we discuss a method to determine the affinity and specificity of nearly all single-point mutants for a full-length protein binder. This method combines deep sequencing, comprehensive mutagenesis, yeast surface display, and fluorescence-activated cell sorting. This approach has been used to study sequence-function relationships for protein-protein interactions. The data can be used to determine the fine conformational epitope on the protein binder. PMID- 29605912 TI - Structurally Guided In Vivo Crosslinking. AB - The focus of modern molecular biology on protein structure and function has reached unparalleled levels. Whether interacting with nucleic acids or other proteins, protein contacts are the basis for fine-tuning all cellular processes. It is for this reason imperative that protein interactions are studied in ways that reflect actual events taking place inside living cells.Here, we describe in detail a method that combines the residue-level resolution provided by structural biology with physiological studies inside living cells, with the overall goal of explaining the contribution of protein-protein interactions in cellular processes. We use as a powerful example our experience with the DNA exit gate interface of the chromosomal cohesin complex, and we argue that this methodology may be followed to address similar questions within any protein complex and in various model systems. PMID- 29605913 TI - Characterizing Intact Macromolecular Complexes Using Native Mass Spectrometry. AB - Native mass spectrometry (MS) enables the characterization of macromolecular assemblies with high sensitivity. It can reveal the stoichiometry of subunits as well as their two-dimensional interaction network and provide information regarding the dynamic behavior of macromolecular complexes. Here, we describe the workflow to perform native MS experiments. In addition, we illustrate the quality control analysis of proteins using MS in denaturing conditions. PMID- 29605914 TI - Hydrogen-Deuterium Exchange Mass Spectrometry to Study Protein Complexes. AB - Hydrogen-deuterium exchange (HDX) mass spectrometry (MS) can provide valuable information about binding, allostery, and other conformational effects of interaction in protein complexes. For protein-ligand complexes, where the ligand may be a small molecule, peptide, nucleotide, or another protein(s), a typical experiment measures HDX in the protein alone and then compares that with HDX for the protein when part of the complex. Multiple factors are critical in the design and implementation of such experiments, including thoughtful consideration of the percent protein bound, the effects of the labeling protocol on the protein complex, and the dynamic range of the analysis method. With careful planning and techniques, HDX MS analysis of protein complexes can be very informative. PMID- 29605915 TI - Structural Analysis of Protein Complexes by Cross-Linking and Mass Spectrometry. AB - Cross-linking and mass spectrometry is used more and more for the structural analysis of large proteins and protein complexes. Although essentially a low resolution method, it avoids the main drawbacks of established structural techniques. Particularly, it is largely insensitive to the inherent flexibility of the studied complexes and is applied under native conditions. It is also applicable to nearly every structural system. Therefore, cross-linking and mass spectrometry is the method of choice for elucidating the general architecture of protein complexes. Advances in instrumentation, techniques, and software now allow every lab that is working with proteins to apply the approach without much difficulty. The most specialized step in the workflow, the mass spectrometry measurement, can be done in most facilities that are performing standard proteomics. We detail here a step-by-step protocol of how to successfully apply the approach in collaboration with the mass spectrometry facility in your institution. PMID- 29605916 TI - Global Characterization of Protein Complexes by Biochemical Purification-Mass Spectrometry (BP/MS). AB - A proteomic platform for global analysis of protein complexes and protein-protein interactions (PPIs) is described. Briefly, after comprehensive physiochemical separation of soluble protein extracts using non-denaturing ion exchange chromatography (IEX), each fraction is subjected to quantitative tandem mass spectrometry analysis. PMID- 29605917 TI - Proteomic Profiling of Integrin Adhesion Complex Assembly. AB - Cell adhesion to components of the cellular microenvironment via cell-surface adhesion receptors controls many aspects of cell behavior in a range of physiological and pathological processes. Multimolecular complexes of scaffolding and signaling proteins are recruited to the intracellular domains of adhesion receptors such as integrins, and these adhesion complexes tether the cytoskeleton to the plasma membrane and compartmentalize cellular signaling events. Integrin adhesion complexes are highly dynamic, and their assembly is tightly regulated. Comprehensive, unbiased, quantitative analyses of the composition of different adhesion complexes over the course of their formation will enable better understanding of how the dynamics of adhesion protein recruitment influence the functions of adhesion complexes in fundamental cellular processes. Here, a pipeline is detailed integrating biochemical isolation of integrin adhesion complexes during a time course, quantitative proteomic analysis of isolated adhesion complexes, and computational analysis of temporal proteomic data. This approach enables the characterization of adhesion complex composition and dynamics during complex assembly. PMID- 29605918 TI - Dual-Color and 3D Super-Resolution Microscopy of Multi-protein Assemblies. AB - Breaking the resolution limit of conventional microscopy by super-resolution microscopy (SRM) led to many new biological insights into protein assemblies at the nanoscale. Here we provide detailed protocols for single-molecule localization microscopy (SMLM) to image the structure of a protein complex. As examples, we show how to acquire single- and dual-color super-resolution images of the nuclear pore complex (NPC) and dual-color 3D data on actin and paxillin in focal adhesions. PMID- 29605919 TI - Correlative 3D Structured Illumination Microscopy and Single-Molecule Localization Microscopy for Imaging Cancer Invasion. AB - Super-resolution microscopy methods enable resolution of biological molecules in their cellular or tissue context at the nanoscale. Different methods have their strengths and weaknesses. Here we present a method that enables correlative confocal, structured illumination microscopy (SIM) and single-molecule localization microscopy (SMLM) imaging of structures involved in formation of invadopodia on the same sample. This enables up to four colors to be visualized in three dimensions at a resolution of between 120 and 10 nm for SIM and SMLM, respectively. PMID- 29605920 TI - Observing the Assembly of Protein Complexes in Living Eukaryotic Cells in Super Resolution Using refSOFI. AB - Few approaches are currently available that allow the detection of protein protein interactions (PPIs) in super-resolution, and the observation of the assembly of protein complexes in living cells has been particularly challenging. We developed reconstituted fluorescence-based stochastic optical fluctuation imaging (refSOFI), which is based on bimolecular fluorescence complementation (BiFC) and SOFI, allowing us to detect protein complex assembly 30 min after the induction of complex formation. Here we describe how to use refSOFI to map the assembly of two proteins of interest into a complex within living cells at super resolution. PMID- 29605921 TI - Detecting Purinosome Metabolon Formation with Fluorescence Microscopy. AB - A long-standing hypothesis in the de novo purine biosynthetic pathway is that there must be highly coordinated processes to allow for enhanced metabolic flux when a cell demands purines. One mechanism by which the pathway meets its cellular demand is through the spatial organization of pathway enzymes into multienzyme complexes called purinosomes. Cellular conditions known to impact the activity of enzymes in the pathway or overall pathway flux have been reflected in a change in the number of purinosome-positive cells or the density of purinosomes in a given cell. The following general protocols outline the steps needed for purinosome detection through transient expression of fluorescent protein chimeras or through immunofluorescence in purine-depleted HeLa cells using confocal laser scanning microscopy. These protocols define a purinosome as a colocalization of FGAMS with one additional pathway enzyme, such as PPAT or GART, and provide insights into the proper identification of a purinosome from other reported cellular bodies. PMID- 29605922 TI - Analysis of Bacterial Pilus Assembly by Shearing and Immunofluorescence Microscopy. AB - Bacterial surface appendages of the type 4 pilus superfamily play diverse roles in adherence, aggregation, motility, signaling, and macromolecular transport. Here we describe two analytical approaches to study assembly of type 4 pili and of pseudopili produced by type 2 protein secretion systems: the shearing assay and immunofluorescence microscopy. These complementary antibody-based methods allow for semiquantitative analysis of fiber assembly. The shearing assay can be scaled up to yield crude extracts of pili that can be further analyzed by electron and atomic force microscopy or by mass spectrometry. PMID- 29605923 TI - Expression, Purification, and Assembly of Archaellum Subcomplexes of Sulfolobus acidocaldarius. AB - The archaellum assembly machinery and its filament consist of seven proteins in the crenarchaeon Sulfolobus acidocaldarius. We have so far expressed, purified, and biochemically characterized four of these archaellum subunits, namely, FlaX, FlaH, FlaI, and FlaF. FlaX, FlaH, and FlaI tightly interact and form the archaellum motor complex important for archaellum assembly and rotation. We have previously shown that FlaH forms an inner ring within a very stable FlaX ring, and therefore FlaX is believed to provide the scaffold for the assembly of the archaellum motor complex. Here we describe how to express and purify FlaX and FlaH and how the double ring structure both form can be obtained. PMID- 29605924 TI - Unstable Protein Purification Through the Formation of Stable Complexes. AB - Purification of proteins containing disordered regions and participating in transient complexes is often challenging because of the small amounts available after purification, their heterogeneity, instability, and/or poor solubility. To circumvent these difficulties, we set up a methodology that enables the production of stable complexes in large amounts for structural and functional studies. In this chapter, we describe the methodology used to establish the best cell culture conditions and buffer compositions to optimize soluble protein production and their stabilization through protein complex formation. Two examples of challenging protein families are described, namely, the human steroid nuclear receptors and the HIV-1 pre-integration complexes. PMID- 29605925 TI - Expressing Multi-subunit Complexes Using biGBac. AB - The reconstitution of recombinant protein complexes is facilitated by methods that allow coexpression of their subunits from a single vector. Here we describe a detailed step-by-step protocol for the biGBac cloning method which can be used to generate baculoviral transfer vectors coding for up to 25 subunits of a protein complex (Weissmann et al., Proc Natl Acad Sci U S A 113(19):E2564-E2569, 2016). biGBac is based on Gibson assembly reactions, optimized DNA linker sequences, and uses a hierarchical two-step assembly procedure. In the first assembly step, up to five expression cassettes are combined to generate a polygene cassette. In the second step, up to five polygene cassettes can then be combined to generate transfer vectors coding for up to 25 subunits. PMID- 29605926 TI - Computational Modelling of Protein Complex Structure and Assembly. AB - Sequence and structure space are nowadays sufficiently large that we can use computational methods to model the structure of proteins based on sequence similarity alone. Not only useful as a standalone tool, homology modelling has also had a transformative effect on the ease with which we can solve crystal structures and electron density maps. Another technique-molecular dynamics-aims to model protein structures from first principles and, thanks to increases in computational power, is slowly becoming a viable tool for studying protein complexes. Finally, the prediction of protein assembly pathways from three dimensional structures of complexes is also now becoming possible. PMID- 29605927 TI - Inferring and Using Protein Quaternary Structure Information from Crystallographic Data. AB - A precise knowledge of the quaternary structure of proteins is essential to illuminate both their function and their evolution. The major part of our knowledge on quaternary structure is inferred from X-ray crystallography data, but this inference process is hard and error-prone. The difficulty lies in discriminating fortuitous protein contacts, which make up the lattice of protein crystals, from biological protein contacts that exist in the native cellular environment. Here, we review methods devised to discriminate between both types of contacts and describe resources for downloading protein quaternary structure information and identifying high-confidence quaternary structures. The use of high-confidence datasets of quaternary structures will be critical for the analysis of structural, functional, and evolutionary properties of proteins. PMID- 29605928 TI - Searching and Extracting Data from the EMBL-EBI Complex Portal. AB - The Complex Portal ( www.ebi.ac.uk/complexportal ) is an encyclopedia of macromolecular complexes. Complexes are assigned unique, stable IDs, are species specific, and list all participating members with links to an appropriate reference database (UniProtKB, ChEBI, RNAcentral). Each complex is annotated extensively with its functions, properties, structure, stoichiometry, tissue expression profile, and subcellular location. Links to domain-specific databases allow the user to access additional information and enable data searching and filtering. Complexes can be saved and downloaded in PSI-MI XML, MI-JSON, and tab delimited formats. PMID- 29605929 TI - Automated Computational Inference of Multi-protein Assemblies from Biochemical Co purification Data. AB - Biology has amassed a wealth of information about the function of a multitude of protein-coding genes across species. The challenge now is to understand how all these proteins work together to form a living organism, and a crucial step for gaining this knowledge is a complete description of the molecular "wiring circuits" that underlie cellular processes. In this chapter, we describe a general computational framework for predicting multi-protein assemblies from biochemical co-fractionation data. PMID- 29605930 TI - A Multiscale Computational Model for Simulating the Kinetics of Protein Complex Assembly. AB - Proteins fulfill versatile biological functions by interacting with each other and forming high-order complexes. Although the order in which protein subunits assemble is important for the biological function of their final complex, this kinetic information has received comparatively little attention in recent years. Here we describe a multiscale framework that can be used to simulate the kinetics of protein complex assembly. There are two levels of models in the framework. The structural details of a protein complex are reflected by the residue-based model, while a lower-resolution model uses a rigid-body (RB) representation to simulate the process of complex assembly. These two levels of models are integrated together, so that we are able to provide the kinetic information about complex assembly with both structural details and computational efficiency. PMID- 29605931 TI - Flexible Protein-Protein Docking with SwarmDock. AB - The atomic structures of protein complexes can provide useful information for drug design, protein engineering, systems biology, and understanding pathology. Obtaining this information experimentally can be challenging. However, if the structures of the subunits are known, then it is often possible to model the complex computationally. This chapter provide practical guidelines for docking proteins using the SwarmDock flexible protein-protein docking method, providing an overview of the factors that need to be considered when deciding whether docking is likely to be successful, the preparation of structural input, generation of docked poses, analysis and ranking of docked poses, and the validation of models using external data. PMID- 29605932 TI - Protein-Protein Docking Using Evolutionary Information. AB - The structural modeling of protein complexes by docking simulations has been attracting increasing interest with the rise of proteomics and of the number of experimentally identified binary interactions. Structures of unbound partners, either modeled or experimentally determined, can be used as input to sample as extensively as possible all putative binding modes and single out the most plausible ones. At the scoring step, evolutionary information contained in the joint multiple sequence alignments of both partners can provide key insights to recognize correct interfaces. Here, we describe a computational protocol based on the InterEvDock web server to exploit coevolution constraints in protein-protein docking methods. We provide methodology guidelines to prepare the input protein structures and generate improved alignments. We also explain how to extract and use the information returned by the server through the analysis of two representative examples. PMID- 29605933 TI - Modeling Structure and Dynamics of Protein Complexes with SAXS Profiles. AB - Small-angle X-ray scattering (SAXS) is an increasingly common and useful technique for structural characterization of molecules in solution. A SAXS experiment determines the scattering intensity of a molecule as a function of spatial frequency, termed SAXS profile. SAXS profiles can be utilized in a variety of molecular modeling applications, such as comparing solution and crystal structures, structural characterization of flexible proteins, assembly of multi-protein complexes, and modeling of missing regions in the high-resolution structure. Here, we describe protocols for modeling atomic structures based on SAXS profiles. The first protocol is for comparing solution and crystal structures including modeling of missing regions and determination of the oligomeric state. The second protocol performs multi-state modeling by finding a set of conformations and their weights that fit the SAXS profile starting from a single-input structure. The third protocol is for protein-protein docking based on the SAXS profile of the complex. We describe the underlying software, followed by demonstrating their application on interleukin 33 (IL33) with its primary receptor ST2 and DNA ligase IV-XRCC4 complex. PMID- 29605934 TI - Modeling the Structure of Helical Assemblies with Experimental Constraints in Rosetta. AB - Determining high-resolution structures of proteins with helical symmetry can be challenging due to limitations in experimental data. In such instances, structure based protein simulations driven by experimental data can provide a valuable approach for building models of helical assemblies. This chapter describes how the Rosetta macromolecular package can be used to model homomeric protein assemblies with helical symmetry in a range of modeling scenarios including energy refinement, symmetrical docking, comparative modeling, and de novo structure prediction. Data-guided structure modeling of helical assemblies with experimental information from electron density, X-ray fiber diffraction, solid state NMR, and chemical cross-linking mass spectrometry is also described. PMID- 29605935 TI - Selecting Conformational Ensembles Using Residual Electron and Anomalous Density (READ). AB - Heterogeneous and dynamic biomolecular complexes play a central role in many cellular processes but are poorly understood due to experimental challenges in characterizing their structural ensembles. To address these difficulties, we developed a hybrid methodology that combines X-ray crystallography with ensemble selections typically used in NMR studies to determine structural ensembles of heterogeneous biomolecular complexes. The method, termed READ, for residual electron and anomalous density, enables the visualization of heterogeneous conformational ensembles of complexes within crystals. Here we present a detailed protocol for performing the ensemble selections to construct READ ensembles. From a diverse pool of binding poses, a selection scheme is used to determine a subset of conformations that maximizes agreement with the X-ray data. Overall, READ is a general approach for obtaining a high-resolution view of dynamic protein-protein complexes. PMID- 29605936 TI - Surface display of metal binding domain derived from PbrR on Escherichia coli specifically increases lead(II) adsorption. AB - OBJECTIVES: To improve the Pb2+ biosorption capacity of the potential E. coli biosorbent, a putative Pb2+ binding domain (PbBD) derived from PbrR was efficiently displayed on to the E. coli cell surface. RESULTS: The PbBD was obtained by truncating the N-terminal DNA-binding domain and C-terminal redundant amino acid residues of the Pb2+-sensing transcriptional factor PbrR. Whole-cell sorbents were constructed with the full-length PbrR and PbBD of PbrR genetically engineered onto the surface of E. coli cells using Lpp-OmpA as the anchor. Followed by a 1.71-fold higher display of PbBD than PbrR, the presence of PbBD on the surface of E. coli cells enabled a 1.92-fold higher Pb2+ biosorption than that found in PbrR-displayed cells. Specific Pb2+ binding via PbBD was the same as Pb2+ binding via the full-length PbrR, with no observable decline even in the presence of Zn2+ and Cd2+. CONCLUSIONS: Since surface-engineered E. coli cells with PbBD increased the Pb2+ binding capacity and did not affect the adsorption selectivity, this suggests that surface display of the metal binding domain derived from MerR-like proteins may be used for the bioremediation of specific toxic heavy metals. PMID- 29605937 TI - Yield enhancement strategies of rare pharmaceutical metabolites from endophytes. AB - Endophytes are barely untapped as vital sources in the medicine. They are microorganisms which mostly exist in plants. As they are exploited, it is accepted that endophytes can produce active metabolites that possess same function as their hosts such as taxol, podophyllotoxin, hypericin, and azadirachtin. These metabolites have been promising potential usefulness in safety and human health concerns. We are supposed to adopt measures to raise production for the low yield of metabolites. This paper summarizes the latest advances in various bioprocess optimization strategies. These techniques can overcome the limitations associated with rare pharmaceutical metabolite-producing endophytic fungi. These strategies include strain improvement, genome shuffling, medium optimization, fermentation conditions optimization, addition of specific factor, addition of solid sorbent, and co-culturing. It will enable endophytes to produce high and sustainable production of rare pharmaceutical metabolites. PMID- 29605938 TI - Establishment of dermal sheath cell line from Cashmere goat and characterizing cytokeratin 13 as its novel biomarker. AB - OBJECTIVE: To establish a dermal sheath cell line, a dermal papilla cell line and a outer root sheath cell line from Cashmere goat and clarify the similarities and differences among them. RESULTS: We established a dermal sheath cell line, a dermal papilla cell line and a outer root sheath cell line from the pelage skin hair follicles of Cashmere goat. The growth rate of dermal sheath cells was intermediate between that of dermal papilla cells and outer root sheath cells. Immunofluorescence experiments and reverse transcription-polymerase chain reaction analysis showed that at both the transcriptional and translational levels, the dermal sheath cells were alpha-smooth muscle actin (alpha SMA)+/cytokeratin 13+, while the dermal papilla cells were alpha-SMA+/cytokeratin 13- and the outer root sheath cells were alpha-SMA-/cytokeratin 13+. Patterns of cytokeratin 13 expression could distinguish the dermal sheath cells from the dermal papilla cells. CONCLUSIONS: These results suggest that cytokeratin 13 could serve as a novel biomarker for dermal sheath cells of Cashmere goat, and should prove useful for researchers investigating dermal stem cells or interaction of different types of cells during hair cycle. PMID- 29605939 TI - Gene expression profiling of human hepatocytes grown on differing substrate stiffness. AB - OBJECTIVE: To study the effects of different substrate stiffness on human hepatocytes using RNA sequencing (RNA-Seq) technology. The stiffness was corresponding to physiology and pathology stiffness of liver tissues. RESULTS: With the aid of RNA-Seq technology, our study characterizes the transcriptome of hepatocytes cultured on soft, moderate, stiff and plastic substrates. Compared to soft substrate, our RNA-Seq results revealed 1131 genes that were up-regulated and 2534 that were down-regulated on moderate substrate, 1370 genes that were up regulated and 2677 down-regulated genes on stiff substrate. Functional enrichment analysis indicated that differentially expressed genes were associated with the regulation of actin cytoskeleton, focal adhesion, tight junction, adherens junction as well as antigen processing and presentation. RNA-Seq results were further verified by a quantitative real-time reverse transcriptase polymerase chain reaction. CONCLUSION: Our study provides a comprehensive picture of the gene expression landscape in hepatocytes grown on different substrate stiffness, offering insights into the role of substrate stiffness in hepatic pathology. PMID- 29605940 TI - Identification and characterization of a novel bacterial pyranose 2-oxidase from the lignocellulolytic bacterium Pantoea ananatis Sd-1. AB - OBJECTIVE: To identify and characterize a novel bacterial pyranose 2-oxidase (P2Ox) and investigate its potential use in lignin degradation applications. RESULTS: A new bacterial P2Ox (PaP2Ox) enzyme was identified in the lignocellulolytic bacterium Pantoea ananatis Sd-1. The PaP2Ox open reading frame was cloned, and the encoded protein was heterologously expressed in an Escherichia coli expression system. Unlike another reported bacterial P2Ox enzyme, the purified PaP2Ox exhibits a homotetrameric spatial conformation that is similar to fungal P2Oxs, with each subunit having a molecular mass of 65 kDa. The recombinant PaP2Ox exhibits maximum activity at 50 degrees C and pH 6.5 with D-glucose as its preferred substrate. In addition, this enzyme was shown to work in combination with bacterial laccase in lignin degradation. CONCLUSIONS: The bacterial enzyme PaP2Ox has potential use in ligninolytic systems and shows promising value in industrial biotechnological applications. PMID- 29605941 TI - Model-based reconstruction of synthetic promoter library in Corynebacterium glutamicum. AB - OBJECTIVE: To develop an efficient synthetic promoter library for fine-tuned expression of target genes in Corynebacterium glutamicum. RESULTS: A synthetic promoter library for C. glutamicum was developed based on conserved sequences of the - 10 and - 35 regions. The synthetic promoter library covered a wide range of strengths, ranging from 1 to 193% of the tac promoter. 68 promoters were selected and sequenced for correlation analysis between promoter sequence and strength with a statistical model. A new promoter library was further reconstructed with improved promoter strength and coverage based on the results of correlation analysis. Tandem promoter P70 was finally constructed with increased strength by 121% over the tac promoter. The promoter library developed in this study showed a great potential for applications in metabolic engineering and synthetic biology for the optimization of metabolic networks. CONCLUSIONS: To the best of our knowledge, this is the first reconstruction of synthetic promoter library based on statistical analysis of C. glutamicum. PMID- 29605942 TI - New trends in aggregating tags for therapeutic protein purification. AB - The rapid growth of the therapeutic protein market calls for more efficient purification methods. Various aggregating tags have recently emerged as simple, fast, cost-effective and column-free technologies for protein (and peptide) purification. In general, these column-free protein purification technologies involve the use of aggregating tags that induce the target protein into insoluble aggregates. These aggregates can be easily separated from soluble impurities and the target protein or peptide is then liberated by a cleavage process. This review summarizes the current state-of-the-art in using aggregating tags for protein purification. The methods are here categorized as follows: (1) tags that allow soluble expression of target protein in vivo and induce aggregation in vitro; (2) tags that induce soluble expression and self-assembling of target protein on insoluble biological polyester beads in vivo; (3) tags that induce formation of inactive aggregates in vivo; (4) tags that induce formation of active aggregates in vivo. PMID- 29605943 TI - Developing a flippase-mediated maker recycling protocol for the oleaginous yeast Rhodosporidium toruloides. AB - OBJECTIVES: To establish a recombinase flippase (FLP) and flippase recognition target (FRT) system-mediated protocol for post-integration excision of exogenous DNA fragments in the oleaginous yeast Rhodosporidium toruloides. RESULTS: Binary vectors were constructed to harbor FLP expressing cassette together with the hygromycin-resistance marker. Results showed that R. toruloides transformants produced FLP, but failed to mediate removal of the bleomycin-resistance marker within two FRT sites. When FLP was fused with a native nuclear localization signal (NLS) peptide, the system was found functional. Moreover, R. toruloides recombinant strains expressing the NLS-fused FLP under the control of PADH2, an promoter of alcohol dehydrogenase 2 gene (RHTO_03062), were obtained to realize homologous recombination upon growing in glucose-deficient medium. CONCLUSIONS: We have devised a homologous recombination method for R. toruloides based on the FLP/FRT system, which may facilitate further metabolic engineering and designing advanced cell factories for value-added chemicals. PMID- 29605944 TI - The GlaA signal peptide substantially increases the expression and secretion of alpha-galactosidase in Aspergillus niger. AB - OBJECTIVE: alpha-Galactosidases are widely used in many fields. It is necessary to improve the production of enzymes through microbiological processes. The aim of this study was to construct recombinant Aspergillus niger strains with high alpha-galactosidase production. RESULTS: Two recombinant A. niger strains were constructed: AB and AGB. The recombinant AB strain contained the alpha galactosidase aglB gene from A. niger with its native AglB signal peptide regulated by the glucoamylase promoter. In the AGB recombinant strain, the AglB signal peptide was replaced with the glucoamylase (GlaA) signal peptide. The extracellular maximum alpha-galactosidase activity of the AGB strain was 215.7 U/ml and that of the AB strain was 9.8 U/mL. The optimal conditions for alpha galactosidase were pH 3.5 and 35 degrees C. CONCLUSIONS: The GlaA signal peptide substantially increased the yield of secreted alpha-galactosidase in A. niger. This recombinant strain holds great potential for industrial applications. PMID- 29605945 TI - GNAS-mutated carcinoma arising from gastric foveolar metaplasia in the duodenum after 9 years of observation. AB - This case involved an 80-year-old man. Screening with esophagogastroduodenoscopy (EGD) in 2004 revealed Brunner's gland hyperplasia (BGH), 5 mm in size, in the duodenal bulb. The size of the lesion increased and its shape has changed since then, as detected in subsequent EGDs. The lesion had increased in size to 15 mm with a depression and biopsy specimens revealed an adenocarcinoma. The patient underwent endoscopic mucosal resection. Histopathological assessments indicated an adenocarcinoma arising from gastric foveolar metaplasia (GFM) adjacent to BGH. BGH stained positive for MUC6, and GFM and the adenocarcinoma stained positive for MUC5AC. Mutations of the GNAS gene were not detected in the GFM biopsied in 2007. On the other hand, common GNAS mutations (R201H) were detected in GFM and the adenocarcinoma in the endoscopically resected specimen in 2013. Moreover, mutant allele frequencies were higher in the carcinoma than in GFM. The patient remains disease-free for 4 years after endoscopic treatment. This case report further supports the notion that GFM may be a precursor lesion in the process of GNAS-mutated, gastric-type duodenal carcinogenesis. PMID- 29605946 TI - Pharmacist supply of sildenafil: pharmacists' experiences and perceptions on training and tools for supply. AB - Background In 2014, New Zealand reclassified sildenafil (for erectile dysfunction) to allow supply by specially trained pharmacists under strict criteria. Objective The study aimed to determine pharmacists' experiences and perspectives on the training for, and supply of sildenafil under this model. Setting New Zealand community pharmacy. Method This qualitative study captured data with a semi-structured interview used with purposively-sampled participants. A maximum variation sample was used to select a wide range of pharmacists working in various pharmacies, including pharmacists who were trained to provide sildenafil and those not trained to supply sildenafil. Consenting pharmacists were interviewed, with interviews audio-recorded and transcribed. Analysis used a framework approach. Main outcome measures Topics explored included: satisfaction and experience of the training; suitability and usability of the screening tools; experiences of the supply process and why some pharmacists chose not to become trained. Results Thirty-five pharmacists were interviewed. Training was seen as uncomplicated and the screening tools provided confidence that key consultation areas were covered. Most consultations reportedly took 15-20 min, some up to 60 min. Pharmacists reported being comfortable with the consultations. Many men requesting supply fell outside of the parameters, resulting in medical referral. This new model of supply was seen as a positive for pharmacists and their patients. Unaccredited pharmacists reported a perceived lack of interest from men, or ability to provide the service as reasons for not seeking accreditation. Conclusion New Zealand's model of pharmacist supply of sildenafil appears workable with some areas for improvement identified. PMID- 29605947 TI - Impact of warfarin discharge education program on hospital readmission and treatment costs. AB - Background Although warfarin is highly effective, management of patients prescribed warfarin is complex due to its narrow therapeutic window. Objective To evaluate the impact of a formal warfarin discharge education program (WDEP) on hospital readmission and treatment costs in patients who received warfarin therapy. Setting Robert Wood Johnson University Hospital Somerset in Somerville, New Jersey, USA. Method In this interventional cohort study, patients were assigned to either the WDEP group or the usual care group. The effects of the WDEP on readmission within 90 days after discharge were analyzed using Cox proportional hazards models. Factors influencing treatment cost were identified using generalized linear model with log-link function and gamma distribution. Main outcome measure Hospital readmission within 90 days and treatment costs associated with hospital readmission. Results Among 692 eligible patients, 203 in each group were matched using propensity scores and there were no statistically significant differences in the patient baseline characteristics between two groups. The risk of all-cause readmission within 90 days was significantly lower in the WDEP group compared to the usual care group (relative risk = 0.46, 95% CI 0.28-0.76). The treatment costs associated with hospital readmission in the WDEP group were 19% lower than those in the usual care group after adjusting for the study variables. Conclusion A formal, individualized WDEP provided by pharmacists resulted in significant reduction of readmission and treatment costs. The economic burden of treatment costs associated with warfarin can be controlled if well-organized warfarin education is provided to patients who received warfarin therapy. PMID- 29605949 TI - Quality pharmacy services and key performance indicators in Polish NICUs: a Delphi approach. AB - Background Currently, there is no literature describing what a quality level of practice entails in Polish neonatal intensive care units (NICUs), nor are there any means of currently measuring the quality of pharmaceutical care provided to NICU patients. Objective To identify a set of essential pharmacist roles and pharmacy-relevant key performance indicators (KPI's) suitable for Polish neonatal intensive units (NICUs). Setting Polish hospital pharmacies and NICUs. Method Using a modified Delphi technique, potential KPI's structured along Donabedian's domains as well as pharmacy services were presented to an expert panel of stakeholders. Two online, consecutive Delphi rounds, were completed by panellists between August and September 2017. Main outcome measure To identify the minimum level of pharmacy services that should be consistently provided to NICU patients. Results A total of 16 panellists contributed to the expert panel. Overall, consensus of 75% was reached for 23 indicators and for 28 roles. When considering pharmacy services for the NICU, the experts were found to highly value traditional pharmacy roles, such as dispensing and extemporaneous compounding, however, they were still eager for roles in the other domains, such as educational and clinical services, to be listed as essential for NICU practice. Panellists were found to positively value the list of indicators presented, and excluded only 9 out of the total list. Conclusion There is a need for future research to establish a minimum standard of practice for Polish pharmacists to encourage the progression and standardisation of hospital pharmacy services to meet the level of practice seen in NICUs worldwide. PMID- 29605948 TI - Testing a healthcare provider-patient communicative relationship quality model of pharmaceutical care in hospitals. AB - : Background Patient-centeredness and participatory care is increasingly regarded as a proxy for high-quality interpersonal care. Considering the development of patient-centeredness and participatory care relationship model in pharmacist patient domain, it is of great significance to explore the mechanism of how pharmacist and patient participative behaviors influence relationship quality and patient outcomes. Objective To validate pharmacist-patient relationship quality model in Chinese hospitals. SETTING: Four tertiary hospitals in 2017. Methods The provision of pharmaceutical care was investigated. A cross-sectional questionnaire survey covering different constructs of communicative relationship quality model was conducted and the associations among pairs of the study constructs were explored. Based on the results of confirmatory factor analysis, path analysis was conducted to validate the proposed communicative relationship quality model. Main outcome measure Model fit indicators including Tucker-Lewis index (TLI), comparative fit index (CFI), root mean square error of approximation (RMSEA) and weighted root mean square residual(WRMR). Results There were 589 patients included in our study. The final path model had an excellent fit (TLI = 0.98, CFI = 0.98, RMSEA = 0.05; WRMR = 1.06). HCP participative behavior/patient centeredness (beta = 0.79, p < 0.001) and interpersonal communication (beta = 0.13, p < 0.001) directly impact the communicative relationship quality. But patient participative behavior was not a predictor of either communicative relationship quality or patient satisfaction. Conclusion HCP participative behavior/patient-centeredness and interpersonal communication are positively related to relationship quality, and relationship quality is mediator between HCP participative behavior and interpersonal communication with patient satisfaction. PMID- 29605950 TI - Distal Nerve Transfer: Perspective of Reconstructive Microsurgery. AB - Recent articles have strongly emphasized the superiority of distal nerve transfers despite indefinite assessment. I would like to introduce the problems associated with functional evaluation following nerve transfers. PMID- 29605951 TI - Future Perspectives in the Management of Nerve Injuries. AB - AIM: The author presents a solicited "white paper" outlining her perspective on the role of nerve transfers in the management of nerve injuries. METHODS: PubMed/MEDLINE and EMBASE databases were evaluated to compare nerve graft and nerve transfer. An evaluation of the scientific literature by review of index articles was also performed to compare the number of overall clinical publications of nerve repair, nerve graft, and nerve transfer. Finally, a survey regarding the prevalence of nerve transfer surgery was administrated to the World Society of Reconstructive Microsurgery (WSRM) results. RESULTS: Both nerve graft and transfer can generate functional results and the relative success of graft versus transfer depended on the function to be restored and the specific transfers used. Beginning in the early 1990s, there has been a rapid increase from baseline of nerve transfer publications such that clinical nerve transfer publication now exceeds those of nerve repair or nerve graft. Sixty-two responses were received from WSRM membership. These surgeons reported their frequency of "usually or always using nerve transfers for repairing brachial plexus injuries as 68%, radial nerves as 27%, median as 25%, and ulnar as 33%. They reported using nerve transfers" sometimes for brachial plexus 18%, radial nerve 30%, median nerve 34%, ulnar nerve 35%. CONCLUSION: Taken together this evidence suggests that nerve transfers do offer an alternative technique along with tendon transfers, nerve repair, and nerve grafts. PMID- 29605952 TI - Is the Oblique Branch a Preferable Vascular Pedicle for Anterolateral Thigh Free Flaps? AB - BACKGROUND: The oblique branch of the lateral circumflex femoral artery is considered an alternative vascular pedicle of the anterolateral thigh (ALT) flap. However, the oblique branch has several advantages over the descending branch. METHODS: A total of 61 consecutive ALT free flaps were harvested according to Yu's ABC system. Vascular pedicle dimensions and length, artery course, perforator origins, and flap harvest time with the oblique branch or the descending branch were recorded. We classified the ALT flaps with oblique branches into three types according to the origin of perforator B. Type I flaps were those where perforator B originated from the descending branch. Type II flaps were those without perforator B. Type III flaps were those where perforator B originated from the oblique branch. RESULTS: The mean +/- standard deviation (SD) diameter of the oblique branch at its origin was 1.68 +/- 0.51 mm, with an average +/- SD pedicle length of 12.92 +/- 3.7 cm, while that of the descending branch was 2.27 +/- 0.49 mm and 18.73 +/- 5.14 cm, respectively. The percentage of septocutaneous perforators from the oblique branch was 35.59%, while that from the descending branch was 15.38%. The flap harvest time with the oblique branch was 33.73 +/- 11.68 minutes, while that of the descending branch was 52.27 +/- 7.21 minutes. Based on the origin of perforator B, 7 cases had type I ALT flaps, 4 had type II ALT flaps, and 10 had type III ALT flaps. Various ALT flaps based on the oblique branch were harvested, and good clinical results were achieved. CONCLUSION: The oblique branch is sufficiently large and can be reliably used as the flap pedicle. It may be the preferred vascular pedicle for ALT free flaps. PMID- 29605953 TI - Does Cigarette Smoking Harm Microsurgical Free Flap Reconstruction? AB - BACKGROUND: Free tissue transfers can successfully address a wide range of reconstructive requirements. While the negative influence of cigarette smoking is well documented, its effects in the setting of microsurgical free flap reconstruction remain debated. This study evaluates the impact of cigarette smoking on microsurgical reconstructions. METHODS: Over a 7-year period, 897 patients underwent 969 microvascular free flap reconstructions at a single surgical center. The cases were divided into "smoker" (S) and "nonsmoker" (NS) groups according to their cigarette smoking status. The data were retrospectively screened for patients' demographics, perioperative details, surgical complications, free flap types, recipient sites, flap survival, and overall outcomes. RESULTS: Both groups were comparable regarding comorbidities including hypertension, peripheral artery disease, diabetes, American Society of Anesthesiologists scores, types of performed free flaps, and recipient sites. While patients in the NS group were significantly older and had a higher prevalence of obesity (p < 0.05), there were no significant differences regarding the rate of major or minor complications during our 3-month follow-up period (p > 0.05). CONCLUSION: While minor and major complications were increased regarding virtually all examined parameters, cigarette smoking did not have significant effects on the overall outcomes of microsurgical free flap reconstructions. PMID- 29605954 TI - Development of Targeted Muscle Reinnervation Model in Hind Limb Amputated Rats. AB - BACKGROUND: Targeted muscle reinnervation (TMR) is a novel approach to postamputation neuroma pain; however, this has not been explicitly studied. The purpose of this study was to develop a TMR model in hind limb amputated rats. METHODS: Ten hind limbs from 5 Sprague Dawley cadaver rats were used. Sciatic nerve, main branches of the sciatic nerve (common peroneal, tibial, sural), motor branches from the sciatic nerve to the biceps femoris and cauda femoris, gluteal nerve and its motor branches to the semimembranosus, and biceps femoris and femoral nerve were dissected to look for consistent nerve anatomy that can be used for TMR in the rat hind limb amputation model. Transfemoral amputation was performed and two types of coaptations were made: common peroneal nerve to motor branch to biceps femoris and tibial nerve to motor branch to semimembranosus. RESULTS: The total surgical time for the dissection, amputation, and coaptation of nerves was ~90 minutes. A total of 100 nerves were dissected in 10 rat hind limbs. Anatomical dissections were straightforward to perform. Anatomy of the dissected nerves was consistent. Hind limb amputations were performed without damaging the target muscles and nerves. Nerve lengths were sufficient for coaptation without any tension. CONCLUSIONS: To the best of our knowledge, this is the first report on TMR model in hind limb amputated rats. This model will allow for mechanical, electromyography (EMG), and histological analysis for future assessment of neuroma prevention. PMID- 29605955 TI - Dynamic Quantitative Assessment of Motor Axon Sprouting after Direct Facial Hypoglossal End-To-Side Neurorrhaphy in Rats. AB - BACKGROUND: End-to-side (ETS) neurorrhaphy is a promising procedure for peripheral nerve repair, yet controversies regarding the efficacy of this repair in facial nerve anastomosis for facial paralysis still exist. MATERIALS AND METHODS: Thirty rats were divided into three groups: intact control group, direct facial-hypoglossal ETS neurorrhaphy, and end-to-end (ETE) neurorrhaphy. Nerve regeneration was assessed with vibrissae motor performance, electrophysiological tests, retrograde labeling, and histomorphological analysis at 4 and 8 months postoperatively. RESULTS: Both ETS and ETE neurorrhaphies resulted in axonal regeneration and functional recovery of the recipient nerve but did not reach the level of intact controls. Significantly higher numbers of myelinated axons and labeled neurons giving regenerating fibers were found in group ETE compared with group ETS at both time points, consistent with the functional and electrophysiological recovery. Group ETS showed significantly smaller fiber diameter and thinner myelin thickness than group ETE at 4 months, but the difference became nonsignificant at 8 months. ETS neurorrhaphy had a very slight effect on the donor nerve, as determined electrophysiologically and histomorphologically. Sparsely distributed double-labeled neurons and relatively large amounts of single-labeled neurons contributing to reinnervation were found through double retrograde neuronal labeling in group ETS. Further quantitative analysis of the percentage of double-labeled neurons showed a pronounced tendency to decline from 19.8% at 4 months to 6.0% at 8 months postoperatively. CONCLUSION: Successful reinnervation after ETS neurorrhaphy could be achieved through both collateral sprouting and terminal sprouting, with the latter seeming to be the principal origin of motor nerve sprouting. PMID- 29605957 TI - Check the Record: Remote CT Scans for Breast Flap Perforator Mapping. AB - BACKGROUND: Perforator mapping with computed tomography angiography (CTA) prior to autologous breast reconstruction reduces donor-site morbidity and operative time, but is costly. The aim of this study was to evaluate whether pre-existing CT scans could be used for dominant perforator identification before autologous reconstruction. METHODS: We identified all female patients who underwent mastectomy with immediate or delayed breast reconstruction with abdominal free flaps at a single institution between 2006 and 2016. Medical records were reviewed to identify patients with pre-existing CT scans of the abdomen/pelvis. CT images were reviewed by the senior surgeon and ranked on a 1 to 3 scale to indicate utility for preoperative planning. An analysis was performed to assess financial savings and radiation avoidance associated with the use of pre-existing scans. RESULTS: Of 301 identified patients, 44.9% (n = 135) had an available pre existing CT. A dominant perforator was identified on 92.6% of scans. A higher proportion of dominant perforators was identified using positron emission tomography (PET)/CT scans compared with CT scans with intravenous (IV) contrast and noncontrast CTs (p < 0.0001). Compared with PET/CTs and CTs with IV contrast, the average utility score for noncontrast CTs was lower (p = 0.0001). Dominant perforators were clearly identified in patients who had both a remote CT scan and a preoperative CTA. Perforator mapping using remote CT scans yielded a projected radiation reduction of 13.2 mGy per patient and yielded a projected annual U.S. health care savings of $28,459,638. CONCLUSION: Our study suggests that pre existing CT scans represent a viable and economical alternative for perforator mapping before abdominal-based free flap breast reconstruction. PMID- 29605956 TI - Alternative Choices for Anterolateral Thigh Flaps Lacking Suitable Perforators: A Systematic Review. AB - BACKGROUND: The anterolateral thigh (ALT) flap has become a predominant option in the field of reconstruction. However, some difficulties in harvesting flap exist due to the anatomical variability of the perforators. Reports have provided solutions for unreliable perforators. Although numerous cases that showed successful conversion to tensor fasciae latae (TFL) flap or anteromedial thigh (AMT) flap have been reported in the literature, none fully addresses the reliability of the perforators that have been described to date. Therefore, we conducted a systematic literature review to compare the reliability of the TFL flap with that of the AMT flap when an ALT flap perforator is not suitable. METHODS: A systematic review of the MEDLINE, PubMed, and Cochrane Library electronic databases was performed to compare the characteristics of TFL and AMT flap perforators. RESULTS: A total of 13 articles were included for review. The mean number of TFL perforators varied from 1.41 to 3.17 per thigh. The mean number of AMT perforators was between 0.59 and 1.3 per thigh. The cumulative assessment of the clinical and anatomical studies showed 456 perforators in 180 TFL flaps (mean, 2.53) and 145 perforators in 162 AMT flaps (mean, 0.90). The mean pedicle length of the TFL and AMT flaps ranged from 7.0 to 9.59 cm and from 7.4 to 11.0 cm, respectively. The mean perforator diameter was similar in both flaps. CONCLUSION: Currently available literature suggests that the TFL flap may be a more reliable alternative when adequate perforators are not found for ALT flap harvest. PMID- 29605958 TI - Developing a Risk Prediction Model for Intensive Care Unit Mortality after Cardiac Surgery. PMID- 29605959 TI - Heparin-Induced Thrombocytopenia in Infants after Heart Surgery. AB - BACKGROUND: Heparin-induced thrombocytopenia (HIT) in infants is a rare disorder, and the diagnosis and management of HIT still remains challenging. Argatroban is a synthetic direct thrombin inhibitor (DTI) that is widely used for treating HIT. However, little is known about the efficacy of the activated clotting time (ACT) test in monitoring DTI treatment as an alternative to the routinely used activated partial thromboplastin time (aPTT). METHODS: Between July 2013 and January 2015, four infants were diagnosed with HIT after surgical correction of congenital anomalies. In all cases, heparin was used during cardiopulmonary bypass (CPB). Diagnosis of HIT was based on the "4 Ts" pretest clinical scoring system, and platelet factor 4 (PF4) antibody was detected using enzyme-linked immunosorbent assay. Argatroban was used in treating HIT. When argatroban was infused, anticoagulation tests (aPTT, prothrombin time [PT], thrombin time [TT], and fibrinogen) were performed every 4 to 12 hours. ACT was used in addition to monitor the anticoagulation effect of argatroban. The target ACT was 1.5 to 3.0 times the baseline. ACT was measured every 2 to 4 hours and remeasured 1 hour after each dosage adjustment. RESULTS: Thrombocytopenia (defined as a 50% decrease in platelet count) occurred during the 3rd to 6th day postoperatively. After the diagnosis of HIT, argatroban was started immediately, and platelet counts stabilized and gradually increased. Anticoagulation effect of argatroban was successful monitored by ACT and aPTT. Poor correlation between the ACT test and aPTT test (R = 0.270, p = 0.092) was noted in one patient. ACT values increased rapidly after 3 to 7 days on argatroban treatment. In most cases, low dosage of argatroban was given ranging from 0.04 to 5.00 MUg/kg/min. CONCLUSION: Argatroban may be an effective medicine in treating HIT in infants, in a reduced dosage. The great fluctuation in argatroban dosage during the course of HIT treatment necessitates close monitoring. ACT test may be reliable and convenient for monitoring HIT treatment and may contribute to positive clinical outcomes in infants. The efficacy of argatroban and the use of ACT monitoring in the management of HIT infants needs further study. PMID- 29605960 TI - Moderate Hypothermic Circulatory Arrest (>= 28 degrees C) with Selective Antegrade Cerebral Perfusion for Total Arch Replacement with Frozen Elephant Trunk Technique. AB - OBJECTIVES: The optimal hypothermic level during circulatory arrest in aortic arch surgery remains controversial, particularly in frozen elephant trunk (FET) procedures. We describe herein our experience for total arch replacement with FET technique under moderate systemic hypothermic circulatory arrest (>= 28 degrees C) during selective antegrade cerebral perfusion. METHODS: Between January 2009 and January 2016, 38 consecutive patients underwent elective total arch replacement for various aortic arch pathologies with FET technique using the E vita Open hybrid prosthesis (Jotec GmbH, Hechingen, Germany). Selective unilateral or bilateral cerebral perfusion under moderate systemic hypothermic circulatory arrest (28.7 degrees C +/- 0.5 degrees C) was used in all patients. Minimally invasive total arch replacement with FET via partial upper sternotomy was performed in 15 patients (39%) and in the remaining 23 patients (61%) via full sternotomy. Mean late follow-up was 3 +/- 2 years and was 98% complete. Clinical data were prospectively entered into our institutional database. RESULTS: Cardiopulmonary bypass time accounted for 198 +/- 58 minutes and the myocardial ischemic time 109 +/- 29 minutes. Selective antegrade cerebral perfusion time was 55 +/- 6 minutes. Lower body circulatory arrest time was 39 +/ 11 minutes. Unilateral cerebral perfusion was performed in 31 patients (82%), and bilateral in 7 patients (18%). Intensive care unit stay was 4 +/- 3 days. Thirty-day mortality was 5% (n = 2). Late survival at 3 years was 87 +/- 3%. Two patients (5%) required reexploration for bleeding. Patients were discharged after a hospital length of stay of 7 +/- 2 days. Postoperative permanent neurologic complication occurred in two patients (5%). Three patients (8%) experienced a transient neurologic disorder. New transient renal replacement therapy was necessary in three patients (8%). No spinal cord injury was noted. CONCLUSIONS: Our data suggest that moderate systemic hypothermic circulatory arrest (>= 28 degrees C) in combination with antegrade cerebral perfusion can safely be applied for total aortic arch replacement with FET and offers sufficient neurologic and visceral organ protection. PMID- 29605961 TI - Factors Affecting Postoperative Lung Expansion in Patients with Pyogenic Empyema. AB - BACKGROUND: In patients with parapneumonic empyema, decortication is usually preferred to ensure functional lung re-expansion. However, there could be patients exhibiting incomplete postoperative lung expansion and inadequate drainage despite decortication. Therefore, we evaluated factors affecting postoperative lung expansion in patients undergoing decortication. METHODS: A total of 221 patients with pyogenic empyema who underwent video-assisted thoracoscopic surgery (VATS) between January and October 2016 in our hospital were reviewed in terms of surgical success. The following factors were evaluated: age; the time between identification of a localized effusion and surgical referral; chest tube drainage durations; any underlying morbidity preoperative blood culture data; and the thickness of the visceral pleura. RESULTS: Several factors that significantly prolonged the postoperative time to lung expansion were evident in patients with diabetes mellitus (DM) and bacteremia; postoperative chest tube drainage was significantly longer in those with DM (p = 0.009) and bacteremia (p = 0.01); and postoperative hospitalization time was significantly longer in patients with bacteremia (p = 0.01). The thickness of the visceral pleura was strongly correlated with postoperative chest tube drainage duration and postoperative hospitalization time (Pearson correlation coefficient, r = 0.245, p = 0.00). CONCLUSIONS: In patients with DM, bacteremia, or thickened pleura, the time to lung expansion after operation was longer. Therefore, stricter pre- and post-operative control of blood-sugar levels and adequate antibiotics are required to facilitate postoperative lung re-expansion. In patients with thickened pleurae, prolonged chest tube placement is unavoidable. PMID- 29605962 TI - Ten Years' Experience in Robotic-Assisted Thoracic Surgery for Early Stage Lung Cancer. AB - BACKGROUND: This study analyzed the short- and long-term outcomes of robotic assisted thoracic surgery (RATS) for early stage non-small cell lung cancer (NSCLC). METHODS: From November 2006 to December 2016, we performed 363 RATS procedures. This study retrospectively reviewed 339 patients who underwent RATS for clinical stages I (n = 318) or II (n = 21) NSCLC. RESULTS: Twenty-nine patients underwent segmentectomy, 307 lobectomy, and 3 pneumonectomy. Conversion occurred in 22 patients (6.5%): 15 (4.4%) due to technical issues, 4 (1.2%) for oncological reasons, and 3 (0.9%) for bleeding. The median number of N1 and N2 stations resected was 2 and 3, respectively, and the median number of N1 and N2 lymph nodes resected was 9 and 6, respectively. Median operative time was 192 minutes for lobectomy, 172 minutes for segmentectomy, and 275 minutes for pneumonectomy. Median length of hospital stay was 5 days (2-191). The most common postoperative complication was prolonged air leak (12.1%). Major complications occurred in eight patients (2.4%). The 30-day and 90-day operative mortality was 0% and 0.3%, respectively. Two and 5-year cancer-specific survival rate was 96.1% and 91.5%, respectively. Five-year survival rate was 96.2% for patients who underwent segmentectomy, and 89.1% for lobectomy. All three patients who underwent pneumonectomy were alive at 5 years with no disease. CONCLUSIONS: Besides the well-known short-term outcomes showing very low morbidity and mortality rates, mediastinal lymph node dissection during RATS adequately assesses lymph node stations detecting occult lymph node metastasis and leading to excellent oncologic results. However, these results await longer follow-up studies. PMID- 29605963 TI - Reply to "Developing a Risk Prediction Model for Intensive Care Unit Mortality after Cardiac Surgery". PMID- 29605964 TI - Broken English. PMID- 29605965 TI - Factorial design optimization of micelle enhanced synchronous spectrofluorimetric assay of Omarigliptin: Applied to content uniformity testing and in vitro drug release. AB - A micelle enhanced spectrofluorimetric method was developed for determination of Omarigliptin (OMG) based on its native fluorescence behavior. The interaction of OMG with surfactants and macromolecules was studied. In aqueous solution, the relative fluorescence intensity (RFI) of OMG was enhanced by 24% in the presence of Tween 80 at pH 3.5. The optimal conditions for the micelle enhanced fluorescence were attained by Minitab(r) program using Plackett-Burman factorial design. Pareto chart, contour plots and surface plots were used to exclude the insignificant variables and optimize the significant factors. The spectrofluorimeter was operated under synchronous mode using ?lambda = 30 nm and recording the RFI of the intense narrow band at 267 nm for OMG in 0.5% w/v Tween 80 + 0.2 M acetate buffer (pH 3.5) system using water as diluent. Using synchronous scan mode offered many advantages including considerable reduction of spectral overlap and enhanced linearity of the calibrators. Validation parameters were satisfied over the concentration range 0.1-2 MUg/ml. The developed method was the first analytical procedure for OMG assay in Marizev(r) tablets. Moreover, content uniformity testing and in vitro drug release of tablets were performed. PMID- 29605966 TI - Patient experience of centralized acute stroke care pathways. AB - BACKGROUND: In 2010, Greater Manchester (GM) and London centralized acute stroke care services into a reduced number of hyperacute stroke units, with local stroke units providing on-going care nearer patients' homes. OBJECTIVE: To explore the impact of centralized acute stroke care pathways on the experiences of patients. DESIGN: Qualitative interview study. Thematic analysis was undertaken, using deductive and inductive approaches. Final data analysis explored themes related to five chronological phases of the centralized stroke care pathway. SETTING AND PARTICIPANTS: Recruitment from 3 hospitals in GM (15 stroke patients/8 family members) and 4 in London (21 stroke patients/9 family members). RESULTS: Participants were impressed with emergency services and initial reception at hospital: disquiet about travelling further than a local hospital was allayed by clear explanations. Participants knew who was treating them and were involved in decisions. Difficulties for families visiting hospitals a distance from home were raised. Repatriation to local hospitals was not always timely, but no detrimental effects were reported. Discharge to the community was viewed less positively. DISCUSSION AND CONCLUSIONS: Patients on the centralized acute stroke care pathways reported many positive aspects of care: the centralization of care pathways can offer patients a good experience. Disadvantages of travelling further were perceived to be outweighed by the opportunity to receive the best quality care. This study highlights the necessity for all staff on a centralized care pathway to provide clear and accessible information to patients, in order to maximize their experience of care. PMID- 29605967 TI - Preliminary results of proton radiotherapy for pediatric rhabdomyosarcoma: a multi-institutional study in Japan. AB - To evaluate preliminary results of proton radiotherapy (PRT) for pediatric patients with rhabdomyosarcoma (RMS). From 1987 to 2014, PRT was conducted as initial radiotherapy in 55 patients (35 males, 20 females, median age 5 years, range 0-19) with RMS at four institutes in Japan. Thirty-one, 18, and six patients had embryonal, alveolar, and other RMS, respectively. One, 11, 37, and six patients were in IRSG groups I, II, III, and IV, respectively, and the COG risk group was low, intermediate, and high for nine, 39, and seven patients, respectively. The irradiation dose was 36-60 GyE (median: 50.4 GyE). The median follow-up period was 24.5 months (range: 1.5-320.3). The 1- and 2-year overall survival rates were 91.9% (95% CI: 84.3-99.5%) and 84.8% (95% CI 75.2-94.3%), respectively, and these rates were 100% and 100%, 97.1% and 90.1%, and 57.1% and 42.9% for COG low-, intermediate-, and high-risk groups, respectively. There were 153 adverse events of Grade >=3, including 141 hematologic toxicities in 48 patients (87%) and 12 radiation-induced toxicities in nine patients (16%). Proton specific toxicity was not observed. PRT has the same treatment effect as photon radiotherapy with tolerable acute radiation-induced toxicity. PMID- 29605968 TI - Sensitive determination of bromhexine hydrochloride based on its quenching effect on luminol/H2 O2 electrochemiluminescence system. AB - In this paper, the electrochemiluminescence (ECL) behavior of luminol/H2 O2 system in the presence of bromhexine hydrochloride (BrH) was investigated. It was found that the ECL intensity of luminol/H2 O2 system on a platinum electrode could be intensely quenched by BrH owing to the scavenging superoxide radical ability of BrH, and therefore the sensitive determination of BrH was possible. Under optimal conditions, the quenched ECL intensity was linear to the concentration of BrH in a wide range of 0.08 to 500 MUM, with a detection limit of 0.02 MUM (signal-to-noise ratio (S/N) = 3). This ECL method possessed the merits of rapid, simple and sensitive, and was successfully applied to the BrH quantification in pharmaceutical preparations with satisfactory recoveries of 91.0 +/- 4.0 to 106.5 +/- 3.4%. The possible route of the quenched ECL of luminol/H2 O2 in the presence of BrH was also discussed. PMID- 29605969 TI - Latent myopathy is more pronounced in patients with low flow versus normal flow aortic stenosis with normal left ventricular ejection fraction who are undergoing surgical aortic valve replacement: Multicenter study with a brief review of the literature. AB - BACKGROUND: Midwall fibrosis and low stroke volume are independent predictors of mortality in severe aortic stenosis (AS) with preserved LV ejection fraction (LVEF). The role of speckle tracking echocardiography (STE) to identify latent myopathy pre- and post- aortic valve replacement (AVR) in high risk AS patients with normal LVEF is limited. METHODS: Demographic, 2D echocardiographic, and STE data were analyzed in patients with severe AS and preserved LVEF who underwent tissue AVR. Velocity vector imaging (VVI) was used to assess regional and global peak systolic longitudinal strain (GLS). Low flow (LF) was defined as an indexed LV stroke volume <35 mL/m2 . RESULTS: Between December 2008 and May 2011, 37 patients (75 +/- 9 years, 51% male) had both pre- and post-AVR echos within 6.6 +/- 6.5 months (median = 4 months; range = 2.5-9.5) of surgery. Compared with pre AVR, GLS (-6.9 +/- 4.9% vs -11.1 +/- 4.1%; P < .001) and strain rate (-0.72 +/- 0.3s-1 vs -0.87 +/- 0.3s-1 ; P = .01) improved post-AVR. Pre-AVR mid-segments showed a similar myopathy as the basal segments (-9.5 +/- 4.3% vs -9.0 +/- 4.2%;P = .3). The 16 (43%) LF patients in this study had lower pre- and post-AVR strain compared to NF patients (GLS Pre-AVR:LF vs NF: -5.1 +/- 4.1% vs -8.4 +/- 4.9% (P = .04) and GLS Post-AVR:LF vs NF: -9.2 +/- 3.7% vs -12.5 +/- 3.9% (P = .01)). However, there was no difference in absolute and %change improvement in GLS post AVR (LF vs NF:? -4.2 +/- 3.5% vs ?-4.1 +/- 5.3% (P = .90) and 193 +/- 214% vs 143 +/- 230% change (P = .5)). The lowest GLS was seen in LF/HG AS followed by LF/LG, NF/LG and NF/HG AS; P = .03. CONCLUSIONS: Latent myopathy is more pronounced in LF AS both pre- and post-AVR. Our study provides evidence of improvement in myopathy in LF AS despite a persistent worse myopathy compared to NF patients post-AVR. PMID- 29605970 TI - Withdrawal versus continuation of long-term antipsychotic drug use for behavioural and psychological symptoms in older people with dementia. AB - BACKGROUND: Antipsychotic agents are often used to treat neuropsychiatric symptoms (NPS) in people with dementia although there is uncertainty about the effectiveness of their long-term use for this indication and concern that they may cause harm, including higher mortality. When behavioural strategies have failed and treatment with antipsychotic drugs is instituted, regular attempts to withdraw them have been recommended in guidelines. Physicians, nurses and families of older people with dementia may be reluctant to stop antipsychotics, fearing deterioration of NPS.This is an update of a Cochrane Review published in 2013. OBJECTIVES: To evaluate whether withdrawal of antipsychotic agents is successful in older people with dementia and NPS in primary care or nursing home settings, to list the different strategies for withdrawal of antipsychotic agents in older participants with dementia and NPS, and to measure the effects of withdrawal of antipsychotic agents on participants' behaviour and assess safety. SEARCH METHODS: We searched the Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (ALOIS), theCochrane Library, MEDLINE, Embase, PsycINFO, CINAHL, LILACS, clinical trials registries and grey literature sources up to 11 January 2018. SELECTION CRITERIA: We included all randomised, controlled trials comparing an antipsychotic withdrawal strategy to continuation of antipsychotics in people with dementia who had been treated with an antipsychotic drug for at least three months. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures according to the Cochrane Handbook for Systematic Reviews of Interventions. We rated the quality of evidence for each outcome using the GRADE approach. MAIN RESULTS: We included 10 studies involving 632 participants. One new trial (19 participants) was added for this update.One trial was conducted in a community setting, eight in nursing homes and one in both settings. Different types of antipsychotics at varying doses were discontinued in the studies. Both abrupt and gradual withdrawal schedules were used. Reported data were predominantly from studies at low or unclear risk of bias.We included nine trials with 575 randomised participants that used a proxy outcome for overall success of antipsychotic withdrawal. Pooling data was not possible due to heterogeneity of outcome measures used. Based on assessment of seven studies, discontinuation may make little or no difference to whether or not participants complete the study (low-quality evidence).Two trials included only participants with psychosis, agitation or aggression who had responded to antipsychotic treatment. In these two trials, stopping antipsychotics was associated with a higher risk of leaving the study early due to symptomatic relapse or a shorter time to symptomatic relapse.We found low-quality evidence that discontinuation may make little or no difference to overall NPS, measured using various scales (7 trials, 519 participants). There was some evidence from subgroup analyses in two trials that discontinuation may reduce agitation for participants with less severe NPS at baseline, but may be associated with a worsening of NPS in participants with more severe NPS at baseline.None of the studies assessed withdrawal symptoms. Adverse effects of antipsychotics (such as falls) were not systematically assessed. Low-quality evidence showed that discontinuation may have little or no effect on adverse events (5 trials, 381 participants), quality of life (2 trials, 119 participants), or cognitive function (5 trials, 365 participants).There were insufficient data to determine whether discontinuation of antipsychotics has any effect on mortality (very low-quality evidence). AUTHORS' CONCLUSIONS: There is low-quality evidence that antipsychotics may be successfully discontinued in older people with dementia and NPS who have been taking antipsychotics for at least three months, and that discontinuation may have little or no important effect on behavioural and psychological symptoms. This is consistent with the observation that most behavioural complications of dementia are intermittent and often do not persist for longer than three months. Discontinuation may have little or no effect on overall cognitive function. Discontinuation may make no difference to adverse events and quality of life. Based on the trials in this review, we are uncertain whether discontinuation of antipsychotics leads to a decrease in mortality.People with psychosis, aggression or agitation who responded well to long-term antipsychotic drug use, or those with more severe NPS at baseline, may benefit behaviourally from continuation of antipsychotics. Discontinuation may reduce agitation for people with mild NPS at baseline. However, these conclusions are based on few studies or small subgroups and further evidence of benefits and harms associated with withdrawal of antipsychotic is required in people with dementia and mild and severe NPS.The overall conclusions of the review have not changed since 2013 and the number of available trials remains low. PMID- 29605971 TI - In Situ Investigations of Mechanochemical One-Pot Syntheses. AB - We present an in situ triple coupling of synchrotron X-ray diffraction with Raman spectroscopy, and thermography to study milling reactions in real time. This combination of methods allows a correlation of the structural evolution with temperature information. The temperature information is crucial for understanding both the thermodynamics and reaction kinetics. The reaction mechanisms of three prototypical mechanochemical syntheses, a cocrystal formation, a C-C bond formation (Knoevenagel condensation), and the formation of a manganese phosphonate, were elucidated. Trends in the temperature development during milling are identified. The heat of reaction and latent heat of crystallization of the product contribute to the overall temperature increase. A decrease in temperature occurs via release of, for example, water as a by-product. Solid and liquid intermediates are detected. The influence of the mechanical impact could be separated from temperature effects caused by the reaction. PMID- 29605972 TI - Role of Fructose Malabsorption in Patients With Irritable Bowel Syndrome. PMID- 29605973 TI - Could Improvement in Subjective Well-being Relieve Gastrointestinal Symptoms in Patients With Irritable Bowel Syndrome? PMID- 29605974 TI - What Is the Future of Impedance Planimetry in Gastroenterology? AB - The gastrointestinal (GI) tract is efficient in transporting ingested material to the site of delivery in healthy subjects. A fine balance exists between peristaltic forces, the mixing and delivery of the contents, and sensory signaling. This fine balance is easily disturbed by diseases. It is mandatory to understand the pathophysiology to enhance our understanding of GI disorders. The inaccessibility and complex nervous innervation, geometry and mechanical function of the GI tract make mechanosensory evaluation difficult. Impedance planimetry is a distension technology that assesses luminal geometry, mechanical properties including muscle dynamics, and processing of nociceptive signals from the GI tract. Since standardized models do not exist for GI muscle function in vivo, models, concepts, and terminology must be borrowed from other medical fields such as cardiac mechanophysiology. The review highlights the impedance planimetric technology, muscle dynamics assessment, and 3 applied technologies of impedance planimetry. These technologies are the multimodal probes that assesses sensory function, the functional luminal imaging probe that dynamically measures the geometry of the lumen it distends, and Fecobionics that is a simulated feces providing high-resolution measurements during defecation. The advanced muscle analysis and 3 applied technologies can enhance the quality of future interdisciplinary research for gaining more knowledge about mechanical function, sensory-motor disorders, and symptoms. This is a step in the direction of individualized treatment for GI disorders based on diagnostic subtyping. There seems to be no better alternatives to impedance planimetry, but only the functional luminal imaging probe is currently commercially available. Wider use depends on commercialization of the multimodal probe and Fecobionics. PMID- 29605975 TI - Advantages and Disadvantages of Long-term Proton Pump Inhibitor Use. AB - Proton pump inhibitors (PPIs) potently inhibit gastric acid secretion and are widely used for treatment of acid-related diseases including gastroesophageal reflux disease and secondary prevention of aspirin/NSAID-induced ulcers. Although clinically important adverse effects of PPIs can occur, just as with other drugs, those are not frequently observed during or after administration. Thus, PPIs are regarded as relatively safe and considered to be clinically beneficial. Recently, PPIs have become frequently administered to patients with functional gastrointestinal diseases or primary prevention of drug-related gastroduodenal damage, even though their beneficial effects for those conditions have not been fully confirmed. PPIs tend to be given for conditions in which the necessity of the drug has not been clarified, thus otherwise rare adverse effects are presented as clinically relevant. Although several PPI-related adverse effects have been reported, their clinical relevance is not yet clear, since the evidence reported in those studies is not at a high enough level, as the majority are based on retrospective observational studies and the reported hazard ratios are low. It is important to administer PPIs only for patients who will gain a substantial clinical benefit and to continue to investigate their adverse effects with high quality prospective studies. PMID- 29605978 TI - Abnormal Gastroesophageal Flap Valve Is Associated With High Gastresophageal Reflux Disease Questionnaire Score and the Severity of Gastroesophageal Reflux Disease in Vietnamese Patients With Upper Gastrointestinal Symptoms. AB - Background/Aims: There have been no studies investigating the distribution of abnormal gastroesophageal flap valve (GEFV) among patients with dyspepsia, non erosive reflux disease (NERD), and reflux esophagitis (RE) in the same set of patients. The aims of this study are to investigate (1) the association between GEFV and gastroesophageal reflux disease questionnaire (GERDQ) score, and (2) the distribution of abnormal GEFV in Vietnamese patients presenting with upper gastrointestinal symptoms. Methods: Three hundred and thirty-one patients recruited in this prospective cross-sectional study were classified into 3 groups: reflux esophagitis (RE), non-erosive reflux disease (NERD) (GERDQ score >= 8, no endoscopic mucosal injury), and dyspepsia (GERDQ score < 8, no endoscopic mucosal injury). The GEFV was graded endoscopically according to the Hill classification. GEFV grades I and II were regarded as normal, while grades III and IV were regarded as abnormal GEFV. Results: There were 215 (65.0%) patients with dyspepsia, 55 (16.6%) patients with NERD, and 61 (18.4%) patients with RE. Abnormal GEFV was an independent risk factor for GERD (OR, 2.93; CI 95%, 1.76-4.88) and RE (OR, 3.41; CI 95%, 1.78-6.53). The mean GERDQ score of patients with abnormal GEFV was significantly higher than that of patients with normal GEFV (5.7 +/- 2.4 vs 4.9 +/- 2.7, P = 0.011). The prevalence of abnormal GEFV gradually increased in patients with dyspepsia (27.4%), NERD (43.6%), grade A RE (56.8%), and grades B/C RE (80.0%) (P < 0.001). Conclusions: Abnormal GEFV was significantly associated with high GERDQ score. Its prevalence gradually increased in patients with dyspepsia, NERD, and RE, respectively. PMID- 29605977 TI - Esophageal Motor Disorders Are a Strong and Independant Associated Factor of Barrett's Esophagus. AB - Background/Aims: Esophageal motor disorder (EMD) has been shown to be associated with gastroesophageal reflux disease (GERD). However, the association of EMD with a Barrett's esophagus (BE) is controversial. Our objective was to evaluate whether the presence of EMD was an independent factor associated with BE. Methods: A retrospective case-control study was conducted in GERD patients who all had oeso-gastroduodenal endoscopy and high-resolution esophageal manometry. The clinical data collected was known or potential risk factors for BE: male gender, smoking and alcohol consumption, age, body mass index, presence of hiatal hernia, frequency, and age of GERD. EMD were classified according to the Chicago classification into: ineffective motor syndrome, fragmented peristalsis and absence of peristalsis, lower esophageal sphincter hypotonia. Results: Two hundred and one patients (101 in the GERD + BE group and 100 in the GERD without BE) were included. In univariate analysis, male gender, alcohol consumption, presence of hiatal hernia, and EMD appeared to be associated with the presence of BE. In a multivariate analysis, 3 independent factors were identified: the presence of EMD (odds ratio [OR], 3.99; 95% confidence interval [CI], 1.71-9.28; P = 0.001), the presence of hiatal hernia (OR, 5.60; 95% CI, 2.45-12.76; P < 0.001), Helicobacter pylori infection (OR, 0.08; 95% CI, 0.01-0.84; P = 0.035). Conclusions: The presence of EMD (particularly ineffective motor syndrome and lower esophageal sphincter hypotonia) is a strong independent associated factor of BE. Searching systematically for an EMD in patients suffering from GERD could be a new strategy to organize the endoscopic follow-up. PMID- 29605976 TI - Clinical Practice Guidelines for Irritable Bowel Syndrome in Korea, 2017 Revised Edition. AB - In 2011, the Korean Society of Neurogastroenterology and Motility (KSNM) published clinical practice guidelines on the management of irritable bowel syndrome (IBS) based on a systematic review of the literature. The KSNM planned to update the clinical practice guidelines to support primary physicians, reduce the socioeconomic burden of IBS, and reflect advances in the pathophysiology and management of IBS. The present revised version of the guidelines is in continuity with the previous version and targets adults diagnosed with, or suspected to have, IBS. A librarian created a literature search query, and a systematic review was conducted to identify candidate guidelines. Feasible documents were verified based on predetermined inclusion and exclusion criteria. The candidate seed guidelines were fully evaluated by the Guidelines Development Committee using the Appraisal of Guidelines for Research and Evaluation II quality assessment tool. After selecting 7 seed guidelines, the committee prepared evidence summaries to generate data exaction tables. These summaries comprised the 4 main themes of this version of the guidelines: colonoscopy; a diet low in fermentable oligosaccharides, disaccharides, monosaccharides, and polyols; probiotics; and rifaximin. To adopt the core recommendations of the guidelines, the Delphi technique (ie, a panel of experts on IBS) was used. To enhance dissemination of the clinical practice guidelines, a Korean version will be made available, and a food calendar for patients with IBS is produced. PMID- 29605979 TI - Acotiamide Has No Effects on Esophageal Motor Activity or Esophagogastric Junction Compliance. AB - Background/Aims: The novel prokinetic drug acotiamide is used for treatment of functional dyspepsia. It is still unclear how acotiamide has effects on esophageal motor function. Esophageal peristalsis and esophagogastric junction (EGJ) compliance has an important role for prevention of esophageal mucosal damage caused by gastroesophageal reflux, however, few studies have analyzed the effects of acotiamide on those former activities and none have investigated its effects on EGJ compliance. The aim of our research was to examine the effects of acotiamide on esophageal motility and EGJ compliance. Methods: We enrolled 3 gastroesophageal reflux disease (GERD) patients as well as 9 healthy volunteers. Using high-resolution manometry, we examined esophageal motor activity parameters, including esophageal body contractions and lower esophageal sphincter (LES) pressure. While, EGJ compliance was evaluated using a functional lumen imaging probe. Following determination of baseline values for esophageal motor activities and EGJ compliance, acotiamide at a standard dose of 300 mg/day was administered for 3 days. All measurements were performed again 2 hours after the last acotiamide administration. Results: In the healthy volunteers, as compared with the baseline values, acotiamide administration did not significantly change esophageal body contractions and LES pressure. And EGJ distensibility was not significantly changed (distensibility index in 40-mL distension: 3.5 +/- 0.4 vs 3.3 +/- 0.5 mm2/mmHg). Similarly in the GERD patients, there were no differences in either esophageal motility or EGJ compliance between before and after acotiamide administration (distensibility index in 40-mL distension: 6.2 +/- 0.5 vs 6.5 +/- 1.1 mm2/mmHg). Conclusion: In both healthy individuals and GERD patients, standard dose acotiamide dose does not have significant effects on esophageal motor activities or EGJ compliance. PMID- 29605980 TI - Diagnostic Trends and Clinical Characteristics of Eosinophilic Esophagitis: A Korean, Single-center Database Study. AB - Background/Aims: The prevalence of eosinophilic esophagitis (EoE) is reportedly increasing in Western countries. However, its prevalence in Korea remains unknown. We investigated the diagnostic trends and clinical characteristics of EoE in Korea. Methods: Using an endoscopic database maintained at a tertiary care center, we retrospectively reviewed the biopsy reports regarding 18 399 biopsy specimens collected from all patients who underwent esophagogastroduodenoscopy and esophageal biopsy at this facility between 2006 and 2014. The presence of more than 15 eosinophils per high-power field with symptoms related to esophageal dysfunction was considered to indicate EoE. Results: A total of 37 patients (male:female ratio, 29:8; mean age, 44.0 +/- 13.0 years) were diagnosed with EoE. These patients presented with dysphagia (21.6%), epigastric pain (21.6%), heartburn (24.3%), and other symptoms (32.4%). Typical endoscopic appearance of EoE was noted in 33 cases (89.1%) and included linear furrows in 24 cases (64.8%), ringed esophagus in 10 cases (27.0%), and white exudates in 11 cases (29.7%). The median eosinophilic count was 25 per high-power field (interquartile range, 20-70). Notable histopathological findings included eosinophilic microabscesses in 21 cases (56.7%). The diagnosis rate of EoE was found to have increased from 2006 and to 2014 (P-value < 0.001 by the Cochran-Armitage trend test). Conclusions: The number of patients with EoE appears to have increased significantly over the 9-year period investigated, while the number of endoscopic investigations increased only marginally. Greater awareness of EoE and the role of esophageal biopsies should be considered. PMID- 29605982 TI - Regional Brain Activity During Rest and Gastric Water Load in Subtypes of Functional Dyspepsia: A Preliminary Brain Functional Magnetic Resonance Imaging Study. AB - Background/Aims: Functional dyspepsia (FD) remains a great clinical challenge since the FD subtypes, defined by Rome III classification, still have heterogeneous pathogenesis. Previous studies have shown notable differences in visceral sensation processing in the CNS in FD compared to healthy subjects (HS). However, the role of CNS in the pathogenesis of each FD subtype has not been recognized. Methods: Twenty-eight FD patients, including 10 epigastric pain syndrome (EPS), 9 postprandial distress syndrome (PDS), and 9 mixed-type, and 10 HS, were enrolled. All subjects underwent a proximal gastric perfusion water load test and the regional brain activities during resting state and water load test were investigated by functional magnetic resonance imaging. Results: For regional brain activities during the resting state and water load test, each FD subtype was significantly different from HS (P < 0.05). Focusing on EPS and PDS, the regional brain activities of EPS were stronger than PDS in the left paracentral lobule, right inferior frontal gyrus pars opercularis, postcentral gyrus, precuneus, insula, parahippocampal gyrus, caudate nucleus, and bilateral cingulate cortices at the resting state (P < 0.05), and stronger than PDS in the left inferior temporal and fusiform gyri during the water load test (P < 0.05). Conclusions: Compared to HS, FD subtypes had different regional brain activities at rest and during water load test, whereby the differences displayed distinct manifestations for each subtype. Compared to PDS, EPS presented more significant differences from HS at rest, suggesting that the abnormality of central visceral pain processing could be one of the main pathogenesis mechanisms for EPS. PMID- 29605981 TI - Axial Movements and Length Changes of the Human Lower Esophageal Sphincter During Respiration and Distension-induced Secondary Peristalsis Using Functional Luminal Imaging Probe. AB - Background/Aims: Efficient transport through the esophago-gastric junction (EGJ) requires synchronized circular and longitudinal muscle contraction of the esophagus including relaxation of the lower esophageal sphincter (LES). However, there is a scarcity of technology for measuring esophagus movements in the longitudinal (axial) direction. The aim of this study is to develop new analytical tools for dynamic evaluation of the length change and axial movement of the human LES based on the functional luminal imaging probe (FLIP) technology and to present normal signatures for the selected parameters. Methods: Six healthy volunteers without hiatal hernia were included. Data were analyzed from stepwise LES distensions at 20, 30, and 40 mL bag volumes. The bag pressure and the diameter change were used for motion analysis in the LES. The cyclic bag pressure frequency was used to distinguish dynamic changes of the LES induced by respiration and secondary peristalsis. Results: Cyclic fluctuations of the LES were evoked by respiration and isovolumetric distension, with phasic changes of bag pressure, diameter, length, and axial movement of the LES narrow zone. Compared to the respiration-induced LES fluctuations, peristaltic contractions increased the contraction pressure amplitude (P < 0.001), shortening (P < 0.001), axial movement (P < 0.001), and diameter change (P < 0.01) of the narrow zone. The length of the narrow zone shortened as function of the pressure increase. Conclusions: FLIP can be used for evaluation of dynamic length changes and axial movement of the human LES. The method may shed light on abnormal longitudinal muscle activity in esophageal disorders. PMID- 29605983 TI - Self-reported Sleep Impairment in Functional Dyspepsia and Irritable Bowel Syndrome. AB - Background/Aims: Sleep impairment is a common complaint among patients with irritable bowel syndrome (IBS) and functional dyspepsia (FD). This study aimed to evaluate the prevalence of sleep impairment in FD or IBS patients, and to determine whether IBS-FD overlap induced more sleep disturbance than FD or IBS alone. Methods: A population-based cohort in South Korea including 2251 subjects was asked about gastrointestinal symptoms including IBS and dyspepsia-related symptoms. In addition, sleep disturbance was measured using the Pittsburgh Sleep Quality Index and Epworth Sleepiness Scale questionnaires. One-way ANOVA and logistic regression were used to assess differences among the 4 groups (healthy subjects, IBS alone, FD alone, and IBS-FD overlap). Results: Of 2251 subjects who were surveyed by questionnaire, 2031 responded (92.5% response rate) and were analyzed. The prevalence of IBS, FD, and IBS-FD overlap was 8.0% (95% confidence interval [CI], 6.8-9.2%), 4.8% (95% CI, 3.9-5.8%), and 1.8% (95% CI, 1.2-2.4%), respectively. FD alone, but not IBS alone, was significantly associated with a poorer sleep quality index (OR, 2.68; 95% CI, 1.43-5.01) and more daytime sleepiness (OR, 2.21; 95% CI, 1.14-4.30), compared to healthy subjects. IBS-FD overlap had the greatest likelihood of a poorer sleep quality index (OR, 3.88; 95% CI, 1.83-8.19), daytime sleepiness (OR, 2.47; 95% CI, 1.01-5.67), and insomnia (OR, 2.84; 95% CI, 1.39-5.82), compared to healthy subjects. Conclusion: A correlation between functional gastrointestinal disorders and sleep disturbance was demonstrated, which was significantly pronounced in the context of IBS-FD overlap. PMID- 29605984 TI - Connecting Our Gut Feeling and How Our Gut Feels: The Role of Well-being Attributes in Irritable Bowel Syndrome. AB - Background/Aims: There is a close relationship between the mind and gut in the pathogenesis of functional bowel disorders. Common psychological disturbances such as depression and anxiety are not uncommon in those with irritable bowel syndrome (IBS). There is little research investigating the role of positive psychology and gastrointestinal (GI) conditions. In this pilot study we investigated the well-being attributes in those with and without IBS. Methods: We used an anonymous online survey and recruited 416 study subjects using social media as the main method of recruitment. We gathered demographic information, GI symptoms, history of mental health issues such as anxiety and depression, assessed several well-being attributes, and finally assessed subjective well being. We hypothesized that those with GI symptoms and IBS have lower scores in their well-being attributes compared to healthy controls. Results: We observed that a history of anxiety and depression is significantly associated with GI symptoms and IBS. In addition, sense of subjective well-being and several well being attributes are negatively associated with GI symptoms and/or IBS. Of interest, the household income showed a negative correlation with the prevalence of GI symptoms and IBS. Conclusions: Subjective well-being, and several well being attributes that contribute to the sense of overall contentment, are negatively associated with GI symptoms and IBS. The link between subjective well being, and GI symptoms and IBS are independent of anxiety and depression. Well being attributes and sense of subjective well-being may be a contributory factor in clinical expression of GI symptoms or IBS consistent with the biopsychosocial model of the disease. PMID- 29605985 TI - Lower and Upper Gastrointestinal Symptoms Differ Between Individuals With Irritable Bowel Syndrome With Constipation or Chronic Idiopathic Constipation. AB - Background/Aims: We evaluated the distribution of lower and upper gastrointestinal (GI) symptoms among individuals with irritable bowel syndrome with constipation (IBS-C) and chronic idiopathic constipation (CIC) in a nationwide survey. Methods: Individuals (>= 18 years of age) were identified from a nationwide sample of > 70 000 United States adults. Participants completed the National Institutes of Health GI Patient Reported Outcomes Measurement Information System (NIH GI-PROMIS) questionnaire. Symptom frequency and intensity in the prior 7 days were assessed using validated PROMIS scores. Odds ratios (OR) with 95% confidence intervals (CI) were calculated to compare symptom prevalence in IBS-C vs CIC, and one-way ANOVA was used to assess differences in PROMIS scores. Regression analysis was performed to adjust for demographic variables. Results: Nine hundred and seventy adults met eligibility criteria (275 with IBS C, 734 with CIC). Demographics were similar among groups except for education, marital and employment status, and income. Adjusting for demographic differences, GI-PROMIS scores of global GI symptoms were higher in IBS-C (251.1; 95% CI, 230.0 273.1) compared to CIC (177.8; 95% CI 167.2-188.4) (P < 0.001). Abdominal pain was more prevalent (OR, 4.3; 95% CI, 2.9-6.6) and more severe (P = 0.007) in IBS C. Constipation was more severe in IBS-C (P = 0.011). Incontinence was more common (OR, 2.9; 95% CI, 1.3-6.3) but just as severe (P = 0.389) in IBS-C versus CIC. Regarding upper GI symptoms, the prevalence of dysphagia, heartburn, and nausea were similar. However, IBS-C individuals had more severe heartburn (P = 0.001). Conclusion: GI symptoms are generally more severe in IBS-C compared to CIC, however abdominal pain, bloating, and upper GI symptoms still commonly occur in CIC. PMID- 29605986 TI - Increased Tone of the Human Colon Muscle by Bisacodyl In Vitro. AB - Background/Aims: Although bisacodyl is a widely administered laxative, its underlying mechanism of action remains generally unknown. This study focuses on investigating the effects of bisacodyl on the human colon muscle contraction, and elucidating its mechanism of action. Methods: Sigmoid colon muscle strips (20 longitudinal and 18 circular muscles) were obtained from 20 subjects who underwent colectomy for colon cancer. Isometric force measurements were calculated in response to electrical field stimulation (EFS, 0.3 milliseconds in trains of 10 Hz for 20 seconds, 150 V). Peak and nadir (tone) during and after EFS, were measured in a controlled state, and after sequential addition of bisacodyl (1 MUM), atropine (1 MUM), N-nitro-L-arginine (L-NNA, 100 MUM), MRS2500 (1 MUM), and tetrodotoxin (TTX, 1 MUM) to the organ bath. Results: Transient phasic contractions were observed during EFS, and after cessation of EFS. In the longitudinal muscles, nadir during EFS, and tone after EFS, significantly increased after addition of bisacodyl, and persisted after sequential addition of atropine, L-NNA, MRS2500, and TTX, indicating a direct action of bisacodyl on the smooth muscle. In the second experiment, pretreatment of TTX abolished EFS induced phasic contractions. Although no phasic contraction was produced after perfusion of bisacodyl, tone was increased, thereby supporting evidence of a direct mechanism of action of bisacodyl on the colon smooth muscle. Conclusions: Bisacodyl increases the tone of longitudinal muscle in the human sigmoid colon through a direct action on the smooth muscle. Further study is warranted to investigate the neural mechanism of action of bisacodyl. PMID- 29605987 TI - A Positive Reflux-Symptom Association Is Not Marked When the Onset of the Reflux Episode Does Not Occur Within the Pre-symptom Time Window. PMID- 29605988 TI - Aging Decreases the Density of Colonic Interstitial Cells of Cajal Associated With Constipation in Rats. PMID- 29605989 TI - MS-5, a Naphthalene Derivative, Induces the Apoptosis of an Ovarian Cancer Cell Caov-3 by Interfering with the Reactive Oxygen Species Generation. AB - Reactive oxygen species (ROS) are widely generated in biological processes such as normal metabolism and response to xenobiotic exposure. While ROS can be beneficial or harmful to cells and tissues, generation of ROS by diverse anti cancer drugs or phytochemicals plays an important role in the induction of apoptosis. We recently identified a derivative of naphthalene, MS-5, that induces apoptosis of an ovarian cell, CAOV-3. Interestingly, MS-5 induced apoptosis by down-regulating the ROS. Cell viability was evaluated by water-soluble tetrazolium salt (WST-1) assay. Apoptosis was evaluated by flow cytometry analysis. Intracellular ROS (H2O2), mitochondrial superoxide, mitochondrial membrane potential (MMP) and effect on cycle were determined by flow cytometry. Protein expression was assessed by western blotting. The level of ATP was measured using ATP Colorimetric/Fluorometric Assay kit. MS-5 inhibited growth of ovarian cancer cell lines, CAOV-3, in a concentration- and time-dependent manner. MS-5 also induced G1 cell cycle arrest in CAOV-3 cells, while MS-5 decreased intracellular ROS generation. In addition, cells treated with MS-5 showed the decrease in MMP and ATP production. In this study, we found that treatment with MS-5 in CAOV-3 cells induced apoptosis but decreased ROS level. We suspect that MS-5 might interfere with the minimum requirements of ROS for survival. These perturbations appear to be concentration-dependent, suggesting that MS-5 may induce apoptosis by interfering with ROS generation. We propose that MS-5 may be a potent therapeutic agent for inducing apoptosis in ovarian cancer cell through regulation of ROS. PMID- 29605990 TI - Metal-Free Iodine-Catalyzed Oxidation of Ynamides and Diaryl Acetylenes into 1,2 Diketo Compounds. AB - Metal-free oxidation of ynamides is described, employing pyridine- N-oxides as oxidants under molecular iodine catalysis. In stark contrast to Bronsted acid catalysis, iodophilic activation of ynamides diverts the reaction manifold into a dioxygenation pathway. This oxidation is very rapid at room temperature with only 2.5 mol % I2. Furthermore, this protocol could be extended to nonactivated alkynes, such as diarylacetylenes, to deliver various benzil derivatives. PMID- 29605991 TI - Deriving in Vivo Bioconcentration Factors of a Mixture of Fragrance Ingredients Using a Single Dietary Exposure and Internal Benchmarking. AB - Chemicals in mixtures that are hydrophobic with Log KOW > 4 are potentially bioaccumulative. Here, we evaluate an abbreviated and benchmarked in vivo BCF measurement methodology by exposing rainbow trout to a mixture of eight test chemicals found in fragrance substances and three benchmark chemicals (musk xylene (MX), hexachlorobenzene (HCB) and PCB52) via a single contaminated feeding event followed by a 28-day depuration period. Concentrations of HCB and PCB52 in fish did not decline significantly (their apparent depuration rate constants, kT, were close to zero), whereas kT for MX was 0.022 d-1. The test chemicals were eliminated much more rapidly than the benchmark chemicals ( kT > 0.117 d-1). The bioconcentration factors (BCFA) for the test chemicals were in the range of 273 L kg-1 (8-cyclohexadecen-1-one (globanone)) to 1183 L kg-1 (alpha-pinene); the benchmarked BCFs (BCFG) calculated relative to HCB ranged from 238 L kg-1 (globanone) to 1147 L kg-1 (alpha-pinene). BCFG were not significantly different from BCFA but had smaller standard errors. BCFs derived here agreed well with values previously measured using the OECD 305 test protocol. We conclude that it will be feasible to derive BCFs of chemicals in mixtures using a single dietary exposure and chemical benchmarking. PMID- 29605992 TI - Electroluminescent Pressure-Sensing Displays. AB - Simultaneous sensing and visualization of pressure provides a useful platform to obtain information about a pressurizing object, but the fabrication of such interactive displays at the single-device level remains challenging. Here, we present a pressure responsive electroluminescent (EL) display that allows for both sensing and visualization of pressure. Our device is based on a two-terminal capacitor with six constituent layers: top electrode/insulator/hole injection layer/emissive layer/electron transport layer/bottom electrode. Light emission upon exposure to an alternating current field between two electrodes is controlled by the capacitance change of the insulator arising from the pressure applied on top. Besides capacitive pressure sensing, our EL display allows for direct visualization of the static and dynamic information of position, shape, and size of a pressurizing object on a single-device platform. Monitoring the pressurized area of an elastomeric hemisphere on a device by EL enables quantitative estimation of the Young's modulus of the elastomer, offering a new and facile characterization method for the mechanical properties of soft materials. PMID- 29605993 TI - Biosynthesis of Jasmine Lactone in Tea ( Camellia sinensis) Leaves and Its Formation in Response to Multiple Stresses. AB - Jasmine lactone has a potent odor that contributes to the fruity, sweet floral aroma of tea ( Camellia sinensis). Our previous study demonstrated that jasmine lactone was mostly accumulated at the turnover stage of the oolong tea manufacturing process. This study investigates the previously unknown mechanism of formation of jasmine lactone in tea leaves exposed to multiple stresses occurring during the growth and manufacturing processes. Both continuous mechanical damage and the dual stress of low temperature and mechanical damage enhanced jasmine lactone accumulation in tea leaves. In addition, only one pathway, via hydroperoxy fatty acids from unsaturated fatty acid, including linoleic acid and alpha-linolenic acid, under the action of lipoxygenases (LOXs), especially CsLOX1, was significantly affected by these stresses. This is the first evidence of the mechanism of jasmine lactone formation in tea leaves and is a characteristic example of plant volatile formation in response to dual stress. PMID- 29605994 TI - Slow Off-Rate Modified Aptamer (SOMAmer) as a Novel Reagent in Immunoassay Development for Accurate Soluble Glypican-3 Quantification in Clinical Samples. AB - Accurate quantification of soluble glypican-3 in clinical samples using immunoassays is challenging, because of the lack of appropriate antibody reagents to provide a full spectrum measurement of all potential soluble glypican-3 fragments in vivo. Glypican-3 SOMAmer (slow off-rate modified aptamer) is a novel reagent that binds, with high affinity, to a far distinct epitope of glypican-3, when compared to all available antibody reagents generated in-house. This paper describes an integrated analytical approach to rational selection of key reagents based on molecular characterization by epitope mapping, with the focus on our work using a SOMAmer as a new reagent to address development challenges with traditional antibody reagents for the soluble glypican-3 immunoassay. A qualified SOMAmer-based assay was developed and used for soluble glypican-3 quantification in hepatocellular carcinoma (HCC) patient samples. The assay demonstrated good sensitivity, accuracy, and precision. Data correlated with those obtained using the traditional antibody-based assay were used to confirm the clinically relevant soluble glypican-3 forms in vivo. This result was reinforced by a liquid chromatography tandem mass spectrometry (LC-MS/MS) assay quantifying signature peptides generated from trypsin digestion. The work presented here offers an integrated strategy for qualifying aptamers as an alternative affinity platform for immunoassay reagents that can enable speedy assay development, especially when traditional antibody reagents cannot meet assay requirements. PMID- 29605996 TI - Molecular Clusters: Nanoscale Building Blocks for Solid-State Materials. AB - The programmed assembly of nanoscale building blocks into multicomponent hierarchical structures is a powerful strategy for the bottom-up construction of functional materials. To develop this concept, our team has explored the use of molecular clusters as superatomic building blocks to fabricate new classes of materials. The library of molecular clusters is rich with exciting properties, including diverse functionalization, redox activity, and magnetic ordering, so the resulting cluster-assembled solids, which we term superatomic crystals (SACs), hold the promise of high tunability, atomic precision, and robust architectures among a diverse range of other material properties. Molecular clusters have only seldom been used as precursors for functional materials. Our team has been at the forefront of new developments in this exciting research area, and this Account focuses on our progress toward designing materials from cluster-based precursors. In particular, this Account discusses (1) the design and synthesis of molecular cluster superatomic building blocks, (2) their self assembly into SACs, and (3) their resulting collective properties. The set of molecular clusters discussed herein is diverse, with different cluster cores and ligand arrangements to create an impressive array of solids. The cluster cores include octahedral M6E8 and cubane M4E4 (M = metal; E = chalcogen), which are typically passivated by a shell of supporting ligands, a feature upon which we have expanded upon by designing and synthesizing more exotic ligands that can be used to direct solid-state assembly. Building from this library, we have designed whole families of binary SACs where the building blocks are held together through electrostatic, covalent, or van der Waals interactions. Using single-crystal X ray diffraction (SCXRD) to determine the atomic structure, a remarkable range of compositional variability is accessible. We can also use this technique, in tandem with vibrational spectroscopy, to ascertain features about the constituent superatomic building blocks, such as the charge of the cluster cores, by analysis of bond distances from the SCXRD data. The combination of atomic precision and intercluster interactions in these SACs produces novel collective properties, including tunable electrical transport, crystalline thermal conductivity, and ferromagnetism. In addition, we have developed a synthetic strategy to insert redox-active guests into the superstructure of SACs via single-crystal-to-single crystal intercalation. This intercalation process allows us to tune the optical and electrical transport properties of the superatomic crystal host. These properties are explored using a host of techniques, including Raman spectroscopy, SQUID magnetometry, electrical transport measurements, electronic absorption spectroscopy, differential scanning calorimetry, and frequency-domain thermoreflectance. Superatomic crystals have proven to be both robust and tunable, representing a new method of materials design and architecture. This Account demonstrates how precisely controlling the structure and properties of nanoscale building blocks is key in developing the next generation of functional materials; several examples are discussed and detailed herein. PMID- 29605995 TI - Lewis Acid-Controlled Regioselective Phosphorylation of 2-Indolylmethanols with Diarylphosphine Oxides: Synthesis of Highly Substituted Indoles. AB - The Lewis acid-promoted phosphorylation of 2-indolylmethanols with diarylphosphine oxides is described. The regioselectivity of the reaction can be modulated by the choice of rare earth metal Lewis acid, offering a highly selective approach to structurally diverse indole derivatives in up to 97% yield for over 50 examples. This strategy features high selectivity, good functional group tolerance, and easy scalability. The utility of this method is further highlighted by facile modification of the products to access novel indole-based phosphine ligand. PMID- 29605998 TI - Humidity-Responsive Gold Aerogel for Real-Time Monitoring of Human Breath. AB - Humidity sensors have received considerable attention in recent years because of their significance and wide applications in agriculture, industries, goods stores, and medical fields. However, the conventional humidity sensors usually possessed a complex sensing mechanism and low sensitivity and required a time consuming, labor-intensive process. The exploration for an ideal sensing material to amplify the sensitivity of humidity sensors is still a big challenge. Herein, we developed a simple, low-cost, and scalable fabrication strategy to construct a highly sensitive humidity sensor based on polymer/gold nanoparticle (AuNP) hybrid materials. The hybrid polymer/AuNP aerogel was prepared by a simple freeze-drying method. By taking advantage of the conductivity of AuNPs and high surface area of the highly porous structure, the hybrid poly- N-isopropylacrylamide (PNIPAm)/AuNP aerogel showed high sensitivity to water molecules. Interestingly, the hybrid PNIPAm/AuNP aerogel-based humidity sensor can be used to detect human breath in different states, such as normal breath, fast breath, and deep breath, or in different individuals such as persons with illness, persons who are smoking, and persons who are normal, which is promising in practical flexible wearable devices for human health monitoring. In addition, the humidity sensor can be used in whistle tune recognition. PMID- 29605997 TI - Development of Novel Melanocortin Receptor Agonists Based on the Cyclic Peptide Framework of Sunflower Trypsin Inhibitor-1. AB - Ultrastable cyclic peptide frameworks offer great potential for drug design due to their improved bioavailability compared to their linear analogues. Using the sunflower trypsin inhibitor-1 (SFTI-1) peptide scaffold in combination with systematic N-methylation of the grafted pharmacophore led to the identification of novel subtype selective melanocortin receptor (MCR) agonists. Multiple bicyclic peptides were synthesized and tested toward their activity at MC1R and MC3-5R. Double N-methylated compound 18 showed a p Ki of 8.73 +/- 0.08 ( Ki = 1.92 +/- 0.34 nM) and a pEC50 of 9.13 +/- 0.04 (EC50 = 0.75 +/- 0.08 nM) at the human MC1R and was over 100 times more selective for MC1R. Nuclear magnetic resonance structural analysis of 18 emphasized the role of peptide bond N methylation in shaping the conformation of the grafted pharmacophore. More broadly, this study highlights the potential of cyclic peptide scaffolds for epitope grafting in combination with N-methylation to introduce receptor subtype selectivity in the context of peptide-based drug discovery. PMID- 29605999 TI - Synthesis and Evaluation of Hydrogen Peroxide Sensitive Prodrugs of Methotrexate and Aminopterin for the Treatment of Rheumatoid Arthritis. AB - A series of novel hydrogen peroxide sensitive prodrugs of methotrexate (MTX) and aminopterin (AMT) were synthesized and evaluated for therapeutic efficacy in mice with collagen induced arthritis (CIA) as a model of chronic rheumatoid arthritis (RA). The prodrug strategy selected is based on ROS-labile 4-methylphenylboronic acid promoieties linked to the drugs via a carbamate linkage or a direct C-N bond. Activation under pathophysiological concentrations of H2O2 proved to be effective, and prodrug candidates were selected in agreement with relevant in vitro physicochemical and pharmacokinetic assays. Selected candidates showed moderate to good solubility, high chemical and enzymatic stability, and therapeutic efficacy comparable to the parent drugs in the CIA model. Importantly, the prodrugs displayed the expected safer toxicity profile and increased therapeutic window compared to MTX and AMT while maintaining a comparable therapeutic efficacy, which is highly encouraging for future use in RA patients. PMID- 29606000 TI - Using Bioluminescence Turn-On To Detect Cysteine in Vitro and in Vivo. AB - Cysteine (Cys) is an essential amino acid and plays important roles in many biological processes. Bioluminescence (BL) is advantageous in sensitivity but BL probes that were intentionally developed for the selective detection of Cys were rarely reported. Herein, employing a fast conjugate addition between Cys and acrylic ester, we synthesized a caged BL probe acrylic ester luciferin (1) and used it to selectively detect Cys in vitro and image Cys in living cells and in tumor sites. We envision that, in the future, probe 1 might be used for evaluating the Cys roles in more biological processes. PMID- 29606001 TI - Organometallic Gold(III) Complexes Similar to Tetrahydroisoquinoline Induce ER Stress-Mediated Apoptosis and Pro-Death Autophagy in A549 Cancer Cells. AB - Agents inducing both apoptosis and autophagic death can be effective chemotherapeutic drugs. In our present work, we synthesized two organometallic gold(III) complexes harboring C^N ligands that structurally resemble tetrahydroisoquinoline (THIQ): Cyc-Au-1 (AuL1Cl2, L1 = 3,4 dimethoxyphenethylamine) and Cyc-Au-2 (AuL2Cl2, L2 = methylenedioxyphenethylamine). In screening their in vitro activity, we found both gold complexes exhibited lower toxicity, lower resistance factors, and better anticancer activity than those of cisplatin. The organometallic gold(III) complexes accumulate in mitochondria and induce elevated ROS and an ER stress response through mitochondrial dysfunction. These effects ultimately result in simultaneous apoptosis and autophagy. Importantly, compared to cisplatin, Cyc-Au 2 exhibits lower toxicity and better anticancer activity in a murine tumor model. To the best of our knowledge, Cyc-Au-2 is the first organometallic Au(III) compound that induces apoptosis and autophagic death. On the basis of our results, we believe Cyc-Au-2 to be a promising anticancer agent or lead compound for further anticancer drug development. PMID- 29606002 TI - Insight into Catechins Metabolic Pathways of Camellia sinensis Based on Genome and Transcriptome Analysis. AB - Tea is an important economic crop with a 3.02 Gb genome. It accumulates various bioactive compounds, especially catechins, which are closely associated with tea flavor and quality. Catechins are biosynthesized through the phenylpropanoid and flavonoid pathways, with 12 structural genes being involved in their synthesis. However, we found that in Camellia sinensis the understanding of the basic profile of catechins biosynthesis is still unclear. The gene structure, locus, transcript number, transcriptional variation, and function of multigene families have not yet been clarified. Our previous studies demonstrated that the accumulation of flavonoids in tea is species, tissue, and induction specific, which indicates that gene coexpression patterns may be involved in tea catechins and flavonoids biosynthesis. In this paper, we screened candidate genes of multigene families involved in the phenylpropanoid and flavonoid pathways based on an analysis of genome and transcriptome sequence data. The authenticity of candidate genes was verified by PCR cloning, and their function was validated by reverse genetic methods. In the present study, 36 genes from 12 gene families were identified and were accessed in the NCBI database. During this process, some intron retention events of the CsCHI and CsDFR genes were found. Furthermore, the transcriptome sequencing of various tea tissues and subcellular location assays revealed coexpression and colocalization patterns. The correlation analysis showed that CsCHIc, CsF3'H, and CsANRb expression levels are associated significantly with the concentration of soluble PA as well as the expression levels of CsPALc and CsPALf with the concentration of insoluble PA. This work provides insights into catechins metabolism in tea and provides a foundation for future studies. PMID- 29606003 TI - Perceptual Image Quality Metrics Concept in Continuous Scanning 2D Laser Ablation Inductively Coupled Plasma Mass Spectrometry Bioimaging. AB - This work focuses on the structural similarity (SSIM) index as a tool for optimization of the perceived visual image quality obtainable by continuous scanning 2D LA-ICPMS bioimaging, but also other mass spec imaging techniques may benefit from this approach. This index quantifies the differences between a distorted image and a reference image based on parameters associated with luminance, contrast, and noise. Since reference images are not normally available, a protocol was developed to virtually apply distortion-related information introduced by the LA-ICPMS imaging system to a reference image of one's choice. Distortion-related information in the form of blur and noise was experimentally retrieved from line scans across a laser milled knife edge on custom-prepared gelatin standards (mimicking proteinaceous biomatrixes). Distorted images were generated via computational procedures developed earlier, warranting objective image quality assessment via the SSIM indices. We illustrate the potential of this approach for image quality optimization for a suite of LA ICPMS imaging conditions. PMID- 29606004 TI - Design of New Isoindigo-Based Copolymer for Ambipolar Organic Field-Effect Transistors. AB - We report the synthesis of a new conjugated polymer composed of isoindigo (IID) and 2,3-bis[thiophenyl-2-yl]thiophene acrylonitrile (CNTVT) subunits for high performance n-type organic field-effect transistors (OFETs). To realize high electron mobility for the IID-based conjugated polymer, an electron-withdrawing nitrile group is incorporated into the vinylene unit, thereby shifting the energy of the lowest unoccupied molecular orbital for efficient electron injection from Au electrodes without disrupting the backbone planarity. Uniaxially aligned IID24 CNTVT-conjugated polymer films for efficient intramolecular charge transport are achieved by off-center spin-coating from preaggregated solutions. To obtain its stable preaggregation in solution, a binary solvent system (a mixture of good and bad solvents) chosen with the assistance of Hansen solubility parameter simulation is used. Through this process, highly aligned IID24-CNTVT films are obtained by off-center spin coating from a solvent mixture of 9:1 dichlorobenzene/2-methoxyethanol as the good and bad solvents, respectively. The properties of the aligned IID24-CNTVT films are characterized with various analytical techniques, including UV-visible absorption spectroscopy, angle resolved near-edge X-ray absorption fine structure spectroscopy, and grazing incidence wide-angle X-ray scattering. Top-gate/bottom-contact OFETs with IID24 CNTVT films aligned in the direction of charge transport exhibit a high-electron field-effect mobility of 0.83 +/- 0.13 cm2/V.s. PMID- 29606005 TI - Superhydrophobic Silicon Nanocrystal-Silica Aerogel Hybrid Materials: Synthesis, Properties, and Sensing Application. AB - Silicon nanocrystals (SiNCs) are abundant and exhibit exquisitely tailorable optoelectronic properties. The incorporation of SiNCs into highly porous and lightweight substrates such as aerogels leads to hybrid materials possessing the attractive features of both materials. This study describes the covalent deposition of SiNCs on and intercalation into silica aerogels, explores the properties, and demonstrates a prototype sensing application of the composite material. SiNCs of different sizes were functionalized with triethoxyvinylsilane (TEVS) via a radical grafting approach and subsequently used for the synthesis of photoluminescent silica hybrids. The resulting SiNC-containing aerogels possess high porosities, SiNC-based size-dependent photoluminescence, transparency, and a superhydrophobic macroscopic surface. The materials were used to examine the photoluminescence response toward low concentrations of 3-nitrotoluene (270 MUM), demonstrating their potential as a sensing platform for high-energy materials. PMID- 29606007 TI - Aerosol-Based Self-Assembly of a Ag-ZnO Hybrid Nanoparticle Cluster with Mechanistic Understanding for Enhanced Photocatalysis. AB - A gas-phase-controlled synthetic approach is demonstrated to fabricate Ag-ZnO hybrid nanostructure as a high-performance catalyst for photodegradation of water pollutants. The degradation of rhodamine B (RhB) was used as representative, which were tested and evaluated with respect to the environmental pH and the presence of dodecyl sulfate corona on the surface of the catalyst. The results show that a raspberry-structure Ag-ZnO hybrid nanoparticle cluster was successfully synthesized via gas-phase evaporation-induced self-assembly. The photodegradation activity increased significantly (20*) by using the Ag-ZnO hybrid nanoparticle cluster as a catalyst. A surge of catalytic turnover frequency of ZnO nanoparticle cluster (>20*) was observed through the hybridization with silver nanoparticles. The dodecyl sulfate corona increased the photocatalytic activity of the Ag-ZnO hybrid nanoparticle cluster, especially at the acidic and neutral pH environments (maximum 6*), and the enhancement in catalytic activity was attributed to the improved colloidal stability of ZnO based nanoparticle cluster under the interaction with RhB. Our work provides a generic route of facile synthesis of the Ag-ZnO hybrid nanoparticle cluster with a mechanistic understanding of the interface reaction for enhancing photocatalysis toward the degradation of water pollutants. PMID- 29606006 TI - A Combined Field and Laboratory Study on Activated Carbon-Based Thin Layer Capping in a PCB-Contaminated Boreal Lake. AB - The in situ remediation of aquatic sediments with activated carbon (AC)-based thin layer capping is a promising alternative to traditional methods, such as sediment dredging. Applying a strong sorbent like AC directly to the sediment can greatly reduce the bioavailability of organic pollutants. To evaluate the method under realistic field conditions, a 300 m2 plot in the PCB-contaminated Lake Kernaalanjarvi, Finland, was amended with an AC cap (1.6 kgAC/m2). The study lake showed highly dynamic sediment movements over the monitoring period of 14 months. This led to poor retention and rapid burial of the AC cap under a layer of contaminated sediment from adjacent sites. As a result, the measured impact of the AC amendment was low: Both the benthic community structure and PCB bioaccumulation were similar on the plot and in surrounding reference sites. Corresponding follow-up laboratory studies using Lumbriculus variegatus and Chironomus riparius showed that long-term remediation success is possible, even when an AC cap is covered with contaminated sediment. To retain a measurable effectiveness (reduction in contaminant bioaccumulation), a sufficient intensity and depth of bioturbation is required. On the other hand, the magnitude of the adverse effect induced by AC correlated positively with the measured remediation success. PMID- 29606008 TI - Mulberry Polyphenol Extract Inhibits FAK/Src/PI3K Complex and Related Signaling To Regulate the Migration in A7r5 Cells. AB - Atherosclerosis is characterized by the buildup of plaque inside arteries. Our recent studies demonstrated that polyphenolic natural products can reduce oxidative stress, inflammation, angiogenesis, hyperlipidemia, and hyperglycemia. A previous study also showed that mulberry water extract (MWE) can inhibit atherosclerosis and contains considerable amounts of polyphenols. Therefore, in the present study, we investigated whether mulberry polyphenol extract (MPE) containing high levels of polyphenolic compounds could affect vascular smooth muscle cell (VSMC; A7r5 cell) motility. We found that MPE inhibited expression of FAK, Src, PI3K, Akt, c-Raf, and suppressed FAK/Src/PI3K interaction. Further investigations showed that MPE reduced expression of small GTPases (RhoA, Cdc42, and Rac1) to affect F-actin cytoskeleton rearrangement, down-regulated expression of MMP2 and vascular endothelial growth factor (VEGF) mRNA through NFkappaB signaling, and thereby inhibited A7r5 cell migration. Taken together, these findings highlight MPE inhibited migration in VSMC through FAK/Src/PI3K signaling pathway. PMID- 29606009 TI - Rings and Things: The Magic of Building Self-Assembled Cages and Macrocycles. PMID- 29606010 TI - Use of a Surgical Debriefing Checklist to Achieve Higher Value Health Care. AB - Efforts to improve surgical care by using checklists have been inconsistent in results and not reproducible at scale. The ideal manner for using checklists, along with the time horizon for achieving meaningful and measurable benefits, has been unclear. This article describes a novel process for utilizing debriefing checklists to improve value in surgical care. Debriefings of 54 003 consecutive surgical cases and subsequent analysis of 4523 defects in care by multidisciplinary teams led to rapid-cycle iterative changes in care design and processes. Four dimensions of health care value were achieved: debrief-driven improvements reduced the proportion of surgical cases with reported defects, was associated with a significant reduction in the 30-day unadjusted surgical mortality, lowered costs by substantial gains in efficiency and productivity, and led to a better workforce safety climate. Meaningful and sustained improvements required consistent broad-based teamwork over multiple years, an evidence-based data-driven approach, and senior leader and governance engagement. PMID- 29606011 TI - Meridian Cuffing Exercises Improved Functional Fitness and Cardiopulmonary Functioning of Community Older Adults. AB - This study was aimed to test the effects of a meridian cuffing exercise, the Healthy Beat Acupunch (HBA) regimen, on the functional fitness and cardiopulmonary functioning of community older adults. A single-blind, cluster randomized controlled trial was conducted. We randomly allocated eight community care centers to the intervention or control group and recruited 228 participants who completed the study (intervention: four centers, n = 111; control: four centers, n = 117). The intervention group underwent a 40-min session of HBA regimen 3 times per week for 6 months. Functional fitness and cardiopulmonary functioning were assessed at baseline, 3 months, and 6 months of the intervention. The intervention group demonstrated significantly greater improvements in functional fitness and cardiopulmonary functioning than the control group between baseline and either 3 months or 6 months. We suggest that activities designed to promote health among community older adults include acupunch exercises. PMID- 29606012 TI - Adverse outcomes in obstetric-atypical haemolytic uraemic syndrome: a case series analysis. AB - OBJECTIVE: The aim of this case series is to raise awareness of obstetric-related atypical haemolytic uraemic syndrome (aHUS) amongst obstetricians and gynaecologists. STUDY DESIGN: Data from 20 consecutive patients, aged 19-38, with obstetric-aHUS manifestation during or immediately after pregnancy are reported. Patients were diagnosed and treatment was initiated between 2012 and 2016. RESULTS: Presentation of aHUS was mainly preceded by preeclampsia and/or haemolysis, elevated liver enzymes and low platelet count syndrome, other obstetric complications, or by diarrhoea. Thrombotic microangiopathy (TMA) was evident in all patients with signs of microangiopathic haemolysis (sharp decline in haemoglobin; mean 67 g/L), elevated lactate dehydrogenase (LDH; mean 2953.1 U/L), schistocytosis, thrombocytopenia (mean platelet count 52.5 * 109/uL), and acute kidney injury (AKI) (hypercreatininaemia, mean 456.4 umol/L; oliguria or anuria). The majority of patients (80%) initially presented with arterial hypertension. Diagnosis of obstetric-aHUS was complicated, as multiple organs were affected. Time taken to make the diagnosis of aHUS delayed the initiation of fresh-frozen plasma infusions and plasma exchange (80% of patients) and subsequent eculizumab treatment (40% of patients). Maternal mortality was high (35%) as was foetal mortality (25%). CONCLUSIONS: Obstetric-aHUS is a serious condition characterized by multiple organ failure (MOF) and a high mortality rate. Presentation of obstetric-aHUS is preceded by various precipitating factors, suggesting pregnancy complications, and not the pregnancy per se, often induce aHUS in women with a genetic predisposition to its development. A delay in the correct diagnosis and initiation of the most effective treatment can have serious consequences, reinforcing the need to raise awareness of obstetric-aHUS. PMID- 29606013 TI - Evaluation of pre- and postnatally diagnosed gastrointestinal tract obstructions. AB - PURPOSE: Signs of congenital obstruction of the gastrointestinal tract (GIT) organs may present on prenatal ultrasonography. Prenatal detection is influenced by several factors, including obstruction site, lesion degree (partial or complete), the occurrence of associated malformations, and gestational week at screening. Here, we aimed to evaluate the success of prenatal diagnosis of GIT obstructions in a tertiary center in Turkey. MATERIALS AND METHODS: The study included 34 prenatally and 22 postnatally diagnosed babies with different GIT malformations. GIT obstructions were divided into five groups according to the level of obstruction (A. esophagus, B. stomach and proximal duodenum, C. small intestine, D. large intestine, E. multiple obstructions). RESULTS: The prenatal detection rate among all cases was 60.7%. The associated structural malformation and aneuploidy rates were 21.4 and 5.4%, respectively. Twelve neonates died within the first day after birth due to various reasons. The remaining 43 babies underwent surgery at different times according to their clinical conditions. The mean time between birth and surgery was 4.5 days (range, 1-56 days). There were 12 postoperative deaths due to various complications, and one case died at 2 years of age. Overall, 31 of the 56 (55.4%) babies were alive during the follow up period. The successful prenatal diagnosis rates were 57.2, 85.8, 75, 25, and 80% in groups A, B, C, D, and E, respectively. The median birth weight increased significantly in groups A through D (p = .04). However, there were no intergroup differences in the Apgar scores, associated abnormality rates, time to surgery, and number of babies operated. CONCLUSIONS: These findings demonstrate the importance of prenatal ultrasonography and success of prenatal detection especially for upper GIT abnormalities. Although there are some prenatal signs of GIT obstructions, such as double bubble, polyhydramnios, enlarged bowel, and failure to visualize the stomach, early prenatal diagnosis is difficult and can be delayed, resulting in the detection of GIT obstruction after birth. When suspecting GIT obstruction, clinicians should evaluate the fetal anatomy carefully and be aware of associated chromosomal abnormalities. PMID- 29606014 TI - Analysis of sudden infant death syndrome coverage in Canadian newspapers. AB - Sudden infant death syndrome (SIDS; also known as crib death) describes the sudden unexpected death of an infant under one year of age, which remains unexplained after a thorough investigation. SIDS is a public health concern. It is the fourth leading cause of infant death in Canada. Newspapers are a major source of health information for the public, shape public perceptions and can direct the discussion around issues. Despite the potential influence of newspapers, no study has examined the portrayal of SIDS in Canadian newspapers over time. The purpose of our study was to gain an understanding of SIDS coverage in Canadian English language newspapers using the Canadian Newsstream database from 1970 to 2015 and the historical database: The Globe and Mail from 1844 to 1977. Generating descriptive quantitative and qualitative data, we noted a decline in SIDS coverage over time. Blame and misdiagnosis were two dominant themes in the coverage of SIDS with many other aspects around SIDS missing; for example, indigenous people, who are at higher risk for SIDS, were rarely mentioned. Our findings suggest problems in the content and frequency of coverage of SIDS that have the potential to shape the public understanding of SIDS. PMID- 29606015 TI - Avoidant coping moderates the relationship between paternal involvement in the child's type 1 diabetes (T1D) care and parenting stress. AB - Fathers may experience greater parenting stress and anxiety when they are more involved in their child's type 1 diabetes (T1D) care. The present study evaluated whether seeking social support and avoidant coping strategies moderate the relationship between paternal involvement in the child's T1D care and parenting stress in an international sample. Two hundred forty-nine fathers of young children with T1D completed the Parenting Stress Index (PSI), Pediatric Inventory for Parents (PIP), Dads' Active Disease Support scale (DADS), COPE Inventory, Self-Care Inventory (SCI-R), and a demographic questionnaire online. Pearson's product moment correlations were computed, and multiple linear regression analysis was conducted with three separate models in which the PSI Child Domain, PIP Frequency, and PIP Difficulty scores represented different parenting stress outcomes. The interaction between use of denial coping and DADS Involvement was significantly correlated with general parenting stress ( p < .05). There were no significant interactions between instrumental social support and DADS Involvement; however, use of instrumental social support coping was significantly correlated with difficulty of pediatric parenting stress ( p < .05), DADS Involvement ( p < .001), and SCI-R better adherence to the child diabetes treatment regimen ( p < .001). Avoidant coping strategies are associated with more general parenting stress, especially when fathers are more involved in T1D management. PMID- 29606016 TI - Laboratory diagnosis of Lyme borreliosis: Current state of the art and future perspectives. AB - This review is directed at physicians and laboratory personnel in private practice and clinics who treat and diagnose Lyme borreliosis (LB) in patients as part of their daily work. A major objective of this paper is to bring together background information on Borrelia (B.) burgdorferi sensu lato (s.l.) and basic clinical knowledge of LB, which is one of the most frequently reported vector borne diseases in the Northern Hemisphere. The goal is to provide practical guidance for clinicians and for laboratory physicians, and scientists for a better understanding of current achievements and ongoing obstacles in the laboratory diagnosis of LB, an infectious disease that still remains one of the diagnostic chameleons of modern clinical medicine. Moreover, in bringing together current scientific information from guidelines, reviews, and original papers, this review provides recommendations for selecting the appropriate tests in relation to the patient's stage of disease to achieve effective, stage-related application of current direct and indirect laboratory methods for the detection of B. burgdorferi s.l. Additionally, the review aims to discuss the current state of the art concerning the diagnostic potential and limitations of the assays and test methods currently in use to optimize LB patient management and provide insight into the possible future prospects of this rapidly changing area of laboratory medicine. PMID- 29606017 TI - Can family-centered programing mitigate HIV risk factors among orphaned and vulnerable adolescents? Results from a pilot study in South Africa. AB - Let's Talk is a structured, family-centered adolescent HIV prevention program developed for use in South Africa using key components adapted from programs successfully implemented in the US and South Africa. It is designed to address individual HIV transmission risk factors common among orphaned and vulnerable adolescents, including elevated risk for poor psychological health and sexual risk behavior. These efforts are accentuated through parallel programing to support caregivers' mental health and parenting skills. Twelve Let's Talk groups, each serving approximately 10 families, were piloted by two local community-based organizations in Gauteng and Kwa-Zulu Natal provinces, South Africa. Face-to-face interviews were conducted among participating caregivers and adolescents at baseline and three months post-intervention to explore the potential effects of the program on intermediate outcomes that may support HIV preventive behavior. Specifically, generalized estimation equations were used to estimate average change on HIV prevention knowledge and self-efficacy, caregiver and adolescent mental health, and family dynamics. Among the 105 adolescents and their 95 caregivers who participated in Let's Talk and completed both surveys, statistically significant improvements were found for adolescents' HIV and condom use knowledge as well as condom negotiation self-efficacy, but not sexual refusal self-efficacy. Both caregivers and adolescents demonstrated significantly better mental health at post-test. Adolescent/caregiver connection and communication about healthy sexuality also improved. These preliminary results highlight the potential of HIV prevention interventions that engage caregivers alongside the vulnerable adolescents in their care to mitigate adolescent HIV risk factors. A more rigorous evaluation is warranted to substantiate these effects and identify their impact on adolescents' risk behavior and HIV incidence. PMID- 29606018 TI - Relationships between psychosocial distress and diet during pregnancy and infant birthweight in a lower-middle income country: 'healthy mothers, healthy communities' study in Vanuatu. AB - BACKGROUND: Maternal stress during pregnancy is associated with birth outcomes, including birthweight. Exposure to natural disasters during pregnancy provides a model to study these relationships. However, few studies assess both stress and diet, which might have interactive effects. Furthermore, most are conducted in high-income countries. Patterns might differ in low- and middle-income countries (LMICs). AIM: To study relationships between stress and diet during pregnancy, and infant birthweight, following a natural disaster in a lower-middle income country. SUBJECTS AND METHODS: In 2015, the island nation of Vanuatu suffered a Category 5 cyclone. Three months later, the authors assessed hardship due to the cyclone, distress, and dietary diversity among 900 women, including 187 pregnant women. Of these, 70 had birth records available. Multivariate linear regression was used to analyse relationships between cyclone exposure and infant birthweight among this sub-sample. RESULTS: Neither hardship nor dietary diversity predicted birthweight. Distress was a robust predictor, explaining 8.5% of variance (p = 0.012). There were no interactive relationships between distress and other exposure variables. CONCLUSIONS: Maternal distress following a natural disaster has important implications for maternal and child health. In LMICs, low birthweight remains a pressing public health concern. Distress during pregnancy might represent one underlying risk factor. PMID- 29606019 TI - Efficacy and safety of low-concentration, bisulphite-containing, intracameral epinephrine and topical atropine treatments for the prevention of intraoperative floppy iris syndrome. AB - PURPOSE: The aim of this study was to evaluate the efficacy and safety of topical atropine and topical atropine combined with intracameral low-concentration, bisulphite-containing epinephrine treatment for the prophylaxis of intraoperative floppy iris syndrome. MATERIALS AND METHODS: Seventy-two eyes of 55 male patients who were treated with alpha-adrenergic antagonist medications for benign prostatic hyperplasia were included in this study. Standard premedication with topical cyclopentolate, phenylephrine, tropicamide and ketorolac was applied to all of the patients. In 22 cases no further prophylactic method was used (Group NP), while in 29 cases topical atropine drops was instilled 12 h and 30 min before surgery (Group-A) and in 21 cases 1:16 000 epinephrine was injected to the anterior chamber at the beginning of surgery (Group-EA) in addition to topical atropine prophylaxis. RESULTS: In Group-NP, 62.8% of the cases developed IFIS, while development of IFIS was significantly lower in Group-A (17.2%, p = 0.0004) and Group-EA (9.5%, p < 0.0001). Posterior capsule rupture was observed in two cases (9.1%) in Group-NP, in one case (3.4%) in Group-A and was not observed in Group-EA. There was no statistically significant difference between the groups for the development of surgical complications. We did not observe any adverse events or significant endothelial cell loss (p = 0.462). CONCLUSIONS: Our results indicate that preoperative use of topical atropine reduces the incidence of IFIS. Use of low-concentration, bisulphite-containing epinephrine is more effective in the prevention of IFIS and does not cause preservative related endothelial damage. This prophylaxis may be preferred when preservative free epinephrine is not available. PMID- 29606020 TI - Hepatitis B Reactivation in the Treatment of Non-Hodgkin Lymphoma. AB - Chronic active hepatitis B infection (HBV) has been implicated in lymphomagenesis of non-Hodgkin lymphoma (NHL). Treatment of cancer including NHL with chemotherapy or immunotherapy can lead to HBV reactivation in previously infected patients. Serological testing of HBV prior to initiation of this therapy is recommended by several national and international medical agencies and expert panels. Patients with positive hepatitis B surface antigen (HBsAg) and anti hepatitis B core antibody (anti-HBc ab) need to start antiviral therapy with entecavir or tenofovir prior to initiation of chemotherapy or immunotherapy and continue this treatment for 6 to 12 months after completion of cancer therapy to avoid late HBV reactivation. Monitoring of HBV DNA viral load and liver function tests should be done during cancer therapy in infected patients. Hepatitis B infection vaccination resulted in decreases prevalence of HBV virus carriers and decreased incidence of virus-induced malignancies. PMID- 29606021 TI - Wastage of standardised parenteral nutrition solution - a challenge for neonatal units. AB - BACKGROUND: Standardised parental nutrition (PN) has been used in many neonatal intensive care unit (NICU). Easy accessibility, better provision of nutrients, reduced prescription errors and cost savings are some of its benefits. Fixed large volume (e.g. 750-1000 mL) and short expiry limit (48 hrs) along with changing metabolic needs of neonates leads to significant wastage of PN solution. OBJECTIVE: To evaluate wastage of PN solution in our 22-bedded NICU. METHODS: The audit was conducted over 21-month period (July 2015-April 2017). Data on PN use (e.g. type, duration, infused volume, residual after use) was obtained from hospital records. The discarded volume of PN was estimated after subtracting the administered volume based on the rate of infusion from the total volume in the bag. Cumulative "discarded" volume as percentage of the total "supplied" volume was calculated. RESULTS: A total of 305-PN bags (Standardised: Preterm: 222, Term: 83) were used. The estimated total used, discarded, and percentage discarded volumes for standard preterm and term PN were 78.1, 88 L, 53% and 33.5, 49.7 L, and 59.8%, respectively. CONCLUSIONS: There was more than 50% wastage of PN solution in our NICU. The estimated cost of this PN wastage was around 21,000 AUD over 21 months. Strategies such as minipack should be explored to prevent such losses. PMID- 29606022 TI - Associations between neural injury markers of intrauterine growth-restricted infants and neurodevelopment at 2 years of age. AB - OBJECTIVES: The aim of this study was to evaluate the relationships between brain injury biomarkers in intrauterine growth-restricted (IUGR) infants (S100B and neuron-specific enolase (NSE)) and neurodevelopment at 2 years of age. METHODS: This prospective case-control study was a cooperative effort among Spanish Maternal and Child Health Network (Retic SAMID) hospitals. At inclusion, biometry for estimated fetal weight and feto-placental Doppler variables were measured for each infant. Maternal venous blood and fetal umbilical arterial blood samples were collected at the time of delivery and neural injury markers S100B and NSE concentrations were measured. Neurodevelopment was evaluated at 2 years of age using the Bayley Scales of Infant and Toddler Development, third edition (Bayley III). RESULTS: Fifty six pregnancies were included. Thirty-one infants were classified as IUGR and 25 as non-IUGR. Neurodevelopmental evaluation at 2 years of age indicated that there were no between-group differences for any of the tests. For all patients in both groups, we found statistically significant inverse relationships between the concentrations of NSE in the cord blood and the results of the cognitive test (r = -271, p = .042), fine motor subtest (r = -280, p = .036), and social-emotional test (r = -349, p = .015). We also found statistically significant differences between the concentrations of S100B in the cord blood and the results of the cognitive test (r = -306, p = .022) and expressive communication subtest (r = -304, p = .023). For the IUGR group, we found a significant inverse relationship between the concentrations of S100B in the maternal serum and the results of adaptive behavior test (p < .05). In the non-IUGR group, we found statistically significant inverse relationships between the concentration of NSE in the cord blood and the results of the fine motor subtest (r = -446, p = .025) and social-emotional test (r = -489, p = .021). The difference between the concentration of S100B in the cord blood and the language composite score was also statistically significant (p = .038). CONCLUSIONS: At 2 years of age, the concentrations of NSE and S100B were higher in the non-IUGR and IUGR groups with the worst scores for some areas of neurodevelopmental evaluation. The value of these biomarkers for prognostic neurodevelopmental use requires further investigation for both non-IUGR and IUGR infants. PMID- 29606023 TI - Equinus Correction During Multilevel Surgery in Adults With Cerebral Palsy. AB - BACKGROUND: Equinus foot deformity constitutes a common gait disorder in ambulatory adults with bilateral spastic cerebral palsy (BSCP). The outcome after intramuscular aponeurotic lengthening in the context of single-event multilevel surgery (SEMLS) in adulthood has not been investigated. METHODS: We followed a group of 31 ambulatory adults with BSCP and equinus who underwent SEMLS including gastrocnemius-soleus intramuscular aponeurotic recession or Achilles tendon lengthening. All patients were analyzed preoperatively and at least 1 year (mean follow-up period: 1.6 years) postoperatively by clinical examination and 3 dimensional instrumented gait analysis including the Gait Profile Score (GPS). RESULTS: Clinical examination showed no significant improvement of ankle dorsiflexion ( P = .5) and an unchanged plantarflexion ( P = .7) with knee extended but a significant postoperative reduction of spasticity in the calf muscle ( P = .0001) as measured by clinical examination following the modified Ashworth scale. Significant improvement of mean ankle dorsiflexion in stance and swing ( P = .0001) was found. The GPS decreased and improved significantly (15.9 +/- 4.6 to 11.4 +/- 3.1; P = .0001). Persistence of equinus and calcaneal gait indicating under- and overcorrection at follow-up was found in 1 patient (3%), respectively. CONCLUSION: Intramuscular gastrocnemius-soleus aponeurotic recession is part of multilevel surgery corrected equinus deformity in adults. The increase in muscle length led to significant improvement of kinetic and kinematic parameters during walking without a loss of muscle strength and push off capacity. The risk of overcorrection after equinus correction in adults with BSCP was found to be relatively low. LEVEL OF EVIDENCE: Level IV, retrospective case series. PMID- 29606024 TI - Return to Sports and Physical Activities After Open Reduction and Internal Fixation of Lisfranc Injuries in Recreational Athletes. AB - BACKGROUND: The purpose of this study was to assess participation in sport and physical activity following open reduction and internal fixation of a Lisfranc injury in a cohort of recreational athletes. METHODS: This study identified all adult patients aged 55 years or younger who presented with a Lisfranc injury and underwent open reduction and internal fixation (ORIF) using a Lisfranc screw combined with bridge plating technique. Sports and physical activity participation was assessed with a new sports-specific, patient-administered questionnaire. Clinical outcomes were assessed with the Foot and Ankle Outcome Score (FAOS). Thirty-three patients qualified for the study (21 men/12 women). Mean age and follow-up were 31.2 (range, 18-55) years and 2.9 (range, 1.5-5.4) years, respectively. RESULTS: Postoperatively, 31 patients (94%) were able to return to some form of sport. Twenty-two patients (66%) returned to playing sport at or above their preinjury level. Of the 11 patients who played less sport, 6 had ongoing pain, and the remaining 5 were asymptomatic but were participating less frequently because of other lifestyle reasons. In addition, of the 33 patients, 11 (33%) had some degree of ongoing pain that might limit their ability to return to sports and physical activities. There was strong correlation between overall FAOS and the Sports Questionnaire. CONCLUSION: Most patients who sustained a Lisfranc injury could return to sport and physical activity after ORIF. Patients should be counseled preoperatively that about 1 in 3 might experience continued pain at the injury site Level of Evidence: Level IV, retrospective case series. PMID- 29606025 TI - A nutritional intervention program improves the nutritional status of geriatric patients at nutritional risk-a randomized controlled trial. AB - OBJECTIVES: To investigate the effect of a nutrition intervention program for geriatric nutritional at-risk patients. DESIGN: A randomized controlled trial. SETTING: Department of geriatric medicine in a university hospital and in the primary healthcare sector, Copenhagen. SUBJECTS: Geriatric patients ( N = 144) at nutritional risk. INTERVENTION: The intervention consisted of an individual dietary plan for home, including pre-discharge advice on nutritional intake, combined with three follow-up visits after discharge (one, four, and eight weeks). MAIN MEASURES: Change in body weight, Barthel Index, hand-grip strength and self-rated health from baseline (discharge) to three months after discharge, readmission, and mortality (90 and 120 days). RESULTS: The mean (SD) age in total sample was 87.2 (6.2) years. Sample size in the intervention group (IG) was N = 72, and in the control group (CG), N = 72. IG had a mean (SD) weight gain of 0.9 (4.2) kg compared to a weight loss of 0.8 (3.6) kg in the CG ( P = 0.032). In addition, an improvement in self-rated health was seen in the IG compared to CG (IG: 23 (47%) vs. CG: 12 (24%); P = 0.021). No significant difference between groups was found in functional status, mortality, or readmission rates. CONCLUSION: An individual dietary plan based on everyday food, combined with three follow-up visits (one, four, and eight weeks) after discharge, led to an improvement in nutritional status and self-rated health in geriatric patients. PMID- 29606026 TI - Strategies for preventing early-onset sepsis and for managing neonates at-risk: wide variability across six Western countries. AB - OBJECTIVE: Group B streptococcus (GBS) early-onset sepsis (EOS) has declined after widespread intrapartum antibiotic prophylaxis. However, strategies for preventing EOS may differ across countries. The analysis of their strategies allows to compare the effectiveness of prevention in different countries and suggests opportunities for improvement. METHODS: We compared six western countries. Prevention strategies, incidence rates of EOS and approaches for managing neonates at-risk were analysed. Countries were selected because of availability of recommendations for prevention and sufficient epidemiological data for comparison. RESULTS: Five of six countries recommend antenatal vagino rectal screening. The decline of GBS cases is relevant in most countries, particularly in those with a screening-based strategy, which have reached incidence rates from 0.1 to 0.3/1000 live births and zero or close to zero mortality in full-term newborns. The recommendation for managing asymptomatic neonates at risk for EOS varies according to gestational age and ranges from observation only to laboratory testing plus empirical antibiotics. Chorioamnionitis (suspected or confirmed) is the main indication for carry out laboratory testing and for administering empirical antibiotics. CONCLUSIONS: Wide variations exists in preventing EOS. They depend on national epidemiology of GBS infections, compliance, cost, and feasibility of the strategy. The extreme variability of approaches for managing neonates at risk for EOS reflects the even greater uncertainty regarding this issue, and may explain the persisting, great use of resources to prevent a disease that has become very rare nowadays. PMID- 29606027 TI - Effects of cisplatin-5-fluorouracil combination therapy on oxidative stress, DNA damage, mitochondrial apoptosis, and death receptor signalling in retinal pigment epithelium cells. AB - AIM: Combination therapies of cisplatin with 5-FU (PF) are an effective solution and have been widely used for the treatment of various categories of cancer including anal, gastrointestinal, and oral cancer, as well as head and neck tumors. The effects of combined PF treatment on vital intracellular signalling pathways in nontargeted cells remain unclear. The aim of this study is to explain the possible mechanisms by which combined PF treatment results in retinal toxicity and to investigate the effects of PF on important vital signalling pathways in ARPE 19 retinal pigmented epithelial cells. MATERIALS AND METHODS: We analysed the cellular and molecular effects of PF on cell viability, oxidative stress, gene repair response, and induction of apoptosis in ARPE 19 cells using molecular probe fluorescent staining, cell cytometer, RAPD, qRT-PCR, and western blot assays. RESULTS: We determined that PF causes excessive generation of reactive oxygen species (ROS) and prevents ROS scavenging by suppressing antioxidant systems. We found induction of DNA damage, particularly mismatch and double strand break repair, in ARPE 19 cells treated with PF. In this study, PF also induced both the intrinsic apoptosis pathway and death receptor signalling in ARPE 19 cells. CONCLUSIONS: Our data proved that PF causes cytotoxicity and genotoxicity, at both the cellular and molecular levels, in ARPE 19 cells following particularly prolonged treatment (48 h). Additionally, our results suggest key molecular signals for prevention strategies that can be developed to reduce the severe side effects of PF chemotherapy. PMID- 29606028 TI - Renoprotective effect of nifuroxazide in diabetes-induced nephropathy: impact on NFkappaB, oxidative stress, and apoptosis. AB - The prevalence of diabetes mellitus (DM) is drastically increased worldwide. Diabetic nephropathy (DN) is a microvascular complication of DM and a common cause of end stage renal disease (ESRD). DN has been recently reported as the most common cause among ESRD patients. Shortage of a definitive cure for DN and the social and economic burden of this disease provide considerable impetus for development of new therapies. In the present study, we evaluated the effect of nifuroxazide, a potent inhibitor of Janus kinase/signal transducers and activators of transcription (JAK2/STAT3), on nuclear factor kappa B (NFkappaB), oxidative stress, and apoptosis in diabetic kidney. Following induction of diabetes by single dose of streptozotocin (50 mg/kg), nifuroxazide was administrated to diabetic rats (25 mg/kg/day, orally) for 8 weeks. Our results showed that nifuroxazide treatment, attenuated diabetes-induced damage in renal structure, ameliorated oxidative stress, triggered antioxidant defense, reduced NFkappaB nuclear translocation and cleaved caspase-3 expression and down regulated the activity of apoptotic enzymes (caspase-3/caspase-8/caspase-9) in diabetic kidney. In conclusion, nifuroxazide exhibited renoprotective effect in diabetic kidney via dampening NFkappaB activation, oxidative stress, and apoptosis. PMID- 29606029 TI - Mitochondrial dysfunction contribute to diabetic neurotoxicity induced by streptozocin in mice: protective effect of Urtica dioica and pioglitazone. AB - INTRODUCTION: Uncontrolled chronic hyperglycemia in diabetic patients could result in various complications, including neurotoxicity. Urtica dioica L. (UD) is known for its hypoglycemic and antioxidant effects. In this study, we evaluated the efficacy of UD and pioglitazone (PIO) in reduction of neurotoxicity and oxidative stress in streptozocin-induced diabetic mice. MATERIALS AND METHODS: Male mice were divided into seven groups: control, diabetic, dimethyl sulfoxide-treated control, PIO-treated, UD-treated, UD-PIO-treated, and vitamin E treated. For induction of diabetes, streptozocin was injected in a single dose (65 mg/kg, i.p.). All treatments were performed for 5 weeks. Neurotoxicity was evaluated through hot plate and formalin test. Then, animals were killed, brain tissue was separated and the mitochondrial fraction was isolated with different centrifuge technique. Also, oxidative stress markers (reactive oxygen species, lipid peroxidation, protein carbonyl, glutathione) were measured in brain. Mitochondrial function was evaluated by MTT test in brain isolated mitochondria. RESULTS: Elevation of oxidative stress markers and mitochondrial damage were observed in diabetic mice compared to control group. Administration of PIO and UD ameliorated the oxidative stress and mitochondrial damage (p < 0.05) in diabetic mice. Also increase in pain score was shown in diabetic mice that treatment with UD and PIO diminished elevation of pain score in diabetic mice. Interestingly, simultaneous administration of PIO and UD showed synergism effect in attenuation of oxidative stress and hyperglycemia. CONCLUSION: UD showed a therapeutic potential for the attenuation of oxidative stress and diabetes-induced hyperglycemia that can be considered as co-treatment in treatment of diabetic neurotoxicity. PMID- 29606030 TI - Toxicity of silver nanoparticles, multiwalled carbon nanotubes, and dendrimers assessed with multicellular organism Caenorhabditis elegans. AB - Nematode Caenorhabditis elegans (C. elegans) was used to investigate the impact of silver nanoparticles (SNP), multiwalled carbon nanotubes (MWCNT), and polyamidoamine dendrimers (PAMAM) used in concentration of 1010 particle/mL. Population-based observations and gene expression analysis were employed in this study. SNP and PAMAM caused decrease in the number of live nematodes and their body length, but MWCNT did not affect the population of nematodes. Gene expression analysis revealed significant changes caused by the presence of all studied nanomaterials, and the results strongly suggest a specific metabolic response of the nematode organism to exposure to various nanomaterials. It was shown that C. elegans is a very sensitive organism capable to respond specifically to the exposure to some nanomaterials and therefore could be considered as a possible biosensor for early warning of presence of some nanoparticles. PMID- 29606032 TI - Men of Mexican Origin Who Abuse Women: A Qualitative Study. AB - BACKGROUND: Current literature indicates that intimate partner violence is a complex phenomenon that exists worldwide. PURPOSE: However, little is known about why some men of Mexican origin abuse women. This descriptive study was conducted to understand the experiences of men of Mexican origin who abuse their intimate partners. METHOD: A qualitative research design was used to conduct this study in a south Texas border community adjacent to the United States-Mexico border. RESULTS: This study builds on existing research and furthers the knowledge related to the factors contributing to intimate partner violence, including cultural factors. The results also reinforce the negative impacts of intimate partner violence on children and the family structure. DISCUSSION: Further research is needed to support the development of a culturally appropriate prevention and intervention program for men of Mexican origin who abuse women and their families. PMID- 29606033 TI - Death Acceptance in Vietnamese Cancer Patients: A Phenomenological Study. AB - INTRODUCTION: To date, death acceptance is not well investigated in the Vietnamese population. Cultural influences may affect death acceptance. The purpose of this phenomenological study is to describe Vietnamese cancer patients' lived experience with death acceptance. METHOD: Eleven Vietnamese patients with various cancer diagnoses participated in the study. Data were analyzed using the Giorgian method of data analysis. RESULTS: Themes of death acceptance found were (1) accepting destiny, (2) knowing and sacrificing the self, (3) believing in living persons and handing over responsibilities, (4) accepting death while continuing to fight for life, and (5) looking for a "role model death." DISCUSSION: Death acceptance is a contextually bound concept, which needs further investigation. To help patients with their death acceptance, nurses should include spiritual support and the involvement of loved ones in patients' care plans. PMID- 29606031 TI - Testicular developmental impairment caused by flutamide-induced and DEHP-induced cryptorchid rat models is mediated by excessive apoptosis and deficient autophagy. AB - BACKGROUND: Cryptorchidism is a common condition of childhood, and it is known to impair fertility potential. However, the underlying mechanisms remain unclear. METHODS: This study constructed two cryptorchid rat models to investigate the roles of apoptosis and autophagy in testicular impairment induced by cryptorchidism. Pregnant rats were randomly divided into three groups. Group I: non-treated rats were used as controls. Group II: injected with drug Flutamide (Flu) 25 mg/kg/bw/d from gestation day (GD) 11-19. Group III: daily intragastric administration of 750 mg/kg/bw/d di-2-ethylhexylphosphate (DEHP) from GD 7-19. The cubs were feed normally and the testes were excised on postnatal day (PND) 30. RESULTS: Our results demonstrated cryptorchidism models induced noticeable decreased fertility, significantly reduced sperm count, increased sperm abnormality rate, decreased testosterone and severe testicular damage in histomorphology. Intriguingly, the level of apoptosis marker FAS, Cytochrome C and caspase-3 increased in Flu-induced and DEHP-induced groups. DEHP-induced treatment simultaneously increased the number of autophagosomes and the levels of autophagy marker LC3-II and p62. Significant decrease of autophagy gene (LC3-II and p62) expression is found in Flu-induced rats testes. CONCLUSION: Taken together, deficient autophagy is involved in testicular spermatogenesis damage of cryptorchidism rats. And this autophagy defect is caused by deficient degradation. PMID- 29606034 TI - Internet Gaming Disorder: An Emergent Health Issue for Men. AB - Internet gaming is a legitimate leisure activity worldwide; however, there are emerging concerns that vast numbers of gamers are becoming addicted. In 2013, the American Psychiatric Association (APA) classified Internet Gaming Disorder (IGD) as a condition warranting more clinical research ahead of formalizing it as a mental disorder. Proposed as a behavioral addiction, IGD shares many similarities in both physical and psychosocial manifestations with substance use disorder, including cerebral changes on functional magnetic resonance imaging (fMRI). Among the gaming population, compared to females, adolescent and adult males demonstrate far more addictive internet gaming use in terms of screen hours, craving, and negative impacts on health, which have, in isolated incidents, also caused death. The current article draws findings from a scoping review of literature related to IGD as a means to raising awareness about an emergent men's health issue. Included are three themes: (a) unveiling the nature, impacts and symptoms of IGD; (b) conceptualizing IGD through neuroscience; and (c) treatment approaches to IGD. Afforded by these themes is an overview and synthesis of the existing literature regarding IGD as a means of providing direction for much needed research on gaming addiction and orientating primary care providers (PCPs) to the specificities of IGD in men's health. The findings are applied to a discussion of the connections between IGD and masculinity and the importance of recognizing how behaviors such as social isolation and game immersion can be maladaptive coping strategies for males. PMID- 29606035 TI - The induction of aryl hydrocarbon receptor (AHR) in immune organs of developing chicks by polycyclic aromatic hydrocarbons. AB - Polycyclic aromatic hydrocarbons are pollutants which are persistent in nature. The aryl hydrocarbon receptor is a ligand-activated cytosolic transcription factor activated by xenobiotics. The objective was to isolate and identify AHR mRNA transcript in immune organs of developing chicks and to interpret the correlation between AHR induction and dose of PAHs. Specific pathogen free embryonated eggs on day nine were inoculated with solutions of pyrene, phenanthrene, and fluoranthene dissolved in tricaprylin (vehicle) through the allantoic route at three dose levels: 0.2 mg/kg, 2 mg/kg, and 20 mg/kg. A 650 base pair product was observed by RNA extraction and reverse transcription PCR from thymus, bursa of Fabricius and spleen on 21st day. When AHR concentration was analyzed by ELISA in these organs, pyrene showed maximum potency in inducing AHR in thymus. Fluoranthene made highest concentration of AHR in bursa of Fabricius. None of these chemicals caused an increase in AHR concentration in spleen. PMID- 29606036 TI - A Comprehensive Theory of Integration. AB - Efforts to transform health care delivery to improve care have increasingly focused on care integration. However, variation in how integration is defined has complicated efforts to design, synthesize, and compare studies of integration in health care. Evaluations of integration initiatives would be enhanced by describing them according to clear definitions of integration and specifying which empirical relationships they seek to test-whether among types of integration or between integration and outcomes of care. Drawing on previous work, we present a comprehensive theoretical model of relationships between types of integration and propose how to measure them. PMID- 29606037 TI - Medical Home-Head Start Partnership to Promote Early Learning for Low-Income Children. AB - OBJECTIVE: To improve Early Head Start/Head Start (EHS/HS) screening, referral, and enrollment for children from diverse, low-income communities. METHOD: Using existing resources, we built a pediatric clinic-Head Start partnership. Key steps included (1) screening protocol and tracking system, (2) a community partner as a single point of referral contact, (3) provider education, and (4) monthly outcome reporting. A pre- and post-cross-sectional study design was used to evaluate outcomes, with medical chart review conducted for all wellness visits among children aged 0 to 4 years pre- and postintervention. RESULTS: The preintervention group included 223 patients. The postintervention group included 235 patients. EHS/HS screening improved significantly after the intervention, rising from 8% in the preintervention period to 46% in the postintervention period (odds ratio [OR] 10.5, 95% confidence interval [CI] [5.9, 19.4]). EHS/HS documented referral rates increased from 1% in the preintervention period to 20% in the postintervention period (OR 18.3, 95% CI [5.7, 93.6]). Thirty-two of the 42 patients in the postintervention group referred to EHS/HS were reached to determine enrollment status. Six children (14%) had enrolled in EHS/HS. CONCLUSION: With use of existing resources, a medical home-Head Start partnership can build an integrated system that significantly improves screening and referral rates to early learning programs. PMID- 29606039 TI - Social Media for Hepatitis B Awareness: Young Adult and Community Leader Perspectives. AB - Screening for hepatitis B (HBV) among high-risk young adults can help prevent its transmission and lead to earlier treatment and better long-term health outcomes. Yet few interventions have focused on increasing HBV awareness among young adults. Social media (SM) may be an effective method for disseminating information and engaging young adults about HBV. In this pilot study, qualitative and quantitative methods were applied to collect information on current use and perceptions toward SM through semistructured interviews and focus groups with young Chinese and Vietnamese adults and community leaders from local organizations in Philadelphia. Additionally, survey items were collected during the interviews and focus groups to provide quantitative data. Results from the interviews provided evidence that young adults and local organizations are already using SM and are open to using it to share general health information that is specific to their community. The focus groups suggested that using group pages or chats could be most appropriate for reaching young adults and that credible sources should be used to deliver messages that are tailored to the audience. The findings from this study will support the development of an SM intervention aimed at increasing HBV awareness. PMID- 29606038 TI - Voluntary Smoke-Free Measures Among Oklahoma Nightlife Owners: Barriers and Facilitators. AB - Smoke-free policies prevent exposure to secondhand smoke and encourage tobacco cessation. Local smoke-free policies that are more comprehensive than statewide policies are not allowed in states with preemption, including Oklahoma, which has the sixth highest smoking prevalence in the United States. In states with preemption, voluntary smoke-free measures are encouraged, but little research exists on venue owners' and managers' views of such measures, particularly in nightlife businesses such as bars and nightclubs. This article draws from semistructured interviews with 23 Oklahoma bar owners and managers, examining perceived risks and benefits of adopting voluntary smoke-free measures in their venues. No respondents expressed awareness of preemption. Many reported that smoke-free bars and nightclubs were an inevitable societal trend, particularly as younger customers increasingly expected smoke-free venues. Business benefits such as decreased operating and cleaning costs, improved atmosphere, and employee efficiency were more convincing than improved employee health. Concerns that voluntary measures created an uneven playing field among venues competing for customers formed a substantial barrier to voluntary measures. Other barriers included concerns about lost revenue and fear of disloyalty to customers, particularly older smokers. Addressing business benefits and a level playing field may increase support for voluntary smoke-free nightlife measures. PMID- 29606040 TI - Decision-making algorithm for minimally invasive approaches to anterior skull base meningiomas. AB - OBJECTIVE Anterior skull base meningiomas are benign lesions that cause neurological symptoms through mass effect on adjacent neurovascular structures. While traditional transcranial approaches have proven to be effective at removing these tumors, minimally invasive approaches that involve using an endoscope offer the possibility of reducing brain and nerve retraction, minimizing incision size, and speeding patient recovery; however, appropriate case selection and results in large series are lacking. METHODS The authors developed an algorithm for selecting a supraorbital keyhole minicraniotomy (SKM) for olfactory groove meningiomas or an expanded endoscopic endonasal approach (EEA) for tuberculum sella (TS) or planum sphenoidale (PS) meningiomas based on the presence or absence of olfaction and the anatomical extent of the tumor. Where neither approach is appropriate, a standard transcranial approach is utilized. The authors describe rates of gross-total resection (GTR), olfactory outcomes, and visual outcomes, as well as complications, for 7 subgroups of patients. Exceptions to the algorithm are also discussed. RESULTS The series of 57 patients harbored 57 anterior skull base meningiomas; the mean tumor volume was 14.7 +/- 15.4 cm3 (range 2.2-66.1 cm3), and the mean follow-up duration was 42.2 +/- 37.1 months (range 2-144 months). Of 19 patients with olfactory groove meningiomas, 10 had preserved olfaction and underwent SKM, and preservation of olfaction in was seen in 60%. Of 9 patients who presented without olfaction, 8 had cribriform plate invasion and underwent combined SKM and EEA (n = 3), bifrontal craniotomy (n = 3), or EEA (n = 2), and one patient without both olfaction and cribriform plate invasion underwent SKM. GTR was achieved in 94.7%. Of 38 TS/PS meningiomas, 36 of the lesions were treated according to the algorithm. Of these 36 meningiomas, 30 were treated by EEA and 6 by craniotomy. GTR was achieved in 97.2%, with no visual deterioration and one CSF leak that resolved by placement of a lumbar drain. Two patients with tumors that, based on the algorithm, were not amenable to an EEA underwent EEA nonetheless: one had GTR and the other had a residual tumor that was followed and removed via craniotomy 9 years later. CONCLUSIONS Utilizing a simple algorithm aimed at preserving olfaction and vision and based on maximizing use of minimally invasive approaches and selective use of transcranial approaches, the authors found that excellent outcomes can be achieved for anterior skull base meningiomas. PMID- 29606041 TI - Safe maximal resection of primary cavernous sinus meningiomas via a minimal anterior and posterior combined transpetrosal approach. AB - OBJECTIVE Meningiomas arising from the cavernous sinus (CS) continue to be a significant technical challenge, and resection continues to carry a relatively higher risk of neurological morbidity in patients with these lesions because of the tumor's proximity to neurovascular structures. The authors report the surgical outcomes of 9 patients with primary CS meningiomas (CSMs) that were surgically treated using a minimal anterior and posterior combined (MAPC) transpetrosal approach, and they emphasize the usefulness of the approach. METHODS This retrospective study included 9 patients who underwent surgery for CSM treatment between 2015 and 2016 via the MAPC transpetrosal approach. Two patients were men and 7 were women, with a mean age of 58.5 years (39-72 years). Five patients (55.5%) had undergone previous treatment. The surgical technique consisted of a temporo-occipito-suboccipital craniotomy and exposure of the posterolateral part of the CS via the presigmoidal MAPC approach. After opening Meckel's cave and identifying the 3rd-5th cranial nerves in the prepontine cistern, Parkinson's triangle and supratrochlear triangles were opened. Finally, the tumor occupying the posterolateral part of the CS was removed. RESULTS All lesions were safely and maximally removed, with preservation of external ocular movements and preoperative Karnofsky Performance Scale scores. The mean extent of resection was 77.0% (range 58.7%-95.4%). Six patients underwent adjuvant therapy in the form of stereotactic radiosurgery (SRS) or stereotactic radiotherapy (SRT) during the follow-up period; none of these patients experienced recurrence. CONCLUSION The authors conclude that the MAPC transpetrosal approach could be superior to other approaches for CSMs, as it provides direct visual access to the posterolateral portion of the CS. In their experience, this approach is an alternative and better option for safe maximal resection of CSMs. PMID- 29606043 TI - Erratum. Defining the minimum clinically important difference for grade I degenerative lumbar spondylolisthesis: insights from the Quality Outcomes Database. PMID- 29606042 TI - Surgical management of giant sphenoid wing meningiomas encasing major cerebral arteries. AB - OBJECTIVE Sphenoid wing meningiomas are a heterogeneous group of tumors with variable surgical risks and prognosis. Those that have grown to a very large size, encasing the major cerebral arteries, are associated with a high risk of stroke. In reviewing the authors' series of giant sphenoid wing meningiomas, the goal was to evaluate how the extent of the tumor's invasion of surrounding structures affected the ability to safely remove the tumor and restore function. METHODS The authors conducted a retrospective study of a series of giant sphenoid wing meningiomas operated on between 1996 and 2016. Inclusion criteria were meningiomas with a globoid component >= 6 cm, encasing at least 1 major intradural cerebral artery. Extent of resection was measured according to Simpson grade. RESULTS This series included 12 patients, with a mean age of 59 years. Visual symptoms were the most common clinical presentation. There was complete or partial encasement of all 3 major cerebral arteries except for 3 cases in which only the anterior cerebral artery was not involved. The lateral wall of the cavernous sinus was invaded in 8 cases (67%) and the optic canal in 6 (50%). Complete resection was achieved in 2 cases (Simpson grades 2 and 3). In the remaining 10 cases of partial resection (Simpson grade 4), radical removal (> 90%) was achieved in 7 cases (70%). In the immediate postoperative period, there were no deaths. Four of 9 patients with visual deficits improved, while the 5 others remained unchanged. Two patients experienced transient neurological deficits. Other than an asymptomatic lacuna of the internal capsule, there were no ischemic lesions following surgery. Tumor recurrence occurred in 5 patients, between 24 and 168 months (mean 61 months) following surgery. CONCLUSIONS Although these giant lesions encasing major cerebral arteries are particularly treacherous for surgery, this series demonstrates that it is possible to safely achieve radical removal and at times even gross-total resection. However, the risk of recurrence remains high and larger studies are needed to see if and how improvement can be achieved, whether in surgical technique or technological advances, and by determining the timing and modality of adjuvant radiation therapy. PMID- 29606044 TI - Impact of preoperative endovascular embolization on immediate meningioma resection outcomes. AB - OBJECTIVE Preoperative embolization of meningiomas can facilitate their resection when they are difficult to remove. The optimal use and timing of such a procedure remains controversial given the risk of embolization-linked morbidity in select clinical settings. In this work, the authors used a large national database to study the impact of immediate preoperative embolization on the immediate outcomes of meningioma resection. METHODS Meningioma patients who had undergone elective resection were identified in the National (Nationwide) Inpatient Sample (NIS) for the period 2002-2014. Patients who had undergone preoperative embolization were propensity score matched to those who had not, adjusting for patient and hospital characteristics. Associations between preoperative embolization and morbidity, mortality, and nonroutine discharge were investigated. RESULTS Overall, 27,008 admissions met the inclusion criteria, and 633 patients (2.34%) had undergone preoperative embolization and 26,375 (97.66%) had not. The embolization group was younger (55.17 vs 57.69 years, p < 0.001) with a lower proportion of females (63.5% vs 69.1%, p = 0.003), higher Charlson Comorbidity Index (p = 0.002), and higher disease severity (p < 0.001). Propensity score matching retained 413 embolization and 413 nonembolization patients. In the matched cohort, preoperative embolization was associated with increased rates of cerebral edema (25.2% vs 17.7%, p = 0.009), posthemorrhagic anemia or transfusion (21.8% vs 13.8%, p = 0.003), and nonroutine discharge (42.8% vs 35.7%, p = 0.039). There was no difference in mortality (<= 2.4% vs <= 2.4%, p = 0.82). Among the embolization patients, the mean interval from embolization to resection was 1.49 days. On multivariate analysis, a longer interval was significantly associated with nonroutine discharge (OR 1.33, p = 0.004) but not with complications or mortality. CONCLUSIONS Relative to meningioma patients who do not undergo preoperative embolization in the same admission, those who do have higher rates of cerebral edema and nonroutine discharge but not higher rates of stroke or death. Thus, meningiomas requiring preoperative embolization represent a distinct clinical entity that requires prolonged, more complex care. Further, among embolization patients, the timing of resection did not affect the risk of in hospital complications, suggesting that the timing of surgery can be determined according to surgeon discretion. PMID- 29606045 TI - Tuberculum sellae meningiomas: grading scale to assess surgical outcomes using the transcranial versus transsphenoidal approach. AB - OBJECTIVE Tuberculum sellae meningiomas (TSMs) are surgically challenging tumors that can severely impair vision. Debate exists regarding whether the transcranial (TC) or endoscopic transsphenoidal (TS) approach is best for resecting these tumors, and there are few large series comparing these approaches. METHODS A retrospective chart review was performed at 2 academic centers comparing TC and TS approaches with respect to vision, extent of resection, recurrence, and complications. The authors report surgical outcomes and propose a simple preoperative tumor grading scale that scores tumor size (1-2), optic canal invasion (0-2), and arterial encasement (0-2). The authors performed univariate, multivariate, and recursive partitioning analysis (RPA) to evaluate outcomes. RESULTS The TSMs were resected in 139 patients. The median follow-up was 29 months. Ninety-five (68%) cases were resected via a TC and 44 (32%) via a TS approach. Tumors treated via a TC approach had a higher tumor (p = 0.0007), artery (p < 0.0001), and total score (p = 0.0012) on the grading scale. Preoperative visual deficits were present in 87% of patients. Vision improved in 47%, stayed the same in 35%, declined in 10%, and was not recorded in 8%. The extent of resection was 65% gross-total resection, 23% near-total resection (95% 99% resection), and 12% subtotal resection (< 95%). A lower tumor score was significantly associated with better or stable vision postoperatively (p = 0.0052). The RPA confirmed low tumor score as the key predictor of postoperative visual improvement or stability. Multivariate analysis and RPA demonstrate that lower canal score (p < 0.0001) and TC approach (p = 0.0019) are associated with gross-total resection. Complications occurred in 20 (14%) patients, including CSF leak (5%) and infection (4%). There was no difference in overall complication rates between TC and TS approaches; however, the TS approach had more CSF leaks (OR 5.96, 95% CI 1.10-32.04). The observed recurrence rate was 10%, and there was no difference between the TC and TS approaches. CONCLUSIONS Tuberculum sellae meningiomas can be resected using either a TC or TS approach, with low morbidity and good visual outcomes in appropriately selected patients. The simple proposed grading scale provides a standard preoperative method to evaluate TSMs and can serve as a starting point for selection of the surgical approach. Higher scores were associated with worsened visual outcomes and subtotal resection, regardless of approach. The authors plan a multicenter review of this grading scale to further evaluate its utility. PMID- 29606046 TI - Preoperative embolization of skull base meningiomas: current indications, techniques, and pearls for complication avoidance. AB - Skull base meningiomas are technically challenging tumors to treat because of their deep vascular supply that can preclude early devascularization during resection. Preoperative embolization of these arterial feeders is thought to decrease blood loss and facilitate resection; however, given the complex and varied anatomy of these skull base lesions, preoperative embolization is not without risk. It is essential for both endovascular and skull base neurosurgeons to understand these risks in light of the potential benefits. The authors review the vascular anatomy of skull base meningiomas, indications for preoperative devascularization, endovascular techniques, and published results regarding embolization of these lesions. PMID- 29606047 TI - Multivariate risk factor analysis and literature review of postoperative deterioration in Karnofsky Performance Scale score in elderly patients with skull base meningioma. AB - OBJECTIVE Elderly patients are particularly at risk for severe morbidity following surgery. Among the various risk factors, age and skull base location of meningioma are known to be poor prognostic factors in meningioma surgery. The authors conducted this study to analyze significant preoperative risk factors in elderly patients with skull base meningioma. METHODS A total of 265 elderly patients (>= 65 years old) with meningioma were surgically treated at the authors' institute and affiliated hospitals between 2000 and 2016, and these cases were reviewed. Among them, 57 patients with skull base meningioma were evaluated. Among the various risk factors, the authors analyzed age, sex, Karnofsky Performance Scale (KPS) score, American Society of Anesthesiologists score, and tumor size, location, and pathology. Body mass index (BMI) and serum albumin were investigated as the frailty factors. The authors also reviewed 11 surgical studies of elderly patients >= 60 years old with meningioma. RESULTS The mean age was 72.4 +/- 5.7 years, and 42 patients were female (73.6%). The mean size of meningioma was 36.6 +/- 14.8 mm at the maximum diameter, and the mean follow-up period was 31.1 +/- 31.5 months. (The continuous variables are expressed as the mean +/- SD.) Histopathological investigation revealed a higher incidence (71.9%) of WHO Grade I. The rates of deterioration after surgery, at 3 months, and at 1 year were 33.3%, 37.3%, and 39.1%, respectively. Univariate analysis revealed location, preoperative KPS score, BMI level 2, and serum albumin level (p = 0.010, 0.017, 0.0012, and 0.0019, respectively) to be poor prognostic factors. Multivariate analysis revealed that location (p = 0.038) and BMI (p = 0.035) were risk factors for KPS score deterioration immediately after surgery. According to the 11 papers reviewed, the median rate (25th-75th percentile) of skull base-related location was 43.5% (39.6-47.75); for asymptomatic status the mean was 24%; and for mortality at 3 months and 1 year the medians were 6.3% (0.7-7.1) and 8% (4.8-9.4), respectively. CONCLUSION Careful preoperative assessment based on the frailty concept was essential for better outcome in elderly patients with skull base meningioma. The BMI is appropriate as a quantitative factor for measure of frailty, particularly in elderly individuals with skull base meningioma. Further prospective randomized controlled trials are necessary to validate frailty as a preoperative risk factor. Not only patient selection but also surgical timing was an important factor. PMID- 29606048 TI - Relationship between tumor location, size, and WHO grade in meningioma. AB - OBJECTIVE Prior studies have investigated preoperative risk factors for meningioma; however, no association has been shown between meningioma tumor size and tumor grade. The objective of this study was to investigate the relationship between tumor size and grade in a large single-center study of patients undergoing meningioma resection. METHODS A retrospective chart review of patients undergoing meningioma resection at the University of California, San Francisco, between 1985 and 2015 was performed. Patients with incomplete information, spinal meningiomas, multiple meningiomas, or WHO grade III meningiomas were excluded. The largest tumor dimension was used as a surrogate for tumor size. Univariate and multivariate logistic regression models were used to investigate the relationship between tumor grade and tumor size. A recursive partitioning analysis was performed to identify groups at higher risk for atypical (WHO grade II) meningioma. RESULTS Of the 1113 patients identified, 905 (81%) had a WHO grade I tumor and in 208 (19%) the tumors were WHO grade II. The median largest tumor dimension was 3.6 cm (range 0.2-13 cm). Tumors were distributed as follows: skull base (n = 573, 51%), convexity/falx/parasagittal (n = 431, 39%), and other (n = 109, 10%). On univariate regression, larger tumor size (p < 0.001), convexity/falx/parasagittal location (p < 0.001), and male sex (p < 0.001) were significant predictors of WHO grade II pathology. After controlling for interactions, multivariate regression found male sex (OR 1.74, 95% CI 1.25-2.43), size 3-6 cm (OR 1.69, 95% CI 1.08-2.66), size > 6 cm (OR 3.01, 95% CI 1.53-5.94), and convexity/falx/parasagittal location (OR 1.83, 95% CI 1.19-2.82) to be significantly associated with WHO grade II. Recursive partitioning analysis identified male patients with tumors > 3 cm as a high-risk group (32%) for WHO grade II meningioma. CONCLUSIONS Larger tumor size is associated with a greater likelihood of a meningioma being WHO grade II, independent of tumor location and male sex, which are known risk factors. PMID- 29606049 TI - Transbasal versus endoscopic endonasal versus combined approaches for olfactory groove meningiomas: importance of approach selection. AB - OBJECTIVE There has been much debate regarding the optimal surgical approach for resecting olfactory groove meningiomas (OGMs). In this paper, the authors analyzed the factors involved in approach selection and reviewed the surgical outcomes in a series of OGMs. METHODS A retrospective review of 28 consecutive OGMs from a prospective database was conducted. Each tumor was treated via one of 3 approaches: transbasal approach (n = 15), pure endoscopic endonasal approach (EEA; n = 5), and combined (endoscope-assisted) transbasal-EEA (n = 8). RESULTS The mean tumor volume was greatest in the transbasal (92.02 cm3) and combined (101.15 cm3) groups. Both groups had significant lateral dural extension over the orbits (transbasal 73.3%, p < 0.001; combined 100%), while the transbasal group had the most cerebral edema (73.3%, p < 0.001) and vascular involvement (66.7%, p < 0.001), and the least presence of a cortical cuff (33.3%, p = 0.019). All tumors in the combined group were recurrent tumors that invaded into the sinonasal cavity. The purely EEA group had the smallest mean tumor volume (33.33 cm3), all with a cortical cuff and no lateral dural extension. Gross-total resection was achieved in 80% of transbasal, 100% of EEA, and 62.5% of combined cases. Near-total resection (> 95%) was achieved in 20% of transbasal and 37.5% of combined cases, all due to tumor adherence to the critical neurovascular structures. The rate of CSF leakage was 0% in the transbasal and combined groups, and there was 1 leak in the EEA group (20%), resulting in an overall CSF leakage rate of 3.6%. Olfaction was preserved in 66.7% in the transbasal group. There was no significant difference in length of stay or 30-day readmission rate between the 3 groups. The mean modified Rankin Scale score was 0.79 after the transbasal approach, 2.0 after EEA, and 2.4 after the combined approach (p = 0.0604). The mean follow-up was 14.5 months (range 1-76 months). CONCLUSIONS The transbasal approach provided the best clinical outcomes with the lowest rate of complications for large tumors (> 40 mm) and for smaller tumors (< 40 mm) with intact olfaction. The role of EEA appears to be limited to smaller, appropriately selected tumors in which olfaction is already absent. EEA also plays an important adjunctive role when combined with the transbasal approach for recurrent OGMs invading the sinonasal cavity. Careful patient selection using an individualized, tailored strategy is important to optimize surgical outcomes. PMID- 29606050 TI - Pretemporal trans-Meckel's cave transtentorial approach for large petroclival meningiomas. AB - OBJECTIVE Despite the advances in skull base techniques, large petroclival meningiomas (PCMs) still pose a challenge to neurosurgeons. The authors' objective of this study was to describe a pretemporal trans-Meckel's cave transtentorial approach for large PCMs and to report the surgical outcomes. METHODS From 2014 to 2017, patients harboring large PCMs (> 3 cm) and undergoing their first resection via this procedure at the authors' institute were included. In combination with pretemporal transcavernous and anterior transpetrosal approaches, the trans-Meckel's cave transtentorial route was created. Surgical details are described and a video demonstrating the procedure is included. Retrospective review of the medical records and imaging studies was performed. RESULTS A total of 18 patients (6 men and 12 women) were included in this study, with mean age of 53 years. The mean sizes of the preoperative and postoperative PCMs were 4.36 cm * 4.09 cm * 4.13 cm (length * width * height) and 0.83 cm * 1.08 cm * 0.75 cm, respectively. Gross-total removal was performed in 7 patients, near-total removal (> 95%) in 7 patients, and subtotal removal in 4 patients (> 90% in 3 patients and > 85% in 1 patient). There were no surgical deaths or patients with postoperative hemiplegia. Surgical complications included transient cranial nerve (CN) III palsy (all patients, resolved in 3 months), transient CN VI palsy (2 patients), CN IV palsy (3 patients, partial recovery), hydrocephalus (3 patients), and CSF otorrhea (1 patient). Temporal lobe retraction-related neurological deficits were not observed. CONCLUSIONS A pretemporal trans-Meckel's cave transtentorial approach offers large surgical exposure and multiple trajectories to the suprasellar, interpeduncular, prepontine, and upper-half clival regions without overt traction, which is mandatory to remove large PCMs. To unlock Meckel's cave where a large PCM lies abutting the cave, pretemporal transcavernous and anterior transpetrosal approaches are prerequisites to create adequate exposure for the final trans-Meckel's cave step. PMID- 29606051 TI - Multistaged, multidirectional strategy for safe removal of large meningiomas in the pineal region. AB - OBJECTIVE Pineal region meningiomas are rare and tend to be discovered only after they grow. Several simultaneous multidirectional approaches performed as a single operation have been proposed, but the best strategy to remove these deeply situated large meningiomas involving the deep vital venous system remains to be established. The authors advocate a multistaged, multidirectional approach to safely remove these challenging tumors. METHODS Four consecutive cases of meningioma in the pineal region were treated between April 2013 and June 2016. The 3 large (> 40 mm diameter) tumors were removed via multistaged, multidirectional approaches (2 surgeries in 2 patients and 3 surgeries in 1 patient) with gravity retraction of the occipital or parietal lobe. The large occipital skin incision extending bilaterally was used for the next operation from the contralateral side. Combinations of the occipital transtentorial approach with or without the transfalcine approach, occipital bitranstentorial/falcine approach, combined supra-/infratentorial transsinus approach, and contralateral parietal interhemispheric transcallosal approach were used. RESULTS Transient visual field deficits occurred after 2 of the 8 operations, but all tumors were removed grossly or subtotally without permanent surgery-related morbidity. The galenic venous system and straight sinus remained intact in all patients. During the follow-up period (mean 29.5 months [range 13 52 months]), there were no recurrences after the final operation. CONCLUSIONS A multistaged, multidirectional strategy with an intentional large occipital scalp incision and gravity retraction of the occipital lobe is a good choice for the safe removal of large meningiomas in the pineal region. PMID- 29606052 TI - Medical management of meningioma in the era of precision medicine. AB - Surgery is curative for most meningiomas, but a minority of these tumors recur and progress after resection. Initial trials of medical therapies for meningioma utilized nonspecific cytotoxic chemotherapies. The presence of hormone receptors on meningioma ushered in trials of hormone-mimicking agents. While these trials expanded clinical understanding of meningioma, they ultimately had limited efficacy in managing aggressive lesions. Subsequent detection of misregulated proteins and genomic aberrancies motivated the study of therapies targeting specific biological disturbances observed in meningioma. These advances led to trials of targeted kinase inhibitors and immunotherapies, as well as combinations of these agents together with chemotherapies. Prospective trials currently recruiting participants are testing a diverse range of medical therapies for meningioma, and some studies now require the presence of a specific protein alteration or genetic mutation as an inclusion criterion. Increasing understanding of the unique and heterogeneous nature of meningiomas will continue to spur the development of novel medical therapies for the arsenal against aggressive tumors. PMID- 29606054 TI - Oral and Electronic Poster Presentations 2018 Lumbar Spine Research Society Annual Scientific Meeting. AB - Abstracts of the Oral and Electronic Poster Presentations 2018 Lumbar Spine Research Society Annual Scientific Meeting. PMID- 29606053 TI - High-grade meningiomas: biology and implications. AB - The epochal developments in the treatment of meningioma-microsurgery, skull base techniques, and radiation therapy-will be appended to include the rational application of targeted and immune therapeutics, previously ill-fitting concepts for a tumor that has traditionally been a regarded as a surgical disease. The genomic and immunological architecture of these tumors continues to be defined in ever-greater detail. Grade I meningiomas are driven by NF2 alterations or mutations in AKT1, SMO, TRAF7, PIK3CA, KLF4, POLR2A, SUFU, and SMARCB1. Higher grade tumors, however, are driven nearly exclusively by NF2/chr22 loss and are marked by infrequent targetable mutations, although they may harbor a greater mutation burden overall. TERT mutations may be more common in tumors that progress in histological grade; SMARCE1 alteration has become a signature of the clear cell subtype; and BAP1 in rhabdoid variants may confer sensitivity to pharmacological inhibition. Compared with grade I meningiomas, the most prominent alteration in grade II and III meningiomas is a significant increase in chromosomal gains and losses, or copy number alterations, which may have behavioral implications. Furthermore, integrated genomic analyses suggest phenotypic subgrouping by methylation profile and a specific role for PRC2 complex activation. Lastly, there exists a complex phylogenetic relationship among recurrent high-grade tumors, which continues to underscore a role for the most traditional therapy in our arsenal: surgery. PMID- 29606055 TI - Introduction. Skull base meningioma treatment strategies. PMID- 29606056 TI - Erratum. Ablative neurosurgery for mental disorders: is there still a role in the 21st century? A personal perspective. PMID- 29606057 TI - Longitudinal Patterns of Electronic Teen Dating Violence Among Middle School Students. AB - We investigated rates and developmental trends of electronic teen dating violence (TDV) perpetration and victimization overall and by gender. Data were collected from a single cohort of seventh-grade students from four schools using paper-and pencil surveys administered at 6-month intervals ( N = 795). Data were analyzed with descriptive statistics and longitudinal growth models to estimate change over time in TDV. Overall, 32% of youth reported electronic TDV perpetration, and 51% reported electronic TDV victimization. Victimization was more prevalent for boys (42%) than for girls (31%) at baseline only ( t = 2.55, p < .05). Perpetration did not differ at any wave. Perpetration and victimization each decreased significantly from the beginning of seventh grade to the end of eighth grade, beta = -.129 (.058), p < .05, for perpetration, and beta = -.138 (.048), p < .01, for victimization. Gender moderated the decrease in reported victimization, with simple slopes indicating girls showed almost no change in victimization, beta = .006 (.066), ns, whereas boys decreased significantly over the 2 years, beta = -.292 (.069), p < .001. Although moderation by gender of change in perpetration was not conventionally significant, the simple slopes revealed that girls again showed a nonsignificant change in TDV across seventh and eighth grades, beta = -.067 (.078), ns, whereas boys showed a significant decline in reported electronic TDV perpetration, beta = -.197 (.083), p < .05. The high prevalence of electronic TDV underscore the need for addressing these behaviors within TDV prevention interventions. PMID- 29606058 TI - Criminal Careers Among Female Perpetrators of Family and Nonfamily Homicide in Australia. AB - Knowledge of women's pathways to serious offending, including homicide, is limited. This study contributes to a small but growing body of literature examining the criminal careers of serious female offenders by using interview data with females convicted of murder or manslaughter in Australia to examine various dimensions of their criminal careers, specifically, prevalence, frequency, age of onset, duration, and offending variety. In particular, in this study we compared criminal career dimensions across women who had killed a family member (e.g., intimate partner, children) and those whose victims were not part of the family unit (i.e., acquaintances or strangers). Our findings reveal differences between female homicide offenders who kill within and outside of the family unit. Although both groups had comparable overall lifetime prevalence of self-reported participation in criminal offending, findings indicate that participation among the family group was typically at low levels of frequency, of limited duration, and with relatively little variety in categories of offending. The family group also reported lower contact with the criminal justice system compared with the nonfamily group, and were less likely to have experienced some form of criminal/legal sanction in the 12 months prior to the homicide incident. This suggests that women who kill family members are more "conventional" than their nonfamily counterparts, in terms of having low and time-limited (i.e., short duration) lifetime participation in criminal offending. PMID- 29606059 TI - A Qualitative Exploration of the Experiences of Veterans Who Are Serving Sentences in Custody. AB - The focus on veterans in research is not a novel topic; however, the majority of studies are related to trauma, employment, mental health, suicide, and substance misuse. The criminal justice system involvement with veterans is a topic that has yet to be examined to a great extent. This study, conducted with adult male prisoners, elicited information from six veterans regarding their experiences of being in the armed forces, leaving the armed forces, and becoming involved in the criminal justice system. Responses were evaluated using interpretative phenomenological analysis (IPA) and three main themes were identified: "you're baptized into the army," "them and us," and "operational mind-set"; each of which comprised a number of superordinate themes. The research highlights that although it is important to acknowledge the heterogenic nature of this group, it is equally important to note that much of their thinking and behavior may be similar to those that have not had these experiences. As such, there is a need to reduce the notion that they are separate and different to other prisoners, requiring different treatment. The study highlights that many of the offending behavior programs and interventions already available to prisoners would be appropriate for this group. The current research supports the merit in creating a service in prisons that will allow ex-servicemen to meet together and access the support that is available to them. The implications of the research are discussed further. PMID- 29606060 TI - The Brain Feels the Pain From Teenage Drinking. PMID- 29606062 TI - Increasing Male Preponderance in Suicide Coinciding With a Reduction by Half in Total Suicides in the Danish Population Should Raise Awareness of Male Depression. PMID- 29606063 TI - Contraceptive Conundrum: Use of Hormonal Contraceptives Is Associated With an Increased Risk of Suicide Attempt and Suicide. PMID- 29606064 TI - Ketamine: Quo Vadis? PMID- 29606065 TI - Disclosure of Editors' Financial Relationships. PMID- 29606066 TI - Substance-Induced Psychosis: An Indicator of Development of Primary Psychosis? PMID- 29606068 TI - Treatment for Patients With a Functional Neurological Disorder (Conversion Disorder): An Integrated Approach. PMID- 29606069 TI - The Cats of Louis Wain: A Thousand Ways to Draw One's Mind. PMID- 29606071 TI - Molecular Pathogenicity of Anti-NMDA Receptor Autoantibody From Patients With First-Episode Psychosis. PMID- 29606072 TI - Addressing Veteran Homelessness to Prevent Veteran Suicides. AB - The U.S. Department of Veterans Affairs (VA) is shifting its focus from ending veteran homelessness to preventing veteran suicides. With supporting data, this Open Forum argues that VA homelessness services also help address veteran suicides. Analysis of a nationally representative survey of U.S. veterans in 2015 shows that veterans with a history of homelessness attempted suicide in the previous two years at a rate >5.0 times higher compared with veterans without a history of homelessness (6.9% versus 1.2%), and their rates of two-week suicidal ideation were 2.5 times higher (19.8% versus 7.4%). Because the majority of veterans who die by suicide are not engaged in VA care, VA services for the homeless that include outreach efforts to engage new veterans may be reaching some of these veterans. Thus continued federal support for VA homelessness services not only may help address homelessness but also may help prevent suicide of veterans. PMID- 29606073 TI - Acceptability of Psychosis Screening and Factors Affecting Its Implementation: Interviews With Community Health Care Providers. AB - OBJECTIVE: Although screening for psychosis may reduce the duration of untreated psychosis, the barriers and facilitators associated with implementing such a procedure in various care settings have not been explored. METHODS: Investigators conducted in-depth, semistructured interviews with 17 members of school counseling services or community mental health staff at sites that administer a psychosis screening tool. Using an inductive approach to thematic analysis, they evaluated the acceptability of psychosis screening and barriers to and facilitators of implementation. RESULTS: Participants reported few barriers to implementation. However, several service-, client-, and program-level factors were considered to significantly affect the implementation of screening. Most participants found that using the screening tool did not significantly affect their overall workload. Facilitators included leadership support, the novelty of using a technology-based screener, regular staff training, and the importance of establishing an effective link between community services and specialty care, with these factors important at different stages of the process. Screening for psychosis was associated with significant advantages over referrals based on clinical judgment alone, including increased speed and accuracy of identification, increased confidence in diagnosis, and the provision of a clear pathway to specialty treatment. CONCLUSIONS: The experiences of school counseling and community mental health teams suggest that incorporating a technology-based screening procedure for early psychosis is feasible. Identifying barriers and facilitators at various stages of the screening procedure may reduce the dropout of clients potentially eligible for early psychosis care. PMID- 29606074 TI - Use of Security Officers on Inpatient Psychiatry Units. AB - OBJECTIVE: Violent and aggressive behaviors are common among psychiatric inpatients. Hospital security officers are sometimes used to address such behaviors. Research on the role of security in inpatient units is scant. This study examined when security is utilized and what happens when officers arrive. METHODS: The authors reviewed the security logbook and the medical records for all patients discharged from an inpatient psychiatry unit over a six-month period. Authors recorded when security calls happened, what behaviors triggered security calls, what outcomes occurred, and whether any patient characteristics were associated with security calls. RESULTS: A total of 272 unique patients were included. A total of 49 patients (18%) generated security calls (N=157 calls). Security calls were most common in the first week of hospitalization (N=45 calls), and roughly half of the patients (N=25 patients) had only one call. The most common inciting behavior was "threats to persons" (N=34 calls), and the most common intervention was intramuscular antipsychotic injection (N=49 calls). The patient variables associated with security calls were having more than one prior hospitalization (odds ratio [OR]=4.56, p=.001, 95% confidence interval [CI]=1.80 11.57), involuntary hospitalization (OR=5.09, p<.001, CI=2.28-11.33), and going to court for any reason (OR=5.80, p=.004, CI=1.75-19.15). CONCLUSIONS: Security officers were often called for threats of violence and occasionally called for actual violence. Patient variables associated with security calls are common among inpatients, and thus clinicians should stay attuned to patients' moment-to moment care needs. PMID- 29606075 TI - Psychotropic Medication Use Among Adults With Schizophrenia and Schizoaffective Disorder in the United States. AB - OBJECTIVE: The authors examined the use of different classes of psychotropic medication in outpatient treatment of schizophrenia and schizoaffective disorder. METHODS: Data from the United States Medicaid program were used to examine psychotropic medication use in a cohort of patients who had a diagnosis of schizophrenia or schizoaffective disorder in the calendar year 2010. RESULTS: The cohort of Medicaid recipients who filled one or more prescriptions for a psychotropic medication in 2010 included 116,249 patients classified as having schizophrenia and 84,537 classified as having schizoaffective disorder. During 2010, 86.1% of patients with schizoaffective disorder and 70.1% with schizophrenia were treated with two or more different classes of psychotropic. CONCLUSIONS: Psychotropic medications other than antipsychotics were commonly prescribed for individuals with a diagnosis of schizophrenia or schizoaffective disorder. Their widespread use and uncertainty about their net benefits signal a need for research on their efficacy, safety, and appropriate use in these conditions. PMID- 29606076 TI - Adapting Disclosure Programs to Reduce the Stigma of Mental Illness. AB - A 2016 report from the National Academy of Sciences describes strategies that reduce the stigma of mental illness. Prominent among these are contact between people with and without mental illness and strategic disclosure for lessening both public and self-stigma. The report also recognizes the complexity of stigma in the realm of psychiatric phenomena. As a socially constructed phenomenon, mental illness stigma intersects with race-ethnicity, gender, age, and sexual orientation to affect ways in which it is perceived and experienced. Stigma also differs by condition, such as mental illness versus substance use disorder. Hence, antistigma strategies need to actively incorporate diversity concerns into future adaptation. This Open Forum reviews adaptations of the Honest, Open, Proud (HOP) program to reflect adaptation challenges for age and condition. HOP is an evidence-based program that involves strategic disclosure to manage both self- and public stigma. This essay ends with consideration of the additional intersectionality challenges of adaptation. PMID- 29606077 TI - Implementation of a Lifestyle Intervention for People With Serious Mental Illness in State-Funded Mental Health Centers. AB - OBJECTIVE: The purpose of this study was to evaluate health outcomes of a state supported implementation in community mental health settings of an evidence-based lifestyle intervention for overweight and obese adults with serious mental illness. METHODS: Weight and fitness outcomes were evaluated for 122 overweight or obese adults with serious mental illness in four community mental health centers (CMHCs) that were participating in a phased statewide implementation of the In SHAPE lifestyle intervention. Six- and 12-month outcomes were compared between two CMHCs that implemented In SHAPE in the first 12 months and two CMHCs with similar characteristics that implemented In SHAPE in a subsequent phase in the statewide implementation 12 months later. RESULTS: Participants in the two In SHAPE sites (N=63 participants) lost significantly more weight (p=.003) and showed greater improvement in fitness (p=.011) compared with participants at the two usual care control sites (N=59 participants). At six months, nearly half (49%) of In SHAPE participants and at 12 months more than half (60%) of In SHAPE participants showed clinically significant cardiovascular risk reduction defined as >=5% weight loss or improved fitness (>50 m [164 feet] increase on the six minute walk test). The difference between the In SHAPE and control groups was not statistically significant. CONCLUSIONS: This natural experiment demonstrated promising public health benefits of a practical implementation of health promotion programming for overweight and obese adults with serious mental illness and offers a potential model for reducing risk of early mortality among individuals served by state-funded mental health centers nationwide. PMID- 29606079 TI - Oral Presentations 2018 AANS Annual Scientific Meeting. AB - Abstracts of the Oral Presentations 2018 AANS Annual Scientific Meeting. PMID- 29606078 TI - Risk Factors for Utilization of Acute Care Services for Lithium Toxicity. AB - OBJECTIVE: This study evaluated risk factors for utilization of acute care services (ACS) (hospitalization or emergency department or urgent care visit) for lithium toxicity and the prevalence of lithium toxicity in a large, ambulatory population. METHODS: A nested case-control study compared lithium users with ACS utilization for lithium toxicity (case group) to lithium users without toxicity (control group) by using data from Kaiser Permanente Colorado for patients with at least one lithium prescription purchase. Patients in the case group were matched 1:5 with patients in the control group who had purchased lithium within 39 days of the ACS encounter. Possible lithium toxicity, identified by lithium level or diagnosis, was confirmed by chart review. Multivariable, conditional logistic regression analysis was used to identify patient and prescription characteristics associated with ACS utilization for lithium toxicity. The prevalence of lithium toxicity was determined. RESULTS: Of 3,115 individuals who took lithium, 70 experienced lithium toxicity, with or without ACS utilization, for a prevalence of 2.2%. Identified risk factors for ACS utilization for lithium toxicity included a newly initiated potentially interacting medication (odds ratio [OR]=30.30, 95% confidence interval [CI]=2.32-394.95), a higher number of treated chronic diseases (OR=1.28, CI=1.12-1.45), older age (OR=1.05, CI=1.02 1.09), and higher total daily lithium dose (OR=1.00, CI=1.00-1.00). CONCLUSIONS: Newly initiated, potentially interacting medications are a major preventable driver of ACS use for lithium toxicity, whereas age, chronic disease, and total daily lithium dose are small but significant factors. Clinicians should use extra caution when initiating a potentially interacting medication. PMID- 29606080 TI - Optimization of a diagnostic platform for oxidation-reduction potential (ORP) measurement in human plasma. AB - OBJECTIVES: Oxidation-reduction potential (ORP) measurement can demonstrate the extent of oxidative stress in patients with severe illness and/or injury. A novel ORP diagnostic platform using disposable sensors (RedoxSYS) has been validated by comparison to mass spectrometry, but the optimal methods of sample handling for best performance of the device have not been described. METHODS: We sought to optimize ORP measurement in human plasma under controlled conditions. We hypothesized that the anticoagulant, freeze-thawing, and storage duration would influence measured ORP levels. RESULTS: The platform was sensitive to exogenous oxidation with hydrogen peroxide and reduction with ascorbic acid. Plasma anticoagulated with heparin was more sensitive to differences in ORP than plasma prepared in citrate. ORP measurements decreased slightly after a freeze-thaw cycle, but once frozen, ORP was stable for up to one month. DISCUSSION: We confirm that ORP detects oxidative stress in plasma samples. Optimal measurement of plasma ORP requires blood collection in heparin anticoagulant tubes and immediate analysis without a freeze-thaw cycle. PMID- 29606081 TI - Persistent anterograde amnesia due to the artery of Percheron occlusion: a case report. AB - Bilateral thalamic infarction involving the artery of Percheron (AOP) can cause diagnostic difficulties due to the varying clinical presentations. AOP infarcts presented with isolated memory impairment are not common and the factors affecting the persistence of memory disorders are still unknown. A 41-year-old male patient was hospitalized with acute unconsciousness. MRI disclosed bilateral paramedian thalamic infarction The patient had isolated memory deficit and his anterograde amnesia continued without any change in the past decade. More cases might answer the questions concerning the intra- and extra-thalamic structures responsible for the amnesic syndrome and the factors affecting the persistence of the symptoms. PMID- 29606082 TI - Worm wounding increases levels of pollen-related food allergens in soybean (Glycine max). AB - The levels of food allergens in worm-wounded or non-wounded green soybeans (edamame) and mature soybeans were investigated by immunoblotting and enzyme linked immunosorbent assay (ELISA), using allergen-specific antibodies. Non wounded and worm-wounded soybeans showed similar total protein profiles after Coomassie brilliant blue staining, but some protein bands were observed to have been changed by worm wounding. Immunoblotting with specific antibodies for major soybean allergens (Gly m 5, Gly m 6, Gly m Bd 30 K, and Kunitz soybean trypsin inhibitor) revealed that protein band profiles and intensities were not significantly changed by worm wounding. In contrast, levels of the pollen-related soybean allergens Gly m 4 and Gly m 3 were strongly increased by worm wounding in both green and mature soybeans, as detected by immunoblotting and ELISA. These results suggested that the pollen-related food allergen risk (i.e., oral allergy syndrome; OAS) from soybeans might be enhanced by worm wounding of soybeans. PMID- 29606083 TI - Carbohydrate-based heteronuclear complexes as topoisomerase Ialpha inhibitor: approach toward anticancer chemotherapeutics. AB - Due to the critical role of cellular enzymes necessary for cell proliferation by deciphering topological hurdles in the process of DNA replication, topoisomerases have been one of the major targets in the anticancer drug development area. A need, therefore, arises for new metallodrugs that specifically recognizes DNA and inhibits the activity of topoisomerase enzymes, herein, we report the synthesis and characterization of new metal-based glycoconjugate entities containing heterobimetallic core CuII-SnIV (1) and NiII-SnIV (2) derived from N-glycoside ligand (L). The optimized structure of complex 1 and other significant vibrational modes have been explained using dispersion corrected B3LYP/DFT calculations. In vitro DNA binding profile of the L and both the complexes 1 and 2 were done by various biophysical studies. Complex 1 breaks pBR322 DNA via a hydrolytic means which was validated by T4 DNA enzymatic assay. To get a mechanistic insight of mode of action topoisomerase I (Topo I) inhibition assay was carried out. Also, we have taken the help of molecular modeling studies in accordance with experimental findings. In vitro cytotoxicity of the complex 1 was evaluated against a panel of cancer cells which exhibited remarkably good anticancer activity (GI50 values <10 MUg/ml). Moreover, intracellular localization of the complex 1 was visualized by confocal microscopy against HeLa cells. PMID- 29606084 TI - Toward novel inhibitors against KdsB: a highly specific and selective broad spectrum bacterial enzyme. AB - KdsB (3-deoxy-manno-octulosonate cytidylyltransferase) is a highly specific and selective bacterial enzyme that catalyzes KDO (3-Deoxy-D-mano-oct-2-ulosonic acid) activation in KDO biosynthesis pathway. Failure in KDO biosynthesis causes accumulation of lipid A in the bacterial outer membrane that leads to cell growth arrest. This study reports a combinatorial approach comprising virtual screening of natural drugs library, molecular docking, computational pharmacokinetics, molecular dynamics simulation, and binding free energy calculations for the identification of potent lead compounds against the said enzyme. Virtual screening demonstrated 1460 druglike compounds in a total of 4800, while molecular docking illustrated Ser13, Arg14, and Asp236 as the anchor amino acids for recognizing and binding the inhibitors. Functional details of the enzyme in complex with the best characterized compound-226 were explored through two hundred nanoseconds of MD simulation. The ligand after initial adjustments jumps into the active cavity, followed by the deep cavity, and ultimately backward rotating movement toward the initial docked site of the pocket. During the entire simulation period, Asp236 remained in contact with the ligand and can be considered as a major catalytic residue of the enzyme. Radial distribution function confirmed that toward the end of the simulation, strengthening of ligand receptor occurred with ligand and enzyme active residues in close proximity. Binding free energy calculations via MM(PB/GB)SA and Waterswap reaction coordinates, demonstrated the high affinity of the compound for enzyme active site residues. These findings can provide new avenues for designing potent compounds against notorious bacterial pathogens. PMID- 29606086 TI - The Brazilian Public Health in Contemporary Capitalism. AB - This article examines some political and economic facts that led to an intensification of austerity measures by the Brazilian government, including ones against the Unified Health System (SUS) and its progressive dismantling. In a country where fundamental human rights were never fully respected, nowadays social and labor rights are under severe attacks. The deepening of the capital crisis and the rise of interest-bearing capital dominance have been causing unemployment, social insecurity growth, and resulting public fund appropriation by the private capital. The Brazilian governments in the 1990s and 2000s have implemented deeper cuts in social policy expenditure, freezing security benefits, privatizing services, and prioritizing the payment of public debt interests. The right wing's project involves the demoralization of not only the Workers' Party but also the left as a whole, so that the adoption of austerity measures could be achieved without popular resistance. It is the duty of the Brazilian left wing to denounce such a project and to provoke firm initiatives to rebuild its bonds with the working class. PMID- 29606085 TI - Racial/Ethnic Differences in Cognitive Symptoms During the Menopausal Transition. AB - The purpose of this study was to explore racial/ethnic differences in midlife women's cognitive symptoms among four major racial/ethnic groups in the United States and to determine multiple factors that influenced the women's cognitive symptoms. This was a secondary analysis of the data from two larger studies among 1,054 midlife women. The instruments included multiple questions on background characteristics and health and menopausal status, and the Cognitive Symptom Index for Midlife Women. The data were analyzed using multiple logistic and Poisson regression analyses. There existed significant racial/ethnic differences in the total numbers and total severity scores of cognitive symptoms ( p < .01); non Hispanic Asians had significantly lower total numbers and total severity scores compared with other racial/ethnic groups. Socioeconomic status and health and menopausal status were significant factors that influenced cognitive symptoms across racial/ethnic groups ( p < .05). Further studies on racial/ethnic differences in cognitive symptoms are needed with diverse groups of midlife women. PMID- 29606087 TI - The double-stranded DNA stability in presence of a flexible polymer. AB - The mixture of the short segments of double-stranded DNA and a flexible polymer are addressed. It is shown that in the condensed phase, rigid DNA molecules exhibit transition between isotropic and orientationally ordered phases. It is shown that orientational ordering stabilizes the secondary structure of double stranded DNA that could be relevant for the regulation of the gene expression at the condensed state of DNA. PMID- 29606088 TI - Prevalence of hepatitis B virus, hepatitis C virus, human immunodeficiency virus and Treponema pallidum infections in hospitalized patients before transfusion in Xiangya hospital Central South University, China from 2011 to 2016. AB - BACKGROUND: Human immunodeficiency virus (HIV), hepatitis B virus (HBV), hepatitis C virus (HCV) and Treponema pallidum (TP) infections are considered classic transfusion-transmissible infections (TTIs). Few data are available about the prevalence of TTIs in patients before blood transfusion in China. This study aimed to investigate the seroprevalence of four TTIs among patients before blood transfusion in Xiangya Hospital Central South University, China. METHODS: From 2011 to 2016, 442,121 hospitalized patients before possible blood transfusion were tested for hepatitis B surface antigen (HBsAg), anti-HCV, syphilis antibody (anti-TP) and anti-HIV. RESULTS: Of the 442,121 patients, the overall positivity of the four TTI serum markers was 15.35%. The positive rates of HBsAg, anti-HCV, anti-HIV and anti-TP were 10.98, 1.43, 0.16 and 2.78%, respectively. TTI serum markers showed a significant difference by gender, with positive rates of 17.98% for males and 12.79% for females. The prevalence of TTI serum markers varied significantly by age. The overall co-infection rate was 0.63%, and the top three multiple infections were HBV-TP, HBV-HCV, and HCV-TP. The co-infection rates of HBV-TP and HBV-HCV showed a significant decrease from 2011 to 2016, while the rates of other co-infections remained stable. CONCLUSIONS: The prevalence of TTIs in patients before blood transfusion is much higher compared to that in blood donors in the region. The infection rates of HIV and TP increased, and the infection rate of HBsAg decreased in recent years. PMID- 29606089 TI - iTRAQ-based quantitative proteomic analysis reveals the lateral meristem developmental mechanism for branched spike development in tetraploid wheat (Triticum turgidum L.). AB - BACKGROUND: Spike architecture mutants in tetraploid wheat (Triticum turgidum L., 2n = 28, AABB) have a distinct morphology, with parts of the rachis node producing lateral meristems that develop into ramified spikelete (RSs) or four rowed spikelete (FRSs). The genetic basis of RSs and FRSs has been analyzed, but little is known about the underlying developmental mechanisms of the lateral meristem. We used isobaric tags for relative and absolute quantitation (iTRAQ) to perform a quantitative proteomic analysis of immature spikes harvested from tetraploid near-isogenic lines of wheat with normal spikelete (NSs), FRSs, and RSs and investigated the molecular mechanisms of lateral meristem differentiation and development. This work provides valuable insight into the underlying functions of the lateral meristem and how it can produce differences in the branching of tetraploid wheat spikes. RESULTS: Using an iTRAQ-based shotgun quantitation approach, 104 differential abundance proteins (DAPs) with < 1% false discovery rate (FDR) and a 1.5-fold change (> 1.50 or < 0.67) were identified by comparing FRS with NS and RS with NS genotypes. To determine the functions of the proteins, 38 co-expressed DAPs from the two groups were annotated using the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analytical tools. We discovered that proteins involved in "post-embryonic development" and "metabolic pathways" such as carbohydrate and nitrogen metabolism could be used to construct a developmentally associated network. Additionally, 6 out of 38 DAPs in the network were analyzed using quantitative real-time polymerase chain reaction, and the correlation coefficient between proteomics and qRT-PCR was 0.7005. These key genes and proteins were closely scrutinized and discussed. CONCLUSIONS: Here, we predicted that DAPs involved in "post-embryonic development" and "metabolic pathways" may be responsible for the spikelete architecture changes in FRS and RS. Furthermore, we discussed the potential function of several vital DAPs from GO and KEGG analyses that were closely related to histone modification, ubiquitin mediated protein degradation, transcription factors, carbohydrate and nitrogen metabolism and heat shock proteins (HSPs). This work provides valuable insight into the underlying functions of the lateral meristem in the branching of tetraploid wheat spikes. PMID- 29606090 TI - Application of intraoperative lung-protective ventilation varies in accordance with the knowledge of anaesthesiologists: a single-Centre questionnaire study and a retrospective observational study. AB - BACKGROUND: The benefits of lung-protective ventilation (LPV) with a low tidal volume (6 mL/kg of ideal body weight [IBW]), limited plateau pressure (< 28-30 cm H2O), and appropriate positive end-expiratory pressure (PEEP) in patients with acute respiratory distress syndrome have become apparent and it is now widely adopted in intensive care units. Recently evidence for LPV in general anaesthesia has been accumulated, but it is not yet generally applied by anaesthesiologists in the operating room. METHODS: This study investigated the perception about intraoperative LPV among 82 anaesthesiologists through a questionnaire survey and identified the differences in ventilator settings according to recognition of lung-protective ventilation. Furthermore, we investigated the changes in the trend for using this form of ventilation during general anaesthesia in the past 10 years. RESULTS: Anaesthesiologists who had received training in LPV were more knowledgeable about this approach. Anaesthesiologists with knowledge of the concept behind LPV strategies applied a lower tidal volume (median (IQR [range]), 8.2 (8.0-9.2 [7.1-10.3]) vs. 9.2 (9.1-10.1 [7.6-10.1]) mL/kg; p = 0.033) and used PEEP more frequently (69/72 [95.8%] vs. 5/8 [62.5%]; p = 0.012; odds ratio, 13.8 [2.19-86.9]) for laparoscopic surgery than did those without such knowledge. Anaesthesiologists who were able to answer a question related to LPV correctly (respondents who chose 'height' to a multiple choice question asking what variables should be considered most important in the initial setting of tidal volume) applied a lower tidal volume in cases of laparoscopic surgery and obese patients. There was an increase in the number of patients receiving LPV (VT < 10 mL/kgIBW and PEEP >=5 cm H2O) between 2004 and 2014 (0/818 [0.0%] vs. 280/818 [34.2%]; p < 0.001). CONCLUSIONS: Our study suggests that the knowledge of LPV is directly related to its implementation, and can explain the increase in LPV use in general anaesthesia. Further studies should assess the impact of using intraoperative LPV on clinical outcomes and should determine the efficacy of education on intraoperative LPV implementation. PMID- 29606091 TI - A cross-sectional study of tuberculosis drug resistance among previously treated patients in a tertiary hospital in Accra, Ghana: public health implications of standardized regimens. AB - BACKGROUND: Mycobacterium tuberculosis drug resistance is a major challenge to the use of standardized regimens for tuberculosis (TB) therapy, especially among previously treated patients. We aimed to investigate the frequency and pattern of drug resistance among previously treated patients with smear-positive pulmonary tuberculosis at the Korle-Bu Teaching Hospital Chest Clinic, Accra. METHODS: This was a cross-sectional survey of mycobacterial isolates from previously treated patients referred to the Chest Clinic Laboratory between October 2010 and October 2013. The Bactec MGIT 960 system for mycobactrerial culture and drug sensitivity testing (DST) was used for sputum culture of AFB smear-positive patients with relapse, treatment failure, failure of smear conversion, or default. Descriptive statistics were used to summarize patient characteristics, and frequency and patterns of drug resistance. RESULTS: A total of 112 isolates were studied out of 155 from previously treated patients. Twenty contaminated (12.9%) and 23 non viable isolates (14.8%) were excluded. Of the 112 studied isolates, 53 (47.3%) were pan-sensitive to all first-line drugs tested Any resistance (mono and poly resistance) to isoniazid was found in 44 isolates (39.3%) and any resistance to streptomycin in 43 (38.4%). Thirty-one (27.7%) were MDR-TB. Eleven (35.5%) out of 31 MDR-TB isolates were pre-XDR. MDR-TB isolates were more likely than non-MDR isolates to have streptomycin and ethambutol resistance. CONCLUSIONS: The main findings of this study were the high prevalence of MDR-TB and streptomycin resistance among previously treated TB patients, as well as a high prevalence of pre-XDR-TB among the MDR-TB patients, which suggest that first-line and second line DST is essential to aid the design of effective regimens for these groups of patients in Ghana. PMID- 29606092 TI - RNA-Seq analysis validates the use of culture-derived Trypanosoma brucei and provides new markers for mammalian and insect life-cycle stages. AB - BACKGROUND: Trypanosoma brucei brucei, the parasite causing Nagana in domestic animals, is closely related to the parasites causing sleeping sickness, but does not infect humans. In addition to its importance as a pathogen, the relative ease of genetic manipulation and an innate capacity for RNAi extend its use as a model organism in cell and infection biology. During its development in its mammalian and insect (tsetse fly) hosts, T. b. brucei passes through several different life cycle stages. There are currently four life-cycle stages that can be cultured: slender forms and stumpy forms, which are equivalent to forms found in the mammal, and early and late procyclic forms, which are equivalent to forms in the tsetse midgut. Early procyclic forms show coordinated group movement (social motility) on semi-solid surfaces, whereas late procyclic forms do not. RESULTS: RNA-Seq was performed on biological replicates of each life-cycle stage. These constitute the first datasets for culture-derived slender and stumpy bloodstream forms and early and late procyclic forms. Expression profiles confirmed that genes known to be stage-regulated in the animal and insect hosts were also regulated in culture. Sequence reads of 100-125 bases provided sufficient precision to uncover differential expression of closely related genes. More than 100 transcripts showed peak expression in stumpy forms, including adenylate cyclases and several components of inositol metabolism. Early and late procyclic forms showed differential expression of 73 transcripts, a number of which encoded proteins that were previously shown to be stage-regulated. Moreover, two adenylate cyclases previously shown to reduce social motility are up-regulated in late procyclic forms. CONCLUSIONS: This study validates the use of cultured bloodstream forms as alternatives to animal-derived parasites and yields new markers for all four stages. In addition to underpinning recent findings that early and late procyclic forms are distinct life-cycle stages, it could provide insights into the reasons for their different biological properties. PMID- 29606093 TI - DNA Methylation variability among individuals is related to CpGs cluster density and evolutionary signatures. AB - BACKGROUND: In recent years, epigenetics has gained a central role in the understanding of the process of natural selection. It is now clear how environmental impacts on the methylome could promote methylation variability with direct effects on disease etiology as well as phenotypic and genotypic variations in evolutionary processes. To identify possible factors influencing inter individual methylation variability, we studied methylation values standard deviation of 166 healthy individuals searching for possible associations with genomic features and evolutionary signatures. RESULTS: We analyzed methylation variability values in relation to CpG cluster density and we found a strong association between them (p-value < 2.2 * 10- 16). Furthermore, we found that genes related to CpGs with high methylation variability values were enriched for immunological pathways; instead, those associated with low ones were enriched for pathways related to basic cellular functions. Finally, we found an association between methylation variability values and signals of both ancient (p-value < 2.2 * 10- 16) and recent selective pressure (p-value < 1 * 10- 4). CONCLUSION: Our results indicate the presence of an intricate interplay between genetics, epigenetic code and evolutionary constraints in humans. PMID- 29606094 TI - Can increased vigilance for chronic kidney disease in hospitalised patients decrease late referral and improve dialysis-free survival? AB - BACKGROUND: Insufficient vigilance for renal insufficiency is associated with late referral, increased morbidity and mortality. The present study examines whether increased vigilance for chronic kidney disease (CKD) leads to quicker referral to and better follow-up by a nephrologist, and whether it is associated with an improved outcome. METHODS: Patients with an eGFR < 45 ml/min/1.73 m2 during hospitalisation at the Ghent University Hospital were enrolled during a period of 100 days. The patients were interviewed about their awareness of CKD. Both the patients and their general practitioner were subsequently informed about CKD. The primary endpoint was the number of patients referred for nephrological follow-up within three months. The secondary endpoint was need for dialysis and mortality from any cause one year after inclusion. RESULTS: Of the 72 included patients, 54 had proven CKD, with eGFR consistently < 45 ml/min/1.73 m2 during at least three months before inclusion. Merely 65% was aware of having CKD and only 41% was in regular nephrological follow-up. After intervention, the percentage of patients with CKD in follow-up increased from 41% to 71% (p = 0.002). The proportion reaching the secondary endpoint was significant lower in the patients who were referred quickly than in those who were not (p = 0.015). Similarly, the proportion was significant lower in the patients who received nephrological follow-up than in those who did not (p = 0.006). CONCLUSION: Vigilance for CKD is poor. Simple interventions to augment the vigilance for CKD, as presented in this study, lead to a quicker referral to and follow-up by a nephrologist, which may result in better outcome. PMID- 29606095 TI - Molecular epidemiology and temporal evolution of norovirus associated with acute gastroenteritis in Amazonas state, Brazil. AB - BACKGROUND: Globally, Norovirus (NoV) is considered the most common cause of diarrheal episodes across all age groups. Despite its wide genetic diversity, the GII.4 strain is the most predominant and has been associated with epidemics worldwide. In this study, we characterized sporadic cases of diarrhea from NoV positive children, during a five-year period (2010-2014). METHODS: A total of 250 NoV-positive samples identified by an enzyme immunoassay (EIA) were subjected to RT-PCR and partial nucleotide sequencing for polymerase and capsid genes. Phylogenetic analysis was performed to identify NoV genotypes using the binary classification. In addition, sequences from the P2 subdomain (capsid) gene of GII 4 variants were characterized by evolutionary analyses, using the MCMC method implemented in the BEAST package. A 3D structure was built using protein modeling. RESULTS: Phylogenetic analysis demonstrated a predominance of genotype GII.4 (52.4% - 99/189), variants New Orleans_2009 and Sydney_2012 followed by GII.P7/GII.6 with 6.3% (12/189). Amino acid analyses of the GII.4 strains showed several important amino acid changes. A higher evolutionary rate was found, 7.7 * 10- 3 in the Sydney variant and 6.3 * 10- 3 in the New Orleans. Based in evolutionary analysis the time to the most recent common ancestor (TMRCA) has been calculated as estimates of the population divergence time. Thus, TMRCA for New Orleans and Sydney variant were 2008.7 and 2010.7, respectively. Also, we observed a lineage of transition between New Orleans and Sydney. CONCLUSION: This study describes the different strains of norovirus isolated from Amazonas state in Brazil during a five-year period. Considering that NoV are capable of changing their antigenic epitopes rapidly, a continuous surveillance is important to monitor the occurrence and changes of the NoV in the community through epidemiological studies. These results contribute to the understanding of NoV molecular epidemiology and its evolutionary dynamics in Amazonas state, Brazil. PMID- 29606096 TI - Hypoxia leads to significant changes in alternative splicing and elevated expression of CLK splice factor kinases in PC3 prostate cancer cells. AB - BACKGROUND: Mounting evidence suggests that one of the ways that cells adapt to hypoxia is through alternative splicing. The aim of this study was firstly to examine the effect of hypoxia on the alternative splicing of cancer associated genes using the prostate cancer cell line PC3 as a model. Secondly, the effect of hypoxia on the expression of several regulators of splicing was examined. METHODS: PC3 cells were grown in 1% oxygen in a hypoxic chamber for 48 h, RNA extracted and sent for high throughput PCR analysis at the RNomics platform at the University of Sherbrooke, Canada. Genes whose exon inclusion rate PSI (psi) changed significantly were identified, and their altered exon inclusion rates verified by RT-PCR in three cell lines. The expression of splice factors and splice factor kinases in response to hypoxia was examined by qPCR and western blotting. The splice factor kinase CLK1 was inhibited with the benzothiazole TG003. RESULTS: In PC3 cells the exon inclusion rate PSI (psi) was seen to change by > 25% in 12 cancer-associated genes; MBP, APAF1, PUF60, SYNE2, CDC42BPA, FGFR10P, BTN2A2, UTRN, RAP1GDS1, PTPN13, TTC23 and CASP9 (caspase 9). The expression of the splice factors SRSF1, SRSF2, SRSF3, SAM68, HuR, hnRNPA1, and of the splice factor kinases SRPK1 and CLK1 increased significantly in hypoxia. We also observed that the splice factor kinase CLK3, but not CLK2 and CLK4, was also induced in hypoxic DU145 prostate, HT29 colon and MCF7 breast cancer cell lines. Lastly, we show that the inhibition of CLK1 in PC3 cells with the benzothiazole TG003 increased expression of the anti-apoptotic isoform caspase 9b. CONCLUSIONS: Significant changes in alternative splicing of cancer associated genes occur in prostate cancer cells in hypoxic conditions. The expression of several splice factors and splice factor kinases increases during hypoxia, in particular the Cdc like splice factor kinases CLK1 and CLK3. We suggest that in hypoxia the elevated expression of these regulators of splicing helps cells adapt through alternative splicing of key cancer-associated genes. We suggest that the CLK splice factor kinases could be targeted in cancers in which hypoxia contributes to resistance to therapy. PMID- 29606097 TI - Mucopolysaccharidosis IIIB and mild skeletal anomalies: coexistence of NAGLU and CYP26B1 missense variations in the same patient in a Chinese family. AB - BACKGROUND: Sanfilippo type B syndrome (mucopolysac-charidosis type IIIB; MPS IIIB) is an autosomal recessive lysosomal storage disorder. It is caused by a critically reduced alpha-2-acetamido-2-deoxy-D-glucoside acetamidodeoxy glucohydrolase (alpha-N-acetylglucosaminidase or NAGLU) activity. Recently, an autosomal recessive disorder of skeletal dysplasia associated with CYP26B1 was reported in three families, in which the patients were all homozygous variations. However, the co-occurrence of two rare diseases in a person is very rare. Here, we reported one patient with two novel pathogenic missense variations in NAGLU and CYP26B1. CASE PRESENTATION: We found an infant with biallelic variation both in NAGLU-compound heterozygous c.1843C > T (p. R615C) and c.1224C > A (p. H408Q) as well as in CYP26B1-compound heterozygous c.529G > A (p. E177K) and c.525C > A (p. H175Q). All variations were novel but predicted pathogenicity according to American College of Medical Genetics and Genomics (ACMG) guidelines. The main phenotypes of the infant were quite different from those previously reported, and some were combinations of the two rare diseases, including epilepsy, early onset epileptic encephalopathy, hypermyotonia, skull deformity, dilatation of the lateral ventricles and premature closure of fontanel. His NAGLU enzyme activity was significantly decreased. CONCLUSIONS: NAGLU and CYP26B1 mutations were related to MPS IIIB and skeletal dysplasia, respectively. Here, we first reported the pathogenic mutations of two genes concurrent in one patient, which not only expands the phenotype and genotype spectra of NAGLU and CYP26B1, but more importantly indicates the possibility of simultaneous occurrence of two rare diseases in one patient. This interesting finding should be attributed to the use of whole exome sequencing (WES), which indicates that we should be aware of the importance of WES in diagnosing rare diseases. PMID- 29606098 TI - Learning from errors: assessing final year medical students' reflection on safety improvement, five year cohort study. AB - BACKGROUND: Investigation of real incidents has been consistently identified by expert reviews and student surveys as a potentially valuable teaching resource for medical students. The aim of this study was to adapt a published method to measure resident doctors' reflection on quality improvement and evaluate this as an assessment tool for medical students. METHODS: The design is a cohort study. Medical students were prepared with a tutorial in team based learning format and an online Managing Incident Review course. The reliability of the modified Mayo Evaluation of Reflection on Improvement tool (mMERIT) was analysed with Generalizability G-theory. Long term sustainability of assessment of incident review with mMERIT was tested over five consecutive years. RESULTS: A total of 824 students have completed an incident review using 167 incidents from NHS Tayside's online reporting system. In order to address the academic practice gap students were supervised by Senior Charge Nurses or Consultants on the wards where the incidents had been reported. Inter-rater reliability was considered sufficiently high to have one assessor for each student report. There was no evidence of a gradient in student marks across the academic year. Marks were significantly higher for students who used Section Questions to structure their reports compared with those who did not. In Year 1 of the study 21 (14%) of 153 mMERIT reports were graded as concern. All 21 of these students achieved the required standard on resubmission. Rates of resubmission were lower (3% to 7%) in subsequent years. CONCLUSIONS: We have shown that mMERIT has high reliability with one rater. mMERIT can be used by students as part of a suite of feedback to help supplement their self-assessment on their learning needs and develop insightful practice to drive their development of quality, safety and person centred professional practice. Incident review addresses the need for workplace based learning and use of real life examples of mistakes, which has been identified by previous studies of education about patient safety in medical schools. PMID- 29606099 TI - Unexpected conservation of the RNA splicing apparatus in the highly streamlined genome of Galdieria sulphuraria. AB - BACKGROUND: Genome reduction in intracellular pathogens and endosymbionts is usually compensated by reliance on the host for energy and nutrients. Free-living taxa with reduced genomes must however evolve strategies for generating functional diversity to support their independent lifestyles. An emerging model for the latter case is the Rhodophyta (red algae) that comprises an ecologically widely distributed, species-rich phylum. Red algae have undergone multiple phases of significant genome reduction, including extremophilic unicellular taxa with limited nuclear gene inventories that must cope with hot, highly acidic environments. RESULTS: Using genomic data from eight red algal lineages, we identified 155 spliceosomal machinery (SM)-associated genes that were putatively present in the red algal common ancestor. This core SM gene set is most highly conserved in Galdieria species (150 SM genes) and underwent differing levels of gene loss in other examined red algae (53-145 SM genes). Surprisingly, the high SM conservation in Galdieria sulphuraria coincides with the enrichment of spliceosomal introns in this species (2 introns/gene) in comparison to other red algae (< 0.34 introns/gene). Spliceosomal introns in G. sulphuraria undergo alternatively splicing, including many that are differentially spliced upon changes in culture temperature. CONCLUSIONS: Our work reveals the unique nature of G. sulphuraria among red algae with respect to the conservation of the spliceosomal machinery and introns. We discuss the possible implications of these findings in the highly streamlined genome of this free-living eukaryote. PMID- 29606100 TI - Intimate relationship characteristics as determinants of HIV risk among men who have sex with regular male sex partners: a cross-sectional study in Guangzhou, China. AB - BACKGROUND: China faces a serious HIV epidemic among men who have sex with men (MSM), and a large proportion of new infections are attributed to their regular male sex partners (RP). The objective of this study was to investigate the association between intimate relationship characteristics and HIV-related behaviors among MSM with RP in Guangzhou, China. METHODS: A convenience-sampling method was used in data collection. A total of 608 MSM were screened, of whom 406 HIV negative MSM with at least one RP in the past six months were used for data analysis. Three-step logistic regressions were used to analyze the data. RESULTS: The prevalence of unprotected anal intercourse (UAI) with regular male sex partners, non-regular male sex partners, and concurrent UAI in the past six months was 53.9%, 23.6%, 20.7%, respectively. Variables associated with UAI with regular male sex partners included expectations for this relationship (adjusted odds ratio in multiple forward stepwise logistic regression, ORm = 1.66) and open communication about the sexual relationship (ORm = 1.79), while expectations for the relationship (ORm = 0.46 to 0.54) and conflicts of interest (ORm = 5.46 to 5.97) were associated with concurrent UAI and UAI with non-regular male sex partners. CONCLUSION: Intimate relationship characteristics were related to HIV related risk behaviors. Future HIV prevention interventions should take MSM couples into consideration, include a focus on the quality of their intimate relationships, and encourage open communication about their sexual relationships. PMID- 29606101 TI - Validation of the Taiwan Chinese version of the EORTC QLQ-CR29 to assess quality of life in colorectal cancer patients. AB - BACKGROUND: The increasing incidence of colorectal cancer in Taiwan has generated a need for a disease-specific quality-of-life measuring instrument. We aimed to validate the Taiwan Chinese version of the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30 and QLQ-CR29. METHODS: A total of 108 patients were interviewed. Convergent and discriminant validity, Cronbach's alpha coefficient, test-retest reliability, and known-groups comparisons were used to examine the reliability and validity. RESULTS: We found good internal consistency reliability for multi-item scales of the QLQ-C30 and QLQ-CR29, except for the cognitive function and pain scale of the QLQ-C30. Patients in the active treatment group reported compromised functional scale scores (global health status/quality of life, QLQ-C30) and worse symptoms (blood and mucus in stool, QLQ-CR29) than those in the follow-up group. Similar results were found in comparisons based on Eastern Cooperative Oncology Group (ECOG) Performance Status and Bristol Stool Scale: higher physical function/sexual interest, less fatigue/urine frequency symptoms for patients with the lowest ECOG Performance Status (Grade 0), and borderline worse stool frequency scores from Types 5 and 6 patients on the Bristol Stool Scale. CONCLUSION: The study validated the Taiwan Chinese version of the EORTC QLQ-C30 and QLQ-CR29. The clinical applicability warrants further studies with greater number of participants. PMID- 29606102 TI - The performance of rapid plasma reagin (RPR) titer in HIV-negative general paresis after neurosyphilis therapy. AB - BACKGROUND: Repeated nontreponemal serologic test for syphilis titers is recommended to evaluate treatment response. However, it is unknown whether serum rapid plasma reagin (RPR) titer can serve as a surrogate for determining the efficacy of treatment in general paresis (GP) remains unknown. METHODS: We retrospectively reviewed data from 105 GP patients, who were divided into two groups (62 CSF RPR+ patients and 43 CSF RPR- patients) according to reactive RPR test status in CSF. Clinical assessment included the Mini-Mental State Examination (MMSE) scores, CSF examinations (WBC count, protein concentration and RPR titer), and serum tests (RPR titer and TPPA). Among the 105 GP patients, 13 CSF RPR+ patients and 6 CSF RPR- patients had a 12 months follow-up of CSF, serum measures and MMSE. RESULTS: The median serum RPR titer was significantly higher in CSF RPR+ patients than that in CSF RPR- GP patients, 1:8 [IQR 1:4-1:32] vs. 1:4 [IQR 1:4-1:8] (P < 0.001). The number of CSF RPR+ patients with serum RPR titer>=1:32 was significantly higher when compared with CSF RPR- patients (P = 0.001). For CSF RPR+ patients, the MMSE scores improved or remained constantly after penicillin treatment. For CSF RPR+ patients, the CSF RPR titer declined four-fold in 85% (11/13) of the patients, whereas the serum RPR titer declined four-fold in only 46% (6/13) of the patients, the odds ratio is 6.4 (95% confidence interval 1.0-41.2). CONCLUSIONS: A four-fold decline in CSF RPR titer is a good predictor for treatment efficacy in CSF RPR+ GP patients within 12 months after the completion of therapy. PMID- 29606103 TI - Study design and baseline characteristics of a combined educational and environmental intervention trial to lower sodium intake in Swiss employees. AB - BACKGROUND: Blood pressure is a primary cardiovascular disease risk factor. Population-wide governmental strategies aim to reduce lifestyle and dietary risk factors for hypertension, one of which is an unbalanced diet with high sodium and low potassium intakes. Nutrition interventions in the workplace are considered a promising approach in encouraging health-promoting behaviors. We developed and conducted the health promoting sodium reduction trial "Healthful & Tasty: Sure!" in worksites in the German-speaking part of Switzerland from May 2015 to Nov 2016, for which we present the study protocol and baseline characteristics. METHODS: Healthful & Tasty, a cluster nonrandomized single-arm trial with calibration arm, aimed to demonstrate the effectiveness of a combined educational and environmental intervention in the workplace in reducing employees' average daily sodium/salt intake by 15%. To this end, health and food literacy of employees and guideline compliance among the catering facility team needed to be improved. The primary outcome measure was sodium/salt intake estimated from sodium excretion in a 24-h urine sample. Secondary outcome measures included changes in the overall qualitative diet composition, blood pressure, anthropometric indices, and health and food literacy. Of eight organizations with catering facilities, seven organizations took part in the nutrition education and catering salt reduction interventions, and one organization participated as a control. Overall, 145 consenting employees were included in the staggered, one year four-phase trial, of which 132 participated in the intervention group. In addition to catering surveys and food sampling, the trial included five follow-up health assessments including questionnaires, blood pressure measurements, anthropometrics, and sodium, potassium, and iodine intake measurements obtained from 24-h and spot urine samples, and a food record checklist. Exploratory and hypothesis generating baseline statistical analysis included 141 participants with adequate 24-h urine samples. DISCUSSION: Despite practice-driven limitations to the study design and small cluster and participant numbers, this trial has methodological strength and will provide important insights into the effectiveness of a combined educational and environmental intervention to reduce salt intake among female and male Swiss employees. TRIAL REGISTRATION: German Clinical Trials Register, DRKS00006790 . Registered 23 September 2014. PMID- 29606104 TI - Study protocol, randomized controlled trial: reducing symptom burden in patients with heart failure with preserved ejection fraction using ubiquinol and/or D ribose. AB - BACKGROUND: Heart failure (HF), the leading cause of morbidity and mortality in the US, affects 6.6 million adults with an estimated additional 3 million people by 2030. More than 50% of HF patients have heart failure with preserved left ventricular ejection fraction (HFpEF). These patients have impaired cardiac muscle relaxation and diastolic filling, which investigators have associated with cellular energetic impairment. Patients with HFpEF experience symptoms of: (1) fatigue; (2) shortness of breath; and (3) swelling (edema) of the lower extremities. However, current HF guidelines offer no effective treatment to address these underlying pathophysiologic mechanisms. Thus, we propose a biobehavioral symptom science study using ubiquinol and D-ribose (therapeutic interventions) to target mitochondrial bioenergetics to reduce the complex symptoms experienced by patients with HFpEF. METHODS: Using a randomized, double blind, placebo-controlled design, the overall objective is to determine if administering ubiquinol and/or D-ribose to HFpEF patients for 12 weeks would decrease the severity of their complex symptoms and improve their cardiac function. The measures used to assess patients' perceptions of their health status and level of vigor (energy) will be the Kansas City Cardiomyopathy Questionnaire (KCCQ) and Vigor subscale of the Profile of Mood States. The 6-min walk test will be used to test exercise tolerance. Left ventricular diastolic function will be assessed using innovative advanced echocardiography software called speckle tracking. We will measure B-type natriuretic peptides (secreted from ventricles in HF) and lactate/ATP ratio (measure of cellular energetics). DISCUSSIONS: Ubiquinol (active form of Coenzyme Q10) and D-ribose are two potential treatments that can positively affect cellular energetic impairment, the major underlying mechanism of HFpEF. Ubiquinol, the reduced form of CoQ10, is more effective in adults over the age of 50. In patients with HFpEF, mitochondrial deficiency of ubiquinol results in decreased adenosine triphosphate (ATP) synthesis and reduced scavenging of reactive oxygen species. D-ribose is a substrate required for ATP synthesis and when administered has been shown to improve impaired myocardial bioenergetics. Therefore, if the biological underpinning of deficient mitochondrial ATP in HFpEF is not addressed, patients will suffer major symptoms including lack of energy, fatigue, exertional dyspnea, and exercise intolerance. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03133793 ; Data of Registration: April 28, 2017. PMID- 29606105 TI - Employment stability and mental health in Spain: towards understanding the influence of gender and partner/marital status. AB - BACKGROUND: The growing demand for labour flexibility has resulted in decreasing employment stability that could be associated with poor mental health status. Few studies have analysed the whole of the work force in considering this association since research on flexible forms of employment traditionally analyses employed and unemployed people separately. The gender division of work, and family characteristics related to employment situation, could modify its association with mental wellbeing. The objective of the study was to examine the relationship between a continuum of employment stability and mental health taking into account gender and partner/marital status. METHODS: We selected 6859 men and 5106 women currently salaried or unemployed from the 2006 Spanish National Health Survey. Employment stability was measured through a continuum from the highest stability among employed to lowest probability of finding a stable job among the long-term unemployed. Mental health was measured with the 12-item version of the General Health Questionnaire. Logistic regression models were fitted for each combination of partner/marital status and gender. RESULTS: In all groups except among married women employment stability was related to poor mental health and a gradient between a continuum of employment stability and mental health status was found. For example, compared with permanent civil servants, married men with temporary contract showed an aOR = 1.58 (95%CI = 1.06-2.35), those working without a contract aOR = 2.15 (95%CI = 1.01-4.57) and aOR = 3.73 (95%CI = 2.43-5.74) and aOR = 5.35 (95%CI = 2.71-10.56) among unemployed of up to two years and more than two years, respectively. Among married and cohabiting people, the associations were stronger among men. Poor mental health status was related to poor employment stability among cohabiting women but not among married ones. The strongest association was observed among separated or divorced people. CONCLUSIONS: There is a rise in poor mental health as the distance from stable employment grows. This result differs according to the interaction with gender and partner/marital status. In Spain this relationship seems to follow a pattern related to the gender division of work in married people but not in other partner/marital situations. Family and socioeconomic context can contribute to explain previous mixed results. Recommendations for research and for action are given. PMID- 29606106 TI - Social value of a nutritional counselling and support program for breastfeeding in urban poor settings, Nairobi. AB - BACKGROUND: In Kenya, poor maternal nutrition, suboptimal infant and young child feeding practices and high levels of malnutrition have been shown among the urban poor. An intervention aimed at promoting optimal maternal infant and young child nutrition (MIYCN) practices in urban poor settings in Nairobi, Kenya was implemented. The intervention involved home-based counselling of pregnant and breastfeeding women and mothers of young children by community health volunteers (CHVs) on optimal MIYCN practices. This study assesses the social impact of the intervention using a Social Return on Investment (SROI) approach. METHODS: Data collection was based on SROI methods and used a mixed methods approach (focus group discussions, key informant interviews, in-depth interviews, quantitative stakeholder surveys, and revealed preference approach for outcomes using value games). RESULTS: The SROI analysis revealed that the MIYCN intervention was assessed to be highly effective and created social value, particularly for mothers and their children. Positive changes that participants experienced included mothers being more confident in child care and children and mothers being healthier. Overall, the intervention had a negative social impact on daycare centers and on health care providers, by putting too much pressure on them to provide care without providing extra support. The study calculated that, after accounting for discounting factors, the input ($USD 419,716) generated $USD 8 million of social value at the end of the project. The net present value created by the project was estimated at $USD 29.5 million. $USD 1 invested in the project was estimated to bring USD$ 71 (sensitivity analysis: USD$ 34-136) of social value for the stakeholders. CONCLUSION: The MIYCN intervention showed an important social impact in which mothers and children benefited the most. The intervention resulted in better perceived health of mothers and children and increased confidence of mothers to provide care for their children, while it resulted in negative impacts for day care center owners and health care providers. PMID- 29606107 TI - Plasmodium knowlesi infection in a returning German traveller from Thailand: a case report on an emerging malaria pathogen in a popular low-risk travel destination. AB - BACKGROUND: Thailand is a major destination for German travellers with more than 760,000 arrivals in 2015. At the same time, malaria is a concern in travel recommendations with regard to this destination. The World Malaria Report of 2016 mentions only P. falciparum and P. vivax as prevalent species for Thailand, however, P. knowlesi infections have been occasionally reported in Thailand. In German travellers, only five cases of P. knowlesi infections have been reported to date. CASE PRESENTATION: A 45-year-old German male tourist travelled to Thailand from 25 December 2016 to 13 January 2017. On 14 January he developed fever with no other symptoms, and presented on 17 January at the Division for Tropical Medicine and Infectious Diseases in Munich, Germany. Malaria was diagnosed, primarily based on a single parasite in the thin smear microscopy, while commercial rapid diagnostic testing remained negative. Only the result of a differential PCR assay revealed P. knowlesi infection. CONCLUSIONS: P. knowlesi has to be considered in travellers returning from Thailand. Cases may present with an extremely low parasitaemia. This is in contrast to the assumption that P. knowlesi was likely to cause high parasitaemia due to its short replication cycle. PMID- 29606108 TI - Prevalence and risk factors of retinopathy of prematurity in Iran: a systematic review and meta-analysis. AB - BACKGROUND: Retinopathy of prematurity (ROP) refers to the developmental disorder of the retina in premature infants and is one of the most serious and most dangerous complications in premature infants. The prevalence of ROP in Iran is different in various parts of Iran and its prevalence is reported to be 1-70% in different regions. This study aims to determine the prevalence and risk factors of ROP in Iran. METHODS: This review article was conducted based on the preferred reporting items for systematic review and meta-analysis (PRISMA) protocols. To find literature about ROP in Iran, a comprehensive search was done using MeSH keywords in several online databases such as PubMed, Ovid, Science Direct, EMBASE, Web of Science, CINAHL, EBSCO, Magiran, Iranmedex, SID, Medlib, IranDoc, as well as the Google Scholar search engine until May 2017. Comprehensive Meta analysis Software (CMA) Version 2 was used for data analysis. RESULTS: According to 42 studies including 18,000 premature infants, the prevalence of ROP was reported to be 23.5% (95% CI: 20.4-26.8) in Iran. The prevalence of ROP stages 1, 2, 3, 4 and 5 was 7.9% (95% CI: 5.3-11.5), 9.7% (95% CI: 6.1-15.3), 2.8% (95% CI: 1.6-4.9), 2.9% (95% CI: 1.9-4.5) and 3.6% (95% CI: 2.4-5.2), respectively. The prevalence of ROP in Iranian girls and boys premature infants was 18.3% (95% CI: 12.8-25.4) and 18.9% (95% CI: 11.9-28.5), respectively. The lowest prevalence of ROP was in the West of Iran (12.3% [95% CI: 7.6-19.1]), while the highest prevalence was associated with the Center of Iran (24.9% [95% CI: 21.8-28.4]). The prevalence of ROP is increasing according to the year of study, and this relationship is not significant (p = 0.181). The significant risk factors for ROP were small gestational age (p < 0.001), low birth weight (p < 0.001), septicemia (p = 0.021), respiratory distress syndrome (p = 0.036), intraventricular hemorrhage (p = 0.005), continuous positive pressure ventilation (p = 0.023), saturation above 50% (p = 0.023), apnea (p = 0.002), frequency and duration of blood transfusion, oxygen therapy and phototherapy (p < 0.05), whereas pre eclampsia decreased the prevalence of ROP (p = 0.014). CONCLUSION: Considering the high prevalence of ROP in Iran, screening and close supervision by experienced ophthalmologists to diagnose and treat the common complications of pre-maturity and prevent visual impairment or blindness is necessary. PMID- 29606109 TI - Neoadjuvant degarelix with or without apalutamide followed by radical prostatectomy for intermediate and high-risk prostate cancer: ARNEO, a randomized, double blind, placebo-controlled trial. AB - BACKGROUND: Recent retrospective data suggest that neoadjuvant androgen deprivation therapy can improve the prognosis of high-risk prostate cancer (PCa) patients. Novel androgen receptor pathway inhibitors are nowadays available for treatment of metastatic PCa and these compounds are promising for early stage disease. Apalutamide is a pure androgen antagonist with a very high affinity with the androgen receptor. The combination of apalutamide with degarelix, an LHRH antagonist, could increase the efficacy compared to degarelix alone. OBJECTIVE: The primary objective is to assess the difference in proportions of minimal residual disease at prostatectomy specimen between apalutamide + degarelix vs placebo + degarelix. Various secondary endpoints are assessed: variations of different biomarkers at the tumour level (tissue microarrays to evaluate DNA-PKs, PARP, AR and splice variants, PSMA, etc.), whole transcriptome sequencing, exome sequencing and clinical (PSA and testosterone kinetics, early biochemical recurrence free survival, quality of life, safety, etc.) and radiological endpoints. METHODS: ARNEO is a single centre, phase II, randomized, double blind, placebo-controlled trial. The plan is to include at least 42 patients per each of the two study arms. Patients with intermediate/high-risk PCa and who are amenable for radical prostatectomy with pelvic lymph node dissection can be included. After signing an informed consent, every patient will undergo a pelvic 68Ga -PSMA 11 PSMA PET/MR and receive degarelix at standard dosage and start assuming apalutamide/placebo (60 mg 4 tablets/day) for 12 weeks. Within thirty days from the last study medication intake the same imaging will be repeated. Every patient will undergo PSA and testosterone testing the day of randomization, before the first drug intake, and after the last dose. Formalin fixed paraffin embedded tumour samples will be collected and used for transcriptome analysis, exome sequencing and immunohistochemistry. DISCUSSION: ARNEO will allow us to answer, first, whether the combined treatment can result in an increased proportion of patients with minimal residual disease. Secondly, It will enable the study of the molecular consequences at the level of the tumour. Thirdly, what the consequences are of new generation androgen receptor pathway inhibitors on 68Ga -PSMA-11 PET/MR. Finally, various clinical, safety and quality of life data will be collected. TRIAL REGISTRATION: EUDRaCT number: 2016-002854-19 (authorization date 3rd August 2017). clinicalTrial.gov: NCT03080116 . PMID- 29606110 TI - Implementation of clinical practice guidelines on lifestyle interventions in Swedish primary healthcare - a two-year follow up. AB - BACKGROUND: Implementation of interventions concerning prevention and health promotion in health care has faced particular challenges resulting in a low frequency and quality of these services. In November 2011, the Swedish National Board of Health and Welfare released national clinical practice guidelines to counteract patients' unhealthy lifestyle habits. Drawing on the results of a previous study as a point of departure, the aim of this two-year follow up was to assess the progress of work with lifestyle interventions in primary healthcare as well as the uptake and usage of the new guidelines on lifestyle interventions in clinical practice. METHODS: Longitudinal study among health professionals with survey at baseline and 2 years later. Development over time and differences between professional groups were calculated with Pearson chi-square test. RESULTS: Eighteen percent of the physicians reported to use the clinical practice guidelines, compared to 58% of the nurses. Nurses were also more likely to consider them as a support in their work than physicians did. Over time, health professionals usage of methods to change patients' tobacco habits and hazardous use of alcohol had increased, and the nurses worked to a higher extent than before with all four lifestyles. Knowledge on methods for lifestyle change was generally high; however, there was room for improvement concerning methods on alcohol, unhealthy eating and counselling. Forty-one percent reported to possess thorough knowledge of counselling skills. CONCLUSIONS: Even if the uptake and usage of the CPGs on lifestyle interventions so far is low, the participants reported more frequent counselling on patients' lifestyle changes concerning use of tobacco and hazardous use of alcohol. However, these findings should be evaluated acknowledging the possibility of selection bias in favour of health promotion and lifestyle guidance, and the loss of one study site in the follow up. Furthermore, this study indicates important differences in physicians and nurses' attitudes to and use of the guidelines, where the nurses reported working to a higher extent with all four lifestyles compared to the first study. These findings suggest further investigations on the implementation process in clinical practice, and the physicians' uptake and use of the CPGs. PMID- 29606111 TI - Appropriateness of bone density measurement in Switzerland: a cross-sectional study. AB - BACKGROUND: According to the WHO, osteoporosis is one of the most important non- communicable diseases worldwide. Different screening procedures are controversially discussed, especially concerning the concomitant issues of overdiagnosis and harm caused by inappropriate Dual X-ray Absorptiometry (DXA). The aim of this study was to evaluate the frequency and appropriateness of DXA as screening measure in Switzerland considering individual risk factors and to evaluate covariates independently associated with potentially inappropriate DXA screening. METHODS: Retrospective cross-sectional study using insurance claim data of 2013. Among all patients with DXA screening, women < 65 and men < 70 years without osteoporosis or risk factors for osteoporosis were defined as receiving potentially inappropriate DXA. Statistics included descriptive measures and multivariable regressions to estimate associations of relevant covariates with potentially inappropriate DXA screening. RESULTS: Of 1,131,092 patients, 552,973 were eligible. Among those 2637 of 10,000 (26.4%) underwent potentially inappropriate DXA screening. Female sex (Odds ratio 6.47, CI 6.41-6.54) and higher age showed the strongest association with any DXA screening. Female gender (Odds ratio 1.84, CI 1.49-2.26) and an income among the highest 5% (Odds ratio 1.40, CI 1.01-1.98) were significantly positively associated with potentially inappropriate DXA screening, number of chronic conditions (Odds ratio 0.67, CI 0.65-0.70) and living in the central region of Switzerland (Odds ratio 0.67, CI 0.48-0.95) negatively. CONCLUSION: One out of four DXAs for screening purpose is potentially inappropriate. Stakeholders of osteoporosis screening campaigns should focus on providing more detailed information on appropriateness of DXA screening indications (e.g. age thresholds) in order to avoid DXA overuse. PMID- 29606112 TI - Risk factors for the occurrence of multidrug-resistant tuberculosis among patients undergoing multidrug-resistant tuberculosis treatment in East Shoa, Ethiopia. AB - BACKGROUND: Multidrug-resistant tuberculosis (MDR-TB) is resistant to the two main first-line anti-tuberculosis drugs: rifampicin and isoniazid. It is a major threat to public health worldwide. The objective of this study was to assess the potential risk factors for multidrug-resistant tuberculosis among patients undergoing MDR-TB treatment at two community hospitals in Ethiopia. METHODS: A case-control study design was conducted from February 1, 2016, to April 29, 2016. TB-positive patients with MDR-TB and non-MDR-TB were considered as cases and controls, respectively. A total of 219 study participants were included in the study. An interviewer-administered structured questionnaire was used to collect primary data from the patients, and a checklist was used to collect data from the clinical records. Bivariate and multivariate logistic regression analyses were used to assess the potential risk factors for the occurrence of MDR-TB. RESULTS: The odds of developing MDR-TB were higher in patients previously treated with anti-TB drugs (odds ratio [OR] = 6.1, 95%CI: 2.92-12.62, P < 0.001), those with a history of contact with known TB patients (OR = 2.1, 95%CI: 1.04-4.43, P < 0.001), those living in a rural setting (OR = 5.6, 95%CI: 2.14-14.46, P = 0.001), those with a history of alcohol consumption (OR = 4.3, 95%CI: 2.29-10.49, P < 0.001) and those without a job (OR = 2.4, 95%CI: 1.06-5.42, P = 0.001). CONCLUSIONS: The study revealed that contact with known TB patients, previous TB treatment, residence area, lack of a job, and alcohol consumption were potential risk factors for the occurrence of MDR-TB. Enhancing public health education, intensifying directly observed therapy programmes for all TB patients and designing control strategies are recommended. PMID- 29606113 TI - MD-1, a poly herbal formulation indicated in diabetes mellitus ameliorates glucose uptake and inhibits adipogenesis - an in vitro study. AB - BACKGROUND: Type 2 Diabetes (T2D) is a polygenic disease requiring a multipronged therapeutic approach. In the current scenario, the use of polyherbals is increasing among the diabetics. MD-1, a poly herbal formulation is constituted as a mixture of six popular anti diabetic herbs, used in the management of Diabetes mellitus (DM). The physicochemical, biochemical and in vitro efficacy studies have been carried out to ascertain the possible mechanisms underlying the anti diabetic action of MD-1. METHODS: MD-1 was evaluated for residual toxins as per Ayurvedic Pharmacoepia of India (API) procedures. The hydro alcoholic extract of the formulation (HAEF) was evaluated for anti oxidant activity against 2, 2 diphenyl-1-picrylhydrazil (DPPH) and nitric oxide radicals in vitro. The effect of HAEF on carbohydrate digestive enzymes alpha-glucosidase and alpha-amylase was studied using biochemical assays. HAEF was studied for its glucose lowering potential in L6 myotubes and 3T3L1 preadipocytes, using 2-deoxy-D-[1-3H] glucose (2-DG) uptake assay. Effect of MD-1 on adipogenesis was evaluated in 3T3L1 adipocytes using oil O red staining. The effect of HAEF on mRNA expression of peroxisome proliferator activated receptor gamma (PPARgamma) and glucose transporter 4 (GLUT4) in 3T3L1 adiocytes was investigated by reverse transcriptase polymerase chain reaction (RT-PCR). Statistical analysis was performed by student t-test, ANOVA. RESULTS: Residual toxins present within the API limits and HAEF demonstrated strong antioxidant potential and significantly inhibited the alpha-glucosidase (IC50 63.6 +/- 0.46 MUg/mL) and alpha-amylase (IC50 242.81 +/- 1.26 MUg/mL) activity. HAEF significantly (p < 0.05) enhanced the insulin stimulated glucose uptake in both the cell lines studied. Unlike standard pioglitazone (PGZ), HAEF modulated the mRNA expression of PPARgamma and GLUT4 (p < 0.0001) in 3T3L1 adipocytes, without inducing adipogenesis. CONCLUSION: Physicochemical parameters established in the study may serve as reference standards in regular quality control. Absence of residual toxins underpins the safety. The enhanced glucose uptake and favorable modulation of insulin sensitivity through a plausible weak PPARgamma agonism is similar to the distinct PPARgamma activation pattern of several reported natural compound agonists. The differential binding modes of such dynamic combinatorial ligands within the formulation unlike synthetic ligands like thiozolidinediones (TZD) can be linked to the safe mitigation of diabetic complications by MD-1. PMID- 29606114 TI - Prognostic factors of a favorable outcome following a supervised exercise program for soldiers with sub-acute and chronic low back pain. AB - BACKGROUND: Low back pain (LBP) encompasses heterogeneous patients unlikely to respond to a unique treatment. Identifying sub-groups of LBP may help to improve treatment outcomes. This is a hypothesis-setting study designed to create a clinical prediction rule (CPR) that will predict favorable outcomes in soldiers with sub-acute and chronic LBP participating in a multi-station exercise program. METHODS: Military members with LBP participated in a supervised program comprising 7 stations each consisting of exercises of increasing difficulty. Demographic, impairment and disability data were collected at baseline. The modified Oswestry Disability Index (ODI) was administered at baseline and following the 6-week program. An improvement of 50% in the initial ODI score was considered the reference standard to determine a favorable outcome. Univariate associations with favorable outcome were tested using chi-square or paired t tests. Variables that showed between-group (favorable/unfavorable) differences were entered into a logistic regression after determining the sampling adequacy. Finally, continuous variables were dichotomized and the sensitivity, specificity and positive and negative likelihood ratios were determined for the model and for each variable. RESULTS: A sample of 85 participants was included in analyses. Five variables contributed to prediction of a favorable outcome: no pain in lying down (p = 0.017), no use of antidepressants (p = 0.061), FABQ work score < 22.5 (p = 0.061), fewer than 5 physiotherapy sessions before entering the program (p = 0.144) and less than 6 months' work restriction (p = 0.161). This model yielded a sensitivity of 0.78, specificity of 0.80, LR+ of 3.88, and LR- of 0.28. A 77.5% probability of favorable outcome can be predicted by the presence of more than three of the five variables, while an 80% probability of unfavorable outcome can be expected if only three or fewer variables are present. CONCLUSION: The use of prognostic factors may guide clinicians in identifying soldiers with LBP most likely to have a favorable outcome. Further validation studies are needed to determine if the variables identified in our study are treatment effect modifiers that can predict success following participation in the multi-station exercise program. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03464877 registered retrospectively on 14 March 2018. PMID- 29606115 TI - Number of cholangitis episodes as a prognostic marker to predict timing of liver transplantation in biliary atresia patients after Kasai portoenterostomy. AB - BACKGROUND: Cholangitis may affect liver failure of biliary atresia (BA) patients after Kasai portoenterostomy (KP). We examined whether the number of cholangitis episodes could be a prognostic marker for liver transplant (LT) in children with BA after Kasai portoenterostomy (KP). METHODS: Data for BA patients born after 1998 and undergoing KP were obtained from National Health Insurance Research Database (NHIRD), Taiwan. Patients were followed up until the end of 2011. Incidence and the number of cholangitis episodes were recorded and compared between patients based on LT status. RESULTS: Ninety-six (26.8%) of the 366 BA patients underwent LT. More patients who underwent KP at < 60 days of age survived with their native liver (P = 0.007). The mean age at first cholangitis was 0.9 years and 0.8 years in the LT and non-LT groups, respectively (P = 0.868). The cumulative incidence of cholangitis within 2 years after KP did not differ between the groups (hazard ratio 1.2; 95% CI 0.9-1.6). However, the total number of cholangitis episodes was higher in the LT group within 2 years after KP (P < 0.001). CONCLUSIONS: Cholangitis occurrence was not related to LT in the first 2 years after KP in BA patients, but the number of cholangitis episodes could be a prognostic marker for future LT. PMID- 29606116 TI - Successful production of genome-edited rats by the rGONAD method. AB - BACKGROUND: Recent progress in development of the CRISPR/Cas9 system has been shown to be an efficient gene-editing technology in various organisms. We recently developed a novel method called Genome-editing via Oviductal Nucleic Acids Delivery (GONAD) in mice; a novel in vivo genome editing system that does not require ex vivo handling of embryos, and this technology is newly developed and renamed as "improved GONAD" (i-GONAD). However, this technology has been limited only to mice. Therefore in this study, we challenge to apply this technology to rats. RESULTS: Here, we determine the most suitable condition for in vivo gene delivery towards rat preimplantation embryos using tetramethylrhodamine-labelled dextran, termed as Rat improved GONAD (rGONAD). Then, to investigate whether this method is feasible to generate genome-edited rats by delivery of CRISPR/Cas9 components, the tyrosinase (Tyr) gene was used as a target. Some pups showed albino-colored coat, indicating disruption of wild type Tyr gene allele. Furthermore, we confirm that rGONAD method can be used to introduce genetic changes in rat genome by the ssODN-based knock-in. CONCLUSIONS: We first establish the rGONAD method for generating genome-edited rats. We demonstrate high efficiency of the rGONAD method to produce knock-out and knock in rats, which will facilitate the production of rat genome engineering experiment. The rGONAD method can also be readily applicable in mammals such as guinea pig, hamster, cow, pig, and other mammals. PMID- 29606117 TI - Inspectors' responses to adolescents' assessment of quality of care: a case study on involving adolescents in inspections. AB - BACKGROUND: Users of care services are increasingly participating in inspections of the quality of care. In practice, incorporating service users' views is difficult, as users may have other views on good care than inspectors and thus give information that does not fit the inspectors' assessment criteria. This study compared the views on good care of young care users (adolescents) and inspectors, seeking to understand what the differences and similarities mean to incorporating the users' views in inspections. METHODS: We conducted a single case study combining document analysis with a meeting with inspectors. The selected case came from a Dutch inspectorate and involved a thematic inspection of care for children growing up poor. RESULTS: Inspectors and adolescents agree on the importance of timely care, creating opportunities for personal development, and a respectful relationship. The views on quality of care differ with regard to sharing information, creating solutions, and the right moment to offer help. We identified three ways inspectors deal with the differences: 1) prioritize their own views, 2) pass the problem onto others to solve, and 3) separate the differing perspectives. With similar viewpoints, inspectors use the adolescents' views to support their assessments. When viewpoints conflict, information from adolescents does not affect the inspectors' judgments. Explanations are related to the vulnerability of the adolescents involved, the inspectorate's organizational rules and routines and the external regulatory context. CONCLUSIONS: Service user involvement in inspections potentially impacts the quality of care. Yet, conflicts between the views of service users and inspectors are not easily overcome in the regulatory context. PMID- 29606118 TI - Theoretical impact of simulated workplace-based primary prevention of carpal tunnel syndrome in a French region. AB - BACKGROUND: Carpal tunnel syndrome (CTS) is the most common nerve entrapment neuropathy in the working-age population. The reduction of CTS incidence in the workforce is a priority for policy makers due to the human, social and economic costs. To assess the theoretical impact of workplace-based primary interventions designed to reduce exposure to personal and/or work-related risk factors for CTS. METHODS: Surgical CTS were assessed using regional hospital discharge records for persons aged 20-59 in 2009. Using work-related attributable fractions (AFEs), we estimated the number of work-related CTS (WR-CTS) in high-risk jobs. We simulated three theoretical scenarios of workplace-based primary prevention for jobs at risk: a mono-component work-centered intervention reducing the incidence of WR CTS arbitrarily by 10% (10%-WI), and multicomponent global interventions reducing the incidence of all surgical CTS by 5% and 10% by targeting personal and work risk factors. RESULTS: A limited proportion of CTS were work-related in the region's population. WR-CTS were concentrated in nine jobs at high risk of CTS, amounting to 1603 [1137-2212] CTS, of which 906 [450-1522] were WR-CTS. The 10% WI, 5%-GI and 10%-GI hypothetically prevented 90 [46-153], 81 [58-111] and 159 [114-223] CTS, respectively. The 10%-GI had the greatest impact regardless of the job. The impact of the 10%-WI interventions was high only in jobs at highest risk and AFEs (e.g. food industry jobs). The 10%-WI and 5%-GI had a similar impact for moderate-risk jobs (e.g. healthcare jobs). CONCLUSION: The impact of simulated workplace-based interventions suggests that prevention efforts to reduce exposure to work-related risk factors should focus on high-risk jobs. Reducing CTS rates will also require integrated strategies to reduce personal risk factors, particularly in jobs with low levels of work-related risk of CTS. PMID- 29606119 TI - Invasive meningococcal disease due to a non-capsulated Neisseria meningitidis strain in a patient with IgG4-related disease. AB - BACKGROUND: Invasive Meningococcal Disease (IMD) is a rare and critical disease in Japan. Most of these cases are caused by capsulated Neisseria meningitidis strains. Non-capsulated (non-typable) strains are considered relatively low pathogenic and can colonize in the nasopharynx of healthy children and young adults. As far as could be ascertained, only twelve IMD cases due to non capsulated strains have been reported in the literature. No clear risk factors could be identified in a literature review (unknown or immunocompetent, seven cases; C6 deficiency, three cases). CASE PRESENTATION: We report a Japanese male taxi driver with bacteremia and meningitis due to non-capsulated N. meningitidis. He had a fever and shaking chills. Ceftriaxone was administered, and the patient finally recovered. During the clinical course, relative adrenal insufficiency occurred and was treated with hydrocortisone. A hidden co-morbidity, immunoglobulin G4 (IgG4)-related disease, was revealed in the past surgical history (a resection of bilateral orbital tumors), which included symptoms (swelling lachrymal glands and lymph nodes), elevated IgG4, immunoglobulin E, and hypocomplementemia. He recovered finally and no recurrence was observed. CONCLUSIONS: Our IMD case is the first reported in Japan, where IMD is not considered pandemic. The patient had a history of IgG4-related disease, although we could not establish a clear relationship between the patient's IMD and co morbidity. A collection of further clinical cases might establish the risk factors and characteristics of IMD that could be caused by this neglected pathogen, non-capsulated N. meningitidis. PMID- 29606120 TI - Angiolymphoid hyperplasia with eosinophilia: a case report. AB - BACKGROUND: Angiolymphoid hyperplasia with eosinophilia is a benign neoplasm that includes blood vessel proliferation and a dense eosinophilic inflammatory infiltrate. Mostly, it affects middle-aged adults manifesting as flesh/plum colored pruritic nodules and papules, most commonly affecting the ear and the periauricular area. CASE PRESENTATION: In this case, we report a 13-year-old Caucasian girl with bilateral, huge, protruding, and yellowish nostril masses which were peculiar in location and of gross appearance. At first, the disease proved to be a diagnostic dilemma. After making a diagnosis of angiolymphoid hyperplasia with eosinophilia, the disease also proved to be a therapeutic dilemma. It did not respond to oral prednisolone or to oral indomethacin, and it proved to be resistant to topical steroids. Although surgery is the standard therapeutic approach, it recurred despite multiple surgical attempts. However, the only regimen that seemed to partially control the lesion was intralesional steroids combined with topical tacrolimus ointment. CONCLUSIONS: Angiolymphoid hyperplasia with eosinophilia proves a therapeutic dilemma, because there is a large variety of proposed treatments, yet there is not enough data on most of them. Although the disease is not deadly by itself, it usually presents with disfiguring lesions that grimly affect the patient's quality of life. This warrants further research and efforts to find an effective cure and a unified therapeutic approach. PMID- 29606121 TI - Polymorphism of the GLIS3 gene in a Caucasian population and among individuals with carbohydrate metabolism disorders in Russia. AB - OBJECTIVE: Earlier, GLIS3 gene polymorphisms have been shown to be associated with the development of maturity onset diabetes of the young (MODY). We screened GLIS3 gene sequences among patients with MODY to identify probably pathogenic variants by whole-exome sequencing. We estimated frequency of rare single nucleotide variants in the coding region of GLIS3 in a Caucasian population and among individuals with carbohydrate metabolism disorders in Russia. RESULTS: We identified 15 single-nucleotide variants in GLIS3. Three rare variants (minor allele frequency < 1%) rs806052, rs143051164, and rs149840771 were genotyped in 126 cases of MODY, in 188 patients with type 2 diabetes mellitus (DM2), and 564 randomly selected Caucasian individuals in Russia. A heterozygous rs806052 variant was identified in one patient with DM2; c.1270T frequency was 0.003. Prevalence of rs143051164 c.844G was 0.003 in the control population and 0.004 and 0.003 in MODY and DM2 samples, respectively. Prevalence of rs149840771 c.2096A was 0.003 and 0.004 in the control population and among MODY patients, respectively. In DM2 patients, rs149840771 c.2096A was not identified. We did not detect any associations of rs806052, rs143051164, and rs149840771 with carbohydrate metabolism disorders among patients with MODY and DM2 in Russia. PMID- 29606122 TI - War zone refugia? Establishing a baseline for protected waterbirds in a wildlife refuge flanked by agriculture and militarization. AB - OBJECTIVES: The welfare of threatened fauna should not be assumed merely because their refuges have been designated with protected status. This is particularly true in geographical areas where social/military events drive an under-reported, but potentially lethal, type of human-wildlife interaction. Waterbirds of Gharana Wetland Conservation Reserve consist mostly of threatened species. However, as occurs globally, 'protected' fauna near contested borders are sometimes affected by military forces. As part of a larger project to document regional avifauna, we report the seasonal status of waterbirds in order to help establish a baseline for comparing conservation of wildlife within contested areas to that of fauna in more secure refuges. We examined 24 avifauna surveys for relationships between seasons, temperature, individuals and species. RESULTS: 28 of 61 waterbird species were rare. We found seasonal variations in individuals (F3,731 = 3.82; P < 0.01) and species (F3,11 = 5.81; P < 0.05) with a major influx in late winter, rather than autumn. Thus, while this sanctuary serves as an over-wintering site, it is also a stop-over site for high-altitude migrations. While providing this baseline, we offer a reminder that the welfare of wildlife in protected areas should be monitored seasonally, with the ongoing threats to their conservation, carefully documented. PMID- 29606123 TI - The impact of temperature on insecticide toxicity against the malaria vectors Anopheles arabiensis and Anopheles funestus. AB - BACKGROUND: It is anticipated that malaria elimination efforts in Africa will be hampered by increasing resistance to the limited arsenal of insecticides approved for use in public health. However, insecticide susceptibility status of vector populations evaluated under standard insectary test conditions can give a false picture of the threat, as the thermal environment in which the insect and insecticide interact plays a significant role in insecticide toxicity. METHODS: The effect of temperature on the expression of the standard WHO insecticide resistance phenotype was examined using Anopheles arabiensis and Anopheles funestus strains: a susceptible strain and the derived resistant strain, selected in the laboratory for resistance to DDT or pyrethroids. The susceptibility of mosquitoes to the pyrethroid deltamethrin or the carbamate bendiocarb was assessed at 18, 25 or 30 degrees C. The ability of the pyrethroid synergist piperonyl-butoxide (PBO) to restore pyrethroid susceptibility was also assessed at these temperatures. RESULTS: Temperature impacted the toxicity of deltamethrin and bendiocarb. Although the resistant An. funestus strain was uniformly resistant to deltamethrin across temperatures, increasing temperature increased the resistance of the susceptible An. arabiensis strain. Against susceptible An. funestus and resistant An. arabiensis females, deltamethrin exposure at temperatures both lower and higher than standard insectary conditions increased mortality. PBO exposure completely restored deltamethrin susceptibility at all temperatures. Bendiocarb displayed a consistently positive temperature coefficient against both susceptible and resistant An. funestus strains, with survival increasing as temperature increased. CONCLUSIONS: Environmental temperature has a marked effect on the efficacy of insecticides used in public health against important African malaria vectors. Caution must be exercised when drawing conclusions about a chemical's efficacy from laboratory assays performed at only one temperature, as phenotypic resistance can vary significantly even over a temperature range that could be experienced by mosquitoes in the field during a single day. Similarly, it might be inappropriate to assume equal efficacy of a control tool over a geographic area where local conditions vary drastically. Additional studies into the effects of temperature on the efficacy of insecticide-based interventions under field conditions are warranted. PMID- 29606124 TI - Transferring skills in quality collaboratives focused on improving patient logistics. AB - BACKGROUND: A quality improvement collaborative, often used by the Institute for Healthcare Improvement, is used to educate healthcare professionals and improve healthcare at the same time. However, no prior research has been done on the knowledge and skills healthcare professionals need to achieve improvements or the extent to which quality improvement collaboratives help enhance both knowledge and skills. Our research focused on quality improvement collaboratives aiming to improve patient logistics and tried to identify which knowledge and skills are required and to what extent these were enhanced during the QIC. METHODS: We defined skills important for logistic improvements in a three-phase Delphi study. Based on the Delphi results we made a questionnaire. We surveyed participants in a national quality improvement collaborative to assess the skills rated as 1) important, 2) available and 3) improved during the collaborative. At two sense making meetings, experts reflected on our findings and hypothesized on how to improve (logistics) collaboratives. RESULTS: The Delphi study found 18 skills relevant for reducing patient access time and 21 for reducing throughput time. All skills retrieved from the Delphi study were scored as 'important' in the survey. Teams especially lacked soft skills connected to project and change management. Analytical skills increased the most, while more reflexive skills needed for the primary goal of the collaborative (reduce access and throughput times) increased modestly. At two sense-making meetings, attendees suggested four improvements for a quality improvement collaborative: 1) shift the focus to project- and change management skills; 2) focus more on knowledge transfer to colleagues; 3) teach participants to adapt the taught principles to their own situations; and 4) foster intra-project reflexive learning to translate gained insights to other projects (inter-project learning). CONCLUSIONS: Our findings seem to suggest that Quality collaboratives could benefit if more attention is paid to the transfer of 'soft skills' (e.g. change, project management and communication skills) and reflexive skills (e.g. adjusting logistics principles to specific situations and inter-project translation of experiences). PMID- 29606125 TI - HIV and early hospital readmission: evaluation of a tertiary medical facility in Lilongwe, Malawi. AB - BACKGROUND: Delivery of quality healthcare in resource-limited settings is an important, understudied public health priority. Thirty-day (early) hospital readmission is often avoidable and an important indicator of healthcare quality. METHODS: We investigated the prevalence of all-cause early readmission and its associated factors using age and sex adjusted risk ratios (RR) and 95% confidence intervals (CI). A retrospective review of the medical ward database at Kamuzu Central Hospital in Lilongwe, Malawi was conducted between February and December 2013. RESULTS: There were 3547 patients with an index admission of which 2776 (74.4%) survived and were eligible for readmission. Among these patients: 49.7% were male, mean age was 39.7 years, 36.1% were HIV-positive, 34.6% were HIV negative, and 29.3% were HIV-unknown. The prevalence of early hospital readmission was 5.5%. Diagnoses associated with 30-day readmission were HIV positive status (RR = 2.41; 95% CI: 1.64-3.53) and malaria (RR = 0.45; 95% CI: 0.22-0.91). Other factors associated with readmission were multiple diagnoses (excluding HIV) (RR = 1.52; 95% CI: 1.11-2.06), and prolonged length of stay (>= 16 days) at the index hospitalization (RR = 3.63; 95% CI: 1.72-7.67). CONCLUSION: Targeting HIV-infected inpatients with multiple diagnoses and longer index hospitalizations may prevent early readmission and improve quality of care. PMID- 29606126 TI - Lymph node cancer of the mediastinum with a putative necrotic primary lesion in the lung: a case report. AB - BACKGROUND: Although mediastinal lymph node cancer is presumed to originate in the lung, the primary site is usually unidentified, so the pathological course remains unclear. We recently encountered a case of mediastinal lymph node cancer having a putative primary lesion remaining in the lung as a necrotic focus. CASE PRESENTATION: The patient was a 56-year-old man who visited our department because computed tomography screening had revealed a nodular shadow in the lingular segment. However, on positron emission tomography, fluorine-18 deoxyglucose accumulation was detected in a subcarinal lymph node and not in the nodule in the lingular segment. Biopsy of the lung tumor and the lymph node was performed via minimal thoracotomy. Intraoperative pathologic examination showed necrosis alone and no malignant findings in the lung tumor. By contrast, carcinoma was detected in the lymph node. Additional subcarinal lymph node dissection was performed. Results of postoperative histopathologic examination indicated poorly differentiated adenocarcinoma of the subcarinal lymph node. Meanwhile, the nodule in the lingular segment was speculated to be a spontaneously resolved primary focus of lung cancer. CONCLUSIONS: In this case, the primary lung cancer focus resolved spontaneously after lymph node metastasis, explaining the pathogenesis underlying mediastinal lymph node cancer of unknown primary site. For similar cases of malignancy, aggressive treatment, including surgery, is effective. PMID- 29606127 TI - Stand-by emergency treatment (SBET) of malaria in Spanish travellers: a cohort study. AB - BACKGROUND: Among strategies for malaria prevention, stand-by emergency treatment (SBET) is a possible approach, but scarce evidences exists investigating travellers' adherence and behaviours toward its use; therefore, the presented study aimed to determine travellers' compliance toward the SBET when prescribed in travel clinics. METHODS: A prospective cohort study was performed at the Travel Health Clinic of the Hospital Universitari de Bellvitge, Barcelona, Spain, during 2017. The research was planned on survey-based design, using pre- and post travel questionnaires. RESULTS: In the study period, of 5436 subjects who attended the HUB Travel Medicine Clinic, 145 travellers to malaria-endemic areas were prescribed SBET, and all patients agreed to participate in the study by completing the pre-travel questionnaire. Approximately half the participants were women (n = 75, 51.7%), and the median age of all travellers was 29 years (range 13-57), mainly travelling to South-East Asia (n = 69, 47.6%), with Indonesia and the Philippines as the most popular destinations. The length of travels had a median duration of 29 days (range 10-213). Of the recruited participants, 98 replied to the online post-travel survey, reaching a response rate of 67.6%. A total of 62.2% of travellers to which SBET was prescribed did not buy and carry drugs while travelling abroad. No participants' baseline or travel characteristic was shown to be significantly associated (p > 0.05) with this behaviour. Four women (4.1%) experienced fever and self-administered SBET, without seeking medical attention. No malaria cases were observed. CONCLUSIONS: This cohort study addressed travellers' adherence and behaviour toward SBET, highlighting an incorrect use of the emergency treatment in case of presumptive malaria symptoms. This should be taken into account during pre-travel consultation, since the success of this strategy for malaria prevention depends on travellers' strong adherence to it. PMID- 29606128 TI - Epidemiology of heart failure in pediatric populations in low- and middle-income countries: a protocol for a systematic review. AB - BACKGROUND: Heart failure (HF) in pediatric populations is a major public health concern. It is associated with high rates of hospital admissions, disability, and mortality in high-income countries (HIC), but its burden is poorly documented in low- and middle-income countries (LMICs). We present a protocol for a systematic review and meta-analysis to summarize available data on the prevalence, incidence, etiologies, treatment, and outcomes including hospital admission and mortality and economic burden of HF in neonates, infants, children, and adolescents in LMICs. METHODS: A comprehensive search of articles published between January 01, 2000, and December 31, 2017, will be performed in PubMed/MEDLINE, EMBASE, Global Index Medicus, and Web of Science. All cross sectional, cohort studies and case-control studies reporting on the prevalence, incidence, etiologies, treatment, prognosis, admission rates, mortality, and economic burden of HF in pediatric populations in LMICs will be included in the review. The methodological quality of included studies will be appraised accordingly. For prognosis data, the Quality in Prognosis Studies (QUIPS) tool will be used. The symmetry of funnel plot and Egger's test will be used to identify publication bias. An overall summary estimate of prevalence/incidence of pediatric HF across studies will be obtained from study-specific estimates pooled through a random-effect model. Heterogeneity of studies will be assessed by the chi2 test on Cochrane's Q statistic. A p value less than 0.05 will be considered significant for factors that predict mortality. This systematic review and meta analysis will be reported following the PRISMA guidelines. DISCUSSION: This study will report and summarize epidemiology data, as well as the economic burden of HF in neonates, infants, children, and adolescents of LMICs. Limitations will mainly arise from the heterogeneity in the diagnostic of HF. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42017070189. PMID- 29606129 TI - Adherence intervention for HIV-infected persons who use drugs: adaptation, open trial, and pilot randomized hybrid type 1 trial protocol. AB - BACKGROUND: HIV-infected people who use drugs (PWUD) exhibit the highest rates of non-adherence to antiretroviral therapy (ART) among people living with HIV. This contributes to poor treatment outcomes, increased morbidity and mortality, and HIV transmission. However, current interventions fail to address the unique barriers to adherence faced by this population. Life Steps is a brief, single session intervention that demonstrated increased ART adherence among HIV-infected individuals. This study protocol seeks to improve clinical practice by adapting Life Steps for HIV-infected PWUD and adding a brief motivational intervention addressing drug use. This intervention will incorporate educational, motivational, and behavioral skills components specifically aimed at improving adherence and linkage to substance use treatment among HIV-infected PWUD. METHODS: This project will consist of three phases using a mixed-methods approach. In Phase 1, qualitative interviews with HIV-infected PWUD and community providers, coupled with feedback from an expert review panel, will be used to enhance the existing Life Steps manual and interventionist training protocol. In Phase 2, the prototype will be pilot tested and qualitative exit interviews with HPWUD will identify the strengths and limitations of the intervention. Data regarding feasibility, acceptability, and barriers to delivery will guide modifications to finalize a modified Life Steps-Drug Use (LS-DU) protocol. In Phase 3, a pilot type 1 hybrid effectiveness-implementation trial will examine the effectiveness of LS-DU relative to a health education intervention control condition on ART adherence and viral load data at 1-, 3-, and 6-months. Data regarding clinic readiness for implementation and intervention sustainability potential will be collected. DISCUSSION: This protocol will adapt and evaluate an intervention to improve adherence among HIV-infected PWUD. Results of this study will provide significant data on the acceptability, initial effectiveness, and sustainability potential of an adherence intervention for a high risk and underserved population. Trial registration NCT02907697. PMID- 29606130 TI - Proteasome inhibitors modulate anticancer and anti-proliferative properties via NF-kB signaling, and ubiquitin-proteasome pathways in cancer cell lines of different organs. AB - BACKGROUND: Cancer is second most common cause of death in the United State. There are over 100 different types of cancer associated with different human organs, predominantly breast, liver, pancreas, prostate, colon, rectum, lung, and stomach. We have recently reported properties of pro-inflammatory (for treatment of various types of cancers), and anti-inflammatory (for cardiovascular disease and diabetes) compounds. The major problem associated with development of anticancer drugs is their lack of solubility in aqueous solutions and severe side effects in cancer patients. Therefore, the present study was carried out to check anticancer properties of selected compounds, mostly aqueous soluble, in cancer cell lines from different organs. METHODS: The anticancer properties, anti proliferative, and pro-apoptotic activity of novel naturally occurring or FDA approved, nontoxic, proteasome inhibitors/activators were compared. In addition to that, effect of delta-tocotrienol on expression of proteasome subunits (X, Y, Z, LMP7, LMP2, LMP10), ICAM-1, VCAM-1, and TNF-alpha using total RNAs derived from plasmas of hepatitis C patients was investigated. RESULTS: Our data demonstrated that following compounds are very effective in inducing apoptosis of cancer cells: Thiostrepton, dexamethasone, 2-methoxyestradiol, delta-tocotrienol, quercetin, amiloride, and quinine sulfate have significant anti-proliferation properties in Hela cells (44% - 87%) with doses of 2.5-20 MUM, compared to respective controls. Anti-proliferation properties of thiostrepton, 2 methoxyestradiol, delta-tocotrienol, and quercetin were 70% - 92%. However, thiostrepton, dexamethasone, 2-methoxyestradiol, delta-tocotrienol, quercetin, and quinine sulphate were effective in pancreatic, prostate, breast, lungs, melanoma, Beta-lymphocytes, and T-cells (Jurkat: 40% to 95%) compared to respective controls. In lung cancer cells, these compounds were effective between 5 and 40 MUM. The IC50 values of anti-proliferation properties of thiostrepton in most of these cell lines were between doses of 2.5-5 MUM, dexamethasone 2.5-20 MUM, 2-methoxyestradiol 2.5-10 MUM, delta-tocotrienol 2.5-20 MUM, quercetin 10-40 MUM, and (-) Corey lactone 40-80 MUM. In hepatitis C patients, delta-tocotrienol treatment resulted in significant decrease in the expression of pro-inflammatory cytokines. CONCLUSIONS: These data demonstrate effectiveness of several natural occurring compounds with anti-proliferative properties against cancer cells of several organs of humans. Thiostrepton, dexamethasone, 2-methoxyestradiol, delta tocotrienol and quercetin are very effective for apoptosis of cancer cells in liver, pancreas, prostate, breast, lung, melanoma, Beta-lymphocytes and T-cells. The results have provided an opportunity to test these compounds either individually or in combination as dietary supplements in humans for treatment of various types of cancers. PMID- 29606131 TI - Cholinesterase research outreach project (CROP): point of care cholinesterase measurement in an Australian agricultural community. AB - BACKGROUND: Australian farmers are routinely exposed to a wide variety of agrichemicals, including herbicides and insecticides. Organophosphate (OP) insecticides are widely used for agricultural production, horticulture and animal husbandry practices. Symptoms of OP toxicity are the results of inhibition of the enzyme acetylcholinesterase (AChE) which is found in many types of conducting tissue in human bodies such as nerve and muscle, central and peripheral tissues, motor and sensory fibres. Cholinesterase can be measured in red blood cells/erythrocytes (AChE) and plasma (PChE). This study aims to explore integration of AChE monitoring into routine health checks for those at risk and also to examine any association between AChE activity and agrichemical use in a Victorian farming community in Australia. METHODS: This was a prospective cohort study, where farmers and non-famers were compared on the levels of AChE at four time points of baseline, 3-4 weeks, 6-weeks and at 9-weeks. Study participants (N = 55) were residents from South West Victoria, aged between 18 and 75 years, spoke English, and had not had a previous known acute chemical accident. A total of 41 farming (had been farming for more than 5 years) and a convenience sample of 14 non-farming individuals met the inclusion criteria. Testing of AChE was repeated for all participants with a maximum of three times over 10 weeks. RESULTS: The integration of AChE monitoring was very well accepted by all participants. There was no significant difference in average AChE activity between farming and non-farming participants (one-way ANOVA p > 0.05) in this study. There was no significant difference between personal use of agricultural chemicals on farm and the levels of AChE at baseline (measurement 1) or any of the follow up periods (p > 0.05). However, the mean activity of AChE was significantly lower within follow up periods [F (2.633, 139.539) = 14.967, p < 0.001]. There was a significant reduction of AChE between the follow up at 3 weeks and 6-weeks period (p = 0.015). CONCLUSIONS: The routine monitoring of AChE may allow for early recognition of chronic low-level exposure to OPs when they are used by farmers, provided a reasonable estimate of baseline AChE is available. This work provides an evidence for recommending the integration of AChE monitoring into point of care (POC) procedures in rural health clinics and quantifying pesticide exposure and personal protection both on the farm and in the home. Farmer engagement is crucial to the successful integration of AChE monitoring into rural health clinics in Australia. TRIAL REGISTRATION: ACTRN12613001256763 . PMID- 29606133 TI - A survey of pharmacists' perception of foundation level competencies in African countries. AB - BACKGROUND: Evidence from published literature in pharmacy practice research demonstrate that the use of competency frameworks alongside standards of practice facilitate improvement in professional performance and aid expertise development. The aim of this study was to evaluate pharmacists' perception of relevance to practice of the competencies and behaviours contained in the FIP Global Competency Framework (GbCF v1). The overall objective of the study was to assess the validity of the GbCF v1 framework in selected countries in Africa. METHODS: A cross-sectional survey of pharmacists practicing in 14 countries in Africa was conducted between November 2012 and December 2014. A combination of purposive and snowball sampling method was used. Data was analysed using SPSS v22. RESULTS: A total of 469 pharmacists completed the survey questionnaire. The majority (91%) of the respondents were from four countries: Ghana, Kenya, Nigeria and South Africa. The study results showed broad agreement on relevance to practice for 90% of the behaviours contained in the GbCF v1 framework. Observed disagreement was associated with area of pharmacy practice and the corresponding patient facing involvement (p <= 0.05). In general, the competencies within the 'pharmaceutical care' and 'pharmaceutical public health' clusters received higher weighting on relevance compared to the research-related competencies which had the lowest. Specific inter-country variability on weighting of relevance was observed in five behaviours in the framework although, this was due to disparity in 'degree of relevance' that was related to sample composition in the respective countries. CONCLUSION: The competencies contained in the GbCF v1 are relevant to pharmacy practice in the study population; however, there are some emergent differences between the African countries surveyed. Overall, the findings provide preliminary evidence that was previously lacking on the relevance of the GbCF v1 competencies to pharmacy practice in the countries surveyed. PMID- 29606132 TI - Evaluation of the impact of telementoring using ECHO(c) technology on healthcare professionals' knowledge and self-efficacy in assessing and managing pain for people with advanced dementia nearing the end of life. AB - BACKGROUND: Pain assessment and management in advanced and end-stage dementia are challenging; patients are at risk of under-diagnosis, under-assessment and under treatment. Previous research has highlighted the importance of needs-driven training and development in this area for physicians, nurses and healthcare assistants (HCAs) across specialties, disciplines and care settings. This study used teleconferencing technology to connect healthcare professionals across multiple settings and disciplines in real-time clinics, based on the Project ECHO(c) model. This paper reports the evaluation of the clinics by physicians, nurses and HCAs, including their knowledge and self-efficacy in pain assessment and management for patients with advanced and end-stage dementia. METHODS: A mixed method evaluation comprising quantitative survey of self-reported knowledge and self-efficacy pre- and post-ECHO clinic participation, and qualitative exploration of experiences of the clinics using focus group interviews. A census approach to sampling was undertaken. Pre- and post-ECHO evaluations were administered electronically using Survey Monkey software. Mann-Whitney U tests were used to explore differences in knowledge and self-efficacy scores pre- and post-ECHO clinic participation. Statistical significance was set a-priori at p = 0.05. Focus groups were video- and audio-recorded, transcribed verbatim and analysed using Braun & Clarke's model of thematic analysis. RESULTS: Eighteen healthcare professionals [HCPs] (physicians [n = 7], nurses [n = 10], HCA [n = 1]) and twenty HCPs (physicians [n = 10], nurses [n = 10]) completed pre- and post-ECHO evaluations respectively, reporting improvements in knowledge and self efficacy on participation in ECHO clinics and perceived utility of the clinics. Seven HCPs (physicians [n = 2], nurses [n = 5]) participated in two focus groups. Four themes emerged: knowledge and skills development and dissemination; protected time; areas for improvement; and the future of ECHO. CONCLUSIONS: Telementoring clinics for HCP education and training in pain assessment and management in advanced and end-stage dementia demonstrate a positive impact on knowledge and self-efficacy of HCPs and highlight the value of a cross-specialty network of practice which spans across disciplines/HCP types, care settings and geographical areas. Further development of ECHO services in this and in other clinical areas, shows significant potential to support delivery of high-quality care to complex patient populations. PMID- 29606134 TI - TGR5 expression in normal kidney and renal neoplasms. AB - BACKGROUND: The G protein-coupled bile acid receptor (TGR5) is a cell surface receptor which induces the production of intracellular cAMP and promotes epithelial-mesenchymal transition in gastric cancer cell lines. TGR5 is found in a wide variety of tissues including the kidney. However, the patterns of TGR5 expression have not been well characterized in physiologic kidney or renal neoplasms. We explore the expression of TGR5 in benign renal tissue and renal neoplasms and assess its utility as a diagnostic marker. METHODS: Sixty-one renal cortical neoplasms from 2000 to 2014 were retrieved. TGR5 protein expression was examined by immunohistochemistry. TGR5 mRNA was also measured by real-time PCR. RESULTS: In normal renal tissue, TGR5 was strongly positive in collecting ducts, distal convoluted tubules and thin loop of Henle. Proximal convoluted tubules showed absent or focal weak staining. In clear cell renal cell carcinomas (RCCs), 25 of 27 cases (92%) were negative for TGR5 (p < 0.001). TGR5 mRNA was also significantly decreased in clear cell RCCs, suggesting that decreased TGR5 protein expression may be attributable to the downregulation of TGR5 mRNA in these tumors. All 11 papillary RCCs expressed TGR5 with 45% (5/11) exhibiting moderate to strong staining. All chromophobe RCCs and oncocytomas were positive for TGR5 with weak to moderate staining. TGR5 mRNA expression in these tumors was similar to normal kidney. All urothelial carcinomas of the renal pelvis strongly expressed TGR5 including a poorly differentiated urothelial carcinoma with sarcomatoid features. CONCLUSION: TGR5 is strongly expressed in collecting ducts, distal convoluted tubules and thin loop of Henle. TGR5 protein and mRNA expression were notably decreased in clear cell RCCs and may be helpful in differentiating these tumors from other RCCs. PMID- 29606135 TI - Fluid hydration to prevent post-ERCP pancreatitis in average- to high-risk patients receiving prophylactic rectal NSAIDs (FLUYT trial): study protocol for a randomized controlled trial. AB - BACKGROUND: Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) is the most common complication of ERCP and may run a severe course. Evidence suggests that vigorous periprocedural hydration can prevent PEP, but studies to date have significant methodological drawbacks. Importantly, evidence for its added value in patients already receiving prophylactic rectal non-steroidal anti-inflammatory drugs (NSAIDs) is lacking and the cost effectiveness of the approach has not been investigated. We hypothesize that combination therapy of rectal NSAIDs and periprocedural hydration would significantly lower the incidence of post-ERCP pancreatitis compared to rectal NSAIDs alone in moderate- to high-risk patients undergoing ERCP. METHODS: The FLUYT trial is a multicenter, parallel group, open label, superiority randomized controlled trial. A total of 826 moderate- to high-risk patients undergoing ERCP that receive prophylactic rectal NSAIDs will be randomized to a control group (no fluids or normal saline with a maximum of 1.5 mL/kg/h and 3 L/24 h) or intervention group (lactated Ringer's solution with 20 mL/kg over 60 min at start of ERCP, followed by 3 mL/kg/h for 8 h thereafter). The primary endpoint is the incidence of post-ERCP pancreatitis. Secondary endpoints include PEP severity, hydration-related complications, and cost-effectiveness. DISCUSSION: The FLUYT trial design, including hydration schedule, fluid type, and sample size, maximize its power of identifying a potential difference in post-ERCP pancreatitis incidence in patients receiving prophylactic rectal NSAIDs. TRIAL REGISTRATION: EudraCT: 2015-000829-37 . Registered on 18 February 2015. ISRCTN: 13659155 . Registered on 18 May 2015. PMID- 29606137 TI - Effect of timing on baseline quality of life scores among surgical cancer patients. AB - OBJECTIVES: To investigate differences between quality of life (QoL) scores obtained preoperatively or recalled in the early postoperative period amongst patients undergoing major cancer surgery. RESULTS: Of the 283 patients included, 133 completed their baseline QoL questionnaire preoperatively and 150 postoperatively. Patient groups were broadly comparable in terms of age however the preoperative group had a lower proportion of patients from non-English speaking backgrounds. There were important and statistically significant differences between mean scores for physical health (overall physical health, physical functioning and role physical domains) and mental health (overall mental health and mental health domains) between pre- and postoperative groups. There were no differences for other domain-specific scores (bodily pain, general health, vitality, social functioning and role emotional). PMID- 29606136 TI - Low omega-3 index values and monounsaturated fatty acid levels in early pregnancy: an analysis of maternal erythrocytes fatty acids. AB - BACKGROUND: It is unanimously recognized that the maternal nutritional status at the pregnancy onset influence both short-term and long-term health of the mother and offspring. Among several nutrients, LCPUFA, particularly from the omega-3 family, are of utmost importance. This study was carried out to determine fatty acids profile of maternal erythrocyte membranes in early pregnancy and to identify potential determinants impacting on this status. METHODS: A cohort of 122 healthy women with a singleton pregnancy was included. Fatty acids were analyzed using gas chromatography. Because of the lack of cutoff values, reference ranges were used to determine fatty acids categories. RESULTS: Of concern, our data revealed low monounsaturated and long-chain omega-3 fatty acid status in most participants. More than 75% of Belgian pregnant women exhibited Pal, AO and EPA levels as well as IOM3 values below the laboratory reference ranges. Higher DHA concentrations and IOM3 values were found among foreign nationality participants, non-smokers and physically active women. With regard to dietary factors, omega-3 supplements and diet seem to be complementary since DHA from supplements (but not from diet) and EPA from diet (but not from supplements) were found to be associated with higher concentrations of DHA and EPA, respectively. CONCLUSIONS: Our study presents evidence demonstrating that the fatty acid status of most early pregnant women is far from being optimal based on the admitted general reference values. Clinicians should be advice to carefully evaluate and improve this status to guarantee the best possible outcome for both the mother and the baby. PMID- 29606138 TI - Attitudes towards community gambling venues and support for regulatory reform: an online panel study of residents in New South Wales, Australia. AB - BACKGROUND: Harmful gambling has been identified as an important public health issue that affects individuals, families and the broader community. One gambling product, electronic gambling machines (EGMs), has been associated with significant gambling harm in Australia. There has been limited research that has explored community perceptions of EGMs and attitudes towards reform. This study, conducted in NSW, Australia, aimed to explore community use of EGM venues (clubs and hotels containing EGMs), attitudes towards EGMs and whether the use of these venues influenced attitudes towards EGM reform. METHODS: An online survey was conducted with 500 adults aged 16 years and over, representative of the population for age and gender. Discrete choice and open-ended questions were used to gather data on gambling behaviours, use of and attitudes towards EGMs and EGM venues and support for gambling harm reduction measures. RESULTS: Three quarters of participants had visited an EGM venue in the previous year. Participants who had attended such venues were significantly more likely to use EGMs at least once per month. Participants attended EGM venues for a range of reasons including use of non-gambling facilities such as restaurants, the social aspects of the venue and ease of access to the venue. Some participants also attended EGM venues specifically for the gambling facilities. Most participants identified some negative impacts of EGMs for local communities and were supportive of measures to reduce the number of EGMs and prevent children's exposure to EGMs in such venues. CONCLUSIONS: This study shows a high level of support for EGM reform amongst both individuals who attend EGM venues and also those who do not. There is potential for government to further regulate EGMs and the environments where they are located. PMID- 29606139 TI - Mathematical modelling of interacting mechanisms for hypoxia mediated cell cycle commitment for mesenchymal stromal cells. AB - BACKGROUND: Existing experimental data have shown hypoxia to be an important factor affecting the proliferation of mesenchymal stromal cells (MSCs), but the contrasting observations made at various hypoxic levels raise the questions of whether hypoxia accelerates proliferation, and how. On the other hand, in order to meet the increasing demand of MSCs, an optimised bioreactor control strategy is needed to enhance in vitro production. RESULTS: A comprehensive, single-cell mathematical model has been constructed in this work, which combines cellular oxygen sensing with hypoxia-mediated cell cycle progression to predict cell cycle commitment as a proxy to proliferation rate. With oxygen levels defined for in vitro cell culture, the model predicts enhanced proliferation under intermediate (2-8%) and mild (8-15%) hypoxia and cell quiescence under severe (< 2%) hypoxia. Global sensitivity analysis and quasi-Monte Carlo simulation revealed that within a certain range (+/- 100%), model parameters affect (with varying significance) the minimum commitment time, but the existence of a range of optimal oxygen tension could be preserved with the hypothesized effects of Hif2alpha and reactive oxygen species (ROS). It appears that Hif2alpha counteracts Hif1alpha and ROS-mediated protein deactivation under intermediate hypoxia and normoxia (20%), respectively, to regulate the response of cell cycle commitment to oxygen tension. CONCLUSION: Overall, this modelling study offered an integrative framework to capture several interacting mechanisms and allowed in silico analysis of their individual and collective roles in shaping the hypoxia-mediated commitment to cell cycle. The model offers a starting point to the establishment of a suitable mechanism that can satisfactorily explain the different existing experimental observations from different studies, and warrants future extension and dedicated experimental validation to eventually support bioreactor optimisation. PMID- 29606140 TI - Identification of immunologic and clinical characteristics that predict inflammatory response to C. Novyi-NT bacteriolytic immunotherapy. AB - BACKGROUND: Clostridium novyi-NT (CNV-NT), has shown promise as a bacterolytic therapy for solid tumors in mouse models and in dogs with naturally developing neoplasia. Factors that impact the immunologic response to therapy are largely unknown. The goal of this pilot study was to determine if plasma immune biomarkers, immune cell function, peripheral blood cytological composition and tumor characteristics including evaluation of a PET imaging surrogate of tumor tissue hypoxia could predict which dogs with naturally developing naive neoplasia would develop an inflammatory response to CNV-NT. RESULTS: Dogs that developed an inflammatory response to CNV-NT had a higher heart rate, larger gross tumor volume, greater tumor [64Cu]ATSM SUVMax, increased constitutive leukocyte IL-10 production, more robust NK cell-like function and greater peripheral blood lymphocyte counts compared to dogs that did not develop an inflammatory response to CNV-NT. Of these, unstimulated leukocyte IL-10 production, heart rate, and gross tumor volume appeared to be the best predictors of which dogs will develop an inflammatory response to CNV-NT. CONCLUSIONS: Development of inflammation in response to CNV-NT is best predicted by pretreatment unstimulated leukocyte IL-10 production, heart rate, and gross tumor volume. PMID- 29606141 TI - 'Researchers have love for life': opportunities and barriers to engage pregnant women in malaria research in post-Ebola Liberia. AB - BACKGROUND: Adoption of prevention and therapeutic innovations to ensure that National Malaria Control Programmes meet their incidence reduction targets is highly dependent on the conduct of rigorous clinical trials. In Liberia, malaria control virtually halted during the recent Ebola epidemic, and could enormously benefit from innovations to protect its most vulnerable populations, including pregnant women, against malaria. Health policy-planners could feel more inclined to adopt novel interventions with demonstrated safety and efficacy when trialled among their women population. However, pregnant women are especially vulnerable when targeted as research participants. Whilst some studies in the region attempted to understand the ethical issues around the conduct of clinical research, there is need of such information from Liberia to inform future malaria research. METHODS: This is a grounded theory study that aims to understand the barriers and opportunities for pregnant women to consent to participate in malaria research in Liberia. The study was conducted between November 2016 and May 2017 at the St Joseph's Catholic Hospital, Monrovia. In-depth interviews and focus group discussions were held with hospital staff, traditional community representatives, and pregnant women. RESULTS: According to the participants, useful strategies to motivate pregnant women to consent to participate in malaria research could be providing evidence-based education on malaria and research to the general population and encouraging engagement of traditional leaders in research design and community mobilization. Fears and suspicions towards research and researchers, which were amplified during the conduct of Ebola vaccine and drug clinical trials, may influence women's acceptance and willingness to engage in malaria research. Population's mistrust in the public healthcare system might hinder their acceptance of research, undermining the probability of their benefiting from any improved malaria control intervention. CONCLUSION: Benchmarking for acceptable practices from previous public health interventions; building community discussion and dissemination platforms; and mapping communication and information errors from how previous research interventions were explained to the Liberian population, are strategies that might help ensure a safe and fully informed participation of pregnant women in malaria research. Inequity issues impeding access and use of biomedical care for women must be tackled urgently. PMID- 29606142 TI - Seroprevalence of anti-Toxoplasma gondii antibodies in Egyptian sheep and goats. AB - BACKGROUND: Toxoplasmosis is a zoonotic disease that affects a wide range of animals, including small ruminants. Sheep and goats are considered as biological indicators for the contamination of the environment with Toxoplasma gondii oocysts. In addition, in countries such as Egypt, where sheep and goat meat is frequently consumed, T. gondii infection in small ruminants may also pose a public health risk. To establish baseline estimates of the prevalence of T. gondii infection in Egyptian small ruminants, we used an indirect immunofluorescence assay (IFA) and an enzyme-linked immunosorbent assay (ELISA) to assess the seroprevalence in 398 sheep from four Egyptian governorates (Cairo, Giza, Dakahlia and Sharkia) and in 100 goats from Dakahlia. The positive and negative agreements of both tests were calculated and the true prevalence was estimated using a Bayesian approach. RESULTS: The true prevalence of antibodies to T. gondii as determined by both tests was higher in Egyptian goats (62%) than in sheep for each province (between 4.1 and 26%). Sheep slaughtered at the Cairo abattoir had the lowest true prevalence (4.1%), while true prevalences in Dakahlia, Giza and Sharkia governorates (26%, 23% and 12%, respectively) were substantially higher. CONCLUSIONS: The high prevalence of antibodies to T. gondii may indicate an important role of goat and sheep in the transmission of human toxoplasmosis in Egypt, given the habit of eating undercooked grilled mutton. PMID- 29606143 TI - Evaluation of mindfulness-based cognitive therapy for life and a cognitive behavioural therapy stress-management workshop to improve healthcare staff stress: study protocol for two randomised controlled trials. AB - BACKGROUND: Healthcare workers experience higher levels of work-related stress and higher rates of sickness absence than workers in other sectors. Psychological approaches have potential in providing healthcare workers with the knowledge and skills to recognise stress and to manage stress effectively. The strongest evidence for effectiveness in reducing stress in the workplace is for stress management courses based on cognitive behavioural therapy (CBT) principles and mindfulness-based interventions (MBIs). However, research examining effects of these interventions on sickness absence (an objective indicator of stress) and compassion for others (an indicator of patient care) is limited, as is research on brief CBT stress-management courses (which may be more widely accessible) and on MBIs adapted for workplace settings. METHODS/DESIGN: This protocol is for two randomised controlled trials with participant preference between the two trials and 1:1 allocation to intervention or wait-list within the preferred choice. The first trial is examining a one-day CBT stress-management workshop and the second trial an 8-session Mindfulness-Based Cognitive Therapy for Life (MBCT-L) course, with both trials comparing intervention to wait-list. The primary outcome for both trials is stress post-intervention with secondary outcomes being sickness absence, compassion for others, depression symptoms, anxiety symptoms, wellbeing, work-related burnout, self-compassion, presenteeism, and mindfulness (MBCT-L only). Both trials aim to recruit 234 staff working in the National Health Service in the UK. DISCUSSION: This trial will examine whether a one-day CBT stress-management workshop and an 8-session MBCT-L course are effective at reducing healthcare staff stress and other mental health outcomes compared to wait-list, and, whether these interventions are effective at reducing sickness absence and presenteeism and at enhancing wellbeing, self-compassion, mindfulness and compassion for others. Findings will help inform approaches offered to reduce healthcare staff stress and other key variables. A note of caution is that individual-level approaches should only be part of the solution to reducing healthcare staff stress within a broader focus on organisational-level interventions and support. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN11723441 . Registered on 16 June 2017. Protocol Version 1: 24 April 2017. Trial Sponsor: Sussex Partnership NHS Foundation Trust (ResearchGovernance@sussexpartnership.nhs.uk). PMID- 29606144 TI - In vitro evaluation of chloroquine-loaded and heparin surface-functionalized solid lipid nanoparticles. AB - BACKGROUND: Use of chloroquine, an otherwise safe and relatively affordable anti malarial drug, was discontinued due to widespread prevalence of resistant parasites. Many entrant anti-malarial drugs for treatment of chloroquine resistant malaria raises the concerns of cost and safety among other challenges. Innovative ways of circumventing chloroquine resistance is of paramount importance. Such may include nanoparticulate delivery strategies and targeting. This study evaluated physicochemical properties and in vitro antiplasmodial activity of chloroquine encapsulated heparin functionalized solid lipid nanoparticles (CQ-Hep-SLNs) and non-heparin functionalized SLNs (CQ-SLN) against Plasmodium falciparum. METHODS: The modified double-emulsion solvent evaporation technique was used to prepare the nanoparticles. HPLC/UV was used to determine the in vitro drug release. The semi-automated micro-dilution technique was adapted in assessing the in vitro antiplasmodial activity to give drug concentration capable of inhibiting 50% of the P. falciparum (IC50), as a function of antiplasmodial efficacy. RESULTS: Prepared nanoparticles were below 500 nm in size with % drug loading (%DL) between 21 and 25% and encapsulation efficiency (%EE) of 78-90%. The drug-loaded SLN exhibited a biphasic drug release profile at pH 7.4, with an initial burst release during the first 24 h followed by sustained release in both formulations. Nanoformulated CQ-SLN (4.72 +/- 0.14 ng/mL) and CQ-Hep-SLN (2.41 +/- 0.27 ng/mL), showed enhanced in vitro antiplasmodial activities against chloroquine sensitive (D6) strain of P. falciparum, albeit with no activity against the chloroquine resistant W2 strain, compared to free CQ standard (5.81 +/- 0.18 ng/mL). CONCLUSIONS: These findings suggest that the nanoformulated drugs displayed enhanced anti-malarial activities against chloroquine sensitive (D6) strains of P. falciparum compared to the free CQ standard. There is some form of potential dual synergistic effect of CQ-loaded heparinized solid lipid nanoparticles (Hep-SLN), meaning that combining heparin and CQ in SLNs has beneficial effects, including potential for specific targeting of parasitized red blood cells as afforded by heparin. Thus, the study has produced SLNs nanoparticles that have superior in vitro activities than CQ on CQ sensitive parasites. PMID- 29606145 TI - Are dietary inequalities among Australian adults changing? a nationally representative analysis of dietary change according to socioeconomic position between 1995 and 2011-13. AB - BACKGROUND: Increasing inequalities in rates of obesity and chronic disease may be partly fuelled by increasing dietary inequalities, however very few nationally representative analyses of socioeconomic trends in dietary inequalities exist. The release of the 2011-13 Australian National Nutrition and Physical Activity Survey data allows investigation of change in dietary intake according to socioeconomic position (SEP) in Australia using a large, nationally representative sample, compared to the previous national survey in 1995. This study examined change in dietary intakes of energy, macronutrients, fiber, fruits and vegetables among Australian adults between 1995 and 2011-13, according to SEP. METHODS: Cross-sectional data were obtained from the 1995 National Nutrition Survey, and the 2011-13 National Nutrition and Physical Activity Survey. Dietary intake data were collected via a 24-h dietary recall (n = 17,484 adults) and a dietary questionnaire (n = 15,287 adults). SEP was assessed according to educational level, equivalized household income, and area-level disadvantage. Survey-weighted linear and logistic regression models, adjusted for age, sex/gender and smoking status, examined change in dietary intakes over time. RESULTS: Dietary intakes remained poor across the SEP spectrum in both surveys, as evidenced by high consumption of saturated fat and total sugars, and low fiber, fruit and vegetable intakes. There was consistent evidence (i.e. according to >=2 SEP measures) of more favorable changes in dietary intakes of carbohydrate, polyunsaturated and monounsaturated fat in higher, relative to lower SEP groups, particularly in women. Intakes of energy, total fat, saturated fat and fruit differed over time according to a single SEP measure (i.e. educational level, household income, or area-level disadvantage). There were no changes in intake of total sugars, protein, fiber or vegetables according to any SEP measures. CONCLUSIONS: There were few changes in dietary intakes of energy, most macronutrients, fiber, fruits and vegetables in Australian adults between 1995 and 2011-13 according to SEP. For carbohydrate, polyunsaturated and monounsaturated fat, more favorable changes in intakes occurred in higher SEP groups. Despite the persistence of suboptimal dietary intakes, limited evidence of widening dietary inequalities is positive from a public health perspective. TRIAL REGISTRATION: Clinical trials registration: ACTRN12617001045303 . PMID- 29606146 TI - The dopamine D1 receptor is expressed and induces CREB phosphorylation and MUC5AC expression in human airway epithelium. AB - Background: Dopamine receptors comprise two subgroups, Gs protein-coupled "D1 like" receptors (D1, D5) and Gicoupled "D2-like" receptors (D2, D3, D4). In airways, both dopamine D1 and D2 receptors are expressed on airway smooth muscle and regulate airway smooth muscle force. However, functional expression of the dopamine D1 receptor has never been identified on airway epithelium. Activation of Gs-coupled receptors stimulate adenylyl cyclase leading to cyclic AMP (cAMP) production, which is known to induce mucus overproduction through the cAMP response element binding protein (CREB) in airway epithelial cells. We questioned whether the dopamine D1 receptor is expressed on airway epithelium, and whether it promotes CREB phosphorylation and MUC5AC expression. Methods: We evaluated the protein expression of the dopamine D1 receptor on native human airway epithelium andthree sources of cultured human airway epithelial cells including primary cultured airway epithelial cells, the bronchial epithelial cell line (16HBE14o-), and the pulmonary mucoepidermoid carcinoma cell line (NCI-H292) using immunohistochemistry and immunoblotting. To characterize the stimulation of cAMP through the dopamine D1 receptor, 16HBE14o- cells and NCI-H292 cells were treated with dopamine or the dopamine D1 receptor agonists (SKF38393 or A68930) before cAMP measurements. The phosphorylation of CREB by A68930 in both 16HBE14o- and NCI-H292 cells was measured by immunoblot. The effect of dopamine or A68930 on the expression of MUC5AC mRNA and protein in NCI-H292 cells was evaluated by real time PCR and immunofluorescence staining, respectively. Results: The dopamine D1 receptor protein was detected in native human airway epithelium and three sources ofcultured human airway epithelial cells. Dopamine or the dopamine D1-like receptor agonists stimulated cAMP production in 16HBE14o- cells and NCI-H292 cells, which was reversed by the selective dopamine D1-like receptor antagonists (SCH23390 or SCH39166). A68930 significantly increased phosphorylation of CREB in both 16HBE14o- and NCI-H292 cells, which was attenuated by the inhibitors of PKA (H89) and MEK (U0126). Expression of MUC5AC mRNA and protein were also increased by either dopamine or A68930 in NCI-H292 cells. Conclusions: These results suggest that the activation of the dopamine D1 receptor on human airway epitheliumcould induce mucus overproduction, which could worsen airway obstructive symptoms. PMID- 29606147 TI - Baseline antibody profiles predict toxicity in melanoma patients treated with immune checkpoint inhibitors. AB - BACKGROUND: Immune checkpoint inhibitors (anti-CTLA-4, anti-PD-1, or the combination) enhance anti-tumor immune responses, yielding durable clinical benefit in several cancer types, including melanoma. However, a subset of patients experience immune-related adverse events (irAEs), which can be severe and result in treatment termination. To date, no biomarker exists that can predict development of irAEs. METHODS: We hypothesized that pre-treatment antibody profiles identify a subset of patients who possess a sub-clinical autoimmune phenotype that predisposes them to develop severe irAEs following immune system disinhibition. Using a HuProt human proteome array, we profiled baseline antibody levels in sera from melanoma patients treated with anti-CTLA-4, anti-PD-1, or the combination, and used support vector machine models to identify pre-treatment antibody signatures that predict irAE development. RESULTS: We identified distinct pre-treatment serum antibody profiles associated with severe irAEs for each therapy group. Support vector machine classifier models identified antibody signatures that could effectively discriminate between toxicity groups with > 90% accuracy, sensitivity, and specificity. Pathway analyses revealed significant enrichment of antibody targets associated with immunity/autoimmunity, including TNFalpha signaling, toll-like receptor signaling and microRNA biogenesis. CONCLUSIONS: Our results provide the first evidence supporting a predisposition to develop severe irAEs upon immune system disinhibition, which requires further independent validation in a clinical trial setting. PMID- 29606148 TI - Telerehabilitation for aphasia - protocol of a pragmatic, exploratory, pilot randomized controlled trial. AB - BACKGROUND: The Cochrane review on the effectiveness of speech and language therapy for aphasia following stroke suggests intensity of therapy is a key predictor for outcome. Current aphasia services cannot provide intervention at the intensity observed within trial contexts because of resource limitations. Telerehabilitation could widen access to speech-language pathologists (SLPs) in geographically remote contexts and reduce the time spent on travel by the therapist and patient. The current academic literature within this field is in its infancy, with few trials of speech and language therapy (SLT) delivered by videoconference. Our pilot randomized controlled trial (RCT) will explore feasibility aspects and effectiveness of telerehabilitation for aphasia in addition to standard SLT. METHOD/DESIGN: Our study is a pragmatic, exploratory, pilot randomized controlled trial, where participants will be randomized to a telerehabilitation group or a control group. Both groups receive standard SLT (usual care) but the telerehabilitation group receives an additional 5 h of telerehabilitation per week over 4 weeks through videoconference. This additional telerehabilitation focuses on spoken language with an emphasis on word naming. We aim to include 40 patients in each group, with inclusion criteria being aphasia any time post stroke. Participants will be assessed blindly at pre-randomization (baseline), and 4 weeks and 4 months after randomization. The primary endpoint is naming ability 3 months after the completed intervention, measured by the Norwegian Basic Aphasia Assessment (NGA) naming subtest. Secondary endpoints include other subtests of the NGA, the VAST (Verb and Sentence Test) subtest sentence production, Communicative Effectiveness Index (CETI) and the Stroke and Aphasia Quality of Life scale (SAQOL-39). Experiences of patients and SLPs with telerehabilitation are assessed using questionnaires and semi-structured interviews. Statistical between group comparisons will be in line with an intention-to-treat analysis. DISCUSSION: This pilot RCT of intensive language training by videoconference will contribute new scientific evidence to the field of aphasia telerehabilitation. Here, we describe our trial which will explore the feasibility of telerehabilitation for aphasia as an intervention, our choice of primary and secondary outcome measures and proposed analyses. Our trial will provide information for the development and delivery of future definitive RCTs. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02768922 . Registered on 11 May 2016. Last updated on 17 November 2017. PMID- 29606149 TI - Influence of 68Ga-DOTATOC on sparing of normal tissue for radiation therapy of skull base meningioma: differential impact of photon and proton radiotherapy. AB - BACKGROUND: To evaluate the impact of 68Ga-DOTATOC-PET on treatment planning and sparing of normal tissue in the treatment of skull base meningioma with advanced photons and protons. METHODS: From the institutional database consisting of 507 skull base meningiomas 10 patients were chosen randomly for the present analysis. Target volume definition was performed based on CT and MRI only, as well as with additional 68Ga-DOTATOC-PET. Treatment plans were performed for Intensity Modulated Radiotherapy (IMRT) and proton therapy using active raster scanning on both target volumes. We calculated doses to relevant organs at risk (OAR), conformity indices as well as differences in normal tissue sparing between both radiation modalities based on CT/MRI planning as well as CT/MRI/PET planning. RESULTS: For photon treatment plans, PET-based treatment plans showed a reduction of brain stem Dmax and Dmedian for different levels of total dose. At the optic chiasm, use of 68Ga-DOTATOC significantly reduces Dmax; moreover, the Dmedian is reduced in most cases, too. For both right and left optic nerve, reduction of dose by addition of 68Ga-DOTATOC-PET is minimal and depends on the anatomical location of the meningioma. In protons, the impact of 68Ga-DOTATOC-PET is minimal compared to photons. CONCLUSION: Addition of 68Ga-DOTATOC-PET information into treatment planning for skull base meningiomas has a significant impact on target volumes. In most cases, PET-planning leads to significant reductions of the treatment volumes. Subsequently, reduced doses are applied to OAR. Using protons, the benefit of additional PET is smaller since target coverage is more conformal and dose to OAR is already reduced compared to photons. Therefore, PET-imaging has the greatest margin of benefit in advanced photon techniques, and combination of PET-planning and high-precision treatment leads to comparable treatment plans as with protons. PMID- 29606152 TI - Bilateral ureterolithiasis: A true positive and false negative PoCUS exam in a patient with renal colic. AB - Acute flank pain from suspected urolithiasis is a common presenting complaint in the Emergency Department. Multiple computed tomography (CT) has traditionally been the standard imaging modality used to diagnose obstructive kidney stones, however point of care ultrasound (PoCUS) can play an important role in the diagnostic algorithm and risk stratification of acute flank pain. Here, we present the case of a 29-year-old female with suspected urolithiasis, who underwent PoCUS that revealed right-sided hydronephrosis and normal left kidney, bladder, and aorta. A subsequent KUB was negative. As the clinical course failed to improve with therapy, an abdominal and pelvic CT was ordered revealing a 5 mm distal obstructing ureteric calculus at the right vesico-ureteric junction and another 5 mm left mid ureteric calculus. To the best of our knowledge, this is the first case in which a patient presenting with acute right-sided flank pain demonstrated unilateral hydronephrosis on PoCUS, but had clinically significant bilateral ureteric stones on CT. Emergency physicians who employ PoCUS for evaluation of flank pain must be aware of its benefits and drawbacks and how they apply to each patient. As such, we have developed a script emergency physicians can use for shared decision-making with renal colic patients when deciding on the appropriate imaging modality. PMID- 29606150 TI - Stereotactic ablative radiotherapy for ultra-central lung tumors: prioritize target coverage or organs at risk? AB - BACKGROUND: Lung stereotactic ablative radiotherapy (SABR) is associated with low morbidity, however there is an increased risk of treatment-related toxicity in tumors directly abutting or invading the proximal bronchial tree, termed 'ultra central' tumors. As there is no consensus regarding the optimal radiotherapy treatment regimen for these tumors, we performed a modeling study to evaluate the trade-offs between predicted toxicity and local control for commonly used high precision dose-fractionation regimens. METHODS: Ten patients with ultra-central lung tumors were identified from our institutional database. New plans were generated for 3 different hypofractionated schemes: 50 Gy in 5 fractions, 60 Gy in 8 fractions and 60 Gy in 15 fractions. For each regimen, one plan was created that prioritized planning target volume (PTV) coverage, potentially at the expense of organ at risk (OAR) tolerance, and a second that compromised PTV coverage to respect OAR dose constraints. Published radiobiological models were employed to evaluate competing treatment plans based on estimates for local control and the likelihood for toxicity to OAR. RESULTS: The risk of esophageal or pulmonary toxicity was low (< 5%) in all scenarios. When PTV coverage was prioritized, tumor control probabilities were 92.9% for 50 Gy in 5 fractions, 92.4% for 60 Gy in 8 fractions, and 52.0% for 60 Gy in 15 fractions; however the estimated risk of grade >= 4 toxicity to the proximal bronchial tree was 68%, 44% and 2% respectively. When dose to OAR was prioritized, the risk of major pulmonary toxicity was reduced to < 1% in all schemes, but this compromise reduced tumor control probability to 60.3% for 50 Gy in 5 fractions, 65.7% for 60 Gy in 8 fractions and 47.8% for 60 Gy in 15 fractions. CONCLUSIONS: The tradeoff between local control and central airway toxicity are considerable in the use of 3 commonly used hypofractionated radiotherapy regimens for ultra-central lung cancer. The results of this planning study predict that the best balance may be achieved with 60 Gy in 8 fractions compromising PTV coverage as required to maintain acceptable doses to OAR. A prospective phase I trial (SUNSET) is planned to further evaluate this challenging clinical scenario. PMID- 29606153 TI - Prospective Memory Is a Key Predictor of Functional Independence in Older Adults. AB - OBJECTIVES: Prospective memory (PM), the ability to execute delayed intentions, has received increasing attention in neuropsychology and gerontology. Most of this research is motivated by the claim that PM is critical for maintaining functional independence; yet, there is a dearth of empirical evidence to back up the claims. Thus, the present study tested whether PM predicts functional independence in older adults using validated behavioral performance measures for both PM and functional independence. METHODS: Fifty-eight healthy older adults performed a computerized PM paradigm, the Virtual Week task, as well as a timed version of an instrumental activities of daily living (TIADL) task. Furthermore, we assessed vocabulary, processing speed, and self-reported prospective remembering. RESULTS: TIADL scores correlated significantly with performance in the Virtual Week task, vocabulary, and processing speed. Hierarchical linear regressions revealed that vocabulary and Virtual Week performance were significant predictors for TIADL. However, self-reported PM scores did not predict everyday functioning. CONCLUSIONS: The findings indicate that PM is an important cognitive ability for successful and independent everyday life beyond vocabulary. Moreover, the results show a substantial incremental contribution of intact PM performance for the prediction of everyday functioning by using objective PM measures. (JINS, 2018, 24, 640-645). PMID- 29606151 TI - FTO variant is not associated with osteoarthritis in the Chinese Han population: replication study for a genome-wide association study identified risk loci. AB - BACKGROUND: Osteoarthritis is the most prevalent form of arthritis worldwide and is the major cause of pain and loss of function in elderly people. A signal of the fat mass and obesity-associated (FTO) gene had been reported in a genome-wide association study of osteoarthritis. The FTO polymorphism (rs8044769) might exert its effect on osteoarthritis through obesity, because it was reported as a body mass index-associated single-nucleotide polymorphism. And replication studies showed inconsistent results for this association. Our present study is to check the association of rs8044769 with osteoarthritis and body mass index in Chinese Han population. METHODS: A case-control association study was conducted by using 890 osteoarthritis cases and 844 controls in Chinese Han population. rs8044769 was genotyped in all subjects. Allelic and genotypic frequencies were compared between osteoarthritis cases and control subjects. Associations between rs8044769 and body mass index, and body mass index and osteoarthritis were also assessed. RESULTS: No significant difference was detected in genotype or allele distribution between osteoarthritis cases and controls (P > 0.05). Stratification by gender and body mass index revealed negative association between rs8044769 and osteoarthritis. We did not find any solid association between rs8044769 and higher body mass index. Meanwhile, we demonstrated that higher body mass index (body mass index >= 25) was associated with osteoarthritis. CONCLUSION: Our present study suggested that rs8044769 was not associated with osteoarthritis susceptibility or higher body mass index, and higher body mass index was a risk factor for osteoarthritis in the Chinese Han population. We also proposed that stratification by clinical parameters was crucial to reduce false-positive result in OA association studies. PMID- 29606154 TI - Relationships among person-centered care, nursing home adjustment, and life satisfaction: a cross-sectional survey study. AB - : ABSTRACTBackground:The purpose of this study was to examine whether a perceived person-centered nursing home environment has a direct relationship with nursing home adjustment and life satisfaction, and whether a perceived person-centered nursing home environment has an indirect relationship with life satisfaction through improved nursing home adjustment. METHODS: 203 nursing home residents who were able to read and speak English and were physically and cognitively able to respond to questionnaires were included in this study. Data were collected from six nursing homes in the Midwestern US. RESULTS: Higher levels of a perceived person-centered nursing home environment had a significantly direct relationship with increased life satisfaction of residents (beta = 0.35), and this relationship was mediated by residents' improved nursing home adjustment (beta = 0.10). In-depth exploration using sub-domains of the main variables demonstrated that "safety" and "everydayness" of a person-centered nursing home environment were directly related to higher levels of life satisfaction (beta = 0.15 and beta = 0.16, respectively); and "everydayness" was related to three sub-domains of nursing home adjustment: better "relationship development," "acceptance of the new residence" (beta = 0.32 and beta = 0.24, respectively), and lower "depressed mood" (beta = 0.05). The positive relationship between "everydayness" and life satisfaction was partially mediated by the "relationship development" sub-domain of nursing home adjustment (beta = 0.07). CONCLUSIONS: The findings provide new evidence for the positive association between person-centered care and nursing home adjustment. The findings also provide insights into the mechanism through which the specific sub-domains of person-centered care and nursing home adjustment operate in the path model. PMID- 29606155 TI - Patient Involvement in Healthcare-Associated Infection Research: A Lexical Review. AB - OBJECTIVEThis review examines patient involvement in healthcare-associated infection (HAI) research. Healthcare-associated infections represent an intractable issue with considerable implications for patients and staff. Participatory methodologies that involve patients in healthcare research are associated with myriad benefits.DESIGNLexical review.METHODSPubMed was searched to identify all publications on patient involvement in HAI research since 2000; publications were also identified from the cited references. A lexical analysis was conducted of the methods sections of 148 publications.RESULTSThe findings reveal that HAI research that actively involves patients and members of the public is limited.CONCLUSIONSPatient involvement is largely limited to recruitment to HAI studies rather than extended to patient involvement in research design, implementation, analysis, and/or dissemination. As such, there is considerable opportunity to further this important research area via alternative methodologies that award primacy to patient expertise and agency.Infect Control Hosp Epidemiol 2018;39:710-717. PMID- 29606156 TI - Correlation of Hand Hygiene Compliance Measured by Direct Observation with Estimates Obtained from Product Usage. AB - Improving compliance with hand hygiene is a cornerstone of infection prevention. However, data regarding practical methods for monitoring compliance are limited. We found that product use metrics have a moderate correlation with direct observation in ward settings and limited correlation in intensive care units.Infect Control Hosp Epidemiol 2018;39:746-749. PMID- 29606157 TI - Co-infection with filarial nematodes in Sapajus macrocephalus and Cebus albifrons (Primates: Cebidae) from the Peruvian Amazon. AB - Dipetalonema caudispina (Molin, 1858) and D. gracile (Rudolphi, 1809) (Filarioidea: Onchocercidae) are two of six known species of filarial nematodes that parasitize Neotropical non-human primates. Adult filariae were collected from the thoracic and abdominal cavities of 38 of 44 specimens of Sapajus macrocephalus (Spix, 1823) and nine of ten specimens of Cebus albifrons (Humboldt, 1812) (Primates: Cebidae), distributed in the Yavari-Mirin river basin and used locally for human consumption. Co-occurrence of D. caudispina and D. gracile is reported for the first time, with a prevalence of 18.5% (10 of 54 hosts examined). Our finding of D. caudispina and D. gracile in cebids from the Peruvian Amazon constitutes a new geographical record for both filariae, two new host records for D. caudispina, and the first report of D. gracile in S. macrocephalus. In addition, we provide morphometric data for D. caudispina, complementing the original description, as well as scanning electron microscopy details on the structure of the area rugosa and number of caudal papillae in males. PMID- 29606158 TI - Time location sampling in men who have sex with men in the HIV context: the importance of taking into account sampling weights and frequency of venue attendance. AB - Sex between men is the most frequent mode of HIV transmission in industrialised countries. Monitoring risk behaviours among men who have sex with men (MSM) is crucial, especially to understand the drivers of the epidemic. A cross-sectional survey (PREVAGAY), based on time-location sampling, was conducted in 2015 among MSM attending gay venues in 5 metropolitan cities in France. We applied the generalised weight share method (GWSM) to estimate HIV seroprevalence for the first time in this population, taking into account the frequency of venue attendance (FVA). Our objectives were to describe the implementation of the sampling design and to demonstrate the importance of taking into account sampling weights, including FVA by comparing results obtained by GWSM and by other methods which use sample weights not including FVA or no weight. We found a global prevalence of 14.3% (95% CI (12.0-16.9)) using GWSM and an unweighted prevalence of 16.4% (95% CI (14.9-17.8)). Variance in HIV prevalence estimates in each city was lower when we did not take into account either the sampling weights or the FVA. We also highlighted an association of FVA and serological status in the most of investigated cities. PMID- 29606159 TI - Review: The variability of the eating quality of beef can be reduced by predicting consumer satisfaction. AB - The Meat Standards Australia (MSA) grading scheme has the ability to predict beef eating quality for each 'cut*cooking method combination' from animal and carcass traits such as sex, age, breed, marbling, hot carcass weight and fatness, ageing time, etc. Following MSA testing protocols, a total of 22 different muscles, cooked by four different cooking methods and to three different degrees of doneness, were tasted by over 19 000 consumers from Northern Ireland, Poland, Ireland, France and Australia. Consumers scored the sensory characteristics (tenderness, flavor liking, juiciness and overall liking) and then allocated samples to one of four quality grades: unsatisfactory, good-every-day, better than-every-day and premium. We observed that 26% of the beef was unsatisfactory. As previously reported, 68% of samples were allocated to the correct quality grades using the MSA grading scheme. Furthermore, only 7% of the beef unsatisfactory to consumers was misclassified as acceptable. Overall, we concluded that an MSA-like grading scheme could be used to predict beef eating quality and hence underpin commercial brands or labels in a number of European countries, and possibly the whole of Europe. In addition, such an eating quality guarantee system may allow the implementation of an MSA genetic index to improve eating quality through genetics as well as through management. Finally, such an eating quality guarantee system is likely to generate economic benefits to be shared along the beef supply chain from farmers to retailors, as consumers are willing to pay more for a better quality product. PMID- 29606160 TI - Molecular identification of zoonotic hookworm species in dog faeces from Tanzania. AB - The presence and distribution of various species of canine hookworms in Africa are poorly known. The main objective of this study, therefore, was to identify the hookworm species present in canine faecal samples from Morogoro, Tanzania, using molecular techniques. Faecal samples from 160 local dogs were collected and hookworm positive samples processed to recover larvae for further molecular characterization. DNA was extracted from pools of larvae from individual samples (n = 66), which were analysed subsequently using two different molecular approaches, polymerase chain reaction-linked restriction fragment length polymorphism (PCR-RFLP) and species-specific PCR coupled with Sanger sequencing. The PCR-RFLP technique detected only the presence of the ubiquitous Ancylostoma caninum in the 66 samples. However, by species-specific PCR coupled with Sanger sequencing we identified ten samples with A. braziliense, two with Uncinaria stenocephala and five with A. ceylanicum. Thus, all four known species of canine hookworms were identified in Morogoro, Tanzania. To our knowledge this is the first report of the detection of the presence of U. stenocephala and A. ceylanicum in Africa using molecular techniques. In addition to their veterinary importance, canine hookworms have zoonotic potential and are of public health concern. PMID- 29606161 TI - "It's in Your Hands-Prevent Sepsis in Health Care": 5 May 2018, World Health Organization (WHO) SAVE LIVES: Clean Your Hands Campaign. PMID- 29606162 TI - Echinococcus granulosus genotypes in Iran: a systematic review. AB - Cystic echinococcosis (CE) caused by Echinococcus granulosus sensu lato (s.l.) is a significant zoonosis, especially in developing countries of the Middle East, with many studies focusing on CE genotypes in Iran. We performed a systematic review to determine the exact status of E. granulosus genotypes in the country. We explored English (Pubmed, Scopus, ISI Web of Science and Science Direct) and Persian (Magiran, Iran Medex and Scientific Information Database) databases along with Google Scholar. Our review included 73 studies published prior to the end of 2015. In total, 2952 animal (intermediate and definitive) hosts were examined, and the prevalent genotypes comprised G1 (92.75%) and G6 (4.53%) in sheep, cattle, camels, goats and buffaloes; G3 (2.43%) in five herbivore hosts and dogs; G7 (0.2%) in sheep and goats; and G2 (0.06%) in dogs. G1 was mostly dominant in West Azerbaijan, whereas G3 and G6 were identified most frequently in the provinces of Isfahan and Fars, respectively. Regarding human CE infection, 340 cases were reported from Iran, with the identified genotypes G1 (n = 320), G6 (n = 13) and G3 (n = 7). Most CE-infected humans originated from Isfahan province (168 cases), whereas the lowest number of infected persons was noted in Kerman province (two cases). The information obtained from this systematic review is central to better understanding the biological and epidemiological characteristics of E. granulosus s.l. genotypes in Iran, leading to more comprehensive control strategies. PMID- 29606163 TI - The Impact of Isolation on Healthcare Worker Contact and Compliance With Infection Control Practices in Nursing Homes. AB - OBJECTIVETo directly observe healthcare workers in a nursing home setting to measure frequency and duration of resident contact and infection prevention behavior as a factor of isolation practiceDESIGNObservational studySETTING AND PARTICIPANTSHealthcare workers in 8 VA nursing homes in Florida, Maryland, Massachusetts, Michigan, Washington, and TexasMETHODSOver a 15-month period, trained research staff without clinical responsibilities on the units observed nursing home resident room activity for 15-30-minute intervals. Observers recorded time of entry and exit, isolation status, visitor type (staff, visitor, etc), hand hygiene, use of gloves and gowns, and activities performed in the room when visible.RESULTSA total of 999 hours of observation were conducted across 8 VA nursing homes during which 4,325 visits were observed. Residents in isolation received an average of 4.73 visits per hour of observation compared with 4.21 for nonisolation residents (P<.01), a 12.4% increase in visits for residents in isolation. Residents in isolation received an average of 3.53 resident care activities per hour of observation, compared with 2.46 for residents not in isolation (P<.01). For residents in isolation, compliance was 34% for gowns and 58% for gloves. Healthcare worker hand hygiene compliance was 45% versus 44% (P=.79) on entry and 66% versus 55% (P<.01) on exit for isolation and nonisolation rooms, respectively.CONCLUSIONSHealthcare workers visited residents in isolation more frequently, likely because they required greater assistance. Compliance with gowns and gloves for isolation was limited in the nursing home setting. Adherence to hand hygiene also was less than optimal, regardless of isolation status of residents.Infect Control Hosp Epidemiol 2018;39:683-687. PMID- 29606164 TI - Accuracy of composite diagnostic standards for pneumococcal pneumonia in vaccine trials. AB - Because of a lack of gold standard diagnostics, a combination of multiple diagnostic tests, or composite diagnostic standard, has been used to measure pneumococcal pneumonia (PP) in pneumococcal vaccine trials. We estimated the accuracy of composite diagnostic standards for PP used in previous randomised controlled trials by simple formulas. A systematic literature review identified five eligible trials and all trials had used different combinations of diagnostic tests for PP. The estimated values of sensitivity and minimum specificity of composite diagnostic standards varied substantially between trials: 48.4% to 98.1% and 71.0% to 97.3%, respectively. Without standardizing the outcome measurements, pneumococcal vaccine efficacy estimates against PP are not comparable between trials and their pooled estimates are biased. PMID- 29606165 TI - Later-Life Homelessness as Disenfranchised Grief. AB - ABSTRACTAlthough interest on older homelessness is gaining momentum, little research has considered the experiences of first-time homelessness from the perspective of older adults themselves. This constructivist grounded-theory study addresses this gap by exploring how societal perceptions of homelessness and aging shape access to housing, services, and perceptions of self for 15 older adults residing in emergency homeless shelters in Montreal, (Quebec, Canada). Findings revealed that homelessness evoked a grief response characterized by shock, despair, anger, and in some cases, relief. Connecting and receiving support from other shelter residents and staff helped participants to acknowledge and grieve their losses. However, difficult shelter conditions, the stigma associated with aging and homelessness, and not having their grief recognized or validated served to disenfranchise grief experiences. Conceptualizing later-life homelessness as disenfranchised grief contributes to the aging and homelessness literature while providing new avenues for understanding and validating the experiences of a growing population of vulnerable older adults. PMID- 29606166 TI - Factors affecting sensitivity and specificity of head-turning sign in the studies. AB - We read with interest the comment by Williamson and Larner on our recent study titled "Attended With and Head-Turning Sign can be clinical markers of cognitive impairment in older adults" (Soysal et al., 2017). After the authors read the study, they re-examined their data according to the presence of Attended With (AW) and Head-Turning Sign (HTS), and compared their results with ours (Larner, 2014). Then, they found that while the sensitivity, specificity, positive predictive value, and negative predictive value of AW in detecting cognitive impairment were similar to ours, HTS had lower sensitivity (80.95% vs. 65.0%) and higher specificity (64.7% vs. 95.0%) than our results (Larner, 2014; Soysal et al., 2017). We think that some methodological and cultural differences may explain these discrepancies between the two. PMID- 29606167 TI - Response to "Parkinson's disease mild cognitive impairment classifications and neurobehavioral symptoms". AB - A recent paper, "Parkinson's disease mild cognitive impairment classifications and neurobehavioral symptoms" (McDermott et al., 2017), provides an interesting comparison of the influence of different criteria for Parkinson's disease with mild cognitive impairment (PD-MCI) on progression to dementia (PDD). Unfortunately, McDermott et al. (2017) incorrectly stated that "only 21% of PD MCI participants (identified with a 1.5 SD cut-off) converted to PDD within four years" (p.6) in our study (Wood et al., 2016). However, the important point made by Wood et al. (2016) was that the proportion of conversions to PDD was 51% when the PD-MCI diagnosis required a minimum of two 1.5 SD impairments within any single cognitive domain, whereas additional PD-MCI patients classified with one impairment at 1.5 SD in each of the two domains (but never two impairments in the same domain) had a non-significant risk of dementia relative to non-MCI patients (11% vs. 6% converted, respectively). Our PDD conversion rate was 38% when combining both 1.5 SD criteria (21/56 PD-MCI patients vs. 4/65 non-MCI patients converted); McDermott et al. (2017) found a 42% conversion rate over three years for similarly described PD-MCI patients (10/24 PD-MCI patients vs. 0/27 non-MCI patients converted). Our study was also part of a multinational study (n = 467) showing that PD-MCI has predictive validity beyond known demographic and PD specific factors of influence (Hoogland et al., 2017). All three studies found that multiple cognitive domain impairments are common in PD-MCI. Nonetheless, the research community needs to clarify the association between PD-MCI subtypes and, especially, the optimal cognitive markers for dementia risk in PD patients. PMID- 29606168 TI - Temperament and dominance relate to feeding behaviour and activity in beef cattle: implications for performance and methane emissions. AB - In beef cattle, feeding behaviour and activity are associated with feed efficiency and methane (CH4) emissions. This study aimed to understand the underlying traits responsible for the contribution of cattle behaviour to individual differences in feed efficiency, performance and CH4 emissions. A total of 84 steers (530+/-114 kg BW) of two different breeds (crossbreed Charolais and Luing) were used. The experiment was a 2*2*3 factorial design with breed, basal diets (concentrate v. mixed) and dietary treatments (no additive, calcium nitrate or rapeseed cake) as the main factors. The individual dry matter intake (DMI; kg) was recorded daily and the BW was measured weekly over a 56-day period. Ultrasound fat depth was measured on day 56. Based on the previous data, the indexes average daily gain, food conversion and residual feed intake (RFI) were calculated. The frequency of meals, the duration per visit and the time spent feeding per day were taken as feeding behaviour measures. Daily activity was measured using the number of steps, the number of standing bouts and the time standing per day. Agonistic interactions (including the number of contacts, aggressive interactions, and displacements per day) between steers at the feeders were assessed as indicators of dominance. Temperament was assessed using the crush score test (which measures restlessness when restrained) and the flight speed on release from restraint. Statistical analysis was performed using multivariate regression models. Steers that spent more time eating showed better feed efficiency (P=0.039), which can be due to greater secretion of saliva. Feeding time was longer with the mixed diet (P<0.001), Luings (P=0.009) and dominant steers (P=0.032). Higher activity (more steps) in the pen was associated with poorer RFI, possibly because of higher energy expenditure for muscle activity. Frequent meals contributed to a reduction in CH4 emissions per kg DMI. The meal frequency was higher with a mixed diet (P<0.001) and increased in more temperamental (P=0.003) and dominant (P=0.017) steers. In addition, feed intake was lower (P=0.032) in more temperamental steers. This study reveals that efficiency increases with a longer feeding time and CH4 emissions decrease with more frequent meals. As dominant steers eat more frequently and for longer, a reduction in competition at the feeder would improve both feed efficiency and CH4 emissions. Feed efficiency can also be improved through a reduction in activity. Selection for calmer cattle would reduce activity and increase feed intake, which may improve feed efficiency and promote growth, respectively. PMID- 29606169 TI - Building Implementation Science for Veterans Affairs Healthcare Associated Infection Prevention: VA Healthcare-Associated Infection Prevention Network (VHIN). PMID- 29606170 TI - False-Positive Tuberculin Skin Test Results Among Low-Risk Healthcare Workers Following Implementation of Fifty-Dose Vials of Purified Protein Derivative. AB - Following large declines in tuberculosis transmission the United States, large scale screening programs targeting low-risk healthcare workers are increasingly a source of false-positive results. We report a large cluster of presumed false positive tuberculin skin test results in healthcare workers following a change to 50-dose vials of Tubersol tuberculin.Infect Control Hosp Epidemiol 2018;39:750 752. PMID- 29606171 TI - Enduring effect of childhood maltreatment on cortisol and heart rate responses to stress: The moderating role of severity of experiences. AB - There is a relative consensus about the detrimental impact of childhood maltreatment on later mental health problems and behavioral difficulties. Prior research suggests that neurophysiological stress mechanisms may partly mediate this association. However, inconsistent findings regarding hypothalamic-pituitary adrenal axis and sympathetic responses to stress complicate this investigation. Furthermore, the concordance in these two stress systems is not well understood. We tested whether the severity of maltreatment affected the association between maltreatment and cortisol and heart rate (HR) stress responses and the symmetry of these responses. Participants were 155 males (56 maltreated and 99 controls) aged 18 to 35 years. Cortisol and HR were measured in response to the Trier Social Stress Test. Childhood maltreatment, sociodemographic factors, and health related factors were measured using self-reported questionnaires. Maltreated participants had higher cortisol responses to stress in comparison to controls. However, a shift from moderate to lower to higher cortisol responses was noted as the severity of the experiences increased. Participants exposed to more experiences of maltreatment also showed a greater symmetry between cortisol and HR stress responses. Our findings provide further support for persistent dysregulation of the HPA axis following childhood maltreatment, of which the expression and symmetry with the sympathetic system may change according to the severity of experiences. PMID- 29606172 TI - Parkinson's disease mild cognitive impairment classifications and neurobehavioral symptoms clarification letter. AB - We thank Ms. Horne et al. for the clarification of our misquoting of their paper (Wood et al., 2016). They clarify that 21% of their overall sample of patients with Parkinson's disease (PD-MCI) converted to dementia in over four years, which we erroneously attributed to the mild cognitive impairment (MCI) group in our discussion (McDermott et al., 2017). This was virtually identical to our overall conversion rate of 20%. Their conversion rate of patients with PD-MCI, as defined by two cognitive tests impaired (1.5 SD) within a single cognitive domain, was 51%, whereas the conversion rate was 38% when the PD-MCI group included patients with impairment within and between cognitive domains. Their conversion rates are similar to our rate of 42% (as defined with 1.5 SD impairment within or across domains) and the rate of 39% in a study with five-years of follow-up of incident cases (Pedersen et al., 2017). Our overall conversion occurred over a slightly shorter time span. In addition to conversion rates, all the studies acknowledge that some patients can revert to normal cognitive status, which varies based on classification criteria and length of follow-up. Comparable conversion across studies using similar criteria is reassuring and can encourage planning of targeted interventions (Hoogland et al., 2017). PMID- 29606173 TI - Got GAS? Ease the Bloat with Real-Time Whole-Genome Sequencing. PMID- 29606174 TI - Reconstruction of a Caregiver Burden Scale: Identifying Culturally Sensitive Items in Saudi Arabia. AB - ABSTRACTFor this study, we adapted the Montgomery Borgatta Caregiver Burden Scale, used widely in the United States, to the Saudi Arabian context. To produce an Arabic, culturally sensitive version of the scale, we conducted semi structured interviews with 20 Saudi family caregivers. The Arabic version of the scale was tested, and participants were asked to comment on the appropriateness of items for the construct of "caregiver burden" using the repertory grid technique and laddering procedure - two constructivist methods derived from personal construct theory. From interview findings, we examined the content of the items and the caregiver burden construct itself. Our findings suggest that the use of constructivist methods to refine constructs and quantitative instruments is highly informative. This strategy is feasible even when little is known about the investigated constructs in the target culture and further elucidates our understanding of cross-cultural variations or invariance of different versions of the scale. PMID- 29606175 TI - Do behavioural defence mechanisms explain different levels of trematode infections in congeneric hosts? AB - Susceptibility and tolerance to parasite infection vary greatly between host species. The congeneric isopod species Austridotea annectens and Austridotea lacustris often occur in sympatry and can both serve as intermediate hosts for the trematode Maritrema poulini. However, the intensity and prevalence of infections vary greatly in natural populations, with A. annectens often being heavily infected and A. lacustris rarely being infected. To shed light on the factors that may be involved in infection avoidance in A. lacustris, 100 isopods were collected and experimentally exposed to M. poulini cercariae. To examine for potential behavioural mechanisms, we used carbonated water as a paralysing agent to temporarily stop any movement by the isopods, and exposed paralysed isopods to cercariae. In the experiments, none of the individuals that were exposed to the parasite were found to be infected, although some cercariae seemed to have penetrated isopod hosts. Behavioural defence mechanisms do not seem to explain the different infection levels between A. lacustris and A. annectens, suggesting a physiological, possibly immunological, factor may be present. At the ecosystem level, this suggests a potential dilution effect caused by this low-competency host, and its effects on parasite transmission dynamics should be investigated. PMID- 29606176 TI - Attended with and head-turning sign can be clinical markers of cognitive impairment in older adults. AB - We read the paper by Soysal et al. (2017) with interest as we have experience of both the Attended With (AW) and the Head-Turning Sign (HTS) in a neurology-led cognitive disorders clinic. PMID- 29606177 TI - Multi-step prediction for influenza outbreak by an adjusted long short-term memory. AB - Influenza results in approximately 3-5 million annual cases of severe illness and 250 000-500 000 deaths. We urgently need an accurate multi-step-ahead time-series forecasting model to help hospitals to perform dynamical assignments of beds to influenza patients for the annually varied influenza season, and aid pharmaceutical companies to formulate a flexible plan of manufacturing vaccine for the yearly different influenza vaccine. In this study, we utilised four different multi-step prediction algorithms in the long short-term memory (LSTM). The result showed that implementing multiple single-output prediction in a six layer LSTM structure achieved the best accuracy. The mean absolute percentage errors from two- to 13-step-ahead prediction for the US influenza-like illness rates were all <15%, averagely 12.930%. To the best of our knowledge, it is the first time that LSTM has been applied and refined to perform multi-step-ahead prediction for influenza outbreaks. Hopefully, this modelling methodology can be applied in other countries and therefore help prevent and control influenza worldwide. PMID- 29606178 TI - Effectiveness of antiviral treatment in preventing death in severe hospitalised influenza cases over six seasons. AB - We investigated the predictors of neuraminidase inhibitor (NAI) treatment in severe hospitalised influenza cases and the association between antiviral treatment and mortality. An observational epidemiological study was carried out in Catalonia (Spain) during 2010-2016 in patients aged ?18 years. Severe hospitalised cases of laboratory-confirmed influenza requiring hospitalisation were included. We collected demographic, virological and clinical characteristics. Mixed-effects logistic regression was used to estimate crude and adjusted odds ratio (aOR). We included 1727 hospitalised patients, of whom 1577 (91.3%) received NAI. Receiving NAI ?48 h after onset of clinical symptoms (aOR 0.37, 95% confidence interval (CI) 0.22-0.63), ?3 days (aOR 0.49, 95% CI 0.30 0.79) and ?5 days (aOR 0.50, 95% CI 0.32-0.79) was associated with a reduction in deaths. In patients admitted to the intensive care unit (ICU) (595; 34.5%), treatment ?48 h (aOR 0.32, 95% CI 0.14-0.74), ?3 days (aOR 0.44, 95% CI 0.20 0.97) and ?5 days (aOR 0.45, 95% CI 0.22-0.96) was associated with a reduction in deaths. Receiving treatment >5 days after onset of clinical symptoms was not associated with the reduction in deaths in hospitalised patients or those admitted to the ICU. NAI treatment of hospitalised patients with severe confirmed influenza was effective in avoiding death, mainly when administered ?48 h after symptom onset, but also when no more than 5 days had elapsed. PMID- 29606179 TI - How children's anxiety symptoms impact the functioning of the hypothalamus pituitary-adrenal axis over time: A cross-lagged panel approach using hierarchical linear modeling. AB - Anxiety symptoms in childhood and adolescence can have a long-term negative impact on mental and physical health. Although studies have shown dysregulation of the hypothalamus-pituitary-adrenal axis is associated with anxiety disorders, it is unclear how and in what direction children's experiences of anxiety symptoms, which include physiological and cognitive-emotional dimensions, impact the functioning of the hypothalamus-pituitary-adrenal axis over time. We hypothesized that higher physiological symptoms would be contemporaneously associated with hypercortisolism, whereas cognitive-emotional symptoms would be more chronic, reflecting traitlike stability, and would predict hypocortisolism over time. One hundred twenty children from the Concordia Longitudinal Risk Research Project were followed in successive data collection waves approximately 3 years apart from childhood through midadolescence. Between ages 10-12 and 13 15, children completed self-report questionnaires of anxiety symptoms and provided salivary cortisol samples at 2-hr intervals over 2 consecutive days. The results from hierarchical linear modeling showed that higher physiological symptoms were concurrently associated with hypercortisolism, involving cortisol levels that remained elevated over the day. In contrast, longitudinal results over the 3 years between data collection waves showed that chronic worry and social concerns predicted hypocortisolism, showing a low and blunted diurnal cortisol profile. These results have implications for broadening our understanding of the links between anxiety, the stress response system, and health across the course of development. PMID- 29606180 TI - Associations of prenatal depressive symptoms with DNA methylation of HPA axis related genes and diurnal cortisol profiles in primary school-aged children. AB - Epigenetic DNA modifications in genes related to the hypothalamic-pituitary adrenal (HPA) axis are discussed as a mechanism underlying the association between prenatal depression and altered child HPA activity. In a longitudinal study, DNA methylation changes related to prenatal depressive symptoms were investigated in 167 children aged 6 to 9 years. At six candidate genes, 126 cytosine-guanine dinucleotides were considered without correcting for multiple testing due to the exploratory nature of the study. Further associations with the basal child HPA activity were examined. Children exposed to prenatal depressive symptoms exhibited lower bedtime cortisol (p = .003, etap2 = 0.07) and a steeper diurnal slope (p = .023, etap2 = 0.06). For total cortisol release, prenatal exposure was related to lower cortisol release in boys, and higher release in girls. Furthermore, prenatal depressive symptoms were associated with altered methylation in the glucocorticoid receptor gene (NR3C1), the mineralocorticoid receptor gene (NR3C2), and the serotonin receptor gene (SLC6A4), with some sex specific effects (p = .012-.040, etap2 = 0.03-0.04). In boys, prenatal depressive symptoms predicted bedtime cortisol mediated by NR3C2 methylation, indirect effect = -0.07, 95% confidence interval [-0.16, -0.02]. Results indicate relations of prenatal depressive symptoms to both child basal HPA activity and DNA methylation, partially fitting a mediation model, with exposed boys and girls being affected differently. PMID- 29606181 TI - Effect of Intranasal Mupirocin Prophylaxis on Methicillin-Resistant Staphylococcus aureus Transmission and Invasive Staphylococcal Infections in a Neonatal Intensive Care Unit. AB - The use of monthly intranasal mupirocin was associated with a significant reduction in the rate of methicillin-resistant Staphylococcus aureus transmission and Staphylococcus aureus invasive infection in a large neonatal intensive care unit. Resistance to mupirocin emerged over time, but it was rare and was not associated with adverse clinical outcomes.Infect Control Hosp Epidemiol 2018;39:741-745. PMID- 29606182 TI - Review: Dairy foods, red meat and processed meat in the diet: implications for health at key life stages. AB - Social and health care provision have led to substantial increases in life expectancy. In the UK this has become higher than 80 years with an even greater proportional increase in those aged 85 years and over. The different life stages give rise to important nutritional challenges and recent reductions in milk consumption have led to sub-optimal intakes of calcium by teenage females in particular when bone growth is at its maximum and of iodine during pregnancy needed to ensure that supply/production of thyroid hormones to the foetus is adequate. Many young and pre-menopausal women have considerably sub-optimal intakes of iron which are likely to be associated with reduced consumption of red meat. A clear concern is the low intakes of calcium especially as a high proportion of the population is of sub-optimal vitamin D status. This may already have had serious consequences in terms of bone development which may not be apparent until later life, particularly in post-menopausal women. This review aims to examine the role of dairy foods and red meat at key life stages in terms of their ability to reduce or increase chronic disease risk. It is clear that milk and dairy foods are key sources of important nutrients such as calcium and iodine and the concentration of some key nutrients, notably iodine can be influenced by the method of primary milk production, in particular, the iodine intake of the dairy cow. Recent meta-analyses show no evidence of increased risk of cardiovascular diseases from high consumption of milk and dairy foods but increasing evidence of a reduction in the risk of type 2 diabetes associated with fermented dairy foods, yoghurt in particular. The recently updated reports from the World Cancer Research Fund International/American Institute for Cancer Research on the associations between dairy foods, red meat and processed meat and various cancers provide further confidence that total dairy products and milk, are associated with a reduced risk of colorectal cancer and high intakes of milk/dairy are not associated with increased risk of breast cancer. Earlier evidence of a significant increase in the risk of colorectal cancer from consumption of red and particularly processed meat has been reinforced by the inclusion of more recent studies. It is essential that nutrition and health related functionality of foods are included in evaluations of sustainable food production. PMID- 29606183 TI - Desperately seeking outcomes: quantifying the effectiveness of community mental healthcare using Health of the Nation Outcome Scales. AB - BACKGROUND: Community mental health services in the UK have struggled to measure the clinical effectiveness of their services.AimsTo measure clinical outcomes for different diagnostic clusters. METHOD: Clinicians measure the clinical status of patients by the Health of the Nation Outcome Scales (HoNOS), and HoNOS scores should be recorded annually after treatment. Clinical outcomes were measured by changes in HoNOS for diagnostic clusters. RESULTS: In two time periods (2014 and 2016), the health of patients with mild to moderate common mental disorders deteriorated after intervention. Patients with severe common mental disorders and psychoses improved in their clinical status. CONCLUSIONS: British community mental health teams may be effective in improving the clinical status of people with severe mental illness, but may have a negative effect on people with mild to moderate illnesses. These teams need to focus on the severely mentally ill and build on this demonstrable effectiveness.Declaration of interestNone. PMID- 29606184 TI - Communicable Disease Surveillance Systems in Disasters: Application of the Input, Process, Product, and Outcome Framework for Performance Assessment. AB - OBJECTIVE: One of the most important measures following disasters is setting up a communicable disease surveillance system (CDSS). This study aimed to develop indicators to assess the performance of CDSSs in disasters. METHOD: In this 3 phase study, firstly a qualitative study was conducted through in-depth, semistructured interviews with experts on health in disasters and emergencies, health services managers, and communicable diseases center specialists. The interviews were analyzed, and CDSS performance assessment (PA) indicators were extracted. The appropriateness of these indicators was examined through a questionnaire administered to experts and heads of communicable diseases departments of medical sciences universities. Finally, the designed indicators were weighted using the analytic hierarchy process approach and Expert Choice software. RESULTS: In this study, 51 indicators were designed, of which 10 were related to the input (19.61%), 17 to the process (33.33%), 13 to the product (25.49%), and 11 to the outcome (21.57%). In weighting, the maximum score was that of input (49.1), and the scores of the process, product, and outcome were 31.4, 12.7, and 6.8, respectively. CONCLUSION: Through 3 different phases, PA indicators for 4 phases of a chain of results were developed. The authors believe that these PA indicators can assess the system's performance and its achievements in response to disasters. (Disaster Med Public Health Preparedness. 2018;page 1 of 7). PMID- 29606186 TI - Can reactivity and regulation in infancy predict inattentive and hyperactive/impulsive behavior in 3-year-olds? AB - A need to identify early infant markers of later occurring inattentive and hyperactive/impulsive behaviors has come to the fore in the current attention deficit/hyperactivity disorder literature. The purpose of such studies is to identify driving mechanisms that could enable early detection of attention deficit/hyperactivity disorder liability and thus facilitate early intervention. Here we study independent and interactive effects of cognitive regulation (inhibition and sustained attention), temperament (reactive and regulatory aspects), and maternal sensitivity (as external regulation) in a sample of 112 typically developing 10-month-old infants (59 boys, 52.7%), in relation to inattentive and hyperactive/impulsive behavior at 3 years. The results showed that infant temperamental regulation and maternal sensitivity made independent contributions to both inattention and hyperactivity/impulsivity, in that higher levels of temperamental regulation and maternal sensitivity were related to less inattentive and hyperactive/impulsive behavior. In addition, the temperamental factor positive affectivity/surgency made a significant contribution to later hyperactivity/impulsivity, in that higher levels of positive affectivity/surgency were related to more hyperactive/impulsive behavior. No interaction effects were found. Our findings suggest temperament and parental regulation as potential and independent markers of later inattentive and hyperactive/impulsive behavior. PMID- 29606185 TI - Developing a neurobehavioral animal model of poverty: Drawing cross-species connections between environments of scarcity-adversity, parenting quality, and infant outcome. AB - Children reared in impoverished environments are at risk for enduring psychological and physical health problems. Mechanisms by which poverty affects development, however, remain unclear. To explore one potential mechanism of poverty's impact on social-emotional and cognitive development, an experimental examination of a rodent model of scarcity-adversity was conducted and compared to results from a longitudinal study of human infants and families followed from birth (N = 1,292) who faced high levels of poverty-related scarcity-adversity. Cross-species results supported the hypothesis that altered caregiving is one pathway by which poverty adversely impacts development. Rodent mothers assigned to the scarcity-adversity condition exhibited decreased sensitive parenting and increased negative parenting relative to mothers assigned to the control condition. Furthermore, scarcity-adversity reared pups exhibited decreased developmental competence as indicated by disrupted nipple attachment, distress vocalization when in physical contact with an anesthetized mother, and reduced preference for maternal odor with corresponding changes in brain activation. Human results indicated that scarcity-adversity was inversely correlated with sensitive parenting and positively correlated with negative parenting, and that parenting fully mediated the association of poverty-related risk with infant indicators of developmental competence. Findings are discussed from the perspective of the usefulness of bidirectional-translational research to inform interventions for at-risk families. PMID- 29606187 TI - The Serum Exosome Derived MicroRNA-135a, -193b, and -384 Were Potential Alzheimer's Disease Biomarkers. AB - OBJECTIVE: MicroRNAs (miRs) are attractive molecules to be considered as one of the blood-based biomarkers for neurodegenerative disorders such as Alzheimer's disease (AD). The goal of this study was to explore their potential value as biomarkers for the diagnosis of AD. METHODS: The expression levels of exosomal miR-135a, -193b, and -384 in the serum from mild cognitive impairment (MCI), dementia of Alzheimer-type (DAT), Parkinson's disease with dementia (PDD), and vascular dementia (VaD) patients were measured with a real-time quantitative reverse transcriptase PCR (qRT-PCR) method. RESULTS: Both serum exosome miR-135a and miR-384 were up-regulated while miR-193b was down-regulated in serum of AD patients compared with that of normal controls. Exosome miR-384 was the best among the three miRs to discriminate AD, VaD, and PDD. Using the cut-off value could better interpret these laboratory test results than reference intervals in the AD diagnosis. ROC curve showed that the combination of miR-135a, -193b, and 384 was proved to be better than a particular one for early AD diagnosis. CONCLUSION: Our results indicated that the exosomal miRs in the serum were not only potential biomarker of AD early diagnosis, but might also provide novel insights into the screen and prevention of the disease. PMID- 29606188 TI - Short Form of Weinstein Noise Sensitivity Scale (NSS-SF): Reliability, Validity and Gender Invariance among Chinese Individuals. AB - OBJECTIVE: Independent from noise exposure, noise sensitivity plays a pivotal role in people's noise annoyance perception and concomitant health deteriorations. The present study empirically investigated the psychometric properties of the Chinese version of the Weinstein Noise Sensitivity Scale-Short Form (CNSS-SF), the widely used inventory measuring individual differences in noise perception. METHODS: In total, 373 Chinese participants (age = 21.41 +/- 3.36) completed the online, anonymous questionnaire package. Examination of the CNSS-SF's reliability (internal consistency), factorial validity through validation and cross-validation, nomological validity and measurement invariance across gender groups were undertaken. RESULTS: The Cronbach alpha coefficients and composite reliabilities indicated sufficient reliability of the CNSS-SF. Two confirmatory factor analyses (CFA), in two randomly partitioned groups of participants, substantiated the factorial validity of the scale. The nomological validity of the scale was also corroborated by the significant positive association of its score with the trait anxiety score. Measurement invariance of the CNSS-SF was also found across genders via multi-group CFA. CONCLUSION: Though not without limitations, findings from the present research provide promising evidence for the utility of the scale in measuring noise sensitivity among the Chinese population. The availability of the CNSS-SF can promote research related to environmental noise and health in China, as well as facilitate cross-cultural comparisons. PMID- 29606189 TI - Serum Uric Acid is Associated with the Predicted Risk of Prevalent Cardiovascular Disease in a Community-dwelling Population without Diabetes. AB - OBJECTIVE: To examine the association between serum uric acid levels and cardiovascular disease risk among individuals without diabetes. METHODS: We investigated the association between serum uric acid levels and the risk of prevalent cardiometabolic diseases, 10-year Framingham risk for coronary heart disease, and 10-year risk for atherosclerotic cardiovascular diseases (ASCVD) among 8,252 participants aged ? 40 years without diabetes from Jiading district, Shanghai, China. RESULTS: Body mass index, waist circumference, blood glucose, glycated hemoglobin, blood pressure, and serum lipids increased progressively across the sex-specific quartiles of uric acid (all P trend < 0.05). Compared with individuals in the lowest quartile, those in the higher quartiles had a significantly higher prevalence of obesity, hypertension, and dyslipidemia (all P trend < 0.05). A fully adjusted logistic regression analysis revealed that individuals in the highest quartile had an increased risk of predicted cardiovascular disease compared with those in the lowest quartile of uric acid. The multivariate adjusted odds ratios (ORs) [95% confidence intervals (CIs)] for the highest quartiles for high Framingham risk were 3.00 (2.00-4.50) in men and 2.95 (1.08-8.43) in women. The multivariate adjusted ORs (95% CIs) for the highest quartile for high ASCVD risk were 1.93 (1.17-3.17) in men and 4.53 (2.57 7.98) in women. CONCLUSION: Serum uric acid level is associated with an increased risk of prevalent obesity, hypertension, dyslipidemia, 10-year Framingham risk for coronary heart disease, and 10-year risk for ASCVD among Chinese adults without diabetes. PMID- 29606191 TI - Bone Loss Induced by Simulated Microgravity, Ionizing Radiation and/or Ultradian Rhythms in the Hindlimbs of Rats. AB - OBJECTIVE: To better understand the pathological causes of bone loss in a space environment, including microgravity, ionizing radiation, and ultradian rhythms. METHODS: Sprague Dawley (SD) rats were randomly divided into a baseline group, a control group, a hindlimb suspension group, a radiation group, a ultradian rhythms group and a combined-three-factor group. After four weeks of hindlimb suspension followed by X-ray exposure and/or ultradian rhythms, biomechanical properties, bone mineral density, histological analysis, microstructure parameters, and bone turnover markers were detected to evaluate bone loss in hindlimbs of rats. RESULTS: Simulated microgravity or combined-three factors treatment led to a significant decrease in the biomechanical properties of bones, reduction in bone mineral density, and deterioration of trabecular parameters. Ionizing radiation exposure also showed adverse impact while ultradian rhythms had no significant effect on these outcomes. Decrease in the concentration of the turnover markers bone alkaline phosphatase (bALP), osteocalcin (OCN), and tartrate-resistant acid phosphatase-5b (TRAP-5b) in serum was in line with the changes in trabecular parameters. CONCLUSION: Simulated microgravity is the main contributor of bone loss. Radiation also results in deleterious effects but ultradian rhythms has no significant effect. Combined-three factors treatment do not exacerbate bone loss when compared to simulated microgravity treatment alone. PMID- 29606190 TI - Potassium Bromate-induced Changes in the Adult Mouse Cerebellum Are Ameliorated by Vanillin. AB - OBJECTIVE: The current study aimed to elucidate the effect of vanillin on behavioral changes, oxidative stress, and histopathological changes induced by potassium bromate (KBrO3), an environmental pollutant, in the cerebellum of adult mice. METHODS: The animals were divided into four groups: group 1 served as a control, group 2 received KBrO3, group 3 received KBrO3 and vanillin, and group 4 received only vanillin. We then measured behavioral changes, oxidative stress, and molecular and histological changes in the cerebellum. RESULTS: We observed significant behavioral changes in KBrO3-exposed mice. When investigating redox homeostasis in the cerebellum, we found that mice treated with KBrO3 had increased lipid peroxidation and protein oxidation in the cerebellum. These effects were accompanied by decreased Na+-K+ and Mg2+ ATPase activity and antioxidant enzyme gene expression when compared to the control group. Additionally, there was a significant increase in cytokine gene expression in KBrO3-treated mice. Microscopy revealed that KBrO3 intoxication resulted in numerous degenerative changes in the cerebellum that were substantially ameliorated by vanillin supplementation. Co-administration of vanillin blocked the biochemical and molecular anomalies induced by KBrO3. CONCLUSION: Our results demonstrate that vanillin is a potential therapeutic agent for oxidative stress associated with neurodegenerative diseases. PMID- 29606192 TI - Three-dimensional Culture of Human Airway Epithelium in Matrigel for Evaluation of Human Rhinovirus C and Bocavirus Infections. AB - OBJECTIVE: Newly identified human rhinovirus C (HRV-C) and human bocavirus (HBoV) cannot propagate in vitro in traditional cell culture models; thus obtaining knowledge about these viruses and developing related vaccines are difficult. Therefore, it is necessary to develop a novel platform for the propagation of these types of viruses. METHODS: A platform for culturing human airway epithelia in a three-dimensional (3D) pattern using Matrigel as scaffold was developed. The features of 3D culture were identified by immunochemical staining and transmission electron microscopy. Nucleic acid levels of HRV-C and HBoV in 3D cells at designated time points were quantitated by real-time polymerase chain reaction (PCR). Levels of cytokines, whose secretion was induced by the viruses, were measured by ELISA. RESULTS: Properties of bronchial-like tissues, such as the expression of biomarkers CK5, ZO-1, and PCK, and the development of cilium like protuberances indicative of the human respiration tract, were observed in 3D cultured human airway epithelial (HAE) cultures, but not in monolayer-cultured cells. Nucleic acid levels of HRV-C and HBoV and levels of virus-induced cytokines were also measured using the 3D culture system. CONCLUSION: Our data provide a preliminary indication that the 3D culture model of primary epithelia using a Matrigel scaffold in vitro can be used to propagate HRV-C and HBoV. PMID- 29606193 TI - Possible Transmission of Irkut Virus from Dogs to Humans. AB - Lyssaviruses, including Rabies virus, Duvenhage virus, European bat lyssavirus 1, European bat lyssavirus 2, Australian bat lyssavirus, and Irkut virus (IRKV), have caused human fatalities, but infection of IRKV in dogs has not been previously reported. In China, a dead dog that previously bit a human was determined to be infected with IRKV. Pathogenicity tests revealed that IRKVs can cause rabies-like disease in dogs and cats after laboratory infection. The close relationship between humans and pets, such as dogs and cats, may generate a new spillover-spreading route for IRKV infection. Therefore, additional attention should be paid to trans-species infection of IRKV between bats and dogs or dogs and humans through investigation of the prevalence and circulation patterns of IRKV in China. PMID- 29606194 TI - Risk Factors for Prevalence of EnterotoxigenicEscherichia coli (ETEC) in Diarrheic and Non-diarrheic Neonatal and Weaner Pigs, South Africa. AB - Enterotoxigenic Escherichia coli (ETEC) causes neonatal and post-weaning diarrhea in pigs. In order to determine the risk factors, rectal/fecal swabs and visceral organs obtained from pig farms in two regions of South Africa were analyzed microbiologically against risk variables. Seventy-two percent of young pigs were found to be positive for ETEC toxin genes; estB (38.9%), estB/STAP (25%), and estB/LT (13.9%) were dominant. Risk factors for ETEC-diarrhea in pigs include: leaving sick piglets in a pen with healthy piglets [odds ratio (OR) = 33.52; P < 0.0001]; water spillage in pen (OR = 42.87; P < 0.0001); hypothermic piglets (OR = 7.29; P < 0.0001); runt piglets in pen with healthy littermates (OR = 3.65; P < 0.0001); and prolonged use of antibiotics (OR = 3.05; P = 0.05). PMID- 29606195 TI - Evaluation of the Protective Efficacy of a Fused OmpK/Omp22 Protein Vaccine Candidate against Acinetobacter baumannii Infection in Mice. AB - Acinetobacter baumannii (A. Baumannii) is an emerging opportunistic pathogen responsible for hospital-acquired infections, and which now constitutes a sufficiently serious threat to public health to necessitate the development of an effective vaccine. In this study, a recombinant fused protein named OmpK/Omp22 and two individual proteins OmpK and Omp22 were obtained using recombinant expression and Ni-affinity purification. Groups of BALB/c mice were immunized with these proteins and challenged with a clinically isolated strain of A. baumannii. The bacterial load in the blood, pathological changes in the lung tissue and survival rates after challenge were evaluated. Mice immunized with OmpK/Omp22 fused protein provided significantly greater protection against A. baumannii challenge than those immunized with either of the two proteins individually. The results provide novel clues for future design of vaccines against A. baumannii. PMID- 29606196 TI - Additive Benefits of Twice Forest Bathing Trips in Elderly Patients with Chronic Heart Failure. AB - Chronic heart failure (CHF), a clinical syndrome resulting from the consequences of various cardiovascular diseases (CVDs), is increasingly becoming a global cause of morbidity and mortality. We had earlier demonstrated that a 4-day forest bathing trip can provide an adjunctive therapeutic influence on patients with CHF. To further investigate the duration of the impact and the optimal frequency of forest bathing trips in patients with CHF, we recruited those subjects who had experienced the first forest bathing trip again after 4 weeks and randomly categorized them into two groups, namely, the urban control group (city) and the forest bathing group (forest). After a second 4-day forest bathing trip, we observed a steady decline in the brain natriuretic peptide levels, a biomarker of heart failure, and an attenuated inflammatory response as well as oxidative stress. Thus, this exploratory study demonstrated the additive benefits of twice forest bathing trips in elderly patients with CHF, which could further pave the way for analyzing the effects of such interventions in CVDs. PMID- 29606197 TI - Study on a New Ultraviolet Sterilizer to the Surface Disinfection of the Ultrasound Probe. AB - We studied the disinfection effect of a new ultraviolet (UV) sterilizer and its utilization on ultrasound probe surfaces. Carrier quantitative germicidal tests, simulated on-the-spot trials, and organic substance influence tests were used to carry out experimental observation. Artificially infected probes were disinfected using the sterilizer or a germicidal lamp for comparison. The total number and types of bacteria were determined and identified. Our results demonstrated the sterilizer had the best disinfection effect among three different disinfection methods in hospital. The sterilizer has been used in a hospital setting for 2 years with no notable damage to the ultrasound probe instrument. It has the advantages of fast disinfection, high disinfection effect, and good compatibility with the ultrasound instrument, worthy of being a promoted application in medical institutions. PMID- 29606198 TI - The Olfactory Receptor Pseudo-pseudogene: A Potential Therapeutic Target in Human Diseases. PMID- 29606199 TI - GPS-identified vulnerabilities of savannah-woodland primates to leopard predation and their implications for early hominins. AB - Predation is thought to have been a key selection pressure in primate evolution, especially in the savannah-woodland habitats where several early hominin species lived. However, predator-primate prey relationships are still poorly understood because human presence often deters predators, limiting our ability to quantify the impact of predation. Synchronized high-resolution tracking of leopards (Panthera pardus), vervets (Chlorocebus pygerythrus), and olive baboons (Papio anubis) during a 14-month study in Kenya revealed that increased vulnerability to leopard predation was not associated with higher encounter rates, smaller body size, smaller group size, or greater distance from refuges, contrary to long standing inferences. Instead, the initiation, rate, timing, and duration of encounters, outcome of approaches, and predation events showed only a diel pattern of differential vulnerability. In the absence of human observers, vervets were more vulnerable during the day, whereas baboons were more vulnerable at night, but overall neither species was more vulnerable than the other. As our results show that leopards avoided baboons during the day and hunted them at night, we suggest that the same pattern would have applied to hominins-because they were even larger than baboons and bipedal, resulting in similarly offensive capability on the ground during the day but poorer agility in the trees at night, especially as they became committed bipeds. Drawing from hominid behavior and archaeopaleontological and ethnographic evidence, we hypothesize that ground sleeping hominins initially dealt with this formidable threat by using stone tools to modify Acacia branches into 'bomas', thorny enclosures that provided nighttime shelter. The ability of hominins to create their own nightly refuges on the ground wherever Acacia spp. were available would have allowed them to range more widely, a crucial step in furthering the spread of hominins across Africa and beyond. PMID- 29606200 TI - Dental topography and the diet of Homo naledi. AB - Though late Middle Pleistocene in age, Homo naledi is characterized by a mosaic of Australopithecus-like (e.g., curved fingers, small brains) and Homo-like (e.g., elongated lower limbs) traits, which may suggest it occupied a unique ecological niche. Ecological reconstructions inform on niche occupation, and are particularly successful when using dental material. Tooth shape (via dental topography) and size were quantified for four groups of South African Plio Pleistocene hominins (specimens of Australopithecus africanus, Paranthropus robustus, H. naledi, and Homo sp.) on relatively unworn M2s to investigate possible ecological differentiation in H. naledi relative to taxa with similar known geographical ranges. H. naledi has smaller, but higher-crowned and more wear resistant teeth than Australopithecus and Paranthropus. These results are found in both lightly and moderately worn teeth. There are no differences in tooth sharpness or complexity. Combined with the high level of dental chipping in H. naledi, this suggests that, relative to Australopithecus and Paranthropus, H. naledi consumed foods with similar fracture mechanics properties but more abrasive particles (e.g., dust, grit), which could be due to a dietary and/or environmental shift(s). The same factors that differentiate H. naledi from Australopithecus and Paranthropus may also differentiate it from Homo sp., which geologically predates it, in the same way. Compared to the great apes, all hominins have sharper teeth, indicating they consumed foods requiring higher shear forces during mastication. Despite some anatomical similarities, H. naledi likely occupied a distinct ecological niche from the South African hominins that predate it. PMID- 29606201 TI - A new fossil cercopithecid tibia from Laetoli and its implications for positional behavior and paleoecology. AB - Detailed analyses and comparisons of postcranial specimens of Plio-Pleistocene cercopithecids provide an opportunity to examine the recent evolutionary history and locomotor diversity in Old World monkeys. Studies examining the positional behavior and substrate preferences of fossil cercopithecids are also important for reconstructing the paleoenvironments of Plio-Pleistocene hominin sites. Here we describe a new fossil cercopithecid tibia (EP 1100/12) from the Australopithecus afarensis-bearing Upper Laetolil Beds (~3.7 Ma) of Laetoli in northern Tanzania. The fossil tibia is attributed to cf. Rhinocolobus sp., which is the most common colobine at Laetoli. In addition to qualitative comparisons, the tibial shape of EP 1100/12 was compared to that of 190 extant cercopithecids using three-dimensional landmarks. Discriminant function analyses of the shape data were used to assess taxonomic affinity and shape variation relating to positional behavior. EP 1100/12 clustered with extant colobines, particularly the large-bodied genera Nasalis and Rhinopithecus. Comparisons reveal that EP 1100/12 belongs to a large-bodied monkey that engaged in arboreal pronograde quadrupedalism. These findings add further support to previous inferences that woodland and forest environments dominated the paleoenvironment of the Upper Laetolil Beds, which supported the diverse community of cercopithecids at Laetoli. The inferred paleoecology and the presence of large-bodied arboreally adapted monkeys at Laetoli show that A. afarensis had access to a range of diverse habitats, including woodlands and forests. This supports the possibility that A. afarensis, with its potential range of positional capabilities, was able to utilize arboreal settings for food acquisition and refuge from predators. PMID- 29606202 TI - Basicranium and face: Assessing the impact of morphological integration on primate evolution. AB - The basicranium and facial skeleton are two integrated structures displaying great morphological diversity across primates. Previous studies focusing on limited taxonomic samples have demonstrated that morphological integration has a significant impact on the evolution of these structures. However, this influence is still poorly understood. A more complete understanding of craniofacial integration across primates has important implications for functional hypotheses of primate evolution. In the present study, we analyzed a large sample of primate species to assess how integration affects the relationship between basicranial and facial evolutionary pathways across the order. First, we quantified integration and modularity between basicranium and face using phylogenetically informed partial least squares analyses. Then, we defined the influence of morphological integration between these structures on rates of evolution, using a time-calibrated phylogenetic tree, and on disparity through time, comparing the morphological disparity across the tree with that expected under a pure Brownian process. Finally, we assessed the correlation between the basicranium and face, and three factors purported to have an important role in shaping these structures during evolution: endocranial volume, positional behavior (i.e., locomotion and posture), and diet. Our findings show that the face and basicranium, despite being highly integrated, display significantly different evolutionary rates. However, our results demonstrate that morphological integration impacted shape disparity through time. We also found that endocranial volume and positional behavior are important drivers of cranial shape evolution, partly affected by morphological integration. PMID- 29606203 TI - The biting performance of Homo sapiens and Homo heidelbergensis. AB - Modern humans have smaller faces relative to Middle and Late Pleistocene members of the genus Homo. While facial reduction and differences in shape have been shown to increase biting efficiency in Homo sapiens relative to these hominins, facial size reduction has also been said to decrease our ability to resist masticatory loads. This study compares crania of Homo heidelbergensis and H. sapiens with respect to mechanical advantages of masticatory muscles, force production efficiency, strains experienced by the cranium and modes of deformation during simulated biting. Analyses utilize X-ray computed tomography (CT) scan-based 3D models of a recent modern human and two H. heidelbergensis. While having muscles of similar cross-sectional area to H. heidelbergensis, our results confirm that the modern human masticatory system is more efficient at converting muscle forces into bite forces. Thus, it can produce higher bite forces than Broken Hill for equal muscle input forces. This difference is the result of alterations in relative in and out-lever arm lengths associated with well-known differences in midfacial prognathism. Apparently at odds with this increased efficiency is the finding that the modern human cranium deforms more, resulting in greater strain magnitudes than Broken Hill when biting at the equivalent tooth. Hence, the facial reduction that characterizes modern humans may not have evolved as a result of selection for force production efficiency. These findings provide further evidence for a degree of uncoupling between form and function in the masticatory system of modern humans. This may reflect the impact of food preparation technologies. These data also support previous suggestions that differences in bite force production efficiency can be considered a spandrel, primarily driven by the midfacial reduction in H. sapiens that occurred for other reasons. Midfacial reduction plausibly resulted in a number of other significant changes in morphology, such as the development of a chin, which has itself been the subject of debate as to whether or not it represents a mechanical adaptation or a spandrel. PMID- 29606204 TI - Carrying capacity, carnivoran richness and hominin survival in Europe. AB - Carrying capacity, the maximum biomass that an ecosystem can sustain over the long term, strongly influences several ecological processes and it is also one of the main determinants of biodiversity. Here, we estimate the carrying capacity (CC) of the late Early and early Middle Pleistocene ecosystems of Europe, using equations describing the relationship between CC and climatic variables observed in the present, as well as maps of inferred paleotemperature and paleoprecipitation. Maps of paleoclimate values were interpolated from the composite benthic stable oxygen isotope ratios and a transfer function was used to estimate ungulate carrying capacity (CCU) from the interpolated mean annual temperature and annual precipitation values. Carnivoran carrying capacity was subsequently estimated from ungulate carrying capacity and the effect of CC on the carnivoran faunas was analyzed in 12 paleocommunities from Southern Europe. Our results show that carnivoran species richness is strongly related to ungulate carrying capacity in recent ecosystems, but the late Early Pleistocene paleocommunities from Southern Europe included much richer carnivore guilds than would be expected for a recent community with a similar ungulate carrying capacity. Thus, those late Early Pleistocene ecosystems supported a high number of carnivoran species, but the carnivoran biomass they could support was relatively low. Consequently, carnivorans occurred at low densities in Southern Europe compared to the recent African savanna ecosystems, but likely also compared to coeval East African ecosystems. Consequently, the first Homo populations that arrived in Europe at the end of the late Early Pleistocene found mammal communities consisting of a low number of prey species, which accounted for a moderate herbivore biomass, as well as a diverse but not very abundant carnivore guild. This relatively low carnivoran density implies that the hominin carnivore encounter rate was lower in the European ecosystems than in the coeval East African environments, suggesting that an opportunistic omnivorous hominin would have benefited from a reduced interference from the carnivore guild. PMID- 29606205 TI - Hominin hand bone fossils from Sterkfontein Caves, South Africa (1998-2003 excavations). AB - We describe eleven hominin metacarpals and phalanges recovered from Jacovec Cavern and Member 4 of the Sterkfontein Formation between 1998 and 2003. Collectively, the fossils date in excess of 2.0 Ma, and are probably attributable to Australopithecus africanus and/or Australopithecus prometheus. When combined with results of previous studies on Australopithecus postcranial functional morphology, the new data presented here suggest that at least some late Pliocene and/or early Pleistocene hominins from Sterkfontein were arboreally adept. This finding accords with the reconstruction of the site's >2.0 Ma catchment area as well-vegetated and containing significant woody components. In addition, most of the new specimens described here evince morphologies that indicate the hands from which they derived lacked complete modern humanlike manual dexterity, which is integral to the manufacture and use of intentionally shaped stone tools. The absence of lithic artifacts from both stratigraphic units from which the fossils were excavated is consistent with this conclusion. PMID- 29606206 TI - H2O2 and NADPH oxidases involve in regulation of 2-(2-phenylethyl)chromones accumulation during salt stress in Aquilaria sinensis calli. AB - 2-(2-Phenylethyl)chromones are the main compounds responsible for the quality of agarwood, which is widely used in traditional medicines, incenses and perfumes. H2O2 and NADPH oxidases (also known as respiratory burst oxidase homologs, Rbohs) mediate diverse physiological and biochemical processes in environmental stress responses. However, little is known about the function of H2O2 and NADPH oxidases in 2-(2-phenylethyl)chromones accumulation. In this study, we found that salt stress induced a transient increase in content of H2O2 and 2-(2 phenylethyl)chromones accumulation in Aquilaria sinensis calli. Exogenous H2O2 remarkably decreased the production of 2-(2-phenylethyl)chromones, while dimethylthiourea (DMTU), a scavenger of H2O2, significantly increased 2-(2 phenylethyl)chromones accumulation in salt treated calli. Three new H2O2 generating genes, named AsRbohA-C, were isolated and characterized from A. sinensis. Salt stress also induced a transient increase in AsRbohA-C expression and NADPH oxidase activity. Furthermore, exogenous H2O2 increased AsRbohA-C expression and NADPH oxidase activity, while DMTU inhibited AsRbohA-C expression and NADPH oxidase activity under salt stress. Moreover, diphenylene iodonium (DPI), the inhibitor of NADPH oxidases, reduced AsRbohA-C expression and NADPH oxidase activity, but significantly induced 2-(2-phenylethyl)chromones accumulation during salt stress. These results clearly demonstrated the central role of H2O2 and NADPH oxidases in regulation of salt-induced 2-(2 phenylethyl)chromones accumulation in A. sinensis calli. PMID- 29606207 TI - Identification of miRNAs that regulate silique development in Brassica napus. AB - MicroRNAs (miRNAs) are a class of non-coding small RNAs (sRNAs) that play crucial regulatory roles in various developmental processes. Silique length indirectly influences seed yield in rapeseed (Brassica napus); however, the molecular roles of miRNAs in silique length are largely unknown. Here, backcross progenies of rapeseed with long siliques (LS) and short siliques (SS) were used to elucidate these roles. Four small RNA libraries from siliques in an early stage of development were sequenced, and a total of 814 non-redundant miRNA precursors were identified, representing 65 known and 394 novel miRNAs. Expression analyses revealed that 17 miRNAs were differentially expressed in LS and SS lines. Furthermore, through degradome sequencing, we identified 522 cleavage events. Correlation analysis of the differentially expressed miRNAs and their targets suggested that miR159 and miR319 represses cell proliferation and miR160 regulates auxin signal transduction to control silique length. Additionally, the upregulation of miR2111, miR399, miR827, and miR408 reflected restricted silique development due to inorganic phosphate/copper deficiency. More significantly, high expression of miR160 in rapeseed may repress auxin response factors and result in increased silique length, illustrating that silique length might be regulated via an auxin-response pathway. PMID- 29606208 TI - Integrating proteomics and enzymatic profiling to decipher seed metabolism affected by temperature in seed dormancy and germination. AB - Temperature is an important environmental factor affecting seed dormancy and germination. The mechanism by which temperature induces germination in dormant seeds is however still unclear. Proteomic study has been performed in dormant sunflower seeds during imbibition at permissive and non-permissive temperatures for germination, 20 and 10 degrees C, respectively. Proteome analysis showed an increase of proteins belonging to metabolism and energy from the first hours of imbibition followed by a decrease of proteins involved in protein metabolism and seed storage in germinating compared to non-germinating seeds. Proteomic study was completed by polysome and proteasome activity assessment and enzymatic profiling on several altered proteins involved in metabolism and energy. Results showed that 20 degrees C treatment induced the activation of both protein synthesis and degradation processes, the latter being related to proteasome activity during the germination sensu stricto, and to other degradation processes such as proteases during the post-germination. Interestingly, enzymatic profiles showed that TCA cycle and glycolysis were more active in non-germinating seeds in the phase I of the germination sensu stricto. This result suggests the regulation of central metabolism activity in germinating seeds. The control of energy production during imbibition seems to be involved in molecular networks controlling seed dormancy and germination. PMID- 29606209 TI - Autophagy contributes to regulate the ROS levels and PCD progress in TMV-infected tomatoes. AB - Programmed cell death (PCD) and autophagy are both important means for plants to resist pathogen. It is also the main biological reaction of plant immunity. In previous studies, we found that TMV local-infection on tomato leaves not only caused the PCD process in the distal root tissues, but also induced autophagy in root-tip cells. However, the reasons for these biological phenomena are unclear. In order to get deeper insight, the role of a putative inducible factor reactive oxidative species (ROS) was investigated. The situ staining and subcellular localization analysis showed that the ROS level in the root tissue of TMV infected plants was significantly promoted. TEM observation showed that the intracellular ROS was excreted into the cell wall and intercellular layer. At the same time, the results of western blot and qRT-PCR showed that the expression of autophagy related protein Atg8 and genes (Atg5, Atg7 and Atg10) were increased. However, in the subsequent DPI inhibition experiments we found that the accumulation of ROS in infected plant root-tip tissues was inhibited and the autophagy in the root-tip cells also decreased. When 3-methyladenine (3-MA) was used to inhibit autophagy, there was no significant change in the ROS level in the apical tissue, while the systemic PCD process of the root-tip cells was elevated. Taken together, these results indicate that local TMV inoculation on the leaves induced the root-tip cells producing and releasing a lot of ROS into the extracellular matrix for defense against pathogen invasion. Meanwhile, ROS acted as a signaling substance and triggered autophagy in root-tip cells, in order to eliminate excessive intracellular ROS oxidative damage and maintain cell survival. PMID- 29606210 TI - Manipulation of VviAGL11 expression changes the seed content in grapevine (Vitis vinifera L.). AB - Seedlessness in grapes is a desirable trait, especially for in natura consumption. Previously, we showed that VviAGL11 is the main responsible gene for seed morphogenesis in grapevine. Here we tested the function of this gene in grapevine with the use of plant plasmids. VviAGL11 was cloned into silencing and overexpression versions of p28iIR plasmid. Reproductive grapevine bunches from different seeded and seedless cultivars were separately treated with VviAGL11 harboring plasmids, along with controls. Plasmids were detected in leaves after a month of treatment, and berries, leaves, stems and seeds were analyzed for ectopic gene expression by RT-qPCR after 90 days of plasmid injection. Fruits from the seedless 'Linda' treated with the VviAGL11-overexpression plasmid showed high expression levels of VviAGL11 and exhibited small seeds that were not found in the untreated control samples. Mature grapes from seeded 'Italia' and 'Ruby' bunches treated with the VviAGL11-silencing plasmid showed decreased VviAGL11 expression, reduced number of seeds and increased number of seed traces. The present study confirms that VviAGL11 is a key master regulator of seed morphogenesis in grapevine and corroborates with the applicability of plant plasmids as promising biotechnological tools to functionally test genes in perennial plants in a rapid and confident way. PMID- 29606211 TI - Review: Shaping a sustainable food future by rediscovering long-forgotten ancient grains. AB - Genetic erosion of crops has been determined way back in the 1940s and accelerated some twenty years later by the inception of the Green Revolution. Claims that the revolution was a complete triumph remain specious, especially since the massive production boost in the global big three grain crops; wheat, maize, and rice that happened back then is unlikely to recur under current climate irregularities. Presently, one of the leading strategies for sustainable agriculture is by unlocking the genetic potential of underutilized crops. The primary focus has been on a suite of ancient cereals and pseudo-cereals which are riding on the gluten-free trend, including, among others, grain amaranth, buckwheat, quinoa, teff, and millets. Each of these crops has demonstrated tolerance to various stress factors such as drought and heat. Apart from being the centuries-old staple in their native homes, these crops have also been traditionally used as forage for livestock. This review summarizes what lies in the past and present for these underutilized cereals, particularly concerning their potential role and significance in a rapidly changing world, and provides compelling insights into how they could one day be on par with the current big three in feeding a booming population. PMID- 29606212 TI - Review: Plant G-quadruplex (G4) motifs in DNA and RNA; abundant, intriguing sequences of unknown function. AB - DNA sequences capable of forming G-quadruplex (G4) structures can be predicted and mapped in plant genomes using computerized pattern search programs. Non telomeric G4 motifs have recently been found to number in the thousands across many plant species and enriched around gene promoters, prompting speculation that they may represent a newly uncovered and ubiquitous family of cis-acting elements. Comparative analysis shows that monocots exhibit five to ten times higher G4 motif density than eudicots, but the significance of this difference has not been determined. The vast scale and complexity of G4 functions, actual or theoretical, are reviewed in relation to the multiple modes of action and myriad genetic functions for which G4s have been implicated in DNA and RNA. Future experimental strategies and opportunities include identifying plant G4 interactomes, resolving the structures of G4s with and without their binding partners, and defining molecular mechanisms through reporter gene, genetic, or genome editing approaches. Given the global importance of plants for food, clothing, medicine, and energy, together with the potential role of G4 motifs as a widely conserved set of DNA sequences that could coordinate gene regulation, future plant G4 research holds great potential for use in plant improvement strategies. PMID- 29606213 TI - Spectrophotometric determination of reaction rates and kinetic parameters of a BAHD acyltransferase using DTNB (5,5'-dithio-bis-[2-nitrobenzoic acid]). AB - Hydroxycinnamoyl-Coenzyme A (CoA) hydroxycinnamoyl transferases are BAHD family acyltransferases that transfer hydroxycinnamoyl moieties from a CoA-thioester to an acceptor amine or alcohol to form an N-hydroxycinnamoyl amide or O hydroxycinnamoyl ester, respectively, with the concomitant release of free CoA. One approach to measure reaction rates for these enzymes is to quantify the hydroxycinnamoyl amide or ester reaction product following chromatographic separation of reaction components. This approach can be labor-intensive and time consuming. As an alternative, we examined the use of 5,5'-dithio-bis-(2 nitrobenzoic acid) (DTNB, Ellman's reagent) to spectrophotometrically quantify, in real time, the release of free CoA during the transferase reaction. Using a hydroxycinnamoyl-CoA:l-DOPA hydroxycinnamoyl transferase as a model, we show that DTNB has little to no effect on the transferase reaction and can be used to provide a good estimate of hydroxycinnamoyl amide formation, thus allowing for the quick and easy collection of reaction rate data and determination of transferase kinetic parameters. This approach should be applicable to a wide range of hydroxycinnamoyl-CoA and other BAHD acyltransferases. PMID- 29606214 TI - Truncated BAM receptors interfere the apical meristematic activity in a dominant negative manner when ectopically expressed in Arabidopsis. AB - Small, secreted signaling peptides that are perceived by receptor-like kinases (RLKs) constitute an important regulatory mechanism in plant organ formation and stem cell maintenance. However, functional redundancy at the level of both ligand and receptor families often makes it difficult to clearly discern the role of individual members by a genetic approach. Here, we show that driven by a constitutive CaMV 35S promoter, a truncated BAM protein (BAMDelta) that lacks either the signal peptide (SP) or the cytoplasmic kinase (Ki) domain could cause defective shoot apical meristem (SAM) maintenance, which phenotypically resembled the triple bam mutant. Such a dominant-negative effect could also be achieved when the same transgene was driven by the native AtBAM1 promoter, but not by the CLV1 promoter. When introduced into a clv1-4 background, BAMDelta proteins abolished the typical clv phenotype by suppressing the transcriptional level of clv1-4. In addition to a clear reduction in root length and a decreased number of meristematic cells, the 35S:BAMDelta transgenic seedlings exhibited considerable resistance to CLE40p- but not to CLV3p-mediated root growth inhibition, implying that BAMs play key roles in the regulation of proximal meristem activity in root through CLE40 peptide. Findings present here not only provide evidence that truncated BAM proteins are strongly dominant negative in regulating apical meristem development but also propose that expression of a truncated version of plant LRR receptor kinase could potentially be used as a powerful tool to reveal its in vivo function in signal transduction. PMID- 29606215 TI - The R2R3 transcription factor HlMYB8 and its role in flavonoid biosynthesis in hop (Humulus lupulus L.). AB - Hop is an important source of medicinally valuable secondary metabolites including bioactive prenylated chalcones. To gain in-depth knowledge of the regulatory mechanisms of hop flavonoids biosynthesis, full-length cDNA of HlMyb8 transcription factor gene was isolated from lupulin glands. The deduced amino acid sequence of HlMyb8 showed high similarity to a flavonol-specific regulator of phenylpropanoid biosynthesis AtMYB12 from Arabidopsis thaliana. Transient expression studies and qRT-PCR analysis of transgenic hop plants overexpressing HlMyb8 revealed that HlMYB8 activates expression of chalcone synthase HlCHS_H1 as well as other structural genes from the flavonoid pathway branch leading to the production of flavonols (F3H, F'3H, FLS) but not prenylflavonoids (PT1, OMT1) or bitter acids (VPS, PT1). HlMyb8 could cross-activate Arabidopsis flavonol specific genes but to a much lesser extent than AtMyb12. Reciprocally, AtMyb12 could cross-activate hop flavonol-specific genes. Transcriptome sequence analysis of hop leaf tissue overexpressing HlMyb8 confirmed the modulation of several other genes related to flavonoid biosynthesis pathways (PAL, 4CL, ANR, DFR, LDOX). Analysis of metabolites in hop female cones confirmed that overexpression of HlMyb8 does not increase prenylflavonoid or bitter acids content in lupulin glands. It follows from our results that HlMYB8 plays role in a competition between flavonol and prenylflavonoid or bitter acid pathways by diverting the flux of CHS_H1 gene product and thus, may influence the level of these metabolites in hop lupulin. PMID- 29606216 TI - Root cell wall solutions for crop plants in saline soils. AB - The root growth of most crop plants is inhibited by soil salinity. Roots respond by modulating metabolism, gene expression and protein activity, which results in changes in cell wall composition, transport processes, cell size and shape, and root architecture. Here, we focus on the effects of salt stress on cell wall modifying enzymes, cellulose microfibril orientation and non-cellulosic polysaccharide deposition in root elongation zones, as important determinants of inhibition of root elongation, and highlight cell wall changes linked to tolerance to salt stressed and water limited roots. Salt stress induces changes in the wall composition of specific root cell types, including the increased deposition of lignin and suberin in endodermal and exodermal cells. These changes can benefit the plant by preventing water loss and altering ion transport pathways. We suggest that binding of Na+ ions to cell wall components might influence the passage of Na+ and that Na+ can influence the binding of other ions and hinder the function of pectin during cell growth. Naturally occurring differences in cell wall structure may provide new resources for breeding crops that are more salt tolerant. PMID- 29606217 TI - Functional characterization of an apple (Malus x domestica) LysM domain receptor encoding gene for its role in defense response. AB - Apple gene, MD09G1111800, was identified as a chitin binding receptor-like kinase based on sequence similarity to AtCERK1 (chitin elicitor receptor kinase 1) from Arabidopsis. Sequence analysis on genomic structure, domain composition and transcriptional response to exogenous chitin treatment indicated that MD09G1111800 is an ortholog to AtCERK1 and was therefore named as MdCERK1. Tissue specific expression patterns indicated that MdCERK1 is primarily functional in vegetative tissues of leaf and root, rather than flower, fruit and seed of apple plant. The transcriptional regulation patterns in response to infection by Rhizoctonia solani demonstrated that MdCERK1 is a functional pattern recognition receptor protein (PRR) in apple root tissues. The ability of purified GST-MdCERK1 fusion protein to bind chitin molecules added biochemical evidence for its role in chitin mediated immune responses. An untargeted proteomic approach was also employed for identifying its putative in vivo interaction partners in apple root cells, and results indicated the existence of a functional receptor complex. These data support the conclusion that MdCERK1 is a chitin binding receptor kinase functioning in apple vegetative tissues, which plays an important role in defense activation in response to pathogen infection. PMID- 29606218 TI - Evolutionary diversification of type-2 HDAC structure, function and regulation in Nicotiana tabacum. AB - Type-2 HDACs (HD2s) are plant-specific histone deacetylases that play diverse roles during development and in responses to biotic and abiotic stresses. In this study we characterized the six tobacco genes encoding HD2s that mainly differ by the presence or the absence of a typical zinc finger in their C-terminal part. Of particular interest, these HD2 genes exhibit a highly conserved intron/exon structure. We then further investigated the phylogenetic relationships among the HD2 gene family, and proposed a model of the genetic events that led to the organization of the HD2 family in Solanaceae. Absolute quantification of HD2 mRNAs in N. tabacum and in its precursors, N. tomentosiformis and N. sylvestris, did not reveal any pseudogenization of any of the HD2 genes, but rather specific regulation of HD2 expression in these three species. Functional complementation approaches in Arabidopsis thaliana demonstrated that the four zinc finger containing HD2 proteins exhibit the same biological function in response to salt stress, whereas the two HD2 proteins without zinc finger have different biological function. PMID- 29606219 TI - Genetic mapping of a lobed-leaf gene associated with salt tolerance in Brassica napus L. AB - Lobed leaf is a common trait, which is related with photosynthesis and plant stress resistance in crops. In order to fine map and isolate the lobed-leaf gene in Brassica napus, an F2:3 population derived from 2205 (salt tolerance) and 1423 (salt sensitive) was constructed, and the quantitative trait locus (QTL) technology was adopted to identify the QTLs related to lobed leaf formation. As a result, one major QTL was identified on LG10, and two intron polymorphic (IP) markers and one sequence characterized amplified region (SCAR) marker were successfully developed in QTL region. The lobed-leaf gene was mapped to a region from 15.701 to 15.817 M on A10. In light of annotations of the genes in candidate region, a leaf morphological development related gene, Bra009510, was primary identified as the candidate gene. The full length of the candidate gene was 1390 bp containing three exons and two introns in the two parents. The open reading frame (ORF) was 693 bp and encoded a protein of 229 amino acids. Eight amino acid differences between the two parents in CDS (coding sequences) region were identified. qRT-PCR analysis showed that the expression of the candidate gene was significantly different between the two parents under salt stress. These results showed that the candidate gene might be related to leaf morphological development and abiotic stresses. Our study will lay a solid foundation for studying lobed leaf mechanism in B. napus L. PMID- 29606220 TI - Functional diversification of structurally alike NLR proteins in plants. AB - In due course of evolution many pathogens alter their effector molecules to modulate the host plants' metabolism and immune responses triggered upon proper recognition by the intracellular nucleotide-binding oligomerization domain containing leucine-rich repeat (NLR) proteins. Likewise, host plants have also evolved with diversified NLR proteins as a survival strategy to win the battle against pathogen invasion. NLR protein indeed detects pathogen derived effector proteins leading to the activation of defense responses associated with programmed cell death (PCD). In this interactive process, genome structure and plasticity play pivotal role in the development of innate immunity. Despite being quite conserved with similar biological functions in all eukaryotes, the intracellular NLR immune receptor proteins happen to be structurally distinct. Recent studies have made progress in identifying transcriptional regulatory complexes activated by NLR proteins. In this review, we attempt to decipher the intracellular NLR proteins mediated surveillance across the evolutionarily diverse taxa, highlighting some of the recent updates on NLR protein compartmentalization, molecular interactions before and after activation along with insights into the finer role of these receptor proteins to combat invading pathogens upon their recognition. Latest information on NLR sensors, helpers and NLR proteins with integrated domains in the context of plant pathogen interactions are also discussed. PMID- 29606221 TI - An apple cyclic nucleotide-gated ion channel gene highly responsive to Botryosphaeria dothidea infection enhances the susceptibility of Nicotiana benthamiana to bacterial and fungal pathogens. AB - Apple ring rot caused by the fungus Botryosphaeria dothidea is one of the devastating diseases. Up to date, the responsive mechanism of apple plant to this disease remains unclear. In the present study, an apple CNGC gene (designated as MdCNGC1) was found among highly expressed genes responding to B. dothidea infection. The expression of MdCNGC1 was different among apple cultivars with different resistance to B. dothidea. Intriguingly, MdCNGC1 expression was not induced by other two apple pathogens, Marssonina coronaria and Valsa ceratosperma. Ectopic overexpression of MdCNGC1 in Nicotiana benthamiana conferred elevated susceptibility to bacterial and fungal pathogens. Notably, overexpression of MdCNGC1 reduced salicylic acid (SA) accumulation induced by Alternaria alternata or Pseudomonas syringae. Decreased induction of pathogenesis related (PR) genes and ROS accumulation were also observed in MdCNGC1 overexpressing plants. Up-regulated scavenging systems as indicated by enhanced expressions of CAT, APX, SOD genes and activities of antioxidative enzymes may in part contribute to reduced ROS accumulation. MdCNGC1 expression in N. benthamiana also decreased flg22 and chitosan-induced callose deposition and lowered the expression of NbPMR4, an ortholog of Arabidopsis callose synthase gene PMR4. These combined results suggested that MdCNGC1 might be a negative factor to plant resistance to bacterial and fungal pathogens. PMID- 29606222 TI - Effectiveness of inpatient withdrawal and residential rehabilitation interventions for alcohol use disorder: A national observational, cohort study in England. AB - BACKGROUND: This was a national English observational cohort study to estimate the effectiveness of inpatient withdrawal (IW) and residential rehabilitation (RR) interventions for alcohol use disorder (AUD) using administrative data. METHODS: All adults commencing IW and/or RR intervention for AUD between April 1, 2014 and March 31, 2015 reported to the National Drug Treatment Monitoring System (n=3812). The primary outcome was successful completion of treatment within 12months of commencement, with no re-presentation (SCNR) in the subsequent six months, analysed by multi-level, mixed effects, multivariable logistic regression. RESULTS: The majority (70%, n=2682) received IW in their index treatment journey; one-quarter (24%, n=915) received RR; 6% (n=215) received both. Of treatment leavers, 59% achieved the SCNR outcome (IW: 57%; RR: 64%; IW/RR: 57%). Positive outcome for IW was associated with older age, being employed, and receiving community-based treatment prior to and subsequent to IW. Patients with housing problems were less likely to achieving the outcome. Positive outcome for RR was associated with paid employment, self/family/peer referral, longer duration of RR treatment, and community-based treatment following discharge. Community-based treatment prior to entering RR, and receiving IW during the same treatment journey as RR, were associated with lower likelihood of SCNR. CONCLUSIONS: In this first national effectiveness study of AUD in the English public treatment system for alcohol-use disorders, 59% of patients successfully completed treatment within 12months and did not represent for more treatment within six months. Longer duration of treatment and provision of structured continuing care is associated with better treatment outcomes. PMID- 29606223 TI - A longitudinal study of the comparative efficacy of Women for Sobriety, LifeRing, SMART Recovery, and 12-step groups for those with AUD. AB - BACKGROUND: Despite the effectiveness of 12-step groups, most people reporting a prior alcohol use disorder (AUD) do not sustain involvement in such groups at beneficial levels. This highlights the need for research on other mutual help groups that address alcohol problems and may attract those who avoid 12-step groups. The current study addresses this need, offering outcome data from the first longitudinal, comparative study of 12-step groups and their alternatives: The Peer ALlternatives for Addiction (PAL) Study. METHODS: Adults with a lifetime AUD were surveyed at baseline (N=647), 6months (81% response rate) and 12months (83% response rate). Members of the largest known secular mutual help alternatives, namely Women for Sobriety (WFS), LifeRing, and SMART, were recruited in collaboration with group directors; current 12-step attendees were recruited from an online meeting hub. Online surveys assessed demographic and clinical variables; mutual help involvement; and alcohol and drug use and severity. Analyses involved multivariate logistic GEEs separately modelling alcohol abstinence, alcohol problems, and total abstinence across 6 and 12months. Key predictors were baseline primary group affiliation (PGA); primary group involvement (PGI) at both baseline and 6months; and the interaction between baseline PGA and 6-month PGI. The critical effects of interest were the interactions, expressing whether associations between changes in PGI from baseline to 6months and substance use outcomes differed by primary group. RESULTS: None of the interactions between baseline PGA and 6-month PGI were significant, suggesting no differences in the efficacy of WFS, LifeRing, or SMART, vs. 12-step groups. Nevertheless, some PGA main effects emerged. Compared to 12-step members, those identifying SMART as their primary group at baseline fared worse across outcomes, and those affiliating with LifeRing showed lower odds of total abstinence. Still, these effects became nonsignificant when controlling for baseline alcohol recovery goal, suggesting that any group differences may be explained by selection of those with weaker abstinence motivation into LifeRing and (especially) SMART. CONCLUSIONS: This study makes a valuable contribution in view of the extremely limited evidence on mutual help alternatives. Results tentatively suggest that WFS, LifeRing, and SMART are as effective as 12-step groups for those with AUDs, and that this population has the best odds of success when committing to lifetime total abstinence. An optimal care plan may thus involve facilitating involvement in a broad array of mutual help groups and supporting abstinence motivation. PMID- 29606224 TI - Individual versus group female-specific cognitive behavior therapy for alcohol use disorder. AB - OBJECTIVES: To test group-based Female-Specific Cognitive Behavioral Therapy (G FS-CBT) for women with Alcohol Use Disorder (AUD) against an individual Female Specific Cognitive Behavioral Therapy (I-FS-CBT). This aims of this paper are to describe G-FS-CBT development, content, feasibility, acceptability, group process, engagement in treatment, and within- and post-treatment outcomes. METHODS: Women with AUD (n=155) were randomly assigned to 12 manual-guided sessions of G-FS-CBT or I-FS-CBT; 138 women attended at least one treatment session. RESULTS: Women in G-FS-CBT attended fewer sessions (M=7.6) than women in I-FS-CBT (M=9.7; p<.001). Women in both conditions reported high satisfaction with the treatments. Independent coders rated high fidelity of delivery of both G FS-CBT and I-FS-CBT. Therapeutic alliance with the therapist was high in both conditions, with I-FS-CBT being slightly but significantly higher than G-FS-CBT. In the first six weeks of treatment, women in both treatment conditions significantly reduced their percent drinking days (PDD) and percent heavy days drinking (PHD) by equivalent amounts, maintained through the rest of treatment and the 12month follow up with no treatment condition effects. Women reported significant improvement in all but one of the secondary outcomes during treatment; gains made during treatment in depression, anxiety, autonomy, and interpersonal problems were maintained during the follow-up period, while gains made during treatment in use of coping skills, self-efficacy for abstinence, self care, and sociotropy deteriorated over follow up but remained improved compared to baseline. CONCLUSIONS: Findings support the feasibility, acceptability, and efficacy of a group format for female-specific CBT for AUD, a new 12-session, single gender, community friendly, group therapy with programming specifically for women. Similar, positive outcomes for individual and group treatment formats were found for drinking, mood, coping skills, self-confidence, interpersonal functioning, and self-care. PMID- 29606225 TI - The buffering effect of belonging on the negative association of childhood trauma with adult mental health and risky alcohol use. AB - More than half of the American population has experienced at least one childhood traumatic event in their lifetime, which can lead to alcohol misuse and mental and physiological health issues. A sense of belonging in close relationships is hypothesized to promote resiliency against the negative outcomes of childhood trauma experiences. Using a sample of 654 adults aged 26-40years old, this study examined the relationship between childhood traumatic experiences and adult risky alcohol use mediated by mental health status and perceptions of belonging. Results indicated that having a greater sense of belonging was associated with greater mental health and reduced reports of risky alcohol use. The negative total association of childhood trauma on adult mental health was partially mediated by a sense of belonging, indicating that a sense of belonging may buffer the impact of childhood trauma on later mental health outcomes and therefor potentially decrease later risky alcohol use in adulthood. Recommendations for systemic treatment and increasing close relationships across the lifespan as resiliency factors are explored. Implementations for public policy changes for Marriage and Family Therapists are discussed. PMID- 29606226 TI - A pilot study of a smartphone application supporting recovery from drug addiction. AB - BACKGROUND: Mobile health (mHealth) technologies have the potential to facilitate self-monitoring and self-management for individuals with substance use disorders (SUD). S-Health is a bilingual smartphone application based on cognitive behavioral principles and is designed to support recovery from drug addiction by trigger recognition so as to allow practice in-the-moment coping to prevent relapse. METHOD: For this pilot randomized controlled study, 75 participants were recruited from methadone maintenance treatment clinics and the social worker consortium in Shanghai, China. Participants in the control group (N=25) received text messages from S-Health (e.g., HIV prevention and other educational materials). Participants in the intervention group (N=50) received both text messages and daily surveys on cravings, affects, triggers, responses to triggers, and social contexts. RESULTS: At the end of the 1-month study trial, 26.2% of the intervention group and 50% of the control group had positive urine test results (p=0.06). Also, the number of days using drug in the past week was significantly lower among participants in the intervention group (Mean=0.71, SD=1.87) relative to the control group (Mean=2.20, SD=3.06) (p<0.05). The two groups did not differ in slopes (i.e., rates of change in outcomes measured weekly) based on the mixed effects model. Participants in the intervention group also preferred answering questions on the cellphone (46.8%) relative to in-person interviews (36.2%). CONCLUSIONS: This pilot demonstrated the feasibility and potential benefits to deliver mobile health intervention among participants with SUD. Further research with larger samples over a longer period of time is needed to test the effectiveness of S-Health as a self-monitoring tool supporting recovery from addiction. PMID- 29606227 TI - Complexities with group therapy facilitation in substance use disorder specialty treatment settings. AB - In spite of increased attention to research-based interventions for substance use disorders (SUDs), a formidable research-practice gap impedes the implementation of evidence-based treatments (EBTs). An underappreciated dimension of this gap is a mismatch in treatment modality: Whereas clinical trial and implementation research has focused primarily on individual therapy, the majority of SUD specialty treatment is in group format, with open-enrolling groups being most common. This study aims to narrow this research-practice gap by exploring clinicians' perspectives on complexities with group therapy facilitation in SUD specialty treatment settings. Semi-structured interviews were conducted with 13 group clinicians from among three outpatient SUD specialty clinics-diverse in their operational structures, treatment philosophies, clientele, and services located in the same Midwestern U.S. metropolitan area. Interview questions addressed organizational characteristics, services provided, group therapy curricula, and use of EBTs or other structured treatments. Clinicians emphasized the importance of having flexibility in facilitating groups, through built-in group processes and clinicians' own adaptions and accommodations; this flexibility was especially emphasized for the use of EBTs or manualized interventions. Clinicians also had difficulties with group facilitation generally, as evidenced by their reported difficulty in managing complex group dynamics, their limited group therapy experience and training, and their reliance on educational groups. We discuss specific strategies for improved innovation and implementation of EBTs for SUD group therapy. PMID- 29606228 TI - Enhancement of curcumin water dispersibility and antioxidant activity using core shell protein-polysaccharide nanoparticles. AB - Curcumin has strong antioxidant activity, but poor water-solubility and chemical stability, which limits its utilization as a nutraceutical in many applications. Previously, we developed a core-shell (zein-pectin) nanoparticle delivery system with high curcumin loading efficiency, high particle yield, and good water dispersibility. However, this system was unstable to aggregation around neutral pH and moderate ionic strengths due to weakening of electrostatic repulsion between nanoparticles. In the current study, we used a combination of alginate (high charge density) and pectin (low charge density) to form the shell around zein nanoparticles. Replacement of 30% of pectin with alginate greatly improved aggregation stability at pH 5 to 7 and at high ionic strengths (2000mM NaCl). Curcumin encapsulated within these core-shell nanoparticles exhibited higher antioxidant and radical scavenging activities than curcumin solubilized in ethanol solutions as determined by Fe (III) reducing power, 1, 1-Diphenyl-2 picrylhydrazyl free radical (DPPH.), and 2, 2'-azinobis-(3-ethylbenzothiazoline) 6-sulfonic acid radical cation (ABTS.+) scavenging analysis. These core-shell nanoparticles may be useful for incorporating chemically unstable hydrophobic nutraceuticals such as curcumin into functional foods, dietary supplements, and pharmaceuticals. PMID- 29606229 TI - Metabolomics reveal that amino acids are the main contributors to antioxidant activity in wheat and rice gochujangs (Korean fermented red pepper paste). AB - Metabolite profiling of gochujangs (Korean fermented red pepper paste) produced from different kinds of raw materials (WG, wheat gochujang; RG, rice gochujang) was performed using gas chromatography time-of-flight mass spectrometry (GC-TOF MS) and ultra-performance liquid chromatography quadrupole time of flight mass spectrometry (UPLC-Q-TOF-MS). Using principal component analysis (PCA), gochujang samples were differentiated based on the differences in starchy source and secondary materials used in their production. The content of amino acids and sugars was higher in WG, whereas the content of flavonoids, soyasaponins, and gamma-aminobutyric acid (GABA) was higher in RG. The content of flavonoids and soyasaponins was related to the higher soybean koji content of RG. The level of antioxidant activity in WG was higher than that in RG and showed a strong positive correlation with amino acid content and a negative correlation with flavonoid content. Although the Trolox equivalent antioxidant capacity of flavonoids was only 10-fold higher than that of amino acids in an antioxidant activity assay, the total amino acid content was as much as several hundred fold higher than total flavonoid content in gochujang. This result suggests that the amino acids could be a main contributor to the antioxidant capacity in gochujang. PMID- 29606230 TI - Incidence, populations and diversity of fungi from raw materials, final products and air of processing environment of multigrain whole meal bread. AB - This study aimed to assess the incidence, to quantify and to assess the diversity of fungi in a multigrain whole meal bread processing plant. Two hundred and eight one (n=281) samples were analyzed, including raw materials (n=120), air samples (n=136) and multigrain breads (n=25). Among the raw materials, the whole corn flour showed the highest counts of fungi (4.8logCFU/g), followed by whole-wheat flour (3.1logCFU/g). The counts of fungi in the air of processing environment were higher in post-baking steps (oven output, cooling, slicing, packaging) than in pre-baking steps (weighing and mixer) (p<0.05). Species of fungi isolated from spoiled bread samples stored at 5, 20, 25 and 30, and 40 degrees C corresponded mostly to Penicillium paneum and Penicillium polonicum isolated from 20 and 24% of samples, respectively. These species were also isolated from raw materials (P. paneum and P. polonicum) and air collected at different processing sampling points (P. polonicum). The high counts of filamentous fungi in raw materials and air samples in processing steps such as cooling, slicing, and packaging, suggest that contamination that may occur in these steps can be critical for the shelf life of breads. The results of this study highlight that the prevention of contamination of breads by fungal spores is still a challenge for bakery industries and that other strategies such as control of germination and growth of spoilage fungi through the development of more stable formulations have to be developed. PMID- 29606231 TI - Characterization of germination of spores of Clostridium estertheticum, the primary causative agent of blown pack spoilage of vacuum packaged beef. AB - The aim of this study was to investigate the effect of various factors on the germination of Clostridium estertheticum endospores (spores) in relation to beef. The effect of heat on germination was determined by recovering C. estertheticum on Columbia agar from spore suspensions not heated or heated at 63, 70 or 80 degrees C for various times. The effects of pH, temperature and oxygen were determined, by enumeration of remaining ungerminated spores during incubation in Meat Juice medium (MJM). Amino acids and lactate were tested for their ability to trigger germination of C. estertheticum spores by monitoring dipicolinic acid (DPA) release. Heat treatment of spores at 80 degrees C for <=20min significantly (p<0.05) increased the numbers of spores recovered on blood agar. Neither incubation temperature nor oxygen affected germination in MJM. The optimal pH for germination was 7.0 to 7.5. Incubation with leucine or aspartic acid caused a 1.3% release of DPA, the highest among all amino acids tested. Incubation with lactate resulted in a 4.1% release of DPA, which was significantly (p<0.05) higher than those from incubation with amino acids. The DPA release from incubation with lactate, lactate with amino acids, or MJM was similar (p>0.05). PMID- 29606232 TI - Effect of pulsed electric fields - assisted extraction on anti-inflammatory and cytotoxic activity of brown rice bioactive compounds. AB - The bioactive compounds of brown rice exhibit many beneficial health effects, ranging from antioxidant to cytotoxic activities. Pulsed Electric Field (PEF) pretreatment can significantly enhance their extraction, through the induction of the electro-permeabilization of the cell membranes. This paper aims to demonstrate that PEF-assisted extraction of brown rice enables not only enhanced yields of antioxidant compounds, such as gamma-oryzanol, polyphenols and phenolic acids, and of saturated and unsaturated fatty acids, but also increased cytotoxic effects on cancer cells. Initially, the PEF-assisted extraction conditions have been defined by the assessment of the cell permeabilization index via impedance measurements and the DPPH antioxidant activity. Subsequently, the biological effects of PEF have been evaluated on the cytotoxicity and anti-inflammatory properties against human colon cancer cell line HT29. The results show that PEF assisted extraction, enhancing the yield of bioactive compounds, with respect to untreated extracts, significantly promotes their antioxidant activity, which is correlated with an increased HT29 cells cytotoxicity. In addition, PEF extracts of brown rice substantially inhibit also gene expression and interleukin production in colon cancer cells, suggesting their exploitation as natural anti inflammatory agents. The integration of PEF pretreatment in the solvent extraction process of bioactives from brown rice appears, therefore, as a promising practice to significantly enhance their biological activity. PMID- 29606233 TI - The water-soluble non-starch polysaccharides from bananas display immunomodulatory properties on cultured macrophages. AB - Some diet components, such as certain indigestible polysaccharides from edible plants, may interact with the gut-associated lymphoid tissue and improve the host immune response to pathogens. The non-starch polysaccharides (NSP) from bananas are non-digestible carbohydrates that resemble some immunomodulatory polysaccharides occurring in the cell wall of cereals. Based on this similarity, the effects of the water-soluble NSP from two banana cultivars (Nanicao and Thap Maeo) on the phagocytic activity, nitric oxide (NO) and cytokines produced by cultured macrophages were investigated. An investigation into the monosaccharide composition and the oligomers released by enzymatic hydrolysis of the ultra filtered fraction above 50kDa and the heat-treated fraction of water-soluble NSP from both cultivars revealed they are mostly composed of mannan and galacturonans (homogalacturonan, xylogalacturonan and rhamnogalacturonan). The NSP tested were able to activate the macrophages, but the effects on the phagocytic activity and the release of tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6) and nitric oxide production were dependent on the polysaccharide concentration and the cultivar origin. Despite some specific differences, the NSP from Nanicao and Thap Maeo banana fruits may be considered prospective food immunomodulators, which contribute to the promotion of a more responsive immune system. PMID- 29606234 TI - Ozone treatments of post harvested wine grapes: Impact on fermentative yeasts and wine chemical properties. AB - Ozone represents a potent antimicrobial compound that is already proposed as a possible sanitizing agent, especially for surface decontamination of fruits and vegetables. The main objective of this study was to evaluate the effect of ozone, either in aqueous or gaseous form, on wine grape mycobiota and its impact during spontaneous and inoculated fermentations. Gaseous (32+/-1MUL/L, 12 and 24h) and aqueous (5+/-0.25mg/L, 6 and 12min) ozone were tested as sanitizing treatments. A multiphasic approach was used employing culture-dependent (traditional plate counts) and -independent techniques, based on DNA and RNA amplification (PCR denaturing gradient gel electrophoresis [DGGE] and reverse transcription PCR [RT PCR]-DGGE), respectively. Microbiological analysis data highlighted a reduction of >0.5LogCFU/mL of the total yeasts present on grape berry surfaces after ozone treatments, mainly due to the reduction of apiculate yeasts. The chemical analysis of the wines, produced from the treated grapes, showed higher acetic acid content in the untreated spontaneous fermentations (0.52g/L) compared to the treated (ranged from 0.16 to 0.38g/L), while all fermentation-inoculated wines contained higher amounts of pleasant volatile compounds. PMID- 29606235 TI - Respective impact of bread structure and oral processing on dynamic texture perceptions through statistical multiblock analysis. AB - Texture perception is a multidimensional and dynamic phenomenon resulting from both the initial structure of food and its breakdown during oral processing. The aim of this study is to identify the respective contribution of food and bolus properties to temporal changes in texture perceptions during bread consumption. For this purpose, the perception dynamics of three French baguettes with dif?ferent structures were assessed through Temporal Dominance of Sensations and Progressive Profiling. Samples of crumb with and without crust were tasted by trained panelists. The intensities of nine texture attributes were evaluated at three key stages of oral processing (10%, 40% and 100% of individual swallowing time) using the Progressive Profiling method. Six of them were related with a Multiblock Partial Least Squares (MB-PLS) regression to the initial bread properties and to some bolus properties measured at these three stages. The evolution during oral processing of some attributes such as "soft", "dry", "doughy" and "sticky" was more influenced by modifications of bolus properties than by the initial characteristics of the breads. Among bolus properties, the MB PLS highlighted that the hydration and texture properties of the bolus had a greater impact on texture perceptions than bolus structure. The "aerated" perception was more affected by the crumb structure, while the "heterogeneousness" and the "crispiness" were more affected by the presence of crust. This study thus contributes to improving our understanding of dynamic texture perceptions through a statistical model that takes the physical properties of bread and bolus during oral processing into account. PMID- 29606236 TI - Study of the effect of H2S, MeSH and DMS on the sensory profile of wine model solutions by Rate-All-That-Apply (RATA). AB - The effect of hydrogen sulfide (H2S), methanethiol (MeSH) and dimethyl sulfide (DMS) on the odor properties of three wine models-WM- (young white, young red and oaked red wines) was studied. Wine models were built by mixing a pool of common wine volatile and non-volatile compounds and further spiked with eight different combinations of the three sulfur compounds present at two levels (level 0: 0MUgL 1 and level 1: 40MUgL-1 of H2S, 12MUgL-1 of MeSH; 55MUgL-1 of DMS). For each wine matrix eight WMs were produced and further submitted to sensory description by Rate-All-That-Apply (RATA) method. Hydrogen sulfide and methanethiol were clearly involved in the formation of reductive aromas and shared the ability to act as strong suppressors of fruity and floral attributes. Specifically, hydrogen sulfide generated aromas of rotten eggs, while methanethiol generated significant increases in camembert and decreases in citrus, smoky/roasted and oxidation aromas. The simultaneous presence of hydrogen sulfide and methanethiol enhanced the intensity of the unspecific term reduction, while the specific nuances individually imparted by each of the two compounds could not be further identified. DMS did not exert any outstanding effect on the reductive character of wines and its sensory effect was matrix-dependent. It was involved in the formation of fruity notes such as cooked/candied and red/black fruits in young wines, and vegetal notes (canned vegetables) in oaked red WMs. PMID- 29606237 TI - Formation of volatile compounds during cupuassu fermentation: Influence of pulp concentration. AB - Cupuassu (Theobroma grandiflorum Schum) is a native fruit of the Amazon region and from its seeds fermentation, it is possible to obtain a product similar to chocolate, known as cupulate. The aim of this study was to evaluate the influence of the pulp concentration on the formation of volatile compounds during fermentation. Considering the high quantity of pulp that naturally involves the seeds (38%), which represents an obstacle for fermentation, two different fermentation experiments were conducted: with seeds totally (0%) and partially (15%) depulped. Seeds collected during and after fermentation, after drying (beans), after roasting and deshelling (nibs) and cupulates (obtained using the same methods of chocolate processing) were analyzed through identification and relative quantification by GC-MS in order to check the profile of volatile compounds formed. Results showed that the depulping implies in considerable reduction of important volatile compounds. A wider diversity of volatile compounds such as aldehydes, ketones and alcohols were found in the experiment with 15% pulp during fermentation. Tetramethylpyrazine was the unique pyrazine found in the cupulate samples that had significant difference (p<0.05) among the samples in its concentration. Among the others compounds identified, it is important to emphasize the presence of compounds with fruity and floral notes, generally present in fine/flavor cocoa. This study demonstrated the importance of the pulp in the development of important compounds responsible for the desirable flavor. PMID- 29606238 TI - Perceived minerality in sauvignon blanc wine: Chemical reality or cultural construct? AB - The study aimed to determine the relationship between perceived mineral character in wine and wine chemical composition. We investigated the sensory properties and chemical composition of sauvignon blanc wines from two major sauvignon-producing countries, New Zealand and France. Sensory experiments employing 16 wines (8 French, 8 New Zealand) were conducted in Marlborough, New Zealand and in three regions of France, namely Bordeaux, Burgundy, and the Sancerre/Loire region. Wine professionals (31 New Zealanders and 32 French professionals) sensorially characterised the 16 wines under three conditions, bouquet only (ortho-nasal olfaction), palate only (nose clip condition), and full tasting (global condition: ortho-nasal olfaction, retronasal olfaction, taste, trigeminal stimulation). Sensory data from the global condition only are reported in this article. Physical and chemical analyses conducted on all wines included wine standard parameters, elemental composition, volatile aroma composition, and measures of organic acids. Major results demonstrate that (i) on average French and New Zealand wines were perceived similarly in intensity of mineral character, although judgments to individual wines differed as a function of participant culture; (ii) French and NZ participants drew on different information to make their sensory judgments; and (iii) several aspects of wine composition associated positively with perception of mineral character while others associated negatively, the significant associations differing as a function of participant culture. PMID- 29606239 TI - Influence of methylcellulose on attributes of beta-carotene fortified starch based filled hydrogels: Optical, rheological, structural, digestibility, and bioaccessibility properties. AB - There is considerable interest in controlling the gastrointestinal fate of nutraceuticals to improve their efficacy. In this study, the influence of methylcellulose (an indigestible polysaccharide) on lipid digestion and beta carotene bioaccessibility was determined. The carotenoids were encapsulated within lipid droplets that were then loaded into rice starch hydrogels containing different methylcellulose levels. Incorporation of 0 to 0.2% of methylcellulose had little impact on the dynamic shear rheology of the starch hydrogels, which may be important for formulating functional foods with desirable textural attributes. The microstructure, lipid digestion, and beta-carotene bioaccessibility of the filled hydrogels were measured as the samples were passed through simulated oral, gastric, and small intestinal phases. The lipid digestion rate and carotenoid bioaccessibility decreased with increasing methylcellulose. This effect was attributed to the ability of the methylcellulose to inhibit molecular diffusion, promote droplet flocculation, or bind gastrointestinal components thereby inhibiting triacylglycerol hydrolysis at the lipid droplet surfaces. This information may be useful for rationally designing functional foods with improved nutritional benefits. PMID- 29606240 TI - Dual modification of starch nanocrystals via crosslinking and esterification for enhancing their hydrophobicity. AB - The aim of this study was to enhance the hydrophobicity of starch nanocrystals (SNCs) and improve their dispersibility in non-polar solvents through dual modifications. The dual modifications were carried out by crosslinking first and then followed esterification. The results of characterizations showed that the dual modifications resulted in a higher degree of substitution of SNCs than single esterification modification. The SNCs with the dual modifications possessed lower polarity and showed stronger hydrophobicity than the SNCs with single crosslinking or esterification modification and therefore could be dispersed in non-polar solvents such as chloroform, dichloromethane and toluene. In addition, the crosslinking protected the crystalline structure of SNCs being disrupted in the followed esterifications. The modified SNCs can be used as reinforcements for nanocomposites with hydrophobic polymer matrices or emulsion stabilizers and rheology modifiers. PMID- 29606241 TI - Effect of pulsed light treatment on structural and functional properties of whey protein isolate. AB - This work aimed at investigating the effects of Pulsed Light (PL) processing at different fluences (from 4 to 16J/cm2) on the structure and functional properties of Whey Protein Isolate (WPI) solution. The determination of the free and total sulfhydryl (SH) groups was used to detect the variation of WPI tertiary and quaternary structure. Additionally, PL-induced changes in secondary structure were determined by FT-IR spectroscopy and the differential scanning calorimetry (DSC), and primary structure by carbonyl content. The experimental data demonstrated that PL treatments increased the concentration of total and free sulfhydryl groups and protein carbonyls. A decrease of the denaturation temperature and enthalpy ratio with increasing the intensity of PL treatments was observed in DSC measurements. Small but significant changes in the secondary structure of PL treated WPI solution were also taking place and detected. The extent of whey protein structure modifications was fluence dependent. The results of this investigation demonstrated the potential of PL treatments to induce dissociation and partial unfolding of WPI, thus improving some of their functional properties, such as solubility and foaming ability. PMID- 29606242 TI - Influence of the botanical origin and toasting level on the ellagitannin content of wines aged in new and used oak barrels. AB - The influence of the botanical origin (French oak: Quercus petraea and American oak: Quercus alba) and different toasting levels (light, medium and heavy) on the ellagitannin content of wines aged in oak barrels has been studied. This took place in two consecutive vintages in order to study what happens after the barrels have been already used for one year with another wine. This study was carried out with two red wines (Cabernet Sauvignon) and with two decolored white wines (Macabeo) from vintages 2012 and 2013 in order to work with a simpler matrix which facilitates chemical analysis. The results show that the botanical origin, toasting level and the number of times that the barrels have been used exert a major influence on the final ellagitannin concentration. In general, the behavior of all the individual ellagitannins was very similar to that described for the total ellagitannins. Briefly, the levels of total ellagitannins concentration in the decolored white wine aged for 12months in new French barrels ranged between 31.2mg/L in the lightly toasted and 4.7mg/L in the heavy toasted. In contrast, these levels were quite lower in American new barrels ranging between 3.6mg/L and 0.9mg/L. Finally, the total ellagitannin concentration decreased an average of 63% in the wines aged in the one year used barrels. PMID- 29606243 TI - The effect of a novel photodynamic activation method mediated by curcumin on oyster shelf life and quality. AB - In this paper, the effect of photodynamic method mediated by curcumin (PDT) on the shelf life and quality of pacific oysters during storage at 5+/-1 degrees C were analyzed. In our previous study we investigated the optimal treatment conditions of photodynamic method mediated by curcumin to sterilization were 10uM photosensitizer concentration and 5.4J/cm2 light energy density. Under these conditions, the effect of a novel photodynamic activation method mediated by curcumin on oyster shelf life and quality was researched. The total bacterial counts, TVB-N content and sensory analysis were used to evaluate the effects on oyster shelf life. The oyster shelf life was prolonged from 8days to 12days after photodynamic treatment and the oysters in the treatment group displayed notable odor retention, produced fewer odor corrupting substances when the control group oysters reached the end of their shelf life (day 8). Texture, free amino acid contents and fatty acid levels were applied to estimate the quality of the treated oysters. The texture had no significant change after treated with PDT. At the end of oyster shelf life, compared PDT group (PDT) with control group (control), total free amino acid contents (control: 234.30mg/100g, PDT: 813.02mg/100g) was higher and free fatty acid levels (control: 0.071mEq/L, PDT: 0.0455mEq/L) displayed lower in PDT group. This indicated that the treated oysters oxidized minimally, decayed slowly, decomposed fewer nutrients and had lower metabolic levels of spoilage microorganisms. PDT has a positive effect on prolonging oyster shelf life and its quality. PMID- 29606244 TI - Consumers as co-creators of new product ideas: An application of projective and creative research techniques. AB - Involving consumers in the process of modification and creation of new food products has been recently identified as a vital factor for new product development. However, little attention has been devoted to consumer-generated product solutions, and instead, researchers continue to view new product development process as a firm-centred activity. This study uses projective and creative research techniques to involve consumers in the process of modification and creation of new aquaculture product ideas. We provide guidelines for the use of these techniques in the new product development process, as well as managerial and practical implications for the future development of new aquaculture products. PMID- 29606245 TI - Dihydrocaffeic acid, a major microbial metabolite of chlorogenic acids, shows similar protective effect than a yerba mate phenolic extract against oxidative stress in HepG2 cells. AB - The hepatoprotective effect of a yerba mate phenolic extract (YMPE), rich in chlorogenic acids, and its main circulating metabolites dihydrocaffeic (DHCA) and dihydroferulic (DHFA) acids were assessed in human hepatoma HepG2 cells subjected to oxidative damage induced by tert-butylhydroperoxide (t-BOOH). Direct treatment of HepG2 cells with realistic concentrations of YMPE (1, 10 and 50MUg/mL), DHCA or DHFA (0.2, 1, 10MUM) for 20h was not cytotoxic and significantly decreased ROS generation. Pre-treatment with YMPE and DHCA prevented the cytotoxicity and macromolecular damage induced by t-BOOH. Moreover, decreased levels of reduced glutathione (GSH), and increased ROS levels and antioxidant enzyme activity induced by t-BOOH were dose-dependently recovered. DHFA only showed a slight protection against cell cytotoxicity, lipid oxidation and GSH depletion. In conclusion, YMPE and one of its major microbial metabolites, DHCA, confer significant protection against oxidative damage, adding evidences to the beneficial health effects associated with mate intake. PMID- 29606246 TI - Taste intensities of ten vegetables commonly consumed in the Netherlands. AB - Bitterness has been suggested to be the main reason for the limited palatability of several vegetables. Vegetable acceptance has been associated with preparation method. However, the taste intensity of a variety of vegetables prepared by different methods has not been studied yet. The objective of this study is to assess the intensity of the five basic tastes and fattiness of ten vegetables commonly consumed in the Netherlands prepared by different methods using the modified Spectrum method. Intensities of sweetness, sourness, bitterness, umami, saltiness and fattiness were assessed for ten vegetables (cauliflower, broccoli, leek, carrot, onion, red bell pepper, French beans, tomato, cucumber and iceberg lettuce) by a panel (n=9) trained in a modified Spectrum method. Each vegetable was assessed prepared by different methods (raw, cooked, mashed and as a cold pressed juice). Spectrum based reference solutions were available with fixed reference points at 13.3mm (R1), 33.3mm (R2) and 66.7mm (R3) for each taste modality on a 100mm line scale. For saltiness, R1 and R3 differed (16.7mm and 56.7mm). Mean intensities of all taste modalities and fattiness for all vegetables were mostly below R1 (13.3mm). Significant differences (p<0.05) within vegetables between preparation methods were found. Sweetness was the most intensive taste, followed by sourness, bitterness, fattiness, umami and saltiness. In conclusion, all ten vegetables prepared by different methods showed low mean intensities of all taste modalities and fattiness. Preparation method affected taste and fattiness intensity and the effect differed by vegetable type. PMID- 29606247 TI - Modulating the gel properties of soy glycinin by crosslinking with tyrosinase. AB - The gelation progression and gel properties of enzymatically crosslinked soy glycinin were evaluated in comparison to non-crosslinked glycinin. Glycinin was initially crosslinked using tyrosinase from Bacillus megaterium (TyrBm) and was later used to form gel upon heating. Gelation was evaluated by small deformation rheological measurements and revealed a significant increase in storage modulus (G') obtained in the crosslinked gel. This was confirmed by temperature sweep and frequency sweep measurements that supported the results and proved that the difference in modulus was not frequency dependent. Texture profile analysis showed an increase in hardness and decrease in elasticity of the crosslinked gels. Scanning electron microscopy (SEM) images displayed a more structural network with larger pore size in the crosslinked gel. The less dense structure of the crosslinked glycinin gel network led to a slight decrease in the water holding capacity. Finally, thermal analysis using differential scanning calorimetry (DSC) confirmed no change in the gelation point induced by denaturation, however thermal gravimetric analysis (TGA) did show a difference in the decomposition profile of the crosslinked protein compared with non crosslinked glycinin. The results suggest that by applying TyrBm mediated crosslinking we may modulate the protein gel properties for tailoring the texture of food products. PMID- 29606248 TI - Insights into milk-clotting activity of latex peptidases from Calotropis procera and Cryptostegia grandiflora. AB - Latex fractions from Calotropis procera, Cryptostegia grandiflora, Plumeria rubra, and Himatanthus drasticus were assayed in order to prospect for new plant peptidases with milk-clotting activities, for use as rennet alternatives. Only C. procera and C. grandiflora latex fractions exhibited proteolytic and milk clotting activities, which were not affected by high concentrations of NaCl and CaCl2. However, pre-incubation of both samples at 75 degrees C for 10min eliminated completely their activities. Both proteolytic fractions were able to hydrolyze k-casein and to produce peptides of 16kDa, a similar SDS-PAGE profile to commercial chymosin. RP-HPLC and mass spectrometry analyses of the k-casein peptides showed that the peptidases from C. procera or C. grandiflora hydrolyzed k-casein similar to commercial chymosin. The cheeses made with both latex peptidases exhibited yields, dry masses, and soluble proteins similar to cheeses prepared with commercial chymosin. In conclusion, C. procera and C. grandiflora latex peptidases with the ability to coagulate milk can be used as alternatives to commercial animal chymosin in the cheese manufacturing process. PMID- 29606249 TI - Development and validation of a LC-ESI-MS/MS method for the determination of phenolic compounds in honeydew honeys with the diluted-and-shoot approach. AB - A simple, reproducible and sensitive method has been optimized and validated for simultaneous determination of 32 phenolic compounds in bracatinga (Mimosa scabrella Benth.) with the diluted-and-shoot approach, without the need of any additional clean-up steps. It has been based on high performance liquid chromatography coupled with triple quadrupole tandem mass spectrometry and electrospray ionization (HPLC-ESI-MS/MS). The chromatography conditions were optimized, and due to the selectivity provided by MRM monitoring, LC separation required only 9min. The developed method was validated on the basis of Eurachem and European Commission Decision 2002/657/EC guidelines. Mean recoveries ranged from 70.4 to 110%. Intra-day and inter-day precision with RSD (relative standard deviations) from 0.14 to 18.9% and 0.34 to 20.0%, respectively were achieved. Limits of detection (LOD) and quantification (LOQ) ranged from 0.03 to 3.20MUgL-1 and 0.20-12.8MUgL-1. Finally, the method was applied to samples and 20 phenolic compounds were quantified in all the samples analyzed, representing a contribution to the characterization and quantification of phenolic compounds from bracatinga (M. scabrella Bentham) honeydew honey. PMID- 29606250 TI - Colour stability of lutein esters in liquid and spray dried delivery systems based on Quillaja saponins. AB - Aim of the present study was to expand the existing knowledge on the functionality of Quillaja saponin extract by comparing micellar systems, nanoemulsions and the corresponding spray-dried formulations for the delivery of lutein esters as colouring agents to foods. A chemically well-defined saponin extract was used, and characterised by MALDI-TOF-MS and HPTLC-MALDI-TOF-MS. The composition of the extract comprised all major saponins described for Quillaja, but the relation between the individual constituents differed considerably from the literature. Colour intensity of lutein ester loaded systems was higher in nanoemulsions compared to micelles. Quillaja saponins provided good stability to lutein ester loaded systems during the process of microencapsulation by spray drying, as indicated by particle size analysis of the dispersed phases and colour determination. Colour stability upon storage was high in microencapsulated formulations. Results therefore prove the high functionality of Quillaja saponins for stabilisation of sensitive, natural food colourants. PMID- 29606251 TI - Metabolite profiles of formula milk compared to breast milk. AB - Breast milk (BM) feeding is the gold standard in neonate nutrition. When BM is not available it can be substituted or integrated with commercial formula milk (FM) usually sold under different brands and formulations. In this work, the low molecular-weight hydrophilic compounds in milk were studied by gas chromatography electronic impact mass spectrometry (GC-MS), comparing eight different FM brands with BM samples. With the aid of multivariate statistical data analysis, a marked variability among FM brands, especially driven by the presence of prebiotics in their formulation, was highlighted. Quali-quantitative differences were found between FM and BM. Orotic acid and isomaltulose were found exclusively in FM, while phenylalanine and tyrosine levels were high in two FM brands. Moreover, higher levels of malic acid, sugars (glucose, fructose and galactose), and mannitol were detected in FM. On the other hand, BM showed a higher amino acid content. In conclusion, GC-MS proved to be a very sensitive analytical technique for the study of FM, highlighting metabolite differences among FM brands, and between FM and BM, that may have a possible strong impact on neonatal nutrition. PMID- 29606252 TI - Development of free-flowing peppermint essential oil-loaded hollow solid lipid micro- and nanoparticles via atomization with carbon dioxide. AB - The main objective of this study was to overcome the issues related to the volatility and strong smell that limit the efficient utilization of essential oils as "natural" antimicrobials in the food industry. Peppermint essential oil loaded hollow solid lipid micro- and nanoparticles were successfully formed using a novel "green" method based on atomization of CO2-expanded lipid mixture. The highest essential oil loading efficiency (47.5%) was achieved at 50% initial essential oil concentration at 200bar expansion pressure and 50MUm nozzle diameter, whereas there was no significant difference between the loading efficiencies (35%-39%) at 5%, 7%, 10%, and 20% initial essential oil concentrations (p>0.05). Particles generated at all initial essential oil concentrations were spherical but increasing the initial essential oil concentration to 20% and 50% generated a less smooth particle surface. After 4weeks of storage, 61.2%, 42.5%, 0.2%, and 2.0% of the loaded essential oil was released from the particles formed at 5%, 10%, 20%, and 50% initial essential oil concentrations, respectively. This innovative simple and clean process is able to form spherical hollow micro- and nanoparticles loaded with essential oil that can be used as food grade antimicrobials. These novel hollow solid lipid micro- and nanoparticles are alternatives to the solid lipid nanoparticles, and overcome the issues associated with the solid lipid nanoparticles. The dry free-flowing products make the handling and storage more convenient, and the simple and clean process makes the scaling up more feasible. PMID- 29606253 TI - Oxidative stress prevention and anti-apoptosis activity of grape (Vitis vinifera L.) stems in human keratinocytes. AB - To date, grape stems have been partially assessed on their content in phenolics and their radical scavenging activity, whilst the potential to modulate oxidative stress in biological models remains underexplored. In the present work, the effect of grape stems' phenolics on redox unbalance was evaluated in human keratinocytes (HaCaT cells). Grape stems' extracts were assessed on their phenolic composition by high performance liquid chromatography coupled with photodiode array detection and electrospray ionization-mass spectrometry (HPLC PAD-ESi-MSn), besides on radical scavenging capacity (ABTS and DPPH). In addition, their protective effect against oxidative stress induced by H2O2 by the determination of the level of glutathione, reactive oxygen species, lipid peroxidation, and overall oxidative stress in HaCaT cells by flow cytometry was evaluated. This characterization allowed to identify five flavonols, one cinnamic acid, and one stilbene. A close correlation between the concentration of these phenolics and the capacity to scavenge free radicals and with the potential to modulate the redox balance in vitro was observed. From the analysis of correlation, the activity of malvidin-3-O-glucoside, malvidin-3-O-(6-O-caffeoyl) glucoside, and malvidin-3-O-rutinoside with respect to the prevention of basal oxidative stress and the capacity of isorhamnetin-3-O-(6-O-feruloyl)-glucoside and kaempferol-3-O-rutinoside to prevent H2O2-induced redox unbalance were stated. Furthermore, grape stems' phenolics also showed an efficient capacity to modulate apoptosis in HaCaT cells, reducing the frequency of annexin V/PI double positive apoptotic cells by up to 99.5% relative to controls, which was further confirmed by the determination of the appearance of the occurrence of apoptotic bodies and the expression of activated (cleaved) caspase-3 by flow cytometry and western-blot, respectively. These results supported the potential of individual phenolics from grape stems to modulate oxidative stress, allowing to envisage dedicated combinations of single compounds for the development of efficient formulations efficient against oxidative stress. PMID- 29606254 TI - Universal Health Coverage and AYUSH systems. PMID- 29606255 TI - Recent advances in the physiopathology of IgA nephropathy. AB - Immunoglobulin A nephropathy or Berger's disease is the most common type of primary glomerulonephritis, which is characterized by IgA1-containing immune deposits in the glomerular mesangium. Microscopic haematuria and proteinuria are the most common presentations. Mesangial cell proliferation with IgA deposition is found on renal biopsy. Mechanims of the disease implicate at least four key molecules have been implicated in immune complex formation: galactose-deficient IgA1, autoantibodies anti-galactose-deficient-IgA1, soluble CD89 (Fc receptor for IgA) and the CD71 mesangial IgA receptor (transferrin receptor). These factors associated with environmental factors (antigens, food and microbiota) are correlated with disease progression and recurrence after transplantation. This review exploits recent data on the role of these molecular players of the disease, which may improve future therapeutic management of immunoglobulin A nephropathy. PMID- 29606256 TI - [Renal toxicity of high-dose methotrexate]. AB - INTRODUCTION: High-dose methotrexate (at least 1g/m2) is used to treat haematologic malignancies and osteosarcomas. Acute kidney injury is a well-known adverse-event after high-dose methotrexate and may lead to delayed drug elimination. Besides usual therapeutics (hyperhydration, urine alkalinisation, leucovorin rescue, renal replacement therapy), a costly specific enzymatic treatment (glucarpidase) is now available but its clinical impact remains elusive. PATIENTS AND METHODS: We analysed high-dose methotrexate prescription charts in 11 clinical centres during the last 15 years to identify and describe adult patients who developed acute kidney injury (according to KDIGO classification). Glucarpidase use was recorded (French temporary regulatory approval criteria: methotrexate at least 10MUmol/L at 48h or at least 3MUmol/L at 48h associated with acute kidney injury). RESULTS: Seventy-six acute kidney injury cases have been studied. Mean peak creatinine was 206MUmol/L after a mean delay of 5.6 days, with 19 cases of stage 1 acute kidney injury (25%), 29 cases of stage 2 (38%) and 27 cases of stage 3 (36%). Anuria (one case) and need for renal replacement therapy (four cases) were unusual whereas fluid overload was often observed (29%). Three months after high-dose methotrexate treatment, mortality-rate was 17%, and 12% of surviving patients developed renal sequelae. CONCLUSION: Sixty-one percent of patients received a glucarpidase perfusion during acute kidney injury. Despite a dramatic decrease of methotrexate serum levels, glucarpidase as compared with conservative treatment did not modify acute kidney injury stage, recovery delay, need for renal replacement therapy or the incidence of extrarenal toxicities. Net clinical benefit was not observed even after stratification according to eligibility criteria for glucarpidase use. Glucarpidase has probably no or little effects on methotrexate localized into tubular lumen or proximal tubular cells and that may account for the absence of nephroprotective effect for enzymatic treatment. PMID- 29606257 TI - [Ifosphamide nephrotoxicity]. AB - Ifosfamide is a cytotoxic drug usually used in malignant sarcomas. The nephrotoxicity of this agent has been described essentially among children, revealed by renal failure and proximal tubulopathy. We recently conducted a retrospective multicentre study, describing 34 adult patients admitted for ifosfamide nephrotoxicity. More than 80% of them presented with renal failure, diagnosed up to 48 months after ifosfamide administration. A Fanconi syndrome with hypophosphoremia, hypokaliemia, glucosuria and low-molecular weight proteinuria, was present in two third of all cases. Median estimated glomerular filtration rate was 31mL/min 1 month and 38mL/min 3 months after ifosfamide infusion, versus 67mL/min at baseline. Renal biopsy, performed in 14 of these patients, showed acute tubular necrosis with vacuolization of proximal tubular epithelial cells with marked nuclear modifications, whereas electron microscopy revealed major changes of mitochondrial structure inside those cells, suggesting a tenofovir-like mechanism of nephrotoxicity. After a median follow-up of 31 months, ten patients out of 34 reached stage 5 chronic kidney disease, requiring dialysis in five cases. Poor renal prognosis was associated with concomitant cisplatin use (P=0.02) and with older age at presentation (P=0.04). In conclusion, ifosfamide nephrotoxicity is often severe and irreversible, leading to proximal tubulopathy and sometimes-severe chronic kidney failure, that can be immediate or delayed, sometimes diagnosed months after chemotherapy completion. PMID- 29606258 TI - Treatment of IgA nephropathy: Recent advances and prospects. AB - IgA nephropathy, identified 50 years ago in France, is the most frequent glomerular disease worldwide. The course is variable, but in most of the cases there is a relentless decline in renal function, reaching end-stage renal failure in 10-60% of the cases after 10 years and in 40% after 20 years. These data justify the interest for finding a suitable therapeutic approach particularly in progressive cases. A supportive care, including renin-angiotensin system inhibitors is the priority in cases with slowly declining renal function, particularly when developing proteinuria. The recent supportive versus immunosuppressive therapy for the treatment of progressive IgA nephropathy (STOP IgAN) randomized and controlled trial has further stressed the benefit of a strict supportive care including also life-style changes, protein and salt restriction. However, there is clear evidence from observational studies (including the European Validation Study of the Oxford Classification of IgA nephropathy [VALIGA]) and a new randomized and controlled trial (Therapeutic Evaluation of Steroids in IgA Nephropathy Global [TESTING]) of additional benefits of corticosteroid treatment in patients with proteinuric IgA nephropathy. However, the present treatment schedules carry severe side effects, mostly infectious complications, which indicate the need for less toxic interventions. The recent focus on the role of gut-kidney axis in IgA nephropathy has led to the search of corticosteroid formulations targeting the intestinal mucosal immune system (gut-associated lymphoid tissue). The NEFIGAN trial obtained interesting results in terms of reduction of proteinuria and stabilization of renal function using a budesonide formulation allowing a selective drug delivery at intestinal gut-associated lymphoid tissue sites. The adverse events, particularly infections, were found to be not clinically relevant. The possibility of a personalized approach to the treatment according to the renal biopsy lesions (Oxford MEST score) is supported by several uncontrolled studies and deserves great attention in the next future. New treatments options for IgA nephropathy include drugs targeting BAFF, a B-cell factor crucial for IgA synthesis or targeting the complement system, and also the possibility of acting directly on the deposited IgA by selective protease digestion. PMID- 29606259 TI - [Vancomycin nephrotoxicity: Frequency and mechanistic aspects]. AB - Vancomycin, discovered in 1953 and widely used today, has a nephrotoxic potential that has long been debated. The frequency of renal involvement is variable and can range from 5% to 30% depending concomitant risk factors: overdose, chronic kidney disease, obesity, hypovolemia, and use of other nephrotoxic drugs as aminoglycosides. Its association with piperacillin-tazobactam also appears to increase the risk of nephrotoxicity. This hypothesis should be confirmed experimentally. Vancomycin-induced oxidative stress in tubular cells and intraluminal cast formation are the two physiopathological mechanisms explaining its nephrotoxicity. Vancomycin may induce acute tubular injury and rapid decline in renal function. These lesions are often reversible when the infusion is discontinued, but sometimes chronic kidney failure may ensue. As vancomycin is widely used and the current tendency is to increase target trough levels, it is necessary to identify risk factors in order to reduce its risk of nephrotoxicity. PMID- 29606260 TI - [Transplantation strategy in type 1 diabetic patients]. AB - Beta cell replacement by pancreas or Langerhans islets transplantation is the only way to restore glucose homeostasis in type 1 diabetic patients. The counterpart is the need for long-term immunosuppression. These transplantations are therefore mainly indicated for patients candidates for kidney transplantation and for patients with poor quality of life due to unstable diabetes with life threatening hypoglycemic events. Both beta cell replacement techniques have different benefits and risks and should be adapted to each type 1 diabetic patient. The transplant strategy must be personalized according to parameters assessed in the pre-transplant period, validated by a multidisciplinary team and reassessed regularly until transplantation. PMID- 29606261 TI - Prognosis and treatment of diabetic nephropathy: Recent advances and perspectives. AB - Approximately 20 to 40% of patients with type 1 or type 2 diabetes develop diabetic kidney disease. It is a clinical syndrome characterized by persistent albuminuria (>300mg/24h, or 300mg/g creatinine), a relentless decline in glomerular filtration rate, raised arterial blood pressure and enhanced cardiovascular morbidity and mortality. The natural course of classical diabetic nephropathy is initially microalbuminuria or moderately increased urine albumin excretion (30-300mg/g creatinine). Untreated microalbuminuria may then rise gradually, reaching severely increased albuminuric (macroalbuminuria) over 5 to 15 years. Glomerular filtration rate then begins to decline and end-stage renal failure is reached without treatment in 5 to 7 years. Regular, systematic screening for diabetic kidney disease is needed to identify patients at risk for, or with presymptomatic stages of diabetic kidney disease. Multifactorial intervention targeting glucose, lipids and blood pressure including blockade of renin angiotensin system and lifestyle, has improved renal and cardiovascular prognosis and reduced mortality with 50%. Recent data suggest beneficial pleiotropic effects on renal endpoint with new glucose lowering agents. It is also being investigated if blocking aldosterone could be an option as a potential new treatment. Thus, although diabetic nephropathy remains a major burden, prognosis has improved and new options for further improvements are currently tested in phase 3 clinical renal outcome studies. PMID- 29606262 TI - [Identifying the specific causes of kidney allograft loss: A population-based study]. AB - INTRODUCTION: Results of kidney transplantation have been improving but long-term allograft survival remains disappointing. The objective of the present study was to identify the specific causes of renal allograft loss, to assess their incidence and long-term outcomes. METHODS: A total of 4783 patients from four French centres, transplanted between January 2004 and January 2014 were prospectively included. A total of 9959 kidney biopsies (protocol and for cause) performed between January 2004 and March 2015 were included. Donor and recipient clinical and biological parameters as well as anti-HLA antibody directed against the donor were included. The main outcome was the long-term kidney allograft survival, including the study of the associated causes of graft loss, the delay of graft loss according to their causes and the determinants of graft loss. RESULTS: There were 732 graft losses during the follow-up period (median time: 4.51 years) with an identified cause in 95.08 %. Kidney allograft survival at 9 years post-transplant was 78 %. The causes of allograft loss were: antibody mediated rejection (31.69 %), thrombosis (25.55 %), medical intercurrent disease (14.62 %), recurrence of primary renal disease (7.1 %), BK- or CMV-associated nephropathy (n=35, 4.78 %), T cell-mediated rejection (4.78 %), urological disease (2.46 %) and calcineurin inhibitor nephrotoxicity (1.09 %). CONCLUSION: The main causes of allograft loss were antibody-mediated rejection and thrombosis. These results encourage efforts to prevent and detect these complications earlier in order to improve allograft survival. PMID- 29606263 TI - [Multidimensional approaches for risk stratification in transplantation]. AB - Despite considerable progress in the short-term outcomes of renal transplantation, there has been little improvement over the last 15years on long term survival. The main limitation is the lack of precise knowledge of the determinants of renal allograft loss and robust prognostic systems providing an individual prediction. Kidney transplantation must address a pressing clinical need to accurately define the determinants of kidney renal allograft survival in order to improve risk stratification. To achieve this goal, four steps need to be considered in the development of prognostic tools: the characterization and identification of the phenotype of the pathology, the assessment of prognostic factors of the event of interest in the population, the assessment of the additional value provided by a newly identified prognostic factor to conventional factors already known in clinical practice as well as the construction of prognostic tools, on the basis of multidimensional integrative models allowing a precise stratification of the risk, at individual and population scale. PMID- 29606264 TI - [Glomerular filtration rate estimation and measurement: The quest for precision]. AB - Glomerular filtration rate measurement is still the best way to assess the global renal function. In daily practice, glomerular filtration rate is estimated by creatinine-based equations. Serum creatinine as a renal biomarker has however several limitations. We discuss the current recommended creatinine-based equations. The potential added value of a new biomarker, cystatin C, and alternative equations will be discussed. Finally, the potential interest of measured glomerular filtration rate by a reference method in specific patients and/or situations will be discussed and justified. PMID- 29606265 TI - [Evaluation of living kidney donors renal function]. AB - End-stage renal disease risk of living kidney donors is lower than the one in general population. In 2014, two independent studies confirmed this result but evidenced an increased risk of end-stage renal disease after donation. In this context, long-term consequences of living donation need to be better defined. Evaluation of renal function is a cornerstone of living donor screening. Precise knowledge of kidney donation physiology is required to propose a relevant predonation screening. In this review, we present the risks of donation, the physiology of living donation and discuss international guidelines. PMID- 29606266 TI - [Pulmonary ultrasound and dialysis]. AB - Profound deficit of the body fluid composition regulation system is present at the end stage kidney disease, leading to the increase the risk of acute or chronic volume overload, which impacts the morbidity and mortality in these patients. Pulmonary ultrasound by its ability to estimate extrapulmonary water at an infraclinical stage has helped to make progress in this area. Line B is the element of fundamental semiology that reflects the presence of water in the pulmonary alveoli. The alteration of left ventricular function and the increase of pulmonary capillary permeability are the determining factors in the genesis of subclinical pulmonary congestion and are positively correlated with B-lines. Because of its non-invasive nature, its ease of use, its intra- and interoperability reproducibility and its ease of learning, nephrologists can be efficiently and quickly trained to use it to measure pulmonary congestion. Recent data have shown an epidemiological association between B-lines and mortality in end stage kidney disease patients. The causal role of subclinical pulmonary congestion assessed by these B lines in the genesis of detrimental events is being evaluated by a randomized, multicentre, open-label European clinical trial (Lung water by ultra-sound guided treatment [LUST] trial). The clinical usefulness of pulmonary ultrasound in the management of subclinical pulmonary congestion in patients with end stage kidney disease remains to be determined, but it could be considered from now as an additional tool to improve the management of this congestion, possibly by complementing bioimpedancemetry data. PMID- 29606267 TI - [Which biological parameters for volemic status estimation?] AB - INTRODUCTION: Estimation of volemic status can be useful in the diagnosis of some hydro-electrolytic disorders such as hyponatremia and dyskalemia. As a matter of fact, clinical examination and classical biological parameters are not discriminant enough. The aim of this study was to determine the biological parameters that are better correlated to volemic status. METHOD: Volemic status was established using extracellular fluid volume, measured by apparent distribution of inuline, in non-edematous patients and without cardiac or hepatic insufficiency. Patients were split in three groups according to their extracellular fluid volume: hypovolemic, normovolemic, and hypervolemic. Clinical and biological parameters were compared between the three groups and were correlated to extracellular fluid volume. RESULTS: Data of 91 explorations were collected. There were no difference between groups regarding clinical parameters, plasma proteins, and urinary sodium excretion. Parameters better correlated to extracellular fluid volume were fasting calcium/creatinine ratio (r=0.51; P<0.0001), fasting urinary pH (r=0.43; P<0.0001), and plasma uric acid (r=-0.39; P=0.002). CONCLUSION: In addition to uric acid, already proposed as a biological marker to estimate volemic status, fasting calciuria and fasting urinary pH could also be useful. PMID- 29606268 TI - [Incremental haemodialysis]. AB - The majority of incidental haemodialysis patients are systematically treated at the rate of three sessions per week, regardless of their level of residual kidney function. Incremental haemodialysis is a therapeutic strategy adapted to the residual kidney function level of each patient, to offer patients only the "dialysis dose" needed to supplement their residual kidney function, while ensuring that they achieve the objective of total clearance (renal+per-HD) recommended (weekly Standard Kt/V urea>2.3 volumes. Incremental haemodialysis therefore allows a lower dose and lower dialysis frequency in patients with residual kidney function. Incremental haemodialysis through better residual kidney function preservation could improve patient survival and also have other benefits in terms of quality of life, preservation of vascular access and in terms of decreased expenditure health. Some logistical hurdles make its safely prescription still difficult but software should soon be made available to practitioners for a simpler and more accurate daily management of this prescription. PMID- 29606269 TI - [IgA nephropathy: Unusual forms]. AB - IgA nephropathy can have various initial presentation and evolutive characteristics. In this article, specific forms of IgA nephropathy are described, such as hypertensive emergency, nephrotic syndrome, rapidly progressive glomerulonephritis, monotypic IgA deposits, or IgA nephropathy associated with inflammatory diseases. Identification of these specific forms is needed to better characterize and treat these rare pathologies. PMID- 29606270 TI - [Sodium, hypertension, chronic kidney diseases, and public health]. AB - Salt consumption has substantially increased these last years in our modern societies and far exceeds our needs. It has a great impact on cardiovascular and renal disease and represents a major issue in public health. The present work is a review of observational and interventional studies exploring the relationship between salt consumption, high-blood pressure and cardiovascular morbimortality in the general population but also in chronic kidney diseases. PMID- 29606272 TI - Editorial overview: Energy biotechnology: Biotechnology solutions for our energy needs. PMID- 29606271 TI - [Low protein diet supplemented with ketoanalogues of amino acids in patients with chronic renal insufficiency]. AB - Restricted protein diets in patients with chronic kidney disease have been debated for several decades. In chronic kidney disease as in other chronic diseases, the modulation of the nutritional intake is the object of a certain renewal. It is supported by recent studies that highlight the importance of modulating nutrient intake by diets that are healthier, less rich in animal proteins and richer in plants. The recent reintroduction in France of amino acid supplements and ketoanalogs of amino acids allows the prescription of a very restricted diet. Historical studies have only focused on the relationship between protein intake and renal function degradation. Recent studies on acid loading, bone metabolism or potassium intake allow revisiting the interest of restricted diets. As with any change in eating habits, the selection of patients, information, education and monitoring during the diet are very important and help prevent undernutrition: this is the purpose of this short review. PMID- 29606273 TI - Editorial overview: Microbial environmental biotechnology. PMID- 29606274 TI - Preface: Special issue on measuring behaviour 2016. PMID- 29606275 TI - Prevalence of oral lesions in and dental needs of patients with newly diagnosed acute leukemia. AB - BACKGROUND: Dentists are generally taught that in a significant number of patients with newly diagnosed acute leukemia (NDAL), the diagnosis may be suspected based on oral signs. In this study, the authors determined the frequency of oral signs of leukemia and tabulated the clinical dental needs and hematologic aspects of these patients. METHODS: Four calibrated dentists performed clinical examinations in 263 consecutive patients with NDAL. A standardized data form was used to direct and record presence or absence of oral signs of leukemia, clinically apparent dental disease, and circulating blood counts. RESULTS: Oral signs of leukemia were detected on oral examination in 30.8% (95% confidence interval [CI], 25.2% to 36.4%) of patients with NDAL on examination. Only 5.7% (95% CI, 2.9% to 8.5%) of patients had gingival enlargement (GE). Although 33.7% (95% CI, 26.6% to 40.9%) of regular dental treatment seekers and 55.3% (95% CI, 45.3% to 65.4%) of nonregular dental treatment seekers had clinically detectable dental disease, only 18.6% (95% CI, 13.9% to 23.3%) had circulating blood counts that precluded all but urgent oral health care. CONCLUSION: Although 30.8% of patients examined had some oral sign of leukemia, most adults with NDAL do not have GE at the initial examination. Even patients receiving regular oral health care may have unmet dental needs at the initial assessment that could safely be addressed before treatment. PRACTICAL IMPLICATIONS: Dentists should not necessarily expect to be able to detect overt oral signs of leukemia, such as GE, in patients with NDAL on oral examination. Once patients receive the diagnosis, dentists may be able to safely eliminate dental disease in most patients in an appropriate setting. Dentists are encouraged to undertake a thorough review of systems. PMID- 29606276 TI - Intracranial tumor manifesting as mandibular pain: A case report. PMID- 29606277 TI - Effect of pre-firing compression on the prevention of pancreatic fistula in distal pancreatectomy. AB - BACKGROUND: Postoperative pancreatic fistula (POPF) is a major complication of distal pancreatectomy (DP). Several procedures for resection and closure of the pancreas have been proposed; however, the rate of POPF remains high. The aims of this study were to investigate the relationship between perioperative factors and POPF and to clarify the advantages of pre-firing compression of the pancreas in the DP. PATIENTS AND METHOD: From 2008 to 2016, records of 75 patients who underwent DP were retrospectively reviewed. The relationship between the perioperative factors and clinically relevant POPF was investigated. RESULTS: Univariate analysis showed that body mass index, thickness of the pancreas, and pre-firing compression were significantly related with clinically relevant POPF. Multivariate analysis showed that the pre-firing compression was an independent factor of clinically relevant POPF (OR = 44.31, 95%CI = 3.394-578.3, P = 0.004). CONCLUSIONS: Pre-firing compression of the pancreas can prevent clinically relevant POPF in DP. PMID- 29606278 TI - Modified Blumgart anastomosis with the "complete packing method" reduces the incidence of pancreatic fistula and complications after resection of the head of the pancreas. AB - BACKGROUND: Postoperative pancreatic fistula (POPF) and its complications remain problems. This study evaluated combination treatment with modified Blumgart anastomosis and an original infection control method (complete packing method) following pancreatic head resection. METHODS: This study included 374 consecutive patients who underwent pancreatic head resection: 103 patients underwent Cattell Warren anastomosis (CWA); 170 patients underwent modified Kakita anastomosis (KA); and 101 patients underwent modified Blumgart anastomosis with the complete packing method (BAC). The outcomes of the KA and BAC groups were compared statistically. RESULTS: The POPF rate was significantly lower in the BAC group than in the KA group (28.8% vs 2.97%; p < 0.01). The overall postoperative complication rate, including SSI and postoperative hemorrhage, was significantly lower in the BAC group. CONCLUSIONS: The combination of modified Blumgart anastomosis and the complete packing method is a simple and useful method for reducing the incidence of POPF and postoperative complications. PMID- 29606279 TI - Therapeutic patient education in adrenal insufficiency. AB - It is essential to encourage patient autonomy in the management of their illness, and notably their participation in treatment education programs; specific programs target avoidance or early preventive treatment of acute adrenal insufficiency, which is a life-threatening complication. Therapeutic patient education is recommended by the two international consensus statements on the management of primary adrenal insufficiency and the French consensus on adrenal insufficiency. Although there is no common international reference framework to date, the objective of the French consensus was to provide a frame of reference to facilitate the development of therapeutic education for patients with adrenal insufficiency. The principal educational objectives were: for the patient to always carry the necessary emergency equipment; be able to identify situations of increased risk and the early signs of adrenal crisis; know how to adjust oral glucocorticoid treatment; be capable of administering hydrocortisone by subcutaneous injection; be able to adjust treatment to different situations (heat, physical exercise, travel); and be able to appropriately use the resources of the healthcare services. Other programs could also be developed to respond to patients' needs and expectations, notably concerning hydrocortisone dose adjustment to avoid overdose in the context of chronic fatigue syndrome. PMID- 29606280 TI - Cardiovascular mortality in patients with subclinical Cushing. AB - Patients with adrenal incidentaloma (AI) and subclinical hypercortisolism (SH) show a high prevalence of cardiovascular risk factors and an increased prevalence and incidence of cardiovascular events. Furthermore, some recent data suggest that in these patients, the cardiovascular mortality is also increased. Unfortunately, to date, the diagnosis of SH is still a matter of debate, and, therefore, it is still not possible to address the treatment of choice (i.e. surgical or conservative approach) in many AI patients. Overall, the available data show that in AI patients with established SH the surgical removal of the adrenal mass causing SH can lead to the improvement of hypertension and diabetes, but in many patients with possible SH the effect of surgery is still largely unknown. Finally, no data are available on the effect of the recovery from SH on the cardiovascular events. Therefore, randomized studies are needed to investigate the possibility of predicting the usefulness of surgery by using the available indexes of cortisol secretion in the individual AI patient. Finally, the development of safe and well-tolerated drugs aimed to control cortisol secretion will be among the goals of the future research. PMID- 29606281 TI - Depressive Symptoms and Suicidal Ideation Among Symptomatic Patients With a History of Lyme Disease vs Two Comparison Groups. AB - BACKGROUND: Depression has been reported in 8-45% of patients with posttreatment Lyme symptoms (PTLS), but little is known about suicidal ideation in these patients. METHOD: Depression and suicidal ideation were assessed using the Beck Depression Inventory (BDI-II). Scores from the PTLS group (n = 81) were compared to those from 2 other groups: HIV+ patients being treated for fatigue (n = 70), and a nonpatient comparison group (NPCG; n = 44). ANOVA and t-tests were used to compare groups; logistic regression was used to identify the strongest correlates of suicidal ideation. RESULTS: Mean BDI-II scores fell in the mildly depressed range for PTLS and HIV+ patients, with both groups having higher depression scores than the NPCG. Suicidal ideation was reported by 19.8% of the PTLS patients and 27.1% of the HIV+ patients, a nonsignificant difference. Among those with mild or no depression, suicidal ideation was uncommon (6.5% PTLS and 11.9% HIV+). Among the patients with moderate-to-severe depression, suicidal ideation was more common (63.2% of 19 PTLS and 50% of 28 HIV+); among these, 2 with PTLS and 1 with HIV+ expressed suicidal intent. Further, 4.5% (n = 2) of the NPCG had suicidal ideation, each had scores in the moderate-to-severe depression range. Higher scores on the cognitive symptoms subscale of the BDI-II predicted greater likelihood of suicidal ideation across patient groups. CONCLUSION: As expected, suicidal ideation is increased among patients who are depressed. The fact that 1 in 5 patients with PTLS reported suicidal ideation highlights the importance of screening for depression and suicidality to optimize patient care. PMID- 29606282 TI - Migration: a core public health ethics issue. AB - OBJECTIVES: In this article, we outline the link between migration, public health and ethics. STUDY DESIGN: Discussing relevant arguments about migration from the perspective of public health and public health ethics. METHODS: Critical review of theories and frameworks, case-based analysis and systematic identification and discussion of challenges. RESULTS: Migration is a core issue of public health ethics and must take a case-based approach: seeking to identify the specific ethical dimensions and vulnerabilities in each particular context. Public health as a practice, built upon the core value of justice, requires the protection and promotion of migrants' well-being (even if this produces tension with immigration services). Ethical analysis should take all phases of migration into account: before, during and after transit. We argue that migration policies, at least as they relate to migrants' well-being, should be founded upon a shared humanity, respect for human rights and on the idea that effective public health cannot and should not be confined within the borders and to the citizens of any host country. CONCLUSIONS: We make the case for migration to be seen as a core issue of public health ethics. PMID- 29606284 TI - SMC Complexes: Universal DNA Looping Machines with Distinct Regulators. AB - What drives the formation of chromatin loops has been a long-standing question in chromosome biology. Recent work provides major insight into the basic principles behind loop formation. Structural maintenance of chromosomes (SMC) complexes, that are conserved from bacteria to humans, are key to this process. The SMC family includes condensin and cohesin, which structure chromosomes to enable mitosis and long-range gene regulation. We discuss novel insights into the mechanism of loop formation and the implications for how these complexes ultimately shape chromosomes. A picture is emerging in which these complexes form small loops that they then processively enlarge. It appears that SMC complexes act by family-wide basic principles, with complex-specific levels of control. PMID- 29606285 TI - Predictors of early, intermediate and late biochemical recurrence after minimally invasive radical prostatectomy in a single-centre cohort with a mean follow-up of 8 years. AB - OBJECTIVE: To determine the predictors of early, intermediate and late biochemical recurrence (BR) following minimally invasive radical prostatectomy in patients with localised prostate cancer (PC). MATERIAL AND METHODS: We included 6195 patients with cT1-3N0M0 prostate cancer treated using radical laparoscopic prostatectomy (RLP) and radical robot-assisted prostatectomy at our institution between 2000 and 2016. None of the patients underwent adjuvant therapy. BR is defined as PSA levels >=0.2 ng/dL. The time to BR is divided into terciles to identify the variables associated with early (<12 months), intermediate (12-36 months) and late (>36 months) recurrence. We employed logistic regression models to determine the risk factors associated with each interval. RESULTS: We identified 1148 (18.3%) patients with BR. The median time to BR was 24 months (IQR, 0.98-53.18). The multivariate analysis showed that preoperative PSA levels, lymph node invasion, positive margins and RLP are associated with early recurrence (P<=.029 for all). Laparoscopic surgery was the only predictor of intermediate recurrence (P=.001). The predictors of late recurrence included a pathological Gleason score >=7, stage >=pT3, positive margins and RLP (P<=.02 for all). CONCLUSIONS: The patients with high-risk prostate cancer can develop late recurrence and require long-term follow-up. Identifying patients with higher PSA levels and lymph node invasion has an important predictive role in the first year after surgery. The association between RLP and BR warrants further assessment. PMID- 29606283 TI - Perspectives on Glycosylation and Its Congenital Disorders. AB - Congenital disorders of glycosylation (CDG) are a rapidly expanding group of metabolic disorders that result from abnormal protein or lipid glycosylation. They are often difficult to clinically diagnose because they broadly affect many organs and functions and lack clinical uniformity. However, recent technological advances in next-generation sequencing have revealed a treasure trove of new genetic disorders, expanded the knowledge of known disorders, and showed a critical role in infectious diseases. More comprehensive genetic tools specifically tailored for mammalian cell-based models have revealed a critical role for glycosylation in pathogen-host interactions, while also identifying new CDG susceptibility genes. We highlight recent advancements that have resulted in a better understanding of human glycosylation disorders, perspectives for potential future therapies, and mysteries for which we continue to seek new insights and solutions. PMID- 29606286 TI - Referral Regions for Time-Sensitive Acute Care Conditions in the United States. AB - STUDY OBJECTIVE: Regional, coordinated care for time-sensitive and high-risk medical conditions is a priority in the United States. A necessary precursor to coordinated regional care is regions that are actionable from clinical and policy standpoints. The Dartmouth Atlas of Health Care, the major health care referral construct in the United States, uses regions that cross state and county boundaries, limiting fiscal or political ownership by key governmental stakeholders in positions to create incentive and regulate regional care coordination. Our objective is to develop and evaluate referral regions that define care patterns for patients with acute myocardial infraction, acute stroke, or trauma, yet also preserve essential political boundaries. METHODS: We developed a novel set of acute care referral regions using Medicare data in the United States from 2011. For acute myocardial infraction, acute stroke, or trauma, we iteratively aggregated counties according to patient home location and treating hospital address, using a spatial algorithm. We evaluated referral political boundary preservation and spatial accuracy for each set of referral regions. RESULTS: The new set of referral regions, the Pittsburgh Atlas, had 326 distinct regions. These referral regions did not cross any county or state borders, whereas 43.1% and 98.1% of all Dartmouth Atlas hospital referral regions crossed county and state borders. The Pittsburgh Atlas was comparable to the Dartmouth Atlas in measures of spatial accuracy and identified larger at-risk populations for all 3 conditions. CONCLUSION: A novel and straightforward spatial algorithm generated referral regions that were politically actionable and accountable for time-sensitive medical emergencies. PMID- 29606287 TI - Cost-effectiveness of HIV screening in high-income countries: A systematic review. AB - INTRODUCTION: Over 2 million people in high-income countries live with HIV. Early diagnosis and treatment present benefits for infected subjects and reduce secondary transmissions. Cost-effectiveness analyses are important to effectively inform policy makers and consequently implement the most cost-effective programmes. Therefore, we conducted a systematic review regarding the cost effectiveness of HIV screening in high-income countries. METHODS: We followed PRISMA statements and included all papers evaluating the cost-effectiveness of HIV screening in the general population or in specific subgroups. RESULTS: Thirteen studies considered routine HIV testing in the general population. The most cost-effective option appeared to be associating one-time testing of the general population with annual screening of high-risk groups, such as injecting drug users. Thirteen studies assessed the cost-effectiveness of HIV screening in specific settings, outlining the attractiveness of similar programmes in emergency departments, primary care, sexually transmitted disease clinics and substance abuse treatment programmes. DISCUSSION: Evidence regarding the health benefits and cost-effectiveness of HIV screening is growing, even in low prevalence countries. One-time screenings offered to the adult population appear to be a valuable choice, associated with repeated testing in high-risk populations. The evidence regarding the benefits of using a rapid test, even in terms of cost-effectiveness, is growing. Finally, HIV screening seems useful in specific settings, such as emergency departments and STD clinics. PMID- 29606288 TI - The impact of pay-for-performance on the quality of care in ophthalmology: Empirical evidence from Germany. AB - BACKGROUND: Pay-for-performance (P4P) has become a popular approach to increase effectiveness and efficiency in healthcare. So far, there is little evidence regarding the potential of P4P in the German healthcare setting. The aim of this study was to determine the impact of P4P on the quality of care in cataract surgery. METHODS: In 2012, a P4P program was implemented in a German surgical centre for ophthalmology. Five quality measures regarding process quality, outcomes, and patient satisfaction were measured over a period of 4.5 years. The P4P scheme consisted of bonus and penalty payments accounting for five per cent of total compensation. Overall, 1657 P4P cases were examined and compared with 4307 control cases. Interrupted time series and group comparisons were conducted to identify quality and spill-over effects. RESULTS: We found a positive impact on process quality and patient satisfaction before the implementation of the P4P scheme, but declining trends during and after the implementation. Our findings did not show an impact of P4P on outcome measures. Furthermore, P4P did not result in better quality of care, compared with the German hospital-based reimbursement scheme. CONCLUSION: This study did not show any positive long-term effects of the implementation of P4P on quality of care. Therefore, our results do not support the hypothesis that P4P leads to significant improvements in quality of care. PMID- 29606289 TI - Indications for MARS-MRI in Patients Treated With Metal-on-Metal Hip Resurfacing Arthroplasty. AB - BACKGROUND: Currently, there are no universally accepted guidelines on when to obtain metal artifact reduction sequence magnetic resonance imaging (MARS-MRI) in metal-on-metal (MoM) hip resurfacing arthroplasty (HRA) patients. Our primary aims were to identify which patient and clinical factors are predictive of adverse local tissue reaction (ALTR) and create an algorithm for indicating MARS MRI in patients with Articular Surface Replacement (ASR) HRA. The secondary aim was to compare our algorithm to existing guidelines on when to perform MARS-MRI in MoM HRA patients. METHODS: The study cohort consisted of 182 patients with unilateral ASR HRA from a prospective, multicenter study. Subjects received MARS MRI at a mean of 7.8 years from surgery, regardless of symptoms. We determined which variables were predictive of ALTR and generated cutoffs for each variable. Finally, we created an algorithm to predict ALTR and indicate MARS-MRI in ASR HRA patients using these cutoffs and compared it to existing guidelines. RESULTS: We found high blood cobalt (Co) (odds ratio = 1.070; P = .011) and high blood chromium (Cr) (odds ratio = 1.162; P = .002) to be significant predictors of ALTR presence. Our algorithm using a blood Co cutoff of 1.15 ppb and a Cr cutoff of 1.09 ppb achieved 96.6% sensitivity and 35.3% specificity in predicting ALTR, which outperformed the existing guidelines. CONCLUSION: Blood Co and Cr levels are predictive of ALTR in ASR HRA patients. Our algorithm considering blood Co and Cr levels predicts ALTR in ASR HRA patients with higher sensitivity than previously established guidelines. PMID- 29606290 TI - Does Prior Bariatric Surgery Affect Implant Survivorship and Complications Following Primary Total Hip Arthroplasty/Total Knee Arthroplasty? AB - BACKGROUND: The purpose of this study is to evaluate the impact of prior bariatric surgery on survivorship, outcome, and complications following primary total hip arthroplasty (THA)/total knee arthroplasty (TKA). METHODS: Using the Medicare 5% part B data from 1999 to 2012, we analyzed patients who underwent primary THA (n = 47,895) and primary TKA (n = 86,609). Patients with prior bariatric surgery before arthroplasty were compared to patients with other common metabolic conditions. Kaplan-Meier risk of revision THA/TKA for those with and without bariatric surgery and each of the metabolic bone conditions was calculated. The risk for infection was also evaluated. Regression analysis was used to determine the relative risk of revision at various time intervals for those with and without each of the metabolic conditions. Analysis was also adjusted for the metabolic conditions, age, gender, socioeconomic status, and Charlson comorbidity index. RESULTS: The prevalence of patients with prior bariatric surgery within 24 months of primary THA/TKA was 0.1%. Benchmarked against other common chronic metabolic conditions, bariatric surgery prior to THA was not associated with an increased risk for revision surgery at all measured intervals but positively correlated with increased risk for developing infections. Conversely, patients undergoing primary TKA following bariatric surgery were at increased risk for revision compared to controls but not at increased risk for infection. CONCLUSION: The impact of bariatric surgery prior to elective THA/TKA remains unclear. These patients remain at increased risk for infections following THA and revisions following TKA. PMID- 29606291 TI - Response to Letter to the Editor on "Incidence, Risk Factors, and Clinical Implications of Pneumonia Following Total Hip and Knee Arthroplasty". PMID- 29606292 TI - Randomized prospective evaluation of the wound integrity of primary clear corneal incisions made with a femtosecond laser versus a manual keratome. AB - PURPOSE: To compare the wound integrity of femtosecond laser-assisted 110-degree reverse side-cut clear corneal incisions (CCIs) with femtosecond laser-assisted 70-degree forward side-cut and manual CCIs in patients having cataract surgery. SETTING: Island Eye Surgicenter, Carle Place, New York, USA. DESIGN: Prospective case series. METHODS: Patients having cataract surgery were randomized into 3 treatment groups as follows: Group A had 110-degree femtosecond reverse side-cut CCIs, Group B had 70-degree femtosecond forward side-cut CCIs, Group C had manual CCIs. At the conclusion of surgery, the integrity of the CCI was measured by raising intraocular pressure (IOP) until the CCI began to leak. Postoperatively, the CCIs were assessed for wound leakage at 1 day, 2 weeks, and 1 month. RESULTS: The study comprised 45 patients (45 eyes, 15 in each treatment group). The mean IOP at which CCIs leaked (in response to anterior chamber balanced salt solution irrigation) was statistically significantly higher in Group A (28.20 mm Hg +/- 11.69 [SD]) than in Group B (15.07 +/- 10.64 mm Hg; P = .005) and Group C (9.93 +/- 9.90 mm Hg; P < .001). At 1 day postoperatively, the Seidel test with pressure showed no leakage in any of the Group A eyes; however, 53% of eyes in Group B and 87% in Group C showed wound leakage. CONCLUSION: The femtosecond laser-created reverse side-cut CCIs required significantly higher IOP intraoperatively before leaking and resulted in better wound integrity with significantly less wound leakage postoperatively than laser-created forward side cut or manual CCIs. PMID- 29606293 TI - Retraction notice to "Notch-1 induces Epithelial-mesenchymal transition consistent with cancer stem cell phenotype in pancreatic cancer cells". AB - This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor in Chief. An investigation by Wayne State University identified a discrepancy between the data reported in Figures 1B, 2B and 3C and the original collected data. The investigation committee concluded that this undermined the scientific basis of the publication, that no credible replacement data were available, and advised that the publication should be retracted. PMID- 29606294 TI - Retraction notice to: Sensitization of squamous cell carcinoma to cisplatin induced killing by natural agents. AB - This article has been retracted: please see Elsevier Policy on Article Withdrawal (http://www.elsevier.com/locate/withdrawalpolicy). This article has been retracted at the request of the Editor in Chief. An investigation by Wayne State University identified a discrepancy between the data reported in Figures 5 and the original collected data. The investigation committee concluded that this undermined the scientific basis of the publication, that no credible replacement data were available, and advised that the publication should be retracted. PMID- 29606295 TI - The roles of macrophages and microglia in multiple sclerosis and experimental autoimmune encephalomyelitis. AB - Multiple sclerosis (MS) is an autoimmune and neurodegenerative disorder characterized by chronic inflammation, demyelination, as well as axonal and neuronal loss in the central nervous system (CNS). Macrophages and microglia are important components of the innate immune system. They participate in the primary response to microorganisms and play a role in inflammatory responses, homeostasis, and tissue regeneration. In the initial phase of MS and experimental autoimmune encephalomyelitis (EAE), an animal model of MS, macrophages from peripheral tissues infiltrate into the CNS and, together with residential microglia, contribute to the pathogenesis of MS. In the early stages, microglia and macrophages are expressed as the M1 phenotype, which can release proinflammatory cytokines, leading to tissue damage in the CNS. However, in the later stage, the M2 phenotype, which is the phenotype that is associated with resolving inflammation and tissue repair, becomes predominant in the CNS. Therefore, it is hypothesized that the M1/M2 phenotype balance plays an important role in disease progression and that the transition from the proinflammatory M1 phenotype to the regulatory or anti-inflammatory M2 phenotype can lead to restoration of homeostasis and improved functional outcomes. This review of recent literature focuses on the discussion of the M1/M2 phenotypes of microglia and macrophages as well as their relevance in the pathophysiology and treatment of MS and EAE. Furthermore, the possibility of directing the polarization of microglia and macrophages toward the M2 phenotype as a therapeutic and preventative strategy for MS is discussed. PMID- 29606296 TI - Corrigendum to "Low-dosage of rituximab in Chinese patients with neuromyelitis optica spectrum disorder" [Journal of Neuroimmunology 317C (2018) pp. 1-4]. PMID- 29606297 TI - Ultra-rapid progression of coronary artery disease or undiagnosed unstable plaque? A brief review from a case report. AB - Coronary artery disease rarely manifests itself in the first decades of life, which explains why this population is underrepresented in clinical studies. The mechanisms and natural history of the disease seem to differ between this population and older patients. Recent studies suggest a more rapid disease progression in youth, presenting more unstable atherosclerotic plaques, although this correlation has yet to be proven. In this paper, we present the case of a 41 year-old man who presented with a non-ST elevation myocardial infarction, with percutaneous coronary intervention of the culprit lesion (70-90% lesion at bifurcation of the circumflex artery with the first marginal obtuse artery and a sub-occlusive lesion of the ramus intermedius). There was also a non-significant lesion (estimated at 30%) located in the left anterior descending coronary artery. Ten days after discharge, the patient suffered another non-ST elevation myocardial infarction. The coronary angiography revealed a surprising sub occlusive lesion of the left anterior descending coronary artery. Regarding this case, the authors reviewed the literature on the pathophysiology of rapidly progressive coronary artery disease and the approach for non-significant lesions in patients with acute coronary syndrome, especially in the younger population. PMID- 29606298 TI - Effect of beta-blocker dose on mortality after acute coronary syndrome. AB - INTRODUCTION: Beta-blocker doses that have been shown to be effective in randomized clinical trials are not commonly used in daily clinical practice. The aim of this study was to analyze whether there is a prognostic benefit of high rather than low doses of beta-blockers after an acute coronary syndrome (ACS). METHODS: In this retrospective cohort study, 2092 ACS patients discharged from hospital between June 2013 and January 2016 were classified according to the beta blocker dose prescribed: high dose (>=50% of the target dose tested in clinical trials) and low dose (<50%). Two groups of 501 matched patients were obtained through propensity score matching according to treatment with high or low doses of beta-blockers. The prognostic impact (mortality) during follow-up of high vs. low dose was analyzed by Cox regression and represented by Kaplan-Meier curves. RESULTS: Of the 2092 patients, 80.5% were discharged under beta-blockers, with lower mortality during follow-up (18.6+/-9.7 months). Of the 1685 patients discharged under beta-blockers, only 31.4% received high doses. There were no differences in mortality during follow-up between patients under high-dose vs. low-dose beta-blockers (HR 0.935, 95% CI 0.628-1.392, p=0.740), and the equivalence between the two doses remained after propensity score matching (HR 1.183, 95% CI 0.715-1.958, p=0.513). CONCLUSION: No prognostic benefit was found in terms of mortality for high-dose vs. low-dose beta-blockers after an ACS. PMID- 29606299 TI - Thrombus in left atrial appendage - Overcoming percutaneous closure limitations. PMID- 29606300 TI - Homozygous Mutations in WEE2 Cause Fertilization Failure and Female Infertility. AB - Fertilization is a fundamental process of development and is a prerequisite for successful human reproduction. In mice, although several receptor proteins have been shown to play important roles in the process of fertilization, only three genes have been shown to cause fertilization failure and infertility when deleted in vivo. In clinical practice, some infertility case subjects suffer from recurrent failure of in vitro fertilization and intracytoplasmic sperm injection attempts due to fertilization failure, but the genetic basis of fertilization failure in humans remains largely unknown. Wee2 is a key oocyte-specific kinase involved in the control of meiotic arrest in mice, but WEE2 has not been associated with any diseases in humans. In this study, we identified homozygous mutations in WEE2 that are responsible for fertilization failure in humans. All four independent affected individuals had homozygous loss-of-function missense mutations or homozygous frameshift protein-truncating mutations, and the phenotype of fertilization failure was shown to follow a Mendelian recessive inheritance pattern. All four mutations significantly decreased the amount of WEE2 protein in vitro and in affected individuals' oocytes in vivo, and they all led to abnormal serine phosphorylation of WEE2 and reduced tyrosine 15 phosphorylation of Cdc2 in vitro. In addition, injection of WEE2 cRNA into affected individuals' oocytes rescued the fertilization failure phenotype and led to the formation of blastocysts in vitro. This work presents a novel gene responsible for human fertilization failure and has implications for future therapeutic treatments for infertility cases. PMID- 29606301 TI - Absence of CFAP69 Causes Male Infertility due to Multiple Morphological Abnormalities of the Flagella in Human and Mouse. AB - The multiple morphological abnormalities of the flagella (MMAF) phenotype is among the most severe forms of sperm defects responsible for male infertility. The phenotype is characterized by the presence in the ejaculate of immotile spermatozoa with severe flagellar abnormalities including flagella being short, coiled, absent, and of irregular caliber. Recent studies have demonstrated that MMAF is genetically heterogeneous, and genes thus far associated with MMAF account for only one-third of cases. Here we report the identification of homozygous truncating mutations (one stop-gain and one splicing variant) in CFAP69 of two unrelated individuals by whole-exome sequencing of a cohort of 78 infertile men with MMAF. CFAP69 encodes an evolutionarily conserved protein found at high levels in the testis. Immunostaining experiments in sperm from fertile control individuals showed that CFAP69 localized to the midpiece of the flagellum, and the absence of CFAP69 was confirmed in both individuals carrying CFPA69 mutations. Additionally, we found that sperm from a Cfap69 knockout mouse model recapitulated the MMAF phenotype. Ultrastructural analysis of testicular sperm from the knockout mice showed severe disruption of flagellum structure, but histological analysis of testes from these mice revealed the presence of all stages of the seminiferous epithelium, indicating that the overall progression of spermatogenesis is preserved and that the sperm defects likely arise during spermiogenesis. Together, our data indicate that CFAP69 is necessary for flagellum assembly/stability and that in both humans and mice, biallelic truncating mutations in CFAP69 cause autosomal-recessive MMAF and primary male infertility. PMID- 29606302 TI - Bi-allelic Alterations in AEBP1 Lead to Defective Collagen Assembly and Connective Tissue Structure Resulting in a Variant of Ehlers-Danlos Syndrome. AB - AEBP1 encodes the aortic carboxypeptidase-like protein (ACLP) that associates with collagens in the extracellular matrix (ECM) and has several roles in development, tissue repair, and fibrosis. ACLP is expressed in bone, the vasculature, and dermal tissues and is involved in fibroblast proliferation and mesenchymal stem cell differentiation into collagen-producing cells. Aebp1-/- mice have abnormal, delayed wound repair correlating with defects in fibroblast proliferation. In this study, we describe four individuals from three unrelated families that presented with a unique constellation of clinical findings including joint laxity, redundant and hyperextensible skin, poor wound healing with abnormal scarring, osteoporosis, and other features reminiscent of Ehlers Danlos syndrome (EDS). Analysis of skin biopsies revealed decreased dermal collagen with abnormal collagen fibrils that were ragged in appearance. Exome sequencing revealed compound heterozygous variants in AEBP1 (c.1470delC [p.Asn490_Met495delins(40)] and c.1743C>A [p.Cys581*]) in the first individual, a homozygous variant (c.1320_1326del [p.Arg440Serfs*3]) in the second individual, and a homozygous splice site variant (c.1630+1G>A) in two siblings from the third family. We show that ACLP enhances collagen polymerization and binds to several fibrillar collagens via its discoidin domain. These studies support the conclusion that bi-allelic pathogenic variants in AEBP1 are the cause of this autosomal-recessive EDS subtype. PMID- 29606304 TI - Fibroblast Growth Factor 23 is Associated With Adiposity in Patients Receiving Hemodialysis: Possible Cross Talk Between Bone and Adipose Tissue. AB - OBJECTIVE: Fibroblast growth factor 23 (FGF-23) may be involved in signaling between bone and adipose tissue in dialysis patients, but its role is uncertain. We sought to examine the association between FGF-23 and adiposity and whether this association is mediated in part by leptin. DESIGN/SETTING: We performed univariate and multivariate linear regression analyses using data from 611 participants in a cohort of prevalent hemodialysis patients recruited from dialysis centers in Atlanta, GA and San Francisco, CA from 2009 to 2011. We also investigated the role of leptin in these relationships. SUBJECTS: Participants were aged >=18 years, English or Spanish speaking, and receiving hemodialysis for at least 3 months. MAIN OUTCOME MEASURES: Outcome measures of adiposity included body mass index, waist circumference, and body fat measured by bioelectrical impedance spectroscopy. RESULTS: Mean age was 56 +/- 14 years, 39.8% were female, and median serum FGF-23 was 807 pg/mL. In fully adjusted models, FGF-23 was inversely associated with body mass index (-0.24 kg/m2 per 50% higher FGF-23, 95% confidence interval [CI]: -0.38 to -0.10), waist circumference (-0.44 cm per 50% higher FGF-23, 95% CI: -0.79 to -0.08), and percent body fat (-0.58% per 50% higher FGF-23, 95% CI: -0.79 to -0.37). Leptin was inversely associated with FGF 23. Addition of leptin to body composition models attenuated the associations between FGF-23 and measures of adiposity, but FGF-23 remained significantly associated with percent body fat (-0.17% per 50% higher FGF-23, 95% CI: -0.32 to 0.02). CONCLUSION: We found a negative association between FGF-23 and adiposity that appears to be mediated in part by leptin. As adipose tissue provides a "protective energy depot" for patients with chronic illness, a decrease in adipose tissue may be one mechanism in which higher FGF-23 levels may contribute to increased mortality in dialysis patients. PMID- 29606305 TI - A Physical View of Cancer. PMID- 29606303 TI - PheWAS and Beyond: The Landscape of Associations with Medical Diagnoses and Clinical Measures across 38,662 Individuals from Geisinger. AB - Most phenome-wide association studies (PheWASs) to date have used a small to moderate number of SNPs for association with phenotypic data. We performed a large-scale single-cohort PheWAS, using electronic health record (EHR)-derived case-control status for 541 diagnoses using International Classification of Disease version 9 (ICD-9) codes and 25 median clinical laboratory measures. We calculated associations between these diagnoses and traits with ~630,000 common frequency SNPs with minor allele frequency > 0.01 for 38,662 individuals. In this landscape PheWAS, we explored results within diseases and traits, comparing results to those previously reported in genome-wide association studies (GWASs), as well as previously published PheWASs. We further leveraged the context of functional impact from protein-coding to regulatory regions, providing a deeper interpretation of these associations. The comprehensive nature of this PheWAS allows for novel hypothesis generation, the identification of phenotypes for further study for future phenotypic algorithm development, and identification of cross-phenotype associations. PMID- 29606306 TI - Reengineering the Tumor Vasculature: Improving Drug Delivery and Efficacy. AB - A solid tumor is like an aberrant organ - comprised of cancer cells and a variety of host cells embedded in an extracellular matrix - nourished by blood vessels and drained by lymphatic vessels. In its journey from the blood stream to cancer cells, a therapeutic agent must cross the vessel wall and the extracellular matrix that cancer cells are ensconced in. Growth of tumors in a confined space along with deposition of matrix components, including collagen (yellow) and hyaluronan (pink), increases 'solid stress', which compresses blood and lymphatic vessels and impairs their function. The leakiness of tumor vessels also impairs tumor blood flow and increases 'intratumor fluid pressure'. The abnormal blood flow not only impedes drug delivery, but the resulting hypoxia also aids tumor invasion, metastasis, immunosuppression, inflammation, fibrosis, and treatment resistance. Engineers and physical scientists have dissected the molecular, cellular, and physical mechanisms underlying these abnormalities and developed a number of strategies to reengineer the tumor microenvironment to overcome these barriers and thus improve delivery and efficacy of treatments. Finally, these strategies have been translated from bench to bedside for treatment of cancer and have the potential to improve the treatment outcome for many diseases characterized by an abnormal microenvironment. PMID- 29606307 TI - New Horizons in Advocacy Engaged Physical Sciences and Oncology Research. AB - To address cancer as a multifaceted adaptive system, the increasing momentum for cross-disciplinary connectivity between cancer biologists, physical scientists, mathematicians, chemists, biomedical engineers, computer scientists, clinicians, and advocates is fueling the emergence of new scientific frontiers, principles, and opportunities within physical sciences and oncology. In parallel to highlighting the advances, challenges, and acceptance of advocates as credible contributors, we offer recommendations for addressing real world hurdles in advancing equitable partnerships among advocacy stakeholders. PMID- 29606308 TI - Single-Cell Transcriptomic Analysis of Tumor Heterogeneity. AB - Intratumoral heterogeneity is among the greatest challenges in precision cancer therapy. However, developments in high-throughput single-cell RNA sequencing (scRNA-seq) may now provide the statistical power to dissect the diverse cellular populations of tumors. In the future these technologies might inform the selection of targeted combination therapies and enrollment criteria for clinical trials. PMID- 29606309 TI - Targeting Biophysical Cues: a Niche Approach to Study, Diagnose, and Treat Cancer. AB - Probing the biophysical properties of the tumor niche offers a new perspective in cancer mechanobiology, and supports the development of next-generation diagnostics and therapeutics for cancer, in particular for metastasis. PMID- 29606311 TI - Mesenchymal Cell Plasticity and Perfidy in Epithelial Malignancy. AB - Stromal complicity in epithelial carcinogenesis contributes to immune suppression and treatment resistance, but not all cancer-associated fibroblasts (CAFs) are bad actors. Identifying and targeting protumorigenic CAFs while preserving their antitumorigenic counterparts is the challenge. The risk is the possibility of making things worse; the reward is the potential to transform the care of and prognosis for patients with solid tumors. PMID- 29606310 TI - Biophysical Properties of Extracellular Matrix: Linking Obesity and Cancer. AB - Obesity has been associated with increased severity of diagnoses for several types of cancer, and recent evidence suggests that the mechanism by which obese tissues contribute to cancer progression involves the extracellular matrix (ECM). Understanding the physicochemical differences between lean and obese ECM, and how cancer cells respond to these differences, promises therapeutic insight. PMID- 29606312 TI - Transport Barriers and Oncophysics in Cancer Treatment. AB - Transport processes in cancer are the focus of transport oncophysics (TOP). In the TOP approach, the sequential negotiation of transport barriers is critical to both drug delivery and metastasis development. New and creative therapeutic opportunities are currently emerging, stimulated by the study of cancer hallmarks with the TOP approach. PMID- 29606313 TI - Beyond Tissue Stiffness and Bioadhesivity: Advanced Biomaterials to Model Tumor Microenvironments and Drug Resistance. AB - Resistance to chemotherapy and pathway-targeted therapies poses a major problem in cancer research. While the fields of tumor biology and experimental therapeutics have already benefited from ex vivo preclinical tissue models, these models have yet to address the reasons for malignant transformations and the emergence of chemoresistance. With the increasing number of ex vivo models poised to incorporate physiological biophysical properties, along with the advent of genomic sequencing information, there are now unprecedented opportunities to better understand tumorigenesis and to design therapeutic approaches to overcome resistance. Here we discuss that new preclinical ex vivo models should consider - in addition to common biophysical parameters such as matrix stiffness and bioadhesivity - a more comprehensive milieu of tissue signaling, nuclear mechanics, immune response, and the gut microbiome. PMID- 29606315 TI - Nuclear Mechanopathology and Cancer Diagnosis. AB - Abnormalities in nuclear and chromatin organization are hallmarks of many diseases including cancer. In this review, we highlight our understanding of how the cellular microenvironment regulates nuclear morphology and, with it, the spatial organization of chromosomes and genes, resulting in cell type-specific genomic programs. We also discuss the molecular basis for maintaining nuclear and genomic integrity and how alterations in nuclear mechanotransduction pathways result in various diseases. Finally, we highlight the importance of digital pathology based on nuclear morphometric features combined with single-cell genomics for early cancer diagnostics. PMID- 29606316 TI - Mobile dynamic passive sampling of trace organic compounds: Evaluation of sampler performance in the Danube River. AB - A "dynamic" passive sampling (DPS) device, consisting of an electrically driven large volume water pumping device coupled to a passive sampler exposure cell, was designed to enhance the sampling rate of trace organic compounds. The purpose of enhancing the sampling rate was to achieve sufficient method sensitivity, when the period available for sampling is limited to a few days. Because the uptake principle in the DPS remains the same as for conventionally-deployed passive samplers, free dissolved concentrations can be derived from the compound uptake using available passive sampler calibration parameters. This was confirmed by good agreement between aqueous concentrations of polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs) and hexachlorobenzene (HCB) derived from DPS and conventional caged passive sampler. The DPS device enhanced sampling rates of compounds that are accumulated in samplers under water boundary layer control (WBL) more than five times compared with the conventionally deployed samplers. The DPS device was deployed from a ship cruising downstream the Danube River to provide temporally and spatially integrated concentrations. A DPS deployed sampler with surface area of 400cm2 can reach sampling rates up to 83Ld 1. The comparison of three passive samplers made of different sorbents and co deployed in the DPS device, namely silicone rubber (SR), low density polyethylene (LDPE) and SDB-RPS EmporeTM disks showed a good correlation of surface specific uptake for compounds that were sampled integratively during the entire exposure period. This provided a good basis for a cross-calibration between the samplers. The good correlation of free dissolved PAHs, PCBs and HCB concentration estimates obtained using SR and LDPE confirmed that both samplers are suitable for the identification of concentration gradients and trends in the water column. We showed that the differences in calculated aqueous concentrations between sampler types are mainly associated with different applied uptake models. PMID- 29606317 TI - Behavioral disorders: The 'blind spot' of neurology and psychiatry. AB - Behavioral disorders occupy the crossroads between neurology and psychiatry, and emerging disorders, such as frontotemporal lobar degeneration of genetic origin and autoimmune encephalitis, can present with both neurological and psychiatric signs. Thus, the primary aim of this introductory article is to review frequently encountered behavioral clinical features, such as apathy and agitation, and their related syndromes, including frontal and anterior temporal syndromes. These behavioral states and their underlying etiologies are also here illustrated with clinical case reports. In addition, this review highlights the idea that in order to progress in the understanding and management of behavioral disorders, there needs to be a strong interest towards developing new forms of cooperation between neurologists, psychiatrists and neuroscientists, such as those who work at university-based hospital neuropsychiatric clinical units. PMID- 29606318 TI - Kleine-Levin syndrome: A neuropsychiatric disorder. AB - Kleine-Levin syndrome (KLS) is a rare, relapsing-remitting disease that affects mostly adolescents. It is characterized by episodes lasting from 1 to several weeks, and comprises neurological (hypersomnia, confusion, slowness, amnesia) and neuropsychiatric symptoms (derealization and apathy). Some psychiatric symptoms (megaphagia, hypersexuality, anxiety, depressed mood, hallucinations, delusions) arise during episodes, albeit less frequently, while patients are normal between episodes. However, sudden severe (>18h/day of sleep) and recurrent hypersomnia helps to differentiate KLS from other psychiatric mimics. Derealization, the striking feeling of unreality or of being in a dream-like environment, is strongly associated with hypoperfusion of the associative temporoparietal junction cortex, whereas apathy is almost complete loss of autoactivation: teenagers stop using their cell phones and their only spontaneous initiative is to sleep. The cause of KLS is not known, but evidence suggests it could be a recurrent inflammatory encephalitis. Up to 5% of cases are familial, although no abnormal gene has yet been found. Hypersomnia episodes tend to become less frequent and to disappear with advancing age. However, 28% of patients have long lasting episodes (>30 days), and around 15% have no signs of recovery after >20 years of living with the disorder. Patients' cognitive and psychiatric status should be regularly checked during asymptomatic periods, as 20-40% develop long term mild cognitive impairment or mood disorders. Lithium therapy is beneficial for reducing episode frequency, and intravenous steroids can reduce the duration of long episodes. PMID- 29606319 TI - Repetitive movements and behaviors in neurological and psychiatric practice: Distinctions and similarities between Tourette disorder and obsessive-compulsive disorder. AB - Repetitive movements are the hallmark of chronic tic disorders such as Tourette disorder (TD), whereas repetitive behaviors are characteristic of obsessive compulsive disorder (OCD). Both disorders tend to frequently co-occur, as a substantial number of patients with TD also suffer from OCD and vice versa. While the clinical distinction between tics and OCD is usually easy, there are borderline forms, and correct symptom recognition is vital for choosing the appropriate treatment modalities for each disorder, be they pharmacological, psychotherapeutic (behavioral therapy) or brain stimulation (deep brain stimulation, repetitive transcranial magnetic stimulation). PMID- 29606314 TI - Reengineering the Physical Microenvironment of Tumors to Improve Drug Delivery and Efficacy: From Mathematical Modeling to Bench to Bedside. AB - Physical forces have a crucial role in tumor progression and cancer treatment. The application of principles of engineering and physical sciences to oncology has provided powerful insights into the mechanisms by which these forces affect tumor progression and confer resistance to delivery and efficacy of molecular, nano-, cellular, and immuno-medicines. Here, we discuss the mechanics of the solid and fluid components of a tumor, with a focus on how they impede the transport of therapeutic agents and create an abnormal tumor microenvironment (TME) that fuels tumor progression and treatment resistance. We also present strategies to reengineer the TME by normalizing the tumor vasculature and the extracellular matrix (ECM) to improve cancer treatment. Finally, we summarize various mathematical models that have provided insights into the physical barriers to cancer treatment and revealed new strategies to overcome these barriers. PMID- 29606320 TI - Recommendations for the use of Rituximab in neuromyelitis optica spectrum disorders AB - There is growing evidence of a preventive effect of Rituximab (RTX) in neuromyelitis optica spectrum disorders (NMO-SD). This monoclonal antibody against CD20 is becoming the most widely used preventive therapy in NMO-SD, as a first-line therapy or as a rescue therapy. Nevertheless, considerable heterogeneity still exists concerning the pre-treatment work-up, the vaccinations required before and under treatment, the number and dosage of infusions, prevention of the risk of infusion-related reactions, prevention of infections under treatment, and frequency of therapeutic cycles. Thanks to a collaborative work among NMO-SD experts belonging to the NOMADMUS project, we provide here recommendations for all these topics concerning RTX use in NMO-SD. PMID- 29606321 TI - Extracorporeal membrane oxygenation and mechanical valves: An unfriendly relationship. PMID- 29606322 TI - Valve performance classification in 630 subcoronary Ross patients over 22 years. AB - OBJECTIVE: To define the function of the "Ross valves" and its clinical meaning in a practical valve performance classification as part of the outcome analysis. METHODS: From 1994 to 2017, 630 consecutive patients underwent the subcoronary Ross procedure at our institution. The valve performance classification combines hemodynamics, symptoms, and management criteria. Median follow-up was 12.5 years (maximum 22.3 years, 7404 patient-years, 99.4% completeness). RESULTS: The mean age of the patients was 44.7 +/- 11.9 years. Hospital deaths was 0.3% (n = 2). Twenty years after the operation survival was 73.1% (95% confidence interval [CI], 65.4%-81.6%) and statistically not different from the age- and gender matched general population; freedom from reoperation was 85.9% (95% CI, 80.2% 92.0%; 0.6% per patient-year), 89.8% (95% CI, 84.3%-95.7%) for autograft, and 91.0% (95% CI, 86.3%-96.0%) for homograft. Preoperative annulus diameter, aortic regurgitation, annulus reinforcement, sinotubular junction reinforcement, and bicuspid aortic valve type were no significant risk factors for reoperation. At 20 years the probability of a patient being in valve performance class I to IV was 5%, 74%, 19%, and 1%, respectively. Time to reoperation was not different in bicuspid and tricuspid aortic valves; preoperative aortic stenosis tended to have better outcome of autograft function. CONCLUSIONS: These up to 22 years data show that the subcoronary Ross procedure continues to provide an excellent tissue aortic valve replacement. The suggested valve performance classification emerged as a practical concept for outcome analysis with the probability of 79% being in the favorable class I or II at 20 years. PMID- 29606323 TI - Impact of Depressive Disorder on Access and Quality of Care in Veterans With Prevalent Cardiovascular Disease. AB - Although depressive disorders have been associated with increased risk of worse outcomes with cardiovascular diseases (CVDs), its relation with access to and quality of cardiovascular care is not well studied. Accordingly, we sought to assess the association between depressive disorders and access and quality of care among United States veterans with CVD. The 2013 Centers for Disease Control's Behavioral Risk Factor Surveillance Survey was utilized to identify a cohort of 13,126 veterans with CVD. Demographic and clinical history were recorded in adults with and without a depressive disorder (defined as self reported diagnosis of depression, major depression, minor depression, or dysthymia). Among 13,126 veterans studied, a total of 2,889 (22.0%) adults had a depressive disorder whereas 10,237 (78.0%) did not. The veterans with a depressive disorder were younger, more often female and non-white, and had higher rates of multiple medical co-morbidities. They were more likely to report a delay in receiving medical care and financial barriers to seeking care and taking prescription drugs. They also reported significantly lower rates of aspirin and antihypertensive drug use. In multivariate analysis, depressive disorder was independently associated with higher risk of delay in receiving medical care (OR [odds ratio] 2.07, 95% CI [confidence interval] 1.65 to 2.60), financial barriers to medical care (OR 1.96, 95% CI 1.45 to 2.65), and prescription drugs (OR 1.45, 95% CI 1.02 to 2.08). In conclusion, depressive disorders were associated with impaired access to care among United States veterans with CVD. PMID- 29606324 TI - Comparison of Outcomes and Intervention Among Patients With Non-ST-Segment Elevation Acute Myocardial Infarction of Those With a Left Circumflex Versus Those With a Non-Left Circumflex-Related Coronary Artery (From the ELISA-3 Trial). AB - Previous studies found that patients with an acute coronary syndrome (ACS) due to occlusion of the left circumflex (LC) coronary artery often present without ST elevation, leading to a delay in diagnosis and revascularization, a larger infarct size, and a worse prognosis. In this subgroup analysis of the ELISA-3 study (early or late intervention in high-risk non-ST-segment elevation acute coronary syndromes [NSTE-ACS]) incidence, characteristics and prognosis of LC related NSTE-ACS was investigated, and the outcome of early versus late invasive strategy was compared. In 383 of 542 patients the culprit vessel could be identified, with the LC artery in 112 (29%) of them. Patients with LC-related ACS had more often single vessel disease and underwent percutaneous coronary intervention more and CABG less frequently. The primary end point of the combined incidences of death, myocardial infarction, and recurrent ischemia at 30-day follow-up occurred in 9.0% of LC versus 16.5% of non-LC-related ACS (p = 0.057). Enzymatic infarct size and incidence of bleeding were comparable. Of patients with LC-related ACS, 62 were assigned to an early and 50 to a late invasive treatment with a median time from admission to angiography of 5.5 and 65.7 hours, respectively. The primary end point occurred in 9.7% and 8.0%, respectively (p = 1.00) with comparable enzymatic infarct size and bleeding. In conclusion, no significant differences in outcome were found between patients with an LC- and a non-LC-related NSTE-ACS. In LC-related NSTE-ACS, angiography within 12 hours of admission is feasible but not superior to angiography after more than 48 hours. PMID- 29606325 TI - Usefulness of Platelet-to-Lymphocyte Ratio to Predict Long-Term All-Cause Mortality in Patients at High Risk of Coronary Artery Disease Who Underwent Coronary Angiography. AB - Platelet-to-lymphocyte ratio (PLR) has recently been studied as a biomarker in patients with established coronary artery disease (CAD). The association between PLR and long-term all-cause mortality is unclear in patients at high risk of CAD who undergo coronary angiography for various indications. Follow-up was completed for 514 patients who underwent coronary angiography in a prospective study cohort. The primary end point was all-cause mortality. Patients were classified into tertiles based on preangiography PLR and also dichotomized based on the optimal cutoff at a PLR of 137, determined from the receiver operating characteristic curve analysis. The mean follow-up period was 5.0 +/- 1.3 years, with 50 all-cause deaths. On the Kaplan-Meier analysis, patients in Tertile 3 (PLR > 145) had worse prognosis than patients in Tertiles 1 (PLR <= 106) and 2 (PLR 106.1 to 145) (p = 0.0075), and patients with PLR >= 137 had a significantly higher rate of all-cause mortality than those with PLR < 137 (p = 0.0006). On multivariate Cox regression adjusting for known cardiovascular risk factors, PLR was a strong, independent predictor of long-term all-cause mortality on the tertile analysis (Tertile 3 vs Tertile 1: hazard ratio 2.52, 95% confidence interval 1.18 to 5.39, p = 0.017) and based on the cutoff at a PLR of 137 (PLR >= 137 vs <137: hazard ratio 2.25, 95% confidence interval 1.21 to 4.20, p = 0.011). In conclusion, elevated PLR is associated with long-term all-cause mortality in patients at high risk of CAD who undergo coronary angiography, and PLR may be a useful prognostic biomarker in this population. PMID- 29606326 TI - Dipeptidyl Peptidase-4 Inhibitor, Vildagliptin, Improves Trabecular Bone Mineral Density and Microstructure in Obese, Insulin-Resistant, Pre-diabetic Rats. AB - OBJECTIVE: Obese insulin resistance and type 2 diabetes mellitus profoundly impair bone mechanical properties and bone quality. However, because several antidiabetes drugs, especially thiazolidinediones, further aggravate bone loss in individuals with diabetes, diabetic osteopathy should not be treated by using simply any glucose-lowering agents. Recently, incretins have been reported to affect osteoblast function positively. The present study aimed to investigate the effects of vildagliptin, an inhibitor of dipeptidyl peptidase-4, on bone of rats with high-fat-diet-induced prediabetes. METHODS: Male rats were fed a high-fat diet for 12 weeks to induce obese insulin resistance and then treated with vildagliptin for 4 weeks. The effects of the drug on bone were determined by microcomputed tomography and bone histomorphometry. RESULTS: Vildagliptin markedly improved insulin resistance in these obese insulin-resistant rats. It also significantly increased volumetric bone mineral density. Specifically, vildagliptin-treated obese insulin-resistant rats exhibited higher trabecular volumetric bone mineral density than vehicle-treated obese insulin-resistant rats, whereas cortical volumetric bone mineral density, cortical thickness and area were not changed. Bone histomorphometric analysis in a trabecular-rich area (i.e. tibial metaphysis) revealed greater trabecular bone volume and number and less trabecular separation without change in trabecular thickness, osteocyte lacunar area or cortical thickness in the vildagliptin-treated group. CONCLUSIONS: Vildagliptin had a beneficial effect on the bone of obese insulin resistant rats with prediabetes, particularly at the trabecular site. Such benefit probably results from enhanced bone formation rather than from suppressed bone resorption. PMID- 29606327 TI - Evaluation of a Diabetes Coach Program Aimed to Improve the Care of Children and Youth With Type 1 Diabetes and With Compromised Control. AB - OBJECTIVE: To evaluate the impact of the Diabetes Coach Program (DCP) on glycated hemoglobin (A1C) levels in youth with type 1 diabetes. The youth were referred to and participated in the DCP between October 2011 and May 2016. METHODS: The Diabetes Coach visited families in their homes every 1 to 2 weeks and updated patients' diabetes teams regularly. A1C levels before the DCP were compared with A1C levels during and after discharge from the DCP. Six participating families completed satisfaction surveys via telephone. RESULTS: The DCP included 23 participants (43% male; median age, 11 years; range, 8.8 to 14.5 years); median duration of type 1 diabetes, 1.7 years (range, 0.1 to 6.3 years); median time in the DCP, 1.5 years (range, 0.2 to 2.5 years). During involvement in the program, median A1C levels decreased from baselines of 11.1% (range, 8.9% to 15.3%) to 10.2% (range, 7.6% to 12.4%) (p=0.0028). For 11 of 13 patients discharged from the DCP, the most recent median A1C levels, 11.2% (range, 9.1% to 13.6%), an average of 2.4 years later, were not different from the initial A1C levels (p=0.85). Family feedback was overwhelmingly positive. CONCLUSIONS: Participation in the DCP decreased A1C values in pediatric patients; however, the levels were not sustained after visits stopped. Pediatric health coaches may play an important role in the management of type 1 diabetes, but further research is needed to explore their benefits and how positive effects can be sustained. PMID- 29606328 TI - Defining RTUs and RRUs for Heart Failure Care. PMID- 29606329 TI - [Efficiency between the different measurement patterns of home blood pressure monitoring in the follow-up of hypertensive patients in primary care]. AB - OBJECTIVE: To identify the most efficient measurement pattern of home blood pressure monitoring (HBPM) for the follow-up of hypertensive patients in primary care. DESIGN: Validation study of a diagnostic test. SETTING: Primary care team in Murcia, Spain. POPULATION: One hundred and fifty three hypertensive patients younger than 80 years who met the inclusion criteria, who used HBPM and ambulatory blood pressure monitoring. MAIN MEASUREMENTS: Performing HBPM for 24hours. The HBPM protocol consisted of recording 2 measurements in the morning and 2 in the evening for 7 days. With the records obtained, the different HBPM patterns were established (7, 6, 5, 4, 3 days). The ROC curves were used for the analysis, together with the correlation coefficients and the Bland-Altman plots. RESULTS: The best areas under the curve for the systolic pressure of the different HBPM patterns corresponded to the 4-day pattern: 0.837 (0.77-0.90); and the 3 day one: 0.834 (0.77-0.90). As for diastolic pressure, the 7-day pattern had an area under the curve of 0.889 (0.84-0.94); followed by the 3 and 4 days patterns, which had the same statistical result both: 0.834 (0.83-0.94). There were no significant differences between correlation coefficients for systolic and diastolic blood pressures. The 3-day pattern showed a lower dispersion in the Bland-Altman plots. CONCLUSION: The 3 days HBPM pattern is proposed for the follow-up of the hypertensive patient, since it does not have an inferior efficiency to the other patterns. PMID- 29606330 TI - Characterization of disability following traumatic through knee and transfemoral amputations. AB - INTRODUCTION: The purpose of this study is to characterize through knee and transfemoral amputations following severe traumatic injuries. METHODS: A retrospective review of all transfemoral and through knee amputations sustained by United States military service members from 1 October 2001 to 30 July 2011 was conducted. Data from the Department of Defense Trauma Registry, the Armed Forces Health Longitudinal Technology Application, inpatient medical records and the Physical Evaluation Board Liaison Offices were queried in order to obtain characteristics related to injury sustained, demographics, treatment, and disability/mental health outcome data. RESULTS: A total of 1631 amputations in 1315 patients were identified. Of these there were 37 through knee and 296 were transfemoral amputations. Adequate records for detailed analysis were available on 140 and 25 transfemoral and through knee amputations respectively. There were no significant differences in demographic information, injury mechanism, initial injury severity score, or associated injuries, to include contralateral amputations. There was no significant difference in average disability rating (67.9% vs 78.3%, p = 0.46) or number of service members determined to be fully disabled (42.2% vs 28.6% p = 0.33) between the transfemoral and through knee amputation groups. Whereas there was no difference between groups preoperatively, the knee disarticulation group displayed a higher rate of mental health diagnoses post-amputation (96% vs 72%, p < 0.001) and a higher preponderance of anxiety related disorders than the transfemoral amputees (26.92% vs 12.96%, p = 0.0129). DISCUSSION/CONCLUSION: Among this military amputee through knee and transfemoral amputees displayed similar physical disability profiles. However, the through knee amputees displayed a higher level of anxiety related disorders and mental health diagnosis overall. While we don't believe this relationship to be causal in nature, this finding reflects the importance of paying particular attention to mental health in the final disposition of traumatic lower extremity amputees. PMID- 29606331 TI - Coronary-Cameral Fistula: Preliminary Diagnosis According to Colour and Continuous Wave Doppler Echocardiography. PMID- 29606332 TI - Reply to "Is It Time to Revise the Guidelines and Recommendations for Digital Echocardiography?" PMID- 29606333 TI - Echocardiographic Assessment of Patients with Fabry Disease. AB - Fabry disease is an X-linked lysosomal storage disorder that results from a deficiency of alpha-galactosidase A. Increased left ventricular wall thickness has been the most commonly described cardiovascular manifestation of the disease. However, a variety of other structural and functional abnormalities have also been reported. Echocardiography is an effective noninvasive method of assessing the cardiac involvement of Fabry disease. A more precise and comprehensive characterization of Fabry cardiomyopathy using conventional and novel echocardiographic techniques may lead to earlier diagnosis, more accurate prognostication, and timely treatment. The aim of this review is to provide a comprehensive overview of the structural and functional abnormalities on echocardiography that have thus far been described in patients with Fabry disease and to highlight potential areas that would benefit from further research. PMID- 29606334 TI - Apical Transverse Motion Is Associated with Interventricular Mechanical Delay and Decreased Left Ventricular Function in Children with Dilated Cardiomyopathy. AB - BACKGROUND: Apical transverse motion (ATM) is associated with electromechanical dyssynchrony in adult dilated cardiomyopathy (DCM). Bundle branch block electromechanical dyssynchrony is uncommon in pediatric DCM, but ATM and its association with ventricular function have not been characterized. METHODS: Fifty six children with DCM were retrospectively studied. Using echocardiography, ATM was assessed visually and by speckle-tracking longitudinal displacement of the interventricular septal and left ventricular (LV) lateral walls in opposite directions. Doppler tissue imaging-derived displacement and velocities were used to time the onset and peak LV and right ventricle motion, from which intra- and interventricular delays were calculated to assess their association with ATM. The timing of aortic valve opening and closure in relation to onset and peak LV displacement was used as a measure of LV mechanical efficiency. RESULTS: LV ATM was observed in 35 of 56 patients (62.5%), occurring in two patterns: 45% had ATM (interventricular septum displacing toward the lateral wall and lateral wall displacing toward the mitral annulus during systole), and 18% showed reverse ATM (r-ATM; lateral wall displaced toward the apex and interventricular septum displaced toward the septal annulus during systole). Both patterns were associated with increased interventricular but not intraventricular mechanical delay (controls: 2 msec, ATM 16 msec, r-ATM 8 msec, both P < .05 vs control subjects). Patients with ATM or r-ATM had lower LV ejection fractions (19% vs 29%, P < .05) and higher mechanical inefficiency compared with those without ATM. Survival was not statistically different in those with ATM or r-ATM compared with those without ATM or r-ATM. CONCLUSIONS: In pediatric DCM, ATM is associated with LV dysfunction, mechanical inefficiency, and interventricular mechanical delay. PMID- 29606335 TI - Spinal Manipulative Therapy and Other Conservative Treatments for Low Back Pain: A Guideline From the Canadian Chiropractic Guideline Initiative. AB - OBJECTIVE: The objective of this study was to develop a clinical practice guideline on the management of acute and chronic low back pain (LBP) in adults. The aim was to develop a guideline to provide best practice recommendations on the initial assessment and monitoring of people with low back pain and address the use of spinal manipulation therapy (SMT) compared with other commonly used conservative treatments. METHODS: The topic areas were chosen based on an Agency for Healthcare Research and Quality comparative effectiveness review, specific to spinal manipulation as a nonpharmacological intervention. The panel updated the search strategies in Medline. We assessed admissible systematic reviews and randomized controlled trials for each question using A Measurement Tool to Assess Systematic Reviews and Cochrane Back Review Group criteria. Evidence profiles were used to summarize judgments of the evidence quality and link recommendations to the supporting evidence. Using the Evidence to Decision Framework, the guideline panel determined the certainty of evidence and strength of the recommendations. Consensus was achieved using a modified Delphi technique. The guideline was peer reviewed by an 8-member multidisciplinary external committee. RESULTS: For patients with acute (0-3 months) back pain, we suggest offering advice (posture, staying active), reassurance, education and self-management strategies in addition to SMT, usual medical care when deemed beneficial, or a combination of SMT and usual medical care to improve pain and disability. For patients with chronic (>3 months) back pain, we suggest offering advice and education, SMT or SMT as part of a multimodal therapy (exercise, myofascial therapy or usual medical care when deemed beneficial). For patients with chronic back-related leg pain, we suggest offering advice and education along with SMT and home exercise (positioning and stabilization exercises). CONCLUSIONS: A multimodal approach including SMT, other commonly used active interventions, self management advice, and exercise is an effective treatment strategy for acute and chronic back pain, with or without leg pain. PMID- 29606337 TI - New insights into the structure of the MHC class I peptide-loading complex and mechanisms of TAP inhibition by viral immune evasion proteins. AB - Several hundred million years of co-evolution of vertebrates and invading pathogens have shaped the adaptive immune system to fight back the unwanted invaders through highly sophisticated defense mechanisms. Herpesviruses manage to dodge this immune response by hampering one of the central hinges of human adaptive immunity, the major histocompatibility complex (MHC) class I antigen presentation pathway. One of the bottlenecks of this pathway is the loading of pathogen-derived peptides onto MHC-I molecules in the endoplasmic reticulum (ER). This task is accomplished by the MHC class I peptide-loading complex (PLC), of which the transporter associated with antigen-processing (TAP) is a central component. In this review, we summarize recent structural and functional insights into the molecular architecture of the PLC, how TAP accomplishes the transport of peptides across the ER membrane, and how herpes- and poxviruses inhibit TAP mediated peptide translocation and subsequent antigen presentation. PMID- 29606338 TI - Deep Learning in Radiology. AB - As radiology is inherently a data-driven specialty, it is especially conducive to utilizing data processing techniques. One such technique, deep learning (DL), has become a remarkably powerful tool for image processing in recent years. In this work, the Association of University Radiologists Radiology Research Alliance Task Force on Deep Learning provides an overview of DL for the radiologist. This article aims to present an overview of DL in a manner that is understandable to radiologists; to examine past, present, and future applications; as well as to evaluate how radiologists may benefit from this remarkable new tool. We describe several areas within radiology in which DL techniques are having the most significant impact: lesion or disease detection, classification, quantification, and segmentation. The legal and ethical hurdles to implementation are also discussed. By taking advantage of this powerful tool, radiologists can become increasingly more accurate in their interpretations with fewer errors and spend more time to focus on patient care. PMID- 29606336 TI - Stability of allergens. AB - For proteins to cause IgE-mediated allergic reactions, several common characteristics have to be defined, including small molecular size, solubility and stability to changing pH levels and enzymatic degradation. Nevertheless, these features are not unique for potent allergens, but are also observed in non allergenic proteins. Due to the increasing awareness by regulatory authorities regarding the allergy pandemic, definition of characteristics unique to potent allergens would facilitate allergenicity assessment in the future. Despite major research efforts even to date the features unique for major allergens have not been elucidated so far. The route of allergen entry into the organism determines to a great extent these required characteristics. Especially orally ingested allergens are exposed to the harsh milieu of the gastrointestinal tract but might additionally be influenced by food processing. Depending on molecular properties such as disulphide bonds contributing to protein fold and formation of conformational IgE epitopes, posttranslational protein modification or protein food matrix interactions, enzymatic and thermal stability might differ between allergens. Moreover, also ligand binding influences structural stability. In the current review article, we aim at highlighting specific characteristics and molecular pattern contributing to a stabilized protein structure and overall allergenicity. PMID- 29606339 TI - A Feasibility Study of Single-inhalation, Single-energy Xenon-enhanced CT for High-resolution Imaging of Regional Lung Ventilation in Humans. AB - RATIONALE AND OBJECTIVES: The objective of this study was to assess the feasibility of single-inhalation xenon-enhanced computed tomography (XeCT) to provide clinically practical, high-resolution pulmonary ventilation imaging to clinics with access to only a single-energy computed tomography scanner, and to reduce the subject's overall exposure to xenon by utilizing a higher (70%) concentration for a much shorter time than has been employed in prior studies. MATERIALS AND METHODS: We conducted an institutional review board-approved prospective feasibility study of XeCT for 15 patients undergoing thoracic radiotherapy. For XeCT, we acquired two breath-hold single-energy computed tomography images of the entire lung with a single inhalation each of 100% oxygen and a mixture of 70% xenon and 30% oxygen, respectively. A video biofeedback system for coached patient breathing was used to achieve reproducible breath holds. We assessed the technical success of XeCT acquisition and side effects. We then used deformable image registration to align the breath-hold images with each other to accurately subtract them, producing a map of lung xenon distribution. Additionally, we acquired ventilation single-photon emission computed tomography computed tomography (V-SPECT-CT) images for 11 of the 15 patients. For a comparative analysis, we partitioned each lung into 12 sectors, calculated the xenon concentration from the Hounsfield unit enhancement in each sector, and then correlated this with the corresponding V-SPECT-CT counts. RESULTS: XeCT scans were tolerated well overall, with a mild (grade 1) dizziness as the only side effect in 5 of the 15 patients. Technical failures in five patients occurred because of inaccurate breathing synchronization with xenon gas delivery, leaving seven patients analyzable for XeCT and single-photon emission computed tomography correlation. Sector-wise correlations were strong (Spearman coefficient >0.75, Pearson coefficient >0.65, P value <.002) for two patients for whom ventilation deficits were visibly pronounced in both scans. Correlations were nonsignificant for the remaining five who had more homogeneous XeCT ventilation maps, as well as strong V-SPECT-CT imaging artifacts attributable to airway deposition of the aerosolized imaging agent. Qualitatively, XeCT demonstrated higher resolution and no central airway deposition artifacts compared to V-SPECT-CT. CONCLUSIONS: In this pilot study, single-breath XeCT ventilation imaging was generally feasible for patients undergoing thoracic radiotherapy, using an imaging protocol that is clinically practical and potentially widely available. In the future, the xenon delivery failures can be addressed by straightforward technical improvements to the patient biofeedback coaching system. PMID- 29606340 TI - Vital Signs in Radiologic Education: Creativity, Innovation, and Change. PMID- 29606341 TI - Myeloid-derived suppressors cells (MDSC) correlate with clinicopathologic factors and pathologic complete response (pCR) in patients with urothelial carcinoma (UC) undergoing cystectomy. AB - BACKGROUND: Myeloid derived suppressor cells (MDSC) are heterogeneous immunosuppressive cells with potential predictive and prognostic roles in cancer. The association between MDSC, clinicopathologic factors, and pathologic response in patients with bladder urothelial carcinoma (UC) was explored. METHODS: Peripheral blood or tissue were collected from patients with UC undergoing definitive surgery. MDSCs levels were measured in peripheral blood mononuclear cells and fresh tumor tissue. MDSCs were identified by flow cytometry and defined as total MDSC (T-MDSC) CD33+/HLADR-. From this population, 3 subsets were identified: polymorphonuclear-MDSC (PMN-MDSC) defined as CD33+/HLADR-/CD15+/CD14 , monocytic-MDSC (M-MDSC) defined as CD33+/HLADR-/CD15-/CD14+, and immature-MDSC (I-MDSC) defined as CD33+/HLADR-/CD15-/CD14-. MDSC populations were presented as % of live nucleated blood cells. Spearman correlations (r) and Wilcoxon rank sum test were used to assess correlations between MDSC populations, clinicopathologic factors, and pathologic complete response (pCR). RESULTS: 85 patients scheduled to undergo cystectomy from February 2015 through Dec 2016 were included. All patients had blood drawn for analysis and 23 patients had residual tumor tissue collected for analysis at the time of surgery. Of these 85, 74 (87%) were men with a median age at diagnosis of 68 (range: 44-87). Pure UC was the most common histology (75%); 28 (35%) patients had prior treatment with intravesical therapy and 36 (42%) were treated with neoadjuvant chemotherapy, primarily gemcitabine plus cisplatin (n = 24). On surgical pathology, 18 (21%) of the patients had pCR, 11 (13%) had positive lymph nodes, and 20 patients (24%) had lymphovascular invasion. Statistically significant associations were found between circulating MDSC levels and pCR rates (P<0.01), absolute neutrophil-lymphocyte ratio (P = 0.008), and histology (P = 0.01). Tumor % M-MDSCs were negatively associated with lymphovascular invasion (P = 0.04). There were no significant correlations between peripheral blood mononuclear cells and tumor MDSC subtypes. CONCLUSIONS: Blood and tissue MDSC levels correlate with several clinicopathologic factors and may predict for pCR. Future studies are needed to highlight the role of MDSC in predicting long-term outcomes and to determine the clinical implications of these findings. PMID- 29606343 TI - The Missed Notch to Bring Down Diabetes. AB - Notch signaling contributes to maintenance of adult tissue homeostasis and is also involved in disease. A recent study demonstrates that inhibition of Dll4 Notch signaling by anti-Dll4 improves pancreatic islet function and insulin production by multiple complementary mechanisms. Thus, anti-Dll4 represents a therapeutic approach for compromised insulin production in diabetes. PMID- 29606342 TI - What Can 'Brown-ing' Do For You? AB - Human stem cell-based models of thermogenic adipocytes provide an opportunity for the establishment of new therapeutics, modeling of disease mechanisms, and understanding of development. Pluripotent stem cells, adipose-derived stem cells/preadipocytes, and programming-reprogramming-based approaches have been used to develop cell-based platforms for drug screening and transplantable therapeutics in the metabolic disease arena. Here we provide a detailed overview of these approaches, the latest advances in this field, and the opportunities and shortcomings they present. Moreover, we comment on how stem-cell-based platforms can be best utilized in the future for the treatment and understanding of metabolic diseases, including type 2 diabetes and associated medical issues such as obesity. PMID- 29606344 TI - Agraphia with reversible splenial corpus callosum lesion caused by hypoglycemia. AB - BACKGROUND: Neurological manifestations caused by hypoglycemia range from reversible focal deficits and transient encephalopathy to irreversible coma or death. Recently, high signal intensity lesions in the splenium of the corpus callosum on diffusion-weighted magnetic resonance imaging were reported in adults experiencing hypoglycemia. However, patients presenting with agraphia are rare. SUBJECT AND METHODS: We examined a 17-year-old left-handed female patient with type 1 diabetes who exhibited transient left agraphia with a reversible splenium lesion of the corpus callosum on diffusion-weighted imaging caused by hypoglycemia, which was improved with blood glucose management alone. CONCLUSION: This rare case indicates that agraphia, a sign of callosal disconnection syndrome, can result from a reversible splenial lesion of the corpus callosum caused by hypoglycemia. PMID- 29606345 TI - Gene Polymorphisms in the CCL5/CCR5 Pathway as a Genetic Biomarker for Outcome and Hand-Foot Skin Reaction in Metastatic Colorectal Cancer Patients Treated With Regorafenib. AB - BACKGROUND: The C-C motif chemokine ligand 5/C-C motif chemokine receptor 5 (CCL5/CCR5) pathway has been shown to induce endothelial progenitor cell migration, resulting in increased vascular endothelial growth factor A expression. We hypothesized that genetic polymorphisms in the CCL5/CCR5 pathway predict efficacy and toxicity in patients with metastatic colorectal cancer (mCRC) treated with regorafenib. PATIENTS AND METHODS: We analyzed genomic DNA extracted from 229 tumor samples from 2 different cohorts of patients who received regorafenib: an evaluation cohort of 79 Japanese patients and a validation cohort of 150 Italian patients. Single nucleotide polymorphisms of CCL5/CCR5 pathway-related genes were analyzed by PCR-based direct sequencing. RESULTS: CCL4 rs1634517 and CCL3 rs1130371 were associated with progression-free survival in the evaluation cohort (hazard ratio [HR] 1.54, P = .043; HR 1.48, P = .064), and progression-free survival (HR 1.74, P < .001; HR 1.66, P = .002) and overall survival (HR 1.65, P = .004; HR 1.65, P = .004) in the validation cohort. The allelic frequencies of CCL5 single nucleotide polymorphisms varied between the evaluation and validation cohorts (G/G variant in rs2280789, 21.5% vs. 1.3%, P < .001; T/T variant in rs3817655, 22.8% vs. 2.7%, P < .001). In the evaluation cohort, patients with the G/G variant in rs2280789 had a higher incidence of grade 3+ hand-foot skin reaction compared to any A allele (53% vs. 27%, P = .078), and similarly to the T/T variant in rs3817655 compared to any A allele (56% vs. 26%, P = .026). CONCLUSION: Genetic variants in the CCL5/CCR5 pathway may serve as prognostic markers and may predict severe hand-foot skin reaction in mCRC patients receiving regorafenib therapy. PMID- 29606346 TI - Accelerated long-term forgetting in resected and seizure-free temporal lobe epilepsy patients. AB - Episodic memory impairments caused by temporal lobe epilepsy (TLE) are well documented in the literature. Standard clinical episodic memory tests typically include a 30-min delayed recall test. However, in the past decade, it has become apparent that this standard test does not capture the full range of memory problems in TLE patients. Some patients perform well on a standard 30-min delayed recall test, but show Accelerated Long-term Forgetting (ALF) after 24 h. Although ALF has been investigated in patients with different types of epilepsy, current research on resected TLE patients is missing. In the present study, resected TLE patients were compared to a control group matched on initial learning. They showed normal performance on verbal recall after 30 min, but impairments became apparent after one week. Moreover, the significant interaction between participant group and memory test delay demonstrated that the patients indeed showed an acceleration in forgetting. Furthermore, ALF was present in both left and right resected TLE patients, which contradicts the presence of material specific hemispheric differences in ALF. In addition, ALF was observed in seizure free resected TLE patients, thereby demonstrating that this factor is not crucial for long-term memory deficits. The outcome shows that clinicians are likely to underestimate memory deficits in resected TLE patients and, therefore, advocates for the inclusion of ALF tests in standard clinical batteries for both pre- and post-surgery testing sessions. PMID- 29606347 TI - Novel mutations in genes encoding subcortical maternal complex proteins may cause human embryonic developmental arrest. AB - Successful human reproduction initiates from normal gamete formation, fertilization and early embryonic development. Abnormalities in any of these steps will lead to infertility. Many infertile patients undergo several failures of IVF and intracytoplasmic sperm injection (ICSI) cycles, and embryonic developmental arrest is a common phenotype in cases of recurrent failure of IVF/ICSI attempts. However, the genetic basis for this phenotype is poorly understood. The subcortical maternal complex (SCMC) genes play important roles during embryonic development, and using whole-exome sequencing novel biallelic mutations in the SCMC genes TLE6, PADI6 and KHDC3L were identified in four patients with embryonic developmental arrest. A mutation in TLE6 was found in a patient with cleaved embryos that arrested on day 3 and failed to form blastocysts. Two patients with embryos that arrested at the cleavage stage had mutations in PADI6, and a mutation in KHDC3L was found in a patient with embryos arrested at the morula stage. No mutations were identified in these genes in an additional 80 patients. These findings provide further evidence for the important roles of TLE6, PADI6 and KHDC3L in embryonic development. This work lays the foundation for the genetic diagnosis of patients with recurrent IVF/ICSI failure. PMID- 29606348 TI - GKAP Acts as a Genetic Modulator of NMDAR Signaling to Govern Invasive Tumor Growth. AB - Genetic linkage analysis previously suggested that GKAP, a scaffold protein of the N-methyl-D-aspartate receptor (NMDAR), was a potential modifier of invasion in a mouse model of pancreatic neuroendocrine tumor (PanNET). Here, we establish that GKAP governs invasive growth and treatment response to NMDAR inhibitors of PanNET via its pivotal role in regulating NMDAR pathway activity. Combining genetic knockdown of GKAP and pharmacological inhibition of NMDAR, we implicate as downstream effectors FMRP and HSF1, which along with GKAP demonstrably support invasiveness of PanNET and pancreatic ductal adenocarcinoma cancer cells. Furthermore, we distilled genome-wide expression profiles orchestrated by the NMDAR-GKAP signaling axis, identifying transcriptome signatures in tumors with low/inhibited NMDAR activity that significantly associate with favorable patient prognosis in several cancer types. PMID- 29606350 TI - Analysis of Quality Indicators for Colorectal Cancer Surgery in Units Accredited by the Spanish Association of Coloproctology. AB - INTRODUCTION: Currently, there is growing interest in analyzing the results from surgical units and the implementation of quality standards in order to identify good healthcare practices. Due to this fact, the Spanish Association of Coloproctology (AECP) has developed a unit accreditation program that contemplates basic standards. The aim of this article is to evaluate and analyze the specific quality indicators for the surgical treatment of colorectal cancer, established by the program. Data were collected from colorectal units during the accreditation process. METHODS: We analyzed prospectively collected data from elective colorectal surgeries at 18 Spanish coloproctology units during the period 2013-2017. Three main and four secondary quality indicators were considered. Colon and rectal surgeries were analyzed independently; furthermore, results were compared according to surgical approach. RESULTS: A total of 3090 patients were included in the analysis. The global anastomotic leak rate was 7.8% (6.6% colon vs 10.6% rectum), while the surgical site infection rate was 12.6% (11.4% colon vs 14.8% rectum). Overall 30-day mortality was 2.3%, and anastomotic leak-related mortality was 10.2%. There were higher surgical site infection and mortality rates in the patients operated by open approach, however there was no difference in the anastomotic leak rate when compared with minimally invasive approaches. CONCLUSIONS: The evaluation of these results has determined optimal quality indices for the units accredited in the treatment of colorectal cancer. Furthermore, it allows us to establish realistic references in our country, thereby providing a better understanding and comparison of outcomes. PMID- 29606349 TI - Angiogenin/Ribonuclease 5 Is an EGFR Ligand and a Serum Biomarker for Erlotinib Sensitivity in Pancreatic Cancer. AB - Pancreatic ribonuclease (RNase) is a secreted enzyme critical for host defense. We discover an intrinsic RNase function, serving as a ligand for epidermal growth factor receptor (EGFR), a member of receptor tyrosine kinase (RTK), in pancreatic ductal adenocarcinoma (PDAC). The closely related bovine RNase A and human RNase 5 (angiogenin [ANG]) can trigger oncogenic transformation independently of their catalytic activities via direct association with EGFR. Notably, high plasma ANG level in PDAC patients is positively associated with response to EGFR inhibitor erlotinib treatment. These results identify a role of ANG as a serum biomarker that may be used to stratify patients for EGFR-targeted therapies, and offer insights into the ligand-receptor relationship between RNase and RTK families. PMID- 29606351 TI - A Huntingtin Knockin Pig Model Recapitulates Features of Selective Neurodegeneration in Huntington's Disease. AB - Huntington's disease (HD) is characterized by preferential loss of the medium spiny neurons in the striatum. Using CRISPR/Cas9 and somatic nuclear transfer technology, we established a knockin (KI) pig model of HD that endogenously expresses full-length mutant huntingtin (HTT). By breeding this HD pig model, we have successfully obtained F1 and F2 generation KI pigs. Characterization of founder and F1 KI pigs shows consistent movement, behavioral abnormalities, and early death, which are germline transmittable. More importantly, brains of HD KI pig display striking and selective degeneration of striatal medium spiny neurons. Thus, using a large animal model of HD, we demonstrate for the first time that overt and selective neurodegeneration seen in HD patients can be recapitulated by endogenously expressed mutant proteins in large mammals, a finding that also underscores the importance of using large mammals to investigate the pathogenesis of neurodegenerative diseases and their therapeutics. PMID- 29606352 TI - Evolutionary Convergence of Pathway-Specific Enzyme Expression Stoichiometry. AB - Coexpression of proteins in response to pathway-inducing signals is the founding paradigm of gene regulation. However, it remains unexplored whether the relative abundance of co-regulated proteins requires precise tuning. Here, we present large-scale analyses of protein stoichiometry and corresponding regulatory strategies for 21 pathways and 67-224 operons in divergent bacteria separated by 0.6-2 billion years. Using end-enriched RNA-sequencing (Rend-seq) with single nucleotide resolution, we found that many bacterial gene clusters encoding conserved pathways have undergone massive divergence in transcript abundance and architectures via remodeling of internal promoters and terminators. Remarkably, these evolutionary changes are compensated post-transcriptionally to maintain preferred stoichiometry of protein synthesis rates. Even more strikingly, in eukaryotic budding yeast, functionally analogous proteins that arose independently from bacterial counterparts also evolved to convergent in-pathway expression. The broad requirement for exact protein stoichiometries despite regulatory divergence provides an unexpected principle for building biological pathways both in nature and for synthetic activities. PMID- 29606353 TI - Direct Promoter Repression by BCL11A Controls the Fetal to Adult Hemoglobin Switch. AB - Fetal hemoglobin (HbF, alpha2gamma2) level is genetically controlled and modifies severity of adult hemoglobin (HbA, alpha2beta2) disorders, sickle cell disease, and beta-thalassemia. Common genetic variation affects expression of BCL11A, a regulator of HbF silencing. To uncover how BCL11A supports the developmental switch from gamma- to beta- globin, we use a functional assay and protein binding microarray to establish a requirement for a zinc-finger cluster in BCL11A in repression and identify a preferred DNA recognition sequence. This motif appears in embryonic and fetal-expressed globin promoters and is duplicated in gamma globin promoters. The more distal of the duplicated motifs is mutated in individuals with hereditary persistence of HbF. Using the CUT&RUN approach to map protein binding sites in erythroid cells, we demonstrate BCL11A occupancy preferentially at the distal motif, which can be disrupted by editing the promoter. Our findings reveal that direct gamma-globin gene promoter repression by BCL11A underlies hemoglobin switching. PMID- 29606354 TI - Visualization of Membrane Pore in Live Cells Reveals a Dynamic-Pore Theory Governing Fusion and Endocytosis. AB - Fusion is thought to open a pore to release vesicular cargoes vital for many biological processes, including exocytosis, intracellular trafficking, fertilization, and viral entry. However, fusion pores have not been observed and thus proved in live cells. Its regulatory mechanisms and functions remain poorly understood. With super-resolution STED microscopy, we observed dynamic fusion pore behaviors in live (neuroendocrine) cells, including opening, expansion, constriction, and closure, where pore size may vary between 0 and 490 nm within 26 milliseconds to seconds (vesicle size: 180-720 nm). These pore dynamics crucially determine the efficiency of vesicular cargo release and vesicle retrieval. They are generated by competition between pore expansion and constriction. Pharmacology and mutation experiments suggest that expansion and constriction are mediated by F-actin-dependent membrane tension and calcium/dynamin, respectively. These findings provide the missing live-cell evidence, proving the fusion-pore hypothesis, and establish a live-cell dynamic pore theory accounting for fusion, fission, and their regulation. PMID- 29606355 TI - Fetal Neuropathology in Zika Virus-Infected Pregnant Female Rhesus Monkeys. AB - The development of interventions to prevent congenital Zika syndrome (CZS) has been limited by the lack of an established nonhuman primate model. Here we show that infection of female rhesus monkeys early in pregnancy with Zika virus (ZIKV) recapitulates many features of CZS in humans. We infected 9 pregnant monkeys with ZIKV, 6 early in pregnancy (weeks 6-7 of gestation) and 3 later in pregnancy (weeks 12-14 of gestation), and compared findings with uninfected controls. 100% (6 of 6) of monkeys infected early in pregnancy exhibited prolonged maternal viremia and fetal neuropathology, including fetal loss, smaller brain size, and histopathologic brain lesions, including microcalcifications, hemorrhage, necrosis, vasculitis, gliosis, and apoptosis of neuroprogenitor cells. High resolution MRI demonstrated concordant lesions indicative of deep gray matter injury. We also observed spinal, ocular, and neuromuscular pathology. Our data show that vascular compromise and neuroprogenitor cell dysfunction are hallmarks of CZS pathogenesis, suggesting novel strategies to prevent and to treat this disease. PMID- 29606356 TI - Tumor-Induced Generation of Splenic Erythroblast-like Ter-Cells Promotes Tumor Progression. AB - Identifying tumor-induced leukocyte subsets and their derived circulating factors has been instrumental in understanding cancer as a systemic disease. Nevertheless, how primary tumor-induced non-leukocyte populations in distal organs contribute to systemic spread remains poorly defined. Here, we report one population of tumor-inducible, erythroblast-like cells (Ter-cells) deriving from megakaryocyte-erythroid progenitor cells with a unique Ter-119+CD45-CD71+ phenotype. Ter-cells are enriched in the enlarged spleen of hosts bearing advanced tumors and facilitate tumor progression by secreting neurotrophic factor artemin into the blood. Transforming growth factor beta (TGF-beta) and Smad3 activation are important in Ter-cell generation. In vivo blockade of Ter-cell derived artemin inhibits hepatocellular carcinoma (HCC) growth, and artemin deficiency abolishes Ter-cells' tumor-promoting ability. We confirm the presence of splenic artemin-positive Ter-cells in human HCC patients and show that significantly elevated serum artemin correlates with poor prognosis. We propose that Ter-cells and the secreted artemin play important roles in cancer progression with prognostic and therapeutic implications. PMID- 29606357 TI - Who, where, and why are patients lost to follow-up? A 20-year study of bladder exstrophy patients at a single institution. AB - INTRODUCTION: Individuals with bladder and cloacal exstrophy are at increased risk for kidney disease, renal failure, and bladder complications. Given the social implications and sensitive nature of the disease, these patients are also at risk for psychosocial problems. Lack of regular medical follow-up visits may pose serious risks to their long-term health status. The aim of this study is determine what factors place an affected individual at risk for limited long term follow up. MATERIALS AND METHODS: We identified all patients with bladder or cloacal exstrophy seen by the pediatric urology department at the Oklahoma University Health Sciences Center (OUHSC) between January 1996 and August 2016. Patient data included demographics, insurance coverage, distance from patient's home to the clinic, medical and surgical history, and the date of their last clinic visit. Two groups for comparison were (1) those that had been seen within the last 2 years, and (2) those that were counted as failing to maintain follow up because 2 or more years had passed since their last clinic visit. These groups were compared using the Student t-test, the chi-square test, or the Fisher exact test and p < 0.05 was treated as significant for the purposes of discussion. RESULTS AND DISCUSSION: Ninety-one patients with bladder or cloacal exstrophy were seen by the pediatric urology department between January 1996 and August 2016. Of the 91 patients, 24 left the clinic for known reasons thus leaving 67 patients that were considered for analyses: 51 had been seen within the last 2 years while 16 were counted as lost to follow-up. These two groups (active and lost to follow-up) did not differ significantly for age at last clinic visit, distance between family's home and clinic, history of bladder reconstruction, sex, or insurance status. There was a significant difference between the two groups in the medical complexity of their condition. The group active in urological care had more patients with cloacal exstrophy and additional anomalies than the group lost to follow-up. CONCLUSIONS: Patients with bladder exstrophy and cloacal exstrophy are less likely to maintain annual follow-up visits with their urologist if they have a simpler diagnosis requiring fewer surgical interventions. For patients with exstrophy, regular clinic visits prioritizing education and psychosocial support may prevent hospitalizations, emergency interventions, and poor overall health outcomes. To maintain contact with the medical team and promote optimal health outcomes, a social worker or care coordinator/educator may play an integral part in addressing the unique needs of this population. PMID- 29606358 TI - Incontinence affects health-related quality of life in children and adolescents with spina bifida. AB - PURPOSE: Despite devoting many resources to managing urinary and fecal incontinence (UI and FI) in children with spina bifida (SB), it remains unclear whether either is associated with lower health-related quality of life (HRQOL). We sought to determine the impact of UI and FI on HRQOL in this population. MATERIALS AND METHODS: Children with SB (8-17 years) living in the United States were surveyed online and in SB clinics (2013-15). We evaluated incontinence over the previous 4 weeks using a UI dry interval (<4 h, >=4 h), FI clean interval (<1 week, >= 1 week), and self-reported amount of UI and FI (for each: a lot, medium, a little, none). HRQOL was assessed with QUALAS, a validated SB-specific instrument. Linear regression was used. RESULTS: The mean age of 298 children was 12.5 years (52.0% male). Overall, 73.1% had UI, 52.3% had FI, and 43.6% had both. Adjusting for concurrent UI and FI, any UI was associated with lower HRQOL in 14 17 year olds (p < 0.0001) and 10-13 year olds (p = 0.048), but not 8-9 year olds (p = 0.98) (Figure). All age groups reported lower HRQOL with FI (p <= 0.0001). On multivariate analysis, UI and FI incontinence intervals were not associated with lower HRQOL for any age group (p >= 0.58 and p >= 0.10, respectively). Higher quantities of UI were associated with ever-lower HRQOL, particularly in 14 17 year olds (p <= 0.02). Any quantity of FI was associated with lower HRQOL in all ages. The findings did not change significantly on exploratory analysis correcting for demographic and clinical variables. DISCUSSION: We report the first evidence that incontinence matters to children and adolescents with SB. Being a cross-sectional study, we were unable to track HRQOL over time. A prospective study is required to assess if HRQOL impact of UI indeed changes as a child grows up and if improving incontinence with treatments improves HRQOL. Findings are similar to those reported in adults with SB and suggest that the concept of "social continence" based on time interval has no HRQOL relevance in children, adolescents or adults with SB. CONCLUSIONS: UI is negatively associated with HRQOL in children with SB in an age-dependent fashion: starting in 10 year olds and increasing until 14 years. FI correlates with lower HRQOL regardless of age. Similar to findings in adults with SB, HRQOL is lower with increasing amounts of UI and not the length of a dry interval. FI impacts HRQOL uniformly, regardless of frequency or amount. PMID- 29606359 TI - Adolescent psychopathology in times of change: Introduction to the special issue. AB - The aim of this special issue is to understand better the many changes in adolescent psychopathology have taken place over the last decades. The factors associated with adjustment problems and psychopathology in adolescence today are not necessarily the same as the factors that predicted problems and psychopathology in the past. But the basic strategies for connecting negative experiences with adolescent psychopathology remain as important today as they were for understanding adolescent psychopathology decades ago. This is well exemplified in the studies included in this Special Issue. What all this studies have in common is that parenting and the family environment are assumed to play a key role in adolescents' adjustment and psychopathology. Finally, given that all papers in this special issue are based on conference presentations at the 15th Biennial Conference of the European Association for Research on Adolescence (EARA), some more information on that conference in included in this introduction. PMID- 29606360 TI - Seasonal variation of delta18O and delta2H in leaf water of Fagus sylvatica L. and related water compartments. AB - The study aims to assess variability in leaf water isotopic enrichment occurring in the field under natural conditions. We focused on seasonal variation and difference between sun-exposed and shaded leaves. Isotopic composition (delta18O, delta2H) of leaf water was monitored in a beech tree (Fagus sylvatica L.) growing in the forest-meadow ecotone together with delta18O (2H) of water compartments which are in close relation to this signal, namely twig and soil water. The sampling was carried out in approximately two-week intervals during five consecutive vegetation seasons. The delta18O (2H) data showed a distinct seasonal pattern and a consistency in relative differences between the seasons and sample categories. Leaf water was the most isotopically enriched water compartment. The leaf water enrichment decreased toward the autumn reflecting the change in delta18O (2H) of source water and evaporative demands. The soil and twig water isotopic signal was depleted against current precipitation as it partly retained the isotopic signature from winter precipitation however the seasonal pattern of soil and twig water followed that of precipitation. No significant differences between sun-exposed and shaded samples were detected. Nevertheless, the observed strong seasonal pattern of isotope composition of leaf, twig and soil water should be taken into account when using leaf water enrichment for further calculations or modeling. PMID- 29606361 TI - Direct Oral Anticoagulants Versus Vitamin K Antagonists in Real-life Patients With Atrial Fibrillation. A Systematic Review and Meta-analysis. AB - INTRODUCTION AND OBJECTIVES: To assess the effectiveness of direct oral anticoagulants vs vitamin K antagonists in real-life patients with atrial fibrillation. METHODS: A systematic review was performed according to Cochrane methodological standards. The results were reported according to the PRISMA statement. The ROBINS-I tool was used to assess risk of bias. RESULTS: A total of 27 different studies publishing data in 30 publications were included. In the studies with a follow-up up to 1 year, apixaban (HR, 0.93; 95%CI, 0.71-1.20) and dabigatran (HR, 0.95; 95%CI, 0.80-1.13) did not significantly reduce the risk of ischemic stroke vs warfarin, whereas rivaroxaban significantly reduced this risk (HR, 0.83; 95%CI, 0.73-0.94). Apixaban (HR, 0.66; 95%CI, 0.55-0.80) and dabigatran (HR, 0.83; 95%CI, 0.70-0.97) significantly reduced the major bleeding risk vs warfarin, but not rivaroxaban (HR, 1.02; 95%CI, 0.95-1.10), although with a high statistical heterogeneity among studies. Apixaban (HR, 0.56; 95%CI, 0.42 0.73), dabigatran (HR, 0.45; 95%CI, 0.39-0.51), and rivaroxaban (HR, 0.66; 95%CI, 0.49-0.88) significantly reduced the risk of intracranial bleeding vs warfarin. Reduced doses of direct oral anticoagulants were associated with a slightly better safety profile, but with a marked reduction in stroke prevention effectiveness. CONCLUSIONS: Data from this meta-analysis suggest that, vs warfarin, the stroke prevention effectiveness and bleeding risk of direct oral anticoagulants may differ in real-life patients with atrial fibrillation. PMID- 29606362 TI - Usefulness of Genetic Study by Next-generation Sequencing in High-risk Arrhythmogenic Cardiomyopathy. AB - INTRODUCTION AND OBJECTIVES: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by progressive fibrofatty replacement of predominantly right ventricular myocardium. This cardiomyopathy is a frequent cause of sudden cardiac death in young people and athletes. The aim of our study was to determine the incidence of pathological or likely pathological desmosomal mutations in patients with high-risk definite ARVC. METHODS: This was an observational, retrospective cohort study, which included 36 patients diagnosed with high-risk ARVC in our hospital between January 1998 and January 2015. Genetic analysis was performed using next-generation sequencing. RESULTS: Most patients were male (28 patients, 78%) with a mean age at diagnosis of 45 +/- 18 years. A pathogenic or probably pathogenic desmosomal mutation was detected in 26 of the 35 index cases (74%): 5 nonsense, 14 frameshift, 1 splice, and 6 missense. Novel mutations were found in 15 patients (71%). The presence or absence of desmosomal mutations causing the disease and the type of mutation were not associated with specific electrocardiographic, clinical, arrhythmic, anatomic, or prognostic characteristics. CONCLUSIONS: The incidence of pathological or likely pathological desmosomal mutations in ARVC is very high, with most mutations causing truncation. The presence of desmosomal mutations was not associated with prognosis. PMID- 29606363 TI - Number of Patients Eligible for PCSK9 Inhibitors Based on Real-world Data From 2.5 Million Patients. AB - INTRODUCTION AND OBJECTIVES: PCSK9 inhibitors (PCSK9i) are safe and effective lipid-lowering drugs. Their main limitation is their high cost. The aim of this study was to estimate the number of patients eligible for treatment with PCSK9i according to distinct published criteria. METHODS: Data were obtained from the Information System for the Development of Research in Primary Care. Included patients were equal to or older than 18 years and had at least 1 low-density lipoprotein cholesterol measurement recorded between 2006 and 2014 (n = 2 500 907). An indication for treatment with PCSK9i was assigned according to the following guidelines: National Health System, Spanish Society of Arteriosclerosis, Spanish Society of Cardiology, National Institute for Health and Care Excellence, and the European Society of Cardiology/European Atherosclerosis Society Task Force. Lipid-lowering treatment was defined as optimized if it reduced low-density lipoprotein levels by >= 50% and adherence was > 80%. RESULTS: Among the Spanish population aged 18 years or older, the number of possible candidates to receive PCSK9i in an optimal lipid-lowering treatment scenario ranged from 0.1% to 1.7%, depending on the guideline considered. The subgroup of patients with the highest proportion of potential candidates consisted of patients with familial hypercholesterolemia, and the subgroup with the highest absolute number consisted of patients in secondary cardiovascular prevention. CONCLUSIONS: The number of candidates to receive PCSK9i in conditions of real-world clinical practice is high and varies widely depending on the recommendations of distinct scientific societies. PMID- 29606365 TI - Widening the options for recurrent malaria. PMID- 29606366 TI - Letter to the Editor. PMID- 29606364 TI - Pyronaridine-artesunate or dihydroartemisinin-piperaquine versus current first line therapies for repeated treatment of uncomplicated malaria: a randomised, multicentre, open-label, longitudinal, controlled, phase 3b/4 trial. AB - BACKGROUND: Artemether-lumefantrine and artesunate-amodiaquine are used as first line artemisinin-based combination therapies (ACTs) in west Africa. Pyronaridine artesunate and dihydroartemisinin-piperaquine are potentially useful for diversification of ACTs in this region, but further safety and efficacy data are required on malaria retreatment. METHODS: We did a randomised, multicentre, open label, longitudinal, controlled phase 3b/4 clinical trial at seven tertiary centres in Burkina Faso, Guinea, and Mali. Eligible participants for first malaria episode and all retreatment episodes were adults and children aged 6 months and older with microscopically confirmed Plasmodium spp malaria (>0 to <200 000 parasites per MUL of blood) and fever or history of fever in the previous 24 h. Individuals with severe or complicated malaria, an alanine aminotransferase concentration of more than twice the upper limit of normal, or a QTc greater than 450 ms were excluded. Using a randomisation list for each site, masked using sealed envelopes, participants were assigned to either pyronaridine artesunate or dihydroartemisinin-piperaquine versus either artesunate-amodiaquine or artemether-lumefantrine. Block sizes were two or four if two treatments were allocated, and three or six if three treatments were allocated. Microscopists doing the parasitological assessments were masked to treatment allocation. All treatments were once-daily or twice-daily tablets or granules given orally and dosed by bodyweight over 3 days at the study centre. Patients were followed up as outpatients up to day 42, receiving clinical assessments on days 0, 1, 2, 3, 7, 14, 21, 28, 35, and 42. Two primary outcomes were compared for non-inferiority: the 2-year incidence rate of all microscopically confirmed, complicated and uncomplicated malaria episodes in patients in the intention-to-treat population (ITT; non-inferiority margin 20%); and adequate clinical and parasitological response (ACPR) in uncomplicated malaria across all episodes (unadjusted and PCR adjusted for Plasmodium falciparum and unadjusted for other Plasmodium spp) in the per-protocol population on days 28 and 42 (non-inferiority margin 5%). Safety was assessed in all participants who received one dose of study drug. This study is registered at the Pan African Clinical Trials Registry (PACTR201105000286876). FINDINGS: Between Oct 24, 2011, and Feb 1, 2016, we assigned 4710 eligible participants to the different treatment strategies: 1342 to pyronaridine artesunate, 967 to artemether-lumefantrine, 1061 to artesunate-amodiaquine, and 1340 to dihydroartemisinin-piperaquine. The 2-year malaria incidence rate in the ITT population was non-inferior for pyronaridine-artesunate versus artemether lumefantrine (1.77, 95% CI 1.63-1.93 vs 1.87, 1.72-2.03; rate ratio [RR] 1.05, 95% CI 0.94-1.17); and versus artesunate-amodiaquine (1.39, 95% CI 1.22-1.59 vs 1.35, 1.18-1.54; RR 0.97, 0.87-1.07). Similarly, this endpoint was non-inferior for dihydroartemisinin-piperaquine versus artemether-lumefantrine (1.16, 95% CI 1.01-1.34 vs 1.42 1.25-1.62; RR 1.22, 95% CI 1.06-1.41) and versus artesunate amodiaquine (1.35, 1.21-1.51 vs 1.68, 1.51-1.88; RR 1.25, 1.02-1.50). For uncomplicated P falciparum malaria, PCR-adjusted ACPR was greater than 99.5% at day 28 and greater than 98.6% at day 42 for all ACTs; unadjusted ACPR was higher for pyronaridine-artesunate versus comparators at day 28 (96.9% vs 82.3% for artemether-lumefantrine and 95.6% vs 89.0% for artesunate-amodiaquine) and for dihydroartemisinin-piperaquine versus comparators (99.5% vs 81.6% for artemether lumefantrine and 99.0% vs 89.0% for artesunate-amodiaquine). For non-falciparum species, unadjusted ACPR was greater than 98% for all study drugs at day 28 and at day 42 was greater than 83% except for artemether-lumefantrine against Plasmodium ovale (in ten [62.5%] of 16 patients) and against Plasmodium malariae (in nine [75.0%] of 12 patients). Nine deaths occurred during the study, none of which were related to the study treatment. Mostly mild transient elevations in transaminases occurred with pyronaridine-artesunate versus comparators, and mild QTcF prolongation with dihydroartemisinin-piperaquine versus comparators. INTERPRETATION: Pyronaridine-artesunate and dihydroartemisinin-piperaquine treatment and retreatment of malaria were well tolerated with efficacy that was non-inferior to first-line ACTs. Greater access to these efficacious treatments in west Africa is justified. FUNDING: The European and Developing Countries Clinical Trial Partnership, Medicines for Malaria Venture (Geneva, Switzerland), the UK Medical Research Council, the Swedish International Development Cooperation Agency, German Ministry for Education and Research, University Claude Bernard (Lyon, France), University of Science, Techniques and Technologies of Bamako (Bamako, Mali), the Centre National de Recherche et de Formation sur le Paludisme (Burkina Faso), Institut de Recherche en Sciences de la Sante (Bobo Dioulasso, Burkina Faso), and Centre National de Formation et de Recherche en Sante Rurale (Republic of Guinea). PMID- 29606367 TI - Tmax is a sensitive indicator of myocardial ischaemia under adenosine stress as determined by static PET imaging: a study in a porcine model. AB - AIM: To evaluate Tmax, defined as the time of residual function R(t) reaching its maximum, as an indicator of myocardial ischaemia and compare its efficacy with other computed tomography perfusion (CTP) parameters. MATERIALS AND METHODS: Eight Bama miniature pigs with 50-90% left anterior descending artery stenosis underwent adenosine stress myocardial CTP and 13NNH3 position-emission tomography (PET) perfusion imaging. Tmax, myocardial blood flow (MBF), myocardial blood volume (MBV), mean transit time (MTT), and time to peak (TTP) were calculated from CTP images. PET images were evaluated as ischaemia or non-ischaemia. Using PET as a reference standard, the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated. Multiple comparisons of the receiver operating characteristic (ROC) curves between Tmax and other parameters were performed. The diagnostic performance of the combination of each two parameters was calculated and compared with Tmax. RESULTS: Tmax was significantly higher in ischaemic segments compared with non ischaemic segments. Multiple comparisons of the ROCs indicated that Tmax was better than MBF or TTP but not statistically different from MBV. Tmax was superior to the combination of (MBF + MBV) but not to (MBF + TTP) or (MBV + TTP). CONCLUSION: Tmax in dynamic stress CTP provides good diagnostic accuracy for detecting myocardial ischaemia, especially in sensitivity and NPV, compared with PET method. Tmax has better performance than MBF or TTP or combination of (MBF + MBV) in diagnosing myocardial ischaemia. PMID- 29606368 TI - Influence of Class V preparation on in vivo temperature rise in anesthetized human pulp during exposure to a Polywave(r) LED light curing unit. AB - OBJECTIVE: This in vivo study evaluated pulp temperature (PT) rise in human premolars having deep Class V preparations during exposure to a light curing unit (LCU) using selected exposure modes (EMs). METHODS: After local Ethics Committee approval, intact first premolars (n=8) requiring extraction for orthodontic reasons, from 8 volunteers, received infiltrative and intraligamental anesthesia and were isolated using rubber dam. A minute pulp exposure was attained and sterile probe from a wireless, NIST-traceable, temperature acquisition system was inserted into the coronal pulp chamber to continuously monitor PT ( degrees C). A deep buccal Class V preparation was prepared using a high speed diamond bur under air-water spray cooling. The surface was exposed to a Polywave(r) LED LCU (Bluephase 20i, Ivoclar Vivadent) using selected EMs, allowing 7-min span between each exposure: 10-s in low (10-s/L), 10-s (10-s/H), 30-s (30-s/H), or 60-s (60 s/H) in high mode; and 5-s-Turbo (5-s/T). Peak PT values and PT increases over physiologic baseline levels (DeltaT) were subjected to 1-way, repeated measures ANOVAs, and Bonferroni's post-hoc tests (alpha=0.05). Linear regression analysis was performed to establish the relationship between applied radiant exposure and DeltaT. RESULTS: All EMs produced higher peak PT than the baseline temperature (p<0.001). Only 60-s/H mode generated an average DeltaT of 5.5 degrees C (p<0.001). A significant, positive relationship was noted between applied radiant exposure and DeltaT (r2=0.8962; p<0.001). SIGNIFICANCE: In vivo exposure of deep Class V preparation to Polywave(r) LED LCU increases PT to values considered safe for the pulp, for most EMs. Only the longest evaluated EM caused higher PT increase than the critical DeltaT, thought to be associated with pulpal necrosis. PMID- 29606369 TI - Various Signaling Pathways in Multiple Myeloma Cells and Effects of Treatment on These Pathways. AB - Multiple myeloma (MM) results from malignancy in plasma cells and occurs at ages > 50 years. MM is the second most common hematologic malignancy after non-Hodgkin lymphoma, which constitutes 1% of all malignancies. Despite the great advances in the discovery of useful drugs for this disease such as dexamethasone and bortezomib, it is still an incurable malignancy owing to the development of drug resistance. The tumor cells develop resistance to apoptosis, resulting in greater cell survival, and, ultimately, develop drug resistance by changing the various signaling pathways involved in cell proliferation, survival, differentiation, and apoptosis. We have reviewed the different signaling pathways in MM cells. We reached the conclusion that the most important factor in the drug resistance in MM patients is caused by the bone marrow microenvironment with production of adhesion molecules and cytokines. Binding of tumor cells to stromal cells prompts cytokine production of stromal cells and launches various signaling pathways such as Janus-activated kinase/signal transduction and activator of transcription, Ras/Raf/MEK/mitogen-activated protein kinase, phosphatidyl inositol 3-kinase/AKT, and NF-KB, which ultimately lead to the high survival rate and drug resistance in tumor cells. Thus, combining various drugs such as bortezomib, dexamethasone, lenalidomide, and melphalan with compounds that are not common, including CTY387, LLL-12, OPB31121, CNTO328, OSI-906, FTY720, triptolide, and AV-65, could be one of the most effective treatments for these patients. PMID- 29606371 TI - Characterization of small (<4cm) solid renal masses by computed tomography and magnetic resonance imaging: Current evidence and further development. AB - Diagnosis of renal cell carcinomas (RCC) subtypes on computed tomography (CT) and magnetic resonance imaging (MRI) is clinically important. There is increased evidence that confident imaging diagnosis is now possible while standardization of the protocols is still required. Fat-poor angiomyolipoma show homogeneously increased unenhanced attenuation, homogeneously low signal on T2-weighted MRI and apparent diffusion coefficient (ADC) map, may contain microscopic fat and are classically avidly enhancing. Papillary RCC are also typically hyperattenuating and of low signal on T2-weighted MRI and ADC map; however, their gradual progressive enhancement after intravenous administration of contrast material is a differentiating feature. Clear cell RCC are avidly enhancing and may show intracellular lipid; however, these tumors are heterogeneous and are of characteristically increased signal on T2-weighted MRI. Oncocytomas and chromophobe tumors (collectively oncocytic neoplasms) show intermediate imaging findings on CT and MRI and are the most difficult subtype to characterize accurately; however, both show intermediately increased signal on T2-weighted with more gradual enhancement compared to clear cell RCC. Chromophobe tumors tend to be more homogeneous compared to oncocytomas, which can be heterogeneous, but other described features (e.g. scar, segmental enhancement inversion) overlap considerably between tumors. Tumor grade is another important consideration in small solid renal masses with emerging studies on both CT and MRI suggesting that high grade tumors may be separated from lower grade disease based upon imaging features. PMID- 29606370 TI - The effect of nurse-led group discussions by race on depressive symptoms in patients with heart failure. AB - BACKGROUND: African Americans with heart failure (HF) have the highest rates of depression among all ethnicities in the USA. OBJECTIVES: To compare the effects by race on depressive symptoms and topics discussed in the first clinic appointment after HF hospitalization. METHODS: This study is a secondary analysis of data from a randomized clinical trial testing a patient group discussion of HF self-management with 93 Caucasians and 77 African Americans. RESULTS: Reduction in depressive symptoms was significantly greater among African American patients within the intervention group (F = 3.99, p = .047) than controls. There were significant differences by race in four topics (dietitian referral, appointment date, help preparing discussion questions, and advice on worsening HF symptoms) concerning patient-physician discussions. CONCLUSION: The intervention showed greater effect in reducing depressive symptoms among African Americans than Caucasians. Preparing patients for discussions at physician appointments on diet, depressive symptoms, and HF symptoms is recommended. PMID- 29606372 TI - Meeting Report: Can We Make Animal Models of Human Mental Illness? AB - Modeling aspects of the human condition in animals has provided invaluable information on the physiology of all organ systems and has assisted in the development of virtually all new therapeutics. Research in cardiovascular disease, cancer, immunology, and other disciplines has benefited substantially from the availability of animal models that capture aspects of specific human diseases and that have been used effectively to advance new treatments. By comparison, animal models for neurological and psychiatric disorders have faced several unique obstacles. This paper highlights topics covered in a recent Cold Spring Harbor Laboratory meeting charged with examining the status of animal models for mental illness. The consensus of the conference is that despite the difficulties inherent with modeling brain disorders in animals, when used judiciously-fully cognizant that models of specific behavioral or biological aspects cannot completely recapitulate the human disorder-animal research is crucial for advancing our understanding of neuropsychiatric disease. PMID- 29606373 TI - Reply to the Letter to the Editor RE: Ropivacaine wound infiltration: a fast track approach in patients undergoing thoracotomy surgery. PMID- 29606374 TI - Evaluation of bacterial run and tumble motility parameters through trajectory analysis. AB - In this paper, a method for extraction of the behavior parameters of bacterial migration based on the run and tumble conceptual model is described. The methodology is applied to the microscopic images representing the motile movement of flagellated Azotobacter vinelandii. The bacterial cells are considered to change direction during both runs and tumbles as is evident from the movement trajectories. An unsupervised cluster analysis was performed to fractionate each bacterial trajectory into run and tumble segments, and then the distribution of parameters for each mode were extracted by fitting mathematical distributions best representing the data. A Gaussian copula was used to model the autocorrelation in swimming velocity. For both run and tumble modes, Gamma distribution was found to fit the marginal velocity best, and Logistic distribution was found to represent better the deviation angle than other distributions considered. For the transition rate distribution, log-logistic distribution and log-normal distribution, respectively, was found to do a better job than the traditionally agreed exponential distribution. A model was then developed to mimic the motility behavior of bacteria at the presence of flow. The model was applied to evaluate its ability to describe observed patterns of bacterial deposition on surfaces in a micro-model experiment with an approach velocity of 200 MUm/s. It was found that the model can qualitatively reproduce the attachment results of the micro-model setting. PMID- 29606375 TI - The roles of vitamin D and cutaneous vitamin D production in human evolution and health. AB - Most of the vitamin D necessary for the maintenance of human health and successful reproduction is made in the skin under the influence of a narrow portion of the electromagnetic spectrum emitted from the sun, namely ultraviolet B radiation (UVB). During the course of human evolution, skin pigmentation has evolved to afford protection against high levels of UVR while still permitting cutaneous production of vitamin D. Similar pigmentation phenotypes evolved repeatedly as the result of independent genetic events when isolated human populations dispersed into habitats of extremely low or high UVB. The gradient of skin color seen in modern human populations is evidence of the operation of two clines, one favoring photoprotection near the equator, the other favoring vitamin D production nearer the poles. Through time, human adaptations to different solar regimes have become more cultural than biological. Rapid human migrations, increasing urbanization, and changes in lifestyle have created mismatches between skin pigmentation and environmental conditions leading to vitamin D deficiency. The prevalence and significance for health of vitamin D deficiencies, and the definition of optimal levels of vitamin D in the bloodstream are subjects of intense research and debate, but two of the causes of vitamin D deficiency - lack of sun exposure and abandonment of vitamin D rich foods in the diet - are traceable to changes in human lifestyles accompanying urbanization in prehistory. PMID- 29606376 TI - Young adults' psychological and physiological reactions to the 2016 U.S. presidential election. AB - Elections present unique opportunities to study how sociopolitical events influence individual processes. The current study examined 286 young adults' mood and diurnal cortisol responses to the 2016 U.S. presidential election in real time: two days before the election, election night, and two days after the election of Donald Trump, with the goal of understanding whether (and the extent to which) the election influenced young adults' affective and biological states. Utilizing piecewise trajectory analyses, we observed high, and increasing, negative affect leading up to the election across all participants. Young adults who had negative perceptions of Trump's ability to fulfill the role of president and/or were part of a non-dominant social group (i.e., women, ethnic/racial minority young adults) reported increased signs of stress before the election and on election night. After the election, we observed a general "recovery" in self reported mood; however, diurnal cortisol indicators suggested that there was an increase in biological stress among some groups. Overall, findings underscore the role of macro-level factors in individuals' health and well-being via more proximal attitudes and physiological functioning. PMID- 29606377 TI - Loss to Follow-Up in Patients with Proliferative Diabetic Retinopathy after Panretinal Photocoagulation or Intravitreal Anti-VEGF Injections. AB - PURPOSE: Loss to follow-up (LTFU) may contribute to vision loss in patients with active proliferative diabetic retinopathy (PDR). The aim of this study is to determine and compare the rates of LTFU in patients with PDR receiving panretinal photocoagulation (PRP) or intravitreal injections (IVIs) with anti-vascular endothelial growth factor (VEGF) over approximately 4 years. Moreover, this study evaluates various risk factors for LTFU. DESIGN: Retrospective cohort study. PARTICIPANTS: A total of 2302 patients with PDR receiving IVIs with anti-VEGF or PRP between January 1, 2012, and April 20, 2016. METHODS: Intervals between each procedure and the subsequent follow-up visit were measured. Loss to follow-up was defined as at least 1 interval exceeding 12 months duration. MAIN OUTCOME MEASURES: The LTFU rates and associated risk factors. RESULTS: A total of 1718 patients (74.6%) followed up postprocedure and 584 patients (25.4%) were LTFU over approximately 4 years. Of the patients receiving PRP, 28.0% were LTFU compared with 22.1% of patients receiving IVI with anti-VEGF (P = 0.001). The LTFU rates decreased as age increased, with rates of 28.1% for patients aged <=55 years, 27.0% for patients aged 56 to 65 years, and 20.9% for patients aged >65 years (P = 0.002). Loss to follow-up also differed by race, with rates of 19.4% for whites, 30.2% for African Americans, 19.7% for Asians, 38.0% for Hispanics, Native Americans, and Pacific Islanders, and 34.9% for patients of unreported race (P < 0.001). The LTFU rates also increased as regional average adjusted gross incomes (AGIs) decreased, with rates of 33.9% for patients with regional average AGI of <=$40 000, 24.0% for patients with regional average AGI from $41 000 to $80 000, and 19.7% for patients with regional average AGI >$80 000 (P < 0.001). Procedure type, age, race, and regional average AGI were all significant (P < 0.05) independent risk factors of LTFU in the multivariate regression. CONCLUSIONS: A large proportion of patients with PDR were LTFU after receiving PRP or an anti-VEGF injection over approximately 4 years. Key risk factors included age, race, and regional average AGI. PMID- 29606378 TI - The Globe's Eccentric Rotational Axis: Why Medial Rectus Surgery Is More Potent than Lateral Rectus Surgery. AB - PURPOSE: Tables typically recommend greater lateral rectus (LR) than medial rectus (MR) surgical doses for horizontal strabismus of any given magnitude, a difference unexplained by mechanical models that assume globe rotation about its center. We tested this assumption during horizontal ductions. DESIGN: Prospective observational study. PARTICIPANTS: Eighteen adult subjects with normal binocular vision. METHODS: Surface coil magnetic resonance imaging at 390 or 430 MUm resolution was obtained using 2-mm-thick contiguous axial planes while subjects fixated targets in central, right, and left gaze. Angular displacements of lines connecting the corneal apex through the minor lens axis to the retina were measured to approximate clinical ductions. Globe centers were calculated from their area centroids. Apparent lens and globe-optic nerve (ON) junction rotations around the globe center were then compared with clinical ductions. MAIN OUTCOME MEASURES: Apparent angular rotations of lenses and globe-ON junctions during horizontal ductions. RESULTS: Globe-ON junctions appeared to rotate significantly less around globe centers than did lenses for abduction (20.6 degrees +/-4.7 degrees vs. 27.4 degrees +/-7.4 degrees , +/- standard deviation (SD), P < 0.001) and adduction (25.3 degrees +/-6.7 degrees vs. 31.9 degrees +/-8.3 degrees , P < 0.001). Both rotations differed significantly from clinical adduction (27.9 degrees +/-8.3 degrees , P < 0.007), but only in abduction was globe-ON junction rotation significantly less than clinical abduction (28.6 degrees +/-9.4 degrees , P < 0.001). The true geometric globe rotational center was 2.2+/-0.5 mm medial and 0.8+/-1.0 mm posterior to the geometric globe center and was displaced farther medially and posteriorly during adduction. This eccentricity imbues each millimeter of MR recession with approximately 30% more trigonometric rotational effect than equivalent LR recession. CONCLUSIONS: The medial and posterior eccentricities of the normal ocular rotational axis profoundly influence horizontal rectus action. The proximity of the globe's rotational axis to the MR shortens its lever arm relative to the LR, explaining why mechanical effects of smaller MR recessions are equivalent to larger LR recessions. PMID- 29606379 TI - Cost Evaluation of Early Vitrectomy versus Panretinal Photocoagulation and Intravitreal Ranibizumab for Proliferative Diabetic Retinopathy. AB - PURPOSE: To evaluate costs and cost-utility of early vitrectomy (pars plana vitrectomy [PPV]) compared with panretinal photocoagulation (PRP) and intravitreal ranibizumab (IVR) for proliferative diabetic retinopathy (PDR) without diabetic macular edema. DESIGN: A decision analysis model of cost utility. PARTICIPANTS: There were no participants. METHODS: A decision analysis was based on results from the Diabetic Retinopathy Clinical Research Network Protocol S comparing treatment of PRP with IVR (0.3 mg) in PDR without incident macular edema to model the total 2-year costs and outcomes for each treatment scenario. These values were compared with the 2-year hypothetical costs of early PPV for PDR. Centers for Medicare and Medicaid Services data were used to calculate associated modeled costs in a hospital/facility-based and nonfacility setting. Cost-utility was calculated on the basis of the preserved visual utility and estimated life years remaining. In addition, costs for lifetime treatment were modeled for all scenarios and used to calculate lifetime quality-adjusted life years (QALY) costs for each scenario. Sensitivity analyses were performed to evaluate the impact of the model's assumptions. MAIN OUTCOME MEASURES: Cost of treatment, utility, and cost per QALY. RESULTS: The modeled cost per QALY of treatment for PDR for 2 years of utility in the facility (nonfacility) setting was $163 988 ($102 559) in the PRP group, $436 992 ($326 424) in the IVR group, and $181 144 ($107 965) in the PPV group. Sensitivity analysis showed that both IVR and PPV groups would have equivalent costs per QALY over the first 2 years if 78% (facility) and 80% (nonfacility) of patients in the PPV group required additional treatment with IVR (at the dose of 10.1 injections as in Protocol S). Beyond 2 years, the cost per QALY in the facility (nonfacility) setting was calculated as $61 695 ($21 752) in the PRP group, $338 348 ($239 741) in the IVR group, and $63 942 ($22 261) in the PPV group. CONCLUSIONS: Early PPV as a strategy for treatment of PDR without macular edema demonstrates cost-utility similar to management with PRP and more favorable cost-utility compared with IVR in the short term. This advantage over IVR continues when lifetime costs are factored. PMID- 29606380 TI - NICE guidance on everolimus in combination with exemestane for treatment of advanced HER2-negative, hormone-receptor-positive breast cancer after endocrine therapy. PMID- 29606381 TI - Pixantrone or doxorubicin for diffuse large B-cell lymphoma? PMID- 29606382 TI - Patent rulings raise hope for cheap cancer drugs in India. PMID- 29606383 TI - Pazopanib or sunitinib for metastatic renal-cell carcinoma? PMID- 29606384 TI - Drinking alcohol before first pregnancy ups breast cancer risk. PMID- 29606385 TI - Stop smoking services in England help break the habit. PMID- 29606386 TI - Rights violation found in HPV vaccine studies in India. PMID- 29606388 TI - Cabozantinib for patients with medullary thyroid cancer. PMID- 29606387 TI - Genetic cause of common childhood leukaemia revealed. PMID- 29606389 TI - Cancer care in northern England rated best in England. PMID- 29606390 TI - Anti-EGFR treatment and RAS-family mutations. PMID- 29606391 TI - New gene biomarker identified for indolent prostate cancer. PMID- 29606392 TI - HSIL linked to anal cancer in MSM with HIV. PMID- 29606393 TI - Microbial community dynamics analysis by high-throughput sequencing in chilled beef longissimus steaks packaged under modified atmospheres. AB - The microbial community dynamics were investigated in this study to understand the spoilage of beef steaks packaged in both modified atmosphere packaging (MAP): 80%O2-MAP (80% O2/20% CO2) and CO-MAP (0.4% CO/30% CO2/69.6% N2). Steaks were stored at 2 degrees C for 20 days. Meat physicochemical changes and microbial counts were monitored, and the microbial communities were evaluated by high throughput-sequencing. The microbial diversity for both MAP decreased over time and it was more complex in CO-MAP steaks than that in 80%O2-MAP steaks. B. thermosphacta and Pseudomonas spp. were dominant bacteria of 80%O2-MAP steaks but Pseudomonas spp. gradually outcompeted the former from day 10. Leuconostoc, Lactobacillus, Lactococcus, Vagococcus and Serratia dominated alternately in CO MAP steaks during storage, and Lactococcus eventually became the most common bacteria. Predicted metagenomes indicated a higher microbial amino acid and lipid metabolism level in 80%O2-MAP compared with CO-MAP at day 20, which may contribute to the dramatic physicochemical deterioration of 80%O2-MAP steaks. PMID- 29606395 TI - From the editor: Weighing the advantages of lipid conference and journal. PMID- 29606396 TI - Apolipoprotein B measurement: Need for standardization. PMID- 29606394 TI - Computed tomography-based fat and muscle characteristics are associated with mortality after transcatheter aortic valve replacement. AB - BACKGROUND: Computed tomography (CT)-based fat and muscle measures are associated with outcome in large populations. We tested if muscle and fat characteristics are associated with long-term outcomes after TAVR. METHODS: We included 403 clinical CTs performed prior to TAVR at our center between 2008 and 2016, measuring area (cm2) and density (Hounsfield units, HU) of both psoas muscles (PM), subcutaneous adipose (SAT), and visceral adipose tissue (VAT). Area measures were indexed to height, log-transformed and both area and density were standardized for analysis. We assessed the association of each measure with all cause mortality (adjusted for age, sex, body mass index (BMI), and the Society of Thoracic Surgeons (STS) risk score. RESULTS: Of the 403 individuals (83 +/- 8 years; 52% female), 167 (41.4%) died during a median follow-up of 458 days (interquartile range IQR 297-840). Fat measures were feasible and rapid. Fat area was available in 242 (60%) patients with an adequate field of view. Individuals with the lowest PM area, SAT area or VAT area exhibited the highest hazard of mortality. In addition, greater SAT density was associated with a higher mortality hazard (adjusted HR per standard deviation increase in density = 1.35, 95%CI 1.10-1.67, P = 0.005). CONCLUSION: Rapid CT-based tissue characterization is feasible in patients referred for TAVR. Decreased PM area and increased SAT density are associated with long-term mortality after TAVR, even after accounting for age, sex, BMI, and STS score. Further studies are necessary to interrogate sex-specific relationships between CT tissue metrics and mortality and whether CT measures are incremental to well-established frailty metrics. PMID- 29606397 TI - [Isolation of Aspergillus tritici from internal environment (Chile): Ecological and clinical scope]. AB - Indoor environments provide important protective habitats for humans, who live or work in them most of the time. Many of these environments lack ventilation, which affects the composition of microbial communities, especially that of the fungal community. The aim of this study is to report the isolation of Aspergillus section Candidi from indoor environments of the School of Medicine at Universidad de Valparaiso, Chile, and identification through morpho-physiological and molecular approaches. Their ecological and clinical features were highlighted. An environmental non-volumetric sampling was performed on PDA medium; 2 petri dishes were exposed in 10 different places to select the Aspergillus samples. Subcultures were performed on agar Czapek with yeast extract (CYA), malt extract agar (MEA) and creatin sacarose agar (CREA) media only for the morpho physiological and later the molecular identification of white spore species. Of the 20 samples analyzed, one Aspergillus belonging to Candidi section was isolated. Based on its morphology and molecular features, it was classified as Aspergillustritici Mehrotra & Basu. Its ecology and medical relevance are reviewed and discussed. PMID- 29606398 TI - Excessive neutrophil extracellular trap formation in ANCA-associated vasculitis is independent of ANCA. AB - Neutrophil extracellular traps (NETs) are auto-antigenic strands of extracellular DNA covered with myeloperoxidase (MPO) and proteinase3 (PR3) that can be a source for the formation of anti-neutrophil cytoplasmic autoantibodies (ANCAs). The presence of NETs was recently demonstrated in renal tissue of patients with ANCA associated vasculitis (AAV). NET formation was enhanced in AAV, suggesting that MPO-ANCA could trigger NET formation, supporting a vicious circle placing NETs in the center of AAV pathogenesis. Here we investigated NET formation in 99 patients with AAV by a novel highly sensitive and automated assay. There was a significant excess of ex vivo NET formation in both MPO-ANCA- and PR3-ANCA-positive patients with AAV compared to healthy individuals. Excessive NET formation did not correlate with serum ANCA levels. Likewise, immunoglobulin G depletion had no effect on excessive NET formation in patients with AAV, indicating an ANCA independent process. Next, we explored the relation of excessive NET formation to clinical disease in ten patients with AAV and showed that excessive NET formation was predominantly found during active disease, more so than during remission. Excessive NET formation was found in patients with AAV hospitalized for disease relapse but not during severe infection. Thus, excessive NET formation in AAV is independent of ANCA, and an excess of ex vivo NET formation was related to active clinical disease in patients with AAV and a marker of autoimmunity rather than infection. PMID- 29606399 TI - Intravital phosphorescence lifetime imaging of the renal cortex accurately measures renal hypoxia. AB - Renal tubulointerstitial hypoxia is recognized as a final common pathway of chronic kidney disease and is considered a promising drug target. However, hypoxia in the tubules is not well examined because of limited detection methods. Here, we devised a method to visualize renal tubular oxygen tension with spatial resolution at a cellular level using the cell-penetrating phosphorescent probe, BTPDM1 (an iridium-based cationic lipophilic dye), and confocal phosphorescence lifetime imaging microscopy to precisely assess renal hypoxia. Imaging with BTPDM1 revealed an oxygen gradient between S1 and S2 segments in mouse kidney. We also demonstrated that our microscopy system can detect subtle changes of hypoxemia and reoxygenation, and the acquired phosphorescence lifetime can be converted to partial pressure of oxygen. This new method allows, for the first time, visualization of intravital oxygen gradients at the renal surface with high spatial resolution. Thus, the confocal phosphorescence lifetime imaging microscopy platform, combined with BTPDM1, will promote an accurate understanding of tissue hypoxia, including renal hypoxia. PMID- 29606400 TI - Cell Homing for Pulp Tissue Engineering with Endogenous Dentin Matrix Proteins. AB - INTRODUCTION: Compelling evidence pinpoints that pulp tissue engineering after the transplantation of stem cells is possible. Although intriguing, severe problems regarding clinical feasibility remain. Cell homing has been proposed as a viable alternative in which dentin-derived growth factors in a conducive scaffold may attract resident cells to form pulplike tissue. In this study, an ectopic animal model for in situ dental pulp tissue engineering was developed to evaluate whether pulplike tissue formation in empty root canals after the attraction of stem cells was possible and whether this could be enhanced by dentin-derived growth factors. METHODS: Three types of fibrin (custom-made fibrin, fibrin sealant, and plasma rich in growth factors [PRGF]) as well as a self-assembling peptide were evaluated in vivo in a modified tooth root model using human teeth. Root canal dentin was conditioned with EDTA, tooth roots were filled with growth factor-laden scaffolds, and dental pulp stem cells in collagen were placed at the root tip. Constructs were implanted into immunocompromised mice for 4 weeks and subsequently analyzed histologically. Differential interference contrast and second harmonic generation imaging were performed for selected sections. RESULTS: For custom-made fibrin and fibrin sealant with dentin matrix proteins, migration into the roots and the formation of a pulplike tissue were observed, whereas the peptide-based scaffold appeared less suitable. PRGF supported tissue formation regardless of the addition of dentin matrix proteins. In the test groups with dentin matrix proteins and EDTA conditioning, differentiated odontoblastlike cells extended cellular processes into the dentinal tubules, which coincided with the deposition of the newly formed collagenous dentin matrix. CONCLUSIONS: This new cell homing model provides evidence that fibrin derivatives make applicable scaffolds and that dentin derived proteins induce chemotaxis and pulplike tissue formation. PMID- 29606401 TI - Clinical Outcome of Non-Surgical Root Canal Treatment Using a Single-cone Technique with Endosequence Bioceramic Sealer: A Retrospective Analysis. AB - INTRODUCTION: One of the important steps in root canal treatment is to create a well-sealed root canal system. EndoSequence BC Sealer (BC; Brasseler USA, Savannah, GA) has several beneficial properties and thus has been incorporated into the practitioner's armamentarium. No studies to date have evaluated the clinical success of using BC. The purpose of this study was to evaluate the outcome of nonsurgical root canal treatment using a single-cone and BC technique and to identify factors associated with success or failure. METHODS: This retrospective cohort study included patients treated in a private practice environment between 2009 and 2015. All cases, including initial and retreatment, were obturated with BC using a single-cone technique with a minimum of a 1-year recall. Patient and treatment factors were analyzed to determine their significance as prognostic factors. Outcome was evaluated based on clinical and radiographic findings at recall. Teeth were classified as healed, healing (success), or not healed (failure). Statistical analysis of potential prognostic factors was performed using the chi-square test (alpha = 0.05). RESULTS: Three hundred seven teeth were included in the analysis, and the average follow-up time was 30.1 months. The overall success rate was 90.9%. Lesions <5 mm in diameter had a significantly higher success rate than lesions >5 mm in diameter. Sealer extrusion was observed in 47.4% of the cases. The presence of sealer extrusion did not have any significant effect on the treatment outcome. CONCLUSIONS: BC used with a single-cone technique is a viable option for obturation. PMID- 29606402 TI - 2018 ACC/AHA Clinical Performance and Quality Measures for Cardiac Rehabilitation: A Report of the American College of Cardiology/American Heart Association Task Force on Performance Measures. PMID- 29606403 TI - Tackling the tobacco epidemic in the Nordic countries and lower cancer incidence by 1/5 in a 30-year period-The effect of envisaged scenarios changing smoking prevalence. AB - BACKGROUND: Tobacco smoking is a leading cause of cancer and the most preventable cause of cancer worldwide. The aim of this study was to quantify the proportion of the cancer burden in the Nordic countries linked to tobacco smoking and estimate the potential for cancer prevention by changes in smoking prevalence. METHODS: The Prevent macro-simulation model was used, estimating the future number of cancer cases in the Nordic countries over a 30-year period (2016-2045), for 13 cancer sites, under different scenarios of changing smoking prevalence, and compared to the projected number of cases if constant prevalence prevailed. RESULTS: A total of 430,000 cancer cases, of the 2.2 million expected for the 13 studied cancer sites, could be avoided in the Nordic countries over the 30-year period if smoking was eliminated from 2016 onwards. If prevalence of smoking is reduced to 5% by year 2030 and to 2% by 2040, 230,000 cancer cases could be avoided. The largest proportion of cancers can be avoided in Denmark, where smoking prevalence is the highest, and similar to the prevalence in many European countries. CONCLUSION: A large amount of cancers could be avoided in the Nordic countries if smoking prevalence was reduced. The results from this study can be used to understand the potential impact and significance of primary prevention programmes targeted towards reducing the prevalence of tobacco smoking in the Nordic countries. PMID- 29606404 TI - The utility of abnormal initial arterial blood gas values in determining clinical futility of trauma cases with severe hemorrhage. AB - BACKGROUND: Patients who experience trauma with severe hemorrhage requiring immediate surgery and massive blood transfusion often present with markedly abnormal laboratory values. These cases require valuable resources; however, little is known regarding prognostic factors that correlate with mortality. The purpose of this study was to determine whether abnormal initial arterial blood gas (ABG) pH, a marker for severe blood loss, could serve as a prognostic indicator for these patients. METHODS: An IRB approved retrospective study was performed at LAC+USC Medical Center Level I Trauma Center. Data was collected from trauma patients with severe hemorrhage admitted between June 2015 and April 2016 who were immediately admitted to the OR following entry into the ER. Baseline variables of age, sex and mechanism of trauma were collected. The pH readings from the initial three ABG data were obtained, and mortality was determined for each patient. RESULTS: We identified 247 patients, 84.2% of which were male. Ages ranged from 1 to 91years (average=38.4). Overall mortality was 13.8%. The average initial pH value for non-survivors (7.10+/-0.13) was significantly lower than for survivors (7.34+/-0.07) [p<0.001]. Among patients whose initial three ABG pH values averaged <=7.15, the survival rate was 8.7%. Ten patients had any single recorded pH value<=6.91. The mortality rate among these patients was 90%. CONCLUSIONS: Consideration should be given to initial pH values when resuscitating "red blanket" patients. However, the pH values alone cannot reliably be used to determine clinical futility in individual patients in the early period after injury. PMID- 29606405 TI - Cervical fasciitis and mediastinal abscess in a young healthy female patient undetected on X-ray or ultrasound. PMID- 29606406 TI - Management of spontaneous soft-tissue hemorrhage secondary to anticoagulant therapy: A cohort study. AB - STUDY OBJECTIVE: The optimal management of patients receiving heparin, warfarin or direct anti-coagulant therapy who experience spontaneous, severe, life threatening soft-tissue hemorrhage (SSTH) is unclear. The purpose of this study is to investigate efficacy and safety of the interventional protocol implemented in our department. METHODS: In this retrospective cohort study, we analyzed data from 80 consecutive patients with SSTH secondary to anticoagulation therapy diagnosed by the appropriate computed tomography scan. All patients received a structured clinical pathway, including aggressive resuscitation, reversal of coagulopathy when indicated, Interventional Radiology procedures by transcatheter embolization (TE), clinical observation and repeated laboratory controls. RESULTS: We enrolled 80 patients from 2013 to 2017. Angiography was performed in 60 patients (75%). It revealed the bleeding site in 46 cases, and a TE was performed in all. The rates of technical success of TE, primary clinical success and bleeding control were 98% (45/46), 91% (73/80) and 89% (71/80) respectively. In 5 patients (6%) the control of the bleeding was obtained with a second TE. Short-term and 30-day mortality was 5% (4 patients) and 11% (9 patients), respectively. No adverse events were observed. CONCLUSION: A structured clinical pathway, including TE seems to be an effective and safe method to manage the patients with SSTH due to anticoagulant treatment. PMID- 29606407 TI - Epidemiology of dermatophytoses in 31 municipalities of the province of Buenos Aires, Argentina: A 6-year study. AB - BACKGROUND: No reliable data are available in the province of Buenos Aires regarding the frequency of dermatophytoses and other fungal diseases. The distribution of the clinical forms and the species involved are also unknown. AIMS: To present the data collected by the laboratories participating in the Mycology Network of the province of Buenos Aires (MNPBA) from a retrospective epidemiological survey on dermatophytoses. METHODS: A descriptive and exploratory analysis was performed on the cases of dermatophytoses gathered between 2002 and 2007 by the Mycology Network of the province of Buenos Aires. RESULTS: Of the 3966 dermatophytosis cases reported by 41 laboratories in 31 municipalities, more than a half occurred in three highly populated urban municipalities. The male:female ratio was 1:1.5. The most frequent clinical form was tinea unguium, diagnosed in 904 cases (51.83%), followed by tinea capitis (19.32%), tinea corporis (15.19%), tinea pedis (6.77%), tinea cruris (3.73%), and tinea manuum (2.18%). The species involved was identified in 1368 (33.49%) cases. Trichophyton rubrum was the most common species, with a frequency of 42.03%. An association was found between urban municipalities and T. rubrum or the Trichophyton mentagrophytes complex. CONCLUSIONS: Results from the MNPBA survey provide valuable information that should enable further interventions to be designed in order to prevent and control the disease. PMID- 29606409 TI - A 10-year retrospective review of perioperative mortality in pediatric general surgery at Ile-Ife Hospital, Nigeria. AB - BACKGROUND/PURPOSE: The analysis of perioperative mortality as well as surgery- and anesthesia-related death in pediatric patients may serve as a potential tool to improve outcome. The aim of this study is to report the 24-h and 30-day overall, and surgery and anesthesia-related, mortality in a tertiary hospital. METHODS: This is a retrospective review of perioperative mortality in children <=15years at a general pediatric surgery unit. All pediatric general surgery cases operated under general anesthesia between January 2007 and December 2016 were included in the study and data analyzed. RESULTS: A total of 4108 surgical procedures were performed in 4040 patients. The age was 1day to 15years with a median age of 2years. The all cause 24-h mortality was 34 per 10,000 procedures and the all cause 30-day mortality was 156 per 10,000 procedures. Septicemia was the most common cause of death. The determinants of mortality were neonatal age group (Adjusted Odd Ratio (AOR)=0.033, 95% CI=0.015-0.070, p=0.001), emergency surgery (AOR=90.91, 95% CI=27.78-333.33, p=0.001), higher ASA status (AOR=0.014, 95% CI=0.005-0.041, p=0.001) and multiple operative procedures (AOR=38.46, 95% CI=10.64-142.85, p=0.001). CONCLUSIONS: Neonatal age group, children with poorer ASA status, emergency and multiple surgeries were predictors of perioperative mortality. LEVEL OF EVIDENCE: Retrospective study. PMID- 29606408 TI - Racial and Ethnic Disparities and Bias in the Evaluation and Reporting of Abusive Head Trauma. AB - OBJECTIVE: To characterize racial and ethnic disparities in the evaluation and reporting of suspected abusive head trauma (AHT) across the 18 participating sites of the Pediatric Brain Injury Research Network (PediBIRN). We hypothesized that such disparities would be confirmed at multiple sites and occur more frequently in patients with a lower risk for AHT. STUDY DESIGN: Aggregate and site-specific analysis of the cross-sectional PediBIRN dataset, comparing AHT evaluation and reporting frequencies in subpopulations of white/non-Hispanic and minority race/ethnicity patients with lower vs higher risk for AHT. RESULTS: In the PediBIRN study sample of 500 young, acutely head-injured patients hospitalized for intensive care, minority race/ethnicity patients (n = 229) were more frequently evaluated (P < .001; aOR, 2.2) and reported (P = .001; aOR, 1.9) for suspected AHT than white/non-Hispanic patients (n = 271). These disparities occurred almost exclusively in lower risk patients, including those ultimately categorized as non-AHT (P = .001 [aOR, 2.4] and P = .003 [aOR, 2.1]) or with an estimated AHT probability of <=25% (P <.001 [aOR, 4.1] and P <.001 [aOR, 2.8]). Similar site-specific analyses revealed that these results reflected more extreme disparities at only 2 of 18 sites, and were not explained by local confounders. CONCLUSION: Significant race/ethnicity-based disparities in AHT evaluation and reporting were observed at only 2 of 18 sites and occurred almost exclusively in lower risk patients. In the absence of local confounders, these disparities likely represent the impact of local physicians' implicit bias. PMID- 29606410 TI - Disparities in pediatric gonadal torsion: Does gender, race and insurance status affect outcomes? AB - PURPOSE: Ovarian and testicular torsions are emergencies requiring prompt surgical treatment to preserve gonadal function. However, diagnosis in females is often delayed owing to nonspecific symptoms. We sought to assess disparities in management and outcomes between males and females with torsion. METHODS: The National Inpatient Sample was queried for pediatric patients with "emergent", "urgent", or "trauma center" admission and ICD-9 codes for ovarian torsion and testicular torsion. Demographic data, operative procedure, gonadal loss, length of stay (LOS), total charges (TC), and mortality were recorded. RESULTS: There were 2254 unweighted encounters. The average age was 11.56+/-5.30years for males and 12.55+/-3.72years for females (p<0.001). Among males, 90% underwent surgery (p<0.001), of which 40% required orchiectomy. Conversely, 73% of females had surgery (p<0.001), of which 78% had oophorectomy. Subsequent analysis with only patients who underwent surgery showed that insurance status (p=0.012), race (p<0.001), and U.S. region (p<0.001) were significantly different between males and females. Gender specific analyses showed that hospital control, hospital location/teaching status, and treatment year were also significant. As such, these six factors in addition to age and gender were used for propensity score matching (PSM). PSM produced two gender cohorts of 755 encounters each. Females had longer LOS (2.44+/-1.84days vs. 1.28+/-2.27days for males, p<0.001) and had higher TC ($20,058.44+/-13,420.82) compared to males ($12,386.58+/-12,793.34), p<0.001. Logistic regression revealed that males (OR 0.163 [0.130-0.206]) and older patients (age OR 0.924 [0.903-0.946]) were less likely to undergo gonadal loss. Compared to those with private insurance, those with Medicare/Medicaid were more likely to have gonadal loss (1.401 [1.101-1.783]). CONCLUSION: Disparities exist in the management of torsion based on gender. Overall, females had higher charges, had longer hospitalization, and were more likely to have gonadal loss despite current data supporting gonadal preservation for nearly all cases of ovarian torsion. CLINICAL STUDY: Level III Evidence. PMID- 29606411 TI - Nonoperative management of pectus excavatum with vacuum bell therapy: A single center study. AB - PURPOSE: The purpose of this study was to determine variables predictive of an excellent correction using vacuum bell therapy for nonoperative treatment of pectus excavatum. METHODS: A single institution, retrospective evaluation (IRB 15 01-WC-0024) of variables associated with an excellent outcome in pectus excavatum patients treated with vacuum bell therapy was performed. An excellent correction was defined as a chest wall depth equal to the mean depth of a reference group of 30 male children without pectus excavatum. RESULTS: Over 4years (11/2012-11/2016) there were 180 patients enrolled with 115 available for analysis in the treatment group. The reference group had a mean chest wall depth of 0.51cm. An excellent correction (depth<=0.51cm) was achieved in 23 (20%) patients. Patient characteristics predictive of an excellent outcome included initial age<=11years (OR=3.3,p=.013), initial chest wall depth<=1.5cm (OR=4.6,p=.003), and chest wall flexibility (OR=14.8,p<.001). Patients that used the vacuum bell over 12 consecutive months were more likely to achieve an excellent correction (OR=3.1,p=.030). Follow-up was 4months to 4years (median 12months). CONCLUSION: Nonoperative management of pectus excavatum with vacuum bell therapy results in an excellent correction in a small percentage of patients. Variables predictive of an excellent outcome include age<=11years, chest wall depth<=1.5cm, chest wall flexibility, and vacuum bell use over 12 consecutive months. TYPE OF STUDY: Retrospective chart review. LEVEL OF EVIDENCE: Level III treatment study. PMID- 29606412 TI - Ensemble Docking in Drug Discovery. AB - Ensemble docking corresponds to the generation of an "ensemble" of drug target conformations in computational structure-based drug discovery, often obtained by using molecular dynamics simulation, that is used in docking candidate ligands. This approach is now well established in the field of early-stage drug discovery. This review gives a historical account of the development of ensemble docking and discusses some pertinent methodological advances in conformational sampling. PMID- 29606413 TI - Fellowship training in extracorporeal life support: Characterization and educational needs assessment. AB - PURPOSE: Adult Extracorporeal Life Support (ECLS) use is rapidly increasing. The structure of fellowship ECLS education is unknown. We sought to define current ECLS education and identify curricular needs. MATERIALS AND METHODS: An anonymous survey with Likert, binary and free response questions was sent to Critical Care Program Directors (CCPDs). RESULTS: A total of 103 CCPDs responded, a response rate of 31. ECLS training was provided by 64% (66/103) of fellowships. Importantly, 50% (52/103) of CCPDs agreed or strongly agreed that fellows should be competent in ECLS and 70% (72/103) agreed or strongly agreed that ECLS will be an important part of critical care in the next 10years. Only 28% (29/103) and 37% (38/103) of CCPDs agreed or strongly agreed their fellows could independently manage veno-arterial or veno-venous ECLS, respectively. Formal ECLS education was 5h or less in 85% (88/103) of programs. Desired curricular improvements were: simulation 50% (51/103), patient volume 47% (48/103), and didactics 44% (45/103). CONCLUSIONS: CCPDs identified ECLS as a critical care skill, but believe that a minority of fellows are prepared for independent practice. Simulation, formal didactics and clinical volume are key needs. These data will guide the development of ECLS curriculum. PMID- 29606414 TI - Poststreptococcal reactive arthritis in Japan. AB - Reactive arthritis after Group A streptococcal infection (poststreptococcal reactive arthritis: PSRA) that does not meet the Jones criteria for acute rheumatic fever (ARF) has been reported as a new entity for over a decade. In Japan there are few reports of PSRA. We encountered four children with arthritis accompanied with Group A streptococcal infection in our department. We investigated our cases and the recent Japanese literature. Japanese cases of PSRA are frequently accompanied with uveitis and erythema nodosum, and tonsillectomy resolved their symptoms in some cases. There were overlap cases between ARF, juvenile idiopathic arthritis, and PSRA. PMID- 29606415 TI - Effect of alirocumab on coronary atheroma volume in Japanese patients with acute coronary syndromes and hypercholesterolemia not adequately controlled with statins: ODYSSEY J-IVUS rationale and design. AB - BACKGROUND: Serial intravascular ultrasound (IVUS) imaging can be used to evaluate the effect of cholesterol-lowering on coronary atheroma progression and plaque volume, with evidence of potential incremental effects with more aggressive lipid-lowering treatments. Alirocumab is a highly specific, fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9). This study will investigate the effect of alirocumab on coronary artery plaque volume in Japanese patients with a recent acute coronary syndrome (ACS) and hypercholesterolemia while on stable statin therapy. METHODS: ODYSSEY J-IVUS is a phase IV, open-label, randomized, blinded IVUS analysis, parallel-group, multicenter study in Japanese adults recently hospitalized for an ACS and who have elevated low-density lipoprotein cholesterol (LDL-C) values [>=100mg/dL (2.6mmol/L)] at ACS diagnosis and suboptimal LDL-C control on stable statin therapy. Patients will be randomized (1:1) to receive alirocumab or standard-of care (SOC). The alirocumab arm will receive alirocumab 75mg every 2 weeks (Q2W) added to statin therapy (atorvastatin >=10mg/day or rosuvastatin >=5mg/day), with a dose increase to 150mg Q2W in patients whose LDL-C value remains >=100mg/dL at week 12. The SOC arm will receive atorvastatin >=10mg/day or rosuvastatin >=5mg/day, with dose adjustment to achieve LDL-C <100mg/dL. Post-treatment IVUS imaging will be done at week 36+/-2. The primary objective is to compare the effect of alirocumab versus SOC on coronary atheroma progression (percent change in normalized total atheroma volume) after 9 months of treatment. CONCLUSION: ODYSSEY J-IVUS will provide insights into the effect of alirocumab on coronary atherosclerotic plaque volume in patients with a recent ACS and hypercholesterolemia while on stable statin therapy. ClinicalTrials.gov number: NCT02984982. PMID- 29606417 TI - Identification of an Intra- and Inter-specific Tear Protein Signal in Rodents. AB - Rodents use the vomeronasal olfactory system to acquire both inter- and intra specific information from the external environment and take appropriate actions. For example, urinary proteins from predator species elicit avoidance in mice, while those from male mice attract female mice. In addition to urinary proteins, recent studies have highlighted the importance of lacrimal proteins for intra specific communications in mice. However, whether the tear fluid of other species also mediates social signals remains unknown. Here, we show that a lacrimal protein in rats (predators of mice), called cystatin-related protein 1 (ratCRP1), activates the vomeronasal system of mice. This protein is specifically produced by adult male rats in a steroid hormone-dependent manner, activates the vomeronasal system of female rats, and enhances stopping behavior. When detected by mice, ratCRP1 activates the medial hypothalamic defensive circuit, resulting in decreased locomotion coupled with lowered body temperature and heart rate. Notably, ratCRP1 is recognized by multiple murine type 2 vomeronasal receptors, including Vmn2r28. CRISPR/Cas9-mediated deletion of vmn2r28 impaired both ratCRP1 induced neural activation of the hypothalamic center and decrease of locomotor activity in mice. Taken together, these data reveal the neural and molecular basis by which a tear fluid compound in rats affects the behavior of mice. Furthermore, our study reveals a case in which a single compound that mediates an intra-specific signal in a predator species also functions as an inter-specific signal in the prey species. PMID- 29606416 TI - Mechanisms Underlying Decision-Making as Revealed by Deep-Brain Stimulation in Patients with Parkinson's Disease. AB - To optimally balance opposing demands of speed and accuracy during decision making, we must flexibly adapt how much evidence we require before making a choice. Such adjustments in decision thresholds have been linked to the subthalamic nucleus (STN), and therapeutic STN deep-brain stimulation (DBS) has been shown to interfere with this function. Here, we performed continuous as well as closed-loop DBS of the STN while Parkinson's disease patients performed a perceptual decision-making task. Closed-loop STN DBS allowed temporally patterned STN stimulation and simultaneous recordings of STN activity. This revealed that DBS only affected patients' ability to adjust decision thresholds if applied in a specific temporally confined time window during deliberation. Only stimulation in that window diminished the normal slowing of response times that occurred on difficult trials when DBS was turned off. Furthermore, DBS eliminated a relative, time-specific increase in STN beta oscillations and compromised its functional relationship with trial-by-trial adjustments in decision thresholds. Together, these results provide causal evidence that the STN is involved in adjusting decision thresholds in distinct, time-limited processing windows during deliberation. PMID- 29606418 TI - Ventral Hippocampal CA1 and CA3 Differentially Mediate Learned Approach-Avoidance Conflict Processing. AB - Approach-avoidance conflict arises when an animal encounters a stimulus that is associated simultaneously with positive and negative valences [1]. The effective resolution of approach-avoidance conflict is critical for survival and is believed to go awry in a number of mental disorders, such as anxiety and addiction. An accumulation of evidence from both rodents and humans suggests that the ventral hippocampus (anterior in humans) plays a key role in approach avoidance conflict processing [2-8], with one influential model proposing that this structure modulates behavioral inhibition in the face of conflicting goals by increasing the influence of negative valences [9]. Very little is known, however, about the contributions of specific hippocampal subregions to this process-an important issue given the functional and anatomical heterogeneity of this structure. Using a non-spatial cue-based paradigm in rats, we found that transient pharmacological inactivation of ventral CA1 produced an avoidance of a conflict cue imbued with both learned positive and learned negative outcomes, whereas inactivation of the ventral CA3 resulted in the opposite pattern of behavior, with significant preference for the conflict cue. In contrast, dorsal CA1- and CA3-inactivated rats showed no change in conflict behavior, and furthermore, additional behavioral tasks confirmed that the observed pattern of approach-avoidance findings could not be explained by other factors, such as differential alterations in novelty detection or locomotor activity. Our data demonstrate that ventral CA1 and CA3 subserve distinct and opposing roles in approach-avoidance conflict processing and provide important insight into the functions and circuitry of the ventral hippocampus. PMID- 29606419 TI - A Dense Starburst Plexus Is Critical for Generating Direction Selectivity. AB - Starburst amacrine cell (SAC) morphology is considered central to retinal direction selectivity. In Sema6A-/- mice, SAC dendritic arbors are smaller and no longer radially symmetric, leading to a reduction in SAC dendritic plexus density. Sema6A-/- mice also have a dramatic reduction in the directional tuning of retinal direction-selective ganglion cells (DSGCs). Here we show that the loss of DSGC tuning in Sema6A-/- mice is due to reduced null direction inhibition, even though strong asymmetric SAC-DSGC connectivity and SAC dendritic direction selectivity are maintained. Hence, the reduced coverage factor of SAC dendrites leads specifically to a loss of null direction inhibition. Moreover, SAC dendrites are no longer strictly tuned to centrifugal motion, indicating that SAC morphology is critical in coordinating synaptic connectivity and dendritic integration to generate direction selectivity. PMID- 29606420 TI - Molecular Evolution at a Meiosis Gene Mediates Species Differences in the Rate and Patterning of Recombination. AB - Crossing over between homologous chromosomes during meiosis repairs programmed DNA double-strand breaks, ensures proper segregation at meiosis I [1], shapes the genomic distribution of nucleotide variability in populations, and enhances the efficacy of natural selection among genetically linked sites [2]. Between closely related Drosophila species, large differences exist in the rate and chromosomal distribution of crossing over. Little, however, is known about the molecular genetic changes or population genetic forces that mediate evolved differences in recombination between species [3, 4]. Here, we show that a meiosis gene with a history of rapid evolution acts as a trans-acting modifier of species differences in crossing over. In transgenic flies, the dicistronic gene, mei-217/mei-218, recapitulates a large part of the species differences in the rate and chromosomal distribution of crossing over. These phenotypic differences appear to result from changes in protein sequence not gene expression. Our population genetics analyses show that the protein-coding sequence of mei-218, but not mei-217, has a history of recurrent positive natural selection. By modulating the intensity of centromeric and telomeric suppression of crossing over, evolution at mei-217/-218 has incidentally shaped gross differences in the chromosomal distribution of nucleotide variability between species. We speculate that recurrent bouts of adaptive evolution at mei-217/-218 might reflect a history of coevolution with selfish genetic elements. PMID- 29606421 TI - A cAMP/PKA/Kinesin-1 Axis Promotes the Axonal Transport of Mitochondria in Aging Drosophila Neurons. AB - Mitochondria play fundamental roles within cells, including energy provision, calcium homeostasis, and the regulation of apoptosis. The transport of mitochondria by microtubule-based motors is critical for neuronal structure and function. This process allows local requirements for mitochondrial functions to be met and also facilitates recycling of these organelles [1, 2]. An age-related reduction in mitochondrial transport has been observed in neurons of mammalian and non-mammalian organisms [3-6], and has been proposed to contribute to the broader decline in neuronal function that occurs during aging [3, 5-7]. However, the factors that influence mitochondrial transport in aging neurons are poorly understood. Here we provide evidence using the tractable Drosophila wing nerve system that the cyclic AMP/protein kinase A (cAMP/PKA) pathway promotes the axonal transport of mitochondria in adult neurons. The level of the catalytic subunit of PKA decreases during aging, and acute activation of the cAMP/PKA pathway in aged flies strongly stimulates mitochondrial motility. Thus, the age related impairment of transport is reversible. The expression of many genes is increased by PKA activation in aged flies. However, our results indicate that elevated mitochondrial transport is due in part to upregulation of the heavy chain of the kinesin-1 motor, the level of which declines during aging. Our study identifies evolutionarily conserved factors that can strongly influence mitochondrial motility in aging neurons. PMID- 29606422 TI - Investigating thermal performance of different chairs at the user-seat interface by a temperature sensor array system while participants perform office work. PMID- 29606423 TI - Integrating calcium chloride treatment with polypropylene packaging improved the shelf life and retained the quality profile of minimally processed cabbage. PMID- 29606424 TI - Lupine allergen detecting capability and cross-reactivity of related legumes by ELISA. AB - Lupine belongs to the genus Lupinus and includes three species commonly consumed by humans. The Lupinus genus is closely related to other legumes, such as peanuts, soya, chickpeas, peas, lentils and beans. However, the consumption of lupine (and related legumes) can cause severe allergenic reactions. Therefore, reliable analytical detection methods are required for the analysis of food samples. In this study three commercially available ELISA test kits were analyzed for the detection capability of three common lupine species, as well as cross reactivity to related legumes. All three ELISA test kits could detect the lupine species, though with different sensitivities. Cross-reactivity varied for the ELISA test kits and all showed some cross-reactivity to related legume samples analyzed. PMID- 29606425 TI - Physicochemical and nutritional characteristics of banana flour during ripening. AB - Banana flour has been recognized as functional ingredient, owing to its healthy nutritional pattern. Nevertheless, unripe and ripe banana flours show different characteristics and scarce information is available about changes undergone during banana ripening. This study evaluates the changes on physiochemical (chemical composition, hydration properties, rheological properties and structural characteristic) and nutritional (resistant starch content, phenolic compound and antioxidant activity) characteristics of banana flour at the initial four ripening stages. The significant increase in protein content and decrease in carbohydrate and apparent amylose content, besides the reduction in pasting properties, between 2nd and 3rd stages suggested a climacteric peak during ripening. Between those stages, a significant decrease in total and resistant starch was produced together with an increase in total phenolic content and antioxidant activity. Therefore, the knowledge of the physicochemical and nutritional characteristics of banana flour at each ripening stage allows better selection depending on the industrial application. PMID- 29606426 TI - Action of trypsin on structural changes of collagen fibres from sea cucumber (Stichopus japonicus). AB - Trypsin, a representative serine proteinase, was used to hydrolyse the collagen fibres from sea cucumber (Stichopus japonicus) to highlight the role of serine proteinase in the autolysis of sea cucumber. Partial disaggregation of collagen fibres into collagen fibrils upon trypsin treatment occurred. The trypsin treatment also caused a time-dependent release of water-soluble glycosaminoglycans and proteins. Therefore, the degradation of the proteoglycan bridges between collagen fibrils might account for the disaggregation of collagen fibrils. For trypsin-treated collagen fibres (72 h), the collagen fibrils still kept their structural integrity and showed characteristic D-banding pattern, and the dissolution rate of hydroxyproline was just 0.21%. Meanwhile, Fourier transform infrared analysis showed the collagen within trypsin-treated collagen fibres (72 h) still retaining their triple-helical conformation. These results suggested that serine proteinase participated in the autolysis of S. japonicus body wall by damaging the proteoglycan bridges between collagen fibrils and disintegrating the latter. PMID- 29606427 TI - alpha- and beta-casein aggregation induced by riboflavin-sensitized photo oxidation occurs via di-tyrosine cross-links and is oxygen concentration dependent. AB - Type I photo-oxidation generates Trp-(TrpN) and Tyr-derived (TyrO) radicals in proteins which can dimerize producing cross-links, or alternatively react with O2. It was therefore hypothesized that the O2 concentration may have a significant effect on dye-photosensitized reactions. We studied photo-oxidation of alpha- and beta-caseins induced by riboflavin (RF), a photosensitizing vitamin present in milk, under aerobic and anaerobic conditions. Triplet-state RF induced oxidative modifications on both caseins, and significant levels of cross-links. The extent of damage, and the yield of cross-links versus oxidized products, was dependent on the O2 concentration. In the absence of O2, the overall extent of damage was decreased, but the yield of cross-linked products was significantly elevated. These cross-links are consistent with inter- and intra-molecular di-Tyr or di-Trp bridges. Alternative cross-links were detected in the presence of O2, consistent with pathways involving the reaction of protein radicals with O2 or O2 . PMID- 29606428 TI - Analysis of the oligosaccharide composition in wort samples by capillary electrophoresis with laser induced fluorescence detection. AB - Determination of the oligosaccharide composition in different wort samples is important to monitor their change during the brewing process with different yeast types. In our work, the concentration of fermentable and non-fermentable sugars were monitored by capillary electrophoresis to observe the effect of two different types of yeasts, Saccharomyces pastorianus and Saccharomycodes ludwigii. The former first ferments the monosaccharides, then the higher sugar oligomers, such as maltose and maltotriose, to ethanol, while the latter fully ferments the monosaccharides, but ferments only very low percentages of the oligosaccharides. Therefore, breweries use Saccharomycodes ludwigii to produce beers with low alcohol content. The CE-LIF traces of the wort samples represented unique oligosaccharide signatures. PMID- 29606429 TI - Simultaneous determination of four sesame lignans and conversion in Monascus aged vinegar using HPLC method. AB - A simple, accurate and specific high-performance liquid chromatography (HPLC) method has been developed and validated for simultaneous determination of sesamol, sesamin, asarinin and sesamolin in Monascus aged vinegar. The effects of acid hydrolysis and four heating treatments on the components content in Monascus aged vinegar were discussed. The results showed that the isomerisation of sesamin to asarinin, and decomposition of sesamolin to sesamol significantly increased, regardless of heating or acid hydrolysis. Thermal processes and acid hydrolysis increased the content of sesamol and asarinin, respectively, but severe thermal processes resulted in the loss of total sesame lignans. Sesamol and asarinin reached the highest (2.720 +/- 0.202 MUg/mL and 2.064 +/- 0.075 MUg/mL) for autoclaving (125 degrees C, 15 min) and acid hydrolysis (25 degrees C, 15 min, nature pH), respectively. Therefore, autoclaving and acid hydrolysis were considered as the optimal way to obtain higher content of sesamol and asarinin. PMID- 29606430 TI - Multiresidue determination of pesticides in tea by liquid chromatography-high resolution mass spectrometry: Comparison between Orbitrap and time-of-flight mass analyzers. AB - Liquid chromatography (LC)-Orbitrap mass spectrometry (MS) and LC-time-of-flight (TOF) MS operating in full scan mode at a mass resolution of 140,000 (m/z 200) and 30,000 (m/z 556), respectively, were compared for quantification of pesticide residues in tea. Both methods were validated for 146 pesticides at spike levels of 0.1 and 0.01 mg/kg and compared in terms of recovery, intra- and inter-day precisions, selectivity, linearity, and matrix effect. The results of both analyses were comparable, and recovery and intra- and inter-day precisions were within the acceptable ranges for most pesticides. LC-Orbitrap MS was slightly superior to LC-TOF MS in terms of sensitivity and selectivity due to its higher resolution. However, even using high-resolution LC-Orbitrap MS with a narrow mass window of +/-3 ppm, interference by coeluting matrix components was observed, indicating that full scan data are insufficient for unequivocal identification, and additional information such as fragment ions is necessary. PMID- 29606431 TI - Optimization of ionic liquids-based microwave-assisted hydrolysis of puerarin and daidzein derivatives from Radix Puerariae Lobatae extract. AB - Ionic liquids-based microwave-assisted hydrolysis was successfully applied for hydrolysis of puerarin and daidzein derivatives from Radix Puerariae Lobatae extract. The ionic liquids with different cations and anions have been investigated, and [Omim]HSO4 was selected as catalyst. In addition, the hydrolysis parameters, including catalyst quantity, ionic liquids concentration, microwave power and microwave time, were optimized by Response Surface Methodology. The optimal conditions were as follows: 0.82 mol/L [Omim]HSO4; catalyst quantity, 1.42 mL; microwave time, 7 min; microwave power, 400 W. Under those condition the average hydrolysis efficiency of puerarin and daidzein derivatives was 57.93 +/- 3.08%. Compared with the traditional acidic catalysts, the [Omim]HSO4 exhibited higher efficiency, which demonstrates that ionic liquids based microwave-assisted hydrolysis was a rapid, efficient, and simple hydrolysis technique. PMID- 29606432 TI - Improvement in the stability of betanin by liposomal nanocarriers: Its application in gummy candy as a food model. AB - Betanin is a red food pigment with health beneficial effects. Despite interest in the use of betanin, low bioaccessibility and oxidation limit its application. To overcome these restrictions, the betanin was loaded in liposomal nanocarriers with the encapsulation efficiency of 80.35 +/- 1%. To assess the efficiency of these nanocarriers, gummy candy was selected as a food model and its nutritional properties such as betanin stability and antioxidant activity were probed. The results showed that the betanin content and antioxidant activity of samples containing betanin-nanoliposomes were at least twice to those of samples containing free betanin. The tests show no differences in the sensory parameters of panelists for gummy candies fortified by betanin-loaded nanoliposomes compared to those fortified by betanin alone. As a result, the liposomal nanoparticles may be introduced as a suitable platform to stabilize and increase the bioavailability of betanin for applications in nutraceutical and medical fields. PMID- 29606433 TI - Changes in phenolic acid composition and associated enzyme activity in shoot and kernel fractions of brown rice during germination. AB - Phenolic acid composition and activities of two associated enzymes such as PAL (phenylalanine ammonia-lyase) and CW-PRX (cell wall peroxidase) in brown rice (BR) were examined during a germination for 4 days. Shoot and kernel fractions of the germinated brown rice were separated, and soluble extracts and insoluble residues of the fractions were analyzed. In the shoot fraction, the PAL activity and soluble phenolic acid content reached to its maximum on the second day of atmospheric germination, and decreased thereafter. In contrast, the amount of insoluble phenolic acids and CW-PRX activity continuously increased during the germination for 4 days. Comparing the shoot fractions, the kernel fraction exhibited lower activities of PAL and CW-PRX, but showed an increase in total phenolic acid content during germination. Germination raised the antioxidant activity of brown rice, especially in the shoot fraction which contained more phenolic acids than the kernel fraction. PMID- 29606434 TI - Phytochemical profiling of the ripening of Chinese mango (Mangifera indica L.) cultivars by real-time monitoring using UPLC-ESI-QTOF-MS and its potential benefits as prebiotic ingredients. AB - Maturity has important effects on the phytochemical and biochemical characteristics of fruits. It affects the quality, nutritional value, harvest time and commercial operations. In this study, Keitt, Sensation and Xiangya mango cultivars in four distinct stages from southwest China were evaluated for their phytochemical profiling and antioxidant activities in real time. Furthermore, the biochemical characteristics indices polyphenol oxidase (PPO), peroxidase (POD), superoxide dismutase (SOD) and pectin methylesterase (PME) activities were determined. Antioxidant compounds such as vitamin C, total phenolic, total flavonoid and total carotenoid content were also analysed. A total of 34 phenolic compounds were identified and quantitatively monitored by UPLC-ESI-QTOF-MS. Consecutive degradation of phenolic acids and its derivatives were observed upon maturity. We found that in addition to carotenoids, phenolic acids could also be used as a measurement index of maturity in mango. Mango juices and its phenolic extracts may be used as potential prebiotics for modulating probiotic proliferation. PMID- 29606435 TI - Vitamin D-biofortified beef: A comparison of cholecalciferol with synthetic versus UVB-mushroom-derived ergosterol as feed source. AB - This study investigates dietary fortification of heifer feeds with cholecalciferol and ergocalciferol sources and effects on beef total vitamin D activity, vitamer, respective 25-hydroxymetabolite contents, and meat quality. Thirty heifers were allocated to one of three dietary treatments [(1) basal diet + 4000 IU of vitamin D3 (Vit D3); (2) basal diet + 4000 IU of vitamin D2 (Vit D2); and (3) basal diet + 4000 IU of vitamin D2-enriched mushrooms (Mushroom D2)] for a 30 day pre-slaughter period. Supplementation of heifer diets with Vit D3 yielded higher (p < 0.001) Longissimus thoracis (LT) total vitamin D activity (by 38-56%; p < 0.05) and serum 25-OH-D concentration (by 20-36%; p < 0.05), compared to that from Vit D2 and Mushroom D2 supplemented animals. Irrespective of vitamin D source, carcass characteristics, sensory and meat quality parameter were unaffected (p > 0.05) by the dietary treatments. In conclusion, vitamin D3 biofortification of cattle diets is the most efficacious way to enhance total beef vitamin D activity. PMID- 29606436 TI - Microencapsulation of lutein by spray-drying: Characterization and stability analyses to promote its use as a functional ingredient. AB - Lutein, a xanthophyll, is associated to decreased risk of age-related macular degeneration, atherosclerosis and other diseases (Bovier et al., 2013; El-raey, Ibrahim, & Eldahshan, 2013). When lutein is extracted, it becomes highly unstable, reducing its functionality as an antioxidant. The aim of this research was to improve the stability of lutein using maltodextrin, arabic gum and a modified starch, to obtain micro-particles using spray-drying. Each of the formulations was characterized in terms of yield, encapsulation efficiency, particle size distribution, water activity and moisture content. The formulations with arabic gum (100%) and arabic gum:maltodextrin:modified starch (33.3:33.3:33.3%), with encapsulation efficiencies of 91.94 +/- 6.88 and 65.72 +/ 0.93%, respectively, were selected to study stability at 45 degrees C and 75% RH (relative humidity). Based on our results, encapsulation could be considered as an alternative for the generation of high value-added functional ingredients that can be used in different industries. PMID- 29606437 TI - Changes in immunoreactivity of allergen-reduced peanuts due to post-enzyme treatment roasting. AB - The objective of this study was to evaluate the effect of enzyme treatment and post-enzyme treatment roasting on allergenicity of raw peanut kernels. Raw peanuts were treated by single- and two-enzyme treatments, respectively. Enzyme treated raw peanuts were dry roasted. Reductions of four major allergens (Ara h 1, 2, 3, and 6) and in vitro allergenicity of peanuts were evaluated. Quantitative measurements show that enzyme treatment of raw peanuts reduced Ara h 1, 2, 3 and 6 in raw peanuts by 99-100%, 95-99%, 35-46% and 85-88%, respectively. Roasting of enzyme-treated peanuts significantly reduced the total soluble protein (P < 0.05), Ara h 3 and 6 (P < 0.0001), slightly increased Ara h 1 in the extracts (P < 0.05), but did not significantly affect Ara h 2. Immunoblot shows that the IgE-bindings of both soluble and insoluble proteins of enzyme-treated peanuts were slightly enhanced by roasting but still tremendously lower than that of untreated peanuts. PMID- 29606438 TI - Application of sequential and orthogonalised-partial least squares (SO-PLS) regression to predict sensory properties of Cabernet Sauvignon wines from grape chemical composition. AB - The current study determined the applicability of sequential and orthogonalised partial least squares (SO-PLS) regression to relate Cabernet Sauvignon grape chemical composition to the sensory perception of the corresponding wines. Grape samples (n = 25) were harvested at a similar maturity and vinified identically in 2013. Twelve measures using various (bio)chemical methods were made on grapes. Wines were evaluated using descriptive analysis with a trained panel (n = 10) for sensory profiling. Data was analysed globally using SO-PLS for the entire sensory profiles (SO-PLS2), as well as for single sensory attributes (SO-PLS1). SO-PLS1 models were superior in validated explained variances than SO-PLS2. SO-PLS provided a structured approach in the selection of predictor chemical data sets that best contributed to the correlation of important sensory attributes. This new approach presents great potential for application in other explorative metabolomics studies of food and beverages to address factors such as quality and regional influences. PMID- 29606439 TI - An approach for degradation of grape seed and skin proanthocyanidin polymers into oligomers by sulphurous acid. AB - To develop an efficient method for degradation of grape seed and skin proanthocyanidins polymers into oligomers, an optimized sulphurous acid degradation conditions for grape seed with the temperature of 60 degrees C, reaction time of 60 min and sample-sulphurous acid ratio of 1:0.2, and for grape skin with the temperature of 40 degrees C, reaction time of 60 min and sample sulphurous acid ratio of 1:0.2, were established. Afterwards, HSCCC and prep-HPLC were used to fractionate and isolate individual proanthocyanidin oligomers from the degradation products. Total of ten dimeric or trimeric procyanidins were obtained, and most of them presented high yield (from 0.7 mg to 13.6 mg per run in grape seed and from 0.5 mg to 4.1 mg per run in grape skin) and high purity (over 90%). The proposed method provides a new way for large preparation of oligomeric proanthocyanidins from naturally abundant and wasted polymeric ones. PMID- 29606440 TI - Ultrasound-assisted surfactant-enhanced emulsification microextraction using a magnetic ionic liquid coupled with micro-solid phase extraction for the determination of cadmium and lead in edible vegetable oils. AB - A novel ultrasound-assisted surfactant-enhanced emulsification microextraction (UASEME) using a magnetic ionic liquid (MIL) coupled with micro-solid phase extraction was developed for the preconcentration of cadmium and lead in edible vegetable oils prior to analysis by graphite furnace atomic absorption spectrometry. MIL [C4mim] [FeCl4] was used as the extractant, non-ionic surfactant Triton X-100 as the emulsifier and Fe3O4 nanoparticles as the sorbent, while ultrasound was applied to assist the dispersion of the extractant and accelerate the mass transfer process. By mixing Fe3O4 nanoparticles with the MIL after UASEME, the phase separation time was shortened and the separation can be simplified by applying an external magnetic field. Under the optimized conditions, the proposed method was validated and the results demonstrated that the method can produce satisfactory linearity, sensitivity, reproducibility and recovery for the analytes. Finally, the method was successfully applied for the determination of Cd and Pb in edible vegetable oil samples. PMID- 29606441 TI - Toward a high-throughput method for determining vicine and convicine levels in faba bean seeds using flow injection analysis combined with tandem mass spectrometry. AB - Although faba bean provides environmental and health benefits, vicine and convicine (v-c) limit its use as a source of vegetable protein. Crop improvement efforts to minimize v-c concentration require low-cost, rapid screening methods to distinguish between high and low v-c genotypes to accelerate development of new cultivars and to detect out-crossing events. To assist crop breeders, we developed a unique and rapid screening method that uses a 60 s instrumental analysis step to accurately distinguish between high and low v-c genotypes. The method involves flow injection analysis (FIA) coupled with tandem mass spectrometry (i.e., selective reaction monitoring, SRM). Using seeds with known v c levels as calibrants, measured v-c levels were comparable with liquid chromatography (LC)-SRM results and the method was used to screen 370 faba bean genotypes. Widespread use of FIA-SRM will accelerate breeding of low v-c faba bean, thereby alleviating concerns about anti-nutritional effects of v-c in this crop. PMID- 29606442 TI - Purification and characterisation of a protease (tamarillin) from tamarillo fruit. AB - A protease from tamarillo fruit (Cyphomandra betacea Cav.) was purified by ammonium sulphate precipitation and diethylaminoethyl-Sepharose chromatography. Protease activity was determined on selected peak fractions using a casein substrate. Sodium dodecyl sulphate polyacrylamide gel electrophoresis analysis showed that the peak with the highest protease activity consisted of one protein of molecular mass ca. 70 kDa. The protease showed optimal activity at pH 11 and 60 degrees C. It was sensitive to phenylmethylsulphonyl fluoride while ethylenediaminetetraacetic acid and p-chloromercuribenzoic acid had little effect on its activity, indicating that this enzyme was a serine protease. Hg2+ strongly inhibited enzyme activity, possibly due to formation of mercaptide bonds with the thiol groups of the protease, suggesting that some cysteine residues may be located close to the active site. De novo sequencing strongly indicated that the protease was a subtilisin-like alkaline serine protease. The protease from tamarillo has been named 'tamarillin'. PMID- 29606443 TI - Affinity and selectivity of plant proteins for red wine components relevant to color and aroma traits. AB - The effects of fining with various plant proteins were assessed on Aglianico red wine, using both the young wine and wine aged for twelve and twenty-four months, and including wine unfined or fined with gelatin as controls. Color traits and fining efficiency were considered, along with the content of various types of phenolics and of aroma-related compounds of either varietal or fermentative origin. All agents had comparable fining efficiency, although with distinct kinetics, and had similar effects on wine color. Individual plant proteins and enzymatic hydrolyzates differed in their ability to interact with some anthocyanins, with specific proanthocyanidins complexes, and with some aroma components of fermentative origin. Changes in varietal aroma components upon fining were very limited or absent. Effects of all the fining agents tested in this study on the anthocyanidin components were most noticeable in young red wine, and decreased markedly with increasing wine ageing. PMID- 29606444 TI - Thermally processed diet greatly affects profiles of amino acids rather than fatty acids in the muscle of carnivorous Silurus meridionalis. AB - This study aimed to evaluate the effects of thermally processed diet (TD) on the muscle nutritional values of southern catfish in two experiments (named E1 and E2). Compared to non-thermally processed diet (ND), TD did not significantly affect proximate composition of southern catfish, but increased moisture content and decreased protein content in E1. Meanwhile, it had no effect on overall fatty acid profiles of the catfish rich in PUFA. Southern catfish had high proportions of indispensable amino acids (IAA, 44.6-46.4% of total fatty acids), with the highest contents of lysine (1551-1808 mg/100 g wet weight muscle). However, TD altered profiles of the IAA, particularly decreased 68.5% and 68.4% of methionine, and 9.5% and 10.7% of lysine in E1 and E2, respectively. Conversely, it increased 45.4% and 83.4% of dispensable fatty acid proline. These results suggest TD could affect the nutritional quality of protein rather than fat in farmed fish. PMID- 29606445 TI - Assessment of the bacterial impact on the post-mortem formation of zinc protoporphyrin IX in pork meat. AB - The post-mortem accumulation of the heme biosynthesis metabolite zinc protoporphyrin IX (ZnPP) in porcine muscle is associated with both a meat inherent and a bacterial enzymatic reaction during meat storage. To estimate the bacterial impact on ZnPP formation, meat and meat-like media were investigated by HPLC-FLD (and MALDI-TOF-MS) after inoculation with a representative microorganism (P. fluorescens). Results indicate the principal ability of meat-inherent bacteria to form ZnPP in meat extracts and meat-like media, but not on the meat muscle. Thus it was concluded that the ZnPP formation in meat is due to a meat inherent enzymatic reaction induced by porcine ferrochelatase (FECH), while the bacterial (FECH) induced reaction seems to be not significant. PMID- 29606446 TI - Changes in bioaccessibility, polyphenol profile and antioxidant potential of flours obtained from persimmon fruit (Diospyros kaki) co-products during in vitro gastrointestinal digestion. AB - The aim was to evaluate (i) the phenol and flavonoid recovery and bioaccessibility indexes, (ii) the stability of individual polyphenolic compounds and (iii) the antioxidant activity of persimmon flours (cultivars 'Rojo Brillante' and 'Triumph') during the in vitro digestion. The recovery index for phenolic and flavonoid content was dependent on flour type and digestion phase. After the dialysis phase, the bioaccessibility for phenolic compounds from both flours was similar; for flavonoids it was higher in 'Triumph' than 'Rojo Brillante' flour. After in vitro digestion, 13 polyphenolic compounds were detected in both flours, of which only six were detected in the intestinal phase. Their antioxidant activity (ABTS+, FRAP and DPPH) decreased after intestinal phase, while their chelating activity (FIC assay) increased in both flours. So, persimmon flours could be included in the formulation of foods to improve either their scarcity of bioactive compounds or an unbalanced nutritional composition. PMID- 29606447 TI - The contribution of autochthonous microflora on free fatty acids release and flavor development in low-salt fermented fish. AB - To investigate the contribution of autochthonous microflora on free fatty acids (FFA) release and flavor development in low-salt fermented fish, three groups of processed fish, including bacteriostatic-acidification group (BAG), bacteriostatic group (BG), and spontaneous fermented fish (CG) were established. Results showed that addition of NaN3 reduced microbial load in BAG and BG below 3.5 log CFU/g after 3 weeks of incubation. Activities of lipases and lipoxygenase declined markedly with increasing time, where BG had the highest activities, followed by CG and BAG. There is a 36.3% higher in the total FFA content in CG than that in BAG, indicating both microbial and endogenous lipases contributed to the FFA liberation in fermented fish while endogenous lipases play a major role. However, compared to BAG and BG, largely higher levels of volatile compounds were observed in CG, suggesting that autochthonous microflora dominated the generation of volatile flavor compounds in fermented fish. PMID- 29606448 TI - Fermentation process optimization and chemical constituent analysis on longan (Dimocarpus longan Lour.) wine. AB - Based on single factor and orthogonal experiments, optimal fermentation conditions for longan wine were Saccharomyces cerevisiae strain of Lalvin KD, juice content of 70% and alcohol content of 10 degrees . Sixteen amino acids were detected. Proline, alanine, glutamic acid and aspartic acid contents were relatively high. Sixty-three volatile aroma compounds were identified using solid phase micro extraction and gas chromatography (SPME-GC). Ethyl lactate content was the highest, followed by octanoic acid ethyl ester, isoamyl alcohol and decanoic acid ethyl ester. Main functional components were polysaccharides. Longan wine polysaccharide (LWP) with molecular weight 10-30 kDa exhibited the highest hypoglycemic and 2,2-diphenyl-1-picrylhydrazyl (DPPH) radical-scavenging activities. 10-30 kDa polysaccharides mainly consisted of glucose, mannose, galactose, arabinose, galacturonic acid and glucuronic acid in molar ratio of 167.72:3.38:3.13:3.46:2.33:1. Infrared and nuclear magnetic resonance spectra confirmed that the sugar ring of 10-30 kDa polysaccharides was in the configuration. PMID- 29606449 TI - Optimized extraction of anthocyanins from Reid Fruits' Prunus avium 'Lapins' cherries. AB - The influence of process parameters on the extraction of anthocyanins from the edible portion of fresh, sweet cherry were investigated. The optimal extraction time and temperature were determined as 90 min and 37 degrees C, respectively. A solvent/solid ratio of 10 mL/g using 100% acidified solvent resulted in the greatest anthocyanin yield. No significant difference was observed between the use of methanol or ethanol as the extraction solvent. Ultra Performance Liquid Chromatography-MS analysis of the extract identified four anthocyanins, with cyanidin-3-rutinoside and peonidin-3-rutinoside accounting for over 95% of the anthocyanin content, while cyanidin-3-glucoside and pelargonidin-3-rutinoside accounted for the remaining 5%. 244 mg/100 g fresh weight total anthocyanins were determined in the fresh cherries using the optimal extraction conditions. PMID- 29606450 TI - Investigation of 'stone fruit' aroma in Chardonnay, Viognier and botrytis Semillon wines. AB - Despite numerous studies, the identity of the compounds that are responsible for 'stone fruit' aroma in wine has not been conclusively established. This study focussed on wine varieties that often display peach and apricot characters, such as Chardonnay, Viognier and botrytis-affected sweet Semillon wines. Wines with high and low 'stone fruit' aroma were evaluated by gas chromatography olfactometry-mass spectrometry (GC-O-MS) using extracts representative of the aroma of the wine in a glass. No aroma-active zone was described as 'stone fruit' aroma across all three wine varietals. However, for the individual varieties, terpenes, such as linalool and geraniol, in the Viognier wines, several esters in the Chardonnay wines, and gamma-nonalactone in the botrytis Semillon were associated with 'stone fruit' aroma. Notably, this is the first study assessing the aroma profile of Viognier wine by GC-O. In addition, an extension study of Viognier grape monoterpene profiles clarified its classification as an aromatic variety. PMID- 29606451 TI - First evidence of ethyl-hydrogen phosphonate (fosetyl) formation in winemaking. AB - The formation of ethylphosphonate (fosetyl) was investigated in wine matrices. In experimental conditions, alcoholic fermentation of grape juices spiked with phosphonic acid resulted in wines with detectable amounts of fosetyl. The ageing period adopted for these wines further increased the fosetyl content in the absence of yeast lees, thus indicating a chemical origin. A model wine assay was performed in order to study the main thermodynamic variables affecting the Fisher reaction. The results obtained allowed us to report evidence of ethylphosphonate formation in winemaking conditions, for the first time to the best of our knowledge. PMID- 29606452 TI - Quadruplex gold immunochromatogaraphic assay for four families of antibiotic residues in milk. AB - In this study, we developed a quadruplex gold immunochromatogaraphic assay (GICA) for the simultaneous determination of four families of antibiotics including beta lactams, tetracyclines, streptomycin and chloramphenicol in milk. For qualitative analysis, the visual cut-off values were measured to be 2-100 ng/mL, 16-32 ng/mL, 50 ng/mL and 2.4 ng/mL for beta-lactams, tetracyclines, streptomycin and chloramphenicol, respectively. For quantitative analysis, the detection ranges were 0.13-1 ng/mL for penicillin G, 0.13-8 ng/mL for tetracycline, 0.78-25 ng/mL for streptomycin, 0.019-1.2 ng/mL for chloramphenicol in milk respectively, with linear correlation coefficients higher than 0.97. The spiked experiment indicated that the mean recoveries ranged from 84.5% to 107.6% with coefficient of variations less than 16.2%, and real sample analysis revealed that the GICA can produce consistent results with instrumental analysis. These results demonstrated that this novel immunoassay is a promising approach for rapidly screening common antibiotic residues in milk. PMID- 29606453 TI - Characterization of wheat endoplasmic reticulum oxidoreductin 1 and its application in Chinese steamed bread. AB - This study investigated characteristics of recombinant wheat Endoplasmic Reticulum Oxidoreductin 1 (wEro1) and its influence on Chinese steamed bread (CSB) qualities. The purified wEro1 monomer, which contained two conserved redox active motif sites, bound to flavin adenine dinucleotide (FAD) cofactor with a molecular weight of ~47 kDa. wEro1 catalyzed the reduction of both bound and free FAD, and its reduction activity of free FAD reached 7.8 U/mg. Moreover, wEro1 catalyzed the oxidation of dithiothreitol and wheat protein disulfide isomerase (wPDI). Both glutathione and the reduced ribonuclease could work as electron donors for wEro1 in catalyzing the oxidation of wPDI. Additionally, wEro1 supplementation improved the CSB qualities with an increased specific volume of CSB and decreased crumb hardness, which was attributed to water-insoluble wheat proteins increasing and gluten network strengthening. The results give an understanding of the properties and function of wEro1 to facilitate its application especially in the flour-processing industry. PMID- 29606455 TI - Analysis of 40 conventional and emerging disinfection by-products in fresh-cut produce wash water by modified EPA methods. AB - Chlorine sanitizers used in washing fresh and fresh-cut produce can lead to generation of disinfection by-products (DBPs) that are harmful to human health. Monitoring of DBPs is necessary to protect food safety but comprehensive analytical methods have been lacking. This study has optimized three U.S. Environmental Protection Agency methods for drinking water DBPs to improve their performance for produce wash water. The method development encompasses 40 conventional and emerging DBPs. Good recoveries (60-130%) were achieved for most DBPs in deionized water and in lettuce, strawberry and cabbage wash water. The method detection limits are in the range of 0.06-0.58 MUg/L for most DBPs and 10 24 ng/L for nitrosamines in produce wash water. Preliminary results revealed the formation of many DBPs when produce is washed with chlorine. The optimized analytical methods by this study effectively reduce matrix interference and can serve as useful tools for future research on food DBPs. PMID- 29606454 TI - Alpha-linolenic acid-loaded oil/water microemulsion: Effects of phase behaviour simulation and environmental stress on phase stabilizing and anti-oxidation capacity. AB - alpha-Linolenic acid (ALA)-loaded microemulsion (ME) was prepared from isoamyl acetate, polyoxyethylene ether 35 (EL-35), ethanol and water. The dynamic phase behaviour was simulated using dissipative particle dynamics (DPD), which showed that spherical ME was formed at water/oil ratios of 1:9 and 9:1, while a lamellar structure with distinctive water-course and oil layer appeared at ratios of 3:7, 5:5, and 7:3. Phase stabilizing and anti-oxidation effect of environmental stresses on ALA-loaded microemulsion were investigated. Results showed that the ME region was large and had good environmental tolerance. Subsequently, the investigation of anti-oxidation stability revealed that more than 60% ALA of ALA loaded ME could be protected from oxidation under environmental stresses. Furthermore, ALA-loaded ME was applied in aqueous-based foods. The transparency, precipitate, stratification and phase separation were used to evaluate influence of ME on product properties, confirming great feasibility and stability of ALA loaded ME for practical applications. PMID- 29606456 TI - Countercurrent chromatographic isolation and purification of 11'-alpha tocomonoenol from the vitamin E extract of palm oil. AB - A new vitamin E homologue, alpha-tocomonoenol was detected in palm oil, but was not isolated in large amounts and with high purity so far. Here we present an easy and fast method to isolate alpha-tocomonoenol from vitamin E rich nutrient capsules with countercurrent chromatography (CCC). With the solvent system n hexane - benzotrifluoride - acetonitrile (10:3.5:6.5, v/v/v) about 30 mg alpha tocomonoenol with a purity of 75% could be enriched in one step from 1 g crude sample. Column chromatography with 20% deactivated silica gel and n-hexane - ethyl acetate (95:5, v/v) was performed to gain 5.6 mg alpha-tocomonoenol with a purity of 99.5% according to GC/MS. Structural verification by 1H NMR spectroscopy verified that the double bond was located in 11'-position (11'-alpha tocomonoenol). The trace impurity detected in the isolate was identified to be 12'-alpha-tocomonoenol, a compound previously detected in marine samples. PMID- 29606457 TI - A new UHPLC-MS/MS method for the determination of flavonoids in supplements and DPPH-UHPLC-UV method for the evaluation of the radical scavenging activity of flavonoids. AB - The aim of study was to analyze the flavonoid composition of dietary supplements using the UHPLC-MS/MS method and to evaluate the antioxidant activity using the DPPH-UV and DPPH-UHPLC-UV methods. In the first part of the study a new method was developed for simultaneous determination of several flavonoids in dietary supplements. The amounts of flavonoids were in the range from 0.013 to 347 ug/g. In the second part of the study, the traditional DPPH-UV method and UHPLC-UV method combined with a 2,2-diphenyl-1-picrylhydrazyl radical (DPPH) assay were used. After application of both methods, the obtained results were similar, and the order of flavonoids depending on their antioxidant activity is the same. The effect of individual compounds on activity in combination with another flavonoid with similar or different antioxidant potentials was evaluated. The dependence of antioxidant activity on the number, type and location of the basal rings in the ring can be noted. PMID- 29606458 TI - Simple and rapid silver nanoparticles based antioxidant capacity assays: Reactivity study for phenolic compounds. AB - A single-step, rapid (10 min), sensitive silver nanoparticles (AgNPs) based spectrophotometric method for antioxidant capacity (AOC) assay has been developed. The assay is based on the ability of natural polyphenols to reduce Ag(I) and stabilize the produced AgNPs(0) at room temperature. Localized surface plasmon resonance (LSPR) of AgNPs at ~420 nm is then measured. Using different conditions of pH (8.4) and temperature (45 degrees C) a further assay based on the production of AgNPs with selectivity for flavonols was also developed. The reactivity of the two AgNPs based assays vs. 15 polyphenols belonging to different chemical classes and 9 different samples has been studied and compared with ABTS, Folin and AuNPs based methods for AOC. The proposed assays had good reproducibility (RSD <= 13) and are simple, sensitive and cost effective. Moreover, used in conjunction with the classical AOC assays, can improve the information on the polyphenolic pool of food samples. PMID- 29606459 TI - Continuous high voltage electrical discharge extraction of flavonoids from peanut shells based on "annular gap type" treatment chamber. AB - A continuous high voltage electric discharge (HVED) extraction system with "annular gap type" treatment chamber was for the first time designed and optimized for flavonoids extraction from peanut shells, and a comparison with the HVED system with the "converged electric field type" treatment chamber and warm maceration was carried out. The optimal conditions for the "annular gap type" design were: 25% ethanol concentration as solvent, 30:1 mL/g liquid to solid ratio, 13 kV peak pulse voltage and 60 mL/min flow rate of material. Under these conditions, the maximum yield of flavonoids was 0.948 +/- 0.014%. Compared with the "converged electric field type" design and warm maceration, the "annular gap type" design possessed shorter duration and higher efficiency for the flavonoids extraction, and had no effects on the composition of extracted flavonoids. The results showed that the "annular gap type" design was a promising alternative method in extracting flavonoids from peanut shells. PMID- 29606460 TI - Magnetic solid-phase extraction based on magnetic zeolitic imazolate framework-8 coupled with high performance liquid chromatography for the determination of polymer additives in drinks and foods packed with plastic. AB - In this study, magnetic zeolitic imazolate framework-8 (Fe3O4@ZIF-8) was successfully synthesized by a typical hydrothermal method. The facile magnetic solid-phase extraction (MSPE) based on Fe3O4@ZIF-8 was proposed for concentrating polymer additives (antioxidants and ultraviolet absorbers). The conditions of MSPE process were optimized. An analytical method of magnetic solid-phase extraction followed by high performance liquid chromatography (MSPE-HPLC) was successfully established for the simultaneous determination of seven polymer additives in drinks and foods packed with plastic. The established method showed good precision, reproducibility, stability, and accuracy with the low limits of detection (0.03-0.15 ng/mL) and limits of quantification (0.08-0.50 ng/mL). The results of this study indicated the Fe3O4@ZIF-8 coupled with HPLC provided an efficient enrichment and determination method for polymer additives in drinks and foods. PMID- 29606461 TI - Effects of raw potato starch on body weight with controlled glucose delivery. AB - Starch digestion in the gastrointestinal tract has different properties depending on its botanical source. In this study, corn, wheat, rice, and potato starches were used to test the digestion properties of mammalian mucosal alpha-glucosidase in an in vitro assay, and their physiological effects were investigated in male C57BL/6 mice. The results clearly demonstrated that potato starch caused the lowest rates of glucose generation, suggesting that it can attenuate the postprandial glucose spike. Interestingly, a potato starch-based diet caused significantly (P < 0.05) lower weight gain and fat accumulation compared to diets based on other starches, through increased insulin sensitivity. This result suggests that potato starch-based products can be used to regulate postprandial blood glucose levels, aiding in the control of metabolic diseases. PMID- 29606462 TI - Effects of dextran with different molecular weights on the quality of wheat sourdough breads. AB - This research aimed at investigating the effects of different weight-average molecular weights (Mw: T10, T70, T250, T750, T2000) of dextran (alpha-(1 -> 6) linked linear backbone, alpha-(1 -> 3)-linked branching) on wheat sourdough bread qualities. Texture analyzer showed that dextran contributed to a significant inhibition of bread staling, particularly dextran T2000. Pasting profiles (Rapid visco-analysis) and steady rheological properties (steady shear measurements) of samples indicated that dextran T2000 suppressed the swelling and gelatinization of wheat starch granules and bound a great amount of water, thus retarding the aging process. Dextran T2000 markedly improved the elastic properties of sourdough-containing dough. Wheat sourdough breads containing dextran T10 exhibited unexpected less firm crumb structure. The improvement of bread qualities was a function of the Mw of dextran. Dextran with high Mw values has the potential for improving the quality of wheat sourdough breads, especially extending shelf life. PMID- 29606463 TI - Know your fish: A novel compound-specific isotope approach for tracing wild and farmed salmon. AB - The rapid expansion of the aquaculture industry with carnivorous fish such as salmon has been accompanied by an equally rapid development in alternative feed ingredients. This has outpaced the ability of prevailing authentication method to trace the diet and origins of salmon products at the retail end. To close this gap, we developed a new profiling tool based on amino acid delta13C fingerprints. With this tool, we discriminated with high-accuracy among wild-caught, organically, and conventionally farmed salmon groups, as well as salmon fed alternative diets such as insects and macroalgae. Substitution of fishmeal with macroalgae was detected at 5% difference level. The delta13C fingerprints of essential amino acids appear particularly well suited for tracing protein sources, and the non-essentials for tracing lipid origins (terrestrial vs. aquatic). In an industry constantly developing new feed proteins and functional additives, our method is a promising tool for tracing salmon and other seafood products. PMID- 29606464 TI - Delaying fat bloom formation in dark chocolate by adding sorbitan monostearate or cocoa butter stearin. AB - Two formulations of dark chocolate were developed by adding cocoa butter stearin (CBSt) or sorbitan monostearate (SMS) and compared to a standard formulation in order to investigate fat bloom formation over time. Fat bloom was monitored by Whiteness Index (WI), melting behavior and polymorphism determinations, in bars stored during 90 days at 20 degrees C and under oscillating temperature between 20 and 32 degrees C. All samples stored at 20 degrees C did not develop fat bloom and the required beta(V) form was maintained. Under oscillating storage condition, samples with CBSt (6.0%, w/w) and SMS (0.15%, w/w) delayed the surface fat bloom formation by at least 45 and 15 days, respectively, compared to standard chocolate, observed visually and through WI increments. The beta(V) to beta(VI) polymorphic transition correlated well with the WI, and also with changes in DSC thermograms, confirming the higher effectiveness of specific triacylglycerol (mainly StOSt) in delaying bloom formation. PMID- 29606465 TI - Ultrafiltration and thermal processing effects on Maillard reaction products and biological properties of date palm sap syrups (Phoenix dactylifera L.). AB - The effect of ultrafiltration process and temperature concentration on MRPs content and antioxidant, antimicrobial and cytotoxic properties of date palm sap syrups were investigated. MRPs were analyzed by HPLC. Antioxidant activity was evaluated by reducing power and DPPH free radical and H2O2 scavenging activities. Antimicrobial activity was evaluated by the agar disk diffusion method. In vitro cytotoxic activity was examined by cell proliferation assay. Date sap syrups displayed strong antioxidant activities which are correlated 5HMF and 2F contents. In addition, concentration at 100 degrees C, unlike ultrafiltration process, enhanced significantly the antioxidant activities sap syrups and total phenolic contents. The antimicrobial activities showed marked activity against S. enterica, P. aeruginosa, S. aureus, L. monocytogenes with an inhibition zone of 21, 34, 27 and 34 mm respectively. Cytotoxicity assays showed that sap syrups can inhibit the proliferation of HeLa cell lines at high concentration. PMID- 29606466 TI - Rapid detection of collagens using a closed-tube LAMP method. AB - Identification methods of collagens and gelatins have been studied many years due to religious and food safety issues. Some researchers detected the collagen while others took up their study based on DNA at the first time. In this work, we used a closed-tube loop-mediated isothermal amplification (LAMP) technique to differentiate collagen and gelatin samples. DNA was extracted by DNeasy mericon Food Kit and was dissolved in 30 ul elution buffer, optimum concentration of Mg2+, deoxyribonucleoside triphosphates(dNTPs), betaine in LAMP reaction is 6.0 mmol/L, 2.0 mmol/L, and 0.8 mmol/L, respectively. After LAMP reaction, samples being detected changed their initial color to green, others' were colorless or brown slightly. The research offered a simple, fast detection technique to differentiate collagen and gelatin samples derived from porcine, bovine and channel catfish (Ictalurus punctatus) , the collagens' species can be determined by color variation in reaction tubes within two hour. PMID- 29606467 TI - Nanostructure and functionality of enzymatically repolymerized whey protein hydrolysate. AB - Whey proteins (WPI) were polymerized with transglutaminase (TGase) before and after partially hydrolyzing the protein with thermolysin to produce protein nanoparticles/polymers. Electrophoresis and atomic force microscopy (AFM) were used to determine the size and structural characteristics of the polymers. The foaming and emulsifying properties of these nanoparticles were studied. The polymerized WPI (WPI-TG) produced more stable foams than the repolymerized WPI hydrolysate (WPIH-TG). In contrast, WPIH-TG produced better emulsions with better storage stability than WPI-TG emulsions. These differences were due to their structure and electrostatic properties: The WPI-TG particles were linear, less than 100 nm in size with lower net negative charge, whereas the WPIH-TG polymers were much larger and were highly negatively charged as judged from zeta potential. This suggested that while protein nanoparticles may provide Pickering stability to both emulsions and foams, strong lateral electrostatic repulsion between nanoparticles within the adsorbed film destabilizes foams but not emulsions. PMID- 29606468 TI - Evaluation studies on the combined effect of hydrothermal treatment and octenyl succinylation on the physic-chemical, structural and digestibility characteristics of sweet potato starch. AB - In order to increase the degree of substitution (DS), a combination of heat moisture treatment (HMT) and octenyl succinylation (OSA) was used to modify sweet potato starch (SPS). The content of OSA had significant influence on the DS of starch, and DS of HMT OSA-modified SPS (HOSA-SPS) was higher than that of OSA modified SPS (OSA-SPS), indicating that prior HMT could enhance the reaction. HOSA-SPS showed higher contents of SDS and RS in comparison with OSA-SPS as OSA concentration was beyond 6%. HMT decreased swelling power of starch while OSA modification had a contrary role (p < 0.05). Scanning electron microscopy (SEM) showed starch was destroyed by OSA modification while HMT had slight effect on the structure. X-ray diffraction (XRD) indicated that crystal type of starch was transformed from C- to A-type resulted from HMT, and remained unchanged by OSA modification. The onset, peak, and conclusion gelatinization temperatures of starch increased by HMT and decreased by OSA modification (p < 0.05). PMID- 29606469 TI - Modifications of konjac glucomannan for diverse applications. AB - Konjac glucomannan (KGM) is a major polysaccharide from the corm of Amorphophallus konjac. Native KGM has limited uses and has been chemically/physically/enzymatically modified to expand the range of functional properties. This mini-review summarises the recent advances of modifying KGM for diverse food and nonfood applications, focusing on the chemical and physical modifications. The chemical methods include substitution, grafting, cross linking, oxidation, and deacetylation, whereas the physical modifications are electrospinning, microfluidic spinning, gamma-irradiation, extrusion, and electric field processing. The modified KGM has been used in a range of different applications, including biodegradable film, emulsion, medical and pharmaceutical material, encapsulation and controlled release, fish feed and functional food ingredient, separation medium, aerogel, liquid crystal, absorbent for removal of pollutants in waste water, and so on. These KGM-based products tend to be biodegradable, biocompatible, and non-toxic with improved functional performance. PMID- 29606470 TI - Reducing the allergenic capacity of beta-lactoglobulin by covalent conjugation with dietary polyphenols. AB - To help produce hypoallergenic food, this study investigated reducing the allergenicity and improving the functional properties of bovine beta lactoglobulin (betaLG) by covalent conjugation with (-)-epigallo-catechin 3 gallate (EGCG) and chlorogenic acid (CA). The covalent bond between the polyphenols and the amino acid side-chains in betaLG was confirmed by MALDI-TOF MS and SDS-PAGE. Structural analysis by fluorescence spectroscopy, circular dichroism (CD) and Fourier transform infrared (FTIR) indicated that the covalent conjugate of EGCG and CA led to the changed protein structure of betaLG. Western blot analysis and enzyme-linked immunosorbent assay indicated that conjugation of betaLG with these polyphenols was effective in reducing the IgE-binding capacity of betaLG. The conjugates maintained the retinol-binding activity without denaturation the protein and enhanced the thermal stability with high antioxidant activity. The study provides an innovative approach to producing hypoallergenic food. PMID- 29606471 TI - Highly specific and sensitive determination of propyl gallate in food by a novel fluorescence sensor. AB - Propyl gallate (PG), one of the most widely used synthetic phenolic antioxidants in edible oil, cookies and fried food, has received extensive concern due to its possible toxic effects on human health. Herein, a novel fluorescence analytical method is firstly proposed to sensitively and selectively determine propyl gallate (PG) by utilizing the unique fluorescence quenching property of organic molybdate complex (OMC) formed by the specific reaction between MoO42- and PG to g-C3N4 nanosheets. Under the optimum conditions, the developed fluorescence sensor allows highly sensitive detection of PG in a wide range from 0.5 to 200 MUg mL-1 with a detection limit of 0.11 MUg mL-1, and possesses excellent specificity and good recoveries. All the analytical results indicate the present method provides an effective approach for rapid detection of PG in common products, which is beneficial for monitoring and reducing the risk of overuse of PG. PMID- 29606472 TI - Application of an advanced and wide scope non-target screening workflow with LC ESI-QTOF-MS and chemometrics for the classification of the Greek olive oil varieties. AB - An optimized and validated LC-ESI-QTOF-MS method with an integrated non-target screening workflow was applied in the investigation of the metabolomic profile of 51 Greek monovarietal extra virgin olive oils (EVOOs) from the varieties: Manaki, Ladoelia, Koroneiki, Amfissis, Chalkidikis and Kolovi. Data processing was carried out with the R language and XCMS package. A local database consisting of 1608 compounds naturally occurring in different organs of Olea Europa L. was compiled in order to accelerate the identification workflow. The preliminary examination of the distribution of EVOOs toward their cultivars was achieved by Principal Component Analysis (PCA). Ant Colony Optimization-Random Forest (ACO RF) was developed to prioritize over 250 features and to establish a classification tree. Apigenin, vanillic acid, luteolin 7-methyl ether and oleocanthal were suggested as the markers responsible for the classification of Greek EVOOs' cultivars. PMID- 29606473 TI - Physical, thermal and thermodynamical study of high oleic palm oil nanoemulsions. AB - Nanoemulsions are useful for encapsulating nutritionally compounds of the high oleic palm oil (HOPO) including beta-carotene and tocopherols. However, some nanoemulsions can be thermodynamically unstable. For this reason, it is important to understand the thermal and thermodynamic stability of nanoemulsions and to investigate both the parameters that cause, and the mechanisms associated with, the destabilization. In this sense, the DSC, TGA and destabilization analysis were used. In this work, the average droplet size (ADS) and zeta potential (zeta) had a significant influence over HOPO nanoemulsions stability. The range of ADS and zeta were between 162 and 839 nm and -9 to -40 mV, respectively. Furthermore, the HOPO nanoemulsions were establish until temperatures of 80 degrees C, showing lower loss of weight when the ADS was higher. Additionally, the destabilization of nanoemulsions occurred by the Ostwald ripening mechanism. The Ostwald ripening rate was provided as stability parameter which increased to nanoemulsions with ADS higher between 5 * 10-23 and 8 * 10-23 m3/s. PMID- 29606474 TI - Levels of terpenoids, mangiferin and phenolic acids in the pulp and peel of ripe mango fruit influenced by pre-harvest spray application of FeSO4 (Fe2+), MgSO4 (Mg2+) and MnSO4 (Mn2+). AB - Fe2+, Mg2+ and Mn2+ are enzyme cofactors in terpenoids biosynthesis. Effects of pre-harvest spray of FeSO4, MgSO4 and MnSO4 (0.2% and 0.3%) 30 d prior to harvest on the levels of terpenoids and phenolic compounds in ripe mango fruit were investigated. All treatments significantly increased lupeol in the peel compared to control and it was highest in pulp of 0.3% FeSO4-treated fruit. Spray of each nutrient (0.3%) increased total carotenoids in the pulp. Mangiferin in pulp was significantly higher in the fruit treated with 0.2% FeSO4, MgSO4 and MnSO4 compared to control and 0.3%. Concentrations of gallic, ferulic and caffeic acids in the peel and chlorogenic acid in pulp and peel were highest in fruit sprayed with 0.2% FeSO4. In conclusion, pre-harvest spray of FeSO4, MgSO4 and MnSO4 regulates concentrations of terpenoids and phenolic compounds in the pulp and peel of ripe mango fruit. PMID- 29606475 TI - Preparation and stability of resistant starch nanoparticles, using acid hydrolysis and cross-linking of waxy rice starch. AB - To develop resistant starch (RS) nanoparticles, waxy rice starch was hydrolyzed with acid for 10 days, and acid-hydrolyzed waxy rice starch (AHW) was cross linked with sodium trimetaphosphate. The RS nanoparticles were collected by freeze-drying (FD), freeze-drying after sonication (SFD), and ethanol dehydration after sonication (SE). The particle size distribution, RS level by modified AOAC, zeta potential, and stability of dispersion were assessed. The hydrolysis rate ranged from 44.62% to 49.43%, and AHW particle size decreased as hydrolysis time increased. All AHW and RS nanoparticles showed A type crystallinity. The particle size and zeta potential of the nanoparticles dried by FD, SFD, and SE were 300.0, 211.9, and 459.7 nm and -37.1, -43.0, and -35.4 mV, respectively. The RS levels were increased by cross-linking. The SFD dispersion was the most stable. The results indicate that the RS4 nanoparticles, for applying to liquid foods, can be prepared by acid hydrolysis, cross-linking, and SFD. PMID- 29606476 TI - Analysis, potency and occurrence of (Z)-6-dodeceno-gamma-lactone in white wine. AB - (Z)-6-Dodeceno-gamma-lactone is a potent aroma compound that has been little studied and its prevalence in wines is unknown. An efficient stable isotope dilution assay was developed using a simple, direct immersion solid-phase microextraction and gas chromatography-tandem mass spectrometry method suitable for routine use with a low ng/L limit of quantitation. Using this method, 99 out of 104 young white wines analysed were found to contain detectable (Z)-6-dodeceno gamma-lactone. The highest concentrations were found in Riesling and Viognier wines. (Z)-6-Dodeceno-gamma-lactone was found to have an aroma detection threshold of 700 ng/L in a neutral white wine. This study established that (Z)-6 dodeceno-gamma-lactone is widely present in Australia's most popular white wine varieties, but generally at concentrations below its aroma detection threshold. PMID- 29606477 TI - Fabrication of a novel magnetic mesoporous molecularly imprinted polymer based on pericarpium granati-derived carrier for selective absorption of bromelain. AB - Bromelain, a cysteine endopeptidase enzyme of great commercial value, has been widely used in food, pharmaceutical, and cosmetic industries. Conventional methods for purification of bromelain are still limited by a low binding efficiency, time-consuming process, and expensive equipment. Therefore, for selective absorption of bromelain, we developed a facile and effective method to fabricate magnetic mesoporous molecularly imprinted polymers using pericarpium granati-derived carbon as the carrier for the first time. The characterizations of the imprinted polymers indicated that a polydopamine layer was coated on the surface of the carrier and the crystallinity of the carrier did not change. The obtained imprinted polymers exhibited favourable saturation magnetization, a high adsorption capacity of 135.96 mg g-1, a fast equilibrium time, and satisfactory reusability. The imprinted polymers were prepared by an eco-friendly method and exhibited rapid separation and good adsorption performance, thus making the method applicable to biomacromolecular separation, proteomic analysis, and biomedical research. PMID- 29606478 TI - Identification of a novel ACE-inhibitory peptide from casein and evaluation of the inhibitory mechanisms. AB - Various bioactive peptides are continuously being identified from casein hydrolysates. In this work, a novel angiotensin I-converting enzyme (ACE) inhibitory (ACEI) peptide, NMAINPSKENLCSTFCK, derived from the alphas2-casein fragment residues 25-41, was screened and identified by UPLC-ESI-Q-TOF-MS/MS from tryptic casein hydrolysate. The IC50 value of the peptide, determined by an HPLC method, was 129.07 MUM. The Lineweaver-Burk plot showed that this peptide acted as a mixed-type inhibitor against ACE, which might be attributed to the peptide being susceptible to degradation by ACE, indicating that the mixed-type inhibition could partly be a result of newly generated peptide fragments. The physicochemical characteristics and the secondary structure were evaluated by circular dichroism analysis and online prediction software (Expasy, PepDraw, and ProtParam) to identify the basic characteristics of this peptide. Moreover, molecular docking was simulated by Discovery Studio 2017 R2 software to provide the potential mechanisms underlying the ACEI activity of the peptides. PMID- 29606479 TI - The future of family-centred care in intensive care. PMID- 29606480 TI - Recovery programme for ICU survivors has no effect on relatives' quality of life: Secondary analysis of the RAPIT-study. AB - BACKGROUND: Relatives of intensive care patients are at risk of developing symptoms of anxiety, depression and posttraumatic stress resulting in reduced health-related quality of life. Recovery programmes for patients have been implemented, but their effect on relatives is uncertain. AIM: To determine whether relatives benefit from a recovery programme intended for intensive care survivors. RESEARCH DESIGN: A randomised controlled trial of 181 adult relatives: intervention group (n = 87), control group (n = 94). SETTING: Ten intensive care units in Denmark. MAIN OUTCOME MEASURES: Primary outcome: health-related quality of life (HRQOL). SECONDARY OUTCOMES: Sense of coherence (SOC), and symptoms of anxiety, depression and posttraumatic stress, compared to standard care at 12 months after intensive care discharge. RESULTS: No difference in HRQOL between groups was observed at 12 months (mean difference in mental component summary score, 1.35 [CI 95%: -3.13; 5.82], p = 0.55; and physical component summery score, 1.86 [CI 95%: -1.88; 5.59], p = 0.33). No differences were found in secondary outcomes. CONCLUSION: The recovery programme intended for intensive care survivors did not have an effect on the relatives. Future recovery programmes should be targeted to help both patient and family, and future research should be conducted on a larger scale to make conclusions with higher probability. PMID- 29606481 TI - Frequency and risk factors for subsyndromal delirium in an intensive care unit. AB - OBJECTIVE: Delirium and subsyndromal delirium in critically ill patients are important determinants of long-term functional disability and cognitive impairment. However, few outcome studies on sub-syndromal delirium have been reported. Thus, this study aimed to evaluate the incidence of delirium and sub syndromal delirium as well as the risk factors and progression to delirium. DESIGN: A prospective cohort study. SETTING: Six bed medical and surgical intensive care unit in Otsu Municipal Hospital in Japan. METHODS: Delirium and sub syndromal delirium were evaluated using the Intensive Care Delirium Screening Checklist scores and the demographic data of the patients recorded. Statistical analyses were conducted using the Mann-Whitney U test and chi-square test for comparison. We also compared groups using multivariate analyses. RESULTS: Of the 380 patients who were screened, 15.8% and 33.9% had delirium or sub syndromal delirium, respectively and 9.5% of patients progressed from a state of sub syndromal delirium to delirium. Older age, predisposing cognitive impairment, blood transfusion, higher Acute Physiology and Chronic Health Evaluation II (APACHE II) score, low red blood cell count and high C-reactive protein levels were the risk factors highly associated with subsyndromal delirium symptoms. Older age, acute admission, steroid use, the utilisation of restraints and lower PaO2 were the determinants of progression to delirium. CONCLUSIONS: A high incidence of sub syndromal delirium was observed in critically ill patients. Patient with sub syndromal delirium must be promptly identified and treated due to the risk of progression to delirium. PMID- 29606482 TI - Planning management and delivery of the growth-restricted fetus. AB - A uniform approach to management of fetal growth restriction (FGR) improves outcome, prevents stillbirth, and allows appropriately timed delivery. An estimated fetal weight below the tenth percentile with coexisting abnormal umbilical artery (UA), middle cerebral artery (MCA), or cerebroplacental ratio Doppler index best identifies the small fetus requiring surveillance. Placental perfusion defects are more common earlier in gestation; accordingly, early-onset (<=32 weeks of gestation) and late-onset (>32 weeks) FGR differ in clinical phenotype. In early-onset FGR, progression of UA Doppler abnormality determines clinical acceleration, while abnormal ductus venosus (DV) Doppler precedes deterioration of biophysical variables and stillbirth. Accordingly, late DV Doppler changes, abnormal biophysical variables, or an abnormal cCTG require delivery. In late-onset FGR, MCA Doppler abnormalities precede deterioration and stillbirth. However, from 34 to 38 weeks, randomized evidence on optimal delivery timing is lacking. From 38 weeks onward, the balance of neonatal versus fetal risks favors delivery. PMID- 29606483 TI - The association between serum squamous cell carcinoma antigen and recurrence and survival of patients with cervical squamous cell carcinoma: A systematic review and meta-analysis. AB - OBJECTIVE: The aim of this systematic review and meta-analysis was to pool association effects of serum squamous cell carcinoma antigen (SCC-Ag) on recurrence and mortality in mainly squamous cell cervical cancer patients. METHODS: MEDLINE and Scopus databases were searched up to June 29, 2016. Studies assessing effects of SCC-Ag on recurrence and death in cervical cancer patients were included. Data extraction was independently performed by two reviewers. A meta-analysis was applied for pooling the effects (i.e., risk ratio (RR), hazard ratio (HR), and unstandardized mean difference (USMD)) of SCC-Ag measured before and after treatment on recurrence and death. RESULTS: A total of 61 studies were included. For pretreatment SCC-Ag and recurrence, the pooled RR, HR, and USMD for high versus low serum SCC-Ag were 2.44(95% CI: 1.91, 3.13), 2.23(95% CI: 2.03, 2.45), -7.7(95% CI: -31.7, 16.4), respectively. The corresponding effects for the posttreatment period were 3.91(95% CI: 2.96, 5.16), 3.14(95% CI: 1.29, 7.65), and 3.2(95% CI: -10.6, 17.0), respectively. In addition, patients with high level of pretreatment serum SCC-Ag were also at a higher risk for death than patients with low serum SCC-Ag with a pooled RR of 3.66(95% CI: 2.24, 5.98), pooled HR of 2.50(95% CI: 1.85, 3.37), and pooled USMD of 7.10(95% CI: 4.26, 9.94). The posttreatment serum SCC-Ag effects also reflected a similar trend. CONCLUSIONS: The serum SCC-Ag was consistently associated with recurrence and mortality of newly diagnosed cervical cancer. This marker may be useful in monitoring disease progression in cervical cancer patients. Prospero registration number is: CRD42016044024. PMID- 29606484 TI - Psychometric properties of three different scales for subjective evaluation of shoulder pain and dysfunction in Italian patients after shoulder surgery for anterior instability. AB - BACKGROUND: The Italian versions of Shoulder Pain and Disability Index (SPADI), Simple Shoulder Test (SST), and University of California-Los Angeles (UCLA) Shoulder Rating Scale have been validated to assess shoulder dysfunction in patients treated for neck cancer. The present study investigated the psychometric properties of the Italian versions of the SPADI, SST, and UCLA in patients after shoulder surgery for anterior instability. MATERIALS AND METHODS: The study population included 98 patients. Patients completed the Italian SPADI, SST, and UCLA, and Western Ontario Shoulder Instability Index (WOSI), American Shoulder and Elbow Surgeons (ASES) Standardized Shoulder Assessment Form, Oxford Shoulder Score (OSS), and 36-Item Short Form Health Survey (SF-36). Reproducibility was assessed by asking patients to complete another UCLA, SPADI, and SST 48 hours after the first. Validity was assessed by calculating the correlation between the SPADI, SST, and UCLA and the WOSI, ASES, OSS, and the SF-36 Physical Health subscales. RESULTS: The internal consistencies of the SPADI (alpha = 0.97) and the SST (alpha = 0.87) were very high. The test-retest reliability was excellent with intraclass correlation coefficient of 0.97 for the SPADI, 0.93 for UCLA pain, 0.95 for UCLA function, and 0.97 for the SST. A significant correlation was found between the Italian SPADI, SST, and UCLA and the WOSI, the ASES and the OSS. DISCUSSION: Psychometric properties of the Italian SPADI, SST, and UCLA compared well with those reported for the original versions, supporting their use as reliable clinimetric instruments in the setting of shoulder disorders after surgery for recurrent anterior instability. PMID- 29606485 TI - Complement: The Emerging Architect of the Developing Brain. AB - Complement activation products have long been associated with roles in the innate immune system, linking the humoral and cellular responses. However, among their recently described non-inflammatory roles, complement proteins also have multiple emerging novel functions in brain development. Within this context, separate proteins and pathways of complement have carved out physiological niches in the formation, development, and refinement of neurons. They demonstrate actions that are both reminiscent of peripheral immune actions and removed from them. We review here three key roles for complement proteins in the developing brain: progenitor proliferation, neuronal migration, and synaptic pruning. PMID- 29606486 TI - Augmented reality fluoroscopy simulation of the guide-wire insertion in DHS surgery: A proof of concept study. AB - BACKGROUND: Hip fractures contribute to a significant clinical burden globally with over 1.6 million cases per annum and up to 30% mortality rate within the first year. Insertion of a dynamic hip screw (DHS) is a frequently performed procedure to treat extracapsular neck of femur fractures. Poorly performed DHS fixation of extracapsular neck of femur fractures can result in poor mobilisation, chronic pain, and increased cut-out rate requiring revision surgery. A realistic, affordable, and portable fluoroscopic simulation system can improve performance metrics in trainees, including the tip-apex distance (the only clinically validated outcome), and improve outcomes. METHOD: We developed a digital fluoroscopic imaging simulator using orthogonal cameras to track coloured markers attached to the guide-wire which created a virtual overlay on fluoroscopic images of the hip. To test the accuracy with which the augmented reality system could track a guide-wire, a standard workshop femur was used to calibrate the system with a positional marker fixed to indicate the apex; this allowed for comparison between guide-wire tip-apex distance (TAD) calculated by the system to be compared to that physically measured. Tests were undertaken to determine: (1) how well the apex could be targeted; (2) the accuracy of the calculated TAD. (3) The number of iterations through the algorithm giving the optimal accuracy-time relationship. RESULTS: The calculated TAD was found to have an average root mean square error of 4.2 mm. The accuracy of the algorithm was shown to increase with the number of iterations up to 20 beyond which the error asymptotically converged to an error of 2 mm. CONCLUSION: This work demonstrates a novel augmented reality simulation of guide-wire insertion in DHS surgery. To our knowledge this has not been previously achieved. In contrast to virtual reality, augmented reality is able to simulate fluoroscopy while allowing the trainee to interact with real instrumentation and performing the procedure on workshop bone models. PMID- 29606487 TI - Chemo-enzymatic synthesis of the exocyclic olefin isomer of thymidine monophosphate. AB - Exocyclic olefin variants of thymidylate (dTMP) recently have been proposed as reaction intermediates for the thymidyl biosynthesis enzymes found in many pathogenic organisms, yet synthetic reports on these materials are lacking. Here we report two strategies to prepare the exocyclic olefin isomer of dTMP, which is a putative reaction intermediate in pathogenic thymidylate biosynthesis and a novel nucleotide analog. Our most effective strategy involves preserving the existing glyosidic bond of thymidine and manipulating the base to generate the exocyclic methylene moiety. We also report a successful enzymatic deoxyribosylation of a non-aromatic nucleobase isomer of thymine, which provides an additional strategy to access nucleotide analogs with disrupted ring conjugation or with reduced heterocyclic bases. The strategies reported here are straightforward and extendable towards the synthesis of various pyrimidine nucleotide analogs, which could lead to compounds of value in studies of enzyme reaction mechanisms or serve as templates for rational drug design. PMID- 29606488 TI - Discovery of new A- and B-type laxaphycins with synergistic anticancer activity. AB - Two new cyclic lipopeptides termed laxaphycins B4 (1) and A2 (2) were discovered from a collection of the marine cyanobacterium Hormothamnion enteromorphoides, along with the known compound laxaphycin A. The planar structures were solved based on a combined interpretation of 1D and 2D NMR data and mass spectral data. The absolute configurations of the subunits were determined by chiral LC-MS analysis of the hydrolysates, advanced Marfey's analysis and 1D and 2D ROESY experiments. Consistent with similar findings on other laxaphycin A- and B-type peptides, laxaphycin B4 (1) showed antiproliferative effects against human colon cancer HCT116 cells with IC50 of 1.7 uM, while laxaphycins A and A2 (2) exhibited weak activities. The two major compounds isolated from the sample, laxaphycins A and B4, were shown to act synergistically to inhibit the growth of HCT116 colorectal cancer cells. PMID- 29606489 TI - [The BeGraft Bentley(r) stent for treatment of aortic coarctation]. PMID- 29606490 TI - Stress induced cardiomyopathy due to a Mexican earthquake. AB - Takotsubo Cardiomyopathy mainly occurs in postmenopausal women, with or without cardiovascular disease, and is commonly associated with emotional or physical stress. After nearly 27 years of extensive efforts towards a better understanding of this disorder, current knowledge remains limited. Many people suffer post traumatic stress, and this situation can be associated to stress cardiomyopathy. The case is presented of a female who suffers stress associated with the earthquake of 19 September 2017 in Mexico City, and arrived in the Emergency Department in cardiogenic shock. PMID- 29606491 TI - [Massive atrial invasion by bronchogenic carcinoma complicated with stroke]. PMID- 29606492 TI - Is it time to include non-alcoholic fatty liver disease in the current risk scores for atrial fibrillation? PMID- 29606493 TI - Ultrasound Detection of Microcalcifications in Surgical Breast Specimens. AB - The objective was to evaluate a commercial image processing technique (MicroPure, Canon Medical Systems, Tustin, CA, USA) for detection of microcalcifications in breast surgical specimens. Twenty women scheduled for surgical excision of an area with breast calcifications were enrolled, their surgical specimens underwent grayscale ultrasound (US) and MicroPure examination using an Aplio XG scanner (Canon). Four independent and blinded readers analyzed 54 US and 54 MicroPure digital clips to determine the number of calcifications and scored image quality and artifacts on a 10-point scale. All readers saw significantly more microcalcifications with MicroPure than with US, 14.0 +/- 12.0 versus 3.0 +/- 3.2 (p <0.0001). Three readers preferred MicroPure image quality over that of US (p <0.009) and vice versa for one reader (p = 0.003). Three readers saw fewer Cooper's ligament artifacts with MicroPure than with US (p <0.0001); one reader saw no significance difference between them (p = 0.58). In conclusion MicroPure identified more breast microcalcifications than grayscale US in ex vivo surgical breast specimens. PMID- 29606494 TI - Adaptive super-twisting observer for fault reconstruction in electro-hydraulic systems. AB - An adaptive-gain super-twisting sliding mode observer is proposed for fault reconstruction in electro-hydraulic servo systems (EHSS) receiving bounded perturbations with unknown bounds. The objective is to address challenging problems in classic sliding mode observers: chattering effect, conservatism of observer gains, strong condition on the distribution of faults and uncertainties. In this paper, the proposed super-twisting sliding mode observer relaxes the condition on the distribution of uncertainties and faults, and the gain adaptation law leads to eliminate observer gain overestimation and attenuate chattering effects. After using the equivalent output-error-injection feature of sliding mode techniques, a fault reconstruction strategy is proposed. The experimental results are presented, confirming the effectiveness of the proposed adaptive super-twisting observer for precise fault reconstruction in electro hydraulic servo systems. PMID- 29606495 TI - Listeria Adhesion Protein Induces Intestinal Epithelial Barrier Dysfunction for Bacterial Translocation. AB - Intestinal epithelial cells are the first line of defense against enteric pathogens, yet bacterial pathogens, such as Listeria monocytogenes, can breach this barrier. We show that Listeria adhesion protein (LAP) induces intestinal epithelial barrier dysfunction to promote bacterial translocation. These disruptions are attributed to the production of pro-inflammatory cytokines TNF alpha and IL-6, which is observed in mice challenged with WT and isogenic strains lacking the surface invasion protein Internalin A (DeltainlA), but not a lap- mutant. Additionally, upon engagement of its surface receptor Hsp60, LAP activates canonical NF-kappaB signaling, facilitating myosin light-chain kinase (MLCK)-mediated opening of the epithelial barrier via cellular redistribution of the epithelial junctional proteins claudin-1, occludin, and E-cadherin. Pharmacological inhibition of MLCK or NF-kappaB in cells or genetic ablation of MLCK in mice prevents mislocalization of junctional proteins and L. monocytogenes translocation. Thus, L. monocytogenes uses LAP to exploit epithelial defenses and cross the intestinal epithelial barrier. PMID- 29606497 TI - Targeting high frequency oscillations in epilepsy. PMID- 29606498 TI - Pre-diagnostic dynamic HPV16 IgG seropositivity and risk of oropharyngeal cancer: Methodologic issues. PMID- 29606496 TI - Small Interfering RNA-Mediated Control of Virus Replication in the CNS Is Therapeutic and Enables Natural Immunity to West Nile Virus. AB - No vaccines or therapeutics are licensed for West Nile virus (WNV), a mosquito transmitted neuroencephalitic flavivirus. The small interfering RNA siFvEJW targets a conserved sequence within the WNV E protein and limits virus infection. Using a rabies virus-derived neuron-targeting peptide (RVG9R) and an intranasal route for delivering siFvEJW to the CNS, we demonstrate that treatment of WNV infected mice at late stages of neuroinvasive disease results in recovery. Selectively targeting virus in the CNS lowers viral burdens in the brain, reduces neuropathology, and results in a 90% survival rate at 5-6 days post-infection (when viral titers peak in the CNS), while placebo-treated mice succumb by days 9 10. Importantly, CNS virus clearance is achieved by humoral and cell-mediated immune responses to WNV infection in peripheral tissues, which also engender sterilizing immunity against subsequent WNV infection. These results indicate that intranasal RVG9R-siRNA treatment offers efficient late-stage therapy and facilitates natural long-term immunity against neuroinvasive flaviviruses. PMID- 29606499 TI - Biotechnologies toward Mitigating, Curing, and Ultimately Preventing Edema through Compression Therapy. AB - For a century-old problem, edema and its treatment have gone remarkably unnoticed by the biomedical community. Given the prevalence of lymphedema and its debilitating repercussions, there is an acute need for both efficacy-based measures and clinical standards to guide compression garment design and therapeutic application. This review outlines the current state of the art in compression treatment and suggests an integrated biomedical engineering approach going forward. Characterizing the pressure gradient profiles of commercial compression sleeves is necessary to better understand the role of compression treatment in the mitigation of swelling. Integration of pressure sensor technologies with advanced materials design and manufacture provides a critical path not only to elucidate the mechanisms of but also to improve on current compression-based therapies and associated therapeutic devices. PMID- 29606500 TI - Preimplantation Genetic Diagnosis Counseling in Autosomal Dominant Polycystic Kidney Disease. AB - Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common hereditary forms of chronic kidney disease. Mutations within PKD1 or PKD2 lead to innumerable fluid-filled cysts in the kidneys and in some instances, end-stage renal disease (ESRD). Affected individuals have a 50% chance of passing the mutation to each of their offspring. Assisted reproductive technology using preimplantation genetic diagnosis (PGD) allows these individuals to reduce this risk to 1% to 2%. We assess the disease burden of 8 individuals with ADPKD who have undergone genetic testing in preparation for PGD. Clinical features that predict high risk for progression to ESRD in patients with ADPKD include genotype, early onset of hypertension, a urologic event before age 35 years, and a large height-adjusted total kidney volume. Patients may have a family history of intracranial aneurysms or complications involving hepatic cysts, which may further influence the decision to pursue PGD. We also explore the cost, risks, and benefits of using PGD. All patients with ADPKD of childbearing potential, regardless of risk for progression to ESRD or risk for a significant disease burden, will likely benefit from genetic counseling. PMID- 29606501 TI - CRISPR Gene Editing in the Kidney. AB - CRISPR is a nuclease guidance system that enables rapid and efficient gene editing of specific DNA sequences within genomes. We review applications of CRISPR for the study and treatment of kidney disease. CRISPR enables functional experiments in cell lines and model organisms to validate candidate genes arising from genetic studies. CRISPR has furthermore been used to establish the first models of genetic disease in human kidney organoids derived from pluripotent stem cells. These gene-edited organoids are providing new insight into the cellular mechanisms of polycystic kidney disease and nephrotic syndrome. CRISPR-engineered cell therapies are currently in clinical trials for cancers and immunologic syndromes, an approach that may be applicable to inflammatory conditions such as lupus nephritis. Use of CRISPR in large domestic species such as pigs raises the possibility of farming kidneys for transplantation to alleviate the shortage of donor organs. However, significant challenges remain, including how to effectively deliver CRISPR to kidneys and how to control gene editing events within the genome. Thorough testing of CRISPR in preclinical models will be critical to the safe and efficacious translation of this powerful young technology into therapies. PMID- 29606502 TI - A Positive Feed-Forward Loop between LncRNA-CYTOR and Wnt/beta-Catenin Signaling Promotes Metastasis of Colon Cancer. AB - We previously demonstrated that long non-coding RNA cytoskeleton regulator RNA (CYTOR), also known as Linc00152, was significantly overexpressed in colon cancer and conferred resistance to oxaliplatin-induced apoptosis. At the same time, elevated CYTOR expression was also reported in gastric cancer and exerted influences on epithelial-mesenchymal transition (EMT) markers. However, the precise mechanism by which CYTOR promotes the EMT phenotype and cancer metastasis remains poorly understood. Here, we showed that loss of epithelial characteristics and simultaneous gain of mesenchymal features correlated with CYTOR expression. Knockdown of CYTOR attenuated colon cancer cell migration and invasion. Conversely, ectopic expression of CYTOR induced an EMT program and enhanced metastatic properties of colon cancer cells. Mechanistically, the binding of CYTOR to cytoplasmic beta-catenin impeded casein kinase 1 (CK1) induced beta-catenin phosphorylation that enabled it to accumulate and translocate to the nucleus. Reciprocally, beta-catenin/TCF complex enhanced the transcription activity of CYTOR in nucleus, thus forming a positive feed-forward circuit. Moreover, elevated CYTOR, alone or combined with overexpression of nuclear beta-catenin, was predictive of poor prognosis. Our findings suggest that CYTOR promotes colon cancer EMT and metastasis by interacting with beta-catenin, and the positive feed-forward circuit of CYTOR-beta-catenin might be a useful therapeutic target in antimetastatic strategy. PMID- 29606503 TI - A Blood-Brain-Barrier-Penetrating Anti-human Transferrin Receptor Antibody Fusion Protein for Neuronopathic Mucopolysaccharidosis II. AB - Mucopolysaccharidosis II (MPS II) is an X-linked recessive lysosomal storage disease caused by mutations in the iduronate-2-sulfatase (IDS) gene. Since IDS catalyzes the degradation of glycosaminoglycans (GAGs), deficiency in this enzyme leads to accumulation of GAGs in most cells in all tissues and organs, resulting in severe somatic and neurological disorders. Although enzyme replacement therapy with human IDS (hIDS) has been used for the treatment of MPS II, this therapy is not effective for defects in the CNS mainly because the enzyme cannot cross the blood-brain barrier (BBB). Here, we developed a BBB-penetrating fusion protein, JR-141, which consists of an anti-human transferrin receptor (hTfR) antibody and intact hIDS. The TfR-mediated incorporation of JR-141 was confirmed by using human fibroblasts in vitro. When administrated intravenously to hTfR knockin mice or monkeys, JR-141, but not naked hIDS, was detected in the brain. In addition, the intravenous administration of JR-141 reduced the accumulation of GAGs both in the peripheral tissues and in the brain of hTfR knockin mice lacking Ids, an animal model of MPS II. These data provide a proof of concept for the translation of JR-141 to clinical study for the treatment of patients with MPS II with CNS disorders. PMID- 29606504 TI - A Chimeric Antibody against ACKR3/CXCR7 in Combination with TMZ Activates Immune Responses and Extends Survival in Mouse GBM Models. AB - Glioblastoma (GBM) is the least treatable type of brain tumor, afflicting over 15,000 people per year in the United States. Patients have a median survival of 16 months, and over 95% die within 5 years. The chemokine receptor ACKR3 is selectively expressed on both GBM cells and tumor-associated blood vessels. High tumor expression of ACKR3 correlates with poor prognosis and potential treatment resistance, making it an attractive therapeutic target. We engineered a single chain FV-human FC-immunoglobulin G1 (IgG1) antibody, X7Ab, to target ACKR3 in human and mouse GBM cells. We used hydrodynamic gene transfer to overexpress the antibody, with efficacy in vivo. X7Ab kills GBM tumor cells and ACKR3-expressing vascular endothelial cells by engaging the cytotoxic activity of natural killer (NK) cells and complement and the phagocytic activity of macrophages. Combining X7Ab with TMZ allows the TMZ dosage to be lowered, without compromising therapeutic efficacy. Mice treated with X7Ab and in combination with TMZ showed significant tumor reduction by MRI and longer survival overall. Brain-tumor infiltrating leukocyte analysis revealed that X7Ab enhances the activation of M1 macrophages to support anti-tumor immune response in vivo. Targeting ACKR3 with immunotherapeutic monoclonal antibodies (mAbs) in combination with standard of care therapies may prove effective in treating GBM. PMID- 29606505 TI - Prevention of Photoreceptor Cell Loss in a Cln6nclf Mouse Model of Batten Disease Requires CLN6 Gene Transfer to Bipolar Cells. AB - The neuronal ceroid lipofuscinoses (NCLs) are inherited lysosomal storage disorders characterized by general neurodegeneration and premature death. Sight loss is also a major symptom in NCLs, severely affecting the quality of life of patients, but it is not targeted effectively by brain-directed therapies. Here we set out to explore the therapeutic potential of an ocular gene therapy to treat sight loss in NCL due to a deficiency in the transmembrane protein CLN6. We found that, although Cln6nclf mice presented mainly with photoreceptor degeneration, supplementation of CLN6 in photoreceptors was not beneficial. Because the level of CLN6 is low in photoreceptors but high in bipolar cells (retinal interneurons that are only lost in Cln6-deficient mice at late disease stages), we explored the therapeutic effects of delivering CLN6 to bipolar cells using adeno associated virus (AAV) serotype 7m8. Bipolar cell-specific expression of CLN6 slowed significantly the loss of photoreceptor function and photoreceptor cells. This study shows that the deficiency of a gene normally expressed in bipolar cells can cause the loss of photoreceptors and that this can be prevented by bipolar cell-directed treatment. PMID- 29606506 TI - Nuclease-free Adeno-Associated Virus-Mediated Il2rg Gene Editing in X-SCID Mice. AB - X-linked severe combined immunodeficiency (X-SCID) has been successfully treated by hematopoietic stem cell (HSC) transduction with retroviral vectors expressing the interleukin-2 receptor subunit gamma gene (IL2RG), but several patients developed malignancies due to vector integration near cellular oncogenes. This adverse side effect could in principle be avoided by accurate IL2RG gene editing with a vector that does not contain a functional promoter or IL2RG gene. Here, we show that adeno-associated virus (AAV) gene editing vectors can insert a partial Il2rg cDNA at the endogenous Il2rg locus in X-SCID murine bone marrow cells and that these ex vivo-edited cells repopulate transplant recipients and produce CD4+ and CD8+ T cells. Circulating, edited lymphocytes increased over time and appeared in secondary transplant recipients, demonstrating successful editing in long-term repopulating cells. Random vector integration events were nearly undetectable, and malignant transformation of the transplanted cells was not observed. Similar editing frequencies were observed in human hematopoietic cells. Our results demonstrate that therapeutically relevant HSC gene editing can be achieved by AAV vectors in the absence of site-specific nucleases and suggest that this may be a safe and effective therapy for hematopoietic diseases where in vivo selection can increase edited cell numbers. PMID- 29606508 TI - Isolation of Salmonella spp. in cattle egrets (Bubulcus ibis) from Fernando de Noronha Archipelago, Brazil. AB - The growth of the population of cattle egrets (Bubulcus ibis) in the archipelago of Fernando de Noronha constitutes a threat to public health and biological diversity because of their competition with and predation on native species and the possibility of transmission of pathogens to human beings, livestock and native wildlife. The aim here was to search for, isolate and identify serovars of Salmonella in clinically healthy local cattle egrets. Cloacal swabs were obtained from 456 clinically healthy cattle egrets of both sexes and a variety of ages. The swabs were divided into 51 pools. Six of these (11.7%) presented four serovars of Salmonella enterica subspecies enterica: Salmonella serovar Typhimurium; Salmonella serovar Newport; Salmonella serovar Duisburg; and Salmonella serovar Zega. One sample was identified as S. enterica subspecies enterica O16:y:-. Results in this study suggest that cattle egrets may be reservoirs of this agent on Fernando de Noronha and represent a risk to public health and biological diversity. PMID- 29606507 TI - Human ISL1+ Ventricular Progenitors Self-Assemble into an In Vivo Functional Heart Patch and Preserve Cardiac Function Post Infarction. AB - The generation of human pluripotent stem cell (hPSC)-derived ventricular progenitors and their assembly into a 3-dimensional in vivo functional ventricular heart patch has remained an elusive goal. Herein, we report the generation of an enriched pool of hPSC-derived ventricular progenitors (HVPs), which can expand, differentiate, self-assemble, and mature into a functional ventricular patch in vivo without the aid of any gel or matrix. We documented a specific temporal window, in which the HVPs will engraft in vivo. On day 6 of differentiation, HVPs were enriched by depleting cells positive for pluripotency marker TRA-1-60 with magnetic-activated cell sorting (MACS), and 3 million sorted cells were sub-capsularly transplanted onto kidneys of NSG mice where, after 2 months, they formed a 7 mm * 3 mm * 4 mm myocardial patch resembling the ventricular wall. The graft acquired several features of maturation: expression of ventricular marker (MLC2v), desmosomes, appearance of T-tubule-like structures, and electrophysiological action potential signature consistent with maturation, all this in a non-cardiac environment. We further demonstrated that HVPs transplanted into un-injured hearts of NSG mice remain viable for up to 8 months. Moreover, transplantation of 2 million HVPs largely preserved myocardial contractile function following myocardial infarction. Taken together, our study reaffirms the promising idea of using progenitor cells for regenerative therapy. PMID- 29606509 TI - Antimicrobial susceptibility and fluctuations in clonal complexes of serogroup 6 Streptococcus pneumoniae isolates collected from children in Beijing, China, between 1997 and 2016. AB - This study examined the antimicrobial susceptibility patterns and clonal complex (CC) characteristics of serogroup 6 Streptococcus pneumoniae isolates collected from children in Beijing, China, between 1997 and 2016. Serotypes were determined using the Quellung reaction, and the antimicrobial susceptibility profiles of the isolates were determined using the disc-diffusion method or by E-test. Sequence types (STs) were assigned based on multilocus sequence typing. A total of 250 isolates were examined, with 55.2%, 30.0%, 12.8%, and 2.0% of isolates identified as serotypes 6A, 6B, 6C, and 6D, respectively. All of the isolates were susceptible to levofloxacin and vancomycin, and the non-suceptibitility rate to penicillin was 41.6%. Eighty-two distinct STs, assigned to 13 CCs and 28 singletons, were identified. CC982 was the most prevalent CC amongst serotype 6A isolates (34%), followed by CC9789 and CC3173. Amongst serotype 6B isolates, CC90 and CC4542 were the most common, accounting for 25.3% and 14.7% of isolates respectively. Over the study period, the prevalence of CC982, CC4542, and CC4536 isolates showing susceptibility to penicillin and cefuroxime decreased, and the proportion of CC3173, CC9789, CC855, and CC902 isolates showing non susceptibility to these two antibiotics increased. PMID- 29606510 TI - Rosai-Dorfman disease: Ultrasonography and histopathology study of a soft tissue mass in the forearm. AB - Rosai-Dorfman disease (RDD) is uncommon in daily practice, but needs to be ruled out in rheumatologic conditions to elucidate a wide differential diagnosis. Beside its typical presentation, soft tissue masses can be easily seen in our Rheumatology clinics. Ultrasonography widely extended in our specialty, could also play a role in the diagnosis, to end up with the histological confirmation of the disease. PMID- 29606513 TI - All That Matters. PMID- 29606511 TI - Modifiable individual and work-related factors associated with neck pain in 740 office workers: a cross-sectional study. AB - BACKGROUND: Office workers have the highest incidence of neck pain of all occupations. However, the relationship between symptoms and the risk factors is unclear. OBJECTIVE: To examine the relationship between self-reported neck pain with a comprehensive range of individual and work-related risk factors. METHODS: This study utilised a cross-sectional study design. Office workers with and without neck pain (n=763) were recruited. Participants completed a survey which included a Pain Numerical Rating Scale (dependent variable), and measures of independent variables including demographic, individual, work-related factors, neck/shoulder muscle strength, endurance, and range of motion (ROM). The relationships between the independent and dependent variables were analysed in a logistic regression model. RESULTS: Neck pain was significantly associated with more senior occupational categories, working more than six hours per day on the computer, female sex, greater fear avoidance beliefs for work, greater psychological distress, and reduced cervical flexion ROM. The low severity of neck pain of the participants in this study may limit a robust determination of their association with the risk factor variables, but the studied sample is a realistic representation of the office worker population. CONCLUSION: Several potentially modifiable individual and work-related factors were identified to be associated with the presence of self-reported neck pain in office workers. Future studies will be needed to investigate whether strategies to alter these modifiable risk factors translate to changes in neck pain. TRIAL REGISTRATION: ACTRN12612001154897 (https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=363209). PMID- 29606512 TI - Continuous and minimally-interrupted direct oral anticoagulant are both safe compared with vitamin K antagonist for atrial fibrillation ablation: An updated meta-analysis. AB - BACKGROUND: The appropriate and safe peri-procedural anticoagulation schedule for patients on a direct oral anticoagulant (DOAC) undergoing AF ablation is not known. We aimed to evaluate the safety and efficacy of both continuous and minimally-interrupted novel oral anticoagulant (DOAC) strategies compared with uninterrupted vitamin K antagonist (VKA) for atrial fibrillation (AF) ablation. METHODS: We searched electronic databases for randomized or prospective controlled observational studies comparing DOAC (continuous or interrupted) versus uninterrupted VKA. The primary endpoint was major bleeding. Secondary endpoints were total bleeding (composite of major and minor bleeding) and symptomatic thromboembolism. Data were analyzed by random-effects modeling and sensitivity analyses performed according to study design and peri-procedural DOAC schedule. RESULTS: Thirteen studies (4 randomized, 9 observational) with 5463 patients were included in final analysis (45% on DOAC). DOAC was associated with less major bleeding compared with VKA in pooled randomized studies (odds ratio [OR] 0.27, 95% confidence interval [CI] 0.09-0.80, p = 0.03, I2 = 0%), however there was no difference on overall analyses (OR 0.70, 95% CI 0.39-1.24, p = 0.22, I2 = 27%). When stratified by DOAC dose schedule, there was no difference in major bleeding for continuous DOAC (OR 0.48, 95% CI 0.21-1.11, p = 0.09, I2 = 6%) or minimally-interrupted DOAC (OR 0.81, 95% CI 0.37-1.76, p = 0.60, I2 = 43%) compared with VKA. There was no difference between DOAC and VKA for risk of total bleeding (p = 0.20) or symptomatic thromboembolism (p = 0.78). CONCLUSION: Continuous and minimally-interrupted DOAC are both safe and non-inferior peri procedural anticoagulation strategies compared with uninterrupted VKA for AF ablation. DOAC in general is associated with reduced major bleeding as demonstrated in pooled randomized studies. PMID- 29606514 TI - Cancer in the Elderly. PMID- 29606515 TI - Plasma Exchange for Neuromyelitis Optica Spectrum Disorders in Chinese Patients and Factors Predictive of Short-term Outcome. AB - PURPOSE: The purposes of this article were to evaluate the short-term outcome of plasma exchange (PLEX) for neuromyelitis optica spectrum disorders (NMOSDs) in Chinese patients and to identify the factors predictive of a favorable response to therapy. METHODS: We retrospectively analyzed data from 29 Chinese patients with NMOSD. All patients received 2 to 7 sessions of PLEX every other day. Expanded Disability Status Scale (EDSS) scores were estimated at baseline, at relapse, and before and at follow-up after PLEX. Patients were assigned to 1 of 2 groups according to treatment responses of marked to moderate improvement and mild to no improvement. FINDINGS: Twenty-four of 29 patients (82.8%) showed functional improvement at 1 month after PLEX, 9 of whom experienced moderate to marked improvement. Early PLEX initiation and a lower baseline EDSS score were independent prognostic factors (both, P < 0.05). In addition, relapse symptoms of nonoptic neuritis and acute transverse myelitis plus circumventricular organs, seronegativity for aquaporin-4 antibodies, shorter initial therapy-PLEX interval, and no prior optic neuritis attacks were predictive factors significantly associated with a favorable response to treatment (all, P < 0.05). The delay time pre-PLEX was inversely correlated with reduction in EDSS score. The percentage reductions in EDSS score in groups receiving PLEX on days <=15 and days 16 to 30 were significantly greater than those in the groups treated on days 31 to 60 and days 61 to 90 (all, P < 0.05). Most PLEX sessions were generally well tolerated. IMPLICATIONS: PLEX is an effective therapy for NMOSD in the Chinese population, and early PLEX initiation was associated with a favorable response. We recommend an optimum PLEX time of 30 days from the time of disease onset. Further long-term prospective, multicenter studies that include a larger sample of patients with NMOSD treated with PLEX are necessary. PMID- 29606516 TI - Knowledge, attitudes and practices related to the influenza virus and vaccine among older adults in Eastern China. AB - BACKGROUND: This study aims to assess the association between socio-demographic and health characteristics of older adults in Eastern China and knowledge, attitudes, and practices (KAP) about the influenza virus and vaccine. METHODS: A prospective cohort of 1506 older adults (aged >=60 years) was enrolled from November to December 2015 in Jiangsu Province. We examined the association between demographics, health and functional status, and cognitive impairment at enrollment with awareness of influenza virus and vaccine and KAP items focused on five Health Belief Model domains. At a 12-month follow-up interview we assessed change in awareness and readiness to be vaccinated. RESULTS: One in five older adults was aware of the influenza virus (21%) or vaccine (20%); even fewer reported having at least "a little" knowledge of the virus and vaccine (7% and 4%, respectively); less than 1% reported ever receiving an influenza vaccine. Retirement, higher education and income, and normal cognitive status were consistently associated with both awareness and knowledge of influenza virus. The odds of having at least "a little" knowledge of the vaccine was 2.9-fold (95% CI = 1.6-5.3) higher among older adults with at least some secondary schooling. Among the 108 with knowledge of the virus, 55% said they "worry about getting the flu this season." Among the 73 with knowledge of the vaccine, 92% believed the vaccine was at least somewhat effective and less than half (43%) thought that influenza vaccination was safe. At a 12-month follow-up interview, 33% (442/1333) increased from no knowledge to at least "a little". CONCLUSIONS: If and when influenza vaccines become widely available to older adults in China, our results indicate that influenza vaccination campaigns with basic information on the virus and vaccine could be beneficial for all older adults, especially those with less education and/or more cognitive impairment. PMID- 29606517 TI - Long-term follow-up of HIV-1-infected adults who received the F4/AS01B HIV-1 vaccine candidate in two randomised controlled trials. AB - This Phase I/II, open, long-term follow-up study was conducted in antiretroviral therapy (ART)-naive (N = 212) and ART-treated (N = 19) human immunodeficiency virus 1 (HIV-1)-infected adults, who received an HIV-1 investigational vaccine (F4/AS01B) or placebo in two previous studies (NCT00814762 and NCT01218113). After a minimum of two years and a maximum of four years of follow-up post vaccination per patient, no significant differences were observed between F4/AS01B and placebo groups in terms of viral load, CD4+ T-cell count and incidence of specific clinical events. Vaccine-induced polyfunctional CD4+ T cells persisted up to study end and no relevant vaccine-related safety events were reported in F4/AS01B groups. This study has been registered at ClinicalTrials.gov (NCT01092611). PMID- 29606518 TI - Factors associated with routine immunization coverage of children under one year old in Lao People's Democratic Republic. AB - BACKGROUND: Routine vaccination is administered free of charge to all children under one year old in Lao People's Democratic Republic (Lao PDR) and the national goal is to achieve at least 95% coverage with all vaccines included in the national immunization program by 2025. In this study, factors related to the immunization system and characteristics of provinces and districts in Lao PDR were examined to evaluate the association with routine immunization coverage. METHODS: Coverage rates for Bacillus Calmette-Guerin (BCG), Diphtheria-Tetanus Pertussis-Hepatitis B (DTP-HepB), DTP-HepB-Hib (Haemophilus influenzae type B), polio (OPV), and measles (MCV1) vaccines from 2002 to 2014 collected through regular reporting system, were used to identify the immunization coverage trends in Lao PDR. Correlation analysis was performed using immunization coverage, characteristics of provinces or districts (population, population density, and proportion of poor villages and high-risk villages), and factors related to immunization service (including the proportions of the following: villages served by health facility levels, vaccine session types, and presence of well functioning cold chain equipment). To determine factors associated with low coverage, provinces were categorized based on 80% of DTP-HepB-Hib3 coverage (<80% = low group; >=80% = high group). RESULTS: Coverages of BCG, DTP-HepB3, OPV3 and MCV1 increased gradually from 2007 to 2014 (82.2-88.3% in 2014). However, BCG coverage showed the least improvement from 2002 to 2014. The coverage of each vaccine correlated with the coverage of the other vaccines and DTP-HepB-Hib dropout rate in provinces as well as districts. The provinces with low immunization coverage were correlated with higher proportions of poor villages. CONCLUSIONS: Routine immunization coverage has been improving in the last 13 years, but the national goal is not yet reached in Lao PDR. The results of this study suggest that BCG coverage and poor villages should be targeted to improve nationwide coverage. PMID- 29606519 TI - Parental acceptability of HPV vaccination for boys and girls aged 9-13 years in China - A population-based study. AB - BACKGROUND: This study was to investigate parental acceptability of HPV vaccination for their sons and daughters aged 9-13 years under different cost scenarios, and factors associated with parental acceptability at market price. METHODS: Participants were: (1) Chinese speaking parents aged 18-60 years with a Hong Kong ID card; (2) had a son or a daughter aged 9-13 years at the date of the survey; (3) the child had the right to abode in Hong Kong. Random telephone numbers were selected from up-to-date telephone directories of Hong Kong. A total of 300 eligible parents (boys' parents: 162; girls' parents: 138, response rate: 68.9% & 69%) provided verbal informed consent and completed the anonymous telephone interview during March to October 2016. Using parental acceptability of HPV vaccination at market price as the dependent variable, univariate and multiple logistic regression models were fitted. RESULTS: The prevalence of HPV vaccination was very low among boys and girls (0.6% vs. 2.2%, p = 0.242). Among those whose children had not taken up HPV vaccination, the prevalence of parental acceptability of HPV vaccination for the index son and daughter were: 14.9% and 27.4% (market price), and 51.6% and 63.0% (free vaccination). Adjusted for sociodemographic variables, attitudinal variables based on the Health Belief Model were associated with parental acceptability of HPV vaccination for their sons (perception that it was not worthy, perceived cue to action from mass media and perceived self-efficacy) and for their daughters (perceived susceptibility and perceived severity of HPV infection among females, perceived benefit of HPV vaccination and perceived self-efficacy). CONCLUSION: Coverage of HPV vaccination among children aged 9-13 years was very low. Instead of waiting for the free universal vaccination to become available, promotion of self-paid HPV vaccination targeting parents is urgently needed. Different strategies should be applied to boys' and girls' parents. PMID- 29606520 TI - The significance of interfamilial relationships on birth preparedness and complication readiness in Pakistan. AB - BACKGROUND: In the interests of improving maternal health care and survival, the issue of birth preparedness and complication readiness has been much debated and has remained a priority for the international health community. The provision of birth preparedness and complications readiness is determined by a range of different factors. AIM: The main aim of this study is to identify and measure the influence of husbands and other family relationships on birth preparedness and complications readiness in the Khyber Pakhtunkhwa province of Pakistan. METHODS: This study is a cross-sectional exploratory study. Data was collected through a survey questionnaire. Logistic regression and descriptive analysis was used. FINDINGS: Analysis indicated that the mother-in-law's role, men's and women's level of education and interfamilial relationships are still the most significant factors influencing birth preparedness and complications readiness. Of the respondents, 86% were receiving antenatal care and 76.5% were planning for the birth to take place in state-run hospitals or private obstetric and gynae clinics. CONCLUSION: The tendency to take up antenatal care in Khyber Pakhtunkhwa can mainly be credited to a mutual understanding between husband and wife and a good relationship between the woman and her mother-in-law. Highlighting the significance of these relationships has implications for ensuring birth preparedness and complications readiness. PMID- 29606521 TI - Pharmacological therapy selection of type 2 diabetes based on the SWARA and modified MULTIMOORA methods under a fuzzy environment. AB - Medication selection for Type 2 Diabetes (T2D) is a challenging medical decision making problem involving multiple medications that can be prescribed to control the patient's blood glucose. The wide range of hyperglycemia lowering agents with varying effects and various side effects makes the decision quite difficult. This paper presents computer-aided medical decision support using a fuzzy Multi Criteria Decision-Making (MCDM) model that hybridizes a Step-wise Weight Assessment Ratio Analysis (SWARA) method with a modification of Fuzzy Multi Objective Optimization on the basis of a Ratio Analysis plus the full multiplicative form (FMULTIMOORA) method for pharmacological therapy selection of T2D. It makes the use of SWARA for obtaining the relative significance of every selected criterion by soliciting experts' opinions and FMULTIMOORA method for evaluation of each alternative according to all criteria based on a published clinical guideline. In this paper, an extended reference point approach is considered in the proposed hybrid MCDM model that resolves the classic reference point limitations and improves the FMULTIMOORA ranking procedure. Computational results indicate that Metformin is confirmed as the first-line medication and Sulfonylurea as the second-line add-on therapy. The Glucagon-like peptide-1 receptor agonist, Dipeptidyl peptidase-4 inhibitor, and Insulin are placed 3rd, 4th, and 5th, respectively. A sensitivity analysis is conducted to validate the model performance by comparing its result with studies in the literature, other fuzzy MCDM techniques and an interval MULTIMOORA method based on an observational dataset. The close correspondence between the final rankings of anti-diabetic agents resulted from the proposed hybrid model and other methodologies provide significant implications for endocrinologists to refer. PMID- 29606523 TI - Influence of deformable image registration on 4D dose simulation for extracranial SBRT: A multi-registration framework study. AB - BACKGROUND AND PURPOSE: To evaluate the influence of deformable image registration approaches on correspondence model-based 4D dose simulation in extracranial SBRT by means of open source deformable image registration (DIR) frameworks. MATERIAL AND METHODS: Established DIR algorithms of six different open source DIR frameworks were considered and registration accuracy evaluated using freely available 4D image data. Furthermore, correspondence models (regression-based correlation of external breathing signal measurements and internal structure motion field) were built and model accuracy evaluated. Finally, the DIR algorithms were applied for motion field estimation in radiotherapy planning 4D CT data of five lung and five liver lesion patients, correspondence model formation, and model-based 4D dose simulation. Deviations between the original, statically planned and the 4D-simulated VMAT dose distributions were analyzed and correlated to DIR accuracy differences. RESULTS: Registration errors varied among the DIR approaches, with lower DIR accuracy translating into lower correspondence modeling accuracy. Yet, for lung metastases, indices of 4D-simulated dose distributions widely agreed, irrespective of DIR accuracy differences. In contrast, liver metastases 4D dose simulation results strongly vary for the different DIR approaches. CONCLUSIONS: Especially in treatment areas with low image contrast (e.g. the liver), DIR-based 4D dose simulation results strongly depend on the applied DIR algorithm, drawing resulting dose simulations and indices questionable. PMID- 29606522 TI - Radiotherapy quality assurance for the RTOG 0834/EORTC 26053-22054/NCIC CTG CEC.1/CATNON intergroup trial "concurrent and adjuvant temozolomide chemotherapy in newly diagnosed non-1p/19q deleted anaplastic glioma": Individual case review analysis. AB - BACKGROUND: The EORTC phase III 26053-22054/ RTOG 0834/NCIC CTG CEC.1/CATNON intergroup trial was designed to evaluate the impact on concurrent and adjuvant temozolomide chemotherapy in newly diagnosed non-1p/19q deleted anaplastic gliomas. The primary endpoint was overall survival. We report the results of retrospective individual case reviews (ICRs) for the first patient randomized per institution to detect the compliance with the study protocol. MATERIAL AND METHODS: Sixty-nine institutions were required to submit the radiotherapy plan of their first randomized patient. Full digital datasets uploaded to the EORTC server were assessed by three independent and blinded reviewers through the EORTC radiotherapy quality assurance platform. RESULTS: Sixty-two (90%) of sixty-nine ICRs were received and assessable. Of the 62 cases, 22 were evaluated as per protocol (35.5%), 11 as acceptable variation (17.7%) and 29 were classified as unacceptable variations (46.8%). Most common unacceptable variations were related to the PTV dose (n = 19, 31%) and delineation (n = 17, 27%) processes. CONCLUSIONS: The ICR analysis showed a significant number of unacceptable variations with potential impact on tumor control and/or toxicity profile. Prospective ICRs are encouraged for future studies to prevent and correct protocol violations before start of treatment. PMID- 29606524 TI - External beam radiation therapy to hepatocellular carcinoma involving inferior vena cava and/or right atrium: A meta-analysis and systemic review. AB - PURPOSE: Hepatocellular carcinoma (HCC) involving inferior vena cava (IVC) and/or right atrium (RA) is a very rare but serious disease. The objective of this meta analysis was to assess efficacy and safety of external beam radiotherapy (EBRT) for HCC involving IVC and/or RA. MATERIALS AND METHODS: Systematic search of Pubmed, MEDLINE, EMBASE, and Cochrane library published was performed. Primary endpoints were 1-year overall survival (OS) rate and 2-year OS rates. Secondary endpoints were response rate, local control (LC) rate, and grade >=3 toxicities. According to heterogeneity evaluated with Cochran Q test and I2 statistics, meta analysis was performed using either random or fixed model. RESULTS: A total of 8 studies and 9 cohorts were included, encompassing 164 patients. Pooled 1- and 2 year OS rates were 53.6% (95% CI: 45.7-61.3%) and 36.9% (95% CI: 27.2-42.4%), respectively. Pooled response rate and LC rate were 59.2% (95% CI: 39.0-76.7%) and 83.8% (95% CI: 78.8-97.1%), respectively. Only one study reported 2 grade >=3 toxicities, an esophageal rupture and a pulmonary embolism cases. The overall rate of possible grade >=3 complications was 1.2% (2 of 164). CONCLUSIONS: EBRT is a feasible and safe option to palliate HCC with IVC and/or RA invasion. PMID- 29606525 TI - Economic data for particle therapy: Dealing with different needs in a heterogeneous landscape. AB - BACKGROUND: In the light of scarce resources to be allocated for cancer care and a steady stream of costly innovations in all modalities applied to treat cancer, particle therapy needs to demonstrate its cost-utility balance to allow its positioning in the context of competing modalities. In the continuous evolving particle therapy landscape, the timely availability of appropriate economic data is crucial. METHODS: Economic data collection and compilation for particle therapy needs to follow health economic standards. Costing related analyses particularly need attention as clinical outcome data follow international standards to provide comparability. Among others, perspective, time horizons and cost categories are critical. RESULTS: In this report from the "Health Economics Work Package" of the European Particle Therapy Network, the approaches commonly applied in health economic assessments are described and tailored to the specific needs of particle therapy. Data collection for cost calculation, economic evaluation and budget impact analysis are discussed. CONCLUSION: The presented data are intended to serve as a guidance for economic data collection, bearing in mind that in each specific case, the heterogeneous requirements of national health systems will need to be considered and assessments adapted accordingly. PMID- 29606526 TI - Prevalence of severe fatigue among adults with cystic fibrosis: A single center study. AB - BACKGROUND: With life expectancy increasing among patients with cystic fibrosis (CF), the prevalence of complications such as fatigue is also expected to increase. Our aim was to investigate the prevalence of severe fatigue among adults with CF and to identify factors associated with fatigue. METHODS: Adult patients with CF receiving treatment at a single center were invited to complete three questionnaires. We then studied the associations between fatigue and clinically measured parameters and between fatigue and patient-reported outcomes. RESULTS: A total of 77 patients (age 19-54years; 56% males; mean FEV1: 63%) completed the questionnaires (43% response rate). The prevalence of severe fatigue among these patients was 26%. The variance in fatigue was explained partially by clinically measured parameters. However, patient-reported outcomes were stronger independently associated with fatigue and included the patients' reported respiratory symptoms, emotional functioning, and social functioning. CONCLUSIONS: Fatigue is a clinically important and highly prevalent issue among adults with CF and is associated with a significant reduction in health-related quality of life and participation in society. In addition, fatigue is associated more strongly with the patient's perception of symptoms and well-being than with clinically measured parameters. PMID- 29606527 TI - A Comparison of International Drunk-Driving Policies and the Role of Drinking Patterns. AB - INTRODUCTION: Effective drunk-driving policies are not adopted consistently in many countries. To understand how drinking behaviors influence national drunk driving policymaking, the associations between drunk-driving policies and country level drinking volumes and patterns were examined. METHODS: Data for 194 countries were obtained from the WHO 2012 Global Information System on Alcohol and Health. Country-level drinking behaviors were measured using average drinking volumes and patterns of drinking scores based on six attributes of risky drinking. Drunk-driving policies were categorized into preemptive measures (random breath testing, breath alcohol concentration limits for driving a vehicle, and sobriety checkpoints), penalties (community service, short- or long term detention, fines, suspension or revocation of license, and vehicle impoundment), mandatory treatment, and ignition interlock. Data analysis was conducted in 2017. The percentages of each policy adoption were examined in countries with different drinking behaviors. The internal consistencies of preemptive measures were calculated using Cronbach's alpha. A structural equation model was established to examine the associations between drinking behaviors and drunk-driving policy categories, after adjusting for national income levels and general alcohol policies. RESULTS: Mandatory treatment and preemptive measures were less commonly adopted than penalties were. The adoption of preemptive measures had a low consistency level, and the consistency level decreased with drinking pattern riskiness. Risky drinking patterns were negatively associated with mandatory treatment policy. CONCLUSIONS: Drinking patterns are associated with national drunk-driving policymaking. Accessible medical treatment and comprehensive preemptive measures should be advocated in countries with risky drinking patterns. PMID- 29606528 TI - Outcomes of rotator cuff augmentation surgery with autologous fascia lata. AB - OBJECTIVE: To evaluate whether augmentation grafts using autologous fascia lata improve functional results for rotator cuff repairs and reduce the retear rate compared to those without augmentation. MATERIAL AND METHODS: This is a prospective evaluation comprising 20 patients with a complete symptomatic rotator cuff tear. The operations were carried out from a superior approach performing a total cuff repair, for 10 patients we used a suture augmented with an autologous graft taken from their own fascia lata while unaugmented sutures were used for the other 10 patients. The follow-up period lasted for one year post intervention. We measured variables for tear type, functionality and pain, both baseline and at 6 and 12-month follow ups. We evaluated retear incidence in each group as well as each group's pain and functionality response. RESULTS: The improved pain levels in the non-graft group evolved gradually over time. Conversely, in the group with the augmentation grafts, average Constant-Murley shoulder outcome scores at six months were already above 10 and were maintained at 12 months. One retear occurred in the graft group and 2 in the group without grafts, thus presenting no significant differences. There were no significant changes in pain and function values at the one year follow up in either group. CONCLUSION: Our preliminary results regarding rotator cuff augmentation surgery with autologous fascia lata showed a significant improvement in pain levels after 6 months compared to the patients with no augmentation, who required 12 months to reach the same values. After a year of follow up, there were no differences between the mean Constant and pain scores in either intervention group The number of retears in the non-graft group was greater than that in the group with grafts although the difference was not significant. PMID- 29606529 TI - Inverted U-shaped curve relationship between red blood cell distribution width and hypertension in a large health checkup population in China. AB - This study was aimed at investigating the relationship between red blood cell distribution width (RDW) and hypertension in a large health check up population in China. A population of 302,527 subjects from Wuhu was enrolled in this cross sectional health check up study between 2011 and 2016. They consisted of 126,369 women (41.78%) and 176,158 men (58.23%) with mean age of 46.9 +/- 13.4 and 48.1 +/- 13.7 years, respectively. The investigations included information on demographic characteristics, physical examination, and laboratory testing. Inverted U-shape relationships were observed between RDW and hypertension with peak RDW values of 14.2 (women) and 15.2 (men). After stratification by sex and adjusted with body mass index, age, white blood cells, and high-density lipoprotein cholesterol, inverted U-shape relationships were also established between RDW and hypertension, systolic blood pressure, and diastolic blood pressure, with peak RDW of 14.2, 14.5, 14.5 in women and 14.2, 16.0, 14.5 in men. Inverted U-shape relationship exists between RDW and hypertension, systolic blood pressure, and diastolic blood pressure among the Chinese health check up population studied. PMID- 29606530 TI - Two-point discrimination and the low back pain: Not as unreliable as it seems, but what about standardised procedures? PMID- 29606531 TI - Differentiated stimulating effects of activated carbon on methanogenic degradation of acetate, propionate and butyrate. AB - Granular activated carbon (GAC) could promote methane production from organic wastes, but a wide range of dosages has been reported. In present study, different GAC dosages of 0, 0.5, 5 and 25 g/L were supplemented into anaerobic digesters and the methanogenic degradation kinetics of acetate, propionate and butyrate were characterized, respectively. At high organic load of 5 g/L, the degradation rates of propionate and butyrate increased by 1.5-4.7 and 2.5-7.0 times at varied GAC dosages. The methane production rates (Rmax) from propionate and butyrate were significantly elevated when increasing GAC dosage up to 5 g/L. However, only a minor increment was found for acetate degradation either at 1 g/L or 5 g/L. The stimulatory mechanism of GAC for accelerated syntrophic degradation of propionate and butyrate can be primarily attributed to the triggering effect on acetogenesis, as evidenced by the enrichment of syntrophic bacteria e.g. Thermovirga, Synergistaceae, and Syntrophomonas etc. PMID- 29606532 TI - Improved properties of recycled polypropylene by introducing the long chain branched structure through reactive extrusion. AB - An approach originated from preparing long chain branched polypropylene (PP) was applied to modify the properties of recycled PP that involved reactive extrusion to introduce a branched chain structure onto recycled PP under the assistance of chemical reaction between maleic anhydride (MAH) monomer and glycidyl methacrylate (GMA) grafts. The results from Fourier transformed infrared spectroscopy (FTIR) indicated the reaction took place during melt mixing, and the intensity of ester increased with increasing amount of MAH. Several rheological plots including complex viscosity, storage modulus, loss modulus, loss tangent and Cole-Cole plot were used to investigate the rheological properties of recycled PP and modified PP with MAH, which indicated an additional longer relaxation time that was not shown in recycled PP. The effects of branched structure on melting and crystallization behaviors were also investigated, demonstrating the branched chains acted as nucleating agent. Moreover, the branched structure of modified samples gave rise to enhance mechanical properties, especially, the higher impact strength compared with recycled PP. PMID- 29606533 TI - Environmental impacts of food waste: Learnings and challenges from a case study on UK. AB - Food waste, particularly when avoidable, incurs loss of resources and considerable environmental impacts due to the multiple processes involved in the life cycle. This study applies a bottom-up life cycle assessment method to quantify the environmental impacts of the avoidable food waste generated by four sectors of the food supply chain in United Kingdom, namely processing, wholesale and retail, food service, and households. The impacts were quantified for ten environmental impact categories, from Global Warming to Water Depletion, including indirect land use change impacts due to demand for land. The Global Warming impact of the avoidable food waste was quantified between 2000 and 3600 kg CO2-eq. t-1. The range reflected the different compositions of the waste in each sector. Prominent contributors to the impact, across all the environmental categories assessed, were land use changes and food production. Food preparation, for households and food service sectors, also provided an important contribution to the Global Warming impacts, while waste management partly mitigated the overall impacts by incurring significant savings when landfilling was replaced with anaerobic digestion and incineration. To further improve these results, it is recommended to focus future efforts on providing improved data regarding the breakdown of specific food products within the mixed waste, indirect land use change effects, and the share of food waste undergoing cooking. Learning from this and previous studies, we highlight the challenges related to modelling and methodological choices. Particularly, food production datasets should be chosen and used carefully, to avoid double counting and overestimation of the final impacts. PMID- 29606534 TI - Timely diagnosis, use of information technology and mosquito control prevents dengue outbreaks: Experience from central India. AB - BACKGROUND: Dengue is most important arboviral disease spreading to newer areas. Timely diagnosis and mosquito control are only ways to prevent outbreaks; however there are very few studies demonstrating this hypothesis. METHODS: During this study laboratory diagnosis for Dengue was provided to patient and the programme manager on the same day of receipt of the sample. The mobile number of the patient/kin of patient was used to contact patient and reach their address to conduct vector control within 24h of case detection. RESULTS: Eighty three present cases were diagnosed within 24h and 82% houses were surveyed within 24h of reporting of the positive cases. The prompt diagnosis proactive vector control model helped keeping dengue outbreaks at bay. CONCLUSION: Timely diagnosis and prompt vector control activities can prevent dengue outbreaks. It is suggested to enhance diagnostic capabilities at local level and use new technologies such as mobile phones and internet to strengthen health systems to curb DEN. PMID- 29606535 TI - Immunochromatography in CSF improves data on surveillance of S. pneumoniae meningitis in India. AB - INTRODUCTION: Streptococcus pneumoniae is a significant cause of childhood bacterial meningitis in India. The United States Food and Drug Administration has licensed an immunochromatographic (ICT) test, Binax(r)NOWTM, to detect the C polysaccharide antigen of S. pneumoniae in cerebrospinal fluids (CSF). Accurate etiological diagnosis of bacterial meningitis in India is essential for effective treatment strategies and preventive interventions. MATERIALS AND METHODS: CSF samples from 2081 children admitted, with clinically suspected bacterial meningitis at 11 sentinel sites of hospital based sentinel surveillance network for bacterial meningitis in India between September 2009 and December 2016 were tested with ICT. Concurrent CSF cultures were processed using standard procedures. RESULTS AND DISCUSSION: S. pneumoniae was detected thrice the number of times by ICT than by CSF culture, with a sensitivity and specificity of 100% and 95.3% respectively. This rapid ICT test proves to be of immense use as a diagnostic test for meningitis patients with/without prior antibiotic treatment, especially in facilities with limited laboratory infrastructure in resource limited settings. PMID- 29606536 TI - The Rise of Big Data in Oncology. AB - OBJECTIVES: To describe big data and data science in the context of oncology nursing care. DATA SOURCES: Peer-reviewed and lay publications. CONCLUSION: The rapid expansion of real-world evidence from sources such as the electronic health record, genomic sequencing, administrative claims and other data sources has outstripped the ability of clinicians and researchers to manually review and analyze it. To promote high-quality, high-value cancer care, big data platforms must be constructed from standardized data sources to support extraction of meaningful, comparable insights. IMPLICATIONS FOR NURSING PRACTICE: Nurses must advocate for the use of standardized vocabularies and common data elements that represent terms and concepts that are meaningful to patient care. PMID- 29606537 TI - Introduction. PMID- 29606538 TI - The Evolution of Radiation Therapy in Treating Cancer. AB - OBJECTIVES: Describe the significant changes that have occurred to elevate radiation therapy as a significant modality in treating cancer. DATA SOURCES: Peer-reviewed and lay publications. CONCLUSION: Radiation has been used in medicine since its discovery in the 19th century. Since the start of the 20th century, radiation has been increasingly used to diagnose and treat cancer. Although, radiation therapy was often known to destroy healthy tissue in its attempt to kill cancer cells, technological advancements have allowed for precise and accurate therapy, providing a viable option as a cure for individuals diagnosed with cancer. IMPLICATIONS FOR NURSING PRACTICE: As radiation therapy is increasingly utilized as a treatment option for patients with cancer, it is critical for oncology nurses to be cognizant of this treatment modality and to understand how it impacts our patients. PMID- 29606539 TI - Anatomy of the Pudendal Nerve and Other Neural Structures Around the Proximal Hamstring Origin in Males. AB - PURPOSE: To define the anatomy of the pudendal nerve in relationship to the proximal hamstring and other nearby neurological structures during proximal hamstring repair. METHODS: Six fresh-frozen human cadaveric hemi-pelvises from male patients ages 64.0 +/- 4.1 years were dissected in prone position with hips in 10 degrees flexion to identify the relationship of proximal hamstring origin to surrounding neurologic structures including the pudendal nerve, sciatic nerve, and posterior femoral cutaneous nerve. Two independent observers used digital calipers to measure distances. RESULTS: The pudendal nerve emerged at the inferior border of the piriformis muscle 6.3 +/- 1.4 cm from the superior aspect of the proximal hamstring origin. It passed the superior border of the sacrotuberous ligament 3.0 +/- 0.6 cm from the superior aspect and 3.9 +/- 0.7 cm from the medial aspect of the hamstring origin. It crossed the inferior border of the sacrotuberous ligament 3.0 +/- 0.4 cm from the superior aspect and 2.7 +/- 0.7 cm from the medial aspect of the proximal hamstring origin. The shortest distance from the hamstring origin to the pudendal nerve was 2.6 +/- 0.5 cm from the superior aspect and 2.3 +/- 0.8 cm from the medial aspect. The shortest distance from the hamstring origin to the pudendal nerve was located deep to the sacrotuberous ligament in all cadavers. The sciatic nerve was an average of 1.1 +/- 0.1 cm lateral to the lateral aspect of the proximal hamstring origin. The posterior femoral cutaneous nerve was located between the hamstring origin and the sciatic nerve, 0.7 +/- 0.2 cm lateral to the lateral aspect of the proximal hamstring origin. CONCLUSIONS: The proximal hamstring origin lies in close proximity to surrounding nerves, including the pudendal, sciatic, and posterior femoral cutaneous nerves. CLINICAL RELEVANCE: Knowledge that the pudendal nerve lies 2 to 3 cm superior and medial to the proximal hamstring origin may help to prevent iatrogenic damage during surgical dissection and retraction when performing proximal hamstring repair or deep gluteal space endoscopy. PMID- 29606540 TI - Diverticulitis with a giant colonic diverticulum. PMID- 29606541 TI - Appendiceal endometriosis simulating acute appendicitis. PMID- 29606542 TI - Proton beam therapy for the management of mediastinal Hodgkin lymphoma in a young female patient. PMID- 29606543 TI - A phase I, open-label, single-dose micro tracer mass balance study of 14C-labeled ASP7991 in healthy Japanese male subjects using accelerator mass spectrometry. AB - ASP7991 is a calcimimetic that acts on the calcium-sensing receptor on parathyroid cell membranes and suppresses parathyroid hormone (PTH) secretion in the treatment of secondary hyperparathyroidism. The mass balance and metabolite profile of [14C]ASP7991 were investigated in six healthy male subjects after a single oral dose of [14C]ASP7991 [1 mg, 18.5 kBq (500 nCi)] in solution. [14C] radioactivity in plasma, urine and feces was analyzed using Accelerator mass spectrometry. ASP7991 was rapidly absorbed, metabolized and excreted. Mean recovery of [14C] radioactivity in urine and feces was 30.08% and 49.31%, respectively, and mean total recovery of [14C] radioactivity was 79.39%. The majority of [14C] radioactivity in urine and feces was excreted within the first 72 h following administration. Seven metabolites were detected in plasma, urine and feces samples, and their structures were determined by mass spectrometry. The main metabolic pathways of ASP7991 in humans were predicted to be N-dealkylation, followed by N-acetylation and taurine conjugation to a carboxylic acid moiety. Our findings show that a mass balance study using micro radioactivity doses is suitable for elucidating the pharmacokinetics of the absorption, metabolism and excretion of administered drugs. PMID- 29606544 TI - Management of duct obstruction in transplanted submandibular glands. AB - BACKGROUND: Submandibular gland (SMG) transplantation is a successful treatment approach for patients with severe dry eye. However, duct obstruction can occur post-transplant. METHODS: We studied nineteen patients with duct obstruction of transplanted SMGs, including five interventional modalities: stone removal; secretory stimulation (to mimic "internal irrigation" with substantial secretory flow); irrigation; surgical opening of stenosis and orifice reconstruction; cephalic vein bypass and Wharton's duct reconstruction. RESULTS: A solitary stone was found and removed in one patient. Duct blockages like mucus plug were cleared by secretory stimulation in three patients, and by normal saline irrigation in two grafts. In the remaining 13 patients, irrigation failed and surgical opening was performed. Orifice reconstruction succeeded in six of the eight patients, whose stenosis was near the orifice. Wharton's duct reconstruction was successful in two of the five cases where stenosis was located in the middle segment of the duct. CONCLUSION: Transplanted SMGs obstruct for various reasons. Stone, which is easy to diagnose and treat, should be excluded first. Non-organic blockage and stenosis were semblable in clinic. Therefore, subsequent steps should be a diagnostic/therapeutic trial of secretory stimulation, followed by irrigation; failure of these interventions suggests the diagnosis of duct stenosis, necessitating surgical recanalization. PMID- 29606545 TI - Should people with psychosis be supported in choosing cognitive therapy as an alternative to antipsychotic medication: A commentary on current evidence. AB - Evidence from randomised controlled trials suggest that both antipsychotic medication and cognitive behaviour therapy (CBT) can be helpful to people with a diagnosis of a schizophrenia spectrum disorder. On this basis, many clinical guidelines recommend that people with psychosis should be offered both antipsychotic medication and CBT and that they should be collaboratively involved in the decisions about which treatment options they choose. The reality of service provision is often very different, with data regarding the availability of such treatment options and the extent of user involvement in decision making suggesting that medication is much more widely available and that service users are often not involved in these decisions, despite retaining decision making capacity. Many patients choose not to take antipsychotic medication, often due to inefficacy or side effects, but there is little evidence regarding whether CBT can be effective as an alternative to antipsychotic medication. However, several recent trials suggest that CBT without medication may be a safe and acceptable option for people with psychosis. The implications for clinical practice and future research are considered and it is recommended that informed choices that include the option to try CBT without antipsychotic medication are supported. PMID- 29606547 TI - Effect of aerobic training on nerve conduction in men with type 2 diabetes and peripheral neuropathy: A randomized controlled trial. AB - OBJECTIVE: Peripheral neuropathy (PN) is one of the long-term complications of diabetes. Few studies have investigated the role of regular exercise on diabetic PN. We examined the effect of aerobic training on nerve conduction velocity and action potential amplitude in the lower limbs of men with type 2 diabetes and PN. METHODS: In a randomized controlled study, 24 volunteers diagnosed with diabetic PN were randomly assigned to exercise or control groups. Aerobic training consisted of 20-45min walking or running at 50-70% of heart rate reserve for three sessions per week over 12weeks. Before and 48h after the experimental period, nerve conduction studies were performed and blood samples were taken to be analyzed for HbA1c, fasting and 2h postprandial glucose concentration. Data were analyzed using repeated-measures ANOVA at significance level of P<0.05. RESULTS: Sural sensory nerve conduction velocity (NCV) in the exercise group significantly increased (from 35.2+/-4.3m/s to 37.3+/-6.2m/s) compared to the control group (P=0.007). Changes in peroneal and tibial motor NCV and nerve action potential amplitude (NAPA) in all nerves studied were not different between groups (P>0.05). Moreover, HbA1c decreased to a greater extent in the exercise group compared to the control (P=0.014). CONCLUSION: Aerobic exercise training may have the potential to hinder the progression of diabetic PN by improving NCV. Given the sparse evidence in this domain, exercise-related mechanisms need to be studied in the future. PMID- 29606546 TI - Smoking does not impact social and non-social cognition in patients with first episode psychosis. AB - BACKGROUND: Many studies having shown significant improvements in non-social and social cognitive performance in smoking FEP patients compared to non-smoking FEP patients. The findings are controversial. This study analyzed the effects of tobacco use on non-social and social cognitive function in a large group of FEP patients and a matched healthy control group. METHODS: A sample of 335 patients with FEP and 253 healthy controls was divided into four subgroups: control tobacco users (CTU), control non-tobacco users (CNTU), patient tobacco users (PTU) and patient non-tobacco users (PNTU). Demographic variables, tobacco use variables (presence or absence, frequency and duration of tobacco use), neurocognitive (non-social) performance and social cognition were assessed. RESULTS: Comparison of 4 subgroups in non-social cognitive function revealed significant differences after controlling for covariables in executive functions (F=13.45; p<=0.001) and working memory domains (F=4.30; p=0.005). CTU and CNTU subgroups scored higher in all the domains compared to the PTU and the PNTU subgroups respectively. Social cognitive function was also significantly different within the four subgroups, with control subgroups showing better social cognition than patient subgroups. Significant differences in the executive functions domain were observed when comparing PTU and CTU groups (F=19.60; p<=0.001). No significant differences were revealed in the comparison between the patient groups. CONCLUSIONS: This large study suggests that tobacco use in FEP patients is not related to better non-social or social cognitive performance. PMID- 29606548 TI - Consecutive postural adjustments (CPAs): A kinetic analysis of variable velocity during a pointing task. AB - AIM: This paper examines the postural adjustments that occur after the end of a voluntary movement (consecutive postural adjustments, CPAs). Its aim is to reinforce the theory that CPAs are necessary to counterbalance the destabilizing effect of a voluntary movement. In addition, we compared the main features of CPAs with those of anticipatory postural adjustments (APAs) in order to gather evidence that could afford new insights into postural programming. METHODS: Nine healthy adults were invited to adopt a sitting position to perform nine pointing movements at decreasing velocities. The antero-posterior component of the reaction forces was measured. Upper limb kinematics were recorded and the kinetics calculated. The main features under study included linear impulses, peak amplitudes and duration of CPAs and APAs. RESULTS: Two main results emerged from our study: the impulse produced after the end of a focal movement (CPAIx) was negative, while the impulse produced before its end (*ASPIx) was positive; their absolute values were not significantly different; when movement velocity increased, CPA impulse and peak amplitude (pCPA) increased significantly, contrary to duration (dCPA). Furthermore, APA impulse, peak amplitude and duration were all increased. CONCLUSIONS: These findings on pointing movements strengthen the hypothesis that CPAs play a role of body stabilization and that the postural chain kinetics is programmed according to focal movement velocity. Evidence on CPA obtained from healthy subjects may contribute to the further specification of the differences associated with motor impairment. PMID- 29606550 TI - How healthcare professionals experience patient participation in designing healthcare services and products. A qualitative study in the field of spinal cord injury in Switzerland. AB - OBJECTIVES: This study explored healthcare professionals' accounts of patient participation, focusing particularly on aspects related to patients' contributions to the planning and design of healthcare services and products. It aimed to determine (1) how healthcare professionals experience patient participation, (2) what factors, in their view, may inhibit or promote it; and (3) through what channels they think it can take place. METHODS: This study adopted a pragmatic epistemological approach. Data was collected through semi structured interviews with healthcare professionals at four specialized centers for spinal cord injury in Switzerland. RESULTS: Healthcare professionals who participated in this study were generally open to patient participation in the healthcare innovation process, highlighting several factors that may influence this process. Participants referred to three types of patient contributions that would usually emerge from informal exchange: (1) bringing in information unknown to staff; (2) reporting problems; and (3) providing concrete suggestions for improvement. CONCLUSION & PRACTICE IMPLICATIONS: Healthcare professionals' positive view on and experiences with patient participation in the healthcare innovation process provide a fertile ground to further explore ways of fostering this new form of collaboration. Ultimately, it will be important to demonstrate its positive impact on both patients' as well as healthcare professionals' experiences. PMID- 29606549 TI - A randomized comparison of the proximal crescentic osteotomy and rotational scarf osteotomy in the treatment of hallux valgus. AB - OBJECTIVES: The aim of this study was to compare clinical and radiological results of proximal crescentic osteotomy (PCO) and rotational scarf osteotomy performed in the treatment of hallux valgus. METHODS: A total of 57 consecutive patients (60 feet) with symptomatic hallux valgus deformity were randomly assigned to one of two groups. The PCO group consisted of 22 women and 5 men (30 feet) and the mean age was 43(+/-14.5) years. The scarf group consisted of 23 women and 7 men (30 feet) and the mean age was 40.9(+/-12.6) years. Outcomes were assessed by using of preoperative and postoperative American Orthopaedic Foot and Ankle Society (AOFAS) scores and visual analogue scale (VAS). Weight bearing X rays were used for radiological evaluation. RESULTS: The mean AOFAS scores improved from 42(+/-16.2) to 66.7(+/-13.4) points in PCO group and from 36.2(+/ 16.1) to 73.2(+/-13.5) points in scarf group. The mean pain score improved from 6.3(+/-1.3) to 2.4(+/-2) in PCO group and from 6.5(+/-1.9) to 2.5(+/-1.3) in scarf group. The mean hallux valgus angle (HVA) decreased from 38.1 degrees (+/ 7.1) preoperatively to 23.8 degrees (+/-8.5) at postoperative first year in PCO group, and from 36.1 degrees (+/-7.5) preoperatively to 22.2 degrees (+/-7.5) at postoperative first year in scarf group. The mean intermetatarsal angle (IMA) decreased from 17.3 degrees (+/-3.8) preoperatively to 11.8 degrees (+/-3.3) at postoperative first year in PCO group, and from 16.2 degrees (+/-2.6) preoperatively to 9.3 degrees (+/-2.4) at postoperative first year in scarf group. When all the patients were assessed together, the relations between preoperative DMAA values and postoperative first year HVA (r = 0,327) and IMA (r = 0,399) values were positive but had low significance. The HVA and IMA values were increased in both groups at the end of the first year when compared to the postoperative sixth week values (p < 0.01 for both groups for both values). CONCLUSION: The PCO and the rotational scarf osteotomy in the treatment of hallux valgus deformity provides a satisfactory correction. The clinical and radiological results of both methods are similar. Especially in patients with high preoperative DMAA, an increase in the HVA and the IMA values may occur in the first postoperative year when compared to the postoperative sixth week values. LEVEL OF EVIDENCE: Level II, therapeutic study. PMID- 29606551 TI - Patient perceived participation in decision making on their antipsychotic treatment: Evidence of validity and reliability of the COMRADE scale in a sample of schizophrenia spectrum disorders. AB - OBJECTIVE: The aim of this paper is to provide evidence of the validity and reliability of the COMRADE scale (Combined Outcome Measure for Risk communication And treatment Decision making Effectiveness) in patients suffering from schizophrenia spectrum disorders. METHOD: 150 patients recruited at five mental health centers were assessed using a cross-sectional study design. The COMRADE, WAIS-S (therapeutic alliance) and TSQM (satisfaction with medication) scales were used. RESULTS: Exploratory Factor Analysis identified three factors from the COMRADE (F1: "Risk communication"; F2: "Confidence in decision" and F3: "Knowledge of decisional balance") which explain 45.2, 8.5 and 6% of the variance, respectively. Statistically significant correlations were observed between the scores of the COMRADE subscales with the subscales of the WAI-S and the TSQM. The internal consistency observed for each of the factorial scores of the COMRADE were (Cronbach's alpha values) 0.90, 0.89 and 0.74, respectively. CONCLUSION: The COMRADE scale offers appropriate psychometric properties for its use as a measure of perceived patient involvement in the shared decision making process in antipsychotic treatment. PRACTICE IMPLICATIONS: The use of the COMRADE measure in psychiatric clinical practice and in research studies provides an outcome measure of interventions from the shared decision making model. PMID- 29606552 TI - Sexual Activity Recommendations in High-Risk Pregnancies: What is the Evidence? AB - BACKGROUND: While sexual activity in normal, healthy pregnant women is safe, concern regarding elements of the sexual act have led to restrictions in pregnancies experiencing complications that are frequently insufficiently addressed in clinical practice. AIM: To comprehensively review the literature for evidence that supports or refutes specific sexual activity restrictions in high risk pregnancy conditions. METHODS: A search of PubMed, MEDLINE, Ovid, UpToDate, Google Scholar, and Google for relevant publications related to any aspect of sexual activity affecting high-risk pregnancies complicated by history of pre term delivery, shortened cervix, presence of cerclage, pre-mature rupture of membranes, placenta abruption, placenta previa, multiple gestation, or history of classical cesarean section was performed. OUTCOMES: The scientific evidence on the pathophysiology of sexual activity and specific high-risk pregnancies, and their interaction. RESULTS: Despite expert opinion restricting sexual acts or intercourse, there are minimal published data that specifically address sexual activity in high-risk pregnancies. CONCLUSIONS: Clinicians need to engage in conversations regarding specific sexual activity for patients experiencing complications in pregnancy. Recommendations for or against restricting sexual activity should be based on evidence-based guidelines. Significant advances in this area of obstetrics are necessary to make validated recommendations. MacPhedran S. Sexual Activity Recommendations in High-Risk Pregnancies: What is the Evidence? Sex Med Rev 2018;6:343-357. PMID- 29606553 TI - New and Emerging Technologies in Treatment of Lower Urinary Tract Symptoms From Benign Prostatic Hyperplasia. AB - INTRODUCTION: Lower urinary tract symptoms (LUTS) from bladder outlet obstruction from benign prostatic hyperplasia (BPH) occur in a large percentage of urologic patients. Treatment of this condition with medical and surgical therapy provides symptom relief but has serious adverse effects and causes sexual dysfunction. New technologies to treat BPH-associated LUTS aim to effectively treat urinary symptoms and minimize side effects and sexual dysfunction. AIM: To review the efficacy of new and emerging therapies for treatment of LUTS from BPH. METHODS: A literature search was performed to identify therapies for LUTS from BPH with early outcomes data within the past 5 years. MAIN OUTCOME MEASURES: Improvement in International Prostate Symptom Score (IPSS) and effect on sexual functions such as erectile and ejaculatory functions as measured on the International Index of Erectile Function and the Male Sexual Health Questionnaire. RESULTS: Technologies introduced within the past 5 years include techniques using intraprostatic injectables, mechanical devices, and prostatic tissue ablation. Most technologies remain in the development phase and have only phase I and II studies available that show promising alleviation of urinary symptoms. Injectables have not typically surpassed placebo or sham effects, although special cohorts could be exceptions. Thus far, convective water vapor ablation therapy and prostatic urethral lift have shown the most promise, with short- and medium-term data available on phase III studies demonstrating significant improvement in IPSS with minimal impact on sexual function. Many of these technologies are limited in their potential treatment population by prostate size and conformation, whereas other therapies might be more generalizable. CONCLUSION: Many new technologies aim to treat LUTS from BPH and minimize sexual side effects. Most therapies remain experimental, although prostatic urethral lift and water vapor ablation therapy have been brought to market and show promise. Long-term durability of symptom relief remains to be demonstrated. Gupta NK, Gange SN, McVary KT. New and Emerging Technologies in Treatment of Lower Urinary Tract Symptoms From Benign Prostatic Hyperplasia. Sex Med Rev 2018;XX:XXX XXX. PMID- 29606554 TI - The Effects of Exercise on Sexual Function in Women. AB - BACKGROUND: Acute exercise is associated with transient changes in metabolic rate, muscle activation, and blood flow, whereas chronic exercise facilitates long-lasting adaptations that ultimately improve physical performance. Exercise in general is known to improve both physical and psychological health, but the differential effects of brief bouts of exercise vs long-term exercise regimens on sexual function are less clear. AIM: The purpose of this review was to assess the direct and indirect effects of both acute and chronic exercise on multiple domains of sexual function in women. METHODS: A literature review of published studies on exercise and sexual function was conducted. Terms including "acute exercise," "chronic exercise," "sexual function," "sexual arousal," "sexual desire," "lubrication," "sexual pain," and "sexual satisfaction" were used. OUTCOMES: This review identifies key relationships between form of exercise (ie, chronic or acute) and domain of sexual function. RESULTS: Improvements in physiological sexual arousal following acute exercise appear to be driven by increases in sympathetic nervous system activity and endocrine factors. Chronic exercise likely enhances sexual satisfaction indirectly by preserving autonomic flexibility, which benefits cardiovascular health and mood. Positive body image due to chronic exercise also increases sexual well-being. Though few studies have examined the efficacy of month-long exercise programs for the treatment of sexual dysfunction, exercise interventions have alleviated sexual concerns in 2 specific clinical populations: women with anti-depressant-induced sexual dysfunction and women who have undergone hysterectomies. CONCLUSIONS: This review highlights the positive effects of acute and chronic exercise on sexual function in women. Directions for future research are discussed, and clinicians are encouraged to tailor specific exercise prescriptions to meet their patients' individual needs. Stanton AM, Handy AB, Meston CM. The Effects of Exercise on Sexual Function in Women. Sex Med Rev 2018;6:548-557. PMID- 29606555 TI - Current methodology of MTT assay in bacteria - A review. AB - The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) tetrazolium assay is a popular tool in estimating the metabolic activity of living cells. The test is based on enzymatic reduction of the lightly colored tetrazolium salt to its formazan of intense purple-blue color, which can be quantified spectrophotometrically. Under properly optimized conditions the obtained absorbance value is directly proportional to the number of living cells. Originally, the MTT assay was devised for use in eukaryotic cells lines and later applied for bacteria and fungi. As the mechanism of MTT reduction was studied in detail mostly considering eukaryotic cells, the lack of information resulted in generating a vast variety of MTT based protocols for bacterial enzymatic activity evaluation. In the presented article the main aspects of the MTT assay applicability in bacterial research were summarized, with special emphasis on sources of inaccuracies and misinterpretation of the test results. PMID- 29606556 TI - Prevalence and mutation spectrum of skeletal muscle channelopathies in the Netherlands. AB - Few reliable data exist on the prevalence of skeletal muscle channelopathies. We determined the minimum point prevalence of genetically-defined skeletal muscle channelopathies in the Netherlands and report their mutation spectrum. Minimum point prevalence rates were calculated as number of genetically-confirmed skeletal muscle channelopathy patients (CLCN1, SCN4A, CACNA1S and KCNJ2 gene mutations) in the Netherlands (1990-2015) divided by the total number of at-risk individuals. Rates were expressed as cases/100.000 and 95% confidence intervals were calculated based on Poisson distribution. Results of standardized genetic diagnostic procedures were used to analyze mutation spectra. We identified 405 patients from 234 unrelated pedigrees, resulting in a minimum point prevalence of 2.38/100.000 (95% CI 2.16-2.63) for skeletal muscle channelopathies in the Netherlands. Minimum point prevalence rates for the disease groups, non dystrophic myotonia and periodic paralysis, were 1.70/100.000 and 0.69/100.000 respectively. Sixty-one different CLCN1 mutations (including 12 novel mutations) were detected in myotonia congenita. Twenty-eight different SCN4A missense mutations (including three novel mutations) were identified in paramyotonia congenita/sodium channel myotonia, hypokalemic periodic paralysis and hyperkalemic periodic paralysis. Four different CACNA1S missense mutations were detected in hypokalemic periodic paralysis and five KCNJ2 missense mutations in Andersen-Tawil syndrome. The minimum point prevalence rates for genetically defined skeletal muscle channelopathies confirm their rare disease status in the Netherlands. Rates are almost twice as high as in the UK and more in line with pre-genetic prevalence estimates in parts of Scandinavia. Future diagnostic and therapeutic studies may benefit from knowledge of the mutation spectrum of skeletal muscle channelopathies. PMID- 29606557 TI - Continuous transversus abdominis plane block for analgesia in three dogs with abdominal pain. PMID- 29606558 TI - Immigrant Bashing and Healthcare: Have We Lost Our Mind? PMID- 29606559 TI - The magnitude of translational and rotational head accelerations experienced by riders during downhill mountain biking. AB - OBJECTIVES: To determine the magnitude of translational and rotational head accelerations during downhill mountain biking. DESIGN: Observational study. METHODS: Sixteen male downhill cyclists (age 26.4+/-8.4years; stature 179.4+/ 7.2cm; mass 75.3+/-5.9kg) were monitored during two rounds of the British Downhill Series. Riders performed two runs on each course wearing a triaxial accelerometer behind the right ear. The means of the two runs for each course were used to determine differences between courses for mean and maximum peak translational (g) and rotational accelerations (rad/s2) and impact duration for each course. RESULTS: Significant differences (p<0.05) were revealed for the mean number of impacts (>10g), FW=12.5+/-7.6, RYF=42.8+/-27.4 (t(22.96)=-4.70; p<0.001; 95% CI=17.00 to 43.64); maximum peak rotational acceleration, FW=6805.4+/-3073.8rad/s2, RYF=9799.9+/-3381.7rad/s2 (t(32)=-2.636; p=0.01; 95% CI=680.31 to 5308.38); mean acceleration duration FW=4.7+/-1.2ms, RYF=6.5+/-1.4ms (t(32)=-4.05; p<0.001; 95% CI=0.91 to 2.76) and maximum acceleration duration, FW=11.6+/-4.5ms, RYF=21.2+/-9.1 (t(29.51)=-4.06; p=0.001; 95% CI=4.21 to 14.94). No other significant differences were found. CONCLUSIONS: Findings indicate that downhill riders may be at risk of sustaining traumatic brain injuries and course design influences the number and magnitude of accelerations. PMID- 29606560 TI - Biospecimens and the ABCD study: Rationale, methods of collection, measurement and early data. AB - Biospecimen collection in the Adolescent Brain Cognitive Development (ABCD) study - of hair samples, shed deciduous (baby) teeth, and body fluids - will serve dual functions of screening for study eligibility, and providing measures of biological processes thought to predict or correlate with key study outcomes on brain and cognitive development. Biosamples are being collected annually to screen for recency of drug use prior to the neuroimaging or cognitive testing visit, and to store for the following future studies: (1) on the effects of exposure to illicit and recreational drugs (including alcohol and nicotine); (2) of pubertal hormones on brain and cognitive developmental trajectories; (3) on the contribution of genomics and epigenomics to child and adolescent development and behavioral outcomes; and (4) with pre- and post-natal exposure to environmental neurotoxicants and drugs of abuse measured from novel tooth analyses. The present manuscript describes the rationales for inclusion and selection of the specific biospecimens, methodological considerations for each measure, future plans for assessment of biospecimens during follow-up visits, and preliminary ABCD data to illustrate methodological considerations. PMID- 29606561 TI - Prognostic value of lymph node count from selective neck dissection in oral squamous cell carcinoma. AB - Unlike the levels of anatomical exploration, there is no consensus on the extent of lymph node dissection, or lymph node count (LNC), during selective neck dissection (SND). The aim of this study was to validate the prognostic impact of LNC on survival and to determine an optimal LNC cut-off value for SND. A retrospective investigation identified 78 patients with a diagnosis of oral squamous cell carcinoma (OSCC) who underwent SND (levels I-III or levels I-IV). LNC and clinicopathological variables were analyzed for any association with survival in Cox proportional hazards models. Based on the receiver operating characteristic curve, a cut-off value of 19 lymph nodes was found to predict overall survival (OS) (area under the curve 0.732, sensitivity 67.8%, specificity 75.0%; P=0.026) and disease-specific survival (DSS) (area under the curve 0.762, sensitivity 68.1%, specificity 77.8%; P=0.011). On Cox regression, LNC (>=19 vs. <19) was the only independent predictor of OS (hazard ratio 5.29, 95% confidence interval 1.39-20.05; P=0.014) and DSS (hazard ratio 6.76, 95% confidence interval 1.40-32.77; P=0.018). Similar results were obtained in the pathologically lymph node-negative subgroup (n=66). Based on the study findings, SND should include 19 or more lymph nodes for a survival benefit. PMID- 29606562 TI - Evaluation of postoperative changes in vascularized iliac bone grafts used for mandibular reconstruction. AB - Vascularized iliac bone grafts are used for mandibular reconstruction, but the factors affecting graft maintenance are unknown. This study explored the postsurgical changes in vascularized iliac bone grafts in patients who had undergone mandibular reconstruction after segmental resection. The study involved 24 patients (16 men and eight women) with oral tumours or osteoradionecrosis. Thirteen patients required bare bone grafting (BBG) and 11 patients required reconstruction with soft tissue coverage (six with a skin paddle and five with direct closure). The bone graft maintenance rate (with regard to the height of the centre of the graft) was calculated immediately after surgery and at 3, 6, 12, 24, and 36months after surgery. The maintenance rate was significantly lower in the BBG group than in the soft tissue coverage group at 3, 6, 12, 24, and 36months, and in those who were fitted with dentures compared to those who were not at 6, 12, 24, and 36months. Local infection also influenced the maintenance rate, but not significantly so. These findings indicate that the reconstruction technique and denture use can affect the bone graft maintenance rate after mandibular reconstruction with vascularized iliac bone grafts. PMID- 29606563 TI - Does two-dimensional vs. three-dimensional surgical simulation produce better surgical outcomes among patients with class III facial asymmetry? AB - The aim of this study was to compare the outcomes of traditional two-dimensional planning (2DP) and three-dimensional surgical simulation (3DS) in the surgical correction of skeletal class III with facial asymmetry. This retrospective cohort study included 37 consecutive adult Taiwanese patients. Preoperative and postoperative three-dimensional cephalometric measurements were obtained from cone beam computed tomography scans. The outcome variables were the differences in preoperative and postoperative linear and angular measurements and the differences between the two groups after surgery. When the surgical result was compared between the 2DP and 3DS groups, significant differences were found for four cephalometric variables: the distance from gonion on the non-deviated side to the midsagittal plane (MSP), mid-gonion to the MSP, upper first molar on the non-deviated side to the Frankfort horizontal plane, and the yaw angle. In the 3DS group, mandibular symmetry was achieved because the centre between the bilateral gonions was improved, and because there was no significant difference in the horizontal gonion (Go to the MSP) between the deviated and non-deviated sides after surgery. 3DS provides all the necessary information for planned surgical movements for the correction of facial asymmetry; it should be considered during surgical planning to improve surgical outcomes, particularly the achievement of bilateral mandibular contour symmetry. PMID- 29606564 TI - Serum concentrations after switching from originator infliximab to the biosimilar CT-P13 in patients with quiescent inflammatory bowel disease (SECURE): an open label, multicentre, phase 4 non-inferiority trial. AB - BACKGROUND: Biological treatment of chronic inflammatory diseases has improved patient outcomes but increased health-care costs. Switching patients from originator infliximab to a biosimilar can reduce costs, but prospective data about pharmacokinetics and potential immunogenicity are scarce. We aimed to show that infliximab serum concentrations with biosimilar CT-P13 are non-inferior to those with originator infliximab after switching from originator infliximab in patients with inflammatory bowel disease. METHODS: SECURE was a prospective, open label, interventional, non-inferiority, multicentre, phase 4 trial at 13 academic and non-academic sites in Belgium and the Netherlands. Eligible participants were aged 18 years or older, had ulcerative colitis or Crohn's disease, were in clinical remission, and were on continuous treatment with originator infliximab for more than 30 weeks. Patients were switched from originator infliximab to CT P13 at a dose and infusion duration identical to those of originator infliximab (ie, ~5 mg/kg every 7-9 weeks). Patients were followed up for 16 weeks after switching, with serum concentrations of infliximab measured at baseline (before the first dose of CT-P13), 8 weeks, and 16 weeks. The primary endpoint was serum concentrations of infliximab 16 weeks after switching, assessed separately in patients with ulcerative colitis and those with Crohn's disease in the per protocol population, which included all patients with available serum concentrations and without major protocol violations. A non-inferiority margin of 15% was set (the null hypothesis was that the geometric mean of the ratio of serum infliximab concentrations at 16 weeks to those at baseline was 85% or less). Safety analyses were done in the safety population, which included participants who received at least one dose of CT-P13 and attended at least one safety assessment after that dose. This trial is registered at www.ClinicalTrialsRegister.eu, number 2014-004904-31, and is completed. FINDINGS: Between June 5, 2015, and April 6, 2016, 120 consecutive patients with inflammatory bowel disease were recruited: 59 with ulcerative colitis and 61 with Crohn's disease. 46 patients with ulcerative colitis and 42 patients with Crohn's disease comprised the per-protocol population. The geometric mean ratio of serum infliximab concentrations at week 16 (CT-P13) compared with those at baseline (originator) was 110.1% (90% CI 96.0-126.3) in patients with ulcerative colitis and 107.6% (97.4-118.8) in those with Crohn's disease. In both cases, the lower bound of the 90% CI was higher than the prespecified non-inferiority margin of 85%. Six serious adverse events were reported in six patients. Only one of these adverse events, a perianal abscess, was judged to be related to study treatment. INTERPRETATION: Switching to CT-P13 is safe and well tolerated in patients with inflammatory bowel disease in remission. Future trials should assess switching to CT-P13 in patients with active disease. FUNDING: Mundipharma. PMID- 29606565 TI - Infliximab biosimilar CT-P13 for inflammatory bowel disease. PMID- 29606566 TI - SPIRIT promotes protocol sharing. PMID- 29606567 TI - Open repair of descending and thoracoabdominal aortic aneurysms in octogenarians. AB - OBJECTIVE: Despite improved outcomes for open repair of descending thoracic aneurysm (DTA) and thoracoabdominal aortic aneurysm (TAAA), these operations remain challenging in octogenarians. Patients unsuitable for thoracic endovascular aortic repair require open surgery to avoid catastrophic rupture. We analyzed our results for DTA/TAAA repair in these elderly patients. METHODS: Our institutional aortic database was queried to identify those >=80 years old and those <80 years old undergoing open DTA/TAAA repair. Logistic and Cox regression analyses were used to account for confounders and to identify predictors of perioperative and long-term outcomes. RESULTS: From 1997 to 2017, there were 783 patients who underwent open repair of DTA or TAAA; 96 (12.3%) were >=80 years old. Octogenarians were more likely to be female (P = .018), with chronic pulmonary disease (P = .012), severe peripheral vascular disease (P < .001), and hypertension (P = .025). Degenerative aneurysms were more common among octogenarians (P < .001), whereas chronic and acute dissections were more common among those younger than 80 years (P < .001 for both). Operative mortality was 5.6% and was not negatively affected by advanced age (<80 years, 5.7%; >=80 years, 5.6%; P = .852). Other than an increased incidence of left recurrent nerve palsy in the younger cohort (<80 years, 6.7%; >= 80 years, 1.0%; P = .029), there were no significant differences in the incidence of major postoperative complications. Logistic regression modeling showed that age >=80 years was not predictive of operative mortality or postoperative complications. A greater percentage of octogenarians had aortic reconstruction with a clamp and sew strategy (85.4% vs 61.6%; P < .001), which led to significantly shorter cross clamp times in this cohort (26.6 minutes vs 30.7 minutes; P < .004). In octogenarians, the incidence of major postoperative adverse events was associated with extent II aneurysms (odds ratio, 2.6; P < .025). Short- and long-term survival was significantly reduced in octogenarians. CONCLUSIONS: In select octogenarians, open repair of DTA/TAAA can be performed with acceptable risk. A simplified surgical approach may provide the best opportunity for a successful outcome. PMID- 29606568 TI - Satisfactory short-term outcomes of the STABILISE technique for type B aortic dissection. AB - OBJECTIVE: The aim of this study was to evaluate the perioperative and short-term results in a cohort of patients treated during the last year at our institution with the stent-assisted balloon-induced intimal disruption and relamination in aortic dissection repair (STABILISE) technique for acute complicated aortic dissection. METHODS: Between June 2016 and June 2017, 10 patients (all male; mean age, 62.6 +/- 7.4 years) received treatment for acute complicated aortic dissection with the STABILISE technique. After a standard provisional extension to induce complete attachment procedure using the commercially available endovascular dissection system (Cook Medical, Bloomington, Ind), the distal stent graft area and the bare stent area were ballooned to completely exclude the thoracic false lumen (FL) and to obtain a single-channeled abdominal aorta. Computed tomography was routinely performed within the first postoperative week before discharge and then at 3 months, at 6 months, and yearly thereafter. The technical and clinical success rates were analyzed. RESULTS: The 30-day technical and clinical success rates were 100%, with complete thrombosis of the thoracic FL and no type I endoleak. Malperfusion was resolved in all cases. No aortic ruptures were recorded, and no open conversion was required. One case of delayed spinal cord ischemia fully resolved within the discharge period. Predischarge computed tomography showed complete thrombosis of the thoracic FL in all cases. In two cases, some degree of patency of the abdominal FL was observed. At short term follow-up, the overall aortic diameters remained stable with no further dilation. CONCLUSIONS: The STABILISE technique was safe and feasible in this cohort of patients, with complete thrombosis of the thoracic FL and creation of a single-channeled aorta in most cases. Further studies are needed to ascertain the long-term behavior of the treated aorta. PMID- 29606569 TI - Preoperative dementia is associated with increased cost and complications after vascular surgery. AB - OBJECTIVE: Dementia represents a major risk factor for medical complications and has been linked to higher rates of complication after surgery. Given the systemic nature of vascular disease, medical comorbidities significantly increase cost and complications after vascular surgery. We hypothesize that the presence of dementia is an independent predictor of increased postoperative complications and higher health care costs after vascular surgery. METHODS: The Vascular Quality Initiative database was queried for all patients undergoing vascular surgery at a single academic medical center from 2012 to 2017. All modules were included (open abdominal aortic aneurysm, suprainguinal bypass, lower extremity bypass, amputation, carotid endarterectomy, endovascular aortic aneurysm repair, thoracic endovascular aortic aneurysm repair, and peripheral endovascular intervention). An institutional clinical data repository was queried to identify patients with International Classification of Diseases, Ninth Revision diagnosis codes for dementia as well as total hospital cost and long-term survival using Social Security records from the Virginia Department of Health. Hierarchical logistic and linear regression models were fit to assess risk-adjusted predictors of any complication and inflation-adjusted cost. Kaplan-Meier and Cox proportional hazards models were used for survival analysis. RESULTS: A total of 2318 patients underwent vascular surgery and were captured by the Vascular Quality Initiative during the past 5 years, with 88 (3.8%) having a diagnosis of dementia. Patients with dementia were older and had higher rates of medical comorbidities, and the most common procedure was major amputation. In addition, dementia patients had a significantly higher rate of any complication (52% vs 16%; P < .0001) and increased 90-day mortality (14% vs 4.8%; P = .0002). Furthermore, dementia was associated with significant resource utilization, including preoperative length of stay (LOS), postoperative LOS, intensive care unit LOS, and inflation-adjusted total hospital cost (all P < .0001). Hierarchical modeling demonstrated that dementia was the strongest preoperative predictor for any complication (odds ratio, 8.64; P < .0001) and had the largest risk-adjusted impact on total hospital cost ($22,069; P < .0001). Finally, survival analysis demonstrated that dementia is independently associated with reduced survival after vascular surgery (hazard ratio, 1.37; P = .018). CONCLUSIONS: This study demonstrated that dementia is one of the strongest predictors of any complication and increased hospital cost after vascular surgery. Given the high risk of clinical and financial maladies, patients with dementia should be carefully considered and counseled before undergoing vascular surgery. PMID- 29606571 TI - Structural analysis and antioxidant activity of the glycoside from Imperial Chrysanthemum. AB - A new glycoside, named as CG-1, was separated from Imperial Chrysanthemum with silica gel column chromatography. The purity was detected by TLC and HPLC. The crystal shape of CG-1 was consisting of a quadrangular and two rectangular pyramids. The analysis of DSC and TGA showed that the melting point of CG-1 crystal was 150.22 degrees C and had good thermal stability. The monosaccharide conformation analysis showed that it was d-glucose. The structure characteristics were compared by FT-IR, NMR spectroscopy and LC-MS and a molecular structure has been deduced which consistent with spectroscopic results. In vitro antioxidant results suggested that the glycoside extracted from Imperial Chrysanthemum could be effectively employed as natural antioxidant in health or functional food. This work is of significance to keep the antioxidant activity in the processing and application of Imperial Chrysanthemum. PMID- 29606570 TI - Femoral artery transposition is a safe and durable option for the treatment of popliteal artery aneurysms. AB - OBJECTIVE: A suitable ipsilateral great saphenous vein (GSV) autograft is widely considered the best material for arterial reconstruction of a popliteal artery aneurysm (PAA). There are, however, cases in which such a GSV is absent, diseased, or of too small diameter for this use. Alternatives to GSV are synthetic conduits, but with a reduced long-term patency, in particular for infragenicular bypass; other venous autografts of marginal use; and stent grafts still in the first stages of their evaluation. However, a sufficiently long segment of the ipsilateral superficial femoral artery (SFA) is often preserved in patients with a PAA. Such a segment may be used as an autograft for popliteal reconstruction. Moreover, the morphometric characteristics of the SFA often optimally match those of the distal native popliteal bifurcation. SFA autografts (SFAAs) have therefore become our choice when the ipsilateral GSV is not suitable. We herein present the long-term results of SFAA for the treatment of PAA in the absence of a suitable GSV. METHODS: Within this single-center study, all cases during the last 26 years were retrospectively reviewed. Demographics, risk factors, comorbidities, morphometrics of the PAA, and preoperative and follow-up data were intentionally sought. RESULTS: From 1997 to 2017, there were 67 PAAs treated with an SFAA. The mean age of the patients was 67.67 +/- 12 years, and 98% were male. Symptoms included intermittent claudication in 25% (17), critical limb ischemia in 7% (5), and acute ischemia in 10% (7) of the patients; 51% (34) of the patients were asymptomatic. The mean aneurysm diameter of the treated PAA was 29 +/- 11 mm (12-61 mm). The mean operative time was 254.8 +/- 65.6 minutes (140-480 minutes), with a mean cross-clamp time of 64.5 +/- 39 minutes (19-240 minutes). The median length of stay was 9 +/- 6.4 days (5-42 days). There were no early amputations or deaths in the series. During a mean follow-up of 47.91 +/- 48.23 months, there were 2 anastomotic stenoses, 11 thromboses, 1 infection, and 1 aneurysmal degeneration of the graft; 6 patients died of unrelated causes. The 1-, 3-, 5-, and 10-year primary and secondary patency rates were 93% and 96%, 85% and 90%, 78% and 87%, and 56% and 87%, respectively. CONCLUSIONS: These data suggest that SFAA use to treat PAA is a safe and durable option. A prospective and comparative work is necessary to confirm these results and to determine the interest of this technique as a first line strategy. PMID- 29606572 TI - Study of the structure-activity relationship of polymyxin analogues. AB - A structure-activity relationship study on three classes of polymyxin analogues focusing on hydrophobicity was conducted. PMID- 29606573 TI - Synthesis, biological evaluation and molecular docking study of 1-amino-2 aroylnaphthalenes against prostate cancer. AB - A series of functionalized naphthalene was synthesized and screened against human prostate cancer cell line (PC-3). The in vitro antiproliferative activity of the synthesized compounds was evaluated by monitoring their cytotoxic effects against PC-3 cells by using MTT assay. We observed that compound 5f resulted in more than 50% cell death at 14 uM. Treatment of PC-3 cells with 5f provides apoptosis by flow cytometry. Western blotting showed decreased expression of pro-caspase 8 and 9. Our study shows that cancer cell treated with 5f has higher concentration of reactive oxygen species as compare to untreated sample, which facilitate cancerous cell to enter apoptosis. Exact mechanism by which ROS is generated after 5f treatment is still under study. Molecular docking study further strengthens the results obtained from in vitro experiments. Compound 5f can be considered as a promising leads for anticancer agent against prostate cancer cells due to its potent cytotoxic activity and apoptotic effect. PMID- 29606574 TI - Synthetic analogues of durantoside I from Citharexylum spinosum L. and their cytotoxic activity. AB - New iridoid glycoside derivatives from durantoside I, the latter from the dried flowers and leaves of Citharexylum spinosum, were synthesized by variously modifying a sugar moiety by silylation or acetylation and/or removal of cinnamate group at C-7 position and subsequent screening for comparative cytotoxicity against several cancer cell lines. Addition of alkylsilane to durantoside I and removal of cinnamate group were most effective in improving cytotoxicity. PMID- 29606575 TI - Diversity-oriented synthesis of pyrazoles derivatives from flavones and isoflavones leads to the discovery of promising reversal agents of fluconazole resistance in Candida albicans. AB - Diversity-oriented synthesis of derivatives of natural products is an important approach for the discovery of novel drugs. In this paper, a series of novel 3,4 diaryl-1H-pyrazoles and 3,5-diaryl-1H-pyrazoles derivatives were synthesized through the one-pot reaction of flavones and isoflavones with the hydrazine hydrate and substituted hydrazine hydrate. Some of these novel compounds exhibited antifungal effects against Candida albicans SC5314, and displayed more potent inhibitory activities against the efflux-pump-deficient strain DSY654. In addition, compounds 25, 28 and 32a displayed outstanding reversal activity of azole resistance against clinical azole-resistant Candida albicans in combination with fluconazole (FLC), with FICI values ranging from 0.012 to 0.141. The preliminary structure-activity relationship (SAR) of these compounds was also discussed. In conclusion, this study provides several novel agents that displayed potent antifungal activities alone or together with fluconazole, which makes progress for development of antifungal drugs. PMID- 29606577 TI - The O-GlcNAc Transferase Intellectual Disability Mutation L254F Distorts the TPR Helix. AB - O-linked beta-N-acetyl-D-glucosamine (O-GlcNAc) transferase (OGT) regulates protein O-GlcNAcylation, an essential post-translational modification that is abundant in the brain. Recently, OGT mutations have been associated with intellectual disability, although it is not understood how they affect OGT structure and function. Using a multi-disciplinary approach we show that the L254F OGT mutation leads to conformational changes of the tetratricopeptide repeats and reduced activity, revealing the molecular mechanisms contributing to pathogenesis. PMID- 29606576 TI - Targeting Phosphopeptide Recognition by the Human BRCA1 Tandem BRCT Domain to Interrupt BRCA1-Dependent Signaling. AB - Intracellular signals triggered by DNA breakage flow through proteins containing BRCT (BRCA1 C-terminal) domains. This family, comprising 23 conserved phosphopeptide-binding modules in man, is inaccessible to small-molecule chemical inhibitors. Here, we develop Bractoppin, a drug-like inhibitor of phosphopeptide recognition by the human BRCA1 tandem (t)BRCT domain, which selectively inhibits substrate binding with nanomolar potency in vitro. Structure-activity exploration suggests that Bractoppin engages BRCA1 tBRCT residues recognizing pSer in the consensus motif, pSer-Pro-Thr-Phe, plus an abutting hydrophobic pocket that is distinct in structurally related BRCT domains, conferring selectivity. In cells, Bractoppin inhibits substrate recognition detected by Forster resonance energy transfer, and diminishes BRCA1 recruitment to DNA breaks, in turn suppressing damage-induced G2 arrest and assembly of the recombinase, RAD51. But damage induced MDC1 recruitment, single-stranded DNA (ssDNA) generation, and TOPBP1 recruitment remain unaffected. Thus, an inhibitor of phosphopeptide recognition selectively interrupts BRCA1 tBRCT-dependent signals evoked by DNA damage. PMID- 29606578 TI - Bacterial Alkaloid Biosynthesis: Structural Diversity via a Minimalistic Nonribosomal Peptide Synthetase. AB - Chemical and biochemical analyses of one of the most basic nonribosomal peptide synthetases (NRPS) from a Pseudomonas fluorescens strain revealed its striking plasticity. Determination of the potential substrate scope enabled us to anticipate novel secondary metabolites that could subsequently be isolated and tested for their bioactivities. Detailed analyses of the monomodular pyreudione synthetase showed that the biosynthesis of the bacterial pyreudione alkaloids does not require additional biosynthetic enzymes. Heterologous expression of a similar and functional, yet cryptic, NRPS of Pseudomonas entomophila was successful and allowed us to perform a phylogenetic analysis of their thioesterase domains. PMID- 29606580 TI - Revealing Detail along the Visual Hierarchy: Neural Clustering Preserves Acuity from V1 to V4. AB - How primates perceive objects along with their detailed features remains a mystery. This ability to make fine visual discriminations depends upon a high acuity analysis of spatial frequency (SF) along the visual hierarchy from V1 to inferotemporal cortex. By studying the transformation of SF across macaque parafoveal V1, V2, and V4, we discovered SF-selective functional domains in V4 encoding higher SFs up to 12 cycles/ degrees . These intermittent higher-SF selective domains, surrounded by domains encoding lower SFs, violate the inverse relationship between SF preference and retinal eccentricity. The neural activities of higher- and lower-SF domains correspond to local and global features, respectively, of the same stimuli. Neural response latencies in high-SF domains are around 10 ms later than in low-SF domains, consistent with the coarse to-fine nature of perception. Thus, our finding of preserved resolution from V1 into V4, separated both spatially and temporally, may serve as a connecting link for detailed object representation. PMID- 29606579 TI - Spontaneous Infra-slow Brain Activity Has Unique Spatiotemporal Dynamics and Laminar Structure. AB - Systems-level organization in spontaneous infra-slow (<0.1Hz) brain activity, measured using blood oxygen signals in fMRI and optical imaging, has become a major theme in the study of neural function in both humans and animal models. Yet the neurophysiological basis of infra-slow activity (ISA) remains unresolved. In particular, is ISA a distinct physiological process, or is it a low-frequency analog of faster neural activity? Here, using whole-cortex calcium/hemoglobin imaging in mice, we show that ISA in each of these modalities travels through the cortex along stereotypical spatiotemporal trajectories that are state dependent (wake versus anesthesia) and distinct from trajectories in delta (1-4 Hz) activity. Moreover, mouse laminar electrophysiology reveals that ISA travels through specific cortical layers and is organized into unique cross-laminar temporal dynamics that are different from higher frequency local field potential activity. These findings suggest that ISA is a distinct neurophysiological process that is reflected in fMRI blood oxygen signals. PMID- 29606581 TI - RIM C2B Domains Target Presynaptic Active Zone Functions to PIP2-Containing Membranes. AB - Rapid and efficient synaptic vesicle fusion requires a pool of primed vesicles, the nearby tethering of Ca2+ channels, and the presence of the phospholipid PIP2 in the target membrane. Although the presynaptic active zone mediates the first two requirements, it is unclear how fusion is targeted to membranes with high PIP2 content. Here we find that the C2B domain of the active zone scaffold RIM is critical for action potential-triggered fusion. Remarkably, the known RIM functions in vesicle priming and Ca2+ influx do not require RIM C2B domains. Instead, biophysical experiments reveal that RIM C2 domains, which lack Ca2+ binding, specifically bind to PIP2. Mutational analyses establish that PIP2 binding to RIM C2B and its tethering to the other RIM domains are crucial for efficient exocytosis. We propose that RIM C2B domains are constitutive PIP2 binding modules that couple mechanisms for vesicle priming and Ca2+ channel tethering to PIP2-containing target membranes. PMID- 29606583 TI - Cost analysis of enhanced recovery after surgery in microvascular breast reconstruction. AB - BACKGROUND: Enhanced recovery after surgery (ERAS) pathways have been shown in multiple surgical specialties to decrease hospital length of stay (LOS) after surgery. ERAS in breast reconstruction has been found to decrease hospital LOS and inpatient opioid use. ERAS protocols can facilitate a patient's recovery and can potentially increase the quality of care while decreasing costs. METHODS: A standardized ERAS pathway was developed through multidisciplinary collaboration. It addressed all phases of surgical care for patients undergoing free-flap breast reconstruction utilizing an abdominal donor site. In this retrospective cohort study, clinical variables associated with hospitalization costs for patients who underwent free-flap breast reconstruction with the ERAS pathway were compared with those of historical controls, termed traditional recovery after surgery (TRAS). All patients included in the study underwent surgery between September 2010 and September 2014. Predicted costs of the study groups were compared using generalized linear modeling. RESULTS: A total of 200 patients were analyzed: 82 in the ERAS cohort and 118 in the TRAS cohort. Clinical variables that were identified to potentially affect costs were found to have a statistically significant difference between groups and included unilateral versus bilateral procedures (p = 0.04) and the need for postoperative blood transfusion (p = 0.03). The cost regression analysis on the two cohorts was adjusted for these significant variables. Adjusted mean costs of patients with ERAS were found to be $4,576 lesser than those of the TRAS control group ($38,688 versus $43,264). CONCLUSIONS: Implementation of the ERAS pathway was associated with significantly decreased costs when compared to historical controls. There has been a healthcare focus toward prudent resource allocation, which dictates the need for plastic surgeons to recognize economic evaluation of clinical practice. The ERAS pathway can increase healthcare accountability by improving quality of care while simultaneously decreasing the costs associated with autologous breast reconstruction. PMID- 29606584 TI - An active drug for TRK-positive paediatric solid tumours. PMID- 29606582 TI - Kir4.1-Dependent Astrocyte-Fast Motor Neuron Interactions Are Required for Peak Strength. AB - Diversified neurons are essential for sensorimotor function, but whether astrocytes become specialized to optimize circuit performance remains unclear. Large fast alpha-motor neurons (FalphaMNs) of spinal cord innervate fast-twitch muscles that generate peak strength. We report that ventral horn astrocytes express the inward-rectifying K+ channel Kir4.1 (a.k.a. Kcnj10) around MNs in a VGLUT1-dependent manner. Loss of astrocyte-encoded Kir4.1 selectively altered FalphaMN size and function and led to reduced peak strength. Overexpression of Kir4.1 in astrocytes was sufficient to increase MN size through activation of the PI3K/mTOR/pS6 pathway. Kir4.1 was downregulated cell autonomously in astrocytes derived from amyotrophic lateral sclerosis (ALS) patients with SOD1 mutation. However, astrocyte Kir4.1 was dispensable for FalphaMN survival even in the mutant SOD1 background. These findings show that astrocyte Kir4.1 is essential for maintenance of peak strength and suggest that Kir4.1 downregulation might uncouple symptoms of muscle weakness from MN cell death in diseases like ALS. PMID- 29606585 TI - Venetoclax plus rituximab for chronic lymphocytic leukaemia. PMID- 29606587 TI - Austrian MPs vote against smoking ban. PMID- 29606586 TI - Larotrectinib for paediatric solid tumours harbouring NTRK gene fusions: phase 1 results from a multicentre, open-label, phase 1/2 study. AB - BACKGROUND: Gene fusions involving NTRK1, NTRK2, or NTRK3 (TRK fusions) are found in a broad range of paediatric and adult malignancies. Larotrectinib, a highly selective small-molecule inhibitor of the TRK kinases, had shown activity in preclinical models and in adults with tumours harbouring TRK fusions. This study aimed to assess the safety of larotrectinib in paediatric patients. METHODS: This multicentre, open-label, phase 1/2 study was done at eight sites in the USA and enrolled infants, children, and adolescents aged 1 month to 21 years with locally advanced or metastatic solid tumours or CNS tumours that had relapsed, progressed, or were non-responsive to available therapies regardless of TRK fusion status; had a Karnofsky (>=16 years of age) or Lansky (<16 years of age) performance status score of 50 or more, adequate organ function, and full recovery from the acute toxic effects of all previous anticancer therapy. Following a protocol amendment on Sept 12, 2016, patients with locally advanced infantile fibrosarcoma who would require disfiguring surgery to achieve a complete surgical resection were also eligible. Patients were enrolled to three dose cohorts according to a rolling six design. Larotrectinib was administered orally (capsule or liquid formulation), twice daily, on a continuous 28-day schedule, in increasing doses adjusted for age and bodyweight. The primary endpoint of the phase 1 dose escalation component was the safety of larotrectinib, including dose-limiting toxicity. All patients who received at least one dose of larotrectinib were included in the safety analyses. Reported here are results of the phase 1 dose escalation cohort. Phase 1 follow-up and phase 2 are ongoing. This trial is registered with ClinicalTrials.gov, number NCT02637687. FINDINGS: Between Dec 21, 2015, and April 13, 2017, 24 patients (n=17 with tumours harbouring TRK fusions, n=7 without a documented TRK fusion) with a median age of 4.5 years (IQR 1.3-13.3) were enrolled to three dose cohorts: cohorts 1 and 2 were assigned doses on the basis of both age and bodyweight predicted by use of SimCyp modelling to achieve an area under the curve equivalent to the adult doses of 100 mg twice daily (cohort 1) and 150 mg twice daily (cohort 2); and cohort 3 was assigned to receive a dose of 100 mg/m2 twice daily (maximum 100 mg per dose), regardless of age, equating to a maximum of 173% of the recommended adult phase 2 dose. Among enrolled patients harbouring TRK fusion-positive cancers, eight (47%) had infantile fibrosarcoma, seven (41%) had other soft tissue sarcomas, and two (12%) had papillary thyroid cancer. Adverse events were predominantly grade 1 or 2 (occurring in 21 [88%] of 24 patients); the most common larotrectinib-related adverse events of all grades were increased alanine and aspartate aminotransferase (ten [42%] of 24 each), leucopenia (five [21%] of 24), decreased neutrophil count (five [21%] of 24), and vomiting (five [21%] of 24). Grade 3 alanine aminotransferase elevation was the only dose-limiting toxicity and occurred in one patient without a TRK fusion and with progressive disease. No grade 4 or 5 treatment-related adverse events were observed. Two larotrectinib-related serious adverse events were observed: grade 3 nausea and grade 3 ejection fraction decrease during the 28-day follow-up after discontinuing larotrectinib and while on anthracyclines. The maximum tolerated dose was not reached, and 100 mg/m2 (maximum of 100 mg per dose) was established as the recommended phase 2 dose. 14 (93%) of 15 patients with TRK fusion-positive cancers achieved an objective response as per Response Evaluation Criteria In Solid Tumors version 1.1; the remaining patient had tumour regression that did not meet the criteria for objective response. None of the seven patients with TRK fusion-negative cancers had an objective response. INTERPRETATION: The TRK inhibitor larotrectinib was well tolerated in paediatric patients and showed encouraging antitumour activity in all patients with TRK fusion-positive tumours. The recommended phase 2 dose was defined as 100mg/m2 (maximum 100 mg per dose) for infants, children, and adolescents, regardless of age. FUNDING: Loxo Oncology Inc. PMID- 29606588 TI - Nivolumab plus ipilimumab in advanced renal-cell carcinoma. PMID- 29606589 TI - The H3K36me2 Methyltransferase Nsd1 Demarcates PRC2-Mediated H3K27me2 and H3K27me3 Domains in Embryonic Stem Cells. AB - The Polycomb repressor complex 2 (PRC2) is composed of the core subunits Ezh1/2, Suz12, and Eed, and it mediates all di- and tri-methylation of histone H3 at lysine 27 in higher eukaryotes. However, little is known about how the catalytic activity of PRC2 is regulated to demarcate H3K27me2 and H3K27me3 domains across the genome. To address this, we mapped the endogenous interactomes of Ezh2 and Suz12 in embryonic stem cells (ESCs), and we combined this with a functional screen for H3K27 methylation marks. We found that Nsd1-mediated H3K36me2 co locates with H3K27me2, and its loss leads to genome-wide expansion of H3K27me3. These increases in H3K27me3 occurred at PRC2/PRC1 target genes and as de novo accumulation within what were previously broad H3K27me2 domains. Our data support a model in which Nsd1 is a key modulator of PRC2 function required for regulating the demarcation of genome-wide H3K27me2 and H3K27me3 domains in ESCs. PMID- 29606590 TI - Structural Basis of Transcription Inhibition by Fidaxomicin (Lipiarmycin A3). AB - Fidaxomicin is an antibacterial drug in clinical use for treatment of Clostridium difficile diarrhea. The active ingredient of fidaxomicin, lipiarmycin A3 (Lpm), functions by inhibiting bacterial RNA polymerase (RNAP). Here we report a cryo-EM structure of Mycobacterium tuberculosis RNAP holoenzyme in complex with Lpm at 3.5-A resolution. The structure shows that Lpm binds at the base of the RNAP "clamp." The structure exhibits an open conformation of the RNAP clamp, suggesting that Lpm traps an open-clamp state. Single-molecule fluorescence resonance energy transfer experiments confirm that Lpm traps an open-clamp state and define effects of Lpm on clamp dynamics. We suggest that Lpm inhibits transcription by trapping an open-clamp state, preventing simultaneous interaction with promoter -10 and -35 elements. The results account for the absence of cross-resistance between Lpm and other RNAP inhibitors, account for structure-activity relationships of Lpm derivatives, and enable structure-based design of improved Lpm derivatives. PMID- 29606591 TI - Visualization of Transvection in Living Drosophila Embryos. AB - How remote enhancers interact with appropriate target genes persists as a central mystery in gene regulation. Here, we exploit the properties of transvection to explore enhancer-promoter communication between homologous chromosomes in living Drosophila embryos. We successfully visualized the activation of an MS2-tagged reporter gene by a defined developmental enhancer located in trans on the other homolog. This trans-homolog activation depends on insulator DNAs, which increase the stability-but not the frequency-of homolog pairing. A pair of heterotypic insulators failed to mediate transvection, raising the possibility that insulator specificity underlies the formation of chromosomal loop domains. Moreover, we found that a shared enhancer co-activates separate PP7 and MS2 reporter genes incis and intrans. Transvecting alleles weakly compete with one another, raising the possibility that they share a common pool of the transcription machinery. We propose that transvecting alleles form a trans-homolog "hub," which serves as a scaffold for the accumulation of transcription complexes. PMID- 29606592 TI - Validating Resolution Revolution. AB - Recent advances in instrumentation and image-processing software have resulted in a resolution revolution in cryo-electron microscopy (cryo-EM) and a surge in the popularity of this technique. However, despite technical progress and hundreds of structures determined so far, development of standards assessing the agreement between the cryo-EM map and the respective model has fallen behind. Here we establish a validation procedure evaluating this agreement and applied it to a set of 565 cryo-EM structures. Analysis of the results revealed that three quarters of the validated structures exhibit moderate or low agreement between the map and the corresponding model, mostly due to limited structural features possessed by these maps. Model re-refinement significantly improved the agreement for only one-fifth of the structures, reaffirming the necessity to re-evaluate map resolution. The presented procedure provides an approach to re-estimate the resolution of cryo-EM map areas interpreted by the model. PMID- 29606593 TI - A Mechanism of Calmodulin Modulation of the Human Cardiac Sodium Channel. AB - The function of the human cardiac sodium channel (NaV1.5) is modulated by the Ca2+ sensor calmodulin (CaM), but the underlying mechanism(s) are controversial and poorly defined. CaM has been reported to bind in a Ca2+-dependent manner to two sites in the intracellular loop that is critical for inactivation of NaV1.5 (inactivation gate [IG]). The affinity of CaM for the complete IG was significantly stronger than that of fragments that lacked both complete binding sites. Structural analysis by nuclear magnetic resonance, crystallographic, and scattering approaches revealed that CaM simultaneously engages both IG sites using an extended configuration. Patch-clamp recordings for wild-type and mutant channels with an impaired CaM-IG interaction revealed CaM binding to the IG promotes recovery from inactivation while impeding the kinetics of inactivation. Models of full-length NaV1.5 suggest that CaM binding to the IG directly modulates channel function by destabilizing the inactivated state, which would promote resetting of the IG after channels close. PMID- 29606594 TI - Long-Lived Folding Intermediates Predominate the Targeting-Competent Secretome. AB - Secretory preproteins carry signal peptides fused amino-terminally to mature domains. They are post-translationally targeted to cross the plasma membrane in non-folded states with the help of translocases, and fold only at their final destinations. The mechanism of this process of postponed folding is unknown, but is generally attributed to signal peptides and chaperones. We herein demonstrate that, during targeting, most mature domains maintain loosely packed folding intermediates. These largely soluble states are signal peptide independent and essential for translocase recognition. These intermediates are promoted by mature domain features: residue composition, elevated disorder, and reduced hydrophobicity. Consequently, a mature domain folds slower than its cytoplasmic structural homolog. Some mature domains could not evolve stable, loose intermediates, and hence depend on signal peptides for slow folding to the detriment of solubility. These unique features of secretory proteins impact our understanding of protein trafficking, folding, and aggregation, and thus place them in a distinct class. PMID- 29606595 TI - [Informative predation: Towards a new species concept]. AB - We distinguish two types of predations: the predation of matter-energy equals the food chain, and the informative predation is the capture of the information brought by the sexual partners. The cell or parent consumes energy and matter to grow, multiply and produce offspring. A fixed amount of resources is divided by the number of organisms, so individual growth and numerical multiplication are limited by depletion resources of the environment. Inversely, fertilization does not destroy information, but instead produces news. The information is multiplied by the number of partners and children, since each fertilization gives rise to a new genome following a combinatorial process that continues without exhaustion. The egg does not swallow the sperm to feed, but exchange good food for quality information. With the discovery of sex, that is, 1.5 Ga ago, life added soft predation to hard predation, i.e. information production within each species to matter-energy flow between species. Replicative and informative structures are subject to two competing biological constraints: replicative fidelity promotes proliferation, but limits adaptive evolution. On the contrary, the offspring of a couple obviously cannot be a copy of both partners, they are a new production, a re-production. Sexual recombination allows the exponential enrichment of the genetic diversity, thus promoting indefinite adaptive and evolutionary capacities. Evolutionary history illustrates this: the bacteria proliferate but have remained at the first purely nutritive stage in which most of the sensory functions, mobility, defense, and feeding have experienced almost no significant novelty in three billion years. Another world appeared with the sexual management of information. Sexual reproduction actually combines two functions: multiplicative by "vertical transfer" and informative by "horizontal transfer". This distinction is very common: polypus - medusa alternations, parasite multiplication cycles, the lytochal and deuterotochal parthenogenesis of aphids, and the innumerable para- and pseudo-sexual strategies of plants opportunistically combine the two modes of asexual replication and sexual combination. However, for the majority of animals and multicellular plants that produce many gametes, numerical proliferation by descendants and informative diversity by sexuality are mutually implicated, for example in the seed. The true discovery of eukaryotes may not be the "true nucleus", as their name implies, but an orderly informative function. The field of recombinations circumscribes a class of partners genetically compatible with each other, each simultaneously prey and predator of the DNA of the other. The mythical Maxwell demon capable of tracing entropy by sorting molecules according to their state does exist: each mate is the other's Maxwell's demon. While a sexless bacterium is simply divided into two cells, two sexual parents work together to produce a single offspring a time. Added to this are the burdens involved in meiosis and crossing-over, cellular diploidy, and mating. Sex produces an information gain that is paid for by a cost of energy-material, and this barter must be fair to survive. The domains of sexual intercourse are very diverse: uniparental reproduction, alternation of asexual proliferation and sexual information, self-fertilization, endogamy, exogamy, panmixis, diffuse or structured polymorphism, fertile or sterile hybridization, horizontal transfers. Each species is a recombination field between two domains, cloning and hybridization. Multiplicative descent and informative fertilization are organically distinct, but selectively associated: the information produced by the parents' sexuality favors the predation of matter energy and therefore the proliferation of offspring, and this proliferation in turn favors the sexed producers of information. The equation specific to each species is: enough energy to proliferate, enough information to diversify. Alternatively, two other reproductive modes obtain or transmit less information at lower cost: not enough recombinations=repetitive clonal proliferation, and too many recombinations=disordered hybridization. But these marginal modes have poor prospects, as the model of the species is successfully attractive. Better discriminate to better inform. In bacteria, the exchanged and incorporated DNA segments are directly identified by the parity of the complementary strands, which determines simultaneously the similarity, the offspring, and the pairing. In eukaryotes, on the contrary, somatic growth and germinal information are segregated. During speciation, adaptive information is compacted, delocalized, codified and published to inform the species about its own state: the prezygotic relationship governs viable mating. Under the effect of sexual selection, the runaway and the reinforcement of the characters related to courtship testifies to their identifying function, which explains the paradox of the singularity and luxuriance of the sexual hypertrophies. The speciation discretizes a balanced recombination field and validates the informative relations. The species is without degree. Mates of a species recognize each other quickly and well because the logic of coding disengages from the ecological game of adaptations. The system of mate recognition has a function of cohesion and its regularity allows the adaptations of the less regular being, it is neither elitist nor normative, it is subjected neither to a level of aptitudes, nor to sexual performances, but permissive; it protects the variability and polymorphism. Two mutually irreducible relationships triggered the debate between the taxonomists who support the phyletic definition of the species by the descendance, and the proponents of the definition by interfertility. Such a taxonomic disagreement is not insurmountable, but the issue is deeper than taxonomic concepts, because these concepts relate to two different modes of evolution. According to the phyletic model, each species is a lineage passively isolated by external circumstances; on the contrary, in the sexual model each species is actively produced by an internal process of adjustment between replicative costs and informative gains. Each species develops a solution of the equation that matches material-energy expenditures with informative gains. A species concept based on a lasting relationship between these two quantities or on the limits of certain values or their equilibrium is therefore legitimate. It is this equilibrium that all couples resolve, without our formulation being as clearly as biology desires and as physics demands. Energy expenditures and informative gains in sexuality are almost impossible to measure, yet observation and experience allow an approximate ranking of the energy/information ratio. For example, endogamy is more economical, but less diversifying than exogamy, polymorphism increases information, the reinforcement of sexual isolation limits the rate of unproductive fertilization, between neighboring species hybridization allows certain genetic contributions, etc. A closed species evolves naturally towards another just as closed. On the contrary, the artificial transfer of DNA opens the species. The natural boundaries that isolate the species are easily trespassed as energy costs and constraints of sexual recognition are easily controlled; and the perspectives of manipulations are visible, whereas natural selection never anticipates and thus works blindly. Informative, artificially directed predation stimulates the evolution of species. PMID- 29606596 TI - Metabolic Maturation during Muscle Stem Cell Differentiation Is Achieved by miR 1/133a-Mediated Inhibition of the Dlk1-Dio3 Mega Gene Cluster. AB - Muscle stem cells undergo a dramatic metabolic switch to oxidative phosphorylation during differentiation, which is achieved by massively increased mitochondrial activity. Since expression of the muscle-specific miR-1/133a gene cluster correlates with increased mitochondrial activity during muscle stem cell (MuSC) differentiation, we examined the potential role of miR-1/133a in metabolic maturation of skeletal muscles in mice. We found that miR-1/133a downregulate Mef2A in differentiated myocytes, thereby suppressing the Dlk1-Dio3 gene cluster, which encodes multiple microRNAs inhibiting expression of mitochondrial genes. Loss of miR-1/133a in skeletal muscles or increased Mef2A expression causes continuous high-level expression of the Dlk1-Dio3 gene cluster, compromising mitochondrial function. Failure to terminate the stem cell-like metabolic program characterized by high-level Dlk1-Dio3 gene cluster expression initiates profound changes in muscle physiology, essentially abrogating endurance running. Our results suggest a major role of miR-1/133a in metabolic maturation of skeletal muscles but exclude major functions in muscle development and MuSC maintenance. PMID- 29606597 TI - The TORC1-Regulated CPA Complex Rewires an RNA Processing Network to Drive Autophagy and Metabolic Reprogramming. AB - Nutrient deprivation induces autophagy through inhibiting TORC1 activity. We describe a novel mechanism in Drosophila by which TORC1 regulates RNA processing of Atg transcripts and alters ATG protein levels and activities via the cleavage and polyadenylation (CPA) complex. We show that TORC1 signaling inhibits CDK8 and DOA kinases, which directly phosphorylate CPSF6, a component of the CPA complex. These phosphorylation events regulate CPSF6 localization, RNA binding, and starvation-induced alternative RNA processing of transcripts involved in autophagy, nutrient, and energy metabolism, thereby controlling autophagosome formation and metabolism. Similarly, we find that mammalian CDK8 and CLK2, a DOA ortholog, phosphorylate CPSF6 to regulate autophagy and metabolic changes upon starvation, revealing an evolutionarily conserved mechanism linking TORC1 signaling with RNA processing, autophagy, and metabolism. PMID- 29606599 TI - Exercise for managing cancer- and treatment-related side effects in older adults. AB - The incidence of cancer in adults aged 60 years and older is expected to rise, and because cancer is associated with aging, the overall prevalence of cancer will rise as well. With advances in cancer treatment, more older adults will receive treatment but they will also suffer the biopsychosocial consequences of cancer and cancer treatment. In this review, we describe the importance of assessing biopsychosocial needs in this vulnerable population and highlight studies supporting the use of exercise in addressing these needs. We discuss challenges and research gaps in several areas including 1) Identifying the exercise doses and modes for specific outcomes, 2) Understanding risks and safety of exercise, and 3) Implementing exercise programs into clinical practice at the individual, health care team, and organizational levels, including strategies to increase adherence. PMID- 29606598 TI - Maternal urinary phthalate metabolites during pregnancy and thyroid hormone concentrations in maternal and cord sera: The HOME Study. AB - BACKGROUND: Phthalates, endocrine-disrupting chemicals that are commonly found in consumer products, may adversely affect thyroid hormones, but findings from prior epidemiologic studies are inconsistent. OBJECTIVES: In a prospective cohort study, we investigated whether maternal urinary phthalate metabolite concentrations and phthalate mixtures measured during pregnancy were associated with thyroid hormones among pregnant women and newborns. METHODS: We measured nine phthalate metabolites [monoethyl phthalate (MEP), mono-n-butyl phthalate, mono-isobutyl phthalate, monobenzyl phthalate (MBzP), and four monoesthers of di(2-ethylhexyl) phthalate] in urine collected at approximately 16 and 26 weeks' gestation among women in the Health Outcomes and Measures of the Environment Study (2003-2006, Cincinnati, Ohio). Thyroid stimulating hormone (TSH) and free and total thyroxine and triiodothyronine were measured in maternal serum at 16 weeks' gestation (n = 202) and cord serum at delivery (n = 276). We used multivariable linear regression to assess associations between individual urinary phthalate metabolites and concentrations of maternal or cord serum thyroid hormones. We used weighted quantile sum regression (WQS) to create a phthalate index describing combined concentrations of phthalate metabolites and to investigate associations of the phthalate index with individual thyroid hormones. RESULTS: With each 10-fold increase in 16-week maternal urinary MEP, maternal serum total thyroxine (TT4) decreased by 0.52 MUg/dL (95% CI: -1.01, -0.03). For each 10-fold increase in average (16- and 26-week) maternal urinary MBzP, cord serum TSH decreased by 19% (95% CI: -33.1, -1.9). Among mothers, the phthalate index was inversely associated with maternal serum TT4 (WQS beta = -0.60; 95% CI: -1.01, -0.18). Among newborns, the phthalate index was inversely associated with both cord serum TSH (WQS beta = -0.11; 95% CI: -0.20, -0.03) and TT4 (WQS beta = 0.53; 95% CI: -0.90, -0.16). CONCLUSION: Our results suggest that co-exposure to multiple phthalates was inversely associated with certain thyroid hormones (TT4 in pregnant women and newborns, and TSH in newborns) in this birth cohort. These findings highlight the need to study chemical mixtures in environmental epidemiology. PMID- 29606600 TI - Growth advantage of Escherichia coli O104:H4 strains on 5-N-acetyl-9-O-acetyl neuraminic acid as a carbon source is dependent on heterogeneous phage-Borne nanS p esterases. AB - Enterohemorrhagic E. coli (EHEC) are serious bacterial pathogens which are able to cause a hemorrhagic colitis or the life-threatening hemolytic-uremic syndrome (HUS) in humans. EHEC strains can carry different numbers of phage-borne nanS-p alleles that are responsible for acetic acid release from mucin from bovine submaxillary gland and 5-N-acetyl-9-O-acetyl neuraminic acid (Neu5,9Ac2), a carbohydrate present in mucin. Thus, Neu5,9Ac2 can be transformed to 5-N-acetyl neuraminic acid, an energy source used by E. coli strains. We hypothesize that these NanS-p proteins are involved in competitive growth of EHEC in the gastrointestinal tract of humans and animals. The aim of the current study was to demonstrate and characterize the nanS-p alleles of the 2011 E. coli O104:H4 outbreak strain LB226692 and analyze whether the presence of multiple nanS-p alleles in the LB226692 genome causes a competitive growth advantage over a commensal E. coli strain. We detected and characterized five heterogeneous phage borne nanS-p alleles in the genome of E. coli O104:H4 outbreak strain LB226692 by in silico analysis of its genome. Furthermore, successive deletion of all nanS-p alleles, subsequent complementation with recombinant NanS-p13-His, and in vitro co-culturing experiments with the commensal E. coli strain AMC 198 were conducted. We could show that nanS-p genes of E. coli O104:H4 are responsible for growth inhibition of strain AMC 198, when Neu5,9Ac2 was used as sole carbon source in co-culture. The results of this study let us suggest that multiple nanS p alleles may confer a growth advantage by outcompeting other E. coli strains in Neu5,9Ac2 rich environments, such as mucus in animal and human gut. PMID- 29606601 TI - Association of choline and betaine levels with cancer incidence and survival: A meta-analysis. AB - BACKGROUND & AIMS: Evidences suggest possible link between betaine and choline, methyl group donors, and cancer progression. We examined the association between choline and betaine levels and cancer incidence and survival in a meta-analysis of observational studies. METHODS: We identified observational studies examining the association between choline and/or betaine levels from diet or blood and cancer incidence and survival by searching the PubMed and Web of Science databases for studies published up to Jan, 2018. After applying the selection criteria, 28 observational studies (9 case-control, 1 cross-sectional, and 18 cohort studies) were included. Relative risks (RRs) and 95% confidence intervals (CIs) were extracted, and combined RRs were calculated using random-effects models. RESULTS: Choline levels were not associated with cancer incidence in a meta-analysis of cohort studies. Betaine levels reduced the risk of cancer incidence in a meta-analysis of cohort studies; combined relative risks (RRs) (95% CIs) comparing the top with the bottom categories were 0.93 (0.87-0.99). When we analyzed separately according to exposure assessment method, combined RRs (95% CIs) comparing the top with the bottom categories of betaine levels were 0.87 (95% CI: 0.78-0.95) for dietary betaine and 0.88 (95% CI: 0.77-0.99) for blood levels of betaine. There were no significant associations with cancer survivorship of choline or betaine levels. CONCLUSIONS: We concluded that high betaine levels were associated with lower risk of the cancer incidence, especially for colorectal cancer. PMID- 29606602 TI - Adductor muscle thickness of the thumb: A new and reliable parameter for nutritional assessment of pediatric inpatients. AB - BACKGROUND & AIMS: The adductor pollicis muscle thickness (APMT) is a promising method for evaluation of muscle loss and, consequently, malnutrition in adult and elderly patients. However, to date, there have been no studies of its applicability to the pediatric population. Within this context, we sought to evaluate the association of APMT with anthropometric variables, body mass index (BMI), pediatric Subjective Global Assessment (SGA) of nutrition, nutritional screening, and clinical outcomes in hospitalized pediatric patients. METHODS: This was a cross-sectional study of inpatients aged 4-8.9 years, recruited via convenience sampling from a pediatric hospital in Porto Alegre, Rio Grande do Sul, Brazil. Data collection took place between December 2014 and February 2016. Patients admitted to the intensive care unit, those unable to feed orally, and those with cerebral palsy or Down syndrome were excluded from the study. General and socioeconomic information was collected and the SGA Ped and STRONGkids were administered at hospital admission. Clinical data were collected from the electronic medical record. Anthropometric parameters and APMT were measured by properly calibrated examiners. Data analysis was carried out in SPSS version 21.0. The significance level was set at 5%. RESULTS: The sample consisted of 447 patients. Most (55.9%) were male; the mean age was 6.2 +/- 1.4 years. Low APMT was significantly associated with underweight, short stature, low body fat percentage, and poor muscle reserve (p < 0.001). There were also significant associations of moderate and severe malnutrition (assessed by the SGA Ped) and high nutritional risk (assessed by the STRONGkids instrument) with reduced APMT (p < 0.001). Regarding clinical outcomes, a longer hospital stay was observed in patients with reduced APMT (p = 0.001). A receiver operating characteristic (ROC) curve, plotted considering the SGA Ped as the gold standard, suggested APMT cutoff points of 10.2 mm for boys and 9.5 mm for girls. Stratification by age yielded APMT cutoff points of 9.8 mm for boys younger than 6 years and 10.2 mm for those older than 6 years, and 9.2 mm and 9.8 mm for girls younger and older than 6 years, respectively. CONCLUSION: The APMT is an efficient parameter for the detection of malnutrition in hospitalized pediatric patients. PMID- 29606603 TI - Surgical management of hepatocellular carcinoma within and beyond BCLC indications in a middle volume center. AB - AIM OF THE STUDY: Current criteria for hepatic resection in patients with hepatocellular carcinoma (HCC) according to Barcellona Clinic Liver Cancer (BCLC) classification is debated. Actually, patients with multinodular or large HCC>5cm are excluded from surgical treatment following the algorithm, but several studies from referral centers showed that such patients may benefit from surgical resection in the clinical practice. The aim of this study was to compare short- and long-term outcomes after liver resection for HCC in stage 0/A or B in a middle volume center. PATIENTS AND METHODS: Patients were grouped according to BCLC classification. Postoperative mortality, morbidity, overall and disease-free survival, univariate analysis of prognostic factors on survival was analyzed. RESULTS: Among 66 surgical procedures in 64 patients included in the study, 41 were BCLC stage 0/A (62.1%) and 25 BCLC stage B (37.9%). The overall 30- and the 90-days mortality rates were 1.5% and 3%. Patients in BCLC stage B had higher transfusion rate (P=0.04) but similar morbidity and mortality compared to patients in BCLC stage 0/A. After a median follow-up of 35 months (range: 14 147), the overall survival at 1, 3 and 5 years resulted 95%, 61.1%, 46.2% for stage 0-A and 83.3%, 50%, 41.2% for stage B (P=0.73). Univariate analysis identified poorly differentiated tumors (P=0.02) and positive margin (P=0.02) as negative prognostic factors on survival. CONCLUSIONS: Surgical treatment of HCC in BCLC stage B offers similar results than the ones in BCLC stage 0/A and consequently should not be considered contraindicated for such patients. PMID- 29606604 TI - Predictors of camptocormia in patients with Parkinson's disease: A prospective study from southwest China. AB - BACKGROUND: Camptocormia is becoming increasingly recognized as a prominent phenomenon in Parkinson's disease (PD). OBJECTIVE: This study aims to investigate the clinical predictors of future camptocormia in a cohort of PD patients. METHODS: A total of 263 PD patients without camptocormia were prospectively monitored for approximately 3 years. The end-point was the occurrence of camptocormia. RESULTS: Overall, camptocormia was observed in 23 patients (8.7%) during the study period. The following variables including the proportion of males; age; disease duration; total levodopa equivalent daily dosage; Unified PD Rating Scale (UPDRS) III score; Hoehn and Yahr stage; the percentages of festination, freezing of gait and falls; and the subscores (e.g., "problems having sex") and frequencies (e.g., "forget to do things") of the Non-Motor Symptoms Scale were significantly higher in patients with camptocormia compared to those variables in patients without camptocormia (P < 0.05). Patients with camptocormia showed lower "orientation" subscore of the Montreal Cognitive Assessment scale than patients without camptocormia (P < 0.05). The binary logistic regression model indicated that the presence of camptocormia was associated with male sex (OR = 6.758, P = 0.001), a higher UPDRS III score (OR = 1.099, P = 0.001), a higher sexual dysfunction score (OR = 1.033, P = 0.038) and a lower orientation score (OR = 0.392, P = 0.018). CONCLUSIONS: Camptocormia may emerge as PD progresses. Male patients and those with sexual dysfunction or disorientation are likely to present with camptocormia in the future. PMID- 29606605 TI - Investigation of non-motor symptoms in first-degree relatives of patients with Parkinson's disease. AB - OBJECTIVE: Non-motor symptoms (NMS) are important prodromal characteristics of Parkinson's disease (PD). However, the incidence of NMS in first-degree relatives, such as siblings of PD patients, is still unknown. METHODS: A total of 98 PD patients of the Affiliated Hospital of Yangzhou University were recruited; 210 siblings of these patients were included in a first-degree relatives (FDR) group and 250 healthy individuals were included in a control group. Various scales were used to assess NMS, including depression, anxiety, cognitive function, sleep status, constipation, daytime sleepiness, Rapid-Eye-Movement Sleep Behavior Disorder (RBD), and Restless Legs Syndrome (RLS). RESULTS: NMS were more common in the PD group than the control group. The incidence of anxiety (OR = 3.434, 95%CI: 2.058-5.731, P < 0.001), depression (OR = 2.438, 95%CI: 1.289 4.609, P = 0.005), and RBD (OR = 4.120, 95%CI: 1.897-8.945, P < 0.001) was higher in the FDR group than the control group. There were non-significant differences in constipation, cognitive impairment, sleep disorder, daytime sleepiness, and RLS between the two groups. The incidence of RLS in FDR of PD with an age of onset <60 years was higher than in the controls (OR = 2.273, 95%CI: 1.107-4.667, P = 0.023). CONCLUSIONS: Siblings of PD are more likely to suffer from anxiety, depression and RBD than the general population. RLS is more common in siblings of PD with onset age<60 than in the general population. It is speculated that PD patients and their siblings have common pathogenic genetic factors and early living environment for neurodegeneration. PMID- 29606606 TI - Gender-specific effect of uric acid on resting-state functional networks in de novo Parkinson's disease. AB - INTRODUCTION: The pattern of resting-state networks is influenced by several factors besides the underlying pathological changes of Parkinson's disease (PD). Uric acid (UA), as an antioxidant, has a neuroprotective property against PD related microenvironment; however, this effect would be gender-specific. We aimed to evaluate a gender-sensitive resting-state networks (RSN) according to the UA level in drug naive de novo patients with PD to elucidate the role of antioxidant in cortical functional networks of PD. METHODS: This study enrolled 135 de novo patients with PD underwent functional magnetic resonance imaging (MRI). Based on the distribution, the serum UA level was stratified into tertiles in the PD patients by gender. With a seed-based approach, we investigated the pattern of RSN within the dorsal attention network (DAN), executive control network (ECN), and default mode network (DMN). RESULTS: Interaction analysis showed a significant interaction between the lowest (PD-L-UA) and the highest UA level (PD H-UA) groups according to gender within the DAN, ECN, and DMN. Compared to the control subjects, male patients with PD-H-UA had higher cortical functional connectivity (FC), while female patients had lower cortical FC regardless of UA level within all seeds. In a direct comparison, male patients with PD-H-UA had increased FC than did those with PD-L-UA. However, there was no significant difference in FC between PD-L-UA and PD-H-UA in female PD patients. CONCLUSIONS: These data suggest that RSN might be closely and gender-specifically associated with the status of serum UA in de novo PD patients. PMID- 29606607 TI - Paradoxical worsening of parkinsonism upon neuroleptic withdrawal: More common than we think? PMID- 29606608 TI - Siblings with unusual presentation of early onset Parkinson's disease with dual heterozygous PARK2 and PARK 9 mutation. PMID- 29606609 TI - Using 340B drug discounts to provide a financially sustainable medication discharge service. AB - The 340B Drug Pricing Program was intended to stretch federal resources by providing significant discounts to covered entities providing care to underserved populations. Program implementation and evidence of expanding services to higher income patients has brought more scrutiny and calls for elimination of the program. While additional review and reform may be warranted, profitability from 340B discounts enables covered entities to provide additional services that may not be feasible in absence of the program. This case report demonstrates one institution's use of 340B discounts to financially justify providing bedside medication delivery services for patients at the time of discharge from an inpatient admission. A simple financial model was developed using hospital data and inputs from available literature to estimate gross profit and earnings before interest, taxes, depreciation, and amortization (EBITDA) with and without 340B discounts. Without the 340B drug price discounts, the service would operate at a financial loss, and further investigation must be done to determine whether other clinical or economic benefits would warrant discharge medication delivery at the institution. PMID- 29606610 TI - Evaluation of methods used for estimating content validity. AB - The assessment of content validity is a critical and complex step in the development process of instruments which are frequently used to measure complex constructs in social and administrative pharmacy research. The aims of this study were to investigate the elements of content validity; to describe a practical approach for assessing content validity; and to discuss existing content validity indices. This is a narrative review of the assessment and quantification of content validity. It describes the key stages of conducting the content validation study and discusses the quantification and evaluation of the content validity estimates. Content validity provides evidence about the degree to which elements of an assessment instrument are relevant to and representative of the targeted construct for a particular assessment purpose. The assessment of content validity relies on using a panel of experts to evaluate instrument elements and rate them based on their relevance and representativeness to the content domain. It is a three-stage process that includes; the development stage, judgment and quantifying stage, and revising and reconstruction stage. To quantify the expert judgments, several indices have been discussed in this paper such as the content validity ratio (CVR), content validity index (CVI), modified-Kappa, and some agreement indices. A practical guide describes the process of content validity evaluation is provided. In summary, content validation processes and content validity indices are essential factors in the instrument development process, should be treated and reported as important as other types of construct validation. Determining item CVI and reporting an overall CVI are important components necessary to instruments especially when the instrument is used to measure health outcomes or to guide a clinical decision making. Content validity deserves a rigorous assessment process as the obtained information from this process are invaluable for the quality of the newly developed instrument. PMID- 29606611 TI - Validation of the King's transaction process for healthcare provider-patient context in the pharmaceutical context. AB - BACKGROUND: With the impressive advantages of patient-pharmacist communication being advocated and poor pharmacist-patient communication in different settings, it is of great significance and urgency to explore the mechanism of the pharmacist-patient communicative relationship. The King's theory of goal attainment is proposed as one of the most promising models to be applied, because it takes into consideration both improving the patient-pharmacist relationship and attaining patients' health outcomes. OBJECTIVES: This study aimed to validate the King's transaction process and build the linkage between the transaction process and patient satisfaction in a pharmaceutical context. METHODS: A cross sectional study was conducted in four tertiary hospitals in two provincial cities (Wuhan and Shanghai) in central and east China in July 2017. Patients over 18 were investigated in the pharmacies of the hospitals. The instrument for the transaction process was revised and tested. Path analysis was conducted for the King's transaction process and its relationship with patient satisfaction. RESULTS: Five hundred eighty-nine participants were investigated for main study. Prior to the addition of covariates, the hypothesised model of the King's transaction process was validated, in which all paths of the transaction process were statistically significant (p < 0.001). The transaction process had direct effects on patient satisfaction (p < 0.001). After controlling the effects of covariates, the Multiple Indicators, Multiple Causes (MIMIC) model showed good fit to data (Tucker-Lewis index [TLI] = 0.99, comparative fit index [CFI] = 0.99, root mean square error of approximation [RMSEA] = 0.05, weighted root mean square residual [WRMR] = 1.00). The MIMIC model showed that chronic disease and site were predictors for both identifying problems and patient satisfaction (p < 0.05). CONCLUSIONS: Based on the well-fitting path analytic model, the transaction process was established as one valid theoretical framework of healthcare provider-patient communication in a pharmaceutical context. PMID- 29606612 TI - Heterogeneity of Human Breast Stem and Progenitor Cells as Revealed by Transcriptional Profiling. AB - During development, the mammary gland undergoes extensive remodeling driven by stem cells. Breast cancers are also hierarchically organized and driven by cancer stem cells characterized by CD44+CD24low/- or aldehyde dehydrogenase (ALDH) expression. These markers identify mesenchymal and epithelial populations both capable of tumor initiation. Less is known about these populations in non cancerous mammary glands. From RNA sequencing, ALDH+ and ALDH-CD44+CD24- human mammary cells have epithelial-like and mesenchymal-like characteristics, respectively, with some co-expressing ALDH+ and CD44+CD24- by flow cytometry. At the single-cell level, these cells have the greatest mammosphere-forming capacity and express high levels of stemness and epithelial-to-mesenchymal transition associated genes including ID1, SOX2, TWIST1, and ZEB2. We further identify single ALDH+ cells with a hybrid epithelial/mesenchymal phenotype that express genes associated with aggressive triple-negative breast cancers. These results highlight single-cell analyses to characterize tissue heterogeneity, even in marker-enriched populations, and identify genes and pathways that define this heterogeneity. PMID- 29606613 TI - Far Upstream Element-Binding Protein 1 Regulates LSD1 Alternative Splicing to Promote Terminal Differentiation of Neural Progenitors. AB - Loss of a cell's ability to terminally differentiate because of mutations is a selected genetic event in tumorigenesis. Genomic analyses of low-grade glioma have reported recurrent mutations of far upstream element-binding protein 1 (FUBP1). Here, we show that FUBP1 expression is dynamically regulated during neurogenesis and that its downregulation in neural progenitors impairs terminal differentiation and promotes tumorigenesis collaboratively with expression of IDH1R132H. Mechanistically, collaborative action between SRRM4 and FUBP1 is necessary for mini-exon splicing of the neurospecific LSD1+8a isoform. LSD1+8a was downregulated upon loss of FUBP1 in neural progenitors, thereby impairing terminal neuronal differentiation and maturation. Reinforcing LSD1+8a expression in FUBP1-downregulated neural progenitors restored terminal differentiation and suppressed tumorigenesis; hence, LSD1+8a is an obligatory effector of FUBP1 dependent neuronal differentiation. These findings establish a direct role for FUBP1 in neuronal differentiation and also explain its tumor-suppressor function in the nervous system. PMID- 29606614 TI - Matched Developmental Timing of Donor Cells with the Host Is Crucial for Chimera Formation. AB - Chimeric mice have been generated by injecting pluripotent stem cells into morula to-blastocyst stage mouse embryo or by introducing more mature cells into later stage embryos that correspond to the differentiation stage of the donor cells. It has not been rigorously tested, however, whether successful chimera formation requires the developmental stage of host embryo and donor cell to be matched. Here, we compared the success of chimera formation following injection of primary neural crest cells (NCCs) into blastocysts or of embryonic stem cells (ESCs) into E8.5 embryos (heterochronic injection) with that of injecting ESCs cells into the blastocyst or NCCs into the E8.5 embryos (isochronic injection). Chimera formation was efficient when donor and host were matched, but no functional chimeric contribution was found in heterochronic injections. This suggests that matching the developmental stage of donor cells with the host embryo is crucial for functional engraftment of donor cells into the developing embryo. PMID- 29606615 TI - Promoting Myelin Repair through In Vivo Neuroblast Reprogramming. AB - Demyelination is frequently observed in a variety of CNS insults and neurodegenerative diseases. In rodents, adult neural stem cells can generate oligodendrocytes and participate to myelin repair. However, these cells mainly produce migratory neuroblasts that differentiate in the olfactory bulb. Here, we show that, in the demyelination context, a small subset of these neuroblasts can spontaneously convert into myelinating oligodendrocytes. Furthermore, we demonstrate that the contribution of neuroblasts to myelin repair can be improved by in vivo forced expression of two transcription factors: OLIG2 and SOX10. These factors promote directed fate conversion of endogenous subventricular zone neuroblasts into mature functional oligodendrocytes, leading to enhanced remyelination in a cuprizone-induced mouse model of demyelination. These findings highlight the unexpected plasticity of committed neuroblasts and provide proof of concept that they could be targeted for the treatment of demyelinated lesions in the adult brain. PMID- 29606616 TI - Direct Conversion of Mouse Fibroblasts into Cholangiocyte Progenitor Cells. AB - Disorders of the biliary epithelium, known as cholangiopathies, cause severe and irreversible liver diseases. The limited accessibility of bile duct precludes modeling of several cholangiocyte-mediated diseases. Therefore, novel approaches for obtaining functional cholangiocytes with high purity are needed. Previous work has shown that the combination of Hnf1beta and Foxa3 could directly convert mouse fibroblasts into bipotential hepatic stem cell-like cells, termed iHepSCs. However, the efficiency of converting fibroblasts into iHepSCs is low, and these iHepSCs exhibit extremely low differentiation potential into cholangiocytes, thus hindering the translation of iHepSCs to the clinic. Here, we describe that the expression of Hnf1alpha and Foxa3 dramatically facilitates the robust generation of iHepSCs. Notably, prolonged in vitro culture of Hnf1alpha- and Foxa3-derived iHepSCs induces a Notch signaling-mediated secondary conversion into cholangiocyte progenitor-like cells that display dramatically enhanced differentiation capacity into mature cholangiocytes. Our study provides a robust two-step approach for obtaining cholangiocyte progenitor-like cells using defined factors. PMID- 29606618 TI - Preventing tick attachment to dogs using essential oils. AB - Preventing tick bites using repellents could make a valuable contribution to an integrated tick management programme for dogs. Here, the ability of a range of essential oils or active ingredients of commercially available repellents, to abolish the orientation and taxis of the tick Ixodes ricinus towards sebum extracted from dog hair was examined in laboratory bioassays. Substantial differences between oils were observed, but turmeric oil was both able to prevent a climbing response by ticks and had a longer residual activity than other oils. A blanket-drag field assay was then used to compare the attachment of ticks to blankets impregnated with one of: turmeric oil, DEET (positive control), orange oil or excipient only (negative controls). In total, 899 ticks were counted, with an average of 23.3 (SD +/- 21.3) ticks per blanket drag for excipient-only (n = 16), 26.9 (SD +/- 28.6) for orange oil (n = 16), 2.6 (SD +/- 2.0) for turmeric oil (n = 16) and 3.4 (SD +/- 3.7) for DEET (n = 16). Finally, in a participatory in vivo trial, tick acquisition by 15 untreated control dogs was compared with 24 dogs sprayed with turmeric-oil and 16 dogs sprayed with orange oil (both 2.5% v/v diluted in water with a 1% coco glucoside excipient) before each walk in known tick infested areas. The percentage of dogs with ticks attached to the legs or belly of dogs sprayed with turmeric oil suspension (15% +/- 19.4%) was significantly lower than that of ticks attached to the same areas of dogs sprayed with orange oil suspension (85% +/- 19.4%) and unsprayed dogs (73% +/- 26.2%) (P < 0.05). The data indicate that turmeric-oil may form a valuable component of a tick management programme for domestic dogs. PMID- 29606617 TI - Functional Studies of Missense TREM2 Mutations in Human Stem Cell-Derived Microglia. AB - The derivation of microglia from human stem cells provides systems for understanding microglial biology and enables functional studies of disease causing mutations. We describe a robust method for the derivation of human microglia from stem cells, which are phenotypically and functionally comparable with primary microglia. We used stem cell-derived microglia to study the consequences of missense mutations in the microglial-expressed protein triggering receptor expressed on myeloid cells 2 (TREM2), which are causal for frontotemporal dementia-like syndrome and Nasu-Hakola disease. We find that mutant TREM2 accumulates in its immature form, does not undergo typical proteolysis, and is not trafficked to the plasma membrane. However, in the absence of plasma membrane TREM2, microglia differentiate normally, respond to stimulation with lipopolysaccharide, and are phagocytically competent. These data indicate that dementia-associated TREM2 mutations have subtle effects on microglia biology, consistent with the adult onset of disease in individuals with these mutations. PMID- 29606619 TI - Spatiotemporal patterns of severe fever with thrombocytopenia syndrome in China, 2011-2016. AB - Severe fever with thrombocytopenia syndrome (SFTS) is emerging and the number of SFTS cases have increased year by year in China. However, spatiotemporal patterns and trends of SFTS are less clear up to date. In order to explore spatiotemporal patterns and predict SFTS incidences, we analyzed temporal trends of SFTS using autoregressive integrated moving average (ARIMA) model, spatial patterns, and spatiotemporal clusters of SFTS cases at the county level based on SFTS data in China during 2011-2016. We determined the optimal time series model was ARIMA (2, 0, 1) * (0, 0, 1)12 which fitted the SFTS cases reasonably well during the training process and forecast process. In the spatial clustering analysis, the global autocorrelation suggested that SFTS cases were not of random distribution. Local spatial autocorrelation analysis of SFTS identified foci mainly concentrated in Hubei Province, Henan Province, Anhui Province, Shandong Province, Liaoning Province, and Zhejiang Province. A most likely cluster including 21 counties in Henan Province and Hubei Province was observed in the central region of China from April 2015 to August 2016. Our results will provide a sound evidence base for future prevention and control programs of SFTS such as allocation of the health resources, surveillance in high-risk regions, health education, improvement of diagnosis and so on. PMID- 29606620 TI - The occurrence of Anaplasmataceae in European populations of invasive carnivores. AB - The raccoon (Procyon lotor) and the raccoon dog (Nyctereutes procyonoides) belong to a group of the invasive species. The introduced species as potential reservoirs for vector-borne pathogens have been the subject of recent research, though there are still no data with reference to the European population of the raccoon, and few studies concern only the raccoon dog. This study shows the occurrence of Anaplasmataceae representatives in raccoons and a sympatric population of the raccoon dogs obtained from the area of Poland and Germany. During the study, the occurrence of Anaplasma phagocytophilum ecotype I in the introduced raccoon in northwestern Poland was revealed. Additionally, Candidatus Neoehrlichia sp. (FU98) was identified for the first time in the raccoon dog in Central Europe and thereby the raccoon dog is a new host for this pathogen. PMID- 29606621 TI - Chemical tick control practices in southwestern and northwestern Uganda. AB - Tick acaricide failure is one of the leading challenges to cattle production in Uganda. To gain an understanding into the possible drivers of acaricide failure, this study characterized the current chemical tick control practices in the southwestern (Mbarara, Mitooma and Rukungiri districts) and northwestern (Adjumani district) regions of Uganda. A total of 85 farms participated in a survey that utilized a semi-structured questionnaire. Moreover, ticks were collected to determine the most common species on the farms. Tick acaricide failure was mainly encountered in the districts where 95% (60/63) of the farms reared exotic cattle (dairy cross-breeds) under a paddocking (fenced) system. In the northwestern region, local cattle were reared in communal grazing areas. All farms used chemical acaricides for tick control, predominantly amidine (amitraz) (48%, 41/85) and co-formulated organophosphates and pyrethroids (38%, 32/85). The spraying method was the most common (91%, 77/85) acaricide application technique, with cattle crush (81%, 69/85) as a common means of physical restraint. Less than optimal tick control practices encountered included use of substandard equipment for spraying, inappropriate dilutions, frequent interaction between animals in neighboring farms despite lack of synchronized chemical tick control and malpractices in acaricide rotation. Only Rhipicephalus appendiculatus and R. (Boophilus) decoloratus ticks were found in the southwestern region, where 51% (32/63) of the farmers used high acaricide concentrations above the manufacturers' recommendation. Farmers in the northwestern region used 2.2 times less acaricide volume per cattle than those in the southwestern region, and more diverse tick species were encountered. Toxic effects of acaricide to cattle and workers were reported by 13% (11/85) and 32% (27/85) of the respondents, respectively. All 27 cases of human acaricide toxicity reported were from the southwestern region. Overall, our findings may inform strategies for more prudent chemical tick control and safe acaricide handling to benefit animal welfare, food safety and public health. PMID- 29606622 TI - Factors responsible for Ixodes ricinus nymph abundance: Are soil features indicators of tick abundance in a French region where Lyme borreliosis is endemic? AB - In Europe, the hard tick Ixodes ricinus (Acari: Ixodidae) is the main vector of Lyme borreliosis spirochetes (Borrelia burgdorferi sensu lato group). A field study was conducted to evaluate the abundance of Ixodes nymphs in the French region of Alsace, where Lyme borreliosis is endemic, and to determine whether environmental factors such as soil moisture and composition may be associated with nymph abundance. In the ten sites studied, ticks were collected by drag sampling from March to October in 2013 and 2014. Temperature, relative humidity, saturation deficit, soil pH, humus composition and type of vegetation were recorded at each site. The abundance of I. ricinus was highly variable from one site to another. Inter-annual variations were also observed, since the nymph abundance were higher in 2013 than in 2014. This study shows that humus type can be indicative of nymph abundance. Three types of humus were observed: (1) moder, (2) mull, and (3) mull-moder humus. One of them, moder humus, which is characterized by a thick layer of fragmented leaves, was found in multivariate analyses to be strongly associated with the nymph abundance. This study demonstrates that factors such as saturation deficit do not suffice to explain the differences in nymph abundance among sites. The composition of the soil and especially the type of humus should also be taken into consideration when assessing acarological risk. PMID- 29606623 TI - Correction. PMID- 29606624 TI - The Iowa new practice model: Advancing technician roles to increase pharmacists' time to provide patient care services. AB - OBJECTIVES: Determine the effects of an 18-month pilot project using tech-check tech in 7 community pharmacies on 1) rate of dispensing errors not identified during refill prescription final product verification; 2) pharmacist workday task composition; and 3) amount of patient care services provided and the reimbursement status of those services. DESIGN: Pretest-posttest quasi experimental study where baseline and study periods were compared. SETTING AND PARTICIPANTS: Pharmacists and pharmacy technicians in 7 community pharmacies in Iowa. OUTCOME MEASURES: The outcome measures were 1) percentage of technician verified refill prescriptions where dispensing errors were not identified on final product verification; 2) percentage of time spent by pharmacists in dispensing, management, patient care, practice development, and other activities; 3) the number of pharmacist patient care services provided per pharmacist hours worked; and 4) percentage of time that technician product verification was used. RESULTS: There was no significant difference in overall errors (0.2729% vs. 0.5124%, P = 0.513), patient safety errors (0.0525% vs. 0.0651%, P = 0.837), or administrative errors (0.2204% vs. 0.4784%, P = 0.411). Pharmacist's time in dispensing significantly decreased (67.3% vs. 49.06%, P = 0.005), and time in direct patient care (19.96% vs. 34.72%, P = 0.003), increased significantly. Time in other activities did not significantly change. Reimbursable services per pharmacist hour (0.11 vs. 0.30, P = 0.129), did not significantly change. Non reimbursable services increased significantly (2.77 vs. 4.80, P = 0.042). Total services significantly increased (2.88 vs. 5.16, P = 0.044). CONCLUSION: Pharmacy technician product verification of refill prescriptions preserved dispensing safety while significantly increasing the time spent in delivery of pharmacist provided patient care services. The total number of pharmacist services provided per hour also increased significantly, driven primarily by a significant increase in the number of non-reimbursed services. This was mostly likely due to the increased time available to provide patient care. Reimbursed services per hour did not increase significantly mostly likely due to lack of payers. PMID- 29606625 TI - S-Nitrosoglutathione Reductase (GSNOR) Deficiency Results in Secondary Hypogonadism. AB - BACKGROUND: Excess reactive oxygen species and reactive nitrogen species are implicated in male infertility and impaired spermatogenesis. AIM: To investigate the effect of excess reactive nitrogen species and nitrosative stress on testicular function and the hypothalamic-pituitary-gonadal axis using the S nitrosoglutathione reductase-null (Gsnor-/-) mouse model. METHODS: Testis size, pup number, and epididymal sperm concentration and motility of Gsnor-/- mice were compared with those of age-matched wild-type (WT) mice. Reproductive hormones testosterone (T), luteinizing hormone (LH), and follicle-stimulating hormone were compared in Gsnor-/- and WT mice. Immunofluorescence for Gsnor-/- and WT testis was performed for 3beta-hydroxysteroid dehydrogenase and luteinizing hormone receptor (LHR) and compared. Human chorionic gonadotropin and gonadotropin releasing hormone stimulation tests were performed to assess and compare testicular and pituitary functions of Gsnor-/- and WT mice. OUTCOMES: Evaluation of fertility and reproductive hormones in Gsnor-/- vs WT mice. Response of Gsnor /- and WT mice to human chorionic gonadotropin and gonadotropin-releasing hormone to evaluate LH and T production. RESULTS: Gsnor-/- mice had smaller litters (4.2 vs 8.0 pups per litter; P < .01), smaller testes (0.08 vs 0.09 g; P < .01), and decreased epididymal sperm concentration (69 vs 98 * 106; P < .05) and motility (39% vs 65%; P < .05) compared with WT mice. Serum T (44.8 vs 292.2 ng/dL; P < .05) and LH (0.03 vs 0.74 ng/mL; P = .04) were lower in Gsnor-/- than in WT mice despite similar follicle-stimulating hormone levels (63.98 vs 77.93 ng/mL; P = .20). Immunofluorescence of Gsnor-/- and WT testes showed similar staining of 3beta-hydroxysteroid dehydrogenase and LHR. Human chorionic gonadotropin stimulation of Gsnor-/- mice increased serum T (>1,680 vs >1,680 ng/dL) and gonadotropin-releasing hormone stimulation increased serum LH (6.3 vs 8.9 ng/mL; P = .20) similar to WT mice. CLINICAL TRANSLATION: These findings provide novel insight to a possible mechanism of secondary hypogonadism from increased reactive nitrogen species and excess nitrosative stress. STRENGTHS AND LIMITATIONS: Limitations of this study are its small samples and variability in hormone levels. CONCLUSION: Deficiency of S-nitrosoglutathione reductase results in secondary hypogonadism, suggesting that excess nitrosative stress can affect LH production from the pituitary gland. Masterson TA, Arora H, Kulandavelu S, et al. S-Nitrosoglutathione Reductase (GSNOR) Deficiency Results in Secondary Hypogonadism. J Sex Med 2018;15:654-661. PMID- 29606626 TI - Gender Dysphoria and Gender Change in Disorders of Sex Development/Intersex Conditions: Results From the dsd-LIFE Study. AB - BACKGROUND: Information on the psychosexual outcome of individuals with disorders of sex development (DSDs) and intersex conditions is of great importance for sex assignment at birth of newborns with DSD. AIM: To assess gender change and gender dysphoria in a large sample of individuals with different DSDs. METHODS: A cross sectional study was conducted in 14 European centers with 1,040 participants (717 female-identifying and 311 male-identifying persons and 12 persons identifying with another gender) with different forms of DSD. The cohort (mean age = 32.36 years, SD = 13.57) was divided into 6 major subgroups: women with 45,X DSD and variants (Turner syndrome; n = 325), men with 47,XXY DSD and variants (Klinefelter syndrome; n = 219), women with XY DSD without androgen effects (n = 107) and with androgen effects (n = 63), men with XY DSD (n = 87), and women with 46,XX congenital adrenal hyperplasia (n = 221). Data on psychosexual outcome were gathered by medical interviews and questionnaires. OUTCOMES: Gender change and gender dysphoria. RESULTS: Although gender changes were reported by 5% of participants, only in 1% (3% if those with Klinefelter and Turner syndromes conditions in which gender issues are not prominent-are excluded) did the gender change take place after puberty and was likely initiated by the patient. 39 participants (4%) reported gender variance: between male and female, a gender other than male or female, or gender queer, alternating gender roles, or a gender expression that differed from the reported gender. This group had lower self esteem and more anxiety and depression than the other participants. CLINICAL IMPLICATIONS: Clinicians should be aware of and sensitive to the possibility that their patients with DSD not only might have transgender feelings and a desire to change gender, but also identify as different from male or female. The complexity of their feelings might require counseling for some patients. STRENGTHS AND LIMITATIONS: The study is unique in the large number of participants from many different clinics, with sizable numbers in most subgroups, and in the large number of aspects that were measured. However, the very broadness of the study made it impossible to focus in detail on gender issues. Also, there is a need for instruments specifically measuring gender dysphoria in individuals with DSD that take non-binary genders into account. CONCLUSION: To make appropriate gender care possible for people with DSD, the gender-normative and gender-variant development of children with DSD should be studied in longitudinal studies. Kreukels BPC, Kohler B, Nordenstrom A, et al. Gender Dysphoria and Gender Change in Disorders of Sex Development/Intersex Conditions: Results From the dsd-LIFE Study. J Sex Med 2018;15:777-785. PMID- 29606627 TI - Psychometric Properties of the Orgasm Rating Scale in Context of Sexual Relationship in a Spanish Sample. AB - BACKGROUND: The Orgasm Rating Scale (ORS) is one of the few self-reported measures that evaluates the multidimensional subjective experience of orgasm. AIM: The objective of this study was to examine the psychometric properties of the ORS in context of sex-with-partner in a Spanish sample. METHODS: We examined a sample of 842 adults from the general Spanish population (310 men, 532 women; mean age = 27.12 years, SD = 9.8). The sample was randomly divided into two, with a balanced proportion of men and women between each sub-sample. Sub-sample 1 consisted of 100 men and 200 women (33.3% and 66.6%) with a mean age of 27.77 years (SD = 10.05). Sub-sample 2 consisted of 210 men and 332 women (38.7% and 61.3%) with a mean age of 26.77 years (SD = 9.65). The ORS, together with the Sexual Opinion Survey-6 and the Massachusetts General Hospital-Sexual Functioning Questionnaire, was administered online. The survey included a consent form, in which confidentiality and anonymity were guaranteed. OUTCOMES: Based on exploratory factor analysis, we obtained a reduced 25-item version of the ORS, distributed along 4 dimensions (affective, sensory, intimacy, and rewards). RESULTS: We performed both exploratory factor analysis and confirmatory factor analysis. The Spanish version of the ORS had adequate values of reliability that ranged from .78-.93. The 4 factors explained 59.78% of the variance. The factor structure was invariant across gender at a configural level. Scores from the ORS positively correlated with erotophilia and sexual satisfaction. The scale was useful to differentiate between individuals with orgasmic difficulties and individuals with no difficulties. We found that individuals with orgasmic difficulties showed a lower intensity in the affective, intimacy, and sensorial manifestations of orgasm. CLINICAL TRANSLATION: This version of the ORS could provide an optimum measure for the clinical assessment to identify individuals with difficulties in their orgasmic capacity, thus, it could be used as screening device for orgasmic dysfunction. CONCLUSIONS: The ORS is an appropriate measure for its use for both research and clinical purposes. As limitations, quota sampling implies that the extent to which the results can be generalized is modest. Measurement invariance did not reach the level of weak invariance, and it was not tested across sexual orientation because most individuals identified themselves as heterosexual. The ORS is a multidimensional measure of the subjective experience of orgasm which has adequate psychometric properties; it is a reliable and valid scale. Arcos-Romero AI, Moyano N, Sierra JC. Psychometric Properties of the Orgasm Rating Scale in Context of Sexual Relationship in a Spanish Sample. J Sex Med 2018;15:741-749. PMID- 29606628 TI - The Relationship Between Environmental Factors and the Profile of Epstein-Barr Virus Antibodies in the Lytic and Latent Infection Periods in Healthy Populations from Endemic and Non-Endemic Nasopharyngeal Carcinoma Areas in China. AB - Our previous study found that smoking was associated with an elevated level of the antibody against VCA in the Epstein-Barr virus (EBV) lytic phase, which was an important predictive marker of the risk of nasopharyngeal carcinoma (NPC). It remained unknown whether environmental factors were associated with the levels of other EBV antibodies, such as Zta-IgA, EA-IgA, EBNA1-IgA, and LMP1-IgA, in the lytic and latent infection periods. We aimed to investigate the possible environmental inducers that could affect EBV antibody levels in two independent healthy male populations from endemic NPC areas in South China (N=1498) and non endemic NPC areas in North China (N=1961). We performed ELISA and immunoenzymatic assays to test the levels of antibodies specific to the EBV antigens. The seropositive rates of antibodies against the antigens expressed in both the EBV latent and lytic infection periods, namely, LMP1-IgA, EBNA1-IgA, and Zta-IgA, in endemic areas (28.65%, 5.43% and 14.49%, respectively) were significantly higher than those in non-endemic areas (14.43%, 1.07% and 6.32%, respectively). Smoking was associated with higher seropositivity for EBNA1-IgA (OR=1.47, 95% CI=1.12 1.93) and Zta-IgA (OR=1.28, 95% CI=0.99-1.66), with dose-response effects, while not associated with the levels of LMP1-IgA. In conclusion, smoking was an important environmental factor, which associated with increased levels of EBNA1 IgA, and Zta-IgA. PMID- 29606629 TI - Trans-Fats Inhibit Autophagy Induced by Saturated Fatty Acids. AB - Depending on the length of their carbon backbone and their saturation status, natural fatty acids have rather distinct biological effects. Thus, longevity of model organisms is increased by extra supply of the most abundant natural cis unsaturated fatty acid, oleic acid, but not by that of the most abundant saturated fatty acid, palmitic acid. Here, we systematically compared the capacity of different saturated, cis-unsaturated and alien (industrial or ruminant) trans-unsaturated fatty acids to provoke cellular stress in vitro, on cultured human cells expressing a battery of distinct biosensors that detect signs of autophagy, Golgi stress and the unfolded protein response. In contrast to cis-unsaturated fatty acids, trans-unsaturated fatty acids failed to stimulate signs of autophagy including the formation of GFP-LC3B-positive puncta, production of phosphatidylinositol-3-phosphate, and activation of the transcription factor TFEB. When combined effects were assessed, several trans unsaturated fatty acids including elaidic acid (the trans-isomer of oleate), linoelaidic acid, trans-vaccenic acid and palmitelaidic acid, were highly efficient in suppressing autophagy and endoplasmic reticulum stress induced by palmitic, but not by oleic acid. Elaidic acid also inhibited autophagy induction by palmitic acid in vivo, in mouse livers and hearts. We conclude that the well established, though mechanistically enigmatic toxicity of trans-unsaturated fatty acids may reside in their capacity to abolish cytoprotective stress responses induced by saturated fatty acids. PMID- 29606631 TI - Workflow Considerations for Incorporation of Contrast-Enhanced Spectral Mammography Into a Breast Imaging Practice. PMID- 29606630 TI - Functional Characterization of Native, High-Affinity GABAA Receptors in Human Pancreatic beta Cells. AB - In human pancreatic islets, the neurotransmitter gamma-aminobutyric acid (GABA) is an extracellular signaling molecule synthesized by and released from the insulin-secreting beta cells. The effective, physiological GABA concentration range within human islets is unknown. Here we use native GABAA receptors in human islet beta cells as biological sensors and reveal that 100-1000nM GABA elicit the maximal opening frequency of the single-channels. In saturating GABA, the channels desensitized and stopped working. GABA modulated insulin exocytosis and glucose-stimulated insulin secretion. GABAA receptor currents were enhanced by the benzodiazepine diazepam, the anesthetic propofol and the incretin glucagon like peptide-1 (GLP-1) but not affected by the hypnotic zolpidem. In type 2 diabetes (T2D) islets, single-channel analysis revealed higher GABA affinity of the receptors. The findings reveal unique GABAA receptors signaling in human islets beta cells that is GABA concentration-dependent, differentially regulated by drugs, modulates insulin secretion and is altered in T2D. PMID- 29606632 TI - Patient Perceptions of Breast Cancer Risk in Imaging-Detected Low-Risk Scenarios and Thresholds for Desired Intervention: A Multi-Institution Survey. AB - PURPOSE: To determine women's perceptions of breast cancer risk and thresholds for desiring biopsy when considering BI-RADS 3 and 4A scenarios and recommendations, respectively. MATERIALS AND METHODS: Women presenting for screening mammography from five geographically diverse medical centers were surveyed. Demographic information and baseline anxiety were queried. Participants were presented with scenarios of short-term imaging follow-up recommendations (ie, BI-RADS 3) and biopsy recommendations (ie, BI-RADS 4A) for low-risk mammographic abnormalities and asked to estimate their breast cancer risk for each scenario. Participants reported the threshold (ie, likelihood of cancer) where they would feel comfortable undergoing short-term imaging follow-up and biopsy and their anticipated regret for choosing short-term follow-up versus biopsy. RESULTS: Analysis of 2,747 surveys showed that participants estimated breast cancer risk of 32.8% for a BI-RADS 3 and 41.1% for a BI-RADS 4A scenarios are significantly greater rates than clinically established rates (<2% [P < .001] and 2%-10% [P < .001], respectively). Over one-half (55.4%) of participants reported they would never want imaging follow-up if there was any chance of cancer; two-thirds (66.2%) reported they would desire biopsy if there was any chance of cancer. Participants reported greater anticipated regret (P < .001) and less relief and confidence (P < .001) with the decision to undergo follow-up imaging versus biopsy. CONCLUSION: Women overestimate breast cancer risk associated with both BI-RADS 3 and 4A scenarios and desire very low biopsy thresholds. Greater anticipated regret and less relief and confidence was reported with the choice to undergo short-term imaging follow-up compared with biopsy. PMID- 29606633 TI - Critical Test Result Notification via Mobile Phone-Based Automated Text Message System in the Radiologic Field: Single Institutional Experience. AB - PURPOSE: To investigate the feasibility of sharing critical test result (CTR) notifications (CTRNs) via automated text messaging. MATERIALS AND METHODS: CTRNs via automated text messaging was used to notify physicians of CTRs in a tertiary hospital with 1,786 beds. From June 2016 to September 2016, notifications for 545 CTRs were given via a CTRN system. Among them, 490 CTRs (292 male and 198 female patients; mean age, 53.6 years old [range, 1-88]) were included in analysis. CTR levels (CTRLs) were assigned to four categories (CTRL1 to CTRL3 and unclassified) when reported, and reclassified into three CTRLs according to their clinical relevance and urgency. Response time was defined as time lapse between CTR reporting and documentation by physicians. Analysis of variance was performed to compare response times according to CTRLs and patients' location. RESULTS: Corresponding actions were taken in 404 of 490 cases (82.4%) without any delayed CTRN-related morbidity. There were 15 CTRL1 (3.1%), 50 CTRL2 (10.2%), 112 CTRL3 (22.9%) cases, and the remaining 313 CTRL cases were unclassified. After reclassification, CTRL1, CTRL2, and CTRL3 were 81 (16.5%), 177 (36.1%), and 232 cases (47.3%), respectively. Response time of reclassified CTRL3 was significantly longer than that of reclassified CTRL1 (median 23.0, [interquartile range 2.0-133.5] hours versus 4.0 [0.0-22.0] hours; P < .001). Response time of outpatient cases (80.0 [6.0 to 157.0] hours) was significantly longer (P < .001) than those of inpatient (3.0 [0.0-16.0]) and emergency department cases (5.0 [1.0 21.0]). CONCLUSION: Automated text messaging could be a feasible option for CTRNs in the radiologic field. Further large-scale investigations regarding efficiency of this system are warranted. PMID- 29606635 TI - Losing Sight. PMID- 29606634 TI - Leveraging Facebook to Brand Radiology. AB - In the current health care climate, radiologists should consider developing their brand. Facebook is the market leader for social media networking in the United States. The authors describe how radiologists can leverage Facebook to develop and market organizational, group, and individual brands. The authors then address concerns related to the use of social media by radiologists. PMID- 29606636 TI - Rising Retrieval Rates of Inferior Vena Cava Filters in the United States: Insights From the 2012 to 2016 Summary Medicare Claims Data. AB - BACKGROUND: To determine recent inferior vena cava filter (IVCF) retrieval volumes and rates in the Medicare population. METHODS: The summary Medicare claims data were searched for the years 2012 to 2016 to identify the frequency of IVCF placements and retrievals. The new Healthcare Common Procedure Coding System code for filter retrieval introduced in 2012, 37193, was used to track filter retrievals. Trends in number of IVCF placements and retrievals over the study period were evaluated, both of which were further stratified by physician specialty and site of service. Aggregate and compound annual growth rates for retrievals were also computed. RESULTS: A total of 255,034 filters were placed over the study period, with the filter placement volume declining from 61,889 in 2012 to 38,095 in 2016. Filter retrievals, however, increased from 4,327 in 2012 to 8,405 in 2016. The net filter retrieval rate per annual filters placed increased from 6.9% in 2012 to 22.1% in 2016, yielding an average filter retrieval rate and compound annual growth rate of 11.6% and 18.1% respectively. Radiologists placed and retrieved the majority of filters (60.4% placed, 63.5% retrieved) compared with nonradiologists. The inpatient setting was the dominant site for filter placement compared with the outpatient setting for filter retrieval across all years and specialties. CONCLUSIONS: Since introduction of the unique Healthcare Common Procedure Coding System code for IVCF retrieval in 2012, IVCF placements in the Medicare population have been declining and net retrieval rates have risen. Radiologists continue to place and retrieve the majority of filters. PMID- 29606637 TI - Oral epithelial dysplasia, atypical verrucous lesions and oral potentially malignant disorders: focus on histopathology. AB - The term oral potentially malignant disorders (OPMDs) describes a recognizable group of mucosal diseases that have a risk of progressing to squamous cell carcinoma. Oral leukoplakia, the most common OPMD, has a 1% prevalence and reported malignant transformation rates of 2% to 5%. Other OPMDs include erythroplakia, erythroleukoplakia, submucous fibrosis, lesions of reverse smokers, and inherited genetic disorders, such as Fanconi anemia. The histopathologic assessment of OPMDs is an area of subjectivity, and oral epithelial dysplasia (OED) is fraught with both interrater variability and intrarater variability. Both architectural and cytologic changes are utilized when developing criteria for grading OED. However, the concept of atypical verrucous lesions, particularly as it pertains to proliferative verrucous leukoplakia, suffers from lack of histopathologic diagnostic criteria. Histopathologic mimics of OPMDs, including reactive/regenerative epithelium, frictional keratosis, and infection, can result in patient mismanagement. This review will focus specifically on the histologic features of OED, including human papillomavirus-associated dysplasia, as well as the histologic features of atypical verrucous keratoses/hyperplasia, particularly those that arise in the setting of proliferative verrucous leukoplakia along with OPMD mimics. PMID- 29606638 TI - Epinephrine in Severe Allergic Reactions: The European Anaphylaxis Register. AB - BACKGROUND: Current guidelines recommend intramuscular administration of epinephrine as the first-line drug for the emergency treatment of severe allergic reactions (anaphylaxis), but no randomized trial evidence supports this consensus. OBJECTIVE: We aimed to assess anaphylaxis treatment practices over 10 years, covering several European regions, all allergen sources, and all age groups. METHODS: The European Anaphylaxis Register tracks elicitors, symptoms, emergency treatment, diagnostic workups, and long-term counseling for anaphylaxis incidents through web-based data entry from tertiary allergy specialists, covering information from the emergency respondent, patient, tertiary referral, and laboratory/clinical test results. RESULTS: We analyzed 10,184 anaphylaxis incidents. In total, 27.1% of patients treated by a health professional received epinephrine and, in total, 10.5% received a second dose. Successful administration was less frequent in German-speaking countries (minimum 19.6%) than in Greece, France, and Spain (maximum 66.7%). Over the last decade, epinephrine administration from a health professional almost doubled to reach 30.6% in 2015-2017, half of which was applied intramuscularly. A total of 14.7% of lay- or self-treated cases were treated with an autoinjector. Of those without treatment, 22.4% carried a device for administration. No change in successful administration by lay emergency respondents was found over the last 10 years. Of the reaction and patient characteristics analyzed, only clinical severity considerably influenced the likelihood of receiving epinephrine, with 66.9% of successful administrations in near-fatal (grade IV) reactions. CONCLUSIONS: Despite clear recommendations, only a small proportion of anaphylaxis incidents are treated with epinephrine. We demonstrated a slight increase in treated patients when handled by professionals, but stagnation in lay- or self-treated anaphylaxis. The reaction circumstances, the respondent's professional background, and patient characteristics did not explain which reactions were treated. PMID- 29606639 TI - The Burden of Rhinitis and the Impact of Medication Management within the Community Pharmacy Setting. AB - BACKGROUND: The burden of rhinitis is high. It is unknown to what extent this burden is related to inappropriate medication use. OBJECTIVE: This study aimed to identify the way in which people with rhinitis medicate their condition and to evaluate the appropriateness of this medication management. METHODS: Pharmacy customers who visited Sydney metropolitan community pharmacies and purchased medication for nasal symptoms were the sampling frame for this study. To determine the condition for which the participants were seeking medication and the appropriateness of their medication selection, the following data were collected with a researcher-administered questionnaire: participant's demographics, symptoms, medication selected. An expert panel of clinical researcher pharmacists and specialist respiratory physician evaluated the appropriateness of medication selection based on the Allergic Rhinitis and its Impact on Asthma international guidelines. RESULTS: Two hundred and ninety-six participants were recruited from 8 pharmacies; 63.2% had a doctor's diagnosis for the symptoms for which they were selecting treatment. Seventy percent of participants self-selected their medications. Seventy-one percent of the participants were identified as having rhinitis. Overall, 16.5% of participants who had rhinitis selected optimal medications. Sixteen percent of participants with allergic rhinitis reported wheezing (6.3% selected optimal medications). CONCLUSIONS: The majority of the participants with rhinitis selected suboptimal medications from community pharmacy highlighting the significant burden of rhinitis in community pharmacy and the contribution of medication management. Pharmacists need to take a proactive and evidence-based role in the management of rhinitis supported by clinical pathways when need to be articulated and promoted in all rhinitis guidelines. PMID- 29606640 TI - Timing of Postdischarge Follow-Up and Medication Adherence Among Patients With Heart Failure. AB - BACKGROUND: Medication adherence improves outcomes for patients with heart failure, but adherence rates remain low. We examined the association between earlier postdischarge follow-up and medication adherence. METHODS AND RESULTS: We performed a retrospective cohort study of patients >=65 years who were hospitalized for heart failure, covered by Medicare Part D, and discharged alive from April 2006 to October 2012 using the Get With The Guidelines-Heart Failure Registry linked to Medicare claims. Patients were categorized into 4 groups by timing of first postdischarge follow-up visit: <=1, 1 to 2, 2 to 6, and >6 weeks. Medication adherence was defined by proportion of days covered of >80% at 90 days and 1-year posthospital discharge to 5 guideline-directed medical therapies (angiotensin-converting enzyme inhibitor/angiotensin receptor blocker, evidence based beta-blocker, aldosterone antagonist, hydralazine/isosorbide dinitrate, and anticoagulation for atrial fibrillation). Among 9878 patients with heart failure, 73% had left ventricular ejection fraction <=40%, median age was 78 years (25th 75th percentile, 71-84), and 48% were male. Overall, 30% had a follow-up appointment within 1-week postdischarge and 25% >6 weeks. At 1 year, medication adherence was 53% for evidence-based beta-blockers, 48% for angiotensin converting enzyme inhibitors/angiotensin receptor blockers, and 8% for hydralazine/isosorbide dinitrate. We found no significant association between timing of first follow-up visit and medication adherence at 1 year (1.04, 0.92 1.17) when comparing follow-up visits >6 weeks to the earliest ones. CONCLUSIONS: Posthospital heart failure discharge, overall adherence to medical therapies in Medicare beneficiaries was low. Early follow-up was not associated with increased medication adherence to guideline-directed medical therapy in the short or long term. PMID- 29606641 TI - Is Transcatheter Aortic Valve Replacement Better Than Surgical Aortic Valve Replacement in Patients With Chronic Obstructive Pulmonary Disease? A Nationwide Inpatient Sample Analysis. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) patients are at increased risk of respiratory related complications after cardiac surgery. It is unclear whether transcatheter aortic valve replacement (TAVR) or surgical aortic valve replacement (SAVR) results in favorable outcomes among COPD patients. METHODS AND RESULTS: Patients were identified from the Nationwide Inpatient Sample database from 2011 to 2014. Patients with age >=60, COPD, and either went transarterial TAVR or SAVR were included in the analysis. A 1:1 propensity matched cohort was created to examine the outcomes. A matched pair of 1210 TAVR and 1208 SAVR patients was identified. Respiratory-related complications such as tracheostomy (0.8% versus 5.8%; odds ratio [OR], 0.14; P<0.001), acute respiratory failure (16.4% versus 23.7%; OR, 0.63; P=0.002), reintubation (6.5% versus 10.0%; OR, 0.49; P<0.001), and pneumonia (4.5% versus 10.1%; OR, 0.41; P<0.001) were significantly less frequent with TAVR versus SAVR. Use of noninvasive mechanical ventilation was similar between TAVR and SAVR (4.1% versus 4.8%; OR, 0.84; P=0.41). Non-respiratory-related complications, such as in hospital mortality (3.3% versus 4.2%; OR, 0.64; P=0.035), bleeding requiring transfusion (9.9% versus 21.7%; OR, 0.38; P<0.001), acute kidney injury (17.7% versus 25.3%; OR, 0.63; P<0.001), and acute myocardial infarction (2.4% versus 8.4%; OR, 0.19; P<0.001), were significantly less frequent with TAVR than SAVR. Cost ($56 099 versus $63 146; P<0.001) and hospital stay (mean, 7.7 versus 13.0 days; P<0.001) were also more favorable with TAVR than SAVR. CONCLUSIONS: TAVR portended significantly fewer respiratory-related complications compared with SAVR in COPD patients. TAVR may be a preferable mode of aortic valve replacement in COPD patients. PMID- 29606642 TI - Transcatheter or Surgical Aortic Valve Replacement in Patients With Chronic Lung Disease? The Answer, My Friend, Is Blowin' in the Wind. PMID- 29606643 TI - Mirror, Mirror, on the Wall, Which Is the Most Effective Biologic of All? PMID- 29606644 TI - Toward a Multibiomarker Panel to Optimize Outcome and Predict Response in Juvenile Idiopathic Arthritis. PMID- 29606645 TI - A Changing Landscape of Gout: Comorbidity Matters. PMID- 29606646 TI - Ocular Involvement in Sarcoidosis. PMID- 29606647 TI - Successful Lung Transplantation in a Case of Rapidly Progressive Interstitial Lung Disease Associated with Antimelanoma Differentiation-associated Gene 5 Antibodies. PMID- 29606649 TI - Reading Journal Articles-Past, Present, and Future. PMID- 29606648 TI - Causes of Hospital Mortality in Patients with Rheumatoid Arthritis and Systemic Lupus Erythematosus in a University Hospital: 1998-2015 Analysis. PMID- 29606650 TI - Clinical Dental Faculty Members' Perceptions of Diagnostic Errors and How to Avoid Them. AB - Diagnostic errors are increasingly recognized as a source of preventable harm in medicine, yet little is known about their occurrence in dentistry. The aim of this study was to gain a deeper understanding of clinical dental faculty members' perceptions of diagnostic errors, types of errors that may occur, and possible contributing factors. The authors conducted semi-structured interviews with ten domain experts at one U.S. dental school in May-August 2016 about their perceptions of diagnostic errors and their causes. The interviews were analyzed using an inductive process to identify themes and key findings. The results showed that the participants varied in their definitions of diagnostic errors. While all identified missed diagnosis and wrong diagnosis, only four participants perceived that a delay in diagnosis was a diagnostic error. Some participants perceived that an error occurs only when the choice of treatment leads to harm. Contributing factors associated with diagnostic errors included the knowledge and skills of the dentist, not taking adequate time, lack of communication among colleagues, and cognitive biases such as premature closure based on previous experience. Strategies suggested by the participants to prevent these errors were taking adequate time when investigating a case, forming study groups, increasing communication, and putting more emphasis on differential diagnosis. These interviews revealed differing perceptions of dental diagnostic errors among clinical dental faculty members. To address the variations, the authors recommend adopting shared language developed by the medical profession to increase understanding. PMID- 29606651 TI - Integration of Basic and Clinical Sciences: Faculty Perspectives at a U.S. Dental School. AB - Although dental education has traditionally been organized into basic sciences education (first and second years) and clinical education (third and fourth years), there has been growing interest in ways to better integrate the two to more effectively educate students and prepare them for practice. Since 2012, The University of Texas School of Dentistry at Houston (UTSD) has made it a priority to improve integration of basic and clinical sciences, with a focus to this point on integrating the basic sciences. The aim of this study was to determine the perspectives of basic and clinical science faculty members regarding basic and clinical sciences integration and the degree of integration currently occurring. In October 2016, all 227 faculty members (15 basic scientists and 212 clinicians) were invited to participate in an online survey. Of the 212 clinicians, 84 completed the clinician educator survey (response rate 40%). All 15 basic scientists completed the basic science educator survey (response rate 100%). The majority of basic and clinical respondents affirmed the value of integration (93.3%, 97.6%, respectively) and reported regular integration in their teaching (80%, 86.9%). There were no significant differences between basic scientists and clinicians on perceived importance (p=0.457) and comfort with integration (p=0.240), but the basic scientists were more likely to integrate (p=0.039) and collaborate (p=0.021) than the clinicians. There were no significant differences between generalist and specialist clinicians on importance (p=0.474) and degree (p=0.972) of integration in teaching and intent to collaborate (p=0.864), but the specialists reported feeling more comfortable presenting basic science information (p=0.033). Protected faculty time for collaborative efforts and a repository of integrated basic science and clinical examples for use in teaching and faculty development were recommended to improve integration. Although questions might be raised about the respondents' definition of "integration," this study provides a baseline assessment of perceptions at a dental school that is placing a priority on integration. PMID- 29606652 TI - Academic Pre-Orientation Program for Dental Students: Beginning and End of Program Evaluations, 1998-2016. AB - Admitting students from non-traditional or disadvantaged backgrounds can increase the diversity of dental school classes. The aims of this study were to analyze how interested non-traditional incoming dental students were at the beginning of an academic pre-orientation program in learning about basic science, dentistry related topics, and academic skills; how confident they were in doing well in basic science and dentistry-related courses; and how they evaluated the program at the end. The relationships between personal (interest/confidence) and structural factors (program year, number of participants) and program evaluations were also explored. All 360 students in this program at the University of Michigan from 1998 to 2016 were invited to participate in surveys at the beginning and end of the educational intervention. A total of 353 students responded at the beginning (response rate 98%), and 338 responded at the end (response rate 94%). At the beginning, students were more interested in learning about basic science and dentistry-related topics than about academic skills, and they were more confident in their dentistry- related than basic science-related abilities. At the end, students valued basic science and dentistry-related education more positively than academic skills training. Confidence in doing well and interest in basic science and dentistry-related topics were correlated. The more recent the program was, the less confident the students were in their basic science abilities and the more worthwhile they considered the program to be. The more participants the program had, the more confident the students were, and the better they evaluated their basic science and dentistry-related education. Overall, this academic pre-orientation program was positively evaluated by the participants. PMID- 29606653 TI - A National Survey of U.S. Dental Students' Experiences with International Service Trips. AB - Globalization, along with the increasing prevalence of non-communicable diseases, their risk factors, and poor oral health, demands global approaches to oral health care. Trained health care workers' providing volunteer services abroad is one model used for improving access to dental services for some communities. Currently, little is known about U.S. dental student involvement in international clinical service volunteerism. The aim of this exploratory study was to capture national survey data from predoctoral dental students about their interest in and experience with global health service trips. The survey sought to assess students' past experiences and current and future interest in programs providing dental and/or medical services in order to lay the foundation for further research. A 12-question web-based survey was distributed in May 2017 to 22,930 students enrolled in U.S. dental schools. A total of 1,555 students responded, for a response rate of 7%. Respondents were evenly distributed across the four academic years. Approximately 22% (n=342) of the respondents had already participated in a service trip experience, 83% reported interest in a service trip while in school, and 92% were interested after graduation. Reported motivations for international trips included the desire to care for the underserved and to obtain a more global view of health and disease. Concerns were expressed regarding costs and time constraints. This study provided preliminary, exploratory data on dental student engagement with international service trips. Both interest and participation in international service trips among responding students were high, reflecting current trends in both dentistry and medicine. Dental education may have an opportunity to guide student engagement in more sustainable and ethical volunteering in the U.S. and abroad. PMID- 29606654 TI - Self-Directed Digital Learning: When Do Dental Students Study? AB - The Growth and Development (G&D) curriculum at the University of North Carolina at Chapel Hill School of Dentistry uses self-directed web-based learning modules in the place of lectures and includes scheduled self-study times during the 8 am 5 pm school hours. The aim of this study was to use direct observation to evaluate dental students' access patterns with the self-directed, web-based learning modules in relation to planned self-study time allocated across the curriculum, proximity to course examinations, and course performance. Module access for all 80 students in the DDS Class of 2014 was recorded for date and time across the four G&D courses. Module access data were used to determine likelihood of usage during scheduled time and frequency of usage in three timeframes: >7, 3 to 7, and 0 to 2 days before the final exam. The results showed a statistically significant difference in the likelihood of module access during scheduled time across the curriculum (p<0.0001). Among the students, 64% accessed modules at least once during scheduled time in G&D1, but only 10%, 19%, and 18% in G&D2, G&D3, and G&D4, respectively. For all courses, the proportion of module accesses was significantly higher 0-2 days before an exam compared to the other two timeframes. Module access also differed significantly within each timeframe across all four courses (p<0.001). There was no association between module access and course performance. In this non-traditional, non-lecture, self-directed curriculum, students rarely accessed learning modules during syllabus-budgeted self-study time and accessed modules more frequently as course exams approached. PMID- 29606655 TI - Should Dental Schools Invest in Training Predoctoral Students for Academic Careers? Two Viewpoints: Viewpoint 1: Dental Schools Should Add Academic Careers Training to Their Predoctoral Curricula to Enhance Faculty Recruitment and Viewpoint 2: Addition of Academic Careers Training for All Predoctoral Students Would Be Inefficient and Ineffective. AB - This Point/Counterpoint considers whether providing dental students with academic career training and teaching experiences during their predoctoral education would be valuable to recruit dental academicians. While training the next generation of dentists continues to be the primary focus for dental schools, the cultivation and recruitment of dental faculty members from the pool of dental students remain challenges. Viewpoint 1 supports the position that providing dental students with exposure to academic career opportunities has positive value in recruiting new dental faculty. The advantages of academic careers training as a required educational experience in dental schools and as a potential means to recruit dental students into the ranks of faculty are described in this viewpoint. In contrast, Viewpoint 2 contends that such career exposure has limited value and argues that, across the board, allocation of resources to support preparation for academic careers would have a poor cost-benefit return on investment. Adding a requirement for educational experiences for all students would overburden institutions, students, and faculty according to this viewpoint. The authors agree that research is needed to determine how and where to make predoctoral curricular changes that will have maximum impact on academic recruitment. PMID- 29606656 TI - Engaging Oral Health Students in Learning Basic Science Through Assessment That Weaves in Personal Experience. AB - Learning basic science forms an essential foundation for oral health therapy and dentistry, but frequently students perceive it as difficult, dry, and disconnected from clinical practice. This perception is encouraged by assessment methods that reward fact memorization, such as objective examinations. This study evaluated use of a learner-centered assessment portfolio designed to increase student engagement with basic science in an oral health therapy program at the University of Sydney, Australia. The aim of this qualitative study based on focus groups was to investigate students' engagement with basic science courses following introduction of the portfolio. Three assessments were conducted in three subsequent semesters: one based on students' interest in everyday phenomena (one student, for example, explored why she had red hair); the second focussed on scientific evidence and understanding of systemic diseases; and the third explored relations between oral and general health. Students were encouraged to begin with issues from their personal experience or patient care, to focus on what they were curious about, and to ask questions they really cared about. Each student prepared a written report and gave an oral presentation to the entire cohort. After the portfolios were completed, the authors held focus groups with two cohorts of students (N=21) in 2016 and analyzed the results using Zepke's framework for student engagement research. The results showed that the students successfully interweaved personal experience into their studies and that it provided significant motivation for learning. The students described their learning in terms of connection to themselves, their peer community, and their profession. Many additional benefits were identified, from increased student engagement in all courses to appreciation of the relevance of basic science. The findings should encourage dental and allied dental educators to reconsider the effects of assessments and seek integrative methods to help students engage in meaningful knowledge production and understand that what they are learning goes beyond acquisition of scientific facts. PMID- 29606657 TI - The Role of Digital 3D Scanned Models in Dental Students' Self-Assessments in Preclinical Operative Dentistry. AB - The aim of this study was to determine how dental student self-assessment and faculty assessment of operative preparations compared for conventional visual assessment versus assessment of scanned digital 3D models. In 2016, all third year students in the Class of 2018 (N=35) at Harvard School of Dental Medicine performed preclinical exams of Class II amalgam preparations (C2AP) and Class III composite preparations (C3CP) and completed self-assessment forms; in 2017, all third-year students in the Class of 2019 (N=34) performed the same exams. Afterwards, the prepared typodont teeth were digitally scanned. Students self assessed their preparations digitally, and four faculty members graded the preparations conventionally and digitally. The results showed that, overall, the students assessed their preparations higher than the faculty assessments. The mean student-faculty gaps for C2AP and C3CP in the conventional assessments were 11% and 5%, respectively. The mean digital student-faculty gap for C2AP and C3CP were 8% and 2%, respectively. In the conventional assessments, preclinical performance was negatively correlated with the student-faculty gap (r=-0.47, p<0.001). The correlations were not statistically significant with the digital assessments (p=0.39, p=0.26). Students in the bottom quartile significantly improved their self-assessment accuracy using digital self-assessments over conventional assessments (C2AP 10% vs. 17% and C3CP 3% vs. 10%, respectively). These results suggest that digital assessments offered a significant learning opportunity for students to critically self-assess themselves in operative preclinical dentistry. The lower performing students benefitted the most, improving their assessment ability to the level of the rest of the class. PMID- 29606658 TI - Comparison of Dental Students' PAT Scores with Their Performance in Preclinical Technique Courses: Identifying the Need for Early Interventions. AB - The aim of this study was to determine if lower scores on the Perceptual Ability Test (PAT) of the Dental Admission Test (DAT) predicted which dental students required remediation in three preclinical restorative dentistry courses at Rutgers School of Dental Medicine. The academic records of 489 dental students from the graduating Classes of 2010 through 2015 were evaluated. The results showed that, for all three courses (Preclinical General Dentistry I, Preclinical General Dentistry II, and Preclinical Fixed Prosthodontics), the remediating students had significantly lower mean PAT scores than did the passing students. A one-unit decrease in a student's PAT score was associated with a 43% increase in the odds of remediating the Preclinical General Dentistry I lab, a 29% increase in the odds of remediating the Preclinical Fixed Prosthodontics lab, and a 47% increase in the odds of remediating the Preclinical General Dentistry II lab. The mean PAT score for passing students was 18.84 (standard deviation 2.35), and the mean PAT score for students requiring remediation was 17.03 (standard deviation 2.18). Studies like this can be useful because if students at risk of failing these courses are identified early and appropriate supports are provided, the need for remediation may be reduced if not eliminated. PMID- 29606659 TI - Rethinking Dental School Admission Criteria: Correlation Between Pre-Admission Variables and First-Year Performance for Six Classes at One Dental School. AB - Admissions committees in dental schools are charged with the responsibility of selecting candidates who will succeed in school and become successful members of the profession. Identifying students who will have academic difficulty is challenging. The aim of this study was to determine the predictive value of pre admission variables for the first-year performance of six classes at one U.S. dental school. The authors hypothesized that the variables undergraduate grade point average (GPA), undergraduate science GPA (biology, chemistry, and physics), and Dental Admission Test (DAT) scores would predict the level of performance achieved in the first year of dental school, measured by year-end GPA. Data were collected in 2015 from school records for all 297 students in the six cohorts who completed the first year (Classes of 2007 through 2013). In the results, statistically significant correlations existed between all pre-admission variables and first-year GPA, but the associations were only weak to moderate. Lower performing students at the end of the first year (lowest 10% of GPA) had, on average, lower pre-admission variables than the other students, but the differences were small (<=10.8% in all categories). When all the pre-admission variables were considered together in a multiple regression analysis, a significant association was found between pre-admission variables and first-year GPA, but the association was weak (adjusted R2=0.238). This weak association suggests that these students' first-year dental school GPAs were mostly determined by factors other than the pre-admission variables studied and has resulted in the school's placing greater emphasis on other factors for admission decisions. PMID- 29606660 TI - Dental Students' Skills Assessments: Comparisons of Daily Clinical Grades and Clinical and Laboratory Assessments. AB - The aim of this study was to compare the daily clinical grades of third-year dental students during routine clinical activities involving direct and indirect operative procedures to clinical and laboratory assessments. The authors compared students' daily clinical grades to graded clinical assessments and compared daily clinical grades to laboratory assessments at one U.S. dental school. A total of 50 third-year students (participation rate: 98%) participated in this study during the school year of 2014-15. The study analyzed the students' daily clinical grades and graded assessments during regular clinical activities and two laboratory examinations. The results found no statistically significant differences between daily grades and the clinical assessments (p=0.2845). There were statistically significant differences between daily clinical grades and laboratory assessments (p=0.0024). This study found higher grades were given for procedures completed and graded in the clinical setting. Further studies are needed to explore the possibility of clinical grades being positively skewed. PMID- 29606661 TI - Relationship Between Dental Students' Pre-Admission Record and Performance on the Comprehensive Basic Science Examination. AB - The Comprehensive Basic Science Examination (CBSE) is the entrance examination for oral and maxillofacial surgery, but its implementation among dental students is a relatively recent and unintended use. The aim of this study was to examine the relationship between pre-admission data and performance on the CBSE for dental students at the Columbia University College of Dental Medicine (CDM). This study followed a retrospective cohort, examining data for the CDM Classes of 2014 19. Data collected were Dental Admission Test (DAT) and CBSE scores and undergraduate GPAs for 49 CDM students who took the CBSE from September 2013 to July 2016. The results showed that the full regression model did not demonstrate significant predictive capability (F[8,40]=1.70, p=0.13). Following stepwise regression, only the DAT Perceptual Ability score remained in the final model (F[1,47]=7.97, p<0.01). Variations in DAT Perceptual Ability scores explained 15% of the variability in CBSE scores (R2=0.15). This study found that, among these students, pre-admission data were poor predictors of CBSE performance. PMID- 29606664 TI - Rheumatoid Arthritis Magnetic Resonance Imaging Score Predicts Therapy Response: Results of the German ArthroMark Cohort. AB - OBJECTIVE: Markers for treatment response in rheumatoid arthritis (RA) are lacking. The aim of the study was to assess the performance of the RA magnetic resonance imaging (MRI) scoring system (RAMRIS) in combination with serum biomarkers to predict response to methotrexate (MTX) treatment in therapy-naive patients with early RA by using high-field MRI. METHODS: Twenty-eight patients with RA were prospectively assessed with baseline 3-T MRI of the clinical dominant hand, 3 and 6 months after MTX. The patients met the 2010 American College of Rheumatology/European League Against Rheumatism (EULAR) criteria [average age 56.8 yrs (range 39-74); positive for rheumatoid factor and/or anticyclic citrullinated peptide antibodies; disease duration < 6 mos (range 2-23 weeks)]. RAMRIS and serum biomarkers consisting of various experimental proteins including receptor activator of nuclear factor-kappaB ligand (RANKL) were obtained. Remission or treatment response was defined according to EULAR. To adjust for intrapersonal correlation, generalized linear mixed models were used. RESULTS: Treatment response at 3 months was associated to low RAMRIS erosion subscores and low total RAMRIS scores (p = 0.019 and 0.03, respectively). Remission at 6 months was associated to low RANKL levels (p = 0.033). In multivariate analyses, response at 3 and 6 months was predicted more accurately with the inclusion of total RAMRIS score, RAMRIS synovitis subscore at the second metacarpophalangeal (MCP) joint, or a combination of the two (p value likelihood ratio test = 0.035, 0.035, and 0.041, respectively). Remission was more accurately predicted with inclusion of RANKL, with no significant predictive effect of MRI. CONCLUSION: Baseline total RAMRIS can predict EULAR response. RAMRIS synovitis subscore at the second MCP joint and RANKL are associated with response and remission, respectively. PMID- 29606665 TI - Simultaneous Response in Several Domains in Patients with Psoriatic Disease Treated with Etanercept as Monotherapy or in Combination with Conventional Synthetic Disease-modifying Antirheumatic Drugs. AB - OBJECTIVE: To evaluate patients with psoriatic arthritis (PsA) receiving etanercept (ETN) monotherapy or ETN plus conventional synthetic disease-modifying antirheumatic drugs (csDMARD) to determine the proportion achieving a clinically meaningful response in arthritis, psoriasis, and quality of life simultaneously. METHODS: A prospective, multicenter, 52-week observational study in patients with active PsA evaluated treatment with ETN in clinical practice (ClinicalTrials.gov: NCT00293722). This analysis assessed simultaneous achievement of 3 treatment targets: low disease activity (LDA) based on 28-joint count Disease Activity Score (DAS28); body surface area (BSA) involvement <= 3%; and a score > 45 on the Medical Outcomes Study Short Form-12 (SF-12) physical component summary. RESULTS: Of 579 patients, 380 received ETN monotherapy and 199 received combination ETN plus csDMARD. At 52 weeks, data for all 3 disease domains were available for 251 patients receiving monotherapy and 151 receiving combination therapy. In the monotherapy and combination therapy groups, 61 (24.3%) and 37 (24.5%) patients, respectively, achieved all 3 treatment targets simultaneously. A significantly greater proportion of patients receiving monotherapy versus combination therapy achieved SF-12 > 45 (43.0% vs 31.8%; p < 0.05) and DAS28 LDA (72.5% vs 62.3%; p < 0.05). Conversely, BSA <= 3% was reached by a significantly greater proportion receiving combination therapy (75.5% vs 56.6%; p < 0.001). However, baseline BSA involvement was higher for the monotherapy group. CONCLUSION: While nearly half the patients achieved arthritis and psoriasis treatment targets simultaneously and one-fourth reached all 3 treatment targets, combining ETN and csDMARD did not substantially improve clinical response compared with ETN monotherapy in this real-world PsA patient population. PMID- 29606666 TI - Comparative Analysis and Predictors of 10-year Tumor Necrosis Factor Inhibitors Drug Survival in Patients with Spondyloarthritis: First-year Response Predicts Longterm Drug Persistence. AB - OBJECTIVE: To evaluate the 10-year drug survival of the first tumor necrosis factor inhibitor (TNFi) administered to patients with spondyloarthritis (SpA) overall and comparatively between SpA subsets, and to identify predictors of drug retention. METHODS: Patients with SpA in the Hellenic Registry of Biologic Therapies, a prospective multicenter observational cohort, starting their first TNFi between 2004-2014 were analyzed. Kaplan-Meier curves and Cox regression models were used. RESULTS: Overall, 404 out of 1077 patients (37.5%) discontinued treatment (followup: 4288 patient-yrs). Ten-year drug survival was 49%. In the unadjusted analyses, higher TNFi survival was observed in patients with ankylosing spondylitis (AS) compared to undifferentiated SpA and psoriatic arthritis [PsA; significant beyond the first 2.5 (p = 0.003) years and 7 years (p < 0.001), respectively], and in patients treated for isolated axial versus peripheral arthritis (p = 0.001). In all multivariable analyses, male sex was a predictor for longer TNFi survival. Use of methotrexate (MTX) was a predictor in PsA and in patients with peripheral arthritis. Absence of peripheral arthritis and use of a monoclonal antibody (as opposed to non-antibody TNFi) independently predicted longer TNFi survival in axial disease because of lower rates of inefficacy. Achievement of major responses during the first year in either axial or peripheral arthritis was the strongest predictor of longer therapy retention (HR 0.33, 95% CI 0.26-0.41 for Ankylosing Spondylitis Disease Activity Score inactive disease, and HR 0.35, 95% CI 0.24-0.50 for 28-joint Disease Activity Score remission). CONCLUSION: The longterm retention of the first TNFi administered to patients with SpA is high, especially for males with axial disease. The strongest predictor of longterm TNFi survival is a major response within the first year of treatment. PMID- 29606667 TI - Origins of Discordant Responses among 3 Rheumatoid Arthritis Improvement Criteria. AB - OBJECTIVE: We examined agreement between the American College of Rheumatology (ACR), European League Against Rheumatism (EULAR), and Simplified Disease Activity Index (SDAI) response criteria in rheumatoid arthritis (RA) and tested whether discordant responses were associated with patients' baseline characteristics or changes in RA activity encapsulated by the different criteria. METHODS: In a prospective longitudinal study, we examined responses of 243 patients with active RA to escalation of antirheumatic treatment. We computed agreement between pairs of response criteria using kappa coefficients and identified patient characteristics associated with unique responses to individual criteria. RESULTS: We found that 110 patients (45.3%) had an ACR 20% improvement (ACR20) response, 135 (55.5%) had a EULAR moderate/good response, and 83 (34.1%) had an SDAI50 response. Agreement was moderate to good (ACR20/EULAR kappa 0.57; ACR20/SDAI50 kappa 0.64; EULAR/SDAI50 kappa 0.59). All who had SDAI50 response also had a EULAR response. Patient characteristics at baseline generally did not distinguish those who responded to both, 1, or neither criterion. Discordance was most often because of improvements in the erythrocyte sedimentation rate or C reactive protein level among EULAR and SDAI50 responders, which were not as common among ACR20 responders. Based on receiver-operating characteristic curves, SDAI35 response had a better balance of sensitivity and specificity relative to ACR20 and EULAR moderate/good responses than SDAI50. CONCLUSION: Discordant responses to RA improvement criteria are most often because of differences in responses of acute-phase reactants. SDAI35 response had higher sensitivity for improvement, as reflected by other response criteria, than SDAI50 response. PMID- 29606668 TI - Rituximab in the Treatment of Interstitial Lung Disease Associated with Antisynthetase Syndrome: A Multicenter Retrospective Case Review. AB - OBJECTIVE: To assess clinical outcomes including imaging findings on computed tomography (CT), pulmonary function testing (PFT), and glucocorticoid (GC) use in patients with the antisynthetase syndrome (AS) and interstitial lung disease (ILD) treated with rituximab (RTX). METHODS: We retrospectively identified all patients at 2 institutions with AS-ILD who were treated with RTX. Baseline demographics, PFT, and chest CT were assessed before and after RTX. Two radiologists independently evaluated CT using a standardized scoring system. RESULTS: Twenty-five subjects at the Brigham and Women's Hospital (n = 13) and University of Pittsburgh Medical Center (n = 12) were included. Antisynthetase antibodies were identified in all patients (16 Jo1, 6 PL-12, 3 PL-7). In 21 cases (84%), the principal indication for RTX use was recurrent or progressive ILD, owing to failure of other agents. Comparing pre- and post-RTX pulmonary variables at 12 months, CT score and forced vital capacity were stable or improved in 88% and 79% of subjects, respectively. Total lung capacity (%) increased from 56 +/- 13 to 64 +/- 13 and GC dose decreased from 18 +/- 9 to 12 +/- 12 mg/day. Although DLCO (%) declined slightly at 1 year, it increased from 42 +/- 17 to 70 +/- 20 at 3 years. The most common imaging patterns on CT were nonspecific interstitial pneumonia (NSIP; n = 13) and usual interstitial pneumonia/fibrotic NSIP (n = 5), of which 5 had concurrent elements of cryptogenic organizing pneumonia. CONCLUSION: Stability or improvement in pulmonary function or severity of ILD on CT was seen in most patients. Use of RTX was well tolerated in the majority of patients. RTX may play a therapeutic role in patients with AS-ILD, and further clinical investigation is warranted. PMID- 29606669 TI - Flares of Disease in Children with Clinically Inactive Juvenile Idiopathic Arthritis Were Not Correlated with Ultrasound Findings. AB - OBJECTIVE: The validity of our current definitions for clinically inactive disease (CID) in juvenile idiopathic arthritis (JIA) based on physical examination is challenged by the development of advanced musculoskeletal imaging tools. We aimed to prospectively determine the prevalence of abnormal ultrasound (US) findings in children with CID in JIA and their clinical significance. METHODS: Children aged >= 4 years with CID and a history of arthritis from a single tertiary center were approached over 1 year. Standard US of knees, tibiotalar joints, subtalar joints, and wrists were performed at baseline and at a followup visit. US images were scored by 2 pediatric musculoskeletal radiologists. RESULTS: Forty children with CID were enrolled and followed clinically. The median duration of inactive disease was 1 year. The most common International League of Associations for Rheumatology JIA categories were extended oligoarticular JIA (30%) and rheumatoid factor-negative polyarthritis (38%). At baseline, among a total of 289 joints scanned, 24 joints (8%) had at least 1 abnormal finding in 18 (45%) of 40 subjects. When evaluated at the individual joint level against flares identified during followup exams, these baseline US findings had a sensitivity of 15% and a positive predictive value of 12%. The predictive performance of the second US was even less. CONCLUSION: Our study demonstrates that nearly half of children with CID had abnormal US findings in 1 of 8 commonly affected joints. These findings did not correlate with subsequent clinical flares in up to 2 years of followup. PMID- 29606671 TI - The Critical Link Between Acute Care Nursing and Military En Route Care. PMID- 29606672 TI - Critical Care Performance in a Simulated Military Aircraft Cabin Environment. AB - BACKGROUND: Critical Care Air Transport Teams care for 5% to 10% of injured patients who are transported on military aircraft to definitive treatment facilities. Little is known about how the aeromedical evacuation environment affects care. OBJECTIVES: To determine the effects of 2 stressors of flight, altitude-induced hypoxia and aircraft noise, and to examine the contributions of fatigue and clinical experience on cognitive and physiological performance of the Critical Care Air Transport Team. METHODS: This repeated measures 2 * 2 * 4 factorial study included 60 military nurses. The participants completed a simulated patient care scenario under aircraft cabin noise and altitude conditions. Differences in cognitive and physiological performance were analyzed using repeated measures analysis of variance. A multiple regression model was developed to determine the independent contributions of fatigue and clinical experience. RESULTS: Critical care scores (P = .02) and errors and omissions (P = .047) were negatively affected by noise. Noise was associated with increased respiratory rate (P = .02). Critical care scores (P < .001) and errors and omissions (P = .002) worsened with altitude-induced hypoxemia. Heart rate and respiratory rate increased with altitude-induced hypoxemia; oxygen saturation decreased (P < .001 for all 3 variables). CONCLUSION: In a simulated military aircraft environment, the care of critically ill patients was significantly affected by noise and altitude-induced hypoxemia. The participants did not report much fatigue and experience did not play a role, contrary to most findings in the literature. PMID- 29606673 TI - Pressure Injury Development in Patients Treated by Critical Care Air Transport Teams: A Case-Control Study. AB - BACKGROUND: The US Air Force transports critically ill patients from all over the world, with transport times commonly ranging from 6 to 11 hours. Few outcome measures have been tracked for these patients. Traditional methods to prevent pressure injuries in civilian hospitals are often not feasible in the military transport environment. OBJECTIVES: The incidence rate and risk factors are described of en route-related pressure injuries for patients overseen by the Critical Care Air Transport Team. METHODS: This retrospective, case-control, medical records review investigated risk factors for pressure injury in patients who developed a pressure injury after their transport flight compared with those with no documented pressure injuries. RESULTS: The pressure injury rate was 4.9%. Between 2008 and 2012, 141 patients in whom pressure injuries developed and who had received care by the team were matched with 141 patients cared for by the team but did not have pressure injury. According to regression analysis, body mass index and 2 or more Critical Care Air Transport Team transports per patient were associated with pressure injury development. CONCLUSION: Although the pressure injury rate of 4.9% in this cohort of patients is consistent with that reported by civilian critical care units, the rate must be interpreted with caution, because civilian study data frequently represent the entire intensive care unit length of stay. Targeted interventions for patients with increased body mass index and 2 or more critical care air transports per patient may help decrease the development of pressure injury in these patients. PMID- 29606674 TI - Reducing the Risk for Pressure Injury During Combat Evacuation. AB - BACKGROUND: Combat casualties undergoing aeromedical evacuation are at increased risk for pressure injuries. The risk factors pressure and shear are potentially modifiable via solutions appropriate for en route care. OBJECTIVES: To compare transcutaneous oxygen levels and skin temperatures in healthy participants under offloaded (side lying) and loaded (supine or supine with 30 degrees backrest elevation) under 4 conditions: control (no intervention), Mepilex sacral and heel dressings, LiquiCell pad, and Mepilex plus LiquiCell. METHODS: Participants were randomly assigned to 4 groups according to ideal body weight. Backrest positions were randomized. Transcutaneous oxygen level and temperature were measured on the sacrum and the heel; skin interface pressure was measured with an XSensor pressure imaging system. Measurements were obtained for 5 minutes at baseline (offloaded), 40 minutes with participants supine, and 15 minutes offloaded. RESULTS: In the 40 healthy participants, interface pressure, transcutaneous oxygen level, and skin temperature did not differ between the 4 groups. Peak interface pressures were approximately 43 mm Hg for the sacrum and 50 mm Hg for the heel. Sacral transcutaneous oxygen level differed significantly between unloaded (mean, 79 mm Hg; SD, 16.5) and loaded (mean, 57 mm Hg; SD, 25.2) conditions (P < .001) in a flat position (mean, 85.2 mm Hg; SD, 13.6) and with 30 degrees backrest elevation (mean, 66.7 mm Hg; SD, 24.2) conditions (P < .001). Results for the heels and the sacrum were similar. Sacral skin temperature increased significantly across time (approximately 1.0 degrees C). CONCLUSIONS: The intervention strategies did not differ in prevention of pressure injuries. PMID- 29606675 TI - Factors That Affect Pain Management in Aeromedical Evacuation: An Ethnographic Approach. AB - BACKGROUND: Pain management is a challenge in the transport setting, but actual factors that influence pain have not been assessed systematically. OBJECTIVE: To describe the environmental factors and social context that affect pain management in military aeromedical evacuation. METHODS: Field notes were taken throughout flight, including observational measures of pain, environmental factors, and interactions between the patient and crew. Data collection was completed on 8 missions and 16 patients; common themes were identified that should be considered in the management of pain in aeromedical evacuation. RESULTS: Communication was a key problem primarily to aircraft noise, the reluctance of patients to speak with crew members while they were wearing headsets, and limited time to assess for pain and provide patient education. Seating and litters appeared to be uncomfortable for ambulatory and litter patients, and preparatory guidance on pain management did not address the stressors of flight or transportation phases. Another compounding factor was the psychological distress, particularly among those leaving a combat zone before the anticipated end of a deployment. Throughout the flight, the military culture of independence, stoicism, and camaraderie also was clearly evident. CONCLUSIONS: Barriers to communication, comfort, and patient education are well known to transport nurses, but it is important to understand the overall effect they have on the management of pain. Developing solutions to address these factors should be a priority to ensure pain is adequately managed throughout transport. PMID- 29606676 TI - An Occupational Paradox: Why Do We Love Really Tough Jobs? AB - BACKGROUND: Sometimes we come upon unexpected or counterfactual results during research that make us wonder and lead us into unknown territory. Such was the experience of a team of Air Force researchers exploring aeromedical evacuation crew members' experiences of safety and patient care concerns throughout the en route care system. OBJECTIVE: To explore what it is about the aeromedical evacuation crew members' occupation that generates a strong motivation to the mission despite the demands it places on its workers. METHODS: Eight focus groups were conducted with 69 Air Force aeromedical evacuation and staging facility active duty, Air National Guard, and Air Force Reserve Command nurses and medical technicians between May 2012 and April 2013 at 5 locations in the contiguous and outside the contiguous United States. RESULTS: An unexpected finding was that despite the austere nature of the Air Force en route care mission and the acuity of the patients being transported, nurses and medical technicians were passionate about bringing home the wounded, sick, and injured warriors and were committed to providing the best and safest care possible. CONCLUSIONS: It is plausible that a high level of commitment and mission focus contributes significantly to the safety and well-being of those transported. Still, we must wonder why nurses and technicians voluntarily serve in such a demanding and sometimes dangerous occupation, and yet find such a high degree of satisfaction and contentment with this type of job. PMID- 29606677 TI - The Role of Spirituality Among Military En Route Care Nurses: Source of Strength or Moral Injury? AB - BACKGROUND: Military nurses provide care to seriously injured service members in flight, on the ground, or at sea during transport from the point of injury to a facility capable of providing higher levels of care. From this experience nurses are at increased risk of developing negative behavioral health symptoms. Spirituality, a belief in someone or something greater than oneself, could provide behavioral health support for military nurses who serve in this role. OBJECTIVE: To determine the impact of spirituality on the behavioral health of nurses who provided en route care while deployed to Iraq or Afghanistan. METHODS: This exploratory mixed-methods study used 5 instruments to determine levels of anxiety, depression, posttraumatic stress, posttraumatic growth, and resilience among 119 military nurses. Interviews provided rich data about the experiences of these nurses and extended quantitative outcomes. RESULTS: Posttraumatic Growth Inventory findings showed no significant change in spirituality based on deployment experiences (mean, 3.07; SD, 3.26). However, interviews revealed that spirituality served as a buffer against developing behavioral health issues. Many relied on spirituality to get them through difficult experiences. There was also a sense of moral injury as a few expressed regrets for things they witnessed or experienced. CONCLUSIONS: Spirituality can insulate military nurses from negative behavioral health symptoms. Nurses included in the study relied on their spirituality to stay mentally fit. For nurses who experienced moral injury, supervisory recognition of this and appropriate referral may decrease the long term effects of deployment on their behavioral health. PMID- 29606678 TI - Resuscitative Endovascular Balloon Occlusion of the Aorta: A Bridge to Flight Survival. AB - Trauma endures as the leading cause of death worldwide, and most deaths occur in the first 24 hours after initial injury as a result of hemorrhage. Historically, about 90% of battlefield deaths occur before the injured person arrives at a theater hospital, and most are due to noncompressible hemorrhage of the torso. Resuscitative endovascular balloon occlusion of the aorta is an evolving technique to quickly place a balloon into the thoracic or abdominal aorta to efficiently block blood flow to distal circulation. Maneuvers, such as resuscitative endovascular balloon occlusion of the aorta, to control endovascular hemorrhage offer a potential intervention to control noncompressible hemorrhage. This technique can be performed percutaneously or open in prehospital environments to restore hemodynamic functions and serve as a survival bridge until the patient is delivered to a treatment facility for definitive surgical hemostasis. This article describes the indications, complications, and application of resuscitative endovascular balloon occlusion of the aorta to military and civilian aeromedical transport. PMID- 29606679 TI - Response to Diversity. PMID- 29606680 TI - Addressing Workplace Violence. PMID- 29606681 TI - Commit to Sit to Improve Nurse Communication. PMID- 29606683 TI - Pulmonary Artery/Central Venous Pressure Monitoring in Adults. PMID- 29606684 TI - En Route Care Provided by US Navy Nurses in Iraq and Afghanistan. AB - BACKGROUND: US Navy nurses provide en route care for critically injured combat casualties without having a formal program for training, utilization, or evaluation. Little is known about missions supported by Navy nurses. OBJECTIVES: To characterize the number and types of patients transported and skill sets required by Navy nurses during 2 combat support deployments. METHODS: All interfacility casualty transfers between 2 separate facilities in Iraq and Afghanistan were assessed. Number of patients treated, number transported, en route care provider type, transport priority level and duration, injury severity, indication for critical care transport, en route care interventions, and vital signs were evaluated. RESULTS: Of 1550 casualties, 630 required medical evacuation to a higher level of care. Of those, 133 (21%) were transported by a Navy nurse, with 131 (98.5%) classified as "urgent," accounting for 46% of all urgent transports. The primary indication for en route care nursing was mechanical ventilation of intubated patients (97%). Mean (SD) patient transport time was 29.8 (7.9) minutes (range, 17-61 minutes). The most common en route care interventions were administration of intravenous sedation (80%), neuromuscular blockade (79%), and opioids (48%); transfusions (18%); and ventilation changes (11%). No intubations, cricothyroidotomies, chest tube placements, or needle decompressions were performed en route. No deaths occurred during transport. CONCLUSIONS: US Navy nurses successfully transported critically injured patients without observed adverse events. Establishing en route care as a program of record in the Navy will facilitate continuous process improvement to ensure that future casualties receive optimized en route care. PMID- 29606685 TI - En Route Critical Care Transfer From a Role 2 to a Role 3 Medical Treatment Facility in Afghanistan. AB - BACKGROUND: En route care is the transfer of patients requiring combat casualty care within the US military evacuation system. No reports have been published about en route care of patients during transfer from a forward surgical facility (role 2) to a combat support hospital (role 3) for comprehensive care. OBJECTIVE: To describe patients transferred from a role 2 to a role 3 US military treatment facility in Afghanistan. METHODS: A retrospective review of data from the Joint Trauma System Role 2 Database was conducted. Patient characteristics were described by en route care medical attendants. RESULTS: More than one-fourth of patients were intubated at transfer (26.9%), although at transfer fewer than 10% of patients had a base deficit of more than 5 (3.5%), a pH of less than 7.3 (5.2%), an international normalized ratio of more than 2 (0.8%), or temporary abdominal or chest closure (7.4%). The en route care medical attendant was most often a nurse (35.5%), followed by technicians (14.1%) and physicians (10.0%). Most patients (75.3%) were transported by medical evacuation (on rotary-wing aircraft). CONCLUSION: This is the first comprehensive review of patients transported from a forward surgical facility to a more robust combat support hospital in Afghanistan. Understanding the epidemiology of these patients will inform provider training and the appropriate skill mix for the transfer of postsurgical patients within a combat setting. PMID- 29606687 TI - Building Capacity in the Sikh Asian Indian Community to Lead Participatory Oral Health Projects. PMID- 29606686 TI - Managing Alarms in Acute Care Across the Life Span: Electrocardiography and Pulse Oximetry. PMID- 29606688 TI - Building Capacity in the Sikh Asian Indian Community to Lead Participatory Oral Health Projects. AB - BACKGROUND: Lack of access to oral health care is a significant burden for disadvantaged populations, yet rarely draws the attention of policymakers or community leaders. OBJECTIVES: To understand how UNITED SIKHS identified oral health care as a priority need through its involvement in community-based participatory research (CBPR) initiatives and local data collection, thereby building its capacity to lead participatory oral health projects. METHODS: The foundation for the partnership between UNITED SIKHS and the New York University (NYU) Prevention Research Center (PRC) was the joint implementation of a CBPR project to prevent diabetes in the Sikh Asian Indian community. Project partners also included a community coalition composed of religious leaders, health providers, members of the media, and dental students and faculty at the NYU College of Dentistry (NYU Dentistry). A community needs and resources assessment survey was jointly developed and conducted in 2010 to better understand health needs in the Sikh community. RESULTS: Fewer than one-half of the Sikh participants (43.0%) reported ever receiving a check-up or screening by a dentist, and of those who did, only one-half (50.0%) reported that it occurred in the past 12 months. Upon clinical assessment, more than one-half of Sikh adults (58.2%) had untreated dental decay. The collection and analysis of local data motivated UNITED SIKHS to develop new priorities based upon the findings. CONCLUSIONS: UNITED SIKHS applied for and received external funding to lead a CBPR project that developed, implemented, evaluated, and disseminated a culturally tailored oral health and healthy living curriculum for the Sikh Asian Indian community. PMID- 29606690 TI - Strategies for Recruiting Women Living with Human Immunodeficiency Virus in Community-Based Research: Lessons from Canada. AB - OBJECTIVES: This study sought to describe the recruitment of women living with HIV (WLWH) into the community-based Canadian HIV Women's Sexual and Reproductive Health Cohort Study (CHIWOS), because women are under-represented in HIV research. METHODS: There were 1,424 WLWH were enrolled from British Columbia, Ontario, and Quebec, who completed detailed questionnaires administered by peer research associates (PRAs; WLWH with research training). During screening, participants were asked: "How did you hear about the study?" We describe recruitment strategies by subpopulation and offer reflections on challenges and successes. RESULTS: Of 1,131 participants with complete data, 40% identified as White, 33% African/Caribbean/Black, and 19% Indigenous. The median age was 45 years (interquartile range, 37-51) and 4% identified as trans women. Overall, 35% were recruited through PRAs/peers, 34% clinics, and 19% AIDS service organizations (ASOs). PRAs/peers were the predominant recruitment method in Ontario (49%), compared with clinics in British Columbia (40%), and Quebec (43%). Nationally, PRAs/peers were more successful in recruiting WLWH commonly considered to be "harder to reach" (e.g., women identifying as trans, using drugs, not receiving HIV care). Clinics were more effective in recruiting younger women (16-29 years) and women not using ASOs. Recruitment challenges centered on engaging these harder to reach women. Successes included hiring PRAs who built participant trust, linking with clinics to reach women isolated from HIV communities, involving outreach workers to engage street-involved women, and disseminating study information to diverse stakeholders. CONCLUSIONS: Having multiple approaches, engaging a diverse team of PRAs, ensuring flexibility, and cultivating reciprocal relationships with community stakeholders were key to recruiting a diverse and representative sample of WLWH. PMID- 29606691 TI - Development and Pilot Testing of a Bilingual Environmental Health Assessment Tool to Promote Asthma-friendly Childcares. AB - BACKGROUND: Childhood marks the highest risk for allergic sensitization to asthma triggers. Hispanic/Latino children are at higher risk for hospitalization for asthma than non-Hispanic White children. Childcare providers lack knowledge about reducing asthma triggers. OBJECTIVES: The purpose of this paper is to describe a community-based participatory research (CBPR) initiative aimed at developing and pilot testing a bilingual walk-through assessment tool for asthma-friendly childcare environments. METHODS: Ten Latina mothers of children with asthma living in the Pacific Northwest collaborated with research partners to develop and pilot test a Childcare Environmental Health (CEH) assessment walk-through survey.Results and Lessons Learned: The women innovated the survey with photography and structural examinations of stress and provision of basic needs. The survey tool identified environmental threats to asthma in all three childcares surveyed. CONCLUSIONS: Parents are well-positioned to build trust with childcare providers, assess asthma triggers, and recommend practical mitigation strategies. PMID- 29606692 TI - A Community-Based Approach to Cervical Cancer Prevention: Lessons Learned in Rural Guatemala. AB - BACKGROUND: One international and three local organizations developed the Santa Ana Women's Health Partnership (SAWHP) to address cervical cancer in Santa Ana Huista, Huehuetenango, Guatemala. This paper describes the structure, outcomes, and lessons learned from our community partnership and program. METHODS: The community partnership developed a singlevisit approach (SVA) program that guided medically underserved women through screening and treatment of cervical cancer. LESSONS LEARNED: The program promoted acceptability of SVA among rural women by engaging local female leaders and improving access to screening services. The program's approach focused on maximizing access and generated interest beyond the coverage area. Distrust among the community partners and weak financial management contributed to the program's cessation after 4 years. CONCLUSIONS: The SAWHP design may guide future implementation of cervical cancer screening programs to reach medically underserved women. Open, ongoing dialogue among leaders in each partner institution is paramount to success. PMID- 29606693 TI - Canadian Alliance for Healthy Hearts and Minds: First Nations Cohort Study Rationale and Design. AB - BACKGROUND: This is the first national indigenous cohort study in which a common, in-depth protocol with a common set of objectives has been adopted by several indigenous communities across Canada. OBJECTIVES: The overarching objective of the Canadian Alliance for Healthy Hearts and Minds (CAHHM) cohort is to investigate how the community-level environment is associated with individual health behaviors and the presence and progression of chronic disease risk factors and chronic diseases such as cardiovascular disease (CVD) and cancer. METHODS: CAHHM aims to recruit approximately 2,000 First Nations indigenous individuals from up to nine communities across Canada and have participants complete questionnaires, blood collection, physical measurements, cognitive assessments, and magnetic resonance imaging (MRI). RESULTS: Through individual- and community level data collection, we will develop an understanding of the specific role of the socioenvironmental, biological, and contextual factors have on the development of chronic disease risk factors and chronic diseases. CONCLUSIONS: Information collected in the indigenous cohort will be used to assist communities to develop local management strategies for chronic disease, and can be used collectively to understand the contextual, environmental, socioeconomic, and biological determinants of differences in health status in harmony with First Nations beliefs and reality. PMID- 29606694 TI - Increasing Healthy Food Availability, Purchasing, and Consumption: Lessons Learned from Implementing a Mobile Grocery. AB - BACKGROUND: A mobile grocery (MoGro) was developed through a partnership with community stakeholders, community advisory boards (CABs), Rick and Beth Schnieders, and the Johns Hopkins Center for American Indian Health (JHCAIH). MoGro provided access to subsidized healthy foods, with complementary events, including fitness activities and cooking classes. OBJECTIVES: MoGro is an innovative approach to promoting food security. METHODS: Within a community-based participatory action research (CPBAR) framework, the JHCAIH and partners designed and administered household surveys at baseline and 3 months after MoGro's launch. A randomly selected 20% of households participated at each timepoint. RESULTS: About 75% of respondents indicated that MoGro had changed the foods they purchased, and 68% reported that MoGro had changed how their families ate. After MoGro's launch, food availability increased significantly and food insecurity decreased. CONCLUSIONS: The evaluation documented MoGro's impact in the community; high self-reported positive changes, significant increases in food availability, and decreases in food insecurity. PMID- 29606695 TI - Implementing a Targeted and Culturally Tailored Policy, Systems, and Environmental Nutrition Strategy to Reach Korean Americans. AB - THE PROBLEM: Policy, systems, and environmental (PSE) approaches have been shown to be effective in increasing rates of healthy behaviors in the overall population, but are not always effective in reaching racial and ethnic minority groups, including Korean Americans (KAs), who may be socially and linguistically isolated from mainstream campaigns and programs. Targeted and tailored PSE strategies are needed to reach these groups. PURPOSE: To describe the process and lessons learned in implementing a targeted and culturally tailored PSE strategy to increase access to healthy foods for KAs. KEY POINTS: A Korean community-based organization (CBO) used its inherent understanding of cultural context, and social and historical viewpoints of KAs to develop PSE strategies to reach more than 13,000 KAs. CONCLUSIONS: Local CBOs can play a significant role in complementing population-level strategies with more tailored and targeted approaches to reach racial and ethnic minority groups. PMID- 29606696 TI - Where Is the Community Dimension in the Updated Common Rule? AB - THE PROBLEM: Changes to the Federal Policy for the Pro tection of Human Subjects (the Common Rule) as presented in the Notice of Proposed Rulemaking (NPRM) are both logical and necessary. However, the proposed changes con tinue to focus entirely on the individual and fail to take into account the rapidlyemerging types of research that involve patients and communities directly in the research process.Purpose of Article: We propose several changes and amendments that address the interests of communities and underscore the principle of justice, especially social justice. KEY POINTS: Our recommendations seek to revise human subjects' protections that currently overemphasize individualism and autonomy to reflect a collectivist ethos that would extend protections to communities engaged in medical research. CONCLUSION: We believe this is necessary to effectively and efficiently conduct the types of research that will ultimately rectify health inequities that continue to exist in many communities, but particularly communities of color. PMID- 29606697 TI - Establishing New Community-Based Participatory Research Partnerships using the Community-Based Participatory Research Charrette Model: Lessons from the Cancer Health Accountability for Managing Pain and Symptoms Study. AB - BACKGROUND: Community-based participatory research (CBPR) is a collaborative and equitable approach to research inquiry; however, the process of establishing and maintaining CBPR partnerships can be challenging. There is an ongoing need for innovative strategies that foster partnership development and long-term sustainability. In 2010, the University of North Carolina at Chapel Hill developed a CBPR charrette model to facilitate stakeholder engagement in translational research. OBJECTIVE: To describe how the Cancer Health Accountability for Managing Pain and Symptoms (CHAMPS) Study leveraged the CBPR charrette process to develop and strengthen its CBPR partnership and successfully implement research objectives. METHODS: Fourteen CHAMPS community, academic, and medical partners participated in the CBPR charrette. Two co-facilitators guided the charrette application process and in-person discussion of partnership strengths, needs, and challenges. Community experts (CEs) and academic experts (AEs) with extensive experience in CBPR and health disparities provided technical assistance and recommendations during the in-person charrette. CONCLUSIONS: Overall, the CHAMPS partnership benefited significantly from the charrette process. Specifically, the charrette process engendered greater transparency, accountability, and trust among CHAMPS partners by encouraging collective negotiation of project goals and implementation, roles and responsibilities, and compensation and communication structures. The process also allowed for the exploration of newly identified challenges and potential solutions with support from CEs and AEs. Furthermore, the charrette also functioned as a catalyst for capacity building among CHAMPS community, academic, and medical partners. Future studies should compare the impact of the CBPR charrette, relative to other approaches, on partnership development and process evaluation outcomes. PMID- 29606698 TI - An Education and Field Experience Program to Increase Detection of Human Immunodeficiency Virus and Hepatitis C Virus. AB - BACKGROUND: Baltimore is an urban center that has been highly impacted by human immunodeficiency virus (HIV) and hepatitis C virus (HCV); however, many individuals are unaware of their HIV and/or HCV status. In 2013, the Johns Hopkins Center for AIDS Research (CFAR) developed Generation Tomorrow, an HIV and HCV education, testing, and counseling program with community input and collaboration. OBJECTIVES: The aims of Generation Tomorrow are to increase HIV and HCV awareness and detection in Baltimore and engage the next generation of health professionals (students) and community members (peers) in HIV and HCV outreach services. METHODS: The Generation Tomorrow educational component includes formal HIV and HCV testing and counselling training, and a lecture series for students and peers. The participants then engage in field assignments and outreach events with Johns Hopkins associated programs or community-based organizations. RESULTS: Generation Tomorrow trained 71 students and peers in three cohorts, 70% of whom reported that they planned to stay in HIV- and/or HCV related work. From October 2014 to May 2015, which represents the first year that Generation Tomorrow ran with the full academic calendar, Generation Tomorrow students and peers worked with partner organizations to conduct 1,104 HIV rapid antibody tests and found 19 individuals (1.72%) to be HIV positive. Additionally, 778 HCV rapid antibody tests were conducted and 175 individuals (22.5%) were HCV antibody positive. CONCLUSIONS: Generation Tomorrow has been successful in engaging students and community peers in HIV and HCV education, testing, and counseling, and has documented HIV and HCV positivity rates well above general community prevalence. PMID- 29606699 TI - Managing the Unmanageable: A Two-Staged Palliative Resection to Control Life Threatening Duodenal Bleeding Due to Recurrent Paraganglioma. AB - BACKGROUND This report presents therapeutic decision-making and management of refractory, life-threatening duodenal bleeding in a young man with recurrent metastatic retroperitoneal paraganglioma. CASE REPORT The patient had been symptom free for 8 years after radioactive MIBG (metaiodobenzylguanidine) therapy. Failure of endoscopic or angiographic bleeding control led to urgent need to evaluate possible endocrine functional status, tumor curability, safety of incomplete resection, intra- and postoperative support needs, and anticipated recovery potential and postoperative function. Aside from these considerations, impact of tumor biology, alternative therapeutic options, current management guidelines, and ethical challenges of resource utilization for such complex palliative operative intervention were reviewed. CONCLUSIONS Based on the observed outcomes after an urgent presentation of an unusual tumor-related complication, palliation-intent therapy was justifiable even if significant treatment-related risks were expected and complex resources were required. PMID- 29606700 TI - Low Expression and Clinical Value of hsa_circ_0049224 and has_circ_0049220 in Systemic Lupus Erythematous Patients. AB - BACKGROUND The aim of this study was to discuss the possible roles and clinical value of 2 circRNAs (hsa_circ_0049224 and has_circ_0049220) in SLE patients. MATERIAL AND METHODS Reverse-transcription real-time polymerase chain reaction (RT-PCR) was conducted to detect the expressions of hsa_circ_0049224, has_circ_0049220, and DNMT1 in peripheral blood mononuclear cells (PBMCs) from 18 diagnosed SLE patients and 10 healthy controls. RESULTS We found that the expressions of hsa_circ_0049224 and has_circ_0049220 in healthy control groups were both much higher than those in inactive and active SLE patients. The expression level of DNMT1 is positively correlated with the expressions of hsa_circ_0049224 and has_circ_0049220. Moreover, there was a negative correlation between the SLE Disease Activity Index (SLEDAI) and the expressions of hsa_circ_0049224 and has_circ_0049220. We also found that these 2 circRNAs are associated with some clinical characteristics of SLE. CONCLUSIONS Hsa_circ_0049224 and has_circ_0049220 are probable factors involved in the pathogenesis of SLE, and they have potential clinical value in SLE. PMID- 29606701 TI - RBL2/p130 is a direct AKT target and is required to induce apoptosis upon AKT inhibition in lung cancer and mesothelioma cell lines. AB - The retinoblastoma (RB) protein family includes RB1/p105, RBL1/p107, and RBL2/p130, which are key factors in cell-cycle regulation and stand at the crossroads of multiple pathways dictating cell fate decisions. The role of RB proteins in apoptosis is controversial because they can inhibit or promote apoptosis depending on the context, on the apoptotic stimuli and on their intrinsic status, impacting on the response to antitumoral treatments. Here we identified RBL2/p130 as a direct substrate of the AKT kinase, a key antiapoptotic factor hyperactive in multiple cancer types. We showed that RBL2/p130 and AKT1 physically interact and AKT phosphorylates RBL2/p130 Ser941, located in the pocket domain, but not when this residue is mutated into Ala. We found that pharmacological inhibition of AKT, through the highly selective AKT inhibitor VIII (AKTiVIII), impairs RBL2/p130 Ser941 phosphorylation and increases RBL2/p130 stability, mRNA expression and nuclear levels in both lung cancer and mesothelioma cell lines, mirroring the more extensively studied effects on the p27 cell-cycle inhibitor. Consistently, AKT inhibition reduced cell viability, induced cell accumulation in G0/G1, and triggered apoptosis, which proved to be largely dependent on RBL2/p130 itself, as shown upon RBL2/p130 silencing. AKT inhibition induced RBL2/p130-dependent apoptosis also in HEK-293 cells, in which re-expression of a short hairpin-resistant RBL2/p130 was able to rescue AKTiVIII induced apoptosis upon RBL2/p130 silencing. Our data also showed that the combination of AKT and cyclin-dependent kinases (CDK) inhibitors, which converge on the re-activation of RBL2/p130 antitumoral potential, could be a promising anticancer strategy. PMID- 29606702 TI - Extracellular vesicles as novel biomarkers and pharmaceutic targets of diseases. PMID- 29606703 TI - The Importance of Medicinal Chemistry Knowledge in the Clinical Pharmacist's Education. AB - Objective. To show why medicinal chemistry must be a key component of the education of pharmacy students, as well as in the pharmacist's practice. Findings. Five case reports were selected by their clinically relevant elements of medicinal chemistry and were explained using structure-activity relationship data of the drugs involved in the case easily obtained from primary literature and in medicinal chemistry textbooks. Summary. This paper demonstrates how critical clinical decisions can be addressed using medicinal chemistry knowledge. While such knowledge may not explain all clinical decisions, medicinal chemistry concepts are essential for the education of pharmacy students to explain drug action in general and clinical decisions. PMID- 29606704 TI - A Scoping Review of Peer-led Education in Patient Safety Training. AB - Objective. To examine the literature pertaining to the use of peer-led education in patient safety. Findings. Four studies met the inclusion criteria: two were conducted in health care students and two in medical practitioners. Three studies used pre-post evaluation, with one containing a comparator group. One study a post-intervention evaluation only. All studies undertook Kirkpatrick Level 2 evaluations, showing significant improvements in attitudes and knowledge. One study undertook Level 3 and 4 evaluations, showing improvement in self-reported behaviors and engagement in quality improvement initiatives. Summary. There are few studies evaluating peer-led education in patient safety and formal and high quality evaluations are lacking. PMID- 29606705 TI - Review of Grit and Resilience Literature within Health Professions Education. AB - Objective. To review literature pertaining to grit and resilience in health professions education. Findings. There is significant interest in grit and resilience throughout the health professions, but little has been published with regard to pharmacy. Although there are methodological issues with defining and measuring grit and resilience, several studies have shown relationships between the constructs and personal and academic well-being. Educational interventions aimed at increasing grit and resilience have produced mixed results. Developing protective factors appears to be the most common approach in helping students become more resilient. Summary. Literature pertaining to grit and resilience reveals that the terms are nuanced, complex, and difficult to measure and understand. Regardless, the general characteristics associated with grit and resilience are of interest to educators and warrant further study. PMID- 29606707 TI - Improving Pharmacy Calculations Using an Instructional Design Model. AB - Objective. To describe an evidence-based instructional design to improve performance and foster retention of pharmacy students' calculation skills longitudinally across the curriculum. Methods. Gagne's nine events of instructional design were employed in a longitudinal pharmacy calculations curriculum. Mean pharmacy calculation examination scores from four courses spanning the didactic curriculum for four different academic years (before and after the redesign) were compared. Results. Students demonstrated more stable outcomes with consistently higher means after the redesign, which may indicate improved retention. Additionally, the post-redesign classes have experienced fewer failures (score of <80%). Conclusion. Using an instructional design model to optimize immediate instructional outcomes is an effective method of enhancing retention of calculation skills over time. PMID- 29606706 TI - A Longitudinal Approach to Changes in the Motivation of Dutch Pharmacists in the Current Continuing Education System. AB - Objective. To explore the changes in motivation of Dutch pharmacists for Continuing Education (CE) in the Dutch CE system. Methods. Pharmacists' motivation was measured across three time points with the Academic Motivation Scale, based on the Self-Determination Theory of motivation. The Latent Growth Modelling technique was used to analyze these data. Results. Over a period of 21 months, Controlled Motivation had increased and Relative Autonomous Motivation of Dutch pharmacists had decreased. Traineeship was the only demographic factor with a significant influence on the change in motivation. No subgroups with different trajectories could be identified. Conclusion. Relative Autonomous Motivation of Dutch pharmacists for CE decreases over time. This indicates a loss of Autonomous Motivation ("good" motivation) in favor of Controlled Motivation ("bad" motivation). Further research needs to be conducted to gain a better understanding of the association between pharmacist motivation and the features of the current CE system. PMID- 29606708 TI - Nordic Pharmacy Students' Opinions of their Patient Communication Skills Training. AB - Objective. To describe Nordic pharmacy students' opinions of their patient communication skills training (PCST), and the association between course leaders' reports of PCST qualities and students' perceptions of their training. Secondary objective was to determine what factors influence these associations. Methods. A cross-sectional questionnaire-based study was performed. The various curricula were categorized into three types (basic, intermediate and innovative training) and students were divided into three groups according to the type of training they had received. Multivariable logistic regression models were fitted with different opinions as outcomes and three types of training as exposure, using generalized estimation equations. Results. There were 370 students who responded (response rate: 77%). Students within the innovative group were significantly more likely to agree that they had received sufficient training, and to agree with the assertion that the pharmacy school had contributed to their level of skills compared to students in the basic group. Conclusion. There appears to be an association between larger and varied programs of training in patient communication skills and positive attitudes toward this training on the part of the students, with students reporting that they received sufficient training, which likely enhanced their skills. PMID- 29606709 TI - A Qualitative Study Identifying Key Components to Standardize Across Inpatient General Medicine Advanced Pharmacy Practice Experiences. AB - Objective. To identify common components of inpatient general medicine advanced pharmacy practice experiences (APPEs) across sites, determine which components were important to standardize, and distinguish a benchmark of each component that would indicate standardization. Methods. In-depth interviews about the student experience were conducted with two students and one or more preceptors at each of 12 inpatient general medicine sites in the greater Seattle metropolitan area. Data from transcribed interviews were analyzed, then collapsed into a single spreadsheet for comparison. Overall themes for component groups were identified and components within each theme tested for importance in overall quality of the student experience. Components important for quality of the student experience were deemed "key components" and component metrics were developed for benchmarking. Results. Three themes were essential in the quality of the learning experience at inpatient general medicine sites: welcoming of the student by the preceptors, integration of the student into the site, and student interaction with patients and other health care providers. Key components to be standardized across sites were a structured orientation, written site-specific student guidelines and performance expectations, regular and meaningful student-preceptor interactions, identified performance competency standards, clear delineation of student patient care load and responsibilities, and daily interactions with patients and other health care providers. Conclusion. Qualitative evidence from sites can be used to identify key components to standardize across practice sites offering the same experiential course. These key components aid in the welcoming of the student to the site, integration of the student into the workflow, and daily opportunities for the student to interact with patients and with health care providers. PMID- 29606710 TI - Student and School-level Predictors of Pharmacy Residency Attainment. AB - Objective. To identify student and school level predictors of pharmacy residency attainment. Methods. Data were collected from the American Association of Colleges of Pharmacy (AACP) and the Carnegie Classification of Institutions of Higher Education. Logistic multilevel modeling was used to examine the effects of select student and school level characteristics on pharmacy residency attainment, as indicated by students on the AACP Graduating Student Survey (GSS) from 2013 to 2015. Results. The dataset included 24,351 graduating pharmacy students from 101 schools and colleges of pharmacy. Predictors of residency attainment included working in an institutional pharmacy, female gender, student age, school age, and Research I classification. Nonsignificant variables included curriculum type, class size, and institutional control. Conclusion. Student and pharmacy school characteristics impact the likelihood of pharmacy residency attainment. Further research is needed to understand the mechanisms associated with these effects. PMID- 29606711 TI - Assessing Mental Health First Aid Skills Using Simulated Patients. AB - Objective. To evaluate mental health first aid (MHFA) skills using simulated patients and to compare self-reported confidence in providing MHFA with performance during simulated patient roleplays. Methods. Pharmacy students self evaluated their confidence in providing MHFA post-training. Two mental health vignettes and an assessment rubric based on the MHFA Action Plan were developed to assess students' observed MHFA skills during audio-recorded simulated patient roleplays. Results. There were 163 students who completed the MHFA training, of which 88% completed self-evaluations. There were 84% to 98% of students who self reported that they agreed or strongly agreed they were confident providing MHFA. Postnatal depression (PND) and suicide vignettes were randomly assigned to 36 students. More students participating in the PND roleplay took appropriate actions, compared to those participating in the suicide role-play. However, more students participating in the suicide role play assessed alcohol and/or drug use. Ten (71%) participants in the PND roleplay and six (40%) in the suicide roleplay either avoided using suicide-specific terminology completely or used multiple terms rendering their inquiry unclear. Conclusion. Self-evaluated confidence levels in providing MHFA did not always reflect observed performance. Students had difficulty addressing suicide with only half passing the suicide vignette and many avoiding suicide-specific terminology. This indicates that both self reported and observed behaviors should be used for post-training assessments. PMID- 29606712 TI - Implementing the Pharmacists' Patient Care Process at a Public Pharmacy School. AB - The Joint Commission of Pharmacy Practitioners has provided the profession of pharmacy a patient-centered care model known as the Pharmacists' Patient Care Process (PPCP). This process will serve to provide consistency throughout the profession as it becomes incorporated throughout pharmacy practice and education. A description of the early stages of implementing the PPCP at one public college of pharmacy provides insights into opportunities for education and assessment. PMID- 29606713 TI - Student Learning with Generated and Answered Peer-written Questions. AB - Objective. To investigate the degree to which student-generated questions or answering student-generated multiple-choice questions predicts course performance in medicinal chemistry. Methods. Students enrolled in Medicinal Chemistry III over a 3-year period were asked to create at least one question per exam period using PeerWise; within the software, they were also asked to answer and rate one peer question per class session. Students' total reputation scores and its components (question authoring, answering, and rating) and total answer scores (correctness of answers submitted indicating agreement with the author's chosen answer) were analyzed relative to final course grades. Results. Students at the non-satellite campus and those who generated more highly rated questions performed better overall in the course accounting for 12% of the variability in course grades. The most notable differences were between the top third and bottom third performing students within the course. The number of questions answered by students was not a significant predictor of course performance. Conclusion. Student generation of more highly rated questions (referred to as more thoughtful in nature by the software program) is predictive of course performance but it only explained a small variability in course grades. The correctness of answers submitted, however, did not relate to student performance. PMID- 29606714 TI - Exploring the Community Pharmacist's Knowledge of Celiac Disease. AB - Objective. To evaluate pharmacists' knowledge of celiac disease, and identify potential areas where additional continuing education may be needed. Methods. A survey was sent to community pharmacists practicing in a national chain pharmacy in one region of New Jersey and New York. Results. There were 418 pharmacists who responded to the survey with a response rate of 38%. Only 27% of all respondents who reported their understanding of celiac disease to be basic or advanced correctly defined celiac disease as both an autoimmune and a chronic lifelong disease. The majority (60%) of respondents correctly stated there are no federal regulations requiring manufacturers to designate medications as gluten-free. Twenty percent of respondents said they often recommended a change in diet to people suspected to have celiac disease before a confirmed diagnosis. Conclusion. Community pharmacists possess some knowledge of the disease and would benefit from and desire additional education about this disorder. PMID- 29606715 TI - A Call for a New Ism in Pharmacy. PMID- 29606716 TI - Critical Race Theory for Pharmacy Diversity Curriculum. PMID- 29606717 TI - Response to Critical Race Theory for Pharmacy Diversity Curriculum. PMID- 29606719 TI - Challenges for the veterinary profession. PMID- 29606718 TI - Intellectual Self-doubt and How to Get Out of It. PMID- 29606720 TI - Veterinary Medical Ethics. PMID- 29606721 TI - Successful management of lymphangiosarcoma in a puppy using a tyrosine kinase inhibitor. AB - A puppy was diagnosed with lymphangiosarcoma associated with lymphedema based on lymphography and histopathology. The lesions resolved after toceranib therapy, and the dog remains in remission 1 year later. This is the first report of a successful outcome following oral toceranib as first-line therapy for lymphangiosarcoma in a dog. PMID- 29606722 TI - Primary colonic hemangiosarcoma in a dog. AB - A 13-year-old spayed female miniature dachshund dog was presented with a history of hematochezia, melena, and weight loss. A colonic mass detected by exploratory celiotomy was resected and diagnosed as hemangiosarcoma (HSA). Liver lobectomy for hepatic HSA was performed 894 days after surgery. Adjuvant chemotherapy was declined. This is the first documentation of a canine colonic HSA. PMID- 29606723 TI - Retrobulbar malignant peripheral nerve sheath tumor in a golden retriever dog: A challenging diagnosis. AB - A 9-year-old golden retriever dog was diagnosed with a left retrobulbar mass. Fine-needle aspirations and incisional biopsies resulted in discordant diagnoses: myxosarcoma/myxoma or rhadomyosarcoma, respectively. Immunohistochemistry following exenteration allowed definitive diagnosis of malignant peripheral nerve sheath tumor with fibromyxomatous differentiation. Fifteen weeks after surgery, an aggressive recurrence resulted in euthanasia. PMID- 29606724 TI - Urethral intussusception following traumatic catheterization in a male cat. AB - An 8-year-old, European male shorthair cat was presented with lower urinary tract obstruction. He was catheterized and referred. Retrograde cysto-urethrography suggested a urethral mass. Intussusception of the urethra with a partial rupture of the urethra was visualized. A perineal urethrostomy was performed. The cat was clinically normal at 15 months' follow-up. PMID- 29606725 TI - Sacrocaudal (sacrococcygeal) intervertebral disc protrusion in 2 cats. AB - One cat was presented for investigation of urinary retention and constipation and a second cat was presented with decreased appetite, reluctance to jump, reduced level of activity, and constipation. Magnetic resonance imaging revealed dorsal bulging of the hypo-intense intervertebral disc at S3-Cd1 on fast spin echo T2. Dorsal laminectomy was performed and both cats recovered with resolution of neurological signs. PMID- 29606726 TI - Surgical management of long bone fractures in cats using cortical bone allografts preserved in honey. AB - This report describes comminuted fractures in 2 cats repaired by stabilization with cortical bone allografts that had been preserved in honey. Both cats exhibited appropriate post-operative weight-bearing. Preservation of bone in honey is a simple and widely available alternative for bone banking. This is the first report of a bone defect in cats repaired with bone preserved in honey. PMID- 29606728 TI - Evaluation of environmental sampling methods for detection of Salmonella enterica in a large animal veterinary hospital. AB - Environmental surveillance for Salmonella enterica can be used for early detection of contamination; thus routine sampling is an integral component of infection control programs in hospital environments. At the Purdue University Veterinary Teaching Hospital (PUVTH), the technique regularly employed in the large animal hospital for sample collection uses sterile gauze sponges for environmental sampling, which has proven labor-intensive and time-consuming. Alternative sampling methods use Swiffer brand electrostatic wipes for environmental sample collection, which are reportedly effective and efficient. It was hypothesized that use of Swiffer wipes for sample collection would be more efficient and less costly than the use of gauze sponges. A head-to-head comparison between the 2 sampling methods was conducted in the PUVTH large animal hospital and relative agreement, cost-effectiveness, and sampling efficiency were compared. There was fair agreement in culture results between the 2 sampling methods, but Swiffer wipes required less time and less physical effort to collect samples and were more cost-effective. PMID- 29606727 TI - Update on the use of trilostane in dogs. AB - Many articles published in the past few years have contributed to a better understanding of the use of trilostane in dogs. Trilostane is a competitive inhibitor of 3beta-hydroxysteroid dehydrogenase, the enzyme essential for synthesis of cortisol and all other steroids. Trilostane is reported to be safe and effective in the treatment of pituitary-dependent hyperadrenocorticism (HAC), adrenal-dependent HAC, and alopecia X. While trilostane controls most of the clinical signs associated with HAC, abnormalities such as hypertension, hypercoagulability, and proteinuria may persist despite therapy. Because the duration of cortisol suppression after a dose of trilostane is often less than 12 hours, many dogs with HAC could benefit from low dose trilostane treatment every 12 hours. Many controversies regarding trilostane still exist. This review provides a comprehensive commentary on trilostane's indications, mode of action, dose, monitoring, efficacy, and adverse effects. PMID- 29606729 TI - Seroprevalence of Cache Valley virus and related viruses in sheep and other livestock from Saskatchewan, Canada. AB - Cache Valley virus, an orthobunyavirus, is an important cause of ovine neonatal malformations. Information on the seroprevalence of this virus in Saskatchewan livestock populations is lacking. The objectives of this study were to determine the seroprevalence of Cache Valley virus and closely related viruses in sheep, cattle, goats, horses, and mule deer in Saskatchewan by performing a plaque reduction neutralization test using Cache Valley virus. In total, sera from 130 sheep from 50 flocks were tested. Seroprevalence in sheep was 64.6% (84/130) and 94.0% (47/50) of flocks had 1 or more seropositive sheep. Antibodies to Cache Valley virus or closely related viruses were also detected in serum samples collected from cattle, goats, horses, and mule deer with seroprevalences of 20.0% (5/25), 33.3% (8/24), 69.0% (40/58), and 50.8% (33/65), respectively. These results suggest widespread exposure to Cache Valley virus or closely related viruses in domestic animals and mule deer in Saskatchewan. PMID- 29606730 TI - Effect of different analgesic techniques on hemodynamic variables recorded with an esophageal Doppler monitor during ovariohysterectomy in dogs. AB - This study compared the efficacy of intravenous (IV) fentanyl and ketamine with lumbosacral epidural lidocaine in dogs undergoing ovariohysterectomy. Dogs with esophageal Doppler monitoring (n = 112) were included in this retrospective study. All dogs were premedicated with dexmedetomidine and methadone, induced with IV propofol or alfaxalone and maintained using isoflurane and IV fentanyl, IV ketamine, or epidural lidocaine. Heart rate (HR), mean arterial pressure (MAP), expired fraction of isoflurane (ETIso), stroke distance (SD), minute distance (MD), peak velocity (PV) and mean acceleration (MA) were recorded before and after ligation of the ovarian pedicle (OvP). There were no differences for ETIso, HR, and MAP among fentanyl, ketamine, and control groups. Minute Distance, SD, MA and PV significantly decreased after OvP in fentanyl, ketamine, and control groups, but remained stable in the epidural group. Lumbosacral epidural lidocaine prevented hemodynamic depression changes caused by OvP ligation, whereas fentanyl and ketamine failed to do so. PMID- 29606731 TI - Estrogen-induced myelotoxicity in a 4-year-old golden retriever dog due to a Sertoli cell tumor. AB - A 4-year-old, unilateral cryptorchid golden retriever dog was presented to the Ontario Veterinary College Health Sciences Centre with gynecomastia, dribbling urine, lethargy, neutropenia, and thrombocytopenia. A Sertoli cell tumor was diagnosed in a cryptorchid testicle with estrogen-induced myelotoxicity. The tumor was removed and bone marrow regenerated within 4 months. PMID- 29606732 TI - First report of atypical porcine pestivirus in piglets with congenital tremor in Canada. PMID- 29606733 TI - The bad news blues. PMID- 29606734 TI - Indigenous Children's Knowledge About Non-timber Forest Products in Suriname. AB - Childhood and adolescence are important life stages for the acquisition of knowledge about non-timber forest products (NTFPs). We show at which stage in life traditional plant knowledge is learned and analyze whether cross-cultural ethnobotanical knowledge transmission takes place. We evaluate whether the degree of forest dependency influences ethnobotanical knowledge by comparing two indigenous communities in Suriname. Traditional knowledge was documented and vouchers collected during forest walks with adult informants. Questionnaires were completed by 74 schoolchildren (age 4 to 14) to capture their knowledge of names and uses of nine important NTFPs. We tested for knowledge differences by ethnicity and NTFP categories. Local names for NTFPs were analyzed to determine cross-cultural transmission of ethnobotanical knowledge. Children from the forest dependent Trio community (n = 23) possessed similar knowledge of NTFPs as their more urbanized peers from Apoera (n = 51). NTFP uses were acquired at an earlier age than plant names. Food and commercial NTFP uses were better known than medicinal plant uses. Cross-cultural transfer of knowledge occurred between the two communities. NTFP knowledge of children appeared to be influenced more by the time they spent within the forest, either walking to school or walking to agricultural plots, than by the level of forest dependency or acculturation. PMID- 29606735 TI - Electrochemical Detection of Dopamine via Assisted Ion Transfer at Nanopipet Electrode Using Cyclic Voltammetry. AB - We present here the detection of dopamine (DA) at nanopipet electrodes with radii of hundreds of nanometers ranging from 160 nm to 480 nm. Dibenzo-18-crown-6 (DB18C6) was employed as an ionophore to facilitate DA transfer, resulting in a half-wave transfer potential, E1/2, DA, of -0.322 (+/-0.020) V vs. E1/2, TBA. Well-defined steady-state sigmoidal cyclic voltammograms were observed for the transfer of DA. High resolution scanning electron microscopy was used to measure the size and taper angle of the nanopipet electrodes. The detection is linear with concentration of DA ranging from 0.25 mM to 2 mM; calculated diffusion coefficient at nanopipet electrodes with above mentioned sizes is 4.87 (+/-0.28) * 10-10 m2/s. The effect of the common interferent ascorbic acid on DA detection with nanopipet electrodes was evaluated, where DA detection still shows linear behavior with well-defined sigmoidal CVs with E1/2, DA being -0.328 (+/-0.029) V vs. E1/2, TBA. The diffusion coefficient for DA transfer in MgCl2 with the presence of 2 mM AA was measured to be 1.93 (+/-0.59) * 10-10 m2/s on nanoelectrodes with radii from 161 nm to 263 nm, but the physiological concentration of 0.1 mM AA had no effect on DA's diffusion coefficient. PMID- 29606736 TI - A new approach for separation and recovery of betaine from beet molasses based on cloud point extraction technique. AB - The aim of this work was to explore the possibility of the application of cloud point extraction (CPE) method in micelle media to recovery betaine from beet molasses. Response surface method was employed to assess the effects of surfactant concentration, molasses concentration, incubation time, pH, electrolyte concentration, mixing time, and surfactant type on efficiency of betaine recovery from beet molasses. Also, a mathematical model was developed to predict the effect of each variable and their interactions on the efficiency of betaine recovery. The model showed that best surfactant was Triton X-114 and under the optimum conditions, betaine recovery from beet molasses was achieved up to 80% when three CPE steps with total of 1.5% (w/v) of surfactant were used. Subsequently, betaine was recovered nearly 100% from surfactant rich phase after adjusting pH at 2.5 and re-incubation at 40 degrees C. The results showed that the proposed method is suitable for extraction of betaine from beet molasses. PMID- 29606737 TI - Bleaching effects of massecuite on some properties of crystallized sugar beet and milk chocolate bars produced. AB - Four kinds of bleached, unbleached, second and third crystal sugars (BCS, UCS, SCS and TCS) were made from different massecuites in a sugar-beet factory, and their physiochemical (polarization, invert sugar, colorants, pH, ash and SO2), microbiological and functional properties were measured. While the polarization of UCS, SCS and TCS were lower than BCS; their invert sucrose, colorants, pH and ash contents were significantly higher than BCS. The phenols and betaine of BCS, UCS, SCS, and TCS were 144, 401, 384 and 673 (mg/100 g); and 244, 791, 4662, and 6589 (mg/100 g); respectively. Whereas the phenol of milk chocolate bars (MCB) made with UCS, SCS, and TCS were only 10% higher than MCB completed with BCS; their betaine contents were substantially (up to 16 times) higher than the ones finished with BCS. Sensory evaluation showed that the MCB prepared with three sugars including UCS, SCS and TCS had significantly higher glossiness, brittleness, flavor and mouth feel than those made with BCS. The greater colorants, ash content and inverted sugars of UCS, SCS and TCS (in comparison with BCS) made considerable improvements in the glossiness, flavor and brittleness of MCB, respectively. BCS had 8 ppm of toxic sulfur; whereas, UCS, SCS and TCS had no detectable sulfur and significantly higher beneficial copper content than BCS. No pathogenic microorganism were detected in UCS, SCS, TCS or their subsequent MCB. Our results highly recommend using UCS, SCS and TCS instead of BCS in food products (such as MCB) due to their higher health benefits. PMID- 29606738 TI - Effect of formulation and baking conditions on the structure and development of non-enzymatic browning in biscuit models using images. AB - The aim of this research was to determine the effect of composition (dietary fiber = DF, fat = F, and gluten = G) and baking time on the target microstructural parameters that were observed using images of potato and wheat starch biscuits. Microstructures were studied Scanning Electron Microscope (SEM). Non-enzymatic browning (NEB) was assessed using color image analysis. Texture and moisture analysis was performed to have a better understanding of the baking process. Analysis of images revealed that the starch granules retained their native form at the end of baking, suggesting their in complete gelatinization. Granules size was similar at several different baking times, with an average equivalent diameter of 9 and 27 um for wheat and potato starch, respectively. However, samples with different levels of DF and G increased circularity during baking to more than 30%, and also increasing hardness. NEB developed during baking, with the maximum increase observed between 13 and 19 min. This was reflected in decreased luminosity (L*) values due to a decrease in moisture levels. After 19 min, luminosity did not vary significantly. The ingredients that are used, as well as their quantities, can affect sample L* values. Therefore, choosing the correct ingredients and quantities can lead to different microstructures in the biscuits, with varying amounts of NEB products. PMID- 29606740 TI - Diversity in protein profiling, pasting, empirical and dynamic dough rheological properties of meal from different durum wheat accessions. AB - The particle size distribution, protein profile, pasting and dough rheological properties of meal from forty-two Indian durum wheat accessions were evaluated. Meal from accessions with higher grain hardness index (GHI) showed a high proportion of large size particles with higher protein content and lower paste viscosities. Elastic and viscous modulii (G' and G") of dough were negatively correlated with paste viscosities, which was associated with the presence/absence of LMW-GS and HMW-GS. Wheat accessions with allelic combinations of (13 + 16) with 97 + 91 kDa polypeptides (PPs) had higher G' and G". The accession with 35 kDa PP showed higher while those with 35 and 62 kDa PPs showed lower paste viscosity. Among all accessions, 25 accessions possess 7 + 8 (97 and 88 kDa) type HMW-GS allelic combination. Durum accessions with diverse GHI, particle size distribution, protein profile, paste and dough rheology indicates their variation in milling and processing behaviour. PMID- 29606739 TI - Effects of Cordyceps militaris (L.) Fr. fermentation on the nutritional, physicochemical, functional properties and angiotensin I converting enzyme inhibitory activity of red bean (Phaseolus angularis [Willd.] W.F. Wight.) flour. AB - The effects of solid-state fermentation with Cordyceps militaris (L.) Fr. on the nutritional, physicochemical, and functional properties as well as angiotensin I converting enzyme (ACE) inhibitory activity of red bean (Phaseolus angularis [Willd.] W.F. Wight.) flour were determined. Fermentation increased the amount of small peptides but significantly decreased large peptides. Fermentation also increased proteins and essential amino acids (by 9.31 and 13.89%, respectively) and improved the in vitro protein digestibility (6.54%) of red beans. Moreover, fermentation increased the water holding capacity (from 2.36 to 2.59 mL/g), fat absorption capacity (from 84.65 to 114.55%), emulsion activity (from 10.96 to 52.77%), emulsion stability (from 5.43 to 53.82%), and foaming stability (from 11.95 to 20.68%). Fermented red bean flour achieved a lower least gelation concentration of 14% than that of the control (18%). In contrast to the non fermented red bean, the fermented red bean showed ACE inhibitory activity, with IC50 value of 0.63 mg protein/mL. Overall, fermentation improved the nutritional, physicochemical, and functional properties as well as the biological activity of red bean flour. Thus, fermented red bean flour may serve as a novel nutritional and functional ingredient for applications in food design. PMID- 29606741 TI - Kinetic modeling of bacteriocin-like inhibitory substance secretion by Pediococcus acidilactici Kp10 and its stability in food manufacturing conditions. AB - This paper deliberates the modelling and validation of bacteriocin-like inhibitory substance (BLIS) secretion by Pediococcus acidilactici Kp10 at different agitation speeds in a stirred tank bioreactor. A range of models namely the re-parameterised logistic, Luedeking-Piret and maintenance energy were assessed to predict the culture performance of the said bacterium. Growth of P. acidilactici Kp10 was enhanced with increased agitation speed up to 600 rpm while BLIS secretion was maximum at 400 rpm but decreased at higher agitation speed. Growth of P. acidilactici aptly subscribed to the re-parameterised logistic model while BLIS secretion and lactose consumption fitted well with the Luedeking-Piret model. The models revealed a relationship between growth of the bacterium and BLIS secretion. Bacterial growth and BLIS secretion were largely affected by the agitation speed of the stirred tank bioreactor which regulated the oxygen transfer to the culture. BLIS secretion by P. acidilactici Kp10 was however enhanced in oxygen-limited culture. The study also assessed BLIS from the perspective of its stability when subjected to factors such as temperature, pH and detergents. Results showed that BLIS produced by this strain was not affected by heat (at 25-100 degrees C for 20 min and at 121 degrees C for 15 min), surfactant (Tween 40, 60 and 80 and urea), detergents (up to 1% SDS), organic solvents (50% each of acetone, methanol and ethanol) and stable in a wide range of pH (2-10). The above information are pertinent with reference to commercial applications of this bacterial product in food manufacturing which invariably involve various sterilization processes and subjected to a wide pH range. PMID- 29606742 TI - Analysis of NO-suppressing activity of Strawberry Wine supplemented with ball milled achenes. AB - Inflammation is generally thought to be involved in the development of several chronical diseases, therefore, phytochemicals to modulate immune responses has attracted great interests. The objective of the present study was to evaluate the potential anti-inflammatory effects of wine supplemented using ball-milled achene on modulating NO production and inducible nitric oxide synthase (iNOS) expression. Ball-milled achenes were added in strawberry must prior to fermentation, and the wine samples were then concentrated and extracted with water and/or ethanol prior to analysis. Bioactivities of wine extracts were evaluated using the cell viability assay, cell cycle measurements, NO production and iNOS expression in lipopolysaccharide (LPS)-stimulated RAW264.7 cells. Treatments of achenes supplemented strawberry wine extract up to 100 MUg/mL inhibited the proliferation of LPS-stimulated RAW264.7 cell via affecting the progression of cell cycle. Moreover, no detectable cytotoxicity in RAW264.7 cells was observed. The supplemented wine extract suppressed the action of LPS and led to a decreased NO production in stimulated cells. The inhibitory effect of the wine extract on NO production was determined to be a 25-40% decrease in the level of 25-100 MUg/mL, in contrast to a 10% decrease for conventional wine samples. Additionally, an alcoholic wine extract (100 MUg/mL) led to a 40.31% decrease in iNOS expression in LPS-stimulated cells, which was more effective than the same dose of tocopherol. The results show that strawberry wine supplemented with ball milled achenes causes a substantial inhibition of NO production, and this biofunction is exerted via the down-regulation of iNOS expression. PMID- 29606743 TI - Flavor characteristics and antioxidant capacities of hihatsumodoki (Piper retrofractum Vahl) fresh fruit at three edible maturity stages. AB - To determine the effect of maturity stage on the food attributes of hihatsumodoki (Piper retrofractum Vahl) fresh fruit, the flavor characteristics and antioxidant capacities were investigated at green (GM), orange (OM), and red maturity (RM) stages. Total organic acids, total free amino acids (FAA), and piperine decreased with increasing fruit maturation, reaching minima at the RM stage. Conversely, total sugars and the FAA that contribute to both umami and sweetness were the highest RM stage. Principal component analysis revealed that the volatile composition of the fruit at the GM stage was clearly different from that at the other stages. The DPPH radical scavenging activity and total phenolic content, as measures of antioxidant capacity, decreased with increasing fruit maturation from GM to RM, which was consistent with the changes in piperine content. Therefore, the maturity stage has a significant influence on the flavor and antioxidant characteristics of hihatsumodoki fresh fruit. PMID- 29606744 TI - Antioxidant degradation kinetics in apples. AB - The effect of shelf storage under ambient conditions of cut apple dices on degradation of bioactive compounds such ascorbic acid, total phenols, antioxidant activity (% DPPH inhibition) and PPO activity were investigated. The results indicated that antioxidant activity declined significantly over 80 min storage of diced apples at ambient temperature. Similar trend was observed for ascorbic acid, total phenols and PPO activity. Ascorbic acid, total phenols and antioxidant activity degradation followed first-order kinetics where the rate constant (k) was found to be in range for all the thirteen cultivars, though initial ascorbic acid and phenol content varied in different apple cultivars. The reaction rate constant (k) for first order degradation ranged from 1.16 to 1.97, 0.89 to 1.29 and 0.37 to 1.54 for antioxidant activity, total phenols and ascorbic acid, respectively. This explains that antioxidant activity degrades at higher rate than total phenols and ascorbic acid, which also corroborates that antioxidant activity is affected by both total phenols and ascorbic acid content. In general, total antioxidant activity for apple dices kept for 80 min under ambient conditions exhibited lower values as compared to control. PMID- 29606745 TI - Production and characterization of vitamin D3 loaded starch nanoparticles: effect of amylose to amylopectin ratio and sonication parameters. AB - Two types of starches with different amylose to amylopectin ratios were used for the production of vitamin D3 loaded nanoparticles and effects of starch type, sonication time and temperature on physicochemical properties of nanocarriers were investigated. Both high amylose corn and potato starches nanocarriers had granular structure with particle size ranging from 32.04 to 99.2 nm and the encapsulation efficiency ranging from 22.34 to 94.8%. The results showed that potato starch nanoparticles had larger size, higher zeta potential, encapsulation efficiency and encapsulation load and lower polydispersity index values in comparison to high amylose corn starch nanoparticle. Increase in sonication time reduced the size of nanoparticles in both starch types and decreasing temperature led to reduction of particle size and increase of zeta potential. Physicochemical features of nanocarriers were analyzed by Fourier transform-infrared spectroscopy, X-ray diffraction and differential scanning calorimetry. The results indicated that vitamin D3 is well incorporated in carriers and ultrasonic treatment led to increase of hydrocarbon chain that resulted in van der Waals and hydrogen bonds of vitamin D3 with the potato starch and greater thermal stability. PMID- 29606746 TI - Mechanical properties of ten-egg boxes made of different materials. AB - This study was conducted to evaluate mechanical properties of ten-egg boxes, which are the most commonly used egg boxes in many countries of Central and South Eastern Europe. Six ten-egg boxes were tested, two made of cardboard, two made of expanded polystyrene and two made of general purpose solid polystyrene, each from a different producer. There were no significant differences in basic dimensions between tested boxes of various materials, while the significant differences were occurred in weight and box wall thickness. Test included measuring of vertical forces required for deforming complete box and at particular place for each egg in a box till contact with eggs. According to the obtained results, cardboard boxes can provide the best mechanical protection for eggs. The average force required for deforming complete cardboard box was 83.6% higher than for solid polystyrene box, and even 289.5% higher than for expanded polystyrene box. The average force required for deforming cardboard box at particular place for each egg in a box was 60.8% higher than for polystyrene box, and 74.0% higher than for expanded polystyrene box. The disadvantage of cardboard boxes is that they are not resistant to the impact of moisture as polystyrene boxes and in the case of an increase in box moisture due to storage in inappropriate conditions their mechanical resistance decreases. PMID- 29606747 TI - Assessment of the reducing capacity of processed fruit juices with the copper(I)/4,4'-dicarboxy-2,2'-biquinoline complexes. AB - An alternative method for quantification of the total reducing capacity (TRC) of processed ready-to-drink fruit juices (orange, grape, peach, mango, cashew, strawberry, apple and guava) is suggested. The spectrophotometric procedure is based on the reduction of Cu(II) to Cu(I) by antioxidants (present in the samples) in aqueous buffered solution (pH 7.0), containing 4,4'-dicarboxy-2,2' biquinoline acid (H2BCA), yielding the [Formula: see text] complexes. The absorbance values at 558 nm (A558 nm) of the [Formula: see text] complexes obtained with juice samples were compared with A558 nm values of the same complexes obtained with a standard ascorbic acid solution and used to quantify and express the reducing capacity of each sample. Regarding orange juices a positive relationship between the TRC values using the [Formula: see text] complexes and the labelled ascorbic acid (AA) content along with the total polyphenol content (TPC) was measured. Grape juices showed the best positive correlation was verified between the TRC (with the [Formula: see text] complexes) and the TPC. While other fruit juices showed good agreement of TRC values with [Formula: see text] complexes and DPPH reagent. The proposed method may be applied to measure the TRC of beers and wines and also for biological samples like serum and follicular fluid. PMID- 29606748 TI - Rapid screening and quantification of major organic acids in citrus fruits and their bioactivity studies. AB - Organic acids (OAs) are small non-volatile molecules with widespread usage in processed foods, feeds and instant beverages. The prime aim of this study was to explore major OAs in local citrus fruits (Citrus limetta, Citrus aurantifolia, Citrus nobilis, Citrus karna, Citrus medica, Citrus ichangensis and Citrus aurantium) and assessment of their bioactivities. A RP-HPLC-DAD method was developed using buffer free solvent system for rapid detection and quantification of major OAs from citrus fruits and derived products. Method validation studies showed good linear calibration curve (0.985-0.998) for all OAs. The values of %RSD ranged between 0.0001-1.129 and 0.142-1.941 for interday and intraday variability respectively. The limit of detection and limit of quantification values for different OAs were ranged between 1.5-12 and 5-40 ug mL-1. The juice of above mentioned citrus fruit cultivars were assessed for OAs, total phenolics, free radical scavenging antioxidants and their antimicrobial potential against selected bacterial and fungal strains. The results showed variable contents of phenolics [0.28 +/- 0.001-1.17 +/- 0.014 mg (GAE) mL-1] and antioxidant compounds (1.26 +/- 0.009-2.84 +/- 0.006 mg of trolox equivalents mL-1) in all juice samples besides significant antifungal activity against C. albicans and A. niger strains. However, in case of antibacterial activity, only C. aurantifolia showed inhibitory effects against selected strains. It was found that citrus fruits have immense potential for their utilization as economic source of natural OAs and development of value added products, beverages and bio-preservatives. PMID- 29606749 TI - Evaluation of storage time effect on saffron chemical profile using gas chromatography and spectrophotometry techniques coupled with chemometrics. AB - Saffron quality is commonly determined by three parameters: color, aroma, and taste. Several factors including harvesting and post-harvesting conditions, affect these parameters. In this study, the effect of storage time on saffron quality was evaluated. At first, the relative concentration of the saffron secondary metabolites in freshly dried and 2 years stored saffron samples prepared with ISO 3632 and UA-DLLME methods and then measured using UV-Vis and GC FID techniques. In order to find saffron storage time biomarkers, the obtained data were subjected to several data analysis steps including data preprocessing, principal component analysis (PCA), partial least square discriminant analysis (PLS-DA) and variable selection methods. Based on the obtained main biomarkers and proposed molecule mechanism, it can be concluded that during the storage periods, the intensity of saffron color reduces, while its aroma increases, reflecting a negative correlation between them. Freshly dried samples have a higher level of the crocins as coloring agents, beta-isophorone, 4-hydroxy-3,5,5 trimethylcyclohex-2-enone and picrocrocin, while the stored samples were more abundant by safranal as the main saffron aroma agent. PMID- 29606750 TI - Preparation of iron-fortified potato starch and its properties. AB - Iron fortification was applied to commercial potato starch by immersion in different concentrations of ferrous sulfate (FeSO4) aqueous solutions. To determine the impact of iron fortification on the properties of potato starch, all of the starches obtained through the process mentioned above were analyzed for their pasting properties, color, gelatinization properties, and resistant starch content. Results indicated that the iron content markedly increased from 16 to 890 ppm when the potato starch was treated with a FeSO4 aqueous solution. During iron fortification, pasting properties markedly changed. Peak viscosity and breakdown decreased while peak viscosity temperature increased with iron fortification. Iron fortification caused a little reduced whiteness (slightly lower L*-value) and enhanced yellowish color (higher b*-value). In contrast, iron fortification had little influence on the gelatinization temperature and enthalpy. Moreover, no significant change in the resistant starch content was observed due to iron fortification. PMID- 29606751 TI - Effects of packaging and pre-storage treatments on aflatoxin production in peanut storage under controlled conditions. AB - This study reports on aflatoxin production and peanut (Bailey's variety) quality, for four peanut pre-storage treatments; [(Raw clean (Raw-Cl), Raw inoculated with Aspergillus flavus NRRL 3357 (Raw-Inf), inoculated partially roasted but not blanched (PRN-blanch); and inoculated partially roasted, blanched with discolored nuts sorted out (PR-blanched)]. All four treated samples were packaged in four different packaging systems [polypropylene woven sacks (PS), hermetic packs (HP), hermetic packs with oxygen absorbers (HPO), and vacuumed hermetic packs (HPV)] and stored under controlled conditions at a temperature of 30 +/- 1 degrees C and water activity of 0.85 +/- 0.02, for 14 weeks. Raw-Inf samples in PS had a higher fungal growth with a mean value of 8.01 * 104 CFU/g, compared to the mean values of samples in hermetic packs: 1.07 * 103 CFU/g for HP, 14.55 CFU/g for HPO, and 57.82 CFU/g for HPV. Similarly, the hermetic bags were able to reduce aflatoxin level of the Raw-Inf samples by 50.6% (HP), 63.0% (HPV), and 66.8% (HPO). Partial roasting and blanching in PS also reduced aflatoxin level by about 74.6%. Quality maintenance was the best for peanuts in HPO, recording peroxide value (PV) of 10.16 meq/kg and p-Anisidine (p-Av) of 3.95 meq/kg compared to samples in polypropylene woven sacks which had PV of 19.25 meq/kg and p-Av of 6.48 meq/kg. These results indicate that using zero-oxygen hermetic packaging, instead of the conventional polypropylene woven sacks, helped to suppress aflatoxin production and quality deterioration. Also, partially roasted, blanched and sorted peanuts showed a potential for reducing aflatoxin presence during storage. PMID- 29606752 TI - Effect of pH adjustment, homogenization and diafiltration on physicochemical, reconstitution, functional and rheological properties of medium protein milk protein concentrates (MPC70). AB - Poor solubility is the major limiting factor in commercial applications of milk protein concentrates (MPC) powders. Retentate treatments such as pH adjustment using disodium phosphate (Na2HPO4), also responsible for calcium chelation with homogenization and; its diafiltration with 150 mM NaCl solution were hypothesized to improve the functional properties of treated MPC70 powders. These treatments significantly improved the solubility, heat stability, water binding, dispersibility, bulk density, flowability, buffer index, foaming and emulsifying capacity of treated powders over control. Rheological behaviour of reconstituted MPC solutions was best explained by Herschel Bulkley model. Compared to rough, large globular structures with dents in control; majorly intact, separate, smaller particles of smooth surface, without any aggregation were observed in SEM micrograph of treated powders. Applied treatments are easy, cost-effective and capable to improve functional properties of treated powders that could replace control MPC70 powder in various food applications where protein functionality is of prime importance. PMID- 29606753 TI - Storage quality of walnut oil containing lycopene during accelerated oxidation. AB - The purpose of investigation was to assess the effect of lycopene on the peroxide value, acid value, fatty acids, total phenolic content and ferric-reducing antioxidant power of walnut oil. Walnut oil was extracted from Xinjiang walnut variety using cold pressing method. Our study reported that after 45 days of accelerated oxidation at 60 degrees C (Schaal oven test), 0.005% lycopene exhibited the greatest antioxidant effect than other addition levels of lycopene. Therefore, under ambient storage conditions, the shelf-life of walnut oil could be extended up to 16 months by 0.005% lycopene. Moreover, 0.005% lycopene added to walnut oil had a significantly higher content of saturated fatty acid, unsaturated fatty acid, total phenol, reducing ability of the polar and non-polar components than the blank sample (walnut oil without any addition of lycopene). In conclusion, lycopene improved the quality of walnut oil because of its antioxidant effect against lipid oxidation. PMID- 29606754 TI - Investigation of the composition and antioxidant activity of acetone and methanol extracts of Daphne sericea L. and Daphne gnidioides L. AB - The compositions of methanol and acetone extracts obtained from Daphne sericea L. and Daphne gnidioides L. were investigated. The antioxidant activities of each extract were determined by various test methods. Phenolic composition profile analysis by HPLC-DAD showed that D. gnidioides extracts contain more phenolic compounds than D. sericea extracts. Among the components, syringic acid was found to be the most abundant one in D. gnidioides extracts (42.8 and 38.4 mg per g dry extract of methanol and acetone, respectively). Total flavonoid, total phenolic and total carotenoid contents of methanolic D. gnidioides extracts were found to be 244.5 mg rutin/g dry weight of extract, 1219.3 mg GAE/g dry weight of extract and 11.9 mg/g dry weight of extract, respectively. DPPH., ABTS.+ and O2.- assays were applied to plant extracts as radical scavenging activity tests. Methanolic extracts of D. sericea and D. gnidioides showed the highest radical scavenging activities according to DPPH. and ABTS.+ tests (61.6 and 147.2 in terms of IC50, respectively). Antioxidant activity tests for measuring lipid oxidation inhibiting capacity were carried in low density lipoprotein (LDL) and bovine brain extract (BBE). Methanolic extracts of D. gnidioides and D. sericea demonstrated remarkable lipid oxidation inhibiting capacity in LDL and BBE tests. PMID- 29606755 TI - Effects of processing parameters on the caffeine extraction yield during decaffeination of black tea using pilot-scale supercritical carbon dioxide extraction technique. AB - In this pilot-scale study supercritical carbon dioxide (SCCO2) extraction technique was used for decaffeination of black tea. Pressure (250, 375, 500 bar), extraction time (60, 180, 300 min), temperature (55, 62.5, 70 degrees C), CO2 flow rate (1, 2, 3 L/min) and modifier quantity (0, 2.5, 5 mol%) were selected as extraction parameters. Three-level and five-factor response surface methodology experimental design with a Box-Behnken type was employed to generate 46 different processing conditions. 100% of caffeine from black tea was removed under two different extraction conditions; one of which was consist of 375 bar pressure, 62.5 degrees C temperature, 300 min extraction time, 2 L/min CO2 flow rate and 5 mol% modifier concentration and the other was composed of same temperature, pressure and extraction time conditions with 3 L/min CO2 flow rate and 2.5 mol% modifier concentration. Results showed that extraction time, pressure, CO2 flow rate and modifier quantity had great impact on decaffeination yield. PMID- 29606756 TI - Chemical, microbiological, and sensory parameters during the refrigerated storage of silver catfish (Rhamdia quelen) exposed in vivo to the essential oil of Lippia alba. AB - This study evaluated whether the essential oil of Lippia alba (EO) used as a sedative for fish transport would increase the stability of silver catfish during ice storage. Fish were transported (6 h) with water alone (control), 30 or 40 uL/L of EO in water. After transport, fish were slaughtered and stored in ice. Data on mesophilic and psychrotrophic bacteria counts during storage did not support the evidence for the antimicrobial activity of EO. However, fish treated with EO (30 and 40 uL/L) had delayed onset of rigor mortis, delayed increase of pH after 34 days of storage, and delayed peak of hypoxanthine formation and its degradation. In addition, the demerit sensory score of EO-treated fish (30 and 40 uL/L) was lower than that of controls along the storage. Thus, the use of EO as a sedative in the water used to transport silver catfish can delay the loss of freshness and the deterioration of whole fish stored in ice. PMID- 29606757 TI - Tetracycline resistance in lactobacilli isolated from Serbian traditional raw milk cheeses. AB - The aim of this study was to investigate the presence of tetracycline resistance in lactobacilli isolated from traditional Serbian white brined raw milk cheeses (Homolje, Sjenica, Zlatar). Isolation of presumptive lactobacilli was initially performed using MRS-S agar without tetracycline, or supplemented with 16 and 64 ug/mL of tetracycline. Rep-PCR (GTG)5 genotyping showed a high diversity of the isolates obtained, as examination of 233 isolates resulted in 156 different Rep PCR fingerprints. Ninety out of 156 (57.69%) of the strains, representatives with different (GTG)5 fingerprints, were identified by MALDI-TOF MS as lactobacilli, while 66 out of 156 (42.31%) strains were identified as members of other LAB genera. All except one out of 90 Lactobacillus isolates further tested by microdilution method, demonstrated unimodal distribution of tetracycline MIC values which were equal to or lower from the breakpoint MIC values (EFSA in EFSA J 10: 1-10, 2012. 10.2903/j.efsa.2012.2740). Only one Lb. paracasei isolate showed the presence of tet(M) gene, while the other analyzed tet genes [tet(A), tet(B), tet(C) tet(K), tet(L), tet(O) and tet(W)] were not detected in any of the isolates. The results of this study indicates that lactobacilli from traditional Serbian raw milk cheeses do not present considerable tetracycline resistance reservoirs. For final conclusions about the safety of these autochthonous cheeses regarding the possible tetracycline resistance transferability, the assessment of the entire cheese microbiota is needed. PMID- 29606758 TI - Some microbiological, physicochemical and ripening properties of Erzincan Tulum cheese produced with added black cumin (Nigella sativa L.). AB - The effects of black cumin (BC) at 0, 1 or 2% in Erzincan Tulum cheese (Tulum cheese) on its microbiological, chemical and proteolysis properties during ripening were investigated. The addition of BC caused an increase in the dry matter, protein, ash, total nitrogen (TN), water-soluble nitrogen (WSN) (% of TN) (ripening index), 5% phosphotungstic acid soluble nitrogen (PTA-SN) (% of TN), and 12% trichloroacetic acid soluble nitrogen (TCA-SN) (% of TN) concentrations compared to BC-free (control) cheese. Additionally, the addition of BC caused a decrease in coliforms, yeasts & moulds, fat-in-dry matter (FDM), pH, and acidity. The ripening period had an increasing effect on the dry matter, protein, FDM, salt, salt-in-dry matter (SDM), ash, acidity, TN, WSN, PTA-SN and TCA-SN concentrations. In addition, the ripening period had a decreasing effect on coliforms, yeasts & moulds, and pH. The count of Staphylococcus aureus in all Tulum cheeses made of raw sheep's milk was < 2 log cfu/g, ripening was faster and favourable Tulum cheese was produced. Therefore, 2 months after adding 2% BC to Tulum cheese that was produced using raw sheep milk immediately after milking as the original production method, it was found that Tulum cheese can be consumed more safely than coliform bacteria and yeasts & moulds. PMID- 29606759 TI - Characterization of Neem (Azadirachta indica A. Juss) seed volatile compounds obtained by supercritical carbon dioxide process. AB - Extraction process employing Supercritical fluid carbon dioxide (SCF) yields bioactive compounds near natural forms without any artifact formation. Neem seed was subjected to SCF at different temperatures and pressure conditions. These extracts were partitioned to separate volatile fraction and were analyzed by Gas Chromatography-Mass spectroscopy along with the volatiles extracted by the hydro distillation method. Experimental results show that there is a significant effect of pressure and temperature on isolation of a number of volatile compounds as well as retention of biologically active compounds. Twenty-five volatile compounds were isolated in the Hydro-distillate compare to the SCF extract of 100 bar, 40 degrees C which showed forty volatile compounds corresponds to 76.38 and 92.39% of total volatiles respectively. The majority of bioactive compounds such as Terpinen-4-ol, 1,2,4-Trithiolane, 3,5-diethyl, allyl isopropyl sulphide, Cycloisolongifolene, a-Bisabolene, (-)-alpha-Panasinsen, Isocaryophyllene, trans Sesquisabinene hydrate, 1-Naphthalenol, were identified in the extract when isolated at 100 bar and 40 degrees C. PMID- 29606761 TI - Effects of ultrasonic/microwave-assisted treatment on the properties of corn distarch phosphate/corn straw cellulose films and structure characterization. AB - Edible films were casted using aqueous solutions of corn distarch phosphate (CDP, 3 wt%) and corn straw cellulose (CSC, 0.5 wt%). The effects of ultrasonic, microwave and ultrasonic/microwave-assisted treatment on mechanical properties and light transmittance, as well as the water vapour permeability (WVP) of edible films, were evaluated. It was found that corn distarch phosphate/corn straw cellulose (CDP/CSC) films treated using ultrasonic waves/microwaves for a certain condition has a distinct increase in tensile strength, elongation at break and light transmittance and a drastic decrease in WVP. Moreover, scanning electron microscopy demonstrated that the surface and cross-section morphology of CDP/CSC films after ultrasonic/microwave-assisted treatment were smoother, denser and without a notable phase separation compared with control films. The results of mechanical properties and barrier properties were in agreement with the changes in molecular interactions detected by Fourier transform infrared spectroscopy and X-ray diffraction analysis. These findings indicate that ultrasonic/microwave assisted treatment can improve the application of biodegradable films. PMID- 29606760 TI - Quercetin enhances stress resistance in Saccharomyces cerevisiae tel1 mutant cells to different stressors. AB - The Saccharomyces cerevisiae TEL1 gene is an ortholog of the human ATM (Ataxia telangiectasia mutated) gene. S. cerevisiae tel1 mutant (tel1?) lacking Tel1p, share some of the cellular defects with ATM mutation that includes prevention of oxidative damage repair, premature aging and apoptosis. In the present study, we investigated the protective effects of quercetin on the sensitivity of yeast S. cerevisiae tel1? cells exposed to oxidative, apoptotic and DNA damaging stress and viability of tel1? cells during chronological aging. Quercetin improved the stress resistance of tel1? cells when challenged with oxidants such as hydrogen peroxide (H2O2), menadine bisulphite (MBS) and tertiary butyl hydroperoxide (t BHP) by scavenging reactive oxygen species (ROS). Quercetin protected the tel1? cells from acetic acid-induced apoptotic cell death and sensitivity against hydroxyurea. We found that quercetin attenuated ROS accumulation and apoptotic markers in tel1? cells and therefore an increase in cell viability during chronological aging. Our results from the S. cerevisiae model, suggest that use of quercetin as a food supplement might alleviate oxidative stress mediated DNA damage, apoptosis and age related damaging effects in AT patients and also improve health beneficial effects in humans. PMID- 29606762 TI - Greening in sunflower butter cookies as a function of egg replacers and baking temperature. AB - Chlorogenic acid (CGA) binding to proteins in alkaline conditions results in the production of green trihydroxy benzacradine (TBA) derivatives. The formation of TBA derivatives could decrease product quality due to the potential losses in soluble protein and antioxidants and the production of an undesirable green color. To determine how cookie formulation affected the formation of TBA derivatives in sunflower butter cookies, two egg replacers (chia and banana) and two baking temperatures (162.8 and 190.6 degrees C) were used. Moisture, greening intensity, CGA content and antioxidant capacity were measured. Cookies made with egg and baked at 162.8 degrees C had the highest moisture, internal greening intensity, and TBA derivative formation, in addition to lower CGA content and antioxidant capacity. Cookies made with banana baked at 190.6 degrees C produced the opposite outcome with 35, 4, and 23% less internal greening, moisture, and TBA derivatives, respectively, and 90 and 76% higher CGA and antioxidant capacity. Internal greening was positively correlated with moisture and adduct concentration, and negatively correlated with spread factor and CGA content. Moisture had a significant impact on greening, which indicates that baking temperature and cookie dough formulation can be modified to produce a less green cookie with more unreacted antioxidants and protein. PMID- 29606763 TI - Apigenin isolated from A. americana encodes Human and Aspergillus oryzae S2 alpha amylase inhibitions: credible approach for antifungal and antidiabetic therapies. AB - Agave americana extract was analyzed by reverse phase HPLC for characterization. Among phenolic compounds identified, apigenin was observed to be present. The finding showed an inhibitory effect of apigenin towards Human and Aspergillus oryzae S2 alpha-amylases. Apigenin inhibition towards Human and A. oryzae alpha amylase activities was observed to be competitive. IC50 and % inhibition of apigenin for A. oryzae alpha-amylase were 3.98 and 1.65 fold higher than for Human alpha-amylase. The inhibition of the described biocatalyst activity was significantly lowered when apigenin was pre-incubated with starch. In addition to the catalytic residues, 44 amino acid residues were involved on A. oryzae alpha amylase-apigenin interactions while only 11 amino acid residues were exposed for Human alpha-amylase-apigenin complex. The binding site of apigenin showed 76 polar contacts for A. oryzae S2 alpha-amylase against 44 interactions for Human alpha-amylase. The docking studies confirmed the mode of action of apigenin and strongly suggested a higher inhibitory activity towards fungal amylase which was experimentally exhibited. These findings provided a rational reason to establish apigenin capability as a therapeutic target for postprandial hyperglycaemia modulation and antifungal therapy. PMID- 29606764 TI - Total phenolic content and total antioxidant capacity of common Indian pulses and split pulses. AB - Pulses are valued for their protein content and are good source of bioactive phytochemicals. The objectives of this study were to estimate total phenolic content (TPC), flavonoid content and total antioxidant capacity (TAC) through six different assay methods from twenty seven different varieties of pulses and split pulses commonly consumed in India. TPC and flavonoid content ranged between 38.6 542.7 mg GAE/100 g and 18.3-344.7 mg RE/100 g respectively. TAC measured by FRAP (90.6-2773.5 mg TE/100 g), RPA (190.8-2128.4 mg TE/100 g), DPPH radical scavenging assay (RSA) (42.9-571.1 mg TE/100 g), ABTS RSA (4.5-194.9 mg TE/100 g), hydroxyl RSA (0.0-106.6 mg AAE/g) and nitric oxide (NO) RSA (11.9-43.7 mg AAE/100 g) varied widely among pulses and split pulses analysed in the present study. TAC measured using different methods showed positively strong and significant correlation with TPC as well as flavonoid content except NORSA, indicating that phenolic compounds are the major contributors to the antioxidant properties of these plants. Food composition data obtained in this study would enrich the composition database at global level, which in turn will guide in improving food and nutrition security of the population. These can be used for further research, diet formulation and epidemiological studies. From the results it can be concluded that cow pea (red, small) had the highest TPC and TAC measured by all the parameters except NORSA. PMID- 29606765 TI - Action of multi-enzyme complex on protein extraction to obtain a protein concentrate from okara. AB - The objective of this study was to optimize the extraction of protein by applying a multi-enzymatic pretreatment to okara, a byproduct from soymilk processing. The multi-enzyme complex Viscozyme, containing a variety of carbohydrases, was used to hydrolyze the okara cell walls and facilitate extraction of proteins. Enzyme assisted extraction was carried out under different temperatures (37-53 degrees C), enzyme concentrations (1.5-4%) and pH values (5.5-6.5) according to a central composite rotatable design. After extraction, the protein was concentrated by isoelectric precipitation. The optimal conditions for maximum protein content and recovery in protein concentrate were 53 degrees C, pH 6.2 and 4% of enzyme concentration. Under these conditions, protein content of 56% (dry weight basis) and a recovery of 28% were obtained, representing an increase of 17 and 86%, respectively, compared to the sample with no enzymatic pretreatment. The multi enzyme complex Viscozyme hydrolyzed the structural cell wall polysaccharides, improving extraction and obtaining protein concentrate from the okara. An electrophoretic profile of the protein concentrate showed two distinct bands, corresponding to the acidic and basic subunits of the protein glycinin. There were no limiting amino acids in the protein concentrate, which had a greater content of arginine. PMID- 29606766 TI - Okara residue as source of antioxidants against lipid oxidation in milk enriched with omega-3 and bioavailability of bioactive compounds after in vitro gastrointestinal digestion. AB - The residue from soy processing (okara) was evaluated for phenolic compounds, flavonoids, radical scavenging activity and reducing power ability. The ability of okara to decelerate the oxidation of omega-3 fatty acids caused by light exposure in a milk matrix, as well as its bioavailability after in vitro digestion, were investigated. Okara contained phenolic compounds (106.7 mg gallic acid equivalents (GAE)/100 g) and flavonoids (32.7 mg quercetin equivalents/100 g) and showed antioxidant activity. The addition of okara to omega-3 fatty acids enriched milk inhibited the production of conjugated dienes and malonaldehyde during 8 days of storage compared to the control (without okara), particularly at the higher (3 g/L) than lower inclusion concentrations studied (1 and 2 g/L). The bioavailability assay demonstrated that polyphenols (41 mg GAE/100 g) were still present after in vitro digestion and had antioxidant activity. Okara, which is considered a residue and is discarded, can potentially be used as an antioxidant ingredient for the enrichment of foods. PMID- 29606767 TI - Evaluation and application of prebiotic and probiotic ingredients for development of ready to drink tea beverage. AB - Ready-to-drink (RTD) ice tea is a ready prepared tea, produced from green and black tea originating from same plant Camellia sinensis. The objective of this study was to determine the effect of prebiotics [galacto-oligosaccharide (GOS), fructo-oligosaccharide (FOS), and inulin] or synbiotic ingredients (GOS, FOS, inulin, and Lactobacillus acidophilus) on the sensory properties and consumer acceptability of RTD. The quality of green tea extract (GTE) and black tea extract (BTE) was improved with pretreatment of cellulase and pectinase enzymes. The combined enzymatic extraction amplified total extractives up to 76% in GTE and 72% in BTE. Total polyphenol was found to be enhanced to 24% in GTE and 19% in BTE. GTE was further selected for development of RTD in two different formats; synbiotic RTD and prebiotic RTD premix and analyzed for sensory attributes (colour, aroma, taste, and acceptability). Synbiotic RTD was also evaluated for stability over a period of 28 days at 4 degrees C. Synbiotic RTD developed an unpleasant flavor and aroma during the shelf life. Premix format of RTD developed using spray drying was reconstituted and found to be functionally and sensorially acceptable. PMID- 29606768 TI - Combination of peracetic acid and ultrasound reduces Salmonella Typhimurium on fresh lettuce (Lactuca sativa L. var. crispa). AB - Salmonella outbreaks related to fruits and vegetables have been reported being lettuce one of the most contaminated. Peracetic acid (PA) at 50 mg/L, sodium dichloroisocyanurate (SD) at 100 mg/L, and the combination of SD at 100 mg/L and babacu coconut (Attalea speciosa) oil detergent at 100 mg/L were applied to fresh lettuce. Natural contaminant microbiota, physicochemical characteristics, and sensory attributes were evaluated. PA and SD reduced mesophilic aerobic counts by 2.1 and 1.5 log cfu/g, respectively. The most efficient treatment in reducing natural microbiota (i.e., PA) was applied alone and in combination with ultrasound (US). It reduced Salmonella enterica Typhimurium counts to undetectable levels (< 1 log cfu/g). US further reduced S. Typhimurium counts by 0.6 log cfu/g in relation to PA, treatment which lessened the pH but increased the titratable acidity of lettuce, but did not cause total color difference. Therefore, the combination of PA and US holds a potential industrial application for sanitization purposes. PMID- 29606769 TI - Metabolite characterization of different palm date varieties and the correlation with their NO inhibitory activity, texture and sweetness. AB - The aim of this study was to examine the variation in metabolite constituents of five commercial varieties of date fruits; Ajwa, Safawi and Ambar which originated from Madinah, the Iranian Bam and Tunisian Deglet Noor. The differences of metabolome were investigated using proton nuclear magnetic resonance (1H NMR) spectroscopy combined with multivariate data analysis (MVDA). Principal Component Analysis (PCA) revealed clear separation between the date varieties. The Tunisian Deglet Noor demonstrated distinct cluster from the rest of the palm date samples based on the metabolite composition as shown by the pattern observed in Hierarchical Clustering Analysis (HCA) and PCA. Deglet Noor exhibited a significant higher level of sucrose (delta 5.40) and fructose (delta 4.16) in comparison with the other four varieties which can be associated with the distinctive sweet taste of this variety. Dates originated from Madinah and Tunisia exhibited a contrast manner in the amount of xylose and moisture content. These two aspects may contribute towards the soft texture of Tunisian dates. All Madinah dates were found to contain phenolic compounds which were well established as great antioxidant and anti-inflammatory agent. Ajwa dates exerted greater effect in inhibiting the generation of nitric oxide (NO) from the stimulated RAW264.7 cells at 95.37% inhibition. Succinic acid was suggested to have the most significant correlation with the trend of NO inhibitory shown by the selected date palm varieties. PMID- 29606770 TI - Analysis of fatty acid methyl esters and oxidative stability of seed purpose watermelon (Citrullus lanatus) genotypes for edible oil. AB - World's vegetable oil demand is increasing day by day and oil seed supply is limited to a dozen oil seed crops on commercial scale. Efforts were made to explore the potential of water melon a traditionally grown native crop of Indian arid zone having oil content over 30% and seed yield potential of 500-600 kg per hectare under rainfed conditions. An analysis was carried out to explore the suitability of watermelon [Citrullus lanatus (Thunb.)] oil for human consumption on the basis of fatty acid (FA) composition in selected genotypes. Total oil content ranged between 10.0 and 31.0%. Eleven FA were identified in seed oil. Linoleic, stearic, palmitic and oleic acid were found as major FA while myristic, heptadecanoic, arachidic, 9-hexadecenoic and 14-eicosenoic acid was present in traces. Linoleic acid single polyunsaturated FA contributor found in the range of 43.95% (WM-44) to 55.29% (WM-18). Saturated FA content ranged between 32.24 and 37.61%. Significant genetic variation was observed for mono-unsaturated FA. Metabolic capacity to inter-conversion of FA and nutritive value of watermelon oil was described on the basis of ratio of FA group. Total phenolics, antioxidant activity, peroxide value and oxidizability were also estimated along with oxidative stability of oil. Multivariate analysis showed that, oil content has positive correlation with linoleic acid. The Euclidean based UPGMA clustering revealed that genotypes WM-18 is most suitable for trait specific breeding program for high linoleic acid (n-6), desaturation ratio and oleic desaturation ratio with higher oil content and lowest palmitic acid. PMID- 29606771 TI - Effect of black cumin oil on the oxidative stability and sensory characteristics of mayonnaise. AB - Mayonnaise is one of the most commonly used sauces all over the world but it is vulnerable to oxidation because of its high oil content. Using natural antioxidants instead of synthetic ones is a popular and promising topic in the food industry. The aim of this study was to increase the oxidative stability of mayonnaise using cold-pressed black cumin oil (BCO), which has high antioxidant activity due to its phenolic content. Four different mayonnaise formulations were used: Mayo-Control, Mayo-5% BCO, Mayo-10% BCO, and Mayo-20% BCO, which refer to a 0 (control), 5, 10, and 20% BCO replacement of total sunflower oil content, respectively. Thymoquinone content of the mayonnaises including BCO increased with the increasing BCO ratios. At the end of the storage for 4 weeks at 20 degrees C, peroxide values of Mayo-Control, Mayo-5% BCO, Mayo-10% BCO, and Mayo 20% BCO samples were recorded as 36.07 +/- 1.51, 26.76 +/- 0.67, 25.60 +/- 0.57, and 17.66 +/- 1.93 meq O2/kg oil, respectively. The conjugated diene and triene values of the mayonnaises prepared by adding BCO were lower than those of the control group during storage. Overall acceptability of Mayo-5% BCO in sensory analysis was higher than that of Mayo-Control. Using BCO in mayonnaise improved its oxidative stability and flavor. PMID- 29606772 TI - An investigation on the relationship among marbling features, physiological age and Warner-Bratzler Shear force of steer longissimus dorsi muscle. AB - Researchers nowadays have paid much attention to the relationships between tenderness and marbling, or physiological age. While the marbling was mainly evaluated qualitatively with scores or grades, and rarely related with physiological age. Present study was carried out to analyze the marbling features of longissimus dorsi muscle between the 12th and 13th ribs from 18, 36, 54 and 72 months old Simmental steers were quantitatively described with area and perimeter using computer vision technique. Relationship between Warner-Bratzler Shear force (WBSF), physiological age and the marbling features were examined performing regression analysis. The results revealed that WBSF positively correlated with physiological age, but negatively with marbling area and perimeter. Regression analysis showed that the relationship between the shear force and the steers' age was more close to the quadratic curve (R2 = 0.996) and exponential curve (R2 = 0.957). It was observed during study that marbling grew with steers age. Marbling features were in linear correlation with the steers' age, with R2 = 0.927 for marbling area and R2 = 0.935 for marbling perimeter. The industries in future may speculate beef tenderness and physiological age based on the marbling features (area and perimeter), which can be determined through the online image acquisition system and image processing. PMID- 29606773 TI - Rheological properties of kuzu starch pastes with galactomannans. AB - The paper describes the effects of galactomannans on viscoelastic properties of commercial Japanese white kuzu starch pastes. The study included morphological, thermal and rheological analyses of the biopolymer. The results obtained in the form of storage modulus G'(omega) and loss modulus G"(omega) were described by the modified fractional Kelvin-Voigt model with two springpot-type elements, created on the basis of differential calculus of fractional order and Fourier transform. It allowed to determine 17 material parameters providing a lot of additional information about structure and viscoelastic properties of the biopolymer in comparison to the classical analysis of oscillatory and creep tests. The study led to the conclusion that commercial Japanese white kuzu starch was so-called type II starch with a high pasting temperature of 75 degrees C and an average granule diameter equal to 10.9 MUm. Rheological properties of the pastes depended on the galactose-to-mannose ratio in galactomannan molecule. The larger substitution degree, the higher viscosity, characteristic relaxation times, polydispersity index, gel stiffness, and the lower cross-linking density and average molecular weights. The presence of galactose side groups favored the hydration and immobilization of water molecules. PMID- 29606774 TI - Assessing the fatty acid, essential oil composition, their radical scavenging and antibacterial activities of Schinus terebinthifolius Raddi leaves and twigs. AB - The fatty acid, essential oil compositions and their respective antioxidant and antibacterial activities was determined in Schinus terebinthifolius Raddi leaves and twigs. The lipid content ranged from 1.75 to 4.65% in twigs and leaves, respectively. Thirteen fatty acids were identified with alpha-linolenic (C18:3), palmitic (C16:0) and linoleic (C18:2) acids being the main components. The essential oils of both organs were characterized by a high amount of monoterpene hydrocarbons (68.91-74.88%) with alpha-phellandrene (33.06-36.18%), alpha-pinene (14.85-15.18%) and limonene (6.62-8.79%) being the chief components. The DPPH radical scavenging assay revealed that both oils have a very weak antiradical activity. In contrast, they showed an appreciable antibacterial activity against the gram-positive Enterococcus feacium (ATCC 19434) and Streptococcus agalactiae (ATCC 13813) bacteria. These results suggest that leaves and twigs of S. terebinthifolius could be considered as an important dietary source of health promoting phytochemicals and has a good potential for use in food industry and pharmacy. PMID- 29606775 TI - Effect of soaking and temperature process on the volatile compounds in soymilk made by soymilk maker. AB - Abstract: The influence of different processing and storage conditions on the aroma and taste of soymilk were investigated. Volatile components in soymilk were made by soymilk machine, half soybeans produced by grinding soaked with water, the other half soybeans without soaking. Then the soymilk was stored in different conditions for 24 h. Dynamic headspace dilution analysis and aroma extract dilution analysis in conjunction and gas chromatography-olfactometry-mass spectrometry were used to identify major aroma-active compounds. Sixteen odor active compounds were identified in dry milling soymilk, while 21 odor-active compounds for wet milling one (smell was also more intense), among them, (E)-2 decanal (fatty, green), (E)-2-nonenal (sweet, fruity), 2-acetyl-1-pyrroline (popcorn), having the highest FD factors in SDE extract, were regarded as the most important odorants in soymilk. Investigation of the volatile components was affected to a greater extent by hot soymilk compared with refrigerated or frozen storage. Sensory results showed that intensities of overall aroma, flower aromatic, flour were affected by the soaking and storage. Graphical Abstract: PMID- 29606777 TI - Stroke Literature Synopses: Basic Science (2017/Dec). PMID- 29606778 TI - Structure of Methanol Solvated Iodozinc(II) Complexes in Solution. AB - The structures of the solvated zinc ion and the solvated zinc-iodide complexes in methanol solution have been determined by EXAFS. The zinc ion is six-coordinated in an octahedral fashion with a mean Zn-O bond distance of 2.071(4) A. According to the stability constants of the zinc-iodide system in methanol solution the first complex, ZnI+, is suppressed, which may indicate that a coordination change takes place at this step. On the other hand, the second complex, ZnI2, predominates at excess of iodide. The methanol solvated ZnI2 complex has a tetrahedral structure with mean Zn-I and Zn-O bond distances of 2.55(1) and 1.99(1) A, respectively. The mean Zn-I bond distance in a solution containing a maximal content of ZnI+, ca. 12%, strongly indicates that the first complex also has a tetrahedral structure. PMID- 29606776 TI - The Value of Clean Air: Comparing Discounting of Delayed Air Quality and Money Across Magnitudes. AB - The detrimental health effects of exposure to air pollution are well established. Fostering behavioral change concerning air quality may be challenging because the detrimental health effects of exposure to air pollution are delayed. Delay discounting, a measure of impulsive choice, encapsulates this process of choosing between the immediate conveniences of behaviors that increase pollution and the delayed consequences of prolonged exposure to poor air quality. In Experiment 1, participants completed a series of delay-discounting tasks for air quality and money. We found that participants discounted delayed air quality more than money. In Experiment 2, we investigated whether the common finding that large amounts of money are discounted less steeply than small amounts of money generalized to larger and smaller improvements in air quality. Participants discounted larger improvements in air quality less steeply than smaller improvements, indicating that the discounting of air quality shares a similar process as the discounting of money. Our results indicate that the discounting of delayed money is strongly related to the discounting of delayed air quality and that similar mechanisms may be involved in the discounting of these qualitatively different outcomes. These data are also the first to demonstrate the malleability of delay discounting of air quality, and provide important public health implications for decreasing delay discounting of air quality. PMID- 29606779 TI - Reports of Therapy Skill Use and Their Efficacy in Daily Life in the Short-term Treatment of Depression. AB - Previous studies have shown that the use of therapy skills in between sessions is an important mechanism of symptom improvement. The current study expands this line of research by using a diary approach to examine the use of therapy skills in daily life. A sample of 39 depressed adults (85% female, mean age 38) were signaled twice per week throughout the course of either cognitive-behavioral therapy (CBT) or self-system therapy (SST). Results showed that, on days when participants reported greater use of therapy skills, they reported better mood and functioning in almost all domains. Additionally, participants in CBT reported greater use of cognitive skills while participants in SST reported greater use of self-regulatory skills. This study demonstrates that repeated assessments of daily events and experiences, which prevent retrospective reporting biases, further confirm the importance of therapy skill use as a mechanism of action in psychotherapy. PMID- 29606780 TI - Estimation of the Continuous and Discontinuous Leverage Effects. AB - This paper examines the leverage effect, or the generally negative covariation between asset returns and their changes in volatility, under a general setup that allows the log-price and volatility processes to be Ito semimartingales. We decompose the leverage effect into continuous and discontinuous parts and develop statistical methods to estimate them. We establish the asymptotic properties of these estimators. We also extend our methods and results (for the continuous leverage) to the situation where there is market microstructure noise in the observed returns. We show in Monte Carlo simulations that our estimators have good finite sample performance. When applying our methods to real data, our empirical results provide convincing evidence of the presence of the two leverage effects, especially the discontinuous one. PMID- 29606781 TI - SEDA: A tunable Q-factor wavelet-based noise reduction algorithm for multi-talker babble. AB - We introduce a new wavelet-based algorithm to enhance the quality of speech corrupted by multi-talker babble noise. The algorithm comprises three stages: The first stage classifies short frames of the noisy speech as speech-dominated or noise-dominated. We design this classifier specifically for multi-talker babble noise. The second stage performs preliminary de-nosing of noisy speech frames using oversampled wavelet transforms and parallel group thresholding. The final stage performs further denoising by attenuating residual high frequency components in the signal produced by the second stage. A significant improvement in intelligibility and quality was observed in evaluation tests of the algorithm with cochlear implant users. PMID- 29606783 TI - A Cladist is a systematist who seeks a natural classification: some comments on Quinn (2017). AB - In response to Quinn (Biol Philos, 2017. 10.1007/s10539-017-9577-z) we identify cladistics to be about natural classifications and their discovery and thereby propose to add an eighth cladistic definition to Quinn's list, namely the systematist who seeks to discover natural classifications, regardless of their affiliation, theoretical or methodological justifications. PMID- 29606784 TI - Binary Classifier Calibration Using an Ensemble of Piecewise Linear Regression Models. AB - In this paper we present a new non-parametric calibration method called ensemble of near isotonic regression (ENIR). The method can be considered as an extension of BBQ (Pakdaman Naeini, Cooper and Hauskrecht, 2015b), a recently proposed calibration method, as well as the commonly used calibration method based on isotonic regression (IsoRegC) (Zadrozny and Elkan, 2002). ENIR is designed to address the key limitation of IsoRegC which is the monotonicity assumption of the predictions. Similar to BBQ, the method post-processes the output of a binary classifier to obtain calibrated probabilities. Thus it can be used with many existing classification models to generate accurate probabilistic predictions. We demonstrate the performance of ENIR on synthetic and real datasets for commonly applied binary classification models. Experimental results show that the method outperforms several common binary classifier calibration methods. In particular, on the real data we evaluated, ENIR commonly performs statistically significantly better than the other methods, and never worse. It is able to improve the calibration power of classifiers, while retaining their discrimination power. The method is also computationally tractable for large scale datasets, as it is O(N logN) time, where N is the number of samples. PMID- 29606782 TI - Self domestication and the evolution of language. AB - We set out an account of how self-domestication plays a crucial role in the evolution of language. In doing so, we focus on the growing body of work that treats language structure as emerging from the process of cultural transmission. We argue that a full recognition of the importance of cultural transmission fundamentally changes the kind of questions we should be asking regarding the biological basis of language structure. If we think of language structure as reflecting an accumulated set of changes in our genome, then we might ask something like, "What are the genetic bases of language structure and why were they selected?" However, if cultural evolution can account for language structure, then this question no longer applies. Instead, we face the task of accounting for the origin of the traits that enabled that process of structure creating cultural evolution to get started in the first place. In light of work on cultural evolution, then, the new question for biological evolution becomes, "How did those precursor traits evolve?" We identify two key precursor traits: (1) the transmission of the communication system through learning; and (2) the ability to infer the communicative intent associated with a signal or action. We then describe two comparative case studies-the Bengalese finch and the domestic dog-in which parallel traits can be seen emerging following domestication. Finally, we turn to the role of domestication in human evolution. We argue that the cultural evolution of language structure has its origin in an earlier process of self-domestication. PMID- 29606785 TI - Validation of parameter estimation methods for determining optical properties of atherosclerotic tissues in intravascular OCT. AB - In this paper we present a new process for assessing optical properties of tissues from 3D pullbacks, the standard clinical acquisition method for iOCT data. Our method analyzes a volume of interest (VOI) consisting of about 100 A lines spread across the angle of rotation (theta) and along the artery, z. The new 3D method uses catheter correction, baseline removal, speckle noise reduction, alignment of A-line sequences, and robust estimation. We compare results to those from a more standard, "gold standard" stationary acquisition where many image frames are averaged to reduce noise. To do these studies in a controlled fashion, we use a realistic optical artery phantom containing of multiple "tissue types." Precision and accuracy for 3D pullback analysis are reported. Our results indicate that when implementing the process on a stationary acquisition dataset, the uncertainty improves at each stage while the uncertainty is reduced. When comparing stationary acquisition dataset to pullback dataset, the values were as follows: calcium: 3.8+/-1.09mm-1 in stationary and 3.9+/-1.2 mm-1 in a pullback; lipid: 11.025+/-0.417 mm-1 in stationary and 11.27+/-0.25 mm 1 in pullback; fibrous: 6.08+/-1.337 mm-1 in stationary and 5.58+/-2.0 mm-1 . These results indicates that the process presented in this paper introduce minimal bias and only a small change in uncertainty when comparing a stationary and pullback dataset, thus paves the way to a highly accurate clinical plaque type discrimination, enabling automatic classification. PMID- 29606786 TI - Classification of calcium in intravascular OCT images for the purpose of intervention planning. AB - The presence of extensive calcification is a primary concern when planning and implementing a vascular percutaneous intervention such as stenting. If the balloon does not expand, the interventionalist must blindly apply high balloon pressure, use an atherectomy device, or abort the procedure. As part of a project to determine the ability of Intravascular Optical Coherence Tomography (IVOCT) to aid intervention planning, we developed a method for automatic classification of calcium in coronary IVOCT images. We developed an approach where plaque texture is modeled by the joint probability distribution of a bank of filter responses where the filter bank was chosen to reflect the qualitative characteristics of the calcium. This distribution is represented by the frequency histogram of filter response cluster centers. The trained algorithm was evaluated on independent ex-vivo image data accurately labeled using registered 3D microscopic cryo-image data which was used as ground truth. In this study, regions for extraction of sub-images (SI's) were selected by experts to include calcium, fibrous, or lipid tissues. We manually optimized algorithm parameters such as choice of filter bank, size of the dictionary, etc. Splitting samples into training and testing data, we achieved 5-fold cross validation calcium classification with F1 score of 93.7+/-2.7% with recall of >=89% and a precision of >=97% in this scenario with admittedly selective data. The automated algorithm performed in close-to-real-time (2.6 seconds per frame) suggesting possible on line use. This promising preliminary study indicates that computational IVOCT might automatically identify calcium in IVOCT coronary artery images. PMID- 29606787 TI - Exposure to predators reduces collective foraging aggressiveness and eliminates its relationship with colony personality composition. AB - Predation is a ubiquitous threat that often plays a central role in determining community dynamics. Predators can impact prey species by directly consuming them, or indirectly causing prey to modify their behavior. Direct consumption has classically been the focus of research on predator-prey interactions, but substantial evidence now demonstrates that the indirect effects of predators on prey populations are at least as strong as, if not stronger than, direct consumption. Social animals, particularly those that live in confined colonies, rely on coordinated actions that may be vulnerable to the presence of a predator, thus impacting the society's productivity and survival. To examine the effect of predators on the behavior of social animal societies, we observed the collective foraging of social spider colonies (Stegodyphus dumicola) when they interact with dangerous predatory ants either directly, indirectly, or both. We found that when colonies were exposed directly and indirectly to ant cues, they attacked prey with approximately 40-50% fewer spiders, and 40-90% slower than colonies that were not exposed to any predator cues. Furthermore, exposure to predatory ants disassociated the well-documented positive relationship between colony behavioral composition (proportion of bold spiders) and foraging aggressiveness (number of attackers) in S. dumicola, which is vital for colony growth. Thus, the indirect effects of predator presence may limit colony success. These results suggest that enemy presence could compromise the organizational attributes of animal societies. PMID- 29606789 TI - Generalizations of the short pulse equation. AB - We classify integrable scalar polynomial partial differential equations of second order generalizing the short pulse equation. PMID- 29606788 TI - Chemical composition of axillary odorants reflects social and individual attributes in rhesus macaques. AB - Abstract: Scents play an important role in the life of most terrestrial mammals and may transmit valuable information about conspecifics. Olfaction was long considered of low importance in Old World monkeys due to their relative reduction of olfactory structures and low incidence of scent-marking behavior but has been increasingly recognized for mediating social relationships in recent years. Yet, studies investigating the composition of their chemical cues remain scarce. In the present study, we analyzed the potential information content of chemicals present on the skin of rhesus macaques (Macaca mulatta). We collected axillary secretions from 60 animals of the semifree-ranging population on Cayo Santiago (Puerto Rico, USA) with precleaned cotton swabs from which the secretions were subsequently extracted and analyzed by gas chromatography-mass spectrometry. Rhesus macaque axillary odorants varied in their overall similarity and composition. This variation was attributable to differences in sex, group membership, and kinship and further appeared to reflect age and rank in parts of our sample. The compounds most strongly associated with this variation primarily comprised larger molecular weight aldehydes and steroids. Such compounds are considered to be perceivable by the primate olfactory system through close-range interactions or through breakdown into smaller molecules by bacterial fermentation. Overall, our results provide additional evidence that odors of Old World monkeys reflect a wealth of potential information about their carrier, which provides the basis for chemical communication via body odors; however, its use by conspecifics needs to be confirmed in bioassays. Significance statement: One prerequisite for olfactory communication is the presence of systematic variation in animal odors that is related to attributes such as age, sex, or kinship. The composition of odors has been examined in numerous mammals but, with the exception of humans, remains poorly understood in Old World monkeys and apes, taxonomic groups in which most species do not show scent-marking behavior. In the present study, we show that the composition of axillary secretions of an Old World monkey, the rhesus macaque, reflects sex, group membership, relatedness, and possibly also age and rank. This variation thus provides a basis for olfactory communication in Old World monkeys. PMID- 29606790 TI - Magnetic zero-modes, vortices and Cartan geometry. AB - We exhibit a close relation between vortex configurations on the 2-sphere and magnetic zero-modes of the Dirac operator on [Formula: see text] which obey an additional nonlinear equation. We show that both are best understood in terms of the geometry induced on the 3-sphere via pull-back of the round geometry with bundle maps of the Hopf fibration. We use this viewpoint to deduce a manifestly smooth formula for square-integrable magnetic zero-modes in terms of two homogeneous polynomials in two complex variables. PMID- 29606791 TI - On the effective field theory of heterotic vacua. AB - The effective field theory of heterotic vacua that realise [Formula: see text] preserving [Formula: see text] supersymmetry is studied. The vacua in question admit large radius limits taking the form [Formula: see text], with [Formula: see text] a smooth threefold with vanishing first Chern class and a stable holomorphic gauge bundle [Formula: see text]. In a previous paper we calculated the kinetic terms for moduli, deducing the moduli metric and Kahler potential. In this paper, we compute the remaining couplings in the effective field theory, correct to first order in [Formula: see text]. In particular, we compute the contribution of the matter sector to the Kahler potential and derive the Yukawa couplings and other quadratic fermionic couplings. From this we write down a Kahler potential [Formula: see text] and superpotential [Formula: see text]. PMID- 29606792 TI - Ultrahigh vacuum dc magnetron sputter-deposition of epitaxial Pd(111)/Al2O3(0001) thin films. AB - Pd(111) thin films, ~245 nm thick, are deposited on Al2O3(0001) substrates at ~0.5Tm, where Tm is the Pd melting point, by ultrahigh vacuum dc magnetron sputtering of Pd target in pure Ar discharges. Auger electron spectra and low energy electron diffraction patterns acquired in situ from the as-deposited samples reveal that the surfaces are compositionally pure 111-oriented Pd. Double axis x-ray diffraction (XRD) omega-2theta scans show only the set of Pd 111 peaks from the film. In triple-axis high-resolution XRD, the full width at half maximum intensity Gammaomega of the Pd 111 omega-rocking curve is 630 arc sec. XRD 111 pole figure obtained from the sample revealed six peaks 60 degrees -apart at a tilt angles corresponding to Pd 111 reflections. XRD phi scans show six 60 degrees -rotated 111 peaks of Pd at the same phi angles for 11[Formula: see text]3 of Al2O3 based on which the epitaxial crystallographic relationships between the film and the substrate are determined as [Formula: see text]||[Formula: see text] with two in-plane orientations of [Formula: see text]||[Formula: see text] and [Formula: see text]||[Formula: see text]. Using triple axis symmetric and asymmetric reciprocal space maps, interplanar spacings of out-of-plane (111) and in-plane (11[Formula: see text]) are found to be 0.2242 +/- 0.0003 and 0.1591 +/- 0.0003 nm, respectively. These values are 0.18% lower than 0.2246 nm for (111) and the same, within the measurement uncertainties, as 0.1588 nm for (11[Formula: see text]) calculated from the bulk Pd lattice parameter, suggesting a small out-of-plane compressive strain and an in-plane tensile strain related to the thermal strain upon cooling the sample from the deposition temperature to room temperature. High-resolution cross-sectional transmission electron microscopy coupled with energy dispersive x-ray spectra obtained from the Pd(111)/Al2O3(0001) samples indicate that the Pd-Al2O3 interfaces are essentially atomically abrupt and dislocation-free. These results demonstrate the growth of epitaxial Pd thin films with (111) out-of-plane orientation with low mosaicity on Al2O3(0001). PMID- 29606793 TI - Quionolone carboxylic acid derivatives as HIV-1 integrase inhibitors: Docking based HQSAR and topomer CoMFA analyses. AB - Quionolone carboxylic acid derivatives as inhibitors of HIV-1 integrase were investigated as a potential class of drugs for the treatment of acquired immunodeficiency syndrome (AIDS). Hologram quantitative structure-activity relationships (HQSAR) and translocation comparative molecular field vector analysis (topomer CoMFA) were applied to a series of 48 quionolone carboxylic acid derivatives. The most effective HQSAR model was obtained using atoms and bonds as fragment distinctions: cross-validation q2 = 0.796, standard error of prediction SDCV = 0.36, the non-cross-validated r2 = 0.967, non-cross validated standard error SD = 0.17, the correlation coefficient of external validation Qext2 = 0.955, and the best hologram length HL = 180. topomer CoMFA models were built based on different fragment cutting models, with the most effective model of q2 = 0.775, SDCV = 0.37, r2 = 0.967, SD = 0.15, Qext2 = 0.915, and F = 163.255. These results show that the models generated form HQSAR and topomer CoMFA were able to effectively predict the inhibitory potency of this class of compounds. The molecular docking method was also used to study the interactions of these drugs by docking the ligands into the HIV-1 integrase active site, which revealed the likely bioactive conformations. This study showed that there are extensive interactions between the quionolone carboxylic acid derivatives and THR80, VAL82, GLY27, ASP29, and ARG8 residues in the active site of HIV-1 integrase. These results provide useful insights for the design of potent new inhibitors of HIV-1 integrase. PMID- 29606794 TI - A Multistage Fluidized Bed for the Deep Removal of Sour Gases: Proof of Concept and Tray Efficiencies. AB - Currently there are significant amounts of natural gas that cannot be produced and treated to meet pipeline specifications, because that would not be economically viable. This work investigates a bench scale multistage fluidized bed (MSFB) with shallow beds for sour gas removal from natural gas using a commercially available supported amine sorbent. A MSFB is regarded as a promising adsorber type for deep sour gas removal to parts per million concentrations. A series of experiments was conducted using carbon dioxide as sour gas and nitrogen to mimic natural gas. Removal below 3 mol ppm was successfully demonstrated. This indicates that gas bypassing is minor (that is, good gas-solid contacting) and that apparent adsorption kinetics are fast for the amine sorbent applied. Tray efficiencies for a chemisorption/adsorption system were reported for one of the first times. Current experiments performed at atmospheric pressure strongly indicate that deep removal is possible at higher pressures in a multistage fluidized bed. PMID- 29606795 TI - The Influence of Internal Migration on Exposure to Extreme Weather Events in Mexico. PMID- 29606796 TI - Dynamics of the Disrupted 2015-16 Quasi-Biennial Oscillation. AB - A significant disruption of the Quasi-Biennial Oscillation (QBO) occurred during the Northern Hemisphere (NH) winter of 2015-16. Since the QBO is the major wind variability source in the tropical lower stratosphere and influences the rate of ascent of air entering the stratosphere, understanding the cause of this singular disruption may provide new insights into the variability and sensitivity of the global climate system. Here we examine this disruptive event using global reanalysis winds and temperatures from 1980-2016. Results reveal record maxima in tropical horizontal momentum fluxes and wave forcing of the tropical zonal mean zonal wind over the NH 2015-16 winter. The Rossby waves responsible for these record tropical values appear to originate in the NH and were focused strongly into the tropics at the 40 hPa level. Two additional NH winters, 1987-88 and 2010 11 were also found to have large, tropical lower stratosphere, momentum flux divergences; however, the QBO westerlies did not change to easterlies in those cases. PMID- 29606798 TI - Popcorn-Shaped Fe x O (Wustite) Nanoparticles from a Single-Source Precursor: Colloidal Synthesis and Magnetic Properties. AB - Colloidal nanoparticles (NPs) with myriads of compositions and morphologies have been synthesized and characterized in recent years. For wustite Fe x O, however, obtaining phase-pure NPs with homogeneous morphologies have remained challenging. Herein, we report the colloidal synthesis of phase-pure Fe x O (x ~ 0.94) popcorn shaped NPs by decomposition of a single-source precursor, [Fe3(MU3-O)(CF3COO)(MU CF3COO)6(H2O)2].CF3COOH. The popcorn shape and multigrain structure had been reconstructed using high-angle annular dark-field scanning transmission electron micrograph (HAADF-STEM) tomography. This morphology offers a large surface area and internal channels and prevents further agglomeration and thermal tumbling of the subparticles. [Fe3(MU3-O)(CF3COO)(MU-CF3COO)6(H2O)2].CF3COOH behaves as an antiferromagnetic triangle whose magnetic frustration is mitigated by the low symmetry of the complex. The popcorn-shaped Fe x O NPs show the typical wustite antiferromagnetic transition at approximately 200 K, but behave very differently to their bulk counterpart below 200 K. The magnetization curves show a clear, unsymmetrical hysteresis, which arises from a combined effect of the superparamagnetic behavior and exchange bias. PMID- 29606797 TI - Surface-Engineered Cationic Nanocrystals Stable in Biological Buffers and High Ionic Strength Solutions. AB - Progress in colloidal synthesis in the last two decades has enabled high-quality semiconductor, plasmonic, and magnetic nanocrystals (NCs). As synthesized, these NCs are usually capped with long-chain apolar ligands. Postsynthetic surface functionalization is required for rendering such NCs colloidally stable in polar media such as water. However, unlike small anionic molecules and polymeric coatings, producing positively charged stable NCs, especially at high ionic strengths, has remained challenging. Here, we present a general approach to achieve aqueously stable cationic NCs using a set of small (<2.5 nm long) positively charged ligands. The applicability of this method is demonstrated for a variety of materials including semiconductor CdSe/CdS core/shell NCs, magnetic Fe@Fe3O4, Fe3O4, and FePt NCs, and three different classes of plasmonic Au NCs including large nanorods. The obtained cationic NCs typically have zeta potential values ranging from +30 to +60 mV and retain colloidal stability for days to months, depending on NC/ligand pair, in several biological buffers at elevated pH and in concentrated salt solutions. This allowed us to demonstrate site-specific staining of cellular structures using fluorescent cationic NCs with several different surface chemistries. Furthermore, colloidal stability of the obtained NCs in the presence of other charged species allowed the assembly of cationic and anionic counterparts driven primarily by electrostatic attraction. With this approach, we prepare highly uniform 3D and 2D binary mixtures of NCs through induced homogeneous aggregation and alternating-charge layer-by-layer deposition, respectively. Such binary mixtures may provide a new route in the engineering of nanocrystalline solids for electronics, thermoelectrics, and photovoltaics. PMID- 29606799 TI - Arrhenius Behavior of the Bulk Na-Ion Conductivity in Na3Sc2(PO4)3 Single Crystals Observed by Microcontact Impedance Spectroscopy. AB - NASICON-based solid electrolytes with exceptionally high Na-ion conductivities are considered to enable future all solid-state Na-ion battery technologies. Despite 40 years of research the interrelation between crystal structure and Na ion conduction is still controversially discussed and far from being fully understood. In this study, microcontact impedance spectroscopy combined with single crystal X-ray diffraction, and differential scanning calorimetry is applied to tackle the question how bulk Na-ion conductivity sigmabulk of sub-mm sized flux grown Na3Sc2(PO4)3 (NSP) single crystals is influenced by supposed phase changes (alpha, beta, and gamma phase) discussed in literature. Although we found a smooth structural change at around 140 degrees C, which we assign to the beta -> gamma phase transition, our conductivity data follow a single Arrhenius law from room temperature (RT) up to 220 degrees C. Obviously, the structural change, being mainly related to decreasing Na-ion ordering with increasing temperature, does not cause any jumps in Na-ion conductivity or any discontinuities in activation energies Ea. Bulk ion dynamics in NSP have so far rarely been documented; here, under ambient conditions, sigmabulk turned out to be as high as 3 * 10-4 S cm-1 at RT (Ea, bulk = 0.39 eV) when directly measured with microcontacts for individual small single crystals. PMID- 29606800 TI - Work-related nonfatal injuries in Alaska's aviation industry, 2000-2013. AB - Aviation is a critical component of life in Alaska, connecting communities off the road system across the state. Crash-related fatalities in the state are well understood and many intervention efforts have been aimed at reducing aircraft crashes and resulting fatalities; however, nonfatal injuries among workers who perform aviation-related duties have not been studied in Alaska. This study aimed to characterize hospitalized nonfatal injuries among these workers using data from the Alaska Trauma Registry. During 2000-2013, 28 crash-related and 89 non crash injuries were identified, spanning various occupational groups. Falls were a major cause of injuries, accounting for over half of non-crash injuries. Based on the study findings, aviation stakeholders should review existing policies and procedures regarding aircraft restraint systems, fall protection, and other injury prevention strategies. To supplement these findings, further study describing injuries that did not result in hospitalization is recommended. PMID- 29606801 TI - Subcutaneous lipomas: A minimally invasive method for resection of subcutaneous lipomas preserving retaining ligaments. AB - Background: Lipomas are common benign tumors usually located in the subcutaneous tissues. Resection of lipomas frequently requires incisions equal to the diameter of the tumor. The "squeeze technique" with a small incision is well-described, but is frequently not successful, particularly for lipomas in the shoulder region. We report a method for resection of subcutaneous lipomas that preserves retaining ligaments. Methods: Lipomas are characterized by high signal intensity on T1- and T2-weighted images on magnetic resonance imaging. Retaining ligaments demonstrate low signal intensity on T1-weighted images and high signal intensity on T2-weighted images with fat-suppression. Through a 1 in. incision, lipomas were detached from the retaining ligaments bluntly with a finger. Tumors were then extracted either in a piecemeal fashion or with the "squeeze technique." Complete lipoma resection was visually confirmed through the incisions. For the current report, we analyzed 18 large lipomas resected by this method, with "large" defined as equal to or greater than 5 cm in diameter. Results: The 18 patients included four males and 14 females with a mean age of 53.4 (26-72). The mean lipoma size was 6.6 cm (5-12). Locations included the shoulder in nine cases (50%), the upper arm in five cases (28%), the back in two cases (11%), and the thigh in two cases (11%). Retaining ligaments were identified by MRI in all cases. Lipomas were located between retaining ligaments at the periphery of the tumor. All three lipomas larger than 10 cm were located in the shoulder. There was no difference in the technical difficulty of resection of these compared with lipomas less than 10 cm in diameter. There were no cases of chronic pain or residual hypoesthesia at the incision sites. Conclusions: The method is an easy and minimally invasive way to achieve complete resection, even for large lipomas, regardless of anatomical location. The method may contribute to reduction of side effects including residual hypoesthesia and chronic pain at the incision site, due to the small incision and preservation of retaining ligaments, which may contain cutaneous nerves.Level of Evidence: Level IV, therapeutic study. PMID- 29606802 TI - Development and validation of a new assessment tool for suturing skills in medical students. AB - Background: In recent years, emphasis has been put on that medical student should demonstrate pre-practice/pre-registration core procedural skills to ensure patient safety. Nonetheless, the formal teaching and training of basic suturing skills to medical students have received relatively little attention and there is no standard for what should be tested and how. The aim of this study was to develop and validate, using scientific methods, a tool for assessment of medical students' suturing skills, measuring both micro- and macrosurgical qualities. Methods: A tool was constructed and content, construct, concurrent validity, and inter-rater, inter-item, inter-test reliability were tested. Three groups were included: students with no training in suturing skills, students who have had training, plastic surgery. Results: The results show promising reliability and validity when assessing novice medical students' suturing skills. Conclusions: Further studies are needed on implementation of the instrument. Moreover, how the instrument can be used to give formative feedback, evaluate if a required standard is met and for curriculum development needs further investigation.Level of Evidence: Not ratable. PMID- 29606803 TI - The double-pedicled dorsal-metacarpal-artery (dpDMCA) flap of the hand: a novel DMCA-derived flap. AB - : The dorsal-metacarpal-artery (DMCA) flap in its standard or extended version is considered as the working horse to cover dorsal soft tissue finger defects with exposed extensor tendon or bone. We hereby present a clinical case of an 80-year old male patient who is right-handed and sustained a soft tissue defect of the proximal dorsal aspect of his left 5th finger and the postoperative outcome employing a modified transposition flap. The double-pedicled DMCA flap (dpDMCA flap) of the hand poses in adequate clinical scenarios a comparably fast and safe solution to cover dorsal finger defects extending just distal to the PIP joint. To the best of our knowledge, this is the first report of a DMCA-based flap with a double pedicle to cover soft tissue defects at the dorsum of the hand. LEVEL OF EVIDENCE: Level V, therapeutic study. PMID- 29606804 TI - When is your experience valuable? Occupation-industry transitions and self employment success. AB - The literature on employee spinoffs has, for a long time, stressed the importance of industry-specific skills and experiences in explaining the success of new firms. We argue that employees also develop skills that are associated with their occupation within an industry, and that success as an entrepreneur, therefore, is also contingent on the relation between the entrepreneurs' previous occupation and the industry in which they operate as self-employed. Using matched employer employee data, we develop a measure, occupational spin-offs, that accounts for this relation. An occupational spin-off is defined as a start-up in the most common industry, given the previous occupation of the founder. We then show that entrepreneurs starting occupational spinoffs enjoy above average income from self employment and have longer spells as business owners. PMID- 29606805 TI - Evolutionarily stable conjectures and other regarding preferences in duopoly games. AB - We study the evolutionary selection of conjectures in duopoly games when players have other regarding preferences, i.e. preferences over payoff distributions. In both the Cournot and Bertrand duopoly games, the consistent conjectures are independent of other regarding preferences. Both duopoly games have evolutionarily stable conjectures that depend on other regarding preferences but that do not coincide with the consistent conjectures. For increasingly spiteful preferences, the evolutionarily stable conjectures implicate low quantities in the Cournot game and high prices in the Bertrand game, whereas the inverse relationships hold for the consistent conjectures. We discuss our findings in the context of ultimate and proximate causation. PMID- 29606806 TI - Escalating impacts of climate extremes on critical infrastructures in Europe. AB - Extreme climatic events are likely to become more frequent owing to global warming. This may put additional stress on critical infrastructures with typically long life spans. However, little is known about the risks of multiple climate extremes on critical infrastructures at regional to continental scales. Here we show how single- and multi-hazard damage to energy, transport, industrial, and social critical infrastructures in Europe are likely to develop until the year 2100 under the influence of climate change. We combine a set of high-resolution climate hazard projections, a detailed representation of physical assets in various sectors and their sensitivity to the hazards, and more than 1100 records of losses from climate extremes in a prognostic modelling framework. We find that damages could triple by the 2020s, multiply six-fold by mid-century, and amount to more than 10 times present damage of ?3.4 billion per year by the end of the century due only to climate change. Damage from heatwaves, droughts in southern Europe, and coastal floods shows the most dramatic rise, but the risks of inland flooding, windstorms, and forest fires will also increase in Europe, with varying degrees of change across regions. Economic losses are highest for the industry, transport, and energy sectors. Future losses will not be incurred equally across Europe. Southern and south-eastern European countries will be most affected and, as a result, will probably require higher costs of adaptation. The findings of this study could aid in prioritizing regional investments to address the unequal burden of impacts and differences in adaptation capacities across Europe. PMID- 29606807 TI - Social Vision: Applying a Social-Functional Approach to Face and Expression Perception. AB - A social-functional approach to face processing comes with a number of assumptions. First, given that humans possess limited cognitive resources, it assumes that we naturally allocate attention to processing and integrating the most adaptively relevant social cues. Second, from these cues, we make behavioral forecasts about others in order to respond in an efficient and adaptive manner. This assumption aligns with broader ecological accounts of vision that highlight a direct action-perception link, even for nonsocial vision. Third, humans are naturally predisposed to process faces in this functionally adaptive manner. This latter contention is implied by our attraction to dynamic aspects of the face, including looking behavior and facial expressions, from which we tend to overgeneralize inferences, even when forming impressions of stable traits. The functional approach helps to address how and why observers are able to integrate functionally related compound social cues in a manner that is ecologically relevant and thus adaptive. PMID- 29606808 TI - Clinical and Prognostic Significance of O6-Methylguanine-DNA Methyltransferase Promoter Methylation in Patients with Melanoma: A Systematic Meta-Analysis. AB - Tumor suppressor gene O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation has been reported in melanoma. However, the clinical and prognostic significance of MGMT promoter methylation in patients with melanoma remained to be determined. A systematic search was performed to identify eligible papers published. The overall odds ratios (ORs) or hazard ratios and their 95% confidence intervals were calculated. Final 12 eligible publications involving Caucasian population were performed in this study, including 1,071 metastatic melanoma patients, 154 primary melanoma patients, and 211 normal controls. MGMT promoter methylation was significantly higher in primary or metastatic melanoma than in normal controls (p<0.05). No difference of MGMT promoter methylation was found in primary and metastatic melanoma (p=0.432). When metastatic melanoma was compared to normal controls, subgroup analysis showed the correlation between MGMT promoter methylation and different sample materials (tissue: OR=7.01, p<0.001 and blood: OR=12.04, p=0.005). MGMT promoter methylation was not associated with response to drug therapy and the prognosis in overall survival and progression-free survival for multivariate analysis. Our results show that MGMT promoter methylation may be correlated with the increased risk of primary or metastatic melanoma. Based on blood samples, MGMT promoter methylation may become a noninvasive biomarker for the detection of metastatic melanoma. Further additional clinical studies are necessary. PMID- 29606809 TI - A Study on Vitamin D and Cathelicidin Status in Patients with Rosacea: Serum Level and Tissue Expression. AB - Background: Rosacea is a chronic inflammatory disease characterized by centrofacial erythema. Excess cathelicidin is suggested to be important to the pathophysiology of the disease. Recently, presence of a vitamin D response element was revealed in the cathelicidin gene promoter. Objective: The aim of this study was to determine whether vitamin D and cathelicidin are associated with rosacea, both serologically and histopathologically. Methods: Subjects with rosacea and without chronic skin disorders were enrolled in the patient and control groups, respectively. Serum 25-hydroxy-vitamin D and cathelicidin levels were measured. Tissue expression of cathelicidin and vitamin D receptor were measured with immunostaining-intensity-distribution index. Results: The mean serum 25-hydroxyvitamin D level of patients with rosacea was 12.18+/-5.65 ng/ml, which is lower than that of the controls (17.41+/-6.75 ng/ml). Mean serum cathelicidin levels in patients with rosacea and the controls were 85.0+/-26.1 ng/ml and 55.0+/-23.3 ng/ml, respectively. Cathelicidin expression in rosacea tissue was significantly higher than that in control tissue (5.21 vs. 4.03). No significant difference was observed in vitamin D receptor expression. Conclusion: Higher cathelicidin expression in rosacea supports the hypothesis that an abnormal inflammatory response of the innate immune system is important in pathogenesis of rosacea, but the role of high cathelicidin serum levels is complicated. Serum vitamin D was lower in patients with rosacea, although serum cathelicidin was higher than that of the controls. This suggests that the role of vitamin D level in the pathogenesis of rosacea merits further investigation. PMID- 29606810 TI - Risk Factors Affecting Adverse Effects of Cyclosporine A in a Real-World Psoriasis Treatment. AB - Background: No study to date has focused on the changes in laboratory test results and related risk factors in patients with psoriasis treated with prolonged Cyclosporine A (CsA) therapy. Objective: The objective of this study was to investigate the changes of laboratory values and related risk factors in patients with psoriasis treated with CsA in a real-world setting. Methods: Records of patients with psoriasis treated with CsA at an outpatient clinic were collected, and a Cox proportional hazards regression model was used. Results: Of the 128 patients included in this study, 28 patients (21.9%) showed laboratory test abnormalities over a mean medication period of 11.6 months. Older age (hazard ratio [HR], 1.174; 95% confidence interval [CI], 1.068~1.370; p=0.007) and pre-existing kidney disease (HR, 0.008; 95% CI, 0~0.205; p=0.001) significantly increased the risk of renal dysfunction. Male sex was the only significant risk factor for liver enzyme elevation (HR, 0.284; 95% CI, 0.081~0.784; p=0.026) and uric acid abnormality (HR, 0.048; 95% CI, 0~0.372; p=0.046). Conclusion: This is an in-depth analysis of laboratory changes and related risk factors in patients with psoriasis treated with CsA. Liver is the most commonly affected organ of CsA toxicity. Older age, male sex, and presence of kidney disease were risk factors associated with laboratory abnormality during CsA treatment. PMID- 29606811 TI - Can the Cytokine Analysis of the Scales on Alopecic Patch Predict the Response to Diphenylcyclopropenone Treatment in Alopecia Areata Patients? AB - Background: Contact immune modulating therapy with diphenylcyclopropenone (DPCP) is a topical treatment option for extensive alopecia areata (AA). Because the response to DPCP treatment varies according to the patient, and it takes several months to evaluate the clinical effectiveness of the treatment, it is necessary to identify the factors that can predict the prognosis of the disease while treating with topical DPCP. Objective: In this study, cytokine levels in the scales of alopecic patches were investigated to identify whether they could predict response to DPCP during the early treatment period. Methods: Scale samples were taken from the alopecic patches in eight AA patients at 1 week, 2 months, and 4 months after DPCP sensitization. The patients were divided into responders and non-responders according to the clinical responses of DPCP treatment. Interferon (IFN)-gamma, interleukin (IL)-2, IL-12 and IL-10 levels of the subjects were compared in several perspectives. Results: Cytokine levels after 1 week of DPCP sensitization showed no statistically significant difference between two groups. After 4 months of treatment, IFN-gamma levels were significantly lower in responders than in non-responders. Conclusion: The results of this study show IFN-gamma levels in the scales of alopecic patches might possibly reflect the clinical response in AA patients treated with DPCP. However, initial cytokine levels could not predict the treatment response. PMID- 29606812 TI - Usefulness of Inflammatory Markers for the Prediction of Postherpetic Neuralgia in Patients with Acute Herpes Zoster. AB - Background: Increasing evidence suggests a pivotal role for neuronal inflammation in response to replicating varicella zoster virus in the development of postherpetic neuralgia (PHN). Objective: In this study, we investigated the value of serum levels of various inflammatory markers in acute herpes zoster (HZ) as predictors for the development of PHN. Methods: A total of 116 patients with acute HZ were enrolled in this study. We measured scores on the pain visual analogue scale (VAS) at baseline and at 1, 3, and 6 months after diagnosis of HZ. We defined PHN as pain greater than 1 on the VAS lasting for more than 6 months. Serum samples for laboratory assay, including complete blood count were obtained at the initial visit. Correlations between the levels of each inflammatory marker and the development of PHN were evaluated. Results: Levels of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), lymphocyte count, and albumin showed significant correlations with development of PHN in univariate analysis. Levels of ESR, CRP, and lymphocyte count also showed significant correlations in multivariate analysis. ESR level showed stronger correlations with development of PHN than levels of CRP and lymphocyte count. Conclusion: In this study, we confirmed that elevated ESR was an independent and significant predictor of PHN in patients with acute HZ. To validate these results, further well-designed, randomized clinical trials are needed. PMID- 29606813 TI - A Histamine-Free Diet Is Helpful for Treatment of Adult Patients with Chronic Spontaneous Urticaria. AB - Background: In adult patients with chronic urticaria (CU), the prevalence of food allergy is low compared to childhood patients. However, there are many patients who report food-related aggravation of CU, and some of them may have histamine intolerance. Objective: The aim of this study was to evaluate the role of ingested histamine and to investigate the effect of a histamine-free diet in adult patients with CU. Methods: Twenty-two adult patients with CU were enrolled. Foods with high amounts of histamine were prohibited to all patients for four weeks. The degree of severity of the urticaria was evaluated using the urticaria severity score (USS) and urticaria activity score (UAS). Plasma histamine levels and diamine oxidase (DAO) activity were determined and compared before (baseline) and after the histamine-free diet. Results: Twenty-two adult patients were recruited and completed four weeks of histamine-free diet. The USS and UAS scores each showed significant differences before and after the histamine-free diet (p=0.010, p=0.006). There was a significant reduction in plasma histamine level after the histamine free-diet, compared with baseline (p=0.010). However, DAO activity did not change after the histamine-free diet (p=0.165). Conclusion: Our study suggested that ingested histamine might be related to CU severity and that a histamine-free diet is helpful for treatment of adult patients with CU. PMID- 29606814 TI - Topical Tacrolimus for the Treatment of Atopic Dermatitis with Truncal Lesion. AB - Background: Topical tacrolimus is an effective anti-inflammatory therapy for acute and chronic states of atopic dermatitis (AD) in both adults and children. Topical tacrolimus has particular use at sensitive areas such as the face, anogenitals, and skin folds of neck and extremities. However, many AD patients also experience aggravated symptoms on trunk. Objective: The aim of this study was to investigate the efficacy and safety of topical tacrolimus for AD patients with truncal lesions. Methods: AD patients with truncal lesions who were aged >=2 years were recruited from 20 centres in Korea. They received treatment with topical tacrolimus ointment twice daily during 4 weeks. The primary end point was change of the local eczema area and severity index (EASI) of the trunk from baseline to day 28. The secondary end points were changes in the patient global assessment (PGA) score and itch visual analogue scale (VAS) score of the trunk between baseline and day 28. Results: Two hundred and ninety-one patients were recruited, and 176 patients completed the full 4-week treatment course. By the end of the treatment, the mean local EASI of the trunk (2.2+/-4.71) was significantly decreased from that at baseline (4.71+/-4.03, p<0.001). PGA (1.71+/ 1.15) and itch VAS score of the trunk (2.61+/-2.19) on day 28 were also profoundly decreased compared with the baseline (2.96+/-1.07 and 5.15+/-2.47, respectively). No serious adverse events were observed during the study period. Conclusion: Topical tacrolimus is an effective and safe therapy for truncal lesions in AD patients. PMID- 29606815 TI - Economic Burden Can Be the Major Determining Factor Resulting in Short-Term Intermittent and Repetitive Ustekinumab Treatment for Moderate-to-Severe Psoriasis. AB - Background: The continuous use of biologic agents in the treatment of psoriasis has been reported to result in successful and sustained therapeutic effects and safety. However, some patients choose intermittent and repetitive treatment. Objective: To determine the factors for selecting intermittent and repetitive ustekinumab treatment for the management of psoriasis. Methods: From January 2011 to October 2016, we enrolled 30 psoriasis patients who discontinued ustekinumab treatment and were followed up for psoriasis treatment. We reviewed data regarding patients' clinical characteristics and the treatment they received, and investigated the factors for selecting intermittent treatment. Results: A total of 52 ustekinumab treatment periods were administered to the 30 patients. Of the 52 treatment periods, 34.6% were covered by insurance and 82.4% were discontinued after sufficient improvement had been made or at the patient's request. Further analysis comparing the first and second ustekinumab treatments revealed that the patients who used ustekinumab in second treatment were more likely to be insured. In addition, the rate of patients reaching psoriasis area and severity index (PASI)75 and PASI90 was similar between the first and subsequent ustekinumab treatments. Conclusion: We found that the patients who used ustekinumab intermittently were those who were satisfied with the outcome of ustekinumab treatment but could not afford the treatment. These results suggested that economic burden can be a factor for the patients' choice of short-term intermittent treatment. The expansion of insurance coverage can increase the effectiveness of, and patients' satisfaction with, the management of psoriasis. PMID- 29606816 TI - Antibiotic Susceptibility and Treatment Response in Bacterial Skin Infection. AB - Background: Bacterial skin infections occur secondarily in conditions involving a vulnerable skin barrier such as atopic eczema, as well as primarily such as impetigo. They are mainly caused by Staphylococcus aureus and Streptococci. Recently, the prevalence of methicillin-resistant S. aureus has been increasing. Objective: To determine the characteristics of community-acquired bacterial skin infections, to observe their antibiotic susceptibility patterns, and to evaluate factors contributing to the treatment response. Methods: We retrospectively reviewed outpatients under 30 years old from 2010 to 2015, from whom we had taken skin swabs for antibiotic susceptibility testing. We collected clinical and microbiological characteristics from the medical records. Results: We evaluated the culture results of 197 patients and reviewed their medical records. Overall, 86.3% (n=170) of the patients responded to the initial treatment regimen. S. aureus was the most commonly isolated pathogen (52.6%) and showed a high resistance rate to penicillin (90.9%) and oxacillin (36.3%). In the multivariable logistic regression analysis, resistance to 3 or more antibiotics (p=0.044), culture amounts described as "many" (p=0.040), and non-systemic antibiotic use (p<0.001) were significantly associated with lower treatment response. However, methicillin resistance was not associated with lower treatment response both in univariable and multivariable analyses. Conclusion: Among young patients, S. aureus was the most predominant pathogen present in bacterial skin infections. Resistance to high numbers of antibiotics and the use of non-systemic antibiotics were associated with lower treatment response. First-generation cephalosporins may be the most effective first-line empirical regimen for bacterial skin infections treated in outpatient settings, regardless of methicillin resistance. PMID- 29606817 TI - Folliculotropic Mycosis Fungoides in 20 Korean Cases: Clinical and Histopathologic Features and Response to Ultraviolet A-1 and/or Photodynamic Therapy. AB - Background: Folliculotropic mycosis fungoides (FMF) is a variant of mycosis fungoides (MF) that is characterized clinically by variable types of skin eruptions, including plaques, acneiform lesions, and alopecic patches. Histopathologically, FMF is characterized by folliculotropic infiltrates. Objective: This study was conducted to scrutinize the clinical and histopathologic features of FMF in Koreans and the responses to phototherapy. Methods: Twenty Koreans diagnosed with MF who had histopathologic evidence of folliculotropism were enrolled. Results: Eighteen patients had head-and-neck region infiltration, while five had solitary lesion. In all patients, the atypical lymphocytic infiltrate had a perifollicular distribution. Twelve patients were treated with ultraviolet A (UVA)-1. Eleven of these 12 patients with early-stage FMF experienced >80% improvement (8: complete remission; 3: partial remission). Four patients, including 2 who relapsed after UVA-1, were treated with photodynamic therapy (PDT), reaching complete remission after PDT. Conclusion: As FMF has variable clinical presentations, skin biopsy is required to confirm the diagnosis. And both UVA-1 and methyl aminolevulinate-PDT are clinically effective in treatment of early-stage FMF. PMID- 29606818 TI - Antifungal Effects of Bee Venom Components on Trichophyton rubrum: A Novel Approach of Bee Venom Study for Possible Emerging Antifungal Agent. AB - Background: Bee venom (BV) has been widely investigated for potential medical uses. Recent inadvertent uses of BV based products have shown to mitigate signs of fungal infections. However, the component mediating the antifungal effect has not been identified. Objective: This investigation compares bee venom in its whole and partial forms to evaluate the possible component responsible for the antifungal effect. Methods: Forty-eight plates inoculated with Trichophyton rubrum were allocated into four groups. The groups were treated with raw BV (RBV), melittin, apamin and BV based mist (BBM) respectively and each group was further allocated accordingly to three different concentrations. The areas were measured every other day for 14 days to evaluate the kinetic changes of the colonies. Results: The interactions of ratio differences over interval were confirmed in groups treated with RBV and BBM. In RBV, the level of differences were achieved in groups treated with 10 mg/100 ul (p=0.026) and 40 mg/100 ul (p=0.000). The mean difference of ratio in groups treated with RBV was evident in day 3 and day 5. The groups that were treated with melittin or apamin did not show any significant interaction. In BBM groups, the significant levels of ratio differences over time intervals were achieved in groups treated with 200 ul/100 ul (p=0.000) and 300 ul/100 ul (p=0.030). Conclusion: The the bee venom in its whole form delivered a significant level of inhibition and we concluded that the venom in separated forms are not effective. Moreover, BV based products may exert as potential antifungal therapeutics. PMID- 29606819 TI - Disseminated Superficial Actinic Porokeratosis in a Patient with Psoriasis, after Long-Term Narrowband Ultraviolet B Phototherapy. AB - Porokeratosis is a rare epidermal disorder characterized by annular or linear hyperkeratotic plaques with slightly raised thread-like borders, and in most cases, atrophic centers. Disseminated superficial porokeratosis and disseminated superficial actinic porokeratosis (DSAP), which primarily involve sun-exposed areas, are common types of porokeratoses. Histologically, a column of parakeratotic cells, a so-called cornoid lamella, is a hallmark of porokeratosis. Porokeratosis is considered to result from the inability to eliminate an abnormal keratinocyte clone induced by genetic factors and various stimuli, including sunlight, artificial ultraviolet light, viral infections, immunosuppressive conditions (hematologic malignancies, organ transplants, or autoimmune disease), and immunosuppressive therapies. Here, we report a 59-year-old Korean woman with DSAP that developed after narrowband ultraviolet B (NB-UVB) therapy for psoriasis. Our case emphasizes the occurrence of DSAP due to NB-UVB that is able to induce local immunosuppression at the irradiated site; the pathogenesis of DSAP remains unclear. PMID- 29606820 TI - Localized Telogen Effluvium Following Hair Transplantation. AB - Telogen effluvium is categorized in nonscarring alopecia, which shows scalp hair thinning and shedding diffusely resulting from inducing factors such as physiological stressful events and several acute or chronic diseases. It usually appears in female patients following parturition, as well as after febrile disease, major surgery, emotional stress, abrupt diet, chronic illness, or the taking of certain medication pills. Two patients who both recalled an operational history of hair transplantation visited our department with their frontal and both temporal hair loss. Physical examination of the both patients showed localized but diffuse hair loss, especially in the frontal and temporal scalp. Histopathological examination of biopsy specimen taken from their temporal scalp revealed normal follicular density and increased numbers of telogen hair follicles without any inflammatory cell infiltration around follicles. These clinical and histopathological findings were consistent with telogen effluvium. Both of them were reassured and placed on close follow-up without any treatment. From these cases, we demonstrate that localized telogen effluvium could be a cause of hair loss after hair transplantation. PMID- 29606821 TI - Pagetoid Bowen Disease Initially Misdiagnosed as Ectopic Extramammary Paget's Disease. AB - Pagetoid Bowen disease is a histological variant of Bowen disease which demonstrates large pale staining cells (pagetoid cells). It requires differential diagnosis from other cutaneous malignancies with similar patterns, such as extramammary Paget's disease (EMPD) and Pagetoid melanoma in situ. Herein, we report a case of Pagetoid Bowen disease which was initially misdiagnosed as ectopic EMPD. PMID- 29606822 TI - Eccrine Poroma with Rapid Growth during Pregnancy: A Case Report and Review of the Literature. AB - Eccrine poroma is a benign solitary tumor with acrosyringeal differentiation that usually occurs on the sole or either side of the foot. Rapid growth of eccrine poroma during pregnancy has rarely been reported. We demonstrate a unique case of a 37-year-old pregnant woman who suffered from enlarged eccrine poroma on her left palm, which was tiny for 10 years but suddenly grew to a size of bean-sized reddish brown colored, pedunculated mass during pregnancy. The patient denied a previous history of trauma or infection to the lesion. Histopathologic findings with a shave biopsy were consistent with eccrine poroma. After the tumor was completely removed by the shave biopsy, no recurrence was noted for 5 months. PMID- 29606823 TI - Recurrent Dermatofibrosarcoma Protuberans of Scalp in a Distant Location 10 Years after Primary Excision. AB - Dermatofibrosarcoma protuberans (DFSP) is a slow growing low-grade cutaneous sarcoma. Local recurrence after excision is common due to the poorly defined periphery that renders histological control of surgical margin difficult, Mohs micrographic surgery is the optimal method for treatment. A 41 years old male patient, who had a previous history of DFSP, came to our dermatology clinic for evaluation of an asymptomatic firm flesh-colored nodule on the forehead. Total excision biopsy was done and the mass was histologically proved as DFSP. Wide excision with reconstruction was performed and showed no sign of recurrence till 18-month follow up. Local recurrence is known to be common for DFSP but a new visible lesion distant from the initial site may be confused as a de novo lesion or a benign neoplasm especially in scalp area, and thus interrupt early detection of DFSP. Herein, we report a case of recurrent DFSP of scalp which recurred distant from the original lesion. PMID- 29606824 TI - A Case of Angiomatoid Fibrous Histiocytoma Presenting as Subcutaneous Nodule in a 4-Year-Old Girl. PMID- 29606825 TI - A Case of Phaeohyphomycosis on the Wrist: Identification of Exophiala spinifera in Korea. PMID- 29606826 TI - Atypical Proliferative Nodule with Melanocytic Intraepidermal Pagetoid Spreading Arising within a Congenital Melanocytic Nevus in a Pregnant Woman. PMID- 29606827 TI - Scrotal Calcinosis in Brothers. PMID- 29606828 TI - A Case-Control Study of Skin Cancer and Exposure of Toxic Heavy Metals. PMID- 29606829 TI - Tinea Faciei in a Mother and Daughter Caused by Arthroderma benhamiae. PMID- 29606830 TI - Cutaneous Abscess as a Complication of Bisphosphonate-Related Osteonecrosis of the Jaw. PMID- 29606831 TI - Dermoscopic Finding in Pigmented Purpuric Lichenoid Dermatosis of Gougerot-Blum: A Useful Tool for Clinical Diagnosis. PMID- 29606832 TI - Fibrous Plaque of the Eyelid in a Patient with Tuberous Sclerosis Responding to Everolimus. PMID- 29606833 TI - Disseminated Superficial Actinic Porokeratosis in a Vitiligo Patient Undergoing Treatment with Long-Term Narrowband Ultraviolet B. PMID- 29606834 TI - Medical Comorbidities and the Onset of Androgenetic Alopecia: A Population-Based, Case-Control Study. PMID- 29606835 TI - Validation of Herpes Zoster Diagnosis Code in the Electronic Medical Record: A Retrospective, Multicenter Study. PMID- 29606836 TI - A Case of Primary Cutaneous Aggressive Epidermotropic CD8+ Cytotoxic T-Cell Lymphoma. PMID- 29606837 TI - Basement Membrane Status Is Intact in Urticarial Dermatitis vs. Adult-Onset Atopic Dermatitis. PMID- 29606838 TI - Relief of Acute Herpetic Pain by Intravenous Vitamin C: The Dosage May Make a Difference. PMID- 29606839 TI - Relief of Acute Herpetic Pain by Intravenous Vitamin C: The Dosage May Make a Difference: Authors' Reply. PMID- 29606840 TI - Regional division and reduction algorithm for minimizing the sum of linear fractional functions. AB - This paper presents a practicable regional division and cut algorithm for minimizing the sum of linear fractional functions over a polyhedron. In the algorithm, by using an equivalent problem (P) of the original problem, the proposed division operation generalizes the usual standard bisection, and the deleting and reduction operations can cut away a large part of the current investigated region in which the global optimal solution of (P) does not exist. The main computation involves solving a sequence of univariate equations with strict monotonicity. The proposed algorithm is convergent to the global minimum through the successive refinement of the solutions of a series of univariate equations. Numerical results are given to show the feasibility and effectiveness of the proposed algorithm. PMID- 29606841 TI - New construction and proof techniques of projection algorithm for countable maximal monotone mappings and weakly relatively non-expansive mappings in a Banach space. AB - In a real uniformly convex and uniformly smooth Banach space, some new monotone projection iterative algorithms for countable maximal monotone mappings and countable weakly relatively non-expansive mappings are presented. Under mild assumptions, some strong convergence theorems are obtained. Compared to corresponding previous work, a new projection set involves projection instead of generalized projection, which needs calculating a Lyapunov functional. This may reduce the computational labor theoretically. Meanwhile, a new technique for finding the limit of the iterative sequence is employed by examining the relationship between the monotone projection sets and their projections. To check the effectiveness of the new iterative algorithms, a specific iterative formula for a special example is proved and its computational experiment is conducted by codes of Visual Basic Six. Finally, the application of the new algorithms to a minimization problem is exemplified. PMID- 29606842 TI - Statistical deferred weighted [Formula: see text]-summability and its applications to associated approximation theorems. AB - The notion of statistical weighted [Formula: see text]-summability was introduced very recently (Kadak et al. in Appl. Math. Comput. 302:80-96, 2017). In the paper, we study the concept of statistical deferred weighted [Formula: see text] summability and deferred weighted [Formula: see text]-statistical convergence and then establish an inclusion relation between them. In particular, based on our proposed methods, we establish a new Korovkin-type approximation theorem for the functions of two variables defined on a Banach space [Formula: see text] and then present an illustrative example to show that our result is a non-trivial extension of some traditional and statistical versions of Korovkin-type approximation theorems which were demonstrated in the earlier works. Furthermore, we establish another result for the rate of deferred weighted [Formula: see text] statistical convergence for the same set of functions via modulus of continuity. Finally, we consider a number of interesting special cases and illustrative examples in support of our findings of this paper. PMID- 29606843 TI - Inequalities on an extended Bessel function. AB - This paper studies an extended Bessel function of the form [Formula: see text] Representation formulations for [Formula: see text] are derived in terms of the parameters a, b, and p. An important consequence is the derivation of an [Formula: see text]-order differential equation satisfied by the function [Formula: see text]. Interesting functional inequalities are established, particularly for the case [Formula: see text], and [Formula: see text]. Monotonicity properties of [Formula: see text] are also studied for non-positive c. Log-concavity and log-convexity properties in terms of the parameters d and p are respectively investigated for the closely related function [Formula: see text] which leads to direct and reverse Turan-type inequalities. PMID- 29606844 TI - A Fluorescence Based Measurement Technique to Quantify Water Contaminants at Pipe Surfaces During Flow. AB - This paper provides a detailed account of the development of a fluorescence based measurement technique for measuring the mass of contaminant on solid surfaces in the presence of water flow. A test apparatus was designed and developed for the purpose of studying adsorption and desorption of diesel to and from a copper test surface in the presence of contaminated and fresh water flow, respectively. A calibration technique was developed to correlate the measured fluorescence intensity to the mass of diesel adsorbed per unit surface area (the excess surface density) and the bulk concentration of the diesel in the flow. Both bulk composition and the excess surface density measurements were achieved via a traverse of the fluorescent measurement probe perpendicular to the test surface. The measured diesel excess surface density varied between zero and 0.02 kg/m2 for the variation in the bulk mass fraction and Reynolds number of the flow. PMID- 29606845 TI - Movement Issues Identified in Movement ABC2 Checklist Parent Ratings for Students with Persisting Dysgraphia, Dyslexia, and OWL LD and Typical Literacy Learners. AB - Movement, which draws on motor skills and executive functions for managing them, plays an important role in literacy learning (e.g., movement of mouth during oral reading and movement of hand and fingers during writing); but relatively little research has focused on movement skills in students with specific learning disabilities as the current study did. Parents completed normed Movement Assessment Battery for Children Checklist, 2nd edition (ABC-2), ratings and their children in grades 4 to 9 (M = 11 years, 11 months; 94 boys, 61 girls) completed diagnostic assessment used to assign them to diagnostic groups: control typical language learning (N = 42), dysgraphia (impaired handwriting) (N = 29), dyslexia (impaired word decoding/reading and spelling) (N = 65), or oral and written language learning disability (OWL LD) (impaired syntax in oral and written language) (N = 19). The research aims were to (a) correlate the Movement ABC-2 parent ratings for Scale A Static/Predictable Environment (15 items) and Scale B Dynamic/Unpredictable Environment (15 items) with reading and writing achievement in total sample varying within and across different skills; and (b) compare each specific learning disability group with the control group on Movement ABC-2 parent ratings for Scale A, Scale B, and Scale C Movement-Related (Non-Motor Executive Functions, or Self-Efficacy, or Affect) (13 items). At least one Movement ABC-2 parent rating was correlated with each assessed literacy achievement skill. Each of three specific learning disability groups differed from the control group on two Scale A (static/predictable environment) items (fastens buttons and forms letters with pencil or pen) and on three Scale C items (distractibility, overactive, and underestimates own ability); but only OWL LD differed from control on Scale B (dynamic/unpredictable environment) items. Applications of findings to assessment and instruction for students ascertained for and diagnosed with persisting specific learning disabilities in literacy learning, and future research directions are discussed. PMID- 29606846 TI - Double Sided-Design of Electrodes Driving Tunable Dielectrophoretic Miniature Lens. AB - We demonstrate the design methodology, geometrical analysis, device fabrication, and testing of a double-sided design (DSD) of tunable-focus dielectrophoretic liquid miniature lenses. This design is intended to reduce the driving voltage for tuning the lens, utilizing a double-sided electrode design that enhances the electric field magnitude. Fabricated devices were tested and measurements on a goniometer showed changes of up to 14 degrees in the contact angle when the dielectrophoretic force was applied under 25 Vrms. Correspondingly, the back focal length of the liquid lens changed from 67.1 mm to 14.4 mm when the driving voltage was increased from zero to 25 Vrms. The driving voltage was significantly lower than those previously reported with similar device dimensions using single sided electrode designs. This design allows for a range of both positive and negative menisci dependent on the volume of the lens liquid initially dispensed. PMID- 29606847 TI - Many-level multilevel structural equation modeling: An efficient evaluation strategy. AB - Structural equation models are increasingly used for clustered or multilevel data in cases where mixed regression is too inflexible. However, when there are many levels of nesting, these models can become difficult to estimate. We introduce a novel evaluation strategy, Rampart, that applies an orthogonal rotation to the parts of a model that conform to commonly met requirements. This rotation dramatically simplifies fit evaluation in a way that becomes more potent as the size of the data set increases. We validate and evaluate the implementation using a 3-level latent regression simulation study. Then we analyze data from a state wide child behavioral health measure administered by the Oklahoma Department of Human Services. We demonstrate the efficiency of Rampart compared to other similar software using a latent factor model with a 5-level decomposition of latent variance. Rampart is implemented in OpenMx, a free and open source software. PMID- 29606848 TI - Implementing Group CBT for Depression Among Latinos in a Primary Care Clinic. AB - Depression in low-income Latino populations can be treated using group cognitive behavioral therapy (GCBT). However, effective delivery of GCBT for depression in primary care settings is often impeded by high dropout rates and poor homework adherence. In this study, we describe the structure, processes, and outcomes (including attendance, homework completion, and symptom measures) of GCBT for Spanish-speaking Latino patients with depression in an urban public sector primary care setting. For this study, 96 Latino patients in a primary care clinic participated in at least 1 session of GCBT. Although depressive symptoms among these patients, as measured by the PHQ-9, significantly decreased during treatment, attendance and homework completion were limited. Even with a strategy in place to allow patients to continue in treatment after missing several sessions, 23% of patients dropped out of therapy following their initial session, and approximately half of all patients completed less than 50% (or 8) therapy sessions. Homework was only completed 23% of the time it was checked. Greater session attendance prospectively predicted lower depressive symptoms over time. We discuss potential strategies to increase engagement, treatment effects, and symptom reduction for depression in primary care settings. PMID- 29606849 TI - Taking Stock of Behavioral Measures of Adolescent Dating Violence. AB - The past 2 decades have witnessed an increase in dating violence awareness and research. As the field evolves, it is critical to examine the definition and measurement of adolescent dating violence. This article summarizes the behavioral measures of adolescent dating violence used in the field. Based on a review of the literature and federally funded studies, we identified 48 different measures. The most commonly used measures were the Conflict Tactics Scale-2, the Safe Dates Scale, and the Conflict in Adolescent Dating Relationship Inventory, which all examine aspects of psychological, physical, and sexual violence. Researchers also adapted or created their own measures. This article concludes with a discussion of developments for consideration as the field moves forward. PMID- 29606850 TI - Sexual Violence Victimization and Associations with Health in a Community Sample of African American Women. AB - Limited information exists on the relationship between sexual violence victimization and health among African American women. Using data from a community sample of African American women, we examine the association between current health and lifetime experiences of sexual violence. Inperson interviews were completed in 2010. Among interviewees, 53.7% of women reported rape victimization and 44.8% reported sexual coercion in their lifetime. Victims of rape or sexual coercion were significantly more likely to report depression and posttraumatic stress disorder during their lifetime. Among victims whose first unwanted sexual experience was rape or sexual coercion, perpetrators were mostly acquaintances and intimate partners, and over one third were injured and needed services. More attention is needed on the health needs of African American women and their association to victimization status. PMID- 29606851 TI - Non-Uniform Sampling for All: More NMR Spectral Quality, Less Measurement Time. PMID- 29606852 TI - Switching from concomitant therapy to tafluprost/timolol fixed combination. AB - Purpose: To evaluate the efficacy and safety of tafluprost/timolol fixed combination (TTFC). Study design: A prospective clinical study. Methods: Twenty eight patients (28 eyes) with primary open-angle glaucoma, who had used tafluprost and timolol gel for at least 3 months with good adherence, were enrolled. Concomitant administration of tafluprost and timolol was switched to TTFC without a washout period. The intraocular pressure (IOP), blood pressure, pulse rate, and ocular signs were compared between before switching (baseline), and 4 and 8 weeks after switching. A questionnaire survey was also performed 4 weeks after switching to investigate ocular comfort and patient preferences. Results: The IOP showed no significant change after switching to TTFC (14.8 +/- 2.8, 14.6 +/- 3.4, and 14.8 +/- 3.7 mmHg at baseline, Week 4, and Week 8, respectively). The pulse rate and systolic blood pressure showed no changes, but diastolic blood pressure was significantly lower at Week 8. At baseline, fluorescein staining revealed corneal abnormalities in 3 patients, which resolved by Week 8 in 1 patient. Hyperemia was noted in 2 patients at baseline, and this also resolved by Week 8 in 1 patient. Three patients discontinued study treatment for the following reasons (1 patient each): blurred vision; ocular irritation, eyelid erythema, and asthenopia; and loss to follow-up from Week 8. The questionnaire survey revealed no significant differences between the 2 treatments, although more patients preferred TTFC. Conclusion: Among 28 patients enrolled, only 2 patients discontinued the study treatment due to adverse reactions. In patients whose adherence was considered relatively good to concomitant therapy, switching to TTFC achieved similar IOP control with good safety and a high level of patient acceptance. PMID- 29606853 TI - The role of corneal hysteresis during the evaluation of patients with possible normal-tension glaucoma. AB - Purpose: There are multiple reports of the role of corneal hysteresis (CH) as an independent risk factor for the diagnosis and risk of progression of normal tension glaucoma (NTG). Our study measured CH with the Ocular Response Analyzer (ORA) in patients with intraocular pressure (IOP) <21 mmHg to investigate if a low CH would identify NTG in this Asian-based practice. Methods: This was a prospective cross-sectional study of patients who underwent routine eye examination during 2016 in a private practice in Honolulu, Hawaii, where most patients are Asian. Inclusion criteria are: 1) >=65 years 2) IOP <21 (compensated IOP by ORA), and 3) CH values <10 using ORA as measured by a single experienced technician. Exclusion criteria are: 1) sight-limiting ocular or corneal disease that would preclude accurate measurements for the purposes of the study. 2) Any patient who had difficulty in being tested with the ORA. 3) Patients who had any history of any type of glaucoma. All patients that met the inclusion criteria underwent fundus photography to measure cup-to-disc ratio and cup-to-disc asymmetry and also had central corneal thickness measured. Thickness of the retina nerve fiber layer was measured by ocular coherence tomography. The eyes with an average retina nerve fiber layer thickness less than 80 MUm were classified as possible NTG and were scheduled for a visual field test. The field examination was considered valid only if the fixation, false positives, and false negatives were within the acceptable range. Patient demographics and data on preexisting diseases were collected including age, sex, coexisting medical conditions, and previous intraocular surgery. Those with thinning of retina nerve fiber layer on optical coherence tomography had a Humphrey visual field test to confirm the diagnosis of glaucoma. Results: Seventy-six eyes of 46 patients that met the eligibility criteria were included in the study. Twenty-one previously undiagnosed eyes were confirmed as having NTG, which corresponds to an incidence of 27.6%. Conclusion: CH measurement is a valuable test to assist in early diagnosis of NTG, especially in the elderly Asian population. With an established diagnosis, aggressive early treatments medically or surgically to further lower IOP can prevent irreversible blindness, which can severely impact the patient's family and socioeconomic status. PMID- 29606854 TI - Rucaparib: a novel PARP inhibitor for BRCA advanced ovarian cancer. AB - Rucaparib is a potent small-molecule inhibitor of poly (ADP-ribose) polymerase (PARP) proteins (PARP-1, PARP-2 and PARP-3) that play an important role in repairing DNA damage and maintaining genomic stability. Tumors with mutations in BRCA1/2 or other homologous recombination deficiency (HRD) genes are particularly sensitive to PARP inhibitors because of "synthetic lethality", whereby a therapeutic agent can take advantage of an intrinsic weakness in DNA repair. Rucaparib has been investigated in several preclinical and clinical studies showing promising activity in BRCA-mutant and BRCA-wild-type epithelial ovarian cancers (EOCs). Dose-escalation Phase I studies have established the recommended Phase II dose to be 600 mg twice a day for oral rucaparib. Phase II and III studies have defined its role as treatment for BRCA-mutant recurrent high-grade EOC and as maintenance treatment for platinum-sensitive relapsed EOC following response to platinum-based chemotherapy. Genomic loss of heterozygosity has also been investigated as a potential signature of HRD and as a potential predictive biomarker of response. Treatment-induced adverse events (AEs) have been observed in almost all patients treated with rucaparib, but mainly lower grade; with the most common being nausea, vomiting, asthenia/fatigue, anemia and transient transaminitis. The majority of AEs occurred early in treatment, were transient and have been easily managed with supportive treatment, dose interruption or discontinuation. This review will analyze the results of clinical trials investigating efficacy and safety of rucaparib in patients with ovarian cancer. PMID- 29606855 TI - Benralizumab in the treatment of severe asthma: design, development and potential place in therapy. AB - Asthma is a widespread and heterogeneous inflammatory disease of the airways, which is characterized by several different phenotypes and endotypes. In particular, eosinophilic airway inflammation is a common pathologic trait of both allergic and nonallergic asthma. The key cytokine responsible for maturation, activation, recruitment, and survival of eosinophils is interleukin (IL)-5, which is mainly produced by T helper 2 (Th2) lymphocytes and group 2 innate lymphoid cells. Therefore, for uncontrolled patients with severe eosinophilic asthma, who are not fully responsive to corticosteroids, IL-5 represents a very important molecular target for add-on biological therapies. Among these new treatments, anti-IL-5 monoclonal antibodies such as mepolizumab and reslizumab have been developed and clinically evaluated. Furthermore, benralizumab is currently the only available biologic drug that specifically binds to the IL-5 receptor, thus preventing the interaction with its ligand and the consequent pro-inflammatory effects. The effectiveness of benralizumab in improving severe eosinophilic asthma has been well-documented by many randomized controlled trials. PMID- 29606856 TI - Sevoflurane post-conditioning attenuates traumatic brain injury-induced neuronal apoptosis by promoting autophagy via the PI3K/AKT signaling pathway. AB - Background: Sevoflurane post-conditioning exerts nerve-protective effects through inhibiting caspase-dependent neuronal apoptosis after a traumatic brain injury (TBI). Autophagy that is induced by the endoplasmic reticulum stress plays an important role in the secondary neurological dysfunction after a TBI. However, the relationship between autophagy and caspase-dependent apoptosis as well as the underlying nerve protection mechanism that occurs with sevoflurane post conditioning following a TBI remains unclear. Methods: The Feeney TBI model was used to induce brain injury in rats. Evaluation of the modified neurological severity scores, measurement of brain water content, Nissl staining, and terminal deoxynucleotidyl transferase dUTP nick end labeling assay were used to determine the neuroprotective effects of the sevoflurane post-conditioning. Both immunofluorescence and Western blot analyses were used to detect the expression of autophagy-related proteins microtubule-associated protein 1 light chain 3-II and Beclin-1, pro-apoptotic factors, as well as the activation of the phosphatidylinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathway within the lesioned cortex. Results: Autophagy and neuronal apoptosis were activated in the lesioned cortex following the TBI. Sevoflurane post-conditioning enhanced early autophagy, suppressed neuronal apoptosis, and alleviated brain edema, which improved nerve function after a TBI (all P < 0.05). Sevoflurane post conditioning induced the activation of PI3K/AKT signaling after the TBI (P < 0.05). The neuroprotective effects of sevoflurane post-conditioning were reversed through the autophagy inhibitor 3-methyladenine treatment. Conclusion: Neuronal apoptosis and the activation of autophagy were involved in the secondary neurological injury following a TBI. Sevoflurane post-conditioning weakened the TBI-induced neuronal apoptosis by regulating autophagy via PI3K/AKT signaling. PMID- 29606857 TI - The reliability of lung ultrasound in assessment of idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is the severest form of idiopathic interstitial pneumonia, with a median survival time estimated at 2-5 years from the time of diagnosis. It occurs mainly in elderly adults, suggesting a strong link between the fibrosis process and aging. Although chest high-resolution computed tomography (HRCT) is currently the method of choice in IPF assessment, diagnostic imaging with typical usual interstitial pneumonia (UIP) provides definitive results in only 55%, requiring an invasive surgical procedure such as lung biopsy or cryobiopsy for the final diagnostic analysis. Lung ultrasound (LUS) as a noninvasive, non-radiating examination is very sensitive to detect subtle changes in the subpleural space. The evidence of diffuse, multiple B-lines defined as vertical, hyperechoic artifacts is the hallmark of interstitial syndrome. A thick, irregular, fragmented pleura line is associated with subpleural fibrotic scars. The total numbers of B-lines are correlated with the extension of pulmonary fibrosis on HRCT, being an LUS marker of severity. The average distance between two adjacent B-lines is an indicator of a particular pattern on HRCT. It is used to appreciate a pure reticular fibrotic pattern as in IPF compared with a predominant ground glass pattern seen in fibrotic nonspecific interstitial pattern. The distribution of the LUS artifacts has a diagnostic value. An upper predominance of multiple B-lines associated with the thickening of pleura line is an LUS feature of an inconsistent UIP pattern, excluding the IPF diagnosis. LUS is a repeatable, totally radiation-free procedure, well tolerated by patients, very sensitive in detecting early changes of fibrotic lung, and therefore a useful imaging technique in monitoring disease progression in the natural course or after initiation of treatment. PMID- 29606858 TI - The perceived feasibility and acceptability of a conceptually challenging exercise training program in older adults. AB - Background: Exercise training is an essential component of falls prevention strategies, but they do not fully address components of physical function that leads to falls. The training approaches to achieve this may not be perceived as appropriate or even feasible in older adults. This study aims to assess the perceived feasibility and acceptability of novel exercise training approaches not usually prescribed to older adults. Patients and methods: Fourteen adults were exposed to conceptually and physically demanding exercises. Interviews were then conducted to determine perceptions and acceptability of individual exercise tasks. Qualitative thematic analysis was used to identify themes. Results: Safety and confidence, acceptability, and population participation were the key themes identified. Staff knowledge, presence, program design, and overt safety equipment were important for alleviating initial apprehension. Although physically demanding, participants expressed satisfaction when challenged. Prior disposition, understanding the value, and the appeal of novel exercises were perceived to influence program engagement. Conclusion: Given the evidence for acceptability, this type of training is feasible and may be appropriate as part of an exercise training program for older adults. Further research should be conducted to confirm that the physical adaptations to exercise training approaches as presented in this study occur in a similar manner to that observed in younger adults, and to also determine whether these adaptations lead to prolonged independence and reduced falls in older adults compared to usual care. PMID- 29606859 TI - PPARgamma-2 and ADRB3 polymorphisms in connective tissue diseases and lipid disorders. AB - Background: The aim of the research genetic study was to investigate the association between variants (C1431T and Pro12Ala) of the peroxisome proliferator activated receptor (PPARgamma-2) gene, Trp64Arg polymorphism of the beta-3 adrenergic receptor gene and lipid profile in Polish population including group of 103 patients with connective tissue disease (CTD) and 103 sex-and age-matched controls in context of statin use. Methods: Anthropometric and biochemical parameters were measured by routine methods, followed by genotyping (TagMan(r) Genotyping Assays, PCR-restriction fragment length polymorphism analysis). Nearly 30% of CTD patients used statins and 10% of the control group. Results: Although there were no differences between alleles and genotypes prevalence between CTD vs control groups, interesting lipid-gene associations were noted in this study. A higher level of triglycerides (TAG) and TAG/high-density lipoprotein (HDL) ratios was observed in CTD patients compared to controls. Similar differences were noted in CTD and control groups without statin treatment. Atherogenic markers: the atherogenic index of plasma, TAG/HDL and low-density lipoprotein/HDL ratio were low in the analyzed groups. Of the six analyzed polymorphisms, the Pro12Pro or C14131C or Trp64Trp genotypes were related to higher TAG and TAG/HDL ratios in patients with CTD; however, the highest TAG values were observed in the presence of the Trp64Trp genotype. Conclusion: Lipid disorders were present in both groups independent of statin treatment (mixed dyslipidemia and hypercholesterolemia were observed in the CTD and control groups, respectively). The risk of dyslipidemia increases with age. The presence of Pro12Pro, C14131C and Trp64Trp genotypes is related to higher TAG level in CTDs, and of these the Trp64Trp variant most reliably predicts hypertriglyceridemia. PMID- 29606860 TI - The effect of religious intervention on depressive symptoms and quality of life among Indonesian elderly in nursing homes: A quasi-experimental study. AB - Purpose: This study aimed to investigate the effect of religious intervention on depressive symptoms and quality of life (QOL) among Indonesian elderly in nursing homes (NHs). Patients and methods: This was a quasi-experimental study with repeated measures. Sixty elderly residents at three NHs in three districts in Yogyakarta, Indonesia, with the Geriatric Depression Scale (GDS) score of 5-11 were recruited and purposively assigned to the religious intervention group (combining 36 sessions of listening to Qur'anic recital and 3 sessions of attending a sermon by a preacher, n=30) and the control group (treatment as usual/TAU, n=30). The primary outcome was depression, measured by a short form GDS questionnaire. The QOL as the secondary outcome was assessed by the World Health Organization Quality of Life (WHOQOL)-BREF Indonesian version. Both groups were evaluated at the baseline, 4th, 8th, and 12th week after the interventions were performed. Results: In both groups, there were statistically significant reductions in depression scores after the 12-week intervention (P<0.001). There was also a statistically significant improvement in QOL mean scores in both intervention and control groups at the 12-week post-intervention. However, the religious intervention group showed a greater decrease in depressive symptoms and a greater improvement in the QOL mean scores than those in the control group. There was a statistically significant difference in geriatric depression and QOL mean scores between groups at the 4th, 8th, and 12th week post-interventions. Conclusions: It can be concluded that religious-based intervention has a greater impact on relieving depressive symptoms and increasing the QOL amongst elderly NH residents. PMID- 29606861 TI - Pharmacokinetics of glycopyrronium/formoterol fumarate dihydrate delivered via metered dose inhaler using co-suspension delivery technology in patients with moderate-to-very severe COPD. AB - Purpose: The efficacy and tolerability of GFF MDI (Bevespi Aerosphere(r)), a fixed-dose combination of glycopyrronium (GP)/formoterol fumarate dihydrate (FF) 14.4/10 MUg (equivalent to glycopyrrolate/formoterol fumarate 18/9.6 MUg) delivered by metered dose inhaler (MDI) using innovative co-suspension delivery technology, has been investigated in a Phase III clinical trial program (NCT01854645, NCT01854658, NCT01970878) in patients with COPD. Here, we present findings from a pharmacokinetic (PK) sub-study of NCT01854645 (PINNACLE-1). Methods: PINNACLE-1 was a multicenter, randomized, double-blind, parallel-group, 24 wk chronic-dosing, placebo- and active-controlled study. The PK sub-study assessed the systemic accumulation of glycopyrronium and formoterol following administration of GFF MDI 14.4/10 MUg, GP MDI 14.4 MUg, or FF MDI 10 MUg (all BID) for 12 wks. Plasma for PK analysis was collected for up to 12 h after dosing, on Day 1 and Week 12. Results: Of 2,103 patients randomized in PINNACLE 1, 292 participated in the PK sub-study. The plasma concentration-time profiles of glycopyrronium were similar following treatment with GFF MDI or GP MDI, both after single dosing and at Week 12. Accumulation at Week 12 relative to Day 1 was up to 2.30-fold for glycopyrronium. The plasma concentration-time profiles of formoterol were similar following treatment with GFF MDI or FF MDI, both after single dosing and at Week 12. Accumulation at Week 12 relative to Day 1 was up to 1.62-fold for formoterol. Conclusion: Overall, the results have characterized the accumulation of glycopyrronium and formoterol associated with GFF MDI, GP MDI, and FF MDI, and indicated that there were no meaningful PK interactions, whether drug-drug or due to formulation, between glycopyrronium and formoterol following treatment with GFF MDI formulated using co-suspension delivery technology. PMID- 29606862 TI - A high COPD assessment test score may predict anxiety in COPD. PMID- 29606863 TI - Cigarette smoke exposure promotes differentiation of CD4+ T cells toward Th17 cells by CD40-CD40L costimulatory pathway in mice. AB - Purpose: This study aimed to investigate the impact of cigarette smoke exposure upon CD40-CD40L ligation between bone marrow-derived dendritic cells (BMDCs)and CD4+T cells, and to examine the effects of cigarette smoke exposure upon differentiation of CD4+T cells toward Th17 cells through blockade of CD40-CD40L pathway in mice. Methods: The study was processed in vivo and in vitro. In vivo, Th17 cells, CD40, interleukin (IL)-17A, and IL-27 in the lung tissues were quantified and compared between mice with and without cigarette smoke exposure. In vitro, Th17 cells, IL-17A, and IL-27 yielded by multiple cell cultivations in which BMDCs from mice with or without cigarette smoke exposure were fostered with CD4+ T cells from healthy mice spleens in the presence of antagonistic CD40 antibody and/or cigarette smoke extract (CSE) were quantified and compared. The flow cytometry was used to detect expressions of Th17 cells and CD40, and the liquid chip was used to detect levels of IL-17A and IL-27. Results: Both in vivo exposed to cigarette smoke and in vitro to CSE, CD40 expressions noticeably escalated on the surfaces of BMDCs. The presence of Th17 cells, IL-17A, and IL-27 in the lung tissues prominently increased in mice exposed to cigarette smoke. The in vitro culture of CD4+ T cells and BMDCs significantly enhanced the differentiation of CD4+ T cells toward Th17 cells and secretions of IL-17A and IL 27 in the case that BMDCs were produced from mice exposed to cigarette smoke or the culture occurred in the presence of CSE. Usage of antagonistic CD40 antibody evidently reduced the number of Th17 cells, IL-17A, and IL-27 that increased due to cigarette smoke exposure. Conclusion: The CD40-CD40L ligation is associated with the quantities of Th17 cells and relevant cytokines in the context of cigarette smoke exposure. Reducing the number of Th17 cells via the usage of antagonistic CD40 antibody can be an inspiration for pursuing a novel therapeutic target for immune inflammation in COPD. PMID- 29606864 TI - Do patients and carers agree on symptom burden in advanced COPD? AB - Objective: Accurate informal carer assessment of patient symptoms is likely to be valuable for decision making in managing the high symptom burden of COPD in the home setting. Few studies have investigated agreement between patients and carers in COPD. We aimed to assess agreement between patients and carers on symptoms, and factors associated with disagreement in a population-based sample of patients with advanced COPD. Patients and methods: This was a prospective, cross-sectional analysis of data from 119 advanced COPD patients and their carers. Patients and carers separately rated symptoms on a 4-point scale. Wilcoxon signed-rank tests and weighted Cohen's kappa determined differences in patient and carer scores and patient-carer agreement, respectively. We identified characteristics associated with incongruence using Spearman's rank correlation and Mann-Whitney U tests. Results: There were no significant differences between group-level patient and carer scores for any symptom. Patient-carer individual-level agreement was moderate for constipation (k=0.423), just below moderate for diarrhea (k=0.393) and fair for depression (k=0.341), fatigue (k=0.294), anxiety (k=0.289) and breathlessness (k=0.210). Estimation of greater patient symptom burden by carers relative to patients themselves was associated with non-spousal patient-carer relationship, non-cohabitating patients and carers, carer symptoms of anxiety and depression and more carer unmet support needs. Greater symptom burden estimation by the patient relative to the carer was associated with younger patients and longer duration of COPD. Conclusion: Overall, agreement between patients and carers was fair to moderate and was poorer for more subjective symptoms. There is a need to encourage open dialogue between patients and carers to promote shared understanding, help patients express themselves and encourage carers to draw attention to symptoms that patients do not report. The findings suggest a need to screen for and address both the psychological morbidities in patients with advanced COPD and their carers and unmet support needs in carers. PMID- 29606865 TI - Long-term oxygen therapy in COPD patients: population-based cohort study on mortality. AB - Purpose: Chronic obstructive pulmonary disease (COPD) is the fourth leading cause of death worldwide and is associated with a growing and substantial socioeconomic burden. Long-term oxygen therapy (LTOT), recommended by current treatment guidelines for COPD patients with severe chronic hypoxemia, has shown to reduce mortality in this population. The aim of our study was to assess the standardized mortality ratios of incident and prevalent LTOT users and to identify predictors of mortality. Patients and methods: We conducted a 2-year follow-up population based cohort study comprising all COPD patients receiving LTOT in the canton of Bern, Switzerland. Comparing age- and sex-adjusted standardized mortality ratios, we examined associations between all-cause mortality and patient characteristics at baseline. To avoid immortal time bias, data for incident (receiving LTOT <6 months) and prevalent users were analyzed separately. Results: At baseline, 475 patients (20% incident users, n=93) were receiving LTOT because of COPD (48/100,000 inhabitants). Mortality of incident and prevalent LTOT users was 41% versus 27%, respectively, p<0.007, and standardized mortality ratios were 8.02 (95% CI: 5.64-11.41) versus 5.90 (95% CI: 4.79-7.25), respectively. Type 2 respiratory failure was associated with higher standardized mortality ratios among incident LTOT users (60.57, 95% CI: 11.82-310.45, p=0.038). Conclusion: Two year mortality rate of COPD patients on incident LTOT was somewhat lower in our study than in older cohorts but remained high compared to the general population, especially in younger patients receiving LTOT <6 months. Type 2 respiratory failure was associated with mortality. PMID- 29606866 TI - Surfactin-based nanoparticles loaded with doxorubicin to overcome multidrug resistance in cancers. AB - Background: Multidrug resistance (MDR) is one of the major obstacles to successful cancer chemotherapy. Developing efficient strategies to reverse MDR remains a major challenge. Surfactin (SUR), a cyclic lipopeptide biosurfactant, has been found to display anticancer activity. Methods: In this paper, SUR was assembled by solvent-emulsion method to load the anticancer drug doxorubicin (DOX). The cytotoxicity of DOX-loaded SUR nanoparticles (DOX@SUR) against DOX resistant human breast cancer MCF-7/ADR is measured by MTT assay. The cellular uptake and intracellular retention of DOX@SUR are determined by flow cytometry. The tumor accumulation and anticancer activity of DOX@SUR are evaluated in MCF 7/ADR-bearing nude mice. Results: DOX@SUR induce stronger cytotoxicity against DOX-resistant human breast cancer MCF-7/ADR cells compared to free DOX. DOX@SUR nanoparticles exhibit enhanced cellular uptake and decreased cellular efflux, which might be associated with reduced P-glycoprotein expression. After internalization into MCF-7/ADR cells by macropinocytosis- and caveolin-mediated endocytosis, DOX@SUR nanoparticles are colocalized with the lysosomes and translocated to the nucleus to exert cytotoxicity. Furthermore, in vivo animal experiment shows that the DOX@ SUR nanoparticles are accumulated more efficiently in tumors than free DOX. Meanwhile, DOX@SUR nanoparticles display stronger tumor inhibition activity and fewer side effects in MCF-7/ADR-bearing nude mice. Conclusion: This study indicates that SUR-based nanocarrier might present a promising platform to reverse MDR in cancer chemotherapy. PMID- 29606867 TI - NaCl: for the safer in vivo use of antibacterial silver based nanoparticles. AB - Background: As antibiotics progressively cease to be effective, silver based nanoparticles (SBNs), with broad antibacterial spectrum, might be the last line of defense against malicious bacteria. Unfortunately, there are still no proper SBNs-based strategies for in vivo antibacterial therapies. In this article, new carbon membrane packaged Ag nanoparticles (Ag-C) were synthesized. We assessed the effect of Ag-C with NaCl on size, cytotoxicity, antibacterial properties, metabolism and sepsis models. Methods: The size of Ag-C with NaCl was accessed with UV-vis, TEM and SEM. Staphylococcus aureus, Escherichia coli and Pseudomonas aeruginosa were used to illustrate the antibacterial properties of SBNs affected by NaCl. L929 and 3T3 cell lines were cultured in vitro; CCK-8 assay was used to test cytotoxicity. Then, we explored the metabolism of Ag-C with NaCl in vivo. Finally, the effect of Ag-C with 4* NaCl on sepsis was observed. Results: NaCl could regulate the size of Ag-C. Ag-C exhibited superior antibacterial properties compared to similar sized pure Ag nanoparticles. Furthermore, the addition of NaCl could not only reduce the cytotoxicity of Ag-C, but could also continue to discharge Ag-C from major organs. Based on these factors, this method was used to treat a sepsis model (induced via cecal ligation and puncture), and it achieved satisfactory survival results. Conclusion: This discovery, though still in its infancy, could significantly improve the safety and feasibility of SBNs and could potentially play an important role in modern in vivo antibacterial applications. Thus, a new method to combating the growing threat from drug-resistant bacteria could be possible. NaCl is the key to excretion of SBNs after in vivo antibacterial use. PMID- 29606869 TI - Propylthiouracil-coated biodegradable polymer inhibited neointimal formation and enhanced re-endothelialization after vascular injury. AB - Background: The drug-eluting stent is a standard approach for the treatment of coronary artery disease. Propylthiouracil (PTU), an antithyroid drug, has been proven to suppress neointimal formation after balloon injury. Materials and methods: This study used a biodegradable polymer coating with PTU to test its effects on platelet function, re-endothelialization, and neointimal formation after vascular injury. Electrospinning was used to fabricate hybrid stents and generate PTU-loaded nanofibers. Results: PTU-eluting stents maintained a stable release of PTU for 3 weeks. The PTU-coated stent markedly decreased the neointimal formation induced by vascular injury in the descending aorta of rabbits. Moreover, the PTU coating reduced platelet adhesion on the surface of the biodegradable membrane, which was reflected by the decreased expression of adhesion molecule in PTU-treated endothelial cells. The PTU coating enhanced re endothelialization in injured aortas. In vitro, PTU exerted less suppressive effect on the proliferation and migration of endothelial cells than on those of vascular smooth muscle cells. Furthermore, treatment of endothelial cells with PTU induced phosphorylation (Ser1177) of endothelial nitric oxide synthase as well as its association with heat shock protein 90, supporting the protective role of PTU in endothelial function. The level of thyroid-stimulating hormone remained unchanged during the experimental period. Conclusion: This study indicates that PTU can be released locally and steadily in injured aortas, with some local effects but without systemic effects. Furthermore, PTU-coated stents may have beneficial effects on neointimal formation, endothelial cell, and platelet functions. PMID- 29606868 TI - A promising magnetic resonance stem cell tracer based on natural biomaterials in a biological system: manganese(II) chelated to melanin nanoparticles. AB - Background: Melanin and manganese are both indispensable natural substances that play crucial roles in the human body. Melanin has been used as a multimodality imaging nanoplatform for biology science research because of its natural binding ability with metal ions (eg, 64Cu2+, Fe3+, and Gd3+). Because of its effects on T1 signal enhancement, Mn-based nanoparticles have been used in magnetic resonance (MR) quantitative cell tracking in vivo. Stem cell tracking in vivo is an essential technology used to characterize engrafted stem cells, including cellular viability, biodistribution, differentiation capacity, and long-term fate. Methods: In the present study, manganese(II) ions chelated to melanin nanoparticles [MNP-Mn(II)] were synthesized. The characteristics, stem cell labeling efficiency, and cytotoxicity of the nanoparticles were evaluated. MR imaging of the labeled stem cells in vivo and in vitro were also further performed. In T1 relaxivity (r1), MNP-Mn(II) were significantly more abundant than Omniscan. Bone marrow-derived stem cells (BMSCs) can be labeled easily by coincubating with MNP-Mn(II), suggesting that MNP-Mn(II) had high biocompatibility. Results: Cell Counting Kit-8 assays revealed that MNP-Mn(II) had almost no cytotoxicity when used to label BMSCs, even with a very high concentration (1,600 ug/mL). BMSCs labeled with MNP-Mn(II) could generate a hyperintense T1 signal both in vitro and in vivo, and the hyperintense T1 signal in vivo persisted for at least 28 days. Conclusion: Taken together, our results showed that MNP-Mn(II) possessed many excellent properties for potential quantitative stem cell tracking in vivo. PMID- 29606870 TI - Construction and application of a liver cancer-targeting drug delivery system based on core-shell gold nanocages. AB - Background: In order to achieve drug targeting and controlled release, we have successfully developed a novel drug release system DOX/AuNCs-PM-HA with gold nanocages (AuNCs) as photothermal cores, thermally responsive copolymer P(NIPAM co-Am) (PM) as the near-infrared (NIR) stimuli gatekeeper and hyaluronic acid as a targeting ligand as well as a capping agent. Methods: Cell uptake and cell viability were investigated. In vivo photoacoustic tomography imaging in H22 tumor bearing mice was analyzed for the tumor targeting effect of the nanocomplexes. Antitumor efficacy and the tissue distribution in vivo were investigated. Results: In vitro results demonstrated that the DOX/AuNCs-PM-HA had significant anticancer activity against SMMC-7721 cells under NIR irradiation. Furthermore, in vivo photoacoustic tomography imaging of the nanocomplexes in H22 tumor bearing mice could indicate effective tumor targeting. Our studies on antitumor efficacy and the tissue distribution in vivo showed that many DOX/AuNCs PM-HA nanocomplexes could efficiently accumulate at the tumor site so that they could inhibit the tumor growth effectively with limited side effects. The in vitro and in vivo results confirmed that the tumor-targeting and controlled release drug system DOX/AuNCs-PM-HA with the combination of chemotherapy and photothermal therapy showed strong anti-tumor effect and would have great potential for future cancer therapy. Conclusion: This tumor targeting DOX/AuNCs PM-HA nanocomplex responded not only to the external stimuli of NIR, but also the internal stimuli of hyaluronidase, providing the potential for pinpointed and multi-stimuli responsive intracellular drug release. PMID- 29606872 TI - Porous Se@SiO2 nanocomposites protect the femoral head from methylprednisolone induced osteonecrosis. AB - Background: Methylprednisolone (MPS) is an important drug used in therapy of many diseases. However, osteonecrosis of the femoral head is a serious damage in the MPS treatment. Thus, it is imperative to develop new drugs to prevent the serious side effect of MPS. Methods: The potential interferences Se@SiO2 nanocomposites may have to the therapeutic effect of methylprednisolone (MPS) were evaluated by classical therapeutic effect index of acute respiratory distress syndrome (ARDS), such as wet-to-dry weight ratio, inflammatory factors IL-1beta and TNF-alpha. And oxidative stress species (ROS) index like superoxide dismutase (SOD) and glutathione (GSH) were tested. Then, the protection effects of Se@SiO2 have in osteonecrosis of the femoral head (ONFH) were evaluated by micro CT, histologic analysis and Western-blot analysis. Results: In the present study, we found that in the rat model of ARDS, Se@SiO2 nanocomposites induced SOD and GSH indirectly to reduce ROS damage. The wet-to-dry weight ratio of lung was significantly decreased after MPS treatment compared with the control group, whereas the Se@SiO2 did not affect the reduced wet-to-dry weight ratio of MPS. Se@SiO2 also did not impair the effect of MPS on the reduction of inflammatory factors IL 1beta and TNF-alpha, and on the alleviation of structural destruction. Furthermore, micro CT and histologic analysis confirmed that Se@SiO2 significantly alleviate MPS-induced destruction of femoral head. Moreover, compared with MPS group, Se@SiO2 could increase collagen II and aggrecan, and reduce the IL-1beta level in the cartilage of femoral head. In addition, the biosafety of Se@SiO2 in vitro and in vivo were supported by cell proliferation assay and histologic analysis of main organs from rat models. Conclusion: Se@SiO2 nanocomposites have a protective effect in MPS-induced ONFH without influence on the therapeutic activity of MPS, suggesting the potential as effective drugs to avoid ONFH in MPS therapy. PMID- 29606871 TI - Ultrasound molecular imaging of breast cancer in MCF-7 orthotopic mice using gold nanoshelled poly(lactic-co-glycolic acid) nanocapsules: a novel dual-targeted ultrasound contrast agent. AB - Background: The development of nanoscale molecularly targeted ultrasound contrast agents (UCAs) with high affinity and specificity is critical for ultrasound molecular imaging in the early detection of breast cancer. Purpose: To prospectively evaluate ultrasound molecular imaging with dual-targeted gold nanoshelled poly(lactide-co-glycolic acid) nanocapsules carrying vascular endothelial growth factor receptor type 2 (VEGFR2) and p53 antibodies (DNCs) in MCF-7 orthotopic mice model. Methods: DNCs were fabricated with an inner PLGA and outer gold nanoshell spherical structure. Its targeting capabilities were evaluated by confocal laser scanning microscopy (CLSM) and flow cytometry (FCM) in vitro. Contrast-enhanced ultrasound imaging (CEUS) with DNCs was evaluated qualitatively and quantitatively in vitro and in MCF-7 orthotopic mice model by two different systems. The biodistribution of NCs in mice was preliminary investigated. Differences were calculated by using analysis of variance. Results: DNCs showed a well-defined spherical morphology with an average diameter of 276.90+/-110.50 nm. In vitro, DNCs exhibited high target specificities (79.01+/ 5.63% vs. 2.11+/-1.07%, P<0.01; 75.54+/-6.58% vs. 5.21+/-3.12%, P<0.01) in VEGFR2 and p53-positive cells compared with control cells. In vivo, CEUS displayed a significantly higher video intensity in two systems using DNCs in comparison with non-targeted PLGA@Au NCs and single-targeted NCs. Biodistribution studies revealed that more DNCs in breast cancer tissue could be detected in mice than in other NCs (P<0.05). Conclusion: DNCs were demonstrated to be novel dual-targeted UCAs and may have potential applications in early non-invasive visualization of breast cancer. PMID- 29606873 TI - Noninvasive evaluation of the migration effect of transplanted endothelial progenitor cells in ischemic muscle using a multimodal imaging agent. AB - Background: Endothelial progenitor cells (EPCs) play an important role in repairing ischemia tissues. However, the survival, migration and therapeutic efficacy of EPCs after transplantation need to be better understood for further cell therapy. Purpose: This study investigated the migration effect of EPCs labeled with a multimodal imaging agent in a murine ischemic hindlimb model, using magnetic resonance imaging (MRI) and optical imaging after transplantation. Methods: EPCs derived from mouse bone marrow were labeled with a multimodal imaging agent and were administered through intracardiac delivery to mice with ischemic hindlimbs. The injected EPCs and their migration effect were observed via MRI and optical imaging in vivo, and then compared to a reference standard based on histological data. The quantification of gadolinium in tissue samples was done using inductively coupled plasma mass spectrometry (ICP-MS). Results: Using in vivo MRI and optical imaging, the labeled EPCs were observed to migrate to ischemic muscle on days 3-5 after injection, while ex vivo, the EPCs were observed in the capillary vessels of the injured tissue. There were significant linear correlations between the Gd contents measured using ICP-MS in samples from the ischemic hindlimbs and livers and T1 relaxation times calculated using MRI, as well as the average fluorescence signal intensities recorded in optical images (T1 relaxation time: r=0.491; average signal from optical imaging: r=0.704, P<0.01). EPC treatment upregulated the levels of C-X-C chemokine receptor 4 and vascular endothelial growth factor (VEGF) receptor 2 and enhanced the expression of stromal cell-derived factor-1 and VEGF. Conclusion: Transplanted EPCs can be monitored with noninvasive MRI and optical imaging in vivo and were found to enhance the paracrine secretion of angiogenic factors. PMID- 29606874 TI - Trastuzumab- and Fab' fragment-modified curcumin PEG-PLGA nanoparticles: preparation and evaluation in vitro and in vivo. AB - Introduction: Nanoparticles (NPs) modified with bio-ligands represent a promising strategy for active targeted drug delivery to tumour. However, many targeted ligands, such as trastuzumab (TMAB), have high molecular weight, limiting their application for targeting. In this study, we prepared Fab' (antigen-binding fragments cut from TMAB)-modified NPs (Fab'-NPs) with curcumin (Cur) as a model drug for more effective targeting of human epidermal growth factor receptor 2 (HER2/ErbB2/Neu), which is overexpressed on breast cancer cells. Material and methods: The release kinetics was conducted by dialysis bags. The ability to kill HER2-overexpressing BT-474 cells of Fab'-Cur-NPs compared with TMAB-Cur-NPs was conducted by cytotoxicity experiments. Qualitative and quantitative cell uptake studies using coumarin-6 (fluorescent probe)-loaded NPs were performed by fluorescence microscopy and flow cytometry. Pharmacokinetics and biodistribution experiments in vivo were assessed by liquid chromatography-tandem mass spectrometry (LC-MS/MS). Results: The release kinetics showed that both Fab'-Cur NPs and TMAB-Cur-NPs provided continuous, slow release of curcumin for 72 h, with no significant difference. In vitro cytotoxicity experiments showed that Fab'-Cur NPs manifested prominent ability to kill HER2-overexpressing BT-474 cells compared with TMAB-Cur-NPs. Qualitative and quantitative cell uptake studies indicated that the accumulation of Fab'-NPs was greater than that of TMAB-NPs in BT-474 (HER2+) cells; However, there was no significant difference in MDA-MB-231 (HER2-) cells. Pharmacokinetics and biodistribution experiments in vivo demonstrated that the half-life (t1/2) and area under the blood concentration time curve (AUC0-t) of Fab'-Cur-NPs increased 5.30-fold and 1.76-fold relative to those of TMAB-Cur-NPs, respectively. Furthermore, the tumor accumulation of Fab' Cur-NPs was higher than that of TMAB-Cur-NPs. Conclusion: Fab' fragment has greater capacity than the intact antibody to achieve tumor targeting through NP based delivery. PMID- 29606875 TI - Dysfunction of cortical synapse-specific mitochondria in developing rats exposed to lead and its amelioration by ascorbate supplementation. AB - Background: Lead (Pb) is a widespread environmental neurotoxin and its exposure even in minute quantities can lead to compromised neuronal functions. A developing brain is particularly vulnerable to Pb mediated toxicity and early life exposure leads to permanent alterations in brain development and neuronal signaling and plasticity, culminating into cognitive and behavioral dysfunctions and elevated risk of neuropsychiatric disorders later in life. Nevertheless, the underlying biochemical mechanisms have not been completely discerned. Methods: Because of their ability to fulfill high energy needs and to act as calcium buffers in events of high intensity neuronal activity as well as their adaptive regulatory capability to match the requirements of the dynamicity of synaptic signaling, synapse-specific or synaptic mitochondria (SM) are critical for synaptic development, function and plasticity. Our aim for the present study hence was to characterize the effects of early-life Pb exposure on the functions of SM of prepubertal rats. For this purpose, employing a chronic model of Pb neurotoxicity, we exposed rat pups perinatally and postnatally to Pb and used a plethora of colorimetric and fluorometric assays for assessing redox and bioenergetic properties of SM. In addition, taking advantage of its ability as an antioxidant and as a metal chelator, we employed ascorbic acid (vitamin C) supplementation as an ameliorative therapeutic strategy against Pb-induced neurotoxicity and dysfunction of SM. Results: Our results suggest that early-life exposure to Pb leads to elevated oxidative stress in cortical SM with consequent compromises in its energy metabolism activity. Ascorbate supplementation resulted in significant recovery of Pb-induced oxidative stress and functional compromise of SM. Conclusion: Alterations in redox status and bioenergetic properties of SM could potentially contribute to the synaptic dysfunction observed in events of Pb neurotoxicity. Additionally, our study provides evidence for suitability of ascorbate as a significant ameliorative agent in tacking Pb neurotoxicity. PMID- 29606876 TI - Factors related to improvement of symptoms, function, and caregiver burden in Chinese patients with schizophrenia after switching to paliperidone palmitate once-monthly from oral antipsychotics. AB - Background: Paliperidone palmitate once-monthly (PP1M) demonstrated symptomatic and functional remission in patients with schizophrenia. This post hoc analysis aimed to identify factors associated with improved clinical outcomes in patients switching to PP1M (75-150 mg eq.). Methods: The improved patient outcomes were observed as Positive and Negative Symptom Scale (PANSS, symptoms) score <70:66.7% (407/610), Personal and Social Performance (PSP, function) score >70:34.3% (199/581), and Involvement Evaluation Questionnaire (IEQ, caregiver burden) reduction >=6:50.2% (270/538). Independent variables including demographics, disease duration, employment status, and clinical scores were screened individually using a univariate analysis and subsequently, variables (cutoff p<0.15) were analyzed using a multivariate regression analysis for association with better clinical outcomes at week 13. Results: The factors significantly associated with favorable clinical outcomes were reduction in PANSS at week 5 (odds ratio [OR]=1.14, 95% CI=1.11-1.17) with symptom reduction; baseline PSP total score (OR=1.07, 95% CI=1.05-1.10), PSP change at week 5 (OR=1.07, 95% CI=1.05-1.10), PANSS reduction at week 5 (OR=1.06, 95% CI=1.03-1.08) with functional improvement, reduction in PANSS at week 5 (OR=1.02, 95% CI=1.01-1.03), and total IEQ score at baseline (OR=1.09, 95% CI=1.07-1.11) with caregiver burden reduction. Conclusion: Thus, symptom and functional improvements with caregiver burden reduction were observed in patients, and PANSS reduction at week 5 was commonly associated with favorable outcomes. PMID- 29606877 TI - Onset and duration of effect of extended-release carbidopa-levodopa in advanced Parkinson's disease. AB - Background: In patients with Parkinson's disease (PD), oral dosing of extended release carbidopa-levodopa (Rytary, IPX066 [ER CD-LD]) achieves peak levodopa plasma concentrations within 1 hour and maintains them for 4-6 hours. Aims: To compare the onset and duration of ER CD-LD benefit with those of immediate release carbidopa-levodopa (IR CD-LD) in PD patients with motor fluctuations, using crossover data, and to evaluate which threshold values of improvement in finger-tapping and Unified Parkinson's Disease Rating Scale (UPDRS) motor scores yield results most similar to those for trained raters' "on"/"off" assessments. Methods: Patients underwent serial "on"/"off" rating and provided serial finger tapping and UPDRS motor scores after receiving, in an "off" state, their usual morning IR dose or an ER dose designed to produce a similar levodopa peak concentration. Predefined improvement thresholds for analysis were 10%, 15%, and 20% increases in finger-tapping score and 2.5, 5, 7, and 11-point decreases in UPDRS motor score. Serial plasma samples were assayed for levodopa. Results: Among 27 patients, mean time to onset of an "on" state was similar for ER compared with IR CD-LD (0.83 vs 0.81 hour), but mean duration was significantly longer for ER CD-LD than for IR CD-LD (5.56 vs 2.69 hours; P<0.0001). Duration was best matched by a $20% improvement in finger-tapping, a $11-point improvement in UPDRS motor score, and a levodopa plasma concentration $1,000 ng/mL. Conclusion: For ER CD-LD, observer assessments of "on" state were corroborated by sustained treatment effects. Correlations among "on"-state duration, finger tapping score, and UPDRS motor score may suggest clinically relevant thresholds for acute assessment of treatment benefit. PMID- 29606878 TI - Aberrant regional brain activities in alcohol dependence: a functional magnetic resonance imaging study. AB - Objective: Whether moderate alcohol consumption has health benefits remains controversial, but the harmful effects of excessive alcohol consumption on behavior and brain function are well recognized. The aim of this study was to investigate alcohol-induced regional brain activities and their relationships with behavioral factors. Subjects and methods: A total of 29 alcohol-dependent subjects (9 females and 20 males) and 29 status-matched healthy controls (11 females and 18 males) were recruited. Severity of alcohol dependence questionnaire (SADQ) and alcohol use disorders identification test (AUDIT) were used to evaluate the severity of alcohol craving. Regional homogeneity (ReHo) analysis was used to explore the alcohol-induced regional brain changes. Receiver operating characteristic (ROC) curve was used to investigate the ability of regional brain activities to distinguish alcohol-dependent subjects from healthy controls. Pearson correlations were used to investigate the relationships between alcohol-induced ReHo differences and behavioral factors. Results: Alcohol dependent subjects related to healthy controls showed higher ReHo areas in the right superior frontal gyrus (SFG), bilateral medial frontal gyrus (MFG), left precentral gyrus (PG), bilateral middle temporal gyrus (MTG), and right inferior temporal gyrus (ITG) and lower ReHo areas in the right cerebellum posterior lobe (CPL), left rectal gyrus (RG), and right cluster of pons and cerebellum anterior lobe (CAL). ROC curve revealed high area under the curve (AUC) values (mean +/- SD: 0.864 +/- 0.028; range: 0.828-0.911) of ReHo differences. Diagnostic analysis showed that these areas alone discriminated alcohol-dependent subjects from healthy controls with high degree of sensitivities (mean +/- SD: 81.25% +/- 11.49%; range: 62.5%-100%) and specificities (mean +/- SD: 81.75% +/- 12.36%; range: 67.5%-100%). Years of drink showed negative correlation with left RG (r = 0.493, p = 0.007), the same finding was shown between AUDIT and right CPL (r = 0.52, p = 0.004). Conclusion: Alcohol dependence is associated with aberrant regional activities in multiple brain areas. ReHo analysis may be a useful biological indicator for the detection of regional brain activities in individuals with alcohol dependence. PMID- 29606879 TI - Targeting DTL induces cell cycle arrest and senescence and suppresses cell growth and colony formation through TPX2 inhibition in human hepatocellular carcinoma cells. AB - Background: Hepatocellular carcinoma (HCC) has an increasing incidence and high mortality. Surgical operation is not a comprehensive strategy for liver cancer. Moreover, tolerating systemic chemotherapy is difficult for patients with HCC because hepatic function is often impaired due to underlying cirrhosis. Therefore, a comprehensive strategy for cancer treatment should be developed. DTL (Cdc10-dependent transcript 2) is a critical regulator of cell cycle progression and genomic stability. In our previous study, the upregulation of DTL expression in aggressive HCC correlated positively with tumor grade and poor patient survival. We hypothesize that targeting DTL may provide a novel therapeutic strategy for liver cancer. DTL small interference RNAs were used to knock down DTL protein expression. Methods: A clonogenic assay, immunostaining, double thymidine block, imaging flow cytometry analysis, and a tumor spheroid formation assay were used to analyze the role of DTL in tumor cell growth, cell cycle progression, micronucleation, ploidy, and tumorigenicity. Results: Our results demonstrated that targeting DTL reduced cell cycle regulators and chromosome segregation genes, resulting in increased cell micronucleation. DTL depletion inhibited liver cancer cell growth, increased senescence, and reduced tumorigenesis. DTL depletion resulted in the disruption of the mitotic proteins cyclin B, CDK1, securin, seprase, Aurora A, and Aurora B as well as the upregulation of the cell cycle arrest gene p21. A rescue assay indicated that DTL should be targeted through TPX2 downregulation for cancer cell growth inhibition. Moreover, DTL silencing inhibited the growth of patient-derived primary cultured HCC cells. Conclusion: Our study results indicate that DTL is a potential novel target gene for treating liver cancer through liver cancer cell senescence induction. Furthermore, our results provide insights into molecular mechanisms for targeting DTL in liver cancer cells. The results also indicate several other starting points for future preclinical and clinical studies on liver cancer treatment. PMID- 29606880 TI - Tooth loss and risk of colorectal cancer: a dose-response meta-analysis of prospective cohort studies. AB - Background: Previous studies have indicated that tooth loss is associated with colorectal cancer risk but have presented controversial results. Methods: We conducted a dose-response meta-analysis in order to investigate the correlation between tooth loss and colorectal cancer risk. Up to August 2017, six eligible studies were included in this meta-analysis. Results: Our results showed statistically significant association between tooth loss and colorectal cancer (OR =1.08, 95% CI: 1.03-1.15, P<0.001). In addition, we obtained the best fit at an inflection point of every two tooth loss in piecewise regression analysis, and the summary relative risk (RR) of colorectal cancer for an increase of every two tooth loss was 1.06 (95% CI: 1.02-1.11, P<0.001). Furthermore, tooth loss was significantly associated with colorectal cancer risk in Caucasia (RR: 1.18; 95% CI: 1.09-1.28; P<0.001) and Asia (RR: 1.06; 95% CI: 1.02-1.10; P<0.001). Moreover, tooth loss was significantly associated with a higher risk of colon cancer (RR: 1.09; 95% CI: 1.02-1.17; P<0.001) and rectal cancer (RR: 1.08; 95% CI: 1.01-1.17; P<0.001). Conclusion: Subgroup meta-analyses showed consistency with the primary findings. Considering these promising results, increasing tooth loss may be harmful to our health, and maintenance of our oral health is essential. PMID- 29606881 TI - Open adrenalectomy versus laparoscopic adrenalectomy for adrenocortical carcinoma: a retrospective comparative study on short-term oncologic prognosis. AB - Purpose: Open adrenalectomy (OA) remains the gold standard of surgical therapy for adrenocortical carcinoma, while the role of laparoscopic approach is controversial. We aim to explore the influence of surgical approaches on the oncologic prognosis of adrenocortical carcinoma by comparing the short-term outcomes of patients undergoing OA with those undergoing laparoscopic adrenalectomy (LA). Patients and methods: We retrospectively analyzed the baseline characteristics, perioperative data and short-term prognosis of 42 patients diagnosed with stage I-III adrenocortical carcinoma, receiving OA (n=22) and LA (n=20) as primary therapy. The primary end point was the first recurrence. Results: OA group had larger mean maximum diameter of tumor (10.1+/-3.6 versus 6.3+/-2.2 cm) and lesser benefits in operative time, bleeding loss and postoperative hospital stay than laparoscopic group. Mean disease-free survival (DFS) of OA was 44.8+/-35.1 months, which was longer than 17.5+/-10.4 months of LA, and the rate of 2-year DFS after primary surgery in the open group was higher than in the laparoscopic group (61.1% versus 21.4%, respectively). Rates of 1- and 3-year DFS showed no significant difference. All patients undergoing LA (11/11) showed local recurrent lesions at the first time of recurrence, while 5 of 13 patients undergoing OA did not show local recurrence (P=0.03). Conclusion: OA for adrenocortical carcinoma is superior to laparoscopic approach in terms of DFS and rate of 2-year DFS, in spite of the larger maximum diameter of tumors and lesser benefit during perioperation. After LA, patients are more likely to show local recurrent lesions at the first time of relapse. PMID- 29606882 TI - Effects of isoliquiritigenin on ovarian cancer cells. AB - Background: Ovarian cancer is one of the most fatal gynecologic malignancies, with most patients diagnosed at the late stage due to insidious onset and lack of early onset specific symptoms. Previous studies have implied that isoliquiritigenin (ILQ) is a promising chemopreventive agent against oral cancer. Aim: This study aimed to investigate effects of ILQ and elucidate the related mechanism. Materials and methods: Ovarian cancer cell lines, SKOV3 and OVCAR3, were treated with various concentrations of ILQ to detect the dose-dependent effects of ILQ and select the suitable concentration. CCK8 assay and clone formation efficiency assays were used to detect viability and proliferation. The cell migration, invasion, and apoptosis were evaluated by wound healing assays, transwell, and flow cytometry assays. The expression of apoptosis-related proteins (Caspase-3, Caspase3-p17, Bcl-2, Bax, and Bim) and related-signaling pathway proteins were also detected by Western blot. Results: It was observed that the treatment of ILQ inhibited the survival and proliferation of SKOV3 and OVCAR3 cells. ILQ treatment inhibited migration and invasion, and induced apoptosis in SKOV3 and OVCAR3 cells. Also, the ILQ treatment increased the Bax/Bcl-2 ratio in SKOV3 and OVCAR3 cells, suggesting that a mitochondrial apoptotic pathway was triggered. It was also observed that, after treated with ILQ, the phosphorylated form of Akt and mTOR decreased and the expression of GSK3beta increased, while P70/S6K decreased. ILQ treatment also decreased the expression of Wnt3a and, therefore, caused the decrease of phosphorylated ERK. ILQ also suppressed the PI3K/Akt/mTOR pathway by reduced the expression level of p-Akt, p-mTOR, P70/S6K and Cyclin D1 in Ishikawa and ES-2 cells. Conclusion: The data suggested that ILQ inhibited viability, proliferation, and invasion, and induced apoptosis of SKOV3 and OVCAR3 cells through the PI3K/Akt/mTOR pathway. Together, the data revealed that ILQ treatment may be used as a novel strategy for ovarian cancer therapy. PMID- 29606883 TI - High frequency equipment promotes antibacterial effects dependent on intensity and exposure time. AB - Background: The indiscriminate use of antibiotics has caused bacteria to develop mechanisms of resistance to antibacterial agents, limiting treatment options. Therefore, there is a great need for alternative methods to control infections, especially those related to skin. One of the alternative methods is the high frequency equipment (HFE), which is used on skin conditions as an analgesic, an anti-inflammatory, and mainly to accelerate cicatricial processes and have a bactericidal effect through the formation of ozone. This research investigated the antibacterial effect of HFE on standard cultures of bacteria. Materials and methods: Dilutions (104 colony forming unit mL-1) were performed for Enterobacter aerogenes and Staphylococcus aureus with 24-hour growth bacteria. Then, 1 MUL of each dilution was pipetted into suitable medium and the HFE flashing technique was used at intensities of 6, 8 and 10 mA for 30, 60, 90, 120 and 180 seconds. The control group received no treatment. Plates were incubated at 37 degrees C for 24 hours and then read. Results: The spark at intensity of 6 mA had no bactericidal effect on the E. aerogenes; however, a significant bacterial growth reduction occurred at intensity of 8 mA after 120 and 180 seconds, and at 10 mA, reduction in bacterial growth could already be verified at 30 seconds and total bacterial growth inhibition occurred in 180 seconds. For S. aureus, there was a strong bacterial growth inhibition at all intensities used; however, at 6 mA, absence of bacterium growth after 120 and 180 seconds was observed. By increasing the flashing intensity to 8 and 10 mA, it was observed that the bacterium growth was inhibited after only 30 seconds of irradiation. Conclusion: The HFE has time dependent antibacterial effects against E. aerogenes and S. aureus bacteria that have several resistance mechanisms. PMID- 29606885 TI - Systemic low-grade inflammation in post-traumatic stress disorder: a systematic review. AB - Studies examining post-traumatic stress disorder (PTSD) have either emphasized a relationship between PTSD and a systemically pro-inflammatory state or identified a link between PTSD and chronic disease. The aim of this study was to evaluate the evidence for a relationship between individuals with PTSD and systemic low grade inflammation that has been proposed to underlie chronic disease development in this population. The authors conducted a systematic review of the literature (January 2006 to April 2017) in accordance with the PRISMA statement in the following four databases: PubMed, MEDLINE, PsycINFO, and SPORTDiscus with Full Text. The search strategy was limited to articles published in peer-reviewed journals and to human studies. Nine studies measuring systemic inflammation and discussing its role in chronic disease development were selected for inclusion in this review. The association between markers of systemic inflammation and PTSD was evaluated by the measurement of a variety of systemic inflammatory markers including acute-phase proteins, complement proteins, pro- and anti-inflammatory cytokines, natural killer cells, and white blood cells. In general, systemic inflammatory biomarkers were elevated across the studies in the PTSD groups. There is evidence that PTSD is underpinned by the presence of a systemic low grade inflammatory state. This inflammation may be the mechanism associated with increased risk for chronic disease in the PTSD population. From this, future research should focus on interventions that help to reduce inflammation, such as exercise. PMID- 29606886 TI - Influence of ABCB1 and CYP3A5 gene polymorphisms on pharmacokinetics of apixaban in patients with atrial fibrillation and acute stroke. AB - Introduction: Difficulties in non-vitamin K anticoagulant (NOAC) administration in acute stroke can be associated with changes in pharmacokinetic parameters of NOAC such as biotransformation, distribution, and excretion. Therefore, obtaining data on pharmacokinetics of NOAC and factors that affect it may help develop algorithms for personalized use of this drug class in patients with acute cardioembolic stroke. Patients and methods: Pharmacokinetics of apixaban in patients with acute stroke was studied earlier by Kryukov et al. The present study enrolled 17 patients with cardioembolic stroke, who received 5 mg of apixaban. In order to evaluate the pharmacokinetic parameters of apixaban, venous blood samples were collected before taking 5 mg of apixaban (point 0) and 1, 2, 3, 4, 10, and 12 hours after drug intake. Blood samples were centrifuged at 3000 rpm for 15 minutes. Separate plasma was aliquoted in Eppendorf tubes and frozen at -70 degrees C until analysis. High-performance liquid chromatography mass spectrometry analysis was used to determine apixaban plasma concentration. Genotyping was performed by real-time polymerase chain reaction. CYP3A isoenzyme group activity was evaluated by determining urinary concentration of endogenous substrate of the enzyme and its metabolite (6-beta-hydroxycortisol to cortisol ratio). Statistical analysis was performed using SPSS Statistics version 20.0. The protocol of this study was reviewed and approved by the ethics committee; patients or their representatives signed an informed consent. Results: ABCB1 (rs1045642 and rs4148738) gene polymorphisms do not affect the pharmacokinetics of apixaban as well as CYP3A5 (rs776746) gene polymorphisms. Apixaban pharmacokinetics in groups with different genotypes did not differ statistically significantly. Correlation analysis showed no statistically significant relationship between pharmacokinetic parameters of apixaban and the metabolic activity of CYP3A. Conclusion: Questions such as depending on genotyping results for apixaban dosing and implementation of express genotyping in clinical practice remain open for NOACs. Large population studies are required to clarify the clinical significance of genotyping for this drug class. PMID- 29606884 TI - Proton pump inhibitor-refractory gastroesophageal reflux disease: challenges and solutions. AB - A significant percentage of patients with gastroesophageal reflux disease (GERD) will not respond to proton pump inhibitor (PPI) therapy. The causes of PPI refractory GERD are numerous and diverse, and include adherence, persistent acid, functional disorders, nonacid reflux, and PPI bioavailability. The evaluation should start with a symptom assessment and may progress to imaging, endoscopy, and monitoring of esophageal pH, impedance, and bilirubin. There are a variety of pharmacologic and procedural interventions that should be selected based on the underlying mechanism of PPI failure. Pharmacologic treatments can include antacids, prokinetics, alginates, bile acid binders, reflux inhibitors, and antidepressants. Procedural options include laparoscopic fundoplication and LINX as well as endoscopic procedures, such as transoral incisionless fundoplication and Stretta. Several alternative and complementary treatments of possible benefit also exist. PMID- 29606887 TI - Electrical peripheral nerve stimulation relieves bone cancer pain by inducing Arc protein expression in the spinal cord dorsal horn. AB - Objective: The analgesic effect on chronic pain of peripheral nerve stimulation (PNS) has been proven, but its underlying mechanism remains unknown. Therefore, this study aimed to assess the analgesic effect of PNS on bone cancer pain in a rat model and to explore the underlying mechanism. Materials and methods: PNS on sciatic nerves with bipolar electrode was performed in both naive and bone cancer pain model rats. Then, the protein levels of activity-regulated cytoskeleton associated protein (Arc), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid-type glutamate receptor 1 (GluA1), and phosphate N-methyl-d-aspartic acid type glutamate receptor subunit 2B (pGluNR2B) in spinal cord were evaluated by immunohistochemistry and Western blotting. Thermal paw withdraw latency and mechanical paw withdraw threshold were used to estimate the analgesic effect of PNS on bone cancer pain. Intrathecal administration of Arc shRNA was used to inhibit Arc expression in the spinal cord. Results: PNS at 60 and 120 Hz for 20 min overtly induced Arc expression in the spinal cord, increased thermal pain thresholds in naive rats, and relieved bone cancer pain; meanwhile, 10 Hz PNS did not achieve those results. In addition, PNS at 60 and 120 Hz also reduced the expression of GluA1, but not pGluNR2B, in the spinal cord. Finally, the anti nociceptive effect and GluA1 downregulation induced by PNS were inhibited by intrathecal administration of Arc shRNA. Conclusion: PNS (60 Hz, 0.3 mA) can relieve bone-cancer-induced allodynia and hyperalgesia by upregulating Arc protein expression and then by decreasing GluA1 transcription in the spinal cord dorsal horn. PMID- 29606889 TI - Management and prognosis of patients with liver metastases from gestational trophoblastic neoplasia: a retrospective cohort study. AB - Purpose: The aims of this study were to analyze the clinical features, identify prognostic factors, and evaluate the survival outcomes of gestational trophoblastic neoplasia (GTN) patients with liver metastases. Patients and methods: Forty patients with liver metastases arising from GTNs, who were treated at the Peking Union Medical College Hospital (Beijing, People's Republic of China) between January 1999 and December 2015, were recruited from the institutional database, and their medical records were reviewed. Univariate and multivariate analyses were performed to identify independent risk factors for survival. Results: Twenty-seven patients (67.5%) achieved complete remission after multidrug chemotherapy treatment. The remaining 13 patients (32.5%) had disease progression. Eighteen patients (45.0%) died during treatment or follow up. A history of failed multidrug chemotherapy was an independent risk factor for survival (OR: 5.57, 95% CI: 1.42-21.86, P=0.014). Moreover, patients with an International Federation of Gynecology and Obstetrics (FIGO) score of >16 had a significantly poorer survival than those with a score of <=16 (P<0.001). Conclusion: GTN with liver metastasis is a very rare disease with a relatively poor prognosis. Patients with a history of failed multidrug chemotherapy and a FIGO score of >16 have poorer survival outcomes. Multidrug chemotherapy is the key to the management of GTN patients with liver metastases. PMID- 29606888 TI - A combination of p53-activating APR-246 and phosphatidylserine-targeting antibody potently inhibits tumor development in hormone-dependent mutant p53-expressing breast cancer xenografts. AB - Background: Between 30 and 40% of human breast cancers express a defective tumor suppressor p53 gene. Wild-type p53 tumor suppressor protein promotes cell-cycle arrest and apoptosis and inhibits vascular endothelial growth factor-dependent angiogenesis, whereas mutant p53 protein (mtp53) lacks these functions, resulting in tumor cell survival and metastasis. Restoration of p53 function is therefore a promising drug-targeted strategy for combating mtp53-expressing breast cancer. Methods: In this study, we sought to determine whether administration of APR-246, a small-molecule drug that restores p53 function, in combination with 2aG4, an antibody that targets phosphatidylserine residues on tumor blood vessels and disrupts tumor vasculature, effectively inhibits advanced hormone-dependent breast cancer tumor growth. Results: APR-246 reduced cell viability in mtp53 expressing BT-474 and T47-D human breast cancer cells in vitro, and significantly induced apoptosis in a dose-dependent manner. However, APR-246 did not reduce cell viability in MCF-7 breast cancer cells, which express wild-type p53. We next examined APR-246's anti-tumor effects in vivo using BT-474 and T47-D tumor xenografts established in female nude mice. Tumor-bearing mice were treated with APR-246 and/or 2aG4 and tumor volume followed over time. Tumor growth was more effectively suppressed by combination treatment than by either agent alone, and combination therapy completely eradicated some tumors. Immunohistochemistry analysis of tumor tissue sections demonstrated that combination therapy more effectively induced apoptosis and reduced cell proliferation in tumor xenografts than either agent alone. Importantly, combination therapy dramatically reduced the density of blood vessels, which serve as the major route for tumor metastasis, in tumor xenografts compared with either agent alone. Conclusion: Based on our findings, we contend that breast tumor growth might effectively be controlled by simultaneous targeting of mtp53 protein and tumor blood vessels in mtp53-expressing cancers. PMID- 29606890 TI - L61H46 shows potent efficacy against human pancreatic cancer through inhibiting STAT3 pathway. AB - Background: Pancreatic cancer is the fourth leading cause of cancer-related death worldwide. The poor prognosis of this disease highlights the urgent need to develop more effective therapies. Activation of the STAT3 represents a potential drug target for pancreatic cancer therapy. Currently, clinically available small molecule inhibitors targeting STAT3 are lacking. Methods: Through bioassay screening and molecular docking, we identified a small molecule L61H46 that can potently target constitutive STAT3 signaling and kill human pancreatic cancer cells in vitro and in vivo. Results: L61H46 effectively reduced colony formation and the viability of pancreatic cancer cells in a dose-dependent manner with half maximal inhibitory concentration (IC50) values in the range between 0.86 and 2.83 uM. L61H46 significantly inhibited STAT3 phosphorylation (Tyr705) and the subsequent nucleus translocation but did not downregulate STAT1 phosphorylation. Moreover, L61H46 demonstrated a potent activity in suppressing pancreatic tumor growth in BXPC-3 xenograft model in vivo. Furthermore, L61H46 showed no signs of adverse effects on liver, heart, and kidney cells in vivo. Conclusion: Collectively, our results suggest that L61H46 could be further optimized into a highly potent STAT3 inhibitor for the treatment of pancreatic cancer. PMID- 29606891 TI - Critical concepts in adaptive clinical trials. AB - Adaptive clinical trials are an innovative trial design aimed at reducing resources, decreasing time to completion and number of patients exposed to inferior interventions, and improving the likelihood of detecting treatment effects. The last decade has seen an increasing use of adaptive designs, particularly in drug development. They frequently differ importantly from conventional clinical trials as they allow modifications to key trial design components during the trial, as data is being collected, using preplanned decision rules. Adaptive designs have increased likelihood of complexity and also potential bias, so it is important to understand the common types of adaptive designs. Many clinicians and investigators may be unfamiliar with the design considerations for adaptive designs. Given their complexities, adaptive trials require an understanding of design features and sources of bias. Herein, we introduce some common adaptive design elements and biases and specifically address response adaptive randomization, sample size reassessment, Bayesian methods for adaptive trials, seamless trials, and adaptive enrichment using real examples. PMID- 29606892 TI - Management of abnormal uterine bleeding - focus on ambulatory hysteroscopy. AB - The rapid evolution in ambulatory hysteroscopy (AH) has transformed the approach to diagnose and manage abnormal uterine bleeding (AUB). The medical management in primary care remains the mainstay for initial treatment of this common presentation; however, many women are referred to secondary care for further evaluation. To confirm the diagnosis of suspected intrauterine pathology, the traditional diagnostic tool of day case hysteroscopy and dilatation and curettage in a hospital setting under general anesthesia is now no longer required. The combination of ultrasound diagnostics and modern AH now allows thorough evaluation of uterine cavity in an outpatient setting. Advent of miniature hysteroscopic operative systems has revolutionized the ways in which clinicians can not only diagnose but also treat menstrual disorders such as heavy menstrual bleeding, intermenstrual bleeding and postmenopausal bleeding in most women predominantly in a one-stop clinic. This review discussed the approach to manage women presenting with AUB with a focus on the role of AH in the diagnosis and treatment of this common condition in an outpatient setting. PMID- 29606893 TI - First-in-man intravenous implantation of stromal vascular fraction in psoriasis: a case study. AB - Background: Stromal vascular fraction (SVF) is a mixture of adipose-derived stem cells/mesenchymal stem cells, endothelial/progenitors, pericytes, fibroblasts, and other cells obtained from fat tissue. A small sample of fat or adipose tissue can be obtained under local anesthesia using a cannula. After an enzymatic digestion and centrifugation, the adipocytes (fat cells) are removed to obtain an SVF. Here, we describe the rationale and, to our knowledge, the first clinical implementation of SVF intravenously in a patient with severe psoriasis. Methods: Adipose tissue (60 mL) was collected under local anesthesia via a mini lipoaspirate procedure. The SVF was separated from the adipocytes via centrifugation after an enzymatic digestion. The cells were resuspended in normal saline and injected via bolus push intravenous. The subject was monitored over a period of 12 months for safety (adverse events), medication changes, and quality of life parameters. Results: The patient did not report any safety concerns and did not experience any severe adverse events. The patient demonstrated a significant decrease in symptoms with a noticeable difference in skin quality appearance. Psoriasis area and severity index score went from 50.4 at baseline to 0.3 at 1 month follow-up. Conclusion: Overall, the patient reported improved quality of life and willingness to continue treatments. This successful initial case study demonstrates that this may be a feasible treatment plan for patients suffering from psoriasis. PMID- 29606894 TI - A new mini-navigation tool allows accurate component placement during anterior total hip arthroplasty. AB - Introduction: Computer-assisted navigation systems have been explored in total hip arthroplasty (THA) to improve component positioning. While these systems traditionally rely on anterior pelvic plane registration, variances in soft tissue thickness overlying anatomical landmarks can lead to registration error, and the supine coronal plane has instead been proposed. The purpose of this study was to evaluate the accuracy of a novel navigation tool, using registration of the anterior pelvic plane or supine coronal plane during simulated anterior THA. Methods: Measurements regarding the acetabular component position, and changes in leg length and offset were recorded. Benchtop phantoms and target measurement values commonly seen in surgery were used for analysis. Measurements for anteversion and inclination, and changes in leg length and offset were recorded by the navigation tool and compared with the known target value of the simulation. Pearson's r assessed the relationship between the measurements of the device and the known target values. Results: The device accurately measured cup position and leg length measurements to within 1 degrees and 1 mm of the known target values, respectively. Across all simulations, there was a strong, positive relationship between values obtained by the device and the known target values (r=0.99). Conclusion: The preliminary findings of this study suggest that the novel navigation tool tested is a potentially viable tool to improve the accuracy of component placement during THA using the anterior approach. PMID- 29606896 TI - Deconstructing programmatic assessment. AB - We describe programmatic assessment and the problems it might solve in relation to assessment and learning, identify some models implemented internationally, and then outline what we believe are programmatic assessment's key components and what these components might achieve. We then outline some issues around implementation, which include blueprinting, data collection, decision making, staff support, and evaluation. Rather than adopting an all-or-nothing approach, we suggest that elements of programmatic assessment can be gradually introduced into traditional assessment systems. PMID- 29606895 TI - Hepatic encephalopathy: current challenges and future prospects. AB - Hepatic encephalopathy (HE) is a common complication of liver dysfunction, including acute liver failure and liver cirrhosis. HE presents as a spectrum of neuropsychiatric symptoms ranging from subtle fluctuating cognitive impairment to coma. It is a significant contributor of morbidity in patients with liver disease. HE is observed in acute liver failure, liver bypass procedures, for example, shunt surgry and transjugular intrahepatic portosystemic shunt, and cirrhosis. These are classified as Type A, B and C HE, respectively. HE can also be classified according to whether its presence is overt or covert. The pathogenesis is linked with ammonia and glutamine production, and treatment is based on mechanisms to reduce the formation and/or removal of these compounds. There is no specific diagnostic test for HE, and diagnosis is based on clinical suspicion, excluding other causes and use of clinical tests that may support its diagnosis. Many tests are used in trials and experimentally, but have not yet gained universal acceptance. This review focuses on the definitions, pathogenesis and treatment of HE. Consideration will be given to existing treatment, including avoidance of precipitating factors and novel therapies such as prebiotics, probiotics, antibiotics, laxatives, branched-chain amino acids, shunt embolization and the importance of considering liver transplant in appropriate cases. PMID- 29606897 TI - A systematic review of primary prevention strategies for sexual violence perpetration. AB - This systematic review examined 140 outcome evaluations of primary prevention strategies for sexual violence perpetration. The review had two goals: 1) to describe and assess the breadth, quality, and evolution of evaluation research in this area; and 2) to summarize the best available research evidence for sexual violence prevention practitioners by categorizing programs with regard to their evidence of effectiveness on sexual violence behavioral outcomes in a rigorous evaluation. The majority of sexual violence prevention strategies in the evaluation literature are brief, psycho-educational programs focused on increasing knowledge or changing attitudes, none of which have shown evidence of effectiveness on sexually violent behavior using a rigorous evaluation design. Based on evaluation studies included in the current review, only three primary prevention strategies have demonstrated significant effects on sexually violent behavior in a rigorous outcome evaluation: Safe Dates (Foshee et al., 2004); Shifting Boundaries (building-level intervention only, Taylor, Stein, Woods, Mumford, & Forum, 2011); and funding associated with the 1994 U.S. Violence Against Women Act (VAWA; Boba & Lilley, 2009). The dearth of effective prevention strategies available to date may reflect a lack of fit between the design of many of the existing programs and the principles of effective prevention identified by Nation et al. (2003). PMID- 29606898 TI - In Situ Structural Characterization of Ageing Kinetics in Aluminum Alloy 2024 across Angstrom-to-Micrometer Length Scales. AB - The precipitate structure and precipitation kinetics in an Al-Cu-Mg alloy (AA2024) aged at 190 degrees C, 208 degrees C, and 226 degrees C have been studied using ex situ Transmission Electron Microscopy (TEM) and in situ synchrotron-based, combined ultra-small angle X-ray scattering, small angle X-ray scattering (SAXS), and wide angle X-ray scattering (WAXS) across a length scale from sub-Angstrom to several micrometers. TEM brings information concerning the nature, morphology, and size of the precipitates while SAXS and WAXS provide qualitative and quantitative information concerning the time-dependent size and volume fraction evolution of the precipitates at different stages of the precipitation sequence. Within the experimental time resolution, precipitation at these ageing temperatures involves dissolution of nanometer-sized small clusters and formation of the planar S phase precipitates. Using a three-parameter scattering model constructed on the basis of TEM results, we established the temperature-dependent kinetics for the cluster-dissolution and S-phase formation processes simultaneously. These two processes are shown to have different kinetic rates, with the cluster-dissolution rate approximately double the S-phase formation rate. We identified a dissolution activation energy at (149.5 +/- 14.6) kJ mol-1, which translates to (1.55 +/- 0.15) eV/atom, as well as an activation energy for the formation of S precipitates at (129.2 +/- 5.4) kJ mol-1, i.e. (1.33 +/- 0.06) eV/atom. Importantly, the SAXS/WAXS results show the absence of an intermediate Guinier-Preston Bagaryatsky 2 (GPB2)/S" phase in the samples under the experimental ageing conditions. These results are further validated by precipitation simulations that are based on Langer-Schwartz theory and a Kampmann Wagner numerical method. PMID- 29606899 TI - Analysis of gob gas venthole production performances for strata gas control in longwall mining. AB - Longwall mining of coal seams affects a large area of overburden by deforming it and creating stress-relief fractures, as well as bedding plane separations, as the mining face progresses. Stress-relief fractures and bedding plane separations are recognized as major pathways for gas migration from gas-bearing strata into sealed and active areas of the mines. In order for strata gas not to enter and inundate the ventilation system of a mine, gob gas ventholes (GGVs) can be used as a methane control measure. The aim of this paper is to analyze production performances of GGVs drilled over a longwall panel. These boreholes were drilled to control methane emissions from the Pratt group of coals due to stress-relief fracturing and bedding plane separations into a longwall mine operating in the Mary Lee/Blue Creek coal seam of the Upper Pottsville Formation in the Black Warrior Basin, Alabama. During the course of the study, Pratt coal's reservoir properties were integrated with production data of the GGVs. These data were analyzed by using material balance techniques to estimate radius of influence of GGVs, gas-in-place and coal pressures, as well as their variations during mining. The results show that the GGVs drilled to extract gas from the stress-relief zone of the Pratt coal interval is highly effective in removing gas from the Upper Pottsville Formation. The radii of influence of the GGVs were in the order of 330 380 m, exceeding the widths of the panels, due to bedding plane separations and stress relieved by fracturing. Material balance analyses indicated that the initial pressure of the Pratt coals, which was around 648 KPa when longwall mining started, decreased to approximately 150 KPa as the result of strata fracturing and production of released gas. Approximately 70% of the initial gas in-place within the area of influence of the GGVs was captured during a period of one year. PMID- 29606900 TI - Leveraging Statistical Physics to Improve Understanding of Cooperation in Multiplex Networks. AB - Understanding how public cooperation emerges and is maintained is a topic of broad interest, with increasing contributions coming from a synergistic combination of evolutionary game theory and statistical physics. The comprehensive study by Battiston et al (2017 New J. Phys., in press) improves our understanding of the role of multiplexity in cooperation, revealing that a significant edge overlap across network layers along with benign conditions for cooperation in at least one of the layers is needed to facilitate the emergence of cooperation in the multiplex. PMID- 29606901 TI - Editorial: Molecular Cyto(post)genomics. PMID- 29606902 TI - Behavioral Variability and Somatic Mosaicism: A Cytogenomic Hypothesis. AB - Behavioral sciences are inseparably related to genetics. A variety of neurobehavioral phenotypes are suggested to result from genomic variations. However, the contribution of genetic factors to common behavioral disorders (i.e. autism, schizophrenia, intellectual disability) remains to be understood when an attempt to link behavioral variability to a specific genomic change is made. Probably, the least appreciated genetic mechanism of debilitating neurobehavioral disorders is somatic mosaicism or the occurrence of genetically diverse (neuronal) cells in an individual's brain. Somatic mosaicism is assumed to affect directly the brain being associated with specific behavioral patterns. As shown in studies of chromosome abnormalities (syndromes), genetic mosaicism is able to change dynamically the phenotype due to inconsistency of abnormal cell proportions. Here, we hypothesize that brain-specific postzygotic changes of mosaicism levels are able to modulate variability of behavioral phenotypes. More precisely, behavioral phenotype variability in individuals exhibiting somatic mosaicism might correlate with changes in the amount of genetically abnormal cells throughout the lifespan. If proven, the hypothesis can be used as a basis for therapeutic interventions through regulating levels of somatic mosaicism to increase functioning and to improve overall condition of individuals with behavioral problems. PMID- 29606903 TI - Mosaic Brain Aneuploidy in Mental Illnesses: An Association of Low-level Post zygotic Aneuploidy with Schizophrenia and Comorbid Psychiatric Disorders. AB - Background: Postzygotic chromosomal variation in neuronal cells is hypothesized to make a substantial contribution to the etiology and pathogenesis of neuropsychiatric disorders. However, the role of somatic genome instability and mosaic genome variations in common mental illnesses is a matter of conjecture. Materials and Methods: To estimate the pathogenic burden of somatic chromosomal mutations, we determined the frequency of mosaic aneuploidy in autopsy brain tissues of subjects with schizophrenia and other psychiatric disorders (intellectual disability comorbid with autism spectrum disorders). Recently, post mortem brain tissues of subjects with schizophrenia, intellectual disability and unaffected controls were analyzed by Interphase Multicolor FISH (MFISH), Quantitative Fluorescent in situ Hybridization (QFISH) specially designed to register rare mosaic chromosomal mutations such as lowlevel aneuploidy (whole chromosome mosaic deletion/duplication). The low-level mosaic aneuploidy in the diseased brain demonstrated significant 2-3-fold frequency increase in schizophrenia (p=0.0028) and 4-fold increase in intellectual disability comorbid with autism (p=0.0037) compared to unaffected controls. Strong associations of low-level autosomal/sex chromosome aneuploidy (p=0.001, OR=19.0) and sex chromosome-specific mosaic aneuploidy (p=0.006, OR=9.6) with schizophrenia were revealed. Conclusion: Reviewing these data and literature supports the hypothesis suggesting that an association of low-level mosaic aneuploidy with common and, probably, overlapping psychiatric disorders does exist. Accordingly, we propose a pathway for common neuropsychiatric disorders involving increased burden of rare de novo somatic chromosomal mutations manifesting as low-level mosaic aneuploidy mediating local and general brain dysfunction. PMID- 29606904 TI - 4q21.2q21.3 Duplication: Molecular and Neuropsychological Aspects. AB - During the last decades, a large amount of newly described microduplications and microdeletions associated with intellectual disability (ID) and related neuropsychiatric diseases have been discovered. However, due to natural limitations, a significant part of them has not been the focus of multidisciplinary approaches. Here, we address previously undescribed chromosome 4q21.2q21.3 microduplication for gene prioritization, evaluation of cognitive abilities and estimation of genomic mechanisms for brain dysfunction by molecular cytogenetic (cytogenomic) and gene expression (meta-) analyses as well as for neuropsychological assessment. We showed that duplication at 4q21.2q21.3 is associated with moderate ID, cognitive deficits, developmental delay, language impairment, memory and attention problems, facial dysmorphisms, congenital heart defect and dentinogenesis imperfecta. Gene-expression meta-analysis prioritized the following genes: ENOPH1, AFF1, DSPP, SPARCL1, and SPP1. Furthermore, genotype/phenotype correlations allowed the attribution of each gene gain to each phenotypic feature. Neuropsychological testing showed visual-perceptual and fine motor skill deficits, reduced attention span, deficits of the nominative function and problems in processing both visual and aural information. Finally, emerging approaches including molecular cytogenetic, bioinformatic (genome/epigenome meta analysis) and neuropsychological methods are concluded to be required for comprehensive neurological, genetic and neuropsychological descriptions of new genomic rearrangements/diseases associated with ID. PMID- 29606905 TI - Polytene Chromosomes - A Portrait of Functional Organization of the Drosophila Genome. AB - This mini-review is devoted to the problem genetic meaning of main polytene chromosome structures - bands and interbands. Generally, densely packed chromatin forms black bands, moderately condensed regions form grey loose bands, whereas decondensed regions of the genome appear as interbands. Recent progress in the annotation of the Drosophila genome and epigenome has made it possible to compare the banding pattern and the structural organization of genes, as well as their activity. This was greatly aided by our ability to establish the borders of bands and interbands on the physical map, which allowed to perform comprehensive side by-side comparisons of cytology, genetic and epigenetic maps and to uncover the association between the morphological structures and the functional domains of the genome. These studies largely conclude that interbands 5'-ends of housekeeping genes that are active across all cell types. Interbands are enriched with proteins involved in transcription and nucleosome remodeling, as well as with active histone modifications. Notably, most of the replication origins map to interband regions. As for grey loose bands adjacent to interbands, they typically host the bodies of house-keeping genes. Thus, the bipartite structure composed of an interband and an adjacent grey band functions as a standalone genetic unit. Finally, black bands harbor tissue-specific genes with narrow temporal and tissue expression profiles. Thus, the uniform and permanent activity of interbands combined with the inactivity of genes in bands forms the basis of the universal banding pattern observed in various Drosophila tissues. PMID- 29606906 TI - Small Supernumerary Marker Chromosome May Provide Information on Dosage insensitive Pericentric Regions in Human. AB - Background: Cytogenetically visible chromosomal imbalances in humans are deleterious and adverse in the majority of the cases. However, healthy persons living with chromosomal imbalances in the range of several megabasepairs (Mbps) in size, like carriers of small Supernumerary Marker Chromosomes (sSMCs) exist. Materials & Methods: The identification of healthy sSMC carriers with euchromatic centromere-near (ECN) imbalances led to the following proposal: ECN-regions do not contain any dosage sensitive genes. Due to own previous work, dosage insensitive pericentric ECN-regions were already determined with an accuracy of 0.3 and 5 Mbp. Based on this data we established 43 new pericentromeric probe sets spanning about 3-5 Mbp of each euchromatic human chromosome arm starting from the known insensitive regions towards distal. Such so called pericentromeric critical region fluorescence in situ hybridization (PeCR-FISH) probe sets were applied exemplarily and successful here in 15 sSMC cases as available from the Else Kroner-Fresenius-sSMC-cellbank . Conclusion: Most of the involved sSMC breakpoints could be characterized as a higher resolution than before. An unexpected result was that in 5/15 cases cryptic mosaicism was characterized. The latter is also to be considered to have potentially an influence on the clinical outcome in these so-called discontinuous sSMCs. Overall, the suitability of PeCR-FISH to characterize sSMCs was proven; the potential of this probe set to further delineate sizes of dosage insensitive pericentric regions is obvious but dependent on suited cases. Furthermore, discontinuous sSMCs can be identified by this approach and this new subtype of sSMC needs to be studied in more detail in future. PMID- 29606907 TI - Detecting Chromosome Condensation Defects in Gulf War Illness Patients. AB - Background: Gulf War Illness (GWI) impacts 25-30% of gulf war veterans. Due to its heterogeneity in both etiology and symptoms, it has been challenging to establish the commonly accepted case definition for GWI. Equally challenging are the understanding of the general mechanism of GWI and the development of biomarkers useful for its clinical diagnosis and treatment. Objective: We have observed that chromosome condensation defects can be detected in GWI patients. To document this phenomenon in GWI, we aim to describe and compare different types of chromosomal condensation defects in GWI patients, if possible. Since chromosomal condensation represents an important step of ensuring genome integrity, condensation defects could be used as a potential biomarker of GWI. Methods: Lymphocytes from GWI patients have been used for short term cell culture followed by chromosome slide preparation. Both Giemsa staining and multiple color spectral karyotyping (SKY) were applied to study chromosome aberrations, focusing on different types of condensation defects. Results: At least three subtypes of Defective Mitotic Figures (DMFs) were observed. Some individuals displayed elevated frequencies of DMFs. Another type of condensation defect identified as sticky chromosomes were also observed. Conclusion: Various types of condensation defects have been observed in GWI patients. It is rather surprising that some GWI patients exhibited a high level of chromosomal condensation defects. Previously, the elevated frequency of DMFs was only observed in cancer patients. Since chromosome condensation can be linked to other types of chromosome aberrations, as well as cellular stress conditions, the detailed mechanism and clinical impact should be further studied, especially with increased sample size. PMID- 29606908 TI - Molecular Cytogenetic Analysis of One African and Five Asian Macaque Species Reveals Identical Karyotypes as in Mandrill. AB - Background: The question how evolution and speciation work is one of the major interests of biology. Especially, genetic including karyotypic evolution within primates is of special interest due to the close phylogenetic position of Macaca and Homo sapiens and the role as in vivo models in medical research, neuroscience, behavior, pharmacology, reproduction and Acquired Immune Deficiency Syndrome (AIDS). Materials & Methods: Karyotypes of five macaque species from South East Asia and of one macaque species as well as mandrill from Africa were analyzed by high resolution molecular cytogenetics to obtain new insights into karyotypic evolution of old world monkeys. Molecular cytogenetics applying human probes and probe sets was applied in chromosomes of Macaca arctoides, M. fascicularis, M. nemestrina, M. assamensis, M. sylvanus, M. mulatta and Mandrillus sphinx. Established two- to multicolor-fluorescence in situ hybridization (FISH) approaches were applied. Locus-specific probes, whole and partial chromosome paint probes were hybridized. Especially the FISH-banding approach multicolor-banding (MCB) as well as probes oriented towards heterochromatin turned out to be highly efficient for interspecies comparison. Conclusion: Karyotypes of all seven studied species could be characterized in detail. Surprisingly, no evolutionary conserved differences were found among macaques, including mandrill. Between the seven here studied and phenotypically so different species we expected several via FISH detectable karyoypic and submicroscopic changes and were surprised to find none of them on a molecular cytogenetic level. Spatial separation, may explain the speciation and different evolution for some of them, like African M. sylvanus, Mandrillus sphinx and the South Asian macaques. However, for the partially or completely overlapping habitats of the five studied South Asian macaques the species separation process can also not be deduced to karyotypic separation. PMID- 29606909 TI - Early Stages of XY Sex Chromosomes Differentiation in the Fish Hoplias malabaricus (Characiformes, Erythrinidae) Revealed by DNA Repeats Accumulation. AB - Background: Species with 'young' or nascent sex chromosomes provide unique opportunities to understand early evolutionary mechanisms (e.g. accumulation of repetitive sequences, cessation of recombination and gene loss) that drive the evolution of sex chromosomes. Among vertebrates, fishes exhibit highly diverse and a wide spectrum of sex-determining mechanisms and sex chromosomes, ranging from cryptic to highly differentiated ones, as well as, from simple to multiple sex chromosome systems. Such variability in sex chromosome morphology and composition not only exists within closely related taxa, but often within races/populations of the same species. Inside this context, the wolf fish Hoplias malabaricus offers opportunity to investigate the evolution of morphologically variable sex chromosomes within a species complex, as homomorphic to highly differentiated sex chromosome systems occur among its different karyomorphs. Materials & Methods: To discover various evolutionary stages of sex chromosomes and to compare their sequence composition among the wolf fish's karyomorphs, we applied multipronged molecular cytogenetic approaches, including C-banding, repetitive DNAs mapping, Comparative Genomic Hybridization (CGH) and Whole Chromosomal Painting (WCP). Our study was able to characterize a cryptically differentiated XX/XY sex chromosome system in the karyomorph F of this species. Conclusion: The Y chromosome was clearly identified by an interstitial heterochromatic block on the short arms, primarily composed of microsatellite motifs and retrotransposons. Additionally, CGH also identified a male specific chromosome region in the same chromosomal location, implying that the accumulation of these repeats may have initiated the Y chromosome differentiation, as well as played a critical role towards the evolution and differentiation of sex chromosomes in various karyomorphs of this species. PMID- 29606911 TI - A Girl with 10 Mb Distal Xp Deletion Arising from Maternal Pericentric Inversion: Clinical Data and Molecular Characterization. AB - Background: Short arm deletions of the X-chromosome are challenging issues for genetic counseling due to their low penetrance in population. Female carriers of these deletions have milder phenotype than male ones, considering the intellectual ability and social skills, probably because of the X-chromosome inactivation phenomenon. Case report: A female patient with a 10Mb distal Xp deletion and an Xq duplication, showing mild intellectual disability, is described in this report. While the deletion arose from a maternal pericentric inversion, the duplication was directly transmitted from the mother who is phenotypically normal. Conclusion: This report underlines the usefulness of molecular cytogenetic technics in postnatal diagnosis. PMID- 29606910 TI - A Postgenomic Perspective on Molecular Cytogenetics. AB - Background: The postgenomic era is featured by massive data collection and analyses from various large scale-omics studies. Despite the promising capability of systems biology and bioinformatics to handle large data sets, data interpretation, especially the translation of -omics data into clinical implications, has been challenging. Discussion: In this perspective, some important conceptual and technological limitations of current systems biology are discussed in the context of the ultimate importance of the genome beyond the collection of all genes. Following a brief summary of the contributions of molecular cytogenetics/cytogenomics in the pre- and post-genomic eras, new challenges for postgenomic research are discussed. Such discussion leads to a call to search for a new conceptual framework and holistic methodologies. Conclusion: Throughout this synthesis, the genome theory of somatic cell evolution is highlighted in contrast to gene theory, which ignores the karyotype mediated higher level of genetic information. Since "system inheritance" is defined by the genome context (gene content and genomic topology) while "parts inheritance" is defined by genes/epigenes, molecular cytogenetics and cytogenomics (which directly study genome structure, function, alteration and evolution) will play important roles in this postgenomic era. PMID- 29606912 TI - Pre-inflation from the multiverse: can it solve the quadrupole problem in the cosmic microwave background? AB - We analyze a quantized toy model of a universe undergoing eternal inflation using a quantum-field-theoretical formulation of the Wheeler-DeWitt equation. This so called third quantization method leads to the picture that the eternally inflating universe is converted to a multiverse in which sub-universes are created and exhibit a distinctive phase in their evolution before reaching an asymptotic de Sitter phase. From the perspective of one of these sub-universes, we can thus analyze the pre-inflationary phase that arises naturally. Assuming that our observable universe is represented by one of those sub-universes, we calculate how this pre-inflationary phase influences the power spectrum of the cosmic microwave background (CMB) anisotropies and analyze whether it can explain the observed discrepancy of the power spectrum on large scales, i.e. the quadrupole issue in the CMB. While the answer to this question is negative in the specific model analyzed here, we point out a possible resolution of this issue. PMID- 29606913 TI - Navigating between two cultures: Immigrants' gender attitudes toward working women. AB - BACKGROUND: Gender attitudes toward women's employment are of particular importance because they positively influence gender-equal outcomes in the labor market. Our understanding of the mechanisms that promote egalitarian gender attitudes among immigrants, however, remains limited. OBJECTIVE: By studying first- and second-generation immigrants from multiple origins and living in different countries, this article seeks to explain under what conditions the prevalent cultural attitudes toward gender roles at the origin and destination influence immigrants' gender attitudes. We address three main research questions. First, does the country-of-origin gender ideology influence immigrants' views toward working women? Second, does the country-of-destination gender ideology influence immigrants' view toward working women? Are these relationships moderated by (1) the immigrant generation; (2) the age at arrival in the country of destination; (3) the length of residence at destination? METHODS: Using data from the European Social Survey, we model immigrants' gender attitudes toward working women using linear cross-classified models to account for clustering into the country of origin and destination. RESULTS: The results highlight the importance of the context of early socialization in shaping immigrants' gender attitudes. First-generation immigrants, and more specifically, adult migrants hold gender attitudes that reflect more strongly the country of origin's gender culture. In contrast, the positive association between gender ideology at destination and immigrants' gender attitudes is stronger among second-generation immigrants and child migrants. CONTRIBUTION: We add to the literature on gender ideology formation by analyzing the influence of gender ideology at the origin- and destination-levels on the gender attitudes of immigrants from 96 countries of origin and residing across 32 countries of destination. PMID- 29606914 TI - An introduction to Item Response Theory and Rasch Analysis of the Eating Assessment Tool (EAT-10). AB - Item response theory has its origins in educational measurement and is now commonly applied in health-related measurement of latent traits, such as function and symptoms. This application is due in large part to gains in the precision of measurement attributable to item response theory and corresponding decreases in response burden, study costs, and study duration. The purpose of this paper is twofold: introduce basic concepts of item response theory and demonstrate this analytic approach in a worked example, a Rasch model (1PL) analysis of the Eating Assessment Tool (EAT-10), a commonly used measure for oropharyngeal dysphagia. The results of the analysis were largely concordant with previous studies of the EAT-10 and illustrate for brain impairment clinicians and researchers how IRT analysis can yield greater precision of measurement. PMID- 29606915 TI - Comprehensive Women-centered Treatment for Substance Use Disorders in Georgia: Current Status and Future Directions. AB - The present paper examines the current status of women-centered substance use disorder treatment in Georgia. Four major issues are identified that adversely impact the delivery of effective services for women with substance use disorders: Policy Issues; Sociocultural Issues; Programmatic/Structural Issues; and Personal/Interpersonal Issues. These four issues are seen to form a complex, dynamic system that serves to maintain the current ineffective service delivery system and suppresses movement toward an effective service delivery for this highly marginalized and at-risk population. How these issues, and their interplay, present continuing barriers to the development and implementation of effective treatment for this population are outlined and discussed. In order to overcome these barriers, solutions must be sought in four areas: Policy reform; Public health campaigns; Development and implementation of comprehensive women specific confidential treatment models; and Empowering women. Specific goals in each of these areas that would achieve a positive impact on various aspects of the functioning of the current service delivery system for women with substance use disorders are suggested. Simultaneously seeking solutions in all four of these areas would improve the service delivery system and benefits women with substance use disorders. PMID- 29606916 TI - Sayette Group Formation Task (GFT) Spontaneous Facial Expression Database. AB - Despite the important role that facial expressions play in interpersonal communication and our knowledge that interpersonal behavior is influenced by social context, no currently available facial expression database includes multiple interacting participants. The Sayette Group Formation Task (GFT) database addresses the need for well-annotated video of multiple participants during unscripted interactions. The database includes 172,800 video frames from 96 participants in 32 three-person groups. To aid in the development of automated facial expression analysis systems, GFT includes expert annotations of FACS occurrence and intensity, facial landmark tracking, and baseline results for linear SVM, deep learning, active patch learning, and personalized classification. Baseline performance is quantified and compared using identical partitioning and a variety of metrics (including means and confidence intervals). The highest performance scores were found for the deep learning and active patch learning methods. Learn more at http://osf.io/7wcyz. PMID- 29606917 TI - FERA 2017 - Addressing Head Pose in the Third Facial Expression Recognition and Analysis Challenge. AB - The field of Automatic Facial Expression Analysis has grown rapidly in recent years. However, despite progress in new approaches as well as benchmarking efforts, most evaluations still focus on either posed expressions, near-frontal recordings, or both. This makes it hard to tell how existing expression recognition approaches perform under conditions where faces appear in a wide range of poses (or camera views), displaying ecologically valid expressions. The main obstacle for assessing this is the availability of suitable data, and the challenge proposed here addresses this limitation. The FG 2017 Facial Expression Recognition and Analysis challenge (FERA 2017) extends FERA 2015 to the estimation of Action Units occurrence and intensity under different camera views. In this paper we present the third challenge in automatic recognition of facial expressions, to be held in conjunction with the 12th IEEE conference on Face and Gesture Recognition, May 2017, in Washington, United States. Two sub-challenges are defined: the detection of AU occurrence, and the estimation of AU intensity. In this work we outline the evaluation protocol, the data used, and the results of a baseline method for both sub-challenges. PMID- 29606918 TI - Optimizing Call Patterns for Landline and Cell Phone Surveys. AB - Cell phone surveys have become increasingly popular and researchers have noted major challenges in conducting cost-effective surveys while achieving high response rates. Previous work has shown that calling strategies that maximize both respondent contact and completed interviews for landline surveys may not be the most cost-effective for cell phone surveys. For example, Montgomery, et al. (2011) found important differences between landline and cell samples for best times to call and declines in contact rates after repeated dialing. Using paradata from the 2010 and 2011 National Flu Surveys (sponsored by the Centers for Disease Control and Prevention), we investigate differences in calling outcomes between landline and cell surveys. Specifically, we predict respondent contact and interview completion using logistic regression models that examine the impact of calling on particular days of the week, certain times of the day, number of previous calls, outcomes of previous calls and length of time between calls. We discuss how these differences can be used to increase the likelihood of contacting cooperative respondents and completing interviews for both sample types. PMID- 29606919 TI - Gluten-Free Diet. PMID- 29606920 TI - Health Benefits and Adverse Effects of a Gluten-Free Diet in Non-Celiac Disease Patients. AB - Gluten-related diseases such as celiac disease and gluten ataxia are rare conditions, affecting less than 1% of the population in the United States. Despite the rarity of these diseases, there have been significant increases in the adoption of a gluten-free lifestyle and the consumption of gluten-free foods in the United States over the last 3 decades. More than $15.5 billion were spent on retail sales of gluten-free foods in 2016. The gluten-free diet is driven by multiple factors, including social and traditional media coverage, aggressive consumer-directed marketing by manufacturers and retail outlets, and reports in the medical literature and mainstream press of the clinical benefits of gluten avoidance. Individuals may restrict gluten from their diets for a variety of reasons, such as improvement of gastrointestinal and nongastrointestinal symptoms, as well as a perception that gluten is potentially harmful and, thus, restriction represents a healthy lifestyle. Emerging evidence shows that gluten avoidance may be beneficial for some patients with gastrointestinal symptoms, such as those commonly encountered with irritable bowel syndrome. However, high quality evidence supporting gluten avoidance for physical symptoms or diseases other than those specifically known to be caused by immune-mediated responses to gluten is neither robust nor convincing. In fact, gluten avoidance may be associated with adverse effects in patients without proven gluten-related diseases. This article provides insight regarding gluten avoidance patterns and effects on patients without gluten-related diseases, and highlights concerns surrounding gluten avoidance in the absence of a gluten-mediated immunologic disease. PMID- 29606922 TI - Elastography and the Risk of Hepatocellular Carcinoma. PMID- 29606923 TI - Novel Bile Acid Therapies for Liver Disease. PMID- 29606924 TI - Managing Intestinal Fibrosis in Patients With Inflammatory Bowel Disease. PMID- 29606921 TI - Overview of Current Concepts in Gastric Intestinal Metaplasia and Gastric Cancer. AB - Gastric intestinal metaplasia is a precancerous change of the mucosa of the stomach with intestinal epithelium, and is associated with an increased risk of dysplasia and cancer. The pathogenesis to gastric cancer is proposed by the Correa hypothesis as the transition from normal gastric epithelium to invasive cancer via inflammation followed by intramucosal cancer and invasion. Multiple risk factors have been associated with the development of gastric intestinal metaplasia interplay, including Helicobacter pylori infection and associated genomics, host genetic factors, environmental milieu, rheumatologic disorders, diet, and intestinal microbiota. Globally, screening guidelines have been established in countries with high incidence. In the United States, no such guidelines have been developed due to lower, albeit increasing, incidence. The American Society for Gastrointestinal Endoscopy recommends a case-by-case patient assessment based upon epidemiology, genetics, and environmental risk factors. Studies have examined the use of a serologic biopsy to stratify risk based upon factors such as H pylori status and virulence factors, along with serologic markers of chronic inflammation including pepsinogen I, pepsinogen II, and gastrin. High-risk patients may then be advised to undergo endoscopic evaluation with mapping biopsies from the antrum (greater curvature, lesser curvature), incisura angularis, and corpus (greater curvature, lesser curvature). Surveillance guidelines have not been firmly established for patients with known gastric intestinal metaplasia, but include repeat endoscopy at intervals according to the histologic risk for malignant transformation. PMID- 29606925 TI - Endoscopic Ultrasound-Guided Coil and Glue Injection for Gastric Variceal Bleeding. PMID- 29606926 TI - Prediction of Microvascular Invasion in Hepatocellular Carcinoma: Preoperative Gd EOB-DTPA-Dynamic Enhanced MRI and Histopathological Correlation. AB - Objective: To investigate the imaging features observed in preoperative Gd-EOB DTPA-dynamic enhanced MRI and correlated with the presence of microvascular invasion (MVI) in hepatocellular carcinoma (HCC) patients. Methods: 66 HCCs in 60 patients with preoperative Gd-EOB-DTPA-dynamic enhanced MRI were retrospectively analyzed. Features including tumor size, signal homogeneity, tumor capsule, tumor margin, peritumor enhancement during mid-arterial phase, peritumor hypointensity during hepatobiliary phase, signal intensity ratio on DWI and apparent diffusion coefficients (ADC), T1 relaxation times, and the reduction rate between pre- and postcontrast enhancement images were assessed. Correlation between these features and histopathological presence of MVI was analyzed to establish a prediction model. Results: Histopathology confirmed that MVI were observed in 17 of 66 HCCs. Univariate analysis showed tumor size (p = 0.003), margin (p = 0.013), peritumor enhancement (p = 0.001), and hypointensity during hepatobiliary phase (p = 0.004) were associated with MVI. A multiple logistic regression model was established, which showed tumor size, margin, and peritumor enhancement were combined predictors for the presence of MVI (alpha = 0.1). R2 of this prediction model was 0.353, and the sensitivity and specificity were 52.9% and 93.0%, respectively. Conclusion: Large tumor size, irregular tumor margin, and peritumor enhancement in preoperative Gd-EOB-DTPA-dynamic enhanced MRI can predict the presence of MVI in HCC. PMID- 29606927 TI - Effect of coffee agriculture management on the population structure of a forest dwelling rodent (Heteromys desmarestianus goldmani). AB - Most of the natural habitat in tropical regions exists as scattered fragments embedded in a matrix of different agricultural uses. As a result of this agricultural expansion, habitat loss and fragmentation have become the main drivers of biodiversity loss. Understanding the long-term effects of agricultural management on populations is of great importance for the development of successful conservation strategies. Our study uses genetic data to determine the effect of agricultural management practices on the population structure of a common tropical forest rodent (Heteromys desmarestianus goldmani). We sampled 136 individuals from one forest fragment and three coffee farms representing varying degrees of management intensity in southern Mexico. Using microsatellite markers, we evaluated the genetic structure of H. d. goldmani in the study area. Our results show higher genetic differentiation and lower connectivity for individuals within high and medium intensity coffee farms than for those near and within the forest fragments. Our results suggest that the population structure observed is driven by landscape characteristics other than distance. PMID- 29606928 TI - Bayesian estimation of the number of protonation sites for urinary metabolites from NMR spectroscopic data. AB - Introduction: To aid the development of better algorithms for [Formula: see text]H NMR data analysis, such as alignment or peak-fitting, it is important to characterise and model chemical shift changes caused by variation in pH. The number of protonation sites, a key parameter in the theoretical relationship between pH and chemical shift, is traditionally estimated from the molecular structure, which is often unknown in untargeted metabolomics applications. Objective: We aim to use observed NMR chemical shift titration data to estimate the number of protonation sites for a range of urinary metabolites. Methods: A pool of urine from healthy subjects was titrated in the range pH 2-12, standard [Formula: see text]H NMR spectra were acquired and positions of 51 peaks (corresponding to 32 identified metabolites) were recorded. A theoretical model of chemical shift was fit to the data using a Bayesian statistical framework, using model selection procedures in a Markov Chain Monte Carlo algorithm to estimate the number of protonation sites for each molecule. Results: The estimated number of protonation sites was found to be correct for 41 out of 51 peaks. In some cases, the number of sites was incorrectly estimated, due to very close pKa values or a limited amount of data in the required pH range. Conclusions: Given appropriate data, it is possible to estimate the number of protonation sites for many metabolites typically observed in [Formula: see text]H NMR metabolomics without knowledge of the molecular structure. This approach may be a valuable resource for the development of future automated metabolite alignment, annotation and peak fitting algorithms. PMID- 29606929 TI - Metal Substitution Modulates the Reactivity and Extends the Reaction Scope of Myoglobin Carbene Transfer Catalysts. AB - Engineered myoglobins have recently emerged as promising scaffolds for catalyzing carbene-mediated transformations. In this work, we investigated the effect of altering the metal center and its first-sphere coordination environment on the carbene transfer reactivity of myoglobin. To this end, we first established an efficient protocol for the recombinant expression of myoglobin variants incorporating metalloporphyrins with non-native metals, including second- and third-row transition metals (ruthenium, rhodium, iridium). Characterization of the cofactor-substituted myoglobin variants across three different carbene transfer reactions (cyclopropanation, N-H insertion, S-H insertion) revealed a major influence of the nature of metal center, its oxidation state and first sphere coordination environment on the catalytic activity, stereoselectivity, and/or oxygen tolerance of these artificial metalloenzymes. In addition, myoglobin variants incorporating manganese- or cobalt-porphyrins were found capable of catalyzing an intermolecular carbene C-H insertion reaction involving phthalan and ethyl alpha-diazoacetate, a reaction not supported by iron-based myoglobins and previously accessed only using iridium-based (bio)catalysts. These studies demonstrate how modification of the metalloporphyrin cofactor environment provides a viable and promising strategy to enhance the catalytic properties and extend the reaction scope of myoglobin-based carbene transfer catalysts. PMID- 29606931 TI - Editorial. PMID- 29606930 TI - Extended Solution Gate OFET-based Biosensor for Label-free Glial Fibrillary Acidic Protein Detection with Polyethylene Glycol-Containing Bioreceptor Layer. AB - A novel organic field effect transistor (OFET) -based biosensor is described for label-free glial fibrillary acidic protein (GFAP) detection. We report the first use of an extended solution gate structure where the sensing area and the organic semiconductor are separated, and a reference electrode is not needed. Different molecular weight polyethylene glycols (PEGs) are mixed into the bio-receptor layer to help extend the Debye screening length. The drain current change was significantly increased with the help of higher molecular weight PEGs, as they are known to reduce the dielectric constant. We also investigated the sensing performance under different gate voltage (Vg). The sensitivity increased after we decreased Vg from -5 V to -2 V, because the lower Vg is much closer to the OFET threshold voltage and the influence of attached negatively charged proteins become more apparent. Finally, the selectivity experiments toward different interferents were performed. The stability and selectivity are promising for clinical applications. PMID- 29606932 TI - Neonatal Screening Programme for Increasing Early Postnatal Diagnosis of Congenital Cytomegalovirus Infection in the West Poland Province. AB - Congenital infection with cytomegalovirus (CMV) is the main cause of sensorineural hearing loss and psychomotor impairment which can develop at birth or later in infant's life. Because of a lack of nation-wide serological screening for pregnant women and accepted antiviral therapy during pregnancy in a high seroprevalence rate population of Poland, we introduced the regional screening programme for CMV infection in neonates from the Poznan Province to diminish a risk of the symptomatic disease. The aims of the study were: (i) to determine the prevalence of specific anti-CMV antibodies in populations of pregnant women and newborns from the Poznan area, (ii) to increase the early postnatal detection of congenital CMV infections, and (iii) to evaluate a risk of perinatal or early postnatal infections with CMV in newborns or infants born to seropositive mothers. Serological testing was performed in 4.192 live born neonates, using dried blood filter-paper specimens. The seropositivity rate in the studied population of neonates and pregnant women was 78.6%. The incidence of perinatal and early postnatal CMV infections was evaluated to be 3.1% or 1 per 25 neonates born to seropositive mothers. Congenital CMV infections confirmed by a presence of specific IgM antibodies were diagnosed in 5 newborns, which represent 1 case per 838 successive deliveries. In a clinical pattern of cytomegalovirus disease respiratory disorders and low birth weight were most frequently observed, and neurological signs, hepatitis, haemorrhagies or jaundice were sporadically diagnosed. Implementation of mass immunodiagnostic screening for congenital CMV infection, combined with other obligatory neonatal tests for metabolic errors, congenital malformations and endocrine disorders seems to be a valuable third line prophylactic strategy to prevent a late development of clinically overt cytomegalovirus disease. PMID- 29606933 TI - Serological Screening of Newborns for Toxoplasma Gondii-Specific IgA and IgM Antibodies in Peripheral Blood Collected on Filter-Papers. AB - : The strategic approach for preventing congenital toxoplasmosis is strictly related to the incidence of primary T. gondii infection during pregnancy in a studied population. Early postnatal diagnosis by mass testing of newborns is an option in areas where obligatory serological screening in pregnant women has not been implemented but it requires sensitive immunodiagnostic methods followed by a good confirmatory analysis. The aims of the regional neonatal screening programme were (i) analysis of the prevalence of congenital T. gondii infection at birth in the West Poland Province, (ii) determination of the value of the serological examination of filter-paper blood specimens collected at birth for the diagnosis of congenital toxoplasmosis, and (iii) evaluation of the duration of T. gondii specific immunoglobulin A and immunoglobulin M antibodies in infants' sera. The neonates born in the obstetric clinics of the University Gynaecology-Obstetrics Hospital in Poznan (Poland) and in the maternity wards of the 10 main district hospitals from the West Poland region were systematically screened for congenital T. gondii infection. Peripheral blood from newborns was collected by a non invasive heel-stick puncture during the first 3 days of life, absorbed onto Guthrie cards and analysed for anti-T. gondii specific IgM (1996-1998) or both IgA and IgM antibodies (1998-2000) by non-commercial immunocapture ELISAs. When the screening result was positive, the diagnosis of congenital infection was confirmed by testing serum samples from the suspected neonate and the mother using a Western blot IgM-IgG comparative immunological profile analysis and traditional serological techniques (ELISA, ISAGA) for anti-Toxoplasma IgA, IgM and IgG specific antibodies. From June 1996 to April 2000, 45,169 filter-paper specimens from liveborn neonates were screened: 27,516 samples were tested for specific IgM and the next 17,653 Guthrie cards were analysed by the combined IgA/IgM assay. The prevalence of anti-Toxoplasma IgM in filter-paper eluates at birth was 1 per 2,117 liveborn neonates (0.47/1000) or 1 per 1,185 infants (0.84/1000) born to seronegative women with a potential risk of primary T. gondii infection during pregnancy. For the joint detection of IgA and IgM, these values significantly increased to 1 per 929 neonates (1.08/1000) or 1 per 520 pregnancies at risk (1.92/1000) respectively, comparing to the seropositivity rate of 43.7% in a pregnant women population in the studied area. In newborns untreated prenatally, the diagnostic sensitivity of the IgM ELISA using neonatal Guthrie cards was not more than 86.7% and that of the combined IgA/IgM ELISA was 95%; the diagnostic specificity of the both methods was calculated to be 99.9%. Congenital T. gondii infection was finally diagnosed in 35 neonates, mostly asymptomatic at birth. CONCLUSIONS: (i) The neonatal screening for anti Toxoplasma IgA and/or IgM antibodies is a good sensitivity method for an early postnatal diagnosis of congenital toxoplasmosis in newborns untreated prenatally. (ii) In the absence of obligatory nation-wide screening during pregnancy followed by an early prenatal treatment, this valuable technique may be considered a preventive option in areas of a high annual number of births associated with a high seroprevalence of T. gondii infection. PMID- 29606934 TI - Vedolizumab Treatment for Ulcerative Colitis in an Elderly Multimorbid Patient with Hemophilia A. AB - The treatment of inflammatory bowel diseases (IBD) can be challenging, especially in elderly multimorbid patients. Since incidence and prevalence rates of IBD are rising steadily, treatment of older patients with relevant and also rare comorbidities will be of increasing relevancy for caregivers. Here we report on a 74-year-old multimorbid patient with severe ulcerative colitis (UC) and hemophilia A. Because of the chronic active disease, therapy with a tumor necrosis factor-alpha inhibitor was started. He suffered from a severe infectious complication (pneumonia) under therapy with infliximab. The therapy was changed to vedolizumab, with which the patient stayed in long-term clinical and endoscopic remission. Because the patient had a non-ST-segment elevation myocardial infarction in April 2016, he received dual platelet inhibitor therapy with aspirin and clopidogrel. Because of consecutive aspirin intolerance, the therapy was changed to clopidogrel monotherapy. Although the UC was treated appropriately with vedolizumab and the patient was in endoscopic mucosal remission, recurrent bleeding episodes from multiple inflammatory pseudopolyps occurred. The bleeding episodes resolved quickly after immediate treatment with factor VIII (Kogenate(r)). In conclusion, we describe the first patient in the literature with UC and hemophilia A who stayed in long-term remission under therapy with vedolizumab. From our point of view, vedolizumab can be safely administered in the setting of UC and hemophilia A. Antiplatelet drugs which inhibit primary hemostasis must be used with caution in this setting. Bleeding episodes can be treated safely and effectively with factor VIII (Kogenate(r)). PMID- 29606935 TI - Eighteen Month Interval Growth of Terminal Ileal Primary Adenocarcinoma: A Consideration for Current Screening Guidelines. AB - Primary adenocarcinoma of the small intestine comprises one of the rarest gastrointestinal malignancies. Further, the terminal ileum is very seldom implicated. This entity occurs sporadically and evades traditional colonoscopic evaluation in which the terminal ileum is not visualized. Herein, a case of interval development of primary terminal ileal adenocarcinoma over a 2-year period is reported as followed by direct endoscopic and colonoscopic visualization. This case demonstrates cecal involvement not found on initial evaluation without the provision of terminal ileum intubation. Relevant guidelines regarding the evaluation of the terminal ileum in routine colonoscopy are reviewed. PMID- 29606936 TI - Vedolizumab as a Potential Culprit in the Development of Ovarian Teratoma? AB - Vedolizumab is a new humanized monoclonal antibody that has been reserved for those with moderate-to-severe Crohn's disease and ulcerative colitis who have failed immunomodulator and TNF-alpha antagonist therapy, and for those who have an increased risk for developing progressive multifocal leukoencephalopathy. Because it targets gastrointestinal tract-specific lymphocytes, meta-analyses and integrated studies have shown that vedolizumab causes fewer extraintestinal adverse effects, such as opportunistic infections and malignancies, compared with anti-TNF therapies. We present the case of a patient who developed an ovarian teratoma after initiation of vedolizumab therapy. PMID- 29606937 TI - Adenosquamous Carcinoma of the Colon. AB - Overall, colorectal cancer is the third most commonly diagnosed cancer in both men and women, meaning that it is one of the more widely recognized preventable cancers. Instances of colorectal malignancies though are overwhelmingly attributable to adenocarcinoma. Colorectal cancers with components of squamous cell carcinoma represent a statistical anomaly. Here, we present the case of a 50 year-old male, who complained of abdominal pain and weight loss over a 3-month period of time. Biopsies from a colonoscopy ultimately revealed that this patient's colon cancer consisted of both adenocarcinoma and squamous cell carcinoma, representing a truly exceptional pathology finding in a patient diagnosed with a colorectal cancer. PMID- 29606938 TI - Spontaneous Hepatitis B Seroclearance upon Development of Hepatocellular Carcinoma. AB - The spontaneous seroclearance of hepatitis B upon development of a hepatocellular carcinoma (HCC) is extremely rare. To date, there has been one published case series reporting hepatitis B seroconversion following HCC resection. We describe two novel cases of spontaneous hepatitis B seroclearance following the development of HCC, prior to resection. Following resection, specimens were HBsAg and HBcAg-negative in both tumor and peritumor tissues. Although the precise mechanism of this is poorly understood, nonuniform integration of hepatitis B virus DNA within the liver could lead to selective tumorigenesis of HBsAg producing cells, explaining the observed clearance of serum HBsAg with the development of HCC. PMID- 29606939 TI - Laparoscopic Resection of an Epithelial Cyst in an Intrapancreatic Accessory Spleen. AB - An epithelial cyst in an intrapancreatic accessory spleen (ECIAS) is rare. We herein report a case of a patient with ECIAS who underwent laparoscopic surgery. A 57-year-old woman was referred to our hospital because of a pancreatic tail tumor. She was asymptomatic, and a physical examination revealed no remarkable abnormalities. The levels of the tumor marker carbohydrate antigen 19-9 (CA19-9) and s-pancreas-1 antigen (SPan-1) were elevated. Ultrasonography showed a well defined homogeneous cystic tumor. Computed tomography showed a well-demarcated cystic tumor in the pancreatic tail. Magnetic resonance imaging showed that the cystic tumor exhibited low intensity on T1-weighted images and high intensity on T2-weighted images. The cystic tumor was diagnosed as mucinous cystic neoplasm preoperatively. The patient underwent laparoscopic spleen-preserving distal pancreatectomy. A histopathological examination revealed the cyst wall to be lined by stratified squamous epithelium within splenic parenchyma, and the ultimate diagnosis was ECIAS. The postoperative course was uneventful, and the patient was discharged on postoperative day 12. ECIAS is very difficult to diagnose preoperatively. Laparoscopic surgery is a safe and minimally invasive procedure for patients with difficult-to-diagnose pancreatic tail tumor suspected of having low-grade malignancy. PMID- 29606940 TI - Successful Fecal Microbiota Transplantation in a Patient with Severe Complicated Clostridium difficile Infection after Liver Transplantation. AB - Clostridium difficile infection (CDI) represents one of the most common healthcare-associated infections. Due to increasing numbers of recurrences and therapy failures, CDI has become a major disease burden. Studies have shown that fecal microbiota transplantation (FMT) can both be a safe and highly efficacious therapy for patients with therapy-refractory CDI. However, patients undergoing solid organ transplantation are at high risk for CDI due to long-term immunosuppression, previous antibiotic therapy, and proton pump inhibitor use. Additionally, these patients may be especially prone to adverse events related to FMT. Here, we report a successful FMT in a patient with severe therapy-refractory CDI after liver transplantation. PMID- 29606941 TI - A Surgically Resected Pancreatic Schwannoma with Obstructive Jaundice with Special Reference to Differential Diagnosis from Other Cystic Lesions in the Pancreas. AB - Pancreatic schwannomas are uncommon. About 60% of pancreatic schwannomas develop cystic lesions, and the differential diagnosis from other cystic pancreatic tumors is difficult. A 43-year-old man presented for evaluation of liver dysfunction detected during a medical checkup. Blood testing detected obstructive jaundice. A computed tomography scan revealed a well-defined polycystic tumor of about 5 cm at the pancreatic head. We performed surgical resection to treat the patient's symptoms and facilitate long-term management. Histopathological examination revealed spindle-shaped cells. Immunohistochemical studies showed S100 protein expression and the absence of CD34 and c-kit protein expression. Finally, we diagnosed a schwannoma. Pancreatic schwannoma is usually asymptomatic. The present case presented with obstructive jaundice, which is reportedly a rare symptom. Pancreatic schwannomas should be considered as a differential diagnosis of pancreatic cystic tumors. Dilatation of the pancreatic duct and the 18-fluorodeoxyglucose positron emission tomography findings are important for the differential diagnosis. PMID- 29606942 TI - Elbasvir/Grazoprevir, an Alternative in Antiviral Hepatitis C Therapy in Patients under Amiodarone Treatment. AB - A sofosbuvir/ledipasvir combination is part of a first-line treatment of hepatitis C. However, in patients concurrently treated with amiodarone, cardiac side effects have been described, resulting in an official warning in 2015 by the American Food and Drug Administration and the European Medicines Agency when combining those substances. This deprived numerous hepatitis C patients with concurrent cardiovascular problems of receiving this highly effective treatment. Here we present a treatment alternative with an elbasvir/grazoprevir regimen, based on our successful treatment of a patient under concurrent amiodarone therapy. Our observations indicate that patients treated with amiodarone can finally benefit from effective antiviral therapy. PMID- 29606943 TI - Successful Treatment of Inflammatory Linear Verrucous Epidermal Nevus with Concomitant Psoriasis Using Etanercept. AB - Linear psoriasis is a rare form of the disease characterized by the linear distribution of lesions involving dermatome or along Blaschko's lines. Clinically, it may resemble inflammatory linear verrucous epidermal nevus; a combination of history, skin examination, and histopathology are required to ensure correct diagnosis and appropriate therapy. This paper describes a case of a 23-year-old male presenting with unilateral erythematous scaly plaques arranged in a linear path on the left leg. Etanercept was initiated after poor response to adalimumab. Improvement of his psoriasis was noted, with PASI 75 reduction after 24 weeks of treatment. Clinical studies have shown excellent efficacy of etanercept, and our patient well tolerated treatment with etanercept for 52 weeks without any adverse effects. PMID- 29606944 TI - Extensive Lepromatous Lymphadenitis Preceding Lesions on the Face and Earlobes: An Unusual Presentation of Leprosy in Singapore. AB - Leprosy is also known as Hansen disease, as in some countries the diagnosis of leprosy carries a negative stigma and patients fear being shunned as outcasts. Presently, leprosy is primarily limited to specific geographical regions in resource-poor countries. As a result, there is increased difficulty for the younger generation of physicians today to correctly identify leprosy due to a lack of exposure and a low-index of suspicion, particularly in developed countries. In this case, the indurated lesions over the face demonstrated a preference for the outer lateral aspects over the maxillary areas, the nose bridge, and the pinna of the ears consistent with the organism's preference for cooler regions of the body. This was also evident in the other skin lesions affecting the more acral regions of the limbs in the early stage of disease progression. There is a need to keep this infective condition as an alternate diagnosis to all unusual cutaneous lesions. PMID- 29606945 TI - A Case of Vulvar Schwannoma Mimicking Epidermoid Cyst. AB - Schwannoma is a generally benign tumor of the peripheral nerve sheath arising from Schwann cells. Most schwannomas are found on the head and neck. Here, we describe a rare case of benign vulvar schwannoma located at the labium majus which was similar to an epidermoid cyst in clinical appearance. PMID- 29606946 TI - The Importance of Excluding Cutaneous T-Cell Lymphomas in Patients with a Working Diagnosis of Papuloerythroderma of Ofuji: A Case Series. AB - Papuloerythroderma of Ofuji (PEO) is an erythroderma-like eruption with flat topped papules that spare the skin folds (a "deck-chair sign" finding). Many infections, medications, and systemic diseases have been associated with PEO, including cutaneous T-cell lymphomas (CTCL). The relationship between the clinical presentation of PEO and CTCL remains poorly elucidated. Clinical, laboratory, and histopathological data were obtained from the Lymphoma Clinic at the Ottawa Hospital, Canada. We report 5 patients with deck-chair-sign-positive CTCL, mycosis fungoides, and Sezary syndrome variants. We contend that PEO should be viewed as a diagnosis of exclusion and that these patients should be monitored carefully for possible emergence of CTCL. Skin biopsy alone is not sufficient to exclude CTCL in these patients. A skin eruption demonstrating a positive deck chair sign may signify systemic/leukemic CTCL and, therefore, warrants a thorough investigation, including skin biopsy, flow cytometry, and T-cell receptor clonality studies. PMID- 29606947 TI - Multiloculated Cavitary Primary Pulmonary Hodgkin Lymphoma: Case Series. AB - Primary pulmonary Hodgkin lymphoma (PPHL) is very rare and typically involves the superior portion of the lung. Pulmonary involvement is observed in 15-40% of Hodgkin lymphoma patients. Three such patients who presented with an unusual form of PPHL in radiological studies, i.e., multiloculated cavitary lesions, were admitted to our hospital. These lesions represent a new pathological and radiological feature of PPHL. PMID- 29606948 TI - Concomitant Non-Small Cell Lung Cancer and Hairy Cell Leukemia in a Patient Harboring BRAF-V600E Mutation in Both Tissues: A Case Report. AB - The BRAF-V600E mutation has been established as a signature alteration occurring almost universally in hairy cell leukemia. Moreover, it can be detected in a small percentage of patients with non-small cell lung cancer. We report the case of a patient with a metastatic BRAF-V600E-mutated lung adenocarcinoma suffering from concomitant hairy cell leukemia. The identification of an identical BRAF mutation in both malignancies raises physiopathological considerations and might offer unique therapeutic strategies for this group of patients. PMID- 29606949 TI - Intensity-Modulated Radiotherapy Triggers Onset of Bullous Pemphigoid in a Patient with Advanced Melanoma Treated with Nivolumab. AB - Since the efficacy of ipilimumab on nivolumab-resistant advanced melanoma is extremely low, additional supportive therapy for anti-PD-1 antibody therapy resistant advanced melanoma is needed. Although several supportive therapies that enhance the antitumor immune response of anti-PD-1 antibodies have already been reported, unexpected immune-related adverse events were detected at the same time. In this report, we describe a patient with advanced melanoma treated with nivolumab followed by intensity-modulated radiotherapy, which might have triggered bullous pemphigoid (BP). Although several cases of BP developing in anti-PD-1 antibody-treated patients have already been reported, in this report, we shed light on the possible pathogenesis of BP developing in a patient treated with nivolumab through M2 macrophages. PMID- 29606950 TI - Severe Adverse Reaction to Vemurafenib in a Pregnant Woman with Metastatic Melanoma. AB - Targeted therapies have drastically changed the management of metastatic melanoma and have shown encouraging results on tumour progression but are also known for their high rates of adverse reactions. In general, targeted therapies are contraindicated during pregnancy due to concerns about teratogenesis. For the BRAF V600 inhibitor vemurafenib, the available literature about the effects on human pregnancy is limited to a single case report. In patients with metastatic melanoma that wish to continue their pregnancy, targeted therapies like vemurafenib offer the only possibility of improving maternal outcome. In this article, we report on a pregnant woman with metastatic melanoma who was treated with vemurafenib during pregnancy and experienced a fatal adverse reaction. PMID- 29606951 TI - Successful Surgical Resection following Bronchial Artery Embolization in a Case of Lung Cancer Complicated with Massive Hemoptysis. AB - Hemoptysis is sometimes observed in lung cancer patients and can be life threatening. We present a case with severe hemoptysis that was resolved by bronchial artery embolization (BAE) followed by surgery. The presence of necrotic tissue in the majority of the resected tumor and only few cancer cells was presumed to be from loss of bronchial artery blood flow. Although BAE is not a standard therapy for lung cancer, it can be useful and may be considered by physicians as one of the treatment options prior to surgical resection in cases with hemoptysis. PMID- 29606952 TI - Cervical Intramedullary Schwannoma: Case Report and Review of the Literature. AB - Cervical intramedullary schwannomas are extraordinarily rare. Gross total resection is the best therapeutic option for these types of tumors. Although rare, intramedullary schwannomas should be considered as a differential diagnosis of intramedullary lesions since a good prognosis can be guaranteed to the majority of these patients. We present a case of a cervical intramedullary schwannoma surgically treated in a 19-year-old male patient who initially presented with motor neuron disease. PMID- 29606953 TI - A Report of a Case Involving Body Lateropulsion with Numbness of the Ipsilesional Fingers Caused by a Small Infarction in the Dorsal Part of the Middle Medulla. AB - Based on the complexity of functional anatomy, a small infarction in the medulla can produce various types of clinical symptoms or signs depending on the location of this infarction. We describe the case of a 46-year-old man who presented with sudden onset of body lateropulsion to the left side and numbness of the ipsilateral fingers. 3-tesla diffusion-weighted magnetic resonance imaging with a section thickness of 2 mm revealed a small infarction in the dorsal part of the left middle medulla. To our knowledge, this is the first case report describing vestibular dysfunction apparent upon otoelectrophysiological examination but without vestibular symptoms or signs except for body lateropulsion. PMID- 29606954 TI - Automatic MRI Quantifying Methods in Behavioral-Variant Frontotemporal Dementia Diagnosis. AB - Aims: We assessed the value of automated MRI quantification methods in the differential diagnosis of behavioral-variant frontotemporal dementia (bvFTD) from Alzheimer disease (AD), Lewy body dementia (LBD), and subjective memory complaints (SMC). We also examined the role of the C9ORF72-related genetic status in the differentiation sensitivity. Methods: The MRI scans of 50 patients with bvFTD (17 C9ORF72 expansion carriers) were analyzed using 6 quantification methods as follows: voxel-based morphometry (VBM), tensor-based morphometry, volumetry (VOL), manifold learning, grading, and white-matter hyperintensities. Each patient was then individually compared to an independent reference group in order to attain diagnostic suggestions. Results: Only VBM and VOL showed utility in correctly identifying bvFTD from our set of data. The overall classification sensitivity of bvFTD with VOL + VBM achieved a total sensitivity of 60%. Using VOL + VBM, 32% were misclassified as having LBD. There was a trend of higher values for classification sensitivity of the C9ORF72 expansion carriers than noncarriers. Conclusion: VOL, VBM, and their combination are effective in differential diagnostics between bvFTD and AD or SMC. However, MRI atrophy profiles for bvFTD and LBD are too similar for a reliable differentiation with the quantification methods tested in this study. PMID- 29606955 TI - An Estimate of Attributable Cases of Alzheimer Disease and Vascular Dementia due to Modifiable Risk Factors: The Impact of Primary Prevention in Europe and in Italy. AB - Background: Up to 53.7% of all cases of dementia are assumed to be due to Alzheimer disease (AD), while 15.8% are considered to be due to vascular dementia (VaD). In Europe, about 3 million cases of AD could be due to 7 potentially modifiable risk factors: diabetes, midlife hypertension and/or obesity, physical inactivity, depression, smoking, and low educational level. Aims: To estimate the number of VaD cases in Europe and the number of AD and VaD cases in Italy attributable to these 7 potentially modifiable risk factors. Methods: Assuming the nonindependence of the 7 risk factors, the adjusted combined population attributable risk (PAR) was estimated for AD and VaD. Results: In Europe, adjusted combined PAR was 31.4% for AD and 37.8% for VaD. The total number of attributable cases was 3,033,000 for AD and 873,000 for VaD. In Italy, assuming a 20% reduction of the prevalence of each risk factor, adjusted combined PAR decreased from 45.2 to 38.9% for AD and from 53.1 to 46.6% for VaD, implying a 6.4 and 6.5% reduction in the prevalence of AD and VaD, respectively. Conclusion: A relevant reduction of AD and VaD cases in Europe and Italy could be obtained through primary prevention. PMID- 29606956 TI - Cognitive Blackouts in Mild Cognitive Impairment and Alzheimer's Dementia. AB - Background: Cognitive blackouts, e.g. moments of amnesia, disorientation, or perplexity may be an early sign of incipient Alzheimer's dementia (AD). A short questionnaire, the checklist for cognitive blackouts (CCB), was evaluated cross sectionally in users of a memory clinic. Methods: The CCB was performed in 130 subjects, who further underwent a neuropsychological and clinical examination. Subjective memory impairment and depressive symptoms were assessed. Differences in the CCB score between diagnostic groups and relationships with cognitive performance, depression, and subjective memory impairment were analyzed. Results: The CCB score was increased in mild cognitive impairment of the amnestic type or mild AD and correctly predicted 69.2% of the respective subjects. It was negatively correlated with cognitive performance, positively correlated with depressive symptoms, and substantially increased in subjects who estimated their memory poorer than that of other persons of their age. Discussion: The CCB may be a helpful screening tool for the early recognition of AD. PMID- 29606957 TI - Impact of Silver and Iron Nanoparticle Exposure on Cholesterol Uptake by Macrophages. AB - Macrophages are central to the development of atherosclerosis by absorbing lipids, promoting inflammation, and increasing plaque deposition. Nanoparticles (NPs) are becoming increasingly common in biomedical applications thereby increasing exposure to the immune and vascular systems. This project investigated the influence of NPs on macrophage function and specifically cholesterol uptake. Macrophages were exposed to 20 nm silver NPs (AgNPs), 110 nm AgNPs, or 20 nm Fe3O4NPs for 2 h and NP uptake, cytotoxicity, and subsequent uptake of fluorescently labeled cholesterol were assessed. Macrophage uptake of NPs did not induce cytotoxicity at concentrations utilized (25 MUg/mL); however, macrophage exposure to 20 nm AgNPs reduced subsequent uptake of cholesterol. Further, we assessed the impact of a cholesterol-rich environment on macrophage function following NP exposure. In these sets of experiments, macrophages internalized NPs, exhibited no cytotoxicity, and altered cholesterol uptake. Alterations in the expression of scavenger receptor-B1 following NP exposure, which likely influences cholesterol uptake, were observed. Overall, NPs alter cholesterol uptake, which may have implications in the progression of vascular or immune mediated diseases. Therefore, for the safe development of NPs for biomedical applications, it is necessary to understand their impact on cellular function and biological interactions in underlying disease environments. PMID- 29606958 TI - A Multiple Kernel Learning Model Based on p-Norm. AB - By utilizing kernel functions, support vector machines (SVMs) successfully solve the linearly inseparable problems. Subsequently, its applicable areas have been greatly extended. Using multiple kernels (MKs) to improve the SVM classification accuracy has been a hot topic in the SVM research society for several years. However, most MK learning (MKL) methods employ L1-norm constraint on the kernel combination weights, which forms a sparse yet nonsmooth solution for the kernel weights. Alternatively, the Lp -norm constraint on the kernel weights keeps all information in the base kernels. Nonetheless, the solution of Lp -norm constraint MKL is nonsparse and sensitive to the noise. Recently, some scholars presented an efficient sparse generalized MKL (L1- and L2-norms based GMKL) method, in which L1 L2 established an elastic constraint on the kernel weights. In this paper, we further extend the GMKL to a more generalized MKL method based on the p-norm, by joining L1- and Lp -norms. Consequently, the L1- and L2-norms based GMKL is a special case in our method when p = 2. Experiments demonstrated that our L1- and Lp -norms based MKL offers a higher accuracy than the L1- and L2-norms based GMKL in the classification, while keeping the properties of the L1- and L2-norms based on GMKL. PMID- 29606959 TI - Permutation Entropy and Signal Energy Increase the Accuracy of Neuropathic Change Detection in Needle EMG. AB - Background and Objective. Needle electromyography can be used to detect the number of changes and morphological changes in motor unit potentials of patients with axonal neuropathy. General mathematical methods of pattern recognition and signal analysis were applied to recognize neuropathic changes. This study validates the possibility of extending and refining turns-amplitude analysis using permutation entropy and signal energy. Methods. In this study, we examined needle electromyography in 40 neuropathic individuals and 40 controls. The number of turns, amplitude between turns, signal energy, and "permutation entropy" were used as features for support vector machine classification. Results. The obtained results proved the superior classification performance of the combinations of all of the above-mentioned features compared to the combinations of fewer features. The lowest accuracy from the tested combinations of features had peak-ratio analysis. Conclusion. Using the combination of permutation entropy with signal energy, number of turns and mean amplitude in SVM classification can be used to refine the diagnosis of polyneuropathies examined by needle electromyography. PMID- 29606960 TI - Automated Text Analysis Based on Skip-Gram Model for Food Evaluation in Predicting Consumer Acceptance. AB - The purpose of this paper is to evaluate food taste, smell, and characteristics from consumers' online reviews. Several studies in food sensory evaluation have been presented for consumer acceptance. However, these studies need taste descriptive word lexicon, and they are not suitable for analyzing large number of evaluators to predict consumer acceptance. In this paper, an automated text analysis method for food evaluation is presented to analyze and compare recently introduced two jjampong ramen types (mixed seafood noodles). To avoid building a sensory word lexicon, consumers' reviews are collected from SNS. Then, by training word embedding model with acquired reviews, words in the large amount of review text are converted into vectors. Based on these words represented as vectors, inference is performed to evaluate taste and smell of two jjampong ramen types. Finally, the reliability and merits of the proposed food evaluation method are confirmed by a comparison with the results from an actual consumer preference taste evaluation. PMID- 29606961 TI - A Pruning Neural Network Model in Credit Classification Analysis. AB - Nowadays, credit classification models are widely applied because they can help financial decision-makers to handle credit classification issues. Among them, artificial neural networks (ANNs) have been widely accepted as the convincing methods in the credit industry. In this paper, we propose a pruning neural network (PNN) and apply it to solve credit classification problem by adopting the well-known Australian and Japanese credit datasets. The model is inspired by synaptic nonlinearity of a dendritic tree in a biological neural model. And it is trained by an error back-propagation algorithm. The model is capable of realizing a neuronal pruning function by removing the superfluous synapses and useless dendrites and forms a tidy dendritic morphology at the end of learning. Furthermore, we utilize logic circuits (LCs) to simulate the dendritic structures successfully which makes PNN be implemented on the hardware effectively. The statistical results of our experiments have verified that PNN obtains superior performance in comparison with other classical algorithms in terms of accuracy and computational efficiency. PMID- 29606962 TI - A Review of Roof Harvested Rainwater in Australia. AB - To address concern regarding water sustainability, the Australian Federal Government and many state governments have implemented regulatory mechanisms and incentives to support households to purchase and install rainwater harvesting systems. This has led to an increase in rainwater harvesting in regional and urban Australia. This review examines the implementation of the regulatory mechanisms across Australia. In addition, the literature investigating the potential health consequences of rainwater consumption in Australia was explored. Studies demonstrated that although trace metals such as arsenic, cadmium, chromium, lead, and iron were present in Australian rainwater, these metallic elements were generally found below the health limit guideline, except in high industrial areas. In addition, pathogenic or indicator microorganisms that include, but are not limited to, Escherichia coli, total and faecal coliforms, Campylobacter, Salmonella, Legionella, Pseudomonas, Cryptosporidium, Enterococci, Giardia, Aeromonas, and Mycobacterium avium Complex (MAC) have been detected in rainwater collected in Australia. However, epidemiological evidence suggests that drinking rainwater does not increase the risk of gastrointestinal disease. It was also identified that there is a need for further research investigating the potential for rainwater to be a source of infection for opportunistic pathogens. PMID- 29606963 TI - Synthesis, characterization, and stability study of desloratadine multicomponent crystal formation. AB - This study describes the formation of multicomponent crystal (MCC) of desloratadine (DES). The objective of this study was to discover the new pharmaceutical MCC of DES using several coformers. The MCC synthesis was performed between DES and 26 coformers using an equimolar ratio with a solvent evaporation technique. The selection of the appropriate solvent was carried out using 12 solvents. The preview of the MCC of DES was performed using polarized light microscopy (PLM). The formation of MCC was confirmed using powder X-ray diffraction (PXRD), differential scanning calorimetry (DSC), fourier transform infrared spectroscopy (FTIR), and scanning electron microscopy (SEM). The accelerated stability of MCC at 40 degrees C and relative humidity of 75% was investigated using PXRD and FTIR. Depending on the prior evaluation, DES and benzoic acid (BA) formed the MCC. PLM and SEM results showed that crystal habit of combination between DES and BA differed from the constituent components. Moreover, the diffractogram pattern of DES-BA was distinct from the constituent components. The DSC thermogram showed a new peak which was distinct from both constituent components. The FTIR study proved a new spectrum. All characterizations indicated that a new solid crystal was formed, ensuring the MCC formation. In addition, DES-BA MCC had both chemical and physical stabilities for a period of 4 months. PMID- 29606964 TI - The immunoinhibitory and apoptosis-inducing activities of Foeniculum vulgare on human peripheral blood lymphocytes. AB - Foeniculum vulgare (F. vulgare, Apiaceae) is an important plant currently used in folk medicine to treat various diseases including infections and inflammatory conditions. In this study we have investigated the immunomodulatory and apoptosis inducing activities of the fractions from this plant. We prepared dichloromethane, hexane, butanol, and water fractions from the aerial parts of the plant. We examined the growth inhibitory effects of the fractions on proliferative lymphocytes by the BrdU incorporation assay. Cell viability was determined by the propidium iodide (PI) assay. AnnexinV/PI staining and cell cycle analysis by flow cytometry was performed to investigate the apoptosis inducing effects of the plant fractions. Cytokine levels were measured by enzyme linked immunosorbent assay. All fractions reduced cell proliferation of the activated lymphocytes. The dichloromethane fraction with the highest inhibitory effect (IC50, 19.8 MUg/mL) significantly reduced cell viability. Although the butanol fraction inhibited cell growth (IC50, 88.2 MUg/mL) it did not affect cell viability. Annexin V/PI and cell cycle analysis showed the maximum apoptosis inducing effect of the dichloromethane fraction at 200 MUg/mL. Cytokines, that included interleukin (IL)-4 (22.8 +/- 0.9 pg/mL, P < 0.05) and interferon (IFN) gamma (651 +/- 37.5 pg/mL, P < 0.01) reduced the activated lymphocyte levels in cultures in the presence of 100 MUg/mL concentration of butanol fraction compared to the untreated control. In conclusion, the dichloromethane fraction of F. vulgare had the capability of inducing apoptosis in the activated lymphocytes, whereas the butanol fraction reduced cell activation and cytokine secretion. These data suggested the potential of these examined fractions for more studies in terms of their beneficial effects on immune-mediated diseases. PMID- 29606965 TI - Synthesis and antileishmanial activity of antimony (V) complexes of hydroxypyranone and hydroxypyridinone ligands. AB - A novel series of antimony (V) complexes with the hydroxypyranone and hydroxypyridinone ligands were synthesized and characterized by 1HNMR, FT-IR and electron spin ionization mass spectroscopic (ESI-MS) techniques. The synthesis process involved protection of hydroxyl group followed by the reaction of the intermediate with primary amines and finally deprotection. All compounds were evaluated for in vitro activities against the amastigote and promastigote forms of Leishmania major. Most of the synthesized compounds exhibited good antileishmanial activity against both forms of L. major. IC50 values of the most active compounds; 9d, 9d and 9e, after 24, 48 and 72 h against amastigote model were 15, 12.5 and 5.5 MUg/mL, respectively. 9e, 11 and 9e inhibited the promastigote form of parasite after 24, 48 and 72 h with IC50 values of 10, 2 and 1 MUg/mL, respectively. PMID- 29606966 TI - Protective effects of glucosamine and its acetylated derivative on serum/glucose deprivation-induced PC12 cells death: Role of reactive oxygen species. AB - Finding products with antiapoptotic activities has been one of the approaches for the treatment of neurodegenerative disorders. Serum/glucose deprivation (SGD) has been used as a model for the investigation of the molecular mechanisms of neuronal ischemia. Recent studies indicated that glucosamine (GlcN) and N-acetyl glucosamine (GlcNAc) have many pharmacological effects including antioxidant activities. The present study aimed to investigate the protective effects of GlcN and GlcNAc against SGD-induced PC12 cells injury. The PC12 cells were pretreated with GlcN and GlcNAc for 2 h, and then exposed to SGD for 6, 12 and 24 h. Cell viability was evaluated by MTT assay. The level of intracellular reactive oxygen species (ROS) was determined by flow cytometry using 2',7'- dichlorofluorescin diacetate (DCFH-DA) as a probe. SGD condition caused a significant reduction in cell survival after 6, 12, and 24 h (P < 0.001). Pretreatment with GlcN and GlcNAc (0.6-20 mM) increased cell viability following SGD insult. A significant increase in cell apoptosis was observed in cells under SGD condition after 12 h (P < 0.001). Pretreatment with GlcN and GlcNAc (5-20 mM) decreased apoptosis following SGD condition after 12 h. SGD resulted in a significant increase in intracellular ROS production after 12 h. Pretreatment with both amino sugars at concentrations of 10 to 20 mM could reverse the ROS increment. Results indicated that GlcN and GlcNAc had a cytoprotective property against SGD-induced cell death via anti-apoptosis and antioxidant activities, suggesting that these aminosugers have the potential to be used as novel therapeutic agents for neurodegenerative disorders. PMID- 29606967 TI - Effects of oregano essential oil on brain TLR4 and TLR2 gene expression and depressive-like behavior in a rat model. AB - The aim of the present study was to evaluate the effects of oregano essential oil (OEO) on the hippocampus and prefrontal cortex TLR 2/4 gene expression and depressive like behavior induced by chronic unpredictable stress (CUS). Sucrose preference and forced swim tests were adopted to examine the antidepressant effect. Control (CON), OEO, CUS, and CUS + OEO groups were used. The OEO and CUS + OEO groups received OEO (0.2 mL/kg, i.p.), CON and CUS received saline (0.2 mL/kg, i.p.), and the positive drug groups of CUS rats received fluoxetine (10 mg/kg) and diazepam (3 mg/kg) once daily for 14 days. The expression of TLR 2/4 was determined using real time quantitative polymerase chain reaction with the SYBR green reporter dye. The compositions of the OEO were determined by gas chromatography-mass spectroscopy. The main constituents were thymol (20.72%), gamma-terpinene (8.83%), borneol (8.72%), cymene (6.83%), carvacrol (6.274%), alfa-terpinene (5.26%), and sabinene (4.92%). Administration of OEO significantly alleviated the depressive symptoms of CUS. A higher level of TLR2/4 mRNA was seen in the brain of CUS group (P < 0.05). The CUS-induced increases in the TLR2/4 levels were not reversed by OEO. According to the present study OEO may have the antidepressant-like activity but have no effect on the stress-induced TLR-2/4 upregulation. PMID- 29606968 TI - The effect of betulinic acid on leptin, adiponectin, hepatic enzyme levels and lipid profiles in streptozotocin-nicotinamide-induced diabetic mice. AB - Diabetes mellitus is developed by lack of insulin secretion or reduction of tissues sensitivity to insulin, which lead to serious complications. The aim of this study is to evaluate antihyperlipidemic effect of betulinic acid (BA) on streptozotocin-nicotinamide (STZ-NA) induced diabetic mice. In this experimental study, seventy adult male NMRI mice (20-25 g) were divided randomly into seven groups (n = 10) of control, sham, diabetes, diabetes + BA (10, 20 and 40 mg/kg), and diabetes + metformin (200 mg/kg). Diabetes was induced by intraperitoneal (i.p.) injection of a single dose of STZ (50 mg/kg) 15 min after an i.p. administration of nicotinamide (NA) (120 mg/kg). BA and metformin were orally administered and after two weeks blood samples were taken. Blood levels of leptin, adiponectin, lipid profile and liver enzyme were then measured. One day after the last drug administration, liver was removed to evaluate the histological changes. A significant increase (P < 0.05) in the plasma levels of leptin, alanine-aminotransferase (ALT), aspartate-aminotransferase (AST), alkaline phosphatase (ALP), low density lipoprotein cholesterol (LDL-C), cholesterol, and a significant decrease in adiponectin and high density lipoprotein cholesterol (HDL-C) were observed in diabetic mice. The groups treated with BA indicated a significant decrease in leptin, AST, ALT, ALP, TG, cholesterol, LDL-C and an increases in adiponectin and HDL levels, while VLDL did not show significant changes. BA was found to have positive effects on liver injury. BA has an effective role on liver damage induced by diabetes through amelioration of leptin, adiponectin, liver enzyme levels and lipid profile. Since BA has a positive effect on lipid profile, adiponectin and leptin, it may improve metabolic syndrome. PMID- 29606969 TI - Bioassay-directed isolation of quaternary benzylisoquinolines from Berberis integerrima with bactericidal activity against Brucella abortus. AB - Berberis integerrima Bonge. (Syn: Berberis densiflora Boiss. & Buhse) is a shrub widely distributed in Middle East and central part of Asia. An ethnobotanical study revealed that indigenous and tribal people in Iran use B. integerrima root decoction for treatment of brucellosis. Therefore, the aim of this study was bioassay directed isolation of antibacterial compounds from this plant based on their in vitro bactericidal activity against Brucella abortus. Briefly, the ethanol extract of B. integerrima was fractioned and subjected to preliminary antibacterial screening tests against Brucella. The more active fraction (Fr.3) was subjected to purification by repeated chromatography systems. Quaternary benzylisoquinoline alkaloids including columbamine, palmatine, berberine, and jatrorhizine were four main components identified in the selected active fraction. Except for berberine which is reported before, palmatine, columbamine and jatrorhizine are isolated for the first time from this plant. Anti brucellosis properties of isolated compounds 1-4 were studied against B. abortus under different test conditions. In minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) results, jatrorhizine (4) showed more antibacterial activity with MIC and MBC of 0.78 and 1.56 MUg/mL, respectively. In both agar well diffusion and disk diffusion ANOVA results showed that there were statistically significant differences between compounds 1-4 versus placebo in all of the tested concentration (P <0.001). In conclusion, all of four alkaloids showed potent antibacterial activity against B. abortus but jatrorhizine and columbamine with free hydroxyl group on C-3 or C-2 showed more activity than palmatine and berberine without any free hydroxyl group on their structures. The antibacterial effects of columbamine (15 MUg/mL) and jatrorhizine (15 MUg/mL) were comparative to streptomycin (10 MUg/mL) as standard drug which candidate them for more pharmacological researches to find new antibacterial agents against brucellosis. PMID- 29606970 TI - The protective role of melatonin in cadmium-induced proliferation of ovarian cancer cells. AB - Cadmium (Cd), a ubiquitous environmental and occupational pollutant, acts as a metalloestrogen to induce cell proliferation. It is suggested that Cd may also contribute to the development of estrogen-related cancers like ovarian cancer which is the most lethal cancer in women. Furthermore, it was shown that melatonin has antiproliferative effect on estradiol (E2)-induced proliferation. The aim of the present study was to evaluate whether melatonin inhibits Cd induced proliferation in ovarian cancer cell lines and also whether Cd and melatonin can modulate estrogen receptor alpha (ERalpha) expression. OVCAR3 and SKOV3 human ovarian cancer cell lines were treated with CdCl2 (1-100 nM) and melatonin (1 MUM) for 48 h. Cell proliferation evaluation was carried out by bromodeoxyuridine (BrdU) incorporation assay. ERalpha expression was detected by western blotting method 24 h after cell treatment. The results were demonstrated that Cd increased proliferation of ovarian cancer cell lines in a dose dependent manner. Melatonin inhibited Cd-induced proliferation of OVCAR3 and SKOV3 cell lines. Moreover, CdCl2 significantly increased ERalpha expression in both OVCAR3 and SKOV3 cell lines compared to control. Melatonin significantly inhibited Cd inducing effect on ERalpha expression of OVCAR3 and SKOV3 cell. In conclusion, due to the proliferative effect on ovarian cancer cell lines, Cd could play an important role in the etiology of ovarian cancer by inducing cells ERalpha expression. Furthermore, melatonin has the protective role on Cd-induced cell proliferation by inhibition of ERalpha expression. PMID- 29606971 TI - Synthesis and cytotoxic evaluation of some novel quinoxalinedione diarylamide sorafenib analogues. AB - A series of novel sorafenib analogues containing a quinoxalinedione ring and amide linker were synthesized. A total of 9 novel compounds in 6 synthetic steps were synthesized. Briefly, the amino group of p-aminophenol was first protected which then followed by O-arylation with 5-chloro-2-nitroaniline to provide compound d. Reduction of the nitro group of compound d and cyclization of the diamine group of compound e with oxalic acid afforded compound f which on deacetylation yeilded compound g. Then compound g was reacted with different acyl halides to afford the target compounds 1h-1p. Chemical structures of synthesized compounds were confirmed by 1H NMR and FT-IR analysis. All compounds were evaluated at 1, 10, 50 and 100 MUM concentrations for their cytotoxicity against HeLa and MCF-7 cancer cell lines. Some of the compounds showed good cytotoxic activity, especially compounds 1i and 1k-1n with the IC50 values of 19, 16, 22, 18, and 16 MUM against MCF-7 cell line and 20, 18, 25, 20, and 18 MUM against HeLa cell line, respectively. PMID- 29606972 TI - Renal vascular response to angiotensin 1-7 in rats: the role of Mas receptor. AB - Recently a cross talk between angiotensin 1-7 (Ang1-7) receptor (MasR) and angiotensin II receptors types 1 and 2 (AT1R and AT2R) has been highlighted. The effects of MasR antagonist (A779) compared to the vehicle on the renal blood flow (RBF) and renal vascular resistance (RVR) responses to Ang1-7 (300 ng/kg/min) infusion in the absence of Ang II receptors in male and female rats were determined at controlled renal perfusion pressure. Ang1-7 infusion did not alter mean arterial pressure in male and female rats. However, A779 compared to vehicle increased RBF (18% vs 3%) and decreased RVR (13% vs 4%) responses to Ang1-7 infusion significantly (P < 0.05) in male when AngII receptors were blocked. Such observation was not occurred in female animals. Finally it was concluded that renal vascular responses to Ang1-7 administration may not be exerted by MasR in male rats, and these responses are not mediated with AngII receptors. PMID- 29606973 TI - The Social Ecology of Public Space: Active Streets and Violent Crime in Urban Neighborhoods. AB - Drawing on one element of Jacobs' (1961) discussion of the social control benefits of "eyes on the street," this paper explores the link between the prevalence of active streets and violence in urban neighborhoods. Three distinct data sources from the Project on Human Development in Chicago Neighborhoods are merged to explore the functional form and potential contingency of the active streets-violence relationship: (1) video data capturing the presence of people on neighborhood streets; (2) longitudinal data on adolescents (ages 11 to 16) and their self-reports of witnessing severe violence; and (3) community survey data on neighborhood social organizational characteristics. Results from multilevel models indicate that the proportion of neighborhood streets with adults present exhibits a nonlinear association with exposure to severe violence. At low prevalence, the increasing prevalence of active streets is positively associated with violence exposure. Beyond a threshold, however, increases in the prevalence of active streets serves to reduce the likelihood of violence exposure. The analyses offer no evidence that the curvilinear association between active streets and violence varies by levels of collective efficacy, and only limited evidence that it varies by anonymity. Analyses of data on homicide and violent victimization corroborate these findings. PMID- 29606974 TI - A PSO-Powell Hybrid Method to Extract Fiber Orientations from ODF. AB - High angular resolution diffusion imaging (HARDI) has opened up new perspectives for the delineation of crossing and branching fiber pathways by orientation distribution function (ODF). The fiber orientations contained in an imaging voxel are the key factor in tractography. To extract real fiber orientations from ODF, a hybrid method is proposed for computing the principal directions of ODF by combining the variation of Particle Swarm Optimization (PSO) algorithm with the modified Powell algorithm. This method is comprised of the global searching ability of PSO and the powerful local optimizing of Powell search. This combination can guarantee finding all the diffusion directions without applying sliding windows and improve the accuracy and efficiency. The proposed approach was evaluated on simulated crossing-fiber datasets, Tractometer, and in vivo datasets. The results show that this method could correctly identify fiber directions under a range of noise levels. This method was compared with the state of-the-art methods, such as modified Powell, ball-stick model, and diffusion decomposition, showing that it outperformed them. As to the multimodal voxels where different fiber populations exist, the proposed approach allows us to improve the estimation accuracy of fiber orientations from ODF. It can play a significant role in the nerve fiber tracking. PMID- 29606975 TI - An exploratory analysis of changes in mood, anxiety and craving from pre- to post single sessions of exercise, over 12 weeks, among patients with alcohol dependence. AB - Aerobic exercise is currently being studied as a relapse prevention strategy for individuals with alcohol use disorders. Negative affect and cravings predict relapse. The acute effects of moderate-intensity exercise have been shown to improve mood and reduce craving. The current study examined the acute effects of exercise on changes in mood, anxiety, and craving from pre- to post-exercise at each week of a 12-week moderate intensity exercise intervention with sedentary alcohol dependent adults. Twenty-six participants in the exercise condition of a larger randomized clinical trial (Brown et al., 2014) exercised in small groups at moderate intensity for 20 to 40 minutes per session. Participants rated mood, anxiety, and cravings in the present moment before and after each exercise session over the course of the 12-week intervention. Data analyses focused on effect size and interval estimation. Joinpoint analysis was used to model longitudinal trends. Increases in mood and decreases in anxiety and craving were apparent at every session. Effect size estimates revealed that average change from pre- to post-exercise was in the small to medium range with some individual sessions reaching the large range. Joinpoint analyses revealed that the pre-post exercise changes in mood increased, anxiety remained stable, and craving diminished across the 12 weeks. This study provides provisional support for a change in mood, anxiety and alcohol cravings for the role of exercise in the early recovery period for alcohol dependence. Acute single bouts of moderate intensity exercise may help individuals with alcohol dependence manage mood, anxiety, and craving thereby reducing relapse risk, but further research is needed with a more rigorous study design. PMID- 29606977 TI - Anti-angiogenic therapies in brain metastases. AB - Brain metastases are a major challenge in modern oncology, as treatment options upon the diagnosis of symptomatic brain metastases are limited. Neo-angiogenesis was identified as a hallmark of brain metastasis development and inhibition using anti-angiogenic therapy might therefore be an experimental promising preventive as well as therapeutic approach. The current review will summarize the current available data on the efficacy of neo-angiogenic therapies in patients with brain metastases. PMID- 29606976 TI - Association of weight loss with improved disease activity in patients with rheumatoid arthritis: A retrospective analysis using electronic medical record data. AB - Objective: To evaluate the association between weight loss and rheumatoid arthritis (RA) disease activity. Methods: We conducted a retrospective cohort study of RA patients seen at routine clinic visits at an academic medical center, 2012-2015. We included patients who had >=2 clinical disease activity index (CDAI) measures. We identified visits during follow-up where the maximum and minimum weights occurred and defined weight change and CDAI change as the differences of these measures at these visits. We defined disease activity improvement as CDAI decrease of >=5 and clinically relevant weight loss as >=5 kg. We performed logistic regression analyses to establish the association between improved disease activity and weight loss and baseline BMI category (>=25 kg/m2 or <25 kg/m2). We built linear regression models to investigate the association between continuous weight loss and CDAI change among patients who were overweight/obese at baseline and who lost weight during follow-up. Results: We analyzed data from 174 RA patients with a median follow-up of 1.9 years (IQR 1.3-2.4); 117 (67%) were overweight/obese at baseline, and 53 (31%) lost >=5 kg during follow-up. Patients who were overweight/obese and lost >=5 kg had three fold increased odds of disease activity improvement compared to those who did not (OR 3.03, 95%CI 1.18-7.83). Among those who were overweight/obese at baseline, each kilogram weight loss was associated with CDAI improvement of 1.15 (95%CI 0.42-1.88). Our study was limited by using clinical data from a single center without fixed intervals for assessments. Conclusion: Clinically relevant weight loss (>=5 kg) was associated with improved RA disease activity in the routine clinical setting. Further studies are needed for replication and to evaluate the effect of prospective weight loss interventions on RA disease activity. PMID- 29606978 TI - My burning issues in the neoadjuvant treatment for breast cancer. AB - A combination of anthracyclines and taxanes remains the standard of care for neoadjuvant chemotherapy (NACT) resulting in increased breast conservation rate (BCR) and decreased recurrence rate [1]. Whether pathological complete response (pCR) could be an appropriate surrogate parameter for long-term survival is still a matter of debate. In patients with triple-negative breast cancer (TNBC) and HER2-positive breast cancer (BC), a six to nine times higher risk for relapse has been reported if no pCR was achieved [2, 3]. Within these aggressive subtypes the strongest association between pCR and long-term outcome could be observed [4]. However, a pooled analysis of recently conducted trials could only identify pCR as a surrogate endpoint for improved event-free survival (EFS) and overall survival (OS) on an individual patient level as opposed to the trial level [5]. Even in TNBC, demonstrating that an increased pCR converts into a significant survival benefit would require a study population markedly larger than calculated for previously conducted trials [6, 7]. PMID- 29606979 TI - PD-1 and PD-L1 inhibitors after platinum-based chemotherapy or in first-line therapy in cisplatin-ineligible patients: Dramatic improvement of prognosis and overall survival after decades of hopelessness in patients with metastatic urothelial cancer. AB - Until recently, there were no true innovations in the management of locally advanced (aUC) and metastatic urothelial cancer (mUC) in the last three decades. Vinflunine has been approved by the EMA (European Medicines Agency) with only limited improvement compared to best supportive care in second line treatment. In addition, gemcitabine/cisplatin has been established as an alternative to methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC). The advent of checkpoint inhibitors (CPI) revolutionized the care of these patients, transforming a unanimously deadly disease into one with hope through sustained disease control. Five immune CPI have recently been approved for aUC/mUC by the US Food and Drug Administration (FDA) including atezolizumab, nivolumab, pembrolizumab, durvalumab and avelumab. All five CPI are FDA-approved as second line therapy with atezolizumab and pembrolizumab also being approved for first line therapy in cisplatin-ineligible patients. The rapid acceptance in the treatment algorithm of UC is based on the impressive clinical efficacy of these agents in some patients, combined with their excellent safety profile. These new agents are indeed the most important advancement in UC care. However, the challenge in the age of precision medicine is to identify the patients who are most likely to benefit from CPIs, as the majority of patients do not respond to CPI. Toward this goal, validation of clinical, molecular and imaging biomarkers that serve for prediction and monitoring of treatment response are of central necessity. PMID- 29606980 TI - Short overview on the current standard of treatment in newly diagnosed multiple myeloma. AB - The treatment of newly diagnosed multiple myeloma has changed dramatically over the past 20 years, from near uniform application of chemotherapy to a patient performance status- and risk-based approach. Furthermore, initiation of treatment criteria have evolved from a pure end-organ damage-based definition to include risk factors of transformation to frank myeloma. Besides, the mainly cytogenetically defined Multiple Myeloma (MM) risk status, transplant eligibility of patients still serves primarily to allocate patients within a rational treatment algorithm. While all transplant-eligible MM patients should receive a triplet induction therapy followed by autologous transplantation and, in most cases, lenalidomide maintenance, other therapeutic elements (e. g., other maintenance strategies, consolidation, tandem transplantation,..) have to be decided on an individualized appraisal of risk and toxicities. Standard-risk patients should never be undertreated, as they derive the highest relative benefit from using the best available registered therapies. However, high-risk patients should be preferentially treated inside clinical trials testing additive innovative treatments, as the improvement in the prognosis of this group of patients by standard therapies has been underwhelming. Furthermore, the evaluation process of non-transplant-eligible patients should always comprise an evaluation of performance status, frailty, and comorbidities (e. g., a comprehensive geriatric assessment) to facilitate the allocation of individualized therapies. PMID- 29606981 TI - Pleural effusion in 11:14 translocation q1 multiple myeloma in the setting of proteasome inhibitor presents therapeutic complexity. AB - Background: Primary malignant pleural effusion has been reported in about 134 cases of multiple myeloma (MM). Associated pleural effusions in cases of MM portend a poor prognosis and identifying them is highly relevant. Reported is the case of a man diagnosed with MM who developed primary myelomatous pleural effusion in the setting of multiple relapses and subsequent mortality within 2 months of the pleural effusion diagnosis. Presentation: A 61-year-old African American man was diagnosed with MM in 2011. He received induction therapy of lenalidomide and dexamethasone and an autologous stem cell transplant in 2012. Over the next 5 years, the patient went through alternating periods of remission and relapse that were treated with two rounds of thoracic spine radiation therapy and chemotherapeutic agents. In September 2017, the patient presented with worsening dyspnea and was found to have pleural effusion. Fluid analysis showed plasma cell dyscrasia. Fluid drainage was performed, then the patient was discharged after 1 week which was followed by rapid re-accumulation of fluid and rehospitalization about 10 days after discharge. The patient passed away a few weeks after the second admission. Conclusion: Pleural effusion carries a differential diagnosis which may include malignancy but is commonly thought to be less specific to multiple myeloma but should still remain in the differential diagnosis. To our knowledge, this is the first case of myelomatous pleural effusion (MPE) that was reported after multiple relapses of MM. MPE is a very rare complication of MM, and its presence is a strong indicator of imminent mortality and need for comfort care in case of multiple relapses. End-stage pleural effusion in MM in the setting of proteasome inhibitor adds more therapeutic and diagnostic challenges. PMID- 29606982 TI - ESMO 2017-my personal highlights. AB - This article is not intended to be a comprehensive review of all highlights presented at the recent ESMO Annual Meeting, but rather a summary from a personal point of view in three very different fields of oncology. Breast cancer and lung cancer are traditionally in the focus of interest, and again, relevant new data were presented. The third part of this overview is focused on novel treatment strategies in malignant lymphoma, a field that is also quickly evolving and traditionally underrepresented at meetings dealing with solid cancers. PMID- 29606983 TI - The inverse scattering problem for orthotropic media in polarization-sensitive optical coherence tomography. AB - In this paper we provide for a first time, to our knowledge, a mathematical model for imaging an anisotropic, orthotropic medium with polarization-sensitive optical coherence tomography. The imaging problem is formulated as an inverse scattering problem in three dimensions for reconstructing the electrical susceptibility of the medium using Maxwell's equations. Our reconstruction method is based on the second-order Born-approximation of the electric field. PMID- 29606984 TI - Elevated Serum Levels of Mixed Lineage Kinase Domain-Like Protein Predict Survival of Patients during Intensive Care Unit Treatment. AB - Mixed lineage kinase domain-like (MLKL), a crucial regulator of necroptotic cell death, was shown to play a role in inflammatory diseases. However, its role as a biomarker in critical illness and sepsis is currently unknown. We analyzed serum levels of MLKL in 136 critically ill patients at admission to the intensive care unit (ICU) and after three days of ICU treatment. Results were compared with 36 healthy controls and correlated with clinical and laboratory patients' data. MLKL serum levels of critically ill patients at admission to the ICU were similar compared to healthy controls. At ICU admission, MLKL serum concentrations were independent of disease severity, presence of sepsis, and etiology of critical illness. In contrast, median serum levels of MLKL after three days of ICU treatment were significantly lower compared to those at admission to the ICU. While serum levels of MLKL at admission were not predictive for short-term survival during ICU treatment, elevated MLKL concentrations at day three were an independent negative predictor of patients' ICU survival. Thus, elevated MLKL levels after three days of ICU treatment were predictive for patients' mortality, indicating that sustained deregulated cell death is associated with an adverse prognosis in critical illness. PMID- 29606985 TI - The Abnormal Expression of MicroRNA-542-3p in Hepatocellular Carcinoma and Its Clinical Significance. AB - Aim: To evaluate the expression of miRNA-542-3p in hepatocellular carcinoma, establish its function, and evaluate whether it could serve as a biomarker for diagnosis and prognosis of HCC patients. Methods: qRT-PCR analysis was performed to determine the expression level of miRNA-542-3p in normal liver cells and HCC cell lines. Additionally, samples from TCGA consortium and from our patients were analyzed using biostatistical methods to ascertain whether miR-542-3p could be a good biomarker for HCC diagnosis and prognosis. The effects of miRNA-542-3p on HCC were investigated in HCCLM9 cells. Results: The expression of miRNA-542-3p in HCC cells was significantly downregulated compared with normal liver cells. A lower level of expression of miRNA-542-3p was found in HCC tissue samples than in adjacent normal liver tissue samples from TCGA cases and our patients. Further evaluation revealed that the downregulation was clearly related to aggressive clinicopathological characteristics and affected the prognosis, as low-expressing patients tended to have shorter overall survival. Moreover, cell assays revealed that miR-542-3p overexpression inhibited HCC cell growth and induced apoptosis. Conclusion: We demonstrated for the first time that miRNA-542-3p appears to function as a novel tumor suppressor in HCC and may serve as a promising prognostic biomarker in HCC patients. PMID- 29606986 TI - Candidate Urine Peptide Biomarkers for IgA Nephropathy: Where Are We Now? AB - Early detection, prognosis, and management of IgA nephropathy (IgAN) remain a challenge. Histological examination of renal tissue still comprises the only way to confirm an IgAN diagnosis. It is of great importance to establish noninvasive diagnostic, prognostic, and predictive biomarkers that would improve the clinical care and outcome of patients suffering from IgAN. This review summarises the findings from previous mass spectrometry- (MS-) based studies dedicated to the discovery of urinary peptide profiles specific to IgAN. There is a substantial number of urinary peptides that have been discovered to date, which show promise as biomarkers of IgAN; however, all of them require further, rigorous validation in well-planned studies, involving a large number of subjects who represent diverse and numerous populations. PMID- 29606987 TI - Evaluation of Individual and Combined Markers of Urine Dipstick Parameters and Total Lymphocyte Count as a Substitute for CD4 Count in Low-Resource Communities in Ghana. AB - We evaluated the individual and combined levels of urine dipstick and total lymphocyte count (TLC) as surrogate markers for CD4 count in a low-resource community in Ghana. This cross-sectional study recruited 200 HIV-infected patients from the Saint Francis Xavier Hospital, Assin Fosu, Ghana. Complete blood count, CD4 count, and urine dipstick analysis were measured for participants. The threshold values were determined as <350 cells/MUl for CD4, <1200 cells/MUl for TLC, and >=+ on urine dipstick analysis. The mean age of participants was 43.09 years. Proteinuria >= + [aOR = 4.30 (3.0-18.5)], leukocyturia >= + [aOR = 2.91 (1.33-12.5)], hematuria >= + [aOR = 2.30 (1.08 9.64)], and TLC < 1200 cells/MUl [aOR = 3.26 (3.94-15.29)] were significantly associated with increased risk of CD4 count < 350 cells/MUl. Using the individual markers, the best substitute marker for predicting CD4 count < 350 cells/MUl was proteinuria at a cutoff point >= 2++, AUC of 0.973, sensitivity of 97.6%, specificity of 100.0%, PPV of 100.0%, and NPV of 89.1%. A combination of <= 1200 TLC + >= 2++ (leukocyturia + proteinuria + hematuria) yielded an AUC of 0.980, sensitivity (72.8%), specificity (100.0%), PPV (100.0%), and NPV (97.9%). Proteinuria could serve as a noninvasive screening tool, but the combination of proteinuria, leukocyturia, hematuria, and TLC serves as a better substitute marker for CD4 count in monitoring the disease progression among HIV patients in low-resource communities. PMID- 29606989 TI - Conservative care as a treatment option for patients aged 75 years and older with CKD stage V: a National survey in the Netherlands. AB - Background and objectives: Conservative care for patients aged 75 years and older with CKD stage 5 as a treatment option besides dialysis was proposed officially in the Netherlands in October 2016. This national survey showed the current implementation of this option in Netherlands nephrology departments. Design setting participants and measurement: A web-based survey was sent to medical managers of 60 nephrology departments in the Netherlands in August 2016. Results: Twenty-one medical managers (35%) completed the survey. The term "conservative care" is frequently used and well known. The estimated number of patients in whom the decision for maximal conservative care was made in 2015 was 310 of 2249 patients with CKD stage 5 age 75 years and older (range 5-50 patients per department). 164 patients became symptomatic and received no dialysis. There is no official registration for this treatment option and patient category. The practice patterns vary widely. Only one of 21 respondents reported a conservative care outpatient clinic. Formal training or education regarding conservative care is not available in most of departments. 95% of respondents discussed this treatment option with their patients. General practitioners are always being informed about their patient's decision. Their main role is providing or organizing palliative care support at the end of life and discussing advance care planning. Most respondents (86%) considered to include their patients in a prospective multicentre observational study, conservative care versus dialysis. Conclusions: Conservative care as a treatment option for patients with CKD stage 5 aged 75 years and older is well established. The practice patterns are varied in the Netherlands. Follow-up studies are needed to see whether the new multidisciplinary guideline facilitates harmonization of practice pattern. Funding is needed to optimize the implementation of conservative care. PMID- 29606988 TI - Methylglyoxal: A Relevant Marker of Disease Activity in Patients with Rheumatoid Arthritis. AB - Background: The contribution of methylglyoxal (MGO) and soluble receptor for advanced glycation end products (sRAGE) in the presence of rheumatoid arthritis (RA) is still unknown. We investigated whether serum MGO and sRAGE were related to the presence of disease activity in RA. Methods: 80 patients with RA and 30 control subjects were included in a cross-sectional study. The severity of RA was assessed using the disease activity score for 28 joints (DAS28). Serum MGO and sRAGE were measured by ELISA. Results: Serum MGO levels were significantly higher in patients with RA versus control subjects (P < 0.001) and were increased in RA patients with higher disease activity versus RA patients with moderate disease activity (P = 0.019). Serum sRAGE concentrations were significantly decreased in RA patients with higher disease activity versus RA patients with moderate disease activity and versus control subjects (P = 0.004; P = 0.002, resp.). A multiple logistic regression analysis demonstrated that MGO was independently associated with the presence of activity disease in RA (OR = 1.17, 95% CI: 1.02-1.31, P = 0.01). Conclusion: Serum MGO and sRAGE levels are inversely related to the activity of RA, and MGO is independently associated with a higher disease activity of RA. PMID- 29606990 TI - A Cross-Sectional Study of Early Childhood Educators' Childhood and Current Food Insecurity and Dietary Intake. AB - In this cross-sectional study, ECEs (N=307) completed an 18-item survey regarding their role (lead vs. assistant), Education level, Program Type, and Current and Childhood Food Insecurity (FI) and Dietary Intake. ECEs in this study reported poor dietary quality and a high rate of FI. Approximately one quarter of ECEs ate fruits and vegetables more than once per day. Of participating ECEs, 34.5% indicated Current FI and 28.7% reported experiencing FI in Childhood. Differences in prevalence of Current FI were found for ECE role, Program Type, and Education (all p <= .03). Regression models with Childhood Dietary Intake, Childhood FI, Education, and Program Type as predictors accounted for a significant portion of variance in Current Dietary outcomes. In both models, Childhood Dietary Intake was uniquely predictive (p < .001) although Program Type was not. Future training and education efforts for ECEs should consider including specific resources to assess and reduce ECE FI and provide practical support for healthy eating on a budget. Additional research is needed to determine the impact of ECE FI on a variety of educator and child outcomes. PMID- 29606991 TI - DESIGN OF VACCINE TRIALS DURING OUTBREAKS WITH AND WITHOUT A DELAYED VACCINATION COMPARATOR. AB - Conducting vaccine efficacy trials during outbreaks of emerging pathogens poses particular challenges. The "Ebola ca suffit" trial in Guinea used a novel ring vaccination cluster randomized design to target populations at highest risk of infection. Another key feature of the trial was the use of a delayed vaccination arm as a comparator, in which clusters were randomized to immediate vaccination or vaccination 21 days later. This approach, chosen to improve ethical acceptability of the trial, complicates the statistical analysis as participants in the comparison arm are eventually protected by vaccine. Furthermore, for infectious diseases, we observe time of illness onset and not time of infection, and we may not know the time required for the vaccinee to develop a protective immune response. As a result, including events observed shortly after vaccination may bias the per protocol estimate of vaccine efficacy. We provide a framework for approximating the bias and power of any given analysis period as functions of the background infection hazard rate, disease incubation period, and vaccine immune response. We use this framework to provide recommendations for designing standard vaccine efficacy trials and trials with a delayed vaccination comparator. Briefly, narrower analysis periods within the correct window can minimize or eliminate bias but may suffer from reduced power. Designs should be reasonably robust to misspecification of the incubation period and time to develop a vaccine immune response. PMID- 29606992 TI - MODELING TEMPORAL GRADIENTS IN REGIONALLY AGGREGATED CALIFORNIA ASTHMA HOSPITALIZATION DATA. AB - Advances in Geographical Information Systems (GIS) have led to the enormous recent burgeoning of spatial-temporal databases and associated statistical modeling. Here we depart from the rather rich literature in space-time modeling by considering the setting where space is discrete (e.g., aggregated data over regions), but time is continuous. Our major objective in this application is to carry out inference on gradients of a temporal process in our data set of monthly county level asthma hospitalization rates in the state of California, while at the same time accounting for spatial similarities of the temporal process across neighboring counties. Use of continuous time models here allows inference at a finer resolution than at which the data are sampled. Rather than use parametric forms to model time, we opt for a more flexible stochastic process embedded within a dynamic Markov random field framework. Through the matrix-valued covariance function we can ensure that the temporal process realizations are mean square differentiable, and may thus carry out inference on temporal gradients in a posterior predictive fashion. We use this approach to evaluate temporal gradients where we are concerned with temporal changes in the residual and fitted rate curves after accounting for seasonality, spatiotemporal ozone levels and several spatially-resolved important sociodemographic covariates. PMID- 29606994 TI - BE AWARE: DUPILUMAB USE. PMID- 29606993 TI - Charge Separation and Triplet Exciton Formation Pathways in Small Molecule Solar Cells as Studied by Time-resolved EPR Spectroscopy. AB - Organic solar cells are a promising renewable energy technology, offering the advantages of mechanical flexibility and solution processability. An understanding of the electronic excited states and charge separation pathways in these systems is crucial if efficiencies are to be further improved. Here we use light induced electron paramagnetic resonance (LEPR) spectroscopy and density functional theory calculations (DFT) to study the electronic excited states, charge transfer (CT) dynamics and triplet exciton formation pathways in blends of the small molecule donors (DTS(FBTTh2)2, DTS(F2BTTh2)2, DTS(PTTh2)2, DTG(FBTTh2)2 and DTG(F2BTTh2)2) with the fullerene derivative PC61BM. Using high frequency EPR the g-tensor of the positive polaron on the donor molecules was determined. The experimental results are compared with DFT calculations which reveal that the spin density of the polaron is distributed over a dimer or trimer. Time-resolved EPR (TR-EPR) spectra attributed to singlet CT states were identified and the polarization patterns revealed similar charge separation dynamics in the four fluorobenzothiadiazole donors, while charge separation in the DTS(PTTh2)2 blend is slower. Using TR-EPR we also investigated the triplet exciton formation pathways in the blend. The polarization patterns reveal that the excitons originate from both intersystem crossing (ISC) and back electron transfer (BET) processes. The DTS(PTTh2)2 blend was found to contain substantially more triplet excitons formed by BET than the fluorobenzothiadiazole blends. The higher BET triplet exciton population in the DTS(PTTh2)2 blend is in accordance with the slower charge separation dynamics observed in this blend. PMID- 29606995 TI - Double-blind, Placebo-controlled Trial to Evaluate the Effectiveness of Polypodium Leucotomos Extract in the Treatment of Melasma in Asian Skin: A Pilot Study. AB - Introduction: Melasma is a common pigmentary disorder with a multifactorial etiology that can hinder its management. The aqueous extract of the fern Polypodium leucotomos (PLE), Fernblock(r) (IFC, Madrid, Spain), has demonstrated antioxidant and photoprotective activities and has been used for the treatment of several pigmentary disorders. The aim of this study was to evaluate the efficacy and safety of oral PLE in the treatment of melasma in Asian patients. Methods: Forty healthy adult patients with clinical diagnoses of melasma who were receiving treatment with topical 4% hydroquinone cream and sunscreen with a sun protection factor (SPF) of 50+ were recruited for inclusion in this study from the National Skin Centre in Singapore. They were randomized to receive either oral PLE supplementation or placebo for 12 weeks. Patients were assessed at baseline, Day 28, Day 56, and Day 84 using the modified Melasma Area and Severity Index (mMASI); melanin and erythema indexes; VISIA(r) photography (Canfield Scientific, Parsippany, New Jersey, USA); and the Melasma Quality of Life (MelasQoL) questionnaire. Adverse events were recorded. Results: Following four, eight, and 12 weeks of treatment, there were statistically significant differences between the mMASI scores of both groups as compared with the baseline scores (p<=0.01). mMASI scores of the PLE group at eight and 12 weeks were also significantly lower than those of the placebo group (p<=0.05). At the end of the study, a significant improvement was reached in both groups (both p<=0.01), with no significant differences between them. The scores of the melanin and erythema indices displayed a slight improvement in both groups, without significant differences among them. MelasQoL score showed an improvement in the PLE group versus the placebo group. Our results demonstrate that the PLE aqueous extract product significantly improves and accelerates the outcome reached with hydroquinone and sunscreen almost from the first month of treatment in comparison with the placebo. There were no significant side effects reported. Conclusions: The oral PLE aqueous extract product appears to be a safe and effective adjunctive treatment for melasma in combination with topical hydroquinone and sunscreen. PMID- 29606996 TI - Structural Changes of Subcutaneous Tissue Valued by Ultrasonography in Patients with Cellulitis Following Treatment with the PnKCelulitis(r) Program. AB - Background: Poor eating habits, a sedentary lifestyle, and limited physical activity are predisposing factors for the development of cellulite. The PnKCelulitis(r) Programme (Pronokal Group, Barcelona, Spain) is a new approach to the treatment of cellulite that combines dietary guidelines, physical exercise, and the application of an anti-cellulite cream. Objective: We sought to objectively and via cutaneous ultrasound assess the benefit of the new multidisciplinary anti-cellulite treatment program and to evaluate any visual changes in the appearance of the skin. Materials and methods: Twenty women with Grades 1 to 3 cellulite were included in the study. All women underwent the multidisciplinary treatment. Clinical controls assessed the evolution of the degree of cellulite; the anthropometric parameters (e.g., weight, body mass index, and mean and low abdominal circumference) and body composition were assessed by bioimpedance. Ultrasound assessments were performed blinded at the beginning and at the end of treatment to assess the following: thickness of the skin, dermis, and hypodermis; areas of indentation; and changes in the echogenicity of the dermis. Results: The degree of cellulite was reduced in all locations, and 90 percent (18/20) of the sample saw their cellulite reduced by at least one degree. Cellulite in the abdomen disappeared in all of the women who had initially presented with it. Most of the subjects with cellulite in the buttocks (70%, 13/19) completed the treatment with Grade 0. There was a decrease in weight and a reduction of abdominal perimeters at the expense of only body fat. Significant decreases in the thickness of the skin and hypodermis and in areas of indentation were observed (p<0.05), in addition to an increase in the echogenicity of the dermis in 18 of the 20 patients. Conclusions: The multidisciplinary treatment program evaluated in this study appears to be an effective and safe treatment for patients with different degrees of cellulite, both clinically and via ultrasound imaging. Additional research with a larger patient cohort is needed to support our findings. PMID- 29606997 TI - Characterization of the 2016-2017 Dermatology Standardized Letter of Recommendation. AB - Objective: We aimed to analyze the reformatted standard letter of recommendation (SLOR) for dermatology residents to examine trends in grading and content based on the positions of the letter writers, their backgrounds, and their relationship with the applicant, as well as to evaluate the SLOR's ability to discriminate applicants. Design: This was a retrospective characterization study of dermatology SLORs from the 2016-17 application cycle. Setting: We examined SLORs received by The Ohio State University, the University of Oklahoma, and Hofstra University Northwell Health dermatology residency programs. Participants: We included dermatology residency applicants and their letter writers from the 2016 17 application cycle. Results: A total of 141 SLORs were analyzed from 115 applicants. SLORs demonstrated grade inflation from letter writers of all backgrounds. Ratings for research potential and inquisitive nature were significantly lower than ratings for other categories. Letter writers with limited clinical and research contact graded applicants significantly lower than did writers who had more extensive contact. Word boxes were underutilized. Conclusion: The dermatology SLOR is useful in differentiating applicants, and ratings correlate with the relationships that letter writers have with their applicants. Residency programs should be aware of these findings when evaluating letters of recommendation for applicants. PMID- 29606998 TI - TATTOOS: What Do People Really Know About the Medical Risks of Body Ink? AB - Background: Tattoos have become increasing popular; however, medical complications and health risks can occur when getting a tattoo. Aim: The objective of this study is to determine whether people are properly informed about the medical risks and complications associated with tattoos and how the level of knowledge differs between those who have gotten tattooed and those who have not. Method: A cross-sectional online survey was performed. One-hundred participants had tattoos (32% male, 67% female) and 111 had no tattoos (53% male, 47% female); the average age was 26.9 years; level of education of both groups was comparable. There was a considerable (but not significant) difference between the two randomly selected samples with respect to sex and age, but both variables had no significant influence on the knowledge about medical risks, so no adjustment of the groups was carried out. The following variables were examined: demographics, characteristics of the tattoo, the intensity of the decision-making process that participants underwent before getting a tattoo, and the knowledge of medical risks and complications of tattoos. Results: More than 50 percent of the answers from both groups were incorrect (i.e., 55% of the answers from tattooed subjects were incorrect, and 58% of the non-tattooed group were incorrect). Neither sex (t-test, p=0.81) nor age (t-test, p=0.11) had any significant influence on the presence of knowledge. No significant correlations between sociodemographic variables and knowledge of medical risks of tattoos were found. No differences were found between characteristics of the tattoo and knowledge of medical risks apart from the size of the tattooed area (i.e., the larger the tattoo, the more information was sought by the person being tattooed). Differences were also found between educational levels and the knowledge of medical risks and complications of tattoos. Conclusions: Educating the public on the medical risks of tattoos might assist individuals in making more optimally informed decisions regarding whether to get a tattoo. PMID- 29606999 TI - Psoriasis and the Digital Landscape: YouTube as an Information Source for Patients and Medical Professionals. AB - Background: YouTube is the second most commonly accessed website worldwide, but little is known about the accuracy of its medical content. We performed a review to analyze the type and quality of content in a YouTube search with respect to the treatment of psoriasis. Methods: The first 10 result pages of YouTube were searched using the term psoriasis treatment with applied filters. One-hundred and eighty-two videos were reviewed and characterized by the source of content. Results: Of the identified videos, 7.1 percent had medical institutions or verified physicians as authors; 12.1 percent had a media-affiliated author; 1.6 percent were posted by a pharmaceutical company; 11.5 percent contained "miracle type" product advertisements with included links to product purchase websites; and 69.2 percent were holistic in nature, describing "natural" supplements and diets necessary for adequate psoriasis treatment and cure. Conclusion: This review emphasizes the need for an increase in the online presence of medical institutions to augment the dissemination of correct health information. PMID- 29607000 TI - Basaloid Follicular Hamartoma: A Case Report and a Novel Cosmetic Treatment. AB - Introduction: Basaloid follicular hamartoma (BFH) is a rare, benign neoplasm of the hair follicle, characterized by multiple brown papules involving the face, scalp, and trunk. It is described by multiple clinical forms, and can present as localized or generalized. Diagnosis is made histologically via biopsy, which is important in order to distinguish BFH from basal cell carcinoma (BCC) or other malignant epithelial neoplasms. Correct diagnosis allows for the avoidance of unnecessary surgeries to remove benign lesions. While benign, lesions can be cosmetically unacceptable. Case Report: A 68-year-old man with a two-year history of brown, homogenous papules on his face presented to discuss treatment options. A physical examination revealed hundreds of dark brown, 1- to 3mm verrucous papules distributed throughout the face. Two punch biopsies revealed histologic features consistent with BFH. Discussion: BFHs classically present with multiple 1- to 2mm tan-to-brown-colored papules distributed on the face, scalp, neck, axilla, trunk, and pubic area. Differential diagnoses can include nevus sebaceous, lichen striatus, linear epidermal nevus, and basal cell nevus. BFH arises from a mutation in the patch gene, the same gene thought to cause nevoid BCC syndrome. Histologic examination of BFH lesions is essential to diagnosis. No standard of care exists for BFH; treatment options remain limited. This patient was treated with three rounds of pulsed dye laser (PDL) therapy and showed marked improvement in the treated areas. The authors propose PDL to be a safe, effective, and novel cosmetic treatment for BFH and potentially other adnexal tumors. PMID- 29607001 TI - Behaviors and Attitudes Toward Cosmetic Treatments Among Men. AB - Background: Cosmetic treatments have gained popularity worldwide. However, little is known about the behaviors and attitudes toward cosmetic treatments in men. Objective: The authors sought to explore the behaviors and attitudes toward cosmetic treatments in male patients. Patients/Methods: A cross-sectional study was conducted involving male patients aged 18 to 70 years, who presented for cosmetic consultation at an outpatient dermatology clinic in a university-based hospital. Behaviors and attitudes were assessed using a self-response questionnaire. For comparison, female patients with the same inclusion criteria were also assessed. Results: A total of 302 male patients completed the questionnaire. The internet and close family members were the two most important sources of cosmetic treatment information. Men preferred oral medication compared to women (p<0.01). Regarding topical medication, men prefer gel formulations, tube containers, and white-colored packaging. The maximum chosen number of topical medication is three items. The most important factor in medical provider selection was the dermatologists' knowledge and expertise. Conclusion: Behaviors and attitudes toward cosmetic treatment in male patients were different from those seen in female patients. It is essential to alter the approaches regarding cosmetic treatments when treating men. PMID- 29607002 TI - The Evolution of Physician Practice Styles: Evidence from Cardiologist Migration. AB - Physician treatment choices for observably similar patients vary dramatically across regions. This paper exploits cardiologist migration to disentangle the role of physician-specific factors such as preferences and learned behavior versus environment-level factors such as hospital capacity and productivity spillovers on physician behavior. Physicians starting in the same region and subsequently moving to dissimilar regions practice similarly before the move. After the move, physician behavior in the first year changes by 0.6-0.8 percentage points for each percentage point change in practice environment, with no further changes over time. This suggests environment factors explain between 60-80 percent of regional disparities in physician behavior. PMID- 29607003 TI - Patients with type 2 diabetes demonstrate proprioceptive deficit in the knee. AB - AIM: To investigate proprioceptive discrepancies in the lower extremity in persons with type 2 diabetes mellitus (T2DM). METHODS: In this cross-sectional study, a total of 46 older persons were divided into a T2DM group (n = 23) and a control group who did not have T2DM (n = 23). Participants were given a brief warm up with stretching exercises. Diabetic neuropathy scores were collected prior to proprioceptive testing. For proprioceptive testing, participants performed leg extensions to randomized target positions of 15 degrees , 30 degrees , 45, 60 degrees degrees of elevation in the sagittal plane, each target was repeated a total of four times. Subjects were guided to target positions in the absence of visual feedback via auditory cues from a custom JPS application. When the participant entered the target position, they memorized the location of their limb in space and subsequently attempted to re-locate this position in space. Proprioceptive errors were measured from the target positioned, target remembered, target repositioned protocol. RESULTS: Proprioceptive accuracy was lower in the diabetic group at all levels of target angle than the control group (P < 0.05). The diabetic group had 46% greater inaccuracy than the control group at all levels of target position. Diabetics also reported greater neuropathy scores than controls in the past 12 mo P < 0.01. CONCLUSION: Deficits in lower limb localization and greater diabetic neuropathy scores were identified in this study. Our findings may be associated with deafferentation as peripheral neuropathy is a common complication with the disease. These findings may help to explain the declining balance function in the older persons with T2DM which is also commonly reported. PMID- 29607004 TI - A prospective year-long follow-up of lurasidone use in clinical practice: factors predicting treatment persistence. AB - Background: Our aim was to follow up patients prescribed lurasidone over 1 year to determine factors predicting treatment persistence. Methods: We used noninterventional, observational, prospective follow up of patients consecutively prescribed lurasidone in a large inner-city NHS mental health trust. We also performed retrospective analysis of outcomes from patient case notes. Results: Data were available for 69 patients consecutively prescribed lurasidone, of whom three (4%) were lost to follow up. Out of the 66 patients not lost to follow-up, 21 (32%) remained on lurasidone at 1 year. The main reasons for discontinuation were perceived ineffectiveness (49% of discontinuers) and adverse effects (36% of discontinuers), whilst a further seven refused all treatment. Median treatment time on lurasidone was 154 days (95% confidence interval (CI), 33-275). Patients who were not treatment-resistant had a substantially reduced risk of discontinuation, relative risk (RR) 0.18 [95% CI 0.08, 0.41, p < 0.001]. Medium doses (>37-74 mg) of lurasidone reduced the risk of discontinuation by 75% [RR 0.25 (95% CI 0.11, 0.58, p = 0.001)]; high doses (>74-148 mg) reduced the risk of discontinuation by 86% [RR 0.14 (95% CI 0.06, 0.35, p < 0.001)]. Risk of discontinuation was approximately doubled when the reason for prescribing lurasidone was poor tolerability of prior treatment [RR 2.01 (95% CI 1.05, 3.85, p = 0.035)]. Conclusion: The likelihood of treatment continuation with lurasidone can be vastly improved by targeting individuals most likely to benefit and by using optimal doses. PMID- 29607005 TI - The antipsychotic landscape: dopamine and beyond. AB - Until recently, the actions of antipsychotic and pro-psychotic drugs have largely been evaluated in the framework of neuronal doctrine - namely, that neurons communicate by releasing transmitters, and that psychiatric disorders are caused by neurotransmitter imbalances. Moreover, the majority of studies have focused on single transmitter systems - neglecting the fact that in the nervous system, different transmitter systems work in concert and impact on not only their immediate receptors but also downstream pathways that shape structural plasticity. In this review, we discuss the history of understanding the antipsychotic and pro-psychotic actions of drugs, recent developments and future perspectives. PMID- 29607007 TI - Count data in biology-Data transformation or model reformation? AB - Statistical analyses are an integral component of scientific research, and for decades, biologists have applied transformations to data to meet the normal error assumptions for F and t tests. Over the years, there has been a movement from data transformation toward model reformation-the use of non-normal error structures within the framework of the generalized linear model (GLM). The principal advantage of model reformation is that parameters are estimated on the original, rather than the transformed scale. However, data transformation has been shown to give better control over type I error, for simulated data with known error structures. We conducted a literature review of statistical textbooks directed toward biologists and of journal articles published in the primary literature to determine temporal trends in both the text recommendations and the practice in the refereed literature over the past 35 years. In this review, a trend of increasing use of reformation in the primary literature was evident, moving from no use of reformation before 1996 to >50% of the articles reviewed applying GLM after 2006. However, no such trend was observed in the recommendations in statistical textbooks. We then undertook 12 analyses based on published datasets in which we compared the type I error estimates, residual plot diagnostics, and coefficients yielded by analyses using square root transformations, log transformations, and the GLM. All analyses yielded acceptable residual versus fit plots and had similar p-values within each analysis, but as expected, the coefficient estimates differed substantially. Furthermore, no consensus could be found in the literature regarding a procedure to back-transform the coefficient estimates obtained from linear models performed on transformed datasets. This lack of consistency among coefficient estimates constitutes a major argument for model reformation over data transformation in biology. PMID- 29607006 TI - Digital photography provides a fast, reliable, and noninvasive method to estimate anthocyanin pigment concentration in reproductive and vegetative plant tissues. AB - Anthocyanin pigments have become a model trait for evolutionary ecology as they often provide adaptive benefits for plants. Anthocyanins have been traditionally quantified biochemically or more recently using spectral reflectance. However, both methods require destructive sampling and can be labor intensive and challenging with small samples. Recent advances in digital photography and image processing make it the method of choice for measuring color in the wild. Here, we use digital images as a quick, noninvasive method to estimate relative anthocyanin concentrations in species exhibiting color variation. Using a consumer-level digital camera and a free image processing toolbox, we extracted RGB values from digital images to generate color indices. We tested petals, stems, pedicels, and calyces of six species, which contain different types of anthocyanin pigments and exhibit different pigmentation patterns. Color indices were assessed by their correlation to biochemically determined anthocyanin concentrations. For comparison, we also calculated color indices from spectral reflectance and tested the correlation with anthocyanin concentration. Indices perform differently depending on the nature of the color variation. For both digital images and spectral reflectance, the most accurate estimates of anthocyanin concentration emerge from anthocyanin content-chroma ratio, anthocyanin content-chroma basic, and strength of green indices. Color indices derived from both digital images and spectral reflectance strongly correlate with biochemically determined anthocyanin concentration; however, the estimates from digital images performed better than spectral reflectance in terms of r2 and normalized root-mean-square error. This was particularly noticeable in a species with striped petals, but in the case of striped calyces, both methods showed a comparable relationship with anthocyanin concentration. Using digital images brings new opportunities to accurately quantify the anthocyanin concentrations in both floral and vegetative tissues. This method is efficient, completely noninvasive, applicable to both uniform and patterned color, and works with samples of any size. PMID- 29607008 TI - Nonadditive effects of consumption in an intertidal macroinvertebrate community are independent of food availability but driven by complementarity effects. AB - Suboptimal environmental conditions are ubiquitous in nature and commonly drive the outcome of biological interactions in community processes. Despite the importance of biological interactions for community processes, knowledge on how species interactions are affected by a limiting resource, for example, low food availability, remains limited. Here, we tested whether variation in food supply causes nonadditive consumption patterns, using the macroinvertebrate community of intertidal sandy beaches as a model system. We quantified isotopically labeled diatom consumption by three macroinvertebrate species (Bathyporeia pilosa, Haustorius arenarius, and Scolelepis squamata) kept in mesocosms in either monoculture or a three-species community at a range of diatom densities. Our results show that B. pilosa was the most successful competitor in terms of consumption at both high and low diatom density, while H. arenarius and especially S. squamata consumed less in a community than in their respective monocultures. Nonadditive effects on consumption in this macroinvertebrate community were present and larger than mere additive effects, and similar across diatom densities. The underlying species interactions, however, did change with diatom density. Complementarity effects related to niche-partitioning were the main driver of the net diversity effect on consumption, with a slightly increasing contribution of selection effects related to competition with decreasing diatom density. For the first time, we showed that nonadditive effects of consumption are independent of food availability in a macroinvertebrate community. This suggests that, in communities with functionally different, and thus complementary, species, nonadditive effects can arise even when food availability is low. Hence, at a range of environmental conditions, species interactions hold important potential to alter ecosystem functioning. PMID- 29607009 TI - Determining threatened species distributions in the face of limited data: Spatial conservation prioritization for the Chinese giant salamander (Andrias davidianus). AB - The purpose of this study was to determine whether limited occurrence data for highly threatened species can provide useful spatial information to inform conservation. The study was conducted across central and southern China. We developed a habitat suitability model for the Critically Endangered Chinese giant salamander (Andrias davidianus) based on one biotic and three abiotic parameters from single-site locality records, which represent the only relevant environmental data available for this species. We then validated model quality by testing whether increased percentage of predicted suitable habitat at the county level correlated with independent data on giant salamander presence. We randomly selected 48 counties containing historical records which were distinct from, and independent of, the single-site records used to develop the model, and 47 additional counties containing >50% predicted suitable habitat. We interviewed 2,812 respondents near potential giant salamander habitat across these counties and tested for differences in respondent giant salamander reports between counties selected using each method. Our model predicts that suitable giant salamander habitat is found widely across central and southern China, with counties containing >=50% predicted suitable habitat distributed in 13 provinces. Counties with historical records contain significantly more predicted suitable habitat than counties without historical records. There are no statistical differences in any patterns of respondent giant salamander reports in surveyed counties selected from our model compared with the areas of known historical giant salamander distribution. A Chinese giant salamander habitat suitability model with strong predictive power can be derived from the restricted range of environmental variables associated with limited available presence-only occurrence records, constituting a cost-effective strategy to guide spatial allocation of conservation planning. Few reported sightings were recent, however, with most being over 20 years old, so that identification of areas of suitable habitat does not necessarily indicate continued survival of the species at these locations. PMID- 29607010 TI - Plant sizes mediate mowing-induced changes in nutrient stoichiometry and allocation of a perennial grass in semi-arid grassland. AB - While mowing-induced changes in plant traits and their effects on ecosystem functioning in semi-arid grassland are well studied, the relations between plant size and nutrient strategies are largely unknown. Mowing may drive the shifts of plant nutrient limitation and allocation. Here, we evaluated the changes in nutrient stoichiometry and allocation with variations in sizes of Leymus chinensis, the dominant plant species in Inner Mongolia grassland, to various mowing frequencies in a 17-yr controlled experiment. Affected by mowing, the concentrations of nitrogen (N), phosphorus (P), and carbon (C) in leaves and stems were significantly increased, negatively correlating with plant sizes. Moreover, we found significant trade-offs between the concentrations and accumulation of N, P, and C in plant tissues. The N:P ratios of L. chinensis aboveground biomass, linearly correlating with plant size, significantly decreased with increased mowing frequencies. The ratios of C:N and C:P of L. chinensis individuals were positively correlated with plant size, showing an exponential pattern. With increased mowing frequencies, L. chinensis size was correlated with the allocation ratios of leaves to stems of N, P, and C by the tendencies of negative parabola, positive, and negative linear. The results of structure equation modeling showed that the N, P, and C allocations were co regulated by biomass allocation and nutrient concentration ratios of leaves to stems. In summary, we found a significant decoupling effect between plant traits and nutrient strategies along mowing frequencies. Our results reveal a mechanism for how long-term mowing-induced changes in concentrations, accumulations, ecological stoichiometry, and allocations of key elements are mediated by the variations in plant sizes of perennial rhizome grass. PMID- 29607011 TI - Extraction of DNA from captive-sourced feces and molted feathers provides a novel method for conservation management of New Zealand kiwi (Apteryx spp.). AB - Although some taxa are increasing in number due to active management and predator control, the overall number of kiwi (Apteryx spp.) is declining. Kiwi are cryptic and rare, meaning current monitoring tools, such as call counts, radio telemetry, and surveys using detection dogs are labor-intensive, yield small datasets, and require substantial resources or provide inaccurate estimates of population sizes. A noninvasive genetic approach could help the conservation effort. We optimized a panel of 23 genetic markers (22 autosomal microsatellite loci and an allosomal marker) to discriminate between all species of kiwi and major lineages within species, while simultaneously determining sex. Markers successfully amplified from both fecal and shed feather DNA samples collected in captivity. We found that DNA extraction was more efficient from shed feathers, but DNA quality was greater with feces, although this was sampling dependent. Our microsatellite panel was able to distinguish between contemporary kiwi populations and lineages and provided PI values in the range of 4.3 * 10-5 to 2.0 * 10-19, which in some cases were sufficient for individualization and mark-recapture studies. As such, we have tested a wide-reaching, noninvasive molecular approach that will improve conservation management by providing better parameter estimates associated with population ecology and demographics such as abundance, growth rates, and genetic diversity. PMID- 29607012 TI - Threat of predation alters aggressive interactions among spotted salamander (Ambystoma maculatum) larvae. AB - Intraspecific aggression represents a major source of mortality for many animals and is often experienced alongside the threat of predation. The presence of predators can strongly influence ecological systems both directly by consuming prey and indirectly by altering prey behavior or habitat use. As such, the threat of attack by higher level predators may strongly influence agonistic interactions among conspecifics via nonconsumptive (e.g., behaviorally mediated) predator effects. We sought to investigate these interactions experimentally using larval salamanders (Ambystoma maculatum) as prey and dragonfly nymphs (Anax junius) as predators. Specifically, we quantified salamander behavioral responses to perceived predation risk (PPR) from dragonfly nymphs and determined the degree to which PPR influenced intraspecific aggression (i.e., intraspecific biting and cannibalism) among prey. This included examining the effects of predator exposure on the magnitude of intraspecific biting (i.e., extent of tail damage) and the resulting change in performance (i.e., burst swim speed). Salamander larvae responded to PPR by reducing activity and feeding, but did not increase refuge use. Predator exposure did not significantly influence overall survival; however, the pattern of survival differed among treatments. Larvae exposed to PPR experienced less tail damage from conspecifics, and maximum burst swim speed declined as tail damage became more extensive. Thus, escape ability was more strongly compromised by intraspecific aggression occurring in the absence of predation risk. We conclude that multitrophic indirect effects may importantly modulate intraspecific aggression and should be considered when evaluating the effects of intraspecific competition. PMID- 29607013 TI - Fresh is best: Accurate SNP genotyping from koala scats. AB - Maintaining genetic diversity is a crucial component in conserving threatened species. For the iconic Australian koala, there is little genetic information on wild populations that is not either skewed by biased sampling methods (e.g., sampling effort skewed toward urban areas) or of limited usefulness due to low numbers of microsatellites used. The ability to genotype DNA extracted from koala scats using next-generation sequencing technology will not only help resolve location sample bias but also improve the accuracy and scope of genetic analyses (e.g., neutral vs. adaptive genetic diversity, inbreeding, and effective population size). Here, we present the successful SNP genotyping (1272 SNP loci) of koala DNA extracted from scat, using a proprietary DArTseqTM protocol. We compare genotype results from two-day-old scat DNA and 14-day-old scat DNA to a blood DNA template, to test accuracy of scat genotyping. We find that DNA from fresher scat results in fewer loci with missing information than DNA from older scat; however, 14-day-old scat can still provide useful genetic information, depending on the research question. We also find that a subset of 209 conserved loci can accurately identify individual koalas, even from older scat samples. In addition, we find that DNA sequences identified from scat samples through the DArTseqTM process can provide genetic identification of koala diet species, bacterial and viral pathogens, and parasitic organisms. PMID- 29607014 TI - Timing and technique impact the effectiveness of road-based, mobile acoustic surveys of bats. AB - Mobile acoustic surveys are a common method of surveying bat communities. However, there is a paucity of empirical studies exploring different methods for conducting mobile road surveys of bats. During 2013, we conducted acoustic mobile surveys on three routes in north-central Indiana, U.S.A., using (1) a standard road survey, (2) a road survey where the vehicle stopped for 1 min at every half mile of the survey route (called a "start-stop method"), and (3) a road survey with an individual using a bicycle. Linear mixed models with multiple comparison procedures revealed that when all bat passes were analyzed, using a bike to conduct mobile surveys detected significantly more bat passes per unit time compared to other methods. However, incorporating genus-level comparisons revealed no advantage to using a bike over vehicle-based methods. We also found that survey method had a significant effect when analyses were limited to those bat passes that could be identified to genus, with the start-stop method generally detecting more identifiable passes than the standard protocol or bike survey. Additionally, we found that significantly more identifiable bat passes (particularly those of the Eptesicus and Lasiurus genera) were detected in surveys conducted immediately following sunset. As governing agencies, particularly in North America, implement vehicle-based bat monitoring programs, it is important for researchers to understand how variations on protocols influence the inference that can be gained from different monitoring schemes. PMID- 29607015 TI - An analysis of the energetic reward offered by field bean (Vicia faba) flowers: Nectar, pollen, and operative force. AB - Global consumption of crops with a yield that is dependent on animal pollinators is growing, with greater areas planted each year. However, the floral traits that influence pollinator visitation are not usually the focus of breeding programmes, and therefore, it is likely that yield improvements may be made by optimizing floral traits to enhance pollinator visitation rates. We investigated the variation present in the floral reward of the bee-pollinated crop Vicia faba (field bean). We examined the genetic potential for breeding flowers with a greater reward into current commercial varieties and used bee behavioral experiments to gain insight into the optimal nectar concentration to maximize bee preference. There was a large range of variation in the amount of pollen and nectar reward of flowers in the genotypes investigated. Bee behavioral experiments using nectar sugar concentrations found in V. faba lines suggest that Bombus terrestris prefers 55% w/w sugar solution over 40% w/w, but has no preference between 55% w/w and 68% w/w sugar solution. We provide a first indication of the force required to open V. faba flowers. Our results provide a valuable starting point toward breeding for varieties with optimized floral reward. Field studies are now needed to verify whether the genetic potential for breeding more rewarding flowers can translate into higher yield and yield stability. PMID- 29607016 TI - Twelve fundamental life histories evolving through allocation-dependent fecundity and survival. AB - An organism's life history is closely interlinked with its allocation of energy between growth and reproduction at different life stages. Theoretical models have established that diminishing returns from reproductive investment promote strategies with simultaneous investment into growth and reproduction (indeterminate growth) over strategies with distinct phases of growth and reproduction (determinate growth). We extend this traditional, binary classification by showing that allocation-dependent fecundity and mortality rates allow for a large diversity of optimal allocation schedules. By analyzing a model of organisms that allocate energy between growth and reproduction, we find twelve types of optimal allocation schedules, differing qualitatively in how reproductive allocation increases with body mass. These twelve optimal allocation schedules include types with different combinations of continuous and discontinuous increase in reproduction allocation, in which phases of continuous increase can be decelerating or accelerating. We furthermore investigate how this variation influences growth curves and the expected maximum life span and body size. Our study thus reveals new links between eco-physiological constraints and life-history evolution and underscores how allocation-dependent fitness components may underlie biological diversity. PMID- 29607018 TI - Effect of climatic variation on the morphological characteristics of 37-year-old balsam fir provenances planted in a common garden in New Brunswick, Canada. AB - The extent of the effect of projected changes in climate on trees remains unclear. This study investigated the effect of climatic variation on morphological traits of balsam fir [Abies balsamea (L.) Mill.] provenances sourced from locations spanning latitudes from 44 degrees to 51 degrees N and longitudes from 53 degrees to 102 degrees W across North America, growing in a common garden in eastern Canada. Lower latitude provenances performed significantly better than higher latitude provenances (p < .05) with regard to diameter at breast height (DBH), height (H), and crown width (CW), a distinction indicative of genotypic control of these traits. There was, however, no significant difference among provenances in terms of survival (p > .05), an indication of a resource allocation strategy directed at survival relative to productivity in higher latitude provenances as seen in their lower DBH, H, and CW compared to the lower latitude provenances. Temperature had a stronger relationship with DBH, H, and CW than precipitation, a reflection of adaptation to local conditions in populations of the species along latitudinal gradients. Both climatic variables had some effect on tree survival. These results suggest that the response of balsam fir to climatic variation will likely not be uniform in the species, but differ based on genetic characteristics between populations located in the northern and southern parts of the species' range. Population differences in response to climatic variation may be evident earlier in growth traits, compared to survival in balsam fir. The findings of this study will facilitate modeling in the species that is reflective of genetic variation in response to climatic conditions, and guide provenance selection for utilization in terms of productivity or resilience as well as breeding programs directed at obtaining species that possibly combine both traits. PMID- 29607017 TI - Nectary tracks as pollinator manipulators: The pollination ecology of Swertia bimaculata (Gentianaceae). AB - Floral nectaries are closely associated with biotic pollination, and the nectar produced by corolla nectaries is generally enclosed in floral structures. Although some Swertia spp. (Gentianaceae), including S. bimaculata, evolved a peculiar form of corolla nectaries (known as "gland patches") arranged in a conspicuous ring on the rotate corolla and that completely expose their nectar, little is known about the pollination of these plants. Two hypotheses were made concerning the possible effects of gland patches: visual attraction and visitor manipulation. The floral traits, mating system, and insect pollination of S. bimaculata were examined, and the pollination effects of gland patches were evaluated. A comparative study was made using Swertia kouitchensis, a species with fimbriate nectaries. Swertia bimaculata flowers were protandrous, with obvious stamen movement leading to herkogamy in the female phase and to a significant reduction in nectary-anther distance. The species is strongly entomophilous and facultatively xenogamous. The daily reward provided per flower decreased significantly after the male phase. The most effective pollinators were large dipterans, and the visiting proportion of Diptera was significantly higher in S. bimaculata than in S. kouitchensis. Most visitors performed "circling behavior" in S. bimaculata flowers. Removing or blocking the nectaries caused no reduction in visiting frequency but a significant reduction in visit duration, interrupting the circling behavior. The circling behavior was encouraged by nectar abundance and promoted pollen dispersal. Visitor species with small body size had little chance to contact the anthers or stigma, revealing a filtration effect exerted by the floral design. These results rejected the "visual attraction" hypothesis and supported the "visitor manipulation" hypothesis. The nectary whorl within a flower acted like a ring-shaped track that urged nectar foragers to circle on the corolla, making pollination in S. bimaculata flowers more orderly and selective than that in classically generalist flowers. PMID- 29607019 TI - Selection by parasitoid females among closely related hosts based on volatiles: Identifying relevant chemical cues. AB - Parasitoid fitness is influenced by the ability to overcome host defense strategies and by the ability of parasitoid females to select high-quality host individuals. When females are unable to differentiate among hosts, their fitness will decrease with an increasing abundance of resistant hosts. To understand the effect of mixed host populations on female fitness, it is therefore necessary to investigate the ability of female parasitoids to select among hosts. Here, we used behavioral assays, headspace volatile collection, and electrophysiology to study the ability of Asecodes parviclava to use olfactory cues to select between a susceptible host (Galerucella calmariensis) and a resistant host (Galerucella pusilla) from a distance. Our studies show that parasitoid females have the capacity to distinguish the two hosts and that the selection behavior is acquired through experiences during earlier life stages. Further, we identified two volatiles (alpha-terpinolene and [E]-beta-ocimene) which amounts differ between the two plant-herbivore systems and that caused behavioral and electrophysiological responses. The consequence of this selection behavior is that females have the capacity to avoid laying eggs in G. pusilla, where the egg mortality is higher due to much stronger immune responses toward A. parviclava than in larvae of G. calmariensis. PMID- 29607020 TI - Patterns of musculoskeletal growth and dimensional changes associated with selection and developmental plasticity in domestic and wild strain turkeys. AB - Domestication is a type of experimental evolution in which humans have artificially selected for specific desired traits. Selected strain animals can be utilized to identify correlated responses by comparing them to the wild strain. In particular, domestic turkeys have been selected for increased body mass and high-growth rate, most significantly over the past 60 years. Yet it remains unclear how artificial selection has affected the morphology and evolution of the musculoskeletal system as a whole. Here, we compare growth rate over 21 weeks, hind limb bone scaling across ontogeny via in vivo CT scanning, and muscle proportions in wild and domestic turkeys to identify differences in structural scaling and the potential contributions of selection and developmental plasticity to whole-organism morphology. The domestic turkeys grew at a higher rate (0.14 kg/day vs. 0.05 kg/day) and reached over 3 times the body mass of wild birds. Comparing the proportional muscle masses in adult turkeys, only the trunk had a greater mass ratio in the domestic turkey, driven solely by M. pectoralis (2.8 times larger). The proportional increase in only breast meat and no other muscles highlights the surgical precision attainable with artificial selection. The domestic turkey femur and tibiotarsus displayed increases in polar moment of area, apparently maintaining torsional strength as body mass increased. The lack of dimensional change in the more vertically held tarsometatarsus is consistent with the pattern expected due to developmental plasticity. These results from the domestic turkey emphasize that there are morphological limits to preserving the balance between growth and function, and varying rates of trait evolution can further complicate this equilibrium. PMID- 29607021 TI - Insectivorous bats respond to vegetation complexity in urban green spaces. AB - Structural complexity is known to determine habitat quality for insectivorous bats, but how bats respond to habitat complexity in highly modified areas such as urban green spaces has been little explored. Furthermore, it is uncertain whether a recently developed measure of structural complexity is as effective as field based surveys when applied to urban environments. We assessed whether image derived structural complexity (MIG) was as/more effective than field-based descriptors in this environment and evaluated the response of insectivorous bats to structural complexity in urban green spaces. Bat activity and species richness were assessed with ultrasonic devices at 180 locations within green spaces in Vienna, Austria. Vegetation complexity was assessed using 17 field-based descriptors and by calculating the mean information gain (MIG) using digital images. Total bat activity and species richness decreased with increasing structural complexity of canopy cover, suggesting maneuverability and echolocation (sensorial) challenges for bat species using the canopy for flight and foraging. The negative response of functional groups to increased complexity was stronger for open-space foragers than for edge-space foragers. Nyctalus noctula, a species foraging in open space, showed a negative response to structural complexity, whereas Pipistrellus pygmaeus, an edge-space forager, was positively influenced by the number of trees. Our results show that MIG is a useful, time- and cost-effective tool to measure habitat complexity that complemented field-based descriptors. Response of insectivorous bats to structural complexity was group- and species-specific, which highlights the need for manifold management strategies (e.g., increasing or reinstating the extent of ground vegetation cover) to fulfill different species' requirements and to conserve insectivorous bats in urban green spaces. PMID- 29607022 TI - Habitat orientation alters the outcome of interspecific competition: A microcosm study with zooplankton grazers. AB - Habitat orientation has recently been demonstrated to affect the foraging behavior, growth, and production of plankton grazers. Because the orientation effect may vary with species, we hypothesize that habitat orientation may alter interspecific interactions between animal species. We experimentally investigated how habitat orientation (placing cuboid chambers in three orientations with long, medium, and small side as the chamber height) affected the interaction between two common cladoceran species, Daphnia magna and Moina micrura, which competitively exploited green algae of Chlorella pyrenoidosa at two volume scales (64 and 512 ml). Results show that chamber orientation and volume additively affected the behavior and species performance of the grazers. Specifically, both grazer species generally decreased their average swimming velocity, grazing rate (on algal cells), body size, and survival and reproduction rates with increasing chamber height for both chamber volumes and with decreasing chamber volume regardless of chamber orientation. Nevertheless, the decrease magnitude was greater for M. micrura with increasing chamber height but was greater for D. magna with decreasing chamber volume. Correspondingly, when cocultured, the density ratio of D. magna to M. micrura increased with increasing chamber height but decreased with decreasing chamber volume. At the end of the experiment, none of D. magna individuals survived in the small and short (large-based) chambers, and few M. micrura individuals survived in large and tall (small-based) chambers. These results indicate that both habitat orientation and size affect the outcome of interspecific competition between grazer species. We suggest that variation in habitat orientation may improve community coexistence and species diversity in nature. PMID- 29607023 TI - Incubation temperature impacts nestling growth and survival in an open-cup nesting passerine. AB - For oviparous species such as birds, conditions experienced while in the egg can have long-lasting effects on the individual. The impact of subtle changes in incubation temperature on nestling development, however, remains poorly understood, especially for open-cup nesting species with altricial young. To investigate how incubation temperature affects nestling development and survival in such species, we artificially incubated American robin (Turdus migratorius) eggs at 36.1 degrees C ("Low" treatment) and 37.8 degrees C ("High" treatment). Chicks were fostered to same-age nests upon hatching, and we measured mass, tarsus, and wing length of experimental nestlings and one randomly selected, naturally incubated ("Natural"), foster nest-mate on days 7 and 10 posthatch. We found significant effects of incubation temperature on incubation duration, growth, and survival, in which experimentally incubated nestlings had shorter incubation periods (10.22, 11.50, and 11.95 days for High, Low, and Natural eggs, respectively), and nestlings from the Low treatment were smaller and had reduced survival compared to High and Natural nestlings. These results highlight the importance of incubation conditions during embryonic development for incubation duration, somatic development, and survival. Moreover, these findings indicate that differences in incubation temperature within the natural range of variation can have important carryover effects on growth and survival in species with altricial young. PMID- 29607024 TI - Subtle variation in size and shape of the whole forewing and the red band among co-mimics revealed by geometric morphometric analysis in Heliconius butterflies. AB - Heliconius are unpalatable butterflies that exhibit remarkable intra- and interspecific variation in wing color pattern, specifically warning coloration. Species that have converged on the same pattern are often clustered in Mullerian mimicry rings. Overall, wing color patterns are nearly identical among co-mimics. However, fine-scale differences exist, indicating that factors in addition to natural selection may underlie wing phenotype. Here, we investigate differences in shape and size of the forewing and the red band in the Heliconius postman mimicry ring (H. erato phyllis and the co-mimics H. besckei, H. melpomene burchelli, and H. melpomene nanna) using a landmark-based approach. If phenotypic evolution is driven entirely by predation pressure, we expect nonsignificant differences among co-mimics in terms of wing shape. Also, a reinforcement of wing pattern (i.e., greater similarity) could occur when co-mimics are in sympatry. We also examined variation in the red forewing band because this trait is critical for both mimicry and sexual communication. Morphometric results revealed significant but small differences among species, particularly in the shape of the forewing of co-mimics. Although we did not observe greater similarity when co mimics were in sympatry, nearly identical patterns provided evidence of convergence for mimicry. In contrast, mimetic pairs could be distinguished based on the shape (but not the size) of the red band, suggesting an "advergence" process. In addition, sexual dimorphism in the red band shape (but not size) was found for all lineages. Thus, we infer that natural selection due to predation by birds might not be the only mechanism responsible for variation in color patterns, and sexual selection could be an important driver of wing phenotypic evolution in this mimicry ring. PMID- 29607025 TI - Nesting strategies and disease risk in necrophagous beetles. AB - While the effects of carcass decomposition on microorganisms have been demonstrated in recent years, little is known of how this impacts necrophagous insects. A common assumption is that insects that exploit carcasses are exposed to a high density of potentially harmful microorganisms, but no field data have so far validated this. Necrophagous beetles such as the Scarabaeinae have complex nesting behaviors with elaborate parental care. So here, we begin to explore whether this conjunction of life history and nesting behavior represents an adaptive response to the threat posed by microbes in these environments, mainly by entomopathogens. We evaluated the density and distribution of fungi and bacteria from soil near the carcasses, and their ability to infect and kill insects that are in contact with this soil during the decomposition process. Our data showed an increase in the density and activity of opportunistic or facultative pathogens during the apex of decomposition, when there is a predominance of necrophagous insects. Meanwhile, the survivorship of bait insects decreased when in contact with soil from this period of decomposition, indicating a potential risk of infection. However, the density and activity of these microorganisms decreased with distance from the carcass, mainly with depth, which would benefit tunneller beetles in particular. We have thus provided the first field data to show that necrophagous insects are indeed exposed to high densities of potentially harmful microorganisms. Furthermore, we propose that some parental care strategies may have arisen not only as a response to competition, but also as adaptations that reduce the risks of disease. Although we have focused on carrion feeders, we suggest that the same occurs with coprophagous beetles, as both carrion and dung are nutrient-rich resources. PMID- 29607027 TI - Intragroup and intragenomic conflict over chemical defense against predators. AB - Insects are often chemically defended against predators. There is considerable evidence for a group-beneficial element to their defenses, and an associated potential for individuals to curtail their own investment in costly defense while benefitting from the investments of others, termed "automimicry." Although females in chemically defended taxa often lay their eggs in clusters, leading to siblings living in close proximity, current models of automimicry have neglected kin-selection effects, which may be expected to curb the evolution of such selfishness. Here, we develop a general theory of automimicry that explicitly incorporates kin selection. We investigate how female promiscuity modulates intragroup and intragenomic conflicts overinvestment into chemical defense, finding that individuals are favored to invest less than is optimal for their group, and that maternal-origin genes favor greater investment than do paternal origin genes. We translate these conflicts into readily testable predictions concerning gene expression patterns and the phenotypic consequences of genomic perturbations, and discuss how our results may inform gene discovery in relation to economically important agricultural products. PMID- 29607026 TI - The effects of allospecific mitochondrial genome on the fitness of northern redbelly dace (Chrosomus eos). AB - Instantaneous mitochondrial introgression events allow the disentangling of the effects of hybridization from those of allospecific mtDNA. Such process frequently occurred in the fish Chrosomus eos, resulting in cybrid individuals composed of a C. eos nuclear genome but with a C. neogaeus mtDNA. This provides a valuable model to address the fundamental question: How well do introgressed individuals perform in their native environment? We infer where de novo production of cybrids occurred to discriminate native environments from those colonized by cybrids in 25 sites from two regions (West-Qc and East-Qc) in Quebec (Canada). We then compared the relative abundance of wild types and cybrids as a measure integrating both fitness and de novo production of cybrids. According to mtDNA variation, 12 introgression events are required to explain the diversity of cybrids. Five cybrid lineages could not be associated with in situ introgression events. This includes one haplotype carried by 93% of the cybrids expected to have colonized West-Qc. These cybrids also displayed a nearly complete allopatric distribution with wild types. We still inferred de novo production of cybrids at seven sites, that accounted for 70% of the cybrids in East-Qc. Wild-type and cybrid individuals coexist in all East-Qc sites while cybrids were less abundant. Allopatry of cybrids restricted to the postglacial expansion suggests the existence of higher fitness for cybrids in specific conditions, allowing for the colonization of different environments and expanding the species' range. However, allospecific mtDNA does not provide a higher fitness to cybrids in their native environment compared to wild types, making the success of an introgressed lineage uncertain. PMID- 29607028 TI - Use of field-portable ultrasonography reveals differences in developmental phenology and maternal egg provisioning in two sympatric viviparous snakes. AB - A thorough understanding of the life cycles underlying the demography of wild species is limited by the difficulty of observing hidden life-history traits, such as embryonic development. Major aspects of embryonic development, such as the rate and timing of development, and maternal-fetal interactions can be critical features of early-life fitness and may impact population trends via effects on individual survival. While information on development in wild snakes and lizards is particularly limited, the repeated evolution of viviparity and diversity of reproductive mode in this clade make it a valuable subject of study. We used field-portable ultrasonography to investigate embryonic development in two sympatric garter snake species, Thamnophis sirtalis and Thamnophis elegans in the Sierra Nevada mountains of California. This approach allowed us to examine previously hidden reproductive traits including the timing and annual variation in development and differences in parental investment in young. Both species are viviparous, occupy similar ecological niches, and experience the same annual environmental conditions. We found that T. sirtalis embryos were more developmentally advanced than T. elegans embryos during June of three consecutive years. We also found that eggs increased in volume more substantially across developmental stages in T. elegans than in T. sirtalis, indicating differences in maternal provisioning of embryos via placental transfer of water. These findings shed light on interspecific differences in parental investment and timing of development within the same environmental context and demonstrate the value of field ultrasonography for pursuing questions relating to the evolution of reproductive modes, and the ecology of development. PMID- 29607029 TI - Males prefer virgin females, even if parasitized, in the terrestrial isopod Armadillidium vulgare. AB - In many species, males increase their reproductive success by choosing high quality females. In natural populations, they interact with both virgin and mated females, which can store sperm in their spermatheca. Therefore, males elaborate strategies to avoid sperm competition. In the terrestrial isopod Armadillidium vulgare, females can store sperm and produce several clutches. Moreover, this species can be parasitized by Wolbachia, which feminizes genetic males, transforming them into functional females. Our study compared attractiveness and mate choice when a male is exposed to both virgin and experienced females (i.e., females who have produced offspring and rested for 6 months), with or without Wolbachia. Our results revealed that males are more attracted to virgin females than experienced females, even if these virgin females are parasitized. Moreover, the chemical analysis highlighted different odors in females according to their reproductive and infection (Wolbachia-free or vertically Wolbachia-infected) status. Males attempted copulation more frequently and for longer with virgin females, even if Wolbachia-infected, while experienced females refused further copulation. The evolutionary consequences of both male choice and female resistance on their fitness are discussed in this study. PMID- 29607030 TI - Timing of precipitation in an arid environment: Effects on population performance of a large herbivore. AB - Climate models predict that shifts in temperature and precipitation patterns are likely to occur across the globe. Changing climate will likely have strong effects on arid environments as a result of increased temperatures, increasing frequency and intensity of droughts, and less consistent pulses of rainfall. Therefore, understanding the link between patterns of precipitation, temperature, and population performance of species occupying these environments will continue to increase in importance as climatic shifts occur within these natural ecosystems. We sought to evaluate how individual, maternal, population, and environmental, particularly temperature and precipitation, level factors influence population performance of a large herbivore in an arid environment. We used mule deer (Odocoileus hemionus) as a representative species and quantified juvenile survival to test hypotheses about effects of environmental factors on population performance. Precipitation events occurring in mid- to late-pregnancy (January-April) leading to spring green-up, as indexed by normalized difference in vegetation index, had the strongest positive effect on juvenile survival and recruitment. In addition, larger neonates had an increased probability of survival. Our findings indicate that timing and amount of precipitation prior to parturition have strong influences on maternal nutritional condition, which was passed on to young. These results have important implications for understanding how animal populations may benefit from timing of precipitation during spring and prior to parturition, especially in arid environments. PMID- 29607031 TI - Fine root responses to temporal nutrient heterogeneity and competition in seedlings of two tree species with different rooting strategies. AB - There is little direct evidence for effects of soil heterogeneity and root plasticity on the competitive interactions among plants. In this study, we experimentally examined the impacts of temporal nutrient heterogeneity on root growth and interactions between two plant species with very different rooting strategies: Liquidambar styraciflua (sweet gum), which shows high root plasticity in response to soil nutrient heterogeneity, and Pinus taeda (loblolly pine), a species with less plastic roots. Seedlings of the two species were grown in sandboxes in inter- and intraspecific combinations. Nutrients were applied in a patch either in a stable (slow-release) or in a variable (pulse) manner. Plant aboveground biomass, fine root mass, root allocation between nutrient patch and outside the patch, and root vertical distribution were measured. L. styraciflua grew more aboveground (40% and 27% in stable and variable nutrient treatment, respectively) and fine roots (41% and 8% in stable and variable nutrient treatment, respectively) when competing with P. taeda than when competing with a conspecific individual, but the growth of P. taeda was not changed by competition from L. styraciflua. Temporal variation in patch nutrient level had little effect on the species' competitive interactions. The more flexible L. styraciflua changed its vertical distribution of fine roots in response to competition from P. taeda, growing more roots in deeper soil layers compared to its roots in conspecific competition, leading to niche differentiation between the species, while the fine root distribution of P. taeda remained unchanged across all treatments. Synthesis. L. styraciflua showed greater flexibility in root growth by changing its root vertical distribution and occupying space of not occupied by P. taeda. This flexibility gave L. styraciflua an advantage in interspecific competition. PMID- 29607032 TI - Maternal hatching synchronization in a subsocial burrower bug mitigates the risk of future sibling cannibalism. AB - Sibling cannibalism-the killing and consumption of conspecifics within broods carries a high risk of direct and inclusive fitness loss for parents and offspring. We reported previously that a unique vibrational behavior shown by the mother of the subsocial burrower bug, Adomerus rotundus (Heteroptera: Cydnidae), induced synchronous hatching. Maternal regulation may be one of the most effective mechanisms for preventing or limiting sibling cannibalism. Here, we tested the hypothesis that synchronous hatching induced by maternal vibration in A. rotundus prevents sibling cannibalism. Mothers and their mature egg masses were allocated to three groups: synchronous hatching by maternal vibration (SHmv), synchronous hatching by artificial vibration (SHav), and asynchronous hatching (AH). We then investigated the influence of each hatching strategy on the occurrence of sibling cannibalism of eggs and early-instar nymphs in the laboratory. No difference in the proportion of eggs cannibalized was observed among the three groups. However, the proportion of nymphs cannibalized was higher in the AH group than in the SHmv group. The difference in the number of days to first molting within clutch was significantly higher in the AH group than in the SHmv group. Junior nymphs were sometimes eaten by senior nymphs. However, immediately after molting, senior nymphs were at a high risk of being eaten by junior nymphs. Our results indicate that synchronous hatching of A. rotundus is necessary to mitigate the risk of sibling cannibalism. PMID- 29607033 TI - What determines prey selection in owls? Roles of prey traits, prey class, environmental variables, and taxonomic specialization. AB - Ecological theory suggests that prey size should increase with predator size, but this trend may be masked by other factors affecting prey selection, such as environmental constraints or specific prey preferences of predator species. Owls are an ideal case study for exploring how predator body size affects prey selection in the presence of other factors due to the ease of analyzing their diets from owl pellets and their widespread distributions, allowing interspecific comparisons between variable habitats. Here, we analyze various dimensions of prey resource selection among owls, including prey size, taxonomy (i.e., whether or not particular taxa are favored regardless of their size), and prey traits (movement type, social structure, activity pattern, and diet). We collected pellets of five sympatric owl species (Athene noctua, Tyto alba, Asio otus, Strix aluco, and Bubo bubo) from 78 sites across the Mediterranean Levant. Prey intake was compared between sites, with various environmental variables and owl species as predictors of abundance. Despite significant environmental impacts on prey intake, some key patterns emerge among owl species studied. Owls select prey by predator body size: Larger owls tend to feed on wider ranges of prey sizes, leading to higher means. In addition, guild members show both specialization and generalism in terms of prey taxa, sometimes in contrast with the expectations of the predator-prey body size hypothesis. Our results suggest that while predator body size is an important factor in prey selection, taxon specialization by predator species also has considerable impact. PMID- 29607034 TI - Projected effects of Climate-change-induced flow alterations on stream macroinvertebrate abundances. AB - Global change has the potential to affect river flow conditions which are fundamental determinants of physical habitats. Predictions of the effects of flow alterations on aquatic biota have mostly been assessed based on species ecological traits (e.g., current preferences), which are difficult to link to quantitative discharge data. Alternatively, we used empirically derived predictive relationships for species' response to flow to assess the effect of flow alterations due to climate change in two contrasting central European river catchments. Predictive relationships were set up for 294 individual species based on (1) abundance data from 223 sampling sites in the Kinzig lower-mountainous catchment and 67 sites in the Treene lowland catchment, and (2) flow conditions at these sites described by five flow metrics quantifying the duration, frequency, magnitude, timing and rate of flow events using present-day gauging data. Species' abundances were predicted for three periods: (1) baseline (1998 2017), (2) horizon 2050 (2046-2065) and (3) horizon 2090 (2080-2099) based on these empirical relationships and using high-resolution modeled discharge data for the present and future climate conditions. We compared the differences in predicted abundances among periods for individual species at each site, where the percent change served as a proxy to assess the potential species responses to flow alterations. Climate change was predicted to most strongly affect the low flow conditions, leading to decreased abundances of species up to -42%. Finally combining the response of all species over all metrics indicated increasing overall species assemblage responses in 98% of the studied river reaches in both projected horizons and were significantly larger in the lower-mountainous Kinzig compared to the lowland Treene catchment. Such quantitative analyses of freshwater taxa responses to flow alterations provide valuable tools for predicting potential climate-change impacts on species abundances and can be applied to any stressor, species, or region. PMID- 29607035 TI - Phenotypic integration and the evolution of signal repertoires: A case study of treefrog acoustic communication. AB - Animal signals are inherently complex phenotypes with many interacting parts combining to elicit responses from receivers. The pattern of interrelationships between signal components reflects the extent to which each component is expressed, and responds to selection, either in concert with or independently of others. Furthermore, many species have complex repertoires consisting of multiple signal types used in different contexts, and common morphological and physiological constraints may result in interrelationships extending across the multiple signals in species' repertoires. The evolutionary significance of interrelationships between signal traits can be explored within the framework of phenotypic integration, which offers a suite of quantitative techniques to characterize complex phenotypes. In particular, these techniques allow for the assessment of modularity and integration, which describe, respectively, the extent to which sets of traits covary either independently or jointly. Although signal and repertoire complexity are thought to be major drivers of diversification and social evolution, few studies have explicitly measured the phenotypic integration of signals to investigate the evolution of diverse communication systems. We applied methods from phenotypic integration studies to quantify integration in the two primary vocalization types (advertisement and aggressive calls) in the treefrogs Hyla versicolor, Hyla cinerea, and Dendropsophus ebraccatus. We recorded male calls and calculated standardized phenotypic variance-covariance (P) matrices for characteristics within and across call types. We found significant integration across call types, but the strength of integration varied by species and corresponded with the acoustic similarity of the call types within each species. H. versicolor had the most modular advertisement and aggressive calls and the least acoustically similar call types. Additionally, P was robust to changing social competition levels in H. versicolor. Our findings suggest new directions in animal communication research in which the complex relationships among the traits of multiple signals are a key consideration for understanding signal evolution. PMID- 29607036 TI - Persistence and space preemption explain species-specific founder effects on the organization of marine sessile communities. AB - Community assembly may not follow predictable successional stages, with a large fraction of the species pool constituted by potential pioneering species and successful founders defined through lottery. In such systems, priority effects may be relevant in the determination of trajectories of developing communities and hence diversity and assemblage structure at later advanced states. In order to assess how different founder species may trigger variable community trajectories and structures, we conducted an experimental study using subtidal sessile assemblages as model. We manipulated the identity of functionally different founders and initial colony size (a proxy of the time lag before the arrival of later species), and followed trajectories. We did not observe any effects of colony size on response variables, suggesting that priority effects take place even when the time lag between the establishment of pioneering species and late colonizers is very short. Late community structure at experimental panels that started either with the colonial ascidian Botrylloides nigrum, or the arborescent bryozoan Bugula neritina, was similar to control panels allowed natural assembling. In spite of high potential for fast space domination, and hence negative priority effects, B. nigrum suffered high mortality and did not persist throughout succession. Bugula neritina provided complex physical microhabitats through conspecific clustering that have enhanced larval settlement of late species arrivals, but no apparent facilitation was observed. Differently, panels founded by the encrusting bryozoan Schizoporella errata led to different and less diverse communities compared to naturally assembled panels, evidencing strong negative priority effects through higher persistence and space preemption. Schizoporella errata founder colonies inhibited further conspecific settlement, which may greatly relax intraspecific competition, allowing resource allocation to colony growth and space domination, thus reducing the chances for the establishment of other species. PMID- 29607037 TI - Temperature and water stress affect plant-pollinator interactions in Borago officinalis (Boraginaceae). AB - Climate change alters the abiotic constraints faced by plants, including increasing temperature and water stress. These changes may affect flower development and production of flower rewards, thus altering plant-pollinator interactions. Here, we investigated the consequences of increased temperature and water stress on plant growth, floral biology, flower-reward production, and insect visitation of a widespread bee-visited species, Borago officinalis. Plants were grown for 5 weeks under three temperature regimes (21, 24, and 27 degrees C) and two watering regimes (well-watered and water-stressed). Plant growth was more affected by temperature rise than water stress, and the reproductive growth was affected by both stresses. Vegetative traits were stimulated at 24 degrees C, but impaired at 27 degrees C. Flower development was mainly affected by water stress, which decreased flower number (15 +/- 2 flowers/plant in well-watered plants vs. 8 +/- 1 flowers/plant under water stress). Flowers had a reduced corolla surface under temperature rise and water stress (3.8 +/- 0.5 cm2 in well-watered plants at 21 degrees C vs. 2.2 +/- 0.1 cm2 in water-stressed plants at 27 degrees C). Both constraints reduced flower-reward production. Nectar sugar content decreased from 3.9 +/- 0.3 mg/flower in the well-watered plants at 21 degrees C to 1.3 +/- 0.4 mg/flower in the water-stressed plants at 27 degrees C. Total pollen quantity was not affected, but pollen viability decreased from 79 +/- 4% in the well watered plants at 21 degrees C to 25 +/- 9% in the water-stressed plants at 27 degrees C. Flowers in the well-watered plants at 21 degrees C received at least twice as many bumblebee visits compared with the other treatments. In conclusion, floral modifications induced by abiotic stresses related to climate change affect insect behavior and alter plant-pollinator interactions. PMID- 29607038 TI - A quantitative analysis on the effects of critical factors limiting the effectiveness of species conservation in future time. AB - The effectiveness of conservation plans depends on environmental, ecological, and socioeconomic factors. Global change makes conservation decisions even more challenging. Among others, the components of most concern in modern-day conservation assessments are as follows: the magnitude of climate and land-use changes; species dispersal abilities; competition with harmful socioeconomic activities for land use; the number of threatened species to consider; and, relatedly, the available budget to act. Here, we provide a unified framework that quantifies the relative effects of those factors on conservation. We conducted an area-scheduling work plan in order to identify sets of areas along time in which the persistence expectancies of species are optimized. The approach was illustrated using data of potential distribution of ten nonvolant mammal species in Iberia Peninsula from current time up to 2080. Analyses were conducted considering possible setups among the factors that are likely to critically impact conservation success: three climate/land-use scenarios; four species' dispersal kernel curves; six land-use layer types; and two planning designs, in which assessments were made independently for each species, or joining all species in a single plan. We identified areas for an array of investments levels capable to circumvent the spatial conflicts with socioeconomic activities. The effect of each factor on the estimated species persistence scores was assessed using linear mixed models. Our results evidence that conservation success is highly reliant on the resources available to abate land-use conflicts. Nonetheless, under the same investment levels, planning design and climate change were the factors that most shaped species persistence scores. The persistence of five species was especially affected by the sole effect of planning design and consequently, larger conservation investments may retard climatic debts. For three species, the negative effects of a changing climate and of multiple-species planning designs added up, making these species especially at risk. Integrated assessments of the factors most likely to limit species persistence are pivotal to achieve effectiveness. PMID- 29607039 TI - An analytical framework for estimating aquatic species density from environmental DNA. AB - Environmental DNA (eDNA) analysis of water samples is on the brink of becoming a standard monitoring method for aquatic species. This method has improved detection rates over conventional survey methods and thus has demonstrated effectiveness for estimation of site occupancy and species distribution. The frontier of eDNA applications, however, is to infer species density. Building upon previous studies, we present and assess a modeling approach that aims at inferring animal density from eDNA. The modeling combines eDNA and animal count data from a subset of sites to estimate species density (and associated uncertainties) at other sites where only eDNA data are available. As a proof of concept, we first perform a cross-validation study using experimental data on carp in mesocosms. In these data, fish densities are known without error, which allows us to test the performance of the method with known data. We then evaluate the model using field data from a study on a stream salamander species to assess the potential of this method to work in natural settings, where density can never be known with absolute certainty. Two alternative distributions (Normal and Negative Binomial) to model variability in eDNA concentration data are assessed. Assessment based on the proof of concept data (carp) revealed that the Negative Binomial model provided much more accurate estimates than the model based on a Normal distribution, likely because eDNA data tend to be overdispersed. Greater imprecision was found when we applied the method to the field data, but the Negative Binomial model still provided useful density estimates. We call for further model development in this direction, as well as further research targeted at sampling design optimization. It will be important to assess these approaches on a broad range of study systems. PMID- 29607040 TI - Land use change has stronger effects on functional diversity than taxonomic diversity in tropical Andean hummingbirds. AB - Land use change modifies the environment at multiple spatial scales, and is a main driver of species declines and deterioration of ecosystem services. However, most of the research on the effects of land use change has focused on taxonomic diversity, while functional diversity, an important predictor of ecosystem services, is often neglected. We explored how local and landscape scale characteristics influence functional and taxonomic diversity of hummingbirds in the Andes Mountains in southern Ecuador. Data was collected in six landscapes along a land use gradient, from an almost intact landscape to one dominated by cattle pastures. We used point counts to sample hummingbirds from 2011 to 2012 to assessed how local factors (i.e., vegetation structure, flowering plants richness, nectar availability) and landscape factors (i.e., landscape heterogeneity, native vegetation cover) influenced taxonomic and functional diversity. Then, we analyzed environment - trait relationships (RLQ test) to explore how different hummingbird functional traits influenced species responses to these factors. Taxonomic and functional diversity of hummingbirds were positively associated with landscape heterogeneity but only functional diversity was positively related to native vegetation coverage. We found a weak response of taxonomic and functional diversity to land use change at the local scale. Environment-trait associations showed that body mass of hummingbirds likely influenced species sensitivity to land use change. In conclusion, landscape heterogeneity created by land use change can positively influence hummingbird taxonomic and functional diversity; however, a reduction of native vegetation cover could decrease functional diversity. Given that functional diversity can mediate ecosystem services, the conservation of native vegetation cover could play a key role in the maintenance of hummingbird pollination services in the tropical Andes. Moreover, there are particular functional traits, such as body mass, that increase a species sensitivity to land use change. PMID- 29607041 TI - Population genetic structure, introgression, and hybridization in the genus Rhizophora along the Brazilian coast. AB - Mangrove plants comprise plants with similar ecological features that have enabled them to adapt to life between the sea and the land. Within a geographic region, different mangrove species share not only similar adaptations but also similar genetic structure patterns. Along the eastern coast of South America, there is a subdivision between the populations north and south of the continent's northeastern extremity. Here, we aimed to test for this north-south genetic structure in Rhizophora mangle, a dominant mangrove plant in the Western Hemisphere. Additionally, we aimed to study the relationships between R. mangle, R. racemosa, and R. * harrisonii and to test for evidence of hybridization and introgression. Our results confirmed the north-south genetic structure pattern in R. mangle and revealed a less abrupt genetic break in the northern population than those observed in Avicennia species, another dominant and widespread mangrove genus in the Western Hemisphere. These results are consistent with the role of oceanic currents influencing sea-dispersed plants and differences between Avicennia and Rhizophora propagules in longevity and establishment time. We also observed that introgression and hybridization are relevant biological processes in the northeastern coast of South America and that they are likely asymmetric toward R. mangle, suggesting that adaptation might be a process maintaining this hybrid zone. PMID- 29607042 TI - Epigenetic population differentiation in field- and common garden-grown Scabiosa columbaria plants. AB - Populations often differ in phenotype and these differences can be caused by adaptation by natural selection, random neutral processes, and environmental responses. The most straightforward way to divide mechanisms that influence phenotypic variation is heritable variation and environmental-induced variation (e.g., plasticity). While genetic variation is responsible for most heritable phenotypic variation, part of this is also caused by nongenetic inheritance. Epigenetic processes may be one of the underlying mechanisms of plasticity and nongenetic inheritance and can therefore possibly contribute to heritable differences through drift and selection. Epigenetic variation may be influenced directly by the environment, and part of this variation can be transmitted to next generations. Field screenings combined with common garden experiments will add valuable insights into epigenetic differentiation, epigenetic memory and can help to reveal part of the relative importance of epigenetics in explaining trait variation. We explored both genetic and epigenetic diversity, structure and differentiation in the field and a common garden for five British and five French Scabiosa columbaria populations. Genetic and epigenetic variation was subsequently correlated with trait variation. Populations showed significant epigenetic differentiation between populations and countries in the field, but also when grown in a common garden. By comparing the epigenetic variation between field and common garden-grown plants, we showed that a considerable part of the epigenetic memory differed from the field-grown plants and was presumably environmentally induced. The memory component can consist of heritable variation in methylation that is not sensitive to environments and possibly genetically based, or environmentally induced variation that is heritable, or a combination of both. Additionally, random epimutations might be responsible for some differences as well. By comparing epigenetic variation in both the field and common environment, our study provides useful insight into the environmental and genetic components of epigenetic variation. PMID- 29607043 TI - How scientists perceive the evolutionary origin of human traits: Results of a survey study. AB - Various hypotheses have been proposed for why the traits distinguishing humans from other primates originally evolved, and any given trait may have been explained both as an adaptation to different environments and as a result of demands from social organization or sexual selection. To find out how popular the different explanations are among scientists, we carried out an online survey among authors of recent scientific papers in journals covering relevant fields of science (paleoanthropology, paleontology, ecology, evolution, human biology). Some of the hypotheses were clearly more popular among the 1,266 respondents than others, but none was universally accepted or rejected. Even the most popular of the hypotheses were assessed "very likely" by <50% of the respondents, but many traits had 1-3 hypotheses that were found at least moderately likely by >70% of the respondents. An ordination of the hypotheses identified two strong gradients. Along one gradient, the hypotheses were sorted by their popularity, measured by the average credibility score given by the respondents. The second gradient separated all hypotheses postulating adaptation to swimming or diving into their own group. The average credibility scores given for different subgroups of the hypotheses were not related to respondent's age or number of publications authored. However, (paleo)anthropologists were more critical of all hypotheses, and much more critical of the water-related ones, than were respondents representing other fields of expertise. Although most respondents did not find the water-related hypotheses likely, only a small minority found them unscientific. The most popular hypotheses were based on inherent drivers; that is, they assumed the evolution of a trait to have been triggered by the prior emergence of another human-specific behavioral or morphological trait, but opinions differed as to which of the traits came first. PMID- 29607045 TI - Effect of maternal foraging habitat on offspring quality in the loggerhead sea turtle (Caretta caretta). AB - Exploring a trade-off between quantity and quality of offspring allows differences in the fitness between alternative life histories to be accurately evaluated. We addressed the mechanism that maintains alternative life histories (small oceanic planktivores vs. large neritic benthivores) observed in a loggerhead sea turtle (Caretta caretta) population, which has been suggested to be environmental, based on the lack of genetic structure and a large difference in reproductive output. We examined whether maternal foraging habitat affects offspring quality, by measuring the morphology, emergence success, and righting response of hatchlings following incubation in a common open sand area over the whole nesting season at Yakushima Island, Japan, and by recording early growth and survival of offspring that were reared in a common environment at a Japanese aquarium. Furthermore, we tested whether sea turtles adjust egg size in response to temporal shifts of the incubation environment. There were no significant differences in any hatchling traits between oceanic and neritic foragers (which were classified by stable isotope ratios), except for clutches laid during the warmest period of the nesting season. There were also no significant differences in the growth and survival of offspring originating from the two foragers. The size of eggs from both foragers significantly increased as the season progressed, even though the rookery had heavy rainfall, negating the need to counteract heat related reduction in hatchling morphology. In comparison, the sizes of adult body and clutches from both foragers did not vary significantly. The results further support our previous suggestions that the size-related foraging dichotomy exhibited by adult sea turtles does not have a genetic basis, but derives from phenotypic plasticity. Adjustment in reproductive investment may be associated with: (1) predation avoidance, (2) founder effect, and/or (3) annual variation in egg size. PMID- 29607044 TI - Ancient pathogen DNA in human teeth and petrous bones. AB - Recent ancient DNA (aDNA) studies of human pathogens have provided invaluable insights into their evolutionary history and prevalence in space and time. Most of these studies were based on DNA extracted from teeth or postcranial bones. In contrast, no pathogen DNA has been reported from the petrous bone which has become the most desired skeletal element in ancient DNA research due to its high endogenous DNA content. To compare the potential for pathogenic aDNA retrieval from teeth and petrous bones, we sampled these elements from five ancient skeletons, previously shown to be carrying Yersinia pestis. Based on shotgun sequencing data, four of these five plague victims showed clearly detectable levels of Y. pestis DNA in the teeth, whereas all the petrous bones failed to produce Y. pestis DNA above baseline levels. A broader comparative metagenomic analysis of teeth and petrous bones from 10 historical skeletons corroborated these results, showing a much higher microbial diversity in teeth than petrous bones, including pathogenic and oral microbial taxa. Our results imply that although petrous bones are highly valuable for ancient genomic analyses as an excellent source of endogenous DNA, the metagenomic potential of these dense skeletal elements is highly limited. This trade-off must be considered when designing the sampling strategy for an aDNA project. PMID- 29607046 TI - A machine-learning approach for extending classical wildlife resource selection analyses. AB - Resource selection functions (RSFs) are tremendously valuable for ecologists and resource managers because they quantify spatial patterns in resource utilization by wildlife, thereby facilitating identification of critical habitat areas and characterizing specific habitat features that are selected or avoided. RSFs discriminate between known-use resource units (e.g., telemetry locations) and available (or randomly selected) resource units based on an array of environmental features, and in their standard form are performed using logistic regression. As generalized linear models, standard RSFs have some notable limitations, such as difficulties in accommodating nonlinear (e.g., humped or threshold) relationships and complex interactions. Increasingly, ecologists are using flexible machine-learning methods (e.g., random forests, neural networks) to overcome these limitations. Herein, we investigate the seasonal resource selection patterns of mule deer (Odocoileus hemionus) by comparing a logistic regression framework with random forest (RF), a popular machine-learning algorithm. Random forest (RF) models detected nonlinear relationships (e.g., optimal ranges for slope and elevation) and complex interactions which would have been very challenging to discover and characterize using standard model-based approaches. Compared with standard RSF models, RF models exhibited improved predictive skill, provided novel insights about resource selection patterns of mule deer, and, when projected across a relevant geographic space, manifested notable differences in predicted habitat suitability. We recommend that wildlife researchers harness the strengths of machine-learning tools like RF in addition to "classical" tools (e.g., mixed-effects logistic regression) for evaluating resource selection, especially in cases where extensive telemetry data sets are available. PMID- 29607047 TI - Fluorescent Probes for Sensitive and Selective Detection of pH Changes in Live Cells in Visible and Near-infrared Channels. AB - We report five fluorescent probes based on coumarin-hybridized fluorescent dyes with spirolactam ring structures (A-E) to detect pH changes in live cell by monitoring visible and near-infrared fluorescence changes. Under physiological or basic conditions, the fluorescent probes A, B, C, D and E preserve their spirolactam ring-closed forms and only display fluorescent peaks in the visible region corresponding to coumarin moieties at 497, 483, 498, 497 and 482 nm, respectively. However, at acidic pH, the rings of the spirolactam forms of the fluorescent probes A, B, C, D and E open up, generating new near-infrared fluorescence peaks at 711, 696, 707, 715, and 697 nm, respectively, through significantly extended pi-conjugation to coumarin moieties of the fluorophores. The fluorescent probes B and E can be applied to visualize pH changes by monitoring visible as well as near-infrared fluorescence changes. This helps avoid fluorescence imaging blind spots at neutral or basic pH, which typical pH fluorescent probes encounter. The probes exhibit high sensitivity to pH changes, excellent photostability, low auto-fluorescence background and good cell membrane permeability. PMID- 29607048 TI - Mexican American and South Asian population-based cohorts reveal high prevalence of type 2 diabetes and crucial differences in metabolic phenotypes. AB - Objective: Prevalence of type 2 diabetes varies by region and ancestry. However, most guidelines for the prevention of diabetes mellitus (DM) are based on European or non-Hispanic white populations. Two ethnic minority populations Mexican Americans (MAs) in Texas, USA, and South Indians (SIs) in Tamil Nadu, India-have an increasing prevalence of DM. We aimed to understand the metabolic correlates of DM in these populations to improve risk stratification and DM prevention. Research design and methods: The Cameron County Hispanic Cohort (CCHC; n=3023) served as the MA sample, and the Population Study of Urban, Rural, and Semi-Urban Regions for the Detection of Endovascular Disease (PURSE; n=8080) served as the SI sample. Using design-based methods, we calculated the prevalence of DM and metabolic comorbidities in each cohort. We determined the association of DM with metabolic phenotypes to evaluate the relative contributions of obesity and metabolic health to the prevalence of DM. Results: In the CCHC (overall DM prevalence 26.2%), good metabolic health was associated with lower prevalence of DM, across age groups, regardless of obesity. In PURSE (overall prevalence 27.6%), probability of DM was not strongly associated with metabolic phenotypes, although DM prevalence was high in older age groups irrespective of metabolic health. Conclusion: Our study provides robust, population-based data to estimate the prevalence of DM and its associations with metabolic health. Our results demonstrate differences in metabolic phenotypes in DM, which should inform DM prevention guidelines in non-European populations. PMID- 29607049 TI - Periodontitis, edentulism and glycemic control in patients with type 2 diabetes: a cross-sectional study. AB - Objectives: To compare the glycemic control in non-smoking patients with type 2 diabetes according to their periodontal and dental status. Research design and methods: This cross-sectional study investigated patients previously diagnosed with type 2 diabetes and under antidiabetic medication. Clinical data and fasting blood glucose (FBG) levels were collected from medical and dental records. Patients were divided into three groups according to dental and periodontal diagnosis: no or mild periodontitis (NO/MILD, n=96), moderate or severe periodontitis (MOD/SEV, n=74) and edentulous (n=141). FBG levels were compared between groups. Logistic regression was also applied to estimate the OR of presenting hyperglycemia. Results: Edentulous patients had significantly higher FBG levels of 155.7+/-70.9 (mean+/-SD mg/dL) than those in the MOD/SEV (136.6+/ 33.8) and the NO/MILD (123.1+/-36.7) groups. Differences between the latter two groups were also significant. Edentulous patients had adjusted ORs of 4.53, 4.27 and 3.95 of having FBG>=126, >=150 and >=180 mg/dL, respectively, in comparison with NO/MILD group. The MOD/SEV group also presented significant odds of having FBG>=126 mg/dL (OR=2.66) and >=150 mg/dL (OR=2.45) than the NO/MILD group. Conclusions: Patients in the MOD/SEV group had worse glycemic control than the ones in the NO/MILD group. However, edentulous patients presented higher glycemic levels than both dentate groups, and also presented with higher odds of having hyperglycemia. PMID- 29607050 TI - Ursodeoxycholic acid potentiates dipeptidyl peptidase-4 inhibitor sitagliptin by enhancing glucagon-like peptide-1 secretion in patients with type 2 diabetes and chronic liver disease: a pilot randomized controlled and add-on study. AB - Objective: We evaluated the effects of ursodeoxycholic acid (UDCA) on glucagon like peptide-1 (GLP-1) secretion and glucose tolerance in patients with type 2 diabetes with chronic liver disease. Research design and methods: Japanese patients with type 2 diabetes (glycated hemoglobin (HbA1c) levels >=7.0%) and chronic liver disease were included in this study. Sixteen patients (HbA1c level, 7.2%+/-0.6%(55.2 mmol/mol)) were randomized to receive 900 mg UDCA for 12 weeks followed by 50 mg sitagliptin add-on therapy for 12 weeks (UDCA-first group; n=8) or 50 mg sitagliptin for 12 weeks followed by 900 mg UDCA add-on therapy for 12 weeks (sitagliptin-first group; n=8). All patients underwent a liquid high-fat meal test before and after 12 or 24 weeks of treatment. Results: The baseline characteristics were similar between the UDCA-first and sitagliptin-first groups. There was a decrease in body weight (72.5+/-8.4 to 70.6+/-8.6 kg; P=0.04) and the HbA1c level (7.0%+/-0.3% to 6.4%+/-0.5%(53.0 to 46.4 mmol/mol); P=0.01) in the UDCA-first group. The HbA1c level decreased further after sitagliptin administration (6.4%+/-0.5% to 6.0%+/-0.4%(46.4 to 42.1 mmol/mol); P<0.01). Although there were no initial changes in the weight and HbA1c level in the sitagliptin-first group, the HbA1c level decreased after UDCA addition (7.1%+/ 1.1% to 6.6%+/-0.9%(54.1 to 48.6 mmol/mol); P=0.04). UDCA alone increased the area under the curve0-30 for GLP-1 response (115.4+/-47.2 to 221.9+/-48.9 pmol.min/L; P<0.01), but not the glucose-dependent insulinotropic polypeptide response, in the UDCA-first group. Conclusions: UDCA treatment resulted in a greater reduction in HbA1c levels, and an increased early phase GLP-1 secretion. Trial registration number: NCT01337440. PMID- 29607051 TI - Comprehensive home-based care coordination for vulnerable elders with dementia: Maximizing Independence at Home-Plus-Study protocol. AB - Introduction: Despite availability of effective care strategies for dementia, most health care systems are not yet organized or equipped to provide comprehensive family-centered dementia care management. Maximizing Independence at Home-Plus is a promising new model of dementia care coordination being tested in the U.S. through a Health Care Innovation Award funded by the Centers for Medicare and Medicaid Services that may serve as a model to address these delivery gaps, improve outcomes, and lower costs. This report provides an overview of the Health Care Innovation Award aims, study design, and methodology. Methods: This is a prospective, quasi-experimental intervention study of 342 community-living Medicare-Medicaid dual eligibles and Medicare-only beneficiaries with dementia in Maryland. Primary analyses will assess the impact of Maximizing Independence at Home-Plus on risk of nursing home long-term care placement, hospitalization, and health care expenditures (Medicare, Medicaid) at 12, 18 (primary end point), and 24 months, compared to a propensity-matched comparison group. Discussion: The goals of the Maximizing Independence at Home-Plus model are to improve care coordination, ability to remain at home, and life quality for participants and caregivers, while reducing total costs of care for this vulnerable population. This Health Care Innovation Award project will provide timely information on the impact of Maximizing Independence at Home-Plus care coordination model on a variety of outcomes including effects on Medicaid and Medicare expenditures and service utilization. Participant characteristic data, cost savings, and program delivery costs will be analyzed to develop a risk adjusted payment model to encourage sustainability and facilitate spread. PMID- 29607052 TI - Changing nationwide trends in endoscopic, medical and surgical admissions for inflammatory bowel disease: 2003-2013. AB - Background and study aims: In the last decade, there have been major advances in inflammatory bowel disease (IBD) management but their impact on hospital admissions requires evaluation. We aim to investigate nationwide trends in IBD surgical/medical elective and emergency admissions, including endoscopy and cytokine inhibitor infusions, between 2003 and 2013. Patients and methods: We used Hospital Episode Statistics and population data from the UK Office for National Statistics. Results: Age-sex standardised admission rates increased from 76.5 to 202.9/100 000 (p<0.001) and from 69.5 to 149.5/100 000 (p<0.001) for Crohn's disease (CD) and ulcerative colitis (UC) between 2003-2004 and 2012-2013, respectively. Mean length of stay (days) fell significantly for elective (from 2.6 to 0.7 and from 2.0 to 0.7 for CD and UC, respectively) and emergency admissions (from 9.2 to 6.8 and from 10.8 to 7.6 for CD and UC, respectively). Elective lower gastrointestinal (GI) endoscopy rates decreased from 6.3% to 3.7% (p<0.001) and from 18.4% to 17.6% (p=0.002) for CD and UC, respectively. Elective major abdominal surgery rates decreased from 2.8% to 1.0% (p<0.001) and from 4.9 to 2.4 (p=0.010) for CD and UC, respectively, with emergency rates also decreasing significantly for CD. Between 2006-2007 and 2012-2013, elective admission rates for cytokine-inhibitor infusions increased from 11.1 to 57.2/100 000 and from 1.4 to 12.1/100 000 for CD and UC, respectively. Conclusions: Rising IBD hospital admission rates in the past decade have been driven by an increase in the incidence and prevalence of IBD. Lower GI endoscopy and surgery rates have fallen, while cytokine inhibitor infusion rates have risen. There has been a concurrent shift from emergency care to shorter elective hospital stays. These trends indicate a move towards more elective medical management and may reflect improvements in disease control. PMID- 29607053 TI - Rate of hepatocellular carcinoma surveillance remains low for a large, real-life cohort of patients with hepatitis C cirrhosis. AB - Background: In patients with chronic hepatitis C (CHC) cirrhosis, imaging for hepatocellular carcinoma (HCC) is recommended every 6 months to maximise eligibility for curative treatment. The aim was to determine the adherence rate and outcomes among patients with CHC cirrhosis and whether the adherence rate has improved over time. Methods: Retrospective cohort study of patients with CHC cirrhosis (n=2366) monitored for >=1 year at Stanford University Medical Center between January 2001 and August 2015. Results: Overall demographics: mean age 54; 62.3% men; 48.3% Caucasian. 24.4% adherent to imaging every 6 months per European Association for the Study of the Liver 2000 and American Association for the Study of Liver Diseases (AASLD) 2011 criteria and 44% at least every 12 months per AASLD 2005 criteria. No significant change in adherence before and after 2011. Predictors of multivariable analysis of adherence were age >54 (OR 1.74, p<0.0001), Asian ethnicity (OR 2.23, p<0.0001), liver decompensation (OR 2.40, p<0.0001) and having >=2 clinical visits per year (OR 1.33, p=0.01). During follow-up, 9.6% were diagnosed with HCC. Adherent patients were more likely to have smaller tumours (2.3 vs 3.3 cm, p=0.0020), be within the Milan criteria for liver transplants (73.2% vs 54.8%, p=0.006) and receive curative HCC treatment (43.6% vs 24.0%, p=0.005). On multivariable analysis, curative treatment (HR 0.32, p=0.001) and every 6-month imaging (HR 0.34, p=0.005), but not every 6-12 month imaging, were associated with reduced risk of mortality. Conclusions: Adherence to HCC surveillance continues to be poor. Adherent patients with HCC were more likely to undergo curative treatment and have better survival. Research understanding barriers to surveillance is needed. PMID- 29607054 TI - Non-alcoholic steatofibrosis (NASF) can independently predict mortality in patients with non-alcoholic fatty liver disease (NAFLD). AB - Background: Hepatic fibrosis in patients with non-alcoholic fatty liver disease (NAFLD) independently predicts mortality. Given liver biopsy's invasive nature, non-invasive method to assess hepatic steatosis and fibrosis provides NAFLD risk stratification algorithm in clinical practice. NAFLD fibrosis score (NFS) is simple and non-invasive predictive model recommended by American Association for the Study of Liver Disease (AASLD) Guideline to identify patients with NAFLD with fibrosis risk. The aim of this study is to assess long-term outcomes of subjects with significant non-alcoholic steatofibrosis (NASF) as established by ultrasound (US) and NFS. Methods: Used National Health and Nutrition Examination Survey (NHANES III) with National Death Index-linked Mortality Files. NAFLD diagnosis established by the presence of moderate to severe hepatic steatosis on US without other causes of chronic liver disease (alcohol consumption <20 gr/day, hepatitis B surface-antigen negative, anti-hepatitis C virus antibody negative, transferrin saturation <50%). Significant hepatic fibrosis was estimated by high NFS (>0.676) and calculated with previously published formula. Subjects with NAFLD and high NFS have significant NASF. Results: NHANES III included 20 050 adult participants. 2515 participants complete data and NAFLD with 5.1% (n=129) meeting criteria for significant SF. Subjects with significant SF were older, had higher body mass index, waist circumference and the homeostasis model assessment (HOMA) scores and higher rates of comorbidities (diabetes, congestive heart failure (CHF), stroke; all p<0.001). After median of 207 months of follow-up, overall mortality in NAFLD cohort was 30.0% (n=754). Crude mortality higher in subjects with significant SF (67.4% vs 28.0%, p<0.001). In multivariate survival analysis, predictors of overall mortality included significant SF (adjusted HR (aHR): 1.37; 95% CI 1.07 to 1.76, p=0.01), older age (aHR:1.08; 95% CI 1.07 to 1.09 per year), male gender (aHR:1.44; 95% CI 1.24 to 1.67), black race (aHR:1.24; 95% CI 1.04 to 1.48)), history of hypertension (aHR:1.40; 95% CI 1.20 to 1.64), diabetes (aHR:1.69; 95% CI 1.43 to 2.00), CHF (aHR:1.77; 95% CI 1.38 to 2.261), stroke (aHR:1.84; 95% CI 1.38 to 2.48) and smoking (aHR:1.74; 95% CI 1.47 to 2.07) (all p<0.02). Sensitivity analysis showed that the best association of SF with mortality is higher at NFS threshold of 0.80 (aHR:1.41; 95% CI 1.09 to 1.83, p=0.01). Conclusions: Significant NASF determined non-invasively is an independent predictor of mortality. These data should help clinicians to easily risk-stratify patients with NAFLD for close monitoring and treatment considerations in clinical trial setting. PMID- 29607055 TI - An in vitro evaluation of resonant frequency analysis to measure fixed bridge stability. AB - Objectives/Aims: To determine whether a clinically available resonance frequency analysis (RFA) device (Osstell Mentor), designed to assess implant integration, could identify a single uncemented retainer on fixed-fixed bridges, in vitro. Materials and Methods: All-metal fixed-fixed bridges were cemented to acrylic tooth analogue abutments with simulated periodontal ligaments. Dental stone bases provided 100 or 50% 'bone support' groups (n = 50 in each). Control groups had both retainers cemented, whereas the test groups had the 'premolar' uncemented, mimicking clinical failure. A RFA device was used to measure bridge stability, expressed as a modified Implant Stability Quotient (Bridge Stability Quotient BSQ) from a Smartpeg temporarily affixed to the bridge via composite. Results: The BSQ recorded at the premolar site in both 100 and 50% support models demonstrated highly statistically significant differences (P <0.003) between the control and test groups. Sensitivity and specificity, area under the curve (receiver operating characteristic), analyses showed moderate test accuracy (0.735) for the 100% support group and good accuracy (0.96) for the 50% support group. Conclusion: The investigation suggests that RFA measurements were able to identify, reliably and non-destructively, in vitro, fixed-fixed bridges where the anterior retainer was uncemented. Further clinical research is required to determine whether this technique may allow early diagnosis of failing bridgework. PMID- 29607056 TI - Tooth extraction education at dental schools across Europe. AB - Objectives/Aims: To explore students' opinion about theoretical and clinical training in tooth extraction at different European dental schools. Materials and Methods: An online questionnaire, containing 36 dichotomous, multiple choice and Likert scale rating questions, was distributed among students of 56 different dental schools. After excluding schools where <20 students responded, 656 questionnaires from 23 dental schools remained for statistical analysis. Results: Dental schools showed a wide variation in the initial practical teaching of tooth extraction, from years 2 to 6. Several schools used a preclinical training model, and most students considered this useful. Some students considered their knowledge about forceps and elevators insufficient (6-60%), as well as their preparation for complications (5-60%). Students usually had received education in forceps and elevator techniques. Inclusion of (non)surgical removal of retained roots and surgical removal of third molars showed a wide variety between dental schools. Less than half of the students reported education in surgical removal of impacted teeth. Students from four of the 23 dental schools felt insufficiently prepared in tooth extraction (Likert scale ?3). Conclusion: There is a wide variation among European dental schools in teaching programs of tooth extraction and the rating of these programs by students. PMID- 29607058 TI - Open for all. PMID- 29607057 TI - The ultrastructure of subgingival dental plaque, revealed by high-resolution field emission scanning electron microscopy. AB - Objectives/Aims: To explore the ultrastructure of subgingival dental plaque using high-resolution field emission scanning electron microscopy (FE-SEM) and to investigate whether extracellular DNA (eDNA) could be visualised in ex vivo samples. Materials and Methods: Ten patients were recruited who fulfilled the inclusion criteria (teeth requiring extraction with radiographic horizontal bone loss of over 50% and grade II/III mobility). In total, 12 teeth were extracted using a minimally traumatic technique. Roots were sectioned using a dental air turbine handpiece, under water cooling to produce 21 samples. Standard fixation and dehydration protocols were followed. For some samples, gold-labelled anti-DNA antibodies were applied before visualising biofilms by FE-SEM. Results: High resolution FE-SEMs of subgingival biofilm were obtained in 90% of the samples. The sectioning technique left dental plaque biofilms undisturbed. Copious amounts of extracellular material were observed in the plaque, which may have been eDNA as they had a similar appearance to labelled eDNA from in vitro studies. There was also evidence of membrane vesicles and open-ended tubular structures. Efforts to label eDNA with immune-gold antibodies were unsuccessful and eDNA was not clearly labelled. Conclusions: High-resolution FE-SEM images were obtained of undisturbed subgingival ex vivo dental plaque biofilms. Important structural features were observed including extracellular polymeric material, vesicles and unusual open tubule structures that may be remnants of lysed cells. The application of an eDNA immune-gold-labelling technique, previously used successfully in in vitro samples, did not clearly identify eDNA in ex vivo samples. Further studies are needed to characterise the molecular composition of the observed extracellular matrix material. PMID- 29607059 TI - Exploring a potential impact of a social marketing campaign on reducing oral cancer incidences in Michigan: an ecological study. AB - Objectives/Aims: The social marketing campaign was launched in 2005-2007 to address excess risk of oral cancer in Detroit tri-county area, Michigan. We assessed the extent to which the campaign might have contributed to decreasing risk of oral cancer using the modified interrupted time-series design. Materials and Methods: Oral cancer incidence and mortality data came from Michigan Department of Community Health, and trends of age-adjusted rates during 1990-2009 were compared between intervention and comparison counties via joinpoint regression. Results: Although mortality rates in both areas decreased in parallel manner, incidence rates decreased during and after the campaign only in the intervention counties. A similar trend was observed in the race-specific analysis. Alternative explanations, including population profiles, health-care access and pre-existing trends, were examined, and these characteristics were comparable between two areas in 1990s and 2000s. Conclusions: These results suggested that the campaign was more likely to be associated with the decreasing trend of oral cancer incidence in the intervention counties than alternative explanations. Although oral cancer is a deadly disease, its awareness has been relatively low. This study highlights a potential impact of concerted efforts to improve the oral cancer awareness in the high-risk communities. PMID- 29607060 TI - Cone-beam CT evaluation of root canal morphology of maxillary and mandibular premolars in a Turkish Cypriot population. AB - Objectives: Because of economic and political issues, Turkish Cypriots have been emigrating from Cyprus since the 1920s, especially to the United Kingdom, other European countries and Australia. Recently, according to the UK House of Commons, Home Affairs Committee, ~300,000 Cypriot Turks were living in the United Kingdom. However, this ethnic population residing in the United Kingdom has been insufficiently analysed. Although many Turkish Cypriots have been living abroad, little is known about the dental characteristics of this group. Premolar teeth, especially maxillary premolars, pose great challenges in endodontic treatment because of the number of roots and canals, and the variation in the configurations of the pulp cavity. Thus, it was considered valuable to determine the morphological characteristic of premolar teeth in a Turkish Cypriot population to aid clinicians in performing endodontic treatment in this ethnic population. Materials and Methods: The sample for this cross-sectional study consisted of a retrospective evaluation of cone-beam CT scans of 263 adult patients (age range 16-80 years). The number of roots and their morphology, the number of canals per root and the canal configuration were examined. The root canal configurations were also classified according to the scheme of Vertucci in the maxillary and mandibular premolar teeth. Pearson's chi2-test was performed among canal configurations, sides and gender (P?0.05). Results: In the present study, most root canal configurations were type IV (76.8%) and type I (49.4%) in the maxillary first and second premolars, respectively, whereas most root canal configurations were type I (93%) in both mandibular first and second premolars. In total, four (0.9%) teeth in the maxillary first premolars and two (0.4%) teeth in the maxillary second molar premolars had three roots. Conclusions: This is the first population-based study to focus solely on Turkish Cypriots' root canal anatomy. Our findings will be valuable for dental professionals who treat many Turkish Cypriot patients, in the United Kingdom, Australia and other countries. PMID- 29607061 TI - Transplantation of human-induced pluripotent stem cells carried by self assembling peptide nanofiber hydrogel improves bone regeneration in rat calvarial bone defects. AB - Objectives/Aims: The requisite conditions for successful bone tissue engineering are efficient stem cell differentiation into osteogenic cells and a suitable scaffold. In this study, we investigated in vivo bone regeneration from transplanted induced pluripotent stem cells (iPSCs). Materials and Methods: Two critical-sized calvarial bone defects were created in 36 rats. The surgical sites were randomly assigned to one of three treatments to test the healing effectiveness of the scaffold alone, scaffold with iPSCs or a salt solution as a control. The effectiveness of the treatments was evaluated after 2 or 4 weeks using radiographic and histological analyses of bone regeneration in the six groups. Results: Micro-computed tomography (CT) analysis of the bone defects found minimal bone regeneration with the salt solution and nanofiber scaffold and increased bone regeneration in defects repaired with iPSCs delivered in the nanofiber scaffold. Conclusion: Transplanted iPSCs encapsulated in a nanofiber scaffold can regenerate bone in critical-sized defects. PMID- 29607062 TI - Genotoxic effects of X-rays in buccal mucosal cells in children subjected to dental radiographs. AB - Objectives/Aims: Bitewing and digital dental panoramic radiographs have become important adjuvants for successful dental practice in pediatric dentistry. Both methods lead to genetic changes in the oral buccal epithelium that have not yet been satisfactorily explored. The aim of the present study was to evaluate the genotoxic effects induced by X-ray radiation from bitewing and panoramic dental radiography in exfoliated buccal epithelial cells of children, using the Buccal Micronucleus Cytome assay. Materials and Methods: Children (n=40) who met the inclusion criteria and provided signed informed consent were included in the study. Children were selected for undergoing bitewing radiographs (group 1; n=20) or digital dental panoramic radiographs (group 2; n=20). Exfoliated buccal mucosal cells were obtained by scraping the right/left buccal mucosa with a wooden spatula immediately before the X-ray exposure and 10+/-2 days after exposure. Results: The frequency of micronuclei increases significantly post exposure to both bitewing and digital dental panoramic radiography in children, but the frequency was higher in bitewing radiographs. Conclusion: It was concluded that the frequency of micronuclei increases post exposure to both bitewing and digital panoramic radiographs. Increased radiation exposure results in an increase in micronuclei frequency. PMID- 29607063 TI - Conscious sedation: is this provision equitable? Analysis of sedation services provided within primary dental care in England, 2012-2014. AB - Aim: Patients receiving primary dental care may occasionally require conscious sedation as an adjunct to care. It is one of a range of options to support anxious patients or those undergoing difficult procedures. The aim of this study was to examine patterns of conscious sedation within primary dental care in relation to patient demography, deprivation status, geography (local authority, region) and type of care (Band) within England to examine equity in distribution of service provision. Materials and Methods: Descriptive analysis of cross sectional primary dental care data, obtained from national claims held by the National Health Service (NHS) Business Services Authority, on patients who had received one or more courses of care involving sedation. Results: Just under 137,000 episodes of care involving sedation are provided for over 120,000 patients per year, the majority of which are for adults. Four out of ten (41%) patients were children, with 6-12-year-olds forming the largest group; 6% were aged under six years. Eleven per cent of patients had more than one course of care involving sedation, with adults aged 25-34 years having the highest rate: 1.17 (s.d.: 0.887) in 2012/2013 and 1.16 (s.d.: 0.724) in 2013/2014. There was a clear social gradient, whereby the most deprived quintile had the highest volume of patients that had received sedation at least once in primary dental care in both years (31.5%). Whilst there was a clear social gradient amongst children and young adults who received sedation, the gradient flattened among middle-aged and was flat amongst older adults. The majority of courses of care involving sedation were associated with Band 2 claims for care (88.6% in 2012/2013; 88.8 in 2013/2014). Whilst one or more patients in all higher tier local authorities received care involving sedation, there were marked geographic inequalities. Discussion: Patients receive sedation in support of NHS primary dental care across the life course and social spectrum. Whilst the pattern of uptake of care parallels the social gradient in younger age groups overall, there are clear geographical inequalities in provision. As sedation is only one of a series of adjuncts to care which may be provided across different sectors of the health system, a wider systems analysis should be undertaken as the findings raise important issues about equitable access to appropriate care. Furthermore, there should be a greater emphasis on prevention to reduce the need for care. The implications for child oral health, access and quality are discussed. PMID- 29607064 TI - The efficacy of disinfectants in the decontamination of dental unit water lines: an in vitro laboratory study. AB - Objectives/Aims: This in vitro laboratory study compared the efficacy of water, sodium percarbonate (SPC) and chlorine dioxide (ClO2) solutions in the disinfection of dental unit water lines (DUWLs). Materials and Methods: New DUWL tubes were cut, split open, and mono-culture and mixed-culture biofilms of Staphylococcus aureus, Enterococcus faecalis and Streptococcus mutans were grown. Harvested biofilms from the sectioned DUWL tubes were exposed to sterile distilled water, SPC or 5 and 10 p.p.m. ClO2 in both a stationary phase and through a constant flow. Bacterial counts were compared using the Kruskal-Wallis nonparametric rank test. Results: In the mono-culture biofilms, SPC, 5 and 10 p.p.m. ClO2 significantly reduced all the test organisms (P<0.01). However, no significant difference was found between SPC and ClO2. In the mixed-culture biofilms exposed to disinfectant without flow, ClO2 significantly reduced the biofilm (P=0.02) compared with water and SPC. Similarly, in the constant flow study, ClO2 proved to be superior to water. Conclusion: At low concentrations, ClO2 with and without flow significantly reduced the mixed-culture biofilm grown in vitro on the sections of the DUWL tubes. Therefore, it has the potential to be used in the patient treatment water, as it is potable at these concentrations, and to decontaminate and limit the biofilm formation in the water lines. PMID- 29607065 TI - Socioeconomic disadvantage and oral-health-related hospital admissions: a 10-year analysis. AB - Objective: The aim of this Western Australian population study was to assess the relationship of socioeconomic disadvantage and: 1) trends in hospitalisations for oral-health-related conditions over 10 years; 2) insurance status, costs and length of stay in hospital; and 3) specific conditions (principal diagnosis) patients were admitted for. Methods: Hospitalisation data (of oral-health-related conditions) were obtained for every episode of discharge from all hospitals in Western Australia for the financial years 1999-2000 to 2008-2009. Area based measures (using the Index of Relative Socioeconomic Disadvantage) was used to determine relationships between socioeconomic status and other variables. Results: The most disadvantaged in the population are being hospitalised at significantly higher rates than other groups, stay in hospital for longer, and at higher costs. This trend remained over a period of 10 years. Those least disadvantaged have the second highest rates of hospitalisation, but the likelihood of being admitted for different procedures differ between these two extremes. Conclusions: The importance of socioeconomic determinants of health are evident when analysing these hospitalisations. Recognition that lifestyle choices are severely restricted among the most marginalised and disadvantaged groups in the population can no longer be ignored in attempts to reduce health inequalities. PMID- 29607066 TI - Clinical and radiographical evaluation of propolis and thymus vulgaris extracts compared with formocresol pulpotomy in human primary molars. AB - Objectives/aims: This study aimed to examine the success of vital pulpotomy using natural extracts on primary teeth. Materials and methods: The study was carried out on 60 primary molars in 20 children indicated for pulpotomy. Primary molars were treated with formocresol (20 teeth), propolis ethanolic extract (20 teeth) or thymus vulgaris ethanolic extract (20 teeth). Treated teeth were clinically and radiographically evaluated after 1, 6 and 12 months. Results: The clinical success of formocresol and propolis groups was 88.2%, whereas the thymus group showed 94.4% with no statistical significance difference. The radiographical success for formocresol and propolis was 73.3%, and thymus was 88.2% without any statistical significance difference detected. Conclusion: Promising clinical and radiographical success rates of propolis and thymus vulgaris obtained when compared with formocresol. PMID- 29607067 TI - Hearing loss and its association with occupational noise exposure among Saudi dentists: a cross-sectional study. AB - Objectives/Aims: Dental practitioners are prone to hearing loss due to noise exposure encountered in dental clinics. The aim of this study was to determine whether the persistent high-frequency sounds produced by the dental equipment could cause hearing decrement among the Saudi dental practitioners. Materials and Methods: This cross-sectional study included 38 randomly selected Saudi dentists from different specialties who were exposed to noise during working hours and 38 individuals as a control group. The participants underwent four audiometric tests that included an otoscopic examination, tympanometry, pure tone audiometry and the distortion product otoacoustic emissions (DPOAE) test. Results: The data revealed that ~15.8% of the dentists and 2.6% of the control group had some hearing loss. No significant difference was found between the two groups in the pure tone audiometry test; however, qualitative analysis revealed a higher percentage of hearing loss among the dentists' group as compared with their control counterparts. A statistically significant difference was found in DPOAEs between the two groups in the left ear (P=0.002), and between the right and left ears (P=0.005). Discussion: In the present cross-sectional study, the prevalence of hearing loss among dentists as assessed with the pure tone audiometry test was 15.8%. Which was in accordance with a previous study performed by Khaimook et al., which revealed the prevalence of hearing loss in dental personnel to be 17.7%; however, no significant differences were observed compared to the control group in both studies. The otoacoustic emission test in the left ear exhibited significant changes. These changes could have been due to the presence and continuity of the sounds produced by high- and low-velocity suction devices on the left side of the dental unit knowing that 97% of the dentists are right handed. Conclusion: Evidence suggests that noise from dental clinics can cause hearing problems, which had a greater effect on the left ear than the right; however, these problems are not severe in nature. Noise-induced hearing loss was more prevalent among the dentists than the control group. PMID- 29607068 TI - Contamination of dental unit waterlines: assessment of three continuous water disinfection systems. AB - Objectives: To assess the efficacy of three continuous water disinfection systems for dental units under real conditions of dental care. Design and settings: A prospective study carried out from 45 days to 20 months on the water microbial quality of the dental units is benefited from three different systems: two chemical treatment systems (IGN EVO/Calbenium/IGN Cartridge and Sterispray) and one physical treatment system (BacTerminator). Studied items were six dental units of the Dental Medicine and Oral Surgery Center within the University Hospital of Strasbourg (HUS), France. Results and disucussion: The IGN EVO/Calbenium/IGN Cartridge and Sterispray systems showed an immediate and long term efficacy on contaminated dental unit waterlines. However, the first system offers ergonomic advantages (automatic system, action on the water from the water supply network). The BacTerminator system took longer to be effective and was less effective than the other two. PMID- 29607069 TI - Interarch comparison of intraoral pH and temperature: a pilot study. AB - Purpose of study: The severity of tooth wear is known to have an association with intraoral pH and temperature depending on the site. Objective: To compare the intraoral pH and temperature between the maxillary and mandibular arch. Methods: Fourteen participants (mean age=25.8 years) wore a custom-made intraoral appliance fitted with a pH probe and thermocouple for 24 h while carrying out normal activities including sleep. All participants wore a maxillary appliance; four participants repeated the process and wore the mandibular appliance. Measurements were taken from the palatal aspect of the upper central incisors and lingual aspect of the lower canines. Both qualitative and quantitative statistical analyses were conducted. Results: The mean intraoral pH from the maxilla was 7.32 (+/-0.52) and 7.07 (+/-0.26) for the mandible. During daytime, there was no statistical significance difference between the two arches (P=0.12). During sleep, there was a significant difference (P<0.001) between the mean pH of the maxilla, 7.0 (+/-0.46), and mandible, 6.46 (+/-0.31). The fluctuation patterns of pH and temperature from both arches were similar, but the maxilla showed more variations. The mean temperature from the mandible was slightly higher (36.18 degrees C (+/-0.96)) than the maxilla, 33.12 degrees C (+/-5.51) during daytime; however, there was no statistically significance difference in temperature between the arches during daytime (awake) or sleep (P=0.27). Conclusion: The results showed that there is significant difference in mean intraoral pH between the maxilla and the mandible during sleep, but not during the day and this difference may be associated variations in tooth wear between the arches. PMID- 29607070 TI - Assessing dental professionals' understanding of tobacco prevention and control: a qualitative study in Vasterbotten County, Sweden. AB - Aim: To assess dental professionals' understanding of tobacco prevention and control. Materials and methods: In Sweden dental hygienists receive training in tobacco prevention and control. The study setting is Vasterbotton County in the north of Sweden where a number of successful tobacco control initiatives have been established. A purposeful sample comprising five male and four female dental professionals and trainees was selected. Data were collected through in-depth semi-structured individual interviews and analysed using content analysis. Results: Informants acknowledged limited adherence to tobacco prevention. They were not confident of their knowledge of tobacco and non-communicable disease prevention and had limited awareness of global oral health policies. Reasons for poor adherence included professional fragmentation, lack of training, and the absence of reimbursement for time spent on prevention activities. Discussion: The success of efforts to reduce smoking in Vasterbotton County is attributed to the network of local public health initiatives with very limited involvement by local dental professionals. Conclusions: The findings highlight the need to more actively engage the dental workforce in tobacco control and prevention. Moreover, it is important to recognise that dental professionals can be public health advocates for tobacco control and prevention at global, national and local levels. PMID- 29607071 TI - Comparing marginal microleakage of three different dental materials in veneer restoration using a stereomicroscope: an in vitro study. AB - Objectives: The objectives were to evaluate the degree of dye penetration of three different dental materials as esthetic veneer restorations on anterior teeth using stereomicroscope, and to provide reference for clinical choice. Materials and Methods: Sixty freshly extracted human maxillary central incisors were selected and randomly divided into three main groups of 20 each. Respectively, the teeth were prepared for veneer restoration by fiber-reinforced composite (FRC) (Everstick NET, Stick Tech), porcelain laminate veneer (PLV) (IPS Empress II(E-Max Press)) and 3M composites (3M ESPE) bonding with G-Cem resin cement (GC). After exposed to thermocycling (500cycles per day (5-55 degrees C, intervals: 30 s)) and immersed in 2% basic fuchsin dye solution for 24 h, the specimens were then sectioned buccolingual into three halves in a vertical plane parallel and measured dye penetration using stereomicroscope (Zeiss). The data collected was recorded by the dye penetration index (0-5) and statistically analysed using one-way analysis of variance (ANOVA) and T-tests using SPSS 13. Results: It is evident that the FRC group showed the lowest mean score of 0.333 mm, and the PLV group showed a highest mean score of 0.749 mm, as compared with the FRC group and the 3M composites group. Overall, when the three groups were compared for microleakage using ANOVA, there was significant difference among the groups. Conclusions: To evaluate the dye penetration of microleakage, the FRC showed a better marginal adaptability for veneer restoration. Therefore, within the limitation of this study, the use of FRC as veneer on anterior teeth can be suggested. PMID- 29607072 TI - Bacterial morphotype grading for periodontal disease assessment. AB - Background: Listgarten and Hellden (1978) used darkfield microscopy of wet mounts to differentiate between healthy and periodontally diseased sites in the mouth by expressing the different bacterial morphotypes observed as a percentage of the total number of bacteria counted. This method of periodontal disease assessment gained favour as a diagnostic tool but presented with the limitation of immediate examination to determine the number of motile rods present and an inability to distinguish between gingivitis and periodontitis. Grading of bacterial morphotypes into several distinct categories of health or disease (Ison and Hay, 2002), simplified the scoring system of Gram-stained smears for the diagnosis of bacterial vaginosis (Nugent et al. 1991). The application of a similar grading system using stained smears rather than wet mounts could be advantageous to the diagnosis of periodontal disease. Objectives/aims: This study tested the hypothesis that stained smears of dental plaque collected from the gingival crevice of individuals with varying probing pocket depths (PD) may provide a grading system for periodontal disease assessment. Materials and methods: Subgingival plaque samples were collected from 49 patients, stained with a silver stain and the proportions of each bacterial morphotype graded relative to their respective PD measurements. Results: This technique allowed for a grading system of I-IV, with grade I indicating health and grade IV indicating severe periodontal disease. Discussion: Stained smear examination eliminates the time restriction for motile rod enumeration and allows for storage of smears for future reference. Conclusion: Standardization of the microscopic areas to be evaluated or examined will facilitate the agreement of cut-off values for the diagnosis of periodontal disease. PMID- 29607073 TI - Tooth wear: a cross-sectional investigation of the prevalence and risk factors in Beijing, China. AB - Objectives: The aim of this study was to evaluate the epidemiology of tooth wear in Beijing and to establish appropriate preventive measures. Materials and Methods: This cross-sectional analysis involved a questionnaire survey conducted for 1,812 individuals aged 12-74 years in Beijing. Subjects were local residents living in the region for >6 months before the survey. Subjects were evaluated using clinical examinations with the basic erosive wear examination index and a self-administered questionnaire. Statistical analyses were performed using SPSS software. Results: The prevalence of maxillary tooth wear was 84.9% for the molars, 68.9% for the premolars, 74.1% for the canines and 97% for the incisors. In the mandible, the corresponding prevalence rates were 85.2%, 59.3%, 78.6% and 97.4%, respectively. The occlusal, incisal and cervical surfaces showed more frequent wear compared with the other surfaces. Age, acidic beverages, xerostomia and brushing habits were identified as risk factors for tooth wear (P<0.05). Conclusions: Tooth wear is common in Beijing. Specific preventive measures should be recommended for individuals reporting excessive consumption of fruits and/or acidic beverages, and those with xerostomia. In particular, incisor wear should be carefully monitored in individuals of all age groups. PMID- 29607074 TI - Interprofessional enhanced skills training in periodontology: a qualitative study of one London pilot. AB - OBJECTIVES/AIMS: Health Education England (HEE) London developed an innovative 2 year pilot educational and training initiative for enhancing skills in periodontology for dentists and dental hygienists/therapists in 2011. This study explores the perceptions and experiences of those involved in initiating, designing, delivering and participating in this interprofessional approach to training. MATERIALS AND METHODS: Semi-structured qualitative interviews were conducted with a purposive sample of key stakeholders including course participants (dentists and dental hygienists and/or therapists), education and training commissioners, and providers towards the end of the 2-year programme. Interviews, based on a topic guide informed by health services and policy literature, were audio-recorded and transcribed verbatim. Data were analysed based on framework methodology, using QSR NVivo 9 software to manage the data. RESULTS: Twenty-two people were interviewed. Although certain challenges were identified in designing, and teaching, a course bringing together different professional backgrounds and level of skills, the experiences of all key stakeholders were overwhelmingly positive relating to the concept. There was evidence of 'creative interprofessional learning', which led to 'enhancing team working', 'enabling role recognition' and 'equipping participants for delivery of new models of care'. Recommendations emerged with regard to future training and wider health policy, and systems that will enable participants on future enhanced skills courses in periodontology to apply these skills in clinical practice. CONCLUSION: The interprofessional approach to enhanced skills training in periodontology represents an important creative innovation to build capacity within the oral health workforce. This qualitative study has provided a useful insight into the benefits and tensions of an interprofessional model of training from the perspectives of different groups of key stakeholders and suggests its application to other areas of dentistry. PMID- 29607075 TI - Pharmacoeconomic analysis of antibiotic therapy in maxillofacial surgery. AB - Objectives/Aims: The aim of this study was to investigate the microbial cultures collected in the years 2013-2014 at the craniomaxillofacial department and outpatient clinic to analyse optimisation of the treatment cost of the bacterial infections and present the results. Design and setting: We analysed 485 cultures from 263 patients, of which 77.28% consisted of Gram-positive bacteria. On the basis of the antibiotic efficacy, antibiotic price and the cost of entire treatment during hospitalisation, the most useful antimicrobial agents for the most common pathogens were selected. Results: The most frequently collected material was pus. The most common pathogens were found to be the Staphylococcus epidermidis (18%), Streptococcus mitis and Str. oralis (14%) and S. aureus (6.5%). Discussion: The most frequently isolated bacteria in other studies were the Streptococcus strain. Other authors showed that ceftriaxone is the most cost efficient agent. The use of postoperative antibiotic prophylaxis remains controversial. Conclusion: The results of this study suggest that the most useful antibiotics for therapy, from the perspective of the cost minimisation, were gentamycin, trimethoprim with sulfamethoxazole and vancomycin. PMID- 29607078 TI - Dental politics and subsidy systems for adults in Sweden from 1974 until 2016. AB - Aims: The dental health sector, as part of the Swedish welfare system, originated in 1974. Since then, the dental insurance has undergone three major changes. The aim of this archive study was to study where in the legislative process the dental politics concerning national dental insurance and subsidies were formed. Materials and Methods: The material, such as Commission of inquiry proposals and Government Bills from four major dental reforms, was collected from the library at the Sveriges Riksdag (Swedish Parliament) and was analysed and structured using a modified version of the Health Field Model. Results: The views on the fundamental ideas, such as the connection between general and dental health, preventive dentistry, rehabilitation of the mouth and promotion of dental health, were the same over the years. The views on dentistry as a market, when it comes to freedom of prices, have undergone a major change since 1974, but the view on the welfare state remains the same. Conclusions: The Swedish dental subsidy systems and how dentistry has been treated politically are the results of a chain of events ranging from care for the population's dental health, political doctrines, 'zeitgeist', dental policy, to state finances. PMID- 29607077 TI - Oral health and oral health-related habits of Finnish prisoners. AB - Objectives/Aims: This cross-sectional study aimed to examine oral health and oral health-related habits among prisoners at the Pelso Prison in Finland. Materials and Methods: Participants in this cross-sectional study comprises 100 inmates. A calibrated dentist recorded the decayed, filled and missed teeth as well as periodontal status (bleeding-on-probing, pocket probing and Community Periodontal Index) among the participants (n=100). Fifty inmates were also interviewed for marital status, education and oral health-related habits. The Ethical Committee of the Northern Ostrobothnia Hospital District and the Criminal Sanctions Agency approved the study protocol. Results: The participants were on average 35 years old and had 5 (s.d. 5.1) decayed teeth in need of restorative treatment, whereas DMFT was 17 (s.d. 8.9). Half of the study population had periodontal disease in need of professional treatment. Almost all reported brushing their teeth daily. Two-third ate sweets, one-third drank fizzy drinks and majority smoked every day. Almost two-third had used illicit drugs at some point of their lives. Almost all drunk alcohol once a week or more often. No statistically significant associations were discovered between dental treatment need and explanatory factors. Discussion: Prisoners appear to be a homogenous group with poor oral health and harmful health behaviours. PMID- 29607076 TI - Associations between sleep bruxism and (peri-) implant complications: a prospective cohort study. AB - Objectives/Aims: To describe the protocol of a prospective cohort study designed to answer the question: 'Is sleep bruxism a risk factor for (peri-)implant complications?'. Materials and Methods: Our study is a single-centre, double blind, prospective cohort study with a follow-up time of 2 years. Ninety-eight participants fulfilling inclusion criteria (planned treatment with implant supported fixed suprastructure(s) and age 18 years or older) will be included. Sleep bruxism will be monitored at several time points as masticatory muscle activity during sleep by means of a portable single-channel electromyographic device. Our main outcomes are biological complications (i.e., related to peri implant bleeding, probing depth, marginal bone height, quality of submucosal biofilm and loss of osseointegration) and technical complications (i.e., suprastructure, abutment, implant body or other). Results: The study is currently ongoing, and data are being gathered. Discussion: The results of this prospective cohort study will provide important information for clinicians treating bruxing patients with dental implants. Furthermore, it will contribute to the body of evidence related to the behaviour of dental implants and their complications under conditions of high mechanical loadings that result from sleep bruxism activity. Conclusion: The protocol of a prospective cohort study designed to investigate possible associations between sleep bruxism and (peri-) implant complications was presented. PMID- 29607079 TI - Eyesight: a study of the staff of a dental school. AB - Objectives/Aims: The aim was to investigate the vision of all 90 dentally qualified staff at a dental school. Materials and Methods: Ethical approval was obtained and a questionnaire-based survey conducted. Data were screened and analysed using Stata 13.1. The chi2 and Fisher's Exact tests were used to test for significance with an alpha level of 0.05. Results: The participation rate was 95.6%. Most of the teachers (92%) considered their eyesight was satisfactory to practice dentistry. Of the 97% who had been tested at some stage, 15% had their eye examination due to sight deterioration with 22% needing correction. Almost two-thirds were myopic and a third were hyperopic. Forty-nine per cent wore spectacles only, with about a quarter of this group alternating between spectacles and contact lenses. Of those with corrected vision, 80% followed their optometrist's recall advice. Four participants reported that they were colour blind. While 4% had had laser-eye surgery, a further 27% were interested in this. Magnification was used by 72% with no significant differences between genders, age of staff member, place of qualification or registration status. Most of the staff (81%) thought that screening of dental student's eyesight should be mandatory, and regular eye examinations as a condition of dental practice was supported by 67%. Discussion: The number of teachers reporting recent vision tests was encouraging; nevertheless, a worrying 8% surveyed were unsure if their eyesight was satisfactory for work. The commonest vision problem was myopia, with almost half of the teachers wearing spectacles. It is clear that visual standards for dentistry would be helpful. Magnification use was high, with many non-users indicating their intention to buy loupes. Conclusions: Within the limits of this study the teachers were conscientious regarding their eye care, irrespective of their training and age. There was strong support for the mandatory testing of vision for all dentists and especially dental students. PMID- 29607080 TI - Dental students' concerns regarding OSPE and OSCE: a qualitative feedback for process improvement. AB - Objectives: Objective structured practical examination (OSPE) and objective structured clinical examination (OSCE) have become established as reliable, valid and objective methods of assessing practical and clinical skills in dental schools. This study explored the perceptions of dental undergraduates' regarding OSPE and OSCE. Design and Setting: Two focus groups were made; the first consisted of students who had recently undergone an OSPE, while the other group was of fresh graduates (FG) who had given an OSCE in the final examination. A trained facilitator conducted the discussion-based interview for each focus group. Both discussions were recorded via audio recorders and transcribed verbatim. The data were thereafter analysed thematically. Results: Findings from the study suggested that the students and FGs were generally satisfied with the OSPE and OSCE. However, they perceived that the time allocated to the stations was not well balanced, nor were the examiners trained to conduct the examination. More importantly, the FGs opined that practical skills were not adequately tested on the OSCE, and thus the curricular content was not adequately covered. Conclusion: The study highlights issues that may arise while conducting the OSPE and OSCE, thus informing future guidelines for conducting OSPE and OSCE. PMID- 29607081 TI - Assessment of noise intensity in a dental teaching clinic. AB - Objectives/Aims: The aim of this study is to evaluate if the duration of the consultation has influence on the intensity of noise in the dental clinic environment. Materials and Methods: The measurement was performed using the decibelmetre IDETEC 300. It was turned on among 10 dental equipment at basal time (BT) and in the first, second and third hours of activity by 10 times with 1-week interval. Results: The average noise was 67.39+/-1.11 dB for BT and 82.38+/-3.85, 80.99+/-4.78, and 70.06+/-6.95 dB for hours 1 to 3, respectively, representing a significant difference (ANOVA, F(3.36)=29.28, P<0.0001). Conclusion: In the first and second hours of clinical care there was more noise intensity in the work environment compared to BT and to the third time. Furthermore, the noise peaks became closer to the limit of 85 dB, which can threaten hearing loss with repeated exposure throughout a dentist's career. Discussion: The findings presented here show how much the dental surgeon is exposed to the level of noise since his time of study. PMID- 29607082 TI - Clinical performance of the near-infrared imaging system VistaCam iX Proxi for detection of approximal enamel lesions. AB - Objectives/Aims: Apart from the visual detection of caries, X-rays can be taken for detection of approximal lesions. The Proxi head of VistaCam iX intraoral camera system uses near-infrared light (NIR) to enable caries detection in approximal surfaces. The aim of this study was to evaluate the performance of the NIR for the detection of approximal enamel lesions by comparison with radiographic findings. Materials and methods: One hundred ninety-three approximal surfaces from 18 patients were examined visually and using digital radiographs for presence or absence of enamel lesions. Then digital images of each surface were produced using the near-infrared light. Correlation between methods was assessed using Spearman's rank correlation coefficient (rs). Agreement between radiographic and NIR findings was calculated using the kappa coefficient. McNemar's test was used to analyse differences between the radiographic and NIR findings (alpha=0.05). Results: Moderate correlation was found between all detection methods (rs=0.33-0.50, P<0.0001). Agreement between the radiographic and NIR findings was moderate (kappa=0.50, 95% CI=0.37-0.62) for the distinction between sound surfaces and enamel caries. No significant differences were found between the findings (P=0.07). Conclusion: Radiographs and NIR were found to be comparable for the detection of enamel lesions in permanent teeth. PMID- 29607083 TI - Emerging paradigm of virtual-microscopy for histopathology diagnosis: survey of US and Canadian oral pathology trainees. AB - Objectives/Aims: The application of virtual microscopy (VM) to research, pre doctoral medical and dental educational training, and diagnostic surgical and anatomic pathology is well-documented but its application to the field of oral and maxillofacial pathology has not been explored. This is the first study to evaluate the enthusiasm and readiness of US-/Canada-based oral and maxillofacial pathology (OMFP) residents toward employing VM use over conventional microscopy (CM) for diagnostic purposes. Materials and Methods: All 46 current US-/Canada based OMFP residents were invited to participate in an anonymous electronic survey via 'Survey Monkey' in 2015. The survey comprised sixteen multiple choice questions and two 'free text' questions. Results: 14% of respondents of the 22 (48%) respondents who completed the survey indicated a willingness to substitute CM with VM in <5 years, and 33% within 10 years. 52% reported they would never substitute CM with VM. Approximately 10 and 57% of respondents thought VM will become an acceptable sole diagnostic tool in most centers within 5 and 10 years, respectively. These findings are irrespective of the fact that overall, 90% of respondents reported being familiar with VM use. Discussion: VM technology is unlikely to substitute CM in diagnostic oral and maxillofacial histopathology practice among future OMFP practitioners in the foreseeable future. PMID- 29607084 TI - A study on light transmittance through red protective shields modified with different window films. AB - Objectives/Aims: This study aimed to improve effectiveness of red protective shields in filtering unwanted light using window films. Materials and Methods: Red protective shields were modified by placing V-Kool (VK), Scotchtint (ST) or Huper Optik (HP) window films on both sides. Percentage transmittance (%T) of light with a wavelength of 190-990 nm was determined using a double-beam ultraviolet (UV) and visible spectrophotometer. Results: In UV light (190-390 nm) and visible light (430-590 nm) ranges, %T in all modified groups and the control was below 2.5%. An increase in %T was observed at the wavelength of 630 nm, when all the modified shields showed superior effectiveness in light filtration over the control. In the infrared spectrum (700-990 nm), %T in the control was constantly high, ranging from 86 to 91%, compared to %T of 2-38% in all the modified groups, with the application of VK on both sides being the most effective group, followed by a combination of VK and HP. Conclusion: This study has introduced an economical and simple, yet highly effective, means of enhancing the efficiency of a red plastic protection shield in filtering unwanted infrared light, thereby additionally providing protection for dental personnel from potential ocular damages. PMID- 29607085 TI - Diurnal variation of intraoral pH and temperature. AB - Objective/Aims: The aim of this study was to measure continuously the intraoral pH and temperature of healthy individuals to investigate their diurnal variations. Materials and Methods: Seventeen participants (mean age, 31+/-9 years) wore a custom-made intraoral appliance fitted with a pH probe and thermocouple for two sets of 24 h, while carrying out normal daily activities including sleep. The continuous changes in intraoral pH and temperature were captured using a sensor placed on the palatal aspect of the upper central incisors. The collected data were categorised into different status (awake and sleep) and periods (morning, afternoon, evening and night). Both quantitative and qualitative analyses were conducted. Results: The intraoral pH change was found to show a distinctive daily rhythm, showing a 12-h interval between maximum (7.73) and minimum (6.6) pH values. The maximum and minimum values were found to repeat after 24 h. The mean pH over 48 h (two sets of 24 h) was found to be 7.27 (+/-0.74). There was significant difference found in pH when subjects were awake and asleep and different periods during the day (P<0.001). The mean intraoral temperature was 33.99 degrees C (+/-4.9), with less distinctive daily rhythm compared with pH. There was a significant difference found in temperature depending on the time of the day, except between morning and afternoon (P=0.78). Conclusion: Our results showed that there is a distinctive daily, circadian-like pattern in intraoral pH variation over a 24-h period, which has been considered as one of the risk factors in sleep-related dental diseases. PMID- 29607086 TI - Actinic cheilitis: proposition and reproducibility of a clinical criterion. AB - Objectives/Aims: The actinic cheilitis (AC) is a precancerous lip lesion seen as a consequence of chronic sun exposure. Clinically, the border between the lip's skin and the semimucosa could be blurred; in the more aggressive cases, leucoplakia and ulcers also represent its clinical feature. It seems that no clinical criterion is universally accepted for this disease yet. Therefore, this study was carried out to make a proposition of a clinical score to actinic cheilitis (Grade I starting from dryness of vermilion to endured ulcers representing Grade IV) and to assess its reproducibility. Materials and Methods: Fifty subjects were assessed, most of whom were male, Caucasian farmers, with an average age of 46.12 (18-74) years. The obtained data were analysed by means of descriptive statistics and by Kappa test to assess the inter-examiners and the clinical Golden-Pattern concordance (95% CI). Results: During calibration, 15 patients were examined three times a week by each examiner (4) until Kappa test observed k=0.8 or more. In the main experiment, the inter-examiner concordance was classified between good (k=0.779; P<0.05) and very good (k=0.925; P<0.05) from the 35 examined subjects. With the Golden-Pattern, it was considered very good (k=0.812; P<0.05 to k=0.925; P<0.05). Discussion: Four examiners with different experiences could strongly suggest that after adequate calibration, it could be well applied by examiners with as much experience as a dental student. Conclusions: The authors concluded that the proposed classification was easily applied and had a very good reproducibility. PMID- 29607087 TI - Peri-implant health, clinical outcome and patient-centred outcomes of implant supported overdentures in the mandible and the maxilla. AB - Objectives/Aims: The primary aim of this retrospective pilot study was to evaluate the clinical outcome of overdentures on four non-splinted maxillary implants compared to the mandible using locator attachments and secondly to assess patient's opinion of the treatment. Materials and Methods: The treatment protocol used here is summarised as a single-stage surgical approach followed by immediate loading (same day in 12 of 17 patients) of a removable prosthesis in the maxilla and mandible. Most of the implants were installed into fresh extraction sockets. Clinical outcomes were evaluated in 68 southern implants, straight (non co-axis) or angulated (co-axis) in 17 patients. Patients were examined by independent examiners at an average follow-up of 14.5 months after implant placement. Results: Outcomes measured were implant survival, bone loss, bleeding on probing, probing pocket depths and plaque score in addition to quality of life measured with OHIP-14 questionnaires. An overall implant survival of 100% was achieved. The mean marginal bone level (mm) over the entire cohort of 66 measured implants was (1.4 mm; range, 0-5.5). A significant difference (P=0.01) was found between bone level, from implant head to bone contact in the maxilla (M, 0.9 mm; s.d., 1.1; range, 0-4) and the mandible (M, 1.7; s.d., 1.0; range, 0-5.5). The marginal bone-to-implant head distance with the angulated co axis implants was 1.9 mm (s.d., 1.5; range, 0-5.5) compared to non co-axis, mean 1.2 mm (s.d., 1.1; range, 0-4) (P=0.01). The OHIP-14 overall mean was 3.3 (out of a maximum of 56). Conclusion: The implant survival was 100% and the patients benefited from the overdenture treatment on four non-connected implants. The extremely low OHIP-14 indicated a very high level of patient satisfaction following treatment. The results of this study merit further long-term investigation to fully investigate the success of immediately loading implants in the maxilla as well as cost-benefit. PMID- 29607088 TI - What reward does a child prefer for behaving well at the dentist? AB - Background: Paediatric dentists often report using positive reinforcement to encourage their young patients to show co-operative behaviour. For effective reinforcement to take place the reward should be salient to the individual. To date, there is little research into what reward a young patient will choose when attending the dentist. Aim: To identify what reward children between the age of 4 8 years will choose when attending the dentist, and to determine the extent of agreement between children and caregivers in reward choice. Method: Observational study. Fifty-two children from different age groups (4-5 years, 6-7 years and 8 years) attending a primary-care dental clinic were asked to choose between a range of different rewards. The caregiver attending with them was also asked to anticipate the child's preferred choice. Results: There was no clear favourite reward for children from both genders and different age group. However, no child chose the 'sticker' reward that is traditionally given out at the dentist. Overall carers agreed with the child's choice of toy on 18 occasions (34.6%), but there were significant differences across the age groups with carers of older children showing less agreement. Conclusion: To ensure that rewards are salient, children should be given a choice of rewards when attending the dental clinic. Parents ability to predict their child's preferred rewards decreases as the child ages. Clinical relevance: A child's motivation to co-operate during dental treatment can be increased by offering a range of rewards. Asking children to choose their reward from a limited range will increase the saliency of the reward for the child. PMID- 29607089 TI - Microstream capnography during conscious sedation with midazolam for oral surgery: a randomised controlled trial. AB - Objectives/Aims: There has been no dentistry-specific published data supporting the use of monitoring with capnography for dental sedation. Our aim was to determine if adding capnography to standard monitoring during conscious sedation with midazolam would decrease the incidence of hypoxaemia. Materials and Methods: A randomised controlled trial was conducted in which all patients (ASA I and II) received standard monitoring and capnography, but were randomised to whether staff could view the capnography (intervention) or were blinded to it (control). The primary outcome was the incidence of hypoxaemia (SpO2?94%). Results: We enrolled 190 patients, mean age 31 years (range, 14-62 years). There were 93 patients in the capnography group and 97 in the control group. The mean cumulative dose of midazolam titrated was 6.94 mg (s.d., 2.31; range, 3-20 mg). Six (3%) patients, three in each group, required temporary supplemental oxygen. There was no statistically significant difference between the capnography and control groups for the incidence of hypoxaemia: 34.4 vs 39.2% (P=0.4962, OR=0.81, 95% CI: 0.45-1.47). Conclusions: We were unable to confirm an additive role for capnography to prevent hypoxaemia during conscious sedation with midazolam for patients not routinely administered supplemental oxygen. PMID- 29607090 TI - Dentists' opinions on knowledge, attitudes and barriers in providing oral health care to older people living independently in the Netherlands and Flanders (Belgium). AB - Objectives: The aim of this study was to investigate how dentists in the Netherlands and Flanders assessed their knowledge on oral health care to older people, what their attitude was and what barriers they experienced in rendering care to older people. Methods: The survey data was collected from a random sample of Dutch and Flemish dentists. Five hundred ninety-five dentists (37%) of the Dutch sample and 494 dentists of the Flemish sample (41%) completed the online questionnaire. Dentists were asked to respond to 15 Likert type items, representing opinions on provision of oral health care to older people and to give information about the number of older patients treated and about some profession-specific and personal characteristics. Results: The average number of patients treated per week was nearly twice as high in the Netherlands as in Flanders. Nevertheless, differences of opinions between dentists in the Netherlands and Flanders were relatively limited. Conclusions: This survey shows that in particular the actual number of older patients treated appears to be related with differences of opinions between Dutch and Flemish dentists about oral health care provided to (vulnerable) older people who live at home. PMID- 29607091 TI - Craniofacial manifestations in osteogenesis imperfecta type III in South Africa. AB - Objectives: Osteogenesis imperfecta type III (OMIM 259420) is a severe autosomal recessive disorder. Affected individuals have multiple fractures, develop limb deformities with spinal malalignment and stunted stature. Materials and methods: The frequency of Osteogenesis imperfecta type III (OI III) is relatively high in the indigenous Black African population of South Africa. A review of the literature revealed a paucity of information regarding the craniofacial manifestations of the disorder in this ethnic group. The findings in 64 affected persons are documented. Results: These abnormalities are related to the abnormal bone matrix which results in a deformed skull and dental malocclusion. The physiological process of swallowing may be an aetiological factor in the progressive development of a flattened palate. Mild changes in the shape of the head of the mandibular condyle and a lack of cortical bone on the joint surfaces were observed on cone beam computed tomography (CBCT) images. Affected persons had marked variations in the paranasal sinuses, including sinus hypoplasia and partial opacification. Cranial base anomalies were diagnosed from cephalometric radiographs and lateral skull radiographs. Platybasia and a 'J' shaped sella turcica were observed. Conclusion: The craniofacial abnormalities emphasize the importance of a raised level of awareness in terms of dental management and the challenges. PMID- 29607092 TI - A randomised study in young subjects of the effects of eating extra fruit or nuts on periodontal inflammation. AB - Objectives/Aims: Fruit is often advocated as a healthy source of nutrients and vitamins. However, the high contents of sugars in many fruits could potentially counteract positive effects on the teeth. Materials and methods: We recruited 30 healthy non-obese participants who were randomised to either supplement their diet with extra fruits or nuts, each at +7 kcal/kg body weight/day, for 2 months. Results: Fructose intake increased from 9.1+/-6.0 to 25.6+/-9.6 g/day, P<0.0001, in the fruit group and was reduced from 12.4+/-5.7 to 6.5+/-5.3 g/day, P=0.007, in the nut group. Serum-vitamin C increased in both groups (fruit: P=0.017; nuts: P=0.009). alpha-Tocopherol/cholesterol ratio increased in the fruit group (P=0.0033) while beta-carotene/cholesterol decreased in the nut group (P<0.0001). The amount of subjects with probing pocket depths ?4 mm in the fruit group was reduced (P=0.045) according to blinded examinations, and the difference in the changes in probing pockets ?4 mm was also statistically significant between the food groups (P=0.010). Conclusion: A large increase of fruit intake, compared with nuts, had a favourable effect on periodontal status in some respects, despite the high sugar contents. To search for potential protective micronutrients in fruit that protect the teeth could be an aim for further research. PMID- 29607093 TI - Factors related to reducing free sugar intake among white ethnic adults in the UK: a qualitative study. AB - Objective/Aims: To determine the barriers and enablers to behavioural change to reduce free sugar intake related to dental caries in a sample of UK adults who identify their ethnicity as White. Materials and methods: Qualitative study comprising semi-structured interviews of 27 participants. Interviews were recorded, transcribed and analysed using thematic analysis methods. The Capability-Opportunity-Motivation-Behaviour model (COM-B) and the Theoretical Domains Framework (TDF) were used to guide the derivation of themes. Results: Data saturation occurred at 27 interviews. The COM-B Model and TDF domains captured various factors that may influence the consumption of free sugar. TDF elements which are reflected in the study are: Knowledge; Psychological skills; Memory, attention, and decision processes; Behavioural regulation; Physical skills; Social influence; Environmental context and resources; Social and professional role and identity; Beliefs about capabilities; Beliefs about consequence; Intentions and goals reinforcement; and Emotions. COM-B Model elements which are reflected in the study are: psychological capabilities, physical capabilities, social opportunities, physical opportunities, reflective motivation, and automatic motivation. Discussion and conclusion: The COM-B model and TDF framework provided a comprehensive account of the barriers and facilitators of reducing sugar intake among white ethnic groups. PMID- 29607094 TI - Assessment of information resources for people with hypodontia. AB - Aim: To assess the adequacy of patient information to support understanding and decision-making for people affected by hypodontia. Methods: 1) Questionnaire to understand the provision of patient information by dentists; 2) Systematic search to identify online open-access patient information; 3) Quality assessment of written patient information. Results: Questionnaire response rate was 49% (319/649); 91% examined and/or treated people with hypodontia. Most general dentists referred patients to specialist services without providing written hypodontia information. The majority of dental specialists provide patient leaflets but less than a third used web-resources. Only 19% of respondents felt current resources were fit-for-purpose. Thirty-one patient resources (18 leaflets and 13 online) were assessed against quality criteria. The aim of the resource was seldom explicit, the content was often incomplete and variation in readability scores indicated high levels of literacy were required. Discussion: Access to, and quality of, patient information for hypodontia is inadequate. Current resources are not sufficiently comprehensive to prepare young patients to engage in shared dental care decisions with their parents and/or dental professionals. Conclusion: There is a need for improved access to, and provision of, information about hypodontia if dental professionals want to meet best practice guidance and involve patients in shared decision-making. PMID- 29607095 TI - Auricular reconstruction from rib to 3D printing. AB - The human ear imparts critical form and function and remains one of the most challenging facial features to reconstruct. Over the past century, surgeons have developed numerous techniques and materials for total auricular reconstruction. Refined costal cartilage techniques have remained the gold standard for the past half-century. Recent advancements with novel materials, tissue engineering and 3D printing provide immense potential; however, prohibitive costs and regulatory steps remain as barriers to clinical translation. PMID- 29607096 TI - Impact of Ebola experiences and risk perceptions on mental health in Sierra Leone, July 2015. AB - Background: The mental health impact of the 2014-2016 Ebola epidemic has been described among survivors, family members and healthcare workers, but little is known about its impact on the general population of affected countries. We assessed symptoms of anxiety, depression and post-traumatic stress disorder (PTSD) in the general population in Sierra Leone after over a year of outbreak response. Methods: We administered a cross-sectional survey in July 2015 to a national sample of 3564 consenting participants selected through multistaged cluster sampling. Symptoms of anxiety and depression were measured by Patient Health Questionnaire-4. PTSD symptoms were measured by six items from the Impact of Events Scale-revised. Relationships among Ebola experience, perceived Ebola threat and mental health symptoms were examined through binary logistic regression. Results: Prevalence of any anxiety-depression symptom was 48% (95% CI 46.8% to 50.0%), and of any PTSD symptom 76% (95% CI 75.0% to 77.8%). In addition, 6% (95% CI 5.4% to 7.0%) met the clinical cut-off for anxiety depression, 27% (95% CI 25.8% to 28.8%) met levels of clinical concern for PTSD and 16% (95% CI 14.7% to 17.1%) met levels of probable PTSD diagnosis. Factors associated with higher reporting of any symptoms in bivariate analysis included region of residence, experiences with Ebola and perceived Ebola threat. Knowing someone quarantined for Ebola was independently associated with anxiety depression (adjusted OR (AOR) 2.3, 95% CI 1.7 to 2.9) and PTSD (AOR 2.095% CI 1.5 to 2.8) symptoms. Perceiving Ebola as a threat was independently associated with anxiety-depression (AOR 1.69 95% CI 1.44 to 1.98) and PTSD (AOR 1.86 95% CI 1.56 to 2.21) symptoms. Conclusion: Symptoms of PTSD and anxiety-depression were common after one year of Ebola response; psychosocial support may be needed for people with Ebola-related experiences. Preventing, detecting, and responding to mental health conditions should be an important component of global health security efforts. PMID- 29607097 TI - Anthropology in public health emergencies: what is anthropology good for? AB - Recent outbreaks of Ebola virus disease (2013-2016) and Zika virus (2015-2016) bring renewed recognition of the need to understand social pathways of disease transmission and barriers to care. Social scientists, anthropologists in particular, have been recognised as important players in disease outbreak response because of their ability to assess social, economic and political factors in local contexts. However, in emergency public health response, as with any interdisciplinary setting, different professions may disagree over methods, ethics and the nature of evidence itself. A disease outbreak is no place to begin to negotiate disciplinary differences. Given increasing demand for anthropologists to work alongside epidemiologists, clinicians and public health professionals in health crises, this paper gives a basic introduction to anthropological methods and seeks to bridge the gap in disciplinary expectations within emergencies. It asks: 'What can anthropologists do in a public health crisis and how do they do it?' It argues for an interdisciplinary conception of emergency and the recognition that social, psychological and institutional factors influence all aspects of care. PMID- 29607098 TI - Developing a multisectoral National Action Plan for Health Security (NAPHS) to implement the International Health Regulations (IHR 2005) in Tanzania. AB - The Ebola outbreak in West Africa precipitated a renewed momentum to ensure global health security through the expedited and full implementation of the International Health Regulations (IHR) (2005) in all WHO member states. The updated IHR (2005) Monitoring and Evaluation Framework was shared with Member States in 2015 with one mandatory component, that is, States Parties annual reporting to the World Health Assembly (WHA) on compliance and three voluntary components: Joint External Evaluation (JEE), After Action Reviews and Simulation Exercises. In February 2016, Tanzania, was the first country globally to volunteer to do a JEE and the first to use the recommendations for priority actions from the JEE to develop a National Action Plan for Health Security (NAPHS) by February 2017. The JEE demonstrated that within the majority of the 47 indicators within the 19 technical areas, Tanzania had either 'limited capacity' or 'developed capacity'. None had 'sustainable capacity'. With JEE recommendations for priority actions, recommendations from other relevant assessments and complementary objectives, Tanzania developed the NAPHS through a nationwide consultative and participatory process. The 5-year cost estimate came out to approximately US$86.6 million (22 million for prevent, 50 million for detect, 4.8 million for respond and 9.2 million for other IHR hazards and points of entry). However, with the inclusion of vaccines for zoonotic diseases in animals increases the cost sevenfold. The importance of strong country ownership and committed leadership were identified as instrumental for the development of operationally focused NAPHS that are aligned with broader national plans across multiple sectors. Key lessons learnt by Tanzania can help guide and encourage other countries to translate their JEE priority actions into a realistic costed NAPHS for funding and implementation for IHR (2005). PMID- 29607099 TI - Building a safety culture in global health: lessons from Guatemala. AB - Programmes to modify the safety culture have led to lasting improvements in patient safety and quality of care in high-income settings around the world, although their use in low-income and middle-income countries (LMICs) has been limited. This analysis explores (1) how to measure the safety culture using a health culture survey in an LMIC and (2) how to use survey data to develop targeted safety initiatives using a paediatric nephrology unit in Guatemala as a field test case. We used the Safety, Communication, Operational Reliability, and Engagement survey to assess staff views towards 13 health climate and engagement domains. Domains with low scores included personal burnout, local leadership, teamwork and work-life balance. We held a series of debriefings to implement interventions targeted towards areas of need as defined by the survey. Programmes included the use of morning briefings, expansion of staff break resources and use of teamwork tools. Implementation challenges included the need for education of leadership, limited resources and hierarchical work relationships. This report can serve as an operational guide for providers in LMICs for use of a health culture survey to promote a strong safety culture and to guide their quality improvement and safety programmes. PMID- 29607100 TI - Proactive community case management and child survival in periurban Mali. AB - The majority of the world's population lives in urban areas, and regions with the highest under-five mortality rates are urbanising rapidly. This 7-year interrupted time series study measured early access to care and under-five mortality over the course of a proactive community case management (ProCCM) intervention in periurban Mali. Using a cluster-based, population-weighted sampling methodology, we conducted independent cross-sectional household surveys at baseline and at 12, 24, 36, 48, 60, 72 and 84 months later in the intervention area. The ProCCM intervention had five key components: (1) active case detection by community health workers (CHWs), (2) CHW doorstep care, (3) monthly dedicated supervision for CHWs, (4) removal of user fees and (5) primary care infrastructure improvements and staff capacity building. Under-five mortality rate was calculated using a Cox proportional hazard survival regression. We measured the percentage of children initiating effective antimalarial treatment within 24 hours of symptom onset and the percentage of children reported to be febrile within the previous 2 weeks. During the intervention, the rate of early effective antimalarial treatment of children 0-59 months more than doubled, from 14.7% in 2008 to 35.3% in 2015 (OR 3.198, P<0.0001). The prevalence of febrile illness among children under 5 years declined after 7 years of the intervention from 39.7% at baseline to 22.6% in 2015 (OR 0.448, P<0.0001). Communities where ProCCM was implemented have achieved an under-five mortality rate at or below 28/1000 for the past 6 years. In 2015, under-five mortality was 7/1000 (HR 0.039, P<0.0001). Further research is needed to elucidate the mechanisms of action and generalizability of ProCCM. PMID- 29607101 TI - Weak surveillance and policy attention to cancer in global health: the example of Mozambique. AB - Cancer is an emerging public health problem in sub-Saharan Africa due to population growth, ageing and westernisation of lifestyles. The increasing burden of cancer calls for urgent policy attention to develop cancer prevention and control programmes. Cancer surveillance is an essential prerequisite. Only one in five low-income and middle-income countries have the necessary data to drive policy and reduce the cancer burden. In this piece, we use data from Mozambique over a 50-year period to illustrate cancer epidemiological trends in low-income and middle-income countries to hypothesise potential circumstances and factors that could explain changes in cancer burden and to discuss surveillance weaknesses and potential improvements. Like many low-income and middle-income countries, Mozambique faces the dual challenge of a still high morbidity and mortality due to infectious diseases in rural areas and increased incidence of cancers associated with westernisation of lifestyles in urban areas, as well as a rise of cancers related to the HIV epidemic. An increase in cancer burden and changes in the cancer profile should be expected in coming years. The Mozambican healthcare and health-information systems, like in many other low-income and middle-income countries, are not prepared to face this epidemiological transition, which deserves increasing policy attention. PMID- 29607102 TI - The 'Ten CRVS Milestones' framework for understanding Civil Registration and Vital Statistics systems. PMID- 29607103 TI - Unraveling PBF effects beyond impact evaluation: results from a qualitative study in Cameroon. AB - Introduction: Performance-based financing (PBF) has acquired increased prominence as a means of reforming health system purchasing structures in low-income and middle-income countries. A number of impact evaluations have noted that PBF often produces mixed and heterogeneous effects. Still, little systematic effort has been channelled towards understanding what causes such heterogeneity, including looking more closely at implementation processes. Methods: Our qualitative study aimed at closing this gap in knowledge by attempting to unpack the mixed and heterogeneous effects detected by the PBF impact evaluation in Cameroon to inform further implementation as the country scales up the PBF approach. We collected data at all levels of the health system (national, district, facility) and at the community level, using a mixture of in-depth interviews and focus group discussions. We combined deductive and inductive analytical techniques and applied analyst triangulation. Results: Our findings indicate that heterogeneity in effects across facilities could be explained by pre-existing infrastructural weaknesses coupled with rigid administrative processes and implementation challenges, while heterogeneity across indicators could be explained by providers' practices, privileging services where demand-side barriers were less substantive. Conclusion: In light of the country's commitment to scaling up PBF, it follows that substantial efforts (particularly entrusting facilities with more financial autonomy) should be made to overcome infrastructural and demand-side barriers and to smooth implementation processes, thus, enabling healthcare providers to use PBF resources and management models to a fuller potential. PMID- 29607104 TI - Surrogate endpoints in global health research: still searching for killer apps and silver bullets? PMID- 29607106 TI - Priorities for global political momentum to end TB: a critical point in time. PMID- 29607105 TI - Unpicking the Gordian knot: a systems approach to traumatic brain injury care in low-income and middle-income countries. PMID- 29607107 TI - Tumor spread through air space, the clinical implications for T factor and effects on the disease recurrence and prognosis. PMID- 29607108 TI - Long non-coding RNA and messenger RNA-the meeting of two worlds. PMID- 29607109 TI - Platelets promoting tumor metastasis: culprits or victims? PMID- 29607110 TI - Small cell lung cancer heterogeneity: elevated a Notch above the Rest! PMID- 29607111 TI - Call for screening for primary aldosteronism: an underdiagnosed and treatable disease. PMID- 29607112 TI - PNUTS at the crossroads of tumorigenesis and metastasis formation. PMID- 29607113 TI - Insight into the regulatory mechanism of VEGFA isoforms in p53 mutant breast cancer: can it be substantiated with solely in vitro studies? PMID- 29607114 TI - Acute respiratory distress syndrome-a worldwide economic perspective. PMID- 29607115 TI - Climbing the hill of left main coronary artery revascularization: percutaneous coronary intervention or coronary artery bypass graft? PMID- 29607116 TI - Spread through air spaces-novel pattern of cancer progression. PMID- 29607117 TI - BRAF inhibitors in metastatic non-small cell lung cancer. PMID- 29607118 TI - Will spread through air spaces be a staging parameter in lung cancer? PMID- 29607119 TI - Low diffusing capacity, emphysema, or pulmonary fibrosis: who is truly pulling the lung cancer strings? PMID- 29607120 TI - Understanding the possibility of image-guided thermal ablation for pulmonary malignancies. PMID- 29607121 TI - Editorial on "Long-term survival outcome after postoperative recurrence of non small cell lung cancer: who is 'cured' from postoperative recurrence?" PMID- 29607122 TI - Who benefit most from catheter ablation of persistent atrial fibrillation? PMID- 29607123 TI - Anti-angiogenic therapy in nonsquamous non-small cell lung cancer (NSCLC) with tyrosine kinase inhibition (TKI) that targets the VEGF receptor (VEGFR): perspective on phase III clinical trials. PMID- 29607124 TI - Consolidative ablative radiotherapy improves outcomes in oligometastatic non small cell lung cancer: a further step toward new evidence. PMID- 29607125 TI - Novel treatments for in-stent restenosis: sirolimus-eluting balloons enter the arena. PMID- 29607126 TI - Disappointing results: a call to action. PMID- 29607127 TI - Is the Sirolimus encapsulated balloon a reliable tool for treating the in-stent restenosis?-insights from the SABRE trial. PMID- 29607128 TI - Malignant pleural mesothelioma-the impact of globalization on rare diseases. PMID- 29607129 TI - Pulmonary metastectomy: impact of tumor histology and size. PMID- 29607130 TI - Utility of stereotactic ablative radiotherapy/stereotactic body radiation therapy in the setting of oligometastatic non-small cell lung cancer. PMID- 29607131 TI - Airway pressure release ventilation (APRV): do good things come to those who can wait? PMID- 29607132 TI - Airway pressure release ventilation in patients with acute respiratory distress syndrome: not yet, we still need more data! PMID- 29607133 TI - Should ultrathin strut drug eluting stents be considered the new benchmark for novel coronary stents approval? The complex interplay between stent strut thickness, polymeric carriers and antiproliferative drugs. PMID- 29607134 TI - Staging in the era of international databases: documented improvements with remaining challenges. PMID- 29607135 TI - Ultrathin strut biodegradable-polymer sirolimus-eluting stents: being wary or going with the flow? PMID- 29607136 TI - Anti-inflammatory therapy with canakinumab for atherosclerotic disease: lessons from the CANTOS trial. PMID- 29607137 TI - Immune checkpoint blockade therapy for esophageal squamous cell carcinoma. PMID- 29607138 TI - Patients reported outcomes in thoracic surgery. PMID- 29607139 TI - Renal denervation therapy beyond resistant hypertension. PMID- 29607140 TI - Comparison of the different cardioplegic strategies in cardiac valves surgery: who wins the "arm-wrestling"? PMID- 29607141 TI - A Spanish thoracic surgeon visits China-reflections on the surgical treatment of lung cancer. PMID- 29607143 TI - Early and mid-term follow-up of patients receiving arterial switch operation: a single-center experience. AB - Background: The arterial switch operation (ASO) has become the preferred method for surgical correction of transposition of the great arteries (TGA) and Taussig Bing anomaly. This study was aimed to analysis the early and mid-term results of patients receiving ASO for TGA and Taussig-Bing anomaly in our institute. Methods: A single-institution retrospective study was conducted to assess cardiovascular outcomes after ASO between January 2007 and December 2013. A total of 119 consecutive patients were included in this study. The median age at operation was 30 days (range, 1 day-8 years), the median weight was 3.8 kg (range, 2.0-23.0 kg). The ventricular septum was intact in 59 (49.6%) patients, 43 (36.1%) had ventricular septal defect, and 17 (14.3%) had a Taussig-Bing anomaly. We followed up patients with echocardiography. Special attention had been paid to the neo-aortic regurgitation and pulmonary stenosis. Results: In hospital deaths occurred in 10 (8.4%) patients. The most cause of death was low cardiac output due to deconditioning of the left ventricle and myocardial infarction. Echocardiographic data after ASO were collected in 93 (85.3%) patients at a mean duration of 60.7+/-20.2 months. Among them, 4 (4.3%) patients had moderate to severe neo-aortic regurgitation, 1 (1.1%) patient had moderate tricuspid regurgitation, 4 (4.3%) patients had moderate pulmonary regurgitation; 1 (1.1%) patients had moderate pulmonary stenosis and no patients had severe stenosis. Only two patients required a surgical reintervention. Conclusions: The early mortality rate has decreased and the most cause of death was low cardiac output. The outcomes of the ASO using our reconstruction and reimplantation techniques were excellent and the reoperation rate was very low in the early and mid-term follow-up. PMID- 29607142 TI - Value of combining serum carcinoembryonic antigen and PET/CT in predicting EGFR mutation in non-small cell lung cancer. AB - Background: We sought to investigate the associations between pretreatment serum Carcinoembryonic antigen (CEA) level, 18F-Fluoro-2-deoxyglucose (18F-FDG) uptake value of primary tumor and epidermal growth factor receptor (EGFR) mutation status in non-small cell lung cancer (NSCLC). Methods: We retrospectively reviewed medical records of 210 NSCLC patients who underwent EGFR mutation test and 18F-FDG positron emission tomography/computed tomography (PET/CT) scan before anti-tumor therapy. The associations between EGFR mutations and patients' characteristics, serum CEA, PET/CT imaging characteristics maximal standard uptake value (SUVmax) of the primary tumor were analyzed. Receiver-operating characteristic (ROC) curve was used to assess the predictive value of these factors. Results: EGFR mutations were found in 70 patients (33.3%). EGFR mutations were more common in high CEA group (CEA >=7.0 ng/mL) than in low CEA group (CEA <7.0 ng/mL) (40.4% vs. 27.6%; P=0.05). Females (P<0.001), non-smokers (P<0.001), patients with adenocarcinoma (P<0.001) and SUVmax <9.0 (P=0.001) were more likely to be EGFR mutation-positive. Multivariate analysis revealed that gender, tumor histology, pretreatment serum CEA level, and SUVmax were the most significant predictors for EGFR mutations. The ROC curve revealed that combining these four factors yielded a higher calculated AUC (0.80). Conclusions: Gender, histology, pretreatment serum CEA level and SUVmax are significant predictors for EGFR mutations in NSCLC. Combining these factors in predicting EGFR mutations has a moderate diagnostic accuracy, and is helpful in guiding anti-tumor treatment. PMID- 29607144 TI - Serum osteopontin in patients with lung cancer and chronic obstructive pulmonary disease: does the co-existence make the difference? AB - Background: Osteopontin (OPN) is involved in cancer development and metastasis. Increased sputum OPN was detected in chronic obstructive pulmonary disease (COPD). Methods: We evaluated serum OPN levels in patients with lung cancer (LC) and/or COPD and aimed to determine OPN prognostic performance in 1-year mortality in LC and also its diagnostic performance in LC among COPD patients. We recruited 167 LC patients, 85 with concomitant COPD. 28 COPD patients served as control group. Results: OPN levels were higher in LC compared to COPD alone (P=0.017) and higher in COPD and LC compared to COPD alone (P=0.031). No difference was observed in OPN levels between LC and COPD vs. LC without COPD (P=0.171). Serum OPN >=50.3 ng/mL was an independent predictor of 1-year mortality in LC. Conclusions: OPN levels >=35 ng/mL could predict the presence of LC among COPD patients. In patients with LC and/or COPD, LC is the major determinant for serum OPN. Serum OPN might be a promising prognostic biomarker of LC and a diagnostic biomarker of LC among COPD patients. PMID- 29607145 TI - Anatomic and surgical factors affecting the switch from minimally invasive transthoracic occlusion to open surgery during ventricular septal defect repair. AB - Background: This study aimed to investigate the specific causes for switching patients from minimally invasive transthoracic occlusion to surgical repair under cardiopulmonary bypass (CPB). By retrospectively analyzing 340 cases, we sought to provide the clinical reference for improving the success rate of minimally invasive transthoracic device closure of ventricular septal defect (VSD). Methods: Among the 340 patients who underwent transthoracic closure of VSDs in the past 3 years at our hospital, 26 patients needed to be switched to surgical repair under CPB due to failure of transthoracic closure. We investigated the causes by retrospectively analyzing the findings from preoperative transthoracic echocardiography (TTE), intraoperative transesophageal echocardiography (TEE) and surgical exploration. Results: Among the 340 patients who underwent transthoracic closure of VSDs, 26 patients (7.65%) were switched to surgical repair under CPB, which included 11 cases of membranous aneurysm (13.10%), 13 cases of perimembranous type (6.22%) and 2 cases of intracristal type (5.00%) according to their anatomic classifications. Among the 186 patients who underwent transthoracic closure during the first 17 months, 20 patients (10.75%) were switched to surgical repair under CPB. The main causes were failure of the delivery system to pass through the VSD in 7 patients, obvious residual shunts after releasing the occluder in 5 patients, significant shedding or shifting after releasing the occluder in 4 patients, significant regurgitation in adjacent valves in 3 patients and severe intraoperative complication (bleeding) in 1 patient. Among the 154 patients who underwent transthoracic closure during the late 17 months, 6 patients (3.90%) were switched to surgical repair under cardiopulmonary bypass. The main causes were significant residual shunts after releasing the occluder in 3 patients, significant regurgitation in adjacent valves in 2 patients after releasing the occluder and failure of the delivery system to pass through the VSD in 1 patient. Conclusions: Among all the anatomic classifications, membranous aneurysm VSD had the highest risk for switching from minimally invasive transthoracic closure to surgical repair under CPB. During the early period, the surgeons were not yet skilled with the minimally invasive transthoracic closure procedure, and the main causes of switching to surgical repair under CPB were that the delivery system could not pass through the ventricular septal defect and significant residual shunts persisted after releasing the occluder. In contrast, in the late period, the surgeons were skilled with the minimally invasive transthoracic closure procedure, and the main causes were significant residual shunts and obvious regurgitation in adjacent valves after releasing the occluder. PMID- 29607146 TI - Erythromycin poudrage versus erythromycin slurry in the treatment of refractory spontaneous pneumothorax. AB - Background: Refractory (recurrent or persistent) spontaneous pneumothorax with high recurrence rates required treatment either by continuous chest drainage or interventional approaches. Pleurodesis by sclerosing agents has become a significant therapy in the treatment of refractory spontaneous pneumothorax (RSP) on account of its high efficiency and safety. However, the efficacy, safety and appropriate mode of administration of intrapleural erythromycin for pleurodesis have not yet been realized in the treatment of RSP. Methods: The trial was performed to compare thoracoscopic erythromycin poudrage with erythromycin slurry via a chest tube for patients with documented RSP. Fifty-seven patients with RSP were enrolled in this study with 30 patients for erythromycin poudrage and 27 patients for erythromycin slurry. Response to pleurodesis, complications and recurrences were recorded. Continuous variables were compared with t-test. Chi square test was performed to compare categorical variables and Fisher's exact test was used for small samples. Results: Twenty-four patients in the erythromycin poudrage group (80%) and sixteen in the erythromycin slurry (ES) group (59.26%) had an immediately successful pleurodesis within 5 days (P=0.087). Patients in erythromycin poudrage had shorter duration of postprocedural chest tube drainage (6.23+/-3.04 days) than patients in ES (10.67+/-9.81 days) (P=0.032). During the follow-up, there was no significant statistical difference in recurrence rates between the two groups. Common adverse reactions included fever and chest pain with no significant difference between the two groups. Conclusions: Erythromycin is an effective and safe sclerosing agent for pleurodesis in management of RSP. Both methods are safe but erythromycin poudrage is more effective than ES. PMID- 29607147 TI - Factors associated with generic health-related quality of life (HRQOL) in patients with chronic obstructive pulmonary disease (COPD): a cross-sectional study. AB - Background: Health-related quality of life (HRQOL) is impaired in chronic obstructive pulmonary disease (COPD) patients, but determining factors for HRQOL are still not unequivocal. This study measures HRQOL among patients with COPD and aims to determine factors associated with HRQOL. Methods: Data for cross sectional analyses were obtained from the baseline of a cohort study. The study population includes adult COPD patients (disease duration >=3 months), recruited from primary and secondary care settings in Germany, without acute psychiatric/neurologic disease (exception: affective/ anxiety disorders). HRQOL was assessed using the Short-Form 12 (SF-12) Health Survey Questionnaire, comprising a physical and mental component. Independent variables encompass socio demographic, disease-specific, treatment-related and psychological factors. Multivariable linear regression analyses were conducted. Results: In total, 206 COPD patients (60.7% male; mean age: 65.3 years) took part in the study. In multivariable analysis, the physical component score showed a significant negative association with the COPD Assessment Test (CAT) (P<0.001) and a higher total number of prescribed medications (P=0.001). A higher forced expiratory volume in 1 second (FEV1) value in percent predicted was significantly related to the physical component score in a positive manner (P=0.006). The mental component score was significantly associated with elevated patient-reported symptoms of anxiety (P=0.002) or depression (P<0.001), measured by the hospital anxiety and depression scale (HADS) in a negative way. Like for the physical component score (P<0.001), a worse CAT score was significantly associated with a lower mental component score (P=0.033). Conclusions: Focusing on patient reported outcomes and screening for depression and anxiety with potential successive treatment might be promising approaches to improve HRQOL in patients with COPD. PMID- 29607148 TI - Ventilator-associated events after cardiac surgery: evidence from 1,709 patients. AB - Background: Ventilator-associated event (VAE) is a new surveillance for nosocomial infections in mechanically ventilated patients. To date, little is known about VAEs after cardiac surgeries. The present study firstly focused on patients who have undergone heart operations, intending to draw a comprehensive description of VAEs. Methods: Postoperative patients from September 2012 to December 2015 were monitored for VAEs. By reviewing electronic medical records and preserved files retrospectively, clinical data were further analyzed. Results: A total of 1,709 adult patients were enrolled, of which 166 episodes met the criteria for VAE. The mean incidence rate reached up to 9.7% and 49.9 per 1,000 mechanical ventilation days. By using both univariate analysis and multiple logistic regression analysis, chronic obstructive pulmonary disease (COPD), left ventricle ejection fraction (LVEF) <30%, cardiopulmonary bypass time, aortic clamping time, mechanical ventilation time, reintubation, dosage of blood products and acute kidney injury (AKI) were found to be risk factors for VAEs. Compared with non-VAE group, VAEs were closely related to higher mortality, longer intensive care unit stay time and hospitalization time. In addition, 91 strains of pathogens were isolated from endotracheal aspirates of 81 patients with VAE, of which Pseudomonas aeruginosa was the most common pathogenic microorganism (30 isolates, 37.0%), followed by Acinetobacter baumannii (27 isolates, 33.3%) and other five types. Conclusions: VAE algorithm is a valid and reliable surveillance for possible infections caused by mechanical ventilation, which could easily occur in patients after cardiac surgery and is associated with poor prognosis. The risks and pathogens that we have investigated will provide potential preventive strategies. PMID- 29607149 TI - Thoracoscopic primary repair with mediastinal drainage is a viable option for patients with Boerhaave's syndrome. AB - Background: Spontaneous esophageal rupture (Boerhaave's syndrome) is an emergency that can cause life-threatening conditions. Various procedures have been used to treat Boerhaave's syndrome. However, a standard surgical procedure has not been established. Herein, we report our experience with primary suture of the ruptured esophagus via a thoracoscopy or laparotomy. Methods: Between November 2002 and May 2015, 11 patients with Boerhaave's syndrome presented to our department and were managed using one of two surgical procedures based on the surgeon's discretion. Six patients underwent a thoracoscopic primary suture and drainage (group A); 5 patients underwent a primary suture via laparotomy followed by thoracoscopic drainage (group B). Patient medical records were retrospectively reviewed. Results: The mean interval between initial perforation and surgery was 13.7 h (group A) and 17.2 h (group B) (P=0.7307). The mean operative time was 190 min (group A) and 249 min (group B) (P=0.106). Patient baseline characteristics and surgical outcomes were similar for both surgical procedures. One patient in each group experienced postoperative leakage that did not require surgical intervention. Conclusions: The results suggest that thoracoscopic esophageal repair, as well as suturing via laparotomy, is a good surgical alternative for patients with Boerhaave's syndrome. PMID- 29607150 TI - Robotic surgery, video-assisted thoracic surgery, and open surgery for early stage lung cancer: comparison of costs and outcomes at a single institute. AB - Background: Robotic surgery is increasingly used to resect lung cancer. However costs are high. We compared costs and outcomes for robotic surgery, video assisted thoracic surgery (VATS), and open surgery, to treat non-small cell lung cancer (NSCLC). Methods: We retrospectively assessed 103 consecutive patients given lobectomy or segmentectomy for clinical stage I or II NSCLC. Three surgeons could choose VATS or open, the fourth could choose between all three techniques. Between-group differences were assessed by Fisher's exact, two-way analysis of variance (ANOVA), and Wilcoxon-Mann-Whitney test. P values <0.05 were considered significant. Results: Twenty-three patients were treated by robot, 41 by VATS, and 39 by open surgery. Age, physical status, pulmonary function, comorbidities, stage, and perioperative complications did not differ between the groups. Pathological tumor size was greater in the open than VATS and robotic groups (P=0.025). Duration of surgery was 150, 191 and 116 minutes, by robotic, VATS and open approaches, respectively (P<0.001). Significantly more lymph node stations were removed (P<0.001), and median length of stay was shorter (4, 5 and 6 days, respectively; P<0.001) in the robotic than VATS and open groups. Estimated costs were 82%, 68% and 69%, respectively, of the regional health service reimbursement for robotic, VATS and open approaches. Discussion: Robotic surgery for early lung cancer was associated with shorter stay and more extensive lymph node dissection than VATS and open surgery. Duration of surgery was shorter for robotic than VATS. Although the cost of robotic thoracic surgery is high, the hospital makes a profit. PMID- 29607151 TI - Lung cancer in connective tissue disease-associated interstitial lung disease: clinical features and impact on outcomes. AB - Backgrounds: Lung cancer (LC) adversely impacts survival in patients with idiopathic pulmonary fibrosis. However, little is known about LC in patients with connective tissue disease-associated interstitial lung disease (CTD-ILD). The aim of this study was to evaluate the prevalence of and risk factors for LC in CTD ILD, and the clinical characteristics and survival of CTD-ILD patients with LC. Methods: We conducted a single-center, retrospective review of patients with CTD ILD from 2003 to 2016. Patients with pathologically diagnosed LC were identified. The prevalence, risk factors, and clinical features of LC and the impact of LC on CTD-ILD patient outcomes were observed. Results: Of 266 patients with CTD-ILD, 24 (9.0%) had LC. CTD-ILD with LC was more likely in patients who were older, male, and smokers; had rheumatoid arthritis, a usual interstitial pneumonia pattern, emphysema on chest computed tomography scan, and lower diffusing capacity of the lung carbon monoxide (DLco)% predicted; and were not receiving immunosuppressive therapy. Multivariate analysis indicated that the presence of emphysema [odds ratio (OR), 8.473; 95% confidence interval (CI), 2.241-32.033] and nonuse of immunosuppressive therapy (OR, 8.111; 95% CI, 2.457-26.775) were independent risk factors for LC. CTD-ILD patients with LC had significantly worse survival than patients without LC (10-year survival rate: 28.5% vs. 81.8%, P<0.001). Conclusions: LC is associated with the presence of emphysema and nonuse of immunosuppressive therapy, and contributes to increased mortality in patients with CTD-ILD. PMID- 29607152 TI - Wet M1a non-small cell lung cancer: is it possible to predict recurrence of pleural effusion? AB - Background: The propose was to recognize risk factors of malignant pleural effusion (MPE) recurrence in patients with symptomatic M1a non-small cell lung cancer (NSCLC). Methods: All patients with NSCLC and MPE submitted to pleural palliative procedures were enrolled in a prospective study. Group I contained patients who had pleural recurrence, and Group II with no pleural recurrence. Prognostic factors for pleural recurrence were identified by univariable analysis, using Fisher's exact test for categorical variables and Student's t test for quantitative variables. Afterwards the significant variables were entered into a multivariable logistic regression analysis (with P<0.05 considered significant). Receiver operating characteristics (ROC) analysis determined the cutoff points for continuous variables. Results: A total of 82 patients were included in the analysis. There were 15 patients (18.3%) in Group I and 67 patients (81.7%) in Group II. Univariable analysis regarding factors affecting postoperative recurrence was: adenosine deaminase concentration in pleural fluid <16 mg/dL (P=0.04), albumin concentration in pleural fluid <2.4 mg/dL (P=0.03), administration of second-line palliative chemotherapy (P=0.018) and type of procedure [therapeutic pleural aspiration (TPA)] (P=0.023). At the multivariable analysis, only the type of procedure (TPA) (P=0.031) was identified as independent predictor of recurrence. Conclusions: The identification of this factor may assist the choice of the optimal palliative technique; at the first episode of MPE in NSCLC patients and definitive procedure as pleurodesis or indwelling pleural catheter are recommended. PMID- 29607153 TI - Assessment of programmed cell death ligand-1 expression with multiple immunohistochemistry antibody clones in non-small cell lung cancer. AB - Background: Programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD L1) have been identified as novel targets for immunotherapy, with PD-L1 as a potential predictive biomarker. However, a specific antibody for PD-L1 expression is an immediate requirement. Meanwhile, the clinicopathological identification of patients with positive PD-L1 remains unclear. Methods: The present study adopted three anti-PD-L1 IHC antibodies, SP142, SP263, and UMAB228 to test PD-L1 expression in 84 non-small cell lung cancer (NSCLC) specimens. The concordance among antibodies was examined by analytical comparison, and the association between PD-L1 expression and clinicopathological factors was assessed. Results: The samples from 41 (48.8%), 51 (60.7%), and 50 (59.5%) patients were detected as PD-L1 positive evaluated by antibody SP142, SP263, and UMAB228, respectively. The kappa coefficient was 0.53, 0.58, and 0.46 for SP263 vs. SP142, SP263 vs. UMAB228, and SP142 vs. UMAB228, respectively. On the other hand, the univariate analysis of consensus cases indicated that the PD-L1 expression was significantly correlated with tobacco use (chi2=4.25, P=0.04). Conclusions: The analytical comparison showed moderate concordance between SP142, SP263 and UMAB228, whereas SP263 exhibited higher overall positive rate. Moreover, PD-L1 positive rate was significantly higher in patients with smoking history, which might help in identifying patients who would benefit from PD-1/PD-L1 checkpoint inhibitors. PMID- 29607154 TI - Decreased expression of hepatic cytochrome P450 1A2 (CYP1A2) in a chronic intermittent hypoxia mouse model. AB - Background: Hepatic cytochrome P450 (CYP) isoforms, CYP1A2, is one of important enzymes for many drugs metabolism. Studies have confirmed that sustained hypoxia can influence the expression of hepatic CYP, including CYP1A2. The impact of chronic intermittent hypoxia (CIH), a marked characteristic of sleep apnea, on CYP1A2 remains unclear. The aim of the present study was to evaluate the effect of CIH on the expression of hepatic CYP1A2 in a mouse model with sleep apnea. Methods: Twenty four old male (6-8 weeks) C57BL/6J mice (n=12 in each group) were randomly assigned to either normoxia group or CIH group. Mice in CIH group underwent 12 weeks intermittent hypoxia exposure. The different gene expression of hepatic CYP1A2 between two groups was analyzed by quantity real-time polymerase chain reaction. The protein levels of hepatic CYP1A2 in each group were observed by using western blotting and immunohistochemistry. Results: After 12 weeks of exposure to intermittent hypoxia, the expression of hepatic CYP1A2, at the mRNA and protein levels was decreased more significantly in the CIH group than the normoxia group (P<0.01). Conclusions: CIH contributes to inhibiting the expression of hepatic CYP1A2. This implies that the dosage of drugs metabolized by CYP1A2, should be adjusted in patients with sleep apnea. PMID- 29607155 TI - Quality of life and influencing factors of coal miners in Xuzhou, China. AB - Background: Coal industry is one of the national pillar industries in China. A large number of coal miners are exposed to various occupational hazards, which might cause occupational disease. The aim of the study was to assess the quality of life (QOL) of coal miners in Xuzhou, China and explore influencing factors to QOL of coal miners. Methods: Six hundred and twelve underground miners and 354 ground workers in one of coal mines of Xuzhou were enrolled in our study. The 36 item Short-Form Health Survey (SF-36) questionnaires were applied to evaluate the QOL of coal miners. Multivariate stepwise regression analysis was used to assess the potential impact factors on QOL. Results: The score of role limitations due to physical health problems (RP) dimension in underground miners was significantly lower than that of ground workers (P=0.005). Multivariate stepwise regression analysis showed that longer job tenure for dust exposure significantly lower coal miners' RP score. Comparing with normal populations, our subjects scored lower in both the physical health components (PHC) and the mental health components (MHC), and many factors accounted for it including job tenure for dust exposure, chronic disease, medical insurance, etc. Conclusions: QOL of coal miners has been affected. Some measures might be taken by enterprise and coal miners themselves to protect the health of coal miners and improve their quality of life. PMID- 29607156 TI - Clinical outcome comparison of patients with septic shock defined by the new sepsis-3 criteria and by previous criteria. AB - Background: We compared the clinical characteristics and outcomes between the new definition of sepsis-3 septic shock and the definition previously used from 1991 until recently. Methods: We conducted an observational study using a prospective, multi-center registry of septic shock from October 2015 to February 2017. Registry data were collected by 10 emergency departments (EDs) in tertiary hospitals that are members of the Korean Shock Society. Data on septic shock patients who met the previous septic shock definition were collected. The patients were divided into a sepsis-3 defined septic shock group, made up of those who met the new criteria for refractory hypotension with hyperlactatemia, and a group of those who met only the 1991 definition for septic shock. The primary outcome was 90-day mortality, and secondary outcomes were 28-day mortality and in-hospital mortality. Results: Of all 1,028 included patients, 574 (55.8%) met the septic shock criteria for sepsis-3, leaving 454 patients who met only the previous definition. Those who met the sepsis-3 criteria demonstrated higher comorbidity than those who met the previous definition (83.1% vs. 75.3%, P<0.01), but there was no difference in infection focus. The sequential organ failure assessment (SOFA) (initial/maximal), the acute physiology, and the chronic health evaluation II scores were significantly higher in for those who met the sepsis-3 criteria [6.5+/-3.1 vs. 5.0+/-2.9, 9.3+/-3.8 vs. 6.6+/-3.4, and 20.0 (15.0-26.0) vs. 15.0 (10.0-20.3), respectively; P<0.01]. The 90-day mortality was significantly higher in the sepsis-3 group (32.1% vs. 23.3%; P<0.01). In-hospital and 28-day mortality were also higher in the sepsis-3 group (26.8% vs. 17.1% and 25.1% vs. 16.5%, respectively; P<0.01). Conclusions: The new definition of septic shock successfully selected patients with greater severities and worse outcomes. PMID- 29607157 TI - Diagnostic accuracy of interferon-gamma in pericardial effusions for tuberculous pericarditis: a meta-analysis. AB - Background: Several studies have investigated the diagnostic accuracy of tests of pericardial effusion interferon-gamma for tuberculous pericarditis in patients with pericardial effusion, but the results have varied. The aim of this study was to investigate the diagnostic accuracy of interferon-gamma for tuberculous pericarditis using meta-analysis. Methods: The PubMed and EMBASE databases were searched to identify studies investigating the diagnostic accuracy of tests for interferon-gamma in pericardial effusion for tuberculous pericarditis. The quality of eligible studies was assessed by the revised Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2), and the sensitivities and specificities of interferon-gamma across eligible studies were pooled by a bivariate model. Results: A total of four studies encompassing 488 subjects were included. The pooled sensitivity, specificity, positive and negative likelihood ratios (NLRs) were 0.97 [95% confidence interval (CI): 0.87-0.99], 0.99 (95% CI: 0.74-1.00), 187 (95% CI: 3-12,542) and 0.03 (95% CI: 0.01-0.14), respectively. Conclusion: Testing for interferon-gamma in cases of pericardial effusion is adequate for identifying or ruling out tuberculous pericarditis. PMID- 29607158 TI - Thoracoscopic wedge resection in single-lung patients. AB - Background: The thoracoscopic approach has become a standard procedure in the field of lung resections. However, its advantage in single-lung patients has not yet been well studied. We describe a series of successful thoracoscopic wedge resections in patients presenting with lung cancer after contralateral pneumonectomy. Methods: Eight patients, with a previous pneumonectomy (5 right and 3 left) for lung cancer, underwent resection for a suspicious neoplasm on the remaining lung. All lesions were detected in the asymptomatic phase during regular follow-up after pneumonectomy based on repeated computer tomography (CT). Only single peripheral lesions less than 2 cm were eligible for wedge resection were eligible for surgery. Video-assisted thoracoscopic, margin-free tumor wedge resections, were performed during apnea windows with the lung in a deflated position. Results: All patients were treated by a wedge resections smaller than a single segment. Only one patient needed a mini-thoracotomy conversion to accomplish a safe margin-free resection. Median total surgical operative time was 37 minutes. There were no postoperative deaths, while morbidity was 12.5%. Conclusions: Thoracoscopic surgery represents a feasible surgical option in selected patients after contralateral pneumonectomy, with careful preoperative assessment and using short apnea windows in good collaboration with anesthesiologists. Histological definition, made possible by the surgical procedure, gives patients the possibility to eventually undergo further targeted therapies. Randomized prospective trials are necessary to assess the best management of peripheral small lung nodules in single-lung patients, in particular to define which patients can benefit from a surgical approach. PMID- 29607159 TI - Application of 3D printing in the surgical planning of hypertrophic obstructive cardiomyopathy and physician-patient communication: a preliminary study. AB - Background: The aim of this study was to evaluate the effect of 3-dimensional (3D) printing in treatment of hypertrophic obstructive cardiomyopathy (HOCM) and its roles in doctor-patient communication. Methods: 3D-printed models were constructed preoperatively and postoperatively in seven HOCM patients received surgical treatment. Based on multi-slice computed tomography (CT) images, regions of disorder were segmented using the Mimics 19.0 software (Materialise, Leuven, Belgium). After generating an STL-file (StereoLithography file) with patients' data, the 3D printer (Objet350 Connex3, Stratasys Ltd., USA) created a 3D model. The pre- and post-operative 3D-printed models were used to make the surgical plan preoperatively and evaluate the outcome postoperatively. Meanwhile, a questionnaire was designed for patients and their relatives to learn the effectiveness of the 3D-printed prototypes in the preoperative conversations. Results: The heart anatomies were accurately printed with 3D technology. The 3D printed prototypes were useful for preoperative evaluation, surgical planning, and practice. Preoperative and postoperative echocardiographic evaluation showed left ventricular outflow tract (LVOT) obstruction was adequately relieved (82.71+/-31.63 to 14.91+/-6.89 mmHg, P<0.001), the septal thickness was reduced from 21.57+/-4.65 to 17.42+/-5.88 mm (P<0.001), and the SAM disappeared completely after the operation. Patients highly appreciated the role of 3D model in preoperative conversations and the communication score was 9.11+/-0.38 points. Conclusions: A 3D-printed model is a useful tool in individualized planning for myectomies and represent a useful tool for physician-patient communication. PMID- 29607160 TI - Prognostic significance of CT-determined emphysema in patients with small cell lung cancer. AB - Background: Although emphysema and small cell lung cancer (SCLC) are prevalent in smokers, no previous study has investigated the prognostic impact of computed tomography (CT)-determined emphysema in SCLC. This study was undertaken to analyze the prognostic value of emphysema scores as determined by baseline CT scans in patients with SCLC. Methods: The data of 149 consecutive patients with SCLC were analyzed. Emphysema severity was semi-quantitatively scored on baseline chest CT images using the Goddard scoring system (possible scores for individual patients ranged from 0 to 24). Data on clinical characteristics and survival were retrospectively collected. Survivals were estimated using the Kaplan-Meier method and compared using the log-rank test. A multivariable Cox proportional hazard model was used to identify prognostic factors. Results: Most of the 149 patients were male (85.2%) and current/ex-smokers (87.2%). The median CT emphysema score was 4 (range, 0 to 23). Univariable analysis, patients with a higher CT emphysema score (>=8) had significantly poorer overall survivals (OS) than those with lower scores (5.0 vs. 12.3 months, P<0.001). Multivariable analysis showed a higher CT emphysema score (treated as a continuous variable) was a significant independent prognostic factor of poor survival [hazard ratio (HR), 1.85; 95% confidence interval (CI), 1.14 to 3.00; P=0.012], along with extensive stage (HR, 2.27; 95% CI, 1.45-3.53; P<0.001), elevated lactate dehydrogenase (LDH) (HR, 1.52; 95% CI, 1.03-2.23; P=0.034), and supportive care only (HR, 6.46; 95% CI, 3.64-11.48; P<0.001). Conclusions: Emphysema severity, as determined by baseline CT, is significantly associated with poor prognosis in SCLC. PMID- 29607161 TI - Effectiveness of high-flow nasal cannula oxygen therapy for acute respiratory failure with hypercapnia. AB - Background: Heated and humidified high-flow nasal cannula (HFNC) oxygen therapy has recently been introduced for hypoxic respiratory failure. However, it has not been well-evaluated for acute respiratory failure with hypercapnia. Methods: This retrospective study included acute respiratory failure patients with hypercapnia in the medical intensive care unit (MICU) from April 2011 to February 2013, who required HFNC oxygen therapy for hypoxemia. Respiratory parameters were recorded and arterial blood gas analyses conducted before, and at 1 and 24 h after initiation of HFNC oxygen therapy. Results: Thirty-three patients were studied [median age, 72 years; range, 17-85 years; men, 24 (72.7%)]. Pneumonia (36.4%) and acute exacerbation of chronic obstructive pulmonary disease (33.4%) were the most common reasons for oxygen therapy. Most patients (60.6%) received oxygen therapy via nasal prong before HFNC application. The mean fraction of inspired oxygen (FiO2) and HFNC flow rate were 0.45+/-0.2 and 41.1+/-7.1 L/min, respectively; mean duration of application was 3.6+/-4.1 days. The partial pressure of arterial carbon dioxide (PaCO2) was 55.0+/-12.2 mmHg at admission, and increased by approximately 1.0+/-7.7 mmHg with conventional oxygen therapy. In contrast, with HFNC therapy, PaCO2 decreased by 4.2+/-5.5 and 3.7+/-10.8 mmHg in 1 and 24 h, respectively, resulting in significant improvement in hypercapnia (P=0.006 and 0.062, respectively). Conclusions: HFNC oxygen therapy with sufficient FiO2 to maintain a normal partial pressure of arterial oxygen (PaO2) significantly reduced PaCO2 in acute respiratory failure with hypercapnia. PMID- 29607162 TI - Early and mid-term haemodynamic performance and clinical outcomes of St. Jude Medical TrifectaTM valve. AB - Background: New models of aortic bioprostheses have proven excellent early haemodynamic profile, but their mid and long-term performance warrants further systematic assessment. The aim of this study is to report clinical and haemodynamic performance of St. Jude Medical Trifecta bioprosthesis during 5 years of implantation. Methods: We performed a single centre, retrospective, observational and descriptive study including all 556 individuals who underwent aortic valve replacement (AVR) with the Trifecta bioprosthesis (between July of 2011 and June of 2016). Survival and re-intervention were censored in February 2017. Postoperative ambulatory echocardiographic data was available for 490 patients. A complete clinical follow-up was available in 463 individuals (mean follow-up time, 27+/-17 months). Results: In our sample the mean age was 73+/-9 years, 57.6% were male and median European System for Cardiac Operative Risk Evaluation (EuroSCORE) II was 2.9 (interquartile range, 1.6-5.8). There were 301 (54.1%) combined procedures, mostly coronary artery bypass grafting in 170 (30.6%). Overall 30-days mortality was 5.4% (n=30) and cumulative survival at 5 years was 72.3%. There were 23 (4.3%) permanent pacemaker implantations. During follow-up, 5 (0.9%) patients presented non-structural valve dysfunction (NSVD) and 4 (0.8%) underwent reoperation due to prosthesis endocarditis. At the first ambulatory evaluation transvalvular mean gradient and effective orifice area (EOA) were 10.9+/-4.1 mmHg and 2.0+/-0.5 cm2, respectively. Severe patient prosthesis mismatch (PPM) was observed in 5 (1.1%) individuals and moderate in 52 (11.3%). Conclusions: In a "real-world" clinical setting, our findings support the good overall mid-term haemodynamic and safety profile of the Trifecta bioprosthesis. PMID- 29607163 TI - Clinico-radiological features and efficacy of anti-fibrotic agents in atypical idiopathic pulmonary fibrosis. AB - Background: Atypical idiopathic pulmonary fibrosis (IPF) including multiple cysts or markedly atelectatic induration in upper lung predominance occasionally can confirm the diagnosis of IPF through a multidisciplinary discussion (MDD) between clinician, radiologist and, pathologist in clinical practice. The aim of this study was to clarify the differences in clinico-radiological characteristics and the efficacy of anti-fibrotic agents between atypical IPF and typical IPF. Methods: We retrospectively evaluated the differences in clinico-radiological characteristics between patients with atypical IPF (n=44) and those with typical IPF (n=87) and examined efficacy of anti-fibrotic agents in atypical IPF. Atypical IPF was characterized by the presence of markedly atelectatic induration in upper lung predominance (pleuroparenchymal fibroelastosis; PPFE like lesion) with and without multiple thick-walled large cysts (TWLC), so-called macrocystic honeycombing (TWLC; >2.5 cm in diameter with 1-3 mm thickness) in addition to honeycombing in the bilateral lower lobes predominance. Results: There was no difference in the baseline disease severity for IPF between both groups. The annual change value of fibrotic score and traction bronchiectasis (TBE) score, and decreased changes in forced vital capacity (FVC) during 6 months were significantly higher in atypical IPF than those in typical IPF. Survival time was significantly lower in patients with atypical IPF (MST: 33.4 vs. 47.9 months, P=0.03). The multivariate Cox regression model demonstrated that the prognostic predictors were presence of atypical IPF and increased Gender-Age-Physiology (GAP) staging. Moreover, the rate of decrease in FVC value 6 months after treatment with anti-fibrotic agents was significantly higher in atypical IPF than those in typical IPF (-11.8%+/-14.0% vs. -1.0%+/-12.7%; P=0.01). Conclusions: This study demonstrated that the prognosis for atypical IPF was significantly worse than that for typical IPF. Future studies are required prospective analyses of efficacy of anti-fibrotic agents for patients with atypical IPF. PMID- 29607164 TI - Effect of comorbidities on long-term outcomes after thoracoscopic surgery for stage I non-small cell lung cancer patients with chronic obstructive pulmonary disease. AB - Background: We assessed how the severity of chronic obstructive pulmonary disease (COPD) and other comorbidities affect long-term survival after thoracoscopic lung resection for c-stage I non-small cell lung cancer (NSCLC). Methods: Patients with c-stage I NSCLC who underwent thoracoscopic lung resection at our hospital between 2006 to 2014 were retrospectively analyzed. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) spirometric grades were used to classify the severity of COPD, and comorbidity was classified according to the Charlson comorbidity index (CCI). Various outcomes were assessed and compared. Results: The cohort comprised 404 patients with NSCLC, of whom 133 were diagnosed with COPD (51 as GOLD 1, 79 as GOLD 2, and 3 as GOLD 3) and 271 were diagnosed without COPD. The 5-year overall survival (OS) rates were 86.0%, 80.2%, and 71.1% for the non-COPD, GOLD 1, and GOLD 2/3 groups, respectively (P=0.0221); the corresponding 5-year disease-specific survival (DSS) rates were 91.7%, 86.9%, and 85.1% (P=0.2136). Univariate analysis indicated that sex, smoking status, pathology, COPD severity, CCI, and pathological stage were associated with OS, and multivariate analysis confirmed the association with CCI and pathological stage. Postoperative complications were significantly more frequent in the GOLD 1 (21.5%) and GOLD 2/3 (26.8%) groups than in the non-COPD group (12.1%) (P=0.0040). Conclusions: Following thoracoscopic surgery (TS) for NSCLC, patients with COPD had a poorer OS than patients without COPD. However, the CCI and not the COPD severity was the independent prognostic factor for OS. Comorbidities adversely affected long-term survival of patients with stage I NSCLC and COPD after TS, and the same effect can be oncologically expected regardless of the COPD severity. PMID- 29607165 TI - A quality improvement program with nutrition therapy: restriction of lipid emulsions in cardiac surgical patients. AB - Background: To evaluate the effect of restriction of soybean-based intravenous fat emulsions (IVFEs) in clinical outcomes in cardiac surgical patients. Methods: This was a before-and-after interventional study comparing the clinical outcomes regarding the intervention of IVFEs restriction. Before August 2015, parenteral nutrition (PN) using a soy-based lipid emulsion was routinely implemented if patients failed to meet >60% of energy requirements in 48 h post cardiac surgery (Period A). Beginning in August 2015, a lipid restriction strategy was implemented in our cardiac surgery intensive care unit (CSICU) unless enteral route could not be established within 7 days (Period B). The ICU and hospital mortality, nosocomial infections during ICU stay, length of ICU and hospital stay, ICU and hospital cost, mechanical ventilation time and postoperative complications were compared between two periods. Results: A total of 761 patients (370 patients in Period A and 391 patients in Period B) were ultimately enrolled in this study. There were no significant differences in demographic characteristics and intraoperative and postoperative parameters between the two groups. After the implementation of IVFEs restriction, the overall ICU mortality and hospital mortality were similar between two groups. Nosocomial infection rate was significantly reduced (3.84% vs. 7.84%, P=0.021). The mean length of ICU stay (3.15 vs. 3.74 days, P<0.001) and hospital stay (12.14 vs. 13.24 days, P<0.001) were significantly lower. The mean in-hospital cost (133,368 vs. 139,383 Yuan, P=0.037) was found to be reduced after implementation of IVFEs restriction. The duration of mechanical ventilation was shorter in the latter period (35.23+/ 10.43 vs. 47.63+/-12.54 hours, P=0.011). IVFEs restriction was also associated with reduced cholestasis (2.81% vs. 6.76%, P=0.013). Conclusions: The implementation of soybean-based IVFEs restriction in cardiac surgical patients was associated with reduced postoperative nosocomial infection rate. It also led to reductions in the length of ICU/hospital stay, hospital costs and mechanical ventilation time and a lower incidence of cholestasis. Further studies are required to validate the conclusions. PMID- 29607166 TI - Comparison of survival between lung cancer patients receiving single or multiple incision thoracoscopic surgery. AB - Background: The effect of single-incision thoracoscopic surgery for lung cancer on long-term survival is unknown and no studies have investigated whether there are differences in survival between single and multiple incision approaches. We aimed to compare long-term overall survival and disease-free survival of patients who underwent single-incision thoracoscopic surgery with those who received multiple-incision thoracoscopic surgery for lung cancer. Methods: We retrospectively analyzed 532 patients with lung cancer who underwent either single-incision (n=150) or multiple-incision thoracoscopic resection (n=382) during the period January 2000 to December 2014. Patients were matched on propensity score at a 1:2 ratio to estimate the effect of treatment on long-term and disease-free survival. Overall survival and disease-free survival were assessed using the Kaplan-Meier method, the log-rank test and Cox proportional hazards regression. Results: Propensity matching resulted in 138 patients in the single-incision group and 276 patients in the multiple-incision group. The matched patients in the single-incision group had a significantly better 5-year overall survival than those in the multiple-incision group (P=0.027). Disease free survival was similar between the two groups before and after matching. The number of chest wall incisions did not influence overall survival or disease-free survival. Conclusions: The long-term outcomes of single-incision thoracoscopic surgery are comparable to those of multiple-incision thoracoscopic surgery for lung cancer. PMID- 29607167 TI - Protective effects of PI3KCG gene on acute myocardial infarction. AB - Background: To study the protective effects of recombinant phosphatidylinositol 3 kinase p110 gamma (rPLV-PI3KCG) lentiviral vector in Sprague-Dawley (SD) rats with acute myocardial infarction (AMI). Method: The AMI rat models were established by ligaturing left anterior descending coronary artery. The rPLV PI3KCG or empty lentiviral vectors were injected at the edge of the infarct zone. The experiment was divided randomly into four groups (n=8): (I) Sham group; (II) AMI group; (III) AMI + empty vector injection group (AMI + E group); and (IV) AMI + PLV-PI3KCG injection group (AMI + PLV-PI3KCG group). The ultrasonic cardiogram (UCG) was used to compare the structural or functional changes among the four groups after operation for 10 days. Meanwhile, the rats were sacrificed and HE staining was used to compare the myocardial tissue changes among the four groups. The immunofluorescence and western blots were performed to compare the angiogenesis in the infarct region and explore the mechanism of the protective effects of PI3KCG gene on AMI rats. Results: Compared with AMI group and AMI + E group, in the AMI + PLV-PI3KCG group, left ventricular end diastolic diameter (LVEDd) was decreased, left ventricular ejection fraction (LVEF%) was significantly increased, and vascular endothelial growth factor (VEGF) expression was significantly increased in the infarct region (P<0.05); PI3KCG, pAkt/Akt, HIF 1a, and Bcl-2/Bax protein expressions were significantly increased (P<0.05). Conclusions: The rPLV-PI3KCG injection could improve the cardiac function, relieve the cardiac injury after the AMI operation. PI3KCG gene could play the protection role in the AMI process possibly by activating PI3K/Akt signal pathway, inhibiting apoptosis and promoting angiogenesis. PMID- 29607168 TI - The outcomes of anatomical lung resection for nontuberculous mycobacterial lung disease. AB - Background: The number of cases of nontuberculous mycobacterial (NTM) lung disease has been increasing in recent years, and the efficacy of surgical treatment has been recognized. We investigated the clinical characteristics and behavior of NTM lung disease and analyzed the outcomes of surgery. Methods: The data of 25 patients who underwent anatomical resection for NTM lung disease in our institution between January 2004 and December 2014 were retrospectively examined. Results: The patients included 10 men and 15 women (mean age, 63.1 years). Twenty patients had Mycobacterium avium, and 5 had Mycobacterium intracellular. The indications for lung resection in 20 definitively diagnosed patients included a remaining or worsening lesion despite medical treatment (n=16), massive hemoptysis or bloody sputum (n=5), and prolonged smear positivity (n=1); multiple reasons were allowed. In five cases without a definitive diagnosis, surgery was performed due to the suspicion of lung cancer. The surgical procedures included pneumonectomy, n=4; lobectomy, n=13; and segmentectomy, n=8. Complete resection was achieved in 10 cases (40.0%). Video assisted thoracoscopic surgery (VATS) was performed in 17 cases (68.0%), especially in 6 of 8 cases (75.0%) that underwent segmentectomy and in 10 of 11 cases (90.9%) that received simple lobectomy. There was one case of hospital mortality. Among the 22 patients who were followed at our institution, relapse occurred in 4 patients, and new infection occurred in 1 patient. NTM lung disease was controlled in 17 patients (77.3%). In the four cases that relapsed, the median relapse-free interval was 29.5 months. Conclusions: Surgical resection was a feasible treatment for NTM lung disease and was associated with favorable outcomes, although there was 1 case of hospital mortality. VATS procedures were considered adequate for the treatment of NTM lung disease; however, the surgical indications must be carefully considered. PMID- 29607169 TI - Neoadjuvant chemoradiotherapy followed by minimally invasive esophagectomy: is it a superior approach for locally advanced resectable esophageal squamous cell carcinoma? AB - Background: Few studies reported the outcomes of minimally invasive esophagectomy (MIE) in treating patients with esophageal squamous cell carcinoma (ESCC) after neoadjuvant chemoradiotherapy (nCRT). The aim of the study was to investigate the feasibility and efficacy of nCRT plus MIE (RM) strategy in treating locally advanced resectable ESCC. Methods: This retrospective study included 175 patients with ESCC undergoing surgical resection after neoadjuvant therapy in our institution from 2010 to 2016. Patients were stratified into three groups: RM, [neoadjuvant chemotherapy (nCT) plus MIE] (CM) and [nCT plus open esophagectomy (OE)] (CO). Results: Seventy-six (43.4%), 42 (24%) and 57 (32.6%) patients received RM, CM and CO approach, respectively. Compared with CO approach, RM or CM approach had shorter operation duration (188+/-39, 185+/-37 vs. 209+/-45 minutes, P=0.004, P=0.009) and less blood loss (124+/-88, 122+/-79 vs. 166+/-92 mL, P=0.001, P=0.003). There was a trend with lower risk of postoperative non surgical complications in RM and CM approach [odds ratio (OR) 0.45, 0.200-1.040; P=0.062; OR 0.41, 0.150-1.160; P=0.093]. There were no differences in 30- and 90 day mortality among all groups. RM approach was more likely to achieve pathological complete regression (27.6% vs. 4.8%, 1.8%, P=0.001, P=0.001) and fewer lymph node metastasis (25.0% vs. 57.1%, 61.4%, P=0.001, P=0.001) than CM or CO approach. Survival analysis revealed a potential trend towards improved overall survival in RM approach compared with CM or CO approach (P=0.098, P=0.166). Conclusions: RM approach was a safe and efficient strategy in treating locally advanced resectable ESCC. PMID- 29607170 TI - Prognostic factors for surgically resected non-small cell lung cancer with cavity formation. AB - Background: Small pulmonary nodules have been detected frequently by computed tomography (CT). Lung cancers with cavity formation are also easily detected. There are a few reports focused on the cavity wall, although cancer cells exist along the cavity wall, not inside. We evaluated the impact of cavity wall thickness on prognosis and assessed the clinicopathological features in non-small cell lung cancer (NSCLC) with cavity formation. Methods: Between 2005 and 2011, 1,313 patients underwent complete resection for NSCLC. Of these cases, we reviewed 65 patients (5.0%) diagnosed with NSCLC with cavity formation by chest CT. We classified the patients into three groups based on the maximum cavity wall thickness, namely, <=4 mm (Group 1, 8 patients), >4 and <=15 mm (Group 2, 33 patients), and >15 mm (Group 3, 24 patients). Results: The number of patients with pathological whole tumor size >3 cm was 2 (25%) in Group 1, 17 (52%) in Group 2, and 23 (96%) in Group 3 (P<0.001). Cases with lymph node metastasis were 0 (0%) in Group 1, 5 (15%) in Group 2, and 10 (42%) in Group 3 (P=0.016). The 5 year overall survival (OS) rates were 100% in Group 1, 84.0% in Group 2, and 52.0% in Group 3, with significant differences between Group 1 and Group 3 (P=0.044) and between Group 2 and Group 3 (P=0.034). In univariate analysis, neither whole tumor size nor lymph node metastasis was a prognostic factor for OS (P=0.51, P=0.27). Only cavity wall thickness was a significant prognostic factor by multivariate analysis (P=0.009). Conclusions: Maximum cavity wall thickness was an important prognostic factor in NSCLCs with cavity formation, comparable with other established prognostic factors. PMID- 29607171 TI - Enhanced recovery after thoracic surgery reduces discharge on highly dependent narcotics. AB - Background: There is large prescription drug epidemic in United States. We want to determine if ERATS (enhanced recovery after thoracic surgery) program can reduce discharge on highly dependent narcotics. Methods: We performed a retrospective analysis of prospectively collected data on patients who underwent lung resection and foregut procedures on thoracic surgery service over an 8-month time period. Patients underwent preoperative conditioning instructions, multimodal non-narcotic pharmaceutical usage, total intravenous anesthesia (TIVA) and minimizing highly addictive narcotics during the post-operative period. We gathered information on demographics, indication and type of surgery, morbidity, mortality and length of stay. We also recorded the type of pain medication patients were given as a prescription based on the Drug Enforcement Agency's classification schedule. Results: Fifty-two patients underwent lung resection and 54 patients underwent foregut surgery. There were no mortalities in either group. Ten percent of patients after lung surgery and 6% after foregut surgery had a greater than grade II complication. The median length of stay after lung resection was 2 days and foregut surgery was 1 day. Only 10% of patients went home after lung resection and 2% after foregut surgery with a prescription for schedule II narcotics. We found that patients who were on schedule II narcotics prior to surgery all went home with schedule II narcotics. Conclusions: We found that ERATS program for thoracic surgical cases can reduce the number of patients going home with highly dependent narcotics. This strategy will decrease the availability of highly addictive prescription drugs in the community. PMID- 29607172 TI - Sublobar resections for small-sized stage Ia lung adenocarcinoma: a Sino-Japanese multicenter study. AB - Background: Segmentectomy for small-sized stage Ia non-small cell lung cancer (NSCLC) may be comparable to lobectomy regarding prognosis and local recurrence. However, the clinical results of wedge resection for such patients are still under debate. In this international multicenter study, we retrospectively studied surgical outcomes of sublobar resections for patients with small-sized stage Ia adenocarcinoma to elucidate whether wedge resection is inferior to segmentectomy for such patients. Methods: Between March 2000 and August 2011, 173 patients underwent segmentectomy (group I), and 181 patients underwent wedge resection (group II) at three institutions in Japan and China. The tumor was defined as Ground glass opacity (GGO) type when the proportion of GGO was equal or more than 50% in HRCT, while solid type was defined as the proportion of GGO less than 50%. Clinicopathologic factors, local recurrence rate, and survival were compared. Results: The two groups were similar in sex, comorbidity rate, and composition of Noguchi type. There was no in-hospital death. Postoperative morbidity rate of group I was significantly higher than that of group II (11.0% vs. 2.2%, P=0.016). Local recurrence rates were similar between group I (4.0%) and group II (4.4%), while no patient with GGO type tumors had local recurrence. Overall and lung cancer-specific survivals were of no significant difference between the two groups. Lung cancer-specific survival rates at 10 years were significantly better in patients with GGO type tumors than in those with solid type tumors (100% vs. 76.9%, P<0.001). In multivariate Cox regression analyses of lung cancer-specific survival of all patients, GGO type turned out to be an independent prognostic factor, while extent of resection did not have any influence. Conclusions: Our data suggests that sublobar resection is an acceptable procedure for small lung adenocarcinomas without nodal involvement, and wedge resection may not be inferior to segmentectomy for small GGO type tumors. Our study also demonstrates that GGO type is an independent prognostic factor of disease-free survival for small-sized (diameter <=2.0 cm) stage Ia lung adenocarcinomas. PMID- 29607173 TI - Dosimetric comparison of helical tomotherapy and conventional Linac-based X-knife stereotactic body radiation therapy for primary lung cancer or pulmonary metastases. AB - Background: To compare helical tomotherapy (HT) with X-knife stereotactic body radiation therapy (HT-SBRT/X-SBRT) for primary or metastatic lung cancer regarding planning target volume (PTV) coverage, such as homogeneity index (HI), conformity index (CI) and dose-volume histogram (DVH) of organs at risk (OARs). Methods: We retrospectively analyzed 21 patients receiving definitive radiation treatment for non-small cell lung cancer (NSCLC) or pulmonary metastases at our institution between March 2015 and October 2016. Tumors were irradiated with 4-10 Gy per fraction in 5-15 fractions. Plans were compared according to PTV coverage and OARs sparing. Results: Significant differences between HT and X-knife were observed for both HI (P=0.003) and CI (P<0.001). The V5 (P=0.001), V10 (P=0.009), V20 (P=0.001), the mean lung dose (P=0.005) of total lung and maximum dose of the spinal cord (P=0.010) were significantly lower in the X-SBRT group than the HT SBRT group. There were no significant differences for the V30 (P=0.075) and the mean heart dose (P=0.584) between the two groups. Conclusions: X-SBRT was dosimetrically superior to HT-SBRT, when applied in these tumors' maximum diameters <5 cm. As HT resulted in increased low-dose volume, it is essential to optimize the patient selection in order to avoid severe radiation pneumonitis in HT-SBRT. PMID- 29607174 TI - Effect of a passive exhalation port on tracheostomy ventilation in amyotrophic lateral sclerosis patients: a randomized controlled trial. AB - Background: Amyotrophic lateral sclerosis (ALS) patients often require long-term tracheostomy ventilation (LT-TV) because of progressive ventilatory failure. Although widely used for non-invasive ventilation (NIV), passive exhalation port systems have not been gaining popularity for TV because of the possibility of carbon dioxide (CO2) rebreathing. The current study set out to investigate the effect of a Whisper Swivel connector in comparison to an active exhalation valve on gas exchange and symptoms in ALS patients requiring LT-TV. Methods: A prospective randomized controlled trial was carried out to compare the clinical outcome of ten ALS patients receiving LT-TV by means of a Trilogy 100 ventilator with a Whisper Swivel passive exhalation port (group A) and of 10 ALS patients connected to an Airox Legendair ventilator with an active exhalation valve (group B). The study's main outcome measure was CO2 retention at the 30-day follow-up assessment. Results: One patient in each of the two cohorts showed significant CO2 retention. At the 30-day assessment, scores on the following measures were not significantly different in the two groups: the Borg dyspnea scale {2 [1-3] vs. 1 [1-3]; P=0.2891}, the visual analogue scale (VAS) dyspnea {20 [10-85] vs. 20 [0-50]; P=0.8571}, the Epworth sleepiness scale (ESS) {8 [4-10] vs. 5.5 [0 12]; P=0.1443}, the EuroQol-VAS (EQ-VAS) {55 [50-80] vs. 50 [30-80]; P=0.4593} and the relative stress scale (RSS) {49 [30-65] vs. 52 [25-64]; P=0.8650}. At the 3-month follow-up assessment, the numbers of hospitalizations and deaths were likewise similar in the two groups. Conclusions: The efficacy of the Whisper Swivel connector is similar to that of an active exhalation valve in ALS patients undergoing LT-TV. PMID- 29607175 TI - 99mTechnetium and methylene blue guided pulmonary nodules resections: preliminary British experience. AB - Background: Subcentimetre pulmonary nodules can be challenging to locate either during video-assisted thoracoscopic surgery (VATS) or by open techniques. In an era of increasing computed tomography scan availability the number of nodules that are identified that are suspicious for malignancy is rising, and thoracic surgeons require a reliable method to locate these nodules intraoperatively. Methods: Our aim was to evaluate, for the first time in the UK, resection of pulmonary nodules using radioactive dye labelling. Local research ethics approval was obtained and the study was submitted to the Integrated Research Application System (IRAS). All data were prospectively collected in our dedicated thoracic surgical database and analyzed at the conclusion of the study. This represents a consecutive series of patients, from January 2016 and until April 2017, who underwent this procedure at our institution: James Cook University Hospital, Middlesbrough, United Kingdom. The primary outcome measured was successful resection rate of the target nodules. Results: Twenty-three patients underwent radiolabeled excision of pulmonary nodules, their average age was 61 years (range, 28-79 years), 13 women and 10 men. The average maximum diameter of the nodule was 8 mm (range, 3-16 mm). All patients underwent successful excision of the target lesion (success rate 100%). One patient (4.3%) sustained pneumothorax following the CT-guided injection of the radio-labelled dye and this required chest drainage prior to general anesthesia. Conclusions: We conclude that technetium guided pulmonary nodule resection is a very reliable method for localization and resection of subcentimetre nodules which may be otherwise be difficult to identify. PMID- 29607176 TI - The potential role of postbronchoscopic fever on the postoperative outcomes in patients with non-small cell lung cancer. AB - Background: Postbronchoscopic fever is a common adverse reaction in operable non small cell lung cancer (NSCLC) patients. To explore the potential role of postbronchoscopic fever on the postoperative outcomes in patients with NSCLC. Methods: Patients diagnosed with NSCLC were enrolled in this study. Patients were divided into two groups: fever group (postbronchoscopic fever) and normal group (without postbronchoscopic fever). Results: Seventy-five cases were enrolled. Twelve cases (16%) developed postbronchoscopic fever. The fever group was found to have longer postoperative fever time (1.9 vs. 0.8 days, P<0.05), more postoperative antibiotic use (3.4 vs. 2.5 days, P<0.05) and longer drainage (7.2 vs. 4.7 days, P<0.05). WBC counts of the fever group were higher than those of the no-fever group on the first (14.5 vs. 11.4*109/L, P<0.05) and third (11.0 vs. 9.2, P<0.05) postoperative day. Outcomes were different especially in the older subgroup (>60 years). Conclusions: Postbronchoscopic fever may be a predictor of longer postoperative fever, longer drainage and more antibiotic use in patients with NSCLC postoperatively. PMID- 29607177 TI - Association of serum leptin levels and pulmonary tuberculosis: a meta-analysis. AB - Background: We performed a meta-analysis to investigate the association of serum leptin levels with the pathogenesis of pulmonary tuberculosis (PTB). Methods: The retrieval of related articles was achieved through searching the electronic databases according to strict inclusion criteria. The STATA version 12.0 statistical software was employed to calculate the standardized mean difference (SMD) and 95% confidence interval (CI) during the statistical analysis. Results: Twelve case-control studies were enrolled in this meta-analysis. Our finding showed that serum leptin levels of healthy controls were markedly higher than those of PTB patients (SMD =0.70, 95% CI =0.51-0.89, P<0.001). Stratified analysis based on ethnicity presented that lower serum leptin levels were apparently associated with the development of PTB among both Asians and Caucasians (Asians: SMD =0.38, 95% CI =0.15-0.61, P=0.001; Caucasians: SMD =1.54, 95% CI =1.17-1.91, P<0.001). Furthermore, subgroups analysis based on the detecting method also showed that there was an association between the serum leptin levels and the development of PTB in both ELISA subgroup and RIA subgroup (ELISA: SMD =1.03, 95% CI =0.81-1.26, P<0.001; RIA: SMD =-0.41, 95% CI =-0.82 to 0.01, P=0.045). Conclusions: In conclusion, our present findings suggest that decreased serum leptin levels may be associated with the pathogenesis of PTB. PMID- 29607178 TI - Correlative factors for the location of tracheobronchial foreign bodies in infants and children. AB - Background: This study aims to analyze factors related to the location of tracheobronchial foreign bodies in infants and children, and provide help in the assessment of the disease, surgical risk and prognosis. Methods: The clinical data of 1,060 pediatric patients with tracheobronchial foreign bodies diagnosed from January 2015 to December 2015 were retrospectively studied, the association of the location of the foreign bodies with age, gender, granulation formation, chest computed tomography and 3D reconstruction results, preoperative complications, operation time, and hospital stay was analyzed. Results: The location of foreign bodies was not correlated with age, gender, operation time and length of hospital stay, but was correlated to granulation formation, chest computed tomography and 3D reconstruction results, and preoperative complications. Conclusions: The location of foreign bodies was correlated to granulation formation, the location of foreign bodies displayed by chest computed tomography, and preoperative complications. PMID- 29607179 TI - Modeling the relationship between baseline lactate dehydrogenase and prognosis in patients with extensive-disease small cell lung cancer: a retrospective cohort study. AB - Background: Elevated pretreatment lactate dehydrogenase (LDH) has been reported to be associated with poor survival in small cell lung cancer (SCLC). The present study aimed to investigate the continuous relationship between baseline LDH level and survival in patients with extensive-disease SCLC (ED-SCLC). Methods: Data were retrospectively collected from Shanghai Health Information Network. Patients primarily diagnosed as ED-SCLC from April 2011 to August 2014 were eligible for our study. Patients' survival status was checked in March 2016. A multivariate Cox proportional hazard model was used to detect the association between baseline serum LDH and overall survival. The corresponding continuous relationship was analyzed by using natural spline functions in the Cox model. Results: A total of 132 eligible ED-SCLC patients were analyzed. Elevated LDH at baseline was associated with poor survival (HR =1.92; 95% CI, 1.29-2.86). An increment of LDH would still raise the risk of death even in abnormal range. Among patients with elevated LDH, those who had relatively higher LDH levels (>370 U/L) would have a poorer prognosis than those with moderately elevated LDH levels (245-370 U/L; median survival time, 114 vs. 274 days; P value of log rank test, 0.007). Conclusions: LDH is a significant prognostic biomarker for ED-SCLC patients. The interpretation of continuous relationship between LDH and patients' survival can provide more accurate information for clinical practice. PMID- 29607182 TI - Acute liver failure with extreme hyperbilirubinemia secondary to endocarditis related severe mitral and tricuspid regurgitation: a challenge and an opportunity for surgeons. AB - Hyperbilirubinemia is a known risk factor in patients undergoing open heart operations. Infective endocarditis often leads to valvular injury, such as rupture of chordae tendineae or leaflet perforation, which can cause acute heart failure in association with pulmonary hypertension and liver dysfunction. Here we present a patient with massive liver congestion, reflected by extreme hyperbilirubinemia, secondary to acute heart failure following mitral valve endocarditis that was successfully treated by emergency mitral and tricuspid valve repair. PMID- 29607180 TI - Society for Translational Medicine Expert Consensus on the prevention and treatment of postoperative pulmonary infection in esophageal cancer patients. PMID- 29607181 TI - Screen-detected multiple primary lung cancers in the ITALUNG trial. AB - Occurrence of multiple primary lung cancers (MPLC) in individuals undergoing low dose computed tomography (LDCT) screening has not been thoroughly addressed. We investigated MPLC in subjects recruited in the ITALUNG randomized clinical trial. Cases of cytologically/histologically proven MPLC detected at screening LDCT or follow-up CT were selected and pathologically re-evaluated according to the WHO 2015 classification. Overall 16 MPLC were diagnosed at screening LDCT (n=14, all present at baseline) or follow-up CT (n=2) in six subjects (4 in one subject, 3 in two and 2 in three subjects), representing 0.43% of the 1,406 screenees and 15.8% of the 38 subjects with at least one screen-detected primary lung cancer. MPLC included 9 adenocarcinomas in three subjects and a combination of 7 different tumour histotypes in three subjects. MPLC, mostly adenocarcinomas, are not uncommon in smokers and ex-smokers with at least one LDCT screen detected primary lung cancer. PMID- 29607183 TI - Predictive value of pulmonary function measures for short-term outcomes following lung resection: analysis of a single high-volume institution. AB - Despite the importance of preoperative risk-stratification, there is a lack of consensus on how to identify high-risk patients for pulmonary resection. Enrollment criteria for national trials propose one definition based on preoperative pulmonary function tests. We sought to examine the value of preoperative forced expiratory volume in 1 second (FEV1) and diffusion capacity for carbon monoxide (DLCO) to predict short-term outcomes following pulmonary resection. Using our institutional Society of Thoracic Surgeons (STS) database we identified 419 consecutive lung cancer patients who presented to our institution for pulmonary resection between 2012 and 2016. We identified patients as "high risk" based on the national trial criteria of FEV1 or DLCO <=50%. Our primary outcome was any postoperative complication within 30 days of surgery. Secondary outcomes included cardiac and pulmonary complications, 30-day readmission, and discharge disposition. DLCO <=50% was associated with any postoperative complication (P=0.03), but not predictive of cardiac events, pulmonary complications, or 30-day readmission. There were no significant differences in any of these short-term outcomes for patients with FEV1 <=50%. On multivariable analysis, neither FEV1 nor DLCO <=50% were significantly associated with occurrence of postoperative complication (OR =1.67, 95% CI: 0.60-4.63; OR =1.66, 95% CI: 0.96-2.86, respectively). Notably, DLCO <=50%-but not FEV1-was associated with discharge to a skilled facility on univariate (P=0.01) and multivariable analysis (OR =2.54; 95% CI: 1.08-5.99; P=0.03). This association between DLCO and discharge to a skilled facility persisted when DLCO was used as a continuous variable. For all-comers presenting to our institution for lung cancer resection, classification based on FEV1 or DLCO <=50% may not reliably identify those at highest risk for short-term postoperative complications. While our findings suggest caution when using pulmonary parameters in isolation, the potential value of DLCO as a proxy for underlying comorbidity warrants further investigation. PMID- 29607184 TI - Thoracoscopic right S6 sleeve segmentectomy for squamous-cell carcinoma arising from the B6 central bronchus. AB - We describe a patient with low respiratory function who underwent thoracoscopic sleeve segmentectomy to preserve lung function as much as possible. The patient had already used home oxygen therapy because of chronic obstructive lung disease. There was a squamous-cell carcinoma at inlet of right B6 bronchus, and cT1aN0M0 disease was diagnosed. Because respiratory function was poor, right S6 segmentectomy was scheduled. Moreover, to preserve the respiratory muscles as much as possible, a thoracoscopic approach was selected. We performed S6 sleeve segmentectomy, and sutured the lower bronchus and basal bronchus. There were some limitations in handling needles during thoracoscopy. To resolve these difficulties, we devised two techniques. One was to suture the bronchus with continuous sutures on the mediastinal side and simple interrupted sutures on the other side. The other was to create a working space for handling the needles to avoid entanglement of the sutures. These techniques allowed us to suture the bronchi relatively easily. PMID- 29607185 TI - A novel suction-based lung-stabilizing device for video-assisted thoracoscopic surgical procedures. AB - Video-assisted thoracoscopic surgery (VATS) has become more commonly used in recent years. To provide a sufficient field of view during these procedures, surgeons must manipulate the lung using conventional devices such as cotton tipped medical applicators and graspers. However, medical applicators are unable to pull on the target lung lobes, and graspers can damage the lung tissue. We developed a novel suction-based lung-stabilizing silicon device to easily and safely manipulate the lung in order to provide an optimal view during VATS procedures. Here, we describe the use of this device to successfully perform VATS lobectomy in a clinical setting. PMID- 29607186 TI - Stem cell therapies for chronic obstructive pulmonary disease: current status of pre-clinical studies and clinical trials. AB - Chronic obstructive pulmonary disease (COPD) is a respiratory disease that has a major impact worldwide. The currently-available drugs mainly focus on relieving the symptoms of COPD patients. Novel regenerative therapeutic approaches have been investigated with the aim of repairing or replacing the injured functional structures of the respiratory system. We summarized the progress made by regenerative therapies for COPD by analyzing results from both pre-clinical studies and completed clinical trials. These approaches include the application of exogenous stem cells or small molecules to stimulate the regeneration by endogenous lung stem/progenitor cells. Exogenous mesenchymal stem cells (MSCs) have been reported to repair the structure and improve the function of the injured respiratory system in COPD models. However, the studies that used MSCs in patients with moderate-to-severe COPD patients did not lead to clear respiratory functional improvements. Exogenous human lung stem cells applied to cryo-injured (CI) lungs of mice have been shown to organize into human-like pulmonary structures, indicating a new property of stem cells that is potentially capable of curing COPD patients. Small molecules like retinoic acid has been shown to lead to regeneration and repair of the damaged lung structures in COPD mouse models probably by activation of endogenous lung stem/progenitor cells. However, retinoic acid or agonists of retinoic acid receptor administered to moderate or severe COPD patients did not improve the density and function of the damaged lung. These novel regenerative approaches have failed in preliminary clinical trials, possibly due to the advanced severity of the disease. Further work should be done to develop the current regenerative approaches for curing patients at different stages of COPD. We suggest that some modifications of the approach in the clinical studies may lead to more successful outcomes of regenerative therapy for COPD. PMID- 29607188 TI - Selective serotonin reuptake inhibitor use and outcomes following cardiac surgery a systematic review. AB - A high prevalence of depression is observed in patients undergoing cardiac surgery, and depression has been shown to be an independent predictor of morbidity and mortality in this patient population. Selective serotonin re-uptake inhibitors (SSRIs) are the first-line recommended therapy for depressive disorders, however due to their platelet inhibitory actions they have been associated with increased incidences of post-operative bleeding. This review has sought to address whether the use of SSRIs is associated with a higher rate of mortality, major adverse events or bleeding events following cardiac surgery. A retrospective literature search selected studies comparing the use of SSRIs with no SSRI use in patients undergoing cardiac surgery. Seven of the ten studies analysed reported no significant difference in mortality in SSRI users. Five of the seven studies reporting bleeding events demonstrated no significant difference in SSRI users. Three of the five studies reporting other significant morbidity demonstrated no significant difference in SSRI users. Our study demonstrates the safety of the use of SSRIs for the treatment of depressive disorders in patients undergoing cardiac surgery. PMID- 29607187 TI - The present and future role of ultrasound targeted microbubble destruction in preclinical studies of cardiac gene therapy. AB - Multiple limitations for cardiac pharmacologic therapies like intolerance, individual variation in effectiveness, side effects, and high cost still remain, despite the recent progress in diagnosis and health support. Gene therapy is poised to be an attractive alternative in various ways for the future, refractory cardiac diseases being one aspect of it. As a novel therapy to deliver the objective gene to organs of living animals, ultrasound targeted microbubble destruction (UTMD) has therapeutic potential in cardiovascular disorders. UTMD, which binds microbubbles with DNA or RNA carriers into the shell and destroys the located microbubbles with low frequency and high mechanical index ultrasound can release target agents to specific organs. UTMD has the ability to transfect markedly through sonoporation, cavitation and other effects by way of intravenous injection that is minimally invasive and highly specific for gene deliverance. Here, we have summarized the present role of UTMD in pre-clinical studies of cardiac gene therapy which covers myocardial infarction, regeneration, ischaemia/reperfusion injury, hypertension, diabetic cardiomyopathy, adriamycin cardiomyopathy and some discussion for further studies. PMID- 29607189 TI - Symptomatic sinus arrest induced by acute marijuana use. AB - Marijuana is considered a drug of low-toxicity, however its chronic and excessive use is regarded as a risk factor for general and cardiovascular health. Although investigated for therapeutic benefits, it can evoke electrocardiographic abnormalities in a dose-dependent manner. We report a case of a 54-year-old female who presented to the emergency department (ED) experiencing intermittent episodes of presyncope with tingling sensations around the left-side of the mouth and arm following acute inhalation of marijuana. Documented episodes of sinus arrest were noted. PMID- 29607190 TI - Hyperprogressive disease in patients with non-small cell lung cancer on immunotherapy. AB - Immunotherapy agents in metastatic non-small cell lung cancer (NSCLC) can result in improved quality of life and survival when compared with platinum-based chemotherapy. Novel response patterns such as pseudoprogression and hyperprogression, however, have been described and pose a challenge to treating physicians. Predictors of hyperprogressive disease (HPD) have not yet been identified. Evaluation and management by a multidisciplinary team involving medical and radiation oncologists, thoracic radiologists, and proceduralists is necessary to identify this subset of patients in a timely manner. Repeat biopsy distinguishes HPD from pseudoprogression and may eventually elucidate predictive biomarkers. We describe the epidemiology of these two phenomena, their diagnostic criteria, and their relevance for interventional pulmonologists. PMID- 29607191 TI - A brief introduction to probability. AB - The theory of probability has been debated for centuries: back in 1600, French mathematics used the rules of probability to place and win bets. Subsequently, the knowledge of probability has significantly evolved and is now an essential tool for statistics. In this paper, the basic theoretical principles of probability will be reviewed, with the aim of facilitating the comprehension of statistical inference. After a brief general introduction on probability, we will review the concept of the "probability distribution" that is a function providing the probabilities of occurrence of different possible outcomes of a categorical or continuous variable. Specific attention will be focused on normal distribution that is the most relevant distribution applied to statistical analysis. PMID- 29607192 TI - How to describe bivariate data. AB - The role of scientific research is not limited to the description and analysis of single phenomena occurring independently one from each other (univariate analysis). Even though univariate analysis has a pivotal role in statistical analysis, and is useful to find errors inside datasets, to familiarize with and to aggregate data, to describe and to gather basic information on simple phenomena, it has a limited cognitive impact. Therefore, research also and mostly focuses on the relationship that single phenomena may have with each other. More specifically, bivariate analysis explores how the dependent ("outcome") variable depends or is explained by the independent ("explanatory") variable (asymmetrical analysis), or it explores the association between two variables without any cause and effect relationship (symmetrical analysis). In this paper we will introduce the concept of "causation", dependent ("outcome") and independent ("explanatory") variable. Also, some statistical techniques used for the analysis of the relationship between the two variables will be presented, based on the type of variable (categorical or continuous). PMID- 29607193 TI - Two cases of combined thoracoscopy and open chest surgery for locally advanced lung carcinoma. AB - Thoracoscopic surgery is becoming more widely used in thoracic surgery and has an increasingly important role to play. However, its use for locally advanced carcinoma (clinical stage T3-4) remains controversial. We adapted our procedure by combining thoracoscopy and open chest surgery (combination surgery) with the aim of reducing invasiveness while ensuring that the operation is safe and curative. Here we describe our experience. Case 1 was a man in his 60s who underwent induction chemoradiotherapy (cisplatin plus vinorelbine plus 40 Gy radiotherapy) followed by radical surgery for a left apical lung carcinoma with chest wall invasion. Case 2 was a woman in her 70s who repeatedly had pneumonia and who underwent radical surgery for left apical adenocarcinoma that was expected to have strong adhesions to the thoracic wall. A thoracotomy incision may be required in cases of stage T3-4 lung cancer to access the hilar region and dissect the resected tumor and surrounding organs. In such cases, adding thoracoscopy to either one of these procedures may enable the use of a smaller incision in the chest wall. In both cases, complete resection with no residual tumor or complications was achieved, with the patients being discharged 3-8 days postoperatively. Cases 1 and 2 both remain recurrence free after 1.5 and 3 years, respectively). This suggests that having a thorough understanding of the features of both thoracoscopic and open chest surgery and integrating the two may enable surgery to be safely and less invasively performed while ensuring a curative effect. PMID- 29607194 TI - Difficult intubation due to unknown congenital tracheal stenosis in the adult: a case report and literature review. AB - Congenital tracheal stenosis (CTS) is a rare disorder almost always diagnosed in infancy due to respiratory failure and other cardiopulmonary abnormalities. We experienced a 42-year-old female undiagnosed with CTS until difficult intubation upon surgery. Chest X-ray and computed tomography (CT) images revealed bronchial narrowing, which could already be seen prior to intubation, but was left unnoticed. Difficult airway management is a potentially lethal airway emergency. This life-threatening situation is preventable with the appropriate awareness. We report this clinically valuable case for the safety of future patient care. In English and Japanese literature, there are only 12 reported cases of CTS diagnosed in the adult. Ours and six previous cases were discovered with difficult intubation, a preventable life-threatening airway emergency. Pre intubation images should be examined carefully for the possibility of CTS, as its frequency may be underestimated. Moreover, in treatment resistant recurrent asthmatic episodes, CTS should be kept in mind. PMID- 29607195 TI - Granulomatous reaction of primary mediastinal seminoma leading to diagnostic delay: a case report. AB - Primary mediastinal seminoma (PMS) is a rare tumor. PMS can be morphologically related to secondary changes in the form of thymic remnants, cystic degeneration, epithelioid granulomas, fibrotic change, and syncytiotrophoblast-like cells. Ours was an interesting case where a 26-year-old male presented with an incidentally found anterior mediastinal mass. Even though he had no pulmonary symptoms, the transthoracic co-axial needle biopsy of the mass suggested tuberculosis (TB). However, on follow-up computed tomography (CT) and magnetic resonance image (MRI) in 2 months, the mass slightly increased in size, and a small part of low density or signal intensity appeared, despite the regular anti-TB treatment regimen. Surgical resection was performed, and the resected specimens revealed scattered and irregular-shaped seminoma cells with an intervening chronic granulomatous reaction. The aim of this article is to report a case of PMS in a young male patient who had a granulomatous reaction that mimicked a neoplastic population of cells leading to an erroneous diagnosis of the small biopsy. Therefore, awareness of the secondary changes that can mimic a primary lesion can help with an early correction of this misdiagnosis. PMID- 29607196 TI - Metastatic small bowel neuroendocrine tumour and carcinoid heart disease with aortic valve involvement-a rare occurrence. AB - Carcinoid disease of the heart commonly affects the tricuspid and pulmonary valves causing thickening and stenosis. However in very rare circumstances, the disease can also involve the mitral and aortic valves. We present an unusual case of left sided carcinoid heart disease (CHD) and triple valve replacement without the presence of proven intra-cardiac shunts or bronchial carcinoid lesions. PMID- 29607197 TI - Kawasaki disease: multiple giant coronary aneurysms intervention and pacemaker implantation due to complete heart block-a case report. AB - Early intravenous immunoglobulin (IVIG) is the standard treatment for Kawasaki disease (KD) to reduce the incidence of coronary aneurysms. Patients with atypical presentation or who live in a rural area are less likely to receive treatment in the early stage of presentation and are more likely to develop severe complications. There is little consensus on how to treat coronary aneurysms effectively in the acute or subacute stage especially when giant aneurysms develop that compromise cardiac function. This case study is of a 19 month-old girl who initially was not treated as KD and developed multivessel giant coronary artery aneurysms (CAAs) (>8 mm), acute myocardial infarction, and complete heart block despite late intravenous IVIG administration. Multiple attempts of percutaneous coronary intervention (PCI) failed to open the occlusion in the right artery; therefore, bradycardia persisted. The girl received a permanent pace-maker and was doing well at 12-month follow up. PMID- 29607198 TI - An acquired transposition of the aortic arch secondary to large esophageal cancer misdiagnosed as a right-side aortic arch. AB - The present study is the first reported case of a patient undergoing esophagectomy with ectopic aortic arch secondary to a large esophageal cancer, which was pre-operatively misdiagnosed with a right-side aortic arch (RAA). The patient, a 54-year-old male, was first admitted to our hospital for esophagectomy owing to esophageal squamous cancer and had complained of progressive dysphasia for 3 months. Chest computed tomography (CT) revealed a mass in the middle thoracic esophagus. Furthermore, the three-dimensional CT of the thoracic great arteries showed a possible RAA and a curved descending aorta. After preoperative evaluation, the approach of using a left thoracotomy with cervical anastomosis was successfully performed and favorable short-term outcomes were achieved. According to previous reports, and the experience of the presented case, we emphasize clear recognition of the anatomical situation in the upper mediastinum and the importance of an optimal surgical approach for esophagectomy. PMID- 29607199 TI - Primary mediastinal leiomyoma: a rare case report and literature review. AB - Primary mediastinal leiomyomas are extremely rare, its etiology unknown, and up to the present has only been described in a few cases in the English literature. In this case report, we describe a 3-year-old girl with asymptomatic left upper quadrant abdominal mass. Chest computed tomography demonstrated a giant solid mass in the anterior mediastinum, which extended to the right hemi-thorax and left upper quadrant abdomen. Fortunately, the girl underwent a complete surgical tumor resection. The definitive diagnosis was primary mediastinal leiomyoma. To our best knowledge, this is the second case report of primary mediastinal leiomyoma of child. PMID- 29607200 TI - Initial experience with a 3D printed model for preoperative simulation of the Nuss procedure for pectus excavatum. AB - The incidence of pectus excavatum has been estimated to be between 0.1% and 0.8% though a large autopsy series reports. After publication of the Nuss procedure for pectus excavatum, it became widely accepted. However, there are still some complications, such as over-correction and recurrence. To reduce differences in the procedure due to surgeons' experience level, preoperative simulation may be useful. Thus, we performed simulated surgery using a specific patient's three dimensional (3D) chest wall model made by a 3D printer before operation. A 13 year-old male patient with a severe deformity of the chest underwent the Nuss procedure. As in the simulation, bars were inserted into the 5th and 7th intercostal spaces (ICS), leading to improvement of the chest wall. This simulation can increase surgeons' confidence to improve the deformity by determination of the number and insertion sites of bars. PMID- 29607201 TI - Clinical implication of MEN1 mutation in surgically resected thymic carcinoid patients. AB - Thymic carcinoid is a rare but very aggressive neuroendocrine tumour derived from the neuroendocrine system. Here we report a male patient with thymic atypical carcinoid. Though thymic carcinoid is relatively common, the gene sequencing profile was performed and the gene sequencing result indicated germline multiple endocrine neoplasia type 1 (MEN1) mutation and two somatic mutations on MEN1 gene and no copy number variation or fusion events were detected. It is well-known that the mutation of MEN1 is the typical manifestation of MEN1 syndrome, which is an autosome dominant disease that includes varying combinations of more than 20 endocrine and non-endocrine tumors. In the English literature, 7 cases of solitary thymic carcinoid harboring somatic variants in MEN1 are reported in the absence of other organs involvement as MEN1 syndrome presents. We summarized the clinical features and prognosis of this rare thymic tumor. PMID- 29607202 TI - Impact of 3D printing on the surgical management of tracheal stenosis associated to pulmonary sling: a case report. AB - Congenital tracheal stenosis (CTS) is rare lesions frequently associated with pulmonary sling (PS). Despite the recent improvement in the results by the introduction of slide tracheoplasty (ST) and multidisciplinary approach, surgical management remains difficult and several authors, for this reason, debate for a conservative approach in these cases. Preoperative planning, require hence the use of the most innovative technology to gain the best possible result. This report describes a complicated, unsuccessful surgically treated case of CTS associated to PS. Based on this result and in order to improve the outcomes, we have built a 3D model of patient's trachea simulating preoperative surgical planning. We have hypnotized that having the model preoperatively the choice of surgical technique would have been different. Since that case, 3D models are introduced in our practice and built before tracheal or cardiac cases considered to have complex anatomy. Future investigations are required but at the moment this experience confirms the utility of 3D model in the evaluation of children considered for tracheal surgery. PMID- 29607203 TI - 3D-printing aided resection of intratracheal adenoid cystic carcinoma and mediastinal mature cystic teratoma in a 26-year-old female: a case report. AB - Complete resection remains the ideal treatment for most patients with primary intratracheal tumors. Due to the limit in the resection length, the localization of the tumor during the surgery could be rather difficult if it hasn't invaded out of the trachea, which might be more difficult when there's another tumor in the anterior mediastinum. A 26-year-old woman with intratracheal adenoid cystic carcinoma (ACC) presented with dyspnea. CT scan revealed not only an ACC without extension out of trachea, but also a mediastinal teratoma (MT) near aorta, making the operation much more complicated than usual. To solve this problem, 3D printing was applied for facilitating surgery plan making and intraoperative locating of ACC. And as we expected, the operation went successfully and the patient achieved full recovery without complications. To the best of our knowledge, the case of both intratracheal ACC and MT in one patient has not been previously reported. PMID- 29607204 TI - Incidental adult polysplenia with situs inversus, interrupted inferior vena cava with azygos continuation, patent ductus arteriosus, and aortic branches variations: a case report. AB - Polysplenia syndrome is a rare condition (about 2.5:100,000 live births) wherein a person has two or more spleens with accompanying various thoracic and abdominal organ abnormalities. Polysplenia is usually associated with situs ambiguous, while polysplenia with situs inversus is very rare. Herein, we report a rare case of incidentally found polysplenia syndrome combined with situs inversus in a 59 year-old female who also had an interrupted inferior vena cava (IVC) with azygos continuation, patent ductus arteriosus (PDA), and variations in the aortic arch branches. An aberrant left subclavian artery with Kommerell's diverticulum and a large aneurysm in the non-aberrant, proximal-right subclavian artery were also noted. PMID- 29607205 TI - A novel strategy for cardiopulmonary support during lung transplantation. AB - Contemporary modalities for cardiopulmonary support during lung transplantation include traditional cardiopulmonary bypass (CPB) and venoarterial extracorporeal membrane oxygenation (VA-ECMO). While highly effective, both are associated with morbidities such as arteriopathy and bleeding diathesis. In this report, we describe a novel approach for cardiopulmonary support during double lung transplantation in a patient with end-stage lung disease, pulmonary hypertension and moderate right ventricle (RV) dysfunction, using a percutaneous dual lumen cannula placed via the jugular vein which allowed us to achieve both RV bypass and membrane oxygenation. The cannula was left in place to provide ongoing RV support and the patient was successfully decannulated at bedside on post operative day (POD) 2. Lack of arterial cannulation, percutaneous access, and bedside decannulation are benefits of this strategy, rendering this approach a useful addition to the armamentarium for CPB techniques in lung transplantation. PMID- 29607206 TI - Primary lung carcinoma combined with pulmonary amyloidosis secondary to syphilis infection. AB - A 55-year-old female patient was found to have a pulmonary nodule combined with multiple lung cysts detected on CT scan. Video-assisted thoracoscopic surgery (VATS) lobectomy was performed and the nodule showed adenocarcinoma while the whole left upper lobe showed a heavy deposition of amyloid. Syphilis infection was detected and was suspected contributing to secondary pulmonary amyloidosis. Although very rare, pulmonary amyloidosis should be added to the differential diagnosis for solid pulmonary nodules. Furthermore, widespread lung cysts located apart from pulmonary nodules is especially rare in pulmonary amyloidosis secondary to syphilis infection. PMID- 29607207 TI - Pneumorrhachis: an under-recognized entity correlates with severity of spontaneous pneumomediastinum. PMID- 29607208 TI - Real-time feedback systems for cardiopulmonary resuscitation training: time for a paradigm shift. PMID- 29607209 TI - Erratum to reintervention after thoracic endovascular aortic repair deserves more attention. AB - [This corrects the article DOI: 10.21037/jtd.2017.04.52.]. PMID- 29607210 TI - Medical students' clerkship experiences and self-perceived competence in clinical skills. AB - Introduction: In a traditional curriculum, medical students are expected to acquire clinical competence through the apprenticeship model using the Halstedian "see one, do one, and teach one, approach". The University of Zambia School of Medicine used a traditional curriculum model from 1966 until 2011 when a competence-based curriculum was implemented. Objective: To explore medical students' clerkships experiences and self-perceived competence in clinical skills. Methods: A cross-sectional survey was conducted on 5th, 6th, and 7th year medical students of the University of Zambia, School of Medicine two months prior to final examinations. Students were asked to rate their clerkship experiences with respect to specific skills on a scale of 1 to 4 and their level of self perceived competence on a scale of 1 to 3. Skills evaluated were in four main domains: history taking and communication, physical examination, procedural, and professionalism, team work and medical decision making. Using Statistical Package for Social Scientist (SPSS), correlations were performed between experiences and self-perceived competence on specific skills, within domains and overall. Results: Out of 197 clinical students 138 (70%) participated in the survey. The results showed significant increase in the proportion of students performing different skills and reporting feeling very competent with each additional clinical year. Overall correlations between experience and self-perceived competence were moderate (0.55). On individual skills, the highest correlation between experience and self-perceived competence were observed on mainly medical and surgical related procedural skills with the highest at 0.82 for nasal gastric tube insertion and 0.76 for endotracheal intubation. Conclusion: Despite the general improvement in skills experiences and self-perceived competence, some deficiencies were noted as significant numbers of final year students had never attempted common important procedures especially those performed in emergency situations. Deficiencies in certain skills may call for incorporation of teaching/learning methods that broaden students' exposure to such skills. PMID- 29607211 TI - Development of a Multisensory Wearable System for Monitoring Cigarette Smoking Behavior in Free-Living Conditions. AB - This paper presents the development and validation of a novel multi-sensory wearable system (Personal Automatic Cigarette Tracker v2 or PACT2.0) for monitoring of cigarette smoking in free-living conditions. The contributions of the PACT2.0 system are: (1) the implementation of a complete sensor suite for monitoring of all major behavioral manifestations of cigarette smoking (lighting events, hand-to-mouth gestures, and smoke inhalations); (2) a miniaturization of the sensor hardware to enable its applicability in naturalistic settings; and (3) an introduction of new sensor modalities that may provide additional insight into smoking behavior e.g., Global Positioning System (GPS), pedometer and Electrocardiogram(ECG) or provide an easy-to-use alternative (e.g., bio-impedance respiration sensor) to traditional sensors. PACT2.0 consists of three custom built devices: an instrumented lighter, a hand module, and a chest module. The instrumented lighter is capable of recording the time and duration of all lighting events. The hand module integrates Inertial Measurement Unit (IMU) and a Radio Frequency (RF) transmitter to track the hand-to-mouth gestures. The module also operates as a pedometer. The chest module monitors the breathing (smoke inhalation) patterns (inductive and bio-impedance respiratory sensors), cardiac activity (ECG sensor), chest movement (three-axis accelerometer), hand-to-mouth proximity (RF receiver), and captures the geo-position of the subject (GPS receiver). The accuracy of PACT2.0 sensors was evaluated in bench tests and laboratory experiments. Use of PACT2.0 for data collection in the community was validated in a 24 h study on 40 smokers. Of 943 h of recorded data, 98.6% of the data was found usable for computer analysis. The recorded information included 549 lighting events, 522/504 consumed cigarettes (from lighter data/self registered data, respectively), 20,158/22,207 hand-to-mouth gestures (from hand IMU/proximity sensor, respectively) and 114,217/112,175 breaths (from the respiratory inductive plethysmograph (RIP)/bio-impedance sensor, respectively). The proposed system scored 8.3 +/- 0.31 out of 10 on a post-study acceptability survey. The results suggest that PACT2.0 presents a reliable platform for studying of smoking behavior at the community level. PMID- 29607212 TI - Further Evidence of Accelerated Aging in Bipolar Disorder: Focus on GDF-15. AB - Background: Bipolar disorder (BD) is a mood disorder associated with cardiovascular and metabolic diseases and premature aging. Growth differentiation factor 15 (GDF-15) has emerged as a biomarker for cardiovascular risk and aging. Our aim was to compare plasma levels of GDF-15 between BD patients and controls, and to evaluate whether they were associated with clinical parameters. Methods: Forty-six patients with type I BD (23 in euthymia and 23 in mania) and 33 healthy controls were recruited for this study. Plasma levels of GDF-15 were measured by immunoassay. Results: The levels of GDF-15 were significantly higher (p < 0.001) in patients with BD in comparison with controls. In patients, GDF-15 levels correlated with age (rho = 0.434; p = 0.003) and illness duration (rho = 0.502; p = 0.001). Conclusion: Our findings corroborate the view that BD is an illness associated with accelerated aging. PMID- 29607213 TI - Reliability of Ocular Aberration Measurements in Children with Moderate and Low Myopia under Scotopic Conditions. AB - Purpose: To investigate the reliability of ocular aberration measurement in myopic children under scotopic conditions and to validate the mathematical Zernike pupil scaling-down technique. Methods: Ocular aberrations of 45 myopic children were examined under scotopic conditions via iTrace aberrometer. The intra- and intersession repeatability was evaluated for both the measured values with the true pupil sizes and the estimated ones that were determined by scaling down the pupil sizes to the largest integer value across all measurements. Results: The intra- and intersession difference of clinically measured aberration was generally insignificant, and the ICCs for each aberration component exhibited good to excellent reliability (ICCs > 0.4). Similar results were found for the estimated aberration using the scaling-down technique. Although the majority of the estimated Zernike components were comparable with the corresponding measured one, the estimated values of defocus, coma, and the corresponding total aberrations were found significantly smaller than the measured values (all P < 0.01). Conclusions: The ocular aberration measurements in myopic children under the circumstances described are reliable. The scaling-down technique is a useful option for comparing the results obtained from different pupil sizes, but the estimated Zernike coefficients were not always comparable with the corresponding measured values. PMID- 29607214 TI - Choroidal and Retinal Thickness of Highly Myopic Eyes with Early Stage of Myopic Chorioretinopathy: Tessellation. AB - Purpose: To investigate the choroidal thickness (CT) and retinal thickness (RT) in highly myopic tessellated eyes. Methods: In this study, 115 highly myopic eyes were recruited and divided as tessellated fundus (n = 93) and normal fundus (n = 22). RT and CT were quantified using optical coherence tomography with enhanced depth imaging (EDI-OCT). Correlation between subfoveal CT (SFCT) and tessellation was analyzed using logistic regression models. Results: Tessellated fundus eyes had thinner CT than did normal fundus eyes, while RT was not statistically different across groups. The tessellated eyes had a thinner choroid than did the control eyes at all measured macular locations (all P < 0.05). After adjustment for AL, age, and gender, the SFCT was significantly associated with tessellation. The odds ratio (OR) and 95% confidence interval (CI) was 0.975 (0.960-0.990, P = 0.001, binary logistics regression) and 0.991 (0.984-0.999, P = 0.022, Cox regression). The area under the curve (AUC) of SFCT was the greatest for detecting tessellation (AUC = 0.824, P < 0.001). For sensitivity and specificity analyses, SFCT had the highest diagnostic value (sensitivity = 81.8%, specificity = 74.2%). Conclusions: Highly myopic eyes with tessellation have thinner CT than do normal highly myopic eyes. CT may serve as an early pathologic predictor of high myopia. PMID- 29607215 TI - Calculation of Unknown Preoperative K Readings in Postrefractive Surgery Patients. AB - Purpose: To determine the unknown preoperative K readings (Kpre) to be used in history-based methods, for intraocular lens (IOL) power calculation in patients who have undergone myopic photorefractive keratectomy (PRK). Methods: A regression formula generated from the left eyes of 174 patients who had undergone PRK for myopia or for myopic astigmatism was compared with other methods in 168 right eyes. The Pearson index and paired t-test were utilized for statistical analysis. Results: The differences between Kpre and those obtained with the other methods were as follows: 0.61 +/- 0.94 D (range: -3.94 to 2.05 D, p < 0.01) subtracting the effective treatment, 0.01 +/- 0.86 D (range: -2.61 to 2.34 D, p = 0.82) with Rosa's formula, -0.02 +/- 1.31 D (range: -3.43 to 3.68 D, p = 0.82) with the current study formula, and -0.43 +/- 1.40 D (range: -3.98 to 3.12 D, p < 0.01) utilizing a mean K (Km) of 43.5 D. Conclusions: These formulas may permit the utilization of history-based methods, that is, the double-K method in calculating the IOL power following PRK when Kpre are unknown. PMID- 29607216 TI - Comparison of Two Toric IOLs with Different Haptic Design: Optical Quality after 1 Year. AB - Background: The purpose of this prospective, randomised study was to interocularly compare the visual performance after implantation of two different toric IOLs with different haptic design. Methods: 59 subjects with corneal astigmatism greater than 1.25 diopter (D) were implanted with an AT TORBI 709M IOL (Carl Zeiss Meditec AG) in one eye and with a Tecnis toric aspheric IOL (Abbot Medical Optics) in the other eye. Observation procedure was performed 12 months postoperatively. Main outcome measures included uncorrected distance visual acuity (UDVA), manifest refraction, IOL rotation, and IOL position. Results: Mean UCDVA was 0.04 +/- 0.14 logMAR for AT TORBI eyes and 0.06 +/- 0.15 logMAR for Tecnis eyes (p = 0.3). The postoperative spherical equivalent values were significantly lower in the AT TORBI group. Mean toric IOL axis rotation was 3.0 +/- 2.26 degrees for AT TORBI eyes and 3.27 +/- 2.37 for Tecnis eyes (p = 0.5). The mean vertical IOL tilt and vertical decentration values measured with the Visante OCT were significantly larger in the AT TORBI group (p < 0.05). Conclusions: Both the Tecnis and the AT TORBI toric IOLs successfully reduced ocular astigmatism. Emmetropia could be better achieved with the AT TORBI IOL, whereas the Tecnis showed better positional stability. This trial is registered with ICMJE NCT03371576. PMID- 29607217 TI - Modern Diagnostic Techniques for the Assessment of Ocular Blood Flow in Myopia: Current State of Knowledge. AB - Myopia is the most common refractive error and the subject of interest of various studies assessing ocular blood flow. Increasing refractive error and axial elongation of the eye result in the stretching and thinning of the scleral, choroid, and retinal tissues and the decrease in retinal vessel diameter, disturbing ocular blood flow. Local and systemic factors known to change ocular blood flow include glaucoma, medications and fluctuations in intraocular pressure, and metabolic parameters. Techniques and tools assessing ocular blood flow include, among others, laser Doppler flowmetry (LDF), retinal function imager (RFI), laser speckle contrast imaging (LSCI), magnetic resonance imaging (MRI), optical coherence tomography angiography (OCTA), pulsatile ocular blood flowmeter (POBF), fundus pulsation amplitude (FPA), colour Doppler imaging (CDI), and Doppler optical coherence tomography (DOCT). Many researchers consistently reported lower blood flow parameters in myopic eyes regardless of the used diagnostic method. It is unclear whether this is a primary change that causes secondary thinning of ocular tissues or quite the opposite; that is, the mechanical stretching of the eye wall reduces its thickness and causes a secondary lower demand of tissues for oxygen. This paper presents a review of studies assessing ocular blood flow in myopes. PMID- 29607220 TI - Remember the Drive Home? An Assessment of Emergency Providers' Sleep Deficit. AB - Objective: Sleep deprivation decreases work performance and predisposes workers to deleterious health outcomes. We sought to evaluate sleep hygiene and fatigue among emergency physicians. Methods: In March-June 2016, physicians and residents at an academic emergency medicine program were invited to complete a survey evaluating sleep and alertness. Results: Six attending physicians and 26 residents completed the survey. Among six personal priorities, sleep ranked fourth behind family, work, and leisure. 75% stated poor sleep impedes effectiveness as a physician while 53% noted difficulty falling asleep before a night shift. In the last three months, 39% of subjects forgot driving home from a shift, and 34% had fallen asleep while driving. 34% used medications to assist with sleep (including melatonin (36%), alcohol (27%), and prescription drugs (9%)). Most providers attested to phone (88%) and television exposure (69%) immediately prior to goal sleep onset. Conclusion: Despite sleep being identified as a priority among EM physicians, deleterious habits remain. Poor sleep affects perceived effectiveness and personal safety, as evidenced by a significant portion of providers falling asleep on the commute home. Night shift is the chief obstacle to optimal sleep hygiene. PMID- 29607219 TI - Lactic Acid Bacteria Isolated from Japanese Fermented Fish (Funa-Sushi) Inhibit Mesangial Proliferative Glomerulonephritis by Alcohol Intake with Stress. AB - The aim of this study was to examine the effect of heat-killed Lactobacillus paracasei NFRI 7415 on kidney and bone in mice fed an ethanol-containing diet with stress. Eight-week-old Cril : CD1 mice were fed a control diet (CD), an alcohol diet (AD) (35.8% of total energy from ethanol), or an alcohol diet containing 20% heat-killed Lb. paracasei NFRI 7415 (107 CFU/g) (LD) for 4 weeks. Mice in the AD and LD groups also underwent restraint stress for two weeks from 13 days. The mice were placed in a 50 mL plastic tube, which had a small hole drilled around its base to allow ventilation, and restrained for 1 h every day. High final body weight was in the following order: CD, LD, and AD (p < 0.05). The heat-killed Lb. paracasei NFRI 7415 lowered liver total cholesterol concentration and plasma glutamic-oxaloacetic transaminase (GOT) level. In addition, fecal bile acids of the LD group were higher than in the AD group (p < 0.05). The glomerulus of the kidney in the AD group was observed to be more fibrotic than in the CD and LD groups with azan stain. Immunostaining confirmed that brown areas indicating the existence of mesangial cells were increased in the AD group, but not in the CD and LD groups. These results indicated that the heat-killed Lb. paracasei NFRI 7415 inhibited mesangial proliferative glomerulonephritis by alcohol intake with stress. PMID- 29607221 TI - A Rare Central Venous Catheter Malposition in a 10-Year-Old Girl. AB - Central venous catheters (CVCs) are placed in operating rooms worldwide via different approaches. Like any other medical procedure, CVC placement can cause a variety of complications. We report the case of an unexpected malposition of a catheter in the right internal jugular vein, where it looped back on itself during placement and went upward into the right internal jugular vein. CVC line placement should always be viewed as a procedure that could become complicated, even in the hands of the most experienced operators. PMID- 29607222 TI - Pulmonary Edema and Diastolic Heart Failure in the Perioperative Period. AB - Heart failure with preserved ejection fraction (HFPEF) is a diagnosis encountered with increasing frequency in the aging population. We present a case of postoperative pulmonary edema in 63-year-old male with HFPEF. This patient highlights the gap in risk stratification with respect to diastolic heart failure. PMID- 29607223 TI - Single Sitting Surgical Treatment of Generalized Aggressive Periodontitis Using GTR Technique and Immediate Implant Placement with 10-Year Follow-Up. AB - This case report exhibits a patient with generalized aggressive periodontitis who has been under maintenance for the past 12 years after being surgically treated in a single sitting and restored with dental implants. A 41-year-old systemically healthy male patient presented complaining of lower anterior teeth mobility and pain in the upper right quadrant. After clinical and radiographic examination, the upper right molars and lower anterior incisors were deemed unrestorable. Covered by doxycycline, the patient received a nonsurgical periodontal treatment. Three weeks later, teeth extraction, immediate implant placement, immediate nonloading provisional prosthesis, and a guided tissue regeneration were performed at indicated areas in a single sitting. The clinical decisions were based on patient compliance, the status of the existing periodontal tissues, and the prognosis of the remaining teeth. During the 12-year follow-up period, no residual pockets were observed and there was no exacerbation of the inflammatory condition. Marginal bone stability is present on all implants. For aggressive periodontal disease, a high risk of relapse as well as limited success and survival of dental implants should be considered. This case shows proper containment of the disease based on appropriate treatment planning and a strict maintenance program. PMID- 29607224 TI - Ellis-van Creveld Syndrome: A Rare Clinical Report of Oral Rehabilitation by Interdisciplinary Approach. AB - Ellis-van Creveld syndrome (EVC) is a very rare genetic disorder that affects various tissues of ectodermal and mesodermal origin; patients with EVC present with typical oral deficiencies. The affected individuals are quite young at the time of oral evaluation. It is, therefore, important that these individuals are diagnosed and receive dental treatment at an early age for their physiologic and psychosocial well-being. Albeit there are numerous articles penned on the EVC, the treatise from an oral perspective is inadequate, covering only oral exhibitions and the preventive treatments. This article reviews the literature and serves as the first disquisition for oral rehabilitation of an EVC patient utilizing surgical, orthodontic, restorative, and prosthodontic management. PMID- 29607225 TI - Breast Implant-Associated Anaplastic Large Cell Lymphoma: Case Report and Review of the Literature. AB - We are reporting the case of a 58-year-old woman with history of bilateral silicone breast implants for cosmetic augmentation. At 2-year interval from receiving the breast implants, she presented with swelling of the right breast with associated chest wall mass, effusion around the implant, and axillary lymphadenopathy. Pathology confirmed breast implant-associated anaplastic large cell lymphoma (stage III, T4N2M0, using BIA-ALCL TNM staging and stage IIAE, using Ann-Arbor staging). The patient underwent bilateral capsulectomy and right partial mastectomy with excision of the right breast mass and received adjuvant CHOP chemotherapy and radiation to the right breast and regional nodes. Since completion of multimodality therapy, the patient has sustained remission on both clinical exam and PET/CT scan. We report this case and review of the literature on this rare form of lymphoma. PMID- 29607226 TI - Prevention of High-Dose Cytosine Arabinoside-Induced Acute Pericarditis with Preemptive Dexamethasone Administration: A Case Report and Literature Review. AB - Pericarditis/pericardial effusion (PC/PEEF) is a rare but fatal complication of cytosine arabinoside (Ara-C). We report an acute myeloid leukemia (AML) patient who developed massive pericardial effusion after a second Ara-C exposure. As Ara C was most beneficial in controlling the leukemia, she was treated with a further cycle of Ara-C along with dexamethasone to prevent the complication from reoccurring. No PC/PEEF was subsequently detected. PMID- 29607227 TI - Rivaroxaban Treatment for Warfarin-Refractory Thrombosis in a Patient with Hereditary Protein S Deficiency. AB - Protein S (PS) deficiency, an autosomal dominant hereditary thrombophilia, is more prevalent in East Asian populations than in Caucasians. PS-deficient patients have historically been administered a heparin product followed by warfarin for the treatment and secondary prevention of venous thromboembolism (VTE). However, warfarin can be ineffective or causes detrimental effects in rare cases. While direct oral anticoagulants (DOACs) are being increasingly used for the treatment and prevention of VTE, their efficacy in PS-deficient patients has not been established. We describe a 91-year-old woman who presented with chronic bilateral lower leg swelling with VTE that was refractory to warfarin anticoagulation therapy for over 1 year. Her recurrent VTE was diagnosed as quantitative hereditary PS deficiency. Rivaroxaban was administered as maintenance therapy instead of warfarin; after 8 weeks, the severities of the patient's leg swelling and venous ulcerations were significantly reduced with rivaroxaban compared to warfarin, thus demonstrating the efficacy of rivaroxaban for warfarin-refractory chronic VTE associated with hereditary PS deficiency. This case illustrates that rivaroxaban can potentially serve as therapeutic agents to treat warfarin-refractory VTE in PS-deficient patients. Further investigations are required to confirm the efficacy of rivaroxaban on the long term in this regard. PMID- 29607218 TI - Nutritional Ketosis and Mitohormesis: Potential Implications for Mitochondrial Function and Human Health. AB - Impaired mitochondrial function often results in excessive production of reactive oxygen species (ROS) and is involved in the etiology of many chronic diseases, including cardiovascular disease, diabetes, neurodegenerative disorders, and cancer. Moderate levels of mitochondrial ROS, however, can protect against chronic disease by inducing upregulation of mitochondrial capacity and endogenous antioxidant defense. This phenomenon, referred to as mitohormesis, is induced through increased reliance on mitochondrial respiration, which can occur through diet or exercise. Nutritional ketosis is a safe and physiological metabolic state induced through a ketogenic diet low in carbohydrate and moderate in protein. Such a diet increases reliance on mitochondrial respiration and may, therefore, induce mitohormesis. Furthermore, the ketone beta-hydroxybutyrate (BHB), which is elevated during nutritional ketosis to levels no greater than those resulting from fasting, acts as a signaling molecule in addition to its traditionally known role as an energy substrate. BHB signaling induces adaptations similar to mitohormesis, thereby expanding the potential benefit of nutritional ketosis beyond carbohydrate restriction. This review describes the evidence supporting enhancement of mitochondrial function and endogenous antioxidant defense in response to nutritional ketosis, as well as the potential mechanisms leading to these adaptations. PMID- 29607228 TI - Chronic Myelomonocytic Leukemia following Multicentric Castleman Disease. AB - Multicentric Castleman disease (MCD) is a rare nonmalignant lymphoproliferative disorder presenting systemic symptoms such as fever, night sweats, fatigue, anemia, effusions, and multifocal lymphadenopathy. The etiology of MCD has not been clarified to date. The coexistence of MCD with chronic myelomonocytic leukemia (CMML) has been rarely reported. Although the pathogenesis remains unclear, this association probably reflects an incidental and fortuitous finding rather than the alteration of a common pluripotent stem cell precursor. Herein, we report on one case of MCD coexisting with CMML and elucidate the underlying mechanism of pathology in some aspects. PMID- 29607229 TI - A Case of Levamisole-Induced Agranulocytosis. AB - A sixty-eight-year-old male with a past medical history of recurrent cocaine use presented to the emergency department with recurrent diarrhea and was found to have a white blood cell (WBC) count of 1.9 * 109/L with agranulocytosis (absolute neutrophil count (ANC) of 95 cell/mm3). At admission, the patient disclosed that he used cocaine earlier during the day, and a urine drug screen tested positive for this. On hospital day one, the patient was found to have a fever with a maximum temperature of 313.6 K. After ruling out other causes and noting the quick turnaround of his neutropenia after four days of cocaine abstinence, the patient's neutropenia was attributed to levamisole-adulterated cocaine. PMID- 29607230 TI - Use of Next Generation Sequencing and Synergy Susceptibility Testing in Diagnosis and Treatment of Carbapenem-Resistant Klebsiella pneumoniae Blood Stream Infection. AB - Early diagnosis and appropriate treatment for carbapenem-resistant Klebsiella pneumoniae (CR-Kp) infection is a big challenge for clinicians due to its high mortality. Every effort has been made to improve its clinical outcomes. However, treatment according to synergy susceptibility testing has never been reported in the literature. We reported a 29-year-old systemic lupus erythematosus female with CR-Kp blood stream infection. We highlighted the identification by next generation sequencing and treatment according to synergy susceptibility testing in the case. PMID- 29607231 TI - A Rare Case Report: A Malignant Histiocytic Tumor in the Form of Ovarian Mass. AB - Histiocytic cell malignancies are very rare. Hence, the information about this disease in hematology is limited. In this case report, we present a case of malignant histiocytic tumor affecting the ovary of a 40-year-old virgin female. Primary ovarian malignancy was not considered for the patient who was approached as if she had ovarian malignancy, since there was an indication of a mass in the ovary. Therefore, an aggressive surgery was not performed. Since our patient was in the reproductive age, fertility-preserving surgery was performed. Our patient was then treated systemically by medical oncology. In conclusion, the rare malignancy group was investigated in the present study along with an evaluation of the current literature. PMID- 29607232 TI - Falsely Elevated CA 15-3 Levels in Ovarian Sarcoidosis with Peritoneal Involvement and Ascites. AB - A rare case of ovarian sarcoidosis with peritoneal and omental involvement presenting as an ovarian malignancy is presented. Clinical, laboratory, and radiological evaluation of the patient revealed ascites and high levels of serum CA 125 and CA 15.3. The diagnosis of sarcoidosis was confirmed with pathology findings on tissues obtained during surgical laparotomy. Establishing the diagnosis of sarcoidosis can be treacherous and was complicated in this case by the falsely elevated biomarkers and ascites. PMID- 29607233 TI - Preterm Parturient with Polyhydramnios and Pancreatitis: Primary Presentation of Hyperparathyroidism. AB - Objective: To report a case of severe hypercalcemia secondary to primary hyperparathyroidism in a late-preterm pregnant patient and review medical and surgical treatments as well as obstetric and neonatal outcomes. Background: Diagnosis of parathyroid disease during pregnancy can be difficult due to nonspecific presentation. Management decisions are complex and require multidisciplinary collaboration. Case: A 29-year-old G2P1001 woman at 35 weeks and 3 days' gestation presented with preterm contractions, polyhydramnios, pancreatitis, and severe hypercalcemia. Work-up revealed primary hyperparathyroidism with multiple thyroid nodules. Patient history, presentation, and biopsy were suspicious for parathyroid carcinoma. Despite severe hypercalcemia, both patient and fetus remained stable and medical management was pursued in an attempt to optimize mother and fetus prior to delivery. Due to recalcitrant hypercalcemia, surgical resection was ultimately required. She was subsequently delivered in the setting of preterm labor. Final pathology revealed parathyroid adenoma with atypia and occult papillary thyroid carcinoma. Conclusion: Symptoms of hypercalcemia can mimic those of a normal third trimester pregnancy and can have serious maternal and fetal effects if left untreated. A coordinated, multidisciplinary approach to these patients is necessary. PMID- 29607234 TI - Large Vaginal Varicosities in the Setting of Pregnancy without Known Hepatic or Vascular Risks: A Case Report and Review of the Literature. AB - Pregnancy may cause the onset of vaginal or vulvar varicosities that may be a concern for hemorrhage risk during childbirth. A 38-year-old female G4P1112 at 34 weeks and 1 day was referred to an outpatient OB/Gyn clinic for evaluation of a large vaginal mass. The referring provider had concern for malignancy. Lesions of the vulva were biopsied and found to be benign. For two months prior to presentation, she was experiencing discomfort with walking, yellow vaginal discharge, and dysuria. Treatment with fluconazole showed no improvement. She denied any personal or family history of malignancies, varicosities, or hepatic issues. Past surgical history was significant for laparoscopic cholecystectomy and two cesarean sections. A large vaginal mass during pregnancy is a concern whether it is malignancy or large vaginal varicosities that may put the patient at risk of severe hemorrhage during childbirth. We concluded that the mass was large vaginal varicosities as there was no discernible etiology. A repeat cesarean section was recommended due to the risk of hemorrhage during childbirth. For long-term management, close observation postpartum was recommended. Spontaneous resolution is a potential outcome and this is what our patient experienced. Without an underlying etiology, supportive measures are the best options. PMID- 29607235 TI - Long-Acting Luteinizing Hormone-Releasing Hormone Agonist for Ovarian Hyperstimulation Induced by Tamoxifen for Breast Cancer. AB - Tamoxifen treatment for breast cancer may induce ovarian cysts and supraphysiological levels of serum estrogen. We report successful management with luteinizing hormone-releasing hormone (LHRH) agonist of ovarian hyperstimulation induced by tamoxifen. A 49-year-old woman was operated on for invasive ductal carcinoma of the right breast. She received breast irradiation and adjuvant tamoxifen therapy. After 2 years, she had a cystic ovarian mass, and her serum concentration of estradiol was 1280 pg/mL. She was treated with an injection of 11.25 mg leuprolide acetate, a long-acting LHRH agonist, without abandoning tamoxifen therapy. The levels of estradiol decreased to <10 pg/mL and the cystic mass disappeared 2 months later. Three-month depot treatment with LHRH agonists can be useful for patients receiving tamoxifen for breast cancer who have ovarian cysts and supraphysiological levels of estrogen. PMID- 29607236 TI - A Case of Primary Uterina Lymphoma Presenting with Bleeding, Pelvic Pain, and Dysmenorrhea. AB - Primary non-Hodgkin's lymphoma (NHL) can arise from lymphatic cells located in solid organs (extranodal) and it accounts for 25 to 35% of all NHL. Primary lymphoma on the female genital tract (PLFGT) is a rare disease, comprising 0.2 to 1.1% of all extranodal lymphomas in the female population. In this paper, the authors report an extremely rare case of a 48-year-old woman who exhibited an abnormal uterine bleeding, pelvic pain, and dysmenorrhea history. The transvaginal ultrasound showed an anteverted uterus measuring 153 cm3 in volume, with intramural leiomyomas. She underwent a total laparoscopic hysterectomy with bilateral salpingectomy. The histologic evaluation of the specimen showed a follicular lymphoma with diffuse pattern in the endometrium. This report illustrates the difficulty in the diagnosis of primary lymphomas of the female genital tract. PMID- 29607237 TI - Adjuvant Radiochemotherapy with a 23-Month Overall Survival Time in a Patient after a Surgery due to Splenic Hemangiosarcoma Rupture: A Case Report with the Literature Review. AB - Spleen sarcoma is one of the most rare soft tissue malignancies. The annual incidence is 0.14-0.25/1,000,000 and the average age of diagnosis is 50 to 73 years. The incidence of this cancer has been increasing. Treatment of choice is surgical splenectomy, which rarely gives good results due to the aggressive course of the disease as well as the high potential for metastasis. Overall survival in primary spleen sarcomas as described by various authors is between 4 and 14 months. 80% of patients after spleen rupture do not survive 6 months. We report the case of a 42-year-old male diagnosed with spleen angiosarcoma. The patient underwent surgery in an emergency mode because of rapid rupture of the organ. Due to positive surgical margins, he underwent adjuvant radiochemotherapy followed by chemotherapy. Overall survival time was relatively long (23 months). The international guidelines provide information based on limited data. The role of postoperative radiotherapy in angiosarcomas remains controversial. Postoperative radiotherapy may increase local disease control, especially after nonradical operation, but this does not translate into improvement in overall survival time of these patients. The case shows that adjuvant radiotherapy as part of cancer treatment strategy may prolong the overall survival. PMID- 29607238 TI - Pulmonary Alveolar Proteinosis in Setting of Inhaled Toxin Exposure and Chronic Substance Abuse. AB - Pulmonary alveolar proteinosis (PAP) is a rare lung disorder in which defects in alveolar macrophage maturation or function lead to the accumulation of proteinaceous surfactant in alveolar space, resulting in impaired gas exchange and hypoxemia. PAP is categorized into three types: hereditary, autoimmune, and secondary. We report a case of secondary PAP in a 47-year-old man, whose risk factors include occupational exposure to inhaled toxins, especially aluminum dust, the use of anabolic steroids, and alcohol abuse, which in mice leads to alveolar macrophage dysfunction through a zinc-dependent mechanism that inhibits granulocyte macrophage-colony stimulating factor (GM-CSF) receptor signalling. Although the rarity and vague clinical presentation of PAP can pose diagnostic challenges, clinician awareness of PAP risk factors may facilitate the diagnostic process and lead to more prompt treatment. PMID- 29607239 TI - Lessons Learned in Evaluating a Multisite, Comprehensive Teen Dating Violence Prevention Strategy: Design and Challenges of the Evaluation of Dating Matters: Strategies to Promote Healthy Teen Relationships. AB - Objective: This paper describes the multisite, longitudinal cluster randomized controlled trial (RCT) design of the evaluation of the Dating Matters: Strategies to Promote Healthy Relationships initiative, and discusses challenges faced in conducting this evaluation. Method: Health departments in 4 communities are partnering with middle schools in high-risk, urban communities to implement 2 models of teen dating violence (TDV) prevention over 4 years. Schools were randomized to receive either the Dating Matters comprehensive strategy or the "standard of care" strategy (an existing, evidence-based TDV prevention curriculum). Our design permits comparison of the relative effectiveness of the comprehensive and standard of care strategies. Multiple cohorts of students from 46 middle schools are surveyed in middle school and high school, and parents and educators from participating schools are also surveyed. Results: Challenges discussed in conducting a multisite RCT include site variability, separation of implementation and evaluation responsibilities, school retention, parent engagement in research activities, and working within the context of high-risk urban schools and communities. We discuss the strengths and weaknesses of our approaches to these challenges in the hopes of informing future research. Conclusions: Despite multiple challenges, the design of the Dating Matters evaluation remains strong. We hope this paper provides researchers who are conducting complex evaluations of behavioral interventions with thoughtful discussion of the challenges we have faced and potential solutions to such challenges. PMID- 29607240 TI - Mining Next Generation Sequencing Data: How to Avoid "Treasure in, Error Out". PMID- 29607242 TI - Genetic Testing Preferences of Individuals in Families with Essential Tremor. AB - Background: The search for essential tremor (ET) genes is active, and it is only a matter of time before genetic tests become available. Genetic testing preferences in families have been studied in numerous other neurological disorders but there are no published data about ET. Methods: We surveyed 34 ET probands and their relatives (43 affected, 28 unaffected) enrolled in our Family Study of Essential Tremor to assess their interest in genetic testing. We examined whether clinical factors influenced their interest in testing. Clinical utility ("Your physician will be able to use the information obtained to improve your care") and penetrance ("How likely an individual who carries an ET gene is to develop ET") were defined for participants. Results: Interest in genetic testing was high in ET families (90/105 [85.7%]). There was a significant difference between affected (including probands and affected relatives) and unaffected relatives in terms of their interest in genetic testing, with the former being more interested (70/77 [90.9%] vs. 20/28 [71.4%] p = 0.04). Participants were more likely to want testing in the scenarios with high clinical utility; disease penetrance was not a determining factor (all p < 0.05). Sixteen hypothetical factors were identified that might influence a participant's decision to undergo genetic testing for ET. Discussion: Interest in genetic testing was high in ET families. While genetic testing is not currently available for ET, the hunt for ET genes is ongoing, and this is a highly familial disorder. Understanding genetic testing preferences will greatly aid clinicians once a genetic test becomes available. PMID- 29607241 TI - Longitudinal Follow-up of Impedance Drift in Deep Brain Stimulation Cases. AB - Background: Impedance is an integral property of neuromodulation devices that determines the current delivered to brain tissue. Long-term variability in therapeutic impedance following deep brain stimulation (DBS) has not been extensively investigated across different brain targets. The aim was to evaluate DBS impedance drift and variability over an extended postoperative period across common DBS targets. Methods: Retrospective data from 1,764 electrode leads were included and drawn from 866 DBS patients enrolled in the University of Florida Institutional Review Board-approved INFORM database and analyzed up to 84 months post implantation. An exploratory analysis was conducted to identify trends in impedances using a Mann-Kendall test of trend. Results: There were 866 patients and 1,764 leads available for analysis. The majority of subjects had Parkinson's disease (60.7%). The mean age at implantation was 58.7 years old and the mean follow-up time was 36.8 months. There were significant fluctuations in the mean impedance of all electrodes analyzed that largely stabilized by 6 months except for the subthalamic nucleus (STN) target, in which fluctuations persisted throughout the duration of follow-up with a continued downward trend (p < 0.001). Discussion: The drift in impedance observed primarily within the first 6 months is in keeping with prior studies and is likely due to surgical micro-lesioning effects and brain parenchyma remodeling at the electrode-tissue interface, typically at values approximating 1,000 Omega. The differences in impedance trends over time in the various DBS targets may be due to underlying differences in structure and tissue composition. PMID- 29607243 TI - Hereditary Myoclonus Dystonia: A Novel SGCE Variant and Phenotype Including Intellectual Disability. AB - Background: Hereditary myoclonus dystonia is often due to changes in the SGCE gene. Dystonia (DYT)-SGCE has a variable phenotype that can involve focal or generalized myoclonus and various forms of task-specific, segmental, or generalized dystonia. Psychiatric comorbidities are common. Case Report: We report a case of a young woman with generalized myoclonus, dystonia, and intellectual disability. She was found to have a novel SGCE splice site variant. Discussion: This novel variant is very likely pathogenic by in silico analysis and has not been previously reported. Additionally, her intellectual disability may constitute a novel phenotype for patients with SGCE variants. PMID- 29607244 TI - Thermal Isomerization of Hydroxyazobenzenes as a Platform for Vapor Sensing. AB - Photoisomerization of azobenzene derivatives is a versatile tool for devising light-responsive materials for a broad range of applications in photonics, robotics, microfabrication, and biomaterials science. Some applications rely on fast isomerization kinetics, while for others, bistable azobenzenes are preferred. However, solid-state materials where the isomerization kinetics depends on the environmental conditions have been largely overlooked. Herein, an approach to utilize the environmental sensitivity of isomerization kinetics is developed. It is demonstrated that thin polymer films containing hydroxyazobenzenes offer a conceptually novel platform for sensing hydrogen bonding vapors in the environment. The concept is based on accelerating the thermal cis-trans isomerization rate through hydrogen-bond-catalyzed changes in the thermal isomerization pathway, which allows for devising a relative humidity sensor with high sensitivity and quick response to relative humidity changes. The approach is also applicable for detecting other hydrogen-bonding vapors such as methanol and ethanol. Employing isomerization kinetics of azobenzenes for vapor sensing opens new intriguing possibilities for using azobenzene molecules in the future. PMID- 29607245 TI - Future of Health: Findings from a survey of stakeholders on the future of health and healthcare in England. AB - This article presents findings from a survey conducted by RAND Europe at the request of the National Institute for Health Research (NIHR) to gather and synthesise stakeholder views on the future of health and healthcare in England in 20 to 30 years' time. The aim of the research was to generate an evidenced-based picture of the future health and healthcare needs, and how it might differ from today, in order to inform strategic discussions about the future priorities of the NIHR and the health and social care research communities more broadly. The survey provided a rich and varied dataset based on responses from 300 stakeholders in total. A wide range of fields were represented, including public health, social care, primary care, cancer, genomics, mental health, geriatrics, child health, patient advocacy and health policy. The respondent group also included a number of professional and private stakeholder categories, such as clinicians, policy experts, academics and patient and public representatives. The study findings validate a number of prominent health research priorities currently visible in England, such as antimicrobial resistance, the burden of dementia and age-related multi-morbidity, digital health and genomics. Interest in these areas and other themes, such as mental health, health inequalities and transforming health service models, cut across multiple disciplinary boundaries. However, it is clear that there are a variety of views among stakeholders on the relative importance of these areas of focus, and the best approach to manage their emergence in the coming decades. The full dataset of survey responses, for which permission to share was given, is a useful resource for those seeking to engage with a particular issue in more depth. The dataset can be found on NIHR's website at: http://nihr.ac.uk/news-and-events/documents/quotes.xls. PMID- 29607246 TI - Understanding mental health in the research environment: A Rapid Evidence Assessment. AB - This study aimed to establish what is known about the mental health of researchers based on the existing literature. There is limited published evidence on the prevalence of specific mental health conditions among researchers. The majority of the identified literature on prevalence relates to work-related stress among academic staff and postgraduate students in university settings. Survey data indicate that the majority of university staff find their job stressful. Levels of burnout appear higher among university staff than in general working populations and are comparable to "high-risk" groups such as healthcare workers. The proportions of both university staff and postgraduate students with a risk of having or developing a mental health problem, based on self-reported evidence, were generally higher than for other working populations. Large proportions (>40 per cent) of postgraduate students report symptoms of depression, emotion or stress-related problems, or high levels of stress. Factors including increased job autonomy, involvement in decision making and supportive management were linked to greater job satisfaction among academics, as was the amount of time spent on research. Opportunities for professional development were also associated with reduced stress. UK higher education (HE) and research staff report worse wellbeing, as compared to staff in other sectors, in most aspects of work that can affect workers' stress levels. The evidence around the effectiveness of interventions to support the mental health of researchers specifically is thin. Few interventions are described in the literature and even fewer of those have been evaluated. PMID- 29607247 TI - Delivering Clinical Practice Guideline-Concordant Care for PTSD and Major Depression in Military Treatment Facilities. AB - Providing accessible, high-quality care for psychological health (PH) conditions, such as posttraumatic stress disorder (PTSD) and major depressive disorder (MDD), is important to maintaining a healthy, mission-ready force. It is unclear whether the current system of care meets the needs of service members with PTSD or MDD, and little is known about the barriers to delivering guideline-concordant care. RAND used existing provider workforce data, a provider survey, and key informant interviews to (1) provide an overview of the PH workforce at military treatment facilities (MTFs), (2) examine the extent to which care for PTSD and MDD in military treatment facilities is consistent with Department of Veterans Affairs/Department of Defense clinical practice guidelines, and (3) identify facilitators and barriers to providing this care. This study provides a comprehensive assessment of providers' perspectives on their capacity to deliver PH care within MTFs and presents detailed results by provider type and service branch. Findings suggest that most providers report using guideline-concordant psychotherapies, but use varied by provider type. The majority of providers reported receiving at least minimal training and supervision in at least one recommended psychotherapy for PTSD and for MDD. Still, more than one-quarter of providers reported that limits on travel and lack of protected time in their schedule affected their ability to access additional professional training. Finally, most providers reported routinely screening patients for PTSD and MDD with a validated screening instrument, but fewer providers reported using a validated screening instrument to monitor treatment progress. PMID- 29607248 TI - Quality of Care for PTSD and Depression in the Military Health System: Final Report. AB - The U.S. Department of Defense (DoD) strives to maintain a physically and psychologically healthy, mission-ready force, and the care provided by the Military Health System (MHS) is critical to meeting this goal. Attention has been directed to ensuring the quality and availability of programs and services for posttraumatic stress disorder (PTSD) and depression. This study is a comprehensive assessment of the quality of care delivered by the MHS in 2013-2014 for over 38,000 active-component service members with PTSD or depression. The assessment includes performance on 30 quality measures to evaluate the receipt of recommended assessments and treatments. These measures draw on multiple data sources including administrative encounter data, medical record review data, and patient self-reported outcome monitoring data. The assessment identified strengths and areas for improvement for the MHS. In particular, the MHS excels at screening for suicide risk and substance use, but rates of appropriate follow-up for service members with suicide risk are lower. Most service members received at least some psychotherapy, but less than half of psychotherapy delivered was evidence-based. In analyses focused on Army soldiers, outcome monitoring increased notably over time, yet preliminary analyses suggest that more work is needed to ensure that services are effective in reducing symptoms. When comparing performance between 2012-2013 and 2013-2014, most measures demonstrated slight improvement, but targeted efforts will be needed to support further improvements. RAND provides recommendations for strategies to improve the quality of care delivered for these conditions. PMID- 29607249 TI - Veterans' Health Insurance Coverage Under the Affordable Care Act and Implications of Repeal for the Department of Veterans Affairs. AB - This article describes the Affordable Care Act's (ACA's) effects on nonelderly veterans' insurance coverage and demand for Department of Veterans Affairs (VA) health care and assesses the coverage and VA utilization changes that could result from repealing the ACA. Although prior research has shown that the number of uninsured veterans fell after the ACA took effect, the implications of ACA repeal for veterans and, especially, for VA have received less attention. Besides providing a new coverage option to veterans who are not enrolled in VA, the ACA also had the potential to affect health care use among VA patients. Findings include the following: In 2013, prior to the major coverage expansions under the ACA, nearly one in ten nonelderly veterans were uninsured, lacking access to both VA coverage and non-VA health insurance. Uninsurance among nonelderly veterans fell by an adjusted 36 percent (3.3 percentage points) after implementation of the ACA, from 9.1 percent in 2013 to 5.8 percent in 2015. By increasing non-VA health insurance coverage for VA patients, the ACA likely reduced demand for VA care; the authors estimate that, if the gains in insurance coverage that occurred between 2013 and 2015 had not occurred, nonelderly veterans would have used about 1 percent more VA health care in 2015: 125,000 more office visits, 1,500 more inpatient surgeries, and 375,000 more prescriptions. Recent congressional proposals to repeal and replace the ACA would increase the number of uninsured nonelderly veterans and further increase demand for VA health care. PMID- 29607250 TI - Letter from the Editor. PMID- 29607251 TI - Pseudotumor from Metal-on-Metal Total Hip Arthroplasty Causing Unilateral Leg Edema: Case Presentation and Literature Review. AB - Metal-on-metal (MoM) total hip arthroplasty (THA) can be associated with adverse metal reactions, including pseudotumors. This case report describes a 58-year-old female with an MoM THA-related pseudotumor that caused unilateral leg edema from compression of her external iliac vein. After thorough preoperative workup to rule out infection and deep vein thrombosis and consultation with a vascular surgeon, the patient underwent revision THA and excision of her pseudotumor. She had complete resolution of her swelling at 4 years after surgery. Review of all available case reports for this rare complication revealed that almost all patients were female. All patients underwent revision THA, with resolution of their symptoms. Literature review demonstrates that women are disproportionally affected by complications associated with MoM THA. We recommend close monitoring of patients with MoM THA, particularly women, for development of adverse metal reactions. PMID- 29607252 TI - Intravital third harmonic generation microscopy of collective melanoma cell invasion: Principles of interface guidance and microvesicle dynamics. AB - Cancer cell invasion is an adaptive process based on cell-intrinsic properties to migrate individually or collectively, and their adaptation to encountered tissue structure acting as barrier or providing guidance. Whereas molecular and physical mechanisms of cancer invasion are well-studied in 3D in vitro models, their topographic relevance, classification and validation toward interstitial tissue organization in vivo remain incomplete. Using combined intravital third and second harmonic generation (THG, SHG), and three-channel fluorescence microscopy in live tumors, we here map B16F10 melanoma invasion into the dermis with up to 600 um penetration depth and reconstruct both invasion mode and tissue tracks to establish invasion routes and outcome. B16F10 cells preferentially develop adaptive invasion patterns along preformed tracks of complex, multi-interface topography, combining single-cell and collective migration modes, without immediate anatomic tissue remodeling or destruction. The data suggest that the dimensionality (1D, 2D, 3D) of tissue interfaces determines the microanatomy exploited by invading tumor cells, emphasizing non-destructive migration along microchannels coupled to contact guidance as key invasion mechanisms. THG imaging further detected the presence and interstitial dynamics of tumor-associated microparticles with submicron resolution, revealing tumor-imposed conditioning of the microenvironment. These topographic findings establish combined THG, SHG and fluorescence microscopy in intravital tumor biology and provide a template for rational in vitro model development and context-dependent molecular classification of invasion modes and routes. PMID- 29607253 TI - Detection of PCV2e strains in Southeast China. AB - Porcine circovirus 2 (PCV2) has been prevalent in swine herds in China since 2002, causing severe economic loss to the pig industry. The number of live pigs in southeast China is > 20 million. Since information on the genetic variation of PCV2 in the Fujian province is limited, the objective of the present work was to investigate the epidemiological and evolutionary characteristics of PCV2 in southeast China from 2013 to 2017. Of the 685 samples collected from 90 different swine herds from 2013 to 2017, 356 samples from 84 different swine herds were positive for PCV2. PCV2a, PCV2b, PCV2d, and PCV2e co-existed in the Fujian province, with PCV2d being the predominant circulating strain in swineherds and PCV2e being reported for the first time in China. Strikingly, PCV2-FJ-water DNA comes from contaminated river water and not infected animals. Sequence comparison among all isolates indicated that 95 isolates shared approximately 78.7%-100% nucleotide identity and 74.5%-100% amino acid identity for open reading frame 2 (ORF2). Amino acid alignment showed that the Cap protein of PCV2e differed markedly from those of PCV2a, PCV2b, PCV2c, and PCV2d. These results indicated that various PCV2 genotypes exist in China, and that PCV2 is continuously evolving, leading to rapid emergence of new variant stains. PMID- 29607254 TI - Temperament and character effects on late adolescents' well-being and emotional behavioural difficulties. AB - Background: Research on adults points to personality as a crucial determinant of well-being. The present study investigates the question of personality's relation to well-being and psychosocial adjustment in adolescence. Methods: We assessed the role of temperament and character (Temperament and Character Inventory, TCI 125), on psychological well-being (PWB; Psychological Well-Being scales), subjective well-being (SWB; Positive and Negative Affect, PA and NA, respectively), and psychosocial adjustment (emotional-behavioural problems measured by the Strengths and Difficulties Questionnaire for Adolescents, SDQ-A), in 72 Italian late adolescents (aged 17.5 +/- 0.75). Multiple regressions were conducted to predict PWB, SWB, and SDQ-A scores using TCI-125 scales as predictors. Results: Character maturity, and in particular Self-Directedness, had a widespread protective effect on well-being and psychosocial adjustment, while different strengths and emotional-behavioural difficulties were associated to specific temperamental and character traits. For example, Harm-Avoidance and Novelty-Seeking positively predicted internalized and externalized problems, respectively. Discussion: The present results suggest the usefulness of continuing to evaluate temperament and, in particular, character dimensions in investigations focused on adolescents' well-being and psychosocial functioning, especially in the contexts of potential interventions aimed at enhancing development of adolescents' character dimensions at the intrapersonal, interpersonal, and transpersonal levels. PMID- 29607255 TI - Playing by the rules? Phenotypic adaptation to temperate environments in an American marsupial. AB - Phenotypic variation along environmental gradients can provide evidence suggesting local adaptation has shaped observed morphological disparities. These differences, in traits such as body and extremity size, as well as skin and coat pigmentation, may affect the overall fitness of individuals in their environments. The Virginia opossum (Didelphis virginiana) is a marsupial that shows phenotypic variation across its range, one that has recently expanded into temperate environments. It is unknown, however, whether the variation observed in the species fits adaptive ecogeographic patterns, or if phenotypic change is associated with any environmental factors. Using phenotypic measurements of over 300 museum specimens of Virginia opossum, collected throughout its distribution range, we applied regression analysis to determine if phenotypes change along a latitudinal gradient. Then, using predictors from remote-sensing databases and a random forest algorithm, we tested environmental models to find the most important variables driving the phenotypic variation. We found that despite the recent expansion into temperate environments, the phenotypic variation in the Virginia opossum follows a latitudinal gradient fitting three adaptive ecogeographic patterns codified under Bergmann's, Allen's and Gloger's rules. Temperature seasonality was an important predictor of body size variation, with larger opossums occurring at high latitudes with more seasonal environments. Annual mean temperature predicted important variation in extremity size, with smaller extremities found in northern populations. Finally, we found that precipitation and temperature seasonality as well as low temperatures were strong environmental predictors of skin and coat pigmentation variation; darker opossums are distributed at low latitudes in warmer environments with higher precipitation seasonality. These results indicate that the adaptive mechanisms underlying the variation in body size, extremity size and pigmentation are related to the resource seasonality, heat conservation, and pathogen-resistance hypotheses, respectively. Our findings suggest that marsupials may be highly susceptible to environmental changes, and in the case of the Virginia opossum, the drastic phenotypic evolution in northern populations may have arisen rapidly, facilitating the colonization of seasonal and colder habitats of temperate North America. PMID- 29607256 TI - The modern spectrum of biopsy-proven renal disease in Chinese diabetic patients-a retrospective descriptive study. AB - Background: Renal biopsies performed in diabetic patients are increasing and becoming more complex. Comprehensive data on modern spectrum of biopsy-proven renal disease in Chinese diabetic patients are lacking. Methods: In a nationwide renal biopsy survey including 71,151 native biopsies from 2004 to 2014, diabetic patients were identified according to the clinical diagnosis from referral records. The clinical data were extracted from referral records and pathological reports. Results: A total of 1,604 diabetic patients, including 61 patients with T1DM, were analyzed in this study. The median age is 51.39 +/- 11.37 years. Male patients accounted for 58% of the population. We found that only 44.7% of diabetic patients had the isolated pathological diagnosis of diabetic nephropathy (DN), while 49.1% had non-diabetic renal disease (NDRD) alone, and 6.2% had NDRD superimposed on DN. Nephrotic syndrome (n = 824, 51.4%) was the most common clinical indication for renal biopsy. Among 887 patients with NDRD, membranous nephropathy (n = 357) was the leading diagnosis, followed by IgA nephropathy (n = 179). Hypertensive renal disease (n = 32), tubulointerstitial nephropathy (n = 27) and acute tubular necrosis (n = 16) accounted for 3.5%, 2.9%, 1.7% of the NDRD cases respectively. Nearly a half (49.2%) of patients with T1DM had NDRD. Discussion: Over 55% diabetic patients with kidney disease were diagnosed as non diabetic renal disease, among which MN and IgAN were the most common two pathological types. PMID- 29607257 TI - The Leuven Embedded Figures Test (L-EFT): measuring perception, intelligence or executive function? AB - Performance on the Embedded Figures Test (EFT) has been interpreted as a reflection of local/global perceptual style, weak central coherence and/or field independence, as well as a measure of intelligence and executive function. The variable ways in which EFT findings have been interpreted demonstrate that the construct validity of this measure is unclear. In order to address this lack of clarity, we investigated to what extent performance on a new Embedded Figures Test (L-EFT) correlated with measures of intelligence, executive functions and estimates of local/global perceptual styles. In addition, we compared L-EFT performance to the original group EFT to directly contrast both tasks. Taken together, our results indicate that performance on the L-EFT does not correlate strongly with estimates of local/global perceptual style, intelligence or executive functions. Additionally, the results show that performance on the L-EFT is similarly associated with memory span and fluid intelligence as the group EFT. These results suggest that the L-EFT does not reflect a general perceptual or cognitive style/ability. These results further emphasize that empirical data on the construct validity of a task do not always align with the face validity of a task. PMID- 29607258 TI - Description of a Zostera marina catalase gene involved in responses to temperature stress. AB - Catalase (CAT) is an antioxidant enzyme that plays a significant role in cellular protection against oxidative damage by degradation of hydrogen peroxide to oxygen and water. In the present study, the complete CAT cDNA sequence of Zostera marina was identified through expressed sequence tags (EST) analysis and the rapid amplification of cDNA ends (RACE) technique. The nucleotide sequence of ZmCAT cDNA consisted of 1,816 bp with a 1,434 bp open reading frame (ORF), encoding a polypeptide of 477 amino acid residues, which possessed significant homology to other known plant CATs. The molecular mass of the predicted protein was 55.3 kDa with an estimated isoelectric point of 6.40. Phylogenetic analysis showed that ZmCAT was closely related to CAT from gramineous species. In response to temperature stress, H2O2 and MDA contents in Z. marina increased significantly with cold stress (<10 degrees C) and heat stress (>25 degrees C). ZmCAT expression was significantly upregulated at temperatures from 5 to 10 degrees C and then gradually downregulated, reaching its lowest expression at 30 degrees C. Recombinant ZmCAT protein exhibited strong antioxidant activity over a wide temperature range, with the highest rZmCAT activity observed at 25 degrees C and a higher relative activity retained even with heat stress. All these results indicated that ZmCAT was a member of the plant CAT family and involved in minimizing oxidative damage effects in Z. marina under temperature stress. PMID- 29607259 TI - Infection by Parorchis acanthus (Trematoda) decreases grazing by the keystone gastropod, Littoraria irrorata. AB - Parasites are well-known to alter the behavior of their hosts, but there is still a paucity of knowledge about how parasites modify the behavior of many ecologically influential host species. I studied the keystone grazer, the salt marsh periwinkle (Littoraria irrorata), to determine the influence of infection by the digenetic trematode, Parorchis acanthus, on its grazing behavior. Comparative laboratory grazing studies of wild-collected and experimentally infected snails revealed that Parorchis decreased grazing on live Spartina by more than 80%. Because of the large ecological influence of Littoraria in southern U.S. marshes, parasite modification of snail grazing may have ramifications for marsh ecosystem stability if parasite prevalence is sufficiently high. PMID- 29607261 TI - Female harbor seal (Phoca vitulina) behavioral response to playbacks of underwater male acoustic advertisement displays. AB - During the breeding season, male harbor seals (Phoca vitulina) make underwater acoustic displays using vocalizations known as roars. These roars have been shown to function in territory establishment in some breeding areas and have been hypothesized to be important for female choice, but the function of these sounds remains unresolved. This study consisted of a series of playback experiments in which captive female harbor seals were exposed to recordings of male roars to determine if females respond to recordings of male vocalizations and whether or not they respond differently to roars from categories with different acoustic characteristics. The categories included roars with characteristics of dominant males (longest duration, lowest frequency), subordinate males (shortest duration, highest frequency), combinations of call parameters from dominant and subordinate males (long duration, high frequency and short duration, low frequency), and control playbacks of water noise and water noise with tonal signals in the same frequency range as male signals. Results indicate that overall females have a significantly higher level of response to playbacks that imitate male vocalizations when compared to control playbacks of water noise. Specifically, there was a higher level of response to playbacks representing dominant male vocalization when compared to the control playbacks. For most individuals, there was a greater response to playbacks representing dominant male vocalizations compared to playbacks representing subordinate male vocalizations; however, there was no statistical difference between those two playback types. Additionally, there was no difference between the playbacks of call parameter combinations and the controls. Investigating female preference for male harbor seal vocalizations is a critical step in understanding the harbor seal mating system and further studies expanding on this captive study will help shed light on this important issue. PMID- 29607260 TI - Genome rearrangements and phylogeny reconstruction in Yersinia pestis. AB - Genome rearrangements have played an important role in the evolution of Yersinia pestis from its progenitor Yersinia pseudotuberculosis. Traditional phylogenetic trees for Y. pestis based on sequence comparison have short internal branches and low bootstrap supports as only a small number of nucleotide substitutions have occurred. On the other hand, even a small number of genome rearrangements may resolve topological ambiguities in a phylogenetic tree. We reconstructed phylogenetic trees based on genome rearrangements using several popular approaches such as Maximum likelihood for Gene Order and the Bayesian model of genome rearrangements by inversions. We also reconciled phylogenetic trees for each of the three CRISPR loci to obtain an integrated scenario of the CRISPR cassette evolution. Analysis of contradictions between the obtained evolutionary trees yielded numerous parallel inversions and gain/loss events. Our data indicate that an integrated analysis of sequence-based and inversion-based trees enhances the resolution of phylogenetic reconstruction. In contrast, reconstructions of strain relationships based on solely CRISPR loci may not be reliable, as the history is obscured by large deletions, obliterating the order of spacer gains. Similarly, numerous parallel gene losses preclude reconstruction of phylogeny based on gene content. PMID- 29607262 TI - Genetic diversity and molecular evolution of Ornithogalum mosaic virus based on the coat protein gene sequence. AB - Ornithogalum mosaic virus (OrMV) has a wide host range and affects the production of a variety of ornamentals. In this study, the coat protein (CP) gene of OrMVwas used to investigate the molecular mechanisms underlying the evolution of this virus. The 36 OrMV isolates fell into two groups which have significant subpopulation differentiation with an FST value of 0.470. One isolate was identified as a recombinant and the other 35 recombination-free isolates could be divided into two major clades under different evolutionary constraints with dN/dS values of 0.055 and 0.028, respectively, indicating a role of purifying selection in the differentiation of OrMV. In addition, the results from analysis of molecular variance (AMOVA) indicated that the effect of host species on the genetic divergence of OrMV is greater than that of geography. Furthermore, OrMV isolates from the genera Ornithogalum, Lachenalia and Diuri tended to group together, indicating that OrMV diversification was maintained, in part, by host driven adaptation. PMID- 29607263 TI - Breast cancer identification via modeling of peripherally circulating miRNAs. AB - Prolonged life expectancy in humans has been accompanied by an increase in the prevalence of cancers. Breast cancer (BC) is the leading cause of cancer-related deaths. It accounts for one-fourth of all diagnosed cancers and affects one in eight females worldwide. Given the high BC prevalence, there is a practical need for demographic screening of the disease. In the present study, we re-analyzed a large microRNA (miRNA) expression dataset (GSE73002), with the goal of optimizing miRNA biomarker selection using neural network cascade (NNC) modeling. Our results identified numerous candidate miRNA biomarkers that are technically suitable for BC detection. We combined three miRNAs (miR-1246, miR-6756-5p, and miR-8073) into a single panel to generate an NNC model, which successfully detected BC with 97.1% accuracy in an independent validation cohort comprising 429 BC patients and 895 healthy controls. In contrast, at least seven miRNAs were merged in a multiple linear regression model to obtain equivalent diagnostic performance (96.4% accuracy in the independent validation set). Our findings suggested that suitable modeling can effectively reduce the number of miRNAs required in a biomarker panel without compromising prediction accuracy, thereby increasing the technical possibility of early detection of BC. PMID- 29607264 TI - Postcranial skeletal anatomy of the holotype and referred specimens of Buitreraptor gonzalezorum Makovicky, Apesteguia and Agnolin 2005 (Theropoda, Dromaeosauridae), from the Late Cretaceous of Patagonia. AB - Here we provide a detailed description of the postcranial skeleton of the holotype and referred specimens of Buitreraptor gonzalezorum. This taxon was recovered as an unenlagiine dromaeosaurid in several recent phylogenetic studies and is the best represented Gondwanan dromaeosaurid discovered to date. It was preliminarily described in a brief article, but a detailed account of its osteology is emerging in recent works. The holotype is the most complete specimen yet found, so an exhaustive description of it provides much valuable anatomical information. The holotype and referred specimens preserve the axial skeleton, pectoral and pelvic girdles, and both fore- and hindlimbs. Diagnostic postcranial characters of this taxon include: anterior cervical centra exceeding the posterior limit of neural arch; eighth and ninth cervical vertebral centra with lateroventral tubercles; pneumatic foramina only in anteriormost dorsals; middle and posterior caudal centra with a complex of shallow ridges on lateral surfaces; pneumatic furcula with two pneumatic foramina on the ventral surface; scapular blade transversely expanded at mid-length; well-projected flexor process on distal end of the humerus; dorsal rim of the ilium laterally everted; and concave dorsal rim of the postacetabular iliac blade. A paleohistological study of limb bones shows that the holotype represents an earlier ontogenetic stage than one of the referred specimens (MPCA 238), which correlates with the fusion of the last sacral vertebra to the rest of the sacrum in MPCA 238. A revised phylogenetic analysis recovered Buitreraptor as an unenlagiine dromaeosaurid, in agreement with previous works. The phylogenetic implications of the unenlagiine synapomorphies and other characters, such as the specialized pedal digit II and the distal ginglymus on metatarsal II, are discussed within the evolutionary framework of Paraves. PMID- 29607265 TI - Pollination implications of the diverse diet of tropical nectar-feeding bats roosting in an urban cave. AB - Background: Intense landscaping often alters the plant composition in urban areas. Knowing which plant species that pollinators are visiting in urban areas is necessary for understanding how landscaping impacts biodiversity and associated ecosystem services. The cave nectar bat, Eonycteris spelaea, is an important pollinator for many plants and is often recorded in human-dominated habitats. Previous studies of the diet of E. spelaea relied on morphological identification of pollen grains found in faeces and on the body of bats and by necessity disregarded other forms of digested plant material present in the faeces (i.e., plant juice and remnants). The main objective of this study was to examine the diet of the nectarivorous bat, E. spelaea, roosting in an urban cave at Batu Caves, Peninsular Malaysia by identifying the plant material present in the faeces of bats using DNA metabarcoding. Methods: Faeces were collected under the roost of E. spelaea once a week from December 2015 to March 2016. Plant DNA was extracted from the faeces, Polymerase chain reaction (PCR) amplified at ITS2 and rbcL regions and mass sequenced. The resultant plant operational taxonomic units were searched against NCBI GenBank for identification. Results: A total of 55 species of plants were detected from faeces of E. spelaea including Artocarpus heterophyllus, Duabanga grandiflora and Musa spp. which are likely to be important food resources for the cave nectar bat. Discussion: Many native plant species that had not been reported in previous dietary studies of E. spelaea were detected in this study including Bauhinia strychnoidea and Urophyllum leucophlaeum, suggesting that E. spelaea remains a crucial pollinator for these plants even in highly disturbed habitats. The detection of many introduced plant species in the bat faeces indicates that E. spelaea are exploiting them, particularly Xanthostemon chrysanthus, as food resources in urban area. Commercial food crops were detected from all of the faecal samples, suggesting that E. spelaea feed predominantly on the crops particularly jackfruit and banana and play a significant role in pollination of economically important plants. Ferns and figs were also detected in the faeces of E. spelaea suggesting future research avenues to determine whether the 'specialised nectarivorous' E. spelaea feed opportunistically on other parts of plants. PMID- 29607266 TI - Phosphate Recovery from Human Waste via the Formation of Hydroxyapatite during Electrochemical Wastewater Treatment. AB - Electrolysis of toilet wastewater with TiO2-coated semiconductor anodes and stainless steel cathodes is a potentially viable onsite sanitation solution in parts of the world without infrastructure for centralized wastewater treatment. In addition to treating toilet wastewater, pilot-scale and bench-scale experiments demonstrated that electrolysis can remove phosphate by cathodic precipitation as hydroxyapatite at no additional energy cost. Phosphate removal could be predicted based on initial phosphate and calcium concentrations, and up to 80% total phosphate removal was achieved. While calcium was critical for phosphate removal, magnesium and bicarbonate had only minor impacts on phosphate removal rates at concentrations typical of toilet wastewater. Optimal conditions for phosphate removal were 3 to 4 h treatment at about 5 mA cm-2 (~3.4 V), with greater than 20 m2 m-3 electrode surface area to reactor volume ratios. Pilot scale systems are currently operated under similar conditions, suggesting that phosphate removal can be viewed as an ancillary benefit of electrochemical wastewater treatment, adding utility to the process without requiring additional energy inputs. Further value may be provided by designing reactors to recover precipitated hydroxyapatite for use as a low solubility phosphorus-rich fertilizer. PMID- 29607267 TI - Lewis Acid Catalyzed Conversion of 5-Hydroxymethylfurfural to 1,2,4-Benzenetriol, an Overlooked Biobased Compound. AB - 5-Hydroxymethylfurfural (HMF) is a platform chemical that can be produced from renewable carbohydrate sources. HMF can be converted to 1,2,4-benzenetriol (BTO) which after catalytic hydrodeoxygenation provides a route to cyclohexanone and cyclohexanol. This mixture, known as KA oil, is an important feedstock for polymeric products such as nylons which use benzene as feedstock that is obtained from the BTX fraction produced in oil refineries. Therefore, the conversion of HMF to BTO provides a renewable, alternative route toward products such as nylons. However, BTO is usually considered an undesired byproduct in HMF synthesis and is only obtained in small amounts. Here, we show that Lewis acid catalysts can be utilized for the selective conversion of HMF to BTO in subsuper critical water. Overall, up to 54 mol % yield of BTO was achieved at 89% HMF conversion using ZnCl2. ZnCl2 and similarly effective Zn(OTf)2 and Fe(OTf)2 are known as relatively soft Lewis acids. Other Lewis acid like Hf(OTf)4 and Sc(OTf)3 gave increased selectivity toward levulinic acid (up to 33 mol %) instead of BTO, a well-known HMF derivative typically obtained by acid catalysis. Catalytic hydrodeoxygenation of BTO toward cyclohexanone in water was achieved in up to 45% yield using 5 wt % Pd on Al2O3 combined with AlCl3 or Al(OTf)3 as catalysts. Additionally, a mild selective oxygen induced dimerization pathway of BTO to 2,2',4,4',5,5'-hexahydroxybiphenyl (5,5'-BTO dimer) was identified. PMID- 29607268 TI - Synthesis of Bio-aromatics from Black Liquors Using Catalytic Pyrolysis. AB - Bio-aromatics (benzene, toluene, xylenes, BTX) were prepared by the catalytic pyrolysis of six different black liquors using both in situ and ex situ approaches. A wide range of catalysts was screened and conditions were optimized in microscale reactors. Up to 7 wt % of BTX, based on the organic fraction of the black liquors, was obtained for both the in situ and ex situ pyrolysis (T = 500 600 degrees C) using a Ga-modified H-ZSM-5 catalyst. The in situ catalytic pyrolysis of black liquors from hardwood paper mills afforded slightly higher yields of aromatics/BTX than softwood black liquors, a trend that could be confirmed by the results obtained in the ex situ catalytic pyrolysis. An almost full deoxygenation of the lignin and carbohydrate fraction was achieved and both organic fractions were converted to a broad range of (substituted) aromatics. The zeolite catalyst used was remarkably stable and even after 100 experiments in batch mode with intermittent oxidative catalyst regeneration, the yields and selectivity toward BTX remained similar. The ex situ pyrolysis of black liquor has potential for large-scale implementation in a paper mill without disturbing the paper production process. PMID- 29607269 TI - Mycophenolate Mofetil in a Lupus Patient with Pulmonary Hypertension. AB - Pulmonary hypertension (PH) is a life-threatening complication of several, different connective tissue diseases, including systemic lupus erythematous (SLE), systemic sclerosis, and rheumatoid arthritis. PH can present early in SLE. The severity does not correlate with other organ disease activity or with disease duration. It is still debatable whether immunosuppressive therapy is useful for PH related to SLE or autoimmune connective tissue disease, as there are no large clinical trials. However, several case reports have shown improvement with cyclophosphamide and prednisone with or without vasodilator therapy. We present a case of SLE-related PH in which a dramatic improvement in mean pulmonary artery pressure and exercise capacity was noted after the institution of treatment with mycophenolate mofetil, resulting in a decrease in corticosteroid dose. Our observations support the potential value of mycophenolate mofetil therapy for PH in SLE. PMID- 29607270 TI - Risks of Colon Injuries in Extreme Lateral Approaches to the Lumbar Spine: An Anatomical Study. AB - Introduction? The extreme lateral interbody fusion technique (XLIF) is a modification of the retroperitoneal approach to the lumbar spine. This is a minimally invasive technique allowing direct access to the disc space without peritoneal or posterior paraspinal musculature damage. Nevertheless, the retroperitoneal part of the colon can be injured in this operative technique. To our knowledge, a study analyzing the anatomical considerations of the extreme lateral interbody fusion technique with regards to potential colon injuries has not been previously performed. Therefore, the aim of this study was to evaluate the potential risk of colon injuries during the extreme lateral approach to the lumbar spine. Materials and Methods? The extreme lateral approach to the lumbar spine was performed on four fresh-frozen cadaveric sides. K-wires were placed into the intervertebral discs and positioned at L1/L2, L2/L3, L3/L4, and L4/L5 levels. Next, the distances from the wires to the most posterior aspect of the adjacent ascending or descending colon were measured.? Results? The mean distance from the intervertebral disc space to the ascending or descending colon was 23.2 mm at the L2/L3 level, 29.5 mm at the L3/L4 level, and 40.3 mm at the L4/L5 level. The L1/L2 level was above the colon on both sides.? Conclusion? Our study quantified the relationship of the retroperitoneal colon during an extreme lateral interbody fusion approach. Our results, as well as previously described cases of bowel perforations, suggest a greater risk for colon injuries at the L2/3 and L3/4 levels.. PMID- 29607271 TI - Anatomical Study of the Extreme Lateral Transpsoas Lumbar Interbody Fusion with Application to Minimizing Injury to the Kidney. AB - Objective Since the extreme lateral lumbar interbody fusion procedure was first reported by Ozgur in 2006, a large number of clinical studies have been published. Anatomical studies which explore methods to avoid visceral structures, such as the kidney, with this approach have not been examined in detail. We dissected the retroperitoneal space to analyze how the extreme lateral transpsoas approach to the lumbar spine could damage the kidney and related structures. Methods Eight sides from four fresh Caucasian cadavers were used for this study. The latissimus dorsi muscle and the thoracolumbar fascia were dissected to open the retroperitoneum. The fat tissue was removed. Steel wires were then put into the intervertebral disc spaces. Finally, the closest distance between kidney and wires on each interdiscal space was measured. Results The closest distance from the wire in the interdiscal space on L1/2, L2/3 and L3/4 to the kidney ranged from 13.2 mm to 32.9 mm, 20.0 mm to 27.7 mm, and 20.5 mm to 46.6 mm, respectively. The distance from the kidney to the interdiscal space at L4/5 was too great to be considered applicable to this study. Conclusions The results of this study might help surgeons better recognize the proximity of the kidney and avoid injury to it during the extreme lateral transpsoas approach to the lumbar spine. PMID- 29607272 TI - A Masquerading and Unconventional Cause of Dynamic Intestinal Obstruction: Strangulated Obturator Hernia. AB - Obturator hernia is an extremely rare type of abdominal wall hernia occurring mostly in elderly, thin females. It is characterized by the herniation of intra abdominal contents through the obturator foramen. Symptoms are often nonspecific, and the patient usually presents with an acute or subacute intestinal obstruction. A high index of suspicion is needed in such females presenting with abdominal distention and positive Howship-Romberg signs. Computed tomography of the abdomen and pelvis are often necessary to arrive at a diagnosis, and immediate surgical intervention is recommended. The high postoperative morbidity and mortality are often attributed to a delay in the diagnosis and in initiating treatment. We present a case of a 65-year-old lady with strangulated obturator hernia who underwent emergent, lower midline laparotomy with resection and anastomosis of the small bowel and purse-string repair of the hernial defect. PMID- 29607273 TI - Recurrent Pneumocystis Pneumonia with Uncommon Radiographic Presentation. AB - Pneumocystis carinii pneumonia (PCP) is a common opportunistic infection of the pulmonary parenchyma seen in the immunocompromised host. The clinical presentation and radiographic findings are varied, with the latter ranging from normal to bilateral ground-glass opacities with cyst formation. We present a case of a 46-year-old woman with a history of human immunodeficiency virus (HIV) with multiple treated prior episodes of PCP, who was found to have an impressive presentation on high-resolution chest computed tomography (HRCT). PMID- 29607274 TI - Use of the Brown-Roberts-Wells Stereotactic Frame in a Developing Country. AB - Stereotactic surgery planning software has been created for use with the Brown Roberts-Wells (BRW) stereotactic frame. This software replaces the Hewlett Packard calculator originally supplied with the BRW frame and provides modern tools for surgery planning to the BRW frame, which facilitate its potential use as a low-cost alternative to the Cosman-Roberts-Wells (CRW) frame in developing countries. PMID- 29607275 TI - Use of an Absorbable Synthetic Polymer Dural Substitute for Repair of Dural Defects: A Technical Note. AB - Repair of the dura after cranial neurosurgery can present a technical challenge and, for certain neurosurgical procedures, is critical to prevent cerebrospinal fluid leak and associated wound complications. Multiple options exist for dural repair, including the patient's own tissues, bovine collagen-derived commercially available grafts, as well as newer, entirely synthetic graft materials. This is the first report of surgical experience with a new synthetic and absorbable dura substitute which has recently gained Food and Drug Administration (FDA) approval. Four patients underwent dural reconstruction with a new graft material after cranial neurosurgery when the dura was unrepairable directly. The synthetic graft material demonstrated satisfactory surgical qualities, was effective in dural repair, and no complications were attributable to the graft. Dural repair after craniotomy is an often desirable surgical outcome in neurosurgery. Surgeons seeking new graft materials may find this new absorbable, entirely synthetic material favorable for dural repair. PMID- 29607276 TI - Central Retinal Artery Occlusion with Sparing of Cilioretinal Artery Post Pulmonary Artery Stenting. AB - Central retinal arterial occlusion is an ocular emergency. Central retinal artery occlusion following cardiac procedures have been described in adults. We describe a pediatric patient who developed central retinal artery occlusion following pulmonary artery stenting. It is important to highlight this potential risk to ensure early diagnosis and prompt treatment. PMID- 29607277 TI - Evidence for the hook supercoiling mechanism of the bacterial flagellum. AB - The bacterial flagellar hook is a short, highly curved tubular structure connecting the basal body as a rotary motor and the filament as a helical propeller to function as a universal joint to transmit motor torque to the filament regardless of its orientation. This highly curved form is known to be part of a supercoil as observed in the polyhook structure. The subunit packing interactions in the Salmonella hook structure solved in the straight form gave clear insights into the mechanisms of its bending flexibility and twisting rigidity. Salmonella FlgE consists of four domains, D0, Dc, D1 and D2, arranged from inside to outside of the tube, and an atomic model of the supercoiled hook built to simulate the hook shape observed in the native flagellum suggested that the supercoiled form is stabilized by near-axial interactions of the D2 domains on the inner surface of the supercoil. Here we show that the deletion of domain D2 from FlgE makes the hook straight, providing evidence to support the proposed hook supercoiling mechanism that it is the near-axial interactions between the D2 domains that stabilize the highly curved hook structure. PMID- 29607278 TI - Molecular dynamics simulation study on the structural instability of the most common cystic fibrosis-associated mutant DeltaF508-CFTR. AB - Cystic fibrosis transmembrane conductance regulator (CFTR) is an anion channel that belongs to the ATP binding cassette protein superfamily. Deletion of phenylalanine at position 508 (DeltaF508) is the most common CF-associated mutation and is present in nearly 90% of CF patients. Currently, atomistic level studies are insufficient for understanding the mechanism by which the deletion of a single amino acid causes greatly reduced folding as well as trafficking and gating defects. To clarify this mechanism, we first constructed an atomic model of the inward-facing DeltaF508-CFTR and performed allatom molecular dynamics (MD) simulations of the protein in a membrane environment. All of the computational methodologies used are based on those developed in our previous study for wild type CFTR. Two important findings were obtained. First, consistent with several previous computational results, the deletion of F508 causes a disruption of a hydrophobic cluster located at the interface between the nucleotide binding domain 1 (NBD1) and intracellular loop 4 (ICL4). This exerts unfavorable influences on the correlated motion between ICLs and transmembrane domains (TMDs), likely resulting in gating defects. Second, the F508 deletion affected the NBD1-NBD2 interface via allosteric communication originating from the correlated motion between NBDs and ICLs. As a result, several unusual inter residue interactions are caused at the NBD1-NBD2 interface. In other words, their correct dimerization is impaired. This study provided insight into the atomic level details of structural and dynamics changes caused by the DeltaF508 mutation and thus provides good insight for drug design. PMID- 29607279 TI - Magnetic structure of manganese cluster in photosystem II investigated by electron paramagnetic resonance. AB - The electronic structure of manganese (Mn) cluster in photosystem II was investigated by electron paramagnetic resonance (EPR) spectroscopy. In order to determine the spin density distribution in magnetically coupled Mn in the S2 state Mn cluster, pulsed electron-electron double resonance (PELDOR) measurement was performed. The local environment of the Mn cluster was investigated by electron-nuclear double resonance (ENDOR). Using spin projections determined by PELDOR, ENDOR signals were assigned to the water molecules ligated to the Mn cluster. The location of a high-affinity Mn2+ site in apo-photosystem II, which is the initial site of photoactivation of the Mn cluster, was determined by PELDOR. PMID- 29607280 TI - Collective motion of rod-shaped self-propelled particles through collision. AB - Self-propelled rods, which propel by themselves in the direction from the tail to the head and align nematically through collision, have been well-investigated theoretically. Various phenomena including true long-range ordered phase with the Giant number fluctuations, and the collective motion composed of many vorices were predicted using the minimal mathematical models of self-propelled rods. Using filamentous bacteria and running microtubules, we found that the predicted phenomena by the minimal models occur in the real world. This strongly indicates that there exists the unified description of self-propelled rods independent of the details of the systems. The theoretically predicted phenomena and the experimental results concerning the phenomena are reviewed. PMID- 29607281 TI - Theoretical framework for analyzing structural compliance properties of proteins. AB - We propose methods for directly analyzing structural compliance (SC) properties of elastic network models of proteins, and we also propose methods for extracting information about motion properties from the SC properties. The analysis of SC properties involves describing the relationships between the applied forces and the deformations. When decomposing the motion according to the magnitude of SC (SC mode decomposition), we can obtain information about the motion properties under the assumption that the lower SC mode motions or the softer motions occur easily. For practical applications, the methods are formulated in a general form. The parts where forces are applied and those where deformations are evaluated are separated from each other for enabling the analyses of allosteric interactions between the specified parts. The parts are specified not only by the points but also by the groups of points (the groups are treated as flexible bodies). In addition, we propose methods for quantitatively evaluating the properties based on the screw theory and the considerations of the algebraic structures of the basic equations expressing the SC properties. These methods enable quantitative discussions about the relationships between the SC mode motions and the motions estimated from two different conformations; they also help identify the key parts that play important roles for the motions by comparing the SC properties with those of partially constrained models. As application examples, lactoferrin and ATCase are analyzed. The results show that we can understand their motion properties through their lower SC mode motions or the softer motions. PMID- 29607282 TI - Recent advancement on chemical arsenal of Bt toxin and its application in pest management system in agricultural field. AB - Bacillus thuringiensis (Bt) is a Gram-positive, spore-forming, soil bacterium, which is very popular bio-control agent in agricultural and forestry. In general, B. thuringiensis secretes an array of insecticidal proteins including toxins produced during vegetative growth phase (such as secreted insecticidal protein, Sip; vegetative insecticidal proteins, Vip), parasporal crystalline delta endotoxins produced during vegetative stationary phase (such as cytolytic toxin, Cyt; and crystal toxin, Cry), and beta-exotoxins. Till date, a wide spectrum of Cry proteins has been reported and most of them belong to three-domain-Cry toxins, Bin-like toxin, and Etx_Mtx2-like toxins. To the best of our knowledge, neither Bt insecticidal toxins are exclusive to Bt nor all the strains of Bt are capable of producing insecticidal Bt toxins. The lacuna in their latest classification has also been discussed. In this review, the updated information regarding the insecticidal Bt toxins and their different mode of actions were summarized. Before applying the Bt toxins on agricultural field, the non-specific effects of toxins should be investigated. We also have summarized the problem of insect resistance and the strategies to combat with this problem. We strongly believe that this information will help a lot to the budding researchers in the field of modern pest control biotechnology. PMID- 29607283 TI - Genotype-independent and enhanced in planta Agrobacterium tumefaciens-mediated genetic transformation of peanut [Arachis hypogaea (L.)]. AB - Agrobacterium infection and regeneration of the putatively transformed plant from the explant remains arduous for some crop species like peanut. Henceforth, a competent and reproducible in planta genetic transformation protocol is established for peanut cv. CO7 by standardizing various factors such as pre culture duration, acetosyringone concentration, duration of co-cultivation, sonication and vacuum infiltration. In the present investigation, Agrobacterium tumefaciens strain EHA105 harboring the binary vector pCAMBIA1301-bar was used for transformation. The two-stage selection was carried out using 4 and 250 mg l 1 BASTA(r) to completely eliminate the chimeric and non-transformed plants. The transgene integration into plant genome was evaluated by GUS histochemical assay, polymerase chain reaction (PCR), and Southern blot hybridization. Among the various combinations and concentrations analyzed, highest transformation efficiency was obtained when the 2-day pre-cultured explants were subjected to sonication for 6 min and vacuum infiltrated for 3 min in Agrobacterium suspension, and co-cultivated on MS medium supplemented with 150 uM acetosyringone for 3 days. The fidelity of the standardized in planta transformation method was assessed in five peanut cultivars and all the cultivars responded positively with a transformation efficiency ranging from minimum 31.3% (with cv. CO6) to maximum 38.6% (with cv. TMV7). The in planta transformation method optimized in this study could be beneficial to develop superior peanut cultivars with desirable genetic traits. PMID- 29607284 TI - Development of a yeast heterologous expression cassette based on the promoter and terminator elements of the Eremothecium cymbalariae translational elongation factor 1alpha (EcTEF1) gene. AB - A new expression cassette (EC0) consisting of the fused 5' and 3' intergenic regions (IGRs) of the Eremothecium cymbalariae translational elongation factor 1alpha (EcTEF1) gene was evaluated through expression of the bacterial hygromycin B phosphotransferase (hph) resistance gene in the common baker's yeast Saccharomyces cerevisiae. Progressively shorter versions of the hph-containing EC cassette (hphEC1 though hphEC6) with trimmed 5' and 3' EcTEF1 IGRs were tested for their ability to confer resistance to hygromycin B in S. cerevisiae. Hygromycin B resistance was retained in all six generated hphEC variants up to a concentration of 400 mg/L. The hphEC6 cassette was the shortest cassette to be assayed in this study with 366 and 155 bp of the EcTEF1 5' and 3' IGRs, respectively. When tested for deletion of the S. cerevisiae proline oxidase gene PUT1, the hphEC6 cassette was shown to successfully act as a selection marker on hygromycin B-containing medium. The hphEC6 cassette could be placed immediately adjacent to a kanMX4 G418 disulfate resistance marker without any discernable effect on the ability of the yeast to grow in the presence of both hygromycin B and G418 disulfate. Co-cultivation experiments under non-selective conditions demonstrated that a PUT1 deletion strain carrying the hphEC6 cassette displayed equivalent fitness to an otherwise isogenic PUT1 deletion strain carrying the kanMX4 cassette. PMID- 29607285 TI - Purification of an alpha amylase from Aspergillus flavus NSH9 and molecular characterization of its nucleotide gene sequence. AB - In this study, an alpha-amylase enzyme from a locally isolated Aspergillus flavus NSH9 was purified and characterized. The extracellular alpha-amylase was purified by ammonium sulfate precipitation and anion-exchange chromatography at a final yield of 2.55-fold and recovery of 11.73%. The molecular mass of the purified alpha-amylase was estimated to be 54 kDa using SDS-PAGE and the enzyme exhibited optimal catalytic activity at pH 5.0 and temperature of 50 degrees C. The enzyme was also thermally stable at 50 degrees C, with 87% residual activity after 60 min. As a metalloenzymes containing calcium, the purified alpha-amylase showed significantly increased enzyme activity in the presence of Ca2+ ions. Further gene isolation and characterization shows that the alpha-amylase gene of A. flavus NSH9 contained eight introns and an open reading frame that encodes for 499 amino acids with the first 21 amino acids presumed to be a signal peptide. Analysis of the deduced peptide sequence showed the presence of three conserved catalytic residues of alpha-amylase, two Ca2+-binding sites, seven conserved peptide sequences, and several other properties that indicates the protein belongs to glycosyl hydrolase family 13 capable of acting on alpha-1,4-bonds only. Based on sequence similarity, the deduced peptide sequence of A. flavus NSH9 alpha-amylase was also found to carry two potential surface/secondary binding site (SBS) residues (Trp 237 and Tyr 409) that might be playing crucial roles in both the enzyme activity and also the binding of starch granules. PMID- 29607286 TI - Production of proteases from organic wastes by solid-state fermentation: downstream and zero waste strategies. AB - Production of enzymes through solid-state fermentation (SSF) of agro-industrial wastes reports high productivity with low investment. The extraction of the final product from the solid waste and solid disposal represent the main cost of the process. In this work, the complete downstream processes of SSF of two industrial residues for the production of proteases, soy fibre (SF) and a mixture of hair and sludge (HS), were studied in terms of activity recovery, using different extraction parameters (extracting solvent, ratio solid: solvent and extraction mode). Activity after lyophilisation was tested. Solid waste valorisation after extraction was studied using respiration techniques and biogas production tests, as part of a zero waste strategy. Results showed a maximum extraction yield of 91% for SF and 121% for HS, both in agitated mode and distilled water as extraction agent. An average activity recovery of 95 +/- 6 and 94 +/- 6% for SF and HS, respectively, was obtained after lyophilisation and redissolution. To reduce the cost of extraction, a ratio 1:3 w:v solid-solvent in static mode is advised for SF, and 1:2 w:v extraction ratio in agitated mode for HS, both with distilled water as extracting agent. Both composting and anaerobic digestion are suitable techniques for valorisation of the waste material. PMID- 29607287 TI - The biocorona: a challenge for the biomedical application of nanoparticles. AB - Formation of the biocorona on the surface of nanoparticles is a significant obstacle for the development of safe and effective nanotechnologies, especially for nanoparticles with biomedical applications. Following introduction into a biological environment, nanoparticles are rapidly coated with biomolecules resulting in formation of the nanoparticle-biocorona. The addition of these biomolecules alters the nanoparticle's physicochemical characteristics, functionality, biodistribution, and toxicity. To synthesize effective nanotherapeutics and to more fully understand possible toxicity following human exposures, it is necessary to elucidate these interactions between the nanoparticle and the biological media resulting in biocorona formation. A thorough understanding of the mechanisms by which the addition of the biocorona governs nanoparticle-cell interactions is also required. Through elucidating the formation and the biological impact of the biocorona, the field of nanotechnology can reach its full potential. This understanding of the biocorona will ultimately allow for more effective laboratory screening of nanoparticles and enhanced biomedical applications. The importance of the nanoparticle-biocorona has been appreciated for a decade; however, there remain numerous future directions for research which are necessary for study. This perspectives article will summarize the unique challenges presented by the nanoparticle-biocorona and avenues of future needed investigation. PMID- 29607288 TI - Neural Correlates of Aggressive Behavior in Real Time: a Review of fMRI Studies of Laboratory Reactive Aggression. AB - Purpose of review: Aggressive behavior has adaptive value in many natural environments; however, it places substantial burden and costs on human society. For this reason, there has long been interest in understanding the neurobiological basis of aggression. This interest, and the flourishing of neuroimaging research in general, has spurred the development of a large and growing scientific literature on the topic. As a result, a neural circuit model of aggressive behavior has emerged that implicates interconnected brain regions that are involved in emotional reactivity, emotion regulation, and cognitive control. Recent findings: Recently, behavioral paradigms that simulate provocative interactions have been adapted to neuroimaging protocols, providing an opportunity to directly probe the involvement of neural circuits in an aggressive interaction. Here we review neuroimaging studies of simulated aggressive interactions in research volunteers. We focus on studies that use a well-validated laboratory paradigm for reactive physical aggression and examine the neural correlates of provocation, retaliation, and evaluating punishment of an opponent. Summary: Overall, the studies reviewed support the involvement of neural circuits that support emotional reactivity, emotion regulation, and cognitive control in aggressive behavior. Based on a synthesis of this literature, future research directions are discussed. PMID- 29607290 TI - Accurate lattice parameters from 2D-periodic images for subsequent Bravais lattice type assignments. AB - Three different algorithms, as implemented in three different computer programs, were put to the task of extracting direct space lattice parameters from four sets of synthetic images that were per design more or less periodic in two dimensions (2D). One of the test images in each set was per design free of noise and, therefore, genuinely 2D periodic so that it adhered perfectly to the constraints of a Bravais lattice type, Laue class, and plane symmetry group. Gaussian noise with a mean of zero and standard deviations of 10 and 50% of the maximal pixel intensity was added to the individual pixels of the noise-free images individually to create two more images and thereby complete the sets. The added noise broke the strict translation and site/point symmetries of the noise-free images of the four test sets so that all symmetries that existed per design turned into pseudo-symmetries of the second kind. Moreover, motif and translation based pseudo-symmetries of the first kind, a.k.a. genuine pseudo-symmetries, and a metric specialization were present per design in the majority of the noise-free test images already. With the extraction of the lattice parameters from the images of the synthetic test sets, we assessed the robustness of the algorithms' performances in the presence of both Gaussian noise and pre-designed pseudo symmetries. By applying three different computer programs to the same image sets, we also tested the reliability of the programs with respect to subsequent geometric inferences such as Bravais lattice type assignments. Partly due to per design existing pseudo-symmetries of the first kind, the lattice parameters that the utilized computer programs extracted in their default settings disagreed for some of the test images even in the absence of noise, i.e., in the absence of pseudo-symmetries of the second kind, for any reasonable error estimates. For the noisy images, the disagreement of the lattice parameter extraction results from the algorithms was typically more pronounced. Non-default settings and re interpretations/re-calculations on the basis of program outputs allowed for a reduction (but not a complete elimination) of the differences in the geometric feature extraction results of the three tested algorithms. Our lattice parameter extraction results are, thus, an illustration of Kenichi Kanatani's dictum that no extraction algorithm for geometric features from images leads to definitive results because they are all aiming at an intrinsically impossible task in all real-world applications (Kanatani in Syst Comput Jpn 35:1-9, 2004). Since 2D Bravais lattice type assignments are the natural end result of lattice parameter extractions from more or less 2D-periodic images, there is also a section in this paper that describes the intertwined metric relations/holohedral plane and point group symmetry hierarchy of the five translation symmetry types of the Euclidean plane. Because there is no definitive lattice parameter extraction algorithm, the outputs of computer programs that implemented such algorithms are also not definitive. Definitive assignments of higher symmetric Bravais lattice types to real-world images should, therefore, not be made on the basis of the numerical values of extracted lattice parameters and their error bars. Such assignments require (at the current state of affairs) arbitrarily set thresholds and are, therefore, always subjective so that they cannot claim objective definitiveness. This is the essence of Kenichi Kanatani's comments on the vast majority of computerized attempts to extract symmetries and other hierarchical geometric features from noisy images (Kanatani in IEEE Trans Pattern Anal Mach Intell 19:246-247, 1997). All there should be instead for noisy and/or genuinely pseudo symmetric images are rankings of the relative likelihoods of classifications into higher symmetric Bravais lattice types, Laue classes, and plane symmetry groups. PMID- 29607289 TI - Plasmonic photocatalyst-like fluorescent proteins for generating reactive oxygen species. AB - The recent advances in photocatalysis have opened a variety of new possibilities for energy and biomedical applications. In particular, plasmonic photocatalysis using hybridization of semiconductor materials and metal nanoparticles has recently facilitated the rapid progress in enhancing photocatalytic efficiency under visible or solar light. One critical underlying aspect of photocatalysis is that it generates and releases reactive oxygen species (ROS) as intermediate or final products upon light excitation or activation. Although plasmonic photocatalysis overcomes the limitation of UV irradiation, synthesized metal/semiconductor nanomaterial photocatalysts often bring up biohazardous and environmental issues. In this respect, this review article is centered in identifying natural photosensitizing organic materials that can generate similar types of ROS as those of plasmonic photocatalysis. In particular, we propose the idea of plasmonic photocatalyst-like fluorescent proteins for ROS generation under visible light irradiation. We recapitulate fluorescent proteins that have Type I and Type II photosensitization properties in a comparable manner to plasmonic photocatalysis. Plasmonic photocatalysis and protein photosensitization have not yet been compared systemically in terms of ROS photogeneration under visible light, although the phototoxicity and cytotoxicity of some fluorescent proteins are well recognized. A comprehensive understanding of plasmonic photocatalyst-like fluorescent proteins and their potential advantages will lead us to explore new environmental, biomedical, and defense applications. PMID- 29607291 TI - Awareness Enhancing and Monitoring Device plus Habit Reversal in the Treatment of Trichotillomania: An Open Feasibility Trial. AB - Habit Reversal Therapy (HRT) is helpful for many persons suffering from trichotillomania. However successful habit reversal therapy requires awareness of hair pulling behaviors. Available methods to monitor hair pulling behaviors are less than ideal, particularly when sufferers are unaware of their pulling-related behaviors. This open feasibility trial included 20 persons with trichotillomania who were treated with nine weeks of HRT with experienced clinicians following a well-established HRT protocol. HRT was augmented with an electronic Awareness Enhancing and Monitoring Device (AEMD) designed to alert users of hand to head contact and to monitor the frequency of pulling-related behaviors. The AEMD included a neck unit and two wrist units, each equipped with vibrating alert functions. The results of the open trial revealed significant improvements in trichotillomania symptoms as measured by clinician and self-report rating scales. Most participants met study criteria for HRT completion and treatment effects were large. Participants reported that the AEMD, when operational, was effective in alerting participants to TTM-related behaviors. The monitoring function of the AEMD did not operate as designed. Subjective feedback focused on the AEMD concept was positive but AEMD reliability problems and complaints about the wearability the units were common. Recommendations for AEMD design modifications were included. PMID- 29607292 TI - Response inhibition and error-monitoring processes in individuals with obsessive compulsive disorder. AB - Response inhibition (RI) has been putatively linked to the symptoms of OCD. Despite the enticing link between RI and OCD, there are points in the relationship that require clarification. We examined the RI-OCD relationship taking into account a) the potentially differential pattern of RI-OCD relationship between obsessions and compulsions, and b) the potentially confounding effect of negative affect, particularly in regards to depression. Additionally, we investigated how error-monitoring processes in the inhibitory context account for OCD symptoms. Results showed that the RI-OCD relationship is robust in regards to compulsion symptoms, but not for obsessions, even when controlling for negative affect. Additionally, while individuals with OCD display behavioral slow-down following commission errors on the stop-signal task, slow down following successful inhibition is significantly related to compulsion symptoms. Findings suggest that future studies investigating RI in OCD should take into account heterogeneous clinical presentations in OCD, as well as incorporate error-monitoring variables to better understand RI processes in OCD. PMID- 29607293 TI - From forced migration to forced arrival: the campization of refugee accommodation in European cities. AB - In the aftermath of large refugee arrivals in 2015, EU regulations and national asylum laws were tightened, especially those regarding reception and accommodation. The current contribution introduces the concept of "campization" to explain the impact of law and policy changes on the socio-spatial configuration and functions of refugee accommodation in European capital regions. Based on qualitative research concerning case studies for Athens, Berlin, and Copenhagen, I argue that refugee accommodation has increasingly been transformed into large, camp-like structures with lowered living standards and a closed character. This is shown by the structural, functional, and socio-spatial characteristics of the accommodation in the three case studies, as well as the political and administrative objectives that determine the campization of accommodation. The contribution lastly highlights changing notions and forms of containment, exclusion, and temporality as part of campization, and links this process to current trends in asylum and urban development. PMID- 29607294 TI - [18F]-choline PET/CT as an imaging biomarker for primary liver cancers. PMID- 29607295 TI - MOAP-1, UBR5 and cisplatin resistance in ovarian cancer. PMID- 29607296 TI - Timing of Anticoagulation for Portal Vein Thrombosis in Liver Cirrhosis: A US Hepatologist's Perspective. PMID- 29607297 TI - Timing of Anticoagulation for Portal Vein Thrombosis in Liver Cirrhosis: An Italian Internist's Perspective. PMID- 29607298 TI - Timing of the Treatment of Portal Vein Thrombosis in Patients with Cirrhosis: A German Hepatologist's Perspective. PMID- 29607299 TI - Therapeutic Approaches of Obstructive Sleep Apnea in China. PMID- 29607300 TI - Do Statins Induce or Protect from Acute Kidney Injury and Chronic Kidney Disease: An Update Review in 2018. AB - Statins essentially are cholesterol-lowering drugs that are extensively prescribed for primary and secondary prevention of cardiovascular disease. Compelling evidence suggests that the beneficial effects of statins may not only be due to its ability to control cholesterol levels but also due to a pleiotropic cholesterol-independent anti-inflammatory, antioxidant, endothelial-protective and plaque-stabilizing activity. Along this line, statins may also exert acute and long-term effects on renal function. We present a narrative literature review that summarizes arguments in favor of or against the preventive and/or therapeutic use of statins in kidney-related diseases or complications. We also highlight the ongoing controversy regarding statin therapy in chronic and end stage kidney disease. PMID- 29607301 TI - Contemporary Situation of Community-acquired Pneumonia in China: A Systematic Review. AB - The prevalence and microbial pattern reported for Community-acquired pneumonia (CAP) differ considerably and contemporary situation remains changing over time. We therefore searched both international and domestic databases for relevant references and pooled incidence of CAP and etiological distribution were estimated separately between children and adults groups. The results showed that CAP remained a major public health issue in China, with a relatively higher incidence than that reported in Western countries. Although pathogens were not detected in nearly half of patients, Mycoplasma pneumoniae remained to be the most frequently detected agent across age groups, the detection yield of which was lower than that reported from other countries. Notably, the incidence of influenza virus A in adults was almost four times higher than that in children while the prevalence of respiratory syncytial virus was much less common in adults than that in children. Despite some limitations, the value of this review, approaching to systematically review grey published data, is to sketch out the contemporary epidemiological and etiological situation of CAP in our country, which could be useful to help policymakers and clinicians make informed choices and to inspire future studies and surveillance. PMID- 29607302 TI - Predisposing Factors for Chemotherapy-induced Nephrotoxicity in Patients with Advanced Esophageal Cancer Who Received Combination Chemotherapy with Docetaxel, Cisplatin, and 5-fluorouracil. AB - Background and Objectives: We retrospectively studied the predisposing factors for nephrotoxicity in the patients with advanced esophageal squamous-cell carcinoma who received combination chemotherapy with docetaxel, cisplatin, and 5 fluorouracil (DCF therapy). Methods: Between January 2010 and March 2014, 41 patients with Stage IB to III esophageal squamous-cell carcinoma received the DCF therapy (docetaxel 70-75 mg/m2, day 1; cisplatin 70-75 mg/m2, day 1; 5 fluorouracil 750 mg/m2, days 1-5) in our hospital. Renal dysfunction was defined as a creatinine clearance (Ccr) of less than 60 mL/min. Predictors of nephrotoxicity were identified through logistic-regression analysis. Results: Nephrotoxicity developed in 20 patients and did not develop in 21 patients. Nephrotoxicity developed during the first course of DCF therapy in 16 patients, the second course in 3 patients, and the third course in 1 patient. The dose of DCF therapy was decreased in 8 patients with nephrotoxicity and 7 patients without nephrotoxicity. Multivariate analysis showed that a low Ccr level immediately before DCF therapy was an independent risk factor for the development of nephrotoxicity (odds ratio, 0.932; 95% confidence interval, 0.876 to 0.992; P = 0.027). On receiver operating characteristic curve analysis, the optimal cutoff value of Ccr for the development of nephrotoxicity was 75.8 mL/min. The 2-year overall survival rate was 84.2% in patients with nephrotoxicity and 90.0% in patients without nephrotoxicity (P = 0.635). Conclusions: Low Ccr levels immediately before DCF therapy are a risk factor for the development of nephrotoxicity. Patients should therefore be carefully monitored. PMID- 29607303 TI - Diagnostic Accuracy of Aspartate Aminotransferase to Platelet Ratio Index and Fibrosis 4 Scores in Predicting Advanced Liver Fibrosis in Patients with End stage Renal Disease and Chronic Viral Hepatitis: Experience from Pakistan. AB - Objectives: The aim was to assess the diagnostic accuracy of APRI and FIB-4 in assessing the stage of liver fibrosis in end stage renal disease (ESRD) patients with chronic viral hepatitis and to compare the two tests with standard tru-cut liver biopsy. Material and Methods: The study was conducted at Sindh Institute of Urology and Transplantation Karachi (SIUT) from May 2010 to May 2014. All ESRD patients, being considered as candidates for renal transplantation and in whom liver biopsy was performed were included. Fibrosis stage was assessed on liver biopsy using Ishak scoring system. The serum transaminases and platelet counts were used to calculate APRI and FIB-4 scores. Results: Out of 109 patients, hepatitis C and B virus infections were present in 104 (95.4%) and 3(2.8%), respectively, while 2 (1.8%) patients had both infections. The mean Ishak fibrosis score was 1.95 +/- 2. Advanced fibrosis was noted in 37 (34%) patients. Univariate analysis showed that advanced liver fibrosis was associated with lower platelets counts (P=0.001) and higher aspartate aminotransferase (AST) (P=0.001), alanine aminotransferase (ALT) (P=0.022), APRI score (P=0.001) and FIB-4 score (P=0.001). On logistic regression analysis, only APRI score (P < 0.001) was found to be the independent variable associated with advanced liver fibrosis. APRI score cutoff >=1 indicating advanced fibrosis showed sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) of 91.9%, 90.3%, 82.9%, 95.6%, respectively with area under the curve (AUC) of 0.97. Similarly, a FIB-4 score cutoff >=1.1 had sensitivity, specificity, PPV and NPV of 70.27%, 66.67%, 52% and 81.36%, respectively with AUC of 0.74. Conclusion: APRI is more accurate noninvasive test for assessing advanced liver fibrosis in ESRD patients as compared to FIB-4. It can be used to obviate the need for liver biopsy in this high risk population. PMID- 29607304 TI - Neutrophil-to-lymphocyte Ratio Relation to Sepsis Severity Scores and Inflammatory Biomarkers in Patients with Community-acquired Pneumonia: A Case Series. AB - Background and Objectives: Neutrophil to lymphocyte ratio (NLR) as calculated from the white cell differential blood count is considered a promising marker for the prognosis of patients with various diseases, including sepsis. This study was designed to assess the possible use of neutrophil-to-lymphocyte ratio in the prediction of survival outcomes in patients with community acquired pneumonia (CAP). A secondary objective was to compare the prognostic accuracy of NLR with the commonly used severity scores of sepsis SOFA, APACHE II and SAPS II. Methods: This was a retrospective study based on data extracted from 26 patients suffering from acute CAP. The study period was from February 01, 2017 until April 30, 2017. All patients with CAP were presented in the Emergency Department (ED) of the University Hospital of Patras, Greece and were treated after admission in the Internal Medicine Department. The neutrophil-to-lymphocyte ratio (NLR) was calculated from the white blood cell count (WBC) values measured from a peripheral venous blood specimen drawn on admission. It was then compared with C reactive protein (CRP) serum levels and the sepsis calculated prognostic scores APACHE II, SAPS II and SOFA. The impact of the above parameters was evaluated in relation to the final outcome. Results: The mean period of hospitalization for the enrolled patients was 9.3 days (SD 5.8 days). Twenty-four patients (92.3%) got finally discharged from the hospital and two (7.7%) died during the hospitalization. Mean NLR and serum CRP values on admission were 10.2 +/- 8.8 (min 1.4; max 34.7) and 11.4 +/- 11 mg/dL (min 0.4; max 42.6) respectively. Based on the correlation analysis, serum CRP was more strongly positively correlated with NLR (r = 0.543, P = 0.004), than total WBC (r = 0.454, P = 0.02). None of the biomarkers of inflammation measured or computed in the study (CRP, WBC, NLR) showed any correlation with either the days of hospitalization or the sepsis prognostic scores. Conclusions: NLR shows a statistical significant correlation to the commonly used inflammatory markers CRP and total WBC in the small sample size of patients with CAP that we assessed. Although NLR is a simple, cheap and rapidly available measurement in the ED, future, larger prospective studies are warranted to confirm its possible value as a prognostic index in sepsis patients with CAP. PMID- 29607306 TI - Resistin Levels in Non-alcoholic Fatty Liver Disease Pathogenesis. PMID- 29607305 TI - Gastric Antral Vascular Ectasia: A Case Report and Literature Review. AB - Gastric antral vascular ectasia (GAVE) is a rare but an important cause of upper gastrointestinal bleeding (UGIB) and commonly presents as occult bleeding that manifests as iron deficiency anemia (IDA). GAVE is commonly associated with chronic illnesses, most frequently liver cirrhosis and connective tissue diseases. The pathogenesis of GAVE is still obscure, and many hypotheses such as mechanical stress, hormonal factors, and autoimmune factors, have been proposed. Upper gastrointestinal endoscopy has a major role in the diagnosis and treatment of GAVE. PMID- 29607307 TI - Current and Future Treatment of Hepatocellular Carcinoma: An Updated Comprehensive Review. AB - Hepatocellular carcinoma (HCC) is among the leading causes of cancer-related mortality. The principal treatment is surgical resection or liver transplantation, depending on whether the patient is a suitable transplant candidate. However, in most patients with HCC the diagnosis is often late, thereby excluding the patients from definitive surgical resection. Medical treatment includes sorafenib, which is the most commonly used systemic therapy; although, it has been shown to only minimally impact patient survival by several months. Chemotherapy and radiotherapy are generally ineffective. Due to the poor prognosis of patients with HCC, newer treatments are needed with several being in development, either in pre-clinical or clinical studies. In this review article, we provide an update on the current and future medical and surgical management of HCC. PMID- 29607308 TI - Hepatitis C Virus and Hepatocellular Carcinoma: A Narrative Review. AB - Hepatocellular carcinoma (HCC) is a leading cause of liver-related death worldwide. Hepatitis C virus (HCV) infection is a major cause of advanced hepatic fibrosis and cirrhosis, with significantly increased risk for development of HCC. The morbidity and mortality of HCV-related HCC remains high, as rates of HCV cirrhosis continue to increase. The long-term goal of antiviral therapy for chronic HCV is to reduce complications from cirrhosis, including HCC. The advent of new direct-acting antivirals with high rates of virological clearance has revolutionized cure of HCV infection. While the development of HCC in HCV patients who achieve disease sustained virologic response is reduced, these patients remain at risk for HCC, particularly those patients with advanced fibrosis and cirrhosis. This review outlines the epidemiology of HCC in chronic HCV, various mechanisms, risk factors and pathophysiology that contribute to this disease process, screening recommendations, and the available data on the impact of new direct-acting antiviral treatment on the development on HCC. PMID- 29607309 TI - Perception of Job-Related Risk, Training, and Use of Personal Protective Equipment (PPE) among Latino Immigrant Hog CAFO Workers in Missouri: A Pilot Study. AB - Hog production in the United States is a large industry that has seen dramatic changes over the last few decades. Concentrated animal feeding operations (CAFOs) are growing in number throughout the country. This pilot study explores the perception of risk, receipt of work-related training, provision and usage of personal protective equipment (PPE), and prevention preferences of Latino immigrant hog CAFO workers in Missouri. Forty workers (M age = 36.08 years, SD = 10.04; 92.5% male; 70.0% Mexican) were interviewed. Results indicate that most workers did not perceive their job as dangerous. Limited English proficient workers were significantly less likely to report receiving any work-related training. Although most workers had access to employer provided PPE, usage was inconsistent. As the demographic composition of the farmworker population in the Midwest becomes increasingly comprised of hired immigrant workers, it will be imperative to develop occupational safety and health educational and outreach efforts focused on the needs of these workers. PMID- 29607310 TI - Urinary Metabolomic Study of Chlorogenic Acid in a Rat Model of Chronic Sleep Deprivation Using Gas Chromatography-Mass Spectrometry. AB - The urinary metabolomic study based on gas chromatography-mass spectrometry (GC MS) had been developed to investigate the possible antidepressant mechanism of chlorogenic acid (CGA) in a rat model of sleep deprivation (SD). According to pattern recognition analysis, there was a clear separation among big platform group (BP), sleep deprivation group (SD), and the CGA (model + CGA), and CGA group was much closer to the BP group by showing a tendency of recovering towards BP group. Thirty-six significantly changed metabolites related to antidepressant by CGA were identified and used to explore the potential mechanism. Combined with the result of the classic behavioral tests and biochemical indices, CGA has significant antidepressant effects in a rat model of SD, suggesting that the mechanism of action of CGA might be involved in regulating the abnormal pathway of nicotinate and nicotinamide metabolism; glyoxylate and dicarboxylate metabolism; glycine, serine, and threonine metabolism; and arginine and proline metabolism. Our results also show that metabolomics analysis based on GC-MS is a useful tool for exploring biomarkers involved in depression and elucidating the potential therapeutic mechanisms of Chinese medicine. PMID- 29607311 TI - Shiftwork-Mediated Disruptions of Circadian Rhythms and Sleep Homeostasis Cause Serious Health Problems. AB - Shiftwork became common during the last few decades with the growing demands of human life. Despite the social inactivity and irregularity in habits, working in continuous irregular shifts causes serious health issues including sleep disorders, psychiatric disorders, cancer, and metabolic disorders. These health problems arise due to the disruption in circadian clock system, which is associated with alterations in genetic expressions. Alteration in clock controlling genes further affects genes linked with disorders including major depression disorder, bipolar disorder, phase delay and phase advance sleep syndromes, breast cancer, and colon cancer. A diverse research work is needed focusing on broad spectrum changes caused by jet lag in brain and neuronal system. This review is an attempt to motivate the researchers to conduct advanced studies in this area to identify the risk factors and mechanisms. Its goal is extended to make the shift workers aware about the risks associated with shiftwork. PMID- 29607312 TI - Metabolic Pathway Genes Associated with Susceptibility Genes to Coronary Artery Disease. AB - Coronary artery disease (CAD) is one of the leading threats to global health. Previous research has proven that metabolic pathway disorders, such as high blood lipids and diabetes, are one of the risk factors that mostly cause CAD. However, the crosstalk between metabolic pathways and CAD was mostly studied on physiology processes by analyzing a single gene function. A canonical correlation analysis was used to identify the metabolic pathways, which were integrated as a unit to coexpress with CAD susceptibility genes, and to resolve additional metabolic factors that are related to CAD. Seven pathways, including citrate cycle, ubiquinone, terpenoid quinone biosynthesis, and N-glycan biosynthesis, were identified as an integrated unit coexpressed with CAD genes. These pathways could not be revealed as a coexpressed pathway through traditional methods as each single gene has weak correlation. Furthermore, sets of genes in these pathways were candidate markers for diagnosis and detection from patients' serum. PMID- 29607313 TI - In Vitro Antidiabetic Effects and Antioxidant Potential of Cassia nemophila Pods. AB - The antidiabetic and antioxidant potential of ethanolic extract of Cassia nemophila pod (EECNP) was evaluated by three in vitro assays, including yeast glucose uptake assay, glucose adsorption assay, and DPPH radical scavenging activity. The result revealed that the extracts have enhanced the uptake of glucose through the plasma membrane of yeast cells. A linear increase in glucose uptake by yeast cells was noticed with gradual increase in the concentration of the test samples. Moreover, the adsorption capacity of the EECNP was directly proportional to the molar concentration of glucose. Also, the DPPH radical scavenging capacity of the extract was increased to a maximum value of 43.3% at 80 MUg/ml, which was then decreased to 41.9% at 100 MUg/ml. From the results, it was concluded that EECNP possess good antidiabetic and antioxidant properties as shown by in vitro assays. PMID- 29607314 TI - Glucagon-Like Peptide-1 Mediates the Protective Effect of the Dipeptidyl Peptidase IV Inhibitor on Renal Fibrosis via Reducing the Phenotypic Conversion of Renal Microvascular Cells in Monocrotaline-Treated Rats. AB - Chronic kidney diseases are characterized by renal fibrosis with excessive matrix deposition, leading to a progressive loss of functional renal parenchyma and, eventually, renal failure. Renal microcirculation lesions, including the phenotypic conversion of vascular cells, contribute to renal fibrosis. Here, renal microcirculation lesions were established with monocrotaline (MCT, 60 mg/kg). Sitagliptin (40 mg/kg/d), a classical dipeptidyl peptidase-4 (DPP-4) inhibitor, attenuated the renal microcirculation lesions by inhibiting glomerular tuft hypertrophy, glomerular mesangial expansion, and microvascular thrombosis. These effects of sitagliptin were mediated by glucagon-like peptide-1 receptor (GLP-1R), since they were blocked by the GLP-1R antagonist exendin-3 (Ex-3, 40 ug/kg/d). The GLP-1R agonist liraglutide showed a similar renal protective effect in a dose-independent manner. In addition, sitagliptin, as well as liraglutide, alleviated the MCT-induced apoptosis of renal cells by increasing the expression of survival factor glucose-regulated protein 78 (GRP78), which was abolished by the GLP-1R antagonist Ex-3. Sitagliptin and liraglutide also effectively ameliorated the conversion of vascular smooth muscle cells (SMCs) from a synthetic phenotype to contractile phenotype. Moreover, sitagliptin and liraglutide inhibited endothelial-mesenchymal transition (EndMT) via downregulating transforming growth factor-beta1 (TGF-beta1). Collectively, these findings suggest that DPP-4 inhibition can reduce microcirculation lesion-induced renal fibrosis in a GLP-1-dependent manner. PMID- 29607315 TI - Antimicrobial Activity of Cerium Oxide Nanoparticles on Opportunistic Microorganisms: A Systematic Review. AB - An evaluation of studies of biologically active nanoparticles provides guidance for the synthesis of nanoparticles with the goal of developing new antibiotics/antifungals to combat microbial resistance. This review article focuses on the physicochemical properties of cerium oxide nanoparticles (CeNPs) with antimicrobial activity. Method. This systematic review followed the Guidelines for Transparent Reporting of Systematic Reviews and Meta-Analyses. Results. Studies have confirmed the antimicrobial activity of CeNPs (synthesized by different routes) using nitrate or chloride salt precursors and having sizes less than 54 nm. Conclusion. Due to the lack of standardization in studies with respect to the bacteria and CeNP concentrations assayed, comparisons between studies to determine more effective routes of synthesis are difficult. The mechanism of CeNP action likely occurs through oxidative stress of components in the cell membrane of the microorganism. During this process, a valence change occurs on the CeNP surface in which an electron is gained and Ce4+ is converted to Ce3+. PMID- 29607316 TI - Application of MRI for the Diagnosis of Neoplasms. AB - Aim: The aim of the study was to determine the most commonly diagnosed neoplasms in the MRI scanned patient population and indicate correlations based on the descriptive variables. Methods: The SPSS software was used to determine the incidence of neoplasms within the specific diagnoses based on the descriptive variables of the studied population. Over a five year period, 791 patients and 839 MRI scans were identified in neoplasm category (C00-D48 according to the International Statistical Classification of Diseases and Related Health Problems ICD-10). Results: More women (56%) than men (44%) represented C00-D48. Three categories of neoplasms were recorded. Furthermore, benign neoplasms were the most numerous, diagnosed mainly in patients in the fifth decade of life, and included benign neoplasms of the brain and other parts of the central nervous system. Conclusions: Males <= 30 years of age with neoplasms had three times higher MRI scans rate than females of the same age group; even though females had much higher scans rate in every other category. The young males are more often selected for these scans if a neoplasm is suspected. Finally, the number of MRI diagnosed neoplasms showed a linear annual increase. PMID- 29607317 TI - Site-Directed Spin Labeling EPR for Studying Membrane Proteins. AB - Site-directed spin labeling (SDSL) in combination with electron paramagnetic resonance (EPR) spectroscopy is a rapidly expanding powerful biophysical technique to study the structural and dynamic properties of membrane proteins in a native environment. Membrane proteins are responsible for performing important functions in a wide variety of complicated biological systems that are responsible for the survival of living organisms. In this review, a brief introduction of the most popular SDSL EPR techniques and illustrations of recent applications for studying pertinent structural and dynamic properties on membrane proteins will be discussed. PMID- 29607319 TI - Availability of Dental Prosthesis Procedures in Brazilian Primary Health Care. AB - Objectives: To describe dental prosthesis provision in the Brazilian public health service and report the performance of dental prosthesis procedures according to the Brazilian macroregions. Methods: A structured interview was conducted with senior-level health professionals from each of the 18,114 oral health teams (OHT). The dependent variables were performance of removable prostheses and prosthesis procedures, including provision of fixed prostheses by OHT. Descriptive statistics were produced together with performing a cluster analysis using SPSS version 19.0. Results: The manufacture of any type of prosthesis was done by a minority of OHT (43%). The most commonly provided types of dental prosthesis were removable full and partial dentures. Cluster 1 (teams that performed prosthesis procedures the most) was composed of a smaller number of teams (n = 5,531), and Cluster 2 (composed of teams that do not perform prosthetics or that perform them in small amounts) consisted of 12,583 teams. The geographic distribution of clusters reveals that the largest proportion of Cluster 1 teams is located in the Northeast (33.9%) and Southeast (33.6%). Conclusions: A minority of OHT produce dental prostheses. There is an unequal geographical distribution of clusters. PMID- 29607318 TI - Calcitriol Prevents Cardiovascular Repercussions in Puromycin Aminonucleoside Induced Nephrotic Syndrome. AB - Puromycin aminonucleoside-induced nephrotic syndrome (PAN-NS) is characterized by cardiac remodeling and increased local inflammatory activity. Patients with NS and animal models of NS have vitamin D3 deficiency. The aim of the present study was to evaluate the influence of calcitriol on cardiac remodeling and local inflammatory state in PAN-NS rat model. Male Sprague-Dawley rats were injected with PAN or vehicle on day 0. PAN and control rats were divided into two subgroups for the administration of calcitriol (PAN-D and Ct-D groups) or the vehicle (PAN-V and Ct-V groups) during 21 days. On day 21, the renal function, metabolic balance, calcitriol and FGF-23 plasma levels, prohypertrophy and proinflammatory markers (ET-1, TGF-beta1, TNF-alpha, and IL-1beta), and calcium signaling molecules (PLB and SERCA-2a) were evaluated. Twenty-one days after injection, PAN-V group presented cardiac hypertrophy and a modulation of proinflammatory markers local expression. Calcitriol treatment of PAN rats prevented cardiac hypertrophy and was associated with marked reduction in the cardiac expression levels of proinflammatory markers. Our results suggest that vitamin D3 deficiency in PAN-NS may contribute to cardiac remodeling and to the increase in local inflammatory activity. Calcitriol treatment prevents both cardiac repercussions and local inflammatory processes in PAN-NS. PMID- 29607320 TI - Antilisterial Effect of Rosa damascena and Nymphaea alba in Mus musculus. AB - The present study was proposed to investigate the toxicological and prophylactic potential of ethanolic extracts of Rosa damascena and Nymphaea alba and their mixture in albino mice. For toxicity study, three different doses of plant extracts were orally administrated to three groups of mice for 14 successive days. Blood biochemistry and histological examinations of liver and kidney revealed that these extracts had no harmful effects up to 1000 mg/kg. To determine the prophylactic effects of Rosa damascena, Nymphaea alba, and their mixture, an infection model of Listeria monocytogenes was established in a pilot study. Establishment of infection was confirmed by changes in haematological parameters and reisolation of Listeria monocytogenes from different tissues. Results showed that these extracts alone or in combination could restrict the growth of Listeria monocytogenes in different organs. Neutrophils were high in positive control group but remained in normal range in all treated groups. Listeria monocytogenes was recovered in low numbers from animals treated with extract of single plant but was negligible in group treated with mixture of extract of plants. Platelets count was increased in treated groups as compared to control. Results confirmed that these extracts are potent source of antimicrobial compounds and that they have synergistic effect in combined form. PMID- 29607321 TI - Influence of Manufacturing Methods of Implant-Supported Crowns on External and Internal Marginal Fit: A Micro-CT Analysis. AB - Aim: To evaluate the influence of different manufacturing methods of single implant-supported metallic crowns on the internal and external marginal fit through computed microtomography. Methods: Forty external hexagon implants were divided into 4 groups (n = 8), according to the manufacturing method: GC, conventional casting; GI, induction casting; GP, plasma casting; and GCAD, CAD/CAM machining. The crowns were attached to the implants with insertion torque of 30 N.cm. The external (vertical and horizontal) marginal fit and internal fit were assessed through computed microtomography. Internal and external marginal fit data (MUm) were submitted to a one-way ANOVA and Tukey's test (alpha = .05). Qualitative evaluation of the images was conducted by using micro-CT. Results: The statistical analysis revealed no significant difference between the groups for vertical misfit (P = 0.721). There was no significant difference (P > 0.05) for the internal and horizontal marginal misfit in the groups GC, GI, and GP, but it was found for the group GCAD (P <= 0.05). Qualitative analysis revealed that most of the samples of cast groups exhibited crowns underextension while the group GCAD showed overextension. Conclusions: The manufacturing method of the crowns influenced the accuracy of marginal fit between the prosthesis and implant. The best results were found for the crowns fabricated through CAD/CAM machining. PMID- 29607322 TI - Identifying Frail-Related Biomarkers among Community-Dwelling Older Adults in Japan: A Research Example from the Japanese Gerontological Evaluation Study. AB - We examined correlating clinical biomarkers for the physical aspect of frailty among community-dwelling older adults in Japan, using Japanese Gerontological Evaluation Study (JAGES). We used information from the JAGES participants (N = 3,128) who also participated in the community health screening in 2010. We grouped participants' response to the Study of Osteoporotic Fracture (SOF) Frailty Index into robust (=0), intermediate frail (=1), and frail (=2+) ones to indicate physical aspect of frailty. Independent of sex and age, results from multinomial logistic regression showed above normal albumin and below normal HDL and haemoglobin levels were positively associated with intermediate frail (RRR = 1.99, 95% CI = 1.22-3.23; RRR = 1.36, 95% CI = 1.33-1.39; RRR = 1.36, 95% CI = 1.23-1.51, resp.) and frail cases (RRR = 2.27, 95% CI = 1.91-2.70; RRR = 1.59, 95% CI = 1.51-1.68; RRR = 1.40, 95% CI = 1.28-1.52, resp.). Limited to women, above normal Hb1Ac level was similarly associated with intermediate frail and frail cases (RRR = 1.18, 95% CI = 1.02, 1.38; RRR = 2.56, 95% CI = 2.23-2.95, resp.). Use of relevant clinical biomarkers can help in assessment of older adults' physical aspect of frailty. PMID- 29607323 TI - Office-Cycling: A Promising Way to Raise Pain Thresholds and Increase Metabolism with Minimal Compromising of Work Performance. AB - Aim: Establishing the effects of low intensity cycling (LC), moderate intensity cycling (MC), and standing at a simulated office workstation on pain modulation, work performance, and metabolic expenditure. Methods: 36 healthy adults (21 females), mean age 26.8 (SD 7.6) years, partook in this randomized 3 * 3 crossover trial with 75 minutes of LC on 20% of maximum aerobic power (MAP) output, 30 minutes of MC on 50% of MAP, and standing 30 minutes with 48-hour wash out periods. Outcome measures were pain modulation (pressure pain threshold (PPT) and thermal pain threshold)), work performance (transcription, mouse pointing, and cognitive performance), and metabolic expenditure. Results: PPTs increased in all conditions. PPT trapezius showed the highest increase after LC, 39.3 kilopascals (kPa) (15.6; 78.6), compared to MC, 17.0 kPa (2.8; 49.9), and standing, 16.8 kPa (-5.6; 39.4), p = 0.015. Transcription was reduced during LC and MC. Mouse pointing precision was best during standing and worst and slowest during MC. Cognitive performance did not differ between conditions. Metabolic expenditure rates were 1.4 (1.3; 1.7), 3.3 (2.3; 3.7), and 7.5 (5.8; 8.7) kcal/minute during standing, LC, and MC, respectively (p < 0.001). Conclusions: LC seems to be the preferred option; it raised PPTs, more than doubled metabolic expenditure, whilst minimally influencing work performance. PMID- 29607324 TI - Mammographic Breast Density and Breast Cancer Molecular Subtypes: The Kenyan African Aspect. AB - Introduction: Data examining mammographic breast density (MBD) among patients in Sub-Saharan Africa are sparse. We evaluated how MBD relates to breast cancer characteristics in Kenyan women undergoing diagnostic mammography. Methods: This cross-sectional study included women with pathologically confirmed breast cancers (n = 123). Pretreatment mammograms of the unaffected breast were assessed to estimate absolute dense area (cm2), nondense area (cm2), and percent density (PD). Relationships between density measurements and clinical characteristics were evaluated using analysis of covariance. Results: Median PD and dense area were 24.9% and 85.3 cm2. Higher PD and dense area were observed in younger women (P < 0.01). Higher dense and nondense areas were observed in obese women (P-trend < 0.01). Estrogen receptor (ER) positive patients (73%) had higher PD and dense area than ER-negative patients (P <= 0.02). Triple negative breast cancer (TNBC) patients (17%) had lower PD and dense area (P <= 0.01) compared with non-TNBCs. No associations were observed between MBD and tumor size and grade. Conclusions: Our findings show discordant relationships between MBD and molecular tumor subtypes to those previously observed in Western populations. The relatively low breast density observed at diagnosis may have important implications for cancer prevention initiatives in Kenya. Subsequent larger studies are needed to confirm these findings. PMID- 29607325 TI - Mechanism of Azalomycin F5a against Methicillin-Resistant Staphylococcus aureus. AB - To investigate the mechanism of azalomycin F5a against methicillin-resistant Staphylococcus aureus (MRSA), the conductivity of MRSA suspension and the adenylate kinase activity of MRSA culture were determined with the intervention of azalomycin F5a, which were significantly increased compared to those of blank controls. This inferred that azalomycin F5a could lead to the leakage of cellular substances possibly by increasing permeability to kill MRSA. As phospholipid bilayer was mainly responsible for cell-membrane permeability, the interaction between azalomycin F5a and cell-membrane lipids was further researched by determining the anti-MRSA activities of azalomycin F5a combined with cell membrane lipids extracted from test MRSA or with 1,2-dipalmitoyl-sn-glycero-3 phospho-glycerol (DPPG) for possible molecular targets lying in MRSA cell membrane. The results indicated that the anti-MRSA activity of azalomycin F5a remarkably decreased when it combined with membrane lipids or DPPG. This indicated that cell-membrane lipids especially DPPG might be important targets of azalomycin F5a against MRSA. PMID- 29607326 TI - Ischemic Preconditioning Promotes Autophagy and Alleviates Renal Ischemia/Reperfusion Injury. AB - Autophagy is important for cellular survival during renal ischemia/reperfusion (I/R) injury. Ischemic preconditioning (IPC) has a strong renoprotective effect during renal I/R. Our study here aimed to explore the effect of IPC on autophagy during renal I/R injury. Rats were subjected to unilateral renal ischemia with or without prior IPC. Hypoxia/reoxygenation (H/R) injury was induced in HK-2 cells with or without prior hypoxic preconditioning (HPC). Autophagy and apoptosis were detected after reperfusion or reoxygenation for different time. The results showed that the levels of LC3II, Beclin-1, SQSTM1/p62, and cleaved caspase-3 were altered in a time-dependent manner during renal I/R. IPC further induced autophagy as indicated by increased levels of LC3II and Beclin-1, decreased level of SQSTM1/p62, and accumulation of autophagosomes compared to I/R groups at corresponding reperfusion time. In addition, IPC reduced the expression of cleaved caspase-3 and alleviated renal cell injury, as evaluated by the levels of serum creatinine (Scr), neutrophil gelatinase-associated lipocalin (NGAL), and kidney injury molecule-1 (KIM-1) in renal tissues. In conclusion, autophagy and apoptosis are dynamically altered during renal I/R. IPC protects against renal I/R injury and upregulates autophagic flux, thus increasing the possibility for a novel therapy to alleviate I/R-induced acute kidney injury (AKI). PMID- 29607327 TI - UGT1A1 Genetic Variations and a Haplotype Associated with Neonatal Hyperbilirubinemia in Indonesian Population. AB - Neonatal hyperbilirubinemia (NH) is a common finding in newborn babies in Indonesia. Common and rare variants of UGT1A1 have been known to contribute to NH etiology. This study aims to identify UGT1A1 genetic variation and haplotype associated with NH in Indonesian population. DNA was isolated from 116 cases and 115 controls and a targeted-deep sequencing approach was performed on the promoter, UTRs, and exonic regions of UGT1A1. Determining association of common variants and haplotype analysis were performed using PLINK and Haploview. Ten and 4 rare variants were identified in cases and controls, respectively. The UGT1A1 rare variants frequency in cases (5.17%) was higher than that in controls (1.7%). Four of those rare variants in cases (p.Ala61Thr, p.His300Arg, p.Lys407Asn, and p.Tyr514Asn) and three in controls (p.Tyr79X, p.Ala346Val, and p.Thr412Ser) are novel variants. The frequencies of p.Gly71Arg, p.Pro229Gln, and TA7 common variants were not significantly different between cases and controls. A haplotype, consisting of 3 major alleles of 3' UTRs common variants (rs8330C>G, rs10929303C>T, and rs1042640C>G), was associated with NH incidence (p = 0.025) in this population. Using targeted-deep sequencing and haplotype analysis, we identified novel UGT1A1 rare variants and disease-associated haplotype in NH in Indonesian population. PMID- 29607328 TI - Maternal, Fetal, and Neonatal Outcomes in Pregnant Dengue Patients in Mexico. AB - To increase our understanding of the consequences of dengue virus infection during pregnancy, a retrospective analysis was performed on the medical records of all completed pregnancies (live births and pregnancy losses) at nine public hospitals in the Gulf of Mexico from January to October 2013. Eighty-two patients developed clinical, laboratory-confirmed dengue virus infections while pregnant. Of these, 54 (65.9%) patients were diagnosed with dengue without warning signs, 15 (18.3%) patients were diagnosed with dengue with warning signs, and 13 (15.9%) patients had severe dengue. Five (38.5%) patients with severe dengue experienced fetal distress and underwent emergency cesarean sections. Four patients delivered apparently healthy infants of normal birthweight while the remaining patient delivered a premature infant of low birthweight. Patients died of multiple organ failure during or within 10 days of the procedure. Severe dengue was also associated with obstetric hemorrhage (30.8%, four cases), preeclampsia (15.4%, two cases), and eclampsia (7.7%, one case). These complications were less common or absent in patients in the other two disease categories. Additionally, nonsevere dengue was not associated with maternal mortality, fetal distress, or adverse neonatal outcomes. In summary, the study provides evidence that severe dengue during pregnancy is associated with a high rate of fetal distress, cesarean delivery, and maternal mortality. PMID- 29607329 TI - Prognostic Roles of mRNA Expression of S100 in Non-Small-Cell Lung Cancer. AB - The S100 protein family is involved in cancer cell invasion and metastasis, but its prognostic value in non-small-cell lung cancer (NSCLC) has not been elucidated. In the present study we investigated the prognostic role of mRNA expression of each individual S100 in NSCLC patients through the Kaplan-Meier plotter (KM plotter) database. Expression of 14 members of the S100 family correlated with overall survival (OS) for all NSCLC patients; 18 members were associated with OS in adenocarcinoma, but none were associated with OS in squamous cell carcinoma. In particular, high mRNA expression level of S100B was associated with better OS in NSCLC patients. The prognostic value of S100 according to smoking status, pathological grades, clinical stages, and chemotherapeutic treatment of NSCLC was further assessed. Although the results should be further verified in clinical trials our findings provide new insights into the prognostic roles of S100 proteins in NSCLC and might promote development of S100-targeted inhibitors for the treatment of NSCLC. PMID- 29607330 TI - The Epidemiology of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in China. AB - Stevens-Johnson syndrome and toxic epidermal necrolysis (SJS/TEN) are life threatening disease. However, there are only few epidemiologic studies of SJS/TEN from China. To analyze the clinical characteristics, causality, and outcome of treatment for SJS/TEN in China, we reviewed case reports of patients with SJS/TEN from the China National Knowledge Infrastructure (CNKI) and Wanfang database from 2006 to 2016 and patients with SJS/TEN who were admitted to the First Affiliated Hospital of Fujian Medical University during the same period. There were 166 patients enrolled, including 70 SJS, 2 SJS/TEN overlap, and 94 TEN. The most common offending drugs were antibiotics (29.5%) and anticonvulsants (24.1%). Carbamazepine, allopurinol, and penicillins were the most common single offending drugs (17.5%, 9.6%, and 7.2%). Chinese patent medicines accounted for 5.4%. There were 76 (45.8%) patients receiving systemic steroid and intravenous immunoglobulin (IVIG) in combination therapy, especially for TEN (80.3%), and others were treated with systemic steroids alone. Mortality rate of combination treatment comparing with steroid alone in TEN patients had no statistical significance. In conclusion, carbamazepine and allopurinol were the leading causative drugs for SJS/TEN in China. Combination of IVIG and steroids is a common treatment for TEN, but its efficacy in improving mortality needs further investigation. PMID- 29607332 TI - Online formative assessments: exploring their educational value. AB - Introduction: Online formative assessments (OFA's) have been increasingly recognised in medical education as resources that promote self-directed learning. Formative assessments are used to support the self-directed learning of students. Online formative assessments have been identified to be less time consuming with automated feedback. This pilot study aimed to determine whether participation and performance in online formative assessments (OFA's) had measurable effects on learning and evaluate the students' experience of using the OFA's in the department of Obstetrics and Gynaecology. Methods: This is a cross-sectional study conducted among fourth year medical students (n=92) during their seven week postings in Obstetrics and Gynaecology. Five sets of online formative assessments in the format of one best answers (OBA), Objective structured practical examination (OSPE) and Short answer question (SAQ) with feedback were delivered over five weeks through the online portal. The mean scores of the end of posting summative exam (EOP) of those who participated in the assessments (OFA users) and of those who did not (non-OFA users) were compared, using Students t test. The frequency of tool usage was analysed and satisfaction surveys were utilized at the end of the course by survey questionnaire using the five point Likert scale. Results: The mean scores of the students in end of posting summative examination marks for students who had participated in the online formative assessment (OFA users) and for those who had not (non OFA users) showed no significant difference in all the three components OBA, SAQ and OSPE (p=0.902, 0.633, 0.248). Majority of the students perceived that OFAs fulfilled the stated aims and objectives and so they would persuade their peers to participate in the OFAs. Conclusions: Online formative assessments are perceived as tools that promote self-directed learning, improved knowledge and tailor learning for individual learning needs and style. PMID- 29607331 TI - Receptors That Inhibit Macrophage Activation: Mechanisms and Signals of Regulation and Tolerance. AB - A variety of receptors perform the function of attenuating or inhibiting activation of cells in which they are expressed. Examples of these kinds of receptors include TIM-3 and PD-1, among others that have been widely studied in cells of lymphoid origin and, though to a lesser degree, in other cell lines. Today, several studies describe the function of these molecules as part of the diverse mechanisms of immune tolerance that exist in the immune system. This review analyzes the function of some of these proteins in monocytes and macrophages and as well as their participation as inhibitory molecules or elements of immunological tolerance that also act in innate defense mechanisms. We chose the receptors TIM-3, PD-1, CD32b, and CD200R because these molecules have distinct functional characteristics that provide examples of the different regulating mechanisms in monocytes and macrophages. PMID- 29607333 TI - The educational effects of mobile learning on students of medical sciences: A systematic review in experimental studies. AB - Introduction: The demand for mobile learning in the medical science educational program is increasing. The present review study gathers evidence highlighted by the experimental studies on the educational effects of mobile learning for medical science students. Methods: The study was carried out as a systematic literature search published from 2007 to July 2017 in the databases PubMed/Medline, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Web of Knowledge (Thomson Reuters) , Educational Resources and Information Center (ERIC), EMBASE (Elsevier), Cochrane library, PsycINFO and Google Scholar. To examine quality of the articles, a tool validated by the BEME Review was employed. Results: Totally, 21 papers entered the study. Three main themes emerged from the content of papers: (1) improvement in student clinical competency and confidence, (2) acquisition and enhancing of students' theoretical knowledge, and (3) students' positive attitudes to and perception of mobile learning. Level 2B of Kirkpatrick hierarchy had been examined by all the papers and seven of them had reported two or more outcome levels, but level 4 was not reported in the papers. Conclusion: Our review showed that the students of medical sciences had positive response and attitudes to mobile learning. Moreover, implementation of mobile learning in medical sciences program might lead to valuable educational benefits and improve clinical competence and confidence along with theoretical knowledge, attitudes, and perception of mobile learning. The results indicated that mobile learning strategy in medical education can positively affect learning in all three domains of Bloom's Taxonomy. PMID- 29607334 TI - The effect of question generation activity on students' learning and perception. AB - Introduction: Student-generated questions can be a very helpful tool in medical education. The use of this activity can allow the students to feel more involved in the subjects covered and may improve their knowledge and learning. The aim of this study was to identify the effect of question-writing activity as a stimulus factor on learning in midwifery students and determine their perception about this activity. Methods: This quasi-experimental study with two groups of pre- and post-tests was conducted on two groups of midwifery students who had taken the immunology course. Two classes of midwifery students (N=62) participated and were randomly assigned to two different groups. One class was selected as the experimental group (n=32) and the other class was considered as the control group (n=30). The experimental group's students were asked to write questions covering different topics of the syllabus components taught during 15 weeks from February 2016 to May 2016. They were asked to write, answer and explain their multiple choice questions (MCQs). The students' performance in immunology course was compared between the two groups at the end of the semester. After their final exam, we asked them to fill in a questionnaire on their views about this activity. The data were analyzed by independent t- test using SPSS software, version 18. Results: The differences between pre- and post-test mean scores of the experimental and control groups were 24.53+/-5.74 and 20.63+/-5.58, respectively. The results of independent t-test showed that these differences in the two groups were significant (p=0.009). Nevertheless, most of the students stated that question-writing activity as a learning tool is an unfamiliar exercise and unpopular learning strategy. Conclusion: Results showed that question writing by students has been found to promote learning when it is implemented as a part of the teaching curriculum in immunology course; therefore, this activity could be effective in improving the students' learning. PMID- 29607335 TI - Using newly deceased patients in teaching clinical skills: its ethical and educational challenges. AB - Introduction: The newly deceased patients have long been used in medical schools to teach clinical skills without any challenges as it helps to train skilled doctors. Nowadays, the use of moulages and simulators are common in teaching clinical skills since these tools provide the opportunity for frequent practice without any pain and injury. There are specific procedures which still require the use of cadavers. However, the increased significance of patient rights has generally challenged the practicality of using the deceased bodies for this purpose. This study was designed with the aim of determining to what extent clinical skill training is dependent on the recently deceased patients. Methods: This was a cross-sectional mixed-method triangulation design conducted in two phases. In the first phase, a researcher-made questionnaire was used to collect quantitative data of the medical students and residents. The data were used to assess the frequency of experience. In the second stage, semi-structured interviews were conducted with faculty members and fellows in order to evaluate the educational impact of this type of procedure and the influential factors. The quantitative data were analyzed using statistical software, and the qualitative codes were extracted following a content analysis. Finally, a comparative analysis was performed. Results: Twenty five residents (26%) and seven medical students (14%) had the experience of performing procedures on the recently deceased patients for training purposes. About half of the residents and 33% of the medical students had observed their colleagues practicing procedures on cadavers. In the qualitative phase, the main categories included professional ethics, law and educational requirements. Conclusion: A relatively low number of medical students and residents had experienced procedures on the newly deceased patients. In this regard, ethical, religious and legal concerns might have played a part despite the desire to learn. It would be effective to direct these educational experiences toward procedures that cannot be mastered through moulages and simulators, and to lay the legal and executive ground so that performing these procedures under the supervision of professors, and with a level of documentation would have no legal challenges. PMID- 29607336 TI - The effect of Cardiac Arrhythmias Simulation Software on the nurses' learning and professional development. AB - Introduction: One of the important tasks of nurses in intensive care unit is interpretation of ECG. The use of training simulator is a new paradigm in the age of computers. This study was performed to evaluate the impact of cardiac arrhythmias simulator software on nurses' learning in the subspecialty Vali-Asr Hospital in 2016. Methods: This study was conducted by quasi-experimental randomized Salomon four group design with the participation of 120 nurses in subspecialty Vali-Asr Hospital in Tehran, Iran in 2016 that were selected purposefully and allocated in 4 groups. By this design other confounding factors such as the prior information, maturation and the role of sex and age were controlled by Solomon 4 design. The valid and reliable multiple choice test tools were used to gather information; the validity of the test was approved by experts and its reliability was obtained by Cronbach's alpha coefficient 0.89. At first, the knowledge and skills of the participants were assessed by a pre-test; following the educational intervention with cardiac arrhythmias simulator software during 14 days in ICUs, the mentioned factors were measured for the two groups again by a post-test in the four groups. Data were analyzed using the two way ANOVA. The significance level was considered as p<0.05. Results: Based on randomized four-group Solomon designs and our test results, using cardiac arrhythmias simulator software as an intervention was effective in the nurses' learning since a significant difference was found between pre-test and post-test in the first group (p<0.05). Also, other comparisons by ANOVA test showed that there was no interaction between pre-test and intervention in all of the three knowledge areas of cardiac arrhythmias, their treatments and their diagnosis (P>0.05). Conclusion: The use of software-based simulator for cardiac arrhythmias was effective in nurses' learning in light of its attractive components and interactive method. This intervention increased the knowledge of the nurses in cognitive domain of cardiac arrhythmias in addition to their diagnosis and treatment. Also, the package can be used for training in other areas such as continuing medical education. PMID- 29607337 TI - Strategies to curb young researchers from predatory publishers. PMID- 29607338 TI - Comparing Kirkpatrick's original and new model with CIPP evaluation model. PMID- 29607339 TI - The Effect of Prangos Ferulacea Vaginal Cream on Accelerating the Recovery of Bacterial Vaginosis: A Randomized Controlled Clinical Trial. AB - Background: The present study was conducted on the effect of prangos ferulacea vaginal cream on accelerating the recovery of bacterial vaginosis. Methods: This randomized controlled clinical trial was conducted on 100 non-pregnant women referring to health centers affiliated to Lorestan University of Medical Sciences in 2016 with the diagnosis of bacterial vaginosis based on the patient's complaints, Amsel's clinical criteria, and the Nugent microscopic criteria. The women were randomly divided into two groups of 50. One group was treated with oral metronidazole plus Prangos ferulacea vaginal cream and the other with oral metronidazole plus a placebo vaginal cream for seven days. The patient's complaints, Amsel's clinical criteria and the Nugent microscopic criteria were assessed seven days after treatment. The data were analyzed using SPSS, version 20, with a significance level of 0.05. Results: The response to oral metronidazole plus Prangos ferulacea vaginal cream treatment was 94% according to Amsel's clinical criteria and 88% according to the Nugent microscopic criteria. The response to oral metronidazole plus placebo vaginal cream treatment was 94% according to Amsel's criteria and 86% according to the Nugent criteria. The analysis of the patients' complaints, Amsel's clinical criteria and the Nugent microscopic criteria showed significant differences in each group before and after the treatment. Conclusion: This trial showed that Prangos ferulacea vaginal cream accelerated the recovery of bacterial vaginosis of patients with bacterial vaginosis. It can be used effectively as a complementary treatment with oral metronidazole in cases of medication resistance and also in people wishing to use herbal remedies Trial Registration Number: IRCT2016042327534N1. PMID- 29607340 TI - Educational Needs on Palliative Care for Cancer Patients in Iran: A SWOT Analysis. AB - Background: By acceptance of palliative care as a part of health system of each country and due to increasing prevalence of cancer, special focus on stakeholder's educational needs is of vital importance so that palliative care services are improved and the quality of life of patients is enhanced. This study was conducted to explore the educational needs of stakeholders of palliative care for cancer patients in Iran. Methods: This qualitative study with 20 semi structured interviews was conducted from August 2016 to February 2017 in Shohadaye Tajrish and Emam Khomeini Hospitals of Tehran. Participants were selected through purposive sampling and included cancer patients and their family caregivers as well as healthcare providers, experts and policy-makers. The data were analyzed through Conventional Content Analysis of Landman and Graneheim using MAXQDA10 software. Statements of each main category of the study were summarized in SWOT categorizes. Result: A total of 546 codes were extracted from the analysis of the interviews and four main categories and four subcategories were identified. The four main identified categories included: "academic education planning", "workforce education", "public awareness", and "patient and caregiver empowerment" that contained our subcategories as follows: "strengths", "weaknesses", "opportunities" and "threats" (SWOT). Conclusion: Meeting the educational needs of the stakeholders of palliative care requires policy-makers to identify the factors leading to strategies that are based on the use of opportunities, the removal of weaknesses, and coping with the threats to which the organization is faced. PMID- 29607341 TI - Contextual Factors for Establishing Nursing Regulation in Iran: A Qualitative Content Analysis. AB - Background: Professional regulation is one of the strategies of the governments which protect the public's right. Nursing practice is not an exception; hence, it is regulated to protect the public against nursing services' adverse effects. Although modern nursing in Iran started from 100 years ago, documents show that there was no regulation mechanism for nursing in Iran till 2016. Hence, this study was conducted to illuminate the contextual factors affecting the nursing regulation process in Iran. Methods: To explore the contextual elements of late establishment of nursing registration as an important part of nursing regulation, we applied directed qualitative content analysis. For this purpose, all the historical events and related materials including articles published in scientific journals, gray literature, statements, news articles, and interviews in the period of 2006-2016 were reviewed and analyzed by expert panel and categorized in predetermined groups. Results: Pooled analysis data showed four contributing elements that affected the emerging nursing regulation in Iran. These elements include 1) cultural determinants, 2) structural determinants, 3) situational determinants, and 4) international or exogenous determinants. Conclusion: Nursing regulation is an important health policy issue in Iran which needs to be facilitated by contextual factors. These factors are complicated and country-specific. Political willingness should be accompanied by nursing association willingness to establish and improve nursing regulation. Other researches are recommended to explore actors and process and content of nursing regulation policy in Iran. PMID- 29607343 TI - The Effect of Teach-Back Training on Self Management in Kidney Transplant Recipients: A Clinical Trial. AB - Background: Kidney transplant recipients need self-management during their lifetime, and training these patients is essential for the realization of self management. Teach-back training (TBT) was used to receive, understand, and retain information. This study aimed to determine the effect of TBT on self-management in kidney transplant recipients. Methods: In this clinical trial study, 84 kidney transplant recipients who referred to the clinic of Imam Khomeini Hospital in Urmia (a city in northwest of Iran), from January to March 2017, were selected through convenience sampling and randomly assigned to intervention and control groups. In the intervention group, educational content was presented for each patient with TBT in 5 sessions of 60 minutes. Data were collected before and after the intervention by a special Self-Management Questionnaire for Kidney Transplant Recipients in five areas as follows: self-monitoring, self-care behavior in daily living, early detecting and coping with abnormalities after kidney transplantation, stress management and the category of non-categorized area. This is a valid and reliable questionnaire (alpha=0.76). Collected data were analyzed by independent t-test and Mann-Whitney test. Statistical analysis was performed using SPSS 20 and P<=0.05 was considered as significant. Results: Independent t-test showed that the mean of self-management score between the control and intervention groups was not statistically significant before the intervention (P=0.90). The mean score of self-management increased after implementation of TBT in the intervention group compared to the control group, and the difference was statistically significant (P=0.001). Conclusion: The implementation of TBT method is effective in promoting self-management of kidney transplant recipients. Therefore, it is recommended that this method should be used to train the patients to better understand the components of self management. Trial Registration Number: IRCT2016122817059N10. PMID- 29607342 TI - Effectiveness of Life Review Therapy on Quality of Life in the Late Life at Day Care Centers of Shiraz, Iran: A Randomized Controlled Trial. AB - Background: Life review therapy, used as part of a comprehensive therapy plan for increasing the quality of life of the elderly, helps them to resolve their past conflicts, reconstruct their life stories, and accept their present conditions. The present study aimed to explore the effectiveness of life review therapy on the quality of life of the elderly. Methods: The present study was a randomized controlled trial with a pre-posttest design during April to Aug 2014. The study was conducted on 35 members of the elderly day care centers in Shiraz, Iran, that were randomly assigned to two groups (experimental and control). The subjects in the experimental group attended 8 two-hour sessions of life review therapy. The quality of life of the elderly participants was evaluated before, immediately, one month, and three months after the intervention using the quality of life questionnaire (WHOQOL_BREF). Data analysis was conducted through SPSS version 22, using statistical tests including Chi-square, repeated measures test and T-test, with the significance level of 0.05. Results: The results of the study showed that life review therapy interventions significantly improved the quality of life of the elderly (P<0.05). Moreover, group interaction with passage of time was also significant, which indicates that the pattern of changes has been different between the two groups. Conclusion: The findings of the study confirm the research hypotheses, showing that the application of life review is effective and viable. It is recommended that all nursing homes and even the families of the elderly should employ this convenient, inexpensive, quick, and practical method. Trial Registration Number: IRCT2015021621106N1. PMID- 29607344 TI - A Qualitative Approach to Women's Perspectives on Exercise in Iran. AB - Background: It is believed that women of all ages do less physical activities compared to men. The development of interventional projects for increasing the women's participation in physical activity needs the recognition of resources and exploration of women's perspectives on exercise in their lives in the Iranian culture and context. Methods: This qualitative study was conducted in an urban area of Iran on 46 women attending healthcare centers, volunteer health care providers, university students, sportswomen and one of the officials of the provincial women's sports. This study was done from April 2015 to June 2016. Four focus group discussions and one in depth semi-structured interview was conducted. A qualitative conventional content analysis approach was used for data analysis. Results: Four categories were developed as follows: 'preferences', 'planning', 'motivators' and 'inhibitors'. Preferences had three distinct subcategories: preferences to do exercise in specific settings, specific exercise and group exercise. The family role, exercise as one part of daily routines, and exercise as a habit were subcategories of planning. Motivators were physical, emotional and social benefits; physician advice and encouragement; being alarmed; and championship. The inhibitors of doing exercise were various: gender issues, economical and costs issues, geographical access, making excuses, cultural infrastructures, shortage of sports experts, fears, concerns and misconceptions, inappropriate facilities and inadequate administrative cooperation and official barriers. Conclusion: The findings showed that the women were sensitive to and interested in doing exercise. However, barriers to exercise were multiple and complex. Nursing interventions are required to increase the individuals' awareness of misconceptions and also develop strategic programs for improving exercise among women. PMID- 29607345 TI - Women's Perceptions and Feelings about Loss of Their Sexual Desire: A Qualitative Study in Iran. AB - Background: Reduced sexual desire leaves serious impacts on women's life. The current study aims to investigate the perceptions and concerns of Iranian women of reproductive age with female sexual interest and arousal disorder (FSIAD). Methods: This qualitative research was conducted using content analysis approach. Data were collected through seventeen in-depth interviews from October 2015 to June 2016. Purposive sampling was carried out from among reproductive-aged women suffering from FSIAD who responded to female sexual function index (FSFI) with mean scores of <=3.3 and <=3.4 in desire and arousal domains, respectively and went through validation by a psychologist. Data analysis was performed using Granheim and Lundman's approach. MAXQDA 10.0 software was used for data organization. Results: The three main themes that emerged in this study included: 1) "Spoiled feminine identity" with two categories of "deteriorated sexual self esteem" and "deteriorated feminine position", 2) "Struggle in sexual issues" with two categories of concern about losing the relationship and spouse, and surrendering to sexual relationship, and 3) "Deterioration of the couple's relationship" with two categories of deteriorated marital interaction and sexual disharmony between the couple. Conclusion: Feeling inability to play gender role as a woman and fear of losing the spouse are the most important concerns of women with lack of interest in sex. Training communication skills for sexual talks with the spouse and expression of feelings are the first steps to help such women. PMID- 29607346 TI - Relationship between Body Image and Psychological Well-being in Patients with Morbid Obesity. AB - Background: Morbid obesity is rising around the world. It can cause unpleasant appearance and body image. Most of the studies have aimed to evaluate the psychopathology of overweight and obesity and paying attention to mental well being in morbid obese individuals is rare. Therefore, this study aimed to assess the relationship between body image and psychological well-being in morbid obese patients. Methods: This cross-sectional study, using simple random sampling method, was done on 124 morbid obese patients who referred to obesity clinic in Shiraz from 2016 to 2017. The data were collected by body image index and psychological well-being questionnaire. Results were analyzed using descriptive statistics, Pearson correlation coefficient test, ANOVA, and Regression analysis. Results: The results showed a significant relationship between body image and psychological well-being (r=0.43) (P<0.001), and between the total score of the body image and all the subscales of psychological well-being except autonomy and purpose in life (P<0.05). There was also a significant relationship between the total score of psychological well-being and all the subscales of body image (P<0.05). However, there was no significant difference between the mean scores of the body image and those of psychological well-being in different categories of body mass index (BMI) (P>0.05). Conclusion: Final results indicated that body image defects caused by obesity could lie in negative psychological well-being in all aspects. This study can promote health clinicians' knowledge in supporting of mental status of obese individuals. It is suggested that preventing and supporting intervention should be performed as effective methods for encountering and coping with psychological effects of obesity. PMID- 29607348 TI - Use of a Targeted Sequential Mixed Mode Protocol in a Nationally Representative Panel Study. AB - Relatively low response rates in mixed mode studies remain a concern. Whether targeting protocols to match respondents' likely mode is an effective strategy remains unclear. For those without a clear likely mode, how the details about sequencing influence response rates, mode, field work effort, and potential response bias remain important questions. This article describes a targeted sequential design implemented in a 2016 mixed mode supplement with individuals ages 30 and older in the Panel Study of Income Dynamics, the longest running national panel study in the US (N=10,784). Respondents predicted to be likely to respond by web were invited to a web study and sent a paper copy after 6 weeks (web-first); those likely to respond by paper were also invited to participate by web but told that a paper copy would be sent shortly (signal-and-send). An embedded experiment measured the impact of the two protocols among a group of respondents with no clear likely mode (N=889). Over 40% of individuals with no likely mode are under the age of 40, and the group falls between the likely web and paper groups in terms of education and internet use and includes more women and single respondents. Compared to the likely web and paper groups, those with no likely mode had lower response rates and required more fieldwork effort. Among those randomly assigned, the signal-and-send protocol increased response over the web-first protocol from weeks 4 through 7. By week 16, both protocols yielded similar response rates (AAPOR 1 RR=71% vs. 68%, p=0.49), field effort (7.9 vs. 8.4 mean weeks, p=0.251), and distributions of respondent characteristics. Among those responding, cases randomized to web-first were more likely than those randomized to signal-and-send to respond by web (62.7% vs. 42.4% p<.001). We discuss implications for targeted protocols in mixed mode panel surveys. PMID- 29607347 TI - Phosphorylation Modulates Aspartyl-(Asparaginyl)-beta Hydroxylase Protein Expression, Catalytic Activity and Migration in Human Immature Neuronal Cerebellar Cells. AB - Background: Abundant aspartyl-asparaginyl-beta-hydroxylase (ASPH) expression supports robust neuronal migration during development, and reduced ASPH expression and function, as occur in fetal alcohol spectrum disorder, impair cerebellar neuron migration. ASPH mediates its effects on cell migration via hydroxylation-dependent activation of Notch signaling networks. Insulin and Insulin-like growth factor (IGF-1) stimulate ASPH mRNA transcription and enhance ASPH protein expression by inhibiting Glycogen Synthase Kinase-3beta (GSK-3beta). This study examines the role of direct GSK-3beta phosphorylation as a modulator of ASPH protein expression and function in human cerebellar-derived PNET2 cells. Methods: Predicted phosphorylation sites encoded by human ASPH were ablated by S/T->A site-directed mutagenesis of an N-Myc-tagged wildtype (WT) cDNA regulated by a CMV promoter. Phenotypic and functional features were assessed in transiently transfected PNET2 cells. Results: Cells transfected with WT ASPH had increased ASPH protein expression, directional motility, Notch-1 and Jagged-1 expression, and catalytic activity relative to control. Although most single- and multi-point ASPH mutants also had increased ASPH protein expression, their effects on Notch and Jagged expression, directional motility and adhesion, and catalytic activity varied such that only a few of the cDNA constructs conferred functional advantages over WT. Immunofluorescence studies showed that ASPH phosphorylation site deletions can alter the subcellular distribution of ASPH and therefore its potential interactions with Notch/Jagged at the cell surface. Conclusions: Inhibition of ASPH phosphorylation enhances ASPH protein expression, but attendant alterations in intra-cellular trafficking may govern the functional consequences in relation to neuronal migration, adhesion and Notch activated signaling. PMID- 29607349 TI - Non-equilibrium lattice dynamics of one-dimensional In chains on Si(111) upon ultrafast optical excitation. AB - The photoinduced structural dynamics of the atomic wire system on the Si(111)-In surface has been studied by ultrafast electron diffraction in reflection geometry. Upon intense fs-laser excitation, this system can be driven in around 1 ps from the insulating [Formula: see text] reconstructed low temperature phase to a metastable metallic [Formula: see text] reconstructed high temperature phase. Subsequent to the structural transition, the surface heats up on a 6 times slower timescale as determined from a transient Debye-Waller analysis of the diffraction spots. From a comparison with the structural response of the high temperature [Formula: see text] phase, we conclude that electron-phonon coupling is responsible for the slow energy transfer from the excited electron system to the lattice. The significant difference in timescales is evidence that the photoinduced structural transition is non-thermally driven. PMID- 29607350 TI - How Dark Are Radial Breathing Modes in Plasmonic Nanodisks? AB - Due to a vanishing dipole moment, radial breathing modes in small flat plasmonic nanoparticles do not couple to light and have to be probed with a near-field source, as in electron energy loss spectroscopy (EELS). With increasing particle size, retardation gives rise to light coupling, enabling probing breathing modes optically or by cathodoluminescence (CL). Here, we investigate single silver nanodisks with diameters of 150-500 nm by EELS and CL in an electron microscope and quantify the EELS/CL ratio, which corresponds to the ratio of full to radiative damping of the breathing mode. For the investigated diameter range, we find the CL signal to increase by about 1 order of magnitude, in agreement with numerical simulations. Due to reciprocity, our findings corroborate former optical experiments and enable a quantitative understanding of the light coupling of dark plasmonic modes. PMID- 29607351 TI - Mapping spontaneous facial expression in people with Parkinson's disease: A multiple case study design. AB - People with Parkinson's disease (PD) often experience a decrease in their facial expressivity, but little is known about how the coordinated movements across regions of the face are impaired in PD. The face has neurologically independent regions that coordinate to articulate distinct social meanings that others perceive as gestalt expressions, and so understanding how different regions of the face are affected is important. Using the Facial Action Coding System, this study comprehensively measured spontaneous facial expression across 600 frames for a multiple case study of people with PD who were rated as having varying degrees of facial expression deficits, and created correlation matrices for frequency and intensity of produced muscle activations across different areas of the face. Data visualization techniques were used to create temporal and correlational mappings of muscle action in the face at different degrees of facial expressivity. Results showed that as severity of facial expression deficit increased, there was a decrease in number, duration, intensity, and coactivation of facial muscle action. This understanding of how regions of the parkinsonian face move independently and in conjunction with other regions will provide a new focus for future research aiming to model how facial expression in PD relates to disease progression, stigma, and quality of life. PMID- 29607352 TI - Tight real-time synchronization of a microwave clock to an optical clock across a turbulent air path. AB - The ability to distribute the precise time and frequency from an optical clock to remote platforms could enable future precise navigation and sensing systems. Here we demonstrate tight, real-time synchronization of a remote microwave clock to a master optical clock over a turbulent 4-km open air path via optical two-way time frequency transfer. Once synchronized, the 10-GHz frequency signals generated at each site agree to 10-14 at one second and below 10-17 at 1000 seconds. In addition, the two clock times are synchronized to +/-13 fs over an 8-hour period. The ability to phase-synchronize 10-GHz signals across platforms supports future distributed coherent sensing, while the ability to time-synchronize multiple microwave-based clocks to a high-performance master optical clock supports future precision navigation/timing systems. PMID- 29607353 TI - Viruses infecting macrofungi. AB - Ever since their discovery just about 56 years ago in the cultivated mushroom Agaricus bisporus, many more viruses infecting fungi have been identified in a wide range of fungal taxa. With mostly being asymptomatic, especially the ones that are detrimental to their phytopathogenic hosts are intensively studied due to their considerable importance in developing novel plant protection measures. Contrary to the rapid accumulation of notable data on viruses of plant pathogenic microfungi, much less information have hitherto been obtained in regards to the viruses whose hosts are macrofungi. According to the current literature, only more than 80 distinct viruses bearing either linear dsRNA or linear positive sense ssRNA genome and infecting a total number of 34 macrofungal species represented with four Ascomycota and 30 Basidiomycota have been identified so far. Among these 34 macrofungal species, 14 are cultivated edible and wild edible mushroom species. According to the 10th ICTV (International Committee on Taxonomy of Viruses) Report, macrofungal viruses with linear dsRNA genome are classified into five families (Partitiviridae, Totiviridae, Chrysoviridae, Endornaviridae and Hypoviridae) and macrofungal viruses with linear positive sense ssRNA genome are classified into seven families (Betaflexiviridae, Gammaflexiviridae, Barnaviridae, Narnaviridae, Virgaviridae, Benyviridae and Tymoviridae). In this review, following a brief overview of some general characteristics of fungal viruses, an up to date knowledge on viruses infecting macrofungal hosts were presented by summarizing the previous, recent and prospective studies of the field. PMID- 29607355 TI - Prevalence of human papilloma virus and their high-risk genotypes in Sri Lankan women. AB - Human papilloma virus (HPV) causes cervical cancer in women and approximately 700 deaths have been reported annually in Sri Lanka due to this cancer. Despite, attempts have not been made to investigate the prevalence of HPV amongst Sri Lankan women with normal cytology. In this study, a polymerase chain reaction based assay was set up to detect HPV in both normal and abnormal cytology and the positive samples were then tested for the genotypes, HPV 16 and HPV 18 as they have been identified as the high-risk types associating with cervical cancer. Eighty-four (number = 84) clinical samples (age range 27-69) analyzed in this study indicated that the prevalence of HPV, regardless of cytological abnormalities was 15.5%, (n = 13, 95% class interval +/- 7.7) while it was 100% (n = 3) for those with abnormal cytology. Association of HPV 16 and HPV 18 among the abnormal cytology was 0 and 50% (n = 1), respectively and further, the prevalence of HPV 16 and HPV 18 in women was found to be 3.6% (n = 3, 95% CI +/- 4.0) and 2.4% (n = 2, 95% CI +/- 3.3), respectively. Moreover, age wise prevalence analysis revealed women of the age of 35-years or more to have higher HPV prevalence. The prevalence of HPV among normal cytology is 12.3% (n = 10, 95% CI +/- 7.2) which is similar to the rates in other regions of Asia (China 15.4%; India 10.43%). Finally, higher prevalence of HPV in women of the age of 35-years or more in Sri Lanka, especially with malignant types call for such age group to be screened for proper clinical intervention to be made in reducing the incident of cervical cancers. This is the first report of prevalence of HPV among women with normal cytology in Sri Lanka. PMID- 29607354 TI - Consequence of HIV and HCV co-infection on host immune response, persistence and current treatment options. AB - Hepatitis C virus (HCV) is a common opportunistic pathogen especially among Human immunodeficiency virus (HIV) infected patients. Due to incongruous studies, the pathological effect of HCV on HIV induced disease are still not fully understood. While some studies have showed no effect of HCV on HIV infection, others reported a defined role of HCV in aggravating the rates of AIDS-related illnesses and mortality. The explanation of such variances may be due to the host immune response, viral genotypes, sub-type and quasi-species distribution. The factors that complicate the management of HIV/HCV patients are: (1) reduced HCV antibody production, (2) drug interactions, (3) liver disease and (4) different epidemiologic characteristics. However, it is abundantly clear that the morbidity and mortality caused by HCV have increased since the introduction of highly active antiretroviral therapy (HAART) against HIV. In this review, the consequence of HIV/HCV co-infection on host immune response, viral replication, disease progression, mortality and morbidity, viral load, persistence and current treatment options have been discussed. Based on the clinical studies, it is necessary to evaluate the effect of HCV therapy on HIV progression and to provide a fully active HCV treatment for patients receiving HIV treatment. In conclusion, it is recommended to provide fully active HAART therapy in combination with a known HCV therapy. PMID- 29607356 TI - Standardization of in vitro assays to evaluate the activity of polyherbal siddha formulations against Chikungunya virus infection. AB - Chikungunya, a viral fever caused by Aedes mosquito results in extreme morbidity in affected individuals and is a major public health concern in India. Currently, modern vaccines or formulations prescribed by physicians can only provide symptomatic relief for the pyretic and post pyretic phase of the disease. Siddha practitioners follows strict medical regimen based on traditional Indian knowledge/concepts to treat Chikungunya with considerable results. The current study was undertaken to standardize assays for the study of these siddha formulations and to check their efficacy and potential mode of action as antivirals for Chikungunya virus infection in in vitro system. Although, siddha practitioners follow a regime containing 4-6 formulations, of these Brahmanandha bairavam mathirai, a part of the regime for Chikungunya followed at National Institute of Siddha and Vishnu chakram along with Brahmanandha bairavam mathirai, a part of Thiruchergodu Regime were found of have antiviral activities. It was observed that both Vishnu chakram and Brahmanandha bairavam mathirai were equally effective in blocking Chikungunya virus from entering susceptible cells in the concentrations range of 0.0625 and 0.5 mg/ml. Additionally, it was also observed that Brahmanandha bairavam mathirai was more effective than Vishnu chakram against entry of Chikungunya in the cells. The assays used in this study provides insights to the possible mode of action of various formulations used by siddha practitioners for the treatment of Chikungunya infection. PMID- 29607357 TI - Simultaneous detection and serotyping of dengue infection using single tube multiplex CDC Dengue Real-Time RT-PCR from India. AB - Four antigenically different dengue virus serotypes (DENV-1, DENV-2, DENV-3 and DENV-4) are known to cause infections in humans. Some of these are known to cause more severe disease than the others. Chances for developing Dengue hemorrhagic fever-dengue shock syndrome (DHF-DSS) increases significantly with history of previous infection with one of the four serotypes. Therefore, early diagnosis, serotyping and providing early warning of dengue fever epidemics to concerned authorities becomes very important for better patient outcome and to curb the rapid spread in the community. During the 2014 outbreak, a total of 100 samples from suspected cases of dengue were collected. NS1 antigen based rapid test was used for serological diagnosis. Dengue complex one step reverse transcription polymerase chain reaction was performed to look for presence of viral RNA. Single tube multiplex RT-PCR was also performed to look for infecting serotype. CDC Dengue Multiplex Real Time PCR assay was performed for rapid diagnosis and simultaneous serotyping of the dengue virus. Out of the 100 samples screened, 69 were found to be positive by NS1Ag Rapid test. 34 samples were found positive by dengue consensus RT-PCR assay. 22 samples were found to be positive by single tube Dengue multiplex RT-PCR assay. Serotype DEN-2 was present in maximum numbers followed by DEN-3. 44 samples were found positive by DENV CDC Multiplex Real time PCR assay. DEN-2 was found in maximum numbers followed by DEN-1. Dengue remains to be an important health problem in India and across the globe. Few serotypes of dengue are more dangerous than the others. Rapid diagnosis and serotyping remains the key for better patient management and prevention of disease spreading in the community. Highly sensitive, specific and rapid CDC real time RT-PCR assay was found to be most promising tool among all available molecular diagnostic methods. This will serve a rapid and reliable simultaneous dengue virus detection as well serotyping assay in near future for rapid identification of dengue suspected sample screening. PMID- 29607358 TI - Rainfall and Chikungunya incidences in India during 2010-2014. AB - Changing climate scenario has resulted in recent emergence and re-emergence of various arboviral diseases including Chikungunya. This disease is caused by Chikungunya virus (CHIKV), which belongs to Togaviridae family of viruses and spread by Aedes mosquitoes. A resurgence of CHIKV and its rapid global spread has been observed since 2004. The disease reemerged in India in 2005, after a gap of 32 years, causing massive outbreaks in some states and circulating thereafter. In the present paper we analyze CHIKV incidence data from India (2010-2014) with a view to understand association with environmental parameters, if any. Data on country-wide occurrences of CHIKV cases were considered from the National Vector Borne Disease Control Board, India. Meteorological data for different climatic subdivisions of India were obtained and processed mathematically. State-wise association of number of cases with rainfall, if any, were studied by statistical analyses. We observe that prevailing temperature range was favorable for CHIKV propagation and the occurrences were modulated by average rainfall. Most affected states were West Bengal, Maharashtra and Karnataka. Overall for India, favorable climatic conditions have contributed to incidences of CHIKV during the study period. There is strong positive association between rainfall variations and occurrence of CHIKV cases. PMID- 29607359 TI - Molecular analysis of hemagglutinin, neuraminidase, matrix genes provide insight into the genetic diversity of seasonal H3N2 human influenza a viruses in Bangladesh during July-August, 2012. AB - Influenza A virus subtype H3 is a threat to public health and it is important to understand the evolution of the viruses for the surveillance and the selection of vaccine strains. Comparative analysis of four Bangladeshi isolates with isolates circulating other parts of the world based on three candidate genes hemagglutinin (HA), neuraminidase (NA), matrix protein (MA) showed no evidence of significant distinct subclade of viruses circulating in the country over the period of study. Despite these findings, we found N161S substitution in all four H3N2 influenza stains resulting in the gain of NSS160-162 glycosylation site. All H3N2 Influenza subtypes in the study had amino acid substitution at position 31 on the M2 protein (Aspartic acid to Asparagine) which is known to be responsible for amantadine drug resistance. PMID- 29607361 TI - Molecular evidence of an isolate of mungbean yellow mosaic India virus with a recombinant DNA B component occurring on mungbean from mid-hills of Meghalaya, India. AB - A new isolate (Mg-mungbean-1) of yellow mosaic virus (YMV) was identified and characterized from mungbean growing in mid-hill condition of Meghalaya, India. Full genome of components (DNA A and DNA B; NCBI accessions number KU95030 and KU95031, respectively) of the virus were amplified through rolling circle amplification and sequenced. Both, DNA A and DNA B shared a common region (CR) with 90.4% similarity. The DNA A of Mg-mungbean-1 showed maximum (97.59%) nucleotide identity with mungbean yellow mosaic India virus (MYMIV) isolate (HF922628) reported from West Bengal, India and DNA B showed ~ 96% nucleotide identity with mungbean yellow mosaic virus (MYMV) isolates having variant DNA B. Phylogenetic tree of DNA A also identified Mg-mungbean-1 as a MYMIV. Based on DNA B the current isolate grouped with the variant Indian MYMV isolates. One recombination event in the CR of DNA B of Mg-mungbean-1 was detected, where MYMV:India:clonePB1 and MYMIV:India:cloneMBB-B31 have been identified as major and minor parents, respectively. Overall, the current study indicated occurrence of an isolate of MYMIV with a recombinant DNA B component on mungbean from mid hills of Meghalaya, India. To the best of our knowledge this is the first molecular characterization of YMV from northeast India. PMID- 29607360 TI - Rolling circle amplification-based analysis of Sri Lankan cassava mosaic virus isolates from Tamil Nadu, India, suggests a low level of genetic variability. AB - Cassava mosaic disease is a widespread disease of cassava in south Asia and the African continent. In India, CMD is known to be caused by two single-stranded DNA viruses (geminiviruses), Indian cassava mosaic virus (ICMV) and Sri Lankan cassava mosdaic virus (SLCMV). Previously, the diversity of ICMV and SLCMV in India has been studied using PCR, a sequence-dependent method. To have a more in depth study of the variability of the above viruses and to detect any novel geminiviruses associated with CMD, sequence-independent amplification using rolling circle amplification (RCA)-based methods were used. CMD affected cassava plants were sampled across eighty locations in nine districts of the southern Indian state of Tamil Nadu. Twelve complete sequence of coat protein genes of the resident geminiviruses, comprising 256 amino acid residues were generated from the above samples, which indicated changes at only six positions. RCA followed by RFLP of the 80 samples indicated that most samples (47) contained only SLCMV, followed by 8, which were infected jointly with ICMV and SLCMV. In 11 samples, the pattern did not match the expected patterns from either of the two viruses and hence, were variants. Sequence analysis of an average of 700 nucleotides from 31 RCA-generated fragments of the variants indicated identities of 97-99% with the sequence of a previously reported infectious clone of SLCMV. The evidence suggests low levels of genetic variability in the begomoviruses infecting cassava, mainly in the form of scattered single nucleotide changes. PMID- 29607362 TI - Elimination of viruses through thermotherapy and meristem culture in apple cultivar 'Oregon Spur-II'. AB - In the present study, an attempt was made to eliminate apple chlorotic leaf spot virus, apple mosaic virus, apple stem grooving virus and apple stem pitting virus from apple cultivar 'Oregon Spur-II'. Thermotherapy was carried out at 37-40 degrees C for 4 weeks followed by culturing of meristems of different sizes. During establishment of explants, highest survival percentage (62.35%) and proliferation (30.68%) was recorded during summer season. However, size of meristems and position of buds from where meristems were excised also influenced their survival. The meristems of size 0.6-0.7 mm were found to be the most appropriate for maximum establishment. Meristems excised from buds positioned on distil portions of actively growing shoots showed better results. MS medium supplemented with BA (1.0 mg/l), IBA (0.05 mg/l) and GA3 (0.1 mg/l) resulted in 56.62% establishment of explants, while maximum number of meristems proliferated with low BA (0.5 mg/l), IBA (0.08 mg/l) and same GA3 concentration. Two to fourfold multiplication was observed. Virus indexing of shoots raised from different sizes of meristems was carried out and found that 0.3-0.6 mm size was able to eliminate ACLSV, ApMV, ASGV and ASPV. However, some of 0.5-0.6 mm sized shoots were found infected with ACLSV. Larger meristems could not completely eliminate the viruses under study. PMID- 29607363 TI - Molecular characterization of fowl adenovirus group I in commercial broiler chickens in Brazil. AB - Avian adenovirus has been reported in many countries and is an infectious agent related with inclusion body hepatitis, hepatitis-hydropericardium syndrome (HHS), and respiratory and enteric conditions in chickens worldwide. The objective of this study was to detect and establish the molecular sequences of the hexon gene from the avian adenovirus strains of group I (FAdV-I) isolated from birds with hepatitis-hydropericardium syndrome (HHS), malabsorption syndrome and runting stunting syndrome, to characterize the serotype of virus affecting commercial flocks in Brazil. Molecular characterization was performed by polymerase chain reaction (PCR), using specific primers to amplify the Loop 1 (L1) variable region of the hexon gene in the FAdV-I genome and subsequent sequencing of the PCR product for each positive sample. The results have revealed the presence of the FAdV-8a, FAdV-8b, and FAdV-11 serotypes circulating in Brazilian chicken flocks. Phylogenetic analysis grouped these sequences into three (3) distinct groups, 14 samples were aligned with the FAdV-11 group, three (3) samples in the FAdV-8b group and one (1) sample in the FAdV-8a group. The serotypes FAdV-8a, FAdV-8b, and FAdV-11 are circulating in Brazilian chicken flocks. Therefore, these results are very important for improvement biosecurity measurements and vaccine production. PMID- 29607364 TI - Detection of classical swine fever virus E2 gene in cattle serum samples from cattle herds of Meghalaya. AB - The present study focused on the detection and genetic characterisation of 5' untranslated region (5'UTR) and E2 gene of classical swine fever virus (CSFV, family Flaviviridae, genus Pestivirus) from bovine population of the northeastern region of India. A total of 134 cattle serum samples were collected from organised cattle farms and were screened for CSFV antigen with a commercial antigen capture enzyme linked immunosorbent assay (Ag-ELISA) and reverse transcription-polymerase chain reaction (RT-PCR). A total of 10 samples were positive for CSFV antigen by ELISA, while all of them were positive in PCR for 5'UTR region. Full length E2 region of CSFV were successfully amplified from two positive samples and used for subsequent phylogenetic analysis and determination of protein 3D structure which showed similarity with reported CSFV isolate from Assam of sub-genogroup 2.1, with minor variations in protein structure. PMID- 29607365 TI - Frequency distribution of porcine rotavirus-A and capsid protein gene based sequence and phylogenetic analysis indicating marked heterogeneity among prevailing strains, India. AB - Rotavirus (RV), is an etiological agent of acute infantile diarrhea in both humans and animals including poultry. Among the eight accepted species/types of RVs, RV-A is genetically and antigenically the most diverse. RV-A associated enteritis is a major problem in the weaning and post-weaning piglets. Due to high genetic variability in the antigenic regions, RV-A is thought to have high interspecies jumping probability. In this study, comparatively a large sized sample (n = 757) was screened, where the samples were collected from diarrheic porcine population of north (Uttar Pradesh), North eastern (Assam, Nagaland, Meghalaya, Tripura, Manipur, Mizoram and Arunachal Pradesh) and Southern states of India (Kerala, Karnataka and Tamil Nadu). The VP6 gene based reverse transcription (RT)-PCR based screening of the samples for RV-A identified 42.4% (321/757) positivity, where highest identification was from Uttar Pradesh 119 (37.07%), followed by 74 (23.05%), 34 (10.6%), 31 (9.65%), 21 (6.54%), 15 (4.67%), 11 (3.43%), 8 (2.49%), 3 (0.93%), 3 (0.93%) and 2 (0.62%) from Assam, Nagaland, Meghalaya, Tripura, Kerala, Manipur, Mizoram, Arunachal Pradesh, Karnataka and Tamil Nadu, respectively. Percentage identity calculation of the VP6 gene sequences from different porcine RV-A revealed 77.1-97.3% identity within the Indian porcine RV-A strains of the current study. Phylodendrogram and percent identity based analysis of the amplified and sequenced full length VP6 gene confirmed the presence of new VP6 genotypes (I1 and I5). Although, there are reports of detection of porcine RV-A based on VP6 gene from India, no lineage/genotype based characterization is available for the target gene. Till date, only a single VP6 type (I2) has been confirmed from pig population of India. Here, the findings confirm the circulation of diverse RV-A strains in porcine population in India. PMID- 29607366 TI - Blood group AB is associated with severe forms of dengue virus infection. AB - Several viral and host factors are believed to contribute to the development of severe forms of dengue such as dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS) following a dengue virus (DENV) infection. The pathogenesis of DHF/DSS is not fully understood, however, host factors like ABO blood groups have been shown to contribute to the severity of DENV infection. The present study investigated the association of blood groups with severity of DENV infection in the northern region of Sri Lanka. The blood-groups of 405 patients positive for DENV NS1 antigen and anti-DENV IgM/IgG were determined using the standard haemagglutination assay recommended by the national blood bank/s. The occurrence of severe dengue in patients with certain blood groups was significantly different (p < 0.001) to those with other blood groups. Patients with AB blood group had more than 2.5 times higher risk of developing DHF than those with other blood groups. On the other hand, patients with blood group O were significantly under represented for DHF relative to the proportion of this blood group in the general population. Thus dengue patients with blood group O appear to have a low risk of developing DHF than those with other blood groups. PMID- 29607367 TI - Differentiation of bovine herpesvirus1 subtypes based on UL0.5 gene sequencing. AB - Infectious bovine rhinotracheitis/infectious pustular vulvovaginitis is one of the high economic importance diseases of cattle and caused by bovine herpesvirus1 (BoHV1). Based on the restriction endonuclease fingerprinting of viral DNA, the BoHV1 can be divided into three subtypes viz., BoHV1.1, 1.2a, and 1.2b. Since this method requires a pure viral DNA, it is time-consuming and labour intense. In the current study, the UL0.5 gene based PCR sequencing has been used for the subtyping of BoHV1. Out of five isolates, four had BoHV1-like signatures and one isolate had BoHV1.2-like signatures. Further, these viruses phylogenetically clustered under the respective subtypes. These results indicate that the UL 0.5 gene based PCR sequencing could be used as an alternate method of subtyping of BoHV1. PMID- 29607368 TI - Canine parvovirus types 2a and 2c detection from dogs with suspected parvoviral enteritis in Peru. AB - Canine parvovirus type 2 (CPV-2) has been reported worldwide as the main agent related to acute hemorrhagic enteritis of high morbidity and variable mortality in puppies. The detection and characterization of this virus is essential to understand the etiology of the disease and to develop control measures. To characterize the virus circulating in Peruvian dogs and to provide new insights into the local diversity of CPV-2, rectal swabs from 39 puppies with clinical symptoms and with no history of previous vaccinations were analyzed. Total DNA was extracted by fast boiling method, and PCR and sequencing were performed using specific primers that amplify a 1316 bp fragment corresponding to the VP2 gene of CPV-2. CPV-2 was detected in 62% of the analyzed samples. The sequencing of PCR product was possible in 9 samples, which were identified as type 2a (4 samples) and type 2c (5 samples). A phylogenetic analysis of both variants circulating in Peruvian dogs showed similarities to Equatorian and Uruguayan strains. This work constitutes the first report about genetic characterization of CPV-2 in Peru. PMID- 29607369 TI - Molecular epidemiological survey of canine parvovirus in domestic dogs in four provinces, China. AB - Canine parvovirus (CPV) can cause severe disease in animals, especially in dogs, and continuously generates new variants. In this study, the complete VP2 genes of 59 CPV isolates from clinical diseased dogs between 2015 and 2016 in 4 Chinese provinces were sequenced and analyzed. The results showed that new CPV-2a was still the prominent CPV genotype, followed by CPV-2c and new CPV-2b. CPV-2c with Ala5Gly and Gln370Arg mutations was first detected in Henan, Guangxi and Jiangsu provinces in China. A phylogenetic tree based on VP2 sequences showed that all isolates in this study formed a close lineage which separated from foreign isolates. The above results indicated that point mutations in VP2 were constantly occurring along with the widespread of CPV in China. PMID- 29607370 TI - The evidence of occurrence of porcine circovirus 2 isolation and characterization in Kazakhstan. AB - This report describes the first isolation and characterization of porcine circovirus 2 (PCV2) in the Republic of Kazakhstan. The virus was isolated from a dead piglet that did not exhibit any typical clinical symptoms of porcine circovirus disease at a pig factory in North Kazakhstan oblast (region). The isolated virus belongs to genotype 2 (PCV2) and shares 96.6% sequence homology with one isolate and two strains from China and two French strains in group 1, cluster 1ab and 96.4% homology with two strains isolated in China and one strain from Hungary. Electron microscopy revealed the isolated virus had the typical morphological structure of PCV. This is the evidence of occurrence of porcine circovirus 2 isolation and characterization in Kazakhstan. PMID- 29607371 TI - Efficacy of H120 and Ma5 avian infectious bronchitis vaccines in early challenge against QX strain. AB - Infectious bronchitis (IB) is a highly infectious avian pathogen, which affects the respiratory tract, gut, reproductive system, and kidney of chicks of all ages. Many different serotypes of IB virus (IBV) are recognized which cause different clinical manifestations. According to the antigenic differences, different serotypes of the virus do not cross-protect. Massachusetts serotype induces the best cross-protection against other serotypes. Recently, the IBV QX strain has been detected in Iran. QX strain causes permanent damage to the oviduct if it occurs in the early life cycle and is a significant factor in layer and breeder chicken flocks. In this study, we compare the H120 and Ma5 vaccines' protection against early challenge with the QX strain in commercial chicks. one day-old commercial chicks were divided into six groups. Groups 1 and 2 were unvaccinated groups. Groups 3 and 5 were vaccinated with the H120 vaccine (eye drop) and groups 4 and 6 were vaccinated with Ma5 (eye drop) on the 6th day (5 days after vaccination). Groups 2, 3 and 4 challenged (oculonasal) with QX strain (10^4 EID50). Ciliostasis test, histopathology, and quantitative real-time RT-PCR were done at 11 days-old of age. Results showed that neither H120 nor Ma5 could induce proper cross-protection against QX early challenge, but the viral load and adverse pathological records in vaccinated chicks were less than that in the non vaccinated groups. It can be concluded that vaccination on the first day of the life of a chick offers not full protection against the IBV QX strain but reduced the viral load and pathological damages in vaccinated chickens. Applying other forms of vaccination and using different genotypes on one-day-old chicks are suggested. PMID- 29607372 TI - Oncology Nurses: Innovating Precision Care in a Changing Treatment Environment. PMID- 29607373 TI - Creating Innovation in Cancer Care Delivery. PMID- 29607374 TI - Targeted Therapy: Attacking Cancer with Molecular and Immunological Targeted Agents. AB - Today, personalized cancer therapy with targeted agents has taken center stage, and offers individualized treatment to many. As the mysteries of the genes in a cell's DNA and their specific proteins are defined, advances in the understanding of cancer gene mutations and how cancer evades the immune system have been made. This article provides a basic and simplified understanding of the available (Food and Drug Administration- approved) molecularly and immunologically targeted agents in the USA. Other agents may be available in Asia, and throughout the USA and the world, many more agents are being studied. Nursing implications for drug classes are reviewed. PMID- 29607376 TI - Test-Retest Reliability of the Short-Form Survivor Unmet Needs Survey. AB - Objective: Reliable and valid needs assessment measures are important assessment tools in cancer survivorship care. A new 30-item short-form version of the Survivor Unmet Needs Survey (SF-SUNS) was developed and validated with cancer survivors, including hematology cancer survivors; however, test-retest reliability has not been established. The objective of this study was to assess the test-retest reliability of the SF-SUNS with a cohort of lymphoma survivors (n = 40). Methods: Test-retest reliability of the SF-SUNS was conducted at two time points: baseline (time 1) and 5 days later (time 2). Test-retest data were collected from lymphoma cancer survivors (n = 40) in a large tertiary cancer center in Western Australia. Intraclass correlation analyses compared data at time 1 (baseline) and time 2 (5 days later). Cronbach's alpha analyses were performed to assess the internal consistency at both time points. Results: The majority (23/30, 77%) of items achieved test-retest reliability scores 0.45-0.74 (fair to good). A high degree of overall internal consistency was demonstrated (time 1 = 0.92, time 2 = 0.95), with scores 0.65-0.94 across subscales for both time points. Conclusions: Mixed test-retest reliability of the SF-SUNS was established. Our results indicate the SF-SUNS is responsive to the changing needs of lymphoma cancer survivors. Routine use of cancer survivorship specific needs based assessments is required in oncology care today. Nurses are well placed to administer these assessments and provide tailored information and resources. Further assessment of test-retest reliability in hematology and other cancer cohorts is warranted. PMID- 29607375 TI - New Trends and Recent Care Approaches in Pediatric Oncology Nursing. AB - Increased incidence of children diagnosed with cancer and survivors was an impact on changes in pediatric hemato-oncology nursing care. In this review article, it is aimed to investigate the new trends and recent care approaches in pediatric oncology nursing. The recent care topics were common in the literature as family centered care, technology-based care, program development, primary care of child, health-care provider, survivors and home care, and nonpharmacological care. All of the topics contribute to perform evidence-based care for health promotion and well-being in pediatric hemato-oncology nursing. Research reviews showed that many current topics for the care of children and their parents have entered in the literature. There is a need for more randomized controlled studies to improve the level of evidence of new nursing approaches. PMID- 29607377 TI - Targeted Therapy-induced Facial Skin Toxicities: Impact on Quality of Life in Cancer Patients. AB - Objective: Targeted therapy-induced facial skin toxicities may reduce overall quality of life (QoL) in cancer patients. We investigated whether facial skin toxicities affect QoL and attempted to identify factors related to QoL in patients with advanced/recurrent cancer. Methods: We performed a cross-sectional study in 34 outpatients with advanced/recurrent cancer showing targeted therapy induced facial skin toxicities in Japan between November 2016 and February 2017. For measurement, we used the Kessler Psychological Distress Scale (K6), Mental Adjustment to Cancer (MAC) Scale, and Dermatology Life Quality Index (DLQI). Data were analyzed using Spearman's rank correlation coefficient. Results: Mean DLQI score in 34 patients was 4.59 (standard deviation +/- 4.70), which was interpreted as a small effect on a patient's life. Acneiform rash was the most common skin condition noted, followed by xerosis, pruritus, and erythema. Analysis of DLQI scores revealed that symptoms and feelings was the domain most commonly affected among different domains constituting the DLQI. MAC analysis revealed that the fighting spirit score was the highest among MAC scales. We found that age, K6, and fatalism construct in MAC were significantly correlated with total DLQI scores (age: Spearman's rho= -0.48, P = 0.004; K6: rho= 0.58, P < 0.001; fatalism; rho= -0.39, P = 0.025). Conclusions: This is the first study investigating targeted therapy-induced facial skin toxicities in cancer patients. Our results suggest potential negative effects of facial skin toxicities on overall QoL in patients with advanced/recurrent cancer in middle and early old age. PMID- 29607378 TI - Symptoms Experienced and Information Needs of Women Receiving Chemotherapy. AB - Objective: This study is carried out to determine the symptoms and information necessity on chemotherapy (CT) treatment of the women with breast cancer. Methods: A total of 170 women older than 18 years old, who receive CT with breast cancer diagnosis, are volunteered to participate in the study. Mixed method was used in the study. Data are collected using Descriptive Data Form, Interview Form and Memorial Symptom Assessment Scale. Results: As a result of the cluster analysis, four clusters and the symptoms within have been obtained. These are: pain, lack of energy, feeling drowsy, sweat, swelling of hands, and feet in the first cluster; feeling nervous, difficulty sleeping, feeling sad, worrying in the second cluster; nausea, feeling bloating, change in the way food tastes, hair loss, constipation in the third cluster; vomiting, diarrhea, problems with sexual interest, lack of appetite, dizziness, and weight loss in the forth cluster. Women's information necessity related to the CT are follows: the effects of CT, other treatment options beyond CT, complementary methods, the effect of the CT treatment on reproductive health and sexuality, nutrition, and symptom control. Conclusions: The results of this study will enable determination of symptom clusters, which health professionals are easier to focus on these symptoms. An understanding information need of patients can help to ensure that individual's coping strategies and self-management. PMID- 29607379 TI - Experiences of the Breast Cancer Patients Undergoing Radiotherapy at a Public Hospital Peshawar Pakistan. AB - Objective: This study aimed to explore the experiences of female breast cancer patients undergoing radiotherapy (RT) in a public hospital in Peshawar, Pakistan. Methods: This study employed a descriptive exploratory method. A purposive sample of 14 breast cancer women undergoing RT was selected for this study. Data were collected over the period of 5 months, using a semi-structured interview guide and conducting in-depth face-to-face interviews. These interviews were audio taped and transcribed by a bilingual transcriber. The translated version of the interview was coded, and the analysis was done manually. Results: Four main categories emerged from data analysis, which were: feelings and perceptions of the patients, their challenges, coping strategies, and teaching and informational needs. Conclusions: Women undergoing RT in this culture experience more intense psychological effects, as compared to the physical effects. Keeping in mind, the magnitude of the emotional stress experienced by the participants, recommendations for policy reforms, and training for female RT staff are suggested based on findings of this research. PMID- 29607380 TI - Effectiveness of an Interventional Package on the Level of Anxiety, Depression, and Fatigue among Patients with Cervical Cancer. AB - Objective: To evaluate the effectiveness of interventional package on the level of anxiety, depression, and fatigue. Methods: The study was conducted in room no. 5, first floor, B Block, Department of Radiotherapy, Nehru Hospital, Postgraduate Institute of Medical Education and Research, Chandigarh Quasi experimental pretest-posttest design was used in the study. A total of 60 patients receiving radiotherapy/chemotherapy were assigned in two groups of 30 each, through total enumeration sampling technique. The tools used for the study were Zung Anxiety Scale, Beck Depression inventory, and Fatigue Scale. The protocol used for the study includes the Jacobson's Progressive muscle relaxtion technique, counsling and home care techniques. Results: Sociodemographic variables and clinical profile of participants in both groups were comparable. Interventional package significantly reduces the anxiety, depression, and fatigue (P < 0.001 in 3 variables) in experimental group. Conclusions: Interventional package for patients with cervical cancer proved to be an effective modality in reducing the anxiety, depression, and fatigue. PMID- 29607381 TI - Education Based on Theory of Planned Behavior over Sexual Function of Women with Breast Cancer in Iran. AB - Objective: Sexual function in patients with breast cancer, especially in younger patients, is an important issue from clinical and psychosocial perspectives. Theory of planned behavior (TPB) is one of the important theories that explain the main process of adopting healthy behaviors. This study investigated the effect of education based on TPB on sexual function of women with breast cancer in Mashhad, Iran. Methods: In this quasi-experimental study, 120 women (60 women in education group, 60 women in control group) visiting Razavi Hospital of Mashhad city were studied, selected by using the random method in 2016. The data collection tool was a questionnaire which was completed during the interview. The validity and reliability of this questionnaire were determined through the face and content validity and through Cronbach's alpha and test-retest, respectively. Results: Data were analyzed using statistical SPSS 22 software. Using linear regression analysis, it was determined that attitudes, subjective norm, and perceived behavioral control (PBC) predict 0.85 overall of the total variance of sexual function intention, which among these variables, the effect of the subjective norm was more than the other ones (P < 0.05). After educational intervention, the average rates of knowledge, attitude, PBC, and intention of sexual function in sex education group were significantly increased (P < 0.05); these changes were not meaningful in the control group. There was no statistically significant difference in subjective norm between the two groups after intervention. Conclusions: The results of this research suggest that TPB can be used in sex education interventions and have relevant results. PMID- 29607382 TI - Longitudinal Study on Quality of Life and Psychosocial Conditions in Light of Responses to Illness-Related Information in Postoperative Cancer Patients. AB - Objective: Illness-related information can be significant for cancer patients after gastrointestinal (GI) surgery in terms of their performing adaptive tasks. This study longitudinally investigated the health outcomes of Japanese patients who read a booklet about cancer patients' problems and adaption tasks and evaluated the association between the responses to the booklet and the patients' health outcomes. Methods: A questionnaire survey about quality of life (QOL), fatigue, anxiety, cognitive plight, and resilience was administered to postoperative patients with GI cancer 1 week after their discharge from hospital and 6 months after surgery. The questionnaires were returned by email. Results: The mean age of the 32 patients at 1 week was 60.9 years; nearly 68.8% of them were men. As a whole, only two variables, QOL and anxiety, were significantly improved at 6 months over those at 1 week. Three statements were taken to gauge the responses to the booklet. In the two-way ANOVA that took QOL and responses to the booklet as independent variables, the post hoc test found that QOL was significantly improved in patients who agreed with the statement "I vaguely understood the content" or "I will deal with my tasks as described in the scenarios" but not in patients who agreed with the statement "The scenarios reflect my situation." The anxiety in patients who agreed with the statement "The scenarios reflect my situation" was high at both survey points. Conclusions: This study suggests that associations between the responses to the informational booklet and patients' health outcomes partially indicate the directional property of how to support their information usage. PMID- 29607383 TI - A Survey on the Relationship between Religiosity and Quality of Life in Patients with Breast Cancer: A Study in Iranian Muslims. AB - Objective: This study aimed to assess the relationship between religiosity and quality of life (QoL) in patients with breast cancer in a Muslim population. Methods: This descriptive-correlational study was conducted in 84 Muslim patients with breast cancer who were admitted to Ahvaz Shafa Hospital, Iran, during 2015. QoL and religiosity were measured with the Short Form-36 questionnaire and Muslim Religiosity questionnaire based on the Glock and Stark model, respectively. Data were analyzed using a software program for descriptive statistics, the Chi-square test, Pearson's correlation, and an independent sample t-test. Results: Most patients had high religiosity (69%) and moderate QoL (46.5%) scores. Total scores and all subscales scores for QoL were significantly higher in patients with high religiosity than patients with moderate religiosity (P < 0.0001). Moreover, a direct correlation was found between religiosity (total and all subscales) and QoL (total and all subscales) (P < 0.0001). Conclusions: A significant relationship was found between religiosity and QoL in patients with breast cancer. Accordingly, care team members, especially midwifery and nursing staff, should pay more attention to religious beliefs among these patients to improve their QoL. PMID- 29607384 TI - Effect of Nursing Intervention on Mothers' Knowledge of Cervical Cancer and Acceptance of Human Papillomavirus Vaccination for their Adolescent Daughters in Abuja - Nigeria. AB - Objective: The aim of this study is to evaluate the effect of nursing intervention on mothers' knowledge of cervical cancer and acceptance of human papillomavirus (HPV) vaccination for their adolescent daughters in Abuja, Nigeria. Methods: This was a quasi-experimental study that utilized two groups pre and post-test design. The study was carried out among civil servant mothers in Bwari (experimental group [EG]) and Kwali (control group[CG]) Area Councils of Abuja, Nigeria. One hundred and forty-six women who met the inclusion criteria were purposively selected for this study. EG consists of 69 women while 77 are from CG. The intervention consisted of two days workshop on cervical cancer and HPV vaccination. Descriptive and inferential analyses of the data were performed using SPSS software 20 version. Results: The mean age of the respondents was 35 years +/- 6.6 in the EG and 41 years +/- 8.2 in the CG. The mean knowledge score of cervical cancer was low at baseline in both EG (9.58 +/- 7.1) and CG (11.61 +/ 6.5). However, there was a significant increase to 21.45 +/- 6.2 after the intervention in EG (P < 0.0001). The baseline acceptance of HPV vaccination was high in EG after intervention from 74% to 99%. Exposure to nursing intervention and acceptance of HPV vaccination was statistically significant after intervention (P < 0.0001). Conclusions: The nursing intervention has been found to increase mothers' knowledge of cervical cancer and acceptance of HPV vaccination. It is therefore recommended that nurses should use every available opportunity in mothers' clinic to educate on cervical cancer and HPV vaccination. PMID- 29607385 TI - Assessment of Nutritional Problems in Pediatric Patients with Cancer and the Information Needs of Their Parents: A Parental Perspective. AB - Objective: The majority of problems and symptoms occur in the gastrointestinal system in children with cancer. Parents have difficulty in coping with the nutritional problems and changing routines of children and need support in this respect. This study aimed to assess the nutritional problems of children with cancer and the information needs of their parents. Methods: This descriptive study was performed among children with cancer aged 3-18 years and their parents (n = 69). The data were collected through a data collection form developed by the researchers based on the literature. Results: The most prominent nutritional problems experienced by children were loss of appetite (85.5%), nausea (84.1%), vomiting (81.2%), fatigue (79.7%), and mucositis (66.7%). According to the parents, the factors causing these nutritional problems in children were physiological factors (100%) and the foods given to children in the hospital (65.2%). The parents mostly needed information about food-drug interactions (58.0%), food-disease interactions (52.2%), foods that children with neutropenia should avoid or should eat (neutropenic diet) (46.4%), and frequency of nutritional intake (36.2%). Conclusions: This study has shown that most children experience at least one nutritional problem, and the parents need comprehensive and regular information about nutrition. Pediatric oncology nurses have a significant responsibility in the evaluation, education, and monitoring of these children. PMID- 29607386 TI - Occupational Stress in the Indian Army Oncology Nursing Workforce: A Cross sectional Study. AB - Objective: This cross-sectional, quantitative epidemiological study was aimed at finding out the degree of work-related stress among the staff nurses working in oncology. Methods: This study was conducted on 81 out of 100 oncology-trained nurses working in various oncology centers of Indian Army who consented to participate in it. It was carried out in five oncology centers of our organization where oncology-related facilities are available. Predesigned and pretested questionnaire covering their sociodemographic variables in part I and professional life stress scale by David Fontana in part II. The association between stress and various variables was found using Chi-square test. Results: Risk for professional stress was found more among unmarried young respondents of 20-30 years age group. No statistically significant association (P < 0.131) was found between department of posting and level of stress. Nurses reported that they had no time for rest, of whom 62.96% were suffering from moderate range of stress for a busy professional while only one admitted to have severe stress requiring remedial action. While 82.7% felt that they are able to achieve major objectives in life, 71.6% of them reported that they feel inadequately valued for their commitment at work. Conclusions: The main nurses' occupational stressors were criticism, feeling of not being appreciated for hard work, and having time for self. This type of assessment should be carried out in all hospitals so that working conditions for this important component of health care can be improved. PMID- 29607388 TI - Malignant struma ovarii with insular carcinoma: A case report and literature review. AB - Image 1 CT image demonstrating the large pelvic mass. Note the sigmoid colon sandwiched between the sacrum and the pelvic mass.Image 1. PMID- 29607387 TI - Effort-Based Decision-Making in Schizophrenia. AB - Motivational impairment has long been associated with schizophrenia but the underlying mechanisms are not clearly understood. Recently, a small but growing literature has suggested that aberrant effort-based decision-making may be a potential contributory mechanism for motivational impairments in psychosis. Specifically, multiple reports have consistently demonstrated that individuals with schizophrenia are less willing than healthy controls to expend effort to obtain rewards. Further, this effort-based decision-making deficit has been shown to correlate with severity of negative symptoms and level of functioning, in many but not all studies. In the current review, we summarize this literature and discuss several factors that may underlie aberrant effort-based decision-making in schizophrenia. PMID- 29607389 TI - The diagnostic yield of open-access endoscopy of the upper gastrointestinal tract in the Netherlands. AB - Background and study aims : Since the introduction of open-access esophago gastroduodenoscopy (OAE) there is an increase in the total number of performed OAEs whilst the frequency of clinical relevant findings has decreased. The aim of this study was to assess the appropriate use and the diagnostic yield of OAE in the Netherlands and to determine which patient variables are able to predict a malignant finding. Patients and methods : A retrospective chart review of all referrals for diagnostic OAE between October 2012 and October 2016 at the Northwest Clinics was performed. The indications were recorded from the referral letter and were classified as "appropriate" or "inappropriate" according to the NHG guideline. Logistic regression was used to detect significant predictive variables for a malignancy. Results : A total of 2006 patients were included, of whom 59.6 % had an 'appropriate' referral indication. The diagnostic yield of finding a clinical relevant finding was significantly higher for OAEs with an "appropriate" referral indication. Independent risk factors for malignancy were alarm symptoms, age and male gender with a combined AUC of 0.868. Conclusions : Only 3.8 % of the malignancies would be missed by strict adherence to the guideline. This indicates that the open-access system in the Netherlands works well. Further improvement of the system can be achieved by only accepting appropriate indications for OAE and by treating patients under the age of 40 without OAE. We showed that a risk-prediction model based on the variables age, alarm symptoms and male gender is a good predictor of malignant finding. PMID- 29607390 TI - Duplication cyst of the ileum presenting with severe anemia detected by double balloon endoscopy. AB - Background and study aims Duplication cysts of the ileum are rare and present with non-specific clinical manifestations such as abdominal pain, vomiting, melena, and intussusception. Therefore, preoperative diagnosis is difficult. Here, we report a case of duplication cyst of the small intestine that was diagnosed preoperatively using double-balloon enteroscopy. A 19-year-old man presented with severe iron deficiency anemia, abdominal pain, and exertional dyspnea. Gastroscopy and colonoscopy revealed no remarkable findings. Abdominal computed tomography revealed a cystic structure in the ileum. Therefore, we performed double-balloon enteroscopy via the anal route. The intestinal tract was bifurcated, with one segment ending in a blind sac containing normal villi and an ulceration. Tc-99 m pertechnetate scintigraphy showed no accumulation in the lesion. Accordingly, we diagnosed a duplication cyst and suspected that this was the cause of severe anemia. Following small bowel resection with cyst excision and anastomosis, the anemia and presenting symptoms resolved. This report highlights the usefulness of double-balloon enteroscopy of the small intestine for preoperative diagnosis of the obscure gastrointestinal bleeding, including duplication cysts . PMID- 29607391 TI - Perspectives on endoscopic submucosal dissection training in the United States: a survey analysis. AB - Background and study aims : Endoscopic submucosal dissection (ESD) is a widely accepted method for en-bloc resection of dysplastic lesions and early cancer in Asia and Europe. A limiting factor in adoption of ESD in the United States is perceived lack of training opportunities. The aims of this study were to: (1) evaluate ESD experience of attendees at a University-sponsored ESD training course; (2) characterize effectiveness of the current ESD training regimen and its impact on ESD adoption in the United States; and (3) gauge trainees' attitude towards ESD. Patients and methods : An electronic anonymous survey was distributed to the 86 physicians who participated in the University of Florida's annual ESD course from 2014 to 2016. Main outcomes included participants' practice setting, prior training, current ESD techniques, and planned training. Results : A total of 34 participants (40 %) completed the survey. Most of the respondents routinely use one or more endoscopic mucosal resection (EMR) techniques (97.1 %) in their practice. Most respondents (79 %) had no experience with ESD on humans prior to the ESD course. Following completion of course training, more participants reported ongoing hands-on ESD exposure, with 15/34 (44 %) having performed ESD in humans. Most participants identified potential hurdles for adoption of ESD. Conclusion : A dedicated ESD training course with hands-on experience, under the guidance of experts, notably increased use of ESD among participants. Limited availability of structured training opportunities, concerns over procedural length, lack of adequate number of lesions, and potential for serious adverse events (AEs) were identified as the main factors slowing adoption of ESD in the United States. PMID- 29607392 TI - Colon cleansing protocol in children: research conditions vs. clinical practice. AB - Background and study aims: Colon preparation rates are the limiting factor for a successful diagnostic colonoscopy in children. Different colon cleansing protocols have been published for use in children. Unfortunately, the applicability of those published research protocols has not been formally evaluated in routine clinical practice. We investigated the success rate of our previously published colon cleansing protocol as utilized in our clinical practice. Patients and methods: This was a retrospective study. In the clinical practice, the colon cleansing protocol included PEG-3350 at a dose of 2 g/kg/day plus Dulcolax (Bisacodyl, Boehringer Ingelheim, TX USA) 5 mg/day for 2 days. Adequate colon preparation was graded between 1 - 5, as previously described, and grade >= 4.0 was considered an adequate preparation. Patients were instructed to complete a questionnaire that included PEG-3350 dose, number of stools per day, consistency of each stool, and side effects (vomiting, abdominal pain). Clinical and endoscopic results were compared between the protocol under research conditions and routine practice. Results: The success rate of the colon preparation in our clinical practice was similar to the results observed under our research protocol (75 % vs. 73.6 %). Moreover, the total number of stools, stool consistency, and the intubation rate of the terminal ileum were also similar. We concluded, that in our experience, the colon cleansing protocol used under research conditions was effective and appropriate for use in routine clinical practice. Conclusion: We recommend testing each new protocol under the routine conditions of clinical practice to confirm its applicability for general practitioners. PMID- 29607393 TI - Accuracy of probe-based confocal laser endomicroscopy (pCLE) compared to random biopsies during endoscopic surveillance of Barrett's esophagus. AB - Background: For surveillance of Barrett's esophagus (BE), the current standard of random 4-quadrant biopsies misses 10 - 50 % of esophageal neoplasms, and does not permit real-time decision-making. Probe-based confocal laser endomicroscopy (pCLE) permits real-time in vivo histologic assessment of esophageal mucosa during upper endoscopy. Prospective studies comparing the accuracy of pCLE to 4 quadrant biopsies in routine clinical practice are lacking. Methods: Consecutive patients with BE underwent high definition white light and narrow-band imaging followed by pCLE and targeted biopsy or mucosal resection. Four-quadrant biopsies were obtained during the same session. Baseline variables, real-time pCLE interpretation, and histology results were prospectively recorded. Blinded expert review of pCLE sequences and histology specimens was performed. A sample size of 64 patients was calculated a priori based on 3 % estimated prevalence of high grade dysplasia (HGD) or cancer. Results: In total, 66 patients were included in the study. The prevalence of HGD or cancer was 4.55 %. Both real-time and blinded pCLE correctly identified all cases of cancer. For the primary outcome, real-time pCLE was 98 % specific but only 67 % sensitive for HGD/cancer compared to non blinded pathologist interpretation. For HGD and cancer, inter-observer agreement was substantial between real-time and blinded endomicroscopists (kappa = 0.6). pCLE identified dysplasia in 75 % of cases where both blinded and unblinded pathology interpretation was low grade dysplasia. Conclusions: pCLE demonstrates high specificity for detecting dysplasia and cancer, but lower sensitivity may limit its utility in routine BE surveillance. pCLE may have a role in confirming LGD in real-time before eradication therapy. PMID- 29607394 TI - Diagnostic adequacy and safety of endoscopic ultrasound-guided fine-needle aspiration in patients with lymphadenopathy in a large cohort. AB - Background and study aims : The role of endoscopic-ultrasound (EUS) guided fine needle aspiration (FNA) in patients with lymphadenopathy in terms of diagnostic adequacy and safety in large population is not well defined. The aim of this study was to evaluate diagnostic adequacy and safety of EUS-FNA in patients with lymphadenopathy. Patients and methods: Retrospective study from October 2010 to September 2015 at tertiary care center in Delhi-NCR. We analyzed data from 1005 EUS- FNAs of lymph nodes. Results: The study cohort comprised 1005 lymph nodes in 865 patients; 68 % were males, mean age was 50 +/- 14 years. Indications of FNA were to look for etiology of pyrexia of unknown origin or staging of malignancy mainly. FNA was taken from mediastinal nodes (n = 528, 52.5 %) and intra-abdominal nodes (n = 477, 47.5 %). Median size of nodes at long axis and short axis was 17 (12 - 25.7) and 10 (8 - 15) mm respectively. Adequate material by FNA was obtained in 92.8 % cases. The cytopathologic diagnosis were malignancy in 153 (15.2 %), granulomatous change in 452 (42 %), and reactive lymphadenopathy in 328 (35.6 %). There was statistically significant difference seen between groups with pathological and reactive lymph nodes regarding size at long and short axis, hypoechoic nature, well defined borders and presence of necrosis and calcification. Procedure-related adverse effects were encountered in 6 patients (0.8 %). Four patients had mild mucosal bleeding in chronic liver disease patients and two had mild hepatic encephalopathy related to sedation. Conclusion: EUS-FNA of lymph nodes has good diagnostic adequacy and safety. PMID- 29607395 TI - Efficacy of Endocuff-assisted colonoscopy in the detection of colorectal polyps. AB - Background and study aims : Colonoscopy is the gold standard for detecting colorectal adenomas and cancers. Endoscopic surveillance has been shown to be effective for preventing colorectal cancer. Although detection of colorectal polyps at an early stage is important, endoscopic visualization of early neoplasia can be difficult. The Endocuff is a new device that can be attached to the tip of the colonoscope to hold the colonic folds away from the field of view during withdrawal. The aim of this study was to compare the adenoma detection rate (ADR) and the mean number of adenomas detected per patient (MAP) achieved using Endocuff-assisted colonoscopy (EAC) and standard colonoscopy (SC). Patients and methods : This randomized prospective study was conducted at two academic endoscopy departments in Japan. A total of 447 patients underwent a complete colonoscopic examination between April 2015 and September 2015. The EAC group included 239 patients. The cecal intubation rate, insertion time, withdrawal time, pain score, complications, polyp detection rate (PDR), ADR, the mean number of polyps detected per patient (MPP), and the MAP were assessed. Results : There were no differences between the EAC and SC groups in terms of cecal intubation rate, insertion time, withdrawal time, or pain scores. The PDR in patients increased by about 12 % (61.9 % vs. 49.2 %, P = 0.013) and ADR increased by 15 % (52.5 % vs. 39.2 %, P = 0.001) with the use of the Endocuff. The advanced ADR was higher in the EAC group but no statistically significant difference was found (7.7 % vs. 4.6 %, P = 0.17). Both MPP and MAP were also higher in the EAC group (mean +/- SD: 1.33 +/- 1.43 vs. 0.83 +/- 0.99 per patient; P < 0.01, 1.11 +/- 1.41 vs. 0.66 +/- 0.99 per patient; P < 0.01, respectively). No major complications occurred. Conclusions: EAC not only enabled a higher ADR but also significantly increased the mean number of adenomas identified per patient, as compared with SC. PMID- 29607396 TI - Prevalence and echo features of mediastinal lymph nodes in EUS for non-malignant indications: a prospective study in a Southern European Population. AB - Background and study aims: Significant heterogeneity in geographic distribution regarding the prevalence of mediastinal lymph nodes (MLN) has been documented in autopsy and computed tomography (CT) studies. Awareness of the local prevalence and characteristics of lymph nodes will be relevant when performing endoscopic ultrasonography (EUS) for staging of malignant neoplasias. The aims of this study were to document the prevalence and echo features of MLN in patients undergoing EUS for non-malignant extrathoracic disease and to identify predictive factors for the presence of MLN. Patients and methods: A prospective single-center study was performed over 6 months. Mediastinal stations 9, 8, 7, 6, 5, 4 L and 2 were systematically evaluated using a linear echoendoscope in all patients undergoing EUS due to benign extrathoracic pathology and without history of oncologic disease. Demographic, clinical and EUS features of the lymph nodes were analysed. Results: Seventy-five patients were included: male/female 32/43; mean age, 63 years. The majority of patients (72 %) had lymph nodes in at least one mediastinal station and 88 % of these were found in stations 7 or 4 L. Overall, 133 MLN were identified: 19 % were hypoechogenic, 6 % had a short-axis diameter > 10 mm, and 6 % were round. The prevalence of lymph nodes was higher in smokers (83 % vs 64 %, P = 0.024), with a higher average number of lymph nodes per patient in this group (2.1 vs 1.6; P = 0.017). By logistic regression analysis, none of the variables analyzed were independently associated with the presence of MLN. Conclusion: This prospective Portuguese study documented a higher prevalence of MLN than previously reported in Northern Europe, in patients with no evidence of oncologic disease. This higher prevalence may negatively influence the specificity and positive predictive value for malignancy of MLN (N) staging by EUS. PMID- 29607397 TI - Initial experience with a novel resection and plication (RAP) method for acid reflux: a pilot study. AB - Background and study aims: Current endoscopic therapies for gastroesophageal reflux disorder (GERD) are limited by technical complexity, and/or cost. We sought to evaluate the success of a novel resection and plication (RAP) anti reflux procedure. Patients and methods: RAP was performed on 10 patients with GERD refractory to proton pump inhibitor (PPI) therapy. RAP consists of semi circumferential mucosectomy along with full-thickness plication of the lower esophageal sphincter (LES) and cardia. We assessed the technical success and safety as well as followed GERD-Health Related Quality of Life (GERD-HRQL) scores and medication usage. Results : All patients underwent RAP without adverse events and were discharged on the same day. Only half of the patients required general anesthesia. Follow-up ranged from 5 to 24 months (median 9 months) and all patients had a significant improvement in their GERD-HRQL scores ( P < 0.0001, 95 % CI 19.3 - 25.3). 8 of 10 eliminated their daily PPI dependence. Conclusions: The RAP method has potential as an effective anti-reflux option. Its main advantages include a short procedure time, simple approach using readily available equipment, and possible avoidance of general anesthesia. PMID- 29607398 TI - Clinicopathological examination of ESD as salvage therapy for esophageal cancer after definitive chemo-radiation therapy. AB - Background and study aims: Salvage therapy for esophageal cancer following chemo radiation therapy (CRT) has not been established. We aimed to evaluate endoscopic submucosal dissection (ESD) as a salvage therapy based on histopathological features of lesions. Patients and methods: We compared 10 lesions in eight patients with local residual, recurrent, or metachronous esophageal squamous cell carcinoma treated by ESD after CRT (CRT group) and 59 lesions treated by ESD without CRT (non-CRT group) during the same period. Results: The en bloc resection rate was 100 % while the complete resection rate was 80.0 % in the lesions after CRT, indicating no difference between the CRT and non-CRT groups. Pathological examination showed that fibrosis was more intense in the lamina propria mucosa, muscularis mucosa, and submucosa. The muscularis mucosa was thicker in both non-tumor and tumor sites in the CRT group compared to the non CRT group. However, severe submucosal fibrosis was observed only in one lesion in the CRT group. The maximum diameter of the submucosal artery was significantly larger in the CRT group ( P < 0.001). Conclusions: Compared to the non-CRT group, the lesions in the CRT group were accompanied by fibrosis while the muscularis mucosa were thicker; however, severe fibrosis of the submucosa was rare. It is important to dissect the muscularis mucosa appropriately during ESD, which makes successful dissection of the submucosa possible. Attention should be paid to bleeding from large arteries. PMID- 29607399 TI - Endoscopic versus percutaneous management for symptomatic pancreatic fluid collections: a systematic review and meta-analysis. AB - Background: Symptomatic pancreatic fluid collections (PFCs) are managed by surgical, percutaneous, or endoscopic drainage. Due to morbidity associated with surgical drainage, percutaneous and/or endoscopic options have increasingly been used as initial management. Aims: We conducted a systematic review and meta analysis comparing the efficacy and safety of endoscopic versus percutaneous drainage for management of PFCs. Methods: We searched several databases from inception through 31 August 2017 to identify comparative studies using endoscopic or percutaneous drainage for PFCs. Our primary outcome was clinical success. Secondary outcomes were technical success, adverse events (AE), rates of recurrence, requirement for subsequent procedures, and length of stay in hospital. Pooled risk ratios (RR) and mean difference (MD) were calculated for categorical and continuous outcomes, respectively. Results: Seven studies with 490 patients were included in the final analysis. Pooled RR for clinical success was 0.40 (0.26, 0.61), I2 = 42 % in favor of endoscopic management. On sensitivity analysis, after excluding one study on patients with walled-off necrosis (WON), the clinical success was 0.43 (0.28, 0.66) with no heterogeneity. Pooled RR for technical success was 1.50 (0.52, 4.37) with no heterogeneity. Pooled RR for AE and rate of recurrence were 0.77 (0.46, 1.28) and 0.60 (0.29, 1.24), respectively. Pooled MD for length of stay in hospital and rate of re intervention were - 8.97 (- 12.88, - 5.07) and - 0.66 (- 0.93, - 0.38), respectively, in favor of endoscopic drainage. Conclusions: Endoscopic drainage should be the preferred therapeutic modality for PFCs compared to percutaneous drainage as it is associated with significantly better clinical success, a lower re-intervention rate, and a shorter hospital length of stay. PMID- 29607400 TI - A circumferential rectal superficial neoplasm resected with endoscopic submucosal dissection using the pocket-creation method. AB - Endoscopic submucosal dissection (ESD) is recognized as an important technique in the nonsurgical management of early gastrointestinal carcinoma and it is continuously undergoing evolution in terms of technique and equipment. The pocket creation method was recently developed for overcoming various difficulties such as large tumor size and severe fibrosis in ESD. Circumferential ESDs are rare and pose technical difficulties. We present a case of a circumferential rectal ESD using a pocket-creation method with two pockets. The associated planning, strategies, and outcome of the procedure are discussed. PMID- 29607401 TI - Additional flap on plastic stents for improved antimigration effect in the treatment of post-cholecystectomy bile leak. AB - Background and study aims: In plastic stent insertion for treatment of post cholecystectomy bile leak, stent migration may be more common due to the absence of a shelf to anchor the stent. We evaluated how adding a flap to straight plastic stents for this indication might influence the rate of stent migration when compared to use of conventional plastic stents. Patients and methods: This is a retrospective study including patients referred for ERCP for treatment of post-cholecystectomy bile leak. Patients with a customized anti-migration flap stent had the additional flap created on the distal end of straight plastic stents, intended to aid in anchoring in the distal supra-sphincteric biliary duct. The primary endpoint is stent migration events. The secondary endpoint is bile leak resolution after first ERCP session. Results: Thirty-two patients were treated with the experimental additional flap stents and 225 patients were treated with standard straight biliary stents. The total failure rate of bile leak resolution after a single endoscopic treatment for all treated was 10.5 % (27/257) and the total stent migration rate for all enrolled was 15.2 % (39/257). Stent migration rate was lower in the additional flap stent group than in the conventional group (3.1 % vs. 16.9 %, respectively, P = 0.04). Furthermore, significantly more patients had resolution of their bile leak after the first ERCP session in the group with the additional flap (100 % vs. 88 %, respectively, P = 0.03). Conclusion: A plastic biliary stent with an extra flap may have improved performance with regard to stent migration and resolution of bile leak over standard plastic biliary stents. PMID- 29607402 TI - Massive Ileal Bleeding Secondary to a Dieulafoy's lesion. AB - Dieulafoy's lesions are a rare cause of gastrointestinal bleeding. This article presents the case of a young woman presenting with a massive ileal bleeding, secondary to a Dieulafoy's lesion. A computed-tomography angiography scan showed an arterial bleeding in the ileum and the diagnosis was confirmed by an emergency peroperative enteroscopy. Surgical treatment was performed. Dieulafoy's lesions account for 1 % to 2 % of acute gastrointestinal bleeding and lesions are mostly located in the upper gastrointestinal tract. This case stresses that Dieulafoy's lesions can be located in the lower gastrointestinal tract and that in such cases, diagnostic imaging and surgical treatment are often warranted. PMID- 29607403 TI - Electromagnetic assisted endoscopic submucosal dissection is more efficient than water-jet assisted and conventional ESD in experimental model. AB - Background and study aims : The adequate visualization of the dissection line, inside the submucosal layer, supposes the main challenging issue in ESD. For this reason, several counter traction methods have been developed focused on overcoming this handicap. One of which, Magnetic anchor guided - ESD (MG-ESD) is an attractive alternative. However, the usefulness of this approach has been scarcely assessed and compared with other ESD strategies. Therefore, the aim of this study is to compare three different ESD alternatives in experimental faction. Methods : This was a prospective non-randomized study, in which three different ESD techniques were performed in an ex-vivo gastric porcine model by an endoscopist slight expertise in ESD: conventional ESD, waterjet assisted ESD and MG-ESD. MG-ESD was performed using two different magnets: inner Neodymiun ringed shape magnet attached to the simulated lesions by an endoclip and external electromagnet connected to a Single Output Adjustable 24V/0.3A Power Supply Unit. Results : Forty-six ESD procedures were performed: 24 conventional ESD, 12 waterjet-assisted ESD and 10 MG-ESD. Average size of the simulated lesions was 33.86 mm. No differences in terms of safety and efficacy were registered between the three approaches. Nevertheless, MG-ESD proved to be faster and more efficient than conventional ESD and water-jet assisted ESD (min per cm 2 10.85 vs. 7.43 vs. 3,41; P = 0.001). Conclusions : MG-ESD could be a feasible alternative to conventional ESD even at the beginning of the learning curve. Therefore, researches focused on developing appropriate ESD magnetic devices and further comparative studies must be promoted, in order to assess the reliable usefulness of the magnet-assistance in ESD. PMID- 29607404 TI - Hand proximity effects are fragile: a useful null result. AB - Placing one's hands near an object has been reported to enhance visual processing in a number of ways. We explored whether hand proximity confers an advantage when applied to complex visual search. In one experiment, participants indicated the presence or absence of a target item in a baggage x-ray image by pressing response boxes located at the edge of a tablet computer screen, requiring them to grip the display between their hands. Alternatively, they responded using a mouse held within their lap. Contrary to expectations, hand position did not influence search performance. In a second experiment, participants used their finger to trace along the x-ray image while searching. In addition to any effect of hand proximity it was predicted that this strategy would encourage a more systematic search strategy. Participants inspected bags longer using this strategy, but this did not translate into improved target detection. A third experiment attempted to replicate the near-hands advantage in a change detection paradigm featuring simple stimuli (Tseng and Bridgeman, Experimental Brain Research 209:257-269, 2011), and the same equipment and hand positions as Experiment 1, but was unable to do so. One possibility is that the grip posture associated with holding a tablet is not conducive to producing a near-hands advantage. A final experiment tested this hypothesis with a direct replication of Tseng and Bridgeman, in which participants responded to stimuli presented on a CRT monitor using keys attached to the side of the monitor. Still, no near-hands advantage was observed. Our results suggest that the near-hands advantage may be sensitive to small differences in procedure, a finding that has important implications for harnessing the near-hands advantage to produce better performance in applied contexts. PMID- 29607405 TI - Scalable Production and Cryostorage of Organoids Using Core-Shell Decoupled Hydrogel Capsules. AB - Organoids, organ-mimicking multicellular structures derived from pluripotent stem cells or organ progenitors, have recently emerged as an important system for both studies of stem cell biology and development of potential therapeutics; however, a large-scale culture of organoids and cryopreservation for whole organoids, a prerequisite for their industrial and clinical applications, has remained a challenge. Current organoid culture systems relying on embedding the stem or progenitor cells in bulk extracellular matrix (ECM) hydrogels (e.g., MatrigelTM) have limited surface area for mass transfer and are not suitable for large-scale productions. Here, we demonstrate a capsule-based, scalable organoid production and cryopreservation platform. The capsules have a core-shell structure where the core consists of MatrigelTM that supports the growth of organoids, and the alginate shell form robust spherical capsules, enabling suspension culture in stirred bioreactors. Compared with conventional, bulk ECM hydrogels, the capsules, which could be produced continuously by a two-fluidic electrostatic co spraying method, provided better mass transfer through both diffusion and convection. The core-shell structure of the capsules also leads to better cell recovery after cryopreservation of organoids probably through prevention of intracellular ice formation. PMID- 29607406 TI - Barriers and Facilitators to HIV Testing Among Women. AB - Aim: The purpose of this secondary analysis was to analyze for barriers and facilitators to HIV testing in women attending community health clinics. Introduction: The Centers for Disease Control and Prevention (CDC), reported that all women account for 20% or 1 in 5 of new HIV cases (CDC, 2012). Of those new cases in heterosexual women, 5,300 were Black, 1,300 were White, and 1,200 were Hispanic/Latina. The CDC estimated that in 2012 there were 9,268 individuals living with a diagnosis of HIV or AIDS, of which 19% were women. Results: The existing de-identified data consisted of thirty individual interviews conducted using a semi-structured interview guide was collected as the initial phase of the parent study, "HIV Testing and Women's Attitudes on HIV Vaccine Trials". This secondary analysis addressed the identification of key obstacles to HIV testing and only those related portions of the transcripts were analyzed. The major themes identified were familiarity with testing, stigma, fear, perceived risks, and access to care. Conclusion: The themes implicated the need to further assess women for barriers and facilitators to testing, tailor community based interventions that have the ability to decrease fear and stigma, increase trust in testing methods and offer counseling to positive results. PMID- 29607407 TI - HIV Knowledge, Perceived Risk and Gender as Modulators of Salivary HIV Rapid Testing in African Americans. AB - Background: Of more than 1.2 million people in the United States (US) living with HIV infection, almost 1 in 8 (12.8%) are unaware of their infection. The introduction of a rapid HIV test using a saliva sample in 2004 made immediate results possible in community-based settings. Despite use of salivary rapid testing (SRT) over the last ten years, not enough is known about barriers to and acceptability of SRT among African Americans (AAs). Purpose: The purpose of this study was to identify factors associated with SRT for HIV among AAs. Methods: A cross-sectional study was conducted with 329 AA men and women recruited from a sexually transmitted infection (STI) clinic. Results: Results of study showed that participants with higher AIDS knowledge (p<0.001) and problem-focused coping (p<0.003) tended to have higher likelihood for participation in testing. In terms of seeking medical help, participants with lower emotional-focused coping, lower risky behavior and higher AIDS knowledge tended to be more likely to seek medical help (p=0.015, p<0.001, p<0.04, respectively). Female participants with higher values of risky behavior tended to be more likely to participate in testing (p=0.001). Conclusions: The findings support the need to assess barriers and facilitators to testing decisions in order to increase testing rates. In particular, AIDS knowledge and either problem or emotional-focused coping and risky behaviors, based on gender may be important in making testing and care entry decisions. PMID- 29607408 TI - Therapeutic Effects of Prolonged Cannabidiol Treatment on Psychological Symptoms and Cognitive Function in Regular Cannabis Users: A Pragmatic Open-Label Clinical Trial. AB - Introduction: Chronic cannabis use has been associated with impaired cognition and elevated psychological symptoms, particularly psychotic-like experiences. While Delta9-tetrahydrocannabinol (THC) is thought to be primarily responsible for these deleterious effects, cannabidiol (CBD) is purported to have antipsychotic properties and to ameliorate cognitive, symptomatic, and brain harms in cannabis users. However, this has never been tested in a prolonged administration trial in otherwise healthy cannabis users. Here, we report the first study of prolonged CBD administration to a community sample of regular cannabis users in a pragmatic trial investigating potential restorative effects of CBD on psychological symptoms and cognition. Materials and Methods: Twenty frequent cannabis users (16 male, median age 25 years) underwent a 10-week open label trial of 200 mg of daily oral CBD treatment, while continuing to use cannabis as usual. The majority of participants were daily cannabis users who had used cannabis for several years (median 5.5 years of regular use). Participants underwent psychological and cognitive assessments at baseline (BL) and post treatment (PT) and were monitored weekly throughout the trial. Results: CBD was well tolerated with no reported side effects; however, participants retrospectively reported reduced euphoria when smoking cannabis. No impairments to cognition were found, nor were there deleterious effects on psychological function. Importantly, participants reported significantly fewer depressive and psychotic-like symptoms at PT relative to BL, and exhibited improvements in attentional switching, verbal learning, and memory. Increased plasma CBD concentrations were associated with improvements in attentional control and beneficial changes in psychological symptoms. Greater benefits were observed in dependent than in nondependent cannabis users. Conclusions: Prolonged CBD treatment appears to have promising therapeutic effects for improving psychological symptoms and cognition in regular cannabis users. Our findings require replication given the lack of a placebo control in this pragmatic trial, but suggest that CBD may be a useful adjunct treatment for cannabis dependence. PMID- 29607409 TI - A Novel Observational Method for Assessing Acute Responses to Cannabis: Preliminary Validation Using Legal Market Strains. AB - Background: The development of novel cannabis research methods that are compatible with current federal regulations is imperative to conduct studies of the effects of legal market cannabis. There is very little research on higher strength, higher Delta9-tetrahydrocannabinol (THC), which has become increasingly available since legalization. Research on strains containing cannabidiol (CBD), a second primary, but nonpsychotomimetic, cannabinoid, is very limited. Materials and Methods: Using a novel observational methodology, regular cannabis users were asked to use one of two legal market cannabis strains that they purchased from a local dispensary (one strain containing 8% THC and 16% CBD (THC+CBD) and one containing a 17% THC concentration, but no CBD (THC). After using their suggested cannabis strain as they typically would for a 3-day period, participants returned to the laboratory immediately after their final use. Measures included a blood draw to measure cannabinoid blood levels and circulating cytokines, self-reported subjective drug effects, and verbal recall memory. Results: Analysis of CBD/THC concentration levels in the blood following the 3-day strain manipulation suggests that all, but one participant (n=23/24) followed instructions and used their assigned strain. Individuals in the THC group (n=11) smoked no more than their usual amount, and participants who used the THC+CBD (n=12) strain smoked more than their reported usual amount, but did not have significantly different THC+metabolite blood levels from the THC group. The THC+CBD strain was also associated with less desire to smoke, lower levels of subjective drug effects, and lower levels of circulating cytokines (TNF-alpha, IL-6, and IL-1beta) immediately after use. Conclusions: Initial results support the feasibility of this novel observational methodology involving brief manipulation of strain use. Preliminary findings indicate that participants may self-titrate cannabis use based on cannabinoid concentration and the THC+CBD strain was associated with lower levels of cannabis craving, subjective intoxication, and circulating cytokines. PMID- 29607410 TI - Willingness to Participate in Longitudinal Research Among People with Chronic Pain Who Take Medical Cannabis: A Cross-Sectional Survey. AB - Background: Regulatory barriers limit clinical trials of medical cannabis in the United States. Longitudinal cohort studies may be one feasible alternative that could yield clinically relevant information. Willingness to participate in such studies is not known. Materials and Methods: In October 2016, we surveyed a convenience sample of patients with chronic pain from two New York registered organizations (responsible for growing, processing, distributing, and retailing medical cannabis products). After a vignette describing a longitudinal cohort study involving weekly patient-reported outcomes and quarterly assessments of physical functioning and urine and blood tests, we asked about respondents' willingness to participate. We examined willingness to participate, duration of participation, and frequency of data collections overall and by subgroups, using multivariable logistic regression models. Results: Of 405 respondents (estimated response rate: 30%), 54% were women and 81% were white non-Hispanic. Neuropathy was the most common pain condition (67%) followed by inflammatory bowel disease (19%). Of respondents, 94% (95% CI 92-97%) thought that the study should be done, 85% (95% CI 81-88%) would definitely or probably enroll if asked, 76% (95% CI 72 81%) would participate for >=1 year, and 59% (95% CI 54-64%) would respond to questions at least daily. Older age was the only factor associated with lower willingness to participate, lower willingness to participate for >=1 year, and lower willingness to respond to questions at least daily. Conclusions: Nearly all respondents were supportive of the proposed study and most reported that they would enroll if asked. Enhanced engagement with older individuals may be needed to promote equal enrollment. Recruitment for longitudinal cohort studies with frequent data collection appears feasible in this patient population. PMID- 29607411 TI - Verbal Memory Performance and Reduced Cortical Thickness of Brain Regions Along the Uncinate Fasciculus in Young Adult Cannabis Users. AB - Introduction: Memory impairment is one of the most commonly reported effects of cannabis use, especially among those who initiate use earlier, perhaps due to the effects of delta-9- tetrahydrocannabinol on cannabinoid (CB1) receptors in the brain. Studies have increasingly investigated whether cannabis use is associated with impairments in verbal memory, and with alterations in brain structures underlying verbal memory. The uncinate fasciculus (UF), a long-range white matter tract, connects regions with densely localized CB1 receptors that are important in verbal memory. This study investigated the impact of cannabis use on UF structures and its association with memory performance in young adult cannabis users (CU) and non-using controls (CON). Materials and Methods: Nineteen CU and 22 CON completed a verbal memory task and a neuroimaging protocol, in which diffusion tensor imaging and structural scans were collected. We compared memory performance, diffusion and tractography measures of the UF, and cortical thickness of regions connected by the UF, between CU and CON. In regions showing a significant group effect, we also examined associations between verbal memory performance, cortical thickness, and age of onset of cannabis use. Results: Compared to non-users, CU had worse memory performance, decreased fiber bundle length in the UF, and decreased cortical thickness of brain regions along the UF such as the entorhinal cortex and fusiform gyrus. Verbal memory performance was significantly associated with age of onset of cannabis use, indicating that those who initiated cannabis use at an earlier age performed worse. Cortical thickness of the entorhinal cortex was significantly correlated with age of first use and memory performance. Conclusion: This study provides evidence that cannabis use, especially when initiated at a young age, may be associated with worse verbal memory and altered neural development along the UF. Reductions in cortical thickness in regions implicated in memory processes may underlie weaknesses in verbal memory performance. PMID- 29607412 TI - Experiences with the Twitter Health Surveillance (THS) System. AB - Social media has become an important platform to gauge public opinion on topics related to our daily lives. In practice, processing these posts requires big data analytics tools since the volume of data and the speed of production overwhelm single-server solutions. Building an application to capture and analyze posts from social media can be a challenge simply because it requires combining a set of complex software tools that often times are tricky to configure, tune, and maintain. In many instances, the application ends up being an assorted collection of Java/Scala programs or Python scripts that developers cobble together to generate the data products they need. In this paper, we present the Twitter Health Surveillance (THS) application framework. THS is designed as a platform to allow end-users to monitor a stream of tweets, and process the stream with a combination of built-in functionality and their own user-defined functions. We discuss the architecture of THS, and describe its implementation atop the Apache Hadoop Ecosystem. We also present several lessons learned while developing our current prototype. PMID- 29607413 TI - Platelet-rich Plasma Protects HUVECs against oX-LDL-induced Injury. AB - : Platelet-rich plasma (PRP) contains a variety of cytokines, some of which ameliorate oX-LDL (oxidized low-density lipoprotein)-induced endothelial cell (EC) injury. Therefore, we hypothesized that PRP might alleviate oX-LDL-induced injury. Methodology: Human umbilical vein endothelial cells (HUVECs) were divided into four groups: a PPP (platelet-poor plasma) group, an oX-LDL group, an oX LDL+PRP group and a PRP group. CCK-8 (Cell Counting Kit) assay, Annexin V-FITC/7 AAD and Hochest 33342 staining were performed to assess cell proliferation and apoptosis. Tube formation and cell migration assays were performed to evaluate HUVEC-mediated vasculogenesis and migration. Expression levels of Bcl-2, Bax, caspase-3, cleaved caspase-3, PI3K, Akt, eNOS p-Akt, p-eNOS, IL-6 and IL-1 were detected by western blotting or immunofluorescence. Principal findings: PRP promoted HUVEC proliferation in a non-linear pattern, protected HUVECs against oX LDL-induced apoptosis and attenuated oX-LDL-mediated inhibition of HUVEC migration and vasculogenesis. Additionally, compared to the PPP group, PRP downregulated pro-apoptotic proteins (ratio of Bax/Bcl-2, caspase-3 and cleaved caspase-3) as well as IL-6 and IL-1. Moreover, the PI3K/Akt/eNOS pathway was activated by PRP and inactivated by oX-LDL. Conclusions: It was demonstrated that PRP protected HUVECs against oX-LDL-induced injury and that the PI3K/Akt/eNOS pathway was activated in this process. PMID- 29607414 TI - Pharmacoeconomics of three Therapeutic Schemes for Anti-tuberculosis Therapy Induced Liver Injury in China. AB - : To evaluate the pharmacoeconomics of three therapeutic schemes in treating anti tuberluosis therapy -induced liver injury (anti-TB DILI). Methods: In the construction of a decision tree model, the efficacy and safety parameters came from the results of the randomized, controlled trial conducted here, the effect parameters were derived from expert advice, and the cost parameters, such as usage specification, number, and unit price, came from literature, expert advice, and so on. Results: The cost-effectiveness analysis (CEA) based on the effect degrees showed that bicyclol had the best effect (4.63562). The incremental cost effectiveness ratio (ICER) (206.03270) of bicyclol was the lowest. The cost effectiveness ratio of silibinin was the lowest (68.59987). The CEA based on the complete normalization rate showed that bicyclol had the highest complete normalization rate (83.562%), the lowest cost-effectiveness ratio (4.63627), and the smallest ICER (4.63504). Sensitivity analyses proved the robustness of the results. Conclusions: Bicyclol is the most cost-effective therapy and the preferred choice for treating anti-TB DILI. PMID- 29607415 TI - Small-cell Lung Cancer Presenting as Fatal Pulmonary Hemorrhage. AB - Small-cell lung cancer (SCLC) is a lung cancer histological subtype unusual in its favorable response to cytotoxic chemotherapy. Life-threatening manifestations at presentation are rarely reported and should be an important clinical concern. We report a case of a 63-year-old man presenting with rapid-onset refractory severe thrombocytopenia, development of massive hemoptysis, and death from respiratory failure. This case provides clinicians a reference for this unusual presentation and carries clinical implications for managing SCLC patients. PMID- 29607416 TI - Correlation of Retinopathy of Prematurity with Bronchopulmonary Dysplasia. AB - : Retinopathy of prematurity (ROP) and bronchopulmonary dysplasia (BPD) are diseases that occur only in preterm infants. The etiology of these disorders is multifactorial; however, it is believed that some of the factors in children presenting with BPD affect both the initiation and severity of ROP. The aim of the study was to evaluate the degree of clinical severity of ROP in infants with BPD compared to those without BPD. Methodology: Infants were divided into two groups: the BPD+ study group and BPD- control group. Parameters including the incidence of ROP and its severity were compared. Results: In neonates with BPD, more severe forms of ROP occurred significantly more frequently than in infants without BPD. Newborns with BPD required significantly longer use of mechanical ventilation; moreover, the number of days in which the concentration of oxygen in the respiratory mixture exceeded 50% was greater in BPD+ children. Children with BPD also received more blood transfusions compared to children without BPD. Conclusions: Newborns in the BPD+ study group showed advanced stages of ROP more often than newborns in the BPD- control group. The etiology of ROP and BPD is multifactorial; however, our findings suggest oxygen plays a significant role in the development of these diseases. PMID- 29607417 TI - Prognosis of Treatment Outcomes by Cognitive and Physical Scales. AB - : The aim of this study was to assess the possibility of using scales for measuring cognitive and physical functions for a prognosis of care outcomes in elderly patients. METHODOLOGY: The survey was carried out in one of the Vilnius City Hospitals for Nursing and Support Treatment. A total number of 177 respondents were involved in the study. The Mini-Mental State Examination (MMSE), The Barthel Index (BI) and The Morse Fall Scale were used. RESULTS: A statistically significant correlation was revealed between the scores of MMSE and BI (Pearson R = 0.41, p < 0.01); those with severe cognitive impairment were more dependent. A statistically significant correlation (Pearson R = -0.181, p < 0.01) was reported between the scores of MMSE and the Morse Fall Scale - the risk of falling was higher in patients with severe cognitive impairment. CONCLUSIONS: The Morse Fall Scale was not suitable for the prognosis of outcomes. The MMSE was suitable for the prognosis of a patient's discharge. The Barthel Index should be considered as the most suitable tool for the prognosis of care outcomes: the sum score of the Barthel Index above 25 may suggest that the patient would be discharged home; the sum-score below this level was associated with a higher likelihood of patient death. PMID- 29607418 TI - Arcuate Fasciculus in Autism Spectrum Disorder Toddlers with Language Regression. AB - : Language regression is observed in a subset of toddlers with autism spectrum disorder (ASD) as initial symptom. However, such a phenomenon has not been fully explored, partly due to the lack of definite diagnostic evaluation methods and criteria. MATERIALS AND METHODS: Fifteen toddlers with ASD exhibiting language regression and fourteen age-matched typically developing (TD) controls underwent diffusion tensor imaging (DTI). DTI parameters including fractional anisotropy (FA), average fiber length (AFL), tract volume (TV) and number of voxels (NV) were analyzed by Neuro 3D in Siemens syngo workstation. Subsequently, the data were analyzed by using IBM SPSS Statistics 22. RESULTS: Compared with TD children, a significant reduction of FA along with an increase in TV and NV was observed in ASD children with language regression. Note that there were no significant differences between ASD and TD children in AFL of the arcuate fasciculus (AF). CONCLUSIONS: These DTI changes in the AF suggest that microstructural anomalies of the AF white matter may be associated with language deficits in ASD children exhibiting language regression starting from an early age. PMID- 29607419 TI - Role of early growth response 1 in liver metabolism and liver cancer. AB - The liver is an essential organ for nutrient and drug metabolism - possessing the remarkable ability to sense environmental and metabolic stimuli and provide an optimally adaptive response. Early growth response 1 (Egr1), an immediate early transcriptional factor which acts as a coordinator of the complex response to stress, is induced during liver injury and controls the expression of a wide range of genes involved in metabolism, cell proliferation, and role of Egr1 in liver injury and repair, deficiency of Egr1 delays liver regeneration process. The known upstream regulators of Egr1 include, but are not limited to, growth factors (e.g. transforming growth factor beta1, platelet-derived growth factor, epidermal growth factor, hepatocyte growth factor), nuclear receptors (e.g. hepatocyte nuclear factor 4alpha, small heterodimer partner, peroxisome proliferator-activated receptor-gamma), and other transcription factors (e.g. Sp1, E2F transcription factor 1). Research efforts using various animal models such as fatty liver, liver injury, and liver fibrosis contribute greatly to the elucidation of Egr1 function in the liver. Hepatocellular carcinoma (HCC) represents the second leading cause of cancer mortality worldwide due to the heterogeneity and the late stage at which cancer is generally diagnosed. Recent studies highlight the involvement of Egr1 in HCC development. The purpose of this review is to summarize current studies pertaining to the role of Egr1 in liver metabolism and liver diseases including liver cancer. PMID- 29607421 TI - Editorial overview of the special issue on genomic toxicology epigenetics. PMID- 29607420 TI - N-FATTY ACYLGLYCINES: UNDERAPPRECIATED ENDOCANNABINOID-LIKE FATTY ACID AMIDES? AB - Long-chain N-fatty acylglycines, R-CO-NH-CH2-COOH (where "R" refers to an unsaturated or saturated alkyl chain of at least 14 carbons) are found in mammals and insects and are structurally related to the cell-signaling, lipid-like, N fatty acylethanolamines, R-CO-NH-CH2-CH2-OH (where "R" refers to an alkyl chain of at least 14 carbons). Accumulating evidence demonstrates that the N-fatty acylglycines have important cellular functions, but much work remains in order to fully appreciate and understand these biomolecules including: (a) more work on their functions in vivo, (b) measuring their concentrations in the cell, (c) defining the pathways for the biosynthesis and degradation, and (d) understanding the metabolic interconversion(s) between the N-fatty acylglycines and other fatty acid amides. The purpose of reviewing the current state-of-knowledge about the N fatty acylglycines is to stimulate future research about this intriguing family of biomolecules. PMID- 29607422 TI - Ion permeation in ionotropic glutamate receptors: Still dynamic after all these years. AB - Ionotropic glutamate receptors (iGluRs) are ligand-gated ion channels that mediate the vast majority of fast synaptic transmission in the nervous system. When the iGluR ion channel is in the open or conducting conformation, it is non selective for monovalent cations, driving membrane excitation. Often the channel is also permeable to Ca2+. This process of Ca2+ permeation and its physiological and pathological consequences depend strongly on the specific iGluR subtype as well as the specific subunits in the oligomeric complex. Recent evidence has highlighted additional levels of diversity to this process including a dependence on specific auxiliary subunits in non-NMDARs and post-translational modifications in NMDARs. Various de novo missense mutations associated with neurological disease in NMDAR subunits have been identified in regions critical to Ca2+ influx. These features highlight the dynamics of Ca2+ influx mediated by iGluRs and its critical role in synaptic physiology and pathology. PMID- 29607424 TI - Preoperative evaluation of liver volume in living donor liver transplantation. AB - OBJECTIVE: The aim of the present study was to retrospectively evaluate the difference between the preoperative estimated volume and the actual intraoperative graft volume determined in donor right hepatectomies and to evaluate the possible effect of age, gender, and body mass index on the difference. METHODS: A total of 225 donor hepatectomies performed at the center between 2016 and 2017 were evaluated for the study. Left hepatectomies and left lateral segmentectomies were excluded from the analysis. As a result, 174 donor right hepatectomies were included in the study. Volumetric analysis was performed with dynamic hepatic computed tomography (CT), including non-contrast analysis, followed by non-ionic, contrast-enhanced arterial, portal, and hepatic-phase, thin-slice scanning. Volumetric analysis was performed based on the CT images using automatic volume calculating software. RESULTS: The mean preoperatively estimated graft volume was 800+/-112 g and the mean intraoperatively measured actual graft volume was 750+/-131 g. There was a statistically significant difference (p=0.003). Age and body mass index had a significant impact on the discrepancy between the predicted and actual graft volume, while gender did not. CONCLUSION: A thorough preoperative evaluation of the donor graft volume should be performed in order to prevent donor morbidity and mortality, as well as small for-size and large-for-size phenomena in the implanted grafts. Physicians working in the field of transplantation should be aware of the fact that a difference of 10% between the predicted and the actual graft volume is usually encountered. PMID- 29607425 TI - Investigation of genotoxicity risk and DNA repair capacity in breast cancer patients using anastrozole. AB - OBJECTIVE: Breast cancer is the most common cancer in women worldwide and the incidence increases in postmenopausal women. Anastrozole is a non-steroidal (type II), third-generation aromatase inhibitor (AI) that is used in the treatment of postmenopausal estrogen-related breast cancer. Several studies have been conducted to assess the efficacy, safety, and superiority of AIs to tamoxifen; however, a literature search did not reveal a study that investigated the genotoxic potential of AIs. The aim of this study was to investigate the possible DNA damage risk profile and individual DNA repair capacity of patients using anastrozole with the modified alkaline comet assay in order to contribute to public health and health economics. METHODS: Women diagnosed with breast cancer after menopause comprised the study group. Six patients who had taken anastrozole for at least 6 months were retrospectively enrolled, and 12 patients who had not yet received treatment were prospectively enrolled as a control group. Peripheral blood lymphocytes were used to measure oxidized DNA damage using formamidopyrimidine DNA-glycosylase (FPG) and endonuclease III (endo III) in a modified comet assay. Individual DNA repair capacity was evaluated with the comet assay after a hydrogen peroxide (H2O2) challenge to examine the difference in DNA damage susceptibility. RESULTS: Analysis of DNA damage, oxidative base damage, susceptibility to DNA damage, and repair capacity revealed no significant difference between the control group and the patients taking anastrozole (p>0.05). Susceptibility to H2O2 damage was observed to increase with age (p<0.05). CONCLUSION: According to the results obtained in this study, anastrozole did not contribute to oxidative DNA damage. An H2O2 challenge with the comet assay is useful to evaluate circumstances of increased vulnerability to damage, such as aging and cancer. PMID- 29607426 TI - Effect of nerve monitoring on complications of thyroid surgery. AB - OBJECTIVE: The most frequent and critical complications of thyroid surgery are recurrent laryngeal nerve palsy and hypocalcemia. In first years of the 21st century, intraoperative neuromonitoring (IONM) was introduced as a new technique to avoid the recurrent laryngeal nerve (RLN) injury. However, the role and the benefits of IONM are still controversial. In this study, we aimed to compare the postoperative complication rates during thyroid surgery with IONM usage (Group 1) and conventional direct visual technique without IONM usage (Group 2). METHODS: We conducted retrospective review of all patients undergoing thyroid surgery in Lutfiye Nuri Burat State Hospital General Surgery Department between 2014 and 2016 years. Patients have been classified in to two groups: Group 1 and 2. RESULTS: Overall, 191 patients were included in the study; Group 1 comprised 79 patients and Group 2 comprised 112 patients. Unilateral RLN paralysis was observed in 7 patients in Group 1 (8.9%) and 15 patients in Group 2 (13.4%) without any significant difference between the groups (p=0.368). Hypocalcemia was encountered in 5 patients (6.3%) in Group 1 and 18 patients (16.1%) in Group 2; this difference was statistically significant (p=0.045). Other complications (such as hematoma and suture reaction) were not significantly different. Operation time was found to be significantly shorter in Group 1 (Mean time, 93.08 min) than in Group 2 (116.54 min) (p=0.03). CONCLUSION: Proven effect of IONM on RLN paralysis is still controversial. However, easy identification of RLN, which gives more confidence to surgeon, and shorter operation time may be factors to lower hypocalcemia rates. PMID- 29607423 TI - Understanding Primate Herpesviruses. AB - Viruses related to the herpes simplex viruses of humans are present in all nonhuman primate (NHP) species tested and cross species transmission has been documented. The herpesvirus present in macaques, Herpes B virus (BV) rarely causes disease in its natural macaque host. However, when transmitted to a nonnative host, BV has occasionally caused severe and even fatal disease if not treated immediately. Here we present a comprehensive review of the taxonomy, molecular biology, physiology, epidemiology, diagnosis and treatment of BV. We also summarizes what is known about related herpesviruses of other NHP species and the zoonotic potential of these viruses. PMID- 29607427 TI - Urban legend or real fact: Coronary artery size varies with demographics. AB - OBJECTIVE: This study aimed to determine the relationship between the diameter of coronary artery stents and age, gender, diabetes mellitus (DM), left ventricular ejection fraction (LVEF), renal dysfunction, and the clinical presentation of myocardial ischemia in the cohort of patients with implanted stents in coronary arteries with severe stenotic lesions. METHODS: This study included 2256 patients (mean age, 59.3+/-10.9 years; men, 62%) who underwent percutaneous coronary intervention (PCI). The clinical status of the patients at presentation was subcategorized as follows: ST-segment elevation myocardial infarction, non-ST segment elevation myocardial infarction, unstable angina pectoris, and stable angina pectoris. The diameters, without any type or brand differentiation, were divided into two groups as follows: Group I, which included 2.5- and 2.75-mm diameter stents, and Group II, which included >=3-mm-diameter stents. RESULTS: The type of procedure, including primary PCI, early invasive strategy, and elective stenting, was not found to be a significant factor affecting the diameter of coronary artery stents. Univariate and multivariate analyses revealed a relationship between the diameter of coronary artery stents and age, gender, DM, and LVEF. CONCLUSION: This study demonstrated that the diameter of coronary artery stents was independently associated with gender, age, a history of DM, and moderate-to-severe systolic left ventricular dysfunction. PMID- 29607428 TI - Investigation of the attitudes of university students to discrimination of the elderly. AB - OBJECTIVE: This study was conducted to determine the attitudes of university students studying in different fields toward discrimination of the elderly. METHODS: This descriptive study was conducted with students who were still studying in the 2015-2016 period. A sample size of 416 students was determined by the stratified sampling method, and students were selected by simple random sampling. Data were collected using an identifying information form and an Age Discrimination Attitude Scale (ADAS) by face-to-face interview. Statistical analysis was performed using the program SPSS 20.0. RESULTS: The mean total ADAS score of students was 67.7+/-6.0. The total ADAS scores and the scores of male students on limiting the life of the elderly was significantly higher than those of female students (p<0.05). CONCLUSION: It was determined that university students studying in different fields have a positive attitude toward the elderly. Action must be taken to remove discrimination of the elderly, and policies must be developed to increase social sensitivity. PMID- 29607429 TI - Sleep quality and anxiety level in employees. AB - OBJECTIVE: The aim of this study was to measure the sleep quality and anxiety level of a group of employees, as well as determine the relationship between sleep quality and anxiety and other factors. METHODS: A total of 130 of 185 employees at a university campus were enrolled in this cross-sectional study. A descriptive questionnaire, the Pittsburgh Sleep Quality Index, and the Beck Anxiety Inventory were the data collection instruments. In addition to univariate analysis, the relationship between the 2 scales was examined with Spearman correlation analysis. RESULTS: Of the participants, 38.9% had poor sleep quality. Gender, income level, presence of a chronic disease, regular medication use, and relationship with family and the social environment were found to affect both sleep quality and anxiety. A decrease in sleep quality was associated with an increase in the level of anxiety. CONCLUSION: Poor sleep quality and a high anxiety level are common in this country, as in the rest of the world. Socioeconomic interventions and psychosocial support to improve the status of individuals with risk factors, such as chronic disease, will reduce anxiety and improve sleep quality and overall psychosocial health. Further prospective studies should be conducted with different groups of participants and with larger samples to expand knowledge of the relationship between sleep quality and anxiety. PMID- 29607430 TI - Immunomodulator effect of topical zinc oxide application in tuberculin skin test. AB - OBJECTIVE: We aimed to evaluate the sensitivity of tuberculin skintest (purified protein derivative-PPD) by topical zinc application on test site to improve diagnostic reliability. METHODS: We performed this study in 100 children aged 6 14 years, and plasma zinc levels were analyzed after 10-12 hours fasting. After PPD, we applied 40% zinc oxide cream on one forearm and placebo on the other forearm. PPD indurations were measured 72 hours later. RESULTS: In this study, 26% of the children showed increases in PPD induration following local zinc applications. There was no correlation between indurations size and serum zinc levels. CONCLUSION: We concluded that topical zinc cream application can enhance sensitivity of tuberculin reactivityin the diagnosis of tuberculosis. PMID- 29607431 TI - Evaluation of patients with gastric polyps. AB - OBJECTIVE: The incidence of gastric polyps (GPs) greatly differs according to study populations and was found to be 0.33%-6.7% in various studies. The majority of GPs are composed of hyperplastic polyps (HPs), fundic gland polyps (FGPs), and adenomatous polyps (APs). Although APs have a high risk of malignant potential, sporadic FGPs have no malignant potential. Conversely, HPs have a low risk of malignant potential. It is not sufficient to perform a biopsy to identify the polyp type and the presence of dysplasia; thus, some polyps may require multiple biopsies or total excision. METHODS: This retrospective study included patients with GPs or polypoid lesions found on esophagogastroscopy with polyp or malignant histology on biopsy at Ankara Numune Training and Research Hospital Endoscopy Unit between 2005 and 2011. RESULTS: In a series of 56.300 upper endoscopies, 192 patients (0.34%) were found to have GPs. Among the patients, 51 (26.6%) were men and 151 (73.4%) were women. The average age of the patients was 61.9+/-13.3 (14 90) years. The frequency of HPs, APs, and FGPs were 88%, 2.6%, and 1.6%, respectively. The size of the polyps was <=1 cm in 137 (70%) patients. One polyp was determined in 141 (73.4%) patients. The most common localizations of polyps were the antrum and corpus. Endoscopic snare polypectomy was performed in 64 patients. One bleeding episode was observed, which required endoscopic treatment after ESP. CONCLUSION: In our study, the GP frequency was low (0.34%), whereas the frequency of HP maybe high due to the high frequency of Helicobacter pylori (HPy) infection in our country. The frequency of FGP is probably low due to the high frequency of HPy infection and the short-term use of proton-pump inhibitors. PMID- 29607432 TI - Gallbladder perforation during elective laparoscopic cholecystectomy: Incidence, risk factors, and outcomes. AB - OBJECTIVE: This study aimed to reveal the risk factors and outcomes of gallbladder perforation (GP) during laparoscopic cholecystectomy. METHODS: Videotapes of all patients who underwent an elective cholecystectomy at our department were retrospectively analyzed, and the patients were divided into two groups based on the presence of GP. The possible risk factors and early outcomes were analyzed. RESULTS: In total, 664 patients [524 (78.9%) females, 49.7+/-13.4 years of age] were observed, and GP occurred in 240 (36.1%) patients, mostly while dissecting the gallbladder from its bed (n=197, 82.1%). GP was not recorded in the operation notes in 177 (73.8%) cases. Among the studied parameters, there was no significant risk factor for GP, except preoperatively elevated alanine transaminase level (p=0.005), but the sensitivity and specificity of this measure in predicting GP were 14.2% and 7.4%, respectively. The two groups had similar outcomes, but the operation time (35.4+/-17.5 vs 41.4+/-18.7 min, p=0.000) and incidence of drain use (25% vs 45.8%, p=0.000) increased in the GP group. CONCLUSION: The present study reveals that GP occurs in 36.1% of patients who undergo laparoscopic elective cholecystectomy, but it may not be recorded in most cases. We did not find any reliable risk factor that increases the possibility of GP. GP causes an increase in the operation time and incidence of drain use; however, the other outcomes were found to be similar in patients with GP and those without. PMID- 29607433 TI - Effect of trabeculectomy on ocular higher-order aberrations in patients with open angle glaucoma. AB - OBJECTIVE: The aim of this study was to evaluate the effect of trabeculectomy on ocular higher-order aberrations following surgery in a group of patients with open angle glaucoma. METHODS: In this prospective study, patients with primary open angle glaucoma underwent wavefront aberrometry before trabeculectomy with mitomycin-C. Coma-like, spherical-like, and total ocular higher-order aberrations were measured as root mean square values. The measurements were repeated 1 month and 3 months after the procedure. RESULTS: A total of 20 eyes from 20 patients were examined. There was a significant decrease in intraocular pressure following surgery at 1 month and 3 months postoperatively. However, there was no statistically significant change in the spherical equivalent of the eyes. One month after surgery, a significant change in coma-like, spherical-like, and total higher-order aberrations of the eyes was observed. However, the repeated measurements performed 3 months after procedure revealed no significant difference compared to the baseline values. CONCLUSION: Ocular higher-order aberrations increased 1 month following trabeculectomy surgery. However, this effect seems to be transient, as the values returned to the preoperative measurement 3 months after the procedure. PMID- 29607434 TI - Gaucher disease in an adult: A rare cause of hepatosplenomegaly in adults. PMID- 29607435 TI - Renal clear cell sarcoma presenting as a spontaneous renal hematoma: A rare presentation. AB - Clear cell sarcoma of the kidney (CCSK) is an uncommon renal neoplasm of childhood. It represents between 2% and 9% of all pediatric renal tumors, and generally arises before the age of 5 years. It often mimics other pediatric renal tumors. Presently described is the case of a 7-year-old girl who presented with complaints of vomiting and abdominal pain. Abdominal ultrasonography revealed a right renal mass, and the patient developed a renal hematoma a few hours after admission. The patient underwent a nephroureterectomy with a provisional diagnosis of Wilms tumor; however, histopathological examination of a specimen revealed CCSK. CCSK is similar to Wilms tumor in terms of the typical age of appearance and clinical and histopathological features, but the treatment method and prognosis are different. Therefore, the differential diagnosis is very important. This case was presented to draw attention to a rare presentation of clear cell sarcoma. CCSK should be kept in mind in the differential diagnosis of a renal mass. PMID- 29607436 TI - Autoimmune hemolytic anemia associated with infliximab infusion in ulcerative colitis. AB - Infliximab is a monoclonal antibody that antagonizes the activity of tumor necrosis factor alpha to induce and maintain remission in patients with inflammatory bowel disease. Adverse effects associated with Infliximab infusions include infusion reactions, risk of infections, development of hematological malignancies, and pancytopenia. Autoimmune hemolytic anemia has rarely been reported in ulcerative colitis. Herein we report a case of drug-induced hemolytic anemia after infliximab infusion for treating ulcerative colitis. PMID- 29607438 TI - Reconstructive surgery of true aneurysm of the radial artery: A case report. AB - True radial artery aneurysms are uncommon pathologies and have an organic cause, unlike trauma-induced false aneurysms. A 52-year-old man presented with a pulsatile mass at the anatomical snuff box area of his left hand. The aneurysm was repaired with reconstructive procedure. Although many posttraumatic and iatrogenic cases of false aneurysm of the radial artery have been reported; there are a few reported cases of a true idiopathic aneurysm. A case of reconstructive surgery for true idiopathic radial artery aneurysm is reported in this paper. PMID- 29607437 TI - Diagnosing between papillary carcinoma and reactive papillary changes in an infarcted thyroid nodule after fine needle aspiration and accompanied by a synchronous brain stem astrocytoma. AB - A 22-year-old patient underwent fine needle aspiration of a nodule at the outer center of the right lobe of the thyroid, and it was reported to be Bethesda system category IV, Hurthle cell follicular neoplasia. The patient, who persented to Onsekiz Mart University Research and Application Hospital, underwent surgery. During right total thyroidectomy, an almost totally infarcted nodule and papillary structures around these infarcted areas were detected. Herein, we report on diagnostic challenges faced in confirming whether the infarcted nodule was a case of reactive papillary changes or an underdiagnosed papillary carcinoma and how the challenges were overcome using immunohistochemistry analysis and molecular genetic testing. In addition, we examined the case along with a literature review because an accompanying synchronous brain stem astrocytoma was detected in the patient after thyroidectomy. PMID- 29607439 TI - Penetrating injury caused by a long iron bar: A case report. AB - Foreign bodies that strike the body with their long edges can cause severe problems. From the hospitalization of the patients to the removal of the foreign body and from surgery to follow-up, working as a team in a well-organized manner is necessary. In the present research, we present our experience, including the hospitalization, initial assessment by the emergency team, examination, and treatment plan, of a pediatric patient who had a 12-m long iron bar that traversed from the right side of the anus to the loin; this impalement happened while the patient was sliding through a snow-covered street, and the patient had to wait on the snow until the fire department arrived and cut the iron bar. PMID- 29607441 TI - In-Hospital Mortality Following Traumatic Brain Injury Among Older Medicare Beneficiaries, Comparing Statin Users With Nonusers. AB - Background: Traumatic brain injury (TBI) is a significant public health concern for older adults. Small-scale human studies have suggested pre-TBI statin use is associated with decreased in-hospital mortality following TBI, highlighting the need for large-scale translational research. Objective: To investigate the relationship between pre-TBI statin use and in-hospital mortality following TBI. Methods: A retrospective study of Medicare beneficiaries 65 and older hospitalized with a TBI during 2006 to 2010 was conducted to assess the impact of pre-TBI statin use on in-hospital mortality following TBI. Exposure of interest included atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, and simvastatin. Beneficiaries were classified as current, recent, past, and nonusers of statins prior to TBI. The outcome of interest was in-hospital mortality. Logistic regression was used to obtain odds ratios (ORs) and 95% confidence intervals (CIs) comparing current, recent, and prior statin use to nonuse. Results: Most statin users were classified as current users (90%). Current atorvastatin (OR = 0.88; 95% = CI 0.82, 0.96), simvastatin (OR = 0.84; 95% CI = 0.79, 0.91), and rosuvastatin (OR = 0.79; 95% CI = 0.67, 0.94) use were associated with a significant decrease in the risk of in-hospital mortality following TBI. Conclusions: In addition to being the most used statins, current use of atorvastatin, rosuvastatin, and simvastatin was associated with a significant decrease in in-hospital mortality following TBI among older adults. Future research must include clinical trials to help exclude the possibility of a healthy user effect in order to better understand the impact of statin use on in hospital mortality following TBI. PMID- 29607440 TI - Fecal microbiota transplantation and its potential therapeutic uses in gastrointestinal disorders. AB - Typical human gut flora has been well characterized in previous studies and has been noted to have significant differences when compared with the typical microbiome of various disease states involving the gastrointestinal tract. Such diseases include Clostridium difficile colitis, inflammatory bowel disease, functional bowel syndromes, and various states of liver disease. A growing number of studies have investigated the use of a fecal microbiota transplant as a potential therapy for these disease states. PMID- 29607442 TI - Admittance Control for Robot Assisted Retinal Vein Micro-Cannulation under Human Robot Collaborative Mode. AB - Retinal vein occlusion is one of the most common retinovascular diseases. Retinal vein cannulation is a potentially effective treatment method for this condition that currently lies, however, at the limits of human capabilities. In this work, the aim is to use robotic systems and advanced instrumentation to alleviate these challenges, and assist the procedure via a human-robot collaborative mode based on our earlier work on the Steady-Hand Eye Robot and force-sensing instruments. An admittance control method is employed to stabilize the cannula relative to the vein and maintain it inside the lumen during the injection process. A pre-stress strategy is used to prevent the tip of microneedle from getting out of vein in in prolonged infusions, and the performance is verified through simulations. PMID- 29607443 TI - Therapeutic Effect of Blueberry Extracts for Acute Myeloid Leukemia. AB - Acute myeloid leukemia (AML) is an aggressive hematological malignancy with high incidence in the aging population. In addition, AML is one of the more common pediatric malignancies. Unfortunately, both of these patient groups are quite sensitive to chemotherapy toxicities. Investigation of blueberries specifically as an anti-AML agent has been limited, despite being a prominent natural product with no reported toxicity. In this study, blueberry extracts are reported for the first time to exert a dietary therapeutic effect in animal models of AML. Furthermore, in vitro studies revealed that blueberry extracts exerted anti-AML efficacy against myeloid leukemia cell lines as well as against primary AML, and specifically provoked Erk and Akt regulation within the leukemia stem cell subpopulation. This study provides evidence that blueberries may be unique sources for anti-AML biopharmaceutical compound discovery, further warranting fractionation of this natural product. More so, blueberries themselves may provide an intriguing dietary option to enhance the anti-AML efficacy of traditional therapy for subsets of patients that otherwise may not tolerate rigorous combinations of therapeutics. PMID- 29607444 TI - OCT-BASED THREE DIMENSIONAL MODELING OF STENT DEPLOYMENT. AB - Stent deployment has been widely used to treat narrowed coronary artery. Its acute outcome in terms of stent under expansion and malapposition depends on the extent and shape of calcifications. However, no clear understanding as to how to quantify or categorize the impact of calcification. We have conducted ex vivo stenting characterized by the optical coherence tomography (OCT). The goal of this work is to capture the ex vivo stent deployment and quantify the effect of calcium morphology on the stenting. A three dimensional model of calcified plaque was reconstructed from ex vivo OCT images. The crimping, balloon expansion and recoil process of the Express stent were characterized. Three cross-sections with different calcium percentages were chosen to evaluated the effect of the calcium in terms of stress/strain, lumen gains and malapposition. Results will be used to the pre-surgical planning. PMID- 29607445 TI - A Review on the General Stability of Mood Disorder Diagnoses Along the Lifetime. AB - PURPOSE OF REVIEW: The purpose of this review is to review the most recent literature regarding diagnostic stability of mood disorders, focusing on epidemiological, clinical-psychopathological, and neurobiological data for unipolar and bipolar affective disorders. RECENT FINDINGS: Unipolar depression follows a chronic course in at least half of all cases and presents a considerable diagnostic stability across all age ranges. Studies using latent class analysis are allowing improved profiling of depressive subtypes and assessment of their prevalence. Advances have been made in our understanding of the neurobiological underpinnings of depression, with data highlighting the roles of amyloid deposits, the ApoE4 allele, and atrophy of the anterior hippocampus or frontal cortex. The diagnostic instability of bipolar disorder is manifest in the early years, seen in both the extent of diagnostic delay and the high rate of diagnostic conversion from unipolar depression. Regarding disruptive mood dysregulation disorder, we have little data to date, but those which exist indicate a high rate of comorbidity and minimal diagnostic stability for this disorder. Diagnostic stability varies substantially among mood disorders, which would be related to the validity of current diagnostic categories and our diagnostic accuracy. PMID- 29607446 TI - The IRB structure and medical research reform. AB - Optimal Independent Review Board (IRB) structure encompasses ongoing process improvement, ethics policies and continuous relationship building, all sound in evidence. With optimal IRB structure, a global research infrastructure will flourish. Evidence for IRB structure must be detailed and expert operational recommendations should guide. Too, health service research oversight should assist in funding as well as collaboration. A national and international research agenda will only benefit from best operations, guided in evidence, supported in best regulatory and research leadership practice. It is imperative that the IRB structure be reformed. PMID- 29607447 TI - Oropharyngeal Dysphagia Evaluation Tools in Adults with Solid Malignancies Outside the Head and Neck and Upper GI Tract: A Systematic Review. AB - Dysphagia is often associated with head and neck and upper gastrointestinal (GI) tract cancers. Evidence suggests that those with solid malignancies in other primary sites may also have swallowing difficulties. Timely and accurate identification of dysphagia is important given the impact it has on hydration, medical treatment, nutrition, prognosis, and quality of life. A systematic review was conducted to identify swallow screening, evaluation, and quality of life tools for those with solid malignancies outside the head and neck and upper GI tract. Ten electronic databases, one journal and two published conference proceedings were searched. Following deduplication, 7435 studies were examined for relevance. No tools were validated solely in this cancer population, though some included this group in larger cohorts. Comments are provided on the diagnostic properties and applicability of these tools. In the absence of appropriate diagnostic instruments, the exact prevalence of dysphagia and its impact on clinical and psychosocial well-being remain unknown. Accurate and adequate measurement of therapeutic intervention is also compromised. This review establishes the need for validated dysphagia evaluation tools for this clinical population. PMID- 29607450 TI - Multiple reaction monitoring targeted LC-MS analysis of potential cell death marker proteins for increased bioprocess control. AB - The monitoring of protein biomarkers for the early prediction of cell stress and death is a valuable tool for process characterization and efficient biomanufacturing control. A representative set of six proteins, namely GPDH, PRDX1, LGALS1, CFL1, TAGLN2 and MDH, which were identified in a previous CHO-K1 cell death model using discovery LC-MSE was translated into a targeted liquid chromatography multiple reaction monitoring mass spectrometry (LC-MRM-MS) platform and verified. The universality of the markers was confirmed in a cell growth model for which three Chinese hamster ovary host cell lines (CHO-K1, CHO S, CHO-DG44) were grown in batch culture in two different types of basal media. LC-MRM-MS was also applied to spent media (n = 39) from four perfusion biomanufacturing series. Stable isotope-labelled peptide analogues and a stable isotope-labelled monoclonal antibody were used for improved protein quantitation and simultaneous monitoring of the workflow reproducibility. Significant increases in protein concentrations were observed for all viability marker proteins upon increased dead cell numbers and allowed for discrimination of spent media with dead cell densities below and above 1 * 106 dead cells/mL which highlights the potential of the selected viability marker proteins in bioprocess control. Graphical abstract Overview of the LC-MRM-MS workflow for the determination of proteomic markers in conditioned media from the bioreactor that correlate with CHO cell death. PMID- 29607449 TI - Pipette-tip solid-phase extraction using polypyrrole as efficient adsorbent for extraction of avermectins and milbemycins in milk. AB - In this work, we developed a HPLC method for the multidetermination of avermectins (AVM) (abamectin-ABA 1b and ABA 1a, eprinomectin-EPR, and ivermectin IVM) and milbemycins (moxidectin-MOX) in milk samples using polypyrrole (PPy) as adsorbent material in pipette-tip solid-phase extraction (PT-PPy-SPE). PPy was characterized by scanning electron microscopy, thermogravimetric analysis, Fourier transform infrared spectroscopy, and X-ray diffraction and the data agreed with the literature. The sample preparation included the clean-up of the milk by protein precipitation (PP) with acetonitrile and extraction of the analytes by PT-PPy-SPE. The chromatographic method was developed in reverse phase and isocratic mode with flow rate at 1.2 mL min-1 and ultraviolet detection at 250 nm. The mobile phase composition was acetonitrile:methanol:water (55:25:20, v/v/v). The studied parameters and the optimized conditions for the sample preparation were washing solvent (300 MUL water), volume and type of eluent (500 MUL methanol), volume and pH of sample (1 mL and pH 10), amount of adsorbent material (50 mg PPy), and without addition of salt (NaCl). The method was linear over the concentration range from 20 to 3000 ng mL-1 with coefficients of correlation (r) >= 0.99 for all analytes and recoveries around 100%. The method developed and validated was used for the analyses of real milk samples from cow treated with Ivomec(r) (IVM 3.5%), in which were found 21.51 +/- 2.94 ng mL-1 of IVM. Finally, the results proved that PT-PPy-SPE coupled to HPLC-UV was economical, simple, and easy-to-perform technique. Graphical abstract Pipette-tip solid phase extraction using polypirrole as adsorbent material for determination of avermectins and milbemycins in milk. PMID- 29607451 TI - The precise physiological definition of tissue perfusion and clearance measured from imaging. PMID- 29607448 TI - Silicone wristbands compared with traditional polycyclic aromatic hydrocarbon exposure assessment methods. AB - Currently there is a lack of inexpensive, easy-to-use technology to evaluate human exposure to environmental chemicals, including polycyclic aromatic hydrocarbons (PAHs). This is the first study in which silicone wristbands were deployed alongside two traditional personal PAH exposure assessment methods: active air monitoring with samplers (i.e., polyurethane foam (PUF) and filter) housed in backpacks, and biological sampling with urine. We demonstrate that wristbands worn for 48 h in a non-occupational setting recover semivolatile PAHs, and we compare levels of PAHs in wristbands to PAHs in PUFs-filters and to hydroxy-PAH (OH-PAH) biomarkers in urine. We deployed all samplers simultaneously for 48 h on 22 pregnant women in an established urban birth cohort. Each woman provided one spot urine sample at the end of the 48-h period. Wristbands recovered PAHs with similar detection frequencies to PUFs-filters. Of the 62 PAHs tested for in the 22 wristbands, 51 PAHs were detected in at least one wristband. In this cohort of pregnant women, we found more significant correlations between OH-PAHs and PAHs in wristbands than between OH-PAHs and PAHs in PUFs-filters. Only two comparisons between PAHs in PUFs-filters and OH-PAHs correlated significantly (rs = 0.53 and p = 0.01; rs = 0.44 and p = 0.04), whereas six comparisons between PAHs in wristbands and OH-PAHs correlated significantly (rs = 0.44 to 0.76 and p = 0.04 to <0.0001). These results support the utility of wristbands as a biologically relevant exposure assessment tool which can be easily integrated into environmental health studies. Graphical abstract PAHs detected in samples collected from urban pregnant women. PMID- 29607452 TI - HAA1 and PRS3 overexpression boosts yeast tolerance towards acetic acid improving xylose or glucose consumption: unravelling the underlying mechanisms. AB - Acetic acid tolerance and xylose consumption are desirable traits for yeast strains used in industrial biotechnological processes. In this work, overexpression of a weak acid stress transcriptional activator encoded by the gene HAA1 and a phosphoribosyl pyrophosphate synthetase encoded by PRS3 in a recombinant industrial Saccharomyces cerevisiae strain containing a xylose metabolic pathway was evaluated in the presence of acetic acid in xylose- or glucose-containing media. HAA1 or PRS3 overexpression resulted in superior yeast growth and higher sugar consumption capacities in the presence of 4 g/L acetic acid, and a positive synergistic effect resulted from the simultaneous overexpression of both genes. Overexpressing these genes also improved yeast adaptation to a non-detoxified hardwood hydrolysate with a high acetic acid content. Furthermore, the overexpression of HAA1 and/or PRS3 was found to increase the robustness of yeast cell wall when challenged with acetic acid stress, suggesting the involvement of the modulation of the cell wall integrity pathway. This study clearly shows HAA1 and/or, for the first time, PRS3 overexpression to play an important role in the improvement of industrial yeast tolerance towards acetic acid. The results expand the molecular toolbox and add to the current understanding of the mechanisms involved in higher acetic acid tolerance, paving the way for the further development of more efficient industrial processes. PMID- 29607453 TI - From plants to herbivores: novel insights into the ecological and evolutionary consequences of plant variation. PMID- 29607454 TI - Molecular dynamics study of T = 3 capsid assembly. AB - Molecular dynamics simulation is used to model the self-assembly of polyhedral shells containing 180 trapezoidal particles that correspond to the T = 3 virus capsid. Three kinds of particle, differing only slightly in shape, are used to account for the effect of quasi-equivalence. Bond formation between particles is reversible and an explicit atomistic solvent is included. Under suitable conditions the simulations are able to produce complete shells, with the majority of unused particles remaining as monomers, and practically no other clusters. There are also no incorrectly assembled clusters. The simulations reveal details of intermediate structures along the growth pathway, information that is relevant for interpreting experiment. PMID- 29607456 TI - Oral health and chemotherapy act as cofactors in malnutrition in the elderly with other cancers than head and neck malignancies. AB - OBJECTIVES: This study explores whether the chemotherapy regimen has a role in inducing oral health problems and malnutrition in elderly patients with other cancers than head and neck malignancies. MATERIAL AND METHODS: An observational cross-sectional study was designed to compare the relationships between oral health and nutritional status between four groups of elderly differing in cancer or chemotherapy regimen. Data were collected using a questionnaire including the Mini-Nutritional Assessment (MNA), the Geriatric Oral Health Assessment Index (GOHAI) and questions about perception of xerostomia. The oral examinations recorded the number of functional dental units (PFU) and the presence of oral lesions. RESULTS: The sample comprised 46 patients receiving chemotherapy, 48 patients on a non-chemotherapy regimen, 45 persons in complete remission not under treatment and 53 non-cancer patients. Oral health perception was significantly worse in chemotherapy patients. They reported limiting the kinds of food they consumed, the discomfort felt when eating and took medications for oral pain. Oral lesions were frequent in chemotherapy participants. Nutritional status was related to the cancer treatment regimen (OR = 4.17; p value = 0.017), the presence of oral lesions (OR = 4.51; p value = 0.003), perception of xerostomia (OR = 3.54; p value = 0.012), the number of PFU (OR = 2.51; p value = 0.046) and GOHAI score (OR = 1.617; p value = 0.019). CONCLUSION: The presence of oral lesions and the chemotherapeutic regimen were highly associated with nutritional status in older patients with cancer. CLINICAL RELEVANCE: Dental professionals should be asked to intervene preventively and per-therapy to optimise oral health status in elderly patients with other cancers than head and neck malignancies. PMID- 29607455 TI - Epigenetic signatures in cardiac fibrosis, special emphasis on DNA methylation and histone modification. AB - Cardiac fibrosis is defined as excess deposition of extracellular matrix (ECM), resulting in tissue scarring and organ dysfunction. In recent years, despite the underlying mechanisms of cardiac fibrosis are still unknown, numerous studies suggest that epigenetic regulation of cardiac fibrosis. Cardiac fibrosis is regulated by a myriad of factors that converge on the transcription of genes encoding extracellular matrix protein, a process the epigenetic machinery plays a pivotal role. Epigenetic modifications contain three main processes: DNA methylation, histone modifications, and noncoding RNAs. Here, we review recent studies that have illustrated key roles for epigenetic events in the control of pro-fibrotic gene expression, and highlight the potential of molecule mechanisms that target epigenetic regulators as a means of treating cardiac fibrosis. PMID- 29607457 TI - Preliminary human application of optical coherence tomography for quantification and localization of primordial follicles aimed at effective ovarian tissue transplantation. AB - PURPOSE: The purpose of this study was to evaluate the possible clinical application of optical coherence tomography for assessing ovarian reserve in individual specimens of human ovarian tissue for fertility preservation. METHODS: Ovarian tissue examination by optical coherence tomography was performed before ovarian tissue cryopreservation. Three of the four subjects had hematological disease or cancer, and they faced a threat to their fertility due to impending chemotherapy. One patient underwent ovarian tissue extraction for in vitro activation of dormant follicles as fertility treatment. RESULTS: The current full field optical coherence tomography technique can detect primordial follicles in non-fixed and non-embedded human ovarian tissue. These images are well correlated with histological evaluation and the ovarian reserve test, including follicle counts. CONCLUSION: It was demonstrated that optical coherence tomography could assess localization of primordial follicles and ovarian reserve in specimens of non-fixed human ovarian cortex, although optimization for examination of human ovarian tissue is needed for clinical application. Additionally, this technique holds the possibility of assessing the ovarian reserve of patients with unevaluable ovarian reserve. TRIAL REGISTRATION NUMBER: UMIN000023141. PMID- 29607458 TI - Impact of high magnification sperm selection on neonatal outcomes: a retrospective study. AB - PURPOSE: The aim of this study was to compare the effect of the deselection of spermatozoa presenting vacuole-like structures using IMSI (intracytoplasmic morphologically selected sperm injection) with ICSI (intracytoplasmic sperm injection) by means of neonatal outcomes. METHODS: In a retrospective two-center analysis, a total of 848 successful IMSI or ICSI cycles ending with a live birth, induced abortion, or intrauterine fetal death (IUFD) were included. RESULTS: The IMSI and ICSI groups included 332 and 655 babies or fetuses, respectively. The parents were older in the IMSI group than in the ICSI group (mothers were 35.1 vs 32.9 years, and fathers were 39.1 vs 36.2 years). The multiple pregnancy rate was higher in the IMSI group. The mean pregnancy duration and mean birth weight were almost identical in both groups. There was no significant difference in major congenital malformations between the two groups. However, this rate was decreased in the IMSI group compared to that in the ICSI group (1.8 vs 3.2%), the difference being mainly found in singletons (1.4 vs 3.3%). Boys were more often affected than girls in both groups. The percentages of chromosomal abnormalities did not differ between the IMSI and ICSI groups (0.6 and 0.8%). The reported congenital malformations mainly affected the heart, urogenital, and musculoskeletal systems. CONCLUSIONS: In the present study, the malformation rates observed in the IMSI and ICSI groups were not significantly different, even if slightly lower after IMSI. However, the observed difference followed the same trends observed in previous reports, indicating the possible impact of IMSI on decreasing congenital malformation occurrences. This highlights the necessity to prospectively evaluate the impact of IMSI on neonatal outcome after IVF treatment. PMID- 29607459 TI - The role of meniscal repair for prevention of early onset of osteoarthritis. AB - BACKGROUND: The meniscus plays an important role in the integrity of the knee joint. Therefore, meniscus tissue preserving techniques for the therapy of meniscus injuries seem to be reasonable. One of the important questions is whether meniscal repair can prevent the knee joint from early onset of osteoarthritis. METHODS: According to the review of the current literature, the principles of a successful meniscal repair are explained and the functional outcome and its impact on the prevention of osteoarthritis are analyzed in this article. RESULTS: Current data show a positive impact of a successful meniscus repair on the functional outcome in long-term. By this a protective effect on the development of osteoarthritis via the repair of meniscus lesions to restore the meniscus integrity can be confirmed. However, higher rates of re-operations in context to meniscus suturing have to be considered. CONCLUSION: Due to the improved functional outcomes as well as preventive effect on the development of osteoarthritis within the knee joint in long-term, it is of importance to preserve as much meniscus tissue as possible in meniscus therapy. Patients previously have to be informed about the higher revision rate in context to meniscus suturing. PMID- 29607460 TI - Neural Correlates of Attentional Processing of Threat in Youth with and without Anxiety Disorders. AB - Late-stage attentional processing of threatening stimuli, quantified through event-related potentials (ERPs), differentiates youth with and without anxiety disorders. It is unknown whether early-stage attentional processing of threatening stimuli differentiates these groups. Examining both early and late stage attentional processes in youth may advance knowledge and enhance efforts to identify biomarkers for translational prevention and treatment research. Twenty one youth with primary DSM-IV-TR anxiety disorders (10 males, ages 8-15 years) and 21 typically developing Controls (15 males, ages 8-16 years) completed a dot probe task while electroencephalography (EEG) was recorded, and ERPs were examined. Youth with anxiety disorders showed significantly larger (more positive) P1 amplitudes for threatening stimuli than for neutral stimuli, and Controls showed the opposite pattern. Youth with anxiety showed larger (more negative) N170 amplitudes compared with Controls. Controls showed significantly larger (more positive) P2 and P3 amplitudes, regardless of stimuli valence, compared with youth with anxiety disorders. ERPs observed during the dot probe task indicate youth with anxiety disorders display distinct neural processing during early stage attentional orienting and processing of faces; this was not the case for Controls. Such results suggest these ERP components may have potential as biomarkers of anxiety disorders in youth. PMID- 29607461 TI - Nanotherapeutic approaches targeting angiogenesis and immune dysfunction in tumor microenvironment. AB - Tumor microenvironment (TME) comprising cellular and non-cellular components is a major source of cancer hallmarks. Notably, angiogenesis responsible for normal physiological remodeling process can otherwise harness vessel abnormalities during tumorigenesis eliciting severe therapeutic inefficiency. Currently, FDA approved antiangiogenic drugs have only shown modest clinical success owing to tumor hypoxia, antiangiogenic therapeutic resistance, and limited knowledge in understanding TME. In order to overcome these limitations, targeting angiogenesis combined with immunosuppressive TME could offer potential therapeutic opportunities. Indeed, these therapeutic approaches can be further revisited with the advent of nanotechnology that can target the key cellular components of TME and tumor cells more precisely. Synergetic targeting without eliciting systemic toxicity achieved by integration of antiangiogenic and immunotherapy in a single nanoplatform is vital for therapeutic success. In this review, we will discuss the most promising nanotechnological advancements oriented to modulate the immunosuppressive TME in association with antiangiogenic therapy that has gained immense popularity in cancer treatment. PMID- 29607462 TI - Injury prevalence across sports: a descriptive analysis on a representative sample of the Danish population. AB - BACKGROUND: Physical activity plays an important role in public health, owing to a range of health-related benefits that it provides. Sports-related injuries are known to be an important barrier to continued physical activity. Still, the prevalence of injuries on a general population level has not yet been explored in a descriptive epidemiological investigation. The purpose of the questionnaire based study, therefore, was to describe the prevalence of injury in a representative sample of the Danish population. METHODS: Two samples of 10,000 adults (> 15 years) and 6500 children and adolescents (7-15 years) were invited to respond to a web-based questionnaire. Of these, 3498 adults (35.0%) and 3221 children (49.6%) responded successfully. The definition of sports injury was time loss and medical attention-based, inhibiting participants from sports activity for at least 7 days, and/or involved contact with a healthcare professional, respectively. RESULTS: Amongst adults, 642 (18.4% [95%CI: 17.1%; 19.6%]) reported to have had an injury within the past 12 months. Males reported significantly more injuries than females (difference in prevalence proportion: 9.2%-points [95%CI: 6.7%-points; 11.8%-points]). The prevalence of injuries was greatest in running (ninj = 198), football (ninj = 94) and strength training (ninj = 89). Amongst children, 621 (19.3% [95%CI: 17.9%; 20.6%]) had been injured. No difference in injury prevalence proportion existed between boys and girls. The prevalence of injuries was greatest in football (ninj = 235), handball (ninj = 86) and gymnastics (ninj = 66). CONCLUSIONS: Sports injuries seem to be very frequent in Denmark, since a total of 18.4% of the adults and 19.3% of the children reported having had one or more injuries within the past 12 months, equal to either time lost with physical activity and/or contact to the health care system. PMID- 29607463 TI - Disease detection, epidemiology and outbreak response: the digital future of public health practice. AB - Inequalities persist when it comes to the attention, resource allocation and political prioritization, and provision of appropriate, adequate, and timely health interventions to populations in need. Set against a complex socio political backdrop, the pressure on public health science is significant: institutions and scientists are accountable for helping to find the origins of disease, and to prevent and respond effectively more rapidly than ever. In the field of infectious disease epidemiology, new digital methods are contributing to a new 'digital epidemiology' and are seen as a promising way to increase effectivity and speed of response to infectious disease and public health events. New types of health data and access to personal information that are available through diverse channels will continue to have wide implications for epidemiology and public health practice. The purpose of this short paper is to introduce the emerging backdrop of practical and ethical challenges for those involved within the practice of public health as they face increasing collaborations with those from fields that have not traditionally applied their methods to epidemiology. PMID- 29607464 TI - CXCL1 and CXCR2 as potential markers for vital reactions in skin contusions. AB - Detection of the vitality of wounds is one of the most important issues in forensic practice. This study investigated mRNA and protein levels of CXCL1 and CXCR2 in skin wounds in mice and humans. Western blot analysis of CXCL1 and CXCR2 protein levels showed no difference between wounded and intact skin. However, mRNA levels demonstrated higher expression of CXCL1 and CXCR2 in contused mouse and human skin, compared with intact skin. At postmortem there were no remarkable changes in CXCL1 and CXCR2 mRNA levels in contused mouse skin. Increased mRNA expression was observed in contused mouse skin up to 96 h and 72 h after death for CXCL1 and CXCR2 respectively. In human samples of wounded skin, increased CXCL1 mRNA levels were detected up to 48 h after autopsy in all 5 cases, while increased CXCR2 mRNA levels were observed 48 h after autopsy in 4 of 5 cases. These findings suggest that the levels of CXCL1 and CXCR2 mRNA present in contused skin can be used as potential markers for a vital reaction in forensic practice. PMID- 29607465 TI - Sirolimus enhances remission induction in patients with high risk acute myeloid leukemia and mTORC1 target inhibition. AB - Background Mammalian Target of Rapamycin Complex 1 (mTORC1) inhibitors enhance chemotherapy response in acute myelogenous leukemia (AML) cells in vitro. However whether inhibiting mTORC1 enhances clinical response to AML chemotherapy remains controversial. We previously optimized measurement of mTORC1's kinase activity in AML blasts during clinical trials using serial phospho-specific flow cytometry of formaldehyde-fixed whole blood or marrow specimens. To validate mTORC1 as a therapeutic target in AML, we performed two clinical trials combining an mTORC1 inhibitor (sirolimus) and MEC (mitoxantrone, etoposide, cytarabine) in patients with relapsed, refractory, or untreated high-risk AML. Methods Flow cytometric measurements of ribosomal protein S6 phosphorylation (pS6) were performed before and during sirolimus treatment to determine whether mTORC1 inhibition enriched for chemotherapy response. Results In 51 evaluable subjects, the overall response rate (ORR) to the combination regimen was 47% (95% confidence interval 33-61%, 33% CR, 2% CRi, 12% PR) and similar toxicity to historic experience with MEC alone. 37 subjects had baseline pS6 measured pre-sirolimus, of whom 27 (73%) exhibited mTORC1 activity. ORR was not significantly different between subjects with and without baseline mTORC1 activity (52% vs 40%, respectively, p = 0.20). The ORR among subjects with baseline target activation and mTORC1 inhibition during therapy was 71% (12/17) compared to 20% (2/10) in subjects without target inhibition. Conclusions Fixed, whole blood pS6 by flow cytometry may be a predictive biomarker for clinical response to mTORC1 inhibitor-based regimens. These data provide clinical confirmation that mTORC1 activation mediates chemotherapy resistance in patients with AML. PMID- 29607466 TI - Autophagy inhibition improves the chemotherapeutic efficacy of cruciferous vegetable-derived diindolymethane in a murine prostate cancer xenograft model. AB - Prostate cancer is the second leading cause of cancer-related deaths in men in North America and there is an urgent need for development of more effective therapeutic treatments against this disease. We have recently shown that diindolylmethane (DIM) and several of its halogenated derivatives (ring-DIMs) induce death and protective autophagy in human prostate cancer cells. However, the in vivo efficacy of ring-DIMs and the use of autophagy inhibitors as adjuvant therapy have not yet been studied in vivo. The objective of this study was to determine these effects on tumor growth in nude CD-1 mice bearing bioluminescent androgen-independent PC-3 human prostate cancer cells. We found that chloroquine (CQ) significantly sensitized PC-3 cells to death in the presence of sub-toxic concentrations of DIM or 4,4'-Br2DIM in vitro. Moreover, a combination of DIM (10 mg/kg) and CQ (60 mg/kg), 3* per week, significantly decreased PC-3 tumor growth in vivo after 3 and 4 weeks of treatment. Furthermore, 4,4'-Br2DIM at 10 mg/kg (3* per week) significantly inhibited tumour growth after 4 weeks of treatment. Tissues microarray analysis showed that DIM alone or combined with CQ induced apoptosis marker TUNEL; the combination also significantly inhibited the cell proliferation marker Ki67. In conclusion, we have confirmed that DIM and 4,4' Br2DIM are effective agents against prostate cancer in vivo and shown that inhibition of autophagy with CQ enhances the anticancer efficacy of DIM. Our results suggest that including selective autophagy inhibitors as adjuvants may improve the efficacy of existing and novel drug therapies against prostate cancer. PMID- 29607468 TI - Perianal Basal Cell Carcinoma: a Case Report. PMID- 29607467 TI - New NO- and H2S-releasing doxorubicins as targeted therapy against chemoresistance in castration-resistant prostate cancer: in vitro and in vivo evaluations. AB - Chemotherapy for castration-resistant prostate cancer (CRPC) is only temporarily effective due to the onset of chemoresistance. We investigated the efficacy of NO and H2S-releasing doxorubicins (NitDox and H2SDox) in overcoming drug resistance and evaluated their safety. New and innovative NO- and H2S-releasing doxorubicins (NitDox and H2SDox) showed a good intracellular accumulation and high cytotoxic activity in vitro in an androgen-independent and doxorubicin-resistant DU-145 prostate cancer cell line. Nude mice were subcutaneously injected with 4*106 DU 145 cells and treated once a week for 3 weeks with 5 mg/kg doxorubicin, NitDox, H2SDox or vehicle, i.p. Animal weight, tumor volume, intra-tumoral drug accumulation, apoptosis and the presence of nitrotyrosine and sulfhydryl (SH) groups within the tumor, were evaluated. Cardiotoxicity was assessed by measuring troponin plasma levels and the left ventricular wall thickness. In vivo, NitDox and H2SDox accumulated inside the tumors, significantly reduced tumor volumes by 60%, increased the percentage of apoptotic cells in both the inner and the outer parts of the tumors and the presence of nitrotyrosine and SH groups. Doxorubicin treatment was associated with reduced body weight and cardiotoxicity. On the contrary, NitDox and H2SDox were well tolerated and had a better safety profile. Combining efficacy with reduced cardiovascular side effects, NitDox and H2SDox are promising novel therapeutic agents for reversing chemoresistance in CRCP. PMID- 29607469 TI - Movement of anterior teeth using clear aligners: a three-dimensional, retrospective evaluation. AB - BACKGROUND: Clear aligner treatment offers several advantages, but the available literature shows that some kind of tooth movements are unpredictable. In addition, the majority of the studies are focused on one clear aligner system, while different characteristics of various systems can provide different treatment outcomes. The aim of the present retrospective cohort study was to evaluate the predictability of Nuvola(r) aligner system in achieving torque movements of anterior teeth. METHODS: Thirty-nine adult patients, who were consecutively treated with clear aligners, were retrospectively selected, and digital models pre-treatment (T0), post-treatment (T1) and the digital setup models (TS) were collected. Only the first phase of treatment made of 12 aligners was considered for the present study. Torque of anterior teeth was measured as labiolingual inclination on digital models at T0, T1, and TS using VAM software. Any difference between the predicted and achieved torque movements was evaluated using Wilcoxon signed-rank test or paired sample t test. First-type error was set as p < 0.008. RESULTS: No statistically significant difference was found for all the anterior teeth between predicted and achieved torque movements. CONCLUSIONS: The studied clear aligner system was able to produce clinical outcomes comparable to the planning of the digital setup relative to torque movements of the anterior teeth. PMID- 29607470 TI - Obesity Indices and Peripheral Artery Disease Measured by Ankle Brachial Index in Nigerian Out-Patients. AB - BACKGROUND: Peripheral artery disease (PAD), an important component of the cardiovascular triad, has been linked with obesity as one of the risk factors for its development. The risk posed by obesity however varies depending on the indices measured. METHODS: We compared the relationship of measures of central and visceral obesity (waist circumference (WC) and waist-hip ratio (WHR) versus that of general obesity (body mass index (BMI) in the development of PAD among Nigerians with hypertension and/or diabetes mellitus. PAD was diagnosed when Ankle Brachial Index (ABI) was <0.9 in either limb. RESULTS: A total of 541 patients (194 males and 347 females) were studied with a mean age of 58.4(+/ 0.46)years. The mean BMI, WC and WHR were 27.8 (+/-0.222)kg/m2, 96.8 (+/-0.515)cm and 0.941 (+/-0.003) respectively. Although the mean BMI, WC and WHR were higher in patients with PAD than those without PAD, the difference was only statistically significant for WC and WHR (p=0.003 and p=0.016) but not BMI (p=0.151). However, the difference in mean BMI was statistically significant in patients <60 years (p=0.015) but not in those >60 years (p=0.953). CONCLUSION: This study has shown that in Nigerian Africans measures of central and visceral obesity were more related to the development of PAD than BMI which is a measure of general obesity and that this lack of significance is probably due to the fact that PAD occurred more in older people as there was a significant relationship with PAD in people younger than 60 years old. PMID- 29607471 TI - Presentation of children with advanced retinoblastoma for treatment in Ghana: the caretakers' perspectives. AB - BACKGROUND: Retinoblastoma, the commonest childhood malignant intraocular tumour, is diagnosed late, with less than 50% survival in developing countries, including Ghana. OBJECTIVES: To determine, from caretakers' perspective, contributing factors to late presentation of children with retinoblastoma. METHODS: A cross sectional study involving questionnaire administration to consenting caretakers of consecutive children diagnosed with advanced retinoblastoma at the Eye Unit, Korle-Bu Teaching Hospital, Accra, Ghana, from September 2008-June 2011. Clinical diagnosis was confirmed by CT scan or ultrasonography. Ethical approval was granted by University of Ghana Medical School. RESULTS: Forty caretakers aged 22 58 years (mean = 32.8 +/- 7.8yrs) were interviewed. Twenty-four (60%) were females, 36(90%) were parents. Thirty-two (80%) had at least primary level of education. Initial symptoms noticed by caretakers were: white spot 35(87.5%), redness 3(7.5%), proptosis 1(2.5%) and squint 1(2.5%). Thirty-five caretakers (87.5%) sought prior treatment between 1-24 months (median=1month) and 7(37%) beyond 3months, mainly from health/eye centres 34(85%). Six caretakers (15.4%) knew their children had cancer, 11(27.5%) had heard about retinoblastoma, but only 2(5.0%) knew treatment existed. Thirty-two caretakers (80%) would accept enucleation with prosthesis and 17(42.5%) without it. Cost: 8(20% respondents) and lack of awareness of prognosis of retinoblastoma 12(30% respondents) were stated as important factors though they did not prove significant. Caretakers' level of education, occupation and gender had no significant association with knowledge about retinoblastoma, awareness of treatment or cure, acceptance of enucleation with or without prosthesis, nor awareness of prognosis without treatment, p>0.05. CONCLUSION: Low awareness of the cause, treatment and prognosis of retinoblastoma exists among caretakers of children with advanced retinoblastoma. This may contribute to the late stage of the disease presentation. PMID- 29607472 TI - Subvastus versus Medial Parapatellar Approach in Primary Total Knee Replacement: An Assessment of Early Function. AB - BACKGROUND: Total knee replacements are increasingly being carried out for the arthritic knee. This procedure is constantly being improved upon in order to improve outcome. There is currently no consensus of the best surgical approach for primary total knee arthroplasty. This study aims to test the hypothesis that the subvastus approach has significantly better early functional outcomes compared to the medial parapatellar approach. STUDY DESIGN: Patients with bilateral knee arthritis who met the inclusion criteria were randomised into either the subvastus or medial parapatellar approach over a twelve month period. All patients had the same prosthesis inserted by one surgeon. Primary outcome measures were the Knee Society Score (KSS) at six (6) weeks post-operatively and evaluation of postoperative pain using the Visual Analogue Score (VAS) on the 2nd and 5th postoperative day. Secondary outcomes included blood loss and transfusion requirements. RESULTS: Twenty-four knees recruited with 11 knees in the subvastus and 13 in the medial parapatellar group. Results showed a significantly lower postoperative pain in the subvastus group versus the medial parapatellar group (2.8 versus 4.62 p < 0.05). Transfusion requirements for subvastus group was half that needed for the medial parapatellar group; this however was not statistically significant. Evaluation of knee score at six weeks did not show any difference in outcome (80.8 versus 84.27 p > 0.05). CONCLUSION: Post-operative pain is significantly reduced in the subvastus group, however short term knee function is not affected by surgical approach. PMID- 29607473 TI - Emergency Blood Transfusion in Children in a Tertiary Hospital in Nigeria: Indications, Frequency and Outcome. AB - BACKGROUND: Blood transfusion is a life-saving procedure in paediatric practice. It is important in replacing blood volume in cases of haemorrhage or providing specific blood components as required. However, the procedure carries some risks and complications. The decision to transfuse, frequency of transfusion and the availability of safe blood and blood products are essential determinants of the success of the procedure. Hence, knowledge of the indications and rate of transfusion is important to ensure that blood for transfusion is safe and made available as at when due. OBJECTIVE: To determine the common indications for blood transfusion, the frequency of transfusion and outcome of transfused patients. METHODS: Transfusion records of children admitted into the Children Emergency Room (CHER) of the University of Benin Teaching Hospital (UBTH), Benin City, Nigeria from January 2010 to December 2011 were retrieved. Information on the patients' biodata, indications for transfusion, type of blood product and outcome were documented. RESULTS: Within the 24 months under review, a total of 4133 patients were admitted, out of which 655 (15.8%) were transfused. The age of the children ranged between one month and 17 years (median and modal age was 2 years). Commonest indications for transfusion were severe malaria (55.4%), sepsis (11.5%) and sickle cell anaemia [SCA] (4.0%). Whole blood constituted the highest type of blood product utilized (99.7%). Of the 655 patients transfused, 226 (34.5%) had multiple transfusions. The frequency of blood transfusion was 1.2 transfusions per day. Ninety two percent (605) of the patients were discharged from CHER while nine (1.4%) discharged against medical advice. Mortality amongst them was 6.2% (41 patients). The ages of the patients (p = 0.56, C.I. = 0.99, 1.01) and the number of blood transfusions (p = 0.66, C.I.= 0.48, 1.60) were not significant predictors of mortality. CONCLUSION AND RECOMMENDATION: Majority of the patients were transfused following preventable disease conditions. Reduction of the burden of these conditions by good environmental hygiene, use of insecticide treated nets (ITN), indoor residual spraying (IRS), prompt hospital presentation and genetic counselling may greatly reduce the need for blood transfusion in the region. PMID- 29607474 TI - Health-Related Quality of Life of the Elderly in Institutional Care and Non Institutional Care in Southwestern Nigeria: A Comparative Study. AB - BACKGROUND: The world population is rapidly ageing and people aged 60 years and above are growing faster than any other age group. In Africa, the most rapid growth of older persons is expected in Western and Northern Africa. STUDY DESIGN: This was a comparative cross-sectional study of a total of 360 respondents. A multi-stage sampling method was used in selecting 240 respondents in the non institutional group while all the respondents (120) in the institutional group were included in the study. The data was collected using a pre-tested, semi structured, interviewer administered quality of life questionnaire (SF-36). Data analysis was done using SPSS version 17. RESULTS: The respondents in the institutional group were older with a mean age of 78.7+/-8.8 years as compared to 70.1+/-8.2 years in the non-institutional group. The mean Health-Related Quality of Life (HRQOL) score was higher (64.5+/-15.6) in the non-institutional group than in the institutional group (52.6+/-15.7) and this was statistically significant (p<0.001). After controlling for the effect of other variables, the respondents who belonged to the non-institutional group (OR=2.37, p=0.018); who were female (OR=2.00, p=0.019); engaged in work (OR=4.93, p=0.009) and had no co morbid condition (OR=7.58, p<0.001) were significantly more likely to have good HRQOL. CONCLUSION: The non-institutional group had better HRQOL than the institutional group in all the domains except in the body pain domain. It is recommended that programs are tailored to the needs of the elderly in institutions and should be targeted towards improving their quality of life and well-being. PMID- 29607475 TI - Idiopathic Cerebrospinal Fluid Rhinorrhoea (An Uncommon Diagnosis): A case report and a Review of the Literature. AB - Cerebrospinal fluid (CSF) rhinorrhoea is often seen among head injured patients from road traffic crashes or physical assault, and sometimes it is a complication of nasal surgical procedures. Intracranial tumours may also result in CSF leakage. Blood stained rhinorrhoea often occur at the time of initial insult or injury, while CSF rhinorrhea may be a delayed manifestation. However, idiopathic CSF rhinorrhoea is uncommon, and it is regarded as a diagnosis of exclusion. In this communication, we report a 54-year old woman who developed CSF rhinorrhoea with no prior history of head trauma, physical assault, neurosurgical or nasal surgery. Further clinical evaluation revealed an obese woman with a body mass index (BMI) of 31mg/m2, and a blood pressure (BP) of 140/80mmHg. Clinical tests for CSF rhinorrhoea were positive, though; nasal endoscopy and cranial CT-scan were not contributory. Conservative management resulted in remarkable relief of symptoms. However further investigations for confirmation of diagnosis were not possible due to non-availability of reagents in the laboratory as well as financial challenge. PMID- 29607476 TI - Epignathus (Palatal teratoma):A case report. AB - BACKGROUND: A case of a 2.7kg term baby with a large epignathus, a rare congenital teratoma arising from the palate is presented. Birth was by spontaneous vaginal delivery (SVD). The baby survived following a timely multidisciplinary approach to her management. This is the first reported case in Ghana. PMID- 29607477 TI - Terson Syndrome in a Patient with Idiopathic Thrombocytopenia. AB - BACKGROUND: The authors report a case of Terson syndrome in an adult with immune thrombocytopenia. Terson syndrome refers to an intraocular hemorrhage secondary to an intracranial hemorrhage or an acute rise in intracranial pressure. It is a rare but life-threatening complication and may be complicated with blindness in those who survive. PMID- 29607478 TI - A Rare Case of Rheumatic Heart Disease with Stenosis and Incompetence of Three Valves in a Nigerian Woman. AB - BACKGROUND: Though valve disease resulting from rheumatic heart disease is common, triple valve involvement is uncommon; with a bleak survival outlook Objective: To report a 38-year-old patient with both stenosis and incompetence of 3 valves, who lived till adulthood and went into heart failure after child-birth. No such report has come from Nigeria Methods: Case report of a Nigerian woman who lived with multiple valve disease up to adulthood when after delivery she developed hypertension and went into heart failure. Recurrent atrial fibrillation kept her in and out of heart failure. Three of her valves: mitral, aortic and tricuspid were both stenosed and incompetent. The consequent pulmonary hypertension and later development of arterial hypertension and atrial fibrillation worsened her morbidity till surgical intervention. CONCLUSION: Mixed triple valve disease of rheumatic origin tough rare, can occur; and is amenable to specialist surgical intervention. PMID- 29607479 TI - Percutaneous Endoscopic Gastrostomy in Ile-Ife, Nigeria:An Initial Report. AB - BACKGROUND: Protein-energy malnutrition is a common problem in critically ill patient and it is a major cause of accelerated morbidity and mortality in this group of patients. Recent dramatic advances in both enteral and parenteral nutritional support have ensured that most of these critically ill patients are adequately nutritionally supported. Unfortunately, most of these advancements in nutritional supports are far from the reach of most patients in developing countries. In this report, we highlighted the indications, success, challenges of the use of percutaneous endoscopic gastrostomy (PEG) in Nigeria patients. PATIENTS AND METHODS: All cases of PEG performed at the Endoscopy Unit of Obafemi Awolowo University Teaching Hospitals complex, Ile-Ife, Osun State from January 2011 and June 2012 were recruited into the study. The data obtained included the sociodemographic parameters, indication and duration of the procedure, complications, and follow up. RESULTS: During the 18 months study period 645 upper gastrointestinal endoscopic procedures were performed. Majority [601(93.2%)] of the cases were for diagnostic purposes. Six (0.9%) cases of PEG were performed. Most (5 of 6) of the patients had central nervous system impairment while only one had severe chronic facial infection with naso-oral fistula. The median age of patients was 60.5 years. The entire procedure including endoscopy lasted an average of 25 minutes with a range of 12-35 minutes. Only one case had peristoma infection which resolved with antibiotics and repeated dressing with povidone iodine. There was no episode of aspiration pneumonitis or procedure related mortality. The average follow up was 6 months with variable weight gain during the follow up period. CONCLUSION: PEG is a simple, cost effective and safe method to rehabilitate nutritionally all chronically ill patients in less developed countries such as Nigeria. The need to increase awareness and acceptability of PEG among physicians managing such patients and the society cannot be overemphasized. PMID- 29607480 TI - Prospective study in bullous pemphigoid: association of high serum anti-BP180 IgG levels with increased mortality and reduced Karnofsky score. AB - BACKGROUND: Bullous pemphigoid (BP) is a subepidermal blistering disease characterized by autoantibodies against the two hemidesmosomal proteins, BP180 (type XVII collagen) and BP230. The multicentre prospective BLISTER (Bullous Pemphigoid Steroids and Tetracyclines) trial randomized 253 patients with BP to compare the benefits and harms between initial treatment with doxycycline or prednisolone. OBJECTIVES: To analyse distinct autoantibody profiles for the prediction of the disease course in a well-characterized cohort of BP sera. METHODS: One hundred and forty-three patients of the BLISTER trial consented to participate in this serological study. Sera taken at baseline were analysed by (i) indirect immunofluorescence, (ii) anti-BP180 NC16A (16th noncollagenous domain) and anti-BP230 enzyme-linked immunosorbent assay and (iii) immunoblotting with various substrates. Results were then linked with clinical parameters including age, Karnofsky score, number of blisters, related adverse events and mortality. RESULTS: Disease activity correlated with immunoglobulin (Ig)G anti BP180 levels but not with levels of anti-BP230 IgG and anti-BP180 IgE. High levels of both anti-BP180 IgG and anti-BP230 IgG were associated with a low Karnofsky score. The presence of anti-BP230 IgG was more frequent in older patients. Those with higher total IgE serum levels suffered from fewer adverse events. Higher IgG anti-BP180 levels were associated with an increased 1-year mortality rate. CONCLUSIONS: Analysis of the autoantibody profile is not only of diagnostic relevance but may also be helpful in predicting the course of the disease. PMID- 29607481 TI - Ancient DNA reveals temporal population structure within the South-Central Andes area. AB - OBJECTIVES: The main aim of this work was to contribute to the knowledge of pre Hispanic genetic variation and population structure among the South-central Andes Area by studying individuals from Quebrada de Humahuaca, North-western (NW) Argentina. MATERIALS AND METHODS: We analyzed 15 autosomal STRs in 19 individuals from several archaeological sites in Quebrada de Humahuaca, belonging to the Regional Developments Period (900-1430 AD). Compiling autosomal, mitochondrial, and Y-chromosome data, we evaluated population structure and differentiation among eight South-central Andean groups from the current territories of NW Argentina and Peru. RESULTS: Autosomal data revealed a structuring of the analyzed populations into two clusters which seemed to represent different temporalities in the Andean pre-Hispanic history: pre-Inca and Inca. All pre-Inca samples fell into the same cluster despite being from the two different territories of NW Argentina and Peru. Also, they were systematically differentiated from the Peruvian Inca group. These results were mostly confirmed by mitochondrial and Y-chromosome analyses. We mainly found a clearly different haplotype composition between clusters. DISCUSSION: Population structure in South America has been mostly studied on current native groups, mainly showing a west to-east differentiation between the Andean and lowland regions. Here we demonstrated that genetic population differentiation preceded the European contact and might have been more complex than thought, being found within the South-central Andes Area. Moreover, divergence among temporally different populations might be reflecting socio-political changes occurred in the evermore complex pre-Hispanic Andean societies. PMID- 29607482 TI - Ecological niche modeling of the genus Papio. AB - OBJECTIVE: Ecological niche modeling (ENM) has been used to assess how abiotic variables influence species distributions and diversity. Baboons are broadly distributed throughout Africa, yet the degree of climatic specialization is largely unexplored for individual taxa. Also, the influence of climate on baboon phylogenetic divergence is unknown. In this study, we constructed ENMs to investigate how niches vary across Papio species to understand how climatic variables have influenced their biogeography and mode of speciation. MATERIALS AND METHODS: We used Maxent to generate ENMs by collating locality data for six Papio species and climate information from WorldClim. In addition, we examined the degree of niche overlap among all possible pairs of taxa, which can provide insight into patterns of species diversity. Lastly, we conducted a Mantel test to assess the relationship between niche overlap and estimated time since divergence. RESULTS: Our models performed moderately to extremely well, with a mean area under the curve value of 0.868. The species with the best models include P. papio and P. kindae, whereas P. hamadryas had the poorest models. We found that most species pairs exhibited significantly different niches. Lastly, we found no significant correlation between niche overlap and divergence times. DISCUSSION: Niche models had good predictive power, which indicates Papio species distributions are correlated with climatic variables to varying degrees. Significantly little niche overlap and incomplete geographic boundaries suggests these models generally support a parapatric speciation scenario for the genus Papio. PMID- 29607484 TI - The Emergence of Forgiveness in Young Children. AB - Humans depend greatly on our cooperative relationships. Thus, when our relationships are damaged by transgressions, they need to be repaired. Such repair requires that the transgressor show remorse and the victim forgive. Previous research demonstrates that as transgressors, young children show remorse and attempt to repair the harm they caused. However, it remains unclear when children, as victims, forgive remorseful transgressors. In Study 1, 5-, but not 4 year-olds, (n = 20 each) were more forgiving of a remorseful transgressor (who did not explicitly apologize) than an unremorseful transgressor. In Study 2, 4 year-olds (n = 20) were more forgiving of an apologetic than unapologetic transgressor. Thus, from early in ontogeny, humans are motivated to repair damaged relationships and thus uphold cooperation. PMID- 29607483 TI - The Tedeschi collection: A collection of documented and undocumented human skeletal remains at the Museum of Anthropology, Padua University (Italy). AB - OBJECTIVE: Documented and undocumented skeletal collections offer unique windows into life in the past and are integral for research in biological anthropology. The objective of this article is to describe the documented and undocumented collections curated by the Museum of Anthropology at Padua University (Italy) to demonstrate their potential for research and encourage researchers to consider them for future projects. MATERIALS: The collection was established by Prof. Enrico Tedeschi at the beginning of 20th century, and dates to the late 19th and early 20th century. The collection consists primarily of individuals excavated from cemeteries, ossarios, or unclaimed individuals donated by hospitals or other institutions. RESULTS: Both documented and undocumented human skeletal remains are included in the collection, totalling 1,580 individuals. Associated documented information including age at death, date of death, sex, occupation, and cause of death is available in different combinations for 293 individuals of varying completeness (188 crania only, 93 crania and postcranial, 12 postcranial only). Origin and chronological period are known for the remaining 1,287 individuals. DISCUSSION: Overall, this little studied collection could be particularly useful for researchers interested in craniometrics, dentition, and 19th and 20th century health and demography in Italy. The documented skeletons will be especially useful for forensic anthropological research. PMID- 29607485 TI - Early detection of differentiation syndrome by chest ultrasound in acute promyelocytic leukaemia. PMID- 29607486 TI - Flesh and bone digital sociality: On how humans may go virtual. AB - Research on virtual reality (VR) has gained momentum over the last fifteen years or so. In their review, Pan and Hamilton (2018, British Journal of Psychology) show how the different types of VR devices have the potential to probe fundamental psychological constructs, like those underlying social interactions. Expanding on their work, we propose a research agenda to increase the sense of co presence and make VR more real than reality through bodily illusions, multisensory stimulation, self-conscious emotions, and multisubject social cognition. PMID- 29607487 TI - Self-organization of human iPS cells into trophectoderm mimicking cysts induced by adhesion restriction using microstructured mesh scaffolds. AB - Cellular dynamics leading to the formation of the trophectoderm in humans remain poorly understood owing to limited accessibility to human embryos for research into early human embryogenesis. Compared to animal models, organoids formed by self-organization of stem cells in vitro may provide better insights into differentiation and complex morphogenetic processes occurring during early human embryogenesis. Here we demonstrate that modulating the cell culture microenvironment alone can trigger self-organization of human induced pluripotent stem cells (hiPSCs) to yield trophectoderm-mimicking cysts without chemical induction. To modulate the adhesion microenvironment, we used the mesh culture technique recently developed by our group, which involves culturing hiPSCs on suspended micro-structured meshes with limited surface area for cell adhesion. We show that this adhesion-restriction strategy can trigger a two-stage self organization of hiPSCs; first into stem cell sheets, which express pluripotency signatures until around day 8-10, then into spherical cysts following differentiation and self-organization of the sheet-forming cells. Detailed morphological analysis using immunofluorescence microscopy with both confocal and two-photon microscopes revealed the anatomy of the cysts as consisting of a squamous epithelial wall richly expressing E-cadherin and CDX2. We also confirmed that the cysts exhibit a polarized morphology with basal protrusions, which show migratory behavior when anchored. Together, our results point to the formation of cysts which morphologically resemble the trophectoderm at the late-stage blastocyst. Thus, the mesh culture microenvironment can initiate self organization of hiPSCs into trophectoderm-mimicking cysts as organoids with potential application in the study of early embryogenesis and also in drug development. PMID- 29607488 TI - Incidental findings in pre-orthodontic treatment radiographs. AB - OBJECTIVES: To determine the frequency, radiodensity characteristics, topographic location and number per patient of incidental findings observed in radiographs taken before orthodontic treatment and to evaluate the relationship of the findings with age and sex. METHODS: This was a cross-sectional study that investigated 1,887 panoramic and lateral cephalogram radiographs from 783 patients (23.31 +/- 13.11 years of age; 453 women and 330 men) who were randomly selected from the orthodontics department of a private university. The images were systematically evaluated by an oral pathologist. A chi-square test was applied to evaluate the association between sex and the presence of pathology, radiodensity characteristics and topographic location. The Mann-Whitney U and Kruskal-Wallis tests were used to establish the association between age or number of findings per patient with other variables in the study. RESULTS: The prevalence of incidental findings was 88.12%. The most frequent finding was maxillary sinus pneumatisation (25.80%). No significant association was detected between frequency or number of findings per patient and either sex or diagnostic hypothesis. A significant association was found between age and the presence of pathology and number of incidental findings per patient (P < 0.001), as well as between the type of radiographic image and incidental finding (P < 0.001). CONCLUSION: The prevalence of incidental findings in the sample studied was high, and the structures most commonly involved were the maxillary sinuses. The results suggest that both the presence and the number of findings per patient increase with age but there is no association with sex. PMID- 29607489 TI - Development of Multifaceted Risk Taking and the Relations to Sex Steroid Hormones: A Longitudinal Study. AB - Risk taking is a multidimensional construct. It is currently unclear which aspects of risk-taking change most during adolescence and if/how sex hormones contribute to risk-taking tendencies. This study applied a longitudinal design with three time-points, separated by 2 years, in participants aged 8-29 years (670 observations). The Balloon Analogue Risk Task, a delay discounting task, and various self-report questionnaires were administered, to measure aspects of risk taking. Longitudinal analyses demonstrated mostly nonlinear age-related patterns in risk-taking behavior and approach-related personality characteristics (peaking in late adolescence). Increased testosterone and estradiol were found to increase risk-taking behavior and impulsive personality, but decrease avoidance-like personality. This study demonstrates that risk taking is most pronounced in mid to-late adolescence and suggests that sex hormones accelerate this maturational process. PMID- 29607490 TI - Are careers in biological anthropology sustainable? PMID- 29607491 TI - Increased single-balloon Foley catheter volume for induction of labor and time to delivery: a systematic review and meta-analysis. AB - INTRODUCTION: Induction of labor is a common intervention. The objective was to investigate whether larger Foley catheter volumes for labor induction decrease the total time from induction to delivery. MATERIAL AND METHODS: Randomized controlled trials comparing larger single-balloon volumes (60-80 mL) during Foley catheter cervical ripening with usual volume (30 mL) in women undergoing labor induction were identified by searching electronic databases (MEDLINE, Scopus, ClinicalTrials.gov, PROSPERO, EMBASE, Scielo and the Cochrane Central Register of Controlled Trials) from inception through 2017. The primary outcome was mean time from induction to delivery in hours. Secondary outcomes included time from induction to vaginal delivery, delivery within 24 h, time to Foley expulsion, cesarean section, chorioamnionitis, epidural use, hemorrhage, meconium staining, and neonatal intensive care unit admission. Meta-analysis was performed using the random effects model of DerSimonian and Laird (PROSPERO CRD42017058885). RESULTS: Seven randomized controlled trials including 1432 singleton gestations were included in the systematic review. Women randomized to larger volumes of balloon had a significantly shorter time from induction to delivery (mean difference 1.97 h, 95% CI -3.88 to -0.06). There was no difference in cesarean section between groups (16 vs. 18%, relative risk 0.84, 95% CI 0.6-1.17). A larger balloon volume was associated with a nonsignificant decrease in time from induction to delivery in multiparous (mean difference 2.67 h, 95% CI -6.1 to 0.76) and nulliparous women (mean difference 1.82 h, 95% CI -4.16 to 0.53). CONCLUSION: Balloon volumes larger than 30 mL during Foley catheter induction reduce total time to delivery by approximately 2 h. PMID- 29607492 TI - Herbivory enhances the resistance of mangrove forest to cordgrass invasion. AB - The biotic resistance hypothesis proposes that biotic interactions, such as competition and herbivory, resist the establishment and spread of non-native species. The relative and interactive role of competition and herbivory in resisting plant invasions, however, remains poorly understood. We investigated the interactive role of competition and herbivory (by the native rodent Rattus losea) in resisting Spartina alterniflora (cordgrass) invasions into mangrove forests. In southern China, although exotic cordgrass numerically dominates intertidal mudflats and open gaps in mangrove forests, intact forests appear to be highly resistant to cordgrass invasion. A field transplant and rodent exclusion experiment showed that while the impact of rodent grazing on cordgrass was weak on mangrove forest edges and open mudflats, rodent grazing strongly suppressed cordgrass in mangrove understory habitats. A greenhouse experiment confirmed a synergistic interaction between grazing and light availability (a proxy for mangrove shading and light competition) in suppressing cordgrass establishment, with the strongest impacts of grazing in low light conditions that likely weakened cordgrass to survive and resprout. When both were present, as in mangrove understory habitats, grazing and low light acted in concert to eliminate cordgrass establishment, resulting in resistance of mangrove forests to cordgrass invasion. Our results reveal that grazing by native herbivores can enhance the resistance of mangrove forests to cordgrass invasion in southern China, and suggest that investigating multifactor interactions may be critical to understanding community resistance to exotic invasions. PMID- 29607494 TI - Inhaled anti-pseudomonal antibiotics for long-term therapy in cystic fibrosis. AB - BACKGROUND: Inhaled antibiotics are commonly used to treat persistent airway infection with Pseudomonas aeruginosa that contributes to lung damage in people with cystic fibrosis. Current guidelines recommend inhaled tobramycin for individuals with cystic fibrosis and persistent Pseudomonas aeruginosa infection who are aged six years or older. The aim is to reduce bacterial load in the lungs so as to reduce inflammation and deterioration of lung function. This is an update of a previously published review. OBJECTIVES: To evaluate the effects long term inhaled antibiotic therapy in people with cystic fibrosis on clinical outcomes (lung function, frequency of exacerbations and nutrition), quality of life and adverse events (including drug sensitivity reactions and survival). SEARCH METHODS: We searched the Cochrane Cystic Fibrosis Trials Register, compiled from electronic database searches and handsearching of journals and conference abstract books. We also searched ongoing trials registries.Date of last search: 13 February 2018. SELECTION CRITERIA: We selected trials if inhaled anti-pseudomonal antibiotic treatment was used for at least three months in people with cystic fibrosis, treatment allocation was randomised or quasi randomised, and there was a control group (either placebo, no placebo or another inhaled antibiotic). DATA COLLECTION AND ANALYSIS: Two authors independently selected trials, judged the risk of bias, extracted data from these trials and judged the quality of the evidence using the GRADE system. MAIN RESULTS: The searches identified 333 citations to 98 trials; 18 trials (3042 participants aged between five and 56 years) met the inclusion criteria. Limited data were available for meta-analyses due to the variability of trial design and reporting of results. A total of 11 trials (1130 participants) compared an inhaled antibiotic to placebo or usual treatment for a duration between three and 33 months. Five trials (1255 participants) compared different antibiotics, two trials (585 participants) compared different regimens of tobramycin and one trial (90 participants) compared intermittent tobramycin with continuous tobramycin alternating with aztreonam. One of the trials (18 participants) compared to placebo and a different antibiotic and so fell into both groups. The most commonly studied antibiotic was tobramycin which was studied in 12 trials.We found limited evidence that inhaled antibiotics improved lung function (four of the 11 placebo-controlled trials, n = 814). Compared to placebo, inhaled antibiotics also reduced the frequency of exacerbations (three trials, n = 946), risk ratio 0.66 (95% confidence interval (CI) 0.47 to 0.93). There were insufficient data for us to be able to report an effect on nutritional outcomes or survival and there were insufficient data for us to ascertain the effect on quality of life. There was no significant effect on antibiotic resistance seen in the two trials that were included in meta-analyses. Tinnitus and voice alteration were the only adverse events significantly more common in the inhaled antibiotics group. The overall quality of evidence was deemed to be low for most outcomes due to risk of bias within the trials and imprecision due to low event rates.Of the eight trials that compared different inhaled antibiotics or different antibiotic regimens, there was only one trial in each comparison. Forced expiratory volume at one second (FEV1) % predicted was only found to be significantly improved with aztreonam lysine for inhalation compared to tobramycin (n = 273), mean difference -3.40% (95% CI -6.63 to -0.17). However, the method of defining the endpoint was different to the remaining trials and the participants were exposed to tobramycin for a long period making interpretation of the results problematic. No significant differences were found in the remaining comparisons with regard to lung function. Pulmonary exacerbations were measured in different ways, but one trial (n = 273) found that the number of people treated with antibiotics was lower in those receiving aztreonam than tobramycin, risk ratio 0.66 (95% CI 0.51 to 0.86). We found the quality of evidence for these comparisons to be directly related to the risk of bias within the individual trials and varied from low to high. AUTHORS' CONCLUSIONS: Inhaled anti-pseudomonal antibiotic treatment probably improves lung function and reduces exacerbation rate, but pooled estimates of the level of benefit were very limited. The best evidence is for inhaled tobramycin. More evidence from trials measuring similar outcomes in the same way is needed to determine a better measure of benefit. Longer-term trials are needed to look at the effect of inhaled antibiotics on quality of life, survival and nutritional outcomes. PMID- 29607493 TI - Tobacco smoking and alcohol drinking at diagnosis of head and neck cancer and all cause mortality: Results from head and neck 5000, a prospective observational cohort of people with head and neck cancer. AB - Tobacco smoking and alcohol consumption are well-established risk factors for head and neck cancer. The prognostic role of smoking and alcohol intake at diagnosis have been less well studied. We analysed 1,393 people prospectively enrolled into the Head and Neck 5000 study (oral cavity cancer, n=403; oropharyngeal cancer, n=660; laryngeal cancer, n=330) and followed up for a median of 3.5 years. The primary outcome was all-cause mortality. We used Cox proportional hazard models to derive minimally adjusted (age and gender) and fully adjusted (age, gender, ethnicity, stage, comorbidity, body mass index, HPV status, treatment, education, deprivation index, income, marital status, and either smoking or alcohol use) mortality hazard ratios (HR) for the effects of smoking status and alcohol intake at diagnosis. Models were stratified by cancer site, stage and HPV status. The fully-adjusted HR for current versus never smokers was 1.7 overall (95% confidence interval [CI] 1.1, 2.6). In stratified analyses, associations of smoking with mortality were observed for oropharyngeal and laryngeal cancers (fully adjusted HRs for current smokers: 1.8 (95% CI=0.9, 3.40 and 2.3 (95% CI=0.8, 6.4)). We found no evidence that people who drank hazardous to harmful amounts of alcohol at diagnosis had a higher mortality risk compared to non-drinkers (HR=1.2 (95% CI=0.9, 1.6)). There was no strong evidence that HPV status or tumour stage modified the association of smoking with survival. Smoking status at the time of a head and neck cancer diagnosis influenced all-cause mortality in models adjusted for important prognostic factors. PMID- 29607495 TI - Acupuncture for acute stroke. AB - BACKGROUND: Sensory stimulation via acupuncture has been reported to alter activities of numerous neural systems by activating multiple efferent pathways. Acupuncture, one of the main physical therapies in Traditional Chinese Medicine, has been widely used to treat patients with stroke for over hundreds of years. This is the first update of the Cochrane Review originally published in 2005. OBJECTIVES: To assess whether acupuncture could reduce the proportion of people with death or dependency, while improving quality of life, after acute ischemic or hemorrhagic stroke. SEARCH METHODS: We searched the Cochrane Stroke Group trials register (last searched on February 2, 2017), the Cochrane Central Register of Controlled Trials Ovid (CENTRAL Ovid; 2017, Issue 2) in the Cochrane Library, MEDLINE Ovid (1946 to February 2017), Embase Ovid (1974 to February 2017), the Cumulative Index to Nursing and Allied Health Literature (CINAHL) EBSCO (1982 to February 2017), the Allied and Complementary Medicine Database (AMED; 1985 to February 2017), China Academic Journal Network Publishing Database (1998 to February 2017), and the VIP database (VIP Chinese Science Journal Evaluation Reports; 1989 to February 2017). We also identified relevant trials in the Chinese Clinical Trial Registry (last searched on Feburuary 20, 2017), the World Health Organization (WHO) International Clinical Trials Registry Platform (last searched on April 30, 2017), and Clinicaltrials.gov (last searched on April 30, 2017). In addition, we handsearched the reference lists of systematic reviews and relevant clinical trials. SELECTION CRITERIA: We sought randomized clinical trials (RCTs) of acupuncture started within 30 days from stroke onset compared with placebo or sham acupuncture or open control (no placebo) in people with acute ischemic or hemorrhagic stroke, or both. Needling into the skin was required for acupuncture. Comparisons were made versus (1) all controls (open control or sham acupuncture), and (2) sham acupuncture controls. DATA COLLECTION AND ANALYSIS: Two review authors applied the inclusion criteria, assessed trial quality and risk of bias, and extracted data independently. We contacted study authors to ask for missing data. We assessed the quality of the evidence by using the GRADE approach. We defined the primary outcome as death or dependency at the end of follow-up . MAIN RESULTS: We included in this updated review 33 RCTs with 3946 participants. Twenty new trials with 2780 participants had been completed since the previous review. Outcome data were available for up to 22 trials (2865 participants) that compared acupuncture with any control (open control or sham acupuncture) but for only six trials (668 participants) that compared acupuncture with sham acupuncture control. We downgraded the evidence to low or very low quality because of risk of bias in included studies, inconsistency in the acupuncture intervention and outcome measures, and imprecision in effect estimates.When compared with any control (11 trials with 1582 participants), findings of lower odds of death or dependency at the end of follow-up and over the long term (>= three months) in the acupuncture group were uncertain (odds ratio [OR] 0.61, 95% confidence interval [CI] 0.46 to 0.79; very low-quality evidence; and OR 0.67, 95% CI 0.53 to 0.85; eight trials with 1436 participants; very low-quality evidence, respectively) and were not confirmed by trials comparing acupuncture with sham acupuncture (OR 0.71, 95% CI 0.43 to 1.18; low quality evidence; and OR 0.67, 95% CI 0.40 to 1.12; low-quality evidence, respectively).In trials comparing acupuncture with any control, findings that acupuncture was associated with increases in the global neurological deficit score and in the motor function score were uncertain (standardized mean difference [SMD] 0.84, 95% CI 0.36 to 1.32; 12 trials with 1086 participants; very low-quality evidence; and SMD 1.08, 95% CI 0.45 to 1.71; 11 trials with 895 participants; very low-quality evidence). These findings were not confirmed in trials comparing acupuncture with sham acupuncture (SMD 0.01, 95% CI -0.55 to 0.57; low-quality evidence; and SMD 0.10, 95% CI -0.38 to 0.17; low-quality evidence, respectively).Trials comparing acupuncture with any control have reported little or no difference in death or institutional care at the end of follow-up (OR 0.78, 95% CI 0.54 to 1.12; five trials with 1120 participants; low quality evidence), death within the first two weeks (OR 0.91, 95% CI 0.33 to 2.55; 18 trials with 1612 participants; low-quality evidence), or death at the end of follow-up (OR 1.08, 95% CI 0.74 to 1.58; 22 trials with 2865 participants; low-quality evidence).The incidence of adverse events (eg, pain, dizziness, faint) in the acupuncture arms of open and sham control trials was 6.2% (64/1037 participants), and 1.4% of these (14/1037 participants) discontinued acupuncture. When acupuncture was compared with sham acupuncture, findings for adverse events were uncertain (OR 0.58, 95% CI 0.29 to 1.16; five trials with 576 participants; low-quality evidence). AUTHORS' CONCLUSIONS: This updated review indicates that apparently improved outcomes with acupuncture in acute stroke are confounded by the risk of bias related to use of open controls. Adverse events related to acupuncture were reported to be minor and usually did not result in stopping treatment. Future studies are needed to confirm or refute any effects of acupuncture in acute stroke. Trials should clearly report the method of randomization, concealment of allocation, and whether blinding of participants, personnel, and outcome assessors was achieved, while paying close attention to the effects of acupuncture on long-term functional outcomes. PMID- 29607496 TI - Enteral nutritional therapy for induction of remission in Crohn's disease. AB - BACKGROUND: Corticosteroids are often preferred over enteral nutrition (EN) as induction therapy for Crohn's disease (CD). Prior meta-analyses suggest that corticosteroids are superior to EN for induction of remission in CD. Treatment failures in EN trials are often due to poor compliance, with dropouts frequently due to poor acceptance of a nasogastric tube and unpalatable formulations. This systematic review is an update of a previously published Cochrane review. OBJECTIVES: To evaluate the effectiveness and safety of exclusive EN as primary therapy to induce remission in CD and to examine the importance of formula composition on effectiveness. SEARCH METHODS: We searched MEDLINE, Embase and CENTRAL from inception to 5 July 2017. We also searched references of retrieved articles and conference abstracts. SELECTION CRITERIA: Randomized controlled trials involving patients with active CD were considered for inclusion. Studies comparing one type of EN to another type of EN or conventional corticosteroids were selected for review. DATA COLLECTION AND ANALYSIS: Data were extracted independently by at least two authors. The primary outcome was clinical remission. Secondary outcomes included adverse events, serious adverse events and withdrawal due to adverse events. For dichotomous outcomes, we calculated the risk ratio (RR) and 95% confidence interval (CI). A random-effects model was used to pool data. We performed intention-to-treat and per-protocol analyses for the primary outcome. Heterogeneity was explored using the Chi2 and I2 statistics. The studies were separated into two comparisons: one EN formulation compared to another EN formulation and EN compared to corticosteroids. Subgroup analyses were based on formula composition and age. Sensitivity analyses included abstract publications and poor quality studies. We used the Cochrane risk of bias tool to assess study quality. We used the GRADE criteria to assess the overall quality of the evidence supporting the primary outcome and selected secondary outcomes. MAIN RESULTS: Twenty-seven studies (1,011 participants) were included. Three studies were rated as low risk of bias. Seven studies were rated as high risk of bias and 17 were rated as unclear risk of bias due to insufficient information. Seventeen trials compared different formulations of EN, 13 studies compared one or more elemental formulas to a non-elemental formula, three studies compared EN diets of similar protein composition but different fat composition, and one study compared non-elemental diets differing in glutamine enrichment. Meta-analysis of 11 trials (378 participants) demonstrated no difference in remission rates. Sixty-four per cent (134/210) of patients in the elemental group achieved remission compared to 62% (105/168) of patients in the non-elemental group (RR 1.02, 95% CI 0.88 to 1.18; GRADE very low quality). A per-protocol analysis (346 participants) produced similar results (RR 1.04, 95% CI 0.91 to 1.18). Subgroup analyses performed to evaluate the different types of elemental and non-elemental diets (elemental, semi-elemental and polymeric) showed no differences in remission rates. An analysis of 7 trials including 209 patients treated with EN formulas of differing fat content (low fat: < 20 g/1000 kCal versus high fat: > 20 g/1000 kCal) demonstrated no difference in remission rates (RR 1.03; 95% CI 0.85 to 1.26). Very low fat content (< 3 g/1000 kCal) and very low long chain triglycerides demonstrated higher remission rates than higher content EN formulas. There was no difference between elemental and non-elemental diets in adverse event rates (RR 1.00, 95% CI 0.63 to 1.60; GRADE very low quality), or withdrawals due to adverse events (RR 1.29, 95% CI 0.80 to 2.09; GRADE very low quality). Common adverse events included nausea, vomiting, diarrhea and bloating.Ten trials compared EN to steroid therapy. Meta-analysis of eight trials (223 participants) demonstrated no difference in remission rates between EN and steroids. Fifty per cent (111/223) of patients in the EN group achieved remission compared to 72% (133/186) of patients in the steroid group (RR 0.77, 95% CI 0.58 to 1.03; GRADE very low quality). Subgroup analysis by age showed a difference in remission rates for adults but not for children. In adults 45% (87/194) of EN patients achieved remission compared to 73% (116/158) of steroid patients (RR 0.65, 95% CI 0.52 to 0.82; GRADE very low quality). In children, 83% (24/29) of EN patients achieved remission compared to 61% (17/28) of steroid patients (RR 1.35, 95% CI 0.92 to 1.97; GRADE very low quality). A per-protocol analysis produced similar results (RR 0.93, 95% CI 0.75 to 1.14). The per-protocol subgroup analysis showed a difference in remission rates for both adults (RR 0.82, 95% CI 0.70 to 0.95) and children (RR 1.43, 95% CI 1.03 to 1.97). There was no difference in adverse event rates (RR 1.39, 95% CI 0.62 to 3.11; GRADE very low quality). However, patients on EN were more likely to withdraw due to adverse events than those on steroid therapy (RR 2.95, 95% CI 1.02 to 8.48; GRADE very low quality). Common adverse events reported in the EN group included heartburn, flatulence, diarrhea and vomiting, and for steroid therapy acne, moon facies, hyperglycemia, muscle weakness and hypoglycemia. The most common reason for withdrawal was inability to tolerate the EN diet. AUTHORS' CONCLUSIONS: Very low quality evidence suggests that corticosteroid therapy may be more effective than EN for induction of clinical remission in adults with active CD. Very low quality evidence also suggests that EN may be more effective than steroids for induction of remission in children with active CD. Protein composition does not appear to influence the effectiveness of EN for the treatment of active CD. EN should be considered in pediatric CD patients or in adult patients who can comply with nasogastric tube feeding or perceive the formulations to be palatable, or when steroid side effects are not tolerated or better avoided. Further research is required to confirm the superiority of corticosteroids over EN in adults. Further research is required to confirm the benefit of EN in children. More effort from industry should be taken to develop palatable polymeric formulations that can be delivered without use of a nasogastric tube as this may lead to increased patient adherence with this therapy. PMID- 29607497 TI - Low dose naltrexone for induction of remission in Crohn's disease. AB - BACKGROUND: Crohn's disease is a transmural, relapsing inflammatory condition afflicting the digestive tract. Opioid signalling, long known to affect secretion and motility in the gut, has been implicated in the inflammatory cascade of Crohn's disease. Low dose naltrexone, an opioid antagonist, has garnered interest as a potential therapy. OBJECTIVES: The primary objective was to evaluate the efficacy and safety of low dose naltrexone for induction of remission in Crohn's disease. SEARCH METHODS: A systematic search of MEDLINE, Embase, PubMed, CENTRAL, and the Cochrane IBD Group Specialized Register was performed from inception to 15 January 2018 to identify relevant studies. Abstracts from major gastroenterology conferences including Digestive Disease Week and United European Gastroenterology Week and reference lists from retrieved articles were also screened. SELECTION CRITERIA: Randomized controlled trials of low dose naltrexone (LDN) for treatment of active Crohn's disease were included. DATA COLLECTION AND ANALYSIS: Data were analyzed on an intention-to-treat basis using Review Manager (RevMan 5.3.5). The primary outcome was induction of clinical remission defined by a Crohn's disease activity index (CDAI) of < 150 or a pediatric Crohn's disease activity index (PCDAI) of < 10. Secondary outcomes included clinical response (70- or 100-point decrease in CDAI from baseline), endoscopic remission or response, quality of life, and adverse events as defined by the included studies. Risk ratios (RR) and 95% confidence intervals (CI) were calculated for dichotomous outcomes. The methodological quality of included studies was evaluated using the Cochrane risk of bias tool. The overall quality of the evidence supporting the primary outcome and selected secondary outcomes was assessed using the GRADE criteria. MAIN RESULTS: Two studies were identified (46 participants). One study assessed the efficacy and safety of 12 weeks of LDN (4.5 mg/day) treatment compared to placebo in adult patients (N = 34). The other study assessed eight weeks of LDN (0.1 mg/kg, maximum 4.5 mg/day) treatment compared to placebo in pediatric patients (N = 12). The primary purpose of the pediatric study was to assess safety and tolerability. Both studies were rated as having a low risk of bias. The study in adult patients reported that 30% (5/18) of LDN treated patients achieved clinical remission at 12 weeks compared to 18% (3/16) of placebo patients, a difference that was not statistically significant (RR 1.48, 95% CI 0.42 to 5.24). The study in children reported that 25% of LDN treated patients achieved clinical remission (PCDAI < 10) compared to none of the patients in the placebo group, although it was unclear if this result was for the randomized placebo-controlled trial or for the open label extension study. In the adult study 70-point clinical response rates were significantly higher in those treated with LDN than placebo. Eighty-three per cent (15/18) of LDN patients had a 70-point clinical response at week 12 compared to 38% (6/16) of placebo patients (RR 2.22, 95% CI 1.14 to 4.32). The effect of LDN on the proportion of adult patients who achieved a 100-point clinical response was uncertain. Sixty one per cent (11/18) of LDN patients achieved a 100-point clinical response compared to 31% (5/16) of placebo patients (RR 1.96, 95% CI 0.87 to 4.42). The proportion of patients who achieved endoscopic response (CDEIS decline > 5 from baseline) was significantly higher in the LDN group compared to placebo. Seventy two per cent (13/18) of LDN patients achieved an endoscopic response compared to 25% (4/16) of placebo patients (RR 2.89; 95% CI 1.18 to 7.08). However, there was no statistically significant difference in the proportion of patients who achieved endoscopic remission. Endoscopic remission (CDEIS < 3) was achieved in 22% (4/18) of the LDN group compared to 0% (0/16) of the placebo group (RR 8.05; 95% CI 0.47 to 138.87). Pooled data from both studies show no statistically significant differences in withdrawals due to adverse events or specific adverse events including sleep disturbance, unusual dreams, headache, decreased appetite, nausea and fatigue. No serious adverse events were reported in either study. GRADE analyses rated the overall quality of the evidence for the primary and secondary outcomes (i.e. clinical remission, clinical response, endoscopic response, and adverse events) as low due to serious imprecision (sparse data). AUTHORS' CONCLUSIONS: Currently, there is insufficient evidence to allow any firm conclusions regarding the efficacy and safety of LDN used to treat patients with active Crohn's disease. Data from one small study suggests that LDN may provide a benefit in terms of clinical and endoscopic response in adult patients with active Crohn's disease. Data from two small studies suggest that LDN does not increase the rate of specific adverse events relative to placebo. However, these results need to be interpreted with caution as they are based on very small numbers of patients and the overall quality of the evidence was rated as low due to serious imprecision. Further randomized controlled trials are required to assess the efficacy and safety of LDN therapy in active Crohn's disease in both adults and children. PMID- 29607498 TI - 1-L-MT, an IDO inhibitor, prevented colitis-associated cancer by inducing CDC20 inhibition-mediated mitotic death of colon cancer cells. AB - Indoleamine 2,3-dioxygenase 1 (IDO1), known as IDO, catabolizes tryptophan through kynurenine pathway, whose activity is correlated with impaired clinical outcome of colorectal cancer. Here we showed that 1-L-MT, a canonical IDO inhibitor, suppressed proliferation of human colorectal cancer cells through inducing mitotic death. Our results showed that inhibition of IDO decreased the transcription of CDC20, which resulted in G2/M cycle arrest of HCT-116 and HT-29. Furthermore, 1-L-MT induced mitochondria injuries and caused apoptotic cancer cells. Importantly, 1-L-MT protected mice from azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon carcinogenesis, with reduced mortality, tumor number and size. What is more, IDO1-/- mice exhibited fewer tumor burdens and reduced proliferation in the neoplastic epithelium, while, 1-L-MT did not exhibit any further protective effects on IDO-/- mice, confirming the critical role of IDO and the protective effect of 1-L-MT-mediated IDO inhibition in CRC. Furthermore, 1-L-MT also alleviated CRC in Rag1-/- mice, demonstrating the modulatory effects of IDO independent of its role in modulating adaptive immunity. Taken together, our findings validated that the anti-proliferation effect of 1-L-MT in vitro and the prevention of CRC in vivo were through IDO-induced cell cycle disaster of colon cancer cells. Our results identified 1-L-MT as a promising candidate for the chemoprevention of CRC. PMID- 29607499 TI - Assessing opportunities and challenges for establishing a national program to distribute cord blood for research. AB - BACKGROUND: Research is needed to enhance cord blood (CB) transplantation outcomes and to develop new clinical applications. Based on quality criteria for transplantation, CB collected by public CB banks (CBBs) is often unsuitable for banking, but may still be valuable for research. Canadian researchers have described a need for a centralized program providing ethically sourced CB for research projects. To meet this need, Canadian Blood Services (CBS), in partnership with The Ottawa Hospital, launched the Cord Blood for Research Program (CBRP) in 2014. STUDY DESIGN AND METHODS: The CBRP developed processes for donor research consent and research project approval with oversight from CBS's CBB and appropriate research ethics boards. The CBRP distributes deidentified CB products to research projects across Canada. RESULTS: Since its inception, the CBRP has distributed more than 525 CB units to researchers, supporting 11 research projects. Of the mothers who donate their baby's CB, 77% have chosen to consent to its use for research if it is not bankable. The number of CB units currently available for research via the CBRP exceeds the requests from researchers. CONCLUSION: The CBRP reliably distributes quality CB products that do not qualify for banking to investigators across Canada in an ethical, legal, and transparent manner. This provides an opportunity for the public to directly support research, helps meet the need expressed by Canada's research community, and maximizes the donor's gift. More research is needed to clarify the factors influencing donor and researcher participation in the CBRP. PMID- 29607500 TI - Discrimination of nitrogen fertilizer levels of tea plant (Camellia sinensis) based on hyperspectral imaging. AB - BACKGROUND: Nitrogen (N) fertilizer plays an important role in tea plantation management, with significant impacts on the photosynthetic capacity, productivity and nutrition status of tea plants. The present study aimed to establish a method for the discrimination of N fertilizer levels using hyperspectral imaging technique. RESULTS: Spectral data were extracted from the region of interest, followed by the first derivative to reduce background noise. Five optimal wavelengths were selected by principal component analysis. Texture features were extracted from the images at optimal wavelengths by gray-level gradient co occurrence matrix. Support vector machine (SVM) and extreme learning machine were used to build classification models based on spectral data, optimal wavelengths, texture features and data fusion, respectively. The SVM model using fused data gave the best performance with highest correct classification rate of 100% for prediction set. CONCLUSION: The overall results indicated that visible and near infrared hyperspectral imaging combined with SVM were effective in discriminating N fertilizer levels of tea plants. (c) 2018 Society of Chemical Industry. PMID- 29607501 TI - Biocrust-forming mosses mitigate the impact of aridity on soil microbial communities in drylands: observational evidence from three continents. AB - Recent research indicates that increased aridity linked to climate change will reduce the diversity of soil microbial communities and shift their community composition in drylands, Earth's largest biome. However, we lack both a theoretical framework and solid empirical evidence of how important biotic components from drylands, such as biocrust-forming mosses, will regulate the responses of microbial communities to expected increases in aridity with climate change. Here we report results from a cross-continental (North America, Europe and Australia) survey of 39 locations from arid to humid ecosystems, where we evaluated how biocrust-forming mosses regulate the relationship between aridity and the community composition and diversity of soil bacteria and fungi in dryland ecosystems. Increasing aridity was negatively related to the richness of fungi, and either positively or negatively related to the relative abundance of selected microbial phyla, when biocrust-forming mosses were absent. Conversely, we found an overall lack of relationship between aridity and the relative abundance and richness of microbial communities under biocrust-forming mosses. Our results suggest that biocrust-forming mosses mitigate the impact of aridity on the community composition of globally distributed microbial taxa, and the diversity of fungi. They emphasize the importance of maintaining biocrusts as a sanctuary for soil microbes in drylands. PMID- 29607502 TI - Amotosalen/UVA treatment inactivates T cells more effectively than the recommended gamma dose for prevention of transfusion-associated graft-versus-host disease. AB - INTRODUCTION: Transfusion-associated graft-versus-host disease (TA-GVHD) is a rare complication after transfusion of components containing viable donor T cells. Gamma irradiation with doses that stop T-cell proliferation is the predominant method to prevent TA-GVHD. Treatment with pathogen inactivation methodologies has been found to also be effective against proliferating white blood cells, including T cells. In this study, T-cell inactivation was compared, between amotosalen/ultraviolet A (UVA) treatment and gamma-irradiation (2500 cGy), using a sensitive limiting dilution assay (LDA) with an enhanced dynamic range. METHODS AND MATERIALS: Matched plasma units (N = 8), contaminated with 1 * 106 peripheral blood mononuclear cells (PBMCs) per mL, were either treated with amotosalen/UVA or gamma irradiation, or retained as untreated control. Posttreatment, cells were cultured under standardized conditions. T-cell proliferation was determined by the incorporation of 3 H-thymidine and correlated with microscopic detection. RESULTS: Range-finding experiments showed that after gamma irradiation (2500 cGy), significant T-cell proliferation could be observed at a 1 * 107 cell culture density, some proliferation at 1 * 106 , and none at 1 * 105 cells/well. Based on these facts, a quantitative comparison was carried out between amotosalen/UVA at the highest challenge of 1 * 107 PBMCs/well, and gamma irradiation at 1 * 106 and 1 * 105 PBMCs/well. Complete inactivation of the T cells after amotosalen/UVA treatment was observed, equivalent to greater than 6.2 log inactivation. Complete inactivation of the T cells was also observed after gamma irradiation when 1 * 105 PBMCs/well were cultured (>4.2 log inactivation). Proliferation was observed when 1 * 106 PBMCs/well were cultured (<=5.2 log inactivation) after gamma irradiation. CONCLUSION: Amotosalen/UVA treatment more effectively inactivates T cells than the current standard of gamma irradiation (2500 cGy) for the prevention of TA-GVHD. PMID- 29607503 TI - Ectopic expression of the Coffea canephora SERK1 homolog-induced differential transcription of genes involved in auxin metabolism and in the developmental control of embryogenesis. AB - Somatic embryogenesis receptor-like kinase 1 (SERK1) is a membrane receptor that might serve as common co-regulator of plant cell differentiation processes by forming heterodimers with specific receptor-like kinases. The Coffea canephora SERK1 homolog (CcSERK1) was cloned in this work, and its early function in the transcription of embryogenesis master genes and of genes encoding proteins involved in auxin metabolism was investigated by externally manipulating its expression in embryogenic leaf explants, before the appearance of embryogenic structures. Overexpression of CcSERK1 early during embryogenesis caused an increase in the number of somatic embryos when the 55-day process was completed. Suppression of CcSERK1 expression by RNA interference almost abolished somatic embryogenesis. Real time-PCR experiments revealed that the transcription of the CcAGL15, CcWUS, CcBBM, CcPKL, CcYUC1, CcPIN1 and CcPIN4 homologs was modified in direct proportion to the expression of CcSERK1 and that only CcLEC1 was inversely affected by the expression levels of CcSERK1. The expression of the CcYUC4 homolog was induced to more than 80-fold under CcSERK1 overexpression conditions, but it was also induced when CcSERK1 expression was silenced. The level of CcTIR1 was not affected by CcSERK1 overexpression but was almost abolished during CcSERK1 silencing. These results suggest that CcSERK1 co-regulates the induction of somatic embryogenesis in Coffea canephora by early activation of YUC-dependent auxin biosynthesis, auxin transport mediated by PIN1 and PIN4, and probably auxin perception by the TIR1 receptor, leading to the induction of early-stage homeotic genes (CcAGL15, CcWUS, CcPKL and CcBBM) and repression of late-stage homeotic genes (CcLec1). PMID- 29607504 TI - Specific barrier response profiles after experimentally induced skin irritation in vivo. AB - BACKGROUND: Recently, natural moisturizing factors (NMFs) and corneocyte surface topography were suggested as biomarkers for irritant dermatitis. OBJECTIVES: To investigate how exposure to different irritants influences corneocyte surface topography, NMF levels and the barrier function of human skin in vivo. METHODS: Eight healthy adult volunteers were exposed to aqueous solutions of 60% n propanol, 0.5% sodium lauryl sulfate (SLS), 0.15% sodium hydroxide, and 2.0% acetic acid, and distilled water, in a repeated irritation test over a period of 96 hours. Erythema, transepidermal water loss (TEWL), skin hydration, the dermal texture index (DTI) and NMF levels were measured at baseline, and after 24 and 96 hours. RESULTS: SLS and sodium hydroxide had the most pronounced effects on erythema and TEWL. Although n-propanol caused only slight changes in TEWL and erythema, it showed pronounced effects on skin hydration, NMF levels, and the DTI. NMF was the only parameter that was significantly altered by all investigated irritants. The changes in the DTI were inversely associated with NMF levels and skin hydration. CONCLUSION: Skin barrier impairment and the inflammatory response are irritant-specific, emphasizing the need for a multiparametric approach to the study of skin irritation. NMF levels seem to be the most sensitive parameter in detecting irritant-induced skin barrier alterations. PMID- 29607505 TI - Brain-heart interaction in perseverative cognition. AB - The move from the concept of homeostasis to that of allostasis has led reactivity stress research to widen the object of its investigation: from the brief physiological response that occurs when one is facing a stressor to what happens when one is anticipating or recovering from a stressor. A paradigmatic example is represented by perseverative cognition, during which human beings react "as if" they were constantly facing a concrete stressor. The core idea behind this review is that the cognitive inflexibility that characterizes perseverative cognition is reflected in both our body (by increased autonomic nervous system rigidity assessed by heart rate variability; HRV) and our brain (by reduced prefrontal amygdala functional connectivity). This is a review of studies conducted in different settings (laboratory, daily life), populations (healthy, major depression, generalized anxiety), location (United States, Europe), and age groups (children, adults) that consistently replicated the association between autonomic, subjective, and behavioral measures of cognitive inflexibility during perseverative cognition. Moreover, compelling neuroimaging data suggest that HRV reduction from pre- to post-induction of perseverative cognition is associated with both structural and functional brain abnormalities reflecting impaired prefrontal inhibitory control over subcortical structures (e.g., diminished prefrontal-amygdala functional connectivity). The integration of neuroscience techniques with clinical autonomic research has advanced our understanding of the neurobiology of brain-heart interaction during perseverative cognition, potentially yielding to more effective treatment packages. This is clinically relevant if one considers that perseverative cognition is a pervasive transdiagnostic factor that carries prognostic risk for both psychological and somatic health. PMID- 29607506 TI - Music-supported therapy in the rehabilitation of subacute stroke patients: a randomized controlled trial. AB - The effect of music-supported therapy (MST) as a tool to restore hemiparesis of the upper extremity after a stroke has not been appropriately contrasted with conventional therapy. The aim of this trial was to test the effectiveness of adding MST to a standard rehabilitation program in subacute stroke patients. A randomized controlled trial was conducted in which patients were randomized to MST or conventional therapy in addition to the rehabilitation program. The intensity and duration of the interventions were equated in both groups. Before and after 4 weeks of treatment, motor and cognitive functions, mood, and quality of life (QoL) of participants were evaluated. A follow-up at 3 months was conducted to examine the retention of motor gains. Both groups significantly improved their motor function, and no differences between groups were found. The only difference between groups was observed in the language domain for QoL. Importantly, an association was encountered between the capacity to experience pleasure from music activities and the motor improvement in the MST group. MST as an add-on treatment showed no superiority to conventional therapies for motor recovery. Importantly, patient's intrinsic motivation to engage in musical activities was associated with better motor improvement. PMID- 29607508 TI - Activation of autophagy in periodontal ligament mesenchymal stem cells promotes angiogenesis in periodontitis. AB - BACKGROUND: Angiogenesis alteration in tooth support tissue plays an essential role in periodontitis. Mesenchymal stem cells (MSCs) can affect vessel formation by endothelial cells (ECs) through paracrine function. Autophagy is reported to be closely related to cell secretion. Here we investigated the angiogenesis promoting ability of MSCs that reside in the periodontal ligament (known as periodontal ligament stem cells, PDLSCs) under inflammatory conditions in order to explore the mechanism of angiogenesis alteration in periodontitis. METHODS: PDLSCs were isolated from healthy and inflamed human periodontal ligament tissues (HPDLSCs and PPDLSCs, respectively). HPDLSCs were subjected to an inflammatory environment (IPDLSCs) in vitro using inflammatory cytokines. Angiogenesis promoting cytokine expression and autophagy were evaluated in PDLSCs by quantitative reverse transcription-polymerase chain reaction and western-blot analysis before co-culturing them with ECs. The angiogenesis ability of ECs in the co-culture system was examined by a matrigel tube formation test. Rapamycin and pcDNA for Beclin-1 (cDNA-Beclin-1) were used to promote autophagy in PDLSCs and siRNA Beclin-1 (siBeclin-1) was used to repress it. RESULTS: The inflammatory environment increased autophagy and the expression of basic fibroblast growth factor (bFGF) and angiogenin (Ang) in PDLSCs. More tube formation was observed in ECs from the co-culture system which was pretreated with tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta. PDLSCs treated with rapamycin or transfected with cDNA-Beclin-1 showed higher expression levels of bFGF and Ang that promoted tube formation by the co-cultured ECs. PDLSCs transfected with siBeclin-1 resulted in the opposite results. CONCLUSION: Autophagy modulates angiogenesis-promoting ability of PDLSCs, which could be increased by an inflammatory environment. PMID- 29607509 TI - Immunohistochemical differentiation of reactive from malignant mesothelium as a diagnostic aid in canine pericardial disease. AB - OBJECTIVES: To develop a provisional immunohistochemistry panel for distinguishing reactive pericardium, atypical mesothelial proliferation and mesothelioma in dogs. MATERIALS AND METHODS: Archived pericardial biopsies were subject to haematoxylin and eosin staining, immunohistochemistry for cytokeratin, vimentin, insulin-like growth factor II mRNA-binding protein 3, glucose transporter 1 and desmin. Samples were scored for intensity and number of cells stained. RESULTS: Ten biopsies of reactive mesothelium, 17 of atypical mesothelial proliferation, 26 of mesothelioma and five of normal pericardium were identified on the basis of haematoxylin and eosin staining. Cytokeratin and vimentin were expressed in all biopsies, confirming mesothelial origin. Normal pericardial samples had the lowest scores for insulin-like growth factor II mRNA binding protein 3, glucose transporter 1 and desmin. Mesothelioma and atypical proliferative samples were similar to each other, with higher scores for insulin like growth factor II mRNA-binding protein 3 and glucose transporter 1 than the reactive samples. Desmin staining was variable. Insulin-like growth factor II mRNA-binding protein 3 was the best to distinguish between disease groups. CLINICAL SIGNIFICANCE: An immunohistochemistry panel of cytokeratin, vimentin, insulin-like growth factor II mRNA-binding protein 3 and glucose transporter 1 could provide superior information compared with haematoxylin and eosin staining alone in the diagnosis of cases of mesothelial proliferation in canine pericardium, but further validation is warranted. PMID- 29607511 TI - Identification of a novel missense mutation (p.Ser230Asn) in RHD allele in a Chinese individual with partial D phenotype. PMID- 29607510 TI - Analgesic effect of S (+)-flurbiprofen plaster in a rat model of knee arthritis: analysis of gait and synovial fluid prostaglandin E2 levels. AB - OBJECTIVES: We developed S (+)-flurbiprofen plaster (SFPP), a novel NSAID patch containing S (+)-flurbiprofen (SFP), a potent cyclooxygenase (COX) inhibitor. The purpose of this study was to assess efficacy of SFPP by analysing its effect on the gait disturbance and measuring the prostaglandin E2 (PGE2 ) production in synovial fluid in a rat model of knee arthritis. METHODS: Knee inflammation was induced in rats by intra-articular injection of a yeast suspension. Subsequently, an NSAID patch containing SFP, ketoprofen or loxoprofen was applied over the affected knee. Gait was assessed at 2, 4 and 6 h after application of the patch. The PGE2 concentration in the synovial fluid was measured after the gait assessment. KEY FINDINGS: Application of SFPP (0.125, 0.25, 0.5 or 1 mg/sheet) was followed by a decrease in the visual gait score at all the doses examined. In the case of the other two NSAID patches, only the ketoprofen patch (1 or 2 mg/sheet) and loxoprofen patch (5 mg/sheet) produced a decrease in the visual gait score. All of the NSAID patches decreased the PGE2 production in the synovial fluid. CONCLUSIONS: These results suggest the potential usefulness of SFPP as an analgesic patch in patients with inflammatory joint pain. PMID- 29607512 TI - Presenteeism in a Dutch hand eczema population-a cross-sectional survey. AB - BACKGROUND: Presenteeism (attending work despite complaints and ill health, which should prompt rest and absence) has been overlooked in the field of hand eczema. OBJECTIVES: To examine the 1-year prevalence of presenteeism related to hand eczema in a population of hand eczema patients who visited a tertiary referral centre. Secondary objectives: to identify intrinsic/extrinsic reasons for presenteeism and to evaluate associated factors. METHODS: This was a cross sectional questionnaire study. Presenteeism was defined as "going to work despite feeling you should have taken sick leave because of hand eczema". Respondents answered questions about socio-demographic factors, clinical features, occupational characteristics, and hand eczema related to occupational exposure. RESULTS: Forty-one per cent (141/346) of patients who had both worked and had hand eczema during the past 12 months reported presenteeism. The most often reported reasons were: "Because I do not want to give in to my impairment/weakness" (46%) and "Because I enjoy my work" (40%). Presenteeism was associated with: mean hand eczema severity; absenteeism because of hand eczema; improvement of hand eczema when away from work; and high-risk occupations. CONCLUSIONS: In this study, presenteeism was common and predominantly observed in patients with more severe hand eczema and occupational exposure. The most frequently reported reasons for presenteeism were of an intrinsic nature. PMID- 29607513 TI - The secret sensitizer gets out of the bag. PMID- 29607514 TI - The novel use of pop-off satellite tags (PSATs) to investigate the migratory behaviour of European sea bass Dicentrarchus labrax. AB - A total of 12 adult European sea bass Dicentrarchus labrax were tagged with pop off satellite archival tags (PSAT) in Irish coastal waters and in offshore waters in the north-east Celtic Sea between 2015 and 2016. Archived data were successfully recovered from five of the 12 tags deployed, three from fish released in inshore Irish waters and two from fish released offshore in the eastern Celtic Sea. All three fish tagged in inshore waters were found to undertake migrations into the open ocean coinciding with the spawning period. These fish also exhibited fidelity to inshore sites post-migration, returning to the same general location (within c. 73 km, which is roughly the predicted mean accuracy of the method) of their original release site. Although the number of tracks obtained here was limited, some degree of aggregation between inshore and offshore tagged fish in the eastern Celtic Sea was noted during the expected spawning period suggesting PSATs can provide new information on specific spawning locations of European sea bass. PMID- 29607515 TI - Implementation of secondary bacterial culture testing of platelets to mitigate residual risk of septic transfusion reactions. AB - BACKGROUND: Bacterial contamination of platelets remains a major transfusion associated risk despite long-standing safety measures in the United States. We evaluated an approach using secondary bacterial culture (SBC) to contend with residual risk of bacterial contamination. STUDY DESIGN AND METHODS: Phased implementation of SBC was initiated in October 2016 for platelets (all apheresis collected) received at our institution from the blood donor center (Day 3 post collection). Platelet products were sampled aseptically (5 mL inoculated into an aerobic bottle [BacT/ALERT BPA, BioMerieux, Inc.]) by the blood bank staff upon receipt, using a sterile connection device and sampling kit. The platelet sample was inoculated into an aerobic blood culture bottle and incubated at 35 degrees C for 3 days. The cost of SBC was calculated on the basis of consumables and labor costs at time of implementation. RESULTS: In the 13 months following implementation (October 6, 2016, to November 30, 2017), 23,044/24,653 (93.47%) platelet products underwent SBC. A total of eight positive cultures were detected (incidence 1 in 2881 platelet products), seven of which were positive within 24 hours of SBC. Coagulase negative Staphyloccus spp. were identified in four cases. Five of the eight cases were probable true positive (repeat reactive) and interdicted (cost per averted case was US$77,935). The remaining three cases were indeterminate. No septic transfusion reactions were reported during the observation period. CONCLUSION: We demonstrate the feasibility of SBC of apheresis platelets to mitigate bacterial risk. SBC is lower cost than alternative measures (e.g., pathogen reduction and point-of-release testing) and can be integrated into workflow at hospital transfusion services. PMID- 29607516 TI - Quantum chemical exploration of formaldehyde clusters (H2 CO)n (n = 2-4). AB - Global exploration of equilibrium structures and interconversion pathways on the quantum chemical potential energy surface (PES) is performed for (H2 CO)n (n = 2 4) by using the Scaled Hypersphere Search-Anharmonic Downward Distortion Following (SHS-ADDF) method. Density functional theoretical (DFT) calculations with empirical dispersion corrections (D3) yielded comparable results for formaldehyde dimer in comparison with recent detailed studies at CCSD(T) levels. Based on DFT-D3 calculations, trimer and tetramer structures and their stabilities were studied. For tetramer, a highly symmetrical S4 structure was found as the most stable form in good accordance with experimentally determined tetramer unit in the formaldehyde crystal. (c) 2018 Wiley Periodicals, Inc. PMID- 29607518 TI - Effects of multidimensional tunneling in the kinetics of hydrogen abstraction reactions of O (3 P) with CH3 OCHO. AB - Quantum tunneling paths are important in reactions when there is a significant component of hydrogenic motion along the potential energy surface. In this study, variational transition state with multidimensional tunneling corrections are employed in the calculations of the thermal rate constants for hydrogen abstraction from the cis-CH3 OCHO by O (3 P) giving CH3 OCO + OH (R1) and CH2 OCHO + OH (R2). The structures and electronic energies are computed with the M06 2X method. Benchmark calculations with the CBSD-T approach give an enthalpy of reaction at 0 K for R1 (-2.8 kcal/mol) and R2 (-2.5 kcal/mol) which are in good agreement with the experiment, i.e. -2.61 and -1.81 kcal/mol. At the low and intermediate values of temperatures, small- and large-curvature tunneling dominate the kinetics of R1, which is the dominant path over the range of temperature from 250 to 1200 K. This study shows the importance of multidimensional tunneling corrections for both R1 and R2, for which the total rate constant at 298 K calculated with the CVT/MUOMT method is 8.2 * 10-15 cm3 molecule-1 s-1 which agrees well with experiment value of 9.3 * 10-15 cm3 molecule-1 s-1 (Mori, Bull. Inst. Chem. Res. 1981, 59, 116). (c) 2018 Wiley Periodicals, Inc. PMID- 29607517 TI - Amorphous solid dispersions of carvedilol along with pH-modifiers improved pharmacokinetic properties under hypochlorhydoria. AB - Carvedilol (CAR) belongs to biopharmaceutics classification system class-II drugs, with poor aqueous solubility and pH-dependent solubility. The present study aimed to develop a novel amorphous solid dispersion (ASD) of CAR with acidic counter ions for pH modifications in microenvironment to improve the pharmacokinetic properties under hypochlorhydric conditions. CAR-ASD was prepared by freeze-drying in combination with counter ions and hydroxypropyl cellulose, and their physicochemical properties including dissolution behavior, storage stability, and photostability were characterized. Pharmacokinetic studies were carried out after oral administration of CAR samples in both normal and omeprazole-treated (30 mg/kg, p.o.) rats as a hypochlorhydria model. Among the tested six counter ions, citric acid (CA) was found to be a preferable pH modifier of CAR with respect to the dissolution profile and photostability (both potency and colorimetric evaluation). In CAR-ASD formulation with 50% loading of CA (CAR-ASD/CA50), amorphization of CAR was observed during the preparation process. After the oral administration of crystalline CAR in rats under hypochlorhydric condition, there was a 34.4% reduction in the systemic exposure of CAR compared with that in normal rats. However, orally-dosed CAR-ASD/CA50 resulted in limited alterations of pharmacokinetic behavior between normal and omeprazole-treated rats. From these findings, addition of CA as pH-modifier in CAR-ASD might provide consistent pharmacokinetic behavior of CAR even under hypochlorhydric conditions. PMID- 29607520 TI - Why do couples seek relationship help online? Description and comparison to in person interventions. AB - Couples are increasingly utilizing newly developed online adaptations of couple therapy; however, different presenting problems could drive couples to seek either online or in-person services. This study compared the presenting problems of 151 couples seeking an online couple intervention for relationship distress (OurRelationship) with responses from 147 couples seeking in-person couple therapy. Presenting problems were generally consistent across gender and whether or not the respondent was the initial help-seeker. Online and in-person samples frequently endorsed difficulties with communication and emotional intimacy; however, they differentially endorsed trust, time together, and child/parenting difficulties. Therefore, while basing online interventions on existing couple therapies is generally supported, efforts should be made to tailor online services to meet the unique needs of this population. PMID- 29607519 TI - Long-term effects of tibial plateau leveling osteotomy and tibial tuberosity advancement on tibial plateau subchondral bone density in dogs. AB - OBJECTIVE: To evaluate long-term loading patterns using subchondral bone density (SBD) distribution of the tibial plateau after tibial plateau leveling osteotomy (TPLO) and tibial tuberosity advancement (TTA). STUDY DESIGN: Cross-sectional study. ANIMALS: Adult (> 2 years), medium to large breed dogs (>20 kg) that had been treated with TPLO or TTA at least 1 year prior to the study were recruited. A normal cohort of similar age and weight dogs with normal physical and orthopedic examinations served as control. METHODS: Dogs were sedated for computed tomography (CT) of the stifle, and DICOM (digital imaging and communications in medicine) files were processed for CT osteoabsorptiometry (CTOAM). Tibial plateaus were sampled at 6 zones, and CTOAM was used to determine regional and maximal areas of SBD as a marker of joint loading. RESULTS: Data were collected on 48 stifles in 31 dogs (15 TPLO, 11 TTA, 22 control). Lower Hounsfield unit (HU) values were measured in the caudal and mid-region of the lateral tibial plateau after TPLO and compared to normal. HU values did not differ between joints treated with TTA and those in the control group. CONCLUSION: TPLO may alter stifle load distribution relative to the normal control group. There were no differences between TTA and the control group. CLINICAL SIGNIFICANCE/IMPACT: Despite ongoing osteoarthritis (OA) in dogs after surgical intervention for cranial cruciate disease, changes in tibial SBD are minor and may not correlate with clinical function. PMID- 29607521 TI - Noninvasive wearable sensor for indirect glucometry. AB - A noninvasive mini-sensor for blood glucose concentration assessment has been developed. The monitoring is performed by gently pressing a wrist or fingertip onto the chemochromic mixture coating a thin glass or polymer film positioned on the back panel of a smart watch with PPG/HRM (photoplethysmographic/heart rate monitoring sensor). The various chemochromic components measure the absolute values of the following metabolites present in the sweat: acetone, acetone beta hydroxybutirate, aceto acetate, water, carbon dioxide, lactate anion, pyruvic acid, Na and K salts. Taken together, all these parameters give information about blood glucose concentration, calculated via multivariate analysis based on neural network algorithms built into the sensor. The Clarke Error Grid shows an excellent correlation between data measured by the standard invasive glucose analyser and the present noninvasive sensor, with all points aligned along a 45 degree diagonal and contained almost exclusively in sector A. Graphs measuring glucose levels five times a day (prior, during and after breakfast and prior, during and after lunch), for different individuals (males and females) show a good correlation between the two curves of conventional, invasive meters vs. the noninvasive sensor, with an error of +/-15%. This novel, noninvasive sensor for indirect glucometry is fully miniaturized, easy to use and operate and could represent a valid alternative in clinical settings and for individual, personal users, to current, invasive tools. PMID- 29607522 TI - Reply to the letter to the editor: RE: Preisser F, et al. Extent of lymph node dissection improves survival in prostate cancer patients treated with radical prostatectomy without lymph node invasion. The Prostate. 2018;1-7. PMID- 29607523 TI - A new cause of ischaemic priapism: Synthetic cannabinoids. AB - Priapism is a urological emergency that needs early intervention and may lead to irreversible cavernosal damage. Ischaemic priapism is the most common type, which is frequently idiopathic and commonly associated with haematological diseases, medications or recreational drugs. Synthetic cannabinoids (SCs) have been increasingly used all over the world, particularly among young-adult population. SCs can cause severe adverse effects on several organ systems. However, there are no studies in the literature which have stated the possible relationship between using of SCs and priapism. We present a case of 28-year-old man who was diagnosed with a 58-hr lasting priapism after regular administrations of SCs. The priapism did not resolve neither after applying aspiration with irrigation nor shunt surgery. Finally, penile prosthesis implantation was performed as last treatment option. The SCs have been increasingly used among young population in recent years; therefore, new SC-related ischaemic priapism cases might be encountered in the emergency departments. PMID- 29607524 TI - Descriptions of two new species of flea of the genus Plocopsylla in northwestern Argentina. AB - Two new species of flea of the genus Plocopsylla, subgenus Plocopsylla, (Siphonaptera: Stephanocircidae) collected from sigmodontine rodents in northwestern Argentina are described and a key to identification of species of the genus Plocopsylla, subgenus Plocopsylla, in Argentina is presented. Plocopsylla (P.) inti is cited for the first time in Argentina, extending its distribution ~ 970 km further south than previously documented. New locality data and flea-host associations are recorded. The contributions of this study are relevant because they increase knowledge of the diversity of flea fauna in northwestern Argentina bordering a plague endemic area and will be useful in the implementation of plague control management plans in the future. PMID- 29607525 TI - Remission of loss of control eating and changes in components of the metabolic syndrome. AB - OBJECTIVE: Pediatric loss of control (LOC) eating prospectively predicts the worsening of metabolic syndrome components. However, it is unknown if remission of LOC eating is associated with improvements in metabolic health. Therefore, we conducted a secondary analysis of a trial that enrolled adolescent girls with LOC eating, examining whether LOC remission (vs. persistence) at end-of-treatment was associated with changes in metabolic syndrome components at 6-month follow-up. METHOD: One hundred three adolescent girls (age 14.5 +/- 1.7 years; BMI-z 1.5 +/- 0.3; 56.3% non-Hispanic White, 24.3% non-Hispanic Black) with elevated weight (75th-97th BMI %ile) and reported LOC eating were assessed for metabolic syndrome components at baseline and again six months following the interventions. The main effects of LOC status at end-of-treatment (persistence vs. remission) on metabolic syndrome components (waist circumference, lipids, glucose, and blood pressure) at 6-month follow-up were examined, adjusting for baseline age, depressive symptoms, LOC frequency, fat mass, and height, as well as race, change in height, change in fat mass, and the baseline value of each respective component. RESULTS: Youth with LOC remission at end-of-treatment had lower glucose (83.9 +/- 6.4 vs. 86.5 +/- 5.8 mg/dL; p = .02), higher high-density lipoprotein cholesterol (50.3 +/- 11.8 vs. 44.8 +/- 11.9 mg/dL; p = .01), and lower triglycerides (84.4 +/- 46.2 vs. 96.9 +/- 53.7 mg/dL; p = .02) at 6-month follow-up when compared with youth with persistent LOC, despite no baseline differences in these components. No other component significantly differed by LOC eating status (ps > .05). DISCUSSION: Reducing LOC eating in adolescent girls may have a beneficial impact on some components of the metabolic syndrome. PMID- 29607527 TI - Simultaneous determination of 20(S)-protopanaxadiol and its three metabolites in rat plasma by LC-MS/MS: application to their pharmacokinetic studies. AB - The aim of this study was to develop an LC-MS/MS method for simultaneous determination of 20(S) protopanaxadiol (PPD) and its three metabolites, PPD glucuronide (M1), (20S,24S)-epoxy-dammarane-3,12,25-triol (M2) and (20S,24R) epoxydammarane-3,12,25-triol (M3), in rat plasma. Precipitation with acetonitrile was employed for sample preparation and chromatographic separations were achieved on a C18 column. The sample was detected using triple quadrupole tandem mass spectrometer with selected reaction monitoring mode. The monitored precursor-to product ion transitions were m/z 459.4 -> 375.3 for PPD, m/z 635.4 -> 113.0 for M1, m/z 477.4 -> 441.4 for M2 and M3 and m/z 475.4 -> 391.3 for IS. The developed assay was validated according to the guidelines of the US Food and Drug Administration. The calibration curves showed good linearity over the tested concentration ranges (r > 0.9993), with the LLOQ being 1 ng/mL for all analytes. The intra- and inter-day precisions (RSD) were < 9.51% while the accuracy (RE) ranged from -8.91 to 12.84%. The extraction recovery was >80% and no obvious matrix effect was detected. The analytes were stable in rat plasma with the RE ranging from -12.34 to 9.77%. The validated assay has been successfully applied to the pharmacokinetic study of PPD as well as its metabolites in rat plasma. According to the pharmacokinetic parameters, the in vivo exposures of M1, M2 and M3 were 11.91, 47.95 and 22.62% of that of PPD, respectively. PMID- 29607526 TI - A hypothesis for the existence of two types of tuberculosis, reflecting two distinct types of immune failure to control the pathogen, based upon prevalence of mycobacterium-specific IgG subclasses. AB - Most people infected by Mycobacterium tuberculosis, about 90%, contain the pathogen and are healthy. Most investigators have concluded that pathogen specific Th1 cells contribute to protection. Pulmonary tuberculosis, the most prevalent form of disease, is associated with destructive granulomas, the formation of which also appears to involve Th1 cells. In what sense then do the two Th1 components of the response, in healthy infected individuals and patients, differ? An insight into this question might provide clues for attaining effective vaccination and better treatment. We approached this question by examining the relative prevalence of different IgG isotypes among anti-mycobacterium-specific antibodies in patients and healthy infected individuals as a surrogate marker for the Th1/Th2 phenotype of the response. Our observations lead us to agree that healthy infected individuals generate a predominant Th1 response. Our observations also lead us to propose that many patients make a similar kind of response as healthy infected individuals, but that this response is too weak to contain the infection. We refer to such individuals as having type I tuberculosis. Other patients appear to have a greater and detrimental Th2 component to their immune response than that of healthy infected individuals. We refer to these individuals as having type II tuberculosis. This proposal that there are two types of tuberculosis, reflecting two distinct types of failure by the immune system, will, if correct, be pertinent to vaccine design, treatment of tuberculosis and in making further progress in our understanding the genetics of susceptibility to M. tuberculosis. PMID- 29607528 TI - Changes in myocardial iron content following administration of intravenous iron (Myocardial-IRON): Study design. AB - Treatment with intravenous ferric carboxymaltose (FCM) has been shown to improve symptoms, functional capacity, and quality of life in patients with heart failure and iron deficiency. However, the underlying mechanisms for these beneficial effects remain undetermined. The aim of this study is to quantify cardiac magnetic resonance changes in myocardial iron content after administration of intravenous FCM in patients with heart failure and iron deficiency and contrast them with parameters of heart failure severity. This is a multicenter, double blind, randomized study. Fifty patients with stable symptomatic heart failure, left ventricular ejection fraction <50%, and iron deficiency will be randomly assigned 1:1 to receive intravenous FCM or placebo. Intramyocardial iron will be evaluated by T2* and T1 mapping cardiac magnetic resonance sequences before and at 7 and 30 days after FCM. After 30 days, patients assigned to placebo will receive intravenous FCM in case of persistent iron deficiency. The main endpoint will be changes from baseline in myocardial iron content at 7 and 30 days. Secondary endpoints will include the correlation of these changes with left ventricular ejection fraction, functional capacity, quality of life, and cardiac biomarkers. The results of this study will add important knowledge about the effects of intravenous FCM on myocardial tissue and cardiac function. We hypothesize that short-term (7 and 30 days) myocardial iron content changes after intravenous FCM, evaluated by cardiac magnetic resonance, will correlate with simultaneous changes in parameters of heart failure severity. The study is registered at http://www.clinicaltrials.gov (NCT03398681). PMID- 29607529 TI - Transplantation of Cold Stored Porcine Kidneys After Controlled Oxygenated Rewarming. AB - The concept of "controlled oxygenated rewarming" (COR) using ex vivo machine perfusion after cold storage was evaluated as tool to improve renal graft function after transplantation. Renal function after 20 min warm ischemia and 21 h cold storage was studied in an auto-transplant model in pigs (25-30 kg, n = 6 per group). In the study group, preimplant ex vivo machine perfusion for 90 min was added after cold storage, including gentle warming up of the graft to 20 degrees C (COR). Kidneys that were only cold stored for 21 h served as controls. In vivo follow up was one week; the remaining native kidney was removed during transplantation. COR significantly improved cortical microcirculation upon early reperfusion and reduced free radical mediated injury and cellular apoptosis. Post transplant kidney function (peak levels in serum) was also largely and significantly improved in comparison to the control group. A weak inverse correlation was found between renal flow during COR and later peak creatinine after transplantation (r2 = 0.5), better values were seen for oxygen consumption, measured during machine perfusion at 20 degrees C (r2 = 0.81). Gentle graft rewarming prior to transplantation by COR improves post-transplant graft outcome and may also be a valuable adjunct in pretransplant graft assessment. PMID- 29607530 TI - Drug induced liver injury with analysis of alternative causes as confounding variables. AB - AIMS: Drug-induced liver injury (DILI) is rare compared to the worldwide frequent acute or chronic liver diseases. Therefore, patients included in series of suspected DILI are at high risk of not having DILI, whereby alternative causes may confound the DILI diagnosis. The aim of this review is to evaluate published case series of DILI for alternative causes. METHODS: Relevant studies were identified using a computerized search of the Medline database for publications from 1993 through 30 October 2017. We used the following terms: drug hepatotoxicity, drug induced liver injury, hepatotoxic drugs combined with diagnosis, causality assessment and alternative causes. RESULTS: Alternative causes as variables confounding the DILI diagnosis emerged in 22 published DILI case series, ranging from 4 to 47%. Among 13 335 cases of suspected DILI, alternative causes were found to be more likely in 4555 patients (34.2%), suggesting that the suspected DILI was probably not DILI. Biliary diseases such as biliary obstruction, cholangitis, choledocholithiasis, primary biliary cholangitis and primary sclerosing cholangitis were among the most missed diagnoses. Alternative causes included hepatitis B, C and E, cytomegalovirus, Epstein-Barr virus, ischemic hepatitis, cardiac hepatopathy, autoimmune hepatitis, nonalcoholic fatty liver disease, nonalcoholic steatohepatitis, and alcoholic liver disease. CONCLUSIONS: In more than one-third of published global DILI case series, alternative causes as published in these reports confounded the DILI diagnosis. In the future, published DILI case series should include only patients with secured DILI diagnosis, preferentially established by prospective use of scored items provided by robust diagnostic algorithms such as the updated Roussel Uclaf causality assessment method. PMID- 29607532 TI - An efficient method to isolate Kupffer cells eliminating endothelial cell contamination and selective bias. AB - Multicolor flow cytometry and cell sorting are powerful immunologic tools for the study of hepatic mphi, yet there is no consensus on the optimal method to prepare liver homogenates for these analyses. Using a combination of mphi and endothelial cell reporter mice, flow cytometry, and confocal imaging, we have shown that conventional flow-cytometric strategies for identification of Kupffer cells (KCs) leads to inclusion of a significant proportion of CD31hi endothelial cells. These cells were present regardless of the method used to prepare cells for flow cytometry and represented endothelium tightly adhered to remnants of KC membrane. Antibodies to endothelial markers, such as CD31, were vital for their exclusion. This result brings into focus recently published microarray datasets that identify high expression of endothelial cell-associated genes by KCs compared with other tissue-resident mphi. Our studies also revealed significant and specific loss of KCs among leukocytes with commonly used isolation methods that led to enrichment of proliferating and monocyte-derived mphi. Hence, we present an optimal method to generate high yields of liver myeloid cells without bias for cell type or contamination with endothelial cells. PMID- 29607531 TI - Vancomycin-induced acute kidney injury in elderly Chinese patients: a single centre cross-sectional study. AB - AIMS: The objective of the present study was to investigate the current situation concerning, and risk factors for, vancomycin (VAN)-induced acute kidney injury (VI-AKI) in elderly Chinese patients, to assess outcomes and risk factors in patients who have developed VI-AKI, in order to provide suggestions for improving the prevention and treatment of this condition in these patients. METHOD: We retrospectively identified elderly older inpatients who had received four or more doses of VAN treatment. We compared patients with VI-AKI with those who received VAN treatment and had not developed AKI (NO-AKI). We defined VI-AKI as developing AKI during VAN therapy or within 3 days after withdrawal of VAN. RESULTS: A total of 647 out of 862 elderly inpatients were included in the study. Among those excluded, in 89.3% of cases (192/215) this was because of lack of data on serum creatinine (SCr). Among included patients, 32.5% (210/647) of patients received therapeutic drug monitoring (TDM) during VAN therapy. In 66.9% of cases (424/634), there was insufficient TDM, and in 3.9% (25/634) this was appropriate. A total of 102 patients had confirmed VI-AKI, with an incidence of 15.8% (102/647). Multiple logistic regression analysis revealed that hyperuricaemia [odds ratio (OR) = 3.045; P = 0.000)], mechanical ventilation (OR = 1.906; P = 0.022) and concomitant vasopressor therapy (OR = 1.919; P = 0.027) were independent risk factors for VI-AKI; higher serum albumin (OR = 0.885; P = 0.000) was determined to be an independent protective factor for VI-AKI. CONCLUSIONS: For the elderly Chinese patients treated with VAN, there was insufficient monitoring of SCr, too little use of VAN TDM, and lower rate of patients whose VAN though serum concentrations were not obtained at the correct time. We recommend that hospital managers increase investment in clinical pharmacists, to strengthen professional management. Patients with concomitant hyperuricaemia and on mechanical ventilation and vasopressor therapy should be paid more attention, and a higher serum albumin was determined to be an independent protective factor for VI-AKI. PMID- 29607534 TI - Dr. Luigi (Gigi) Varesio: A memorial. PMID- 29607533 TI - Population pharmacokinetics of voriconazole and CYP2C19 polymorphisms for optimizing dosing regimens in renal transplant recipients. AB - AIMS: The aims of the present study were to characterize the pharmacokinetics of voriconazole in renal transplant recipients and to identify factors significantly affecting pharmacokinetic parameters. We also aimed to explore the optimal dosing regimens for patients who developed invasive fungal infections. METHODS: A total of 105 patients (342 concentrations) were included prospectively in a population pharmacokinetic analysis. Nonlinear mixed-effects models were developed using Phoenix NLME software. Dosing simulations were performed based on the final model. RESULTS: A one-compartment model with first-order absorption and elimination was used to characterize voriconazole pharmacokinetics. Population estimates of clearance, volume of distribution and oral bioavailability were 2.88 l.h-1 , 169.3 l and 58%, respectively. The allele frequencies of cytochrome P450 gene (CYP) 2C19*2, *3 and *17 variants were 29.2%, 5.2% and 0.5%, respectively. CYP2C19 genotype had a significant effect on the clearance. Voriconazole trough concentrations in poor metabolizers were significantly higher than in intermediate metabolizers and extensive metabolizers alike. The volume of distribution increased with increased body weight. The oral bioavailability was substantially lower within 1 month after transplantation but increased with postoperative time. Dosing simulations indicated that during the early postoperative period, poor metabolizers could be treated with 150 mg intravenously or 250 mg orally twice daily; intermediate metabolizers with 200 mg intravenously or 350 mg orally twice daily; and extensive metabolizers with 300 mg intravenously twice daily. CONCLUSIONS: Using a combination of CYP2C19 genotype and postoperative time to determine the initial voriconazole dosing regimens followed by therapeutic drug monitoring could help to advance individualized treatment in renal transplantation patients with invasive fungal infections. PMID- 29607535 TI - Overestimation of cardiac lactate production caused by liver metabolism of hyperpolarized [1-13 C]pyruvate. AB - PURPOSE: The purpose of this work was to study the contribution of liver [1-13 C]lactate to the lactate signal detected in the heart following injection of hyperpolarized [1-13 C]pyruvate. METHODS: A slice-selective saturation scheme was incorporated into a hybrid metabolic imaging and spectroscopy approach to selectively presaturate lactate in the liver. Imaging and slice-selective spectroscopy of [1-13 C]pyruvate and its downstream metabolites were sequentially interleaved in the same experiment with optional presaturation of liver [1-13 C]lactate. Six healthy rats were measured, and metabolic data in the heart acquired with and without presaturation of liver lactate were compared. RESULTS: When using liver lactate presaturation, a statistically significant reduction of the lactate/pyruvate ratio was observed in the spectroscopic data of the left ventricle (0.18 +/- 0.03 versus 0.24 +/- 0.04; p < .05) as well as in the imaging data of the blood pool (0.05 +/- 0.01 versus 0.11 +/- 0.01; p < .05). No significant difference in myocardial lactate was observed when using myocardium only as the region of interest in the imaging data (0.08 +/- 0.01 versus 0.11 +/- 0.02; p = .2). CONCLUSION: Liver metabolism leads to statistically significant overestimation of cardiac lactate production in slice-selective or nonselective spectroscopic experiments. Therefore, metabolic imaging is preferred over spectroscopy to separate left-ventricular compartments within the slice and hence avoid contamination of cardiac lactate signals. Alternatively, presaturation pulses should be used in combination with spectroscopy approaches. PMID- 29607537 TI - Gastrointestinal: Unusual cause of acute cholangitis in a chronic pancreatitis patient. PMID- 29607536 TI - DP1 receptor signaling prevents the onset of intrinsic apoptosis in eosinophils and functions as a transcriptional modulator. AB - Prostaglandin (PG) D2 is the ligand for the G-protein coupled receptors DP1 (D type prostanoid receptor 1) and DP2 (also known as chemoattractant receptor homologous molecule, expressed on Th2 cells; CRTH2). Both, DP1 and DP2 are expressed on the cellular surface of eosinophils; although it has become quite clear that PGD2 induces eosinophil migration mainly via DP2 receptors, the role of DP1 in eosinophil responses has remained elusive. In this study, we addressed how DP1 receptor signaling complements the pro-inflammatory effects of DP2. We found that PGD2 prolongs the survival of eosinophils via a DP1 receptor-mediated mechanism that inhibits the onset of the intrinsic apoptotic cascade. The DP1 agonist BW245c prevented the activation of effector caspases in eosinophils and protected mitochondrial membranes from depolarization which-as a consequence sustained viability of eosinophils. DP1 activation in eosinophils enhanced the expression of the anti-apoptotic gene BCL-XL , but also induced pro-inflammatory genes, such as VLA-4 and CCR3. In HEK293 cells that overexpress recombinant DP1 and/or DP2 receptors, activation of DP1, but not DP2, delayed cell death and stimulated proliferation, along with induction of serum response element (SRE), a regulator of anti-apoptotic, early-response genes. We conclude that DP1 receptors promote the survival via SRE induction and induction of pro-inflammatory genes. Therefore, targeting DP1 receptors, along with DP2, may contribute to anti inflammatory therapy in eosinophilic diseases. PMID- 29607539 TI - Gastrointestinal: Abdominal pain, vomiting, and fatal intra-abdominal hemorrhage in a patient with Sjogren's syndrome. PMID- 29607538 TI - Free-breathing cine DENSE MRI using phase cycling with matchmaking and stimulated echo image-based navigators. AB - PURPOSE: This study aimed to develop a self-navigated method for free-breathing spiral cine displacement encoding with stimulated echoes (DENSE), a myocardial strain imaging technique that uses phase-cycling for artifact suppression. The method needed to address 2 consequences of motion for DENSE: striping artifacts from incomplete suppression of the T1 -relaxation echo and blurring. METHODS: The method identifies phase-cycled spiral interleaves at matched respiratory phases by minimizing the residual signal due to T1 relaxation after phase-cycling subtraction. Next, the method reconstructs image-based navigators from matched phase-cycled interleaves that are comprised of the stimulated echo (ste-iNAVs). Ste-iNAVs are used for motion estimation and compensation of k-space data. The method was demonstrated in phantoms and compared to diaphragm-based navigator (dNAV) and conventional iNAV (c-iNAV) methods for the reconstruction of free breathing volunteer data sets (N = 10). RESULTS: Phantom experiments demonstrated that the proposed method removes striping artifacts and blurring due to motion. Volunteer results showed that respiratory motion measured by ste-iNAVs was better correlated than c-iNAVs to dNAV data (R2 = 0.82 +/- 0.03 vs. 0.70 +/- 0.05, P < 0.05). Match-making reconstructions of free-breathing data sets achieved lower residual T1 -relaxation echo energy (1.04 +/- 0.01 vs. 1.18 +/- 0.04 for dNAV and 1.18 +/- 0.03 for c-iNAV, P < 0.05), higher apparent SNR (11.93 +/- 1.05 vs. 10.68 +/- 1.06 for dNAV and 10.66 +/- 0.99 for c-iNAV, P < 0.05), and better phase quality (0.147 +/- 0.012 vs. 0.166 +/- 0.017 for dNAV, P = 0.06, and 0.168 +/- 0.015 for c-iNAV, P < 0.05) than dNAV and c-iNAV methods. CONCLUSION: For free-breathing cine DENSE, the proposed method addresses both types of breathing induced artifacts and provides better quality images than conventional dNAV and iNAV methods. PMID- 29607540 TI - Melatonin improves insulin resistance and hepatic steatosis through attenuation of alpha-2-HS-glycoprotein. AB - Melatonin plays an important role in regulating circadian rhythms. It also acts as a potent antioxidant and regulates glucose and lipid metabolism, although the exact action mechanism is not clear. The alpha2-HS-glycoprotein gene (AHSG) and its protein, fetuin-A (FETUA), are one of the hepatokines and are known to be associated with insulin resistance and type 2 diabetes. The aim of this study was to determine whether melatonin improves hepatic insulin resistance and hepatic steatosis in a FETUA-dependent manner. In HepG2 cells treated with 300 MUmol/L of palmitic acid, phosphorylated AKT expression decreased, and FETUA expression increased, but this effect was inhibited by treatment with 10 MUmol/L of melatonin. However, melatonin did not improve insulin resistance in FETUA overexpressing cells, indicating that improvement in insulin resistance by melatonin was dependent on downregulation of FETUA. Moreover, melatonin decreased palmitic acid-induced ER stress markers, CHOP, Bip, ATF-6, XBP-1, ATF-4, and PERK. In addition, in the high-fat diet (HFD) mice, oral treatment with 100 mg/kg/day melatonin for 10 weeks reduced body weight gain to one-third of that of the HFD group and hepatic steatosis. Insulin sensitivity and glucose intolerance improved with the upregulation of muscle p-AKT protein expression. FETUA expression and ER stress markers in the liver and serum of HFD mice were decreased by melatonin treatment. In conclusion, melatonin can improve hepatic insulin resistance and hepatic steatosis through reduction in ER stress and the resultant AHSG expression. PMID- 29607542 TI - Gastrointestinal: An unusual cause of thickening of the rectal wall. PMID- 29607543 TI - Gastrointestinal: Disseminated Kaposi's sarcoma. PMID- 29607541 TI - Zinc finger of Arabidopsis thaliana 6 is involved in melatonin-mediated auxin signaling through interacting INDETERMINATE DOMAIN15 and INDOLE-3-ACETIC ACID 17. AB - Although accumulating evidence demonstrates the cross talk between melatonin and auxin as derivatives of tryptophan, the underlying signaling events remain unclear. In this study, we found that melatonin and auxin mediated the transcriptional levels of zinc finger of Arabidopsis thaliana (ZAT6) in a mutually antagonistic manner. ZAT6 negatively modulated the endogenous auxin level, and ZAT6 knockdown plants were less sensitive to melatonin-regulated auxin biosynthesis, indicating its involvement in melatonin-mediated auxin accumulation. Additionally, the identification of INDETERMINATE DOMAIN15 (IDD15) and INDOLE-3-ACETIC ACID 17 (IAA17) in Arabidopsis that interacted with ZAT6 in vivo provided new insight of ZAT6-mediated auxin signaling. Further investigation showed that ZAT6 repressed the transcription activation of IDD15 on the YUC2 promoter, while ZAT6 inhibited the interaction of TRANSPORT INHIBITOR RESPONSE 1 (TIR1) and IAA17 through competitively binding to IAA17. Thus, both auxin synthesis and the auxin response were negatively modulated by ZAT6. Taken together, ZAT6 is involved in melatonin-mediated auxin signaling through forming an interacting complex of auxin signaling pathway in Arabidopsis. PMID- 29607544 TI - Outcome of pediatric heart transplantation in blood culture positive donors in the United States. AB - Active donor infection at the time of organ procurement poses a potential infection risk and may increase post-transplant morbidity and mortality in recipients. Our hypothesis was that pediatric heart transplant recipients from blood culture positive donors (BCPD) would have increased morbidity and mortality compared to non-blood culture positive donors (NBCPD). A retrospective analysis of pediatric heart transplant recipients using the organ procurement and transplant network (OPTN) between 1987 and 2015 was conducted. Recipient as well as donor data were analyzed. Propensity score matching with 1:2 ratios was performed for recipient variables. Post-transplant morbidity and mortality were compared for recipients of BCPD and NBCPD. Among 9618 heart transplant recipients, 450 (4.7%) were from culture positive donors. Recipients of BCPD had longer duration of listing as Status 1; diagnosis of congenital heart disease or restrictive cardiomyopathy and required support (IV inotropes, Inhaled NO and LVAD) prior to transplant. Post-transplant survival between the 2 groups was not different. Propensity-matched recipients had similar length of stay; stroke rate; need for dialysis; pacemaker implantation and treated rejection episodes in the first year post-transplant. Careful acceptance of BCPD may have the potential to increase availability of donor hearts in the pediatric population. PMID- 29607546 TI - Erratum. PMID- 29607545 TI - Effectiveness to identify acute myocardial infarction using the Manchester screening in patients with chest pain at the emergency service. AB - BACKGROUND: Among cardiovascular diseases (CVD), acute coronary syndrome (ACS) is the main manifestation, corresponding to signs and symptoms that occur with ischemia and outcome of angina or acute myocardial infarction (AMI). The aim of this study was to investigate the performance of biochemical markers eligible in a chest pain protocol, using Point of care Test (POCT), in patients in a reference emergency room. METHODS: In this study, 1380 medical records of patients of both genders were evaluated, ranked by applying chest pain protocol using the Manchester Triage System (MTS). Markers for myocardial injury were measured in serial analysis including myoglobin (Mgb), creatine kinase MB fraction mass (CK-MB), and cardiac troponin I (cTnI). RESULTS: Acute myocardial infarction was predominant in males (P < .001), in patients with hypertension (P < .001), and in those with previous myocardial infarction (P < .026) and significant electrocardiogram (ECG) data for AMI screening (P < .001). A multivariate regression model showed as predictors for AMI the variables ECG data by admittance at the emergency room, previous AMI history, levels of both Mgb at the third hour, and cTnI at the sixth hour after admission. CONCLUSION: This study showed the importance of a rapid and serial test as a cardiac marker for AMI screening, as well as has indicated the importance of time between the onset of chest pain and admission to the emergency room as an efficient aid in diagnosing this life-threatening disease. PMID- 29607549 TI - Melatonin is involved in skotomorphogenesis by regulating brassinosteroid biosynthesis in rice plants. AB - Serotonin N-acetyltransferase (SNAT) is the penultimate enzyme in melatonin biosynthesis catalyzing the conversion of serotonin into N-acetylserotonin. In plants, SNAT is encoded by 2 isogenes of which SNAT1 is constitutively expressed and its overexpression confers increased yield in rice. However, the role of SNAT2 remains to be clarified. In contrast to SNAT1, the diurnal rhythm of SNAT2 mRNA expression peaks at night. In this study, transgenic rice plants in which SNAT2 expression were suppressed by RNAi technology showed a decrease in melatonin and a dwarf phenotype with erect leaves, reminiscent of brassinosteroids (BR)-deficient mutants. Of note, the dwarf phenotype was dependent on the presence of dark, suggesting that melatonin is involved in dark growth (skotomorphogenesis). In support of this suggestion, SNAT2 RNAi lines exhibited photomorphogenic phenotypes such as inhibition of internodes and increased expression of light-inducible CAB genes in the dark. The causative gene for the melatonin-mediated BR biosynthetic gene was DWARF4, a rate-limiting BR biosynthetic gene. Exogenous melatonin treatment induced several BR biosynthetic genes, including DWARF4, D11, and RAVL1. As expected from the erect leaves, the SNAT2 RNAi lines produced less BR than the wild type. Our results show for the first time that melatonin is a positive regulator of dark growth or shade outgrowth by regulating BR biosynthesis in plants. PMID- 29607548 TI - Motion-robust sub-millimeter isotropic diffusion imaging through motion corrected generalized slice dithered enhanced resolution (MC-gSlider) acquisition. AB - PURPOSE: To develop an efficient MR technique for ultra-high resolution diffusion MRI (dMRI) in the presence of motion. METHODS: gSlider is an SNR-efficient high resolution dMRI acquisition technique. However, subject motion is inevitable during a prolonged scan for high spatial resolution, leading to potential image artifacts and blurring. In this study, an integrated technique termed Motion Corrected gSlider (MC-gSlider) is proposed to obtain high-quality, high resolution dMRI in the presence of large in-plane and through-plane motion. A motion-aware reconstruction with spatially adaptive regularization is developed to optimize the conditioning of the image reconstruction under difficult through plane motion cases. In addition, an approach for intra-volume motion estimation and correction is proposed to achieve motion correction at high temporal resolution. RESULTS: Theoretical SNR and resolution analysis validated the efficiency of MC-gSlider with regularization, and aided in selection of reconstruction parameters. Simulations and in vivo experiments further demonstrated the ability of MC-gSlider to mitigate motion artifacts and recover detailed brain structures for dMRI at 860 MUm isotropic resolution in the presence of motion with various ranges. CONCLUSION: MC-gSlider provides motion robust, high-resolution dMRI with a temporal motion correction sensitivity of 2 s, allowing for the recovery of fine detailed brain structures in the presence of large subject movements. PMID- 29607550 TI - Mapping the trajectory of the amygdalothalamic tract in the human brain. AB - Although the thalamus is not considered primarily as a limbic structure, abundant evidence indicates the essential role of the thalamus as a modulator of limbic functions indirectly through the amygdala. The amygdala is a central component of the limbic system and serves an essential role in modulating the core processes including the memory, decision-making, and emotional reactions. The amygdalothalamic pathway is the largest direct amygdalo-diencephalic connection in the primates including the human brain. Given the crucial role of the amygdalothalamic tract (ATT) in memory function and diencephalic amnesia in stroke patients, diffusion tensor imaging may be helpful in better visualizing the surgical anatomy of this pathway noninvasively. To date, few diffusion weighted studies have focused on the amygdala, yet the fine neuronal connection of the amygdala and thalamus known as the ATT has yet to be elucidated. This study aimed to investigate the utility of high spatial resolution diffusion tensor tractography for mapping the trajectory of the ATT in the human brain. We studied 15 healthy right-handed human subjects (12 men and 3 women with age range of 24-37 years old). Using a high-resolution diffusion tensor tractography technique, for the first time, we were able to reconstruct and measure the trajectory of the ATT. We further revealed the close relationship of the ATT with the temporopontine tract and the fornix bilaterally in 15 healthy adult human brains. PMID- 29607552 TI - Pathophysiology and management of glaucoma associated with phakomatoses. AB - The phakomatoses, encephalotrigeminal angiomatosis (ETA; Sturge-Weber Syndrome), neurofibromatosis type 1 (NF1 or von Recklinghausen disease), Von Hippel-Lindau (VHL) disease, tuberous sclerosis (TSC), oculodermal melanocytosis (ODM), and phakomatosis pigmentovascularis are a group of neurocutaneous disorders that have characteristic systemic and ocular manifestations. Through many different mechanisms, they may cause glaucomatous damage of the optic nerve and subsequent vision loss varying from mild to severe. Glaucoma commonly affects patients with ETA (43-72%), orbito-facial NF1 (23-50%), and ODM (10%). Rarely, it may present as neovascular glaucoma in VHL and TSC. In ETA, glaucoma typically occurs ipsilateral to the port-wine stain, which is caused by a mutation in the GNAQ gene. Specifically, mechanical malformation of the anterior chamber angle and elevated episcleral venous pressure has been implicated as causes of glaucoma in ETA. In NF1, which is caused by a mutation in the NF1 tumor suppressor gene, glaucoma commonly occurs ipsilateral to lid plexiform neurofibromas. Histological studies of eyes with NF1 have revealed direct anterior chamber infiltration by neurofibromas, secondary angle closure, fibrovascularization, and developmental angle abnormalities as mechanisms of glaucoma. Lastly, phakomatosis pigmentovascularis is a rare combination of ODM and port-wine stain. Affected patients are at very high risk of developing glaucoma. Despite the many different mechanisms of glaucomatous damage, management follows similar principles as that for congenital glaucoma and primary open angle glaucoma. First-line therapy is topical intraocular pressure-lowering eye drops. Surgical management, including goniotomy, trabeculotomy, trabeculectomy, and tube shunt placement may be required for more severe cases. PMID- 29607551 TI - High peak and high average radiofrequency power transmit/receive switch for thermal magnetic resonance. AB - PURPOSE: To study the role of temperature in biological systems, diagnostic contrasts and thermal therapies, RF pulses for MR spin excitation can be deliberately used to apply a thermal stimulus. This application requires dedicated transmit/receive (Tx/Rx) switches that support high peak powers for MRI and high average powers for RF heating. To meet this goal, we propose a high performance Tx/Rx switch based on positive-intrinsic-negative diodes and quarter wavelength (lambda/4) stubs. METHODS: The lambda/4 stubs in the proposed Tx/Rx switch design route the transmitted RF signal directly to the RF coil/antenna without passing through any electronic components (e.g., positive-intrinsic negative diodes). Bench measurements, MRI, MR thermometry, and RF heating experiments were performed at f = 297 MHz (B0 = 7 T) to examine the characteristics and applicability of the switch. RESULTS: The proposed design provided an isolation of -35.7dB/-41.5dB during transmission/reception. The insertion loss was -0.41dB/-0.27dB during transmission/reception. The switch supports high peak (3.9 kW) and high average (120 W) RF powers for MRI and RF heating at f = 297 MHz. High-resolution MRI of the wrist yielded image quality competitive with that obtained with a conventional Tx/Rx switch. Radiofrequency heating in phantom monitored by MR thermometry demonstrated the switch applicability for thermal modulation. Upon these findings, thermally activated release of a model drug attached to thermoresponsive polymers was demonstrated. CONCLUSION: The high-power Tx/Rx switch enables thermal MR applications at 7 T, contributing to the study of the role of temperature in biological systems and diseases. All design files of the switch will be made available open source at www.opensourceimaging.org. PMID- 29607553 TI - Combined use of xenogeneic bone substitute material covered with a native bilayer collagen membrane for alveolar ridge preservation: A randomized controlled clinical trial. AB - AIM: The aim of this split-mouth randomized controlled study was to evaluate radiographic dimensional changes after tooth extraction in posterior sites treated with a ridge preservation technique or left for spontaneous healing. MATERIALS AND METHODS: In a total of 18 patients, tooth extraction in posterior sites of the upper and lower jaw was performed in a split-mouth design. The post extraction sockets were randomly assigned to the following two treatment modalities: deproteinized bovine bone mineral (DBBM) with 10% collagen (DBBM-C) covered with a native bilayer collagen membrane (NBCM) (test group) and spontaneous healing (control group). Cone beam computed tomography (CBCT) scans were performed after extractions, 3 and 6 months later. The following parameters were measured: the height of the buccal bone plate (BH), height of the palatal bone plate (PH), horizontal width of the extraction socket at 1 mm, 3 mm, and 5 mm (HW-1, HW-3, HW-5), and the horizontal width (thickness) of the buccal bone plate at 1 mm, 3 mm, and 5 mm (BHP-1, BHP-3, BHP-5). Statistical analysis was performed applying a nonparametric Wilcoxon signed-rank test. RESULTS: The CBCT analysis showed a bone loss compared to baseline in test and control group. The measurements which have reached statistically significant differences at 6 months were BH (test: -2.31% vs control: -13.11%), PH (test: -2.07% vs control: 15.32%), HW-1 (test: -17.14% vs control: -32.47%), and HW-3 (test: -11.65% vs control: -28.47%). CONCLUSIONS: The posterior ridge preservation technique using DBBM-C covered with a NBCM is a valid approach reducing the amount of the radiographic loss in alveolar ridge dimensions. PMID- 29607555 TI - Crystal structure of the trimeric N-terminal domain of ciliate Euplotes octocarinatus centrin binding with calcium ions. AB - Centrin is a member of the EF-hand superfamily of calcium-binding proteins, a highly conserved eukaryotic protein that binds to Ca2+ . Its self-assembly plays a causative role in the fiber contraction that is associated with the cell division cycle and ciliogenesis. In this study, the crystal structure of N terminal domain of ciliate Euplotes octocarinatus centrin (N-EoCen) was determined by using the selenomethionine single-wavelength anomalous dispersion method. The protein molecules formed homotrimers. Every protomer had two putative Ca2+ ion-binding sites I and II, protomer A, and C bound one Ca2+ ion, while protomer B bound two Ca2+ ions. A novel binding site III was observed and the Ca2+ ion was located at the center of the homotrimer. Several hydrogen bonds, electrostatic, and hydrophobic interactions between the protomers contributed to the formation of the oligomer. Structural studies provided insight into the foundation for centrin aggregation and the roles of calcium ions. PMID- 29607554 TI - Anti-inflammatory potency testing of topical corticosteroids and calcineurin inhibitors in human volunteers sensitized to diphenylcyclopropenone. AB - AIMS: To quantify the anti-inflammatory potency of topical corticosteroids and topical calcineurin inhibitors by measuring the contact allergic response to a diphenylcyclopropenone (DPCP) challenge in de novo sensitized human volunteers. METHODS: Two randomized, double-blind, vehicle-controlled studies were performed encompassing 76 volunteers: 29 in the first and 47 in the second study. Topical drugs were applied pre- and/or post-treatment in block designs. The compounds were tested simultaneously under occluded patch tests covering DPCP-induced dermatitis. Inhibitory responses were assessed by visual scoring and measurements of the oedema thickness with ultrasound. RESULTS: When applied both before and after the DPCP challenge, significant anti-inflammatory effects were seen in descending order for tacrolimus 0.1% ointment, clobetasol propionate ointment, betamethasone valerate ointment and hydrocortisone butyrate ointment, while pimecrolimus cream, hydrocortisone ointment and vehicles had no significant effect. Only tacrolimus ointment (P < 0.01) demonstrated a consistent significant pre-treatment inhibitory effect compared with an untreated DPCP control. CONCLUSIONS: This human testing method in which the inflammation of experimentally induced allergic patch test reactions is quantified by objective measurement allows an analysis of the anti-inflammatory potency of not only topical corticosteroids, but also of drugs that have no effect on vasoconstriction. The method allowed comparison of the potencies of four topical corticosteroids and two calcineurin inhibitors. PMID- 29607556 TI - John Kendrew and myoglobin: Protein structure determination in the 1950s. AB - The essay reviews John Kendrew's pioneering work on the structure of myoglobin for which he shared the Nobel Prize for Chemistry in 1962. It reconstructs the status of protein X-ray crystallography at the time Kendrew entered the field in 1945, after distinctive service in operational research during the war. It reflects on the choice of sperm whale myoglobin as research material. In particular, it highlights Kendrew's early use of digital electronic computers for crystallographic computations and the marshaling of other tools and approaches that made it possible to solve the structure at increasing resolution. The essay further discusses the role of models in structure resolution and their broader reception. It ends by briefly reviewing Kendrew's other contributions in the formation and institutionalization of molecular biology. PMID- 29607557 TI - Maternal hemodynamics, fetal biometry and Doppler indices in pregnancies followed up for suspected fetal growth restriction. AB - OBJECTIVES: To assess whether, in a cohort of patients with a small-for gestational-age (SGA) fetus with estimated fetal weight <= 10th percentile, maternal hemodynamics, fetal biometry and Doppler indices at presentation can predict the subsequent development of an abnormal fetal Doppler index or delivery of a baby with birth weight < 3rd percentile. METHODS: This was a prospective observational cohort study conducted at a specialist clinic for the management of pregnancies with a SGA fetus at King's College Hospital, London, UK. The study population comprised 86 singleton pregnancies with a SGA fetus, presenting at a median gestational age of 32 (range, 26-35) weeks. We measured maternal cardiac function using a non-invasive transthoracic bioreactance monitor, as well as mean arterial pressure, fetal biometry, and umbilical artery (UA), fetal middle cerebral artery (MCA) and uterine artery (UtA) pulsatility indices (PI), and the deepest vertical pool of amniotic fluid. Z-scores of these variables were calculated based on reported reference ranges and the values were compared between pregnancies with evidence of an abnormal fetal Doppler index at presentation (Group 1), those that had developed an abnormal Doppler index at a subsequent visit (Group 2) and those that did not develop an abnormal Doppler index throughout pregnancy (Group 3). Abnormal fetal Doppler was defined as UA-PI > 95th percentile and/or MCA-PI < 5th percentile. Differences in measured variables at presentation were also compared between pregnancies delivering a baby with birth weight < 3rd percentile and those delivering a baby with birth weight >= 3rd percentile. Multivariate logistic regression analysis was used to determine significant predictors of birth weight < 3rd percentile and evolution from normal to abnormal fetal Doppler. RESULTS: In the study population, 14 (16%) cases were in Group 1, 19 (22%) in Group 2 and 53 (62%) in Group 3. Birth weight was < 3rd percentile in 39 (45%) cases and >= 3rd percentile in 47 (55%). There was decreased cardiac output and stroke volume and increased peripheral vascular resistance compared with a normal population, and the deviations from normal were most marked in Group 1. Pregnancies with birth weight < 3rd percentile, compared with those with birth weight >= 3rd percentile, had greater deviations from normal in fetal biometry, maternal cardiac output, stroke volume, heart rate, peripheral vascular resistance and UtA-PI. Multivariate logistic regression analysis demonstrated that, in the prediction of birth weight < 3rd percentile, maternal hemodynamic profile provided significant improvement to the prediction provided by maternal demographics, fetal biometry, UtA-PI, UA-PI and MCA-PI (difference between areas under receiver-operating characteristics curves, 0.18 (95% CI, 0.06-0.29); P = 0.002). In contrast, there was no significant independent contribution from maternal hemodynamics in the prediction of the subsequent development of abnormal fetal Doppler. CONCLUSIONS: In pregnancies with a SGA fetus, there is decreased maternal cardiac output and stroke volume and increased peripheral vascular resistance, and the deviations from normal are most marked in cases of redistribution in the fetal circulation and reduced amniotic fluid volume. Copyright (c) 2018 ISUOG. Published by John Wiley & Sons Ltd. PMID- 29607558 TI - Outcome reporting across randomized trials and observational studies evaluating treatments for twin-twin transfusion syndrome: systematic review. AB - OBJECTIVE: Twin-twin transfusion syndrome (TTTS) is associated with significant mortality and morbidity. Potential treatments for the condition require robust evaluation. The aim of this study was to evaluate outcome reporting across observational studies and randomized controlled trials assessing treatments for TTTS. METHODS: Cochrane Central Register of Controlled Trials, EMBASE and MEDLINE were searched from inception to August 2016. Observational studies and randomized controlled trials reporting outcome following treatment for TTTS in monochorionic diamniotic twin pregnancy and monochorionic-triamniotic or dichorionic triamniotic triplet pregnancy were included. Outcome reporting was systematically extracted and categorized. RESULTS: Six randomized trials and 94 observational studies were included, reporting data from 20 071 maternal participants and 3199 children. Six different treatments were evaluated. Included studies reported 62 different outcomes, including six fetal, seven offspring mortality, 25 neonatal, six early childhood and 18 maternal/operative outcomes. Outcomes were reported inconsistently across trials. For example, when considering offspring mortality, 31 (31%) studies reported live birth, 31 (31%) reported intrauterine death, 49 (49%) reported neonatal mortality and 17 (17%) reported perinatal mortality. Four (4%) studies reported respiratory distress syndrome. Only 19 (19%) studies were designed for long-term follow-up and 11 (11%) of these reported cerebral palsy. CONCLUSIONS: Studies evaluating treatments for TTTS have often neglected to report clinically important outcomes, especially neonatal morbidity outcomes, and most are not designed for long-term follow-up. The development of a core outcome set could help standardize outcome collection and reporting in TTTS studies. Copyright (c) 2018 ISUOG. Published by John Wiley & Sons Ltd. PMID- 29607559 TI - Neck hematoma after major head and neck surgery: Risk factors, costs, and resource utilization. AB - BACKGROUND: Postoperative cervical hematoma after major head and neck surgery is a feared complication. However, risk factors for developing this complication and attributable costs are not well-established. METHODS: The Nationwide Inpatient Sample database was utilized compare patients with and without postoperative cervical hematoma. Logistic regression was used to analyze risk factors for hematoma formation and 30-day mortality. Total inpatient length of stay (LOS) and costs were fit to generalized linear models. RESULTS: Of 32 071 patients, 1098 (3.4%) experienced a postoperative cervical hematoma. Male sex (odds ratio [OR] 1.38; P < .0001), black race (OR 1.35; P = .010), 4 or more comorbidities (OR 1.66; P < .0001), or presence of a preoperative coagulopathy (OR 6.76; P < .0001) were associated. Postoperative cervical hematoma was associated with 540% increased odds of death (P < .0001). The LOS and total excess costs were 5.14 days (P < .0001) and $17 887.40 (P < .0001), respectively. CONCLUSION: Although uncommon, postoperative cervical hematoma is a life-threatening complication of head and neck surgery with significant implications for outcomes and resource utilization. PMID- 29607560 TI - Intrauterine vaccination induces a dose-sensitive primary humoral response with limited evidence of recall potential. AB - PROBLEM: Induction of the local mucosal immune system within the reproductive tract is widely considered to be a key component in the development of effective prophylactic vaccines to control the spread of sexually transmitted infections. Here, we examine the capacity of the upper reproductive tract to act as a site of immune induction following. METHOD OF STUDY: Two vaccines formulated with a triple adjuvant combination and either recombinant bovine herpesvirus (tgD) protein or ovalbumin (OVA) were delivered at varying doses to the uterine lumen of rabbits and the resulting immune response evaluated after 32 days. RESULTS: Intrauterine vaccination produced a dose-dependent induction of both antigen specific IgG and IgA in serum. Both uterine and broncheoalveolar lavage of the high and medium-dose vaccine group contained a significant increase in both anti OVA and anti-tgD IgG, but no significant quantities of antigen-specific IgA were observed. The restimulation of splenocytes from the high-dose vaccine group with ovalbumin (OVA) only resulted in a small but significant increase in gene expression of the Th1 cytokines (IL2/IFNgamma) in the absence of an observable increase in proliferation. CONCLUSION: Collectively, the results confirm the capacity of the uterine immune system to generate a primary response following stimulation. PMID- 29607561 TI - Effectiveness of emotional skills training for patients with anorexia nervosa with autistic symptoms in group and individual format. AB - OBJECTIVE: The aim of this study was to examine the effectiveness of CREST interventions in individual and group formats for adult anorexia nervosa. Furthermore, this study also aims to analyse whether patients with high levels of autistic symptoms respond differently. METHODS: Participants' self-report measures were taken before and after individual and group interventions (N = 66 and N = 62, respectively). Mixed effects analysis was used to analyse overall response to both formats and assess interaction with autism symptoms. RESULTS: Significant improvements were observed for patients' alexithymia in individual format, and motivation increased for participants in both interventions. Significant interactions were observed between alexithymia, social anhedonia, and autism symptoms in individual format and alexithymia in group format. No interactions between autism and time were observed for either format. CONCLUSIONS: CREST in both formats offers participants improvements in social emotional and motivational domains. Patients with high levels of autism symptoms also score high on both social anhedonia and alexithymia measures, but this does not affect their response to treatment. PMID- 29607562 TI - Risk factors and topographies for self-injurious behaviour in a sample of adults with intellectual developmental disorders. AB - BACKGROUND: Self-injurious behaviour (SIB) is a prevalent form of challenging behaviour in people with intellectual developmental disorders (IDD). Existing research has yielded conflicting findings concerning the major risk factors involved, and in addition, SIB shows multiple topographies and presentations. Although presence of autism spectrum disorders (ASD) and severity of intellectual disability (ID) are known risk factors for SIB, there are no studies comparing SIB topographies by severity degrees of ID and ASD. The purpose of the present paper has been to identify risk factors and topographies for SIB in a representative, stratified and randomised sample of adults with IDD. METHOD: This study was conducted on the basis of data collected by the POMONA-ESP project, in a sample of 833 adults with IDD. Data concerning demographic and health information, ASD symptoms, psychopathology and ID, have been analysed to determine the presence of risk factors for SIB among participants and to explore the occurrence and topographies of SIB across different severity levels of ID and ASD symptoms. RESULTS: Self-injurious behaviour prevalence in the sample was 16.2%. Younger age, oral pain, greater severity of ID, presence of dual diagnosis, psychiatric medication intake and higher scores on Childhood Autism Rating Scale were risk factors for SIB among participants, whereas number of areas with functioning limitations, place of residence, diagnosis of epilepsy and sex were not. SIB was more frequent in participants with ASD symptoms regardless of its severity level, and they displayed a higher number of different topographies of SIB. People with profound ID without co-morbid ASD symptoms showed similar results concerning SIB prevalence and topographies. CONCLUSIONS: Knowledge on risk factors and topographies of SIB might play a vital role in the development of prevention strategies and management of SIB in people with IDD. The mere presence of ASD symptoms, regardless of its severity level, can be a crucial factor to be taken into account in assessing SIB. Accordingly, the presence of SIB in people with ID, especially when presented with a varied number of topographies, might provide guidance on ASD differential diagnosis. PMID- 29607563 TI - Investigation of thyroid nodules: A practical algorithm and review of guidelines. AB - BACKGROUND: High resolution ultrasound has led to early detection of subclinical tumors and drastic increase in incidence of thyroid malignancy. To achieve a balance in appropriate investigation without perpetuating an overdiagnosis phenomenon, a concise set of evidence-based recommendations to stratify risk is required. METHODS: We sought to assemble an evidence-based diagnostic algorithm and accompanying pictorial review for workup of thyroid nodules that summarizes the most recent guidelines. In addition, we conducted a literature search and analysis of our imaging databases. RESULTS: Although many imaging features of benign and malignant nodules can be nonspecific, others, such as microcalcifications, lymphadenopathy, and peripheral invasion, are highly suggestive of malignancy. The predictive values of salient imaging characteristics are presented. CONCLUSION: Evidence-based guidelines are available such that a cost-effective algorithm for thyroid nodule workup can be devised. Conservative management with a focus on periodic monitoring is the working clinical consensus on the approach to thyroid nodules. PMID- 29607564 TI - Ambient ionisation mass spectrometry for in situ analysis of intact proteins. AB - Ambient surface mass spectrometry is an emerging field which shows great promise for the analysis of biomolecules directly from their biological substrate. In this article, we describe ambient ionisation mass spectrometry techniques for the in situ analysis of intact proteins. As a broad approach, the analysis of intact proteins offers unique advantages for the determination of primary sequence variations and posttranslational modifications, as well as interrogation of tertiary and quaternary structure and protein-protein/ligand interactions. In situ analysis of intact proteins offers the potential to couple these advantages with information relating to their biological environment, for example, their spatial distributions within healthy and diseased tissues. Here, we describe the techniques most commonly applied to in situ protein analysis (liquid extraction surface analysis, continuous flow liquid microjunction surface sampling, nano desorption electrospray ionisation, and desorption electrospray ionisation), their advantages, and limitations and describe their applications to date. We also discuss the incorporation of ion mobility spectrometry techniques (high field asymmetric waveform ion mobility spectrometry and travelling wave ion mobility spectrometry) into ambient workflows. Finally, future directions for the field are discussed. PMID- 29607566 TI - Effects of gadolinium-based MRI contrast agents on liver tissue. AB - BACKGROUND: MRI with contrast is often used clinically. However, recent studies have reported a high accumulation of gadolinium-based contrast agents (GBCAs) in kidney, liver, and spleen tissues in several mouse models. PURPOSE: To compare the effects on liver tissue of gadolinium-based MRI contrast agents in the light of biochemical and histopathological evaluation. STUDY TYPE: Institutional Review Board (IRB)-approved controlled longitudinal study. ANIMAL MODEL: In all, 32 male Sprague-Dawley rats were divided into a healthy control group subjected to no procedure (Group 1), a sham group (Group 2), a gadodiamide group (Group 3), and a gadoteric acid group (Group 4). FIELD STRENGTH/SEQUENCE: Not applicable. ASSESSMENT: Liver tissues removed at the end of the fifth week and evaluated pathologically (scored Knodell's histological activity index [HAI] method by two histopathologists) immunohistochemical (caspase-3 and biochemical tests (AST, ALT, TAS, TOS, and OSI method by Erel et al) were obtained. STATISTICAL TESTS: Differences between groups were analyzed using the nonparametric Kruskal-Wallis test followed by the Tamhane test, and one-way analysis of variance (ANOVA) followed by Turkey's HSD test. RESULTS: An increase was observed in histological activity scores in sections from rats administered gadodiamide and gadoteric acid, and in caspase-3, AST and ALT values (P < 0.05). In contrast, we determined no change in TOS (P = 0.568 and P = 0.094, respectively), TAS (P = 0.151 and P = 0.055, respectively), or OSI (P = 0.949 and P = 0.494, respectively) values. DATA CONCLUSION: These data suggest that gadodiamide and gadoteric acid trigger hepatocellular necrosis and apoptosis by causing damage in hepatocytes, although no change occurs in total antioxidant and antioxidant capacity. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2018;47:1367 1374. PMID- 29607565 TI - Prognostic implications of CD44, NANOG, OCT4, and BMI1 expression in tongue squamous cell carcinoma. AB - BACKGROUND: Tongue squamous cell carcinoma (SCC) contains a cell subpopulation referred to as cancer stem cells (CSCs), which are responsible for tumor growth, metastasis, and resistance to chemotherapy and radiotherapy. The CSC markers have been used to isolate these cells and as biomarkers to predict overall survival. METHODS: The CSC markers CD44, NANOG, OCT4, and BMI1 were investigated using reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) and immunohistochemistry and correlated with clinicopathological parameters. RESULTS: The CD44 overexpression was associated with disease-related death (P = 0.02) and worst prognosis. NANOG was upregulated in nontumoral margins and associated with T1/T2 classification, lymph node metastasis, and worst prognosis. OCT4 was associated with lymph node metastasis and worst overall survival. BMI1 and CD44v3 were overexpressed in tongue SCC. Coexpression of CD44++ /NANOG++ was associated with worst overall survival when compared with patients with CD44-/+ /NANOG-/+ . CONCLUSION: The CSC markers might play an important role not only in CSC trait acquisition but also in tongue SCC development and progression. PMID- 29607567 TI - Shear strain rate from phase contrast velocity encoded MRI: Application to study effects of aging in the medial gastrocnemius muscle. AB - BACKGROUND: Strain rate (SR) is a measure of the rate of regional deformation that can be computed by analyzing velocity-encoded phase-contrast 2D images. Recent studies have explored the changes in normal components of the strain tensor in aging muscle, while shear strain may also provide valuable information. PURPOSE: To compute the shear SR from velocity-encoded MRI of the lower leg and to study the correlation of SR parameters measured in the medial gastrocnemius (MG) to muscle force in a cohort of young and senior subjects. STUDY TYPE: Prospective cohort study. SUBJECTS: Six young (26.1 +/- 2.3 years) and six senior (76.7 +/- 8.3 years) healthy females; two other subjects were scanned on three separate occasions for repeatability studies. FIELD STRENGTH/SEQUENCE: 1.5T using a single oblique sagittal slice with velocity-encoding in three directions (velocity-encoded phase contrast gradient echo sequence). ASSESSMENT: Age-related and regional differences in the SR eigenvalues (SRfiber , SRin-plane ), normal SRs (SRff , SRcc ), and shear SRs (SRfc , SRfc_max ) were statistically analyzed. STATISTICAL TESTS: Difference between young and senior cohorts were assessed using two-way analysis of variance (ANOVAs). The coefficient of variation and repeatability coefficient were calculated from repeat studies. Univariate and stepwise multivariable linear regression was performed to identify predictors of force. RESULTS: During isometric plantarflexion contraction, SRs in the principal basis (SRfiber , SRin-plane ) and maximum shear SR (SRfc_max ) was significantly lower in the senior cohort (P < 0.05). On multiple variable regression, maximum shear SR (SRfc_max ) and normal SR in the fiber cross-section (SRcc ) were significantly associated with force (R = 0.681, F = 14.034, P < 0.001). DATA CONCLUSION: This study establishes that computation of shear strain is feasible and is a significant predictor of force variability with age. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1351-1357. PMID- 29607569 TI - Neurodevelopmental outcome of fetal isolated ventricular asymmetry without dilation: a cohort study. AB - OBJECTIVE: Fetal isolated ventricular asymmetry (IVA) is a relatively common finding in pregnancy, but data regarding its effect on neurodevelopmental outcome are scarce and founded principally on ultrasound-based studies. The purpose of this study was to assess the neurodevelopmental outcome of IVA cases in a magnetic resonance imaging (MRI)-based study. METHODS: Cases referred for fetal brain MRI as part of the assessment of IVA without ventriculomegaly (lateral ventricular atrial diameter <= 10 mm), identified during routine ultrasound examination, were assessed for possible inclusion. Asymmetry was defined as a difference in width of >= 2 mm between the two lateral ventricles. Forty-three cases were included in the study group and compared with a control group of 94 normal cases without IVA. Children were assessed at ages 13-74 months using the Vineland-II Adaptive Behavior Scales (VABS-II). RESULTS: VABS-II scores were within normal range. There was no significant difference in composite VABS-II score between the study and control groups (106.5 vs 108.0; P = 0.454). VABS-II scores did not differ between the groups when matched for gender and age at VABS II interview (109.6 in study group vs 107.8 in control group; P = 0.690). CONCLUSION: In cases of IVA without ventriculomegaly on MRI, neurodevelopmental test scores were normal and did not differ from cases without IVA. Copyright (c) 2018 ISUOG. Published by John Wiley & Sons Ltd. PMID- 29607568 TI - Reducing potentially inappropriate drug prescribing in nursing home residents: effectiveness of a geriatric intervention. AB - AIMS: Potentially inappropriate drug prescribing (PIDP) is frequent in nursing home (NH) residents. We aimed to investigate whether a geriatric intervention on quality of care reduced PIDP. METHODS: We performed an ancillary study within a multicentric individually-tailored controlled trial (IQUARE trial). All NH received a baseline and 18-month audit regarding drug prescriptions and other quality of care indicators. After the initial audit, NHs of the intervention group benefited of an in-site intervention (geriatric education for NH staff) provided by a geriatrician from the closest hospital. The analysis included 629 residents of 159 NHs. The main outcome was PIDP, defined as the presence of at least one of the following criteria: (i) drug with an unfavourable benefit-to risk ratio; (ii) with questionable efficacy; (iii) absolute contraindication; (iv) significant drug-drug interaction. Multivariable multilevel logistic regression models were performed including residents and NH factors as confounders. RESULTS: PIDP was 65.2% (-3.6% from baseline) in the intervention group (n = 339) and 69.9% (-2.3%) in the control group (n = 290). The intervention significantly decreased PIDP [odds ratio (OR) = 0.63; 95% confidence interval 0.40-0.99], as a special care unit in NH (OR = 0.60; (0.42 to 0.85)), and a fall in the last 12 months (OR = 0.63; 0.44-0.90). Charlson Comorbidity Index [ORCCI = 1 vs. 0 = 1.38; 0.87-2.19, ORCCI >= 2 vs. 0 = 2.01; (1.31-3.08)] and psychiatric advice and/or hospitalization in a psychiatric unit (OR = 1.53; 1.07-2.18) increased the likelihood of PIDP. CONCLUSION: This intervention based on a global geriatric education resulted in a significant reduction of PIDP at patient level. PMID- 29607570 TI - Incidence and Etiology of Microinfarcts in Patients with Ischemic Stroke. AB - BACKGROUND AND PURPOSE: Cerebral microinfarcts (CMI) are associated with intracerebral hemorrhage due to small vessel disease (SVD) in studies not including an ischemic etiologic workup. We aimed to determine their incidence and potential causes in a large ischemic stroke (IS) cohort. METHODS: Consecutive patients with MRI-confirmed IS within 72 hours of onset were enrolled. Subjects had either single high-risk embolic source (cardioembolic or large vessel disease) or no embolic source. CMIs were classified by their relationship to the primary infarct as within or outside the same vascular territory. White matter hyperintensities (WMH) and microbleeds were markers SVD severity. Multivariable regression tested the association between CMIs and potential etiologies. RESULTS: We analyzed 946 IS patients, mean age 69 +/- 15 years, 46% female. We detected CMI (<=5 mm) on diffusion-weighted imaging in 269 (28%) subjects, 190 (71%) within the vascular territory of the primary infarct. Large-vessel atherosclerosis (P <.001), cardioembolic source (P <.001), higher WMH (P = .032) and lower systolic blood pressure (SBP, P = .024) were independently associated with the presence of CMI. While SBP was associated with CMI in any location (P <.05), WMH was only associated with CMI outside the territory of the primary infarct (P = .033), and large vessel atherosclerosis with CMI within the primary infarct territory (P = .004). CONCLUSIONS: CMIs occurring within the vascular territory of a larger infarct are more likely embolic, but those occurring outside are probably related to SVD. Our findings suggest a role for SVD in pathogenesis of CMIs and emphasize the importance of etiologic workup to identify alternate etiologies. PMID- 29607571 TI - The impact of NHS expenditure on health outcomes in England: Alternative approaches to identification in all-cause and disease specific models of mortality. AB - Several recent studies have estimated the responsiveness of mortality to English National Health Service spending. Although broadly similar, the studies differ in how they identify the outcome equation. One approach uses conventional socio economic variables as instruments for endogenous health care expenditure, whereas the other exploits exogenous elements in the resource allocation formula for local budgets. The former approach has usually been applied to specific disease areas (e.g., for cancer and circulatory disease), whereas the other has only been applied to all-cause mortality. In this letter, we compare the two approaches by using them to estimate the direct all-cause elasticity as well as disease specific elasticities. We also calculate the implied all-cause elasticity associated with the disease-specific results. We find that the "funding rule" approach to identification can be successfully replicated and applied to disease area models. This is important because disease area models reduce the danger of aggregation bias present in all-cause analysis, and they offer the opportunity to link estimated mortality effects to more complete measures of health outcome that reflect what is currently known about the survival and morbidity disease burden in different programmes. PMID- 29607572 TI - A clinical guidance to DFNA22 drawn from a Korean cohort study with an autosomal dominant deaf population: A retrospective cohort study. AB - BACKGROUND: The MYO6 gene, if altered, can cause nonsyndromic hearing loss (NSHL) either in an autosomal dominant (AD) (DFNA22) or recessive form. The present study identified MYO6 variants in the cohort of Korean AD NSHL families and investigated the audiological phenotypes of DFNA22 with respect to suggesting clinical guides for the counseling of DFNA22. METHODS: A retrospective cohort study was performed on 81 AD NSHL families in two hospitals. Among them, five families (SH21, SB60, SB247, SB290 and SB305) segregating with MYO6 variant were genetically and clinically assessed. RESULTS: We identified two novel missense variants of MYO6: p.G223R (SB290) and p.T158R (SB305). A known heterozygous truncation variant, p.R205X, reported previously (SH21, SB60), was identified (SB247). The overall frequency of DFNA22 among such cases was 6.2%. Specifically, we found p.R205X from three of five DFNA22 families (60%). Five DFNA22 families demonstrated extremely diverse audiogram configurations and age of onset with even intrafamilial variations, whereas the severity of hearing loss mostly ranged within moderate. CONCLUSIONS: We report a recurring predominant allele and two new missense variants of MYO6, highlighting the significant contribution of MYO6 to AD NSHL in the Korean population. Extremely diverse audiological configurations of DFNA22 suggest that MYO6 should be considered in future genetic studies of patients with AD NSHL. Gradual progression with a good speech audiometry score could provide physicians with clinical insight with respect to advising patients to use hearing aids or consider middle ear implants, whereas, in the case of certain exceptional circumstances, physicians could provide patients with the option to consider a cochlear implant. PMID- 29607573 TI - Lithium and nephrotoxicity: Unravelling the complex pathophysiological threads of the lightest metal. AB - While lithium remains the most efficacious treatment for bipolar disorder, it can cause significant nephrotoxicity. The molecular mechanisms behind both this process and the development of nephrogenic diabetes insipidus still remain to be fully elucidated but appear to involve alterations in glycogen synthase kinase 3 signalling, G2 cell cycle progression arrest, alterations in inositol and prostaglandin signalling pathways, and dysregulated trafficking and transcription of aquaporin 2 water channels. The end result of this is a tubulointerstitial nephropathy with microcyst formation and relative glomerular sparing, both visible on pathology specimens and increasingly noted on non-invasive imaging. This paper will elucidate the current evidence pertaining to the pathophysiology of lithium induced nephrotoxicity. PMID- 29607574 TI - Wall shear stress estimation in the aorta: Impact of wall motion, spatiotemporal resolution, and phase noise. AB - BACKGROUND: Wall shear stress (WSS) presents an important parameter for assessing blood flow characteristics and evaluating flow-mediated lesions in the aorta. PURPOSE: To investigate the robustness of WSS and oscillatory shear index (OSI) estimation based on 4D flow MRI against vessel wall motion, spatiotemporal resolution, and velocity encoding (VENC). STUDY TYPE: Simulated and prospective. POPULATION: Synthetic 4D flow MRI data of the aorta, simulated using the Lattice Boltzmann method; in vivo 4D flow MRI data of the aorta from healthy volunteers (n = 11) and patients with congenital heart defects (n = 17). FIELD STRENGTH/SEQUENCE: 1.5T; 4D flow MRI with PEAK-GRAPPA acceleration and prospective electrocardiogram triggering. ASSESSMENT: Predicated upon 3D cubic B splines interpolation of the image velocity field, WSS was estimated in mid systole, early-diastole, and late-diastole and OSI was derived. We assessed the impact of spatiotemporal resolution and phase noise, and compared results based on tracked-using deformable registration-and static vessel wall location. STATISTICAL TESTS: Bland-Altman analysis to assess WSS/OSI differences; Hausdorff distance (HD) to assess wall motion; and Pearson's correlation coefficient (PCC) to assess correlation of HD with WSS. RESULTS: Synthetic data results show systematic over-/underestimation of WSS when different spatial resolution (mean +/- 1.96 SD up to -0.24 +/- 0.40 N/m2 and 0.5 +/- 1.38 N/m2 for 8-fold and 27 fold voxel size, respectively) and VENC-depending phase noise (mean +/- 1.96 SD up to 0.31 +/- 0.12 N/m2 and 0.94 +/- 0.28 N/m2 for 2-fold and 4-fold VENC increase, respectively) are given. Neglecting wall motion when defining the vessel wall perturbs WSS estimates to a considerable extent (1.96 SD up to 1.21 N/m2 ) without systematic over-/underestimation (Bland-Altman mean range -0.06 to 0.05). DATA CONCLUSION: In addition to sufficient spatial resolution and velocity to noise ratio, accurate tracking of the vessel wall is essential for reliable image-based WSS estimation and should not be neglected if wall motion is present. LEVEL OF EVIDENCE: 2 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018. PMID- 29607575 TI - Regulation of muscle protein synthesis in an in vitro cell model using ex vivo human serum. AB - NEW FINDINGS: What is the central question of this study? Can medium conditioned by ex vivo human serum regulate muscle protein synthesis in skeletal muscle cells in vitro? What is the main finding and its importance? This study demonstrates that medium conditioned by ex vivo human serum can regulate muscle protein synthesis in skeletal muscle cells in vitro via the mammalian Target of Rapomycin (mTOR) pathway, and this can be regulated differentially by fed and fasted ex vivo human serum. ABSTRACT: Human serum embodies the integrated systemic response to any condition or perturbation, which may regulate muscle protein synthesis (MPS). Conditioning of medium with human serum represents a physiologically relevant method of regulating MPS in vitro. The primary purpose of the study was the development of a model using ex vivo human serum to condition medium and regulate MPS in in vitro skeletal muscle cells. Four young healthy men reported to the laboratory after an overnight fast and were fed with 0.33 g (kg body mass) 1 whey protein. Blood samples were taken before (Fasted) and 60 min postprandial (Fed). Fully differentiated C2C12 skeletal muscle cells were nutrient and serum deprived for 1 h and subsequently treated with medium conditioned with Fasted or Fed ex vivo human serum (20%) for 4 h. The MPS was measured using the surface sensing of translation technique and activation of mTOR, P70S6K and 4EBP1 by Western blot. Fasted and fed ex vivo human serum increased MPS (P < 0.05). Although a strong effect (n2 = 0.36) for increased MPS in Fed relative to Fasted was observed, this was not statistically significant (P > 0.05). Activation of mTOR, P70S6K and 4EBP1 was significantly increased after treatment with Fed compared with Fasted ex vivo human serum (P < 0.05). Here, we developed and optimized the conditions for culture of C2C12 skeletal muscle cells, measurement of MPS and signalling in medium conditioned by ex vivo human serum. Furthermore, the functionality of the model was demonstrated by comparison of the response to medium conditioned by Fasted and Fed ex vivo human serum. PMID- 29607576 TI - Letter to 'Management of pregnancy complicated with intracranial arteriovenous malformation'. PMID- 29607577 TI - Clinical course of dengue fever and its impact on renal function in renal transplant recipients and patients with chronic kidney disease. AB - BACKGROUND: Dengue fever is a mosquito-borne viral disease endemic in many tropical and sub-tropical countries. There is only limited data in the literature about dengue fever in renal transplant recipients and patients with chronic kidney disease. This study compares the clinical course of dengue fever and its impact on renal function in renal transplant recipients, patients with chronic kidney disease and patients with normal base line renal function. METHODS: An observational study was conducted from 1st May to 31st July 2017, at a tertiary care centre of South India. A major epidemic of dengue had occurred during the study period. Twelve renal transplant recipients, 22 patients with CKD and 58 patients with normal baseline renal function (control group) admitted with dengue fever were prospectively studied. RESULTS: Nadir WBC count was lowest in renal transplant recipients (2575 + 1187/mm3 ), [P<0.001]. Renal transplant recipients took more time for normalisation of platelet count (6 + 4.5 days), [P<0.001]. All 22 patients with CKD and 11 of 12 renal transplant recipients had worsening of renal function where as only 17 of 58 patients in the control group had worsening [P<0.001]. Sixteen patients with CKD, one renal transplant recipient and none among control group required hemodialysis [P<0.001]. Dialysis requiring patients had more hemoconcentration (52.5+ 19.9% increase in haemoglobin), [P<0.001]. Seven patients with CKD were dialysis dependent at the end of 2 weeks. CONCLUSIONS: Clinical features of dengue fever were different in renal transplant recipients and patients with CKD. Severe worsening of renal function was common in CKD patients. Worsening of renal function in renal transplant recipients was less severe and transient. PMID- 29607578 TI - Anti-Hu antibody-mediated limbic encephalitis associated with cervical cancer: A case report. AB - A 55-year-old postmenopausal and multiparous woman presented to our department with recent memory disturbances associated with rapidly progressive positive Anti Hu antibodies. She was subsequently diagnosed with anti-Hu antibody-related paraneoplastic limbic encephalitis. Clinical examination and imaging studies revealed a bulky cervical tumor with both parametrial and vaginal fornix extension; biopsy confirmed the tumor as cervical squamous cell carcinoma. In this case, we encountered a patient with anti-Hu-mediated paraneoplastic limbic encephalitis with a subsequent diagnosis of cervical cancer. PMID- 29607579 TI - Ultrasonographic prediction of antepartum deterioration of growth-restricted fetuses after late preterm. AB - AIM: To examine the predictive value of ultrasound parameters for antepartum non reassuring fetal status (NRFS) in fetal growth restriction (FGR) cases after late preterm. METHODS: Retrospective review of singleton FGR cases before 37 weeks gestation who delivered after 34 weeks gestation was performed. The association between ultrasound parameters that was assessed from 34 to 36 weeks gestation and the development of antepartum NRFS that was diagnosed by nonstress test and biophysical profile was analyzed by using multivariate Cox proportional hazards analyses. RESULTS: A total of 214 patients were included in final data analyses. Antepartum NRFS occurred in 23 cases (10.7%) including five cases of placental abruption. Lower standard deviation (SD) of estimated fetal weight (EFW), lower cerebroplacental ratio (CPR) and the presence of oligohydramnios were independently associated with antepartum NRFS. The prevalence of antepartum NRFS was highest (50.4%) in the group of EFW <=-2.5 SD with CPR <=1.45. CONCLUSION: Ultrasound parameters of lower SD of EFW, lower CPR and oligohydramnios were predictive for antepartum NRFS in FGR after late preterm. PMID- 29607580 TI - Effectiveness of antenatal perineal massage in reducing perineal trauma and post partum morbidities: A randomized controlled trial. AB - AIM: The study aimed to evaluate the effectiveness of antenatal perineal massage (APM) in reducing perineal trauma and post-partum morbidities. METHODS: A randomized controlled trial of 108 primigravidae at the University of Nigeria Teaching Hospital, Enugu, Nigeria, was conducted from January 2013 to May 2014. The intervention group received APM, while the control group did not receive APM. RESULTS: Women who received APM were significantly more likely to have an intact perineum after childbirth [27/53 (50.9%) vs 16/55 (29.1%); RR: 1.75; 95% CI: 1.07 2.86; P = 0.02]. The incidence of episiotomy was lower in the intervention group [20/53 (37.7%) vs 32/55 (58.2%); RR: 0.65; 95% CI: 0.43-0.98; P = 0.03; NNT = 5]. Women who received APM were significantly less likely to develop flatus incontinence [4/53 (8.3%) vs 13/55 (26.0%); RR: 0.32; 95% CI: 0.11-0.91; P = 0.03]. However, the incidences of premature rupture of membranes, preterm labor and birth asphyxia were similar between the two groups (P > 0.05). CONCLUSION: APM reduces the incidence of episiotomy and increases the incidence of women with an intact perineum after vaginal delivery. It also reduces the risk of flatus incontinence after childbirth without increased maternal or neonatal complications. Women should therefore be counseled on the likely benefits of APM and the information provided during antenatal care. Obstetricians should consider the technique as routine prenatal care for nulliparous women so as to reduce the incidence of perineal trauma during vaginal birth. PMID- 29607581 TI - Roux-en-Y enterolith leading to obstruction and ischemic necrosis after pediatric orthotopic liver transplantation. AB - Biliary complications are a common cause of morbidity after liver transplantation, with biliary stone formation being a known occurrence generally upstream of a stricture. A 12-year-old boy, who underwent an orthotopic liver transplantation at 11 months of age for biliary atresia, presented acutely with fever and abdominal pain. Cross-sectional imaging revealed Roux-en-Y limb dilatation and thickening. He was explored and was found to have an ischemic Roux limb secondary to an obstructing enterolith. A segmental bowel resection and revision of his hepaticojejunostomy was performed. While rare, biliary enteroliths may present as either a bowel obstruction or cholangitis and should be considered in the differential diagnosis of a patient following biliary reconstruction. Additionally, anatomic etiologies should be considered and potentially surgically corrected. PMID- 29607582 TI - Female paraurethral leiomyoma successfully excised through a vaginal approach: A case report. AB - Paraurethral leiomyomas are extremely rare, and few cases have been reported in the literature. Because of the rarity of the disease and its anatomical complexity, diagnosis and management is challenging for clinicians. Here, we herein report the case of a 50-year-old woman who complained of a protruding mass at the urethral opening. Magnetic resonance imaging revealed a sharply defined tumor measuring 43 * 36 * 26 mm in diameter, located in the anterior vaginal wall, compressing the urethra. Based on the perioperative diagnosis of leiomyoma, the paraurethral tumor was excised via the vaginal approach. The patient was discharged 4 days postoperatively without any complications. Pathological features confirmed the diagnosis of leiomyoma. This case implies that, although there is the possibility of complications due to the surgical procedure, tumor removal is a reasonable choice for management to exclude malignancy and relieve symptoms. PMID- 29607583 TI - Occupancy rate and adverse patient outcomes in general hospitals in Thailand: A predictive study. AB - Patient outcomes are important indicators of the quality of care. Occupancy rate is one factor that significantly affects adverse patient outcomes. The aim of the present study was to determine factors associated with adverse patient outcomes in Thailand. A retrospective study was conducted with 146 inpatient units from 16 general hospitals. Hospital characteristics and adverse patient outcomes were recorded, and data were analyzed by using frequency, percentage, and binomial logistic regression. The results revealed that the average number of beds per hospital was 430.5 (standard deviation [SD] = 108.6), the average number of beds per unit was 27.9 (SD = 8.9), and the average occupancy rate was 81.1% (SD = 20.6, range = 28.8-133.1%). Data were adjusted for hospital size, unit type, and number of beds in each unit; a 1% increase in occupancy rate increased the likelihood of pressure ulcers by 4.3% (P = 0.001), of hospital-acquired pneumonia by 2.4% (P = 0.032), and of hospital-acquired urinary tract infections by 2.1% (P = 0.033). The findings suggest that a higher level of occupancy rates predicted a greater likelihood of adverse patient outcomes. PMID- 29607585 TI - Arabidopsis thaliana expressing PbBSMT, a gene encoding a SABATH-type methyltransferase from the plant pathogenic protist Plasmodiophora brassicae, show leaf chlorosis and altered host susceptibility. AB - The plant pathogenic protist Plasmodiophora brassicae causes clubroot disease of Brassicaceae. This biotrophic organism can down-regulate plant defence responses. The previously characterised P. brassicae PbBSMT methyltransferase has substrate specificity for salicylic, benzoic and anthranilic acids. We therefore propose a role for the methylation of SA in attenuating plant defence response in infected roots as a novel strategy for intracellular parasitism. We overexpressed PbBSMT under the control of an inducible promoter in Arabidopsis thaliana and performed physiological, molecular and phytopathological analyses with the transgenic plants under control and induced conditions in comparison to the wild type. Upon induction, transcription of PbBSMT was associated with: (1) strong leaf phenotypes from anthocyanin accumulation and chlorosis followed by browning; (2) increased plant susceptibility after infection with P. brassicae that was manifested as more yellow leaves and reduced growth of upper plant parts; and (3) induced transgenic plants were not able to support large galls and had a brownish appearance of some clubs. Microarray data indicated that chlorophyll loss was accompanied by reduced transcription of genes involved in photosynthesis, while genes encoding glucose metabolism, mitochondrial functions and cell wall synthesis were up-regulated. Our results indicate a role for PbBSMT in attenuation of host defence responses in the roots by metabolising a plant defence signal. PMID- 29607584 TI - Perceived sources of stress amongst dental students: A multicountry study. AB - AIMS: The aim of this study was to explore the perceived sources of stress reported by dental students from fourteen different countries. METHODS: A total of 3568 dental students were recruited from 14 different dental schools. The dental environmental stress (DES) questionnaire was used including 7 domains. Responses to the DES were scored in 4-point Likert scale. Comparison between students was performed according to the study variables. The top 5 stress provoking questions were identified amongst dental schools. Data were analysed using SPSS software program. Mann-Whitney and Kruskal-Wallis tests were used as appropriate. Logistic regression analysis was also conducted to determine the effect of the studied variables on the stress domains. The level of statistical significance was set at <.05. RESULTS: Internal consistency of the scale was excellent (0.927). Female students formed the majority of the total student population. The percentage of married students was 4.8%. Numbers of students in pre-clinical and clinical stages were close together. The most stress-provoking domain was "workload" with a score of 2.05 +/- 0.56. Female students scored higher stress than male students did in most of the domains. Significant differences were found between participating countries in all stress-provoking domains. Dental students from Egypt scored the highest level of stress whilst dental students from Jordan scored the lowest level of stress. CONCLUSION: The self-reported stress in the dental environment is still high and the stressors seem to be comparable amongst the participating countries. Effective management programmes are needed to minimise dental environment stress. PMID- 29607587 TI - On the move through time - a historical review of plant clock research. AB - The circadian clock is an important regulator of growth and development that has evolved to help organisms to anticipate the predictably occurring events on the planet, such as light-dark transitions, and adapt growth and development to these. This review looks back in history on how knowledge about the endogenous biological clock has been acquired over the centuries, with a focus on discoveries in plants. Key findings at the physiological, genetic and molecular level are described and the role of the circadian clock in important molecular processes is reviewed. PMID- 29607586 TI - Exploring the feasibility and utility of exome-scale tumour sequencing in a clinical setting. AB - BACKGROUND: Technology has progressed from single gene panel to large-scale genomic sequencing. This is raising expectations from clinicians and patients alike. The utility and performance of this technology in a clinical setting needs to be evaluated. AIM: This pilot study investigated the feasibility of using exome-scale sequencing (ESS) to identify molecular drivers within cancers in real time for Precision Oncology in the clinic. METHODS: Between March 2014 and March 2015, the Victorian Comprehensive Cancer Centre Alliance explored the feasibility and utility of ESS in a pilot study. DNA extracted from the tumour specimens underwent both ESS and targeted 'hotspot' sequencing (TS). Blood was taken for germline analysis. A multi-disciplinary molecular tumour board determined the clinical relevance of identified mutations; in particular, whether they were 'actionable' and/or 'druggable'. RESULTS: Of 23 patients screened, 15 (65%) met the tissue requirements for genomic analysis. TS and ESS were successful in all cases. ESS identified pathogenic somatic variants in 73% (11/15 cases) versus 53% (8/15 cases) using TS. Clinically focused ESS identified 63 variants, consisting of 30 somatic variants (including all 13 identified by TS) and 33 germline variants. Overall, there were 48 unique variants. ESS had a clinical impact in 53% (8/15 cases); 47% (7/15 cases) were referred to the familial cancer clinic, and 'druggable' targets were identified in 53% (8/15 cases). CONCLUSION: ESS of tumour DNA impacted clinical decision-making in 53%, with 20% more pathogenic variants identified through ESS than TS. The identification of germline variants in 47% was an unexpected finding. PMID- 29607588 TI - Atomically Precise Nanocluster Assemblies Encapsulating Plasmonic Gold Nanorods. AB - The self-assembled structures of atomically precise, ligand-protected noble metal nanoclusters leading to encapsulation of plasmonic gold nanorods (GNRs) is presented. Unlike highly sophisticated DNA nanotechnology, this strategically simple hydrogen bonding-directed self-assembly of nanoclusters leads to octahedral nanocrystals encapsulating GNRs. Specifically, the p-mercaptobenzoic acid (pMBA)-protected atomically precise silver nanocluster, Na4 [Ag44 (pMBA)30 ], and pMBA-functionalized GNRs were used. High-resolution transmission and scanning transmission electron tomographic reconstructions suggest that the geometry of the GNR surface is responsible for directing the assembly of silver nanoclusters via H-bonding, leading to octahedral symmetry. The use of water dispersible gold nanoclusters, Au~250 (pMBA)n and Au102 (pMBA)44 , also formed layered shells encapsulating GNRs. Such cluster assemblies on colloidal particles are a new category of precision hybrids with diverse possibilities. PMID- 29607590 TI - Assessing transcriptional network changes accompanying cell differentiation. PMID- 29607589 TI - Analytical Chemistry: Current Trends in Light of the Historic Beginnings. AB - Selected current trends in analytical chemistry are discussed and traced back to original work published more than a hundred years ago in the same field. Gravimetric microanalysis has been transformed into a mass-sensitive sensor technology. New developments in molecular spectroscopy are seen in Raman spectroscopy. In the area of chemical sensors, paper-based devices with visual readout (dipsticks, microfluidic pads) celebrate a revival. In "green" applications, the separation of analytes from complicated matrices is often the key to successful analysis. Continuous separation techniques are essential for the 24/7 production of goods with certified quality. Finally, micro- and nanoscale techniques rely on highly selective receptors, and their development is based on detailed understanding of the structure of ligand-receptor complexes. PMID- 29607591 TI - Correction. PMID- 29607592 TI - Atomic Layer Deposition of the Metal Pyrites FeS2 , CoS2 , and NiS2. AB - Atomic layer deposition (ALD) of the pyrite-type metal disulfides FeS2 , CoS2 , and NiS2 is reported for the first time. The deposition processes use iron, cobalt, and nickel amidinate compounds as the corresponding metal precursors and the H2 S plasma as the sulfur source. All the processes are demonstrated to follow ideal self-limiting ALD growth behavior to produce fairly pure, smooth, well-crystallized, stoichiometric pyrite FeS2 , CoS2 , and NiS2 films. By these processes, the FeS2 , CoS2 , and NiS2 films can also be uniformly and conformally deposited into deep narrow trenches with aspect ratios as high as 10:1, which thereby highlights the broad and promising applicability of these ALD processes for conformal film coatings on complex high-aspect-ratio 3D architectures in general. PMID- 29607593 TI - Massive transfusions for critical bleeding: is everything old new again? AB - Massive transfusion or major haemorrhage protocols have been widely adopted in the treatment of critically bleeding patients. Following evidence that higher ratios of transfused plasma and platelets to red blood cells may offer survival benefits in military trauma patients, these ratios are now commonly incorporated into massive transfusion protocols. They more closely resemble the effects of whole blood transfusion, which in the second half of last century was largely replaced by individual blood component transfusion based on laboratory-guided indicators. However, high-quality evidence to guide transfusion support for critically bleeding patients across the range of bleeding contexts is lacking, including for both trauma and non-trauma patients. More data on major haemorrhage support and clinical outcomes are needed to inform guidelines and practice. PMID- 29607594 TI - Management of the female athlete triad. AB - The female athlete triad (FAT) is defined by the American College of Sports Medicine (ACSM) as low energy availability (low EA), functional hypothalamic amenorrhoea and osteoporosis. In low EA, lutein dysfunction first develops, followed by anovulation and, subsequently, oligomenorrhea, leading to amenorrhea. Moreover, low estradiol concentrations due to amenorrhea decrease bone mineral density (BMD). In athletes with one of the factors of FAT, the risk of a stress fracture is 2.4-4.9 times higher and may increase the risk of fracture throughout the lifespan. Low EA is the starting point of FAT, and the FAT concept emphasizes the importance of energy intake that is commensurate with exercise energy expenditure in athletes. In amenorrheic athletes who undergo gynecological examination, it is important to appropriately evaluate whether the cause is low EA and to review exercise energy expenditure and energy intake. It remains difficult even for experts to calculate available energy using the ACSM definition formula when evaluating energy deficiency. Moreover, performing early FAT screening during teenage years and cooperation between the department of obstetrics and gynecology and sports dietitians are also issues. The aim of this paper is to review the management of FAT from the viewpoint of gynecologists. PMID- 29607595 TI - Effectiveness of a telephone follow-up nursing intervention in postsurgical patients. AB - BACKGROUND: Surgical recovery can be defined as the days required to initiate activities that maintain life, health, and well-being. AIM: The main study objective was to compare the effectiveness of telephone versus conventional follow-up in postsurgical older adult patients. METHODS: This is a quasi experimental study with random sampling. Postsurgical patients over 60 years old who had undergone gastrectomy and colectomy were selected from 2 hospitals and randomly divided into intervention group (22 patients) and control group (21 patients). Data collection was performed from January to September 2014. The differences in surgical recovery between the control and intervention groups were measured at 48 hours, 4 weeks, and 8 weeks after surgery. RESULTS: Patients in the control group took significantly longer duration in the length of surgical recovery from the first to the second (P = .007) and to the third evaluation time points (P = .013). Patients in the intervention group had significant less impaired mobility (P = .003), need for assistance for self-care (P = .009), fatigue (P = .048), and time required for recuperation (P = .048). CONCLUSION: Telephone follow-up reduced the occurrence of delayed surgical recovery. PMID- 29607596 TI - Epidemiological, clinical and mechanistic perspectives of tuberculosis in older people. AB - With the ageing population globally, tuberculosis (TB) in older people becomes a major clinical and public health challenge. In many Asian countries, especially those located in the eastern and southeastern parts of the continent, geriatric TB is a significant problem. TB in the older patients is more difficult to diagnose in the early course of disease, and has poorer treatment outcomes, largely as increased failure and death. More drug-induced adverse reactions are also experienced by this population during TB therapy. Oxidative stress and mitochondrial dysfunction are now well recognized to be associated with the ageing process, and it is likely that the cellular and molecular perturbations interact inextricably with the immunological dysfunction biophysiologically inherent to ageing. These underlying mechanistic bases putatively contribute to the development of TB in the geriatric population and worsen the disease outcomes, especially when the TB is compounded by co-morbid conditions such as smoking and diabetes mellitus. Unravelling these mechanisms further would yield knowledge that might potentially help to prevent reactivated TB in older people, and also to better manage the established disease with drug regimens and other new therapeutic strategies. In addition, addressing the social elements associated with geriatric TB is also imperative in the relief of individual patient suffering and improvement of overall disease control. PMID- 29607597 TI - The Role of Bi3+ in Promoting and Stabilizing Iron Oxo Clusters in Strong Acid. AB - Metal oxo clusters and metal oxides assemble and precipitate from water in processes that depend on pH, temperature, and concentration. Other parameters that influence the structure, composition, and nuclearity of "molecular" and bulk metal oxides are poorly understood, and have thus not been exploited. Herein, we show that Bi3+ drives the formation of aqueous Fe3+ clusters, usurping the role of pH. We isolated and structurally characterized a Bi/Fe cluster, Fe3 BiO2 (CCl3 COO)8 (THF)(H2 O)2 , and demonstrated its conversion into an iron Keggin ion capped by six Bi3+ irons (Bi6 Fe13 ). The reaction pathway was documented by X ray scattering and mass spectrometry. Opposing the expected trend, increased cluster nuclearity required a pH decrease instead of a pH increase. We attribute this anomalous behavior of Bi/Fe(aq) solutions to Bi3+ , which drives hydrolysis and condensation. Likewise, Bi3+ stabilizes metal oxo clusters and metal oxides in strongly acidic conditions, which is important in applications such as water oxidation for energy storage. PMID- 29607598 TI - Diagnostic value of signal peptide-CUB-EGF domain-containing protein 1 as an early and late biochemical marker in the ovarian torsion rat model. AB - AIMS: Signal peptide-CUB-EGF (epidermal growth factor-like protein) domain containing protein 1 (SCUBE1) is an experimental marker of ischemia that has been previously studied both in rat models and humans. In this study, we aim to investigate the importance of SCUBE1 levels in ovarian torsion using an ovarian torsion model in rats. METHODS: A total of 18 Sprague-Dawley rats were equally divided into three groups. Group 1 (n = 6) was the Sham group and was only given a laparotomy procedure. Group 2 (n = 6) underwent bilateral ovarian torsion and ovarian ischemia lasting 8 h. Group 3 (n = 6) was subjected to bilateral ovarian torsion and ischemia lasting 24 h. Blood samples were collected from all three groups after the operations, and SCUBE1 levels were studied. Ovarian samples were collected, and microscopic evaluation was performed. The correlation of SCUBE1 levels and histopathological findings were investigated. RESULTS: The mean SCUBE1 level of group 3 was statistically higher than other groups (P < 0.01). Follicular degeneration and infiltration of inflammatory cells were, respectively, statistically significant in groups 2 and 3 (P = 0.002 and P = 0.045, respectively). CONCLUSION: SCUBE1 can be useful in diagnosing ovarian torsion during the first 24 h, but more randomized controlled studies are necessary in order to implement it in clinical settings. PMID- 29607600 TI - Opposing effects of floral visitors and soil conditions on the determinants of competitive outcomes maintain species diversity in heterogeneous landscapes. AB - Theory argues that both soil conditions and aboveground trophic interactions have equivalent potential to limit or promote plant diversity. However, it remains unexplored how they jointly modify the niche differences stabilising species coexistence and the average fitness differences driving competitive dominance. We conducted a field study in Mediterranean annual grasslands to parameterise population models of six competing plant species. Spatially explicit floral visitor assemblages and soil salinity variation were characterised for each species. Both floral visitors and soil salinity modified species population dynamics via direct changes in seed production and indirect changes in competitive responses. Although the magnitude and sign of these changes were species-specific, floral visitors promoted coexistence at neighbourhood scales, while soil salinity did so over larger scales by changing the superior competitors' identity. Our results show how below and aboveground interactions maintain diversity in heterogeneous landscapes through their opposing effects on the determinants of competitive outcomes. PMID- 29607599 TI - Evaluation of the neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, and mean platelet volume as inflammatory markers in children with attention-deficit hyperactivity disorder. AB - AIM: The neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), monocyte/lymphocyte ratio (MLR), and mean platelet volume (MPV) have recently been used as indicators of a systemic inflammatory response. The aim of this study was to investigate the relations of the NLR, PLR, MLR, and MPV with attention-deficit hyperactivity disorder (ADHD). METHODS: The study group consisting of 82 children diagnosed with ADHD was compared with a healthy control (HC) group of 70 age-, sex-, and body-mass-index-matched subjects. The NLR, PLR, MLR, and MPV were measured according to the complete blood count. RESULTS: The NLR, PLR, MLR, MPV, and neutrophil count of the ADHD group were significantly higher than those of the HC group. The lymphocyte counts of the patients were significantly lower than those of the HC group. CONCLUSION: Inflammation might play a role in the etiopathogenesis of ADHD. The NLR, PLR, MLR, and MPV may be potential inflammation markers for ADHD in children. PMID- 29607601 TI - Low-dose-rate brachytherapy for the treatment of localised prostate cancer in men with a high risk of disease relapse. AB - OBJECTIVES: To report clinical outcomes of 125 I low-dose-rate prostate brachytherapy (LDR-PB) as monotherapy or combined with androgen-deprivation therapy (ADT) and/or external beam radiotherapy (EBRT) in high-risk localised prostate cancer. PATIENTS AND METHODS: Analysis of clinical outcomes from a prospective cohort of patients treated with LDR-PB alone or combined treatment in a single institution. Men with a high risk of disease relapse were identified by the National Institute for Health and Care Excellence (NICE) criteria or by the National Comprehensive Cancer Network (NCCN) criteria. Relapse-free survival (RFS), overall survival (OS), prostate cancer-specific survival (PCSS), and metastases-free survival (MFS), were analysed together with patient-reported symptom scores and physician-reported adverse events. RESULTS: The NICE and NCCN criteria identified 267 and 202 high-risk patients, respectively. NICE-defined patients had significantly lower pre-treatment PSA levels, Gleason scores <7, and a greater proportion of patients who received LDR-PB monotherapy. At 9 years after implantation RFS was 89% and 87% in the NICE and NCCN groups, respectively (log-rank P = 0.637), and OS 93% and 94%, respectively (log-rank P = 0.481). All of the survival estimates were similar between LDR-PB monotherapy and combined therapies. Cox proportional hazards regression confirmed RFS was similar between the treatment types. Treatment-related toxicity was also similar between the treatment methods. CONCLUSION: LDR-PB is effective at controlling localised prostate cancer in patients with a high risk of disease relapse. As the present study was not randomised, it is not possible to define those patients who need the addition of ADT and/or EBRT. However, the NICE criteria appear suitable to define treatment options where patients could benefit from LDR-PB as monotherapy or combined treatment. This choice should be discussed with the patient taking into account comorbidities and presence of multiple high-risk factors. PMID- 29607603 TI - Nursing knowledge: A middle ground exploration. AB - The discipline of nursing has long maintained that is has a unique contribution to make within the health care arena. This assertion of uniqueness lies in great part in the discipline's claim to a distinct body of knowledge. Nursing knowledge is characterized by diverse and multiple forms of knowing and underpins the work of all nurses, regardless of field of practice. Unfortunately, it has been challenging for the discipline to take full ownership of its epistemological diversity, largely due to factors such as competing worldviews, and ideological and binary positioning. A philosophical middle ground stance is proposed as a way for the discipline to contemplate, discuss and develop nursing knowledge; a middle space that provides the freedom to consider competing worldviews while still allowing for the discipline to fully express itself in all of its epistemological diversity. In being able to enact its multiple forms of knowledge in a creative and open space that is open to different ideas and worldviews, not only can nursing take full ownership of its practice and its unique knowledge, it can also demonstrate how best to navigate an increasingly polarized world. In a world that is increasingly fixated on binary solutions and dualistic points of view, it is time for nursing to celebrate its epistemological diversity. PMID- 29607602 TI - Bedside nurses' roles in discharge collaboration in general internal medicine: Disconnected, disempowered and devalued? AB - Collaboration among nurses and other healthcare professionals is needed for effective hospital discharge planning. However, interprofessional interactions and practices related to discharge vary within and across hospitals. These interactions are influenced by the ways in which healthcare professionals' roles are being shaped by hospital discharge priorities. This study explored the experience of bedside nurses' interprofessional collaboration in relation to discharge in a general medicine unit. An ethnographic approach was employed to obtain an in-depth insight into the perceptions and practices of nurses and other healthcare professionals regarding collaborative practices around discharge. Sixty-five hours of observations was undertaken, and 23 interviews were conducted with nurses and other healthcare professionals. According to our results, bedside nurses had limited engagement in interprofessional collaboration and discharge planning. This was apparent by bedside nurses' absence from morning rounds, one way flow of information from rounds to the bedside nurses following rounds, and limited opportunities for interaction with other healthcare professionals and decision-making during the day. The disconnection, disempowerment and devaluing of bedside nurses in patient discharge planning has implications for quality of care and nursing work. Study findings are positioned within previous work on nurse-physician interactions and the current context of nursing care. PMID- 29607604 TI - An international collaborative study to calibrate the WHO 2nd International Standard for Ancrod (15/106) and the WHO Reference Reagent for Batroxobin (15/140): communication from the SSC of the ISTH. PMID- 29607605 TI - Predictors and causes. PMID- 29607606 TI - Detection of chronic lung allograft dysfunction using ventilation-weighted Fourier decomposition MRI. AB - Chronic lung allograft dysfunction (CLAD) remains the leading cause of morbidity and mortality after lung transplantation. Diagnosis requires spirometric change, which becomes increasingly difficult with advancing CLAD. Fourier decomposition magnetic resonance imaging (FD-MRI) permits acquisition of ventilated-weighted images during free-breathing. This study evaluates FD-MRI in detecting CLAD in selected patients after bilateral lung transplantation (DLTx). DLTx recipients demonstrating CLAD at various stages participated. Radiologists remained blinded to clinical status until completion of image analysis. Image acquisition used a 1.5-T MR scanner using a spoiled gradient echo sequence. After FD processing and regional fractional ventilation (RFV) quantification, the volume defect percentage at 2 thresholds (VDP1,2 ), median lung RFV and quartile coefficient of dispersion (QCD) were calculated. Sixty-two patients participated. CLAD was present in 29/62 (47%) patients, of whom 17/62 (27%) had forced expiratory volume in 1 second <=65% at image acquisition. VDP1 was higher among these participants compared to other groups (P < .001). Increased VDP1 was associated with subsequent graft loss, with values >2% showing reduced survival, independent of degree of graft dysfunction (P = .005). VDP2 discriminated between presence or absence of CLAD (area under the curve = 0.71; P = .03). QCD increased significantly with advancing disease (P < .001). In conclusion, FD-MRI-derived parameters demonstrate potential in quantitative CLAD diagnosis and assessment after DLTx. PMID- 29607607 TI - Alpha-1-antitrypsin in cell and organ transplantation. AB - Limited availability of donor organs and risk of ischemia-reperfusion injury (IRI) seriously restrict organ transplantation. Therapeutics that can prevent or reduce IRI could potentially increase the number of transplants by increasing use of borderline organs and decreasing discards. Alpha-1 antitrypsin (AAT) is an acute phase reactant and serine protease inhibitor that limits inflammatory tissue damage. Purified plasma-derived AAT has been well tolerated in more than 30 years of use to prevent emphysema in AAT-deficient individuals. Accumulating evidence suggests that AAT has additional anti-inflammatory and tissue-protective effects including improving mitochondrial membrane stability, inhibiting apoptosis, inhibiting nuclear factor kappa B activation, modulating pro- vs anti inflammatory cytokine balance, and promoting immunologic tolerance. Cell culture and animal studies have shown that AAT limits tissue injury and promotes cell and tissue survival. AAT can promote tolerance in animal models by downregulating early inflammation and favoring induction and stabilization of regulatory T cells. The diverse intracellular and immune-modulatory effects of AAT and its well-established tolerability in patients suggest that it might be useful in transplantation. Clinical trials, planned and/or in progress, should help determine whether the promise of the animal and cellular studies will be fulfilled by improving outcomes in human organ transplantation. PMID- 29607608 TI - Three-dimensional coculture of primary hepatocytes and stellate cells in silk scaffold improves hepatic morphology and functionality in vitro. AB - A vigorous in vitro model of liver that could recapitulate hepatic phenotype and functionality in vivo would exclusively improve the efficiency of bioartificial liver, drug discovery, or even transplantation therapy. Owing to the indispensable role of three-dimensional (3D) microenvironment in supporting viability and function of hepatocytes in vitro, much effort recently has been focused on improving reproducibility and standardization of primary hepatocyte cultures with a paradigm shift to 3D culture system, In the present study, an improved 3D coculture system of hepatocytes was established in which rat primary hepatocytes were cocultured with hepatic stellate cells in silk porous scaffolds. Silk scaffolds with incorporated extracellular matrix provided a suitable microenvironment for maintaining the viability, morphology and gene expression of the primary hepatocyte in vitro. The presence of stromal cells promoted primary hepatocyte to generate cellular aggregates with well-organized 3D architecture after 3 days of coculture in vitro. These aggregates exhibited proper morphology similar to liver tissue in vivo. Consistent with their phenotypic appearance, well-maintained functionality of hepatocytes was also observed in the cocultures, where albumin secretion/expression, urea synthesis as well as messenger ribonucleic acid expression of multiple cytochrome Ps (CYPs) enzymes increased significantly compared to either the 3D monocultures or monolayer cultures. Additionally, this 3D multicellular coculture model displayed an improved metabolic activity of CYPs enzymes to the probe drugs treatment. Thus, this culture system would not only contribute to the construction of micro-organoid tissue of liver but also potentially provide a robust tool for drug metabolism evaluation in vitro. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2171-2180, 2018. PMID- 29607609 TI - Vanadium-Doped WS2 Nanosheets Grown on Carbon Cloth as a Highly Efficient Electrocatalyst for the Hydrogen Evolution Reaction. AB - Two-dimensional transition-metal dichalcogenides have been widely studied as electrocatalysts for the hydrogen evolution reaction (HER). However, limited active sites and poor conductivity hinder their application. To solve these disadvantages, heteroatom doping has attracted wide attention because it can not only increase the active sites but also affect the intrinsic catalytic properties of the electrocatalyst. Herein, we grew vanadium-doped WS2 nanosheets on carbon cloth (V-WS2 /CC) as an electrocatalyst for HER under acidic and alkaline conditions. With a proper vanadium doping concentration, the electrochemical surface areas of V0.065 -WS2 /CC were 9.6 and 2.6 times as large as that of pure WS2 electrocatalyst under acidic and alkaline conditions, respectively. In addition, the charge-transfer resistance also decreased with moderate vanadium doping. Based on this, the synthesized vanadium-doped WS2 nanosheets exhibited good stability with high HER catalytic activity and could reach a current density of 10 mA cm-2 at overpotentials of 148 and 134 mV in 0.5 m H2 SO4 and 1 m KOH, respectively. The corresponding Tafel slopes were 71 and 85 mV dec-1 . Therefore, our synthesized vanadium-doped WS2 nanosheets can be a promising electrocatalyst for the production of hydrogen over a wide pH range. PMID- 29607610 TI - Recurrent IgG4-related tubulointerstitial nephritis concurrent with chronic active antibody mediated rejection: A case report. AB - IgG4-related disease is a relatively newly described entity that can affect nearly any organ, including the kidneys, where it usually manifests as tubulointerstitial nephritis (IgG4-TIN). The diagnosis can be suggested by characteristic histological features, including an inflammatory infiltrate with increased IgG4-positive plasma cells associated with "storiform" fibrosis. Serum IgG4 is usually elevated. In the native kidney and other organs, there is typically a brisk response to treatment with immunosuppression. Recurrence of IgG4-TIN after renal transplant has not been described in the literature. Here, we describe the first case of recurrent IgG4-TIN in a young patient concomitant with chronic active antibody mediated rejection five years after kidney transplant. Recurrent IgG4-TIN could be diagnosed by the characteristic histopathologic features and increased IgG4-positive plasma cells. Despite maintenance immunosuppression, this disease may recur in the kidney allograft. PMID- 29607611 TI - Herd-level prevalence and incidence of porcine epidemic diarrhoea virus (PEDV) and porcine deltacoronavirus (PDCoV) in swine herds in Ontario, Canada. AB - Porcine epidemic diarrhoea virus (PEDV) and porcine deltacoronavirus (PDCoV) were first identified in Canada in 2014. Surveillance efforts have been instrumental in controlling both diseases. In this study, we provide an overview of surveillance components for the two diseases in Ontario (Canada), as well as PEDV and PDCoV incidence and prevalence measures. Swine herds located in the Province of Ontario, of any type, whose owners agreed to participate in a voluntary industry-led disease control programme (DCP) and with associated diagnostic or epidemiological information about the two swine coronaviruses, were eligible to be included for calculation of disease frequency at the provincial level. PEDV and PDCoV data stored in the industry DCP database were imported into the R statistical software and analysed to produce weekly frequency of incidence counts and prevalence counts, in addition to yearly herd-level incidence risk and prevalence between 2014 and 2016. The yearly herd-level incidence risk of PEDV, based on industry data, was 13.5%, 3.0% and 1.4% (95% CI: 11.1-16.2, 2.0-4.2, 0.8 2.3), while the yearly herd-level incidence risk of PDCoV was 1.1%, 0.3%, and 0.1% (95% CI: 0.5-2.2, 0.1-0.9, 0.0-0.5), for 2014, 2015 and 2016, respectively. Herd-level prevalence estimates for PEDV in the last week of 2014, 2015 and 2016 were 4.4%, 2.3% and 1.4%, respectively (95% CI: 3.1-6.0, 1.5-3.3, 0.8-2.2), while herd-level prevalence estimates for PDCoV in the last week of 2014, 2015 and 2016 were 0.5%, 0.2% and 0.2%, respectively (95% CI: 0.1-1.2, 0.0-0.6, 0.0-0.6). Collectively, our results point to low and decreasing incidence risk and prevalence for PEDV and PDCoV in Ontario, making both diseases possible candidates for disease elimination at the provincial level. PMID- 29607612 TI - The Human Cell Atlas Project by the numbers: Relationship to the Banff Classification. PMID- 29607613 TI - Prognosis of multi-level N2-positive non-small cell lung cancer according to lymph node staging using endobronchial ultrasound-transbronchial biopsy. AB - BACKGROUND: The optimal treatment for stage IIIA-N2 non-small cell lung cancer (NSCLC) remains controversial, and multidisciplinary team approaches are needed. Downstaging after induction therapy is a good prognostic factor in surgical patients; however, re-evaluation of nodal status before surgery is challenging. The aim of this study was to evaluate the prognosis of patients with multi-level N2 NSCLC who received surgery or chemoradiation therapy (CRT) according to restaging using endobronchial ultrasound-transbronchial aspiration (EBUS-TBNA). METHODS: This was a single center, prospective study that included 16 patients with biopsy-proven multi-level N2 disease on initial EBUS-TBNA that was restaged using EBUS-TBNA after induction therapy. Cases downstaged after rebiopsy were treated surgically. Three-year progression-free survival (PFS) and locoregional PFS were determined using Kaplan-Meier analysis. RESULTS: Of the 16 patients (median age 58 years, male 63%), eight had persistent N2 disease and eight showed N2 clearance on restaging using EBUS-TBNA. Ten patients underwent surgery, including two patients without N2 clearance. Recurrence and locoregional recurrence occurred in eight and five patients, respectively. The three-year PFS was longer in patients with N2 clearance than in those with N2 persistent disease (57.1% vs. 37.5%). Patients with N2 clearance also had longer three-year locoregional PFS than those with N2 persistent disease (71.4% vs. 62.5%). CONCLUSIONS: EBUS-TBNA could be an effective diagnostic method for restaging in multi-level N2 NSCLC patients after induction CRT. As this was a pilot study, further large-scale randomized studies are needed. PMID- 29607614 TI - Serum Wisteria floribunda agglutinin-positive Mac-2-binding protein evaluates liver function and predicts prognosis in liver cirrhosis. AB - OBJECTIVE: Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA+ M2BP) is a novel glycobiomarker for evaluating liver fibrosis, but less is known about its role in liver cirrhosis (LC). This study aimed to investigate the utility of WFA+ -M2BP in evaluating liver function and predicting prognosis of cirrhotic patients. METHODS: We retrospectively included 197 patients with LC between 2013 and 2016. Serum WFA+ -M2BP and various biochemical parameters were measured in all patients. With a median follow-up of 23 months, liver-related complications and deaths of 160 patients were recorded. The accuracy of WFA+ M2BP in evaluating liver function, predicting decompensation and mortality were measured by the receiver operating characteristic (ROC) curve, logistic and Cox's regression analyses, respectively. RESULTS: WFA+ -M2BP levels increased with elevated Child-Pugh classification, especially in patients with hepatitis B virus (HBV) infection. ROC analysis confirmed the high reliability of WFA+ -M2BP for the assessment of liver function using Child-Pugh classification. WFA+ -M2BP was also significantly positively correlated with the model for end-stage liver disease (MELD) score. Multivariate logistic regression analysis indicated WFA+ M2BP as an independent predictor of clinical decompensation for compensated patients (odds ratio 11.958, 95% confidence interval [CI] 1.876-76.226, P = 0.009), and multivariate Cox's regression analysis verified WFA+ -M2BP as an independent risk factor for liver-related death in patients with HBV infection (hazards ratio 10.596, 95% CI 1.356-82.820, P = 0.024). CONCLUSION: Serum WFA+ M2BP is a reliable predictor of liver function and prognosis in LC and could be incorporated into clinical surveillance strategies for LC patients, especially those with HBV infection. PMID- 29607615 TI - A nursing theory-guided framework for genetic and epigenetic research. AB - The notion that genetics, through natural selection, determines innate traits has led to much debate and divergence of thought on the impact of innate traits on the human phenotype. The purpose of this synthesis was to examine how innate theory informs genetic research and how understanding innate theory through the lens of Martha Rogers' theory of unitary human beings can offer a contemporary view of how innate traits can inform epigenetic and genetic research. We also propose a new conceptual model for genetic and epigenetic research. The philosophical, theoretical, and research literatures were examined for this synthesis. We have merged philosophical and conceptual phenomena from innate theory with the theory of unitary beings into the University of Illinois at Chicago model for genetic and epigenetic research. Innate traits are the cornerstone of the framework but may be modified epigenetically by biological, physiological, psychological, and social determinants as they are transcribed. These modifiers serve as important links between the concept of innate traits and epigenetic modifications, and, like the theory of unitary human beings, the process is understood in the context of individual and environmental interaction that has the potential to evolve as the determinants change. PMID- 29607616 TI - A real-time fluorescence assay for protease activity and inhibitor screening based on the aggregation-caused quenching of a perylene probe. AB - We have established a real-time and label-free fluorescence turn-on strategy for protease activity detection and inhibitor screening via peptide-induced aggregation-caused quenching of a perylene probe. Because of electrostatic interactions and high hydrophilicity, poly-l-glutamic acid sodium salt (PGA; a negatively charged peptide) could induce aggregation of a positively charged perylene probe (probe 1) and the monomer fluorescence of probe 1 was effectively quenched. After a protease was added, PGA was enzymatically hydrolyzed into small fragments and probe 1 disaggregated. The fluorescence recovery of probe 1 was found to be proportional to the concentration of protease in the range from 0 to 1 mU/ml. The detection limit was down to 0.1 mU/ml. In the presence of a protease inhibitor, protease activity was inhibited and fluorescence recovery reduced. Moreover, we demonstrated the potential application of our method in a complex mixture sample including 1% human serum. Our method is simple, fast and cost effective. PMID- 29607617 TI - A novel heterozygous missense mutation of DSP in a Chinese Han pedigree with palmoplantar keratoderma. AB - BACKGROUND: Mutations in the desmoplakin (DSP) gene have been demonstrated to be associated with lethal acantholytic epidermolysis bullosa, cardiomyopathy, and palmoplantar keratoderma (PPK). AIMS: To better understand the relationship between PPK and the gene mutations in DSP. METHODS: A pedigree of PPK was subjected to heterozygous missense mutation analysis in the DSP gene. Dermoscopy, reflectance confocal microscopy, and histopathological examination were performed from each epidermis layer in this study. Samples were derived from the blood of patients and normal healthy controls. DSP gene sequence analysis and Q-PCR analysis was performed for evaluating DSP gene mutation and expression. RESULTS: A novel heterozygous missense mutation c.3550 C>T in the coding region of the DSP gene, predicting substitution of arginine (Arg,R) by tryptophan (Trp,W) in the desmoplakin polypeptide, was discovered in a Chinese pedigree of PPK. In the meanwhile, this mutation was not found in 100 healthy individuals. CONCLUSIONS: The novel missense mutation c.3550 C>T(p.Arg1184Trp) of DSP gene expanded the mutation spectrum in palmoplantar keratoderma. PMID- 29607618 TI - Effects of adhesive used as modeling liquid on the stability of the color and opacity of composites. AB - OBJECTIVE: This study evaluated the effects of adhesive type used as modeling liquid on the stability of the color and opacity of composites submitted to thermal cycling in staining solutions followed by a bleaching procedure. METHODS: Thirty cylinder-shaped composite specimens (10 mm diameter * 1.5 mm thickness) were built using or not using (control) an adhesive (Adper Universal or Scotchbond Multipurpose) as the modeling liquid. After polishing procedures, the color and opacity were measured, and the specimens were submitted to 200 thermal cycles with 10 s of dwell time in baths of grape juice at 5 degrees C, water at 37 degrees C, and coffee at 55 degrees C. Changes in opacity and color caused by the staining solutions were measured. Then, the specimens were bleached with 35% hydrogen peroxide for 45 minutes followed by color/opacity measurements. Data were analyzed by ANOVA and Tukey's test (alpha = 0.05). RESULTS: The use of modeling liquids did not affect the initial color and opacity of composite. Reduced changes to color (E00 = 3.44) and opacity (+2.67%) were observed for specimens modeled using Adper Universal. Bleaching procedures reduced the color (E00 = 1.9-3.8) and opacity (-2.3 to 3.1%) alterations caused by staining solutions but were unable to restore the values observed at baseline. CONCLUSION: The use of universal adhesive as modeling liquid significantly reduced the color and opacity changes caused by staining solutions, and the bleaching procedure partially re-established the opacity and color of the composites. CLINICAL SIGNIFICANCE: This study evaluates whether using adhesive systems for modeling a composite affects the color and opacity changes caused by staining solutions followed by a bleaching procedure. The findings suggest that the use of a universal adhesive as modeling liquid can reduce the alterations in optical properties caused by staining solutions, and the application of high-concentrated hydrogen peroxide over the composite reduce the color changes without fully recover the initial color. PMID- 29607619 TI - Identification and metabolite profiling of alkaloids in aerial parts of Papaver rhoeas by liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry. AB - Papaver plants can produce diverse bioactive alkaloids. Papaver rhoeas Linnaeus (common poppy or corn poppy) is an annual flowering medicinal plant used for treating cough, sleep disorder, and as a sedative, pain reliever, and food. It contains various powerful alkaloids like rhoeadine, benzylisoquinoline, and proaporphine. To investigate and identify alkaloids in the aerial parts of P. rhoeas, samples were collected at different growth stages and analyzed using liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry. A liquid chromatography with mass spectrometry method was developed for the identification and metabolite profiling of alkaloids for P. rhoeas by comparing with Papaver somniferum. Eighteen alkaloids involved in benzylisoquinoline alkaloid biosynthesis were used to optimize the liquid chromatography gradient and mass spectrometry conditions. Fifty-five alkaloids, including protoberberine, benzylisoquinoline, aporphine, benzophenanthridine, and rhoeadine-type alkaloids, were identified authentically or tentatively by liquid chromatography coupled with quadrupole time-of-flight tandem mass spectrometry in samples taken during various growth stages. Rhoeadine alkaloids were observed only in P. rhoeas samples, and codeine and morphine were tentatively identified in P. somniferum. The liquid chromatography coupled with quadrupole time-of flight tandem mass spectrometry method can be a powerful tool for the identification of diverse metabolites in the genus Papaver. These results may help understand the biosynthesis of alkaloids in P. rhoeas and evaluate the quality of this plant for possible medicinal applications. PMID- 29607621 TI - Antileukotriene therapy by reducing tau phosphorylation improves synaptic integrity and cognition of P301S transgenic mice. AB - The 5-lipoxygenase (5LO) is a source of inflammatory leukotrienes and is upregulated in Alzheimer's disease and related tauopathies. However, whether it directly modulates tau phosphorylation and the development of its typical neuropathology in the absence of Abeta or is a secondary event during the course of the disease pathogenesis remains to be fully elucidated. The goal of this study was to evaluate the effect that pharmacologic blockade of this inflammatory pathway has on the phenotype of a transgenic mouse model of tauopathy, the P301S mice. Starting at 3 months of age, P301S mice were randomized to receive zileuton, a specific 5LO blocker, for 7 months; then, its effect on their behavioral deficits and neuropathology was assessed. Inhibition of leukotrienes formation was associated with a reduction in tau phosphorylation and an amelioration of memory and learning as well as synaptic integrity, which were secondary to a downregulation of the cdk5 kinase pathway. Our results demonstrate that the 5LO enzyme is a key player in modulating tau phosphorylation and pathology and that blockade of its enzymatic activity represents a desirable disease-modifying therapeutic approach for tauopathy. PMID- 29607620 TI - Regulation of carbohydrate degradation pathways in Pseudomonas involves a versatile set of transcriptional regulators. AB - Bacteria of the genus Pseudomonas are widespread in nature. In the last decades, members of this genus, especially Pseudomonas aeruginosa and Pseudomonas putida, have acquired great interest because of their interactions with higher organisms. Pseudomonas aeruginosa is an opportunistic pathogen that colonizes the lung of cystic fibrosis patients, while P. putida is a soil bacterium able to establish a positive interaction with the plant rhizosphere. Members of Pseudomonas genus have a robust metabolism for amino acids and organic acids as well as aromatic compounds; however, these microbes metabolize a very limited number of sugars. Interestingly, they have three-pronged metabolic system to generate 6 phosphogluconate from glucose suggesting an adaptation to efficiently consume this sugar. This review focuses on the description of the regulatory network of glucose utilization in Pseudomonas, highlighting the differences between P. putida and P. aeruginosa. Most interestingly, It is highlighted a functional link between glucose assimilation and exotoxin A production in P. aeruginosa. The physiological relevance of this connection remains unclear, and it needs to be established whether a similar relationship is also found in other bacteria. PMID- 29607622 TI - Ischemic oculomotor nerve palsy due to hyaluronic acid filler injection. AB - Hyaluronic acid (HA) is the most popular agent today for intradermal injections to improve wrinkles and other cosmetic defects. Ischemic necrosis due to injection of HA is one of the serious complications. Because there are many vascular branches around the nose, caution and care should be given during facial filler injection. Although the incidence is rare, blindness and permanent visual loss may occur. We describe a 29-year-old woman presented with painful erythematous swelling with violaceous patch on right periocular area and glabella after HA filler injection. After injecting the filler, she felt pain and dizziness, and her vision became blurred. She immediately received hyaluronidase around the HA filler inject area and during hospitalized for 10 days, she was successfully treated with systemic steroid, vasodilator, prophylactic antibiotics, and LLLT (low-level laser therapy) without any defects. PMID- 29607623 TI - Efficacy and safety of the G protein-coupled receptor 119 agonist DS-8500a in Japanese type 2 diabetes mellitus patients with inadequate glycemic control on sitagliptin: A phase 2 randomized placebo-controlled study. AB - INTRODUCTION: We evaluated the efficacy and safety of DS-8500a as add-on therapy to sitagliptin in Japanese type 2 diabetes mellitus patients. MATERIALS AND METHODS: This multicenter, randomized, double-blind, placebo-controlled, phase 2 trial randomized patients aged >=20 years with hemoglobin A1c >=7.0% and <9.0%, and inadequate glycemic control with sitagliptin 50-mg monotherapy to receive 25 or 75 mg DS-8500a, or a placebo, orally. The primary end-point was change from baseline to day 28 in 24-h weighted mean glucose. Secondary end-points included change from baseline in fasting plasma glucose, 2-h postprandial plasma glucose and lipid profiles. RESULTS: Overall, 29, 28 and 27 patients in the placebo, 25- and 75-mg groups, respectively, were analyzed. A significant dose-dependent reduction was observed in 24-h weighted mean glucose (linear: P = 0.0006, saturated at 25 mg: P = 0.0003, responded from 75 mg: P = 0.0176) when compared with the placebo (25 mg: -13.19 mg/dL [-0.73 mmol/L], P = 0.0044 vs placebo and 75 mg: -16.12 mg/dL [-0.89 mmol/L], P = 0.0006 vs placebo). A significant reduction in fasting plasma glucose at 75 mg vs placebo was observed (P < 0.001). At 25 and 75 mg, significant reductions of 2-h postprandial plasma glucose (after breakfast), total cholesterol, low-cholesterol and triglycerides were observed (all P < 0.05), with a (non-significant) trend towards increased high-density lipoprotein cholesterol. Both doses of DS-8500a were well tolerated. There were no significant treatment-emergent adverse events leading to discontinuation during the study. CONCLUSIONS: DS-8500a was well tolerated, and showed significant glycemic benefits and favorable changes in lipid profile in Japanese type 2 diabetes mellitus patients with inadequate glycemic control with sitagliptin therapy. PMID- 29607624 TI - Burden and consequences of retained cardiovascular implantable electronic device lead fragments after heart transplantation. AB - We performed a retrospective review of 402 consecutive patients who underwent heart transplantation at our institution between January 2009 and March 2017. A retained cardiovascular implantable electronic device (CIED) fragment was identified after transplantation in 49 of the 301 patients (16.2%) with CIED at baseline. Patients with retained fragments had leads with longer dwell times (median 2596 [1982, 3389] vs 1384 [610, 2202] days, P < .001), higher prevalence of previously abandoned leads (14.3% vs 2.8%, P = .003), and dual-coil defibrillator leads (98% vs 81%, P = .001) compared with patients without retained fragments. Five patients (10%) with retained CIED fragments underwent magnetic resonance imaging without adverse events. There was no difference in overall mortality between patients with and without CIED fragments (12% vs 11%, P = .81) Patients with retained fragments located in the superior vena cava had significantly higher fluoroscopic times (3.3 vs 2.9 minutes, P = .024) during subsequent endomyocardial biopsies. In a competing risk analysis, presence of a retained CIED fragment was associated with upper extremity deep venous thrombosis (sub hazard ratio [HR] 2.19, 95% confidence interval [CI] 1.17-4.10, P = .014) but not bloodstream infection after adjusting for potential confounders. In summary, retained CIED fragments are common after heart transplantation, and are associated with longer radiation exposure during biopsy procedures and upper extremity deep venous thrombosis. PMID- 29607625 TI - Turmeric tonic as a treatment in scalp psoriasis: A randomized placebo-control clinical trial. AB - BACKGROUND: Psoriasis is an autoimmune and recurrent chronic inflammatory skin disorder with a strong genetic basis. The characteristic features are hyperproliferation of keratinocytes, leading to redness, thickening, and scaling of the epidermis followed by itching and the appearance of lesions, which in most cases can affect the patients both medically and psychologically. The scalp is one of the most common sites for psoriasis. This condition is predominantly managed with steroids, which are associated with various side effects. Turmeric (Curcuma longa L.), a spice commonly used throughout the world, has been shown to exhibit anti-inflammatory, antimicrobial, antioxidant, and antineoplastic properties. It has been reported to exhibit inhibitory activity on potassium channels in T cells and plays a key role in psoriasis. AIM: We were prompted to investigate the turmeric tonic as an immune modulation and anti-inflammatory therapy on scalp psoriasis. METHOD: Forty patients with mild-to-moderate scalp psoriasis who fulfilled the inclusion criteria were randomly allocated into two groups. The case group received turmeric tonic twice a day for 9 weeks, whereas the other group received a placebo applied in the same manner. Patients were evaluated at the following points: baseline, weeks 3, 6, and 9. The dermatology life quality index (DLQI) questionnaire and PASI (psoriasis area & severity index) scores, as well as medical photos before, during and after treatment were also evaluated. The probable adverse effects were also recorded and reported. RESULTS: Compared to the placebo, turmeric tonic significantly reduced the erythema, scaling and induration of lesions (PASI score), and also improved the patients' quality of life (P value < .05). CONCLUSIONS: The clinical effects of turmeric tonic on scalp psoriasis were satisfactory overall. This formulation could be considered as a treatment for scalp psoriasis. PMID- 29607626 TI - Drug fever and acute inflammation from hypercytokinemia triggered by dipeptidyl peptidase-4 inhibitor vildagliptin. AB - A 69-year-old man started taking the dipeptidyl peptidase-4 inhibitor, vildagliptin. One week later, C-reactive protein and plasma immunoglobulin E levels were markedly elevated, and the vildagliptin was stopped. After the patient's laboratory findings were normalized, we decided to restart vildagliptin with the patient's agreement. The next day, he had a high fever, and C-reactive protein and procalcitonin levels were elevated. Although we failed to find a focus of infection, we started antibiotics therapy. Two days later, the high fever had improved, and the C-reactive protein level had decreased. A drug lymphocyte stimulation test showed a positive result for vildagliptin. We examined various kinds of cytokine and infection markers just before and after the treatment with vildagliptin. Finally, we diagnosed the patient with vildagliptin-induced drug fever, probably based on the increase of various inflammatory cytokine levels and the response to this. Taken together, we should be aware of the possibility of vildagliptin inducing drug fever and/or acute inflammation. PMID- 29607627 TI - Safety and complications of absorbable threads made of poly-L-lactic acid and poly lactide/glycolide: Experience with 148 consecutive patients. AB - BACKGROUND: Thread lifting is a minimally invasive procedure for lifting and repositioning tissues. Few articles with absorbable sutures exist in the literature. Furthermore there is no study focusing on complications of absorbable sutures. OBJECTIVE: To describe complications of thread lifting using a totally absorbable suture composed of poly-L-lactic acid affixed with poly lactide/glycolide cones. METHODS: Data regarding complications were analyzed retrospectively for 148 patients underwent thread lifting between June 2014 and February 2017. RESULTS: A total of 321 pairs of sutures used in the 148 patients studied. Overall 40 (27%) patients had complications regarded as minimal or moderate without permanent sequela. The most common complication was skin dimpling and irregularity (n = 17, 11.4%) followed by ecchymosis (n = 12, 8.1%), suture extrusion (n = 4, 2.7%), and pain (n = 4, 2.7%) Except one patient, dimpling, and irregularity resolved in all patients after 3-7 days spontaneously. Suture migration was observed in 2 (1.35%) patients. Hematoma and infection were seen in 2 patients one for each. CONCLUSIONS: The procedure using sutures made of absorbable poly-L-lactic acid and poly lactide/glycolide is a relatively safe procedure without major complications. PMID- 29607628 TI - Pattern of antibiotic prescription among dentists in Riyadh, Saudi Arabia. AB - AIM: The aim of the present study was to investigate the pattern of antibiotic prescription and dentists' awareness about the recent guidelines for antibiotic prescription. METHODS: This cross-sectional study was conducted among 282 dentists practicing in Riyadh, Saudi Arabia. The data were collected from 20 randomly-selected dental clinics from each of the five administrative blocks in Riyadh. In addition, data were also collected from four tertiary care centers and three academic universities. The questionnaire measured the antibiotic prescription pattern of the dentists and their choice of antibiotics for various dental conditions. RESULTS: Amoxicillin was the most commonly prescribed antibiotic. More than 70% of dentists prescribed antibiotics for dental patients with various cardiac conditions. Bivariate analysis showed that female dentists had significantly higher mean scores for ideal prescription pattern (P = .04) compared to male dentists. Saudi nationals, especially those working in the government sector were found to have better prescription pattern compared with others (P = .02). Dentists with higher educational qualifications (board certificate and above) had a more ideal prescription pattern than other dentists (P = .04). CONCLUSION: Inappropriate antibiotic prescription practice was highly prevalent in this population. PMID- 29607631 TI - Treatment of gingival recession using a coronally-advanced flap procedure with or without placental membrane. AB - AIM: The aim of the present study was to compare the treatment of gingival recession defects using a coronally-advanced flap procedure with or without placental membrane. METHODS: Sixty teeth in 15 patients with single and multiple Miller's class I and II gingival recession defects bilaterally in the anterior and premolar region of the maxilla and mandible were divided into two groups. In group I (control), 30 recession defects were treated with coronally-advanced flap alone using Zucchelli's technique. In group II (test), 30 recession defects were treated with coronally-advanced flap along with placental membrane. Probing depth, height of the gingival recession (HGR), clinical attachment level (CAL), width of the gingival recession, and width of the keratinized tissue (WKT) were recorded at baseline and 3 and 6 months after the surgical procedures. RESULTS: There was a statistically-significant reduction in the HGR, gain in the CAL, and WKT in group II compared to group I. CONCLUSION: Coronally-advanced flap with placental allograft provides a reliable technique for root coverage when compared to coronally-advanced flap alone. PMID- 29607632 TI - Trichloroethylene Hypersensitivity Syndrome: Should Be Considered When Diagnosing DRESS Syndrome. AB - Trichloroethylene (TCE) is an organic solvent that is used for degreasing and removing impurities from metal parts. However, this solvent's characteristics and hypersensitivity can produce clinical patterns and laboratory data that mimic drug rash with eosinophilia and systemic symptoms (DRESS) syndrome. Thus, exposure confirmation is critical to making an accurate diagnosis. This is a case of TCE-induced hypersensitivity syndrome (TCE HS) in a 24-year-old Indonesian man who was working in an electro-plating business. He was admitted to a referral hospital after one month of working, and exhibited a fever with skin symptoms. He was administered immunosuppressive therapy based on an assumed diagnosis of DRESS syndrome, although he subsequently experienced cardiac arrest and did not respond to resuscitation. An investigation into his disease history confirmed that he was prescribed medications one week before he developed the skin disease, and had been periodically exposed to TCE for the previous 4 weeks. Based on these findings, it was believed that his clinical course was caused by TCE HS, rather than DRESS syndrome. PMID- 29607633 TI - Analysis of Motion-dependent Clinical Outcome of Tumor Tracking Stereotactic Body Radiotherapy for Prostate Cancer. AB - BACKGROUND: To analyze clinical outcome of CyberKnife (CK) tumor-tracking stereotactic body radiotherapy (SBRT) for prostate cancer (Pca) according to the magnitude of intra-fractional prostate motion. METHODS: Medical records and daily treatment logs for 71 patients who received CK tumor-tracking SBRT were retrospectively analyzed. Statistical relationships between prostate motion and various outcome results, including local recurrence (LR), biochemical failure (BF), and treatment-related toxicity, were investigated in order to evaluate motion-dependent efficacy of tumor-tracking SBRT for Pca. RESULTS: In a total 71 patients, 3 (4.2%) patients with LR, 12 (16.9%) patients with BF, and 22 (31%) patients with grade-II or worse toxicities to rectal or bladder (22 to rectal, 22 to bladder and 8 patients to both) were observed in a median follow-up of 47 months. Magnitudes of intra-fractional tumor motion along superior-inferior, right-left, and anterior-posterior (AP) axes were 0.15 +/- 0.31, 0.12 +/- 0.19, and 0.73 +/- 0.32 mm, respectively. Radial magnitude was estimated to be 1.0 +/- 0.35 mm. Intra-fractional movement was not significantly correlated with tumor control. However, it was significant correlated with the incidence of grade-II or worse toxicity to rectum or bladder particularly when tumor motion was in the AP axis. CONCLUSION: Our quantitative results revealed that toxicity related to SBRT treatment was highly sensitive to intra-fractional prostate movements, although local-tumor control was not affected by such movements. Our results demonstrate that precise motion correction is essential in prostate SBRT, even if it seems to be small. PMID- 29607634 TI - Bath-related Deaths in Korea between 2008-2015. AB - BACKGROUND: The diagnostic criteria for bathtub drownings are not standardized, and the risk factors associated with bath-related deaths are unclear. METHODS: We analyzed a Korean nationwide database of bath-related deaths that occurred between January 2008 and December 2015. Eighty-four cases were enrolled after reviewing 31,123 autopsy records. RESULTS: The subjects' ages ranged from 18 to 91 years, with a mean age +/- standard deviation of 61.3 +/- 16.0 years. Bath related deaths in the winter were approximately 4.6-fold greater than those in the summer. Of the 84 subjects, the primary cause of death in 57 (67.9%) was drowning in the bath; 24 (28.6%) drowned of other causes such as natural diseases, and 3 (3.6%) died of acute alcohol intoxication. We analyzed water inhalation signs to establish criteria for bathtub drowning diagnosis. There were significantly higher incidences of hyperinflated lungs, water in the sphenoid sinus and stomach/duodenal contents, and Paltauf's spots (subpleural hemorrhage) in bathtub-drowned subjects compared to non-drowned individuals (P < 0.01). Multiple signs of water inhalation were significantly associated with bathtub drowning (P < 0.01). The two leading contributory causes of bath-related death were cardiovascular diseases and alcohol intoxication (binge drinking before bathing). CONCLUSION: The diagnosis of bath-related deaths could present considerable medico-legal problems; therefore, a comprehensive autopsy with a thorough scene investigation can clarify the cause of death in these situations. Preventive strategies for reducing such deaths should target alcohol drinking before bathing and long soaking times in bathtubs, especially among elderly individuals with preexisting cardiovascular diseases. PMID- 29607635 TI - Estimated Prevalence of Adolescents with Nonalcoholic Fatty Liver Disease in Korea. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) has become prevalent worldwide in the last decade. However, the recent prevalence of NAFLD in adolescents has not yet been investigated in Korea. METHODS: Data were obtained from 1,416 participants aged 10-18 years from the Korea National Health and Nutrition Examination Survey conducted in 2010 and 2015. Systolic blood pressure (SBP), diastolic blood pressure (DBP), height, weight, waist circumference (WC), body mass index (BMI), fasting glucose, total cholesterol, high-density lipoprotein (HDL), aspartate aminotransferase (AST), alanine aminotransferase (ALT) level, waist-to-height ratio (WHtR), and pediatric NAFLD fibrosis index (PNFI) were analyzed. RESULTS: SBP, weight, WC, BMI, WHtR, and total cholesterol level were significantly higher in 2015 than in 2010. Prevalence of NAFLD (BMI >= 85th percentile plus ALT > 30 U/L for boys and ALT > 19 U/L for girls) were 4.7% in 2010 and 5.9% in 2015 (P = 0.360). Using various cutoffs for the ALT level (> 40, > 30, > 25.8 U/L for boys and >22.1 U/L for girls) NAFLD prevalence rates were 3.0%, 4.1%, and 5.5% in 2010; 2.9%, 5.0%, and 7.1% in 2015, respectively (P = 0.899, 0.469, and 0.289). Boys had a higher SBP, DBP, height, weight, WC, BMI, WHtR, fasting glucose, total cholesterol, ALT, and lower HDL level than girls. The probability of liver fibrosis using the PNFI varies between 21.3% and 24.5% among NAFLD participants (P < 0.001). CONCLUSION: The Korean society needs to quickly control the increasing prevalence of NAFLD in adolescents and reduce its complications. PMID- 29607637 TI - Erratum: Correction of Author Order: Reduced Mortality by Physician-Staffed HEMS Dispatch for Adult Blunt Trauma Patients in Korea. AB - This corrects the article on p. 1656 in vol. 31, PMID: 27550497. PMID- 29607636 TI - The Quality of Life of Hemodialysis Patients Is Affected Not Only by Medical but also Psychosocial Factors: a Canonical Correlation Study. AB - BACKGROUND: The quality of life (QoL) of patients with end-stage renal disease (ESRD) is very poor, plausibly due to both psychosocial and medical factors. This study aimed to determine the relationship among psychosocial factors, medical factors, and QoL in patients with ESRD undergoing hemodialysis (HD). METHODS: In total, 55 male and 47 female patients were evaluated (mean age, 57.1 +/- 12.0 years). The QoL was evaluated using the Korean version of World Health Organization Quality of Life Scale-Abbreviated Version. The psychosocial factors were evaluated using the Hospital Anxiety and Depression Scale, Multidimensional Scale of Perceived Social Support, Montreal Cognitive Assessment, Pittsburgh Sleep Quality Index, and Zarit Burden Interview. The medical factors were assessed using laboratory examinations. Correlation and canonical correlation analyses were performed to investigate the association patterns. RESULTS: The QoL was significantly correlated with the psychosocial factors, and to a lesser extent with the medical factors. The medical and psychosocial factors were also correlated. The canonical correlation analysis indicated a correlation between QoL and psychosocial factors (1st canonical correlation = 0.696, P < 0.001; 2nd canonical correlation = 0.421, P = 0.191), but not medical factors (1st canonical correlation = 0.478, P = 0.475; 2nd canonical correlation = 0.419, P = 0.751). The medical and psychosocial factors were also correlated (1st canonical correlation = 0.689, P < 0.001; 2nd canonical correlation = 0.603, P = 0.009). CONCLUSION: Psychosocial factors influence QoL in patients with ESRD, and should thus be carefully considered when caring for these patients in clinical practice. PMID- 29607638 TI - Potential Role of Psychosocial Factors on Health-Related Quality of Life in Hemodialysis Patients. PMID- 29607639 TI - Na2(UO2)(BO3): An All-Uranium(V) Borate Synthesized under Mild Hydrothermal Conditions. AB - The first entirely pentavalent uranium borate, Na2(UO2)(BO3), was synthesized under mild hydrothermal conditions. The single-crystal structure was solved in the orthorhombic space group Cmcm with a = 10.0472(3) A, b = 6.5942(2) A, and c = 6.9569(2) A. Magnetic susceptibility measurements revealed an antiferromagnetic transition at 12 K and an effective magnetic moment of 2.33 MUB. Density functional theory calculations indicated dynamic stability of the structure above 0 K. PMID- 29607640 TI - Ligand-Enhanced CO Activation by the Early Lanthanide-Nickel Heterodimers: Photoelectron Velocity-Map Imaging Spectroscopy of LnNi(CO) n- (Ln = La, Ce). AB - Heterobimetallic lanthanum-nickel and cerium-nickel carbonyls, LnNi(CO) n- (Ln = La, Ce; n = 2-5), were generated using a pulsed laser vaporization/supersonic expansion ion source. These compounds were characterized by photoelectron velocity-map imaging spectroscopy and quantum chemical calculations. The binding motif in the most stable isomers of the n = 2 and 3 clusters consists of one side on-bonded carbonyl. A new building block of two side-on-bonded carbonyls is favored at n = 4, which is retained at n = 5, evidencing the increase of the number of extremely activated CO molecule in the larger clusters. The experimental and theoretical results demonstrate the ligand-enhanced CO activation by the early lanthanide-nickel heterodimers, which would have important implications for the design of alloy catalysts for activation of a molecular ligand. PMID- 29607641 TI - Phosphine-Free and Reusable Palladium Nanoparticles-Catalyzed Domino Strategy: Synthesis of Indanone Derivatives. AB - The carbene migratory insertion involving a domino reaction by highly stable, reusable, and binaphthyl-stabilized Pd-nanoparticles (Pd-BNP) is disclosed. The reaction was catalyzed by 2 mol % of a heterogeneous Pd-BNP catalyst under external ligand-free conditions, and it afforded 3-aryl-substituted indanone derivatives in up to a 90% yield with exclusive E-selectivity. Furthermore, a one pot reaction and derivatization of indanone derivatives were also successfully demonstrated. PMID- 29607642 TI - The Role of the Active Site Flap in Streptavidin/Biotin Complex Formation. AB - Obtaining a detailed description of how active site flap motion affects substrate or ligand binding will advance structure-based drug design (SBDD) efforts on systems including the kinases, HSP90, HIV protease, ureases, etc. Through this understanding, we will be able to design better inhibitors and better proteins that have desired functions. Herein we address this issue by generating the relevant configurational states of a protein flap on the molecular energy landscape using an approach we call MTFlex-b and then following this with a procedure to estimate the free energy associated with the motion of the flap region. To illustrate our overall workflow, we explored the free energy changes in the streptavidin/biotin system upon introducing conformational flexibility in loop3-4 in the biotin unbound ( apo) and bound ( holo) state. The free energy surfaces were created using the Movable Type free energy method, and for further validation, we compared them to potential of mean force (PMF) generated free energy surfaces using MD simulations employing the FF99SBILDN and FF14SB force fields. We also estimated the free energy thermodynamic cycle using an ensemble of closed-like and open-like end states for the ligand unbound and bound states and estimated the binding free energy to be approximately -16.2 kcal/mol (experimental -18.3 kcal/mol). The good agreement between MTFlex-b in combination with the MT method with experiment and MD simulations supports the effectiveness of our strategy in obtaining unique insights into the motions in proteins that can then be used in a range of biological and biomedical applications. PMID- 29607643 TI - A Matter of Time: Faster Percolator Analysis via Efficient SVM Learning for Large Scale Proteomics. AB - Percolator is an important tool for greatly improving the results of a database search and subsequent downstream analysis. Using support vector machines (SVMs), Percolator recalibrates peptide-spectrum matches based on the learned decision boundary between targets and decoys. To improve analysis time for large-scale data sets, we update Percolator's SVM learning engine through software and algorithmic optimizations rather than heuristic approaches that necessitate the careful study of their impact on learned parameters across different search settings and data sets. We show that by optimizing Percolator's original learning algorithm, l2-SVM-MFN, large-scale SVM learning requires nearly only a third of the original runtime. Furthermore, we show that by employing the widely used Trust Region Newton (TRON) algorithm instead of l2-SVM-MFN, large-scale Percolator SVM learning is reduced to nearly only a fifth of the original runtime. Importantly, these speedups only affect the speed at which Percolator converges to a global solution and do not alter recalibration performance. The upgraded versions of both l2-SVM-MFN and TRON are optimized within the Percolator codebase for multithreaded and single-thread use and are available under Apache license at bitbucket.org/jthalloran/percolator_upgrade . PMID- 29607644 TI - Hyaluronic Acid and Polyethylene Glycol Hybrid Hydrogel Encapsulating Nanogel with Hemostasis and Sustainable Antibacterial Property for Wound Healing. AB - Immediate hemorrhage control and anti-infection play important roles in the wound management. Besides, a moist environment is also beneficial for wound healing. Hydrogels are promising materials in urgent hemostasis and drug release. However, hydrogels have the disadvantage of rapid release profiles, leading to the exposure to high drug concentrations. In this study, we constructed hybrid hydrogels with rapid hemostasis and sustainable antibacterial property combining aminoethyl methacrylate hyaluronic acid (HA-AEMA) and methacrylated methoxy polyethylene glycol (mPEG-MA) hybrid hydrogels and chlorhexidine diacetate (CHX) loaded nanogels. The CHX-loaded nanogels (CLNs) were prepared by the enzyme degradation of CHX-loaded lysine-based hydrogels. The HA-AEMA and mPEG-MA hybrid hydrogel loaded with CLNs (labeled as Gel@CLN) displayed a three-dimensional microporous structure and exhibited excellent swelling, mechanical property, and low cytotoxicity. The Gel@CLN hydrogel showed a prolonged release period of CHX over 240 h and the antibacterial property over 10 days. The hemostasis and wound healing properties were evaluated in vivo using a mouse model. The results showed that hydrogel had the rapid hemostasis capacity and accelerated wound healing. In summary, CLN-loaded hydrogels may be excellent candidates as hemostasis and anti infection materials for the wound dressing application. PMID- 29607645 TI - Synthesis and Self-Aggregation of pi-Expanded Chlorophyll Derivatives to Construct Light-Harvesting Antenna Models. AB - Chlorosomes are one of the elegant light-harvesting antenna systems in anoxygenic photosynthetic bacteria, whose core is constructed from J-type self-aggregation of bacteriochlorophyll- c, bacteriochlorophyll- d, bacteriochlorophyll- e, and bacteriochlorophyll- f molecules without the influence of polypeptides. Chlorosomal supramolecular models were built up using synthetic porphyrin-type bacteriochlorophyll- d analogues with a methoxycarbonylethenyl, formyl, vinyl, or ethyl group at the 8-position. Their chlorosomal self-aggregates in an aqueous micelle solution showed relatively intense absorption bands around 500-600 nm where antennas of natural oxygenic phototrophs, as well as green sulfur bacteria possessing bacteriochlorophylls- c/ d, absorb light less efficiently; this observation is called the "green gap". Furthermore, the functional chlorosomal models were constructed by simple addition of a small amount of an energy acceptor model bearing a bacteriochlorin moiety to the pigment self-assemblies in an aqueous micelle. The resulting excited energy donor-acceptor supramolecules played the roles of chlorosomal light-harvesting and energy-transfer antenna systems and were efficient at light absorption in the "green gap" region. PMID- 29607646 TI - Gradient-Based Colorimetric Sensors for Continuous Gas Monitoring. AB - Colorimetry detects a color change resulted from a chemical reaction or molecular binding. Despite its widespread use in sensing, continuous monitoring of analytes with colorimetry is difficult, especially when the color-producing reaction or binding is irreversible. Here, we report on a gradient-based colorimetric sensor (GCS) to overcome this limitation. Lateral transport of analytes across a colorimetric sensor surface creates a color gradient that shifts along the transport direction over time, and GCS tracks the gradient shift and converts it into analyte concentration in real time. Using a low cost complementary metal oxide semiconductor imager and imaging processing algorithm, we show submicrometer gradient shift tracking precision and continuous monitoring of ppb level ozone. PMID- 29607647 TI - Construction of (Dihydro)naphtho[1,8- bc]pyrans via Rh(III)-Catalyzed Twofold C-H Activation of Benzoylacetonitriles. AB - Rh(III)-catalyzed cascade C-H activation of benzoylacetonitriles and annulation with sulfoxonium ylides was realized, leading to selective synthesis of naphthols, 2,3-dihydronaphtho[1,8- bc]pyrans, and naphtho[1,8- bc]pyrans. This step-economic reaction proceeded efficiently under mild and redox-neutral conditions via multiple C-H activations. PMID- 29607648 TI - Illuminating the Energy Landscape of GPCRs: The Key Contribution of Solution State NMR Associated with Escherichia coli as an Expression Host. AB - Conformational dynamics of GPCRs are central to their function but are difficult to explore at the atomic scale. Solution-state NMR has provided the major contribution in that area of study during the past decade, despite nonoptimized labeling schemes due to the use of insect cells and, to a lesser extent, yeast as the main expression hosts. Indeed, the most efficient isotope-labeling scheme ever to address energy landscape issues for large proteins or protein complexes relies on the use of 13CH3 probes immersed in a perdeuterated dipolar environment, which is essentially out of reach of eukaryotic expression systems. In contrast, although its contribution has been underestimated because of technical issues, Escherichia coli is by far the best-adapted host for such labeling. As it is now tightly controlled, we show in this review that bacterial expression can provide an NMR spectral resolution never achieved in the GPCR field. PMID- 29607649 TI - Selection of Collision Energies in Proteomics Mass Spectrometry Experiments for Best Peptide Identification: Study of Mascot Score Energy Dependence Reveals Double Optimum. AB - Collision energy is a key parameter determining the information content of beam type collision induced dissociation tandem mass spectrometry (MS/MS) spectra, and its optimal choice largely affects successful peptide and protein identification in MS-based proteomics. For an MS/MS spectrum, quality of peptide match based on sequence database search, often characterized in terms of a single score, is a complex function of spectrum characteristics, and its collision energy dependence has remained largely unexplored. We carried out electrospray ionization quadrupole-time of flight (ESI-Q-TOF)-MS/MS measurements on 2807 peptides from tryptic digests of HeLa and E. coli at 21 different collision energies. Agglomerative clustering of the resulting Mascot score versus energy curves revealed that only few of them display a single, well-defined maximum; rather, they feature either a broad plateau or two clear peaks. Nonlinear least-squares fitting of one or two Gaussian functions allowed the characteristic energies to be determined. We found that the double peaks and the plateaus in Mascot score can be associated with the different energy dependence of b- and y-type fragment ion intensities. We determined that the energies for optimum Mascot scores follow separate linear trends for the unimodal and bimodal cases with rather large residual variance even after differences in proton mobility are taken into account. This leaves room for experiment optimization and points to the possible influence of further factors beyond m/ z. PMID- 29607650 TI - Factors Associated with High-Grade Anal Intraepithelial Lesion in HIV-Positive Men in a Southern U.S. City. AB - The incidence of anal cancer is increased in HIV-infected patients compared with the general population. Risk factors associated with the anal cancer precursor, high-grade squamous intraepithelial lesion (HSIL), have not been extensively studied in an urban black population with late-stage HIV disease. We performed a retrospective chart review of HIV-infected men at the Grady Ponce de Leon Center HIV Clinic (Atlanta, GA) referred for high-resolution anoscopy (HRA), a procedure where anal tissue is examined under magnification and abnormal areas are biopsied. Between December 2013 and September 2015, 147 men underwent HRA: 72% were black, and 94% were men who have sex with men. CD4 count closest to time of HRA was a median 325 cells/mm3 (interquartile range 203-473), and 69% had an undetectable HIV viral load. Ninety-four percent had abnormal anal cytology [80% atypical squamous cells of undetermined significance/low-grade squamous intraepithelial lesion (LSIL) and 20% atypical squamous cells, cannot exclude HSIL/HSIL], and 97% had abnormal histology (35% LSIL, 65% HSIL). Statistically significant variables associated with HSIL included number of biopsies [odds ratio (OR) 1.55, 95% confidence interval (CI) 1.13-2.14] and having >=1 high grade anal cytology in the last 12 months (OR 3.76, 95% CI 1.38-10.23). No significant association was found between HSIL and CD4, HIV viral load, or recent sexually transmitted infection. In this population, the burden of anal HSIL was extremely high, regardless of most recent anal cytology result. In newly diagnosed HIV-infected men with no history of anal cancer screening, performing HRA as primary anal cancer screening instead of cytology appears to be a viable option. PMID- 29607652 TI - Stable Caloric Intake and Continued Virologic Suppression for HIV-Positive Antiretroviral Treatment-Experienced Women After Switching to a Single-Tablet Regimen of Emtricitabine, Rilpivirine, and Tenofovir Disoproxil Fumarate. AB - Benefits of switching to a single-tablet regimen (STR) of emtricitabine/rilpivirine/tenofovir (FTC/RPV/TDF) in virologically suppressed antiretroviral treatment (ART) experienced HIV-positive women include pregnancy category B rating and lack of clinically significant drug interactions between RPV and oral contraceptives. Unfortunately, studies involving switching to FTC/RPV/TDF enrolled fewer than 25% women. We undertook this 48-week study to assess the ability of virologically suppressed HIV-positive women switching to RPV STR to remain virologically suppressed and comply with the caloric intake requirement. HIV-positive women on ART with viral load <50 c/mL for 6 months before study entry and no known resistance to FTC, TDF, or RPV were enrolled and switched to STR RPV/FTC/TDF. Caloric intake (>=400 kcal) compliance and concurrency with oral STR RPV/FTC/TDF were evaluated with a 3-day food diary, which was validated by obtaining participant's caloric consumption through phone calls on randomly chosen dates. For each 3-day food diary, the daily median caloric intake and median value for each macronutrient consumed concurrent with FTC/RPV/TDF were computed. Medication adherence was measured using a visual analog scale. We enrolled 33 women, 73% of whom were African American. At week 48, virologic suppression (HIV RNA <40 c/mL) was maintained in 96% of women, including those (n = 4) who reported imperfect ART adherence. The daily median caloric intake concurrent with FTC/RPV/TDF was 820 kcal by food diary and 677 kcal by random phone call. Median kcal intake (food diary) did not change significantly from baseline (684 kcal) to week 48 (820 kcal); median change 102 kcal, p = .15. Women who reported noncompliance with a >=400 kcal meal did not experience virologic failure. Significant concordance between caloric adherence and virologic suppression was not detected. Our study demonstrated that HIV positive women who switched to STR FTC/RPV/TDF continued to experience virologic suppression and were readily able to comply with the recommended caloric intake requirement. PMID- 29607651 TI - Lower Concentrations of Circulating Medium and Long-Chain Acylcarnitines Characterize Insulin Resistance in Persons with HIV. AB - In human immunodeficiency virus (HIV)-negative individuals, a plasma metabolite profile, characterized by higher levels of branched-chain amino acids (BCAA), aromatic amino acids, and C3/C5 acylcarnitines, is associated with insulin resistance and increased risk of diabetes. We sought to characterize the metabolite profile accompanying insulin resistance in HIV-positive persons to assess whether the same or different bioenergetics pathways might be implicated. We performed an observational cohort study of 70 nondiabetic, HIV-positive individuals (50% with body mass index >=30 kg/m2) on efavirenz, tenofovir, and emtricitabine with suppressed HIV-1 RNA levels (<50 copies/mL) for at least 2 years and a CD4+ count over 350 cells/MUL. We measured fasting insulin resistance using the homeostatic model assessment 2, plasma free fatty acids (FFA) using gas chromatography, and amino acids, acylcarnitines, and organic acids using liquid chromatography/mass spectrometry. We assessed the relationship of plasma metabolites with insulin resistance using multivariable linear regression. The median age was 45 years, median CD4+ count was 701 cells/MUL, and median hemoglobin A1c was 5.2%. Insulin resistance was associated with higher plasma C3 acylcarnitines (p = .01), but not BCAA or C5 acylcarnitines. However, insulin resistance was associated with lower plasma levels of C18, C16, C12, and C2 acylcarnitines (p <= .03 for all), and lower C18 and C16 acylcarnitine:FFA ratios (p = .002, and p = .03, respectively). In HIV-positive persons, lower levels of plasma acylcarnitines, including the C2 product of complete fatty acid oxidation, are a more prominent feature of insulin resistance than changes in BCAA, suggesting impaired fatty acid uptake and/or mitochondrial oxidation is a central aspect of glucose intolerance in this population. PMID- 29607653 TI - Older, Seriously Ill Veterans' Views on the Role of Religion and Spirituality in Health-Care Delivery. AB - OBJECTIVES: To describe older Veteran's perspectives on the current delivery of religious or spiritual (R/S) care. METHODS: Semi-structured interviews with older veterans with advanced stage cancer, heart failure, or pulmonary disease to elicit views on when, how, and by whom religious and spiritual care is preferred. RESULTS: The sample (n = 17) was largely male (94%), non-Hispanic white (52.9%), Christian (82.3%), and most had at least some college education (64.7%). Participants shared diagnoses of cancer (47%), heart failure (35.2%), or chronic obstructive pulmonary disease (17.6%). As a group, participants had moderate religiosity. Themes relevant to the study goal of improving VA care delivery are as follows: (1) process of R/S engagement, (2) timing of R/S engagement, and (3) awareness of services. Veterans discussed the need for VA providers to accommodate diverse spiritual beliefs, importance of screening for spiritual needs, inclusion of family spiritual support, need for higher visibility of services, use of nonchaplains for R/S support, and times when R/S is important. DISCUSSION: Veterans recognize the diversity of their fellow veterans and note the opportunities and challenges in providing R/S support in the VA care setting. The findings have implications for quality improvement in VA care including efforts focused on enhanced outreach to veterans, bolstered education for staff, and more nuanced approaches to R/S support. PMID- 29607654 TI - Differences Between APOE Carriers and Non-APOE Carriers on Neurocognitive Tests: Jensen Effects? AB - BACKGROUND: Being a carrier of the apolipoprotein E (APOE) epsilon4 allele is a clear risk factor for development of Alzheimer's disease (AD). On some neurocognitive tests, there are smaller differences between carriers and noncarriers, while other tests show larger differences. AIMS: We explore whether the size of the difference between carriers and noncarriers is a function of how well the tests measure general intelligence, so whether there are Jensen effects. METHODS: We used the method of correlated vectors on 441 Korean older adults at risk for AD and 44 with AD. RESULTS: Correlations between APOE carriership and test scores ranged from -.05 to .11 (normal), and -.23 to .54 (AD). The differences between carriers and noncarriers were Jensen effects: r = .31 and r = .54, respectively. CONCLUSION: A composite neurocognitive score may show a clearer contrast between APOE carriers and noncarriers than a large number of scores of single neurocognitive tests. PMID- 29607655 TI - 'You have to treat the person, not the mouth only': UK dentists' perceptions of communication in patient consultations. AB - Effective communication between patients and health professionals is a key component of patient-centred care. Although there is a large body of literature focusing on doctor-patient communication, there has been limited research related to dentist-patient communication, especially presented from the dentists' perspective. The aim of our study was to explore UK dentists' perceptions of communication in their consultations, and the factors they perceive may influence this. We conducted semi-structured interviews with eight dentists in UK dental NHS practices. Thematic analysis revealed three themes ('Treating the whole person', 'Barriers to patient-centred communication' and 'Mutuality of communication'), which reflected the dentists' perceptions of their own communication during consultations, the patients' interaction skills, attitudes (and characteristics that may affect them), and external factors, such as time constraints, that can influence dentist-patients' encounters. These in-depth accounts are valuable, in that we see what dentists perceive is important, obstructive and facilitative. They report using a patient-centred approach in their everyday dental practice; however this is often difficult due to factors such as time constraints. Although they emphasized that the patient has an active role to play in the communication process, it may be the case that they also need to play their part in facilitating this. PMID- 29607656 TI - Implanting a posterior chamber phakic intraocular lens in highly myopic eyes with peripheral primary iris and ciliary body cysts. AB - PURPOSE: To investigate the safety and efficacy of implanting a posterior chamber implantable collamer lens with a central hole in cases of high myopia with peripheral primary iris or ciliary body cysts. METHODS: A total of 37 eyes of 19 patients with primary iris or ciliary body cysts detected by ultrasonic biological microscope were included, with spherical powers of -10.26 +/- 3.28 D and cylinder powers of -1.71 +/- 1.18 D. Each patient received ultrasonic biological microscope and a routine examination before implantation of the implantable collamer lens. A routine postoperative follow-up was performed to observe changes in the iris or ciliary body cyst, ranging from 3 to 18 months. RESULTS: There were no complications. At the last follow-up, 56.8% (21/37) of eyes achieved the same corrected distance visual acuity as their preoperative measurements, 43.2% of eyes were enhanced by >=1 line, and no patients' corrected distance visual acuity declined. The efficacy index and safety index were 0.95 and 1.11, respectively. After 18 months, 66.7% of the spherical equivalents were between +/-0.5 D with 100% between +/-1.0 D. The postoperative mean spherical equivalents at 1, 3, 6, 12, and 18 months were -0.45 +/- 0.31 D, -0.39 +/- 0.29 D, -0.36 +/- 0.30 D, -0.39 +/- 0.38 D, and -0.48 +/- 0.23 D (p = 0.789). The vaults were 516 +/- 140, 548 +/- 124, 498 +/- 133, 582 +/- 161, and 557 +/- 110 MUm (p = 0.355). There were no changes in size (p > 0.05), number, or position of the iris or ciliary body cysts. CONCLUSION: Implantable collamer lens implantation is safe and effective for highly myopic patients with peripheral primary iris and ciliary body cysts. The cysts did not change after operation in this study. PMID- 29607657 TI - Synthesis and antiproliferative activity of new mycophenolic acid conjugates with adenosine derivatives. AB - New conjugates of mycophenolic acid (MPA) and adenosine derivatives were synthesized and assessed as potential immunosuppressants on Jurkat cell line and peripheral blood mononuclear cells (PBMC) from healthy donors. As compared to MPA, all compounds were found to be more active against Jurkat cell line. The antiproliferative activities were compared with MPA and adenosine, in both 2',3' O-isopropylidene protected and free hydroxyl groups possessing forms. The obtained results were also discussed in terms of selectivity index, defined as SI = IC50/EC50. PMID- 29607658 TI - Syndemic effect of mental illness and substance use on viral suppression among recently-incarcerated, HIV-infected individuals in the CARE+ Corrections study. AB - Few studies on HIV-related syndemics of co-occurring and mutually reinforcing psychosocial conditions have assessed clinical outcomes in criminal justice (CJ) involved populations. Baseline data from the CARE+ Corrections study were used to quantify co-occurring mental illness and substance use and examine syndemic effects on viral suppression among 106 CJ-involved HIV-infected individuals. Ninety-one (86%) reported a mental illness diagnosis, 30 (28%) reported hazardous alcohol use, and 61 (58%) were drug dependent. Eighteen (17%) experienced all three conditions. Drug dependence was clustered with mental illness (prevalence odds ratio [POR] 3.20, 95% CI 1.01-10.14) and hazardous alcohol use (POR 2.61, 95% CI 1.03-6.56). The association between syndemic score, representing the number of conditions reported by each individual, and viral suppression was not statistically significant, although 86% of participants with none of these conditions were virally suppressed, compared to 56% of those with all three (p = 0.56). Mental illness and substance use were concentrated in this sample, indicating a need for integrated care services. PMID- 29607659 TI - Ketamine as an Analgesic Adjuvant in Adult Trauma Intensive Care Unit Patients With Rib Fracture. AB - BACKGROUND: Rib fracture associated pain is difficult to control. There are no published studies that use ketamine as a therapeutic modality to reduce the amount of opioid to control rib fracture pain. OBJECTIVE: To examine the analgesic effects of adjuvant ketamine on pain scale scores in trauma intensive care unit (ICU) rib fracture. METHODS: This retrospective, case-control cohort chart review evaluated ICU adult patients with a diagnosis of >=1 rib fracture and an Injury Severity Score >15 during 2016. Patients received standard-of-care pain management with the physician's choice analgesics with or without ketamine as a continuous, fixed, intravenous infusion at 0.1 mg/kg/h. RESULTS: A total of 15 ketamine treatment patients were matched with 15 control standard-of-care patients. Efficacy was measured via Numeric Pain Scale (NPS)/Behavioral Pain Scale (BPS) scores, opioid use, and ICU and hospital length of stay. Safety of ketamine was measured by changes in vital signs, adverse effects, and mortality. Average NPS/BPS, severest NPS/BPS, and opioid use were lower in the ketamine group than in controls (NPS: 4.1 vs 5.8, P < 0.001; severest NPS: 7.0 vs 8.9, P = 0.004; opioid use: 2.5 vs 3.5 mg morphine equivalents/h/d, P = 0.015). No difference was found between the cohort's length of stay or mortality. Average diastolic blood pressure was higher in the treatment group versus the control group (75.3 vs 64.6 mm Hg, P = 0.014). CONCLUSION: Low-dose ketamine appears to be a safe and effective adjuvant option to reduce pain and decrease opioid use in rib fracture. PMID- 29607660 TI - Two new triterpenes from the roots of Pfaffia glomerata. AB - Pfaffia paniculata is a commercialized dietary supplement used as the substitute for the Asian ginseng in Brazil. We conducted the systematic isolation of the EtOAc fraction with anti-inflammatory effect and two new triterpenoids, along with 26 known compounds were characterized by means of MS and NMR analysis. Interestingly, the new compound 1 is the first seco-ring triterpenoid reported in the Pfaffia genus. Furthermore, among the known compounds, 14 and 15 exhibited anti-inflammatory activity in Caco-2 cells, but two new compounds showed no anti inflammatory. PMID- 29607662 TI - Immunohistochemistry in Anaplastic Lymphoma Kinase and Proto-Oncogene Tyrosine Protein Kinase ROS. PMID- 29607661 TI - Suicidality among nonadherent patients living with HIV in Buenos Aires, Argentina: prevalence and correlates. AB - Of those in the general population hospitalized for suicidal ideation and suicide attempts in Argentina, many reattempt suicide and are readmitted. However, few studies in Argentina have examined suicidal ideation and suicide-related behaviors among people living with HIV (PLHIV) and none have examined these factors among nonadherent PLHIV, though the prevalence of suicidal ideation in this group may be higher than in the general population and also than in other groups of PLHIV. This study of PLHIV in Buenos Aires, Argentina, examined the correlates of suicidal ideation in nonadherent PLHIV. Nonadherent patients with HIV (N = 118) were recruited from two clinics providing outpatient healthcare services to PLHIV in Buenos Aires, Argentina. Participants completed assessments on demographic characteristics, depression and suicidality, stigma, and self efficacy. Participants were HIV-infected men (51%) and women (49%) with a median age of 40 years (IQR = 11). About half had completed high school or more, two thirds were employed, and had a mean monthly income of 4196.79 (SD = 3179.64) Argentine pesos (USD$221). Thirty-three (28% [95% CI 20.3, 37.3]) participants reported suicidal ideation in the past two weeks, and one-third (35.6% [27.1, 44.9]) reported lifetime suicidal ideation. In bivariate analyses, attending a public clinic, being female, younger, unemployed, and experiencing greater stigma and depression were associated with suicidal ideation. In multivariable logistic regression, stigma interacted with the number of years since HIV diagnosis to predict suicidal ideation. The impact of stigma on suicidal ideation decreased with time since HIV diagnosis, suggesting that suicidal ideation may arise following HIV diagnosis due to perception of HIV-related stigma. Interventions to reduce perceived stigma during the period following HIV diagnosis may reduce suicidal ideation in this population. Organizational initiatives that explore HIV stigma microagressions in the healthcare setting may be needed to optimize health outcomes. PMID- 29607663 TI - Optimal Evaluation of Programmed Death Ligand-1 on Tumor Cells Versus Immune Cells Requires Different Detection Methods. AB - CONTEXT: - The benefit of programmed death ligand-1 (PD-L1) immunohistochemistry (IHC) as a method to select patients who may benefit from programmed death receptor-1 (PD-1)/PD-L1 immunotherapies remains uncertain in many tumor indications. OBJECTIVES: - To compare the commercially available, approved PD-L1 IHC assays (22C3, 28-8, SP142, SP263), specifically identifying the changes in staining output created by altering the detection method. DESIGN: - This pilot study investigates the respective PD-L1 kit assay staining patterns and related scoring of tumor cells and immune cells on lung carcinoma and melanoma. Furthermore, the influence of the detection method (platform and related reagents) on PD-L1 antibody performance is studied. RESULTS: - The SP142 kit reveals more immune cell staining but less tumor cell staining than the other PD L1 kits. Alternatively, the 22C3 and 28-8 kits show good tumor cell sensitivity, but less pronounced immune cell staining, even in tonsil. Tumor cell staining by the SP263 kit is comparable to that of 22C3 and 28-8 kits, while immune cell staining is better. Strikingly, the selection of the detection method has a major impact on the sensitivity of the assay for PD-L1 detection per cell type. Switching the detection method of the kits could largely circumvent the observed staining differences. CONCLUSIONS: - The diverse sensitivities caused by the choice of the detection method should be taken into consideration when selecting PD-L1 kits or developing PD-L1 IHC laboratory-developed tests. When using alternative kits or laboratory-developed tests, it is strongly recommended to reestablish their clinical utility per therapeutic agent or compare them with the original kit. PMID- 29607664 TI - Cell-Free DNA Utility and Value of Recommendation. PMID- 29607665 TI - Toxicity and phototoxicity in human ARPE-19 retinal pigment epithelium cells of dyes commonly used in retinal surgery. AB - PURPOSE: To compare, for the first time, systematically the toxicity and phototoxicity of dyes and dye combinations used in vitreoretinal surgery. The dyes were trypan blue, brilliant blue G, trypan blue + brilliant blue G, indocyanine green, bromophenol blue, bromophenol blue + brilliant blue G, and acid violet 17, in clinically used concentrations. METHODS: Human ARPE retinal pigment epithelium cells were exposed to the dyes for 30 min. For phototoxicity, the cells were exposed for 15 min to high-intensity light from a light emitting diode source with an intensity similar to surgical conditions. Toxicity was assayed either directly after exposure to either dye alone or dye and light, or with a delay of 24 h. RESULTS: None of the dyes or their combinations was toxic when cells were exposed to them at ambient light. Acid violet led to a reduction viability by 90% already immediately after light exposure. Bromophenol blue and its combination with brilliant blue G showed strong phototoxicity (reduction of viability by 83%) when assayed with delay. Indocyanine green with different agents to adjust osmolarity (balanced salt solution, glucose, and mannitol) was not found to be toxic. CONCLUSION: The strong immediate phototoxicity of acid violet reflects its clinical toxicity. Bromophenol blue might also be disadvantageous for patient outcome because of its delayed phototoxicity. The other dyes (trypan blue, brilliant blue g, and indocyanine green) were not found to be toxic neither with exposure to ambient light nor after exposure to light of intensities used in surgery. PMID- 29607666 TI - Depression and anxiety mediate perceived social support to predict health-related quality of life in pregnant women living with HIV. AB - Pregnant women living with HIV represent one of the most high-priority groups for HIV treatment and health assessment. Although social support has been shown to be a protective factor for improved health-related quality of life (HRQoL), and depression and anxiety have been identified as two major causes of psychological distress among people living with HIV, it is still unclear how social support, anxiety, and depression interact to influence HRQoL. The objective of our study was to demonstrate the nature of predictors, direct effects and mediator effects among social support, anxiety, depression symptoms and HRQoL in pregnant women living with HIV. We investigated a total of 101 pregnant women living with HIV in Yunnan province in China from April 2016 to June 2016. All participants completed the Social Support Rating Scale (SSRS), the Chinese version of the Hospital Anxiety and Depression Scales (HADS) and Quality of Life instruments (EuroQoL Five Dimensions Questionnaire, EQ-5D). The relationships between the variables were examined by Pearson's or Spearman's correlation analysis. Predictor effects were tested using separate multiple regressions, controlling for demographic variables and HIV diagnosis variables. Direct and mediation effects of social support on HRQoL were tested using a structural equation model (SEM). Anxiety and depression symptoms were negatively correlated with subjective social support, support utilization, social support and HRQoL. Social support significantly predicted better HRQoL, and anxiety and depression symptoms significantly predicted poorer HRQoL. Anxiety and depression symptoms partially mediated the associations between social support and HRQoL. Anxiety and depression symptoms completely mediated the associations of objective support and support utilization with HRQoL. Interventions to improve HRQoL in pregnant women living with HIV must consider the mediation effect of anxiety and depression symptoms on the association between social support and HRQoL. Social support interventions are valid only when anxiety and depression symptoms are managed effectively. PMID- 29607667 TI - Application of Multiantigen Profiling To Detect Pecan. AB - A problem often encountered in the detection and identification of undeclared tree nut food allergens is the lack of analytical methods. This problem is accentuated by the current trend, whereby the primary methods used to detect food allergens are antibody-based enzyme-linked immunosorbent assays (ELISAs) and the development of analyte-specific antibodies takes months. The recently developed xMAP food allergen detection assay (xMAP FADA) has the ability to generate multiantigen profiles with tree nuts, thereby providing a potential solution to this problem. The xMAP FADA includes 22 antibodies targeting peanut, soy, and nine tree nuts. The high number of antibodies to a diverse group of tree nuts and legumes and the propensity of tree nuts to cross-react have enabled the development of multiantigen profiling, whereby an analyte reacts with the various antibodies to generate a profile. Recently, a question arose regarding the possible presence of pecan dust at a manufacturer of pecan products that also stored fresh produce. The lack of suitable pecan ELISAs created an analytical challenge that was resolved using multiantigen profiling with the xMAP FADA. Pecan was detected on swab samples by using multiantigen profiling and confirmed by DNA analysis. The use of multiantigen profiling provided an analytical capability beyond what was possible with an analyte-specific analytical method. PMID- 29607669 TI - Phytochemical investigation on Myristica fragrans stem bark. AB - Myristica fragrans Houtt., the source of very important spice 'nutmeg' used world over is native to India, Indonesia, Sri Lanka, South Africa and Southeast Asia. Phytochemical investigation of M. fragrans stem bark led to the isolation of bis aryl dimethyl tetrahydrofuran lignans, such as grandisin [(7S,8S,7'S,8'S) 3,3',4,4',5,5'-hexamethoxy-7,7',8,8'-lignan] and (7S,8S,7'R,8'R)-3,3',4,4',5,5' hexamethoxy-7,7',8,8'-lignan along with important lignans and neolignans, licarinA, licarin B, odoratisol A, (2S, 3R)-7-methoxy-3-methyl-5-((E)-prop-1 enyl)-2-(5-methoxy,3,4-methylenedioxyphenyl)-2,3-dihydrobenzofuran, elemicin, fragransin B1, raphidecursinol B, erythro-(7S,8R)-Delta8'-4,7-dihydroxy-3,5,3' trimethoxy-8-O-4'-neolignan, erythro-(7S,8R)-Delta8'-7-hydroxy-3,4,3',5' tetramethoxy-8-O-4'-neolignan, surinamensin.and beta-sitosterol. Structures of the 12 compounds isolated were unambiguously identified by various spectroscopic methods. The former two compounds were isolated from M. fragrans for the first time. Furthermore, the X-ray crystal structure of odoratisol A is reported in this paper for the first time. PMID- 29607668 TI - Weight-Bearing Radiographic Analysis of the Tibiofibular Syndesmosis. AB - BACKGROUND: Diagnosis of distal tibiofibular syndesmotic injuries includes assessment of radiographs; however, there exist no agreed on standard diagnostic criteria. Previous studies lack consistency with radiographic evaluation methods. The dynamic nature of the ankle joint supports analyzing anatomical parameters using weight-bearing films to assess for tibiofibular syndesmotic integrity. METHODS: Weight-bearing tibiofibular syndesmosis radiographs of 39 male and 40 female patients were retrospectively analyzed by 3 investigators, at different levels of orthopaedic training. Measurements 1 cm above the tibial plafond for the anterior tibiofibular overlap (TFO) and tibiofibular clear space (TCS) were recorded and standardized by the fibular width (FW) at 2 time points. Data were compared to check for agreement between the sets of measurements for each rater and agreement between investigators, and to ascertain underlying gender differences. RESULTS: There was good intraobserver correlation (intraclass correlation coefficient [ICC] > 0.90) among investigators for each parameter. A significant difference in the TFO was noted between genders (P < .05). We establish the following radiographic (anteroposterior view) parameters for an intact syndesmosis: male patients, TCS <4.57 mm or TCS/FW <29% and TFO >9.29 mm or TFO/FW > 57%; female patients, TCS <4.28 mm or TCS/FW <30% and TFO >7.41 mm or TFO/FW >51%. CONCLUSIONS: Our study provides a more objective approach by utilizing weight-bearing radiographs and performing all measurements 1 cm above the tibial plafond. LEVELS OF EVIDENCE: Level IV. PMID- 29607670 TI - Screening Programs for Abdominal Aortic Aneurysms: Luxury or Necessity? PMID- 29607671 TI - The Applied Effectiveness of Clay Art Therapy for Patients With Parkinson's Disease. AB - This study investigates how clay art therapy affects Parkinson's disease patients' overall mental and physical condition as well as future treatment potentiality. The research was nonequivalent control groups pre and post study. A total of 54 patients with Parkinson's disease (control = 28, experimental = 26) were recruited from 3 setting locations in South Korea. Test measures were completed before and after the 16 sessions. The experimental group received two 80-minute evaluations per week for 8 weeks. Demographic information: hand dexterity, self-expression, mood depression, and quality of life measurements. There were significant differences in hand dexterity ( t = 4.96, P < .001), self expression ( t = 3.74, P < .001), mood depression ( t = -11.85, P < .001), and quality of life ( t = 8.07, P < .001) between the 2 groups. Further research and development of clay art therapy can advocate the benefits, highlight practicality and demonstrate the possibility for its usage as a treatment methodology. PMID- 29607672 TI - Lithium chloride reduces orthodontically induced root resorption and affects tooth root movement in rats. AB - OBJECTIVE: To investigate the influence of lithium chloride (LiCl) on orthodontic tooth movement (OTM), orthodontically induced root resorption (OIRR), and bone morphometry. MATERIALS AND METHODS: Ten-week-old female Sprague Dawley rats (n = 32) were divided into four groups based on the concentration of LiCl administered daily per kilogram body weight: 0 (control group), 0.32, 0.64, and 1.28 mM/kg body weight. The maxillary left first molars were moved mesially by a 10 cN coil spring for 14 days. Micro-computed tomography, scanning electron microscope, and scanning laser microscope images were taken to measure the amount of OTM, the volume of OIRR, and bone morphometry. RESULTS: OIRR clearly decreased depending on the amount of LiCl administered, although OTM moderately decreased. The tooth inclined mesially and the root apex moved distally in the control and 0.32 mM groups. On the other hand, the tooth inclination angle became smaller and the root apex moved mesially in the 0.64 and 1.28 mM groups. In bone morphometry, the cortical bone mineral content and bone volume increased because of LiCl administration, and the trabecular bone measurements decreased. OIRR negatively correlated to the cortical bone measurements, and the amount of OTM significantly correlated to the cortical bone morphometry. CONCLUSIONS: In rats, LiCl reduced OIRR, which induced mesial movement of the tooth root apex. OIRR positively correlated to cortical bone morphometry. PMID- 29607673 TI - Anorexia Nervosa is a Body-Image Disorder. PMID- 29607674 TI - A rare oesophageal inflammatory myofibroblastic tumour treated by endoscopy. AB - An inflammatory myofibroblastic tumour is a mesenchymal neoplasm that mostly involves the lung and rarely involves the oesophagus. Surgery has been most commonly used for the treatment of oesophageal inflammatory myofibroblastic tumours but there are no definite guidelines for their diagnosis and treatment. We describe the case of a 60-year-old woman presenting with dysphagia and poor appetite who was diagnosed with a submucosal oesophageal tumour by contrast enhanced computed tomography and ultrasonography endoscopy. She was treated successfully by endoscopic submucosal dissection with no complications. The final diagnosis was confirmed by pathological examination. PMID- 29607675 TI - 'Sharing things with people that I don't even know': help-seeking for psychological symptoms in injured Black men in Philadelphia. AB - OBJECTIVES: Psychological distress is common in survivors of traumatic injury, yet across United States' trauma systems, it is rare that standard injury care integrates psychological evaluation and professional mental healthcare. The purpose of this study was to explore help-seeking for psychological symptoms in injured Black men living in Philadelphia. DESIGN: A subset of a cohort of 551 injured Black men admitted to a Trauma Center in Philadelphia participated in qualitative interviews that explored their perceptions of psychological symptoms after injury and the factors that guided their decision to seek professional mental health help. Data from 32 participants were analyzed for narrative and thematic content. RESULTS: Three overarching themes emerged: (1) facilitators of help-seeking, (2) barriers to help-seeking, and (3) factors underlying the decision not to consider professional help. Five participants felt that their injury-related psychological distress was severe enough to merit professional help despite any perceived barriers. Seventeen participants identified systemic and interpersonal obstacles to professional help that prevented them from seeking this kind of care. These included: financial constraints, limited access to mental healthcare services, and fear of the judgments of mental healthcare professionals. Ten participants would not consider professional help; these men perceived a lack of need and sufficiency in their existing social support networks. CONCLUSIONS: Research is needed to inform or identify interventions that diminish the impact of barriers to care, and identify from whom, where, and how professional mental health help might be more effectively offered to injured Black men in recovery environments like Philadelphia. PMID- 29607676 TI - Comparing the Effect of Psyllium Seed on Gastroesophageal Reflux Disease With Oral Omeprazole in Patients With Functional Constipation. AB - Gastroesophageal reflux disease (GERD) is one of the most common gastrointestinal diseases. Several studies have been carried out on the treatment of symptoms associated with GERD. The present study aimed to compare the effect of Psyllium seed and oral omeprazole on GERD in patients with functional constipation. In this trial, 132 patients were divided into 2 groups. The impact of omeprazole and Psyllium seed on the treatment and recurrence of GERD was studied. Among the patients, the rate of response to treatment was 89.2% (n = 58) in the Psyllium seed group, while in omeprazole group, it was 94% (n = 63; P = .31). The recurrence rates of Psyllium seed and omeprazole groups were 24.1% (n =14) and 69.8% (n = 44), respectively ( P < .001). The results showed that treatment of functional constipation by Psyllium seed in patients with GERD leads to improvement of GERD and its recurrences in comparison with omeprazole. PMID- 29607677 TI - Participation of children and youth with neurodevelopmental disorders in after school activities. AB - AIM: The aim of this study was to compare the level of participation in social, leisure and recreational activities in a group with intellectual disability, a group with autistic spectrum disorders, and a typically developing group. METHOD: The sample included 157 children of both genders, between 7 and 16 years of age (M = 11.03, SD =2.59). The Activities Questionnaire, which consists of: social, leisure, recreational activities, and friendship, was used in the research. RESULTS: Participants with intellectual disability participated in a significantly larger number of all assessed activities than their peers with autistic spectrum disorders. There were no statistically significant differences in the frequency of participation in observed activities among the three groups of participants. Participants with intellectual disability were more independent than participants with autistic spectrum disorders in social and leisure activities, and needed less parental support in leisure activities. Participants with intellectual disability and autistic spectrum disorders had friendly relationships mainly with peers with disabilities. The influence of gender was detected in certain activities in all three groups of participants. CONCLUSIONS: Participants with disability participate in social, leisure and recreational activities less than their typically developing peers. The activities in which they participate are mainly stereotypical, highly structured, and take place in the presence of parents. IMPLICATIONS FOR REHABILITATION Forming a richer network of support services which would be oriented towards organizing social, leisure and recreational activities of persons with disabilities in the community. It is necessary to improve support programs which would focus on strengthening the competencies and resources of parents. The improvement of formal and informal support should provide a wider network, and better and more frequent social relationships between persons with and without disabilities. PMID- 29607678 TI - Coat Clipping of Horses: A Survey. AB - Coat clipping is a common practice in sport horses; however, timing, purpose, technique, and clips vary widely, as do the management and feeding of a clipped horse. The aim of this study was to collect data regarding common clipping practices. A questionnaire was published online in Germany and contained 32 questions. Four hundred ninety-eight people answered at least one question, and 373 individuals (7% male, 93% female; ages 14-59 years) completed all the questions. Clipped horses were predominantly used as sport horses (68%), and they were either clipped immediately before or during the winter season (88%) or year round (7%). The clipping date was scheduled according to hair length (52%), sweat amount (47%), and drying time (47%). Participants primarily used two clips: the hunter clip and the blanket clip, both without clipping the head (23% each). The majority of the clipped horses wore a blanket day and night (> 90%). Future studies with observations in the field are needed to support survey data in an effort to develop welfare recommendations for clipping practices utilized with horses. PMID- 29607679 TI - Time to implement a national referral pathway for suspected cauda equina syndrome: review and outcome of 250 referrals. AB - INTRODUCTION: Cauda equina syndrome (CES) is a condition with significant implications and medico-legal profile. The literature still lacks large primary studies to provide strong evidence for a robust management pathway. Statements from Neurosurgical and Spinal societies support early diagnosis and imaging but this has not resulted in any noticeable shift in referral pattern. We strongly feel the need for a nationally agreed, evidence-based referral pathway in practice. We present our large series and in-depth analysis of the referral pathway to provide strong evidence for more robust referrals and management. METHODS: We reviewed 250 referrals of suspected CES (sCES) to the regional neurosurgical unit, evaluating the importance of clinical findings and the imaging pathway. RESULTS: After clinico-radiological evaluation only 32 (13%) had confirmed CES requiring urgent surgery. There was no significant difference in terms of clinical presentation between these true cases of CES (tCES) and false cases (fCES). Imaging was therefore the key rate-limiting step. MRI was the most common investigation used. 73 patients presented without imaging out of hours (OOH). In this group, investigation was delayed to the next day in 60/73 (82%) patients while only 13 (18%) patients underwent OOH MRI. Only 2 (3%) were able to have this at their local hospital. CONCLUSIONS: As with previous studies we conclude that signs/symptoms are insufficient to identify tCES. Taking into consideration the improved outcome with early diagnosis, the importance of early scanning in diagnosing tCES, and the poor availability of OOH MRI scanning outside of neurosurgical units, we recommend a national policy of 24/7 MRI availability for cases of sCES at all hospitals with MRI scanners. This would remove the 87% of patients not requiring urgent surgery from an unnecessary and distracting referral process. PMID- 29607680 TI - Concurrent Neuroendocrine Carcinoma of the Skin (Merkel Cell Carcinoma) and Squamous Cell Carcinoma of the Skin on the Right Ear Helix. PMID- 29607681 TI - Principal States of Dynamic Functional Connectivity Reveal the Link Between Resting-State and Task-State Brain: An fMRI Study. AB - Task-related reorganization of functional connectivity (FC) has been widely investigated. Under classic static FC analysis, brain networks under task and rest have been demonstrated a general similarity. However, brain activity and cognitive process are believed to be dynamic and adaptive. Since static FC inherently ignores the distinct temporal patterns between rest and task, dynamic FC may be more a suitable technique to characterize the brain's dynamic and adaptive activities. In this study, we adopted [Formula: see text]-means clustering to investigate task-related spatiotemporal reorganization of dynamic brain networks and hypothesized that dynamic FC would be able to reveal the link between resting-state and task-state brain organization, including broadly similar spatial patterns but distinct temporal patterns. In order to test this hypothesis, this study examined the dynamic FC in default-mode network (DMN) and motor-related network (MN) using Blood-Oxygenation-Level-Dependent (BOLD)-fMRI data from 26 healthy subjects during rest (REST) and a hand closing-and-opening (HCO) task. Two principal FC states in REST and one principal FC state in HCO were identified. The first principal FC state in REST was found similar to that in HCO, which appeared to represent intrinsic network architecture and validated the broadly similar spatial patterns between REST and HCO. However, the second FC principal state in REST with much shorter "dwell time" implied the transient functional relationship between DMN and MN during REST. In addition, a more frequent shifting between two principal FC states indicated that brain network dynamically maintained a "default mode" in the motor system during REST, whereas the presence of a single principal FC state and reduced FC variability implied a more temporally stable connectivity during HCO, validating the distinct temporal patterns between REST and HCO. Our results further demonstrated that dynamic FC analysis could offer unique insights in understanding how the brain reorganizes itself during rest and task states, and the ways in which the brain adaptively responds to the cognitive requirements of tasks. PMID- 29607682 TI - Epileptic Seizure Detection Based on Time-Frequency Images of EEG Signals Using Gaussian Mixture Model and Gray Level Co-Occurrence Matrix Features. AB - The electroencephalogram (EEG) signal analysis is a valuable tool in the evaluation of neurological disorders, which is commonly used for the diagnosis of epileptic seizures. This paper presents a novel automatic EEG signal classification method for epileptic seizure detection. The proposed method first employs a continuous wavelet transform (CWT) method for obtaining the time frequency images (TFI) of EEG signals. The processed EEG signals are then decomposed into five sub-band frequency components of clinical interest since these sub-band frequency components indicate much better discriminative characteristics. Both Gaussian Mixture Model (GMM) features and Gray Level Co occurrence Matrix (GLCM) descriptors are then extracted from these sub-band TFI. Additionally, in order to improve classification accuracy, a compact feature selection method by combining the ReliefF and the support vector machine-based recursive feature elimination (RFE-SVM) algorithm is adopted to select the most discriminative feature subset, which is an input to the SVM with the radial basis function (RBF) for classifying epileptic seizure EEG signals. The experimental results from a publicly available benchmark database demonstrate that the proposed approach provides better classification accuracy than the recently proposed methods in the literature, indicating the effectiveness of the proposed method in the detection of epileptic seizures. PMID- 29607683 TI - Petroclival tension pneumocephalus: an unrivalled life threatening complication linked to molecular-targeted therapy. AB - A 73-year-old man with a petroclival tumor (metastatic renal cell carcinoma) presented with a progressive consciousness disturbance attributed to tension pneumocephalus during molecular-targeted therapy following low-dose fractionated radiotherapy for a petroclival tumor. The skull base defect was successfully reconstructed vi an endoscopic endonasal approach. PMID- 29607684 TI - Tumour microenvironment on mitochondrial dynamics and chemoresistance in cancer. AB - Mitochondria, evolutionally acquired symbionts of eukaryotic cells, are essential cytoplasmic organelles. They are structurally dynamic organelles that continually go through fission and fusion processes in response to various stimuli. Tumour tissue is composed of not just cancer cells but also various cell types like fibroblasts, mesenchymal stem and immune cells. Mitochondrial dynamics of cancer cells has been shown to be significantly affected by features of tumour microenvironment such as hypoxia, inflammation and energy deprivation. The interactions of cancer cells with tumour microenvironment like hypoxia give rise to the inter- and intratumoural heterogeneity, causing chemoresistance. In this review, we will focus on the chemoresistance by tumoural heterogeneity in relation to mitochondrial dynamics of cancer cells. Recent findings in molecular mechanisms involved in the control of mitochondrial dynamics as well as the impact of mitochondrial dynamics on drug sensitivity in cancer are highlighted in the current review. PMID- 29607685 TI - Integrative Oncology in Supportive Cancer Care in Israel. AB - PURPOSE: Integrative oncology (IO) services provide complementary/integrative medicine (CIM) therapies to patients as part of their supportive cancer care. In this study, we examine and compare the structural, operational, financial and academic/research-related aspects of IO services in Israeli oncology centers. METHODS: The medical directors of seven Israeli IO programs completed questionnaires which explored the objectives and organizational features of their service within the context of supportive cancer care. RESULTS: All participating IO services addressed patient-reported concerns related to quality of life and function, within the context of conventional supportive cancer care. The centers shared similar characteristics regarding the procedure of referral to their service and emphasized research and teaching initiatives within an academic framework, as part of their clinical practice. A number of obstacles to integration were identified, primarily those related to financial considerations, such as the need for patients to carry the cost of the CIM treatments. CONCLUSIONS: IO services situated within conventional oncology departments in Israel share a number of characteristics, as well as obstacles to their incorporation into standard care. All participating centers described both clinical and academic activities, including research initiatives and the promotion of CIM in an academic setting. Further research is needed in order to better understand the place of CIM in the oncology setting and prioritize the allocation of resources in order to advance the inclusion of CIM in standard supportive cancer care. PMID- 29607686 TI - Use of Integrative Oncology, Involvement in Decision-Making, and Breast Cancer Survivor Health-Related Quality of Life in the First 5 Years Postdiagnosis. AB - OBJECTIVE: This study sought to describe changes in the health-related quality of life (HRQOL) of women who do and do not seek naturopathic oncology (NO) complementary and alternative medicine (CAM) care during and immediately after breast cancer treatment, and to explore the predictive role of NO CAM care, demographic characteristics, and involvement in decision-making on HRQOL in breast cancer survivors. METHODS: Matched cohorts of breast cancer survivors who did and did not choose to supplement their breast cancer treatment with NO care within 2 years of diagnosis participated. NO users were identified through naturopathic doctors' clinics and usual care (UC) controls with similar prognosis were identified through a cancer registry. The registry provided information about all participants' age, race, ethnicity, marital status, stage of cancer at time of diagnosis, date of diagnosis, and use of conventional medical treatments (surgery, chemotherapy, radiation, and endocrine therapy). Data of participants' self-reported involvement in decision-making and HRQOL were collected at study enrollment and at 6-month follow-up. RESULTS: At 6-month follow-up, the NO patients reported significantly more involvement in decision-making about care and better general health than did UC patients ( P < .05). Self-reported involvement in decision-making about cancer treatment was associated with better role-physical, role-emotional, and social-functional well-being ( P < .05). Race, age, marital status, and congruence of preferred and achieved levels of involvement also predicted aspects of HRQOL in breast cancer survivors ( P < .05). CONCLUSIONS: Both NO CAM care and involvement in decision-making about cancer treatment may be associated with better HRQOL in breast cancer survivors. PMID- 29607687 TI - Have there been improvements in Alzheimer's disease drug discovery over the past 5 years? AB - INTRODUCTION: Alzheimer's disease (AD) is the most important neurodegenerative disorder with a global cost worldwide of over $700 billion. Pharmacological treatment accounts for 10-20% of direct costs; no new drugs have been approved during the past 15 years; and the available medications are not cost-effective. Areas covered: A massive scrutiny of AD-related PubMed publications (ps)(2013 2017) identified 42,053ps of which 8,380 (19.60%) were associated with AD treatments. The most prevalent pharmacological categories included neurotransmitter enhancers (11.38%), multi-target drugs (2.45%), anti-Amyloid agents (13.30%), anti-Tau agents (2.03%), natural products and derivatives (25.58%), novel drugs (8.13%), novel targets (5.66%), other (old) drugs (11.77%), anti-inflammatory drugs (1.20%), neuroprotective peptides (1.25%), stem cell therapy (1.85%), nanocarriers/nanotherapeutics (1.52%), and others (<1% each). Expert opinion: Unsuccessful outcomes in AD therapeutics are attributed to pathogenic misconceptions, erratic procedures in drug development and inappropriate regulations. Recommendations for the future are as follows: (i) the reconsideration of dominant pathogenic theories, (ii) the identification of reliable biomarkers, (iii) the redefinition of diagnostic criteria, (iv) new guidelines for disease management, (v) the reorientation of drug discovery programs, (vi) the updating of regulatory requirements, (vii) the introduction of pharmacogenomics in drug development and personalized treatments, and (viii) the implementation of preventive programs. PMID- 29607688 TI - Posterior fossa metastasis of lung carcinoid tumor: case report. AB - Carcinoid tumors are generally indolent neoplasms. Brain metastases are rare and when present, yield a poor prognosis. We present the case of a 76-year old female surgically treated for an atypical bronchial carcinoid, staged as T2aN0M0G2. Without further adjuvant treatment she remained stable for four years, when she presented with headaches and gait imbalance. Brain MRI revealed a midline, intra axial infratentorial lesion that was completely removal, of which histolology confirmed a carcinoid metastasis. At 14 months of follow-up, the patient showed no signs of systemic disease or brain recurrence, and thus no adjuvant radiotherapy was prescribed. PMID- 29607689 TI - Curcumin and resveratrol rescue cortical-hippocampal system from chronic fluoride induced neurodegeneration and enhance memory retrieval. AB - OBJECTIVE: The aim of this study was: (1) to evaluate the neuroprotective effect of resveratrol and curcumin on nicotinamide adenine dinucleotide phosphate diaphorase activity in neuronal cell in subregions of mice brain, (2) to evaluate the effects on antioxidant status and (3) to evaluate the protective effects of phytochemicals on learning and memory following fluoride exposure. METHOD: Young mice (one month old, body weight (BW) 30 +/- 5 mg) were provided with 120 ppm sodium fluoride dissolved in drinking water. They were given curcumin (30 mg/kg BW) or resveratrol (30 mg/kg BW) orally once in a day up to 30 days. Effects of resveratrol and curcumin on spatial learning and memory were studied using Morris water maze and classic maze test. Effects on brain antioxidants' (lactose dehydrogenase (LDH), malondialdehyde and reactive oxygen species) status were also studied in vitro. Histochemistry was done to assess the effect of treatments on nitric oxide neurotransmitter. RESULT: Our study showed that in fluoride treated animals, the number of nicotinamide adenine dinucleotide phosphate diaphorase positive neurons, intracellular Ca2+, reactive oxygen species level, LDH and malondialdehyde concentration increased significantly. Interestingly, after treatment with curcumin or resveratrol, a significant decrease in the number of nicotinamide adenine dinucleotide phosphate diaphorase positive neurons and antioxidant status was observed. This decrease was more considerable in resveratrol-treated group. CONCLUSION: Our study indicates that both antioxidants, curcumin and resveratrol, are useful in reducing neurodegeneration in selective areas of cornus ammonis 1 (CA1), CA3, dentate gyrus (DG) and the cortex of mice brain and in recuperating the loss of memory and learning caused due to fluoride exposure. PMID- 29607690 TI - Antitumor and Immunomodulatory Activities of Ganoderma lucidum Polysaccharides in Glioma-Bearing Rats. AB - Malignant gliomas are the most common brain tumors with high rates of recurrence and mortality. Novel approaches are in research, and immunotherapy emerges as a promising strategy. Recently, scientific attention has been focused on Ganoderma lucidum polysaccharides (GL-PS), one of the critical bioactive components of G lucidum, which have been recognized as a promising natural source of immunomodulatory and anticancer compounds. It remains unknown whether the GL-PS have any immunomodulatory and anticancer effects on brain glioma. This study was designed to identify and characterize the antitumor action and influence of immune system of GL-PS in glioma-bearing rats. Results showed that GL-PS increased the concentration of serum interleukin-2, tumor necrosis factor-alpha, and interferon-gamma, and enhanced the cytotoxic activity of natural killer cells and T cells, promoting the functional maturation of dendritic cells, thus resulting in the inhibition of glioma growth and prolonged survival of rats. Therefore, GL-PS may be potentially useful as part of the treatment regimen to regulate host immune responses and increase the antitumor effects of immunotherapy for glioma. PMID- 29607691 TI - Effects of ionizing radiation on bio-active plant extracts useful for preventing oxidative damages. AB - Humans are exposed to ionizing radiations in medical radiodiagnosis and radiotherapy that cause oxidative damages and degenerative diseases. Airplane pilots, and even more astronauts, are exposed to a variety of potentially harmful factors, including cosmic radiations. Among the phytochemicals, phenols are particularly efficient in countering the oxidative stress. In the present study, different extracts obtained from plant food, plant by-products and dietary supplements, have been compared for their antioxidant properties before and after irradiation of 140 cGy, a dose absorbed during a hypothetical stay of three years in the space. All the dry extracts, characterized in terms of vitamin C and phenolic content, remained chemically unaltered and maintained their antioxidant capability after irradiation. Our results suggest the potential use of these extracts as nutraceuticals to protect humans from oxidative damages, even when these extracts must be stored in an environment exposed to cosmic radiations as in a space station. PMID- 29607692 TI - Feasibility of bipolar radiofrequency ablation in patients with parathyroid adenoma: a first evaluation. AB - AIM: The aim of this study was to first assess the feasibility of bipolar radiofrequency ablation in patients with parathyroid adenoma. MATERIAL AND METHODS: Bipolar RFA was performed in 9 patients with primary parathyroid adenoma in one single session. Measured parameters were PTH and calcium serum levels prior to and after bRFA. Furthermore, using an NRS pain scale (1-10), the individual, subjective maximum sensation of pain was documented. RESULTS: The bRFA resulted in a highly significant (p = .003906) decrease of serum PTH levels (median 67 ng/l) in comparison to those prior to the intervention (median 199 ng/l). Regarding calcium levels, there was no statistical significance (p = .460938), with a decrease of median serum levels comparing pre- and post-bRFA values from 2.82 mmol/l to 2.66 mmol/l. The evaluation of the individual pain sensation during the procedure was assessed by the patients with a median of 5/10 on the NRS scale. In none of the 9 cases complications such as infections, persisting pain or nerve injury occurred. CONCLUSION: For the first time, it was possible to depict the successful therapy of parathyroid adenoma by means of bRFA. This work thus proves bRFA to be an effective, safe, applicable and, concerning sensation of pain, very well tolerable thermoablative technique in the treatment of parathyroid adenoma. PMID- 29607693 TI - Sublingual spray drug delivery of ketorolac-loaded chitosan nanoparticles. AB - INTRODUCTION: The aim of this study was to investigate ketorolac (KT) systemic absolute bioavailability after sublingual (SL) administration in vivo to conscious rabbits. Furthermore, the study investigated the potential use of chitosan nanoparticles as a delivery system to enhance the systemic bioavailability of KT following SL administration. METHODS: Ketorolac-loaded chitosan nanoparticles were prepared through ionotropic gelation of chitosan with tripolyphosphate anions. The KT-nanoparticles were administered SL as a spray to rabbits and KT plasma concentration at predetermined time points was compared to SL spray administration of KT in solution. The concentrations of KT in plasma were analyzed by ultra-performance liquid chromatography mass spectroscopy (UPLC/MS). RESULTS: KT-loaded chitosan nanoparticles significantly (p < .05) enhanced systemic absorption with 97% absolute bioavailability as compared to 70% after SL administration of KT solution. CONCLUSIONS: The results of the present study suggest that SL absorption of KT illustrated flip-flop kinetics with prolonged persistence in the body compared to intravenous administration. Formulation of KT as chitosan nanoparticles has increased its systemic bioavailability after SL spray administration. The new delivery system could be an attractive approach for the delivery of KT. PMID- 29607694 TI - Taurine attenuates acrylamide-induced apoptosis via a PI3K/AKT-dependent manner. AB - As a potent neurotoxic agent, acrylamide (ACR) is formed in food processing at higher temperature. Taurine (TAU), a nonessential amino acid, is used to cure neurodegenerative disorders, followed by activation of the phosphatidylinositol 3 kinase/protein kinase B (PI3K/AKT) signaling pathway. In this article, we certified that antiapoptotic efficacy of TAU in vivo and vitro. ACR-treated rats received TAU by drinking water 2 weeks after ACR intoxication. The results showed that in treated rats, TAU alleviated ACR-induced neuronal apoptosis, which was associated with the activation of PI3K/AKT signaling pathway. TAU attenuated apoptosis caused by ACR through observing terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL)-positive cells, measure of protein expression of Bcl-2, Bax, and caspase 3 activity. TAU-induced antiapoptotic effect is PI3K/AKT-dependent, which was proved in ACR-intoxicated ventral spinal cord 4.1 cells in the presence of AKT inhibitor, MK-2206. Therefore, our results demonstrated that TAU-attenuated ACR-induced apoptosis in vivo through a PI3K/AKT dependent manner provided new sights in the molecular mechanism of TAU protection against ACR-induced neurotoxicity. PMID- 29607695 TI - "ALS reversals": demographics, disease characteristics, treatments, and co morbidities. AB - OBJECTIVE: To identify differences in demographics, disease characteristics, treatments, and co-morbidities between patients with "amyotrophic lateral sclerosis (ALS) reversals" and those with typically progressive ALS. METHODS: Cases of possible ALS reversals were found in prior publications, in the Duke ALS clinic, through self-referral or referral from other Neurologists, and on the internet. Of 89 possible reversals identified, 36 cases were included because chart or literature review confirmed their diagnosis and a robust, sustained improvement in at least one objective measure. Controls were participants in the Pooled Resource Open-Access ALS Clinical Trials database and the National ALS Registry. Cases and controls were compared using descriptive statistics. RESULTS: ALS reversals were more likely to be male, have limb onset disease, and initially progress faster. The prevalences of myasthenia gravis (MG) and purely lower motor neuron disease in cases were higher than estimates of these prevalences in the general population. The odds of taking curcumin, luteolin, cannabidiol, azathioprine, copper, glutathione, vitamin D, and fish oil were greater for cases than controls. CONCLUSIONS: When compared to patients with typically progressive ALS, patients with reversals differed in their demographics, disease characteristics, and treatments. While some of these patients may have had a rare antibody-mediated ALS mimicker, such as atypical myasthenia gravis, details of their exams, EMGs and family histories argue that this was unlikely. Instead, our data suggest that ALS reversals warrant evaluation for mechanisms of disease resistance and that treatments associated with multiple ALS reversals deserve further study. PMID- 29607696 TI - A network approach to the analysis of psychosocial risk factors and their association with health. AB - We modeled early psychosocial risks as a network of interconnected variables to study their associations with later depressive symptoms and cardiometabolic outcomes. The participants were a nationally representative sample of 2580 men and women aged 3-18 years in 1980. Their parents reported the psychosocial risks in 1980, including the following: (1) child-specific life events, (2) parental health behavior, (3) parental socioeconomic status, and (4) parental psychological problems. Adulthood depressive symptoms and cardiometabolic outcomes were measured in 2007-2012. The most central risks (most number of connections to other risks) were socioeconomic risks that also predicted health outcomes more consistently than others. PMID- 29607697 TI - 'To give is better than to receive?' Couples massage significantly benefits both partners' wellbeing. AB - This experimental study evaluated the differential effects of 'giving' and 'receiving' massage on wellbeing in healthy but stressed couples. Forty-two volunteers started the study and of these, 38 (i.e. 19 couples) completed a 3 week massage course. Emotional stress and mental clarity were assessed before and after mutual massage between each pair of adults belonging to a couple at home. While massage benefitted both parties' wellbeing within a session, critically we found no differences in wellbeing between those 'giving' and 'receiving' massage. These novel findings suggest that home-based massage may be advocated to couples as a 'selves-care', health-promoting behaviour. PMID- 29607698 TI - The role of MPL and imiquimod adjuvants in enhancement of immune response and protection in BALB/c mice immunized with soluble Leishmania antigen (SLA) encapsulated in nanoliposome. AB - Adjuvants play an essential role in the induction of immunity against leishmaniasis. In this study, monophosphoryl lipid A (MPL) and imiquimod (IMQ) were used as TLR ligands adjuvants to enhance immunogenicity and rate of protection against leishmaniasis. Nanoliposomes containing soluble Leishmania antigens (SLA) and adjuvants were consisted of DSPC, DSPG and Chol prepared by using lipid film method followed by bath sonication. The size of nanoliposomes was around 95 nm and their zeta potential was negative. BALB/c mice were immunized by liposomal formulations of lip/SLA, lip/MPL/SLA, lip/IMQ/SLA, lip/MPL/IMQ/SLA, lip/SLA + lip/IMQ, lip/SLA + lip/MPL, lip/SLA + lip/MPL/IMQ and five controls of SLA, lip/MPL, lip/IMQ, lip/MPL/IMQ and buffer by subcutaneously (SC) injections, three times in 2 weeks intervals. The synergic effect of two adjuvants when they are used in one formulation showed significantly (p < .001) smaller footpad swelling and the lowest parasite burden in lymph node and foot after the challenge. IgG2a in these groups showed the higher titre compared to control groups, which is compatible with the high IFN-gamma production and lowest IL-4. Taken together the results indicated that co-delivery of MPL and IMQ adjuvants and antigen in nanoliposome carrier could be an appropriate delivery system to induce cellular immunity pathway against leishmaniasis. PMID- 29607699 TI - Synergic highly effective photothermal-chemotherapy with platinum prodrug linked melanin-like nanoparticles. AB - Cisplatin is widely used in cancer treatment, but the application is limited due to toxicities and its acquired resistance. In this study, we delivered cisplatin to prostate cancer cells by linking the platinum prodrug Pt(IV) to melanin-like nanoparticles (MeNPs), a promising photothermal therapeutic agent with excellent biocompatibility. As expected, the Pt(IV)-MeNPs exhibited brilliant synergic photothermal-chemotherapy upon near-infrared reflection exposure. Compared with free cisplatin, Pt(IV)-MeNPs displayed highly effective antitumour activity both in vitro and in vivo. PMID- 29607700 TI - Effect of simple and low-cost enrichment items on behavioral, clinical, and productive variables of caged laying hens. AB - Housing layers in battery cages is a practice still used by many countries but it has been criticized because of its influence on behavioral repertoire of birds. We investigated whether simple and affordable enrichment devices alone impact behavior, foot condition and performance of laying hens housed in conventional cages. Hens were divided into plain cages (CON), cages with perches (PER), and cages with tassels and scratch-pads (ENR), and parameters were evaluated before and after enrichment placement. After perch placement inactivity, drinking and competition for space reduced 35.6%, 40.8% and 70.3%, respectively, whereas social interaction increased 19.3%. Both modifications decreased locomotion (75.0% and 42.4% for PER and ENR respectively) and abnormal behaviors (62.5% and 43.9.4% for PER and ENR respectively). None of the performance variables were affected by ENR or PER. Thermography was more efficient than visual inspection in detecting subclinical bumblefoot, and it confirmed that PER reduced subclinical and clinical cases. Our findings indicate that perches increased welfare-related behaviors and foot health of hens, supporting the use of these inexpensive and highly adaptable alternatives for the enrichment of battery cages. PMID- 29607701 TI - Role of activation of lipid peroxidation in the mechanisms of acute methanol poisoning. AB - CONTEXT: The role of activation of lipid peroxidation in the mechanisms of acute methanol poisoning has not been studied. OBJECTIVE: We measured the concentrations of lipid peroxidation markers in acutely intoxicated patients with known serum concentrations of methanol and leukotrienes. METHODS: Blood serum samples were collected from 28 patients hospitalized with acute intoxication and from 36 survivors 2 years after discharge. In these samples, concentrations of 4 hydroxy-trans-2-hexenal (HHE), 4-hydroxynonenal (HNE), and malondialdehyde (MDA) were measured using the method of liquid chromatography-electrospray ionization tandem mass spectrometry. RESULTS: The maximum acute serum concentrations of all three lipid oxidative damage markers were higher than the follow-up serum concentrations: HNE 71.7 +/- 8.0 ng/mL versus 35.4 +/- 2.3 ng/mL; p < .001; HHE 40.1 +/- 6.7 ng/mL versus 17.7 +/- 4.1 ng/mL; p < .001; MDA 80.0 +/- 7.2 ng/mL versus 40.9 +/- 1.9 ng/mL; p < .001. The survivors without methanol poisoning sequelae demonstrated higher acute serum concentrations of the markers than the patients with sequelae. A correlation between measured markers and serum leukotrienes was present: HNE correlated with LTC4 (r = 0.663), LTD4 (r = 0.608), LTE4 (r = 0.771), LTB4 (r = 0.717), HHE correlated with LTC4 (r = 0.713), LTD4 (r = 0.676), LTE4 (r = 0.819), LTB4 (r = 0.746), MDA correlated with LTC4 (r = 0.785), LTD4 (r = 0.735), LTE4 (r = 0.814), LTB4 (r = 0.674); all p < .001. Lipid peroxidation markers correlated with anion gap (r= -0.428, -0.388, -0.334; p = .026, .045, .080 for HNE, HHE, MDA, respectively). The follow-up serum concentrations of lipid oxidation markers measured in survivors with and without visual/neurological sequelae 2 years after discharge did not differ. CONCLUSION: Our results demonstrate that lipid peroxidation plays a significant role in the mechanisms of acute methanol poisoning. The acute concentrations of three measured biomarkers were elevated in comparison with the follow-up concentrations. Neuronal membrane lipid peroxidation seems to activate leukotriene-mediated inflammation as a part of the neuroprotective mechanisms. No cases of persistent elevation were registered among the survivors 2 years after discharge. PMID- 29607702 TI - Adverse outcomes after single acute methotrexate exposures in pediatric patients are rare. PMID- 29607703 TI - Resource allocation and rationing in nursing care: A discussion paper. AB - Driven by interests in workforce planning and patient safety, a growing body of literature has begun to identify the reality and the prevalence of missed nursing care, also specified as care left undone, rationed care or unfinished care. Empirical studies and conceptual considerations have focused on structural issues such as staffing, as well as on outcome issues - missed care/unfinished care. Philosophical and ethical aspects of unfinished care are largely unexplored. Thus, while internationally studies highlight instances of covert rationing/missed care/care left undone - suggesting that nurses, in certain contexts, are actively engaged in rationing care - in terms of the nursing and nursing ethics literature, there appears to be a dearth of explicit decision making frameworks within which to consider rationing of nursing care. In reality, the assumption of policy makers and health service managers is that nurses will continue to provide full care - despite reducing staffing levels and increased patient turnover, dependency and complexity of care. Often, it would appear that rationing/missed care/nursing care left undone is a direct response to overwhelming demands on the nursing resource in specific contexts. A discussion of resource allocation and rationing in nursing therefore seems timely. The aim of this discussion paper is to consider the ethical dimension of issues of resource allocation and rationing as they relate to nursing care and the distribution of the nursing resource. PMID- 29607704 TI - Perceived Barriers to Goals of Care Discussions With Patients With Advanced Cancer and Their Families in the Ambulatory Setting: A Multicenter Survey of Oncologists. AB - BACKGROUND: Earlier goals of care (GOC) discussions in patients with advanced cancer are associated with less aggressive end-of-life care including decreased use of medical technologies. Unfortunately, conversations often occur late in the disease trajectory when patients are acutely unwell. Here, we evaluate practitioner perspectives of patient, family, physician, and external barriers to early GOC discussions in the ambulatory oncology setting. METHODS: A previously published survey to assess barriers to GOC discussions among clinicians on inpatient medical wards was modified for the ambulatory oncology setting and distributed to oncologists from 12 centers in Ontario, Canada. Physicians were asked to rank the importance of various barriers to having GOC discussions (1 = extremely unimportant to 7 = extremely important). RESULTS: Questionnaires were completed by 30 (24%) of 127 physicians. Respondents perceived patient- and family-related factors as the most important barriers to GOC discussions. Of these, patient difficulty accepting prognosis or desire for aggressive treatment were perceived as most important. Patients' inflated expectation of treatment benefit was also considered an important barrier to discontinuing active cancer directed therapy. While physician barriers were ranked lower than patient-related factors, clinicians' self-identified difficulty estimating prognosis and uncertainty regarding treatment benefits were also considered important. Patient's refusal for referral was the most highly rated barrier to early palliative care referral. Most respondents were nonetheless very or extremely willing to initiate (90%) or lead (87%) GOC discussions. CONCLUSION: Oncologists ranked patient- and family-related factors as the most important barriers to GOC discussions, while clinicians' self-identified difficulty estimating prognosis and uncertainty regarding treatment benefits were also considered important. Further work is required to assess patient preferences and perceptions and develop targeted interventions. PMID- 29607705 TI - Impact of Mobility Device Use on Quality of Life in Children With Friedreich Ataxia. AB - OBJECTIVE: To determine how mobility device use impacts quality of life in children with Friedreich ataxia. STUDY DESIGN: Data from 111 pediatric patients with genetically confirmed Friedreich ataxia were collected from a prospective natural history study utilizing standardized clinical evaluations, including health-related quality of life using the Pediatric Quality of Life Inventory (PedsQL) 4.0 Generic Core Module. RESULTS: Mobility device use was associated with worse mean PedsQL total, physical, emotional, social, and academic subscores, after adjusting for gender, age of disease onset, and Friedreich Ataxia Rating Scale score. The magnitude of the difference was greatest for the physical subscore (-19.5 points, 95% CI = -30.00, -8.99, P < .001) and least for the emotional subscore (-10.61 points, 95% CI = -20.21, -1.02, P = .03). Transition to or between mobility devices trended toward worse physical subscore (-16.20 points, 95% CI = -32.07, -0.33, P = .05). CONCLUSIONS: Mobility device use is associated with significant worsening of all domains of quality of life in children with Friedreich ataxia. PMID- 29607706 TI - Slow lorises (Nycticebus spp.) display evidence of handedness in the wild and in captivity. AB - It has been suggested that strepsirrhines (lemurs, lorises, and galagos) retain the more primitive left-hand preference, whilst monkeys and apes more regularly display a right-hand preference at the individual-level. We looked to address questions of laterality in the slow loris (Nycticebus spp.) using spontaneous observations of 7 wild individuals, unimanual tests in 6 captive individuals, and photos of 42 individuals in a bilateral posture assessing handedness at the individual- and group-level. During the unimanual reach task, we found at the individual-level, only 4 slow lorises showed a hand use bias (R: 3, L: 1), Handedness index (HI) ranged from -0.57 to 1.00. In the wild unimanual grasp task, we found at the individual-level two individual showed a right-hand bias, the HI ranged from -0.19 to 0.70. The bilateral venom pose showed a trend toward a right-hand dominant grip in those photographed in captivity, but an ambiguous difference in wild individuals. There are many environmental constraints in captivity that wild animals do not face, thus data collected in wild settings are more representative of their natural state. The presence of right-handedness in these species suggests that there is a need to re-evaluate the evolution of handedness in primates. PMID- 29607707 TI - A prologue to nostalgia: savouring creates nostalgic memories that foster optimism. AB - How are nostalgic memories created? We considered savouring as one process involved in the genesis of nostalgia. Whereas nostalgia refers to an emotional reflection upon past experiences, savouring is a process in which individuals deeply attend to and consciously capture a present experience for subsequent reflection. Thus, having savoured an experience may increase the likelihood that it will later be reflected upon nostalgically. Additionally, to examine how cognitive and emotional processes are linked across time, we tested whether nostalgia for a previously savoured experience predicts optimism for the future. Retrospective reports of having savoured a positive event were associated with greater nostalgia for the event (Study 1). Retrospective reports of savouring a time period (college) were associated with greater nostalgia for that time period when participants were in a setting (alumni reunion event) that prompted thoughts of the time period (Study 2). Savouring an experience predicted nostalgia for the experience 4-9 months later (Study 3). Additionally, nostalgia was associated with greater optimism (Studies 2-3). Thus, savouring provides a foundation for nostalgic memories and an ensuing optimism. PMID- 29607708 TI - The impact of cultural background on outcome following traumatic brain injury. AB - Most traumatic brain injury (TBI) outcome studies have been conducted in developed countries involving individuals from the dominant culture. The present study compared outcomes following TBI in individuals from Culturally and Linguistically Diverse (CALD) backgrounds with those from non-CALD backgrounds. 103 CALD and 103 non-CALD participants with predominantly moderate to severe TBI completed a series of questionnaires an average of 22 months post-injury. Groups were comparable in most demographic and injury-related variables, but CALD participants had lower pre-injury employment rates. Individuals in the CALD group were significantly less independent in light domestic duties, shopping, and financial management and reported significantly lower cognitive independence, mobility, and participation in occupational and social activities than non-CALD participants post-injury. They also reported heightened awareness of post-injury deficits, different beliefs regarding injury consequences and factors aiding recovery, more anxiety and depression symptoms, and less problem-focused coping. Higher functional outcome was associated with having a value system that is Australian, younger age at injury, and higher education. Overall, independent of rehabilitation access, individuals from a CALD background showed poorer functional outcome following TBI than those from a non-CALD background. Addressing this discrepancy should be a priority for rehabilitation programmes. PMID- 29607709 TI - Impact of food quantity and quality on the biochemical risk of renal stone formation. AB - OBJECTIVE: This study evaluated the role of body mass index (BMI) and dietary potential renal acid load (PRAL) with urinary saturation for calcium oxalate (US CaOx), calcium phosphate (US-CaP) and uric acid (US-UA) in renal stone formers. MATERIALS AND METHODS: A retrospective analysis was conducted of laboratory data collected on 442 renal stone-forming patients. Demographic information, BMI and 24 h urinary samples were collected from patients on their regular diets. PRAL was calculated as the Load of Acid to Kidney Evaluation (LAKE) score through a short questionnaire. RESULTS: Urinary risk factors, but also inhibitors of calcium stone formation such as magnesium, tended to increase in relation to BMI (p = .000). Urinary pH (p = .002) and ammonium/sulfate ratio (p = .000) were negatively related to BMI. This resulted in a positive correlation between BMI and US-UA (p = .000), whereas US-CaOx and US-CaP were not influenced by BMI. LAKE score was positively correlated with US-CaOx (p = .022) and US-CaP (p = .000) as a consequence of the inverse relationship between LAKE score and citrate (p = .000). Multiple linear regression analysis identified BMI (p = .009) and male gender (p = .002) as independent predictors of US-UA, and LAKE score (p = .004) and age (p = .001) as independent predictors of US-CaP. CONCLUSIONS: BMI, which depends on excessive intake of energy from food, is not related to an increased biochemical risk of calcium stone formation, which is more dependent on the renal acid load of the diet. In contrast, obesity is associated with an increased risk of uric acid stone formation due to insulin resistance, impaired ammoniagenesis and low urinary pH. PMID- 29607710 TI - Comparison of Ketamine- Versus Nonketamine-Based Sedation on Delirium and Coma in the Intensive Care Unit. AB - BACKGROUND: At this time, there are no studies evaluating the risk of delirium or coma with the use of ketamine in mechanically ventilated adult patients, compared to conventional therapies such as propofol or dexmedetomidine. OBJECTIVE: The objective of this study was to evaluate the number of days alive without delirium or coma in mechanically ventilated patients in the intensive care unit receiving analgosedation infusions with ketamine versus without ketamine. METHODS: This was a retrospective cohort study conducted at an academic medical center in the United States. Consecutive mechanically ventilated adult patients between November 2015 and April 2017 were evaluated. Patients were divided into 2 groups based on the sedative regimen used: ketamine based or nonketamine based. The primary outcome was the number of days alive without delirium or coma. The secondary outcomes were incidence of delirium, incidence of coma, and ventilator free days at day 28. RESULTS: The study cohort consisted of 79 patients, of which 39 received ketamine- and 40 received nonketamine-based sedation. The number of days alive without delirium or coma was 6 days (interquartile range [IQR]: 2-9 days) with ketamine and 4 days (IQR: 3-7 days) with nonketamine ( P = .351). Delirium occurred in 29 (74%) of 39 patients with ketamine and 34 (85%) of 40 patients with nonketamine ( P = .274). Coma occurred in 16 (41%) of 39 patients with ketamine and 6 (15%) of 40 patients with nonketamine ( P = .013). The median ventilator-free days were 13 days (IQR: 0-23 days) with ketamine and 21 days (0 25 days) with nonketamine ( P = .229). CONCLUSIONS: Sustained ketamine-based sedation in mechanically ventilated patients may be associated with a higher rate of observed coma but similar delirium- and coma-free days compared nonketamine based regimens. PMID- 29607711 TI - Pediatric Multiple Sclerosis in the United Arab Emirates: Characteristics From a Multicenter Study and Global Comparison. AB - We delineate the clinical characteristics, incidence, and prevalence of pediatric onset multiple sclerosis in Abu Dhabi, United Arab Emirates, from 2010 to 2014. Eighty-two patients (65% female) were identified. Fifty-three (64.6%) were Emiratis (45 from Abu Dhabi and 8 from 5 other emirates) and 29 were expatriates. Mean age of onset was 15.9 years overall, 15.3 years in males and 16.3 years in females. Patients with onset before age 12 years presented with visual symptoms while those with onset after age 12 years presented with a mixture of visual, motor and sensory symptoms. Interferon beta-1a was the most frequently used disease-modifying therapy (48%). In Abu Dhabi Emirati nationals, the age- and sex adjusted prevalences were 26/100 000 for males and 36/100 000 for females. The total incidence in Emirati nationals from 2010 to 2014 was 2.3/100 000 for ages 10 to 14 years and 7.2/100 000 for ages 15 to 19 years. By comparison with international cohorts, the incidence of pediatric-onset multiple sclerosis in Abu Dhabi is higher whereas gender distribution is similar. PMID- 29607712 TI - Expression of aquaporins mRNAs in patients with otitis media. AB - OBJECTIVE: This study analyzed the associations between measured levels of aquaporin (AQP) mRNAs and clinical manifestations in patients with various types of otitis media (OM). METHODS: AQP1, 2, 3, 4, 5, 6, 8, and 10 mRNA levels were assayed by real-time PCR from 57 patients with chronic otitis media (COM), 24 patients with cholesteatomatous otitis media (choleOM), and 82 patients with otitis media with effusion (OME). The relationships of these mRNA levels with the presence of bacteria, the type of hearing loss, and clinical manifestations of OM types were evaluated. RESULTS: All eight AQP mRNAs were expressed in inflammatory tissue, chole matrix, and effusion fluid obtained from all 163 patients with OM. The levels in OME of AQP2, 4, 6, and 10 mRNA; and the levels in choleOM of AQP1, 3, 4, and 10 mRNA were elevated significantly compared to the corresponding levels in COM (p < .05). The expression level of AQP8 mRNA did not differ among OM types. Among samples positive for bacterial culture, AQP1 mRNA was significantly higher in OME than in COM and choleOM, AQP5 mRNA was significantly lower in OME than in COM and choleOM, and AQP10 mRNA was significantly higher in OME and choleOM than in COM (p < .05). CONCLUSIONS: The levels of expression of AQP mRNA are associated with the pathophysiology of OM. PMID- 29607713 TI - Association of 24 h maternal deprivation with a saline injection in the neonatal period alters adult stress response and brain monoamines in a sex-dependent fashion. AB - Maternal deprivation (MD) disinhibits the adrenal glands, rendering them responsive to various stressors, including saline injection, and this increased corticosterone (CORT) response can last for as long as 2 h. In the present study, we tested the hypothesis that association of MD on day 11 with a saline injection would alter emotional behavior, CORT response, and brain monoamine levels, in male and female adult rats. Rats were submitted to the novelty suppressed feeding (NSF), the sucrose negative contrast test (SNCT), social investigation test (SIT), and the elevated plus maze (EPM). One quarter of each group was not tested (providing basal values of CORT and brain monoamines) and the remainder was decapitated 15, 45, or 75 min after the EPM, to assess CORT reactivity. Monoamine levels were determined in the hypothalamus (HPT), frontal cortex (FC), amygdala (AMY), ventral, and dorsal hippocampus (vHPC, dHPC, respectively). MD reduced food intake, in the home-cage, and latency to eat in the NSF in both sexes; females explored less the target animal in the SIT and explored more the open arms of the EPM than males; the CORT response to the EPM was greater in maternally-deprived males and females than in their control counterparts, and this response was further elevated in maternally-deprived females injected with saline. Regarding monoamine levels, females were less affected, showing isolated effects of the stressors, while in males, MD increased 5-HT levels in the HPT and decreased this monoamine in the FC, MD associated with saline reduced dopamine levels in all brain regions, except the HPT. MD at 11 days did not alter emotional behaviors in adult rats, but had an impact in neurobiological parameters associated with this class of behaviors. The impact of MD associated with saline on dopamine levels suggests that males may be vulnerable to motivation-related disorders. PMID- 29607714 TI - Availability of Dutch General Practitioners for After-Hours Palliative Care. AB - BACKGROUND: Continuity of care is important for palliative patients in their end of life. In the Netherlands, after-hours primary care for palliative patients is either provided by large-scale general practitioner (GP) cooperatives or GPs choose to give palliative care by themselves while they are not on duty. AIM: To examine the availability of, perceived problems by, and attitude of Dutch GPs regarding providing palliative care for their own patients outside office hours. DESIGN AND SETTING: Cross-sectional observational study among 1772 GPs from 10 Dutch regions. METHOD: Online questionnaire among GPs affiliated with 10 GP cooperatives. RESULTS: Five hundred twenty-four (29.6%) eligible questionnaires were returned. Of the GPs, 60.8% were personally available outside office hours for their own palliative patients on their own private cell phone and performed home visits if needed. In 33.0%, GPs were willing to make home visits in private time instigated by the GP cooperative and 26.8% were only accessible for telephone consultation by the GP cooperative. In 12.2%, the GP delegated after hours palliative care completely to the GP cooperative. The GPs predominantly reported "time pressure" problems (17.3%) as a barrier and 61.7% stated that after-hours palliative care is the responsibility of the own GP. CONCLUSION: The large majority of Dutch GPs is personally available for telephone consultation and/or willing to provide palliative care for their own patients outside office hours. For the future, it is important to maintain the willingness of GPs to remain personally available for their palliative patients. PMID- 29607715 TI - Hedgehog signaling contributes to bone cancer pain by regulating sensory neuron excitability in rats. AB - Treating bone cancer pain continues to be a clinical challenge and underlying mechanisms of bone cancer pain remain elusive. Here, we reported that sonic hedgehog signaling plays a critical role in the development of bone cancer pain. Tibia bone cavity tumor cell implantation produces bone cancer-related mechanical allodynia, thermal hyperalgesia, and spontaneous and movement-evoked pain behaviors. Production and persistence of these pain behaviors are well correlated with tumor cell implantation-induced up-regulation and activation of sonic hedgehog signaling in primary sensory neurons and spinal cord. Spinal administration of sonic hedgehog signaling inhibitor cyclopamine prevents and reverses the induction and persistence of bone cancer pain without affecting normal pain sensitivity. Inhibiting sonic hedgehog signaling activation with cyclopamine, in vivo or in vitro, greatly suppresses tumor cell implantation induced increase of intracellular Ca2+ and hyperexcitability of the sensory neurons and also the activation of GluN2B receptor and the subsequent Ca2+ dependent signals CaMKII and CREB in dorsal root ganglion and the spinal cord. These findings show a critical mechanism underlying the pathogenesis of bone cancer pain and suggest that targeting sonic hedgehog signaling may be an effective approach for treating bone cancer pain. PMID- 29607716 TI - Chasing ghosts in Cuba: Is mass psychogenic illness masquerading as an acoustical attack? PMID- 29607717 TI - Psychometric evaluation of the Swedish version of Rosenberg's self-esteem scale. AB - BACKGROUND: The widely used Rosenberg's self-esteem scale (RSES) has not been evaluated for psychometric properties in Sweden. AIMS: This study aimed at analyzing its factor structure, internal consistency, criterion, convergent and discriminant validity, sensitivity to change, and whether a four-graded Likert type response scale increased its reliability and validity compared to a yes/no response scale. METHODS: People with mental illness participating in intervention studies to (1) promote everyday life balance (N = 223) or (2) remedy self-stigma (N = 103) were included. Both samples completed the RSES and questionnaires addressing quality of life and sociodemographic data. Sample 1 also completed instruments chosen to assess convergent and discriminant validity: self-mastery (convergent validity), level of functioning and occupational engagement (discriminant validity). Confirmatory factor analysis (CFA), structural equation modeling, and conventional inferential statistics were used. RESULTS: Based on both samples, the Swedish RSES formed one factor and exhibited high internal consistency (>0.90). The two response scales were equivalent. Criterion validity in relation to quality of life was demonstrated. RSES could distinguish between women and men (women scoring lower) and between diagnostic groups (people with depression scoring lower). Correlations >0.5 with variables chosen to reflect convergent validity and around 0.2 with variables used to address discriminant validity further highlighted the construct validity of RSES. The instrument also showed sensitivity to change. CONCLUSIONS: The Swedish RSES exhibited a one component factor structure and showed good psychometric properties in terms of good internal consistency, criterion, convergent and discriminant validity, and sensitivity to change. The yes/no and the four-graded Likert-type response scales worked equivalently. PMID- 29607718 TI - Insertion of a Lester Jones canalicular bypass tube: a simple, quick and convenient approach. PMID- 29607719 TI - Predictors of success in the Intercollegiate Membership of the Royal College of Surgeons (MRCS) examination. AB - Introduction The Intercollegiate Membership of the Royal College of Surgeons (MRCS, Parts A and B) is designed to safeguard patients and ensure high standards for trainees wishing to pursue a surgical career. We investigated which factors predict Part A and B success. Methods UK graduates who had attempted both parts of MRCS from September 2007 to February 2016 were included. Pearson correlation coefficients were used to examine the linear relationship between each part of MRCS and logistic regression analysis to identify potential independent predictors of MRCS pass/fail outcome. Results A positive correlation between Part A and B score was identified (r = 0.41, P < 0.01). In Part A, males had higher pass rates than females (odds ratio, OR, 2.78, 95% confidence interval, CI, 1.83 4.19), white candidates were more likely to pass than black minority and ethnic doctors (OR 1.70, 95% CI 1.52-1.89), foundation year 1 doctors had higher pass rates than all other grades (e.g. core surgical year 2 trainees vs. foundation year 1 doctors, OR 0.50, 95% CI 0.32-0.77) and younger graduates were more likely to pass than older graduates (OR 2.60, 95% CI 1.81-3.63). In addition to ethnicity and stage of training, Part A performance (number of attempts and score) was an independent predictor for Part B. Conclusions Part A performance is related to Part B score. Many independent predictors of MRCS success were identified, but only stage of training and ethnicity were found to be common predictors of both parts. This article summarises the findings of our most recent MRCS study which was published in The Surgeon (online) in October 2017. 1. PMID- 29607720 TI - A practical 'safe zone' technique for lag screw fixation of the fibula. AB - Introduction During ankle fracture fixation, iatrogenic trauma to retro fibula structures can result in morbidity and reoperation. We describe a safe zone for lag screw insertion. Materials and methods This study was completed in three sections. We identified the average entry and exit points for the lag screw using 45 Weber B ankle fractures identified from our trauma database. We then analysed 26 sequentially presented ankle magnetic resonance images, concentrating on axial sections at 4, 8, 12 and 16 mm above the ankle joint. Finally, we used 63 sequentially performed magnetic resonance scans to confirm the safe zone from these consistent structures. Results The typical lag screw exit point was 14.2 mm above the ankle joint (95% confidence Interval 11.3-17.1 mm). A safe zone trajectory occurred between 31 and 45 degrees taken from the anterior aspect of the flat fibular surface at this level. The obvious palpable landmark to direct screw trajectory and avoid 'at risk' structures was found to be the medial edge of the Achilles tendon. Our final dataset confirmed in 63 scans, the medial aspect of the Achilles tendon to be a consistent safe zone with a minimum distance of at risk structures of 4 mm. Conclusion This simple method of directing the fibula lag screw towards the palpable medial edge of the Achilles tendon is practical, easy to teach and directs the screw on a safe trajectory away from the most commonly injured structures around the back of the fibula. PMID- 29607721 TI - Removing a metal foreign object successfully from a patient's retroperitoneal space using laparoscopy and a novel navigation system. AB - Trauma with foreign objects retained within the human body has become a common surgical emergency condition. Traditional surgical methods often involve creating large incisions in soft tissue and may lead to additional complications during wound healing. We have developed a new method of removing foreign bodies from patients' abdomens by using laparoscopy with the help of a novel navigation system that provides accurate positioning. This approach is minimally invasive and simple. This is the first combination of both technologies in this field. PMID- 29607722 TI - Ethmoidal metastasis as a first presentation of breast cancer: a case report. AB - Distant metastasis in advanced breast cancer is not uncommon; however, spread to the paranasal sinuses is extremely rare. We present a case of a woman who presented to our ophthalmology colleagues with worsening unilateral proptosis secondary to a tumour mass within her ethmoid sinuses. Biopsy of the ethmoid tumour showed adenocarcinoma of unknown origin. Whole-body positron emission computed tomography demonstrated a breast primary lesion. The patient was treated with palliative chemotherapy, and the patient remains well at this point. The importance of specialist head and neck radiological interpretation of imaging cannot be underestimated. Early tissue diagnosis is essential before ascribing patients with orbital symptoms to non-malignant process. PMID- 29607723 TI - Complete nasal obstruction secondary to pacemaker insertion. AB - We present the case of a 71-year-old man who presented to the ear, nose and throat department with complete nasal obstruction and facial plethora on bending forward. Clinical examination was positive for Pemberton's sign. Computed tomography and ultrasonography demonstrated bilateral brachiocephalic vein thrombosis secondary to pacemaker insertion. This case highlights a novel complication of pacemaker insertion. PMID- 29607724 TI - Synovial sarcoma of the tongue: report of a case and review of the literature. AB - This report outlines the work-up and management of a 35-year-old man with a synovial sarcoma of the lateral border of the tongue. Synovial sarcoma of the tongue is an extremely rare tumour with variable morphological microscopic types and characters of immunohistochemical profile. There have only been 15 cases previously reported. This report aims to update the literature on this subject and explore the best treatment options. PMID- 29607725 TI - A strangled hernia through the Winslow's hiatus: about a rare situation. AB - Winslow's hiatus hernia is the rarest of the internal hernias. Its diagnosis is difficult and requires an urgent laparotomy to avoid necrosis of the incarcerated loop or even the death of the patient. We report the case of a patient operated urgently for acute intestinal obstruction caused by a strangled hernia through the Winslow's hiatus. A reduction by traction of the hernia was undertaken. Rapid management of this pathology is important using clinical and radiographical elements. PMID- 29607726 TI - A rare case of Schneiderian papilloma of the middle ear presenting with pulsatile tinnitus. AB - Schneiderian papillomas (ISP) of the middle ear are uncommon conditions, with only 45 cases published within literature. They are locally aggressive tumours, with a high rate of recurrence and associated malignancy. We present a rare case of a 53-year-old man presenting with unilateral pulsatile tinnitus, otorrhoea, aural fullness, pruritis and hearing loss. Angiography was employed to exclude a glomus tumour and the patient underwent a modified radical mastoidectomy. Tissue samples confirmed a histological diagnosis of ISP of the middle ear. Follow-up magnetic resonanc imaging one year postoperatively showed no evidence of disease recurrence. PMID- 29607727 TI - Lateral orbital propeller flap technique for reconstruction of the lower eyelid defect. AB - The lower eyelid, which has a unique anatomy and esthetic importance, is a common site of basal cell carcinoma. The reconstruction of the defect after the wide excision of the tumour is a special concern of many plastic surgeons. How to achieve the most satisfying effect through minimal invasive is important for patients. We successfully applied the lateral orbital propeller flap for one stage reconstruction of a large lower eyelid defect after tumour resection. We consider that this flap can achieve better tissue mobilisation as it provides effective coverage of soft tissue defects and thus is especially useful for repairing facial defects. PMID- 29607728 TI - Pseudogout - a rare manifestation of hungry bone syndrome after focused parathyroidectomy. AB - Pseudogout, also known as calcium pyrophosphate deposition disease, is a rheumatological condition arising from accumulation of calcium pyrophosphate dihydrate crystals in connective tissues. We present a case of a 56-year-old Bangladeshi woman who underwent focused right inferior parathyroidectomy for primary hyperparathyroidism from a right inferior parathyroid adenoma. On the first post-operative day, she complained of left elbow painful swelling with redness and warmth. Arthrocentesis of left elbow was done due to suspicion of septic arthritis. Two weeks prior to this surgery, she had sudden bilateral knee swelling was diagnosed in her home country of bilateral knee osteoarthritis with effusion and arthrocentesis showed no crystals. Aspiration of left elbow showed calcium pyrophosphate crystals, associated with post parathyroidectomy hypocalcemia, hypomagnesemia confirming pseudogout. Her uric acid level was normal. Bilateral wrist x-rays showed triangular fibrocartilage complex chondrocalcinosis. The patient's condition improved with colchicine and naproxen, as well as calcium and magnesium replacement. Her left elbow swelling and pain resolved. Pseudogout flare is a rare but known sequelae after parathyroidectomy. Early recognition and expeditious treatment is essential. PMID- 29607729 TI - In vitro and in vivo assessment of biomedical Mg-Ca alloys for bone implant applications. AB - BACKGROUND: Magnesium (Mg)-based alloys are considered to be promising materials for implant application due to their excellent biocompatibility, biodegradability, and mechanical properties close to bone. However, low corrosion resistance and fast degradation are limiting their application. Mg-Ca alloys have huge potential owing to a similar density to bone, good corrosion resistance, and as Mg is essential for Ca incorporation into bone. The objective of the present work is to determine the in vitro degradation and in vivo performance of binary Mg- xCa alloy ( x = 0.5 or 5.0 wt%) to assess its usability for degradable implant applications. METHODS: Microstructural evolutions for Mg- xCa alloys were characterized by optical, SEM, EDX, and XRD. In vitro degradation tests were conducted via immersion test in phosphate buffer saline solution. In vivo performance in terms of interface, biocompatibility, and biodegradability of Mg- xCa alloys was examined by implanting samples into rabbit femoral condyle for 2 and 4 weeks. RESULTS: Microstructural results showed the enhancement in intermetallic Mg2Ca phase with increase in Ca content. Immersion tests revealed that the dissolution rate varies linearly, with Ca content exhibiting more hydrogen gas evolution, increased pH, and higher degradation for Mg-5.0Ca alloy. In vivo studies showed good biocompatibility with enhanced bone formation for Mg 0.5Ca after 4 weeks of implantation compared with Mg-5.0Ca alloy. Higher initial corrosion rate with prolonged inflammation and rapid degradation was noticed in Mg-5.0Ca compared with Mg-0.5Ca alloy. CONCLUSIONS: The results suggest that Mg 0.5Ca alloy could be used as a temporary biodegradable implant material for clinical applications owing to its controlled in vivo degradation, reduced inflammation, and high bone-formation capability. PMID- 29607730 TI - A Validation Study of the Rank-Preserving Structural Failure Time Model: Confidence Intervals and Unique, Multiple, and Erroneous Solutions. AB - BACKGROUND: The rank-preserving structural failure time model (RPSFTM) is used for health technology assessment submissions to adjust for switching patients from reference to investigational treatment in cancer trials. It uses counterfactual survival (survival when only reference treatment would have been used) and assumes that, at randomization, the counterfactual survival distribution for the investigational and reference arms is identical. Previous validation reports have assumed that patients in the investigational treatment arm stay on therapy throughout the study period. OBJECTIVES: To evaluate the validity of the RPSFTM at various levels of crossover in situations in which patients are taken off the investigational drug in the investigational arm. METHODS: The RPSFTM was applied to simulated datasets differing in percentage of patients switching, time of switching, underlying acceleration factor, and number of patients, using exponential distributions for the time on investigational and reference treatment. RESULTS: There were multiple scenarios in which two solutions were found: one corresponding to identical counterfactual distributions, and the other to two different crossing counterfactual distributions. The same was found for the hazard ratio (HR). Unique solutions were observed only when switching patients were on investigational treatment for <40% of the time that patients in the investigational arm were on treatment. LIMITATIONS: Distributions other than exponential could have been used for time on treatment. CONCLUSIONS: An HR equal to 1 is a necessary but not always sufficient condition to indicate acceleration factors associated with equal counterfactual survival. Further assessment to distinguish crossing counterfactual curves from equal counterfactual curves is especially needed when the time that switchers stay on investigational treatment is relatively long compared to the time direct starters stay on investigational treatment. PMID- 29607731 TI - Pre-verbal infants perceive emotional facial expressions categorically. AB - Adults perceive emotional expressions categorically, with discrimination being faster and more accurate between expressions from different emotion categories (i.e. blends with two different predominant emotions) than between two stimuli from the same category (i.e. blends with the same predominant emotion). The current study sought to test whether facial expressions of happiness and fear are perceived categorically by pre-verbal infants, using a new stimulus set that was shown to yield categorical perception in adult observers (Experiments 1 and 2). These stimuli were then used with 7-month-old infants (N = 34) using a habituation and visual preference paradigm (Experiment 3). Infants were first habituated to an expression of one emotion, then presented with the same expression paired with a novel expression either from the same emotion category or from a different emotion category. After habituation to fear, infants displayed a novelty preference for pairs of between-category expressions, but not within-category ones, showing categorical perception. However, infants showed no novelty preference when they were habituated to happiness. Our findings provide evidence for categorical perception of emotional expressions in pre-verbal infants, while the asymmetrical effect challenges the notion of a bias towards negative information in this age group. PMID- 29607732 TI - alpha-Pyrone derivatives with cyto-protective activity from two Takla Makan desert soil derived actinomycete Nocardiopsis strains recovered in seawater based medium. AB - In this paper, we described the discovery of two Nocardiopsis strains HDN154-146 and HDN154-168 from Takla Makan desert soil samples using seawater based medium. Chemical investigation of these two strains led to the discovery of eight new alpha-pyrone derivatives named nocahypyrones A-H (1-8), together with one known analogue germicidin G (9). The structures of these compounds, including absolute configurations, were elucidated by extensive NMR, MS, and CD analyses. Compounds 1-9 were tested for their cyto-protective activities and for the first time we found alpha-pyrones 5 and 8 exhibited capabilities to induce expression of phase II detoxifying enzymes. PMID- 29607733 TI - Face, content, and construct validity of a simulator for training in endovascular procedures. AB - AIM: In recent years the interest in structured training programs in endovascular surgical procedures has increased. In this study we assess face, content, and construct validity of a simulator to teach basic skills of endovascular surgery. MATERIAL AND METHODS: A cohort of 21 medical students, 26 residents, and 14 expert surgeons participated in the study. Experts assessed face and content validity. Then, they executed four tasks once, while medical students and residents were allowed two attempts to reach a five-minute threshold under expert supervision. Medical students and residents repeated the same exercises during a second session plus three new additional ones, without expert supervision. RESULTS: The simulator was rated as good by experts (four out of five on a Likert scale) in terms of realism (face validity) and usefulness as training tool for the training of basic skills (content). For construct validity, experts outperformed with a statistically significant difference (p < .05) medical students and residents in all tasks, except cannulation of upper mesenteric (p = .053). Differences between novices and intermediates persisted in the second session in the same four tasks and in the three additional ones, with statistically significant difference (p < .05) in the last four exercises. CONCLUSIONS: This study showed face, content, and construct validity of BEST simulator. PMID- 29607734 TI - Hormesis and radiation safety norms: Comments for an update. AB - Hormesis can be explained by evolutionary adaptation to the current level of a factor present in the natural environment or to some average from the past. This pertains also to ionizing radiation as the natural background has been decreasing during the time of the life existence. DNA damage and repair are normally in a dynamic balance. The conservative nature of the DNA repair suggests that cells may have retained some capability to repair damage from higher radiation levels than that existing today. According to this concept, the harm caused by radioactive contamination would tend to zero with a dose rate tending to a wide range level of the natural radiation background. Existing evidence in favor of hormesis is substantial, experimental data being partly at variance with results of epidemiological studies. Potential bias, systematic errors, and motives to exaggerate risks from low-dose low-rate ionizing radiation are discussed here. In conclusion, current radiation safety norms are exceedingly restrictive and should be revised on the basis of scientific evidence. Elevation of the limits must be accompanied by measures guaranteeing their observance. PMID- 29607735 TI - Brain and disease: an insight into new developments in the pathogenesis and novel therapies for neurological disorders. PMID- 29607736 TI - Muscle activation and local muscular fatigue during a 12-minute rotational bridge. AB - Due to anecdotal reports of back pain during a 12-minute rotational bridge test by uniformed services, the level of fatigue leading to possible back pain and or injury was investigated. We hypothesised a high level of fatigue due to diminishing core muscle activation. Nineteen highly trained uniformed service members were measured by surface electromyography of the rectus abdominis, external oblique, internal oblique, lumbar erector spinae, thoracic erector spinae and latissimus dorsi. Average rectified electromyography amplitude (AEMG) and median power frequency were analysed to determine activation and fatigue. All AEMG were normalised and expressed as a percentage of maximal voluntary isometric contraction (%MVIC). Significant increases in AEMG were observed over the test duration for the rectus abdominis (+19.5%MVIC), external oblique (+18.0%MVIC) and internal oblique (+23.2%MVIC) during the prone position; and for the external oblique (+21.8%MVIC) when bracing on the measurement side (all, p < 0.05). No significant changes in median power frequency were observed (all, p > 0.05). Combining prone and side bridge positions is a reasonable measure of anterior, posterior and lateral trunk musculature. Muscular fatigue remained low throughout making this a safe assessment in trained individuals. PMID- 29607737 TI - Dual antiplatelet therapy after percutaneous left atrial appendage occlusion: single center experience with the Amplatzer Cardiac Plug. AB - BACKGROUND: Percutaneous left atrial appendage occlusion (LAAO) is an alternative to anticoagulation in atrial fibrillation patients at high bleeding risk. Dual antiplatelet therapy (DAPT) is generally recommended in the months following the procedure to prevent thrombotic complications. The aim of this study was to evaluate the safety and efficacy of DAPT after LAAO in a single-centre population of high bleeding risk patients. METHODS: All patients who received DAPT after LAAO using the Amplatzer Cardiac Plug at Jessa Hospital (Hasselt, BE) between February 2011 and October 2016 were included. Patient characteristics, procedural outcome and clinical events (bleeding, stroke and adverse events) were prospectively followed. Changes in antithrombotic and/or anticoagulant regimens were assessed. RESULTS: Thirty-nine patients (77 +/- 7 years, 51% male, CHA2DS2 VASc 5(3-6), Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly (HAS BLED) 3(3-4)) were included. An initial strategy of one month DAPT (n = 2) was changed to six months DAPT (n = 37) after one thrombotic complication (device thrombosis) at 4.5 months. Post-procedural DAPT duration was 6.1 +/- 3.7 months, after which aspirin monotherapy (62%), no antiplatelet/anticoagulant therapy (15%) or a tailored antithrombotic regimen was maintained. At mean follow-up of 21 +/- 13 months, seven patients had died (18%), no strokes had occurred (0%) and nine bleedings of which four were major (10%). All major bleedings occurred within the first six months after the procedure during DAPT. CONCLUSION: Antithrombotic therapy after percutaneous LAAO is needed to prevent thrombotic complications, yet these impose bleeding complications in this high-risk population. Further efforts are needed to define the optimal duration of DAPT, aimed at reducing bleeding complications while maintaining a low thrombosis rate. PMID- 29607738 TI - In silico development of new acetylcholinesterase inhibitors. AB - In this work, we made use of fragment-based drug design (FBDD) and de novo design to obtain more powerful acetylcholinesterase (AChE) inhibitors. AChE is associated with Alzheimer's disease (AD). It was found that the cholinergic pathways in the cerebral cortex are compromised in AD and the accompanying cholinergic deficiency contributes to the cognitive deterioration of AD patients. In the FBDD approach, fragments are docked into the active site of the protein. As fragments are molecular groups with a low number of atoms, it is possible to study their interaction with localized amino acids. Once the interactions are measured, the fragments are organized by affinity and then linked together to form new molecules with a high degree of interaction with the active site. In the other approach, we used the de novo design technique starting from reference drugs used in the AD treatment. These drugs were broken into fragments (seeds). In the growing strategy, fragments were added to each seed, growing new molecules. In the linking strategy, two or more separated seeds were linked with different fragments. Both strategies combined produced a library of more than 2 million compounds. This library was filtered using absorption, distribution, metabolism, and excretion properties. The resulting library with around six thousand compounds was filtered again. In this case, structures with Tanimoto coefficients >.85 were discarded. The final library with 1500 compounds was submitted to docking studies. As a result, 10 compounds with better interaction energy than the reference drugs were obtained. PMID- 29607739 TI - Parenting after stroke: a systematic review. AB - Background Stroke is a leading cause of disability in the United States, resulting in physical, cognitive, and emotional impairments. One in ten strokes occur in adults younger than 50 years of age and the incidence has increased approximately 44% from 2000 to 2010. Young adult survivors have specific needs related to their developmental stage including childcare responsibilities. Despite the high value placed on parenting by society, parenting is currently not assessed at any stage of stroke rehabilitation. Objective To determine the state of the science on parenting after stroke Methods A literature search of multiple electronic databases was conducted from 1964 to February 2018. Select key words were adapted for use in each database. Preferred Reporting Items for Systematic Reviews and Meta Analyses guidelines were followed. Results One thousand two hundred and forty-one articles were identified from electronic databases. After deduplication, abstract/title review, and full-text review, ten studies were included. Nine of the studies were qualitative and one was a retrospective cohort study. Survivors in all but one of the qualitative studies reported limitations in parenting tasks after stroke. Changes in social relationships and participation as a parent in other life domains as a result of stroke were also described by survivors. Conclusion Findings from this systematic review of the perspectives of stroke survivors actively parenting suggest that residual stroke impairments lead to both activity limitations and participation restrictions. However, the literature available on parenting after stroke is limited and there is a significant opportunity to advance this area of stroke research. PMID- 29607740 TI - Effects of nano-encapsulated curcumin-chrysin on telomerase, MMPs and TIMPs gene expression in mouse B16F10 melanoma tumour model. AB - Due to the high rate of drug resistance among malignant melanoma cases, it seems necessary to introduce an efficient pharmaceutical approach to melanoma treatment. For this purpose, Curcumin (Cur) and Chrysin (Chr), two natural anti cancers, were co-encapsulated in PLGA-PEG nanoparticles (NPs), characterized by DLS, FTIR and FE-SEM and investigated for their effects on MMPs, TIMPs and TERT genes expression in C57B16 mice bearing B16F10 melanoma tumours. The results showed that the expression of MMP-9, MMP-2 and TERT genes were significantly decreased in all treated groups compared to the control. This reduction had the highest amount in CurChr NPs group and then CurChr group for each three genes. Likewise, the expression of TIMP-1 and TIMP-2 genes was significantly increased in all treated groups, compared to the control. Combination groups showed the highest rise in expression of these two genes and the observed increase was greater in nano groups. Moreover, the highest melanoma tumour growth inhibition was detected for CurChr NPs, followed by CurChr = Cur NPs > Cur > Chr NP > Chr. Overall, it is speculated that the nano-combination of Cur and Chr into polymeric NPs with a one-step fabricated co-delivery system may be a promising and convenient approach to improve their efficiency in melanoma cancer therapy. PMID- 29607741 TI - Intragastric quinine administration decreases hedonic eating in healthy women through peptide-mediated gut-brain signaling mechanisms. AB - OBJECTIVES: Intragastric bitter tastants may decrease appetite and food intake. We aimed to investigate the gut-brain signaling and brain mechanisms underlying these effects. METHODS: Brain responses to intragastric quinine-hydrochloride (QHCl, 10 umol/kg) or placebo infusion were recorded using functional magnetic resonance imaging in 15 healthy women. Appetite-related sensations, plasma levels of gastrointestinal hormones and hedonic food intake (ad libitum drink test) were assessed. RESULTS: Lower octanoylated ghrelin (P<0.04), total ghrelin (P<0.01), and motilin (P<0.01) plasma levels were found after QHCl administration, along with lower prospective food consumption ratings (P<0.02) and hedonic food intake (P<0.05). QHCl increased neural activity in the hypothalamus and hedonic (anterior insula, putamen, caudate, pallidum, amygdala, anterior cingulate cortex, orbitofrontal cortex, midbrain) regions, but decreased activity in the homeostatic medulla (all pFWE-corrected<0.05). Differential brain responses to QHCl versus placebo covaried with subjective and hormonal responses and predicted differences in hedonic food intake. DISCUSSION: Intragastric QHCl decreases prospective and actual food intake in healthy women by interfering with homeostatic and hedonic brain circuits in a ghrelin- and motilin-mediated fashion. These findings suggest a potential of bitter tastants to reduce appetite and food intake, through the gut-brain axis. PMID- 29607742 TI - Evaluation of cardiac autonomic functions in myasthenia gravis. AB - OBJECTIVE: We aimed to comprehensively evaluate cardiac autonomic function in patients with MG and to investigate the relationship between this disorder and disease duration, thymoma and acetylcholine receptor antibody positivity in cases of cardiac autonomic disorder. METHODS: The study included 30 patients with MG and 30 age-matched healthy control subjects. Haemodynamic parameters (heart rate, systolic and diastolic blood pressure) and autonomic parameters (low frequency [LF], high-frequency [HF], sympathovagal balance [LF/HF], baroreceptor reflex sensitivity [BRS]) of the patients were automatically measured at rest and in a tilted position with the Task Force Monitor. RESULTS: The mean systolic and diastolic blood pressure measurements obtained at rest and during the tilt test were higher in patients with MG. Sympathovagal balance has been disturbed in favour of sympathetic tone, and parasympathetic insufficiency has become more prominent. When baroreceptor sensitivity was used as the second parameter to evaluate autonomic heart functions, BRS at rest and during the tilt test was lower in the MG group compared with the control group. DISCUSSION: These results suggest that sympathovagal balance has been disturbed in favour of sympathetic tone and that parasympathetic insufficiency has become more prominent. The current findings support the presence of cardiac autonomic involvement in patients with MG. The determination of cardiac autonomic function via noninvasive methods among patients with MG has high predictive value. The identification of autonomic dysfunction at an early stage and the early treatment of cardiovascular diseases can reduce morbidity and mortality. PMID- 29607743 TI - Consistency of adults' earliest memories across two years. AB - The consistency of earliest memories in content, dating, and memory qualities was investigated. A total of 84 (27 males; Mage = 24.93, SD = 1.36) adults reported earliest memories, estimated ages, and rated their recollections on memory qualities with a two-year time lag. At Time 2, their original reports at Time 1 were presented and they were asked to report whether the earliest memories they recalled at Time 2 were the same. Fifty-six per cent of the participants reported the same earliest memories and those remembering the same events had earlier memories than those remembering different ones. Although no significant differences were observed in estimated ages on the basis of mean ages, a predating bias of later memories and a tendency to postdate earlier memories were observed on the basis of a 48-month cut-off point. Thus, how the data is analysed is critical in detecting dating biases or errors affecting conclusions and interpretations about the dating consistency of earliest memories. Finally, memory qualities of earliest memories displayed a high level of consistency with a two-year time lag regardless of remembering the same versus different event. PMID- 29607745 TI - Outpatient diode laser treatment of intermediate-risk non-invasive bladder tumors without sedation: efficacy, safety and economic analysis. AB - OBJECTIVE: This study aimed to validate a new method for outpatient diode laser ablation of bladder tumors without sedation or pain control. METHODS: Twenty-one patients with stage Ta low-grade intermediate-risk bladder tumors underwent photodynamic-guided laser ablation of their bladder tumors and 1 month later follow-up cystoscopy with photodynamic and IMAGE1 STM-guided biopsies. Pain was measured using a visual analog scale (range 0-10). Symptoms and worries about the future disease course were calculated using the Quality of Life Questionnaire for Non-Muscle-Invasive Bladder Cancer (range 0-100, high scores indicating worse symptoms or worry). Costs of outpatient laser treatment versus inpatient conventional bladder tumor resection in the operating theatre were compared. RESULTS: Patients had a median of three tumors (range 1-12). The median pain score was 1.0 (range 0-7) during laser ablation. Median quality of life scores were 24 (range 0-67) for symptoms and 42 (0-100) for worry. Two patients had minor hematuria and five had dysuria after laser therapy. Five patients (24%) had new Ta low-grade recurrence within 13 months that was biopsied and laser treated. No tumors progressed. Four patients had tumors identified using photodynamic diagnosis, and two had flat low-grade dysplasia identified using IMAGE1 S SPECTRA A and B and photodynamic diagnosis, none of which was seen using white-light cystoscopy. Outpatient laser treatment could save about ?140,000 per million inhabitants versus inpatient bladder tumor surgery. CONCLUSION: Fluorescence guided diode lasers provide efficient and almost pain-free treatment of low-grade urothelial cancer in conscious patients and could reduce healthcare costs. PMID- 29607744 TI - Pretreatment lymphocyte-to-monocyte ratio as an independent prognostic factor for hypopharyngeal squamous cell carcinoma. AB - OBJECTIVE: The aim of this work was to analyze the clinical characteristics and pretreatment peripheral blood cell counts of patients with hypopharyngeal squamous cell carcinoma (HPSCC) and determine their relationship with clinical outcomes. METHODS: One hundred ninety-seven patients were eligible for the study. The relationship between survival and pretreatment peripheral absolute neutrophil count (ANC), absolute lymphocyte count (ALC), absolute monocyte count (AMC), neutrophil-to-lymphocyte ratio (NLR), and lymphocyte-to-monocyte ratio (LMR) were analyzed by one-way analysis of variance, t-test, and univariate and multivariate analysis. RESULTS: The median follow-up time was 30.95 months (range 1-82 months). The 3-year disease-free survival (DFS), cancer-specific survival (CSS), and overall survival (OS) rates for all patients were 40.8, 51.0, and 48.1%, respectively. The ANC, AMC, NLR, and LMR were significantly associated with tumor stage and clinical stage (p < .05). A high NLR (>=2.69) and low LMR (<2.98) were significantly associated with poor DFS, CSS, and OS. The LMR was a significant independent prognostic factor for DFS, CSS, and OS (p = .035, .047, and .045, respectively). CONCLUSION: The pretreatment LMR should be considered as an independent prognostic factor for patients with HPSCC. PMID- 29607747 TI - Development and validation of polar RP-HPLC method for screening for ectoine high yield strains in marine bacteria with green chemistry. AB - A novel, green, rapid, and precise polar RP-HPLC method has been successfully developed and screened for ectoine high-yield strain in marine bacteria. Ectoine is a polar and extremely useful solute which allows microorganisms to survive in extreme environmental salinity. This paper describes a polar-HPLC method employed polar RP-C18 (5 MUm, 250 * 4.6 mm) using pure water as the mobile phase and a column temperature of 30 degrees C, coupled with a flow rate at 1.0 mL/min and detected under a UV detector at wavelength of 210 nm. Our method validation demonstrates excellent linearity (R2 = 0.9993), accuracy (100.55%), and a limit of detection LOQ and LOD of 0.372 and 0.123 MUgmL-1, respectively. These results clearly indicate that the developed polar RP-HPLC method for the separation and determination of ectoine is superior to earlier protocols. PMID- 29607746 TI - In vivo effects of PCB-126 and genistein on vitellogenin expression in zebrafish. AB - In this study, the vitellogenin (Vtg) modulation by genistein and polychlorinated biphenyl-126 (PCB-126) exposure in zebrafishes has been investigated. Both PCB 126 and genistein have been identified as aquatic pollutants and can further increase estrogenicity of waterways. Vtg is egg yolk precursor protein release by the hepatocytes during vitellogenesis. This process occurs normally in the hepatocytes in response to the activation with the estrogens such as 17-beta estradiol. Our immunohistochemical findings showed a Vtg expression that increases at 12 h and at 72 h in the liver of treated fishes with both PCB-126 and genistein, individually and in combination. Furthermore, for the first time, also hepatic stellate cells (HSC) in the liver parenchyma were strongly positive for vitellogenin. PMID- 29607749 TI - A Home for Endocrine Surgery Research. PMID- 29607748 TI - Auditory brainstem implant in postmeningitis totally ossified cochleae. AB - INTRODUCTION: An auditory brainstem implant (ABI) is an option for auditory rehabilitation in patients with totally ossified cochleae who cannot receive a conventional cochlear implant. OBJECTIVE: To evaluate the outcomes in audiometry and speech perception tests after the implantation of an ABI via the extended retrolabyrinthine approach in patients with postmeningitis hearing loss. MATERIALS AND METHODS: Ten patients, including children and adults, with postmeningitis hearing loss and bilateral totally ossified cochleae received an ABI in a tertiary center from 2009 to 2015. The extended retrolabyrinthine approach was performed in all the patients by the same surgeons. A statistical analysis compared pure tonal averages and speech perception tests before and at least 12 months after the ABI activation. RESULTS: Eight patients (80%) showed improvements in tonal audiometry and the word and vowel perception tests after an average follow-up of 3.3 years. Two patients recognized up to 40% of the closed set sentences without lip-reading. Two patients had no auditory response. CONCLUSIONS: The ABI improved hearing performance in audiometry and speech perception tests in cases of postmeningitis hearing loss. The extended retrolabyrinthine approach is a safe surgical option for patients with postmeningitis hearing loss and bilateral totally ossified cochleae. PMID- 29607751 TI - Aiming for an Ideal Drug-Induced Sleep Endoscopy (DISE) Scoring System. PMID- 29607750 TI - Highlights from the Current Issue: April 2018. PMID- 29607752 TI - Drug-Induced Sleep Endoscopy (DISE) Scoring Systems: Ideal DISE Scoring System and Comparability Properties. PMID- 29607753 TI - Histopathology of Cutaneous Inflammatory Disorders in Children. AB - Inflammatory dermatoses encompass a variety of histologic patterns that affect different portions of the skin. In spongiotic, psoriasiform, lichenoid, pityriasiform, and blistering disorders, there are predominately epidermal and junctional activities with variable superficial dermal inflammation. Hypersensitivity reactions can show either epidermal or mostly dermal changes depending on whether the exposure of the exogenous allergen occurs through an external or internal route, respectively. Exceptions include erythema multiforme and Stevens-Johnson syndrome/toxic epidermal necrolysis, where the etiology is often due to infection or ingested medications, but the histologic features are almost exclusively confined to the epidermis and dermoepidermal junction. Autoimmune disorders are unique in that lesions typically incorporate a mixture of epidermal and dermal inflammatory patterns with periadnexal inflammation, while the vast majority of vasculitis/vasculopathy and alopecia have changes limited to only the vessels and hair follicles, respectively. It is critical to recognize that a relatively limited number of histologic patterns are seen in a large array of clinical entities. Therefore, clinicopathologic correlation and careful examination of histologic details are of the utmost importance when evaluating skin biopsies for inflammatory disorders. PMID- 29607754 TI - Founders of Pediatric Pathology: Francisco Gonzalez-Crussi. PMID- 29607755 TI - Common and not so Common Melanocytic Lesions in Children and Adolescents. AB - The acquired melanocytic nevus is the most common lesion encountered by pediatric pathologists and dermatopathologists in their daily practice. In most cases, there are few difficulties in histopathologic diagnosis. However, it is the acquired melanocytic lesion known as the Spitz nevus, with its intrinsic atypical features which becomes the challenge since it exists along a histopathologic and biologic continuum from the atypical Spitz tumor to spitzoid melanoma. The frustration with some of these spitzoid lesions is that even the "experts" cannot agree as to the differentiation of one from the other even at the level of molecular genetics. Other melanocytic lesions are discussed including the congenital melanocytic nevus with its proliferative nodule(s) and melanoma as the ultimate complication. Although uncommon, cutaneous melanoma in the first 2 decades is emerging as a clinical problem especially in young women in the second decade of life. These are ultraviolet-associated neoplasms whose histopathologic and prognostic features are identical to the adult experience. Considerable progress has been made over the past 15 to 20 years in our understanding of cutaneous melanocytic lesions, but gaps still exist in the important group of spitzoid lesions. It can also be anticipated that more cutaneous melanomas in children will be seen in the future based upon epidemiologic studies. PMID- 29607757 TI - Cutaneous Hematolymphoid and Histiocytic Proliferations in Children. AB - This article focuses on cutaneous hematopoietic neoplasms that are more likely to be encountered in the pediatric age-group and includes both lymphoproliferative and histiocytic disorders. The cutaneous hematologic disorders in children have a different epidemiologic profile to what is seen during adulthood. Although mycosis fungoides is the most frequent form of cutaneous lymphoma in adults, it is very rare in children. Because lymphoblastic leukemias and lymphomas are more frequent in the pediatric setting, cutaneous leukemic infiltrates are relatively common in this age-group. Similarly, histiocytic disorders are more common in children, particularly Langerhans cell histiocytosis and juvenile xanthogranuloma. Notably, the histiocytic disorders have undergone significant modifications on their nomenclature in the basis of the molecular characteristics that are present in them. A summary of the most frequent cutaneous hematopoietic disorders in children will be discussed further in this review. PMID- 29607758 TI - Nonepithelial Tumors and Tumor-like Lesions of the Skin and Subcutis in Children. AB - This overview of mesenchymal tumors presenting in the skin and/or subcutis in children brings together the range of neoplasms and hamartomas which are seen in this age-group. It is not surprising from the perspective of the pediatric or general surgical pathologist that vascular anomalies, including true neoplasms and vascular malformations, are the common phenotypic category. Since there is considerable morphologic overlap among these lesions, clinicopathologic correlation may be more important than for many of the other mesenchymal tumors. The skin and subcutis are the most common sites of clinical presentation for the infantile myofibroma which is the most common of fibrous mesenchymal tumors in children. Several of the other mesenchymal tumors are more common adults-like dermatofibrosarcoma protuberans, but nonetheless have an important presence in children, even as a congenital neoplasm. A lipomatous tumor in a young child should be considered as a possible manifestation of an overgrowth syndrome. PMID- 29607759 TI - 'It's like being a slave to your own body in a way': a qualitative study of adolescents with chronic fatigue syndrome. AB - BACKGROUND: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is a relatively common disabling illness in adolescents that may limit participation in daily life. AIM: This study explored interactions between the illness experiences of adolescents with CFS/ME, their occupational lives and expectations for the future. METHODS: Seven adolescents with CFS/ME were interviewed. The interviews were analyzed using thematic analysis. RESULTS: Three themes were developed. 'Being ruled by an unfamiliar and inexplicable body', which illustrated that altered and strange bodies seemed to separate and disrupt the participants from their former occupational lives. 'On the sideline of life with peers', which demonstrated that the informants spent time at home, doing undemanding activities instead of participating in activities with peers. 'A coherent connection between present and future life', which was reflected by how the participants eventually accepted their situation and rebuilt a meaningful occupational life and value of self. CONCLUSION: CFS/ME made the body unfamiliar and disconnected informants from participating in their usual daily occupations. A coherent interaction between body, occupational life and social self was achieved by taking their new body into account and adjusting their occupations accordingly. This practice enabled the participants to hope for a better future life. PMID- 29607760 TI - April 2018 New Products. AB - A selection of products and developments of interest to JOSPT readers. J Orthop Sports Phys Ther 2018;48(4):345. doi:10.2519/jospt.2018.48.4.345. PMID- 29607761 TI - Arthroscopic Surgical Procedures Versus Sham Surgery for Patients With Femoroacetabular Impingement and/or Labral Tears: Study Protocol for a Randomized Controlled Trial (HIPARTI) and a Prospective Cohort Study (HARP). AB - Study Design Study protocol for a randomized controlled trial and a prospective cohort. Background The number of arthroscopic surgical procedures for patients with femoroacetabular impingement syndrome (FAIS) has significantly increased worldwide, but high-quality evidence of the effect of such interventions is lacking. Objectives The primary objective will be to determine the efficacy of hip arthroscopic procedures compared to sham surgery on patient-reported outcomes for patients with FAIS (HIP ARThroscopy International [HIPARTI] Study). The secondary objective will be to evaluate prognostic factors for long-term outcome after arthroscopic surgical interventions in patients with FAIS (Hip ARthroscopy Prospective [HARP] Study). Methods The HIPARTI Study will include 140 patients and the HARP Study will include 100 patients. The international Hip Outcome Tool 33 will be the primary outcome measure at 1 year. Secondary outcome measures will be the Hip disability and Osteoarthritis Outcome Score, Arthritis Self-Efficacy Scale, fear of movement (Tampa Scale of Kinesiophobia), Patient-Specific Functional Scale, global rating of change score, and expectations. Other outcomes will include active hip range of motion, hip muscle strength tests, functional performance tests, as well as radiological assessments using radiographs and magnetic resonance imaging. Conclusion To determine the true effect of surgery, beyond that of placebo, double-blinded placebo-controlled trials including sham surgery are needed. The HIPARTI Study will direct future evidence-based treatment of FAIS. Predictors for long-term development and progression of degenerative changes in the hip are also needed for this young patient group with FAIS; hence, responders and nonresponders to treatment could be determined. J Orthop Sports Phys Ther 2018;48(4):325-335. doi:10.2519/jospt.2018.7931. PMID- 29607762 TI - Hip Strength and Range of Movement Are Associated With Dynamic Postural Control Performance in Individuals Scheduled for Arthroscopic Hip Surgery. AB - Study Design Cross-sectional. Background Hip pain is associated with reduced muscle strength and range of movement (ROM). These impairments may contribute to decreased postural stability and balance. The Star Excursion Balance Test (SEBT) is a reliable and valid method to measure dynamic postural control. Objectives To evaluate the association between SEBT performance and hip strength, hip ROM, trunk endurance, and group characteristics in individuals with hip pain. Methods One hundred eleven individuals with hip pain, scheduled for arthroscopic hip surgery, were matched with 62 healthy controls. Hip ROM and muscle strength, trunk endurance, and SEBT reach were measured prior to surgery. Data were analyzed for between-group differences using t tests, and associations between SEBT reach and hip strength, hip ROM, and population characteristics were evaluated with Pearson correlation coefficients and stepwise backward regression analyses. Results Star Excursion Balance Test performance (P<.01), hip strength (P<.01), and hip ROM (P<.05) were lower in the presurgery group compared to controls. In the presurgery group, when adjusted for height and weight, hip flexion strength and internal rotation ROM accounted for 44% of the variance in anteromedial SEBT reach. In the posteromedial direction, hip adduction strength and sex accounted for 53% of the variance. For the posterolateral direction, hip adduction and internal rotation strength accounted for 46% of reach variance. Conclusion The individuals who were scheduled for arthroscopic hip surgery were significantly weaker, had less hip mobility, and had reduced dynamic balance compared to controls. In this population, dynamic balance performance was associated with various hip strength and ROM measurements in a direction-specific manner. J Orthop Sports Phys Ther 2018;48(4):280-288. doi:10.2519/jospt.2018.7946. PMID- 29607763 TI - Heterotopic Ossification Following Hip Arthroscopy. AB - A 21-year-old woman initiated physical therapy 4 days following hip arthroscopic labrum debridement and osteochondroplasty. During postoperative rehabilitation, the patient's status regressed. With persistent symptoms, at 10 weeks postsurgery a computed tomography scan revealed, as confirmed by radiographs, heterotopic ossification development. J Orthop Sports Phys Ther 2018;48(4):344. doi:10.2519/jospt.2018.7420. PMID- 29607764 TI - Impairment-Based Rehabilitation Following Hip Arthroscopy: Postoperative Protocol for the HIP ARThroscopy International Randomized Controlled Trial. AB - Synopsis The number of hip arthroscopies for the management of femoroacetabular impingement syndrome and other hip intra-articular conditions has grown exponentially in the last decade. Postoperative rehabilitation is part of the treatment algorithm, although there is a lack of high-quality studies on the efficacy of both surgery and postoperative rehabilitation programs. It is known that impairments can be present up to 2 years after hip arthroscopy, with individuals exhibiting reduced function and quality of life when compared to those of similar age, highlighting a need to improve postoperative care. Postoperative rehabilitation programs aim to improve hip function; however, the description of interventions as well as criteria for progression are lacking in the literature. The aim of this clinical commentary was to present a targeted clinical rehabilitation approach for individuals undergoing hip arthroscopy. J Orthop Sports Phys Ther 2018;48(4):336-342. doi:10.2519/jospt.2018.8002. PMID- 29607765 TI - Significant Knowledge Gaps Between Clinical Practice and Research on Femoroacetabular Impingement: Are We on the Same Path? AB - Femoroacetabular impingement (FAI) is the abnormal osseous contact between the femur (cam impingement) and/or acetabular rim (pincer impingement) during end range hip motions. This special issue on FAI aims at closing some of the gaps between clinical practice and research findings, important for all health professions treating patients with hip pain. This special issue will explore several aspects of FAI syndrome. Specifically, it will provide clinicians with a greater understanding of the etiology and prevalence of hip morphology seen in FAI syndrome, and its relationship with hip range of motion, muscle strength, and hip osteoarthritis (OA). J Orthop Sports Phys Ther 2018;48(4):228-229. doi:10.2519/jospt.2018.0103. PMID- 29607766 TI - The Physiotherapy for Femoroacetabular Impingement Rehabilitation STudy (physioFIRST): A Pilot Randomized Controlled Trial. AB - Study Design A pilot double-blind randomized controlled trial (RCT). Background The effectiveness of physical therapy for femoroacetabular impingement syndrome (FAIS) is unknown. Objectives To determine the feasibility of an RCT investigating the effectiveness of a physical therapy intervention for FAIS. Methods Participants were 17 women and 7 men (mean +/- SD age, 37 +/- 8 years; body mass index, 25.4 +/- 3.4 kg/m2) with FAIS who received physical therapy interventions provided over 12 weeks. The FAIS-specific physical therapy group received personalized progressive strengthening and functional retraining. The control group received standardized stretching exercises. In addition, both groups received manual therapy, progressive physical activity, and education. The primary outcome was feasibility, including integrity of the protocol, recruitment and retention, outcome measures, randomization procedure, and sample-size estimate. Secondary outcomes included hip pain and function (international Hip Outcome Tool-33 [iHOT-33]) and hip muscle strength. Poststudy interviews were conducted to determine potential improvements for future studies. Results Twenty four (100%) patients with known eligibility agreed to participate. Four patients (17%) were lost to follow-up. All participants and the tester remained blinded, and the control intervention was acceptable to participants. The between-group mean differences in change scores were 16 (95% confidence interval [CI]: -9, 38) for the iHOT-33 and 0.24 (95% CI: 0.02, 0.47) Nm/kg for hip adduction strength, favoring the FAIS-specific physical therapy group. Using an effect size of 0.61, between-group improvements for the iHOT-33 suggest that 144 participants are required for a full-scale RCT. Conclusion A full-scale RCT of physical therapy for FAIS is feasible. A FAIS-specific physical therapy program has the potential for a moderate to large positive effect on hip pain, function, and hip adductor strength. Level of Evidence Therapy, level 2b. J Orthop Sports Phys Ther 2018;48(4):307-315. doi:10.2519/jospt.2018.7941. PMID- 29607767 TI - Femoral Neck Stress Fracture in a Female Runner. AB - A 23-year-old woman was referred to physical therapy by her primary care physician for a 4-week history of right groin pain that had progressively worsened while training for a half-marathon. Before the physical therapy referral, the primary care physician ordered radiography of the right hip, which was unremarkable for fracture. Following examination, the physical therapist suspected osseous or soft tissue abnormality and requested that the primary care physician order magnetic resonance imaging without contrast, which revealed a femoral neck stress fracture. J Orthop Sports Phys Ther 2018;48(4):343. doi:10.2519/jospt.2018.7479. PMID- 29607768 TI - The Dutch Hip and Groin Outcome Score: Cross-cultural Adaptation and Validation According to the COSMIN Checklist. AB - Study Design Clinical measurement. Background The Copenhagen Hip and Groin Outcome Score (HAGOS) was developed as a patient-reported outcome measure for young, active individuals with hip and groin pain. Objectives To cross-culturally adapt and validate a Dutch version of the HAGOS. Methods Adaptation and validation were performed according to existing guidelines and the COnsensus based Standards for the selection of health Measurement INstruments checklist. Physically active (Tegner activity score of greater than 2) adults between 18 and 50 years of age with hip and groin pain (numeric pain score of 1 or greater) were included in the study. Reliability (test-retest, internal consistency) was assessed in clinically stable patients. Construct validity was determined by calculating Spearman correlations between the scores on the HAGOS and scores on the Hip disability and Osteoarthritis Outcome Score and European Quality of Life 5 Dimensions subscales. Fifteen hypotheses were defined a priori. Interpretability was considered good when floor and ceiling effects were present in less than 15% of individuals. Results A Dutch version of the HAGOS was created. Its reliability was tested in 129 individuals and its validity in 194 participants. Test-retest reliability was good (intraclass correlation coefficient = 0.83-0.87). Internal consistency was good (Cronbach alpha = .81 .92). Construct validity was considered good: 13 of 15 (87%) hypotheses were confirmed. Floor effects (21%) were present for the physical activity subscale. Conclusion The Dutch HAGOS is a reliable and valid patient-reported outcome measure and performs similarly to the original version in its target population. It can be used in clinical as well as research settings. Presence of floor effects should be considered for the physical activity subscale. J Orthop Sports Phys Ther 2018;48(4):299-306. doi:10.2519/jospt.2018.7883. PMID- 29607769 TI - Framing the "Self" in Self-Determination and Recovery. PMID- 29607770 TI - Mirror Neurons and the Clubhouse Model. PMID- 29607771 TI - Empowering People With Mental Illness in Workplace Settings. PMID- 29607772 TI - The Truth About Mental Health First Aid Training. PMID- 29607773 TI - Acceptability and Perceived Effectiveness of Cognitive Remediation in Clinical Practice. PMID- 29607774 TI - Civil Commitment for Opioid and Other Substance Use Disorders: Does It Work? AB - Many states are turning to civil commitment for substance use disorders as a potential solution to address rising rates of overdose deaths. Civil commitment allows family members or others to seek court-ordered involuntary treatment for a substance-abusing person. In contrast to mandatory treatment ordered by drug courts, civil commitment does not require involvement with the criminal justice system. Although these laws are understandably appealing, statutes and their implementation are highly variable, ethical concerns about deprivation of liberty continue to be raised, and outcome data are limited and often not generalizable. Above all, more studies are needed to determine effectiveness. PMID- 29607775 TI - Identifying diffusion patterns of research articles on Twitter: A case study of online engagement with open access articles. AB - The growing presence of research shared on social media, coupled with the increase in freely available research, invites us to ask whether scientific articles shared on platforms like Twitter diffuse beyond the academic community. We explore a new method for answering this question by identifying 11 articles from two open access biology journals that were shared on Twitter at least 50 times and by analyzing the follower network of users who tweeted each article. We find that diffusion patterns of scientific articles can take very different forms, even when the number of times they are tweeted is similar. Our small case study suggests that most articles are shared within single-connected communities with limited diffusion to the public. The proposed approach and indicators can serve those interested in the public understanding of science, science communication, or research evaluation to identify when research diffuses beyond insular communities. PMID- 29607776 TI - Enhancing municipal solid waste recycling through reorganizing waste pickers: A case study in Nanjing, China. AB - Waste pickers (WPs) play an indispensable role by helping to control municipal solid waste (MSW). However, they constitute the entry-level workforce of the waste recycling industry and receive little attention from the general public. In China, approximately 4 million WPs make their living by collecting MSW recyclable materials. To assess the role of WPs, an extensive social survey including urban management decision-makers, recycling industrial circle insiders, WPs, as well as common citizen respondents has been conducted in the city of Nanjing, China. The results confirmed that 70-80% of recyclable MSW materials were collected by WPs in the informal sector, which are an integral component of the waste recycling system. In Nanjing, the recyclable material collected annually by WPs is about 505,000 tons, which creates annual economic value of about 78.6-84.7 million USD. However, WPs account for only 6.8-7.3% of the entire industrial chain of the recycling economy. In Nanjing, WPs are able to save an annual MSW disposal cost of about 17.6-22.0 million USD. The resource recovery rate is also increased by 1.9-8.0%. The survey results support the experience of establishing a community based semi-official picker organizational framework, accompanied by relevant laws, regulations, and preferential policies that would improve the resource recovery rate and pickers' living and working conditions in order to achieve more effective and hazard-free MSW resource utilization. It is anticipated that the results of this research will be instrumental for the improvement of the MSW recycling system and WP management in other cities in China and other developing countries. PMID- 29607777 TI - The Cognitive Assessment by Visual Election (CAVE): A pilot study to develop a cognitive assessment tool for people emerging from disorders of consciousness. AB - Instruments for assessing people with disorders of consciousness have been developed over the last 15 years, but there remains a dearth of suitable assessment paradigms for those who have emerged from disorders of consciousness. This paper presents a pilot study for the development of the Cognitive Assessment by Visual Election (CAVE), a short assessment designed to investigate a number of cognitive domains in very severely brain injured patients who are in or have emerged from minimally conscious states (EMCS). Reliability and validity data are presented. The challenge of determining neuropsychological profiles of EMCS patients is discussed, current published assessments are briefly reviewed and suggestions for a wider assessment framework are made. PMID- 29607778 TI - Targeting human telomeric DNA quadruplex with novel berberrubine derivatives: insights from spectroscopic and docking studies. AB - Study on bioactive molecules, capable of stabilizing G-Quadruplex structures is considered to be a potential strategy for anticancer drug development. Berberrubine (BER) and two of its analogs bearing alkyl phenyl and biphenyl substitutions at 13-position were studied for targeting human telomeric G quadruplex DNA sequence. The structures of berberrubine and analogs were optimized by density functional theory (DFT) calculations. Time-dependent DFT (B3LYP) calculations were used to establish and understand the nature of the electronic transitions observed in UV-vis spectra of the alkaloid. The interaction of berberrubine and its analogs with human telomeric G-quadruplex DNA sequence 5'-(GGGTTAGGGTTAGGGTTAGGG)-3' was investigated by biophysical techniques and molecular docking study. Both the analogs were found to exhibit higher binding affinity than natural precursor berberrrubine. 13-phenylpropyl analog (BER1) showed highest affinity [(1.45 +/- 0.03) * 105 M-1], while the affinity of the 13-diphenyl analog (BER2) was lower at (1.03 +/- 0.05) * 105 M-1, and that of BER was (0.98 +/- 0.03) * 105 M-1. Comparative fluorescence quenching studies gave evidence for a stronger stacking interaction of the analog compared to berberrubine. The thiazole orange displacement assay has clearly established that the analogs were more effective in displacing the end stacked dye in comparison to berberrubine. Molecular docking study showed that each alkaloid ligand binds primarily at the G rich regions of hTelo G4 DNA which makes them G specific binder towards hTelo G4 DNA. Isothermal titration calorimetry studies of quadruplex-berberrubine analog interaction revealed an exothermic binding that was favored by both enthalpy and entropy changes in BER in contrast to the analogs where the binding was majorly enthalpy dominated. A 1:1 binding stoichiometry was revealed in all the systems. This study establishes the potentiality of berberrubine analogs as a promising natural product based compounds as G-quadruplex-specific ligands. PMID- 29607779 TI - Detection of ciprofloxacin through surface plasmon resonance nanosensor with specific recognition sites. AB - The novel nanosensor based on Surface Plasmon Resonance (SPR) was developed for sensitive and selective detection of ciprofloxacin via molecularly imprinted nanoparticles (MIP/NPs). NPs were synthesized through miniemulsion polymerization technique with methacrylic acid as a functional monomer. FTIR, SEM, zetasizer and contact angle measurements were used for the characterization of MIP/NPs. After modification the SPR chip surface, the nanosensor was used for detection of ciprofloxacin in aqueous solution. According to selected concentration range, the correlation coefficient and limit of detections were obtained as 0.993 (R2) and 3.21 and 7.1 ppb in ultrapure water and SWW, respectively. Association kinetic analysis, Scatchard, Freundlich, Langmuir and Freundlich-Langmuir isotherms were also performed on the data to investigate adsorption behaviour of ciprofloxacin on the surface of nanosensor. Tetracycline and enrofloxacin were used as competitor agents to examine the selectivity of nanosensor. Performance of the SPR nanosensor was also investigated by using synthetic wastewater (SWW) for detection of CPX. The reusability of nanosensor was investigated and good repeatability was obtained with 5.81% RSD. As a result, selective, simple and low cost method to detect ciprofloxacin in aqueous solution was developed by combining MIP/NPs and SPR. PMID- 29607780 TI - Brain Death in Intensive Care Units: Problems, Differences in Methods of Diagnosis, and Donor Care. AB - OBJECTIVES: Our aim was to investigate the most common problems in diagnosing brain death, the care of the organ donor, and organ donation after death. MATERIALS AND METHODS: A survey was sent randomly to clinicians working in national intensive care units in Turkey. The survey, which consisted of 17 questions for clinicians, had 163 responders. RESULTS: The most common cause of brain death was traumatic brain injury. Although 22% of clinicians found the apnea test necessary for brain death diagnosis, 78% stated that it could be used as an optional confirmatory test. However, 65.6% of the clinicians were not familiar with the modified apnea test. The most frequently used vasoactive agent for hypotension in patients with brain death was noradrenaline (54.6%) and dopamine (41.6%). Regarding time of death, 50.3% of clinicians considered it as the time and date when the patient was diagnosed with brain death and 47.8% as the time and date of cardiac arrest. When asked whether they terminate the treatment of a patient with brain death when organ donation is rejected, only 16.1% discontinued all advanced life support. According to the survey, the most common reason for not accepting organ transplant was for religious reasons. CONCLUSIONS: In intensive care units, differences in definitions and care of patients with brain death continue to be a complication. There has been a lack of progress in criterion standards of brain death diagnosis and donor care, as verified by our survey. PMID- 29607781 TI - Effect of Donor Cornea on the Surgical Outcomes of Penetrating Keratoplasty: Imported Cornea Versus Domestic Cornea. AB - OBJECTIVES: In this study, we compared the surgical outcomes of penetrating keratoplasty using domestic and imported donor corneas. MATERIALS AND METHODS: We retrospectively evaluated 200 eyes and 200 consecutive patients who underwent penetrating keratoplasty by using domestic and imported donor corneas between January 2013 and December 2013. The donor characteristics, preoperative clinical features, and clinical outcomes at 6, 12, 24, and 36 months were assessed. RESULTS: No significant differences existed between the 2 groups with respect to age, sex, lateralization, and penetrating keratoplasty indication (P > .05). Donor age was lower (P = .012), the death-to-preservation time and the preservation-to-surgery time were shorter, the rate of epithelial defect was lower, and the endothelial cell count was higher in the domestic group (P < .001). The 2 groups were also similar in terms of developing persistent epithelial defect, glaucoma, keratitis, and graft survival (P > .05). CONCLUSIONS: We observed no significant differences in clinical outcomes during and after penetrating keratoplasty surgery between imported and domestic donor corneas. PMID- 29607783 TI - Teratogenic Effects of Third-Generation Antiepileptic Drug, Pregabalin: An In vivo Study. AB - BACKGROUND: In the recent past, many third-generation antiepileptic drugs (AEDs) including Pregabalin (PGB) were launched for the treatment of diverse forms of epilepsy with better efficacy and safety profile than first-and-second-generation AEDs, but their teratogenic safety has not been established so far. OBJECTIVE: The present study has been undertaken to evaluate the reproductive and teratogenic potential (external and skeletal) of a novel and third generation AED, PGB in pregnant albino rats. METHODS: In this study, pregnant subjects were exposed to clinically relevant doses (41, 82 and 123 mg) of PGB from gestation days 6-20, and sacrificed on GD-21, and their fetuses were collected and examined to identify the birth defects and skeletal anomalies. RESULTS: This study revealed that prenatal exposure to PGB induced dose-dependent substantial fetal resorptions, litter size, fetal length and weight; and variety of minor external and internal malformations in fetuses predominant with limbs, tail, eyes, abdomen including hemorrhages, and poor skeletal ossification. CONCLUSION: Thus, PGB was found to be teratogenic in rats at equivalent therapeutic doses, hence precaution should be taken before prescribing PGB to pregnant women with epilepsy. PMID- 29607784 TI - Sertraline-Induced Acute Eosinophilic Pneumonia. AB - BACKGROUND: Acute Eosinophilic Pneumonia (AEP) is a rare, potentially fatal disease often characterized by a short febrile illness, hypoxemic respiratory failure, diffuse pulmonary opacities and evidence of pulmonary eosinophilia. AEP can be idiopathic, but has documented associations with multiple drugs. CASE REPORT: We present the first case highlighting Sertraline specifically as a cause of drug-induced AEP in the English literature. PMID- 29607782 TI - Influence of Overweight and Obesity on Circulating Inflammation-Related microRNA. AB - BACKGROUND: Increased cardiovascular disease risk and prevalence associated with overweight and obesity is due, in part, to heightened inflammatory burden. The mechanisms underlying adiposity-related amplification of inflammation are not fully understood. Alterations in regulators of inflammatory processes such as microRNAs (miRs), however, are thought to play a pivotal role. OBJECTIVE: The aim of this study was to determine the influence of overweight and obesity, independent of other cardiovascular risk factors, on circulating expression of miR-34a, miR-126, miR-146a, miR-150 and miR-181b. METHODS: Forty-five sedentary, middle-aged (47-64 years) adults were studied: 15 were normal weight (8M/7F; BMI: 23.3 +/- 0.3 kg/m2); 15 were overweight (8M/7F; 28.2 +/- 0.3 kg/m2); and 15 were obese (7M/8F; 32.3 +/- 0.5 kg/m2). All subjects were non-smokers, normotensive and free of overt cardiometabolic disease. Circulating levels of the following inflammation-related miRs: miR-34a, miR-126, miR-146a, miR-150 and miR-181b were determined in plasma using standard RT-PCR techniques. miR expression was normalized to exogenous C. elegans miR-39 and reported as relative expression (AU). RESULTS: Circulating miR-34a was ~200% higher (P< 0.05) in the obese as compared with normal weight and overweight groups. Whereas, miR-126, miR-146a and miR-150 were significantly lower (~65%) in both the obese and overweight groups than the normal weight group. There were no significant group differences in circulating expression of miR-181b. miR-34a was positively related (r = 0.43; P< 0.05); whereas, miR-126 (r = -0.48), miR-146a (r = -0.33) and miR-150 (r = -0.43) levels were significantly inversely related to BMI. CONCLUSION: Overweight and obesity, independent of other cardiometabolic risk factors, negatively influences circulating inflammation-related miRs. Dysregulation of circulating miRs may contribute mechanistically to the heightened inflammatory state associated with overweight and obesity. PMID- 29607785 TI - The Use of Probiotics in Different Phases of Diverticular Disease. AB - BACKGROUND & AIMS: Diverticular Disease (DD) is a common clinical condition with a dramatic increasing of the prevalence among industrialized countries. Based on the most used classification, DD may be divided into asymptomatic diverticulosis, symptomatic uncomplicated diverticular disease and complicated diverticular disease. Since recent studies pointed out the role of GUT microbiota imbalance in promoting diverticular formation and inflammation, we have designed a systematic review focusing on the possible role of probiotics in the management of this condition. METHODS: According to PRISMA, we identified studies on DD patients treated with probiotics, by searching on Pubmed, Embase, Cochrane and ResearchGate. RESULTS: 13 studies were included in this review based on our selection criteria: 3 double-blind randomized placebo-controlled, 6 open randomized, and 4 non-randomized open studies. CONCLUSION: This is the first systematic review providing an updated measure of evidence on the efficacy of probiotics in a different phase of DD. Even though the majority of studies are still preliminary, current data show a possible clinical application of certain probiotic strains in all stages of DD. Further investigation is then required to better understand when and how probiotics can be used in different phases of DD. PMID- 29607786 TI - Association Between Hypothyroidism and Takotsubo Cardiomyopathy: Analysis of Nationwide Inpatient Sample Database. AB - BACKGROUND: Takotsubo Cardiomyopathy (TC), also called transient left ventricular (LV) ballooning syndrome, resembles myocardial infarction and is characterized by LV dysfunction in the absence of coronary artery disease. Hypothesis described for TC has been an intense social stressor, pheochromocytoma, thyrotoxicosis among others. We performed this study to analyze the association of hypothyroidism with TC. METHODS: We queried the Nationwide Inpatient Sample which represents 20% of all the United States hospital data for our study. We identified TC and hypothyroidism through their respective ICD9. Codes for years 2006-2012. SAS 9.4 was used to perform a chi-square analysis to find any statistical significance and p < 0.05 used to determine statistical significance. Significant differences were identified using odds ratio (OR) estimates. RESULTS: A total of 19,713 cases with TC were identified of which 17,340 (87.96%) were females and 2,373 (12.04%) were males. 3,272 patients with TC had diagnosis of hypothyroidism. There is statistically significant evidence of an association between TC and hypothyroidism (OR 2.21 (95% CI: 2.11- 2.31); p<0.0001). There is evidence of increased statistical significance of females having TC 5.24 (95% CI: 4.96-5.53; (p<0.0001)) compared to males, with an increased statistically significance of females with hypothyroidism having TC, OR 6.65 (95% CI: 5.57 7.93; p< 0.001) compared to males. CONCLUSION: There is an increased association of hypothyroidism, especially hypothyroidism for females with TC. PMID- 29607787 TI - Synthesis and Cytotoxic Evaluation of Kojic Acid Derivatives with Inhibitory Activity on Melanogenesis in Human Melanoma Cells. AB - In the present study, Mannich bases of kojic acid with the structure of 2 substituted-3-hydroxy-6 hyroxymethyl/chloromethyl/methyl/morpholinomethyl/piperidinylmethyl/pyrrolidinylm thyl-4H-pyran-4-one (compounds 1-23) were synthesized by the reaction of kojic acid/chlorokojic acid/allomaltol and substituted benzylpiperazine derivatives in presence of formaline. To obtain the cyclic amine (morpholine, piperidine and pyrrolidine) derivatives of the 6th-position of chlorokojic acid derivatives, nucleophilic substitutions were carried out. Thereafter, cytotoxic effects on A375 human malignant melanoma, HGF-1 human gingival fibroblasts, and MRC-5 human lung cell lines were investigated by sulphorhodamine B assay. Efficacy of all these compounds has been compared to those of vemurafenib, dacarbazine, temozolomide, and lenalidomide, which are the commercially available drugs for the treatment of malignant melanoma. Cytotoxic action against melanoma cells was significantly more efficacious (IC50: 11.26-68.58 uM) than the FDA-approved drugs except for vemurafenib. Fourteen of the compounds were proven to have higher IC50 values for the non-cancerous cell lines, HGF-1, and MRC-5 cells. Melanogenesis inhibition assay was performed to observe the ability of the drugs to inhibit melanin production and certain compounds were shown to be capable of actively inhibiting melanin production in melanoma cells. In conclusion, Mannich bases of kojic acid derivatives may be promising therapeutic agents, since some have more potent effects on melanoma cells than previously FDA-approved drugs for the treatment of malignant melanoma. PMID- 29607788 TI - Inhibitory Effect of Filipendula ulmaria on Mammary Carcinogenesis Induced by Local Administration of Methylnitrosourea to Target Organ in Rats. AB - BACKGROUND: The meadowsweet (Filipendula ulmaria (L.) Maxim.) may have a cancer prophylactic activity, since its extracts exhibits antioxidant, antiinflammatory and other effects. We investigated the ability of a meadowsweet decoction to inhibit mammary carcinogenesis induced by intramammary injections of methylnitrosourea (MNU) to the target organ in rats. MATERIALS AND METHODS: The chemical composition of meadowsweet extracts was studied by traditional methods. In animal experiments adult outbred female rats received single injections of MNU at a dose 1mg directly into the tissue of each mammary gland. After carcinogenic exposure one group (MNU) of rats continued to receive standard feed and tap water throughout life. In another group (MNU+meadowsweet), rats were given daily a decoction of the meadowsweet instead of drinking water and standard feed. RESULTS: Meadowsweet extracts showed a sufficiently high content of flavonoids and tannins and also some individual phenolic compounds. In rats after injections of MNU the overall incidence of tumors was 90% with tumor multiplicity of 3.1. The majority of rats (86%) developed multiple malignant tumors of mammary gland (most often adenocarcinomas). In rats from the group MNU+meadowsweet there was a statistically significant decrease of the overall tumor multiplicity - by 1.5 times, and the incidence and multiplicity of breast tumors - by 1.6 and 2.2 times, respectively. CONCLUSIONS: Meadowsweet extract can be considered an effective inhibitor of breast carcinogenesis. PMID- 29607789 TI - 7-O-aminoalkyl-2,3-dehydrosilibinins: synthesis and in vitro anti-cancer efficacy. AB - A series of 7-O-aminoalkyl-2,3-dehydrosilibinin derivatives were synthesized and evaluated for their antiproliferative activities against several cancer cell lines. A number of them exhibited greatly enhanced potency with 50% growth inhibition at low micromolar concentrations. Structure activity study indicated that the distance between N and 7-O on the side chain has a limited influence on the antiproliferative activity, while the presence of a morpholino group decreases the antiproliferative activities dramatically. Flow cytometry based assays on human colon cancer HCT116 cells revealed that 6a and 6c, two of the most potent derivatives, effectively arrest the cell cycle in the G2 phase and stimulate cell apoptosis. Our findings suggest that attaching an appropriate tertiary amino alkyl side chain through 7-O-alkylation on 2,3-dehydrosilibinin, would be a viable strategy for the development of silibinin derivatives as anticancer agents. PMID- 29607790 TI - Protective Effects of Diuretics Against the Development of Cardiovascular Disease in Patients with Chronic Kidney Disease: A Systematic Review. AB - Cardiovascular disease is one of the most important risk factors for mortality and morbidity in patients with Chronic Kidney Disease (CKD). This systematic review focuses on the protective effects of diuretics against the development of cardiovascular disease in patients with CKD. Among various kinds of diuretics, spironolactone, a mineralocorticoid receptor antagonist, has been shown to have protective effects against cardiovascular disease in patients with all stages of CKD, including predialysis, hemodialysis, and peritoneal dialysis. Low-dose loop diuretics have also been shown to have cardioprotective effects in patients with CKD during the pre-dialysis and hemodialysis stages; however, high-dose loop diuretics have failed to show these cardioprotective effects. The protective effects of other classes of diuretics, including thiazide and tolvaptan, against cardiovascular diseases in patients with CKD remain unclear. PMID- 29607791 TI - Attention-deficit/hyperactivity disorder and risk for psychiatric and neurodevelopmental disorders in siblings. AB - BACKGROUND: Probands with attention-deficit/hyperactivity disorder (ADHD) are at increased risk for several psychiatric and neurodevelopmental disorders. The risk of these disorders among the siblings of probands has not been thoroughly assessed in a population-based cohort. METHODS: Every child born in Finland in 1991-2005 and diagnosed with ADHD in 1995-2011 were identified from national registers. Each case was matched with four controls on sex, place, and date of birth. The full siblings of the cases and controls were born in 1981-2007 and diagnosed in 1981-2013. In total, 7369 cases with 12 565 siblings and 23 181 controls with 42 753 siblings were included in the analyses conducted using generalized estimating equations. RESULTS: 44.2% of the cases and 22.2% of the controls had at least one sibling diagnosed with any psychiatric or neurodevelopmental disorder (risk ratio, RR = 2.1; 95% CI 2.0-2.2). The strongest associations were demonstrated for childhood-onset disorders including ADHD (RR = 5.7; 95% CI 5.1-6.3), conduct and oppositional disorders (RR = 4.0; 95% CI 3.5 4.5), autism spectrum disorders (RR = 3.9; 95% CI 3.3-4.6), other emotional and social interaction disorders (RR = 2.7; 95% CI 2.4-3.1), learning and coordination disorders (RR = 2.6; 95% CI 2.4-2.8), and intellectual disability (RR = 2.4; 95% CI 2.0-2.8). Also, bipolar disorder, unipolar mood disorders, schizophrenia spectrum disorders, other neurotic and personality disorders, substance abuse disorders, and anxiety disorders occurred at increased frequency among the siblings of cases. CONCLUSIONS: The results offer potential utility for early identification of neurodevelopmental and psychiatric disorders in at-risk siblings of ADHD probands and also argue for more studies on common etiologies. PMID- 29607792 TI - Nutritional strategies to prevent gastrointestinal toxicity during pelvic radiotherapy. AB - Radiotherapy-induced damage to non-cancerous gastrointestinal mucosa has effects on secretory and absorptive functions and can interfere with normal gastrointestinal physiology. Nutrient absorption and digestion may be compromised. Dietary manipulation is an attractive option with sound rationale for intervention. The aim of this review was to synthesise published evidence for the use of elemental formulae, low or modified fat diets, fibre, lactose restriction and probiotics, prebiotics and synbiotics to protect the bowel from gastrointestinal side effects during long-course, radical pelvic radiotherapy. Thirty original studies (recruiting n 3197 patients) were identified comprising twenty-four randomised controlled trials, four cohort studies and two comparator trials. Endpoints varied and included symptom scales (Inflammatory Bowel Disease Questionnaire, Common Technology Criteria for Adverse Events, Radiation Therapy Oncology Group) and Bristol Stool Scale. Dietary and supplement interventions were employed with many studies using a combination of interventions. Evidence from RCT was weak for elemental, low or modified fat and low-lactose interventions and modestly positive for the manipulation of fibre during radiotherapy. Evidence for probiotics as prophylactic interventional agents was more promising with a number of trials reporting positive results but strength and strains of interventions vary, as do methodologies and endpoints making it difficult to arrive at firm conclusions with several studies lacking statistical power. This consolidated review concludes that there is insufficient high-grade evidence to recommend nutritional intervention during pelvic radiotherapy. Total replacement of diet with elemental formula could be effective in severe toxicity but this is unproven. Probiotics offer promise but cannot be introduced into clinical practice without rigorous safety analysis, not least in immunocompromised patients. PMID- 29607793 TI - Dietary intake in the early years and its relationship to BMI in a bi-ethnic group: the Born in Bradford 1000 study. AB - OBJECTIVE: To assess relationships between dietary intake at age 12, 18 and 36 months and BMI Z-scores at age 36 months in a bi-ethnic group. DESIGN: A prospective cohort study comparing cross-sectional and longitudinal data. Exposures included dietary intake at 12, 18 and 36 months (FFQ) with an outcome of BMI Z-score at age 36 months. SETTING: Born in Bradford 1000 study, Bradford, UK. SUBJECTS: Infants at age 12 months (n 722; 44 % White British, 56 % Pakistani), 18 months (n 779; 44 % White British, 56 % Pakistani) and 36 months (n 845; 45 % White British, 55 % Pakistani). RESULTS: Diet at age 12 months was not associated with BMI Z-score at age 36 months. Higher consumption of vegetables at 18 and 36 months was associated with a lower BMI Z-score at 36 months (model coefficient (95 % CI): -0.20 (-0.36, -0.03) and -0.16 (-0.31, 0.02), respectively). Higher consumption of high-fat chips at age 36 months was associated with a lower BMI Z-score at age 36 months (-0.16 (-0.32, 0.00)). Overall, White British children had higher 36-month BMI Z-scores than Pakistani children (adjusted mean difference (95 % CI): 0.21 (0.02, 0.41)). CONCLUSIONS: Our findings indicate that dietary intake at 18 and 36 months was somewhat related to BMI Z-score at age 36 months and suggest the importance of early interventions aimed at establishing healthy eating behaviours. PMID- 29607794 TI - Widening socio-economic disparities in early childhood obesity in Los Angeles County after the Great Recession. AB - OBJECTIVE: While economic crises can increase socio-economic disparities in health, little is known about the impact of the 2008-09 Great Recession on obesity prevalence among children, especially low-income children. The present study examined whether socio-economic disparities in obesity among children of pre-school age participating in a federal nutrition assistance programme have changed since the recession. DESIGN: A pre-post observational study using administrative data of pre-school-aged programme participants from 2003 to 2014. Logistic regression was used to examine whether the relationship between obesity prevalence (BMI>=95th percentile of the Centers for Disease Control and Prevention's growth charts) and three measures of socio-economic status (household income, household educational attainment, neighbourhood-level median household income) changed after the recession by examining the interaction between each socio-economic status measure and a 5-year time-period variable (2003-07 v. 2010-14), stratified by child's age and adjusted for child's sociodemographic characteristics. SETTING: Los Angeles County, California, USA. SUBJECTS: Children aged 2-4 years (n 1 637 788) participating in the Special Supplemental Nutrition Program for Women, Infants, and Children. RESULTS: The magnitude of the association of household income and household education with obesity increased after 2008-09 among 3- and 4-year-olds and 2- and 3-year-olds, respectively. However, the magnitude of the association of neighbourhood-level median household income with obesity did not change after 2008-09. CONCLUSIONS: Disparities in obesity by household-level socio-economic status widened after the recession, while disparities by neighbourhood-level socio-economic status remained the same. The widening household-level socio-economic disparities suggest that obesity prevention efforts should target the most vulnerable low income children. PMID- 29607796 TI - The etiology of social aggression: a nuclear twin family study. AB - BACKGROUND: Social aggression is a form of antisocial behavior in which social relationships and social status are used to damage reputations and inflict emotional harm on others. Despite extensive research examining the prevalence and consequences of social aggression, only a few studies have examined its genetic environmental etiology, with markedly inconsistent results. METHOD: We estimated the etiology of social aggression using the nuclear twin family (NTF) model. Maternal-report, paternal-report, and teacher-report data were collected for twin social aggression (N = 1030 pairs). We also examined the data using the classical twin (CT) model to evaluate whether its strict assumptions may have biased previous heritability estimates. RESULTS: The best-fitting NTF model for all informants was the ASFE model, indicating that additive genetic, sibling environmental, familial environmental, and non-shared environmental influences significantly contribute to the etiology of social aggression in middle childhood. However, the best-fitting CT model varied across informants, ranging from AE and ACE to CE. Specific heritability estimates for both NTF and CT models also varied across informants such that teacher reports indicated greater genetic influences and father reports indicated greater shared environmental influences. CONCLUSIONS: Although the specific NTF parameter estimates varied across informants, social aggression generally emerged as largely additive genetic (A = 0.15-0.77) and sibling environmental (S = 0.42-0.72) in origin. Such findings not only highlight an important role for individual genetic risk in the etiology of social aggression, but also raise important questions regarding the role of the environment. PMID- 29607795 TI - Ovarian cycle in Devario aequipinnatus with emphasis on oogenesis. AB - SummaryThis study aimed to understand how germ cell development occurs in females of Devario aequipinnatus, by morphologically describing oogenesis and the reproductive phases. Sexually mature females of D. aequipinnatus (n = 70) were obtained from commercial fisheries and delivered to the Laboratorio de Ictiologia Neotropical, UNESP, Ilha Solteira, SP, Brazil. The ovaries were removed, fragmented and fixed following the usual techniques for light microscopy. The stages of ovarian development in D. aequipinnatus begin with the oogonia, which proliferate into new cells or differentiate into prophasic oocytes that, at the end of this process, form the ovarian follicle and end folliculogenesis. In the previtellogenic stage, the oocytes were characterized mainly by the gradual loss of basophilia and an increase in oocyte diameter. Vitellogenesis was marked mainly by the incorporation of yolk granules. Mature oocytes were defined by their migration from the nucleus to the micropyle. Postovulatory follicles and atresic oocytes were also observed. The reproductive phases were classified as: immature, early and final developing, spawning capable, regressing and regenerating. Therefore, the development of an understanding of cell modifications that occurs up to oogenesis is a basic step that is essential for the description of the reproductive biology of D. aequipinnatus, given the lack of information about the reproductive aspects of this species. PMID- 29607797 TI - Distinguishing the Signs of Fungal and Burial-Induced Degradation in Waterlogged Wood from Biskupin (Poland) by Scanning Electron Microscopy. AB - A scanning electron microscopy (SEM) investigation of pine (Pinus sylvestris) and oak (Quercus sp.) wood samples exposed to various types of natural degradation is presented with the aim of discussing the correct identification of multiple degradation signs in waterlogged wood. This is part of an experiment performed at the archeological site of Biskupin (Poland) to evaluate the dynamics of short term wood degradation during reburial and the suitability of excavated wood as substrate for the fungal attack. The final aim is to support and inform the in situ conservation strategy currently applied to archeological woods. To replicate the burial conditions, wood samples were put into lake water and peat. The samples were removed from the burial environments after 4, 6, 8, and 10 years, and then exposed to laboratory-controlled attack by a brown rot fungus Coniophora puteana and a white rot fungus Coriolus versicolor. SEM images were acquired for all samples before and after the fungal attack. The results showed a slight degradation occurred in the burial environments (soft rot and bacteria). In addition, both typical and previously neglected features of fungal attack were observed, highlighting that the extent of the fungal decay varies according to the previous degree of wood degradation. Some comparisons are provided with archeological wood samples from the Biskupin site. PMID- 29607798 TI - Development of Phasmarhabditis hermaphrodita (and members of the Phasmarhabditis genus) as new genetic model nematodes to study the genetic basis of parasitism. AB - The genetic mechanisms of how free-living nematodes evolved into parasites are unknown. Current genetic model nematodes (e.g. Caenorhabditis elegans) are not well suited to provide the answer, and mammalian parasites are expensive and logistically difficult to maintain. Here we propose the terrestrial gastropod parasite Phasmarhabditis hermaphrodita as a new alternative to study the evolution of parasitism, and outline the methodology of how to keep P. hermaphrodita in the lab for genetic experiments. We show that P. hermaphrodita (and several other Phasmarhabditis species) are easy to isolate and identify from slugs and snails from around the UK. We outline how to make isogenic lines using 'semi-natural' conditions to reduce in-lab evolution, and how to optimize growth using nematode growth media (NGM) agar and naturally isolated bacteria. We show that P. hermaphrodita is amenable to forward genetics and that unc and sma mutants can be generated using formaldehyde mutagenesis. We also detail the procedures needed to carry out genetic crosses. Furthermore, we show natural variation within our Phasmarhabditis collection, with isolates displaying differences in survival when exposed to high temperatures and pH, which facilitates micro and macro evolutionary studies. In summary, we believe that this genetically amenable parasite that shares many attributes with C. elegans as well as being in Clade 5, which contains many animal, plant and arthropod parasites, could be an excellent model to understand the genetic basis of parasitism in the Nematoda. PMID- 29607799 TI - l-Ergothioneine improves the developmental potential of in vitro sheep embryos without influencing OCTN1-mediated cross-membrane transcript expression. AB - SummaryThe objective of the study was to investigate the effect of l ergothioneine (l-erg) (5 mM or 10 mM) supplementation in maturation medium on the developmental potential and OCTN1-dependant l-erg-mediated (10 mM) change in mRNA abundance of apoptotic (Bcl2, Bax, Casp3 and PCNA) and antioxidant (GPx, SOD1, SOD2 and CAT) genes in sheep oocytes and developmental stages of embryos produced in vitro. Oocytes matured with l-erg (10 mM) reduced their embryo toxicity by decreasing intracellular ROS and increasing intracellular GSH in matured oocytes that in turn improved developmental potential, resulting in significantly (P < 0.05) higher percentages of cleavage (53.72% vs 38.86, 46.56%), morulae (34.36% vs 20.62, 25.84%) and blastocysts (14.83% vs 6.98, 9.26%) compared with other lower concentrations (0 mM and 5 mM) of l-erg without change in maturation rate. l-Erg (10 mM) treatment did not influence the mRNA abundance of the majority of apoptotic and antioxidant genes studied in the matured oocytes and developmental stages of embryo. A gene expression study found that the SLC22A4 gene that encodes OCTN1, an integral membrane protein and specific transporter of l-erg was not expressed in oocytes and developmental stages of embryos. Therefore it was concluded from the study that although there was improvement in the developmental potential of sheep embryos by l-erg supplementation in maturation medium, there was no change in the expression of the majority of the genes studied due to the absence of the SLC22A4 gene in oocytes and embryos that encode OCTN1, which is responsible for transportation of l-erg across the membrane to alter gene expression. PMID- 29607800 TI - Feasibility and impact study of a reward-based mobile application to improve adolescents' snacking habits. AB - OBJECTIVE: Adolescents' snacking habits are driven by both explicit reflective and implicit hedonic processes. Hedonic pathways and differences in sensitivity to food rewards in addition to reflective determinants should be considered. The present study evaluated the feasibility and impact of a mobile phone-delivered intervention, incorporating explicit reflective and implicit rewarding strategies, on adolescents' snack intake. DESIGN: Adolescents (n 988; mean age 14.9 (sd 0.70) years, 59.4 % boys) completed a non-randomized clustered controlled trial. Adolescents (n 416) in the intervention schools (n 3) were provided with the intervention application for four weeks, while adolescents (n 572) in the control schools (n 3) followed the regular curriculum. Outcomes were differences in healthy snacking ratio and key determinants (awareness, intention, attitude, self-efficacy, habits and knowledge). Process evaluation data were collected via questionnaires and through log data of the app. RESULTS: No significant positive intervention effects on the healthy snack ratio (b=-3.52 (se 1.82), P>0.05) or targeted determinants were observed. Only 268 adolescents started using the app, of whom only fifty-five (20.5 %) still logged in after four weeks. Within the group of users, higher exposure to the app was not significantly associated with positive intervention effects. App satisfaction ratings were low in both high and low user groups. Moderation analyses revealed small positive intervention effects on the healthy snack ratio in high compared with low reward-sensitive boys (b=1.38 (se 0.59), P<0.05). CONCLUSIONS: The intervention was not able to improve adolescents' snack choices, due to low reach and exposure. Future interventions should consider multicomponent interventions, teacher engagement, exhaustive participatory app content development and tailoring. PMID- 29607801 TI - Developmental sensitivity to cannabis use patterns and risk for major depressive disorder in mid-life: findings from 40 years of follow-up. AB - BACKGROUND: Evidence regarding the association between cannabis use and depression remain conflicting, especially as studies have not typically adopted a longitudinal design with a follow-up period that was long enough to adequately cover the risk period for onset of depression. METHOD: Males from the Cambridge Study in Delinquent Development (CSDD) (N = 285) were assessed seven times from age 8 to 48 years to prospectively investigate the association between cannabis use and risk of major depressive disorder (MDD). A combination of multiple analyses (logistic regression, Cox regression, fixed-effects analysis) was employed to explore the strength and direction of effect within different developmental stages. RESULTS: Multiple regression analyses revealed that early onset cannabis use (before age 18) but not late-onset cannabis use (after age 27) was associated with a higher risk and shorter time until a subsequent MDD diagnosis. This effect was present in high-frequency [(odds ratio (OR) 8.83, 95% confidence interval (CI) 1.29-70.79]; [hazard ratio (HR) 8.69, 95% CI 2.07 36.52)] and low-frequency early-onset users (OR 2.41, 95% CI 1.22-4.76; HR 2.09, 95% CI 1.16-3.74). Effect of increased frequency of cannabis use on increased risk of subsequent MDD was observed only for use during adolescence (age 14-18) but not at later life stages, while controlling for observed and non-unobserved time-invariant factors. Conversely, MDD in adulthood (age 18-32) was linked to a reduction in subsequent cannabis use (age 32-48). CONCLUSIONS: The present findings provide evidence implicating frequent cannabis use during adolescence as a risk factor for later life depression. Future studies should further examine causality of effects in larger samples. PMID- 29607802 TI - Intakes of magnesium, calcium and risk of fatty liver disease and prediabetes. AB - OBJECTIVE: Obesity and insulin resistance play important roles in the pathogenesis of non-alcoholic fatty liver disease (NAFLD). Mg intake is linked to a reduced risk of metabolic syndrome and insulin resistance; people with NAFLD or alcoholic liver disease are at high risk of Mg deficiency. The present study aimed to investigate whether Mg and Ca intakes were associated with risk of fatty liver disease and prediabetes by alcohol drinking status. DESIGN: We analysed the association between Ca or Mg intake and fatty liver disease, prediabetes or both prediabetes and fatty liver disease in cross-sectional analyses. SETTING: Third National Health and Nutrition Examination Survey (NHANES III) follow-up cohort of US adults. SUBJECTS: Nationally representative sample of US adults in NHANES (n 13 489). RESULTS: After adjusting for potential confounders, Mg intake was associated with approximately 30 % reduced odds of fatty liver disease and prediabetes, comparing the highest intake quartile v. the lowest. Mg intake may only be related to reduced odds of fatty liver disease and prediabetes in those whose Ca intake is less than 1200 mg/d. Mg intake may also only be associated with reduced odds of fatty liver disease among alcohol drinkers. CONCLUSIONS: The study suggests that high intake of Mg may be associated with reduced risks of fatty liver disease and prediabetes. Further large studies, particularly prospective cohort studies, are warranted to confirm the findings. PMID- 29607804 TI - IgG4-Associated Inflammatory Pseudotumor with Bilobar Hepatic Foci. PMID- 29607803 TI - Molecular Imaging in Oncology Using Positron Emission Tomography. AB - BACKGROUND: Anatomical and molecular data can be acquired simultaneously through the use of positron emission tomography (PET) in combination with computed tomography (CT) or magnetic resonance imaging (MRI) as a hybrid technique. A variety of radiopharmaceuticals can be used to characterize various metabolic processes or to visualize the expression of receptors, enzymes, and other molecular target structures. METHODS: This review is based on pertinent publications retrieved by a selective search in PubMed, as well as on guidelines from Germany and abroad and on systematic reviews and meta-analyses. RESULTS: Established radiopharmaceuticals for PET, such as 2-[18F]fluoro-2- deoxyglucose ([18F]FDG), enable the visualization of physiological processes on the molecular level and can provide vital information for clinical decision-making. For example, PET can be used to evaluate pulmonary nodules for malignancy with 95% sensitivity and 82% specificity. It can be used both for initial staging and for the guidance of further treatment. Alongside the PET radiopharmaceuticals that have already been well studied and evaluated, newer ones are increasingly becoming available for the noninvasive phenotyping of tumor diseases, e.g., for analyzing the expression of prostate-specific membrane antigen (PSMA), of somatostatin receptors, or of chemokine receptors on tumor cells. CONCLUSION: PET is an important component of diagnostic algorithms in oncology. It can help make diagnosis more precise and treatment more individualized. An increasing number of PET radiopharmaceuticals are now expanding the available options for imaging. Many radiopharmaceuticals can be used not only for noninvasive analysis of the expression of therapeutically relevant target structures, but also for the ensuing, target-directed treatment with radionuclides. PMID- 29607805 TI - Intestinal Ostomy. AB - BACKGROUND: About 100 000 ostomy carriers are estimated to live in Germany today. The creation of an ostomy represents a major life event that can be associated with impaired quality of life. Optimal ostomy creation and proper ostomy care are crucially important determinants of the success of treatment and of the patients' quality of life. METHODS: This article is based on pertinent publications retrieved by a selective search in PubMed, GoogleScholar, and Scopus, and on the authors' experience. RESULTS: Intestinal stomata can be created using either the small or the large bowel. More than 75% of all stomata are placed as part of the treatment of colorectal cancer. The incidence of stoma-related complications is reported to be 10-70%. Skin irritation, erosion, and ulceration are the most common early complications, with a combined incidence of 25-34%, while stoma prolapse is the most common late complication, with an incidence of 8-75%. Most early complications can be managed conservatively, while most late complications require surgical revision. In 19% of cases, an ostomy that was initially planned to be temporary becomes permanent. Inappropriate stoma location and inadequate ostomy care are the most common causes of early complications. Both surgical and patient-related factors influence late complications. CONCLUSION: Every step from the planning of a stoma to its postoperative care should be discussed with the patient in detail. Preoperative marking is essential for an optimal stoma site. Optimal patient management with the involvement of an ostomy nurse increases ostomy acceptance, reduces ostomy-related complications, and improves the quality of life of ostomy carriers. PMID- 29607806 TI - The Expert's Duty of Confidentiality. PMID- 29607807 TI - Fitness to Drive After Sternotomy. PMID- 29607808 TI - In Reply. PMID- 29607809 TI - Leukemia Cutis. PMID- 29607810 TI - Correction of the Definition of MGUS. PMID- 29607811 TI - In Reply. PMID- 29607813 TI - Urine Culture is the Crucial Basis. PMID- 29607812 TI - Guidelines for Interpretation Required. PMID- 29607814 TI - In Reply. PMID- 29607815 TI - Cytomorphologic Spectrum of Hurthle Cell Lesions of Thyroid: A Study of 54 Cases. AB - INTRODUCTION: Lesions of the thyroid gland composed of Hurthle cells constitute a wide spectrum of pathological entities ranging from benign hyperplastic nodules with Hurthle cell metaplasia at one end to malignancies like Hurthle cell carcinomas. The cytological distinction of these entities is not only diagnostically challenging but are also critical since they influence treatment decisions. AIM: To critically analyze the cytomorphology of cases of Hurthle cell lesions in FNACs and to characterize cytological features shown to be statistically signific ant in predicting Hurthle cell neoplasm (HCN). METHODS: During the period from January 2014 to August 2015, 1667 cases of thyroid FNAs were done at our centre, of which 54cases,showed a predominance of hurthle cells, i.e. more than or equal to 50% hurthle cells (>==50%).These cases were included in the study and were critically reviewed for 9 cytomorphologic features which included cellularity, architecture, and percentage of Hurthle cells, background colloid, chronic inflammation, nucleoli, intranuclear cytoplasmic inclusions (INCI), nuclear grooves and transgressing blood vessels (TBV). The results were evaluated by using univariate and stepwise logistic regression (SLR) analysis; statistical significance was achieved at P-value < 0.05. RESULTS: Out of the 9 parameters studied, the cytological features shown to be statistically significant in predicting HCN and distinguishing them from benign hurthle cell lesions(BHCLs) were increased cellularity, non-macro follicular architecture, >90% Hurthle cells, absence of background colloid and absence of chronic inflammation. PMID- 29607816 TI - Rosai-Dorfman Disease - Five Years Retrospective Analysis from Tertiary Cancer Center. AB - AIM: To study the pattern of presentation and management of nodal and extranodal primary RDD. METHODOLOGY: From 2010 to 2015, eleven patients diagnosed with Rosai Dorfman Disease (RDD) presented at our institute. Nine of them were analyzed as they received treatment at our center. We had five neck primaries, three intracranial and one cutaneous disease. Hematological, radiological, histopathological and immunohistochemistry evaluation along with the treatment data was collected and analyzed. RESULTS: Nine cases treated at our institute had a median follow up of 41 months. Four of the five neck node primaries were treated with corticosteroids. Of the four, two had complete and two partial responses locally. Remaining one patient had partial response to surgery and corticosteroids. Three patients with CNS presentation treated with radiotherapy to a total dose of 20-40 Gy, had complete response locally. However, two patients had simultaneous neck nodes during presentation. Partial response was seen with corticosteroids alone in one and with radiation to the neck in the other patient, of which one succumbed to myocardial infarction within 3 months post treatment. Two of them received re-irradiation to the recurrent lesions with good results. CONCLUSION: Due to its rarity there is no particular guidelines regarding the management of patients with RDD. We conclude that low dose radiation either in combination with surgery or corticosteroids in nodal or extranodal lesions has shown a better local control. PMID- 29607817 TI - Lung cancer epidemiology among the Bahraini population, 1998-2011. AB - BACKGROUND: Lung cancer is the fourth most common cancer in the Gulf Cooperation Council countries among males and the third among females. It is the commonest cancer among Bahraini males accounting for 16.9% of all cancers and the third in Bahraini females contributing to 5.8 % of all female cancers. The aim of this study was to describe the epidemiology of lung cancer among the Bahraini population during the period 1998-2011. METHODS: All Bahraini registered lung cancer cases in the national cancer registry from 1 January 1998 to 31 December 2011 were included in the study. Incidence rates were calculated using the CANREG software, in which the annual crude incidence rates, age specific incidence rates and the age standardized incidence rate (ASR) were computed. RESULTS: Six hundred sixty-four lung cancer cases (72.4%, males and 27.6% females) were diagnosed during the study period. The annual average number of cases was 47.5 per year. The mean age at diagnosis during the study period was 68.7+/-11.7 years. The average annual ASR was 26.1/100,000 among males and 10.0/100,000 among females. There was a tendency for a decreased trend of the ASR during 1998-2011 in both sexes. Twenty-six percent of lung cancer cases were squamous cell carcinoma and 17.9% adenocarcinoma. The grades of 70.3% were unknown and 13.4% were poorly differentiated. The stage was unknown for 65.0% of the cases, while 18.5% had distant metastasis and 9.8% were localized. The majority (88.9 %) of the lung cancer cases were dead by the end of the study period with a five-year survival rate of 3.0%. CONCLUSION: A welcomed decline in the incidence of lung cancer has been noted over the past 14 years. However, more efforts should be put to reduce the proportion of lung cancer cases with unknown stage and grade. The incidence of histological types, which are strongly dependent on tobacco smoking, notably small cell, squamous cell and large cell carcinomas, accounted for over one third of lung cancer cases. Future research should be directed towards better understanding of the lung cancer risk factors and the effectiveness of tobacco control measures in in the country. PMID- 29607818 TI - Epidemiology of Colorectal Cancer in Iraq, 2002-2014. AB - OBJECTIVES: After cardiovascular diseases, cancer is one of the major causes of death in Iraq but there is scarcity of data on cancer. This study aimed to estimate the incidence rate of colorectal cancer in Iraq and its distribution and determine its trend in Iraq from 2002 to 2011. METHODS: The necessary data for recording the incidence of colorectal cancer in Iraq were obtained from three main sources including the cancer registry for the period of 2002-2014. Data included information on gender, age, geographical distribution, site of tumors, and histology types. RESULTS: A total of 7,246 cases of CRC were registered in the cancer registry for the period 2002-2011 and 706 cases in the National Cancer Hospital between 2012 and 2014. Male to female ratio varied from 1.17:1 to 1.28:1. About 40%-46% of cases were diagnosed in the age group of 40-59 years. The incidence rate increased from 2.75/105 pop in 2002 to 3.26/105 pop in 2011. Adenocarcinoma constituted 84.0% of all cases. Of the 706 registered cases during 2012-2014, 95% were diagnosed by histology of primary site. The degree of differentiation was moderate in 56% of cases. About 26% of cases were localized, 55.9% and 16% were with regional, and distant metastasis, respectively. CONCLUSION: Iraq has a low CRC incidence rate but with a steady increase overtime. It is crucial to implement preventive strategies to control CRC in Iraq and to establish public awareness program about CRC and the importance of screening. PMID- 29607819 TI - Profile of High Grade Gliomas - A Single Center Experience. AB - INTRODUCTION: The term high grade glioma (HGG), is usually used to describe WHO grade III and IV tumours. There has been a recent increase in incidence of HGGs in the Western world, particularly in the elderly population. This probably reflects the easy availability of vastly improved diagnostic imaging. A five year retroprospective study was planned to study demography, clinical presentation, imaging, surgical intervention, histopathological examination of specimens and postoperative outcome of patients of high grade gliomas. OBJECTIVES: To determine the demographic, clinical, histopathogical and radiological profile of patients of High Grade Gliomas (HGG) and to ascertain post-operative mortality at 24 hours and 7 days Material and Methods: The present study of 226 cases from our institute for the last 5 years (retrospective 3 years and prospective 2 years) extending from August 2010 to July 2015 is based on study about demography, clinical presentation, imaging, surgical intervention, histopathological examination of specimens and postoperative outcome. The clinic-pathological vis-a vis imaging was also studied. The analyzed data from the results and observations of this study were compared with the previous studies. RESULTS: The study was retrospective as well as prospective. Total of 226 patients were registered. Out of these, 225 patients were operated (except one patient). The provisional diagnosis was based on the radio-imaging basis and the final diagnosis confirmed by histopathological examination. Majority of patients operated for HGG, irrespective of the procedure or extent of resection had good surgical outcome after the procedure. CONCLUSION: The overall survival is multifactorial in HGGs. The surgical intervention particularly in patients with features of raised ICP due to mass lesion provides symptomatic relief and improves quality of life in majority of patients and are discharged reasonably in better state of health. PMID- 29607820 TI - Assessment of Sunitinib Alternative Prescription Schedules in Metastatic Kidney Cancer: A Study of 10 Cases. AB - BACKGROUND: Managing metastatic Renal Cell Carcinoma (mRCC) has been revolutionized during the first decade of the 21st century due to the development of targeted therapies. The sunitinib is an oral multi-targeted receptor Tyrosine Kinase Inhibitor (TKI). It became the first targeted therapy as first-line treatment to improve the survival of patients with metastatic kidney cancer. This treatment consists in the oral intake of 50 mg of sunitinib per day in a 6 -week cycle including 4 weeks of treatment intake (the "on" week) followed by a 2-week break (the off week). The strong impact of the treatment dose reduction or discontinuation and the associated adverse effects encouraged the investigators to enquire about other sunitinib schedules: continuous regimen at 37.5 mg of sunitinib, 2 weeks out of 3 at the dose of 50 mg. The aim of this work is to assess the efficiency and the tolerance of the other prescription regimens of sunitinib. METHODS: This is a transversal study conducted from March 2013 until November 2017 in the Oncology/Hematology Center of the Med VI University Hospital Center in Marrakech. All patients under supervision and treatment for metastatic kidney cancer evaluated after 3, 6 and 9 months are part of our study. The parameters studies are epidemiological data, histological type, used protocols efficiency and tolerance. RESULTS: A total of 10 patients under supervision for metastatic kidney cancer were gathered in the Oncology/Hematology Center of the Med VI University Hospital Center in Marrakech. At the end of the 9-month evaluation period, 10 patients (40%) had radiological and clinical stability, 1 patient had complete lesion response, 3 patients had radiological progression and 1 case of death was recorded. As regards toxicity, all different regimen used during the study were well tolerated by the majority of the patients. The toxicities mostly encountered were asthenia, hand-foot skin reactions, mucositis and grade II diarrhea for 4 patients (40%) and 1 case of HTA. In only one case of temporary cessation vomiting and grade II diarrhea were noted. CONCLUSION: The regimen 2/1 appears to be effective and demonstrates a better toxicity profile, treatment adherence, and dose intensity in relation to treatment, suggesting that the 2/1 regimen may become the future standard sunitinib treatment for patients with mRCC. PMID- 29607821 TI - Human Papilloma Virus (HPV) in Sinonasal Papillomas and Squamous Cell Carcinomas: A PCR-based Study of 60 cases. AB - This study was carried out to observe the association of Human Papilloma Virus (HPV) with papillomas and squamous cell carcinomas of the sinonasal region. The present study was a hospital-based study conducted over a period of three years from May, 2014 to May, 2017 in the Department of Pathology, Government Medical College, Srinagar. A total of 196 cases of non-neoplastic and neoplastic lesions of nasal cavity and paranasal sinuses were observed during the study period. Out of total 196 cases, 102 were non-neoplastic and 94 were neoplastic. Of the 94 neoplastic lesions, 58 were benign and 36 were malignant. A total of 60 cases which included 38(63.33%) inverted papillomas, 12(20%) exophytic papillomas and 10 (16.66%) squamous cell carcinomas were included in the present study for HPV association. We studied the association of HPV with sinonasal papillomas and squamous cell carcinomas by polymerase chain reaction (PCR). HPV positivity was seen in 5(13.16%) out of 38 cases of inverted papillomas, whereas 4 out of 12(33.33%) exophytic papillomas tested positive for HPV. Out of 10 squamous cell carcinomas HPV positivity was seen in 2(20%) cases. Low risk HPV types 6 and 11 showed an association with sinonasal papillomas and oncogenic HPV types 16 and 18 with squamous cell carcinomas. PMID- 29607822 TI - Cancer Statistics in Giresun Province, Turkey: A 12-Years Retrospective Review. AB - AIM: The aim of this retrospective study was to analyze 6,613 diagnosed cancer cases in the Black Sea Turkish province of Giresun over a period of 12 years. MATERIAL AND METHOD: Data of this retrospective crosssectional study was collected from 6,613 cancer patients at Prof. Dr. A. Ilhan Ozdemir Education and Research Hospital between 2005- 2016. MINITAB 15 package software was used for statistical analysis. Chi-Square test and differences between two ratios significance test were used to calculate the relationship between two nominal (categorical) variables. RESULTS: Total 6,613 cancer patient's (3,759 men, 56.8% and 2,854 women, 43.2%) average age is 66.27+/-17.17. The most frequent types of cancer found among men included prostate (24.4%), bronchus-lung (12.5%) and colorectal (11.15%) cancer; whilst among for women it was breast (26%), thyroid (14.9%) and skin (10.6%) cancer, respectively. Kidney, bronchus-lung, skin, larynx, breast, bladder and thyroid cancer types were determined to be statistically significant according to gender (p<0.05). CONCLUSION: We reviewed the diagnosed cancer cases in Giresun province from 2005 to 2016. For men, the order of the most frequent cancer types mentioned is consistent with the statistics of both the European Union (EU) as well as the United States of America (USA); whereas for women it was consistent with Turkey's own national statistics. However, our findings state that thyroid cancer is the second most common cancer type among Turkish women, this is in contrast to most other parts of the world, the EU and USA. PMID- 29607823 TI - Risk Factors of Cancer in the United Arab Emirates. AB - Cancer is recognized to be a major healthcare problem globally. Cancer is a disease that mainly occurs when alterations in a normal cell group within the body leads to uncontrolled growth, mainly causing a lump referred to as a tumor. The aim of this study is to systematically review and extract studies reporting the risk factors of cancer in UAE between 2007 and 2016. A systematic literature search was performed by using "PubMed, Scopus databases, Science direct, and local journals" and appropriate key terms to retrieve studies carried out in United Arab Emirates with regards to risk factors of the cancer. 75 articles were extracted in the beginning. After screening for exclusion criteria and retrieval of full texts, overall 16 articles were used in this study. Search limits were restricted to studies in English language, between 2007 and 2016, and on UAE population (both citizens and expatriates). This review yielded 16 studies about the cancer risk factors in United Arab Emirates, including cross sectional studies (n = 9), population-based crosssectional retrospective survey (n = 1), retrospective cohort studies (n = 4) and qualitative studies (n = 2). Tobacco use, unhealthy diet, family history, infection with HPV, physical activity, and radiation exposure were among the factors investigated. There was insufficient evidence available on some potentially essential risk factors such as use of alcohol, aging, and being overweight. This systematic review signifies an increasing cancer prevalence in the United Arab Emirates and suggests that extra effort is needed with a multi-sectorial approach in future at both the national and international level to effectively tackle the burden of cancer. PMID- 29607824 TI - Lymphoid proliferation in Eyelid: A Primary Follicular Lymphoma Case. AB - Ocular adnexal lymphoma (OAL) constitutes 8% of all extranodal lymphomas, being rare in the eyelids (5-20%). The objective was to report a case of eyelid follicular lymphoma in a young adult woman. A 35-year-old female with swelling in left lower eyelid with development for 2 months. The visual acuity was 20/20 in both eyes, the tumor mass was 3 cm wide and 1.5 cm long. The contrast-enhanced computed tomography showed a soft-tissue injury in the left lower eyelid but had no signs of local spread according to description. Grade 2 follicular lymphoma was diagnosed by biopsy. Oncological evaluation assessed positron emission tomography scan and bone marrow aspiration with negative results for systemic spread of disease. Patient started radiotherapy. This case highlights that young patients may present painless swelling lesions that may be largely underdiagnosed and should take into consideration some oncological pathologies. PMID- 29607826 TI - Tumor Recurrence at Donor Site of Pectoralis Major Myocutaneous Flap with Tumor free Primary Oral Carcinoma. AB - Pectoralis major myocutaneous flap is an important option for post onco reconstruction in head and neck region. Among the several complications mentioned in the literature, tumor recurrence at the donor site of flap is late and rare complication. Tumor implantation at the donor site of flap is a possible explanation. The occurrence of this type case is rare. We are reporting a case of tumor recurrences of pectoralis major myocutaneous flap donor site without presence of index tumor or detectable systemic disease. The recurrence was operated in our case. Clinicians should be aware of this condition for better management of patients with similar presentation. PMID- 29607825 TI - Transanal Minimally Invasive Surgery (TAMIS), First in Kuwait: A Case Report. AB - Transanal Minimally Invasive Surgery (TAMIS) is a one of new platform used to help and achieve better outcome in using transanal approach for the treatment of rectal neoplasm. High definition camera and high tech equipment are used to perform this kind of surgery. The main benefit of using this approach is to provide the best outcome or the patient compared to the traditional transanal approach. This platform can be used for a variety of cases, benign and malignant tumor and for the benign condition. We report the first TAMIS perfo b rmed in the Kuwait and probably in the Middle East with 2 years of follow up. We had no complication and patient returned home and to normal activity in next day. More studies needed to validate this technique. PMID- 29607827 TI - Vaginal metastasis of renal clear-cell cancer. AB - BACKGROUND: Vaginal metastases originating from renal cancer remain a rare event, with less than 100 cases reported in the literature. The spreading mechanism is still under scrutiny. The tumoral bleeding often is a symptom revealing vaginal metastases. CASE: The present work reports patient case having vaginal metastasis of renal clear-cell cancer. The vaginal metastasis was treated by a 3-D conformational radiotherapy. Our experience is discussed with respect to an updated literature review concerning the medical management of vaginal metastasis related to kidney cancer. CONCLUSION: In our case, a 15 Gy hypofractionatedradiotherapy is efficient to control bleeding on the vaginal metastases of the kidney cancer. To add up a 15 Gy hypofractionated-radiotherapy in 5 fractions is an option if bleeding is still present. The tolerance of the treatment is excellent and no side effects have been described. PMID- 29607828 TI - T cell Large Granular Lymphocytic Leukemia with Pulmonary Hypertension. AB - T cell large granular lymphocytic leukemia is a hematological disorder which is characterized by the proliferation of CD 3+ cytotoxic T cells. We present a case about a patient who was diagnosed with T cell large granular lymphocytic leukemia and then developed pulmonary hypertension. He was treated for his leukemia with methotrexate and simultaneously treated for his pulmonary hypertension with selexipag and ambrisentan. As his leukemia improved, we also noticed an improvement in his pulmonary hypertension from a NYHA class IV to class I. Hence, we believe there is an etiopathological link between the T cell large granular leukemia and associated pulmonary hypertension. PMID- 29607829 TI - Fatal Outcome of Recurrent Infantile Pelvic Desmoid Tumor Treated with Tamoxifene. AB - Desmoid tumors are rare benign neoplasms with an aggressive local growth. In children, intra-abdominal localization is less frequent and few reports exist in the literature about the management of DTs in those special patients. In our report, we describe a case of a 13-year old patient with a bifocal intra abdominal DT, treated unsuccessfully with tamoxifene, and we discuss briefly the existing literature data. PMID- 29607830 TI - Pedodontist at play-"Say Ahh" WHO campaign. PMID- 29607831 TI - Audiovisual distraction methods for anxiety in children during dental treatment: A systematic review and meta-analysis. AB - Background: Dental treatment can cause symptoms such as fear and anxiety. Audiovisual distraction (AD) is a simple and low-cost technique that does not interfere with the dental treatment. Aim: The aim of this study was to perform a systematic review and meta-analysis to evaluate the effectiveness of AD methods for children who experience anxiety during dental treatment. Materials and Methods: Two reviewers performed a database search of the studies published between January 1950 and November 2015. The inclusion criteria were papers published in the English language, child samples aged 4-10 years, and use of AD. All potentially relevant studies were identified by the title and the abstract. After the full-text analysis of the potentially relevant studies, the selected studies were included in the systematic review. A meta-analysis calculation was performed for the overall data and the subgroup data. Results: Thirty-seven nonduplicated studies were found. However, after reviewing the articles, only five were included. A high variability was observed among the papers. Tools and questionnaires used to measure the anxiety during dental treatment presented the most common variability. Meta-analysis demonstrated a lower anxiety level in AD method groups when Modified Child Dental Anxiety Scale was used (P = 0.02) with a mean difference (confidence interval) of -8.72 (-16.7, -1.38). Conclusion: The AD method is effective for controlling dental anxiety in children. PMID- 29607832 TI - Morphological and dimensional characteristics of dental arch in children with beta thalassemia major. AB - Background and Objectives: The aim of this study was to examine the arch dimensions of beta thalassemia major patients in comparison with normal individuals. Materials and Methods: Dental arch dimensions were compared between thalassemic patients and normal individuals in the age group of 12-16 years in the maxillary and mandibular arch corresponding to each other regarding age, sex and Angle's molar relationship. A total number of sixty cases in each group were taken. Maxillary and mandibular impressions were made with alginate for all the sixty participants in each group and poured with die stone. Measurement of inter incisor, inter canine, inter premolar and intermolar arch width, arch depth, right anterior, right posterior, left anterior, and left posterior arch length was carried out from each cast using digital Vernier caliper. Results: Unpaired t test was used for comparison between the two groups. Statistically, a significant difference was found between the case and control groups in the maxillary arch in intercanine width, inter premolar width, intermolar width, right anterior arch length, right posterior arch length, and left anterior arch length. However, no statistically significant difference was found between the groups in inter incisor width, left posterior arch length, and arch depth in the maxillary arch. In the mandibular arch, statistically significant difference was found between the case and control groups in inter canine width, inter premolar width, inter molar width, and left anterior arch length. However, no statistically significant difference was found between the case and control groups in the mandibular arch in interincisor width, right anterior arch length, right posterior arch length, and left posterior arch length. Conclusion: Dental arch widths and arch lengths were significantly reduced in thalassemic patients as compared to normal individuals for the maxillary and mandibular arches. PMID- 29607833 TI - Assessing clinical sequelae of untreated caries among 5-, 12-, and 15-year-old school children in ambala district: A cross-sectional study. AB - Background: Dental caries is a public health problem globally, especially in children. Thus, it is important to quantify its clinical consequences in terms of its prevalence and severity. Aim: This study aims to assess the prevalence and severity of oral conditions linked with untreated dental caries using pulp involvement, ulceration, fistula, abscess (pufa/PUFA) index in 5-, 12-, and 15 year-old school children in Ambala district. Settings and Design: This cross sectional study was conducted among 433 school children of 5-, 12-, and 15-year old age group in Ambala district. Materials and Methods: In the present study, participants were recruited from randomly selected schools and were examined according to pufa/PUFA index and Oral Health Surveys Dentition Status. Statistical Analysis Used: Data were analyzed using SPSS Software Version 20.0 (Chicago, USA). The statistical significance was determined by Chi-square test, and level of significance was set at P < 0.05. Correlation analysis was expressed in terms of Pearson's correlation coefficient (r). Results: Caries prevalence was reported to be 58.4% while the prevalence of odontogenic infections was 45.3%. Untreated caries pufa/PUFA ratio among 5, 12, and 15 years old was 44.58%, 38.33%, and 36.18%, respectively. The care index among 5, 12, and 15 years old was 0, 3.31%, and 36.18% emphasizing the lack of utilization of dental services by school children. Conclusions: The use of PUFA/pufa index as an adjunct to the classical caries indices can address the neglected problem of untreated caries and its consequences. PMID- 29607834 TI - Knowledge, attitude, and behavior of nurses toward delivery of Primary Oral Health Care in Dakshina Kannada, India. AB - : Majority of young children in many countries do not visit dental clinics for examinations before the age of three though they frequently visit primary health care providers for routine medical check-ups. Nurses are easily accessible and are in frequent contact with waiting mothers and children for routine check-ups and this provides an opportunity to integrate oral health promotion and care into health care. The purpose of this study was thus to study the knowledge, attitude and behaviour towards oral health care among nurses. Methods: The study was a cross-sectional questionnaire survey. Total of 170 medical nurses working in the Institutional Hospital and who provided care for paediatric patients and pregnant mothers participated in the study. Statistical Analysis: Chi-Square test was used to analyse the data using SPSS version 17.0 with a significance value of P < 0.05. Results: All the nurses were aware that good oral health is important for overall health of the child. About 70% of the respondents had poor knowledge regarding dental caries. Good response was obtained regarding importance of oral hygiene maintenance for both the child and mother for prevention of caries. Majority of the nurses showed positive attitudes toward preventive OHC and the role of medical nurses. Routinely the nurses do not refer pregnant mothers and children for dental check up nor do they counsel them regarding oral hygiene and its importance. Conclusion: Appropriate training and encouragement for promotion of oral health and to provide suitable care for the prevention of dental diseases should be included in the curriculum of nurses training. PMID- 29607835 TI - Comparative evaluation and applicability of three different regression equation based mixed dentition analysis in Northern Uttar Pradesh population. AB - Aims: This study aims to examine the accuracy and comparative correlation of three regression equation-based mixed dentition analysis in children of Moradabad city, North Uttar Pradesh. Settings and Design: Tanaka-Johnston, Bernabe-Flores Mir, and Ling-Wong regression equations were developed from a sample of North European, Peru, and Southern Chinese children population, respectively. Hence, it becomes questionable when applied to children of Moradabad city situated in North Uttar Pradesh, India. Subjects and Methods: The study was conducted on a sample of 100 school going children, age range is 11-14 years with complete permanent teeth except third molars. The mesiodistal crown dimensions of all erupted incisors, canines, premolars, and molars were measured with digital calipers with a calibration accuracy of 0.01 mm. The actual tooth measurements were then compared with predicted values using Tanaka-Johnston, Bernabe-Flores-Mir, and Ling-Wong regression equations, respectively using paired t-test. Results: The mean difference between the actual and estimated values of canines and premolars using Tanaka-Johnston, Bernabe-Flores-Mir, and Ling-Wong were clinically and statistically significant (P< 0.001). Conclusions: Mesiodistal dimensions of male samples are larger than female samples. All the three regression equations are not accurately applicable to this population. PMID- 29607836 TI - Impact of oral health-related behaviors on dental caries among children with special health-care needs in Goa: A cross-sectional study. AB - Background: Children with special health-care needs (CSHCNs) have high unmet dental needs and are at increased risk of poor oral health. The aim of the present study was to evaluate the relationship between oral health behavior and dental caries experience among CSHCN. Materials and Methods: The cross-sectional study sample comprised of 223 CSHCNs from special educational schools in Goa. A self-administered parental questionnaire was used to collect data on sociodemographic characteristics and oral health behavior variables. Type III clinical examination for dental caries was done using the World Health Organization criteria. Statistical analysis was done using SPSS version 19.0. Results: The mean age of the study sample was 13.85 +/- 7.2 years. Seventy-two percent of the study sample had never visited a dentist. Majority of the study participants (57.4%) brushed their teeth once daily. The caries prevalence was 68.6%. The mean decayed, missing, and filled teeth index for permanent dentition and primary dentition of the study participants was 2.83 +/- 3.23 and 0.35 +/- 1.00, respectively. Dental caries was significantly associated with frequency of brushing and dental visits. Conclusion: The caries experience was high among children with special needs in Goa. There is a significant association between oral health behavior and dental caries experience. Oral health promotion may lead to reduction in dental caries level, thus reducing the emotional, physical, and financial drain on their caregivers. PMID- 29607837 TI - Oral health and glycosylated hemoglobin among type 1 diabetes children in South India. AB - Background: The study was an attempt to evaluate the relationship between oral health status and the level of glycemic control in type 1 diabetes patients. Methods: The study was carried out in 87 children with type 1 diabetes, aged 8-16 years, attending a diabetes specialty hospital. The oral health of these patients was measured using the WHO 1997 Oral Health Survey criteria for diagnosis of dental caries, gingival index, and plaque index. Samples were then divided into two groups as controlled (<=6.99% glycosylated hemoglobin [HbA1c]) and uncontrolled (>=7% HbA1c) diabetes as per the guidelines for glycemic control in diabetics given by the American Diabetes Association. The oral health between the groups was compared. Results: Data were statistically analyzed using student t test. Results showed a significant difference in decayed, missing, and filled surface component (P = 0.043) and gingival index scores (P< 0.001) in the permanent dentition between controlled and uncontrolled groups but not in case of the primary dentition. Conclusions: The data findings suggest that metabolic control had an impact on caries prevalence and gingival health of these patients, in case of permanent dentition. As the glycemic control became poorer, the caries prevalence and gingival inflammation increased. When primary dentition was taken into consideration, the correlation was not significant. PMID- 29607838 TI - Estimation of malondialdehyde levels in serum and saliva of children affected with sickle cell anemia. AB - Background: Sickle cell anemia (SCA) is an inherited disorder of hemoglobin synthesis characterized by deformed erythrocytes. Hemoglobin S present in sickle shaped erythrocytes exhibits an enhanced rate of auto-oxidation compared with normal hemoglobin A. It produces more of reactive oxygen species (ROS) which promotes oxidatively stressed environment. ROS degrade the membranes of sickle cell erythrocytes composed of polyunsaturated lipids and form malondialdehyde (MDA) as a by-product. Aim: The aim of the study is to evaluate and compare the MDA levels of serum and saliva in SCA patients. Design: A total of 150 children aged 4-12 years were divided into two groups: Group A (n = 75) consisting of children suffering from SCA and Group B (n = 75) consisting of healthy children. Blood and saliva samples were collected aseptically from both the groups, and they were subjected to thiobarbituric acid assay. Absorbance was evaluated spectrophotometrically at 531 nm, and the values of concentration of MDA were derived. Results: The mean MDA levels in serum and saliva were 8.9825 +/- 1.04 and 0.5152 +/- 0.28, respectively, in Group A and they were found to be higher than mean MDA levels of serum (5.87 +/- 0.92) and saliva (0.2929 +/- 0.06) of Group B and the difference of their mean was found to be statistically significant. Conclusion: A significant correlation of the MDA was found in saliva and serum of the patients with SCA. This finding suggests that saliva can be effectively used as a noninvasive alternative for assessing the oxidative stress in patients with SCA. PMID- 29607839 TI - Antibacterial effect of propolis derived from tribal region on Streptococcus mutans and Lactobacillus acidophilus: An in vitro study. AB - Aim: The study aimed at investigating in vitro antimicrobial activity of ethanolic extract of propolis (EEP) and water extract of propolis against two main cariogenic oral pathogens: Streptococcus mutans and Lactobacillus acidophilus. Material and Methodology: Propolis was obtained from beehives in the Jhabua region of India. Ethanolic and water extracts were prepared at concentrations of 5% and 20% weight/volume (w/v). To support the results, a positive control (chlorhexidine 0.2%) and a negative control (distilled water) were used. S. mutans was cultured on brain-heart infusion agar and L. acidophilus was cultured on De Man, Rogosa, and Sharpe agar. Results: The results showed that at concentrations of 5% and 20%, EEP was effective against S. mutans and L. acidophilus. However, at similar concentrations, water extract was effective only against L. acidophilus. The highest activity was shown by chlorhexidine (0.2%) with mean zones of inhibition of 13.9 mm and 15.1 mm against S. mutans and L. acidophilus, respectively. Conclusion: It can be concluded that the propolis extracted from tribal regions of Jhabua possesses antibacterial efficacy against S. mutans and L. acidophilus. PMID- 29607841 TI - Evaluation of nickel releasing from stainless steel crowns regarding to "trimming": An in vitro study. AB - Context: Stainless steel crowns (SSCs) are the most durable and effective restorations for the primary teeth. Allergy to nickel as major components is common. Aims: The purpose of this study is to evaluate the effect of pH, time, oral temperature, and SSCs trimming on the nickel releasing. Settings and Design: This in vitro study was done on 18 same size crowns. Subjects and Methods: Group A (without trim 0 and Group B (with trim) were immersed in 5 ml artificial saliva. The amount of nickel releasing in each 18 subgroup composed from 3 pH (3.5, 5, and 6.75) and 3 temperatures (27 degrees C, 37 degrees C, and 47 degrees C) in 3 times (1, 7, and 21 days), was measured by Atomic Absorption Spectrophotometer. Statistical Analysis: Data were analyzed by SPSS software (SPSS 20, IBM, Armonk, NY, USA) and use of t-test, Duncan, and Tukey's test for analysis of variances. Results were reported with 95% confidence. Results: The amount of nickel releasing reduced with crown trimming, significantly (P = 0.0001). A significant difference was observed in the amount of released nickel in temperature 47 degrees C in comparison with 37 degrees C (P = 0.0001); this measurement was not significant between 47 degrees C and 27 degrees C (P = 0.442). There was no significant difference between concentration of released nickel in 3 pH conditions and also in 3-time situations. The concentration of nickel was lower in trimmed group in comparison to intact group (P = 0.0001). Conclusions: The concentration of released nickel decreased with trimming of margins and increased when temperature increased. Time and pH had no significant effect on released nickel. PMID- 29607840 TI - A quantitative analysis of total carbohydrate content from the salivary expectorants in young children. AB - Background: In this postfluoride era, the concentration of fermentable carbohydrate in saliva after food intake is important to determine the risk of developing dental caries. Aim: The aim of this study is to estimate the total carbohydrate content of salivary expectorants following consumption of commercially processed snacks. Design: Thirty children aged 6-8 years were selected for estimation of total carbohydrate content of salivary expectorants using modified calorimetric anthrone-sulfuric acid-glucose reaction. The test foods analyzed were as follows: Test food A - potato chips, Test food B - glucose biscuits, Test food C - Oreo biscuits, Test food D - cake, and Test food E - cornflakes. The data obtained were analyzed using student's t-test and ANOVA. Results: The difference between the mean carbohydrate values of salivary expectorants of various processed test food groups at 0 and 10 min was statistically significant (P <= 0.001). After 10 min interval, cornflakes were found to have highest total carbohydrate content in salivary expectorant (5.186 mg/ml). Conclusion: The foods with high starch content such as cornflakes and potato chips exhibited higher total carbohydrate content, thus depicting lower salivary clearance rate. PMID- 29607842 TI - A clinicoradiographic comparison of the effects of platelet-rich fibrin gel and platelet-rich fibrin membrane as scaffolds in the apexification treatment of young permanent teeth. AB - Aims: This triple blinded clinical trial was undertaken to check whether Platelet rich firin in its membrane form is as reliable as when it is in the gel form. Settings and Design: Triple blinded randomized clinical trial. Methods and Material: 20 patients in PRF gel group and 20 patients in PRF membrane group selected after randomization and considering inclusion and exclusion criteria were taken up for this study. The samples were clinically and radiographically evaluated for success. Results and Conclusions: Regenerative endodontics with PRF membrane is easier and less time consuming. They have similar clinical success.PRF gel gave a better radiographic success in 12 months period. PMID- 29607843 TI - A comparative In vivo efficacy of three spiral techniques versus incremental technique in obturating primary teeth. AB - Background: The aim of this study was to evaluate the efficiency of four different obturating techniques in filling the radicular space in primary teeth. Materials and Methods: This clinical trial was carried out on 34 healthy, cooperative children (5-9 years) who had 63 carious primary teeth indicated for pulpectomy. They were divided into four groups, such that in each group, a total of 40 canals were allotted for obturation with respective technique. The root canals of selected primary teeth were filled with Endoflas obturating material using either bi-directional spiral (Group 1); incremental technique (Group 2), past inject (Group 3) or lentulo spiral (Group 4) according to the groups assigned. The effectiveness of the obturation techniques was assessed using postoperative radiographs. The assessment was made for a depth of fill in the canal, the presence of any voids using Modified Coll and Sadrian criteria. The obtained data were analyzed by using ANOVA test and unpaired t-test. Results: Bi directional spiral and lentulo spiral were superior to other techniques in providing optimally filled canals (P< 0.05). The bi-directional spiral was superior to lentulo spiral in preventing overfill (P< 0.05). Conclusion: Based on the present study results, bi-directional spiral can be recommended as an alternate obturating technique in primary teeth. PMID- 29607844 TI - RMS tactile scale: An innovative tactile anxiety scale for visually impaired children. AB - Introduction: Behavior guidance is considered to be the backbone of pediatric dentistry which differentiates us from the other fields in dental sciences. Anxiety and fear being the primary concern in pediatric patients, has to be taken into consideration for the visually impaired children too. In the present study, an innovative anxiety scale RMS tactile scale (RMS-TS) was designed for the visually impaired children. Introducing newer concept other than Braille in the dental clinic for such patients can help in coping up and bringing out positive behavior in the special children. Aims and Objective: The study aimed to validate and assess the efficacy of RMS-TS for visually impaired child and compare it with modified dental anxiety scale (MDAS) and Braille scale. Materials and Methods: A total of hundred children of age 12-15 years from the special school were selected for the study. MDAS, RMS-TS, and Braille scale were used to determine the pretreatment anxiety scores in the visually impaired children. Results: The validity of the RMS-TS in the pretreatment anxiety in the assessment of child's dental anxiety is supported by its strong correlation with both the scales. Conclusions: The RMS-TS can be reliable anxiety assessment scale for measuring child's dental anxiety in visually impaired children. It can be used alone or in combination with other methods to improve assessment of dental anxiety. PMID- 29607845 TI - Impact of oral health education by audio aids, braille and tactile models on the oral health status of visually impaired children of Bhopal City. AB - Context: Children with special needs face unique challenges in day-to-day practice. They are dependent on their close ones for everything. To improve oral hygiene in such visually impaired children, undue training and education are required. Braille is an important language for reading and writing for the visually impaired. It helps them understand and visualize the world via touch. Audio aids are being used to impart health education to the visually impaired. Tactile models help them perceive things which they cannot visualize and hence are an important learning tool. Aim: This study aimed to assess the improvement in oral hygiene by audio aids and Braille and tactile models in visually impaired children aged 6-16 years of Bhopal city. Settings and Design: This was a prospective study. Materials and Methods: Sixty visually impaired children aged 6 16 years were selected and randomly divided into three groups (20 children each). Group A: audio aids + Braille, Group B: audio aids + tactile models, and Group C: audio aids + Braille + tactile models. Instructions were given for maintaining good oral hygiene and brushing techniques were explained to all children. After 3 months' time, the oral hygiene status was recorded and compared using plaque and gingival index. Statistical Analysis Used: ANNOVA test was used. Results: The present study showed a decrease in the mean plaque and gingival scores at all time intervals in individual group as compared to that of the baseline that was statistically significant. Conclusions: The study depicts that the combination of audio aids, Braille and tactile models is an effective way to provide oral health education and improve oral health status of visually impaired children. PMID- 29607846 TI - Integration of oral health in primary health care through motivational interviewing for mothers of young children: A pilot study. AB - Introduction: Early childhood caries (ECC) continues to affect children worldwide. In India, primary health centers (PHCs) comprises the primary tier where Accredited Social Health Activist (ASHA) provide integrated curative and preventive health care. The aim of the study was to pilot test the integration of oral health in primary health care through motivational interviewing (MI) for mothers of young children provided by ASHAs. Subjects and Methods: The pilot study was conducted in Kashipur, Uttarakhand. From the six PHCs in Kashipur, three were randomly selected, one each was assigned to MI group, traditional health education group, and control group. From 60 mothers with 8-12 months child, ASHAs of all three groups gathered mother's knowledge regarding child's oral health using close-ended questionnaire and diagnosed clinical risk markers of ECC in children and ASHAs of Group A and B imparted the oral health education as per their training. Results: The comparison of ASHA's performances on the MI training competency pre- and post-test showed an overall average of 74% improvement in post-test scores. Interexaminer reliability of the parallel clinical measurements by 6 ASHAs and the investigator for the maxillary central incisors showed 93% of agreement for both dental plaque and dental caries assessment with 0.86 and 0.89 kappa values, respectively. Conclusion: The health education through MI is feasible and can be cost-effective by utilization of ASHAs at PHCs to provide the oral health education to mothers which will in turn improve the oral health status of children. PMID- 29607847 TI - Bilateral congenital mucous extravasation phenomenon: A rare case with literature review. AB - The purpose of this paper is to discuss a rare case of bilateral congenital mucous extravasation phenomenon on buccal mucosa near commissure of mouth. The lesions were noted at birth, subsequently enlarged to interfere with feeding. The lesion frequently ruptured, regressed, and again enlarged to interfere with normal function. The lesions were surgically removed under general anesthesia at 11 months of age and the diagnosis was confirmed by histopathological examination. Postoperative follow-up after 14 months showed no recurrence. PMID- 29607848 TI - Neonatal osteomyelitis: An unusual complication of natal tooth extraction. AB - Osteomyelitis of mandible, if it affects the neonate presents as a diagnostic and therapeutic challenge to the clinician. Symptoms and signs are often non specific, and the consequences of a missed diagnosis could lead to long-lasting functional limitations. A rare case of a 52 days old infant with osteomyelitis of the mandible following natal tooth extraction is presented in this report. The diagnosis, pathogenesis and management have been explained. The accompanying review briefly summarizes the main clinical, pathophysiological and radiological aspects of the condition and gives an update on the treatment. PMID- 29607849 TI - From birth till palatoplasty: Prosthetic procedural limitations and safeguarding infants with palatal cleft. AB - The most imminent issue to be addressed in a child born with cleft lip and/or palate is restoration of normal feeding. Early surgical treatment for cleft repair is crucial but may need to be postponed until certain age and weight gain is attained in an infant. When other feeding interventions fail in these children, prosthetic obturation of the defect with feeding instructions in the interim period is indicated to ward off the prevailing concerns. However, the entire prosthetic management presents a significant challenge with respect to the child's age, scope of iatrogenic injury to the delicate oral tissues, and potential for life-threatening situation during the procedures. This article draws attention toward preemptive measures which should be undertaken in the clinical setting during the fabrication of obturator to ascertain a desirable outcome without experiencing a grave complication that may arise due to ignorance and/or lack of facilities. PMID- 29607850 TI - The neuroprotection effect of oxygen therapy: A systematic review and meta analysis. AB - This study reviews the oxygen therapy (normobaric oxygen [NBO] and hyperbaric oxygen [HBO]) in both stroke and traumatic brain injury (TBI) patients and meta analyzes the efficacy of two oxygen therapies in different kinds of injuries. In stroke patients, NBO showed significant improvement in reperfusion rate while there is no favorable outcome effect of HBO treatment. In patients with TBI, HBO showed significant improvement of Glasgow outcome scale score and reduction of overall mortality while NBO may play a favorable role in improving brain metabolism. PMID- 29607851 TI - Evaluation of the fracture resistance of computer-aided design/computer-aided manufacturing monolithic crowns prepared in different cement thicknesses. AB - Introduction: The purpose of this study was to evaluate the fracture resistance of monolithic computer-aided design/computer-aided manufacturing (CAD/CAM) crowns that are prepared with different cement thickness. Materials and Methods: For this investigation, a human maxillary premolar tooth was selected. Master model preparation was performed with a demand bur under water spray. Master die was taken to fabricate 105 epoxy resin replicas. The crowns were milled using a CEREC 4 CAD/CAM system (Software Version, 4.2.0.57192). CAD/CAM crowns were made using resin nanoceramic, feldspathic glass ceramic, lithium disilicate, and leucite reinforced ceramics. Each group was subdivided into three groups in accordance with three different cement thicknesses (30, 90, and 150 MUm). Crowns milled out. Then RelyXTM U200 was used as a luting agent to bond the crowns to the prepared samples. After one hour cementations, the specimens were stored in water bath at 37 degrees C for 1 week before testing. Seven unprepared and unrestored teeth were kept and tested as a control group. A universal test machine was used to assume the fracture resistance of all specimens. The compressive load (N) that caused fracture was recorded for each specimen. Fracture resistance data were statistically analyzed by one-way ANOVA and two-factor interaction modeling test (alpha = 0.001). Results: There are statistically significant differences between fracture resistances of CAD/CAM monolithic crown materials (P < 0.001). It is seen that cement thickness is not statistically significant for fracture resistance of CAD/CAM monolithic crowns (P > 0.001). Conclusions: CAD/CAM monolithic crown materials affected fracture resistance. Cement thickness (30, 90, and 150 MUm) was not effective on fracture resistance of CAD/CAM monolithic crowns. PMID- 29607852 TI - Beliefs, perceptions, and views of pregnant women about cesarean section and reproductive decision-making in a specialist health facility in Enugu, Southeast Nigeria. AB - Context: Through the process of socialization, women and men are conditioned to behave and play different roles in society. While the African culture "rewards" women who have vaginal birth despite the cost to their health, the burden of reproductive decision-making is placed on the menfolk. However, these seem to be changing. Aims: Our aim was to assess the beliefs and perceptions of pregnant women about cesarean section (CS), including their views regarding decision making on the mode of delivery, in Enugu, Southeast Nigeria. Settings and Design: : A cross-sectional descriptive study. Subjects and Methods: A structured questionnaire was administered to 200 pregnant women, following an oral informed consent. Statistical Analysis Used: : Statistical Package for the Social Sciences version 17 with descriptive statistics of frequencies and percentages. Results: All the respondents believe that CS is done for the safety of the mother/baby. Thirteen percent reject the procedure for themselves no matter the circumstance. Joint decision-making was the view of two-thirds of the women. Majority of them will accept CS if their husbands consent. Younger women were of the view that husbands decide on the delivery mode (P = 0.019). Conclusions: Culture remains an impediment to CS uptake. Most women preferred joint decision-making on the mode of delivery. PMID- 29607853 TI - Evaluation of oral health status and influential factors in children with autism. AB - Aims: The aim of the present study was to comparatively analyze oral health status and influential factors in children with autism living in the Western Mediterranean Region of Turkey. Subjects and Methods: This cross-sectional study was conducted in two steps: 1 - questionnaire and 2 - interview. This study was conducted at the Department of Pediatric Dentistry, Faculty of Dentistry, Suleyman Demirel University, Isparta, Turkey, within the period from March to July 2016. Although the questionnaire part involved 126 children with autism and 111 children without autism, 63 children who did not satisfy the inclusion criteria were excluded from the study in the interview part. The forms were sent to previously determined schools, and factors such as age, socioeconomic status, medical history, dental history, eating habits, bad habits, and treatment methods preferred by children's parents were analyzed. Later, interviews with the children were carried out by the same researcher and their oral health conditions were recorded. Results: Children with autism often have nutritional problems, and early initiation of special education appears effective in preventing these conditions. Although children with autism apply for dental services, the rate for these children receiving dental services is considerably low and most of the services rendered are tooth extractions. Conclusion: It appears that the oral status of children with autism is affected negatively by many factors. Thus, the parents, the educators, and the dentists should be aware of this fact and encouraged to improve such children's oral hygiene and provide the dental care they need. PMID- 29607854 TI - Risk factors for breast cancer among Indian women: A case-control study. AB - Background: Breast cancer is the most common malignancy among females all over the world. The incidence of breast cancer is persistently on the rise due to urbanization and lifestyle changes. Although various risk factors have been suggested for estimating the risk of developing breast cancer, most of these have been studied in the Western population. A better understanding of local characteristics of risk factors may help in devising locally effective prevention strategies for breast cancer. The primary objective of the study was to study the risk factors for carcinoma breast among Indian women. Materials and Methods: This was a case-control study, conducted from January 2011 to December 2012, at a tertiary level teaching institution. A total of 100 patients of Indian origin, attending the General Surgery Department with carcinoma breast during this period were the cases. Controls were the blood relatives of patients with other diagnosed malignancies. Results: The major risk factors for breast cancer are found to be age, diet, waist size, hip size, waist-hip ratio (WHR), body mass index, high-density lipoprotein cholesterol, triglyceride, more than three pregnancies, number of years of menstruation, atypical hyperplasia in the previous biopsy, and history of carcinoma in relatives. Conclusions: Waist size and WHR are the major risk factors for carcinoma of breast. Adequate exercise and weight control are the most effective lifestyle changes that can reduce the risk of developing breast cancer. PMID- 29607855 TI - Factors associated with sarcopenia among older patients attending a geriatric clinic in Nigeria. AB - Context: Aging is characterized by progressive and generalized loss of skeletal muscle mass and strength called sarcopenia which causes poor health and disability. There is paucity of data on this syndrome of public health importance among older Nigerians. Aim: This study determined the prevalence and factors associated with sarcopenia among persons aged 60 years and above at a geriatric center in Nigeria. Materials and Methods: A cross-sectional study of 642 persons aged >=60 years who attended the geriatric center between March and July 2014. Sarcopenia was diagnosed using the European Working Group on Sarcopenia in Older People criteria. Bivariate and multivariate analyses were carried out using SPSS 20. Alpha was set at 0.05. Results: The mean age +/- standard deviation of the respondents was 69.1 +/- 7.2 years, and 378 (60.6%) were females. The point prevalence of sarcopenia was 5.4% which was significantly higher among the females compared with the males (7.1% vs. 2.8%) P = 0.02. Low muscle mass and low gait speed were found in 10.9% and 36.1%, respectively. Logistic regression analysis showed age (odds ratio [OR] =1.090; 95% confidence interval [CI] =1.034 1.149, P = 0.01), having no formal education (OR = 2.810; 95% CI = 1.043-7.573, P = 0.04), malnutrition (OR = 5.817; 95% CI = 1.471-23.434, P = 0.01), and female gender (OR = 3.068; 95% CI = 1.068-8.817, P = 0.04) to be the predictors of sarcopenia. Conclusion: Older people in this setting are at risk of developing sarcopenia, especially the females. Healthcare workers should address the social and health-related factors which could lead to sarcopenia. PMID- 29607856 TI - Hybrid contact lenses for visual management of patients after keratoplasty. AB - Aim: This study aims to report the outcomes of new-generation hybrid contact lenses for visual rehabilitation of postkeratoplasty patients. Materials and Methods: Twenty eyes of twenty postkeratoplasty patients were fitted with hybrid lenses. Each patient's keratometric values, ocular surface irregularity indices, central corneal thickness (CCT), uncorrected visual acuity (UCVA), spectacle corrected visual acuity, contact lens-corrected visual acuity, contact lens fitting data, and contact lens daily wearing time were recorded. Follow-up examinations were performed at 1st week, 1st month, and 3rd month visit after successful fitting of the lenses. Results: The mean age of the patients was 38.42 +/- 4.89 years. The mean spherical component of refractive error was -4.46 +/- 2.1 D, and the mean astigmatism was -5.31 +/- 1.55 D. The median UCVA was 1.00 logarithm of the minimum angle of resolution (logMAR) which improved to 0.40 logMAR after spectacle correction. The median visual acuity with hybrid contact lenses was 0.05 logMAR. The median CCT was 544.4 MUm and increased to 549.2 MUm at 3 months after contact lens wear. The difference was not statistically significant (P = 0.38). The mean follow-up of patients was 4.32 +/- 0.45 months. Eighteen of twenty patients reported a mean of 8.37 +/- 1.95 h comfortable wearing time per day during this period. Two patients discontinued contact lens wearing due to conjunctival hyperemia. No graft-related complications such as decompensation, rejection, and infection were documented during the follow-up period. Conclusion: The new-generation hybrid contact lenses can be considered helpful in the visual management of postcorneal graft patients, particularly who are unable to achieve an adequate visual outcome with spectacles. PMID- 29607857 TI - Analysis of corneal astigmatism with NIDEK axial length scan in caucasian cataract surgery candidates. AB - Aims and Objectives: The aim of the study was to analyze and quantify the pattern of corneal astigmatism in Caucasian cataract surgery patients using a new optical biometer (axial length [AL] Scan, NIDEK Co., Gamagori, Japan). Patients and Methods: The datasets of cataract surgery patients acquired between March 1, 2014, and April 15, 2016, were collected and analyzed. The corneal power (flat keratometry, steep keratometry, and mean keratometry), negative cylinder power, and axis of astigmatism were recorded. Keratometry values were optically measured by optical low coherence interferometry (AL-Scan, NIDEK Co., Ltd.,) before cataract extraction. Results: The study comprised 1233 eyes of 838 consecutive cataract candidates with a mean age of 66.8 +/- 10.7 years (range 40-97 years). The mean keratometry value and corneal astigmatism were 43.69 +/- 1.61 D and 0.84 +/- 0.70 D, respectively. Corneal astigmatism of 1.00 D or greater was found in 344 eyes (27.9%), and 548 eyes (44.4%) had against-the-rule astigmatism. A trend toward decreasing J0 and J45 with age was found by linear regression models. The per-year increase in age was associated with a J0 and J45 decrease of 0.002 D and 0.001D, respectively. Conclusion: This study provides the distribution of astigmatism axis and power for cataract patients in age subsets from Turkey. PMID- 29607858 TI - Evaluation of root canal morphology of human primary mandibular second molars by using cone beam computed tomography. AB - Objectives: The aim of the present study was to investigate the root canal configurations of primary mandibular second molars (PMSMs) using Vertucci classification. Materials and Methods: The root canal types of 228 PMSMs (228 mesial and 228 distal roots) were evaluated. In addition, the relationship between external root morphology and Vertucci classification was investigated. The Chi-square test or Fisher Exact Chi-square test was used for the evaluations, and P < 0.05 was considered statistically significant for all tests. Results: The most commonly observed root canal type, which was observed in 228 roots (50%), was Type 4 followed by Type 8 (15.79%), Type 5 (14.47%), Type 1 (9.21%), and Type 3 (6.57%). In 150 mesial roots, the root canal Type 4 was observed whereas the same type was observed in 78 distal roots, and the difference was significant (P < 0.001). In flat roots (82.9%), the most frequently observed root canal type was Type 4 (50.8%) (P < 0.001). Conclusion: Various root canal types were observed in both mesial and distal roots although Type 4 was the most commonly observed. Root canal types showed a consistent relationship with separated and conical root shapes whereas the flat roots showed different root canal types. PMID- 29607859 TI - Challenges in the management of bleeding disorders in Nigeria. AB - Background: Bleeding disorders (BDs) are characterized by abnormal bleeding for which effective management requires a combination of skill, workforce, diagnostic facilities, and adequate therapeutic options. Objectives: The objectives of this study were to determine the capacity of Nigerian hematologists to handle BDs and to assess availability of required infrastructure, equipment, and treatment options. Materials and Methods: This descriptive study was conducted during the 2016 scientific conference of the Nigerian Society for Hemetology and Blood Transfusion. A structured questionnaire was distributed to hematologists in attendance. Data were analyzed with SPSS version 21. Results: A total of 55 (76.4%) hematologists from 27 centers responded. The most frequently carried out tests to assess bleeding were hemoglobin or packed cell volume (100%), full blood count (96.3%), and prothrombin time/international normalized ratio and activated partial thromboplastin time (77%). Many centers did not have a coagulometer (47.8%) or cold centrifuge (43.4%) and none had thromboelastography or rotational thromboelastometry. Fresh whole blood was the most accessible (88.5%) and up to one-third of the centers did not have access to component therapy. Only 39.1% centers had factor concentrates available. Conclusion: Facilities required for diagnosing and treating BD are significantly deficient in most centers in Nigeria. Funding to provide facility and training is required to improve on this inadequacy. PMID- 29607860 TI - Buccal infiltration versus inferior alveolar nerve block in mandibular 2nd premolars with irreversible pulpitis. AB - Purpose: The purpose of this study is to compare the success rates of inferior alveolar nerve block (IANB) and buccal infiltration anesthesia of mandibular second premolar with irreversible pulpitis and to evaluate the level of patient discomfort with these methods. Matherials and Methods: Forty patients, who had irreversible pulpitis in the mandibular 2nd premolar teeth, were included in the study. Patients were randomly distributed in two groups. In one group IANB, in the other group buccal infiltration anesthesia were performed. The efficacy of these two different anesthesia techniques on the related teeth was investigated with the Heft-Parker visual analog scale. In addition, with a pulse oximetry device, the changes in the patients' heart rates were compared between the groups. The obtained data were evaluated statistically. Results: Both anesthesia techniques reduced the pain significantly in patients before the administration (P < 0.05), but there was no significant difference among the groups regarding the pain control and success rates of anesthesia (P > 0.05). Both of the anesthesia techniques increased the heart rate (P < 0.05). The increase in the heart rate of the patients was significantly higher in the buccal infiltration anesthesia group than the other anesthesia group (P < 0.05). Conclusion: Within the limitation of this in vivo study, there was no difference between the efficacies of the buccal infiltration anesthesia and IANB anesthesia in the mandibular 2nd premolar teeth with irreversible pulpitis. Buccal infiltration anesthesia caused more discomfort in the patients compared with the IANB during the administration. PMID- 29607861 TI - Knowledge, attitude, and practice of diabetic retinopathy among physicians in Northwestern Nigeria. AB - Background: Diabetic retinopathy (DR) is the leading cause of preventable blindness in the productive population that poses a considerable global public health burden. Objective: The objective of this study is to assess the knowledge, attitude, and practice of DR screening among physicians in Northwestern Nigeria. Materials and Methods: Survey responses were obtained from 105 physicians in 4 tertiary hospitals using a Likert scale questionnaire. The internal consistency of the questionnaire was calculated using Cronbach's alpha coefficient. Principal component analysis was used for data reduction and grouping with the varimax rotation method, and the factors were extracted based on an Eigenvalue> 1. Results: Most of the respondents (78.8%) were aware of the most effective method of delaying the onset of DR and frequency of eye examination (94.1%). Lack of ophthalmoscopes (70.6%) and dilating eye drops (50.6%) form important barriers to performing a good eye examination. Conclusion: DR screening among physicians practicing in Northwestern Nigeria was suboptimal, which prompts the need for improved training of physicians managing persons with diabetes on eye examination in a bid to strengthen DR screening and reduce the burden of visual impairment in our environment. PMID- 29607862 TI - An analysis of patients in palliative care with pressure injuries. AB - Aim: The aim of this study was to evaluate the factors that are effective for the treatment, recovery of pressure injury (PI) and costs in palliative care (PC) patients. Materials and Methods: From a retrospective review of patient records, the PI localization, the presence of infection, PI stage on admission, discharge and treatment costs were recorded. Patients were grouped according to diagnoses, and PI localizations (sacrum, trochanter, ischium, and heel). The comparison was made of changes in wound stage in the groups. Results: PI was present in all 154 patients during hospitalization and in 94 (61%) on discharge. Full recovery was determined in 52/129 (40.3%) patients with PI in the sacrum, in 23/46 (50%) in the trochanter, in 22/40 (55.0%) in the heel, and in 10/12 (83.3%) in the ischium. Worsening PI stage was observed in 5 (3.9%) in the sacrum, in 1 in the trochanter and in 4 in the heel. Improvement in PI stage was seen in 96 (74.4%) in the sacrum, in 35 (3.9%) in the trochanter, in 27 (50.5%) in the heel, and in 10 (83.3%) in the ischium. Regardless of wound localization, the improvement was observed in 168 (74%) of 227 PI and worsening in 10 (4.4%). The group with no change in the PI stage had prolonged hospital stay and higher costs. The Karnovsky Performance Score and Glasgow Coma Score of fully recovered patients were determined to be higher, and no statistically significant difference was seen in respect of age. Conclusions: PC patients are prone to PI due to many chronic diseases. The localization of PI and infection are effective factors in the healing of ulcers. The treatment costs for PC patients is higher if they have a pressure ulcer. More comprehensive studies will be useful to clarify the economic and social dimensions of this issue. PMID- 29607863 TI - Total hip replacement in sickle cell disorder: A preliminary report of challenges and early outcome of 21 consecutive patients. AB - Objective: The aim of this study is to describe the pattern of presentation osteoarthritic patients with sickle cell disorder (SCD) in our environment, determine the implant sizes taking the peculiar nature of the pathology and our operating environment into consideration, highlight the challenges and technical difficulties encountered during the procedure, measure the functional outcome and observe complications of treatment, recommend ways of improving outcome. Patients and Methods: Between November 2008 and November 2012, 29 consecutive primary total hip replacements (THRs) were performed on 21 patients with avascular necrosis of the head of femur secondary to SCD. Patients' evaluation was performed at two different times of follow-up (1 and 5 years, respectively). Results: Twenty-one patients were available at 1 year as well as 5-year follow up. The mean preoperative Harris Hip Score was 20.17 +/- 11. The mean postoperative Harris Hip Score was 92.25 +/- 13 (P < 0.001) at 1 year and 88.75 +/- 10 (P < 0.001) at 5 years. Eighteen patients had regional anesthesia while three had general anesthesia. The average cup size used was 49.43 with a range of 46-54. The average liner size was 49.43 with a range of 46-54. The head size used in all patients was 28. The average stem size was 6.57 with a range of 6-8. The offset used in all the patients was standard All the patients had 1-2 screw fixation of the acetabular shell. Four patients had complications as follows: periprosthetic fracture 1, superficial wound infection 1, pulmonary complication 1, and abdominal crisis 1. Conclusion: : THR is a veritable means of treatment of patients with avascular necrosis of the femoral head arising from SCDs. The challenges encountered during the surgery are related to the quality of bone of the affected patient. Arthroplasty Surgeons in our environment must be fully prepared for the challenges by ensuring a preoperative plan that will take care of the technical problems such as recreating femoral canals, wiring of intraoperative fractures as well as treatment of acetabular defects. A detailed planned total hip arthroplasty can be performed in patients with SCD in younger patients with good clinical benefits. PMID- 29607864 TI - Retreatability of root canals obturated using mineral trioxide aggregate-based and two resin-based sealers. AB - Background: The aim of this study was to compare the retreatment time and the removal efficiency of different root canal sealers using WaveOne Gold reciproc file system by measuring required time. Materials and Methods: Forty-five mandibular premolars were prepared and randomly divided into three groups (n = 15). In Groups 1-3, the canals were filled with gutta-percha and mineral trioxide aggregate (MTA) Fillapex, EndoREZ, and AH26, respectively. After 7 days, root canal filling materials (RCFM) were removed with WaveOne Gold reciproc files by measuring time. Teeth were grooved and sectioned longitudinally, then remaining RCFM was evaluated using digital camera. The images were transferred to image analysis software to measure the areas of remaining RCFM. Data were analyzed using one-way analysis of variance and Tukey's test (alpha = 0.05). Results: There was a statistically significant difference between groups according to time required for removing RCFM (P < 0.05). The time required for removing RCFM was significantly shorter in Group 1 and longer in Group 3 than the other groups (P < 0.05). In Group 1, the remaining RCFM was more than other groups at middle third (P < 0.05), but there was no statistically significant difference between groups at coronal and apical thirds (P > 0.05). Conclusions: None of the sealers evaluated in this study could completely be removed from the root canals. MTA based sealer was removed faster than resin-based sealers. PMID- 29607866 TI - Shear bond strength of a novel porcelain repair system for different computer aided design/computer-assisted manufacturing ceramic materials. AB - Objectives: The purpose of this study was to compare the shear bond strength of a novel repair system, Nova Compo SF with Ceramic Repair, Ivoclar, to computer aided design/computer-assisted manufacturing (CAD/CAM) restorative materials (IPS e.max CAD and Empress CAD). Materials and Methods: The specimens of each CAD/CAM restorative material were randomly divided into two subgroups of nine specimens, using one of two repair systems. All specimens were etched with hydrofluoric acid and rinsed under a water spray for 10 s, then air-dried for 10 s. Next, repair systems were applied according to the manufacturer's instructions. All specimens were stored in distilled water at 37 degrees C for 24 h and then additionally aged for 5000 thermal cycles. A shear bond strength test was performed using a universal testing machine. Each fracture type was examined under a stereomicroscope at *12.5 magnification. A two-way ANOVA test was used to detect significant differences between the CAD/CAM restorative materials and the composite repair systems. Subgroup analyses were performed using Tukey's honest significant difference. Results: No statistically significant differences were observed between the repair systems (P = 0.9). The bond strength values from Empress CAD were statistically higher than those from e.max CAD (P < 0.05). Conclusions: Within limitations, SuperFlow may be an alternative to the ceramic repair materials we routinely used in the clinic. Empress CAD can be preferable to e.max CAD in terms of esthetically suitable clinical indications. PMID- 29607865 TI - The relationship of erythropoietin receptor expression and prognosis in glioblastoma multiforme patients. AB - Background: : Glioblastoma multiforme (GBM) is the most common primary brain tumor characterized with poor prognosis and short survival. In addition to the standard treatment protocols, targeted molecular treatment options are under trial. In the recent trials, erythropoietin and erythropoietin receptor were found to be linked with the progression of GBM cells. Aim: : In this study, we compared the expression of EPOR with survival in GBM patients with mortality. Materials and Methods: : Twenty-six patients operated for GBM in 2012-2014 were enrolled in this study. Tumor tissues were stained with EPOR, epidermal growth factor receptor, vascular endothelial growth factor, and assigned as (1+), (2+), and (3+) according to their immunohistochemical staining levels. The average postoperative follow-up time was 9.3 months. Kaplan-Meier's survival test and Spearman's correlation test were used in statistical analysis. Results: : EPOR 1(+) stained group showed a median survival of 8 months (95% confidence interval [CI]: 0.954-15.046). EPOR 2(+) stained group showed a median survival of 6 months (95% CI: 2.901-9.090) EPOR 3(+) stained group showed a median survival of 2 months (95% CI: 0.400-3.600). (Kaplan-Meier P = 0.002). Conclusion: : These results portrayed that EPOR staining levels were inversely proportional with average survival time. In the future, specific inhibitors of this molecule could be used to form a novel treatment option for GBM. PMID- 29607867 TI - Effects of varying entry points and trendelenburg positioning degrees in internal jugular vein area measurements of newborns. AB - Background: Recent guidelines from the National Institute for Clinical Excellence recommend the use of ultrasonography in the central venous catheterization of children. In this study, we aimed to compare area measurements using ultrasonography and efficiency of varying Trendelenburg degrees on the area measurements, for two different entry points used as internal jugular vein (IJV) cannulation points in newborns. Methods: Fifty-eight healthy newborns, weighing between 3000 and 3500 g, were recruited for this prospective study. Right IJV (RIJV) consecutive measurements were performed in three different Trendelenburg positions at 0 degrees , 15 degrees , and 30 degrees , at two different entry points: The superior approach and an inferior approach. The landmark used in the superior approach was the top of the triangle formed by the two heads of the sternocleidomastoid muscle with the clavicle; while in the inferior approach, it was taken as the midpoint of the clavicle, as measured from the upper edge of the clavicle. Results: The cross-sectional area (CSA) of the RIJV was significantly increased when using the inferior approach, compared to that in the superior approach, in all Trendelenburg degrees, including the neutral position. Both 15 degrees and 30 degrees Trendelenburg positioning resulted in a significant increase in CSA, both in superior and inferior approaches, when compared to neutral positioning. Conclusion: The use of 15 degrees Trendelenburg positioning may have significant advantage for increasing the CSA when used with the inferior approach. PMID- 29607868 TI - Three-dimensional evaluation of alveolar bone thickness of mandibular anterior teeth in different dentofacial types. AB - Aim: The aim of this randomized study was to compare the alveolar bone thickness (ABT) of the mandibular incisor teeth of dental and skeletal Class I, II, and III adult patients at labial and lingual aspects of the bone and develop recommendations for the associated movements of teeth in this region, taking vertical facial type into consideration. Material and Methods: : Sixty-two Class I, 74 Class II, and 63 Class III patients - aged between 20 and 45 - were assigned to three subgroups - high (H), low (L), and normal (N) growth patterns. On the axial slices of computerized tomographies, the measurements for the ABT on labial and lingual sides of the mandibular incisors were carried out at three levels. Results: In Class I group, at apex region, ABT of subgroups N and L were greater than H, at labial side. In Class II, ABT of subgroups N and L were greater than H, at apex at both sides and cervical lingual region. Similarly, ABT of subgroup L of Class III group was greater than H, at labial and lingual apex, mid-root regions. In Class II, the ABT of subgroup H was greater than L, at lingual cementoenamel junction. Conclusions: ABT of mandibular incisors of Class I patients is not affected from vertical pattern except for apical region. There is not a thick bone on the lingual side of the Class II, high-angle patients. The ABT of the Class III, high-angle patients is thin as a risk factor for proclination. PMID- 29607869 TI - Fracture resistance force of primary molar crowns milled from polymeric computer aided design/computer-assisted manufactured resin blocks. AB - : Purpose: To compare fracture resistance force (FRF) and failure types of crowns milled from resin nanoceramic (Lava Ultimate)-, and modified polymethylmethacrylate (PMMA) (Vita computer-aided design (CAD)-Temp)-, and PMMA (Telio CAD)-based CAD/computer-assisted manufactured (CAM) blocks. Materials and Methods: Three experimental groups of 10 milled crowns were arranged: Group-1 (Lava Ultimate), Group-2 (Vita CAD-Temp), and Group-3 (Telio CAD). Crowns were machined in sizes similar to a primary second molar stainless steel crown (SSC) and stored in water at 37 degrees C for 30 days. The crowns were seated on Cr-Co dies. Their FRFs were measured using a universal test machine until fracture. FRFs and failure types were recorded and statistically analyzed (P < 0.05). Results: There were statistically significant differences among the groups for both FRFs and failure types. The sources of significant differences for FRFs and failure types were Group-3 and Group-1, respectively. Conclusion: Crowns milled from different chemical structural CAD/CAM blocks may be used for restoration of primary molar teeth. PMID- 29607870 TI - Usefulness of C1 esterase inhibitor protein concentrate in the management of hereditary angioedema of oropharyngeal tissue. AB - Hereditary angioedema is an autosomal-dominant disorder caused by mutation of the gene encoding the C1 esterase inhibitor (C1-INH). It manifests as painless, nonpruritic, nonpitting episodic swelling of the subcutaneous tissues, gastrointestinal, and upper respiratory tracts in the absence of urticaria. An attack typically takes 24 h to peak and resolves over 48-72 h. The most serious manifestation is a laryngeal attack associated with upper airway swelling. The aim of this case report is to describe the lifesaving use of a novel C1-INH protein concentrate in a patient with mild-to-moderate dyspnea caused by swelling of the upper airway (larynx) and tongue. PMID- 29607871 TI - Herpes zoster-induced acute urinary retention: Two cases and literature review. AB - We report two uncommon cases of acute urinary retention in Chinese patients caused by reactivation of sacral herpes zoster and requiring bladder drainage. Indwelling urinary catheterization, antiviral medication (ganciclovir), and physiotherapy with infrared light (830 nm) led to successful recovery of the micturition reflex in both cases. PMID- 29607872 TI - A Case of Primary Mediastinal Leiomyosarcoma in Which Long-Term Survival Was Achieved. AB - INTRODUCTION: Primary leiomyosarcomas (LMS) of the mediastinum are extremely rare malignant mesenchymal tumors developing from soft tissues or great vessels. We present a case of a primary leiomyosarcoma of the middle mediastinum in which long-term survival was achieved. CASE REPORT: A 77-year-old man presented to us for examination with an extrapleural sign in his upper mediastinum on chest X ray. Computed tomography (CT) revealed a well- circumscribed mass in the middle mediastinum. Thoracoscopic resection of the mediastinal tumor and immunohistological findings, which were positive for smooth muscle actin (SMA), HHF-35, vimentin, and desmin confirmed primary leiomyosarcoma. It recurred twice with solid right pulmonary metastases, which were resected. He was followed-up for a total of 9 years and 6 months from the first surgery with no signs of recurrence after his last surgery. CONCLUSION: Surgical resection of both the primary tumor and pulmonary metastases remains the mainstay of treatment of primary leiomyosarcomas. PMID- 29607873 TI - Internal migration and regional differences of population aging: An empirical study of 287 cities in China. AB - In addition to birth and death, migration is also an important factor that determines the level of population aging in different regions, especially under the current context of low fertility and low mortality in China. Drawing upon data from the fifth and sixth national population census of 287 prefecture-level cities in China, this study explored the spatial patterns of population aging and its trends from 2000 to 2010 in China. We further examined how the large-scale internal migration was related to the spatial differences and the changes of aging by using multivariate quantitative models. Findings showed that the percentage of elder cities (i.e. proportion of individuals aged 65 and above to total population is higher than 7%) increased from 50% to 90% in the total 287 cities within the decade. We also found that regional imbalances of population aging have changed since 2000 in China. The gap of aging level between East zone and the other three zones (i.e. West, Central, and North-east) has considerably narrowed down. In 2000, Eastern region had the greatest number (65) of and the largest proportion (74.7%) of elder cities among all four regions. By 2010, the proportion (87.4%) of elder cities in the eastern region was slightly lower than Central (91.4%), Western (88.2%) and North-east sectors (91.2%). Results from multivariate quantitative models showed that the regional differences of population aging appear to be affected much more by the large-scale internal migration with clear age selectivity and orientation preference than by the impact of fertility and mortality. Population aging is expected to continue in China, which will in turn exacerbate regional imbalances. Policies and implications are discussed to face the challenges that the divergent aging population may present in China. PMID- 29607874 TI - Astraglaus polysaccharide protects diabetic cardiomyopathy by activating NRG1/ErbB pathway. AB - Diabetic cardiomyopathy (DCM) is one of the main cardiac complications among diabetic patients. According to previous studies, the pathogenesis of DCM is associated with oxidative stress, apoptosis and proliferation of local cardiac cells. It showed, NRG1 can improve the function of mitochondria, and thereby, increasing proliferation and decreasing apoptosis of cardiac muscle cell via ErbB/AKT signaling, also, exert antioxidative function. Besides, NRG1/ErbB pathway was impaired in the DCM model which suggested this signaling played key role in DCM. Astraglaus polysaccharide (APS), one of the active components of Astragalus mongholicus, showed striking antioxidative effect. Here, in this study, our data showed that APS can promote proliferation and decrease apoptosis in AGE-induced DCM cell model, besides, APS can decrease intracellular ROS level, increase activity of SOD, GSH-Px and lower level of MDA and NO in DCM cell model, indicating APS exerted antioxidative function in DCM model cells. Besides, western blot results revealed APS induced NRG1 expressing and the phosphorylation level of ErbB2/4. In addition, the elevated NRG1 promoted AKT and PI3k phosphorylation which indicated APS may exert its function by NRG1/ErbB and the downstream AKT/PI3K signaling. Canertinib is ErbB inhibitor. The effect of APS on proliferation, apoptosis, antioxidation and NRG1/ErbB pathway was partly abolished after the cells were co-treated with APS and canertinib. Taken together, these results suggested APS may display its protective function in DCM cells by activating NGR1/ErbB signaling pathway. And our study increased potential for prevention and therapy to DCM. PMID- 29607875 TI - Comparison of gene expression levels of appA, ppsR, and EL368 in Erythrobacter litoralis spheroplasts under aerobic and anaerobic conditions, and under blue light, red light, and dark conditions. AB - We compared the gene expression levels of the blue-light-responsive genes, appA (encoding photosynthesis promoting protein AppA), ppsR (encoding photosynthesis suppressing protein PpsR), and EL368 (encoding a blue-light-activated histidine kinase with a light, oxygen, or voltage domain) between aerobic and anaerobic conditions in spheroplasts of the aerobic photosynthetic bacterium Erythrobacter litoralis. The spheroplasts conducted photosynthesis under red light but not under blue light. All three blue-light-responsive genes showed higher expression under aerobic conditions than under anaerobic conditions under blue light. In contrast, under red light, although the expression level of appA was higher in the presence of oxygen than in the absence of oxygen, the expression levels of ppsR and EL368 were similar in the presence and absence of oxygen. Our findings demonstrate that the expression of blue-light-responsive genes is strongly affected by oxygen in E. litoralis spheroplasts. PMID- 29607876 TI - Functional and expression studies of two novel STL1 genes of the osmotolerant and glycerol utilization yeast Candida glycerinogenes. AB - Candida glycerinogenes is an osmotolerant yeast used for commercial glycerol production, as well as a glycerol utilization yeast which produces high biomass on glycerol medium. In the present study, two STL1 homologues CgSTL1 and CgSTL2 encoding the putative glycerol transporters were identified, and their products were found to be localized to plasma membranes by tagging GFP protein. The functions of CgSTL1 and CgSTL2 on glycerol transport were confirmed by their expression in S. cerevisiae STL1 null mutant and simultaneous deletion in C. glycerinogenes. The expression of CgSTL1 were osmotic-induced, whereas that of CgSTL2 was constitutive. Over-expression of CgSTL1 and CgSTL2 in C. glycerinogenes resulted in improved glycerol consumption rate and cell growth. Our study provided more details on the glycerol transporter of C. glycerinogenes, the potential cell factory for using glycerol as a carbon source. PMID- 29607877 TI - Variations in mating-type-like (MTL) loci direct PCR-based tracking of Zygosaccharomyces strains formed by mating. AB - Variations of chromosomal structures and nucleotide sequences around mating-type like (MTL) loci among Zygosaccharomyces species have been reported. We have analyzed these differences in more detail and, on the basis of PCR- and next generation sequencing data, we describe the MTL loci on chromosomes C and F for Z. rouxii type-strain NBRC1130, Z. rouxii NBRC0740 and Zygosaccharomyces sp. NBRC1876. We developed a mating strategy for Zygosaccharomyces sp. NBRC1876 and Z. rouxii NBRC0740, and found that the mated stains could be identified from parental strains on the basis of nucleotide sequence variations of the MTL loci. We further obtained evidence that Zygosaccharomyces sp. NBRC1876 is a natural interspecies hybrid between Z. rouxii and a related species. PMID- 29607878 TI - Oxidative stress tolerance of a spore clone isolated from Shirakami kodama yeast depends on altered regulation of Msn2 leading to enhanced expression of ROS degrading enzymes. AB - We analyzed the stress response in a spore clone from Shirakami kodama yeast, Saccharomyces cerevisiae, with an exceptional high tolerance to oxidative stress. The levels of reactive oxygen species (ROS) in this clone were very low, whereas the genes for superoxide dismutase (SOD2) and catalase (CTT1) were highly expressed and those enzymes also had high activities even under non-stress conditions. Both genes are regulated by general stress-responsive transcription factors Msn2 and Msn4, and Yap1, a transcription factor required for oxidative stress tolerance, and the removal of Msn2 or Yap1 caused a significant decrease in CTT1-expression. Under non-stress conditions, Msn2 was ~3.6-fold more abundant in the nucleus of the spore clone compared with a laboratory strain, whereas the nuclear abundance of Yap1 remained unchanged. Thus, a high tolerance to oxidative stress in this spore clone results from a high expression of ROS-degrading enzymes by the abundant accumulation of Msn2 in the nucleus. We found that oxidative stress caused by the presence of furfural did not impair fermentation by this strain, which could make it attractive for ethanol production from lignocellulosic biomass. PMID- 29607879 TI - Genetic variation and structure of Ubame oak, Quercus phillyraeoides, in Japan revealed by chloroplast DNA and nuclear microsatellite markers. AB - Genetic variation and structure of Ubame oak (Quercus phillyraeoides A. Gray), a shrub tree on the Pacific coast of Japan, were examined to elucidate historical population dynamics using five chloroplast DNA (cpDNA) marker regions and 11 nuclear microsatellite loci. Three cpDNA haplotypes (A, B and C) were identified in a screen of 41 populations across the entire distribution range in Japan. Haplotype A was the most prevalent and was found in the entire range. Haplotype B was locally restricted to the Kii Peninsula, while haplotype C was restricted to the southwestern part of Japan. These haplotypes corresponded with the nuclear genetic constitution revealed by microsatellite markers. Two genetically differentiated major groups were identified by STRUCTURE analysis applied to 536 individuals from 28 populations, and they mostly corresponded with the two major cpDNA haplotypes, A and C. These populations were further divided into three geographically identified groups: group 1 in the area including Kanto and Tokai regions, the Kii Peninsula and the Muroto-misaki Cape on the Pacific coast; group 2 in the Bungo-suido Channel area; and group 3 in southern Kyushu and Okinawa. Populations in the Seto Inland Sea were divided into two groups: one was included in group 1 and appears to have originated from last glacial maximum (LGM) refugia located in the Kii Peninsula, while the other was included in group 2 and appears to have originated from LGM refugia located in southern Kyushu. These groups can be considered as conservation units for the preservation of unique seashore ecosystems, or as a seed source to foster coastal protection forests and next generation production forests. Considerable care should be taken to protect isolated populations that may be specialized to unique local environments, such as those on the islands of Koshikijima and Izenajima. PMID- 29607880 TI - A novel nuclear localization signal spans the linker of the two DNA-binding subdomains in the conserved paired domain of Pax6. AB - Paired box (Pax) 6, a member of the Pax family of transcription factors, contains two DNA-binding domains, called the paired domain (PD) and the homeodomain (HD), and plays pivotal roles in development of structures such as the eye, central nervous system and pancreas. Pax6 is a major developmental switching molecule because, for example, ectopic expression of the Pax6 gene can induce ectopic whole eye development. Intensive research has been devoted to elucidating the molecular mechanism(s) involved in the function(s) of Pax6, but many issues remain unexplained. One of the important issues is to identify the nuclear localization signal (NLS) in the PD of Pax6, which is predicted to have a stronger NLS activity than that in the HD. We produced expression plasmid constructs that encode the chick Pax6 protein modified to delete the entire PD except for fragments containing putative NLS sequences, and electroporated them in ovo into the developing chick midbrain to define the NLS of the PD. The results show that the NLS in the PD of chick Pax6 consists of an unusually long sequence of 36 amino acid residues. Within this long NLS motif, the central 18 amino acids comprising two consecutive nine-residue segments showed highest NLS activity; this central area corresponds to the C-terminal half of the third alpha helix of the PAI subdomain and the subsequent 11 amino acids of a 16-residue linker between PAI and the adjacent RED subdomain. This information helps to elucidate the molecular mechanism by which Pax6 plays a pivotal role during ontogeny. PMID- 29607881 TI - Melanocytes contribute to the vasculature of the choroid. AB - Melanocytes develop from the vertebrate embryo-specific neural crest, migrate, and localize in various organs, including not only the skin but also several extracutaneous locations such as the heart, inner ear and choroid. Little is known about the functions of extracutaneous melanocytes except for cochlear melanocytes, which are essential for hearing ability. In this study, we focused on the structure of the choroid, in which melanocytes are abundant around the well-developed blood vascular system. By comparing structural differences in the choroid of wild-type and melanocyte-deficient Mitfmi-bw/Mitfmi-bw mutant mice, our observations suggest that choroidal melanocytes contribute to the morphogenesis and/or maintenance of the normal vasculature structure of that tissue. PMID- 29607882 TI - Encephalitis induced by a newly discovered ruminant rhadinovirus in a free-living Formosan sambar deer (Rusa unicolor swinhoei). AB - We documented a case of a free-living Formosan sambar deer (Rusa unicolor swinhoei) infected with a newly discovered ruminant Rhadinovirus (RuRv). Non purulent encephalitis was the primary histological lesion of the sambar deer. We conducted nested PCR to screen for herpesvirus using generic primers targeting the DNA polymerase gene. In addition, we found that DNA polymerase gene of the sambar deer RuRv was present in the macrophage distributed in the Virchow Robin space with histopathologic lesions by chromogenic in-situ hybridization (CISH). The phylogenetic analysis indicated a high similarity between the viral sequence isolated from fallow deer and our case. This result suggests the possibility of cross-species transmission from other exotic Cervidae reservoir to the Formosan sambar deer. PMID- 29607883 TI - Massa versus Haller: Priority of the Cerebrospinal Fluid Discovery. AB - The commonly accepted practice in recognizing the scientific priority of a discovery requires finding a hitherto unknown phenomenon, publishing it to other scholars and doing it for the first time. And this is what happened regarding the discovery of the intracranial fluid presence by the Venetian anatomist Massa in 1536. This finding fulfills all the conditions necessary for the recognition of the scientific discovery. PMID- 29607885 TI - Association analysis of NUCKS1 and INPP5K polymorphism with Parkinson's disease. AB - Genome-wide association studies have reported numerous candidate loci associated with Parkinson's disease (PD). NUCKS1 and INPP5K are two such candidate loci, although they have rarely been reported in Asian populations. To explore these potential genes for PD susceptibility, we investigated the association between PD and two SNPs, rs823114 and rs1109303, located on the NUCKS1 and INPP5K genes, respectively, in the Han population of northern China. We genotyped the two SNPs using the multiplex PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) technique. A total of 685 subjects including 322 sporadic PD patients and 363 healthy controls were recruited from the population. After Bonferroni correction, our results suggested that there was a significant association of a minor allele (G) in rs823114 with reduced risk of PD development (P = 0.017, OR = 0.768, 95%CI = 0.618 - 0.955), and the difference in genotypes between the PD patients and healthy controls was significant under the dominant model (GA + GG vs. AA). After stratification by gender, males had a lower risk than females (P = 0.008, OR = 0.666, 95%CI = 0.495 - 0.898). However, the distribution of genotype frequency exhibited no significant differences between the PD and control groups (P > 0.025) in INPP5K rs1109303 (P = 0.048, OR = 0.806, 95%CI = 0.650 - 0.998). We conclude that NUCKS1 rs823114 indicates a decreased risk of susceptibility to PD and shows a male genetic distribution bias in the Han Chinese population. PMID- 29607886 TI - Estimating the Asymptomatic Ratio of Norovirus Infection During Foodborne Outbreaks With Laboratory Testing in Japan. AB - BACKGROUND: Foodborne norovirus outbreak data in Japan from 2005-2006, involving virological surveillance of all symptomatic and asymptomatic individuals, were reanalyzed to estimate the asymptomatic ratio of norovirus infection along with the risk of infection and the probability of virus shedding. METHODS: Employing a statistical model that is considered to capture the data-generating process of the outbreak and virus surveillance, maximum likelihood estimation of the asymptomatic ratio was implemented. RESULTS: Assuming that all norovirus outbreaks (n = 55) were the result of random sampling from an identical distribution and ignoring genogroup and genotype specificities, the asymptomatic ratio was estimated at 32.1% (95% confidence interval [CI], 27.7-36.7). Although not significant, separate estimation of the asymptomatic ratio of the GII.4 genotype appeared to be greater than other genotypes and was estimated at 40.7% (95% CI, 32.8-49.0). CONCLUSION: The present study offered the first explicit empirical estimates of the asymptomatic ratio of norovirus infection in natural infection settings. The estimate of about 30% was consistent with those derived from volunteer challenge studies. Practical difficulty in controlling GII.4 outbreaks was supported by the data, considering that a large estimate of the asymptomatic ratio was obtained for the GII.4 genotype. PMID- 29607887 TI - Pilot Study of a Device to Induce the Hanger Reflex in Patients with Cervical Dystonia. AB - The hanger reflex (HR) is an involuntary head rotation that occurs in response to a clothes hanger encircling the head and compressing the unilateral fronto temporal area. Here, we developed an elliptical device to induce the HR and examined its utility for the treatment of cervical dystonia (CD). The study included 19 patients with rotational-type CD. The device was applied to each subject's head for at least 30 min/day for 3 months. Severity scores on part 1 of the Toronto Western Spasmodic Torticollis Rating Scale were evaluated at baseline and after the 3-month trial. Mean scores without and with the device were significantly different both at baseline (16.6 vs. 14.7, respectively; P < 0.05) and after the trial (14.9 vs. 13.6, respectively; P < 0.05). This preliminary trial suggests that our device can improve abnormal head rotation in patients with CD. PMID- 29607888 TI - Cholesterol-Induced Formation of Liquid Ordered Phase-Like Structures in Non Phospholipid Systems. AB - The formation of liquid ordered (Lo) phase-like structures in stearyltrimethylammonium chloride/cholesterol/1,3-butanediol/water and hepta(oxyethylen) octadecyl ether/cholesterol/1,3-butanediol/water systems was investigated. Differential scanning calorimetry and X-ray scattering measurements confirmed that Lo phase-like structures were formed in both surfactant/cholesterol systems, similar to the lysophospholipid/cholesterol system. It was revealed that the concentration of cholesterol at which only Lo phase-like structures are formed increases in the order stearyltrimethylammonium chloride < lysophospholipid < hepta(oxyethylen) octadecyl ether. In addition, for both surfactants, the interlayer spacing, d, was larger for Lo phase-like structures than for alpha-gel structures. These results suggest that the ionicity and structure of the hydrophilic group of each surfactant play important roles. PMID- 29607889 TI - Effects of Medium Chain Triacylglycerols on the Pathological Condition and Energy Bioavailability of Streptozotocin-induced Diabetic Rats. AB - Diabetes is a disease characterized not only by a high blood glucose level but also by high ketone levels. Medium chain triacylglycerols (MCT) are known as functional lipids, but they are rapidly metabolized to produce ketone bodies. In this study, we examined the effects of MCT intake on the pathological condition and energy bioavailability of diabetic animals. Streptozotocin (STZ)-induced diabetic rats were used as animal models for type I diabetes. The pathological condition was estimated through blood biochemical values, and the energy expenditure was calculated based on the respiratory quotient, which was analyzed using a mass spectrometer.Eight-week-old male STZ-induced diabetic Wistar rats were prepared and fed soybean oil (LCT) or MCT diets for 60 days. The survival rate of rats fed the MCT diet was higher than that of rats fed the LCT diet, although no ameliorating effects in the blood biochemical values were observed. In rats fed the LCT diet, their energy expenditure was much higher than their energy intake, whereas the energy balance was approximately equal in rats fed the MCT diet.These results indicated that energy bioavailability may contribute, at least in part, to the high survival rates in the diabetic MCT group, although MCT intake did not definitely improve the pathological condition of the experimental rats. PMID- 29607892 TI - Novel Risk Score Efficiently Prevents Tolvaptan-Induced Hypernatremic Events in Patients With Heart Failure. AB - BACKGROUND: It has been 7 years since tolvaptan was approved in Japan for the indication of heart failure in patients with volume overload; the drug can be used in patients with normonatremia. Hypernatremia was identified as a significant adverse event to be prevented.Methods and Results:We compiled and analyzed data from 3,349 patients over 5 years to identify patients at high risk of hypernatremia with tolvaptan treatment. The incidence of hypernatremia, defined as serum sodium >=150 mEq/L, was 3.65%. Baseline serum sodium concentrations, serum potassium concentrations, blood urea nitrogen : creatinine ratio, initial tolvaptan dose, and age were identified as risk factors for hypernatremia. A hypernatremia risk score was developed using the odds ratios for these factors. The high-risk population was defined as patients with a risk score >=17.80. CONCLUSIONS: To prevent the occurrence of hypernatremic events in patients taking tolvaptan, we recommend a very low starting dose (i.e., 3.75 mg/day) in patients identified as being at high risk of hypernatremia using our new scoring process. PMID- 29607890 TI - Aerobic metabolism on muscle contraction in porcine gastric smooth muscle. AB - Exposure to chronic hypoxic conditions causes various gastric diseases, including gastric ulcers. It has been suggested that gastric smooth muscle contraction is associated with aerobic metabolism. However, there are no reports on the association between gastric smooth muscle contraction and aerobic metabolism, and we have investigated this association in the present study. High K+- and carbachol (CCh)-induced muscle contractions involved increasing O2 consumption. Aeration with N2 (hypoxia) and NaCN significantly decreased high K+- and CCh induced muscle contraction and O2 consumption. In addition, hypoxia and NaCN significantly decreased creatine phosphate (PCr) contents in the presence of high K+. Moreover, decrease in CCh-induced contraction and O2 consumption was greater than that of high K+. Our results suggest that hypoxia and NaCN inhibit high K+- and CCh-induced contractions in gastric fundus smooth muscles by decreasing O2 consumption and intracellular PCr content. However, the inhibition of CCh-induced muscle contraction was greater than that of high K+-induced muscle contraction. PMID- 29607891 TI - Effects of leucovorin (folinic acid) in the methotrexate-treated rat brain. AB - Folinic acid (FA) is generally administered to patients with CNS tumors in order to treat severe neurological disorders caused by methotrexate (MTX); therefore, we herein examined the effects of the co-administration of FA on MTX concentrations in the rat brain and cerebrospinal fluid (CSF) as well as the pharmacokinetics of MTX. MTX was intravenously or intrathecally administered to rats with or without FA. MTX concentrations were assessed by HPLC. No significant differences were observed in pharmacokinetic parameters, including kel, Vd, AUC, Cltot and t1/2, between the FA-treated and non-treated groups. MTX concentrations were not significantly different in the brain or CSF 6 hr after the intrathecal administration of MTX. However, compare to intravenous administration of MTX, intravenous administration of both FA and MTX significantly decreased MTX concentrations in the brains and CSF. These results suggest that FA inhibits the influx of MTX into the brain and CSF, possibly by competing with folate carriers, but has no effect on its efflux from these regions. Therefore, FA may be administered to CNS tumor patients receiving intrathecal MTX therapy in order to treat the adverse effects of MTX without affecting its concentrations in the brain and CSF. PMID- 29607894 TI - High Cardiac Troponin I Is Associated With Transesophageal Echocardiographic Risk of Thromboembolism and Ischemic Stroke Events in Non-Valvular Atrial Fibrillation Patients. AB - BACKGROUND: Abnormalities in the left atrium (LA) detected on transesophageal echocardiography (TEE) are reliable predictors of thromboembolism in patients with atrial fibrillation (AF). Cardiac troponin I, a marker of subclinical myocardial damage, may also be a predictor of thromboembolic events in patients with AF. The relationship between cardiac troponin I and thromboembolic risk on TEE, however, remains unclear.Methods and Results:TEE and laboratory data, including high sensitivity cardiac troponin I (hs-cTnI) and CHA2DS2-VASc score, were analyzed in 199 patients with non-valvular AF (NVAF). Patients were stratified into those with or without LA abnormality, defined as LA appendage flow velocity <20 cm/s or dense spontaneous echo contrast. On multiple logistic analysis of the clinical variables, hs-cTnI was associated with LA abnormality (95% CI: 1.0003-1.020, P=0.034). The area under the curve for LA abnormality increased on addition of hs-cTnI to CHA2DS2-VASc score. The incidence rate of ischemic stroke was higher in the high hs-cTnI group than in the low-hs-cTnI group (log-rank test, P<0.05). CONCLUSIONS: Elevated hs-cTnI was independently associated with LA abnormality in NVAF patients. hs-cTnI level may be a useful biomarker for risk stratification of thromboembolism in NVAF patients. PMID- 29607893 TI - Impacts of Predischarge Diastolic Functional Recovery on Clinical Outcomes in Patients With Hypertensive Heart Failure. AB - BACKGROUND: Diastolic function is an independent predictor of death in heart failure (HF), but the effect of a change in diastolic function during hospitalization on clinical outcomes in patients with hypertensive HF (HHF) has been poorly studied. Therefore, the aim of this study was to investigate the effect of predischarge diastolic functional recovery (DFR) on future clinical outcomes in hospitalized patients with a first diagnosis of HHF.Methods and Results:A total of 175 hospitalized patients with HHF were divided into 2 groups according to the change in diastolic function on predischarge echocardiography in comparison with baseline echocardiography: DFR group (n=74, 54.2+/-17.1 years, 55 males) vs. no DFR group (n=101, 59.1+/-16.8 years, 72 males). During 66.5+/-37 months of clinical follow-up, major adverse cardiac events (MACE) occurred in 89 patients: 85 HF rehospitalizations, 4 deaths, no MI. The number of MACE were significantly higher in the no DFR group than in the DFR group (61.6% vs. 32.4%, P<0.001). Predischarge systolic functional recovery was not a predictor of MACE, but impaired DFR was an independent predictor of MACE (RR=2.952, P=0.010, confidence interval, 1.878-6.955). CONCLUSIONS: Impaired predischarge DFR, regardless of the type of HF or predischarge systolic functional recovery, is an independent predictor of future MACE in HHF. Changes in diastolic function should be carefully monitored and would be useful in risk stratification of HHF. PMID- 29607895 TI - Seasonal Variations in Neurological Severity and Outcomes of Ischemic Stroke - 5 Year Single-Center Observational Study. AB - BACKGROUND: Seasonal variations in the severity and outcomes of stroke remain unclarified.Methods and Results:A total of 2,965 acute ischemic stroke patients from a single-center prospective registry were studied. Among the total patients, stroke onset did not vary by season, though it varied with a peak in winter when limited to patients >75 years old (P=0.026), when limited to patients with moderate-to-severe initial neurological deficits (National Institutes of Health Stroke Scale Score >=10, P=0.014), and when limited to those with cardioembolic stroke (n=1,031, P=0.010). In 1,934 patients with noncardioembolic stroke, stroke onset did not vary by season. After multivariable adjustment, moderate-to-severe neurological deficits were more common in winter (odds ratio 1.37, 95% confidence interval 1.10-1.72) and spring (1.27, 1.01-1.60), and death at 1 year was more common in summer than in fall (1.55, 1.03-2.36); death or dependency (modified Rankin Scale score 3-6) and death or bedridden (score of 5-6) were not differently common among the seasons. CONCLUSIONS: Overall ischemic stroke showed a fairly even distribution among the 4 seasons. Cardioembolic stroke was more common in winter. Ischemic stroke patients had more moderate-to-severe initial neurological deficits in winter and spring. Poor clinical outcomes at 1 year were generally similar among the seasons. Ischemic stroke is not necessarily a winter dominant disease. PMID- 29607896 TI - Detrimental Effects of Insufficient Warfarin Therapy - A Warning Against Imprudent Use of Warfarin for Atrial Fibrillation Patients. PMID- 29607897 TI - An Application of X-Ray Fluorescence as Process Analytical Technology (PAT) to Monitor Particle Coating Processes. AB - An attempt to apply X-Ray Fluorescence (XRF) analysis to evaluate small particle coating process as a Process Analytical Technologies (PAT) was made. The XRF analysis was used to monitor coating level in small particle coating process with at-line manner. The small particle coating process usually consists of multiple coating processes. This study was conducted by a simple coating particles prepared by first coating of a model compound (DL-methionine) and second coating by talc on spherical microcrystalline cellulose cores. The particles with two layered coating are enough to demonstrate the small particle coating process. From the result by the small particle coating process, it was found that the XRF signal played different roles, resulting that XRF signals by first coating (layering) and second coating (mask coating) could demonstrate the extent with different mechanisms for the coating process. Furthermore, the particle coating of the different particle size has also been investigated to evaluate size effect of these coating processes. From these results, it was concluded that the XRF could be used as a PAT in monitoring particle coating processes and become powerful tool in pharmaceutical manufacturing. PMID- 29607898 TI - Studies on Catalytic Activation of Olefins Using Cobalt Complex. AB - In this review, I tell the story of the cobalt chemistry that has been developed in my group since 2011. First, we achieved the total synthesis of polyketide natural product trichodermatide A, which involved a late-stage Isayama-Mukaiyama hydration of an enol ether using cobalt(II) acetylacetonate (Co(acac)2) that gave the desired product chemo-, regio-, and diastereoselectively. After our report of this total synthesis in 2013, we were required to revise the originally reported structure of trichodermatide A following the accurate and important report from the Trauner group. Second, we found unique cobalt-catalyzed hydroelementation reactions of olefins involving a cobalt-salen complex, N-fluoro-2,4,6 trimethylpyridinium salt, and a silane reagent. Under these reaction conditions, a carbocationic or carbon radical species is generated from an olefin, and then C X (X=O, N, C, F) bond formation occurs with good functional group tolerance for a broad substrate scope. This review also covers recent examples of switching chemistry and natural product synthesis involving my cobalt chemistry reported by several groups. PMID- 29607899 TI - Quality Characterization of Japanese Medicinal Paeoniae Radix by Metallomic Analysis. AB - Paeoniae Radix is one of the crude drugs frequently used in traditional Japanese medicine (Kampo medicine). It takes abundant labor and time to cultivate Paeonia lactiflora for medicinal use; high production cost is one of the main reasons why the domestic production of Paeoniae Radix is decreasing in Japan. To promote the production of Paeoniae Radix, we focused on Paeonia cultivars that produce commercially valuable flowers and investigated their possibility for medicinal use. We prepared 28 batches of peony roots derived from P. lactiflora, which were cultivated in Japan; 4 batches were crude drug samples, and 24 batches were cultivar roots. The elements contained in these samples were measured using inductively coupled plasma (ICP)-MS. The obtained data were then analyzed by principal component analysis (PCA) and back propagation artificial neural network (BPANN) analysis. No significant differences were found between the profiles of elements contained in crude drugs and cultivar roots. However, PCA results indicated a high similarity of the multielement fingerprints of crude drugs. Using the PCA results, we also assessed visible cluster trends and found that 5 batches of cultivars also showed fingerprints related to those of crude drugs. We certified this classification by BPANN. From the perspective of metallomics, our findings suggest that these 5 batches of Paeonia cultivars could be alternatives to crude drugs. PMID- 29607900 TI - Design, Synthesis and Biological Evaluation of Novel Pyrazole Sulfonamide Derivatives as Potential AHAS Inhibitors. AB - Acetohydroxy acid synthase (AHAS; EC 2.2.1.6, also referred to as acetolactate synthase, ALS) has been considered as an attractive target for the design of herbicides. In this work, an optimized pyrazole sulfonamide base scaffold was designed and introduced to derive novel potential AHAS inhibitors by introducing a pyrazole ring in flucarbazone. The results of in vivo herbicidal activity evaluation indicates compound 3b has the most potent activity with rape root length inhibition values of 81% at 100 mg/L, and exhibited the best inhibitory ability against Arabidopsis thaliana AHAS. With molecular docking, compound 3b insert into Arabidopsis thaliana AHAS stably by an H-bond with Arg377 and cation pi interactions with Arg377, Trp574, Tyr579. This study suggests that compound 3b may serve as a potential AHAS inhibitor which can be used as a novel herbicides and provides valuable clues for the further design and optimization of AHAS inhibitors. PMID- 29607901 TI - Chemical Structures of Novel Maillard Reaction Products under Hyperglycemic Conditions. AB - Two novel and two known compounds, 4-quinolylaldoxime and indole-3-aldehyde, were isolated from a reaction mixture consisting of D-glucose and L-tryptophan at physiological temperature and pH. The chemical structures of the two novel compounds were elucidated by spectroscopic analysis such as X-ray crystallography. One of the novel compound and the indole-3-aldehyde showed mutagenicity toward Salmonella typhimurium YG1024 with S9 mix. Furthermore, 4 quinolylaldoxime was detected from streptozotocin-induced diabetic rat plasma by LC-MS/MS analysis; however, the isolated compounds were not detected in rat diet extracts. To our knowledge, this is the first report in which 4-quinolylaldoxime was detected in rat plasma. These results suggest that amino-carbonyl reaction products may be formed in diabetic condition and induce genetic damage. PMID- 29607902 TI - Sugar-Responsive Layer-by-Layer Film Composed of Phenylboronic Acid-Appended Insulin and Poly(vinyl alcohol). AB - Previous studies have shown that reversible chemical bond formation between phenylboronic acid (PBA) and 1,3-diol can be utilized as the driving force for the preparation of layer-by-layer (LbL) films. The LbL films composed of a PBA appended polymer and poly(vinyl alcohol) (PVA) disintegrated in the presence of sugar. This type of LbL films has been recognized as a promising approach for sugar-responsive drug release systems, but an issue preventing the practical application of LbL films is combining them with insulin. In this report, we have proposed a solution for this issue by using PBA-appended insulin as a component of the LbL film. We prepared two kinds of PBA-appended insulin derivatives and confirmed that they retained their hypoglycemic activity. The LbL films composed of PBA-appended insulin and PVA were successfully prepared through reversible chemical bond formation between the boronic acid moiety and the 1,3-diol of PVA. The LbL film disintegrated upon treatment with sugars. Based on the results presented herein, we discuss the suitability of the PBA moiety with respect to hypoglycemic activity, binding ability, and selectivity for D-glucose. PMID- 29607903 TI - Effects of the Chemical Structures of Oligoarginines Conjugated to Biocompatible Polymers as a Mucosal Adjuvant on Antibody Induction in Nasal Cavities. AB - We have been investigating the potential of oligoarginine-linked polymers as an adjuvant for mucosal vaccination that induces immunoglobulin G (IgG) in systemic circulation and immunoglobulin A (IgA) secreted on the mucosa. Our latest infection experiments demonstrated that mice immunized nasally with a mixture of inactivated influenza viruses and poly(N-vinylacetamide-co-acrylic acid) (PNVA-co AA) modified with D-octaarginine were perfectly protected from homologous virus infection. On the contrary, virus infection was observed in mice immunized with the antigen alone. This difference was presumably due to insignificant induction of secreted IgA on the nasal mucosa in the latter mice. Since it was unclear whether the current induction level was sufficient for heterologous virus infection, we evaluated the effects of the chemical structures of oligoarginines conjugated to PNVA-co-AA on induction of intranasal IgA. The number and optical activity of the arginine residues and the degree of modification with oligoarginines in the polymer backbone were listed as a factor that would influence IgA induction. Mouse experiments revealed that maximization of the modification resulted in an increase in adjuvant activities of oligoarginine linked polymers most effectively. Glycine segments inserted between oligoarginines and the polymer backbone were a prerequisite for the maximization. The highest IgA level was observed when antigens were coadministered with diglycine-D-octaarginine-linked PNVA-co-AA. PMID- 29607904 TI - Preparation and in Vitro Analysis of Human Serum Albumin Nanoparticles Loaded with Anthracycline Derivatives. AB - Nanoparticles prepared using human serum albumin (HSA) have emerged as versatile carriers for improving the pharmacokinetic profile of drugs. The desolvation of HSA using ethanol followed by stabilization through crosslinking with glutaraldehyde is a common technique for preparing HSA nanoparticles, but our knowledge concerning the characteristics (or functions) of HSA nanoparticles and their efficiency when loaded with drugs is limited. To address this issue in more detail, we prepared anthracycline-loaded HSA nanoparticles. Doxorubicin-loaded HSA nanoparticles with a size similar to doxorubicin-unloaded particles could be prepared by desolvating at a higher pH (8-9), and the size (100-150 nm) was optimum for delivery to tumor tissues. Using this procedure, HSA nanoparticles were loaded with other anthracycline derivatives, and all showed cytotoxicity in cancer cells. However, the efficiency of drug loading and dissolution rate were different among them possibly due to the differences in the type of association of the drugs on nanoparticles (doxorubicin and daunorubicin; covalently bound to nanoparticles, pirarubicin; both covalently bound to and adsorbed on nanoparticles, aclarubicin; adsorbed on nanoparticles). Since the formulation of such drug-loaded HSA nanoparticles should be modified for efficient delivery to tumors, the findings reported herein provide the useful information for optimizing the formulation and the production process for the HSA nanoparticles using a desolvation technique. PMID- 29607905 TI - Linear Discriminant Analysis for the in Silico Discovery of Mechanism-Based Reversible Covalent Inhibitors of a Serine Protease: Application of Hydration Thermodynamics Analysis and Semi-empirical Molecular Orbital Calculation. AB - We recently reported that the Gibbs free energy of hydrolytic water molecules (DeltaGwat) in acyl-trypsin intermediates calculated by hydration thermodynamics analysis could be a useful metric for estimating the catalytic rate constants (kcat) of mechanism-based reversible covalent inhibitors. For thorough evaluation, the proposed method was tested with an increased number of covalent ligands that have no corresponding crystal structures. After modeling acyl trypsin intermediate structures using flexible molecular superposition, DeltaGwat values were calculated according to the proposed method. The orbital energies of antibonding pi* molecular orbitals (MOs) of carbonyl C=O in covalently modified catalytic serine (Eorb) were also calculated by semi-empirical MO calculations. Then, linear discriminant analysis (LDA) was performed to build a model that can discriminate covalent inhibitor candidates from substrate-like ligands using DeltaGwat and Eorb. The model was built using a training set (10 compounds) and then validated by a test set (4 compounds). As a result, the training set and test set ligands were perfectly discriminated by the model. Hydrolysis was slower when (1) the hydrolytic water molecule has lower DeltaGwat; (2) the covalent ligand presents higher Eorb (higher reaction barrier). Results also showed that the entropic term of hydrolytic water molecule (-TDeltaSwat) could be used for estimating kcat and for covalent inhibitor optimization; when the rotational freedom of the hydrolytic water molecule is limited, the chance for favorable interaction with the electrophilic acyl group would also be limited. The method proposed in this study would be useful for screening and optimizing the mechanism based reversible covalent inhibitors. PMID- 29607906 TI - Highly Diastereoselective Synthesis of 2-(1-N-Boc-aminoalkyl)thiazole-5 carboxylates by Reduction of tert-Butylsulfinyl Ketimines. AB - Positional isomers of naturally occurring peptide subunits were synthesized via highly diastereoselective reduction of tert-butylsulfinyl ketimines as a key reaction. While NaBH4 reduction of ketimines derived from 2-thiazolyl ketones afforded the (RS,R)-isomer with moderate diastereoselectivity, L-Selectride(r) reduction afforded the (RS,S)-isomer as the sole product. In contrast, ketimines derived from tert-butyl 2-thiazolyl ketone afforded the (RS,R)-isomer with low diastereoselectivity by both NaBH4 and L-Selectride(r) reduction. Stereochemistry of the reaction was discussed based on calculation of the conformational energies for ketimines. PMID- 29607907 TI - Synthesis of Novel Benzimidazole-2-carboxamide Derivatives and in Vivo Antihyperlipidemic Activity Evaluation. AB - Hyperlipidemia is known as an elevation of plasma lipid components. It contributes significantly to atherosclerosis which is one of the most important causative factors in cardiovascular diseases. Agents that cause a dramatic decrease in serum lipid levels are of great value in the treatment of cardiovascular diseases. For this purpose, a new series of benzimidazole propyl carboxamide benzophenone derivatives have been synthesized (7, 8, and 9). These compounds were tested in vivo to evaluate their potential hypolipidemic activity using Triton WR-1339 induced hyperlipidemic rats. All the synthesized compounds have proved to be highly biologically active, with compound 9 being the most active derivative. PMID- 29607908 TI - Efficient 1,3,4-Thiadiazole-4,5-dihydropyridazin-3(2H)-ones as Antimicrobial Agents. AB - A set of novel series of 1,3,4-thiadiazolyl-sulfanyl-4,5-dihydropyridazin-3(2H) ones with anticipated antimicrobial activity has been synthesized. The synthetic protocol of the targeted compounds was accomplished by treating beta-aroylacrylic acid 1 with 5-amino-1,3,4-thiadiazole-2-thiol (2) to afford the thia-Michael adduct 3. Afterwards, the obtained thia-Michael adduct 3 was cyclized to 4,5 dihydropyridazin-3(2H)-ones 4a-d and the non-cyclized product hydrazone 5 by using different hydrazines. Moreover, adduct 3 was reacted with esters like diethyl malonate and ethyl acetoacetate affording 1,3,4-thiadiazolobutanamides 6a, b. Furthermore, the concurrent reaction of later butamides 6a, b with the hydrazine derivatives furnished thiadiazolopyridazin-3(2H)-ones 7a-d, 8, and butanoic acid 9. PMID- 29607909 TI - Prenylflavonoids from the Twigs of Artocarpus nigrifolius. AB - Two new prenylated flavones, artocarnin A (2) and carpachromenol (12), together with 13 known prenylflavonoids (1, 3-11, 13-15) were isolated from the twigs of Artocarpus nigrifolius for the first time. Their structures were elucidated by high resolution-electrospray ionization (HR-ESI)-MS, NMR spectroscopic analysis, and in comparison with the reported data. Compounds 1-15 were evaluated for their antiproliferative effects against SiHa and SGC-7901 human cancer cell lines in vitro. The most active compound, eleocharin A (10), showed significant cytotoxicity on SiHa cells (IC50=0.7+/-0.1 uM) and inhibitory activity against SGC-7901 cells (IC50=8.3+/-0.2 uM) and could be considered as potential lead compound for further development of novel anti-tumor agents. PMID- 29607910 TI - Syntheses and Biological Evaluation of Novel Hydroxamic Acid Derivatives Containing Purine Moiety as Histone Deacetylase Inhibitors. AB - The novel hydroxamates containing purine scaffold were designed, synthesized and screened for their biological activities as histone deacetylase (HDAC) inhibitors. Some of them exhibited excellent acti-HDACs activities and antiproliferative activities, the most promising compound was 7m'. Western blot analysis indicated the compounds 7f', 7l', 7m', 7o' could increase histone H3 acetylation levels in HCT116 and K562 cell lines, and 7m' increased the level of acetyl histone H3 in a dose-dependent manner, which is similar to the behavior of suberoylanilide hydroxamic acid (SAHA). Molecular docking study revealed that the conformation of 7m' in the active site of HDAC2 was similar to positive drug SAHA, which were oriented with the hydroxamic acid towards the catalytic center and formed metal binding with zinc ion. PMID- 29607911 TI - Palatability and Preference of Gummi Formulations with Various Pharmaceutical Characteristics. AB - This study aimed to elucidate the appropriate physical characteristics that are clinically acceptable for gummi formulations. We prepared 11 placebo gummi formulations containing different amounts of gelatin and water and evaluated their penetration and restitution using a penetrometer and rheometer, respectively. Clinical sensory tests in 16 healthy volunteers (age, 23.4+/-0.9 years, mean+/-standard deviation) were conducted on the placebo gummi formulations using the visual analog scale (VAS) score to evaluate elasticity, hardness, and overall palatability, with a 5-point rating scale of preference. The penetration increased with decreasing amounts of gelatin or increasing amounts of water in the gummi formulations. Similarly, the VAS score of elasticity and hardness from the clinical sensory tests increased with increasing amounts of gelatin but decreased with increasing amounts of water. The relationship between the penetration and VAS scores of elasticity and hardness revealed good linear correlations. This suggests that the penetration was well reflected by the hardness results of the clinical VAS scores. The overall palatability evaluated using the VAS score increased until the penetration was 10 mm and then plateaued at >10 mm penetration. The 5-point rating score for preference revealed that >50% of volunteers "prefer" the gummi formulations with penetration values of 9.8 to 13.5 mm. These results suggest that gummi formulations likely have an appropriate window of hardness. Furthermore, appropriate gummi formulations with clinically preferred physical characteristics could be prepared by adjusting the amount of gelatin and water and measuring their penetration. PMID- 29607912 TI - Adsorption of Nitrite and Nitrate Ions from an Aqueous Solution by Fe-Mg-Type Hydrotalcites at Different Molar Ratios. AB - In this study, we prepared Fe-Mg-type hydrotalcites (Fe-HT3.0 and Fe-HT5.0) with different molar ratios and evaluated their adsorption capability for nitrite and nitrate ions from aqueous solution. Fe-HT is a typical hydrotalcite-like layered double hydroxide. Adsorption isotherms, as well as the effects of contact time and pH were investigated, and it was found that Fe-HT can adsorb larger amounts of nitrite and nitrate ions than Al-HT (normal-type hydrotalcite). Adsorption isotherm data were fitted to both Freundlich (correlation coefficient: 0.970 1.000) and Langmuir (correlation coefficient: 0.974-0.999) equations. Elemental analysis and binding energy of Fe-HT surface before and after adsorption indicated that the adsorption mechanism was related to the interaction between the adsorbent surface and anions. In addition, the ion exchange process is related to the adsorption mechanism. The adsorption amount increased with increasing temperature (7-25 degrees C). The experimental data fit the pseudo second-order model better than the pseudo-first-order model. The effect of pH on adsorption was not significant, which suggested that Fe-HT could be used over a wide pH range (4-12). These results indicate that Fe-HT is a good adsorbent for the removal of nitrite and nitrate ions from aqueous solution. PMID- 29607913 TI - Eldecalcitol increases bone mass in patients with Turner syndrome who have insufficient bone mass acquisition after estrogen replacement therapy. AB - Most patients with Turner syndrome (TS) exhibit amenorrhea due to premature ovarian failure. Therefore, estrogen replacement therapy (ERT) is required; however, even after undergoing ERT, it is not rare for bone mass acquisition to be insufficient. This study was conducted in two stages, involving a cross sectional and a prospective interventional study. We recruited 52 TS patients undergoing ERT due to amenorrhea (categorized into low (LB group; n = 23), and normal (NB group; n = 29) bone mass groups) and 7 TS patients who maintained ovarian function (spontaneous menstrual cycle group (MC group)) as controls. We compared bone associated markers between the three groups (LB, NB, and MC). Furthermore, the LB group had concomitant treatment with eldecalcitol (ELD) and ERT for 12 months. The bone mineral density (BMD) of the lumber spine (L2-4) and the bone metabolism markers were then compared before and after the treatment. The bone metabolism markers were significantly higher in the LB group than the NB and MC groups. Furthermore, with the concomitant use of ELD and ERT in the LB group, BMD increased significantly (pre-treatment 0.710 +/- 0.056 g/cm2 vs. 0.736 +/- 0.062 g/cm2 after 12 months; p < 0.001). TS patients with insufficient bone mass acquisition even after ERT were characterized by a higher turnover in bone metabolism. Therefore, the concomitant use of ELD was considered an effective adjuvant therapy for increasing bone mass. PMID- 29607914 TI - [A case of neurolymphomatosis presented as cauda equine syndrome accompanied with M-proteinemia]. AB - A 63-year-old man developed a syndrome of cauda equine, with the numbness which is a left lower extremity from the left buttocks, weakness of left leg, and a dysfunction of bladder and bowel. Enhanced MRI revealed the enhancement of lower cauda equine, and a nerve conduction test revealed decreased F-wave persistency in the tibial nerve and increased F-wave latency in the peroneal nerve on the both sides. M-proteinemia was admitted and myeloma was suspected. By a biopsy of a vertebral arch, we diagnosed with diffuse large B-cell lymphoma. We treated with dexamethasone and R-CHOP (rituximab, cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone (prednisolone)), then the symptom was improved. In case of caude equine syndrome with M-proteinemia, a possibility of the malignant lymphoma should also be considered. PMID- 29607915 TI - [A case of limbic encephalitis associated with Sjogren's syndrome mimicking anti N-methyl D-aspartate receptor encephalitis]. AB - A 25-year-old woman in her 37 weeks and 5 days pregnant presented with abnormal behavior and memory impairment following a high fever. Her manifestations were diagnosed as limbic encephalitis, and she delivered a baby by Cesarean section. In the operation, bilateral ovarian tumors were found and resected, though they were revealed as non-teratoma afterward. After operation, she became agitated, and started to present oral dyskinesia, intractable systemic myoclonus, central hypoventilation, and autonomic manifestations such as labile blood pressure, but her symptoms responded well to immunotherapy. Her clinical course was typical for anti-N-methyl D-aspartate (NMDA) receptor encephalitis, but anti-NMDA receptor antibody was not detected in her serum and CSF. On the other hand, anti SS-A antibody was positive in her serum, and the lip biopsy findings confirmed Sjogren's syndrome (SjS). Only several cases of SjS-associated limbic encephalitis have been reported, but none of them mimicked anti-NMDA receptor encephalitis. This patient indicates that SjS should be considered even in a case of limbic encephalitis with a typical clinical spectrum of anti-NMDAR encephalitis. PMID- 29607916 TI - [A nationwide multi-center questionnaire survey on the management and treatment of post-stroke seizure and epilepsy in Japan]. AB - Seizures may occur after stroke. Though the majority of clinicians are aware of this, a consensus-based treatment and management strategy for post-stroke seizures is not available because there have only been a few large-scale studies that have explored this. This study has surveyed the actual state of medical treatment for post-stroke seizure and epilepsy in Japan. We conducted a nationwide questionnaire survey of the top 500 institutions regarding the number of cerebral infarction cases between February 2015 and May 2015. The questionnaire contained 14 items regarding the number of patients, type of tests and treatments conducted, and patient response to the treatments. Surveys from 189 institutions were obtained. A history of previous stroke was reported in 41% of hospitalized patients with epilepsy. The sensitivity of diffusion-weighted MRI and electroencephalography was not sufficient to detect the abnormalities seen in epilepsy. Carbamazepine was the most chosen antiepileptic drug for secondary prophylaxis, followed by valproate acid, and levetiracetam. PMID- 29607917 TI - [CADASIL with cysteine-sparing NOTCH3 mutation manifesting as dissociated progression between cognitive impairment and brain image findings in 3 years: A case report]. AB - A 55-year-old man with no history of stroke or migraine presented to the clinic with cognitive impairment and depression that had been experiencing for two years. Neurological examination showed bilateral pyramidal signs, and impairments in cognition and attention. Brain MRI revealed multiple lacunar lesions and microbleeds in the deep cerebral white matter, subcortical regions, and brainstem, as well as diffuse white matter hyperintensities without anterior temporal pole involvement. Cerebral single-photon emission computed tomography (SPECT) revealed bilateral hypoperfusion in the basal ganglia. Gene analysis revealed an arginine-to-proline missense mutation in the NOTCH3 gene at codon 75. The patient was administered lomerizine (10 mg/day), but the patient's cognitive impairment and cerebral atrophy continued to worsen. Follow-up testing with MRI three years after his initial diagnosis revealed similar lacunar infarctions, cerebral microbleeds, and diffuse white matter hyperintensities to those observed three years earlier. However, MRI scans revealed signs of increased cerebral blood flow. Together, these findings suggest that the patient's cognitive impairments may have been caused by pathogenesis in the cerebral cortex. PMID- 29607918 TI - [A case of histoplasmosis with chronic basilar meningitis diagnosed relatively early]. AB - A 41-year-old man left for Mexico in May 2015. Right pulmonary nodule was detected at a health examination in May 2016, and he subsequently showed headache and slight fever. Contrast-enhanced magnetic resonance imaging of the brain revealed basilar meningitis, so he was admitted to our hospital. We considered imported mycosis due to his travel history to Mexico. We diagnosed histoplasmosis based on the presence of antibodies against Histoplasma in both serum and cerebrospinal fluid. Symptoms almost completely recovered with a liposomal formulation of amphotericin B. Central nervous system histoplasmosis is very rare in Japan. Immunocompetent hosts can develop histoplasmosis, and this pathology is important to consider in patients presenting with basilar meningitis and a positive travel history. PMID- 29607919 TI - [Rapidly deteriorated lobar intracerebral hemorrhages: possible association of varicella zoster virus-vasculopathy]. AB - A 75-year-old man having dementia and lifestyle related diseases developed a lobar intracerebral hemorrhage (LICH) in the left parietal and a small cerebellar infarction in the left occipital lobe. Many micro bleeds (MB) due to cerebral amyloid angiopathy (CAA) in the subcortical areas and multiple vascular stenosis were also found by MRI and MRA. He developed herpes zoster in his buttocks on day 6 of hospitalization and complicated with varicella zoster virus (VZV) meningitis with positive for VZV-DNA in the cerebrospinal fluid. Subsequently, LICHs occurred in the left frontal lobe and in the right parietal lobe for a short period of time and died on the day 18. We speculated that the repeating hemorrhages was primarily caused by VZV vasculopathy and additionally the subcortical MBs increased the hemorrhagic risk. The relationship between VZV vasculopathy and CAA should be studied in the future. PMID- 29607920 TI - Nobiletin Reduces Intracellular and Extracellular beta-Amyloid in iPS Cell Derived Alzheimer's Disease Model Neurons. AB - Alzheimer's disease (AD) is the most common cause of dementia, with progressive memory impairment. Recently, neprilysin, a beta-amyloid (Abeta)-degrading enzyme has become featured as a drug target for AD. Previously, we identified nobiletin from citrus peels as a natural compound possessing anti-dementia activity. In addition, we demonstrated that nobiletin improved memory in memory-impaired animals and, further, that Abeta levels were markedly decreased in the brains of these animals. We demonstrated in vitro that nobiletin up-regulates neprilysin expression and activity in human neuroblastoma cells. However, the action of nobiletin with regard to Abeta degradation under in vitro AD pathological conditions remains unclear. In this study, we examined whether nobiletin could enhance the degradation of intra- and extracellular Abeta using human induced pluripotent stem cell-derived AD model neurons, which generate an excess of Abeta1-42 due to the familial AD presenilin-1 mutation. The neurons were treated in the presence or absence of nobiletin. The results of real-time quantitative RT PCR indicated that neprilysin mRNA levels were significantly up-regulated by nobiletin. Furthermore, immunostaining with an anti-Abeta antibody revealed that nobiletin substantially reduced the intraneuronal content of Abeta. Interestingly, the results of Abeta1-42 immunoassays confirmed that nobiletin also significantly decreased the levels of Abeta1-42 released into the cellular medium. These results suggest that nobiletin enhanced the reduction of intra- and that extracellular Abeta levels under AD pathologic conditions, and this is associated with the up-regulation of neprilysin expression. Collectively, nobiletin appears to be a promising novel prophylactic seed drug or functional food for AD. PMID- 29607921 TI - A Novel Peptide from Vespa ducalis Induces Apoptosis in Osteosarcoma Cells by Activating the p38 MAPK and JNK Signaling Pathways. AB - Osteosarcoma (OS) is a typical bone cancer, and most frequently used cancer treatments for OS are limited due to severe drug-related toxicities. Wasp venoms contain functional components that may offer pharmaceutical components for the treatment of cancers. This study aimed to isolate and characterize a novel peptide (venom anti-cancer peptide 1, VACP1) derived from the wasp venom of Vespa ducalis SMITH. Toxins from Vespa ducalis crude venom were separated by gel filtration and purified by C18 reverse-phase HPLC. As examined by Edman degradation, the amino acid sequence of VACP1 is AQKWLKYWKADKVKGFGRKIKKIWFG. 3 (4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays revealed that VACP1 inhibited the cell proliferation of MG-63, U-2 OS and Saos-2 cells. Furthermore, annexin V and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL) staining revealed that VACP1 could induce the apoptosis of OS cell lines. In addition, VACP1 increased the protein levels of cleaved poly ADP-ribose polymerase (PARP), caspase 3, but decreased B-cell lymphoma 2 (Bcl-2). Apoptotic signaling pathway screening in MG 63 cells via an antibody array revealed that VACP1 activated the p38 mitogen activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) pathways. The present study demonstrates that VACP1 potently suppressed cell proliferation and induced the cell apoptosis of OS cells by inducing the activation of the p38 MAPK and JNK signaling pathways, suggesting that VACP1 is a promising agent for OS therapy. PMID- 29607922 TI - A Standard Intervention Practice to Promote Appropriate Lamotrigine Therapy by Pharmacists. AB - The dosage and frequency of lamotrigine administration for each patient must be prescribed carefully according to the disease, age, concomitant medications, and administration period. According to Pharmaceuticals and Medical Devices Agency (PMDA) reports, either the number of patients with adverse events caused by the inappropriate use of lamotrigine or the ratio of the patients who have benefited from the Relief System for Adverse Drug Reactions did not change even after the revision of the package insert in 2015. The procedure for auditing lamotrigine prescriptions was standardized to improve patient safety in our hospitals. The efficacy of standardization was evaluated by investigating the patients' records and prescriptions. A total of 77 patients treated with lamotrigine were examined to evaluate the appropriateness of the dosage and frequency of administration as well as the number of prescription enquiries made by pharmacists retrospectively. In addition, the presence of adverse events such as skin rash was examined using medical records. The number of inappropriate cases found and the prescription questions asked by pharmacists during the 24-month period before and after standardization were compared. The rate of inappropriate prescriptions after standardization was significantly lower than that before (12.1 vs. 29%; p<0.05). The rate of prescription questions raised after standardization was significantly higher than that before (37.0 vs. 1.7%; p<0.05). Moreover, there was no adverse event after standardization. Our standardization practice was effective to easily identify inappropriate prescriptions and provide physicians with the appropriate dosage or frequency of administration for the patients. PMID- 29607923 TI - Fluorescence Coupled with Macro and Microscopic Examinations of Morphological Phenotype Give Key Characteristics for Identification of Crude Drugs Derived from Scorpions. AB - Microscopic examination of crude drug components has been the traditional method to identify the origin of biological materials. For the identification of components in a given mixture via microscopy, standard reference photographs of fragments derived from different organs and tissues of individual species are required. In addition to these reference photographs, a highly observant eye is needed to compare the morphological characteristics observed under the microscope with those of the references and to then identify the origin of the materials. Therefore, if other indexes are available to be coupled with microscope examination, the accuracy of identification would be significantly improved. Here, we prepared standard reference photographs for microscopic examination to identify powdered and fragmented materials in the crude drug "Quanxie" derived from individual organs of dried scorpion (Buthus martensii KARSCH). Since a remarkable characteristic of scorpion bodies is that they fluoresce under UV light, two methods to identify "Quanxie" were established, including fluorescence fingerprint analysis and microscopic fluorescent luminance imaging analysis. In the former, at least 0.1 g of powered materials was used, which could be recovered after the measurement, and in the latter, only small amounts of powders were used for microscopic examinations. Both methods could distinguish powders of "Quanxie" from those of other micro-morphologically similar crude drugs, namely, "Chantui," "Sangpiaoxiao," and "Jiangcan." The combination of these methods should improve the swiftness and accuracy of "Quanxie" identification. PMID- 29607924 TI - Inhibitory Effect of (-)-Epigallocatechin-3-O-gallate on Octanoylated Ghrelin Levels in Vitro and in Vivo. AB - Ghrelin is an orexigenic peptide hormone produced in the stomach. The major active form is octanoylated ghrelin, which is modified with an n-octanoic acid at the serine-3 residue. Inhibition of octanoylated ghrelin production is useful for the prevention and improvement of obesity. We previously developed a cell-based assay system employing a ghrelin-expressing cell line, AGS-GHRL8, and found various compounds that decreased octanoylated ghrelin levels using this system. ( )-Epigallocatechin-3-O-gallate (EGCG) is a bioactive catechin in green tea and reportedly has an anti-obesity effect; however, it remains unclear whether EGCG inhibits octanoylated ghrelin production. Therefore, in this study, we investigated the effect of EGCG on octanoylated ghrelin levels in AGS-GHRL8 cells and C57BL/6J mice. EGCG significantly reduced the octanoylated ghrelin level in AGS-GHRL8 cells. In mice, three days of treatment with TEAVIGO(r), which contains 97.69% EGCG, lowered the plasma octanoylated ghrelin level by 40% from that in control mice. In addition, TEAVIGO(r) reduced the mRNA expression of ghrelin and prohormone convertase 1/3, an enzyme responsible for the processing of proghrelin to mature ghrelin, in the mouse stomach, suggesting that the reduced expression of these genes may contribute to the inhibition of octanoylated ghrelin production. These results suggest a decrease in the octanoylated ghrelin level to be involved in the anti-obesity effect of EGCG, which thus has potential for the development of anti-obesity agents with ghrelin-lowering effect. PMID- 29607925 TI - ATRA Regulates Innate Immunity in Liver Ischemia/Reperfusion Injury via RARalpha/Akt/Foxo1 Signaling. AB - All-trans retinoic acid (ATRA) has been proved to protect liver from ischemia/reperfusion (IR) injury, however, its mechanism is still unclear. This study is to investigate the mechanism of effect of ATRA on innate immunity in mice liver IR injury. Before operation, mice were gavaged by ATRA at 15 mg/kg/d for two weeks, and then the liver was underwent 70% ischemia (90 min) and reperfusion (6 h). Liver function was assessed by serum alanine aminotransferase (sALT), serum aspartate aminotransferase (sAST). Real-time PCR and Western blot were to detect the level of mRNA and protein. In vitro, RAW264.7 macrophages were treatment with ATRA (1 uM) or LE540 (5 uM, a retinoic acid receptor alpha (RARalpha) receptor antagonist) before lipopolysaccharide (100 ng/mL) stimulation. In vivo, ATRA protected the liver from IR injury by improving hepatocellular function (sALT and sAST), decreasing cell apoptosis and inhibiting inflammatory response (i.e., the level of toll-like receptor 4, transcription factor nuclear factor-kappaBp65, interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha). When RARalpha was blocked by LE540 in RAW264.7 macrophages, the inflammatory cytokines were enhancing, along with a decline of Akt phosphorylation but Forkhead box o (Foxo) 1, compared with the ATRA group. In summary, ATRA regulates in part the innate immunity to protect liver from IR injury by RARalpha/Akt/Foxo1 pathway. PMID- 29607926 TI - Characterization of the SN35N Strain-Specific Exopolysaccharide Encoded in the Whole Circular Genome of a Plant-Derived Lactobacillus plantarum. AB - Lactobacillus plantarum SN35N, which has been previously isolated from pear, secretes exopolysaccharide (EPS). The aim of the present study is to characterize the EPS chemically and to find the EPS-biosynthesizing gene cluster. The present study demonstrates that the strain produces an acidic EPS carrying phosphate residue, which is composed of glucose, galactose, and mannose at a molecular ratio of 15.0 : 5.7 : 1.0. We also show that acidic EPS strongly inhibits the catalytic activity of hyaluronidase (EC 3.2.1.35), promoting an inflammatory reaction. In the present study, we also determined the complete genome sequence of the SN35N strain, demonstrating that the genome is a circular DNA with 3267626 bp, and the number of predicted coding genes is 3146, with a GC content of 44.51%. In addition, the strain harbors four plasmids, designated pSN35N-1, -2, 3, and -4. Although four EPS-biosynthesizing genes, designated lpe1, lpe2, lpe3, and lpe4, are present in the SN35N chromosomal DNA, another EPS gene cluster, lpe5, is located in the pSN35N-3 plasmid, composed of 35425 bp. EPS low-producing mutants, which were obtained by treating SN35N cells with novobiocin, lost the lpe5 gene cluster in the plasmid-curing experiment, suggesting that the gene cluster for the biosynthesis of acidic EPS is present in the plasmid. The present study shows the chemical characterization of the acidic EPS and its inhibitory effect to the hyaluronidase. PMID- 29607927 TI - Noncovalent Strategy with Cell-Penetrating Peptides to Facilitate the Brain Delivery of Insulin through the Blood-Brain Barrier. AB - To overcome the difficulty in delivery of biopharmaceuticals such as peptides and proteins to the brain, several approaches combining the ligands and antibodies targeting the blood-brain barrier (BBB) have been tried. However, these are inefficient in terms of their permeability through the BBB and structural modification of bioactive drugs. In the present study, we therefore examined the usefulness of a noncovalent method using the cell-penetrating peptides (CPPs) such as octaarginine (R8) as a suitable brain delivery strategy for biopharmaceuticals. A safety examination using microvascular endothelial model bEnd.3 cells clarified that R8 was the safest among the CPPs tested in this study. The cellular uptake study demonstrated that coincubation with R8 enhanced the uptake of model peptide drug insulin by bEnd.3 cells in a concentration dependent and a temperature-independent manner. Furthermore, an in vivo study with rats showed that the accumulation of insulin in the deeper region of the brain, i.e., hippocampus, significantly increased after the intravenous coadministration of insulin with D-R8 without altering the insulin disposition in plasma. Thus, the present study provided the first evidence suggesting that the noncovalent method with CPPs is one of the strategic options for brain delivery of biopharmaceuticals via intravenous injection. PMID- 29607928 TI - Mechanisms of the pH- and Oxygen-Dependent Oxidation Activities of Artesunate. AB - Artemisinin was discovered in 1971 as a constituent of the wormwood genus plant (Artemisia annua). This plant has been used as an herbal medicine to treat malaria since ancient times. The compound artemisinin has a sesquiterpene lactone bearing a peroxide group that offers its biological activity. In addition to anti malarial activity, artemisinin derivatives have been reported to exert antitumor activity in cancer cells, and have attracted attention as potential anti-cancer drugs. Mechanisms that might explain the antitumor activities of artemisinin derivatives reportedly induction of apoptosis, angiogenesis inhibitory effects, inhibition of hypoxia-inducible factor-1alpha (HIF-1alpha) activation, and direct DNA injury. Reactive oxygen species (ROS) generation is involved in many cases. However, little is known about the mechanism of ROS formation from artemisinin derivatives and what types of ROS are produced. Therefore, we investigated the iron-induced ROS formation mechanism by using artesunate, a water-soluble artemisinin derivative, which is thought to be the underlying mechanism involved in artesunate-mediated cell death. The ROS generated by the coexistence of iron(II), artesunate, and molecular oxygen was a hydroxyl radical or hydroxyl radical-like ROS. Artesunate can reduce iron(III) to iron(II), which enables generation of ROS irrespective of the iron valence. We found that reduction from iron(III) to iron(II) was activated in the acidic rather than the neutral region and was proportional to the hydrogen ion concentration. PMID- 29607929 TI - Enhanced Activity of Immunosuppressive Oligodeoxynucleotides by Incorporating Them into Hexapod-Like Nanostructured DNA. AB - A151 and other immunosuppressive oligodeoxynucleotides that act as Toll-like receptor (TLR) 9 antagonists are candidate agents for the treatment of autoimmune and inflammatory diseases in which TLR9 activation leads to harmful immune responses. Their efficient delivery to TLR9-positive target cells will increase their potency, but few attempts have been made to enhance their delivery. We previously reported that hexapod-like nanostructured DNA (hexapodna) enhanced the activity of immunostimulatory cytosine-phosphate-guanine (CpG) DNA by efficiently delivering it to immune cells. In this study, to enhance the immunosuppressive activity of A151, we designed a hexapodna containing six copies of the complementary sequence to A151. Structural analyses showed that A151-loaded hexapodna (supHexapodna) was obtained as designed. CpG 1668, which is a typical synthetic CpG DNA, induced tumour necrosis factor-alpha release from mouse macrophage-like RAW264.7 cells, and supHexapodna inhibited this more efficiently than A151. A flow cytometric analysis showed that the uptake of Alexa Fluor 488 labelled A151 by RAW264.7 cells significantly increased when it was incorporated into supHexapodna, whereas the uptake of Alexa Fluor 488-labelled CpG 1668 was hardly affected by A151 or supHexapodna. These results suggest that the hexapodna mediated delivery of A151 can increase the potency of its TLR9-inhibitory activity towards immune cells. PMID- 29607930 TI - Isosteviol Sodium Inhibits Astrogliosis after Cerebral Ischemia/Reperfusion Injury in Rats. AB - Previous reports have indicated that isosteviol sodium (STVNa) has neuroprotective effects against acute focal cerebral ischemia in rats; however, the exact underlying mechanisms and ideal treatment paradigm are not known. To find a reasonable method for STVNa administration and to determine its possible therapeutic mechanisms, we characterized the protective effects of single-dose and multiple-dose STVNa in cerebral ischemic/reperfusion (I/R) injury in rats. Single and multiple treatments with 10 mg/kg STVNa were administered intraperitoneally after injury to investigate its neuroprotective effects. Neurobehavioral deficits and infarct volume were assessed 7 d after ischemia. Both STVNa treatments reduced infarct volumes, improved neurological behaviors, preserved cellular morphology, enhanced neuronal survival, and suppressed cell apoptosis. Multiple treatments performed better than single treatment. Reactive astrogliosis was apparent at 7 d after injury and was significantly inhibited by multiple STVNa treatments but not single treatment. These results indicate that STVNa exerts neuroprotection by different mechanisms in the acute and delayed phases of I/R. Specifically, STVNa neuroprotection in the delayed phase of injury was found to be accompanied with the inhibition of astrogliosis. PMID- 29607931 TI - Ginsenoside-Rg1 Protects against Renal Fibrosis by Regulating the Klotho/TGF beta1/Smad Signaling Pathway in Rats with Obstructive Nephropathy. AB - Ginsenoside-Rg1 (G-Rg1) is an agent isolated from Panax ginseng that exerts anti fibrotic effects; however, the mechanism is still unclear. Herein, we investigated whether G-Rg1 administration can mitigate or reverse unilateral ureteral obstruction (UUO)-induced renal fibrosis by regulating the Klotho/transforming growth factor (TGF)-beta1/Smad signaling pathway in rats. Sprague-Dawley male rats were subjected to UUO, and rats in the treatment group were administered G-Rg1 or G-Rg1 plus Klotho short hairpin RNA interference (shRNA), while rats in the control and model groups were administered vehicle for 14 d. Epithelial-mesenchymal transition (EMT) biomarkers and Klotho/TGF-beta1 signaling molecules were examined by immunohistochemistry, quantitative real-time PCR and Western blotting. Immunohistochemistry showed that UUO induced increased pro-fibrotic TGF-beta1 expression, overexpression of the mesenchymal marker, alpha-smooth muscle actin (alpha-SMA), and suppression of the epithelial marker, E-cadherin. Moreover, Western blotting analysis indicated that UUO promoted TGF beta1 and phosphorylated Smad3 (p-Smad3) expression (p<0.01), but blocked Klotho and Smad7 expression (p<0.01). After G-Rg1 administration, the UUO-induced TGF beta1 and p-Smad3 expression was suppressed (p<0.01), whereas the reduced Klotho and Smad7 expression was reversed (p<0.05), followed by amelioration of the EMT process. Intriguingly, the G-Rg1 effects were largely abrogated by Klotho knockdown. Furthermore, Klotho expression was upregulated by G-Rg1 treatment at the mRNA and protein levels. Our results suggest that G-Rg1 may be beneficial for ameliorating renal fibrosis by targeting Klotho/TGF-beta1/Smad signaling in UUO rats. PMID- 29607932 TI - Studies on the Unusual 1beta-Hydroxylated Bile Acid Biosynthesis in Infants. AB - Unusual bile acids (1beta-hydroxylated bile acids), particularly 1beta-hydroxyl cholic acid (CA-1beta-ol) and 1beta-hydroxyl-chenodeoxycholic acid (CDCA-1beta ol), have been detected in the urine of infants. These acids are conjugated with amino acids, such as taurine, and are then excreted mainly via the urine. CA 1beta-ol and CDCA-1beta-ol are the predominant bile acids during infancy and are present in relatively large amounts in the urine. However, the biosynthetic pathway of 1beta-hydroxylated bile acids in infants remains unclear. To investigate the biosynthetic pathway of 1beta-hydroxylated bile acids during infancy, we performed a metabolic reaction using infant hepatocytes at 3 months after delivery. Glyco- and tauro-CA-1beta-ol were identified by LC/tandem mass spectrometry (MS/MS) analysis of the extracted culture medium incubated with cholic acids (CAs). Further, we identified that ketoconazole suppressed CA 1beta hydroxylation and that the CYP3A subfamily was the primary group of enzymes responsible for CA-1beta-ol formation. The present study provides new information about the biosynthetic pathway of 1beta-hydroxylated bile acids during infancy. PMID- 29607933 TI - Reduction of Membrane Protein CRIM1 Decreases E-Cadherin and Increases Claudin-1 and MMPs, Enhancing the Migration and Invasion of Renal Carcinoma Cells. AB - CRIM1 is a membrane protein that has been reported to be related to cell proliferation. CRIM1 is expressed in renal carcinoma cells, but its involvement in proliferation and malignant transformation remains unclear. We analyzed whether alterations in the characteristics of cancer cells are observed following knockdown of CRIM1. Decreased expression of CRIM1 did not affect proliferation or anchorage-independent growth. The results of wound healing and invasion assays showed that reduced expression of CRIM1 increased cells' migratory and invasive abilities. Expression analysis of factors involved in migration and invasion in CRIM1-knockdown cells revealed that expression of the cell adhesion factor E cadherin declined and expression of claudin-1, which is upregulated in metastatic cancer cells, increased. In addition, increased expression of matrix metalloproteinase (MMP) 2 and MMP9, protease essential for cancer cell invasiveness, was observed. Furthermore, an increase in phosphorylated focal adhesion kinase (FAK), which increases cell migration, was observed. Increased expression of the E-cadherin transcription repressors Snail, Slug, and ZEB-1 were observed, and mRNA levels of E-cadherin were decreased. Therefore, expression of E-cadherin is thought to be decreased by both suppression of E-cadherin mRNA expression and promotion of degradation of the E-cadherin protein. In addition, expression of CRIM1 was decreased in renal cancer cells undergoing epithelial mesenchymal transition (EMT) stimulated by tumor necrosis factor alpha (TNF alpha). Thus, CRIM1 regulates the expression of several EMT-related factors and appears to play a role in suppressing migration and invasion through control of EMT. PMID- 29607934 TI - Virion-Packaged Pyruvate Kinase Muscle Type 2 Affects Reverse Transcription Efficiency of Human Immunodeficiency Virus Type 1 by Blocking Virion Recruitment of tRNALys3. AB - Human immunodeficiency virus type 1 (HIV-1) recruits diverse cellular factors into viral particles during its morphogenesis, which apparently play roles in modulating its infectivity. In our study, proteomic techniques demonstrated that a key glycolytic protein, pyruvate kinase muscle type 2 (PKM2), is incorporated into viral particles. Here, we show that virion-packaged PKM2 significantly reduces viral infectivity by affecting the incorporation level of a cellular tRNALys3 into virions. Enhanced expression of PKM2 in HIV-1-producing cells led to a higher incorporation level of PKM2 into progeny virions without affecting the viral maturation process. Compared with the control virus, the high-level PKM2-packaging virus showed decreased levels of both reverse transcription products and cellular tRNALys3 packaging, suggesting that the shortage of intravirion tRNALys3 suppresses reverse transcription efficiency in target cells. Interestingly, the enhanced expression of PKM2 also suppressed the virion recruitment of other nonpriming cellular tRNAs such as tRNALys1,2 and tRNAAsn, which are known to be selectively packaged into virions, without affecting the steady level of the cytoplasmic pool of those tRNAs in producer cells, suggesting that PKM2 specifically impedes the selective incorporation of tRNAs into virions. Taken together, our findings indicate that PKM2 is a vital host factor that negatively affects HIV-1 infectivity by targeting the tRNALys3-mediated initiation of reverse transcription in target cells. PMID- 29607935 TI - Investigation of Metabolomic Changes in Sunitinib-Resistant Human Renal Carcinoma 786-O Cells by Capillary Electrophoresis-Time of Flight Mass Spectrometry. AB - Acquired resistance to sunitinib is a challenge in the treatment of renal cell carcinoma (RCC). The dysregulation of cellular metabolism is prevalent during resistance acquisition. It is known that in sunitinib-resistant RCC 786-O (786-O Res) cells sunitinib is mainly sequestered in the intracellular lysosomes. However, the relevance between sunitinib resistance and cellular metabolism has not been examined. In this study, we examined the metabolic changes in 786-O Res by using capillary electrophoresis-time of flight mass spectrometry. The cell line 786-O Res was established via persistent treatment with sunitinib, where increase in intracellular sunitinib, and sizes of lysosomes and nuclei were enhanced as compared with those in the parental 786-O (786-O Par) cells. Metabolic analyses revealed that out of the 110 metabolites examined, 13 were up regulated and 4 were down-regulated in the 786-O Res cells. The glycolysis, tricarboxylic acid cycle and pentose phosphate pathway (PPP) were identified as being altered in the sunitinib-resistant cells, which resulted in the enhanced metabolisms of energy, nucleic acids, and glutathione redox cycle. As sunitinib was sequestered in the enlarged lysosomes in 786-O Res, the enriched energy metabolism might contribute to the maintenance of luminal pH in lysosomes via the H+ ATPase. The changes in the PPP could contribute to nuclei enlargement through up-regulation of nucleic acid biosynthesis and protect 786-O Res from cytotoxicity induced by sunitinib through up-regulation of reduced glutathione. Though the direct link between sunitinib resistance and metabolic alternation remains to be elucidated, this metabolomics study provides fundamental insights into acquisition of sunitinib resistance. PMID- 29607936 TI - Characterization of Non-amyloidogenic G101S Transthyretin. AB - Transthyretin (TTR) is a tetrameric beta-sheet-rich protein that is important in the plasma transport of thyroxine and retinol. Mutations in the TTR gene cause TTR tetramer protein to dissociate to monomer, which is the rate-limiting step in familial amyloid polyneuropathy. Amyloidogenicity of individual TTR variants depends on the types of mutation that induce significant changes in biophysical, biochemical and/or biological properties. G101S TTR variant was previously identified in a Japanese male without amyloidotic symptom, and was considered as a non-amyloidogenic TTR variant. However, little is known about G101S TTR. Here, we found slight but possibly important biophysical differences between wild-type (WT) and G101S TTR. G101S TTR had slower rate of tetramer dissociation and lower propensity for amyloid fibril formation, especially at mild low pH (4.2 and 4.5), and was likely to have strong hydrophobic interaction among TTR monomers, suggesting relatively higher stability of G101S TTR compared with WT TTR. Cycloheximide (CHX)-based assay in HEK293 cells revealed that intracellular G101S TTR expression level was lower, but extracellular expression was higher than WT TTR, implying enhanced secretion efficiency of G101S TTR protein compared with WT TTR. Moreover, we found that STT3B-dependent posttranslational N-glycosylation at N98 residue occurred in G101S TTR but not in other TTR variants, possibly due to amino acid alterations that increase N-glycosylation preference or accelerate rigid structure formation susceptible to N-glycosylation. Taken together, our study characterizes G101S TTR as a stable and N-glycosylable TTR, which may be linked to its non-amyloidogenic characteristic. PMID- 29607937 TI - Anti-mouse RANKL Antibodies Inhibit Alveolar Bone Destruction in Periodontitis Model Mice. AB - Denosumab is an anti-bone resorptive drug consisting of complete human monoclonal antibodies that targets receptor activator of nuclear factor kappaB ligand (RANKL), which is responsible for osteoclast formation. The drug has been adapted for bone diseases, such as osteoporosis and bone metastasis related to cancer, but is not used for alveolar bone destruction related to periodontitis. In the present study, we aimed to clarify whether denosumab prevents bone destruction associated with lipopolysaccharide (LPS)-induced calvaria inflammation and experimental periodontitis in model mice. Denosumab does not bind to mouse RANKL, thus we used anti-mouse monoclonal RANKL antibodies. We also examined the inhibitory effects toward bone destruction of another anti-bone resorptive drug zoledronate, a nitrogen-containing bisphosphonate. Local administration of anti- RANKL antibodies into the calvaria area inhibited LPS-induced osteoclast formation and bone destruction, while zoledronate inhibited bone destruction but not osteoclast formation due to its different action mechanism. In periodontitis model mice, in which the second molars were ligated with a silk suture to induce inflammation, intraperitoneal administration of anti-RANKL antibodies significantly inhibited alveolar bone destruction and tooth root exposure. On the other hand, zoledronate only weakly repressed alveolar bone destruction and failed to inhibit root exposure. These results suggest that denosumab is a promising candidate to prevent alveolar bone destruction associated with periodontitis. PMID- 29607939 TI - A Novel Method for Determination of Methadone in the Serum by High-Performance Liquid Chromatography with Electrochemical Detection. AB - In March 2013, the clinical use of oral methadone tablets was initiated in Japan. There are many factors responsible for the change in blood concentrations of methadone, and its pharmacokinetics is very complex. Therefore, a simple and accurate measurement method for methadone blood concentrations was developed using HPLC/electrochemical detector (ECD). An eluent of 10 mM Na2HPO4/CH3CN/CH3OH (20 : 19 : 3) was used as the mobile phase. The column was used the XTerra(r) RP18, and the voltage of the ECD was set at 400 to 800 mV. As a result, the calibration curve was linear in the ranges of 10 to 100 ng/mL (y=5012.7x+1041.1, r=0.999). The intra- and inter-day coefficients of variation were <5.2 and <5.8%, respectively. Therefore, this method was considered to be useful for the measurement of methadone blood levels in cancer patients. Also, using this method, blood methadone concentration was measured over time in a patient with cancer-associated pain who was treated with methadone. The estimated clearance (CL/F) and distribution volume (Vd/F) of methadone were 2.84 L/h and 502.8 L, respectively, and took about two weeks to reach steady state. PMID- 29607938 TI - Hypertension and Proteinuria as Predictive Factors of Effects of Bevacizumab on Advanced Breast Cancer in Japan. AB - Bevacizumab (BV), an inhibitor of vascular endothelial growth factor, is used in combination with paclitaxel (PTX) to treat advanced breast cancer. Hypertension and proteinuria are characteristic adverse events of BV therapy. We assessed the potential of these adverse events as predictors of BV treatment responses. Our results revealed that groups that developed hypertension and proteinuria early (by day 56) had a stronger antitumor response (Fisher's exact test p<0.05). However, no significant difference was observed in progression-free survival (the Kaplan-Meier method and Log-rank test). As a reference, age, the treatment line, subtypes, liver and renal function, diabetes mellitus and hyperlipidemia history, body mass index, influencing concomitant medicine, average relative dose intensity and hematotoxicity did not significantly differ between groups with or without hypertension and with or without proteinuria. These results indicate the potential of the development of hypertension and proteinuria as predictors of improved outcomes with PTX plus BV therapy in patients with breast cancer. However, since both adverse events may preclude the continuation of treatment, their earlier management may be required. PMID- 29607940 TI - Involvement of Tumor Lymphatic System in Translocation of Intratumorally Injected Liposomes. AB - The tumor microenvironment is one of the key factors contributing to the efficiency of drug delivery to a tumor. It has been reported that lymphangiogenesis is induced in certain tumors. Because the lymphatic system functions as a drainage one, it is possible that tumor lymphatic vessels alter not only the tumor microenvironment, but also the distribution of drug nanocarriers accumulated in the tumor tissue. Herein, we aimed to elucidate the involvement of the tumor lymphatic system in the translocation of intratumoral liposomes to regional lymph nodes by using vascular endothelial growth factor (VEGF)-C-overexpressing B16F10 tumor-bearing mice (B16/VEGF-C). When the amount of polyethylene glycol (PEG)-modified liposomes in lymph nodes (cervical, brachial, axillary, and inguinal lymph nodes) was measured after the radiolabeled liposomes had been intratumorally injected into B16/VEGF-C-bearing mice or wild type B16-bearing mice, the accumulation of liposomes in the axillary and inguinal lymph nodes was significantly higher on the tumor-implanted side of B16/VEGF-C bearing mice than on that of the B16-bearing ones. On the other hand, the accumulation of liposomes in these lymph nodes on the control side (no implantation) of either type of tumor-bearing mice was very low; and no difference could be observed between the 2 sides. Furthermore, the intratumoral distribution of liposomes was observed to be located near the lymphatic vessels. These results indicate that the tumor lymphatic system contributed to the extrusion of a portion of PEG-modified liposomes from the tumor tissue, suggesting that tumor lymphangiogenesis would be one of the key factors to determine the intratumoral distribution of liposomes and their subsequent fate. PMID- 29607942 TI - Errata for Biological and Pharmaceutical Bulletin. PMID- 29607941 TI - GYY4137, an Extended-Release Hydrogen Sulfide Donor, Reduces NMDA-Induced Neuronal Injury in the Murine Retina. AB - We previously reported that systemic administration with sodium hydrogen sulfide, a rapid-release donor compound of hydrogen sulfide (H2S), protected retinal neurons against N-methyl-D-aspartic acid (NMDA)-induced injury. For clinical application of H2S donors for retinal neurodegeneration, topical administration with an extended-release donor compound will be better. In the present study, we histologically investigated whether GYY4137, an extended-release hydrogen sulfide donor, had a protective effect on NMDA-induced retinal injury in the mice in vivo. Male and female B6.Cg-Tg(Thy1-CFP)23Jrs/J and C57BL/6J mice anesthetized with a mixture of ketamine and xylazine were subjected to intravitreal NMDA injection (80 nmol/eye). GYY4137 was intravitreally administered with NMDA simultaneously. Morphometric evaluation was carried out seven days after NMDA injection. Intravitreal NMDA induced retinal ganglion cell loss. GYY4137 (1, 10 and 100 nmol/eye) significantly reduced retinal ganglion cell loss seven days after NMDA injection. GYY4137 (10 nmol/eye) decreased the numbers of terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling (TUNEL)-positive and 8-hydroxy-2'-deoxyguanosine (8-OHdG)-positive cells 12 h after NMDA injection. These results suggest that extended release donor compounds of H2S protect retinal neurons against excitotoxicity induced by intravitreal NMDA in the mice in vivo through its anti-oxidative activity. PMID- 29607943 TI - Primary Localized Esophageal Mucosa-associated Lymphoid Tissue Lymphoma Treated by Endoscopic Submucosal Dissection. AB - A 69-year-old Japanese woman presented to our hospital for the further investigation of an esophageal subepithelial tumor. A diagnosis of extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) was made by an endoscopic biopsy. The patient had no involvement other than the esophagus. The tumor was resected using endoscopic submucosal dissection. Lymphoma recurrence has not been documented in the 57 months since resection. This case suggests that although a detailed preoperative evaluation is required to determine the extent of tumor, endoscopic resection may be an option for the long-term disease control of MALT lymphoma of the esophagus. PMID- 29607944 TI - An Autopsy Case of Pulmonary Tumor Thrombotic Microangiopathy Due to Rapidly Progressing Colon Cancer in a Patient with Type 2 Diabetes. AB - We herein describe a case of pulmonary tumor thrombotic microangiopathy (PTTM) with rapidly progressing colon cancer. A 61-year-old man who had been receiving treatment for type 2 diabetes mellitus for 3 years was hospitalized due to critical hypoxemia. Computed tomography, which had not shown any abnormalities 3 months previously, revealed a tumor in the ascending colon, multiple nodules in the liver, and the absence of any lung abnormalities. On day 3 of hospitalization, a sudden onset of severe dyspnea and tachycardia occurred, followed by death. Autopsy revealed microscopic metastatic tumor emboli in multiple pulmonary vessels with fibrin thrombus and intimal proliferation, which led to a diagnosis of PTTM. PMID- 29607946 TI - Clinical Characteristics, Phenotype of Lipodystrophy and a Genetic Analysis of Six Diabetic Japanese Women with Familial Partial Lipodystrophy in a Diabetic Outpatient Clinic. AB - Objective Our aim was to examine the clinical characteristics and phenotype of lipodystrophy of six diabetic Japanese women with partial lipodystrophy (PL) who received a genetic analysis at a diabetic outpatient clinic. Methods We screened for PL using dual energy X-ray absorptiometry (DEXA) and magnetic resonance imaging (MRI) among patients who had a reduced peripheral skinfold thickness at the diabetic outpatient clinic of Kusatsu General Hospital between August 2003 and August 2013. We performed a mutation analysis of candidate genes, including LMNA and PPARG, in two patients with PL and whole-exome sequencing in four patients with PL. Results We identified 15 patients with PL and performed a genetic analysis in 6 of them. They had no mutations in candidate genes known to be associated with familial partial lipodystrophy (FPLD). They all had near complete loss of subcutaneous fat, particularly in the antero-lateral and posterior thigh region and the calf region. As almost all patients were characterized by fat loss in the lower limbs with abdominal fat accumulation, a high rate of positivity for a family history, diabetes, and an unknown genetic cause, we suspected they might have FPLD1. Some patients have shown relatively severe insulin resistance, while others have shown insulin deficiency. Four and one had severe atherosclerosis and liver cirrhosis, probably due to nonalcoholic steatohepatitis, respectively. Conclusion Almost all patients with PL identified in a diabetic outpatient clinic had subcutaneous fat loss in the lower limbs with excess truncal fat and might have had FPLD1. PMID- 29607945 TI - Atrial Fibrillation Had Less Impact on the Risk of Ischemic Stroke in Non anticoagulated Patients Undergoing Hemodialysis: Insight from the RAKUEN study. AB - Objective The progress of non-anticoagulated patients with atrial fibrillation (AF) undergoing hemodialysis has not been determined. Using data from the RAKUEN (Registry of Atrial fibrillation in chronic Kidney disease Under hEmodialysis from Niigata) study, we examined the clinical characteristics and outcomes among hemodialysis patients with AF who were not receiving a vitamin K antagonist (VKA). Methods and Results Forty-three of 423 patients undergoing hemodialysis ( 10%) were prescribed a VKA. The remaining 380 patients (age 64.8+/-12.8 years, male 70%) were enrolled in the present study. During a mean observation period of 36 months, AF (n=55) was independently associated with all-cause death (hazard ratio, 1.82; 95% confidence interval, 1.12-2.94; p=0.014), but was not associated with ischemic stroke (hazard ratio, 1.91; 95% confidence interval, 0.74-4.92; p=0.177) and major bleeding (hazard ratio, 1.80; 95% confidence interval, 0.80 4.08; p=0.150). The crude incidence rates of all-cause death and ischemic stroke in the AF patients were 15.75 (2.5-fold higher compared to the non-AF patients) and 3.63 (1.7-fold higher compared to the non-AF patients) per 100 person-years, respectively. Conclusion A great impact on death, but not ischemic stroke, was observed in non-anticoagulated hemodialysis patients with AF in comparison to those without AF from the analysis of the RAKUEN study. PMID- 29607948 TI - Borrelia miyamotoi Disease Rash. PMID- 29607947 TI - Multimodality Therapy Including Proton Beam Therapy for AFP Producing Esophageal Cancer with Multiple Liver Metastases. AB - A 50-year-old man who presented with a fever and epigastralgia was diagnosed to have esophageal carcinoma which was identified as poorly differentiated adenocarcinoma producing alpha-fetoprotein (AFP) with Barrett's esophagus. Computed tomography revealed multiple liver metastases and lymph node metastases surrounding the stomach. We first performed chemotherapy for the systemic lesions and proton beam therapy for the local control of lesions without complete remission and we were able to successfully control the frequently recurring lesions by proton beam therapy, cryotherapy and chemotherapy. A complete response has been maintained for 16 months and the overall survival time is 4 years and 2 months. Proton beam therapy for primary esophageal cancer and metastatic lesions was thus found to be an effective therapeutic option for such cases. PMID- 29607949 TI - Risk Factors for Death from Psychiatric Hospital-acquired Pneumonia. AB - Objectives Pneumonia is a major cause of death among inpatients at psychiatric hospitals. Psychiatric hospital-acquired pneumonia (PHAP) is defined as pneumonia developed in inpatients at psychiatric hospitals. PHAP is a type of nursing and healthcare-associated pneumonia (NHCAP). The purpose of this study was to clarify the risk factors for mortality among PHAP patients. Methods We retrospectively reviewed the clinical files of patients transferred to Tokyo Metropolitan Matsuzawa Hospital from psychiatric hospitals for PHAP treatment during the 10 year period from September 2007 to August 2017. We analyzed the clinical differences between the survivors and non-survivors and assessed the usefulness of severity classifications (A-DROP, I-ROAD, and PSI) in predicting the prognosis of PHAP. Results This study included a total of 409 PHAP patients, 87 (21.3%) of whom expired and 322 (78.7%) of whom survived. The mortality rates, according to the A-DROP classifications, were 4.9% in the mild cases, 21.6% in the moderate cases, 40.7% in the severe cases, and 47.6% in the very severe cases. The mortality rates, according to the I-ROAD classifications, were 9.5% in group A, 34.7% in group B, and 36.2% in group C. The mortality rates, according to the PSI classifications, were 0% in class II and III, 23.1% in class IV, and 44.9% in class V. The mortality rate increased as the severity increased. We identified 3 factors (age >=65 years, body mass index <=18.5 kg/m2, and bilateral pneumonic infiltration) as significant predictors of mortality. We therefore added two factors (body mass index <=18.5 kg/m2 and bilateral pneumonic infiltration) to the A-DROP classification and established a modified A-DROP classification with a range of 0 to 7. The area under the receiver operation characteristic curves for predicting mortality were 0.699 for the A-DROP classification and 0.807 for the modified A-DROP classification. Conclusion The mortality rate in PHAP patients tended to increase with increasing classifications of severity. The modified A DROP classification may be useful for predicting the prognosis of PHAP patients. PMID- 29607950 TI - A Novel Diagnostic Scoring System to Differentiate between Legionella pneumophila Pneumonia and Streptococcus pneumoniae Pneumonia. AB - Objective We investigated a novel diagnostic scoring system to differentiate Legionella pneumophila pneumonia from Streptococcus pneumoniae pneumonia. Methods We retrospectively reviewed the clinical data of 62 patients with L. pneumophila pneumonia (L-group) and 70 patients with S. pneumoniae pneumonia (S-group). Results The serum sodium (Na) levels tended to be lower according to the severity [age, dehydration, respiratory failure, orientation disturbance, low blood pressure (A-DROP)] score in the L-group. On a multivariate analysis, we found that four factors were independent predictive markers for inclusion in the L group: relative bradycardia [hazard ratio (HR) 5.177, 95% confidence interval (CI): 1.072-24.993, p=0.041], lactate dehydrogenase (LDH) levels >=292 IU/L (HR 6.804, 95% CI: 1.629-28.416, p=0.009), C-reactive protein (CRP) levels >=21 mg/dL (HR 28.073, 95% CI: 5.654-139.462, p<0.001), and Na levels <=137 meq/L (HR 5.828, 95% CI: 1.411-24.065, p=0.015). Furthermore, a total score [ranging from 0 to 4, the sum of the points for each factor (0 or 1)] >=3 points indicated a higher probability of inclusion in the L-group than in the S-group. The diagnostic accuracy of a total score of 3 had a sensitivity of 36.3%, specificity of 100%, and area under the curve of 0.682 (95% CI: 0.558-0.806, p=0.004), and that of a total score of 4 had a sensitivity 27.4%, specificity of 98.2%, and area under the curve (AUC) of 0.627 (95% CI: 0.501-0.754, p=0.045). The diagnostic accuracy had low sensitivity but high specificity. Conclusions We found four markers that might be useful for differentiating L-group from S-group and created a novel diagnostic scoring system. PMID- 29607951 TI - Efficacy of Vonoprazan for Gastroesophageal Reflux Symptoms in Patients with Proton Pump Inhibitor-resistant Non-erosive Reflux Disease. AB - Objective Clinically, patients with proton pomp inhibitor (PPI)-resistant gastroesophageal reflux disease (GERD) are very challenging to treat. The aim of this study was to determine the rates of symptom relief and adverse events among PPI-resistant GERD patients that changed their therapy from a PPI to vonoprazan. Methods Patients with severe gastroesophageal reflux symptoms (total GERD-Q score >=8) without endoscopic findings of mucosal breaks who changed their medication from a PPI to vonoprazan during a 12-week period from 2015 to 2016 at 2 hospitals were selected. The primary outcome was the self-reported relief of gastroesophageal reflux symptoms. The odds ratio (OR) for the improvement of symptoms was calculated based on an exact binomial distribution using a matched pair analysis. The secondary outcome was the GERD-Q score and adverse events. Results Twenty-six patients (6 men) with a mean age of 67.5 years were analyzed. After the therapy was changed from a PPI to vonoprazan, 18 patients (69.2%) reported an improvement, 6 (23.1%) reported no change, and 2 (7.7%) reported an exacerbation of symptoms. A change in therapy was significantly associated with improved self-reported symptoms (OR 9.0, p<0.001). The mean total GERD-Q score during vonoprazan treatment was significantly lower than that during PPI therapy (11.96 vs. 8.92). There were no significant differences in the incidence of adverse events between the therapies. Conclusion Changing the medication from a PPI to vonoprazan was significantly associated with an improvement in gastroesophageal reflux symptoms. Vonoprazan is one of the most promising treatment options for patients with PPI-resistant GERD. PMID- 29607952 TI - A Unique Case with Oral Dyskinesia, Chorea, Ataxia, and Mild Cognitive Impairment with Caudate Atrophy and Characteristic Brain Calcifications. AB - The authors report a man who developed oral dyskinesia at 46 years of age, followed by slowly progressive choreic movement and mild cognitive impairment over 20 years. He showed caudate atrophy and four types of intracranial calcification in the hippocampus (dot-like), cerebellar white matter (vague mass), occipital cortices (laminar), and cerebral white matter (linear). Linear calcification in the corona radiata seems to be deposition along small veins, which may be related to the white matter changes and to the decreased regional cerebral blood flow in the frontal and parietal lobes. The present case shows a slowly progressive disease with caudate atrophy and characteristic brain calcifications. PMID- 29607953 TI - A Rare Case of Ampullary Goblet Cell Carcinoid. AB - An asymptomatic 70-year-old woman was referred to our hospital because of liver enzyme elevation. Enhanced abdominal computed tomography demonstrated a small, round-shaped tumor with dilation of the common bile duct and main pancreatic duct. A biopsy specimen from the papilla showed mucin-containing cells that were positive for endocrine markers on immunohistochemical staining. Endoscopic snare resection was done, and there was a positive vertical margin on pathology. Pancreaticoduodenectomy was then performed later. The final diagnosis was goblet cell carcinoid, pT2N0M0, pStage IIA [Union for International Cancer Control (UICC) 7th edition]. Ampullary goblet cell carcinoid is an extremely rare disease of which there have been no recent reports. PMID- 29607954 TI - Pulmonary Reinfection by Nocardia in an Immunocompetent Patient with Bronchiectasis. AB - Pulmonary reinfection by Nocardia has been rarely reported. We describe a case of pulmonary reinfection by Nocardia in an immunocompetent patient. An 82-year-old immunocompetent woman with bronchiectasis presented with exacerbation of cough. She had a history of pulmonary nocardiosis three years earlier. At that time, Nocardia species were cultured from the sputum and identified as N. cyriacigeorgica with 16S ribosomal RNA gene sequencing. In the present episode, cultures of sputum and bronchial washing specimens grew N. beijingensis, which was identified with 16S ribosomal RNA gene sequencing. Pulmonary reinfection by different Nocardia species can occur in immunocompetent patients. PMID- 29607955 TI - Successful Long-term Management of Two Cases of Moderate Hemoptysis Due to Chronic Cavitary Pulmonary Aspergillosis with Bronchial Occlusion Using Silicone Spigots. AB - Chronic pulmonary aspergillosis is a major cause of life-threatening hemoptysis. In symptomatic patients with simple aspergillomas, surgery is the main therapeutic method for preventing or treating life-threatening hemoptysis. However, the risks of both death and complications are higher in chronic cavitary pulmonary aspergillosis than in simple aspergilloma. We herein report two patients with persistent moderate hemoptysis due to chronic cavitary pulmonary aspergillosis who were not indicated for surgery, but were able to undergo successful long-term management with bronchial occlusion using silicone spigots. In diseases with a high recurrence rate of hemoptysis, the continuous placement of silicone spigots might therefore be effective to prevent rebleeding. PMID- 29607958 TI - Gastric Cavernous Hemangioma Resected by Endoscopic Submucosal Dissection. PMID- 29607957 TI - The Effectiveness of the Rectal Administration of Low-dose Diclofenac for the Prevention of Post-endoscopic Retrograde Cholangiopancreatography Pancreatitis. AB - Objective A 50-100-mg rectal dose of nonsteroidal anti-inflammatory drugs (NSAIDs; diclofenac or indomethacin) has been shown to prevent post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). However, this is higher than the recommended 25-mg dose that is commonly administered to Japanese patients. The objective of this study was to evaluate the safety and efficacy of 25-mg rectal dose of diclofenac in preventing PEP. Methods Between January 2016 and March 2017, a total of 147 patients underwent ERCP with or without the rectal administration of diclofenac (25 mg) 20 min before the procedure. A retrospective analysis was conducted to evaluate the efficacy and safety of this dose in preventing PEP. Results Thirteen patients (8.8%) developed PEP: 3 patients (4.1%) in the diclofenac group and 10 (13.7%) in the control group (p=0.0460). After ERCP, there were no cases of gastrointestinal hemorrhage, ulceration, acute renal failure, or death. A multivariate logistic regression analysis revealed that the non-administration of rectal diclofenac was a risk factor for PEP (odds ratio=3.530; 95% confidence interval=1.017-16.35; p=0.0468). Conclusions A 25-mg rectal dose of diclofenac might prevent PEP. PMID- 29607956 TI - Perforation and Postoperative Bleeding Associated with Endoscopic Submucosal Dissection in Colorectal Tumors: An Analysis of 398 Lesions Treated in Saga, Japan. AB - Objective The aim of this study was to clarify the safety of colorectal endoscopic submucosal dissection (ESD) during the era of health insurance coverage starting from April 2012 in Japan. Methods Between April 2012 and May 2016, ESD was applied to 398 lesions in 373 patients. Risk factors for serious complications of colorectal ESD, perforation and post-ESD bleeding, were evaluated focusing on the resected specimen size, location, growth pattern, invasion depth, histopathology, postoperative clipping, and procedure time. In addition, the relationship between serious complications and patients' background characteristics was analyzed. Results Among 373 patients, perforation occurred in 12 patients and post-ESD bleeding in 19 patients. A univariate analysis showed that the risk factors for perforation were the lesion size, the resected specimen size, and a long operation time. A multivariate analysis showed that a long operation time was a risk factor for perforation during colorectal ESD. A univariate analysis indicated that significant risk factors for postoperative bleeding were a long operation time, rectal lesion, and cancer. All patients with serious complications were treated by an endoscopic procedure without blood transfusion or the need to convert to open surgery. Conclusion The present study suggests that colorectal ESD may be accepted with relative safety in Japan as a common therapeutic approach for early colorectal cancer. PMID- 29607960 TI - Rapidly Progressive Systemic Lupus Erythematosus-related Meningitis with Asymmetric Magnetic Resonance Imaging Findings. PMID- 29607959 TI - Successful Treatment of Aggressive Mature B-cell Lymphoma Mimicking Immune Thrombocytopenic Purpura. AB - A 55-year-old woman suffered from hemorrhagic tendency. She had severe thrombocytopenia without any hematological or coagulatory abnormalities, and a bone marrow examination revealed an increased number of megakaryocytes without any abnormal cells or blasts. No lymphadenopathy or hepatosplenomegaly was observed on computed tomography. She was initially diagnosed with immune thrombocytopenic purpura (ITP). None of the treatments administered for ITP produced a response. However, abnormal cells were eventually found during the third bone marrow examination. The pathological diagnosis was mature B-cell lymphoma. Rituximab-containing chemotherapy produced a marked increase in the patient's platelet count, and her lymphoma went into complete remission. PMID- 29607961 TI - A Patient with HCV Infection and a Sustained Virological Response to Direct acting Antiviral Treatment Who Developed Inclusion Body Myositis. AB - We report the case of a 75-year-old woman who was found to have hepatitis C virus (HCV) infection in 1987. Before treatment in 2016, she was found to have mixed cryoglobulinemia (MC). Direct-acting antiviral (DAA) treatment produced a sustained virological response 12 (SVR12). She noticed gradual muscle weakness in 2015 and the gradual development of dysarthria and dysphagia in 2017. We performed a muscle biopsy that showed inclusion body myositis (IBM). To the best of our knowledge, this is first case of a patient with HCV infection, MC, and IBM, in which MC and IBM did not improve after an SVR12 was obtained by DAA treatment. PMID- 29607962 TI - Listeria Meningitis during Infliximab-based Treatment for Ulcerative Colitis. PMID- 29607964 TI - Gender Differences in the Severity of Sleep Apnea. PMID- 29607965 TI - Tendonitis on the Fingers in Behcet's Disease. PMID- 29607963 TI - Association between the Serum Sodium Levels and the Response to Tolvaptan in Liver Cirrhosis Patients with Ascites and Hyponatremia. AB - Objective Hyponatremia is closely associated with the pathophysiology of cirrhosis. However, the association between the serum sodium level and the response to tolvaptan is unclear. This study evaluated the factors related to the tolvaptan response and the prognosis in cirrhosis patients with ascites and hyponatremia. Methods We retrospectively reviewed the clinical records of cirrhosis patients hospitalized for treatment with tolvaptan. The associations of patient baseline characteristics with the tolvaptan response after one week and of the characteristics after one-month tolvaptan treatment with the prognosis were analyzed. Results We analyzed 83 cirrhosis patients with ascites, including 34 patients with hyponatremia. The response rates to tolvaptan in patients with serum sodium <130 mEq/L, 130-135 mEq/L, and >135 mEq/L were 20%, 66%, and 58%, respectively (p=0.22). The serum sodium level was associated with the response to tolvaptan [odds ratio=1.18; 95% confidence interval (CI) =1.02-1.37; p=0.029]. In patients with hyponatremia, the serum sodium level after 1-month tolvaptan treatment was increased compared to baseline (132 mEq/L vs. 136 mEq/L, p=0.006), and an increasing serum sodium level was associated with a lower risk of mortality (hazard ratio=0.85; 95% CI=0.75-0.97; p=0.016). The survival rate was higher in patients with an increase in the serum sodium level after 1 month than in patients with a decreased serum sodium level (p=0.023). Conclusion Tolvaptan treatment was effective in cirrhosis patients with ascites and hyponatremia, but a low serum sodium level was associated with non-responsiveness to tolvaptan. An increased serum sodium level after one-month tolvaptan treatment may positively influence the mortality risk in cirrhosis patients with hyponatremia. PMID- 29607967 TI - Immune Checkpoint Inhibitor Therapy: A Boon to Elderly Patients with Advanced Melanoma? PMID- 29607966 TI - Allergic Bronchopulmonary Mycosis Due to Schizophyllum commune Treated Effectively with Voriconazole. AB - A 63-year-old woman presented to our hospital for cough, sputum, and abnormal shadows on chest X-ray. Schizophyllum commune was isolated from mucous plugs. Positive specific IgE and IgG against the fungi, elevated serum IgE, and mucous plugs with typical histologic findings of allergic bronchopulmonary mycosis (ABPM) led to the diagnosis of ABPM due to S. commune. We initially administered itraconazole unsuccessfully. Changing the antifungal agent to voriconazole resulted in improvement of the symptoms and chest imaging findings. Her ABPM has not relapsed for two years since the cessation of voriconazole, which was administered for one year. PMID- 29607968 TI - The SGLT2 Inhibitor Dapagliflozin Significantly Improves the Peripheral Microvascular Endothelial Function in Patients with Uncontrolled Type 2 Diabetes Mellitus. AB - Objective Sodium-glucose co-transporter 2 (SGLT2) inhibitors reduce cardiovascular events and decrease the body fat mass in patients with type 2 diabetes mellitus (T2DM). We examined whether or not the SGLT2-inhibitor dapagliflozin can improve the endothelial function associated with a reduction in abdominal fat mass. Methods We prospectively recruited patients with uncontrolled [hemoglobin A1c (HbA1c) >7.0%] T2DM who were not being treated by SGLT2 inhibitors. Patients were treated with add-on dapagliflozin (5 mg/day) or non SGLT2 inhibitor medicines for 6 months to improve their HbA1c. We measured the peripheral microvascular endothelial function as assessed by reactive hyperemia peripheral arterial tonometry (RH-PAT) and calculated the natural logarithmic transformed value of the RH-PAT index (LnRHI). We then investigated changes in the LnRHI and abdominal fat area using computed tomography (CT). Results The subjects were 54 patients with uncontrolled T2DM (72.2% men) with a mean HbA1c of 8.1%. The HbA1c was significantly decreased in both groups, with no significant difference between the groups. Dapagliflozin treatment, but not non-SGLT2 inhibitor treatment, significantly increased the LnRHI. The changes in the LnRHI were significantly greater in the dapagliflozin group than in the non-SGLT2 inhibitor group. Dapagliflozin treatment, but not non-SGLT2 inhibitor treatment, significantly decreased the abdominal visceral fat area, subcutaneous fat area (SFA), and total fat area (TFA) as assessed by CT and significantly increased the plasma adiponectin levels. The percentage changes in the LnRHI were significantly correlated with changes in the SFA, TFA, systolic blood pressure, and adiponectin. Conclusion Add-on treatment with dapagliflozin significantly improves the glycemic control and endothelial function associated with a reduction in the abdominal fat mass in patients with uncontrolled T2DM. PMID- 29607969 TI - Phlegmonous Gastritis: A Report of Three Cases with Clinical and Imaging Features. AB - Phlegmonous gastritis is a rare but often fatal acute pyogenic infection of the stomach. We herein report three cases of phlegmonous gastritis with different causes: the long-term placement of a nasogastric feeding tube, bacteremia associated with cellulitis in a diabetic patient, and an adverse reaction to paclitaxel/carboplatin chemotherapy for cancer of unknown primary cause, which were classified as primary, secondary, and idiopathic types, respectively. Coping with the increasing morbidity rate associated with the diverse background of such patients requires a thorough understanding of the clinical features and image findings associated with this entity. PMID- 29607970 TI - Atrial Fibrillation in Patients with End-stage Kidney Disease on Dialysis. PMID- 29607971 TI - Prolonged Epigastric Pain Caused by a Leaf Stem Embedded in the Gastric Wall. AB - A 67-year-old woman underwent esophagogastroduodenoscopy to determine the cause of her prolonged epigastric pain. During the examination, a sharp-pointed foreign body was observed; the edge of the object had been embedded in the gastric wall. The object was removed via an endoscope, and the patients' symptoms improved immediately. Based on a dietary history and an electron microscope examination, we identified the object as a stem of mizuna, a potherb mustard. Our report indicates that commonly eaten leafy green vegetables can act as sharp-pointed foreign bodies with the potential to injure the upper gastrointestinal tract. PMID- 29607972 TI - Gender Differences in the Clinical Features of Sleep Apnea Syndrome. AB - Objective Sleep apnea syndrome is more prevalent among men than women and is frequently accompanied by metabolic syndrome (MetS). However, gender differences in the effect of sleep-disordered breathing (SDB) leading to the risk of MetS remain unclear. The aim of our study was to investigate the clinical characteristics of SDB in women and the differential influence of SDB on MetS between genders. Methods In a single-center retrospective study, we compared the data of 1,809 consecutive SDB patients by gender to clarify the characteristics of sleep disorders in women. We also compared the prevalence of MetS and its related abnormalities by gender. A logistic regression analysis was used to determine the contributory factors for MetS. Results The mean age and proportion of patients over 50 years of age were higher in women than in men. SDB was milder in women than in men according to polysomnography findings. Elevated Hemoglobin A1c levels and hyperlipidemia were less frequent in women than in men. The MetS prevalence was similar in women and men (30.0% vs. 35.2%). A logistic regression analysis showed that the apnea-hypopnea index (AHI) was an independent risk factor for MetS in both genders, but that female gender was independently associated with a decreased prevalence of MetS and its related abnormalities. Conclusion Female SDB patients tend to be older with milder apnea and sleepiness than male SDB patients. A higher AHI is a significant risk factor for MetS in both genders, although female gender is an independent inhibitory factor for developing MetS in SDB patients. PMID- 29607973 TI - Malignant Pleural Mesothelioma with Bone Marrow Metastases. AB - A 64-year-old man with the bone marrow metastasis due to malignant pleural mesothelioma (MPM) was diagnosed with anemia, leukoerythroblastosis, thrombocytopenia, and lower back pain. A bone marrow biopsy demonstrated infiltrative malignant mesothelioma lesions in the bone marrow. The patient died within 15 days of the detection of the bone marrow involvement. Physicians should consider performing a bone marrow biopsy to diagnose bone marrow metastasis and treat patients with palliative chemotherapy at an earlier phase of the disease. To our knowledge, this is the first report of an MPM patient having bone marrow metastasis with anemia, leukoerythroblastosis, and thrombocytopenia. PMID- 29607974 TI - Silent Native-valve Endocarditis Caused by Propionibacterium acnes. AB - We describe a rare case of Propionibacterium acnes native-valve endocarditis that silently progressed in a 67-year-old man with hybrid dialysis. The patient was scheduled for kidney transplantation, and pre-operative investigation incidentally detected a vegetative structure at his native mitral valve that had increased in size. He underwent cardiac surgery and P. acnes was detected in cultures of a resected cardiac valve specimen and blood. This case highlights that P. acnes can silently cause infective endocarditis in a native-valve, and that physicians should consider the possibility of infection when P. acnes is isolated in blood cultures. PMID- 29607975 TI - Pseudomembranous Invasive Tracheobronchial Aspergillosis with Fulminant Hepatitis and Hemophagocytic Syndrome. AB - Invasive tracheobronchial aspergillosis (ITBA), a rare form of invasive pulmonary Aspergillus infection (IPA), is predominantly confined to the tracheobronchial tree. We herein report a case of ITBA with severe necrotic pseudomembrane in a 57 year-old woman with fulminant hepatitis and hemophagocytic syndrome. Bronchoscopic findings revealed a widespread pseudomembranous formation of the trachea and bronchi. Aspergillus fumigatus was cultured from bronchial lavage fluid, and the histological findings of an endobronchial biopsy revealed necrosis and invasive hyphae. Although she responded to antifungal treatment, she ultimately died of a septic shock with Burkholderia cepacia 57 days after admission. PMID- 29607976 TI - Tattoo-like Spread of Malignant Melanoma. PMID- 29607977 TI - A Fungus Ball Caused by Candida Pyelonephritis. PMID- 29607979 TI - HCM. PMID- 29607980 TI - Correlation between Nutritional State and Prognosis of Heart Failure, with a Focus on the Immune System. PMID- 29607978 TI - The Efficacy of Minodronate in the Treatment of Glucocorticoid-induced Osteoporosis. AB - Objective To investigate the efficacy of minodronate in the treatment of glucocorticoid-induced osteoporosis (GIO). Methods The study population included patients in whom the administration of minodronate (50 mg, once every 4 weeks) had been newly started for the treatment of GIO in Niigata Rheumatic Center from 2012 to 2015. Patients who were bisphosphonate-naive and those who switched from other bisphosphonates were classified into the naive and switch groups, respectively. The changes in the bone mineral density (BMD) and bone metabolic markers after one year of minodronate treatment were retrospectively evaluated. We also compared the BMD and bone turnover marker changes of minodronate-naive patients with those in whom alendronate or risedronate had been prescribed as a first bisphosphonate (control group). Results Minodronate was prescribed to 142 patients, and data were successfully obtained from 120 patients. New vertebral fractures were observed in 5 of the 142 patients; 1 fracture occurred during the cessation of minodronate for dental treatment, and 3 patients already had multiple vertebral fractures before the initiation of minodronate. The patients' tartrate-resistant acid phosphatase 5b (TRACP-5b) (-27.0%, p<0.001) and bone alkaline phosphatase (BAP) (-15.7%, p<0.01) levels were decreased, but no patients showed a decrease to below the normal range. One year of treatment with minodronate significantly increased the lumbar BMD in the naive (+3.9%, p<0.001) and switch (+2.3%, p<0.001) groups. Although the femoral BMD did not change to a significant extent overall, the patients with a low young adult mean (YAM) (<80%) at baseline showed a significant increase in their femoral BMD (+2.1%, p=0.034) values. Compared with the control group, the minodronate-naive group showed a significant decrease in the TRACP-5b levels and a significant increase in the lumbar BMD. Conclusion The administration of minodronate appears to be an effective treatment for GIO. PMID- 29607981 TI - The Future of Women in Japanese Cardiology. PMID- 29607982 TI - Erratum: Shorter Heart Failure Duration Is a Predictor of Left Ventricular Reverse Remodeling During Adaptive Servo-Ventilator Treatment in Patients With Advanced Heart Failure. AB - An error appeared in the article entitled "Shorter Heart Failure Duration Is a Predictor of Left Ventricular Reverse Remodeling During Adaptive Servo-Ventilator Treatment in Patients With Advanced Heart Failure" by Teruhiko Imamura, Koichiro Kinugawa, Daisuke Nitta, and Issei Komuro (Vol. 57, No. 2, 198-203, 2016). The Figure 1 on page 201 should be replaced by the following figure. PMID- 29607983 TI - Non-Ischemic Heart Failure With Reduced Ejection Fraction Is Associated With Altered Intestinal Microbiota. AB - BACKGROUND: Research suggests that heart failure with reduced ejection fraction (HFrEF) is a state of systemic inflammation that may be triggered by microbial products passing into the bloodstream through a compromised intestinal barrier. However, whether the intestinal microbiota exhibits dysbiosis in HFrEF patients is largely unknown.Methods and Results:Twenty eight non-ischemic HFrEF patients and 19 healthy controls were assessed by 16S rRNA analysis of bacterial DNA extracted from stool samples. After processing of sequencing data, bacteria were taxonomically classified, diversity indices were used to examine microbial ecology, and relative abundances of common core genera were compared between groups. Furthermore, we predicted gene carriage for bacterial metabolic pathways and inferred microbial interaction networks on multiple taxonomic levels.Bacterial communities of both groups were dominated by the Firmicutes and Bacteroidetes phyla. The most abundant genus in both groups wasBacteroides. Although alpha diversity did not differ between groups, ordination by beta diversity metrics revealed a separation of the groups across components of variation.StreptococcusandVeillonellawere enriched in the common core microbiota of patients, whileSMB53was depleted. Gene families in amino acid, carbohydrate, vitamin, and xenobiotic metabolism showed significant differences between groups. Interaction networks revealed a higher degree of correlations between bacteria in patients. CONCLUSIONS: Non-ischemic HFrEF patients exhibited multidimensional differences in intestinal microbial communities compared with healthy subjects. PMID- 29607985 TI - Towards the Application of Endovascular Treatment for Superficial Femoral Artery. PMID- 29607984 TI - Assessment of Second- and Third-Generation Drug-Eluting Stents on Chronic Coronary Angioscopy - Multicenter Study on Intra-Coronary AngioScopy After Stent (MICASA) Prospective Data Analysis. AB - BACKGROUND: The vascular response, in terms of quality and quantity, of the second- and third-generation drug-eluting stents (2G- and 3G-DES, respectively) was assessed prospectively on coronary angioscopy (CAS).Methods and Results:The Multicenter study on Intra-Coronary AngioScopy After Stent (MICASA) is a multicenter CAS registry. A total of 107 DES (71 2G- and 36 3G-DES) were prospectively observed on CAS 8.7+/-2.7 months after percutaneous coronary intervention. Neointimal coverage (NC) grade was evaluated using a 4-point grading scale, from 0 (no coverage) to 3 (complete coverage). Plaque yellow color (YC) was also assessed using a 4-point grading system, from 0 (white) to 3 (bright yellow). Max-NC (2G-DES vs. 3G-DES: 2.14+/-0.68 vs. 2.44+/-0.73, P=0.023); min-NC (1.07+/-0.48 vs. 1.39+/-0.60, P=0.002), and dominant-NC (1.57+/ 0.69 vs. 2.08+/-0.84, P=0.002) were significantly higher and the YC grade (1.23+/ 0.82 vs. 0.86+/-0.76, P=0.031) significantly lower in the 3G-DES group than in the 2G-DES group. There was no significant difference in the presence of thrombus (28.2% vs. 22.2%, P=0.51) between the 2G- and 3G-DES groups. CONCLUSIONS: The higher NC grade and lower YC grade in 3G-DES than in 2G-DES might be associated with better long-term clinical outcome, which remains to be determined in future studies. PMID- 29607986 TI - [Development of Noninvasive Drug Delivery Systems to the Brain for the Treatment of Brain/Central Nervous System Diseases]. AB - In general, the blood-brain barrier (BBB) poses a major challenge to drug development efforts targeting brain/central nervous system (CNS) diseases, since it limits the distribution of systemically administered therapeutics to the brain/ CNS. Therefore, the development of effective strategies for enhancing drug delivery to the brain has been a topic of great interest in both the clinical and pharmaceutical fields. Intranasal administration has been noted as a method for noninvasive delivery of a drug to the brain/CNS by bypassing the BBB via the "nose-to-brain" route. This nose-to-brain delivery system has the potential to be highly versatile, and a combination of this system with new drugs and siRNA shows promise in the treatment of CNS diseases. Cell-penetrating Tat peptide-modified block copolymer micelles have the potential for improving mucosal permeability and nose-to-brain transport efficiency. In addition, nano-sized drug carriers can improve nose-to-brain delivery through their ability to increase the stability of encapsulated drugs against biological degradation in the nasal cavity and brain/CNS. In this review, we introduce the assessment of and mechanisms for delivery to the brain after intranasal drug/siRNA administration with our cell penetrating peptide-modified nano-sized polymer micelles. Our findings show that the use of polymer micelles with surface modification by cell-penetrating peptides for intranasal administration enables the noninvasive delivery of therapeutic agents to the brain/CNS by increasing the nose-to-brain transfer of the drug or siRNA administered from the nasal cavity. PMID- 29607987 TI - [Establishing Individualized Medicine for Intractable Cancer Based on Clinical Molecular Pathogenesis]. AB - Although cancer treatment has dramatically improved with the development of molecular-targeted agents over the past decade, identifying eligible patients and predicting the therapeutic effects remain a major challenge. Because intratumoral heterogeneity represents genetic and molecular differences affecting patients' responses to these therapeutic agents, establishing individualized medicine based on precise molecular pathological analysis of tumors is urgently required. This review focuses on the pathogenesis of oral squamous cell carcinoma (OSCC), a common head and neck neoplasm, and introduces our approaches toward developing novel anticancer therapies particularly based on clinical molecular pathogenesis. Deeper understanding of more precise molecular pathogenesis in clinical settings may open up novel strategies for establishing individualized medicine for OSCC. PMID- 29607988 TI - [How Do We Promote Research Integrity?] PMID- 29607989 TI - [Research Misconduct in Japan and How It Is Covered by the Media]. AB - Cases of research misconduct (fabrication, falsification, and plagiarism) have been increasing worldwide, including in Japan. In particular, since 2006, many cases of research misconduct have been reported in Japan, and these cases have also been covered by the media. The 2014 case of the withdrawal of articles on STAP cells followed a rare course in which research misconduct became a full blown social phenomenon. In recent years, even the University of Tokyo has experienced reported cases of research misconduct. In this report, I would like to introduce some representative cases of research misconduct in the field of life sciences over the past decade. These examples include studies conducted at Osaka University Graduate School of Medicine (2006), Osaka University Graduate School of Frontier Bioscience (2006), Ryukyu University School of Medicine (2010), Toho University School of Medicine (2012), The University of Tokyo Institute of Molecular and Cellular Biosciences (2013), and several cases outside of Japan. I will discuss what researchers should do to reduce the incidence of research misconduct. In addition, I will discuss how these cases were covered by the media, because the public's impression of research misconduct is formed by media coverage. PMID- 29607990 TI - [Efforts to Promote Research Integrity in Academia]. AB - The revised model/core curriculum for pharmaceutical education in Japan was introduced in 2015. The need to provide ethics education, which includes research integrity for pharmacists and those conducting pharmaceutical research, was clearly described in the document: "G: pharmaceutical research (2) rule of law and ethics essential for research activity." Additionally, this newly introduced model/core curriculum was officially requested within each pharmaceutical university. As recently as 2014, a severe situation was exposed in the field of life sciences and clinical research: many reports emerged about scientific misconduct in Japan. The members of Kyoto Pharmaceutical University were deeply concerned about this situation and thus decided that our guidelines of action for research integrity would be approached as follows: All members of Kyoto Pharmaceutical University would individually rethink the university's research integrity and ethics with a strong sense of ownership and importance, discuss concrete countermeasures and future plans to establish our university's research integrity, and collectively implement these strategies through education programs. In this review, we introduce several examples of educational activities undertaken by our university, and use them as a basis for discussing how we should address research integrity and the responsible conduct of research in education for academics, graduate students, and undergraduates. PMID- 29607991 TI - [Promoting Research Integrity]. AB - Japan Agency for Medical Research and Development (AMED) was launched in April 2015 to promote integrated medical research and development (R&D) ranging from basic research to practical applications, in order to smoothly achieve the nationwide application of research outcomes, and to establish an environment therefor. AMED consolidates budgets for R&D expenses, which had previously been allocated from different sources, such as the Ministry of Education, Culture, Sports, Science and Technology, the Ministry of Health, Labour and Welfare, and the Ministry of Economy, Trade and Industry. It provides funds strategically to universities, research institutions, etc. By promoting medical R&D, AMED aims to achieve the world's highest level of medical care/services to contribute to a society in which people live long and healthy lives. To achieve this mission, it is imperative that R&D funded by AMED is widely understood and supported. Maintaining and improving research integrity is a prerequisite to this end. AMED is taking various measures to ensure fair and appropriate R&D. It is asking researchers to participate in its responsible conduct in research (RCR) education program and to comply with its rules for managing conflicts of interest (COI). In addition, AMED also conducts a grant program to create and distribute a variety of educational materials on RCR and other matters. Further, AMED is establishing a platform that allows researchers to exchange information about research integrity, and it is undertaking additional measures, such as holding meetings and international symposia on research integrity. PMID- 29607992 TI - [Recent Progress in Promoting Research Integrity]. AB - An increasing number of cases of research misconduct and whistle-blowing in the fields of medicine and life sciences has created public concern about research integrity. In Europe and the United States, there has been a large focus on poor reproducibility in life science research, and poor reproducibility is largely associated with research misconduct. Research integrity is equally crucial in the pharmaceutical sciences, which play an important role in medical and life sciences. Individual cases of research misconduct have not been investigated in detail in Japan, because it was generally believed that only researchers with strong or strange personalities would participate in misconduct. However, a better understanding of research misconduct will enable more in-depth discussions about research integrity, which is now known to be closely associated with normal research activities. Here I will introduce information on various contemporary activities being performed to create a sound research environment, drawn from practices in universities, pharmaceutical companies, and government agencies. I will also discuss ways in which individual researchers can promote research integrity. PMID- 29607993 TI - [Fascination of Sacran, a Polysaccharide from Aphanothece sacrum]. PMID- 29607994 TI - [Super Liquid Crystalline Polysaccharides Produced by Ultimately-ecological Microreactors]. AB - Cyanobacteria fix carbon dioxide and nitrogen from the atmosphere using solar energy to produce various biomolecules, and thus are regarded as ultimately ecological microreactors. Sacran is a cyanobacterial polysaccharide with a very high molecular weight of 29 Mg/mol, which is extracted from Aphanothece sacrum cyanobacterium mass-cultivated in freshwater environments such as river or spring. Sacran is a water-soluble heteropolysaccharide comprising more than 6 kinds of sugar residues and contains 12% sulfate anionic groups and 27% carboxyls. Sacran has a super-absorbent function of water, which can retain 6000 mL for 1 g specimen, due to very long hydrating chains. The value is much higher than hyaluronic acid or conventional super-absorbent polymers. Sacran exhibits self-orienting behavior in dilute solution at a concentration range over 0.25 wt%, which is quite low when compared with conventional liquid crystalline polysaccharides. Mesogenic helical chains of sacrans have extremely high aspect ratios of 1600 for highly persistent lengths of 32 micrometer. Through the liquid crystallinity, sacran solution shows a shear-thinning behavior and the solution spread over a substrate such as biological skin very efficiently to create a thin layer. Applied on atopic dermatitis skin sacran solution exerts excellent moisturizing effect and anti-itching action. PMID- 29607995 TI - [Negative Thixotropic Behavior for Sacran Aqueous Solutions]. AB - We investigated the electric and viscoelastic properties for the aqueous solution of cyanobacterial megamolecules, named sacran. Sacran is an anionic polyelectrolyte that has carboxylate and sulfate groups on the saccharide chain. The electric conductivity and shear viscosity demonstrated three crossover concentrations; overlap concentration at 0.004 wt%, entanglement concentration at 0.02 wt%, and gelation concentration at 0.1 wt%. The decrease in the charge density of the sacran chains reduces the repulsive force between the chains and this would cause transformation from the dilute to condensed states. At extremely low flow rates, sacran demonstrated a behavior called negative thixotropy in which the shear viscosity increased over time. In this review, the conformation of sacran chain in pure water is discussed and its negative thixotropy is briefly described. PMID- 29607996 TI - [Unidirectionally-oriented Membrane Formation of Supra-polysaccharides Sacran and Application to Drug Delivery System]. AB - The geometric structures of soft materials can be controlled on the macro-scale using interfacial or mechanical instability, e.g., fingering patterns of viscous liquid and buckling patterns of gels during swelling/deswelling. These patterns can be used as smart materials for capturing/releasing and mass-transportation applications. Here we introduce the emergence of a uniaxially oriented membrane by drying an aqueous liquid-crystalline solution, composed of megamolecular supra polysaccharides "sacran", from a limited space. By controlling the geometries of the evaporation front, multiple nuclei emerge that grow into upright membranes with uniaxial orientation. Notably, the uniaxially orientated membrane composed of rod-like microdomains is rationally formed along the dynamic three-phase contact line. Besides, the membrane macroscopically partitions the three dimensional cuboid cell for evaporating the aqueous solution. We envision that such a uniaxially oriented membrane can be used as soft biomaterials such as dialysis membranes with directional controllability in medical and pharmaceutical fields. PMID- 29607998 TI - [Potential Use of Sacran Hydrogels as Wound Dressing Material]. AB - A wound dressing is one of the essential approaches to prevent further harm to cutaneous wounds as well as to promote wound healing. Therefore, to achieve ideal wound healing, the development of advanced dressing materials is necessary. Sacran, a novel megamolecular polysaccharide derived from the cyanobacterium Aphanothece sacrum, has a very high molecular weight that exceeds 107 g/mol and water-superabsorbent capacity. Recently, we demonstrated that sacran exerts anti inflammatory activity by ameliorating the skin barrier function in patients with atopic dermatitis. In this study, to develop and characterize sacran hydrogel films (Sac-HGFs) for wound dressing materials, we prepared a physically crosslinked-Sac-HGFs, and evaluated their physicochemical properties, cytotoxicity, skin hydration and wound healing ability. Additionally, we encapsulated curcumin, as a model drug for wound healing, into Sac-HGFs by complexation with 2-hydroxypropyl-gamma-cyclodextrin (HP-gamma-CyD), and investigated their potential for wound dressing application. Sac-HGF has potentially good properties for wound dressing application, due to not only the moisturizing effect but also the anti-inflammatory effect of sacran. Additionally, Sac-HGF has the potential to deliver water soluble complex of curcumin/HP-gamma-CyD at the wound site and thereby promote wound healing. These findings may be useful information for preparation of wound dressing materials using sacran, CyDs and drugs. PMID- 29607997 TI - [Anti-inflammatory Effect of Sacran on Atopic Dermatitis]. AB - Atopic dermatitis (AD) is a chronic skin disease characterized by inflammation, pruritus, and eczematous lesions. Recently, sacran, a new polysaccharide isolated from cyanobacterium Aphanothece sacrum (Sur.) OKADA discovered by Suringar in the 19th century, has received considerable attention as a novel biomaterial. Previously, it was reported that sacran exhibits potent anti-inflammatory effects for skin diseases produced by various stimulants with optimum effective concentrations at 0.01% (w/v) and 0.05% (w/v) in rats and mice. Importantly, we demonstrated clinically that almost all of the average scores for AD symptoms in patient treated with sacran solutions were improved. In AD model mice, sacran treatment markedly down-regulated inflammatory cytokine and chemokine mRNA levels compared with non-treated controls. Furthermore, sacran solution significantly suppressed inflammation response in RAW264.7 cells. In RBL-2H3 cells, the sacran solution significantly lowered degranulation. Taken together, our studies suggest sacran may have the potential to improve AD through functional recovery of skin barrier and anti-inflammatory effects. PMID- 29607999 TI - [Appropriate Planning and Management of Annual Meeting for All Attendees; Application of Active Learning]. PMID- 29608000 TI - [The 10th Annual Meeting of the Japanese Society for Pharmaceutical Palliative Care and Sciences]. AB - The 10th Annual Meeting of the Japanese Society for Pharmaceutical Palliative Care and Sciences was held at Act City Hamamatsu, Japan, with a total of 2634 participants in attendance. The theme of the meeting was realized through a number of new concepts, such as a debate symposium, information sessions, nurses' workshops, and so on. The results obtained from the participation questionnaire (n=438), which were aggregated up to 1 month following the end of this year's meeting, revealed that 89% of the participants at considered it to have been appealing. In particular, 63% of the participants favored the adoption of a debate symposium whereby it was possible to ask and respond to questions in real time. In the free comments section of the questionnaire, the participants expressed how they felt the debate symposium made it easy to give their opinions, and that this element might be further developed in the future. They also stated that they found the introduction of the Clica system effective in terms of making the annual meeting an active learning place. One issue that was highlighted concerned the observation that the hall used to host the symposium was designed as a concert venue, which meant it was highly shielded from the outside environment, in addition to access to the internet being blocked. I hope that many of the projects from this Annual Meeting will serve to guide the future style of the Society's Annual Meetings. PMID- 29608001 TI - [Supporting an Academic Society with the Active Learning Tool Clica]. AB - Within school classrooms, Active Learning has been receiving unprecedented attention. Indeed, Active Learning's popularity does not stop in the classroom. As more and more people argue that the Japanese government needs to renew guidelines for education, Active Learning has surfaced as a method capable of providing the necessary knowledge and training for people in all areas of society, helping them reach their full potential. It has become accepted that Active Learning is more effective over the passive listening of lectures, where there is little to no interaction. Active Learning emphasizes that learners explain their thoughts, ask questions, and express their opinions, resulting in a better retention rate of the subject at hand. In this review, I introduce an Active Learning support tool developed at Digital Knowledge, "Clica". This tool is currently being used at many educational institutions. I will also introduce an online questionnaire that Digital Knowledge provided at the 10th Annual Meeting of the Japanese Society for Pharmaceutical Palliative Care and Sciences. PMID- 29608002 TI - [Designing the Annual Meeting and Active Learning System]. AB - At the 10th Annual Meeting of the Japanese Society for Pharmaceutical Palliative Care and Sciences our theme centered on active learning systems where adult learners engage on their own initiative. Many of the participants were pharmacists active in clinical practices. Regardless of their specialized skill sets, pharmacists are constantly faced with difficult challenges in their daily work. Passive, one-way lectures are one resource for them, but unfortunately such lectures provide limited insights for resolving concrete problems. The present meeting aimed to show participants how to obtain information they need to solve specific real-world problems. This paper summarizes how we planned this year's meeting, including details about the debate symposium, social lunch, and online questionnaires. All these elements had the end goal of enabling learners proactivity to become their own best resource for learning. It is sincerely hoped that the design and execution of this meeting will prove resourceful for future annual meetings. PMID- 29608003 TI - [Participants-centered Design of Annual Meeting: From the Perspectives of Instructional Systems]. AB - This paper examines the reform experience of the 10th Annual Meeting of the Japanese Society for Pharmaceutical Palliative Care and Sciences from Instructional Systems perspectives, to check whether it was effective, efficient, and appealing for participants. "Instructional Systems" has been a research area in educational technology for the past 50 years, and has also been applied to training and human resource development in healthcare domains. If an annual meeting is to be designed for participants' learning, then perspectives of Instructional Systems can be applied to interpret the effort of the reform. First, fill in the gaps of participants' knowledge, using before-and-after comparison. Design a conference to meet the needs of its participants by checking why they attend (expectations) and what they bring in (starting status). Second, design the conference as a process of innovation. The bigger the expected changes, the more carefully participants should be prepared to accommodate them. Third, follow plan-do-check-action cycles with data for confirming and revising the new ways of running the meeting. Plan to check "exportability" of the new ways, to assess whether it can be generalized to future meetings. PMID- 29608004 TI - [Acquiring Science English: A Plan and System Are Needed]. AB - Literary English is different from science English (SE) and pharmaceutical science English (PSE). Therefore, a totally new approach was adopted for students to learn PSE at Kyoto Pharmaceutical University (KPU). In 2012, a 4-year program for teaching PSE was proposed, and a stepwise-stepup tertiary science English education (SSTSEE) system was introduced at KPU. The system provides a novel form of PSE teaching that stretches from year 1 to 4, where the PSE level progresses to higher levels of learning with each passing academic year. With the launch of the SSTSEE system, relevant science-educated staff were provided with training and were also requested to study the syllabi of the respective academic years to write textbooks with the appropriate PSE content for their respective levels. From 2012 to 2015, textbooks and curricula for 4 year academic levels were developed and published to meet the needs for PSE learning at each academic level. Based on results of the SSTSEE system, year 1 students acquired the SE basics, and year 2 students applied the SE basics acquired. In years 3 and 4, students further pursued and developed their PSE ability. Additionally, students participated actively in developing skills in the reading, listening, writing, and speaking of SE/PSE. Active-plus-deep learning prompted students in developing those skills using illustrations, posters, and power-point slideshow presentations. By year 4, average achievers had established an independent level of competency in reading, listening, speaking, and writing PSE. Moreover, the SSTSEE system accommodated students timely in developing communication skills for practical fieldwork (clerkships) at pharmacies/hospitals in year 5 and for their future endeavors. PMID- 29608005 TI - [Ensuring Traceability Using qNMR in the Quantitative Analysis of Formaldehyde and Acetaldehyde]. AB - Currently, indoor air quality guidelines for formaldehyde and acetaldehyde are set by the Ministry of Health, Labour and Welfare of Japan. Aldehydes are widely used in adhesives and preservatives, and exposure to these compounds via indoor air is a matter of concern. Considering that contact with indoor air is part of daily life, evaluation of indoor air quality is extremely important. 2,4 Dinitrophenylhydrazine (DNPH) derivatization is widely used for quantitative analysis of aldehydes. A certified reference material with traceability to the International System of Units (SI) is required for this method. However, currently, there are no certified reference materials available for aldehyde-DNPH derivatives, which means that the quantified values obtained by this method are not sufficiently reliable. In this study, we determined the actual content and purity of commercially available aldehyde-DNPH derivatives using 1H-quantitative NMR (qNMR), which can be measured with SI-traceability. Although the commercial DNPH derivatives of formaldehyde and acetaldehyde were low concentration solutions, we were able to determine their purities using 1H-qNMR. Furthermore, we were able to separate and quantify the acetaldehyde isomers generated by the derivatization reaction. In conclusion, it is possible to obtain highly accurate results using 1H-qNMR with commercially available reagents that are not certified metrologically. PMID- 29608006 TI - [Evaluation of the Association between Topical Prostaglandin F2alpha Analogs and Asthma Using the JADER Database: Comparison with beta-Blockers]. AB - Prostaglandin F2alpha (PGF2alpha) analog formulations are the most commonly used drugs for glaucoma treatment. They are known to be superior to beta-blockers for reducing intraocular pressure and can be effective all through the day. Because of the action, topical beta-blockers are contraindicated for patients with bronchial asthma. PGF2alpha is also known to act as a constrictor of the respiratory tract. The present study aims to analyze the relationship between PGF2alpha analogs and asthma. In addition, we utilized beta-blockers and combined formulations of both contents to evaluate for comparison with PGF2alpha analogs. Data from Japanese adverse drug event reports (JADERs) from April 2004 to January 2016 were used for analysis. The drugs of interest were 4 PGF2alpha analogs, 4 beta-blockers, and 2 combined formulations of both. For quantitative signal detection, the reporting odds ratios (RORs) with Haldane-Anscombe 1/2 correction were calculated. The corrected RORs (95%CI) were detected to be 4.73 (2.30-9.75) for PGF2alpha analogs, 4.61 (1.82-11.7) for beta-blockers, and 28.7 (12.1-68.1) for combined formulations. Our results suggest that not only topical beta blockers but also PGF2alpha analogs are associated with asthma, and the combined formulations have stronger associations with asthma than when administered alone. Therefore, further clinical research will be necessary, and careful attention should be paid to any glaucoma patient using PGF2alpha analogs for asthma symptoms. PMID- 29608007 TI - [Evaluation of the Stability of Indomethacin Oral Spray in Two Different Formulation Conditions]. AB - Indomethacin (IM) oral spray is a hospital preparation that is used to reduce pain from oral mucositis induced by radiotherapy and chemotherapy. IM oral spray consists of IM (0.25%) dissolved in KH2PO4-NaOH buffer (Formulation A) or Formulation A containing xylitol (Xyl) and glycerin (Gly) (Formulation B). To clarify the stability of IM oral spray in two different formulation conditions, we evaluated the residual rates of IM in these formulations to determine the optimal storage temperature and shelf-life. IM oral spray was stored at freezer temperature (-20 degrees C), refrigerator temperature (4 degrees C) and room temperature (25 degrees C) for up to 16 weeks after preparation. The residual rate of IM was determined by using HPLC. The residual rates of IM in Formulation A and Formulation B after storage for 16 weeks at freezer temperature were >=95%. When stored at refrigerator temperature, the residual rate of IM in Formulation A was 96.1% after 12 weeks, and the residual rates of IM in Formulation B were 95.8% after 2 weeks, 90.1% after 4 weeks and 72.7% after 12 weeks. These results suggested that Formulation A is stable for at least 12 weeks when stored at 4 degrees C. However, degradation of IM seemed to be accelerated in the formulation containing Xyl and Gly, suggesting that the expiration date should be shortened to 2 weeks at 4 degrees C. In addition, both formulations were stable for at least 16 weeks in a freezer, indicating that long-term preservation is possible. PMID- 29608008 TI - [Retrospective Analysis of Factors Decreasing the Efficacy of Tazobactam/Piperacillin for Pneumonia in Elderly Patients]. AB - Tazobactam/piperacillin (TAZ/PIPC) is an antimicrobial drug agent with a broad spectrum of antibacterial activity and is recommended as first-line therapy for hospital-acquired pneumonia, nursing- and healthcare-associated pneumonia, and other severe pneumonias. Nevertheless, in clinical settings, TAZ/PIPC is not fully effective in the treatment of pneumonia in the elderly. In the present study, we retrospectively investigated the efficacy of TAZ/PIPC for pneumonia in elderly patients and identified factors that reduced its efficacy. Ninety-nine patients (mean age of 83.4 years and no significant difference in the sex ratio) were included in the present study. The efficacy rate of TAZ/PIPC for pneumonia in elderly patients was 81.8%, which was approximately 7 to 10% lower than that in domestic phase III trials. A multivariate analysis identified the complications of chronic respiratory disease as a significant factor attenuating the therapeutic effects of TAZ/PIPC [odds ratio 4.050, 95% confidence interval (CI) 1.008-16.271]. In conclusion, TAZ/PIPC may not be sufficiently effective for pneumonia in elderly patients with the complications of chronic respiratory disease as a background. PMID- 29608010 TI - ? PMID- 29608009 TI - [Errata: Economic Evaluation of mFOLFOX6-based First-line Regimens for Unresectable Advanced or Recurrent Colorectal Cancer Using Clinical Decision Analysis]. PMID- 29608011 TI - ? PMID- 29608012 TI - ? PMID- 29608014 TI - Expression of EMT inducers integrin-linked kinase (ILK) and ZEB1 in phyllodes breast tumors is associated with aggressive phenotype. AB - Phyllodes tumors (PTs) of the breast constitute an uncommon group of mammary fibroepithelial lesions with ambiguous biologic behavior. Recent evidence suggests that epithelial mesenchymal transition (EMT), a driving force of cancer progression is implicated in PTs pathogenesis. Integrin-linked kinase (ILK), a focal adhesion kinase, has been implicated in cancer and EMT and represents a novel cancer therapeutic target. In this study, we aimed to investigate ILK and EMT markers expression in phyllodes breast tumors in relation to tumor grade. Expression of ILK and EMT markers E-cadherin, beta-catenin, Nu-cadherin, vimentin, Snail, ZEB1 and Twist was evaluated by immunohistochemistry in paraffin embedded tissue sections from 96 human phyllodes breast tumors (48 benign, 27 borderline, 21 malignant). Cytoplasmic and nuclear immunopositivity of ILK were observed in both the epithelial and the stromal component of phyllodes breast tumors and were significantly higher with increasing tumor grade. An EMT-related expression profile consisting of decreased membranous and increased nuclear/cytoplasmic immunoreactivity of E-cadherin and beta-catenin and increased expression of N-cadherin, vimentin, Snail, ZEB1 and Twist was observed in tumor epithelial and stromal component and was significantly associated with malignant phyllodes breast tumor histopathology. Interestingly, there was a significant correlation of ILK expression with all of the EMT markers examined. Our results suggest that EMT significantly contributes to phyllodes tumor pathogenesis and originally implicate ILK and ZEB1 in phyllodes tumors malignant phenotype. PMID- 29608013 TI - 17beta-Estradiol on the Expression of G-Protein Coupled Estrogen Receptor (GPER/GPR30) Mitophagy, and the PI3K/Akt Signaling Pathway in ATDC5 Chondrocytes In Vitro. AB - BACKGROUND Osteoarthritis is a progressive inflammatory joint disease resulting in damage to articular cartilage. G-protein coupled estrogen receptor (GPER/GPR30) activates cell signaling in response to 17beta-estradiol, which can be blocked by the GPR30 agonist, G15, an analog of G-1. The aims of this study were to investigate the effects of 17beta-estradiol on the expression of G protein coupled estrogen receptor (GPER/GPR30) on mitophagy and the PI3K/Akt signaling pathway in ATDC5 chondrocytes in vitro. MATERIAL AND METHODS Cultured ATDC5 chondrocytes were treated with increasing concentrations of 17beta estradiol with and without G15, p38 inhibitor (SB203580), JNK inhibitor (SP600125), PI3K inhibitor (LY294002, S1737), and mTOR inhibitor (S1842). Expression of GPER/GPR30 and components of the PI3K/Akt pathway in cultured ATDC5 chondrocytes were detected by immunofluorescence (IF) staining, Western blot, and real-time polymerase chain reaction (RT-PCR). Transmission electron microscopy (TEM) and IF were used to detect mitophagosomes. Expression of LC-3, LAMP2, TOM20, Hsp60, p-Akt, p-mTOR, p-p38, and p-JNK was investigated by Western blot. Proliferation and viability of the ATDC5 chondrocytes were determined using BrdU and MTT assays. RESULTS In 17beta-estradiol-treated ATDC5 chondrocytes, increased expression of GPER/GPR30 was found, but fewer mitophagosomes were observed, and decreased numbers of TOM20-positive granules were co-localized with decreased LAMP2 and increased expression levels of TOM20, Hsp60, p-Akt, and p-mTOR, and reduced expression of LC3-II, were found. In 17beta-estradiol-treated ATDC5 chondrocytes, the proliferation and viability of the 17beta-estradiol-treated ATDC5 chondrocytes were significantly elevated. CONCLUSIONS Treatment with 17beta estradiol protected ATDC5 chondrocytes against mitophagy via the GPER/GPR30 and the PI3K/Akt signaling pathway. PMID- 29608015 TI - Factor XI deficiency is not associated with an increased risk of pneumonia and pneumonia-related mortality. AB - INTRODUCTION: Drugs targeting factor XI (FXI) shows promising results in reducing postoperative VTE. Recently, researchers have shown that FXI knockout mice had a worse outcome when infected with pathogens for pneumonia, raising concerns about the safety of these drugs. AIM: To investigate the effect of FXI deficiency on the incidence of pneumonia and outcomes of pneumonia in humans. METHODS: Using the computerized database of the largest healthcare provider in Israel, we identified adults who were tested for FXI activity between January of 2002 and December of 2014 (n = 10 193). Patients were followed up until December of 2016 for the occurrence of pneumonia and pneumonia requiring hospitalization as a proxy of severe pneumonia. RESULTS: A total of 8958 (87.9%) had normal FXI activity, 804 (7.9%) had partial deficiency and 431 (4.2%) had severe deficiency; 722 individuals had pneumonia during 70 881 person-years of follow-up (incidence rate: 10.2 per 1000 person-years). Compared to those with normal FXI activity, the adjusted HR for pneumonia was 0.87 (95% CI, 0.67-1.14), and 0.95 (0.69-1.30) for those with partial and severe FXI deficiency, respectively. Overall, 256 individuals were hospitalized for pneumonia during 72 209 person-years of follow up (incidence rate: 3.5 per 1000 person-years). The corresponding HR for severe pneumonia was 1.0 (0.70-1.48) and 0.86 (0.53-1.40) in those with partial and severe FXI deficiency, respectively. FXI deficiency was not significantly associated with 30-day and 90-day mortality among patients with pneumonia. CONCLUSION: FXI deficiency was not associated with an increased risk of pneumonia, pneumonia severity or short-term mortality among patients with pneumonia. PMID- 29608016 TI - Cell Damage Index as Computational Indicator for Blood Cell Activation and Damage. AB - Shear-induced hemolysis is a major concern in the design and optimization of blood-contacting devices. Even with a small amount of mechanical stress, inflammatory reactions can be triggered in the cells. Blood damage is typically estimated using continuum fluid dynamics simulations. In this study, we report a novel cell damage index (CDI) obtained by simulations on the single-cell level in a lattice Boltzmann fluid flow. The change of the cell surface area gives important information on mechanical stress of individual cells as well as for whole blood. We are using predefined basic channel designs to analyze and compare the newly developed CDI to the conventional blood damage calculations in very weak shear stress scenarios. The CDI can incorporate both volume fraction and channel geometry information into a single quantitative value for the characterization of flow in artificial chambers. PMID- 29608017 TI - Improvement of functional properties of a thermostable beta-glycosidase for milk lactose hydrolysis. AB - In this work, a new exploitation of the thermostable beta-glycosidase from Sulfolobus solfataricus expressed in Saccharomyces cerevisiae to create functional foods for low lactose diets was evaluated. For this purpose, the lactose hydrolysis reaction using immobilized and soluble enzymes was investigated. Activity and stability at different conditions of pH and temperature were tested. The immobilization process had a big impact on the catalysis performance, leading to an enhancement of the enzymatic reaction rate on lactose, as demonstrated by the increasing of 2 and 2.5 folds of Kcat and Kcat /KM , respectively. Moreover, the maximal activity for the immobilized form was referred at pH 6.5 instead of 7.0, leading to an improvement of the catalytic performance at milk pHs. Although the soluble enzyme was already weakly inhibited by the reaction products, the immobilization further reduced the inhibitory action of glucose increasing the Ki from 96.7 to 110.4 mM. Finally, the immobilized enzyme showed high hydrolysis rate in whole milk that yielded 99% of lactose breakdown in 10 and 30 min at 60 and 40 degrees C, respectively. These results support the application of the immobilized beta-glycosidase for the development of new functional foods particularly suitable to the alleviation of lactose intolerance. PMID- 29608018 TI - Role of serum response factor expression in prostate cancer biochemical recurrence. AB - BACKGROUND: Up to a third of prostate cancer patients fail curative treatment strategies such as surgery and radiation therapy in the form of biochemical recurrence (BCR) which can be predictive of poor outcome. Recent clinical trials have shown that men experiencing BCR might benefit from earlier intervention post radical prostatectomy (RP). Therefore, there is an urgent need to identify earlier prognostic biomarkers which will guide clinicians in making accurate diagnosis and timely decisions on the next appropriate treatment. The objective of this study was to evaluate Serum Response Factor (SRF) protein expression following RP and to investigate its association with BCR. MATERIALS AND METHODS: SRF nuclear expression was evaluated by immunohistochemistry (IHC) in TMAs across three international radical prostatectomy cohorts for a total of 615 patients. Log-rank test and Kaplan-Meier analyses were used for BCR comparisons. Stepwise backwards elimination proportional hazard regression analysis was used to explore the significance of SRF in predicting BCR in the context of other clinical pathological variables. Area under the curve (AUC) values were generated by simulating repeated random sub-samples. RESULTS: Analysis of the immunohistochemical staining of benign versus cancer cores showed higher expression of nuclear SRF protein expression in cancer cores compared with benign for all the three TMAs analysed (P < 0.001, n = 615). Kaplan-Meier curves of the three TMAs combined showed that patients with higher SRF nuclear expression had a shorter time to BCR compared with patients with lower SRF expression (P < 0.001, n = 215). Together with pathological T stage T3, SRF was identified as a predictor of BCR using stepwise backwards elimination proportional hazard regression analysis (P = 0.0521). Moreover ROC curves and AUC values showed that SRF was better than T stage in predicting BCR at year 3 and 5 following radical prostatectomy, the combination of SRF and T stage had a higher AUC value than the two taken separately. CONCLUSIONS: SRF assessment by IHC following RP could be useful in guiding clinicians to better identify patients for appropriate follow up and timely treatment. PMID- 29608019 TI - Comparison of Urodynamics and Perineal Ultrasonography for the Diagnosis of Mixed Urinary Incontinence in Women. AB - OBJECTIVES: This study aimed to compare urodynamic studies (UDS) and perineal ultrasonography (US) for the assessment of mixed urinary incontinence (MUI) in women in China. METHODS: Adult women with MUI and healthy control participants were enrolled from 2 centers in China (Zhejiang and Beijing) between September 2010 and April 2017. Baseline clinical characteristics were recorded. The MUI type was categorized by the King's Health Questionnaire: stress-predominant, urge predominant, or equal predominance. Urodynamic studies were performed, followed within 1 week by perineal US. Tolerability of the investigations was compared by a 3-point scale: better than, worse than, or equal to. RESULTS: For UDS parameters, compared with controls, the urge-predominant MUI group had a lower maximal flow rate, smaller bladder volume, higher detrusor pressure at urethral opening, higher detrusor pressure at maximal flow, and higher incidence of detrusor overactivity; the stress-predominant MUI group had a lower maximal urethral closure pressure and functional urethral length; and the equal MUI group had a higher detrusor pressure at maximal flow and lower maximal urethral closure pressure (P < .05). For US parameters, compared with controls, the stress predominant MUI group had a greater dynamic posterior urethral angle, dynamic angle of urethral inclination, descent of the bladder neck, and dynamic pubourethral distance; the urge-predominant MUI group had a greater detrusor thickness; and the equal MUI group had a greater descent of the bladder neck (P < .05). All UDS and US parameters differed significantly between the stress predominant and urge-predominant groups (P < .05). The dynamic angle of urethral inclination, descent of the bladder neck, and dynamic pubourethral distance were inversely correlated with detrusor pressure at maximal flow and functional urethral length, while detrusor wall thickness was positively correlated with detrusor pressure at maximal flow and functional urethral length. Perineal US was better tolerated than UDS. CONCLUSIONS: Perineal US parameters show good correlations with UDS parameters. Ultrasonography is better tolerated than UDS and provides additional morphologic data. Perineal US could facilitate the diagnosis of urge-predominant MUI. PMID- 29608020 TI - Prostatic stromal inflammation is associated with bladder outlet obstruction in patients with benign prostatic hyperplasia. AB - BACKGROUND: Benign prostatic hyperplasia (BPH) is a common urologic disease in older men. Prostatic inflammation research has focused on the magnitude of inflammation; its location has received little attention. We investigated whether the anatomic location of prostatic inflammation is related to the severity of lower urinary tract symptoms (LUTS), measured subjectively and objectively. METHODS: We retrospectively analyzed hematoxylin+eosin-stained tissue specimens from 179 BPH patients who underwent transurethral resection of the prostate (TURP) or holmium laser enucleation of the prostate (HoLEP). Chronic prostatic inflammation was assessed by the grade (lymphocyte density), extent (lymphocyte distribution), and location of inflammation. Each inflammation-finding type was evaluated in relation to these clinical parameters: age, prostate volume, prostate-specific antigen (PSA) value, body mass index (BMI), the frequency of acute urinary retention (AUR) episodes, the international prostatic symptom score (IPSS), and urodynamic study results. RESULTS: The magnitude and extent of inflammation were not associated with any clinical parameters. We classified the BPH patients into stromal (n = 72) versus non-stromal (n = 105) groups based on their inflammation's dominant location. The stromal group's prostatic volume was significantly larger than the non-stromal group's (63.8 vs 53.8 mL; P = 0.032). AUR episodes were more significantly frequent in the stromal group (36.1% vs 11.4%; P = 0.006). Between-group differences in storage parameters (ie, maximum cystometric capacity) in the urodynamic study were not significantly different. Voiding parameters differed significantly between the stromal and non-stromal groups: maximum detrusor pressure (maxPdet) (116.8 vs 94.5 cmH2 O, P = 0.014), Pdet at the maximum flow rate (Qmax) (95.8 vs 75.4 cmH2 O, P = 0.014), and the bladder outlet obstruction index (BOOI) (78.5 vs 56.3, P = 0.014). The stromal group's Qmax was significantly lower than the non-stromal group's (7.3 vs 9.8 mL/s, P = 0.004). CONCLUSIONS: The location of inflammation in the prostate might be an important factor affecting the severity of LUTS, especially voiding dysfunction. PMID- 29608024 TI - Minimally Invasive Ultrasound-Guided Carpal Tunnel Release: Preliminary Clinical Results. AB - Ultrasound-guided carpal tunnel release was performed on 14 patients (18 wrists) using dynamic expansion of the transverse safe zone. Our patient population included able-bodied patients and those with impairments. The first 8 cases (12 wrists) underwent the procedure in an operating room, the remainder in an outpatient setting. No complications occurred, and all patients were able to immediately resume use of their hands without therapy. Improvements in the Quick Form of the Disabilities of the Arm, Shoulder, and Hand Index and Boston Carpal Tunnel Questionnaire at 3 months were comparable to results reported with mini open and endoscopic release. Our results show that ultrasound-guided carpal tunnel release can be safely and effectively performed in an outpatient setting. PMID- 29608021 TI - Curcumin enhances the anti-cancer effects of Paris Saponin II in lung cancer cells. AB - OBJECTIVES: To investigate the synergistic mechanisms of Paris Saponin II (PSII) and Curcumin (CUR) in lung cancer. MATERIALS AND METHODS: The combination changed the cellular uptake of CUR and PSII, apoptosis, cell cycle arrest and cytokine levels were analysed on different lung cancer cells. RESULTS: The combination displayed a synergistic anti-cancer effect through promoting the cellular uptake of CUR on different lung cancer cells. Hoechst H33258 staining and FACS assay indicated that the combination of PSII and CUR induced cell cycle arrest and apoptosis. Western blot and cytokine antibody microarray suggested that the combination activated death receptors such as DR6, CD40/CD40L, FasL and TNF-alpha to induce cancer cells apoptosis, and up-regulated IGFBP-1 leading to inhibition of PI3K/Akt pathway and increase of p21 and p27, which therefore induced a G2 phase arrest in NCI-H446 cells. Meanwhile, the combination suppressed PCNA and NF kappaB pathway in 4 kinds of lung cancer cells. They activated the phosphorylation of p38 and JNK, and inhibited PI3K in NCI-H460 and NCI-H446 cells, enhanced the phosphorylation of JNK in NCI-H1299 cells, and increased the phosphorylation of p38 and ERK, and suppressed PI3K in NCI-H520 cells. CONCLUSIONS: PSII combined with CUR had a synergistic anti-cancer effect on lung cancer cells. These findings provided a rationale for using the combination of curcumin and PSII in the treatment of lung cancer in future. PMID- 29608022 TI - Ivermectin and permethrin for treating scabies. AB - BACKGROUND: Scabies is an intensely itchy parasitic infection of the skin. It occurs worldwide, but is particularly problematic in areas of poor sanitation, overcrowding, and social disruption. In recent years, permethrin and ivermectin have become the most relevant treatment options for scabies. OBJECTIVES: To assess the efficacy and safety of topical permethrin and topical or systemic ivermectin for scabies in people of all ages. SEARCH METHODS: We searched the following databases up to 25 April 2017: the Cochrane Infectious Diseases Group Specialized Register, CENTRAL, MEDLINE, Embase, LILACS, and IndMED. We searched the World Health Organization International Clinical Trials Registry Platform, the ISRCTN registry, CenterWatch Clinical Trials Listing, ClinicalTrials.gov, TrialsCentral, and the UK Department of Health National Research Register for ongoing trials. We also searched multiple sources for grey literature and checked reference lists of included studies for additional trials. SELECTION CRITERIA: We included randomized controlled trials that compared permethrin or ivermectin against each other for people with scabies of all ages and either sex. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the identified records, extracted data, and assessed the risk of bias for the included trials.The primary outcome was complete clearance of scabies. Secondary outcomes were number of participants re-treated, number of participants with at least one adverse event, and number of participants withdrawn from study due to an adverse event.We summarized dichotomous outcomes using risk ratios (RR) with 95% confidence intervals (CI). If it was not possible to calculate the point estimate, we described the data qualitatively. Where appropriate, we calculated combined effect estimates using a random-effects model and assessed heterogeneity. We calculated numbers needed to treat for an additional beneficial outcome when we found a difference.We assessed the certainty of the evidence using the GRADE approach. We used the control rate average to provide illustrative clearance rates in the comparison groups. MAIN RESULTS: Fifteen studies (1896 participants) comparing topical permethrin, systemic ivermectin, or topical ivermectin met the inclusion criteria. Overall, the risk of bias in the included trials was moderate: reporting in many studies was poor. Nearly all studies were conducted in South Asia or North Africa, where the disease is more common, and is associated with poverty.EfficacyOral ivermectin (at a standard dose of 200 MUg/kg) may lead to slightly lower rates of complete clearance after one week compared to permethrin 5% cream. Using the average clearance rate of 65% in the trials with permethrin, the illustrative clearance with ivermectin is 43% (RR 0.65, 95% CI 0.54 to 0.78; 613 participants, 6 studies; low-certainty evidence). However, by week two there may be little or no difference (illustrative clearance of permethrin 74% compared to ivermectin 68%; RR 0.91, 95% CI 0.76 to 1.08; 459 participants, 5 studies; low-certainty evidence). Treatments with one to three doses of ivermectin or one to three applications of permethrin may lead to little or no difference in rates of complete clearance after four weeks' follow-up (illustrative cures with 1 to 3 applications of permethrin 93% and with 1 to 3 doses of ivermectin 86%; RR 0.92, 95% CI 0.82 to 1.03; 581 participants, 5 studies; low-certainty evidence).After one week of treatment with oral ivermectin at a standard dose of 200 MUg/kg or one application of permethrin 5% lotion, there is probably little or no difference in complete clearance rates (illustrative cure rates: permethrin 73%, ivermectin 68%; RR 0.93, 95% CI 0.74 to 1.17; 120 participants, 1 study; moderate-certainty evidence). After two weeks of treatment, one dose of systemic ivermectin compared to one application of permethrin lotion may lead to similar complete clearance rates (extrapolated cure rates: 67% in both groups; RR 1.00, 95% CI 0.78 to 1.29; 120 participants, 1 study; low-certainty evidence).There is probably little or no difference in rates of complete clearance between systemic ivermectin at standard dose and topical ivermectin 1% lotion four weeks after initiation of treatment (illustrative cure rates: oral ivermectin 97%, ivermectin lotion 96%; RR 0.99, 95% CI 0.95 to 1.03; 272 participants, 2 studies; moderate-certainty evidence). Likewise, after four weeks, ivermectin lotion probably leads to little or no difference in rates of complete clearance when compared to permethrin cream (extrapolated cure rates: permethrin cream 94%, ivermectin lotion 96%; RR 1.02, 95% CI 0.96 to 1.08; 210 participants, 1 study; moderate-certainty evidence), and there is little or no difference among systemic ivermectin in different doses (extrapolated cure rates: 2 doses 90%, 1 dose 87%; RR 0.97, 95% CI 0.83 to 1.14; 80 participants, 1 study; high-certainty evidence).SafetyReporting of adverse events in the included studies was suboptimal. No withdrawals due to adverse events occurred in either the systemic ivermectin or the permethrin group (moderate-certainty evidence). Two weeks after treatment initiation, there is probably little or no difference in the proportion of participants treated with systemic ivermectin or permethrin cream who experienced at least one adverse event (55 participants, 1 study; moderate-certainty evidence). After four weeks, ivermectin may lead to a slightly larger proportion of participants with at least one adverse event (extrapolated rates: permethrin 4%, ivermectin 5%; RR 1.30, 95% CI 0.35 to 4.83; 502 participants, 4 studies; low-certainty evidence).Adverse events in participants treated with topical ivermectin were rare and of mild intensity and comparable to those with systemic ivermectin. For this comparison, it is uncertain whether there is any difference in the number of participants with at least one adverse event (very low-certainty evidence). No withdrawals due to adverse events occurred (62 participants, 1 study; moderate-certainty evidence).It is uncertain whether topical ivermectin or permethrin differ in the number of participants with at least one adverse event (very low-certainty evidence). We found no studies comparing systemic ivermectin in different doses that assessed safety outcomes. AUTHORS' CONCLUSIONS: We found that for the most part, there was no difference detected in the efficacy of permethrin compared to systemic or topical ivermectin. Overall, few and mild adverse events were reported. Our confidence in the effect estimates was mostly low to moderate. Poor reporting is a major limitation. PMID- 29608025 TI - Thermally Induced Chemiluminescence of Barley Leaves. AB - Abstract- An unconventional band in the thermoluminescence glow curve of barley leaves at about +50 degrees C was examined. In contrast to bands usually observed around +50 degrees C, this band (designated as CL) is not related to photosynthetic electron transport in photosystem II. The appearance of the CL band (1) requires previous freezing of the sample, (2) is not influenced by light excitation and (3) depends on the presence of oxygen. In pure oxygen the glow curves for both leaves and chloroplast suspension exhibit three maxima at about +40 degrees C, +65 degrees C and +90 degrees C. Based on the emission spectra of the CL band and measurements with etiolated leaves, we suppose that the majority of emission corresponding to the CL band originates from chlorophyll. A lipoxygenase inhibitor, butylated hydroxytoluene, and sodium azide decrease the intensity of the CL band. We propose that the mechanism leading to emission of the CL band involves thermally stimulated production of an active oxygen species that results in lipid peroxidation. PMID- 29608026 TI - Laser Flash Photolysis of Tolmetin: A Photoadiabatic Decarboxylation with a Triplet Carbanion as the Key Intermediate in the Photodecomposition. AB - Abstract- The transient photochemistry of tolmetin (TM), 5-(p-toluoyl)-1-methyl-2 pyrrolyacetic acid, a drug belonging to the nonsteroidal anti-inflammatory class, has been studied in aqueous solution by using nanosecond laser flash photolysis techniques. The photoreactivity of TM is characterized by an adiabatic pathway involving a triplet carbanion as the key intermediate in the photodecarboxylation. A short-lived triplet is proposed as the precursor of this transient species. A minor channel for laser photodecomposition involving photoionization has also been identified. This latter photoprocess occurs predominantly through a biphotonic mechanism. PMID- 29608027 TI - Light Induces lnositol Trisphosphate Elevation in Blepharisma japonicum. AB - Abstract- Photoinduced formation of inositol 1,4,5-trisphosphate (Ins[1,4,5]P3 ) was examined using a specific radioimmu-noassay to investigate the molecular mechanisms of light signal transduction mediating photophobic responses in the ciliate Blepharisma japonicum. Application of light stimuli of moderate intensity to dark-adapted cells induced a rapid and significant increase in the basal level of Ins (1,4,5)P3 , with a peak at about 20 s. Thereafter, the level of Ins (1,4,5)P3 declined to the resting value within the subsequent 100 s. Light stimuli of higher intensity raised the cell Ins (1,4,5)P3 content to still higher levels within about 20 s, but the decaying time course was considerably prolonged. In ciliates incubated under dark conditions with agents interfering with the inositol signalling pathway, like neomycin and Li+ the basal levels of Ins (1,4,5)P3 were lower than in control cells. A photoinduced rise of Ins (1,4,5)P3 , content in ciliates treated with neomycin or Li+ was significantly inhibited in a dose-dependent manner. Depolarizing ionic stimuli in dark-adapted ciliates induced no significant alterations of the resting Ins (1,4,5)P3 level, indicating a lack of a contribution of this kind of stimulation to the inositol turnover. These studies are the first in vivo demonstration of a possible role for inositol trisphosphate as a second messenger in the light signal transduction process in the ciliate B. japonicum. PMID- 29608028 TI - Control by Ring Substitution of the Conformation Change Dynamics in Photochromic Polypeptides. AB - Abstract- In order to develop new systems that couple photochromism with molecular conformation change, a series of spiropyrans having different ring substituents were attached to poly(L-glutamic acid). The polypeptides were dissolved in hexafluoroisopropanol and dark adapted so that the dye was in the merocyanine form. Following adaptation by white light and dye photoconversion from the merocyanine to spiropyran forms, polypeptide dark-adaptation kinetics were monitored by circular dichroism (CD) and dye dark adaptation was monitored by UV/ visible. Light adaptation caused a light-induced coil-to-helix transition, with dark adaptation resulting in relaxation back to the coil. The dark adaptation rate constant measured by UV/visible was equal to that measured by CD, demonstrating close coupling between dye state and polypeptide conformation. By varying the substituents on the spiropyran ring, dark-adaptation half lives were varied from less than a minute to 2 h, representing nearly three orders of magnitude. PMID- 29608029 TI - Natural UV-Screening Mechanisms of Norway Spruce (Picea abies [L.] Karst.) Needles. AB - Abstract- Ultraviolet-light screening potential of Norway spruce (Picea abies [L.] Karst.) needles was investigated by UV-spectroscopic, microscopic, fluorescence spectroscopic techniques as well as by HPLC, mass spectrometry and NMR spectroscopy. Results showed four potential barriers of UV screening by Norway spruce needles: (1) UV-light screening via reflectance of UV/violet light by epidermis, (2) UV-light screening via reduction of transmission of UV light by special anatomical arrangement of the epidermal cells containing the UV-screening allomelanins as well as by the light-reflecting hyaline hypodermal cells, (3) conversion of UV light by epidermis into photosynthetically active radiation (PAR; blue and red spectral bands) via fluorescence and (4) UV-light screening by absorption of UV light by UV-screening substances contained in the epidermis, whereby the latter was found to be the most important UV-screening mechanism. Staining of needle cross sections with Naturstoffreagenz A showed the localization of bound flavonoids and its derivatives in the cell walls of the outer epidermal cell layer as revealed by confocal laser scanning microscopy. By fluorescence spectroscopy and confocal laser scanning microscopy, the conversion of UVA light into PAR in the epidermis was related to various UV-screening substances contained in the epidermis. The methanol-soluble UV-absorbing substances were found to create novel UV-screening barrier zones: UVC, >200-253 nm; UVC/UVB, >253-300/303 nm; and UVB/UVA, >300-362/368 nm in epidermis as well as in mesophyll (+/-vascular bundles) tissues, suggesting the protective functions of epidermis for the underlying mesophyll as well as of mesophyll for the underlying vascular bundles. The following sequence of efficiency of UV screening barrier zones of the methanol-soluble extracts of the needle epidermis and mesophyll (+/- vascular bundles) for various UV-spectral bands was detected: UVC screening at less than 265 nm > UVC screening at 265-280 nm > UVB screening at 280-320 nm > UVA screening at 280-320 nm, whereby the UV screening at 280-320 nm was suggested as the most relevant barrier against enhanced UVB radiation. A blend of various UV-screening substances occurred in the methanol-soluble fractions of needle epidermis, whereby p-hydroxybenzoic acid 4-O-beta-D glucopyranoside, picein, (+)-catechin, p-hydroxyacetophenone, benzoic acid and astragalin were identified as UVC/UVB-screening substances; picein, (+)-catechin, astringin, p-hydroxyacetophenone and astragalin(s) as UVB-screening substances and astragalin(s) as UVA/B-screening substances. Alkaline hydrolysis of methanol insoluble epidermal cell wall fractions released p-coumaric acid, ferulic acid and as-tragalin(s) as major UVB-screening substances. Loss of vitality of Norway spruce trees (forest decline disease) led to a significant reduction of UVB (315 nm)-screening ability of methanol-soluble fractions from epidermis, mesophyll (+/ vascular bundles) and whole needles. The HPLC analysis showed that the loss of vitality is due to a reduction in accumulation of UVB-absorbing substances, mainly picein, (+)-catechin, isorhapontin and astragalin(s) in the epidermis of needles from the second needle year in accordance with the detected loss of UVB screening ability. It is concluded that the natural UV-screening mechanisms of Norway spruce needles are highly complex but mainly actively mediated by the ability of methanol-soluble UV-absorbing substances to form variable UVB-AJVA screening barrier zones and passively by the ability of epidermal cell wall-bound UV-screening substances to screen UV light, whereby in the epidermis a conversion of excess UV light into PAR takes place. PMID- 29608030 TI - Time-Resolved Studies of Light Propagation in Crassula and Phaseolus Leaves. AB - Abstract- Time-resolved transmittance was used to extract in vivo optical properties of leaves of green plants experimentally. In time-resolved transmittance measurements an ultrashort light pulse is directed onto the surface of the object and the transmitted light is measured with a time resolution in the range of picoseconds. A table-top terawatt laser was used to generate 200 fs light pulses at 790 nm with a repetition rate of 10 Hz. The light pulses were focused through a cuvette filled with water to produce white light pulses and optical filters were placed in the beam path to select the wavelength of the light focused onto the leaf surface. The time profiles of the light transmitted through the leaves was recorded with a streak camera having a time resolution of about 2.5 ps. Results from Crassula falcata and Phaseolus vulgaris studied at 550, 670 and 740 nm are reported. The three selected wavelength regions represent medium, high and a low absorption of light, respectively. A library of curves was generated using Monte Carlo simulation, and the absorption and scattering coefficients were extracted by comparison of experimental curves with this library. Our results suggest that in the case of the thin (200 MUm) Phaseolus leaves and certainly in the case of the thick (4 mm) Crassula leaves, light scattering plays an important role in light transport through the leaf and should also affect light flux in these leaves. PMID- 29608031 TI - The Electronic Structure of Carcinogenic Dibenzopyrenes: Linear Dichroism, Fluorescence Polarization Spectroscopy and Quantum Mechanical Calculations. AB - Abstract- In studies of polycyclic aromatic hydrocarbon carcinogenicity three dibenzopyrenes have been named as the strongest mutagens together with the frequently studied benzo[a]pyrene. A detailed study of the electronic structure of one of the three compounds, dibenzo [a, i] pyrene, was performed several years ago. Here we present a similar study of the two remaining compounds, dibenzo [a, h] pyrene and dibenzo [a, e] pyrene. The studies include electronic linear dichroism spectra, fluorescence polarization spectra and quantum mechanical calculations for both molecules, as well as vibrational linear dichroism spectra for the former of the two. PMID- 29608032 TI - A Model-Derived Global Climatology of UV Irradiation at the Earth's Surface. AB - Abstract- We present calculations of the geographical distribution of the dose rate at the surface of UVB (280-320 nm), UVA (320-400 nm) and, using biological action spectra, the effective radiation for erythema, cataracts and keratitis. A multistream radiative transfer model is used in conjunction with a multiyear climatology of ozone, cloud, surface pressure, surface albedo, temperature and a rudimentary representation of aerosols to calculate the clear-sky and all-sky irradiances. Model outputs are evaluated using daily UV measurements and found to be accurate to about +/-10% for clear skies and +/-20% for all-sky conditions. The effects of UV-weighted surface albedo, surface altitude, sun-earth separation and the vertical distribution of ozone and temperature are included. The results show that the sun's position is the most important factor in determining the geographical pattern of global daily UV rather than column ozone, cloud, surface pressure, daylength or surface albedo. Over elevated regions, the effect of the differences in surface pressure on daily doses was found to be more significant than the effect of the differences in column ozone. Clouds reduce the clear-sky UV dose from a few percent over arid and semiarid regions to 45% in regions with frequent midlatitude depressions. PMID- 29608033 TI - The CDC Opioid Guideline: Proponent Interpretation Has Led to Misinformation. AB - Pain management epitomizes the value of a multidisciplinary approach to caring for patients, yet regrettably, the term pain management has too often become synonymous with prescribing opioids only. Optimal chronic pain management requires a skillset most conducive to a multidisciplinary team approach and should be performed in a scientifically and clinically sound manner. It is with these facts in mind that we offer our view of the Centers for Disease Control and Prevention (CDC) Guideline for Prescribing Opioids for Chronic Pain. PMID- 29608035 TI - Working hours of obstetrics and gynaecology trainees in Australia and New Zealand. PMID- 29608036 TI - Intravenous iron use in pregnancy: Ironing out the issues and evidence. PMID- 29608034 TI - Simulated Transcatheter Aortic Valve Flow: Implications of Elliptical Deployment and Under-Expansion at the Aortic Annulus. AB - Clinical use of transcatheter aortic valves (TAVs) has been associated with abnormal deployment, including oval deployment and under-expansion when placed into calcified aortic annuli. In this study, we performed an integrated computational and experimental investigation to quantify the impact of abnormal deployment at the aortic annulus on TAV hemodynamics. A size 23 mm generic TAV computational model, developed and published previously, was subjected to elliptical deployment at the annulus with eccentricity levels up to 0.68 and to under-expansion of the TAV at the annulus by up to 25%. The hemodynamic performance was quantified for each TAV deployment configuration. TAV opening geometries were fabricated using stereolithography and then subjected to steady forward flow testing in accordance with ISO-5840. Centerline pressure profiles were compared to validate the computational model. Our findings show that slight ellipticity of the TAV may not lead to degeneration of hydrodynamic performance. However, under large ellipticity, increases in transvalvular pressure gradients were observed. Under-expanded deployment has a much greater negative effect on the TAV hemodynamics compared with elliptical deployment. The maximum turbulent viscous shear stress (TVSS) values were found to be significantly larger in under expanded TAVs. Although the maximum value of TVSS was not large enough to cause hemolysis in all cases, it may cause platelets activation, especially for under expanded deployments. PMID- 29608037 TI - Pain and structural alterations in knee joints in patients with haemophilia. AB - INTRODUCTION: Patients with haemophilia (PwH) suffer from haemophilic arthropathy which leads to an enhanced pain sensitivity. The aim of this study was to determine whether the individual pain condition in terms of pressure pain thresholds (PPT) at the knee joints is linked to changes of underlying anatomical structures in PwH. MATERIAL AND METHODS: Eleven landmarks at both knee joints of 36 PwH and 36 controls were examined in terms of PPT and ultrasound sonography (US). PPT were used to generate four groups: pain sensitive and insensitive knees of PwH and controls. RESULTS: PPT of the knee joints were significantly decreased at all landmarks in PwH when compared to controls (P <= .004). US findings revealed that especially osteophytes are more pronounced in pain-sensitive knees of PwH in comparison with pain-insensitive knees of PwH or pain-(in)sensitive knees of controls. The synovia tissue was also thickened in PwH when PPT was altered. In contrast to findings in osteoarthritis-related pain, no differences between the groups were found regarding effusion, whether assessed, for example on the distal edge of m. vastus lateralis (P = .893) or on the lateral joint space (P = .417). CONCLUSION: Particular degenerative changes in terms of osteophytes and thickness of synovial tissue are associated with an enhanced pain sensitivity in PwH. Altered PPT which were not associated with structural findings may be an indicator for a complex peripheral and/or central sensitization of the affected joints in PwH. The role of this mechanism should be clarified in further studies. PMID- 29608038 TI - Physical therapy needs for patients with physical function injuries post earthquake disasters: A systematic review of Chinese and Western literature. AB - BACKGROUND AND PURPOSE: Over the last 500 years, the most earthquakes with 10,000 or more fatalities and the most overall fatalities have occurred in China. Physical therapists must develop a better understanding of the patient and injury types that they are likely to treat post-earthquake disasters. This systematic review of Chinese and Western literature identified the primary patients treated by physical therapists post-earthquake disasters for injuries that negatively impacted physical function, activity, and participation. METHODS: Comparisons were made between reports of earthquakes in China and reports from the rest of the world combined. RESULTS: Sixty-seven studies of 71,986 patients (51.8% male) at 40.6 +/- 15 years of age were included. Studies were mostly prospective (n = 48, 71.6%). Reports of earthquakes in China represented more recently occurring disasters (p = .003) and more prospective research designs (p = .003). Reports from China also had a higher median fracture number (p = .004). Studies from China used manual muscle testing (p = .02), visual analogue pain scales (p = .008), Barthel index or modified Barthel index (p < .0001), and joint motion assessment (p = .007) with greater frequencies. DISCUSSION: Physical therapists from China are more likely to treat patients with a fracture; however, physical therapists from both regions are likely to treat patients with general injuries representing poly-trauma to multiple body regions, traumatic brain-closed head injuries, spinal cord injuries, peripheral nerve injuries, and soft tissue injuries. IMPLICATIONS ON PHYSIOTHERAPY PRACTICE: These data can help improve earthquake disaster planning, infrastructure development, and resource needs assessment effectiveness. More prospective research study designs and more recent earthquake disasters in China are likely associated with greater explicit use of valid and reliable outcome measurements such as joint motion assessment, manual muscle testing, visual analogue pain scale, and the Barthel index or modified Barthel index. PMID- 29608039 TI - Evaluation of substantivity of hypochlorous acid as an antiplaque agent: A randomized controlled trial. AB - BACKGROUND: Hypochlorous acid (HOCl) is a non-antibiotic antimicrobial substance with significant effects on pathogenic oral micro-organisms. The effects of HOCl as an antiplaque agent have not been studied. OBJECTIVE: The aim of this study was to evaluate the substantivity of HOCl mouthwashes compared with chlorhexidine (CHX) rinses and a placebo. MATERIALS AND METHODS: A double-blind randomized controlled trial with 75 participants was conducted. Participants were divided into five groups using block randomization: 0.025% HOCl, 0.05% HOCl, 0.12% CHX, 0.2% CHX, and sterile water as a placebo. Participants were instructed to use each rinse solution for 30 seconds after dental prophylaxis. Samples of saliva were taken at baseline and after 30 seconds, 1, 3, 5 and 7 hours to assess substantivity, and bacterial viability was established by the fluorescence method. Visible plaque in all participants was assessed with the Turesky index at baseline and at 7 hours, and adverse events were also assessed. RESULTS: HOCl led to a 33% reduction in bacterial counts in the saliva after 30 seconds compared with a 58% reduction by CHX. HOCl has no substantivity, and bacterial counts returned to baseline after 1 hour. Placebo treatment led to the highest plaque count after 7 hours compared with the CHX and HOCl groups, although the differences were not significant. HOCl rinsing induced the highest percentages of unpleasant taste and dryness sensations. CONCLUSIONS: HOCl rinses have an initial effect on bacterial viability in saliva but have no substantivity. Other mechanisms may explain its antiplaque effect. PMID- 29608041 TI - Trajectories of arterial stiffness and all-cause mortality among community dwelling older Japanese. AB - AIM: Aortic pulse wave velocity (PWV) is a strong predictor of all-cause mortality in later life. The present prospective study used repeated measures analysis to examine sex-specific age trends in brachial-ankle PWV (baPWV), identify baPWV trajectories and determine whether potential baPWV trajectories were associated with all-cause mortality among community-dwelling older Japanese. METHODS: A total of 1744 adults (mean age 71.0 years [SD 5.8 years]; 57.0% women) aged 65-90 years participated in annual geriatric health assessments during the period from April 2003 through July 2015. The average number of follow-up assessments was 4.3, and the total number of observations was 7419. We checked local registries to identify deaths from any cause; 289 (16.6%) participants died during the period through December 2015. RESULTS: baPWV similarly and significantly increased with advancing age in men and women. We identified four distinct trajectory patterns (very high, high, moderate, and low) in adults aged 65-90 years, and these trajectories showed parallel increases. After adjusting for important confounders, participants in the moderate, high and very high baPWV trajectory groups had hazard ratios of 1.12 (95% CI 0.84-1.44), 1.04 (95% CI 0.74 1.45) and 1.98 (95% CI 1.20-3.29), respectively, for all-cause mortality, as compared with those in the low trajectory group. CONCLUSIONS: baPWV increased with age in men and women, and there was no significance between sexes in later life. This prospective study identified four major baPWV trajectory patterns in community-dwelling older adults. Individuals in the very high baPWV trajectory group, especially younger seniors, had a higher mortality risk. Geriatr Gerontol Int 2018; 18: 1108-1113. PMID- 29608040 TI - Muscle-restricted nuclear receptor interaction protein knockout causes motor neuron degeneration through down-regulation of myogenin at the neuromuscular junction. AB - BACKGROUND: Nuclear receptor interaction protein (NRIP) is a calcium/calmodulin (CaM) binding protein. Nuclear receptor interaction protein interacts with CaM to activate calcineurin and CaMKII signalling. The conventional NRIP knockout mice (global knockout) showed muscular abnormality with reduction of muscle oxidative functions and motor function defects. METHODS: To investigate the role of NRIP on neuromuscular system, we generated muscle-restricted NRIP knockout mice [conditional knockout (cKO)]. The muscle functions (including oxidative muscle markers and muscle strength) and lumbar motor neuron functions [motor neuron number, axon denervation, neuromuscular junction (NMJ)] were tested. The laser captured microdissection at NMJ of skeletal muscles and adenovirus gene therapy for rescued effects were performed. RESULTS: The cKO mice showed muscular abnormality with reduction of muscle oxidative functions and impaired motor performances as global knockout mice. To our surprise, cKO mice also displayed motor neuron degeneration with abnormal architecture of NMJ. Specifically, the cKO mice revealed reduced motor neuron number with small neuronal size in lumbar spinal cord as well as denervating change, small motor endplates, and decreased myonuclei number at NMJ in skeletal muscles. To explore the mechanisms, we screened various muscle-derived factors and found that myogenin is a potential candidate that myogenin expression was lower in skeletal muscles of cKO mice than wild-type mice. Because NRIP and myogenin were colocalized around acetylcholine receptors at NMJ, we extracted RNA from synaptic and extrasynaptic regions of muscles using laser capture microdissection and showed that myogenin expression was especially lower at synaptic region in cKO than wild-type mice. Notably, overexpression of myogenin using intramuscular adenovirus encoding myogenin treatment rescued abnormal NMJ architecture and preserved motor neuron death in cKO mice. CONCLUSIONS: In summary, we demonstrated that deprivation of NRIP decreases myogenin expression at NMJ, possibly leading to abnormal NMJ formation, denervation of acetylcholine receptor, and subsequent loss of spinal motor neuron. Overexpression of myogenin in cKO mice can partially rescue abnormal NMJ architecture and motor neuron death. Therefore, muscular NRIP is a novel trophic factor supporting spinal motor neuron via stabilization of NMJ by myogenin expression. PMID- 29608042 TI - Vitamin D insufficiency is associated with insulin resistance independently of obesity in primary schoolchildren. The healthy growth study. AB - OBJECTIVES: To explore the associations of vitamin D status and obesity with insulin resistance (IR) in children. METHODS: A sample of 2282 schoolchildren (9 13 years old) in Greece was examined. Sociodemographic, anthropometric (weight, height), biochemical (fasting plasma glucose, serum insulin and 25(OH)D), pubertal status and physical activity data were collected, using standard methods. The "Vitamin D Standardization Program" protocol was applied to standardize serum 25(OH)D values. RESULTS: The prevalence of vitamin D insufficiency (serum 25(OH)D < 50 nmol/L) was higher in obese children compared to their over- and normal-weight counterparts (60.5% vs 51.6% and 51%, P = .017). Furthermore, children with IR (both obese and non-obese) had higher prevalence of vitamin D insufficiency compared to non-obese, non-insulin resistant children (66% and 59.2% vs 49.8%, P < .05), possibly indicating that IR is associated with vitamin D insufficiency, independently of obesity. In line with the above, the results from logistic regression analyses controlled for several potential confounders, showed a 1.48 (95% C.I: 1.2-1.84) higher likelihood for vitamin D insufficiency for insulin resistant children compared to the non-insulin resistant ones, while no significant association was observed with obesity. CONCLUSIONS: The present study revealed a high prevalence of vitamin D insufficiency among schoolchildren in Greece, particularly among obese and insulin resistant ones. In addition, it highlighted that the significant association of vitamin D insufficiency with IR is possibly independent of obesity. Further clinical trials are needed to confirm this possible independent association but also explore the potential beneficial effect of vitamin D supplementation on IR and possibly on weight management too. PMID- 29608043 TI - Physical frailty and mortality risk in Japanese older adults. AB - AIM: The association between frailty and increased mortality risk is unknown. The present study assessed the longitudinal relationship between frailty and mortality risk in Japanese community-dwelling older adults. METHODS: Participants included 841 randomly chosen community-dwelling Japanese individuals, including 175 older adults aged 65-88 years with incomplete data at the baseline examination (July 2006-July 2008). Participants were followed from baseline to 31 December 2015 (mean 7.9 years). Frailty was diagnosed according to frailty criteria, including unintentional weight loss (shrinking), exhaustion, low activity, low grip strength and low gait speed. Information on deaths was obtained from a population dynamics survey. The relationship between frailty and mortality was assessed using Kaplan-Meier survival curves and Cox proportional hazards regression. The Cox proportional hazards model was used to control for potential confounders, including age at baseline, body fat, education, the Mini Mental State Examination score, the Center for Epidemiologic Studies Depression Scale score, total physical activity, total caloric intake, alcohol intake, current smoking, household income and the number of current diseases. RESULTS: The fully adjusted hazard ratio for all-cause mortality in the frailty group was 2.63 (95% confidence interval, 1.28-5.39; P for trend <0.01). The age- and sex adjusted hazard ratio for mortality of cancer in the frailty group was 3.33 (95% confidence interval, 1.15-9.62; P for trend <0.05). CONCLUSION: Complications of frailty, which include shrinking, exhaustion, low activity, weakness, and slowness, appear to be significant risks for mortality in Japanese older adults. Geriatr Gerontol Int 2018; 18: 1085-1092. PMID- 29608044 TI - More variety with the Journal of Cachexia, Sarcopenia and Muscle: JCSM Clinical Reports and JCSM Rapid Communications have both gone live. PMID- 29608045 TI - Surface Functional Groups and Interlayer Water Determine the Electrochemical Capacitance of Ti3C2 T x MXene. AB - MXenes, an emerging class of conductive two-dimensional materials, have been regarded as promising candidates in the field of electrochemical energy storage. The electrochemical performance of their representative Ti3C2 T x, where T represents the surface termination group of F, O, or OH, strongly relies on termination-mediated surface functionalization, but an in-depth understanding of the relationship between them remains unresolved. Here, we studied comprehensively the structural feature and electrochemical performance of two kinds of Ti3C2 T x MXenes obtained by etching the Ti3AlC2 precursor in aqueous HF solution at low concentration (6 mol/L) and high concentration of (15 mol/L). A significantly higher capacitance was recognized in a low-concentration HF-etched MXene (Ti3C2 T x-6M) electrode. In situ Raman spectroscopy and X-ray photoelectron spectroscopy demonstrate that Ti3C2 T x-6M has more components of the -O functional group. In combination with X-ray diffraction analysis, low field 1H nuclear magnetic resonance spectroscopy in terms of relaxation time unambiguously underlines that Ti3C2 T x-6M is capable of accommodating more high mobility H2O molecules between the Ti3C2 T x interlayers, enabling more hydrogen ions to be more readily accessible to the active sites of Ti3C2 T x-6M. The two main key factors ( i.e., high content of -O functional groups that are involved bonding/debonding-induced pseudocapacitance and more high-mobility water intercalated between the MXene interlayers) simultaneously account for the superior capacitance of the Ti3C2 T x-6M electrode. This study provides a guideline for the rational design and construction of high-capacitance MXene and MXene-based hybrid electrodes in aqueous electrolytes. PMID- 29608046 TI - Cornucopia of Structures in the Pseudobinary System (SnSe) xBi2Se3: A Crystal Chemical Copycat. AB - Pseudobinary phases (SnSe) xBi2Se3 exhibit a very diverse structural chemistry characterized by different building blocks, all of which are cutouts of the NaCl type. For SnSe contents between x = 5 and x = 0.5, several new phases were discovered. Next to, for example, Sn4Bi2Se7 ( x = 4) in the NaCl structure type and SnBi4Se7 ( x = 0.5) in the layered defect GeSb2Te4 structure type, there are at least four compounds (0.8 <= x <= 3) with lillianite-like structures built up from distorted NaCl-type slabs (L4,4-type Sn2.22Bi2.52Se6, L4,5-type Sn9.52Bi10.96Se26, L4,7-type Sn11.49Bi12.39Se30, and L7,7-type Sn3.6Bi3.6Se9). For two of them (L4,7 and L7,7), the cation distributions were determined by resonant X-ray scattering, which also confirmed the presence of significant amounts of cation vacancies. Thermoelectric figures of merit ZT range from 0.04 for Sn4Bi2Se7 to 0.2 for layered SnBi4Se7; this is similar to that of the related compounds SnBi2Te4 or PbBi2Te4. Compounds of the lillianite series exhibit rather low thermal conductivities (~0.75 W/mK for maximal ZT). More than other "sulfosalts", compounds in the pseudobinary system SnSe-Bi2Se3 adapt to changes in the cation-anion ratio by copying structure types of compounds containing lighter or heavier homologues of Sn, Bi, or Se and can incorporate significant amounts of vacancies. Thus, (SnSe) xBi2Se3 is a multipurpose model system with vast possibilities for substitutional and structural modification aiming at the optimization of thermoelectric or other properties. PMID- 29608047 TI - Buried MoO x/Ag Electrode Enables High-Efficiency Organic/Silicon Heterojunction Solar Cells with a High Fill Factor. AB - Silicon (Si)/organic heterojunction solar cells based on poly(3,4 ethylenedioxythiophene):poly(styrenesulfonate) (PEDOT:PSS) and n-type Si have attracted wide interests because they promise cost-effectiveness and high efficiency. However, the limited conductivity of PEDOT:PSS leads to an inefficient hole transport efficiency for the heterojunction device. Therefore, a high dense top-contact metal grid electrode is required to assure the efficient charge collection efficiency. Unfortunately, the large metal grid coverage ratio electrode would lead to undesirable optical loss. Here, we develop a strategy to balance PEDOT:PSS conductivity and grid optical transmittance via a buried molybdenum oxide/silver grid electrode. In addition, the grid electrode coverage ratio is optimized to reduce its light shading effect. The buried electrode dramatically reduces the device series resistance, which leads to a higher fill factor (FF). With the optimized buried electrode, a record FF of 80% is achieved for flat Si/PEDOT:PSS heterojunction devices. With further enhancement adhesion between the PEDOT:PSS film and Si substrate by a chemical cross-linkable silance, a power conversion efficiency of 16.3% for organic/textured Si heterojunction devices is achieved. Our results provide a path to overcome the inferior organic semiconductor property to enhance the organic/Si heterojunction solar cell. PMID- 29608048 TI - Free-Standing Mn3O4@CNF/S Paper Cathodes with High Sulfur Loading for Lithium Sulfur Batteries. AB - Free-standing paper cathodes with layer-by-layer structure are synthesized for high-loading lithium-sulfur (Li-S) battery. Sulfur is loaded in a three dimensional (3D) interconnected nitrogen-doped carbon nanofiber (CNF) framework impregnated with Mn3O4 nanoparticles. The 3D interconnected CNF framework creates an architecture with outstanding mechanical properties. Synergetic effects generated from physical and chemical entrapment could effectively suppress the dissolution and diffusion of the polysulfides. Electrochemical measurements suggest that the rationally designed structure endows the electrode with high utilization of sulfur and good cycle performance. Specifically, the cathode with a high areal sulfur loading of 11 mg cm-2 exhibits a reversible areal capacity over 8 mAh cm-2. The fabrication procedure is of low cost and readily scalable. We believe that this work will provide a promising choice for potential practical applications. PMID- 29608049 TI - High Frequency Data Exposes Nonlinear Seasonal Controls on Dissolved Organic Matter in a Large Watershed. AB - We analyzed a five year, high frequency time series generated by an in situ fluorescent dissolved organic matter (fDOM) sensor installed near the Connecticut River's mouth, investigating high temporal resolution DOM dynamics in a larger watershed and longer time series than previously addressed. We identified a gradient between large, saturating summer fDOM responses to discharge and linear, subdued responses during colder months. Seasonal response patterns were not consistent with multiple linear regression. Alternatively, we binned measurements across the yearly cycle using environmental indices, such as temperature, and applied moving regression, a novel approach which produced superior fits to calendar day binning. Spatially averaged watershed soil temperature at 10 cm was the best overall index of discharge-fDOM response. DOM fractionation showed fDOM was primarily a surrogate for hydrophobic organic acid (HPOA) concentrations. HPOAs were highly correlated with discharge, but hydrophilics (HPIs) were not. Discharge dependent DOM concentrations driven by the HPOA fraction may be controlled by soil temperature and water table position relative to organic and mineral soil horizons. HPI concentrations were correlated with average watershed soil temperature at 10 cm but were rather stationary throughout the year, further indicating a consistent groundwater source for this nonfluorescent DOM. We present a resolved subseasonal empirical model of DOM concentrations and fluxes, showing that riverine DOM flux and quality depend heavily on seasonal terrestrial carbon dynamics and hydrologic flow paths. High frequency monitoring reveals readily discernible patterns demonstrating that upland biogeochemical signals are maintained even at this large watershed scale. PMID- 29608050 TI - Semiconducting CuO Nanotubes: Synthesis, Characterization, and Bifunctional Photocathodic Enzymatic Bioanalysis. AB - This work reports the synthesis, characterization, and application of bifunctional semiconducting CuO nanotubes (NTs) electrode for innovative synergized cathodic photoelectrochemical (PEC) enzymatic bioanalysis. Specifically, CuO NTs electrode was fabricated by surface oxidation of the copper foil in an alkaline aqueous solution with (NH4)2S2O8 and then annealed in air at 200 degrees C. After the subsequent coupling with the model enzyme of xanthine oxidase (XOD), the resulted photocathodic enzyme biosensor exhibited good analytical performance of rapid response, high stability, and good sensitivity. Especially, due to the unique catalytic property of CuO toward H2O2, a novel enzymatic cascade design between biological catalyst (XOD as natural enzyme) and biomimetic catalyst (CuO as the peroxidase mimetics) was constructed, and the dual-catalyst system with special synergy effect could achieve the cathodic PEC guanine bioanalysis with enhanced efficiency. In the determination, the cathodic photocurrent was found to be proportional to the guanine concentration, which was different from the commonly observed O2-dependent suppression of the photocurrent. In all, such a bifunctional CuO NTs-based PEC bioassay format has not been reported. The success of this work can offer great chances for further development and implementation of novel CuO-based PEC bioanalytical systems. More importantly, the strategy proposed here could contribute to the development of an original prototype for general PEC enzymatic bioanalysis. PMID- 29608051 TI - En Route to Practicality of the Polymer Grafting Technology: One-Step Interfacial Modification with Amphiphilic Molecular Brushes. AB - Surface modification with polymer grafting is a versatile tool for tuning the surface properties of a wide variety of materials. From a practical point of view, such a process should be readily scalable and transferable between different substrates and consist of as least number of steps as possible. To this end, a cross-linkable amphiphilic copolymer system that is able to bind covalently to surfaces and form permanently attached networks via a one-step procedure is reported here. This system consists of brushlike copolymers (molecular brushes) made of glycidyl methacrylate, poly(oligo(ethylene glycol) methyl ether methacrylate), and lauryl methacrylate, which provide the final product with tunable reactivity and balance between hydrophilicity and hydrophobicity. The detailed study of the copolymer synthesis and properties has been carried out to establish the most efficient pathway to design and tailor this amphiphilic molecular brush system for specific applications. As an example of the applications, we showed the ability to control the deposition of graphene oxide (GO) sheets on both hydrophilic and hydrophobic surfaces using GO modified with the molecular brushes. Also, the capability to tune the osteoblast cell adhesion with the copolymer-based coatings was demonstrated. PMID- 29608052 TI - Modern Approaches for Asymmetric Construction of Carbon-Fluorine Quaternary Stereogenic Centers: Synthetic Challenges and Pharmaceutical Needs. AB - New methods for preparation of tailor-made fluorine-containing compounds are in extremely high demand in nearly every sector of chemical industry. The asymmetric construction of quaternary C-F stereogenic centers is the most synthetically challenging and, consequently, the least developed area of research. As a reflection of this apparent methodological deficit, pharmaceutical drugs featuring C-F stereogenic centers constitute less than 1% of all fluorine containing medicines currently on the market or in clinical development. Here we provide a comprehensive review of current research activity in this area, including such general directions as asymmetric electrophilic fluorination via organocatalytic and transition-metal catalyzed reactions, asymmetric elaboration of fluorine-containing substrates via alkylations, Mannich, Michael, and aldol additions, cross-coupling reactions, and biocatalytic approaches. PMID- 29608053 TI - The Effects of Galvanic Interactions with Pyrite on the Generation of Acid and Metalliferous Drainage. AB - Although the acid generating properties of pyrite (FeS2) have been studied extensively, the impact of galvanic interaction on pyrite oxidation, and the implications for acid and metalliferous drainage, remain largely unexplored. The relative galvanic effects on pyrite dissolution were found to be consistent with relative sulfide mineral surface area ratios with sphalerite (ZnS) having greater negative impact in batch leach tests (sulfide minerals only, controlled pH) and galena (PbS) having greater negative impact in kinetic leach column tests (KLCs, uncontrolled pH, >85 wt% silicate minerals). In contrast the presence of pyrite resulted consistently in greater increase in galena than sphalerite leaching suggesting that increased anodic leaching is dependent on the difference in anodic and cathodic sulfide mineral rest potentials. Acidity increases occurred after 44, 20, and 12 weeks in the pyrite-galena, pyrite-sphalerite, and the pyrite containing KLCs. Thereafter acid generation rates were similar with the Eh consistently above the rest potential of pyrite (660 mV, SHE). This suggests that treatment of waste rocks or tailings, to establish and maintain low Eh conditions, may help to sustain protective galvanic interactions and that monitoring of Eh of leachates is potentially a useful indicator for predicting changes in acid generation behavior. PMID- 29608054 TI - Effect of Gallium Substitution on Lithium-Ion Conductivity and Phase Evolution in Sputtered Li7-3 xGa xLa3Zr2O12 Thin Films. AB - Replacing the liquid electrolyte in conventional lithium-ion batteries with thin film solid-state lithium-ion conductors is a promising approach for increasing energy density, lifetime, and safety. In particular, Li7La3Zr2O12 is appealing due to its high lithium-ion conductivity and wide electrochemical stability window. Further insights into thin-film processing of this material are required for its successful integration into solid-state batteries. In this work, we investigate the phase evolution of Li7-3 xGa xLa3Zr2O12 in thin films with various amounts of Li and Ga for stabilizing the cubic phase. Through this work, we gain valuable insights into the crystallization processes unique to thin films and are able to form dense Li7-3 xGa xLa3Zr2O12 layers stabilized in the cubic phase with high in-plane lithium-ion conductivities of up to 1.6 * 10-5 S cm-1 at 30 degrees C. We also note the formation of cubic Li7La3Zr2O12 at the relatively low temperature of 500 degrees C. PMID- 29608055 TI - A Reversibly pH-Switchable Open/Closed Cage Constructed from Triangular Polyoxometalate Hybrid [(C7H7AsO3)6W12O36]12- Cluster Anions Exhibiting Supramolecular Chirality. AB - A new nanosized polyoxometalate modified by benzylarsonate ligands, [(C7H7AsO3)6W12O36]12- (1a), was successfully isolated and structurally characterized as Na2(C2H8N)4H6[(C7H7AsO3)6W12O36].30H2O (1). Controlled protonation of 1a led it to self-reorganize into isomer cage cluster [(C7H7AsO3)6W12O30(OH)4(H2O)2]4- (2a) with an organic ligand arranging in "half open" mode. The reversibly switchable cage transform was monitored by 1H NMR. Also, the origin of the solid supramolecular chirality in the crystal 1 and the aggregation process of 1a were preliminarily studied. PMID- 29608056 TI - A Graphene-Silver Nanoparticle-Silicon Sandwich SERS Chip for Quantitative Detection of Molecules and Capture, Discrimination, and Inactivation of Bacteria. AB - There currently exists increasing concerns on the development of a kind of high performance SERS platform, which is suitable for sensing applications ranging from the molecular to cellular (e.g., bacteria) level. Herein, we develop a novel kind of universal SERS chip, made of graphene (G)-silver nanoparticle (AgNP) silicon (Si) sandwich nanohybrids (G@AgNPs@Si), in which AgNPs are in situ grown on a silicon wafer through hydrofluoric acid-etching-assisted chemical reduction, followed by coating with single-layer graphene via a polymer-protective etching method. The resultant chip features a strong, stable, reproducible surface enhanced Raman scattering (SERS) effect and reliable quantitative capability. By virtues of these merits, the G@AgNPs@Si platform is capable for not only molecular detection and quantification but also cellular analysis in real systems. As a proof-of-concept application, the chip allows ultrahigh sensitive and reliable detection of adenosine triphosphate (ATP), with a detection limit of ~1 pM. In addition, the chip, serving as a novel multifunctional platform, enables simultaneous capture, discrimination, and inactivation of bacteria. Typically, the bacterial capture efficiency is 54% at 108 CFU mL-1 bacteria, and the antibacterial rate reaches 93% after 24 h of treatment. Of particular note, Escherichia coli and Staphylococcus aureus spiked into blood can be readily distinguished via the chip, suggesting its high potential for clinical applications. PMID- 29608057 TI - Low-Cost, Rapidly Responsive, Controllable, and Reversible Photochromic Hydrogel for Display and Storage. AB - Traditional optoelectronic devices without stretchable performance could be limited for substrates with irregular shape. Therefore, it is urgent to explore a new generation of flexible, stretchable, and low-cost intelligent vehicles as visual display and storage devices, such as hydrogels. In the investigation, a novel photochromic hydrogel was developed by introducing the negatively charged ammonium molybdate as a photochromic unit into polyacrylamide via ionic and covalent cross-linking. The hydrogel exhibited excellent properties of low cost, easy preparation, stretchable deformation, fatigue resistance, high transparency, and second-order response to external signals. Moreover, the photochromic and fading process of hydrogels could be precisely controlled and repeated under the irradiation of UV light and exposure of oxygen at different time and temperature. The photochromic hydrogel could be considered applied for artificial intelligence system, wearable healthcare device, and flexible memory device. Therefore, the strategy for designing a soft photochromic material would open a new direction to manufacture flexible and stretchable devices. PMID- 29608058 TI - Structural Incorporation of Manganese into Goethite and Its Enhancement of Pb(II) Adsorption. AB - Natural goethite (alpha-FeOOH) commonly accommodates various metal elements by substituting for Fe, which greatly alters the surface reactivity of goethite. This study discloses the enhancement of Mn-substitution for the Pb2+adsorption capacity of goethite. The incorporated Mn in the synthesized goethite presents as Mn(III) and causes a slight decrease in the a and c of the unit cell parameters and an observable increase in the b direction due to the Jahn-Teller effect of the Mn(III)O6 octahedra. With the Mn content increasing, the particle size decreases gradually, and the surface clearly becomes roughened. The Pb2+ adsorption capacity of goethite is observably enhanced by Mn substitution due to the modified surface complexes. And the increased surface-area-normalized adsorption capacity for Mn-substituted goethite indicated that the enhancement of Pb adsorption is not only attributed to the increase of surface area but also to the change of binding complexes. Extended X-ray absorption fine structure (EXAFS) analysis indicates that the binding structures of Pb2+ on goethite presents as edge-sharing complexes with a regular RPb-Fe = 3.31 A. In the case of Mn goethite, Pb2+ is also bound with the Mn surface site on the edge-sharing complex with a larger RPb-Mn = 3.47 A. The mechanism for enhancing Pb2+ adsorption on Mn goethite can be interpreted as the preferred Pb2+ binding on the Mn site of Mn goethite surface. In a summary, the Mn-goethite has great potential for material development in environmental remediation. PMID- 29608059 TI - (C6H13N)2BiI5: A One-Dimensional Lead-Free Perovskite-Derivative Photoconductive Light Absorber. AB - Lead-free organic-inorganic hybrid perovskites have recently attracted intense interest as environmentally friendly, low-cost, chemically stable light absorbers. Here, we reported a new one-dimensional (1D) zigzag chainlike light absorbing hybrid material of (C6H13N)2BiI5, in which the corner-sharing octahedral bismuth halide chains are surrounded by organic cations of tetramethylpiperidinium. This unique zigzag 1D hybrid perovskite-derivative material shows a narrow direct band gap of 2.02 eV and long-lived photoluminescence, which is encouraging for optoelectronic applications. Importantly, it behaves as a typical semiconducting material and displays obvious photoresponse in the visible-light range. This work opens a potential pathway for the further application of 1D lead-free hybrids. PMID- 29608060 TI - Surface Modifier-Free Organic-Inorganic Hybridization To Produce Optically Transparent and Highly Refractive Bulk Materials Composed of Epoxy Resins and ZrO2 Nanoparticles. AB - Surface modifier-free hybridization of ZrO2 nanoparticles (NPs) with epoxy-based polymers is demonstrated for the first time to afford highly transparent and refractive bulk materials. This is achieved by a unique and versatile hybridization via the one-pot direct phase transfer of ZrO2 NPs from water to epoxy monomers without any aggregation followed by curing with anhydride. Three types of representative epoxy monomers, bisphenol A diglycidyl ether (BADGE), 3,4 epoxycyclohexylmethyl-3',4'-epoxycyclohexane carboxylate (CEL), and 1,3,5-tris(3 (oxiran-2-yl)propyl)-1,3,5-triazinane-2,4,6-trione (TEPIC), are used to produce transparent viscous dispersions. The resulting ZrO2 NPs are thoroughly characterized using dynamic light scattering (DLS), transmission electron microscopy (TEM), Fourier transform infrared (FT-IR), and solid-state 13C CP/MAS NMR measurements. The results from DLS and TEM analyses indicate nanodispersion of ZrO2 into epoxy monomers as a continuous medium. A surface modification mechanism and the binding fashion during phase transfer are proposed based on the FT-IR and solid-state 13C CP/MAS NMR measurements. Epoxy-based hybrid materials with high transparency and refractive index are successfully fabricated by heat curing or polymerizing a mixture of monomers containing epoxy-functionalized ZrO2 NPs and methylhexahydrophthalic anhydride in the presence of a phosphoric catalyst. The TEM and small-angle X-ray scattering measurements of the hybrids show a nanodispersion of ZrO2 in the epoxy networks. The refractive index at 594 nm ( n594) increases up to 1.765 for BADGE-based hybrids, 1.667 for CEL-based hybrids, and 1.693 for TEPIC-based hybrids. Their refractive indices and Abbe's numbers are quantitatively described by the Lorentz-Lorenz effective medium expansion theory. Their transmissivity is also reasonably explained using Fresnel refraction, Rayleigh scattering, and the Lambert-Beer theories. This surface modifier-free hybridization provides a versatile, fascinating, and promising method for synthesizing a variety of epoxy-based hybrid materials. PMID- 29608061 TI - Advances in Spray-Cast Perovskite Solar Cells. AB - Spray-coating is a deposition technique that is widely used in industry and could in principle be used to fabricate perovskite photovoltaic (PV) devices at low cost and high volume. As with any deposition technique, the fabrication of thin films requires optimization of a range of parameter space in order to control film uniformity and homogeneity. This is particularly important in PV fabrication as the quality of the thin film has an important effect on device efficiency. This Perspective summarizes the developments in spray-cast perovskite solar cells made over the past few years, with particular attention paid to strategies employed to control the crystallization of the perovskite. Steady progress has now been made with spray-cast perovskite PV devices recently demonstrated having a power conversion efficiency of 18.3%. We highlight trends within the research field and discuss challenges that will be necessary to drive such techniques toward practical application. PMID- 29608062 TI - Metal-Organic Framework Derived Core-Shell Co/Co3O4@N-C Nanocomposites as High Performance Anode Materials for Lithium Ion Batteries. AB - Metal-organic frameworks (MOFs) with diverse structures, adjustable pore sizes, and high surface areas have exhibited awesome potential in many fields. Here we report a simple carbonization strategy to obtain a series of core-shell structured Co/Co3O4 nanoparticles encapsulated into nitrogen-doped carbon shells from cobalt-based metal-organic framework precursors at different carbonization temperatures. When it is applied as an anodes for lithium ion batteries, the Co/Co3O4@N-C-700 electrode delivers a maximum initial discharge capacity of 1535 mAh g-1, the highest reversible capacity (903 mAh g-1 at a current density of 100 mA g-1 after 100 cycles), and the best rate performance (i.e., 774 mAh g-1 at a current density of 1.0 A g-1 after 100 cycles) in comparison with those of Co/Co3O4@N-C-600 and Co/Co3O4@N-C-800 electrodes. The excellent electrochemical performance could be mainly attributed to the unique core-shell structure, abundant graphited carbon, and the well-dispersed Co/Co3O4 nanoparticles which can promote the specific capacity through conversion reactions. PMID- 29608063 TI - Electroenzymatic C-C Bond Formation from CO2. AB - Over the past decade, there has been significant research in electrochemical reduction of CO2, but it has been difficult to develop catalysts capable of C-C bond formation. Here, we report bioelectrocatalysis of vanadium nitrogenase from Azotobacter vinelandii, where cobaltocenium derivatives transfer electrons to the catalytic VFe protein, independent of ATP-hydrolysis. In this bioelectrochemical system, CO2 is reduced to ethylene (C2H4) and propene (C3H6), by a single metalloenzyme. PMID- 29608064 TI - A Family of Layered Phosphates Crystallizing in a Rare Geometrical Isomer of the Phosphuranylite Topology: Synthesis, Characterization, and Computational Modeling of A4[(UO2)3O2(PO4)2] (A = Alkali Metal) Exhibiting Intralayer Ion Exchange. AB - Single crystals of eight new layered uranyl phosphates were grown from alkali chloride fluxes: Cs1.4K2.6[(UO2)3O2(PO4)2], Cs0.7K3.3[(UO2)3O2(PO4)2], Rb1.4K2.6[(UO2)3O2(PO4)2], K4[(UO2)3O2(PO4)2], K2.9Na0.9Rb0.2[(UO2)3O2(PO4)2], K2.1Na0.7Rb1.2[(UO2)3O2(PO4)2], Cs1.7K4.3[(UO2)5O5(PO4)2], and Rb1.6K4.4[(UO2)5O5(PO4)2]. All structures crystallize in the monoclinic space group, P21/ c and contain uranyl phosphate layers with alkali metals located between the layers for charge balance. Ion exchange experiments on Cs0.7K3.3[(UO2)3O2(PO4)2], Rb1.4K2.6[(UO2)3O2(PO4)2], and K4[(UO2)3O2(PO4)2] demonstrated that Cs and Rb cations cannot be exchanged for K cations; however, K cations can be readily exchanged for Na, Rb, and Cs. Enthalpies of formation were calculated from density functional theory (DFT) and volume-based thermodynamics (VBT) for all six structures. A value for the enthalpy of formation of the phosphuranylite sheet, [(UO2)3O2(PO4)2]4-, was derived using single-ion additive methods coupled with VBT. DFT and VBT calculations were used to justify results of the ion exchange experiments. Cs0.7K3.3[(UO2)3O2(PO4)2], Rb1.4K2.6[(UO2)3O2(PO4)2], and K4[(UO2)3O2(PO4)2] exhibit typical luminescence of the uranyl group. PMID- 29608065 TI - Correction to "Divergent Asymmetric Syntheses of Podophyllotoxin and Related Family Members via Stereoselective Reductive Ni-Catalysis". PMID- 29608066 TI - Embonic Acid Functionalized Niobium Complexes with Selective Dye Sorption Properties. AB - Presented here are binuclear Nb2, tetranuclear Ti2Nb2, and dodecanuclear Nb12 complexes decorated by embonic acid ligands. These structures feature a unique Ti O-Nb or Nb-O-Nb subunit. Besides, the unprecedented dodecanuclear Nb12 cluster further displays a porous three-dimensional packing framework and stability in water, affording an interesting selective uptake for methylene blue molecules over rhodamine B. PMID- 29608067 TI - Vibrational Characterization of Radical Ion Adducts between Imidazole and CO2. AB - We address the molecular level origins of the dramatic difference in the catalytic mechanisms of CO2 activation by the seemingly similar molecules pyridine (Py) and imidazole (Im). This is accomplished by comparing the fundamental interactions of CO2 radical anions with Py and Im in the isolated, gas phase PyCO2- and ImCO2- complexes. These species are prepared by condensation of the neutral compounds onto a (CO2) n- cluster ion beam by entrainment in a supersonic jet ion source. The structures of the anionic complexes are determined by theoretical analysis of their vibrational spectra, obtained by IR photodissociation of weakly bound CO2 molecules in a photofragmentation mass spectrometer. Although the radical PyCO2- system adopts a carbamate-like configuration corresponding to formation of an N-C covalent bond, the ImCO2- species is revealed to be best described as an ion-molecule complex in which an oxygen atom in the CO2- radical anion is H-bonded to the NH group. Species that feature a covalent N-C interaction in ImCO2- are calculated to be locally stable structures, but are much higher in energy than the largely electrostatically bound ion-molecule complex. These results support the suggestion from solution phase electrochemical studies (Bocarsly et al. ACS Catal. 2012, 2, 1684-1692) that the N atoms are not directly involved in the catalytic activation of CO2 by Im. PMID- 29608068 TI - Impact of Dynamically Exposed Polarity on Permeability and Solubility of Chameleonic Drugs Beyond the Rule of 5. AB - Conformational flexibility has been proposed to significantly affect drug properties outside rule-of-5 (Ro5) chemical space. Here, we investigated the influence of dynamically exposed polarity on cell permeability and aqueous solubility for a structurally diverse set of drugs and clinical candidates far beyond the Ro5, all of which populated multiple distinct conformations as revealed by X-ray crystallography. Efflux-inhibited (passive) Caco-2 cell permeability correlated strongly with the compounds' minimum solvent-accessible 3D polar surface areas (PSA), whereas aqueous solubility depended less on the specific 3D conformation. Inspection of the crystal structures highlighted flexibly linked aromatic side chains and dynamically forming intramolecular hydrogen bonds as particularly effective in providing "chameleonic" properties that allow compounds to display both high cell permeability and aqueous solubility. These structural features, in combination with permeability predictions based on the correlation to solvent-accessible 3D PSA, should inspire drug design in the challenging chemical space far beyond the Ro5. PMID- 29608069 TI - Two Iron Complexes as Homogeneous and Heterogeneous Catalysts for the Chemical Fixation of Carbon Dioxide. AB - Two new bimetallic iron-alkali metal complexes of amino acid (serine)-based reduced Schiff base ligand were synthesized and structurally characterized. Their efficacy as catalysts for the chemical fixation of carbon dioxide was explored. The heterogeneous version of the catalytic reaction was developed by the immobilization of these homogeneous bimetallic iron-alkali metal complexes in an anion-exchange resin. The resin-bound complexes can be used as recyclable catalysts up to six cycles. PMID- 29608070 TI - Metabolism of Antifungal Thiochroman-4-ones by Trichoderma viride and Botrytis cinerea. AB - Biotransformation of 6-methylthiochroman-4-one (1) and 6-chlorothiochroman-4-one (2) was performed using Trichoderma viride in order to obtain new derivatives with antifungal properties against the phytopathogen Botrytis cinerea. Two thiochromanone derivatives are described for the first time. Antifungal activity of these compounds was tested against two different strains of Botrytis cinerea; 1 and 2 gave 100% inhibition of Bc2100 at 100-250 MUg/mL, and 3 gave a maximal inhibition of 96% of BcUCA992 at 200 MUg/mL. The detoxification mechanism of 1 and 2 by B. cinerea was also investigated. PMID- 29608071 TI - Fluorescence-Detected Two-Quantum and One-Quantum-Two-Quantum 2D Electronic Spectroscopy. AB - We demonstrate two-quantum (2Q) coherent two-dimensional (2D) electronic spectroscopy using a shot-to-shot-modulated pulse shaper and fluorescence detection. Broadband collinear excitation is realized with the supercontinuum output of an argon-filled hollow-core fiber, enabling us to excite multiple transitions simultaneously in the visible range. The 2Q contribution is extracted via a three-pulse sequence with 16-fold phase cycling and simulated employing cresyl violet as a model system. Furthermore, we report the first experimental realization of one-quantum-two-quantum (1Q-2Q) 2D spectroscopy, offering less congested spectra as compared with the 2Q implementation. We avoid scattering artifacts and nonresonant solvent contributions by using fluorescence as the observable. This allows us to extract quantitative information about doubly excited states that agree with literature expectations. The high sensitivity and background-free nature of fluorescence detection allow for a general applicability of this method to many other systems. PMID- 29608073 TI - Is self-regard a sociometer or a hierometer? Self-esteem tracks status and inclusion, narcissism tracks status. AB - What adaptive function does self-regard serve? Sociometer theory predicts that it positively tracks social inclusion. A new theory, hierometer theory, predicts that it positively tracks social status. We tested both predictions with respect to two types of self-regard: self-esteem and narcissism. Study 1 (N = 940), featuring a cross-sectional design, found that both status and inclusion covaried positively with self-esteem, but that status alone covaried positively with narcissism. These links held independently of gender, age, and the Big Five personality traits. Study 2 (N = 627), a preregistered cross-sectional study, obtained similar results with alternative measures of self-esteem and narcissism. Studies 3-4 featured experimental designs in which status and inclusion were orthogonally manipulated. Study 3 (N = 104) found that both higher status and higher inclusion promoted higher self-esteem, whereas only higher status promoted higher narcissism. Study 4 (N = 259) obtained similar results with alternative measures of self-esteem and narcissism. The findings suggest that self-esteem operates as both sociometer and hierometer, positively tracking both status and inclusion, whereas narcissism operates primarily as a hierometer, positively tracking status. (PsycINFO Database Record PMID- 29608072 TI - A smartphone-based ecological momentary assessment of parental behavioral consistency: Associations with parental stress and child ADHD symptoms. AB - Inconsistent parental discipline is a robust correlate of child attention deficit/hyperactivity disorder (ADHD) symptoms, but few studies have considered the role of inconsistent positive parenting on ADHD, as well as the effects of stress on negative and positive parental consistency. This study advanced a novel ecological momentary assessment (EMA) using participant smartphones to measure parental consistency, and examined its associations with family, social, and parenting-related dimensions of stress and child ADHD symptoms. Participants were 184 kindergartners with and without ADHD and their parents. Harsh and warm dimensions of parental behavior were assessed using questionnaires, observations, and an EMA administered through parents' smartphones, which measured parent-child behaviors every day for a period of 1 week. Family, social, and parenting-related stress were assessed from questionnaires, and child ADHD symptoms were assessed from a fully structured diagnostic interview with the parent. Child ADHD symptoms were associated with variability in warm parenting behaviors, and higher levels of parenting-related stress were related to greater variability in harsh parenting behaviors. No significant interactions were detected between parental stress and child ADHD on parental variability. These findings suggest that different factors influence the consistency in parenting behavior, depending on whether positive parenting or negative parenting is assessed. Parent-based treatment programs for children with ADHD should include a stronger focus on reducing stress from parenting (e.g., teaching coping skills for parents), as this may lead to greater consistency in parental behavior more generally, and presumably better child outcomes. (PsycINFO Database Record PMID- 29608074 TI - The devil's in the g-tails: Deficient letter-shape knowledge and awareness despite massive visual experience. AB - Knowledge of letter shapes is central to reading. In experiments focusing primarily on a single letter shape-the "looptail" lowercase print G-we found surprising gaps in skilled readers' knowledge. In Experiment 1 most participants failed to recall the existence of looptail g when asked if G has two lowercase print forms, and almost none were able to write looptail g accurately. In Experiment 2 participants searched for Gs in text with multiple looptail gs. Asked immediately thereafter to write the g form they had seen, half the participants produced an "opentail" g (the typical handwritten form), and only one wrote looptail g accurately. In Experiment 3 participants performed poorly in discriminating looptail g from distractors with important features mislocated or misoriented. These results have implications for understanding types of knowledge about letters, and how this knowledge is acquired. For example, our findings speak to hypotheses concerning the role of writing in learning letter shapes. More generally, our findings raise questions about the conditions under which massive exposure does, and does not, yield detailed, accurate, accessible knowledge. In this context we relate our findings to studies showing poor knowledge or memory for various types of stimuli despite extensive exposure. (PsycINFO Database Record PMID- 29608075 TI - Examining the "why" of vaccine hesitancy. AB - Comments on the original article by Hornsey and colleagues (see record 2018-03974 001) which present findings on a 24-nation survey of the underlying roots of vaccine hesitancy and antivaccination attitudes. Their findings provide a solid foundation on which to build the next generation of research into vaccine communication and ways to address vaccine hesitancy. Where do we go from here? Although the work of Hornsey et al. (2018) is a good first step, their primary outcome was vaccination attitudes. Future research is needed to evaluate these findings in the context of actual vaccine uptake. (PsycINFO Database Record PMID- 29608076 TI - Body image and self-esteem in disorders of sex development: A European multicenter study. AB - OBJECTIVE: Disorders/differences of sex development (DSD) refer to congenital conditions with atypical sex development and are associated with psychosexual issues. The aim of this study was to assess body image and self-esteem across the DSD spectrum and to study the impact of diagnosis and mediating characteristics. METHOD: Data collection was part of dsd-LIFE, a cross-sectional study conducted by 14 European expert clinics on wellbeing and health care evaluation of adults diagnosed with DSD. Main outcome measures in the present analyses were the Body Image Scale and Rosenberg Self-Esteem Scale. Additional data were obtained on treatments, openness, body embarrassment, sexual satisfaction, anxiety, and depression. RESULTS: The participating sample (n = 1,040) included 226 classified as Congenital Adrenal Hyperplasia, 225 as Klinefelter Syndrome, 322 as Turner Syndrome, and 267 as conditions with 46,XY karyotype. Many participants had received hormonal and surgical treatments. Participants scored lower on body image and self-esteem compared to control values, whereas each diagnosis showed different areas of concern. Limited openness, body embarrassment, and sexual issues were frequently reported. Overall body satisfaction was associated with BMI, hormone use, openness, body embarrassment, anxiety, and depression; genital satisfaction with age at diagnosis, openness, sexual satisfaction, and body embarrassment. Body embarrassment, anxiety, and depression predicted lower self esteem. CONCLUSIONS: While each DSD showed specific issues related to body image and self-esteem, our findings indicate that the related factors were similar across the conditions. Clinical care on this subject could be improved by giving specific attention to factors like openness, body embarrassment, sexuality, anxiety, and depression. (PsycINFO Database Record PMID- 29608077 TI - Overt attention in contextual cuing of visual search is driven by the attentional set, but not by the predictiveness of distractors. AB - Two experiments examined biases in selective attention during contextual cuing of visual search. When participants were instructed to search for a target of a particular color, overt attention (as measured by the location of fixations) was biased strongly toward distractors presented in that same color. However, when participants searched for targets that could be presented in 1 of 2 possible colors, overt attention was not biased between the different distractors, regardless of whether these distractors predicted the location of the target (repeating) or did not (randomly arranged). These data suggest that selective attention in visual search is guided only by the demands of the target detection task (the attentional set) and not by the predictive validity of the distractor elements. (PsycINFO Database Record PMID- 29608078 TI - How do task characteristics affect learning and performance? The roles of variably mapped and dynamic tasks. AB - For well over a century, scientists have investigated individual differences in performance. The majority of studies have focused on either differences in practice, or differences in cognitive resources. However, the predictive ability of either practice or cognitive resources varies considerably across tasks. We are the first to examine task characteristics' impact on learning and performance in a complex task while controlling for other task characteristics. In 2 experiments we test key theoretical task characteristic thought to moderate the relationship between practice, cognitive resources, and performance. We devised a task where each of several key task characteristics can be manipulated independently. Participants played 5 rounds of a game similar to the popular tower defense videogame Plants vs. Zombies where both cognitive load and game characteristics were manipulated. In Experiment 1, participants either played a consistently mapped version-the stimuli and the associated meaning of their properties were constant across the 5 rounds-or played a variably mapped version the stimuli and the associated meaning of their properties changed every few minutes. In Experiment 2, participants either played a static version-that is, turn taking with no time pressure-or played a dynamic version-that is, the stimuli moved regardless of participants' response rates. In Experiment 1, participants' accuracy and efficiency were substantially hindered in the variably mapped conditions. In Experiment 2, learning and performance accuracy were hindered in the dynamic conditions, especially when under cognitive load. Our results suggest that task characteristics impact the relative importance of cognitive resources and practice on predicting learning and performance. (PsycINFO Database Record PMID- 29608079 TI - Learning nonadjacent dependencies embedded in sentences of an artificial language: When learning breaks down. AB - The structure of natural languages give rise to many dependencies in the linear sequences of words, and within words themselves. Detecting these dependencies is arguably critical for young children in learning the underlying structure of their language. There is considerable evidence that human adults and infants are sensitive to the statistical properties of sequentially adjacent items. However, the conditions under which learners detect nonadjacent dependencies (NADs) appears to be much more limited. This has resulted in proposals that the kinds of learning mechanisms learners deploy in processing adjacent dependencies are fundamentally different from those deployed in learning NADs. Here we challenge this view. In 4 experiments, we show that learning both kinds of dependencies is hindered in conditions when they are embedded in longer sequences of words, and facilitated when they are isolated by silences. We argue that the findings from the present study and prior research is consistent with a theory that similar mechanisms are deployed for adjacent and nonadjacent dependency learning, but that NAD learning is simply computationally more complex. Hence, in some situations NAD learning is only successful when constraining information is provided, but critically, that additional information benefits adjacent dependency learning in similar ways. (PsycINFO Database Record PMID- 29608080 TI - Behavioral health integration and the risks of reductionism. AB - This editorial focuses on the topic of behavioral health integrations. It discusses the differences in types of integrated care and provides examples of practice elements that could be included under the umbrella of integrated care. (PsycINFO Database Record PMID- 29608081 TI - Observation in medical education: Time for a broader conversation? AB - Comments on the original article by Dr. Butler (see record 2018-03109-001) in which Butler lays out a series of concerns and controversies regarding the use of video recording to assess the competence of medical students, residents and other learners. (PsycINFO Database Record PMID- 29608082 TI - Clinician barriers to initiating sexual health conversations with breast cancer survivors: The influence of assumptions and situational constraints. AB - INTRODUCTION: Sexual health (SH) is an important dimension of physical, emotional, and social functioning after breast cancer (BC). Research suggests that survivors' SH concerns are not being adequately addressed in oncology or primary care settings. It is important to understand why these conversations are not taking place and what can be done to enhance care for women in this context. This research aims to identify when clinicians initiate SH conversations with survivors and to uncover factors that influence these decisions. METHOD: Thirty six clinicians from family medicine, internal medicine, oncology, and gynecology participated in semistructured interviews. Analysis uncovered themes that influence clinicians' decisions about initiating SH conversations with survivors. Attention was given to capturing the personal, professional, and system-level issues that inform clinicians' communication choices. RESULTS: Clinicians reported their decisions are based on (a) beliefs about patients, (b) inability to address survivors' concerns, (c) time constraints that affect the delivery of care, and (d) views of professional function in survivor health care. DISCUSSION: Clinician decisions are based on sometimes-erroneous assumptions and situational constraints. This suggests the need for medical education and support regarding SH care. Several practice points are outlined to facilitate clinicians' efforts to improve SH care for female BC survivors. (PsycINFO Database Record PMID- 29608083 TI - Reflections on clinician barriers to sexual health conversations: The need for education and encouragement. AB - Comments on the original article by M. R. Canzona et al. (see record 2018-12809 003) on the topic of initiating sexual health conversations with breast cancer survivors. In this qualitative study, four themes that the authors describe as limiting the ability of clinicians to address issues of sexuality in breast cancer survivors emerge. This study demonstrates that barriers to initiating conversations about sexual health have a lot more to do with the assumptions, attitudes, and knowledge of the clinicians' and their view of what is best for patient care than with the patient herself. (PsycINFO Database Record PMID- 29608084 TI - Integrated Primary Care Readiness and Behaviors Scale: Development and validation in behavioral health professionals. AB - INTRODUCTION: Although integrated primary care (IPC) is growing, several barriers remain. Better understanding of behavioral health professionals' (BHPs') readiness for and engagement in IPC behaviors could improve IPC research and training. This study developed measures of IPC behaviors and stage of change. METHOD: The sample included 319 licensed, practicing BHPs with a range of interests and experience with IPC. Sequential measurement development procedures, with split-half cross-validation were conducted. RESULTS: Exploratory principal components analyses (N = 152) and confirmatory factor analyses (N = 167) yielded a 12-item scale with 2 factors: consultation/practice management (CPM) and intervention/knowledge (IK). A higher-order Integrated Primary Care Behavior Scale (IPCBS) model showed good fit to the data, and excellent internal consistencies. The multivariate analysis of variance (MANOVA) on the IPCBS demonstrated significant large-sized differences across stage and behavior groups. DISCUSSION: The IPCBS demonstrated good psychometric properties and external validation, advancing research, education, and training for IPC practice. (PsycINFO Database Record PMID- 29608085 TI - The unexpected memorial. AB - In this article, the current author tells the story of an unexpected musical memorial he and his fellow band mates performed as a tribute to a man named Gordon "Gizmo," a husband and father. (PsycINFO Database Record PMID- 29608086 TI - Say their names. AB - Many of us pursue medical careers for the direct impact we have on patients' lives. Complicating those ideals is a mosaic of extraclinical factors-economic, social, cultural, political, historical-that more immediately affect patient health than medical care, especially for countless communities of color. As a medical student witnessing the excessive rates of black lives lost to police brutality, I am reminded of the limits of medicine. (PsycINFO Database Record PMID- 29608088 TI - Carry on. AB - Presents a poem about a patient of the author who is experiencing grief at the loss of his wife. (PsycINFO Database Record PMID- 29608087 TI - Raising voices: A commentary on "Say their names" by Sandhira Wijayaratne. AB - Comments on a poem by Sandhira Wijayaratne (see record 2018-12809-007). This poem uses the power of language to speak to the consequences of silence and complacency and points to the role of healers in the social narrative. In his work, Wijayaratne highlights the structural and systemic racism that plagues our nation today, and affects our work as healthcare providers. "Say Their Names" represents a timely contribution to this field and echoes much of the current national discourse around racial oppression. It highlights the role of systemic racism in setting the stage for health disparities, disease, and trauma. (PsycINFO Database Record PMID- 29608092 TI - Don Bloch Award acceptance speech: 2017. AB - Provides Dr. Mary Talen's acceptance speech for the 2017 CFHA Don Bloch Award. (PsycINFO Database Record PMID- 29608093 TI - Megacystis Microcolon Intestinal Hypoperistalsis Syndrome in Which a Different De Novo Actg2 Gene Mutation was Detected: A Case Report. AB - INTRODUCTION: Megacystis microcolon intestinal hypoperistalsis syndrome (MMIHS) is characterized by bladder distension without urinary tract obstruction, decreased or absent intestinal peristalsis and microcolon. Although the definitive cause remains unknown, changes in the ACTG2 gene are thought to be responsible for the intestinal and bladder hypoperistalsis. CASE REPORT: This female newborn with MMIHS had a c.532C>A /p.Arg178Ser heterozygous de novo mutation detected in the ACTG2 gene. Normal immature ganglion cells, normal calretinin punctate positivity, maintence of smooth muscle actin immunoreactivity, and decreased numbers of interstitial cells of Cajal(ICCs) were detected. CONCLUSION: This previously unreported c.532C>A /p.Arg178Ser heterozygous de novo mutation in the ACTG2 gene may lead to a severe form of MMIHS. PMID- 29608094 TI - Utility of Resazurin, Horseradish Peroxidase, and NMR Assays to Identify Redox Related False-Positive Behavior in High-Throughput Screens. AB - Discerning false positives from true actives in high-throughput screening (HTS) output is fraught with difficulty as the reason of anomalous activity seen for compounds is often not clear-cut. In this study, we introduce a novel medium throughput NMR assay for the identification of redox-cycling compounds (RCCs), which is based on detection of oxidation of a reducing agent. We compare its outcomes to those from horseradish peroxidase (HRP)/phenol red and resazurin (RZ) based assays that are more commonly used for triaging HTS outputs. Data from NMR, RZ, and HRP redox assay are shown to correlate, with the NMR assay showing the greatest accuracy. In addition, historical data analysis was used to identify compounds frequently active in assays for redox-susceptible targets. We provide examples of compound classes found and conclude that the NMR redox assay offers a novel and reliable way of identifying RCCs at a medium throughput. The HRP and RZ assays are reasonable higher-throughput alternatives, with both showing similar sensitivity to redox-cycling and false-positive compounds. The RZ assay has a higher hit rate, reflecting its ability to pick up multiple modes of action. PMID- 29608095 TI - Stable COPD Treatment: Where are We? AB - The number of pharmacological treatments available for COPD has increased markedly in the last years, mostly corresponding to new agents, combinations and devices within know pharmacological classes. Hierarchizing these options is not straightforward since expected effects are limited by the intrinsically fixed character of the underlying lung damage. In addition, all options have not been directly compared face-to-face. Therefore, guidelines derive from some level of subjective interpretation of the available evidence. Determining which magnitude of change can be taken as clinically relevant is complex although crucial to define long-term strategies. Similarly, estimating not only the possible benefits but also the risks of treatments at the individual level is of major importance to guide choices. In the future biomarkers may be of help in that respect. They will hopefully emerge from progresses in systems biology and medicine. Before then, prescriptions should be restricted to the appropriate treatment indications, as established by high level studies and formalized by guidelines. PMID- 29608097 TI - A Case of "Pseudo-Tardise Dyskinesia". PMID- 29608096 TI - Reporting non-adherence in cluster randomised trials: A systematic review. AB - BACKGROUND: Treatment non-adherence in randomised trials refers to situations where some participants do not receive their allocated treatment as intended. For cluster randomised trials, where the unit of randomisation is a group of participants, non-adherence may occur at the cluster or individual level. When non-adherence occurs, randomisation no longer guarantees that the relationship between treatment receipt and outcome is unconfounded, and the power to detect the treatment effects in intention-to-treat analysis may be reduced. Thus, recording adherence and estimating the causal treatment effect adequately are of interest for clinical trials. OBJECTIVES: To assess the extent of reporting of non-adherence issues in published cluster trials and to establish which methods are currently being used for addressing non-adherence, if any, and whether clustering is accounted for in these. METHODS: We systematically reviewed 132 cluster trials published in English in 2011 previously identified through a search in PubMed. RESULTS: One-hundred and twenty three cluster trials were included in this systematic review. Non-adherence was reported in 56 cluster trials. Among these, 19 reported a treatment efficacy estimate: per protocol in 15 and as treated in 4. No study discussed the assumptions made by these methods, their plausibility or the sensitivity of the results to deviations from these assumptions. LIMITATIONS: The year of publication of the cluster trials included in this review (2011) could be considered a limitation of this study; however, no new guidelines regarding the reporting and the handling of non-adherence for cluster trials have been published since. In addition, a single reviewer undertook the data extraction. To mitigate this, a second reviewer conducted a validation of the extraction process on 15 randomly selected reports. Agreement was satisfactory (93%). CONCLUSION: Despite the recommendations of the Consolidated Standards of Reporting Trials statement extension to cluster randomised trials, treatment adherence is under-reported. Among the trials providing adherence information, there was substantial variation in how adherence was defined, handled and reported. Researchers should discuss the assumptions required for the results to be interpreted causally and whether these are scientifically plausible in their studies. Sensitivity analyses to study the robustness of the results to departures from these assumptions should be performed. PMID- 29608098 TI - PKSAP II: Some Criticisms. PMID- 29608099 TI - Comments on "An Overview of Schizophrenia". PMID- 29608100 TI - PKSAP II: Some Criticisms. PMID- 29608101 TI - Dr. Schwartz Replies. PMID- 29608102 TI - Position Statement on Public Law 92-603 (PSRO). PMID- 29608103 TI - Drs. McDermott and Putman Reply. PMID- 29608104 TI - The "Personhood" of Children. PMID- 29608105 TI - Dr. Arieti Replies. PMID- 29608107 TI - A Randomized Clinical Trial of the Effect of Continuous Glucose Monitoring on Nocturnal Hypoglycemia, Daytime Hypoglycemia, Glycemic Variability, and Hypoglycemia Confidence in Persons with Type 1 Diabetes Treated with Multiple Daily Insulin Injections (GOLD-3). AB - BACKGROUND: To evaluate the effects of continuous glucose monitoring (CGM) on nocturnal and daytime hypoglycemia in persons with type 1 diabetes treated with multiple daily insulin injections (MDI); we also evaluated factors related to differences in hypoglycemia confidence in this population. METHODS: Evaluations were performed from the GOLD randomized trial, an open-label multicenter crossover randomized clinical trial (n = 161) over 69 weeks comparing CGM to self measurement of blood glucose (SMBG) in persons with type 1 diabetes treated with MDI. Masked CGM and the hypoglycemia confidence questionnaire were used for evaluations. RESULTS: Time with nocturnal hypoglycemia, glucose levels <70 mg/dL was reduced by 48% (10.2 vs. 19.6 min each night, P < 0.001) and glucose levels <54 mg/dL by 65%. (3.1 vs. 8.9 min, P < 0.001). For the corresponding glucose cutoffs, daytime hypoglycemia was reduced by 40% (29 vs. 49 min, P < 0.001) and 54% (8 vs. 18 min., P < 0.001), respectively. Compared with SMBG, CGM use improved hypoglycemia-related confidence in social situations (P = 0.016) and confidence in more broadly avoiding serious problems due to hypoglycemia (P = 0.0020). Persons also reported greater confidence in detecting and responding to decreasing blood glucose levels (thereby avoiding hypoglycemia) during CGM use (P = 0.0033) and indicated greater conviction that they could more freely live their lives despite the risk of hypoglycemia (P = 0.022). CONCLUSION: CGM reduced time in both nocturnal and daytime hypoglycemia in persons with type 1 diabetes treated with MDI and improved hypoglycemia-related confidence, especially in social situations, thus contributing to greater well-being and quality of life. TRIAL REGISTRATION: ClinicalTrials.gov , number NCT02092051. PMID- 29608109 TI - What Experiences in Medical School Trigger Professional Identity Development? AB - : Phenomenon: This qualitative inquiry used conceptual change theory as a theoretical lens to illuminate experiences in medical school that trigger professional identity formation. According to conceptual change theory, changes in personal conceptualizations are initiated when cognitive disequilibrium is introduced. We sought to identify the experiences that trigger cognitive disequilibrium and to subsequently describe students' perceptions of self-in profession prior to the experience; the nature of the experience; and, when applicable, the outcomes of the experience. APPROACH: This article summarizes findings from portions of data collected in a larger qualitative study conducted at a new medical school in the United States that utilizes diverse pedagogies and experiences to develop student knowledge, clinical skills, attitudes, and dispositions. Primary data sources included focus groups and individual interviews with students across the 4 years of the curriculum (audio data). Secondary data included students' comments from course and end-of-year evaluations for the 2013-2017 classes (text data). Data treatment tools available in robust qualitative software, NVivo 10, were utilized to expedite coding of both audio and text data. Content analysis was adopted as the analysis method for both audio and text data. FINDINGS: We identified four experiences that triggered cognitive disequilibrium in relationship to students' perceptions of self-in profession: (a) transition from undergraduate student to medical student, (b) clinical experiences in the preclinical years, (c) exposure to the business of medicine, and (d) exposure to physicians in clinical practice. Insights: We believe these experiences represent vulnerable periods of professional identity formation during medical school. Educators interested in purposefully shaping curriculum to encourage adaptive professional identity development during medical school may find it useful to integrate educational interventions that assist students with navigating the disequilibrium that is introduced during these periods. PMID- 29608108 TI - Folate-targeting annonaceous acetogenins nanosuspensions: significantly enhanced antitumor efficacy in HeLa tumor-bearing mice. AB - Annonaceous acetogenins (ACGs) are one of the most active constituents isolated from Annona species with potent antitumor activity. However, the poor solubility and severe side effect greatly limit their use in clinic. In this study, folic acid (FA) modified annonaceous acetogenins nanosuspensions (FA-PEG-ACGs-NSps) had been successfully prepared using DSPE-PEG-FA and soybean lecithin (SPC) as stabilizers. The resultant FA-PEG-ACGs-NSps had a mean particle size of 119.7 nm, a zeta potential of -23.0 mV and a high drug payload of 49.68%. The obtained ACGs NSps had a good stability in various physiological media, and showed sustained drug release. Compared to common ACGs nanoparticles (PEG-ACGs-NSps), FA-PEG-ACGs NSps showed significantly enhanced in vitro cytotoxicity against folate receptor positive HeLa cell lines (IC50, 0.483 MUg/mL vs. 0.915 MUg/mL, p < .05), which could be effectively reversed simply by pretreatment of free FA. In vivo experiments demonstrated that FA-PEG-ACGs-NSps brought more drug molecules into tumors and greatly improved the antitumor efficacy (TIR, 76.45% vs. 25.29%, p < .001). Therefore, DSPE-PEG-FA is considered as a proper stabilizer with active targeting effect for ACGs-NSps to reduce toxicity, enlarge the safe dosage range and apply in clinic for the treatment of folate-positive tumors. Therefore, FA PEG-ACGs-NSps may be a prospective drug delivery system for ACGs to improve their therapeutic window and find application in clinic to treat FR over-expressed tumors. PMID- 29608110 TI - Fitting the right non-vitamin K antagonist oral anticoagulant to the right patient with non-valvular atrial fibrillation: an evidence-based choice. AB - Atrial fibrillation (AF) is the most prevalent arrhythmia and is associated with an increased risk of ischemic stroke (IS) and systemic embolism (SE). Stroke prevention is a key element for the overall management of AF patients. The non vitamin K antagonist oral anticoagulants (NOACs), such as dabigatran, rivaroxaban, apixaban and edoxaban, are at least as effective as warfarin in reducing IS/SE with a lower rate of major bleeding. Various analyses from the large Phase III randomized trials demonstrated different efficacy and safety of NOACs in specific subgroups of patients. The randomized trials are supplemented by effectiveness and safety data from real-world observational cohorts following the availability of these drugs for use in everyday clinical practice. Given the clinical heterogeneity of AF patients, the available data from trials and real world studies allow us to fit the right NOAC to the particular patient's characteristics, with the aim of optimizing outcomes for the individual patient. This review article aims to provide a summary of the evidence on the performance of NOACs in AF patients with specific clinical characteristics. Evidence-based suggestions are presented to provide a simple and viable strategy for clinicians for the choice of a particular NOAC. KEY MESSAGE Given the different performance of the new-oral anticoagulants in patients with the different clinical situation, evidence-based choice of fitting the right new-oral anticoagulants to the patients is provided in this review article. PMID- 29608111 TI - Profile of Non-Hematological Pediatric Tumors: A Clinicopathological Study at a Tertiary Health Care Centre. AB - BACKGROUND: Tumors in pediatric age group are biologically different from tumors in adults and emerging as a significant contributor to morbidity/mortality in children. OBJECTIVES: This study evaluated the epidemiological profile of pediatric solid tumors in 0-18 years of age over a period of 5 years in a general hospital in India. RESULTS: A total of 510 cases of tumors were included, which accounted for 5.1% of the total tumor burden of the hospital. Benign tumors were more common than malignant tumors. Most common age group affected was 14-18 years. Among benign tumors, vascular tumors were the most common, while malignant bone tumors outnumbered all other malignant tumors. Neuroblastomas comprised only 0.9% of our malignancies. CONCLUSION: Our study provides an insight into the patterns of childhood tumors for which exists little literature in India. With lack of a dedicated pediatric cancer registry from India, tracking of the diverse histological spectrum of tumors is difficult. PMID- 29608112 TI - Protective Factors as an Explanation for the "Paradox" of Black-White Differences in Heavy Drinking. AB - BACKGROUND: African Americans are generally known to have lower heavy drinking prevalence than Whites despite often greater individual and community risk factors. While it is supposed that their protective resources explain this "paradox," studies have not explicitly examined this. OBJECTIVE: Assess the contribution of protective resources to Black-White differences in heavy drinking, and (secondarily) whether protective resources operate by reducing heavy drinking and/or increasing abstinence. METHODS: Using data from the 2009 2010 U.S. National Alcohol Survey (N = 3,133 Whites and 1,040 Blacks ages 18+), we applied propensity score (PS) weighting to estimate racial differences in heavy drinking and abstinence under hypothetical conditions in which Whites are similar to Blacks in: (1) age and marital status; (2) socioeconomic position and unfair treatment; (3) neighborhood socioeconomic conditions and alcohol outlet density; and (4) protective resources (proscriptive religiosity, area-level religiosity, "drier" network drinking norms and patterns, and family social support). RESULTS: The Black-White gap in male and female drinkers' baseline heavy drinking increased after weighting adjustments for demographics. In women, this gap was reduced after weighting on disadvantage and eliminated after adjusting for protective resources. In men, adjustment for disadvantage increased the racial gap, and protective resources reduced it. Protective resources had a stronger effect on Black-White differences in men's abstinence than heavy drinking, but similar effects on these outcomes in women. CONCLUSION: Protective resources help explain Black-White differences in men's and particularly women's heavy drinking. Future research is needed to elucidate mechanisms of action and additional factors underlying racial differences in men's heavy drinking. PMID- 29608114 TI - Prolonged toxicity from Kambo cleansing ritual. AB - CONTEXT: Kambo cleanse is a purification, cleansing ritual traditionally performed by South American shaman to confer luck and health to hunters. CASE DETAILS: We report a patient who presented to the emergency department with prolonged symptoms of vomiting, flushing, facial swelling, altered mental status, and agitation requiring chemical restraints, 22 h after a Kambo cleanse. The patient was found with four small, circular, superficial burns to the ankle at the site where the resin was introduced. DISCUSSION: The cleanse consists of rubbing resin obtained from the secretions of the giant leaf frog (Phyllomedusa bicolor) into superficial wounds to produce intense gastrointestinal symptoms followed by a sensation of increased stamina and strength. The cleanse is now being increasingly performed in Europe and USA. PMID- 29608113 TI - 3D Virtual Broncoscopy before FETO Procedure in a Fetus with Severe, Isolated Left Congenital Diaphragmatic Hernia. AB - INTRODUCTION: Congenital diaphragmatic hernia (CDH) is a life-threatening event in severe forms and fetuses affected may benefit from in utero treatment by fetoscopic endotracheal occlusion (FETO). MATERIALS AND METHODS: Application of 3D virtual bronchoscopy in a case of severe, isolated, left CDH before performing FETO procedure at 27 week's gestation is reported. RESULTS: The 3D virtual imaging of the fetal trachea was technically useful in planning the real FETO procedure. FETO successfully promoted fetal lung growth by decreasing the herniation of abdominal organs into the thorax and decreasing the risk of pulmonary hypoplasia. Ultrasound calculation of lung to head ratio (LHR) and fetal-MRI were used to assess lung development following FETO procedure. CONCLUSION: 3D virtual fetal reality enabled the fetal surgeon to review and navigate on demand inside the upper airway, reducing the risk of unexpected intervention complications. PMID- 29608115 TI - Improving colloidal stability of silica nanoparticles when stored in responsive gel: application and toxicity study. AB - When silica nanoparticles (SiNP) are stored in aqueous solution, even for few hours, they have a tendency to form agglomerates and therefore adapt inhomogeneous structures. Here we present a very practical method to store SiNP in responsive hydrogel. We have confirmed that SiNP kept in the responsive hydrogel do not undergo through undesirable morphological changes and while in storage they maintain their excellent colloidal stability. The effect of SiNP hollowing (i.e. dissolution of the core of the particles that leaves empty cavity inside) was significantly inhibited in the hydrogel, which is a critical feature for any nano-medical applications (e.g. controlled drug release). To demonstrate the applicability of the hydrogel-storing concept within a biologically relevant context, in this work we have evaluated the toxicological effects of the responsive SiNP-gel formulation in a model in vitro (human cell line U87GM and hemocompatibility using red blood cells) and ex ovo (hen's egg test) experiments. Particles stored in the gel as well as the pure gel did not affect the hemocompatibility (hemolysis and erythrocyte aggregation) up to a concentration of 100 ug/mL. Furthermore, systemic injections into the blood circulation of the chick area vasculosa confirmed the biocompatibility in a more complex biological environment. All evaluated toxicological values (hemorrhage, thrombosis, vascular lysis, and lethality) were comparable with the negative control, and no differences in toxicological response could be observed between the SiNP stored in hydrogel and the control nanoparticles stored in the solution. PMID- 29608116 TI - Modified mixed nanomicelles with collagen peptides enhanced oral absorption of Cucurbitacin B: preparation and evaluation. AB - Polymer nanoparticles modified with collagen peptides (CPs) are an attractive strategy for the oral delivery of active ingredients from Chinese medicine. Thus, in the present study, collagen cationic CPs were simply separated using ion exchange resin from bovine CPs, to modify mixed nanomicelles (MMs) on the surface to improve the oral bioavailability of Cucurbitacin B (CuB). The physicochemical property of micelles was characterized, which confirmed the successful modification of the nanomicelles. CPs-modified nanomicelles in vitro were found to significantly increase cellular uptake and transportation. Compared to unmodified micelles, the quantity of CPs-modified micelles internalized by Caco-2 cells were 3.74 times greater and the cumulative transportation flux (AP-BL) was 2.81 times greater. The membrane transportation process of CuB-MMs-CPs was found to be associated with energy consumption and clathrin- and caveolin-mediated endocytosis. In vivo studies performed on rats indicated that in comparison to CuB and CuB-MMs, the relative bioavailability of CuB-MMs-CPs increased by 3.43 times and 2.14 times, respectively. In addition, the tumor inhibition caused by CuB-MMs-CPs was increased significantly. Therefore, the nanomicelles co-modified with isolated CPs could act as attractive carriers for oral delivery of CuB. PMID- 29608117 TI - Clinical impact of rapid bacterial identification by MALDI-TOF MS combined with the beta-LACTATM test on early antibiotic adaptation by an antimicrobial stewardship team in bloodstream infections. AB - BACKGROUND: Bloodstream infections (BSI) can potentially be life-threatening infections and are associated with a high crude mortality, moreover with an inappropriate first-line antibiotic therapy. Bacterial resistance is more and more frequently observed. New strategies of BSI management are urgently needed. MATERIALS AND METHODS: During an 18-months period, we prospectively evaluated the clinical impact of rapid bacterial identification by MALDI-TOF MS technology combined with an antimicrobial stewardship team (AST) intervention. Furthermore, during an 8-months period, we combined this strategy with the rapid detection of third-generation cephalosporin (3GC) resistance by the Beta-LACTATM test (BLT) directly on blood cultures. We then evaluated the theoretical impact of BLT on antibiotic therapy adaptation and establishment of infection control measures. RESULTS: A total of 335 blood cultures were enrolled during the study. MALDI-TOF MS gave accurate identification for 301 blood cultures (89,8%) and led to early antibiotic therapy adaptation for 73 episodes (21.8%). BLT was performed on 141 blood cultures, revealing 28 3GC-resistant bacteria (19.9%). Twenty-one patients (75%) received a non-adapted first-line treatment. The antibiotic therapy adaptation was delayed by 28.1 hours and the establishment of infection control measures by 35 hours with antimicrobial susceptibility testing, compared to the theoretical adaptation with BLT result. CONCLUSIONS: These tools can be included in a strategy of bloodstream infections management for a better patient care, optimizing and saving the use of antibiotics, notably carbapenems as well as diminishing the spread of multi-drug resistant bacteria by applying rapidly infection control measures. PMID- 29608118 TI - A global health training model for teaching pediatric clinical decision making skills to Rwandan physical therapists: A case report. AB - BACKGROUND AND PURPOSE: There is increasing interest among physical therapists from high-income countries to participate in education development projects in low-income countries. However, there are few examples in the literature of effective developmental models or projects. This case report describes a model for improving pediatric clinical decision making skills among Rwandan physical therapists using best practices in clinical decision making, evidence-based practice where possible, and use of the International Classification of Functioning and Disability (ICF) model. CASE DESCRIPTION: A 48-hour continuing professional development course based on the pediatric section of the Advancement of Rwandan Rehabilitation Services Project (ARRSP) was presented to 66 Rwandan physical therapists in the form of classroom lectures, laboratory and case study practice, and clinical visits to the course participant's work place. Interactive teaching and learning was emphasized. OUTCOMES: Course participants completed a pre- and post-course assessment addressing course content. There was a 53% improvement in post-course assessment scores. A post-course evaluation eliciting participants' confidence in eight clinical decision making skills emphasized in course material was also administered. Comments were strongly positive (92%) for the value of clinical visits in reinforcing the participant's new clinical skills. DISCUSSION: This case report documents a global health continuing professional development project that improved pediatric rehabilitation knowledge and clinical skill confidence. The project incorporated sustainability by soliciting both input and involvement of the target audience from start to finish; from the needs assessment to classroom teaching. Building on these two aspects promotes a sense of ownership and longevity. PMID- 29608120 TI - Concurrent Validity of Two Standardized Measures of Gross Motor Function in Young Children with Autism Spectrum Disorder. AB - AIMS: This study provides information on how two standardized measures based on different theoretical frameworks can be used in collecting information on motor development and performance in 4- and 5-year-olds with autism spectrum disorder (ASD). The purpose of the study was to determine the concurrent validity of the Miller Function and Participation Scales (M-FUN) with the Peabody Developmental Motor Scales, Second Edition (PDMS-2) in young children with ASD. METHODS: The gross motor sections of the PDMS-2 and the M-FUN were administered to 22 children with ASD between the ages of 48 and 71 months. Concurrent validity between overall motor scores and agreement in identification of motor delay were assessed. RESULTS: A very strong correlation (Pearson's r =.851) was found between the M-FUN scale scores and the PDMS-2 gross motor quotients (GMQs). Strong agreement in identification of children with average motor skills and delayed motor skills at 1.5 standard deviations below the mean was also found. CONCLUSIONS: This study supports the concurrent validity of the M-FUN with the PDMS-2 for young children with ASD. While both tests provide information regarding motor delay, the M-FUN may provide additional information regarding the neurological profile of the child. PMID- 29608119 TI - Peri-tumor administration of 5-fluorouracil sol-gel using a hollow microneedle for treatment of gastric cancer. AB - The aim of this study was to investigate the effectiveness of treating gastric cancer by injecting a pluronic F-127 sol-gel formulation of 5-fluorouracil (5-FU) into normal tissue surrounding the tumor using a hollow microneedle. The MTS tetrazolium assay was performed to assess the cytotoxicity of 5-FU after application to gastric cancer cells at different concentrations for 1, 5 and 10 h. Gastric cancer cells were inoculated subcutaneously into 30 male nude mice (CrjBALB/c-nu/nu mice, male); the inoculated mouse were divided into three groups. One group received no treatment, whereas the two other groups received free 5-FU gel (40 mg/kg) and 5-FU gel (40 mg/kg) for 4 days, respectively. Mean tumor volume, apoptotic index (TUNEL) and proliferative index (Ki 67) were evaluated in all groups. Cell viability was 77.3% when 1.22 g of free 5-FU was administered, whereas cell viability was 37.4% and 43.5% when 0.122 g of free 5 FU was administered per hour for 10 h and 0.244 g of free 5-FU was administered for 5 h (p < .01). The 5-FU sol-gel induced apoptosis and significantly inhibited cell proliferation compared to the free 5-FU (p < .01). In addition, xenografted tumor growth was significantly suppressed by administration of the 5-FU sol-gel formulation to inoculated mice (p < .01), and 71% (5/7) of xenografted tumors disappeared after 4 weeks. In conclusion, peri-tumor injection of a 5-FU sol-gel formulation into normal tissue surrounding the tumor mass using a hollow microneedle is an effective method for treating gastric cancer. PMID- 29608121 TI - Global rating of change: perspectives of patients with lumbar impairments and of their physical therapists. AB - BACKGROUND: Global rating of change (GROC) scores provide a means of measuring patients' self-perceived change in health status over time. OBJECTIVES: The purposes of the study were to examine agreement of GROC ratings between the patient (GROCp) and the treating therapist (GROCt), the impact on the minimal clinically important difference (MCID) estimates by reporting resources, and the relationships between the subjective GROC scores and objective outcome measures. METHODS: Data from 52,767 patients with orthopedic lumbar spine impairments treated in 623 outpatient rehabilitation clinics in 34 states (United States) were analyzed. Patient's functional status (FS) before and after the treatment was measured using the Lumbar Computerized Adaptive Testing (LCAT) survey (0-100 scale). The GROC ratings were obtained from both the patients and their caring therapists at discharge. RESULTS: On average, GROCp (mean [(SD] = 3.1 [4.1]) was 1.9 points lower than GROCt (mean [SD] = 5.0 [1.9]). There were negligible differences between MCID estimates derived from the patients' GROC ratings (MCID cutoff = 9.2) and from the therapists' GROC ratings (MCID cutoff = 9.5). While only analyzing patient data whose GROCp >= 0, the intraclass correlation coefficient between GROCp and GROCt was 0.61, the GROCp correlated with FS at intake at r = 0.12, with FS at discharge at r = 0.56, and with FS change scores at r = 0.47. CONCLUSIONS: Therapists tended to report higher GROC ratings than their patients did but there were negligible differences between MCID estimates derived from GROCp and that derived from GROCt. PMID- 29608122 TI - Ecological Genomics: genes in ecology and ecology in genes. PMID- 29608124 TI - Young Urban Adolescents' Activity Spaces, Close Peers, and the Risk of Cannabis Use: A Social-Spatial Longitudinal Analysis. AB - BACKGROUND: An understudied, yet important area of youth development research is the examination of how place affects critical psychosocial processes such as identity formation, problem solving, emotional regulation, and in particular with adolescents, belongingness, autonomy, social competency, and behavioral health. A growing spatially informed literature indicates that youth interact with meaningful places as environmental strategies, shaping developmental trajectories related to behavioral health. OBJECTIVES: The objective is to investigate the relationship between place preference and health behavior among adolescents, with a focus on substance use behavior, specifically, cannabis use. We theorize that cannabis use is associated with place preference for urban, city types of places, and that this particular place preference interacts with close peer network behaviors. METHODS: To understand the role of preferred locations, close peer relations, and mental health on cannabis use, 248 adolescents (ages 13 to 14) were studied longitudinally. Logistic regression models tested the moderating effects of peer network health (sum of close friends risk and protective behaviors) on selecting city locations (urban stress/neighborhoods) as preferred places, and subsequent cannabis use. RESULTS: Results indicated that peer network health moderated the effects of choosing city locations as favorite, increasing the odds of cannabis use more than eight-fold at 24 months. CONCLUSIONS: Favorite places located in city environments appear to interact with peer risk behaviors influencing the cannabis use of young urban adolescents, even after controlling for the influence of baseline cannabis use, neighborhood disorder the home neighborhood, age, gender, and mental health effects. PMID- 29608125 TI - Kinesiologic tape for labor pain control: Randomized controlled trial. AB - BACKGROUND: Kinesiologic taping has been studied for managing diverse types of dysfunctions and pain, but not for managing pain during labor. OBJECTIVE: This study evaluated the effectiveness and safety of using kinesiologic tape (KT) during labor relative to pain, maternal satisfaction, and obstetric and neonatal outcomes. METHOD: The study was a single-blind randomized controlled trial composed of 60 pregnant women divided into two groups. In the kinesiologic tape group (KTG), the tape was applied to the region of spinal nerves T10-L1 and S2 S4; in the control group (CG), the tape was applied to the region of spinal nerves T1-T4. Study participants were low-risk pregnant women with spontaneous onset of labor and no previous Cesarean section. Outcomes evaluated were pain, duration of labor, type of delivery, uterotonic and anesthetic requirement, neonatal vitality, and satisfaction with delivery and tape use. Intention-to treat analysis was performed, and risk ratios with a 95% CI were estimated. RESULTS: After the first hour of tape use, a significant increase in pain was observed in the CG (p = 0.002). However, there were no differences between groups relative to the remaining outcomes assessed. In the KTG, 59% of participants reported satisfaction with tape use, whereas in the CG, 44% reported satisfaction with tape use. CONCLUSION: Despite its safety, the KT technique did not prove to effectively control labor pain. PMID- 29608126 TI - Gender Differences in the Prevalence of Fibromyalgia and in Concomitant Medical and Psychiatric Disorders: A National Veterans Health Administration Study. AB - BACKGROUND: Fibromyalgia is a poorly understood, chronically disabling pain syndrome. While research has focused on its clinical presentation and treatment, less is known about fibromyalgia's clinical epidemiology in real-world healthcare systems. Gender differences have been difficult to study because relatively few males are diagnosed with fibromyalgia. METHODS: Veterans Health Administration (VHA) patients diagnosed with fibromyalgia nationwide in FY 2012 were compared to Veterans with other pain diagnoses on sociodemographic characteristics, medical and psychiatric diagnoses, health service use, and opioid and psychotropic prescription fills. Additional analyses compared characteristics of men and women diagnosed with fibromyalgia. Risk ratios and Cohen's d were used for bivariate comparisons, followed by logistic regression analyses to identify independent factors associated with a diagnosis of fibromyalgia in the VHA. RESULTS: Altogether, 77,087 of 2,216,621 Veterans with pain diagnoses (3.48%) were diagnosed with fibromyalgia. They were more likely to be female, younger than patients with other pain conditions, more likely to have multiple psychiatric comorbidities and other types of pain, and used more medical outpatient services. Women diagnosed with fibromyalgia were younger and more likely to have headaches, connective tissue diseases (CTD), and psychiatric comorbidities, while men had more comorbid medical conditions. CONCLUSIONS: In this large, predominantly older male sample of Veterans with pain diagnoses, those with fibromyalgia were far more likely to be women. Gender comparisons showed women with fibromyalgia were more likely to be diagnosed with psychiatric disorders and CTD, while males were more likely to be diagnosed with medical conditions. Fibromyalgia shows a striking, gender-dependent picture of multimorbidity, which should be considered in treatment. PMID- 29608127 TI - The Effect of Gestational Weight Gain on Persistent Increase in Body Mass Index in Adolescents: A Longitudinal Study. AB - BACKGROUND: Weight retention after pregnancy is a concern for adolescents who may be entering adulthood at unhealthy weights. METHODS: We studied associations between each of three measures: prepregnancy body mass index (BMI), gestational weight gain (GWG), and postpregnancy BMI in a longitudinal follow-up of an adolescent pregnancy study cohort. BMI and GWG were compared using t-tests and linear regression. RESULTS: Among 91 adolescents, mean prepregnancy BMI was 24.6 [standard deviation (SD) 5.7] and mean GWG was 15.5 kg [SD 6.3]. Overall, prepregnancy BMI was not significantly related to GWG (p = 0.145). Among 42 teens with postpregnancy weight data, within 4 years of their first delivery, mean postpregnancy BMI was 26.3 [SD 5.0] with an average BMI increase of 2.0 points [SD 5.1] (p = 0.013) from prepregnancy. Within 4 years of their first delivery, 45% of teens moved to a higher BMI category. For every 4.5 kg (10 lb) increase in GWG, BMI within 4 years increased on average by 1.6 points (p = 0.006). The association persisted (1.0 points, p = 0.049) after controlling for prepregnancy BMI. CONCLUSIONS: Teens experienced an increase in BMI from prepregnancy to within 4 years after their first delivery, and this increase was related to GWG. Adolescent mothers are at risk for developing and maintaining unhealthy BMI after pregnancy, which may be amplified by GWG. PMID- 29608128 TI - Prenatal and Postnatal Mother-to-Child Transmission of Acculturation's Health Effects in Hispanic Americans. AB - BACKGROUND: Hispanic Americans consistently exhibit an intergenerational increase in the prevalence of many noncommunicable chronic physical and mental disorders. METHODS: We review and synthesize evidence suggesting that a constellation of prenatal and postnatal factors may play crucial roles in explaining this trend. We draw from relevant literature across several disciplines, including epidemiology, anthropology, psychology, medicine (obstetrics, neonatology), and developmental biology. RESULTS: Our resulting model is based on evidence that among women, the process of postmigration cultural adjustment (i.e., acculturation) is associated, during pregnancy and after delivery, with psychological and behavioral states that can affect offspring development in ways that may alter susceptibility to noncommunicable chronic disease risk in subsequent-generation Hispanic Americans. We propose one integrated process model that specifies the biological, behavioral, psychological, and sociocultural pathways by which maternal acculturation may influence the child's long-term health. We synthesize evidence from previous studies to describe how acculturation among Hispanic American mothers is associated with alterations to the same biobehavioral systems known to participate in the processes of prenatal and postnatal developmental programming of disease risk. In this manner, we focus on the concepts of biological and cultural mother-to-child transmission across the prenatal and postnatal life phases. We critique and draw from previous hypotheses that have sought to explain this phenomenon (of declining health across generations). We offer recommendations for examining the transgenerational effects of acculturation. CONCLUSION: A life course model with a greater focus on maternal health and well-being may be key to understanding transgenerational epidemiological trends in minority populations, and interventions that promote women's wellness may contribute to the elimination or reduction of health disparities. PMID- 29608130 TI - Evaluation of a 2 to 1 peer placement supervision model by physiotherapy students and their educators. AB - OBJECTIVES: The objective of the study was to investigate student and practice educator evaluations of practice placements using a structured 2 to 1 supervision and implementation model. DESIGN: Cross-sectional pilot study set in clinical sites providing placements for physiotherapy students in Ireland. PARTICIPANTS: Students and practice educators completing a 2.1 peer placement between 2013 and 2015 participated. OUTCOME MEASURE: A self-reported questionnaire which measured indicators linked to quality assured placements was used. Three open-ended questions captured comments on the benefits and challenges associated with the 2 to 1 model. RESULTS: Ten students (10/20; 50% response rate) and 10 practice educators (10/10; 100% response rate) responded to the questionnaire. Student responses included four pairs of students and one student from a further two pairs. There was generally positive agreement with the questionnaire indicating that placements using the 2 to 1 model were positively evaluated by participants. There were no significant differences between students and practice educators. The main benefits of the 2 to 1 model were shared learning experiences, a peer supported environment, and the development of peer evaluation and feedback skills by students. A key component of the model was the peer scripting process which provided time for reflection, self-evaluation, and peer review. CONCLUSIONS: 2 to 1 placements were positively evaluated by students and educators when supported by a structured supervision model. Clear guidance to students on the provision of peer feedback and support for educators providing feedback to two different students is recommended. PMID- 29608129 TI - HIV-Infected Women Gain More Weight than HIV-Infected Men Following the Initiation of Antiretroviral Therapy. AB - BACKGROUND: Obesity is prevalent among HIV-infected individuals on antiretroviral therapy (ART). Cross-sectional studies have suggested that HIV-infected women are more likely to be overweight than men, but observational studies evaluating sex differences in body mass index (BMI) increases following ART initiation are conflicting. MATERIALS AND METHODS: We pooled data from three randomized clinical trials of ART initiation in persons with HIV in the United States. BMIs were compared between 760 women and 3041 men to test whether BMI changes in the first 96 weeks following initiation of ART differed by sex at birth. Linear regression estimated the relationship between sex and change in BMI from pre-ART initiation to week 96. RESULTS: After 96 weeks, women gained an average of 1.91 kg/m2 (95% confidence interval [CI] 1.64-2.19), men gained an average of 1.39 kg/m2 (95% CI 1.30-1.48); p for sex difference <0.001; the sex difference persisted within each pre-ART initiation BMI subgroup. After adjusting for pre-ART initiation age, CD4+ count, HIV-1 viral load, race/ethnicity, study, and ART regimen, mean BMI change for women was 0.59 kg/m2 (95% CI 0.37-0.81) more than for men (p < 0.001). Statistical interactions were observed between sex and both pre-ART CD4+ count and HIV-1 viral load and suggest that for subgroups with higher viral load and lower CD4+ at baseline, the estimated BMI changes in women are even larger than the average estimated difference. CONCLUSIONS: HIV-1-infected women experienced a significantly greater increase in BMI following ART initiation than men. These differences are a problem of clinical significance to women living with HIV. PMID- 29608131 TI - Do patients with different psychiatric disorders show altered social decision making? A systematic review of ultimatum game experiments in clinical populations. AB - BACKGROUND: Impairments in social functioning are a common feature of psychiatric disorders. Game paradigms pose a unique way for studying how people make decisions in interpersonal contexts. In the last decade, researchers have started to use these paradigms to study social decision-making in patients with psychiatric disorders. PURPOSE: The aim of this systematic literature review is to summarise the currently available evidence on the behaviour of patients with psychiatric disorders in the commonly used Ultimatum Game (UG). METHOD: A systematic literature search including MEDLINE, PsycINFO, PSYNDEXplus Tests, PSYNDEXPLUS Literature, EBM Reviews-Cochrane Central Register of Controlled Trials, Embase and PASCAL was performed via the Ovid interface. RESULTS: We found evidence for alterations in UG behaviour for patients with frontotemporal dementia, schizophrenia, affective disorders, alcohol, cocaine, heroin and 3,4 methylenedioxymethamphetamine consumption, alcohol dependence, anxiety disorders, borderline personality disorder, autism, Tourette syndrome and oppositional defiant disorder. CONCLUSION: There is some evidence that different psychiatric disorders might go along with alterations in social decision-making. However, in general, data are currently limited and studies are hard to compare due to differences in methodologies. PMID- 29608132 TI - Mental Health and Substance Use Disorder Comorbidity among Methamphetamine-Using Men Who have Sex with Men. AB - Men who have sex with men (MSM) exhibit elevated rates of mental health and substance use disorder relative to their non-MSM male counterparts. Methamphetamine use in particular has been associated with both neuronal damage and mental health disorders among MSM, and this study reports on the prevalence and comorbidity of DSM-5 mental health and substance use disorders in a sample of methamphetamine-using MSM. From March 2014 through January 2015, 286 methamphetamine-using MSM enrolled in a study to reduce methamphetamine use and sexual risk behaviors. At baseline, participants demonstrated high rates of current major depressive episode (35.8%), antisocial personality disorder (23.9%), suicide risk (23.2%), obsessive-compulsive disorder (23.2%), and social phobia (20.4%), as well as methamphetamine use disorder (89.1%), marijuana use disorder (41.0%), alcohol use disorder (39.6%), cocaine use disorder (30.9%), and inhalants use disorder (15.4%). Analyses revealed significant (p < 0.05) associations between methamphetamine use disorder severity and all listed mental health disorders, as well as between alcohol use disorder and all listed mental health disorders. Mental health disorder prevalence and substance use disorder severity were both elevated, and both methamphetamine and alcohol use disorder severity were associated with increased likelihood of comorbid mental health disorder. PMID- 29608133 TI - Knowledge maps: a tool for online assessment with automated feedback. AB - In higher education, most assessments or examinations comprise either multiple choice items or open-ended questions such as modified essay questions (MEQs). Online concept and knowledge maps are potential tools for assessment, which might emphasize meaningful, integrated understanding of phenomena. We developed an online knowledge-mapping assessment tool, which provides automated feedback on student-submitted maps. We conducted a pilot study to investigate the potential utility of online knowledge mapping as a tool for automated assessment by comparing the scores generated by the software with manual grading of a MEQ on the same topic for a cohort of first-year medical students. In addition, an online questionnaire was used to gather students' perceptions of the tool. Map items were highly discriminating between students of differing knowledge of the topic overall. Regression analysis showed a significant correlation between map scores and MEQ scores, and responses to the questionnaire regarding use of knowledge maps for assessment were overwhelmingly positive. These results suggest that knowledge maps provide a similar indication of students' understanding of a topic as a MEQ, with the advantage of instant, consistent computer grading and time savings for educators. Online concept and knowledge maps could be a useful addition to the assessment repertoire in higher education. PMID- 29608134 TI - Hip stem fatigue: : The implications of increasing patient mass. AB - General trends of increasing body mass index have been observed in many western countries along with an increasing demand for joint replacement. Standards have been developed for testing the fatigue properties of femoral stems; however, the loads that these apply are based on a historic patient weight and may not be valid in the current patient population. Several fatigue tests were conducted using distally fixed titanium alloy stems positioned according to the ISO standard but with a cyclic load based on a current 75th percentile patient sample. Smaller sized stems (currently not weight restricted) fractured in; 30,000 cycles, while larger sized stems were found to have excellent durability under loads simulating walking and stumbling. The results suggest that while the fatigue properties of medical grade titanium are very good, the ISO pre-clinical durability testing standard does not represent the influence of femoral offset or stem size sufficiently to reflect safe design practice. PMID- 29608135 TI - New special issue calls for the Journal of Gerontological Social Work. PMID- 29608136 TI - Effects of risk disclosure prominence in direct-to-consumer advertising (DTCA) of prescription drugs: An integrative cognitive process model. AB - The literature shows that the prominence of risk disclosure influences consumer responses to direct-to-consumer advertising of prescription drugs. However, little is known about the psychological process whereby disclosure prominence exerts its influences on health beliefs and behavior. Based on a review of the literature on health cognition and behavior, the current study proposed and tested a model to show that risk disclosure prominence affects consumers' drug choice intention through the mediating roles of awareness of drug adverse reactions (ARs), perceived control over ARs, and perceived risk of ARs. The findings were discussed in terms of their theoretical and managerial implications. PMID- 29608138 TI - A conversation with Charles Sawyers. PMID- 29608137 TI - Mechanisms and functions of cellular senescence. AB - Cellular senescence is a highly stable cell cycle arrest that is elicited in response to different stresses. By imposing a growth arrest, senescence limits the replication of old or damaged cells. Besides exiting the cell cycle, senescent cells undergo many other phenotypic alterations such as metabolic reprogramming, chromatin rearrangement, or autophagy modulation. In addition, senescent cells produce and secrete a complex combination of factors, collectively referred as the senescence-associated secretory phenotype, that mediate most of their non-cell-autonomous effects. Because senescent cells influence the outcome of a variety of physiological and pathological processes, including cancer and age-related diseases, pro-senescent and anti-senescent therapies are actively being explored. In this Review, we discuss the mechanisms regulating different aspects of the senescence phenotype and their functional implications. This knowledge is essential to improve the identification and characterization of senescent cells in vivo and will help to develop rational strategies to modulate the senescence program for therapeutic benefit. PMID- 29608139 TI - Senescent cells and osteoarthritis: a painful connection. AB - Senescent cells (SnCs) are associated with age-related pathologies. Osteoarthritis is a chronic disease characterized by pain, loss of cartilage, and joint inflammation, and its incidence increases with age. For years, the presence of SnCs in cartilage isolated from patients undergoing total knee artificial implants has been noted, but these cells' relevance to disease was unclear. In this Review, we summarize current knowledge of SnCs in the multiple tissues that constitute the articular joint. New evidence for the causative role of SnCs in the development of posttraumatic and age-related arthritis is reviewed along with the therapeutic benefit of SnC clearance. As part of their senescence-associated secretory phenotype, SnCs secrete cytokines that impact the immune system and its response to joint tissue trauma. We present concepts of the immune response to tissue trauma as well as the interactions with SnCs and the local tissue environment. Finally, we discuss therapeutic implications of targeting SnCs in treating osteoarthritis. PMID- 29608140 TI - Strategies targeting cellular senescence. AB - Cellular senescence is a physiological phenomenon that has both beneficial and detrimental consequences. Senescence limits tumorigenesis and tissue damage throughout the lifetime. However, at the late stages of life, senescent cells increasingly accumulate in tissues and might also contribute to the development of various age-related pathologies. Recent studies have revealed the molecular pathways that preserve the viability of senescent cells and the ones regulating their immune surveillance. These studies provide essential initial insights for the development of novel therapeutic strategies for targeting senescent cells. At the same time they stress the need to understand the limitations of the existing strategies, their efficacy and safety, and the possible deleterious consequences of senescent cell elimination. Here we discuss the existing strategies for targeting senescent cells and upcoming challenges in translating these strategies into safe and efficient therapies. Successful translation of these strategies could have implications for treating a variety of diseases at old age and could potentially reshape our view of health management during aging. PMID- 29608142 TI - Joseph Heitman receives the 2018 ASCI/Korsmeyer Award. PMID- 29608143 TI - Host expression of PD-L1 determines efficacy of PD-L1 pathway blockade-mediated tumor regression. PMID- 29608141 TI - Senescent cells: a therapeutic target for cardiovascular disease. AB - Cellular senescence, a major tumor-suppressive cell fate, has emerged from humble beginnings as an in vitro phenomenon into recognition as a fundamental mechanism of aging. In the process, senescent cells have attracted attention as a therapeutic target for age-related diseases, including cardiovascular disease (CVD), the leading cause of morbidity and mortality in the elderly. Given the aging global population and the inadequacy of current medical management, attenuating the health care burden of CVD would be transformative to clinical practice. Here, we review the evidence that cellular senescence drives CVD in a bimodal fashion by both priming the aged cardiovascular system for disease and driving established disease forward. Hence, the growing field of senotherapy (neutralizing senescent cells for therapeutic benefit) is poised to contribute to both prevention and treatment of CVD. PMID- 29608144 TI - iNKT cells require TSC1 for terminal maturation and effector lineage fate decisions. PMID- 29608145 TI - Intraperitoneal Glucose Tolerance Test, Measurement of Lung Function, and Fixation of the Lung to Study the Impact of Obesity and Impaired Metabolism on Pulmonary Outcomes. AB - Obesity and respiratory disorders are major health problems. Obesity is becoming an emerging epidemic with an expected number of over 1 billion obese individuals worldwide by 2030, thus representing a growing socioeconomic burden. Simultaneously, obesity-related comorbidities, including diabetes as well as heart and chronic lung diseases, are continuously on the rise. Although obesity has been associated with increased risk for asthma exacerbations, worsening of respiratory symptoms, and poor control, the functional role of obesity and perturbed metabolism in the pathogenesis of chronic lung disease is often underestimated, and underlying molecular mechanisms remain elusive. This article aims to present methods to assess the effect of obesity on metabolism, as well as lung structure and function. Here, we describe three techniques for mice studies: (1) assessment of intraperitoneal glucose tolerance (ipGTT) to analyze the effect of obesity on glucose metabolism; (2) measurement of airway resistance (Res) and respiratory system compliance (Cdyn) to analyze the effect of obesity on lung function; and (3) preparation and fixation of the lung for subsequent quantitative histological assessment. Obesity-related lung diseases are probably multifactorial, stemming from systemic inflammatory and metabolic dysregulation that potentially adversely influence lung function and the response to therapy. Therefore, a standardized methodology to study molecular mechanisms and the effect of novel treatments is essential. PMID- 29608146 TI - An Improved Method for Collection of Cerebrospinal Fluid from Anesthetized Mice. AB - The cerebrospinal fluid (CSF) is a valuable body fluid for analysis in neuroscience research. It is one of the fluids in closest contact with the central nervous system and thus, can be used to analyze the diseased state of the brain or spinal cord without directly accessing these tissues. However, in mice it is difficult to obtain from the cisterna magna due to its closeness to blood vessels, which often contaminate samples. The area for CSF collection in mice is also difficult to dissect to and often only small samples are obtained (maximum of 5-7 uL or less). This protocol describes in detail a technique that improves on current methods of collection to minimize contamination from blood and allow for the abundant collection of CSF (on average 10-15 uL can be collected). This technique can be used with other dissection methods for tissue collection from mice, as it does not impact any tissues during CSF extraction. Thus, the brain and spinal cord are not affected with this technique and remain intact. With greater CSF sample collection and purity, more analyses can be used with this fluid to further aid neuroscience research and better understand diseases affecting the brain and spinal cord. PMID- 29608147 TI - Recording Horizontal Saccade Performances Accurately in Neurological Patients Using Electro-oculogram. AB - Electro-oculogram (EOG) has been widely used for clinical eye movement recording, especially horizontal saccades, although the video-oculography (VOG) has largely taken the place of it nowadays due to its higher spatial accuracy. However, there are situations in which EOG has clear advantages over VOG, e.g., subjects with narrow eye clefts or having cataract lenses, and patients with movement disorders. The present article shows that if properly implemented, EOG can achieve an accuracy almost as good as VOG with substantial stability for recording, while circumventing problems associated with VOG recording. The present paper describes a practical method for recording horizontal saccades using oculomotor paradigms with high accuracy and stability by EOG in neurological patients. The necessary measures are to use an Ag-AgCl electrode with a wide plastic fringe capable of reducing noise, and to wait for sufficient light adaptation to occur. This waiting period also helps to lower the impedance between the electrodes and the skin, thereby ensuring stable signal recorded as time goes by. Furthermore, re-calibration is performed as needed during the task performance. Using this method, the experimenter can avoid drifts of signals, as well as contamination of artifacts or noise from the electromyogram and electroencephalogram, and can collect sufficient data for clinical evaluation of saccades. Thus when implemented, EOG can still be a method of high practicability that can be widely applied to neurological patients, but may be effective also for studies in normal subjects. PMID- 29608148 TI - In Vivo EPR Assessment of pH, pO2, Redox Status, and Concentrations of Phosphate and Glutathione in the Tumor Microenvironment. AB - This protocol demonstrates the capability of low-field electron paramagnetic resonance (EPR)-based techniques in combination with functional paramagnetic probes to provide quantitative information on the chemical tumor microenvironment (TME), including pO2, pH, redox status, concentrations of interstitial inorganic phosphate (Pi), and intracellular glutathione (GSH). In particular, an application of a recently developed soluble multifunctional trityl probe provides unsurpassed opportunity for in vivo concurrent measurements of pH, pO2 and Pi in Extracellular space (HOPE probe). The measurements of three parameters using a single probe allow for their correlation analyses independent of probe distribution and time of the measurements. PMID- 29608149 TI - A RANKL-based Osteoclast Culture Assay of Mouse Bone Marrow to Investigate the Role of mTORC1 in Osteoclast Formation. AB - Osteoclasts are unique bone-resorbing cells that differentiate from the monocyte/macrophage lineage of bone marrow. Dysfunction of osteoclasts may result in a series of bone metabolic diseases, including osteoporosis. To develop pharmaceutical targets for the prevention of pathological bone mass loss, the mechanisms by which osteoclasts differentiate from precursors must be understood. The ability to isolate and culture a large number of osteoclasts in vitro is critical in order to determine the role of specific genes in osteoclast differentiation. Inactivation of the mammalian/mechanistic target of rapamycin complex 1 (TORC1) in osteoclasts can decrease osteoclast number and increase bone mass; however, the underlying mechanisms require further study. In the present study, a RANKL-based protocol to isolate and culture osteoclasts from mouse bone marrow and to study the influence of mTORC1 inactivation on osteoclast formation is described. This protocol successfully resulted in a large number of giant osteoclasts, typically within one week. Deletion of Raptor impaired osteoclast formation and decreased the activity of secretory tartrate-resistant acid phosphatase, indicating that mTORC1 is critical for osteoclast formation. PMID- 29608150 TI - Trans-Tympanic Drug Delivery for the Treatment of Ototoxicity. AB - The systemic administration of protective agents to treat drug-induced ototoxicity is limited by the possibility that these protective agents could interfere with the chemotherapeutic efficacy of the primary drugs. This is especially true for the drug cisplatin, whose anticancer actions are attenuated by antioxidants which provide adequate protection against hearing loss. Other current or potential otoprotective agents could pose a similar problem, if administered systemically. The application of various biologicals or protective agents directly to the cochlea would allow for high levels of these agents locally with limited systemic side effects. In this report, we demonstrate a trans-tympanic method of delivery of various drugs or biological reagents to the cochlea, which should enhance basic science research on the cochlea and provide a simple way of directing the use of otoprotective agents in the clinics. This report details a method of trans-tympanic drug delivery and provides examples of how this technique has been used successfully in experimental animals to treat cisplatin ototoxicity. PMID- 29608151 TI - Guided Protocol for Fecal Microbial Characterization by 16S rRNA-Amplicon Sequencing. AB - The human intestinal microbiome plays a central role in protecting cells from injury, in processing energy and nutrients, and in promoting immunity. Deviations from what is considered a healthy microbiota composition (dysbiosis) may impair vital functions leading to pathologic conditions. Recent and ongoing research efforts have been directed toward the characterization of associations between microbial composition and human health and disease. Advances in high-throughput sequencing technologies enable characterization of the gut microbial composition. These methods include 16S rRNA-amplicon sequencing and shotgun sequencing. 16S rRNA-amplicon sequencing is used to profile taxonomical composition, while shotgun sequencing provides additional information about gene predictions and functional annotation. An advantage in using a targeted sequencing method of the 16S rRNA gene variable region is its substantially lower cost compared to shotgun sequencing. Sequence differences in the 16S rRNA gene are used as a microbial fingerprint to identify and quantify different taxa within an individual sample. Major international efforts have enlisted standards for 16S rRNA-amplicon sequencing. However, several studies report a common source of variation caused by batch effect. To minimize this effect, uniformed protocols for sample collection, processing, and sequencing must be implemented. This protocol proposes the integration of broadly used protocols starting from fecal sample collection to data analyses. This protocol includes a column-free, direct-PCR approach that enables simultaneous handling and DNA extraction of large numbers of fecal samples, along with PCR amplification of the V4 region. In addition, the protocol describes the analysis pipeline and provides a script using the latest version of QIIME (QIIME 2 version 2017.7.0 and DADA2). This step-by-step protocol is aimed to guide those interested in initiating the use of 16S rRNA-amplicon sequencing in a robust, reproductive, easy to use, detailed way. PMID- 29608152 TI - The Hawaii Protocol for Scientific Monitoring of Coffee Berry Borer: a Model for Coffee Agroecosystems Worldwide. AB - Coffee berry borer (CBB) is the most devastating insect pest for coffee crops worldwide. We developed a scientific monitoring protocol that is aimed at capturing and quantifying the dynamics and impact of this invasive insect pest as well as the development of its host plant across a heterogeneous landscape. The cornerstone of this comprehensive monitoring system is timely georeferenced data collection on CBB movement, coffee berry infestation, mortality by the fungus Beauveria bassiana, and coffee plant phenology via a mobile electronic data recording application. This electronic data collection system allows field records to be georeferenced through built-in global positioning systems, and is backed by a network of weather stations and records of farm management practices. Comprehensive monitoring of CBB and host plant dynamics is an essential part of an area-wide project in Hawaii to aggregate landscape-level data for research to improve management practices. Coffee agroecosystems in other parts of the world that experience highly variable environmental and socioeconomic factors will also benefit from implementing this protocol, in that it will drive the development of customized integrated pest management (IPM) to manage CBB populations. PMID- 29608153 TI - Use of a Video Scoring Anchor for Rapid Serial Assessment of Social Communication in Toddlers. AB - Reciprocal social behavior (RSB), an early-emerging capacity to engage in social contingency-which is foundational for both social learning and social competency is hypothesized to be disrupted in autism spectrum disorder (ASD). The ability to quantify the full range of RSB during the toddler period, when core symptoms of ASD often arise, is pivotal for evaluating early risk for ASD, characterizing social development, and tracking response to early interventions. However, important parameters of variation in RSB-especially prior to the development of verbal language-can be nuanced and difficult to characterize using questionnaire based methods. To address this challenge, we developed a system for measuring quantitative variation in RSB in toddlers (ages 18 - 30 months) that incorporated not only standard questionnaire data from caregivers but also a novel set of video-referenced items, through which a respondent compares the behavior of a subject to that observed in a short video of a young child manifesting a highly competent level of social communication. Testing of this measure in a general population sample of twins confirmed that both the video-referenced items and the RSB Total Score (video-referenced items plus non-video-referenced items) displayed unimodal, continuous distributions, strong internal consistency, marked preservation of individual differences, and extremely high heritability. In addition, video-referenced items were particularly sensitive to quantifying incremental changes in social communication, a major element of RSB, over the course of early childhood development. Scores on the vrRSB clearly differentiated children with and without ASD and these data comprise an initial validation of this promising method for quantifying early RSB-cross-sectionally, over time, and as a function of early intervention. PMID- 29608154 TI - Quantification of Endogenous Auxin and Cytokinin During Internode Culture of Ipecac. AB - Adventitious shoot formation is an important technique for the propagation of economically important crops and for the regeneration of transgenic plants. Phytohormone treatment is required for the induction of adventitious shoots in most species. Whether adventitious shoots can be induced is determined by the balance between auxin and cytokinin (CK) levels. Much effort goes into determining optimum concentrations and combinations of phytohormones in each tissue used as explants and in each plant species. In ipecac, however, adventitious shoots can be induced on internodal segments in culture medium without phytohormone treatment. This allows the inherent plasticity of ipecac for cell differentiation to be evaluated. To induce adventitious shoots in ipecac, we cultured internodal segments at 24 degrees C under 15 umol m-2 s-1 of light in a 14-h light/10-h dark cycle on phytohormone-free B5 medium solidified with 0.2% gellan gum for 5 weeks. To investigate phytohormone dynamics during adventitious shoot formation, we measured endogenous indole-3-acetic acid and CKs in the segments by liquid chromatography-tandem mass spectrometry LC-MS/MS. This method allows analysis of endogenous indole-3-acetic acid and CKs levels in a simple manner. It can be applied to investigate the dynamics of endogenous auxin and CK during organogenesis in other plant species. PMID- 29608155 TI - Primary Cell Cultures from the Mouse Retinal Pigment Epithelium. AB - The retinal pigment epithelium (RPE) is a highly polarized multi-functional epithelium that is located between the neural retina and the choroid of the eye. It is a single sheet of pigmented cells that are hexagonally packed and connected by tight junctions. The main functions of the RPE include absorption of light, phagocytosis of the shed photoreceptor outer segments, spatial buffering of ions, transport of nutrients, ions and water as well as active involvement in the visual cycle. With such important and diverse functions, it is critically important to study the biology of RPE cells. A number of RPE cell lines have been established; however, passaged and immortalized cells are known to quickly lose some of the morphological and physiological characteristics of natural RPE cells. Thus, primary cells are more suitable for studying different aspects of RPE cell biology and function. Mouse primary RPE cell culture is very useful to researchers since mouse models are widely used in biological studies, however collecting RPE cells from mouse is also very challenging due to their small size. Here, we present a protocol for establishing primary mouse RPE cell cultures which includes enucleation and dissection of the eyes and isolation of the RPE sheets to yield the cells for culturing. This method enables efficient cell recovery. The RPE cells obtained from two mice can reach confluency on one 12 mm polyester membrane insert pre-loaded in culture plate after one week of culture and display some of the original properties of bona fide RPE cells such as hexagonal shape and pigmentation after two weeks of culture. PMID- 29608156 TI - Effects of Allogeneic Platelet-Rich Plasma (PRP) on the Healing Process of Sectioned Achilles Tendons of Rats: A Methodological Description. AB - This article describes the experimental procedures used to observe if PRP can positively affect tendon healing. There are 4 main steps to follow: induce a lesion in the Achilles tendon; prepare PRP and inject it (or the saline solution); remove the tendon; and perform biomechanical, molecular, and histological evaluations. At each step, all the procedures and methods are described in detail, so they can be reproduced easily. Achilles tendons have been surgically sectioned (removal of a 5-mm long section). Afterwards, PRP or saline solution was injected to study whether PRP has a positive effect on the healing of the tendon. Three groups of 40 animals (a total of 120 rats were used in this study) were subdivided into 2 subgroups: PRP injection group and a saline injection control group. Rats were sacrificed at increasing time points (Group A: 5 days; Group B: 15 days; Group C: 30 days) and tendons were removed. 90 tendons underwent biomechanical testing before performing transcriptomic analysis and the 30 remaining tendons were submitted to histological analysis. PMID- 29608157 TI - Radionuclide-fluorescence Reporter Gene Imaging to Track Tumor Progression in Rodent Tumor Models. AB - Metastasis is responsible for most cancer deaths. Despite extensive research, the mechanistic understanding of the complex processes governing metastasis remains incomplete. In vivo models are paramount for metastasis research, but require refinement. Tracking spontaneous metastasis by non-invasive in vivo imaging is now possible, but remains challenging as it requires long-time observation and high sensitivity. We describe a longitudinal combined radionuclide and fluorescence whole-body in vivo imaging approach for tracking tumor progression and spontaneous metastasis. This reporter gene methodology employs the sodium iodide symporter (NIS) fused to a fluorescent protein (FP). Cancer cells are engineered to stably express NIS-FP followed by selection based on fluorescence activated cell sorting. Corresponding tumor models are established in mice. NIS FP expressing cancer cells are tracked non-invasively in vivo at the whole-body level by positron emission tomography (PET) using the NIS radiotracer [18F]BF4-. PET is currently the most sensitive in vivo imaging technology available at this scale and enables reliable and absolute quantification. Current methods either rely on large cohorts of animals that are euthanized for metastasis assessment at varying time points, or rely on barely quantifiable 2D imaging. The advantages of the described method are: (i) highly sensitive non-invasive in vivo 3D PET imaging and quantification, (ii) automated PET tracer production, (iii) a significant reduction in required animal numbers due to repeat imaging options, (iv) the acquisition of paired data from subsequent imaging sessions providing better statistical data, and (v) the intrinsic option for ex vivo confirmation of cancer cells in tissues by fluorescence microscopy or cytometry. In this protocol, we describe all steps required for routine NIS-FP-afforded non-invasive in vivo cancer cell tracking using PET/CT and ex vivo confirmation of in vivo results. This protocol has applications beyond cancer research whenever in vivo localization, expansion and long-time monitoring of a cell population is of interest. PMID- 29608158 TI - A Rat Model of Orthotopic Liver Transplantation Using a Novel Magnetic Anastomosis Technique for Suprahepatic Vena Cava Reconstruction. AB - The rat model of orthotopic liver transplantation (OLT) is essential for transplant research. It is a very sophisticated animal model and requires a steep learning curve. The introduction of the cuff technique for anastomosis of the portal vein (PV) and infrahepatic vena cava (IHVC) has significantly simplified the transplant procedure in rats. However, due to the short anterior wall of the recipients' suprahepatic vena cava (SHVC), the cuff technique is very difficult to use for the reconstruction of the SHVC. Most researchers in this field still use the hand-suture technique for SHVC reconstruction, which makes it the bottleneck step in rat orthotopic liver transplantation. The magnetic anastomosis technique (i.e., magnamosis) is a method of connecting two vessels using the attractive force between two magnets. Our recent study has shown that the magnetic anastomosis technique is superior to the hand-suture technique for SHVC reconstruction in rats. In this article, we show a step-by-step protocol for SHVC reconstruction in rats using the novel magnetic anastomosis technique. In this model, the reconstruction of the PV and IHVC was performed by the standard cuff technique, while the reconstruction of the bile duct (BD) was performed by a stent technique. The hepatic re-arterialization was not performed. The magnetic anastomosis technique made SHVC reconstruction much easier and significantly shortened the anphepatic phase. After a reasonable learning curve, even researchers without advanced microsurgical skills can produce reliable and reproducible results using this rat model of OLT. PMID- 29608159 TI - Two-photon Calcium Imaging in Neuronal Dendrites in Brain Slices. AB - Calcium (Ca2+) imaging is a powerful tool to investigate the spatiotemporal dynamics of intracellular Ca2+ signals in neuronal dendrites. Ca2+ fluctuations can occur through a variety of membrane and intracellular mechanisms and play a crucial role in the induction of synaptic plasticity and regulation of dendritic excitability. Hence, the ability to record different types of Ca2+ signals in dendritic branches is valuable for groups studying how dendrites integrate information. The advent of two-photon microscopy has made such studies significantly easier by solving the problems inherent to imaging in live tissue, such as light scattering and photodamage. Moreover, through combination of conventional electrophysiological techniques with two-photon Ca2+ imaging, it is possible to investigate local Ca2+ fluctuations in neuronal dendrites in parallel with recordings of synaptic activity in soma. Here, we describe how to use this method to study the dynamics of local Ca2+ transients (CaTs) in dendrites of GABAergic inhibitory interneurons. The method can be also applied to studying dendritic Ca2+ signaling in different neuronal types in acute brain slices. PMID- 29608160 TI - Methods of Pairing and Pair Maintenance of New Zealand White Rabbits (Oryctolagus Cuniculus) Via Behavioral Ethogram, Monitoring, and Interventions. AB - New Zealand White (NZW) laboratory rabbits (Oryctolagus cuniculus), as well as their ancestors the European Rabbit, are a social species that exhibit numerous benefits to being housed accordingly. Although these rabbits are innately gregarious, certain behaviors can still arise when kept in captivity, which if left unchecked, can confound research results or lead to wounding, which in extreme cases can be severe. To prevent these issues, there must be a well structured plan for the monitoring and maintenance of paired laboratory rabbits. The purpose of this protocol is to present effective procedures for establishing newly paired NZW rabbits as well as methods for successful maintenance. Multiple methods have been tested for the creation of newly paired female rabbits from the vendor, but the most efficacious technique emphasizes capitalizing on the stress bonding from transport, urine marking, pairing in a neutral cage with no forced sharing of resources and a system of monitoring and intervention. To determine the best method of housing paired rabbits in a standard caging environment, data were collected to generate a behavioral ethogram. Behaviors were then quantified as positive, neutral or negative and were tracked across the lifespan of the pair to determine which behaviors indicated pair success or failure. With the newfound knowledge of socially housed laboratory NZW rabbit behavior, enrichment intervention was applied to alleviate aggression and prevent wounding, thus resulting in a higher percentage of successful pairs. Through several years of trialing different pairing methods, the development of the ethogram and the resulting enrichment interventions, understanding of the highly complex social constructs that dominate pair housed rabbit behavior has dramatically increased and allowed for the provision of more species-specific care and increased standards of welfare. PMID- 29608161 TI - Isolation of Dendritic Cells from the Human Female Reproductive Tract for Phenotypical and Functional Studies. AB - The characterization of the human dendritic cells (DCs) resident in mucosal tissues is challenging due to the difficulty in obtaining samples, and the low numbers of DCs present per tissue. Yet, as the phenotype and function of DCs is modified by the tissue environment, it is necessary to analyze tissue resident DC populations, since blood derived DCs incompletely reflect the complexities of DCs in tissues. Here we present a protocol to isolate DCs from the human female reproductive tract (FRT) using hysterectomy specimens that allows both phenotypical and functional analyses. The protocol consists of tissue digestion to generate a single cell mixed cell suspension, followed by positive magnetic bead selection. Our tissue digestion protocol does not cleave surface markers, which allows phenotypical and functional analysis of DCs in the steady state, without overnight incubation or cell activation. This protocol can be adapted for the isolation of other immune cell types or isolation of DCs from other tissues. PMID- 29608162 TI - A Novel In Vitro Wound Healing Assay to Evaluate Cell Migration. AB - The aim of this work is to show a novel method to evaluate the ability of some immunomodulatory molecules, such as antimicrobial peptides (AMPs), to stimulate cell migration. Importantly, cell migration is a rate-limiting event during the wound-healing process to re-establish the integrity and normal function of tissue layers after injury. The advantage of this method over the classical assay, which is based on a manually made scratch in a cell monolayer, is the usage of special silicone culture inserts providing two compartments to create a cell-free pseudo wound field with a well-defined width (500 MUm). In addition, due to an automated image analysis platform, it is possible to rapidly obtain quantitative data on the speed of wound closure and cell migration. More precisely, the effect of two frog-skin AMPs on the migration of bronchial epithelial cells will be shown. Furthermore, pretreatment of these cells with specific inhibitors will provide information on the molecular mechanisms underlying such events. PMID- 29608163 TI - Production of Single Tracks of Ti-6Al-4V by Directed Energy Deposition to Determine the Layer Thickness for Multilayer Deposition. AB - Directed Energy Deposition (DED), which is an additive manufacturing technique, involves the creation of a molten pool with a laser beam where metal powder is injected as particles. In general, this technique is employed to either fabricate or repair different components. In this technique, the final characteristics are affected by many factors. Indeed, one of the main tasks in building components by DED is the optimization of process parameters (such as laser power, laser speed, focus, etc.) which is usually carried out through an extensive experimental investigation. However, this sort of experiment is extremely lengthy and costly. Thus, in order to accelerate the optimization process, an investigation was conducted to develop a method based on the melt pool characterizations. In fact, in these experiments, single tracks of Ti-6Al-4V were deposited by a DED process with multiple combinations of laser power and laser speed. Surface morphology and dimensions of single tracks were analyzed, and geometrical characteristics of melt pools were evaluated after polishing and etching the cross-sections. Helpful information regarding the selection of optimal process parameters can be achieved by examining the melt pool features. These experiments are being extended to characterize the larger blocks with multiple layers. Indeed, this manuscript describes how it would be possible to quickly determine the layer thickness for the massive deposition, and avoid over or under-deposition according to the calculated energy density of the optimum parameters. Apart from the over or under deposition, time and materials saving are the other great advantages of this approach in which the deposition of multilayer components can be started without any parameter optimization in terms of layer thickness. PMID- 29608164 TI - Single-cell Photoconversion in Living Intact Zebrafish. AB - Animal and plant tissue is composed of distinct populations of cells. These cells interact over time to build and maintain the tissue and can cause disease when disrupted. Scientists have developed clever techniques to investigate characteristics and natural dynamics of these cells within intact tissue by expressing fluorescent proteins in subsets of cells. However, at times, experiments require more selected visualization of cells within the tissue, sometimes at the single-cell or population-of-cells manner. To achieve this and visualize single cells within a population of cells, scientists have utilized single-cell photoconversion of fluorescent proteins. To demonstrate this technique, we show here how to direct UV light to an Eos-expressing cell of interest in an intact, living zebrafish. We then image those photoconverted Eos+ cells 24 h later to determine how they changed in the tissue. We describe two techniques: single cell photoconversion and photoconversions of populations of cell. These techniques can be used to visualize cell-cell interactions, cell-fate and differentiation, and cell migrations, making it a technique that is applicable in numerous biological questions. PMID- 29608165 TI - The Effect of the Application of Thyme Essential Oil on Microbial Load During Meat Drying. AB - Meat is a high protein meal that is used in the preparation of jerky, a popular food snack, where preservation and safety are important. To assure food safety and to extend the shelf life of meat and meat products, the use of either synthetic or natural preservatives have been applied to control and eliminate foodborne bacteria. A growing interest in the application of natural food additives for meat has increased. Microorganisms, such as Escherichia coli, contaminate meat and meat products, causing foodborne illnesses. Therefore, it is necessary to improve the meat conservation process. However, the use of essential oils when the meat is being dried has not been deeply studied. In this regard, there is an opportunity to increase the value of dried meat and reduce the risk of foodborne illnesses by applying essential oils during the drying process. In this protocol, we present a novel method of applying thyme essential oil (TEO) during meat drying, specifically in vapor form directly in a drying chamber. For evaluation, we use Minimal Inhibitory Concentration (MIC) to detect the number of harmful bacteria in the treated samples compared to raw samples. The preliminary results show that this method is a viable and alternative option to synthetic preservatives and that it significantly reduces microbial load in dried meat. PMID- 29608166 TI - On the Preparation and Testing of Fuel Cell Catalysts Using the Thin Film Rotating Disk Electrode Method. AB - We present a step-by-step tutorial to prepare proton exchange membrane fuel cell (PEMFC) catalysts, consisting of Pt nanoparticles (NPs) supported on a high surface area carbon, and to test their performance in thin film rotating disk electrode (TF-RDE) measurements. The TF-RDE methodology is widely used for catalyst screening; nevertheless, the measured performance sometimes considerably differs among research groups. These uncertainties impede the advancement of new catalyst materials and, consequently, several authors discussed possible best practice methods and the importance of benchmarking. The visual tutorial highlights possible pitfalls in the TF-RDE testing of Pt/C catalysts. A synthesis and testing protocol to assess standard Pt/C catalysts is introduced that can be used together with polycrystalline Pt disks as benchmark catalysts. In particular, this study highlights how the properties of the catalyst film on the glassy carbon (GC) electrode influence the measured performance in TF-RDE testing. To obtain thin, homogeneous catalyst films, not only the catalyst preparation, but also the ink deposition and drying procedures are essential. It is demonstrated that an adjustment of the ink's pH might be necessary, and how simple control measurements can be used to check film quality. Once reproducible TF-RDE measurements are obtained, determining the Pt loading on the catalyst support (expressed as Pt wt%) and the electrochemical surface area is necessary to normalize the determined reaction rates to either surface area or Pt mass. For the surface area determination, so-called CO stripping, or the determination of the hydrogen underpotential deposition (Hupd) charge, are standard. For the determination of the Pt loading, a straightforward and cheap procedure using digestion in aqua regia with subsequent conversion of Pt(IV) to Pt(II) and UV-vis measurements is introduced. PMID- 29608168 TI - Combining Optogenetics with Artificial microRNAs to Characterize the Effects of Gene Knockdown on Presynaptic Function within Intact Neuronal Circuits. AB - The purpose of this protocol is to characterize the effect of gene knockdown on presynaptic function within intact neuronal circuits. We describe a workflow on how to combine artificial microRNA (miR)-mediated RNA interference with optogenetics to achieve selective stimulation of manipulated presynaptic boutons in acute brain slices. The experimental approach involves the use of a single viral construct and a single neuron-specific promoter to drive the expression of both an optogenetic probe and artificial miR(s) against presynaptic gene(s). When stereotactically injected in the brain region of interest, the expressed construct makes it possible to stimulate with light exclusively the neurons with reduced expression of the gene(s) under investigation. This strategy does not require the development and maintenance of genetically modified mouse lines and can in principle be applied to other organisms and to any neuronal gene of choice. We have recently applied it to investigate how the knockdown of alternative splice isoforms of presynaptic P/Q-type voltage-gated calcium channels (VGCCs) regulates short-term synaptic plasticity at CA3 to CA1 excitatory synapses in acute hippocampal slices. A similar approach could also be used to manipulate and probe the neuronal circuitry in vivo. PMID- 29608167 TI - Assembly and Purification of Prototype Foamy Virus Intasomes. AB - A defining feature and necessary step of the retrovirus life cycle is the integration of the viral genome into the host genome. All retroviruses encode an integrase (IN) enzyme that catalyzes the covalent joining of viral to host DNA, which is known as strand transfer. Integration may be modeled in vitro with recombinant retroviral IN and DNA oligomers mimicking the ends of the viral genome. In order to more closely recapitulate the integration reaction that occurs in vivo, integration complexes are assembled from recombinant IN and synthetic oligomers by dialysis in a reduced salt concentration buffer. The integration complex, called an intasome, may be purified by size exclusion chromatography. In the case of prototype foamy virus (PFV), the intasome is a tetramer of IN and two DNA oligomers and is readily separated from monomeric IN and free oligomer DNA. The integration efficiency of PFV intasomes may be assayed under a variety of experimental conditions to better understand the dynamics and mechanics of retroviral integration. PMID- 29608169 TI - Fabricating Optical-quality Glass Surfaces to Study Macrophage Fusion. AB - Visualizing the formation of multinucleated giant cells (MGCs) from living specimens has been challenging due to the fact that most live imaging techniques require propagation of light through glass, but on glass macrophage fusion is a rare event. This protocol presents the fabrication of several optical-quality glass surfaces where adsorption of compounds containing long-chain hydrocarbons transforms glass into a fusogenic surface. First, preparation of clean glass surfaces as starting material for surface modification is described. Second, a method is provided for the adsorption of compounds containing long-chain hydrocarbons to convert non-fusogenic glass into a fusogenic substrate. Third, this protocol describes fabrication of surface micropatterns that promote a high degree of spatiotemporal control over MGC formation. Finally, fabricating glass bottom dishes is described. Examples of use of this in vitro cell system as a model to study macrophage fusion and MGC formation are shown. PMID- 29608171 TI - Outer-Boundary Assisted Segmentation and Quantification of Trabecular Bones by an Imagej Plugin. AB - Micro-computed tomography (micro-CT) is routinely used to assess bone quantity and trabecular microstructural properties in small animals under different bone loss conditions. However, the standard approach for trabecular analysis of micro CT images is slice-by-slice semi-automatic hand-contouring, which is labor intensive and error prone. Described here is an efficient method for automatic segmentation of trabecular bones according to the bone's outer boundaries, where trabecular bones can be identified and segmented automatically with accuracy with less operator bias when appropriate segmentation parameters are set. To profile satisfactory segmentation parameters, an image stack of segmentation results is displayed, where all possible combinations of the segmentation parameters are changed one by one in sequence, and segmentation results with associated parameters can easily be visually checked. As a quality-control feature of the plugin, simulated standard objects are quantified where the measured quantities can be compared with theoretical values. Layer-by-layer quantification of trabecular properties and trabecular thicknesses are reported by such a plugin, and the distributions of such properties within the selected regions can be profiled easily. Although layer-by-layer quantification retains more information about trabecular bones and facilitates further statistical analysis of structural changes, such measures are unavailable from the output of current commercial software, where only a single quantified value for each parameter is reported for each sample. Therefore, the described workflows are better approaches for analyzing trabecular bones with accuracy and efficiency. PMID- 29608170 TI - Multiplexed Isothermal Amplification Based Diagnostic Platform to Detect Zika, Chikungunya, and Dengue 1. AB - Zika, dengue, and chikungunya viruses are transmitted by mosquitoes, causing diseases with similar patient symptoms. However, they have different downstream patient-to-patient transmission potentials, and require very different patient treatments. Thus, recent Zika outbreaks make it urgent to develop tools that rapidly discriminate these viruses in patients and trapped mosquitoes, to select the correct patient treatment, and to understand and manage their epidemiology in real time. Unfortunately, current diagnostic tests, including those receiving 2016 emergency use authorizations and fast-track status, detect viral RNA by reverse transcription polymerase chain reaction (RT-PCR), which requires instrumentation, trained users, and considerable sample preparation. Thus, they must be sent to "approved" reference laboratories, requiring time. Indeed, in August 2016, the Center for Disease Control (CDC) was asking pregnant women who had been bitten by a mosquito and developed a Zika-indicating rash to wait an unacceptable 2 to 4 weeks before learning whether they were infected. We very much need tests that can be done on site, with few resources, and by trained but not necessarily licensed personnel. This video demonstrates an assay that meets these specifications, working with urine or serum (for patients) or crushed mosquito carcasses (for environmental surveillance), all without much sample preparation. Mosquito carcasses are captured on paper carrying quaternary ammonium groups (Q-paper) followed by ammonia treatment to manage biohazards. These are then directly, without RNA isolation, put into assay tubes containing freeze-dried reagents that need no chain of refrigeration. A modified form of reverse transcription loop-mediated isothermal amplification with target-specific fluorescently tagged displaceable probes produces readout, in 30 min, as a three color fluorescence signal. This is visualized with a handheld, battery-powered device with an orange filter. Forward contamination is prevented with sealed tubes, and the use of thermolabile uracil DNA glycosylase (UDG) in the presence of dUTP in the amplification mixture. PMID- 29608172 TI - Live Cell Imaging of Chromosome Segregation During Mitosis. AB - Chromosomes must be reliably and uniformly segregated into daughter cells during mitotic cell division. Fidelity of chromosomal segregation is controlled by multiple mechanisms that include the Spindle Assembly Checkpoint (SAC). The SAC is part of a complex feedback system that is responsible for prevention of a cell progress through mitosis unless all chromosomal kinetochores have attached to spindle microtubules. Chromosomal lagging and abnormal chromosome segregation is an indicator of dysfunctional cell cycle control checkpoints and can be used to measure the genomic stability of dividing cells. Deregulation of the SAC can result in the transformation of a normal cell into a malignant cell through the accumulation of errors during chromosomal segregation. Implementation of the SAC and the formation of the kinetochore complex are tightly regulated by interactions between kinases and phosphatase such as Protein Phosphatase 2A (PP2A). This protocol describes live cell imaging of lagging chromosomes in mouse embryonic fibroblasts isolated from mice that had a knockout of the PP2A-B56gamma regulatory subunit. This method overcomes the shortcomings of other cell cycle control imaging techniques such as flow cytometry or immunocytochemistry that only provide a snapshot of a cell cytokinesis status, instead of a dynamic spatiotemporal visualization of chromosomes during mitosis. PMID- 29608173 TI - Manipulation of Ploidy in Caenorhabditis elegans. AB - Mechanisms that involve whole genome polyploidy play important roles in development and evolution; also, an abnormal generation of tetraploid cells has been associated with both the progression of cancer and the development of drug resistance. Until now, it has not been feasible to easily manipulate the ploidy of a multicellular animal without generating mostly sterile progeny. Presented here is a simple and rapid protocol for generating tetraploid Caenorhabditis elegans animals from any diploid strain. This method allows the user to create a bias in chromosome segregation during meiosis, ultimately increasing ploidy in C. elegans. This strategy relies on the transient reduction of expression of the rec 8 gene to generate diploid gametes. A rec-8 mutant produces diploid gametes that can potentially produce tetraploids upon fertilization. This tractable scheme has been used to generate tetraploid strains carrying mutations and chromosome rearrangements to gain insight into chromosomal dynamics and interactions during pairing and synapsis in meiosis. This method is efficient for generating stable tetraploid strains without genetic markers, can be applied to any diploid strain, and can be used to derive triploid C. elegans. This straightforward method is useful for investigating other fundamental biological questions relevant to genome instability, gene dosage, biological scaling, extracellular signaling, adaptation to stress, development of resistance to drugs, and mechanisms of speciation. PMID- 29608174 TI - Executing Complexity-Increasing Queries in Relational (MySQL) and NoSQL (MongoDB and EXist) Size-Growing ISO/EN 13606 Standardized EHR Databases. AB - This research shows a protocol to assess the computational complexity of querying relational and non-relational (NoSQL (not only Structured Query Language)) standardized electronic health record (EHR) medical information database systems (DBMS). It uses a set of three doubling-sized databases, i.e. databases storing 5000, 10,000 and 20,000 realistic standardized EHR extracts, in three different database management systems (DBMS): relational MySQL object-relational mapping (ORM), document-based NoSQL MongoDB, and native extensible markup language (XML) NoSQL eXist. The average response times to six complexity-increasing queries were computed, and the results showed a linear behavior in the NoSQL cases. In the NoSQL field, MongoDB presents a much flatter linear slope than eXist. NoSQL systems may also be more appropriate to maintain standardized medical information systems due to the special nature of the updating policies of medical information, which should not affect the consistency and efficiency of the data stored in NoSQL databases. One limitation of this protocol is the lack of direct results of improved relational systems such as archetype relational mapping (ARM) with the same data. However, the interpolation of doubling-size database results to those presented in the literature and other published results suggests that NoSQL systems might be more appropriate in many specific scenarios and problems to be solved. For example, NoSQL may be appropriate for document-based tasks such as EHR extracts used in clinical practice, or edition and visualization, or situations where the aim is not only to query medical information, but also to restore the EHR in exactly its original form. PMID- 29608175 TI - Quantification of Intracellular Growth Inside Macrophages is a Fast and Reliable Method for Assessing the Virulence of Leishmania Parasites. AB - The lifecycle of Leishmania, the causative agent of leishmaniasis, alternates between promastigote and amastigote stages inside the insect and vertebrate hosts, respectively. While pathogenic symptoms of leishmaniasis can vary widely, from benign cutaneous lesions to highly fatal visceral disease forms depending on the infective species, all Leishmania species reside inside host macrophages during the vertebrate stage of their lifecycle. Leishmania infectivity is therefore directly related to its ability to invade, survive and replicate within parasitophorous vacuoles (PVs) inside macrophages. Thus, assessing the parasite's ability to replicate intracellularly serves as a dependable method for determining virulence. Studying leishmaniasis development using animal models is time-consuming, tedious and often difficult, particularly with the pathogenically important visceral forms. We describe here a methodology to follow the intracellular development of Leishmania in bone marrow-derived macrophages (BMMs). Intracellular parasite numbers are determined at 24 h intervals for 72 - 96 h following infection. This method allows for a reliable determination of the effects of various genetic factors on Leishmania virulence. As an example, we show how a single allele deletion of the Leishmania Mitochondrial Iron Transporter gene (LMIT1) impairs the ability of the Leishmania amazonensis mutant strain LMIT1/DeltaLmit1 to grow inside BMMs, reflecting a drastic reduction in virulence compared to wild-type. This assay also allows precise control of experimental conditions, which can be individually manipulated to analyze the influence of various factors (nutrients, reactive oxygen species, etc.) on the host-pathogen interaction. Therefore, the appropriate execution and quantification of BMM infection studies provide a non-invasive, rapid, economical, safe and reliable alternative to conventional animal model studies. PMID- 29608176 TI - Preparations and Protocols for Whole Cell Patch Clamp Recording of Xenopus laevis Tectal Neurons. AB - The Xenopus tadpole retinotectal circuit, comprised of the retinal ganglion cells (RGCs) in the eye which form synapses directly onto neurons in the optic tectum, is a popular model to study how neural circuits self-assemble. The ability to carry out whole cell patch clamp recordings from tectal neurons and to record RGC evoked responses, either in vivo or using a whole brain preparation, has generated a large body of high-resolution data about the mechanisms underlying normal, and abnormal, circuit formation and function. Here we describe how to perform the in vivo preparation, the original whole brain preparation, and a more recently developed horizontal brain slice preparation for obtaining whole cell patch clamp recordings from tectal neurons. Each preparation has unique experimental advantages. The in vivo preparation enables the recording of the direct response of tectal neurons to visual stimuli projected onto the eye. The whole brain preparation allows for the RGC axons to be activated in a highly controlled manner, and the horizontal brain slice preparation allows recording from across all layers of the tectum. PMID- 29608177 TI - Batch effects in single-cell RNA-sequencing data are corrected by matching mutual nearest neighbors. AB - Large-scale single-cell RNA sequencing (scRNA-seq) data sets that are produced in different laboratories and at different times contain batch effects that may compromise the integration and interpretation of the data. Existing scRNA-seq analysis methods incorrectly assume that the composition of cell populations is either known or identical across batches. We present a strategy for batch correction based on the detection of mutual nearest neighbors (MNNs) in the high dimensional expression space. Our approach does not rely on predefined or equal population compositions across batches; instead, it requires only that a subset of the population be shared between batches. We demonstrate the superiority of our approach compared with existing methods by using both simulated and real scRNA-seq data sets. Using multiple droplet-based scRNA-seq data sets, we demonstrate that our MNN batch-effect-correction method can be scaled to large numbers of cells. PMID- 29608178 TI - Simultaneous single-cell profiling of lineages and cell types in the vertebrate brain. AB - The lineage relationships among the hundreds of cell types generated during development are difficult to reconstruct. A recent method, GESTALT, used CRISPR Cas9 barcode editing for large-scale lineage tracing, but was restricted to early development and did not identify cell types. Here we present scGESTALT, which combines the lineage recording capabilities of GESTALT with cell-type identification by single-cell RNA sequencing. The method relies on an inducible system that enables barcodes to be edited at multiple time points, capturing lineage information from later stages of development. Sequencing of ~60,000 transcriptomes from the juvenile zebrafish brain identified >100 cell types and marker genes. Using these data, we generate lineage trees with hundreds of branches that help uncover restrictions at the level of cell types, brain regions, and gene expression cascades during differentiation. scGESTALT can be applied to other multicellular organisms to simultaneously characterize molecular identities and lineage histories of thousands of cells during development and disease. PMID- 29608180 TI - Spore concentration and modified host resistance as a cause of anthrax outbreaks A comment. PMID- 29608179 TI - Integrating single-cell transcriptomic data across different conditions, technologies, and species. AB - Computational single-cell RNA-seq (scRNA-seq) methods have been successfully applied to experiments representing a single condition, technology, or species to discover and define cellular phenotypes. However, identifying subpopulations of cells that are present across multiple data sets remains challenging. Here, we introduce an analytical strategy for integrating scRNA-seq data sets based on common sources of variation, enabling the identification of shared populations across data sets and downstream comparative analysis. We apply this approach, implemented in our R toolkit Seurat (http://satijalab.org/seurat/), to align scRNA-seq data sets of peripheral blood mononuclear cells under resting and stimulated conditions, hematopoietic progenitors sequenced using two profiling technologies, and pancreatic cell 'atlases' generated from human and mouse islets. In each case, we learn distinct or transitional cell states jointly across data sets, while boosting statistical power through integrated analysis. Our approach facilitates general comparisons of scRNA-seq data sets, potentially deepening our understanding of how distinct cell states respond to perturbation, disease, and evolution. PMID- 29608181 TI - The state of the art in the development of a panel of biomarkers for the early detection of lung cancer. PMID- 29608182 TI - 2D or 3D measurements of pulmonary nodules: preliminary answers and more open questions. PMID- 29608183 TI - Outcome of red blood cell transfusion: ladies first, but perhaps not in donation. PMID- 29608184 TI - Corrigendum. AB - [This corrects the article DOI: 10.1002/ece3.3398.]. PMID- 29608185 TI - Correction to: Lack of relationship between PTEN 32-bp and TP53 16-bp Ins/Del polymorphisms and chronic hepatitis B virus infection. AB - [This corrects the article DOI: 10.1007/s13337-017-0391-7.]. PMID- 29608186 TI - Lung surgery in elderly patients: are we doing enough? PMID- 29608187 TI - Postdiagnosis Changes in Cigarette Smoking and Survival Following Breast Cancer. AB - Background: The purpose of this study was to examine whether at-diagnosis smoking and postdiagnosis changes in smoking within five years after breast cancer were associated with long-term all-cause and breast cancer-specific mortality. Methods: A population-based cohort of 1508 women diagnosed with first primary in situ or invasive breast cancer in 1996 to 1997 were interviewed shortly after diagnosis and again approximately five years later to assess smoking history. Participants were followed for vital status through December 31, 2014. After 18+ years of follow-up, 597 deaths were identified, 237 of which were breast cancer related. Multivariable Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Results: Compared with never smokers, risk of all-cause mortality was elevated among the 19% of at-diagnosis smokers (HR=1.69, 95% CI=1.36 to 2.11), those who smoked 20 or more cigarettes per day (HR=1.85, 95% CI=1.42 to 2.40), women who had smoked for 30 or more years (HR=1.62, 95% CI=1.28 to 2.05), and women who had smoked 30 or more pack-years (HR=1.82, 95% CI=1.39 to 2.37). Risk of all-cause mortality was further increased among the 8% of women who were at-/post-diagnosis smokers (HR=2.30, 95% CI=1.56 to 3.39) but was attenuated among the 11% women who quit smoking after diagnosis (HR=1.83, 95% CI=1.32 to 2.52). Compared with never smokers, breast cancer-specific mortality risk was elevated 60% (HR=1.60, 95% CI=0.79 to 3.23) among at-/postdiagnosis current smokers, but the confidence interval included the null value and elevated 175% (HR=2.75, 95% CI=1.26 to 5.99) when we considered postdiagnosis cumulative pack-years. Conclusions: Smoking negatively impacts long-term survival after breast cancer. Postdiagnosis cessation of smoking may reduce the risk of all cause mortality. Breast cancer survivors may benefit from aggressive smoking cessation programs starting as early as the time of diagnosis. PMID- 29608188 TI - The reality of complexity: concomitant genomic alterations in patients with EGFR mutations. PMID- 29608189 TI - Moxalactam is not more active on extended spectrum beta-lactamase (ESBL) producing bacteria than on non-ESBL producers. PMID- 29608190 TI - Immediate non-culprit vessel percutaneous coronary intervention (PCI) in patients with acute myocardial infarction and cardiogenic shock: a swinging pendulum. PMID- 29608191 TI - What is the most appropriate procedure for intraoperative localization of small pulmonary nodules? PMID- 29608192 TI - Peeling back the onion: addressing nuances of CT screening for lung cancer. PMID- 29608193 TI - Compounded Oral Viscous Budesonide is Effective and Provides a Durable Response in Eosinophilic Esophagitis. AB - Aim: Because no approved medications exist for eosinophilic esophagitis (EoE), patients must use off-label drugs or create their own formulations. We assessed the efficacy of a standardized compounded budesonide suspension for treatment of EoE. Materials and methods: We conducted a retrospective cohort study of EoE patients at the University of North Carolina treated with compounded budesonide dispensed by a specialty compounding pharmacy. Outcomes (symptomatic global response [yes/no], endoscopic response [% with individual findings], and histologic response [absolute eosinophil count; % with <15 eos/hpf])were assessed after the initial and last treatment in our system. Results: We identified 48 patients treated with compounded budesonide (mean age 33.6; 69% male; 96% white; 2.4 mg mean initial dose). After a mean length of follow-up of 17.0 months (range: 4.2 - 56.3), there was a significant decrease in symptoms of dysphagia (95% vs. 32%, p < 0.001), improvements in heartburn (37% vs. 11%, p=0.06) and global symptom response (81%). The median of the peak eosinophil counts decreased from 55 to 20 eos/hpf (p<0.001) with 42% achieving a response of <15 eos/hpf. Esophageal candidiasis was rare (6%). In the 18 patients with prior non-response to corticosteroids or dietary elimination, 83% had symptomatic and 38% had histologic response. Conclusion: Compounded budesonide suspension produced a durable symptomatic, endoscopic, and histologic response in a cohort followed for more than a year. Many patients previously refractory to prior therapy responded to compounded budesonide. This formulation can be used clinically until there are approved drugs with esophageal formulations for EoE. PMID- 29608194 TI - Missing ingredients for a lifestyle recipe to treat hypertension. PMID- 29608195 TI - Endoscopy and surgery for achalasia: the two sides of myotomy. PMID- 29608196 TI - Mortality after red blood cell transfusions from previously pregnant donors: complexities in the interpretation of large data. PMID- 29608197 TI - Air sampling to assess potential generation of aerosolized viable bacteria during flow cytometric analysis of unfixed bacterial suspensions. AB - This study investigated aerosolized viable bacteria in a university research laboratory during operation of an acoustic-assisted flow cytometer for antimicrobial susceptibility testing by sampling room air before, during and after flow cytometer use. The aim was to assess the risk associated with use of an acoustic-assisted flow cytometer analyzing unfixed bacterial suspensions. Air sampling in a nearby clinical laboratory was conducted during the same period to provide context for the existing background of microorganisms that would be detected in the air. The three species of bacteria undergoing analysis by flow cytometer in the research laboratory were Klebsiella pneumoniae, Burkholderia thailandensis and Streptococcus pneumoniae. None of these was detected from multiple 1000 L air samples acquired in the research laboratory environment. The main cultured bacteria in both locations were skin commensal and environmental bacteria, presumed to have been disturbed or dispersed in laboratory air by personnel movements during routine laboratory activities. The concentrations of bacteria detected in research laboratory air samples were reduced after interventional cleaning measures were introduced and were lower than those in the diagnostic clinical microbiology laboratory. We conclude that our flow cytometric analyses of unfixed suspensions of K. pneumoniae, B. thailandensis and S. pneumoniae do not pose a risk to cytometer operators or other personnel in the laboratory but caution against extrapolation of our results to other bacteria and/or different flow cytometric experimental procedures. PMID- 29608198 TI - Disparities in lymphoma on the basis of race, gender, HIV status, and sexual orientation. AB - Lymphoid malignancies account for the sixth leading cause of death in the US, and, although survival is improving overall, this trend is not applicable to all patients. In this review, we describe disparities in the initial presentation, treatment, and outcomes across a diverse group of lymphoma patients on the basis of gender, race, HIV status, and sexual orientation. Identifying these disparities will hopefully lead to improved outcomes in these groups of lymphoma patients in the future. PMID- 29608199 TI - Is microRNA-31 a key regulator of breast tumorigenesis? PMID- 29608201 TI - Erratum to acute rejection. AB - [This corrects the article DOI: 10.21037/jtd.2017.11.83.]. PMID- 29608200 TI - The first transcriptomes from field-collected individual whiteflies ( Bemisia tabaci, Hemiptera: Aleyrodidae): a case study of the endosymbiont composition. AB - Background:Bemisia tabaci species ( B. tabaci), or whiteflies, are the world's most devastating insect pests. They cause billions of dollars (US) of damage each year, and are leaving farmers in the developing world food insecure. Currently, all publically available transcriptome data for B. tabaci are generated from pooled samples, which can lead to high heterozygosity and skewed representation of the genetic diversity. The ability to extract enough RNA from a single whitefly has remained elusive due to their small size and technological limitations. Methods: In this study, we optimised a single whitefly RNA extraction procedure, and sequenced the transcriptome of four individual adult Sub-Saharan Africa 1 (SSA1) B. tabaci. Transcriptome sequencing resulted in 39-42 million raw reads. De novo assembly of trimmed reads yielded between 65,000 162,000 Contigs across B. tabaci transcriptomes. Results: Bayesian phylogenetic analysis of mitochondrion cytochrome I oxidase (mtCOI) grouped the four whiteflies within the SSA1 clade. BLASTn searches on the four transcriptomes identified five endosymbionts; the primary endosymbiont Portieraaleyrodidarum and four secondary endosymbionts: Arsenophonus, Wolbachia, Rickettsia, and Cardinium spp. that were predominant across all four SSA1 B. tabaci samples with prevalence levels of between 54.1 to 75%. Amino acid alignments of the NusG gene of P. aleyrodidarum for the SSA1 B. tabaci transcriptomes of samples WF2 and WF2b revealed an eleven amino acid residue deletion that was absent in samples WF1 and WF2a. Comparison of the protein structure of the NusG protein from P. aleyrodidarum in SSA1 with known NusG structures showed the deletion resulted in a shorter D loop. Conclusions: The use of field-collected specimens means time and money will be saved in future studies using single whitefly transcriptomes in monitoring vector and viral interactions. Our method is applicable to any small organism where RNA quantity has limited transcriptome studies. PMID- 29608202 TI - 3D Printed Organ Models with Physical Properties of Tissue and Integrated Sensors. AB - The design and development of novel methodologies and customized materials to fabricate patient-specific 3D printed organ models with integrated sensing capabilities could yield advances in smart surgical aids for preoperative planning and rehearsal. Here, we demonstrate 3D printed prostate models with physical properties of tissue and integrated soft electronic sensors using custom formulated polymeric inks. The models show high quantitative fidelity in static and dynamic mechanical properties, optical characteristics, and anatomical geometries to patient tissues and organs. The models offer tissue-mimicking tactile sensation and behavior and thus can be used for the prediction of organ physical behavior under deformation. The prediction results show good agreement with values obtained from simulations. The models also allow the application of surgical and diagnostic tools to their surface and inner channels. Finally, via the conformal integration of 3D printed soft electronic sensors, pressure applied to the models with surgical tools can be quantitatively measured. PMID- 29608204 TI - Complications from brachial arterial pressure monitoring are rare in patients having cardiac surgery. PMID- 29608203 TI - Teaching an old dog new TRICS: re-evaluating transfusion triggers in high-risk cardiac surgery. PMID- 29608205 TI - Correction to: Efficacy of H120 and Ma5 avian infectious bronchitis vaccines in early challenge against QX strain. AB - [This corrects the article DOI: 10.1007/s13337-017-0414-4.]. PMID- 29608206 TI - Effectiveness of peer teaching in medical education: medical student's perspective. PMID- 29608207 TI - Perspective and clinical relevance of intrapulmonary lymph node retrieval: response to the editorial by Tantraworasin and colleagues and the editorial by Marc Riquet and colleagues. PMID- 29608208 TI - Effects of the Good Behavior Game on student and teacher behavior in an alternative school. AB - The Good Behavior Game (GBG) is a classroom behavior management procedure that has been shown to be effective in reducing disruptive behavior across many settings and populations (Flower, McKenna, Bunuan, Muething, & Vega, 2014). We investigated the effects of the GBG on student and teacher behavior in two classrooms containing fourth- to eighth-grade students in an alternative school for students with emotional and behavioral disorders. Results indicated the GBG reduced disruption and increased the teacher's use of praise relative to reprimands. Social validity measures, collected from both teachers and students, indicated strong approval of the GBG. PMID- 29608209 TI - Higher ploidy is associated with reduced range breadth in the Potentilleae tribe. AB - PREMISE OF THE STUDY: Polyploids are predicted to have greater niche breadth and larger ranges than diploids because of higher ecological tolerances, self compatibility, and increased genetic variation. However, empirical support for this prediction is mixed, and most studies compare diploids and polyploids, rather than accounting for quantitative variation in ploidy. We test the prediction that species of higher ploidy have greater range breadth and abiotic breadth than those of lower ploidy. METHODS: We estimate range breadth (latitudinal range, altitudinal range, and range size) and abiotic breadth (range in temperature, precipitation, and ultraviolet-B irradiance) for 109 species in the Potentilleae tribe of Rosaceae. We assess the contribution of ploidy to variation in range breadth, while accounting for shared evolutionary history and time of species divergence using phylogenetic comparative methods. KEY RESULTS: Ploidy varied widely among species from 2* to 12*. Phylogenetic relatedness explained little of the variation in ploidy, range breadth, and abiotic breadth. Transitions to higher ploidy were associated with reduced latitudinal and altitudinal ranges, smaller overall range size, and reduced abiotic breadth for temperature and UV-B. CONCLUSIONS: In contrast to predictions, this study shows that transitions to higher ploidy are associated with reduced range size and abiotic breadth. It also highlights the importance of considering continuous variation in ploidy when evaluating ecological correlates with ploidy. We discuss how genome duplication may contribute to the observed negative relationship between ploidy and range breadth. PMID- 29608210 TI - Intrapartum fetal death and doctors: a qualitative exploration. AB - INTRODUCTION: The death of an infant during a pregnancy is profoundly traumatic, both for the parents and for the involved healthcare professionals. Most research focuses on the impact of antenatal stillbirth with very little research examining the specific impact an intrapartum fetal death has on obstetricians. The aim of this study was to provide an in-depth qualitative exploration of the attitudes and responses that Irish obstetricians have following direct involvement with an intrapartum fetal death. MATERIAL AND METHODS: Qualitative semi-structured interviews were used. Interpretative phenomenology was used for data analysis. The setting was a tertiary university maternity unit in Ireland with 8200 deliveries per year. Ten obstetricians were purposively sampled. The main outcome measures were the attitudes and responses of Irish obstetricians following exposure to an intrapartum death. RESULTS: Obstetricians were profoundly and negatively affected by a personal involvement with an intrapartum death. Analysis of the data revealed two superordinate themes; the doctor as a person, and supporting each other. The doctor as person was characterized by two subordinate themes; emotional impact and frustration. Supporting each other was also characterized by two subordinate themes; an unmet need and incidental support and what might work. CONCLUSIONS: Obstetric doctors who are directly involved in an intrapartum death are the second victims of this event and this is something that needs to be acknowledged by the public, by the healthcare system, by the media and by the doctors themselves. The development of effective emotional support interventions for all obstetricians is extremely important. PMID- 29608211 TI - Annexin-1 as a salivary biomarker for gingivitis during pregnancy. AB - BACKGROUND: It is well established that there is higher susceptibility to gingival inflammation during pregnancy. Annexin-1 (ANXA1) is an anti-inflammatory protein which has been identified in gingival tissue exudates by discovery proteomics. This cross-sectional case-control study investigated the levels and association of ANXA1 and pro-inflammatory mediator interleukin (IL)-1beta in the saliva of pregnant and non-pregnant women. METHODS: Whole unstimulated saliva from 69 non-pregnant and 78 pregnant women was collected prior to measurement of probing depth, clinical attachment level, bleeding on probing, and plaque. Then, the women were split into 3 subgroups depending on their periodontal status (healthy, gingivitis, and periodontitis). The levels of ANXA1 and IL-1beta were measured with enzyme-linked immunosorbent assay and reported as pg/mg after normalizing against the total protein levels. RESULTS: Significantly higher ANXA1 levels were exhibited in pregnant women with gingivitis compared with health (P < 0.05) and in pregnant women with gingivitis compared with the respective non pregnant group (P < 0.0001). There was a significantly higher level of IL-1beta in gingivitis than in health in pregnant women (P < 0.05) and significantly higher levels in periodontitis compared with health in non-pregnant women (P < 0.05). Looking at the IL-1 beta:ANXA1 ratio, the non-pregnant periodontitis group displayed a significantly higher ratio compared with the respective pregnant group (P < 0.05). In the non-pregnant subpopulation, the ratio was significantly higher in periodontitis compared with health (P < 0.01). CONCLUSION: Salivary ANXA1 levels are elevated in the presence of gingivitis only in pregnant, but not non-pregnant women, rendering this molecule as a potential salivary biomarker for non-invasive early screening for gingival inflammation during pregnancy. PMID- 29608212 TI - Glycan-metabolizing enzymes in microbe-host interactions: the Streptococcus pneumoniae paradigm. AB - Streptococcus pneumoniae is a frequent colonizer of the upper airways; however, it is also an accomplished pathogen capable of causing life-threatening diseases. To colonize and cause invasive disease, this bacterium relies on a complex array of factors to mediate the host-bacterium interaction. The respiratory tract is rich in functionally important glycoconjugates that display a vast range of glycans, and, thus, a key component of the pneumococcus-host interaction involves an arsenal of bacterial carbohydrate-active enzymes to depolymerize these glycans and carbohydrate transporters to import the products. Through the destruction of host glycans, the glycan-specific metabolic machinery deployed by S. pneumoniae plays a variety of roles in the host-pathogen interaction. Here, we review the processing and metabolism of the major host-derived glycans, including N- and O linked glycans, Lewis and blood group antigens, proteoglycans, and glycogen, as well as some dietary glycans. We discuss the role of these metabolic pathways in the S. pneumoniae-host interaction, speculate on the potential of key enzymes within these pathways as therapeutic targets, and relate S. pneumoniae as a model system to glycan processing in other microbial pathogens. PMID- 29608213 TI - My possessions need me: Anthropomorphism and hoarding. AB - Hoarding disorder (HD), a new DSM-5 classification, is characterized by difficulty discarding and the excessive acquisition of possessions to the extent that living spaces are compromised by clutter. Individuals with hoarding difficulties have a variety of motivations for object ownership, including emotional attachment towards their possessions which sometimes manifests through imbuing possessions with human-like terms. Limited extant evidence suggests that anthropomorphism, attributing human qualities to non-human objects, is related to hoarding, possibly because of difficulties with interpersonal attachment and social isolation. The current study investigated the relationship between hoarding behaviors (i.e., difficulty discarding, excessive acquisition, and clutter), hoarding beliefs (i.e., motivations for ownership including responsibility, emotional attachment, memory, control), anthropomorphism (i.e., generally in childhood, generally in adulthood, and towards three different personally-owned objects), and loneliness. Moderation analyses examined whether hoarding beliefs or loneliness impacted how anthropomorphism related to hoarding symptoms. Results suggested that all dimensions of anthropomorphism were related to hoarding behaviors. Regression analyses indicated that anthropomorphism in adulthood and of personally owned-objects were the best predictors of hoarding behavior. Mixed evidence was found for hoarding beliefs and loneliness moderating these associations. Findings successfully replicated and extended previous literature and provide a novel measure of anthropomorphism specifically incorporating personal ownership. PMID- 29608214 TI - Heart Rate and Bone Mineral Density in Older Women with Hypertension: Results from the Korea National Health and Nutritional Examination Survey. AB - OBJECTIVES: To determine whether high heart rate is associated with low bone mineral density (BMD) in older women with hypertension. DESIGN: Retrospective cohort study. SETTING: Population-based study conducted in Korea (Korea National Health and Nutritional Examination Survey 2009-10). PARTICIPANTS: Postmenopausal women aged 60 and older with hypertension (N=981) divided into 2 groups according to resting heart rate, with a cut-off value of 80 bpm, which has been found to be associated with osteoporosis. MEASUREMENTS: BMD profiles and clinical and laboratory data were collected. Osteoporosis was defined as a T-score of -2.5 or less, according to World Health Organization criteria. RESULTS: BMD was significantly lower in participants with a high heart rate, even after adjustment for age, diabetes mellitus, white blood cell count, and fasting glucose and triglyceride levels. The prevalence of osteoporosis was also significantly higher in those participants. In multivariate logistic regression analysis, the group with high heart rate was 1.7 times as likely (95% confidence interval=1.2-2.3) to have osteoporosis as those with a lower heart rate, independent of age, body mass index, comorbidities, and laboratory findings. CONCLUSION: High heart rate is independently associated with lower BMD in older women with hypertension; proactive surveillance of BMD could be helpful when managing older women with hypertension and a high heart rate. PMID- 29608215 TI - Prospective study of removing solar lentigines in Asians using a novel dual wavelength and dual-pulse width picosecond laser. AB - OBJECTIVES: Quality-switched (QS) lasers are known to be an effective treatment for removing solar lentigines, however, high incidence of post-inflammatory hyperpigmentation (PIH) is a concern in darker skin types. The objective of this study was to evaluate the efficacy and safety of a dual-wavelength and dual-pulse width picosecond Nd:YAG laser for removing solar lentigines in Asians. METHODS: This was a prospective, IRB-approved study. Twenty cases with solar lentigines on the face were enrolled for treatment and evaluated at 1- and 3-month after the final treatment. Results were assessed by blinded evaluators using a 5-grade percentage improvement scale and Melanin index (MI) measured by a reflectance spectrophotometer. A patient self-assessment questionnaire was also administered using a 5-grade improvement scale. Additional treatment was performed if the improvement was less than 75% or the lentigo partially remained after 4 weeks. Histological evaluation was performed to compare the differences between the current picosecond laser and a QS Nd:YAG laser 532-nm using light and electron microscopy. RESULTS: Forty-three lesions in 20 females, skin type III or IV, age 53.7 +/- 9.75 were treated and evaluated. The laser setting was: 532-nm, 750 picoseconds, average fluence of 0.35 +/- 0.06 J/cm [2] using a spot size of 3 or 4 mm. Forty lesions (93.02%) achieved over 75% clearance with a single treatment and the other three lesions (6.98%) needed two treatments. PIH occurred only in 4.65% of lesions. The average score of the blinded evaluators' assessment was 4.77 and 4.58 on a 5-grade percentage improvement scale. The patients' self assessment rating was 4.76 and 4.67 on a 5-grade scale at 1- and 3-month follow up, respectively. The improvement rate of relative MI (MI in the lesion minus that of the normal area) was 77.60 +/- 36.27% and 76.93 +/- 20.95% at 1-and 3 month follow-up. Histology showed vacuolar formation by both lasers in the epidermis that were different sizes between lasers. Electron microscopy showed destruction of melanosomes with surrounding tissue damage with the QS laser and without particular damage with the picosecond laser. CONCLUSIONS: To the best of our knowledge, this is the first study using a picosecond Nd:YAG laser 532-nm for removing solar lentigines in darker skin types that includes histological evaluation. Although there are many options to treat solar lentigines, our results suggest that picosecond laser with preferable endpoint determination can be a safer and more effective treatment over conventional treatments in Asian patients. Lasers Surg. Med. 50:851-858, 2018. (c) 2018 Wiley Periodicals, Inc. PMID- 29608216 TI - Comparisons of the topographic characteristics and electrical charge distributions among Babesia-infected erythrocytes and extraerythrocytic merozoites using AFM. AB - Tick-borne Babesia parasites are responsible for costly diseases worldwide. Improved control and prevention tools are urgently needed, but development of such tools is limited by numerous gaps in knowledge of the parasite-host relationships. We hereby used atomic force microscopy (AFM) and frequency modulated Kelvin probe potential microscopy (FM-KPFM) techniques to compare size, texture, roughness and surface potential of normal and infected Babesia bovis, B. bigemina and B. caballi erythrocytes to better understand the physical properties of these parasites. In addition, AFM and FM-KPFM allowed a detailed view of extraerythrocytic merozoites revealing shape, topography and surface potential of paired and single parasites. B. bovis-infected erythrocytes display distinct surface texture and overall roughness compared to noninfected erythrocytes. Interestingly, B. caballi-infected erythrocytes do not display the surface ridges typical in B. bovis parasites. Observations of extraerythrocytic B. bovis, B. bigemina and B. caballi merozoites using AFM revealed differences in size and shape between these three parasites. Finally, similar to what was previously observed for Plasmodium-infected erythrocytes, FM-KPFM images reveal an unequal electric charge distribution, with higher surface potential above the erythrocyte regions that are likely associated with Babesia parasites than over its remainder regions. In addition, the surface potential of paired extraerythrocytic B. bovis Mo7 merozoites revealed an asymmetric potential distribution. These observations may be important to better understand the unique cytoadhesive properties of B. bovis-infected erythrocytes, and to speculate on the role of differences in the distribution of surface charges in the biology of the parasites. PMID- 29608217 TI - Recovering missing mesothelioma deaths in death certificates using hospital records. AB - BACKGROUND: In Brazil, underreporting of mesothelioma and cancer of the pleura (MCP) is suspected to be high. Records from death certificates (SIM) and hospital registers (SIH-SUS) can be combined to recover missing data but only anonymous databases are available. This study shows how common data can be used for linkage and as an assessment of accuracy. METHODS: Mesothelioma (all sites, ICD-10 codes C45.0-C45.9) and cancer of the pleura (C38.4) were retrieved from both information systems and combined using a linkage algorithm. Accuracy was examined with non-anonymous databases, limited to the state of Sao Paulo. RESULTS: We found 775 cases in death certificates and 283 in hospital registers. The linkage matched 57 cases, all accurately paired. Three cases, 0.4% in SIM and 1.3% in SIH SUS, could not be matched because of data inconsistencies. CONCLUSIONS: A computer linkage can recover MCP cases from hospital records not found in death certificates in Brazil. PMID- 29608218 TI - Mental health visits and low socio-economic status in adolescence are associated with complications of Type 1 diabetes in early adulthood: a population-based cohort study. AB - AIM: To determine the association of mental health visits and socio-economic status in late adolescence with the risk of mortality and acute and chronic diabetes complications in early adulthood. METHODS: We conducted a population based cohort study of individuals in Ontario, Canada, who had their 20th birthday between January 1999 and March 2015 and a diagnosis of diabetes prior to their 15th birthday, using linked administrative databases (n=8491). The main outcome was death; other outcomes were hypoglycaemia or hyperglycaemia-related hospitalizations and emergency department visits and chronic diabetes complications (dialysis, ophthalmological and macrovascular complications). RESULTS: Over the course of 59 361 person-years there were 127 deaths.. Low socio economic status and mental health visits were both associated with a higher risk of death [hazard ratio 2.03, (95% CI 1.13 to 3.64) and 2.45 (95% CI 1.71 to 3.51), respectively]. Those with the lowest socio-economic status and a mental health visit had a higher rate of diabetes-related hospitalizations (rate ratio 4.84, 95% CI 3.64 to 6.44) and emergency department visits (rate ratio 3.15, 95% CI 1.79 to 5.54). Low socio-economic status and mental health visits were both associated with an increased risk of any chronic complication [hazard ratio 1.54 (95% CI 1.21 to 1.96) and 1.57 (95% CI 1.35 to 1.81), respectively]. CONCLUSION: We identified significant socio-economic and mental health disparities in the risk of death and acute and chronic complications in early adulthood for people with childhood-onset diabetes. Targeted interventions to prevent adverse events for these adolescents at highest risk should be evaluated. PMID- 29608219 TI - Archaeal and eukaryal translation initiation factor 1 differ in their RNA interacting loops. AB - The archaeal translation initiation factor 1 (aIF1) is reported to be functionally homologous to the eukaryotic translation initiation factor 1 (eIF1). However, lack of a structural comparison between aIF1 and eIF1 has limited our understanding of the structural (dis)similarities. Herein, we have determined the three-dimensional crystal structure of an open reading frame PH1771.1 encoding aIF1 in Pyrococcus horikoshii OT3. Results reveal that although aIF1 has low sequence similarity with eIF1, high structural homology exists between the two proteins. Nonetheless, notable critical differences between aIF1 and eIF1 could still be perceived at the beta1 -beta2 basic loop, the acidic loop and the solvent-exposed surface. These differences might lead to a slightly divergent mode of action of aIF1 during archaeal translation initiation. PMID- 29608220 TI - Nanoecotoxicity assessment of graphene oxide and its relationship with humic acid. AB - The risk assessment of nanomaterials is essential for regulatory purposes and for sustainable nanotechnological development. Although the application of graphene oxide has been widely exploited, its environmental risk is not well understood because several environmental conditions can affect its behavior and toxicity. In the present study, the graphene oxide effect from aquatic ecosystems was assessed considering the interaction with humic acid on 9 organisms: Raphidocelis subcapitata (green algae), Lemna minor (aquatic plant), Lactuca sativa (lettuce), Daphnia magna (planktonic microcrustacean), Artemia salina (brine shrimp), Chironomus sancticaroli (Chironomidae), Hydra attenuata (freshwater polyp), and Caenorhabditis elegans and Panagrolaimus sp. (nematodes). The no-observed-effect concentration (NOEC) was calculated for each organism. The different criteria used to calculate NOEC values were transformed and plotted as a log-logistic function. The hypothetical 5 to 50% hazardous concentration values were, respectively, 0.023 (0.005-0.056) and 0.10 (0.031-0.31) mg L-1 for graphene oxide with and without humic acid, respectively. The safest scenario associated with the predicted no-effect concentration values for graphene oxide in the aquatic compartment were estimated as 20 to 100 MUg L-1 (in the absence of humic acid) and 5 to 23 MUg L-1 (in the presence of humic acid). Finally, the present approach contributed to the risk assessment of graphene oxide-based nanomaterials and the establishment of nano-regulations. Environ Toxicol Chem 2018;37:1998 2012. (c) 2018 SETAC. PMID- 29608221 TI - Maternal vitamin D and markers of glycaemia during pregnancy in the Belfast centre of the Hyperglycaemia and Adverse Pregnancy Outcome study. AB - AIMS: To measure total 25-hydroxyvitamin D levels in women in mid-pregnancy who participated in the Belfast centre of the Hyperglycaemia and Adverse Pregnancy Outcome (HAPO) observational study, and to investigate the associations between levels of 25-hydroxyvitamin D and markers of gestational diabetes mellitus and lipid biomarkers. METHODS: A total of 1585 pregnant women had serum samples available for measurement. Participants were recruited from the Royal Jubilee Maternity Hospital, Belfast, Northern Ireland, at 24-32 weeks' gestation, as part of the HAPO study. 25-hydroxyvitamin D concentrations were measured using liquid chromatography tandem mass spectrometry. Glucose, C-peptide and lipid levels were previously analysed in a central laboratory. Statistical analysis was performed. RESULTS: The median (interquartile range) 25-hydroxyvitamin D concentration during pregnancy was 38.6 (24.1-60.7) nmol/l, with 65.8% of women being vitamin D deficient (<=50 nmol/l). In regression analysis, the association between maternal 25-hydroxyvitamin D and fasting plasma glucose levels approached significance [regression coefficient -0.017 (95% CI -0.034 to 0.001); P=0.06], and a significant positive association was observed between maternal 25-hydroxyvitamin D and beta-cell function [1.013 (95% CI 1.001 to 1.024); P=0.031]. Maternal 25 hydroxyvitamin D level was positively associated with HDL [0.047 (95% CI 0.021 to 0.073) P<= 0.001] and total cholesterol [0.085 (95% CI 0.002 to 0.167); P=0.044] in regression analysis. CONCLUSIONS: These results indicate a high prevalence of vitamin D deficiency during pregnancy, which requires identification and treatment; however, only weak associations were observed between 25 hydroxyvitamin D level and markers of glucose and insulin metabolism. This would suggest that these are of doubtful clinical significance. PMID- 29608222 TI - Theoretical study on the reaction mechanisms of Michael chirality addition between propionaldehyde and nitroalkene catalyzed by an enantioselective catalyst. AB - The asymmetric Michael addition between propionaldehyde and nitroalkene catalyzed by 8-(ethoxycarbonyl)-1,2,3,3a,8,8a-hexahydropyrrolo[2,3-b]indole-2-carboxylic acid has obtained relatively high yields and excellent enantioselectivities at room temperature. In this study, the molecular structures and optical activity of the most stable conformation I are optimized at B3LYP/6-311++ G(d,p) level. We find that levorotatory conformation I catalyzing the same Michael addition can produce laevo-product A and dextrorotatory conformation I' can obtain the dextral product A'. These results have guiding significance for further studying on the new chemzymes and the mechanism of the obtained different chiral products. PMID- 29608223 TI - The effect of an active shooter response intervention on hospital employees' response knowledge, perceived program usefulness, and perceived organizational preparedness. AB - Active shooter events occur frequently across the United States in a variety of locations, including health care facilities. Hospital health care worker response to an active shooter event may mean the difference in life or death for self or others. There is little research on how hospitals prepare nonmanagers to respond to active shooter events. We conducted a study to explore differences in knowledge, perceived organizational preparedness, and program utility following participation in an active shooter response program. Self-efficacy, personal characteristics, and professional characteristics were also explored. Program evaluation was conducted via a one-group pretest/posttest design. There was a significant increase in knowledge and perceived organizational preparedness postintervention. Trait-level self-efficacy did not have a significant effect on retained knowledge and perceived organizational preparedness. The current study is the first known to evaluate the efficacy of an active shooter response program for nonmanagers within an inpatient health care facility. Findings from this study may inform risk managers on how to educate employees on what to expect and how to react should an active shooter event occur. PMID- 29608224 TI - Is it safe to stop oral anticoagulation after catheter ablation of atrial fibrillation? PMID- 29608225 TI - Prediction of ventricular tachyarrhythmia in Brugada syndrome by right ventricular outflow tract conduction delay signs. AB - BACKGROUND: Brugada syndrome (BrS) is an autosomal dominant disease responsible for sudden cardiac death in young individuals without structural anomalies. The most critical part in the management of this channelopathy is identification of high-risk patients, especially asymptomatic subjects. Prior studies have shown that conduction delay in the right ventricular outflow tract (RVOT) is the main mechanism for developing ventricular tachyarrhythmia (VTA) in BrS patients. The aim of this study was to investigate the significance of electrocardiographic RVOT conduction delay parameters as predictors for development of VTA in patients with BrS. METHODS AND RESULTS: We retrospectively analyzed electrocardiograms obtained from 147 BrS patients (43 +/- 15 years, 65% men) and assessed the following electrocardiographic parameters: (1) Tzou criteria (V1R > 0.15 mV, V6S > 0.15 mV, and V6S:R > 0.2), (2) prominent S wave in lead I, lead II, and lead III, (3) SII > SIII, and (4) prominent Q wave in lead III as possible predictors of VTA occurrences during follow-up. Prominent SI, SII, SIII, SII > SIII, QIII, and +ve Tzou criteria occurred more frequently in patients who either presented with VTA or developed VTA during the follow-up of 56 (IQR: 40-76) months. SII > SIII has the highest area under the curve for prediction of VTA (AUC: 0.84, sensitivity: 80%, specificity: 89%). Multivariable regression analysis showed that prominent S waves in lead I, SII > SIII and +ve Tzou criteria are independent predictors for VTA in BrS patients. CONCLUSION: Prominent S in lead I, SII > SIII and +ve Tzou criteria can be used as effective signs for predicting VTA in patients with BrS. PMID- 29608226 TI - Clinical implications of food allergen thresholds. AB - Food allergy has increased in recent decades and has a major impact on patients' quality of life. There is currently no treatment in routine clinical practice, and patients are often faced with accidental reactions. Precautionary allergen labelling (PAL) has been used by the food industry to attempt to minimize this risk, although not standardized and often ambiguous. Estimating the risk of reacting to traces in foods is complicated by heterogeneous amounts of allergens in foods with precautionary labelling and individual variability in reaction thresholds. In recent years, oral food challenge studies have shown that low individual reaction thresholds do not necessarily correlate with severe reactions, and current understanding of thresholds is evolving with novel low dose challenge protocols better adapted to estimate them. Future tools to provide a better estimation of minimal eliciting doses, including basophil activation tests, may improve our management of food-allergic patients. PMID- 29608228 TI - Old Docs, New Clicks: The ConCert Examination and the Aging Emergency Physician. PMID- 29608227 TI - Estimating Long-Term Vagus Nerve Stimulation Effectiveness: Accounting for Antiepileptic Drug Treatment Changes. AB - OBJECTIVE: To investigate the effectiveness of vagus nerve stimulation (VNS) in combination with pharmacological therapy in a longitudinal retrospective study at a single center. MATERIALS AND METHODS: Data from 130 consecutive patients implanted with a VNS device between the years 2000 and 2013 was analyzed. Seizure frequency and pharmacological antiepileptic drug (AED) treatments were recorded prior to as well as at one, two, and five years after VNS implantation. RESULTS: Median age at epilepsy onset was five years and mean years from diagnosis to VNS implantation was 16.5 years. There was a significant seizure reduction overall (all p < 0.001). The responder (>=50% seizure frequency reduction) rate increased from 22.1 to 43.8% between the first and fifth year for the cohort as a whole, with the largest increase between the first and second year (22.1-38.1%) and regardless of AED changes. VNS effectiveness did not differ between patients who altered or remained on the same AEDs. Patients were treated with a median of three AEDs throughout the study and the number of AEDs significantly increased after two (p = 0.007) and five (p = 0.001) years. CONCLUSIONS: VNS is a well tolerated palliative neuromodulatory treatment for drug resistant epilepsy with a 43.8% seizure reduction after five years. Our data supports the idea that VNS effectiveness increases with time. Therefore we suggest that VNS should be evaluated for at least two years after implantation. AED changes should try to be kept to a minimum during evaluation in order to determine the effectiveness of VNS. PMID- 29608229 TI - Prospective, Randomized, Sham-Control, Double Blind, Crossover Trial of Subthreshold Spinal Cord Stimulation at Various Kilohertz Frequencies in Subjects Suffering From Failed Back Surgery Syndrome (SCS Frequency Study). AB - INTRODUCTION: The increasing use of high frequency paresthesia-free spinal cord stimulation has been associated with improved outcomes in the therapy of neuropathic pain. What is unknown is the effect of varying frequency on pain relief and the placebo effect. MATERIALS AND METHODS: This is a prospective, randomized, sham-controlled double blind crossover study. Subjects with predominantly axial low back pain undergoing spinal cord stimulation therapy for failed back surgery syndrome were randomized to sham, 1200 Hz, 3030 Hz, and 5882 Hz with a four-phase crossover design over 12 weeks. RESULTS: Twenty-four patients were randomized in the study. The mean low back pain score at baseline was 7.75. The mean low back pain scores on a 10 cm visual analog scale during the randomized crossover phase were 4.83, 4.51, 4.57, and 3.22, for sham, 1200 Hz, 3030 Hz, and 5882 Hz, respectively, with the lowest low back pain score observed in the 5882 Hz frequency group (p = 0.002). Of note, sham stimulation resulted in a reduction of pain by -2.92 cm and was not significantly different from stimulation at 1200 Hz and 3030 Hz. CONCLUSIONS: This randomized crossover study demonstrated that 5882 Hz stimulation can produce significant pain relief for axial low back pain compared with lower frequencies and sham stimulation. Sham stimulation produced similar analgesic effects to 1200 Hz and 3030 Hz and this effect may influence future neuromodulation clinical trial designs. PMID- 29608230 TI - Comparisons of self and proxy report on health-related factors in people with intellectual disability. AB - BACKGROUND: The intellectual disability field has learned about the lives of people with intellectual disabilities (ID), largely from the perspective of their family and caregivers. Information from caregivers has been critical to scientific advancement, especially when caregivers are engaged on behalf of individuals with significant language impairment. On the other hand, the perspective of individuals with ID themselves is critical for internal subjective content such as thoughts and feelings. METHODS: Participants were 90 adults with ID and a proxy of their choosing. RESULTS: Overall, self and caregiver report were significantly related for subjective health but varied for physical activity, social support and stress. CONCLUSIONS: These findings add to the growing literature establishing the importance of considering the self-report of adults with ID, particularity when the subject matter focuses on internal thoughts or feelings. Clinical considerations for the use of self and proxy report are discussed. PMID- 29608231 TI - Is home-based HIV testing universally acceptable? Findings from a case-control study nested within the HPTN 071 (PopART) trial. AB - OBJECTIVE: The HPTN 071 (PopART) trial is examining the impact of a package including universal testing and treatment on community-level HIV incidence in Zambia and South Africa. We conducted a nested case-control study to examine factors associated with acceptance of home-based HIV testing and counselling (HB HTC) delivered by community HIV-care providers (CHiPs) in PopART intervention communities. METHODS: Of 295 447 individuals who were offered testing, random samples of individuals who declined HB-HTC (cases) and accepted HB-HTC (controls), stratified by gender and community, were selected. Odds ratios comparing cases and controls were estimated using multivariable logistic regression. RESULTS: Data from 642 participants (313 cases, 329 controls) were analysed. There were no differences between cases and controls by demographic or behavioural characteristics including age, marital or socio-economic position. Participants who felt they could be open with CHiPs (AOR: 0.46, 95% CI: 0.30 0.71, P < 0.001); self-reported as not previously tested (AOR: 0.64; 95% CI: 0.43 0.95, P = 0.03); considered HTC at home to be convenient (AOR: 0.38, 95% CI: 0.27 0.54, P = 0.001); knowing others who had accepted HB-HTC from the CHiPs (AOR: 0.49, 95% CI: 0.31-0.77, P = 0.002); or were motivated to get treatment without delay (AOR: 0.60, 95% CI: 0.43-0.85, P = 0.004) were less likely to decline the offer of HB-HCT. Those who self-reported high-risk sexual behaviour were also less likely to decline HB-HCT (AOR: 0.61, 95% CI: 0.39-0.93, P = 0.02). Having stigmatising attitudes about HB-HTC was not an important barrier to HB-HCT uptake. Men who reported fear of HIV were more likely to decline HB-HCT (AOR: 2.68, 95% CI: 1.33-5.38, P = 0.005). CONCLUSION: Acceptance of HB-HTC was associated with lack of previous HIV testing, positive attitudes about HIV services/treatment and perception of high sexual risk. Uptake of HB-HCT among those offered it was similar across a range of demographic and behavioural subgroups suggesting it was 'universally' acceptable. PMID- 29608233 TI - Introduction to the Specific Aims Page of a Grant Proposal. AB - Grant writing starts with crafting an effective specific aims page. This page should be a succinct combination of sales pitch and science. The specific aims page demonstrates a problem and a gap in current knowledge and suggests a solution. It proposes aims that work toward a defended solution and reveal the impact of the proposal on the problem, the field, and future research. The language must be efficient and persuasive; the presentation must drive a reviewer to support the proposal. Here we present a recipe for an effective specific aims page. PMID- 29608234 TI - Corrigendum. PMID- 29608232 TI - Cytokine-induced interleukin-1 receptor antagonist protein expression in genetically engineered equine mesenchymal stem cells for osteoarthritis treatment. AB - BACKGROUND: A combination of tissue engineering methods employing mesenchymal stem cells (MSCs) together with gene transfer takes advantage of innovative strategies and highlights a new approach for targeting osteoarthritis (OA) and other cartilage defects. Furthermore, the development of systems allowing tunable transgene expression as regulated by natural disease-induced substances is highly desirable. METHODS: Bone marrow-derived equine MSCs were transduced with a lentiviral vector expressing interleukin-1 receptor antagonist (IL-1Ra) gene under the control of an inducible nuclear factor-kappa B-responsive promoter and IL-1Ra production upon pro-inflammatory cytokine stimulation [tumor necrosis factor (TNF)alpha, interleukin (IL)-1beta] was analysed. To assess the biological activity of the IL-1Ra protein that was produced and the therapeutic effect of IL 1Ra-expressing MSCs (MSC/IL-1Ra), cytokine-based two- and three-dimensional in vitro models of osteoarthritis using equine chondrocytes were established and quantitative real-time polymerase chain reaction (PCR) analysis was used to measure the gene expression of aggrecan, collagen IIA1, interleukin-1beta, interleukin-6, interleukin-8, matrix metalloproteinase-1 and matrix metalloproteinase-13. RESULTS: A dose-dependent increase in IL-1Ra expression was found in MSC/IL-1Ra cells upon TNFalpha administration, whereas stimulation using IL-1beta did not lead to IL-1Ra production above the basal level observed in nonstimulated cells as a result of the existing feedback loop. Repeated cycles of induction allowed on/off modulation of transgene expression. In vitro analyses revealed that IL-1Ra protein present in the conditioned medium from MSC/IL-1Ra cells blocks OA onset in cytokine-treated equine chondrocytes and co-cultivation of MSC/IL-1Ra cells with osteoarthritic spheroids alleviates the severity of the osteoarthritic changes. CONCLUSIONS: Thus, pro-inflammatory cytokine induced IL 1Ra protein expression from genetically modified MSCs might represent a promising strategy for osteoarthritis treatment. PMID- 29608235 TI - An electrocardiographic diagnostic model for differentiating left from right ventricular outflow tract tachycardia origin. AB - INTRODUCTION: Although several electrocardiographic (ECG) algorithms have been proposed for differentiating the origins of outflow tract ventricular arrhythmias, the most optimal one has not been agreed on. The purpose of this study was to establish an ECG diagnostic model based on the previous ECG algorithms. METHODS AND RESULTS: The following ECG diagnostic model, Y=-1.15*( TZ )-0.494*(V2S/V3R), was developed by standard 12-lead ECG algorithms in 488 patients with idiopathic premature ventricular contractions or ventricular tachycardia with a left bundle branch block pattern and inferior axis QRS morphology. Binary logistic regression analysis was performed to establish the ECG diagnostic model. The ECG diagnostic model consisted of two ECG algorithms the transition zone (TZ) index and V2S/V3R index. The area under the curve by receiver operating characteristic curve analysis for the ECG diagnostic model was 0.88, with a cut-off value of >= -0.76 predicting a left ventricular outflow tract (LVOT) origin with a sensitivity of 82% and a specificity of 86%, which was higher than other ECG algorithms in this study. The predictive accuracy of the ECG diagnostic model was also the best among all ECG algorithms in patients with a lead V3 precordial transition. This model was tested prospectively in 207 patients with a sensitivity of 90%, a specificity of 87%, and Youden index of 0.77. CONCLUSIONS: A highly accurate ECG diagnostic model for correctly differentiating LVOT origin from right ventricular outflow tract origin was developed. PMID- 29608236 TI - An exploration of the participation of people with intellectual disabilities in research-a structured interview survey. AB - BACKGROUND: Even though participation of people with intellectual disabilities in research is increasingly common, there is little insight into how many people with intellectual disabilities participate, their motivations to participate and their interests regarding study results. METHOD: Five questions were added to the Panel Living Together (PLT) survey among 508 people with intellectual disabilities. The questions aimed to gain insight into the (i) frequency of participation; (ii) methods used to participate; (iii) motivations to participate; and (iv) interests regarding study results. RESULTS: Although 73.5% (n = 347) of the respondents enjoyed their participation and 71.6% (n = 312) found it important to participate, only 11.8% (n = 60) participated in research other than PLT. Of the respondents, 61% (n = 261) indicated they wanted to be informed about study results, 29.1% (n = 148) of this group stated they wanted to compare, learn and share information. CONCLUSIONS: Future research should focus on how motivations of people with intellectual disabilities to participate in inclusive research, such as "empowerment," can be supported to facilitate their involvement in research. PMID- 29608237 TI - Designer nuclease-mediated gene correction via homology-directed repair in an in vitro model of canine hemophilia B. AB - BACKGROUND: Gene correction at specific target loci provides a powerful strategy for overcoming genetic diseases. In the present study, we aimed to use an in vitro model for canine hemophilia B containing a single point mutation in the catalytic domain of the canine coagulation factor IX (cFIX) gene. To correct the defective gene via homology-directed repair (HDR), we designed transcription activator like effector nucleases and clustered regularly interspaced short palindromic repeats including Cas9 (CRISPR/Cas9) for introduction of double strand breaks at the mutation site. METHODS: To generate a stable cell line containing the mutated cFIX locus, a 2-kb genomic DNA fragment derived from a hemophilia B dog was amplified and integrated utilizing the phiC31 integrase system. Designer nucleases were assembled and cloned into vectors for constitutive and inducible expression. To detect mutations, insertions and deletions, and HDR events after nuclease treatment T7E1 assays, an amplification refractory mutation system-quantitative polymerase chain reaction and pyrosequencing were performed. RESULTS: To perform HDR correction experiments, we established a cell line carrying the mutated cFIX locus. In HDR approaches we either explored a wild-type or an optimized cFIX sequence and we found that our modified HDR cassette showed higher gene correction efficiencies of up to 6.4%. Furthermore, we compared inducible and constitutive designer nuclease expression systems and found that the inducible system resulted in comparable HDR efficiencies. CONCLUSIONS: In conclusion, the present study demonstrates the potential of this strategy for gene therapeutic approaches in vitro and in a canine model for hemophilia B. PMID- 29608239 TI - Current Resources for Evidence-Based Practice, May/June 2018. PMID- 29608238 TI - Tabata protocol: a review of its application, variations and outcomes. AB - PURPOSE: The great popularity of the Tabata Protocol is accompanied by an uncomfortable lack of consistency and criteria in its use, which results in many controversies in the results obtained from its utilization. The purpose of this study was to analyse the studies that based their interventions on the Tabata Protocol and to provide a critical analysis of its use. METHODS: A systematic literature search was conducted in PubMed and Scopus. All articles published between 1996 and October 2017 that cited at least one of the original studies of Tabata et al. were considered. Inclusion criteria were as follows: original articles, human trials and English language. RESULTS: Thirty studies were included for analysis. Almost 37% of the studies (n = 11) used a variation of the Tabata Protocol on a cycle ergometer. Only five studies stated the use of the original Tabata Protocol. Exercise intensity was controlled by percentage of i CONCLUSION: Based on our results, variations of the Tabata Protocol seem to be indicated to provide increases in aerobic power that are similar to traditional aerobic training while being less time consuming. These adaptations seem to be mainly due to peripheral adaptations. Moreover, the use of Tabata Protocols to promote weight loss is not substantiated by the reviewed studies. PMID- 29608240 TI - Analysis of trace-level nitrated polycyclic aromatic hydrocarbons in water samples by solid-phase microextraction with gas chromatography and mass spectrometry. AB - A solid-phase microextraction coupled with gas chromatography and mass spectrometry method has been developed for the determination of ten nitrated polycyclic aromatic hydrocarbons in water samples. Five different kinds of commerical fibers were used to compare the extraction efficiency, including 65 MUm polydimethylsiloxane/divinylbenzene, 100 MUm polydimethylsiloxane, 30 MUm polydimethylsiloxane, 7 MUm polydimethylsiloxane, and 85 MUm polyacrylate fibers. Five factors were also selected to optimize conditions, including extraction temperature, time, stirring speed, salt concentration, and headspace volume. Taguchi design was applied to design the experiments and obtain the best parameters. The results show that 65 MUm polydimethylsiloxane/divinylbenzene fiber directly immersed into aqueous solution for 35 min at 55 degrees C with a constant stirring rate of 1150 rpm were the optimal conditions. Under these conditions, the limits of quantification were 0.007-0.063 MUg/L, and the relative standard deviation based on six replicates ranged from 2.8 to 9.5%. The spiked recoveries ranged from 69.1 to 110.1%. Intra- and inter day relative standard deviations at three concentration levels were less than 12%, and the recoveries were 66.4-111.5%. The proposed method is reliable for analyzing nitrated polycyclic aromatic hydrocarbons in different water samples. PMID- 29608241 TI - An analysis of the effect of statins on the risk of Non-Hodgkin's Lymphoma in the Women's Health Initiative cohort. AB - Statins have been shown to induce a phosphoprotein signature that modifies MYC (myelocytomatosis viral oncogene) activation and to have anti-inflammatory activity that may impact the risk of Non-Hodgkin's lymphoma (NHL). We analyzed the relationship between statins and risk of NHL using data from the Women's Health Initiative (WHI). The study population included 161,563 postmenopausal women ages 50-79 years from which 712 cases of NHL were diagnosed after 10.8 years of follow-up. Information on statin use and other risk factors was collected by self- and interviewer-administered questionnaires. Multivariable adjusted HR and 95% CI evaluating the relationship between statin use at baseline, as well as in a time-dependent manner and risk of NHL, were computed from Cox proportional hazards analyses. A separate analysis was performed for individual NHL subtypes: diffuse large B-Cell lymphoma (DLBCL) (n = 228), follicular lymphoma (n = 169), and small lymphocytic lymphoma (n = 74). All statistical tests were two-sided. There was no significant association between use of statins at baseline and risk of NHL (HR 0.85, 95% C.I. 0.67-1.08). However, in the multivariable-adjusted time-dependent models, statin use was associated with a borderline lower risk of NHL (HR 0.81, 95% C.I. 0.66-1.00). Considering subtypes of NHL, statin use was associated with a lower risk of DLBCL (HR 0.62, 95% C.I. 0.42-0.91). This effect was driven by lipophilic statins (HR 0.62, 95% C.I. 0.40-0.96). In the WHI, statins were associated with a lower overall risk of DLBCL, particularly attributable to lipophilic statins. These results may have impact on primary or secondary prevention of NHL, particularly DLBCL. PMID- 29608242 TI - Autophagy is induced by resistance exercise in young men, but unfolded protein response is induced regardless of age. AB - AIM: Autophagy and unfolded protein response (UPR) appear to be important for skeletal muscle homoeostasis and may be altered by exercise. Our aim was to investigate the effects of resistance exercise and training on indicators of UPR and autophagy in healthy untrained young men (n = 12, 27 +/- 4 years) and older men (n = 8, 61 +/- 6 years) as well as in resistance-trained individuals (n = 15, 25 +/- 5 years). METHODS: Indicators of autophagy and UPR were investigated from the muscle biopsies after a single resistance exercise bout and after 21 weeks of resistance training. RESULTS: Lipidated LC3II as an indicator of autophagosome content increased at 48 hours post-resistance exercise (P < .05) and after a resistance training period (P < .01) in untrained young men but not in older men. Several UPRER markers, typically induced by protein misfolding in endoplasmic reticulum, were increased at 48 hours post-resistance exercise in untrained young and older men (P < .05) but were unaltered after the 21-week resistance training period regardless of age. UPR was unchanged within the first few hours after the resistance exercise bout regardless of the training status. Changes in autophagy and UPRER indicators did not correlate with a resistance training-induced increase in muscle strength and size. CONCLUSION: Autophagosome content is increased by resistance training in young previously untrained men, but this response may be blunted by ageing. However, unfolded protein response is induced by an unaccustomed resistance exercise bout in a delayed manner regardless of age. PMID- 29608243 TI - Impact of bacterial translocation in calves with atresia coli. AB - OBJECTIVE: To identify whether enteric bacteria pass into the mesenteric lymph nodes (MLNs) and peritoneal cavity in calves with atresia coli and to evaluate whether the presence of bacterial translocation (BT) has an impact on the success of surgical treatment. DESIGN: Prospective clinical study. ANIMALS: Twenty-six client-owned calves. INTERVENTIONS: During laparotomy, swab samples were collected from the peritoneal cavity and MLNs using a sterile swab stick and were submitted for microbiological analysis. MEASUREMENTS AND MAIN RESULTS: Bacterial cultures of swab samples revealed that 65% (n = 17) of the calves experienced BT. Of these, 14 calves experienced BT to the MLNs, 9 to the peritoneal cavity, and 5 to both regions. Of the bacteria isolated from the MLNs, 72% (n = 10) were Escherichia coli. Of the samples isolated from the peritoneal fluid, 33% (n = 3) contained E. coli and 33% (n = 3) contained E. coli + coagulase-negative Staphylococcus (CNS). In calves with BT that were discharged (n = 13) and without BT that were discharged (n = 7), the median survival was 30 days; these data were found to be similar in the 2 groups. CONCLUSIONS: This study revealed that BT is observed in the majority of atresia coli cases. E. coli is more common in BT, and translocation occurs primarily through the lymphatic route. These results suggest that the presence of BT is closely related to the success of the operation for correction of atresia coli. PMID- 29608245 TI - Case Studies of Interprofessional Education Initiatives From Five Countries. AB - BACKGROUND: Although teamwork and interprofessional collaboration are critical to patient safety, nursing, medical, and allied health graduates often feel ill prepared to confidently communicate and collaborate with other team members. While interprofessional education (IPE) has been advocated as a way of addressing this issue, there are multiple barriers to its systematic and sustained integration in undergraduate healthcare programs. Despite these challenges, examples of effective IPE initiatives have emerged. INNOVATION: This article profiles seven case studies of innovative interprofessional education activities that have been successfully implemented across five countries, for a variety of learners, using different delivery modalities, and with evaluation results attesting to their success. CONCLUSIONS: The case studies demonstrate innovative ideas that have the potential to overcome some of the barriers to IPE through the use of creative and targeted approaches. This article provides a wealth of ideas for the successful design and implementation of IPE initiatives and will be of benefit to educators wishing to expand their repertoire of teaching approaches. CLINICAL RELEVANCE: A body of research attests to the relationship between interprofessional communication, teamwork, and patient outcomes. IPE is imperative for facilitating the development of nursing graduates' communication and teamwork skills; however, innovative approaches are needed to overcome the perceived and actual impediments to its implementation. PMID- 29608244 TI - microRNA-181a inhibits ocular neovascularization by interfering with vascular endothelial growth factor expression. AB - AIM: Excess angiogenesis or neovascularization plays a key role in the pathophysiology of several ocular diseases such as retinopathy of prematurity, diabetic retinopathy, and exudative age-related macular degeneration. microRNA 181a (miR-181a) was found highly expressed in retina and choroidal tissues. This study intends to investigate the role of miR-181a in the regulation of ocular neovascularization in different pathophysiological conditions. METHOD: We performed the RNA sequence to identify the microRNAs components of anti angiogenic lymphocyte-derived microparticles (LMPs). The effect of miR-181a on human retinal endothelial cells proliferation was assessed in vitro. The impact of miR-181a on angiogenesis was confirmed using in vitro angiogenesis assay, ex vivo choroidal explant, and in vivo retinal neovascularization. The expression of major angiogenic factors was assessed by real-time qPCR. RESULTS: RNA sequence revealed that miR-181a is selectively enriched in LMPs. Importantly, the inhibition of miR-181a significantly abrogated the effect of LMPs on endothelial viability, but overexpression of miR-181a reduced endothelial cell viability in a dose-dependent manner. miR-181a strongly inhibited in vitro angiogenesis and ex vivo choroidal neovascularization. The strong anti-angiogenic effect of miR-181a was also displayed on the retinal neovascularization of the in vivo mouse model of oxygen-induced retinopathy. In keeping with its effect, several angiogenesis related genes were dysregulated in the miR-181a overexpressed endothelial cells. CONCLUSION: These data may open unexpected avenues for the development of miR 181a as a novel therapeutic strategy that would be particularly useful and relevant for the treatment of neovascular diseases. PMID- 29608246 TI - The Global Landscape of Nursing and Genomics. AB - PURPOSE: Nurses have a pivotal role in bringing the benefits of genomics and precision medicine to everyday health care, but a concerted global effort is needed to transform nursing policy and practice to address widely acknowledged deficits in nurses' genomic literacy. The purpose was to conduct a global country and organization review of nursing engagement with genomics, informing a landscape analysis to assess readiness for integration of genomics into nursing. DESIGN: Global nursing leaders and nursing organizations were recruited using a purposive sampling strategy to complete an online survey that assessed the scope of genomic integration in practice and education, challenges and barriers, and priorities for action. METHODS: The survey was administered online following an orientation webinar. Given the small numbers of nurse leaders globally, results were analyzed and presented descriptively. FINDINGS: Delegates consisted of 23 nurse leaders from across the world. Genomic services were offered predominantly in specialty centers consisting mostly of newborn screening (15/18) and prenatal screening (11/18). Genomic literacy and infrastructure deficits were identified in both practice and education settings, with only one country reporting a genetic/genomic knowledge and skill requirement to practice as a general nurse. CONCLUSIONS: These data provide insights into the commitment to and capacity for nursing to integrate genomics, revealing common themes and challenges associated with adoption of genomic health services and integration into practice, education, and policy. Such insights offer valuable context and baseline information to guide the activities of a new Global Genomics Nursing Alliance (G2NA). The G2NA will use the landscaping exercise as a springboard to explore how to accelerate the integration of genomics into nursing healthcare. CLINICAL RELEVANCE: Genomics is relevant to all healthcare providers across the healthcare continuum. It provides an underpinning for understanding health, risks for and manifestations of disease, therapeutic decisions, development of new therapies, and responses to interventions. Harnessing the benefits of genomics to improve health and care outcomes and reduce costs is a global nursing challenge. PMID- 29608247 TI - Regulation of NCAPG by miR-99a-3p (passenger strand) inhibits cancer cell aggressiveness and is involved in CRPC. AB - Effective treatments for patients with castration-resistant prostate cancer (CRPC) have not yet been established. Novel approaches for identification of putative therapeutic targets for CRPC are needed. Analyses of RNA sequencing of microRNA (miRNA) expression revealed that miR-99a-3p (passenger strand) is significantly downregulated in several types of cancers. Here, we aimed to identify novel miR-99a-3p regulatory networks and therapeutic targets for CRPC. Ectopic expression of miR-99a-3p significantly inhibited cancer cell proliferation, migration, and invasion in PCa cells. Non-SMC condensin I complex subunit G (NCAPG) was a direct target of miR-99a-3p in PCa cells. Overexpression of NCAPG was detected in CRPC clinical specimens and was significantly associated with shorter disease-free survival and advanced clinical stage. Knockdown of NCAPG inhibited cancer cell aggressiveness. The passenger strand miR-99a-3p acted as an antitumor miRNA in naive PCa and CRPC. NCAPG was regulated by miR-99a-3p, and its overexpression was involved in CRPC pathogenesis. Involvement of passenger strand of miRNA in cancer pathogenesis is novel concept, and identification of antitumor miRNA regulatory networks in CRPC might be provided novel prognostic markers and therapeutic targets for this disease. PMID- 29608249 TI - Targeted and non-targeted metabolite identification of MAM-2201 in human, mouse, and rat hepatocytes. AB - MAM-2201 is a fluorinated naphthoylindole synthetic cannabinoid with potent psychoactive properties that has been detected as an active ingredient in herbal incense blends. To gain a greater understanding of MAM-2201 metabolism and to compare its metabolic fate in humans with those in animals, the metabolism of MAM 2201 in human, mouse, and rat hepatocytes was investigated using liquid chromatography-high-resolution mass spectrometry combined with targeted and non targeted metabolite profiling approaches. Nineteen phase I metabolites (M1-M19) reported previously in human liver microsomes and 13 novel metabolites were identified in human, mouse, and rat hepatocytes: 1 phase I metabolite (M20) and 12 phase II metabolites including 6 glucuronides (G1-G6), 1 sulfate (S1), and 5 glutathione (GSH) conjugates (GS1-GS5) of MAM-2201 metabolites. G3 was human specific, but M20, G1, G2, and 5 GSH conjugates were rat-specific, indicating species-related differences in MAM-2201 metabolism. The findings in the present study can be useful for the experimental design and assessment of metabolism mediated toxic risk of MAM-2201. PMID- 29608248 TI - Livestock ownership is associated with higher odds of anaemia among preschool aged children, but not women of reproductive age in Ghana. AB - Livestock ownership may influence anaemia through complex and possibly contradictory mechanisms. In this study, we aimed to determine the association of household livestock ownership with anaemia among women aged 15-49 years and children aged 6-59 months in Ghana and to examine the contribution of animal source foods (ASFs) to consumption patterns as a potential mechanism mediating this association. We analysed data on 4,441 women and 2,735 children from the 2014 Ghana Demographic and Health Survey and 16,772 households from the Ghana Living Standards Survey Round 6. Haemoglobin measurements were used to define anaemia (non-pregnant women: <120 g/L; children: <110 g/L). Child- and household level ASF consumption data were collected from 24-hour food group intake and food consumption and expenditure surveys, respectively. In multiple logistic regression models, household livestock ownership was associated with anaemia among children (OR, 95% CI: 1.5 [1.1, 2.0]), but not women (1.0 [0.83, 1.2]). Household ownership of chickens was associated with higher odds of anaemia among children (1.6 [1.2, 2.2]), but ownership of other animal species was not associated with anaemia among women or children. In path analyses, we observed no evidence of mediation of the association of household livestock ownership with child anaemia by ASF consumption. Ownership of livestock likely has limited importance for consumption of ASFs among young children in Ghana and may in fact place children at an increased risk of anaemia. Further research is needed to elucidate if and how pathogen exposure associated with livestock rearing may underlie this increased risk of anaemia. PMID- 29608250 TI - Formative research to explore the acceptability and use of infant food grinders for the promotion of animal source foods and micronutrient powders in rural Peru. AB - According to global recommendations, quality diets for complementary feeding (CF) should include a diversity of foods including vitamin A-rich fruits and vegetables and sources of high-quality proteins and essential nutrients, particularly animal-source foods (ASF). A key barrier to feeding ASF surrounds beliefs that the preparation of foods of a thicker consistency may cause problems of digestion, "heaviness" or stomach problems, swallowing, and choking. The objective of this study was to explore, through systematic formative research, the acceptability, use, and feasibility of a simple technology, commercial infant food grinders, in two rural Peruvian settings where there is delayed and low consumption of complementary foods of a thick consistency, including ASF. Phase I explored the barriers, constraints, and opportunities related to the provision of foods of a thicker consistency with a focus on ASF. Phase II encompassed household behavioural trials with mothers and infants to assess the acceptability and use of the grinders in the home setting, using key concepts and messages developed from the information obtained during Phase I. The technology was highly acceptable, used by the majority of mothers (87.8%), and led to changes in cultural perceptions, facilitating increased feeding of appropriate textures (thick purees), ASF, and multimicronutrient powders. Energy, protein, and micronutrient intakes were all significantly greater after the household behavioural trials. This simple technology, paired with systematic formative research to appropriately promote its use across cultures, may have a significant effect on improving CF practices globally, particularly for young infants beginning CF at 6 months. PMID- 29608251 TI - Cervical lymph node carcinoma metastasis from unknown primary site: a retrospective analysis of 154 patients. AB - Despite advances in diagnosis and treatment, the existence of cervical lymph node carcinoma of unknown primary site (CCUP) has always been an urgent problem worldwide. There is still no consensus on the optimal management for CCUP. In this retrospective review, we analyze the clinical characteristics of CCUP patients treated at our institution and examine how these characteristics and treatments were associated with survival. Clinicopathologic features, treatments, and survival outcomes of 154 CCUP patients were collected from the hospital records and analyzed. Survival was estimated by Kaplan-Meier methods and compared by the log-rank test. Cox proportional hazards regression analysis was used to assess the factors independently associated with overall survival (OS) and progression-free survival (PFS). Median follow-up period was 26.44 months (range, 0.53-146.53 months). Multivariate analysis showed N stage, pathologic type, and lymph node extranodal extension (ENE) to be independent prognostic factors for OS in CCUP patients, but not PFS. Subgroup analysis of patients who received radiotherapy showed that radiotherapy to the pharyngeal mucosa was associated with better OS (P = 0.045), but not with better PFS. Advanced N stage, nonsquamous cell carcinoma, and lymph node ENE predict poor prognosis in patients with CCUP. In addition, radiotherapy to suspicious mucosa is accompanied by better OS. These study findings should be useful to clinicians when selecting the treatment approach. PMID- 29608252 TI - Updates From the Literature, May/June 2018. PMID- 29608253 TI - The direct and indirect association of cervical microbiota with the risk of cervical intraepithelial neoplasia. AB - Cervical microbiota composition is associated with cervical HPV infection and CIN severity. Previous studies only assessed the total association between cervical microbiota and HPV infections or CINs, and yet no study reported the direct and indirect associations between cervical microbiota and CINs mediated by HPV infection, respectively. The aim of this study was to investigate the direct and indirect associations between microbiotas and CIN severity. Cervical microbiota of 126 women with CIN 1- (normal cytology and CIN 1) and 40 with CIN 2+ (CIN 2 and CIN 3) were analyzed using Illumina sequencing based on the 16S rRNA gene. HPV was detected using a highly sensitive PCR primer set (SPF1/GP6+). Indirect effects of Pseudomonas stutzeri, Bacteroides fragilis, Lactobacillus delbrueckii, Atopobium vaginae, and Streptococcus agalactiae mediated by HPV infection on CIN status were observed. The directions of the direct and the indirect associations between CIN status and Ps. stutzeri were opposite. The directions of the direct and the indirect associations between CIN status and A. vaginae were the same. B. fragilis, L. delbrueckii, and S. agalactiae only had indirect association with CIN status. In summary, our study provided suggestive evidence that some microbial populations could have direct or indirect effects mediated by affecting HPV infection on CIN progression. Besides HPV infection, microbial community composition possibly plays a role in cervical carcinogenesis. PMID- 29608254 TI - Pretreatment subcutaneous adipose tissue predicts the outcomes of patients with head and neck cancer receiving definitive radiation and chemoradiation in Taiwan. AB - We aimed to determine whether body composition assessment before treatment can predict outcomes in patients with head and neck cancer (HNC). All 881 patients with locoregional head and neck cancer treated with curative intent radiotherapy (RT) between 2005 and 2012 were retrospectively investigated. Body composition was analyzed via pre-RT planning computed tomography (CT) images. Subcutaneous adipose tissue (SAT) and skeletal muscle (SM) indices were measured cross sectionally at the level of the third thoracic vertebra. Overall survival (OS), locoregional control (LRC), and distant metastasis-free survival (MFS) were analyzed by body composition index and body mass index (BMI). Survivors were followed up for a median of 4.68 years. The SAT indices in female patients were significantly higher than those in males (P < 0.001). The median SAT and muscle indices were 18.6 and 34.3 cm2 /m2 for women and 6.19 and 51.74 cm2 /m2 for men, respectively. The 5- and 10-year MFS, LRC, and OS rates were 83% and 82.1%, 73.4% and 71.4%, and 66.4 and 57.6%, respectively. Higher pretreatment SAT index was associated with MFS (hazard ratio [HR]: 0.65; P = 0.015), LRC (HR: 0.758; P = 0.047), and OS (HR: 0.604; P < 0.001). Higher pretreatment BMI was associated with MFS (HR: 0.642; P = 0.031) and OS (HR: 0.615; P < 0.001). The pretreatment SM index had no significant effect on MFS, LRC, and OS. Multivariate analysis revealed that T-stage, N-stage, lesion sites, age, and RT treatment days are independent factors associated with OS; T-stage, N-stage, and lesion sites are independent factors associated with MFS; and N-stage, smoking history, and betel quid chewing history are independent factors associated with LRC. A higher CT assessed SAT index predicts superior MSF, LCR, and OS in patients with curative HNC, whereas SM does not predict survival or locoregional control. PMID- 29608255 TI - Twenty-five-year trajectories of insulin resistance and pancreatic beta-cell response and diabetes risk in nonalcoholic fatty liver disease. AB - BACKGROUND & AIMS: Insulin resistance is a risk marker for non-alcoholic fatty liver disease, and a risk factor for liver disease progression. We assessed temporal trajectories of insulin resistance and beta-cell response to serum glucose concentration throughout adulthood and their association with diabetes risk in non-alcoholic fatty liver disease. METHODS: Three thousand and sixty participants from Coronary Artery Risk Development in Young Adults, a prospective bi-racial cohort of adults age 18-30 years at baseline (1985-1986; Y0) who completed up to 5 exams over 25 years and had fasting insulin and glucose measurement were included. At Y25 (2010-2011), non-alcoholic fatty liver disease was assessed by noncontrast computed tomography after exclusion of other liver fat causes. Latent mixture modelling identified 25-year trajectories in homeostatic model assessment insulin resistance and beta-cell response homeostatic model assessment-beta. RESULTS: Three distinct trajectories were identified, separately, for homeostatic model assessment insulin resistance (low stable [47%]; moderate-increasing [42%]; and high-increasing [12%]) and homeostatic model assessment-beta (low-decreasing [16%]; moderate-decreasing [63%]; and high-decreasing [21%]). Y25 non-alcoholic fatty liver disease prevalence was 24.5%. Among non-alcoholic fatty liver disease, high-increasing homeostatic model assessment insulin resistance (referent: low-stable) was associated with greater prevalent (OR 95% CI = 8.0, 2.0-31.9) and incident (OR = 10.5, 2.6-32.8) diabetes after multivariable adjustment including Y0 or Y25 homeostatic model assessment insulin resistance. In contrast, non-alcoholic fatty liver disease participants with low-decreasing homeostatic model assessment-beta (referent: high-decreasing) had the highest odds of prevalent (OR = 14.1, 3.9 50.9) and incident (OR = 10.3, 2.7-39.3) diabetes. CONCLUSION: Trajectories of insulin resistance and beta-cell response during young and middle adulthood are robustly associated with diabetes risk in non-alcoholic fatty liver disease. Thus, how persons with non-alcoholic fatty liver disease develop resistance to insulin provides important information about risk of diabetes in midlife above and beyond degree of insulin resistance at the time of non-alcoholic fatty liver disease assessment. PMID- 29608256 TI - Aging-related prognosis analysis of definitive radiotherapy for very elderly esophageal cancer. AB - Because of the exclusion for the patients more than 75 years (very elderly patients) in many clinical trials of esophageal cancer (EC), there is no consensus on prognosis and treatment for this population. We aim to evaluate the outcomes and aging-related prognostic factors of definitive radiotherapy (RT) for very elderly EC patients. We retrospectively analyzed 149 very elderly EC patients consecutively treated between January 2015 and June 2016 by definitive intensity-modulated radiotherapy (IMRT) with or without chemotherapy. The clinical outcome and toxicities were assessed, and the potential prognostic factors, such as nutritional risk index (NRI) and neutrophil-lymphocyte ratio (NLR), were analyzed statistically. The median follow-up time for survivors was 22.5 months. The 2-year overall survival (OS), local-regional failure-free survival (LRFFS), and distant metastasis-free survival (DMFS) were 51.6%, 54.7%, and 85.2%, respectively. Independent predictors for poorer OS were higher American Joint Committee on Cancer (AJCC) stage, lower NRI, and higher NLR value before RT. Meanwhile, the total dose (cutoff value 60 Gy) of planning gross tumor volume (PGTV) and chemotherapy was also identified as independent prognostic indicator for LRFFS and DMFS, respectively. 72 patients had treatment failure and 58 (80.6%), 6 (8.3%), and 18 (25.0%) patients had experienced local, regional, and distant failure, respectively. Few severe toxicities were observed. The conservative definitive RT with modern technique was effective for very elderly EC patients in short term with low rate and tolerable toxicities. Local residue or recurrence was the most common failure pattern. The aging-related prognostic factors concerned nutrition and immune, such as NRI and NLR before RT, should be considered for use in future clinical practice. PMID- 29608258 TI - Shifting the conversation on outcomes reporting. PMID- 29608262 TI - Dual-Excitation Polyoxometalate-Based Frameworks for One-Pot Light-Driven Hydrogen Evolution and Oxidative Dehydrogenation. AB - Dehydrogenation of the tetrahydroisoquinoline derivatives coupled with hydrogen production is important for hydrogen storage applications. Herein, we formulated a new system that embedded Dawson-type polyoxometalates as efficient photosensitizers into the pores of redox-active coordination polymers for the light-driven photocatalytic oxidative Mannich reaction and hydrogen evolution. In the designed Co-POM polymer, UV light excitation gives the excited state of the Dawson-type polyoxometalate first to oxidize electron donors or substrates; the reduced form (i.e., heteropolyblue) adsorbs visible light to achieve a new excited state, which reduced the cobalt redox sites and facilitates hydrogen evolution reaction. The photosensitizer recovered to the ground state, completing the catalytic cycle. Under the optimized conditions, Co-POM enabled the hydrogen evolution and dehydrogenation of tetrahydroisoquinoline without the presence of any other additives. The high catalytic efficiency and robustness indicated the advantages of the combining functional polyoxometalate-based catalysts and porous characters of the coordination polymers for the development of highly active heterogeneous catalysts. PMID- 29608263 TI - Revisiting of Pd Nanoparticles in Cancer Treatment: All-Round Excellence of Porous Pd Nanoplates in Gene-Thermo Combinational Therapy. AB - Gold nanomaterials are commonly used in biomedical applications owing to their excellent biocompatibility and unique physicochemical and optical properties, whereas Pd nanomaterials are mainly used as catalysts. Here, we re-examined the possible applications of Pd nanomaterials. Reducing agent-assisted excessive galvanic replacement-mediated porous Au nanoplates, porous Pt nanoplates, and porous Pd nanoplate synthesis enabled us to compare the properties and efficiency of nanoplates composed of three metal elements (Au, Pt, and Pd). According to our analytical results, porous Pd nanoplates exhibited exceptional all-round excellence in photothermal conversion, therapeutic gene loading/releasing, cytotoxicity, and in vitro combination cancer treatment. We believe that this discovery broadens the potential applications of metal nanomaterials, with an emphasis on more efficient biomedical applications in limited conventional fields. PMID- 29608257 TI - Genetic overlap between endometriosis and endometrial cancer: evidence from cross disease genetic correlation and GWAS meta-analyses. AB - Epidemiological, biological, and molecular data suggest links between endometriosis and endometrial cancer, with recent epidemiological studies providing evidence for an association between a previous diagnosis of endometriosis and risk of endometrial cancer. We used genetic data as an alternative approach to investigate shared biological etiology of these two diseases. Genetic correlation analysis of summary level statistics from genomewide association studies (GWAS) using LD Score regression revealed moderate but significant genetic correlation (rg = 0.23, P = 9.3 * 10-3 ), and SNP effect concordance analysis provided evidence for significant SNP pleiotropy (P = 6.0 * 10-3 ) and concordance in effect direction (P = 2.0 * 10-3 ) between the two diseases. Cross-disease GWAS meta-analysis highlighted 13 distinct loci associated at P <= 10-5 with both endometriosis and endometrial cancer, with one locus (SNP rs2475335) located within PTPRD associated at a genomewide significant level (P = 4.9 * 10-8 , OR = 1.11, 95% CI = 1.07-1.15). PTPRD acts in the STAT3 pathway, which has been implicated in both endometriosis and endometrial cancer. This study demonstrates the value of cross-disease genetic analysis to support epidemiological observations and to identify biological pathways of relevance to multiple diseases. PMID- 29608264 TI - Chemical Probe to Identify the Cellular Targets of the Reactive Lipid Metabolite 2- trans-Hexadecenal. AB - Lipid-derived electrophiles (LDEs) are reactive metabolites, which can covalently modify proteins and DNA and regulate diverse cellular processes. 2- trans Hexadecenal (2-HD) is a byproduct of sphingolipid metabolism, involved in cytoskeletal reorganization, DNA damage, and apoptosis. In addition, the loss of ALDH3A2, an enzyme removing 2-HD in cells, is responsible for Sjorgen-Larsson Syndrome (SJS), suggesting that accumulation of 2-HD could lead to pathogenesis. However, the targets and the precise mechanisms of 2-HD are not well characterized. Herein, we report an alkyne-2-HD derivative as a bioorthogonal probe to explore the functions of 2-HD. We identified more than 500 potential cellular targets. Among them, the pro-apoptotic protein Bax can be covalently modified by 2-HD directly at the conserved Cys62 residue. Our work provided new chemical tools to explore the cellular functions of LDEs and revealed new mechanistic insights of the deregulation of lipid metabolism in diseases. PMID- 29608265 TI - Facile Synthesis of Pt-Functionalized Meso/Macroporous SnO2 Hollow Spheres through in Situ Templating with SiO2 for H2S Sensors. AB - Although single-nozzle electrospraying seems a versatile technique in the synthesis of spherical semiconducting metal oxide structures, the synthesized structures find limited use in gas-sensing applications because of their thick and dense morphology, which minimizes the accessibility of their inner surfaces. Herein, unprecedented spherical SiO2@SnO2 core-shell structures are synthesized upon calcination of single-nozzle as-electrosprayed spheres (SPs) containing tin (Sn) and silicon (Si) precursors. Subsequent etching of SiO2 in NaOH (pH 12) affords meso/macroporous SnO2 hollow spheres (HSPs) with short diffusion length (31.4 +/- 3.1 nm), small crystallites (15.5 nm), and large Brunauer-Emmett-Teller surface area (124.8 m2 g-1). Apart from surface meso/macropores, diffusion of gases into porous SnO2 sensing layers is realized through inner interconnection of voids of the SnO2 HSPs into a three-dimensional network. Functionalization of the postetched SnO2 HSPs with platinum (Pt) nanoparticles at 0.08 wt % yields gas sensing materials with outstanding response ( Ra/ Rg = 1.6, 10.8, and 105.1-0.1, 1, and 5 ppm of H2S, respectively) and selectivity toward H2S against interfering gas molecules at 250 degrees C. The SiO2 phase in the postcalcined SiO2@SnO2 SPs acts as a sacrificial template for pore creation and crystal growth inhibition, whereas the small amount of SiO2 residues in HSPs enhances the selectivity. PMID- 29608266 TI - Redefinition of Crystal Structure and Bi3+ Yellow Luminescence with Strong Near Ultraviolet Excitation in La3BWO9:Bi3+ Phosphor for White Light-Emitting Diodes. AB - Bi3+-activated photonic materials have received increased interest recently because they can be excited effectively with near-ultraviolet (NUV) but not visible light, thereby avoiding the reabsorption among phosphors, which cannot be solved intrinsically by traditional rare earth (e.g., Eu2+, Ce3+) phosphors. Such unique property suggests their potential application in NUV chip-based WLEDs. However, few Bi3+ phosphors exhibit strong excitation peak in NUV, though the excitation tail of some can extend to NUV. Herein, we report a novel yellow emitting La3BWO9:Bi3+ (LBW:Bi3+) phosphor with strong NUV excitation. The photoluminescence (PL) spectroscopy analysis indicates that there are two Bi3+ luminescent centers in LBW:Bi3+ phosphor, which is clearly in contradiction with the established hexagonal structure of La3BWO9 with P63 space group because only one La site in this structure can accommodate Bi3+ ions. Combining the luminescent properties of Bi3+ with Rietveld refinement, La3BWO9 was redefined as a trigonal structure with the lower space group of P3 in which there are two independent crystallographic La sites. In addition, the rationalization of P3 space group was further confirmed by the finding of the reflection (0001) according to the extinction rule. Therefore, the PL behavior of Bi3+ can act as a complementary tool to determinate the real crystal structure especially when it is hard to distinguish by conventional X-ray diffraction techniques. PMID- 29608267 TI - Additive Manufacturing of Catalytically Active Living Materials. AB - Living materials, which are composites of living cells residing in a polymeric matrix, are designed to utilize the innate functionalities of the cells to address a broad range of applications such as fermentation and biosensing. Herein, we demonstrate the additive manufacturing of catalytically active living materials (AMCALM) for continuous fermentation. A multi-stimuli-responsive yeast laden hydrogel ink, based on F127-dimethacrylate, was developed and printed using a direct-write 3D printer. The reversible stimuli-responsive behaviors of the polymer hydrogel inks to temperature and pressure are critical, as they enabled the facile incorporation of yeast cells and subsequent fabrication of 3D lattice constructs. Subsequent photo-cross-linking of the printed polymer hydrogel afforded a robust elastic material. These yeast-laden living materials were metabolically active in the fermentation of glucose into ethanol for 2 weeks in a continuous batch process without significant reduction in efficiency (~90% yield of ethanol). This cell immobilization platform may potentially be applicable toward other genetically modified yeast strains to produce other high-value chemicals in a continuous biofermentation process. PMID- 29608268 TI - Dually Synergetic Network Hydrogels with Integrated Mechanical Stretchability, Thermal Responsiveness, and Electrical Conductivity for Strain Sensors and Temperature Alertors. AB - The first example of dually synergetic network hydrogel, which has integrated mechanical stretchability, thermal responsiveness, and electrical conductivity, has been constructed by a versatile and topological co-cross-linking approach. Poly( N-isopropylacrylamide) (PNIPAAm) is introduced as the thermally responsive ingredient, and polyaniline (PANI) is selected as the electrically conductive ingredient. PNIPAAm network is cross-linked by double-bond end-capped Pluronic F127 (F127DA). PANI network is doped and cross-linked by phytic acid. These two ingredients are further mechanically interlocked. Due to the integrated multiple functionalities, the topologically co-cross-linked hydrogels, as will be mentioned as F-PNIPAAm/PANI hydrogels, can be fabricated into resistive-type strain sensors. The strain sensors can achieve a gauge factor of 3.92, a response time of 0.4 s, and a sensing stability for at least 350 cycles and can be further applied for monitoring human motions, including motion of two hands, bending of joints, and even swallowing and pulse rate. Moreover, F-PNIPAAm/PANI hydrogels are utilized to construct efficient temperature alertors based on the disconnection of circuits induced by volume shrinkage at high temperature. PMID- 29608269 TI - Chemical Genetic Screens Identify Kinase Inhibitor Combinations that Target Anti Apoptotic Proteins for Cancer Therapy. AB - The study presented here provides a framework for the discovery of unique inhibitor combinations that target the apoptosis network for cancer therapy. A pair of doxycycline (Dox)-inducible cell lines that specifically report on the ability of an inhibitor to induce apoptosis by targeting either the Mcl-1 arm or the Bcl-2/Bcl-xL/Bcl-w arm were used. Cell-based assays were optimized for high throughput screening (HTS) with caspase 3/7 as a read out. HTS with a 355-member kinase inhibitor library and the panel of Dox-inducible cell lines revealed that cyclin dependent kinase (CDK) inhibitors induced apoptosis by targeting the Mcl-1 arm, whereas PI3K inhibitors induced apoptosis by targeting the Bcl-2/Bcl-xL/Bcl w arm. Validation studies identified unique combinations that synergistically inhibited growth and induced apoptosis in a panel of cancer cell lines. Since these inhibitors have been or are currently in clinical trials as single agents, the combinations can be rapidly translated to the clinics. PMID- 29608270 TI - Incorporating Graphene Oxide into Alginate Polymer with a Cationic Intermediate To Strengthen Membrane Dehydration Performance. AB - Two-dimensional graphene oxide (GO) in hybrid membranes provides fast water transfer across its surface due to the abundant oxygenated functional groups to afford water sorption and the hydrophobic basal plane to create fast transporting pathways. To establish more compatible and efficient interactions for GO and sodium alginate (SA) polymer chains, cations sourced from lignin are employed to decorate GO (labeled as cation-functionalized GO (CG)) nanosheets via cation-pi and pi-pi interactions, providing more interactive sites to confer synergetic benefits with polymer matrix. Cations from CG are also functional to partially interlock SA chains and intensify water diffusion. And with the aid of two dimensional pathways of CG, fast selective water permeation can be realized through hybrid membranes with CG fillers. In dehydrating aqueous ethanol solution, the hybrid membrane exhibits considerable performance compared with bare SA polymer membrane (long-term stable permeation flux larger than 2500 g m-2 h-1 and water content larger than 99.7 wt %, with feed water content of 10 wt % under 70 degrees C). The effects of CG content in SA membrane were investigated, and the transport mechanism was correspondingly studied through varying operation conditions and membrane materials. In addition, such a membrane possesses long term stability and almost unchanged high dehydration capability. PMID- 29608271 TI - Tough and Conductive Hybrid Hydrogels Enabling Facile Patterning. AB - Conductive polymer hydrogels (CPHs) that combine the unique properties of hydrogels and electronic properties of conductors have shown their great potentials in wearable/implantable electronic devices, where materials with remarkable mechanical properties, high conductivity, and easy processability are demanding. Here, we have developed a new type of polyion complex/polyaniline (PIC/PAni) hybrid hydrogels that are tough, conductive, and can be facilely patterned. The incorporation of conductive phase (PAni) into PIC matrix through phytic acid resulted in hybrid gels with ~65 wt % water; high conductivity while maintaining the key viscoelasticity of the tough matrix. The gel prepared from 1 M aniline (Ani) exhibited the breaking strain, fracture stress, tensile modulus, and electrical conductivity of 395%, 1.15 MPa, 5.31 MPa, and 0.7 S/m, respectively, superior to the most existing CPHs. The mechanical and electrical performance of PIC/PAni hybrid hydrogels exhibited pronounced rate-dependent and self-recovery behaviors. The hybrid gels can effectively detect subtle human motions as strain sensors. Alternating conductive/nonconductive patterns can be readily achieved by selective Ani polymerization using stencil masks. This facile patterning method based on PIC/PAni gels can be readily scaled up for fast fabrication of wavy gel circuits and multichannel sensor arrays, enabling real time monitoring of the large-extent and large-area deformations with various sensitivities. PMID- 29608272 TI - Flavin Storage and Sequestration by Mycobacterium tuberculosis Dodecin. AB - Dodecins are small flavin binding proteins occurring in archaea and bacteria. They are remarkable for binding dimers of flavins with their functional relevant aromatic isoalloxazine rings deeply covered. Bacterial dodecins are widely spread and found in a large variety of pathogens, among them Pseudomonas aeruginosa, Streptococcus pneumonia, Ralstonia solanacearum, and Mycobacterium tuberculosis ( M. tuberculosis). In this work, we seek to understand the function of dodecins from M. tuberculosis dodecin. We describe flavin binding in thermodynamic and kinetic properties and achieve mechanistic insight in dodecin function by applying spectroscopic and electrochemical methods. Intriguingly, we reveal a significant pH dependence in the affinity and specificity of flavin binding. Our data give insight in M. tuberculosis dodecin function and advance the current understanding of dodecins as flavin storage and sequestering proteins. We suggest that the dodecin in M. tuberculosis may specifically be important for flavin homeostasis during the elaborate lifestyle of this organism, which calls for the evaluation of this protein as drug target. PMID- 29608273 TI - Nanoscaled Na3PS4 Solid Electrolyte for All-Solid-State FeS2/Na Batteries with Ultrahigh Initial Coulombic Efficiency of 95% and Excellent Cyclic Performances. AB - Nanosized Na3PS4 solid electrolyte with an ionic conductivity of 8.44 * 10-5 S cm 1 at room temperature is synthesized by a liquid-phase reaction. The resultant all-solid-state FeS2/Na3PS4/Na batteries show an extraordinary high initial Coulombic efficiency of 95% and demonstrate high energy density of 611 Wh kg-1 at current density of 20 mA g-1 at room temperature. The outstanding performances of the battery can be ascribed to good interface compatibility and intimate solid solid contact at FeS2 electrode/nanosized Na3PS4 solid electrolytes interface. Meanwhile, excellent cycling stability is achieved for the battery after cycling at 60 mA g-1 for 100 cycles, showing a high capacity of 287 mAh g-1 with the capacity retention of 80%. PMID- 29608274 TI - Azide-Alkyne Click Conjugation on Quantum Dots by Selective Copper Coordination. AB - Functionalization of nanocrystals is essential for their practical application, but synthesis on nanocrystal surfaces is limited by incompatibilities with certain key reagents. The copper-catalyzed azide-alkyne cycloaddition is among the most useful methods for ligating molecules to surfaces, but has been largely useless for semiconductor quantum dots (QDs) because Cu+ ions quickly and irreversibly quench QD fluorescence. To discover nonquenching synthetic conditions for Cu-catalyzed click reactions on QD surfaces, we developed a combinatorial fluorescence assay to screen >2000 reaction conditions to maximize cycloaddition efficiency while minimizing QD quenching. We identify conditions for complete coupling without significant quenching, which are compatible with common QD polymer surfaces and various azide/alkyne pairs. Based on insight from the combinatorial screen and mechanistic studies of Cu coordination and quenching, we find that superstoichiometric concentrations of Cu can promote full coupling if accompanied by ligands that selectively compete with the Cu from the QD surface but allow it to remain catalytically active. Applied to the conjugation of a K+ channel-specific peptidyl toxin to CdSe/ZnS QDs, we synthesize unquenched QD conjugates and image their specific and voltage dependent affinity for K+ channels in live cells. PMID- 29608275 TI - The Effect of Molecular Structure on Cytotoxicity and Antitumor Activity of PEGylated Nanomedicines. AB - Fundamental studies on the cellular uptake and drug release of PEGylated nanomedicines are beneficial to understand their fate in vivo and construct ideal nanoparticle formulations. In this work, the detailed metabolic process of PEGylated doxorubicin (Dox) nanomedicines were investigated via confocal laser scanning microscopy (CLSM), flow cytometry (FCM), cytotoxicity test, fluorescence imaging in vivo (FLIV) and liquid chromatography tandem mass spectrometry (LC MS/MS). Among them, only LC-MS/MS could accurately determine the content of PEGylated Dox and Dox in vitro and in vivo. To the best of our knowledge, this was the first time the PEGylated Dox and released Dox were simultaneously quantified. The interplay of molecular structures, cellular uptake, drug release, and antitumor effect was well characterized. PEG with high molecular weight impeded the cellular uptake of nanoparticles, and the acid-labile hydrazone bond between Dox and PEG promoted Dox release significantly. Cellular uptake and drug release play decisive roles in cytotoxicity and antitumor effect, as evidenced by LC-MS/MS. We emphasized that LC-MS/MS would be a practicable method to quantify PEGylated drugs without complex tags, which could be more in-depth to understand the interaction between PEGylated nanomedicines and their antitumor efficacy. PMID- 29608276 TI - Engineered Reciprocal Chromosome Translocations Drive High Threshold, Reversible Population Replacement in Drosophila. AB - Replacement of wild insect populations with transgene-bearing individuals unable to transmit disease or survive under specific environmental conditions using gene drive provides a self-perpetuating method of disease prevention. Mechanisms that require the gene drive element and linked cargo to exceed a high threshold frequency in order for spread to occur are attractive because they offer several points of control: they bring about local, but not global population replacement; and transgenes can be eliminated by reintroducing wildtypes into the population so as to drive the frequency of transgenes below the threshold frequency required for drive. Reciprocal chromosome translocations were proposed as a tool for bringing about high threshold population replacement in 1940 and 1968. However, translocations able to achieve this goal have only been reported once, in the spider mite Tetranychus urticae, a haplo-diploid species in which there is strong selection in haploid males for fit homozygotes. We report the creation of engineered translocation-bearing strains of Drosophila melanogaster, generated through targeted chromosomal breakage and homologous recombination. These strains drive high threshold population replacement in laboratory populations. While it remains to be shown that engineered translocations can bring about population replacement in wild populations, these observations suggest that further exploration of engineered translocations as a tool for controlled population replacement is warranted. PMID- 29608277 TI - 3D Synergistical MXene/Reduced Graphene Oxide Aerogel for a Piezoresistive Sensor. AB - A piezoresistive sensor based on ultralight and superelastic aerogel is reported to fabricate MXene/reduced graphene oxide (MX/rGO) hybrid 3D structures and utilize their pressure-sensitive characteristics. The MX/rGO aerogel not only combines the rGO's large specific surface area and the MXene's (Ti3C2 T x) high conductivity but also exhibits rich porous structure, which leads to performance better than that of single-component rGO or MXene in terms of the pressure sensor. The large nanosheets of rGO can prevent the poor oxidization of MXene by wrapping MXene inside the aerogel. More importantly, the piezoresistive sensor based on the MX/rGO aerogel shows extremely high sensitivity (22.56 kPa-1), fast response time (<200 ms), and good stability over 10 000 cycles. The piezoresistive sensor based on the MX/rGO hybrid 3D aerogel can easily capture the signal below 10 Pa, thus clearly testing the pulse of an adult at random. Based on its superior performance, it also demonstrates potential applications in measuring pressure distribution, distinguishing subtle strain, and monitoring healthy activity. PMID- 29608278 TI - Development of a Plasmid-Free Biosynthetic Pathway for Enhanced Muconic Acid Production in Pseudomonas chlororaphis HT66. AB - Muconic acid is a platform chemical and an important intermediate in the degradation process of a series of aromatic compounds. Herein, a plasmid-free synthetic pathway in Pseudomonas chlororaphis HT66 is constructed for the enhanced biosynthesis of muconic acid by connecting endogenous ubiquinone biosynthesis pathway with protocatechuate degradation pathway using chromosomal integration. Instead of being plasmid and inducer dependent, the engineered strains could steadily produce the high muconic acid using glycerol as a carbon source. The engineered strain HT66-MA6 achieved a 3376 mg/L muconic acid production with a yield of 187.56 mg/g glycerol via the following strategies: (1) block muconic acid conversion and enhance muconic acid efflux pumping with phenazine biosynthesis cluster; (2) increase the muconic acid precursors supply through overexpressing the rate-limiting step, and (3) coexpress the "3 dehydroshikimate-derived" route in parallel with the "4-hydroxybenzoic acid derived" route to create a synthetic "metabolic funnel". Finally, on the basis of the glycerol feeding strategies, the muconic acid yield reached 0.122 mol/mol glycerol. The results suggest that the construction of synthetic pathway with a plasmid-free strategy in P. chlororaphis displays a high biotechnological perspective. PMID- 29608279 TI - In Vitro Liquid Extraction Surface Analysis Mass Spectrometry (ivLESA-MS) for Direct Metabolic Analysis of Adherent Cells in Culture. AB - Conventional metabolomic methods include extensive sample preparation steps and long analytical run times, increasing the likelihood of processing artifacts and limiting high throughput applications. We present here in vitro liquid extraction surface analysis mass spectrometry (ivLESA-MS), a variation on LESA-MS, performed directly on adherent cells grown in 96-well cell culture plates. To accomplish this, culture medium was aspirated immediately prior to analysis, and metabolites were extracted using LESA from the cell monolayer surface, followed by nano electrospray ionization and MS analysis in negative ion mode. We applied this platform to characterize and compare lipidomic profiles of multiple breast cancer cell lines growing in culture (MCF-7, ZR-75-1, MDA-MB-453, and MDA-MB-231) and revealed distinct and reproducible lipidomic signatures between the cell lines. Additionally, we demonstrated time-dependent processing artifacts, underscoring the importance of immediate analysis. ivLESA-MS represents a rapid in vitro metabolomic method, which precludes the need for quenching, cell harvesting, sample preparation, and chromatography, significantly shortening preparation and analysis time while minimizing processing artifacts. This method could be further adapted to test drugs in vitro in a high throughput manner. PMID- 29608280 TI - Trophodynamics of Emerging Brominated Flame Retardants in the Aquatic Food Web of Lake Taihu: Relationship with Organism Metabolism across Trophic Levels. AB - Despite the increasing use and discharge of novel brominated flame retardants, little information is available about their trophodynamics in the aquatic food web, and their subsequent relationships to compound metabolism. In this study, concentrations of 2,4,6-tribromophenyl allyl ether (ATE), 1,2-dibromo-4-(1,2 dibromoethyl)cyclohexane (TBECH), tetrabromo- o-chlorotoluene (TBCT), pentabromobenzyl acrylate (PBBA), 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE), bis(2-ethylhexyl)-3,4,5,6-tetrabromo-phthalate (TBPH), and decabromodiphenyl ethane (DBDPE) were measured in 17 species, including plankton, invertebrates, and fish from Lake Taihu, South China. Trophodynamics of the compounds were assessed, and metabolic rates were measured in the liver microsomes of crucian (trophic level [TL]: 2.93), catfish (TL: 3.86), and yellow-head catfish (TL: 4.3). Significantly positive relationships were found between trophic levels and lipid-normalized concentrations of ATE, BTBPE, and TBPH; their trophic magnification factors (TMFs) were 2.85, 2.83, and 2.42, respectively. Consistently, the three chemicals were resistant to metabolism in all fish microsomes. No significant relationship was observed for betaTBECH ( p = 0.116), and DBDPE underwent trophic dilution in the food web (TMFs = 0.37, p = 0.021). Moreover, these two chemicals showed steady metabolism with incubation time in all fish microsomes. TBCT and PBBA exhibited significant trophic magnifications in the food web (TMF = 4.56, 2.01). Though different metabolic rates were observed for the two compounds among the tested fish species, TBCT and PBBA both showed metabolic resistance in high-trophic-level fish. These results indicated that metabolism of organisms at high trophic levels plays an important role in the assessment of trophic magnification potentials of these flame retardant chemicals. PMID- 29608281 TI - Harvesting Water from Air: Using Anhydrous Salt with Sunlight. AB - Atmospheric water is an abundant alternative water resource, equivalent to 6 times the water in all rivers on Earth. This work screens 14 common anhydrous and hydrated salt couples in terms of their physical and chemical stability, water vapor harvesting, and release capacity under relevant application scenarios. Among the salts screened, copper chloride (CuCl2), copper sulfate (CuSO4), and magnesium sulfate (MgSO4) distinguish themselves and are further made into bilayer water collection devices, with the top layer being the photothermal layer, while the bottom layer acts as a salt-loaded fibrous membrane. The water collection devices are capable of capturing water vapor out of the air with low relative humidity (down to 15%) and releasing water under regular and even weakened sunlight (i.e., 0.7 kW/m2). The work shines light on the potential use of anhydrous salt toward producing drinking water in water scarce regions. PMID- 29608282 TI - Genetic Engineering of Bee Gut Microbiome Bacteria with a Toolkit for Modular Assembly of Broad-Host-Range Plasmids. AB - Engineering the bacteria present in animal microbiomes promises to lead to breakthroughs in medicine and agriculture, but progress is hampered by a dearth of tools for genetically modifying the diverse species that comprise these communities. Here we present a toolkit of genetic parts for the modular construction of broad-host-range plasmids built around the RSF1010 replicon. Golden Gate assembly of parts in this toolkit can be used to rapidly test various antibiotic resistance markers, promoters, fluorescent reporters, and other coding sequences in newly isolated bacteria. We demonstrate the utility of this toolkit in multiple species of Proteobacteria that are native to the gut microbiomes of honey bees ( Apis mellifera) and bumble bees (B ombus sp.). Expressing fluorescent proteins in Snodgrassella alvi, Gilliamella apicola, Bartonella apis, and Serratia strains enables us to visualize how these bacteria colonize the bee gut. We also demonstrate CRISPRi repression in B. apis and use Cas9-facilitated knockout of an S. alvi adhesion gene to show that it is important for colonization of the gut. Beyond characterizing how the gut microbiome influences the health of these prominent pollinators, this bee microbiome toolkit (BTK) will be useful for engineering bacteria found in other natural microbial communities. PMID- 29608284 TI - A Pseudoisostructural Type II DAH7PS Enzyme from Pseudomonas aeruginosa: Alternative Evolutionary Strategies to Control Shikimate Pathway Flux. AB - The shikimate pathway is responsible for the biosynthesis of key aromatic metabolites in microorganisms and plants. The enzyme 3-deoxy-d- arabino heptulosonate 7-phosphate synthase (DAH7PS) catalyzes the first step of the pathway and DAH7PSs are classified as either type I or type II. The DAH7PSs from Pseudomonas aeruginosa are of particular interest as open reading frames encoding four putative DAH7PS isoenzymes, two classified as type Ialpha and two classified as type II, have been identified. Here, the structure of a type II DAH7PS enzyme from P. aeruginosa (PAO1) has been determined at 1.54 A resolution, in complex with its allosteric inhibitor tryptophan. Structural differences in the extra barrel elements, when compared to other type II DAH7PS enzymes, directly relate to the formation of a distinct quaternary conformation with consequences for allosteric function and the control of flux to branching pathways. In contrast to the well-characterized Mycobacterium tuberculosis type II DAH7PS, which binds multiple allosteric inhibitors, this PaeDAH7PSPA2843 is observed to be modestly allosterically inhibited by a single aromatic amino acid, tryptophan. In addition, structures in complex with tyrosine or with no allosteric ligand bound were determined. These structures provide new insights into the linkages between the active and allosteric sites. With four putative DAH7PS enzymes, P. aeruginosa appears to have evolved control of shikimate pathway flux at the genetic level, rather than control by multiple allosteric effectors to a single type II DAH7PS, as in M. tuberculosis. Type II DAH7PSs, thus, appear to have a more varied evolutionary trajectory than previously indicated. PMID- 29608283 TI - Converting Insulin-like Growth Factors 1 and 2 into High-Affinity Ligands for Insulin Receptor Isoform A by the Introduction of an Evolutionarily Divergent Mutation. AB - Insulin-like growth factors 1 and 2 (IGF-1 and -2, respectively) are protein hormones involved not only in normal growth and development but also in life span regulation and cancer. They exert their functions mainly through the IGF-1R or by binding to isoform A of the insulin receptor (IR-A). The development of IGF-1 and IGF-2 antagonists is of great clinical interest. Mutations of A4 and A8 sites of human insulin lead to disproportionate effects on hormone IR binding and activation. Here, we systematically modified IGF-1 sites 45, 46, and 49 and IGF-2 sites 45 and 48, which correspond, or are close, to insulin sites A4 and A8. The IGF-1R and IR-A binding and autophosphorylation potencies of these analogues were characterized. They retained the main IGF-1R-related properties, but the hormones with His49 in IGF-1 and His48 in IGF-2 showed significantly higher affinities for IR-A and for IR-B, being the strongest IGF-1- and IGF-2-like binders of these receptors ever reported. All analogues activated IR-A and IGF-1R without major discrepancies in their binding affinities. This study revealed that IR-A and IGF 1R contain specific sites, likely parts of their so-called sites 2', which can interact differently with specifically modified IGF analogues. Moreover, a clear importance of IGF-2 site 44 for effective hormone folding was also observed. These findings may facilitate novel and rational engineering of new hormone analogues for IR-A and IGF-1R studies and for potential medical applications. PMID- 29608285 TI - Magnesium Hydride Nanoparticles Self-Assembled on Graphene as Anode Material for High-Performance Lithium-Ion Batteries. AB - MgH2 nanoparticles (NPs) uniformly anchored on graphene (GR) are fabricated based on a bottom-up self-assembly strategy as anode materials for lithium-ion batteries (LIBs). Monodisperse MgH2 NPs with an average particle size of ~13.8 nm are self-assembled on the flexible GR, forming interleaved MgH2/GR (GMH) composite architectures. Such nanoarchitecture could effectively constrain the aggregation of active materials, buffer the strain of volume changes, and facilitate the electron/lithium ion transfer of the whole electrode, leading to a significant enhancement of the lithium storage capacity of the GMH composite. Furthermore, the performances of GMH composite as anode materials for LIBs are enabled largely through robust interfacial interactions with poly(methyl methacrylate) (PMMA) binder, which plays multifunctional roles in forming a favorable solid-electrolyte interphase (SEI) film, alleviating the volume expansion and detachment of active materials, and maintaining the structural integrity of the whole electrode. As a result, these synergistic effects endow the obtained GMH composite with a significantly enhanced reversible capacity and cyclability as well as a good rate capability. The GMH composite with 50 wt % MgH2 delivers a high reversible capacity of 946 mA h g-1 at 100 mA g -1 after 100 cycles and a capacity of 395 mAh g-1 at a high current density of 2000 mA g-1 after 1000 cycles. PMID- 29608287 TI - Triphenylene-Imidazolium Salts and Their NHC Metal Complexes, Materials with Segregated Multicolumnar Mesophases. AB - Two imidazolium salts containing one or two pentadodecyloxytriphenylene units linked through a hexyloxy chain and Br-, [AuBr mCl4- m]-, or [PtBr mCl4- m]2- ( m = 0-3) as counterion have been prepared. Reaction of the imidazolium bromides with M2O (M = Cu, Ag), or carbene transmetalation from the silver product, leads to N-heterocyclic carbene complexes [MX(NHC)] (M = Cu, X = Br; M = Au, X = Cl, C=CPh), [Ag(NHC)2][AgBr2], and [PtCl2(NHC)2], with NHC bearing one or two triphenylene fragments. Except for the gold derivatives and one Cu complex, the rest of them behave as liquid crystals organized in columnar mesophases (rectangular c2 mm or p2mg or hexagonal p6mm symmetries) with melting points in the range 30 to 60 degrees C and clearing points in the range 57-112 degrees C. The mesophase structures were determined by small-angle X-ray scattering. Structural studies and models point to nanosegregation of triphenylene columns and imidazolium/metal carbene moieties, separated by alkoxy chains, leading to multicolumnar systems. The compounds display emission spectra related to the triphenylene core in solution, in the mesophase, in the isotropic liquid, and in the solid state. PMID- 29608286 TI - Promoting Vibrations and the Function of Enzymes. Emerging Theoretical and Experimental Convergence. AB - A complete understanding of enzyme catalysis requires knowledge of both transition state features and the detailed motions of atoms that cause reactant molecules to form and traverse the transition state. The seeming intractability of the problem arises from the femtosecond lifetime of chemical transition states, preventing most experimental access. Computational chemistry is admirably suited to short time scale analysis but can be misled by inappropriate starting points or by biased assumptions. Kinetic isotope effects provide an experimental approach to transition state structure and a method for obtaining transition state analogues but, alone, do not inform how that transition state is reached. Enzyme structures with transition state analogues provide computational starting points near the transition state geometry. These well-conditioned starting points, combined with the unbiased computational method of transition path sampling, provide realistic atomistic motions involved in transition state formation and passage. In many, but not all, enzymatic systems, femtosecond local protein motions near the catalytic site are linked to transition state formation. These motions are not inherently revealed by most approaches of transition state theory, because transition state theory replaces dynamics with the statistics of the transition state. Experimental and theoretical convergence of the link between local catalytic site vibrational modes and catalysis comes from heavy atom ("Born-Oppenheimer") enzymes. Fully labeled and catalytic site local heavy atom labels perturb the probability of finding enzymatic transition states in ways that can be analyzed and predicted by transition path sampling. Recent applications of these experimental and computational approaches reveal how subpicosecond local catalytic site protein modes play important roles in creating the transition state. PMID- 29608288 TI - Determination of Collision Cross-Sections of Protein Ions in an Orbitrap Mass Analyzer. AB - We demonstrate a method for determining the collision cross-sections (CCSs) of protein ions based on the decay rate of the time-domain transient signal from an Orbitrap mass analyzer. Multiply charged ions of ubiquitin, cytochrome c, and myoglobin were generated by electrospray ionization of both denaturing solutions and ones with high salt content to preserve native-like structures. A linear relationship between the pressure in the Orbitrap analyzer and the transient decay rate was established and used to demonstrate that the signal decay is primarily due to ion-neutral collisions for protein ions across the entire working pressure range of the instrument. The CCSs measured in this study were compared with previously published CCS values measured by ion mobility mass spectrometry (IMS), and results from the two methods were found to differ by less than 7% for all charge states known to adopt single gas-phase conformations. PMID- 29608289 TI - Aggregation-Induced Electrochemiluminescence from a Cyclometalated Iridium(III) Complex. AB - Aggregation-induced emission has been extensively found in organic compounds and metal complexes. In contrast, aggregation-induced electrochemiluminescence (AI ECL) is rarely observed. Here, we employ two tridentate ligands [2,2':6',2" terpyridine (tpy) and 1,3-bis(1 H-benzimidazol-2-yl)benzene (bbbiH3)] to construct a cyclometalated iridium(III) complex, [Ir(tpy)(bbbi)] (1), showing strong AI-ECL. Its crystal structure indicates that neighboring [Ir(tpy)(bbbi)] molecules are connected through both pi-pi-stacking interactions and hydrogen bonds. These supramolecular interactions can facilitate the self-assembly of complex 1 into nanoparticles in an aqueous solution. The efficient restriction of molecular vibration in these nanoparticles leads to strong AI-ECL emission of complex 1. In a dimethyl sulfoxide-water (H2O) mixture with a gradual increase in the H2O fraction from 20% to 98%, complex 1 showed a ~39-fold increase in the electrochemiluminescence (ECL) intensity, which was ~4.04 times as high as that of [Ru(bpy)3]2+ under the same experimental conditions. Moreover, the binding of bovine serum albumin to the nanoparticles of complex 1 can improve the ECL emission of this complex, facilitating the understanding of the mechanism of AI ECL for future applications. PMID- 29608290 TI - Ferritin Nanocarrier Traverses the Blood Brain Barrier and Kills Glioma. AB - Over the last decades, considerable efforts have been put into developing active nanocarrier systems that cross the blood brain barrier (BBB) to treat brain related diseases such as glioma tumors. However, to date none have been approved for clinical usage. Here, we show that a human H-ferritin (HFn) nanocarrier both successfully crosses the BBB and kills glioma tumor cells. Its principle point of entry is the HFn receptor (transferrin receptor 1), which is overexpressed in both BBB endothelial cells (ECs) and glioma cells. Importantly, we found that HFn enters and exits the BBB via the endosome compartment. In contrast, upon specifically targeting and entering glioma cells, nearly all of the HFn accumulated in the lysosomal compartment, resulting in the killing of glioma tumor cells, with no HFn accumulation in the surrounding healthy brain tissue. Thus, HFn is an ideal nanocarrier for glioma therapy and possesses the potential to serve as a therapeutic approach against a broad range of central nervous system diseases. PMID- 29608291 TI - Genetic Bioaugmentation of Activated Sludge with Dioxin-Catabolic Plasmids Harbored by Rhodococcus sp. Strain p52. AB - Horizontal transfer of catabolic plasmids is used in genetic bioaugmentation for environmental pollutant remediation. In this study, we examined the effectiveness of genetic bioaugmentation with dioxin-catabolic plasmids harbored by Rhodococcus sp. strain p52 in laboratory-scale sequencing batch reactors (SBRs). During 100 days of operation, bioaugmentation decreased the dibenzofuran content (120 mg L 1) in the synthetic wastewater by 32.6%-100% of that in the nonbioaugmented SBR. Additionally, dibenzofuran was removed to undetectable levels in the bioaugmented SBR, in contrast, 46.8 +/- 4.1% of that in the influent remained in the nonbioaugmented SBR after 96 days. Moreover, transconjugants harboring pDF01 and pDF02 were isolated from the bioaugmented SBR after 2 days, and their abilities to degrade dibenzofuran were confirmed. After 80 days, the copy numbers of strain p52 decreased by 3 orders of magnitude and accounted for 0.05 +/- 0.01% of the total bacteria, while transconjugants were present at around 106 copies mL-1 sludge and accounted for 8.2 +/- 0.3% of the total bacteria. Evaluation of the bacterial community profile of sludge by high-throughput 16S rRNA gene sequencing revealed that genetic bioaugmentation led to a bacterial community with an even distribution of genera in the SBR. This study demonstrates the promise of genetic bioaugmentation with catabolic plasmids for dioxins remediation. PMID- 29608292 TI - Mix-and-Melt Colloidal Engineering. AB - Increasing significance is being placed on the synthesis of smart colloidal particles, since the route to various meta-materials has been outlined through their bottom-up self-assembly. Unfortunately, making particles with well-defined shape and surface chemistry often requires considerable effort and time, and as such, they are available only in restrictive yields. Here we report a synthetic methodology, which we refer to as mix-and-melt reactions (MMR), that allows for rapid prototyping and mass production of anisotropic core-shell colloids. MMR take advantage of the synergistic properties between common colloidal suspensions by aggregating then reconfiguring polystyrene shell particles onto core particle substrates. By systematically exchanging cores and shells, the resultant core shell particle's properties are manipulated in a modular fashion. The influence of the constituent particles' size ratio is extensively explored, which is shown to tune shell thickness, change the aspect ratio of shells on anisotropic cores, and access specific shapes such as tetrahedra. Beyond particle shape, mixed shell systems are utilized to create regular surface patches. Surface Evolver simulations are used to demonstrate how randomly packed clusters melt into regular shapes via a shell compartmentalization mechanism. PMID- 29608293 TI - Differential-Mobility Spectrometry of 1-Deoxysphingosine Isomers: New Insights into the Gas Phase Structures of Ionized Lipids. AB - Separation and structural identification of lipids remain a major challenge for contemporary lipidomics. Regioisomeric lipids differing only in position(s) of unsaturation are often not differentiated by conventional liquid chromatography mass spectrometry approaches leading to the incomplete, or sometimes incorrect, assignation of molecular structure. Here we describe an investigation of the gas phase separations by differential-mobility spectrometry (DMS) of a series of synthetic analogues of the recently described 1-deoxysphingosine. The dependence of the DMS behavior on the position of the carbon-carbon double bond within the ionized lipid is systematically explored and compared to trends from complementary investigations, including collision cross-sections measured by drift tube ion mobility, reaction efficiency with ozone, and molecular dynamics simulations. Consistent trends across these modes of interrogation point to the importance of direct, through-space interactions between the charge site and the carbon-carbon double bond. Differences in the geometry and energetics of this intramolecular interaction underpin DMS separations and influence reactivity trends between regioisomers. Importantly, the disruption and reformation of these intramolecular solvation interactions during DMS are proposed to be the causative factor in the observed separations of ionized lipids which are shown to have otherwise identical collision cross-sections. These findings provide key insights into the strengths and limitations of current ion-mobility technologies for lipid isomer separations and can thus guide a more systematic approach to improved analytical separations in lipidomics. PMID- 29608294 TI - Assessment of Sample Preparation Bias in Mass Spectrometry-Based Proteomics. AB - For mass spectrometry-based proteomics, the selected sample preparation strategy is a key determinant for information that will be obtained. However, the corresponding selection is often not based on a fit-for-purpose evaluation. Here we report a comparison of in-gel (IGD), in-solution (ISD), on-filter (OFD), and on-pellet digestion (OPD) workflows on the basis of targeted (QconCAT-multiple reaction monitoring (MRM) method for mitochondrial proteins) and discovery proteomics (data-dependent acquisition, DDA) analyses using three different human head and neck tissues (i.e., nasal polyps, parotid gland, and palatine tonsils). Our study reveals differences between the sample preparation methods, for example, with respect to protein and peptide losses, quantification variability, protocol-induced methionine oxidation, and asparagine/glutamine deamidation as well as identification of cysteine-containing peptides. However, none of the methods performed best for all types of tissues, which argues against the existence of a universal sample preparation method for proteome analysis. PMID- 29608295 TI - TBBPA and Its Alternatives Disturb the Early Stages of Neural Development by Interfering with the NOTCH and WNT Pathways. AB - Tetrabromobisphenol A (TBBPA), as well as its alternatives Tetrabromobisphenol S (TBBPS) and Tetrachlorobisphenol A (TCBPA), are widely used halogenated flame retardants. Their high detection rates in human breast milk and umbilical cord serum have raised wide concerns about their adverse effects on human fetal development. In this study, we evaluated the cytotoxicity and neural developmental toxicity of TBBPA, TBBPS, and TCBPA with a mouse embryonic stem cell (mESC) system, at human body fluid and environmental relevant doses. All the three compounds showed similar trends in their cytotoxic effects. However, while TBBPA and TBBPS stimulated ESC neural differentiation, TCBPA significantly inhibited neurogenesis. Mechanistically, we demonstrated that, as far as the NOTCH (positive regulator) and WNT (negative regulator) pathways were concerned, TBBPA only partially and slightly disturbed them, whereas TBBPS significantly inhibited the WNT pathway, and TCBPA down-regulated the expression of NOTCH effectors but increased the WNT signaling, actions which both inhibited neural specification. In conclusion, our findings suggest that TBBPS and TCBPA may not be safe alternatives to TBBPA, and their toxicity need to be comprehensively evaluated. PMID- 29608296 TI - Electronic and Structural Effects of Inner Sphere Coordination of Chloride to a Homoleptic Copper(II) Diimine Complex. AB - The reaction of CuCl2 with 2,9-dimethyl-1,10-phenanthroline (dmp) does not lead to the formation of [Cu(dmp)2](Cl)2 but instead to [Cu(dmp)2Cl]Cl, a 5 coordinated complex, in which one chloride is directly coordinated to the metal center. Attempts at removing the coordinated chloride by changing the counterion by metathesis were unsuccessful and resulted only in the exchange of the noncoordinated chloride, as confirmed from a crystal structure analysis. Complex [Cu(dmp)2Cl]PF6 exhibits a reversible cyclic voltammogram characterized by a significant peak splitting between the reductive and oxidative waves (0.85 and 0.60 V vs NHE, respectively), with a half-wave potential E1/2 = 0.73 V vs NHE. When reduced electrochemically, the complex does not convert into [Cu(dmp)2]+, as one may expect. Instead, [Cu(dmp)2]+ is isolated as a product when the reduction of [Cu(dmp)2Cl]PF6 is performed with l-ascorbic acid, as confirmed by electrochemistry, NMR spectroscopy, and diffractometry. [Cu(dmp)2]2+ complexes can be synthesized starting from Cu(II) salts with weakly and noncoordinating counterions, such as perchlorate. Growth of [Cu(dmp)2](ClO4)2 crystals in acetonitrile results in a 5-coordinated complex, [Cu(dmp)2(CH3CN)](ClO4)2, in which a solvent molecule is coordinated to the metal center. However, solvent coordination is associated with a dynamic decoordination-coordination behavior upon reduction and oxidation. Hence, the cyclic voltammogram of [Cu(dmp)2(CH3CN)]2+ is identical to the one of [Cu(dmp)2]+, if the measurements are performed in acetonitrile. The current results show that halide ions in precursors to Cu(II) metal-organic coordination compound synthesis, and most likely also other multivalent coordination centers, are not readily exchanged when exposed to presumed strongly binding and chelating ligand, and thus special care needs to be taken with respect to product characterization. PMID- 29608297 TI - Uncoupled Redox-Inactive Lewis Acids in the Secondary Coordination Sphere Entice Ligand-Based Nitrite Reduction. AB - Metal complexes composed of redox-active pyridinediimine (PDI) ligands are capable of forming ligand-centered radicals. In this Forum article, we demonstrate that integration of these types of redox-active sites with bioinspired secondary coordination sphere motifs produce direduced complexes, where the reduction potential of the ligand-based redox sites is uncoupled from the secondary coordination sphere. The utility of such ligand design was explored by encapsulating redox-inactive Lewis acidic cations via installation of a pendant benzo-15-crown-5 in the secondary coordination sphere of a series of Fe(PDI) complexes. Fe(15bz5PDI)(CO)2 was shown to encapsulate the redox-inactive alkali ion, Na+, causing only modest (31 mV) anodic shifts in the ligand-based redox-active sites. By uncoupling the Lewis acidic sites from the ligand-based redox sites, the pendant redox-inactive ion, Na+, can entice the corresponding counterion, NO2-, for reduction to NO. The subsequent initial rate analysis reveals an acceleration in anion reduction, confirming this hypothesis. PMID- 29608298 TI - Mechanism of N-N Bond Formation by Transition Metal-Nitrosyl Complexes: Modeling Flavodiiron Nitric Oxide Reductases. AB - Nitric oxide (NO) has a number of important biological functions, including nerve signaling transduction, blood pressure control, and, at higher concentrations, immune defense. A number of pathogenic bacteria have developed methods of degrading this toxic molecule through the use of flavodiiron nitric oxide reductases (FNORs), which utilize a nonheme diiron active site to reduce NO -> N2O. The well-characterized diiron model complex [Fe2(BPMP)(OPr)(NO)2]2+ (BPMP- = 2,6-bis[(bis(2- pyridylmethyl)amino)methyl]-4-methylphenolate), which mimics both the active site structure and reactivity of these enzymes, offers key insight into the mechanism of FNORs. Presently, we have used computational methods to elucidate a coherent reaction mechanism that shows how one and two-electron reduction of this complex induces N-N bond formation and N2O generation, while the parent complex remains stable. The initial formation of a N-N bond to generate hyponitrite (N2O22-) follows a radical-type coupling mechanism, which requires strong Fe-NO pi-interactions to be overcome to effectively oxidize the iron centers. Hyponitrite formation provides the largest activation barrier with Delta G? = 7-8 kcal/mol (average of several functionals) in the two-electron, super-reduced mechanism. This is followed by the formation of a N2O22- complex with a novel binding mode for nonheme diiron systems, allowing for the facile release of N2O with the assistance of a carboxylate shift. This provides sufficient thermodynamic driving force for the reaction to proceed via N2O formation alone. Surprisingly, the one-electron "semireduced" mechanism is predicted to be competitive with the super-reduced mechanism. This is due to the asymmetry imparted by the BPMP- ligand, allowing a one-electron reduction to overcome one of the primary Fe-NO pi-interactions. Generally, mediation of N2O formation by high-spin [{M-NO-}]2 cores depends on the ease of oxidizing the M centers and breaking of the M-NO pi-bonds to formally generate a "full" 3NO- unit, allowing for the critical step of N-N bond formation to proceed (via a radical-type coupling mechanism). PMID- 29608299 TI - Computational Study on the Unimolecular Decomposition of JP-8 Jet Fuel Surrogates III: Butylbenzene Isomers ( n-, s-, and t-C14H10). AB - Ab initio G3(CCSD,MP2)//B3LYP/6-311G(d,p) calculations of potential energy surfaces have been carried out to unravel the mechanism of the initial stages of pyrolysis of three C10H14 isomers: n-, s-, and t-butylbenzenes. The computed energy and molecular parameters have been utilized in RRKM-master equation calculations to predict temperature- and pressure-dependent rate constants and product branching ratios for the primary unimolecular decomposition of these molecules and for the secondary decomposition of their radical fragments. The results showed that the primary dissociation of n-butylbenzene produces mostly benzyl (C7H7) + propyl (C3H7) and 1-phenyl-2-ethyl (C6H5C2H4) + ethyl (C2H5), with their relative yields strongly dependent on temperature and pressure, together with a minor amount of 1-phenyl-prop-3-yl (C9H11) + methyl (CH3). Secondary decomposition reactions that are anticipated to occur on a nanosecond scale under typical combustion conditions split propyl (C3H7) into ethylene (C2H4) + methyl (CH3), ethyl (C2H5) into ethylene (C2H4) + hydrogen (H), 1-phenyl 2-ethyl (C6H5C2H4) into mostly styrene (C8H8) + hydrogen (H) and to a lesser extent phenyl (C6H5) + ethylene (C2H4), and 1-phenyl-prop-3-yl (C9H11) into predominantly benzyl (C7H7) + ethylene (C2H4). The primary decomposition of s butylbenzene is predicted to produce 1-phenyl-1-ethyl (C6H5CHCH3) + ethyl (C2H5) and a minor amount of 1-phenyl-prop-1-yl (C9H11) + methyl (CH3), and then 1 phenyl-1-ethyl (C6H5CHCH3) and 1-phenyl-prop-1-yl (C9H11) rapidly dissociate to styrene (C8H8) + hydrogen (H) and styrene (C8H8) + methyl (CH3), respectively. t Butylbenzene decomposes nearly exclusively to 2-phenyl-prop-2-yl (C9H11) + methyl (CH3), and further, 2-phenyl-prop-2-yl (C9H11) rapidly eliminates a hydrogen atom to form 2-phenylpropene (C9H10). If hydrogen atoms or other reactive radicals are available to make a direct hydrogen-atom abstraction from butylbenzenes possible, the C10H13 radicals (1-phenyl-but-1-yl, 2-phenyl-but-2-yl, and t-phenyl-isobutyl) can be formed as the primary products from n-, s-, and t-butylbenzene, respectively. The secondary decomposition of 1-phenyl-but-1-yl leads to styrene (C8H8) + ethyl (C2H5), whereas 2-phenyl-but-2-yl and t-phenyl-isobutyl dissociate to 2-phenylpropene (C9H10) + methyl (CH3). Thus, the three butylbenzene isomers produce distinct but overlapping nascent pyrolysis fragments, which likely affect the successive oxidation mechanism and combustion kinetics of these JP-8 fuel components. Temperature- and pressure-dependent rate constants generated for the initial stages of pyrolysis of butylbenzenes are recommended for kinetic modeling. PMID- 29608300 TI - Structure-Activity Relationship Study of Cyclic Pentapeptide Ligands for Atypical Chemokine Receptor 3 (ACKR3). AB - The atypical chemokine receptor 3 (ACKR3)/CXC chemokine receptor 7 (CXCR7) recognizes stromal cell-derived factor 1 (SDF-1)/CXCL12 and is involved in a number of physiological and pathological processes. Here, we investigated the SAR of the component amino acids in an ACKR3-selective ligand, FC313 [ cyclo(-d-Tyr-l Arg-l-MeArg-l-Nal(2)-l-Pro-)], for the development of highly active ACKR3 ligands. Notably, modification at the l-Pro position with a bulky hydrophobic side chain led to improved bioactivity toward ACKR3. PMID- 29608301 TI - Model Behavior: Characterization of Hydroxyacetone at the Air-Water Interface Using Experimental and Computational Vibrational Sum Frequency Spectroscopy. AB - Small atmospheric aldehydes and ketones are known to play a significant role in the formation of secondary organic aerosols (SOA). However, many of them are difficult to experimentally isolate, as they tend to form hydration and oligomer species. Hydroxyacetone (HA) is unusual in this class as it contributes to SOA while existing predominantly in its unhydrated monomeric form. This allows HA to serve as a valuable model system for similar secondary organic carbonyls. In this paper the surface behavior of HA at the air-water interface has been investigated using vibrational sum frequency (VSF) spectroscopy and Wilhelmy plate surface tensiometry in combination with computational molecular dynamics simulations and density functional theory calculations. The experimental results demonstrate that HA has a high degree of surface activity and is ordered at the interface. Furthermore, oriented water is observed at the interface, even at high HA concentrations. Spectral features also reveal the presence of both cis and trans HA conformers at the interface, in differing orientations. Molecular dynamics results indicate conformer dependent shifts in HA orientation between the subsurface (~5 A deep) and surface. Together, these results provide a picture of a highly dynamic, but statistically ordered, interface composed of multiple HA conformers with solvated water. These results have implications for HA's behavior in aqueous particles, which may affect its role in the atmosphere and SOA formation. PMID- 29608302 TI - Evidence for a Bis(Elongated sigma)-Dihydrideborate Coordinated to Osmium. AB - The formation and Atoms in Molecules (AIM) analysis of osmium(IV) and osmium(II) complexes containing dihydrideborate groups and primary aminoborane ligands are reported. Complex OsH6(P iPr3)2 (1) loses a hydrogen molecule and the resulting unsaturated OsH4(P iPr3)2 species coordinates 9-borabicycle[3.3.1]nonane (HBbn) and pinacolborane (HBpin) to give the dihydrideborate derivatives OsH3{kappa2- H, H-(H2BR2)}(P iPr3)2 (BR2 = Bbn (2), Bpin (3)). The bonding situation in these compounds and in the related osmium(II) derivative Os(Bcat){kappa2- H, H (H2Bcat)}(CO)(P iPr3)2 (4) (HBcat = catecholborane) has been analyzed by the AIM method. The Laplacian distributions in the Os-H-B plane exhibit a four-membered cyclic topology possessing two Os-H and two B-H bond critical points associated with one OsHHB ring critical point, which resembles that found for B2H6. The tetrahydride OsH4(P iPr3)2 also coordinates catecholborane, which initially affords OsH3{kappa2- H, H-(H2Bcat)}(P iPr3)2 (5). In contrast to 2 and 3, complex 5 reacts with a second molecule of HBcat to give the elongated sigma-borane {bis(elongated sigma) -dihydrideborate}-osmium(II) derivative OsH(eta3 H2Bcat)(eta2-HBcat)(P iPr3)2 (6). Complexes 5 and 6 have been also analyzed via the AIM method. Complex 5 displays the same topology as complexes 2-4. However, the OsH2B unit of 6 shows, besides the Os-H and B-H bond critical points, an additional Os-B bond critical point, which is associated with a bond path running between these atoms. This double triangular topology is completed with the respective ring critical points. Reactions of 1 with dimethylamine-borane (H3B.NHMe2) and tert-butylamine-borane (H3B.NH2tBu) give OsH2(eta2:eta2-H2BNR2)(P iPr3)2 (NR2 = NMe2 (7), NH tBu (8)). The AIM analyses of 7 and 8 also reveal the occurrence of an Os-B bond critical point associated with a bond path running between those atoms. However, neither Os-H bond critical points nor bond paths are observed in the latter species. PMID- 29608303 TI - Virtual Screening of Novel and Selective Inhibitors of Protein Tyrosine Phosphatase 1B over T-Cell Protein Tyrosine Phosphatase Using a Bidentate Inhibition Strategy. AB - Protein tyrosine phosphatase 1B (PTP1B), a promising target for type II diabetes, obesity, and cancer therapeutics, plays an important negative role in insulin signaling pathways. However, the lack of selectivity over other PTPs, especially for T-cell protein tyrosine phosphatase (TCPTP), is still a challenge for inhibitor development. Recent studies have suggested that the second phosphotyrosine (pTyr) binding site, close to the catalytic domain, may elevate binding affinity while bringing selectivity to inhibitors. Inspired by these studies, a virtual screening method based on a bidentate strategy was employed to identify novel selective inhibitors of PTP1B. Targeting both the active site and the second pTyr binding site of PTP1B, three compounds (CD00466, JFD02943, JFD02945) were found to be competitive inhibitors ( Ki range from 1.79 to 10.49 MUM). The most effective compound, CD00466, exhibited selectivity over TCPTP (31 fold). Using molecular dynamics simulation and the MM/GBSA binding free energy calculation, this study confirmed that the three inhibitors bound to PTP1B in a bidentate pattern. Our work indicates that bidentate virtual screening is a potential approach to the further investigation of selective PTP1B inhibitors. PMID- 29608304 TI - Cations Modulate Actin Bundle Mechanics, Assembly Dynamics, and Structure. AB - Actin bundles are key factors in the mechanical support and dynamic reorganization of the cytoskeleton. High concentrations of multivalent counterions promote bundle formation through electrostatic attraction between actin filaments that are negatively charged polyelectrolytes. In this study, we evaluate how physiologically relevant divalent cations affect the mechanical, dynamic, and structural properties of actin bundles. Using a combination of total internal reflection fluorescence microscopy, transmission electron microscopy, and dynamic light scattering, we demonstrate that divalent cations modulate bundle stiffness, length distribution, and lateral growth. Molecular dynamics simulations of an all-atom model of the actin bundle reveal specific actin residues coordinate cation-binding sites that promote the bundle formation. Our work suggests that specific cation interactions may play a fundamental role in the assembly, structure, and mechanical properties of actin bundles. PMID- 29608305 TI - Dual Tuning of Ni-Co-A (A = P, Se, O) Nanosheets by Anion Substitution and Holey Engineering for Efficient Hydrogen Evolution. AB - Seeking earth-abundant electrocatalysts with high efficiency and durability has become the frontier of energy conversion research. Mixed-transition-metal (MTM) based electrocatalysts, owing to the desirable electrical conductivity, synergistic effect of bimetal atoms, and structural stability, have recently emerged as new-generation hydrogen evolution reaction (HER) electrocatalysts. However, the correlation between anion species and their intrinsic electrocatalytic properties in MTM-based electrocatalysts is still not well understood. Here we present a novel approach to tuning the anion-dependent electrocatalytic characteristics in MTM-based catalyst for HER, using holey Ni/Co based phosphides/selenides/oxides (Ni-Co-A, A = P, Se, O) as the model materials. The electrochemical results, combined with the electrical conductivity measurement and DFT calculation, reveal that P substitution could modulate the electron configuration, lower the hydrogen adsorption energy, and facilitate the desorption of hydrogen on the active sites in Ni-Co-A holey nanostructures, resulting in superior HER catalytic activity. Accordingly we fabricate the NCP holey nanosheet electrocatalyst for HER with an ultralow onset overpotential of nearly zero, an overpotential of 58 mV, and long-term durability, along with an applied potential of 1.56 V to boost overall water splitting at 10 mA cm-2, among the best electrocatalysts reported for non-noble-metal catalysts to date. This work not only presents a deeper understanding of the intrinsic HER electrocatalytic properties for MTM-based electrocatalyst with various anion species but also offers new insights to better design efficient and durable water splitting electrocatalysts. PMID- 29608306 TI - Hydrothermal Synthesis, Study, and Classification of Microporous Uranium Silicates and Germanates. AB - Four novel uranyl silicates and germanates with framework structures, K4Na2(UO2)3(Si2O7)2.3H2O, K4Na2(UO2)3(Ge2O7)2.3H2O, H3O(UO2)2(HGe2O7).2H2O, and Na2(UO2)GeO4, have been synthesized by means of the hydrothermal method. The structures of the title compounds were refined by single-crystal X-ray diffraction and characterized by Raman spectroscopy. We used the method of secondary building units (SBUs) for a crystal chemical analysis of the 3D framework and their topologies. The framework of the K4Na2(UO2)3(T2O7)2.3H2O (T = Si, Ge) series exhibits large 14-membered rings and smaller 8-membered rings which are built upon [UT4] pentamers. The internal size of the largest pores is approximately 12.39 * 3.33 A2. H3O(UO2)2(HGe2O7).2H2O is based on 10-membered rings with intermediate sized pores. They are built upon [U2Ge2] tetramers with 7 fold-coordinated U. The internal dimension of the pores in H3O(UO2)2(HGe2O7).2H2O is smaller compared to the K4Na2(UO2)3(T2O7)2.3H2O (T = Si, Ge) series with ~5.91 * 5.33 A2. Its topology is similar to several uranium germanate synthetic phases and silicate minerals, especially alpha- and beta-uranophane which are constructed from similar building units. A novel 3D framework type of Na2(UO2)GeO4 with 8-membered rings demonstrates the smallest free volume in the family of porous uranium germanates. It crystallizes in tetragonal symmetry and is built upon corner sharing of [UGe4] pentamers. The size of the channels is ~6.76 * 4.27 A2. The vibrational bands in Raman spectra were associated with pyro (Si2O7)6- and -(Ge2O7)6- groups, with the Ge-OH bond and with H3O+ cations, confirming the results of the X-ray crystallographic structural characterization. We systemized existing uranyl silicates and germanates based on their building units and chemical composition. We found a simple structural dependence between synthetic conditions and chemical composition. PMID- 29608307 TI - Metabolite Profiling of Candidatus Liberibacter Infection in Hamlin Sweet Oranges. AB - Huanglongbing (HLB), also known as citrus greening disease, caused by Candidatus Liberibacter asiaticus (CLas), is considered the most serious citrus disease in the world. CLas infection has been shown to greatly affect metabolite profiles in citrus fruits. However, because of uneven distribution of CLas throughout the tree and a minimum bacterial titer requirement for polymerase chain reaction (PCR) detection, the infected trees may test false negative. To prevent this, metabolites of healthy Hamlin oranges (CLas-) obtained from the citrus undercover protection systems (CUPS) were investigated. Comparison of the metabolite profile of juice obtained from CLas- and CLas+ (asymptomatic and symptomatic) trees revealed significant differences in both volatile and nonvolatile metabolites. However, no consistent pattern could be observed in alcohols, esters, sesquiterpenes, sugars, flavanones, and limonoids as compared to previous studies. These results suggest that CLas may affect metabolite profiles of citrus fruits earlier than detecting infection by PCR. Citric acid, nobiletin, malic acid, and phenylalanine were identified as the metabolic biomarkers associated with the progression of HLB. Thus, the differential metabolites found in this study may serve as the biomarkers of HLB in its early stage, and the metabolite signature of CLas infection may provide useful information for developing a potential treatment strategy. PMID- 29608308 TI - Halterman Corroles and Their Use as a Probe of the Conformational Dynamics of the Inherently Chiral Copper Corrole Chromophore. AB - Halterman corroles have been synthesized for the first time from pyrrole and Halterman's aldehyde via Gryko's "water-methanol method". These were derivatized to the corresponding copper complexes and subsequently to the beta-octabromo complexes. Electronic circular dichroism spectra were recorded for the enantiopure copper complexes, affording the first such measurements for the inherently chiral Cu corrole chromophore. Interestingly, for a given configuration of the Halterman substituents, X-ray crystallographic studies revealed both P and M conformations of the Cu-corrole core, proving that the substituents, even in conjunction with beta-octabromination, are unable to lock the Cu-corrole core into a given chirality. The overall body of evidence strongly indicates a dynamic equilibrium between the P and M conformations. Such an interconversion, which presumably proceeds via saddling inversion, provides a rationale for our failure so far to resolve sterically hindered Cu corroles into their constituent enantiomers by means of chiral HPLC. PMID- 29608309 TI - Synergistic Anion-(pi) n-pi Catalysis on pi-Stacked Foldamers. AB - In this report, we demonstrate that synergistic effects between pi-pi stacking and anion-pi interactions in pi-stacked foldamers provide access to unprecedented catalytic activity. To elaborate on anion-(pi) n-pi catalysis, we have designed, synthesized and evaluated a series of novel covalent oligomers with up to four face-to-face stacked naphthalenediimides (NDIs). NMR analysis including DOSY confirms folding into pi stacks, cyclic voltammetry, steady-state and transient absorption spectroscopy the electronic communication within the pi stacks. Catalytic activity, assessed by chemoselective catalysis of the intrinsically disfavored but biologically relevant addition reaction of malonate half thioesters to enolate acceptors, increases linearly with the length of the stacks to reach values that are otherwise beyond reach. This linear increase violates the sublinear power laws of oligomer chemistry. The comparison of catalytic activity with ratiometric changes in absorption and decreasing energy of the LUMO thus results in superlinearity, that is synergistic amplification of anion-pi catalysis by remote control over the entire stack. In computational models, increasing length of the pi-stacked foldamers correlates sublinearly with changes in surface potentials, chloride binding energies, and the distances between chloride and pi surface and within the pi stack. Computational evidence is presented that the selective acceleration of disfavored but relevant enolate chemistry by anion-pi catalysis indeed originates from the discrimination of planar and bent tautomers with delocalized and localized charges, respectively, on pi-acidic surfaces. Computed binding energies of keto and enol intermediates of the addition reaction as well as their difference increase with increasing length of the pi stack and thus reflect experimental trends correctly. These results demonstrate that anion-(pi) n-pi interactions exist and matter, ready for use as a unique new tool in catalysis and beyond. PMID- 29608310 TI - Copying of Mixed-Sequence RNA Templates inside Model Protocells. AB - The chemical replication of RNA inside fatty acid vesicles is a plausible step in the emergence of cellular life. On the primitive Earth, simple protocells with the ability to import nucleotides and short oligomers from their environment could potentially have replicated and retained larger genomic RNA oligonucleotides within a spatially defined compartment. We have previously shown that short 5'-phosphoroimidazolide-activated "helper" RNA oligomers enable the nonenzymatic copying of mixed-sequence templates in solution, using 5' phosphoroimidazolide-activated mononucleotides. Here, we report that citrate chelated Mg2+, a catalyst of nonenzymatic primer extension, enhances fatty acid membrane permeability to such short RNA oligomers up to the size of tetramers, without disrupting vesicle membranes. In addition, selective permeability of short, but not long, oligomers can be further enhanced by elevating the temperature. The ability to increase the permeability of fatty acid membranes to short oligonucleotides allows for the nonenzymatic copying of RNA templates containing all four nucleotides inside vesicles, bringing us one step closer to the goal of building a protocell capable of Darwinian evolution. PMID- 29608311 TI - Determinative Surface-Wrinkling Microstructures on Polypyrrole Films by Laser Writing. AB - We report a simple and efficient laser-writing strategy to fabricate hierarchical nested wrinkling microstructures on conductive polypyrrole (PPy) films, which enables us to develop advanced functional surfaces with diverse applications. The present strategy adopts the photothermal effect of PPy films to mimick the formation of hierarchical nested wrinkles observed in nature and design controlled microscale wrinkling patterns. Here, the PPy film is grown on a poly(dimethylsiloxane) (PDMS) substrate via oxidation polymerization of pyrrole in an acidic solution, accompanied by in situ self-wrinkling with wavelengths of two different scales (i.e., lambda1 and lambda2). Subsequent laser exposure of the PPy/PDMS bilayer induces a new surface wrinkling with a larger wavelength (i.e., lambda3). Owing to the retention of the initial lambda1 wrinkles, we obtain hierarchical nested wrinkles with the smaller lambda1 wrinkles nested in the larger lambda3 ones. Importantly, we realize the large-scale path determinative fabrication of complex oriented wrinkling microstructures by controlling the relative motion between the bilayer and the laser. Combined with the induced changes in surface color, surface-wrinkling microstructures, and conductivity in the PPy films, the laser-writing strategy can find broad applications, for example, in modulation of surface wetting properties and fabrication of microcircuits, as demonstrated in this work. PMID- 29608312 TI - Short Drug-Light Intervals Improve Liposomal Chemophototherapy in Mice Bearing MIA PaCa-2 Xenografts. AB - Chemophototherapy (CPT) is an emerging tumor treatment that combines phototherapy and chemotherapy. Long-circulating (LC) liposomes can stably incorporate 2 mol % porphyrin-phospholipid (PoP) in the bilayer and load doxorubicin (Dox) to generate LC-Dox-PoP liposomes, for single-agent CPT. Following intravenous administration to mice, LC-Dox-PoP liposomes (2 mg/kg Dox) circulated with similar blood concentration ranges produced by a typical human clinical dose of DOXIL (50 mg/m2 Dox). This dosing approach aims to achieve physiologically relevant Dox and PoP concentrations as well as CPT vascular responses in mice bearing subcutaneous human pancreatic MIA PaCa-2 xenografts. Phototreatment with 2 mg/kg LC-Dox-PoP induced vascular permeabilization, leading to a 12.5-fold increase in Dox tumor influx estimated by a pharmacokinetic model, based on experimental data. Shorter drug-light intervals (0.5-3 h) led to greater tumoral drug deposition and improved treatment outcomes, compared to longer drug-light intervals. At 2 mg/kg Dox, CPT with LC-Dox-PoP liposomes induced tumor regression and growth inhibition, whereas chemotherapy using several other formulations of Dox did not. LC-Dox-PoP liposomes were well tolerated at the 2 mg/kg dose. PMID- 29608313 TI - Remote Electronic Control of DNA-Based Reactions and Nanostructure Assembly. AB - The use of synthetic DNA to design and build molecular machines and well-defined structures at the nanoscale has greatly impacted the field of nanotechnology. Here we expand the current toolkit in this field by demonstrating an efficient, quantitative, and versatile approach that allows us to remotely control DNA-based reactions and DNA nanostructure self-assembly using electronic inputs. To do so we have deposited onto the surface of disposable chips different DNA input strands that upon the application of a cathodic potential can be desorbed in a remote and controlled way and trigger DNA-based reactions and DNA nanostructure self-assembly. We demonstrate that this effect is specific and versatile and allows the orthogonal control of multiple reactions and multiple structures in the same solution. Moreover, the strategy is highly tunable and can be finely modulated by varying the cathodic potential, the period of applied potential, and the density of the DNA strand on the chip surface. Our approach thus represents a versatile way to remotely control DNA-based circuits and nanostructure assembly and can allow new possible applications of DNA-based nanotools. PMID- 29608314 TI - Stereoselective Synthesis of Optically Pure 2-Amino-2'-hydroxy-1,1'-binaphthyls. AB - Direct entry to optically pure 2-amino-2'-hydroxy-1,1'-binaphthyl (NOBIN) derivatives by an iron-catalyzed stereoselective oxidative cross-coupling reaction between 2-naphthol and 2-aminonaphthalene with a labile chiral auxiliary is reported. This efficient method offers entry to tailor-designed ( R a)- and ( S a)-NOBINs that are not accessible by any other means. PMID- 29608315 TI - One-Pot Synthesis of a Bismuth Selenide Hexagon Nanodish Complex for Multimodal Imaging-Guided Combined Antitumor Phototherapy. AB - For integrating therapy and diagnosis into a single nanoparticle for higher antitumor efficiency and lower toxicity, our group designed a smart theranostic nanoplatform based on a hyaluronic acid-doped polypyrrole-coated bismuth selenide loading with a zinc phthalocyanine nanodish complex (Bi2Se3@HA-doped PPy/ZnPc) for multimodal imaging-guided combined phototherapy. Moreover, we expect that the HA-doped PPy smart shell for the surface functionalization will also be applied to a variety of 2D nanomaterials sharing a similar structure with Bi2Se3 to broaden their applications in biomedicine. The Bi2Se3 hexagon nanodish was synthesized via a simple and safe solution-based method compared to the commonly adopted ones. A one-pot synthesis of the naoncomplex was carried out by adding HA during the polypyrrole coating on the Bi2Se3 process, and then it was further loaded with ZnPc. Besides the good ability for infrared thermal, photoacoustic, fluorescence, and X-ray computed tomography imaging, the nanodish complex has its own high photoheat conversion efficiency for photothermal therapy, and it has remarkable optical absorption of the coefficient for photodynamic therapy. With the EPR effect of nanoparticles and the CD44-targeted effect of HA, the tumor growth inhibition ratio of Bi2Se3@HA-doped PPy/ZnPc for PTT/PDT was as high as 96.4%, compared with that of the PTT (68.0%) or PDT (24.3%) alone, showing an excellent combined therapeutic effect. Moreover, no obvious toxicity in vivo was caused by the nanoparticles. Thus, such a Bi2Se3@HA-doped PPy/ZnPc nanodish complex has promise for real-time monitoring and precise, high-efficiency antitumor treatment. PMID- 29608316 TI - Room Temperature Intrinsic Ferromagnetism in Epitaxial Manganese Selenide Films in the Monolayer Limit. AB - Monolayer van der Waals (vdW) magnets provide an exciting opportunity for exploring two-dimensional (2D) magnetism for scientific and technological advances, but the intrinsic ferromagnetism has only been observed at low temperatures. Here, we report the observation of room temperature ferromagnetism in manganese selenide (MnSe x) films grown by molecular beam epitaxy (MBE). Magnetic and structural characterization provides strong evidence that, in the monolayer limit, the ferromagnetism originates from a vdW manganese diselenide (MnSe2) monolayer, while for thicker films it could originate from a combination of vdW MnSe2 and/or interfacial magnetism of alpha-MnSe(111). Magnetization measurements of monolayer MnSe x films on GaSe and SnSe2 epilayers show ferromagnetic ordering with a large saturation magnetization of ~4 Bohr magnetons per Mn, which is consistent with the density functional theory calculations predicting ferromagnetism in monolayer 1T-MnSe2. Growing MnSe x films on GaSe up to a high thickness (~40 nm) produces alpha-MnSe(111) and an enhanced magnetic moment (~2*) compared to the monolayer MnSe x samples. Detailed structural characterization by scanning transmission electron microscopy (STEM), scanning tunneling microscopy (STM), and reflection high energy electron diffraction (RHEED) reveals an abrupt and clean interface between GaSe(0001) and alpha MnSe(111). In particular, the structure measured by STEM is consistent with the presence of a MnSe2 monolayer at the interface. These results hold promise for potential applications in energy efficient information storage and processing. PMID- 29608317 TI - Highly Efficient Visible Colloidal Lead-Halide Perovskite Nanocrystal Light Emitting Diodes. AB - Lead-halide perovskites have been attracting attention for potential use in solid state lighting. Following the footsteps of solar cells, the field of perovskite light-emitting diodes (PeLEDs) has been growing rapidly. Their application prospects in lighting, however, remain still uncertain due to a variety of shortcomings in device performance including their limited levels of luminous efficiency achievable thus far. Here we show high-efficiency PeLEDs based on colloidal perovskite nanocrystals (PeNCs) synthesized at room temperature possessing dominant first-order excitonic radiation (enabling a photoluminescence quantum yield of 71% in solid film), unlike in the case of bulk perovskites with slow electron-hole bimolecular radiative recombination (a second-order process). In these PeLEDs, by reaching charge balance in the recombination zone, we find that the Auger nonradiative recombination, with its significant role in emission quenching, is effectively suppressed in low driving current density range. In consequence, these devices reach a maximum external quantum efficiency of 12.9% and a power efficiency of 30.3 lm W-1 at luminance levels above 1000 cd m-2 as required for various applications. These findings suggest that, with feasible levels of device performance, the PeNCs hold great promise for their use in LED lighting and displays. PMID- 29608319 TI - Warm autoadsorption using ZZAP. AB - CONCLUSIONS: The masking of clinically significant alloantibodies by warm autoantibodies presents challenges in pretransfusion testing. The adoption of transfusion practices such as the issuing of "least incompatible" red blood cells (RBCs) without a complete antibody workup is potentially unsafe for patients. Several autoadsorption methods can be used to remove autoantibody reactivity. ZZAP treatment of autologous RBCs is an efficient way to prepare the cells for autoadsorption. Autoadsorbed serum or plasma can then be used to remove autoantibody reactivity and identify clinically significant alloantibodies. PMID- 29608320 TI - A brief overview of clinical significance of blood group antibodies. AB - CONCLUSIONS: This review was derived from a presentation made on September 2, 2016 for the first Academy Day presented by the Working Party on Immunohematology at the International Society of Blood Transfusion (ISBT) Congress in Dubai. The focus of this review is to provide a brief overview of the clinical significance of blood group antibodies. Blood group antibodies can be naturally occurring (e.g., anti-A and anti-B through exposure to naturally occurring red blood cell [RBC] antigen-like substances) or can occur via exposure to foreign (donor) RBC antigens through previous transfusions, transplants, or exposure to fetal RBCs during or after pregnancy. However, not all blood group antibodies are clinically significant. Clinically significant blood group antibodies can cause adverse events after blood component transfusion or transplantation and/or can cause hemolytic disease of the fetus and newborn. PMID- 29608321 TI - Management of pregnancy sensitized with anti-Inb with monocyte monolayer assay and maternal blood donation. AB - CONCLUSIONS: Maternal red blood cell (RBC) alloantibodies can cause hemolytic disease of the fetus and newborn (HDFN). Although much is described about common antibodies associated with HDFN, management of a pregnancy complicated by a maternal rare antibody presents several challenges related to assessment of fetal anemia risk, availability of blood for transfusion to the mother and/or the fetus or newborn if needed, and planning for delivery in the case of maternal hemorrhage. Here we report the laboratory medicine workup of a patient who presented for obstetrical care in the United States in the third trimester and had a rare antibody (anti-Inb). Prenatal antibody detection testing demonstrated maternal anti-Inb in a 28-year-old woman (gravida 4 para 1021). Ultrasound could not rule out fetal anemia. Monocyte monolayer assay was performed to assess for the clinical significance of the anti-Inb and revealed that the antibody may be capable of causing accelerated clearance of antigen-positive RBCs. A local and national query revealed that no appropriate units of RBCs were available for either the mother or neonate. Given this information, serial maternal autologous blood donations were performed, and a comprehensive care plan with a multidisciplinary approach for delivery, neonatal management, and preparation for hemorrhage was developed. Published data and our experience suggest that maternal blood donation appears to be a safe and effective way to manage mothers who cannot safely use the community blood supply. Involvement of obstetric, transfusion medicine, anesthesia, and neonatology providers was imperative for a favorable outcome. The antibody did not cause clinically significant anemia in this infant. PMID- 29608322 TI - A review of in vitro methods to predict the clinical significance of red blood cell alloantibodies. AB - CONCLUSIONS: This review was derived from a presentation made on September 2, 2016, for the first Academy Day presented by the Working Party on Immunohematology at the International Society of Blood Transfusion (ISBT) Congress in Dubai. The focus of this review is on the clinical significance of alloimmunization in transfusion-specifically, the parameters that contribute to a clinically significant alloantibody. The areas of focus were as follows: Introduction, Technical Aspects, and Indications and Limitations. Each section contains a brief review of selected literature and experiential knowledge. Case reports are needed to collect data on current outcomes of incompatible transfusion. The ISBT Working Party on Rare Donors has developed a form to capture case-specific information. PMID- 29608323 TI - Recovery of autologous sickle cells by hypotonic wash. AB - CONCLUSIONS: It is important to isolate autologous red blood cells (RBCs) from transfused RBCs in samples from recently transfused patients to ensure that accurate serologic results are obtained. Typically, this isolation can be performed using methods that separate patient reticulocytes from transfused, older donor RBCs. Patients with sickle cell disease (SCD), however, characteristically have RBCs with altered membrane and morphological features, causing their RBCs to take on a sickle-shape appearance different from the biconcave disc-shape appearance of "normal" RBCs. These characteristics enable the use of hypotonic saline solution to lyse normal RBCs while allowing "sickle cells" to remain intact. Because many patients with SCD undergo frequent transfusions to treat their condition, the use of hypotonic saline solution provides a rapid method to obtain autologous RBCs for serologic testing from this patient population using standard laboratory equipment and supplies. PMID- 29608318 TI - Improved Predictions of Drug-Drug Interactions Mediated by Time-Dependent Inhibition of CYP3A. AB - Time-dependent inactivation (TDI) of cytochrome P450s (CYPs) is a leading cause of clinical drug-drug interactions (DDIs). Current methods tend to overpredict DDIs. In this study, a numerical approach was used to model complex CYP3A TDI in human-liver microsomes. The inhibitors evaluated included troleandomycin (TAO), erythromycin (ERY), verapamil (VER), and diltiazem (DTZ) along with the primary metabolites N-demethyl erythromycin (NDE), norverapamil (NV), and N-desmethyl diltiazem (NDD). The complexities incorporated into the models included multiple binding kinetics, quasi-irreversible inactivation, sequential metabolism, inhibitor depletion, and membrane partitioning. The resulting inactivation parameters were incorporated into static in vitro-in vivo correlation (IVIVC) models to predict clinical DDIs. For 77 clinically observed DDIs, with a hepatic CYP3A-synthesis-rate constant of 0.000 146 min-1, the average fold difference between the observed and predicted DDIs was 3.17 for the standard replot method and 1.45 for the numerical method. Similar results were obtained using a synthesis-rate constant of 0.000 32 min-1. These results suggest that numerical methods can successfully model complex in vitro TDI kinetics and that the resulting DDI predictions are more accurate than those obtained with the standard replot approach. PMID- 29608324 TI - The devil is in the details: retention of recipient group A type 5 years after a successful allogeneic bone marrow transplant from a group O donor. AB - CONCLUSIONS: ABO-incompatible (ABOi) hematopoietic stem cell transplants (HSCTs) can present challenges in the blood bank. During transplantation, patients receive components that are ABO-compatible with both the donor graft and recipient; this practice can strain group O red blood cell (RBC) inventories.1 In addition, there are risks for acute hemolysis at the time of infusion and in the early post-transplant period.1,2 In ABO major-incompatible bone marrow HSCTs, which contain significant quantities of donor RBCs that are ABOi with recipient plasma, it is common to perform a RBC depletion of the bone marrow in an effort to minimize hemolysis at the time of infusion.2 Furthermore, patients with high titer ABO antibodies may undergo a prophylactic, pre-transplant plasma exchange to further reduce the risk of acute hemolysis, delayed RBC engraftment, and pure RBC aplasia.2-4 ABO minor-incompatible HSCTs, in which donor plasma is ABOi with the recipient, have less risk for hemolysis at the time of infusion but can result in transient hemolysis approximately 10-21 days post-transplant, especially in patients undergoing nonmyeloablative HSCT and/or patients who have not received methotrexate for graft-versus-host-disease (GVHD) prophylaxis.1-4 In these patients, viable donor B-lymphocytes in the graft may expand and produce ABO antibodies capable of hemolyzing patient RBCs. PMID- 29608325 TI - Discrimination, Harassment, and Gendered Health Inequalities: Do Perceptions of Workplace Mistreatment Contribute to the Gender Gap in Self-reported Health? AB - This study examines the extent to which discrimination and harassment contribute to gendered health disparities. Analyzing data from the 2006, 2010, and 2014 General Social Surveys ( N = 3,724), we ask the following: (1) To what extent are perceptions of workplace gender discrimination and sexual harassment associated with self-reported mental and physical health? (2) How do multiple forms of workplace mistreatment (e.g., racism, ageism, and sexism) combine to structure workers' self-assessed health? and (3) To what extent do perceptions of mistreatment contribute to the gender gap in self-assessed health? Multivariate analyses show that among women, but not men, perceptions of workplace gender discrimination are negatively associated with poor mental health, and perceptions of sexual harassment are associated with poor physical health. Among men and women, perceptions of multiple forms of mistreatment are associated with worse mental health. Gender discrimination partially explains the gender gap in self reported mental health. PMID- 29608326 TI - A Statewide Quality Improvement Collaborative to Increase Breastfeeding Rates in Tennessee. AB - BACKGROUND AND OBJECTIVES: Tennessee has low breastfeeding rates and has identified opportunities for improvement to enhance maternity practices to support breastfeeding mothers. We sought a 10% relative increase in the aggregate Joint Commission measure of breastfeeding exclusivity at discharge (TJC PC-05) by focusing on high-reliability (>=90%) implementation of processes that promote breastfeeding in the delivery setting. METHODS: A statewide, multidisciplinary development team reviewed evidence from the WHO-UNICEF "Ten Steps to Successful Breastfeeding" to create a consensus toolkit of process indicators aligned with the Ten Steps. Hospitals submitted monthly TJC PC-05 data for 6 months while studying local implementation of the Ten Steps to identify improvement opportunities, and for an additional 11 months while conducting tests of change to improve Ten Steps implementation using Plan-Do-Study-Act cycles, local process audits, and control charts. Data were aggregated at the state level and presented at 12 monthly webinars, 3 regional learning sessions, and 1 statewide meeting where teams shared their local data and implementation experiences. RESULTS: Thirteen hospitals accounting for 47% of live births in Tennessee submitted data on 31,183 mother-infant dyads from August 1, 2012, to December 31, 2013. Aggregate monthly mean PC-05 demonstrated "special cause" improvement increasing from 37.1% to 41.2%, an 11.1% relative increase. Five hospitals reported implementation of >=5 of the Ten Steps and two hospitals reported >=90% reliability on >=5 of the Ten Steps using locally designed process audits. CONCLUSION: Using large-scale improvement methodology, a successful statewide collaborative led to >10% relative increase in breastfeeding exclusivity at discharge in participating Tennessee hospitals. Further opportunities for improvement in implementing breastfeeding supportive practices were identified. PMID- 29608327 TI - Association Between Breastfeeding and Childhood Breathing Patterns: A Systematic Review and Meta-Analysis. AB - OBJECTIVES: This systematic review aimed to evaluate the association between breastfeeding and breathing patterns in children. MATERIALS AND METHODS: We searched PubMed, EMBASE, Web of Science, CINAHL, and the Cochrane Central Register of Controlled Trials for publications from inception to October 1, 2017. The breastfeeding duration and period of exclusive breastfeeding were selected as primary outcomes. The odds ratio (OR) and 95% confidence interval (CI) were calculated. A meta-analysis was conducted to synthesize the evidence. The Newcastle-Ottawa Score was used for quality and comparability assessment. RESULTS: Of the 54 articles identified, three observational studies met the inclusion criteria for this meta-analysis, representing 1,046 participants. The results of the meta-analysis revealed that the prevalence rate of mouth breathing (OR = 2.04; 95% CI, 1.26-3.31; p = 0.004) was significantly higher in subjects who were breastfed for less than 6 months, but no significant difference was observed within the periods of exclusive breastfeeding (6 months or less) (OR = 1.27; 95% CI, 0.73-2.21; p = 0.40). CONCLUSION: We found only limited evidence about the association between breastfeeding and breathing patterns. However, the current evidence supports the association between breastfeeding and childhood breathing patterns. Based on this review, we found that the frequency of normal nasal respiration increases with the duration of breastfeeding. The methodological quality of the studies included was moderate. Thus, future studies should aim to correct the confounding factors related to breathing patterns, to use standardized diagnostic criteria of mouth breathing, and to conduct a prospective research to reduce the recall bias. PMID- 29608328 TI - Mental health care treatment seeking among African Americans and Caribbean Blacks: what is the role of religiosity/spirituality? AB - OBJECTIVES: As adults increase in age, the likelihood for using mental health care services decrease. Underutilization, expecially among racial/ethnic minorities such as African American and Caribbean Blacks, can result in a decrease in quality of life, as well as significant costs to families, employers, and health systems. METHODS: The study explored the differences in relationships between mental health care usage and strength of religious/spiritual beliefs between African American and Caribbean Black older adults (54 years or older) and adults (18-53 years) using data from the National Survey of American Life (NSAL). Descriptive statistics and logistic regression analyses were conducted using Stata version 13.1. RESULTS: Subjective ratings about the strength of religious/spiritual beliefs (OR = 1.26; 95 CI: 0.99, 1.61), age (OR = 0.62; 95 CI: 0.48, 0.81), and sex (OR = 1.59; 95 CI: 1.25, 2.02) were significantly associated with the odds of seeking mental health care. Additionally, persons living in the South were less likely to seek mental health care services (OR = 0.47; 95 CI: 0.37, 0.60). CONCLUSION: Strong religious/spiritual beliefs may promote mental health care usage. Future studies should examine the strength of religious/spiritual beliefs on mental health care usage among different demographic groups. PMID- 29608329 TI - Treating Diabetes During Breastfeeding. PMID- 29608330 TI - A Novel Target of p53, TCF21, Can Respond to Hypoxia by MAPK Pathway Inactivation in Uterine Corpus Endometrial Carcinoma. AB - Uterine corpus endometrial carcinoma (UCEC) is a common malignancy in the female reproductive system, associated with high morbidity and mortality. Despite the high prevalence of UCEC, molecular understanding of uterine endothelium tumorigenesis remains poorly understood. In this study, we reported that transcription factor 21 (TCF21) inhibits cancer cell proliferation and invasion following overexpression, in vitro and in vivo. Moreover, in response to hypoxia, TCF21 is highly expressed in UCEC cells carrying wild-type p53, and is transcriptional target of p53. We observed that TCF21 interferes with the MAP kinase pathway, which is supported by a substantially reduced level of phosphorylated mitogen-activated protein kinase 1 (MAPK1 or ERK) in cells expressing a higher level of TCF21. Furthermore, we identified the specific region of TCF21 that is responsible for its interaction with mitogen-activated protein kinase 1 (MEK) and a subsequently reduced activity of ERK. Using molecular docking and mutagenesis analysis, we validated a special domain of TCF21, which can reduce the activity of the MAPK pathway and inhibit uterine endothelium tumor cell growth in vitro. Overall, our study determined that TCF21, a hypoxia-driven p53 target, functions as a tumor suppressor in UCEC and presents as a therapeutic target for tumor treatment. PMID- 29608331 TI - rSjP40 protein promotes PPARgamma expression in LX-2 cells through microRNA-27b. AB - miR-27b is reported to participate in the proliferation and differentiation of hepatic stellate cells (HSCs) and to regulate fat metabolism of rat HSCs by targeting retinoid X receptor alpha. Our previous study also indicated that the recombinant P40 protein from Schistosoma japonicum (rSjP40) inhibited the activation of HSCs. In this study, we observed the expression of miR-27b in rSjP40-treated LX-2 cells and explored its potential mechanisms. Quantitative real-time PCR showed that rSjP40 inhibits the expression of miR-27b in LX-2 cells. Further results obtained by Western blot and dual-luciferase reporter assay confirmed that miR-27b regulates peroxisome proliferator-activated receptor gamma (PPARgamma) expression in rSjP40-treated LX-2 cells by targeting the 3'-UTR of PPARgamma. 5-AZA-2'-deoxycytidine (5-AZA-dC), which inhibits methylation of HSCs, partially reversed rSjP40-induced down-regulation expression of miR-27b in LX-2 cells. 5-AZA-dC also partially reversed rSjP40-induced up-regulation expression of PPARgamma in LX-2 cells. The increased expression of PPARgamma in rSjP40-treated LX-2 cells may be partially due to miR-27b methylation. Therefore, our study provides further insight into the mechanism by which rSjP40 inhibits HSC activation and provides a basis for future study of the blocking effect of rSjP40 in liver fibrosis.-Zhu, D., Lyu, L., Shen, P., Wang, J., Chen, J., Sun, X., Chen, L., Zhang, L., Zhou, Q., Duan, Y. rSjP40 protein promotes PPARgamma expression in LX-2 cells through microRNA-27b. PMID- 29608332 TI - Immune tolerance of vector beetle to its partner plant parasitic nematode modulated by its insect parasitic nematode. AB - Immune response of insect vectors to transmitted pathogens or insect hosts against parasites are well studied, whereas the mechanism of tripartite interactions remains elusive. In this study, we investigated the immune interactions of the vector beetle Monochamus alternatus ( Ma) to the devastating plant parasitic nematode Bursaphelenchus xylophilus ( Bx) and the insect parasitic nematode Howardula phyllotretae ( Hp). We report the unique immune mechanism by which the vector beetle tolerates many devastating Bx in its trachea, yet that immune tolerance is compromised by the parasitic nematode Hp. Contact with either nematode species triggers epithelial reactive oxygen species (ROS) production in Ma. Only the entry of Bx, not Hp, infection, induces increased expression of antioxidative genes, through which the ROS levels are balanced in the trachea of beetles. Furthermore, we found that up-regulation of antioxidative genes was induced by the interaction of Toll receptors. In contrast, beetles infected by Hp retain high levels of oxidative stress and melanization in trachea, and as a result, decrease Bx loading. This study highlights the role of Toll receptors in mediating the activation of antioxidative genes in immune tolerance to plant parasitic nematodes, and suggests the use of insect parasites as a biologic control.-Zhou, J., Zhao, L. L., Yu, H.-Y., Wang, Y.-H., Zhang, W., Hu, S.-N., Zou, Z., Sun, J.-H. Immune tolerance of vector beetle to its partner plant parasitic nematode modulated by its insect parasitic nematode. PMID- 29608333 TI - Predictive Modeling for the Growth of Salmonella Enteritidis in Chicken Juice by Real-Time Polymerase Chain Reaction. AB - The goals of this study were to monitor the growth kinetics of Salmonella Enteritidis in chicken juice using real-time polymerase chain reaction (PCR) and to evaluate its efficacy by comparing the results with an experimental database. Salmonella Enteritidis was inoculated in chicken juice samples at an initial inoculum of 104 CFU/mL with inoculated samples incubated at six different temperatures (10, 15, 20, 25, 30, and 35 degrees C). Sampling was carried out for 36 h to observe the growth of Salmonella Enteritidis. The total DNA was extracted from the samples, and the copy number of the Salmonella invasion gene (invA) was quantified by real-time PCR and converted to Salmonella Enteritidis cell concentration. Growth kinetics data were analyzed by the Baranyi and Roberts model to obtain growth parameters, whereas the Ratkowsky's square-root model was used to describe the effect of the interactions between growth parameters and temperature on the growth of Salmonella Enteritidis. The growth parameters of Salmonella Enteritidis obtained from an experiment conducted at a constant temperature were validated with growth data from chicken juice samples that were incubated under fluctuating temperature conditions between 5 degrees C and 30 degrees C for 30-min periods. A high correlation was observed between maximum growth rate (MUmax) and storage temperature, indicating that the real-time PCR monitoring method provides a precise estimation of Salmonella Enteritidis growth in food material with a microbial flora. Moreover, the MUmax data reflected data from microbial responses viewer database and ComBase. The results of this study suggested that real-time PCR monitoring provides a precise estimation of Salmonella Enteritidis growth in food materials with a background microbial flora. PMID- 29608334 TI - Genome-Wide DNA Methylation Analysis During Palatal Fusion Reveals the Potential Mechanism of Enhancer Methylation Regulating Epithelial Mesenchyme Transformation. AB - Epithelial mesenchyme transformation (EMT) of the medial edge epithelium (MEE) is the crucial process during palatal fusion. This work is aimed to elucidate the enhancer regulatory mechanism by genome-wide DNA methylation analysis of EMT during palatal fusion. Over 800 million clean reads, 325 million enzyme reads, and 234 million mapping reads were generated. The mapping rate was 68.85-74.32%, which included differentially methylated 17299 CCGG sites and 2363 CCWGG sites (p < 0.05, log2FC >1). Methylated sites in intron and intergenic regions were more compared to other regions of all DNA elements. GO and KEGG analysis indicated that differential methylation sites related to embryonic palatal fusion genes (HDAC4, TCF7L2, and PDGFRB) at the enhancer were located on CCWGG region of non CpG islands. In addition, the results showed that the enhancer for HDAC4 was hypermethylated, whereas the enhancers for TCF7L2 and PDGFRB were hypomethylated. The methylation status of enhancer regions of HDAC4, PDGFRB, and TCF7L2, involved in the regulation of the EMT during palatal fusion, may enlighten the development of novel epigenetic biomarkers in the treatment of cleft palate. PMID- 29608335 TI - Assessment of Mitigation Methods to Reduce the Risk of Hypoglycemia for Announced Exercise in a Uni-hormonal Artificial Pancreas. AB - BACKGROUND: Moderate physical activity improves overall health conditions in subjects with type 1 diabetes. However, insulin management during and after exercise is challenging due to the effects of exercise on glycemic control. Artificial pancreas (AP) systems aim to automatically control blood glucose levels, but exercise-induced hypoglycemia is a major challenge for these systems, especially in uni-hormonal configurations. The aim of this work was to evaluate the ability of several feed-forward (FF) actions to prevent exercise-induced hypoglycemia in a closed-loop setting. METHODS: A closed-loop control algorithm combined with FF actions aimed at eliminating exercise-induced hypoglycemia was evaluated in silico using the UVa/Padova type 1 diabetes simulator. The simulator was modified with an exercise model fitted to clinical data. The FF actions were evaluated in two scenarios: (1) exercise sessions during postprandial period and (2) exercise sessions during fasting period. RESULTS: The mitigation methods proposed in this work were able to minimize the occurrence of hypoglycemic events related with exercise in both scenarios. The time spent in hypoglycemic range in the 2-h period after exercise decreased from 33.3% to 0.0% (P < 0.01) and from 41.3% to 0.0% (P < 0.01) in both scenarios tested. Besides that, the occurrence of hypoglycemic events after exercise sessions was also reduced. CONCLUSIONS: The combination of the FF actions presented in this article within an AP system showed to be an effective strategy to mitigate the risk of hypoglycemia in front of aerobic exercise. PMID- 29608336 TI - Achievement of Virtual and Real Objects Using a Short-Term Motor Learning Protocol in People with Duchenne Muscular Dystrophy: A Crossover Randomized Controlled Trial. AB - OBJECTIVE: To evaluate whether people with Duchenne muscular dystrophy (DMD) practicing a task in a virtual environment could improve performance given a similar task in a real environment, as well as distinguishing whether there is transference between performing the practice in virtual environment and then a real environment and vice versa. METHODS: Twenty-two people with DMD were evaluated and divided into two groups. The goal was to reach out and touch a red cube. Group A began with the real task and had to touch a real object, and Group B began with the virtual task and had to reach a virtual object using the Kinect system. RESULTS: ANOVA showed that all participants decreased the movement time from the first (M = 973 ms) to the last block of acquisition (M = 783 ms) in both virtual and real tasks and motor learning could be inferred by the short-term retention and transfer task (with increasing distance of the target). However, the evaluation of task performance demonstrated that the virtual task provided an inferior performance when compared to the real task in all phases of the study, and there was no effect for sequence. CONCLUSIONS: Both virtual and real tasks promoted improvement of performance in the acquisition phase, short-term retention, and transfer. However, there was no transference of learning between environments. In conclusion, it is recommended that the use of virtual environments for individuals with DMD needs to be considered carefully. PMID- 29608337 TI - Age-Specific Association of CCL5 Gene Polymorphism with Pulmonary Tuberculosis: A Case-Control Study. AB - OBJECTIVES: Chemokines play a key role in immune regulation and response, and have been implicated in the pathogenesis of tuberculosis (TB). In this study, we investigated whether functional polymorphisms of the chemokines CCL5, CCL2, and CXCL8 are associated with pulmonary TB in a Moldavian population. MATERIALS AND METHODS: A total of 250 patients with TB and 184 healthy controls were screened for CCL5 -403G/A (rs2107538), CCL5 In1.1T/C (rs2280789), CCL2 -2518A/G (rs1024611), and CXCL8 -251A/T (rs4073) polymorphisms using standard polymerase chain reaction techniques. RESULTS: None of the analyzed variants were found to be significantly associated with overall pulmonary TB susceptibility. However, the CCL5 In1.1T/C polymorphism was significantly associated with early-onset TB in patients younger than 30 (dominant model, odds ratio [OR] = 3.01, p = 0.0046) or younger than 40 years (dominant model, OR = 2.17, p = 0.0099), and the conducted case-only analysis demonstrated that CCL5 In1.1T/C C-allele carriers exhibited an earlier TB onset than TT homozygotes (36.14 years vs. 40.13 years, p = 0.0065). In addition, nominal significance was observed for an association between TB incidence and both the eight paired genotypes in the overall patient cohort (0.017 < p < 0.05) and the CCL2 -2518A/G polymorphism among males (dominant model, OR = 0.55, p = 0.041; log-additive model, OR = 0.57, p = 0.018). CONCLUSION: The CCL5 In1.1T/C polymorphism may modulate pulmonary early-onset TB risk. PMID- 29608339 TI - The multifaceted roles of platelets in inflammation and innate immunity. PMID- 29608338 TI - Exploring provider-surrogate communication during POLST discussions for individuals with advanced dementia. AB - OBJECTIVES: This qualitative descriptive study explored provider-surrogate communication during Physician Orders for Life-Sustaining Treatment (POLST) discussions for patients with advanced dementia. METHODS: Data from participant observations and audio-recordings of ten POLST discussions were analyzed using directed content analysis within the context of an existing conceptual model of Communication and Surrogate Decision Making. RESULTS: Surrogates primarily focused on making sense of the clinical information about life-sustaining treatments during POLST conversations. Providers delivered clinical information about the trajectory of dementia, life-sustaining treatments, and/or features of POLST. They also demonstrated emotional support, by valuing what the surrogate said, acknowledging the surrogate's emotions, listening carefully, understanding the patient as a person, and eliciting questions. However, providers rarely conveyed comprehensive information about the patient's current condition and end of-life treatment options. Also, open communication of expectations and preferred decision-making roles was rarely observed during the discussions. CONCLUSION: Findings highlight areas that require providers' attention to conduct effective communication, such as delivering comprehensive information about life-sustaining treatments including discussion of risks and benefits in the context of dementia. Findings also support the use of the conceptual model as a framework to examine provider-surrogate communication in the context of POLST discussions, advanced dementia, and non-hospital settings. Additional research is necessary to confirm these findings in larger, more diverse groups of patients, surrogates, and providers. PMID- 29608340 TI - The impact of exercise on depressive symptoms in older Hispanic/Latino adults: results from the '!Caminemos!' study. AB - OBJECTIVES: We examined the prospective effects of an evidence-based exercise intervention on depressive symptoms in older Hispanics/Latinos and the potential synergistic effects (if any) of an attribution-retraining component to counter negative ascriptions to the aging process. METHOD: We analyzed baseline, 1-, 12-, 24-month data collected from Hispanics/Latinos >= 60 years participating in an exercise intervention ("!Caminemos!") across 27 senior centers (N = 572). All participants were given 4 weekly 1-hour group-based exercise classes targeting strength training, endurance, balance and flexibility. In addition, they were randomly assigned to one of two conditions: a) treatment group-a 1-hour attribution retraining session where participants were taught that aging does not mean one inevitably becomes sedentary, or b) control group-generic health education. The Geriatric Depression Scale was used to assess depressive symptoms. Covariates included age, sex, education, income, marital status, acculturation, and number of chronic conditions. RESULTS: In prospective analyses, participants in both trial arms displayed lower scores for depressive symptoms at 12- (beta1 = -0.17, p = 0.04) and 24-months (beta2 = -0.33, p < 0.001) when compared to baseline values. CONCLUSION: Given expected growth of the older Hispanic/Latino adult population, exercise programs are a promising strategy in promoting favorable mental health. PMID- 29608341 TI - Methylene Blue Attenuates Diabetic Retinopathy by Inhibiting NLRP3 Inflammasome Activation in STZ-induced Diabetic Rats. AB - PURPOSE: This study aimed to investigate the regulatory effects of methylene blue (MB) on diabetic retinopathy (DR) and explored the molecular mechanisms of MB as a retina protection agent. METHODS: The thicknesses of retinal layers and permeability of the blood-retinal barrier (BRB) were measured by histology analysis, and the expression levels of NLRP3, ASC, procaspase-1, caspase-1, IL 1beta, and IL-18 were measured by western blotting. Lentivirus-based knockdown of NLRP3 gene was used to confirm the role of NLRP3 inflammasome. RESULTS: MB treatment attenuates DR supported by the increase of relative thicknesses of retinal layers and the reduction of BRB permeability when compared with the untreated diabetic group. Further, MB significantly downregulated the levels of all detected inflammation mediators and showed inhibition on NLRP3 inflammasome activation similar to NLRP3 gene silencing. CONCLUSIONS: This study revealed a novel mechanism underlying the protection role of MB in the pathogenesis of DR. PMID- 29608342 TI - Negative Appendectomy. It is Really Preventable? PMID- 29608343 TI - Child Mortality Trends: The Authors Reply. PMID- 29608344 TI - Most Primary Care Physicians Provide Appointments, But Affordability Remains A Barrier For The Uninsured. AB - The US uninsurance rate has nearly been cut in half under the Affordable Care Act, and access to care has improved for the newly insured, but less is known about how the remaining uninsured have fared. In 2012-13 and again in 2016 we conducted an experiment in which trained auditors called primary care offices, including federally qualified health centers, in ten states. The auditors portrayed uninsured patients seeking appointments and information on the cost of care and payment arrangements. In both time periods, about 80 percent of uninsured callers received appointments, provided they could pay the full cash amount. However, fewer than one in seven callers in both time periods received appointments for which they could make a payment arrangement to bring less than the full amount to the visit. Visit prices in both time periods averaged about $160. Trends were largely similar across states, despite their varying changes in the uninsurance rate. Federally qualified health centers provided the highest rates of primary care appointment availability and discounts for uninsured low income patients. PMID- 29608345 TI - Meal Delivery Programs Reduce The Use Of Costly Health Care In Dually Eligible Medicare And Medicaid Beneficiaries. AB - Delivering food to nutritionally vulnerable patients is important for addressing these patients' social determinants of health. However, it is not known whether food delivery programs can reduce the use of costly health services and decrease medical spending among these patients. We sought to determine whether home delivery of either medically tailored meals or nontailored food reduces the use of selected health care services and medical spending in a sample of adults dually eligible for Medicare and Medicaid. Compared with matched nonparticipants, participants had fewer emergency department visits in both the medically tailored meal program and the nontailored food program. Participants in the medically tailored meal program also had fewer inpatient admissions and lower medical spending. Participation in the nontailored food program was not associated with fewer inpatient admissions but was associated with lower medical spending. These findings suggest the potential for meal delivery programs to reduce the use of costly health care and decrease spending for vulnerable patients. PMID- 29608346 TI - The Affordable Care Act's Marketplaces Expanded Insurance Coverage For Adults With Chronic Health Conditions. AB - The Affordable Care Act (ACA) made private nongroup health insurance more accessible to nonelderly adults with chronic conditions, with enrollment growth occurring through the federal and state-based Marketplaces. During the July through December reference period in 2014-15, 45 percent of Marketplace enrollees ages 18-64 were treated for chronic conditions, compared with 35 percent of non Marketplace nongroup enrollees and 38 percent of adults with employer-sponsored insurance. Marketplace enrollees also had higher service use than other privately insured adults did, which likely contributed to rising premiums in the nongroup market. As repeal of the ACA individual mandate takes effect in 2019, protecting coverage gains for adults with chronic conditions while stabilizing nongroup premiums may depend on state-level efforts to spread the risk of Marketplace enrollees' health care costs across a balanced insurance pool. PMID- 29608347 TI - Employer-Sponsored Insurance Stable For Low-Income Workers In Medicaid Expansion States. AB - We assessed rates of employer health insurance offer, take-up, and coverage in June 2013 and March 2017 among workers. Overall, offer rates remained stable, and take-up and coverage rates increased. In Medicaid expansion states, the share of workers with family incomes at or below 138 percent of the federal poverty level who had employer-based coverage held steady, while uninsurance rates declined. PMID- 29608348 TI - The Complexity Of Billing And Paying For Physician Care. AB - The administrative costs of providing health insurance in the US are very high, but their determinants are poorly understood. We advance the nascent literature in this field by developing new measures of billing complexity for physician care across insurers and over time, and by estimating them using a large sample of detailed insurance "remittance data" for the period 2013-15. We found dramatic variation across different types of insurance. Fee-for-service Medicaid is the most challenging type of insurer to bill, with a claim denial rate that is 17.8 percentage points higher than that for fee-for-service Medicare. The denial rate for Medicaid managed care was 6 percentage points higher than that for fee-for service Medicare, while the rate for private insurance appeared similar to that of Medicare Advantage. Based on conservative assumptions, we estimated that the health care sector deals with $11 billion in challenged revenue annually, but this number could be as high as $54 billion. These costs have significant implications for analyses of health insurance reforms. PMID- 29608349 TI - A Balanced Investment Portfolio For Equitable Health And Well-Being Is An Imperative, And Within Reach. AB - Health investments, defined as formal expenditures to either produce or care for health, in the US are extremely inefficient and have yet to unlock the country's full potential for equitable health and well-being. A major reason for such poor performance is that the US health investment portfolio is out of balance, with too much spent on certain aspects of health care and not enough spent to ensure social, economic, and environmental conditions that are vital to maintaining health and well-being. This commentary summarizes the evidence for this assertion, along with the opportunities and challenges involved in rebalancing investments in ways that would improve overall population health, reduce health gaps, and help build a culture of health for all Americans. PMID- 29608350 TI - Avoiding Malpractice Suits: The Authors Reply. PMID- 29608351 TI - Communication-And-Resolution Programs. PMID- 29608352 TI - The Evolving Moral Landscape Of Palliative Care. AB - Deactivating a patient's medical device provides a "good" death, which reflects how perspectives on hastening death have changed. PMID- 29608353 TI - Errata. PMID- 29608354 TI - Culture Of Health, The ACA, And More. PMID- 29608355 TI - Child Mortality Trends, 1961-2010. PMID- 29608356 TI - Veterans' Care: The Author Replies. PMID- 29608357 TI - Pervasive Income-Based Disparities In Inpatient Bed-Day Rates Across Conditions And Subspecialties. AB - Building a culture of health in hospitals means more than participating in community partnerships. It also requires an enhanced capacity to recognize and respond to disparities in utilization patterns across populations. We identified all pediatric hospitalizations at Cincinnati Children's Hospital Medical Center, in the period 2011-16. Each hospitalized child's address was geocoded, allowing us to calculate inpatient bed-day rates for each census tract in Hamilton County, Ohio, across all causes and for specific conditions and pediatric subspecialties. We then divided the census tracts into quintiles based on their underlying rates of child poverty and calculated bed-day rates per quintile. Poorer communities disproportionately bore the burden of pediatric hospital days. If children from all of the county's census tracts spent the same amount of time in the hospital each year as those from the most affluent tracts, approximately twenty-two child years of hospitalization time would be prevented. Of particular note were "hot spots" in high-poverty census tracts neighboring the hospital, where bed-day rates were more than double the county average. Hospitals that address disparities would benefit from a more comprehensive understanding of the culture of health-a culture that is more cohesive inside the hospital and builds bridges into the community. PMID- 29608358 TI - Medicare And VA Care Of Veterans. PMID- 29608359 TI - In Puerto Rico, Counting Deaths And Making Deaths Count. AB - Island officials have struggled to capture Hurricane Maria's full impact in mortality statistics. PMID- 29608360 TI - Affordable Care Act's Cadillac Tax Could Affect One-Fourth Of Workers With Employer Health Coverage By 2025. AB - The excise tax on high-cost health insurance plans (known as the Cadillac tax) under the Affordable Care Act (ACA) is an important part of the law's attempt to control rising health care costs. Analysts using different data sources have come to divergent estimates of how many people would be affected by this tax. We used the National Compensation Survey from the Bureau of Labor Statistics, which is better suited to this analysis because of its law-relevant details on employer provided health benefits. Our research clarifies an important area of empirical uncertainty, thereby informing the debate about the ACA and its proposed replacements. Our base estimate of impact, 12 percent of workers participating in employer-provided health plans in 2020, lies in the middle of other estimates, but it is considerably more comprehensive, accurate, and delineated by worker characteristics (region, number of employees at the firm, industry, occupation, and so on) than others. Workers affected at the highest rate include those in education occupations and high-income workers, while those in industries involving manual labor and public safety are affected at some of the lowest rates. PMID- 29608361 TI - AIR Louisville: Addressing Asthma With Technology, Crowdsourcing, Cross-Sector Collaboration, And Policy. AB - Cross-sector partnerships benefit public health by leveraging ideas, resources, and expertise from a wide range of partners. In this study we documented the process and impact of AIR Louisville (a collaboration forged among the Louisville Metro Government, a nonprofit institute, and a technology company) in successfully tackling a complex public health challenge: asthma. We enrolled residents of Louisville, Kentucky, with asthma and used electronic inhaler sensors to monitor where and when they used medication. We found that the use of the digital health platform achieved positive clinical outcomes, including a 78 percent reduction in rescue inhaler use and a 48 percent improvement in symptom free days. Moreover, the crowdsourced real-world data on inhaler use, combined with environmental data, led to policy recommendations including enhancing tree canopy, tree removal mitigation, zoning for air pollution emission buffers, recommended truck routes, and developing a community asthma notification system. AIR Louisville represents a model that can be replicated to address many public health challenges by simultaneously guiding individual, clinical, and policy decisions. PMID- 29608362 TI - A Balanced Portfolio Model For Improving Health: Concept And Vermont's Experience. AB - A successful strategy for improving population health requires acting in several sectors by implementing a portfolio of interventions. The mix of interventions should be both tailored to meet the community's needs and balanced in several dimensions-for example, time frame, level of risk, and target population. One obstacle is finding sustainable financing for both the interventions and the community infrastructure needed. This article first summarizes Vermont's experience as a laboratory for health reform. It then presents a conceptual model for a community-based population health strategy, using a balanced portfolio and diversified funding approaches. The article then reviews Vermont's population health initiative, including an example of a balanced portfolio and lessons learned from the state's experience. PMID- 29608363 TI - Care For Patients With Opioid Use Disorders. PMID- 29608364 TI - High-Risk Patients And ACO Savings. PMID- 29608365 TI - Primary Care Practices' Abilities And Challenges In Using Electronic Health Record Data For Quality Improvement. AB - Federal value-based payment programs require primary care practices to conduct quality improvement activities, informed by the electronic reports on clinical quality measures that their electronic health records (EHRs) generate. To determine whether EHRs produce reports adequate to the task, we examined survey responses from 1,492 practices across twelve states, supplemented with qualitative data. Meaningful-use participation, which requires the use of a federally certified EHR, was associated with the ability to generate reports-but the reports did not necessarily support quality improvement initiatives. Practices reported numerous challenges in generating adequate reports, such as difficulty manipulating and aligning measurement time frames with quality improvement needs, lack of functionality for generating reports on electronic clinical quality measures at different levels, discordance between clinical guidelines and measures available in reports, questionable data quality, and vendors that were unreceptive to changing EHR configuration beyond federal requirements. The current state of EHR measurement functionality may be insufficient to support federal initiatives that tie payment to clinical quality measures. PMID- 29608366 TI - Medicare Program Associated With Narrowing Hospital Readmission Disparities Between Black And White Patients. AB - The Hospital Readmissions Reduction Program has been associated with improvements in readmission rates, yet little is known about its effect on racial disparities. We compared trends in thirty-day readmission rates for congestive heart failure, acute myocardial infarction, and pneumonia among non-Hispanic whites versus non Hispanic blacks, and among minority-serving hospitals versus others. During the penalty-free implementation period (April 2010-September 2012), readmission rates improved over pre-implementation trends (January 2007-March 2010) for both whites and blacks, with a significantly greater decline among blacks than among whites ( 0.45 percent versus -0.36 percent per quarter, respectively). In the period October 2012-December 2014, after penalties began, readmission improvements slowed for both races. Following a similar pattern, minority-serving hospitals saw greater reductions in readmissions than other hospitals did. Despite the narrowing of the two race-based gaps after announcement of the Hospital Readmissions Reduction Program, both persist. It remains to be seen whether new policy efforts will narrow these gaps and reduce the disproportionately high penalties that minority-serving hospitals face. PMID- 29608368 TI - Long-Term Care: Efforts Supported By Foundations. PMID- 29608367 TI - Innovative Population Health Model Associated With Reduced Emergency Department Use And Inpatient Hospitalizations. AB - Population health strategies that improve access to health care and address social determinants of health may reduce the use of costly emergency services. Here we describe a strategy adopted by Baylor Scott & White Health to reduce rising rates of emergency department use and inpatient hospitalizations in an underserved Dallas community that is home to many people with low socioeconomic status. Baylor Scott & White partnered with the Dallas Park and Recreation Department to create a level-three primary care clinic integrating wellness and prevention programs in a city recreational center. The clinic, known as the Baylor Scott & White Health and Wellness Center, exemplifies the integration of social determinants of health within a population health strategy. Emergency department (ED) and inpatient care use was examined over twelve months after initiation of services at the center. People who used the center's services showed a reduction in ED use of 21.4 percent and a reduction in inpatient care use of 36.7 percent, with an average cost decrease of 34.5 percent and 54.4 percent, respectively. These data support the use of population health strategies to reduce the use of emergency services. PMID- 29608369 TI - Integrating Data On Social Determinants Of Health Into Electronic Health Records. AB - As population health becomes more of a focus of health care, providers are realizing that data outside of traditional clinical findings can provide a broader perspective on potential drivers of a patient's health status and can identify approaches to improving the effectiveness of care. However, many challenges remain before data related to the social determinants of health, such as environmental conditions and education levels, are as readily accessible and actionable as medical data are. Key challenges are a lack of consensus on standards for capturing or representing social determinants of health in electronic health records and insufficient evidence that once information on them has been collected, social determinants can be effectively addressed through referrals or other action tools. To address these challenges and effectively use social determinants in health care settings, we recommend creating national standards for representing data related to social determinants of health in electronic health records, incentivizing the collection of the data through financial or quality measures, and expanding the body of research that measures the impact of acting on the information collected. PMID- 29608370 TI - Changes In Hospital Utilization Three Years Into Maryland's Global Budget Program For Rural Hospitals. AB - In a substantial shift in payment policy, the State of Maryland implemented a global budget program for acute care hospitals in 2010. Goals of the program include controlling hospital use and spending. Eight rural hospitals entered the program in 2010, while urban and suburban hospitals joined in 2014. Prior analyses, which focused on urban and suburban hospitals, did not find consistent evidence that Maryland's program had contributed to changes in hospital use after two years. However, these studies were limited by short follow-up periods, may have failed to isolate impacts of Maryland's payment change from other state trends, and had limited generalizability to rural settings. To understand the effects of Maryland's global budget program on rural hospitals, we compared changes in hospital use among Medicare beneficiaries served by affected rural hospitals versus an in-state control population from before to after 2010. By 2013-three years after the rural program began-there were no differential changes in acute hospital use or price-standardized hospital spending among beneficiaries served by the affected hospitals, versus the within-state control group. Our results suggest that among Medicare beneficiaries, global budgets in rural Maryland hospitals did not reduce hospital use or price-standardized spending as policy makers had anticipated. PMID- 29608371 TI - Assessing The Value Of 40 Years Of Local Public Expenditures On Health. AB - The US public and private sectors now spend more than $3 trillion on health each year. While critical studies have examined the relationship between public spending on health and health outcomes, relatively little is known about the impact of broader public-sector spending on health. Using county-level public finance data for the period 1972-2012, we estimated the impact of local public hospital spending and nonhospital health spending on all-cause mortality in the county. Overall, a 10 percent increase in nonhospital health spending was associated with a 0.006 percent decrease in all-cause mortality one year after the initial spending. This effect was larger and significant in counties with greater proportions of racial/ethnic minorities. Our results indicate that county nonhospital health spending has health benefits that can help reduce costs and improve health outcomes in localities across the nation, though greater focus on population-oriented services may be warranted. PMID- 29608372 TI - Effects Of The ACA's Health Insurance Marketplaces On The Previously Uninsured: A Quasi-Experimental Analysis. AB - Descriptive studies have suggested that the Affordable Care Act's (ACA's) health insurance Marketplaces improved access to care. However, no evidence from quasi experimental studies is available to support these findings. We used longitudinal survey data to compare previously uninsured adults with incomes that made them eligible for subsidized Marketplace coverage (138-400 percent of the federal poverty level) to those who had employer-sponsored insurance before the ACA with incomes in the same range. Among the previously uninsured group, the ACA led to a significant decline in the uninsurance rate, decreased barriers to medical care, increased the use of outpatient services and prescription drugs, and increased diagnoses of hypertension, compared to a control group with stable employer sponsored insurance. Changes were largest among previously uninsured people with incomes of 138-250 percent of poverty, who were eligible for the ACA's cost sharing reductions. Our quasi-experimental approach provides rigorous new evidence that the ACA's Marketplaces led to improvements in several important health care outcomes, particularly among low-income adults. PMID- 29608373 TI - Cold Susceptibility of Digit Stumps Resulting from Amputation After Freezing Cold Injury in Elite Alpinists. AB - : Gorjanc, Jurij, Shawnda A. Morrison, Rok Blagus, and Igor B. Mekjavic. Cold susceptibility of digit stumps resulting from amputation after freezing cold injury in elite alpinists. High Alt Med Biol. 19:185-192, 2018. AIM: The aim of the study was to assess whether previous freezing cold injury in fingers and/or toes might predispose alpinists to greater risk of further freezing cold injury, primarily due to a greater vasoconstrictor response to cold, resulting in a lower perfusion, reflected in lower skin temperature. METHODS: Ten elite alpinists (N = 10; 8 male and 2 female) with amputations after freezing cold injury participated in a cold-water (8 degrees C) immersion stress test of the hands and feet. Digit skin temperatures of amputated digits, their noninjured counterparts, noninjured digits of the affected side and noninjured digits of the corresponding side were measured. The skin temperatures were compared during three consecutive phases of the cold stress test: prewarming, cold water immersion, and passive heating. RESULTS: Amputated toes cooled much faster compared to their uninjured counterparts (n = 26, p < 0.001), and attained lower skin temperatures during the cold exposure test (n = 26, p < 0.001). Higher cooling rate was observed in all the toes on the injured limb compared with the toes on the uninjured limb (n = 40, p < 0.001). In contrast to the toes, the fingers on the injured limb after freezing cold injury were warmer during cooling phase compared to uninjured fingers (n = 15, p < 0.001). CONCLUSIONS: The lower digit temperatures observed in affected toe stumps during the cold stress test compared to the nonamputated toes may indicate a heightened risk of future freezing cold injury with subsequent cold exposures, as a consequence of less perfusion, reflected in the lower skin temperature. This relationship was not confirmed in the fingers. PMID- 29608374 TI - Exploration of Acute Phase Proteins and Inflammatory Cytokines in Early Stage Diagnosis of Acute Mountain Sickness. AB - : Wang, Chi, Hui Jiang, Jinyan Duan, Jingwen Chen, Qi Wang, Xiaoting Liu, and Chengbin Wang. Exploration of acute phase proteins and inflammatory cytokines in early stage diagnosis of acute mountain sickness. High Alt Med Biol. 19:170-177, 2018. BACKGROUND: Early diagnosis of acute mountain sickness (AMS) is currently based on personal appreciation of the severity of symptoms. A more objective method to diagnose AMS is required. Inflammatory cytokines and acute phase proteins have been reported to be different at high altitude. METHODS: A total of 104 male soldiers rapidly ascending from Beijing (20-60 m) to Germu, Qinghai (3200 m), were divided into AMS group and non-AMS group according to the Lake Louis Score system. Blood pressure, pulse rate, and oxygen saturation were measured. Forty-nine blood samples were collected before and on the 3rd day after ascending to the high altitude. Serum haptoglobin (Hp), transferrin (Tf), and complement C3 were detected by immune scattered nephelometry, whereas serum interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha) were detected by chemical luminescence immunity analyzer. The sensitivity, specificity, and receiver operating characteristic curve were evaluated. Youden index with the maximum value was used to determine cutoff values of each parameter. Logistic regression was performed to determine the diagnostic efficiency of combination of three cytokines. RESULTS: Differences of physical indexes between AMS group and non-AMS group were of no statistical significance. In AMS group, serum Tf significantly increased while Hp decreased when compared with non-AMS group. Serum IL-1beta, IL-6, and TNF-alpha were higher in the AMS group than in the non-AMS group. The cutoff values for Tf, Hp, IL-1beta, IL-6, and TNF-alpha were 263.5 mg/dL, 119.35 mg/dL, 6.2 pg/mL, 15.05 pg/mL, and 18.35 pg/mL, respectively. Area under the curve (AUC) of combining three cytokines together was higher than AUC of each cytokine separately. CONCLUSIONS: Acute phase proteins and inflammatory cytokines (IL-1beta, IL-6, and TNF-alpha) show significant changes between the AMS group and the non-AMS group. Combination of inflammatory cytokines or acute phase proteins improves the specificity for diagnosis of AMS. This might provide objective indexes for scanning and screening individuals susceptible to AMS in the early stage of rapid ascending. PMID- 29608375 TI - Accumulation and fractionation of rare earth elements (REEs) in the naturally grown Phytolacca americana L. in southern China. AB - The widespread use of rare earth elements (REEs) has resulted in problems for soil and human health. Phytolacca americana L. is a herbaceous plant widely distributed in Dingnan county of Jiangxi province, China, which is a REE mining region (ion absorption rare earth mine) and the soil has high levels of REEs. An investigation of REE content of P. americana growing naturally in Dingnan county was conducted. REE concentrations in the roots, stems, and leaves of P. americana and in their rhizospheric soils were determined. Results showed that plant REEs concentrations varied among the sampling sites and can reach 1040 mg/kg in the leaves. Plant REEs concentrations decreased in the order of leaf > root > stem and all tissues were characterized by a light REE enrichment and a heavy REE depletion. However, P. americana exhibited preferential accumulation of light REEs during the absorption process (from soil to root) and preferential accumulation of heavy REEs during the translocation process (from stem to leaf). The ability of P. americana to accumulate high REEs in the shoot makes it a potential candidate for understanding the absorption mechanisms of REEs and for the phytoremediation of REEs contaminated soil. PMID- 29608376 TI - Subcellular distribution and chemical forms of cadmium in Morus alba L. AB - Morus alba L. (mulberry) is a perennial woody tree and a species with great potential for Cd phyremediation owing to its large biomass and extensive root system. The mechanisms involved in Cd detoxification were investigated by analyzing the subcellular distribution and chemical forms of Cd in mulberry in the present study. These results indicated that 53.27-70.17% of Cd mulberry accumulated was stored in the root and only about 10% were in the leaves. Lots of the Cd was located in the cell wall of the mulberry root and in soluble fraction of the mulberry leaf. Moreover, in roots, the largest amount of Cd was in the form of undissolved Cd-phosphate. While in mulberry leaves and stems, most of the Cd was extracted by 2% Acetic acid and 0.6 M HCl, representing Cd-phosphate and Cd-oxalate. It could be concluded that the Cd combination with peptides and organo-ligands in vacuole of leaf or complexed with proteins or cellulose in the cell wall of root might be contributed to the tolerance of mulberry to Cd stress. The mulberry could be used to remediate the Cd polluted farmland soils. PMID- 29608377 TI - Effects of summer and winter harvesting on element phytoextraction efficiency of Salix and Populus clones planted on contaminated soil. AB - The clones of fast-growing trees (FGTs) were investigated for phytoextraction of soil contaminated with risk elements (REs), especially Cd, Pb, and Zn. As a main experimental factor, the potential effect of biomass harvesting time was assessed. The field experiment with two Salix clones (S1 - (Salix schwerinii * Salix viminalis) * S. viminalis, S2 - S. * smithiana) and two Populus clones (P1 Populus maximowiczii * Populus nigra, P2 - P. nigra) was established in April 2009. Shoots of all clones were first harvested in February 2012. After two further growing seasons, the first half of the trees was harvested in September 2013 before leaf fall (summer harvest) and the second half in February 2014 (winter harvest). Remediation factors (RFs) for all clones and all REs (except Pb for clone S1) were higher in the summer harvest. The highest annual RFs for Cd and for Zn (1.34 and 0.67%, respectively) were found for clone S2 and were significantly higher than other clones. Although no increased mortality of trees harvested in the summer was detected in the following season, the effect of summer harvesting on the phytoextraction potential of FGTs clones should be investigated in long-term studies. PMID- 29608378 TI - Assessment of plant growth attributes, bioaccumulation, enrichment, and translocation of heavy metals in water lettuce (Pistia stratiotes L.) grown in sugar mill effluent. AB - This study was conducted to assess the pollutant uptake capability of water lettuce (Pistia stratiotes L.) in terms of bioaccumulation, enrichment, and translocation of heavy metals grown in sugar mill effluent. Results showed that the maximum fresh weight (328.48 +/- 2.04 gm kg-1), total chlorophyll content (2.13 +/- 2.03 mg g-1 fwt), and relative growth rate, RGR (11.89 gg-1 d-1) of P. stratiotes were observed at 75% concentration of the sugar mill effluent after 60 days of phytoremediation experiment. The bioaccumulation factor (BF) of different heavy metals was greater than 1 with 50% and 75% concentrations of sugar mill effluent and this indicated that P. stratiotes was hyperaccumulator or phytoremediator of these metals. The enrichment factor (EF < 2 for Cu, Fe, Cr, Pb, Zn, and Mn) and (EF > 2 for Cd) indicated that P. stratiotes mineral enrichment deficient and it moderately enriched the different heavy metals. Moreover, translocation factor (TF) was less than 1 which indicated the low mobility of metals in different parts (root and leaves) of P. stratiotes after phytoremediation. Therefore, P. stratiotes can be used for phytotreatment of sugar mill effluent up to 50% to 75% concentrations and considered as hyperaccumulator aquatic plant for different heavy metals and other pollutants from the contaminated effluents. PMID- 29608379 TI - Physical Activity Interventions to Decrease Substance Use in Youth: A Review of the Literature. AB - BACKGROUND: Adolescent substance use, a major problem in the United States, has a significant negative effect on both short- and long-term mental and physical health. Physical activity (PA) may offer potentially effective strategies to combat substance use in youth. Like substance use, PA behaviors developed during adolescence persist into adulthood, so adolescence may be an ideal period in which to implement PA interventions to prevent substance abuse. However, there are no known systematic literature reviews of PA-based interventions that target substance use in adolescence. OBJECTIVES: To review PA interventions for adolescents, including research designs, intervention characteristics, and measures of substance use. METHODS: Five databases were searched for articles published in English peer-reviewed journals. Search terms were related to the adolescent population, substance use, and PA interventions. RESULTS: 17 articles fit inclusion criteria. The results suggest that PA interventions may decrease substance use in teens. A majority of the interventions were delivered in high schools. Substance use measures/outcomes included intention or willingness to use, cessation, and actual use. Alcohol use was measured most, followed by marijuana and tobacco use. Although most of the studies utilized group sessions to deliver interventions, decreased substance use was also associated with one time, multi-health consultations. Conclusions/Importance: School-based interventions targeting multiple health behaviors may offer a particularly effective and efficient way to decrease substance use in adolescents. PMID- 29608380 TI - The Alzheimer's Disease Home Hospice Knowledge Scale: development, validity and reliability. AB - BACKGROUND: Several instruments are available to assess knowledge about hospice care, but none specifically address knowledge about home hospice for persons with Alzheimer's disease (AD). AIM: To develop and validate the Alzheimer's Disease Home Hospice Knowledge Scale (AD-HHK-S). METHODS: A total of 107 Israeli family caregivers of persons with dementia (mean age=71.2; 73% female) participated in the study. RESULTS: The AD-HHK-S included 28 true/false items assessing 3 areas of knowledge: knowledge about hospice, knowledge about home hospice, and knowledge about home hospice for AD. Good internal reliability was found, with Cronbach alpha ranging from 0.72 to 0.85. Good face, construct and predictive validity were found. CONCLUSIONS: The AD-HHK-S proved to be a valid and reliable tool to assess knowledge about hospice care in the area of AD. It might provide an effective tool for palliative care nurses to communicate with family caregivers of persons with AD at the end of life. PMID- 29608381 TI - Research roundup. AB - Synopses of a selection of recently published research articles of relevance to palliative care. PMID- 29608382 TI - Perspectives on advance care planning in haematopoietic stem cell transplantation: a qualitative study. AB - BACKGROUND: Advance care planning (ACP) engagement and completion of advance directives remain low in patients undergoing haematopoietic stem cell transplantation, despite the high risk of treatment-related mortality. AIM: To understand the barriers to and facilitators of ACP in haematopoietic stem cell transplantation. METHODS: This qualitative study used interpretive description methodology. The researchers conducted audio-recorded semi-structured interviews with participants. The constant comparative method was used to analyse data. RESULTS: A total of six patients, five family members and eight clinicians participated in the study. Perceived barriers to ACP included: lack of time, lack of process, lack of understanding of disease/treatment and ACP, need to keep positive and prognostic uncertainty. Potential facilitators of ACP included: early and frequent discussion of ACP, incorporating ACP into routine care, involvement of the multidisciplinary team and framing discussions on ACP as positive. CONCLUSIONS: Haematopoietic stem cell transplantation poses unique challenges for patients, families and clinicians when it comes to ACP. Introducing advance care planning as part of standard care and providing ongoing facilitation of ACP, including discussion of disease and treatment expectations at the outset and when complications arise may assist patients and families in recognising how ACP can fit into and enhance their care. PMID- 29608383 TI - Politics and palliative care: Democratic Republic of the Congo. AB - Dion Smyth's review of palliative nursing on the internet. PMID- 29608384 TI - Asking terminally ill patients about their preferences concerning place of care and death. AB - BACKGROUND: Asking patients with palliative care needs about their end-of-life (EoL) preferences is widely acknowledged as an important aspect of EoL care. However, the issue of how to ask patients these questions has not been fully explored. Most prior studies in this area do not differentiate between patients' pragmatic preferences and ideal preferences, and between preferences concerning place of care (PoC) and place of death (PoD). AIM: The aim of this study was to examine possible differences between pragmatic and ideal preferences of terminally ill patients, as well as differences between asking patients about preferences concerning PoC and PoD. METHODS: Structured interviews were performed with terminally ill cancer patients at inclusion and a follow-up questionnaire was completed 1 month later. Answers were compared using kappa (k) statistics and Pearson's c2-test. RESULTS: Among 96 cancer patients, agreement between pragmatic and ideal preferences was statistically significantly different (p=<0.001). Agreement between preferences for PoC and PoD was high (k:0.76-0.85). CONCLUSION: Differences exist between pragmatic and ideal EoL preferences, whereas preferences for PoC and PoD were found to be similar. These findings highlight the importance of the phrasing of questions when uncovering patients' preferences for EoL care. PMID- 29608385 TI - The efficacy of complementary therapy for patients receiving palliative cancer care. AB - Involving patients in their own care is associated with improved health outcomes. Complementary therapies are popular among patients and enable them to receive the palliative care they want and need. However, the range of complementary therapy services available to patients need to be evaluated for efficacy. This study evaluated the complementary therapy services offered at one cancer outpatient clinic in the UK, with the aim of evaluating the effect of complementary therapies on patient wellbeing and to systematise concerns and categories of wellbeing in order to improve service provision. A sample of 60 patients rated their feelings of wellbeing on a Likert scale before and after a series of six complementary therapies. They were also asked which concerns they had and, after treatment, were asked about factors that may influence their wellbeing. The data were analysed quantitatively by t-test and Wilcoxon signed ranks and the results show a statistically significant improvement in wellbeing. The concerns were assigned into super categories to aid service provision and the other factors that influence general wellbeing were assessed to categorise areas of patient needs that may be addressed in patient care. These results highlight important areas for investigation, which have implications for service provision in palliative cancer care. PMID- 29608386 TI - Patient-centred goal setting in a hospice: a comparative case study of how health practitioners understand and use goal setting in practice. AB - BACKGROUND: Goal setting is recognised as an important way of supporting people to live as actively as possible until death. However, there is little agreement about how goal setting should be handled or delivered by health professionals in everyday practice. AIM: To investigate health-care practitioners' understanding and practice of patient-centred goal setting in a hospice. METHODS: A comparative case study of 10 healthcare practitioners in one hospice. Non-participant observations (n=28), semi-structured interviews (n=10) and case-note analysis (n=67) were undertaken. Data were analysed using framework analysis. RESULTS: Participants viewed goal setting as part of routine practice. However, goal setting focused around what was seen as important from the health practitioner's perspective, rather than being patient-centred. Participants' goal-setting practice was implicit and opportunities to support patients to pursue goals were missed. Participants emphasised problem solving and alleviating symptoms rather than focusing on patient priorities and establishing patient-centred goals. CONCLUSION: While goal setting is valued, it is practiced in an implicit, practitioner-centred and inconsistent manner. A more explicit, person-centred goal setting process may support practitioners more consistently in helping patients to identify their priorities and enhance their quality of life. PMID- 29608388 TI - Surveillance of Drug-Resistant Tuberculosis in Spain (2001-2015). AB - Multidrug-resistant tuberculosis (MDR-TB) is a cause of increasing concern. This study investigated first-line anti-TB drug resistance in Mycobacterium tuberculosis strains submitted to the Tuberculosis Reference Center in Cordoba (Spain) between 2001 and 2015. A total of 1,207 cultures were tested against first-line drugs using the BACTEC MGIT 960 system. Resistance to first-line drugs was detected in 207 strains (17.2%), the greatest resistance being found in INH (5.3%) followed by streptomycin (3%), pyrazinamide (2.2%), rifampicin (1%), and ethambutol (0.2%). A total of 1.9% of strains were MDR-TB. Six strains displayed resistance to four drugs, and three strains to five drugs. In view of resistance observed, careful surveillance of drug resistance is recommended. PMID- 29608387 TI - Rapid Determination of Resistance to Antibiotic Inhibitors of Protein Synthesis in Staphylococcus aureus Through In Situ Evaluation of DNase Activity. AB - A rapid assay was designed for the detection of resistant strains of Staphylococcus aureus to antibiotic inhibitors of protein synthesis. The assay was based on the fact that a brief cell wall digestion with lysostaphin resulted in fragmentation of the chromosomal DNA by releasing the characteristic DNase stored in the cell wall. DNase activity was ascertained by visualization of the DNA fragments released from the isolated nucleoids. Lysostaphin-released DNase activity was found to be influenced by ribosomal protein synthesis. Inhibition of protein synthesis resulted in the prevention of lysostaphin-DNase induced DNA fragmentation when susceptible clinical strains were incubated with erythromycin, azithromycin, or doxycycline for 2 hr before enzymatic treatment. However, in nonsusceptible strains where protein synthesis was unsuccessfully inhibited, this suppression of lysostaphin-DNase was not, or only very slightly, evident. This assay was highly efficient, identifying resistance to erythromycin and azithromycin with 88-90.9% sensitivity and 100% specificity and with 100% sensitivity and specificity to gentamicin and doxycycline, within a 2 hr and 45 min period. PMID- 29608389 TI - One-tailed asymptotic inferences for the difference of proportions: Analysis of 97 methods of inference. AB - Two-tailed asymptotic inferences for the difference d = p2 - p1 with independent proportions have been widely studied in the literature. Nevertheless, the case of one tail has received less attention, despite its great practical importance (superiority studies and noninferiority studies). This paper assesses 97 methods to make these inferences (test and confidence intervals [CIs]), although it also alludes to many others. The conclusions obtained are (1) the optimal method in general (and particularly for errors alpha = 1% and 5%) is based on arcsine transformation, with the maximum likelihood estimator restricted to the null hypothesis and increasing the successes and failures by 3/8; (2) the optimal method for alpha = 10% is a modification of the classic model of Peskun; (3) a more simple and acceptable option for large sample sizes and values of d not near to +/-1 is the classic method of Peskun; and (4) in the particular case of the superiority and inferiority tests, the optimal method is the classic Wald method (with continuity correction) when the successes and failures are increased by one. We additionally select the optimal methods to make compatible the conclusions of the homogeneity test and the CI for d, both for one tail and for two (methods which are related to arcsine transformation and the Wald method). PMID- 29608390 TI - Strategies implemented to address vaccine hesitancy in France: A review article. AB - Vaccination has been identified many decades ago as an effective means to prevent several diseases. However, in France, there is an emergence of vaccine hesitancy, that has caused a reduction of vaccination coverage rates. This issue reduces the effectiveness of the immunization process, and represents a real threat to public health that should be urgently addressed. The purpose of this review is to present actions that have been taken to fight against vaccine hesitancy and thus enhance vaccine uptake. The results indicate that different strategies have been proposed to reach this goal, mainly by vaccination campaigns. These findings highlight the strong implication of national health authorities and the medical staff of hospitals and health-care centers. However, actions implemented should be part of a long-term approach, and further studies are required to identify the most effective strategies to address vaccine hesitancy. PMID- 29608391 TI - A Fragment Library Screening Approach to Identify Selective Inhibitors against an Essential Fungal Enzyme. AB - Pathogenic fungi represent a growing threat to human health, with an increase in the frequency of drug-resistant fungal infections. Identifying targets from among the selected metabolic pathways that are unique to microbial species presents an opportunity to develop new antifungal agents against new and untested targets to combat this growth threat. Aspartate semialdehyde dehydrogenase (ASADH) catalyzes a key step in a uniquely microbial amino acid biosynthetic pathway and is essential for microbial viability. This enzyme, purified from four pathogenic fungal organisms ( Candida albicans, Aspergillus fumigatus, Cryptococcus neoformans, and Blastomyces dermatitidis), has been screened against fragment libraries to identify initial enzyme inhibitors. The binding of structural analogs of the most promising lead compounds was measured against these fungal ASADHs to establish important structure-activity relationships among these different inhibitor classes. The most potent of these inhibitors have been docked into structures of this fungal enzyme target to identify important structural elements that serve as critical binding determinants. Several inhibitors with low micromolar inhibition constants have been identified that showed selectivity against these related enzymes from different fungal species. Subsequent screening against a library of drugs and drug candidates identified some additional inhibitors containing a consistent set of functional groups required for fungal ASADH inhibition. Additional elaboration of these core structures will likely lead to more potent and selective inhibitors. PMID- 29608392 TI - Illegal product manufacturing and exportation from Pakistan: Revealing the factuality of highly processed wildlife skin samples via DNA mini-barcoding. AB - Illegal trade is a major threat to the biodiversity and the efforts initiated for the conservation of wildlife. The shortcomings of the traditional taxonomic identification methods have been coped by a revolutionary and emerging technique, the "DNA (Deoxyribonucleic Acid) barcoding". Here we report a case of trader who was allegedly making footwear for a famous international celebrity from wild animal cutis. The samples confiscated during a raid on a footwear manufacturing industry by KP Wildlife department in August, 2016, were received by Bioresource Research Centre (BRC) for molecular identification on 1st September, 2016. The study costed about USD 88 from processing to the identification of the samples. The samples identified via DNA mini-barcoding by targeting cytochrome oxidase I (COI) gene belong to Gazella bennettii and Bos taurus. Such studies are helpful for credible investigations that only lead to effective prosecution and control of illegal wildlife trade ultimately helping in conservation of wild animals. PMID- 29608393 TI - Histological Comparison of New Bone Formation Using Amnion Membrane Graft Versus Resorbable Collagen Membrane: An Animal Study. AB - The purpose of this article was to evaluate the bone induction effects of an amnion membrane-protected graft compared with a collagen membrane-protected graft in the repair of tibial bony defects in dogs. This study was performed using the tibial bone of dogs. After the removal of periosteum, similar holes were made with a 16-mm trephine drill (38 holes in total). For the study group, 10 holes were covered by absorbable collagen and 16 holes by amniotic membrane. In the control group, 12 holes were made and covered by the overlying soft tissue. Tibial bones were exposed after 6 and 12 weeks, and the samples were harvested and histologically processed. New bone formation was evaluated by histomorphometric study. Four Iranian mixed dogs older than 1.5 years were included in this study. The new bone formation was less in the control group when compared with the collagen group ( P = .863). The collagen group showed less bone formation than the amnion group ( P = .194), but this difference was not significant. However, bone formation in the amnion group was significantly more than in the control group ( P = .050). Using the amniotic membrane appears to accelerate bone formation in guided bone regeneration. However, further studies should investigate its clinical impact on bone healing. PMID- 29608394 TI - Surrogate Decision Makers' Perspectives on Family Members' Prognosis after Intracerebral Hemorrhage. AB - BACKGROUND: Surrogate communication with providers about prognosis in the setting of acute critical illness can impact both patient treatment decisions and surrogate outcomes. OBJECTIVES: To examine surrogate decision maker perspectives on provider prognostic communication after intracerebral hemorrhage (ICH). DESIGN: Semistructured interviews were conducted and analyzed qualitatively for key themes. SETTING/SUBJECTS: Surrogate decision makers for individuals admitted with ICH were enrolled from five acute care hospitals. RESULTS: Fifty-two surrogates participated (mean age = 54, 60% women, 58% non-Hispanic white, 13% African American, 21% Hispanic). Patient status at interview was hospitalized (17%), in rehabilitation/nursing facility (37%), deceased (38%), hospice (4%), or home (6%). Nineteen percent of surrogates reported receiving discordant prognoses, leading to distress or frustration in eight cases (15%) and a change in decision for potentially life-saving brain surgery in three cases (6%). Surrogates were surprised or confused by providers' use of varied terminology for the diagnosis (17%) (e.g., "stroke" vs. "brain hemorrhage" or "brain bleed") and some interpreted "stroke" as having a more negative connotation. Surrogates reported that physicians expressed uncertainty in prognosis in 37%; with physician certainty in 56%. Surrogate reactions to uncertainty were mixed, with some surrogates expressing a negative emotional response (e.g., anxiety) and others reporting understanding or acceptance of uncertainty. CONCLUSIONS: Current practice of prognostic communication in acute critical illness has many gaps, leading to distress for surrogates and variability in critical treatment decisions. Further work is needed to limit surrogate distress and improve the quality of treatment decisions. PMID- 29608396 TI - Metabolic Syndrome and Vitamin D Levels in Patients with Obstructive Sleep Apnea Syndrome. AB - BACKGROUND: Numerous studies have indicated that obstructive sleep apnea syndrome (OSAS), may contribute to the development of metabolic syndrome (MetS) and diabetes. Moreover, OSAS has been associated with lowered vitamin D (Vit D) levels, but reports are inconclusive. Aim of the study was to compare Vit D levels according to the presence of MetS and its components in OSAS patients. METHODS: The presence of MetS was evaluated and serum 25-hydroxy vitamin D [25(OH)D] levels were measured in consecutive newly diagnosed, by polysomnography, subjects with OSAS. RESULTS: A total of 107 subjects (88 men) with OSAS were included in the study. Patients were divided into group A (OSAS with MetS group: 55 subjects) and group B (OSAS without MetS: 52 subjects). There were no differences between the two groups in terms of age, body mass index, and sleep parameters. Patients in group A exhibited higher levels of daytime sleepiness, as expressed by Epworth Sleepiness Scale score (12 +/- 5.5 vs. 9.3 +/ 4.8 for groups A vs. B, p = 0.008). Serum 25(OH)D levels were significantly decreased in group A, as compared with group B (18 +/- 8.6 ng/mL vs. 23.9 +/- 14.1 ng/mL, respectively, p = 0.012). Group A was then subdivided in two smaller groups, according to patients' metabolic index: OSAS patients with metabolic score = 3 and OSAS patients with metabolic score >3. Serum 25(OH)D levels were higher in OSAS patients with metabolic score = 3 compared with OSAS patients with metabolic score >3 (19.8 +/- 8.9 ng/mL vs. 15.1 +/- 7.3 ng/mL respectively, p = 0.038). CONCLUSIONS: OSAS patients with concurrent MetS exhibit lower serum Vit D levels, as compared with those without MetS. PMID- 29608397 TI - Optimizing Anticancer Therapy in Metastatic Non-Castrate Prostate Cancer: American Society of Clinical Oncology Clinical Practice Guideline. AB - Purpose This clinical practice guideline addresses abiraterone or docetaxel with androgen-deprivation therapy (ADT) for metastatic prostate cancer that has not been treated (or has been minimally treated) with testosterone-lowering agents. Methods Standard therapy for newly diagnosed metastatic prostate cancer has been ADT alone. Three studies have compared ADT alone with ADT and docetaxel, and two studies have compared ADT alone with ADT and abiraterone. Results Three prospective randomized studies (GETUG-AFU 15, STAMPEDE, and CHAARTED) examined overall survival (OS) with adding docetaxel to ADT. STAMPEDE and CHAARTED favored docetaxel (hazard ratio [HR], 0.78; 95% CI, 0.66 to 0.93; n = 2,962 and HR, 0.73; 95% CI, 0.59 to 0.89; n = 790, respectively). GETUG-AFU 15 was negative. LATITUDE and STAMPEDE examined the impact on OS of adding abiraterone (with prednisone or prednisolone) to ADT. LATITUDE and STAMPEDE favored abiraterone (HR, 0.62; 95% CI, 0.51 to 0.76; n = 1,199 and HR, 0.63; 95% CI, 0.52 to 0.76; n = 1,917, respectively). Recommendations ADT plus docetaxel or abiraterone in newly diagnosed metastatic non-castrate prostate cancer offers a survival benefit as compared with ADT alone. The strongest evidence of benefit with docetaxel is in men with de novo high-volume (CHAARTED criteria) metastatic disease. Similar survival benefits are seen using abiraterone acetate in high-risk patients (LATITUDE criteria) and in the metastatic population in STAMPEDE. ADT plus abiraterone and ADT plus docetaxel have not been compared, and it is not known if some men benefit more from one regimen as opposed to the other. Fitness for chemotherapy, patient comorbidities, toxicity profiles, quality of life, drug availability, and cost should be considered in this decision. Additional information is available at www.asco.org/genitourinary-cancer-guidelines . PMID- 29608395 TI - An engineered cell sheet composed of human islets and human fibroblast, bone marrow-derived mesenchymal stem cells, or adipose-derived mesenchymal stem cells: An in vitro comparison study. AB - BACKGROUND: We previously reported the utility of engineered cell sheets composed of human islets and supporting cells in vitro and in vivo. It is unclear which type of supporting cell is most suitable for constructing cell sheets with human islets. The present study aimed to compare human fibroblasts, bone marrow-derived mesenchymal stem cells (BM-MSCs), and adipose-derived mesenchymal stem cells (ADSCs) as a supporting source for cell sheets. METHODS: Engineered cell sheets were fabricated with human islets using human fibroblasts, BM-MSCs, or ADSCs as supporting cells. The islet viability, recovery rate, glucose-stimulated insulin release (determined by the stimulation index), and cytokine secretion (TGF-beta1, IL-6, and VEGF) of groups-including an islet-alone group as a control-were compared. RESULTS: All three sheet groups consistently exhibited higher viability, recovery rate, and stimulation index values than the islet-alone group. The ADSC group showed the highest viability and recovery rate among the three sheet groups. There were no discernible differences in the stimulation index values of the groups. The fibroblast group exhibited significantly higher TGF-beta1 values in comparison to the other groups. The IL-6 level of the ADSC group was more than five times higher than that of the other groups. The ADSC group showed the VEGF level; however, it did not differ from that of the BM-MSC group to a statistically significant extent. CONCLUSION: Engineered cell sheets composed of islets and supporting cells had a cytoprotective effect on islets. These results suggest that individual cell types could be a more attractive source for crafting engineered cell sheets in comparison to islets alone. PMID- 29608398 TI - A High-Throughput Flow Cytometry Screen Identifies Molecules That Inhibit Hantavirus Cell Entry. AB - Hantaviruses cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardiopulmonary syndrome (HCPS), which infects more than 200,000 people worldwide. Sin Nombre virus (SNV) and Andes virus (ANDV) cause the most severe form of HCPS, with case fatality ratios of 30%-40%. There are no specific therapies or vaccines for SNV. Using high-throughput flow cytometry, we screened the Prestwick Chemical Library for small-molecule inhibitors of the binding interaction between UV-inactivated and fluorescently labeled SNVR18 particles, and decay-accelerating factor (DAF) expressed on Tanoue B cells. Eight confirmed hit compounds from the primary screen were investigated further in secondary screens that included infection inhibition, cytotoxicity, and probe interference. Antimycin emerged as a bona fide hit compound that inhibited cellular infection of the major HCPS (SNV)- and HCPS (Hantaan)-causing viruses. Confirming our assay's ability to detect active compounds, orthogonal testing of the hit compound showed that antimycin binds directly to the virus particle and blocks recapitulation of physiologic integrin activation caused by SNV binding to the integrin PSI domain. PMID- 29608399 TI - Eyes on New Product Development: Preclinical Research. PMID- 29608401 TI - A Modification to Schneiderian Membrane Perforation Repair Technique: The Hammock Approach. PMID- 29608400 TI - Cell-SELEX-Based Identification of a Human and Mouse Cross-Reactive Endothelial Cell-Internalizing Aptamer. AB - Increased interest and insights gained by researchers on the roles of endothelial cells in the pathophysiology of cancer, inflammatory, and cardiovascular diseases have led to the design of pharmacological interventions aimed at the endothelium lining in the diseased sites. Toward this end, we used established brain microvascular endothelial cell lines mouse (bEND3), human (hCMEC/D3), and Toggle Cell-SELEX to identify a species cross-reactive, endothelial cell-internalizing aptamer R11-3. This 2'F-modified RNA aptamer is specific for endothelial cells as no internalization was seen with cells of nonendothelial origin. R11-3 was truncated in size, and its potential in endothelial targeted therapeutics was established using VEGFR2 targeting long interfering RNA (liRNA) aptamer chimera. Due to its specificity for both mouse and human endothelial cells, we believe that this aptamer not only fits for development of endothelial targeted drug development for human diseases but is also suitable for preclinical evaluation in mice. PMID- 29608402 TI - An Introduction to Copepod Diversity. PMID- 29608403 TI - Design, synthesis, molecular docking and anti-hepatocellular carcinoma evaluation of novel acyclic pyridine thioglycosides. AB - A novel series of acyclic pyridine thioglycosides has been synthesized. Evaluation of the anti proliferative activity of these compounds against HEPG-2 cell lines (liver carcinoma cell lines) shows that most of the compounds have high anti-tumor activities especially 6b, 6c, 7b and 7c. Furthermore, in the modeling study, these compounds showed that they have high binding affinity with thymidylate synthase dihydrofolate reductase (TS-DHFR). PMID- 29608404 TI - Apicoectomy and Scanning Electron Microscopy Analysis of an Implant Infected by Apical (Retrograde) Peri-implantitis: A Case Letter. PMID- 29608405 TI - Immediate Implant Placement at a Periapical Lesion Site: A Case Series. PMID- 29608406 TI - Immunohistochemical Expression of FXR1 in Canine Normal Tissues and Melanomas. AB - Fragile X mental retardation-related protein 1 (FXR1) is a cytoplasmic RNA binding protein highly conserved among vertebrates. It has been studied for its role in muscle development, inflammation, and tumorigenesis, being related, for example, to metastasizing behavior in human and canine uveal melanoma. Anti-FXR1 antibodies have never been validated in the canine species. To investigate FXR1 expression in canine melanocytic tumors, the present study tested two commercially available polyclonal anti-human FXR1 antibodies, raised in goat and rabbit, respectively. The cross-reactivity of the anti-FXR1 antibodies was assessed by Western blot analysis, and the protein was localized by IHC in a set of normal canine tissues and in canine melanocytic tumors (10 uveal and 10 oral). Western blot results demonstrated that the antibody raised in rabbit specifically recognized the canine FXR1, while the antibody raised in goat did not cross-react with this canine protein. FXR1 protein was immunodetected using rabbit anti-FXR1 antibody, in canine normal tissues with different levels of intensity and distribution. It was also detected in 10/10 uveal and 9/10 oral melanocytic tumors. The present study validated for the first time the use of anti-FXR1 antibody in dogs and highlighted different FXR1 protein expression in canine melanocytic tumors, the significance of which is undergoing further investigations. PMID- 29608407 TI - Epitope Mapping of Monoclonal Antibody PMab-48 Against Dog Podoplanin. AB - Podoplanin (PDPN), a type I transmembrane sialoglycoprotein, is expressed on normal renal podocytes, pulmonary type I alveolar cells, and lymphatic endothelial cells. Increased expression of PDPN in cancers is associated with poor prognosis and hematogenous metastasis through interactions with C-type lectin-like receptor 2 (CLEC-2) on platelets. We previously reported a novel PMab 48 antibody, which is an anti-dog PDPN (dPDPN) monoclonal antibody (mAb) recognizing PDPN expressed in lymphatic endothelial cells. However, the binding epitope of PMab-48 is yet to be clarified. In this study, an enzyme-linked immunosorbent assay and flow cytometry were used to investigate epitopes of PMab 48. The results revealed that the critical epitope of PMab-48 comprises Asp29, Asp30, Ile31, Ile32, and Pro33 of dPDPN. PMID- 29608408 TI - Monoclonal Antibody L1Mab-13 Detected Human PD-L1 in Lung Cancers. AB - Programmed cell death ligand-1 (PD-L1) is a type I transmembrane glycoprotein expressed on antigen-presenting cells. It is also expressed in several tumor cells such as melanoma and lung cancer cells. A strong correlation has been reported between human PD-L1 (hPD-L1) expression in tumor cells and negative prognosis in cancer patients. Here, a novel anti-hPD-L1 monoclonal antibody (mAb) L1Mab-13 (IgG1, kappa) was produced using a cell-based immunization and screening (CBIS) method. We investigated hPD-L1 expression in lung cancer using flow cytometry, Western blot, and immunohistochemical analyses. L1Mab-13 specifically reacted hPD-L1 of hPD-L1-overexpressed Chinese hamster ovary (CHO)-K1 cells and endogenous hPD-L1 of KMST-6 (human fibroblast) in flow cytometry and Western blot. Furthermore, L1Mab-13 reacted with lung cancer cell lines (EBC-1, Lu65, and Lu99) in flow cytometry and stained lung cancer tissues in a membrane-staining pattern in immunohistochemical analysis. These results indicate that a novel anti hPD-L1 mAb, L1Mab-13, is very useful for detecting hPD-L1 of lung cancers in flow cytometry, Western blot, and immunohistochemical analyses. PMID- 29608409 TI - Changes in Withdrawal and Craving Scores in Participants Undergoing Opioid Detoxification Utilizing Ibogaine. AB - Opioid use disorder (OUD) is currently an epidemic in the United States (US) and ibogaine is reported to have the ability to interrupt opioid addiction by simultaneously mitigating withdrawal and craving symptoms. This study examined opioid withdrawal and drug craving scores in 50 participants with OUD undergoing a week-long detoxification treatment protocol with ibogaine. The Addiction Severity Index (ASI) was used for baseline characterization of participants' OUD. Clinical Opioid Withdrawal Scale (COWS), Subjective Opioid Withdrawal Scale (SOWS), and Brief Substance Craving Scale (BSCS) scores were collected at 48 and 24 hours prior to ibogaine administration, as well as 24 and 48 hours after ibogaine administration. At 48 hours following ibogaine administration, withdrawal and craving scores were significantly lowered in comparison to baseline: 78% of patients did not exhibit objective clinical signs of opioid withdrawal, 79% reported minimal cravings for opioids, and 68% reported subjective withdrawal symptoms in the mild range. Ibogaine appears to facilitate opioid detoxification by reducing opioid withdrawal and craving in participants with OUD. These results warrant further research using rigorous controlled trials. PMID- 29608410 TI - Armillaria mexicana, a newly described species from Mexico. AB - Armillaria mexicana (Agaricales, Physalacriaceae) is described as a new species based on morphology, DNA sequence data, and phylogenetic analyses. It clearly differs from previously reported Armillaria species in North, Central, and South America. It is characterized by the absence of fibulae in the basidioma, abundant cheilocystidia, and ellipsoidal, hyaline basidiospores that are apparently smooth under light microscope, but slightly to moderately rugulose under scanning electron microscope. It is differentiated from other Armillaria species by macromorphological characters, including annulus structure, pileus and stipe coloration, and other structures. DNA sequence data (nuc rDNA internal transcribed spacers [ITS1-5.8S-ITS2 = ITS], 28S D-domain, 3' end of 28S intergenic spacer 1, and translation elongation factor 1-alpha [TEF1]) show that A. mexicana sequences are quite distinct from sequences of analogous Armillaria species in GenBank. In addition, sequences of ITS of the A. mexicana ex-type culture reveal an ITS1 of 1299 bp and an ITS2 of 582 bp, the longest ITS regions reported thus far in fungi. Phylogenetic analysis based on TEF1 sequences place A. mexicana in a well-separated, monophyletic clade basal to the polyphyletic A. mellea complex. PMID- 29608411 TI - Subjective Confidence Predicts Information Seeking in Decision Making. AB - There is currently little direct evidence regarding the function of subjective confidence in decision making: The tight correlation between objective accuracy and subjective confidence makes it difficult to distinguish each variable's unique contribution. Here, we created conditions in a perceptual decision task that were matched in accuracy but differed in subjective evaluation of accuracy by orthogonally varying the strength versus variability of evidence. Confidence was reduced with variable (vs. weak) evidence, even across conditions matched for difficulty. Building on this dissociation, we constructed a paradigm in which participants ( N = 20) could choose to seek further information before making their decision. The data provided clear support for the hypothesis that subjective confidence predicts information seeking in decision making: Participants were more likely to sample additional information before giving a response in the condition with low confidence, despite matched accuracy. In a preregistered replication ( N = 50), these findings were replicated with increased task difficulty levels. PMID- 29608412 TI - Physicians report adopting safer opioid prescribing behaviors after academic detailing intervention. AB - BACKGROUND: This study evaluated an educational intervention intended to increase physician use of patient prescription history information from the state prescription monitoring program (PMP) and their adoption of clinical behaviors consistent with opioid prescription guidelines to reduce patient risk. METHODS: Physician volunteers (N = 87) in community practices and Veterans Administration medical settings in South Carolina received an office-based, individualized, educational intervention (academic detailing) from a trained pharmacist who promoted 3 key messages about safer opioid prescribing. Physicians were registered for the state PMP, guided through retrieving patient information from the PMP, and given patient-centered materials. Physicians consented to completing Web surveys; 68 (78%) completed follow-up surveys on average 12.2 weeks post intervention. RESULTS: Of 43 respondents who did not use the PMP before the intervention, 83% adopted PMP use. Self-reports also revealed a significant increase in frequency of the following behaviors: (1) using patient report information from the PMP; (2) using a standardized scale to monitor pain intensity and interference with daily functioning; and (3) issuing orders for urine toxicology screens for patients maintained long-term on opioids. CONCLUSIONS: The intervention was effective in promoting physician adoption of prescribing behaviors intended to reduce risks associated with prescription opioids. The self-report findings of this study should be confirmed by analysis using data on the number of queries submitted to the state's PMP. The present study suggests that a single academic detailing visit may be an effective tool for increasing physician voluntary registration and utilization of data on patient prescription history contained in a state PMP. PMID- 29608413 TI - The relationship between discrimination and memory for spacing and feature changes in houses. AB - Adults need to discriminate between stimuli and recognize those previously seen. For faces, feature changes (e.g., different eyes) and spacing changes (e.g., distances between eyes) are important cues. In two experiments, we assessed the influence of these on discrimination and recognition of houses, a commonly used control in face studies. In both experiments, discrimination was better for feature than spacing changes. Memory for spacing changes was generally poor but aided by extra learning and intermixing change types. Conversely, memory for features was good, especially when there were few houses, and change type was blocked. Unexpectedly, memory was best for differences that might signal something about occupants (e.g., changes to garden or bins), perhaps akin to hairstyles for faces. Overall, results are consistent with previous work showing poor discrimination of spacing in non-face objects and extends them to show that, unlike for faces, spacing differences are also not well remembered. PMID- 29608414 TI - Bigger, stronger, faster, fitter: the differences in physical qualities of school and academy rugby union players. AB - Limited research has compared the physical qualities of adolescent rugby union (RU) players across differing playing standards. This study therefore compared the physical qualities of academy and school Under-18 RU players. One-hundred and eighty-four (professional regional academy, n = 55 school, n = 129) male RU players underwent a physical testing battery to quantify height, body mass, strength (bench press and pull-up), speed (10, 20 and 40 m), 10 m momentum (calculated; 10 m velocity * body mass) and a proxy measure of aerobic fitness (Yo-Yo Intermittent Recovery Test Level 1; IRTL1). The practical significance of differences between playing levels were assessed using magnitude-based inferences. Academy players were taller (very likely small), heavier (likely moderate) and stronger (bench press possibly large; pull-up plus body mass likely small) than school players. Academy players were faster than school players over 20 and 40 m (possibly and likely small), although differences in 10 m speed were not apparent (possibly trivial). Academy players displayed greater 10 m momentum (likely moderate) and greater IRTL1 performance (likely small) than school players. These findings suggest that body size, strength, running momentum, 40 m speed and aerobic fitness contribute to a higher playing standard in adolescent rugby union. PMID- 29608415 TI - Participation in intergenerational service-learning benefits older adults: A brief report. AB - Most research on intergenerational service-learning has focused on the benefits for college students, with fewer studies examining the benefits to older adults. The present study was designed to assess the impact on older adults of participating in Working Together: Intergenerational Student/Senior Exchange, a brief intergenerational service-learning program that brings together college students and older adults as equal partners to promote intergenerational understanding and communication. Older adults from an assisted living community met up to six times with students enrolled in aging-related courses to discuss a variety of topics and get to know one another. Results showed brief intergenerational service-learning benefits older adults with significant increases in generativity from pre-to post-program assessment. Additionally, a large percentage of the participants expressed interest in participating again and a willingness to refer others to the program. Limitations and future directions are discussed. PMID- 29608416 TI - Trends in the Implementation of Active Surveillance for Low-Risk Papillary Thyroid Microcarcinomas at Kuma Hospital: Gradual Increase and Heterogeneity in the Acceptance of This New Management Option. AB - BACKGROUND: Active surveillance (AS) of low-risk papillary thyroid microcarcinoma (PMC) was adopted as a management modality in both the Japanese guidelines in 2011 and the American Thyroid Association guidelines in 2015. AS was initiated at Kuma Hospital in 1993 but was not immediately accepted by all physicians. This study investigated the history of acceptance of AS at Kuma Hospital over time. The results should assist in the implementation of AS at other hospitals in Japan and other countries. METHODS: This study included 4023 patients who were cytologically diagnosed with low-risk PMC at Kuma Hospital during the 24-year period between October 1993 and June 2016. The trend in the frequency of AS use over time was analyzed, dividing the 24-year study period into five parts based on the change in frequency of AS use: 1993-1997, 1998-2002, 2003-2006, 2007-2013, and 2014-2016. RESULTS: The frequency of AS use in the present cohort was 65%. The frequency gradually increased from 30% in 1993-1997 to 88% in 2014-2016, with a slight decrease from 51% in 1998-2002 to 42% in 2003-2006. Until 2007, patients were mostly seen by surgeons, and the frequency of AS use varied remarkably among individual surgeons. Since 2007, the number of patients whose therapeutic strategies are determined by endocrinologists has increased, and the frequency of AS use for low-risk PMC by endocrinologists has been higher than that by surgeons. CONCLUSIONS: At Kuma Hospital, acceptance of AS for low-risk PMC gradually increased over the 24-year study period, but AS was not equally accepted by all physicians. Such variations in the acceptance of AS among individual physicians are also expected to exist in other hospitals. However, due to increasing evidence of the safety and superiority of AS over immediate surgery for this indolent disease, it is expected that AS will gain faster acceptance in other hospitals in Japan and around the world. PMID- 29608417 TI - Assessing the Impact of Case Management on Medicaid Clients with Chronic Diseases. AB - State Medicaid programs increasingly use case management to manage enrollees with chronic conditions who may become cost intensive for the program. The authors examined the impact of Alabama Department of Public Health (ADPH)'s case management on care expenditures for Medicaid enrollees with various chronic diseases, over 2011 to 2014. The authors matched case-managed enrollees with three controls per case using health conditions and sociodemographics. Thereafter, the authors used a quasi-experimental approach to estimate how per member-per-month costs changed following case management. Case -management appeared to result in program savings, driven largely by inpatient and emergency department cost-savings. There was noticeable variation in savings for members with different chronic conditions. PMID- 29608418 TI - Mood, cognitive structuring and medication adherence. AB - A study with a placebo was conducted. Healthy university students were given a placebo and were told to make one pill every day for a week. Participants were informed that the medicine improved mood. The extent to which they conformed to this instruction was treated as an index of compliance. Our results show that for women, but not for men, positive mood and cognitive structuring or negative mood and lack of cognitive structuring significantly predicted participants' compliance. A new model of medication adherence, based on the role of the patient's mood and cognitive structuring processes in decision making is presented in the paper. PMID- 29608419 TI - The Effect of Early Positive Cultures on Mortality in Ventilated Trauma Patients. AB - BACKGROUND: The purpose was to examine the incidence of positive cultures in a highly susceptible subset of trauma patients admitted to the surgical intensive care unit (SICU) for mechanical ventilation and to examine the impact of their timing on outcomes. PATIENTS AND METHODS: A retrospective review was conducted of blunt trauma patients admitted to the SICU for mechanical ventilation at a level I trauma center over a five-year period. All urine, blood, and sputum cultures were abstracted. Patients with at least one positive culture were compared with those with negative or no cultures. The primary outcome was mortality. A Cox regression model with a time-dependent variable was utilized to calculate the adjusted hazard ratio (AHR). RESULTS: The median age of 635 patients meeting inclusion criteria was 46 and 74.2% were male. A total of 298 patients (46.9%) had at least one positive culture, with 28.9% occurring within two days of admission. Patients with positive cultures were more likely to be severely injured with an injury severity score (ISS) >=16 (68.5% vs. 45.1%, p < 0.001). Overall mortality was 22%. Patients who had their first positive culture within two and three days from admission had a significantly higher AHR for mortality (AHR: 14.46, p < 0.001 and AHR: 10.59, p = 0.028, respectively) compared to patients with a positive culture at day six or later. CONCLUSIONS: Early positive cultures are common among trauma patients requiring mechanical ventilation and are associated with higher mortality. Early identification with "damage control cultures" obtained on admission to aid with early targeted treatment might be justified. PMID- 29608421 TI - Implementing Wearable Sensors for Continuous Assessment of Daytime Heart Rate Response in Inpatient Rehabilitation. AB - BACKGROUND: It is unclear whether wearable heart rate (HR) sensors can be worn continuously in inpatient rehabilitation to assess cardiorespiratory training response. If feasible, these sensors offer a low-cost low-maintenance method for assessing HR response in this setting. We determined feasibility of wearable sensors for assessing HR response to daytime therapy activities in inpatient rehabilitation within a cardiorespiratory training zone equal to 55-80% of maximal HR (target HR [THR]) for at least two 10-min bouts, 3-5 days per week. Secondarily, we determined episodes of excessive HR (EHR >80% of maximal HR). MATERIALS AND METHODS: Subjects 44-80 years of age with diagnoses of stroke, cardiac disorders, orthopedic disorders, medically complex conditions, or pulmonary disorders wore wrist-mounted HR sensors day and night throughout inpatient rehabilitation. The proportion of subjects meeting THR thresholds and experiencing EHR episodes was quantified. Multiple regression predicted THR and EHR outcomes from age, sex, length of stay, and motor function at admission and discharge. RESULTS: Across subjects, 97,800 min of HR data were analyzed. Sixty percent of subjects met THR thresholds for cardiorespiratory benefit. Age was the single significant predictor of percent of days meeting the THR threshold (R = 0.58, p = 0.024). Forty-seven percent of subjects experienced EHR episodes on at least 1 day. No subjects experienced sensor-related adverse events, and no protocol deviations occurred from inadvertent sensor removal. CONCLUSIONS: Most subjects experienced HR increases sufficient to obtain cardiorespiratory benefit. Likewise, most subjects had episodes of EHR. Wearable sensors were feasible for continuously assessing HR response, suggesting expanded opportunity in inpatient rehabilitation research and treatment. PMID- 29608420 TI - Influence of Long-Term Feeding Antibiotics on the Gut Health of Zebrafish. AB - The use of antibiotics for anti-infection and growth promotion has caused the overuse of antibiotics in aquaculture. However, the benefit or risk of the long term use of antibiotics on fish growth or health has not been fully addressed. In the present study, zebrafish were fed with sulfamethoxazole (SMX) or oxytetracycline (OTC) at the therapeutic concentrations (100 and 80 mg/kg body weight per day, respectively) for 6 weeks to mimic the long-term use of antibiotics. The digestive enzyme activities were higher in both antibiotic treatments, and higher oxygen consumption rate was found in OTC treated group. As a result, SMX increased the weight gain of zebrafish, and OTC treatment did not show significant prompting effect on growth. The mortality was higher in SMX or OTC treated group on 2nd-4th day after exposure to Aeromonas hydrophila. Lower alkaline phosphatase (AKP) and acid phosphatase (ACP) activities were found in OTC treated group, while higher malondialdehyde (MDA) content was found in the intestine of both SMX and OTC treated zebrafish. Furthermore, feeding OTC decreased the intestinal microbial richness. This study revealed that long-term use of legal aquaculture concentrations of antibiotics caused systemic adverse effects on fish gut health; stringent policy for use of antibiotics in fish is urgent. PMID- 29608423 TI - Integrating student-focused career planning into undergraduate gerontology programs. AB - As our global older adult populations are increasing, university programs are well-positioned to produce an effective, gerontology-trained workforce (Morgan, 2012; Silverstein & Fitzgerald, 2017). A gerontology curriculum comprehensively can offer students an aligned career development track that encourages them to: (a) learn more about themselves as a foundation for negotiating career paths; (b) develop and refine career skills; (c) participate in experiential learning experiences; and (d) complete competency-focused opportunities. In this article, we discuss a programmatic effort to help undergraduate gerontology students integrate development-based career planning and decision-making into their academic programs and achieve postgraduation goals. PMID- 29608422 TI - A Systematic Review of Pericolic Extraluminal Air in Left-Sided Acute Colonic Diverticulitis. AB - BACKGROUND: Although approximately 15% of all patients with acute colonic diverticulitis have pericolic extraluminal air found on computed tomography (CT), studies on the natural course and treatment of these patients are scarce. It is not clear whether these patients behave as mild uncomplicated diverticulitis or as severe diverticulitis needing more aggressive treatment. Consequently, there is no consensus about the treatment, guidelines do not discuss this group of patients, and physicians treat these patients based on their own experiences and opinion. An evidence-based approach is needed to prevent overtreatment or undertreatment in patients with pericolic extraluminal air. METHODS: PubMed and EMBASE databases were searched for all studies reporting clinical outcomes of the initial diverticulitis episode of CT-proven left-sided colonic diverticulitis. Primary outcome measures were the need for emergency surgery and percutaneous abscess drainage. RESULTS: A total of eight studies with 251 patients with pericolic extraluminal air were included. Rates of emergency surgery in isolated patients with pericolic extraluminal air were reported in six studies, yielding a pooled rate of 6% (95% confidence interval [CI] 3%-12%). In three studies reporting a combined total of only 56 patients, no patient underwent percutaneous abscess drainage. The long-term (6 mo) need for surgery was 38% in one study, although reasons for surgery were lacking. CONCLUSION: An initial 94% success rate of non-operative treatment in left-sided colonic diverticulitis patients with pericolic extraluminal air seems to justify a conservative approach including antibiotic agents. Low-quality evidence indicates the need for surgery in up to 38% in the medium-long term. PMID- 29608424 TI - The construction and validation of the Stellenbosch Endometriosis Quality of life measure (SEQOL). AB - In this paper, we describe the process of construction and validation of a health related quality of life (HRQOL) measure for patients with endometriosis. The items in the measure were initially constructed, edited, and reduced using a consultative process with endometriosis experts. We then determined the test reliability, validity, and factor structure of the measure by administering the measure and several other measures to 203 patients with endometriosis. The 35 item measure produced an eight-dimension factor structure. The measure and its subscales demonstrated excellent internal consistency reliability and promising validity. PMID- 29608426 TI - Identification of Hub Genes and Pathways in Zika Virus Infection Using RNA-Seq Data: A Network-Based Computational Approach. AB - Zika virus (ZIKV), a single-strand RNA flavivirus, is transmitted primarily through Aedes aegypti. The recent outbreaks in America and unexpected association between ZIKV infection and birth defects have triggered the global attention. This vouches to understand the molecular mechanisms of ZIKV infection to develop effective drug therapy. A systems-level understanding of biological process affected by ZIKV infection in fetal brain sample led us to identify the candidate genes for pharmaceutical intervention and potential biomarkers for diagnosis. To identify the key genes, transcriptomics data (RNA-Seq) with GSE93385 of ZIKV (Strain: MR766) infected human fetal neural stem cell are analyzed. In total, 1,084 differentially expressed genes (DEGs) are identified, that is, 471 upregulated and 613 downregulated genes. Further analysis such as the gene ontology term suggested that the downregulated genes are mostly enriched in defense response to virus, receptor binding, laminin binding, extracellular matrix, endoplasmic reticulum, and for upregulated DEGs: translation initiation, RNA binding, cytosol, and nucleosome are enriched. And through pathway analysis, systemic lupus erythematosus (SLE) is found to be the most enriched pathway. Protein-protein interaction (PPI) network is constructed to find the hub genes using STRING database. The seven key genes namely cyclin-dependent kinase 1 (CDK1), cyclin B1 (CCNB1), histone cluster 1 H2B family member K, (HIST1H2BK) histone cluster 1 H2B family member O (HIST1H2BO), and histone cluster 1 H2B family member B (HIST1H2BB), polo-like kinase 1 (PLK1), and cell division cycle 20 (CDC20) with highest degree are found to be hub genes using Centiscape, a Cytoscape plugin. The modules of PPI network using Molecular Complex Detection plugin are found significant in structural constituent of ribosome, defense response to virus, nucleosome, SLE, extracellular region, and regulation of gene silencing. Thus, identified key hub genes and pathways shed light on molecular mechanism that may contribute to the discovery of novel therapeutic targets and development of new strategies for the intervention of ZIKV disease. PMID- 29608425 TI - Deregulated TNF-Alpha Levels Along with HPV Genotype 16 Infection Are Associated with Pathogenesis of Cervical Neoplasia in Northeast Indian Patients. AB - Multiple factors are associated with human papillomavirus (HPV) infection related cervical anomalies and its progression to cervical carcinoma (CaCx), but data vary with respect to the underlying HPV genotype and with population being studied. No data are available regarding the role of immunological imbalance in HPV infected CaCx pathogenesis from Northeast India, which has an ethnically distinct population, and was aimed to be addressed through this study. The study included 76 CaCx cases, 25 cervical intraepithelial neoplasia (CIN) cases, and 50 healthy female controls. HPV screening and genotyping were performed by PCR. Differential expression of tumor necrosis factor alpha (TNF-alpha) was studied at serum level by enzyme-linked immunosorbent assay and tissue level by immunohistochemistry and messenger RNA (mRNA) level by real-time PCR. The data were correlated with interferon gamma (IFN-gamma) and NF-kappabetap65 levels at protein level, as well as HPV16 E6 and E7 expression at transcript level statistically. HPV infection and HPV16 genotype were predominant in the studied cohort. TNF-alpha was found to be downregulated at both mRNA and protein levels in CaCx cases compared to controls; and the gradient downregulation correlated with progression of the disease from normal->CIN->CaCx. TNF-alpha expression correlated with insufficient modulation of both IFN-gamma and NF-kappabetap65. The HPV16 E6 and E7 transcripts were found to be sharply upregulated in CaCx cases strongly inversely correlated with the TNF-alpha expression. Significant role of TNF-alpha downregulation associated with insufficient IFN-gamma and total NF-kappabetap65 modulation and the resulting significant upregulation of viral transcripts E6 and E7 are key to the HPV16 infection mediated CaCx pathogenesis in northeast Indian patients. PMID- 29608427 TI - New insight for activity intensity relativity, metabolic expenditure during object projection skill performance. AB - This study examined the metabolic cost (METs) of performing object projection skills at three practice trial intervals (6, 12, and 30 seconds). Forty adults (female n = 20) aged 18-30 (M = 23.7 +/- 2.9 years) completed three, nine-minute sessions of skill trials performed at 6, 12, and 30 second intervals. Participants performed kicking, throwing and striking trials in a blocked schedule with maximal effort. Average METs during each session were measured using a COSMED K4b2. A three (interval condition) X two (sex) ANOVA was conducted to examine differences in METs across interval conditions and by sex. Results indicated a main effect for interval condition (F(5,114) = 187.02, p < .001, eta2 = 0.76) with decreased interval times yielding significantly higher METs [30 sec = 3.45, 12 sec = 5.68, 6 sec = 8.21]. A main effect for sex (F(5, 114) = 35.39, p < .001, eta2 = 0.24) also was found with men demonstrating higher METs across all intervals. At a rate of only two trials/min, participants elicited moderate physical activity, with 12 and 6-second intervals exhibiting vigorous PA. Demonstrating MVPA during the performance of object projection skill performance has potential implications for PA interventions. PMID- 29608428 TI - Is Ayahuasca an Option for the Treatment of Crack Cocaine Dependence? AB - The low efficacy of crack cocaine addiction treatment available in Brazil has led Brazilian users to find alternatives to reduce drug consumption or even to reach abstinence. One of them is the use of entheogenic substances, like ayahuasca, an infusion obtained from two native plant species from the Amazon. The present report aimed to understand how crack cocaine users recover from drug addiction by consuming ayahuasca tea in a religious context. This is a qualitative study with a purposeful sample of 40 crack cocaine users, based on in-depth, semi-structured interviews. Participants reported that ayahuasca allowed them to access a consciousness dimension which enabled them to solve problems and traumas and reduce crack cocaine consumption. The religious ceremony increased the user's spirituality and the reception from the community gave them a sense of self esteem, strengthening them in an emotional and social way. That positive experience has been incorporated into the daily routine of most participants. Findings indicate that ayahuasca, in a religious context, may have therapeutic value for crack cocaine dependence treatment. PMID- 29608429 TI - Fully Soft 3D-Printed Electroactive Fluidic Valve for Soft Hydraulic Robots. AB - Soft robots are designed to utilize their compliance and contortionistic abilities to both interact safely with their environment and move through it in ways a rigid robot cannot. To more completely achieve this, the robot should be made of as many soft components as possible. Here we present a completely soft hydraulic control valve consisting of a 3D-printed photopolymer body with electrorheological (ER) fluid as a working fluid and gallium-indium-tin liquid metal alloy as electrodes. This soft 3D-printed ER valve weighs less than 10 g and allows for onboard actuation control, furthering the goal of an entirely soft controllable robot. The soft ER valve pressure-holding capabilities were tested under unstrained conditions, cyclic valve activation, and the strained conditions of bending, twisting, stretching, and indentation. It was found that the max holding pressure of the valve when 5 kV was applied across the electrodes was 264 kPa, and that the holding pressure deviated less than 15% from the unstrained max holding pressure under all strain conditions except for indentation, which had a 60% max pressure increase. In addition, a soft octopus-like robot was designed, 3D printed, and assembled, and a soft ER valve was used to stop the fluid flow, build pressure in the robot, and actuate six tentacle-like soft bending actuators. PMID- 29608430 TI - Mobile Technologies for Managing Heart Failure: A Systematic Review and Meta analysis. AB - BACKGROUND: Randomized clinical trials (RCTs) conducted among heart failure (HF) patients have reported that mobile technologies can improve HF-related outcomes. Our aim was to conduct a meta-analysis to evaluate m-Health's impact on healthcare services utilization, mortality, and cost. METHODS: We searched MEDLINE, Cochrane, CINAHL, and EMBASE for studies published between 1966 and May 2017. We included studies that compared the use of m-Health in HF patients to usual care. m-Health is defined as the use of mobile computing and communication technologies to record and transmit data. The outcomes were HF-related and all cause hospital days, cost, admissions, and mortality. RESULTS: Our search strategy resulted in 1,494 articles. We included 10 RCTs and 1 quasi-experimental study, which represented 3,109 patients in North America and Europe. Patient average age range was 53-80 years, New York Heart Association (NYHA) class III, and Left Ventricular Ejection Fraction <50%. Patients were mostly monitored daily and followed for an average of 6 months. A reduction was seen in HF-related hospital days. Nonsignificant reductions were seen in HF-related cost, admissions, and mortality and total mortality. We found no significant differences for all-cause hospital days and admissions, and an increase in total cost. CONCLUSIONS: m-Health reduced HF-related hospital days, showed reduction trends in total mortality and HF-related admissions, mortality and cost, and increased total costs related to more clinic visits and implementation of new technologies. More studies reporting consistent quality outcomes are warranted to give conclusive information about the effectiveness and cost-effectiveness of m Health interventions for HF. PMID- 29608431 TI - Postoperative Pain Outcomes After Nuss Procedures: Comparison of Epidural Analgesia, Continuous Infusion of Local Anesthetic, and Preoperative Self Hypnosis Training. AB - BACKGROUND/PURPOSE: The Nuss procedure to correct pectus excavatum is associated with severe postoperative pain. The purpose of this retrospective study was to compare pain management outcomes of thoracic epidural analgesia and continuous infusion of local anesthetic (CILA) with and without preoperative self-hypnosis training (SHT) after Nuss procedure (4 treatment groups). METHODS: Between February 2010 and December 2013, 24 of 53 adolescents who underwent Nuss procedure received SHT. Of these, 16 received thoracic epidural analgesia and 8 received CILA postoperatively. Of the 29 patients who did not receive SHT, 19 received thoracic epidural analgesia and 10 received CILA. All patients received intravenous patient-controlled opioid analgesia and intravenous nonsteroidal anti inflammatory drugs (IVNSAIDs) and then were transitioned to oral opioids and NSAIDs. Postoperative mean and maximum pain scores, opioid (morphine equivalents) use and side effects, and hospital length of stay (LOS) were compared between groups. RESULTS: Patients who received SHT reported lower mean (P = .0047) and maximum (P = .0028) pain scores and used less morphine equivalents/hour over time (P = .046) compared to patients who did not receive SHT. Patients who received thoracic epidural analgesia reported lower mean (P = .0092) and maximum (P = .0083) postoperative pain scores and used more morphine equivalents/hour (P = .01) compared to those who received CILA. In addition, patients who received SHT and CILA had shorter LOS (P = .0013) than patients who received thoracic epidural analgesia without SHT. CONCLUSIONS: SHT before pectus excavatum repair by Nuss procedure results in less postoperative pain and requires less morphine equivalents over time for postoperative pain management. Opioid-sparing CILA, when paired with SHT, results in shorter LOS. PMID- 29608432 TI - Treatment of Achalasia with Per-Oral Endoscopic Myotomy: Analysis of 50 Consecutive Patients. AB - BACKGROUND: Peroral endoscopic myotomy (POEM) has become an acceptable incisionless treatment for achalasia based on encouraging outcomes in multiple series worldwide. This report reflects our early experience. METHODS: Data were collected prospectively on all patients undergoing POEM between June 2011 and April 2016 under IRB approval. Diagnosis of achalasia was confirmed by standard preoperative work-up. Primary outcome was symptom relief, measured by Eckardt score. Secondary outcomes were operative time, length of stay (LOS), adverse events, failure, and recurrence. RESULTS: Fifty patients were included; 30 were female. Mean age was 55.7 +/- 17.7 years. Mean BMI was 29.5 +/- 9.2. Median OR time was 133.5 minutes (range 70-462); average myotomy was 13.1 +/- 2.3 cm. One early case was converted to a laparoscopic Heller myotomy due to extensive submucosal fibrosis from a recent Botox injection. Two cases were aborted; one due to extensive submucosal fibrosis and the other to intraoperative capnopericardium. Median LOS was 1 day (range 0.8-8). Two major complications occurred: intraoperative cardiac arrest due to capnopericardium and postoperative submucosal hemorrhage. There were no deaths. Mean postoperative Eckardt score was 1.0 +/- 1.9 (range 0-8) at 2-6 weeks (vs. preoperative score 7.7 +/- 2.8; P < .0001); mean dysphagia component 0.35 +/- 0.28 (vs. preoperative score 2.6 +/- 0.7; P < .0001). Two recurrences were identified, both at 6 months. CONCLUSIONS: POEM is a safe and durable treatment for achalasia in the short term. We demonstrated marked improvement of symptoms in all completed cases. There was an acceptable serious adverse event rate of 4%, failure of 6% due to patient selection, and recurrences occurring in only 4% of cases. PMID- 29608434 TI - Food Tolerance and Quality of Alimentation Following Laparoscopic Sleeve Gastrectomy Calibrated with a 50-Fr Bougie: Long-Term Results. AB - BACKGROUND: Adjustable gastric banding and vertical banded gastroplasty are associated with the worst postoperative food tolerance of all bariatric techniques. However, food tolerance tends to improve over time. The aim of this study was to assess food tolerance and diet quality in patients undergoing a sleeve gastrectomy, 1 and 5 years after surgery. PATIENTS AND METHODS: A prospective observational study of all the morbidly obese patients undergoing laparoscopic sleeve gastrectomy was performed. Food tolerance was assessed using the Quality of Alimentation questionnaire validated in bariatric patients. RESULTS: Ninety-three patients were analyzed. One year after surgery, mean excess weight loss (EWL) was 81.1% +/- 8.3%, and 5 years after surgery, mean EWL was 79.9% +/- 6.4%. Preoperatively, 39.8% of patients perceived their eating patterns as good or excellent, 1 year after surgery, 79.6% and 5 years postoperatively, 86%. One year after surgery, the patients reported some difficulty in tolerance of rice, pasta, and red meat. Five years after surgery, these difficulties disappeared and very few patients just refer some tolerance difficulties with red meat. One year after surgery, 10% of the patients reported that they suffered postprandial vomiting often and 22% rarely. Five years postoperatively, only 8% of subjects describe rarely vomiting. CONCLUSION: After sleeve gastrectomy, the patients recognize an improvement in the quality of alimentation. During the first postoperative year, they present tolerance problems with rice, pasta, and red meat, and that disappeared 5 years after surgery. PMID- 29608433 TI - Effects of Education and Health Literacy on Postoperative Hospital Visits in Bariatric Surgery. AB - BACKGROUND: Hospital readmissions following bariatric surgery are high and it is necessary to identify modifiable risk factors to minimize this postoperative cost. We hypothesize that lower levels of education and health literacy are associated with increased risks of nonadherence, thus leading to increased emergency department (ED) visits and preventable readmissions postoperatively. METHODS: Bariatric surgery patients presenting between October 2015 and December 2016 were administered a preoperative questionnaire that measured education level and the Rapid Estimate of Adult Literacy in Medicine-Short Form (REALM-SF) health literacy test. The rates of postoperative ED visits and readmissions were across education levels (<=12th grade versus >12th grade) and health literacy scores (<=8th grade versus high school level). A composite "hospital visit" outcome was also assessed. RESULTS: Ninety-five patients were enrolled; 23 had <=12th grade level education and 7 scored <=8th grade on the REALM-SF. Patients with <=12th grade education were significantly more likely to have a hospital visit after surgery, compared with patients with >12th grade education (incidence rate ratio [IRR] 3.06, P = .008). No significant difference in ED visits, readmission, or hospital visits was seen when stratified by REALM-SF health literacy score. CONCLUSIONS: Lower level of education was associated with more than threefold increased risk of postoperative ED visits and readmission in our center's bariatric surgery patients. A patient's education level is a low-cost means to identify patients who are at risk for postoperative hospital visits, and who may benefit from enhanced educational efforts or more intensive postoperative follow up. PMID- 29608435 TI - Use of Iodized Oil and Gelatin Sponge Embolization in Splenic Artery Coiling Reduces Bleeding from Laparoscopic Splenectomy for Cirrhotic Portal Hypertension Patients with Complicating Hypersplenic Splenomegaly: A Comparative Study. AB - OBJECTIVE: Laparoscopic splenectomy (LS) is relatively contraindicated in cirrhotic portal hypertension (CPH) patients with complicating hypersplenic splenomegaly (HS). This study aimed to evaluate the effectiveness and safety of incorporation of iodized oil and gelatin sponge embolization to conventional splenic artery embolization (cSAE) with coiling in CPH/HS patients undergoing LS. PATIENTS AND METHODS: Between April 2012 and March 2014, eligible CPH/HS patients (n = 56) were assigned to preoperative modified SAE (mSAE) with LS (mSAE+LS group, n = 16), cSAE with LS (cSAE+LS group, n = 20) or LS alone (LS group, n = 20). Main outcome measures included frequency of conversion to laparotomy, operative time, intraoperative bleeding, and transfusion. RESULTS: The three groups had similar baseline characteristics (all P > .05). mSAE and cSAE similarly decreased LS conversion frequency (mSAE+LS versus cSAE+LS versus LS, 0.0% versus 10.0% versus 30.0%, P = .030) and operative time (155 +/- 23 minutes versus 170 +/- 26 minutes versus 221 +/- 42 minutes, P < .001) compared with LS alone. mSAE significantly reduced bleeding (178 +/- 22 mL versus 250 +/- 27 mL versus 328 +/- 67 mL, P < .001) compared with cSAE and LS alone. The three groups had similar postoperative recovery times and surgical morbidities (all P > .05). CONCLUSIONS: In CPH/HS patients, preoperative SAE reduced LS conversion frequency and reduced operative time compared with LS alone, while mSAE further decreased volume of blood loss. PMID- 29608436 TI - Dental Anxiety Among Israeli Postgraduate Pediatric Dental Students and their Instructors. AB - OBJECTIVE: To measure the dental anxiety levels of post-graduate pediatric dental students (PGS) and their instructors, and their ranking of the most anxiety provoking situations in the dental situation; to investigate gender differences with regard to dental anxiety. STUDY DESIGN: Twenty-four PGS and 31 of their instructors completed a three-section questionnaire on socio demographic information, dental anxiety scale (DAS) and dental fear survey (DFS). RESULTS: The overall mean DAS and DFS scores were similar for both groups. The scores of the PGS were significantly higher on the DFS for perspiration when dental work was done (p = 0.032), the smell of the dentist's office (p = 0.009), and seeing the dentist enter the treatment room (p = 0.005). The total DAS score was significantly higher among females than among males (8.03 +/- 3.08 and 6.63 +/- 1.77, p = 0.037), and for item on waiting for the dentist to scrape the teeth, (p = 0.05). The DAS and DFS scores were strongly correlated (r = 0.768, p = 0.000). The highest DAS score was for the item on anticipation of dental treatment before arrival to the clinic and waiting for the drilling. The response pattern for both groups was similar. CONCLUSIONS: Overall dental anxiety of PGS and their instructors was similar. Female PGS and instructors had higher dental anxiety levels than males. PMID- 29608437 TI - Intra-Operative Inspired Fraction of Oxygen and the Risk of Surgical Site Infections in Patients with Type 1 Surgical Incisions. AB - BACKGROUND: Whether the fraction of inspired oxygen (FIO2) influences the risk of surgical site infection (SSI) is controversial. The World Health Organization and the World Federation of Societies of Anesthesiologists offer conflicting recommendations. In this study, we evaluate simultaneously three different definitions of FIO2 exposure and the risk of SSI in a large surgical population. PATIENTS AND METHODS: Patients with clean (type 1) surgical incisions who developed superficial and deep organ/space SSI within 30 days after surgery from January 2003 through December 2012 in five surgical specialties were matched to specialty-specific controls. Fraction of inspired oxygen exposure was defined as (1) nadir FIO2, (2) percentage of operative time with FIO2 greater than 50%, and (3) cumulative hyperoxia exposure, calculated as the area under the curve (AUC) of FIO2 by time for the duration in which FIO2 greater than 50%. Stratified univariable and multivariable logistic regression models tested associations between FIO2 and SSI. RESULTS: One thousand two hundred fifty cases of SSI were matched to 3,248 controls. Increased oxygen exposure, by any of the three measures, was not associated with the outcome of any SSI in a multivariable logistic regression model. Elevated body mass index (BMI; 35+ vs. <25, odds ratio [OR] 1.78, 95% confidence interval [CI] 1.43-2.24), surgical duration (250+ min vs. <100 min, OR 1.93, 95% CI 1.48-2.52), diabetes mellitus (OR 1.37, 95% CI 1.13 1.65), peripheral vascular disease (OR 1.52, 95% CI 1.10-2.10), and liver cirrhosis (OR 2.48, 95% CI 1.53-4.02) were statistically significantly associated with greater odds of any SSI. Surgical sub-group analyses found higher intra operative oxygen exposure was associated with higher odds of SSI in the neurosurgical and spine populations. CONCLUSION: Increased intra-operative inspired fraction of oxygen was not associated with a reduction in SSI. These findings do not support the practice of increasing FIO2 for the purpose of SSI reduction in patients with clean surgical incisions. PMID- 29608438 TI - Seasonal Changes in Serum Thyrotropin Concentrations Observed from Big Data Obtained During Six Consecutive Years from 2010 to 2015 at a Single Hospital in Japan. AB - BACKGROUND: This study analyzed big data for serum thyrotropin (TSH), free triiodothyronine (fT3), and free thyroxine (fT4) concentrations in patients who had attended the outpatient clinic of Ito Hospital (Tokyo, Japan) during a recent six-year period (between January 1, 2010, and December 31, 2015) in order to investigate for seasonal changes. METHODS: The serum TSH concentrations were reviewed for all 135,417 patients aged >20 years. Patients with any thyroid diseases were included, irrespective of whether they were receiving drug therapy. In total 1,637,721 serum samples were analyzed for TSH, 1,626,269 for fT3, and 1,669,381 for fT4. RESULTS: It was observed that the TSH concentrations showed annual changes during the six-year period. They decreased during the summer, while they increased during the winter. The TSH concentrations were negatively correlated with the daily temperatures (Spearman rank correlation coefficient 0.4486; p < 0.0001). The same applied for the correlation between fT3 concentrations and daily temperatures. CONCLUSIONS: The fact that the TSH concentrations show annual changes in areas where the temperature ranges during the year are rather wide should be borne in mind for interpretation of results. PMID- 29608439 TI - Quantitative Analysis of the Benefits and Risk of Thyroid Nodule Evaluation in Patients >=70 Years Old. AB - BACKGROUND: In older patients, thyroid nodules are frequently detected and referred for evaluation, though usually prove to be benign disease or low-risk cancer. Therefore, management should be guided not solely by malignancy risk, but also by the relative risks of any intervention. Unfortunately, few such data are available for patients >=70 years old. METHODS: All consecutive patients >=70 years old assessed by ultrasound (US) and fine-needle aspiration (FNA) between 1995 and 2015 were analyzed. Clinical, US, and histologic data, including patient comorbidities and outcomes, were obtained. Imaging and cytology results from initial evaluation were reviewed to detect significant-risk thyroid cancer (SRTC), which was defined as anaplastic, medullary, or poorly differentiated carcinoma, or the presence of distant metastases. Overall survival analyses were then performed to assist with risk-to-benefit assessment. RESULTS: A total of 1129 patients >=70 years old with 2527 nodules >=1 cm were evaluated. FNA was safe in all, and cytology proved benign in 67.3% of patients. However, FNA led to surgery in 208 patients, of whom 93 (44.7%) had benign histopathology. Among all patients who underwent FNA, only 17 (1.5%) SRTC were identified, all of which were preoperatively identifiable by imaging and/or cytology. These SRTC were responsible for all (n = 10; 0.9%) thyroid cancer deaths. Among all other patients (n = 1112), 160 deaths (14.4%) were confirmed during a median follow-up of four years. None of these were thyroid cancer related. Survival analysis for these 1112 patients demonstrated that a separate non-thyroidal malignancy or coronary artery disease at the time of nodule evaluation was associated with increased mortality compared to those without these diagnoses (hazard ratio = 2.32 [confidence interval 1.66-3.26]; p < 0.01), confirming these are important variables to identify prior to thyroid nodule evaluation. CONCLUSIONS: For patients >=70 years old, US and FNA are safe and prove helpful in identifying SRTC and benign cytology. However, the surgical management of patients >=70 years old presenting without high-risk findings should be tempered, especially when comorbid illness is identified. PMID- 29608440 TI - Serum and urine toxicometabolomics following gentamicin-induced nephrotoxicity in male Sprague-Dawley rats. AB - Gentamicin (GM) is an aminoglycoside antibiotic used in treatment of various types of bacterial infections, but the major adverse effect is drug-induced nephrotoxicity. This study aimed to determine biomarkers that might predict nephrotoxicity initiated by GM using serum or urinary proton nuclear magnetic resonance (1H NMR) spectral data in male Sprague-Dawley rats. GM (0, 30, or 300 mg/kg/d) was intraperitoneally administered for 3 consecutive days. Animals were sacrificed 2 d (D2) or 8 d (D8) after last administration of GM in order to perform analysis of serum biochemistries and histopathologic examination. Urine samples were collected every 24 h from prior to treatment until sacrifice. Serum and urinary 1H NMR spectral data revealed apparent differential clustering between control and GM-treated groups as evidenced by principal component analysis (PCA) and orthogonal projections to latent structure-discriminant analysis (OPLS-DA) in global and targeted profiling. The concentrations of endogenous serum metabolites including 3-hydroxybutyrate, alanine, citrate, creatine, glucose, and glycine were increased significantly on D2 or D8. Urinary levels of glucose, glycine, and succinate were significantly elevated on D2 or D8, whereas the concentration of hippurate was significantly decreased on D2 and D8. Correlation of serum and urinary 1H NMR OPLS-DA with serum biochemistry and renal histopathologic changes suggests that 1H NMR urinalysis may be used to reliably predict or screen for GM-induced nephrotoxicity. In contrast, Western blot analysis of kidney injury molecule-1 (KIM-1) demonstrated that protein expression was not markedly altered indicating this biomarker was not sensitive to detect GM-mediated renal damage. Data suggest that these altered metabolites might serve as specific and sensitive biomarkers for GM-mediated renal damage. PMID- 29608441 TI - Diesel engine exhaust exposure in underground mines: Comparison between different surrogates of particulate exposure. AB - Exposure to diesel particulate matter (DPM) is frequently assessed by measuring indicators of carbon speciation, but these measurements may be affected by organic carbon (OC) interference. Furthermore, there are still questions regarding the reliability of direct-reading instruments (DRI) for measuring DPM, since these instruments are not specific and may be interfered by other aerosol sources. This study aimed to assess DPM exposure in 2 underground mines by filter based methods and DRI and to assess the relationship between the measures of elemental carbon (EC) and the DRI to verify the association of these instruments to DPM. Filter-based methods of respirable combustible dust (RCD), EC, and total carbon (TC) were used to measure levels of personal and ambient DPM. For ambient measurements, DRI were used to monitor particle number concentration (PNC; PTrak), particle mass concentration (DustTrak DRX and DustTrak 8520), and the submicron fraction of EC (EC1;Airtec). The association between ambient EC and the DRI was assessed by Spearman correlation. Geometric mean concentrations of RCD, respirable TC (TCR) and respirable elemental EC (ECR) were 170 ug/m3, 148 ug/m3, and 83 ug/m3 for personal samples, and 197 ug/m3, 151 ug/m3, and 100 ug/m3 for ambient samples. Personal measurements had higher TCR:ECR ratios compared to ambient samples (1.8 vs. 1.50) and weaker association between ECR and TCR. Among the DRI, the measures of EC1 by the Airtec (rho = 0.86; P < 0.001) and the respirable particles by the DustTrak 8520 (rho = 0.74; P < 0.001) showed the strongest association with EC, while PNC showed a weak and non-significant association with EC. In conclusion, this study provided important information about the concentrations of DPM in underground mines by measuring several indicators using filter-based methods and DRI. Among the DRI, the Airtec proved to be a good tool for estimating EC concentrations and, although the DustTrak showed good association with EC, interferences from other aerosol sources should be considered when using this instrument to assess DPM. PMID- 29608442 TI - Cognitive assessment of patients with nonalcoholic fatty liver disease. AB - OBJECTIVE: The aim of this study was to investigate cognitive performance for the first time in participants with nonalcoholic fatty liver disease (NAFLD) using the Montreal Cognitive Assessment (MoCA). PARTICIPANTS AND METHODS: In total, 70 participants with NAFLD and 73 age-matched and sex-matched healthy participants were enrolled in this prospective cross-sectional study. The diagnosis of NAFLD was made on the basis of abdominal ultrasonography findings. Anthropometric indices were calculated, and routine laboratory analyses were carried out for each participant. All participants provided sociodemographic data and completed the Beck Depression Inventory-II. Cognitive functions were evaluated using the Turkish version of the MoCA, with a cut-off score for mild cognitive impairment of less than 21 points. RESULTS: The MoCA scores were significantly lower in participants with NAFLD than in the healthy group (P<0.05). In addition, more NAFLD participants than healthy participants presented with deficits in the visuospatial (P<0.05) and executive function domains (P<0.05). In the multivariate model, education level [2.79 (1.12-6.96); P<0.05] and area of residence [5.68 (2.24-14.38); P<0.001] were associated independently with cognitive dysfunction in both the NAFLD and the healthy groups. The MoCA scores were correlated negatively with fibrosis 4 scores in NAFLD participants (r= 0.359; P<0.05). However, hepatosteatosis grade and the presence of metabolic syndrome were not correlated with MoCA scores in the NAFLD group (P>0.05). CONCLUSION: Our results show that NAFLD patients may have early or subtle cognitive dysfunction, including in the visuospatial and executive function domains, as indexed by scores on the MoCA test. Further targeted psychometric testing will be required to confirm the presence of cognitive impairment in this population. PMID- 29608443 TI - Myocardial infarction with nonobstructive coronary arteries: a single-center retrospective study. AB - BACKGROUND: Myocardial infarction (MI) with nonobstructive coronary arteries (MINOCA) is a heterogeneous entity often overlooked in contemporary medicine. We aim to determine MINOCA differential characteristics, the main etiologies, and prognostic outcomes. PATIENTS AND METHODS: We carried out a retrospective longitudinal analysis including 1047 patients with MI, from 1 January 2011 to 1 January 2016, subjected to coronary angiography and classified according to the presence [MI and obstructive coronary artery disease (MICAD)] or absence (MINOCA) of any coronary stenosis of at least 50%. Studied data included clinical, demographic, laboratorial, and angiographic features. The median follow-up duration was 35 (interquartile range: 25) months. Mortality was the primary endpoint. To identify MINOCA underlying etiologies, only the final diagnosis obtained according to the European Society of Cardiology proposed algorithm was accepted. To determine MINOCA predictors, multivariate analysis with logistic regression was carried out. RESULTS: The mean age of the patients was 66.3+/-13.4 years; 319 (30.5%) patients were women. The MINOCA group included 114 (10.8%) patients. The underlying final diagnosis in the MINOCA group was obtained in 78 (68.4%) patients. The total mortality rate was 8.8% (n=10) in the MINOCA group versus 17.7% (n=165) in the MICAD group, P=0.018. After multivariate analysis, age [odds ratio (OR)=1.05, 95% confidence interval (CI): 1.03-1.07, P<0.001], female sex (OR=3.91, 95% CI: 2.53-6.06, P<0.001), no previous tobacco use (OR=3.41, 95% CI: 1.68-3.90, P=0.001), atrial fibrillation (OR=3.62, 95% CI: 1.56 8.40, P=0.003), no previous AMI (OR=6.85, 95% CI: 1.65-28.5, P=0.008), and non-ST segment elevation myocardial infarction diagnosis (OR=5.36, 95% CI: 2.62-10.96, P<0.001) remained independent predictors of MINOCA. CONCLUSION: MINOCA represents a challenging group of heterogeneous patients whose clinical characteristics contrast with classical cardiovascular risk factors. Despite lower mortality than MICAD, the commonly attributed low-risk classification for MINOCA may be erroneous. PMID- 29608444 TI - Multivariate Pattern Analysis of Volumetric Neuroimaging Data and Its Relationship With Cognitive Function in Treated HIV Disease. AB - BACKGROUND: Accurate prediction of longitudinal changes in cognitive function would potentially allow for targeted intervention in those at greatest risk of cognitive decline. We sought to build a multivariate model using volumetric neuroimaging data alone to accurately predict cognitive function. METHODS: Volumetric T1-weighted neuroimaging data from virally suppressed HIV-positive individuals from the CHARTER cohort (n = 139) were segmented into gray and white matter and spatially normalized before entering into machine learning models. Prediction of cognitive function at baseline and longitudinally was determined using leave-one-out cross-validation. In addition, a multivariate model of brain aging was used to measure the deviation of apparent brain age from chronological age and assess its relationship with cognitive function. RESULTS: Cognitive impairment, defined using the global deficit score, was present in 37.4%. However, it was generally mild and occurred more commonly in those with confounding comorbidities (P < 0.001). Although multivariate prediction of cognitive impairment as a dichotomous variable at baseline was poor (area under the receiver operator curve 0.59), prediction of the global T-score was better than a comparable linear model (adjusted R = 0.08, P < 0.01 vs. adjusted R = 0.01, P = 0.14). Accurate prediction of longitudinal changes in cognitive function was not possible (P = 0.82). Brain-predicted age exceeded chronological age by mean (95% confidence interval) 1.17 (-0.14 to 2.53) years but was greatest in those with confounding comorbidities [5.87 (1.74 to 9.99) years] and prior AIDS [3.03 (0.00 to 6.06) years]. CONCLUSION: Accurate prediction of cognitive impairment using multivariate models using only T1-weighted data was not achievable, which may reflect the small sample size, heterogeneity of the data, or that impairment was usually mild. PMID- 29608445 TI - HIV Testing With and Without a Clinical Consultation Among Men Who Have Sex With Men: A Randomized Controlled Trial. AB - BACKGROUND: Increasing the frequency of HIV testing among men who have sex with men (MSM) maximizes the preventive effect of antiretroviral therapy, by reducing time to diagnosis and treatment. SETTING: Melbourne Sexual Health Centre, Australia. METHODS: This randomized controlled trial evaluated whether access to testing, without seeing a clinician would increase testing frequency. MSM attending for HIV testing between July 2014 and April 2015 were randomized in 1:1 ratio to the intervention arm (access to HIV and syphilis testing at 300 pathology centers, without requiring consultations) or the control arm (consultation at every test), without blinding. The primary outcome was the incidence of HIV testing over 12 months. RESULTS: Of 443 men referred, 422 were randomized, 3 HIV positives at baseline were excluded, and 419 were analyzed. Of 208 control, 202 (97.1%) and 200 (94.8%) of 211 intervention group members were followed to 12 months. The intervention group had 453 tests in 205.6 person years, incidence rate was 2.2 (95% confidence interval [CI]: 2.0 to 2.4) tests per year. The control group had 432 tests during 204.0 person-years, incidence rate was 2.1 (95% CI: 1.9 to 2.3) tests per year, and incidence rate ratio was 1.04 (95% CI: 0.89 to 1.2; P = 0.63). The annual rate of consultations was as follows: intervention, 1.61 (95% CI: 1.44 to 1.79); controls, 2.12 (95% CI: 1.92 to 2.33); rate ratio, 0.76 (95% CI: 0.65 to 0.88; P = 0.0001). There was no difference in quality of life scores (P = 0.61). CONCLUSIONS: MSM permitted HIV and syphilis testing outside of clinical consultations did not test more frequently than controls but had 24% fewer consultations, reducing service demand. TRIAL REGISTRATION: ACTRN12614000760673. PMID- 29608446 TI - Challenges and needs in experimental therapies for multiple sclerosis. AB - PURPOSE OF REVIEW: Despite dramatic advances in the treatment of people with multiple sclerosis over the last decade, several unmet medical needs still remain and should be approached with new compounds in experimental clinical trials. The prerequisites for successful clinical trials in multiple sclerosis have changed considerably over time and activities have started to improve clinical development of new drugs in several aspects including trial designs, patient selection and outcome parameters. This review will address some of the challenges in early experimental trials in multiple sclerosis and recent approaches in the field. RECENT FINDINGS: Highly intensive treatment regimens like autologous hematopoietic stem cell transplantation provide evidence for sustained long-term treatment effects in multiple sclerosis patients. Several different approaches towards neuroprotection and remyelination have entered the clinical phase and demonstrated that stabilization, even improvement of disability is achievable in short-term studies. SUMMARY: New therapeutic strategies have entered the clinic with the prospects of long-term efficacy and enduring effects on disability progression. PMID- 29608447 TI - Is Routine Bracing of Benefit Following Posterior Instrumented Lumbar Fusion for Degenerative Indications? PMID- 29608448 TI - Is Structural Allograft Superior to Synthetic Graft Substitute in Anterior Cervical Discectomy and Fusion? PMID- 29608449 TI - Conservative Treatment of Hangman Variant Fractures. AB - STUDY DESIGN: This is retrospective cohort study. OBJECTIVE: Investigate the stability of patients with hangman variant fractures and outcomes of treatment with external immobilization. SUMMARY OF BACKGROUND DATA: Traumatic spondylolisthesis of the axis (C2) with the fracture extending into the vertebral body has been incompletely characterized. Small case series have showed high rates of neurological injury and cite difficulty treating closed due to greater instability secondary to extensive ligamentous injury. MATERIALS AND METHODS: Retrospectively, all patients admitted to a level 1 trauma center from 2004 to 2015 with acute C2 fractures were identified and classified based on computed tomographic imaging. Study cohort included patients with anterior translation <5 mm and C2-3 angulation <15 degrees that were followed to conclusion of treatment. RESULTS: In total, 107 hangman's variant fractures (14.5%) were identified from a database of 735 acute C2 fractures. In total, 106 of the 107 patients displayed no neurological injury related to the cervical spine at the time of presentation. A total of 63 patients met the inclusion criteria and were followed as outpatients until collar or halo vest removal. All fractures progressed to union without progressive displacement or late neurological injury. No difference was observed in radiographic outcome between patients treated in a hard collar versus halo orthosis. CONCLUSIONS: Although widely considered a difficult fracture to treat with closed means, hangman variants are relatively neurologically benign injuries with low incidence of ligamentous injury. Fractures with <5 mm of horizontal translation and 15 degrees of angulation can be treated with external immobilization. Our results suggest no advantage of halo immobilization versus hard collar orthosis. PMID- 29608450 TI - Does Day of Surgery Affect Hospital Length of Stay and Charges Following Minimally Invasive Transforaminal Lumbar Interbody Fusion? AB - STUDY DESIGN: Retrospective Cohort. OBJECTIVE: To determine if an association exists between surgery day and length of stay or hospital costs after minimally invasive transforaminal lumbar interbody fusion (MIS TLIF). SUMMARYOF BACKGROUND DATA: Length of inpatient stay after orthopedic procedures has been identified as a primary cost driver, and previous research has focused on determining risk factors for prolonged length of stay. In the arthroplasty literature, surgery performed later in the week has been identified as a predictor of increased length of stay. However, no such investigation has been performed for MIS TLIF. MATERIALS AND METHODS: A surgical registry of patients undergoing MIS TLIF between 2008 and 2016 was retrospectively reviewed. Patients were grouped based on day of surgery, with groups including early surgery and late surgery. Day of surgery group was tested for an association with demographics and perioperative variables using the student t test or chi analysis. Day of surgery group was then tested for an association with direct hospital costs using multivariate linear regression. RESULTS: In total, 438 patients were analyzed. In total, 51.8% were in the early surgery group, and 48.2% were in the late surgery group. There were no differences in demographics between groups. There were no differences between groups with regard to operative time, intraoperative blood loss, length of stay, or discharge day. Finally, there were no differences in total hospital charges between early and late surgery groups (P=0.247). CONCLUSIONS: The specific day on which a MIS TLIF procedure occurs is not associated with differences in length of inpatient stay or total hospital costs. This suggests that the postoperative course after MIS TLIF procedures is not affected by the differences in hospital staffing that occurs on the weekend compared with weekdays. PMID- 29608451 TI - Nonalcoholic Fatty Liver is Contributing to the Increase in Cases of Liver Disease in US Emergency Departments. AB - GOALS/BACKGROUND: We aimed to assess temporal changes in the different types of liver disease (LD) cases and outcomes from emergency departments (EDs) across the United States. STUDY: We used data from the National Inpatient Survey database from 2005 to 2011. The International Classification of Diseases, Ninth Revision (ICD-9) clinical modification codes identified hepatitis C virus (HCV), hepatitis B virus (HBV), alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), and other LDs including autoimmune hepatitis. We excluded cases without LD, nonhepatocellular carcinoma-related cancers, human immunodeficiency virus infection, or those with missing information. Logistic regression was used to estimate odds ratios with 95% confidence intervals. Controls were matched to cases without LD. RESULTS: During the study period, 20,641,839 cases were seen in EDs. Of these, 1,080,008 cases were related to LD and were matched to controls without LD (N=19,557,585). The number of cases with LD increased from 123,873 (2005) to 188,501 (2011) (P<0.0001). Among cases with LD, diagnosis of HCV, HBV, and ALD remained stable during the study years (41.60% vs. 38.20%, 3.70% vs. 2.80%, and 41.4% vs. 38.5%, respectively), whereas NAFLD doubled [6.00% of all LD (2005) to 11.90% of all LD (2011) (P<0.0001)]. Diagnosis of LD in the ED independently predicted increased patient mortality [odds ratio, 1.20 (1.17 to 1.22)]. CONCLUSIONS: The number of LD cases presenting to EDs is increasing, and a diagnosis of LD is associated with a higher patient mortality for those admitted through the ED. There is a dramatic increase of NAFLD diagnoses in the ED. PMID- 29608452 TI - Barrett Esophagus Length, Nodularity, and Low-grade Dysplasia are Predictive of Progression to Esophageal Adenocarcinoma. AB - GOALS: To investigate factors predictive of progression from nondysplastic Barrett esophagus (NDBE) or low-grade dysplasia (LGD) to high-grade dysplasia (HGD) or esophageal adenocarcinoma (EAC) using a large, prospective cohort of patients, wherein all esophageal biopsies undergo expert gastrointestinal pathologist review. BACKGROUND: Efficacy and cost-effectiveness of endoscopic surveillance to detect incident EAC in the setting of Barrett esophagus (BE), particularly in NDBE patients, is questioned. Previous studies have reported factors predictive of progression to EAC to guide surveillance intervals, but their strength is limited by small sample size and absence of expert gastrointestinal pathologist involvement in esophageal biopsy review. STUDY: NDBE and LGD subjects were identified from a prospective registry in a tertiary care center. "Progressors" were BE subjects who developed HGD/EAC>12 months after the initial NDBE or LGD diagnosis. Cox proportional hazards model were used to identify predictors of progression. RESULTS: In total, 318 with NDBE and 301 with BE-LGD (mean age, 62.6 y, 85% male) were included. The mean follow-up was 5.3 years. The 7 NDBE and 21 LGD subjects progressed to HGD/EAC. BE length [hazards ratio (HR), 1.16; 95% confidence interval (CI), 1.03-1.29], presence of nodularity (HR, 4.98; 95% CI, 1.80-11.7), and baseline LGD (HR, 2.57; 95% CI, 1.13-6.57) were significant predictors of progression on multivariate analysis. CONCLUSIONS: In this well-defined cohort of NDBE and BE-LGD subjects, BE length, presence of LGD, and nodularity were independent predictors of progression to HGD/EAC. These factors may aid in identifying high-risk patients who may benefit from closer endoscopic surveillance/therapy. PMID- 29608453 TI - Time to rethink the use of bone biopsy to prevent fractures in patients with chronic kidney disease. AB - PURPOSE OF REVIEW: The purpose of this review is to provide evidence to justify the use of bone biopsy data to guide decisions regarding fracture prevention in patients with chronic kidney disease (CKD). To date, no data can support the use of bone biopsy for this purpose. However, we believe that bone turnover, mineralization and volume (TMV) data might help decide, which therapy to use. RECENT FINDINGS: Previous bone biopsy-based prospective and intervention studies have used bone turnover as an outcome measure. Recent data have shown that bone volume (trabecular and cortical) and mineralization should also be evaluated. Moreover, crystal quality and osteocytic protein expression can be analyzed using bone fragments. Noninvasive analysis of bone volume and bone turnover markers can be performed during patient follow-up. SUMMARY: Only bone biopsy can provide information on the TMV parameters. Case reports and retrospective studies suggest that bone histomorphometric analysis can guide better therapeutic decisions to prevent fractures in patients with CKD. However, prospective data are still lacking. PMID- 29608454 TI - Do Dads Make a Difference? Family Feeding Dynamics and Child Fussy Eating. AB - OBJECTIVE: Few studies on child feeding have focused on family dynamics or disadvantaged families, yet feeding occurs in the complex social, economic, and relational context of the family. We examined how the level (high vs low) and concordance (concordant vs discordant) of nonresponsive feeding practices of mothers and fathers are associated with child fussy eating, in a socioeconomically disadvantaged Australian sample. METHODS: Mother-father pairs (N = 208) of children aged 2 to 5 years old independently completed validated questionnaires reporting their "persuasive feeding," "reward for eating," "reward for behavior," and child's "food fussiness." The fussiness scores did not differ between mother-father pairs and were averaged to derive a single dependent variable. K-means cluster analyses were used to assign mother-father pairs to clusters for each feeding practice, based on mean scores. Three ANCOVAs, corresponding to each feeding practice, tested differences in child fussiness across clusters while controlling for covariates. RESULTS: Four clusters were identified for each feeding practice-concordant: (1) high (MHi/FHi) for both parents and (2) low (MLo/FLo) for both parents; and discordant: (3) high for mother but low for father (MHi/FLo); and (4) low for mother but high for father (MLo/FHi). For "persuasive feeding," MLo/FLo reported lower levels of fussiness compared with MHi/FLo, MHi/FHi, and MLo/FHi (p values < 0.05). For "reward for eating," MLo/FLo reported lower levels of fussiness than did MHi/FHi (p < 0.05). Child fussiness did not differ across "reward for behavior" clusters. CONCLUSION: In socioeconomically disadvantaged families, when parents are concordant in avoiding nonresponsive feeding practices, less child "food fussiness" is reported. Findings suggest that feeding interventions should consider inclusion of both parents in 2-parent households. PMID- 29608456 TI - The pulmonary artery catheter: is it still alive? AB - PURPOSE OF REVIEW: The present review discusses the current role of the pulmonary artery catheter (PAC) in the hemodynamic monitoring of critically ill patients. RECENT FINDINGS: The PAC has an important role in the characterization and management of hemodynamic alterations in critically ill patients. Use of the PAC has decreased in the last 30 years because of recent advances in less invasive hemodynamic monitoring techniques, in particular transpulmonary thermodilution and echocardiography, combined with the publication of the results of several randomized trials that failed to show improvements in outcome with the use of the PAC in various settings. Although it is obvious that the PAC should not be used in most critically ill patients, the PAC is still indicated in some patients with circulatory and/or respiratory failure, especially when associated with pulmonary hypertension or left heart dysfunction. As for any technique, optimal PAC use requires expertise in insertion, acquisition, and interpretation of measurements. The decrease in use of the PAC may unfortunately limit exposure of junior doctors and nurses to this device, so that they become less familiar with using the PAC, making it more complicated and less optimal. SUMMARY: The PAC still has an important role in the cardiopulmonary monitoring of critically ill patients. PMID- 29608455 TI - Extravascular lung water measurements in acute respiratory distress syndrome: why, how, and when? AB - PURPOSE OF REVIEW: Increase in pulmonary vascular permeability accompanied with accumulation of excess extravascular lung water (EVLW) is the hallmark of acute respiratory distress syndrome (ARDS). Currently, EVLW and pulmonary vascular permeability index (PVPI) can be quantitatively measured using the transpulmonary thermodilution (TPTD) technique. We will clarify why, how, and when EVLW and PVPI measurements should be performed. RECENT FINDINGS: Although the Berlin criteria of ARDS are simple and widely used, several criticisms of them have been published. The last 2 decades have witnessed the introduction and evolution of the TPTD technique for measuring EVLW and PVPI. Several publications have recommended to evaluate EVLW and the PVPI during the treatment of critically ill patients. Accurate and objective diagnoses can be made for ARDS patients using EVLW and PVPI. EVLW more than 10 ml/kg is a reasonable criterion for pulmonary edema, and EVLW more than 15 ml/kg for a severe condition. In addition to EVLW more than 10 mL/kg, PVPI more than three suggests increased vascular permeability (i.e., ARDS), and PVPI less than 2 represent normal vascular permeability (i.e., cardiogenic pulmonary edema). SUMMARY: EVLW and PVPI measurement will open the door to future ARDS clinical practice and research, and have potential to be included in the future ARDS definition. PMID- 29608457 TI - Can the plasmaderived factor VIII still play a role in the treatment of acquired hemophilia A at the time of new drugs? AB - : Bypassing agents are the first-line therapy in the treatment of acquired hemophilia A (AHA), but not the only one. Other options as recombinant porcine factor VIII or plasmaderived concentrates (pdFVIII) are available to clinicians. Aim of this study was to evaluate whether the pdFVIII can still play a role in the treatment of AHA, and which patients could benefit from this therapy. All patients with AHA, presenting severe cardiovascular comorbidities, and treated with pdFVIII with or without von Willebrand factor (vWF), referred to two different hospitals, were initially considered. Eight patients were studied and divided into two groups: first, patients treated with daily infusion of pdFVIII; second, patients treated with pdFVIII continuous infusion. After 6 months of follow-up, all patients reached complete response. Mean consumption of clotting factor (219 000 vs. 142 000 IU), mean duration of therapy (61.5 vs. 10.5 days), and mean time necessary to disappearance of the inhibitors (INHs) (64 vs. 9 days) were higher in group 1, and the differences between the two groups were statistically significant (P < 0.05). Patients in group 1 also had a mean INH titer of 20.4 BU, higher than that of group 2 patients (8.4 BU), with a lower detectable FVIII level. Our study showed that pdFVIII can be an effective option for patients at high thromboembolic risk, even for those with high-titer INHs, especially if combined with vWF. The immunomodulatory role of vWF should, however, be better investigated in wider trials. The days of treatment with pdFVIII continuous infusion was proven to be similar to those reported with other drugs. PMID- 29608458 TI - The prevalence of disability among people with cancer, cardiovascular disease, chronic respiratory disease and/or diabetes: a systematic review. AB - BACKGROUND: Cardiovascular disease (CVD), cancer, diabetes and chronic respiratory disease are noncommunicable diseases (NCDs) that cause extensive social and economic burden worldwide, particularly in low-income and middle income countries. There is growing recognition of the importance of the disabilities that individuals experience as a consequence of these NCDs. OBJECTIVES: This systematic review examined the prevalence of disabilities associated with cancer, CVD, chronic respiratory disease and diabetes. METHODS: A comprehensive literature search was conducted in PubMed, CINAHL, Embase, Web of Science, PsycINFO, CIRRIE, WHO database, LILACS and AIM. Studies were included if their samples were representative of people with at least one of these four conditions and if prevalence estimates of disability were provided. As random sampling was not feasible in the majority of cases, studies were included where they offered evidence that their sample was representative of the general population being investigated. RESULTS: A total of 105 articles were included in the review. Most studies were conducted in high-income countries. The prevalence of difficulties with activities of daily living (i.e. eating, bathing, dressing) was reported to be 10.4-34.5% amongst cancer survivors, 21.1-64.1% in those with CVD, 7.4-49.8% in those with chronic respiratory disease and 12.2-54.5% for those with diabetes. The prevalence of a range of other physical, cognitive and psychological impairments (systemic or structural) was additionally described for each disease. CONCLUSION: Substantial proportions of people with cancer, CVD, chronic respiratory disease or diabetes experience some form of disability - although there was great variance in prevalence and definitions. The findings of this review support the evidence base of global impact associated with NCD, indicate frequency measures for specific disabilities and inabilities associated with each NCD and provide direction for future systematic reviews. WHAT IS KNOWN ABOUT THE TOPIC: WHAT THIS ARTICLE ADDS. PMID- 29608459 TI - Measuring work functioning in individuals with musculoskeletal disorders with reference to the International Classification of Functioning, Disability, and Health: a systematic literature review. AB - The assessment of work functioning is important to define needs in the context of vocational rehabilitation. The International Classification of Functioning, Disability, and Health (ICF) serves as a framework to describe functioning and health. In reference to the ICF, work functioning can be described as consisting of work activities and work participation. A range of instruments are used in rehabilitation practice to assess work functioning. The purpose of this systematic review was to identify questionnaires measuring work functioning with reference to the ICF and to describe these instruments, their linkage to the ICF, and their psychometric properties. Instruments should be suitable for individuals with musculoskeletal disorders. Web of Science and PubMed were searched for English and German studies published between 2001 and 2015. We focused on self reported questionnaires measuring work functioning with reference to the ICF. Sixteen questionnaires fulfilled the inclusion criteria. The instruments varied in their linkage to the ICF and in their focus on work functioning. Questionnaires measuring concrete work activities differ from instruments measuring aspects of work participation in terms of absenteeism. The Work Rehabilitation Questionnaire is the instrument covering most ICF categories. The results show a range of different instruments that could be useful in certain settings. The description and comparison of the questionnaires can help to choose appropriate instruments in practice. PMID- 29608460 TI - Effectiveness of parental training, methylphenidate treatment, and their combination on academic achievements and behavior at school of children with attention-deficit hyperactivity disorder. AB - This study aimed to compare the effectiveness of parental training (PT), methylphenidate treatment (MPH), and the combination of PT and MPH treatment (PT/MPH) on school achievements in children with attention-deficit hyperactivity disorder (ADHD). Twenty eight ADHD patients (age: 10.1+/-1.11 years) were divided into three groups: (a) PT (N=10), (b) PT/MPH (N=8), and (c) MPH alone (N=10). Their grades in academics and conduct, from their school reports before and after treatment (6 months), were coded as achievement scores. No significant differences in baseline academic and conduct scores were found between the groups (F=0.033, d.f.=2, P=0.97 and F=0.024, d.f.=2, P=0.98, respectively). No significant changes before versus after treatment were detected in academic (3.83+/-0.93 vs. 3.85+/-0.88, paired t=0.086, d.f.=9, P=0.93, NS) or conduct (3.90+/-1.10 vs. 4.10+/-1.00, paired t=1.50, d.f.=9, P=0.17, NS) scores in the PT group. The same was true for the PT/MPH group (academic scores: 3.75+/-0.98 vs. 4.05+/-0.83, d.f.=7, t=0.927, P=0.38; conduct scores: 3.85+/-0.83 vs. 4.12+/ 0.83, d.f.=7, t=0.79, P=0.45). Only the MPH group showed significant improvements in those scores (academic scores: 3/73+/-0.85 vs. 4/44+/-0.48, d.f.=9, t=3.33, P=0.0088; conduct scores: 3.80+/-0.70 vs. 4.60+/-0.70, d.f.=9, t=3.2, P=0.011). Methylphenidate alone is superior to either parental training or parental training/methylphenidate in improving academics and conduct at school. PMID- 29608463 TI - Pupillary Unrest in Ambient Light and Prediction of Opioid Responsiveness: Case Report on Its Utility in the Management of 2 Patients With Challenging Acute Pain Conditions. AB - Pupillary unrest in ambient light (PUAL), the normal pattern of pupil diameter fluctuation present in awake humans, has been proposed as a marker of central opioid effect. We report 2 cases in which PUAL identified the appropriate pain management for 2 patients, each with unique, challenging acute pain conditions. In both cases, PUAL accurately predicted opioid responsiveness, suggesting an effective, individualized analgesic approach for both patients. PMID- 29608462 TI - Management of a Patient With a History of Nonanesthesia-Related Malignant Hyperthermia Undergoing Laparoscopic Cholecystectomy: A Case Report. AB - A 36-year-old African American with a medical history of nonanesthesia-related malignant hyperthermia (MH) who was taking chronic oral dantrolene therapy presented with right upper quadrant pain for a laparoscopic cholecystectomy. A multidisciplinary perioperative plan was implemented with the goal of avoiding triggering an MH episode or rhabdomyolysis. He developed a postoperative left brachial vein thrombus of unclear etiology, possibly related to dantrolene administration or his underlying susceptibility to MH. PMID- 29608461 TI - Vilazodone efficacy in subgroups of patients with major depressive disorder: a post-hoc analysis of four randomized, double-blind, placebo-controlled trials. AB - The efficacy of antidepressants to treat major depressive disorder (MDD) varies by patient characteristics. This post-hoc analysis evaluated the effects of vilazodone across patient subgroups in adults with MDD. Data were pooled from four trials of vilazodone (NCT00285376, NCT00683592, NCT01473394, and NCT01473381). Mean change from baseline to week 8 in Montgomery-Asberg Depression Rating Scale (MADRS) total score, MADRS response (>=50% total score improvement), and MADRS remission (total score<=10) were analyzed in the pooled intent-to-treat population (vilazodone=1254, placebo=964) and in subgroups of patients categorized by sex, age, MDD duration, recurrent episodes, baseline MADRS total score, and current episode duration. MADRS total score improvement was significantly greater with vilazodone versus placebo in the intent-to-treat population and in all patient subgroups (P<0.001). MADRS response and remission rates significantly separated from placebo (P<0.05) regardless of age, sex, MDD duration, recurrent MDD, and baseline symptom severity [except remission in patients with very severe baseline symptoms (MADRS score>=35)] and in patients with a shorter current episode duration (<=12 months). Despite the limitations associated with analyzing uncommon outcomes (e.g. MADRS remission) in small subgroups, vilazodone was an effective treatment in multiple patient populations, including those where reduced efficacy has previously been reported: males, older individuals, patients with a longer duration of MDD, and patients with recurrent depression. PMID- 29608464 TI - How to feed patients with gastrointestinal mucositis. AB - PURPOSE OF REVIEW: Gastrointestinal mucositis is a frequent side effect of systemic anticancer treatment and radiotherapy. The occurrence endangers body resources by decreasing food intake and absorption. This review highlights new developments in treatment and prevention. RECENT FINDINGS: Recent clinical practice guidelines recommend supplying adequate amounts of energy and nutrients to cancer patients undergoing anticancer treatments. This requires repeated screening for risk of malnutrition and in at-risk patients, assessment of food intake and nutritional status, followed by nutritional interventions targeted at individual deficiencies and tolerance to oral, enteral or parenteral feeding. Recent preclinical data report beneficial effects of stimulating the sensor for cell damage signals TRPA1, blocking histamine H2 receptors or supplying probiotics. In a recent clinical trial, amifostine reduced gastrointestinal symptoms and was well tolerated. Probiotics are studied in ongoing clinical trials and glucagon-like peptide 2 analogues are considered for future trials. Due to limited options available today, it has been suggested to also consider several plant-based complementary therapies. SUMMARY: Although options for prevention and treatment of chemotherapy or radiotherapy-induced gastrointestinal mucositis today are still limited, inadequate energy and nutrient intake should trigger nutritional interventions, including counselling, oral nutritional supplements, tube feeding and parenteral nutrition. To prevent gastrointestinal mucositis, several new agents have shown promising results in preclinical trials. PMID- 29608465 TI - Editorial for Pain: Nonmalignant Diseases in 2018. PMID- 29608466 TI - Editorial for Pain: Cancer in 2018. PMID- 29608467 TI - How to cope with food allergy symptoms? AB - PURPOSE OF REVIEW: Food allergy symptoms may involve a wide variety of organs (skin, gastrointestinal tract, and eyes) and systems (respiratory, circulatory, and neurological). They are often associated. Their severity ranges from mild to potentially life-threatening reactions and the presentation from acute to chronic. RECENT FINDINGS: Food allergies have been the focus of multiple studies, position papers, and guidelines in recent years. They have defined an approach in classifying symptoms as mild to anaphylactic, distinguishing objective from subjective symptoms, and describing their heterogeneity, specific phenotypes or syndromes (e.g., lipid transfer protein syndrome or pollen food syndrome). Cofactors can also influence food allergy reactions. Symptoms of non-IgE gastrointestinal food allergies, illustrated by eosinophilic esophagitis and food protein-induced enterocolitis syndrome, are also now better understood and defined. Improvement in the knowledge of food allergy symptoms is crucial for correct diagnosis and a personalized treatment approach. SUMMARY: Through a better description and understanding of symptoms, the diversity of food allergies is now better known. The next step is to harmonize symptom assessment not only for clinicians but also for patients, researchers, and public health stakeholders, to describe food allergy phenotypes and their underlying mechanisms and endotypes, to develop targeted management. PMID- 29608469 TI - Protamine-induced Cardiotoxicity Is Prevented by Anti-TNF-alpha Antibodies and Heparin: Erratum. PMID- 29608468 TI - Oral food challenge using different target doses and time intervals between doses. AB - PURPOSE OF REVIEW: The oral food challenge (OFC) is a specific and vital tool used in clinical practice to identify the level of tolerance a person exhibits toward certain foods while diagnosing food-related allergies. OFC methods differ among countries. The aim of this review is to evaluate different target doses and determine the time interval between doses used for OFC. RECENT FINDINGS: We analyzed recent articles on target doses and time between doses, and noted that some papers reported low target doses and less time between doses. A low-dose OFC appears to be a useful strategy; a time interval of 15 min between doses is short and that of at least 1 h is appropriate. SUMMARY: Low-dose OFCs appear to be well tolerated and effective to avoid complete elimination of the consumption of foods causing allergies. For the safety of the OFC method, the time interval between doses should be more than 30 min. PMID- 29608470 TI - Aortic systolic pressure derived with different calibration methods: associations to brachial systolic pressure in the general population. AB - BACKGROUND: There is increasing evidence that the method of calibration directly influences the association between brachial systolic blood pressure (bSBP) and estimated aortic systolic blood pressure (aSBP) and subsequently affects prognostic and diagnostic differentiation power of the latter. OBJECTIVE: The aim of this study was to investigate associations between different methods of systolic pressure assessment in a large cohort and its comparison with recently published evidence. PARTICIPANTS AND METHODS: During a public health campaign, cardiovascular hemodynamic data were assessed using a validated oscillometric device in a pharmacy setting. The device measures bSBP, mean arterial pressure, and diastolic blood pressure (DBP), and records brachial waveforms at the DBP level. aSBP1 was derived using bSBP and DBP and aSBP2 using measured mean arterial pressure and DBP for waveform calibration. In addition to pressures, age, sex, and anthropometric data were recorded. Regression analysis was carried out to investigate associations. RESULTS: A total of 7409 (5133/2276, female/male) individuals with a median age of 54 years were sampled. aSBPs differed significantly from bSBP (126.0 mmHg) for aSBP1 (117.0 mmHg) and aSBP2 (127.5 mmHg, both P<0.0001). Regression analysis showed that aSBP2 (R=0.853) is significantly less associated with bSBP than aSBP1 (R=0.937) (Williams' test, P<0.001 for comparison). Subgroup analysis showed the major influence of sex and heart rate. The association between bSBP, aSBP1 (R=0.83), and aSBP2 (R=0.66), respectively, reduced significantly for borderline hypertensives (P<0.001 for comparison). CONCLUSION: In contrast to aSBP1, the association between bSBP and aSBP2 is significantly less dominant and therefore aSBP2 may have potential prognostic superiority over bSBP. PMID- 29608471 TI - Impact of Nasal Septal Surgery on Sleep Quality and Attention Deficit/Hyperactivity Disorder. AB - OBJECTIVE: To evaluate the effect of nasal septal surgery on quality of life. METHODS: A total of 49 patients who underwent septoplasty and/or inferior turbinate radiofrequency operations for nasal septal deviation and inferior turbinate hypertrophy were prospectively enrolled in the study. All patients completed the adult attention-deficit/hyperactivity disorder scale (ADHD scale) and Pittsburgh sleep quality index (PSQI) before and after septoplasty. Acoustic rhinometric measurements were also recorded. RESULTS: Acoustic rhinometric measurements and PSQI showed statistically significant improvement after nasal surgery (P < 0.05), but no statistically significant difference was present between pre- and postoperative ADHD scores (P > 0.05). CONCLUSION: Besides the functional improvement of septoplasty, a long-lasting improvement in the quality of life is observed in patients with that undergo this surgery. PMID- 29608472 TI - Clinical Study of Second Branchial Cleft Anomalies. AB - OBJECTIVE: The objective of this study was to review the clinical characteristics and surgical treatment outcomes of second branchial cleft anomalies, and to evaluate the usefulness and accuracy of preoperative fine-needle aspiration cytology (FNAC) in the diagnosis of branchial cleft cysts. METHODS: A retrospective chart review was performed at Chonnam National University Hwasun Hospital from January 2010 to December 2016. RESULTS: Among 25 patients with second branchial cleft anomalies, in 23 patients (92.0%), these anomalies presented as cysts, and in the remaining 2 patients (8.0%), these anomalies presented as fistulas. Fine-needle aspiration cytology had a diagnostic sensitivity of 100%, a positive-predictive value of 100%, and accuracy of 100% for diagnosing second branchial cleft cyst. All patients of second branchial cleft anomalies were treated surgically under general anesthesia. No recurrence of second branchial cleft anomalies was observed. CONCLUSION: Branchial cleft cysts were the most common type of second branchial cleft anomalies. Preoperative FNAC is a useful and accurate method for preoperative evaluation of branchial cleft cysts. Surgical excision of second branchial cleft anomalies is the treatment of choice without any complications and with no recurrence. PMID- 29608473 TI - Cavernous Sinus Aneurysm Associated With Cerebellar Hemangioblastoma in an Adult With von Hippel-Lindau Disease. AB - A case of cerebellar hemangioblastoma with von Hippel-Lindau disease and an aneurysm of the cavernous sinus segment of the internal carotid artery is presented here. A 60-year-old woman presented with a cerebellar solid tumor manifesting as headache of 4 months, progressive vomiting, and ataxia of half a month. Four-vessel angiography revealed a high stain mass tumor located in the posterior fossa; an aneurysm on the cavernous sinus segment of the internal carotid artery was demonstrated at the same time. The ipsilateral anterior inferior cerebellar artery (AICA) and posterior inferior cerebellar artery (PICA) branches were the main feeding vessels of the hemangioblastoma. The patient underwent left-lateral suboccipital craniectomy to remove the highly vascular hemangioblastoma. Successful total excision of the tumor was demonstrated on postoperative magnetic resonance (MR) images. The unruptured cavernous sinus aneurysm in this case was not on the feeding artery, which was asymptomatic and has not been treated further. The patient was in good condition in 1-year follow up. PMID- 29608474 TI - Cleft Palate Repair Using Single Flap Palatoplasty in Patient With Associated Palatal Hemangioma. AB - Hemangiomas are the most common tumors of childhood with an average incidence of 10%. It is unusual for hemangiomas, which are already rarely seen isolated on the palate, to coexist with cleft palate as in the authors' patient. Four months old baby was admitted with isolated Veau 2 cleft palate and a red-purple colored raised lesion involving almost the whole right side of the hard palate. Magnetic resonance imaging revealed intensive contrasting solid nodule with a lobulated contour that was covering the right half of the hard palate, measuring 2.2*1.3 cm. To reduce the size of the vascular lesion 7 mg/d oral propranolol treatment was initiated. Following reduction in the size of hemangioma, the cleft palate was repaired at 11 months of age. Single mucoperiosteal flap from the left side of the palate preserving the major palatine artery was elevated whereas right mucoperisteal flap was minimally dissected not to interfere with the hemangioma. No intraoperative and postoperative complications in both the early and late term were experienced. As a result, since early palatal repair is important to obtain ideal speech outcomes in cleft patients, repair should be performed in similar patients with hemangiomas without delaying the timing. PMID- 29608475 TI - Percutaneous Autologous Fat Injection Following 2-Layer Flap Lower Blepharoplasty for the Correction of Tear Trough Deformity. AB - Tear trough deformity has been an area that has received much attention in terms of esthetic improvements. Fat transposition has been commonly used for the treatment of tear trough deformity. As some patients have had minimal improvement by that method, we propose the use of fat grafting combined with open blepharoplasty to complement the sunken area, including some of anterior maxilla region, and evaluate and precisely remove the excessive tissue.Lower blepharoplasty was performed by separating the skin and muscle flap. The excessive or laxed tissue was evaluated during the procedure and resected in each flap. Fat grafting was performed after completing a lower blepharoplasty, to ensure accurate placement on the spot where the surgeon originally intended. Overcorrection is not recommended.No serious complications were reported during a period of 10 years. Only 4 patients required a secondary fat injection.Patients who require structural correction of the lower eyelid area (eg, aggressive herniated fat, excessive skin laxity, or bulky orbicularis oculi muscle) and who need complementary material to fill the lower lid area (eg, deep, wide sunken area or relative exophthalmos) are good candidates for blepharoplasty with a fat grafting procedure. PMID- 29608476 TI - Outcomes After Open Reduction With Internal Fixation of Mandible Fractures. AB - INTRODUCTION/HYPOTHESIS: Mandible fractures contribute substantially to morbidity after blunt trauma. Controversy exists surrounding the appropriate timing of surgical intervention and benefit from routine postreduction imaging. METHODS: The authors retrospectively reviewed 146 patients who sustained traumatic mandible fractures at a level 2 trauma center over a 5-year period, between January 2012 and December 2016. The authors excluded all patients who did not undergo surgery, underwent operative closed reduction only, sustained other significant maxillofacial injuries, penetrating mechanisms, and other major injuries based on injury severity scores (ISS) over 15. There were 51 patients meeting inclusion criteria. The authors reviewed admission face computed tomography (CT) scans and Panorex x-rays. Patients were divided into early (<72 hours) and late (>72 hours) open reduction with internal fixation (ORIF) groups. The authors reviewed demographics, mechanism of injury, postreduction imaging, and ISS. All statistical analyses were performed using Stata 15. RESULTS: There were 39 males (76%) and 12 females (24%) in the authors' study, with a mean age of 32 years. Twenty-eight patients (55%) underwent early ORIF and 23 patients (45%) underwent late ORIF, with no mortalities. There was no statistically significant difference in ISS between the 2 groups (P = 0.081). Preoperative face CT scans were performed in 49 patients (96%) and Panorex in 2 patients (4%). Eight patients (16%) had both modalities, with CT face identifying fractures in 5 patients not seen on Panorex, resulting in a change in operative approach. Postreduction imaging was obtained in 33 patients (65%), of whom 26 were Panorex X-rays. These demonstrated adequate reduction in 31 patients (94%) and did not change management in any instance. Complications occurred in 19 patients (37%), of whom there were 11 with uncontrolled pain after 1 week, 6 abscesses, 5 nonunions/malunions, 2 hardware extrusions, and 1 incisional dehiscence. A positive urine drug screen predicted uncontrolled pain (P < 0.05). There was no statistically significant difference in complications between the 2 groups. CONCLUSION: The authors' data suggest that CT scans of the face are superior to panoramic radiographs in traumatic mandible fracture evaluation, with no apparent benefit from routine postreduction imaging in detecting complications. Open reduction with internal fixation remains an effective treatment with favorable outcomes, and operative delays > 72 hours do not appear to increase complication rates. PMID- 29608477 TI - Cardiac Arrest and Death Attributable to the "Diving Response" Triggered During Incision and Debridement of an Abscess of the Forehead. AB - The authors discuss about a patient who, while undergoing a routine procedure to drain a subcutaneous abscess within his forehead, suffered cardiac arrest that we conclude was caused by an activation of the diving response. This reflex affects homeostatic function which alters respiration and preferentially distributes oxygen stores to the heart and brain. Under some conditions, however, this reflex can also trigger cardiovascular collapse and death. The diving reflex is can begin with triggering receptors that are sensitive to cold water, submersion, or pressure within the nasal cavity and other areas supplied by the trigeminal nerve. Studies have shown that this afferent response primarily involves branches of the infraorbital nerve and the anterior ethmoidal nerve. However, other more superior nerves such as those exclusive to the forehead region may also be involved. This study demonstrates for the first time the risks and dangers involved in surgical procedures or manipulation of the trigeminal innervated areas of the human face and in particular the forehead. PMID- 29608478 TI - Sex Difference in the Morphology of Pineal Gland in Adults Based on Brain Magnetic Resonance Imaging. AB - PURPOSE: We aimed to figure out the anatomical features of pineal gland region on magnetic resonance imaging (MRI) and to explore the sex difference in pineal gland-related parameters with increasing age. METHODS: We measured the pineal gland on MRI images from 198 healthy adults (96 males and 102 females). Included subjects were divided into 4 age groups. After 3-dimensional reconstruction, the anatomic features of pineal gland and its distances to superior colliculus and splenium of corpus callosum were analyzed in each group. The prevalence of cystic pineal gland was calculated. Moreover, we calculated the volume of pineal gland (PGV) and explored the differences of PGV in males and females across different age groups. Linear regression analysis was performed to detect the relationship between age and pineal gland-related parameters. RESULTS: In 198 subjects, the mean length, width, and height of pineal gland were 7.58 +/- 0.45 mm, 4.92 +/- 0.40 mm, and 2.90 +/- 0.20 mm. The distances between pineal gland and superior colliculus as well as splenium of corpus callosum were 3.96 +/- 0.92 mm and 4.3 +/- 1.89 mm, respectively. The PGV was 54.1 +/- 7.02 mm. Significant sex differences were found in pineal gland length (P < 0.001), cranial cavity diameter (P < 0.001), pineal gland index (P < 0.001) and PGV values (P = 0.02). The prevalence of cystic pineal gland was 36.4% in total subjects, 41.7% in males and 32.4% in females. No linear relationship was found between age and pineal gland parameters. CONCLUSION: We measured the pineal gland morphology based on MRI images. Significant influences on pineal gland parameters were found in subjects with different sex, whereas no effect was observed from age. PMID- 29608479 TI - Comparison of Outpatient and Inpatient Pediatric Rhinoplasty: Results From National Surgical Quality Improvement Program-Pediatric, 2012-2014. AB - INTRODUCTION: Outpatient management of patients undergoing elective surgical procedures has been associated with significantly decreased health care costs compared with inpatient management. This study investigates current practices in outpatient versus inpatient management of pediatric rhinoplasty patients. METHODS: A query was performed of the 2012 to 2014 National Surgical Quality Improvement Program-Pediatric data sets. Patients age 17 or younger undergoing rhinoplasty as the primary surgical procedure were included. Clinical characteristics and complications were compared among patients managed as inpatients versus outpatients using both univariate and multivariate logistic regression analyses. RESULTS: Among 938 pediatric rhinoplasty patients, 199 (21.2%) were managed as inpatients. Multivariate analysis revealed multiple variables significantly associated with an increased odds of inpatient management, including young patient age, presence of a congenital malformation, neurologic or nutritional disease, lengthy procedure time, management by a plastic surgeon compared with an otolaryngologist, and certain procedure types including cleft septorhinoplasty, secondary rhinoplasty with intermediate or major revision, and rib cartilage grafting. Complications among both inpatients and outpatients were rare, with the most common complication being readmission among 15 patients (1.6%). CONCLUSIONS: This study indicates that multiple subgroups of pediatric patients undergoing rhinoplasty procedures have a significantly increased likelihood of inpatient management without any significantly increased likelihood of a complication or need for readmission. Future efforts to manage appropriately selected children on an ambulatory basis may be safe, while improving costs and quality of care. PMID- 29608480 TI - Orbital Fracture Reconstruction Using Prebent, Anatomic Titanium Plates: Technical Tips to Avoid Complications. AB - Orbital fractures are common. In patients where there is significant loss of the medial wall and orbital floor, anatomic prebent 3-dimensional plates allow efficacious restoration of orbital volume. However, the large size of these plates can result in technical difficulties with plate placement, especially in fractures with complete loss of 2 walls of the orbit. In this article, the authors review the pertinent anatomy of the bony orbit with respect to fracture and landmarks in fracture reduction. The authors also note the 3 most commonly encountered problems with the placement of anatomic plates: poor exposure, failure to identify the posterior ledge for the plate, and rotational issues with plate placement resulting in impingement. Technical tips are given to help overcome these issues intraoperatively. PMID- 29608481 TI - Bilateral Post-Traumatic Facial Paralysis That Contains Longitudinal and Transverse Temporal Fracture. AB - Acute bilateral post-traumatic facial paralysis is rare in the literature. Post traumatic facial paralysis is frequently accompanied transverse fractures of temporal more. The incidence of acute bilateral post-traumatic facial paralysis has been reported as 1 to 5 per million in the literature. Trauma and concurrent facial paralysis are usually in the same subsite (right temporal bone fracture and right facial paralysis). There is one pathophysiological pattern for a single temporal bone fracture in a subsite. The authors present a bilateral isolated different pathophysiological pattern sudden onset facial paralysis in a patient herein. PMID- 29608482 TI - Posterior Fossa Re-Exploration for Recurrent Trigeminal Neuralgia: Operative Findings and Surgical Techniques. AB - OBJECTIVE: Microvascular decompression (MVD) is considered the first choice for the surgical treatment of trigeminal neuralgia (TN). However, recurrence after MVD is still a problem and a challenge for neurosurgeons. In this study, we share our experience in the posterior fossa re-exploration of the recurrent cases. METHODS: From January 2014 to January 2015, 15 recurrent TN patients who received fossa re-exploration were retrospectively studied. Surgeries were performed by retrosigmoid suboccipital approach. Brainstem auditory evoked potentials (BAEP) were monitored throughout the operation. Intraoperative findings and surgical techniques were recorded. Postoperative outcomes and complications were analyzed. RESULTS: Among the 15 patients, Teflon adhesion was found in 14. Teflon felt displacement was found in 4 patients, and additional Teflon felt was used to interpose. New offending vessels were found in 5 patients. Three of them were small arteries and the other 2 were petrosal veins. After dissected, small pieces of wet gelatin sponge and Teflon felt were implanted respectively to ensure complete decompression. The remaining 6 patients had no vascular compression except severe adhesion, and nerve combing was performed. After surgery, 12 achieved complete pain relief, 2 gained partial pain relief, and 1 failed. Six patients experienced facial numbness postoperatively. There was no hearing impairment or other complications. During the mean 26-month follow-up, no recurrence occurred and all of 6 cases with facial numbness after surgery improved. CONCLUSIONS: Teflon adhesion is a significant cause of recurrent TN. Wet gelatin-assisted method is good for Teflon interposition. If no vascular compression is found during re-exploration, trigeminal nerve combing can be used. Intraoperative BAEP monitoring is helpful to reduce the incidence of hearing loss. PMID- 29608483 TI - Rare Cause of Tinnitus: Spontaneous Temporomandibular Joint Herniation Into the External Auditory Canal. AB - The herniation of temporomandibular joint (TMJ) into external auditory canal (EAC) may occur due to trauma, neoplastic, infectious, and inflammatory processes. On the other hand, spontaneous herniation of TMJ into EAC is an extremely rare conduction and occurs as a consequence of patent retention of foramen of Huschke (FH). Patent FH is usually an asymptomatic situation. In this article, a patient having otologic symptoms as a result of spontaneous herniation of TMJ into EAC was presented in the light of current literature. PMID- 29608484 TI - Evaluation of Facial Anthropometry Using Three-Dimensional Photogrammetry and Direct Measuring Techniques. AB - In this study, 14 standard facial distances on 10 adult volunteers were measured directly with a caliper and indirectly on two-dimensional images using the 3dMDtrio system. Two raters performed the measurements with at least 1 week between rating sessions. The intra- and inter-rater reliabilities and agreement of the measurements were calculated using intra-class correlation coefficient (ICC), mean absolute difference (MAD), and Bland-Altman plots with limits of agreement (LOA). The 2 raters had an average discrepancy (MAD) of 1.6 mm when their digital measurements were compared to their direct measurements. The reliability of the digital and direct methods varied greatly depending on which of the 14 anthropometric distances that was being assessed. Only 6 digitally and 5 directly measured anthropometric distances showed both an ICC >0.75 and a MAD <1 mm, in the intra-rater as well as the inter-rater measurements. The Bland Altman plots and LOA displayed the same pattern. In summary, the digital and direct methods were generally compatible in terms of reliability and agreement. However, the reliability and agreement between the 14 anthropometric measurements varied considerably, indicating that poor landmark identification is the main limitation to both modern and traditional measuring techniques in the face. Consequently, some anthropometric landmarks warrant further definition or prior anthropometric training by the evaluators. The authors also recommend that the MADs and LOAs provided in this report are put into relation to the facial distance that is being evaluated and its clinical context. PMID- 29608485 TI - New Rhizotomy Procedure for Primary Spasmodic Torticollis. AB - OBJECTIVE: Spasmodic torticollis (ST) is an idiopathic neurologic disorder affecting the muscles of the neck. Surgery is a preferred treatment, when conservative treatments or Botulinum neurotoxin injections fail to relieve the symptoms. Our objective here is to report the outcome of a new surgical method for treating ST patients in our department. METHODS: The new procedure consists of rhizotomy of the spinal accessory nerve (SAN) and C1-C2 nerve roots, coagulation of the distal end of SAN (Group A). The results of this procedure were compared with a group of patients who underwent only rhizotomy of the SAN and anterior C1-C2 nerve roots (Group B). Clinical data were retrospectively collected from 39 patients with laterocollis and rotatory torticollis subtypes of ST from Jun 1, 2014 to Jun 1, 2015. The effect of the surgery was evaluated by the reduction in the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) total scores preoperatively and postoperatively. The mean duration of the postoperative follow-up period was 2.57 years, ranging from 2 to 3 years. RESULTS: The mean preoperative TWSTRS score was 65.89 +/- 3.55 and 65.80 +/- 3.45 in Groups A and B, respectively. Six months after the surgery, the TWSTRS scores decreased to 40.00 +/- 12.14 and 26.04 +/- 11.77, respectively. There was a statistically significant improvement preoperatively and postoperatively in both groups (P < 0.05). The decrease in TWSTRS score of Group B was more significant than that of Group A (P < 0.05). The main complications included shoulder numbness, shoulder weakness, and hoarseness. CONCLUSIONS: The procedure in this study provides a new and effective surgical method for patients with ST. This procedure should be recommended if conservative therapy does not offer satisfactory relief of symptoms. PMID- 29608486 TI - Simultaneous Quantification of Adalimumab and Infliximab in Human Plasma by Liquid Chromatography-Tandem Mass Spectrometry. AB - BACKGROUND: Adalimumab (ADA) and infliximab (IFX) are therapeutic monoclonal antibodies targeting tumor necrosis factor-alpha (TNFalpha). They are used to treat inflammatory diseases. Clinical trials have suggested that therapeutic drug monitoring for ADA or IFX could improve treatment response and cost effectiveness. However, ADA and IFX were quantified by ELISA in all these studies, and the discrepancies between the results obtained raise questions about their reliability. We describe here the validation of a liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the simultaneous quantification of ADA and IFX in human samples. METHODS: Full-length antibodies labeled with stable isotopes were added to plasma samples as an internal standard. Samples were then prepared using Mass Spectrometry Immunoassay followed by trypsin digestion before ADA and IFX quantification by LC-MS/MS. ADA and IFX were quantified in serum from patients treated with ADA (n = 21) or IFX (n = 22), and the concentrations obtained were compared with those obtained with a commercial ELISA kit. RESULTS: The chromatography run lasted 8.6 minutes, and the quantification range was 1-26 mg/L. The method was reproducible, repeatable, and accurate. For both levels of internal quality control, for ADA and IFX, interday and intraday coefficients of variation and accuracies were all within 15%, in accordance with FDA recommendations. No significant cross-contamination effect was noted. Good agreement was found between LC-MS/MS and ELISA results, for both ADA and IFX. CONCLUSIONS: This LC-MS/MS method can be used for the quantification of ADA and IFX in a single analytical run and for the optimization of LC-MS/MS resource use in clinical pharmacology laboratories. PMID- 29608488 TI - Latexin and hematopoiesis. AB - PURPOSE OF REVIEW: Hematopoietic stem cells (HSCs) produce mature blood cells throughout lifetime. Natural genetic diversity offers an important yet largely untapped reservoir for deciphering regulatory mechanisms of HSCs and hematopoiesis. In this review, we explore the role of latexin, identified by natural variation, in regulating homeostatic and stress hematopoiesis, unravel the underlying signaling pathways, and propose its therapeutic implication. RECENT FINDINGS: Latexin acts endogenously in HSCs to negatively regulate their population size by enhancing apoptosis and by decreasing self-renewal. Deletion of latexin in vivo increases HSC repopulation capacity and survival, expands the entire hematopoietic system, and mitigates myelosuppression. Latexin inactivation downregulates thrombospondin 1 (Thbs1). It inhibits nuclear translocation of ribosomal protein subunit 3 (Rps3), a novel latexin-binding protein, and sensitizes hematopoietic cells to radiation-induced cell death. However, how latexin-Rps3 pathway regulates Thbs1 transcription is unclear. Latexin is downregulated in cancer cells because of promoter hypermethylation, but latexin depleted mice do not inherently develop hematologic malignancies even with aging. The mechanism of action of latexin in tumorigenesis remains largely unknown. SUMMARY: Understanding how latexin regulates HSC survival, self-renewal, and stress response will advance our knowledge of HSC biology. It will facilitate the development of a novel therapeutic strategy for hematopoietic regeneration and cancer treatment. PMID- 29608487 TI - Enhancing human cord blood hematopoietic stem cell engraftment by targeting nuclear hormone receptors. AB - PURPOSE OF REVIEW: Allogeneic hematopoietic cell transplantation (HCT) is a life saving therapy for hematological and nonhematological diseases. Cord blood is a source of transplantable hematopoietic stem cells (HSCs), but limited numbers of HSCs in single cord blood units, which may cause delayed neutrophil, platelet, and immune cell reconstitution, is a major problem for efficient transplantation. Ex-vivo expansion and enhanced homing of cord blood HSC may overcome this disadvantage and improve its long-term engraftment. Here, we discuss the role of nuclear hormone receptors signaling in human cord blood HSC engraftment. RECENT FINDINGS: Antagonizing retinoid acid receptor (RAR) signaling promotes human HSC expansion and increases myeloid cell production. Cord blood CD34 cells expanded by SR1 promotes efficient myeloid recovery after transplantation compared with control groups, and leads to successful engraftment. Short-term treatment of glucocorticoids enhances homing and long-term engraftment of human HSCs and HPCs in NSG mice. Peroxisome proliferator-activated receptor-gamma (PPARgamma) antagonism expands human HSCs and HPCs by preventing differentiation and enhancing glucose metabolism. These findings demonstrate that nuclear hormone receptor signaling components might be promising targets for improving human cord blood HCT. SUMMARY: Better understanding of molecular mechanisms underlying human HSC expansion and homing mediated by nuclear hormone receptor signaling pathways will facilitate enhanced HCT efficacy. PMID- 29608489 TI - Enhanced Osteogenic Differentiation of Mesenchymal Stem Cells on Electrospun PES/PVA/PRP Nanofibrous Scaffolds. AB - Over the last few decades, great advancements have been achieved in the field of bone tissue engineering (BTE). Containing a great number of growth factors needed in the process of osteogenesis, platelet rich plasma (PRP) has gained a great deal of attention. However, due to the contradictory results achieved in different studies, its effectiveness remains a mystery. Therefore, in this study, we investigated in vitro performance of co-electrospun PRP/poly ether sulfone/poly(vinyl) alcohol (PRP/PES/PVA) composite scaffolds for the osteogenic differentiation of human adipose-derived mesenchymal stem cells. The activated PRP was mixed with PVA solution to be used alongside PES solution for the electrospinning process. Fourier transform infrared spectroscopy, scanning electron microscopy and tensile tests were performed to evaluate the scaffolds. After confirmation of sustained release of protein, osteogenic potential of the co-electrospun PRP/polymer scaffolds was evaluated by measuring relative gene expression, calcium content, and alkaline phosphatase (ALP) activity. Alizarin red and Hematoxylin and Eosin staining were performed as well. The results of ALP activity and calcium content demonstrated the effectiveness of PRP when combined with PRP-incorporated scaffold in comparison with the other tested groups. In addition, the results of tensile mechanical testing indicated that addition of PRP improves the mechanical properties. Taking these results into account, it appears PES/PVA/PRP scaffold treated with PRP 5% enhances osteogenic differentiation most. In conclusion, incorporation of PRP into electrospun PES/PVA scaffold in this study had a positive influence on osteogenic differentiation of AdMSCs, and thus it may have great potential for BTE applications. PMID- 29608490 TI - Veno-Venous Extracorporeal Membrane Oxygenation for Respiratory Failure: How Long Is Too Long? AB - The use of veno-venous extracorporeal membrane oxygenation (VV ECMO) in adults with respiratory failure has steadily increased during the past decade. Recent literature has demonstrated variable outcomes with the use of extended ECMO. The purpose of this study is to evaluate survival to hospital discharge in patients with extended ECMO runs compared with patients with short ECMO runs at a tertiary care ECMO referral center. We retrospectively reviewed all patients on VV ECMO for respiratory failure between August 2014 and February 2017. Bridge to lung transplant, post-lung transplant, and post-cardiac surgery patients were excluded. Patients were stratified by duration of ECMO: extended ECMO, defined as >504 hours; short ECMO as <=504 hours. Demographics, pre-ECMO data, ECMO-specific data, and outcomes were analyzed. One hundred and thirty-nine patients with respiratory failure were treated with VV ECMO. Overall survival to discharge was 76%. Thirty-one (22%) patients had extended ECMO runs with an 87% survival to discharge. When compared with patients with short ECMO runs, there was no difference in median age, body mass index (BMI), body surface area (BSA), PaO2/FiO2 (P/F), and survival to discharge. However, time from intubation to cannulation for ECMO was significantly longer in patients with extended ECMO runs. (p = 0.008). Our data demonstrate that patients with extended ECMO runs have equivalent outcomes to those with short ECMO runs. Although the decision to continue ECMO support in this patient population is multifactorial, we suggest that time on ECMO should not be the sole factor in this challenging decision. PMID- 29608491 TI - Ready, Set, Go: How Patients and Caregivers Are Prepared for Self-Management of an Implantable Ventricular Assist Device. AB - Since the first use of an implantable ventricular assist device (VAD) nearly 3 decades ago, many VAD Centers in the United States expect patients and caregivers to manage the device and related care following hospital discharge. Despite this customary practice and the rapid advancements in VAD technology, no research data about the patient and caregiver preparations exist for self-management of VAD. This study explored the process of preparing patients and caregivers for VAD care before hospital discharge along with their perceived experiences of the discharge process. Using an exploratory research design, we collected the data with self administered demographics and VAD Hospital Discharge Survey questionnaires. We analyzed the data provided by 102 patients and 116 caregivers from different regions in the United States. Patients' mean age was 51.4 +/- 13.8 years; they were predominantly White (78%); male (66%); and duration of device between 2 and 74 months. Caregivers were predominantly White (80%); female (81%); and had a mean of age 48.9 +/- 12.7 years. Participants reported that their VAD care preparations, a crucial component of hospital discharge, were extensive and intensive processes comprising education, training, competency validation, and provision of resources for VAD self-management in home settings. Participants were satisfied with the process and felt prepared for discharge. Further research is needed to rectify the study limitations, advance the science of VAD self management, and develop evidenced-based VAD self-management guidelines that are aimed at optimizing longevity of the VAD, patients' health, and quality of life. PMID- 29608492 TI - Impact of Cardiac Resynchronization Therapy on Left Ventricular Unloading in Patients with Implanted Left Ventricular Assist Devices. AB - Cardiac resynchronization therapy (CRT) and left ventricular assist devices (LVADs) are common heart failure therapies; however, little is known regarding the concomitant use of these devices. We aim to evaluate unloading differences in LVAD patients with and without active biventricular pacing. Left ventricular assist device patients with and without CRT prospectively underwent ramp hemodynamic/echocardiographic testing. Patients with >95% biventricular pacing comprised the active CRT pacing group; all others (no device, implantable cardioverter defibrillator only, CRT without biventricular pacing) were categorized into the non-CRT pacing group. Invasive hemodynamics and echocardiographic characteristics (left ventricular end-diastolic/systolic diameter and valvular regurgitation) were measured at baseline and at incremental speed changes. Unloading slopes were calculated using linear regression modeling for individual hemodynamics and echocardiographic characteristics across speeds. Among 62 LVAD patients (age 59.6 +/- 11.4 years, 60% male), 25 had active CRT pacing. There was no significant difference in echocardiographic or hemodynamic characteristics at baseline or final set speeds between CRT groups. Similarly, no significant differences were noted in the unloading characteristics. In LVAD patients, active biventricular pacing is unlikely to improve echocardiographic or hemodynamic characteristics. PMID- 29608493 TI - Left Ventricular Distension in Veno-arterial Extracorporeal Membrane Oxygenation: From Mechanics to Therapies. AB - Veno-arterial (V-A) extracorporeal membrane oxygenation (ECMO) is increasingly commonly used to treat acute cardiac or pulmonary failure because of a wide range of etiologies. However, although the despite progressively improving outcomes, the mortality associated with V-A ECMO, particularly when used to treat cardiac failure (its most common indication), continues to be high. Consistent with this, V-A ECMO is associated with numerous morbid complications. Left ventricular (LV) distension is a major complication of V-A ECMO, and is challenging both to treat and diagnose. We review the pathophysiology underlying LV distension, and construct a systematic diagnostic and therapeutic approach. PMID- 29608494 TI - Stretchable Electronic Wearable Motion Sensors Delineate Signatures of Human Motion Tasks. AB - Digital tracking of human motion offers the potential to monitor a wide range of activities detecting normal versus abnormal performance of tasks. We examined the ability of a wearable, conformal sensor system, fabricated from stretchable electronics with contained accelerometers and gyroscopes, to specifically detect, monitor, and define motion signals and "signatures," associated with tasks of daily living activities. The sensor system was affixed to the dominant hand of healthy volunteers (n = 4) who then completed four tasks. For all tasks examined, motion data could be captured, monitored continuously, uploaded to the digital cloud, and stored for further analysis. Acceleration and gyroscope data were collected in the x-, y-, and z-axes, yielding unique patterns of component motion signals for each task studied. Upon analysis, low-frequency (<10 Hz) tasks (walking, drinking from a mug, and opening a pill bottle) showed low intersubject variability (<0.3g difference) and low interrepetition variability (<0.1g difference) when comparing the acceleration of each axis for a single task. High frequency (>=10 Hz) activity (brushing teeth) yielded low intersubject variability of peak frequencies in acceleration of each axis. Each motion task was readily distinguishable and identifiable (with >=70% accuracy) by independent observers from motion signatures alone, without the need for direct visual observation. Stretchable electronic technologies offer the potential to provide wireless capture, tracking, and analysis of detailed directional components of motion for a wide range of individual activities and functional status. PMID- 29608495 TI - Medical Management of Rheumatic Heart Disease: A Systematic Review of the Evidence. AB - Rheumatic heart disease (RHD) is an important cause of heart disease globally. Its management can encompass medical and procedural (catheter and surgical) interventions. Literature pertaining to the medical management of RHD from PubMed 1990-2016 and via selected article reference lists was reviewed. Areas included symptom management, left ventricular dysfunction, rate control in mitral stenosis, atrial fibrillation, anticoagulation, infective endocarditis prophylaxis, and management in pregnancy. Diuretics, angiotensin blockade and beta-blockers for left ventricular dysfunction, and beta-blockers and If inhibitors for rate control in mitral stenosis reduced symptoms and improved left ventricular function, but did not alter disease progression. Rhythm control for atrial fibrillation was preferred, and where this was not possible, rate control with beta-blockers was recommended. Anticoagulation was indicated where there was a history of cardioembolism, atrial fibrillation, spontaneous left atrial contrast, and mechanical prosthetic valves. While warfarin remained the agent of choice for mechanical valve implantation, non-vitamin K antagonist oral anticoagulants may have a role in RHD-related AF, particularly with valvular regurgitation. Evidence for anticoagulation after bioprosthetic valve implantation or mitral valve repair was limited. RHD patients are at increased risk of endocarditis, but the evidence supporting antibiotic prophylaxis before procedures that may induce bacteremia is limited and recommendations vary. The management of RHD in pregnancy presents particular challenges, especially regarding decompensation of previously stable disease, the choice of anticoagulation, and the safety of medications in both pregnancy and breast feeding. PMID- 29608496 TI - Antithrombotic Management of Patients With Prosthetic Heart Valves. AB - Valvular heart disease is a major public health issue. The prevalence of valvular heart disease is expected to increase due to an aging population. Valve dysfunction manifests as valve stenosis, regurgitation, or both due to various etiologies. Valve repair and replacement are the main treatment options for severe valve dysfunction. Valve replacement is achieved by using either a mechanical or a bioprosthetic valve. Mechanical valves are more durable but require lifelong anticoagulation with associated complications. Bioprosthetic valves usually require anticoagulation only transiently after implantation but are less durable and degenerate more rapidly. In this article, we discuss antithrombotic regimens in persons after valve operations. We discuss general issues and antithrombotic recommendations for patients undergoing surgical bioprosthetic valve replacement, mechanical valve replacement (including different regimens for different positions and types of mechanical valves), mitral valve repair, and transcatheter aortic valve replacement. In addition, we discuss the antithrombotic management of patients in special circumstances, including patients with mechanical valves who have recurrent bleeding or thrombotic events, patients with mechanical valves undergoing surgery, and pregnant women with mechanical valves. PMID- 29608497 TI - His Bundle Pacing: Hemodynamics and Clinical Outcomes. AB - From 1993 to 2009, nearly 2.9 million pacemakers were implanted in the United States; the majority of which were dual-chamber pacemakers. One of the major physiologic advantages of dual-chamber pacing over single-chamber ventricular pacing is atrioventricular synchrony, which prevents the pacemaker syndrome. However, patients who are pacemaker dependent or use right ventricle (RV) apical pacing more than 40% of the time are at a risk of developing heart failure from electromechanical dyssynchrony. Studies have also shown that RV pacing results in nonphysiological activation of the left ventricle, leading to adverse clinical outcomes. Hence, alternative pacing sites, including the RV outflow tract, the high-RV septal region, bi-ventricular pacing, or His bundle pacing, have been explored for a better physiological electromechanical coupling of the ventricles. Although His bundle pacing has gained attention due to favorable data and clinical outcomes, it has not gained widespread acceptance into clinical practice. Hence, we aim to review the current experience with His bundle pacing and its clinical implications in this article. PMID- 29608498 TI - Cardioprotection in the Modern Era of Cancer Chemotherapy. AB - The current arsenal of cancer chemotherapy is broad and rapidly expanding and includes conventional cytotoxic agents and targeted and immune-based therapies. As cancer survival rates have improved, the acute and latent cardiotoxicities of chemotherapy have emerged as important contributors to morbidity and mortality in cancer survivors. All chemotherapeutic agents have the potential for cardiac complications, with manifestations ranging from subclinical left ventricular dysfunction and asymptomatic QT prolongation, to congestive heart failure, myocardial ischemia, myocarditis, arrhythmia, and sudden cardiac death. Efforts are ongoing to identify patients at high risk of cardiac complications and to develop evidence-based approaches to cardioprotection. In this review, we describe antitumor agents commonly associated with cardiotoxicity, with a focus on risk assessment, surveillance strategies, and pharmacologic and nonpharmacologic interventions aimed at preventing and mitigating chemotherapy induced myocardial dysfunction. PMID- 29608500 TI - Frank Cole Spencer, MD-Surgeon, Innovator, and Educator. PMID- 29608499 TI - Diagnosis, Treatment, and Management of Orthotopic Liver Transplant Candidates With Portopulmonary Hypertension. AB - Portopulmonary hypertension (POPH) is seen in 5-8% of orthotopic liver transplantation (OLT) candidates and has significant implications for clinical outcomes. POPH is characterized by vasoconstriction and remodeling of the pulmonary vasculature. It is exacerbated by the hyperdynamic circulation that is common in advanced liver disease. Screening all OLT candidates with transthoracic echocardiography to assess pulmonary pressures and right ventricular function is crucial, as clinical symptoms alone are not reliable. Any significant right ventricular dysfunction or dilatation along with an elevation in estimated pulmonary pressures usually triggers further investigation with right heart catheterization. The mainstays of therapy of POPH are vasodilators that are used in pulmonary arterial hypertension. They include monotherapy or combination therapy with prostanoids, endothelin receptor antagonists, and phosphodiesterase 5 inhibitors/guanylate cyclase stimulator. Limited evidence from smaller studies and case series suggests that a timely diagnosis of POPH and the early initiation of treatment improve patient outcomes, whether or not OLT is ultimately undertaken. Given the historically high perioperative mortality rate of more than 35%, POPH remains a contraindication to OLT unless it is treated and responsive to vasodilator therapy. We review the current literature and International Liver Transplant Society practice guidelines (2016) for the latest in understanding POPH, its pathogenesis, diagnosis, modern pharmacological treatment, indications, and contraindications for OLT, as well as perioperative management. PMID- 29608501 TI - Through the Decades: beta-Blocker Use and Outcomes in Acute Coronary Syndromes. AB - Beta-adrenergic receptor antagonists, or beta-blockers, have been a cornerstone of treatment in patients with acute coronary syndromes (ACS) for more than 4 decades. First studied in the 1960s, beta-blockers in ACS have been shown to decrease the risk of death, recurrent ischemic events, and arrhythmias by reducing catecholamine-mediated effects and reducing myocardial oxygen demand. Through the decades, the beta-blocker of choice, timing of initiation, duration of therapy, and dosing have evolved considerably. Despite having clear benefits in certain patient populations (eg, patients with systolic dysfunction who are hemodynamically stable), the benefit of beta-blockers in other populations (ie, in patients at low risk for complications receiving modern revascularization therapies and optimal medical management) remains unclear. This article provides a review of the landmark clinical trials of beta-blockers in ACS and highlights the chronology and evolution of guideline recommendations through the decades. PMID- 29608503 TI - Risk-Adjusted Overall Mortality as a Quality Measure in the Cardiovascular Intensive Care Unit. AB - Risk-adjusted mortality has been proposed as a quality of care indicator to gauge cardiovascular intensive care Unit (CICU) performance. Mortality is easily measured, readily understandable, and a meaningful outcome for the patient, provider, administrative agencies, and other key stakeholders. Disease-specific risk-adjusted mortality is commonly used in cardiovascular medicine as an indicator of care quality, for external accreditation, and to determine payer reimbursement. However, the evidence base for overall risk-adjusted mortality in the CICU is limited, with most available data coming from the general critical care literature. In addition, existing risk-adjusted mortality models vary considerably in terms of approach and composition, and there is no nationally recognized standard. Thus, the objective of this study was to review the use of risk-adjusted mortality as a measure of overall unit performance and quality of care in the CICU. We found a considerable variability in the risk-adjustment methodology for cardiovascular disease. Although predictive models for disease specific risk-adjusted mortality in cardiovascular disease have been developed, there are limited published data on overall risk-adjusted mortality for the CICU. Without standardization of risk-adjustment methodology, researchers are often required to use existing risk-adjustment models developed in noncardiac patient populations. Further studies are needed to establish whether risk-adjusted overall CICU mortality is a valid performance measure and whether it reflects care quality. PMID- 29608502 TI - Xenon: An Emerging Neuroprotectant With Potential Application for Cardiac Arrest Care. AB - Xenon is an inert, highly polarizable noble gas with demonstrated safety and application in general anesthesia for over 50 years. A potent inhibitor of the N methyl-D-aspartate subtype of glutamate receptors, xenon has a well-documented ameliorating effect on excitotoxic neuronal injury in numerous cellular and animal models of hypoxic-ischemic brain injury. The most important determinant of overall survival and morbidity in out-of-hospital cardiac arrest is the severity of neurological injury. The only approved neuroprotective strategy in this setting is mild therapeutic hypothermia, which has demonstrated significant, albeit modest, improvements in mortality. The combination therapy of therapeutic hypothermia and xenon in porcine models of cardiac arrest has shown a greater improvement in functional outcomes than either intervention alone, thereby prompting the study of combination therapy in randomized clinical trials. The treatment of postarrest patients with xenon and mild hypothermia is safe and demonstrates favorable cardiovascular features, including a reduced heart rate, a reduction in troponin elevations, and a decreased need for vasopressors. Combination therapy is superior in protecting white matter integrity than hypothermia alone, but did not significantly impact neurological outcomes at 6 month follow-up. Despite an abundance of preclinical evidence supporting xenon's neuroprotective properties, its translational potential in postcardiac arrest care is indeterminate due to a lack of adequately-powered studies. PMID- 29608504 TI - INTER-ATRIAL SHUNTING, A NOVEL DEVICE-BASED THERAPY FOR PATIENTS WITH HEART FAILURE. AB - Heart failure patients with either reduced ejection fraction (HFrEF) or preserved ejection fraction (HFpEF) experience a high mortality rate. The most recent pharmacologic advance for treating patients with HFrEF has been with sacubitril/valsartan. Along with pharmaceutical research, there has been interest in device-based therapies as another treatment approach. One novel interventional device therapy that has shown promise in early tests and trials is the inter atrial shunt device developed by Corvia Medical Inc. and the V-Wave device by V Wave Ltd. Inserted between the atria in the atrial septum, both devices create a left-to-right unidirectional shunt. The aim is to decompress the left atrium, thereby possibly reducing symptoms related to pulmonary congestion. With encouraging initial results and a favorable safety profile in non-randomized studies involving less than 100 patients, inter-atrial shunting may be a viable therapeutic approach for HF patients who remain symptomatic despite optimal medical therapy. It is hoped that these devices will be especially effective in HFpEF, which has seen very few successful treatments in the past decade. In order to solidify its place as a successful treatment option, however, the results from randomized controlled trials, which are currently underway, will be crucial. PMID- 29608505 TI - Sodium-Glucose Cotransporter-2 Inhibition in Type 2 Diabetes Mellitus: A Review of Large-Scale Cardiovascular Outcome Studies and Possible Mechanisms of Benefit. AB - Cardiovascular (CV) disease remains the leading cause of morbidity and mortality in individuals with type 2 diabetes mellitus (T2DM). However, conventional antihyperglycemic medications seem to have minimal effect on lowering CV risk despite achieving excellent reductions in glycated hemoglobin A1c and associated reductions in microvascular risk. Sodium-glucose cotransporter 2 (SGLT2) inhibitors have emerged as noteworthy antihyperglycemic agents with concomitant CV and renal protection in T2DM patients. In this comprehensive review, we present the key CV findings from major large-scale outcome trials of SGLT2 inhibitors to date. We also review the mechanistic studies that might explain the CV benefits of SGLT2 inhibition in patients with T2DM. PMID- 29608506 TI - The Physiological Rationale for Incorporating Pulsatility in Continuous-Flow Left Ventricular Assist Devices. AB - Over the past few decades, left ventricular assist device (LVAD) support has extended the lives of many patients with end-stage heart failure. The most common devices are continuous-flow (CF) LVADs. The use of the CF-LVADs has required that clinicians learn the physiological and clinical consequences of long-term continuous blood flow. While this alteration in the normal physiology still offers advantages from mechanical circulatory support, the lack of pulsatility may also increase the likelihood of adverse events. However, it is currently unknown whether newly evolved devices should incorporate pulsatility. In this article, we discuss the possible benefits of incorporating pulsatility, while maintaining the benefits of the CF-LVAD, to maximize the treatment of patients. PMID- 29608507 TI - Optimization of the CT component of SPECT-CT and establishment of local CT diagnostic reference levels for clinical practice. AB - OBJECTIVE: The aim of this study was to perform a process of optimization and establish local diagnostic reference levels (DRLs) for the computed tomography (CT) component of single-photon emission computed tomography (SPECT)-CT imaging, for use in clinical practice. METHODS: A multidisciplinary group defined categories for the clinical purpose of the CT component of local SPECT-CT examinations. Each of the examinations were assigned a category, and optimization of acquisition and reconstruction parameters was performed to achieve the required image quality. Dose data were collated for 754 SPECT-CT scans performed on three systems over 10 months. The third quartile values for volume CT dose index and dose length product were calculated and established as local DRLs. RESULTS: Four categories of CT examinations were defined: attenuation correction; localization and attenuation correction; localization, characterization and attenuation correction; and diagnostic and attenuation correction. Local DRLs were established for 11 examinations. Reference was made to the proposed national DRLs set by a recent UK survey. CONCLUSION: This work describes a process of optimization and the creation of practical and effective local DRLs. These can be used in local audit of practice. In future, improved descriptors and standardization of SPECT-CT use would allow more practicable UK national DRLs to be created. PMID- 29608508 TI - Tumor heterogeneity, hypoxia, and immune markers in surgically resected non-small cell lung cancer. AB - OBJECTIVES: This study aimed to determine the prognostic role of textural features and their association with metabolic parameters, hypoxia, and cancer related immune markers in non-small-cell lung cancer (NSCLC) patients. PATIENTS AND METHODS: The trial was registered at http://www.clinicaltrials.gov (NCT02519062). From January 2010 to May 2014, 44 patients (male : female=33 : 11; median age: 69.5 years), referred to our Institution for NSCLC resection, were enrolled. Tumor specimens were assessed for HIF-1alpha, CD68-TAMs, CD8-TILs, PD-1 TILs, and PD-L1 expressions. All patients underwent fluorine-18 fluorodeoxyglucose (F-FDG) PET before surgery. Semiquantitative parameters included maximum standardized uptake value (SUVmax), SUVpeak, SUVmean, metabolic tumor volume, and total lesion glycolysis, whereas for heterogeneity, we considered tumor sphericity, skewness, kurtosis, entropy, and energy. Parameters were correlated with disease-free survival (DFS) considering a median follow-up of 22.7 months. RESULTS: SUVmax (cutoff: 7.9; P=0.015), SUVpeak (cutoff: 6.7; P=0.013), SUVmean (cutoff: 5.5; P=0.028), metabolic tumor volume (cutoff: 3.6 cm; P=0.027), and entropy (cutoff: 1.89; P=0.045) showed a statistically significant association with DFS. Also, a high expression of cytoplasmic HIF-1alpha (score 3) was associated with DFS (hazard ratio: 0.09; P=0.003). All F-FDG PET variables differed significantly in tumors with high or low entropy (<=1.89). Also, a significantly higher level of mean CD8-TILs was observed in tumors with higher entropy (P=0.041).Using identified prognostic factors, we developed a scoring system, which was confirmed to be associated with DFS (P<0.004). On receiver operating characteristics analysis, a score above 3 was defined as the optimal cutoff point. CONCLUSION: Tumor heterogeneity, metabolic parameters, and high expression of hypoxia were found to be prognostic factors in NSCLC patients who were candidates for surgery. Higher levels of entropy appear to be associated with increased density of CD8-TILs. The combination of investigated prognostic factors enabled the development of a potential scoring system associated with DFS. PMID- 29608509 TI - Comparison of the psychometric properties of 3 pain scales used in the pediatric emergency department: Visual Analogue Scale, Faces Pain Scale-Revised, and Colour Analogue Scale. AB - Appropriate pain measurement relies on the use of valid, reliable tools. The aim of this study was to determine and compare the psychometric properties of 3 self reported pain scales commonly used in the pediatric emergency department (ED). The inclusion criteria were children aged 6 to 17 years presenting to the ED with a musculoskeletal injury and self-reported pain scores >=30 mm on the mechanical Visual Analogue Scale (VAS). Self-reported pain intensity was assessed using the mechanical VAS, Faces Pain Scale-Revised (FPS-R), and Colour Analogue Scale (CAS). Convergent validity was assessed by Pearson correlations and the Bland Altman method; responsiveness to change was assessed using paired sample t tests and standardized mean responses; and reliability was estimated using relative and absolute indices. A total of 456 participants were included, with a mean age of 11.9 years +/- 2.7 and a majority were boys (252/456, 55.3%). Correlations between each pair of scales were 0.78 (VAS/FPS-R), 0.92 (VAS/CAS), and 0.79 (CAS/FPS-R). Limits of agreement (95% confidence interval) were -3.77 to 2.33 (VAS/FPS-R), -1.74 to 1.75 (VAS/CAS), and -2.21 to 3.62 (CAS/FPS-R). Responsiveness to change was demonstrated by significant differences in mean pain scores among the scales (P < 0.0001). Intraclass correlation coefficient and coefficient of repeatability estimates suggested acceptable reliability for the 3 scales at, respectively, 0.79 and +/-2.29 (VAS), 0.82 and +/-2.07 (CAS), and 0.76 and +/-2.82 (FPS-R). The scales demonstrated good psychometric properties for children with acute pain in the ED. The VAS and CAS showed a strong convergent validity, whereas FPS-R was not in agreement with the other scales. PMID- 29608510 TI - Pressure-induced referred pain areas are more expansive in individuals with a recovered fracture. AB - Musculoskeletal trauma and pain can sensitize central pain mechanisms, but whether these normalize on recovery is unknown. This study compared the extent of pain referral in individuals recovered from a musculoskeletal trauma and healthy controls. Twenty pain-free participants recovered from a shoulder fracture and 20 age-/sex-matched controls participated in 2 experimental sessions (day-0 and day 1) separated by 24 hours. On both days, pressure pain thresholds were measured bilaterally at infraspinatus, supraspinatus, trapezius, and gastrocnemius muscles. Referred pain towards the shoulder region was induced by a 60-second pressure stimulation (pressure pain threshold + 20%) at the infraspinatus muscle and recorded on an electronic body chart. After day-0 assessments, delayed onset muscle soreness (DOMS) was induced to challenge the pain systems by exercising the external rotators of the recovered/dominant shoulder. The size of pressure induced pain referral on day-0 did not differ between groups, although there was a tendency for a smaller referred pain area in recovered group. Pressure pain thresholds at the infraspinatus muscle on the DOMS side were reduced on day-1 in both groups (P = 0.03). An expansion of pressure-induced pain referral was found in both groups following the DOMS protocol on day-1 (P = 0.05) with a relatively larger expansion (P = 0.05) and higher frequency of pain in the shoulder (P = 0.04) in the recovered pain group. After complete recovery and absence of pain symptoms after a fracture, central pain mechanisms seem to normalize in the region of the trauma after recovery but when sensitized a heightened response can emerge. Such mechanisms could be important for recurrence of pain conditions. PMID- 29608511 TI - Reply to Oude Groeniger and van Lenthe. PMID- 29608512 TI - Re: The Spillover Influence of Partner's Education on Myocardial Infarction Incidence and Survival. PMID- 29608513 TI - Clinical Predictors of Survival and Functional Outcome of Stroke Patients Admitted to Critical Care. AB - OBJECTIVES: To determine the predictive value of commonly used clinical variables upon ICU admission for long-term all-cause mortality and functional outcome of adult stroke patients admitted to the ICU. DESIGN: Retrospective observational cohort study. SETTING: General and neurosurgical ICUs of the University College London Hospitals in North Central London. PATIENTS: All adult ICU patients with a clinical diagnosis of acute stroke admitted between February 2010 and May 2012. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Demographic and clinical data concerning the first 24 hours after ICU admission were obtained. Patients were followed until February 2016 to assess long-term survival. Functional outcome was determined using the modified Rankin Scale. We evaluated 131 critically ill stroke patients, with a median (interquartile range) age of 70 years (55-78 yr). One-year mortality rate was 52.7%. Surviving patients were followed up over a median (interquartile range) period of 4.3 years (4.0-4.8 yr). The multivariable model that best predicted long-term all-cause mortality indicated that mortality of critically ill stroke patients was predicted by high Acute Physiology and Chronic Health Evaluation II score, impaired consciousness (Glasgow Coma Scale score <= 8) as reason for ICU admission, low Glasgow Coma Scale sum score after 24 hours, and absence of brainstem reflexes. Long-term independent functional status occurred in 30.9% of surviving patients and was predicted by low Acute Physiology and Chronic Health Evaluation II score, high Glasgow Coma Scale sum score at ICU admission, and absence of mass effect on CT scan. CONCLUSIONS: Mortality in critically ill stroke patients is high and occurs most often shortly after the event. Less than one in three surviving patients is able to function independently after 1 year. This study has identified several clinical variables that predict long-term all-cause mortality and functional outcome among critically ill stroke patients and found that mainly acute physiologic disturbance and absolute values of neurologic clinical assessment are predictive. PMID- 29608515 TI - "Successful non-invasive treatment of festoons." PMID- 29608514 TI - Primary Septal Cartilage Graft for the Unilateral Cleft Rhinoplasty. PMID- 29608516 TI - Reply: Primary Septal Cartilage Graft for the Unilateral Cleft Rhinoplasty. PMID- 29608517 TI - A Hidden Legacy of D. Ralph Millard, Jr., M.D. PMID- 29608518 TI - Autologous Fat Grafting as a Novel Antiestrogen Vehicle for the Treatment of Breast Cancer. PMID- 29608519 TI - Muscle versus Fasciocutaneous Free Flaps in Lower Extremity Traumatic Reconstruction: A Multicenter Outcomes Analysis. PMID- 29608520 TI - Digital Native Plastic Surgeons. PMID- 29608521 TI - Is There Value to Seeing a Transgender Fellowship-Trained Surgeon? PMID- 29608522 TI - Does Orthognathic Surgery have a Significant Impact on Patients' Perceived Attractiveness, Personality Traits, and Emotional Expressions? PMID- 29608523 TI - Treating Breast Conservation Therapy Defects with Brava and Fat Grafting: Technique, Outcomes, and Safety Profile. PMID- 29608524 TI - Reply: Muscle versus Fasciocutaneous Free Flaps in Lower Extremity Traumatic Reconstruction: A Multicenter Outcomes Analysis. PMID- 29608525 TI - Reply: Orthognathic Surgery Has a Significant Effect on Perceived Personality Traits and Emotional Expressions. PMID- 29608526 TI - Analysis of Craniofacial Remodeling in the Aging Midface Using Reconstructed Three-Dimensional Models in Paired Individuals. PMID- 29608527 TI - A New Microtia Reconstruction Method Using Delayed Postauricular Skin Flap. PMID- 29608528 TI - Reply: Analysis of Craniofacial Remodeling in the Aging Midface Using Reconstructed Three-Dimensional Models in Paired Individuals. PMID- 29608529 TI - Pursuing Mirror Image Reconstruction in Unilateral Microtia: Customizing Auricular Framework by Application of Three-Dimensional Imaging and Three Dimensional Printing. PMID- 29608530 TI - Optimal Use of Surgical Drains: Evidence-Based Strategies. AB - BACKGROUND: Closed-suction drains are widely used to reduce the incidence of seroma whenever potential spaces are surgically created. However, few studies have examined the parameters that affect drain efficacy. METHODS: An in vitro model was created to assess the effects of tubing length, tubing size, tubing type, fluid viscosity, fluid clotting, evacuator type, evacuator squeeze method, evacuator fill, and evacuator pressure on the performance of closed-suction drains. RESULTS: Fluid flow rate through the drain increases with increasing intracavitary tubing length, decreasing extracavitary tubing length, increasing tubing diameter, increasing negative pressure, decreasing fluid viscosity, and the use of perforated rather than fluted drains. Bulbs generate more effective suction when squeezed "side-to-side" than when squeezed "bottom-up," and evacuators were only able to generate half the maximal negative pressure when 25 percent full or greater. Stripping the drain tubing helped relieve obstruction caused by clotting. CONCLUSIONS: The authors' findings have practical clinical implications for surgeons hoping to maximize the efficacy of closed-suction drains. Through this comprehensive review of the literature and in vitro analysis of relevant variables that affect drain function, the performance of closed suction drains can be optimized by increasing intracavitary tubing length, decreasing extracavitary tubing length, increasing tubing diameter, increasing the pressure differential, using perforated drains, squeezing bulbs side-to-side, stripping drain tubing frequently, and evacuating containers whenever they are 25 percent full. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 29608531 TI - Pathways to Academic Leadership in Plastic Surgery: A Nationwide Survey of Program Directors, Division Chiefs, and Department Chairs of Plastic Surgery. AB - BACKGROUND: Many aspire to leadership in academic plastic surgery yet there is no well-documented pathway. METHODS: Information regarding plastic surgery residencies and program directors was obtained from the American Medical Association's FREIDA database. The division chief or department chair (academic head) of every academic plastic surgery program was identified. One Internet based survey was distributed to academic heads; another, to program directors. RESULTS: Ninety academic heads were identified, 35 of whom also serve as program director. Sixty-seven unique program directors were identified. There was a 51 percent academic head response rate and a 65 percent program director response rate. Academic plastic surgery is overwhelmingly administered by midcareer men. The average program director was appointed at age 45 and has served for 7 years. She or he was trained through the independent track, completed additional training in hand surgery, and is a full professor. She or he publishes two or three peer-reviewed manuscripts per year and spends 9 hours per week in administration. The average academic head was appointed at age 45 and has held the position for 12 years. She or he was trained in the independent model, completed fellowship training, and is a full professor. She or he publishes five peer-reviewed manuscripts per year and spends 12 hours per week involved in administration. CONCLUSIONS: Program directors and academic heads serve nonoverlapping roles. Few program directors will advance to the role of academic head. Successful applicants to the program director position often serve as an associate program director and are seen as motivated resident educators. In contrast, those faculty members selected for the academic head role are academically accomplished administrators with business acumen. PMID- 29608532 TI - Wound Surface Area as a Risk Factor for Flap Complications among Patients with Open Fractures. AB - BACKGROUND: Soft-tissue complications often dictate the success of limb salvage and the overall outcome of open fractures. Based on prior work at the R Adams Cowley Shock Trauma Center, the authors hypothesize that wounds larger than 200 cm are associated with a greater likelihood of both flap-related reoperation and wound complications among patients requiring soft-tissue reconstruction with a rotational flap or free tissue transfer. METHODS: This study was a secondary analysis of Fluid Lavage in Open Wounds trial data that included all patients who received a rotational or free tissue flap transfer for an open fracture. The primary outcome was flap-related reoperation within 12 months of injury. The secondary outcome was wound complication, which included events treated operatively or nonoperatively. Multivariable logistic regression was used to assess the association between wound size and outcomes, adjusting for confounders. RESULTS: Seventeen percent of the 112 patients required a flap related reoperation. A wound size greater than 200 cm(2) was not associated with reoperation in an unadjusted model (p = 0.64) or adjusting for Gustilo type (p = 0.70). The sample had an overall wound complication rate of 47.3 percent. Patients with a wound size of greater than 200 cm(2) were three times more likely to experience wound complications (OR, 3.05; 95 percent CI, 1.08 to 8.62; p = 0.04) when adjusting for moderate to severe wound contamination and wound closure in the operating room. CONCLUSION: The findings of this study demonstrate that wound surface area is an integral determinant for wound complication following soft-tissue flap treatment, but found no association between wound surface area and flap-related reoperation rates. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III. PMID- 29608534 TI - Response of Letter to Editor: Macro textured breast implants with defined steps to minimize bacterial contamination around the device. PMID- 29608533 TI - Twice-Daily Enoxaparin among Plastic Surgery Inpatients: An Examination of Pharmacodynamics, 90-Day Venous Thromboembolism, and 90-Day Bleeding. AB - BACKGROUND: Low anti-factor Xa level, indicative of inadequate enoxaparin dosing, has a significant association with 90-day venous thromboembolism events. The authors examined the pharmacodynamics of enoxaparin 40 mg twice daily and its correlation with anti-factor Xa level, postoperative venous thromboembolism, and bleeding. METHODS: Adult patients were admitted after plastic and reconstructive surgery and received enoxaparin 40 mg twice daily. Peak anti-factor Xa levels, which quantify enoxaparin's antithrombotic effect, were drawn, with a goal level of 0.2 to 0.4 IU/ml. Ninety-day symptomatic venous thromboembolism and clinically relevant bleeding were identified. RESULTS: The authors enrolled 118 patients who received enoxaparin 40 mg twice daily. Of these patients, 9.6 percent had low peak anti-factor Xa levels (<0.2 IU/ml), 62.6 percent had in-range peak anti factor Xa levels (0.2 to 0.4 IU/ml), and 27.8 percent had high anti-factor Xa levels (>0.4 IU/ml). With enoxaparin 40 mg twice daily, 90.4 percent of patients received at least adequate prophylaxis. Patient weight predicted the rapidity of enoxaparin metabolism. Zero acute 90-day venous thromboembolism occurred. Eight patients (6.8 percent) had clinically relevant 90-day bleeding: clinical consequences ranged from cessation of enoxaparin prophylaxis to transfusion to operative hematoma evacuation. CONCLUSIONS: When enoxaparin 40 mg twice daily is provided, 90 percent of patients receive at least adequate venous thromboembolism prophylaxis (anti-factor Xa level >0.2 IU/ml). However, 27 percent of the overall population is overtreated (anti-factor Xa level >0.4 IU/ml). These pharmacodynamics data likely explain the low rate of 90-day acute venous thromboembolism (0 percent) and the high rate of clinically relevant bleeding (6.8 percent) observed. Future studies are needed to better optimize the risks and benefits of enoxaparin prophylaxis in plastic and reconstructive surgery patients. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 29608535 TI - Genetic Survey of Adult-Onset Idiopathic Intracranial Hypertension. AB - BACKGROUND: Idiopathic intracranial hypertension (IIH) is a condition characterized by increased intracranial pressure of unknown cause. IIH has been shown to be associated with female sex as well as obesity. This genome-wide association study was performed to determine whether genetic variants are associated with this condition. METHODS: We analyzed the chromosomal DNA of 95 patients with IIH enrolled in the Idiopathic Intracranial Hypertension Treatment Trial and 95 controls matched on sex, body mass index, and self-reported ethnicity. The samples were genotyped using Illumina Infinium HumanCoreExome v1-0 array and analyzed using a generalized linear mixed model that accounted for population stratification using multidimensional scaling. RESULTS: A total of 301,908 single nucleotide polymorphisms (SNPs) were evaluated. The strongest associations observed were for rs2234671 on chromosome 2 (P = 4.93 * 10), rs79642714 on chromosome 6 (P = 2.12 * 10), and rs200288366 on chromosome 12 (P = 6.23 * 10). In addition, 3 candidate regions marked by multiple associated SNPs were identified on chromosome 5, 13, and 14. CONCLUSIONS: This is the first study to investigate the genetics of IIH in a rigorously characterized cohort. The study was limited by its modest size and thus would have only been able to demonstrate highly significant association on a genome-wide scale for relatively common alleles exerting large effects. However, several variants and loci were identified that might be strong candidates for follow-up studies in other well phenotyped cohorts. PMID- 29608536 TI - Eight Syndrome: Horizontal Gaze Palsy Plus Ipsilateral Seventh Nerve Palsy. AB - A 62-year-old woman developed a right horizontal gaze palsy and ipsilateral facial nerve palsy due to a right pontine tegmentum infarct. This constitutes a forme fruste of the eight-and-a-half syndrome that we have termed the eight syndrome. PMID- 29608537 TI - Role and Value of the Corporate Medical Director. AB - : The role of the corporate medical director (CMD) has evolved over the last 300 years since Ramazzini first identified diseases of Italian workers in the early 1700s. Since then, there has been a gradual blurring of the boundaries between private and workplace health concerns. Today's CMD must have intimate knowledge of their corporation's industry and the businesses that they support, particularly the occupational and environmental programs that comply with all local, state, and/or national standards and regulations. Leading companies not only measure compliance with such standards but also may hold programs to their own internal corporate global standards even if these go beyond local government requirements. This document will explore in greater depth the strength and importance that the CMD brings to the business operations to support a healthy, engaged, and high performing workforce. Part 1 describes the role and value of the CMD, while Part 2 provides collective wisdom for the new CMD from current and past highly experienced CMDs. PMID- 29608538 TI - Asbestos Fiber Concentrations in the Lungs of Brake Repair Workers: An Updated Analysis Using Several Regression Methods to Handle Nondetectable Measurements. AB - OBJECTIVES: The aim of the study was to reanalyze an updated database of lung asbestos fiber levels for 21 brake repair workers who died of mesothelioma using robust maximum likelihood-based regression methods to address nondetectable measurements. METHODS: We applied bivariate normal regression to address the doubly left-censored situation where both the lung fiber concentration of noncommercial (TAA) and commercial amphiboles (AC) were subject to detection limits. For the single left-censored situation, we applied censored normal regression to study the relationship between duration of employment (DOE) and TAA. RESULTS: We found a statistically significant positive relationship between TAA and AC (beta = 0.49, 95% confidence interval [CI], 0.11 to 0.86) and a not statistically significant relationship between DOE and TAA (beta = 0.02, 95% CI, 0.03 to 0.06). CONCLUSIONS: Our results provide additional support for the conclusion that exposure to commercial amphibole asbestos, and not chrysotile, is related to the occurrence of mesothelioma among some brake workers. PMID- 29608539 TI - Acute Effects of Interrupting Sitting on Discomfort and Alertness of Office Workers. AB - OBJECTIVE: The aim of this study was to compare the effect of 4 hours of sitting interrupted with hourly bouts of standing and/or pedaling versus uninterrupted sitting on alertness and discomfort among sedentary office workers. METHODS: Fifteen middle-aged sedentary workers were randomized to three 4-hour conditions: (1) uninterrupted sitting; (2) sitting interrupted with 10 minutes of standing/hour; and (3) sitting interrupted with 10 minutes of pedaling/hour. Self reported measures of alertness and discomfort were collected. RESULTS: Uninterrupted sitting significantly increased discomfort (P < 0.001). Discomfort was lower in both the standing (P < 0.001) and pedaling (P < 0.001) conditions than the uninterrupted sitting condition. Short-lived improvements in alertness were observed immediately following several standing (50%) and pedaling (100%) interruptions. CONCLUSION: Prolonged sitting increases discomfort while brief standing and pedaling interruptions attenuate impairments in discomfort among sedentary workers. PMID- 29608540 TI - Work-Related Determinants of Burnout in a Nationally Representative Sample of German Employees: Results From the Study on Mental Health at Work. AB - OBJECTIVE: The aim of the study was to present first representative data on burnout measured as exhaustion in German employees. METHODS: Data were taken from the Study on Mental Health at Work (n = 4058). Computer-assisted personal interviews were conducted in 2011 to 2012. Multiple linear regression models were estimated to investigate the association between work-related and personal variables and burnout. RESULTS: Severe burnout was detected in nearly 3% of employees. Job demands were associated with higher burnout scores, more resources with lower scores. Independent of personal factors, higher quantitative demands (men: regression coefficient [beta] = 0.19; 95% confidence interval [CI], 0.16 to 0.23; women: beta = 0.24; 95% CI, 0.20 to 0.27) was identified as the strongest predictor of burnout measured as exhaustion. The model explained 28% to 33% of the total variance. CONCLUSIONS: Quantitative demands seem to be important risk factors for burnout independent of critical life events and general self efficacy. PMID- 29608541 TI - The Effect of Interrupting Sedentary Behavior on the Cardiometabolic Health of Adults With Sedentary Occupations: A Pilot Study. AB - OBJECTIVE: The aim of this study was to determine whether mobile phone text messages could modify objectively measured sedentary behavior and cardiometabolic health in office workers. METHODS: Nine males and 12 females [mean (SD): 27.5 (5.7) years, 23.8 (2.8) kg/m] were assigned to a control (CON) or intervention (PROMPT) group. PROMPT received an activity-promoting text message during office hours. Participants wore an actiGraph and activPAL accelerometer for 7 days during and after the intervention. Blood pressure, lipid, and metabolic profiles were measured before and after the intervention. RESULTS: PROMPT sat less [mean (95% confidence interval, 95% CI): 4.9 (4.4 to 5.4) hours/day] than CON [6.0 (5.5 to 6.4) hours/day; P = 0.04] during the message-receiving period. There was no difference between groups after the intervention and for the other activity variables. There were no changes in cardiometabolic health markers following the intervention. CONCLUSION: Sitting time was lower during the message-receiving period, but the difference between groups was no longer apparent after the intervention. PMID- 29608542 TI - Expanding the Paradigm of Occupational Safety and Health: A New Framework for Worker Well-Being. AB - OBJECTIVE: This article describes the National Institute for Occupational Safety and Health's (NIOSH) development of a conceptual framework for worker well-being. While well-being research is growing, there is a need to translate theoretical concepts into practical models for measurement and action. METHODS: Multidisciplinary literature reviews informed development of the worker well being framework and major domains and subdomains. An expert panel helped prioritize constructs for measurement. RESULTS: The framework includes five domains and 20 subdomains and conceptualizes worker well-being as a subjective and objective phenomenon inclusive of experiences both within and beyond work contexts. CONCLUSION: Well-being is a positive and unifying concept that captures multiple factors that contribute to workers' health and quality of life. This work lays the foundation for larger well-being measurement efforts and will provide tools for NIOSH partners to help workers flourish. PMID- 29608543 TI - Deep Learning and Clinical Decision Support. PMID- 29608545 TI - Adherence to 20 Emergency General Surgery Best Practices: Results of a National Survey. AB - OBJECTIVE: To examine national adherence to emergency general surgery (EGS) best practices. BACKGROUND: There is a national crisis in access to high-quality care for general surgery emergencies. Acute care surgery (ACS), a specialty leveraging strengths of trauma systems, may ameliorate this crisis. A critical component of trauma care is adherence to clinical guidelines. We previously established best practices for EGS using RAND Appropriateness Methodology and pilot data. METHOD: A hybrid (postal/electronic) questionnaire measuring adherence to 20 EGS best practices was administered to respondents overseeing EGS at all eligible adult acute care general hospitals across the US (N = 2811). Questionnaire responses were analyzed using bivariate methods and multiple logistic regression. RESULTS: The response rate was 60.1%. Adherence ranged from 8.5% for having an EGS registry to 86.2% for auditing 30-day postoperative readmissions. Adherence was higher for practices not restricted to EGS (eg, auditing readmissions) compared to EGS-specific practices (eg, registry, activation system). Adopting an ACS model of care increased adherence to practices for deferring elective cases; tiering urgent operations; following National Comprehensive Cancer Network guidelines; reversing anticoagulants; auditing returns to intensive care, time to evaluation, time to operation, and time to source control; and having transfer agreements to receive patients, ICU admission protocols, as well as EGS-specific activation systems, outpatient clinics, morbidity and mortality conferences, and registries. CONCLUSIONS: There is substantial room for performance improvement, and adopting an ACS model predicts better performance. This novel overview of adherence to EGS best practices will enable surgeons and policymakers to address variations in EGS care nationally. PMID- 29608544 TI - Treatment Optimization for Hepatocellular Carcinoma in Elderly Patients in a Japanese Nationwide Cohort. AB - OBJECTIVE: We reviewed nationwide follow-up data to determine outcomes of different treatments for early-stage hepatocellular carcinoma (HCC) in elderly patients. SUMMARY BACKGROUND DATA: Outcomes of early-stage HCC treatments in elderly patients have not been prospectively compared. METHODS: We included 6490 HCC patients, aged >=75 years at treatment, who underwent curative hepatic resection (HR, n = 2020), radiofrequency ablation (RFA, n = 1888), microwave ablation (MWA, n = 193), or transcatheter arterial chemoembolization (TACE, n = 2389), and compared their characteristics and survival. We used matching propensity score analysis (PSA) between the HR and RFA subgroups with tumors <=3 cm to overcome baseline bias. RESULTS: The HR group had significantly longer recurrence-free survival (RFS) than the RFA, MWA, and TACE groups [RFA vs HR hazard ratio: 1.22, 95% confidence interval (CI): 1.09-1.37, P < 0.001; MWA vs HR hazard ratio: 1.51, 95% CI: 1.22-1.88, P < 0.001; TACE vs HR-hazard ratio: 2.70, 95% CI: 2.44-2.99, P < 0.001). HR and RFA patients had significantly longer overall survival (OS) than the TACE group (RFA vs HR-hazard ratio: 1.01, 95% CI: 0.87-1.17, P = 0.919, TACE vs HR-hazard ratio: 2.11, 95% CI: 1.86-2.40, P < 0.001). PSA successfully matched HR and RFA patients from with primary HCC tumors <=3.0 cm and similar liver function and tumor characteristics; and showed significantly longer RFS (hazard ratio: 1.64, 95% CI: 1.29-2.10, P < 0.001) and OS (hazard ratio: 1.57, 95% CI: 1.12-2.20, P = 0.009) for HR than for RFA (including subgroup analyses). In Cox proportional hazard analysis, HR offered better prognosis than RFA. CONCLUSIONS: HR decreases recurrence risk and improves OS in patients aged >=75 years with primary HCC tumors <=3.0 cm.This is an open access article distributed under the terms of the Creative Commons Attribution Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0. PMID- 29608546 TI - Postdiagnostic Calcium Channel Blocker Use and Breast Cancer Mortality: A Population-based Cohort Study. AB - BACKGROUND: There have long been concerns that calcium channel blockers (CCBs), widely used to treat hypertension, may contribute to malignant growth through the evasion of apoptosis and proliferation of cancer cells. Worryingly, a recent cohort study found breast cancer patients who used CCBs had higher death rates, but interpreting these results was difficult as they were based on all-cause mortality and medication use before cancer diagnosis. We used UK population-based data to more robustly investigate the association between CCB use and cancer specific mortality. METHODS: We selected a cohort of patients with breast cancer diagnosed between 1998 and 2012 from English cancer registries. We linked to prescription and clinical records from the Clinical Practice Research Datalink, and to death records from the Office for National Statistics. We used adjusted, time-dependent Cox regression models to calculate hazard ratios (HRs) comparing breast cancer-specific and all-cause mortality between postdiagnostic CCB users and nonusers. RESULTS: Our cohort included 23,669 breast cancer patients, of whom 5,141 used CCBs and 3,053 died due to their breast cancer during follow-up. After adjustment, CCB users had similar breast cancer-specific mortality to nonusers (HR = 0.98, 95% confidence interval [CI] = 0.88, 1.08). There was no evidence of a dose-response relationship. We found similar associations for specific CCBs, and for all-cause mortality. CONCLUSIONS: In this large population-based breast cancer cohort, we did not find any evidence that CCB use is associated with increased mortality. PMID- 29608547 TI - Erratum: Sensitivity Analysis Without Assumptions. PMID- 29608548 TI - Reassessment of the Risk-stratified GD-2008 ALL Protocol. AB - OBJECTIVE: To explore the clinical features and outcomes of relapsed childhood acute lymphoblastic leukemia (ALL) at our center, achieve the early detection of risk factors for recurrence and assess the risk-stratified Guangdong (GD)-2008 ALL protocol. MATERIALS AND METHODS: In total, 59 Chinese childhood ALL patients treated with the GD-2008 ALL protocol who relapsed between July 2008 and March 2015 were enrolled in this study. Their clinical features and outcomes were retrospectively analyzed and compared with those of 218 patients who achieved continuous complete remission. RESULTS: Of the 285 study participants, 8 died of treatment-related infections or other complications before remission, 218 achieved continuous complete remission, and 59 patients relapsed, yielding a relapse rate of 20.7%. The number of relapsed patients in the standard-risk, intermediate-risk, and high-risk groups were 15 (17.0%), 27 (19.7%), and 17 (32.7%), respectively. Risk factors included age 10 years and above at first diagnosis, white blood cell (WBC) count >=50*10/L, poor prednisone response, failure to achieve bone marrow complete remission at day 15 of induction chemotherapy. High-risk stratification and a high level (>=0.1%) of minimal residual disease at day 33 were the risk factors for relapse. Multivariate analysis showed that a high WBC at first diagnosis was an independent risk factor for relapse (P=0.000). CONCLUSION: For the GD-2008 ALL risk stratification based on age and initial WBC, 10 years of age and WBC 50*10/L can be used as cut-offs. Patients at high risk benefited from the GD-2008 ALL protocol. In addition, the impact of minimal residual disease on prognosis should be considered. PMID- 29608549 TI - Budding Uninhibited by Benzimidazole-1 Insufficiency Prevents Acute Renal Failure in Severe Sepsis by Maintaining Anti-Coagulant Functions of Vascular Endothelial Cells. AB - Severe sepsis is critical to health and can result in acute renal failure (ARF). Tissue factor (TF) and thrombomodulin (TM) play key roles in vascular endothelial functions by helping maintain microcirculation in the kidney. Budding uninhibited by benzimidazole-1 (Bub1) plays a role in Akt and JNK signaling, which control TF and TM, respectively. We hypothesized that Bub1 could control vascular endothelial function in sepsis. The aim of this study was to determine the role of Bub1 in septic ARF. We used Mouse cecum ligation and puncture (CLP) using low Bub1 expressing (Bub1) and wild-type (Bub1) mice in vivo and lipopolysaccharide (LPS) stimulation of human aortic endothelial cell (HAEC) in vitro. Bub1 mice had a higher survival rate after CLP than Bub1. Bub1 mice had more severe ARF after CLP than Bub1 with blood biochemical and pathological analyses. TF expression in Bub1 mice and control HAEC (control) significantly increased in the septic model compared with Bub1 and Bub1 silenced HAEC (siBub1). TM expression in the control significantly decreased after LPS stimulation compared with siBub1. Akt and JNK phosphorylation of siBub1 were attenuated after LPS stimulation. Associations of Bub1 with Akt or JNK after LPS stimulation of HAEC were detected using immunoprecipitation, suggesting that Bub1 is involved in the phosphorylation of Akt and JNK after LPS stimulation. Bub1 insufficiency attenuates TF expression and reduces TM suppression by blocking Akt and JNK phosphorylation, respectively, thus leading to the prevention of ARF and death caused by sepsis. PMID- 29608550 TI - Amitriptyline Treatment Mitigates Sepsis-Induced Tumor Necrosis Factor Expression and Coagulopathy. AB - During sepsis, the early innate response and inflammatory cytokine cascade are associated with activation of the coagulation cascade. Acute hypercoagulability can contribute to lethal sequela of vascular thrombosis, tissue ischemia, and organ failure. We investigated if amitriptyline (AMIT), an antidepressant drug with a number of anti-inflammatory effects, could ameliorate sepsis in a murine model of sepsis - cecal ligation and puncture (CLP). We hypothesized that AMIT treatment would reduce inflammation and mitigate sepsis-induced coagulopathy. Coagulation was measured using thromboelastometry and ferric chloride-induced carotid artery thrombosis. Our findings demonstrate a dynamic early hypercoagulability, followed by delayed hypocoagulability in septic mice. However, septic mice treated with AMIT were unaffected by these coagulation changes and exhibited a coagulation profile similar to sham mice. TNFalpha was markedly elevated in septic mice, but decreased in AMIT-treated mice. Exogenous administration of recombinant TNFalpha in naive mice recapitulated the acute sepsis-induced hypercoagulability profile. Following sepsis and endotoxemia, peritoneal macrophages were the predominant source of TNFalpha expression. AMIT treatment significantly decreased macrophage TNFalpha expression and blunted M1 polarization. Altogether, during polymicrobial sepsis, AMIT treatment suppressed macrophage TNFalpha expression and the M1 phenotype, mitigating an initial hypercoagulable state, and protecting septic mice from delayed hypocoagulability. We propose that AMIT treatment is a promising therapeutic approach in the treatment of sepsis-associated coagulopathy and prevention of acute thromboembolic events or delayed bleeding complications. PMID- 29608551 TI - Early Lactate Values After Out-of-Hospital Cardiac Arrest: Associations with One Year Outcome. AB - BACKGROUND: Previous studies have shown associations between high admission serum lactate, lower lactate clearance and increased short-term mortality after out hospital cardiac arrest (OHCA). We studied whether lactate levels predict long- term outcome after OHCA. METHODS: We included 458 OHCA patients with lactate measurements during intensive care unit (ICU) stay from the prospective FINNRESUSCI study. We evaluated thresholds for time-weighted (TW) mean lactate values for the first 24, 48 and 72 hours. We analyzed lactate clearance and used multivariate regression to assess the prognostic value of the different measurement time points. RESULTS: The admission lactate (median [IQR] 3.06 [2.68 3.44] mmol/l vs 4.76 [4.29-5.23] mmol/l) and the last measured lactate (0.98 [0.90-1.06] mmol/l vs 2.40 [2.03-2.78] mmol/l) were higher in non-survivors than in survivors, as were the lowest (0.73 [0.67-0.79] mmol/l vs 1.83 [1.52-2.14] mmol/l) and the highest (3.44 [3.05-3.83] mmol/l vs 5.25 [4.76-5.74] mmol/l) lactate values (all p < 0.001). Time-weighted mean lactate values for the first 24 h, 48 h, 72 h and for the entire ICU stay were lower in patients with good outcome (p < 0.001). In multivariate backward regression models, time-weighted mean lactate for the entire ICU stay (OR 1.41 per mmol/l, CI 95% 1.08-1.86, p = 0.013) and the last measured lactate in the ICU (OR 2.16 per mmol/l, CI 95% 1.47 3.18, p < 0.001) were independent predictors of poor one-year outcome. CONCLUSIONS: In the present study time-weighted mean lactate values for the entire ICU stay, and the last measured lactate value in the ICU, but not admission lactate or lactate clearance were independent predictors of poor one year outcome. PMID- 29608552 TI - GTS-21 Reduces Inflammation in Acute Lung Injury by Regulating M1 Polarization and Function of Alveolar Macrophages. AB - BACKGROUND: Acute lung injury (ALI) is a severe outcome of sepsis. Alveolar macrophages (AMs) play key roles in defense, resolution in ALI. The polarization of AMs is dependent on micro environmental stimuli and might influence the progression of ALI. GTS-21, a selective alpha7 nicotinic acetylcholine receptor agonist of the cholinergic anti-inflammatory pathway (CAP), has recently been established to be promising in the treatment of ALI. However, the molecular mechanism underlying the GTS-21-mediated suppression of inflammatory responses has been explored only partially. In this study, we examined the relation between GTS-21 and AM polarization in ALI. METHODS: The adoptive transfer of M1 (classically activated) and M2 (alternatively activated)-polarized AMs was performed to AM-depleted ALI mice, along with the administration of GTS-21 in a murine model of lipopolysaccharide (LPS)-induced ALI and in isolated AMs that had been stimulated by LPS in vitro. RESULTS: The adoptive transfer of M1-polarized AMs aggravated the inflammatory response in the lung in contrast to the adoptive transfer of M2-polarized AMs. GTS-21 protected the lung from the effect of LPSs, preventing injury and decreasing the number of AMs, AM-related pro-inflammatory cytokine levels, high mobility group box 1 expression levels in AMs. In addition, GTS-21 significantly diminished the number of M1-polarized AM and increased the number of M2-polarized AM, by flow cytometry, RT-PCR, ELISA, and the Arg1 and iNOS activity assays. CONCLUSION: The GTS-21 substantially ameliorates LPS induced ALI. This protection is predominantly associated with the inhibition of pulmonary AM M1 polarization and alteration in AM function. PMID- 29608553 TI - Effect of Salt Intervention on Serum Levels of Fibroblast Growth Factor 23 (FGF23) in Chinese Adults: An Intervention Study. AB - BACKGROUND Fibroblast growth factor 23 (FGF23), a prominent regulator of phosphate and calcium metabolism, regulates sodium excretion in distal tubules through sodium-chloride cotransporter. This effect regulates blood pressure. Salt intake exerts effects on serum levels of FGF23 in mice. The aim of this study was to explore whether salt intervention affects serum concentrations of FGF23 in Chinese adults. MATERIAL AND METHODS We enrolled 44 participants from Lantian, a rural community of Shaanxi, China. All participants were maintained on a three day normal diet, which was sequentially followed by a seven-day low-Na+ diet and seven-day high-Na+ diet. Serum FGF23 concentrations were assessed by ELISA. RESULTS Serum FGF23 concentrations elevated during low-salt diet compared with levels at baseline (66.20+/-44.21 pg/mL versus 86.77+/-53.74 pg/mL, p<0.05) and remarkably decreased when changed from low to high salt intake (86.77+/-53.74 pg/mL versus 49.26+/-42.67 pg/mL, p<0.001). Responses of FGF23 to salt intervention were more prominent in normotensive, older than 60 years, BMI <24 kg/m2 and salt-resistant individuals. Furthermore, a significant inverse correlation was observed between 24-hour urinary sodium and serum concentrations of FGF23 after adjusting age, sex, BMI and hypertension status. CONCLUSIONS Dietary salt intervention significantly affects serum FGF23 in Chinese adults. PMID- 29608554 TI - Specter: linear deconvolution for targeted analysis of data-independent acquisition mass spectrometry proteomics. AB - Mass spectrometry with data-independent acquisition (DIA) is a promising method to improve the comprehensiveness and reproducibility of targeted and discovery proteomics, in theory by systematically measuring all peptide precursors in a biological sample. However, the analytical challenges involved in discriminating between peptides with similar sequences in convoluted spectra have limited its applicability in important cases, such as the detection of single-nucleotide polymorphisms (SNPs) and alternative site localizations in phosphoproteomics data. We report Specter (https://github.com/rpeckner-broad/Specter), an open source software tool that uses linear algebra to deconvolute DIA mixture spectra directly through comparison to a spectral library, thus circumventing the problems associated with typical fragment-correlation-based approaches. We validate the sensitivity of Specter and its performance relative to that of other methods, and show that Specter is able to successfully analyze cases involving highly similar peptides that are typically challenging for DIA analysis methods. PMID- 29608555 TI - scmap: projection of single-cell RNA-seq data across data sets. AB - Single-cell RNA-seq (scRNA-seq) allows researchers to define cell types on the basis of unsupervised clustering of the transcriptome. However, differences in experimental methods and computational analyses make it challenging to compare data across experiments. Here we present scmap (http://bioconductor.org/packages/scmap; web version at http://www.sanger.ac.uk/science/tools/scmap), a method for projecting cells from an scRNA-seq data set onto cell types or individual cells from other experiments. PMID- 29608556 TI - Real-time fluorescence and deformability cytometry. AB - The throughput of cell mechanical characterization has recently approached that of conventional flow cytometers. However, this very sensitive, label-free approach still lacks the specificity of molecular markers. Here we developed an approach that combines real-time 1D-imaging fluorescence and deformability cytometry in one instrument (RT-FDC), thus opening many new research avenues. We demonstrated its utility by using subcellular fluorescence localization to identify mitotic cells and test for mechanical changes in those cells in an RNA interference screen. PMID- 29608557 TI - A high throughput, functional screen of human Body Mass Index GWAS loci using tissue-specific RNAi Drosophila melanogaster crosses. AB - Human GWAS of obesity have been successful in identifying loci associated with adiposity, but for the most part, these are non-coding SNPs whose function, or even whose gene of action, is unknown. To help identify the genes on which these human BMI loci may be operating, we conducted a high throughput screen in Drosophila melanogaster. Starting with 78 BMI loci from two recently published GWAS meta-analyses, we identified fly orthologs of all nearby genes (+/- 250KB). We crossed RNAi knockdown lines of each gene with flies containing tissue specific drivers to knock down (KD) the expression of the genes only in the brain and the fat body. We then raised the flies on a control diet and compared the amount of fat/triglyceride in the tissue-specific KD group compared to the driver only control flies. 16 of the 78 BMI GWAS loci could not be screened with this approach, as no gene in the 500-kb region had a fly ortholog. Of the remaining 62 GWAS loci testable in the fly, we found a significant fat phenotype in the KD flies for at least one gene for 26 loci (42%) even after correcting for multiple comparisons. By contrast, the rate of significant fat phenotypes in RNAi KD found in a recent genome-wide Drosophila screen (Pospisilik et al. (2010) is ~5%. More interestingly, for 10 of the 26 positive regions, we found that the nearest gene was not the one that showed a significant phenotype in the fly. Specifically, our screen suggests that for the 10 human BMI SNPs rs11057405, rs205262, rs9925964, rs9914578, rs2287019, rs11688816, rs13107325, rs7164727, rs17724992, and rs299412, the functional genes may NOT be the nearest ones (CLIP1, C6orf106, KAT8, SMG6, QPCTL, EHBP1, SLC39A8, ADPGK /ADPGK-AS1, PGPEP1, KCTD15, respectively), but instead, the specific nearby cis genes are the functional target (namely: ZCCHC8, VPS33A, RSRC2; SPDEF, NUDT3; PAGR1; SETD1, VKORC1; SGSM2, SRR; VASP, SIX5; OTX1; BANK1; ARIH1; ELL; CHST8, respectively). The study also suggests further functional experiments to elucidate mechanism of action for genes evolutionarily conserved for fat storage. PMID- 29608559 TI - The metabolic theory of ecology and the cost of parasitism. AB - With over 1 million species on earth, each biologically unique, do we have any hope of understanding whether species will persist in a warming world? We might, because it turns out that there is surprising regularity in how warming accelerates the major metabolic processes that power life. A persistent challenge has been to understand ecological effects of temperature in the context of species interactions, especially when individuals not only experience temperature but also mortality due to parasitism or predation. Kirk et al. have shown how the effects of parasites vary with warming in a manner entirely consistent with general temperature dependence of host and parasite metabolism. PMID- 29608558 TI - High-throughput interaction screens illuminate the role of c-di-AMP in cyanobacterial nighttime survival. AB - The broadly conserved signaling nucleotide cyclic di-adenosine monophosphate (c di-AMP) is essential for viability in most bacteria where it has been studied. However, characterization of the cellular functions and metabolism of c-di-AMP has largely been confined to the class Bacilli, limiting our functional understanding of the molecule among diverse phyla. We identified the cyclase responsible for c-di-AMP synthesis and characterized the molecule's role in survival of darkness in the model photosynthetic cyanobacterium Synechococcus elongatus PCC 7942. In addition to the use of traditional genetic, biochemical, and proteomic approaches, we developed a high-throughput genetic interaction screen (IRB-Seq) to determine pathways where the signaling nucleotide is active. We found that in S. elongatus c-di-AMP is produced by an enzyme of the diadenylate cyclase family, CdaA, which was previously unexplored experimentally. A cdaA-null mutant experiences increased oxidative stress and death during the nighttime portion of day-night cycles, in which potassium transport is implicated. These findings suggest that c-di-AMP is biologically active in cyanobacteria and has non-canonical roles in the phylum including oxidative stress management and day-night survival. The pipeline and analysis tools for IRB Seq developed for this study constitute a quantitative high-throughput approach for studying genetic interactions. PMID- 29608560 TI - Molecular basis of hemoglobin adaptation in the high-flying bar-headed goose. AB - During the adaptive evolution of a particular trait, some selectively fixed mutations may be directly causative and others may be purely compensatory. The relative contribution of these two classes of mutation to adaptive phenotypic evolution depends on the form and prevalence of mutational pleiotropy. To investigate the nature of adaptive substitutions and their pleiotropic effects, we used a protein engineering approach to characterize the molecular basis of hemoglobin (Hb) adaptation in the high-flying bar-headed goose (Anser indicus), a hypoxia-tolerant species renowned for its trans-Himalayan migratory flights. To test the effects of observed substitutions on evolutionarily relevant genetic backgrounds, we synthesized all possible genotypic intermediates in the line of descent connecting the wildtype bar-headed goose genotype with the most recent common ancestor of bar-headed goose and its lowland relatives. Site-directed mutagenesis experiments revealed one major-effect mutation that significantly increased Hb-O2 affinity on all possible genetic backgrounds. Two other mutations exhibited smaller average effect sizes and less additivity across backgrounds. One of the latter mutations produced a concomitant increase in the autoxidation rate, a deleterious side-effect that was fully compensated by a second-site mutation at a spatially proximal residue. The experiments revealed three key insights: (i) subtle, localized structural changes can produce large functional effects; (ii) relative effect sizes of function-altering mutations may depend on the sequential order in which they occur; and (iii) compensation of deleterious pleiotropic effects may play an important role in the adaptive evolution of protein function. PMID- 29608561 TI - Kampala manifesto: Building community-based One Health approaches to disease surveillance and response-The Ebola Legacy-Lessons from a peer-led capacity building initiative. AB - OVERVIEW: International activities to respond to the Ebola crisis in West Africa were mainly developed and focussed around the biomedical paradigm of Western health systems. This approach was often insensitive to societal perception, attitude, and behavioural determinants and clashed with community-based health traditions, narratives, and roles, e.g., of community health workers. In this peer-led capacity-building initiative, these deficiencies were identified and analysed. Innovative, more locally focussed, community-based solutions were articulated. The new approaches described put local people at the centre of all preparedness, response, and recovery strategies. This paradigm shift reframed the role of communities from victims to active managers of their response and reacknowledged the strength of community-based One Health. We conclude that strategies should aim at empowering, not just engaging, communities. Communities can improve short-term crisis management and build longer-term resilience and capacities that are much needed in the current global health climate. BACKGROUND: The Ebola outbreak in West Africa, 2014-2016, was unprecedented in scale, extent, and duration. The international community was slow to step up its assistance in this global public health emergency and then faltered when its infection control management approaches clashed with West African realities [1]. Outbreak response evaluations have identified the need to better integrate social science intelligence [2], better collaborate with communities [3,4], more effectively draw on the strength of community health workers [5], and critically question the paradigm of Western health systems, which focus on imposing 'evidence-based' solutions that lack external validity in affected communities; i.e., they too often recommend actions that are inconsistent with, ignore, or violate traditional behaviours [6]. While there appears to be a consensus now on what needs to be done, how to achieve these goals remains a challenge. PMID- 29608562 TI - Meta-research matters: Meta-spin cycles, the blindness of bias, and rebuilding trust. AB - Meta-research is research about research. Meta-research may not be as click worthy as a meta-pug-a pug dog dressed up in a pug costume-but it is crucial to understanding research. A particularly valuable contribution of meta-research is to identify biases in a body of evidence. Bias can occur in the design, conduct, or publication of research and is a systematic deviation from the truth in results or inferences. The findings of meta-research can tell us which evidence to trust and what must be done to improve future research. We should be using meta-research to provide the evidence base for implementing systemic changes to improve research, not for discrediting it. PMID- 29608563 TI - A field study of the survival and dispersal pattern of Lutzomyia longipalpis in an endemic area of visceral leishmaniasis in Brazil. AB - Zoonotic Visceral leishmaniasis (ZVL) is a neglected tropical disease that in the Americas is caused by the infection of Leishmania infantum and the domestic dog (Canis familiaris) is the main parasite reservoir in urban areas. The parasite is mainly transmitted by populations of the sibling species Lutzomyia longipalpis that has been spreading in countries including Brazil, Argentina, Paraguay and more recently Uruguay. Although bionomic parameters such as population survival and the duration of the gonotrophic cycle are critical in evaluating vector capacity, field studies have rarely been applied to sand fly populations. The present study sought to evaluate basic bionomic parameters related to the vectorial capacity of the (S)-9-methylgermacrene-B population of the Lu. longipalpis complex in a visceral leishmaniasis area of Sao Paulo state. The daily survival rate, the duration of the gonotrophic cycle and the dispersal pattern were evaluated through the mark- release-recapture method. A total of 1,547 males and 401 females were marked and released in five experiments carried out between February 2013 and February 2014. The higher recapture rates occurred within 100 meters of the release point and the estimated daily survival rates varied between 0.69 and 0.89 for females and between 0.69 and 0.79 for males. The minimum duration of the gonotrophic cycle observed was five days. The absolute population size, calculated ranged from 900 to 4,857 females and from 2,882 to 9,543 males. Our results demonstrate a high survival rate of this vector population and low dispersal that could be associated with the presence of all necessary conditions for its establishment and maintenance in the peridomiciles of this area. Our findings contribute to the basic data necessary for the understanding of ZVL dynamics and the evaluation of the implementation of prevention and control measures. PMID- 29608565 TI - Natural allelic variation of the AZI1 gene controls root growth under zinc limiting condition. AB - Zinc is an essential micronutrient for all living organisms and is involved in a plethora of processes including growth and development, and immunity. However, it is unknown if there is a common genetic and molecular basis underlying multiple facets of zinc function. Here we used natural variation in Arabidopsis thaliana to study the role of zinc in regulating growth. We identify allelic variation of the systemic immunity gene AZI1 as a key for determining root growth responses to low zinc conditions. We further demonstrate that this gene is important for modulating primary root length depending on the zinc and defence status. Finally, we show that the interaction of the immunity signal azelaic acid and zinc level to regulate root growth is conserved in rice. This work demonstrates that there is a common genetic and molecular basis for multiple zinc dependent processes and that nutrient cues can determine the balance of growth and immune responses in plants. PMID- 29608567 TI - ParBiBit: Parallel tool for binary biclustering on modern distributed-memory systems. AB - Biclustering techniques are gaining attention in the analysis of large-scale datasets as they identify two-dimensional submatrices where both rows and columns are correlated. In this work we present ParBiBit, a parallel tool to accelerate the search of interesting biclusters on binary datasets, which are very popular on different fields such as genetics, marketing or text mining. It is based on the state-of-the-art sequential Java tool BiBit, which has been proved accurate by several studies, especially on scenarios that result on many large biclusters. ParBiBit uses the same methodology as BiBit (grouping the binary information into patterns) and provides the same results. Nevertheless, our tool significantly improves performance thanks to an efficient implementation based on C++11 that includes support for threads and MPI processes in order to exploit the compute capabilities of modern distributed-memory systems, which provide several multicore CPU nodes interconnected through a network. Our performance evaluation with 18 representative input datasets on two different eight-node systems shows that our tool is significantly faster than the original BiBit. Source code in C++ and MPI running on Linux systems as well as a reference manual are available at https://sourceforge.net/projects/parbibit/. PMID- 29608564 TI - Actin organization and endocytic trafficking are controlled by a network linking NIMA-related kinases to the CDC-42-SID-3/ACK1 pathway. AB - Molting is an essential process in the nematode Caenorhabditis elegans during which the epidermal apical extracellular matrix, termed the cuticle, is detached and replaced at each larval stage. The conserved NIMA-related kinases NEKL 2/NEK8/NEK9 and NEKL-3/NEK6/NEK7, together with their ankyrin repeat partners, MLT-2/ANKS6, MLT-3/ANKS3, and MLT-4/INVS, are essential for normal molting. In nekl and mlt mutants, the old larval cuticle fails to be completely shed, leading to entrapment and growth arrest. To better understand the molecular and cellular functions of NEKLs during molting, we isolated genetic suppressors of nekl molting-defective mutants. Using two independent approaches, we identified CDC 42, a conserved Rho-family GTPase, and its effector protein kinase, SID-3/ACK1. Notably, CDC42 and ACK1 regulate actin dynamics in mammals, and actin reorganization within the worm epidermis has been proposed to be important for the molting process. Inhibition of NEKL-MLT activities led to strong defects in the distribution of actin and failure to form molting-specific apical actin bundles. Importantly, this phenotype was reverted following cdc-42 or sid-3 inhibition. In addition, repression of CDC-42 or SID-3 also suppressed nekl associated defects in trafficking, a process that requires actin assembly and disassembly. Expression analyses indicated that components of the NEKL-MLT network colocalize with both actin and CDC-42 in specific regions of the epidermis. Moreover, NEKL-MLT components were required for the normal subcellular localization of CDC-42 in the epidermis as well as wild-type levels of CDC-42 activation. Taken together, our findings indicate that the NEKL-MLT network regulates actin through CDC-42 and its effector SID-3. Interestingly, we also observed that downregulation of CDC-42 in a wild-type background leads to molting defects, suggesting that there is a fine balance between NEKL-MLT and CDC-42-SID 3 activities in the epidermis. PMID- 29608566 TI - FIGL1 and its novel partner FLIP form a conserved complex that regulates homologous recombination. AB - Homologous recombination is central to repair DNA double-strand breaks, either accidently arising in mitotic cells or in a programed manner at meiosis. Crossovers resulting from the repair of meiotic breaks are essential for proper chromosome segregation and increase genetic diversity of the progeny. However, mechanisms regulating crossover formation remain elusive. Here, we identified through genetic and protein-protein interaction screens FIDGETIN-LIKE-1 INTERACTING PROTEIN (FLIP) as a new partner of the previously characterized anti crossover factor FIDGETIN-LIKE-1 (FIGL1) in Arabidopsis thaliana. We showed that FLIP limits meiotic crossover together with FIGL1. Further, FLIP and FIGL1 form a protein complex conserved from Arabidopsis to human. FIGL1 interacts with the recombinases RAD51 and DMC1, the enzymes that catalyze the DNA strand exchange step of homologous recombination. Arabidopsis flip mutants recapitulate the figl1 phenotype, with enhanced meiotic recombination associated with change in counts of DMC1 and RAD51 foci. Our data thus suggests that FLIP and FIGL1 form a conserved complex that regulates the crucial step of strand invasion in homologous recombination. PMID- 29608568 TI - Dual-modal photoacoustic and magnetic resonance tracking of tendon stem cells with PLGA/iron oxide microparticles in vitro. AB - Reliable cell tracking is essential to understand the fate of stem cells following implantation, and thus promote the clinical application of stem cell therapy. Dual or multiple modal imaging modalities mediated by different types of multifunctional contrast agent are generally needed for efficient cell tracking. Here, we created a new contrast agent-PLGA/iron oxide microparticles (PLGA/IO MPs) and characterized the morphology, structure and function of enhancing both photoacoustic (PA) and magnetic resonance imaging (MRI). Both PA and MRI signal increased with increased Fe concentration of PLGA/IO MPs. Fluorescent staining, Prussian blue staining and transmission electron microscope (TEM) certified that PLGA/IO MPs were successfully encapsulated in the labeled TSCs. The established PLGA/IO MPs demonstrated superior ability of dual-modal PA/MRI tracking of TSCs without cytotoxicity at relatively lower Fe concentrations (50, 100 and 200 MUg/mL). The optimal Fe concentration of PLGA/IO MPs was determined to be 100 MUg/mL, thus laying a foundation for the further study of dual-modal PA/MRI tracking of TSCs in vivo and promoting the repair of injured tendon. PMID- 29608569 TI - Expanding the toolbox for Trypanosoma cruzi: A parasite line incorporating a bioluminescence-fluorescence dual reporter and streamlined CRISPR/Cas9 functionality for rapid in vivo localisation and phenotyping. AB - BACKGROUND: Infection with Trypanosoma cruzi causes Chagas disease, a major public health problem throughout Latin America. There is no vaccine and the only drugs have severe side effects. Efforts to generate new therapies are hampered by limitations in our understanding of parasite biology and disease pathogenesis. Studies are compromised by the complexity of the disease, the long-term nature of the infection, and the fact that parasites are barely detectable during the chronic stage. In addition, functional dissection of T. cruzi biology has been restricted by the limited flexibility of the genetic manipulation technology applicable to this parasite. METHODOLOGY/PRINCIPAL FINDINGS: Here, we describe two technical innovations, which will allow the role of the parasite in disease progression to be better assessed. First, we generated a T. cruzi reporter strain that expresses a fusion protein comprising red-shifted luciferase and green fluorescent protein domains. Bioluminescence allows the kinetics of infection to be followed within a single animal, and specific foci of infection to be pinpointed in excised tissues. Fluorescence can then be used to visualise individual parasites in tissue sections to study host-parasite interactions at a cellular level. Using this strategy, we have been routinely able to find individual parasites within chronically infected murine tissues for the first time. The second advance is the incorporation of a streamlined CRISPR/Cas9 functionality into this reporter strain that can facilitate genome editing using a PCR-based approach that does not require DNA cloning. This system allows the rapid generation of null mutants and fluorescently tagged parasites in a background where the in vivo phenotype can be rapidly assessed. CONCLUSIONS/SIGNIFICANCE: The techniques described here will have multiple applications for studying aspects of T. cruzi biology and Chagas disease pathogenesis previously inaccessible to conventional approaches. The reagents and cell lines have been generated as a community resource and are freely available on request. PMID- 29608570 TI - Transfer of the left-side bias effect in perceptual expertise: The case of simplified and traditional Chinese character recognition. AB - The left-side bias (LSB) effect observed in face and expert Chinese character perception is suggested to be an expertise marker for visual object recognition. However, in character perception this effect is limited to characters printed in a familiar font (font-sensitive LSB effect). Here we investigated whether the LSB and font-sensitive LSB effects depend on participants' familiarity with global structure or local component information of the stimuli through examining their transfer effects across simplified and traditional Chinese scripts: the two Chinese scripts share similar overall structures but differ in the visual complexity of local components in general. We found that LSB in expert Chinese character processing could be transferred to the Chinese script that the readers are unfamiliar with. In contrast, the font-sensitive LSB effect did not transfer, and was limited to characters with the visual complexity the readers were most familiar with. These effects suggest that the LSB effect may be generalized to another visual category with similar overall structures; in contrast, effects of within-category variations such as fonts may depend on familiarity with local component information of the stimuli, and thus may be limited to the exemplars of the category that experts are typically exposed to. PMID- 29608572 TI - Development and properties of duplex MgF2/PCL coatings on biodegradable magnesium alloy for biomedical applications. AB - The present work addresses the performance of polycaprolactone (PCL) coating on fluoride treated (MgF2) biodegradable ZK60 magnesium alloy (Mg) for biomedical application. MgF2 conversion layer was first produced by immersing Mg alloy substrate in hydrofluoric acid solution. The outer PCL coating was then prepared using dip coating technique. Morphology, elements profile, phase structure, roughness, mechanical properties, invitro corrosion, and biocompatibility of duplex MgF2/PCL coating were then characterized and compared to those of fluoride coated and uncoated Mg samples. The invivo degradation behavior and biocompatibility of duplex MgF2/PCL coating with respect to ZK60 Mg alloy were also studied using rabbit model for 2 weeks. SEM and TEM analysis showed that the duplex coating was uniform and comprised of porous PCL film (~3.3 MUm) as upper layer with compact MgF2 (~2.2 MUm) as inner layer. No significant change in microhardness was found on duplex coating compared with uncoated ZK60 Mg alloy. The duplex coating showed improved invitro corrosion resistance than single layered MgF2 or uncoated alloy samples. The duplex coating also resulted in better cell viability, cell adhesion, and cell proliferation compared to fluoride coated or uncoated alloy. Preliminary invivo studies indicated that duplex MgF2/PCL coating reduced the degradation rate of ZK60 Mg alloy and exhibited good biocompatibility. These results suggested that duplex MgF2/PCL coating on magnesium alloy might have great potential for orthopedic applications. PMID- 29608573 TI - Development of a Trypanosoma cruzi strain typing assay using MS2 peptide spectral libraries (Tc-STAMS2). AB - BACKGROUND: Chagas disease also known as American trypanosomiasis is caused by the protozoan Trypanosoma cruzi. Over the last 30 years, Chagas disease has expanded from a neglected parasitic infection of the rural population to an urbanized chronic disease, becoming a potentially emergent global health problem. T. cruzi strains were assigned to seven genetic groups (TcI-TcVI and TcBat), named discrete typing units (DTUs), which represent a set of isolates that differ in virulence, pathogenicity and immunological features. Indeed, diverse clinical manifestations (from asymptomatic to highly severe disease) have been attempted to be related to T.cruzi genetic variability. Due to that, several DTU typing methods have been introduced. Each method has its own advantages and drawbacks such as high complexity and analysis time and all of them are based on genetic signatures. Recently, a novel method discriminated bacterial strains using a peptide identification-free, genome sequence-independent shotgun proteomics workflow. Here, we aimed to develop a Trypanosoma cruzi Strain Typing Assay using MS/MS peptide spectral libraries, named Tc-STAMS2. METHODS/PRINCIPAL FINDINGS: The Tc-STAMS2 method uses shotgun proteomics combined with spectral library search to assign and discriminate T. cruzi strains independently on the genome knowledge. The method is based on the construction of a library of MS/MS peptide spectra built using genotyped T. cruzi reference strains. For identification, the MS/MS peptide spectra of unknown T. cruzi cells are identified using the spectral matching algorithm SpectraST. The Tc-STAMS2 method allowed correct identification of all DTUs with high confidence. The method was robust towards different sample preparations, length of chromatographic gradients and fragmentation techniques. Moreover, a pilot inter-laboratory study showed the applicability to different MS platforms. CONCLUSIONS AND SIGNIFICANCE: This is the first study that develops a MS-based platform for T. cruzi strain typing. Indeed, the Tc-STAMS2 method allows T. cruzi strain typing using MS/MS spectra as discriminatory features and allows the differentiation of TcI-TcVI DTUs. Similar to genomic-based strategies, the Tc STAMS2 method allows identification of strains within DTUs. Its robustness towards different experimental and biological variables makes it a valuable complementary strategy to the current T. cruzi genotyping assays. Moreover, this method can be used to identify DTU-specific features correlated with the strain phenotype. PMID- 29608571 TI - Endocytic recycling via the TGN underlies the polarized hyphal mode of life. AB - Intracellular traffic in Aspergillus nidulans hyphae must cope with the challenges that the high rates of apical extension (1MUm/min) and the long intracellular distances (>100 MUm) impose. Understanding the ways in which the hyphal tip cell coordinates traffic to meet these challenges is of basic importance, but is also of considerable applied interest, as fungal invasiveness of animals and plants depends critically upon maintaining these high rates of growth. Rapid apical extension requires localization of cell-wall-modifying enzymes to hyphal tips. By combining genetic blocks in different trafficking steps with multidimensional epifluorescence microscopy and quantitative image analyses we demonstrate that polarization of the essential chitin-synthase ChsB occurs by indirect endocytic recycling, involving delivery/exocytosis to apices followed by internalization by the sub-apical endocytic collar of actin patches and subsequent trafficking to TGN cisternae, where it accumulates for ~1 min before being re-delivered to the apex by a RAB11/TRAPPII-dependent pathway. Accordingly, ChsB is stranded at the TGN by Sec7 inactivation but re-polarizes to the apical dome if the block is bypassed by a mutation in geaAgea1 that restores growth in the absence of Sec7. That polarization is independent of RAB5, that ChsB predominates at apex-proximal cisternae, and that upon dynein impairment ChsB is stalled at the tips in an aggregated endosome indicate that endocytosed ChsB traffics to the TGN via sorting endosomes functionally located upstream of the RAB5 domain and that this step requires dynein-mediated basipetal transport. It also requires RAB6 and its effector GARP (Vps51/Vps52/Vps53/Vps54), whose composition we determined by MS/MS following affinity chromatography purification. Ablation of any GARP component diverts ChsB to vacuoles and impairs growth and morphology markedly, emphasizing the important physiological role played by this pathway that, we propose, is central to the hyphal mode of growth. PMID- 29608574 TI - Healing potentials of polymethylmethacrylate bone cement combined with platelet gel in the critical-sized radial bone defect of rats. AB - Polymethylmethacrylate (PMMA) is the most commonly used filler material that lacks biological properties and osteoconductivity or osteoinductivity. Platelet gel (PG) is a typical source of growth factors, cytokines and molecules efficient for bone formation and remodeling. The aim of this study was to evaluate bone healing and regeneration of bone defect in rat model by combining PMMA with PG. A total of 50 defects were created in the diaphysis of the radii of 25 male Sprague Dawley rats. These defects were randomly divided into five groups (n = 10 defects for each group) and treated by autograft, plain PMMA, PG and PMMA-PG or left untreated. The rats were examined clinically and radiologically during the experiment and also after euthanasia at the 8th post-operative week, the healed defects were evaluated by gross morphology, histopathology, histomorphometry, computed tomography, scanning electron microscopy and biomechanical testing. PG could function as efficiently as autograft in promoting bone healing of the radial bones. Additionally, bone formation, and densities of cartilaginous and osseous tissues in the defects treated with autograft, PG and PMMA-PG were more satisfactory than the untreated and PMMA treated defects. Compared with the PMMA PG implant, more PMMA residuals remained in the defect area and induced more intense inflammatory reaction. In conclusion, addition of PG could improve the bone regenerative properties of PMMA bone cement compared with PMMA alone in vivo. Therefore, the PG-PMMA can be proposed as a promising option to increase regenerative potential of PMMA, particularly when it is used as fixator, filler or adhesive in the dentistry, neurosurgery and bone tissue engineering applications. PMID- 29608576 TI - A novel catheter with retractable stent that can prevent aortic insufficiency during left ventricular assist. AB - Left ventricle (LV) assist, which refers to the use of a mini-pump or catheter implanted across the aortic valve connected to the pump, can promote myocardial recovery after left ventricle failure. However, conventional LV assist catheters compress the aortic valve, which can induce aortic insufficiency. Here we describe a novel LV assist catheter containing a retractable stent at its distal end that may prevent such insufficiency. The device was tested in six goats in which the coronary artery was ligated to induce acute LV failure, and then an LV assist was installed with a novel catheter in the left ventricle via the left subclavian artery. Inserting the catheter into the left ventricle caused mild to moderate aortic insufficiency. Releasing the stent maintained the catheter in the center of the three valve leaflets, which resolved the aortic insufficiency and, within a few minutes, led to significantly lower left ventricle end diastolic pressure (9.0+/-3.0 mmHg) than without stent release (17.6+/-5.0 mmHg, p = 0.012) as well as significantly higher left ventricle dP/dtmax (614+/-299 mmHg/s) than without stent release (343+/-245 mmHg/s, p = 0.03). Our results indicate that this novel drainage catheter with retractable stent can effectively prevent aortic insufficiency by maintaining the catheter in the center of the aortic valve leaflets, thereby lowering left ventricular end diastolic pressure and improving systolic function. PMID- 29608575 TI - Ozanimod (RPC1063), a selective S1PR1 and S1PR5 modulator, reduces chronic inflammation and alleviates kidney pathology in murine systemic lupus erythematosus. AB - Ozanimod (RPC1063) is a specific and potent small molecule modulator of the sphingosine 1-phosphate receptor 1 (S1PR1) and receptor 5 (S1PR5), which has shown therapeutic benefit in clinical trials of relapsing multiple sclerosis and ulcerative colitis. Ozanimod and its active metabolite, RP-101075, exhibit a similar specificity profile at the S1P receptor family in vitro and pharmacodynamic profile in vivo. The NZBWF1 mouse model was used in therapeutic dosing mode to assess the potential benefit of ozanimod and RP-101075 in an established animal model of systemic lupus erythematosus. Compared with vehicle treated animals, ozanimod and RP-101075 reduced proteinuria over the duration of the study and serum blood urea nitrogen at termination. Additionally, ozanimod and RP-101075 reduced kidney disease in a dose-dependent manner, as measured by histological assessment of mesangial expansion, endo- and exo-capillary proliferation, interstitial infiltrates and fibrosis, glomerular deposits, and tubular atrophy. Further exploration into gene expression changes in the kidney demonstrate that RP-101075 also significantly reduced expression of fibrotic and immune-related genes in the kidneys. Of note, RP-101075 lowered the number of plasmacytoid dendritic cells, a major source of interferon alpha in lupus patients, and reduced all B and T cell subsets in the spleen. Given the efficacy demonstrated by ozanimod and its metabolite RP-101075 in the NZBWF1 preclinical animal model, ozanimod may warrant clinical evaluation as a potential treatment for systemic lupus erythematosus. PMID- 29608577 TI - The role of the State Security Service (Stasi) in the context of international clinical trials conducted by western pharmaceutical companies in Eastern Germany (1961-1990). AB - BACKGROUND: After the building of the Berlin Wall in the 1960s, a number of international pharmaceutical manufacturers from the West had their drugs tested in Eastern Germany (GDR). So far, the extensive collection of documents on the subject stored in the archives of the GDR State Security Service (Stasi, MfS) has not been systematically analysed. Until now, the role of the Stasi with respect to the surveillance of the trials has been unclear. METHODS: A keyword search within the database of the Stasi files was conducted. All available files were screened in order to identify institutions, companies and personnel involved in the clinical trials. On this basis, further files were requested. A total of 259 files were available for analysis. Relevant data was derived from 160 of these files. A contextualised approach was applied, which critically explored the origin, content, and impact of the data. In addition, an approach guided by the central steps of document analysis was applied. RESULTS: At least 400 clinical trials were conducted during the GDR period. The exact number remains speculative. According to references found in the Stasi files, it might have been considerably higher. Initially, the main goal of the trials was for the GDR authorities to decide whether to import certain Western drugs. By 1983, this intention had changed. Now, the primary aim of the trials was the procurement of foreign currency. The Stasi feared that the pharmaceutical companies could have a significant influence on GDR Health System. Stasi spies were holding positions in the responsible medical committees, universities, and hospitals. Constant surveillance by the Stasi served the purpose of monitoring any contact between people from the West and the East. Unknowingly, representatives of Western companies were surveilled by the Stasi. The studied documents also point to the fact that a number of clinical trials conducted during the GDR period did not comply with GDR regulations, and were therefore deemed illegal by the Stasi. The Stasi was not particularly interested in medico-ethical questions. CONCLUSIONS: Clinical trials conducted during the GDR period were surveilled by the Stasi. It was their aim to monitor all people involved in the trials, including their Western contacts. Relevant medico-ethical questions like patient consent and safety with respect to the clinical trials were not the focus. Considering the significant number of conducted trials, only limited evidence exists of doctors having discussed them critically. The public was not officially informed about the trials. PMID- 29608578 TI - Body mass index and weight change during initial period of chemotherapy affect survival outcome in advanced biliary tract cancer patients. AB - BACKGROUND: The impact of obesity on survival is known to vary in different cancers. Advanced biliary tract cancer was rarely analyzed about the relationship between obesity and prognosis. We performed this study to evaluate the BMI and body weight change as prognostic factors for advanced biliary tract cancer patients with palliative chemotherapy. METHODS: Between January 2005 and December 2016, two hundred and seventy-six patients who underwent chemotherapy for biliary tract cancer were retrospectively analyzed. The relationship between BMI (kg/m2) and clinical outcomes including overall and progression-free survival was assessed. Additionally the relationship between change in body composition and overall survival was evaluated. RESULTS: Median overall survival was 9.7 months for underweight patients, 10.1 months for normal patients, 15.8 months for overweight group, 13.1 months for obese patients, respectively. (p = 0.047) Univariate analysis showed that BMI, stage III, age less than 64 year-old, gallbladder cancer, operation, radiotherapy and ECOG performance were significantly associated with better survival. Compared with normal patients, overweight patients (BMI 23-24.9kg/m2) had a reduced risk of mortality in multivariate analysis (HR 0.632; 95% CI 0.436-0.918, p = 0.016). In the additional analysis for the effect of changes in body weight and BMI to the overall survival, decrease in body weight and BMI (HR 1.410, 95% CI 1.168-1.986, p = 0.046) was associated with a shorter in overall survival. CONCLUSION: Overweight status and the maintenance of body weight during the initial period of chemotherapy are important and independent predictors of better overall survival in advanced biliary tract cancer patients. PMID- 29608579 TI - Genome-wide association mapping for eyespot disease in US Pacific Northwest winter wheat. AB - Eyespot, caused by the soil-borne necrotrophic fungi Oculimacula yallundae and O. acuformis, is a disease of major economic significance for wheat, barley and rye. Pacific Northwest (PNW) winter wheat (Triticum aestivum L.) grown in areas of high rainfall and moderate winters is most vulnerable to infection. The objective of this research was to identify novel genomic regions associated with eyespot resistance in winter wheat adapted to the PNW. Two winter wheat panels of 469 and 399 lines were compiled for one of the first genome-wide association studies (GWAS) of eyespot resistance in US winter wheat germplasm. These panels were genotyped with the Infinium 9K and 90K iSelect SNP arrays. Both panels were phenotyped for disease resistance in a two-year field study and in replicated growth chamber trials. Growth chamber trials were used to evaluate the genetic resistance of O. acuformis and O. yallundae species separately. Best linear unbiased predictors (BLUPs) were calculated across all field and growth chamber environments. A total of 73 marker-trait associations (MTAs) were detected on nine different chromosomes (1A, 2A, 2B, 4A, 5A, 5B, 7A, 7B and 7D) that were significantly associated (p-value <0.001) with eyespot resistance in Panel A, and 19 MTAs on nine different chromosomes (1A, 1B, 2A, 2D, 3B, 5A, 5B, 7A, and 7B) in Panel B. The most significant SNPs were associated with Pch1 and Pch2 resistance genes on the long arms of chromosome 7D and 7A. Most of the novel MTAs appeared to have a minor effect on reducing eyespot disease. Nevertheless, eyespot disease scores decreased as the number of resistance alleles increased. Seven SNP markers, significantly associated with reducing eyespot disease across environments and in the absence and presence of Pch1 were identified. These markers were located on chromosomes 2A (IWB8331), 5A (IWB73709), 5B (IWB47298), 7AS (IWB47160), 7B (IWB45005) and two SNPs (Ex_c44379_2509 and IAAV4340) had unknown map positions. The additive effect of the MTAs explained most of the remaining phenotypic variation not accounted for by Pch1 or Pch2. This study provides breeders with adapted germplasm and novel sources of eyespot resistance to be used in the development of superior cultivars with increased eyespot resistance. PMID- 29608580 TI - Al6061 surface roughness and optical reflectance when machined by single point diamond turning at a low feed rate. AB - Ultra-precision face turning of Al6061 mirrors using single point diamond turning (SPDT) was undertaken to investigate the correlation between the surface roughness and reflectance. By reducing the feed rate, the optimal feed rate when the chip formation became unstable was studied. Most importantly, the impact on the roughness and reflectance was examined when the chip formation ceased to be continuous. It was determined that for a feed rate below 3 mm/min, the surface roughness always improved as the feed rate decreased, at the cost of a reduction of the normalized reflectance. The reduction of reflectance was determined to be the result of the lower material removal rates that led to a discontinuous chip formation. PMID- 29608581 TI - Correlates of domestic violence experience among recently-married women residing in slums in Pune, India. AB - The high risk of experiencing domestic violence (DV) among married women in India who reside in slum communities underscores the need for effective, evidence based, and culturally-tailored primary prevention. To inform such DV primary prevention strategies for this population, we herein aimed to identify correlates of DV experience in early marriage. Utilizing a cross-sectional design, potential correlates of DV experience were explored among a geographically-clustered random sample of 100 recently-married women residing in slums in Pune, India. In multivariable regression, DV experience was associated with less educational attainment by the participant's spouse (standardized beta = -0.281, p = 0.004), less satisfaction of the spouse's family with the maanpaan (wedding-related gifts provided by the bride's family) they received at the time of marriage (standardized beta = -0.298, p<0.001), poorer conflict negotiation skills (standardized beta = -0.308, p<0.001), and greater acknowledgement of DV occurrence in family and friends (standardized beta = 0.436, p<0.001). These correlates suggest strategies that could be incorporated into future DV primary prevention interventions for this vulnerable population (i.e. promoting completion of formal education of boys alongside girls, mitigating causes of familial dowry harassment, improving conflict negotiation skills, and challenging norms surrounding DV). PMID- 29608582 TI - Asthma and COPD overlap (ACO) is related to a high burden of sleep disturbance and respiratory symptoms: Results from the RHINE and Swedish GA2LEN surveys. AB - BACKGROUND: The term Asthma and COPD Overlap (ACO) describes a condition where asthma and COPD overlap. We aimed to investigate associations between ACO and insomnia and respiratory symptoms, and to investigate the prevalence of ACO and the characteristics of subjects with ACO in two Northern European population studies. METHODS: The study comprised 25 429 subjects aged >= 40 years who participated in one of two Northern European general population surveys. Both surveys included questions on asthma, COPD, respiratory and sleep-related symptoms, including difficulty initiating sleep, difficulty maintaining sleep, early-morning awakening, and excessive daytime sleepiness. ACO was defined as having both self-reported asthma and COPD. RESULTS: The prevalence of ACO was 1.0%. The group with ACO had a higher prevalence of both insomnia and respiratory symptoms than subjects with only asthma or COPD. Having ACO was independently associated with a 2-3 times higher probability of having sleep-related symptoms as compared with the group without asthma or COPD, after adjustment for age, sex, BMI, smoking history and educational level (adjusted odds ratio 2.14-3.36, 95% CI). CONCLUSION: Subjects with ACO have a high prevalence of insomnia and respiratory symptoms. To our knowledge, this is the first study to assess the association between sleep-related symptoms and ACO. PMID- 29608583 TI - Investigating the development of causal inference by studying variability in 2- to 5-year-olds' behavior. AB - This study investigated the development of young children's causal inference by studying variability in behavior. Two possible sources of variability, strategy use and accuracy in strategy execution, were discriminated and related to age. To this end, a relatively wide range of causal inference trials was administered to children of a relatively broad age range: 2- to 5-year-olds. Subsequently, individuals' response patterns over trials were analyzed with a latent variable technique. The results showed that variability in children's behavior could largely be explained by strategy use. Three different strategies were distinguished, and tentative interpretations suggest these could possibly be labeled as "rational", "associative", and "uncertainty avoidance" strategies. The strategies were found to be related to age, and this age-related strategy use better explained the variability in children's behavior than age-related increase in accuracy of executing a single strategy. This study can be considered a first step in introducing a new, fruitful approach for investigating the development of causal inference. PMID- 29608584 TI - The endangered Florida pondweed (Potamogeton floridanus) is a hybrid: Why we need to understand biodiversity thoroughly. AB - Thorough understanding of biodiversity is a fundamental prerequisite for biological research. A lack of taxonomic knowledge and species misidentifications are particularly critical for conservation. Here we present an example of Potamogeton floridanus, the Florida Pondweed, an endangered taxon endemic to a small area in the Florida panhandle, whose taxonomic status remained controversial for more than a century, and all previous attempts to elucidate its identity have failed. We applied molecular approaches to tackle the origin of the mysterious taxon and supplemented them with morphological and anatomical investigations of both historical herbarium collections and plants recently collected in the type area for a comprehensive taxonomic reassessment. Sequencing of two nuclear ribosomal markers and one chloroplast non-coding spacer resulted in the surprising discovery that P. floridanus is a hybrid of P. pulcher and P. oakesianus, with the former being the maternal parent. The hybrid colony is currently geographically isolated from the distribution range of P. oakesianus. We show that previous molecular analyses have failed to reveal its hybrid identity due to inadequate nuclear DNA sequence editing. This is an example how the uncritical use of automized sequence reads can hamper molecular species identifications and also affect phylogenetic tree construction and interpretation. This unique hybrid taxon, P. *floridanus, adds another case study to the debate on hybrid protection; consequences for its conservation are discussed. PMID- 29608585 TI - Some oscillatory phenomena of blood glucose regulation: An exploratory pilot study in pigs. AB - It is well-known that blood glucose oscillates with a period of approximately 15 min (900 s) and exhibits an overall complex behaviour in intact organisms. This complexity is not thoroughly studied, and thus, we aimed to decipher the frequency bands entailed in blood glucose regulation. We explored high-resolution blood glucose time-series sampled using a novel continuous intravascular sensor in four pigs under general anaesthesia for almost 24 hours. In all time series, we found several interesting oscillatory components, especially in the 5000-10000 s, 500-1000 s, and 50-100 s regions (0.0002-0.0001 Hz, 0.002-0.001 Hz, and 0.02 0.01 Hz). The presence of these oscillations is not permanent, as they come and go. This is the first report of glucose oscillations in the 50-100 s range. The origin of these oscillations and their role in overall blood glucose regulation is unknown. Although the sample size is small, we believe this finding is important for our understanding of glucose regulation and perhaps for our understanding of general homeostatic regulation in intact organisms. PMID- 29608586 TI - Dengue forecasting in Sao Paulo city with generalized additive models, artificial neural networks and seasonal autoregressive integrated moving average models. AB - Globally, the number of dengue cases has been on the increase since 1990 and this trend has also been found in Brazil and its most populated city-Sao Paulo. Surveillance systems based on predictions allow for timely decision making processes, and in turn, timely and efficient interventions to reduce the burden of the disease. We conducted a comparative study of dengue predictions in Sao Paulo city to test the performance of trained seasonal autoregressive integrated moving average models, generalized additive models and artificial neural networks. We also used a naive model as a benchmark. A generalized additive model with lags of the number of cases and meteorological variables had the best performance, predicted epidemics of unprecedented magnitude and its performance was 3.16 times higher than the benchmark and 1.47 higher that the next best performing model. The predictive models captured the seasonal patterns but differed in their capacity to anticipate large epidemics and all outperformed the benchmark. In addition to be able to predict epidemics of unprecedented magnitude, the best model had computational advantages, since its training and tuning was straightforward and required seconds or at most few minutes. These are desired characteristics to provide timely results for decision makers. However, it should be noted that predictions are made just one month ahead and this is a limitation that future studies could try to reduce. PMID- 29608587 TI - Investigation of safety and efficacy of the new more thermostable formulation of Flolan (epoprostenol) in Japanese patients with pulmonary arterial hypertension (PAH)-An open-label, single-arm study. AB - OBJECTIVE: This study was conducted to evaluate the safety and efficacy of a new more thermostable Flolan (epoprostenol) solution prepared with the reformulated pH 12.0 diluent in Japanese patients with pulmonary arterial hypertension (PAH) receiving higher doses of Flolan than those typically administered in Western countries. METHODS: This open-label, single-arm study was conducted in 10 Japanese PAH patients. During the run-in period, patients were intravenously infused with Flolan (45 ng/kg/min or higher doses) solution prepared with the existing pH 10.5 diluent. The patients were then switched to a new more thermostable Flolan solution prepared with the reformulated pH 12.0 diluent and observed for a 4-week treatment period. As a primary endpoint, safety after switching to the new Flolan solution was evaluated. Secondary endpoints included hemodynamics and the necessity for dose adjustment of Flolan in these patients. RESULTS: All 10 patients completed the study period. Observed adverse events were nausea and hepatic function abnormal in 1 patient each, and both events were mild. No patients required dose adjustment due to the change from baseline in mean pulmonary artery pressure (mPAP) measured 3 hrs after switching to Flolan solution prepared with the reformulated diluent. No major changes from baseline in mPAP, pulmonary vascular resistance, or right atrial pressure were observed at 24 hrs and at 4 weeks after switching to the Flolan solution prepared with pH 12.0 diluent. Although some patients showed increases in cardiac output (CO) from baseline at 24 hrs and 4 weeks, no patients required dose reduction as a result of an increase in CO. CONCLUSION: Neither safety/efficacy concerns nor any dose adjustments of Flolan after switching to a more thermostable Flolan solution prepared with the reformulated pH 12.0 diluent could be required in Japanese patients with PAH receiving higher doses of Flolan. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02705807. PMID- 29608588 TI - Spatial clusters of gonorrhoea in England with particular reference to the outcome of partner notification: 2012 and 2013. AB - BACKGROUND: This study explored spatial-temporal variation in diagnoses of gonorrhoea to identify and quantify endemic areas and clusters in relation to patient characteristics and outcomes of partner notification (PN) across England, UK. METHODS: Endemic areas and clusters were identified using a two-stage analysis with Kulldorff's scan statistics (SaTScan). RESULTS: Of 2,571,838 tests, 53,547 diagnoses were gonorrhoea positive (positivity = 2.08%). The proportion of diagnoses in heterosexual males was 1.5 times that in heterosexual females. Among index cases, men who have sex with men (MSM) were 8 times more likely to be diagnosed with gonorrhoea than heterosexual males (p<0.0001). After controlling for age, gender, ethnicity and deprivation rank, 4 endemic areas were identified including 11,047 diagnoses, 86% of which occurred in London. 33 clusters included 17,629 diagnoses (34% of total diagnoses in 2012 and 2013) and spanned 21 locations, some of which were dominated by heterosexually acquired infection, whilst others were MSM focused. Of the 53,547 diagnoses, 14.5% (7,775) were the result of PN. The proportion of patients who attended services as a result of PN varied from 0% to 61% within different age, gender and sexual orientation cohorts. A third of tests resulting from PN were positive for gonorrhoea. 25% of Local Authorities (n = 81, 95% CI: 20.2, 29.5) had a higher than expected proportion for female PN diagnoses as compared to 16% for males (n = 52, 95% CI: 12.0, 19.9). CONCLUSIONS: The English gonorrhoea epidemic is characterised by spatial-temporal variation. PN success varied between endemic areas and clusters. Greater emphasis should be placed on the role of PN in the control of gonorrhoea to reduce the risk of onward transmission, re-infection, and complications of infection. PMID- 29608589 TI - The effectiveness of water treatment processes against schistosome cercariae: A systematic review. AB - BACKGROUND: Schistosomiasis is one of the most disabling neglected tropical diseases, ranking second in terms of years lived with disability. While treatment with the drug praziquantel can have immediate beneficial effects, reinfection can occur rapidly if people are in contact with cercaria-infested water. Water treatment for schistosomiasis control seeks to eliminate viable cercariae from water, thereby providing safe alternative water supplies for recreational and domestic activities including laundry and bathing. This provision may reduce contact with infested water, which is crucial for reducing reinfection following chemotherapy and cutting schistosome transmission. METHODOLOGY: A qualitative systematic review was carried out to summarize the existing knowledge on the effectiveness of water treatment in removing or inactivating human schistosome cercariae. Four online databases were searched. Studies were screened and categorized into five water treatment processes: storage, heating, chlorination, filtration, and ultraviolet (UV) disinfection. CONCLUSIONS: All five water treatment methods can remove or inactivate cercariae in water, and hence produce cercaria-free water. However, reliable design guidelines for treating water do not exist as there are insufficient data. Overall, the review found that cercariae are inactivated when storing water for 10-72 hours (depending on temperature), or with chlorination values of 3-30 mg-min/l. UV fluences between 3 60 mJ/cm2 may significantly damage or kill cercariae, and sand filters with 0.18 0.35 mm grain size have been shown to remove cercariae. This systematic review identified 67 studies about water treatment and schistosomiasis published in the past 106 years. It highlights the many factors that influence the results of water treatment experiments, which include different water quality conditions and methods for measuring key parameters. Variation in these factors limit comparability, and therefore currently available information is insufficient for providing complete water treatment design recommendations. PMID- 29608590 TI - Cost-effectiveness of longer-term versus shorter-term provision of antibiotics in patients with persistent symptoms attributed to Lyme disease. AB - BACKGROUND: The treatment of persistent symptoms attributed to Lyme disease remains controversial. Recently, the PLEASE study did not demonstrate any additional clinical benefit of longer-term versus shorter-term antibiotic treatment. However, the economic impact of the antibiotic strategies has not been investigated. METHODS: This prospective economic evaluation, adhering a societal perspective, was performed alongside the PLEASE study, a multicenter, placebo controlled, double-blind 1:1:1 randomized clinical trial in which all patients received open-label intravenous ceftriaxone for two weeks before the 12-week randomized blinded oral antibiotic regimen (doxycycline, clarithromycin plus hydroxychloroquine, or placebo). Between 2010 and 2013, patients (n = 271) with borreliosis-attributed persistent symptoms were enrolled and followed for one year. Main outcomes were costs, quality-adjusted life years, and incremental net monetary benefit of longer-term versus shorter-term antibiotic therapy. RESULTS: Mean quality-adjusted life years (95% CI) were not significantly different (p = 0.96): 0.82 (0.77-0.88) for ceftriaxone/doxycycline (n = 82), 0.81 (0.76-0.88) for ceftriaxone/clarithromycin-hydroxychloroquine (n = 93), and 0.81 (0.76-0.86) for ceftriaxone/placebo (n = 96). Total societal costs per patient (95% CI) were not significantly different either (p = 0.35): ?11,995 (?8,823-?15,670) for ceftriaxone/doxycycline, ?12,202 (?9,572-?15,253) for ceftriaxone/clarithromycin hydroxychloroquine, and ?15,249 (?11,294-?19,781) for ceftriaxone/placebo. Incremental net monetary benefit (95% CI) for ceftriaxone/doxycycline compared to ceftriaxone/placebo varied from ?3,317 (-?2,199-?8,998) to ?4,285 (-?6,085 ?14,524) over the willingness-to-pay range, and that of ceftriaxone/clarithromycin-hydroxychloroquine compared to ceftriaxone/placebo from ?3,098 (-?888-?7,172) to ?3,710 (-?4,254-?11,651). For every willingness-to pay threshold, the incremental net monetary benefits did not significantly differ from zero. CONCLUSION: The longer-term treatments were similar with regard to costs, effectiveness and cost-effectiveness compared to shorter-term treatment in patients with borreliosis-attributed persistent symptoms after one year of follow up. Given the results of this study, and taking into account the external costs associated with antibiotic resistance, the shorter-term treatment is the antibiotic regimen of first choice. PMID- 29608592 TI - webpic: A flexible web application for collecting distance and count measurements from images. AB - Despite increasing ability to store and analyze large amounts of data for organismal and ecological studies, the process of collecting distance and count measurements from images has largely remained time consuming and error-prone, particularly for tasks for which automation is difficult or impossible. Improving the efficiency of these tasks, which allows for more high quality data to be collected in a shorter amount of time, is therefore a high priority. The open source web application, webpic, implements common web languages and widely available libraries and productivity apps to streamline the process of collecting distance and count measurements from images. In this paper, I introduce the framework of webpic and demonstrate one readily available feature of this application, linear measurements, using fossil leaf specimens. This application fills the gap between workflows accomplishable by individuals through existing software and those accomplishable by large, unmoderated crowds. It demonstrates that flexible web languages can be used to streamline time-intensive research tasks without the use of specialized equipment or proprietary software and highlights the potential for web resources to facilitate data collection in research tasks and outreach activities with improved efficiency. PMID- 29608591 TI - Novel monoclonal antibodies targeting the microtubule-binding domain of human tau. AB - Tauopathies including Alzheimer's disease and Progressive Supranuclear Palsy are a diverse group of progressive neurodegenerative disorders pathologically defined by inclusions containing aberrantly aggregated, post-translationally modified tau. The tau pathology burden correlates with neurodegeneration and dementia observed in these diseases. The microtubule binding domain of tau is essential for its physiological functions in promoting neuronal cytoskeletal stability, however it is also required for tau to assemble into an amyloid structure that comprises pathological inclusions. A series of novel monoclonal antibodies were generated which recognize the second and fourth microtubule-binding repeat domain of tau, thus enabling the identification specifically of 4-repeat tau versus 3-/4 repeat tau, respectively. These antibodies are highly specific for tau and recognize pathological tau inclusions in human tauopathies including Alzheimer's disease and Progressive Supranuclear Palsy and in transgenic mouse models of tauopathies. These new antibodies will be useful for identifying and characterizing different tauopathies and as tools to target tau pathology in these diseases. PMID- 29608593 TI - Heart rate dynamics during cardio-pulmonary exercise testing are associated with glycemic control in individuals with type 1 diabetes. AB - INTRODUCTION: This study investigated the degree and direction (kHR) of the heart rate to performance curve (HRPC) during cardio-pulmonary exercise (CPX) testing and explored the relationship with diabetes markers, anthropometry and exercise physiological markers in type 1 diabetes (T1DM). MATERIAL AND METHODS: Sixty-four people with T1DM (13 females; age: 34 +/- 8 years; HbA1c: 7.8 +/- 1% (62 +/- 13 mmol.mol-1) performed a CPX test until maximum exhaustion. kHR was calculated by a second-degree polynomial representation between post-warm up and maximum power output. Adjusted stepwise linear regression analysis was performed to investigate kHR and its associations. Receiver operating characteristic (ROC) curve was performed based on kHR for groups kHR < 0.20 vs. > 0.20 in relation to HbA1c. RESULTS: We found significant relationships between kHR and HbA1c (beta = -0.70, P < 0.0001), age (beta = -0.23, P = 0.03) and duration of diabetes (beta = 0.20, P = 0.04). Stepwise linear regression resulted in an overall adjusted R2 of 0.57 (R = 0.79, P < 0.0001). Our data revealed also significant associations between kHR and percentage of heart rate at heart rate turn point from maximum heart rate (beta = 0.43, P < 0.0001) and maximum power output relativized to bodyweight (beta = 0.44, P = 0.001) (overall adjusted R2 of 0.44 (R = 0.53, P < 0.0001)). ROC curve analysis based on kHR resulted in a HbA1c threshold of 7.9% (62 mmol.mol-1). CONCLUSION: Our data demonstrate atypical HRPC during CPX testing that were mainly related to glycemic control in people with T1DM. PMID- 29608595 TI - Factors associated with sexual and reproductive health stigma among adolescent girls in Ghana. AB - OBJECTIVE: Using our previously developed and tested Adolescent Sexual and Reproductive Health (SRH) Stigma Scale, we investigated factors associated with perceived SRH stigma among adolescent girls in Ghana. METHODS: We drew upon data from our survey study of 1,063 females 15-24yrs recruited from community- and clinic-based sites in two Ghanaian cities. Our Adolescent SRH Stigma Scale comprised 20 items and 3 sub-scales (Internalized, Enacted, Lay Attitudes) to measure stigma occurring with sexual activity, contraceptive use, pregnancy, abortion and family planning service use. We assessed relationships between a comprehensive set of demographic, health and social factors and SRH Stigma with multi-level multivariable linear regression models. RESULTS: In unadjusted bivariate analyses, compared to their counterparts, SRH stigma scores were higher among girls who were younger, Accra residents, Muslim, still in/dropped out of secondary school, unemployed, reporting excellent/very good health, not in a relationship, not sexually experienced, never received family planning services, never used contraception, but had been pregnant (all p-values <0.05). In multivariable models, higher SRH stigma scores were associated with history of pregnancy (beta = 1.53, CI = 0.51,2.56) and excellent/very good self-rated health (beta = 0.89, CI = 0.20,1.58), while lower stigma scores were associated with older age (beta = -0.17, 95%CI = -0.24,-0.09), higher educational attainment (beta = -1.22, CI = -1.82,-0.63), and sexual intercourse experience (beta = 1.32, CI = -2.10,-0.55). CONCLUSIONS: Findings provide insight into factors contributing to SRH stigma among this young Ghanaian female sample. Further research disentangling the complex interrelationships between SRH stigma, health, and social context is needed to guide multi-level interventions to address SRH stigma and its causes and consequences for adolescents worldwide. PMID- 29608594 TI - Personal exposure measurements of school-children to fine particulate matter (PM2.5) in winter of 2013, Shanghai, China. AB - OBJECTIVE: The aim of this study was to perform an exposure assessment of PM2.5 (particulate matter less than 2.5MUm in aerodynamic diameter) among children and to explore the potential sources of exposure from both indoor and outdoor environments. METHODS: In terms of real-time exposure measurements of PM2.5, we collected data from 57 children aged 8-12 years (9.64 +/- 0.93 years) in two schools in Shanghai, China. Simultaneously, questionnaire surveys and time activity diaries were used to estimate the environment at home and daily time activity patterns in order to estimate the exposure dose of PM2.5 in these children. Principle component regression analysis was used to explore the influence of potential sources of PM2.5 exposure. RESULTS: All the median personal exposure and microenvironment PM2.5 concentrations greatly exceeded the daily 24-h PM2.5 Ambient Air Quality Standards of China, the USA, and the World Health Organization (WHO). The median Etotal (the sum of the PM2.5 exposure levels in different microenvironment and fractional time) of all students was 3014.13 (MUg.h)/m3. The concentration of time-weighted average (TWA) exposure of all students was 137.01 MUg/m3. The median TWA exposure level during the on campus period (135.81 MUg/m3) was significantly higher than the off-campus period (115.50 MUg/m3, P = 0.013 < 0.05). Besides ambient air pollution and meteorological conditions, storey height of the classroom and mode of transportation to school were significantly correlated with children's daily PM2.5 exposure. CONCLUSIONS: Children in the two selected schools were exposed to high concentrations of PM2.5 in winter of 2013 in Shanghai. Their personal PM2.5 exposure was mainly associated with ambient air conditions, storey height of the classroom, and children's transportation mode to school. PMID- 29608596 TI - Proteomics and transcriptomics analyses of ataxia telangiectasia cells treated with Dexamethasone. AB - Ataxia telangiectasia (A-T) is an incurable and rare hereditary syndrome. In recent times, treatment with glucocorticoid analogues has been shown to improve the neurological symptoms that characterize this condition, but the molecular mechanism of action of these analogues remains unknown. Hence, the aim of this study was to gain insight into the molecular mechanism of action of glucocorticoid analogues in the treatment of A-T by investigating the role of Dexamethasone (Dexa) in A-T lymphoblastoid cell lines. We used 2DE and tandem MS to identify proteins that were influenced by the drug in A-T cells but not in healthy cells. Thirty-four proteins were defined out of a total of 746+/-63. Transcriptome analysis was performed by microarray and showed the differential expression of 599 A-T and 362 wild type (WT) genes and a healthy un-matching between protein abundance and the corresponding gene expression variation. The proteomic and transcriptomic profiles allowed the network pathway analysis to pinpoint the biological and molecular functions affected by Dexamethasone in Dexa treated cells. The present integrated study provides evidence of the molecular mechanism of action of Dexamethasone in an A-T cellular model but also the broader effects of the drug in other tested cell lines. PMID- 29608597 TI - A clinical study of peroral endoscopic myotomy reveals that impaired lower esophageal sphincter relaxation in achalasia is not only defined by high resolution manometry. AB - BACKGROUND AND AIM: Achalasia is an esophageal motility disorder characterized by impaired lower esophageal sphincter (LES) relaxation. On high-resolution manometry (HRM), impaired LES relaxation is defined by elevated integrated relaxation pressure (IRP). However, a new category of achalasia within the normal IRP range has been suggested. METHODS: HRM was performed using a Starlet device and an IRP threshold of 26 mmHg. Peroral endoscopic myotomy (POEM) was performed for cases of achalasia diagnosed using established methods. During POEM, the histology of the LES was assessed. Follow-up was performed 2 months post operatively. RESULTS: Forty-one patients with achalasia (18 women, mean age 53 +/ 18.6 years) were included. Among them, 27 were placed in the IRP > 26 mmHg subgroup (impaired LES relaxation on HRM) and 14 in the IRP <= 26 mmHg subgroup (normal LES relaxation on HRM). In the IRP <= 26 mmHg subgroup, patients were older, had longer symptom duration, and had more esophageal dilation. The IRP <= 26 mmHg subgroup had the same symptom severity as the higher IRP subgroup and POEM significantly improved symptoms and IRP, although four patients still had severe LES fibrosis. CONCLUSIONS: The clinical presentation of achalasia has a gap between a HRM-defined impaired LES relaxation, with aging or disease progression considered reasons for a lowered LES pressure. POEM can be a feasible treatment option, even for cases of achalasia with a normal IRP. However, patients with severe LES fibrosis need more attention for the therapeutic indication. PMID- 29608598 TI - Sequestration of synaptic proteins by alpha-synuclein aggregates leading to neurotoxicity is inhibited by small peptide. AB - alpha-Synuclein (alpha-syn) is a major component of Lewy bodies found in synucleinopathies including Parkinson's disease (PD) and Dementia with Lewy Bodies (DLB). Under the pathological conditions, alpha-syn tends to generate a diverse form of aggregates showing toxicity to neuronal cells and able to transmit across cells. However, mechanisms by which alpha-syn aggregates affect cytotoxicity in neurons have not been fully elucidated. Here we report that alpha syn aggregates preferentially sequester specific synaptic proteins such as vesicle-associated membrane protein 2 (VAMP2) and synaptosomal-associated protein 25 (SNAP25) through direct binding which is resistant to SDS. The sequestration effect of alpha-syn aggregates was shown in a cell-free system, cultured primary neurons, and PD mouse model. Furthermore, we identified a specific blocking peptide derived from VAMP2 which partially inhibited the sequestration by alpha syn aggregates and contributed to reduced neurotoxicity. These results provide a mechanism of neurotoxicity mediated by alpha-syn aggregates and suggest that the blocking peptide interfering with the pathological role of alpha-syn aggregates could be useful for designing a potential therapeutic drug for the treatment of PD. PMID- 29608599 TI - Prevalence of mcr-type genes among colistin-resistant Enterobacteriaceae collected in 2014-2016 as part of the INFORM global surveillance program. AB - A set of 908 clinically derived colistin-resistant Enterobacteriaeae isolates collected worldwide in 2014-2016 were screened for the presence of the plasmid borne mcr-1, mcr-2, mcr-3, mcr-4 and mcr-5 genes. In total 3.2% (29/908) of the collection were positive for mcr, including 27 Escherichia coli, 1 Klebsiella pneumoniae and 1 Enterobacter cloacae. Twenty-four isolates possessed genes from the mcr-1 family, including the original mcr-1 (n = 22), as well as mcr-1.2 (n = 1) and mcr-1.5 (n = 1), which each differ from mcr-1 by encoding single amino acid variations. Genes from the mcr-3 family were found in isolates from Thailand, including mcr-3.1 (n = 3) and mcr-3.2 (n = 1). An E. coli isolated from a patient with a urinary tract infection in Colombia contained the recently discovered mcr-5. The full colistin-resistant collection was tested against a panel of antimicrobial agents with ceftazidime-avibactam and tigecycline exhibiting the highest activity. PMID- 29608600 TI - Tethering of CHROMATOR and dCTCF proteins results in decompaction of condensed bands in the Drosophila melanogaster polytene chromosomes but does not affect their transcription and replication timing. AB - Instulator proteins are central to domain organization and gene regulation in the genome. We used ectopic tethering of CHROMATOR (CHRIZ/CHRO) and dCTCF to pre defined regions of the genome to dissect the influence of these proteins on local chromatin organization, to analyze their interaction with other key chromatin proteins and to evaluate the effects on transcription and replication. Specifically, using UAS-GAL4DBD system, CHRO and dCTCF were artificially recruited into highly compacted polytene chromosome bands that share the features of silent chromatin type known as intercalary heterochromatin (IH). This led to local chromatin decondensation, formation of novel DHSes and recruitment of several "open chromatin" proteins. CHRO tethering resulted in the recruitment of CP190 and Z4 (PZG), whereas dCTCF tethering attracted CHRO, CP190, and Z4. Importantly, formation of a local stretch of open chromatin did not result in the reactivation of silent marker genes yellow and mini-white immediately adjacent to the targeting region (UAS), nor did RNA polII become recruited into this chromatin. The decompacted region retained late replicated, similarly to the wild type untargeted region. PMID- 29608602 TI - ER-positive breast cancer cells are poised for RET-mediated endocrine resistance. AB - The RET tyrosine kinase signaling pathway is involved in the development of endocrine resistant ER+ breast cancer. However, we know little about how ER+ cells activate RET signaling and initiate an endocrine resistant phenotype. Here we show that both ER+ endocrine resistant and sensitive breast cancers have a functional RET tyrosine kinase signaling pathway, but that endocrine sensitive breast cancer cells lack RET ligands that are necessary to drive endocrine resistance. Transcription of one RET ligand, GDNF, is necessary and sufficient to confer resistance in the ER+ MCF-7 cell line. Endogenous GDNF produced by endocrine resistant cells is translated, secreted into the media, and activates RET signaling in nearby cells. In patients, RET ligand expression predicts responsiveness to endocrine therapies and correlates with survival. Collectively, our findings show that ER+ tumor cells are "poised" for RET mediated endocrine resistance, expressing all components of the RET signaling pathway, but endocrine sensitive cells lack high expression of RET ligands that are necessary to initiate the resistance phenotype. PMID- 29608601 TI - STING agonists enable antiviral cross-talk between human cells and confer protection against genital herpes in mice. AB - In recent years, there has been an increasing interest in immunomodulatory therapy as a means to treat various conditions, including infectious diseases. For instance, Toll-like receptor (TLR) agonists have been evaluated for treatment of genital herpes. However, although the TLR7 agonist imiquimod was shown to have antiviral activity in individual patients, no significant effects were observed in clinical trials, and the compound also exhibited significant side effects, including local inflammation. Cytosolic DNA is detected by the enzyme cyclic GMP AMP (2'3'-cGAMP) synthase (cGAS) to stimulate antiviral pathways, mainly through induction of type I interferon (IFN)s. cGAS is activated upon DNA binding to produce the cyclic dinucleotide (CDN) 2'3'-cGAMP, which in turn binds and activates the adaptor protein Stimulator of interferon genes (STING), thus triggering type I IFN expression. In contrast to TLRs, STING is expressed broadly, including in epithelial cells. Here we report that natural and non natural STING agonists strongly induce type I IFNs in human cells and in mice in vivo, without stimulating significant inflammatory gene expression. Systemic treatment with 2'3'-cGAMP reduced genital herpes simplex virus (HSV) 2 replication and improved the clinical outcome of infection. More importantly, local application of CDNs at the genital epithelial surface gave rise to local IFN activity, but only limited systemic responses, and this treatment conferred total protection against disease in both immunocompetent and immunocompromised mice. In direct comparison between CDNs and TLR agonists, only CDNs acted directly on epithelial cells, hence allowing a more rapid and IFN-focused immune response in the vaginal epithelium. Thus, specific activation of the STING pathway in the vagina evokes induction of the IFN system but limited inflammatory responses to allow control of HSV2 infections in vivo. PMID- 29608604 TI - Indian pharmaceutical patent prosecution: The changing role of Section 3(d). AB - India, like many developing countries, only recently began to grant pharmaceutical product patents. Indian patent law includes a provision, Section 3(d), which tries to limit grant of "secondary" pharmaceutical patents, i.e. patents on new forms of existing molecules and drugs. Previous research suggests the provision was rarely used against secondary applications in the years immediately following its enactment, and where it was, was redundant to other aspects of the patent law, raising concerns that 3(d) was being under-utilized by the Indian Patent Office. This paper uses a novel data source, the patent office's first examination reports, to examine changes in the use of the provision. We find a sharp increase over time in the use of Section 3(d), including on the main claims of patent applications, though it continues to be used in conjunction with other types of objections to patentability. More surprisingly, see a sharp increase in the use of the provision against primary patent applications, contrary to its intent, raising concerns about potential over-utilization. PMID- 29608603 TI - Heart rate variability in type 2 diabetes mellitus: A systematic review and meta analysis. AB - BACKGROUND: Cardiac autonomic neuropathy in type 2 dibetes mellitus (T2DM) patients is frequent and associated with high cardiovascular mortality. Heart rate variability (HRV) is the gold standard to measure cardiac autonomic neuropathy. We aimed to conduct a systematic review and meta-analysis to evaluate the impact of T2DM on HRV parameters. METHODS: The PubMed, Cochrane Library, Embase and Science Direct databases were searched on 1st October 2017 using the keywords "diabetes" AND ("heart rate variability" OR "HRV"). Included articles had to report HRV parameters in T2DM patients and healthy controls measured during 24 hours with a Holter-electrocardiogram. Measurements of HRV retieved were: RR-intervals (or Normal to Normal intervals-NN), standard deviation of RR intervals (SDNN), percetange of adjacent NN intervals differing by more than 50 milliseconds (pNN50), square root of the mean squared difference of successive RR intervals (RMSSD), total power, Low Frequency (LF), High Frequency (HF) and LF/HF ratio, as per Task Force recommendations. RESULTS: We included twenty-five case control studies with 2,932 patients: 1,356 with T2DM and 1,576 healthy controls. T2DM patients had significantly (P<0.01) lower RR-intervals (effect size = -0.61; 95%CI -1.21 to -0.01), lower SDNN (-0.65; -0.83 to -0.47), lower RMSSD (-0.92; 1.37 to -0.47), lower pNN50 (-0.46; -0.84 to -0.09), lower total power (-1.52; 2.13 to -0.91), lower LF (-1.08; -1.46 to -0.69]), and lower HF (-0.79; -1.09 to 0.50). LF/HF did not differ between groups. Levels of blood glucose and HbA1c were associated with several HRV parameters, as well as Time from diagnosis of T2DM. CONCLUSIONS: T2DM was associated with an overall decrease in the HRV of T2DM patients. Both sympathetic and parasympathetic activity were decreased, which can be explained by the deleterious effects of altered glucose metabolism on HRV, leading to cardiac autonomic neuropathy. PMID- 29608606 TI - Lung density change after SABR: A comparative study between tri-Co-60 magnetic resonance-guided system and linear accelerator. AB - Radiation-induced lung damage is an important treatment-related toxicity after lung stereotactic ablative radiotherapy (SABR). After implementing a tri-60Co magnetic-resonance image guided system, ViewRayTM, we compared the associated early radiological lung density changes to those associated with a linear accelerator (LINAC). Eight patients treated with the tri-60Co system were matched 1:1 with patients treated with LINAC. Prescription doses were 52 Gy or 60 Gy in four fractions, and lung dose-volumetric parameters were calculated from each planning system. The first two follow-up computed tomography (CT) were co registered with the planning CT through deformable registration software, and lung density was measured by isodose levels. Tumor size was matched between the two groups, but the planning target volume of LINAC was larger than that of the tri-60Co system (p = 0.036). With regard to clinically relevant dose-volumetric parameters in the lungs, the ipsilateral lung mean dose, V10Gy and V20Gy were significantly poorer in tri-60Co plans compared to LINAC plans (p = 0.012, 0.036, and 0.017, respectively). Increased lung density was not observed in the first follow-up scan compared to the planning scan. A significant change of lung density was shown in the second follow-up scan and there was no meaningful difference between the tri-60Co system and LINAC for all dose regions. In addition, no patient developed clinical radiation pneumonitis until the second follow-up scan. Therefore, there was no significant difference in the early radiological lung damage between the tri-60Co system and LINAC for lung SABR despite of the inferior plan quality of the tri-60Co system compared to that of LINAC. Further studies with a longer follow-up period are needed to confirm our findings. PMID- 29608605 TI - TGA2 signaling in response to reactive electrophile species is not dependent on cysteine modification of TGA2. AB - Reactive electrophile species (RES), including prostaglandins, phytoprostanes and 12-oxo phytodienoic acid (OPDA), activate detoxification responses in plants and animals. However, the pathways leading to the activation of defense reactions related to abiotic or biotic stress as a function of RES formation, accumulation or treatment are poorly understood in plants. Here, the thiol-modification of proteins, including the RES-activated basic region/leucine zipper transcription factor TGA2, was studied. TGA2 contains a single cysteine residue (Cys186) that was covalently modified by reactive cyclopentenones but not required for induction of detoxification genes in response to OPDA or prostaglandin A1. Activation of the glutathione-S-transferase 6 (GST6) promoter was responsive to cyclopentenones but not to unreactive cyclopentanones, including jasmonic acid suggesting that thiol reactivity of RES is important to activate the TGA2 dependent signaling pathway resulting in GST6 activation We show that RES modify thiols in numerous proteins in vivo, however, thiol reactivity alone appears not to be sufficient for biological activity as demonstrated by the failure of several membrane permeable thiol reactive reagents to activate the GST6 promoter. PMID- 29608607 TI - Pharmacokinetics-adapted Busulfan-based myeloablative conditioning before unrelated umbilical cord blood transplantation for myeloid malignancies in children. AB - Unrelated umbilical cord blood transplantation (UCBT) is an alternative to provide transplants in children with acute leukemia or myelodysplastic syndrome who lack a related donor. Intravenous Busulfan (Bu) combined with therapeutic drug monitoring-guided dosing has been increasingly used, with more predictable bioavailability and better outcomes comparing to oral Bu. There is still an important variation in Bu pharmacokinetic between patients that is associated with an increased risk of toxicity and graft failure. The objective of the study was to analyze the impact of first-dose pharmacokinetic adapted myeloablative conditioning regimen of intravenous Bu on the different outcomes after transplantation. Data of 36 children who underwent allogeneic HSCT with Bu plus a second alkylating agent at Sainte Justine Hospital in Montreal, Canada, between December 2000 and April 2012 were analyzed. For children with high risk myeloid malignancies receiving an UCBT, first dose Bu pharmacokinetic seems to be a significant prognostic factor, influencing neutrophil (100% vs 67.9%) and platelet recovery (95.5% vs 70.5%), non-relapse mortality (0% vs 18.6%), EFS (64% vs 28.6%) and OS (81.3% vs 37.5%) for a first-dose steady-state concentration (Css) <600ng/mL vs >600ng/mL, respectively. These data reinforce the importance of Busulfan therapeutic drug monitoring-guided dosing in pediatric HSCT patients, particularly in the context of UCBT. PMID- 29608608 TI - Solution scattering study of the Bacillus subtilis PgdS enzyme involved in poly gamma-glutamic acids degradation. AB - The PgdS enzyme is a poly-gamma-glutamic (gamma-PGA) hydrolase, which has potential application for a controllable degradation of gamma-PGA by enzymatic depolymerization; however, the structure of PgdS is still unknown. Here, to study in detail the full-length PgdS structure, we analyze the low-resolution architecture of PgdS hydrolase from Bacillus subtilis in solution using small angle X-ray scattering (SAXS) method. Combining with other methods, like dynamic light scattering and mutagenesis analyses, a model for the full length structure and the possible substrate delivery route of PgdS are proposed. The results will provide useful hints for future investigations into the mechanisms of gamma-PGA degradation by the PgdS hydrolase and may provide valuable practical information. PMID- 29608609 TI - A novel encryption scheme for high-contrast image data in the Fresnelet domain. AB - In this paper, a unique and more distinctive encryption algorithm is proposed. This is based on the complexity of highly nonlinear S box in Flesnelet domain. The nonlinear pattern is transformed further to enhance the confusion in the dummy data using Fresnelet technique. The security level of the encrypted image boosts using the algebra of Galois field in Fresnelet domain. At first level, the Fresnelet transform is used to propagate the given information with desired wavelength at specified distance. It decomposes given secret data into four complex subbands. These complex sub-bands are separated into two components of real subband data and imaginary subband data. At second level, the net subband data, produced at the first level, is deteriorated to non-linear diffused pattern using the unique S-box defined on the Galois field [Formula: see text]. In the diffusion process, the permuted image is substituted via dynamic algebraic S-box substitution. We prove through various analysis techniques that the proposed scheme enhances the cipher security level, extensively. PMID- 29608610 TI - Strategic purchasing and health system efficiency: A comparison of two financing schemes in Thailand. AB - Strategic purchasing is an essential health financing function. This paper compares the strategic purchasing practices of Thailand's two tax-financed health insurance schemes, the Universal Coverage Scheme (UCS) and the Civil Servant Medical Benefit Scheme (CSMBS), and identifies factors contributing to successful universal health coverage outcomes by analysing the relationships between the purchaser and government, providers and members. The study uses a cross-sectional mixed-methods design, including document review and interviews with 56 key informants. The Comptroller General Department (CGD) of Ministry of Finance manages CSMBS as one among civil servant welfare programmes. Their purchasing is passive. Fee for service payment for outpatient care has resulted in rapid cost escalation and overspending of their annual budget. In contrast, National Health Security Office (NHSO) manages purchasing for UCS, which undertakes a range of strategic purchasing actions, including applying closed ended provider payment, promoting primary healthcare's gate keeping functions, exercising collective purchasing power and engaging views of members in decision making process. This difference in purchasing arrangements resulted in expenditure per CSMBS member being 4 times higher than UCS in 2014. The governance of the purchaser organization, the design of the purchasing arrangements including incentives and use of information, and the institutional capacities to implement purchasing functions are essential for effective strategic purchasing which can improve health system efficiency as a whole. PMID- 29608611 TI - Specifically bound lambda repressor dimers promote adjacent non-specific binding. AB - Genetic switches frequently include DNA loops secured by proteins. Recent studies of the lambda bacteriophage repressor (CI), showed that this arrangement in which the protein links two sets of three operators separated by approximately 2.3 kbp, optimizes both the stability and dynamics of DNA loops, compared to an arrangement with just two sets of two operators. Because adjacent dimers interact pairwise, we hypothesized that the odd number of operators in each set of the lambda regulatory system might have evolved to allow for semi-specific, pair-wise interactions that add stability to the loop while maintaining it dynamic. More generally, additional CI dimers may bind non-specifically to flanking DNA sequences making the genetic switch more sensitive to CI concentration. Here, we tested this hypothesis using spectroscopic and imaging approaches to study the binding of the lambda repressor (CI) dimer protein to DNA fragments. For fragments with only one operator and a short flanking sequence, fluorescence correlation spectroscopy measurements clearly indicated the presence of two distinct DNA-CI complexes; one is thought to have a non-specifically bound CI dimer on the flanking sequence. Scanning force micrographs of CI bound to DNA with all six operators revealed wild-type or mutant proteins bound at operator positions. The number of bound, wild-type proteins increased with CI concentration and was larger than expected for strictly specific binding to operators. In contrast, a mutant that fails to oligomerize beyond a dimer, D197G, only bound to operators. These data are evidence that CI cooperativity promotes oligomerization that extends from operator sites to influence the thermodynamics and kinetics of CI-mediated looping. PMID- 29608612 TI - Structural priming in sentence comprehension: A single prime is enough. AB - Experiencing a syntactic structure affects how we process subsequent instances of that structure. This phenomenon, called structural priming, is observed both in language production and in language comprehension. However, while abstract syntactic structures can be primed independent of lexical overlap in sentence production, evidence for structural priming in comprehension is more elusive. In addition, when structural priming in comprehension is found, it can often be accounted for in terms of participants' explicit expectations. Participants may use the structural repetition over several sentences and build expectations, which create a priming effect. Here, we use a new experimental paradigm to investigate structural priming in sentence comprehension independent of lexical overlap and of participants' expectations. We use an outcome dependent variable instead of commonly used online measures, which allows us to more directly compare these effects with those found in sentence production studies. We test priming effects in syntactically homogeneous and heterogeneous conditions on a sentence-picture matching task that forces participants to fully parse the sentences. We observe that, while participants learn the structural regularity in the homogeneous condition, structural priming is also found in the heterogeneous condition, in which participants do not expect any particular structure. In fact, we find that a single prime is enough to trigger priming. Our results indicate that-like in sentence production-structural priming can be observed in sentence comprehension without lexical repetition and independent of participants' expectation. PMID- 29608614 TI - Successional dynamics of marine fouling hydroids (Cnidaria: Hydrozoa) at a finfish aquaculture facility in the Mediterranean Sea. AB - Aquaculture is increasing rapidly to meet global seafood demand. Some hydroid populations have been linked to mortality and health issues in finfish and shellfish, but their dynamics in and around aquaculture farms remain understudied. In the present work, two experiments, each with 36 panels, tested colonization (factors: depth, season of immersion) and succession (factors: depth, submersion duration) over one year. Hydroid surface cover was estimated for each species, and data were analyzed with multivariate techniques. The assemblage of hydrozoans was species-poor, although species richness, frequency and abundance increased with time, paralleling the overall increase in structural complexity of fouling assemblages. Submersion duration and season of immersion were particularly important in determining the species composition of the assemblages in the succession and colonization experiments, respectively. Production of water-borne propagules, including medusae, from the hydroids was observed from locally abundant colonies, among them the well-known fouling species Obelia dichotoma, potentially representing a nuisance for cultured fish through contact-driven envenomations and gill disorders. The results illustrate the potential importance of fouling hydroids and their medusae to the health of organisms in the aquaculture industry. PMID- 29608613 TI - Proteomic fingerprinting in HIV/HCV co-infection reveals serum biomarkers for the diagnosis of fibrosis staging. AB - BACKGROUND: Hepatic complications of hepatitis C virus (HCV), including fibrosis and cirrhosis are accelerated in human immunodeficiency virus (HIV)-infected individuals. Although, liver biopsy remains the gold standard for staging HCV associated liver disease, this test can result in serious complications and is subject to sampling errors. These challenges have prompted a search for non invasive methods for liver fibrosis staging. To this end, we compared serum proteome profiles at different stages of fibrosis in HIV/HCV co- and HCV mono infected patients using surface-enhanced laser desorption ionization time-of flight mass spectrometry (SELDI-TOF MS). METHODS: Sera from 83 HIV/HCV co- and 68 HCV mono-infected subjects in 4 stages of fibrosis were tested. Sera were fractionated, randomly applied to protein chip arrays (IMAC, CM10 and H50) and spectra were generated at low and high laser intensities. RESULTS: Sixteen biomarkers achieved a p value < 0.01 (ROC values > 0.75 or < 0.25) predictive of fibrosis status in co-infected individuals and 14 in mono infected subjects. Five of these candidate biomarkers contributed to both mono- and co-infected subjects. Candidate diagnostic algorithms were created to distinguish between non-fibrotic and fibrotic individuals using a panel of 4 biomarker peaks. CONCLUSION: These data suggest that SELDI MS profiling can identify diagnostic serum biomarkers for fibrosis that are both common and distinct in HIV/HCV co-infected and HCV mono infected individuals. PMID- 29608615 TI - Executive function associated with sexual risk in young South African women: Findings from the HPTN 068 cohort. AB - PURPOSE: Heightened sexual risk in adolescence and young adulthood may be partially explained by deficits in executive functioning, the set of cognitive processes used to make reasoned decisions. However, the association between executive function and sexual risk is understudied among adolescent girls and young women, particularly in low- and middle-income countries. METHODS: In a cohort of 853 young women age 18-25 in rural Mpumalanga province, South Africa, we evaluated executive function with three non-verbal cognitive tests: I. a rule finding test, II. a trail-making test, and III. a figure drawing test. Using log binomial regression models, we estimated the association between lower executive function test scores and indicators of sexual risk (unprotected sex acts, concurrent partnerships, transactional sex, and recent HSV-2 infection). RESULTS: In general, young women with lower executive function scores reported higher frequencies of sexual risk outcomes, though associations tended to be small with wide confidence intervals. Testing in the lowest quintile of Test I was associated with more unprotected sex [aPR (95% CI): 1.4 (1.0, 1.8)]. Testing in the lowest quintile of Test II was associated with more concurrent relationships and transactional sex [aPR (95% CI): 1.6 (1.1, 2.5) and 1.7 (1.3, 2.4), respectively], and testing in the lowest four quintiles of Test III was associated with more concurrent relationships [aPR (95% CI): 1.7 (1.0, 2.7)]. CONCLUSIONS: These results demonstrate an association between low executive function and sexual risk in South African young women. Future work should seek to understand the nature of this association and whether there is promise in developing interventions to enhance executive function to reduce sexual risk. PMID- 29608616 TI - Factors associated with linkage to HIV care and TB treatment at community-based HIV testing services in Cape Town, South Africa. AB - BACKGROUND: Diagnosing HIV and/or TB is not sufficient; linkage to care and treatment is conditional to reduce the burden of disease. This study aimed to determine factors associated with linkage to HIV care and TB treatment at community-based services in Cape Town, South Africa. METHODS: This retrospective cohort study utilized routinely collected data from clients who utilized stand alone (fixed site not attached to a health facility) and mobile HIV testing services in eight communities in the City of Cape Town Metropolitan district, between January 2008 and June 2012. Clients were included in the analysis if they were >=12 years and had a known HIV status. Generalized estimating equations (GEE) logistic regression models were used to assess the association between determinants (sex, age, HIV testing service and co-infection status) and self reported linkage to HIV care and/or TB treatment. RESULTS: Linkage to HIV care was 3 738/5 929 (63.1%). Linkage to HIV care was associated with the type of HIV testing service. Clients diagnosed with HIV at mobile services had a significantly reduced odds of linking to HIV care (aOR 0.7 (CI 95%: 0.6-0.8), p<0.001. Linkage to TB treatment was 210/275 (76.4%). Linkage to TB treatment was not associated with sex and service type, but was associated with age. Clients in older age groups were less likely to link to TB treatment compared to clients in the age group 12-24 years (all, p-value<0.05). CONCLUSION: A large proportion of clients diagnosed with HIV at mobile services did not link to care. Almost a quarter of clients diagnosed with TB did not link to treatment. Integrated community-based HIV and TB testing services are efficient in diagnosing HIV and TB, but strategies to improve linkage to care are required to control these epidemics. PMID- 29608617 TI - Prevalence and risk factors of sexually transmitted infections among French service members. AB - INTRODUCTION: Sexually Transmitted Infections (STIs) have always represented a public health concern in the military, yet most studies rely on self-reports among non-random samples of military populations. In addition, most of the studies exploring STI rates among the military focus on US service members. This paper assesses the prevalence and correlates of STIs in the French military using biomarkers and compares self-reported versus diagnosed STIs. METHODS: Data are drawn from the COSEMIL study, a national sexual health survey conducted in the French military in 2014 and 2015. A random sample of 784 men and 141 women aged 18-57 years completed a self-administered questionnaire and provided biological samples for STI testing. We used logistic regression modeling to identify the correlates of STI diagnosis and self-reports. RESULTS: The prevalence of diagnosed STIs was 4.7% [3.8-5.9], mostly due to Chlamydia trachomatis. This rate was four times higher than the 12 months self-reported rate of 1.1% [0.6-2.3]. Reported STI rates were similar among men and women (1.1% versus 1.8%), but diagnosed STI rates were twice as high among females versus males (10.4% versus 4.1%, p = 0.007). There were significant differences in the determinants of reported versus diagnosed STIs. In particular, age and sexual orientation were associated with reported STIs, but not with diagnosed STIs. Conversely, STI counseling and depression were associated with STI diagnosis but not with STI reports. CONCLUSION: This study underlines the need to use biomarkers in population-based surveys, given the differential and substantial underreporting of STIs. Results also highlight the need for programmatic adaptation to address gender inequalities in STI rates, by developing women's health services in the French military. Addressing such needs not only benefits women but could also serve as a strategy to reduce overall STI rates as most military women have military partners, increasing the risk of internal transmission. PMID- 29608618 TI - Association between pregnancy at enrollment into HIV care and loss to care among women in the Democratic Republic of Congo, 2006-2013. AB - BACKGROUND: Loss to care is high among asymptomatic HIV-infected women initiated on antiretroviral therapy (ART) during pregnancy or in the postpartum period. However, whether pregnancy itself plays a role in the high loss to care rate is uncertain. We compared loss to care over seven years between pregnant and non pregnant women at enrollment into HIV care in the Democratic Republic of Congo (DRC). METHODS: We conducted a retrospective analysis of all ART-naive women aged 15-45 initiating HIV care at two large clinics in Kinshasa, DRC, from 2007-2013. Pregnancy status was recorded at care enrollment. Patients were classified as having no follow-up if they did not return to care after the initial enrollment visit. Among those with at least one follow-up visit after enrollment, we classified patients as lost to care if more than 365 days had passed since their last clinic visit. We used logistic regression to model the association between pregnancy status and no follow-up, and Cox proportional hazards regression to model the association between pregnancy status and time to loss to care. RESULTS: Of 2175 women included in the analysis, 1497 (68.8%) were pregnant at enrollment. Compared to non-pregnant women, pregnant women were less likely to be over 35 years of age (19.1% vs. 31.9%, p<0.0001) and less likely to be in WHO stage III or IV (9.0% vs. 26.3%, p<0.0001). Among pregnant women, 106 (7.1%) were not seen after enrollment, versus 25 (3.7%) non-pregnant women (adjusted odds ratio 2.01, 95% CI 1.24-3.24). Of the 2,044 women with at least one follow-up visit, 46.5% of pregnant women and 46.7% of non-pregnant women were lost to care by 5 years; hazards of loss to care were similar for pregnant and non-pregnant women (adjusted hazard ratio 1.08, 95% CI 0.93-1.26). CONCLUSIONS: In this large cohort of HIV-infected women, patients pregnant at care enrollment were more likely to never return for follow-up. Among those who attended at least one follow-up visit, loss to care was not different between pregnant and non-pregnant women, suggesting that pregnancy itself may not be the main driver of the high attrition observed in this cohort. PMID- 29608619 TI - Genome-wide pleiotropy and shared biological pathways for resistance to bovine pathogens. AB - Host genetic architecture is a major factor in resistance to pathogens and parasites. The collection and analysis of sufficient data on both disease resistance and host genetics has, however, been a major obstacle to dissection the genetics of resistance to single or multiple pathogens. A severe challenge in the estimation of heritabilities and genetic correlations from pedigree-based studies has been the confounding effects of the common environment shared among relatives which are difficult to model in pedigree analyses, especially for health traits with low incidence rates. To circumvent this problem we used genome wide single-nucleotide polymorphism data and implemented the Genomic-Restricted Maximum Likelihood (G-REML) method to estimate the heritabilities and genetic correlations for resistance to 23 different infectious pathogens in calves and cows in populations undergoing natural pathogen challenge. Furthermore, we conducted gene-based analysis and generalized gene-set analysis to understand the biological background of resistance to infectious diseases. The results showed relatively higher heritabilities of resistance in calves than in cows and significant pleiotropy (both positive and negative) among some calf and cow resistance traits. We also found significant pleiotropy between resistance and performance in both calves and cows. Finally, we confirmed the role of the B lymphocyte pathway as one of the most important biological pathways associated with resistance to all pathogens. These results both illustrate the potential power of these approaches to illuminate the genetics of pathogen resistance in cattle and provide foundational information for future genomic selection aimed at improving the overall production fitness of cattle. PMID- 29608620 TI - High density SNP mapping and QTL analysis for time of leaf budburst in Corylus avellana L. AB - The growing area of European hazelnut (Corylus avellana L.) is increasing, as well as the number of producing countries, and there is a pressing need for new improved cultivars. Hazelnut conventional breeding process is slow, due to the length of juvenile phase and the high heterozygosity level. The development of genetic linkage maps and the identification of molecular markers tightly linked to QTL (quantitative trait loci) of agronomic interest are essential tools for speeding up the selection of seedlings carrying desired traits through marker assisted selection. The objectives of this study were to enrich a previous linkage map and confirm QTL related to time of leaf budburst, using an F1 population obtained by crossing Tonda Gentile delle Langhe with Merveille de Bollwiller. Genotyping-by-Sequencing was used to identify a total of 9,999 single nucleotide polymorphism markers. Well saturated linkage maps were constructed for each parent using the double pseudo-testcross mapping strategy. A reciprocal translocation was detected in Tonda Gentile delle Langhe between two non homologous chromosomes. Applying a bioinformatic approach, we were able to disentangle 'pseudo-linkage' between markers, removing markers around the translocation breakpoints and obtain a linear order of the markers for the two chromosomes arms, for each linkage group involved in the translocation. Twenty nine QTL for time of leaf budburst were identified, including a stably expressed region on LG_02 of the Tonda Gentile delle Langhe map. The stability of these QTL and their coding sequence content indicates promise for the identification of specific chromosomal regions carrying key genes involved in leaf budburst. PMID- 29608621 TI - Genetic characterization of the oxytocin-neurophysin I gene (OXT) and its regulatory regions analysis in domestic Old and New World camelids. AB - Oxytocin is a neurohypophysial peptide linked to a wide range of biological functions, including milk ejection, temperament and reproduction. Aims of the present study were a) the characterization of the OXT (Oxytocin-neurophysin I) gene and its regulatory regions in Old and New world camelids; b) the investigation of the genetic diversity and the discovery of markers potentially affecting the gene regulation. On average, the gene extends over 814 bp, ranging between 825 bp in dromedary, 811 bp in Bactrian and 810 bp in llama and alpaca. Such difference in size is due to a duplication event of 21 bp in dromedary. The main regulatory elements, including the composite hormone response elements (CHREs), were identified in the promoter, whereas the presence of mature microRNAs binding sequences in the 3'UTR improves the knowledge on the factors putatively involved in the OXT gene regulation, although their specific biological effect needs to be still elucidated. The sequencing of genomic DNA allowed the identification of 17 intraspecific polymorphisms and 69 nucleotide differences among the four species. One of these (MF464535:g.622C>G) is responsible, in alpaca, for the loss of a consensus sequence for the transcription factor SP1. Furthermore, the same SNP falls within a CpG island and it creates a new methylation site, thus opening future possibilities of investigation to verify the influence of the novel allelic variant in the OXT gene regulation. A PCR-RFLP method was setup for the genotyping and the frequency of the allele C was 0.93 in a population of 71 alpacas. The obtained data clarify the structure of OXT gene in domestic camelids and add knowledge to the genetic variability of a genomic region, which has received little investigation so far. These findings open the opportunity for new investigations, including association studies with productive and reproductive traits. PMID- 29608622 TI - A novel Triclosan Methacrylate-based composite reduces the virulence of Streptococcus mutans biofilm. AB - The use of antimicrobial monomers, linked to the polymer chain of resin composites, is an interesting approach to circumvent the effects of bacteria on the dental and material surfaces. In addition, it can likely reduce the incidence of recurrent caries lesions. The aim of this study was to evaluate the effects of a novel Triclosan Methacrylate (TM) monomer, which was developed and incorporated into an experimental resin composite, on Streptococcus mutans (S. mutans) biofilms, focusing on the analyses of vicR, gtfD, gtfC, covR, and gbpB gene expression, cell viability and biofilm characteristics. The contact time between TM-composite and S. mutans down-regulated the gbpB and covR and up-regulated the gtfC gene expression, reduced cell viability and significantly decreased parameters of the structure and characteristics of S. mutans biofilm virulence. The presence of Triclosan Methacrylate monomer causes harmful effects at molecular and cellular levels in S. mutans, implying a reduction in the virulence of those microorganisms. PMID- 29608623 TI - Lipid and fatty acid dynamics in mature female albacore tuna (Thunnus alalunga) in the western Indian Ocean. AB - Lipid composition in the reproductive and somatic tissues were investigated for female albacore tuna, Thunnus alalunga, in the western Indian Ocean, between latitude 18-21 degrees S and longitude 56-60 degrees E, from January 2014 to March 2015. Highest total lipids (TL) were found in the gonads of spawning capable females (SCP) (mainly phospholipids, PL, triacylglycerols, TAG and wax esters, WE) and in the liver of females in the late regressing and regenerating ovary phases (mainly TAG, PL and sterols, ST). Muscle TL was low but exhibited high inter-individual variability. Correlations between gonadosomatic and hepatosomatic indices with TL and the lipid classes in albacore gonads and liver describes a pattern of reallocation of energy from the liver to the gonads during SCP. Female albacore were also observed to pursue foraging activities even during this period. Therefore, female albacore can be considered as a capital-income breeder relying mostly on stored lipids before the onset of reproduction and to a lesser extent on energy derived from concurrent feeding during the spawning season. Overall, the three examined tissues had similar general fatty acid profiles with the dominance of 22:6omega3 (docosahexaenoic acid, DHA), 16:0, 18:0 and 18:1omega9. The proportions of fatty acids varied with maturity stage and ovary lobe, with the smaller lobe having significantly higher proportions of essential fatty acids, as well as 16:0 and 18:1n9, compared to the larger one. Our results provide new information on the life-history and energy allocation strategy of albacore which will assist fisheries managers. PMID- 29608625 TI - Thinking too much is bad for some brains. PMID- 29608624 TI - Association between rural clinical clerkship and medical students' intentions to choose rural medical work after graduation: A cross-sectional study in western China. AB - BACKGROUND: A large number of programs have been implemented in many countries to increase the healthcare workforce recruitment in rural and remote areas. Rural early exposure programs for medical students have been shown to be effective strategies. However, no related studies have been reported before in China. This study was carried out to determine the association between medical students' participation in rural clinical clerkships and their intentions to choose rural medical work after graduation from western medical schools in China. METHODS: Based on a two-stage random sampling method, the cross-sectional survey was carried out in ten western provinces in China. A brief questionnaire filled in by medical students was used for data collection. A total of 4278 medical students participated in the study. The response rate was approximately 90.34%. Pearson's chi-squared tests and binary logistic regression analyses were performed for data analyses. RESULTS: Approximately 52.0% of medical students disclosed intentions to work in rural medical institutions after graduation. Only one in five participants had experience with a rural clinical clerkship. Rural clinical clerkships were significantly associated with medical students' intentions to work in rural medical institutions (OR: 1.24, 95%CI: 1.05-1.46); further analyses indicated that such clerkships only had a significant impact among the medical students with an urban background (OR: 2.10, 95%CI: 1.48-2.97). In terms of the sociodemographic characteristics, younger age, low level of parental education, majoring in general practice, and studying in low-level medical schools increased the odds of having intentions to engage in rural medical work among medical students; however, rural origins was the only positive univariate predictor. In addition, the predictors of intentions to choose rural medical work were different between medical students with a rural background and those with an urban background. CONCLUSIONS: Rural clinical clerkship is likely to increase the odds of having intentions to work in rural medical institutions after graduation among medical students in western China, especially for those with an urban background. Related policy makers could consider developing compulsory rural clerkship programs and implement them among medical students to increase early rural exposure. PMID- 29608626 TI - On Mentoring. PMID- 29608627 TI - On the Practice of Medicine. PMID- 29608628 TI - AMA Code of Ethics: Roots, Revisions and Relevance Today. PMID- 29608629 TI - ED Doc for a Month. PMID- 29608630 TI - Why Aren't More Women in Academic Medicine Reaching the Top? PMID- 29608631 TI - Review of the public health risks of widespread cannabis use. AB - This article is a review of the public health risks of widespread cannabis use based on a recent review of the literature. The purpose of this article is to help physicians better educate the public about the dangers of widespread cannabis products. PMID- 29608632 TI - Sister Mary Joseph Nodule as Presenting Complaint in First Diagnosis of Intra Abdominal Malignancy. PMID- 29608633 TI - The Association Between Postpartum Healthcare Encounters and Contraceptive Use among Rhode Island Mothers, 2012-2015. PMID- 29608634 TI - Q&A: Clinical Faculty Advisory Committee (CFAC) at the medical school. PMID- 29608635 TI - Older Adult Normative Data for the Sniffin' Sticks Odor Identification Test. AB - Objective: The current study establishes normative Sniffin' Sticks Odor Identification Test (SS-OIT) scores for cognitively intact older adults. Method: Two hundred and twenty-six cognitively normal older adults were identified as eligible for the current study (Mean Age = 70.49 years; 71.7% female). Important demographic covariates were identified using step-wise regression, and a normative regression equation was developed. Results: Analyses of the effects of demographic variables (including age, education, and sex) on SS-OIT performance revealed that age was the only significant predictor, b = -0.07, SEb = .01, p < .01. A final regression equation was determined and normative data are reported in 5-year increments for a number of percentile ranks. Conclusions: Normative performance on the SS-OIT for adults over the age of 50 was established in a large and demographically diverse sample. These data are needed in order for clinicians to be able to include olfactory testing, a sensitive marker of neurodegeneration, in their assessment armamentarium. PMID- 29608636 TI - Four-Subtest Index-based Short Form of WAIS-IV: Psychometric Properties and Clinical Utility. AB - Short form of the Wechsler Adult Intelligence Scale is often needed to quickly estimate intelligence for time-saving or screening in clinical practice. The present study aims to examine the psychometric properties of Chinese version of the four-subtest index-based short form (SF4) of WAIS-IV (FS) and to confirm its clinical application. 1,757 adults from the WAIS-IV Chinese version standardization sample and 239 mixed clinical samples including patients with schizophrenia or schizoaffective disorder (SCH), obsessive-compulsive disorder (OCD), and mild or moderate intellectual disability (ID) were used. Demographic data were collected and intelligence was assessed with WAIS-IV. The SF4 split half reliability, test-retest stability coefficients and corrected SF4-FS correlations were good to excellent. The result of the Bland-Altman plot showed that the difference fell within 2SD was 95% and indicated a random error. The sensitivity, specificity positive predictive value (PPV), and negative predictive value (NPV) of the stepwise screening were good. There was an interaction (p < .001) between the IQ level (>=111) and gender on the accuracy of SF4, SF4 might get underestimated on females with the IQ level (>=111) than on males. In conclusion, SF4 is a valid and reliable instrument for use in the clinic, and its clinical application, stepwise screening and influencing factors in clinical use are discussed herein. PMID- 29608637 TI - NIH Toolbox Picture Sequence Memory Test for Assessing Clinical Memory Function: Diagnostic Relationship to the Rey Auditory Verbal Learning Test. AB - Background: The NIH Cognitive Toolbox Picture Sequence Memory Test (PSMT) was developed as a measure of learning ability. PSMT use in clinical populations is only beginning to be investigated. Method: PSMT performance was analyzed in a retrospective series of 221 patients referred to either the Deep Brain Stimulation Clinic (n = 128) for presurgical evaluation, or to the Cognitive Screening Clinic (n = 93). Patients were also administered the Rey Verbal Auditory Verbal Learning test (AVLT). In addition to correlation between measures, classification agreement was examined based upon performance ratings of normal (>16th percentile), borderline (5-16th percentile), or impaired (<5th percentile). Results: Correlation between measures was significant (r = 0.48, p < .0001), with classification agreement of 62% (weighted Kappa = 0.43). For patients with valid PVT scores (n = 147), correlation between tests was 0.67 (p < .0001) with a classification agreement of 72% (weighted Kappa = 0.44). Multiple level likelihood ratios (LRs) relating PSMT to various dichotomous AVLT learning classifications were modest, with the largest group LR obtained for impaired PSMT increasing the likelihood of obtaining impaired AVLT by 7.62 (95% CI = 3.54 16.42). Conclusion: Despite significant correlations between measures, the NIH Toolbox PSMT and AVLT learning score often generate different interpretive results. Impaired PSMT appears better at predicting impaired AVLT performance rather than predicting combined borderline/impaired AVLT performance. Ultimately, individual clinicians will need to determine whether the PSMT can be used independently without other memory tests in the clinical environment in which they practice while further validation studies are performed. PMID- 29608639 TI - Transition to Nonopioid Analgesia Does Not Impair Pain Control After Major Aesthetic Plastic Surgery. AB - Background: Multimodal analgesic protocols are increasingly favored over traditional opioid regimens due to decreased adverse side effects and reduced opioid consumption. Concomitant use of selective cyclooxygenase (COX)-2 inhibitor celecoxib and anticonvulsant gabapentin have been proposed to adequately control acute postoperative pain. Objectives: To determine efficacy of postoperative pain control using nonopioid pain regimen vs traditional opioids for all aesthetic plastic surgery procedures. Methods: A retrospective chart review was performed on 462 consecutive outpatient plastic surgery procedures by a single surgeon between November 2015 and July 2017. Procedures in the historical control group (n = 275) received traditional postoperative narcotic, hydrocodone-acetaminophen. Patients in the more recent nonopioid study group (n = 187) received a pre-, peri , and postoperative regimen of celecoxib and gabapentin. Results: Similar demographic characteristics between the control and study groups were observed: mean age, 39.7 vs 39.5 years; BMI, 24.6 vs 24.4 kg/m2; and ratio of female patients 92.7% vs 92.4%. A significant reduction in rescue analgesia (meperidine 44.6% vs 14.9%, P < 0.001) and antiemetic use (ondansetron 24.2% vs 16.3%, P < 0.05; promethazine 17.0% vs 4.7%, P < 0.001) in postanesthesia recovery unit (PACU) was noted in the nonopioid group compared to the control. The average stay in PACU also decreased in the study group (82 +/- 39 min vs 70 +/- 22 min, P < 0.001). Both groups reported low numbers of adverse events and need for additional pain prescriptions. These findings were reproducible in the breast subgroup. Conclusions: This nonopioid regimen is as effective as traditional opioid use for acute postoperative pain control and decreased recovery time for outpatient aesthetic plastic breast surgeries. Level of Evidence 3: PMID- 29608638 TI - MetaboCraft: building a Minecraft plugin for metabolomics. AB - Motivation: The rapid advances in metabolomics pose a significant challenge in presentation and interpretation of results. Development of new, engaging visual aids is crucial to advancing our understanding of new findings. Results: We have developed MetaboCraft, a Minecraft plugin which creates immersive visualizations of metabolic networks and pathways in a 3D environment and allows the results of user experiments to be viewed in this context, presenting a novel approach to exploring the metabolome. Availability and implementation: https://github.com/argymeg/MetaboCraft/; https://hub.docker.com/r/ronandaly/metabocraft/. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29608640 TI - LSMM: a statistical approach to integrating functional annotations with genome wide association studies. AB - Motivation: Thousands of risk variants underlying complex phenotypes (quantitative traits and diseases) have been identified in genome-wide association studies (GWAS). However, there are still two major challenges towards deepening our understanding of the genetic architectures of complex phenotypes. First, the majority of GWAS hits are in non-coding region and their biological interpretation is still unclear. Second, accumulating evidence from GWAS suggests the polygenicity of complex traits, i.e. a complex trait is often affected by many variants with small or moderate effects, whereas a large proportion of risk variants with small effects remain unknown. Results: The availability of functional annotation data enables us to address the above challenges. In this study, we propose a latent sparse mixed model (LSMM) to integrate functional annotations with GWAS data. Not only does it increase the statistical power of identifying risk variants, but also offers more biological insights by detecting relevant functional annotations. To allow LSMM scalable to millions of variants and hundreds of functional annotations, we developed an efficient variational expectation-maximization algorithm for model parameter estimation and statistical inference. We first conducted comprehensive simulation studies to evaluate the performance of LSMM. Then we applied it to analyze 30 GWAS of complex phenotypes integrated with nine genic category annotations and 127 cell-type specific functional annotations from the Roadmap project. The results demonstrate that our method possesses more statistical power than conventional methods, and can help researchers achieve deeper understanding of genetic architecture of these complex phenotypes. Availability and implementation: The LSMM software is available at https://github.com/mingjingsi/LSMM. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29608641 TI - Validation of a new prognostic model to easily predict outcome in renal cell carcinoma: the GRANT score applied to the ASSURE trial population. PMID- 29608642 TI - Downregulation of myosin VI reduced cell growth and increased apoptosis in human colorectal cancer. PMID- 29608643 TI - Prolonged Baby-Nursing-Related Sphygmomanometric Protection: Breast, Brain, Blood Biomolecules, or Bacteria? PMID- 29608644 TI - Prefrontal Oxytocin is Involved in Impairments in Prefrontal Plasticity and Social Memory Following Acute Exposure to High Fat Diet in Juvenile Animals. AB - Juvenility represents a critical developmental phase during which exposure to a high fat diet (HFD) can severely modify cognitive and emotional functioning. The purpose of this study was to address how short and acute exposure to a HFD during juvenility affects social memory recognition and prefrontal long-term potentiation (LTP). As LTP and social memory depend on the neuromodulator oxytocin (OXY) and due to its role in metabolism, we also examined the effects of OXY in mediating HFD-induced alterations in social memory and LTP. Our results show that short exposure to a HFD during juvenility impairs social preference memory and prefrontal LTP. Interestingly, whereas systemic injections of OXY reversed the impairments in HFD-fed animals and impaired LTP and memory in control animals; prefrontal injections of the OXY agonist TGOT reversed the effects in HFD animals without affecting control animals. Exposure to HFD was associated with a reduction in the levels of OXY in the prefrontal compared to control animals. Interestingly, the restoration of social memory by TGOT in HFD animals was also associated with normalization of OXY in the prefrontal. These results point to a role that prefrontal OXY has in mediating the effects of HFD on memory and plasticity. PMID- 29608645 TI - Distinct dynamic profiles of microglial activation are associated with progression of Alzheimer's disease. AB - Although brain neuroinflammation may play an instrumental role in the pathophysiology of Alzheimer's disease, its actual impact on disease progression remains controversial, being reported as either detrimental or protective. This work aimed at investigating the temporal relationship between microglial activation and clinical progression of Alzheimer's disease. First, in a large cohort of patients with Alzheimer's disease we analysed the predictive value of microglial activation assessed by 18F-DPA-714 PET imaging on functional, cognitive and MRI biomarkers outcomes after a 2-year follow-up. Second, we analysed the longitudinal progression of 18F-DPA-714 binding in patients with Alzheimer's disease by comparison with controls, and assessed its influence on clinical progression. At baseline, all participants underwent a clinical assessment, brain MRI, 11C-PiB, 18F-DPA-714 PET imaging and TSPO genotyping. Participants were followed-up annually for 2 years. At the end of the study, subjects were asked to repeat a second 18F-DPA-714-PET imaging. Initial 18F-DPA 714 binding was higher in prodromal (n = 33) and in demented patients with Alzheimer's disease (n = 19) compared to controls (n = 17). After classifying patients into slow and fast decliners according to functional (Clinical Dementia Rating change) or cognitive (Mini-Mental State Examination score decline) outcomes, we found a higher initial 18F-DPA-714 binding in slow than fast decliners. Negative correlations were observed between initial 18F-DPA-714 binding and the Clinical Dementia Rating Sum of Boxes score increase, the MMSE score loss and the progression of hippocampal atrophy. This suggests that higher initial 18F-DPA-714 binding is associated with better clinical prognosis. Twenty four patients with Alzheimer's disease and 15 control subjects performed a second DPA-PET. We observed an increase of 18F-DPA-714 in patients with Alzheimer's disease as compared with controls (mean 13.2% per year versus 4.2%) both at the prodromal (15.8%) and at the demented stages (8.3%). The positive correlations between change in 18F-DPA-714 binding over time and the three clinical outcome measures (Clinical Dementia Rating, Mini-Mental State Examination, hippocampal atrophy) suggested a detrimental effect on clinical Alzheimer's disease progression of increased neuroinflammation after the initial PET examination, without correlation with PiB-PET uptake at baseline. High initial 18F-DPA-714 binding was correlated with a low subsequent increase of microglial activation and favourable clinical evolution, whereas the opposite profile was observed when initial 18F-DPA-714 binding was low, independently of disease severity at baseline. Taken together, our results support a pathophysiological model involving two distinct profiles of microglial activation signatures with different dynamics, which differentially impact on disease progression and may vary depending on patients rather than disease stages. PMID- 29608646 TI - Quantification of Human Microbiome Stability Over 6 Months: Implications for Epidemiologic Studies. AB - Temporal variation in microbiome measurements can reduce statistical power in research studies. Quantification of this variation is essential for designing studies of chronic disease. We analyzed 16S ribosomal RNA profiles in paired biological specimens separated by 6 months from 3 studies conducted during 1985 2013 (a National Cancer Institute colorectal cancer study, a Costa Rica study, and the Human Microbiome Project). We evaluated temporal stability by calculating intraclass correlation coefficients (ICCs). Sample sizes needed in order to detect microbiome differences between equal numbers of cases and controls for a nested case-control design were calculated on the basis of estimated ICCs. Across body sites, 12 phylum-level ICCs were greater than 0.5. Similarly, 11 alpha diversity ICCs were greater than 0.5. Fecal beta-diversity estimates had ICCs over 0.5. For a single collection with most microbiome metrics, detecting an odds ratio of 2.0 would require 300-500 cases when matching 1 case to 1 control at P = 0.05. Use of 2 or 3 sequential specimens reduces the number of required subjects by 40%-50% for low-ICC metrics. Relative abundances of major phyla and alpha diversity metrics have low temporal stability. Thus, detecting associations of moderate effect size with these metrics will require large sample sizes. Because beta diversity for feces is reasonably stable over time, smaller sample sizes can detect associations with community composition. Sequential prediagnostic specimens from thousands of prospectively ascertained cases are required to detect modest disease associations with particular microbiome metrics. PMID- 29608648 TI - Conscientious objection in medicine: accommodation versus professionalism and the public good. AB - Introduction: In recent years questions have arisen about the moral justification for the accommodation of health care professionals who refuse, on conscience grounds as opposed to professional grounds, to provide particular professional services to eligible patients who request that kind of service. Source of data: Literature review. Areas of disagreement: Central to concerns about the accommodation claims of conscientious objectors is that health care professionals volunteer to join their professions that typically they are the monopoly providers of such services and that a health care professional's refusal to provide professional services on grounds that are not professional judgements amounts to unprofessional conduct. Defenders of conscientious objection maintain that in a liberal society respect for a professional's conscience is of sufficient importance that conscientious objectors ought to be accommodated. To deny conscientious objectors accommodation would reduce diversity in the health care professions, it would deny objectors unfairly equality of opportunity, and it would constitute a serious threat to the moral integrity of conscientious objectors. Growing points: The legal literature on the subject is growing due to the impossibility of satisfactory compromises. PMID- 29608647 TI - BART: a transcription factor prediction tool with query gene sets or epigenomic profiles. AB - Summary: Identification of functional transcription factors that regulate a given gene set is an important problem in gene regulation studies. Conventional approaches for identifying transcription factors, such as DNA sequence motif analysis, are unable to predict functional binding of specific factors and not sensitive enough to detect factors binding at distal enhancers. Here, we present binding analysis for regulation of transcription (BART), a novel computational method and software package for predicting functional transcription factors that regulate a query gene set or associate with a query genomic profile, based on more than 6000 existing ChIP-seq datasets for over 400 factors in human or mouse. This method demonstrates the advantage of utilizing publicly available data for functional genomics research. Availability and implementation: BART is implemented in Python and available at http://faculty.virginia.edu/zanglab/bart. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29608649 TI - The ROC curve for regularly measured longitudinal biomarkers. AB - The receiver operating characteristic (ROC) curve is a commonly used graphical summary of the discriminative capacity of a thresholded continuous scoring system for a binary outcome. Estimation and inference procedures for the ROC curve are well-studied in the cross-sectional setting. However, there is a paucity of research when both biomarker measurements and disease status are observed longitudinally. In a motivating example, we are interested in characterizing the value of longitudinally measured CD4 counts for predicting the presence or absence of a transient spike in HIV viral load, also time-dependent. The existing method neither appropriately characterizes the diagnostic value of observed CD4 counts nor efficiently uses status history in predicting the current spike status. We propose to jointly model the binary status as a Markov chain and the biomarkers levels, conditional on the binary status, as an autoregressive process, yielding a dynamic scoring procedure for predicting the occurrence of a spike. Based on the resulting prediction rule, we propose several natural extensions of the ROC curve to the longitudinal setting and describe procedures for statistical inference. Lastly, extensive simulations have been conducted to examine the small sample operational characteristics of the proposed methods. PMID- 29608650 TI - RP-HPLC-UV Method for Estimation of Fluorouracil-Epirubicin-Cyclophosphamide and Their Metabolite Mixtures in Human Plasma (Matrix). AB - A combination of 5-fluorouracil (FU), epirubicin (EP) and cyclophosphamide (CP) is routinely employed in the treatment of breast cancer. The objective of this study was to develop a reverse phase high-performance liquid chromatography (HPLC)-UV method for simultaneous quantitative analysis of the triple-drug and their metabolites in plasma. RP-HPLC system with a C18 column and a diode array detector was employed. The plasma samples were precipitated with acetonitrile and the supernatant was dried under a flow of nitrogen gas. The mobile phase comprised of two combinations, water (pH 4.0) and methanol (98:2 v/v), and water (pH 4.0):methanol:acetonitrile (70:13:17 v/v/v). The retention times for the compounds were determined and the parameters of validation established in plasma indicated the robustness and reliability. The corresponding HPLC peaks were confirmed using electron spray ionization mass spectrometry. FU and metabolites had a recovery of >93%; EP, epirubicinol and CP were >78% from plasma. Stability at 28-30 degrees C in water (pH 4.0) of FU, 5,6-dihydro-5-fluorouracil and EP were higher followed by CP, EPol, fluorodeoxyuridine and fluorouridine (FUR). Storage of the drug-spiked plasma at -80 degrees C assessed for 72 h showed a small but significant (P < 0.05) change in the recovery of FUR and EP. The method was validated in patient's plasma samples (n = 6). PMID- 29608651 TI - High performance thin-layer and high performance liquid chromatography coupled with photodiode array and fluorescence detectors for analysis of valsartan and sacubitril in their supramolecular complex with quantitation of sacubitril related substance in raw material and tablets. AB - Valsartan (VAL) and sacubitril (SAC) are combined in a supramolecular complex, LCZ696, which is a newly approved remedy for heart failure. SAC-related substance (biphenyl methyl pyrrolidinone [BMP]) which also appears as an intermediate during SAC synthesis is considered to be a suspected impurity for SAC and/or LCZ696 tablets. The study investigates the analysis of VAL and SAC in their supramolecular complex along with SAC-related substance, BMP, using high performance thin-layer chromatography (HPTLC) and high performance liquid chromatography (HPLC) with two different detectors; fluorescence detector (FLD) and diode array detector (DAD). The work aimed at analyzing BMP at low levels in the presence of its parent drug, SAC. BMP was successfully analyzed at a level of 0.167, 1 and 3% of its parent drug, SAC upon using HPLC-FLD, HPLC-DAD and HPTLC, respectively. For HPLC-FLD, the detector was set at lambdaex/lambdaem (nm/nm): 0 4.5 min at 255/374; 4.5-6 min at 255/314, for achieving an adequate sensitivity of the method to monitor and quantify VAL and SAC in the presence of BMP. Low limits of detection (8.3, 3.3 and 1.7 ng mL-1) and limits of quantitation (25, 10 and 5 ng mL-1) values obtained for VAL, SAC and BMP, respectively, upon using FLD suggest that low level of baseline noise enables the detection and quantitation of low BMP concentration. PMID- 29608653 TI - Commentary on: Reassessing Surgical Management of the Bony Vault in Rhinoplasty. PMID- 29608652 TI - Targeting Gpr52 lowers mutant HTT levels and rescues Huntington's disease associated phenotypes. AB - See Huang and Gitler (doi:10.1093/brain/awy112) for a scientific commentary on this article.Lowering the levels of disease-causing proteins is an attractive treatment strategy for neurodegenerative disorders, among which Huntington's disease is an appealing disease for testing this strategy because of its monogenetic nature. Huntington's disease is mainly caused by cytotoxicity of the mutant HTT protein with an expanded polyglutamine repeat tract. Lowering the soluble mutant HTT may reduce its downstream toxicity and provide potential treatment for Huntington's disease. This is hard to achieve by small-molecule compound drugs because of a lack of effective targets. Here we demonstrate Gpr52, an orphan G protein-coupled receptor, as a potential Huntington's disease drug target. Knocking-out Gpr52 significantly reduces mutant HTT levels in the striatum and rescues Huntington's disease-associated behavioural phenotypes in a knock-in Huntington's disease mouse model expressing endogenous mutant Htt. Importantly, a novel Gpr52 antagonist E7 reduces mutant HTT levels and rescues Huntington's disease-associated phenotypes in cellular and mouse models. Our study provides an entry point for Huntington's disease drug discovery by targeting Gpr52. PMID- 29608655 TI - Symptom Reporting Patterns of US Military Service Members with a History of Concussion According to Duty Status. AB - Objective: To compare symptom reporting patterns of service members with a history of concussion based on work status: full duty, limited duty, or in the Medical Evaluation Board (MEB)/disability process. Methods: Retrospective analysis of 181 service members with a history of concussion (MEB n = 56; limited duty n = 62; full duty n = 63). Neurobehavioral Symptom Inventory (NSI) Validity 10 cutoff (>22) and Mild Brain Injury Atypical Symptoms Scale (mBIAS) cutoffs (>=10 and >=8) were used to evaluate potential over-reporting of symptoms. Results: The MEB group displayed significantly higher NSI scores and significantly higher proportion scored above the mBIAS >=10 cutoff (MEB = 15%; limited duty = 3%; full duty = 5%). Validity-10 cutoff did not distinguish between groups. Conclusions: MEB but not limited duty status was associated with increased risk of over-reporting symptoms in service members with a history of concussion. Results support the use of screening measures for over-reporting in the MEB/disability samples. PMID- 29608654 TI - The ventrolateral medulla and medullary raphe in sudden unexpected death in epilepsy. AB - Sudden unexpected death in epilepsy (SUDEP) is a leading cause of premature death in patients with epilepsy. One hypothesis proposes that sudden death is mediated by post-ictal central respiratory depression, which could relate to underlying pathology in key respiratory nuclei and/or their neuromodulators. Our aim was to investigate neuronal populations in the ventrolateral medulla (which includes the putative human pre-Botzinger complex) and the medullary raphe. Forty brainstems were studied comprising four groups: 14 SUDEP, six epilepsy controls, seven Dravet syndrome cases and 13 non-epilepsy controls. Serial sections through the medulla (from obex 1 to 10 mm) were stained for Nissl, somatostatin, neurokinin 1 receptor (for pre-Botzinger complex neurons) and galanin, tryptophan hydroxylase and serotonin transporter (neuromodulatory systems). Using stereology total neuronal number and densities, with respect to obex level, were measured. Whole slide scanning image analysis was used to quantify immunolabelling indices as well as co-localization between markers. Significant findings included reduction in somatostatin neurons and neurokinin 1 receptor labelling in the ventrolateral medulla in sudden death in epilepsy compared to controls (P < 0.05). Galanin and tryptophan hydroxylase labelling was also reduced in sudden death cases and more significantly in the ventrolateral medulla region than the raphe (P < 0.005 and P < 0.05). With serotonin transporter, reduction in labelling in cases of sudden death in epilepsy was noted only in the raphe (P <= 0.01); however, co localization with tryptophan hydroxylase was significantly reduced in the ventrolateral medulla. Epilepsy controls and cases with Dravet syndrome showed less significant alterations with differences from non-epilepsy controls noted only for somatostatin in the ventrolateral medulla (P < 0.05). Variations in labelling with respect to obex level were noted of potential relevance to the rostro-caudal organization of respiratory nuclear groups, including tryptophan hydroxylase, where the greatest statistical difference noted between all epilepsy cases and controls was at obex 9-10 mm (P = 0.034), the putative level of the pre Botzinger complex. Furthermore, there was evidence for variation with duration of epilepsy for somatostatin and neurokinin 1 receptor. Our findings suggest alteration to neuronal populations in the medulla in SUDEP with evidence for greater reduction in neuromodulatory neuropeptidergic and mono-aminergic systems, including for galanin, and serotonin. Other nuclei need to be investigated to evaluate if this is part of more widespread brainstem pathology. Our findings could be a result of previous seizures and may represent a pathological risk factor for SUDEP through impaired respiratory homeostasis during a seizure. PMID- 29608656 TI - Fortune and hindsight: gene patents' muted effect on medical practice. AB - Introduction: Physicians have long worried about gene patents' potential to restrict their medical practices. Fortune and hindsight have proven these worries exaggerated both in the UK and elsewhere. Neither current nor future medical practices appear to be impinged by gene patents, although they may be subject to future intellectual property disputes. Sources of data: Qualitative and quantitative (survey) studies of gene patents' effects on medical practice; recent developments in patent law. Areas of agreement: Traditional gene patents do not appear to have restricted medical practice in the UK, although their effect elsewhere has been more nuanced. Areas of controversy: Whether patents will restrict the spread of newer medical technologies is unresolved. Areas timely for developing research: Continuing survey data on practitioners' views concerning patents' role in the distribution of newer technologies would be beneficial. PMID- 29608657 TI - Understanding sequencing data as compositions: an outlook and review. AB - Motivation: Although seldom acknowledged explicitly, count data generated by sequencing platforms exist as compositions for which the abundance of each component (e.g. gene or transcript) is only coherently interpretable relative to other components within that sample. This property arises from the assay technology itself, whereby the number of counts recorded for each sample is constrained by an arbitrary total sum (i.e. library size). Consequently, sequencing data, as compositional data, exist in a non-Euclidean space that, without normalization or transformation, renders invalid many conventional analyses, including distance measures, correlation coefficients and multivariate statistical models. Results: The purpose of this review is to summarize the principles of compositional data analysis (CoDA), provide evidence for why sequencing data are compositional, discuss compositionally valid methods available for analyzing sequencing data, and highlight future directions with regard to this field of study. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29608658 TI - Unusual Initial Abdominal Presentations of Invasive Meningococcal Disease. AB - Background: Invasive meningococcal disease (IMD) is recognized as septicemia and/or meningitis. However, early symptoms may vary and are frequently nonspecific. Early abdominal presentations have been increasingly described. We aimed to explore a large cohort of patients with initial abdominal presentations for association with particular meningococcal strains. Methods: Confirmed IMD cases in France between 1991 and 2016 were screened for the presence within the 24 hours before diagnosis of at least 1 of the following criteria (1) abdominal pain, (2) gastroenteritis with diarrhea and vomiting, or (3) diarrhea only. Whole genome sequencing was performed on all cultured isolates. Results: We identified 105 cases (median age, 19 years) of early abdominal presentations with a sharp increase since 2014. Early abdominal pain alone was the most frequent symptom (n = 67 [64%]), followed by gastroenteritis (n = 26 [25%]) and diarrhea alone (n = 12 [11%]). Twenty patients (20%) had abdominal surgery. A higher case fatality rate (24%) was observed in these cases compared to 10.4% in all IMD in France (P = .007) with high levels of inflammation markers in the blood. Isolates of group W were significantly more predominant in these cases compared to all IMD. Most of these isolates belonged to clonal complex 11 of the sublineages of the South American-UK strain. Conclusions: Abdominal presentations are frequently provoked by hyperinvasive isolates of meningococci. Delay in the management of these cases and the virulence of the isolates may explain the high fatality rate. Rapid recognition is a key element to improve their management. PMID- 29608661 TI - The scales of functional assessment of activities of daily living in geriatrics. PMID- 29608660 TI - Branched endografts in the aortic arch following open repair for DeBakey Type I aortic dissection. AB - OBJECTIVES: DeBakey Type I aortic dissections are frequently treated by an ascending aortic tube graft or hemiarch replacement with the residual dissection remaining untreated. We investigated the outcomes of branched thoracic endovascular repair for post-dissection aneurysms of the aortic arch. METHODS: We conducted a retrospective, single-centre evaluation of 20 consecutive patients with a false-lumen aneurysm after a DeBakey I aortic dissection treated with branched thoracic endovascular repair. The indication for endovascular repair was agreed on in an interdisciplinary case conference. Study end points were technical success, 30-day mortality rate, complications and late complications and reinterventions. RESULTS: Between 2012 and 2016, 20 patients (14 men, age 65 +/- 9 years) were treated for false-lumen aneurysm formation after a DeBakey Type I aortic dissection. All patients had undergone open ascending aortic repair either isolated (n = 16) or with partial arch repair (n = 4). Technical success was achieved in 19 of 20 cases. The 30-day mortality rate and incidence of stroke were each 5% (1/20). Simultaneous procedures to exclude false-lumen perfusion included implantation of a Knickerbocker graft in 3 (15%) patients and a candy plug graft in 7 (35%) patients. Early postoperative computed tomography angiography revealed persistent false-lumen perfusion in 10 cases that required secondary interventions in 6 cases. During 17 +/- 14 months of mean follow-up, there was 1 aortic-related death and 2 deaths of non-aortic reasons. The estimated overall survival was 89 +/- 7% and 75 +/- 15% at 12 and 36 months, respectively. CONCLUSIONS: Treatment of residual aortic arch dissections with branched thoracic endovascular repair appears feasible and safe with few deaths and low stroke rates. A high rate of secondary procedures is required to achieve thoracic false-lumen occlusion. PMID- 29608659 TI - Long-term Impact of Oral Azithromycin Taken by Gambian Women During Labor on Prevalence and Antibiotic Susceptibility of Streptococcus pneumoniae and Staphylococcus aureus in Their Infants: Follow-up of a Randomized Clinical Trial. AB - Background: Oral azithromycin given to women in labor decreases maternal and neonatal bacterial carriage but increases azithromycin-resistant bacteria during at least 4 weeks following the intervention. We assessed the prevalence of bacterial carriage and azithromycin resistance 12 months after treatment among study infants. Methods: Nasopharyngeal swabs (NPSs) were collected between November 2014 and May 2015 from children aged 11-13 months whose mothers had received azithromycin or placebo during labor. Streptococcus pneumoniae and Staphylococcus aureus were isolated using conventional microbiological methods. Antibiotic susceptibility was determined by disk diffusion and confirmed by Etest or VITEK-2. Results: NPSs were collected from 461 children. The prevalence of S. pneumoniae and S. aureus was similar between children from the azithromycin and placebo arms (85.0% vs 82.1%; odds ratio [OR], 1.23 [95% confidence interval {CI}, .73-2.08] for S. pneumoniae and 21.7% vs 21.3%; OR, 1.02 [95% CI, .64-1.64] for S. aureus). Prevalence of azithromycin-resistant S. pneumoniae was similar in both arms (1.8% vs 0.9% in children from the azithromycin and placebo arms, respectively; OR, 2.10 [95% CI, .30-23.38]); resistance to other antibiotics was also similar between arms. For S. aureus, there was no difference in azithromycin resistance between children in the azithromycin (3.1%) and placebo (2.6%) arms (OR, 1.22 [95% CI, .35-4.47]) or resistance to any other antibiotics. Conclusions: The higher prevalence of S. aureus azithromycin resistance observed among women treated during labor and their babies 4 weeks after treatment had waned 12 months after delivery. Azithromycin intervention did not induce other antibiotic resistance to S. pneumoniae or S. aureus. Clinical Trials Registration: NCT01800942. PMID- 29608663 TI - pyNBS: a Python implementation for network-based stratification of tumor mutations. AB - Summary: We present pyNBS: a modularized Python 2.7 implementation of the network based stratification (NBS) algorithm for stratifying tumor somatic mutation profiles into molecularly and clinically relevant subtypes. In addition to release of the software, we benchmark its key parameters and provide a compact cancer reference network that increases the significance of tumor stratification using the NBS algorithm. The structure of the code exposes key steps of the algorithm to foster further collaborative development. Availability and implementation: The package, along with examples and data, can be downloaded and installed from the URL https://github.com/idekerlab/pyNBS. PMID- 29608664 TI - What is the optimal surgical strategy for Stanford Type A acute aortic dissection in patients with a patent false lumen at the descending aorta? AB - OBJECTIVES: Aggressive total arch replacement (TAR) to obtain thrombosis of the distal false lumen (FL) in patients with Stanford Type A acute aortic dissection, particularly with a patent FL at the descending aorta, is discussed. The aim of this study was to examine the efficacy of our strategy. METHODS: In the last 20 years, we retrospectively reviewed the records of 518 patients with Type A acute aortic dissection who underwent an emergent surgery. Among them, 290 patients with a preoperative patent FL at the descending aorta were enrolled in this study. Patients were divided in 2 groups: the non-TAR group (n = 124; 68 +/- 14 years) and the TAR group (n = 166; 61 +/- 13 years). RESULTS: In-hospital mortality was 11% (32/290) without significant difference between the 2 groups (the non-TAR group 13% vs the TAR group 10%, P = 0.45). The rates of FL thrombosis of the entire descending aorta were detected at 32% in the non-TAR group and 41% in the TAR group (P = 0.16). Freedom from distal aortic dilatation >=50 mm was significantly higher in the TAR group (P = 0.03) than in the non-TAR group. Independent predictors of distal aortic dilatation >50 mm were patients in the non-TAR group (P = 0.01; hazard ratio 3.1, 95% confidence interval 1.28-8.05) and unachieved primary entry tear resection (P = 0.002; hazard ratio 6.2, 95% confidence interval 1.38-8.66). CONCLUSIONS: Our surgical strategy with an aggressive entry resection with higher rate of TAR was acceptable. In patients with a patent FL at the descending aorta, TAR should be considered to prevent the future growth of the distal aorta. PMID- 29608662 TI - Development of Reliable, Valid and Responsive Scoring Systems for Endoscopy and Histology in Animal Models for Inflammatory Bowel Disease. AB - Background and Aims: Although several endoscopic and histopathologic indices are available for evaluating the severity of inflammation in mouse models of colitis, the reliability of these scoring instruments is unknown. Our aim was to evaluate the reliability of the individual items in the existing indices and develop new scoring systems by selection of the most reliable index items. Methods: Two observers scored the histological slides [n = 224] and endoscopy videos [n = 201] from treated and untreated Interleukin[IL]-10 knock-out and T-cell transferred SCID mice. Intra-rater and inter-rater reliability for endoscopy and histology scores, and each individual item, were measured using intraclass correlation coefficients [ICCs]. The Mouse Colitis Histology Index [MCHI] and Mouse Colitis Endoscopy Index [MCEI] were developed using the most reliable items. Both were correlated to the colon density and to each other and were evaluated for their ability to detect changes in pathobiology. Results: The intraclass correlation coefficients (ICCs) for inter-rater agreement (95% CIs) for the total histology and endoscopy scores were 0.90 [0.87-0.92] and 0.80 [0.76-0.84], respectively. The MCHI and MCEI were highly correlated with colon density, with a Spearman Rho = 0.81[0.75-0.85] and 0.73 [0.66-0.79], respectively, and with each other, Spearman Rho = 0.71 [0.63-0.77]. The MCHI and MCEI were able to distinguish between the experimental groups within the models, with pairwise differences between the treated and untreated groups being statistically significant [p < 0.001]. Conclusions: These histological and endoscopic indices are valid and reliable measures of intestinal inflammation in mice, and they are responsive to treatment effects in pre-clinical studies. PMID- 29608665 TI - Transoesophageal echocardiography guided emergency valve-in-valve transcatheter aortic valve implantation. PMID- 29608666 TI - Success of palatal implants or mini-screws placed median or paramedian for the reinforcement of anchorage during orthodontic treatment: a systematic review. AB - Objectives: To assess the failure rates of palatal implants and palatal mini screws, independently and comparatively, used for supplementing anchorage during orthodontic treatment. Protocol and registration: The protocol was not registered prior to the study. This study was not registered in any publicly assessable database. Materials and methods: Screening for inclusion eligibility, quality assessment of studies, and data extraction was performed independently by two authors. The electronic databases MEDLINE, EMBASE, and CENTRAL, as well as unpublished literature, were searched with no restrictions on publication date or language using detailed strategies. The main outcome assessed was palatal implant or mini-screw failure. Randomized controlled trials were evaluated according to the Cochrane risk of bias tool. Prospective and retrospective studies were graded employing the adjusted predetermined criteria of Bondemark. Results: Twenty-seven studies satisfied the inclusion criteria. Four were RCTs of low risk of bias, 12 were prospective (2 low, 7 unclear, 3 high risk of bias) and 11 were retrospective studies (6 unclear, 5 high risk of bias). Only one retrospective study assessed both palatal implants and mini-screws. Seventeen studies, including the four RCTs, assessed solely palatal implants and nine studies palatal mini-screws. The median failure risk of palatal implants was 6.0 per cent (range: 0.0-26.1%) and of mini-screws 6.1 per cent (range: 0.0-33.3%). The median follow-up period was 17.9 months for palatal implants and 6 months for mini screws. Limitations: Significant clinical and methodological heterogeneity among studies and highly variable outcomes. Conclusions: Both palatal implants and mini screws have quite low failure rates that are also comparable, though the median follow-up period of palatal implants was quite larger. Therefore, in regular orthodontic cases, the choice between anchoring devices may rely on other factors, such as costs, patient comfort, personal preferences, familiarity with the device, and insertion procedures. PMID- 29608667 TI - Evaluation of a Hollow-Fiber Liquid-Phase Microextraction Technique for the Simultaneous Determination of PPI Drugs in Human Plasma by LC-DAD. AB - This study involved the development, validation and application of a three-phase hollow-fiber liquid-phase microextraction (HF-LPME) and liquid chromatography with diode array detection (LC-DAD) method for the simultaneous determination of the proton pump inhibitor (PPI) drugs omeprazole, pantoprazole and lansoprazole in human plasma. The evaluation of the HF-LPME parameters was crucial for the determination of the drugs and the conditions selected were: 1-octanol as solvent; phosphate buffer at pH 5 as donor phase; borate buffer at pH 10 as acceptor phase; extraction time of 15 min; stirring at 750 rpm and NaCl was added at 5% (w/v). Validation of the method according to US-FDA recommendations showed a good linear range (0.2-2.0 MUg/mL) for all analytes, with a determination coefficient >0.9910. Precision was evaluated using intra- and inter-day assays, which showed relative standard deviations (RSD), <15% for all concentrations, with a limit of quantification (LOQ) of 0.2 MUg/mL. Accuracy was also assessed at these concentration levels and was in the range from 80 to 130%. Finally, the sensitive, selective and reproducible HF-LPME/LC-DAD developed method was successfully applied to human plasma samples from patients undergoing therapy with the PPI drugs. PMID- 29608668 TI - Pericardial tunnel technique in the surgical management of the vertical form of scimitar syndrome. AB - OBJECTIVES: To optimize the surgical strategy and individualized treatment for scimitar syndrome (SS) by summarizing the clinical outcomes of the pericardial tunnel technique for the vertical form of SS at a single centre. METHODS: The vertical form was defined as an angle of scimitar vein (SV) insertion to the inferior vena cava (theta) <= 45 degrees , whereas the horizontal form was defined as theta > 45 degrees . Nine patients with vertical form were operated on from June 2011 to June 2017. The mean age of patients during surgery was 3.1 +/- 3.63 (range 0.3-12) years. Five patients were with infantile form and 4 with childhood/adult form per Dupuis' classification. The pericardial tunnel technique entailed attaching the SV to the right lateral pericardium and directing blood flow to the left atrium through a left atriotomy inside the pericardial tunnel. All patients had associated intracardiac anomalies repaired concomitantly; 3 patients had major collateral arteries occluded or ligated. RESULTS: There was no in-hospital postoperative death or residual SV obstruction. The postoperative ventilation time was 88.3 +/- 63.8 (range 36-264) h. Eight survivors were followed up for 33.4 +/- 19.2 (range 2-72) months, with 1 lost to follow-up. Echocardiography demonstrated that 7 survivors had no pulmonary hypertension and 1 had mild pulmonary hypertension; none developed SV obstruction during the follow-ups. CONCLUSIONS: The pericardial tunnel technique is suitable for the vertical form of SS and is a reasonable option for individualized treatment of SS. PMID- 29608669 TI - Predictors of post-operative cardiovascular events, focused on atrial fibrillation, after valve surgery for primary mitral regurgitation. AB - Aims: Primary mitral regurgitation (PMR) can be considered as a heterogeneous clinical disease. The optimal timing of valve surgery for severe PMR remains unknown. To determine whether unbiased clustering analysis using dense phenotypic data (phenomapping) could identify phenotypically distinct PMR categories of patients. Methods and results: One hundred and twenty-two patients who underwent surgery were analysed, excluding patients with pre-operative permanent atrial fibrillation (AF), were prospectively included before surgery. They were given an extensive echocardiographic evaluation before surgery, and clinical data were collected. These phenotypic variables were grouped in clusters using hierarchical clustering analysis. Then, different groups were created using a dedicated phenomapping algorithm. Post-operative outcomes were compared between the groups. The primary endpoint was post-operative cardiovascular events (PCE), defined as a composite of: deaths, AF, stroke, and rehospitalization. The secondary endpoint was post-operative AF. Data from three phenogroups with different characteristics and prognoses were identified. Phenogroup-1 (67 patients) was the reference group. Phenogroup-2 (33 patients) included intermediate-risk male and smoker patients with heart remodelling. Phenogroup-3 (22 patients) included older female patients with comorbidities (chronic renal failure, paroxysmal AF) and diastolic dysfunction. They had a higher risk of developing both PCE [(hazard ratio) HR = 3.57(1.72-7.44), P < 0.001] and post-operative AF [HR = 4.75(2.03-11.10), P < 0.001]. Pre-operative paroxysmal AF was identified as an independent risk factor for PCE. Conclusion: Classification of PMR can be improved using statistical learning algorithms to define therapeutically homogeneous patient subclasses. High-risk patients can be identified, and these patients should be carefully monitored and may even be treated earlier. PMID- 29608670 TI - Parsing the Potential Neuroendocrine Actions of FGF21 in Primates. AB - Fibroblast growth factor (FGF) 21, a unique, largely liver-derived endocrine member of the FGF superfamily, is often thought of as a fasting factor owing to its induction in rodents during starvation. However, FGF21 is not increased by fasting for periods of <7 days in humans; instead, it rises sharply after acute alcohol and sugar intake and also after several days of overfeeding, suggesting another role in states of positive energy balance. Recent studies suggest that in the postingestive state, FGF21 may regulate energy intake and discourage consumption of alcohol and sugars, most likely through effector circuits in the central nervous system. FGF21 also increases fat oxidation in the liver, improves markers of insulin sensitivity, and stimulates adiponectin production. Thus, in primates, FGF21 may defend against hepatic nutrient overload by promoting adaptations that reduce ectopic lipid storage, including inhibiting sugar and alcohol appetite and promoting lipid sequestration in adipose tissue. PMID- 29608671 TI - Working Memory Load Modulates Neuronal Coupling. AB - There is a severe limitation in the number of items that can be held in working memory. However, the neurophysiological limits remain unknown. We asked whether the capacity limit might be explained by differences in neuronal coupling. We developed a theoretical model based on Predictive Coding and used it to analyze Cross Spectral Density data from the prefrontal cortex (PFC), frontal eye fields (FEF), and lateral intraparietal area (LIP). Monkeys performed a change detection task. The number of objects that had to be remembered (memory load) was varied (1 3 objects in the same visual hemifield). Changes in memory load changed the connectivity in the PFC-FEF-LIP network. Feedback (top-down) coupling broke down when the number of objects exceeded cognitive capacity. Thus, impaired behavioral performance coincided with a break-down of Prediction signals. This provides new insights into the neuronal underpinnings of cognitive capacity and how coupling in a distributed working memory network is affected by memory load. PMID- 29608672 TI - 'It Opened My Eyes'-examining the impact of a multifaceted chlamydia testing intervention on general practitioners using Normalization Process Theory. AB - Background: Chlamydia is the most common notifiable sexually transmissible infection in Australia. Left untreated, it can develop into pelvic inflammatory disease and infertility. The majority of notifications come from general practice and it is ideally situated to test young Australians. Objectives: The Australian Chlamydia Control Effectiveness Pilot (ACCEPt) was a multifaceted intervention that aimed to reduce chlamydia prevalence by increasing testing in 16- to 29-year olds attending general practice. GPs were interviewed to describe the effectiveness of the ACCEPt intervention in integrating chlamydia testing into routine practice using Normalization Process Theory (NPT). Methods: GPs were purposively selected based on age, gender, geographic location and size of practice at baseline and midpoint. Interview data were analysed regarding the intervention components and results were interpreted using NPT. Results: A total of 44 GPs at baseline and 24 at midpoint were interviewed. Most GPs reported offering a test based on age at midpoint versus offering a test based on symptoms or patient request at baseline. Quarterly feedback was the most significant ACCEPt component for facilitating a chlamydia test. Conclusions: The ACCEPt intervention has been able to moderately normalize chlamydia testing among GPs, although the components had varying levels of effectiveness. NPT can demonstrate the effective implementation of an intervention in general practice and has been valuable in understanding which components are essential and which components can be improved upon. PMID- 29608673 TI - Mental health in primary care. PMID- 29608674 TI - Pharmacist interventions in high-risk obstetric inpatient unit: a medication safety issue. AB - Objectives: The aim of this study was to report number, type and severity of prescribing errors and pharmacist interventions in high-risk pregnant and postpartum women. Design: A prospective cross-sectional, observational study. Setting: A high-risk obstetric inpatient unit of a Women's Hospital in Brazil. Participants: About 1826 electronic prescriptions for 549 women in the high-risk obstetrics inpatient unit were included. Interventions: When the pharmacist detected potential prescribing errors, interventions were suggested. Main Outcome Measures: Prescriptions were evaluated by clinical pharmacist to identify the type, frequency and severity of prescribing errors and rate of clinical pharmacist intervention acceptance in a high-risk obstetric inpatient. Results: A total of 1826 prescriptions were reviewed with 128 errors (7.0%). The most frequent errors were drug interaction (43.8%), incorrect frequency (21.5%) and improper dose (13.1%). One-hundred and sixty-eight interventions were made by pharmacists, 98.8% of which were accepted by prescribers. Higher maternal age (OR 1.0 (95%CI 1.0-1.1)), higher number of prescribed medications (OR 1.2 (95%CI 1.1 1.3)), obstetric conditions (OR 2.2 (95%CI 1.4-3.3)) and non-breastfeeding postpartum women (OR 3.9 (95% CI 2.5-6.1)) were the independent factors associated with prescribing errors identified through multivariate analysis. Conclusions: The most common prescription errors related to drug interactions, incorrect frequency and higher number of prescribed medications. The rate of pharmacist acceptance intervention was high. PMID- 29608675 TI - Corrigendum: Bisphenol-A exposure and gene expression in human luteinized membrana granulosa cells in vitro. PMID- 29608676 TI - Is health literacy associated with greater medical care trust? AB - Objective: To examine the relationship between health literacy and trust in physicians and in the healthcare system. Design: A cross-sectional survey of a nationally representative sample of adults. Setting: Taiwan. Participants: Non institutionalized adults (N = 2199). Main measures: Trust in physicians was a composite measure assessing respondents' general trust in physicians and their perceptions of their physician's communication, medical skills, beneficence, honesty, confidentiality, respect and fairness. Trust in the healthcare system was a single-item measure. Health literacy was measured by four items. Results: Respondents with higher health literacy had, overall, higher levels of trust in physicians (P<0.001) and in the healthcare system (P = 0.04). Health literacy remained significantly and positively associated with trust in physicians (P<0.001) and in the healthcare system (P = 0.001) after adjusting for respondents' sociodemographic characteristics. Conclusions: Our findings demonstrate that health literacy is positively associated with trust. Actionable plans targeting health literacy at the national and local levels to establish a health literate care environment may contribute to enhancing trust in physicians and the healthcare system. PMID- 29608677 TI - Regional GABA Concentrations Modulate Inter-network Resting-state Functional Connectivity. AB - Coordinated activity within and differential activity between large-scale neuronal networks such as the default mode network (DMN) and the control network (CN) is a critical feature of brain organization. The CN usually exhibits activations in response to cognitive tasks while the DMN shows deactivations; in addition, activity between the two networks is anti-correlated at rest. To address this issue, we used functional MRI to measure whole-brain BOLD signal during resting-state and task-evoked conditions, and MR spectroscopy (MRS) to quantify GABA and glutamate concentrations, in nodes within the DMN and CN (MPFC and DLPFC, respectively) in 19 healthy individuals at 3 Tesla. We found that GABA concentrations in the MPFC were significantly associated with DMN deactivation during a working memory task and with anti-correlation between DMN and CN at rest and during task performance, while GABA concentrations in the DLPFC weakly modulated DMN-CN anti-correlation in the opposite direction. Highlighting specificity, glutamate played a less significant role related to brain activity. These findings indicate that GABA in the MPFC is potentially involved in orchestrating between-network brain activity at rest and during task performance. PMID- 29608679 TI - A left atrial versus a biatrial lesion set for persistent atrial fibrillation ablation during open heart surgery. AB - OBJECTIVES: To compare the outcomes of left atrial ablation and biatrial (BA) ablation in patients with persistent and long-standing persistent atrial fibrillation undergoing open heart surgery. METHODS: Between January 2007 and December 2016, 588 consecutive patients with either persistent (20.9%) or long standing persistent atrial fibrillation (79.1%) were enrolled in this study. To reduce between-group differences, propensity score-matched groups (156 patients/group) were obtained, with similar preoperative and perioperative characteristics. RESULTS: The propensity score-matched left atrial and BA groups did not differ regarding 30-day mortality (1.9% vs 0.6%; P = 0.617), 5-year overall survival (93.5 +/- 2.2% vs 92.8 +/- 2.9%, P = 0.998) or survival free from thromboembolic events (97.1 +/- 2.8% vs 96.2 +/- 2.7%, P = 0.309). The BA lesion set was more beneficial in terms of freedom from atrial arrhythmia recurrence (85.3 +/- 4.5% vs 91.9 +/- 3.1%, P = 0.049; hazard ratio 3.26; 95% confidence interval 1.33-7.99), but it was associated with higher pacemaker implantation rate (3.8% vs 17.3%; P < 0.001) due to sinus node dysfunction. There was no significant between-group difference regarding the incidence of atrioventricular conduction disturbances (3.2% vs 7.0%, respectively; P = 0.211). CONCLUSIONS: The 2 lesion sets (left atrial and BA) are associated with similar 30-day mortality, survival rates, incidences of embolic events and atrioventricular conduction disturbances. In patients with persistent atrial fibrillation, concomitant surgical ablation with BA lesion set provided better freedom from atrial arrhythmia recurrence, but BA ablation was associated with a higher incidence of sinus node dysfunction and a higher rate of pacemaker implantation. PMID- 29608678 TI - FA-SAT Is an Old Satellite DNA Frozen in Several Bilateria Genomes. AB - In recent years, a growing body of evidence has recognized the tandem repeat sequences, and specifically satellite DNA, as a functional class of sequences in the genomic "dark matter." Using an original, complementary, and thus an eclectic experimental design, we show that the cat archetypal satellite DNA sequence, FA SAT, is "frozen" conservatively in several Bilateria genomes. We found different genomic FA-SAT architectures, and the interspersion pattern was conserved. In Carnivora genomes, the FA-SAT-related sequences are also amplified, with the predominance of a specific FA-SAT variant, at the heterochromatic regions. We inspected the cat genome project to locate FA-SAT array flanking regions and revealed an intensive intermingling with transposable elements. Our results also show that FA-SAT-related sequences are transcribed and that the most abundant FA SAT variant is not always the most transcribed. We thus conclude that the DNA sequences of FA-SAT and their transcripts are "frozen" in these genomes. Future work is needed to disclose any putative function that these sequences may play in these genomes. PMID- 29608680 TI - Extended vs Bolus Infusion of Broad-Spectrum beta-Lactams for Febrile Neutropenia: An Unblinded, Randomized Trial. AB - Background: Febrile neutropenia may be a sign of severe infection and is associated with significant morbidity and mortality in high-risk patients with hematologic malignancies. Extended infusion of beta-lactam antibiotics is associated with greater clinical response than is bolus infusion in nonneutropenic critically ill patients, but data are lacking for febrile neutropenic patients. Methods: We designed a single-center, nonblinded, randomized trial to compare extended infusion (4 hours) and bolus infusion (30 minutes) of piperacillin-tazobactam or ceftazidime in high-risk patients with febrile neutropenia. The primary endpoint was overall response on day 4, defined as the combination of resolution of fever, sterile blood cultures, resolution of clinical signs and symptoms, and no need for a change in the antibiotic regimen. Outcome was adjudicated by investigators blinded to treatment allocation. Results: Of 123 enrolled patients, 105 had febrile neutropenia and were included in the intention-to-treat analysis: 47 in the extended infusion arm and 58 in the bolus infusion arm. Overall response occurred in 35 (74.4%) patients treated with extended infusion and 32 (55.1%) patients treated with bolus infusion (P = .044). The superiority of extended infusion was greatest for patients with clinically documented infections (overall response, 68.4% [13/19] vs 35.7% [10/28]; P = .039) and specifically for those with pneumonia (80% [4/5] vs 0% [0/8]; P = .007). Conclusions: Extended infusion of beta-lactams is associated with superior treatment outcomes compared with bolus infusion for high-risk patients with febrile neutropenia. The benefit of extended beta-lactam infusion may be greatest for patients with pulmonary infections. Clinical Trials Registration: NCT02463747. PMID- 29608681 TI - Response to the Letter "Associations Between Inflammation and Endothelial Dysfunction in Resistant Hypertension". PMID- 29608682 TI - Associations Between Inflammation and Endothelial Dysfunction in Resistant Hypertension. PMID- 29608683 TI - Lymph node dissection along the recurrent laryngeal nerves in patients with oesophageal cancer who had undergone chemoradiotherapy: is it safe? AB - OBJECTIVES: Upper mediastinal lymph node dissection (LND)-especially along the recurrent laryngeal nerve (RN)-is the most challenging part of oesophageal cancer surgery. We investigated whether thoracoscopic RN LND may be safely performed in patients with oesophageal cancer who had undergone chemoradiotherapy (CRT). METHODS: Patients with oesophageal cancer who had undergone thoracoscopic RN LND (n = 103) were divided into 2 groups according to whether they had prior treatment with CRT or not [the CRT group (n = 65) vs the upfront surgery group (n = 38), respectively]. All patients were operated on by a single surgeon. Intergroup comparisons were made in terms of (i) the number of dissected nodes, (ii) rates of RN palsy and (iii) rates of perioperative complications. The learning curve for the RN LND procedure was investigated using the cumulative sum method. RESULTS: RN LND after CRT was more technically challenging when performed in the left side. Complete skeletonization of the left RN was achieved only in 66.2% of patients in the CRT group (vs 86.8% in the upfront surgery group; P = 0.022). The rate of postoperative left side RN palsy was significantly higher in the CRT group (26.6%) than in the upfront surgery group (7.9%, P = 0.022), albeit resulting in neither higher pneumonia rates nor longer hospital stays. The cumulative sum analysis revealed a steep learning curve for left RN LND in the CRT group. Unfortunately, an acceptable proficiency (left RN palsy rate: 15%) was not achievable even after treatment in 65 cases. CONCLUSIONS: Thoracoscopic RN LND is safe but poses significant challenges in CRT-treated patients. PMID- 29608684 TI - Microsphere controlled drug delivery for local control of tooth movement. AB - Background: Because orthodontic tooth movement is dependent upon osteoclast mediated resorption of alveolar bone adjacent to the pressure side of tooth roots, biologic mediators that regulate osteoclasts can be utilized to control tooth movement. Objectives: To develop a novel method to locally enhance orthodontic anchorage. Methods: We encapsulated osteoprotegerin (OPG) in polymer microspheres and tested the effectiveness of microsphere encapsulated versus non encapsulated OPG for enhancing orthodontic anchorage in a rodent model of tooth movement. A single injection of 1 mg/kg non-encapsulated or microsphere encapsulated OPG was delivered into the palatal mucosa mesial to the first maxillary molar 1 day prior to tooth movement. A positive control group received injections of 5 mg/kg non-encapsulated OPG every 3 days during tooth movement. After 28 days of tooth movement, hemi-maxillae and femurs were dissected. Molar mesial and incisor distal tooth movement was measured using stone casts that were scanned and magnified. Local alveolar, distant femur bone, and tooth root volumes were analyzed by micro computed tomography. Serum OPG levels were measured by ELISA. Osteoclast numbers were quantified by histomorphometry. Results: The single injection of microsphere encapsulated OPG significantly enhanced orthodontic anchorage, while the single injection of non-encapsulated OPG did not. Injection of encapsulated OPG inhibited molar mesial movement but did not inhibit incisor tooth movement, and did not alter alveolar or femur bone volume fraction, density, or mineral content. Multiple injections of 5 mg/kg non encapsulated OPG enhanced orthodontic anchorage, but also inhibited incisor retraction and altered alveolar and femur bone quality parameters. Increased OPG levels were found only in animals receiving multiple injections of non encapsulated 5 mg/kg OPG. Osteoclast numbers were higher upon tooth movement in animals that did not receive OPG. Osteoclast numbers in OPG injected animals were variable within groups. Conclusions: Microsphere encapsulation of OPG allows for controlled drug release, and enhances site-specific orthodontic anchorage without systemic side effects. With additional refinements, this drug delivery system could be applicable to a broad array of potential biologic orthodontic therapeutics. PMID- 29608685 TI - Dolutegravir-based maintenance monotherapy versus dual therapy with lamivudine: a planned 24 week analysis of the DOLAM randomized clinical trial. AB - Background: No controlled comparisons between dolutegravir/lamivudine or dolutegravir maintenance therapy have been done. We hypothesized that these options would have similar efficacy to triple ART. Methods: We used an open-label non-inferiority randomized controlled trial comprising two phases: phase A was established to test that experimental arms did not have an unacceptable (>=5%) failure rate; phase B was intended to include the full number of patients followed for 48 weeks. Treated HIV-1-infected adults with viral load <50 copies/mL for >=12 months, no prior viral failure or resistance mutations to study drugs, nadir CD4 >200 cells/mm3, and hepatitis B virus surface antigen negative were randomized 1:1:1 to maintain triple therapy (control arm), or to switch to dolutegravir/lamivudine, or to dolutegravir monotherapy stratifying by anchor drug. Premature discontinuation was considered if viral failure or therapy interruption due to adverse events, concurrent illness, protocol deviation or patient's wish occurred. Blips were registered. Planned phase A results at 24 weeks are reported here. The study is registered at EudraCT: 201500027435. Results: Ninety-one (control, n = 31; dual therapy, n = 29; monotherapy, n = 31) patients were randomized. Three patients (none previously exposed to integrase inhibitors) prematurely discontinued treatment due to viral failure: dolutegravir/lamivudine (n = 1), no resistance mutations (subject A); dolutegravir (n = 2), N155H, S147G and Q148R resistance mutations (subject B), and E138K, G140S and N155H resistance mutations (subject C). There were no discontinuations for other reasons. One patient (dolutegravir/lamivudine) experienced a blip in viral load. The Data Safety Monitoring Board recommended stopping the dolutegravir monotherapy arm. Conclusions: In contrast to dolutegravir/lamivudine, a higher than expected risk of viral failure with development of cross-resistance integrase mutations occurred with dolutegravir maintenance monotherapy. PMID- 29608686 TI - Papillary fibroelastoma arising from left ventricular outflow tract. PMID- 29608687 TI - Darunavir/ritonavir 600/100 mg once daily: it's time for larger non-inferiority randomized trials. PMID- 29608689 TI - Corrigendum to "Investigation of the Relationship Between Radiation Dose and Gene Mutations and Fusions in Post-Chernobyl Thyroid Cancer". PMID- 29608688 TI - Oxytetracycline does not cause growth promotion in finfish. AB - Until recently, use of antibiotics to enhance terrestrial animal growth performance was a common, U.S. Food and Drug Administration (FDA)-approved, but controversial practice. There are no FDA-approved production claims for antibiotic drug use in fish, but it is a common misconception that antibiotics are widely used for this purpose in U.S. aquaculture. Antibiotics are not thought to be effective growth promoters in fish, but there is little quantitative data available to address whether there are growth-promoting effects that might incentivize the use of antibiotics in this way, despite legal prohibitions. Therefore, this study was conducted to determine if oral administration of oxytetracycline, an antibiotic with known growth-promoting effects in terrestrial livestock, has a similar effect when applied to channel catfish Ictalurus punctatus, hybrid striped bass Morone chrysops * M. saxatilis, Nile tilapia Oreochromis niloticus, or rainbow trout Oncorhynchus mykiss. Oxytetracycline products with production claims are typically applied at doses substantially lower than the approved therapeutic doses for the same products. Medication (0, 0.24, or 1.2 g oxytetracycline dihydrate kg-1 feed) and feeding rates (3% BW d-1) were selected to achieve target daily doses of 0, 16, or 80 mg kg-1 fish representing control, subtherapeutic, and therapeutic treatments. Replicate groups of fish (N = 4) were fed accordingly for 8 wk. Overall, oral administration of oxytetracycline did not affect survival or promote growth of the selected taxa, with no significant differences observed for weight gain, feed conversion ratio, or specific growth rate (P > 0.05 in all cases). Few differences were observed in organosomatic indices and in the frequency of tissue abnormalities; where present, these differences tended to suggest a negative effect of long-term dietary exposure to oxytetracycline. These data demonstrate that there is no benefit to dietary supplementation with oxytetracycline for nontherapeutic purposes in a range of economically important finfish species. As such, our results indicate there is little incentive to misuse oxytetracycline products for purposes of growth promotion in U.S. aquaculture. PMID- 29608690 TI - Loss of MicroRNA-21 Influences the Gut Microbiota, Causing Reduced Susceptibility in a Murine Model of Colitis. AB - Background and Aims: microRNAs regulate gene expression and influence the pathogenesis of human diseases. The present study investigated the role of microRNA-21 [miR-21] in the pathogenesis of intestinal inflammation, because miR 21 is highly expressed in inflammatory bowel disease. Inflammatory bowel disease is associated with intestinal barrier dysfunction and an altered gut microbiota. Recent studies have demonstrated that host microRNAs can shape the microbiota. Thus, we determined the influence of miR-21 on the gut microbiota and observed the subsequent impact in a dextran sodium sulphate [DSS]-induced colitis model. Methods: The influence of miR-21 on the gut microbiota and inflammation was assessed in wild-type [WT] and miR-21-/- mice, in co-housed mice, following antibiotic depletion of the microbiota, or by colonization of germ-free [GF] mice with fecal homogenate, prior to DSS administration. We carried out 16S rRNA sequencing on WT and miR-21-/- mice to dissect potential differences in the gut microbiota. Results: miR-21-/- mice have reduced susceptibility to DSS-induced colitis compared with WT mice. Co-housing conferred some protection to WT mice, while GF mice colonized with fecal homogenate from miR-21-/- were protected from DSS colitis compared with those colonized with WT homogenate. Further supporting a role for the microbiota in the observed phenotype, the protection afforded by miR-21 depletion was lost when mice were pre-treated with antibiotics. The 16S rRNA sequencing revealed significant differences in the composition of WT and miR 21-/- intestinal microbiota. Conclusions: These findings suggest that miR-21 influences the pathogenesis of intestinal inflammation by causing propagation of a disrupted gut microbiota. PMID- 29608691 TI - Using routinely available data and statistical methods to monitor and evaluate quality of care. PMID- 29608692 TI - Cervical vertebral maturation method and mandibular growth peak: a longitudinal study of diagnostic reliability. AB - Background/objectives: The capability of the cervical vertebral maturation (CVM) method in the identification of the mandibular growth peak on an individual basis remains undetermined. The diagnostic reliability of the six-stage CVM method in the identification of the mandibular growth peak was thus investigated. Subjects/Methods: From the files of the Oregon and Burlington Growth Studies (data obtained between early 1950s and middle 1970s), 50 subjects (26 females, 24 males) with at least seven annual lateral cephalograms taken from 9 to 16 years were identified. Cervical vertebral maturation was assessed according to the CVM code staging system, and mandibular growth was defined as annual increments in Co Gn distance. A diagnostic reliability analysis was carried out to establish the capability of the circumpubertal CVM stages 2, 3, and 4 in the identification of the imminent mandibular growth peak. Results: Variable durations of each of the CVM stages 2, 3, and 4 were seen. The overall diagnostic accuracy values for the CVM stages 2, 3, and 4 were 0.70, 0.76, and 0.77, respectively. These low values appeared to be due to false positive cases. Limitations: Secular trends in conjunction with the use of a discrete staging system. In most of the Burlington Growth Study sample, the lateral head film at age 15 was missing. Conclusions/Implications: None of the CVM stages 2, 3, and 4 reached a satisfactorily diagnostic reliability in the identification of imminent mandibular growth peak. PMID- 29608694 TI - scanPAV: a pipeline for extracting presence-absence variations in genome pairs. AB - Motivation: The recent technological advances in genome sequencing techniques have resulted in an exponential increase in the number of sequenced human and non human genomes. The ever increasing number of assemblies generated by novel de novo pipelines and strategies demands the development of new software to evaluate assembly quality and completeness. One way to determine the completeness of an assembly is by detecting its Presence-Absence variations (PAV) with respect to a reference, where PAVs between two assemblies are defined as the sequences present in one assembly but entirely missing in the other one. Beyond assembly error or technology bias, PAVs can also reveal real genome polymorphism, consequence of species or individual evolution, or horizontal transfer from viruses and bacteria. Results: We present scanPAV, a pipeline for pairwise assembly comparison to identify and extract sequences present in one assembly but not the other. In this note, we use the GRCh38 reference assembly to assess the completeness of six human genome assemblies from various assembly strategies and sequencing technologies including Illumina short reads, 10* genomics linked reads, PacBio and Oxford Nanopore long reads, and Bionano optical maps. We also discuss the PAV polymorphism of seven Tasmanian devil whole genome assemblies of normal animal tissues and devil facial tumour 1 (DFT1) and 2 (DFT2) samples, and the identification of bacterial sequences as contamination in some of the tumorous assemblies. Availability and implementation: The pipeline is available under the MIT License at https://github.com/wtsi-hpag/scanPAV. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29608693 TI - The Function of G-Protein-Coupled Receptor-Regulatory Cascade in Southern House Mosquitoes (Diptera: Culicidae). AB - G-protein-coupled receptors (GPCRs) are a large family of seven-transmembrane domain proteins that exist in plants and animals, playing critical physiological functions through intracellular cascades. Previous studies revealed an important regulation pathway of GPCR/Guanine nucleotide-binding protein (G protein)/Adenylyl Cyclase (AC)/cAMP-dependent protein kinase A (PKA) in the insecticide resistance and regulation of resistance-related P450 gene expression in highly resistant southern house mosquitoes, Culex quinquefasciatus Say (Diptera: Culicidae). However, the function of this regulation pathway in field collected and laboratory-susceptible mosquitoes is still unknown. In the current study, we characterized the function of each effector (GPCR, G-protein, AC, and PKA) in this GPCR intracellular pathway in both field-collected and laboratory Cx. quinquefasciatus strains, showing that knockdown of the expression of each effector gene can cause 1) decreased expression of their downstream respective genes and 2) increased sensitivity of the mosquitoes to permethrin insecticide. These results, together with our previous findings, strongly suggest the universal function of the GPCR-regulation cascade in the mosquito's sensitivity to insecticides and its regulation of resistance development through P450 mediated detoxification. PMID- 29608695 TI - 'You are still a human being, you still have needs, you still have wants': a qualitative exploration of patients' experiences and views of HIV support. AB - Background: The importance of patient involvement in service redesign is gaining increasing recognition, particularly for chronic conditions. This study explored the experience, views and needs of people living with HIV to identify areas for improvement and service development. Methods: Face-to-face, semi-structured interviews were conducted with people living with HIV being treated in two clinics in Grampian, Scotland. The topic guide was developed, based on a proposed care pathway, which emphasized support systems. Thematic analysis was undertaken. Results: A total of 14 people living with HIV participated, with time since diagnosis ranging from <1 to >15 years. Most were males, white British and were men who had sex with men. Interviewees highlighted the need for different types of support throughout different stages of the HIV journey, including timely provision of information, post-diagnosis follow-up support, peer support, family support, and support regarding employment, benefits and housing. Many interviewees expressed a preference for support to be provided by people with knowledge or experience of HIV but had mixed feelings towards group support. Interviewees reported concerns with confidentiality and potential stigmatization. Conclusions: Support services should be tailored to reflect changing needs throughout the HIV journey with particular emphasis on maximizing confidentiality whilst minimizing stigma. PMID- 29608697 TI - Acute HIV Infection Results in Subclinical Inflammatory Cardiomyopathy. AB - The impact of excess viral RNA on myocardial function and morphology in the setting of acute human immunodeficiency virus (HIV) infection remains unknown. In this study, 49 patients with acute HIV infection showed increased levels of N terminal prohormone of brain natriuretic peptide, a surrogate of myocardial function, which decreased with viral suppression and normalization of systemic inflammation (79 pg/mL vs 28 pg/mL; P < .001). A comparable change was seen with levels of troponin T, a marker of morphologic myocardial damage (4.9 ng/L vs 1.5 ng/L; P < .001). In conclusion, we observed significant functional and morphological myocardial impairment during acute HIV infection, fueled by inflammatory activation and extensive viral replication, resulting in a reversible subclinical inflammatory cardiomyopathy. PMID- 29608696 TI - Serum Cortisol Levels via Radioimmunoassay vs Liquid Chromatography Mass Spectrophotometry in Healthy Control Subjects and Patients With Adrenal Incidentalomas. AB - Background: Adrenal incidentalomas (AIs) are present in 4% of adults. As many as 30% may secrete cortisol autonomously in the absence of specific signs of overt hypercortisolism, in a phenomenon called subclinical hypercortisolism (SH). Diagnosis of SH is established by serum cortisol resistance to dexamethasone suppression. Methods: We compared serum cortisol concentrations, as determined by radioimmunoassay (RIA) and liquid chromatography/tandem mass spectronomy (LC/MS MS), in 73 patients with AI group (52 with unilateral AI) and 34 control subjects in 3 scenarios: basal; after 1-mg dexamethasone suppression; and after 0.25-mg stimulation with cosyntropin, a synthetic derivative of adrenocorticotropic hormone (ACTH). To bolster evidence for the diagnosis of SH, we also measured salivary cortisol levels at 11 PM and after DST, as well as plasma ACTH and serum dehydroepiandrosterone sulfate (DHEA-S) levels. Results: We observed significant positive correlation (r = 0.9345, P <.001) for all 318 pairs of serum cortisol values, as measured by both methods. Conclusions: Serum cortisol concentrations in patients with AI and in control subjects were very similar, as measured by RIA and LC/MS-MS. PMID- 29608698 TI - Circulating pro-angiogenic micro-ribonucleic acid in patients with coronary heart disease. AB - OBJECTIVES: Our goal was to evaluate the expressions of 14 selected pro angiogenic micro-ribonucleic acids in patients with coronary heart disease (CHD) and healthy controls (HCs) and to assess the correlations of those micro ribonucleic acids with risk and severity of CHD. METHODS: In the exploration stage, 20 patients with CHD were enrolled; in the validation stage, 102 patients with CHD and 92 age- and gender-matched HCs with the same eligibility of those in the exploration stage were recruited. Blood samples were collected from all participants, and plasma levels of micro-ribonucleic acids were measured by the quantitative polymerase chain reaction method. RESULTS: In the exploration stage, the expression of miR-126, miR-17-5p, miR-19a, miR-92a, miR-210 and miR-378 in patients with CHD was down-regulated compared with that of HCs. In the validation stage, miR-126, miR-17-5p, miR-92a, miR-210 and miR-378 levels decreased remarkably in patients with CHD compared with the HCs. Plasma levels of miR-126, miR-17-5p, miR-92a, miR-210 and miR-378 were independent prediction factors for CHD. The combination of miR-126, miR-17-5p, miR-92a, miR-210 and miR-378 was of good diagnostic value for CHD with an area under the curve of 0.756. Additionally, plasma levels of miR-126, miR-210 and miR-378 correlated negatively with Gensini scores. CONCLUSIONS: Circulating miR-126, miR-17-5p, miR-92a, miR 210 and miR-378 could serve as novel, promising biomarkers for risk and severity of CHD. Additionally, miR-126, miR-210 and miR-378 were negatively associated with Gensini scores. PMID- 29608699 TI - Development of Proximal Junctional Kyphosis After Minimally Invasive Lateral Anterior Column Realignment for Adult Spinal Deformity. AB - BACKGROUND: Development of proximal junctional kyphosis (PJK) after correction of adult spinal deformity (ASD) undermines sagittal alignment. Minimally invasive anterior column realignment (ACR) is a powerful tool for correction of ASD; however, long-term PJK rates are unknown. OBJECTIVE: To characterize PJK after utilization of ACR in ASD correction. METHODS: A retrospective multi-institution cohort analysis per STROBE criteria was conducted of all patients who underwent lateral lumbar interbody fusion (LLIF) or ACR for ASD from 2010 to 2015. All patients obtained preoperative and follow-up upright radiographs, assessing spinal alignment and development of PJK. Patients without proper imaging or minimum 1-yr follow-up were excluded. RESULTS: A total of 73 of 112 patients who underwent either LLIF or ACR for ASD met inclusion criteria. Mean follow-up was 22.8 mo. There was significant improvement of all spinopelvic parameters. Overall, PJK and proximal junctional failure (PJF) rates were 20.5% and 11%, respectively. The incidence of PJK increased with greater corrective surgery (0% LLIF, 30% ACR, 42.9% ACR + posterior column osteotomy (PCO); P < .001). PJF rates increased (0% LLIF, 11% ACR, 40% ACR + PCO; P = .005). Risk factors included location of the upper-instrumented vertebra at T10-L1 vs L2-L4 (P = .007), age (P = .029), severity of ASD, and overcorrection of sagittal imbalance. CONCLUSION: The incidence of PJK after minimally invasive ACR is slightly lower than reported after open surgery but greater than in LLIF only and increases with PCO utilization. The PJK rate increases when crossing the TL junction, sagittal imbalance severity, and overcorrection. Elderly patients are at an increased risk, suggesting need for age appropriate correction goals. PMID- 29608701 TI - Stereotactic Radiosurgery for Intracranial Ependymomas: An International Multicenter Study. AB - BACKGROUND: Stereotactic radiosurgery (SRS) is a potentially important option for intracranial ependymoma patients. OBJECTIVE: To analyze the outcomes of intracranial ependymoma patients who underwent SRS as a part of multimodality management. METHODS: Seven centers participating in the International Gamma Knife Research Foundation identified 89 intracranial ependymoma patients who underwent SRS (113 tumors). The median patient age was 16.3 yr (2.9-80). All patients underwent previous surgical resection and radiation therapy (RT) of their ependymomas and 40 underwent previous chemotherapy. Grade 2 ependymomas were present in 42 patients (52 tumors) and grade 3 ependymomas in 48 patients (61 tumors). The median tumor volume was 2.2 cc (0.03-36.8) and the median margin dose was 15 Gy (9-24). RESULTS: Forty-seven (53%) patients were alive and 42 (47%) patients died at the last follow-up. The overall survival after SRS was 86% at 1 yr, 50% at 3 yr, and 44% at 5 yr. Smaller total tumor volume was associated with longer overall survival (P = .006). Twenty-two patients (grade 2: n = 9, grade 3: n = 13) developed additional recurrent ependymomas in the craniospinal axis. The progression-free survival after SRS was 71% at 1 yr, 56% at 3 yr, and 48% at 5 yr. Adult age, female sex, and smaller tumor volume indicated significantly better progression-free survival. Symptomatic adverse radiation effects were seen in 7 patients (8%). CONCLUSION: SRS provides another management option for residual or recurrent progressive intracranial ependymoma patients who have failed initial surgery and RT. PMID- 29608700 TI - Trophoblast retrieval and isolation from the cervix: origins of cervical trophoblasts and their potential value for risk assessment of ongoing pregnancies. AB - BACKGROUND: Early during human development, the trophoblast lineage differentiates to commence placentation. Where the placenta contacts the uterine decidua, extravillous trophoblast (EVT) cells differentiate and invade maternal tissues. EVT cells, identified by expression of HLA-G, invade into uterine blood vessels (endovascular EVT), as well as glands (endoglandular EVT), and open such luminal structures towards the intervillous space of the placenta. Endoglandular invasion diverts the contents of uterine glands to the intervillous space, while glands near the margin of the placenta that also contain endoglandular EVT cells open into the reproductive tract. Cells of the trophoblast lineage have thus been recovered from the uterine cavity and endocervical canal. An emerging non invasive technology [trophoblast retrieval and isolation from the cervix (TRIC)] isolates and examines EVT cells residing in the cervix to explore their origin, biology and relationship to pregnancy and fetal status. OBJECTIVE AND RATIONALE: This review explores the origins and possible uses of trophoblast cells obtained during ongoing pregnancies (weeks 5-20) by TRIC. We hypothesize that endoglandular EVT cells at the margins of the expanding placenta enter the uterine cavity and are carried together with uterine secretion products to the cervix where they can be retrieved from a Papanicolaou (Pap) smear. The advantages of TRIC for investigation of human placentation and prenatal testing will be considered. Evidence from the literature, and from archived in utero placental histological sections, is presented to support these hypotheses. SEARCH METHODS: We used 52 out of 80 publications that appeared between 1966 and 2017 and were found by searching the PubMed and Google Scholar databases. The studies described trophoblast invasion of uterine vessels and glands, as well as trophoblast cells residing in the reproductive tract. This was supplemented with literature on human placental health and disease. OUTCOMES: The literature describes a variety of invasive routes taken by EVT cells at the fetal-maternal interface that could displace them into the reproductive tract. Since the 1970s, investigators have attempted to recover trophoblast cells from the uterus or cervix for prenatal diagnostics. Trophoblast cells from Pap smears obtained at 5 20 weeks of gestation have been purified (>95% beta-hCG positive) by immunomagnetic isolation with nanoparticles linked to anti-HLA-G (TRIC). The isolated cells contain the fetal genome, and have an EVT-like expression profile. Similar EVT-like cells appear in the lumen of uterine glands and can be observed entering the uterine cavity along the margins of the placenta, suggesting that they are the primary source of cervical trophoblast cells. Cells isolated by TRIC can be used to accurately genotype the embryo/fetus by targeted next-generation sequencing. Biomarker protein expression quantified in cervical trophoblast cells after TRIC correlates with subsequent pregnancy loss, pre-eclampsia and fetal growth restriction. A key remaining question is the degree to which EVT cells in the cervix might differ from those in the basal plate and placental bed. WIDER IMPLICATIONS: TRIC could one day provide a method of risk assessment for maternal and fetal disease, and reveal molecular pathways disrupted during the first trimester in EVT cells associated with placental maldevelopment. As perinatal interventions emerge for pregnancy disorders and inherited congenital disorders, TRIC could provide a key diagnostic tool for personalized precision medicine in obstetrics. PMID- 29608702 TI - Flow Diversion of Posterior Circulation Cerebral Aneurysms: A Single-Institution Series of 59 Cases. AB - BACKGROUND: Posterior circulation cerebral aneurysms are at higher risk of rupture and are more symptomatic than those in the anterior circulation. Existing treatments carry significant morbidity. Early reports of flow diversion for posterior circulation aneurysms have suggested high complication and low occlusion rates. OBJECTIVE: To report safety and efficacy of flow diversion with the pipeline embolization device (ev3, Medtronic Inc, Dublin, Ireland) for aneurysms located throughout the posterior circulation. METHODS: A prospective, institutional review board-approved database was analyzed for all patients with posterior circulation aneurysms treated by flow diversion at our institution. RESULTS: Fifty-nine embolization procedures were performed on 55 patients. Average aneurysm size was 9.4 mm. Morphology was saccular (45%), fusiform (29%), or dissecting/pseudo-aneurysms (25%). Sixty-two percent of aneurysms arose along the vertebral artery. There were 7 mid-basilar (13%) and 7 basilar apex (13%) aneurysms. Procedural success was 98%; 1 Pipeline embolization device was placed in 85%; and coiling was performed in 17% of cases. There were 5 major complications (8%), all strokes. Patients with major stroke had modified Rankin Scale score at last follow-up of 1, 3, 4, 6, and 6 (2 mortalities). There were zero intracerebral or subarachnoid hemorrhages. No variable predicted complications on univariate or multivariate analysis. Follow-up digital subtraction angiography was performed for 43 patients (78%). Complete occlusion was 68% at 6 mo and 78% at 12 mo. Average follow-up was 11.8 mo. Fusiform or dissecting morphology and large or giant aneurysm size were predictors of aneurysm persistence at 6 mo on multivariate logistic regression. CONCLUSION: This is a large single-institution series of Pipeline (Medtronic Inc) for posterior circulation aneurysms and demonstrates acceptable safety and effectiveness in these challenging cases. PMID- 29608704 TI - Neuropsychological Changes in Patients Undergoing Treatment of Unruptured Intracranial Aneurysms. AB - BACKGROUND: Evaluation of differences in neuropsychological outcomes in patients undergoing surgical clipping (SC) vs endovascular coiling (EC) for unruptured cerebral aneurysms is essential in guiding patients seeking treatment of asymptomatic cerebral aneurysms. OBJECTIVE: To perform a prospective longitudinal analysis of neuropsychological outcomes in patients who underwent microsurgery or coiling for unruptured cerebral aneurysms. METHODS: SC (50 patients), EC (35 patients), and healthy controls (43 individuals) were included. A detailed neuropsychological evaluation was performed at baseline and at 2 wk, 3 mo, 6 mo, and 12 mo. Student's t-test was utilized for comparing neuropsychological outcomes among the 3 groups. A mixed-effects model allowed for evaluation of neuropsychological outcome changes among the groups over time. RESULTS: Both the SC and EC groups had nonsignificant differences in procedure-related complications. SC patients had the greatest initial declines in short-term memory, fine motor control, and executive functioning; however, these patients also recovered to a greater degree in neuropsychological functionality. Over the next year, all groups achieved similar neuropsychological outcomes with no significant differences among groups. CONCLUSION: Whereas the initial decline in neuropsychological functioning was greater for SC patients, 1 yr after treatment there was no significant difference in neuropsychological outcome among the SC, EC, and healthy control groups. PMID- 29608703 TI - riboSeed: leveraging prokaryotic genomic architecture to assemble across ribosomal regions. AB - The vast majority of bacterial genome sequencing has been performed using Illumina short reads. Because of the inherent difficulty of resolving repeated regions with short reads alone, only ~10% of sequencing projects have resulted in a closed genome. The most common repeated regions are those coding for ribosomal operons (rDNAs), which occur in a bacterial genome between 1 and 15 times, and are typically used as sequence markers to classify and identify bacteria. Here, we exploit the genomic context in which rDNAs occur across taxa to improve assembly of these regions relative to de novo sequencing by using the conserved nature of rDNAs across taxa and the uniqueness of their flanking regions within a genome. We describe a method to construct targeted pseudocontigs generated by iteratively assembling reads that map to a reference genome's rDNAs. These pseudocontigs are then used to more accurately assemble the newly sequenced chromosome. We show that this method, implemented as riboSeed, correctly bridges across adjacent contigs in bacterial genome assembly and, when used in conjunction with other genome polishing tools, can assist in closure of a genome. PMID- 29608706 TI - Risks and outcomes of invasive fungal infections in pediatric allogeneic hematopoietic stem cell transplant recipients receiving fluconazole prophylaxis: a multicenter cohort study by the Turkish Pediatric Bone Marrow Transplantation Study Group. AB - Invasive fungal infections (IFIs) are a major cause of infection-related morbidity and mortality in patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Data from pediatric settings are scarce. To determine the incidence, risk factors and outcomes of IFIs in a 180-day period post transplantation, 408 pediatric patients who underwent allogeneic HSCT were retrospectively analyzed. The study included only proven and probable IFIs. The cumulative incidences of IFI were 2.7%, 5.0%, and 6.5% at 30, 100, and 180 days post-transplantation, respectively. According to the multivariate analysis, the factors associated with increased IFI risk in the 180-day period post-HSCT were previous HSCT history (hazard ratio [HR], 4.57; 95% confidence interval [CI] 1.42 14.71; P = .011), use of anti-thymocyte globulin (ATG) (HR, 2.94; 95% CI 1.27 6.80; P = .012), grade III-IV acute graft-versus-host-disease (GVHD) (HR, 2.91; 95% CI 1.24-6.80; P = .014) and late or no lymphocyte engraftment (HR, 2.71; 95% CI 1.30-5.62; P = .007). CMV reactivation was marginally associated with an increased risk of IFI development (HR, 1.91; 95% CI 0.97-3.74; P = .063). IFI related mortality was 1.5%, and case fatality rate was 27.0%.The close monitoring of IFIs in pediatric patients with severe acute GVHD who receive ATG during conditioning is critical to reduce morbidity and mortality after allogeneic HSCT, particularly among those with prior HSCT and no or late lymphocyte engraftment. PMID- 29608705 TI - FoldX accurate structural protein-DNA binding prediction using PADA1 (Protein Assisted DNA Assembly 1). AB - The speed at which new genomes are being sequenced highlights the need for genome wide methods capable of predicting protein-DNA interactions. Here, we present PADA1, a generic algorithm that accurately models structural complexes and predicts the DNA-binding regions of resolved protein structures. PADA1 relies on a library of protein and double-stranded DNA fragment pairs obtained from a training set of 2103 DNA-protein complexes. It includes a fast statistical force field computed from atom-atom distances, to evaluate and filter the 3D docking models. Using published benchmark validation sets and 212 DNA-protein structures published after 2016 we predicted the DNA-binding regions with an RMSD of <1.8 A per residue in >95% of the cases. We show that the quality of the docked templates is compatible with FoldX protein design tool suite to identify the crystallized DNA molecule sequence as the most energetically favorable in 80% of the cases. We highlighted the biological potential of PADA1 by reconstituting DNA and protein conformational changes upon protein mutagenesis of a meganuclease and its variants, and by predicting DNA-binding regions and nucleotide sequences in proteins crystallized without DNA. These results opens up new perspectives for the engineering of DNA-protein interfaces. PMID- 29608707 TI - A Practical Primer on Prion Pathology. AB - Prion diseases comprise a group of transmissible degenerative encephalopathies resulting from propagation of a misfolded cellular protein of uncertain function. As is generally the case with rare diseases, lack of institutional experience compromises individual familiarity with the varying, and apparently protean, manifestations of prion diseases, both clinically and pathologically. Coupled with the documented transmissibility of these diseases both within and between species, the Centers for Disease Control and Prevention (CDC) has established the National Prion Disease Pathology Surveillance Center to both aid with diagnosis of prion disease and to survey the United States for evidence of zoonotic transmission. We have assembled this primer with the hope that our accumulated experience will enable the neuropathological community to help the CDC "save lives and protect people." PMID- 29608708 TI - Effects of intradialytic cycling exercise on exercise capacity, quality of life, physical function and cardiovascular measures in adult haemodialysis patients: a systematic review and meta-analysis. AB - Background: Intradialytic cycling (IDC), delivered during haemodialysis (HD), has the potential to improve many health issues. This systematic review and meta analysis examine the evidence on the effects of IDC on exercise capacity, quality of life (QoL), physical function and cardiovascular health. Methods: Twenty-four databases were searched alongside Internet and hand searching, and consultation with experts. Eligibility criteria were cluster randomized, randomized and quasi randomized controlled trials (RCTs) of IDC versus usual care in prevalent adult HD patients. Primary outcome measures were exercise capacity (VO2 peak and field tests) and QoL. Secondary measures were cardiac and physical function. Results: Thirteen RCTs were eligible. Eight provided data for use in meta-analyses, which indicated no significant change in VO2 peak (mean difference, MD 1.19 mL/kg/min, 95% confidence interval -1.15 to 3.52, P = 0.3), physical (mean change, MC 1.97, 8.27 to 12.22, P = 0.7) or mental component (MC 3.37, -7.94 to 14.68, P = 0.6) summary scores of the Medical Outcomes Short Form 36, pulse wave velocity (MD 0.57 m/s, -1.55 to 0.41, P = 0.4), systolic (MD -2.28 mmHg, -14.46 to 9.90, P = 0.7) or diastolic blood pressure (MD 2.25 mmHg, -3.01 to 7.50, P = 0.4) following IDC. IDC, however, leads to an improvement in performance on the 6-min walk test (MD 87.84 m, 39.60-136.09, P = 0.0004). All included studies were considered to have high risk of bias. Conclusions: There is insufficient evidence demonstrating whether cycling exercise during HD improves patient outcomes. High-quality, adequately powered RCTs of IDC are required. PMID- 29608709 TI - In Reply: Guidelines for the Use of Electrophysiological Monitoring for Surgery of the Human Spinal Column and Spinal Cord. PMID- 29608710 TI - Cardiovascular syphilis: down but not out! PMID- 29608711 TI - Clinical Signs and Blood Test Results Among Humans Infected With Zoonotic Simian Foamy Virus: A Case-Control Study. AB - Background: A spillover of simian foamy virus (SFV) to humans, following bites from infected nonhuman primates (NHPs), is ongoing in exposed populations. These retroviruses establish persistent infections of unknown physiological consequences to the human host. Methods: We performed a case-control study to compare 24 Cameroonian hunters infected with gorilla SFV and 24 controls matched for age and ethnicity. A complete physical examination and blood test were performed for all participants. Logistic regression and Wilcoxon signed rank tests were used to compare cases and controls. Results: The cases had significantly lower levels of hemoglobin than the controls (median, 12.7 vs 14.4 g/dL; P = .01). Basophil levels were also significantly lower in cases than controls, with no differences for other leukocyte subsets. Cases had significantly higher urea, creatinine, protein, creatinine phosphokinase, and lactate dehydrogenase levels and lower bilirubin levels than controls. Cases and controls had similar frequencies of general, cutaneous, gastrointestinal, neurological, and cardiorespiratory signs. Conclusions: The first case-control study of apparently healthy SFV-infected Cameroonian hunters showed the presence of hematological abnormalities. A thorough clinical and laboratory workup is now needed to establish the medical relevance of these observations because more than half of cases had mild or moderate anemia. Clinical Trials Registration: NCT03225794. PMID- 29608712 TI - Influence of early-life risk factors on socioeconomic inequalities in weight gain. AB - Background: Previous research has examined the role of early-life risk factors on childhood weight gain.The extent to which these factors drive socioeconomic differences in weight is unclear. We aimed to quantify the influence of early life risk factors on the development of socioeconomic inequalities in children's body mass index (BMI) z-score at 10-11 years. Methods: Overall, 2186 children from the Longitudinal Study of Australian Children were examined. Socioeconomic position (SEP) was measured as a continuous composite of parent's education, occupation and income. The Product of Coefficients mediation method was used to quantify the contribution of maternal smoking during pregnancy, gestational diabetes, prematurity, caesarean section, birthweight, not being breastfed, early introduction of solid food, maternal BMI and paternal BMI to the relationship between SEP and BMI z-score. Results: Each increasing decile of SEP (higher SEP) was associated with a 0.05 unit lower (95% CI: -0.06, -0.03) BMI z-score at 10-11 years. In total, 83.5% of these differences in BMI z-score could be explained by socioeconomic differences in maternal smoking during pregnancy (26.9%), maternal BMI (39.6%) and paternal BMI (17.0%). Conclusions: Interventions to reduce socioeconomic inequalities in excess weight gain during childhood should support the attainment of a healthy parental weight and prevent smoking during pregnancy. PMID- 29608713 TI - Letter: Guidelines for the Use of Electrophysiological Monitoring for Surgery of the Human Spinal Column and Spinal Cord. PMID- 29608714 TI - Are Electronic Cigarettes an Effective Aid to Smoking Cessation or Reduction Among Vulnerable Groups? A Systematic Review of Quantitative and Qualitative Evidence. AB - Introduction: Smoking prevalence remains high in some vulnerable groups, including those who misuse substances, have a mental illness, are homeless or are involved with the criminal justice system. E-cigarette use is increasing and may support smoking cessation/reduction. Methods: Systematic review of quantitative and qualitative data on the effectiveness of e-cigarettes for smoking cessation/reduction among vulnerable groups. Databases searched were MEDLINE, EMBASE, PsychINFO, CINAHL, ASSIA, ProQuest Dissertations and Theses and Open Grey. Narrative synthesis of quantitative data and thematic synthesis of qualitative data. Results: 2628 records and 46 full texts were screened; 9 studies were identified for inclusion. Due to low quality of evidence, it is uncertain whether e-cigarettes are effective for smoking cessation in vulnerable populations. A moderate quality study suggested e-cigarettes were as effective as nicotine replacement therapy. Four studies suggested significant smoking reduction, however three were uncontrolled and had sample sizes below 30. A prospective cohort study found no differences between e-cigarette users and non users. No significant adverse events and minimal side effects were identified. Qualitative thematic synthesis revealed barriers and facilitators associated with each component of the COM-B (capability, opportunity, motivation, behaviour) model, including practical barriers; perceptions of effectiveness for cessation/reduction; design features contributing to automatic and reflective motivation; smoking bans facilitating practical opportunity; and social connectedness increasing social opportunity. Conclusion: Further research is needed to identify the most appropriate device types for practicality and safety, level of support required in e-cigarette interventions, and to compare e cigarettes with current best practice smoking cessation support among vulnerable groups. Implications: Smoking prevalence among people with mental illness, substance misuse, homelessness or criminal justice system involvement remains high. E-cigarettes could support cessation. This systematic review found limited quantitative evidence assessing effectiveness. No serious adverse events were identified. Qualitative thematic synthesis revealed barriers and facilitators mapping to each component of the COM-B (capability, opportunity, motivation, behaviour) model, including practical barriers; perceived effectiveness; design features contributing to automatic and reflective motivation; smoking bans facilitating practical opportunity; and social connectedness increasing social opportunity. Further research should consider appropriate devices for practicality and safety, concurrent support, and comparison with best practice smoking cessation support. PMID- 29608715 TI - GC Content of Early Metazoan Genes and Its Impact on Gene Expression Levels in Mammalian Cell Lines. AB - With the genomes available for many animal clades, including the early-branching metazoans, one can readily study the functional conservation of genes across a diversity of animal lineages. Ectopic expression of an animal protein in, for instance, a mammalian cell line is a generally used strategy in structure function analysis. However, this might turn out to be problematic in case of distantly related species. Here we analyzed the GC content of the coding sequences of basal animals and show its impact on gene expression levels in human cell lines, and, importantly, how this expression efficiency can be improved. Optimization of the GC3 content in the coding sequences of cadherin, alpha catenin, and paracaspase of Trichoplax adhaerens dramatically increased the expression of these basal animal genes in human cell lines. PMID- 29608716 TI - Modeling Interactions between Transposable Elements and the Plant Epigenetic Response: A Surprising Reliance on Element Retention. AB - Transposable elements (TEs) compose the majority of angiosperm DNA. Plants counteract TE activity by silencing them epigenetically. One form of epigenetic silencing requires 21-22 nt small interfering RNAs that act to degrade TE mRNA and may also trigger DNA methylation. DNA methylation is reinforced by a second mechanism, the RNA-dependent DNA methylation (RdDM) pathway. RdDM relies on 24 nt small interfering RNAs and ultimately establishes TEs in a quiescent state. These host factors interact at a systems level, but there have been no system level analyses of their interactions. Here, we define a deterministic model that represents the propagation of active TEs, aspects of the host response and the accumulation of silenced TEs. We describe general properties of the model and also fit it to biological data in order to explore two questions. The first is why two overlapping pathways are maintained, given that both are likely energetically expensive. Under our model, RdDM silenced TEs effectively even when the initiation of silencing was weak. This relationship implies that only a small amount of RNAi is needed to initiate TE silencing, but reinforcement by RdDM is necessary to efficiently counter TE propagation. Second, we investigated the reliance of the host response on rates of TE deletion. The model predicted that low levels of deletion lead to few active TEs, suggesting that silencing is most efficient when methylated TEs are retained in the genome, thereby providing one explanation for the large size of plant genomes. PMID- 29608717 TI - Divergent Evolutionary Trajectories of Two Young, Homomorphic, and Closely Related Sex Chromosome Systems. AB - There exists extraordinary variation among species in the degree and nature of sex chromosome divergence. However, much of our knowledge about sex chromosomes is based on comparisons between deeply diverged species with different ancestral sex chromosomes, making it difficult to establish how fast and why sex chromosomes acquire variable levels of divergence. To address this problem, we studied sex chromosome evolution in two species of African clawed frog (Xenopus), both of whom acquired novel systems for sex determination from a recent common ancestor, and both of whom have female (ZW/ZZ) heterogamy. Derived sex chromosomes of one species, X. laevis, have a small region of suppressed recombination that surrounds the sex determining locus, and have remained this way for millions of years. In the other species, X. borealis, a younger sex chromosome system exists on a different pair of chromosomes, but the region of suppressed recombination surrounding an unidentified sex determining gene is vast, spanning almost half of the sex chromosomes. Differences between these sex chromosome systems are also apparent in the extent of nucleotide divergence between the sex chromosomes carried by females. Our analyses also indicate that in autosomes of both of these species, recombination during oogenesis occurs more frequently and in different genomic locations than during spermatogenesis. These results demonstrate that new sex chromosomes can assume radically different evolutionary trajectories, with far-reaching genomic consequences. They also suggest that in some instances the origin of new triggers for sex determination may be coupled with rapid evolution sex chromosomes, including recombination suppression of large genomic regions. PMID- 29608718 TI - Influence of Effective Population Size on Genes under Varying Levels of Selection Pressure. AB - The ratio of diversities at amino acid changing (nonsynonymous) and neutral (synonymous) sites (omega = piN/piS) is routinely used to measure the intensity of selection pressure. It is well known that this ratio is influenced by the effective population size (Ne) and selection coefficient (s). Here, we examined the effects of effective population size on omega by comparing protein-coding genes from Mus musculus castaneus and Mus musculus musculus-two mouse subspecies with different Ne. Our results revealed a positive relationship between the magnitude of selection intensity and the omega estimated for genes. For genes under high selective constraints, the omega estimated for the subspecies with small Ne (M. m. musculus) was three times higher than that observed for that with large Ne (M. m. castaneus). However, this difference was only 18% for genes under relaxed selective constraints. We showed that the observed relationship is qualitatively similar to the theoretical predictions. We also showed that, for highly expressed genes, the omega of M. m. musculus was 2.1 times higher than that of M.m. castaneus and this difference was only 27% for genes with low expression levels. These results suggest that the effect of effective population size is more pronounced in genes under high purifying selection. Hence the choice of genes is important when omega is used to infer the effective size of a population. PMID- 29608719 TI - The Prevalence and Evolutionary Conservation of Inverted Repeats in Proteobacteria. AB - Perfect short inverted repeats (IRs) are known to be enriched in a variety of bacterial and eukaryotic genomes. Currently, it is unclear whether perfect IRs are conserved over evolutionary time scales. In this study, we aimed to characterize the prevalence and evolutionary conservation of IRs across 20 proteobacterial strains. We first identified IRs in Escherichia coli K-12 substr MG1655 and showed that they are overabundant. We next aimed to test whether this overabundance is reflected in the conservation of IRs over evolutionary time scales. To this end, for each perfect IR identified in E. coli MG1655, we collected orthologous sequences from related proteobacterial genomes. We next quantified the evolutionary conservation of these IRs, that is, the presence of the exact same IR across orthologous regions. We observed high conservation of perfect IRs: out of the 234 examined orthologous regions, 145 were more conserved than expected, which is statistically significant even after correcting for multiple testing. Our results together with previous experimental findings support a model in which imperfect IRs are corrected to perfect IRs in a preferential manner via a template switching mechanism. PMID- 29608720 TI - Homologous Recombination between Genetically Divergent Campylobacter fetus Lineages Supports Host-Associated Speciation. AB - Homologous recombination is a major driver of bacterial speciation. Genetic divergence and host association are important factors influencing homologous recombination. Here, we study these factors for Campylobacter fetus, which shows a distinct intraspecific host dichotomy. Campylobacter fetus subspecies fetus (Cff) and venerealis are associated with mammals, whereas C. fetus subsp. testudinum (Cft) is associated with reptiles. Recombination between these genetically divergent C. fetus lineages is extremely rare. Previously it was impossible to show whether this barrier to recombination was determined by the differential host preferences, by the genetic divergence between both lineages or by other factors influencing recombination, such as restriction-modification, CRISPR/Cas, and transformation systems. Fortuitously, a distinct C. fetus lineage (ST69) was found, which was highly related to mammal-associated C. fetus, yet isolated from a chelonian. The whole genome sequences of two C. fetus ST69 isolates were compared with those of mammal- and reptile-associated C. fetus strains for phylogenetic and recombination analysis. In total, 5.1-5.5% of the core genome of both ST69 isolates showed signs of recombination. Of the predicted recombination regions, 80.4% were most closely related to Cft, 14.3% to Cff, and 5.6% to C. iguaniorum. Recombination from C. fetus ST69 to Cft was also detected, but to a lesser extent and only in chelonian-associated Cft strains. This study shows that despite substantial genetic divergence no absolute barrier to homologous recombination exists between two distinct C. fetus lineages when occurring in the same host type, which provides valuable insights in bacterial speciation and evolution. PMID- 29608721 TI - Glutamine Codon Usage and polyQ Evolution in Primates Depend on the Q Stretch Length. AB - Amino acid usage in a proteome depends mostly on its taxonomy, as it does the codon usage in transcriptomes. Here, we explore the level of variation in the codon usage of a specific amino acid, glutamine, in relation to the number of consecutive glutamine residues. We show that CAG triplets are consistently more abundant in short glutamine homorepeats (polyQ, four to eight residues) than in shorter glutamine stretches (one to three residues), leading to the evolutionary growth of the repeat region in a CAG-dependent manner. The length of orthologous polyQ regions is mostly stable in primates, particularly the short ones. Interestingly, given a short polyQ the CAG usage is higher in unstable-in-length orthologous polyQ regions. This indicates that CAG triplets produce the necessary instability for a glutamine stretch to grow. Proteins related to polyQ-associated diseases behave in a more extreme way, with longer glutamine stretches in human and evolutionarily closer nonhuman primates, and an overall higher CAG usage. In the light of our results, we suggest an evolutionary model to explain the glutamine codon usage in polyQ regions. PMID- 29608722 TI - Comparative Serum Challenges Show Divergent Patterns of Gene Expression and Open Chromatin in Human and Chimpanzee. AB - Humans experience higher rates of age-associated diseases than our closest living evolutionary relatives, chimpanzees. Environmental factors can explain many of these increases in disease risk, but species-specific genetic changes can also play a role. Alleles that confer increased disease susceptibility later in life can persist in a population in the absence of selective pressure if those changes confer positive adaptation early in life. One age-associated disease that disproportionately affects humans compared with chimpanzees is epithelial cancer. Here, we explored genetic differences between humans and chimpanzees in a well defined experimental assay that mimics gene expression changes that happen during cancer progression: A fibroblast serum challenge. We used this assay with fibroblasts isolated from humans and chimpanzees to explore species-specific differences in gene expression and chromatin state with RNA-Seq and DNase-Seq. Our data reveal that human fibroblasts increase expression of genes associated with wound healing and cancer pathways; in contrast, chimpanzee gene expression changes are not concentrated around particular functional categories. Chromatin accessibility dramatically increases in human fibroblasts, yet decreases in chimpanzee cells during the serum response. Many regions of opening and closing chromatin are in close proximity to genes encoding transcription factors or genes involved in wound healing processes, further supporting the link between changes in activity of regulatory elements and changes in gene expression. Together, these expression and open chromatin data show that humans and chimpanzees have dramatically different responses to the same physiological stressor, and how a core physiological process can evolve quickly over relatively short evolutionary time scales. PMID- 29608723 TI - Ancient Evolution of Mammarenaviruses: Adaptation via Changes in the L Protein and No Evidence for Host-Virus Codivergence. AB - The Mammarenavirus genus includes several pathogenic species of rodent-borne viruses. Old World (OW) mammarenaviruses infect rodents in the Murinae subfamily and are mainly transmitted in Africa and Asia; New World (NW) mammarenaviruses are found in rodents of the Cricetidae subfamily in the Americas. We applied a selection-informed method to estimate that OW and NW mammarenaviruses diverged less than ~45,000 years ago (ya). By incorporating phylogeographic inference, we show that NW mammarenaviruses emerged in the Latin America-Caribbean region ~41,400-3,300 ya, whereas OW mammarenaviruses originated ~23,100-1,880 ya, most likely in Southern Africa. Cophylogenetic analysis indicated that cospeciation did not contribute significantly to mammarenavirus-host associations. Finally, we show that extremely strong selective pressure on the viral polymerase accompanied the speciation of NW viruses. These data suggest that the evolutionary history of mammarenaviruses was not driven by codivergence with their hosts. The viral polymerase should be regarded as a major determinant of mammarenavirus adaptation. PMID- 29608724 TI - Higher Rates of Protein Evolution in the Self-Fertilizing Plant Arabidopsis thaliana than in the Out-Crossers Arabidopsis lyrata and Arabidopsis halleri. AB - The common transition from out-crossing to self-fertilization in plants decreases effective population size. This is expected to result in a reduced efficacy of natural selection and in increased rates of protein evolution in selfing plants compared with their outcrossing congeners. Prior analyses, based on a very limited number of genes, detected no differences between the rates of protein evolution in the selfing Arabidopsis thaliana compared with the out-crosser Arabidopsis lyrata. Here, we reevaluate this trend using the complete genomes of A. thaliana, A. lyrata, Arabidopsis halleri, and the outgroups Capsella rubella and Thellungiella parvula. Our analyses indicate slightly but measurably higher nonsynonymous divergences (dN), synonymous divergences (dS) and dN/dS ratios in A. thaliana compared with the other Arabidopsis species, indicating that purifying selection is indeed less efficacious in A. thaliana. PMID- 29608725 TI - Homo sapiens-Specific Binding Site Variants within Brain Exclusive Enhancers Are Subject to Accelerated Divergence across Human Population. AB - Empirical assessments of human accelerated noncoding DNA frgaments have delineated presence of many cis-regulatory elements. Enhancers make up an important category of such accelerated cis-regulatory elements that efficiently control the spatiotemporal expression of many developmental genes. Establishing plausible reasons for accelerated enhancer sequence divergence in Homo sapiens has been termed significant in various previously published studies. This acceleration by including closely related primates and archaic human data has the potential to open up evolutionary avenues for deducing present-day brain structure. This study relied on empirically confirmed brain exclusive enhancers to avoid any misjudgments about their regulatory status and categorized among them a subset of enhancers with an exceptionally accelerated rate of lineage specific divergence in humans. In this assorted set, 13 distinct transcription factor binding sites were located that possessed unique existence in humans. Three of 13 such sites belonging to transcription factors SOX2, RUNX1/3, and FOS/JUND possessed single nucleotide variants that made them unique to H. sapiens upon comparisons with Neandertal and Denisovan orthologous sequences. These variants modifying the binding sites in modern human lineage were further substantiated as single nucleotide polymorphisms via exploiting 1000 Genomes Project Phase3 data. Long range haplotype based tests laid out evidence of positive selection to be governing in African population on two of the modern human motif modifying alleles with strongest results for SOX2 binding site. In sum, our study acknowledges acceleration in noncoding regulatory landscape of the genome and highlights functional parts within it to have undergone accelerated divergence in present-day human population. PMID- 29608726 TI - Progress and Prospects in Gender Visibility at SMBE Annual Meetings. AB - Reduced visibility of women in science is thought to be one of the causes of their underrepresentation among scientists, in particular at senior positions. Visibility is achieved through publications, and through conference attendance and presentations. Here, we investigated gender differences in visibility at the annual meetings of the Society of Molecular Biology and Evolution. The analysis of meeting programs showed a regular increase in female speakers for the last 16 years. Data on abstract submission suggest that there are no gender-related preferences in the acceptance of contributed presentations at the most recent meetings. However, data collected on-site in 2015 and 2016 show that women asked only ~25% of the questions, that is, much less than expected given the female attendance. Understanding the reasons for this pattern is necessary for the development of policies that aim to reduce imbalance in visibility. PMID- 29608727 TI - Genetic Ancestry of Hadza and Sandawe Peoples Reveals Ancient Population Structure in Africa. AB - The Hadza and Sandawe populations in present-day Tanzania speak languages containing click sounds and therefore thought to be distantly related to southern African Khoisan languages. We analyzed genome-wide genotype data for individuals sampled from the Hadza and Sandawe populations in the context of a global data set of 3,528 individuals from 163 ethno-linguistic groups. We found that Hadza and Sandawe individuals share ancestry distinct from and most closely related to Omotic ancestry; share Khoisan ancestry with populations such as ?Khomani, Karretjie, and Ju/'hoansi in southern Africa; share Niger-Congo ancestry with populations such as Yoruba from Nigeria and Luhya from Kenya, consistent with migration associated with the Bantu Expansion; and share Cushitic ancestry with Somali, multiple Ethiopian populations, the Maasai population in Kenya, and the Nama population in Namibia. We detected evidence for low levels of Arabian, Nilo Saharan, and Pygmy ancestries in a minority of individuals. Our results indicate that west Eurasian ancestry in eastern Africa is more precisely the Arabian parent of Cushitic ancestry. Relative to the Out-of-Africa migrations, Hadza ancestry emerged early whereas Sandawe ancestry emerged late. PMID- 29608728 TI - Insights into an Extensively Fragmented Eukaryotic Genome: De Novo Genome Sequencing of the Multinuclear Ciliate Uroleptopsis citrina. AB - Ciliated protists are a large group of single-celled eukaryotes with separate germline and somatic nuclei in each cell. The somatic genome is developed from the zygotic nucleus through a series of chromosomal rearrangements, including fragmentation, DNA elimination, de novo telomere addition, and DNA amplification. This unique feature makes them perfect models for research in genome biology and evolution. However, genomic research of ciliates has been limited to a few species, owing to problems with DNA contamination and obstacles in cultivation. Here, we introduce a method combining telomere-primer PCR amplification and high throughput sequencing, which can reduce DNA contamination and obtain genomic data efficiently. Based on this method, we report a draft somatic genome of a multimacronuclear ciliate, Uroleptopsis citrina. 1) The telomeric sequence in U. citrina is confirmed to be C4A4C4A4C4 by directly blunt-end cloning. 2) Genomic analysis of the resulting chromosomes shows a "one-gene one-chromosome" pattern, with a small number of multiple-gene chromosomes. 3) Amino acid usage is analyzed, and reassignment of stop codons is confirmed. 4) Chromosomal analysis shows an obvious asymmetrical GC skew and high bias between A and T in the subtelomeric regions of the sense-strand, with the detection of an 11-bp high AT motif region in the 3' subtelomeric region. 5) The subtelomeric sequence also has an obvious 40 nt strand oscillation of nucleotide ratio. 6) In the 5' subtelomeric region of the coding strand, the distribution of potential TATA-box regions is illustrated, which accumulate between 30 and 50 nt. This work provides a valuable reference for genomic research and furthers our understanding of the dynamic nature of unicellular eukaryotic genomes. PMID- 29608729 TI - Molecular Footprints of Aquatic Adaptation Including Bone Mass Changes in Cetaceans. AB - Cetaceans (whales, dolphins, and porpoises) are a group of specialized mammals that evolved from terrestrial ancestors and are fully adapted to aquatic habitats. Taking advantage of the recently sequenced finless porpoise genome, we conducted comparative analyses of the genomes of seven cetaceans and related terrestrial species to provide insight into the molecular bases of adaptation of these aquatic mammals. Changes in gene sequences were identified in main lineages of cetaceans, offering an evolutionary picture of cetacean genomes that reveal new pathways that could be associated with adaptation to aquatic lifestyle. We profiled bone microanatomical structures across 28 mammals, including representatives of cetaceans, pinnipeds, and sirenians. Subsequent phylogenetic comparative analyses revealed genes (including leptin, insulin-like growth factor 1, and collagen type I alpha 2 chain) with the root-to-tip substitution rate significantly correlated with bone compactness, implicating these genes could be involved in bone mass control. Overall, this study described adjustments of the genomes of cetaceans according to lifestyle, phylogeny, and bone mass. PMID- 29608731 TI - Genome Reports: Contracted Genes and Dwarfed Plastome in Mycoheterotrophic Sciaphila thaidanica (Triuridaceae, Pandanales). AB - With a reduced need for photosynthesis, the plastome of parasitic and mycoheterotrophic plants degrades. In the tiny, fully mycoheterotrophic plant Sciaphila thaidanica, we find one of the smallest plastomes yet encountered. Its size is just 12,780 bp and it contains only 20 potentially functional housekeeping genes. Thus S. thaidanica fits the proposed model of gene loss in achlorophyllous plants. The most astonishing feature of the plastome is its extremely compact nature, with more than half of the genes having overlapping reading frames. Additionally, intergenic sequences have been reduced to a bare minimum, and the retained genes have been reduced in length both compared with the orthologous genes in another mycoheterotrophic species of Sciaphila and in the autotrophic relative Carludovica. PMID- 29608733 TI - A Physical Therapist-Administered Physical Activity Intervention After Total Knee Replacement: Protocol for a Randomized Controlled Trial. AB - Background: The definitive treatment for knee osteoarthritis is a total knee replacement, which results in a clinically meaningful improvement in pain and physical function. However, evidence suggests that physical activity (PA) remains unchanged after total knee replacement (TKR). Objective: The objective of this study is to investigate the efficacy, fidelity, and safety of a physical therapist-administered PA intervention for people after TKR. Design: This study will be a randomized controlled trial. Setting: The setting is an outpatient physical therapy clinic. Participants: The participants are 125 individuals who are over the age of 45 and are seeking outpatient physical therapy following a unilateral TKR. Intervention: In addition to standardized physical therapy after TKR, the intervention group will receive, during physical therapy, a weekly PA intervention that includes a wearable activity tracking device, individualized step goals, and face-to-face feedback provided by a physical therapist. Control: The control group will receive standardized physical therapy alone after TKR. Measurements: The efficacy of the intervention will be measured as minutes per week spent in moderate to vigorous PA at enrollment, at discharge, and at 6 months and 12 months after discharge from physical therapy. The fidelity and safety of the intervention will be assessed throughout the study. Limitations: Participants will not be masked, PA data will be collected after randomization, and the trial will be conducted at a single site. Conclusions: The goal of this randomized controlled trial is to increase PA after TKR. A protocol for investigating the efficacy, fidelity, and safety of a physical therapist administered PA intervention for people after TKR is presented. The findings will be used to support a large multisite clinical trial to test the effectiveness, implementation, and cost of this intervention. PMID- 29608730 TI - Signatures of Long-Term Balancing Selection in Human Genomes. AB - Balancing selection maintains advantageous diversity in populations through various mechanisms. Although extensively explored from a theoretical perspective, an empirical understanding of its prevalence and targets lags behind our knowledge of positive selection. Here, we describe the Non-central Deviation (NCD), a simple yet powerful statistic to detect long-term balancing selection (LTBS) that quantifies how close frequencies are to expectations under LTBS, and provides the basis for a neutrality test. NCD can be applied to a single locus or genomic data, and can be implemented considering only polymorphisms (NCD1) or also considering fixed differences with respect to an outgroup (NCD2) species. Incorporating fixed differences improves power, and NCD2 has higher power to detect LTBS in humans under different frequencies of the balanced allele(s) than other available methods. Applied to genome-wide data from African and European human populations, in both cases using chimpanzee as an outgroup, NCD2 shows that, albeit not prevalent, LTBS affects a sizable portion of the genome: ~0.6% of analyzed genomic windows and 0.8% of analyzed positions. Significant windows (P < 0.0001) contain 1.6% of SNPs in the genome, which disproportionally fall within exons and change protein sequence, but are not enriched in putatively regulatory sites. These windows overlap ~8% of the protein-coding genes, and these have larger number of transcripts than expected by chance even after controlling for gene length. Our catalog includes known targets of LTBS but a majority of them (90%) are novel. As expected, immune-related genes are among those with the strongest signatures, although most candidates are involved in other biological functions, suggesting that LTBS potentially influences diverse human phenotypes. PMID- 29608732 TI - Evolutionary Interplay between Symbiotic Relationships and Patterns of Signal Peptide Gain and Loss. AB - Can orthologous proteins differ in terms of their ability to be secreted? To answer this question, we investigated the distribution of signal peptides within the orthologous groups of Enterobacterales. Parsimony analysis and sequence comparisons revealed a large number of signal peptide gain and loss events, in which signal peptides emerge or disappear in the course of evolution. Signal peptide losses prevail over gains, an effect which is especially pronounced in the transition from the free-living or commensal to the endosymbiotic lifestyle. The disproportionate decline in the number of signal peptide-containing proteins in endosymbionts cannot be explained by the overall reduction of their genomes. Signal peptides can be gained and lost either by acquisition/elimination of the corresponding N-terminal regions or by gradual accumulation of mutations. The evolutionary dynamics of signal peptides in bacterial proteins represents a powerful mechanism of functional diversification. PMID- 29608734 TI - Results of Surgery for Low-Grade Brain Arteriovenous Malformation Resection by Early Career Neurosurgeons: An Observational Study. AB - BACKGROUND: For sustainability of arteriovenous malformation (AVM) surgery, results from early career cerebrovascular neurosurgeons (ECCNs) must be acceptably safe. OBJECTIVE: To determine whether ECCNs performance of Spetzler Ponce Class A AVM (SPC A) resection can be acceptably safe. METHODS: ECCNs completing a cerebrovascular fellowship (2004-2015) with the last author were included. Inclusion of the ECCN cases occurred if they: had a prospective database of all AVM cases since commencing independent practice; were the primary surgeon on SPC A; and had made the significant management decisions. All SPC A surgical cases from the beginning of the ECCN's independent surgical practice to a maximum of 8 yr were included. An adverse outcome was considered a complication of surgery leading to a new permanent neurological deficit with a last modified Rankin Scale score >1. A cumulative summation (Cusum) plot examined the performance of each surgery. The highest acceptable level of adverse outcomes for the Cusum was 3.3%, derived from the upper 95% confidence interval of the last author's reported series. RESULTS: Six ECCNs contributed 110 cases for analysis. The median number of SPC A cases operated by each ECCN was 16.5 (range 4-40). Preoperative embolization was performed in 5 (4.5%). The incidence of adverse outcomes was 1.8% (95% confidence interval: <0.01%-6.8%). At no point during the accumulated series did the combined cohort become unacceptable by the Cusum plot. CONCLUSION: ECCNs with appropriate training appointed to large-volume cerebrovascular centers can achieve results for surgery for SPC A that are not appreciably worse than those published from high-volume neurosurgeons. PMID- 29608735 TI - Does air pollution contribute to travelers' illness and deaths?-evidence from a case report and need for further studies. AB - Annual increases in global travel have resulted in more individuals being exposed to varying environmental conditions abroad and, thereby, subject to air pollution related health risks. Individuals who travel abroad may be exposed to varying levels of air pollution within a matter of hours. We wish to consider whether exposure to air pollution could be a significant contributor to the risk of illness and death in travelers, particularly those who travel to highly polluted cities. We report the findings of a study in which the peak expiratory flow (PEF) of a traveler decreased in Shanghai relative to baseline in New York City; the decline in PEF correlated to concentration of particulate matter (PM2.5). We discuss the health implication of these results on global travel. PMID- 29608736 TI - Listening to the deaf international traveller. PMID- 29608737 TI - Comments on 'Protecting the health of medical students on international electives in low-resource settings'. PMID- 29608738 TI - Improving access and provision of pre-travel healthcare for travellers visiting friends and relatives: a review of the evidence. AB - Background: Travellers visiting friends and relatives (VFR travellers) in their country of origin are at increased risk of a range of preventable infections. Risks are broadly related to circumstances of travel, risk misconceptions and access to health services. Despite nearly two decades of literature highlighting these increased risks little impact has been made on their risk disparity. Methods: This review draws on evidence from travel medicine literature, supplemented by evidence from the broader field of immigrant health, and is structured to include strategies that aim to reduce barriers at the patient, provider and health system level. Results: For the travel medicine provider, tailored risk communication that is cognisant of the unique health beliefs and barriers to travel health for VFR travellers is needed, including enhanced communication through the use of interpreters and supplementary written communication. Primary care providers are uniquely placed to identify future travel plans among immigrant patients, however, greater awareness of VFR traveller risks and training in travel medicine are required. Community health promotion interventions that are culturally appropriate, translated into multiple languages and takes into account the cumulative risk of multiple return visits are key to normalizing travel healthcare seeking behaviours and improving awareness of VFR travel risks. Currently, there are few examples of novel strategies to engage migrant communities in travel health with no formal evaluations of their effectiveness. Best practice includes the use of community consulted approaches in collaboration with government, primary care and travel medicine. Conclusions: Multifactorial barriers related to health beliefs and access to health services require a range of strategies and interventions in both reaching and providing advice to VFR travellers. To improve the evidence base, future research should focus on the evaluation of novel strategies that address these barriers and improve access and provision of pre-travel healthcare to VFR travellers. PMID- 29608739 TI - Submaximal exercise testing at low altitude for prediction of exercise tolerance at high altitude. AB - Annually, thousands of air travellers visit high altitude destinations to enjoy hiking tours to attractions in surrounding areas. However, many of them are not adequately trained, not sufficiently acclimatized and/or may suffer from pre existing diseases. To prevent adverse health effects and unpleasant experiences at high altitude, simple submaximal exercise testing at low altitude for the prediction of exercise tolerance at high altitude would be helpful. Therefore, 40 healthy males and females performed submaximal exercise tests at low (600 m) and high altitude (3500 m). We demonstrate that exercise tolerance during acute exposure to high altitude can be predicted by the individual heart rate response to submaximal exercise assessed at low altitude. PMID- 29608740 TI - Prolonged antibiotic use leading to Clostridium difficile colitis in an ill returned traveller with acute fascioliasis. AB - We report a case of a 29-year-old woman who presented to hospital with fever, right upper quadrant pain, marked eosinophilia, and liver abscesses after returning to Canada from Bali, Indonesia. Diagnostic delay and prolonged antibiotic use led to morbidity before the eventual diagnosis and treatment of fascioliasis. PMID- 29608741 TI - Critically Elevated Potassium in a 55-Year-Old Female With Chronic Lymphocytic Leukemia. AB - Hyperkalemia in specimens from patients with chronic lymphocytic leukemia (CLL) may be due to tumor lysis syndrome (TLS) or specimen processing. This report describes a 55-year-old Caucasian woman with CLL who presented to an outside hospital with hyperkalemia and was transferred to a second hospital. Initial evaluation on the core laboratory chemistry analyzer (the VITROS 5600) and the ABL90 FLEX blood gas analyzer showed markedly elevated levels of potassium (K+). TLS was subsequently diagnosed, and dialysis was initiated. However, follow-up K+ measurements in whole blood (WB) yielded low levels that were unexpected after a single dialysis treatment. We then discovered that the initially elevated K+ level was from centrifuged plasma specimens and concluded that it indicated pseudohyperkalemia, likely from centrifugation. This case demonstrates that medical teams need be alert to potentially false K+ results in patients with elevated white blood cell counts. WB specimens are preferable, and steps to minimize trauma to the specimen and immediate analysis using blood gas instruments are recommended. PMID- 29608742 TI - Distribution of the Related Weevil Species Sitophilus oryzae and S. zeamais (Coleoptera: Curculionidae) in Farmer Stored Grains of China. AB - Sitophilus oryzae (Coleoptera: Curculionidae) and Sitophilus zeamais (Coleoptera: Curculionidae) are major insect pests of farm-stored grains in China. Moreover, their respective distribution and prevalence are not yet assessed for grain storage facilities in China. The two species are often difficult to identify by morphology because they are immature or their presence is only evident from fragments. Species-specific primers were, therefore, designed based on the cytochrome c oxidase subunit I (COI) of 34 populations found throughout China and three foreign populations. Following the validation of this molecular-based approach for species identification, the distribution of the two species in China was determined from 68 different grain storage facilities. The results indicate that S. zeamais is prevalent throughout the country whereas S. oryzae is mainly present in the south and the center of China. It is believed that this distribution pattern is in function of ecological adaptation, mostly determined by temperature and the grain species. This is the first report of its kind, demonstrating the distribution of S. zeamais and S. oryzae in grain storage facilities throughout China and analyzed by species-specific primers of COI. PMID- 29608744 TI - SECOND CANCER RISK FROM RADIATION THERAPY FOR COMMON SOLID TUMORS DIAGNOSED IN REPRODUCTIVE-AGED FEMALES. AB - This study provided second cancer risk estimates from radiation therapy for common solid tumors presented in reproductive-aged females. Three-dimensional treatment plans were generated for 10 patients with cervical, uterine, rectal, lung or breast carcinomas. The organ equivalent dose (OED) and the lifetime attributable risk (LAR) for carcinogenesis to organs receiving high doses were estimated for all study participants with a mechanistic model. This model accounts for cell-killing, tissue repair and dose fractionation effects. The patient- and organ-specific relative risk was assessed by using the LARs and the respective lifetime intrinsic cancer risks for unexposed population. The OED of the organs-at-risk varied from 17.3 to 1423.1 rad. The LAR range for bladder, colon, lung and breast cancer induction was 0.12-0.14%, 10.88-12.71%, 1.66-8.62% and 0.71-3.75%, respectively. The relative risk for the appearance of bladder, colon, lung and breast malignancies following radiotherapy was up to 1.12, 4.05, 2.42 and 1.31, respectively. PMID- 29608743 TI - Multiple cAMP Phosphodiesterases Act Together to Prevent Premature Oocyte Meiosis and Ovulation. AB - Luteinizing hormone (LH) acts on the granulosa cells that surround the oocyte in mammalian preovulatory follicles to cause meiotic resumption and ovulation. Both of these responses are mediated primarily by an increase in cyclic adenosine monophosphate (cAMP) in the granulosa cells, and the activity of cAMP phosphodiesterases (PDEs), including PDE4, contributes to preventing premature responses. However, two other cAMP-specific PDEs, PDE7 and PDE8, are also expressed at high levels in the granulosa cells, raising the question of whether these PDEs also contribute to preventing uncontrolled activation of meiotic resumption and ovulation. With the use of selective inhibitors, we show that inhibition of PDE7 or PDE8 alone has no effect on the cAMP content of follicles, and inhibition of PDE4 alone has only a small and variable effect. In contrast, a mixture of the three inhibitors elevates cAMP to a level comparable with that seen with LH. Correspondingly, inhibition of PDE7 or PDE8 alone has no effect on meiotic resumption or ovulation, and inhibition of PDE4 alone has only a partial and slow effect. However, the fraction of oocytes resuming meiosis and undergoing ovulation is increased when PDE4, PDE7, and PDE8 are simultaneously inhibited. PDE4, PDE7, and PDE8 also function together to suppress the premature synthesis of progesterone and progesterone receptors, which are required for ovulation. Our results indicate that three cAMP PDEs act in concert to suppress premature responses in preovulatory follicles. PMID- 29608745 TI - Clinical image: bullous lupus erythematosus. PMID- 29608746 TI - Genome-by-genome approach for fast bacterial genealogical relationship evaluation. AB - Motivation: Large-scale whole-genome sequencing dataset-based studies are becoming increasingly common in pathogen surveillance and outbreak investigations. A highly discriminative and time-efficient bioinformatics tool is needed to transform large amounts of sequencing data into usable biological information. To replace the intuitive, yet inefficient, way of gene-by-gene allele calling algorithm, a new algorithm using genome-by-genome approach was developed. Results: Tests showed that the program equipped with the new algorithm achieved significant improvements in allele calling efficiency compared to a conventional gene-by-gene approach. The new program, Fast-GeP, rendered a fast and easy way to infer high-resolution genealogical relationships between bacterial isolates using whole-genome sequencing data. Availability and implementation: FAST-GeP is freely available from: https://github.com/jizhang nz/fast-GeP. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29608747 TI - Pharmacy-Mediated Antiplatelet Management Protocol Compared to One-time Platelet Function Testing Prior to Pipeline Embolization of Cerebral Aneurysms: A Propensity Score-Matched Cohort Study. AB - BACKGROUND: There is ongoing controversy regarding the optimal antiplatelet regimen, and extent or even need for platelet function testing surrounding Pipeline flow diverter (Medtronic Inc, Dublin, Ireland) embolization of cerebral aneurysms. OBJECTIVE: To compare a unique pharmacy-mediated antiplatelet medication management protocol to a 1-time platelet function testing strategy prior to Pipeline placement. METHODS: A retrospective review of patients with cerebral aneurysms who underwent Pipeline embolization at 2 academic institutions was performed. The first line antiplatelet regimen consisted of aspirin and clopidogrel at both institutions. At institution A, the pharmacy-mediated antiplatelet medication management protocol consisted of repeat platelet function testing using VerifyNow (Accriva Diagnostics, San Diego, California), and dosing adjustments prior to and after Pipeline placement. At institution B, a 1-time platelet function test using light transmission aggregometry was obtained prior to Pipeline placement. Both strategies were compared using propensity score matching. RESULTS: A total of 63 and 165 Pipeline embolization procedures were performed at institutions A and B, respectively. Baseline characteristics differed in aneurysm location and aneurysm maximal diameter. Propensity score matching resulted in 25 matched pairs and demonstrated that the number of procedures in which the patient was switched to an alternative platelet agent was significantly smaller at institution A. There were no differences between the sites with regard to aneurysm occlusion rate, the incidence of thromboembolic and hemorrhagic complications, and modified Rankin scale at last follow-up after propensity score matching. CONCLUSION: Pharmacy-mediated antiplatelet management using VerifyNow is a safe and efficacious alternative to a more traditional approach, and significantly reduces the need to utilize other, potentially more expensive antiplatelet agents. PMID- 29608748 TI - Increases in Neuroticism May Be an Early Indicator of Dementia: A Coordinated Analysis. AB - Objectives: Although personality change is typically considered a symptom of dementia, some studies suggest that personality change may be an early indication of dementia. One prospective study found increases in neuroticism preceding dementia diagnosis (Yoneda et al, 2017). The current study extends this research by examining trajectories of personality traits in additional longitudinal studies of aging. Method: Three independent series of latent growth curve models were fitted to data from the Longitudinal Aging Study Amsterdam (LASA) and Einstein Aging Study (EAS) to estimate trajectories of personality traits in individuals with incident dementia diagnosis (Total N = 210), in individuals with incident Mild Cognitive Impairment (N = 135), and in individuals who did not receive a diagnosis during follow-up periods (Total N = 1740). Results: Controlling for sex, age, education, depressive symptoms, and the interaction between age and education, growth curve analyses consistently revealed significant linear increases in neuroticism preceding dementia diagnosis in both datasets and in individuals with MCI. Analyses examining individuals without a diagnosis revealed non-significant change in neuroticism overtime. Discussion: Replication of our previous work in two additional datasets provides compelling evidence that increases in neuroticism may be early indication of dementia, which can facilitate development of screening assessments. PMID- 29608749 TI - Evaluation of novel protease enzymes on growth performance and apparent ileal digestibility of amino acids in poultry: enzyme screening. AB - Three experiments were conducted to evaluate eight neutral and six acid proteases on growth performance and apparent ileal amino acid digestibility (AID) of poults (Experiment 1) or chicks (Experiments 2 and 3). Two basal diets were formulated: a nutrient adequate positive control (PC), which met or exceeded the nutrient requirements for poults (Experiment 1) or chicks (Experiments 2 and 3) and a negative control (NC) formulated to achieve 85% (Experiments 1 and 2) or 80% (Experiments 3) of the requirement for protein and amino acids. Phytase was included in all diets to provide 500 phytase units (FTU)/kg and xylanase was included in all diets to provide 10,000 (Experiments 1 and 2) or 16,000 (Experiments 3) xylanase units (BXU)/kg. Proteases were supplemented in the NC diet at an equivalent amount of enzyme protein to create 16 experimental diets. There were five birds/pen and 10 replicate pens per treatment in each experiment. In experiment 1, birds fed the PC diet gained more (P < 0.05) than birds fed the NC. There were no differences in growth performance in birds fed the PC or NC in experiments 2 or 3. In all three experiments, birds fed the NC supplemented with neutral protease 1 had reduced (P < 0.05) feed intake (FI) or body weight gain (BWG) and increased (P < 0.05) feed conversion ratio (FCR) compared with birds fed the NC. Birds fed the NC diet supplemented with neutral protease 3, 7 (Experiment 1), or acid protease 4 (Experiment 3) had increased (P < 0.05) FCR and birds fed neutral protease 6 (Experiment 2) had reduced (P < 0.05) BWG compared with birds fed the NC. Apparent ileal amino acid digestibility was improved (P < 0.05) with protease supplementation to the NC diets (Experiment 1 or 3), but this was dependent on the protease and the amino acid. In conclusion, novel protease supplementation improved AID of amino acids but this was not reflected in improvements in growth performance of poults or chicks. PMID- 29608750 TI - Impact of rapid, culture-independent diagnosis of candidaemia and invasive candidiasis in a community health system. AB - Background: Delay in treatment of candidaemia and invasive candidiasis remains a cause of significant morbidity and mortality in high-risk patients. Widespread empirical utilization of antifungal therapy often occurs in an effort to minimize this risk. Objectives: This study assessed the impact of the T2Candida Panel in a multi-hospital community health system on time to initiation of antifungal therapy in candidaemic patients as well as the utilization of micafungin. Methods: Outcomes were compared between those patients with candidaemia prior to T2Candida implementation and those after implementation. Micafungin utilization for patients with suspected candidaemia/invasive candidiasis was compared with that for patients with a negative T2Candida Panel post-implementation. Results: There was a significant decrease in time to appropriate therapy in the post T2Candida group (34 versus 6 h, P = 0.0147). Empirical antifungal therapy was avoided in 58.4% of T2Candida-negative patients. Conclusions: These results support the implementation of T2Candida to improve time to appropriate therapy for candidaemic patients while simultaneously expanding antimicrobial stewardship efforts to appropriately utilize antifungals. PMID- 29608751 TI - T2Candida MR as a predictor of outcome in patients with suspected invasive candidiasis starting empirical antifungal treatment: a prospective pilot study. AB - Objectives: We assessed the potential role of T2Candida MR (T2MR) and serological biomarkers [beta-d-glucan (BDG) or Candida albicans germ tube antibodies (CAGTA)], alone or in combination with standard cultures, for identifying patients with suspected invasive candidiasis (IC), who may benefit from maintaining antifungal therapy. Methods: Prospective observational multicentre study including all adult patients receiving empirical antifungal therapy for suspected IC, from January to June 2017. CAGTA, BDG and T2MR were determined at baseline and at +2 and +4 days after enrolment. Primary endpoint was the diagnostic value of CAGTA, BDG and T2MR, alone or in combination with standard culture, to predict diagnosis of IC and/or mortality in the first 7 days after starting antifungal therapy (poor outcome). Results: Overall, 14/49 patients (28.6%) had a poor outcome (7 died within the first 7 days of antifungal therapy, whereas 7 ended with a diagnosis of IC). CAGTA [3/14 (21.4%) versus 8/35 (22.9%), P = 1] and BDG [8/14 (57.1%) versus 17/35 (48.6%), P = 0.75] results were similar in poor- and good-outcome patients. Conversely, a positive T2MR was associated with a higher risk of poor outcome [5/14 (35.7%) versus 0/35 (0.0%) P = 0.0001]. Specificity and positive predictive value of a positive T2MR for predicting poor outcome were both 100%, with a negative predictive value of 79.6%. After testing the combinations of biomarkers/standard cultures and T2MR/standard cultures, the combination of T2MR/standard cultures showed a high capacity to discriminate patients with poor outcome from those with good clinical evolution. Conclusions: T2MR may be of significant utility to identify patients who may benefit from maintaining antifungal therapy. PMID- 29608753 TI - T2Bacteria magnetic resonance assay for the rapid detection of ESKAPEc pathogens directly in whole blood. AB - Objectives: To evaluate the magnetic resonance-based T2Bacteria Panel assay for direct detection of ESKAPEc (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Escherichia coli) pathogens in blood samples of patients with suspected bloodstream infection (BSI). Patients and methods: Adult patients admitted to the Emergency Medicine Department, Infectious Diseases Unit and ICU of a large tertiary-care hospital were included if they had a blood culture (BC) ordered concomitantly with a whole-blood sample for T2Bacteria testing. Results were compared with those of BC and other clinically relevant information. Results: A total of 140 samples from 129 BSI patients were studied. Single bacteria were detected in 15.7% (22/140) and 12.1% (17/140), and multiple bacteria in 2.9% (4/140) and 1.4% (2/140), of samples tested by T2Bacteria and BC, respectively. With respect to the six target (ESKAPEc) species, overall sensitivity and specificity of T2Bacteria across all detection channels in comparison with BC were 83.3% and 97.6%, respectively; these values increased to 89.5% and 98.4%, respectively, when a true-infection criterion (i.e. the same microorganism detected only by T2Bacteria was cultured from another sample type reflecting the source of infection) was used as the comparator. There were 808 T2Bacteria detection results across 112 samples, with concordant negative results, yielding a negative predictive value of 99.8%. The mean time to negative result was 6.1 +/ 1.5 h, whereas the mean time to detection/species identification was 5.5 +/- 1.4 h. Conclusions: The T2Bacteria Panel assay has the potential to provide accurate and timely diagnosis of ESKAPEc bacteraemia, which might support the direct therapeutic management of BSI patients. PMID- 29608754 TI - T2 magnetic resonance for the diagnosis of bloodstream infections: charting a path forward. AB - We discuss four studies in this issue of the Journal of Antimicrobial Chemotherapy that describe experience with T2 magnetic resonance (T2MR) nanodiagnostics for Candida and bacterial bloodstream infections, in the context of the T2MR literature. T2Candida and T2Bacteria panels use a dedicated instrument to detect amplified DNA from microbial cells directly in whole blood. T2Candida gives positive or negative results for C. albicans/C. tropicalis, C. glabrata/C. krusei, and C. parapsilosis. T2Bacteria detects Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Escherichia coli. In recent trials, T2Candida sensitivity and specificity for candidaemia were ~90% and ~98%, respectively. Two studies from Spanish hospitals now provide the first data on T2Candida as a prognostic tool. T2Candida was superior to cultures or serum beta-d-glucan in identifying patients with complicated candidaemia, and in predicting the outcomes of empirical antifungal therapy for suspected candidiasis. In a retrospective study from US community hospitals, use of T2Candida was reported to reduce times to appropriate antifungal therapy, shorten courses of empirical therapy, and save an average of US$280 in antifungal costs per patient tested. Finally, a study from a hospital in Rome provides the first clinical data for T2Bacteria: sensitivity and specificity were 89% and 98%, respectively, among patients with positive blood cultures for bacteria detected by the panel, or fulfilling criteria for infection. We conclude that T2MR diagnostics are promising both for detecting bloodstream infections due to Candida and bacteria, and for providing prognostic information. More studies that present real-world performance data are needed. PMID- 29608752 TI - T2MR contributes to the very early diagnosis of complicated candidaemia. A prospective study. AB - Objectives: Diagnosis of complicated candidaemia represents a challenge for clinicians since early clinical manifestations may be non-specific and difficult to identify, thus precluding an appropriate treatment. Patients and methods: This was a multicentre prospective study for predicting complicated episodes in patients with bloodstream infection caused by Candida species, while assessing the value of follow-up blood cultures (BCs) and the persistence of positive results for T2Candida MR (T2MR) and blood beta-d-glucan (BDG) tests. Immediately after the first positive BC yielding Candida species, samples were obtained on days 0, +2, +4, +7 and +14, to simultaneously perform follow-up BC, T2MR and BDG. An episode of candidaemia was defined as 'complicated' when (i) it caused septic metastasis; and/or (ii) it was the cause of the patient's death. Results: From January to June 2017, 30 patients were enrolled in the study. Of these, nine (30%) had complicated candidaemia. Values of persistently positive samples for the prediction of complicated episodes for BCs, T2MR and BDG, respectively, were as follows: sensitivity (44.4%, 100%, 100%); specificity (76.1%, 76.1%, 38.9%); positive predictive value (PPV) (44.4%, 64.2%, 40.9%) and negative predictive value (NPV) (76.1%, 100%, 100%). In multivariate analysis, having a positive T2MR within the first 5 days was associated with an almost 37-fold higher risk of developing complicated candidaemia. Conclusions: The T2MR test performed in patients with proven candidaemia may be a better marker of complicated infection than follow-up BCs or BDG. It is possible that this test may change current clinical practice, influencing the length and type of antifungal therapy in this population. PMID- 29608755 TI - Factor structure and psychometric properties of the Pittsburgh Sleep Quality Index in community-based adolescents. AB - Study Objectives: The Pittsburgh Sleep Quality Index (PSQI) is a widely used self report questionnaire that assesses general sleep quality. This study aimed to validate the single-factor scoring structure and related psychometric properties in the English language version of the PSQI in community-based adolescents. Methods: Participants were 889 (352 males, 39.6%) students (age M = 15.71 +/- 1.57; 12.08-18.92 years) recruited from 14 Australian secondary schools. Participants completed the PSQI, Center for Epidemiological Studies-Depression (CES-D) scale, and Spence Children's Anxiety Scale (SCAS). Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) of PSQI component scores were performed on two independent random half-samples (i.e. cross-validation approach). The internal consistency of PSQI components and convergent validity of the PSQI global score with CES-D and SCAS total scores were also assessed. Results: EFA yielded a single-factor model. CFA of the single-factor model in a separate sample yielded acceptable model fit to the data after important relationships were modeled. Namely, modification indices suggested improved model fit by correlating residual scores of PSQI components of sleep duration and sleep efficiency, and sleep efficiency and sleep latency. Internal consistency was acceptable (Cronbach's alpha = 0.73). The PSQI global score had moderate-to-large positive correlations with CES-D (r = 0.58) and SCAS (r = 0.45) total scores, demonstrating good convergent validity with emotional problems as predicted. Conclusions: The findings validate the single-factor scoring structure of the PSQI in an adolescent sample and highlight important covariation between poor sleep duration, efficiency, and latency in this age group. Further validation studies are required to determine an appropriate PSQI clinical cut-off score for adolescents. PMID- 29608756 TI - Letter: Enrollment-To-Screening Ratio: An Undervalued Data in Randomized Clinical Trials. PMID- 29608757 TI - Prevalence and antimicrobial resistance patterns of Salmonella isolated from poultry farms in southeastern United States. AB - Salmonella spp. are among the most common foodborne pathogens, and increase in the occurrence of antimicrobial drug-resistant Salmonella poses a severe risk to public health. The main objective of this study was to determine changes in Salmonella prevalence and their antimicrobial resistance on poultry farms following recommendations to changes in biosecurity practices. Four poultry farms were sampled by collecting cloacal swabs, drag swabs, and litter samples prior to recommended biosecurity changes (March-April) and post recommendations (October November). Prevalence of Salmonella was 3 to 4% during pre-recommendations, while the prevalence was higher (P > 0.05), ranging from 5 to 14% during post recommendations. Higher Salmonella prevalence was observed for pre- and post recommendation phases by sample type in cloacal and drag samples -5% for farm 1, drag swab -6% on farm 2, cloacal swab -6% for farm 3, and drag swab -17% on farm 4. The PCR confirmed Salmonella were serotyped and tested for antimicrobial resistance. Six serotypes of Salmonella were identified with S. Enteritidis (52%) being the most prevalent, followed by S. Berta (38%), S. Mbandaka (7%), S. Typhimurium (2%), S. Kentucky (0.4%), and S. Tennessee (0.4%). A total of 7% isolates exhibited resistance to at least one of the 8 antimicrobials. Higher resistance was observed for tetracycline, streptomycin, and nalidixic acid. A single isolate of S. Mbandaka exhibited multidrug resistance to tetracycline, amoxicillin/clavulanic acid, and ampicillin. Based on these prevalence results, it can be inferred that, irrespective of implementation of improved biosecurity practices, seasonal variation can cause changes in the prevalence of Salmonella on the farms. Resistance to clinically important antimicrobials used to treat salmonellosis is a concern to public health. PMID- 29608758 TI - Neutrophil extracellular trap release is associated with antinuclear antibodies in systemic lupus erythematosus and anti-phospholipid syndrome. AB - Objectives: Increased release of neutrophil extracellular traps (NETs) is implicated in the activation of plasmacytoid dendritic cells, vascular disease and thrombosis in SLE and APS. However, studies comparing NET release between patients with SLE and APS are lacking. Here we evaluated plasma-induced NET release in a large cohort of patients with SLE, SLE + APS and primary APS in relation to clinical and serological parameters. Methods: Neutrophils from healthy controls were exposed to plasma of heterologous healthy controls (n = 27) or SLE (n = 55), SLE + APS (n = 38) or primary APS (PAPS) (n = 28) patients and NET release was quantified by immunofluorescence. In a subset of SLE patients, NET release was assessed in longitudinal samples before and after a change in treatment. Results: Plasma-induced NET release was increased in SLE and APS patients, with the highest NET release found in patients with SLE (+/-APS). Plasma of 60% of SLE, 61% of SLE + APS and 45% of PAPS patients induced NET release. NET release did not correlate with disease activity in SLE or APS. However, increased levels of anti-nuclear and anti-dsDNA autoantibodies were associated with increased NET release in SLE and APS. Only in SLE patients, elevated NET release and an increased number of low-density granulocytes were associated with a high IFN signature. Conclusion: Increased NET release is associated with autoimmunity and inflammation in SLE and APS. Inhibition of NET release thus could be of potential benefit in a subset of patients with SLE and APS. PMID- 29608760 TI - Forearm myo-fasciitis and arthritis in a female with metastatic ovarian carcinoma. PMID- 29608759 TI - Negative Schizotypy and Altered Functional Connectivity During Facial Emotion Processing. AB - Background: Impairment in facial emotion perception is an important domain of social cognition deficits in schizophrenia. Although impaired facial emotion perception has been found in individuals with negative schizotypy (NS), little is known about the corresponding change in brain functional connectivity. Methods: Sixty-four participants were classified into a high NS group (n = 34) and a low NS group (n = 30) based on their total scores on the Chapman scales for physical and social anhedonia. All participants undertook a facial emotion discrimination functional imaging task that consisted of four emotional valences (angry, fear, happy, and neutral). For univariate analysis, the signal change at the bilateral amygdala was compared for each emotional contrast using SPSS (P < .05). For the functional connectivity analysis, we calculated the beta-series functional connectivity of the bilateral amygdala with the medial prefrontal cortex (mPFC) and compared the group differences in SPM12 (P < .05, small volume family-wise error correction). Results: No significant differences were found between the high and low NS groups in accuracy and reaction time in the facial emotion discrimination task. The high NS group showed reduced brain activations at the amygdala under fearful and neutral conditions. Reduced functional connectivity between the amygdala and the mPFC/dorsal anterior cingulate cortex under the happy and fearful conditions in the high NS group was also found. Conclusions: Our findings suggest that the individuals with high NS showed altered brain activity and functional connectivity at the amygdala during facial emotion processing and provide new evidence for understanding social cognition deficits in at-risk individuals. PMID- 29608761 TI - Correlates and consequences of central sleep apnea in a national sample of US veterans. AB - The prevalence and consequences of central sleep apnea (CSA) in adults are not well described. By utilizing the large Veterans Health Administration (VHA) national administrative databases, we sought to determine the incidence, clinical correlates, and impact of CSA on healthcare utilization in Veterans. Analysis of a retrospective cohort of patients with sleep disorders was performed from outpatient visits and inpatient admissions from fiscal years 2006 through 2012. The CSA group, defined by International Classification of Diseases-9, was compared with a comparison group. The number of newly diagnosed CSA cases increased fivefold during this timeframe; however, the prevalence was highly variable depending on the VHA site. The important predictors of CSA were male gender (odds ratio [OR] = 2.31, 95% confidence interval [CI]: 1.94-2.76, p < 0.0001), heart failure (HF) (OR = 1.78, 95% CI: 1.64-1.92, p < 0.0001), atrial fibrillation (OR = 1.83, 95% CI: 1.69-2.00, p < 0.0001), pulmonary hypertension (OR = 1.38, 95% CI:1.19-1.59, p < 0.0001), stroke (OR = 1.65, 95% CI: 1.50-1.82, p < 0.0001), and chronic prescription opioid use (OR = 1.99, 95% CI: 1.87-2.13, p < 0.0001). Veterans with CSA were at an increased risk for hospital admissions related to cardiovascular disorders compared with the comparison group (incidence rate ratio [IRR] = 1.50, 95% CI: 1.16-1.95, p = 0.002). Additionally, the effect of prior HF on future admissions was greater in the CSA group (IRR: 4.78, 95% CI: 3.87-5.91, p < 0.0001) compared with the comparison group (IRR = 3.32, 95% CI: 3.18-3.47, p < 0.0001). Thus, CSA in veterans is associated with cardiovascular disorders, chronic prescription opioid use, and increased admissions related to the comorbid cardiovascular disorders. Furthermore, there is a need for standardization of diagnostics methods across the VHA to accurately diagnose CSA in high-risk populations. PMID- 29608762 TI - The Zn-finger domain of human PrimPol is required to stabilize the initiating nucleotide during DNA priming. AB - Human PrimPol is a monomeric enzyme whose DNA primase activity is required to rescue stalled replication forks during nuclear and mitochondrial DNA replication. PrimPol contains an Archeal-Eukaryotic Primases (AEP) core followed by a C-terminal Zn finger-containing domain (ZnFD), that is exclusively required for primer formation and for PrimPol function in vivo. The present study describes the sequential substrate interactions of human PrimPol during primer synthesis, and the relevance of the ZnFD at each individual step. Both the formation of a PrimPol:ssDNA binary complex and the upcoming interaction with the 3'-nucleotide (pre-ternary complex) remained intact when lacking the ZnFD. Conversely, the ZnFD was required for the subsequent binding and selection of the 5'-nucleotide that will become the first nucleotide of the new primer strand. Providing different 5'-site nucleotides, we can conclude that the ZnFD of PrimPol most likely interacts with the gamma-phosphate moiety of the 5'-site nucleotide, optimizing formation of the initial dimer. Moreover, the ZnFD also contributes to recognize the cryptic G at the preferred priming sequence 3'GTC5'. Dimer elongation to obtain long DNA primers occurs processively and is facilitated by the 5'-terminal triphosphate, indicating that the ZnFD is also essential in the subsequent translocation/elongation events during DNA primer synthesis. PMID- 29608763 TI - Gas exchange by the mesic-origin, arid land plantation species Robinia pseudoacacia under annual summer reduction in plant hydraulic conductance. AB - The mesic-origin plantation species Robinia pseudoacacia L. has been successfully grown in many arid land plantations around the world but often exhibits dieback and reduced growth due to drought. Therefore, to explore the behavior of this species under changing environmental conditions, we examined the relationship between ecophysiological traits, gas exchange and plant hydraulics over a 3-year period in trees that experienced reduced plant hydraulic conductance (Gp) in summer. We found that the transpiration rate, stomatal conductance (Gs) and minimum leaf water potential (Psilmin) decreased in early summer in response to a decrease in Gp, and that Gp did not recover until the expansion of new leaves in spring. However, we did not observe any changes in the leaf area index or other ecophysiological traits at the leaf level in response to this reduction in Gp. Furthermore, model simulations based on measured data revealed that the canopy scale photosynthetic rate (Ac) was 15-25% higher than the simulated Ac when it was assumed that Psilmin remained constant after spring but almost the same as the simulated Ac when it was assumed that Gp remained high even after spring. These findings indicate that R. pseudoacacia was frequently exposed to a reduced Gp at the study site but offset its effects on Ac by plastically lowering Psilmin to avoid experiencing any further reduction in Gp or Gs. PMID- 29608764 TI - mTOR inhibition in glioblastoma: requiem for a dream? PMID- 29608765 TI - Dampening of IL-2 Function in Infants With Severe Respiratory Syncytial Virus Disease. AB - Background: FOXP3+ regulatory T cells (Tregs) restrain the destructive potential of the immune system. We have previously reported a pronounced reduction in circulating Tregs in infants with severe respiratory syncytial virus (RSV) disease. Because interleukin-2 (IL-2) is critical for Treg growth, survival, and activity, we here analyzed IL-2 production and function in RSV-infected infants. Methods: Phenotype, proliferation, IL-2 production, and IL-2 signaling in CD4+ T cells were analyzed by flow cytometry. Serum soluble CD25 levels were quantified by ELISA. Results: CD4+ T cells from RSV-infected infants produced lower amounts of IL-2 and showed a reduced proliferative response compared with healthy infants. IL-2 increased CD4+ T-cell proliferation and FOXP3 expression in both healthy and RSV-infected infants. However, although IL-2 induced a similar pattern of STAT5 phosphorylation, the proliferative response of CD4+ T cells and the expression of FOXP3+ remained significantly lower in RSV-infected infants. Interestingly, we found a negative correlation between disease severity and both the production of IL-2 by CD4+ T cells and the ability of exogenous IL-2 to restore the pool of FOXP3+CD4+ T cells. Conclusions: A reduced ability to produce IL-2 and a limited response to this cytokine may affect the function of CD4+ T cells in RSV-infected infants. PMID- 29608766 TI - Life-threatening reversible bone marrow toxicity in a rheumatoid arthritis patient switched from leflunomide to infliximab. PMID- 29608767 TI - Descriptive Analysis of a Baseline Concussion Battery Among U.S. Service Academy Members: Results from the Concussion Assessment, Research, and Education (CARE) Consortium. AB - Introduction: The prevalence and possible long-term consequences of concussion remain an increasing concern to the U.S. military, particularly as it pertains to maintaining a medically ready force. Baseline testing is being used both in the civilian and military domains to assess concussion injury and recovery. Accurate interpretation of these baseline assessments requires one to consider other influencing factors not related to concussion. To date, there is limited understanding, especially within the military, of what factors influence normative test performance. Given the significant physical and mental demands placed on service academy members (SAM), and their relatively high risk for concussion, it is important to describe demographics and normative profile of SAMs. Furthermore, the absence of available baseline normative data on female and non-varsity SAMs makes interpretation of post-injury assessments challenging. Understanding how individuals perform at baseline, given their unique individual characteristics (e.g., concussion history, sex, competition level), will inform post-concussion assessment and management. Thus, the primary aim of this manuscript is to characterize the SAM population and determine normative values on a concussion baseline testing battery. Materials and Methods: All data were collected as part of the Concussion Assessment, Research and Education (CARE) Consortium. The baseline test battery included a post-concussion symptom checklist (Sport Concussion Assessment Tool (SCAT), psychological health screening inventory (Brief Symptom Inventory (BSI-18) and neurocognitive evaluation (ImPACT), Balance Error Scoring System (BESS), and Standardized Assessment of Concussion (SAC). Linear regression models were used to examine differences across sexes, competition levels, and varsity contact levels while controlling for academy, freshman status, race, and previous concussion. Zero inflated negative binomial models estimated symptom scores due to the high frequency of zero scores. Results: Significant, but small, sex effects were observed on the ImPACT visual memory task. While, females performed worse than males (p < 0.0001, peta2 = 0.01), these differences were small and not larger than the effects of the covariates. A similar pattern was observed for competition level on the SAC. There was a small, but significant difference across competition level. SAMs participating in varsity athletics did significantly worse on the SAC compared to SAMs participating in club or intramural athletics (all p's < 0.001, eta2 = 0.01). When examining symptom reporting, males were more than two times as likely to report zero symptoms on the SCAT or BSI-18. Intramural SAMs had the highest number of symptoms and severity compared to varsity SAMs (p < 0.0001, Cohen's d < 0.2). Contact level was not associated with SCAT or BSI-18 symptoms among varsity SAMs. Notably, the significant differences across competition level on SCAT and BSI-18 were sub clinical and had small effect sizes. Conclusion: The current analyses provide the first baseline concussion battery normative data among SAMs. While statistically significant differences may be observed on baseline tests, the effect sizes for competition and contact levels are very small, indicating that differences are likely not clinically meaningful at baseline. Identifying baseline differences and significant covariates is important for future concussion-related analyses to inform concussion evaluations for all athlete levels. PMID- 29608769 TI - Erratum. PMID- 29608768 TI - A Randomized, Double-Blind, Double-Dummy, Placebo-Controlled, Intranasal Human Abuse Potential Study of Oxycodone ARIR, a Novel, Immediate-Release, Abuse Deterrent Formulation. AB - Objective: Prescription opioid abuse continues to be a public health concern. Oxycodone ARIR is an immediate-release (IR) oxycodone tablet composed of multiple overlapping barriers that deter manipulation of the tablet for non-oral abuse. Design: This randomized, double-blind, double-dummy, active- and placebo controlled, four-way crossover, intranasal human abuse potential study assessed the pharmacodynamics and pharmacokinetics of crushed intranasal oxycodone ARIR compared with crushed intranasal IR oxycodone and intact oral oxycodone ARIR. Outcome Measures: Pharmacodynamic end points included mean maximum drug liking (Emax), as measured by subjects on a bipolar 100-mm visual analog scale (primary), and desire to take the drug again, overall drug liking, drug high, and good effects (secondary). Pharmacokinetic assessments included peak concentration and time to peak concentration. Results: Twenty-nine subjects completed the treatment phase. Crushed intranasal oxycodone ARIR demonstrated a significant reduction of 46.9% and 23.4% in drug liking Emax compared with crushed intranasal IR oxycodone and intact oral oxycodone ARIR, respectively (P < 0.0001 for both). Significant reductions also were observed in desire to take the drug again, drug high, overall drug liking, and good effects when comparing crushed intranasal oxycodone ARIR with crushed intranasal IR oxycodone and intact oral oxycodone ARIR (P < 0.001 for all). Crushed intranasal oxycodone ARIR exhibited lower peak oxycodone plasma concentrations and slower time to peak concentration compared with crushed intranasal IR oxycodone and intact oral oxycodone ARIR. All treatments were well tolerated; adverse effects were typical of opioids or intranasal administration. Conclusions: These data indicate that oxycodone ARIR has the potential to reduce abuse via the intranasal route. PMID- 29608770 TI - Corrigendum: Internet Blogs, Polar Bears, and Climate-Change Denial by Proxy. PMID- 29608771 TI - Aberrant and accidental trichomonad flagellate infections: rare or underdiagnosed? AB - The clinical significance and frequency of human infections with trichomonad flagellates in aberrant locations (locations other than the predilection sites) and accidental infections (infections with non-human trichomonads) are unclear. The total number of case reports in the literature is low, with the identification of the infection largely the outcome of investigations for the cause of clinical signs. At least seven species have been identified in either aberrant or accidental infections, with these infections occurring worldwide. Results of prospective and retrospective surveys of adults with respiratory disease suggest that aberrant and accidental trichomonad infections are less rare than the number of case reports suggest, with Trichomonas tenax being the most frequent. Surveys of neonates and infants suggest that aberrant Trichomonas vaginalis infections can be higher and more serious than suggested by the few case reports. The density and location of infection might be as important, if not more so, than species in determining pathogenicity. Molecular diagnostic methods including DNA sequencing can be used to better diagnose infections and enable identification to assist in determining the clinical significance of different species. Raising awareness of these infections among clinicians and adding them to their differential lists are strongly suggested. PMID- 29608772 TI - AN IMPROVED METHOD FOR THE COMPUTERISED ANALYSIS OF GR-200A LiF:Mg,Cu,P TL SIGNALS. AB - The profile of the residual signals of LiF:Mg,Cu,P within the region of dosimetric interest was approximated by a cubic curve. The conventional analysis, the GCA developed in CIEMAT and the GCA developed in this laboratory were compared. For GCA developed in this laboratory, the 5 MUGy test dose could be well measured even after measurement at 10 mGy and obviously at lower doses. The 20 MUGy test dose could be well measured even after measurement at 50 mGy. The residual signals caused by previous irradiations in the case of using only reader anneal can be more effectively eliminated by GCA developed in this laboratory than GCA developed in CIEMAT. The program developed in this laboratory, effectively estimating the contribution of the residual signals caused by previous irradiations, permits work to be done using only reader anneal in a dose range of more than three orders of magnitude. PMID- 29608773 TI - Mining for recurrent long-range interactions in RNA structures reveals embedded hierarchies in network families. AB - The wealth of the combinatorics of nucleotide base pairs enables RNA molecules to assemble into sophisticated interaction networks, which are used to create complex 3D substructures. These interaction networks are essential to shape the 3D architecture of the molecule, and also to provide the key elements to carry molecular functions such as protein or ligand binding. They are made of organised sets of long-range tertiary interactions which connect distinct secondary structure elements in 3D structures. Here, we present a de novo data-driven approach to extract automatically from large data sets of full RNA 3D structures the recurrent interaction networks (RINs). Our methodology enables us for the first time to detect the interaction networks connecting distinct components of the RNA structure, highlighting their diversity and conservation through non related functional RNAs. We use a graphical model to perform pairwise comparisons of all RNA structures available and to extract RINs and modules. Our analysis yields a complete catalog of RNA 3D structures available in the Protein Data Bank and reveals the intricate hierarchical organization of the RNA interaction networks and modules. We assembled our results in an online database (http://carnaval.lri.fr) which will be regularly updated. Within the site, a tool allows users with a novel RNA structure to detect automatically whether the novel structure contains previously observed RINs. PMID- 29608774 TI - B-cell activity markers are associated with different disease activity domains in primary Sjogren's syndrome. AB - Objectives: B-cell activating factor (BAFF), beta-2 microglobulin (beta2M) and serum free light chains (FLCs) are elevated in primary SS (pSS) and associated with disease activity. We aimed to investigate their association with the individual disease activity domains of the EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI) in a large well-characterized pSS cohort. Methods: Sera from pSS patients enrolled in the UK Primary Sjogren's Syndrome Registry (UKPSSR) (n = 553) and healthy controls (n = 286) were analysed for FLC (kappa and lambda), BAFF and beta2 M. Pearson correlation coefficients were calculated for patient clinical characteristics, including salivary flow, Schirmer's test, EULAR Sjogren's Syndrome Patient Reported Index and serum IgG levels. Poisson regression was performed to identify independent predictors of total ESSDAI and ClinESSDAI (validated ESSDAI minus the biological domain) scores and their domains. Results: Levels of BAFF, beta2M and FLCs were higher in pSS patients compared to controls. All three biomarkers associated significantly with the ESSDAI and the ClinESSDAI. BAFF associated with the peripheral nervous system domain of the ESSDAI, whereas beta2M and FLCs associated with the cutaneous, biological and renal domains. Multivariate analysis showed BAFF, beta2M and their interaction to be independent predictors of ESSDAI/ClinESSDAI. FLCs were also shown to associate with the ESSDAI/ClinESSDAI but not independent of serum IgG. Conclusion: All biomarkers were associated with total ESSDAI scores but with differing domain associations. These findings should encourage further investigation of these biomarkers in longitudinal studies and against other disease activity measures. PMID- 29608775 TI - Structural and Functional Neuroimaging of Polygenic Risk for Schizophrenia: A Recall-by-Genotype-Based Approach. AB - Risk profile scores (RPS) derived from genome-wide association studies (GWAS) explain a considerable amount of susceptibility for schizophrenia (SCZ). However, little is known about how common genetic risk factors for SCZ influence the structure and function of the human brain, largely due to the constraints of imaging sample sizes. In the current study, we use a novel recall-by-genotype (RbG) methodological approach, where we sample young adults from a population cohort (Avon Longitudinal Study of Parents and Children: N genotyped = 8365) based on their SCZ-RPS. We compared 197 healthy individuals at extremes of low (N = 99) or high (N = 98) SCZ-RPS with behavioral tests, and structural and functional magnetic resonance imaging (fMRI). We first provide methodological details that will inform the design of future RbG studies for common SCZ genetic risk. We further provide an between group analysis of the RbG individuals (low vs high SCZ-RPS) who underwent structural neuroimaging data (T1-weighted scans) and fMRI data during a reversal learning task. While we found little evidence for morphometric differences between the low and high SCZ-RPS groups, we observed an impact of SCZ-RPS on blood oxygen level-dependent (BOLD) signal during reward processing in the ventral striatum (PFWE-VS-CORRECTED = .037), a previously investigated broader reward-related network (PFWE-ROIS-CORRECTED = .008), and across the whole brain (PFWE-WHOLE-BRAIN-CORRECTED = .013). We also describe the study strategy and discuss specific challenges of RbG for SCZ risk (such as SCZ RPS related homoscedasticity). This study will help to elucidate the behavioral and imaging phenotypes that are associated with SCZ genetic risk. PMID- 29608776 TI - The Unexpected Relationship Between Retrieval Demands and Memory Performance When Older Adults are Faced with Age-Related Stereotypes. AB - Objectives: In two studies, we examined the effects of age-related stereotype threat on eyewitness memory using the misinformation paradigm to (1) examine stereotype threat in the context of a more ecologically valid memory task and (2) determine the relationship between task difficulty and susceptibility to stereotype threat. Methods: After watching a video that depicted a crime, older and younger adult participants were presented with a written synopsis in which information consistent or inconsistent with the original event was presented. Half of the participants were then presented with information designed to activate negative stereotypes about aging. Finally, participants completed a memory test. Results: In Study 1, when participants were instructed to report information from either the video or the synopsis to complete the final memory test, older adults under high stereotype threat were less accurate than those under low threat. In Study 2, when participants were required to engage in more controlled processes at retrieval and respond with only video information, older adults under stereotype threat performed as well or better than those under low threat. Discussion: The results are consistent with the Regulatory Focus Model of Stereotype Threat. PMID- 29608777 TI - Decreased Km to dNTPs is an essential M-MuLV reverse transcriptase adoption required to perform efficient cDNA synthesis in One-Step RT-PCR assay. AB - Personalized medicine and advanced diagnostic tools based on RNA analysis are focusing on fast and direct One-Step RT-PCR assays. First strand complementary DNA (cDNA) synthesized by the reverse transcriptase (RT) is exponentially amplified in the end-point or real-time PCR. Even a minor discrepancy in PCR conditions would result in big deviations during the data analysis. Thus, One Step RT-PCR composition is typically based on the PCR buffer. In this study, we have used compartmentalized ribosome display technique for in vitro evolution of the Moloney Murine Leukemia Virus reverse transcriptase (M-MuLV RT) that would be able to perform efficient full-length cDNA synthesis in PCR buffer optimized for Thermus aquaticus DNA polymerase. The most frequent mutations found in a selected library were analyzed. Aside from the mutations, which switch off RNase H activity of RT and are beneficial for the full-length cDNA synthesis, we have identified several mutations in the active center of the enzyme (Q221R and V223A/M), which result in 4-5-fold decrease of Km for dNTPs (<0.2 mM). The selected mutations are in surprising agreement with the natural evolution process because they transformed the active center from the oncoretroviral M-MuLV RT-type to the lenitiviral enzyme-type. We believe that this was the major and essential phenotypic adjustment required to perform fast and efficient cDNA synthesis in PCR buffer at 0.2-mM concentration of each dNTP. PMID- 29608778 TI - Erratum. PMID- 29608780 TI - Motor and Cognitive Trajectories Before Dementia: Results from Gait and Brain Study. AB - OBJECTIVES: To compare the trajectories of motor and cognitive decline in older adults who progress to dementia with the trajectories of those who do not. To evaluate the added value of measuring motor and cognitive decline longitudinally versus cross-sectionally for predicting dementia. DESIGN: Prospective cohort study with 5 years of follow-up. SETTING: Clinic based at a university hospital in London, Ontario, Canada. PARTICIPANTS: Community-dwelling participants aged 65 and older free of dementia at baseline (N=154). MEASUREMENTS: We evaluated trajectories in participants' motor performance using gait velocity and cognitive performance using the MoCA test twice a year for 5 years. We ascertained incident dementia risk using Cox regression models and attributable risk analyses. Analyses were adjusted using a time-dependent covariate. RESULTS: Overall, 14.3% progressed to dementia. The risk of dementia was almost 7 times as great for those whose gait velocity declined (hazard ratio (HR)=6.89, 95% confidence interval (CI)=2.18-21.75, p=.001), more than 3 times as great for those with cognitive decline (HR=3.61, 95% CI=1.28-10.13, p=.01), and almost 8 times as great in those with combined gait velocity and cognitive decline (HR=7.83, 95% CI=2.10-29.24, p=.002), with an attributable risk of 105 per 1,000 person years. Slow gait at baseline alone failed to predict dementia (HR=1.16, 95% CI=0.39 3.46, p=.79). CONCLUSION: Motor decline, assessed according to serial measures of gait velocity, had a higher attributable risk for incident dementia than did cognitive decline. A decline over time of both gait velocity and cognition had the highest attributable risk. A single time-point assessment was not sufficient to detect individuals at high risk of dementia. PMID- 29608781 TI - Predicting Dementia from Decline in Gait Speed: Are We There Yet? PMID- 29608779 TI - Interdisciplinary Home Visits for Individuals with Advanced Parkinson's Disease and Related Disorders. AB - Parkinson's disease (PD) is a complex, multisymptom, neurodegenerative disease affecting primarily older adults. With progression, many individuals become homebound and removed from coordinated, expert care, resulting in excess morbidity, mortality, and healthcare expenditures in acute care settings and institutions. Home visit care models have achieved the triple aim of improving individual and population health while reducing costs in many frail, community dwelling geriatric cohorts. This study details a novel, interdisciplinary home visit program specifically designed for individuals with PD and related disorders and their family caregivers built upon best practice principles in the care of multimorbid older adults. At each quarterly home visit, a movement disorders trained neurologist, social worker, and nurse work in parallel with the individual and caregiver to complete a history, physical, detailed medication reconciliation, psychosocial needs assessment, and home safety assessment. A comprehensive, person-centered plan is agreed upon, referrals to community resources are made, standardized documentation is shared, and follow-up communication is instituted. In the first 2 years, 272 visits were conducted with 85 individuals who represent one of the oldest, most disabled PD populations reported. Satisfaction with and retention in the program were high. This study represents the first translation of the success of interdisciplinary and home based geriatric care models to a population with a specific neurological disease. Preliminary evidence supports the need for such programs in vulnerable populations. Future studies will prospectively assess person-centered outcomes, the effect of using telemedicine on sustainability, and cost effectiveness. PMID- 29608782 TI - One-Year Effect of the Medicare Annual Wellness Visit on Detection of Cognitive Impairment: A Cohort Study. AB - OBJECTIVES: To examine the effect of the Medicare Annual Wellness Visit (AWV) on the detection of cognitive impairment and on follow-up cognitive care for older adults. DESIGN: Retrospective matched-cohort study. SETTING: United States. PARTICIPANTS: A 5% random sample of fee-for-service Medicare beneficiaries continuously enrolled for 12 months before and after an index ambulatory visit occurring from 2011 to 2013 with no claims evidence of cognitive impairment before index. MEASUREMENTS: Outcomes include 12-month post-index visit claims based measurements of cognitive impairment, including new Alzheimer's disease and related dementia (ADRD) diagnoses; medications for ADRD; and cognitive care related diagnostic examination such as neurobehavioral testing, brain imaging, and blood tests for thyroid-stimulating hormone (TSH), serum B12, folate, and syphilis. We also measured changes in burden of anticholinergic medication. RESULTS: There were no clinically relevant differences between the AWV and control groups in the rates of incident ADRD diagnoses (6.16% vs 6.86%, p<.001) and initiation of ADRD medications (1.00% vs 1.08%, p=.15), although there were differences favoring the AWV group in rates of TSH (39.80% vs 28.36%, p<.001), B12 (9.41% vs 6.97%, p<.001), folate (4.76% vs 3.72%, p<.001), and neurobehavioral (0.75% vs 0.55%, p<.001) testing. CONCLUSIONS: Although the AWV is correlated with an increase in some measures of cognitive care, such as laboratory testing for reversible causes of cognitive impairment, it does not appear to substantially increase recognition of undetected ADRD. PMID- 29608783 TI - Wild-type isolates of Porphyromonas gingivalis derived from periodontitis patients display major variability in platelet activation. AB - : In vitro studies revealed that Porphyromonas gingivalis (Pg), a pathogen intimately associated with the onset and progression of periodontitis, is able to activate platelets, thus linking periodontal inflammation with the endangerment of vascular health. As wild-type Pg strains are characterized by major genetic heterogeneity, the commonness of platelet-activating Pg strains in periodontitis patients is unknown as of yet. Therefore, this study evaluated the platelet activation capacity of wild-type Pg isolates sampled from patients with aggressive periodontitis. METHODS: Extent and velocity of platelet aggregation were determined by light transmission aggregometry. Platelet surface expression of P-selectin was measured by flow cytometry, activation of p38 MAP kinase, and protein kinase C by Western blot using phospho-specific antibodies. RESULTS: Pg isolates displayed high variability regarding extent and velocity of platelet activation, as well as the involved activating pathways. Corresponding results were observed for platelet P-selectin expression, activation of p38 MAP kinase, or protein kinase C. Inhibitors of platelet immune receptor FcgammaRIIA and protease-activated receptors revealed several, diverging pathways of activation. Some isolates induced platelet aggregation even in the presence of potent therapeutical platelet inhibitors. CONCLUSIONS: Chronic bacteremia involving specific, platelet-activating Pg strains may constitute a substantial hazard for the integrity of cardiovascular health. PMID- 29608784 TI - Asymmetric biotic interactions and abiotic niche differences revealed by a dynamic joint species distribution model. AB - A species' distribution and abundance are determined by abiotic conditions and biotic interactions with other species in the community. Most species distribution models correlate the occurrence of a single species with environmental variables only, and leave out biotic interactions. To test the importance of biotic interactions on occurrence and abundance, we compared a multivariate spatiotemporal model of the joint abundance of two invasive insects that share a host plant, hemlock woolly adelgid (HWA; Adelges tsugae) and elongate hemlock scale (EHS; Fiorina externa), to independent models that do not account for dependence among co-occurring species. The joint model revealed that HWA responded more strongly to abiotic conditions than EHS. Additionally, HWA appeared to predispose stands to subsequent increase of EHS, but HWA abundance was not strongly dependent on EHS abundance. This study demonstrates how incorporating spatial and temporal dependence into a species distribution model can reveal the dependence of a species' abundance on other species in the community. Accounting for dependence among co-occurring species with a joint distribution model can also improve estimation of the abiotic niche for species affected by interspecific interactions. PMID- 29608785 TI - Phylotranscriptomic analysis and genome evolution of the Cypripedioideae (Orchidaceae). AB - PREMISE OF THE STUDY: The slipper orchids (Cypripedioideae) are a morphologically distinct subfamily of Orchidaceae. They also have some of the largest genomes in the orchids, which may be due to polyploidy or some other mechanism of genome evolution. We generated 10 transcriptomes and incorporated existing RNA-seq data to infer a multilocus nuclear phylogeny of the Cypripedioideae and to determine whether a whole-genome duplication event (WGD) correlated with the large genome size of this subfamily. Knowing more about timing of ancient polyploidy events can help us understand the evolution of one of the most species-rich plant families. METHODS: Transcriptome data were used to identify low-copy orthologous genes to infer a phylogeny of Orchidaceae and to identify paralogs to place any WGD events on the species tree. KEY RESULTS: Our transcriptome phylogeny confirmed relationships published in previous studies that used fewer markers but incorporated more taxa. We did not find a WGD event at the base of the slipper orchids; however, we did identify one on the Orchidaceae stem lineage. We also confirmed the presence of a previously identified WGD event deeper in the monocot phylogeny. CONCLUSIONS: Although WGD has played a role in the evolution of Orchidaceae, polyploidy does not appear to be responsible for the large genome size of slipper orchids. The conserved set of 775 largely single-copy nuclear genes identified in this study should prove useful in future studies of orchid evolution. PMID- 29608786 TI - DNA methylation of the BRD2 promoter is associated with juvenile myoclonic epilepsy in Caucasians. AB - OBJECTIVE: Juvenile myoclonic epilepsy (JME) is a common adolescent-onset genetic generalized epilepsy (GGE) syndrome. Multiple linkage and association studies have found that BRD2 influences the expression of JME. The BRD2-JME connection is further corroborated by our murine model; Brd2 haploinsufficiency produces characteristics that typify the clinical hallmarks of JME. Neither we, nor several large-scale studies of JME, found JME-related BRD2 coding mutations. Therefore, we investigated noncoding BRD2 regions, seeking the origin of BRD2's JME influence. BRD2's promoter harbors a JME-associated single nucleotide polymorphism (rs3918149) and a CpG (C-phosphate-G dinucleotides) island (CpG76), making it a potential "hotspot" for JME-associated epigenetic variants. Methylating promoter CpG sites causes gene silencing, often resulting in reduced gene expression. We tested for differences in DNA methylation at CpG76 in 3 different subgroups: (1) JME patients versus their unaffected family members, (2) JME versus patients with other forms of GGE, and (3) Caucasian versus non Caucasian JME patients. METHODS: We used DNA pyrosequencing to analyze the methylation status of 10 BRD2 promoter CpG sites in lymphoblastoid cells from JME patients of Caucasian and non-Caucasian origin, unaffected family members, and also non-JME GGE patients. We also measured global methylation levels and DNA methyl transferase 1 (DNMT1) transcript expression in JME families by standard methods. RESULTS: CpG76 is highly methylated in JME patients compared to unaffected family members. In families with non-JME GGE, we found no relationship between promoter methylation and epilepsy. In non-Caucasian JME families, promoter methylation was mostly not associated with epilepsy. This makes the BRD2 promoter a JME-specific, ethnicity-specific, differentially methylated region. Global methylation was constant across groups. SIGNIFICANCE: BRD2 promoter methylation in JME, and the lack of methylation in unaffected relatives, in non JME GGE patients, and in non-Caucasian JME, demonstrate that methylation specificity is a possible seizure susceptibility motif in JME risk and suggests JME therapeutics targeting BRD2. PMID- 29608787 TI - Clinical risk factors for depressive syndrome in Type 2 diabetes: the Fremantle Diabetes Study. AB - AIMS: To identify early clinical predictors of depressive syndrome in people with Type 2 diabetes. METHODS: Depressive syndrome was assessed in 325 individuals with Type 2 diabetes 15 years after a baseline assessment, which included information on antidepressant use and depressive symptoms obtained using a quality-of-life scale. Follow-up current and lifetime depressive syndrome were assessed using the nine-item Patient Health Questionnaire and the Brief Lifetime Depression Scale and taking account of antidepressant use. Analyses were conducted inclusive and exclusive of antidepressant use where Patient Health Questionnaire criteria were not met. RESULTS: At baseline, the participants were aged 57.2+/-9.3 years and the median (interquartile range) diabetes duration was 2.2 (0.6-6.0) years. After a mean of 14.7+/-1.1 years' follow-up, 81 participants (24.9%) had depressive syndrome (14.8% defined by the Patient Health Questionnaire, 10.2% defined by antidepressants) and 31.4% reported lifetime depression, and in 10.2% of participants this preceded diabetes onset. With logistic regression (inclusive of antidepressants), follow-up depressive syndrome was negatively associated with education level [odds ratio 0.39 (95% CI 0.20 0.75)] and antidepressant use [odds ratio 0.11 (95% CI 0.03-0.36)] and was positively associated with depression history before diabetes onset [odds ratio 2.79 (95% CI 1.24-6.27)]. In the model exclusive of antidepressants, depressive syndrome was positively associated with baseline depressive symptoms [odds ratio 2.57 (95% CI 1.32-5.03)] and antidepressant use [odds ratio 3.54 (95% CI 1.20 10.42)] and was negatively associated with education level [odds ratio 0.39 (95% CI 0.19-0.81)]. CONCLUSIONS: Risk factors for depressive syndrome can be identified early after the onset of Type 2 diabetes. The early presence of depressive symptoms or its treatment and/or history of depression are likely indicators of vulnerability. Early risk stratification for late depressive syndrome is feasible in people with Type 2 diabetes and could assist with depression treatment or prevention. PMID- 29608788 TI - A retrospective study of 30,959 implants: Risk factors associated with early and late implant loss. AB - AIM: This retrospective study assessed the risk factors associated with early and late implant loss at the patient- and implant-based analysis. MATERIALS AND METHODS: A total of 18,199 patients received 30,959 dental implants during the years 2011-2015. Age, gender, jaw, location, implant brands, implant length and diameter, bone augmentation procedures, and the number of implants placed per patient were recorded. A multivariate generalized estimating equation (GEE) logistic regression was used to identify risk factors related to both early and late implant loss. RESULTS: The cumulative survival rates were 98.0% for patients and 98.7% for implants after 1-6 years observation time. A total of 183 patients with 194 implants were lost before or at the abutment connection, and 193 patients with 209 implants were lost after occlusal loading of the implant fixture. The multivariable GEE logistic regression showed that males, patients aged >=41 years, and mandibular anterior location were risk factors for early implant loss. In the case of late implant loss, males, patients aged >=41 years, bone augmentation and short implants were correlated with a significantly increased failure rate. CONCLUSIONS: General factors such as male sex, elderly patients, mandibular anterior location, bone augmentation and short implants were associated with implant loss. PMID- 29608789 TI - Advance Care Planning in Frail Older Adults: A Cluster Randomized Controlled Trial. AB - OBJECTIVES: To determine the effectiveness of advance care planning (ACP) in frail older adults. DESIGN: Cluster randomized controlled trial. SETTING: Residential care homes in the Netherlands (N=16). PARTICIPANTS: Care home residents and community-dwelling adults receiving home care (N=201; n=101 intervention; n=100 control). Participants were 75 years and older, frail, and capable of consenting to participation. INTERVENTION: Adjusted Respecting Choices ACP program. MEASUREMENTS: The primary outcome was change in patient activation (Patient Activation Measure, PAM-13) between baseline and 12-month follow-up. Secondary outcomes included change in quality of life (SF-12), advance directive (AD) completion, and surrogate decision-maker appointment. Use of medical care in the 12 months after inclusion was also assessed. Multilevel analyses were performed, controlling for clustering effects and differences in demographics. RESULTS: Seventy-seven intervention participants and 83 controls completed the follow-up assessment. There were no statistically significant differences between the intervention (-0.26+/-11.2) and control group (-1.43+/-10.6) in change scores of the PAM (p=.43) or the SF-12. Of intervention group participants, 93% completed an AD, and 94% appointed a decision-maker. Of control participants, 34% completed an AD, and 67% appointed a decision-maker (p<.001). No differences in the use of medical care were found. CONCLUSIONS: ACP did not increase levels of patient activation or quality of life but did increase completion of ADs and appointment of surrogate decision-makers. It did not affect use of medical care. PMID- 29608790 TI - Increase in perfused boundary region of endothelial glycocalyx is associated with higher prevalence of ischemic heart disease and lesions of microcirculation and vascular wall. AB - OBJECTIVE: PBR characterizes penetration of red blood cells inside glycocalyx and its thickness can have profound impact on microcirculation and other vascular parameters. The goal of our study was to reliably quantify PBR and assess its potential use as a new marker of cardiovascular pathology. METHODS: The study included 208 patients (123 men and 85 women from 40 to 65 years of age) with various grades of cardiovascular SCORE risk index and IHD. PBR was quantified by sidestream dark field capillaroscopy with green light excitation. Cutaneous microcirculation was evaluated with laser Doppler fluorometry. RESULTS: Elevated PBR values over 2 mm were associated with morphological and functional lesions of arterial wall and microcirculation and lowered levels of ApoA1 lipoprotein. Moreover, elevated PBR values were associated with 2.07-fold increase in prevalence of cerebral atherosclerosis (P = .015) and 2.42-fold increase in prevalence of IHD (P = .024). Increase in PBR was associated with elevated systolic blood pressure. CONCLUSIONS: Thus, PBR can be considered a new highly reproducible and promising marker candidate for non-invasive diagnostics of IHD and cerebral atherosclerosis suggesting important role of microcirculation in development and progression of cardiovascular diseases. PMID- 29608791 TI - Integrated massively parallel sequencing of 15 autosomal STRs and Amelogenin using a simplified library preparation approach. AB - Massively parallel sequencing (MPS) technologies, also termed as next-generation sequencing (NGS), are becoming increasingly popular in study of short tandem repeats (STR). However, current library preparation methods are usually based on ligation or two-round PCR that requires more steps, making it time-consuming (about 2 days), laborious and expensive. In this study, a 16-plex STR typing system was designed with fusion primer strategy based on the Ion Torrent S5 XL platform which could effectively resolve the above challenges for forensic DNA database-type samples (bloodstains, saliva stains, etc.). The efficiency of this system was tested in 253 Han Chinese participants. The libraries were prepared without DNA isolation and adapter ligation, and the whole process only required approximately 5 h. The proportion of thoroughly genotyped samples in which all the 16 loci were successfully genotyped was 86% (220/256). Of the samples, 99.7% showed 100% concordance between NGS-based STR typing and capillary electrophoresis (CE)-based STR typing. The inconsistency might have been caused by off-ladder alleles and mutations in primer binding sites. Overall, this panel enabled the large-scale genotyping of the DNA samples with controlled quality and quantity because it is a simple, operation-friendly process flow that saves labor, time and costs. PMID- 29608792 TI - Prevalence of proteinuria in a canine oncology population. AB - OBJECTIVE: To evaluate the point prevalence of proteinuria in dogs presenting to the University of Georgia Oncology Service for the first time. MATERIALS AND METHODS: In this prospective study, 60 client-owned dogs with a confirmed cancer diagnosis were included but those with lower urinary tract neoplasia were excluded. Each dog's signalment, cancer diagnosis, previous cancer treatments, current medications and travel history were recorded. Renal values, electrolytes, packed cell volume, total solids, systolic blood pressure, urinalysis, urine protein:urine creatinine and retinal examinations were recorded. Non-proteinuric, borderline proteinuria and overt proteinuria were defined as urine protein:urine creatinine <0.2, >=0.2 but <0.5, and >=0.5, respectively. Urine culture was performed in dogs with active urine sediments or overt proteinuria. RESULTS: Twenty-nine dogs were non-proteinuric (48.3%), 22 (36.7%) borderline proteinuric and nine (15%) overtly proteinuric. None were azotaemic. Hypertension (systolic blood pressure >=160 mmHg) was detected in 18 (30%) dogs. Of these, six were non proteinuric, nine borderline proteinuric, and three overtly proteinuric. Proteinuria was detected in 51% of dogs presented to our oncology service, the majority of which were classified as borderline. CLINICAL SIGNIFICANCE: The high proportion of proteinuria in dogs in this study suggests that screening for proteinuria in dogs with cancer may be prudent. Larger studies are required to correlate specific cancer types and the impact of treatment with the development, magnitude and persistence of proteinuria. PMID- 29608793 TI - A randomized controlled study on the accuracy of free-handed, pilot-drill guided and fully guided implant surgery in partially edentulous patients. AB - AIM: To compare the accuracy of free-handed (FH), pilot-drill guided (PG) and fully guided (FG) implant surgery. MATERIALS AND METHODS: Partially edentulous patients in need of >=2 implants in the posterior maxilla were randomly allocated to one of the following treatment groups: FH, PG and FG. Ideal implant positions were determined in designated software following the fusion of bony information (CBCT data in DICOM format) to the prosthetic wax-up (optical scan data in STL format). The position of every implant as surgically realized was compared to its "ideal position". The apical global deviation (AGD) was the primary outcome of the study. Secondary outcome variables were angular deviation (AD), coronal global deviation (CGD), coronal lateral deviation (CLD), coronal vertical deviation (CVD), apical lateral deviation (ALD) and apical vertical deviation (AVD). RESULTS: Eleven patients (mean age 57; three males; eight females; altogether 26 implants) were treated by FH surgery, 11 (mean age 53; four males; seven females; altogether 24 implants) by PG surgery and 10 (mean age 60; four males; six females; altogether 21 implants) by FG surgery. FG surgery was most accurate (mean AGD: 0.97 mm; maximum AGD: 1.98 mm) followed by PG surgery (mean AGD: 1.43 mm; maximum AGD: 2.72 mm). FH surgery resulted in huge deviation from the ideal position (mean AGD: 2.11 mm; maximum AGD: 4.84 mm). The results on most secondary outcome variables followed the same order. Although screw-retained restorations were planned for all implants, five of 26 in the FH group and one of 24 in the PG group had to be restored by means of a cement-retained restoration. CONCLUSION: When perfect implant positioning is required, FG surgery should be considered the gold standard approach. PMID- 29608796 TI - Hyoid Bone Movement at Rest by Peripheral Magnetic Stimulation of Suprahyoid Muscles in Normal Individuals. AB - OBJECTIVES: Neuromuscular electrical stimulation has been widely used in patients with dysphagia. However, obtaining sufficient hyoid bone movement through surface electrodes seems difficult. The aim of this study was to evaluate hyoid bone movement at rest through peripheral magnetic stimulation of the suprahyoid muscles in normal individuals. METHODS: Healthy adult men were recruited. A specially designed coil was connected to the peripheral magnetic stimulator. The coil was placed on the submental area of the subjects. Magnetic stimulation was performed at 30 Hz for 2 sec. The intensity level selected induces hyoid bone movement without causing intolerable pain to the subjects. The hyoid bone at rest between on- and off-magnetic stimulations of the suprahyoid muscles were identified using fluoroscopy at 30 frames/sec in lateral projection. Pain during peripheral magnetic stimulation was evaluated using the numerical rating scale (NRS). RESULTS: Eleven subjects aged 32 +/- 9 years participated in this study. Magnetic stimulation resulted in 10.9 +/- 2.8 mm forward displacement and 8.3 +/- 4.1 mm (mean +/- SD) upward displacement of the hyoid bone. The median NRS score during magnetic stimulation was 1. CONCLUSIONS: Peripheral magnetic stimulation is noninvasive and easy to perform. It does not require skin preparation, facilitates sufficient hyoid bone movement, and causes minimum level of pain. PMID- 29608795 TI - Gait Speed and Mobility Disability: Revisiting Meaningful Levels in Diverse Clinical Populations. AB - OBJECTIVES: To investigate the heterogeneity of clinically meaningful levels of gait speed relative to self-reported mobility disability (SR-MD). DESIGN: Five longitudinal studies with older adults in different health states (onset of acute event, presence of chronic condition, sedentary, community living) were used to explore the relationship between gait speed and SR-MD. SETTING: Lifestyle Interventions and Independence for Elders Pilot (LIFE-P), LIFE, Trial of Angiotensin-Converting Enzyme Inhibition and Novel Cardiovascular Risk Factors (TRAIN), Baltimore Hip Fracture Study (BHS2), Invecchiare in Chianti (InCHIANTI). PARTICIPANTS: Individuals aged 65 and older (N=3,540): sedentary, community dwelling (LIFE-P/LIFE), with hip fracture (BHS2), random population-based sample (InCHIANTI), high cardiovascular risk (TRAIN). MEASUREMENTS: Usual-pace gait speed across 3 to 4 m and SR-MD, defined as inability to walk approximately 1 block or climb 1 flight of stairs. RESULTS: The mean gait speed of participants without SR-MD was greater than 1.0 m/s in InCHIANTI and TRAIN, 0.79 m/s in LIFE P/LIFE, and 0.46 m/sec in BHS2. Of individuals with SR-MD, mean gait speed was 0.08 m/s slower in LIFE-P/LIFE, 0.19 m/s slower in TRAIN, 0.22 m/s slower in BHS2, and 0.36 m/s slower in InCHIANTI. The optimal gait speed cutpoint for minimizing SR-MD misclassification rates ranged from 0.3 m/s in BHS2 to 1.0 m/s in TRAIN. In longitudinal analyses, development of SR-MD was dependent on initial gait speed and change in gait speed (p<.001). CONCLUSION: The relationship between absolute levels of gait speed and SR-MD may be context specific, and there may be variations between populations. Across diverse clinical populations, clinical interpretations of how change in usual pace gait speed relates to development of SR-MD depend on where on the gait speed continuum change occurs. PMID- 29608797 TI - The use of bipolar electrosurgical forceps for haemostasis in open surgical ovariectomy of bitches and queens and castration of dogs. AB - OBJECTIVES: To describe a technique using bipolar electrosurgical forceps for haemostasis during open ovariectomy of bitches and queens and for castration of dogs and to determine whether these forceps reduced surgical time compared to ligation with suture. MATERIALS AND METHODS: Bipolar electrosurgical forceps were used for haemostasis in 3744 open surgeries including ovariectomies in bitches (n=1406) and queens (n=859) and castrations in dogs (n=1335). The forceps were also used to assist with ovariohysterectomy in bitches (n=89) and queens (n=55). The effect of bipolar electrocoagulation and other likely factors influencing surgical time was examined using linear regression analysis of 367 surgeries. RESULTS: The use of the forceps reduced surgical time by 9.7 +/-2.8 minutes in bitches and by 3.0 +/-1.5 minutes in queens. The complications encountered initially were small superficial skin burns requiring topical treatment and one case of haemorrhage associated with surgical technique. CLINICAL SIGNIFICANCE: Bipolar electrosurgical forceps reduce surgical time in ovariectomies, and complications are rare. This technique has promise for widespread application in veterinary practice to assist with haemostasis in ovariectomy of bitches and queens. PMID- 29608794 TI - Genome-wide analysis of the regulation of Cu metabolism in Cryptococcus neoformans. AB - The ability of the human fungal pathogen Cryptococcus neoformans to adapt to variable copper (Cu) environments within the host is key for successful dissemination and colonization. During pulmonary infection, host alveolar macrophages compartmentalize Cu into the phagosome and C. neoformans Cu detoxifying metallothioneins, MT1 and MT2, are required for survival of the pathogen. In contrast, during brain colonization the C. neoformans Cu+ importers Ctr1 and Ctr4 are required for virulence. Central for the regulation and expression of both the Cu detoxifying MT1/2 and the Cu acquisition Ctr1/4 proteins is the Cu-metalloregulatory transcription factor Cuf1, an established C. neoformans virulence factor. Due to the importance of the distinct C. neoformans Cu homeostasis mechanisms during host colonization and virulence, and to the central role of Cuf1 in regulating Cu homeostasis, we performed a combination of RNA-Seq and ChIP-Seq experiments to identify differentially transcribed genes between conditions of high and low Cu. We demonstrate that the transcriptional regulation exerted by Cuf1 is intrinsically complex and that Cuf1 also functions as a transcriptional repressor. The Cu- and Cuf1-dependent regulon in C. neoformans reveals new adaptive mechanisms for Cu homeostasis in this pathogenic fungus and identifies potential new pathogen-specific targets for therapeutic intervention in fungal infections. PMID- 29608798 TI - Physician Age and Performance on the American Board of Emergency Medicine ConCert Examination. AB - OBJECTIVE: This study was undertaken to expand on results from a 2014 study on the association between physician age and performance on the American Board of Emergency Medicine (ABEM) ConCert examination. METHODS: This was a retrospective, longitudinal growth study comparing performance on the ConCert examination and physicians' ages at the time of examination. All examination attempts from 1990 to 2016 made by residency-trained physicians were eligible for inclusion. Multilevel growth models were constructed to examine the relationship between age at time of examination and performance, controlling for physician characteristics. RESULTS: The study group included 15,533 examination attempts by 12,786 physicians. The mean (+/-SD) age of the physicians across all examination administrations was 45.02 (+/-5.18) years (range = 35 to 72 years). The mean (+/ SD) ConCert examination score across all administrations was 85.39 (+/-5.71; range = 51 to 100). Among first-time ConCert examination takers, older age was associated with lower examination scores (r = -0.25, p < 0.0001). Across all examination attempts, age was negatively correlated to examination scores (r = 0.24; p < 0.0001). CONCLUSIONS: After physician characteristics were controlled for, there was an association between advancing age and declining performance on the ABEM ConCert examination. This information may be important to the individual physician to develop targeted competency assessment and professional development. PMID- 29608800 TI - Morphological plasticity of the depth generalist coral, Montastraea cavernosa, on mesophotic reefs in Bermuda. PMID- 29608799 TI - One-stop microvascular screening service: an effective model for the early detection of diabetic peripheral neuropathy and the high-risk foot. AB - AIMS: To evaluate the feasibility of a one-stop microvascular screening service for the early diagnosis of diabetic distal symmetrical polyneuropathy, painful distal symmetrical polyneuropathy and the at-risk diabetic foot. METHODS: People with diabetes attending retinal screening in hospital and community settings had their feet examined by a podiatrist. Assessment included: Toronto Clinical Neuropathy Score evaluation; a 10-g monofilament test; and two validated, objective and quick measures of neuropathy obtained using the point-of-care devices 'DPN-Check', a hand-held device that measures sural nerve conduction velocity and amplitude, and 'Sudoscan', a device that measures sudomotor function. The diagnostic utility of these devices was assessed against the Toronto Clinical Neuropathy Score as the 'gold standard'. RESULTS: A total of 236 consecutive people attending the retinal screening service, 18.9% of whom had never previously had their feet examined, were evaluated. The prevalence of distal symmetrical polyneuropathy, assessed using the Toronto Clinical Neuropathy Score, was 30.9%, and was underestimated by 10-g monofilament test (14.4%). The prevalence of distal symmetrical polyneuropathy using DPN-check was 51.5% (84.3% sensitivity, 68.3% specificity), 38.2% using Sudoscan foot electrochemical skin conductance (77.4% sensitivity, 68.3% specificity), and 61.9% using abnormality in either of the results (93.2% sensitivity, 52.8% specificity). The results of both devices correlated with Toronto Clinical Neuropathy Score (P<0.001). A new diagnosis of painful distal symmetrical polyneuropathy was made in 59 participants (25%), and 56.6% had moderate- or high-risk foot. Participants rated the service very highly. CONCLUSIONS: Combined, eye, foot and renal screening is feasible, has a high uptake, reduces clinic visits, and identifies painful distal symmetrical polyneuropathy and the at-risk foot. Combined large- and small-nerve fibre assessment using non-invasive, quantitative and quick point-of-care devices may be an effective model for the early diagnosis of distal symmetrical polyneuropathy. PMID- 29608801 TI - Recent Publications of Interest. PMID- 29608802 TI - King's Parkinson's Disease Pain Scale for Assessment of Pain Relief Following Deep Brain Stimulation for Parkinson's Disease. AB - OBJECTIVE: Pain is a prevalent and debilitating nonmotor symptom of Parkinson's disease (PD) that is often inadequately managed. Deep brain stimulation (DBS) has been shown to relieve pain in PD but an effective method of identifying which types of PD pain respond to DBS has not been established. We examine the effects of DBS on different types of PD pain using the King's Parkinson's disease pain scale (KPDPS), the only validated scale of PD pain. METHODS: We prospectively followed 18 PD patients undergoing subthalamic nucleus (STN) or Globus pallidus interna (GPi) DBS. Subjects completed the KPDPS, low back disability index (LBDI), and McGill pain questionnaire (MPQ), preoperatively and at six months postoperatively. Subjects underwent the unified Parkinson's disease rating scale III (UPDRS-III) with preoperative scores ON medication and postoperative scores ON medication/DBS stimulation. RESULTS: Of the 18 patients, a total of 12 subjects had STN DBS and 6 had GPi DBS. As a group, subjects showed improvement in total KPDPS score at six-month postoperative follow-up (p = 0.004). Fluctuation and nocturnal pain were most significantly improved (p = 0.006, 0.01, respectively). Significant improvements were found in fluctuation-related pain domain following GPi DBS. CONCLUSIONS: In this pilot study, we are the first group to employ KPDPS to monitor pain relief following DBS in PD patients. We demonstrate that fluctuation-related pain and nocturnal pain significantly improve with DBS. Use of the KPDPS in the future will allow better understanding of how STN and GPi DBS treat PD pain over time. PMID- 29608803 TI - Comments on Jiang et al. PMID- 29608804 TI - Relationship between vitamin D receptor gene polymorphism and susceptibility to chronic kidney disease and periodontal disease in community-dwelling elderly. AB - OBJECTIVES: The aim of this study was to investigate the possible correlation between vitamin D receptor (VDR) gene polymorphism and susceptibility to chronic kidney disease (CKD) and periodontal disease. MATERIAL AND METHODS: This study analysed 345 participants, who were all 79 years of age. Kidney function levels were determined based on the estimated glomerular filtration rate (eGFR; non reduced function: >=60 and reduced function: <60 ml min-1 1.73 m-2 ). VDR TaqI genotyping was also studied. We calculated the periodontal inflamed surface area (PISA). After classifying participants into quartile groups according to eGFR or PISA values, the subjects were then split into two groups (highest quartile versus the other three groups combined). Multiple logistic regression analysis was performed to evaluate the odds ratios between the eGFR and VDR TaqI genotype with the different PISA groups. The eGFR was set as the dependent variable while the VDR TaqI genotype, HbA1C, gender, smoking habits and body mass index were defined as independent variables. RESULTS: A significant association was observed between the VDR TaqI genotype and eGFR in the PISA high group (odds ratio = 3.97, p = .027). CONCLUSION: Study results suggest that VDR TaqI genotype might be associated with CKD during inflammatory conditions caused by periodontal disease. PMID- 29608805 TI - Rebuilding the bridge between transcription and translation. AB - In Bacteria, ribosomes may bind to the nascent RNA emerging from the transcribing RNA polymerase and initiate translation. Transcription-translation coupling plays diverse roles in cellular physiology, including attenuation control, mRNA surveillance and maintenance of genome integrity. While the existence of coupling is broadly accepted, its mechanism and ubiquity are debated. Structural evidence supports mutually exclusive modes of RNA polymerase-ribosome contacts. In a model based on nuclear magnetic resonance data, NusG binds to a ribosomal protein S10 and acts as an adapter between RNA polymerase and the 30S subunit. Recent single particle cryo electron microscopy analyses of RNA polymerase bound to 30S and 70S ribosomes revealed extensive, and very distinct, contacts which are incompatible with bridging by NusG. Saxena et al. provide the first evidence for NusG-mediated coupling in vivo. Their results demonstrate that Escherichia coli NusG interacts with the 70S ribosomes through a previously established interface and that these interactions are required for survival when translation elongation is hindered to weaken coupling. Future studies will address a likely possibility that distinct bridging mechanisms underpin context-dependent coupling in the cell. PMID- 29608806 TI - Graphene particles supported on silica as sorbent for residue analysis of tetracyclines in milk employing microextraction by packed sorbent. AB - This paper describes the use of graphene-based sorbents for determination of four tetracyclines in milk. The synthesized materials were combined with microextraction by packed sorbent (MEPS) to act as the sample preparation step. The extraction performance of these sorbents was compared to commercial phases, and graphene supported on silica provided the best results. The analytical method optimization was carried out by employing experimental design. Firstly, an evaluation of the experimental variables (elution solvent, use of EDTA, ionic force, and pH of the washing solution) was made by a 24-1 factorial experimental design. The variables sampling, washing and elution cycles of MEPS were further optimized under a full 23 experimental design. The validation parameters were determined under optimized conditions resulting in a linearity ranging from 15 to 110 MUg/L with R2 values above 0.98, and LOQs ranging from 0.05 to 0.9 MUg/L. The accuracy ranged from 87.9 to 118.4% and intra/inter-day precision reported by the RSDs were lower than 19%. The proposed and validated method was successfully applied to the analysis of 11 milk samples from different animals, revealing traces of tetracyclines in only two of them. This study focused on the evaluation of graphene-based sorbents combined with MEPS for tetracycline analysis provided equivalent or even better results than other proposed methods, suggesting being a sensitive, fast and reliable alternative method for the determination of tetracyclines in milk samples. PMID- 29608807 TI - Long-Term Effect of Peripheral Nerve Field Stimulation as Add-On Therapy to Spinal Cord Stimulation to Treat Low Back Pain in Failed Back Surgery Syndrome Patients: A 12-Month Follow-Up of a Randomized Controlled Study. AB - OBJECTIVE: Different approaches in neuromodulation have been used to treat chronic low back pain in failed back surgery syndrome (FBSS) patients. We previously randomized 52 FBSS patients to be treated with spinal cord stimulation (SCS) and additional peripheral nerve field stimulation (PNFS) or SCS alone. At three months, we found a significant reduction of back pain in the PNFS-SCS group compared to the SCS group. In the subsequent open phase part of the study, all patients received optimal SCS and PNFS simultaneously. Here, we present the 12 month follow-up data on back and leg pain. MATERIALS AND METHODS: Data regarding back and leg pain, function, quality of life, patient satisfaction, anxiety and depression, and use of medication were collected by analyzing patients' questionnaires at 12 months and compared with data collected at baseline. Data were analyzed using multilevel regression models. RESULTS: A combined group of 50 subjects completed the 12-month follow-up. Back pain, measured on a 100-mm visual analog scale (VAS), significantly decreased over this period by 30.0 mm (95% CI: [-37.7/-22.4]; p < 0.001), while leg pain decreased by 43.7 mm (95% CI: [-51.5/ 36.2]; p < 0.001). We observed statistically significant improvement in almost all secondary outcome measurements. CONCLUSIONS: At 12-month follow-up, PNFS in addition to SCS continues to provide a statistically significant and clinically relevant relief of low back pain in FBSS patients in whom SCS alone is effective for relief of leg pain only. PMID- 29608808 TI - An unusual cause of gastrointestinal bleeding in a hemodialysis patient. AB - Iron deficiency caused by gastrointestinal (GI) bleeding is a common cause of anemia in hemodialysis patient. Herein, we report the case of an 89-year-old hemodialysis patient who presented with acute anemia and melena. Endoscopy found gastritis and diverticulosis without active bleeding. A capsule endoscopy (CE) was then performed and revealed multiple vascular lesions that lead to the diagnosis of Blue Rubber Bleb Nevus syndrome (BRBNS). This rare disease is associated with multiple venous malformations in the skin and the GI tract, usually observed in children. The patient developed 4 months latter 2 skin lesions compatible with BRBNS. Treatment included blood transfusion and intravenous iron supplementation. We reported an unusual presentation of venous malformation BRBS which differs from angioectasia, in an adult hemodialysis patient. Overall prognosis is good. PMID- 29608809 TI - Chronic thromboembolic pulmonary hypertension from the perspective of patients with pulmonary embolism. AB - Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare but feared long term complication of acute pulmonary embolism (PE), although CTEPH may occur in patients with no history of symptomatic venous thromboembolism. It represents the most severe presentation of the so-called 'post-PE syndrome', a phenomenon of permanent functional limitations after PE caused by deconditioning after PE or ventilatory or circulatory impairment as a result of unresolved pulmonary artery thrombi. Because the post-PE syndrome may occur in up to 50% of PE survivors, and CTEPH tends to have an insidious and non-specific clinical presentation, CTEPH is often not diagnosed or diagnosed after a very long delay. Once the diagnosis is confirmed, the treatment of choice is pulmonary endarterectomy which effectively lowers the pulmonary vascular resistance and normalizes resting pulmonary artery pressures, leading to recovery of the right ventricle. When pulmonary endarterectomy is not technically feasible, balloon pulmonary angioplasty may be a potential acceptable alternative. Also, medical treatment may help to improve patient's symptoms and hemodynamics. Current studies are focusing on strategies for earlier CTEPH diagnosis after acute PE, as well as the most optimal treatment of inoperable patients. This review will focus on the epidemiology, risk factors, diagnosis and treatment of CTEPH from the perspective of the PE patient. PMID- 29608810 TI - Menstruation-related headache in adolescents: Point prevalence and associated factors. AB - BACKGROUND: The aim of this study was to investigate the prevalence of menstruation-related headache and the impact of associated factors in adolescents. METHODS: This cross-sectional study was conducted in seven randomly selected high schools, and 3,886 girls attending those schools were invited to take part. After the consent of the school principals, a final total of 2,485 girls (63.9%) were involved in the study. A specific questionnaire was distributed to adolescent girls (14-19 years old). The first part of the survey investigated the features of menstruation (age at first menstruation, duration of period, pad fully soaked per day). The last part of the questionnaire surveyed the presence of headache during the menstrual period. The severity of headache was measured using a visual analog scale. Last, participants were requested to complete the Beck Depression Inventory (BDI). The prevalence of menstruation related headache and associated factors were studied. RESULTS: Mean subject age was 15.89 +/- 1.07 years (range, 14-19 years) and mean age at menarche was 12.96 +/- 1.09 years old. The prevalence of menstruation-related headache was 25.9% (n = 646). Onset of menstruation at <12 years of age, longer duration of menstruation period, dysmenorrhea, daily consumption of coffee and cola and smoking significantly affected the frequency of menstruation-related headache. Mean BDI score was 21.68 +/- 13.65 and was significantly associated with menstruation headache. CONCLUSION: Menstruation-related headache is a common problem in adolescent girls. It might be associated with different comorbidities such as depression. Accordingly, a multidisciplinary treatment approach must be considered to improve the quality of life. PMID- 29608811 TI - Metastatic pulmonary calcification: Experience from a single center in Singapore. AB - Metastatic pulmonary calcification (MPC) was seen in 79% of patients with end stage renal disease (ESRD) during autopsy. However, it is not commonly diagnosed in vivo. Its pathogenesis is not fully understood. We report a retrospective series of 5 cases of MPC from a single center in Singapore. MPC were diagnosed using radiological or histological features. Mean onset of MPC from diagnosis of ESRD was 22.6 +/- 3.1 years. One patient remains asymptomatic. Four patients died, one was related to MPC. All patients had calcifications at the lung apices on radiological studies. Three patients with MPC were diagnosed based on radiological features while 2 had histological features. Four patients underwent parathyroidectomy without radiological changes before parathyroidectomy. Median intact parathyroid hormone of this series was 5.6 pmol/L (IQR 1.3-139.4), alkaline phosphatase 74 U/L (IQR 62-461), calcium 2.10 mmol/L (IQR 1.85-2.40), and phosphate 1.30 mmol/L (IQR 0.87-1.63). The observed low iPTH suggests that MPC might occur in low iPTH. Our case series showed MPC might occur in low iPTH after parathyroidectomy, in contrast to existing literature that suggests MPC is diagnosed in patients with elevated iPTH. Parathyroidectomy does not prevent MPC. PMID- 29608812 TI - To salt or not to salt?-That is the question in cirrhosis. AB - Ascites is the most common complication of patients with cirrhosis, resulting from portal hypertension and vasodilatation. It is associated with an increased risk for the development of hyponatraemia and renal failure and has a high mortality rate of 20% per year. The development of ascites represents a baleful sign in the course of disease in cirrhosis. To prevent complications of cirrhosis and improve quality of life, an effective management of ascites is pivotal. Combined salt restriction and diuretic therapy is recommended as first-line therapy in numerous clinical practice guidelines. In contrast, there has been a debate on whether a strict salt-restricted diet for cirrhosis patients should be used at all since salt restriction may increase the risk for malnutrition which in turn may negatively impact on quality of life and survival. This review aims to summarize the current pros and cons regarding salt restriction in patients with cirrhosis and proposes the importance of achieving a sodium balance throughout different stages of cirrhosis. PMID- 29608814 TI - Impact of "high" implantation on functionality of self-expandable bioprosthesis during the short- and long-term outcome of patients who undergo transcatheter aortic valve implantation: Is high implantation beneficial? AB - AIM: High position of the self-expandable bioprosthesis CoreValve/Evolut R has been proved to affect immediate hemodynamics of the valve. Whether this may have any impact on long-term procedural outcome has not been defined yet. The purpose of this study was to assess whether the final position of aortic bioprosthesis affects its long-term functionality. METHOD: Consecutive patients (pts) who underwent successful TAVI procedure were evaluated and separated into 2 groups according to the implantation depth (ID): Group I: pts with 4 mm C) substituting the isoleucine at codon 101 to a threonine, a single nucleotide insertion (c. 327-328insC) causing a frame shift mutation and termination at codon 109, and a nonsense variant (c. 1003C > T) truncated the protein at codon 335 were identified. The I101T mutation significantly reduced PTEN protein expression levels by 2.5- to 4.0-fold. Mechanistically, I101T reduced the protein half-life of PTEN possibly due to enhanced polyubiquitination at Lysine 13. However, the I101T mutant retained almost 30% of the lipid phosphatase activity of the wild-type protein. Finally, the I101T mutant has reduced phosphorylation at a PTEN auto-dephosphorylation site at Threonine 366 and a lowered ratio of nuclear to cytosolic protein level. These partial losses of multiple PTEN biochemical functions may contribute to the tissue overgrowth and autistic features of this PHTS patient. Autism Res 2018, 11: 1098-1109. (c) 2018 The Authors Autism Research published by International Society for Autism Research and Wiley Periodicals, Inc. LAY SUMMARY: The genetics of autism spectrum disorders is highly complex with individual risk influenced by both genetic and environmental factors. Mutation in the human PTEN gene confers a high risk of developing autistic behavior. This report revealed that PTEN mutations occurred in 23% of a selected group of Hong Kong patients harboring autistic features with gross overgrowth symptoms. Detailed characterization of a PTEN mutation revealed reduced protein stability as one of the underlying mechanisms responsible for reduced PTEN activity. PMID- 29608816 TI - Metastasis in patients with hepatocellular carcinoma: Prevalence, determinants, prognostic impact and ability to improve the Barcelona Clinic Liver Cancer system. AB - BACKGROUND & AIM: Patients with hepatocellular carcinoma and metastasis are classified as advanced or terminal stage by the Barcelona Clinic Liver Cancer system. This study investigates the prevalence, determinants, and prognostic effect of metastasis and its ability to improve the Barcelona Clinic Liver Cancer system. METHODS: A total of 3414 patients were enrolled. The Kaplan-Meier and Cox regression methods were used to determine survival predictors. Akaike information criterion was used to compare the prognostic performance of staging systems. RESULTS: There were 357 (10%) patients having extrahepatic metastasis at the time of diagnosis. Metastases were associated with old age, alcoholism, hepatitis B, poorer liver function, higher alpha-foetoprotein level and larger tumour burden (all P < .05). Vascular invasion was associated with metastasis regardless of total tumour volume, and higher alpha-foetoprotein level and multiple tumours were associated with metastasis in patients with smaller tumour volume (all P < .05). Patients with both vascular invasion and metastasis had significantly worse outcome compared to patients with either vascular invasion or metastasis (P < .05). In the Cox proportional model, the co-existence of vascular invasion and metastasis was an independent predictor of decreased survival (P < .05). Re allocating 181 Barcelona Clinic Liver Cancer stage C patients with both vascular invasion and metastasis into stage D was associated with lower Akaike information criterion, indicating enhanced prognostic power of the Barcelona Clinic Liver Cancer. CONCLUSIONS: Metastasis is not uncommon, and is strongly associated with tumoural factors and poor long-term survival in hepatocellular carcinoma. Modification of the Barcelona Clinic Liver Cancer system based on vascular invasion and metastasis may further improve its predictive accuracy in advanced stage patients. PMID- 29608817 TI - Going Beyond the Limits of the Biorenewable Platform: Sodium Dithionite-Promoted Stabilization of 5-Hydroxymethylfurfural. AB - The lack of thermal and storage stability and occurrence of side reactions during the processing of 5-hydroxymethylfurfural (5-HMF) limits its potential as biorenewable platform molecule. The addition of small amounts of the readily available sodium dithionite has a remarkable effect on promoting the stability of 5-HMF and inhibiting side reactions, thus helping to circumvent such limitations. The addition of sodium dithionite led to improvements in thermal stability (120 degrees C, 4 h, neat; 100 % vs. 37 %), under distillation (yield: 85 % vs. 52 %), and in a wide range of reactions, including 5-HMF synthesis under biphasic conditions (yield: 98 % vs. 67 %; purity: 92 % vs. 83 %) and 5-HMF transformations, such as Knoevenagel condensation with Meldrum's acid (yield: 96 % vs. 74 %), Cannizaro reaction (yield: quantitative vs. 83 %), and condensation with primary diamines to give pyridinium salts (yield: 88 % vs. 60 %). PMID- 29608818 TI - Transcanal Approach for Type 2 Tympanoplasty with Incus Interposition Ossiculoplasty: Our Experience on 134 Patients. PMID- 29608819 TI - [Elderly and state: specificity of relationships in contemporary Russia on the example of elderly residents of Saint-Petersburg.] AB - The article presents the sociological research results of paternalistic attitudes that determine relationships between the state and the elderly in the context of new socio-economic conditions. It was revealed that the previous paternalistic expectations of the elderly are stable and manifested more in the older age group (71-90 years old). The younger age group of the elderly (55-70 years old) begins to distance themselves from the guardianship of the state and relies more on their own resources under new circumstances. Four types of elderly persons were revealed that are differentiated by the degree of social situation reflection adequacy, the state resources reliance, and their own activity. Paternalism takes on new forms, reflected in older generation citizens' mentality. PMID- 29608820 TI - [Age-related changes of sensory peripheral nerve system in healthy subjects.] AB - Our aim was to present and evaluate age-related changes of peripheral nerves of limbs on a huge population of healthy subjects of different ages. In 2009-2016 subjects aged from 1months to 90 years were studied by nerve conduction velocity studies (NCV). Data of those confirmed healthy was included in our study. In total there were 372 healthy subjects. NCV for nn. Medianus et Ulnaris was registered, with NCV and amplitude of compound sensory action potential (CSAP) being analyzed. There were significant differences on both these parameters between different age groups. Since the childhood the improvement of conduction (which was reflected in rising of CSAP amplitudes and NCV quickening) was registered; from 40-50 years steady decline of both these parameters were observed in both nerves. Conduction studies of peripheral nerves may be implemented in gerontology for early detection of neurophysiology patterns reflecting physiological aging. Also our results may be implemented for accelerated aging detection. PMID- 29608821 TI - [Molecular markers of Alzheimer disease early diagnostic: investigation perspectives of peripheral tissues.] AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder of elderly and old age people. For intravital diagnosis of the expression of signaling molecules - AD markers, cerebrospinal fluid (CSF) and peripheral tissues are used: lymphocytes and blood platelets, buccal and olfactory epithelium, skin fibroblasts. There are several changes in the production of hyper phosphorylated form of tau-protein, BACE1 and peptide Abeta42 in CSF in case of AD, but CSF taking may have a number of side effects. Less traumatic taking of sampling tissues for the diagnosis of AD is in use of epithelium biopsy and blood portion. An increase in the expression of the hyper phosphorylated form of tau-protein is shown in blood lymphocytes of AD patients. An increase in the content of high molecular weight forms of phosphorylated t-protein and amyloid precursor protein APP was also revealed in blood platelets of AD patients. Changes in the amount of 2 miRNA families - miR-132 family and miR-134 family were revealed in blood cells 1-5 years before the manifestation of clinical signs of AD. An increase in the concentration of bound calcium, synthesis of peptides Abeta40 and Abeta42, tau protein was observed in AD skin fibroblasts. In the olfactory and buccal epithelium an increase in the expression of hyper phosphorylated form of tau protein and Abeta peptide was detected in patients with AD. Verification of AD markers in peripheral tissues for biopsy have the important significant for life diagnostics, prevention and and target AD treatment. PMID- 29608822 TI - [Age-related risks of cancer (analytical indicators of registration and early diagnosis).] AB - Malignant tumors have a particular specificity of the frequency of tumors in different age groups. The risk of cancer among people under 35 years of age is extremely low - 10-15 cases per 100 000 population of each age group. After 35 years of age with each age-related year the likelihood of cancer increases by 10% and for a five-year period by 50-70% reaching values of 2-5 thousand cases per 100 000 population in older groups. Knowing these patterns and details of localization structure for the each age it is possible to plan the implementation of a complex of anti-cancer measures correctly. There are certain difficulties in the formation of state statistics of malignant tumors. Not all administrative territories of Russia since 2011 had and have an access to database of deceased, which leads to the accumulation of "dead souls" in patient contingents. Also there are distorted other analytical indicators. There is a difficulty in staffing specialists of territorial cancer registries as well. Despite a significant improvement in relative 5-year survival rates of cancer patients this process is much more modest in older age groups. PMID- 29608823 TI - [High life expectancy of Muscovites at old ages: reality or statistical artifact?] AB - Since the mid-2000s, after a few decades of negative trends and fluctuations, Russia has experienced the longest and most stable period of life expectancy increasing for the entire period of observation which was determined not only by a decrease in mortality at the middle ages, but also at the old ages. This period has been marked by a very fast increase in life expectancy of Muscovites. The paper shows that the mortality at old ages in Moscow systematically deviates from the patterns observed in economically developed countries with reliable mortality statistics. We assume that experience of these countries is applicable to regions of Russia. Based on this assumption the adjusted estimates of life expectancy at old ages in Moscow and Russia were calculated, as well as effect of the underestimation of mortality over age 80 on life expectancy at birth and at the age of retirement. PMID- 29608824 TI - [Is aging a disease?] AB - Recently, among gerontologists and the community, adjoining them for scientific interests, an acute discussion has arisen about the need to recognize the aging as a disease. The author discusses the philosophical, deontological, nosological, pathophysiological, clinical and biological aspects of this issue. PMID- 29608825 TI - [Is aging a disease? Biodemographers' point of view.] PMID- 29608826 TI - [Is aging a disease? Geneticist' point of view.] PMID- 29608828 TI - [Is aging a disease? Geriatrician' point of view.] PMID- 29608827 TI - [Is aging a disease? Biogerontologist' point of view: the old age ? disease.] PMID- 29608829 TI - [Co-administration of intranasally delivered insulin and proinsulin C-peptide to rats with the types 1 and 2 diabetes mellitus restores their metabolic parameters.] AB - The C-peptide, the product of proinsulin proteolysis, not only is a signal molecule, but also, forming a complex with insulin, is able to modulate the signaling functions of insulin. The signaling systems sensitive to insulin in the hypothalamus and other brain areas are among the targets of insulin. We hypothesized that in systemic deficiency of insulin and C-peptide in the type 1 diabetes mellitus (DM) and in severe forms of the type 2 DM, the increase in the level of C-peptide in the CNS will improve central effects of insulin, including its influence on peripheral metabolism. To verify this, the influence of separate and co-administration of intranasal insulin (II) and C-peptide (IP) on their metabolic parameters and sensitivity to insulin in rats with acute and mild type 1 DM induced by the treatment with streptozotocin at the doses of 60 and 35 mg/kg and in rats with neonatal type 2 DM corresponding to severe long-term form of type 2 DM in human was studied. The treatment of animals with II and IP was carried out for 7 days in the daily doses of 20 and 10 MUg/rat, respectively. The co-administration of II and IP leading to an increase of insulin and C-peptide levels in the brain was most effective. In rats with type 1 DM treated with the combination of II plus IP, hyperglycemia was decreased and weight loss was prevented. In rats with type 2 DM, co-administration of II and IP led to the normalization of glucose homeostasis and the increase in insulin sensitivity, as shown by glucose-tolerance and insulin-glucose tolerance tests, and to improvement of lipid metabolism, as demonstrated by the decrease in the atherogenic index. The effectiveness of monotherapy with II was lower than in the case of a combination of II+IP, while monotherapy with C-peptide had little effect on the indicators studied. Thus, the simultaneous increase of insulin and C-peptide levels in the brain in the conditions of their deficiency in diabetic pathology can be considered as one of the promising approaches to restore the central insulin-dependent regulation of peripheral metabolism and to improve the utilization of glucose in different forms of DM. PMID- 29608830 TI - [The age-dependent changes of reproductive function in offspring Drosophila melanogaster.] AB - It was analyzed a comparative study of age-dependent changes in the parameters of reproductive function and embryonic development of offspring from adults w1c-s, w1Or mutant strains and Canton-S, Oregon-R wild-type strains D. melanogaster. In investigation three age groups of adult drosophila: 3, 10 and 20-days old were used. Reciprocal crosses between young and aging parents enable to define the influence of age of the maternal and/or paternal organism on the parameters of reproductive function. It is shown that the various features of reproductive function in F1 offspring of mutants and wild-type strains are forming differently by the different influence of the age of parents. The established effect of the white mutation, either as an independent factor or in combination with the parental age, is reflected in the low values of the fertility and viability and high values of dominant lethal mutations and mortality on the metamorphosis stage and consequently the appearance of less adapt and viable offspring in the population. PMID- 29608831 TI - [Age-related traits of cytogenetic abnormalities in synovial cells of knee-joint in residents of the North of Siberia with arthritis of different etiology depending on the GSTM1 gene polymorphism of glutathion-S-transferase.] AB - It was studied the frequency of cells with cytogenetic abnormalities in the synovial fluid cells of the knee joint in patients of different age groups suffering from chronic arthritis associated with Lyme borreliosis (CAALB) or post traumatic arthritis (PTA), depending on the polymorphism of the GSTM1 gene of glutathione-S-transferase. The study included 135 residents of the north of the Tomsk and Tyumen regions, 68 of whom suffered from CAALB, and the rest of the 67 patients who made up the control group were diagnosed with PTA. The results of this study have demonstrated that there are significant age-related differences in the frequency of cytogenetic abnormalities of the synovial fluid cells of the knee joint between young and elderly patients of SAALB. The integrative assessment of clinical and cytogenetic parameters in the group of elderly SAALB patients with mutant GSTM1 (0/0) allele, as compared with the other groups, enable to conclude that there are significant positive correlations between the indices of the severity disruption of articular locomotor function and the frequency of synovial fluid cells with trisomy of chromosome 7. PMID- 29608832 TI - [Vitamin D deficiency as a risk factor for chronic non-infectious diseases.] AB - Vitamin D deficiency is an important risk factor for a number of chronic non infectious diseases. The results of the study showed a high prevalence of vitamin D deficiency in patients with cardiovascular and bronchial obstruction diseases. Patients with coronary artery disease in association with hypertension were diagnosed with a vitamin D deficiency in 60% of cases, a pronounced deficiency in 40%; in patients with arterial hypertension - a vitamin D deficiency in 80%, and a pronounced deficit - in 20%; in patients with chronic obstructive pulmonary disease - vitamin D deficiency in 33%, and a pronounced deficit - in 67%; in patients with bronchial asthma - vitamin D deficiency in 75%, a severe deficit in 25%, and a vitamin D deficiency in 25% of the subjects. According to the received results, vitamin D deficiency is associated with intensity of chronic heart failure, arterial hypertension in patients with cardiovascular diseases, and also with the degree of respiratory failure accompanying glucocorticoid therapy in patients with bronchial obstructive pathology. The intensity of hypovitaminosis of vitamin D is aggravated with age and the duration of menopause in women. The article shows that patients with chronic non-infectious diseases have a high risk of osteoporotic fractures, most patients with bronchial obstructive and cardiovascular diseases need anti-osteoporotic therapy and osteodensitometry. PMID- 29608833 TI - The effect of resistance training on quadriceps muscle volume and some growth factors in elderly and young men. AB - Aging process is associated with loss of muscle mass, strength and growth factors dysfunction. Resistance training is one of the effective methods to overcome a decline in muscle mass, strength and also can modulate the level of myostatin, follistatin and insulin-like growth factor-1 (IGF-1) factors. The purpose of this study was to investigate the effect of 8 week resistance training on different anabolic factors which influence muscle hypertrophy in elderly and young men. Fifteen elderly and sixteen young men volunteered and participated in a periodized 3-day per week progressive resistance training program for a total of 8 weeks. Daily calorie intake, muscle volume, cross-sectional area (by computed tomography) and myostatin, follistatin, IGF-1, growth hormone (GH) and testosterone were calculated before and after the training protocol. At the end of the training period, the strength in the elderly group increased significantly compared to the young group (p<0,05); no differences of daily nutrient intake were found in both groups (p>0,05). Quadriceps muscle volume and cross-sectional area increased more in the younger group (p<0,05). Myostatin concentration significantly decreased in both groups (p<0,05), yet the amount of change was not different in either groups (p>0,05). Follistatin and testosterone increased in both groups (p<0,05), but growth hormone and IGF-1 increased in the younger group only (p<0,05). Resistance training improved hypertrophy and lead to anabolic conditions in elder and young subjects, but in different ways. In this regard, GH IGF-1 axis and growth factors profile at the baseline had an important role in different age-related hypertrophy. PMID- 29608834 TI - [Psychological defense mechanism of elderly people having mild cognitive impairments.] AB - The article presents the results of psychological defense mechanism research of elderly persons group having mild cognitive impairments (51 persons). The leading defense mechanisms in this group were "reactive entity" and "denial". Reliable correlation between capacity of short-term memory, the MMSE test and "substitution", attention rate and "regression", leading psychological defense and indicators of anxiety, fear, depression and aggression of the studied group are found. The found correlation between defense tension and psychological parameters disclose features of intra personal adaptation of elderly persons having mild cognitive impairments. The received results can be used for psychological diagnostics and correction of emotional, personal and cognitive disorders of the elderly people. PMID- 29608835 TI - [The formation and dynamics of cognitive disordersin acute period of stroke in representatives different ages.] AB - In a sample of 116 patients aged 23 to 82 years was conducted study of the state of the cognitive sphere in the final stage of the acute period of ischemic and hemorrhagic stroke. Signs of cognitive deficits were detected in 80 (70%) of them, often over the age of 60 years and against the background of ischemic stroke. But only 8,6% of the representatives of elderly and senile patients disorders of cognitive functions are first diagnosed on a background of stroke. The majority of elderly patients they mentioned earlier, and the stroke only caused further progression of cognitive deficit. Due to the age and background of stroke, cardiovascular disease negative impact on the cognitive functions, especially in ischemic stroke. However, hypertension can help to reduce the volume of the ischemic lesion and thus prevent the development of severe cognitive disorders. Surgical intervention was performed due to stroke, can contribute to the formation and progression of cognitive impairment, and thrombolytic therapy, on the contrary, reduces the risk of cognitive deficit. Continued employment in retirement age has a positive effect on maintaining cognitive functions. PMID- 29608836 TI - [Strategy of surgical treatment of strangulated inguinal hernias in elderly and senile age.] AB - We analyzed the results of treatment of 80 patients of elderly and senile age with strangulated inguinal hernias, which were divided into two groups. From 2011 to 2014 were treated 58 patients (group 2) - in the treatment of this group used the traditional approach without the use of endovideosurgical technologies. From 2015 to 2016, it treated 22 patients (group 1) in the treatment of this group used individual diagnostic and treatment tactics with the use of diagnostic laparoscopy and laparoscopic hernioplasty. In the course of work were developed indications and contraindications to the use of prosthetic hernioplasty and endovideosurgical methods. The proposed algorithm allowed to reduce the level of complications from 27,6% (16) to 4,5% (1) (p<0,05) and local complications from 24,1% (14) to 4,6% (1) (p<0,05), as well as the fatality rate from 10,3% (6) to 0%. PMID- 29608837 TI - [A study of the duration of the disease as a risk factor for the development of hospitalization in elderly psychiatric patients.] AB - Phenomenon of hospitalism in elderly patients with mental disorders is an extremely important clinical, social and economic problem. 155 patients of the gerontopsychiatric hospital were examined, 75 of them showed signs of hospitalism, and 80 made up a control group. A subgroup of patients with signs and short duration of the disease was isolated, the duration of treatment in the hospital of these patients was 133,5+/-42,24 days (in the corresponding control subgroup 72,11+/-37,11 days, p<0,05). This subgroup was characterized by greater impulsiveness as a personality trait and less adaptive coping strategies. A subgroup of patients with signs of hospitalism and a longer duration of the disease also had a longer stay in the hospital compared to patients with a similar experience of illness without hospitalism (249,67+/-63,56 and 79,58+/ 39,52 days, respectively, p<0,05). For this subgroup of patients, the factors associated with the development of hospitalism were higher anxiety and depression in the current psychoemotional state, a smaller representation of adaptive cognitive coping and less sensitivity to the disease, all differences are significant at p<0,05. PMID- 29608838 TI - [The dynamics of formation of psychic disordersof combatants and pensioners of the ministry of internal affairs.] AB - Retrospective analysis of the dynamics of formation and nosological structure of mental disorders among the pensioners of the Ministry of internal Affairs (MIA) with the retirement on superannuation of mental disorder impeding further passage of service. All respondents were divided into two groups according to the criterion of participation in hostilities. It is shown that the ex-combatants, pensioners of MIA in the clinic dominated by organic disorder associated with the consequences of closed traumatic brain injury mine blast etiology, despite the rendered medical aid, the formation of personality disorders that violate social functioning and lead to disability. Pensioners of MIA, who was not involved in pain action, revealed the presence of severe neurotic with a decline in socialization and the formation of chemical dependency and the subsequent development of organic disorders of the Central nervous system predominantly alcoholic etiology, resulting in poor social functioning and to disability. The data obtained indicate certain weaknesses in the organization of psychiatric care to this population: the limited psycho-prophylactic and correctional activities, late diagnosis of borderline mental disorders. To reduce the risk of the formation of personality disorders and chemical dependency have retired police officers it is necessary to improve the organizational and methodological approaches to carrying out annual medical examination of personnel of the interior MIA. PMID- 29608839 TI - [The treatment of elderly and senile patients with venous trophic ulcers and type 2 diabetes mellitus.] AB - The effectiveness of the inclusion of sulodexide in the pharmacotherapy of complex treatment of patients (n=52) elderly and senile with a combination of chronic diseases of the veins complicated by refractory trophic ulcers of the lower extremities, and type 2 diabetes mellitus was studied. Patients were randomly randomized in the 1st (n=26) and the 2nd (n=26) groups, the statistical differences between them in age (t1-2=0,2, p1-2=0,833), sex (chi21-2=0,008, p1 2=0,991), nosology (chi21-2=0,004, r1-2=0,993); the anamnesis of chronic diseases of veins (t1-2=0,14, p1-2=0,893); duration of trophic ulcers (t1-2=0,21, p1 2=0,827); planimetric parameters of trophic ulcers (t1-2=0,18, p1-2=0,865) were not recorded. Patients of the 1st group received treatment with sulodexide according to the standard schedule for 50 days. The primary outcome of the study is the complete closure of the trophic ulcer after 1 month. Secondary outcomes are epithelization after 2 months and dynamic planimetric indices within 12 months. The effectiveness of the use of sulodexide was assessed according to the VCSS scale, dynamic changes in the malleolar volume and changes in planimetric parameters. A statistically significant improvement in the overall VSCC score was observed in both the 1st (p=0,002) and the 2nd (p=0,0016) groups in all study outcomes. At the same time, a statistically significant improvement in the VSCC scores was more pronounced in the 1st group (p<0,05). After 2 and 6 months, a statistically significant decrease in the malleolar volume of the affected lower extremity was recorded both in the 1st (t=4,17, p=0,001) and in the 2nd (t=2,4, p=0,37) groups. Clinically and statistically significant decrease in malleolar volume was more pronounced in the 1st group (p<0,05). After 30 days, trophic ulcers were closed in 9 (34,6%) cases in the 1st group and in 5 (19,2%) patients in the 2nd group (p<0,05). On day 60 epithelization was achieved in 22 (84,6%) and 12 (46,1%) patients, respectively. The time of complete epithelization in patients of the 1st and the 2nd groups was 51,2+/-1,6 and 78,4+/-2,6 days (p<0,05). The conclusion is made that sulodexide is an effective and pathogenetically grounded pharmacological preparation for the treatment of patients of elderly and senile age with chronic clinical disease C6 of clinical class and type 2 diabetes mellitus. PMID- 29608840 TI - Silicon Decreases Dimethylarsinic Acid Concentration in Rice Grain and Mitigates Straighthead Disorder. AB - While root Si transporters play a role in the uptake of arsenite and organic As species dimethylarsinic acid (DMA) and monomethylarsonic acid (MMA) in rice ( Oryza sativa L.), the impact of Si addition on the accumulation of DMA and MMA in reproductive tissues has not been directly evaluated, particularly in isolation from inorganic As species. Furthermore, DMA and MMA are suspected causal agents of straighthead disorder. We performed a hydroponic study to disentangle the impact of Si on accumulation of DMA and MMA in rice grain. At 5 MUM, MMA was toxic to rice, regardless of Si addition, although Si significantly decreased root MMA concentrations. Plants dosed with 5 MUM DMA grew well vegetatively but exhibited straighthead disorder at the lowest Si dose, and this DMA-induced yield loss reversed with increasing solution Si. Increasing Si also significantly decreased DMA concentrations in roots, straw, husk, and grain, particularly in mature plants. Si restricted grain DMA through competition for root uptake and downregulation of root Si transporters particularly at later stages of growth when Si uptake was greatest. Our finding that DMA causes straighthead disorder under low Si availability but not under high Si availability suggests Si as a straighthead management strategy. PMID- 29608841 TI - Rhodium-Catalyzed [4 + 1] Cyclization via C-H Activation for the Synthesis of Divergent Heterocycles Bearing a Quaternary Carbon. AB - The development of an efficient approach to construct fused polycyclic systems bearing a quaternary carbon center represents a great challenge to synthetic chemistry. Herein, we report a Rh(III)-catalyzed [4 + 1] annulation of propargyl alcohols with various heterocyclic scaffolds under an air atmosphere. Diverse fused heterocycles containing a quaternary carbon center were obtained in moderate to good yields. Additionally, this method features a high atom-economy, metal oxidant free, simple operation, and compatibility with various functional groups. PMID- 29608842 TI - Molecular Adsorption Mechanism of Elemental Carbon Particles on Leaf Surface. AB - Plant leaves can effectively capture and retain particulate matter (PM), improving air quality and human health. However, little is known about the adsorption mechanism of PM on leaf surface. Black carbon (BC) has great adverse impact on climate and environment. Four types of elemental carbon (EC) particles, carbon black as a simple model for BC, graphite, reduced graphene oxide, and graphene oxide, and C36H74/C44H88O2 as model compounds for epicuticular wax were chosen to study their interaction and its impact at the molecular level using powder X-ray diffraction and vibrational spectroscopy (infrared and Raman). The results indicate that EC particles and wax can form C-H...pi type hydrogen bonding with charge transfer from carbon to wax; therefore, strong attraction is expected between them due to the cooperativity of hydrogen bonding and London dispersion from instantaneous dipoles. In reality, once settled on the leaf surface, especially without wax ultrastructures, BC with extremely large surface to-volume ratio will likely stick and stay. On the other hand, BC particles can lead to phase transition of epicuticular wax from crystalline to amorphous structures by creating packing disorder and end- gauche defects of wax molecular chain, potentially causing water loss and thereby damage of plants. PMID- 29608843 TI - Localized Visualization and Autonomous Detection of Cell Surface Receptor Clusters Using DNA Proximity Circuit. AB - Cell surface receptors play an important role in mediating cell communication and are used as disease biomarkers and therapeutic targets. We present a one-pot molecular toolbox, which we term the split proximity circuit (SPC), for the autonomous detection and visualization of cell surface receptor clusters. Detection was powered by antibody recognition and a series of autonomous DNA hybridization to achieve localized, enzyme-free signal amplification. The system under study was the human epidermal growth factor receptor (HER) family, that is, HER2:HER2 homodimer and HER2:HER3 heterodimer, both in cell lysate and in situ on fixed whole cells. The detection and imaging of receptors were carried out using standard microplate scans and confocal microscopy, respectively. The circuit operated specifically with minimal leakages and successfully captured the receptor expression profiles on three cell types without any intermediate washing steps. PMID- 29608845 TI - Prostate-Specific Membrane Antigen Targeted Therapy of Prostate Cancer Using a DUPA-Paclitaxel Conjugate. AB - Prostate cancer (PCa) is the most prevalent cancer among men in the United States and remains the second-leading cause of cancer mortality in men. Paclitaxel (PTX) is the first line chemotherapy for PCa treatment, but its therapeutic efficacy is greatly restricted by the nonspecific distribution in vivo. Prostate-specific membrane antigen (PSMA) is overexpressed on the surface of most PCa cells, and its expression level increases with cancer aggressiveness, while being present at low levels in normal cells. The high expression level of PSMA in PCa cells offers an opportunity for target delivery of nonspecific cytotoxic drugs to PCa cells, thus improving therapeutic efficacy and reducing toxicity. PSMA has high affinity for DUPA, a glutamate urea ligand. Herein, a novel DUPA-PTX conjugate is developed using DUPA as the targeting ligand to deliver PTX specifically for treatment of PSMA expressing PCa. The targeting ligand DUPA enhances the transport capability and selectivity of PTX to tumor cells via PSMA mediated endocytosis. Besides, DUPA is conjugated with PTX via a disulfide bond, which facilitates the rapid and differential drug release in tumor cells. The DUPA-PTX conjugate exhibits potent cytotoxicity in PSMA expressing cell lines and induces a complete cessation of tumor growth with no obvious toxicity. Our findings give new insight into the PSMA-targeted delivery of chemotherapeutics and provide an opportunity for the development of novel active targeting drug delivery systems for PCa therapy. PMID- 29608844 TI - Iron Redox Chemistry Promotes Antiparallel Oligomerization of alpha-Synuclein. AB - Brain metal dyshomeostasis and altered structural dynamics of the presynaptic protein alpha-synuclein (alphaS) are both implicated in the pathology of Parkinson's disease (PD), yet a mechanistic understanding of disease progression in the context of alphaS structure and metal interactions remains elusive. In this Communication, we detail the influence of iron, a prevalent redox-active brain biometal, on the aggregation propensity and secondary structure of N terminally acetylated alphaS (NAcalphaS), the physiologically relevant form in humans. We demonstrate that under aerobic conditions, Fe(II) commits NAcalphaS to a PD-relevant oligomeric assembly, verified by the oligomer-selective A11 antibody, that does not have any parallel beta-sheet character but contains a substantial right-twisted antiparallel beta-sheet component based on CD analyses and descriptive deconvolution of the secondary structure. This NAcalphaS-FeII oligomer does not develop into the beta-sheet fibrils that have become hallmarks of PD, even after extended incubation, as verified by TEM imaging and the fibril specific OC antibody. Thioflavin T (ThT), a fluorescent probe for beta-sheet fibril formation, also lacks coordination to this antiparallel conformer. We further show that this oligomeric state is not observed when O2 is excluded, indicating a role for iron(II)-mediated O2 chemistry in locking this dynamic protein into a conformation that may have physiological or pathological implications. PMID- 29608846 TI - A Dealloying Synthetic Strategy for Nanoporous Bismuth-Antimony Anodes for Sodium Ion Batteries. AB - Metal-based anodes have recently aroused much attention in sodium ion batteries (SIBs) owing to their high theoretical capacities and low sodiation potentials. However, their progresses are prevented by the inferior cycling performance caused by severe volumetric change and pulverization during the (de)sodiation process. To address this issue, herein an alloying strategy was proposed and nanoporous bismuth (Bi)-antimony (Sb) alloys were fabricated by dealloying of ternary Mg-based precursors. As an anode for SIBs, the nanoporous Bi2Sb6 alloy exhibits an ultralong cycling performance (10 000 cycles) at 1 A/g corresponding to a capacity decay of merely 0.0072% per cycle, due to the porous structure, alloying effect and proper Bi/Sb atomic ratio. More importantly, a (de)sodiation mechanism ((Bi,Sb) <-> Na(Bi,Sb) <-> Na3(Bi,Sb)) is identified for the discharge/charge processes of Bi-Sb alloys by using operando X-ray diffraction and density functional theory calculations. PMID- 29608847 TI - Crystallization-Induced Morphological Tuning Toward Denim-like Graphene Nanosheets in a KCl-Copolymer Solution. AB - Although nucleation and crystallization in solution-processed materials synthesis is a natural phenomenon, the morphology design of graphene nanosheets by controlling the dual crystallization has not been established. In this work, we systematically demonstrate how the dual crystallization of ice and potassium chloride induces the morphological variation of the freeze-dried scaffold from fractal structure toward stepped sheet-like structure. A denim-like graphene nanosheet (DGNS) has been fabricated by annealing the F127-coated stepped sheet like scaffold in nitrogen. DGNS shows parallel and straight stripes with an average stripe spacing of 10 nm. When used as a lithium-ion battery anode, DGNS possesses a superhigh reversible capacity of 1020 mAh g-1 at the current density of 1 A g-1 after 600 cycles. This work reports the control of dual crystallization of ice and salt crystals and provides an efficient way to design the morphology of two-dimensional materials by adjusting the crystallization. PMID- 29608848 TI - Lifting the Curse of Dimensionality on Enhanced Sampling of Reaction Networks with Parallel Bias Metadynamics. AB - A common challenge to applying metadynamics to the study of complex systems is selecting the proper collective variables to bias. The advent of generic collective variables, specifically social permutation invariant (SPRINT) coordinates, has helped to address this challenge by reducing the level of a priori knowledge required to just basic chemical fundamentals. However, the efficiency of biasing SPRINT coordinates can be severely handicapped by the high dimensionality of the bias potential. Here, we circumvent this deficiency by biasing SPRINT coordinates using the parallel bias metadynamics framework. We demonstrate the efficacy of this method to efficiently explore a complex system, without any prior knowledge about transition pathways, by applying it to study the decomposition of gamma-ketohydroperoxide and generating a comprehensive reaction network of relevant pathways. The reduction in both computational cost and chemical intuition makes this method a promising option for studying complex reacting systems. PMID- 29608849 TI - Dynamic Shaping of Femtoliter Dew Droplets. AB - Herein, we show that wetting properties such as giant wetting anisotropy and dynamic shaping can be observed when femtoliter (submicron scale) dew droplets are condensed on nanopatterned mildly hydrophilic surfaces. Large-scale, optically transparent, nanopatterned TiO2 surfaces were fabricated by direct nanoimprinting lithography of sol-gel-derived films. Square, infinitely elongated, or circular droplets were obtained with square, line, or concentric patterns, respectively, and were visualized in situ during formation and recession using optical microscopy and environmental scanning electronic microscopy. We first describe how extremely elongated droplets could form on mildly hydrophilic surfaces, naturally contaminated in real environmental conditions. In this configuration, the dew droplet shape can be dynamically and reversibly varied by controlling the out-of-equilibrium conditions associated with condensation/evaporation kinetics. As an example of the application, we propose a "morphological" sensor that exploits the shape of the dew droplets as a transduction mode for detecting organic vapors in the outer atmosphere. Importantly, this study is underlining that environmentally stable, purely hydrophilic surfaces can be smartly engineered to induce wetting phenomena at very small scale never observed so far for hydrophobic or heterogeneous surfaces. Our versatile approach based on nanoimprinted, transparent sol-gel films could open great perspectives for the implementation of environmentally stable, mildly hydrophilic materials for "dew engineering" applications such as open microfluidics, fuming for fingerprints, vapor sensing, or water harvesting on glass windows, for instance. PMID- 29608851 TI - Photodissociation Spectroscopy of Cold Protonated Synephrine: Surprising Differences between IR-UV Hole-Burning and IR Photodissociation Spectroscopy of the O-H and N-H Modes. AB - We report the UV and IR photofragmentation spectroscopies of protonated synephrine in a cryogenically cooled Paul trap. Single (UV or IR) and double (UV UV and IR-UV) resonance spectroscopies have been performed and compared to quantum chemistry calculations, allowing the assignment of the lowest-energy conformer with two rotamers depending on the orientation of the phenol hydroxyl (OH) group. The IR-UV hole burning spectrum exhibits the four expected vibrational modes in the 3 MUm region, i.e., the phenol OH, Cbeta-OH, and two NH2+ stretches. The striking difference is that, among these modes, only the free phenol OH mode is active through IRPD. The protonated amino group acts as a proton donor in the internal hydrogen bond and displays large frequency shifts upon isomerization expected during the multiphoton absorption process, leading to the so-called IRMPD transparency. More interestingly, while the Cbeta-OH is a proton acceptor group with moderate frequency shift for the different conformations, this mode is still inactive through IRPD. PMID- 29608850 TI - Accurate Binding of Sodium and Calcium to a POPC Bilayer by Effective Inclusion of Electronic Polarization. AB - Binding affinities and stoichiometries of Na+ and Ca2+ ions to phospholipid bilayers are of paramount significance in the properties and functionality of cellular membranes. Current estimates of binding affinities and stoichiometries of cations are, however, inconsistent due to limitations in the available experimental and computational methods. In this work, we improve the description of the binding details of Na+ and Ca2+ ions to a 1-palmitoyl-2-oleoyl phosphatidylcholine (POPC) bilayer by implicitly including electronic polarization as a mean field correction, known as the electronic continuum correction (ECC). This is applied by scaling the partial charges of a selected state-of-the-art POPC lipid model for molecular dynamics simulations. Our improved ECC-POPC model reproduces not only the experimentally measured structural parameters for the ion-free membrane, but also the response of lipid headgroup to a strongly bound cationic amphiphile, as well as the binding affinities of Na+ and Ca2+ ions. With our new model, we observe on the one side negligible binding of Na+ ions to POPC bilayer, while on the other side stronger interactions of Ca2+ primarily with phosphate oxygens, which is in agreement with the previous interpretations of the experimental spectroscopic data. The present model results in Ca2+ ions forming complexes with one to three POPC molecules with almost equal probabilities, suggesting more complex binding stoichiometries than those from simple models used to interpret the NMR data previously. The results of this work pave the way to quantitative molecular simulations with realistic electrostatic interactions of complex biochemical systems at cellular membranes. PMID- 29608852 TI - Shear Stress-Enhanced Internalization of Cell Membrane Proteins Indicated by a Hairpin-Type DNA Probe. AB - Shear stress is an important mechanical stimulus that plays a critical role in modulating cell functions. In this study, we investigated the regulating effects of shear stress on the internalization of cell membrane proteins in a microfluidic chip. A hairpin-type DNA probe was developed and indiscriminately anchored to the cell surface, acting as an indicator for the membrane proteins. When cells were exposed to shear stress generated from fluid cell medium containing external proteins, strong fluorescence was emanated from intracellular regions. With intensive investigation, results revealed that shear stress could enhance the specific cell endocytosis pathway and promote membrane protein internalization. This process was indicated by the enhanced intracellular fluorescence, generated from the internalized and mitochondria accumulated DNA probes. This study not only uncovered new cellular mechanotransduction mechanisms but also provided a versatile method that enabled in situ and dynamic indication of cell responses to mechanical stimuli. PMID- 29608853 TI - Nitrogen Dioxide Reaction with Nitroxide Radical Derived from Hydroxamic Acids: The Intermediacy of Acyl Nitroso and Nitroxyl (HNO). AB - Hydroxamic acids (RC(O)NHOH) form a class of compounds that display interesting chemical and biological properties The chemistry of RC(O)NHOH) is associated with one- and two-electron oxidations forming the respective nitroxide radical (RC(O)NHO*) and acyl nitroso (RC(O)N?O), respectively, which are relatively unstable species. In the present study, the kinetics and mechanism of the *NO2 reaction with nitroxide radicals derived from acetohydroxamic acid, suberohydroxamic acid, benzohydroxamic acid, and suberoylanilide hydroxamic acid have been studied in alkaline solutions. Ionizing radiation was used to generate about equal yields of these radicals, demonstrating that the oxidation of the transient nitroxide radical by *NO2 produces HNO and nitrite at about equal yields. The rate constant of *NO2 reaction with the nitroxide radical derived from acetohydroxamic acid has been determined to be (2.5 +/- 0.5) * 109 M-1 s-1. This reaction forms a transient intermediate absorbing at 314 nm, which decays via a first-order reaction whose rate increases upon increasing the pH or the hydroxamic acid concentration. Transient intermediates absorbing around 314 nm are also formed during the oxidation of hydroxamic acids by H2O2 catalyzed by horseradish peroxidase. It is shown that HNO is formed during the decomposition of these intermediates, and therefore, they are assigned to acyl nitroso compounds. This study provides for the first time a direct spectrophotometric detection of acyl nitroso compounds in aqueous solutions allowing the study of their chemistry and reaction kinetics. PMID- 29608854 TI - Interface Engineering and its Effect on WO3-Based Photoanode and Tandem Cell. AB - During photoelectrochemical (PEC) water splitting, the reactions occur on the surface of the photoelectrode. Therefore, the properties of the interfaces between the various components of the electrode (semiconductor/semiconductor, semiconductor/catalyst, or photoelectrode/electrolyte) affect the PEC performance of the composite material. Notably, surface trap states may hinder charge transfer and transport properties, and also cause Fermi pinning, affecting the quasi-Fermi level and onset potential under illumination, which may in turn influence the PEC performance of the corresponding tandem cells. In this study, plate-like WO3 array films prepared by an aqueous chemical growth method were employed to highlight the effect of interfacial properties on the performance of a WO3-based photoanode. The Mott-Schottky and linear sweep voltammetry experiments prove the existence of surface trap states and Fermi pinning for pristine WO3, which are alleviated after an "etching" treatment and disappeared after surface passivation by a Ga2O3 layer. Both etching and passivation increase the oxygen evolution activity and the Faradaic efficiency for the oxygen evolution reaction (OER). After loading a permeable catalyst (FeOOH), the photocurrent is further increased, and there is a synergistic effect between loading of the electrocatalyst with etching or passivation. The onset potentials of the samples follow the trends: etch-WO3/FeOOH < WO3/FeOOH <= WO3/Ga2O3/FeOOH < etch-WO3 < WO3 < WO3/Ga2O3, indicating that the interfacial properties have a significant effect on the PEC performance. Meanwhile, the modified WO3-based electrode was combined with a dye-sensitized solar cell to fabricate tandem cell, which showed 2.42-fold photocurrent density compared with the pristine WO3-based tandem cell. PMID- 29608855 TI - Relative Populations of Some Tautomeric Forms of 2'-Deoxyguanosine-5 Fluorouridine Mismatch. AB - The importance of the 2'-deoxyguanosine-uridine mispair as the most occurring mismatch in transcriptional studies of RNAs from DNAs is multiplied when 5-halo substituted uridine species cause a serious increase in the probability of its occurrence. Many studies relate this higher probability to the existence of possible tautomeric and ionic forms of its constituent bases. According to these statements, relative populations of mismatches between 5-fluorouridine and both keto and enol forms of 2'-deoxyguanosine are computed by using a conformational search. In order to have a complete scan of all of the highly probable conformers in a moderate computational time, an extensive conformational search methodology is employed here, which benefits from the advantages of both the molecular dynamics simulations and quantum mechanics calculations. The population of an enolic tautomer of normal wobble orientation is about 0.057% of that of its keto tautomer, whereas the population of an enolic tautomer of reverse wobble orientation is about 0.0054% of that of its keto tautomer. Totally, the reverse wobble orientation is about six times more populated than the normal wobble orientation. Calculated populations are in good agreement with experimental populations of closely related compounds. The reliability of the applied methodology is certified, in part, by a good agreement obtained between some experimental data and corresponding Boltzmann-weighted average data of most probable conformers such as NMR parameters. The validation of this methodology is certified with high accuracy by applying it on the substituted diuridine pairs, where experimental populations are available. Not only are the calculated populations and NMR parameters of this test in very good agreement with the experimental data, but also they are free of the ambiguities mentioned by experimentalists. PMID- 29608856 TI - Formulation and Stabilization of Concentrated Edible Oil-in-Water Emulsions Based on Electrostatic Complexes of a Food-Grade Cationic Surfactant (Ethyl Lauroyl Arginate) and Cellulose Nanocrystals. AB - We report on high-internal-phase, oil-in-water Pickering emulsions that are stable against coalescence during storage. Viscous, edible oil (sunflower) was emulsified by combining naturally derived cellulose nanocrystals (CNCs) and a food-grade, biobased cationic surfactant obtained from lauric acid and L-arginine (ethyl lauroyl arginate, LAE). The interactions between CNC and LAE were elucidated by isothermal titration calorimetry (ITC) and supplementary techniques. LAE adsorption on CNC surfaces and its effect on nanoparticle electrostatic stabilization, aggregation state, and emulsifying ability was studied and related to the properties of resultant oil-in-water emulsions. Pickering systems with tunable droplet diameter and stability against oil coalescence during long-term storage were controllably achieved depending on LAE loading. The underlying stabilization mechanism was found to depend on the type of complex formed, the LAE structures adsorbed on the cellulose nanoparticles (as unimer or as adsorbed admicelles), the presence of free LAE in the aqueous phase, and the equivalent alkane number of the oil phase (sunflower and dodecane oils were compared). The results extend the potential of CNC in the formulation of high-quality and edible Pickering emulsions. The functional properties imparted by LAE, a highly effective molecule against food pathogens and spoilage organisms, open new opportunities in food, cosmetics, and pharmaceutical applications, where the presence of CNC plays a critical role in achieving synergistic effects with LAE. PMID- 29608857 TI - Stretchable Transparent Electrode Arrays for Simultaneous Electrical and Optical Interrogation of Neural Circuits in Vivo. AB - Recent developments of transparent electrode arrays provide a unique capability for simultaneous optical and electrical interrogation of neural circuits in the brain. However, none of these electrode arrays possess the stretchability highly desired for interfacing with mechanically active neural systems, such as the brain under injury, the spinal cord, and the peripheral nervous system (PNS). Here, we report a stretchable transparent electrode array from carbon nanotube (CNT) web-like thin films that retains excellent electrochemical performance and broad-band optical transparency under stretching and is highly durable under cyclic stretching deformation. We show that the CNT electrodes record well defined neuronal response signals with negligible light-induced artifacts from cortical surfaces under optogenetic stimulation. Simultaneous two-photon calcium imaging through the transparent CNT electrodes from cortical surfaces of GCaMP expressing mice with epilepsy shows individual activated neurons in brain regions from which the concurrent electrical recording is taken, thus providing complementary cellular information in addition to the high-temporal-resolution electrical recording. Notably, the studies on rats show that the CNT electrodes remain operational during and after brain contusion that involves the rapid deformation of both the electrode array and brain tissue. This enables real-time, continuous electrophysiological monitoring of cortical activity under traumatic brain injury. These results highlight the potential application of the stretchable transparent CNT electrode arrays in combining electrical and optical modalities to study neural circuits, especially under mechanically active conditions, which could potentially provide important new insights into the local circuit dynamics of the spinal cord and PNS as well as the mechanism underlying traumatic injuries of the nervous system. PMID- 29608858 TI - Recovery of the Formation and Function of Oxidized G-Quadruplexes by a Pyrene Modified Guanine Tract. AB - Oxidation is one of the frequent causes of DNA damage, especially to guanine bases. Guanine bases in the G-quadruplex (G4) are sensitive to damage by oxidation, resulting in transformation to 8-oxo-7,8-dihydroguanine (8-oxoG). Because the formation of G4 represses the expression of some cancer-related genes, the presence of 8-oxoG in a G4 sequence might affect G4 formation and induce cancer progression. Thus, oxidized-G4 formation must be controlled using a chemical approach. In the present study, we investigated the effect of introduction of 8-oxoG into a G4 sequence on the formation and function of the G4 structure. The 8-oxoG-containing G4 derived from the promoter region of the human vascular endothelial growth factor ( VEGF) gene differed topologically from unoxidized G4. The oxidized VEGF G4 did not act as a replication block and was not stabilized by the G4-binding protein nucleolin. To recover G4 function, we developed an oligonucleotide consisting of a pyrene-modified guanine tract that replaces the oxidized guanine tract and forms stable intermolecular G4s with the other intact guanine tracts. When this oligonucleotide was used, the oxidized G4 stalled replication and was stabilized by nucleolin as with the unmodified G4. This strategy generally enables recovery of the function of any oxidized G4s and therefore has potential for cancer therapy. PMID- 29608859 TI - Dynamic Formation of Bipolaron-Exciton Complexes in Conducting Polymers. AB - The recombination dynamics of two oppositely charged bipolarons within a single polymer chain is numerically studied in the scope of a one-dimensional tight binding model that considers electron-electron and electron-phonon (e-ph) interactions. By scanning among values of e-ph coupling and electric field, novel channels for the bipolaron recombination were yielded based on the interplay between these two parameters. The findings point to the formation of a compound species formed from the coupling between a bipolaron and an exciton. Depending on the electric field and e-ph coupling strengths, the recombination mechanism may yield two distinct products: a trapped (and almost neutral) or a moving (and partially charged) bipolaron-exciton. These results might enlighten the understanding of the electroluminescence processes in organic light-emitting devices. PMID- 29608860 TI - Eckmaxol, a Phlorotannin Extracted from Ecklonia maxima, Produces Anti-beta amyloid Oligomer Neuroprotective Effects Possibly via Directly Acting on Glycogen Synthase Kinase 3beta. AB - Alzheimer's disease is a progressive neurodegenerative disorder that mainly affects the elderly. Soluble beta-amyloid oligomer, which can induce neurotoxicity, is generally regarded as the main neurotoxin in Alzheimer's disease. Here we report that eckmaxol, a phlorotannin extracted from the brown alga Ecklonia maxima, could produce neuroprotective effects in SH-SY5Y cells. Eckmaxol effectively prevented but did not rescue beta-amyloid oligomer-induced neuronal apoptosis and increase of intracellular reactive oxygen species. Eckmaxol also significantly reversed the decreased expression of phospho-Ser9 glycogen synthase kinase 3beta and increased expression of phospho-extracellular signal-regulated kinase, which was induced by Abeta oligomer. Moreover, both glycogen synthase kinase 3beta and mitogen activated protein kinase inhibitors produced neuroprotective effects in SH-SY5Y cells. Furthermore, eckmaxol showed favorable interaction in the ATP binding site of glycogen synthase kinase 3beta and mitogen activated protein kinase. These results suggested that eckmaxol might produce neuroprotective effects via concurrent inhibition of glycogen synthase kinase 3beta and extracellular signal-regulated kinase pathways, possibly via directly acting on glycogen synthase kinase 3beta and mitogen activated protein kinase. Based on the central role that beta-amyloid oligomers play in the pathogenesis of Alzheimer's disease and the high annual production of Ecklonia maxima for alginate and other nutritional ingredients, this report represents a new candidate for the treatment of Alzheimer's disease, and also expands the potential application of Ecklonia maxima and its constituents in the field of pharmacology. PMID- 29608862 TI - Micropatterned Silica Films with Nanohydroxyapatite for Y-TZP Implants. AB - This investigation aimed at developing micropatterned silica thin films (MSTFs) containing nanohydroxyapatite (nano-HA) microaggregates that were not completely covered by silica so that they could directly interact with the surrounding cells. The objectives were 1) to evaluate the effect of the presence of 2 films (MSTF with or without nano-HA addition) on the characteristic strength (sigma0) and Weibull modulus ( m) of a yttria-stabilized tetragonal zirconia polycrystal (Y-TZP) and 2) to evaluate the effect of these 2 films, as applied onto the Y-TZP surface, on the morphology, orientation, and proliferation of MG63 cells. Sol-gel process and soft lithography were used to apply the MSTF onto the Y-TZP specimens. Three experimental groups were produced: Y-TZP, Y-TZP + MSTF, and Y TZP + MSTF + sprayed nano-HA. All surfaces were characterized by scanning electron microscopy and energy-dispersive X-ray spectroscopy and tested for 4 point flexural strength ( n = 30) in water at 37 degrees C. Weibull analysis was used to determine m and sigma0 (maximum likelihood method). In vitro biological behavior was performed with human osteoblast-like cells (MG63). Y-TZP was successfully coated with MSFT and MSFT + nano-HA. Scanning electron microscopy micrographs indicated that the microaggregates of nano-HA were not entirely covered by the silica. There was no statistically significant difference among the experimental groups for sigma0 and m. In the groups containing the films, the cells were elongated and aligned along the lines. The MSFT + nano-HA group showed significantly higher cell metabolic activity than that obtained for the Y-TZP group at day 7. This investigation was successful in producing an MSTF containing nano-HA microaggregates that remained exposed to the environment. The developed films did not jeopardize the structural reliability of a commercial Y-TZP, as confirmed by the Weibull statistics. The MG63 cells seeded over the films became elongated and aligned along the films' micropatterned lines. Y-TZP specimens coated with MSTF and nano-HA showed a higher cell metabolic activity and proliferation after 7 d of culture when compared with uncoated Y-TZP. PMID- 29608861 TI - Atomic Structure of the E2 Inner Core of Human Pyruvate Dehydrogenase Complex. AB - Pyruvate dehydrogenase complex (PDC) is a large multienzyme complex that catalyzes the irreversible conversion of pyruvate to acetyl-coenzyme A with reduction of NAD+. Distinctive from PDCs in lower forms of life, in mammalian PDC, dihydrolipoyl acetyltransferase (E2; E2p in PDC) and dihydrolipoamide dehydrogenase binding protein (E3BP) combine to form a complex that plays a central role in the organization, regulation, and integration of catalytic reactions of PDC. However, the atomic structure and organization of the mammalian E2p/E3BP heterocomplex are unknown. Here, we report the structure of the recombinant dodecahedral core formed by the C-terminal inner-core/catalytic (IC) domain of human E2p determined at 3.1 A resolution by cryo electron microscopy (cryoEM). The structure of the N-terminal fragment and four other surface areas of the human E2p IC domain exhibit significant differences from those of the other E2 crystal structures, which may have implications for the integration of E3BP in mammals. This structure also allowed us to obtain a homology model for the highly homologous IC domain of E3BP. Analysis of the interactions of human E2p or E3BP with their adjacent IC domains in the dodecahedron provides new insights into the organization of the E2p/E3BP heterocomplex and suggests a potential contribution by E3BP to catalysis in mammalian PDC. PMID- 29608863 TI - Correction. PMID- 29608864 TI - Structural Determinants and Children's Oral Health: A Cross-National Study. AB - Much research on children's oral health has focused on proximal determinants at the expense of distal (upstream) factors. Yet, such upstream factors-the so called structural determinants of health-play a crucial role. Children's lives, and in turn their health, are shaped by politics, economic forces, and social and public policies. The aim of this study was to examine the relationship between children's clinical (number of decayed, missing, and filled teeth) and self reported oral health (oral health-related quality of life) and 4 key structural determinants (governance, macroeconomic policy, public policy, and social policy) as outlined in the World Health Organization's Commission for Social Determinants of Health framework. Secondary data analyses were carried out using subnational epidemiological samples of 8- to 15-y-olds in 11 countries ( N = 6,648): Australia (372), New Zealand (three samples; 352, 202, 429), Brunei (423), Cambodia (423), Hong Kong (542), Malaysia (439), Thailand (261, 506), United Kingdom (88, 374), Germany (1498), Mexico (335), and Brazil (404). The results indicated that the type of political regime, amount of governance (e.g., rule of law, accountability), gross domestic product per capita, employment ratio, income inequality, type of welfare regime, human development index, government expenditure on health, and out-of-pocket (private) health expenditure by citizens were all associated with children's oral health. The structural determinants accounted for between 5% and 21% of the variance in children's oral health quality-of-life scores. These findings bring attention to the upstream or structural determinants as an understudied area but one that could reap huge rewards for public health dentistry research and the oral health inequalities policy agenda. PMID- 29608865 TI - Vascularization in Craniofacial Bone Tissue Engineering. AB - Craniofacial bones, separate from the appendicular skeleton, bear a significant amount of strain and stress generated from mastication-related muscles. Current research on the regeneration of craniofacial bone focuses on the reestablishment of an elaborate vascular network. In this review, current challenges and efforts particularly in advances of scaffold properties and techniques for vascularization remodeling in craniofacial bone tissue engineering will be discussed. A microenvironment of ischemia and hypoxia in the biomaterial core drives propagation and reorganization of endothelial progenitor cells (EPCs) to assemble into a primitive microvascular framework. Co-culture strategies and delivery of vasculogenic molecules enhance EPCs' differentiation and stimulate the host regenerative response to promote vessel sprouting and strength. To optimize structural and vascular integration, well-designed microstructures of scaffolds are biologically considered. Proper porous structures, matrix stiffness, and surface morphology of scaffolds have a profound influence on cell behaviors and thus affect revascularization. In addition, advanced techniques facilitating angiogenesis and vaculogenesis have also been discussed. Oxygen delivery biomaterials, scaffold-free cell sheet techniques, and arteriovenous loop-induced axial vascularization strategies bring us new understanding and powerful strategies to manage revascularization of large craniofacial bone defects. Although promising histological results have been achieved, the efficient perfusion and functionalization of newly formed vessels are still challenging. PMID- 29608866 TI - Improving Understanding of Diagnostic Test Outcomes. AB - BACKGROUND: Understanding diagnostic test outcomes requires determining the positive predictive value (PPV) of the test, which most laypeople and medical professionals struggle to do. Despite advances found with frequency formats and visual aids, less than 40% of people can typically identify this value. This study tests the impact of using congruent reference classes in problem-question pairings, evaluates the role of numeracy, and assesses how diagnostic value estimates affect the reported likelihood to use the test. METHOD: A 3 * 2, Pairing (congruent test-focus, congruent condition-focus, incongruent) * Response Format (frequency, percentage) mixed design experiment was conducted, in which participants answered diagnostic questions about 7 medical problems presented in a format focusing either on the reference class of those who test positive or those who have the condition. Answer accuracy, numeracy, and ratings of likelihood to use estimates were assessed. RESULTS: Focusing on the congruent test reference class allowed 87% of participants to consistently identify the PPV, and focusing on the congruent condition reference class led 63% of participants to consistently identify the sensitivity (SEN). Aligning reference classes was especially beneficial for those with lower numeracy, increasing accuracy on problems from 21% for incongruent pairings to 66% for congruent pairings. Ratings of likelihood to use the test were closely tied to participants' estimates of diagnostic values, regardless of the accuracy of those estimates. CONCLUSIONS: Although often overlooked, a straightforward mapping of reference classes from the relevant diagnostic information to the question of interest reduces confusion and substantially increases accuracy in estimates of diagnostic values. These findings can be used to strengthen training in the assessment of uncertainties associated with medical test results. PMID- 29608867 TI - An Evaluation of Psoriasis Patient Perceptions and Understanding of Biosimilars: A Canadian Survey Comparing Biologic and Nonbiologic Users. PMID- 29608869 TI - Mobile Sensing in Environmental Health and Neighborhood Research. AB - Public health research has witnessed a rapid development in the use of location, environmental, behavioral, and biophysical sensors that provide high-resolution objective time-stamped data. This burgeoning field is stimulated by the development of novel multisensor devices that collect data for an increasing number of channels and algorithms that predict relevant dimensions from one or several data channels. Global positioning system (GPS) tracking, which enables geographic momentary assessment, permits researchers to assess multiplace personal exposure areas and the algorithm-based identification of trips and places visited, eventually validated and complemented using a GPS-based mobility survey. These methods open a new space-time perspective that considers the full dynamic of residential and nonresidential momentary exposures; spatially and temporally disaggregates the behavioral and health outcomes, thus replacing them in their immediate environmental context; investigates complex time sequences; explores the interplay among individual, environmental, and situational predictors; performs life-segment analyses considering infraindividual statistical units using case-crossover models; and derives recommendations for just-in-time interventions. PMID- 29608868 TI - Biomechanics of Immediate Postextraction Implant Osseointegration. AB - The aim of this study was to gain insights into the biology and mechanics of immediate postextraction implant osseointegration. To mimic clinical practice, murine first molar extraction was followed by osteotomy site preparation, specifically in the palatal root socket. The osteotomy was positioned such that it removed periodontal ligament (PDL) only on the palatal aspect of the socket, leaving the buccal aspect undisturbed. This strategy created 2 distinct peri implant environments: on the palatal aspect, the implant was in direct contact with bone, while on the buccal aspect, a PDL-filled gap existed between the implant and bone. Finite element modeling showed high strains on the palatal aspect, where bone was compressed by the implant. Osteocyte death and bone resorption predominated on the palatal aspect, leading to the loss of peri implant bone. On the buccal aspect, where finite element modeling revealed low strains, there was minimal osteocyte death and robust peri-implant bone formation. Initially, the buccal aspect was filled with PDL remnants, which we found directly provided Wnt-responsive cells that were responsible for new bone formation and osseointegration. On the palatal aspect, which was devoid of PDL and Wnt-responsive cells, adding exogenous liposomal WNT3A created an osteogenic environment for rapid peri-implant bone formation. Thus, we conclude that low strain and high Wnt signaling favor osseointegration of immediate postextraction implants. The PDL harbors Wnt-responsive cells that are inherently osteogenic, and if the PDL tissue is healthy, it is reasonable to preserve this tissue during immediate implant placement. PMID- 29608870 TI - Increasing Disparities in Mortality by Socioeconomic Status. AB - This review focuses on the widening disparities in death rates by socioeconomic class. In recent years, there has been a major increase in the availability of data linking mortality risk and measures of socioeconomic status. The result has been a virtual explosion of new empirical research showing not only the existence of large inequities in the risk of death between those at the top and those at the bottom of the socioeconomic distribution, but also that the gaps have been growing. This assessment of the empirical research finds a consistent pattern of growing disparities within the United States. However, this widening gap in death rates does appear to be a uniquely American phenomenon, as the disparities by socioeconomic class appear to be stable or even declining in Europe and Canada. PMID- 29608871 TI - From Crowdsourcing to Extreme Citizen Science: Participatory Research for Environmental Health. AB - Environmental health issues are becoming more challenging, and addressing them requires new approaches to research design and decision-making processes. Participatory research approaches, in which researchers and communities are involved in all aspects of a research study, can improve study outcomes and foster greater data accessibility and utility as well as increase public transparency. Here we review varied concepts of participatory research, describe how it complements and overlaps with community engagement and environmental justice, examine its intersection with emerging environmental sensor technologies, and discuss the strengths and limitations of participatory research. Although participatory research includes methodological challenges, such as biases in data collection and data quality, it has been found to increase the relevance of research questions, result in better knowledge production, and impact health policies. Improved research partnerships among government agencies, academia, and communities can increase scientific rigor, build community capacity, and produce sustainable outcomes. PMID- 29608872 TI - Policy Approaches for Regulating Alcohol Marketing in a Global Context: A Public Health Perspective. AB - Alcohol consumption is responsible for 3.3 million deaths globally or nearly 6% of all deaths. Alcohol use contributes to both communicable and noncommunicable diseases, as well as violence and injuries. The purpose of this review is to discuss, in the context of the expansion of transnational alcohol corporations and harms associated with alcohol use, policy options for regulating exposure to alcohol marketing. We first provide an overview of the public health problem of harmful alcohol consumption and describe the association between exposure to alcohol marketing and alcohol consumption. We then discuss the growth and concentration of global alcohol corporations and their marketing practices in low and middle-income countries, as well as in higher-income societies. We review the use and effectiveness of various approaches for regulating alcohol marketing in various countries before discussing challenges and opportunities to protect public health. PMID- 29608873 TI - Spatiotemporal responses of dengue fever transmission to the road network in an urban area. AB - Urbanization is one of the important factors leading to the spread of dengue fever. Recently, some studies found that the road network as an urbanization factor affects the distribution and spread of dengue epidemic, but the study of relationship between the distribution of dengue epidemic and road network is limited, especially in highly urbanized areas. This study explores the temporal and spatial spread characteristics of dengue fever in the distribution of road network by observing a dengue epidemic in the southern Chinese cities. Geographic information technology is used to extract the spatial location of cases and explore the temporal and spatial changes of dengue epidemic and its spatial relationship with road network. The results showed that there was a significant "severe" period in the temporal change of dengue epidemic situation, and the cases were mainly concentrated in the vicinity of narrow roads, the spread of the epidemic mainly along the high-density road network area. These results show that high-density road network is an important factor to the direction and scale of dengue epidemic. This information may be helpful to the development of related epidemic prevention and control strategies. PMID- 29608874 TI - Meta-Analysis of Repeat Revascularization of Off-Pump and On-Pump Coronary Artery Bypass Surgery. AB - BACKGROUND: There is an ongoing debate focusing on clinical outcomes after off pump coronary artery bypass graft surgery (OPCABG) and on-pump coronary artery bypass graft surgery (ONCABG). The objective of the present meta-analysis is to update and compare repeat revascularization rates between OPCABG and ONCABG procedures. METHODS: Data sources including PubMed, EMBASE, Cochrane Library, and ISI Web of Knowledge were searched between 1966 and October 2017. Studies considered for inclusion should conform to the following criteria: prospective randomized clinical trials comparing OPCABG and ONCABG. Outcome should include repeat revascularization rate at the time of 1-month, 1-year, or 5-year follow up. RESULTS: A literature search yielded 11 randomized controlled trials, and a total of 11,246 patients were randomly allocated to OPCABG or ONCABG procedures. Pooled analysis demonstrated a statistically significant 53% increase in repeat revascularization rate at 1-year follow-up with OPCABG relative to ONCABG in the fixed effects model (odds ratio 1.53, 95% confidence interval: 1.17 to 2.00, p = 0.002), whereas there was no significant difference in repeat revascularization rate at 5-year follow-up between OPCABG and ONCABG in the fixed effects model (OR 1.16, 95% confidence interval: 0.95 to 1.41, p = 0.14). In general, exclusion of any single trial did not affect repeat revascularization rate at 1-year and 5 year follow-up. There was no evidence of significant publication bias. CONCLUSIONS: The result of our meta-analysis suggests that compared with ONCABG, OPCABG increases repeat revascularization rate at 1-year follow-up, but does not affect that of 5-year follow-up. PMID- 29608875 TI - Blue-green discoloration of urine and false nephrotic range proteinuria at dipstick urinalysis. AB - A 32 year-old woman presented to the emergency department with symptoms of urinary tract infection. Over the past 2 days, she reported the use of a medication whose active compounds were methenamine (120 mg) + methylthioninium chloride (20 mg). A collected urine sample had a strong blue-green discoloration. Uroculture was negative and dipstick urinalysis revealed the following results: SG 1.015, pH 7, Albumin 3+, Bilirubin 2+ and Haemoglobin 2+. Urine microscopic analysis revealed 5-6 squamous epithelial cells/high power field (HPF), 5-6 leukocytes/HPF and 7-8 erythrocytes/HPF. No bacteria, cellular casts, or renal tubular epithelial cells were present in the urine sample. The most remarkable feature of the urine sediment was that some cells (squamous epithelial cells, macrophages, leukocytes and erythrocytes) were strongly stained in blue. The albuminuria measured by dipstick shows 3+ (300 mg/dL), but in turbidimetric method the urine protein concentration was 18 mg/dL, showing an important interference of methylene blue on the dipstick albumin area. PMID- 29608876 TI - Work-Life Balance, Burnout, and the Electronic Health Record. PMID- 29608877 TI - The role of ADHD associated genes in neurodevelopment. AB - Attention deficit hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder of childhood. It is primarily characterised by high levels of activity, inattention, and impulsivity, and has strong negative impacts on academic functioning. Children with ADHD show a reduction in volume, and hypoactivity, in a range of brain regions. The underlying mechanisms behind these phenotypes are unknown, however, variants in several genes with known roles in neurodevelopment are associated with ADHD. In this review we discuss how these ADHD associated genes contribute to neurodevelopment, and how variants in these genes could give rise to the neurological phenotypes seen in ADHD. PMID- 29608878 TI - Long noncoding RNA SNHG6 promotes osteosarcoma cell proliferation through regulating p21 and KLF2. AB - The effects of long non-coding RNAs (lncRNAs) on cellular biological processes and even the tumorigenesis have been widely reported. Small nucleolar RNA host gene 6 (SNHG6) has been reported to participate in regulating biological behaviors of multiple types of cancers. Nevertheless, the functions of SNHG6 in osteosarcoma still remain to be uncovered. This study intended to determine the clinical significance and biological functions of SNHG6 in osteosarcoma. It was confirmed by qRT-PCR that SNHG6 was highly expressed in osteosarcoma tissues and cell lines. Highly expressed SNHG6 predicted poor survival rate and advanced clinical stage for osteosarcoma patients, according to Kaplan-Meier method and Cox regression analysis. Loss-of-function assays were performed to examine the effects of silenced SNHG6 on the progression of osteosarcoma, indicating that silenced SNHG6 suppressed cell proliferation through inducing cell cycle arrest in G0/G1 phase and causing cell apoptosis. In vitro assays exposed the potential oncogenic role of SNHG6 in osteosarcoma, further affirmed by in vivo nude mice assays. Mechanistic assays demonstrated that SNHG6 was negatively correlated with p21 and KLF2 in osteosarcoma. And biological functions of SNHG6 in osteosarcoma were realized through regulating p21 and KLF2. Collectively, SNHG6 was a new type of molecule involving in the progression of osteosarcoma. PMID- 29608879 TI - (-)-Epicatechin and its metabolites prevent palmitate-induced NADPH oxidase upregulation, oxidative stress and insulin resistance in HepG2 cells. AB - While diets rich in fruit and vegetables can decrease the risk for type 2 diabetes (T2D), diets rich in fat and carbohydrates can increase it. The flavanol 3-ol (-)-epicatechin (EC) can improve insulin sensitivity both in humans and animal models of T2D. NADPH oxidases and oxidative stress can contribute to the development of insulin resistance. This study investigated the capacity of EC and EC metabolites (ECM) to downregulate NADPH oxidases and oxidative stress, and its association to an improvement of insulin sensitivity. This was studied in in vivo (high fat-fed mice) and in vitro (HepG2 cells) conditions of hepatic lipid overload. EC decreased NOX3/NOX4 liver expression and mitigated oxidative stress in high fat-fed mice. In HepG2 cells, incubation with palmitate increased: i) lipid deposition, ii) NOX3/NOX4 expression, iii) NADPH oxidase activity, and iv) oxidative stress; promoting v) the activation of redox-sensitive kinases (JNK and IKK), and vi) impaired insulin responses. Physiological concentrations of EC and ECM, and NADPH oxidase inhibitors (apocynin, VAS2870) prevented all those deleterious effects of palmitate. The obtained results points to NADPH oxidases as an important target in the capacity of EC to improve insulin sensitivity in conditions of liver lipid overload, as those associated with Western-style diets. PMID- 29608880 TI - Limitations of the rat medial forebrain lesion model to study prefrontal cortex mediated cognitive tasks in Parkinson's disease. AB - Parkinson's Disease (PD) is a progressive movement disorder characterized by the loss of dopaminergic neurons in the midbrain. Besides motor impairment, PD patients exhibit non-motor symptoms that negatively impact their quality of life and often manifest prior to motor deficits. One such symptom is mild cognitive impairment (PD-MCI), which is comprised of deficits in executive function such as working memory, attention, cognitive flexibility, and spatial memory. The 6 hydroxydopamine (6-OHDA) induced unilateral medial forebrain bundle (MFB) lesion animal model successfully recapitulates PD motor impairment but is also used to assess non-motor deficits. The present study utilizes a unilateral 6-OHDA induced MFB lesion rodent model to investigate prefrontal cortex (PFC)-mediated cognitive processes that are impaired in PD patients. In a test of attentional set shifting, PD rodents demonstrated deficits in simple discrimination, but not in rule reversal or extradimensional shifts. PD rodents also exhibited deficits in a temporal order memory task but had no deficits in novel/spatial object recognition or object-in-place tasks. These results reveal limitations of the 6 OHDA induced unilateral MFB lesion model to completely recapitulate PD-MCI symptoms suggesting a need for better lesion models to study PD-MCI. PMID- 29608881 TI - The detection of a mismatched DNA by using hairpin DNA-templated silver nanoclusters. AB - Fluorescence assays have been developed to detect biomolecules using DNA templated silver nanoclusters (DNA-AgNCs) utilizing their unique physical and optical properties. This study was designed to detect single-mismatched DNA by the hybridization of target DNA to template DNA either before or after DNA-AgNCs synthesis. The results showed that the detection specificity of a single mismatched DNA was clearly enhanced when the target DNA (cDNA) was hybridized to template DNA prior to DNA-AgNCs synthesis compared with cDNA hybridization subsequent to DNA-AgNCs synthesis. PMID- 29608882 TI - Diagnostic Ability of a Dynamic Multidisciplinary Discussion in Interstitial Lung Diseases: A Retrospective Observational Study of 938 Cases. AB - BACKGROUND: The advice of a dynamic multidisciplinary discussion (MDD) is believed to be important in the diagnosis of interstitial lung diseases (ILDs). However, to what extent MDD diagnoses differ from the preliminary diagnoses before formal workup and MDD (preMDD diagnoses) is still insufficiently studied. METHODS: We compared preMDD and MDD diagnoses in patients discussed at the Leuven University Hospitals MDDs between January 2005 and December 2015. RESULTS: Of 938 consecutive patients discussed in an MDD, 755 (80.5%) received a specific diagnosis. From the 183 patients with unclassifiable ILD, 150 patients (16.0%) received suggestions concerning further investigations to establish a definite diagnosis. In 191 patients (41.9% of patients with a preMDD diagnosis), the MDD changed the diagnosis. In 384 patients (79.5% of patients without preMDD diagnosis), MDD provided a diagnosis when the referring physician did not. MDD diagnosis showed a trend toward better prognostic discrimination between idiopathic pulmonary fibrosis and other ILDs compared with preMDD diagnosis (Harrell C-index, 0.666 vs 0.631; P = .08), which was particularly clear in patients with discordant MDD and preMDD diagnoses (hazard ratio, 2.68 vs 0.84; P = .012 vs .768). CONCLUSIONS: The MDD provided a definite diagnosis in 80.5% of presented cases, suggesting further investigations in almost all others. Given the high number of patients without preMDD diagnosis, the rate of change in preMDD diagnoses (41.9% of patients with a preMDD diagnosis) probably is an underestimation. The better prognostic discrimination among ILDs by using MDD indicates the added value of MDD in ILD. PMID- 29608883 TI - What Hides Behind Bloody Diarrhea? PMID- 29608885 TI - MicroRNA-223 protects neonatal rat cardiomyocytes and H9c2 cells from hypoxia induced apoptosis and excessive autophagy via the Akt/mTOR pathway by targeting PARP-1. AB - Myocardial infarction (MI), characterized by interruption of blood and oxygen to myocardium, is a common yet fatal cardiovascular event that causes progressive damage to myocardial tissue and eventually leads to heart failure. Previous studies have shown increased expression of microRNA-223 (miR-223) in infarcted myocardial tissues of humans and in rat models of MI. However, the role of miR 223 in cell survival during MI has not been elucidated. Thus, we aimed to investigate whether miR-223 participates in the regulation of cardiac ischemia induced injury and to elucidate the underlying mechanisms of this process. qRT PCR revealed that miR-223 expression levels are significantly upregulated in the myocardial tissues of rats with post-MI heart failure and in hypoxia-treated neonatal rat cardiomyocytes (NRCMs) and H9c2 cells, which indicates that miR-223 may be associated with chronic ischemia. We also transfected NRCMs and H9c2 cells with miR-223 mimics or inhibitors in vitro, and the results revealed that increasing miR-223 expression protected cells from hypoxia-induced apoptosis and excessive autophagy, whereas decreasing miR-223 expression had contrasting effects. Further exploration of the mechanism showed that poly(ADP-ribose) polymerase 1 (PARP-1) is a target gene of miR-223 and that silencing PARP-1 prevented hypoxia-induced cell injury; additionally, silencing PARP-1 blocked the aggravated impact of miR-223 inhibitors. Thus, PARP-1 mediates the protective effects of miR-223 in hypoxia-treated cardiomyocytes. We also investigated the involvement of the Akt/mTOR pathway in the above phenomena. We found that miR-223 overexpression and PARP-1 silencing positively regulated the Akt/mTOR pathway and that treating cells with NVP-BEZ235 (BEZ235), a novel dual Akt/mTOR inhibitor, could reverse the inhibitory effects of both the miR-223 mimics and PARP-1 siRNA on hypoxia-induced apoptosis and autophagy. Taken together, our findings showed that miR-223 protects NRCMs and H9c2 cells from hypoxia-induced apoptosis and excessive autophagy via the Akt/mTOR pathway by targeting PARP-1; thus, miR-223 may be a potential target in the treatment of MI in the future. PMID- 29608884 TI - Detection of Mutations in Barrett's Esophagus Before Progression to High-Grade Dysplasia or Adenocarcinoma. AB - BACKGROUND & AIMS: Barrett's esophagus (BE) is the greatest risk factor for esophageal adenocarcinoma (EAC), but only a small proportion of patients with BE develop cancer. Biomarkers might be able to identify patients at highest risk of progression. We investigated genomic differences in surveillance biopsies collected from patients whose BE subsequently progressed compared to patients whose disease did not progress. METHODS: We performed a retrospective case control study of 24 patients with BE that progressed to high-grade dysplasia (HGD, n = 14) or EAC (n = 10). The control group (n = 73, called non-progressors) comprised patients with BE and at least 5 years of total endoscopic biopsy surveillance without progression to HGD or EAC. From each patient, we selected a single tissue sample obtained more than 1 year before progression (cases) or more than 2 years before the end of follow-up (controls). Pathogenic mutations, gene copy numbers, and ploidy were compared between samples from progressors and non progressors. RESULTS: TP53 mutations were detected in 46% of samples from progressors and 5% of non-progressors. In this case-control sample set, TP53 mutations in BE tissues increased the adjusted risk of progression 13.8-fold (95% confidence interval, 3.2-61.0) (P < .001). We did not observe significant differences in ploidy or copy-number profile between groups. We identified 147 pathogenic mutations in 57 distinct genes-the average number of pathogenic mutations was higher in samples from progressors (n = 2.5) than non-progressors (n = 1.2) (P < .001). TP53 and other somatic mutations were recurrently detected in samples with limited copy-number changes (aneuploidy). CONCLUSIONS: In genomic analyses of BE tissues from patients with or without later progression to HGD or EAC, we found significantly higher numbers of TP53 mutations in BE from patients with subsequent progression. These mutations were frequently detected before the onset of dysplasia or substantial changes in copy number. PMID- 29608886 TI - Using Computational Fluid Dynamics to Compare Shear Rate and Turbulence in the TIM-Automated Gastric Compartment With USP Apparatus II. AB - We use computational fluid dynamics to compare the shear rate and turbulence in an advanced in vitro gastric model (TIMagc) during its simulation of fasted state Migrating Motor Complex phases I and II, with the United States Pharmacopeia paddle dissolution apparatus II (USPII). A specific focus is placed on how shear rate in these apparatus affects erosion-based solid oral dosage forms. The study finds that tablet surface shear rates in TIMagc are strongly time dependant and fluctuate between 0.001 and 360 s-1. In USPII, tablet surface shear rates are approximately constant for a given paddle speed and increase linearly from 9 s-1 to 36 s-1 as the paddle speed is increased from 25 to 100 rpm. A strong linear relationship is observed between tablet surface shear rate and tablet erosion rate in USPII, whereas TIMagc shows highly variable behavior. The flow regimes present in each apparatus are compared to in vivo predictions using Reynolds number analysis. Reynolds numbers for flow in TIMagc lie predominantly within the predicted in vivo bounds (0.01-30), whereas Reynolds numbers for flow in USPII lie above the predicted upper bound when operating with paddle speeds as low as 25 rpm (33). PMID- 29608887 TI - Prediction of Human Brain Penetration of P-glycoprotein and Breast Cancer Resistance Protein Substrates Using In Vitro Transporter Studies and Animal Models. AB - Four P-glycoprotein (P-gp) and breast cancer resistance protein (BCRP) substrates with human cerebrospinal fluid (CSF) concentrations and preclinical neuropharmacokinetics were used to assess in vitro-in vivo extrapolation of brain penetration in preclinical species and the ability to predict human brain penetration. Unbound brain (Cb,u), unbound plasma (Cp,u), and CSF compound concentrations (CCSF) were measured in rats and nonhuman primates (NHPs), and the unbound partition coefficients (Cb,u/Cp,u and CCSF/Cp,u) were used to assess brain penetration. The results indicated that for P-gp and BCRP dual substrates, brain penetration was severally impaired in all species. In comparison, for P-gp substrates that are weak or non-BCRP substrates, improved brain penetration was observed in NHPs and humans than in rats. Overall, NHP appears to be more predictive of human brain penetration for P-gp substrates with weak or no interaction with BCRP than rat. Although CCSF does not quantitatively correspond to Cb,u for efflux transporter substrates, it is mostly within 3-fold higher of Cb,u in rat and NHP, suggesting that CCSF can be used as a surrogate for Cb,u. Taken together, a holistic approach including both in vitro transporter and in vivo neuropharmacokinetics data enables a better estimation of human brain penetration of P-gp/BCRP substrates. PMID- 29608888 TI - Age-structure density-dependent fertility and individuals dispersal in a population model. AB - In this work, we analyze the interplay between general age structured density dependent fertility functions and age classes dispersal in a patchy environment. As novelties, (i) the fertility function depends on age classes (instead of on the total population size) and (ii) dispersal patterns are also allowed to be different for individuals belonging to different age classes. Our results highlight the interplay between the shape of the age structured density-dependent fertility function and the age classes dispersal patterns. We analyze this interaction from an environmental management point of view by exploring the consequences of connecting patches that can sustain a population (source patch) or cannot (sink patch), as well as its relation to component Allee effects and strong Allee effects. In particular, we have found scenarios such that the metapopulation goes extinct when two isolated source patches are connect due to heterogeneous age classes distribution. On the contrary, there are settings such that heterogeneous age classes distribution enables two isolated sink patches to be sustainable when connected. Besides, we discuss what kind of local interventions are helpful to manage component Allee effect and its impact at the metopopulation level. The source code used to simulations is fully available. The code is presented as a knitr reproducible document in the open source R computing system. Thus, free access and usability of the code are granted. PMID- 29608889 TI - Benign and malignant scientific irreproducibility. AB - Irreproducibility is a widely recognized problem harming scientific progress. Here, we classify types of scientific irreproducibility based on deleteriousness using a cancer analogy: benign, pre-malignant and malignant. We discuss the difficulties of challenging potentially irreproducible papers, especially in high impact journals and/or by famous authors. We advocate for high impact journals publishing papers with large translation value, to implement mandatory author reflections on the reproducibility, utility and relevance of their work 5 to 10 years after publication. We suggest testing this idea with 100 papers published in elite journals between 2003 and 2008, to show the utility and need for these reflections. Knowing they will have to report on their results, will make researchers more careful and likely lead to a drop in scientific irreproducibility. PMID- 29608890 TI - Ischemic acute kidney injury and klotho in renal transplantation. AB - Post-transplant ischemic acute kidney injury (AKI), secondary to ischemia reperfusion injury (IRI), is a major problem influencing on the short and long term graft and patient survival. Many molecular and cellular modifications are observed during IRI, for example, tissue damage result production of reactive oxygen species (ROS), cytokines, chemokines, and leukocytes recruitment which are activated by NF-kappaB (nuclear factor kappa B) signaling pathway. Therefore, inhibiting these processes can significantly protect renal parenchyma from tissue damage. Klotho protein, mainly produced in distal convoluted tubules (DCT), is an anti-senescence protein. There is increasing evidence to confirm a relationship between Klotho levels and renal allograft function. Many studies have also demonstrated that expression of the Klotho gene would be down regulated with IRI, so it will be used as an early biomarker for acute kidney injury after renal transplantation. Other studies suggest that Klotho may have a renoprotective effect for attenuating of kidney injury. In this review, we will discuss pathophysiology of IRI-induced acute kidney injury and its relation with klotho level in renal transplantation procedure. PMID- 29608891 TI - Change of the 5alpha/5beta ratio of urinary steroid metabolites in benign prostatic hyperplasia patients treated with dutasteride. AB - BACKGROUND: The effects of the administration of dutasteride (DUT) on steroid metabolite pathways in BPH patients have not been examined. METHODS: Urine and blood samples as well as clinical parameters were prospectively collected after the administration of DUT to 60 BPH patients, and after its withdrawal in another set of 25 BPH patients. Urine samples were assessed using gas chromatography/mass spectrometry for the urinary steroid profile (USP), which simultaneously measures 63 steroid metabolites. We examined pharmacological changes in the 5alpha/5beta ratio of urinary metabolites and their relationships with clinical parameters in patients treated with DUT. RESULTS: The mean urinary androsterone/etiocholanolone (An/Et) ratio in sex-steroid pathways significantly decreased from 1.39 to 0.02 (p < 0.01). Urinary metabolites in other steroid pathways such as 5alphaTHF/5betaTHF in the glucocorticoid pathway and 5alphaTHB/5betaTHB in the mineralocorticoid pathway also significant decreased after the DUT treatment. As compared to baseline level, the mean An/Et ratios in patients with the withdrawal of DUT were 0.7%, 1.4%, 12.6%, and 82.4% at just before, one month, 3 months, and 6 months after the withdrawal of DUT, respectively. All other steroid pathways changed in a similar manner without the aggravation of urinary symptoms. The recovery ratio of An/Et in USP before and 3 months after the withdrawal of DUT correlated with the recovery ratio of serum PSA levels (rho = 0.61, p < 0.01). CONCLUSION: Urinary 5alpha/5beta metabolites in all pathways were strongly suppressed after the administration of DUT for one month and the pharmacological effect of DUT prolonged even after withdrawal of DUT. PMID- 29608892 TI - Evaluation of the LIA-ANA-Profile-17S for the detection of autoantibodies to nuclear antigens. AB - OBJECTIVES: The diagnostic tests for autoimmune disease include screening for autoantibodies for nuclear antigens (ANA) and antibodies against extractable nuclear antigens (ENA). Using the line immunoassay (LIA) method, various kinds of ENA antibodies can be detected simultaneously. We evaluated the performance of the newly launched LIA-ANA-Profile-17S (Shenzhen YHLO Biotech, Shenzhen, China) as compared to a conventional LIA kit. METHODS: Residual samples were collected from 200 patients who had been tested for ANA using indirect immunofluorescence. The LIA-ANA-Profile-17S was compared to the EuroLine ANA (Euroimmun, Oberlausitz, Germany) for the analysis of 17 different autoantibodies. The concordance rate and agreement between assays were determined. Samples showing discrepancies between the LIA-ANA-Profile-17S and EuroLine tests were further examined through additional analysis. RESULTS: The overall agreement was moderate (kappa = 0.759, 95% CI = 0.712-0.805). Agreement between assays ranged from weak to almost perfect, except for those tests targeting nucleosomes, histones, and PM-Scl. Of the 57 disparate results between LIA-ANA-Profile-17S and EuroLine, 38 (66.7%) samples tested positive under an additional assay, showing variable patterns between types of autoantibodies. The positive rate of each autoantibody between LIA-ANA-Profile-17S and EuroLine did not differ significantly, except for anti nucleosome and anti-histone assays in samples from patients diagnosed with systemic lupus erythematosus (P = 0.004 and 0.001, respectively). CONCLUSIONS: Compared to those from the conventional EuroLine assay, the LIA-ANA-Profile-17S results showed variable agreement in samples showing different prevalence of each autoantibody. The most frequently detected antibodies showed almost perfect agreement. The LIA-ANA-Profile-17S could play a role in the diagnosis of systemic autoimmune disease in ANA-positive samples. PMID- 29608893 TI - Circular RNA circC3P1 suppresses hepatocellular carcinoma growth and metastasis through miR-4641/PCK1 pathway. AB - In the recent years, increasing evidences identify circular RNAs (circRNAs) as a class of important regulators in various human cancers. Nevertheless, the functions and mechanisms of most circRNAs in cancer cells remain largely unknown. In this study, we found out a significantly downregulated circRNA circC3P1 in hepatocellular carcinoma (HCC) tissues compared to adjacent normal tissues. And our results indicated that circC3P1 expression level was negatively correlated with TNM stage, tumor size and vascular invasion in HCC. Moreover, we found that circC3P1 overexpression dramatically inhibited the proliferation, migration and invasion of HCC cells in vitro and in vivo. In terms of mechanism, we found that circC3P1 could promote PCK1 expression through sponging miR-4641 in HCC cells. We showed that miR-4641 expression was negatively correlated with that of either circC3P1 or PCK1 in HCC tissues. Finally, by functional experiments, we demonstrated that knockdown of PCK1 significantly attenuated the effects of circC3P1 overexpression on HCC cell proliferation, migration and invasion. In summary, our findings illustrated that circC3P1 acts as a tumor suppressor via enhancing PCK1 expression by sponging miR-4641 in HCC. PMID- 29608894 TI - Food polyphenols targeting peptidyl prolyl cis/trans isomerase Pin1. AB - We searched for inhibitors against prolyl isomerase Pin1 in order to develop functional foods to prevent and cure various Pin1 related diseases such as cancer, diabetes, cardiovascular disease, Alzheimers's disease, and so on. We created a polyphenol library consisting of ingredients in healthy foods and beverages, since polyphenols like epigallocatechin gallate (EGCG) in green tea and 974B in brown algae had been identified as its Pin1 inhibitors. Several polyphenols such as EGCG derivatives, caffeic acid derivatives and tannic acid inhibited Pin1 activity. These results provide a first step in development of the functional foods and beverage targeting Pin1 and its related diseases. PMID- 29608895 TI - A tomato proline-, lysine-, and glutamic-rich type gene SpPKE1 positively regulates drought stress tolerance. AB - Plant abiotic resistance in cultivated species features limited variability. Using genes of wild species serves as a valid approach for improving abiotic resistance of cultivated plants. In this study, we uncovered a previously uncharacterized proline-, lysine-, and glutamic-rich protein gene (SpPKE1), which was isolated from drought-resistant wild tomato species Solanum pennellii (LA0716). When M82, which is a drought-sensitive tomato cultivar, was engineered to overexpress SpPKE1, its tolerance under drought stress was significantly improved by the accumulation of more chlorophyll, proline, and limited malondialdehyde compared with that in RNA interference (RNAi)-suppression lines, which were more sensitive than the wild-type plants. Several ion transporter genes, abiotic-related transcriptional factors, and reactive oxygen species scavenging genes were upregulated in PKE1 overexpression (OE) lines but downregulated in RNAi plants. OE of SpPKE1 enhanced drought tolerance in tobacco. Screening results of yeast two-hybrid protein-protein interaction revealed that SpPKE1 can bind to an F-box protein that plays an important role in plant drought resistance. We posited that PKE1 enhanced drought tolerance by modulating the expressions of stress-responsive genes and interacting with the F-box protein. PMID- 29608896 TI - Crystal structure of oleate hydratase from Stenotrophomonas sp. KCTC 12332 reveals conformational plasticity surrounding the FAD binding site. AB - Unsaturated fatty acids are toxic to various bacteria, causing their death or growth inhibition. To prevent this toxicity, unsaturated fatty acids should be converted into saturated fatty acids via hydrogenation reaction, which is the complete reduction of double bonds on the carbon chain. In a recent report, we observed that Stenotrophomonas sp. KCTC 12332 exhibited a high biotransformation activity of oleic acid (OA) in 10-hydroxystearic acid and identified the gene encoding oleate hydratase (OhySt) by complete genomic analysis. In the present study, to further investigate the structural features of OhySt, the recombinant protein was expressed in Escherichia coli, and then purified and crystallized. Biochemical assay showed that OhySt produces 10-hydroxystearic acid in a flavin adenosine dinucleotide (FAD)-dependent manner, indicating that it requires FAD as a cofactor. The OhySt structure, which is determined in its apo state, allows for a structural comparison with the previously reported FAD bound structure of oleate hydratase. The comparison of structures indicates remarkable conformational change of the loop region surrounding the FAD molecule upon binding of FAD. This change forces one of the important catalytic residues into position for catalysis. PMID- 29608897 TI - Uses of fluoxetine in nociceptive pain management: A literature overview. AB - Fluoxetine is one of the top ten prescribed antidepressants. Other therapeutic applications were approved for fluoxetine including, anxiety disorders, bulimia nervosa, and premature ejaculation. However, the role of fluoxetine in nociceptive pain management is still unclear. In this review, we discuss an overview of five possible roles of fluoxetine in pain management: intrinsic antinociceptive effect, enhancement of acute opioid analgesia, attenuation of tolerance development to opioid analgesia, attenuation of dependence development and abstinence syndrome, and attenuation of opioid induced hyperalgesia. Conflicting data were reported about fluoxetine intrinsic anti-nociceptive effect in preclinical and clinical studies except for inflammatory pain. Similar controversy was described in preclinical and clinical studies which explored the possible enhancement of opioid analgesia by fluoxetine co-administration. However, fluoxetine was found to have a promising effect on opioid tolerance and dependence in animal and human studies. Regarding opioid induced hyperalgesia, no studies examined fluoxetine effects in this regard. Our literature review revealed that, the most likely beneficial use of fluoxetine in nociceptive pain management is for alleviation of inflammatory pain and attenuation of opioid tolerance and dependence. Non-steroidal anti-inflammatory and corticosteroids carry many adverse effects and toxicities. Effective alleviation of opioid tolerance and dependence represents a huge health burden and growing unmet medical need. Moreover, most agents used to attenuate these phenomena are either experimental or poorly tolerable drugs which limit their transitional value. Fluoxetine offers an effective, safe, and tolerable alternative for management of both inflammatory pain and opioid tolerance and dependence presently available to clinicians. PMID- 29608898 TI - Canagliflozin protects against non-alcoholic steatohepatitis in type-2 diabetic rats through zinc alpha-2 glycoprotein up-regulation. AB - : Elevated blood glucose and insulin resistance are triggering factors for non alcoholic steatohepatitis (NASH). We investigated the effects of the Sodium Glucose co-Transporter 2 (SGLT2) inhibitor canagliflozin on NASH development in rats with type 2 diabetes mellitus as well as the possible underlying mechanisms and for the first time the effect of canagliflozin on the hepatic zinc-alpha2 glycoprotein (ZAG) levels. Rats were treated with nicotinamide and streptozotocin to reduce the insulin secretory capacity then fed high fat diet for 8 weeks. The diabetic high fat diet rats were divided into three groups; untreated group, canagliflozin 10 mg/kg treated group and canagliflozin 20 mg/kg treated group during this period. The elevated blood glucose and glycated haemoglobin (HbA1c) levels in the diabetic high fat diet rats were significantly reduced by canagliflozin. Moreover, the diabetic high fat diet induced NASH development as evidenced by liver weight gain, hepatic lipid accumulation and low hepatic ZAG expression as well as increased serum alanine aminotransferase; all these changes were reversed in rats treated with canagliflozin. Additionally, canagliflozin succeeded to upregulate the hepatic ZAG levels in both normal and diabetic high fat fed rats, lower the serum and hepatic inflammatory cytokines levels as well as lower the serum caspase-3 levels and enhanced hepatic Bcl-2 expression. Also, canagliflozin attenuated hepatic oxidative stress and elevated the antioxidant enzymes activity as well as the total antioxidant capacity. All these effects of canagliflozin were dose dependant. CONCLUSION: SGLT2 inhibitor-canagliflozin- has beneficial effects in treatment of NASH associated with diabetes mellitus. PMID- 29608899 TI - Knockdown of NLRC5 inhibits renal fibroblast activation via modulating TGF beta1/Smad signaling pathway. AB - NLRC5, the largest member of the Nucleotide-binding domain and leucine-rich repeat (NLR) protein family, is recently proven to be a critical modulator in fibrogenesis. However, the role of NLRC5 in renal fibrosis remains unknown. In the present study, we investigated the effects of NLRC5 on transforming growth factor beta1 (TGF-beta1)-stimulated rat renal fibroblasts in vitro. Our results showed that the expression of NLRC5 was also obviously upregulated in renal fibrosis tissues and TGF-beta1-treated NRK-49F cells. Knockdown of NLRC5 inhibited the proliferation of NRK-49F cells induced by TGF-beta1, as well as suppressed the accumulation of extracellular matrix (ECM) in NRK-49F cells induced by TGF-beta1. Furthermore, knockdown of NLRC5 inhibited the expression of phosphorylated Smad3 in TGF-beta1-treated NRK-49F cells. In conclusion, our results show that knockdown of NLRC5 inhibits renal fibroblast activation via modulating TGF-beta1/Smad signaling pathway. Therefore, NLRC5 may act as a key mediator in renal fibroblast activation and fibrogenesis. PMID- 29608901 TI - Improving Dual-Task Control With a Posture-Second Strategy in Early-Stage Parkinson Disease. AB - OBJECTIVE: To examine the task prioritization effects on postural-suprapostural dual-task performance in patients with early-stage Parkinson disease (PD) without clinically observed postural symptoms. DESIGN: Cross-sectional study. Participants performed a force-matching task while standing on a mobile platform, and were instructed to focus their attention on either the postural task (posture first strategy) or the force-matching task (posture-second strategy). SETTING: University research laboratory. PARTICIPANTS: Individuals (N=16) with early-stage PD who had no clinically observed postural symptoms. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Dual-task change (DTC; percent change between single-task and dual-task performance) of posture error, posture approximate entropy (ApEn), force error, and reaction time (RT). Positive DTC values indicate higher postural error, posture ApEn, force error, and force RT during dual-task conditions compared with single-task conditions. RESULTS: Compared with the posture-first strategy, the posture-second strategy was associated with smaller DTC of posture error and force error, and greater DTC of posture ApEn. In contrast, greater DTC of force RT was observed under the posture-second strategy. CONCLUSIONS: Contrary to typical recommendations, our results suggest that the posture-second strategy may be an effective dual-task strategy in patients with early-stage PD who have no clinically observed postural symptoms in order to reduce the negative effect of dual tasking on performance and facilitate postural automaticity. PMID- 29608900 TI - Sensitivity of the SCI-FI/AT in Individuals With Traumatic Spinal Cord Injury. AB - OBJECTIVE: To examine the ability of the Spinal Cord Injury-Functional Index/Assistive Technology (SCI-FI/AT) measure to detect change in persons with spinal cord injury (SCI). DESIGN: Multisite longitudinal (12-mo follow-up) study. SETTING: Nine SCI Model Systems programs. PARTICIPANTS: Adults (N=165) with SCI enrolled in the SCI Model Systems database. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: SCI-FI/AT computerized adaptive test (CAT) (Basic Mobility, Self-Care, Fine Motor Function, Wheelchair Mobility, and/or Ambulation domains) completed at discharge from rehabilitation and 12 months after SCI. For each domain, effect size estimates and 95% confidence intervals were calculated for subgroups with paraplegia and tetraplegia. RESULTS: The demographic characteristics of the sample were as follows: 46% (n=76) individuals with paraplegia, 76% (n=125) male participants, 57% (n=94) used a manual wheelchair, 38% (n=63) used a power wheelchair, 30% (n=50) were ambulatory. For individuals with paraplegia, the Basic Mobility, Self-Care, and Ambulation domains of the SCI FI/AT detected a significantly large amount of change; in contrast, the Fine Motor Function and Wheelchair Mobility domains detected only a small amount of change. For those with tetraplegia, the Basic Mobility, Fine Motor Function, and Self-Care domains detected a small amount of change whereas the Ambulation item domain detected a medium amount of change. The Wheelchair Mobility domain for people with tetraplegia was the only SCI-FI/AT domain that did not detect significant change. CONCLUSIONS: SCI-FI/AT CAT item banks detected an increase in function from discharge to 12 months after SCI. The effect size estimates for the SCI-FI/AT CAT vary by domain and level of lesion. Findings support the use of the SCI-FI/AT CAT in the population with SCI and highlight the importance of multidimensional functional measures. PMID- 29608902 TI - Effectiveness of Home-Based Exercises Without Supervision by Physical Therapists for Patients With Early-Stage Amyotrophic Lateral Sclerosis: A Pilot Study. AB - OBJECTIVE: To verify the effects of structured home-based exercises without supervision by a physical therapist in patients with early-stage amyotrophic lateral sclerosis (ALS). DESIGN: A historical controlled study that is part of a multicenter collaborative study. SETTING: Rehabilitation departments at general hospitals and outpatient clinics with a neurology department. PARTICIPANTS: Patients (N=21) with ALS were enrolled and designated as the home-based exercise (Home-EX) group, and they performed unsupervised home-based exercises. As a control group, 84 patients with ALS who underwent supervised exercise with a physical therapist for 6 months were extracted from a database of patients with ALS and matched with the Home-EX group in terms of their basic attributes and clinical features. INTERVENTION: The Home-EX group was instructed to perform structured home-based exercises without supervision by a physical therapist that consisted of muscle stretching, muscle training, and functional training for 6 months. MAIN OUTCOME MEASURES: The primary outcome was the score on the ALS Functional Rating Scale-Revised (ALSFRS-R), which is composed of 3 domains: bulbar function, limb function, and respiratory function. The score ranges from 0 to 48 points, with a higher score indicating better function. RESULTS: In the Home-EX group, 15 patients completed the home-based exercises for 6 months, and 6 patients dropped out because of medical reasons or disease progression. No adverse events were reported. The Home-EX group was found to have a significantly higher respiratory function subscore and total score on the ALSFRS-R than the control group at follow-up (P<.001 and P<.05, respectively). CONCLUSIONS: Structured home-based exercises without supervision by a physical therapist could be used to alleviate functional deterioration in patients with early-stage ALS. PMID- 29608903 TI - The Efficacy of Touch Smear Cytology in the Diagnosis of Salivary Gland Cancers. AB - PURPOSE: Methods for cytologic diagnosis, such as fine-needle aspiration (FNA) and touch smear (TS) cytology, have been frequently used for malignant tumor screening; however, false-negative cases often result in misdiagnosis. The purpose of this study was to investigate the causes of false-negative cases and methods to decrease the false-negative rate in salivary gland tumor TS cytology. MATERIALS AND METHODS: In this cross-sectional study, the authors examined pathologically confirmed salivary gland tumors in 127 cases in which FNA and TS cytology were performed before the operation or open biopsy at Numazu City Hospital (Numazu, Japan) from 2002 to 2016. The authors evaluated the false negative rates of TS and FNA cytology separately and when used in combination and other variables, such as age, gender, sensitivity, accuracy, specificity, and overall pathologic diagnosis by resection. RESULTS: The overall false-negative rate of postoperative pathologic diagnosis was lower when TS and FNA were combined (1 of 127 cases; 0.8%) compared with FNA cytology alone (10 of 127 cases; 7.9%; P = .034). Suggested causes of a false-negative FNA (or TS) result include cytologic difficulties present in certain malignancies, such as mucoepidermoid carcinoma, adenoid cystic carcinoma, and others. CONCLUSION: False negative cases were decreased when a combination of preoperative FNA and intraoperative TS cytology was performed. TS cytology appears to be a useful method to avoid misdiagnosis in salivary gland diseases. PMID- 29608904 TI - Foreign Body Giant Cell Reaction to a Proplast/Teflon Interpositional Implant: A Case Report and Literature Review. AB - After discectomy, interpositional implants (IPIs) are believed to provide temporomandibular joint stability and protect against degenerative joint space remodeling. Alloplastic IPIs gained popularity in the late 1970s because the practice showed early success without donor site morbidity. Unfortunately, these implants were subject to substantial fragmentation resulting in an exuberant foreign body giant cell response that progressively eroded adjacent structures. Most of these alloplastic implants were removed in the years following their recall by the US Food and Drug Administration in 1991, however some remained in circulation. This report describes a case of a failed Proplast/Teflon IPI 27 years after its placement. This case highlights the considerations for managing a patient with a Proplast/Teflon IPI and serves to remind providers that, although increasingly rare, these implants are still present and subject to delayed failure. PMID- 29608905 TI - Regional differences in endothelial cell cytoskeleton, junctional proteins and phosphorylated tyrosine labeling in the porcine vortex vein system. AB - We previously demonstrated endothelial phenotype heterogeneity in the vortex vein system. This study is to further determine whether regional differences are present in the cytoskeleton, junctional proteins and phosphorylated tyrosine labeling within the system. The vortex vein system of twenty porcine eyes was perfused with labels for f-actin, claudin-5, VE-Cadherin, phosphorylated tyrosine and nucleic acid. The endothelial cells of eight different regions (choroidal veins, pre-ampulla, anterior ampulla, mid-ampulla, posterior ampulla, post ampulla, intra-scleral canal and the extra-ocular vortex vein) were studied using confocal microscopy. There were regional differences in the endothelial cell structures. Cytoskeleton labeling was relatively even in intensity throughout Regions 1 to 6. Overall VE-Cadherin had a non-uniform distribution and thicker width endothelial cell border staining than claudin-5. Progressing downstream there was an increased variation in thickness of VE-cadherin labeling. There was an overlap in phosphorylated tyrosine and VE-Cadherin labeling in the post ampulla, intra-scleral canal and extra-ocular vortex vein. Intramural cells were observed that were immune-positive for VE-Cadherin and phosphorylated tyrosine. There were significant differences in the number of intramural cells in different regions. Significant regional differences with endothelial cell labeling of cytoskeleton, junction proteins, and phosphorylated tyrosine were found within the vortex vein system. These findings support existing data on endothelial cell phenotype heterogeneity, and may aid in the knowledge of venous pathologies by understanding regions of vulnerability to endothelial damage within the vortex vein system. It could be valuable to further investigate and characterize the VE cadherin and phosphotyrosine immune-positive intramural cells. PMID- 29608906 TI - Excess homocysteine upregulates the NRF2-antioxidant pathway in retinal Muller glial cells. AB - This study evaluated the effects of elevated homocysteine (Hcy) on the oxidative stress response in retinal Muller glial cells. Elevated Hcy has been implicated in retinal diseases including glaucoma and optic neuropathy, which are characterized by retinal ganglion cell (RGC) loss. To understand the mechanisms of Hcy-induced RGC loss, in vitro and in vivo models have been utilized. In vitro isolated RGCs are quite sensitive to elevated Hcy levels, while in vivo murine models of hyperhomocysteinemia (HHcy) demonstrate a more modest RGC loss (~20%) over a period of many months. This differential response to Hcy between isolated cells and the intact retina suggests that the retinal milieu invokes mechanisms that buffer excess Hcy. Oxidative stress has been implicated as a mechanism of Hcy-induced neuron loss and NRF2 is a transcription factor that plays a major role in regulating cytoprotective responses to oxidative stress. In the present study we investigated whether HHcy upregulates NRF2-mediated stress responses in Muller cells, the chief retinal glial cell responsible for providing trophic support to retinal neurons. Primary Muller cells were exposed to L-Hcy thiolactone [50MUM-10mM] and assessed for viability, reactive oxygen species (ROS), and glutathione (GSH) levels. Gene/protein levels of Nrf2 and levels of NRF2-regulated antioxidants (NQO1, CAT, SOD2, HMOX1, GPX1) were assessed in Hcy exposed Muller cells. Unlike isolated RGCs, isolated Muller cells are viable over a wide range of Hcy concentrations [50 MUM - 1 mM]. Moreover, when exposed to elevated Hcy, Muller cells demonstrate decreased oxidative stress and decreased ROS levels. GSH levels increased by ~20% within 24 h exposure to Hcy. Molecular analyses revealed 2-fold increase in Nrf2 expression. Expression of antioxidant genes Nqo1, Cat, Sod2, Hmox1, Gpx1 increased significantly. The consequences of Hcy exposure were evaluated also in Muller cells harvested from Nrf2-/- mice. In contrast to WT Muller cells, in which oxidative stress decreased upon exposure to Hcy, the Nrf2-/- Muller cells showed a significant increase in oxidative stress. Our data suggest that at least during early stages of Hhcy, a cytoprotective response may be in place, mediated in part by NRF2 in Muller cells. PMID- 29608907 TI - M to L cone ratios determine eye sizes and baseline refractions in chickens. AB - Following a hypothesis raised by M. and J. Neitz, Seattle, we have tested whether the abundance and the ratio of Long wavelength-sensitive (L) to Middle wavelength sensitive (M) cones may affect eye size and development of myopia in the chicken. Fourteen chickens were treated with frosted plastic diffusers in front of one eye on day 10 post-hatching for a period of 7 days to induce deprivation myopia. Ocular dimensions were measured by A-scan ultrasonography at the beginning and at the end of the treatment and development of refractive state was tracked using infrared photorefraction. At the end of the treatment period, L and M cone densities and ratios were analyzed in retinal flat mounts of both myopic and control eyes, using the red and yellow oil droplets as markers. Because large numbers of cones were counted (>10000), software was written in Visual C++ for automated cone detection and density analysis. (1) On average, 9.7 +/- 1.7D of deprivation myopia was induced in 7 days (range from 6.8D to 13.7D) with an average increase in axial length by 0.65 +/- 0.20 mm (range 0.42 mm-1.00 mm), (2) the increase in vitreous chamber depth was correlated with the increase in myopic refractive error, (3) average central M cone densities were 10,498 cells/mm2, and L cone densities 9574 cells/mm2. In the periphery, M cone densities were 6343 cells/mm2 and L cones 5735 cells/mm2 (4) M to L cone ratios were highly correlated in both eyes of each animal (p < 0.01 in all cases), (5) the most striking finding was that ratios of M to L cones were significantly correlated with vitreous chamber depths and refractive states in the control eyes with normal vision, both in the central and peripheral retinas (p < 0.05 to p < 0.01), (6) M to L cone ratios did however not predict the amount of deprivation myopia that could be induced. M and L cone ratios are most likely genetically determined in each animal. The more L cones, the deeper the vitreous chambers and the more myopic were the refractions in eyes. M to L cone ratios may determine the set point of emmetropization and thereby ultimately the probability of becoming myopic. Deprivation myopia was not determined by M to L cone ratios. PMID- 29608908 TI - CINPA1 binds directly to constitutive androstane receptor and inhibits its activity. AB - The constitutive androstane receptor (CAR) and pregnane X receptor (PXR) are xenobiotic sensors that regulate the expression of drug-metabolizing enzymes and efflux transporters. CAR activation promotes drug elimination, thereby reducing therapeutic effectiveness, or causes adverse drug effects via toxic metabolites. CAR inhibitors could be used to attenuate these adverse drug effects. CAR and PXR share ligands and target genes, confounding the understanding of the regulation of receptor-specific activity. We previously identified a small-molecule inhibitor, CINPA1, that inhibits CAR (without activating PXR at lower concentrations) by altering CAR-coregulator interactions and reducing CAR recruitment to DNA response elements of regulated genes. However, solid evidence was not presented for the direct binding of CINPA1 to CAR. In this study, we demonstrate direct interaction of CINPA1 with the CAR ligand-binding domain (CAR LBD) and identify key residues involved in such interactions through a combination of biophysical and computational methods. We found that CINPA1 resides in the ligand-binding pocket to stabilize the CAR-LBD in a more rigid, less fluid state. Molecular dynamics simulations, together with our previously reported docking model, enabled us to predict which CAR residues were critical for interactions with CINPA1. The importance of these residues for CINPA1 binding were then validated by directed mutations and testing the mutant CAR proteins in transcription reporter and coregulatory interaction assays. We demonstrated strong hydrogen bonding of CINPA1 with N165 and H203 and identified other residues involved in hydrophobic contacts with CINPA1. Overall, our data confirm that CINPA1 directly binds to CAR. PMID- 29608909 TI - Activation of autophagy by stress-activated signals as a cellular self-defense mechanism against the cytotoxic effects of MBIC in human breast cancer cells in vitro. AB - We recently reported that methyl 2-(-5-fluoro-2-hydroxyphenyl)-1H benzo[d]imidazole-5-carboxylate (MBIC) is a microtubule targeting agent (MTA) with multiple mechanisms of action including apoptosis in two human breast cancer cell-lines MCF-7 and MDA-MB-231. In the present study, investigation of early molecular events following MBIC treatment demonstrated the induction of autophagy. This early (<24 h) response to MBIC was characterized by accumulation of autophagy markers; LC3-II, Beclin1, autophagic proteins (ATGs) and collection of autophagosomes but with different variations in the two cell-lines. MBIC induced autophagy was associated with generation of reactive oxygen species (ROS). In parallel, an increased activation of SAPK/JNK pathway was detected, as an intersection of ROS production and induction of autophagy. The cytotoxic effect of MBIC was enhanced by inhibition of autophagy through blockage of SAPK/JNK signaling, suggesting that MBIC-induced autophagy, is a possible cellular self-defense mechanism against toxicity of this agent in both breast cancer cell-lines. The present findings suggest that inhibition of autophagy eliminates the cytoprotective activity of MDA-MB-231 and MCF-7 cells, and sensitizes both the aggressive and non-aggressive human breast cancer cell-lines to the cytotoxic effects of MBIC. PMID- 29608910 TI - Pre-clinical and translational pharmacology of a human interleukin-22 IgG fusion protein for potential treatment of infectious or inflammatory diseases. AB - Interleukin (IL)-22 plays protective roles in infections and in inflammatory diseases that have been linked to its meditation of innate immunity via multiple mechanisms. IL-22 binds specifically to its heterodimeric receptor, which is expressed on a variety of epithelial tissues. UTTR1147A is a recombinant fusion protein that links the human cytokine IL-22 with the Fc portion of human immunoglobulin (Ig) G4. Here, we report extensive in vitro and in vivo nonclinical studies that were conducted to characterize the pharmacological activity of UTTR1147A. The in vitro activity and potency of UTTR1147A were analyzed using primary human hepatocytes and human colonic epithelial cell lines. Assessment of in vivo efficacy was performed in a mouse colitis model and by measuring relevant pharmacodynamic biomarkers, including antimicrobial peptides REG3A/beta, serum amyloid protein A (SAA) and lipopolysaccharide binding protein (LBP). The pharmacokinetic and pharmacodynamic characteristics of UTTR1147A were assessed in healthy mice, rats and cynomolgus monkeys. UTTR1147A induced STAT3 activation through binding to IL-22 receptor expressed in primary human hepatocytes and human colon cell lines. In both, activation occurred in a concentration-dependent manner with similar potencies. In the mouse colitis model, murine IL-22Fc- (muIL-22Fc) treated groups at doses of 1.25 MUg and above had statistically lower average histologic colitis scores compared to the control treated group. Administration of muIL-22Fc or UTTR1147A was associated with a dose-dependent induction of PD markers REG3beta and SAA in rodents as well as REG3A, SAA and LBP in cynomolgus monkeys. The combined data confirm pharmacological activity of IL-22Fc and support potential regenerative and protective mechanisms in epithelial tissues. PMID- 29608911 TI - Renal aquaporin-4 associated pathology in TG-26 mice. AB - Human immunodeficiency virus-associated nephropathy (HIVAN) is a leading cause of end-stage renal disease in HIV patients, which is characterized by glomerulosclerosis and renal tubular dysfunction. Aquaporin-4 (AQP-4) is a membrane bound water channel protein that plays a distinct role in water reabsorption from renal tubular fluid. It has been proven that failure of AQP-4 insertion into the renal tubular membrane leads to renal dysfunction. However, the role of AQP-4 in HIVAN is unclear. We hypothesize that impaired water reabsorption leads to renal injury in HIVAN, where AQP-4 plays a crucial role. Renal function is assessed by urinary protein and serum blood urea nitrogen (BUN). Kidneys from HIV Transgenic (TG26) mice (HIVAN animal model) were compared to wild type mice by immunostaining, immunoblotting and quantitative RT-PCR. TG26 mice had increased proteinuria and BUN. We found decreased AQP-4 levels in the renal medulla, increased endothelin-1, endothelin receptor A and reduced Sirtuin1 (SIRT-1) levels in TG26 mice. Also, oxidative and endoplasmic reticulum stress was enhanced in kidneys of TG26 mice. We provide the first evidence that AQP-4 is inhibited due to induction of HIV associated stress in the kidneys of TG26 mice which limits water reabsorption in the kidney which may be one of the cause associated with HIVAN, impairing kidney physiology. AQP-4 dysregulation in TG26 mice suggests that similar changes may occur in HIVAN patients. This work may identify new therapeutic targets to be evaluated in HIVAN. PMID- 29608912 TI - Glomerular mitochondrial changes in HIV associated renal injury. AB - HIV-associated nephropathy (HIVAN) is an AIDs-related disease of the kidney. HIVAN is characterized by severe proteinuria, podocyte hyperplasia, collapse, glomerular, and tubulointerstitial damage. HIV-1 transgenic (Tg26) mouse is the most popular model to study the HIV manifestations that develop similar renal presentations as HIVAN. Viral proteins, including Tat, Nef, and Vpr play a significant role in renal cell damage. It has been shown that mitochondrial changes are involved in several kidney diseases, and therefore, mitochondrial dysfunction may be implicated in the pathology of HIVAN. In the present study, we investigated the changes of mitochondrial homeostasis, biogenesis, dynamics, mitophagy, and examined the role of reactive oxygen species (ROS) generation and apoptosis in the Tg26 mouse model. The Tg26 mice showed significant impairment of kidney function, which was accompanied by increased blood urea nitrogen (BUN), creatinine and protein urea level. In addition, histological, western blot and PCR analysis of the Tg26 mice kidneys showed a downregulation of NAMPT, SIRT1, and SIRT3 expressions levels. Furthermore, the kidney of the Tg26 mice showed a downregulation of PGC1alpha, MFN2, and PARKIN, which are coupled with decrease of mitochondrial biogenesis, imbalance of mitochondrial dynamics, and downregulation of mitophagy, respectively. Furthermore, our results indicate that mitochondrial dysfunction were associated with ER stress, ROS generation and apoptosis. These results strongly suggest that the impaired mitochondrial morphology, homeostasis, and function associated with HIVAN. These findings indicated that a new insight on pathological mechanism associated with mitochondrial changes in HIVAN and a potential therapeutic target. PMID- 29608914 TI - Spatial and temporal translocation of PKCalpha in single endothelial cell in response to mechanical stimulus. AB - Endothelial cells (ECs) are exposed to various environmental forces, and a Ca2+ wave is occurred in mechanical stimulated cells. Pharmacological studies reveal that the translocation of protein kinase Calpha (PKCalpha) to the membrane is observed simultaneously with intracellular Ca2+ wave. In this study, we investigate whether and how the kinetics of PKCalpha in ECs is induced in response to mechanical stress. The results show that a mechanical stimulus induced biphasic and directional PKCalpha translocation; PKCalpha initially translocated near or at the membrane and then accumulated at the stimulus point. The initial translocation occurred simultaneously with Ca2+ increase. Initial translocation was inhibited in spite of Ca2+ increase when the diacylglycerol (DAG) binding domain of PKCalpha was inhibited, suggesting that translocation requires intracellular Ca2+ increase and DAG. On the other hand, secondary translocation was delayed, occurring after the Ca2+ wave; however, this translocation occurred even when Ca2+ release from the endoplasmic reticulum was inhibited, while it did not occur when the mechanosensitive (MS) channel was inhibited. These results indicated that at least Ca2+ influx from extracellular space through MS channel is required. Our results support the implication of PKCalpha in the Ca2+ signaling pathway in response to mechanical stress in ECs. PMID- 29608913 TI - Shallow whole genome sequencing for robust copy number profiling of formalin fixed paraffin-embedded breast cancers. AB - Pathology archives with linked clinical data are an invaluable resource for translational research, with the limitation that most cancer samples are formalin fixed paraffin-embedded (FFPE) tissues. Therefore, FFPE tissues are an important resource for genomic profiling studies but are under-utilised due to the low amount and quality of extracted nucleic acids. We profiled the copy number landscape of 356 breast cancer patients using DNA extracted FFPE tissues by shallow whole genome sequencing. We generated a total of 491 sequencing libraries from 2 kits and obtained data from 98.4% of libraries with 86.4% being of good quality. We generated libraries from as low as 3.8 ng of input DNA and found that the success was independent of input DNA amount and quality, processing site and age of the fixed tissues. Since copy number alterations (CNA) play a major role in breast cancer, it is imperative that we are able to use FFPE archives and we have shown in this study that sWGS is a robust method to do such profiling. PMID- 29608915 TI - NUSAP1 gene silencing inhibits cell proliferation, migration and invasion through inhibiting DNMT1 gene expression in human colorectal cancer. AB - Colorectal cancer (CRC) is one of the most common cause of cancer-related death in both female and male patients, with a high capacity for tumor migration and invasion. Recently, aberrant nucleolar and spindle-associated protein 1 (NUSAP1) expression has been reported in several cancers. However, the biological function and molecular mechanism of NUSAP1 in CRC have not been reported. Here, we demonstrated that NUSAP1 gene expression was notably upregulated in CRC tissues and cell lines (Caco2, LS174T, SW480, and LoVo). Subsequently, SW480 and LoVo cells were transfected with NUSAP1 siRNA, respectively, and the biological function of NUSAP1 was investigated. Results indicated that NUSAP1 silencing by siRNA inhibited CRC cell proliferation, and induces cell apoptosis. Moreover, NUSAP1 knockdown suppressed cell migration, cell invasion, and epithelial-to mesenchymal transition (EMT). Furthermore, NUSAP1 silencing notably inhibited the mRNA and protein expression level of DNA methyltransferase 1 (DNMT1). DNMT1 overexpression partly rescued the effect of NUSAP1 silencing on colorectal cancer biological function. Taken together, NUSAP1 gene silencing induced cell apoptosis, and inhibited cell proliferation, cell migration, cell invasion, and EMT in colorectal cancer through inhibiting DNMT1 gene expression. These findings indicat that NUSAP1 is a promising molecular target for CRC treatment. PMID- 29608916 TI - Overexpression of miR-133 decrease primary endothelial cells proliferation and migration via FGFR1 targeting. AB - Angiogenesis is one of the essential hallmarks of cancer that is controlled by the balance between positive and negative regulators. FGFR1 signaling is crucial for the execution of bFGF-induced proliferation, migration, and tube formation of endothelial cells (ECs) and onset of angiogenesis on tumors. The purpose of this study is to identify whether or not miR-133 regulates FGFR1 expression and accordingly hypothesize if it plays a crucial role in modulating bFGF/FGFR1 activity in ECs and blocking tumor angiogenesis through targeting FGFR1. The influences of miR-133 overexpression on bFGF stimulated endothelial cells were assessed by cell growth curve, MTT assaying, tube formation, and migration assays. Forced expression of miR-133 caused significant reductions in bFGF induced proliferation and migratory ability of ECs. MiR-133 Expression was negatively correlated with both mRNA and protein levels of FGFR1 in the transfected ECs isolated from peripheral blood. Moreover, overexpression of miR 133 drastically reduced the rate of cell division and disturbed capillary network formation of transfected ECs. These findings suggest that miR-133 plays an important function in bFGF-induced angiogenesis processes in ECs and provides a rationale for new therapeutic approaches to suppress tumor angiogenesis and cancer. PMID- 29608917 TI - Time-dependent, bidirectional, anti- and pro-spinal hyper-reflexia and muscle spasticity effect after chronic spinal glycine transporter 2 (GlyT2) oligonucleotide-induced downregulation. AB - The loss of local spinal glycine-ergic tone has been postulated as one of the mechanisms contributing to the development of spinal injury-induced spasticity. In our present study using a model of spinal transection-induced muscle spasticity, we characterize the effect of spinally-targeted GlyT2 downregulation once initiated at chronic stages after induction of spasticity in rats. In animals with identified hyper-reflexia, the anti-spasticity effect was studied after intrathecal treatment with: i) glycine, ii) GlyT2 inhibitor (ALX 1393), and iii) GlyT2 antisense oligonucleotide (GlyT2-ASO). Administration of glycine and GlyT2 inhibitor led to significant suppression of spasticity lasting for a minimum of 45-60 min. Treatment with GlyT2-ASO led to progressive suppression of muscle spasticity seen at 2-3 weeks after treatment. Over the subsequent 4-12 weeks, however, the gradual appearance of profound spinal hyper-reflexia was seen. This was presented as spontaneous or slight-tactile stimulus-evoked muscle oscillations in the hind limbs (but not in upper limbs) with individual hyper reflexive episodes lasting between 3 and 5 min. Chronic hyper-reflexia induced by GlyT2-ASO treatment was effectively blocked by intrathecal glycine. Immunofluorescence staining and Q-PCR analysis of the lumbar spinal cord region showed a significant (>90%) decrease in GlyT2 mRNA and GlyT2 protein. These data demonstrate that spinal GlyT2 downregulation provides only a time-limited therapeutic benefit and that subsequent loss of glycine vesicular synthesis resulting from chronic GlyT2 downregulation near completely eliminates the tonic glycine-ergic activity and is functionally expressed as profound spinal hyper reflexia. These characteristics also suggest that chronic spinal GlyT2 silencing may be associated with pro-nociceptive activity. PMID- 29608919 TI - Morphological properties of the occlusion body of Adoxophyes orana granulovirus. AB - A granulovirus (GV) that produces occlusion bodies (OBs) having an unusual morphology was found in an Adoxophyes sp. (Lepidoptera: Tortricidae) larva in a tea field in Miyazaki Prefecture, Japan. This isolate is considered to be a mutant of Adoxophyes orana granulovirus, designated AdorGV-M, because the nucleotide sequence of its genome is 99.7% identical to that of an English isolate of AdorGV, AdorGV-E. AdorGV-E produces typical ovocylindrical OBs that contain one occlusion-derived virus (ODV) per OB. On the other hand, AdorGV-M produces large cuboidal OBs, but the number of ODVs per OB was unknown. In this study, we quantified viral DNA in OBs of both AdorGV-E and -M, and determined the number of ODVs occluded in an OB of AdorGV-M. The two isolates had the same quantity of viral DNA in each OB, and we thus confirmed that one OB of AdorGV-M contains one ODV. To investigate the process of OB formation, fat body tissue of A. honmai larvae inoculated with each isolate was observed in a time course by transmission electron microscopy, and OB sizes were measured from micrographs. The main difference in OB formation was that AdorGV-M required more time to mature than AdorGV-E. In AdorGV-E, ODVs began to be covered from one end with an ovocylindrical OB at 96 h post-inoculation (hpi), and most of them were completely occluded at 120 hpi. Occlusion of AdorGV-M ODVs also began at 96 hpi, but the OB shape was cuboidal. Moreover, the OB size of AdorGV-M was similar to that of AdorGV-E at 120 hpi, but continued to grow until 192 hpi. AdorGV-M thus took more time to complete OB formation. Consequently, AdorGV-E has mature OBs with a diameter 0.22 MUm and length 0.39 MUm, but those of AdorGV-M are 1.34 * 1.23 MUm. PMID- 29608918 TI - A new multiplex PCR protocol to detect mixed trypanosomatid infections in species of Apis and Bombus. AB - Trypanosomatids are highly prevalent pathogens of Hymenoptera; however, most molecular methods used to detect them in Apis and Bombus spp. do not allow the identification of the infecting species, which then becomes expensive and time consuming. To overcome this drawback, we developed a multiplex PCR protocol to readily identify in a single reaction the main trypanosomatids present in these hymenopterans (Lotmaria passim, Crithidia mellificae and Crithidia bombi), which will facilitate the study of their epidemiology and transmission dynamics. A battery of primers, designed to simultaneously amplify fragments of the RNA polymerase II large subunit (RPB1) of L. passim, the glyceraldehyde-3-phosphate dehydrogenase (GAPDH) of C. mellificae and the DNA topoisomerase II (TOPII) of C. bombi, was tested for target specificity under single and mixed template conditions using DNA extracted from cell cultures (L. passim ATCC PRA403; C. mellificae ATCC 30254) and from a bumblebee specimen infected with C. bombi only (14_349). Once validated, the performance of the method was assessed using DNA extractions from seven Apis mellifera (Linnaeus, 1758) and five Bombus terrestris (Linnaeus, 1758) field samples infected with trypanosomatids whose identity had been previously determined by PCR-cloning and sequencing (P-C-S). The new method confirmed the results obtained by P-C-S: two of the honeybee samples were parasitized by L. passim, C. mellificae and C. bombi at the same time, whereas the other five were infected with L. passim only. The method confirmed the simultaneous presence of L. passim and C. mellificae in two B. terrestris, where these parasites had not previously been reported. PMID- 29608920 TI - The metabotropic glutamate receptor 5 radioligand [11C]AZD9272 identifies unique binding sites in primate brain. AB - The metabotropic glutamate receptor 5 (mGluR5) is a target for drug development and for imaging studies of the glutamate system in neurological and psychiatric disorders. [11C]AZD9272 is a selective mGluR5 PET radioligand that is structurally different from hitherto applied mGluR5 radioligands. In the present investigation we compared the binding patterns of radiolabeled AZD9272 and other mGluR5 radioligands in the non-human primate (NHP) brain. PET studies were undertaken using [11C]AZD9272 and the commonly applied mGluR5 radioligand [11C]ABP688. Autoradiography studies were performed in vitro using [3H]AZD9272 and the standard mGluR5 radioligands [3H]M-MTEP and [3H]ABP688 in NHP tissue. Competition binding studies were undertaken in vivo and in vitro using different mGluR5 selective compounds as inhibitors. In comparison to other mGluR5 radioligands radiolabeled AZD9272 displayed a distinct regional distribution pattern with high binding in ventral striatum, midbrain, thalamus and cerebellum. While the binding of [11C]AZD9272 was almost completely inhibited by the structurally unique mGluR5 compound fenobam (2.0 mg/kg; 98% occupancy), it was only partially inhibited (46% and 20%, respectively) by the mGluR5 selective compounds ABP688 and MTEP, at a dose (2.0 mg/kg) expected to saturate the mGluR5. Autoradiography studies using [3H]AZD9272 confirmed a distinct pharmacologic profile characterized by preferential sensitivity to fenobam. The distinctive binding in ventral striato-pallido-thalamic circuits and shared pharmacologic profile with the pro-psychotic compound fenobam warrants further examination of [11C]AZD9272 for potential application in psychiatric neuroimaging studies. PMID- 29608921 TI - Cardiac arrest and atrial fibrillation in a patient after hump-nosed pit viper (Hypnale hypnale) bite. AB - A 42-year-old previously healthy male patient died 16 days after a proven hump nosed pit viper (Hypnale hypnale) envenoming due to multi-organ failure. On admission he had cardiac arrest that recovered from cardiopulmonary resuscitation then developed atrial fibrillation which was reverted to normal rhythm by application of synchronized electrical cardioversion. He also had persistent coagulopathy and thrombotic microangiopathy comprising the triad of microangiopathic haemolysis, acute kidney injury and thrombocytopenia. This is the second reported case with cardiac complications following hump-nosed pit viper bites in Sri Lanka. PMID- 29608922 TI - Conservation analysis and decomposition of residue correlation networks in the phospholipase A2 superfamily (PLA2s): Insights into the structure-function relationships of snake venom toxins. AB - Phospholipases A2 (PLA2s) comprise a superfamily of glycerophospholipids hydrolyzing enzymes present in many organisms in nature, whose catalytic activity was majorly unveiled by analysis of snake venoms. The latter have pharmaceutical and biotechnological interests and can be divided into different functional sub classes. Our goal was to identify important residues and their relation to the functional and class-specific characteristics in the PLA2s family with special emphasis on snake venom PLA2s (svPLA2s). We identified such residues by conservation analysis and decomposition of residue coevolution networks (DRCN), annotated the results based on the available literature on PLA2s, structural analysis and molecular dynamics simulations, and related the results to the phylogenetic distribution of these proteins. A filtered alignment of PLA2s revealed 14 highly conserved positions and 3 sets of coevolved residues, which were annotated according to their structural or functional role. These residues are mostly involved in ligand binding and catalysis, calcium-binding, the formation of disulfide bridges and a hydrophobic cluster close to the binding site. An independent validation of the inference of structure-function relationships from our co-evolution analysis on the svPLA2s family was obtained by the analysis of the pattern of selection acting on the Viperidae and Elapidae lineages. Additionally, a molecular dynamics simulation on the Lys49 PLA2 from Agkistrodon contortrix laticinctus was carried out to further investigate the correlation of the Lys49-Glu69 pair. Our results suggest this configuration can result in a novel conformation where the binding cavity collapses due to the approximation of two loops caused by a strong salt bridge between Glu69 and Arg34. Finally, phylogenetic analysis indicated a correlation between the presence of residues in the coevolved sets found in this analysis and the clade localization. The results provide a guide for important positions in the family of PLA2s, and potential new objects of investigation. PMID- 29608923 TI - Harnessing the potential of epigenetic therapies for childhood acute myeloid leukemia. AB - There is a desperate need for new and effective therapeutic approaches to acute myeloid leukemia (AML) in both children and adults. Epigenetic aberrations are common in adult AML, and many novel epigenetic compounds that may improve patient outcomes are in clinical development. Mutations in epigenetic regulators occur less frequently in AML in children than in adults. Investigating the potential benefits of epigenetic therapy in pediatric AML is an important issue and is discussed in this review. PMID- 29608924 TI - A20 ameliorates inflammatory bowel disease in mice via inhibiting NF-kappaB and STAT3 activation. AB - A20 is a zinc finger protein that effectively inhibits the activation of nuclear factor (NF)-kappaB to downregulate the expression of tumor necrosis factor-alpha, interleukin (IL)-1beta, and IL-17. A20 also plays a crucial role as a feedback inhibitor of the inflammatory response. Due to its inhibitory role, A20 may be useful in regulating diseases resulting from chronic inflammation and excessive pro-inflammatory cytokine production, such as colitis. Patients with colitis produce high levels of pro-inflammatory cytokines in the intestine. Therefore, this study aimed to investigate whether A20 improves experimental colitis by reducing high levels of inflammation in the intestine. An A20 overexpression vector was administered to mice by intrarectal injection after colitis induction. Histological analysis by immunohistochemistry was used to score sections of the intestine. Confocal laser scanning microscopy was used to identify the expression of IL-17 and forkhead box p (FOXP) 3 protein in spleen tissues. Protein expression induced by STAT3 and NF-kappaB signaling was analyzed by western blot. We found that A20 reduced the colitis activity index score and the histological score of the intestine. A20 also decreased inflammatory cytokine levels in the intestine and increased colon length. Additionally, A20 overexpression downregulated the activation of NF-kB and STAT3. A20 also reduced IL-17 expression in CD4+ T cells from spleen sections. In contrast, A20 overexpression enhanced the expression of FOXP3 in CD4+ T cells. These results suggest that A20 may inhibit the progression of colitis by decreasing inflammation via inhibition of NF-kappaB, phosphorylated STAT3, and IL-17. PMID- 29608925 TI - Transdiagnostic and diagnosis-specific dynamic functional connectivity anchored in the right anterior insula in major depressive disorder and bipolar depression. AB - Dysfunctional and abnormal functional connectivity in the right anterior insula (rAI) may underlie the pathophysiology of depression episode in bipolar disorder (BD) and of major depressive disorder (MDD). In this study, we examined the dynamic functional connectivity (dFC) of the rAI of 30 patients with BD, 30 patients with MDD, and 30 healthy controls. In the functional separation of rAI, the right dorsal AI (rdAI) and ventral AI (rvAI) were defined as seed regions. Sliding-window correlation of rAI subregions was implemented to measure the variance of dFC. BD and MDD shared abnormality in dFC, such as the decreased dFC between the rvAI and right ventrolateral prefrontal cortex. Others were disorder specific and included MDD-related increases in dFC between the rvAI and right precuneus, temporal pole, and left dorsolateral prefrontal cortex. This observation is in stark contrast to BD-related increases in the dFC between the rdAI and left inferior parietal lobule and right middle occipital gyrus. The abnormal dFC of rAI shared by BD and MDD supports the importance of rAI in the common pathophysiology of these disorders. Meanwhile, disorder-specific abnormalities that attribute to the dorsal and ventral divisions of rAI can be used as biomarkers to differentiate BD from MDD. PMID- 29608926 TI - Increased temporal variability of striatum region facilitating the early antidepressant response in patients with major depressive disorder. AB - The aim of this study is to identify the difference of temporal variability among major depressive disorder (MDD) patients (with different early antidepressant responses) and healthy controls (HC), and further explore the relationship between pre-treatment temporal variability and early antidepressant response. At baseline, 77 treatment-naive inpatients with MDD and 42 matched HC received clinical assessments and 3.0 Tesla resting-state functional magnetic resonance imaging scans. After 2 weeks' antidepressant treatment, the patients were subgrouped into responsive depression (RD, n = 40) and non-responding depression (NRD, n = 37) based on the reduction of Hamilton depression rating scale (HAMD). The temporal variability of 90 brain nodes was calculated for further analysis. Compared with the HC group, both the RD and NRD subjects showed greater baseline temporal variability (i.e., greater dynamic) in the left inferior occipital gyrus. Significantly greater temporal variability in the left pallidum was found in the RD group than the NRD and the HC groups, and the higher variability of left pallidum correlated positively with the HAMD reduction. Moreover, the pooled MDD (i.e., RD and NRD) group showed greater baseline temporal variability in the right inferior frontal gyrus, the left inferior occipital gyrus, the bilateral fusiform gyri and the left Heschl gyrus than the HC group. The distinctive pattern of dynamically reorganized networks may provide a crucial scaffold to facilitate early antidepressant response, and the temporal variability may serve as a promising indicator for the personalized therapy of MDD. PMID- 29608927 TI - Assessment of UV-C-induced water disinfection by differential PCR-based quantification of bacterial DNA damage. PMID- 29608928 TI - An improved in-house lysis-filtration protocol for bacterial identification from positive blood culture bottles with high identification rates by MALDI-TOF MS. AB - Matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) is now a well-established method for identification of microorganisms from positive blood cultures. Pretreatments to effectively remove non-bacterial proteins are a prerequisite for successful identification, and a variety of protocols have been reported. Although commercially available kits, mainly the Sepsityper Kit, are increasingly used, the identification rates reported often are not satisfactory, particularly for Gram-positive isolates. We developed a new, in-house lysis-filtration protocol and prospectively evaluated its performance compared to the Sepsityper kit. The in-house protocol consists of three simple steps: lysis by ammonium chloride, aspiration with a syringe fitted with a 0.45-MUm membrane, and centrifugation to collect microbes. The novel protocol requires only 20 min. Performance of the in-house protocol was evaluated using a total of 117 monomicrobial cases of positive blood culture. Medium from blood culture bottles was pretreated by the in-house protocol or the commercial kit, and isolated cells were subjected to direct identification by mass spectrometry fingerprinting in parallel with conventional subculturing for reference identification. The overall MALDI-TOF MS-based identification rates with score > 1.7 and > 2.0 obtained using the in-house protocol were 99.2% and 85.5%, respectively, whereas those obtained using the Sepsityper Kit were 85.4% and 61.5%, respectively. For Gram-positive cases, the in-house protocol yielded scores >1.7 and > 2.0 at 98.5% and 76.1%, respectively, whereas the commercial kit yielded these scores at 76.1% and 43.3%, respectively. Although these are preliminary results, these values suggest that this easy lysis-filtration protocol deserves assessment in a larger-scale test. PMID- 29608929 TI - Regulation of LH secretion by RFRP-3 - From the hypothalamus to the pituitary. AB - RFamide-related peptides (RFRPs) have long been identified as inhibitors of the hypothalamus-pituitary-gonad axis in mammals. However, less progress has been made in the detailed roles of RFRPs in the control of LH secretion. Recent studies have suggested that RFRP-3 neurons in the hypothalamus can regulate the secretion of LH at different levels, including kisspeptin neurons, GnRH neurons, and the pituitary. Additionally, conflicting results regarding the effects of RFRP-3 on these levels exist. In this review, we collect the latest evidence related to the effects of RFRP-3 neurons in regulating LH secretion by acting on kisspeptin neurons, GnRH neurons, and the pituitary and discuss the potential role of the timely reduction of RFRP-3 signaling in the modulation of the preovulatory LH surge. PMID- 29608930 TI - Atomoxetine, a selective norepinephrine reuptake inhibitor, improves short-term histological outcomes after hypoxic-ischemic brain injury in the neonatal male rat. AB - BACKGROUND: Despite the recent progress of perinatal medicine, perinatal hypoxic ischemic (HI) insult remains an important cause of brain injury in neonates, and is pathologically characterized by neuronal loss and the presence of microglia. Neurotransmitters, such as norepinephrine (NE) and glutamate, are involved in the pathogenesis of hypoxic-ischemic encephalopathy via the interaction between neurons and microglia. Although it is well known that the monoamine neurotransmitter NE acts as an anti-inflammatory agent in the brain under pathological conditions, its effects on perinatal HI insult remains elusive. Atomoxetine, a selective NE reuptake inhibitor, has been used clinically for the treatment of attention-deficit hyperactivity disorder in children. Here, we investigated whether the enhancement of endogenous NE by administration of atomoxetine could protect neonates against HI insult by using the neonatal male rat model. We also examined the involvement of microglia in this process. METHODS: Unilateral HI brain injury was induced by the combination of left carotid artery dissection followed by ligation and hypoxia (8% O2, 2 h) in postnatal day 7 (P7) male rat pups. The pups were randomized into three groups: the atomoxetine treatment immediately after HI insult, the atomoxetine treatment at 3 h after HI insult, or the vehicle treatment group. The pups were euthanized on P8 and P14, and the brain regions including the cortex, striatum, hippocampus, and thalamus were evaluated by immunohistochemistry. RESULTS: HI insult resulted in severe brain damage in the ipsilateral hemisphere at P14. Atomoxetine treatment immediately after HI insult significantly increased NE levels in the ipsilateral hemisphere at 1 h after HI insult and reduced the neuronal damage via the increased phosphorylation of cAMP response element-binding protein (pCREB) in all brain regions examined. In addition, the number of microglia was maintained under atomoxetine treatment compared with that of the vehicle treatment group. To determine the involvement of microglia in the process of neuronal loss by HI insult, we further examined the influence of hypoxia on rat primary cultured microglia by the quantitative real-time polymerase chain reaction. Hypoxia did not cause the upregulation of interleukin-1beta (IL-1beta) mRNA expression, but decreased the microglial intrinsic nitric oxide synthase (iNOS)/arginase1 mRNA expression ratio. NE treatment further decreased the microglial iNOS/arginase1 mRNA expression ratio. In contrast, no significant neuroprotective effect was observed at P14 when atomoxetine was administered at 3 h after HI insult. CONCLUSIONS: These findings suggested that the enhancement of intrinsic neurotransmitter NE signaling by a selective NE reuptake inhibitor, atomoxetine, reduced the perinatal HI insult brain injury. In addition, atomoxetine treatment was associated with changes of TUNEL, pCREB, and BDNF expression levels, and microglial numbers, morphology, and responses. PMID- 29608931 TI - Hybrid, randomized and high capacity conservative mutations DNA-based steganography for large sized data. AB - In this paper, a well secured, high capacity, preserved algorithm is proposed through integrating the cryptography and steganography concepts with the molecular biology concepts. We achieved this by first encrypting the confidential data using the DNA Playfair cipher to avoid extra information sent to the receiver and it consequently acts as a trap for an attacker. Second, it achieves a randomized steganography process by exploiting the DNA conservative mutations. The DNA conservative mutations are utilized in a way that allows a DNA base to be substituted by another base to allow carrying two bits. Consequently, a high capacity feature is obtained with no payload for the used sequence. There are three main achieved contributions in this work. First, is hiding high capacity of data within DNA by exploiting each codon to hide two bits whilst preserving the sequence properties of protein after the steganography process, which is a trade off in the field. Secondly, using the conservative mutation with all its valid biological permutations, leads to the lowest cracking probability achieved and published till now, as proven in the security analysis section. Finally, a comparison is conducted between the proposed algorithm and five recent substitution based algorithms using large sized data up to three megabytes, to prove the algorithm's scalability. PMID- 29608932 TI - Assessing the role of deoD gene in Mycobacterium tuberculosis in vitro growth and macrophage infection. AB - Purine nucleoside phosphorylase from Mycobacterium tuberculosis (MtPNP), encoded by deoD gene (Rv3307), is an enzyme from the purine salvage pathway, which has been widely studied as a molecular target for the development of inhibitors with potential antimycobacterial activity. However, the role of MtPNP in tuberculosis pathogenesis and dormancy is still unknown. The present work aims to construct a deoD knockout strain from M. tuberculosis, to evaluate the role of MtPNP in the growth of M. tuberculosis under oxygenated condition and in a dormancy model, and to assess whether deoD gene is important for M. tuberculosis invasion and growth in macrophages. The construction of a knockout strain for deoD gene was confirmed at DNA level by PCR and protein level by Western blot and LC-MS/MS. The deoD gene is not required for M. tuberculosis growth and survival under oxygenated and hypoxic conditions. The disruption of deoD gene did not affect mycobacterial ability to invade and grow in RAW 264.7 cells under the experimental conditions employed here. PMID- 29608933 TI - Treatment of Anal Cancer Pain-A Case Report. PMID- 29608934 TI - Transition Points for the Routine Integration of Palliative Care in Patients With Advanced Cancer. AB - CONTEXT: Increasing emphases are being placed on early integration of palliative care for patients with advanced cancers, yet barriers to implementation in clinical practice remain. Criteria to standardize referral have been endorsed, but their application is yet to be tested at the population level. OBJECTIVES: This study sought to establish the need for standardized referral by examining current end-of-life care outcomes of decedents with cancer and define transition points within a cancer illness course, which are associated with poor prognosis, whereby palliative care should be routinely introduced to augment clinician-based decision making. METHODS: Population cohort study of admitted patients with advanced cancer diagnosed with non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), prostate or breast cancer between 2000 and 2010 in Victoria, Australia, identified from routinely collected, linked, hospital discharge, emergency department, and death registration data. Descriptive statistics described quality indicators for end-of-life care outcomes for decedents. Kaplan Meier analyses were used to test the predefined transition point that mostly accurately predicted survival of six months or lesser. RESULTS: About 46,700 cases (56% females) were admitted with metastatic NSCLC (n = 14,759; 31.6%), SCLC (n = 2932; 6%), prostate (n = 9445; 20.2%), and breast cancer (n = 19,564; 41.9%). Of the 29,680 decedents, most (80%) died in hospital, had suboptimal end of-life care outcomes (83%), and 59% received a palliative approach to care, a median of 27 days before death. Transition points in the cancer illness course of all cases were identified as first admission with any metastatic disease (NSCLC: 3.8 months [interquartile range {IQR} 1.1, 16.0]; n = 14,666; and SCLC: 4.2 months [IQR 1.0, 10.6]; n = 2914); first multiday admission with any metastatic disease (prostate: 6.0 months [IQR 1.3, 26.4]; n = 7174); and first multiday admission with at least one visceral metastatic site (breast: 6.0 months [IQR 1.2, 29.8]; n = 7120). CONCLUSION: Despite calls for integrated palliative care, this occurs late or not at all for many patients with cancer. Our findings demonstrate the application of targeted cancer-specific transition points to trigger integration of palliative care as a standard part of quality oncological care and augment clinician-based referral in routine clinical practice. PMID- 29608935 TI - Comparative analysis of rhizobial chromosomes and plasmids to estimate their evolutionary relationships. AB - In the present study, complete genomic sequences retrieved from 57 rhizobial strains that covered four genera including 11 species were analyzed comprehensively. The four types of replicons: chromosomes, chromids, nonsymbiotic plasmids, and symbiotic plasmids were investigated and compared among these strains. Results showed that co-evolution occurred among these four replicons based on the similarities in average nucleotide identity. High correlation coefficient r values were observed between chromosomes and chromids, as well as between chromosomes and nonsymbiotic plasmids. Chromosomes and symbiotic plasmids showed different phylogenetic topology based on their core genes. Population structure analyses were performed to extrapolate the evolutionary histories of the test strains based on their chromosomal and symbiotic plasmid background. This resulted in seven ancestral types for chromosomal genes and three ancestral types for symbiotic plasmid genes. Rhizobial strains containing chromosome genes with ancestral type E tend to contain symbiotic plasmid genes with ancestral type II, while rhizobial strains containing chromosome genes with ancestral type G tend to contain symbiotic plasmid genes with ancestral type III. Seventeen strains associated with different host plant species which harbored the symbiotic genes with ancestral type I, exhibited high genetic diversity. In addition, Fu's test of the symbiotic plasmid genes with ancestral type III had undergone an expansion event, implying the influence of negative selection on these symbiotic plasmid genes. PMID- 29608936 TI - Entrainment to the CIECAM02 and CIELAB colour appearance models in the human cortex. AB - In human visual processing, information from the visual field passes through numerous transformations before perceptual attributes such as colour are derived. The sequence of transforms involved in constructing perceptions of colour can be approximated by colour appearance models such as the CIE (2002) colour appearance model, abbreviated as CIECAM02. In this study, we test the plausibility of CIECAM02 as a model of colour processing by looking for evidence of its cortical entrainment. The CIECAM02 model predicts that colour is split in to two opposing chromatic components, red-green and cyan-yellow (termed CIECAM02-a and CIECAM02-b respectively), and an achromatic component (termed CIECAM02-A). Entrainment of cortical activity to the outputs of these components was estimated using measurements of electro- and magnetoencephalographic (EMEG) activity, recorded while healthy subjects watched videos of dots changing colour. We find entrainment to chromatic component CIECAM02-a at approximately 35 ms latency bilaterally in occipital lobe regions, and entrainment to achromatic component CIECAM02-A at approximately 75 ms latency, also bilaterally in occipital regions. For comparison, transforms from a less physiologically plausible model (CIELAB) were also tested, with no significant entrainment found. PMID- 29608937 TI - The role of experience-based perceptual learning in the face inversion effect. AB - Perceptual learning of the type we consider here is a consequence of experience with a class of stimuli. It amounts to an enhanced ability to discriminate between stimuli. We argue that it contributes to the ability to distinguish between faces and recognize individuals, and in particular contributes to the face inversion effect (better recognition performance for upright vs inverted faces). Previously, we have shown that experience with a prototype defined category of checkerboards leads to perceptual learning, that this produces an inversion effect, and that this effect can be disrupted by Anodal tDCS to Fp3 during pre-exposure. If we can demonstrate that the same tDCS manipulation also disrupts the inversion effect for faces, then this will strengthen the claim that perceptual learning contributes to that effect. The important question, then, is whether this tDCS procedure would significantly reduce the inversion effect for faces; stimuli that we have lifelong expertise with and for which perceptual learning has already occurred. Consequently, in the experiment reported here we investigated the effects of anodal tDCS at Fp3 during an old/new recognition task for upright and inverted faces. Our results show that stimulation significantly reduced the face inversion effect compared to controls. The effect was one of reducing recognition performance for upright faces. This result is the first to show that tDCS affects perceptual learning that has already occurred, disrupting individuals' ability to recognize upright faces. It provides further support for our account of perceptual learning and its role as a key factor in face recognition. PMID- 29608938 TI - Tuberculosis infection via the emergency department among inpatients in South Korea: a propensity score matched analysis of the National Inpatient Sample. AB - BACKGROUND: Emergency departments (EDs) carry a high risk of infectious disease transmission and have also been implicated in tuberculosis (TB) outbreaks. AIM: To determine if patients who visit EDs have an increased risk of TB infection. Using South Korean inpatient sample data (2012), the risk of TB occurrence during 90 days after hospitalization for patients admitted via EDs was compared with that for patients admitted via outpatient clinics. METHODS: The data of the 2012 Health Insurance Review and Assessment Service - National Inpatient Sample were used. TB diagnosis was based on International Classification of Diseases Version 10 [all TB (A15-A19), pulmonary TB (A15-A16) and extrapulmonary TB (A17-A18)]. FINDINGS: After propensity score matching using the demographic and clinical characteristics of the patients, 191,997 patients (64,017 patients admitted via EDs and 127,908 patients admitted via outpatient clinics) were included in this study. There was no significant difference in baseline patient characteristics between the two groups. The percentage of patients with TB admitted via EDs was higher than that of patients admitted via outpatient clinics. The likelihood of active TB occurrence was 30% higher for all TB [hazard ratio (HR) 1.30; 95% confidence interval (CI) 1.12-1.52] and pulmonary TB (HR 1.30; 95% CI 1.10-1.53) in patients admitted via EDs compared with patients admitted via outpatient clinics; this difference was significant. However, no difference in the occurrence of extrapulmonary TB was observed between the two groups. CONCLUSIONS: The likelihood of TB infection was greater in patients admitted via EDs than in patients admitted via outpatient clinics. PMID- 29608939 TI - Testicular Yolk Sac Tumor and Mature Teratoma: Synchronous Bilateral Occurrence in an Infant. AB - Yolk sac tumor (YST) is a rare malignancy typically occurring in children. However, bilateral testicular YSTs are a quite rare situation, which can occur metachronously or synchronously with same histologic type, as well as different histology. We present a case of synchronous YST of the left testis and mature teratoma of the right in a 7-month-old infant treated with testis-sparing surgery at right testis and high radical orchiectomy at left. By follow-up of 28th month, no atrophy, or residual tumor in right testis and no recurrence or evidence of disease in left scrotum was found. PMID- 29608940 TI - An update on the role of irisin in the regulation of endocrine and metabolic functions. AB - Irisin is a novel myokine and adipokine that has gained much attention recently due to its mechanisms of action. Irisin is secreted following proteolytic cleavage of its precursor fibronectin type III domain containing 5 (FNDC5). Following its release, irisin exerts its major action by increasing the expression of mitochondrial uncoupling protein 1 (UCP 1), which facilitates the conversion of white adipose tissue (WAT) into beige adipose tissue. Irisin is distributed in various body tissues and several actions have been attributed to its presence in those tissues. It has been suggested that it plays a role in metabolic diseases, ageing, inflammation and neurogenesis. However, the circulating levels of irisin are modulated by several factors such as diet, obesity, exercise, pharmacological agents and different pathological conditions. In this review, we have discussed the mechanisms by which irisin influences the functions of different body systems and how external factors in turn affect the circulating level of irisin. In conclusion, modification of circulating irisin level may help in the management of a variety of endocrine and metabolic disorders. PMID- 29608941 TI - Ultimate explanations and suboptimal choice. AB - Researchers have unraveled multiple cases in which behavior deviates from rationality principles. We propose that such deviations are valuable tools to understand the adaptive significance of the underpinning mechanisms. To illustrate, we discuss in detail an experimental protocol in which animals systematically incur substantial foraging losses by preferring a lean but informative option over a rich but non-informative one. To understand how adaptive mechanisms may fail to maximize food intake, we review a model inspired by optimal foraging principles that reconciles sub-optimal choice with the view that current behavioral mechanisms were pruned by the optimizing action of natural selection. To move beyond retrospective speculation, we then review critical tests of the model, regarding both its assumptions and its (sometimes counterintuitive) predictions, all of which have been upheld. The overall contention is that (a) known mechanisms can be used to develop better ultimate accounts and that (b) to understand why mechanisms that generate suboptimal behavior evolved, we need to consider their adaptive value in the animal's characteristic ecology. PMID- 29608942 TI - Paradoxical choice in rats: Subjective valuation and mechanism of choice. AB - Decision-makers benefit from information only when they can use it to guide behavior. However, recent experiments found that pigeons and starlings value information that they cannot use. Here we show that this paradox is also present in rats, and explore the underlying decision process. Subjects chose between two options that delivered food probabilistically after a fixed delay. In one option ("info"), outcomes (food/no-food) were signaled immediately after choice, whereas in the alternative ("non-info") the outcome was uncertain until the delay lapsed. Rats sacrificed up to 20% potential rewards by preferring the info option, but reversed preference when the cost was 60%. This reversal contrasts with the results found with pigeons and starlings and may reflect species' differences worth of further investigation. Results are consistent with predictions of the Sequential Choice Model (SCM), that proposes that choices are driven by the mechanisms that control action in sequential encounters. As expected from the SCM, latencies to respond in single-option trials predicted preferences in choice trials, and latencies in choice trials were the same or shorter than in single option trials. We argue that the congruence of results in distant vertebrates probably reflects evolved adaptations to shared fundamental challenges in nature, and that the apparently paradoxical overvaluing of information is not sub-optimal as has been claimed, even though its functional significance is not yet understood. PMID- 29608943 TI - Differential reinforcement of low rates differentially decreased timing precision. AB - Timing processes have been implicated as potential mechanisms that underlie self controlled choice. To investigate the impact of an intervention that has been shown to increase self-controlled choice on timing processes, accuracy and precision of temporal discrimination were assessed in an 18-s peak procedure (18 s fixed interval trials; 54-s peak trials). During an intervention phase, mice in three treatment groups experienced differential reinforcement of low rate (DRL) schedules of reinforcement of 27 s, 18 s, or 9 s. A fourth group received continued exposure to the peak procedure. After the DRL intervention, timing was reassessed using the peak procedure. In contrast to previous reports, the DRL intervention resulted in less precise timing as indicated by increased peak spread and disrupted single-trial measures of temporal control. These effects were only detected just after the DRL intervention suggesting a transient effect of DRL exposure on timing. The increase in peak spread in the present experiment suggests delay exposure via DRL schedules may produce a "dose-dependent" effect on temporal discrimination, which may also increase self-controlled choice. PMID- 29608944 TI - Previous Early-life Stress Modifies Acute Corticosterone-induced Synaptic Plasticity in the Medial Prefrontal Cortex of Adolescent Rats. AB - Stress can either strengthen coping strategies or enhance the risk of depression and anxiety. Synaptic plasticity is one of the key brain functions that can be affected by stress. We have previously shown that early-life stress in the form of maternal separation (MS) impairs functional synaptic plasticity in the medial prefrontal cortex (mPFC), i.e., long-term potentiation (LTP), in adolescent rats. It has been postulated that a previous experience of prolonged stress can modify the response to a subsequent acute stress challenge and influence coping strategies. Therefore, in the present study, we examined how previous MS experience influenced acute stress-induced changes in the LTP and expression of genes and proteins engaged in synaptic plasticity in the mPFC of adolescent rats. To mimic acute stress, we applied acute injections of corticosterone (CORT) and its vehicle (VEH). In control rats, acute CORT injection enhanced LTP in the mPFC. In contrast, MS rats generally exhibited an impairment of LTP that was not further affected by CORT. Moreover, for many studied parameters, such as induction of cFos and Arc mRNA and protein and activation of BDNF, GDNF and NCAM mRNA, MS rats showed diminished, vague or absent responses to acute VEH/CORT compared with those of control rats. These results suggest that previous early life stress experiences may induce adaptive plasticity within the mPFC, which influences the response to acute stress challenge and coping strategies in adolescents. Depending on the specific environmental context, this phenomenon may lead to either future vulnerability or future resilience to stress-related psychopathologies. PMID- 29608945 TI - Phase-specific Surround suppression in Mouse Primary Visual Cortex Correlates with Figure Detection Behavior Based on Phase Discontinuity. AB - In the primary visual cortex (V1), neuronal responses to stimuli within the receptive field (RF) are modulated by stimuli in the RF surround. A common effect of surround modulation is surround suppression, which is dependent on the feature difference between stimuli within and surround the RF and is suggested to be involved in the perceptual phenomenon of figure-ground segregation. In this study, we examined the relationship between feature-specific surround suppression of V1 neurons and figure detection behavior based on figure-ground feature difference. We trained freely moving mice to perform a figure detection task using figure and ground gratings that differed in spatial phase. The performance of figure detection increased with the figure-ground phase difference, and was modulated by stimulus contrast. Electrophysiological recordings from V1 in head fixed mice showed that the increase in phase difference between stimuli within and surround the RF caused a reduction in surround suppression, which was associated with an increase in V1 neural discrimination between stimuli with and without RF-surround phase difference. Consistent with the behavioral performance, the sensitivity of V1 neurons to RF-surround phase difference could be influenced by stimulus contrast. Furthermore, inhibiting V1 by optogenetically activating either parvalbumin (PV)- or somatostatin (SOM)-expressing inhibitory neurons both decreased the behavioral performance of figure detection. Thus, the phase specific surround suppression in V1 represents a neural correlate of figure detection behavior based on figure-ground phase discontinuity. PMID- 29608946 TI - Phytoestrogens and mycoestrogens interacting with breast cancer proteins. AB - Breast cancer is a highly heterogeneous disease influenced by the hormonal microenvironment and the most common malignancy in women worldwide. Some phytoestrogens and mycoestrogens have been epidemiologically linked as risk factors or protectors, however their mechanisms of action are complex and not fully understood. The aim of this study was to predict the potential of 36 natural xenoestrogens to interact with 189 breast cancer proteins using AutoDock Vina. In order to validate our protocol, an in silico docking pose and binding site determination was compared with the crystallographic structure and the power of prediction to distinguish between ligand and decoys was evaluated through a receiver operating characteristic curve (ROC) of the resultant docking affinities and in vitro data. The best affinity score was obtained for glyceollin III interacting with the sex hormone binding globulin (-11.9 Kcal/mol), a plasma steroid transport protein that regulates sex steroids bioavailability. Other natural xenoestrogens such as beta-carotene, chrysophanol 8-O-beta-d glucopyranoside and glyceollin I, also presented good affinity for proteins related to this disease and the validation was successful. This study may help to prioritize compounds for toxicity tests or drug development from natural scaffolds, and to elucidate their mechanisms of action. PMID- 29608947 TI - Microencapsulated Schwann cell transplantation inhibits P2X2/3 receptors overexpression in a sciatic nerve injury rat model with neuropathic pain. AB - Transplantation of Schwann cells (SCs) can promote axonal regeneration and formation of the myelin sheath, reduce inflammation, and promote repair to the damaged nerve. Our previous studies have shown that transplantation of free or micro-encapsulated olfactory ensheathing cells can relieve neuropathic pain. There are no related reports regarding whether the transplantation of micro encapsulated SCs can alleviate neuropathic pain mediated by P2X2/3 receptors. In the present study, we micro-encapsulated SCs in alginic acid and transplanted them into the region surrounding the injured sciatic nerve in the rat model of chronic constriction injury (CCI). The mechanical withdrawal threshold and thermal withdrawal latency were measured to assess changes in behavior 14 days after the surgery in CCI model rats. Ultrastructural changes in the injured sciatic nerve were assessed using transmission electron microscopy. Co-expression of P2X2/3 receptors with other markers in neurons in the L4-5 dorsal root ganglia (DRG) were assessed using double-label immunofluorescence 14 days after surgery. We determined P2X2/3 mRNA expression and protein level changes in the DRG using quantitative real-time polymerase change reaction technology and Western blotting analysis. We have investigated that the transplantation of micro-encapsulated SCs can alleviate pathological pain caused by P2X2/3 receptor stimulation and explored new methods for the prevention and treatment of neuropathic pain. PMID- 29608948 TI - MiR-181b regulates autophagy in a model of Parkinson's disease by targeting the PTEN/Akt/mTOR signaling pathway. AB - OBJECTIVE: Parkinson's disease (PD) is the second most common neurodegenerative disease. Recent studies have shown that dysregulation of microRNA plays an important role in PD, and defects in autophagy are also critically associated with mechanisms underlying PD. We aim to investigate the effect of miR-181b on autophagy, particularly the involvement of miR-181b in the regulation of the phosphatase and tensin homolog (PTEN)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) pathway and neuronal autophagy in a 1-methyl-4- phenylpyridinium iodide(MPP+)-induced cellular model of Parkinson's disease. MATERIALS AND METHODS: We used MPP+ as a tool to construct the PD cell model, using miR-181b mimics or inhibitors to regulate the expression of miR-181b. PC12 cell viability was detected by MTT. The expression of miR-181b was determined by quantitative real-time PCR analysis. The expression of autophagy protein markers (LC3II) and PTEN/Akt/mTOR signaling proteins (PTEN, p-AKT,p-mTOR and p-p70S6K) were determined by Western blotting analysis. RESULTS: The expression of miR-181b and autophagy-related proteins was gradually decreased with increasing MPP+ content. Overexpression of miR-181b significantly decreased the LC3II/GAPDH ratio and increased cell viability compared to the MPP+ treated group, whereas inhibition of miR-181b attenuated these effects. In addition, we observed that PTEN expression was reduced by miR-181b mimics and induced by its inhibitors in MPP+ treated PC12 cells. Additionally, the indicators of AKT/mTOR signaling, phosphorylated (active) AKT, mTOR and p70S6K were both increased by miR-181b mimics and decreased by its inhibitors. CONCLUSIONS: Our results suggest that miR 181b regulates autophagy by targeting the PTEN/Akt/mTOR signaling pathway, thereby affecting cell viability in PD. PMID- 29608949 TI - Recent advances on production of 2, 3-butanediol using engineered microbes. AB - As a significant platform chemical, 2, 3-butanediol (2, 3-BD) has found wide applications in industry. The success of microbial 2, 3-BD production was limited by the use of pathogenic microorganisms and low titer in engineered hosts. The utilization of cheaply available feedstock such as lignocellulose was another major challenge to achieve economic production of 2, 3-BD. To address those issues, engineering strategies including both genetic modifications and process optimization have been employed. In this review, we summarized the state-of-the art progress in the biotechnological production of 2, 3-BD. Metabolic engineering and process engineering strategies were discussed. PMID- 29608950 TI - Process engineering for microbial production of 3-hydroxypropionic acid. AB - Due to concerns about the unsustainability and predictable shortage of fossil feedstocks, research efforts are currently being made to develop new processes for production of commodities using alternative feedstocks. 3-Hydroxypropionic acid (CAS 503-66-2) was recognised by the US Department of Energy as one of the most promising value-added chemicals that can be obtained from biomass. This article aims at reviewing the various strategies implemented thus far for 3 hydroxypropionic acid bioproduction. Special attention is given here to process engineering issues. The variety of possible metabolic pathways is also described in order to highlight how process design can be guided by their understanding. The most recent advances are described here in order to draw up a panorama of microbial 3-hydroxypropionic acid production: best performances to date, remaining hurdles and foreseeable developments. Important milestones have been achieved, and process metrics are getting closer to commercial relevance. New strategies are continuously being developed that involve new microbial strains, new technologies, or new carbon sources in order to overcome the various hurdles inherent to the different microbial routes. PMID- 29608952 TI - LncRNA UCA1 inhibits epilepsy and seizure-induced brain injury by regulating miR 495/Nrf2-ARE signal pathway. AB - BACKGROUND: Both LncRNA UCA1 and miR-495 are crucial gene regulators in various disorders. This study aims to investigate their role in epilepsy and seizure induced brain injury. METHODS: In this research, rat model of epilepsy was established by pilocarpine induction. The RNA and protein expression in hippocampal tissues and neurons were determined by qRT-PCR and western blot, respectively. The hippocampal neurons were isolated from hippocampal tissues, and treated with magnesium-free (MGF) physiological solution for epileptiform activity induction. The endogenous expression of related genes was modulated by recombinant plasmids and cell transfection. Flow cytometry was used to analyze the cell apoptosis. Dual luciferase reporter assay was performed to determine the interaction between miR-495 and Nrf2 in HEK-293 cells. RESULTS: The lncRNA UCA1 and Nrf2 were down-regulated in epileptiform hippocampal tissues and neurons, while the miR-495 was up-regulated. Over-expression of UCA1 inhibited apoptosis of hippocampal neurons by suppressing miR-495. MiR-495 negatively regulated Nrf2. UCA1 inhibited apoptosis of hippocampal neurons through miR-495/Nrf2-ARE pathway. UCA1 suppressed pilocarpine-induced epilepsy in rat. CONCLUSION: LncRNA UCA1 suppressed pilocarpine-induced epilepsy by inhibiting apoptosis of hippocampal neurons through miR-495/Nrf2-ARE pathway, and thereby inhibiting brain injury induced by seizure. PMID- 29608951 TI - Aspergillus-specific antibodies - Targets and applications. AB - Aspergillus is a fungal genus comprising several hundred species, many of which can damage the health of plants, animals and humans by direct infection and/or due to the production of toxic secondary metabolites known as mycotoxins. Aspergillus-specific antibodies have been generated against polypeptides, polysaccharides and secondary metabolites found in the cell wall or secretions, and these can be used to detect and monitor infections or to quantify mycotoxin contamination in food and feed. However, most Aspergillus-specific antibodies are generated against heterogeneous antigen preparations and the specific target remains unknown. Target identification is important because this can help to characterize fungal morphology, confirm host penetration by opportunistic pathogens, detect specific disease-related biomarkers, identify new candidate targets for antifungal drug design, and qualify antibodies for diagnostic and therapeutic applications. In this review, we discuss how antibodies are raised against heterogeneous Aspergillus antigen preparations and how they can be characterized, focusing on strategies to identify their specific antigens and epitopes. We also discuss the therapeutic, diagnostic and biotechnological applications of Aspergillus-specific antibodies. PMID- 29608953 TI - Training memory without aversion: Appetitive hole-board spatial learning increases adult hippocampal neurogenesis. AB - Learning experiences are potent modulators of adult hippocampal neurogenesis (AHN). However, the vast majority of findings on the learning-induced regulation of AHN derive from aversively-motivated tasks, mainly the water maze paradigm, in which stress is a confounding factor that affects the AHN outcome. Currently, little is known regarding the effect of appetitively-motivated training on AHN. Hence we studied how spatial learning to find food rewards in a hole-board maze modulates AHN (cell proliferation and immature neurons) and AHN-related hippocampal neuroplasticity markers (BDNF, IGF-II and CREB phosphorylation) in mice. The 'Trained' mice were tested for both spatial reference and working memory and compared to 'Pseudotrained' mice (exposed to different baited holes in each session, thus avoiding the reference memory component of the task) and 'Control' mice (exposed to the maze without rewards). In contrast to Pseudotrained and Control mice, the number of proliferating hippocampal cells were reduced in Trained mice, but they notably increased their population of immature neurons assessed by immunohistochemistry. This evidence shows that hole board spatial reference learning diminishes cell proliferation in favor of enhancing young neurons' survival. Interestingly, the enhanced AHN in the Trained mice (specifically in the suprapyramidal blade) positively correlated with their reference memory performance, but not with their working memory. Furthermore, the Trained animals increased the hippocampal protein expression of all the neuroplasticity markers analyzed by western blot. Results show that the appetitively-motivated hole-board task is a useful paradigm to potentiate and/or investigate AHN and hippocampal plasticity minimizing aversive variables such as fear or stress. PMID- 29608954 TI - Hybrid nanoparticles as a new technological approach to enhance the delivery of cholesterol into the brain. AB - Restoration of the Chol homeostasis in the Central Nervous System (CNS) could be beneficial for the treatment of Huntington's Disease (HD), a progressive, fatal, adult-onset, neurodegenerative disorder. Unfortunately, Chol is unable to cross the blood-brain barrier (BBB), thus a novel strategy for a targeted delivery of Chol into the brain is highly desired. This article aims to investigate the production of hybrid nanoparticles composed by Chol and PLGA (MIX-NPs) modified with g7 ligand for BBB crossing. We described the impact of ratio between components (Chol and PLGA) and formulation process (nanoprecipitation or single emulsion process) on physico-chemical and structural characteristics, we tested MIX-NPs in vitro using primary hippocampal cell cultures evaluating possible toxicity, uptake, and the ability to influence excitatory synaptic receptors. Our results elucidated that both formulation processes produce MIX-NPs with a Chol content higher that 40%, meaning that Chol is a structural particle component and active compound at the same time. The formulation strategy impacted the architecture and reorganization of components leading to some differences in Chol availability between the two types of g7 MIX-NPs. Our results identified that both kinds of MIX-NPs are efficiently taken up by neurons, able to escape lysosomes and release Chol into the cells resulting in an efficient modification in expression of synaptic receptors that could be beneficial in HD. PMID- 29608955 TI - Pseudomonas aeruginosa pyocyanin production reduced by quorum-sensing inhibiting nanocarriers. AB - Pseudomonas aeruginosa is an opportunistic gram-negative pathogen that causes a wide range of infections; it is becoming increasingly difficult to treat due to antibiotic resistance. Quorum-sensing (QS) based therapeutics, which function by disabling pathogen virulence without killing pathogens, are a promising class of drugs that may be used to treat bacterial infections without eliciting resistance development. The use of QS drugs to treat pulmonary P. aeruginosa infections, however, has been greatly limited due to the inability to deliver QS drugs at sufficiently high concentrations past physiological barriers such as pulmonary mucus. Here we apply a block copolymer-directed self-assembly process, Flash NanoPrecipitation, to develop a series of QS-active formulations that are fully water dispersible, stable, and mucus-penetrating. These formulations inhibit P. aeruginosa virulence without inhibiting cell growth. Particle size (70 nm-400 nm) and release rate (1 h-14 days) can be tuned by altering constructs' physical properties and formulation excipients. We also demonstrate, to the best of our knowledge, the first instance of a QS nanocarrier platform technology that can penetrate through human cystic fibrosis pulmonary mucus. This work highlights the need to incorporate nanoformulation strategies into the development of next generation antimicrobial therapeutics. PMID- 29608956 TI - Detection and validation of EST-SSR markers associated with sugar-related traits in sugarcane using linkage and association mapping. AB - Sugar-related traits are of great importance in sugarcane breeding. In the present study, quantitative trait loci (QTL) mapping validated with association mapping was used to identify expressed sequence tag-simple sequence repeats (EST SSRs) associated with sugar-related traits. For linkage mapping, 524 EST-SSRs, 241 Amplified Fragment Length Polymorphisms, and 10 genomic SSR markers were mapped using 283 F1 progenies derived from an interspecific cross. Six regions were identified using Multiple QTL Mapping, and 14 unlinked markers using single marker analysis. Association analysis was performed on a set of 200 accessions, based on the mixed linear model. Validation of the EST-SSR markers using association mapping within the target QTL genomic regions identified two EST-SSR markers showing a putative relationship with uridine diphosphate (UDP) glycosyltransferase, and beta-amylase, which are associated with pol and sugar yield. These functional markers can be used for marker-assisted selection of sugarcane. PMID- 29608957 TI - ASBMT Practice Guidelines Committee Survey on Long-Term Follow-Up Clinics for Hematopoietic Cell Transplant Survivors. AB - Significant advances in hematopoietic cell transplantation (HCT) have increased the long-term survivorship of its recipients, but because of unique complications arising from radiation and chemotherapy, recipients require lifelong follow-up. To evaluate current survivorship or long-term follow-up (LTFU) clinics specifically for HCT survivors and to evaluate the potential barriers in their establishment, the American Society for Blood and Marrow Transplantation (ASBMT) Practice Guidelines Committee electronically surveyed 200 HCT programs to gather quantitative and qualitative data about models of care. Among 77 programs (38.5%) that responded, 45% indicated presence of an LTFU clinic; however, LTFU care models varied with respect to services provided, specialist availability, type of patients served, and staffing. Among 55% of programs without an LTFU clinic, 100% agreed that allogeneic HCT survivors have unique needs separate from graft-versus host disease and that complications could arise during the transition of care either from pediatric to adult settings or away from the HCT center. Lack of expertise, logistics, financial issues, and the observation that 84% of individual practitioners prefer to provide survivorship care were the identified obstacles to establishing new LTFU clinics. The ASBMT hopes that policymakers, HCT providers, and institutions will benefit from the results of this survey and recommends that delivering guidelines-driven screening and expert management of late effects is the goal of first-rate HCT survivorship care. PMID- 29608958 TI - Point prevalence surveys of antimicrobial use among eight neonatal intensive care units in India: 2016. AB - BACKGROUND: Information about antimicrobial use is scarce and poorly understood among neonatal intensive care units (NICUs) in India. In this study, we describe antimicrobial use in eight NICUs using four point prevalence surveys (PPSs). METHODS: As part of the Global Antimicrobial Resistance, Prescribing, and Efficacy in Neonates and Children (GARPEC) study, one-day, cross-sectional, hospital-based PPSs were conducted four times between 1 February 2016 and 28 February 2017 in eight NICUs. Using a standardized web-based electronic data entry form, detailed data were collected for babies on antimicrobials. RESULTS: A total of 403 babies were admitted to NICUs across all survey days, and 208 (51.6%) were prescribed one or more antimicrobials. Among 208 babies, 155 (74.5%) were prescribed antimicrobials for treatment of an active infection. Among 155 babies with an active infection, treatment was empiric in 109 (70.3%). Sepsis (108, 49.1%) was the most common reason for prescribing antimicrobials. Amikacin (17%) followed by meropenem (12%) were the two most commonly prescribed antimicrobials. For community-acquired sepsis, piperacillin-tazobactam (17.5%) was the most commonly prescribed drug. A combination of ampicillin and gentamicin was prescribed in only two babies (5%). CONCLUSIONS: The recommended first-line antimicrobial agents, ampicillin and gentamicin, were rarely prescribed in Indian NICUs for community acquired neonatal sepsis. PMID- 29608959 TI - Clinical diagnostic and therapeutic aspects of 221 consecutive anorectal Chlamydia trachomatis and Neisseria gonorrhoeae sexually transmitted infections among men who have sex with men. AB - OBJECTIVES: Proctitis caused by Chlamydia trachomatis (CT) and Neisseria gonorrhoeae (NG) are known as sexually transmitted infections (STI). This study describes their clinical, diagnostic and therapeutic aspects. METHODS: Between 01/2013-03/2015, all MSM consulting for proctitis at proctology Institute-Saint Joseph's Hospital, Paris, were included. Demographic, past-medical history, STI status and medical treatment were collected. Detection of CT/NG was performed by Transcription-Mediated Amplification (TMA) and antimicrobial susceptibilities for Ng by agar diffusion method. RESULTS: On 441 rectal samples collected, 221 (50.1%) were positive: 109 Ct (49.3%), 70 Ng (31.7%), 42 positive for both etiologies (19%). Among Ng infections, no resistance was detected to azithromycin and ceftriaxone. However, 84 strains (43.2%) were resistant to fluoroquinolones. More than one episode was diagnosed for 10 (5.1%) and 12 (6.2%) patients with CT and NG infections respectively. Anal abscesses were found for 27 (13.9%) patients, and 14 (7.2%) of them underwent surgery for anal fistula. CONCLUSIONS: The prevalence of CT/NG anorectal infections described is high on symptomatic patients, and a significant level of abscess was reported. These results confirm the interest of the association of recommended antibiotics excluding quinolones. Prospective studies would be relevant on complicated forms of anorectal infections. PMID- 29608960 TI - Update on the main use of biomaterials and techniques associated with tissue engineering. AB - Regenerative medicine involves the study of cells, signaling cues and biomatrices to restore normal function of tissues and organs. To develop the matrices for use in tissue engineering there are three main groups of biomaterials: (i) naturally derived materials; (ii) synthetic polymers; and (iii) decellularized organ or tissue scaffolds. These biomaterials, in various forms such as hydrogels, nanofibers and 3D scaffolds, among others, have been employed for different tissue regeneration purposes, with several techniques involved in their production, including rapid prototyping, tissue decellularization and electrospinning. In this review, the main topics of hydrogels, 3D printing and electrospun scaffolds, other biomaterials and decellularization and recellularization will be discussed. PMID- 29608961 TI - Genetic diversity analysis of Blastocystis subtypes from both symptomatic and asymptomatic subjects using a barcoding region from the 18S rRNA gene. AB - Blastocystis is the most prevalent protozoa found in human stool samples. This study aimed to evaluate genetic diversity among Blastocystis subtypes isolated from both symptomatic and asymptomatic subjects as well as the potential correlation between subtypes and symptoms. A total of 55 Blastocystis-positive isolates were included in this study. A barcoding region of the small subunit rDNA was amplified and genetically assessed using MEGA6 and DnaSP regarding the presence of symptoms. BLAST analyses revealed the presence of 5 different subtypes (ST1, ST2, ST3, ST6 and ST7) among the samples. ST3 was the most prevalent subtype (25/55, 45%) while only one ST7 isolate was detected. Moreover, alleles 4 and 86 for ST1; alleles 9, 11 and 12 for ST2; alleles 31, 34, 36, 37 and 52 for ST3; allele 122 for ST6 and allele 137 for ST7 were detected. No statistically significant association was found between gender and symptoms with certain subtypes. Analysis of the intra-subtype variability in both symptomatic and asymptomatic subjects revealed highest similarity among ST1 isolates while lowest similarity was seen among ST3 isolates. Neutrality indices, Tajima's D and Fu's Fs, were negative but only statistically significant for ST3. Furthermore, highest values of Hd, pi and S were observed among ST1, ST2 and ST3 isolated from symptomatic patients indicating high level of diversity among isolates obtained from these subjects. In addition, inter-subtype analysis showed the highest similarity between ST1 and ST2 isolates and the lowest similarity between ST2 and ST7 isolates. This is the first study revealing the presence of both ST6 and ST7 isolates in human from Iran. Phylogenetic analysis did not suggest any significant correlation between clinical manifestations and certain subtypes although genetic analysis showed highest value of diversity and significant neutrality indices among ST3 isolates obtained from symptomatic patients. PMID- 29608962 TI - Molecular phylogenetics supports the origin of an endemic Balearic shrew lineage (Nesiotites) coincident with the Messinian Salinity Crisis. AB - The red-toothed shrews (Soricinae) are the most widespread subfamily of shrews, distributed from northern South America to North America and Eurasia. Within this subfamily, the tribe Nectogalini includes the fossil species Nesiotites hidalgo recorded from the Late Pleistocene to Holocene of the Balearic Islands (Western Mediterranean). Although there is a consensus about the close relationship between the extinct red-toothed shrew genera Nesiotites and Asoriculus based on morphology, molecular data are necessary to further evaluate the phylogenetic relationships of the Balearic fossils. We obtained a near complete mitochondrial genome of N. hidalgo, allowing the first molecular phylogenetic analysis of this species. Analyses based on 15,167 bp of the mitochondrial genome placed N. hidalgo as close relative to the extant Himalayan shrew (Soriculus nigrescens), and a combined analysis using molecular and morphological data confirm that N. hidalgo and Asoriculus gibberodon are sister-taxa with S. nigrescens as the immediate outgroup. Molecular clock and divergence estimates suggest that the split between N. hidalgo and its closest living relative occurred around 6.44 Ma, which is in agreement with the previously proposed colonisation of the Balearic Islands from mainland Europe by nectogaline shrews during the Messinian Salinity Crisis (5.97-5.33 My ago). Our results highlight that it is possible to retrieve genetic data from extinct small mammals from marginal environments for DNA preservation. Additional finds from the fossil record of Soricinae from the Eurasian Late Miocene/Early Pliocene are needed to shed further light on the still confusing taxonomy and paleobiogeography of this clade. PMID- 29608963 TI - Inconsistent high sensitivity troponin T and I measurements in a patient with rheumatoid arthritis. PMID- 29608964 TI - Purification of membrane proteins free from conventional detergents: SMA, new polymers, new opportunities and new insights. AB - Membrane proteins remain a somewhat enigmatic group of biomolecules. On the one hand they mediate some of the most important processes in biology with molecular mechanisms that are often elegantly complex. On the other hand they are exceptionally challenging to produce, making studies of membrane protein structure and function among the most difficult projects undertaken by biochemists. The central issue with studies of a membrane protein has been the need to extract them from their native lipid environment before purification and production of a homogenous sample. Historical approaches have utilized detergent solubilisation but these often lead to a sample with low activity and stability. In the past 15 years a new approach that focuses on preserving the local lipid environment surrounding the membrane proteins has been developed. The latest, and perhaps most complete, incarnation of this method has been the use of polymers based on styrene maleic acid (SMA) to stabilise nanoscale discs of lipid that contain membrane proteins. In this review we examine the range of SMA-related polymers that have now been shown to have utility in the production of membrane proteins. We discuss the differences between the polymers and attempt to discover rules and trends that explain their behavior. PMID- 29608965 TI - Peak decay analysis and biointeraction studies of immunoglobulin binding and dissociation on protein G affinity microcolumns. AB - Protein G can be a valuable binding agent for antibodies and immunoglobulins in methods such as immunosensors, chromatographic-based immunoassays, and immunoaffinity chromatography. This report used the method of peak decay analysis along with frontal analysis and zonal elution studies to characterize the binding, elution and regeneration properties of affinity microcolumns that contained immobilized protein G. Frontal analysis was employed with rabbit immunoglobulin G (IgG) to characterize the binding capacity of these affinity microcolumns. Zonal elution experiments looking at the retained peaks for small injections of labeled rabbit IgG were used to optimize the column regeneration conditions. Peak decay analysis was then used to look at the effects of flow rate and elution pH on the release of several types of IgG from the protein G microcolumns. This approach made it possible to obtain detailed information on the use and behavior of such columns, as could be used in future work to optimize the capture or analysis of IgG and antibodies by such devices. The same approach and tools that were used in this report could also be adapted for work with affinity columns that make use of other supports, binding agents or targets. PMID- 29608966 TI - Re: The impact of antibiotics on the Intestinal microbiota needs to be re-defined in order to optimize the antibiotic usage; by Ruppe et al. PMID- 29608968 TI - Next-Generation Sequencing Assisted in Establishing the Diagnosis and Treatment for a Chinese Patient With Breast and Lung Multiple Primary Malignancies. PMID- 29608969 TI - Apps from the World Health Organization - The World Malaria Report and more. PMID- 29608967 TI - Time-to-Treatment-Failure and Related Outcomes Among 1000+ Advanced Non-Small Cell Lung Cancer Patients: Comparisons Between Older Versus Younger Patients (Alliance A151711). AB - INTRODUCTION: Time-to-treatment-failure (TTF) is the interval from chemotherapy initiation to premature discontinuation. We evaluated TTF based on age. METHODS: Pooled analyses were conducted with first-line chemotherapy trials for advanced NSCLC (CALGB 9730, 30203, and 30801). Comparisons among patients who were 65 years and older and 70 years and older were performed for TTF (primary endpoint), reasons for early chemotherapy cessation, grade 3+ adverse events, and overall survival. RESULTS: Among 1006 patients, 460 (46%) were older than 65 years of age. One hundred forty-five older patients (32% of this age cohort) completed all six planned chemotherapy cycles as did 170 (32%) younger patients. Median TTF was 2.9 months (95% confidence interval: 2.7- 3.2) in older patients and 3 months (95% confidence interval: 2.9-3.5) in younger patients; adjustment for performance status and stratification by chemotherapy by trial yielded no statistically significant age-based difference in TTF. However, reasons for early chemotherapy cessation differed between age groups (multivariate p = 0.004). Older patients were less likely to discontinue from cancer progression (41% versus 55%) and more likely from toxicity or patient choice (16% and 15%, respectively) compared to younger patients (13% and 6%, respectively). Older patients were more likely to experience grade 3+ adverse events (86% versus 79%) with no statistically significant difference in survival. An age cutpoint of 70+ years showed no difference in TTF, a lower trend of early cessation due to cancer progression, and somewhat shorter older patient survival. CONCLUSIONS: TTF was comparable between older and younger patients; but different, age-based, and potentially modifiable reasons account for it. PMID- 29608970 TI - Characterization of Vibrio cholerae neuraminidase as an immunomodulator for novel formulation of oral allergy immunotherapy. AB - To improve current mucosal allergen immunotherapy Vibrio cholerae neuraminidase (NA) was evaluated as a novel epithelial targeting molecule for functionalization of allergen-loaded, poly(D,L-lactide-co-glycolide) (PLGA) microparticles (MPs) and compared to the previously described epithelial targeting lectins wheat germ agglutinin (WGA) and Aleuria aurantia lectin (AAL). All targeters revealed binding to Caco-2 cells, but only NA had high binding specificity to alpha-L fucose and monosialoganglioside-1. An increased transepithelial uptake was found for NA-MPs in a M-cell co-culture model. NA and NA-MPs induced high levels of IFN gamma and IL10 in naive mouse splenocytes and CCL20 expression in Caco-2. Repeated oral gavage of NA-MPs resulted in a modulated, allergen-specific immune response. In conclusion, NA has enhanced M-cell specificity compared to the other targeters. NA functionalized MPs induce a Th1 and T-regulatory driven immune response and avoid allergy effector cell activation. Therefore, it is a promising novel, orally applied formula for allergy therapy. PMID- 29608971 TI - More intensive CMV-infection in chronic heart failure patients contributes to higher T-lymphocyte differentiation degree. AB - Immunosenescence in chronic heart failure (CHF) is characterized by a high frequency of differentiated T-lymphocytes, contributing to an inflammatory status and a deficient ability to generate immunocompetent responses. CMV is the best known inducer of T-lymphocyte differentiation, and is associated with the phenomenon of immunosenescence. In this study, we included 58 elderly chronic heart failure patients (ECHF), 60 healthy elderly controls (HEC), 40 young chronic heart failure patients (YCHF) and 40 healthy young controls (HYC). High differentiation of CD8+ T-lymphocytes was found in CMV-seropositive patients; however, the differentiation of CD4+ T-lymphocytes was increased in CMV seropositive but also in CHF patients. Anti-CMV antibody titers showed positive correlation with more differentiated CD4+ and CD8+ subsets and inverse correlation with CD4/CD8 ratio. Immunosenescence found in CHF patients is mainly due to the dynamics of CMV-infection, since the differentiation of T-lymphocyte subsets is related not only to CMV-infection, but also to anti-CMV antibody titers. PMID- 29608972 TI - Alternative methodological approach to randomized trial for surgical procedures routinely used. AB - BACKGROUND: In medical oncology, changes in practices are almost always based on randomized trials but medical history shows that it is different in surgical oncology. In the past, many surgical procedures were routinely performed without a rigorous evaluation of the risk-benefit. To highlight the complexity of developing randomized surgical trials, disquisitions on methodology presented in the medical literature. This is particularly true when we consider breast reconstruction after surgical treatment for breast cancer. It is illusory to perform and conduct a randomized clinical trial (RCT) when a surgical procedure is routinely used by most surgeons. METHODS: As a case study, we present the scientific rationale and the design of the MAPAM01 trial which evaluates the security of the nipple sparing mastectomy. Other alternative approaches, such as propensity score and CUSUM, are presented. RESULTS: In this situation, to design surgical trials using alternative methodological approaches present a particularly important challenge both for surgeons and methodologists. Alternative approach to randomized trials can be useful to evaluate surgical procedures routinely used. CONCLUSION: Close collaboration between surgeons and methodologists is needed to propose appropriate and well-designed surgical trials. PMID- 29608973 TI - Health Care Utilization and Costs Associated With Pediatric Chronic Pain. AB - : The population prevalence of pediatric chronic pain is not well characterized, in part because of a lack of nationally representative data. Previous research suggests that pediatric chronic pain prolongs inpatient stay and increases costs, but the population-level association between pediatric chronic pain and health care utilization is unclear. We use the 2016 National Survey of Children's Health to describe the prevalence of pediatric chronic pain, and compare health care utilization among children ages 0 to 17 years according to the presence of chronic pain. Using a sample of 43,712 children, we estimate the population prevalence of chronic pain to be 6%. In multivariable analysis, chronic pain was not associated with increased odds of primary care or mental health care use, but was associated with greater odds of using other specialty care (odds ratio [OR] = 2.01, 95% confidence interval [CI] = 1.62-2.47; P < .001), complementary and alternative medicine (OR = 2.32, 95% CI = 1.79-3.03; P < .001), and emergency care (OR = 1.62, 95% CI = 1.29-2.02; P < .001). In this population-based survey, children with chronic pain were more likely to use specialty care but not mental health care. The higher likelihood of emergency care use in this group raises the question of whether better management of pediatric chronic pain could reduce emergency department use. PERSPECTIVE: Among children with chronic pain, we show high rates of use of emergency care but limited use of mental health care, which may suggest opportunities to increase multidisciplinary treatment of chronic pain. PMID- 29608975 TI - Chonopeltis australis (Crustacea: Branchiura); the female reproductive system. AB - The female reproductive system has been described for Dolops ranarum (Stuhlman, 1891) and various Argulus spp. but, there is no description of the reproductive system for Dipteropeltis spp. Calman, 1912 or Chonopeltis spp. Thiele, 1900. This paper describes the female reproductive system and egg laying behaviour of Chonopeltisaustralis Boxshall, 1976 using histology, light microscopy, scanning electron microscopy and observations. The histological study of six specimens showed that the organ structure is similar to that of Argulus spp. and D. ranarum. The oocytes therefore develop in the gonocoel, are ovulated into the lumen of the ovary which is continuous with the functional oviduct and eventually the gonopore. Females of C. australis deposit eggs on the surrounding substrate while the fish is at rest, without leaving the host, thereby mitigating the risk of not locating a host again. PMID- 29608976 TI - Respiratory muscles stretching acutely increases expansion in hemiparetic chest wall. AB - : Individuals post-stroke may present restrictive ventilatory pattern generated from changes in the functionality of respiratory system due to muscle spasticity and contractures. Objective was to assess the acute effects after respiratory muscle stretching on the ventilatory pattern and volume distribution of the chest wall in stroke subjects. Ten volunteers with right hemiparesis after stroke and a mean age of 60 +/- 5.7 years were randomised into the following interventions: respiratory muscle stretching and at rest (control). The ventilatory pattern and chest wall volume distribution were evaluated through optoelectronic plethysmography before and immediately after each intervention. Respiratory muscle stretching promoted a significant acute increase of 120 mL in tidal volume, with an increase in minute ventilation, mean inspiratory flow and mean expiratory flow compared with the control group. Pulmonary ribcage increased 50 mL after stretching, with 30 mL of contribution to the right pulmonary rib cage (hemiparetic side) in comparison to the control group. Respiratory muscle stretching in patients with right hemiparesis post-stroke demonstrated that acute effects improve the expansion of the respiratory system during tidal breathing. CLINICAL TRIAL REGISTRATION: NCT02416349 (URL: https://clinicaltrials.gov/ct2/show/ NCT02416349). PMID- 29608977 TI - Ethnic differences in antepartum glucose values that predict postpartum dysglycemia and neonatal macrosomia. AB - BACKGROUND AND OBJECTIVE: Gestational diabetes (GDM) occurs more often in women from certain ethnic groups and is also associated with fetal macrosomia. In this study, we investigated the ability of a gestational diabetes screening test (GDS), the 2 h 75 g-Oral Glucose Tolerance Test (OGTT), and glycated hemoglobin (HbA1c) in predicting postpartum dysglycemia and fetal macrosomia in women of Caucasian, Filipino, Chinese and South-Asian descent. METHODS: 848 women diagnosed with carbohydrate intolerance in pregnancy who completed a 2 h 75 g- OGTT within 6 months postpartum, were included in the study. Receiver Operating Characteristic curve analysis was used to test the ability of antepartum GDS, HbA1c and OGTT in predicting postpartum hyperglycemia, type 2 diabetes (T2D) and neonatal macrosomia (birth weight >4000 g). RESULTS: 20.2% had postpartum hyperglycemia while 3.8% had T2D. Those with postpartum dysglycemia were more likely to be non-Caucasian (South-Asian > Filipino > Chinese), have higher antepartum glucose values, require insulin during pregnancy and have cesarean births. Of HbA1c and the antepartum glucose values, a fasting glucose of >=5.25 mmol/L was predictive of fetal macrosomia in Caucasians. 1 h glucose of >=11.05 mmol/L was predictive of postpartum hyperglycemia, while 2 h glucose of >=9.75 mmol/L was predictive of T2D; ethnicity influenced the predictive ability of these tests. CONCLUSIONS: Ethnicity influences the ability of antepartum glucose and HbA1c to predict the risk of macrosomia and postpartum dysglycemia. This information will help detect those most at risk of T2D. PMID- 29608974 TI - Pain Neuroimaging in Humans: A Primer for Beginners and Non-Imagers. AB - : Human pain neuroimaging has exploded in the past 2 decades. During this time, the broader neuroimaging community has continued to investigate and refine methods. Another key to progress is exchange with clinicians and pain scientists working with other model systems and approaches. These collaborative efforts require that non-imagers be able to evaluate and assess the evidence provided in these reports. Likewise, new trainees must design rigorous and reliable pain imaging experiments. In this article we provide a guideline for designing, reading, evaluating, analyzing, and reporting results of a pain neuroimaging experiment, with a focus on functional and structural magnetic resonance imaging. We focus in particular on considerations that are unique to neuroimaging studies of pain in humans, including study design and analysis, inferences that can be drawn from these studies, and the strengths and limitations of the approach. PERSPECTIVE: This article provides an overview of the concepts and considerations of structural and functional magnetic resonance neuroimaging studies. The primer is written for those who are not familiar with brain imaging. We review key concepts related to recruitment and study sample, experimental design, data analysis and data interpretation. PMID- 29608978 TI - Psychosocial working conditions and diabetes self-management at work: A qualitative study. AB - AIMS: We conducted a qualitative study to expand our current understanding of the potential link between psychosocial working conditions and diabetes self management at work. METHODS: Thirty employed adults with diabetes mellitus living in Germany (n = 19 with type 1, n = 11 with type 2, 57% female, aged 24-64 years) were recruited. Using a topic guide, we carried out in-depth interviews in face to-face contact or by telephone. Interviews were transcribed and content-analyzed using MaxQDA. RESULTS: Psychosocial working conditions perceived to detrimentally affect self-management activities included, amongst others, a high workload, poor job control, unhygienic working environments, the requirement to work under high or fluctuating temperature, perceived social norms at the workplace, and the attitude to prioritize work-related demands as opposed to diabetes-related demands. The types of self-management activities considered to be adversely affected related to glucose monitoring, insulin injections, dietary control, the ability to recognize hypoglycemia and health care use. CONCLUSIONS: Various types of occupational psychosocial factors may determine diabetes self-management practices at the workplace. Quantitative studies are needed to confirm our observations. Subsequently, interventions could be developed and evaluated to improve opportunities to adequately engage into diabetes self-management at work. PMID- 29608979 TI - A population-based study of epilepsy incidence in association with type 2 diabetes and severe hypoglycaemia. AB - AIMS: This study was conducted to investigate potential link between type 2 diabetes mellitus (T2DM) and epilepsy, and the role of severe hypoglycaemia (SH) might play in the relationship. METHODS: This was a cohort study based on Taiwan's National Health insurance claims. Totally 751,792 people with T2DM and 824,253 matched controls were identified in 2002-2003 and followed to incidence of epilepsy or end of 2011. We used Cox proportional hazard model to relate epilepsy incidence to separate and joint effects of T2DM and SH. A possible mediation effect of SH on the association between T2DM and epilepsy was analyzed. RESULTS: Over a 10-year follow-up, patients with T2DM had a higher incidence rate of epilepsy than controls (35.0 vs 21.9 per 10,000 person-years). After controlling for potential confounders including SH, T2DM increased the hazard of epilepsy by some 50%. The stratified analysis further indicated that T2DM (hazard ratio (HR)=1.44, 95% confidence interval (CI) = 1.40-1.47), and SH (HR = 2.22, 95% CI = 1.76-2.81) were both independent risk factors for epilepsy. SH did not modify but mediated 12% of the association between T2DM and epilepsy. CONCLUSION: Our findings supported that SH may increase the risk of epilepsy, and that T2DM may increase risk of epilepsy independent of SH. PMID- 29608980 TI - Renoprotective effects of umbelliferone on methotrexate-induced renal injury through regulation of Nrf-2/Keap-1, P38MAPK/NF-kappaB, and apoptosis signaling pathways. AB - Nephrotoxicity is the major dose-limiting adverse effect of methotrexate (MTX). Umbelliferone (UMB) is a known coumarin derivative. The current study aimed to investigate possible protective effects of UMB against MTX-induced nephrotoxicity. Adult male albino rats were divided into: control group, UMB group (30 mg/kg, p.o), MTX group (single i.p. injection of 20 mg/kg) and MTX + UMB group. Serum urea and creatinine were evaluated. The renoprotective effects of UMB were evaluated by estimation of renal Nrf-2/Keap-1 and P38MAPK/NF-kappaB, GSH, MDA, NO2- contents and SOD activity. Moreover, expression of Bcl-2, Bax and caspase-3 were determined. The results demonstrated that UMB significantly reduced serum creatinine and urea levels with alleviations of histopathological abrasions induced by MTX. It limited oxidative stress via lowering both renal MDA and NO2- contents and restoring renal content of reduced GSH and SOD activity with downregulation of Keap-1 and upregulation of Nrf-2. UMB downregulated P38MAPK and NF-kappaB expression levels. In addition, UMB increased Bcl-2 protein expression while decreasing both Bax and caspase-3 expression levels. Importantly, UMB enhanced the cytotoxic activity of MTX human cancer cell lines. In conclusion, UMB possess marked renoprotective effects against MTX-induced renal damage through modulating oxidative stress, inflammation and apoptosis with enhancement of its cytotoxic activity. PMID- 29608981 TI - Phytol isolated from watermelon (Citrullus lanatus) sprouts induces cell death in human T-lymphoid cell line Jurkat cells via S-phase cell cycle arrest. AB - The phytol isolated from watermelon (Citrullus lanatus) sprouts inhibited the growth of a human T-cell leukemia line Jurkat cell and suppressed tumor progression in a xenograft model of human lung adenocarcinoma epithelial cell line A549 in nude mice. To elucidate the mechanisms underlying the phytol-induced cell death in the present study, we examined the changes in cell morphology, DNA fragmentation, and intracellular reactive oxygen species (ROS) levels and performed flow cytometric analysis to evaluate cell cycle stage. There were no significant changes in apoptosis, autophagy, and necrosis marker in cells treated with the phytol. But, we found, for the first time, that phytol remarkably induced S-phase cell cycle arrest accompanied with intracellular ROS production. Western blot analyses showed that phytolinduced S-phase cell cycle arrest was mediated through the decreased expression of cyclins A and D and the downregulations of MAPK and PI3K/Akt. The tumor volume levels in mice treated with phytol were lower than those of non-treatment groups, and it showed very similar suppression compared with those of mice treated with cyclophosphamide. Based on the data of in vitro and in vivo studies and previous studies, we suggest phytol as a potential therapeutic compound for cancer. PMID- 29608982 TI - Stochastic exposure and health risk assessment of rice contamination to the heavy metals in the market of Iranshahr, Iran. AB - An investigation of some heavy metals content in rice (Oryza sativa) and associated health risks was carried out for residents of Iranshahr city, Iran. Average daily rice consumption of the citizens and most widely used rice brands in the market of Iranshahr were determined using a questionnaire. Besides, the concentration of heavy metals in the gathered rice samples was measured by inductively coupled plasma mass spectrometry (ICP-MS). Monte Carlo uncertainty simulation was utilized in conducting exposure assessment and investigating the non-carcinogenic effects of the studied elements as well as the carcinogenic effect of As. Concentrations of As, Cd, Pb, Cu, Al, and Mo were 0.369 +/- 0.094, 0.0337 +/- 0.039, 0.123 +/- 0.14, 3.095 +/- 439.42, 39.6 +/- 14.73, and 1.106 +/- 0.133 mg kg-1, respectively. Al (0.18 +/- 0.15 mg kg-1 d-1) and Cd (0.00015 +/- 0.00034 mg kg-1 d-1) were the highest and lowest estimated daily intake, respectively. Except As (5.23 +/- 4.01), the calculated hazard quotient for investigated elements showed no non-carcinogenic health risk. Besides, the simulation of the carcinogenic risk effect for As (2.37E-3) revealed that the ingestion of the studied rice brands would cause cancer risk due to lifetime consumption. Results show that consumption of rice in the Iranshahr city is a potential source of exposure to the studied elements. PMID- 29608983 TI - Radon 222 in drinking water resources of Iran: A systematic review, meta-analysis and probabilistic risk assessment (Monte Carlo simulation). AB - The current study was performed to review the conducted studies regarding the concentration of radon 222 in the tap drinking water; furthermore, by estimation of ingestion and inhalation effective dose, the health risk assessment in the adults and children using MCS technique was assessed. All related studies published among January 1990 to October 2016; were screened in the available databases such as Web of Science, PubMed, Science Direct, Scopus, SID, and Irandoc. The total effective dose was estimated by calculating Eing (Effective dose of ingestion) and Einh (Effective dose of inhalation) by Monte Carlo simulation (MCS) method. The range of ND ? 40.9 Bq/L for radon 222 in water resources was proposed after evaluation of data collected from 13 studies with 1079 samples. The overall concentration of radon 222 in drinking water in Iran was 3.98: 95%CI (3.79 ? 4.17 Bq/L). Also, the effective ingestion dose of radon 222 in adults age groups was 1.35 times higher than children. The rank order of drinking water resources based on the concentration of radon 222 was Spring > Spring and Well > Well > Spring and Qanat > Tap water. The overall concentration of radon 222 in drinking water in Iran was lower than WHO and EPA standard limits. Also, the rank order regarding area studied based on the concentration of radon 222 was Gillan > Mashhad > Mazandaran > Kerman > Yazd > Tehran > Kermanshah > Golestan > Hormozgan. The effective ingestion dose of radon 222 to consumers in the Gillan, Mashhad, Mazandaran, and Kerman were higher than WHO guidance (0.1 mSv/y). Also except consumers in the Hormozgan, inhalation effective dose radon 222, in the other investigated areas were higher than WHO guidance (0.1 mSv/y). Therefore, it is recommended to conduct the required programs regarding control and elimination of radon 222 concentration in Iranian drinking water supply. PMID- 29608985 TI - A novel strategy of integrated microarray analysis identifies CENPA, CDK1 and CDC20 as a cluster of diagnostic biomarkers in lung adenocarcinoma. AB - Lung adenocarcinoma (LAC) is the most lethal cancer and the leading cause of cancer-related death worldwide. The identification of meaningful clusters of co expressed genes or representative biomarkers may help improve the accuracy of LAC diagnoses. Public databases, such as the Gene Expression Omnibus (GEO), provide rich resources of valuable information for clinics, however, the integration of multiple microarray datasets from various platforms and institutes remained a challenge. To determine potential indicators of LAC, we performed genome-wide relative significance (GWRS), genome-wide global significance (GWGS) and support vector machine (SVM) analyses progressively to identify robust gene biomarker signatures from 5 different microarray datasets that included 330 samples. The top 200 genes with robust signatures were selected for integrative analysis according to "guilt-by-association" methods, including protein-protein interaction (PPI) analysis and gene co-expression analysis. Of these 200 genes, only 10 genes showed both intensive PPI network and high gene co-expression correlation (r > 0.8). IPA analysis of this regulatory networks suggested that the cell cycle process is a crucial determinant of LAC. CENPA, as well as two linked hub genes CDK1 and CDC20, are determined to be potential indicators of LAC. Immunohistochemical staining showed that CENPA, CDK1 and CDC20 were highly expressed in LAC cancer tissue with co-expression patterns. A Cox regression model indicated that LAC patients with CENPA+/CDK1+ and CENPA+/CDC20+ were high risk groups in terms of overall survival. In conclusion, our integrated microarray analysis demonstrated that CENPA, CDK1 and CDC20 might serve as novel cluster of prognostic biomarkers for LAC, and the cooperative unit of three genes provides a technically simple approach for identification of LAC patients. PMID- 29608986 TI - Survivin-targeted drug screening platform identifies a matrine derivative WM-127 as a potential therapeutics against hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is the second leading cause of cancer related death which needs novel drugs to improve patient outcome. Survivin overexpresses in HCC and contributes to HCC malignant progression. In this study, we established a Survivin-targeted drug screening platform, a cell model HepG2-Sur5P EGFP-Sur3U stably transfected with lentivirus carrying an EGFP expression cassette, in which the EGFP expression was regulated by the upstream Survivin promoter and downstream Survivin 3'-UTR. By using this platform, we screened and easily identified one of matrine derivatives, WM-127, from hundreds of matrine derivatives. WM-127 was demonstrated to be a strong Survivin inhibitor that inhibited cell proliferation, induced cell cycle arrest and apoptosis of HCC cells, and suppressed the growth of HCC xenografted tumors in nude mice, suggesting that WM-127 might be a promising drug for HCC treatment. WM-127 exhibited less cytotoxicity in normal cells. Mechanistic studies showed that WM 127 suppressed the activity of Survivin/beta-catenin pathway and the expression of Bax to induce cell cycle arrest and apoptosis. Taken together, we constructed an economical, practical, efficient and convenient cell platform for screening the Survivin-targeted drugs from the enormous diversity of chemicals or factors, which would be a potential tool for antitumor drug research and development. PMID- 29608987 TI - RIP1 and RIP3 contribute to shikonin-induced glycolysis suppression in glioma cells via increase of intracellular hydrogen peroxide. AB - RIP1 and RIP3 are necroptosis initiators, but their roles in regulation of glycolysis remain elusive. In this study, we found shikonin activated RIP1 and RIP3 in glioma cells in vitro and in vivo, which was accompanied with glycolysis suppression. Further investigation revealed that shikonin-induced decreases of glucose-6-phosphate and pyruvate and downregulation of HK II and PKM2 were significantly prevented when RIP1 or RIP3 was pharmacologically inhibited or genetically knocked down with SiRNA. Moreover, shikonin also triggered accumulation of intracellular H2O2 and depletion of GSH and cysteine. Mitigation of intracellular H2O2 via supplement of GSH reversed shikonin-induced glycolysis suppression. The role of intracellular H2O2 in regulation of glycolysis suppression was further confirmed in the cells treated with exogenous H2O2. Notably, inhibition of RIP1 or RIP3 prevented intracellular H2O2 accumulation, which was correlated with preventing shikonin-induced downregulation of x-CT and depletion of GSH and cysteine. In addition, supplement of pyruvate effectively inhibited shikonin- or exogenous H2O2-induced accumulation of intracellular H2O2 and glioma cell death. Taken together, we demonstrated in this study that RIP1 and RIP3 contributed to shikonin-induced glycolysis suppression via increasing intracellular H2O2. PMID- 29608984 TI - Sorafenib improves alkylating therapy by blocking induced inflammation, invasion and angiogenesis in breast cancer cells. AB - Molecular targeted compounds are emerging as a strategy to improve classical chemotherapy. Herein, we describe that using low dose of the multikinase inhibitor sorafenib improves cyclophosphamide antitumor activity by inhibiting angiogenesis, metastasis and promoting tumor healing in MDA-MB231 xenografts and the 4T1-12B syngeneic breast cancer metastasis model. Mechanistic studies in MDA MB231 cells revealed that alkylation upregulates inflammatory genes/proteins such as COX-2, IL8, CXCL2 and MMP1 in a MEK1/2-ERK1/2-dependent manner. These proteins enrich the secretome of cancer cells, stimulating cell invasion and angiogenesis via autocrine and paracrine mechanisms. Sorafenib inhibits MEK1/2-ERK1/2 pathway thereby decreasing inflammatory genes and mitigating cell invasion and angiogenesis at basal and alkylation-induced conditions whereas NRF2 and ER stress pathways involved in alkylation survival are not affected. In non invasive/non-angiogenic breast cancer cells (SKBR3 and MCF7), alkylation did not elicit inflammatory responses with the only sorafenib effect being ERK1/2 independent ROS-dependent cytotoxicity when using higher drug concentrations. In summary, our data show that alkylating agents may elicit inflammatory responses that seems to contribute to malignant progression in specific breast cancer cells. Identifying and targeting drivers of this phenotype may offer opportunities to optimize combined drug regimens between classical chemotherapeutics and targeted agents. PMID- 29608988 TI - Interaction between blood-brain barrier and glymphatic system in solute clearance. AB - Neurovascular pathology concurs with protein accumulation, as the brain vasculature is important for waste clearance. Interstitial solutes, such as amyloid-beta, were previously thought to be primarily cleared from the brain by blood-brain barrier transport. Recently, the glymphatic system was discovered, in which cerebrospinal fluid is exchanged with interstitial fluid, facilitated by the aquaporin-4 water channels on the astroglial endfeet. Glymphatic flow can clear solutes from the interstitial space. Blood-brain barrier transport and glymphatic clearance likely serve complementary roles with partially overlapping mechanisms providing a well-conditioned neuronal environment. Disruption of these mechanisms can lead to protein accumulation and may initiate neurodegenerative disorders, for instance amyloid-beta accumulation and Alzheimer's disease. Although both mechanisms seem to have a similar purpose, their interaction has not been clearly discussed previously. This review focusses on this interaction in healthy and pathological conditions. Future health initiatives improving waste clearance might delay or even prevent onset of neurodegenerative disorders. Defining glymphatic flow kinetics using imaging may become an alternative way to identify those at risk of Alzheimer's disease. PMID- 29608989 TI - Advances, challenges, and promises in pediatric neuroimaging of neurodevelopmental disorders. AB - Recent years have witnessed the proliferation of neuroimaging studies of neurodevelopmental disorders (NDDs), particularly of children with autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and Tourette's syndrome (TS). Neuroimaging offers immense potential in understanding the biology of these disorders, and how it relates to clinical symptoms. Neuroimaging techniques, in the long run, may help identify neurobiological markers to assist clinical diagnosis and treatment. However, methodological challenges have affected the progress of clinical neuroimaging. This paper reviews the methodological challenges involved in imaging children with NDDs. Specific topics include correcting for head motion, normalization using pediatric brain templates, accounting for psychotropic medication use, delineating complex developmental trajectories, and overcoming smaller sample sizes. The potential of neuroimaging-based biomarkers and the utility of implementing neuroimaging in a clinical setting are also discussed. Data-sharing approaches, technological advances, and an increase in the number of longitudinal, prospective studies are recommended as future directions. Significant advances have been made already, and future decades will continue to see innovative progress in neuroimaging research endeavors of NDDs. PMID- 29608991 TI - How orchids concentrate? The relationship between physiological stress reactivity and cognitive performance during infancy and early childhood. AB - The Autonomic Nervous System (ANS) is involved both in higher-order cognition such as attention and learning, and in responding to unexpected, threatening events. Increased ANS reactivity may confer both superior short-term cognitive performance, and heightened long-term susceptibility to adverse events. Here, we evaluate this hypothesis within the Differential Susceptibility Theory (DST) framework. We hypothesise that individuals with increased reactivity may show heightened biological sensitivity to context, conferring both positive (development-enhancing) effects (superior attention and learning) and negative (risk-promoting) effects (increased sensitivity to unsupportive environments). First, we examine how ANS reactivity relates to early cognitive performance. We hypothesise that increased phasic ANS reactivity, observed at lower tonic (pre stimulus) ANS activity, is associated with better attention and learning. We conclude that the evidence is largely in support. Second we discuss whether ANS reactivity to 'positive', attention-eliciting and to 'negative', aversive stimuli is a one-dimensional construct; and evaluate evidence for how the real-world environment influences physiological stress over short and long time-frames. We identify three areas where the evidence is currently inconclusive. PMID- 29608992 TI - Central fatigue theory and endurance exercise: Toward an interoceptive model. AB - We propose a model of exercise-induced central fatigue based on interoception and motivation. Predictions of the expected sensory feedback are fed forward by the dorsolateral (DL) prefrontal cortex (PFC) to the anterior insula cortex (AIC). During exercise, the AIC receives feedback from lamina I lateral spinothalamic and nucleus tractus solitarii medullothalamic pathways. The feedback is compared to the predictions in order to generate a current awareness state, which is forwarded to the anterior cingulate cortex (ACC), ventromedial (VM)PFC and lateral (L)PFC. The LPFC integrates the information and makes a decision as to whether to continue or stop. The decision is dependent upon interaction with the substantia nigra pars compacta and ventral tegmental area dopamine (DA), and locus coeruleus (LC)-norepinephrine (NE) systems. Phasic activation of DA and NE neurons appears to be necessary for maintenance of goal-related action but the VMPFC and ACC, which project to the LC, induce tonic NE activity when the rewards are thought to be not worth the cost thus fatigue is perceived. PMID- 29608993 TI - Kynurenine pathway in depression: A systematic review and meta-analysis. AB - Abnormalities of the kynurenine (KYN) pathway may be implicated in the pathophysiology of depression. However, the relationships between depression and each metabolite of the KYN pathway remain uncertain. Therefore, we conducted a meta-analysis about the levels of the metabolites of KYN pathway between patients with depression and controls. Out of 899 initial records, we identified 22 articles to form the empirical basis. Seventeen, 10, and 18 studies examined levels of kynurenic acid (KYNA), quinolinic acid (QUIN), and KYN, respectively. KYNA and KYN levels were lower in patients with depression in comparison to controls, while QUIN levels did not differ between the two groups. Antidepressant free patients showed decreased KYNA levels and increased QUIN levels compared with controls. Male ratios of the samples were negatively associated with study SMDs for KYNA. In conclusion, this meta-analysis revealed that patients with depression had decreased level of KYNA and KYN, whereas antidepressant-free patients showed increased level of QUIN. Nevertheless, given the heterogeneity among their sample characteristics, further research is clearly needed. PMID- 29608990 TI - Dynamic coupling between the central and autonomic nervous systems during sleep: A review. AB - Sleep is characterized by coordinated cortical and cardiac oscillations reflecting communication between the central (CNS) and autonomic (ANS) nervous systems. Here, we review fluctuations in ANS activity in association with CNS defined sleep stages and cycles, and with phasic cortical events during sleep (e.g., arousals, K-complexes). Recent novel analytic methods reveal a dynamic organization of integrated physiological networks during sleep and indicate how multiple factors (e.g., sleep structure, age, sleep disorders) affect "CNS-ANS coupling". However, these data are mostly correlational and there is a lack of clarity of the underlying physiology, making it challenging to interpret causality and direction of coupling. Experimental manipulations (e.g., evoking K complexes or arousals) provide information on the precise temporal sequence of cortical-cardiac activity, and are useful for investigating physiological pathways underlying CNS-ANS coupling. With the emergence of new analytical approaches and a renewed interest in ANS and CNS communication during sleep, future work may reveal novel insights into sleep and cardiovascular interactions during health and disease, in which coupling could be adversely impacted. PMID- 29608994 TI - Implications of and lessons learned from external assurance of eight influenza diagnostics in China. AB - This study evaluated the ability of laboratories in the Chinese mainland to conduct molecular detection of seasonal A(H1N1), A(H1N1)pdm09, A(H3N2), A(H5N1), A(H7N9), A(H9N2), B(Victoria), and B(Yamagata). Based on a genetically engineered system of virus-like particles (VLPs), the National Center for Clinical Laboratories of China (NCCLs) developed an external quality assessment (EQA) panel. The panel was distributed to 35 laboratories in mainland China to investigate the proficiency of the 16 assays for influenza molecular detection. Using genetic engineering technology, VLPs encapsulating the 37 target genes of 8 influenza viruses were generated. After verification and quantification, 26 influenza virus surrogates with different concentrations were prepared for EQA. Among the 35 participating laboratories, 319 datasets were returned to the NCCLs. Overall, 95.6% (305/319) of datasets correctly reported all 30 samples, while 2.2% (7/319) of datasets with more than one incorrect result were considered as "improvable". A total of 16 misdiagnosed and 18 undiagnosed results were reported. The data analyzed in this study showed good reproducibility in China, but improvements are needed to decrease misdiagnosed and undiagnosed cases, particularly for the A(H9N2) NA gene. Moreover, VLPs are a good alternative specimen type for assay training and proficiency testing purposes. PMID- 29608996 TI - H1N1 seasonal influenza virus evolutionary rate changed over time. AB - It was previously shown that the seasonal H1N1 influenza virus antigenic drift occurred at a slower rate than the seasonal H3N2 virus during the first decade of the 21th century. It was hypothesized that the slower antigenic evolution led to a decrease in average ages of infection, which in turn resulted in lower level of global viral circulation. It is unclear what caused the difference between the two viruses, but a plausible explanation may be related to the fact that the H1N1 virus had been in human population for much longer than the H3N2 virus. This would suggest that H1N1 antigenic drift in an earlier period may have been different from a more recent period. To test this hypothesis, we analyzed seasonal H1N1 influenza sequences during various time periods. In comparison to more recent H1N1 virus, the older H1N1 virus during the first half of the 20th century showed evidences of higher nonsynnonymous/synonymous ration (dN/dS) in its hemagglutinin (HA) gene. We compared amino acid sequence changes in the HA epitopes for each outbreak season and found that there were less changes in later years. Amino acid sequence diversity in the epitopes as measured by sequence entropy became smaller for each passing decade. These suggest that there might be some limit to the antigenic drift. The longer an influenza virus has drifted in human population, the less flexibility it may become. With less flexibility to adapt and escape the host immunity, the virus may have to rely more on younger naive population. PMID- 29608995 TI - Coat protein complex I facilitates dengue virus production. AB - Dengue hemorrhagic fever is a life-threatening disease caused by the dengue virus (DENV). After DENV enters into host cells, it replicates to generate viral particles to infect other cells. DENV exploits components of the cellular trafficking pathway to achieve effective virion production. Understanding of the proteins required for this trafficking process is essential for revealing the pathogenesis of DENV infection. Coat protein complex and soluble N-ethylmaleimide sensitive factor attachment protein receptors (SNAREs), two host protein families in the cellular trafficking pathway, were investigated to elucidate their respective roles during DENV infection. Coat proteins (COPI and COPII) and SNAREs (STX 5 and NSF) were knocked down in a DENV-infected Huh7 cells by RNA interference. Depletion of COPI and COPII, but not of STX5 and NSF, decreased DENV production in DENV-infected Huh7 cells. DENV proteins, including DENV C, prM, E, and NS1, were significantly reduced in COPI-silenced DENV-infected Huh7 cells, when compared to those of control cells. COPI also facilitated DENV production in an endothelial cell line and in all DENV serotypes, indicating the importance of coat protein complex in facilitating DENV infection. PMID- 29608997 TI - The Beneficial Effects of Electroacupuncture at PC6 Acupoints (Neiguan) on Myocardial Ischemia in ASIC3 -/- mice. AB - This study aims to investigate the possible mechanisms of electroacupuncture (EA) at PC6 to improve myocardial ischemia (MI) by regulating the cardiac transient outward potassium current channel (Ito). According to the random number table, the mice were divided into six groups of six mice each: control group, MI group, PC6, LU7 (Lieque-point), ST36 (Zusanli-point), and nonacupoint group. Mice in the control group were injected with saline (20 mg/kg, 24 hours interval), and the other ASIC3 -/- mice were injected subcutaneously twice with isoproterenol (ISO) (20 mg/kg, 24 hours interval). In the preexperiment, 5 mg/kg, 10 mg/kg, 20 mg/kg, and 30 mg/kg of ISO were used, and the results showed that 5 mg/kg and 10 mg/kg of ISO both could induce acute MI, but shorter duration of sustained MI. On the other hand, an injection of 30 mg/kg can make the mice experience arrhythmia or die immediately, and EA was operated at PC6, LU7, ST36 acupoints, and nonacupoint in the mice of PC6, LU7, ST36, and nonacupoint groups, respectively, after injecting twice. Then Western blotting techniques (Western Blot) were used to analyze the protein expressions of Kv1.4, Kv4.2, Kv4.3, and KchIP2. The results of this experiment showed that the protein expressions of Kv1.4, Kv4.2, Kv4.3, and KChIP2 in MI group were significantly lower than those in the control group (p < 0.01). Compared with MI group, the results of PC6, LU7, and ST36 groups obviously increased (p < 0.05). Furthermore, the expressions of PC6 group were higher than LU7 group and ST36 group (p < 0.05). And electrocardiogram's T-waves showed obvious pathological changes in the MI group compared to the control group (p < 0.01). After EA, the abnormal T-waves voltage of ECG in PC6, LU7, and ST36 groups was improved (p < 0.05). In addition, the rate change of PC6 group was larger than that of both LU7 and ST36 groups (p < 0.05). But the T-waves voltage of the nonacupoint group was not significantly different than that of the MI group (p > 0.05). PMID- 29608998 TI - Retraining automatic action tendencies in obesity. AB - Eating behavior in obesity resembles addictive disorders in that individuals have difficulties inhibiting problematic eating behavior. They show an approach bias - a tendency to approach rather than avoid problematic stimuli. Here, we investigate the existence of such a bias towards healthy and unhealthy food in individuals with normal-weight and obesity. We further aimed to assess whether it is possible to retrain a bias, and whether training would differentially affect our two weight groups. 60 participants completed a training form of the Approach Avoidance Task (AAT) on three consecutive days. Using a joystick, they were implicitly trained to approach healthy and to avoid unhealthy food pictures. Prior to training, individuals with obesity showed stronger approach tendencies towards food pictures than normal-weight individuals. In individuals with obesity, approach tendencies could be diminished for unhealthy food through one training session and stayed weakened for the following days. In normal-weight participants, approach tendencies towards healthy food could be enhanced over the days of training. Findings indicate that automatic approach tendencies can be changed through training, thus offering possibilities for obesity treatment. Future studies should expand on these findings, for example by including pictures of neutral objects or a no-training control condition. PMID- 29608999 TI - Experimental effects of acute exercise and music listening on cognitive creativity. AB - OBJECTIVE: The purpose of this study was to extend previous experimental work suggesting that both exercise and music-based interventions may influence creativity processes, by investigating the independent influences of exercise or music stimuli on verbal creative performances in the laboratory environment. METHODS: 32 students at the University of Mississippi participated in this within subject intervention, which included three laboratory visits per participant. Individuals participated in three 15-min, randomized experimental conditions: Treadmill walking, self-selected music, or a seated control period, and subsequently completed four creativity assessments during each visit (three tests of divergent thinking, and one test of convergent thinking), with the order of divergent thinking tasks counterbalanced. Creativity task performance was independently scored across four dependent parameters, which included fluency (i.e., total number of ideas), flexibility (i.e., total number of categories), originality (i.e., responses thought of by <5% of the sample), and elaboration (i.e., degree of supplementary detail included per idea). RESULTS: Repeated Measures ANOVAs indicated that creativity scores for fluency (F(2, 60) = 0.63, p = 0.94), flexibility (F(2, 60) = 0.64, p = 0.53), originality (F(2, 60 = 0.23, p = 0.78), and elaboration (F(2, 60) = 2.74, p = 0.07), were not statistically significant across the visits. CONCLUSIONS: These findings add to the equivocal body of creativity research, uniquely assessing the effects of exercise and music on verbal creativity performance. The present study further highlights the critical need for improvement in the assessment and evaluation of laboratory assessed cognitive creativity. Methodological strategies must be examined and refined for the meaningful and credible measurement and interpretation of experimental creativity. PMID- 29609001 TI - Toxicological assessment of PEGylated single-walled carbon nanotubes in early developing zebrafish. AB - Functionalization of single-walled carbon nanotubes (SWCNT) with polyethylene glycol (PEG) is among the most promising strategies to avoid SWCNT aggregation in aqueous media, improving its interactions with biological systems. However, the best molecular PEG weight and functionalization strategy remain under investigation. In this work we assessed the toxicological effects of SWCNT functionalized with PEG at 600 Da in zebrafish embryos. Embryos were exposed to SWCNT at 0.01, 0.1 and 1 mg/L from 3 to 96 h post-fertilization (hpf). At the highest concentration, SWCNT led to toxic effects at several endpoints, including mortality, delayed hatching, malformations, reduced body length, increased ROS production and DNA damage. Even with these effects, SWCNT could not be detected within the bodily tissues of the larvae. Our results give evidence that the tested PEGylation approach was unsuitable to avoid SWCNT aggregation in aqueous media, and that SWCNT can induce toxicity even without being absorbed by the organism by obstructing the chorion pores. PMID- 29609000 TI - Eating in the absence of hunger: Stability over time and associations with eating behaviours and body composition in children. AB - BACKGROUND/OBJECTIVES: Eating in the absence of hunger (EAH) has been linked to obesity in adults and children. This study examined the stability of EAH in children between 4.5 and 6 years old, and associations with energy intake and portion selection, as well as cross-sectional and prospective associations with body composition. METHODS: The participants were 158 boys and girls from the Growing Up in Singapore Towards healthy Outcomes cohort. At ages 4.5 and 6 years old children were provided lunch ad libitum, and immediately afterwards were exposed to palatable snacks to measure energy intake in the absence of hunger. At age 6 children completed an additional computer-based task to measure ideal portion size, where they selected pictures of the portions they would like to eat across eight foods. Measures of anthropometry (height/weight/skinfolds) were collected at both ages. RESULTS: Children who consumed energy during the EAH task at age 4.5 years were 3 times more likely to also do so at age 6 years. Children with high EAH intakes at age 4.5 years had high EAH intakes at age 6, highlighting stability of this behaviour over time. Energy consumed at lunch was unrelated to energy consumed during the EAH task, but children who ate in the absence of hunger cumulatively consumed more energy over lunch and the EAH task. Children who showed EAH tended to select larger ideal portions of foods during the computer task. EAH was not associated with measures of body composition. CONCLUSIONS: EAH is a stable behavioural risk factor for increased energy intake, but was not associated with body composition in this cohort. The majority of children ate in the absence of hunger, suggesting that interventions aimed at reducing responsiveness to external food cues could help to reduce energy intakes. Trial Registry Number: NCT01174875; https://clinicaltrials.gov/. PMID- 29609002 TI - Angiotensin II facilitates neointimal formation by increasing vascular smooth muscle cell migration: Involvement of APE/Ref-1-mediated overexpression of sphingosine-1-phosphate receptor 1. AB - Angiotensin II (Ang II) is implicated in the development of cardiovascular disorders including hypertension and atherosclerosis. However, the role of Ang II in the interaction between apurinic/apyrimidinic endonuclease/redox factor-1 (APE/Ref-1) and sphingosine-1-phosphate (S1P) signals in relation to vascular disorders remains to be clarified. This study aimed to determine whether APE/Ref 1 plays a role in epigenetic regulation of the S1P receptor (S1PR) in response to Ang II in vascular smooth muscle cell (VSMC) migration and vascular neointima formation. Ang II augmented the expression of S1PR1 in aortic smooth muscle cells of Sprague Dawley rats (RASMCs), which was attenuated by Ang II receptor (AT) 1 inhibitors, antioxidants, and APE/Ref-1 knockdown with small interference RNA. Ang II stimulation produced H2O2, and exogenous H2O2 elevated S1PR1 expression in RASMCs. Moreover, Ang II caused translocation of cytoplasmic APE/Ref-1 into the nucleus in RASMCs. H3 histone acetylation and APE/Ref-1 binding at the S1PR1 promoter were increased in RASMCs treated with Ang II. In addition, Ang II induced migration in RASMCs, which was suppressed by AT1 and S1PR1 inhibitors. The expression of S1PR1, and colocalization of APE/Ref-1 and acetylated histone H3 in vascular neointima, were greater in Ang II-infused rats compared with a control group. These findings demonstrate that Ang II stimulates the epigenetic regulation of S1PR1 expression via H2O2-mediated APE/Ref-1 translocation, which may consequently be involved in Ang II-induced VSMC migration and vascular neointima formation. Therefore, APE/Ref-1-mediated overexpression of S1PR1 may be implicated in the vascular dysfunction evoked by Ang II. PMID- 29609004 TI - Emerging biological therapies for treating chronic obstructive pulmonary disease: A pairwise and network meta-analysis. AB - Inflammation in chronic obstructive pulmonary disease (COPD) is often corticosteroid resistant and, thus, alternative anti-inflammatory approaches are needed. Since it is still not clear whether blocking specific pro-inflammatory factors may provide clinical benefit in COPD, we have performed a meta-analysis to quantify the impact of monoclonal antibodies (mABs) targeting the cytokine/chemokine-mediated inflammation in COPD. A pairwise and network meta analyses were performed by extracting data from randomized clicnial trials on COPD concerning the impact of mABs vs. placebo on the risk of exacerbation, forced expiratory volume in 1 s (FEV1), and St. George's Respiratory Questionnaire (SGRQ). Data on the interleukin (IL)-1beta antagonist canakinumab, IL-1R1 antagonist MEDI8986, IL-5 antagonist mepolizumab, IL-5R antagonist benralizumab, IL-8 antagonist ABX-IL8, and TNF-alpha antagonist infliximab were found. Overall, mAB therapy had a moderate impact on the risk exacerbation, but not on FEV1 and SGRQ. The pairwise meta-analysis performed in eosinophilic patients, and the network approach, indicated that mepolizumab elicited a beneficial effect against the risk of exacerbation, whereas benralizumab was more effective in improving both FEV1 and SGRQ. This study demonstrates that targeting the pathway activated by IL-5 may have a beneficial impact in eosinophilic COPD patients. PMID- 29609003 TI - Fluoride induces apoptosis via inhibiting SIRT1 activity to activate mitochondrial p53 pathway in human neuroblastoma SH-SY5Y cells. AB - There has been a great concern about the neurotoxicity of fluoride since it can pass through the blood-brain barrier and accumulate in the brain. It has been suggested that apoptosis plays a vital role in neurotoxicity of fluoride. However, whether p53-mediated apoptotic pathway is involved is still unclear. Our results showed that apoptosis was induced after treatment with 40 and 60 mg/L of NaF for 24 h in human neuroblastoma SH-SY5Y cells. Exposure to 60 mg/L of NaF for 24 h significantly upregulated the levels of p53 and apoptosis-related proteins including PUMA, cytochrome c (cyto c), cleaved caspase-3 and cleaved PARP, whereas downregulated Bcl-2 in SH-SY5Y cells. Meanwhile, fluoride increased p53 nuclear translocation, cyto c release from mitochondria to cytoplasm and mitochondrial translocation of Bax in SH-SY5Y cells. Fluoride-induced increases of apoptotic rates and apoptosis-related protein levels were significantly attenuated by inhibiting p53 transcriptional activity with pifithrin-alpha. In addition, fluoride inhibited the deacetylase activity of SIRT1 and increased p53 (acetyl K382) level in SH-SY5Y cells. Apoptosis and upregulation of cleaved caspase-3, cleaved PARP and p53 (acetyl K382) induced by fluoride could be ameliorated by SIRT1 overexpression or its activator resveratrol in SH-SY5Y cells. Taken together, our study demonstrates that fluoride induces apoptosis by inhibiting the deacetylase activity of SIRT1 to activate mitochondrial p53 pathway in SH-SY5Y cells, which depends on p53 transcriptional activity. Thus, SIRT1 may be a promising target to protect against neurotoxicity induced by fluoride. PMID- 29609005 TI - Decreased PD-1 expression on circulating CD4+T cell and PD-L1 expression on myeloid dendritic cell correlate with clinical manifestations in systemic juvenile idiopathic arthritis. AB - OBJECTIVES: Programmed cell death-1 (PD-1) and its ligand (PD-L1) mediate negative signal in autoimmune diseases. While little is known about its role in juvenile idiopathic arthritis (JIA). The study aimed to reveal the circulating cell profile and the relative PD-1/PD-L1 expression of JIA subsets, elucidating their underlying immunomodulatory mechanisms. METHODS: We detected the circulating cells and the relative PD-1/PD-L1 signaling in 101 JIA patients and 50 controls by flow cytometry and analyzed their association with disease activity and clinical manifestations. RESULTS: Different from other JIA types, active systemic JIA (sJIA) patients had lower percentage and count of CD4+T cells and lower PD-1 expression on them compared with healthy controls (P<0.05), active polyarthritis (P<0.05) and enthesitis-related arthritis (ERA) patients (P<0.05). Also, they had higher percentage and count of myeloid dendritic cell (mDC) and lower PD-L1 expression on mDC compared with healthy controls (P<0.05). Both PD-1 on CD4+T cell and PD-L1 on mDC were negatively correlated with JADAS-27 in sJIA patients (P<0.05). In addition, PD-1 expression on CD4+T cell was negatively associated with the number of involved joints (P<0.05) and PD-L1 on mDC was lower in patients with fever (P<0.01), which could further divide patients into two groups of different manifestations. CONCLUSIONS: Our finding displayed decreased CD4+T cell, increased mDC and reduced PD-1/PD-L1 signal in sJIA PBMC comparing with other JIA subsets, which might be helpful in JIA differential diagnosis and responsible for distinct clinical manifestations via different mechanisms. PMID- 29609006 TI - Can anomalous diffusion models in magnetic resonance imaging be used to characterise white matter tissue microstructure? AB - PURPOSE: During the time window of diffusion weighted magnetic resonance imaging experiments (DW-MRI), water diffusion in tissue appears to be anomalous as a transient effect, with a mean squared displacement that is not a linear function of time. A number of statistical models have been proposed to describe water diffusion in tissue, and parameters describing anomalous as well as Gaussian diffusion have previously been related to measures of tissue microstructure such as mean axon radius. We analysed the relationship between white matter tissue characteristics and parameters of existing statistical diffusion models. METHODS: A white matter tissue model (ActiveAx) was used to generate multiple b-value diffusion-weighted magnetic resonance imaging signals. The following models were evaluated to fit the diffusion signal: 1) Gaussian models - 1a) mono-exponential decay and 1b) bi-exponential decay; 2) Anomalous diffusion models - 2a) stretched exponential, 2b) continuous time random walk and 2c) space fractional Bloch Torrey equation. We identified the best candidate model based on the relationship between the diffusion-derived parameters and mean axon radius and axial diffusivity, and applied it to the in vivo DW-MRI data acquired at 7.0 T from five healthy participants to estimate the same selected tissue characteristics. Differences between simulation parameters and fitted parameters were used to assess accuracy and in vivo findings were compared to previously reported observations. RESULTS: The space fractional Bloch-Torrey model was found to be the best candidate in characterising white matter on the base of the ActiveAx simulated DW-MRI data. Moreover, parameters of the space fractional Bloch-Torrey model were sensitive to mean axon radius and axial diffusivity and exhibited low noise sensitivity based on simulations. We also found spatial variations in the model parameter beta to reflect changes in mean axon radius across the mid sagittal plane of the corpus callosum. CONCLUSION: Simulations have been used to define how the parameters of the most common statistical magnetic resonance imaging diffusion models relate to axon radius and diffusivity. The space fractional Bloch-Torrey equation was identified as the best model for the characterisation of axon radius and diffusivity. This model allows changes in mean axon radius and diffusivity to be inferred from spatially resolved maps of model parameters. PMID- 29609007 TI - Intra-hemispheric integration underlies perception of tilt illusion. AB - The integration of inputs across the entire visual field into a single conscious experience is fundamental to human visual perception. This integrated nature of visual experience is illustrated by contextual illusions such as the tilt illusion, in which the perceived orientation of a central grating appears tilted away from its physical orientation, due to the modulation by a surrounding grating with a different orientation. Here we investigated the relative contribution of local, intra-hemispheric and global, inter-hemispheric integration mechanisms to perception of the tilt illusion. We used Dynamic Causal Modelling of fMRI signals to estimate effective connectivity in human early visual cortices (V1, V2, V3) during bilateral presentation of a tilt illusion stimulus. Our analysis revealed that neural responses associated with the tilt illusion were modulated by intra- rather than inter-hemispheric connectivity. Crucially, across participants, intra-hemispheric connectivity in V1 correlated with the magnitude of the tilt illusion, while no such correlation was observed for V1 inter-hemispheric connectivity, or V2, V3 connectivity. Moreover, when the illusion stimulus was presented unilaterally rather than bilaterally, the illusion magnitude did not change. Together our findings suggest that perception of the tilt illusion reflects an intra-hemispheric integration mechanism. This is in contrast to the existing literature, which suggests inter-hemispheric modulation of neural activity as early as V1. This discrepancy with our findings may reflect the diversity and complexity of integration mechanisms involved in visual processing and visual perception. PMID- 29609008 TI - Atypical cortical entrainment to speech in the right hemisphere underpins phonemic deficits in dyslexia. AB - Developmental dyslexia is a multifaceted disorder of learning primarily manifested by difficulties in reading, spelling, and phonological processing. Neural studies suggest that phonological difficulties may reflect impairments in fundamental cortical oscillatory mechanisms. Here we examine cortical mechanisms in children (6-12 years of age) with or without dyslexia (utilising both age- and reading-level-matched controls) using electroencephalography (EEG). EEG data were recorded as participants listened to an audio-story. Novel electrophysiological measures of phonemic processing were derived by quantifying how well the EEG responses tracked phonetic features of speech. Our results provide, for the first time, evidence for impaired low-frequency cortical tracking to phonetic features during natural speech perception in dyslexia. Atypical phonological tracking was focused on the right hemisphere, and correlated with traditional psychometric measures of phonological skills used in diagnostic dyslexia assessments. Accordingly, the novel indices developed here may provide objective metrics to investigate language development and language impairment across languages. PMID- 29609009 TI - Effects of Dahuang zhechong pill on doxorubicin-resistant SMMC-7721 xenografts in mice. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Dahuang zhechong pill (DHZCP) is a famous traditional Chinese medicinal prescription from the "Synopsis of Prescriptions of the Golden Chamber (Jin Kui Yao Lue)",Lue)", an ancient Chinese medical classic. DHZCP is commonly used for clinical treatment of liver cancer by promoting blood circulation to dissolve blood stasis and by removing pathogenic vegetations.vegetations. DHZCP-based treatment has been derived from Traditional Chinese Medicine (TCM) and is officially recorded in the Chinese Pharmacopoeia. AIM OF THE STUDY: The aim of this study was to investigate the ability of DHZCP to reverse doxorubicin (DOX) resistance of SMMC-7721 cells in a xenograft mouse model, and to explore the underlying mechanisms. MATERIALS AND METHODS: Liquid chromatography-mass spectrometry was used to verify the composition of DHZCP. H&E staining was used to observe the pathological changes in hepatocellular carcinoma samples. Intracellular DOX accumulation was observed as intrinsic fluorescence by microscopy. Cell apoptosis was detected by the TUNEL assay. Human antibody arrays were used to analyze the expression of apoptotic- and angiogenic-related proteins. ATP levels were assessed and western blots were used to detect the protein expression of key enzymes of energy metabolism. RESULTS: DHZCP significantly reduced the tumor volume and weight of subcutaneous xenografts of drug-resistant hepatoma cells, and combining DHZCP with lower doses of DOX significantly increased the content of DOX in tumor tissue, increased the apoptosis of hepatoma cells, and reversed Dox resistance. With respect to 43 apoptosis-associated proteins, DHZCP regulated the expression of 5 of them. When combined with low-dose DOX, the expression of 40 apoptosis-related proteins was significantly altered. With respect to 23 angiogenesis-associated proteins, DHZCP upregulated the expression of endostatin and inhibited the expression of matrix metallopeptidase 9. When combined with low-dose DOX, DHZCP significantly downregulated protein expression of urokinase receptor, as well as vascular endothelial growth factor receptors 2 and 3. Especially, DHZCP significantly inhibited the expression of key enzymes of the tricarboxylic acid cycle and of oxidative phosphorylation, reducing the level of ATP in tumor tissue. CONCLUSIONS: DHZCP inhibited the growth of DOX-resistant hepatocellular carcinoma subcutaneous xenografts in nude mice and promoted increased apoptosis caused by DOX, thus reversing DOX resistance. This was associated with a decline in energy metabolism and regulated expression of pro-apoptotic proteins. PMID- 29609010 TI - Artemisia asiatica ethanol extract exhibits anti-photoaging activity. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia asiatica Nakai is a traditional herbal plant that has long been used in anti-inflammatory, anti-infective and skin protective remedies. AIM OF THE STUDY: In this study, traditionally known skin protective activity of Artemisia asiatica Nakai was examined with its ethanol extract (Aa-EE) under various photoaging conditions using skin-originated cells, and the underlying mechanism was also examined using various types of cells. MATERIALS AND METHODS: Effects of Aa-EE on cell viability, photocytotoxicity, and expression of matrix metalloproteinases (MMPs), cyclooxygenase (COX)-2, and moisturizing factors were measured in B16F10, HEK293, NIH3T3, and HaCaT cells under untreated and ultraviolet B (UVB)-irradiation conditions. Anti-melanogenic effect of Aa-EE was also examined by measuring both melanin content in B16F10 cells and tyrosinase activity. Anti-photoaging mechanism of Aa-EE was explored by determining the activation levels of signaling molecules by immunoblotting analysis. RESULTS: Aa-EE protected HaCaT cells from UVB irradiation-induced death. Aa-EE increased the expression of a type 1 pro-collagen gene and decreased the expression of matrix metalloproteinases, and COX-2 in NIH3T3 cells induced by UVB. Aa-EE increased the expression of transglutamase-1, hyaluronic acid synthase (HAS)-2, and HAS-3 in HaCaT cells and decreased the production of melanin in alpha-melanocyte-stimulating hormone-stimulated B16F10 cells by suppressing tyrosinase activity and the expression of tyrosinase, microphthalmia-associated transcription factor, tyrosinase-related protein (TRP)-1 and TRP-2. CONCLUSION: The results suggest that Aa-EE could be skin-protective remedy with anti photoaging, anti-apoptotic, skin remodeling, moisturizing, and anti-melanogenesis properties. PMID- 29609012 TI - Antrodia cinnamomea produces anti-angiogenic effects by inhibiting the VEGFR2 signaling pathway. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The medicinal mushroom Antrodia cinnamomea has been used to treat cancer but its anti-angiogenic effects have not been studied in detail. AIM OF THE STUDY: The main objective of this study was to determine the molecular mechanism of activity underlying the anti-angiogenic effects of A. cinnamomea. MATERIALS AND METHODS: The effects of an A. cinnamomea ethanol extract (ACEE) on cell migration and microvessel formation were investigated in endothelial cells in vitro and Matrigel plugs implanted into mice in vivo. Activation of intracellular signaling pathways was examined using Western blotting. Protein expression was assessed using immunohistochemistry in a mouse model of lung metastasis. RESULTS: We show that treatment with ACEE inhibits cell migration and tube formation in human umbilical vein endothelial cells (HUVECs). ACEE suppresses phosphorylation of vascular endothelial growth factor receptor 2 (VEGFR2) and expression of pro-angiogenic kinases in vascular endothelial growth factor (VEGF)-treated HUVECs, in addition to reducing expression of Janus kinase 2 (JAK2) and phosphorylation of signal transducer and activator of transcription 3 (STAT3). ACEE treatment inhibits VEGF-induced microvessel formation in Matrigel plugs in vivo. In addition, ACEE significantly reduces VEGFR2 expression in Lewis lung carcinoma cells and downregulates the expression of cluster of differentiation 31 (CD31) and VEGFR2 in murine lung metastases. CONCLUSION: These results indicate that A. cinnamomea produces anti-angiogenic effects by inhibiting the VEGFR2 signaling pathway. PMID- 29609011 TI - Relaxant effect of Lippia origanoides essential oil in guinea-pig trachea smooth muscle involves potassium channels and soluble guanylyl cyclase. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Lippia origanoides H.B.K. is an aromatic species used in folk medicine to treat respiratory diseases, including asthma. AIM OF THE STUDY: The aim of this work was to evaluate the relaxing potential and mechanism of action of the L. origanoides (LOO) essential oil in isolated guinea-pig trachea. MATERIALS AND METHODS: Leaves from L. origanoides were collected at experimental fields under organic cultivation, at the Forest Garden of Universidade Estadual de Feira de Santana. Essential oil was extracted by hydrodistillation, analyzed by GC/FID and GC/MS and the volatile constituents were identified. Spasmolytic activity and relaxant mechanism of LOO were assayed in isolated guinea-pig trachea contracted with histamine, carbachol or hyperpolarizing KCl. RESULTS: Chemical analysis revealed the presence of carvacrol (53.89%) as major constituent. LOO relaxed isolated guinea-pig trachea pre-contracted with KCl 60 mM [EC50 = 30.02 MUg/mL], histamine 1 uM [EC50 = 9.28 MUg/mL] or carbachol 1 uM [EC50 = 51.80 MUg/mL]. The pre-incubation of glibenclamide, CsCl, propranolol, indomethacin, hexamethonium, aminophylline or L NAME in histamine-induced contractions did not alter significantly the relaxant effect of LOO. However, the presence of 4-aminopyridine, tetraethylammonium or methylene blue reduced LOO effect, while the presence of dexamethasone or atropine potentialized the LOO relaxant effect. LOO pre-incubation inhibited carbachol-evoked contractions, with this effect potentialized in the presence of sodium nitroprusside and blocked in the presence of ODQ. CONCLUSIONS: The relaxant mechanism of LOO on the tracheal smooth muscle possibly involves stimulating of soluble guanylyl cyclase with consequent activation of the voltage gated and Ca2+-activated K+ channels. PMID- 29609013 TI - Dual neutralization of both interleukin 17A and interleukin 17F with bimekizumab in patients with psoriasis: Results from BE ABLE 1, a 12-week randomized, double blinded, placebo-controlled phase 2b trial. AB - BACKGROUND: Neutralizing interleukin (IL) 17F in addition to IL-17A might provide a more complete and specific approach to inhibiting inflammation. OBJECTIVE: Assess the efficacy and safety of bimekizumab, a monoclonal antibody that potently and selectively neutralizes IL-17A and IL-17F, in patients with moderate to-severe plaque psoriasis. METHODS: Double-blinded, placebo-controlled phase 2b study (NCT02905006). Patients (randomized 1:1:1:1:1:1) received subcutaneous bimekizumab every 4 weeks at doses of 64 mg, 160 mg, 160 mg with 320 mg loading dose, 320 mg, 480 mg, or placebo. Primary endpoint was >=90% reduction in Psoriasis Area Severity Index (PASI90) at week 12. RESULTS: There was a significant (P < .0001) dose-dependent response for PASI90 (week 12); more patients achieved PASI90 in the bimekizumab groups (46.2%-79.1%) than patients in the placebo group (0%; P < .0001 all doses). Across all doses, there were significant improvements from baseline for all secondary endpoints (PASI90 week 8, PASI75 week 12, PASI100 week 12, and Investigators Global Assessment clear or almost clear weeks 8 and 12; P <= .0003) compared with placebo. More bimekizumab treated patients than placebo-treated patients achieved PASI100 (week 12) (27.9% 60.0% vs 0%; P <= .0002 all doses). Treatment-emergent adverse events were reported by 126 of 208 (61%) bimekizumab-treated patients and 15 of 42 (36%) placebo-treated patients. LIMITATIONS: No active comparator. CONCLUSION: Dual neutralization of IL-17A and IL-17F with bimekizumab provided rapid and substantial clinical improvements in patients with psoriasis, with no unexpected or dose-related safety findings. PMID- 29609014 TI - Biologics for pityriasis rubra pilaris treatment: A review of the literature. AB - Pityriasis rubra pilaris (PRP) is a rare inflammatory papulosquamous skin disease that is often refractory to conventional therapies. The off-label use of biologics, such as anti-tumor necrosis factor, anti-interleukin (IL) 12/IL-23, and anti-IL-17 agents, has been proven successful in the past 2 decades for PRP treatment. Our aim was to analyse the literature for the use of biologics in PRP treatment. We conducted a review by performing PubMed and ClinicalTrials.gov searches. Sixty-eight articles met our selection criteria and are herein discussed. Out of 86 PRP patients, the vast majority were treated with anti-tumor necrosis factor, anti-IL-12/IL-23, or anti-IL-17 biologics, either alone or in combination therapy. A marked-to-complete response was observed in 50%-78%, a partial response in 11%-25%, and no or poor response in 11%-25%. This review has several limitations, including small sample sizes and the lack of shared study design criteria. In some instances, PRP might have resolved spontaneously. Further, the presence of concomitant therapy or the lack of detailed data on previous treatments, makes it difficult to strictly define a therapeutic role per se of specific biologics in PRP. This review shows that biologics may be regarded as a tool for PRP treatment alone or in combination therapy although clinical trials are needed to better assess their efficacy and safety. PMID- 29609015 TI - Comparison of ethylenediaminetetraacetic acid-treated desmoglein ELISA and conventional desmoglein ELISA in the evaluation of pemphigus vulgaris in remission. PMID- 29609016 TI - The effect of dentine pre-treatment using bioglass and/or polyacrylic acid on the interfacial characteristics of resin-modified glass ionomer cements. AB - OBJECTIVE: To evaluate the effect of load-cycle aging and/or 6 months artificial saliva (AS) storage on bond durability and interfacial ultramorphology of resin modified glass ionomer cement (RMGIC) applied onto dentine air-abraded using Bioglass 45S5 (BAG) with/without polyacrylic acid (PAA) conditioning. METHODS: RMGIC (Ionolux, VOCO) was applied onto human dentine specimens prepared with silicon-carbide abrasive paper or air-abraded with BAG with or without the use of PAA conditioning. Half of bonded-teeth were submitted to load cycling (150,000 cycles) and half immersed in deionised water for 24 h. They were cut into matchsticks and submitted immediately to microtensile bond strength (MUTBS) testing or 6 months in AS immersion and subsequently MUTBS tested. Results were analysed statistically by two-way ANOVA and Student-Newman-Keuls test (alpha = 0.05). Fractographic analysis was performed using FE-SEM, while further RMGIC bonded specimens were surveyed for interfacial ultramorphology characterisation (dye-assisted nanoleakage) using confocal microscopy. RESULTS: RMGIC applied onto dentine air-abraded with BAG regardless PAA showed no significant MUTBS reduction after 6 months of AS storage and/or load cycling (p > 0.05). RMGIC-dentine interface showed no sign of degradation/nanoleakage after both aging regimens. Conversely, interfaces created in PAA-conditioned SiC-abraded specimens showed significant reduction in MUTBS (p < 0.05) after 6 months of storage and/or load cycling with evident porosities within bonding interface. CONCLUSIONS: Dentine pre-treatment using BAG air-abrasion might be a suitable strategy to enhance the bonding performance and durability of RMGIC applied to dentine. The use of PAA conditioner in smear layer-covered dentine may increase the risk of degradation at the bonding interface. CLINICAL SIGNIFICANCE: A combined dentine pre-treatment using bioglass followed by PAA may increase the bond strength and maintain it stable over time. Conversely, the use of PAA conditioning alone may offer no significant contribute to the immediate and prolonged bonding performance. PMID- 29609017 TI - Enhancing predicted fluoride varnish efficacy and post-treatment compliance by means of calcium-containing gummy bears. AB - OBJECTIVES: This study determined whether consumption of calcium-containing gummies prior to fluoride varnish application enhances plaque fluoride retention and compliance with post-varnish application instructions. METHODS: The present study followed a multi-center, parallel, randomized, and laboratory analyst-blind design. Following IRB approval, parent consent and child assent, 44 subjects (7 12 years), were randomized to either gummy or no-gummy study groups. A baseline plaque sample was obtained after a wash-out period. Fluoride varnish (5% NaF) was applied; subjects in the gummy group received two calcium-containing gummies prior to varnish application. Subjects were given two questionnaires to complete (subject and parent) to investigate adherence to post-treatment instructions. Three days later, a second plaque sample was obtained. Plaque was analyzed for plaque fluid and solid fluoride concentrations. Fluoride data were analyzed using Wilcoxon Rank Sum tests, questionnaire data using Pearson chi-square tests. RESULTS: Plaque fluid fluoride did not change pre- to post-treatment in the gummy group (mean +/- sd: 8.8 +/- 5.7 MUmol/l vs. 10.0 +/- 6.3 MUmol/l; p = 0.265) or in the no-gummy group (8.1 +/- 4.4 MUmol/l vs. 16.1 +/- 20.0 MUmol/l; p = 0.058). Groups were not different for plaque fluid fluoride pre-treatment (p = 1.000), post-treatment (p = 0.904), or change (p = 0.904). Plaque solid fluoride did not change pre- to post-treatment in the gummy group (0.89 +/- 1.10 MUmol/g vs. 1.37 +/- 1.77 MUmol/g; p = 0.073) or in the no-gummy group (0.68 +/- 0.77 MUmol/g vs. 2.01 +/- 5.00 MUmol/g; p = 0.190). Groups were not different for plaque solid fluoride pre-treatment (p = 1.000), post-treatment (p = 0.466), or change (p = 0.874). No significant differences were found between groups for questionnaire responses. CONCLUSION: This study failed to demonstrate an effect of calcium containing gummies in enhancing plaque fluoride retention. CLINICAL SIGNIFICANCE: The consumption of calcium-containing gummies prior to fluoride varnish application does not promote greater intra-oral fluoride retention or better adherence to post-treatment instructions. PMID- 29609018 TI - Curative resection of advanced esophageal cancer with metachronous stage IV breast cancer: A case report. AB - INTRODUCTION: Recent studies have shown the safety and efficacy of curative resection of esophageal cancer with multiple primary cancers. However, our literature search revealed no curative surgery cases for esophageal cancer in patients with multiple primary cancers with distant metastasis. CASE PRESENTATION: A 75-year-old woman visited our hospital with dysphagia. She had a history of breast cancer with multiple bone metastasis. Esophagogastroduodenoscopy revealed a circumferential mass in the upper intrathoracic esophagus. Histopathological examination of the biopsy showed squamous cell carcinoma. Other imaging findings revealed multiple nodules in the liver. The nodules were thought to have originated from the breast, but metastasis of esophageal cancer was considered a possibility. Intraoperative frozen sections of the liver and peritoneal nodules showed adenocarcinoma. Thoracoscopic esophagectomy was then performed. Following surgery, the patient received fulvestrant therapy, followed by capecitabine therapy, and the liver tumors decreased in size. She is currently alive after 1.5 years of the surgery without local recurrence of esophageal cancer. DISCUSSION: Although the patient had metastatic breast cancer, her relapse-free interval of 20 years and good response to hormone therapy for 15 years were favorable prognostic factors. Her life expectancy was estimated to be a few years and surgery was performed. CONCLUSION: Curative resection could be considered for patients with esophageal cancer who have an additional cancer with distant metastasis when the prognosis of the additional cancer is not poor. PMID- 29609019 TI - Designing aptamers which respond to intracellular oxidative stress and inhibit aggregation of mutant huntingtin. AB - Targeted expression of a therapeutic agent is a major bottleneck in designing a drug delivery system. Protein aggregation and elevated oxidative stress are associated with the onset of many neurodegenerative disorders, including Huntington's disease (HD). An oxidative stress-inducible promoter, i.e. Thioredoxin 2, was employed to design a sensor for protein aggregation. RNA aptamers specific for mutant huntingtin were expressed only in cells where aggregation of mutant huntingtin occurred. A nine-fold increase in RNA expression was seen when aptamer sequences were cloned under the Trx2 promoter. Expression of aptamer resulted in reduced protein aggregation and decreased oxidative stress, which, in turn, reduced the expression of aptamers by two-fold. Reduction in aggregation led to increased cell survival. The aptamers were not expressed in cells expressing wild-type huntingtin in the soluble form. This rational and simple design will allow the use of this construct for the targeted expression of other therapeutic nucleic acid molecules as well. PMID- 29609020 TI - Up-regulation of NOX1/NADPH oxidase following drug-induced myocardial injury promotes cardiac dysfunction and fibrosis. AB - Cardiac fibrosis is a common feature in failing heart and therapeutic strategy to halt the progression of fibrosis is highly needed. We here report on NOX1, a non phagocytic isoform of superoxide-producing NADPH oxidase, which promotes cardiac fibrosis in a drug-induced myocardial injury model. A single-dose administration of doxorubicin (DOX) elicited cardiac dysfunction accompanied by increased production of reactive oxygen species and marked elevation of NOX1 mRNA in the heart. In mice deficient in Nox1 (Nox1-/Y), cardiac functions were well retained and overall survival was significantly improved. However, increased level of serum creatine kinase was equivalent to that of wild-type mice (Nox1+/Y). At 4 days after DOX treatment, severe cardiac fibrosis accompanied by increased hydroxyproline content and activation of matrix metalloproteinase-9 was demonstrated in Nox1+/Y, but it was significantly attenuated in Nox1-/Y. When H9c2 cardiomyocytes were exposed to their homogenate, a dose-dependent increase in NOX1 mRNA was observed. Up-regulation of NOX1 mRNA in H9c2 co-incubated with their homogenate was abolished in the presence of TAK242, a TLR4 inhibitor. When isolated cardiac fibroblasts were exposed to H9c2 homogenates, increased proliferation and up-regulation of collagen 3a1 mRNA were demonstrated. These changes were significantly attenuated in cardiac fibroblasts exposed to homogenates from H9c2 harboring disrupted Nox1. These findings suggest that up regulation of NOX1 following cellular damage promotes cardiac dysfunction and fibrosis by aggravating the pro-fibrotic response of cardiac fibroblasts. Modulation of the NOX1/NADPH oxidase signaling pathway may be a novel therapeutic strategy for preventing heart failure after myocardial injury. PMID- 29609021 TI - Activation of the monocytic alpha7 nicotinic acetylcholine receptor modulates oxidative stress and inflammation-associated development of coronary artery spasm via a p38 MAP-kinase signaling-dependent pathway. AB - OBJECTIVE: Smoking and high-sensitivity C-reactive protein (hs-CRP) are risk factors for coronary artery spasm (CAS), which is characterized by the increased interleukin-6 (IL-6) level and monocyte counts; however, limited data are available regarding the role of cigarette-embedded nicotine in the modulation of monocytic inflammatory activity in CAS. APPROACH: We investigated and elucidated the putative roles and associations of nicotine, monocytic IL-6, alpha7 nicotinic acetylcholine receptor (alpha7-nAChR), and CRP in CAS development. RESULTS: We demonstrated that a significantly increased alpha7-nAChR (p = 0.001) and IL-6 (p = 0.0036) messenger RNA (mRNA) expression in the serum of patients with CAS. Serum hs-CRP levels exhibited a strong positive correlation with the monocytic mRNA expression of alpha7-nAChR (r = 0.71, p < 0.001) and IL-6 (r = 0.49, p = 0.006). The alpha7-nAChR and IL-6 expression levels of the CAS group were also positively correlated (r = 0.63, p < 0.001). Compared with the untreated controls, THP-1 cells and patient-derived monocytes treated with different concentrations of CRP displayed significantly increased expression levels of alpha7-nAChR mRNA and protein (p = 0.0054), in a dose-dependent manner. We also demonstrated that compared with the IL-6 expression elicited by CRP alone (p = 0.0489), the CRP-induced rise in monocytic IL-6 mRNA and protein expression in the presence of nicotine (p = 0.0002), is mediated by alpha7-nAChR activation and the deregulation of the human p38 mitogen-activated protein kinases (MAPK) signaling pathway. CONCLUSIONS: Our data demonstrate that the elevated monocytic IL-6 and alpha7-nAChR mRNA and protein expression levels are associated with the interaction between nicotine and CRP positively modulates CAS development. Our study suggests the potential role of alpha7-nAChR mRNA and/or protein expression as a diagnostic biomarker for CAS. PMID- 29609023 TI - Transient lens vacuoles in premature infants. AB - We report 6 cases of bilateral vacuolar lens opacities in premature infants. These uncommon opacities were multiple, located peripherally in the lens, and unrelated to the severity of retinopathy. The vacuoles were transient in nature, did not interfere with ROP examination, and were not adversely affected by antivascular endothelial growth factor treatment. On long-term follow-up, the cataracts had no effect on vision. PMID- 29609024 TI - Anastomotic Leakage and Interval between Preoperative Short-Course Radiotherapy and Operation for Rectal Cancer. AB - BACKGROUND: Short-course preoperative radiotherapy is indicated in patients with resectable rectal cancer to control local recurrence. Although no clear evidence is available, short-course radiotherapy with operation within a week is common practice. The aim of this study was to investigate the impact of timing of operation for rectal cancer after short-course radiotherapy on anastomotic leakage. STUDY DESIGN: Data from the Dutch Colorectal Audit were used. All patients who received short-course preoperative radiotherapy and underwent elective operation within 14 days for rectal cancer between January 1, 2011 and December 31, 2016 were included. Interval between radiotherapy and operation was calculated by extracting date of start of radiotherapy from the date of operation. Patients were divided into short interval (<4 days) and long interval (4 or more days). The interval and other patient or perioperative parameters were included in univariable and multivariable logistic regression analyses to identify independent associations with anastomotic leakage. RESULTS: In total, 2,131 patients were eligible for analysis: 1,055 (49.5%) patients had operations <4 days after radiotherapy and 1,076 (50.5%) patients had operations after 4 or more days. One hundred and eighty-five (8.7%) patients experienced anastomotic leakage. The incidence of anastomotic leakage was significantly higher in patients who underwent operation within <4 days (10.1% vs 7.2%; p = 0.018). In the multivariable analysis, an interval of <4 days was significantly associated with anastomotic leakage (odds ratio 1.438; 95% CI 1.054 to 1.962; p = 0.022). CONCLUSIONS: Elective surgery for rectal cancer <4 days after preoperative short course radiotherapy resulted in an increase of anastomotic leakage. PMID- 29609022 TI - NADPH-dependent and -independent disulfide reductase systems. AB - Over the past seven decades, research on autotrophic and heterotrophic model organisms has defined how the flow of electrons ("reducing power") from high energy inorganic sources, through biological systems, to low-energy inorganic products like water, powers all of Life's processes. Universally, an initial major biological recipient of these electrons is nicotinamide adenine dinucleotide-phosphate, which thereby transits from an oxidized state (NADP+) to a reduced state (NADPH). A portion of this reducing power is then distributed via the cellular NADPH-dependent disulfide reductase systems as sequential reductions of disulfide bonds. Along the disulfide reduction pathways, some enzymes have active sites that use the selenium-containing amino acid, selenocysteine, in place of the common but less reactive sulfur-containing cysteine. In particular, the mammalian/metazoan thioredoxin systems are usually selenium-dependent as, across metazoan phyla, most thioredoxin reductases are selenoproteins. Among the roles of the NADPH-dependent disulfide reductase systems, the most universal is that they provide the reducing power for the production of DNA precursors by ribonucleotide reductase (RNR). Some studies, however, have uncovered examples of NADPH-independent disulfide reductase systems that can also support RNR. These systems are summarized here and their implications are discussed. PMID- 29609025 TI - Regulation of growth, intestinal microbiota, non-specific immune response and disease resistance of sea cucumber Apostichopus japonicus (Selenka) in biofloc systems. AB - Bioflocs are not only a source of supplemental nutrition but also provide substantial probiotic bacteria and bioactive compounds, which play an important role in improving physiological health of aquatic organisms. A 60-day experiment was conducted to investigate the growth, intestinal microbiota, non-specific immune response and disease resistance of sea cucumber in biofloc systems with different carbon sources (glucose, sucrose and starch). Control (no biofloc) and three biofloc systems were set up, and each group has three replicates. The results showed that biofloc volume (BFV) and total suspended solids (TSS) increased in the sequences of glucose > sucrose > starch and green sea cucumber > white sea cucumber during the experiment. The highest specific growth rates (SGRs) were observed in biofloc system with glucose as carbon source, which also had relatively lower glucose, lactate and cortisol levels in coelomic fluid and higher glycogen content in muscle compared to other groups. There were significant increased Bacillus and Lactobacillus counts of sea cucumber intestine in biofloc systems, and the activities of superoxide dismutase (SOD), catalase (CAT) and glutathione peroxidase (GPx) also showed obvious ascending trends. Significant increases in total coelomocytes counts (TCC), phagocytosis, respiratory burst, complement C3 content and lysozyme (LSZ) and acid phosphatase (ACP) activities of sea cucumber were all found in biofloc system (glucose). The expression patterns of most immune-related genes (i.e. Hsp90, Hsp70, c-type lectin (CL), toll-like receptor (TLR)) were up-regulated, suggesting the promotion of pathogen recognition ability and immune signaling pathways activation by biofloc. Furthermore, green and white sea cucumber had significantly higher survival rates in biofloc systems during the 14-day challenge test. In conclusion, biofloc technology could improve growth and physiological health of A. japonicus, by optimizing intestinal microbiota, strengthening antioxidant ability, enhancing non-specific immune response and disease resistance against pathogens, meanwhile glucose was recommended as optimal carbon source in biofloc system of sea cucumber culturing. PMID- 29609026 TI - Waterborne Cd2+ weakens the immune responses of blood clam through impacting Ca2+ signaling and Ca2+ related apoptosis pathways. AB - Exposure to heavy metals such as Cadmium (Cd) may exert detrimental impacts on the immune responses of marine bivalve species. However, the immunotoxicity of Cd on blood clams remains unknown to date. Furthermore, though Cd2+ is known to compete with calcium (Ca2+) ions for their binding sites in cells and inhibit Ca2+ influx, whether Cd2+ weakens the immune responses of marine bivalves through inducing intracellular Ca2+ disorders still remains unclear. Therefore, the immunotoxicity of Cd2+ at different waterborne Ca2+ concentrations on blood clam, Tegillarca granosa, were investigated in the present study. Results obtained demonstrated that the total number, phagocytic activity, and red granulocytes ratio of the haemocytes were all significantly reduced after 10 days exposure of individuals to 25 MUg/L Cd2+. However, when the waterborne Ca2+ concentrations were elevated by 10% and 20% (approximately 370 and 410 mg/L, respectively), mitigation effects on the immune responses of individuals were detected. In addition, though the expressions of genes from the Ca2+ signaling and Ca2+ related apoptosis pathways were significantly altered by Cd2+ exposure, the expression patterns of these genes were similar to that of the control when the waterborne Ca2+ concentrations were elevated, suggesting a relieving effect of waterborne Ca2+ on Cd2+ induced toxicity to haemocytes. The results obtained in the present study revealed that waterborne Cd2+ may hamper the immune responses of T. granosa through influencing Ca2+ signaling and Ca2+-related apoptosis pathways, which can be partially mitigated by elevating the waterborne Ca2+ concentrations. PMID- 29609027 TI - Identification, characterization and expression analysis of MAVS in Pelodiscus sinensis after challenge with Poly I:C. AB - Pelodiscus sinensis, which is one of the important reptile species in the aquaculture industry in China, frequently suffers from serious infectious diseases caused by viruses. However, there is a lack of biological knowledge about its antiviral innate immunity. In this study, we identified and characterized the open reading frame (ORF) of PsMAVS cDNA in P. sinensis. It consisted of 2691 nucleotides encoding a protein of 896 amino acid residues, which were composed of an N-terminal CARD, a central proline-rich domain and a C terminal TM domain. Based on the amino acid sequence, phylogenetic analyses revealed a closer relationship of PsMAVS with those of Chelonia. qRT-PCR analysis indicated that PsMAVS was ubiquitously expressed in all of the examined healthy tissues with different expression levels; it was expressed at high levels in spleen, muscle and heart and at moderate levels in kidney, liver, intestine, intestinum crissum and oesophagus. PsMAVS was detected in embryos at 10 days post hatching, and it gradually upregulated with the embryonic development stage. Its expression levels in the examined tissues were all upregulated significantly after challenge with Poly I:C. The PsMAVS protein was detected in the intestinal tissues from both the challenge and the control groups, and it was distributed widely in the cytoplasm of the intestinal cells, suggesting PsMAVS plays multiple roles in the complicated mechanisms of immune defence against virus invasion in P. sinensis. PMID- 29609028 TI - Identification of clam plasma proteins that bind its pathogen Quahog Parasite Unknown. AB - The hard clam (Mercenaria mercenaria) is among the most economically-important marine species along the east coast of the United States, representing the first marine resource in several Northeastern states. The species is rather resilient to infections and the only important disease of hard clams results from an infection caused by Quahog Parasite Unknown (QPX), a protistan parasite that can lead to significant mortality events in wild and aquacultured clam stocks. Though the presence of QPX disease has been documented since the 1960s, little information is available on cellular and molecular interactions between the parasite and the host. This study examined the interactions between the clam immune system and QPX cells. First, the effect of clam plasma on the binding of hemocytes to parasite cells was evaluated. Second, clam plasma proteins that bind QPX cells were identified through proteomic (LC-MS/MS) analyses. Finally, the effect of prior clam exposure to QPX on the abundance of QPX-reactive proteins in the plasma was evaluated. Results showed that plasma factors enhance the attachment of hemocytes to QPX. Among the proteins that specifically bind to QPX cells, several lectins were identified, as well as complement component proteins and proteolytic enzymes. Furthermore, results showed that some of these lectins and complement-related proteins are inducible as their abundance significantly increased following QPX challenge. These results shed light on plasma proteins involved in the recognition and binding of parasite cells and provide molecular targets for future investigations of factors involved in clam resistance to the disease, and ultimately for the selection of resistant clam stocks. PMID- 29609029 TI - A time course study of glucose levels and innate immune response in gilthead seabream (Sparus aurata L.) after exposure to clove oil-eugenol derived anaesthetic. AB - Clove oil is used as an anaesthetic for many species of fish worldwide; however, relatively few studies have assessed its effects on the innate immune response on these species. The present work aimed to investigate the effects of clove oil eugenol derived anaesthetic on some humoral and cellular immune response in gilthead seabream (Sparus aurata L.). To compare with an unexposed control group, fish were exposed to 55 ppm clove oil for 5 min, before being sampled at 1, 24 and 48 h post-exposure. Serum glucose level was also measured to obtain information on the fish physiological response after clove oil anaesthesia. One hour after exposure the haemolytic complement activity of fish was lower than in the unexposed group. By contrast, the leucocyte peroxidase activity in head kidney was significantly stimulated 24 h after exposure to clove oil-eugenol. The rest of innate immune parameters evaluated and the glucose levels not were affected by clove oil exposure at any sampling point. Overall, the use of clove oil at 55 ppm as anaesthetic did not seem to alter the innate immune response and neither did it trigger a stress response. The use of clove oil-eugenol derived had become common practice in aquaculture, and its use with gilthead seabream can be considered safe as it does not cause immunodepression in anesthetized fish. PMID- 29609030 TI - A Prokineticin (PK)-like cytokine from Chinese mitten crab Eriocheir sinensis promotes the production of hemocytes via reactive oxygen species. AB - Astakine is a cytokine-like factor containing a prokineticin domain, which directly participates in hematopoiesis and blood cell differentiation. In the present study, a novel Astakine gene was identified from Chinese mitten crab Eriocheir sinensis (designated as EsAst). The full-length cDNA of EsAst was of 1163 bp, consisting of a 5' untranslated region (UTR) of 120 bp, a 3' UTR of 656 bp, and an open reading frame (ORF) of 387 bp encoding a polypeptide of 128 amino acids. There were a signal peptide and a prokineticin domain with nine conserved cysteine residues in the deduced amino acid sequence of EsAst. EsAst shared higher similarity with Astakines from Penaeus monodon and Pacifastacus leniusculus, and it was closely clustered with the Astakine from shrimp P. monodon in the phylogenetic tree. The EsAst mRNA transcript was higher expressed in hemocytes and hepatopancreas. The relative expression level of EsAst in hemocytes was continuously increased from 1.5 to 48 h after Vibro anguillarum challenge compared that in the untreated control group. After Pichia pastoris GS115 challenge, the relative expression level of EsAst in hemocytes was also up regulated. After rEsAst injection, ROS levels in HPT cells were also increased at 12 and 24 h, and the total hemocyte counts were also significantly increased at 6, 9, 12, and 24 h post rEsAst injection. The interference of EsAst expression with dsRNA injection could delay the recovery of hemocytes production post A. hydrophila stimulation. When mitochondrial complexes I was knock down by dsRNA, ROS levels were decreased and THCs were also decreased. Recovery of hemocyte production inducing by A. hydrophila stimulation and rEsAst injection were delayed with dsEsbc1 injection. When ROS levels were increased after RNAi of Lon protease, THCs were also increased. The expression levels of five genes (EsJNK, EsSTAT, EsPI3K, EsAKT1, EsP70S6K) involved in SAPK-JNK and mTOR signaling pathways were up-regulated at 12 and 24 h in rEsAst group and EsLon dsRNA group compared with that in EGFP dsRNA group, and were similar to the trend of ROS levels. These results collectively suggested that EsAst should be a novel Astakine to promote the production of hemocytes in a ROS-dependent way in E. sinensis. PMID- 29609031 TI - Laparoscopic Ligation of Uterine Vasculature for Fertility-Sparing Management of Postabortal Hemorrhage. AB - STUDY OBJECTIVE: To present a surgical video in which bilateral uterine vasculature was ligated laparoscopically in order to preserve the uterus in a patient with postabortal hemorrhage. DESIGN: A case report (Canadian Task Force classification III). SETTING: A tertiary referral center in New Haven, CT. INTERVENTIONS: This is a step-by-step demonstration of laparoscopic ligation of the uterine vasculature in a patient with postabortal hemorrhage. The patient was a 33-year-old Para 4014 woman who presented with postabortal hemorrhage after she underwent an urgent dilation and evacuation for the management of symptomatic placenta accreta at 19 weeks of pregnancy. The patient underwent a physical examination when she presented to the emergency department with postabortal hemorrhage. She was hemodynamically stable, and the examination was negative for cervical or vaginal lacerations. Coagulation studies were negative for any coagulopathy. A pelvic ultrasound did not show any retained products of conception. As per the Society of Family Planning guidelines, uterine massage was performed, and uterotonics (i.e., methylergonovine maleate 0.2 mg intramuscularly and misoprostol 1000 mg per rectum) were given [1]. The postabortal hemorrhage persisted despite medical therapy with an approximate blood loss of 600 mL over 2 hours. An intrauterine tamponade balloon was placed, and the patient then underwent a uterine angiogram and bilateral uterine artery embolization secondary to continued vaginal bleeding despite medical management. She was closely monitored and noted to have another 500 mL of blood loss over 2 hours after completion of uterine artery embolization. At this point, she was resuscitated with 2 U red blood cells because she developed symptoms of hemodynamic instability. Her hematocrit was increased suboptimally after transfusion with stabilization of her vitals. The patient was then counseled on her surgical options because she had failed medical management, intrauterine balloon tamponade, and uterine artery embolization. She stated a strong desire to preserve her uterus. Given her overall hemodynamic stability, laparoscopic ligation of the uterine vessels was proposed, which she agreed on [2]. Risks of the laparoscopic approach were explained to the patient, which included injury to the uterus, ureters, blood vessels, and nerves as well as the possibility of conversion to laparotomy. The surgery started with exploration of the peritoneal cavity. Her uterus was noted to be significantly enlarged with many engorged vessels. In order to decrease the risk of uterine perforation in this bulky and highly vascular uterus, the surgeon decided not to place a uterine manipulator. The retroperitoneum was entered at the right pelvic sidewall. Pararectal and paravesical spaces were then developed. Ureterolysis was performed in order to free its peritoneal and uterine artery attachments. The uterine artery was skeletonized cephalad to the hypogastric bifurcation and was ligated with 5-mm vascular clips. The attention was then turned to the ovarian vessels at the cornu of the uterus. Peritoneal avascular windows were created inferior and superior to the vessels. The blood supply was then ligated with an absorbable suture, and the ligature was secured using the extracorporeal knot tying technique. The same steps were repeated on the left pelvic sidewall. The procedure was completed once excellent hemostasis was assured. Besides the technical steps of the procedure, pelvic anatomic landmarks have also been emphasized in this video for educational purposes. MEASUREMENTS AND MAIN RESULTS: Laparoscopic ligation of the uterine vasculature was performed without any complications. The operative time was 65 minutes, and blood loss was minimal. The patient had an uneventful postoperative course and was discharged home the day after her laparoscopic surgery. CONCLUSION: The uterus was preserved with this minimally invasive approach for the management of postabortal hemorrhage. Laparoscopic ligation of the uterine vessels should be considered in hemodynamically stable patients who desire future fertility when managing postabortal hemorrhage. PMID- 29609032 TI - Surgical Excision Versus Ablation for Superficial Endometriosis-Associated Pain: A Randomized Controlled Trial. AB - STUDY OBJECTIVE: To compare surgical excision and ablation of endometriosis for treatment of chronic pelvic pain. DESIGN: Randomized clinical trial with 12-month follow-up (Canadian Task Force classification I). SETTING: Single academic tertiary care hospital. PATIENTS: Women with minimal to mild endometriosis undergoing laparoscopy. INTERVENTIONS: Excision or ablation of superficial endometriosis at the time of robot-assisted laparoscopy. MEASUREMENTS AND MAIN RESULTS: Primary outcome was visual analog scale (VAS) scoring at baseline and 6 and 12 months for menstrual pain, nonmenstrual pain, dyspareunia, and dyschezia. Secondary outcomes included survey results at baseline and 6 and 12 months from the Short Form Health Survey, Pelvic Organ Prolapse/Urinary Incontinence Sexual Function Questionnaire, and the International Pelvic Pain Assessment. From December 2013 to October 2014, 73 patients were randomized intraoperatively to excision (n = 37) or ablation (n = 36) of endometriosis. Patients were followed at 6 and 12 months to evaluate the above outcomes. After ablation of endometriosis, dyspareunia (VAS scores) improved at 6 months (mean change [MC], 14.07; 95% confidence interval [CI], -25.93 to -2.21; p = .02), but improvement was not maintained at 12 months. Dysmenorrhea improved at 6 months (MC, -26.99; 95% CI, -41.48 to -12.50; p < .001) and 12 months (MC, -24.15; 95% CI, 39.62 to 8.68; p = .003) with ablation. No significant changes were seen in VAS scores after excision at 6 or 12 months. When comparing ablation and excision, the only significant difference was a change in dyspareunia at 6 months (MC, -22.96; 95% CI, -39.06 to -6.86; p = .01). CONCLUSION: Treatment with ablation improved dysmenorrhea at 6 and 12 months and improved dyspareunia at 6 months as compared with preoperative data. However, only dyspareunia demonstrated a significant difference between ablation and excision. Excision and ablation showed similar effectiveness for the treatment of pain associated with superficial endometriosis, with ablation showing more significant individual changes. Careful patient counseling regarding expectations of surgical intervention is vital in the management of endometriosis. PMID- 29609033 TI - Transvaginal Natural Orifice Transluminal Endoscopic Surgery Sacrocolpopexy: Tips and Tricks. AB - STUDY OBJECTIVE: To demonstrate helpful tips and tricks for the successful use of transvaginal natural orifice transluminal endoscopic surgery (NOTES) for performing sacrocolpopexy and salpingo-oophorectomy surgery. Minimally invasive approaches for treating pelvic organ prolapse via sacrocolpopexy have traditionally included laparoscopy either with or without robotic assistance. Transvaginal NOTES is a novel minimally invasive approach that both avoids abdominal incisions and provides improved visualization; however, it can be technically challenging. DESIGN: Stepwise demonstration with narrated video footage (Canadian Task Force classification III). SETTING: An academic tertiary care hospital in Guangdong, China. PATIENT: A 61-year-old gravida 3, para 3 woman with 3 spontaneous vaginal deliveries and stage III uterine prolapse, stage III cystocele, and stage III rectocele. The preoperative vaginal length was 6 cm. INTERVENTION: After performing vaginal hysterectomy, we show the usefulness of NOTES for salpingo-oophorectomy. We also demonstrate useful techniques for transvaginal NOTES sacrocolpopexy including hydrodissection, division of the Y mesh, anchoring of the anterior mesh before reducing prolapse, retroperitoneal tunneling, and hand suturing of the mesh and vaginal cuff. MEASUREMENTS AND MAIN RESULTS: The procedure was successfully performed in approximately 190 minutes. The postoperative vaginal length was 5 cm. Postoperative pelvic organ prolapse quantification was stage 0. CONCLUSION: The transvaginal NOTES approach is feasible and efficient for sacrocolpopexy and salpingo-oophorectomy; additionally, it is a reasonable option for patients who desire a minimally invasive approach with excellent cosmetic results. Surgical techniques that aid in effectively performing transvaginal NOTES sacrocolpopexy include the use of hydrodissection, Y mesh division, anterior mesh anchoring before reducing prolapse, retroperitoneal tunneling, and hand suturing. Using the techniques presented here, we were able to insert the port only 1 time, which improves the efficiency and safety of this surgery. PMID- 29609034 TI - Magnetic Resonance Imaging-Guided High-Intensity Focused Ultrasound is a Noninvasive Treatment Modality for Patients with Abdominal Wall Endometriosis. AB - Two women (29 and 35 years of age) presented with an abdominal wall mass in close proximity to a cesarean scar. The main complaints consisted of pain at the site of the mass with catamenial exacerbations. Clinical and imaging findings were consistent with abdominal wall endometriosis in both cases. First, hormonal treatment was started, which proved unsuccessful. Typically, at this point, the proposed treatment would be wide surgical excision. Alternatively, magnetic resonance imaging-guided high-intensity focused ultrasound treatment was offered with the goal to diminish pain complaints noninvasively. Upon treatment, both patients' complaints diminished although some cyclic pain persisted. Overall, these cases show that magnetic resonance imaging-guided high-intensity focused ultrasound can be used as a noninvasive treatment method to reduce complaints in patients with abdominal wall endometriosis. PMID- 29609035 TI - Effect of Pregnancy on the Management and Outcomes of Ovarian Torsion: A Population-Based Matched Cohort Study. AB - STUDY OBJECTIVE: To compare the treatment and surgical outcomes of ovarian torsion in pregnant and nonpregnant women. DESIGN: A population-based matched cohort study (Canadian Task Force classification II.1). SETTING: The United States Health Care Cost and Utilization Project Nationwide Inpatient Sample from 2003 to 2011. PATIENTS: All cases of ovarian torsion among pregnant women and nonpregnant women with ovarian torsion (matched by age in a ratio of 1:1). INTERVENTIONS: Outcomes of interest included the type of treatment received for ovarian torsion and the complications of surgery. MEASUREMENTS AND MAIN RESULTS: There were 1366 women diagnosed with ovarian torsion among 8 532 163 pregnant women for an incidence of 1.6 in 10 000. Surgery was the predominant treatment, with laparotomy being more commonly performed on pregnant women versus nonpregnant women (57.0% vs 51.0%; odds ratio = 1.28; 95% confidence interval, 1.08-1.51; p < .01). Overall conservative management was less likely performed; however, it was more common among pregnant women versus nonpregnant women (odds ratio = 1.85; 95% confidence interval, 1.44-2.37; p < .01). In general, adverse events were uncommon in both groups although ovarian infarction was more commonly reported among nonpregnant women. CONCLUSION: The diagnosis of ovarian torsion in pregnancy is rare. Compared with nonpregnant women, laparotomy and conservative management are more common among pregnant women. Treatment of ovarian torsion in pregnancy has comparable outcomes with treatment in nonpregnant women. PMID- 29609037 TI - alpha-cyano-4-hydroxycinnamate impairs pancreatic cancer cells by stimulating the p38 signaling pathway. AB - Multiple studies are currently targeting dysregulated cancer cell metabolism with distinct combinations of inhibitors. In this study, we evaluated in pancreatic cancer cells metformin, which blocks oxidative phosphorylation, in combination with alpha-cyano-4-hydroxycinnamate, which has been reported to inhibit the export of lactate from the cytosol. The combination of metformin with alpha-cyano 4-hydroxycinnamate had a major inhibitory effect on the migration of 6606PDA cells. Monotherapy with alpha-cyano-4-hydroxycinnamate and especially the combination with metformin also caused significant inhibition of cell proliferation and induced cell death. alpha-cyano-4-hydroxycinnamate in combination with metformin reduced the export of lactate significantly, whereas alpha-cyano-4-hydroxycinnamate monotherapy only modestly influenced lactate export. None of these two drugs inhibited the expression of distinct glycolytic enzymes. Interestingly, alpha-cyano-4-hydroxycinnamate rather inhibited the ERK and very strongly stimulated the p38 signaling pathway in 6606PDA as well as in 7265PDA cells. In addition, the inhibition of the p38 signaling pathway by PH 797804 partially reversed the effect of alpha-cyano-4-hydroxycinnamate on cell apoptosis in both cell lines. We conclude that alpha-cyano-4-hydroxycinnamate monotherapy and especially the combinatorial therapy with metformin has strong anti-cancerous effects. alpha-cyano-4-hydroxycinnamate causes cancer cell apoptosis by a novel mechanism for this drug, namely the stimulation of the p38 signaling pathway. PMID- 29609036 TI - RNA-seq analysis reveals differences in transcript abundance between cultured and sand fly-derived Leishmania infantum promastigotes. AB - Leishmania infantum is responsible for human and canine leishmaniasis in the Mediterranean basin, where the major vector is Phlebotomus perniciosus. Because isolation of sufficient parasites from the sand fly gut is technically challenging, axenic cultivation of promastigotes is routinely used to obtain material for biochemical and genetic analyses. Here, we report the use of Spliced Leader RNA-seq (SL-seq) to compare transcript abundance in cultured promastigotes and those obtained from the whole midgut of the sand fly 5 days after infection. SL-seq allows for amplification of RNA from the parasite avoiding contamination with RNA from the gut of the insect. The study has been performed by means of a single technical replicate comparing pools of samples obtained from sand fly derived (sfPro) and axenic culture promastigotes (acPro). Although there was a moderate correlation (R2 = 0.83) in gene expression, 793 genes showed significantly different (>=2-fold, p <0.05) mRNA levels in sand fly-derived promastigotes and in culture, of which 31 were up-regulated >=8-fold (p < 10-8 in most cases). These included several genes that are typically up-regulated during metacyclogenesis, suggesting that sand fly-derived promastigotes contain a substantial number of metacyclics, and/or that their differentiation status as metacyclics is more advanced in these populations. Infection experiments and studies evaluating the proportion of metacyclic promastigotes in culture and within the sand fly gut, previously reported by us, support the last hypothesis. PMID- 29609038 TI - A novel HRM assay for differentiating classical strains and highly pathogenic strains of type 2 porcine reproductive and respiratory syndrome virus. AB - Differentiation of classical strains and highly pathogenic strains of porcine reproductive and respiratory syndrome virus is crucial for effective vaccination programs and epidemiological studies. We used nested PCR and high resolution melting curve analysis with unlabeled probe to distinguish between the classical and the highly pathogenic strains of this virus. Two sets of primers and a 20 bp unlabeled probe were designed from the NSP3 gene. The unlabeled probe included two mutations specific for the classical and highly pathogenic strains of the virus. An additional primer set from the NSP2 gene of the highly pathogenic vaccine strain JXA1-R was used to detect its exclusive single nucleotide polymorphism. We tested 107 clinical samples, 21 clinical samples were positive for PRRSV (consistent with conventional PCR assay), among them four were positive for the classical strain with the remainder 17 for the highly pathogenic strain. Around 10 degrees C difference between probe melting temperatures showed the high discriminatory power of this method. Among highly pathogenic positive samples, three samples were determined as positive for JXA1-R vaccine-related strain with a 95% genotype confidence percentage. All these genotyping results using the high resolution melting curve assay were confirmed with DNA sequencing. This unlabeled probe method provides an alternative means to differentiate the classical strains from the highly pathogenic porcine reproductive and respiratory syndrome virus strains rapidly and accurately. PMID- 29609039 TI - Computer-aided diagnosis of cavernous malformations in brain MR images. AB - Cavernous malformation or cavernoma is one of the most common epileptogenic lesions. It is a type of brain vessel abnormality that can cause serious symptoms such as seizures, intracerebral hemorrhage, and various neurological disorders. Manual detection of cavernomas by physicians in a large set of brain MRI slices is a time-consuming and labor-intensive task and often delays diagnosis. In this paper, we propose a computer-aided diagnosis (CAD) system for cavernomas based on T2-weighted axial plane MRI image analysis. The proposed technique first extracts the brain area based on atlas registration and active contour model, and then performs template matching to obtain candidate cavernoma regions. Texture, the histogram of oriented gradients and local binary pattern features of each candidate region are calculated, and principal component analysis is applied to reduce the feature dimensionality. Support vector machines (SVMs) are finally used to classify each region into cavernoma or non-cavernoma so that most of the false positives (obtained by template matching) are eliminated. The performance of the proposed CAD system is evaluated and experimental results show that it provides superior performance in cavernoma detection compared to existing techniques. PMID- 29609040 TI - Clinico-hematological profile and thrombotic/hemorrhagic events in 150 chinese patients with essential thrombocythemia. AB - Essential thrombocythemia (ET) is an uncommon chronic myeloproliferative disorder with no cure. Patients with ET are at risk of different complications, and currently there are no optimal prognostic standards to predict severe post diagnosis complications such as thrombosis and hemorrhage. In this study, we retrospectively analyzed the full set of clinical data from 150 Chinese patients with ET enrolled from 2013 to 2016. We discovered that neutrophil-to-lymphocyte ratio (NLR), along with other known clinical parameters such as age, leukocyte count, incidence of thrombotic events is higher in patients with JAK2 V617F mutation. NLR is also higher in patients at high-risk stratification of thrombosis. Multivariate analysis showed that age (P = 0.001, 95% CI 1.023-1.089) and JAK2 V617F mutation (P = 0.003, 95% CI 1.837-21.035) were independent factors for thrombotic events, while age (P = 0.005, 95% CI 1.019-1.111) was the only predictive factor for hemorrhagic events at diagnosis. For future thrombotic events, multivariate analysis revealed NLR as the best predictive parameter (P < 0.001, 95% CI 1.173-1.486) when compared with other clinical parameters such as age (P = 0.037, 95% CI 1.004-1.126), thrombosis at diagnosis (P = 0.036, 95% CI 1.077-9.099) and WBC count (P = 0.047, 95% CI 1.001-1.109). Further ROC curve and Kaplan Meier analysis validated NLR as better prognostic marker for future thrombotic events and thrombosis-free survival. In summary, our data suggest that NLR parameter may possess great prognostic significance for future thrombosis in ET patients. PMID- 29609041 TI - Lifetime physical inactivity is associated with increased risk for Hodgkin and non-Hodgkin lymphoma: A case-control study. AB - BACKGROUND: Although physical activity is a well-established risk factor for several cancer types, studies evaluating its association with lymphoma have yielded inconclusive results. In such cases where physical activity is not clearly associated with cancer risk in a dose-dependent manner, investigators have begun examining physical inactivity as an independent exposure of interest. METHODS: Associations of self-reported, lifetime physical inactivity with risk of developing Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL) were evaluated in a hospital-based case control study using data from the Patient Epidemiology Data System at Roswell Park Comprehensive Cancer Center. Participants included 87 patients with HL and 236 patients with NHL as well as 348 and 952 cancer-free controls, respectively. Multivariable-adjusted logistic regression models were fit to calculate odds ratios (OR) and 95% confidence intervals (CI) estimating the association between physical inactivity and lymphoma risk. RESULTS: We observed significant, positive associations between lifetime recreational physical inactivity and risk of both HL (OR = 1.90, 95% CI: 1.15-3.15) and NHL (OR = 1.35, 95% CI: 1.01-1.82). CONCLUSIONS: The current analysis provides evidence for a positive association between physical inactivity and risk of both HL and NHL. These results add to a growing body of research suggesting that lifetime physical inactivity may be an important independent, modifiable behavioral risk factor for cancer. PMID- 29609042 TI - The primate fovea: Structure, function and development. AB - A fovea is a pitted invagination in the inner retinal tissue (fovea interna) that overlies an area of photoreceptors specialized for high acuity vision (fovea externa). Although the shape of the vertebrate fovea varies considerably among the species, there are two basic types. The retina of many predatory fish, reptilians, and birds possess one (or two) convexiclivate fovea(s), while the retina of higher primates contains a concaviclivate fovea. By refraction of the incoming light, the convexiclivate fovea may function as image enlarger, focus indicator, and movement detector. By centrifugal displacement of the inner retinal layers, which increases the transparency of the central foveal tissue (the foveola), the primate fovea interna improves the quality of the image received by the central photoreceptors. In this review, we summarize - with the focus on Muller cells of the human and macaque fovea - data regarding the structure of the primate fovea, discuss various aspects of the optical function of the fovea, and propose a model of foveal development. The "Muller cell cone" of the foveola comprises specialized Muller cells which do not support neuronal activity but may serve optical and structural functions. In addition to the "Muller cell cone", structural stabilization of the foveal morphology may be provided by the 'z-shaped' Muller cells of the fovea walls, via exerting tractional forces onto Henle fibers. The spatial distribution of glial fibrillary acidic protein may suggest that the foveola and the Henle fiber layer are subjects to mechanical stress. During development, the foveal pit is proposed to be formed by a vertical contraction of the centralmost Muller cells. After widening of the foveal pit likely mediated by retracting astrocytes, Henle fibers are formed by horizontal contraction of Muller cell processes in the outer plexiform layer and the centripetal displacement of photoreceptors. A better understanding of the molecular, cellular, and mechanical factors involved in the developmental morphogenesis and the structural stabilization of the fovea may help to explain the (patho-) genesis of foveal hypoplasia and macular holes. PMID- 29609043 TI - Evaluation of HE4 and TTR for diagnosis of ovarian cancer: Comparison with CA 125. AB - OBJECTIVE: Serum human epididymis protein 4 (HE4) and transthyretin (TTR) are new markers for ovarian cancer. We compared HE4 and TTR with the gold marker CA-125 for the diagnosis of ovarian cancer patients. METHODS: One hundred and thirty serum samples from benign ovarian tumor and 400 serum samples from healthy women were used to set up the cut-off. One hundred and twenty-six serum samples from ovarian cancer patients before operation were collected to test the diagnostic value of these ELISA assays. The sensitivity, positive predictive value (PPV) and ROC curves were used to evaluate the diagnostic value. RESULTS: For CA-125, the sensitivity and PPV were respectively 64.29% and 53.57% for stage I-II cancer patients, and respectively 91.43% and 88.57% for stage III-IV cancer patients. For HE4, the sensitivity and PPV were respectively 46.4% and 43.3% for stage I-II cancer patients, and respectively 88.6% and 49.2% for stage III-IV cancer patients. For TTR, the sensitivity and PPV were respectively 78.6% and 68.8% for stage I-II cancer patients, and respectively 82.9% and 74.3% for stage III-IV cancer patients. For CA125, the ROC was respectively 0.7941 and 0.9520 for stage I-II patients and stage III-IV patients. For HE4, the diagnostic value of ROC was 0.7071 for stage I-II cancer patients and 0.9250 for stage III-IV cancer patients. For TTR, the diagnostic value of ROC was 0.9112 for stage I-II cancer patients and 0.9322 for stage III-IV cancer patients. CONCLUSION: Our results support that TTR is an efficient serum marker for the diagnosis of early stage ovarian cancer patients. PMID- 29609044 TI - Design, development and application of whole-cell based antibiotic-specific biosensor. AB - Synthetic biology techniques hold great promise for optimising the production of natural products by microorganisms. However, evaluating the phenotype of a modified bacterium represents a major bottleneck to the engineering cycle - particularly for antibiotic-producing actinobacteria strains, which grow slowly and are challenging to genetically manipulate. Here, we report the generation and application of antibiotic-specific whole-cell biosensor derived from TetR transcriptional repressor for use in identifying and optimising antibiotic producers. The constructed biosensor was successfully used to improve production of polyketide antibiotic pamamycin. However, an initial biosensor based on native genetic elements had inadequate dynamic and operating ranges. To overcome these limitations, we fine-tuned biosensor performance through alterations of the promoter and operator of output module and the ligand affinity of transcription factor module, which enabled us to deduce recommendations for building and application of actinobacterial biosensors. PMID- 29609045 TI - CRISPR/Cas9 editing genome of extremophile Halomonas spp. AB - Extremophiles are suitable chassis for developing the next generation industrial biotechnology (NGIB) due to their resistance to microbial contamination. However, engineering extremophiles are not an easy task. Halomonas, an industrially interesting halophile able to grow under unsterile and continuous conditions in large-scale processes, can only be engineered using suicide plasmid-mediated two step homologous recombination which is very laborious and time-consuming (up to half a year). A convenient approach for the engineering of halophiles that can possibly be extended to other extremophiles is therefore urgently required. To meet this requirement, a rapid, efficient and scarless method via CRISPR/Cas9 system was developed in this study for genome editing in Halomonas. The method achieved the highest efficiency of 100%. When eight different mutants were constructed via this special CRISPR/Cas9 method to study the combinatorial influences of four different genes on the glucose catabolism in H. bluephagenesis TD01, it took only three weeks to complete the deletion and insertion of up to 4.5 kb DNA. H. bluephagenesis was designed to produce a microbial copolymer P(3HB co-3HV) consisting of 3-hydroxybutyrate (3HB) and 3-hydroxyvalerate (3HV). The CRISPR/Cas9 was employed to delete the prpC gene in H. bluephagenesis TD01. Shake flask studies showed that the 3HV fraction in the copolymers increased approximately 16-folds, demonstrating enhanced effectiveness of the DeltaprpC mutant to synthesize PHBV. This genome engineering strategy significantly speeds up the studies on Halomonas engineering, opening up a wide area for developing NGIB. PMID- 29609046 TI - A novel technique for cervical gastro-oesophageal anastomosis during minimally invasive oesophagectomy. AB - BACKGROUND: Anastomotic leakage, fibrous stricture and gastro-oesophageal reflux are three major complications of gastro-oesophageal anastomosis, particularly in cervical anastomosis. Our aim was to evaluate the safety and efficacy of a novel cervical anastomosis technique (NA) by comparing it to traditional side-to-side anastomosis (SS) and end-to-side anastomosis using a circular stapler (CS) in terms of postoperative leakage, stricture and reflux. METHODS: A total of 390 patients with thoracic oesophageal cancer underwent minimally invasive oesophagectomy with cervical anastomosis (192 with NA, 34 with SS and 164 with CS) in our institute from January 2013 and May 2016. A detailed description of the surgical procedure is provided, and the major postoperative complications, including postoperative leakage, stricture and reflux, were compared using a three-armed controlled study. RESULTS: The anastomotic method was an independent risk factor for anastomotic leakage, as well as stricture and reflux. The rate of anastomotic leakage of the NA group (1.0%) was significantly lower than that in the SS group (8.8%, P = 0.025) and in the CS group (8.5%, P = 0.001). The rate of anastomotic stricture in the NA group was not significantly different than that in the SS group (1.5% vs. 2.9%, P = 0.368) but was significantly lower than that in the CS group (1.5% vs. 18.9%, P < 0.001). The incidence of gastro-oesophageal reflux in the NA group was significantly lower than that in the SS group and the CS group (5.7% vs. 23.5% and 18.3%, P = 0.003 and 0.001, respectively). CONCLUSION: Jiang's anastomosis technique remarkably reduces the incidence of gastro-oesophageal anastomotic leakage, stricture and reflux, and it is a safe and effective technique for minimally invasive oesophagectomy. PMID- 29609047 TI - Lymphovascular invasion as a predictor for lymph node metastasis and a prognostic factor in gastric cancer patients under 70 years of age: A retrospective analysis. AB - BACKGROUND: Accumulating evidence has confirmed the potential prognostic value of LVI in patients with cancers. This aim of the current study was to clarify the potential relationship between LVI and lymph node metastasis, establish predictive clinicopathologic prognostic factors for LVI and lymph node metastasis, and determine the prognostic significance of LVI for patients younger than 70 years with resected gastric cancer. METHODS: Overall survival rates were calculated using Kaplan-Meier analysis. Differences in proportions of patients were tested with the chi2 test. Univariate and multivariate analyses were applied to identify independent prognostic factors. Logistic regression analysis was employed to identify the risk factors predicting the presence of LVI and LN metastasis. RESULTS: Univariate analysis led to the identification of tumor size, LVI and pN stage as factors significantly correlated with prognosis. Multivariate analysis demonstrated that tumor size, LVI, pN stage, and number of LNs retrieved are independent prognostic factors for the entire population. Logistic regression analysis proved that LVI and pT stage were significantly associated with LN metastasis. CONCLUSION: LVI is an independent prognostic factor predicting LN metastasis and a strongly independent predictor of survival for patients with resected gastric cancer. We recommend that LVI should be taken into account as an important adjuvant prognostic factor, specially for pN0 cases with inadequate LNs retrieved. And the maximum number of LNs possible should be retrieved for optimal staging, especially for patients with higher cT stage. PMID- 29609048 TI - Use of immunology and immunodeficiency topics in UpToDate. PMID- 29609049 TI - Type 2 Biomarkers and Prediction of Future Exacerbations and Lung Function Decline in Adult Asthma. AB - BACKGROUND: Type 2 biomarkers that predict both likelihood of future severe exacerbations and response to mAb therapy in asthma would be useful clinically in identifying patients both at greater risk of hospitalization and most likely to benefit from mAb therapy. OBJECTIVE: To describe the association between type 2 biomarkers, blood eosinophils, fractional exhaled nitric oxide (Feno), serum periostin, and serum IgE, and time to severe exacerbation in a broad asthma population. METHODS: Participants from 2 adult asthma cohorts with baseline measurements of blood eosinophils, Feno, serum periostin, and serum IgE were reviewed after at least 12 months to obtain an exacerbation history, corroborated with general practitioner and hospital medical records. The association between baseline type 2 biomarkers and time to exacerbation was described by Cox proportional hazard ratios (HRs) using multivariate models. RESULTS: A total of 212 participants were followed for a median (range) 3.8 (1.1-5.3) years; 67 of 212 (32%) had at least 1 severe exacerbation. The HRs (95% CI) of baseline type 2 biomarkers and time to exacerbation were as follows: blood eosinophils per 0.1 * 109/L increase, 0.89 (0.76-1.05), P = .17; log Feno per 0.693 increase, 0.65 (0.52-0.81), P < .001; log serum periostin per 0.693 increase, 0.62 (0.35-1.09), P = .10; log serum IgE per 0.693 increase, 0.89 (0.80-1.00), P = .05. CONCLUSIONS: The positive association between type 2 biomarkers and risk of severe exacerbations in populations with severe refractory asthma does not extend to mild and moderate asthma. Non-type 2 asthma may represent a phenotype associated with an increased risk of severe exacerbations in a broad asthma population. PMID- 29609050 TI - Poisoning histories in the Italian renaissance: The case of Pico Della Mirandola and Angelo Poliziano. AB - Giovanni Pico della Mirandola and Angelo Poliziano were two of the most important humanists of the Italian Renaissance. They died suddenly in 1494 and their deaths have been for centuries a subject of debate. The exhumation of their remains offered the opportunity to study the cause of their death through a multidisciplinary research project. Anthropological analyses, together with documentary evidences, radiocarbon dating and ancient DNA analysis supported the identification of the remains attributed to Pico. Macroscopic examination did not reveal paleopathological lesions or signs related to syphilis. Heavy metals analysis, carried out on bones and mummified tissues, showed that in Pico's remains there were potentially lethal levels of arsenic, supporting the philosopher's poisoning theory reported by documentary sources. The arsenic concentrations obtained from analysis of Poliziano's remains, are probably more related to an As chronic exposure or diagenetic processes rather than poisoning. PMID- 29609051 TI - Effects of sucrose ester structures on liposome-mediated gene delivery. AB - : Sucrose esters (SEs) have great potential applications in gene delivery because of their low toxicity, excellent biocompatibility, and biodegradability. By using tripeptide-based lipid (CDO) as a model lipid and SEs as helper lipids, a series of liposomes were prepared. The SEs with hydrophilic-lipophilic balance (HLB) values of 1, 6, 11, or 16 and the fatty acids of laurate, stearate, or oleate were used in the liposomes. We investigated the effect of HLB values of SEs and fatty acid types on gene transfection efficiency and toxicity of liposomes. The results showed that transfection efficiencies of the liposomes containing SEs with HLB value of 6 were superior to other liposomes in HeLa, MCF-7, NCI-H460, and A549 tumor cells. For the same HLB value, liposomes of laurate SEs were preferable to transfect cells compared to SEs of stearate and oleate. The liposomes with SEs showed higher cellular uptake than liposome without SEs (LipoCDO). LipoL12-6/Luc-siRNA treatment on tumor-bearing mice exhibited about 60% in vivo gene silencing of luciferase, and LipoL12-6 could mediate IGF-1R siRNA to greatly inhibit tumor growth. Moreover, liposomes with SEs revealed remarkably low toxicity in vitro and in vivo. The illustration of SE structures on gene delivery will promote the use of SEs for clinical trials of liposomes. STATEMENT OF SIGNIFICANCE: This article is the first to study the effects of various chain lengths and hydrophilic-lipophilic balance (HLB) of sucrose esters (SEs) on gene transfection efficiency and safety of liposomes for gene delivery. The in vitro delivery of pDNA and siRNA by lipoplexes against HeLa, MCF-7, NCI H460, and A549 tumor cells showed that the lipoplexes could lead to better transfection and lower cytotoxicity after the addition of SEs. SEs with shorter chain and a median HLB value could provide the liposomes with much higher gene transfection efficiency than others. The in vivo delivery of siRNA to tumor bearing mice further confirmed that liposome containing laurate SE (LipoL12-6) could be a potential therapeutic vector, as it delivered siRNA to silence nearly 60% of the luciferase in tumors and also greatly inhibited the tumor growth. Therefore, the addition of SEs to liposomes proved to be relatively safe in vitro and in vivo. These preliminary results demonstrated that SEs show great potential for constructing controlled-release systems for gene delivery. The readers will get insights into a series of gene vectors and deepen their understanding about gene delivery. PMID- 29609052 TI - Measurements and analysis of leakage neutron spectra from multiple-slab sample assemblies comprising W,U,C, and CH2 with D-T neutron irradiation. AB - The accelerator driven subcritical system (ADS) is regarded as a safe and clean nuclear power system, which can be used for the transmutation of nuclear waste and the breeding of nuclear fuel. In this study, in order to validate nuclear data and the neutron transportation performance of the materials related to ADS, we measured the leakage neutron spectra from multiple-slab sample assemblies using 14.8 MeV D-T neutrons. Two types of assemblies comprising A-1 (W+U+C+CH2) and A-2 (U+C+CH2) were both built up gradually starting with the first wall. The measured spectra were compared with those calculated using the Monte Carlo code neutron transport coed (MCNP)-4C. A comparison of the results showed that the experimental leakage neutron spectra for both A-1 or A-2 were reproduced well by the three evaluated nuclear data libraries with discrepancies of less than 15% (A 1) and 12% (A-2), except when below 3 MeV. For 2-cm and 5-cm uranium samples, the CENDL-3.1 calculations exhibited large discrepancies in the energy range of 2-8 MeV and above 13 MeV. Thus, the CENDL-3.1 library for uranium should be reevaluated, especially around this energy range. It was significant that the leakage neuron spectra changed clearly when the latest material layer was added during the building of assemblies A-1 and A-2. PMID- 29609053 TI - Spectral components in electromyograms from four regions of the human masseter, in natural dentate and edentulous subjects with removable prostheses and implants. AB - OBJECTIVE: To compare the frequency or spectral components between different regions of the superficial masseter in young natural dentate and total edentulous older adults rehabilitated with removable prostheses and fixed-implant support. A secondary objective was to compare these components between the three groups. DESIGN: 21 young natural dentate and 28 edentulous (14 with removable prostheses and 14 with fixed-implant support) were assessed. High-density surface electromyography (sEMG) was recorded in four portions of the superficial masseter during submaximal isometric bites. Spectral components were obtained through a spectral analysis of the sEMG signals. An analysis of mixed models was used to compare the spectral components. RESULTS: In all groups, the spectral components of the anterior portion were lower than in the posterior region (p < 0.05). Both edentulous groups showed lower spectral components and median frequency slope than the natural dentate group (p < 0.05). The removable prostheses group showed the greatest differences with natural dentate group. CONCLUSIONS: There were significant differences in the spectral components recorded in the different regions of the superficial masseter. The lower spectral components and fatigability of older adults rehabilitated with prostheses could be a cause of a greater loss of type II fibers, especially in the removable prostheses group. PMID- 29609054 TI - Fully automatic detection and segmentation of abdominal aortic thrombus in post operative CTA images using Deep Convolutional Neural Networks. AB - Computerized Tomography Angiography (CTA) based follow-up of Abdominal Aortic Aneurysms (AAA) treated with Endovascular Aneurysm Repair (EVAR) is essential to evaluate the progress of the patient and detect complications. In this context, accurate quantification of post-operative thrombus volume is required. However, a proper evaluation is hindered by the lack of automatic, robust and reproducible thrombus segmentation algorithms. We propose a new fully automatic approach based on Deep Convolutional Neural Networks (DCNN) for robust and reproducible thrombus region of interest detection and subsequent fine thrombus segmentation. The DetecNet detection network is adapted to perform region of interest extraction from a complete CTA and a new segmentation network architecture, based on Fully Convolutional Networks and a Holistically-Nested Edge Detection Network, is presented. These networks are trained, validated and tested in 13 post-operative CTA volumes of different patients using a 4-fold cross-validation approach to provide more robustness to the results. Our pipeline achieves a Dice score of more than 82% for post-operative thrombus segmentation and provides a mean relative volume difference between ground truth and automatic segmentation that lays within the experienced human observer variance without the need of human intervention in most common cases. PMID- 29609055 TI - Not intended, still embarrassed: Social anxiety is related to increased levels of embarrassment in response to unintentional social norm violations. AB - BACKGROUND: Social anxiety disorder (SAD) is associated with altered social norm (SN) processing: SAD-patients rate stories on SN violations as more inappropriate and more embarrassing than healthy participants, with the most prominent effect for stories on unintentional SN violations (i.e. committing a blunder). Until now it's unknown how levels of social anxiety (SA) are related to ratings of SN violations in the general population, in which SA-symptoms are present at a continuum. More insight in this relationship could improve our understanding of the symptom profile of SAD. Therefore, we investigated the relation between ratings of SN violations and SA-levels in the general population. METHODS: Adults and adolescents (n = 87) performed the revised Social Norm Processing Task (SNPT R) and completed self-report questionnaires on social anxiety. Repeated-measures ANCOVAs were used to investigate the effect of SA on the ratings of inappropriateness and embarrassment. RESULTS: As hypothesized, participants with higher SA-levels rated SN violations as more inappropriate and more embarrassing. Whereas participants with low-to-intermediate SA-levels rated unintentional SN violations as less embarrassing than intentional SN violations, participants with high SA-levels (z-score SA >= 1.6) rated unintentional SN violations as equally embarrassing as intentional SN violations. CONCLUSIONS: These findings indicate that increased embarrassment for unintentional SN violations is an important characteristic of social anxiety. These high levels of embarrassment are likely related to the debilitating concern of socially-anxious people that their skills and behavior do not meet expectations of others, and to their fear of blundering. This concern might be an important target for future therapeutic interventions. PMID- 29609056 TI - Smoking cessation treatment outcomes among people with and without mental and substance use disorders: An observational real-world study. AB - BACKGROUND: There is a lack of studies evaluating smoking cessation treatment protocols which include people with and without mental and substance use disorders (MSUD), and which allows for individuals with MSUD undergoing their psychiatric treatment. METHODS: We compared treatment success between participants with (n = 277) and without (n = 419) MSUD among patients in a 6-week treatment provided by a Brazilian Psychosocial Care Center (CAPS) from 2007 to 2013. Sociodemographic, medical and tobacco use characteristics were assessed at baseline. Tobacco treatment consisted of 1) group cognitive behavior therapy, which included people with and without MSUD in the same groups, and 2) pharmacotherapy, which could include either nicotine patches, nicotine gum, bupropion or nortriptyline. For participants with MSUD, tobacco treatment was integrated into their ongoing mental health treatment. The main outcome was 30 day point prevalence abstinence, measured at last day of treatment. RESULTS: Abstinence rates did not differ significantly between participants with and without MSUD (31.1% and 34.4%, respectively). Variables that were significantly associated with treatment success included years smoking, the Heaviness of Smoking Index, and use of nicotine patch or bupropion. CONCLUSION: The inclusion of individuals with and without MSUD in the same protocol, allowing for individuals with MSUD undergoing their psychiatric treatment, generates at least comparable success rates between the groups. Predictors of treatment success were similar to those found in the general population. Facilities that treat patients with MSUD should treat tobacco use in order to reduce the disparities in morbidity and mortality experienced by this population. PMID- 29609058 TI - Sperm cell purification from mock forensic swabs using SOMAmerTM affinity reagents. AB - We have demonstrated a proof of concept with affinity-based purification of sperm cells from mock forensic samples using SOMAmerTM reagents, DNA-based affinity reagents developed by SomaLogic, Inc. SOMAmer reagents were selected in vitro using whole-cell SELEX to bind specifically with intact, detergent-treated sperm cells. Successful separation of sperm from epithelial cells and their debris was demonstrated using buccal swabs with added semen. Primarily male DNA profiles were generated from sperm cells eluted from the types of cotton swabs typically used for rape kit evidence collection. The quality of sperm DNA isolated from samples purified using SOMAmers is comparable to existing commercially available differential extraction-based methods at higher sperm concentrations. This purification method is simple, offers relatively rapid (<2hr) sperm purification, and can potentially be automated using robotic workstations. This work serves as proof of concept that demonstrates the first use of SOMAmer reagents as affinity ligands to bind sperm cells. With further development, this technique can potentially be used for high-throughput sexual assault forensic casework. PMID- 29609057 TI - Designing a global monitoring system for pilot introduction of a new contraceptive technology, subcutaneous DMPA (DMPA-SC). AB - In collaboration with ministries of health, PATH and key partners launched the first pilot introductions of subcutaneous depot medroxyprogesterone acetate (DMPA SC, brand name Sayana(r) Press) in Burkina Faso, Niger, Senegal, and Uganda from July 2014 through June 2016. While each country implemented a unique introduction strategy, all agreed to track a set of uniform indicators to chart the effect of introducing this new method across settings. Existing national health information systems (HIS) were unable to track new methods or delivery channels introduced for a pilot, thus were not a feasible source for project data. We successfully monitored the four-country pilot introductions by implementing a four-phase approach: 1) developing and defining global indicators, 2) integrating indicators into existing country data collection tools, 3) facilitating consistent reporting and data management, and 4) analyzing and interpreting data and sharing results. Project partners leveraged existing family planning registers to the extent possible, and introduced new or modified data collection and reporting tools to generate project-specific data where necessary. We routinely shared monitoring results with global and national stakeholders, informing decisions about future investments in the product and scale up of DMPA-SC nationwide. Our process and lessons learned may provide insights for countries planning to introduce DMPA-SC or other new contraceptive methods in settings where stakeholder expectations for measureable results for decision-making are high. PMID- 29609060 TI - Kayexalate-Induced Colonic Pseudotumor. PMID- 29609059 TI - What can rodents teach us about empathy? AB - While many consider empathy an exclusively human trait, non-human animals are capable of simple forms of empathy, such as emotional contagion, as well as consolation and helping behavior. Rodent models are particularly useful for describing the neuronal background of these phenomena. They offer the possibility of employing single-cell resolution mapping of the neuronal activity as well as novel techniques for manipulation of in vivo activity, which are currently unavailable in human studies. Here, we review recent developments in the field of rodent empathy research with special emphasis on behavioral paradigms and data on neuronal correlates of emotional contagion. We hope that the use of rodent models will enhance our understanding of social deficits in neuropsychiatric disorders characterized with empathy impairments and the evolutionary continuity of the empathic trait. PMID- 29609061 TI - Unusual Liver Masses Found After Evaluation for Asymptomatic Alkaline Phosphatase Elevation. PMID- 29609062 TI - Gastric Metastasis From Uveal Melanoma. PMID- 29609063 TI - Comparison of Diagnostic Performance of the IgA Anti-tTG Test vs IgA Anti-Native Gliadin Antibodies Test in Detection of Celiac Disease in the General Population. PMID- 29609064 TI - Massive Epithelioid Hemangioendothelioma Causing Noncirrhotic Portal Hypertension. PMID- 29609065 TI - Low Incidence of Esophageal Adenocarcinoma After Eradication of Helicobacter pylori in Japan. PMID- 29609066 TI - Palliation of Malignant Pyloric Stenosis Using a Lumen-Apposing Metal Stent. PMID- 29609067 TI - Veterans' Attitudes Towards De-Intensification of Surveillance Colonoscopy for Low-Risk Adenomas. PMID- 29609068 TI - Cost Effectiveness of Early Insertion of Transjugular Intrahepatic Portosystemic Shunts for Recurrent Ascites. AB - BACKGROUND & AIMS: Treatment options for recurrent ascites resulting from decompensated cirrhosis include serial large-volume paracentesis and albumin infusion (LVP+A) or insertion of a transjugular intrahepatic portosystemic shunt (TIPS). Insertion of TIPSs with covered stents during early stages of ascites (early TIPS, defined as 2 LVPs within the past 3 weeks and <6 LVPs in the prior 3 months) significantly improves chances of survival and reduces complications of cirrhosis compared with LVP+A. However, it is not clear if TIPS insertion is cost effective in these patients. METHODS: We developed a Markov model using the payer perspective for a hypothetical cohort of patients with cirrhosis with recurrent ascites receiving early TIPSs or LVP+A using data from publications and national databases collected from 2012 to 2018. Projected outcomes included quality adjusted life-year (QALY), costs (2017 US dollars), and incremental cost effectiveness ratios (ICERs; $/QALY). Sensitivity analyses (1-way, 2-way, and probabilistic) were conducted. ICERs less than $100,000 per QALY were considered cost effective. RESULTS: In base-case analysis, early insertion of TIPS had a higher cost ($22,770) than LVP+A ($19,180), but also increased QALY (0.73 for early TIPSs and 0.65 for LVP+A), resulting in an ICER of $46,310/QALY. Results were sensitive to cost of uncomplicated TIPS insertion and transplant, need for LVP+A, probability of transplant, and decompensated QALY. In probabilistic sensitivity analysis, TIPS insertion was the optimal strategy in 59.1% of simulations. CONCLUSIONS: Based on Markov model analysis, early placement of TIPSs appears to be a cost-effective strategy for management of specific patients with cirrhosis and recurrent ascites. TIPS placement should be considered early and as a first-line treatment option for select patients. PMID- 29609069 TI - Is the Objective of Treatment for Crohn's Disease Mucosal or Transmural Healing? PMID- 29609070 TI - Equivalent Efficacies of Reverse Hybrid and Bismuth Quadruple Therapies in Eradication of Helicobacter pylori Infection in a Randomized Controlled Trial. AB - BACKGROUND & AIMS: Bismuth quadruple therapy is recommended as a first-line treatment for Helicobacter pylori infection in the United States but hybrid therapy is an alternative option. Reverse hybrid therapy (proton pump inhibitor plus amoxicillin for 14 days, and clarithromycin plus metronidazole for the initial 7 days) is a simplified hybrid treatment. We aimed to assess the efficacies of reverse hybrid therapy vs bismuth quadruple therapy as first-line treatments for patients with H pylori infection in a randomized trial. METHODS: In a prospective study, patients with H pylori infection were randomly assigned to groups that received either reverse hybrid therapy (n = 176) or a bismuth quadruple therapy (pantoprazole, bismuth, tetracycline, and metronidazole for 14 days; n = 176). Patients were examined the end of therapy for adverse events. The study was performed from August 2015 through February 2017. The primary outcome was cure of H pylori infection, determined based on a negative result from the urea breath test, or negative results from histologic analysis, the urease test, and bacterial culture analyses. RESULTS: H pylori infection was eradicated from 96.6% of patients who received reverse hybrid therapy and 96.0% who received bismuth quadruple therapy-this difference was not significant in the intention-to treat analysis (95% CI, 8.0% ~ 2.2%; P = .281). There were no significant differences between therapies eradication of clarithromycin-resistant strains (88.2% with reverse hybrid therapy vs 92.3% with bismuth quadruple therapy) or metronidazole-resistant strains (100% vs 96.9%). However, reverse hybrid therapy was associated with fewer adverse events (18.7% of patients) than bismuth quadruple therapy (47.7%) (P < .001). CONCLUSIONS: In a randomized trial, we found 14-day reverse hybrid therapy to not be inferior to bismuth quadruple therapy as a first-line treatment for H pylori infection. Reverse hybrid therapy was associated with fewer adverse events. ClincialTrials.gov no: NCT02547038. PMID- 29609072 TI - Combining Fourier phase encoding and broadband inversion toward J-edited spectra. AB - Nuclear magnetic resonance (NMR) spectra are often utilized for gathering accurate information relevant to molecular structures and composition assignments. In this study, we develop a homonuclear encoding approach based on imparting a discrete phase modulation of the targeted cross peaks, and combine it with a pure shift experiments (PSYCHE) based J-modulated scheme, providing simple 2D J-edited spectra for accurate measurement of scalar coupling networks. Chemical shifts and J coupling constants of protons coupled to the specific protons are demonstrated along the F2 and F1 dimensions, respectively. Polychromatic pulses by Fourier phase encoding were performed to simultaneously detect several coupling networks. Proton-proton scalar couplings are chosen by a polychromatic pulse and a PSYCHE element. Axis peaks and unwanted couplings are complete eradicated by incorporating a selective COSY block as a preparation period. The theoretical principles and the signal processing procedure are laid out, and experimental observations are rationalized on the basis of theoretical analyses. PMID- 29609071 TI - Human papillomavirus type 16 E5-mediated upregulation of Met in human keratinocytes. AB - Human papillomaviruses (HPVs) cause benign lesions that can lead to malignancy. How cellular changes induced by viral oncogenes contribute to the progeny virion production is not always clear. Stromally-derived growth factors and their receptors are critical for development of malignancy, but their impact on the pre malignant HPV life cycle is unknown. We show that HPV16 increases levels of Met, a growth factor receptor critical for tumor cell invasion, motility, and cancer metastasis. The viral oncogene E5 is primarily responsible for Met upregulation, with E6 playing a minor role. Met induction by E5 requires the epidermal growth factor receptor, which is also increased by E5 at the mRNA level. E5-induced Met contributes motility of HPV-containing cells. Finally, Met signaling is necessary for viral gene expression, particularly in the differentiation-dependent phase of the viral life cycle. These studies show a new role for E5 in epithelial-stromal interactions, with implications for cancer development. PMID- 29609073 TI - Comparative assessment of heat stress induced changes in carcass traits, plasma leptin profile and skeletal muscle myostatin and HSP70 gene expression patterns between indigenous Osmanabadi and Salem Black goat breeds. AB - The primary objective of the study was to compare the impact of heat stress on meat production characteristics of Osmanabadi and Salem Black breed goats based on changes in carcass characteristics, meat quality attributes, plasma leptin concentration, skeletal muscle myostatin and heat shock protein 70 (HSP70) gene expression patterns. The goats were randomly distributed into four groups: OSC (n = 6; Osmanabadi Control), OSHS (n = 6; Osmanabadi Heat Stress), SBC (n = 6; Salem Black Control) and SBHS (n = 6; Salem Black Heat Stress). The animals were slaughtered at the end of the study and their meat characteristics were assessed. This study established the impact of heat stress on a wide variety of carcass and meat quality characteristics in OS and SB goat breeds. The results from the study also provided some crucial evidence for a better resilience capacity of Salem Black breed as compared to Osmanabadi goats in maintaining the meat production during heat stress. The study also established plasma leptin and HSP70 genes to be the ideal biomarkers to reflect the impact of heat stress on meat characteristics in indigenous goats. PMID- 29609074 TI - Combination of intravenous immunoglobulin and steroid pulse therapy improves outcomes of febrile refractory status epilepticus. AB - BACKGROUND: Febrile infections are an important cause of paediatric refractory status epilepticus, and immune-mediated mechanisms and inflammatory processes have been associated with neurological manifestations in such patients. The aim of this study was to investigate the effects of immunotherapy as adjuvant treatment for febrile refractory status epilepticus. METHODS: We retrospectively reviewed cases of febrile refractory status epilepticus in a paediatric intensive care unit between January 2000 and December 2013 and analysed their clinical characteristics. Patients positive for antineuronal antibodies against surface antigens were excluded. RESULTS: We enrolled 63 patients (38 boys), aged 1-18 years, all of whom received multiple antiepileptic drugs. Twenty-nine (46%) of the patients received intravenous immunoglobulin alone, 16 (25.4%) received a combination of intravenous immunoglobulin and methylprednisolone pulse therapy, and 18 (28.6%) did not receive immunotherapy treatment. Overall, 12 (19%) patients died within 1 month. After 6 months, 12 (20%) patients had good neurological outcomes, including two who returned to baseline and 13 (29.5%) who had favourable seizure outcomes. We compared the outcomes of the different treatments, and found that a combination of intravenous immunoglobulin and methylprednisolone pulse therapy had the best neurological and seizure outcomes at 6 months compared to intravenous immunoglobulin alone and no immunotherapy. CONCLUSIONS: Our observational study showed that a combination of intravenous immunoglobulin and methylprednisolone pulse therapy as adjuvant treatment for febrile refractory status epilepticus was associated with better neurological and seizure outcomes. Further prospective studies are needed to confirm these findings. PMID- 29609075 TI - The prevalence rates of medication adherence and factors influencing adherence to antiepileptic drugs in children with epilepsy: A systematic review and meta analysis. AB - OBJECTIVE: We conducted a systematic review to assess antiepileptic drug (AED) adherence rates, and to identify the characteristics associated with nonadherence in children. METHODS: We searched PubMed, EMBASE, and the Cochrane Library from inception to June 2017. Observational studies addressing medication adherence or examining factors influencing AED adherence were included. RESULTS: We included 22 studies, involving 3955 participants. The general quality of included studies were rated as high quality. Adherence rates were reported in 18 studies, varying between 22.1% and 96.5%. Meta analysis of 13 studies (n = 2051) revealed a pooled adherence rate assessed by objective methods of 58% (95% CI [0.46, 0.74]). Meta analysis of nine studies (n = 1217) revealed a pooled adherence rate assessed by subjective Methods of 73%, (95% CI [0.63, 0.85]). Family support, smaller family size, stable parental marriage status, support from healthcare providers and higher family socioeconomic status were associated with better medication adherence. However, contradictory results were found regarding the effects of age, the frequency of seizure, type of seizures, type of medication and the number of administered drugs. CONCLUSIONS: Adherence to AEDs is challenging for pediatric patients with epilepsy. Few factors which influence adherence can be drawn because of differing variables and results. Future prospective research should be designed with longer study periods and larger samples in naturalistic settings. PMID- 29609077 TI - Compromise of cortical proNGF maturation causes selective retrograde atrophy in cholinergic nucleus basalis neurons. AB - The degeneration of basal forebrain cholinergic neurons (BFCNs) in Alzheimer's disease (AD) contributes to cognitive impairment. Nerve growth factor (NGF) secreted in the cerebral cortex is necessary for the phenotypic maintenance of BFCNs. AD is associated with disturbances in NGF metabolism, leading to reduced mature NGF levels and to an accumulation of its precursor, proNGF. We previously described that, in rats, this neurotrophic imbalance is sufficient to induce a loss of cortical cholinergic synapses. In the present study, we investigated whether this neurotrophic imbalance can produce an AD-like retrograde degeneration of BFCNs. Using a combination of retrograde labeling and quantitative cell imaging, we could demonstrate that inhibiting cortical proNGF maturation results in an atrophy of BFCNs, a downregulation of the NGF receptors p75 neurotrophin receptor and tropomyosin receptor kinase A, and a reduction in choline acetyltransferase protein expression. The transient increase in sortilin levels and the sustained colocalization with p75 neurotrophin receptor suggest a participation of proNGF in this degenerative process. This study demonstrates that impairments in the extracellular maturation of proNGF are sufficient to cause a somatodendritic retrograde degeneration of the BFCNs. PMID- 29609076 TI - Negative fateful life events in midlife and advanced predicted brain aging. AB - Negative fateful life events (FLEs) such as interpersonal conflict, death in the family, financial hardship, and serious medical emergencies can act as allostatic stressors that accelerate biological aging. However, the relationship between FLEs and neuroanatomical aging is not well understood. We examined 359 men (mean age 62 years) participating in the Vietnam Era twin study of aging (VETSA) to determine whether negative midlife FLEs are associated with advanced brain aging after controlling for physical, psychological, and lifestyle factors. At two different time points, participants were assessed for negative FLEs, health and well-being, general cognitive ability, socioeconomic status, depression, and ethnicity. Participants underwent a magnetic resonance imaging examination, and T1-weighted images were processed with FreeSurfer. Subsequent neuroanatomical measurements were entered into the Brain-Age Regression Analysis and Computation Utility software (BARACUS) to predict brain age. Having more midlife FLEs, particularly relating to interpersonal relationships, was associated with advanced predicted brain aging (i.e., higher predicted brain age relative to chronological age). This association remained after controlling for the significant covariates of alcohol consumption, cardiovascular risk, adult socioeconomic status, and ethnicity. PMID- 29609078 TI - Chromogranin A levels in the cerebrospinal fluid of patients with amyotrophic lateral sclerosis. AB - Chromogranin A (CgA) is a protein found in large dense-core vesicles of neuroendocrine cells and neurons and regulating secretion. A relevance to amyotrophic lateral sclerosis (ALS) was suggested as its overexpression accelerates disease onset in model systems and it interacts with mutant forms of SOD1. Recently, increased cerebrospinal fluid (CSF) CgA levels have been reported in ALS patients relative to controls. With the aim of confirming this finding, we measured CgA and phosphorylated neurofilament heavy chain (pNFH), an established ALS biomarker, in the CSF of 32 ALS patients and 32 disease controls. ALS patients had clearly increased pNFH levels (p < 0.0001), while CgA levels were only modestly lower relative to controls (p = 0.0265), with wide value overlap and consequently poor discriminative performance. CgA did not correlate with any disease parameters among ALS patients. Our findings suggest that CgA is not a promising clinical biomarker for ALS. PMID- 29609079 TI - Tooth loss is associated with accelerated cognitive decline and volumetric brain differences: a population-based study. AB - Tooth loss has been related to cognitive impairment; however, its relation to structural brain differences in humans is unknown. Dementia-free participants (n = 2715) of age >=60 years were followed up for up to 9 years. A subsample (n = 394) underwent magnetic resonance imaging at baseline. Information on tooth loss was collected at baseline, and cognitive function was assessed using the Mini Mental State Examination at baseline and at follow-ups. Data were analyzed using linear mixed effects models and linear regression models. At baseline, 404 (14.9%) participants had partial tooth loss, and 206 (7.6%) had complete tooth loss. Tooth loss was significantly associated with a steeper cognitive decline (beta: -0.18, 95% confidence interval [CI]: -0.24 to -0.11) and remained significant after adjusting for or stratifying by potential confounders. In cross sectional analyses, persons with complete or partial tooth loss had significantly lower total brain volume (beta: -28.89, 95% CI: -49.33 to -8.45) and gray matter volume (beta: -22.60, 95% CI: -38.26 to -6.94). Thus, tooth loss may be a risk factor for accelerated cognitive aging. PMID- 29609080 TI - Behavioral tagging and capture: long-term memory decline in middle-aged rats. AB - Decline in cognitive functions, including hippocampus-dependent spatial memory, is commonly observed at a later stage of aging (e.g., >20 months old in rodents) and typically studied after a discrete learning event. How normal aging, particularly at an early stage, affects the modulatory aspect of memory persistence is underinvestigated. Previous studies in young animals show that weak, fading memories can last longer if a modulating event, such as spatial novelty, is introduced around memory encoding. This is known as behavioral tagging and capture (BTC). Here, we investigated how early aging (10-13 months old) affects BTC in an appetitive delayed-matching-to-place task. We trained rats when they were young and middle aged and found that novelty facilitated long-term memory persistence in young but not in middle-aged rats. However, re-exposure to the encoded environment after learning improved memory persistence in middle-aged rats. BTC, combined with memory reactivation, facilitated memory persistence through reconsolidation. Our results point toward a weakened tagging and capture mechanism before reduction of plasticity-related proteins at an early stage of aging. PMID- 29609081 TI - Biomechanical Analysis of Lateral Lumbar Interbody Fusion Constructs with Various Fixation Options: Based on a Validated Finite Element Model. AB - BACKGROUND: Lateral lumbar interbody fusion using cage supplemented with fixation has been used widely in the treatment of lumbar disease. A combined fixation (CF) of lateral plate and spinous process plate may provide multiplanar stability similar to that of bilateral pedicle screws (BPS) and may reduce morbidity. The biomechanical influence of the CF on cage subsidence and facet joint stress has not been well described. The aim of this study was to compare biomechanics of various fixation options and to verify biomechanical effects of the CF. METHODS: The surgical finite element models with various fixation options were constructed based on computed tomography images. The lateral plate and posterior spinous process plate were applied (CF). The 6 motion modes were simulated. Range of motion (ROM), cage stress, endplate stress, and facet joint stress were compared. RESULTS: For the CF model, ROM, cage stress, and endplate stress were the minimum in almost all motion modes. Compared with BPS, the CF reduced ROM, cage stress, and endplate stress in all motion modes. The ROM was reduced by more than 10% in all motion modes except for flexion; cage stress and endplate stress were reduced more than 10% in all motion modes except for rotation-left. After interbody fusion, facet joint stress was reduced substantially compared with the intact conditions in all motion modes except for flexion. CONCLUSIONS: The combined plate fixation may offer an alternative to BPS fixation in lateral lumbar interbody fusion. PMID- 29609082 TI - Risk Factors of Adjacent Segment Disease After Anterior Cervical Arthrodesis: A Retrospective Study of Sagittal Measurement of Thoracic Inlet Parameters. AB - BACKGROUND: To explore the predictive parameters for adjacent segment disease (ASD) after anterior cervical arthrodesis at the sagittal measurement of thoracic inlet. METHODS: We included 212 subjects treated with anterior cervical fusion surgery to identify predictive parameters for ASD. We applied multivariate logistic regression to find the relevant parameters. RESULTS: Two hundred patients completed the final follow-up. The results of logistic regression analysis showed that T1 slope of less than 19.50 could be a predictive parameter of ASD after the anterior cervical arthrodesis (P < 0.05). CONCLUSIONS: Sagittal balance of thoracic inlet is vital to avoid the. cervical degenerative disease, while T1 slope of less than 19.50 appears to be an independent risk factor for the ASD, keeping the T1 slope of more than 19.5 is reasonable. PMID- 29609083 TI - Constructional Apraxia in Older Patients with Brain Tumors: Considerations with an Up-To-Date Review of the Literature. AB - BACKGROUND: Constructional apraxia (CA) is a neuropsychological impairment of either basic perceptual and motor abilities or executive functions, in the absence of any kind of motor or perceptual deficit. Considering patients with focal brain tumors, CA is common in left or right parietal and parieto-occipital lesions. In neuropsychology, the Rey-Osterrieth Complex Figure Test (ROCFT; or parallel forms) is commonly used for the assessment of CA. This study stems from a clinical observation of a difficulty with CA tests for the majority of older neurosurgical patients without occipitoparietal lesions. METHODS: Patients were tested at 3 points: before surgery, 3 months after surgery, and 12 months after surgery. Thirty patients (15 meningiomas and 15 glioblastomas) were studied retrospectively. RESULTS: Older patients with focal brain lesions, regardless of the nature of the tumor, performed poorly at CA tests. More than 50% of patients obtained pathologic results at all 3 times considered. CONCLUSIONS: Our findings suggest that as CA complex tests involve multiple domains, poor results in copy task may reflect a global cognitive deficit of older patients with tumors, without a specific constructional praxis deficit. CA complex tests (such as the ROCFT) do not give significant informations about visuo-constructional abilities. PMID- 29609084 TI - Risk Factors for Thirty-Day Morbidity and Mortality in Extradural Lumbar Spine Tumor Resection. AB - BACKGROUND: Epidural tumors in the lumbar spine represent a unique cohort of lesions with individual risks and challenges to resection. Knowledge of modifiable risk factors are important in minimizing postoperative complications. OBJECTIVE: To determine the risk factors for 30-day morbidity and mortality in patients undergoing extradural lumbar tumor resection. METHODS: A retrospective study of prospectively collected data using the American College of Surgeons National Quality Improvement Program database was performed. Adults who underwent laminectomy for excision of lumbar spine tumors between 2011 and 2014 were included in the study. Demographics and medical comorbidities were collected, along with morbidities and mortalities within 30 postoperative days. A multivariate binary logistic analysis of these clinical variables was performed to determine covariates of morbidity and mortality. RESULTS: The database search yielded 300 patients, of whom 118 (39.3%) were female. Overall, complications within 30 days of surgery occurred in 102 (34%) patients. Significant risk factors for morbidity included preoperative anemia (P < 0.0001), the need for preoperative blood transfusion (P = 0.034), preoperative hypoalbuminemia (P = 0.002), American Society of Anesthesiologists score 3 or 4 (P = 0.0002), and operative time >4 hours (P < 0.0001). Thirty-day mortality occurred in 15 (5%) patients and was independently associated with preoperative anemia (odds ratio 3.4, 95% confidence interval 1.8-6.5) and operative time >4 hours (odds ratio 2.6, 95% confidence interval 1.1-6.0). CONCLUSIONS: Excision of epidural lumbar spinal tumors carries a relatively high complication rate. This series reveals distinct risk factors that contribute to 30-day morbidity and mortality, which may be optimized preoperatively to improve surgical safety. PMID- 29609085 TI - Prevalence and Impact of Left-Handedness in Neurosurgery. AB - BACKGROUND: Approximately 10%-13% of the population is left-handed (LH), and certain professions have varied representation of LH individuals. LH surgeons must overcome unique difficulties owing to the right-handed (RH) operative environment. This study assesses prevalence and impact of left-handedness on training and operative experience of neurosurgeons. METHODS: An e-mail survey was designed and sent to 5109 U.S. neurosurgeons and neurosurgical trainees. The survey was completed by 1482 responders (29.0% response rate). RESULTS: Of respondents, 252 (17.0%) reported being LH. LH neurosurgeons were more likely than RH neurosurgeons to report ambidexterity in the operating room (36.5% vs. 13.3%, P < 0.001). During neurosurgical training, 23.5% of RH trainers addressed LH-specific issues compared with 44.7% of LH trainers. LH trainers were more likely to describe LH trainees as having greater technical ability (18.9%). Most trainers reported equal comfort teaching LH and RH trainees. LH trainees reported difficulties with RH surgical tools (42.7%) and a tendency to alter handedness for surgery (62.7%). The impact of these areas lessens in LH attendings (27.8% and 39.9%, respectively). Most LH neurosurgeons denied specific training for left handedness and access to LH-specific tools, and 24.0% of LH trainees reported feeling disadvantaged owing to their handedness. CONCLUSIONS: LH neurosurgeons may be overrepresented in neurosurgery, yet handedness is rarely addressed in neurosurgical training. Despite this, there is evidence of some degree of adaptation through training. There may be some benefit from recognizing differences in handedness in the operating room and attempting to give access for LH-specific mentorship during training. PMID- 29609086 TI - Primary Central Nervous System Hodgkin Lymphoma-Like Posttransplant Lymphoproliferative Disorder. AB - BACKGROUND: Posttransplant lymphoproliferative disorder (PTLD) is a rare condition occurring after organ transplantation. PTLD comprises 4 subtypes, of which Hodgkin lymphoma (HL) type and HL-like type (currently included in polymorphic type) account for only about 1%-3% of cases. Primary central nervous system PTLD is also rare; most cases are Epstein-Barr virus-positive, B-cell PTLD. To our knowledge, no case of HL-like PTLD has been documented. CASE DESCRIPTION: A 43-year-old woman who underwent kidney transplantation for IgA nephropathy 14 years previously presented to the emergency department with seizure. Gadolinium-enhanced T1-weighted magnetic resonance imaging showed a ring enhancing mass in the left temporal lobe. Gross total removal of the tumor was performed, and pathologic examination revealed findings consistent with HL-like PTLD. The patient's immunosuppressants were subsequently reduced, and she received postoperative systemic therapy with rituximab and radiation therapy. Follow-up magnetic resonance imaging showed no signs of relapse. CONCLUSIONS: This represents an extremely rare case of a patient with HL-like PTLD occurring as a primary central nervous system lesion. PMID- 29609087 TI - The Tonsillouvular Fissure Approach: Access to Dorsal and Lateral Aspects of the Fourth Ventricle. AB - OBJECTIVE: Although approaches to the fourth ventricle (FV) have been studied well, approaches to the lesions located in the dorsal and lateral aspects of the FV have not been shown in anatomic or clinical studies. The aim of this study is to show for the first time in the literature the tonsillouvular fissure approach (TUFA) in anatomic dissections and its use in surgical series. METHODS: For anatomic studies, 4 formalin-fixed human cadaveric heads infused with colored silicone and 10 cerebellar specimens were dissected in a stepwise manner. Records of 12 patients operated on via TUFA were also retrospectively reviewed. RESULTS: Neurosurgical anatomy and critical steps of TUFA were described in detail. Among 12 patients with lesions around the FV (4 cavernous malformation, 2 pilocytic astrocytoma, 2 hemangioblastoma, 1 B-cell lymphoma, 1 metastatic papillary carcinoma, 1 dermoid cyst, and 1 arteriovenous malformation), 11 gross total and 1 subtotal resection were achieved via TUFA without any mortality or morbidity. Comparative analyses of 4 surgical approaches to FV (TUFA, telovelar/cerebellomedullary fissure, supratonsillar/tonsillobiventral lobule fissure, and transvermian approaches) were also presented. CONCLUSIONS: TUFA provides a direct route and excellent surgical view to lesions around the FV, particularly on dorsal and lateral aspects, inferior vermis, and medial part of the dentate nucleus and cerebellar peduncles. It minimizes traversing the normal cerebellar tissue compared with a transvermian approach. PMID- 29609088 TI - Milrinone-Associated Cardiomyopathy and Arrhythmia in Cerebral Vasospasm. AB - BACKGROUND: Milrinone is an inotropic and vasodilatory drug proven safe for use in treatment of cerebral vasospasm. Despite its reported safety profile, its use is not free of side effects. Milrinone-associated cardiomyopathy and arrhythmia can occur in patients with cerebral vasospasm. CASE DESCRIPTION: This is a retrospective chart review of a patient who presented with aneurysmal subarachnoid hemorrhage and developed clinical vasospasm twice over a period of 2 weeks. Sustained intravenous milrinone infusion was used in association with norepinephrine infusion during this period. The patient developed R-on-T triggered torsades de pointes and cardiogenic shock requiring resuscitation. Follow-up echocardiogram showed decreased ejection fraction from 64% to 43% consistent with cardiac remodeling. Systemic complications such as cardiotoxicity and arrhythmias with the use of intravenous milrinone can be seen particularly when used in combination with catecholamines. CONCLUSIONS: With increased combined milrinone and catecholamine use for the treatment of cerebral vasospasm, physicians should be aware of the potential cardiac complications of these agents. Close monitoring with daily electrocardiograms may be helpful to detect changes that suggest cardiotoxicity. If changes are noted, an echocardiogram and cardiology consultation may be warranted. PMID- 29609089 TI - Comparative conformational studies of 3,4,6-tri-O-acetyl-1,5-anhydro-2-deoxyhex-1 enitols at the DFT level. AB - B3LYP and M06-2X optimization and MP2 single point calculations are reported for the 4H5 and 5H4 conformations of 3,4,6-tri-O-acetyl-D-allal, 3,4,6-tri-O-acetyl-D galactal, 3,4,6-tri-O-acetyl-D-glucal, and 3,4,6-tri-O-acetyl-D-gulal. Significant discrepancies in predictions of relative energies and conformers' population for B3LYP and M06-2X optimized geometries are observed. Generally, B3LYP overestimates the conformers' energies with respect to MP2, whereas M06-2X slightly underestimates the conformers' energies. B3LYP failed to estimate the 4H5?5H4 conformational equilibrium for 3,4,6-tri-O-acetyl-D-galactal and 3,4,6 tri-O-acetyl-D-glucal. The M06-2X functional showed good agreement with experimental results for all glycals studied. The 4H5?5H4 conformational equilibrium for 3,4,6-tri-O-acetyl-D-allal and 3,4,6-tri-O-acetyl-D-gulal is governed by the vinylogous anomeric effect (VAE), whereas competition between the VAE and quasi 1,3-diaxial interactions influence this equilibrium for 3,4,6-tri-O acetyl-D-galactal and 3,4,6-tri-O-acetyl-D-glucal. The orientation of the 4-OAc group influences the strength of the quasi 1,3-diaxial interactions between the 3 OAc and 5-CH2OAc groups. AIM analysis shows weak bonding interaction between the 3-OAc and 5-CH2OAc groups. PMID- 29609090 TI - N-Glycosyltransferase from Aggregatibacter aphrophilus synthesizes glycopeptides with relaxed nucleotide-activated sugar donor selectivity. AB - N-Glycosyltransferase (NGT) is an inverting glycosyltransferase for an unusual pathway of N-linked protein glycosylation and glycosylates polypeptides in the consensus sequon (N-(X?P)-T/S) with hexose monosaccharides. Here, we expressed and characterized a novel N-glycosyltransferase from Aggregatibacter aphrophilus (named AaNGT). RP-HPLC and Mass Spectrometry were used to assay and quantify glycopeptide formation by AaNGT and determine its substrate specificities. AaNGT could utilize a variety of nucleotide-activated sugar donors, including UDP-Glc, UDP-Gal, UDP-Xyl, GDP-Glc, dGDP-Glc and UDP-GlcN, to glycosylate the tested peptides. To the best of our knowledge, AaNGT was the first identified natural glycosyltransferase able to transfer GlcN moiety onto asparagine residues. AaNGT also exhibited a different position-specific residue preference of substrate peptides from the NGT of Actinobacillus pleuropneumoniae (ApNGT). In vitro assays with diverse synthesized peptides revealed that AaNGT preferred different peptide substrates from ApNGT. The efficient glycosylation of natural short peptides by AaNGT showed its potential to modify important therapeutic mammalian N glycoproteins. PMID- 29609093 TI - Histological and electron microscopy observations on the testis and spermatogenesis of the butterfly Dione juno (Cramer, 1779) and Agraulis vanillae (Linnaeus, 1758) (Lepidoptera: Nymphalidae). AB - Lepidopteran species present an interesting case of sperm polymorphism and testicular fusion. The study of these features are of great importance in understanding the reproductive biology of these insects, especially in the case of those considered pests. Dione juno and Agraulis vanillae stand out as the most important pests of passion fruit (Passiflora sp.) crops in Brazil. Therefore, the objective of the present study was to characterize the testes and germ cells of Dione juno and Agraulis vanillae at different life stages, using light microscopy and scanning and transmission electron microscopy, to understand the maturation mechanisms of the male gametes in these species. The study showed that the larvae of both species have a pair of brown kidney-shaped testes, covered by epithelial cells which divide the organ into four follicles. The testes are full of spermatogonia which begin to differentiate in the third larval instar. In the fifth larval instar, spermatozoa can be observed. When they enter the prepupal stage the testes begin a fusion process that is completed in the adult insects, where they present as spherical organs divided into eight follicles, containing all the cells of the germ line. Spermatogenesis occurs centripetally, and in both species, sperm dimorphism is observed, where two different types of spermatozoa are formed, eupyrene (nucleated) and apyrene (anucleate), which differ in morphology and function. Apart from contributing to scientific basic research on the reproductive biology of these insects, the present study provides important data that can aid in research on the physiology, systematics, and control of these species. PMID- 29609092 TI - Does fluoxetine exposure affect hypoxia tolerance in the Gulf toadfish, Opsanus beta? AB - Due to ineffective wastewater treatment technologies, pharmaceuticals such as the selective serotonin reuptake inhibitors (SSRIs)-a common class of antidepressants which inhibit the serotonin transporter (SERT)-can be found in surface waters and marine receiving waters near wastewater effluents. Understanding how exposure to these chemicals might impact non-target organisms, especially combined with other environmental stressors like hypoxia, is essential in order to thoroughly evaluate environmental risk. It was hypothesized that both acute and chronic exposure to the SSRI fluoxetine (FLX) would interfere with the metabolic hypoxia response of the Gulf toadfish, Opsanus beta. Here we demonstrate that acute intraperitoneal treatment with 50 MUg g-1 FLX significantly reduces the regulation index, or degree of metabolic regulation, in toadfish. Acute FLX exposure significantly reduced SERT mRNA expression in the first and third gill arches, but mRNA expression was not affected in heart tissues or in the second gill arch. In contrast, the regulation index was unaffected by 14-17 day waterborne FLX exposure to environmentally relevant (0.01 MUg L-1) and approximately 1000-fold higher (8.5 MUg L-1) concentrations. However, the higher concentration was sufficient to induce a systemic elevation in plasma serotonin concentrations. Chronic FLX exposure did not alter SERT mRNA expression in heart or gill tissues. The results of this study implicate the involvement of 5-HT pathways in hypoxia tolerance but demonstrate that current environmental levels of FLX are insufficient to impair the metabolic hypoxia response in marine fish. PMID- 29609091 TI - Heparin-Poloxamer Thermosensitive Hydrogel Loaded with bFGF and NGF Enhances Peripheral Nerve Regeneration in Diabetic Rats. AB - Peripheral nerve injury (PNI) is a major burden to society with limited therapeutic options, and novel biomaterials have great potential for shifting the current paradigm of treatment. With a rising prevalence of chronic illnesses such as diabetes mellitus (DM), treatment of PNI is further complicated, and only few studies have proposed therapies suitable for peripheral nerve regeneration in DM. To provide a supportive environment to restore structure and/or function of nerves in DM, we developed a novel thermo-sensitive heparin-poloxamer (HP) hydrogel co-delivered with basic fibroblast growth factor (bFGF) and nerve growth factor (NGF) in diabetic rats with sciatic nerve crush injury. The delivery vehicle not only had a good affinity for large amounts of growth factors (GFs), but also controlled their release in a steady fashion, preventing degradation in vitro. In vivo, compared with HP hydrogel alone or direct GFs administration, GFs HP hydrogel treatment is more effective at facilitating Schwann cell (SC) proliferation, leading to an increased expression of nerve associated structural proteins, enhanced axonal regeneration and remyelination, and improved recovery of motor function (all p < 0.05). Our mechanistic investigation also revealed that these neuroprotective and neuroregenerative effects of the GFs-HP hydrogel may be associated with activations of phosphatidylinositol 3 kinase and protein kinase B (PI3K/Akt), janus kinase/signal transducer and activator of transcription 3 (JAK/STAT3), and mitogen-activated protein kinase kinase/extracellular signal-regulated kinase (MAPK/ERK) signaling pathways. Our work provides a promising therapy option for peripheral nerve regeneration in patients with DM. PMID- 29609094 TI - Differential biotin labelling of the cell envelope proteins in lipopolysaccharidic diderm bacteria: Exploring the proteosurfaceome of Escherichia coli using sulfo-NHS-SS-biotin and sulfo-NHS-PEG4-bismannose-SS biotin. AB - : Surface proteins are the major factor for the interaction between bacteria and its environment, playing an important role in infection, colonisation, virulence and adaptation. However, the study of surface proteins has proven difficult mainly due to their hydrophobicity and/or relatively low abundance compared with cytoplasmic proteins. To overcome these issues new proteomic strategies have been developed, such as cell-surface protein labelling using biotinylation reagents. Sulfo-NHS-SS-biotin is the most commonly used reagent to investigate the proteins expressed at the cell surface of various organisms but its use in lipopolysaccharidic diderm bacteria (archetypical Gram-negative bacteria) remains limited to a handful of species. While generally pass over in silence, some periplasmic proteins, but also some inner membrane lipoproteins, integral membrane proteins and cytoplasmic proteins (cytoproteins) are systematically identified following this approach. To limit cell lysis and diffusion of the sulfo-NHS-SS-biotin through the outer membrane, biotin labelling was tested over short incubation times and proved to be as efficient for 1 min at room temperature. To further limit labelling of protein located below the outer membrane, the use of high-molecular weight sulfo-NHS-PEG4-bismannose-SS-biotin appeared to recover differentially cell-envelope proteins compared to low molecular weight sulfo-NHS-SS-biotin. Actually, the sulfo-NHS-SS-biotin recovers at a higher extent the proteins completely or partly exposed in the periplasm than sulfo-NHS-PEG4-bismannose-SS-biotin, namely periplasmic and integral membrane proteins as well as inner membrane and outer membrane lipoproteins. These results highlight that protein labelling using biotinylation reagents of different sizes provides a sophisticated and accurate way to differentially explore the cell envelope proteome of lipopolysaccharidic diderm bacteria. SIGNIFICANCE: While generally pass over in silence, some periplasmic proteins, inner membrane lipoproteins (IMLs), integral membrane proteins (IMPs) and cytoplasmic proteins (cytoproteins) are systematically identified following cell surface biotin labelling in lipopolysaccharidic diderm bacteria (archetypal Gram negative bacteria). The use of biotinylation molecules of different sizes, namely sulfo-NHS-SS-biotin and sulfo-NHS-PEG4-bismannose-SS-biotin, was demonstrated to provide a sophisticated and accurate way to differentially explore the cell envelope proteome of lipopolysaccharidic diderm bacteria. PMID- 29609095 TI - A comparative proteomic characterization and nutritional assessment of naturally- and artificially-cultivated Cordyceps sinensis. AB - : Cordyceps sinensis has gained increasing attention due to its nutritional and medicinal properties. Herein, we employed label-free quantitative mass spectrometry to explore the proteome differences between naturally- and artificially-cultivated C. sinensis. A total of 22,829 peptides with confidence >=95%, corresponding to 2541 protein groups were identified from the caterpillar bodies/stromata of 12 naturally- and artificially-cultivated samples of C. sinensis. Among them, 165 proteins showed significant differences between the samples of natural and artificial cultivation. These proteins were mainly involved in energy production/conversion, amino acid transport/metabolism, and transcription regulation. The proteomic results were confirmed by the identification of 4 significantly changed metabolites, thus, lysine, threonine, serine, and arginine via untargeted metabolomics. The change tendencies of these metabolites were partly in accordance with changes in abundance of the proteins, which was upstream of their synthetic pathways. In addition, the nutritional value in terms of the levels of nucleosides, nucleotides, and adenosine between the artificially- and naturally-cultivated samples was virtually same. These proteomic data will be useful for understanding the medicinal value of C. sinensis and serve as reference for its artificial cultivation. SIGNIFICANCE: C. sinensis is a precious and valued medicinal product, the current basic proteome dataset would provide useful information to understand its development/infection processes as well as help to artificially cultivate it. This work would also provide basic proteome profile for further study of C. sinensis. PMID- 29609096 TI - Reactive oxygen species activate differentiation gene transcription of acute myeloid leukemia cells via the JNK/c-JUN signaling pathway. AB - Reactive oxygen species (ROS) and altered cellular redox status are associated with many malignancies. Acute myeloid leukemia (AML) cells are maintained at immature state by differentiation blockade, which involves deregulation of transcription factors in myeloid differentiation. AML cells can be induced to differentiate by phorbol-12-myristate-13-acetate (PMA), which possesses pro oxidative activity. However, the signaling events mediated by ROS in the activation of transcriptional program during AML differentiation has not been fully elucidated. Here, we investigated AML cell differentiation by treatment with PMA and ROS scavenger N-acetyl-l-cysteine (NAC). We observed elevation of intracellular ROS level in the PMA-treated AML cells, which correlated with differentiated cell morphology and increased CD11b+ mature cell population. The effect of PMA can be abolished by NAC co-treatment, supporting the involvement of ROS in the process. Moreover, we demonstrated that short ROS elevation mediated cell cycle arrest, but failed to activate myeloid gene transcription; whereas prolonged ROS elevation activated JNK/c-JUN signaling pathway. Inhibition of JNK suppressed the expression of key myeloid transcriptional regulators c-JUN, SPI-1 and MAFB, and prevented AML cells from undergoing terminal differentiation. These findings provide new insights into the crucial role of JNK/c-Jun signaling pathway in the activation of transcriptional program during ROS-mediated AML differentiation. PMID- 29609097 TI - Case report on implication of E-sport for changing platform of expression of bullying. PMID- 29609098 TI - The sentence wrap-up dogma. AB - Current sentence processing research has focused on early effects of the on-line incremental processes that are performed at each word or constituent during processing. However, less attention has been devoted to what happens at the end of the clause or sentence. More specifically, over the last decade and a half, a lot of effort has been put into avoiding measuring event-related brain potentials (ERPs) at the final word of a sentence, because of the possible effects of sentence wrap-up. This article reviews the evidence on how and when sentence wrap up impacts behavioral and ERP results. Even though the end of the sentence is associated with a positive-going ERP wave, thus far this effect has not been associated with any factors hypothesized to affect wrap-up. In addition, ERP responses to violations have not been affected by this positivity. "Sentence final" negativities reported in the literature are not unique to sentence final positions, nor do they obscure or distort ERP effects associated with linguistic manipulations. Finally, the empirical evidence used to argue that sentence-final ERPs are different from those recorded at sentence-medial positions is weak at most. Measuring ERPs at sentence-final positions is therefore certainly not to be avoided at all costs, especially not in cases where the structure of the language under investigation requires it. More importantly, researchers should follow rigorous method in their experimental design, avoid decision tasks which may induce ERP confounds, and ensure all other possible explanations for results are considered. Although this article is directed at a particular dogma from a particular literature, this review shows that it is important to reassess what is regarded as "general knowledge" from time to time. PMID- 29609099 TI - Direct speech quotations promote low relative-clause attachment in silent reading of English. AB - The implicit prosody hypothesis (Fodor, 1998, 2002) proposes that silent reading coincides with a default, implicit form of prosody to facilitate sentence processing. Recent research demonstrated that a more vivid form of implicit prosody is mentally simulated during silent reading of direct speech quotations (e.g., Mary said, "This dress is beautiful"), with neural and behavioural consequences (e.g., Yao, Belin, & Scheepers, 2011; Yao & Scheepers, 2011). Here, we explored the relation between 'default' and 'simulated' implicit prosody in the context of relative-clause (RC) attachment in English. Apart from confirming a general low RC-attachment preference in both production (Experiment 1) and comprehension (Experiments 2 and 3), we found that during written sentence completion (Experiment 1) or when reading silently (Experiment 2), the low RC attachment preference was reliably enhanced when the critical sentences were embedded in direct speech quotations as compared to indirect speech or narrative sentences. However, when reading aloud (Experiment 3), direct speech did not enhance the general low RC-attachment preference. The results from Experiments 1 and 2 suggest a quantitative boost to implicit prosody (via auditory perceptual simulation) during silent production/comprehension of direct speech. By contrast, when reading aloud (Experiment 3), prosody becomes equally salient across conditions due to its explicit nature; indirect speech and narrative sentences thus become as susceptible to prosody-induced syntactic biases as direct speech. The present findings suggest a shared cognitive basis between default implicit prosody and simulated implicit prosody, providing a new platform for studying the effects of implicit prosody on sentence processing. PMID- 29609100 TI - The development of principled connections and kind representations. AB - Kind representations draw an important distinction between properties that are understood as existing in instances of a kind by virtue of their being the kind of thing they are and properties that are not understood in this manner. For example, the property of barking for the kind dog is understood as being had by dogs by virtue of the fact that they are dogs. These properties are said to have a principled connection to the kind. In contrast, the property of wearing a collar is not understood as existing in instances by virtue of their being dogs, despite the fact that a large percentage of dogs wear collars. Such properties are said to have a statistical connection to the kind. Two experiments tested two signatures of principled connections in 4-7 year olds and adults: (i) that principled connections license normative expectations (e.g., we judge there to be something wrong with a dog that does not bark), and (ii) that principled connections license formal explanations which explain the existence of a property by reference to the kind (e.g., that barks because it is a dog). Experiment 1 showed that both the children and adults have normative expectations for properties that have a principled connection to a kind, but not those that have a mere statistical connection to a kind. Experiment 2 showed that both children and adults are more likely to provide a formal explanation when explaining the existence of properties with a principled connection to a kind than properties with statistical connections to their kinds. Both experiments showed no effect of age (over ages 4, 7, and adulthood) on the extent to which participants differentiated principled and statistical connections. We discuss the implications of the results for theories of conceptual representation and for the structure of explanation. PMID- 29609101 TI - Studies on the O-polysaccharide of Escherichia albertii O2 characterized by non stoichiometric O-acetylation and non-stoichiometric side-chain l-fucosylation. AB - An O-polysaccharide was isolated from the lipopolysaccharide of Escherichia albertii O2 and studied by chemical methods and 1D and 2D 1H and 13C NMR spectroscopy. The following structure of the O-polysaccharide was established: . The O-polysaccharide is characterized by masked regularity owing to a non stoichiometric O-acetylation of an l-fucose residue in the main chain and a non stoichiometric side-chain l-fucosylation of a beta-GlcNAc residue. A regular linear polysaccharide was obtained by sequential Smith degradation and alkaline O deacetylation of the O-polysaccharide. The content of the O-antigen gene cluster of E. albertii O2 was found to be essentially consistent with the O polysaccharide structure established. PMID- 29609102 TI - The relationship between executive functioning and weight loss and maintenance in children and parents participating in family-based treatment for childhood obesity. AB - We examined the relationship between executive function and weight loss among children (8-12 years) and parents enrolled in a behavioral weight-loss program. 150 overweight/obese children and their parents participated in a 6-month family based weight-loss intervention and completed baseline (month 0), post-treatment (month 6) and 18-month follow-up assessments (month 24), which included Digit Span (DS), Stop Signal Task (SST), and Wisconsin Card Sorting Test (WCST). Anthropometrics were additionally measured at mid-treatment (month 3) and 6-month follow-up (month 12). Children with more baseline WCST perseverative errors regained more weight (p = .002) at 18-month follow-up. Change in child BMIz was not associated with change in child executive function (p > .05) or parent executive function (p > .05). Among parents, baseline measure of DS-backward (p < .001) and post-treatment changes in WCST perseverative errors (p < .001) were associated with post-treatment changes in parent BMI. SST was not related to parent or child weight loss. Thus, children's baseline set-shifting was associated with weight regain during follow-up whereas changes in parent set shifting was associated with changes in parent weight. Future research is needed to examine the relationship between executive function and weight loss and how this translates to intervention success for both overweight/obese children and participating parents. PMID- 29609103 TI - Cognitive control training for emotion-related impulsivity. AB - Many forms of psychopathology are tied to a heightened tendency to respond impulsively to strong emotions, and this tendency, in turn, is closely tied to problems with cognitive control. The goal of the present study was to test whether a two-week, six-session cognitive control training program is efficacious in reducing emotion-related impulsivity. Participants (N = 52) reporting elevated scores on an emotion-related impulsivity measure completed cognitive control training targeting working memory and response inhibition. A subset of participants were randomized to a waitlist control group. Impulsivity, emotion regulation, and performance on near and far-transfer cognitive tasks were assessed at baseline and after completion of training. Emotion-related impulsivity declined significantly from pre-training to post-training and at two week follow-up; improvements were not observed in the waitlist control group. A decrease in brooding rumination and an increase in reappraisal were also observed. Participants showed significant improvements on trained versions of the working memory and inhibition tasks as well as improvements on an inhibition transfer task. In sum, these preliminary findings show that cognitive training appears to be well-tolerated for people with significant emotion-driven impulsivity. Results provide preliminary support for the efficacy of cognitive training interventions as a way to reduce emotion-related impulsivity. PMID- 29609104 TI - Duckweed diversity decreases heavy metal toxicity by altering the metabolic function of associated microbial communities. AB - Mono-cultured and mix-cultured duckweed species were investigated with respect to the function of their associated microbial communities in heavy metal contaminated wastewater. Results show that the carbon source utilization patterns of the L. aequinoctialis- and S. polyrhiza-associated microbial communities were different. The relationships between microbial activity, antioxidant enzyme activity (CAT, GSH, and SOD) and growth was positive and significant. The microbial activity of L. aequinoctialis and S. polyrhiza in mixture was higher than in monoculture in low and high heavy metal, respectively, thereby altering the utilization of specific carbon source types and increasing duckweed growth and antioxidant enzyme activity, when compared to the monocultured duckweed. Furthermore, results indicate that duckweed species in mixture are protected from damage through regulation of the associated bacterial communities. PMID- 29609105 TI - Health risk assessment of dermal exposure to chlorpyrifos among applicators on rice farms in Ghana. AB - Generally, there is limited information on pesticide absorbed dose levels and health risk attributable to the dermal route of exposure among applicators. The objective of this study was to evaluate the absorbed dose levels and consequent health risk from dermal exposure to chlorpyrifos among applicators on rice farms in Ghana. The whole-body dosimetry technique was used to capture chlorpyrifos residues penetrating the applicators' clothing and reaching their skin, as well as residues reaching uncovered body areas of the applicators. Acute (ADDD) and chronic (LADDD) absorbed dose levels of chlorpyrifos were estimated from the residues and plotted as cumulative probability distributions. Health risk from chlorpyrifos exposure was characterized using the Hazard Quotient (HQ) technique. Three of the four acute exposure guideline values used in the study indicated that applicators, represented by the median-exposed (ADDD, 15 MUg/kg/day) and the 5% - highly exposed (ADDD, 27 MUg/kg/day) groups were at high risk of acute adverse health effects due to chlorpyrifos exposure, with HQ values ranging from 1.5 to 5 and 2.7 to 9, respectively. Regarding chronic adverse health effects, none of the guideline values suggested risk among the median-exposed group (LADDD, 0.3 MUg/kg/day), with HQ values ranging from 0.03 to 1. However, two of the chronic exposure guideline values suggested that the 5%- highly exposed group (LADDD, 0.6 MUg/kg/day) may be adversely affected, with HQ values ranging from 1.2 to 2. These findings highlight the importance of the dermal route as a major pesticide exposure pathway and suggest possible exposure minimization strategies. PMID- 29609106 TI - Supercritical water treatment of heavy metal and arsenic metalloid bioaccumulating-biomass. AB - Hyperaccumulator biomass, as a promising resource for renewable energy that can be converted into valuable fuel productions with high conversion efficiency, must be considered as hazardous materials and be carefully treated before further reuse due to the high contents of heavy metals. In this study, Pteris vittata L., an As-hyperaccumulator biomass was treated by an effective and environmental friendly method-supercritical water gasification (SCWG) using a bench-scale batch reactor. The contents of heavy metals (Cd, Pb and Zn) and arsenic metalloid in solid, liquid and gaseous products during SCWG process were thoroughly investigated. The speciation fractions including exchangeable, reducible, oxidizable and residual fractions of each heavy metal as the proportion of the total contents in solid residue were presented and the transformations trend of these heavy metals during the SCWG process was especially demonstrated. The significant operating parameters, including reaction temperature (395-445 degrees C), pressure (21-27 MPa) and residence time (0-40 min) were varied to explore their effects on the contents and forms. Moreover, the environmental risks of heavy metals in solid residues were evaluated based on risk assessment code, taking into consideration the speciation fractions and bioavailability. It was highlighted that although heavy metals particularly Pb and Zn tended to accumulate in solid residues with a maximum increment of about 50% in the total content, they were mostly converted to more stable oxidizable and residual fractions, and thus the ecotoxicity and bioavailability were greatly mitigated with no obvious increase in direct toxicity fractions. Each tested heavy metal presented no or low risk to the environments after SCWG treatments, meaning that the environmental pollution levels were markedly reduced with no or low risk to the environment. This study highlights the remarkable ability of SCWG for the heavy metal stabilization. PMID- 29609107 TI - Effects of the decomposing liquid of Cladophora oligoclona on Hydrilla verticillata turion germination and seedling growth. AB - Excessive proliferation of filamentous green algae (FGA) has been considered an important factor resulting in the poor growth or even decline of submerged macrophytes. However, there is a lack of detailed information regarding the effect of decaying FGA on submerged macrophytes. This study aimed to investigate whether the decomposing liquid from Cladophora oligoclona negatively affects Hydrilla verticillata turion germination and seedling growth. The results showed that the highest concentrations of decomposing liquid treatments inhibited the turion germination rate, which was the lowest than other treatments, at only 84%. The chlorophyll a fluorescence (JIP test) and physiological indicators (chlorophyll a content, soluble sugars, Ca2+/Mg2+-ATPase and PAL activity) were also measured. The chlorophyll a content in the highest concentration (40% of original decomposing liquid) treatment group decreased by 43.53% than that of the control; however, soluble sugars, Ca2+/Mg2+-ATPase, and PAL activity increased by 172.46%, 271.19%, and 26.43% respectively. The overall results indicated that FGA decay has a considerable effect on submerged macrophyte turion germination and seedling growth, which could inhibit their expansion and reproduction. This study emphasized the need to focus on effects of FGA decomposition on the early growth stages of submerged macrophytes and offered technological guidance for submerged vegetation restoration in lakes and shallow waters. PMID- 29609108 TI - Role of fluoranthene and pyrene associated with suspended particles in their bioaccumulation by zebrafish (Danio rerio). AB - Hydrophobic organic compounds (HOCs) tend to be associated with suspended particles in surface aquatic systems, however, the bioavailability of HOCs on suspended particles to fish is not well understood. In this study, a passive dosing device was used to control the freely dissolved concentrations (Cfree) of polycyclic aromatic hydrocarbons (PAHs) including fluoranthene and pyrene, and the influence of particle-associated PAHs on their bioaccumulation by zebrafish was investigated. The results showed that, when the Cfree of PAHs were kept constant, the presence of suspended particles did not significantly affect the steady state of PAH bioaccumulation in zebrafish tissues excluding head and digestive tracts, suggesting that the bioaccumulation steady state was controlled by the freely dissolved concentrations of PAHs. However, suspended particles promoted the uptake and elimination rate constants of PAHs in zebrafish body excluding head and digestive tracts. The uptake rate constants with 0.5 g/L suspended particles were approximately twice of those without suspended particles, and the body burden in zebrafish increased by 16.4% - 109.3% for pyrene and 21.8% - 490.4% for fluoranthene during the first 8-d exposure. This was due to the reasons that suspended particles could be ingested, and part of PAHs associated with them could be desorbed in digestive tract and absorbed by the zebfrafish, leading to the enhancement of uptake rates of PAHs in zebfrafish. The findings obtained from this study indicate that PAHs on suspended particles are partly bioavailable to zebrafish and particle ingestion is an important route in PAH bioaccumulation. Therefore, it is important to consider the bioavailability of HOCs on suspended particles to improve ecological risk assessment. PMID- 29609109 TI - Effects of cadmium on calcium homeostasis in the white-rot fungus Phanerochaete chrysosporium. AB - Due to the widespread application of white-rot fungi for the treatment of pollutants, it's crucial to exploit the special effects of pollutants on the microbes. Here, we studied the effects of cadmium on calcium homeostasis in the most studied white-rot fungus Phanerochaete chrysosporium. The response of P. chrysosporium to cadmium stress is concentration-dependent. A high concentration of cadmium caused the release of calcium from P. chrysosporium, while a hormesis effect was observed at a lower cadmium concentration (10 MUM), which resulted in a significant increase in calcium uptake and reversed the decrease in cell viability. Calcium (50 MUM) promoted cell viability (127.2% of control), which reflects that calcium can protect P. chrysosporium from environmental stress. Real-time changes in the Ca2+ and Cd2+ fluxes of P. chrysosporium were quantified using the noninvasive microtest technique. Ca2+ influx decreased significantly under cadmium exposure, and the Ca2+ channel was involved in Ca2+ and Cd2+ influx. The cadmium and/or calcium uptake results coupled with the real-time Ca2+ and Cd2+ influxes microscale signatures can enhance our knowledge of the homeostasis of P. chrysosporium with respect to cadmium stress, which may provide useful information for improving the bioremediation process. PMID- 29609110 TI - Psychoneuroimmunology and immunopsychiatry of zebrafish. AB - Despite the high prevalence of neural and immune disorders, their etiology and molecular mechanisms remain poorly understood. As the zebrafish (Danio rerio) is increasingly utilized as a powerful model organism in biomedical research, mounting evidence suggests these fish as a useful tool to study neural and immune mechanisms and their interplay. Here, we discuss zebrafish neuro-immune mechanisms and their pharmacological and genetic modulation, the effect of stress on cytokines, as well as relevant models of microbiota-brain interplay. As many human brain diseases are based on complex interplay between the neural and the immune system, here we discuss zebrafish models, as well as recent successes and challenges, in this rapidly expanding field. We particularly emphasize the growing utility of zebrafish models in translational immunopsychiatry research, as they improve our understanding of pathogenetic neuro-immune interactions, thereby fostering future discovery of potential therapeutic agents. PMID- 29609112 TI - Hair cortisol concentration (HCC) as a measure for prenatal psychological distress - A systematic review. AB - Prenatal environment reportedly affects the programming of developmental trajectories in offspring and the modification of risks for later morbidity. Among the increasingly studied prenatal exposures are maternal psychological distress (PD) and altered maternal hypothalamus-pituitary-adrenal (HPA) axis functioning. Both prenatal PD and maternal short-term cortisol concentrations as markers for HPA axis activity have been linked to adverse child outcomes and it has been assumed that maternal PD affects the offspring partially via altered cortisol secretion patterns. Yet, the existing literature on the interrelations between these two measures is conflicting. The assessment of cortisol levels by using hair cortisol concentration (HCC) has gained interest, as it offers a way to assess long-term cortisol levels with a single non-invasive sampling. According to our review, 6 studies assessing the associations between maternal HCC during pregnancy and various types of maternal PD have been published so far. Measures of prenatal PD range from maternal symptoms of depression or anxiety to stress related to person's life situation or pregnancy. The aim of this systematic review is to critically evaluate the potential of HCC as a biomarker for maternal PD during pregnancy. We conclude that HCC appears to be inconsistently associated with self-reported symptoms of prenatal PD, especially in the range of mild to moderate symptom levels. Self-reports on PD usually cover short time periods and they seem to depict partly different phenomena than HCC. Thus, methodological aspects are in a key role in future studies evaluating the interconnections across different types of prenatal PD and maternal HPA axis functioning. Further, studies including repetitive measurements of both HCC and PD during the prenatal period are needed, as timing of the assessments is one important source of variation among current studies. The significance of prenatal HCC in the context of offspring outcomes needs to be further investigated. PMID- 29609111 TI - Regulation of anxiety-like behavior and Crhr1 expression in the basolateral amygdala by LMO3. AB - The LIM domain only protein LMO3 is a transcriptional regulator that has been shown to regulate several behavioral responses to alcohol. Specifically, Lmo3 null (Lmo3Z) mice consume more ethanol in a binge-drinking test and show enhanced ethanol-induced sedation. Due to the high comorbidity of alcohol use and anxiety, we investigated anxiety-like behavior in Lmo3Z mice. Lmo3Z mice spent more time in the open arms of the elevated plus maze compared with their wild-type littermates, but the effect was confounded by reduced locomotor activity. To verify the anxiety phenotype in the Lmo3Z mice, we tested them for novelty induced hypophagia and found that they also showed reduced anxiety in this test. We next explored the mechanism by which LMO3 might regulate anxiety by measuring mRNA and protein levels of corticotropin releasing factor (encoded by the Crh gene) and its receptor type 1 (Crhr1) in Lmo3Z mice. Reduced Crhr1 mRNA and protein was evident in the basolateral amygdala (BLA) of Lmo3Z mice. To examine whether Lmo3 in the amygdala is important for anxiety-like behavior, we locally reduced Lmo3 expression in the BLA of wild type mice using a lentiviral vector expressing a short hairpin RNA targeting the Lmo3 transcript. Mice with Lmo3 knockdown in the BLA exhibited decreased anxiety-like behavior relative to control mice. These results suggest that Lmo3 promotes anxiety-like behavior specifically in the BLA, possibly by altering Crhr1 expression. This study is the first to support a role for Lmo3 in anxiety-like behavior. PMID- 29609113 TI - Prevention of alcohol-induced DNA damage by a proprietary glycyrrhizin/D-mannitol product: A randomized, placebo-controlled, cross-over human study. AB - OBJECTIVES: The purpose of the present study was to evaluate the ability of a proprietary combination of glycyrrhizin and D-mannitol to protect against oxidative damage to DNA associated with acute alcohol consumption by human subjects in a randomized, placebo-controlled cross-over designed study. Excessive alcohol consumption is associated with numerous diseases. Alcohol has been shown to generate reactive oxygen species that can result in DNA damage, leading to genetic and epigenetic changes. METHODS: A total of 25 subjects (13 male and 12 female) were enrolled. Alcohol intake in the form of vodka (40% ethanol) was adjusted based on 1.275 g of 100% ethanol/kg body weight for men and 1.020 g/kg body weight for women, which was consumed with and without the study product. Blood samples were drawn at 2 h after alcohol consumption, lymphocytes were isolated, and were subjected to DNA comet electrophoresis on a blinded basis. RESULTS: Acute alcohol consumption increased lymphocyte DNA damage by approximately 8.36%. Co-consumption of the glycyrrhizin/D-mannitol study product with alcohol reduced DNA damage to baseline levels. No adverse effects were associated with use of the study product, and no differences were observed in blood alcohol concentrations in the presence or absence of the study product in males and females. CONCLUSIONS: Acute alcohol ingestion resulted in measurable increases in DNA damage, which were prevented by the addition of the proprietary glycyrrhizin/D-mannitol (NTX(r)) study product to the alcohol, suggesting that the tissue-damaging effects of alcohol consumption can be ameliorated. PMID- 29609114 TI - Mechanism on emulsified vegetable oil stimulating nitrobenzene degradation coupled with dissimilatory iron reduction in aquifer media. AB - Microbial dissimilatory iron reduction could remediate reducible pollutants in groundwater, such as nitrobenzene (NB). But the natural attenuation rate in aquifer is limited. To stimulate this process, emulsified vegetable oil (EVO) was injected as a remediation agent. The mechanism of this process was studied. Results showed that the addition of EVO made iron easier used by microorganisms and thus promoted dissimilatory iron reduction. The readily used Fe(III) served as electron acceptor and was reduced to Fe(II). Fe(II) supplied electrons to NB, with NB reduced to aniline. Sulphide in the aquifer media also donated electrons and oxidized to polysulfide, then forming precipitates with Fe(II) to the surface of aquifer media, and thus slowing down the electron supplying of EVO and forming permanent efficiency for NB remediation. The work helps to complete a systematic understanding of NB remediation process under stimulation of EVO. PMID- 29609115 TI - NanoRNase from Aeropyrum pernix shows nuclease activity on ssDNA and ssRNA. AB - In cells, degrading DNA and RNA by various nucleases is very important. These processes are strictly controlled and regulated to maintain DNA integrity and to mature or recycle various RNAs. NanoRNase (Nrn) is a 3'-exonuclease that specifically degrades nanoRNAs shorter than 5 nucleotides. Several Nrns have been identified and characterized in bacteria, mainly in Firmicutes. Archaea often grow in extreme environments and might be subjected to more damage to DNA/RNA, so DNA repair and recycling of damaged RNA are very important in archaea. There is no report on the identification and characterization of Nrn in archaea. Aeropyrum pernix encodes three potential Nrns: NrnA (Ape1437), NrnB (Ape0124), and an Nrn like protein Ape2190. Biochemical characterization showed that only Ape0124 could degrade ssDNA and ssRNA from the 3'-end in the presence of Mn2+. Interestingly, unlike bacterial Nrns, Ape0124 prefers ssDNA, including short nanoDNA, and degrades nanoRNA with lower efficiency. The 3'-DNA backbone was found to be required for efficiently hydrolyzing the phosphodiester bonds. In addition, Ape0124 also degrads the 3'-overhang of double-stranded DNA. Interestingly, Ape0124 could hydrolyze pAp into AMP, which is a feature of bacterial NrnA, not NrnB. Our results indicate that Ape0124 is a novel Nrn with a combined substrate profile of bacterial NrnA and NrnB. PMID- 29609116 TI - Syringomyelia with intramedullary ectopic choroid plexus: Case report. AB - BACKGROUND: Intramedullary ectopic choroid plexus is rarely reported, here, we reported a rare case of symptomatic syringomyelia resulted of intramedullary ectopic choroid plexus. CASE DESCRIPTION: The patient was a 30-year-old female who presented with a 2-month history of progressive pain of upper back and bilateral ankle joint and progressive loss of upper-extremity function. MRI examination showed an intramedullary cystic lesion at T2-T4 without enhancement. Operative exploration was indicated. A reddish vascular villus-like lesion was found being located in the left dorsal part of the cyst, which was enblock removed and was confirmed as an ectopic choroid plexus tissue by pathological examination. The patient recovered uneventful and the symptom resolved during follow-up. CONCLUSIONS: Although ectopic choroid plexus is extremely rare, it should be taken into acount in the differential diagnosis of pathogenesis in syringomyelia or intramedullary cyst, aggressive surgical exploration should be considered when necessary. PMID- 29609117 TI - Giant convexity chondroma with meningeal attachment. AB - OBJECTIVE: Intracranial chondroma is a rare and benign tumor with usual onset in young adulthood. The skull base is the most common site of occurrence although, less often, the tumors can appear at the falx cerebri or at the dural convexity. The differentiation of these lesions from meningiomas through imaging is generally difficult. PATIENT AND METHODS: Clinical case presentation and review of the current literature. RESULTS / CASE PRESENTATION: We report a case of a 25 year-old male patient with a giant convexity chondroma with meningeal attachment in the right frontal lobe that was detected after a first generalized seizure. Based on the putative diagnosis of meningioma, the tumor was completely resected via an osteoplastic parasagittal craniotomy. The postoperative MRI confirmed the complete tumor resection. Histopathological analysis revealed the presence of a chondroma. CONCLUSION: Intracranial chondromas are a rarity and their preoperative diagnosis based on neuroimaging is difficult. In young patients and those with skeletal disease, the differential diagnosis of a chondroma should be considered. In symptomatic patients, operative resection is sensible. In most cases total removal of the tumor is possible and leads to full recovery. When the finding is merely incidental in older patients, a watchful waiting approach is acceptable, given the benign and slow-growing nature of the lesion. PMID- 29609118 TI - TMS over the supramarginal gyrus delays selection of appropriate grasp orientation during reaching and grasping tools for use. AB - Tool use, a ubiquitous part of human behaviour, requires manipulation control and knowledge of tool purpose. Neuroimaging and neuropsychological research posit that these two processes are supported by separate brain regions, ventral premotor and inferior parietal for manipulation control, and posterior middle temporal cortex for tool knowledge, lateralised to the left hemisphere. Action plans for tool use need to integrate these two separate processes, which is likely supported by the left supramarginal gyrus (SMG). However, whether this integration occurs during action execution is not known. To clarify the role of the SMG we conducted two experiments in which healthy participants reached to grasp everyday tools with the explicit instruction to use them directly following their grasp. To study the integration of manipulation control and tool knowledge within a narrow time window we mechanically perturbed the orientation of the tool to force participants to correct grasp orientation 'on-line' during the reaching movement. In experiment 1, twenty healthy participants reached with their left hand to grasp a tool. Double-pulse transcranial magnetic stimulation (TMS) was applied, in different blocks over left or right SMG at the onset of perturbation. Kinematic data revealed delayed and erroneous online correction after TMS over left and right SMG. In Experiment 2 twelve participants reached, in different blocks, with their left or right hand and TMS was applied over SMG ipsilateral to the reaching hand. A similar effect on correction was observed for ipsilateral stimulation when reaching with the left and right hands, and no effect of or interaction with hemisphere was observed. Our findings implicate a bilateral role of the SMG in correcting movements and selection of appropriate grasp orientation during reaching to grasp tools for use. PMID- 29609120 TI - Recent progress of the development of dipeptidyl peptidase-4 inhibitors for the treatment of type 2 diabetes mellitus. AB - Diabetes is a fast growing chronic metabolic disorder around the world. Dipeptidyl peptidase-4 (DPP-4) is a new promising target during type 2 diabetes glycemic control. Thus, a number of potent DPP-4 inhibitors were developed and play a rapidly evolving role in the management of type 2 diabetes in recent years. This article reviews the development of synthetic and natural DPP-4 inhibitors from 2012 to 2017 and provides their physico-chemical properties, biological activities against DPP-4 and selectivity over dipeptidyl peptidase 8/9. Moreover, the glucose-lowering mechanisms and the active site of DPP-4 are also discussed. We also discuss strategies and structure-activity relationships for identifying potent DPP-4 inhibitors, which will provide useful information for developing potent DPP-4 drugs as type 2 diabtes treatments. PMID- 29609119 TI - Benzopyrroloxazines containing a bridgehead nitrogen atom as promising scaffolds for the achievement of biologically active agents. AB - The present review lists the papers and patents dealing with the class of polycondensed heterocycles called benzopyrroloxazines published in the last decades. The survey is limited to substances characterized by the presence of a bridgehead N atom, which means that the present N atom serves to connect different rings within the same molecule. In the case of benzopyrroloxazines, the bridgehead N atom belongs at the same time to the pyrrole and oxazine rings. All other compounds not possessing this feature were kept out accordingly. Relevant synthetic methods to such compounds have been outlined. Many different biological properties have been attributed to several functionalized derivatives of these heterocycles and cited within the review. PMID- 29609121 TI - Incorporation of nitric oxide donor into 1,3-dioxyxanthones leads to synergistic anticancer activity. AB - Fifty 1,3-dioxyxanthone nitrates (4a ~ i-n, n = 1-6) were designed and synthesized based on molecular similarity strategy. Incorporation of nitrate into 1,3-dioxyxanthones with electron-donating groups at 6-8 position brought about synergistic anticancer effect. Among them, compound 4g-4 was confirmed the most active agent against HepG-2 cells growth with an IC50 of 0.33 +/- 0.06 MUM. It dose-dependently increased intramolecular NO levels. This activity was attenuated by either NO scavenger PTIO or mitochondrial aldehyde dehydrogenase (mtADH) inhibitor PCDA. Apoptosis analysis indicated different contributions of early/late apoptosis and necrosis to cell death for different dose of 4g-4. 4g-4 arrested more cells on S phase. Results from Western Blot implied that 4g-4 regulated p53/MDM2 to promote cancer cell apoptosis. All the evidences support that 4g-4 is a promising anti-cancer agent. PMID- 29609122 TI - Microwave-assisted one-pot synthesis of new phenanthrene fused-tetrahydrodibenzo acridinones as potential cytotoxic and apoptosis inducing agents. AB - An expeditious microwave-assisted one-pot synthesis of new cytotoxic phenanthrene fused-tetrahydrodibenzo-acridinones has been successfully accomplished. This protocol offers wide substrate scope, catalyst-free synthesis, atom-economy, simple recrystallization, high yields, and ethanol was used as green solvent. These new compounds were tested for their in vitro cytotoxicity against cervical (HeLa), prostate (PC-3), fibrosarcoma (HT-1080), ovarian (SKOV-3) cancer cells, and were safer to normal (Hek-293T) kidney cell line. All the compounds have displayed significant cytotoxicity profile, among them 8m being the most potent compound with an IC50 0.24 +/- 0.05 MUM against SKOV-3 ovarian cancer cells. Flow cytometry analysis revealed that cells were blocked at the G2/M phase of the cell cycle. The effect of 8m on F-actin polymerisation was also studied. Hoechst staining clearly showed the decreased number of viable cells and indicated apoptosis progression. Compound 8m caused the collapse of mitochondrial membrane potential as observed via JC-1 staining and also enhanced the generation of reactive oxygen species. The increase of caspase-3 activation by 3.7 folds supported the strong apoptosis induction. In addition, an in vitro 3D-spheroid progression assay was performed with 8m that significantly suppressed the tumor cells. PMID- 29609123 TI - Proteases catalyzing vicilin cleavage in developing pea (Pisum sativum L.) seeds. AB - Legume species differ in whether or not the 7S globulins stored in seeds undergo proteolytic processing during seed development, while preserving the bicupin structure and trimeric assembly necessary for accumulation and packing into protein storage vacuoles. Two such cleavage sites have been documented for the vicilins in pea cotyledons: one in the linker region between the two cupin domains, and another in an exposed loop in the C-terminal cupin. In this report, we explain the occurrence of vicilin cleavage in developing pea by showing that the storage vacuoles are already acidified before germination, in contrast to soybean and peanut where acidification occurs only after germination. We also show that the two cleavage reactions are catalyzed by two different proteases. The vicilin cleavage at the linker region was inhibited by AEBSF (4-(2 aminoethyl)benzenesulfonyl fluoride), indicative of a serine protease. The cleavage in the C-terminal cupin domain was sensitive to the sulfhydryl-reactive reagents p-chloromercuriphenylsulfonate and iodoacetate, but not to E-64 (N-[N-(L 3-transcarboxyirane-2-carbonyl)-l-leucyl]-agmatine), characteristic of the legumain class of cysteine proteases. During seed development, we found the predominant vicilin cleavage in this pea cultivar (Knight) to be at the site in the second cupin domain; but after germination, both sites were cleaved at about the same rate. PMID- 29609124 TI - EDTA modified beta-cyclodextrin/chitosan for rapid removal of Pb(II) and acid red from aqueous solution. AB - EDTA modified beta-cyclodextrin/chitosan (CDCS-EDTA) was fabricated successfully by a two-step method and applied to remove Pb(II) and anionic dye acid red 73 (AR). CDCS-EDTA was characterized by scanning electron microscopy (SEM), Fourier transform infrared spectroscopy (FTIR), and zeta potential analysis. The effects of experimental parameters including adsorbent dose, contact time and pH value on the adsorption efficiency of CDCS-EDTA for the pollutants were investigated. The maximum adsorption capacities were 114.8 mg g-1 for Pb(II) and 754.6 mg g-1 for AR under the optimal conditions. 93.4% of Pb(II) and 92.1% of AR could be adsorbed within 5 min, and the adsorptions reached equilibrium rapidly within 20 min and 10 min for Pb(II) and AR, respectively. A possible adsorption mechanism had been proposed that chelation of EDTA and electrostatic attraction of hydroxyl and amino groups dominated the adsorption of Pb(II), while the adsorption of AR mainly by the formation of inclusion complex with cyclodextrin cavities and electrostatic attraction with functional groups. For these two pollutants, the adsorption kinetic and isotherm data fitted well with the pseudo-second-order model and the Langmuir model, respectively. Thermodynamic studies implied that the adsorption process of Pb(II) and AR were spontaneous. Furthermore, the excellent regeneration performance indicated that CDCS-EDTA has a promising application in water treatment. PMID- 29609125 TI - CO2-switchable foams stabilized by a long-chain viscoelastic surfactant. AB - Smart foams sensitive to external stimulation have gained increasing attention recently. However, reversibly switchable CO2 foams have been less documented. In this work, a novel kind of CO2-switchable foams was developed using a long-chain cationic surfactant, N-erucamidopropyl-N,N-dimethylammonium bicarbonate (UC22AMPM?H+), as both the foaming agent and stabilizer. The foams can be rapidly transformed between stable and unstable states at ambient temperature with CO2/NH3.H2O as the triggers. The foaming properties and switchable performance were examined by a combination of confocal microscopy, cryogenic transmission electron microscopy, and rheological techniques. The results demonstrated that the enhanced foam stability in the presence of CO2 is attributed to the high bulk phase viscosity and gas/liquid surface viscosity, resulting from the entanglement of wormlike micelles (WLMs) formed from UC22AMPM?H+. When NH3.H2O is added, the network structure of WLMs is disrupted, and the bulk phase viscosity and surface viscosity subsequently drop, consequently leading to an ultimate foam destabilization. Such a CO2-sensitive viscoelastic surfactant could not only be used to fabricate smart CO2 foams but can also enable CO2 to play dual roles as both the dispersed phase, as most gases do, and an "activator" to protonate long chain tertiary surfactants into cationic analogs to form viscoelastic WLMs to stabilize foams. PMID- 29609126 TI - Removal of monoethylene glycol from wastewater by using Zr-metal organic frameworks. AB - Mono-ethylene glycol (MEG), used in the oil and gas industries as a gas hydrate inhibitor, is a hazardous chemical present in wastewater from those processes. Metal-organic frameworks (MOFs) (modified UiO-66* and UiO-66-2OH) were used for the effective removal of MEG waste from effluents of distillation columns (MEG recovery units). Batch contact adsorption method was used to study the adsorption behavior toward these types of MOFs. Adsorption experiments showed that these MOFs had very high affinity toward MEG. Significant adsorption capacity was demonstrated on UiO-66-2OH and modified UiO-66 at 1000 mg.g-1 and 800 mg.g-1 respectively. The adsorption kinetics were fitted to a pseudo first-order model. UiO-66-2OH showed a higher adsorption capacity due to the presence of hydroxyl groups in its structure. A Langmuir model gave the best fitting for isotherm of experimental data at pH = 7. PMID- 29609127 TI - A rapid deposition of polydopamine coatings induced by iron (III) chloride/hydrogen peroxide for loose nanofiltration. AB - Mussel-inspired polydopamine (PDA) coatings have received widespread concern due to the advantages of eco-friendliness, adhesion nature, and film-forming feasibility. However, self-polymerization of dopamine assisted by air-oxidation under alkaline condition is time-consuming, and the ensuing uneven PDA coatings restrict their applications. In this study, we proposed a rapid PDA deposition triggered by a facile system of iron (III) chloride/hydrogen peroxide (FeCl3/H2O2) under acidic condition. The oxygen-radical species generated by FeCl3/H2O2 largely promote covalent polymerization and deposition rate of dopamine. This not only considerably shortens the deposition time of PDA, but also improves the stability of PDA coatings, combined with the chelation of Fe ions in PDA matrices. SEM, AFM, XPS, zeta potential and water contact angle analyses confirmed the formation of a hydrophilic, smooth, and negatively charged PDA layer onto several membrane substrates. Herein, PDA-coated hydrolyzed polyacrylonitrile membranes yield a remarkable NF performance with superior dye retentions (direct red 23: 98.6%, Congo red: 99.0%, reactive blue 2: 98.2%) and a high water permeability (17.5 L m-2 h-1 bar-1). Furthermore, a low salt rejection (NaCl: 5.6%) of PDA-modified membranes demonstrates their great potential in fractionation of dye/salt mixtures. Meanwhile, the PDA-modified membranes show an excellent organic fouling resistance and a long-term stability. This facile, environmental-friendly method provides a rapid PDA deposition onto various substrates for a wide range of applications, including filtration membranes. PMID- 29609128 TI - A monodisperse anionic silver nanoparticles colloid: Its selective adsorption and excellent plasmon-induced photodegradation of Methylene Blue. AB - To address the pollution problem of organic dyes, monodispersed anionic silver nanoparticles (AgNPs) with an average size of 6 nm were prepared in water media via chemical reduction method from oleic acid and n-butyl amine. The aqueous solution of the resultant AgNPs was utilized as a photocatalyst to investigate the adsorption and photodegradation behaviors of organic dyes under different light irradiation. The morphology and surface characteristics of the synthesized AgNPs were probed using TEM, XRD, FTIR and zeta potential analysis. The adsorption and degradation process of organic dyes on the AgNPs were characterized in details by UV-Vis spectrophotometer. The results showed that the AgNPs exhibited a characteristic charge- and size-selective adsorption of dyes owing to the profoundly negative charged surface, which enables the AgNPs to possess high selective degradation of Methylene Blue. More still, due to the surface plasmon resonance (SPR) effect of AgNPs, the obtained AgNPs presented a higher photocatalytic activity to Methylene Blue under UV light, visible light, and solar light compared with commercial photocatalysts. The 5 cyclic reactions revealed its high stability and reusability. In a nutshell, the proposed mechanism systematically combined the selective adsorption and the SPR effect to explain the detailed photocatalytic process of the obtained AgNPs. PMID- 29609129 TI - Nebulized lidocaine ameliorates allergic airway inflammation via downregulation of TLR2. AB - Nebulized lidocaine has been suggested to be beneficial in asthma therapy, but the underlying mechanisms are little known. We aimed to investigate whether Toll like receptor (TLR) 2 was involved in the protective effect of lidocaine on allergic airway inflammation. Female C57BL/6 mice were sensitized and challenged with ovalbumin (OVA). Meanwhile, some of the mice were treated with TLR2 agonist (Pam3CSK4, 100 MUg) intraperitoneally in combination with OVA on day 0. Just after allergen provocation, mice were treated with inhaled lidocaine or vehicle for 30 min. In this model, we found that lidocaine markedly attenuated OVA-evoked airway inflammation, leukocyte recruitment and mucus production. Moreover, lidocaine abrogated the increased concentrations of T cytokines and TNF-alpha in bronchoalveolar lavage fluid (BALF) of allergic mice, as well as reducing the expression of phosphorylated nuclear factor (P-NF)-kappaBp65 and the NOD-like receptor pyridine containing 3 (NLRP3), which are important for the production of pro-inflammatory cytokines. In addition, our study showed that lidocaine dramatically decreased OVA-induced increased expression of TLR2 in the lung tissues. Furthermore, activation of TLR2 aggravated OVA-challenged airway inflammation, meanwhile, it also elevated OVA-induced expression of P-NF kappaBp65 and NLRP3 in the lungs. However, lidocaine effectively inhibited airway inflammation and counteracted the expression of P-NF-kappaBp65 and NLRP3 in allergic mice pretreated with Pam3CSK4. Taken together, the present study demonstrated that lidocaine prevented allergic airway inflammation via TLR2 in an OVA-induced murine allergic airway inflammation model. TLR2/NF-kappaB/NLRP3 pathway may serve as a promising therapeutic strategy for allergic airway inflammation. PMID- 29609130 TI - Understanding the role of non-coding RNA (ncRNA) in stent restenosis. AB - Coronary heart disease (CHD) is one of the leading disorders with the highest mortality rate. Percutaneous angioplasty and stent implantation are the currently available standard methods for the treatment of obstructive coronary artery disease. However, the stent being an exogenous substance causes several complications by promoting the proliferation of vascular smooth muscle cells, immune responses and neointima formation after implantation, leading to post stent restenosis (ISR) and late thrombosis. The prevention of these adverse vascular events is important to achieve long-term proper functioning of the heart after stent implantation. Non-coding ribonucleic acids (ncRNAs) are RNA molecules not translated into proteins, theyhave a great potential in regulating endothelial cell and vascular smooth muscle function as well as inflammatory reactions. In this review, we outline the regulatory functions of different classes of ncRNA in cardiovascular disease and propose ncRNAs as new targets for stent restonosis treatment. PMID- 29609131 TI - Hepatocyte growth factor is associated with progression of atherosclerosis: The Multi-Ethnic Study of Atherosclerosis (MESA). AB - BACKGROUND AND AIMS: Hepatocyte growth factor (HGF) has previously been associated with risk of stroke, coronary heart disease, and atherosclerosis. We hypothesized that higher circulating HGF is associated with greater progression of measures of atherosclerosis: coronary artery calcium (CAC) and carotid plaque. METHODS: Participants aged 45-84 years from the prospective cohort study Multi Ethnic Study of Atherosclerosis had HGF measured at baseline (between 2000 and 2002) and were followed for progression of atherosclerosis for up to 12 years. CAC was measured at all five exams using the Agatston method. Mixed-effects models were used to examine the association of HGF and CAC progression among 6695 participants with available data. Relative risk regression was used to assess the association between HGF and new or additional carotid plaque between exams 1 and 5 in 3400 participants with available data. All point estimates were adjusted for potential confounding variables. RESULTS: Each standard deviation higher HGF at baseline was associated with 2.9 Agatston units/year greater CAC progression (95% CI: 1.6-4.2, p < 0.0001), and the magnitude of this association differed by race/ethnicity (p value for interaction by race = 0.003). Each standard deviation higher HGF at baseline was associated with a 4% higher risk of new or additional carotid plaque (95% CI: 1.01-1.08, p = 0.005). CONCLUSIONS: Higher levels of HGF were significantly associated with greater progression of atherosclerosis in this large and diverse population. Circulating HGF continues to show promise as a potential clinical biomarker for cardiovascular disease. PMID- 29609132 TI - The Self-Report Habit Index: Assessing habitual marijuana, alcohol, e-cigarette, and cigarette use. AB - BACKGROUND: Substance use is partially driven by habitual processes that occur automatically in response to environmental cues and may be central to users' identities. This study was designed to validate the Self-Report Habit Index (SRHI) for assessing habitual marijuana, alcohol, cigarette, and e-cigarette use. METHODS: We examined the SRHI's psychometrics in separate samples of adult marijuana (Ns = 189;170), alcohol (Ns = 100;133), cigarette (Ns = 58;371), and e cigarette (N = 239) users. RESULTS: A 6-item, single-factor solution evidenced good fit across substances (CFI marijuana/alcohol/cigarettes/e-cigarettes = 0.996/0.997/0.996/0.994, RMSEA = 0.046/0.047/0.067/0.068, SRMR = 0.017/0.017/0.010/0.015) and internal consistency (alpha = 0.88/0.94/0.95/0.91). The SRHI was scalar invariant for sex and race. However, independent-samples t tests indicated only that women endorsed stronger habitual e-cigarette use and that men endorsed stronger habitual marijuana use. The SRHI also was scalar invariant by product type in dual-users (cigarettes/e-cigarettes[N = 371]; alcohol/cigarettes [n = 58]), although differences in habit strength only were observed for cigarettes versus e-cigarettes, with dual-users reporting stronger habitual cigarette use. Finally, the SRHI predicted frequency of marijuana, alcohol, cigarette, and e-cigarette use (np2 [marijuana/alcohol/cigarettes/e cigarettes] = 0.37/0.48/0.31/0.17) and quantity of alcohol and cigarette use (np2 = 0.43/0.33). CONCLUSIONS: The SRHI is a psychometrically sound measure of adults' habitual substance use. The SRHI detected mean differences by sex and substance type and predicted the frequency of using each substance. Future research should determine if the SRHI is appropriate for use with other substances or age groups (e.g., adolescents), how it relates to task-based, behavioral measures of habit strength, and the degree to which habit predicts the development or maintenance of addiction. PMID- 29609133 TI - Factors related to cigarette smoking and intent to quit among adolescent inpatients with psychiatric and substance use disorders. AB - PURPOSE: Smoking behaviors and intent to quit have not been well studied among adolescent psychiatric patients. The current study examined the relationships between smoking-related variables (smoking status/heaviness and intent to quit), psychiatric diagnoses and symptomatology, and substance use among adolescents receiving psychiatric inpatient care. METHODS: Baseline data from a randomized controlled trial, testing the effect of a brief intervention on substance use, with 151 psychiatrically hospitalized adolescents with comorbid psychiatric and substance use disorders (diagnosed using semi-structured interviews) were examined for this study. RESULTS: Of 151 inpatients aged 13-17 years, 112 (74.2%) were smokers (self-report), of whom 59 (52.7%) expressed intent to quit within 3 months and 36 (32.1%) within 30 days. There were no differences in psychiatric diagnoses or alcohol, marijuana, or any drug use among smokers and nonsmokers. On the other hand, smokers reported significantly greater occurrences of negative consequences from alcohol use, drug use, and total substance use than nonsmokers. Separate analyses also revealed that heavier smokers reported greater negative consequences from alcohol/drug/total use. Similarly, while no difference in externalizing or internalizing symptoms was observed across smokers vs. nonsmokers, heavier smokers reported significantly more severe externalizing symptoms, but not internalizing symptoms, than lighter smokers. Intention to quit smoking did not vary as a function of psychiatric symptomatology or substance use. CONCLUSIONS: Smoking was related to several psychiatric and substance use problems. Notably, adolescent psychiatric inpatient smokers reported intention to quit smoking regardless of psychiatric disorders, psychiatric symptom severity, or other substance use. PMID- 29609135 TI - Childhood maltreatment: A predictor of mental health problems among adolescents and young adults. AB - Child maltreatment is a risk factor for detrimental effects on mental health that may extend to adulthood. This study aimed to examine the association between exposure to childhood maltreatment, socio-demographic factors, and students' mental health status and self-esteem. A cross-sectional study enrolled a representative sample of 1270 students from Kuwait University. An anonymous self administered questionnaire included students' socio-demographic characteristics, history of exposure to childhood physical and/or emotional maltreatment, DASS-21 to assess mental health status, and Rosenberg self-esteem scale was used. Chi square test and binary logistic regression models were applied. The study found that among participants, 49.6%(95% CI: 64.8%-52.4%), 63.0%(95% CI: 60.3%-65.7%), and 43.8%(95% CI: 41.1%-46.6%) reported having depression, anxiety, and stress respectively. Moreover, 22.5%(95% CI: 20.1%-24.8%) and 18.6%(95% CI:16.5%-20.9%) reported childhood physical and emotional maltreatment, respectively; while 12.7% reported both. Multivariate analysis revealed that experiencing childhood physical and emotional maltreatment were independent contributors to reporting depression and anxiety; while exposure to only emotional maltreatment contributed to reporting stress. Gender, GPA, childhood enrollment in private/public schools, number of close friends, were other contributors to mental health problems. Participants' median score of self-esteem was 17/30, and only childhood emotional maltreatment was a significant predictor to low self-esteem after adjustment for other confounders. Mental health problems, and experiencing childhood physical and emotional maltreatment were prevalent relatively high among university students. Childhood corporal and emotional maltreatment were independent predictors to adolescents and young adults' mental health problems. Experiencing childhood emotional maltreatment predicted low self-esteem. Further research to assess culture factors associated with childhood maltreatment is recommended. PMID- 29609134 TI - Effect of methamphetamine exposure on the plasma levels of endothelial-derived microparticles. AB - BACKGROUND: Methamphetamine (Meth), a neurotoxin, induces inflammation, oxidative stress, and triggers endothelial dysfunction and cardiovascular disease which is the second cause of death among individuals with Meth-use disorder. Oxidative stress and inflammation trigger the microparticle (MP) release. These are extracellular vesicles extracted from cell surface and identified in biological fluids. MP levels alter during pathological conditions, suggesting its potential biomarker role. In this respect, we designed the present experiment to investigate the effects of Meth on the plasma level of the endothelial-derived microparticle (EMP). METHODS: Animals received Meth (4 mg/kg i.p.) for 1, 7 and 14 days and then, the plasma level of EMPs was evaluated, using cell surface markers, including AnnexinV, CD144, CD31, CD41a antigens with the flow cytometry method. The biochemical indices and locomotor activity were also assessed in a rat model. RESULTS: Meth increased locomotor activity (Meth-1, 277.12 +/- 20.17; Meth-7, 262.25 +/- 11.95; Meth-14, 265.75 +/- 14.75), inflammatory and oxidative indices as evidenced by rising of the C-reactive protein (Meth-7, 39.4 +/- 1.24; Meth-14, 38.58 +/- 2.19, vs 8.65 +/- 0.45, mg/L) and malondialdehyde (Meth-7, 9.74 +/- 1.38; Meth-14, 14.6 +/- 1.45, vs 4.43 +/- 0.32 nmol/L) plasma levels. We also found that Meth triggered endothelial injury, as demonstrated by elevated levels of EMP (Meth-7, 4.77 +/- 0.22; Meth-14, 5.91 +/- 0.34, % total events/mL) compared with control group. CONCLUSION: Our data showed that Meth exposure stimulates inflammatory and oxidative pathways and facilitates the EMPs shedding. Measuring the level of EMPs might be applied as a potential diagnostic index to monitor the endothelial dysfunction in substance-use disorders. PMID- 29609136 TI - Fetuin-B links nonalcoholic fatty liver disease to type 2 diabetes via inducing insulin resistance: Association and path analyses. AB - OBJECTIVE: Laboratory models suggested that Fetuin-B impaired insulin action in myotubes and hepatocytes and caused glucose intolerance in mice. We aimed to explore the independent associations and pathways among serum Fetuin-B, nonalcoholic fatty liver disease (NAFLD) and type 2 diabetes (T2D). METHODS: A cross-sectional study of 1318 obese adults who underwent serum Fetuin-B test and hepatic ultrasonography scanning was conducted in Xiamen, China. Multivariable logistic regression was used to calculate adjusted odds ratio (OR) and 95% confidence intervals (CI) of serum Fetuin-B level and NAFLD for T2D in different models with adjustment for potential confounders. Structural equation modeling (SEM) was used to examine the paths among NAFLD, serum Fetuin-B, metabolic/insulin resistance syndrome and T2D. RESULTS: Subjects with T2D or NAFLD showed significantly increased serum Fetuin-B levels compared to their controls (4.25 +/- 1.35 vs. 4.08 +/- 1.38 ug/ml for diabetes; and 4.26 +/- 1.41 vs. 4.07 +/- 1.33 ug/ml for NAFLD; both p-values < 0.05). NAFLD and higher serum Fetuin-B were significantly associated with higher risk of T2D with adjustment for sociodemographic and lifestyle habits; and the adjusted ORs (95%CIs) were 2.90 (2.17-3.87, p < 0.001) and 1.16 (1.01-1.32, p = 0.032), respectively. With further adjustment for metabolic/insulin resistance syndrome (BMI, systolic and diastolic BP, triglyceride, total cholesterol, HDL- and LDL-cholesterol, HOMA-IR and serum uric acid), NAFLD but not serum Fetuin-B was significantly associated with increased risk of T2D (ORs (95%CIs): 1.58 (1.12-2.21, p = 0.009) and 1.07 (0.92-1.23, p = 0.384), respectively). A one pathway model by using SEM fitted well (chi2 = 497.92, p < 0.001; CFI = 0.965; TLI = 0.926; and RMSEA = 0.097) and showed that NAFLD increased serum Fetuin-B and elevated Fetuin-B increased fasting insulin level, which in turn induced insulin resistance and T2D. Besides, NAFLD increased the risk of T2D directly in addition to its indirect effects of inducing metabolic/insulin resistance syndrome which in turn increased the risk of T2D. CONCLUSIONS: Fetuin-B links NAFLD to T2D via inducing insulin resistance, and NAFLD contributes to the pathogenesis of T2D via multiple mechanisms. PMID- 29609137 TI - Cytokine-mediated therapeutic resistance in breast cancer. AB - Therapeutic resistance leading to tumor relapse is a major challenge in breast cancer (BCa) treatment. Numerous factors involved in multiple mechanisms promote the development of tumor chemo/radio-resistance. Cytokines/chemokines are important inflammatory factors and highly related to tumorigenesis, metastasis and tumors responses to treatment. A large number of studies have demonstrated that the network of cytokines activates multiple cell signaling pathways to promote tumor cell survival, proliferation, invasion, and migration. Particularly in BCa, cytokines-enhanced the epithelial-mesenchymal transition (EMT) process plays a pivotal role in the progression of metastatic phenotypes and resistance to the traditional chemo/radio-therapy. Virtually, therapeutic resistance is not entirely determined by tumor cell intrinsic characteristics but also dependent upon synchronized effects by numerous of local microenvironmental factors. Emerging evidence highlighted that exosomes secreted from various types of cells promote intercellular communication by transferring bioactive molecules including miRNAs and cytokines, suggesting that exosomes are essential for sustentation of tumor progression and therapeutic resistance within the tumor microenvironment. In this review, we discuss the mechanisms by which cytokines promote therapeutic resistance of BCa and suggest a potential approach for improving BCa therapeutics by inhibition of exosome function. PMID- 29609139 TI - Mechanical properties and superficial characterization of a milled CAD-CAM glass fiber post. AB - Computer-aided design and computer-aided manufacturing (CAD-CAM) technology may be used to produce custom intraradicular posts, but studies are lacking. The purpose of this in vitro study was to evaluate the flexural properties (strength and modulus), failure mode, superficial morphology, and roughness of two CAD-CAM glass fiber posts (milled at different angulations) compared with a commercially available prefabricated glass fiber post. Three groups were tested (n = 10): PF (control group)- prefabricated glass fiber post; C-Cd-diagonally milled post; and C-Cv-vertically milled post. A 3-dimensional virtual image was obtained from a prefabricated post, which guided the posterior milling of posts from a glass fiber disk (Trilor Blanks; Bioloren). Surface roughness and morphology were evaluated using confocal laser microscopy. Flexural strength and modulus were evaluated with the 3-point bend test. Data were submitted to one-way analysis of variance followed by the Student-Newman-Keuls post hoc test (alpha = 0.05). The fractured surfaces were evaluated with scanning electron microscopy. The superficial roughness was highest for PF and similar for the experimental groups. Morphological analysis shows different sizes and directions of the glass fibers along the post. The flexural strength was highest for PF (900.1 +/- 30.4 > C-Cd - 357.2 +/- 30.7 > C-Cv 101.8 +/- 4.3 MPa) as was the flexural modulus (PF 19.3 +/- 2.0 GPa > C-Cv 10.1 +/- 1.9 GPa > C-Cd 7.8 +/- 1.3 GPa). A CAD-CAM milled post seems a promising development, but processing requires optimizing, as the prefabricated post still shows better mechanical properties and superficial characteristics. PMID- 29609140 TI - Nanoscale characterization of dynamic cellular viscoelasticity by atomic force microscopy with varying measurement parameters. AB - Cell mechanics plays an important role in regulating the physiological activities of cells. The advent of atomic force microscopy (AFM) provides a novel powerful instrument for quantifying the mechanics of single cells at the nanoscale. The applications of AFM in single-cell mechanical assays in the past decade have significantly contributed to the field of cell and molecular biology. However, current AFM-based cellular mechanical studies are commonly carried out with fixed measurement parameters, which provides limited information about the dynamic cellular mechanical behaviors in response to the variable external stimuli. In this work, we utilized AFM to investigate cellular viscoelasticity (portrayed as relaxation time) with varying measurement parameters, including ramp rate and surface dwell time, on both cell lines and primary cells. The experimental results show that the obtained cellular relaxation times are remarkably dependent on the parameter surface dwell time and ramp rate during measurements. Besides, the dependencies to the measurement parameters are variable for different types of cells, which can be potentially used to indicate cell states. The research improves our understanding of single-cell dynamic rheology and provides a novel idea for discriminating different types of cells by AFM-based cellular viscoelastic assays with varying measurement parameters. PMID- 29609141 TI - Exploring the novel heterocyclic derivatives as lead molecules for design and development of potent anticancer agents. AB - This paper deals with in silico evaluation of newly proposed heterocyclic derivatives in search of potential anticancer activity. Best possible drug candidates have been proposed using a rational approach employing a pipeline of computational techniques namely MetaPrint2D prediction, molinspiration, cheminformatics, Osiris Data warrior, AutoDock and iGEMDOCK. Lazar toxicity prediction, AdmetSAR predictions, and targeted docking studies were also performed. 27 heterocyclic derivatives were selected for bioactivity prediction and drug likeness score on the basis of Lipinski's rule, Viber rule, Ghose filter, leadlikeness and Pan Assay Interference Compounds (PAINS) rule. Bufuralol, Sunitinib, and Doxorubicin were selected as reference standard drug for the comparison of molecular descriptors and docking. Bufuralol is a known non selective adreno-receptor blocking agent. Studies showed that beta blockers are also used against different types of cancers. Sunitinib is well known Food and Drug administration (FDA) approved pyrrole containing tyrosine kinase inhibitor and our proposed molecules possess similarities with both drug and doxorubicin is another moiety having anticancer activity. All heterocyclic derivatives were found to obey the drug filters except standard drug Doxorubicin. Bioactivity score of the compounds was predicted for drug targets including enzymes, nuclear receptors, kinase inhibitors, G protein-coupled receptor (GPCR) ligands and ion channel modulators. Absorption, distribution, metabolism and toxicity (ADMET) prediction of all proposed compound showed good Blood-brain barrier (BBB) penetration, Human intestinal absorption (HIA), Caco-2 cell permeability except compound-11 and was found to have no AdmetSAR toxicity as well as carcinogenic effect. Compounds 1-9 were slightly mutagenic while compound 2, 11, 20 and 21 showed carcinogenic effect according to Lazar toxicity prediction. Rests of the compounds were predicted to have no side effect. Molecular docking was performed with vascular endothelial growth factor receptor-2(VEGFR2) and glutathione S transferase-1 (GSTP1) because both are common cancer causing proteins. Sunitinib and Doxorubicin possess great affinity to inhibit these cancers causing protein. Self-organizing map (SOM) was used to depict data in a simple 2D presentation. Our studies justify that good oral bioavailability and therapeutic efficacy of 10, 12-19 and 22-27 compounds can be considered as potential anticancer agents. PMID- 29609138 TI - Delineation of the androgen-regulated signaling pathways in prostate cancer facilitates the development of novel therapeutic approaches. AB - Although androgen deprivation therapy (ADT) is initially effective for the treatment of progressive prostate cancer, it inevitably fails due to the onset of diverse resistance mechanisms that restore androgen receptor (AR) signaling. Thus, AR remains a desired therapeutic target even in the relapsed stages of the disease. Given the difficulties in stopping all AR reactivation mechanisms, we propose that the identification of the driver signaling events downstream of the receptor offer viable, alternative therapeutic targets. Here, we summarize recently described, AR-regulated processes that have been demonstrated to promote prostate cancer. By highlighting these signaling events and describing some of the ongoing efforts to pharmacologically modulate these pathways, our goal is to advocate potential new therapeutic targets that would represent an alternative approach for blocking AR actions. PMID- 29609142 TI - An efficient strategy for identifying cancer-related key genes based on graph entropy. AB - Gene networks are beneficial to identify functional genes that are highly relevant to clinical outcomes. Most of the current methods require information about the interaction of genes or proteins to construct genetic network connection. However, the conclusion of these methods may be bias because of the current incompleteness of human interactome. In this paper, we propose an efficient strategy to use gene expression data and gene mutation data for identifying cancer-related key genes based on graph entropy (iKGGE). Firstly, we construct a gene network using only gene expression data based on the sparse inverse covariance matrix, then, cluster genes use the algorithm of parallel maximal cliques for quickly obtaining a series of subgraphs, and at last, we introduce a novel metric that combine graph entropy and the influence of upstream gene mutations information to measure the impact factors of genes. Testing of the three available cancer datasets shows that our strategy can effectively extract key genes that may play distinct roles in tumorigenesis, and the cancer patient risk groups are well predicted based on key genes. PMID- 29609143 TI - Multi-Dimensional Scaling based grouping of known complexes and intelligent protein complex detection. AB - Protein-Protein Interactions (PPI) play a vital role in cellular processes and are formed because of thousands of interactions among proteins. Advancements in proteomics technologies have resulted in huge PPI datasets that need to be systematically analyzed. Protein complexes are the locally dense regions in PPI networks, which extend important role in metabolic pathways and gene regulation. In this work, a novel two-phase protein complex detection and grouping mechanism is proposed. In the first phase, topological and biological features are extracted for each complex, and prediction performance is investigated using Bagging based Ensemble classifier (PCD-BEns). Performance evaluation through cross validation shows improvement in comparison to CDIP, MCode, CFinder and PLSMC methods Second phase employs Multi-Dimensional Scaling (MDS) for the grouping of known complexes by exploring inter complex relations. It is experimentally observed that the combination of topological and biological features in the proposed approach has greatly enhanced prediction performance for protein complex detection, which may help to understand various biological processes, whereas application of MDS based exploration may assist in grouping potentially similar complexes. PMID- 29609144 TI - A thermodynamics-based approach for examining the suitability of cementitious formulations for solidifying and stabilizing coal-combustion wastes. AB - Cementitious binders are often used to immobilize industrial wastes such as residues of coal combustion. Such immobilization stabilizes wastes that contain contaminants by chemical containment, i.e., by uptake of contaminants into the cementitious reaction products. Expectedly, the release ("leachability") of contaminants is linked to: (i) the stability of the matrix (i.e., its resistance to decomposition on exposure to water), and, (ii) its porosity, which offers a pathway for the intrusion of water and egress of contaminant species. To examine the effects of the matrix chemistry on its suitability for immobilization, an equilibrium thermodynamics-based approach is demonstrated for cementitious formulations based on: ordinary portland cement (OPC), calcium aluminate cement (CAC) and alkali activated fly ash (AFA) binding agents. First, special focus is placed on computing the equilibrium phase assemblages using the bulk reactant compositions as an input. Second, the matrix's stability is assessed by simulating leaching that is controlled by progressive dissolution and precipitation of solids across a range of liquid (leachant)-to-(reaction product) solid (l/s) ratios and leachant pH's; e.g., following the LEAF 1313 and 1316 protocols. The performance of each binding formulation is evaluated based on the: (i) relative ability of the reaction products to chemically bind the contaminant(s), (ii) porosity of the matrix which correlates to its hydraulic conductivity, and, (iii) the extent of matrix degradation that follows leaching and which impact the rate and extent of release of potential contaminants. In this manner, the approach enables rapid, parametric assessment of a wide-range of stabilization solutions with due consideration of the matrix's mineralogy, porosity, and the leaching (exposure) conditions. PMID- 29609146 TI - Effects of a psychotherapeutic group intervention in patients with refractory mesial temporal lobe epilepsy and comorbid psychogenic nonepileptic seizures: A nonrandomized controlled study. AB - PURPOSE: Psychogenic nonepileptic seizures (PNES) are paroxysmal episodes superficially resembling epileptic seizures but are not associated with any electrical abnormalities. Despite the existence of recent evidence addressing psychological interventions on PNES, there is a scarcity of studies investigating such interventions on patients with dual diagnoses, such as in temporal lobe epilepsy/mesial temporal sclerosis (TLE-MTS) with comorbid PNES; TLE-MTS is a very frequent epilepsy syndrome found in tertiary centers. We aimed to investigate the effects of a group psychotherapeutic intervention program based on cognitive-behavioral therapy (CBT) on patients dually diagnosed with TLE-MTS and PNES treated in a tertiary center. METHOD: Patients with TLE-MTS and PNES who were followed-up in a tertiary center were invited. The intervention consisted of eight weekly, semi-structured group meetings. The Brazilian versions of the Quality of Life Scale (SF-36), the Toronto Alexithymia Scale (TAS), the Hamilton Depression Scale (HAM-D), the Hamilton Anxiety Scale (HAM-A), and the Ways of Coping Checklist (WCC) were applied before and after the intervention. RESULTS: Forty-seven patients were enrolled (25 females; 53.2%). Psychiatric disorders (PD) were observed in all 47 patients (100%); Major Depressive Disorder (MDD) was the most frequent PD (24; 51.0%). There were improvements on quality of life (P = 0.003), decreased depression (P<0.0001) and anxiety symptoms (P = 0.02), decreased levels of alexithymia (P = 0.02) and a reduction in seizure frequency (P = 0.02) after the intervention. CONCLUSIONS: Present data suggest a positive impact of a group psychological intervention based on CBT in patients with TLE MTS and PNES, highlighting this therapeutic possibility for this specific subgroup. PMID- 29609145 TI - Seizure characteristics and the use of anti-epileptic drugs in children and young people with brain tumours and epileptic seizures: Analysis of regional paediatric cancer service population. AB - PURPOSE: Epileptic seizures complicate the management of childhood brain tumours. There are no published standards for clinical practice concerning risk factors, treatment selection or strategies to withdraw treatment with antiepileptic drugs (AED). METHOD: we undertook a case note review of 120 patients with newly diagnosed brain tumours, referred to a regional paediatric cancer service. RESULTS: data was available on 117/120 (98%) children <18 years: median age at tumour presentation was 8.1 years (IQR 25 degrees -75 degrees : 3.6-12.7), median follow up was 33 months (IQR 25 degrees -75 degrees : 24-56), and 35/117 (29%) experienced seizures. A cortical tumour location was associated with the highest risk of seizures (OR: 7.1; CI 95% 2.9-17.3). At a median follow up of 24 months (IQR25 degrees -75 degrees : 15-48), 22/35 (63%) with seizures, had a single seizure episode, 15/35 (43%) were seizure free (SF) on AEDs, 13/35 (37%) were SF off AEDs, and 7/35 (20%) experienced continuing epileptic seizures. Overall 34/35 (97%) were treated with AEDs after a seizure, of whom 12/35 (35%) withdrew from AED medication, and although 4/35 (12%) had seizure relapse, all were after further acute events. The median duration of AED before withdrawal was 11 months (IQR25 degrees -75 degrees 5-14 months), and the median follow up after withdrawal was 15 months (IQR25 degrees -75 degrees 5-34 months). CONCLUSIONS: Seizures affect about 1/3rd of children and young people presenting with and being treated for brain tumours particularly when the tumour is in the cerebral cortex. The low risk of recurrent seizures after AED treatment justifies consideration of early withdrawal of AED after seizure control. PMID- 29609147 TI - The clinical characteristics of posttraumatic epilepsy following moderate-to severe traumatic brain injury in children. AB - PURPOSE: Children with traumatic brain injury (TBI) are at increased risk of posttraumatic epilepsy (PTE); the risk increases according to TBI severity. We examined the long-term incidence and risk factors for developing PTE in a cohort of children hospitalised at one medical centre with moderate or severe TBI. METHODS: Moderate brain injury was classified as Glasgow Coma Score on Arrival (GCSOA) of 9-13, and severe brain injury as GCSOA <=8. We collected demographics and clinical data from medical records and interviewed patients and parents at 5 11 years following the TBI event. RESULTS: During a median follow-up period of 7.3 years, 9 (9%) of 95 children with moderate-to-severe TBI developed PTE; 4 developed intractable epilepsy. The odds for developing PTE was 2.9 in patients with severe compared to moderate TBI. CT findings showed fractures in 7/9 (78%) of patients with PTE, compared to 40/86 (47%) of those without PTE (p = 0.09). Of the patients with fractures, all those with PTE had additional features on CT (such as haemorrhage, contusion and mass effect), compared to 29/40 (73%) of those without PTE. One of nine (11%) PTE patients and 10 of 86 (12%) patients without PTE had immediate seizures. Two (22%) children with PTE had their first seizure more than 2 years after the TBI. CONCLUSION: Among children with moderate or severe TBI, the presence of additional CT findings, other than skull fractures, seem to increase the risk of PTE. In our cohort, the occurrence of an early seizure did not confer an increased risk of PTE. PMID- 29609148 TI - Debromination of polybrominated diphenyl ethers (PBDEs) by zero valent zinc: Mechanisms and predicting descriptors. AB - Polybrominated diphenyl ethers (PBDEs) are a class of brominated flame retardants that are ubiquitous in the environment. The physical and chemical properties of PBDEs make them difficult to degrade, with the conventional remediation methods being relatively inefficient. In this study, the reactivity of zero valent zinc (ZVZ) toward 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) was evaluated under aqueous solution. First-order rate constants (kobs) for BDE-47 disappearance increased with decreased pH, which is attributed to the dissolution of surface zinc oxides that promote the contact between the active site on zinc surface and BDE molecules. The kobs of ten investigated PBDEs in ZVZ system are positively correlated with the energy of lowest unoccupied orbitals (ELUMO) of PBDEs (R2 = 0.902). The debromination pathways of BDE-47 in ZVZ system are: BDE-47 -> BDE-28 > BDE-15 -> BDE-3 -> DE, which is the same to the debromination pathways of BDE 47 in zero valent iron (ZVI) in previous study. In addition, the singly occupied molecular orbitals (SOMOs) of the BDE anions can well reflect the actual debromination pathways of PBDEs by comparing the size of the CBr antibonding characterized lobes. Our results suggest that the debromination of PBDEs by ZVZ is based on the electron transfer mechanism, and the SOMOs of BDE anions can be used to predict the debromination pathways of untested PBDEs. PMID- 29609149 TI - Mechanochemical formation of chlorinated phenoxy radicals and their roles in the remediation of hexachlorobenzene contaminated soil. AB - Mechanochemical degradation (MCD) is a promising eco-friendly method to dispose persistent organic pollutants (POPs). Mechanically induced free-radical attack was thought to be one of the key elements in initiating and accelerating the dechlorination and degradation of POPs. In this study, mechanochemical formation of free-radicals and their roles in the remediation of hexachlorobenzene (HCB) contaminated soil were explored using both of experimental analysis and quantum chemical calculations. It was found that chlorinated phenoxy radicals(CB-O) can be produced in the milling process and they played a vital role in the dechlorination of HCB, based on the results of electron spin-resonance (ESR) and X-ray photoelectron spectra (XPS). Two transition states of mechanochemical reaction along the formation of pentachlorinated phenoxy radical (PeCB-O) were located, with the energy barriers of 39.4 and 3.4 kJ/mol. The localized orbital locator (LOL), Mayer bond order and topological analysis were also implemented to depict the process in detail. Free-radical attack dominated dechlorination pathway of HCB in the MCD process was also verified by the Fukui function analysis. The study on the mechanically-induced generation of free-radicals and their associated modes of action on the degradation of HCB will provide a deep insight into mechanochemical remediation mechanism of POPs contaminated soil. PMID- 29609150 TI - Phase control synthesis of alpha, beta and alpha/beta Bi2O3 hetero-junction with enhanced and synergistic photocatalytic activity on degradation of toxic dye, Rhodamine-B under natural sunlight. AB - Nano particles of a few alpha/beta Bi2O3 hetero-junctions of various compositions synthesized by one- pot hydrothermal method, exhibit exceptional and synergistic photo-catalytic activity for the degradation of Rhodamine-B in aqueous solution under natural sunlight. Pure alpha and pure beta Bi2O3 are also synthesized by control post heating of synthesized hetero-junction. The nano-materials were characterized by diffraction (XRD), microscopic and spectroscopic techniques. The XRD reveals alpha-beta phase hetero-junctions of Bi2O3 are made of alpha-Bi2O3 and beta-Bi2O3 with average dimensions within 13-113 and 5-71 nm respectively and having band gap range of 2.4- 2.9 eV. The spectrophotometrically determined % degradation of the dye and associated rate constant on the best hetero-junction are increased by 4.5(/2.1) and 3.3(/1.2) times than these on pure alpha (/beta). The effects of operational parameters and trapping agents have been analyzed. The maximum removal of the dye was achieved up to 99.6% in 3 h using 0.5 g/L photo catalyst at pH 3. The reusability test shows that the photo-catalytic activity is retained excellently due to change in chemical nature of the catalyst from alpha Bi2O3 to beta-Bi2O3, Bi2O2CO3 and BiOCl. A suitable mechanism is proposed. PMID- 29609151 TI - Development of copper recovery process from flotation tailings by a combined method of high-pressure leaching-solvent extraction. AB - Sulfide copper mineral, typically Chalcopyrite (CuFeS2), is one of the most common minerals for producing metallic copper via the pyrometallurgical process. Generally, flotation tailings are produced as a byproduct of flotation and still consist of un-recovered copper. In addition, it is expected that more tailings will be produced in the coming years due to the increased exploration of low grade copper ores. Therefore, this research aims to develop a copper recovery process from flotation tailings using high-pressure leaching (HPL) followed by solvent extraction. Over 94.4% copper was dissolved from the sample (CuFeS2 as main copper mineral) by HPL in a H2O media in the presence of pyrite, whereas the iron was co-dissolved with copper according to an equation given as CCu = 38.40 * CFe. To avoid co-dissolved iron giving a negative effect on the subsequent process of electrowinning, solvent extraction was conducted on the pregnant leach solution for improving copper concentration. The result showed that 91.3% copper was recovered in a stripped solution and 98.6% iron was removed under the optimal extraction conditions. As a result, 86.2% of copper was recovered from the concentrate of flotation tailings by a proposed HPL-solvent extraction process. PMID- 29609152 TI - Experiences of police contact among young adult recreational drug users: A qualitative study. AB - BACKGROUND: While young adults who engage in recreational drug use are at increased risk of contact with police, their experiences of police contact have been largely overlooked. METHOD: In-depth qualitative interviews were conducted with 70 young adult amphetamine-type stimulant (ATS; i.e., ecstasy [MDMA] and methamphetamine) users who had experienced intensive alcohol and other drug related police contact (e.g., being arrested, charged, or raided by police). These interviews focused on perceptions of personal experiences of alcohol and other drug-related police contact and general perceptions of police and policing and were conducted as part of a larger longitudinal study of drug use among a population-based sample of young adults from South-East Queensland, Australia. RESULTS: ATS users' perceptions of their personal interactions with police and general perceptions of police and policing were influenced by a number of factors, including police behaviour, prior contact with police, friends and family members' contact with police, and perceptions of their own behaviour leading to their contact with police. While a majority of ATS users reported that their contact with police had either a neutral or negative impact on their general perceptions of police and policing, some ATS users reported that police contact had a positive impact. For 70% of ATS users, police contact was reported to have had an impact on their substance use behaviours, resulting in either modification of their substance use behaviours to avoid further police contact or reduction in their substance use. CONCLUSIONS: These findings suggest that police contact among young adult ATS users can impact on both perceptions of police and policing and substance use behaviours, emphasising the importance of the quality and nature of police contact and its potential role in harm reduction. PMID- 29609153 TI - The effect of Housing First on adherence to methadone maintenance treatment. AB - BACKGROUND: Opioid overdose deaths have become a public health crisis in North America, and those who are homeless are particularly vulnerable. Methadone maintenance treatment (MMT) may prevent overdose and death among homeless people with opioid dependence, but suboptimal medication adherence is a common limitation. Previous research found that Housing First (HF) increases antipsychotic medication adherence among formerly homeless people. However, no experimental trials have examined whether HF has a significant impact on MMT adherence. We examined the intervention effect of HF on MMT adherence in a randomized sample of homeless adults experiencing mental illness and opioid dependence in Vancouver, Canada. METHODS: Comprehensive administrative and self reported data from homeless adults living with serious mental illness recruited to the Vancouver At Home study were analyzed. Only methadone recipients were included (n = 97). The medication possession ratio (MPR) was utilized as the measure of adherence, and relevant data were obtained from provincial administrative pharmacy records. Study arms were HF and treatment as usual (TAU). Student t-tests were used to test for differences in MMT MPR between HF and TAU. RESULTS: No significant differences were observed in MMT MPR between participants in HF and TAU (0.52 vs. 0.57, p = 0.559) in the post-randomization period. CONCLUSION: HF was not associated with significantly different MMT MPR compared to TAU. Additional interventions are indicated as HF alone was insufficient to facilitate improved MMT adherence among formerly homeless adults experiencing concurrent opioid dependence and serious mental illness. PMID- 29609154 TI - The use of computer mediated communication in providing patient support: A review of the research literature. AB - OBJECTIVES: The aim of this study is to explore how computer mediated communication has been used by a variety of healthcare,professionals to support their patients and discuss the implication that this may have for future practice. DESIGN: A systematized review of the literature. DATA SOURCES: A review of empirical studies within the literature was carried out in April 2016 in CINAHL, MEDLINE, ASSIA, BNI, Psychinfo, and Web of Science databases. REVIEW METHODS: The databases searched produced 2930 titles, of which 190 publications were considered relevant to the objectives. Titles and abstracts were then reviewed and duplicates removed producing 67 publications. Exclusion and inclusion criteria were applied. The inclusion criteria were (1) interventions that facilitate two-way communication between any healthcare professional and their patients via a computer; (2) Interventions aimed at providing any type of support e.g. emotional, tangible, informational, or esteem support; (3) English language; (4) Primary empirical studies. Data quality was assessed and thematic analysis applied. RESULTS: Thirty-one publications were included in this study. Intervention types included Email (n = 8), Videoconferencing (n = 7), Online Social Support Groups (n = 9) and multifaceted interventions (n = 7). Three themes emerged from the data including increasing access to healthcare, adding value to healthcare delivery and improving patient outcomes. Twenty-five (81%) of the studies found that computer mediated communication could produce positive effects. CONCLUSIONS: Computer mediated communication could be both what patients want and a way of delivering support to patients in a resource tight environment. This has implications for a range of health support needs and professionals including nurses, midwives and allied healthcare professionals. Reviewing the lessons learnt will ensure future interventions are tailored to the support needs of the patients, carefully planned and mindful of the risks. PMID- 29609155 TI - Probing the DOM-mediated photodegradation of methylmercury by using organic ligands with different molecular structures as the DOM model. AB - Photodegradation is the main depletion pathway for methylmercury (MeHg) in surface water. The formation of MeHg-dissolved organic matter (DOM) complexes has been found to be a key step in MeHg photodegradation. However, the major functional groups involved in the DOM-mediated process have yet to be clearly resolved. In this work, we systematically investigated the effects of DOM molecular structures on MeHg photodegradation by using a variety of organic ligands with different functional groups (e.g., thiosalicylate, thiophenol, and thioaniline). The results showed that thiol and phenyl groups may be the major functional groups governing DOM-mediated MeHg photodegradation, with photodegradation rates also dependent on the type (carboxyl, hydroxyl, and amino group) and position (ortho-, meta-, and para-) of other chemical substituents. The addition of "non-photochemically active" thiol ligands (e.g., mercaptoethanol and dithiothreitol) and high concentrations of Cl- can significantly inhibit the o-thiosalicylate-induced MeHg photodegradation, indicating that complexation of MeHg with these ligands is necessary for MeHg photodegradation. Sparging with O2 had a negligible effect on MeHg photodegradation, while sparging with N2 significantly enhanced MeHg photodegradation. This finding suggests that MeHg photodegradation may be a reductive process, which was further supported by identification of the degradation products of MeHg. A possible protonolysis mechanism of MeHg photodegradation in the presence of o-thiosalicylate was then proposed based on the findings of this study. PMID- 29609156 TI - Relevance of protein-protein interactions on the biological identity of nanoparticles. AB - Considering that the use of nanoparticles (NPs) as carriers of therapeutic or theranostic agents has increased in the last years, it is mandatory to understand the interaction between NPs and living systems. In contact with biological fluids, the NPs (synthetic identity) are covered with biomolecules that form a protein corona, which defines the biological identity. It is well known that the protein corona formation is mediated by non-specific physical interactions, but protein-protein interactions (PPI), involving specific recognition sites of the polypeptides, are also involved. This work explores the relationship between the synthetic and biological identities of layered double hydroxides nanoparticles (LDH-NPs) and the effect of the protein corona on the cellular response. With such a purpose, the synthetic identity was modified by coating LDH-NPs with either a single protein or a complex mixture of them, followed by the characterization of the protein corona formed in a commonly used cell culture medium. A proteomic approach was used to identify the protein corona molecules and the PPI network was constructed with a novel bioinformatic tool. The coating on LDH-NPs defines the biological identity in such a way that the composition of the protein corona as well as PPI are changed. Electrostatic interactions appear not to be the only driving force regulating the interactions between NPs, proteins and cells since the specific recognition also play a fundamental role. However, the biological identity of LDH-NPs does not affect the interactions with cells that shows negligible cytotoxicity and high internalization levels. PMID- 29609157 TI - Acute and mid-term (six-week) effects of an ankle-foot-orthosis on biomechanical parameters, clinical outcomes and physical activity in knee osteoarthritis patients with varus malalignment. AB - BACKGROUND: Knee osteoarthritis (KOA) is a painful disease commonly caused by high loads on the articular cartilage. Orthotic interventions aim to reduce mechanical loading, thereby alleviating pain. Traditional orthotics appear effective, but high drop-out rates have been reported over prolonged periods. RESEARCH QUESTION: The aim of this study was to examine the effect of a novel ankle-foot orthosis (AFO) on gait parameters, physical function and activity of KOA patients. METHODS: 29 clinically diagnosed KOA patients with varus malalignment wore an AFO for 6 weeks. Prior to and after the intervention period, 3D gait analysis, physical function tests and the KOOS questionnaire were administered. Physical activity was objectively assessed with accelerometers. RESULTS: The AFO immediately reduced the first peak of the knee adduction moment (KAM) and the KAM impulse by 41% and 19%. The knee flexion moment (KFM) was increased by 48%. After six weeks, the first KAM peak and KAM impulse were decreased by 27% and 19% while using the AFO. The KFM was increased by 71%. Furthermore, patients completed the functional tests faster (1.4-2.6%). The KOOS scores decreased significantly. No significant differences were found in physical activity parameters. SIGNIFICANCE: The six-week AFO application significantly reduced the KAM. The patients' physical function appeared improved; yet these improvements were only minor and therefore arguably clinically irrelevant. The KFM appeared to be negatively affected after six weeks, as were the scores on the KOOS subscales. In summary, even though the AFO reduced the KAM and improved physical function, the clinical benefit for KOA patients with varus malalignment after the 6-week AFO application is debatable. PMID- 29609158 TI - Lower extremity power training improves healthy old adults' gait biomechanics. AB - PURPOSE: Age-related slowing of gait speed predicts many clinical conditions in later life. We examined the kinematic and kinetic mechanisms of how lower extremity power training increases healthy old adults' gait speed. METHODS: We randomly allocated old adults to a training (age 74.3 y, 9 males, 6 females) and a control group (age 73.6 y, 3 males, 4 females) and compared the biomechanics of habitual and fast gait before and after 16 sessions (8 weeks) of lower extremity power training. RESULTS: Training increased maximal leg press load by ~40% (P < 0.05) and maximal voluntary force in five groups of leg muscles by ~32% (P < 0.05) in the training group. Training vs. control tended to increase habitual (10.8 vs. 7.6%) and fast gait speed (17.6 vs. 9.0%; all P < 0.05) more. In the training group only, these increases in gait speed correlated with increases in stride length (habitual: r2 = 0.84, fast: r2 = 0.89). Training made old adults' gait more erect: hip and knee extension increased in the stance phase of gait. Training increased ankle joint positive work by 3.3 J (control: -0.4 J, Group by Time interaction: P < 0.05), which correlated r2 = 0.58 and r2 = 0.67 with increases in habitual and fast gait speed without changes in hip and knee joint powers. CONCLUSION: Increases in leg muscle power increased healthy old adults' gait speed through correlated increases in stride length and ankle plantarflexor work generation. PMID- 29609159 TI - Net ankle quasi-stiffness is influenced by walking speed but not age for older adult women. AB - BACKGROUND: Insufficient plantar flexor resistance due to plantar flexor weakness, an impairment common in patient populations, causes substantial gait deficits. The bending stiffness of passive-dynamic ankle-foot orthoses (PD-AFOs) has the capacity to replace lost plantar flexor resistance. Many patients who are prescribed PD-AFOs are older adults. While PD-AFO bending stiffness should be customized for patients, a method to objectively prescribe this stiffness does not exist. Quantifying natural plantar flexor resistance during non-pathological gait could provide a reference value for objectively prescribing PD-AFO bending stiffness. RESEARCH QUESTION: This study investigated the effect of age on plantar flexor resistance in 113 participants above the age of 65 years. We did so while also considering the confounding influence of gait speed, an aspect known to be reduced with old age. METHODS: Ambulatory, community-dwelling older adult women (ages 65-91 years) with no current or recent lower-extremity injuries or surgeries underwent an instrumented gait analysis at a self-selected speed. Plantar flexor resistance was quantified via net ankle quasi-stiffness (NAS) defined as the slope of ankle joint moment-angle curve during late stance. RESULTS: showed that NAS was not significantly influenced by age (r = -0.11, p = 0.12), and that the confounding factor of walking speed had a significant, positive relationship with NAS (r = 0.59, p < 0.001). SIGNIFICANCE: By determining that gait speed, not age, is related to NAS in older adults, this study represents the initial step towards objectively prescribing PD-AFO bending stiffness to achieve a targeted gait speed for older adults with plantar flexor weakness. PMID- 29609160 TI - Isolation of HL-60 cancer cells from the human serum sample using MnO2 PEI/Ni/Au/aptamer as a novel nanomotor and electrochemical determination of thereof by aptamer/gold nanoparticles-poly(3,4-ethylene dioxythiophene) modified GC electrode. AB - Herein, aptamer-modified self-propelled nanomotors were used for transportation of human promyelocytic leukemia cells (HL-60) from a human serum sample. For this purpose, the fabricated manganese oxide nanosheets-polyethyleneimine decorated with nickel/gold nanoparticles (MnO2-PEI/Ni/Au) as nanomotors were added to a vial containing thiolated aptamer KH1C12 solution as a capture aptamer to attach to the gold nanoparticles on the surface of nanomotors covalently. The aptamer modified self-propelled nanomotors (aptamerKH1C12/nanomotors) were then separated by placing the vial in a magnetic stand. The aptamer-modified self-propelled nanomotors were rinsed three times with water to remove the non-attached aptamers. Then, the resulting aptamerKH1C12/nanomotors were applied for the on the-fly" transporting of HL-60 cancer cell from a human serum sample. To release of the captured HL-60 cancer cells, the complementary nucleotide sequences of KH1C12 aptamer solution (releasing aptamer) that has a with capture aptamer was added to phosphate buffer solution (1 M, pH 7.4) containing HL 60/aptamerKH1C12/nanomotors. Because of the high affinity of capture aptamer to complementary nucleotide sequences of aptamerKH1C12, the HL-60 cancer cells released on the surface of aptamerKH1C12/nanomotors into the solution. The second goal of the present work was determining the concentration of HL-60 cancer cell in the human serum samples. The electrochemical impedance spectroscopy technique (EIS) was used for the determination of HL-60 cancer cell. The concentration of separated cancer cell was determined by aptamer/gold nanoparticles-poly(3,4 ethylene dioxythiophene) modified GC electrode (GC/PEDOT-Aunano/aptamer KH1C12). The proposed aptasensor exhibited a good response to the concentration of HL-60 cancer cells in the range of 2.5 * 101 to 5 * 105 cells mL-1 with a low limit of detection of 250 cells mL-1. PMID- 29609161 TI - Electrochemical genoassays on gold-coated magnetic nanoparticles to quantify genetically modified organisms (GMOs) in food and feed as GMO percentage. AB - The integration of nanomaterials in the field of (bio)sensors has allowed developing strategies with improved analytical performance. In this work, ultrasmall core-shell Fe3O4@Au magnetic nanoparticles (MNPs) were used as the platform for the immobilization of event-specific Roundup Ready (RR) soybean and taxon-specific DNA sequences. Firstly, monodisperse Fe3O4 MNPs were synthesized by thermal decomposition and subsequently coated with a gold shell through reduction of Au(III) precursor on the surface of the MNPs in the presence of an organic capping agent. This nanosupport exhibited high colloidal stability, average particle size of 10.2 +/- 1.3 nm, and spherical shape. The covalent immobilization of ssDNA probe onto the Au shell of the Fe3O4@Au MNPs was achieved through a self-assembled monolayer (SAM) created from mixtures of alkane thiols (6-mercapto-1-hexanol and mercaptohexanoic acid). The influence of the thiols ratio on the electrochemical performance of the resulting electrochemical genoassays was studied, and remarkably, the best analytical performance was achieved for a pure mercaptohexanoic acid SAM. Two quantification assays were designed; one targeting an RR sequence and a second targeting a reference soybean gene, both with a sandwich format for hybridization, signaling probes labelled with fluorescein isothiocyanate (FITC), enzymatic amplification and chronoamperometric detection at screen-printed carbon electrodes (SPCE). The magnetogenoassays exhibited linear ranges from 0.1 to 10.0 nM and from 0.1 to 5.0 nM with similar detection limits of 0.02 nM and 0.05 nM for the event-specific (RR) and the taxon-specific (lectin) targets, respectively. The usefulness of the approach was demonstrated by its application to detect genetically modified organisms (GMOs) in feed and food. PMID- 29609162 TI - Determining mean corpuscular volume and red blood cell count using electrochemical collision events. AB - Blood tests (e.g., red blood cell (RBC) count) are crucial for detecting, diagnosing, and monitoring the progression of blood disorders. Here, we report the development of a new and rapid method for electrochemically detecting RBCs using single-particle collision events. The principle of this method relies on the electrochemical oxidation of an electroactive redox species (potassium ferrocyanide) hindered by an RBC attached to an electrode surface. A decrease in staircase current, caused by the collision of RBCs on the electrode, was observed. The magnitude of this current decrease could provide quantitative information on the size and concentration of RBCs, which could be converted into the mean corpuscular volume (MCV) and used for diagnosis. Anemia-related diseases caused by abnormal count of RBCs (e.g., erythrocytosis, pernicious anemia) or abnormal RBC size (e.g. megaloblastic anemia, microcytic anemia) could be detected easily and quickly using this electrochemical collision method, potentially leading to extensive applications in hematology and point-of-care blood testing devices. PMID- 29609163 TI - Corrigendum to "A nonenzymatic DNA nanomachine for biomolecular detection by target recycling of hairpin DNA cascade amplification" [Biosens. Bioelectron. 107 (2018) 40-46]. PMID- 29609164 TI - Aptamer selection and application in multivalent binding-based electrical impedance detection of inactivated H1N1 virus. AB - The type A influenza viruses are the most virulent and variable human pathogens with epidemic or even pandemic threat. The development of sensitive, specific and safe field testing methods is in particular need and quite challenging. We report here the selection and practical utilization of the inactivated influenza virus specific aptamers. The DNA aptamers against inactivated intact H1N1 virus particles were identified through the systematic evolution of ligands by exponential enrichment (SELEX) procedure. The discriminative aptamers and their truncated sequences showed selectively high affinity to inactive H1N1 virus and H3N2 virus with the Kd in the low nanomolar range and collective binding properties. The truncated sequences were first applied in a sandwich enzyme linked oligonucleotide assay (ELONA) with a H1N1 detection limit (LOD, S/N = 3) of 0.3 ng/MUL and then in an electrochemical impedance (EIS) aptasensor with more than 300 times improved LOD (0.9 pg/MUL) and the excellent selectivity over other viruses (> 100 times). Therefore the developed aptasensors represent the safer, simpler, and possibly better virus-variation adaptable means of virus diagnostics. PMID- 29609165 TI - Field-effect biosensor using virus particles as scaffolds for enzyme immobilization. AB - A field-effect biosensor employing tobacco mosaic virus (TMV) particles as scaffolds for enzyme immobilization is presented. Nanotubular TMV scaffolds allow a dense immobilization of precisely positioned enzymes with retained activity. To demonstrate feasibility of this new strategy, a penicillin sensor has been developed by coupling a penicillinase with virus particles as a model system. The developed field-effect penicillin biosensor consists of an Al-p-Si-SiO2-Ta2O5-TMV structure and has been electrochemically characterized in buffer solutions containing different concentrations of penicillin G. In addition, the morphology of the biosensor surface with virus particles was characterized by scanning electron microscopy and atomic force microscopy methods. The sensors possessed a high penicillin sensitivity of ~ 92 mV/dec in a nearly-linear range from 0.1 mM to 10 mM, and a low detection limit of about 50 uM. The long-term stability of the penicillin biosensor was periodically tested over a time period of about one year without any significant loss of sensitivity. The biosensor has also been successfully applied for penicillin detection in bovine milk samples. PMID- 29609166 TI - In-vitro model for assessing glucose diffusion through skin. AB - Pig ear skin membrane-covered glucose biosensor based on oxygen electrode has been assessed as a tool to evaluate glucose penetration through skin in-vitro. For this, glucose oxidase (GOx) was immobilised on oxygen electrode and covered with the skin membrane. Exposing this electrode to the solution of glucose resulted in glucose penetration though skin membrane, its oxidation catalysed by GOx, consumption of O2 and decrease of the current of the oxygen electrode. By processing the biosensor responses to glucose, we found that glucose penetration through 250 um thick skin membrane is slow; 90% of steady-state current response was reached in 32( +/- 22) min. Apparent diffusion coefficient for glucose in skin was found to be equal to 0.15( +/- 0.07)* 10-6 cm2 s-1. This value is 45 times lower than glucose diffusion coefficient in water. Tape-stripping of stratum corneum (SC) allows considerably faster glucose penetration. The electrodes covered with tape-stripped skin reached 90% of steady-state current response in 5.0(+/- 2.7) min. The theoretical estimate of glucose flux through SC was considered exploiting four-pathway theory of transdermal penetration. Theoretical flux values were more that three orders lower than measured experimentally. This high discrepancy might indicate that glucose penetration through healthy human skin could be even slower, allowing much lower flux, than it was found in our study for skin membranes from pig ears. PMID- 29609167 TI - Varicella Zoster Immunoglobulin G (VZIG)-Do current guidelines advocate overuse? PMID- 29609168 TI - Comprehensive analysis of microbial communities in full-scale mesophilic and thermophilic anaerobic digesters treating food waste-recycling wastewater. AB - Microbes were sampled for a year in a full-scale mesophilic anaerobic digester (MD) and a thermophilic anaerobic digester (TD) treating food waste-recycling wastewater (FRW), then microbial community structure, dynamics and diversity were quantified. In the MD, Fastidiosipila, Petrimonas, vadinBC27, Syntrophomonas, and Proteiniphilum were dominant bacterial genera; they may contribute to hydrolysis and fermentation. In the TD, Defluviitoga, Gelria and Tepidimicrobium were dominant bacteria; they may be responsible for hydrolysis and acid production. In the MD, dominant methanogens changed from Methanobacterium (17.1 +/- 16.9%) to Methanoculleus (67.7 +/- 17.8%) due to the increase in ammonium concentration. In the TD, dominant methanogens changed from Methanoculleus (42.8 +/- 13.6%) to Methanothermobacter (49.6 +/- 11.0%) due to the increase of pH. Bacteria and archaea were more diverse in the MD than in the TD. These results will guide development of microbial management methods to improve the process stability of MD and TD treating FRW. PMID- 29609169 TI - Emission characteristics for gaseous- and size-segregated particulate PAHs in coal combustion flue gas from circulating fluidized bed (CFB) boiler. AB - The partitioning behavior of polycyclic aromatic hydrocarbons (PAHs) between gaseous and particulate phases from coal-fired power plants (CFPPs) is critically important to predict PAH removal by dust control devices. In this study, 16 US EPA priority PAHs in gaseous and size-segregated particulate phases at the inlet and outlet of the fabric filter unit (FFs) of a circulating fluidized bed (CFB) boiler were analyzed. The partitioning mechanisms of PAHs between gaseous and particulate phases and in particles of different size classes were investigated. We found that the removal efficiencies of PAHs are 45.59% and 70.67-89.06% for gaseous and particulate phases, respectively. The gaseous phase mainly contains low molecular weight (LMW) PAHs (2- and 3-ring PAHs), which is quite different from the particulate phase that mainly contains medium and high molecular weight (MMW and HMW) PAHs (4- to 6-ring PAHs). The fractions of LMW PAHs show a declining trend with the decrease of particle size. The gas-particle partitioning of PAHs is primarily controlled by organic carbon absorption, in addition, it has a clear dependence on the particle sizes. Plot of log (TPAH/PM) against logDp shows that all slope values were below -1, suggesting that PAHs were mainly adsorbed to particulates. The adsorption effect of PAHs in size-segregated PMs for HMW PAHs is more evident than LMW PAHs. The particle size distributions (PSDs) of individual PAHs show that most of PAHs exhibit bi-model structures, with one mode peaking in the accumulation size range (2.1-1.1 MUm) and another mode peaking in coarse size range (5.8-4.7 MUm). The intensities of these two peaks vary in function of ring number of PAHs, which is likely attributed to Kelvin effect that the less volatile HMW PAH species preferentially condense onto the finer particulates. The emission factor of PAHs was calculated as 3.53 mg/kg of coal burned, with overall mean EFPAH of 0.55 and 2.98 mg/kg for gaseous and particulate phase, respectively. Moreover, the average emission amount of PAHs for the investigated CFPP was 1016.6 g/day and 371073.6 g/y, respectively. PMID- 29609170 TI - Multisurface modeling of Ni bioavailability to wheat (Triticum aestivum L.) in various soils. AB - Continual efforts have been made to determine a simple and universal method of estimating heavy metal phytoavailability in terrestrial systems. In the present study, a mechanism-based multi-surface model (MSM) was developed to predict the partition of Ni(II) in soil-solution phases and its bioaccumulation in wheat (Triticum aestivum L.) in 19 Chinese soils with a wide range of soil properties. MSM successfully predicted the Ni(II) dissolution in 0.01 M CaCl2 extracting solution (R2 = 0.875). The two-site model for clay fraction improved the prediction, particularly for alkaline soils, because of the additional consideration of edge sites. More crucially, the calculated dissolved Ni(II) was highly correlated with the metal accumulation in wheat (R2 = 0.820 for roots and 0.817 for shoots). The correlation coefficients for the MSM and various chemical extraction methods have the following order: soil pore water > MSM ~ diffuse gradient technique (DGT) > soil total Ni > 0.43 M HNO3 > 0.01 M CaCl2. The results suggested that the dissolved Ni(II) calculated using MSM can serve as an effective indicator of the bioavailability of Ni(II) in various soils; hence, MSM can be used as an supplement for metal risk prediction and assessment besides chemical extraction techniques. PMID- 29609171 TI - Nitrate reduction pathways in the presence of excess nitrogen in a shallow eutrophic estuary. AB - The eutrophication of estuaries results from increasing anthropogenic nutrient inputs to coastal waters. Ecosystem recovery from eutrophication is partly dependent on the ability of a system to assimilate or remove nutrients, and denitrification and dissimilatory nitrate reduction to ammonium (DNRA) are important pathways for nitrogen (N) removal or retention. We measured rates of denitrification and DNRA over an annual cycle at two stations in Weeks Bay, AL, a shallow microtidal estuary receiving freshwater from two rivers with agricultural watersheds and high N inputs. We hypothesized that rates of DNRA would exceed denitrification in the sulfidogenic sediments in this estuary. Consistent with our hypothesis, we found that DNRA (44.4 +/- 5.5 MUmol N m-2 hr-1) exceeded in situ denitrification (0.9 +/- 2.3 MUmol N m-2 hr-1) and that even in the presence of abundant water column nitrate DNRA was favored over denitrification by a factor of two. DNRA is estimated to provide N to the water column at a rate equivalent to 15% of the N input that is retained within the estuary and is a significant component of the N budget in this highly impacted estuary. DNRA by retaining N in the system contributes to the N demand by primary producers and can impact this estuary through enhanced rates of primary production. Weeks Bay, like many coastal estuaries, experiences periods of hypoxia, blooms of harmful algae and fish kills. Future management efforts should focus on reducing nutrient input to this estuary without which the significant retention of N in this system through DRNA will contribute to the undesirable ecosystem attributes associated with eutrophication. PMID- 29609172 TI - The use of time-averaged concentrations of metals to predict the toxicity of pulsed complex effluent exposures to a freshwater alga. AB - Intermittent, fluctuating and pulsed contaminant discharges may result in organisms receiving highly variable toxicant exposures. This study investigated the toxicity of continuous and pulsed exposures of a complex, neutralised drainage water (NDW) and dissolved copper-spiked dilute NDW to the green alga, Pseudokirchneriella subcapitata. The effects of single pulses of between 1 and 48 h duration and continuous exposures (72 h) on algal growth rate inhibition were compared on a time-averaged concentration (TAC) basis. Algal growth rates generally recovered to control levels within 24-48 h of the pulse removal. Continuous exposures to NDW resulted in similar or marginally higher toxicity to the algae when compared to pulsed exposures of equivalent TAC (% NDW). The toxicity of the NDW was attributed mostly to the metals, with the major cations potentially causing effects that are both additive (direct toxicity) and antagonistic (lower bioavailability of trace metals). For dissolved copper in dilute NDW, the pulsed exposures caused slightly higher toxicity than continuous exposures of equivalent dissolved copper TAC, with much of the difference explained by differences in labile copper concentrations between treatments. The results indicate that water quality guideline values for toxicants derived from continuous chronic exposures may be relaxed for pulsed exposures by a factor related to the TAC with the intent to provide an adequately protective but not overly-conservative outcome. The study highlights the influence that natural water quality parameters such as water hardness and DOC can have metal speciation and toxicity, and indicates that these parameters are particularly important for site-specific water quality guideline value derivation where, on a TAC basis, pulsed exposures may be more toxic than continuous exposures typically used in guideline value derivation. PMID- 29609173 TI - Redox changes in speciation and solubility of arsenic in paddy soils as affected by sulfur concentrations. AB - A substantial amount of sulfate is often supplied in paddy fields with concomitant applications of chemical fertilizers and manure for rice growth. It is unclear how solubility and speciation of arsenic (As) are affected by the levels of soil sulfate and their relationship to soil redox status and sulfur (S) and iron (Fe) speciation in a short cycle of soil reducing (flooding) and oxidizing (drying) periods. The objective of this study was to investigate the solubility of As in relation to chemical speciation of As and S in different levels of soil sulfate through a time series of measurements during a 40-day reduction period (Eh < -130 mV) followed by a 32-day reoxidation period (Eh > 400 mV) using X-ray absorption fine structure (XAFS) spectroscopy. An excess of sulfate decreased extractable and dissolved As in the soil reducing period due to retardation of soil reduction process that decreased soluble As(III) in the soil solid phase. The As species at the end of soil reducing period were 38-41% As(V), 46-51% As(III), and 11-13% As2S3-like species, regardless of initial S treatments. In the following soil reoxidation, As2S3-like species were sensitive to oxidation and disappeared completely in the first 2 days when the Eh value increased rapidly above 160 mV. The addition of extra sulfate to the soil did not result in the formation of neither reduced S species nor As2S3-like species. About 50% of As(III) to the total As persisted over 32 days of soil reoxidation period (Eh > 400 mV), suggesting some mechanisms against oxidation of As(III) such as physical sequestration in soil microsites. This study demonstrates that the extra SO4 in paddy soils can help mitigate the dissolution of As in reduction and reoxidation periods. PMID- 29609174 TI - Uptake and metabolism of ammonium and nitrate in response to drought stress in Malus prunifolia. AB - Using a hydroponics culture system, we monitored morphological, physiological, and molecular changes in Malus prunifolia seedlings when drought conditions induced by 5% polyethylene glycol (PEG) were combined with a low or normal supply of N (0.05 mM or 1 mM NH4NO3, respectively). Under either nutrient level, drought stress negatively inhibited seedling performance, as manifested by reduced photosynthesis and biomass production, decreased accumulations of total N, and inhibited root growth. Concentrations of NO3- and NH4+ and the activities of enzymes involved in N metabolism (nitrate reductase, glutamine synthetase, and glutamate synthase) were also significantly decreased under drought stress. The net influx of NO3- at the surface of the fine roots declined while that of NH4+ rose markedly, suggesting that the latter may play a more important role in improving drought tolerance in M. prunifolia. Consistently, two ammonium transporters (AMT1;2 and AMT4;2) were notably up-regulated in response to drought stress, whereas most genes related to nitrate uptake, reduction, and N metabolism were down-regulated. At the normal N level, PEG-treated plants showed higher values for biomass production, root growth, and N uptake/reduction when compared with plants exposed to the lower N supply. These results suggest that the negative effect of drought stress on M. prunifolia may be alleviated when more nitrogen is available. PMID- 29609175 TI - Involvement of ascorbate peroxidase and heat shock proteins on citrus tolerance to combined conditions of drought and high temperatures. AB - Usually several environmental stresses occur in nature simultaneously causing a unique plant response. However, most of the studies until now have focused in individually-applied abiotic stress conditions. Carrizo citrange (Poncirus trifoliata L. Raf. X Citrus sinensis L. Osb.) and Cleopatra mandarin (Citrus reshni Hort. ex Tan.) are two citrus rootstocks with contrasting tolerance to drought and heat stress and have been used in this work as a model for the study of plant tolerance to the combination of drought and high temperatures. According to our results, leaf integrity and photosynthetic machinery are less affected in Carrizo than in Cleopatra under combined conditions of drought and heat stress. The pattern of accumulation of three proteins (APX, HSP101 and HSP17.6) involved in abiotic stress tolerance shows that they do not accumulate under water stress conditions individually applied. However, contents of APX and HSP101 are higher in Carrizo than in Cleopatra under stress combination whereas HSP17.6 has a similar behavior in both types of plants. This, together with a better stomatal control and a higher APX activity of Carrizo, contributes to the higher tolerance of Carrizo plants to the combination of stresses and point to it as a better rootstock than Cleopatra (traditionally used in areas with scare water supplies) under the predictable future climatic conditions with frequent periods of drought combined with high temperatures. This work also provides the basis for testing the tolerance of different citrus varieties grafted on these rootstocks and growing under different field conditions. PMID- 29609176 TI - An altered tocopherol composition in chloroplasts reduces plant resistance to Botrytis cinerea. AB - Tocopherols are lipid-soluble antioxidants that contribute to plant resistance to abiotic stresses. However, it is still unknown to what extent alterations in tocopherol composition can affect the plant response to biotic stresses. The response to bacterial and fungal attack of the vte1 mutant of Arabidopsis thaliana, which lacks both alpha- and gamma-tocopherol, was compared to that of the vte4 mutant (which lacks alpha- but accumulates gamma-tocopherol) and the wild type (with accumulates alpha-tocopherol in leaves). Both mutants exhibited similar kinetics of cell death and resistance in response to Pseudomonas syringae. In contrast, both mutants exhibited delayed resistance when infected with Botrytis cinerea. Lipid and hormonal profiling was employed with the aim of assessing the underlying cause of this differential phenotype. Although an altered tocopherol composition in both mutants strongly influenced fatty acid composition, and strongly altered jasmonic acid and cytokinin contents upon infection with B. cinerea, differences between genotypes in these phytohormones were observed during late stages of infection only. By contrast, genotype-related effects on lipid peroxidation, as indicated by malondialdehyde accumulation, were observed early upon infection with B. cinerea. We conclude that an altered tocopherol composition in chloroplasts may negatively influence the plant response to biotic stress in Arabidopsis thaliana through changes in the membrane fatty acid composition, enhanced lipid peroxidation and delayed defence activation when challenged with B. cinerea. PMID- 29609177 TI - Arsenic removal from water and river water by the combined adsorption - UF membrane process. AB - In this study, a pilot-scale adsorption-UF process equipped with an aerated system is established for arsenic removal from As-spiked Songhua river water. A newly synthesized amino-functionalized coffee cellulose adsorbent (PEI-coffee) which is derived from spent coffee powder is fully characterized and used for arsenic removal from water. The batch experiments revealed that the adsorption process could be well described by Langmuir model with a maximum adsorption capacity of 13.2 and 46.1 mg/g for As(III) and As(V), respectively. The negative value of ?H and ?G indicated the exothermic and spontaneous nature of As adsorption on PEI-coffee. The effects of operating parameters such as pH, initial concentration and adsorbent dosage, were optimized by response surface methodology (RSM) based on a central composite design (CCD). The combined adsorption - UF process was employed for arsenic removal from As-spiked Songhua river water. It was demonstrated that aeration not only increased the removal efficiency by oxidizing As(III) to As(V), but mitigated the membrane fouling process. Besides of the adsorption process, UF membrane could also reject arsenic through the electrostatic repulsion between arsenic species and membrane surface. After UF filtration, the dissolved As, suspended solids (SS), and TOC can be effectively eliminated. The saturated adsorbent was regenerated by using an eluting agent of 10 wt% NaCl and 10 wt% NaOH, the regenerated adsorbent still sustained a very high adsorption capacity after 6 cycles of adsorption regeneration process. PMID- 29609178 TI - An investigation of mercury sources in the Puyango-Tumbes River: Using stable Hg isotopes to characterize transboundary Hg pollution. AB - Mercury (Hg) concentrations and stable isotopes along with other trace metals were examined in environmental samples from Ecuador and Peru's shared Puyango Tumbes River in order to determine the extent to which artisanal- and small-scale gold mining (ASGM) in Portovelo-Zaruma, Ecuador contributes to Hg pollution in the downstream aquatic ecosystem. Prior studies investigated the relationship between ASGM activities and downstream Hg pollution relying primarily on Hg concentration data. In this study, Hg isotopes revealed an isotopically heavy Hg signature with negligible mass independent fractionation (MIF) in downstream sediments, which was consistent with the signature observed in the ASGM source endmember. This signature was traced as far as ~120 km downstream of Portovelo Zaruma, demonstrating that Hg stable isotopes can be used as a tool to fingerprint and trace sources of Hg over vast distances in freshwater environments. The success of Hg isotopes as a source tracer in fresh waters is largely due to the particle-reactive nature of Hg. Furthermore, the magnitude and extent of downstream Hg, lead, copper and zinc contamination coupled with the Hg isotopes suggest that it is unlikely that the smaller artisanal-scale activities, which do not use cyanidation, are responsible for the pollution. More likely it is the scale of ores processed and the cyanide leaching, which can release other metals and enhance Hg transport, used during small-scale gold mining that is responsible. Thus, although artisanal- and small-scale gold mining occur in tandem in Portovelo-Zaruma, a distinction should be made between these two activities. PMID- 29609179 TI - Organizing membrane-curving proteins: the emerging dynamical picture. AB - Lipid membranes play key roles in cells, such as in trafficking, division, infection, remodeling of organelles, among others. The key step in all these processes is creating membrane curvature, typically under the control of many anchored, adhered or included proteins. However, it has become clear that the membrane itself can mediate the interactions among proteins to produce highly ordered assemblies. Computer simulations are ideally suited to investigate protein organization and the dynamics of membrane remodeling at near-micron scales, something that is extremely challenging to tackle experimentally. We review recent computational efforts in modeling protein-caused membrane deformation mechanisms, specifically focusing on coarse-grained simulations. We highlight work that exposed the membrane-mediated ordering of proteins into lines, meshwork, spirals and other assemblies, in what seems to be a very generic mechanism driven by a combination of short and long-ranged forces. Modulating the mechanical properties of membranes is an underexplored signaling mechanism in various processes deserving of more attention in the near future. PMID- 29609180 TI - Angiocoupling between the dominant follicle and corpus luteum during waves 1 and 2 in Bos taurus heifers. AB - The local two-way effect of the future and established dominant follicle (DF) and corpus luteum (CL) on color-Doppler signals of blood flow on each other (angiocoupling) was studied from ovulation to 16 days after ovulation during wave 1 and for the first time in wave 2 in Bos taurus heifers (N = 24). Identity of follicles greater than 4 mm was maintained from day to day. Blood-flow signals in the follicle wall and in the CL were estimated after scanning the entire structure. Ovarian patterns were defined based on the presence of a DF and CL: DF CL pattern (DF and CL in the same ovary), DF pattern or CL pattern (DF and CL in opposite ovaries), and devoid pattern (neither DF nor CL). Comparisons were made of blood flow in each structure when in the same ovary vs opposite ovaries. Data were normalized to expected diameter deviation (DF closest to 8.5 mm). Blood-flow signals were detected in most growing follicles when they attained 6 mm (6.0-6.9 mm). Combined for waves 1 and 2, the percentage of all 6-mm growing follicles that displayed blood-flow signals was greater (P < 0.0001) for the DF-CL pattern (21/26, 81%) than for the patterns of DF alone, CL alone, or neither DF nor CL (total for the three patterns (17/42, 40.5%); there was no effect of left vs right ovaries. For each wave, the percentage of DF wall and percentage of CL tissue with blood-flow signals were greater for the DF-CL pattern vs the DF pattern or CL pattern. Percentage of DF wall with blood-flow signals for the DF CL vs DF patterns was 30.0 +/- 1.5% vs 19.5 +/- 1.1% (P < 0.02) in wave 1 and 30.8 +/- 1.3% vs 20.2 +/- 1.1% (P < 0.0001) in wave 2. Percentage of CL tissue with blood-flow signals for the DF-CL vs CL patterns was 61.7 +/- 2.4% vs 56.9 +/ 1.7% (P < 0.03) in wave 1 and 78.8 +/- 1.3% vs 74.0 +/- 0.9% (P < 0.03) in wave 2. During wave 1, the percentage of CL tissue with blood-flow signals was greater (P < 0.002) when the DF and CL were in close proximity (distance between structures, < 2 mm; 66.9 +/- 3.0%) than when separated (>=2 mm; 53.8 +/- 3.5%). Normalization to the maximal DF diameter in wave 1 resulted in the novel finding that the percentage of blood-flow signals in the DF wall began to decrease 1 day before maximal diameter. Results supported the hypotheses that (1) percentage of DF wall and CL tissue with blood-flow signals in wave 2 is greater in the DF-CL pattern than in the DF or CL patterns and (2) percentage of DF wall with blood flow signals in wave 1 decreases before the beginning of a decrease in diameter. PMID- 29609181 TI - Improved uterine immune mediators in Holstein cows supplemented with rumen protected methionine and discovery of neutrophil extracellular traps (NET). AB - During the transition from prepartum to early lactation, dairy cows often experience negative energy balance (NEB) that may result in reproductive stress and decreased fertility. The objective of this study was to observe the effects of rumen-protected methionine (RPM) on plasma amino acid concentrations, uterine cytology, immunohistochemistry (IHC) of glutathione peroxidase 1 (GPX) and superoxide dismutase 1 (SOD), and to confirm neutrophil extracellular trap (NET) formation. Multiparous Holstein cows (n = 20) were randomly assigned to two treatments starting at 21 d before calving until 73 days in milk (DIM). Treatments were: CON (n = 9, no supplementation, TMR with a Lys:Met = 3.5:1) and MET (n = 11, TMR + Smartamine(r) M with a Lys:Met = 2.8:1). Uterine endometrial biopsies, uterine cytology, and blood samples from the coccygeal artery or vein were collected at 15, 30, and 73 DIM. Blood plasma samples were analyzed for amino acids and metabolites. Uterine biopsies were analyzed for NET formation, neutrophil numbers, as well as GPX and SOD by IHC. Additionally, uterine cytology was analyzed for polymorphonuclear neutrophil (PMN) to epithelial cell percentage. Cows in CON had lower methionine plasma concentrations (18.05 +/- 2.0 MUM) than cows in MET (30.39 +/- 1.6 MUM). Cows in CON had greater cystine plasma concentrations (3.62 +/- 0.3 MUM) than cows in MET (2.8 +/- 0.3 MUM). No treatment differences were observed for SOD or GPX in the endometrium. Cows in CON tended to have a high score for positively immunolabeled GPX cells at 15 DIM than cows in MET. No treatment differences were observed for the percentage of PMN in uterine cytology, number of neutrophils, or extent of NET formation in the endometrium. A treatment by time interaction was observed for PMN percentage and the number of neutrophils: cows in MET tended to have greater PMN percentages than cows in CON at 15 DIM which decreased for subsequent days and cows in MET had greater neutrophil numbers in the endometrium at 30 DIM than cows in CON. In conclusion, dietary supplementation of RPM altered plasma amino acid concentrations and increased neutrophil infiltration in the postpartum period, suggesting improved uterine immunity. PMID- 29609182 TI - Effects of natural infection by L. borgpetersenii serovar Hardjo type Hardjo bovis, L. interrogans serovar Pomona and leptospiral vaccination on sheep reproduction. AB - Most New Zealand sheep flocks are seropositive to Leptospira serovars Hardjo and/or Pomona, yet vaccination is rare. This study evaluated the impact of exposure to these serovars and of vaccination, on primiparous one- (P1) and two year-old (P2) sheep reproduction outcomes. The study was designed as a split flock vaccination trial, with a third of the animals vaccinated starting at one month of age. Reproduction outcomes were the proportion of bred P1 (7 months old) and as P2 (19 months old) scanned pregnant, the proportion of pregnant ewes rearing a lamb to tail docking and the proportion of docked lambs that were weaned. Odds ratios and their 95% confidence intervals were calculated to compare reproductive performance between vaccinated and control sheep, and within the control group, between seropositive and seronegative sheep. Odds ratios (OR) were also calculated to assess the relationship between vaccination and loss to follow up. There was no difference in pregnancy and docking rates between vaccinated and control sheep, or between seropositive and seronegative sheep. P1 with a Hardjo titre >=1536 were significantly less likely (OR = 0.41, 95%CI = 0.19-0.93) to keep a lamb between docking and weaning than P1 with both Hardjo and Pomona titres <1536, for an observed difference in weaning rate of up to 22.6% points on one farm. A reduction of weaning rates in 2-tooths seropositive for Pomona alone and both Hardjo and Pomona was observed but this was non-significant, possibly because of a lack of power. No difference in weaning rate was observed between vaccinated and control P1 or P2. On one farm vaccinated P1 were less likely to be lost to follow-up (OR = 0.27, 95% CI 0.08 to 0.95) between breeding and weaning. Comparing reproductive performance of vaccinated and control sheep revealed no significant difference. However, comparing exposed and non-exposed ewes revealed a possible adverse effect of Leptospira on weaning rates. This suggests that a full vaccination program may result in an improvement of reproductive outcomes, possibly by providing herd immunity. PMID- 29609183 TI - Ambient temperature and age-related notified Campylobacter infection in Israel: A 12-year time series study. AB - BACKGROUND: Campylobacter spp. are the leading cause of foodborne infection worldwide, with a seasonal disease peak that might be affected by temperature increase. We studied the relationship between ambient temperature and weekly notified Campylobacter spp.infections. METHODS: Data on 29,762 laboratory confirmed cases of Campylobacter infection for the period, January, 1999 to December, 2010 were retrieved from the Ministry of Health registry. To estimate the association between the number of weekly cases of Campylobacter infection and the national average temperature at lags 0-3 weeks, firstly, we used GAM models, and secondly two-segment piecewise linear Poisson regressions. The effect of temperature was adjusted for seasonality, long-term trends and holidays. RESULTS: We found a J-shaped relationship between ambient temperature and notified Campylobacter spp. CASES: For C. jejuni in all ages, the curve below the threshold was constant and the percent increase in cases for 1 degrees C above a threshold of 27 degrees C was 15.4% (95%CI: 6.7-24.1%). For ages 3-10 yr and > =26 yr the curve was constant below the threshold and positive above it; the percent increase in cases for 1 degrees C was 17.7%(95%CI: 6.0-29.4%) and 23.7%(95%CI: 11.6-35.8%), respectively. For ages 0-2 yr the curve was linear with no threshold and the percent increase for 1 degrees C was 5.1%(95%CI: 2.1-8.1%). For ages 11-25 yr the curve was always constant. Results for C. coli were similar. CONCLUSION: Our findings indicate that higher temperatures throughout the year affect Campylobacter spp. morbidity, especially in younger children. This should be taken into consideration in public education and health system preparedness for temperature increases as a result of climate change. PMID- 29609184 TI - Cesarean delivery: A predisposing factor for autoimmune thyroid disease in iodine replete women? PMID- 29609185 TI - Bladder function after sacrospinous hysteropexy and vaginal wall repair in women with uterovaginal prolapse. AB - OBJECTIVE: To evaluate the impact of repair of uterovaginal prolapse using sacrospinous hysteropexy and vaginal wall repair on the bladder function. STUDY DESIGN: The study was conducted at the urogynecology clinic of Suez Canal University Hospitals, Ismailia from January 2014 to March 2016. This study included women with a diagnosis of uterovaginal prolapse and wishing to preserve their uteri. Bladder function was evaluated through assessment of urological symptoms using a standardized questionnaire - the urogenital distress inventory (UDI-6) - in addition to urodynamic studies just before and six-months after the sacrospinous hysteropexy +/- associated vaginal wall repair operation. RESULTS: Twenty-seven patients completed the study with a mean age of 36.5 +/- 4 years. Only 3 women had sacrospinous hysteropexy with no additional procedures. Other procedures included anterior colporrhaphy (12), posterior colporrhaphy (9) and perineorrhaphy (15). Based on UDI-6, there was no significant difference between the pre- and post-operative symptoms of stress urinary incontinence (SUI) [8/27 (29.6%) vs. 9/27 (33.3%) respectively; p value = 0.7]. The pre- and post operative symptoms of urge urinary incontinence were also insignificantly different [13/27 (48.1%) vs. 15/27 (55.5%); p value = 0.5]. The total score of UDI-6 increased from 24.5 +/- (14.2) to 32.8 +/- (29.4) which was not statistically significant (p value = 0.12). Urodynamically, voiding dysfunction was found less frequently after the operation, however the difference was statistically insignificant [9/27 (33.3%) vs. 8/27 (29.6%); p value = 0.7]. CONCLUSION: Sacrospinous hysteropexy and associated vaginal wall repair do not affect the bladder function either subjectively or objectively. PMID- 29609186 TI - Improvement in health utility after transcervical radiofrequency ablation of uterine fibroids with the sonata system: Health utility after radiofrequency ablation. AB - OBJECTIVES: To establish the improvement in patient health utilities following treatment of symptomatic uterine fibroids with the SonataTM System. STUDY DESIGN: A prospective, single-arm trial was conducted in which 49 women in the United Kingdom, Netherlands and Mexico with fibroids were treated with transcervical, intrauterine ultrasound- guided radiofrequency ablation. The EQ-5D-3L system was utilized to collect patient health status at baseline, 3, 6, and, 12 months post procedure. Patient-reported health states at each time point were converted into a health utility value using time-trade off methodology. RESULTS: In the overall cohort, patient health utility increased from a mean of 0.745 at baseline, to means of 0.838, 0.852, and 0.914 at 3 months, 6 months, and 12 months, respectively. The change from baseline at 12 months was significant. When stratified by country, the 12-month improvement in health utility remained significant for both the Mexican and Dutch cohorts. CONCLUSIONS: Transcervical radiofrequency ablation of uterine fibroids with the Sonata System resulted in statistically significant 12-month improvements in health utility for the overall patient cohort and for the Mexican and Dutch sub-populations. PMID- 29609187 TI - Reproductive and relational trajectories leading to pregnancy: Differences between adolescents and adult women who had an abortion. AB - OBJECTIVES: The literature has been conceptualizing pregnancy occurrence as a multiphase event. However, the different combinations of decisions and behaviors leading to pregnancy that end in abortion remain unexplored in the literature. The aims of the study were to describe the reproductive and relational trajectories leading to pregnancy in women who decide to abort and to explore the differences in this process according to women's age [adolescents (<20 years old) vs. adults]. STUDY DESIGN: In this cross-sectional study, 426 women [246 adolescents (58.4%), 177 adults (41.6%)] who chose abortion were recruited. Data on reproductive and relational characteristics were collected through a self report questionnaire at 16 healthcare services that provide abortion. The variables were introduced in trajectories according to the criterion of temporal sequence between them: age at first sexual intercourse, relationship type, pregnancy planning, use of contraception, identification of contraceptive failure, and occurrence of pregnancy. RESULTS: Seven trajectories leading to pregnancy were identified. The most frequent trajectory (30.8%) included women who 1) were involved in a long-term romantic relationship, 2) did not plan the pregnancy, 3) were using contraception, and 4) did not identify the contraceptive failure that led to pregnancy. Although this was the most frequent trajectory for both age groups, the remaining trajectories showed a different distribution. Compared to adolescents, adult women's trajectories more frequently included casual relationships with non-use of contraception, or contraceptive use with no contraceptive failure identification. CONCLUSION: Our study highlights the need to recognize the multiplicity of reproductive and relational trajectories leading to pregnancies that end in abortion and their specificities according to women's age. These findings have important implications for abortion counselling and for the development of age-appropriate guidelines for preventive interventions, by drawing attention to prioritization of different contexts of intervention according women's age. PMID- 29609188 TI - Does Knowing Someone with Breast Cancer Influence the Prevalence of Adherence to Breast and Cervical Cancer Screening? AB - OBJECTIVE: To evaluate the prevalence of adherence to screening methods for breast and cervical cancer in patients attended at a university hospital and to investigate whether knowing someone with breast cancer, moreover belonging to the patient's family, affects the adherence to the screening recommendations. METHODS: This was a cross-sectional and quantitative study. A structured interview was applied to a sample of 820 women, between 20 and 69 years old, who attended a university hospital in the city of Juiz de for a, MG, Brazil. For the analysis, the chi-square test was used to assess possible associations between the variables, and the significance level was set at p-value <= 0.05 for a confidence interval (CI) of 95%. RESULTS: More than 95.0% of the sample performed mammography and cervical cytology exam; 62.9% reported knowing someone who has or had breast cancer, and this group was more likely to perform breast self-examination (64.9%; odds ratio [OR] 1.5; 95% CI 1.12-2.00), clinical breast examination (91.5%; OR 2.11; 95% CI 1.37-3.36), breast ultrasound (32.9%; OR 1.81, 95% CI 1.30-2.51), and to have had an appointment with a breast specialist (28.5%; OR 1.98, 95% CI 1.38-2.82). Women with family history of breast cancer showed higher propensity to perform breast self-examination (71.0%; OR 1.53 95% CI 1.04-2.26). CONCLUSION: There was high adherence to the recommended screening practices; knowing someone with breast cancer might make women more sensitive to this issue as they were more likely to undergo methods which are not recommended for the screening of the general population, such as breast ultrasound and specialist consultation; family history is possibly an additional cause of concern. PMID- 29609189 TI - Changes in Autonomic Tone in Premature Infants Developing Necrotizing Enterocolitis. AB - BACKGROUND: Necrotizing enterocolitis (NEC) is a complication of prematurity with a high mortality rate. Currently, there are no reliable biomarkers capable of identifying infants at risk for developing NEC. We sought to determine the autonomic nervous system antecedents of NEC in premature infants, using heart rate variability (HRV). MATERIALS AND METHODS: HRV was quantified by retrieving archived electrocardiogram (EKG) data from 30 premature infants from 4 days prior, through 4 days after, the clinical NEC diagnosis. HRV metrics were compared with those on the diagnosis day using the receiver operating characteristic (ROC) analysis. RESULTS: HRV metrics showed a depression of autonomic tone that preceded the clinical NEC diagnosis by 2 days, and which recovered to baseline by 2 days after diagnosis (area under the curve [AUC] < 0.7). The pattern of HRV change was significantly associated with the clinical severity of NEC (stage II vs. stage III). CONCLUSION: Our studies suggest that readily accessible metrics of autonomic depression might expedite the diagnosis of NEC and its severity in a clinically meaningful manner. Clearly, these studies need to be extended prospectively to determine the diagnostic utility of this approach. PMID- 29609190 TI - Stillbirth, Inflammatory Markers, and Obesity: Results from the Stillbirth Collaborative Research Network. AB - BACKGROUND: Obesity is associated with increased risk of stillbirth, although the mechanisms are unknown. Obesity is also associated with inflammation. Serum ferritin, C-reactive protein, white blood cell count, and histologic chorioamnionitis are all markers of inflammation. OBJECTIVE: This article determines if inflammatory markers are associated with stillbirth and body mass index (BMI). Additionally, we determined whether inflammatory markers help to explain the known relationship between obesity and stillbirth. STUDY DESIGN: White blood cell count was assessed at admission to labor and delivery, maternal serum for assessment of various biomarkers was collected after study enrollment, and histologic chorioamnionitis was based on placental histology. These markers were compared for stillbirths and live births overall and within categories of BMI using analysis of variance on logarithmic-transformed markers and logistic regression for dichotomous variables. The impact of inflammatory markers on the association of BMI categories with stillbirth status was assessed using crude and adjusted odds ratios (COR and AOR, respectively) from logistic regression models. The interaction of inflammatory markers and BMI categories on stillbirth status was also assessed through logistic regression. Additional logistic regression models were used to determine if the association of maternal serum ferritin with stillbirth is different for preterm versus term births. Analyses were weighted for the overall population from which this sample was derived. RESULTS: A total of 497 women with singleton stillbirths and 1,414 women with live births were studied with prepregnancy BMI (kg/m2) categorized as normal (18.5-24.9), overweight (25.0-29.9), or obese (30.0 + ). Overweight (COR, 1.48; 95% confidence interval [CI]: 1.14-1.94) and obese women (COR, 1.60; 95% CI: 1.23-2.08) were more likely than normal weight women to experience stillbirth. Serum ferritin levels were higher (geometric mean: 37.4 ng/mL vs. 23.3, p < 0.0001) and C reactive protein levels lower (geometric mean: 2.9 mg/dL vs. 3.3, p = 0.0279), among women with stillbirth compared with live birth. Elevated white blood cell count (15.0 uL * 103 or greater) was associated with stillbirth (21.2% SB vs. 10.0% live birth, p < 0.0001). Histologic chorioamnionitis was more common (33.2% vs. 15.7%, p < 0.0001) among women with stillbirth compared with those with live birth. Serum ferritin, C-reactive protein, and chorioamnionitis had little impact on the ORs associating stillbirth with overweight or obesity. Adjustment for elevated white blood cell count did not meaningfully change the OR for stillbirth in overweight versus normal weight women. However, the stillbirth OR for obese versus normal BMI changed by more than 10% when adjusting for histologic chorioamnionitis (AOR, 1.38; 95% CI: 1.02-1.88), indicating confounding. BMI by inflammatory marker interaction terms were not significant. The association of serum ferritin levels with stillbirth was stronger among preterm births (p = 0.0066). CONCLUSION: Maternal serum ferritin levels, elevated white blood cell count, and histologic chorioamnionitis were positively and C-reactive protein levels negatively associated with stillbirth. Elevated BMIs, both overweight and obese, were associated with stillbirth when compared with women with normal BMI. None of the inflammatory markers fully accounted for the relationship between obesity and stillbirth. The association of maternal serum ferritin with stillbirth was stronger in preterm than term stillbirths. PMID- 29609191 TI - Strategy for Zero Maternal Deaths by Hemorrhage in Brazil: A Multidisciplinary Initiative to Combat Maternal Morbimortality. PMID- 29609192 TI - The Burden of Indirect Causes of Maternal Morbidity and Mortality in the Process of Obstetric Transition: A Cross-Sectional Multicenter Study. AB - OBJECTIVE: The aim of this study is to evaluate the burden of indirect causes of maternal morbidity/mortality in Brazil. METHODS: Secondary analysis of a multicenter cross-sectional study conducted in 27 referral obstetric units within the Brazilian Network for Surveillance of Severe Maternal Morbidity. RESULTS: A total of 82,388 women were surveilled: 9,555 women with severe maternal morbidity were included, and 942 (9.9%) of them had indirect causes of morbidity/mortality. There was an increased risk of higher severity among the indirect causes group, which presented 7.56 times increased risk of maternal death (prevalence ratio [PR]: 7.56; 95% confidence interval [95%CI]: 4.99-11.45). The main indirect causes of maternal death were H1N1 influenza, sepsis, cancer and cardiovascular disease. Non-public antenatal care (PR: 2.52; 95%CI: 1.70-3.74), diabetes (PR: 1.90; 95%CI: 1.24-2.90), neoplasia (PR: 1.98; 95%CI: 1.25-3.14), kidney diseases (PR: 1.99; 95%CI: 1.14-3.49), sickle cell anemia (PR: 2.50; 95%CI: 1.16-5.41) and drug addiction (PR: 1.98; 95%CI: 1.03-3.80) were independently associated with worse results in the indirect causes group. Some procedures for the management of severity were more common for the indirect causes group. CONCLUSION: Indirect causes were present in less than 10% of the overall cases, but they represented over 40% of maternal deaths in the current study. Indirect causes of maternal morbidity/mortality were also responsible for an increased risk of higher severity, and they were associated with worse maternal and perinatal outcomes. In middle-income countries there is a mix of indirect causes of maternal morbidity/mortality that points to some advances in the scale of obstetric transition, but also reveals the fragility of health systems. PMID- 29609193 TI - Female Sexual Function in Women with Suspected Deep Infiltrating Endometriosis. AB - OBJECTIVE: To evaluate the quality of the sexual function of women with suspected deep infiltrating endometriosis. METHODS: A cross-sectional, observational and prospective study was conducted between May 2015 and August 2016, in which 67 patients with deep infiltrating endometriosis, suspected or diagnosed, were assessed for epidemiological and clinical characteristics, such as pain level through a visual analog scale (VAS), features of deep infiltrating endometriosis lesions and score on the Female Sexual Function Index (FSFI) before the onset of treatment. The statistical analysis was performed using the software STATA version 12.0 (StataCorp LLC, College Station, TX, USA) to compare the variables through multiple regression analysis. RESULTS: The average age of the patients was 39.2 years old; most patients were symptomatic (92.5%); and the predominant location of the deep infiltrating lesions was on the rectosigmoid colon (50%), closely followed by the retrocervical region (48.3%). The median overall score on the FSFI was 23.4; in 67.2% of the cases the score was <= 26.5 (cutoff point for sexual dysfunction). Deep dyspareunia (p = 0.000, confidence interval [CI]: 0.64-0.83) and rectosigmoid endometriosis lesions (p = 0.008, CI: 0.72-0.95) showed significant correlation with lower FSFI scores, adjusted by bladder lesion, patients' age and size of lesions. Deep dyspareunia (p = 0.003, CI: 0.49-0.86) also exhibited significant correlation with FSFI pain domain, adjusted by cyclic bowel pain, vaginal lesion and use of gonadotropin-releasing hormone (GnRH) analog. These results reflect the influence of deep dyspareunia on the sexual dysfunction of the analyzed population. CONCLUSION: Most patients exhibited sexual dysfunction, and deep dyspareunia was the pelvic painful symptom that showed correlation with sexual dysfunction. PMID- 29609194 TI - Perhaps quality of life should not be used as a trigger for discussing resuscitation and advance care plans. AB - As a subjective measure, quality of life should not be used as a trigger for discussing resuscitation, goals of care or advanced care plans. Limitations and challenges in measurement and assessment of quality of life have been recognised. It is a fluid construct and subject to changes and response shifts. Surrogate quality of life estimations may misrepresent individual worth and self-perceived quality of life. Disagreement over quality of life statements may cause harm. PMID- 29609195 TI - Service user experiences of specialist mental health supported accommodation: A systematic review of qualitative studies and narrative synthesis. AB - Specialist supported accommodation services have become a key component of most community-based mental healthcare systems. While mental health policies highlight the importance of service user involvement in service development and care planning, there are no comprehensive literature reviews synthesising services users' perspectives on, or experiences of, supported accommodation services. This systematic review was undertaken to fill this gap. We searched electronic databases (January 2015, updated June 2017), conducted hand searches and used forward-backward snowballing to identify 13,678 papers. We inspected the full text of 110 papers and included 50 of these in the final review. Data extraction and quality assessments were conducted. We used narrative synthesis to develop a conceptual model of service users' experiences that included structural, process, relational and contextual factors, such as the characteristics of the service, relationships with staff and other service users, the intensity and nature of support, the physical environment, and social and community integration. The review highlights the complex interplay of individual, service-level and community factors in shaping the lived experience of service users and their impact on personal identity and recovery. Our approach addressed some of the widely reported limitations of the quantitative research in this field, providing a conceptual model relevant to service user experiences across supported accommodation service types, population groups and countries. PMID- 29609196 TI - Separable covariance models for health care quality measures across years and topics. AB - Public quality reports for Medicare Advantage health plans include 11 measures of patient experiences reported in the annual Consumer Assessment of Healthcare Providers and Systems surveys. Computing summaries at the health plan level (of multiple measures in multiple years) yields an array-structured random variable. To summarize associations among measures and years, we model the variance covariance matrix governing the plan-level vectors of yearly quality measures as a Kronecker product of an across-measure matrix and an across-year matrix, or a sum of such Kronecker products. This approach extends separable covariance structure to Fay-Herriot models. In addition, we develop linear combinations of Kronecker products similar to principal components for array random variables. To each Kronecker-product term, we apply post hoc analyses suited to the corresponding dimension of the cross-classification: 1-way factor analysis for the across-measure factor and time-series analysis to the across-year factor. These methods draw out key patterns of variation in the quality measures over time and suggest new strategies for reporting quality information to consumers. PMID- 29609197 TI - The Impact of Illness Perceptions and Coping on the Association Between Back Pain and Health Outcomes in Patients Suspected of Having Axial Spondyloarthritis: Data From the SPondyloArthritis Caught Early Cohort. AB - OBJECTIVE: To investigate whether illness perceptions and coping influence the relationship between back pain and health outcomes in patients suspected of having axial spondyloarthritis (SpA). METHODS: In the SPondyloArthritis Caught Early cohort, regression models were computed at baseline, with back pain intensity (range 0-10) as the determinant and health-related quality of life, the physical component summary score (PCS) and mental component summary (MCS) of the Short Form 36 (SF-36) health survey, or work productivity loss as outcomes. Subsequently, using Leventhal's Common-Sense Model of Self-Regulation, illness perceptions and, thereafter, coping were added to the models. Analyses were repeated for patients diagnosed and classified as having axial SpA according to the Assessment of SpondyloArthritis international Society axial SpA criteria (ASAS axial SpA), patients only diagnosed with axial SpA (axial SpA-diagnosed only), and those with chronic back pain. RESULTS: A total of 424 patients (145 with ASAS axial SpA, 81 with only a diagnosis of axial SpA, and 198 with chronic back pain); 64% of the total group were female, the mean +/- SD age was 30.9 +/- 8.1 years, and the mean +/- SD symptom duration was 13.3 +/- 7.1 months) were studied. In all patients, the strength of the associations between back pain and the PCS, back pain and the MCS score, and back pain and loss of work productivity were decreased by adding illness perceptions to the model, but explained variance improved. Adding coping to these models did not change the results. Comparable results were observed in all subgroups. CONCLUSION: Illness perception, but not coping, is important in the relationship between back pain and HRQoL and work productivity loss in patients suspected of having axial SpA, irrespective of subgroup. This finding suggests that targeting illness perceptions could improve health outcomes in patients suspected of having axial SpA. PMID- 29609198 TI - ? PMID- 29609199 TI - Incidence and Prevalence of Major Adverse Cardiovascular Events in Rheumatoid Arthritis, Psoriatic Arthritis, and Axial Spondyloarthritis. AB - OBJECTIVE: To compare the risk of major adverse cardiovascular events (MACE) in a large observational cohort of patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA), or axial spondyloarthritis (SpA) patients. METHODS: We conducted a mixed retrospective and prospective cohort study using data from patients with RA, PsA, or axial SpA included in the Swiss Clinical Quality Management registry. The primary outcome of interest was a composite of myocardial infarction, transient or permanent cerebrovascular event, or cardiovascular-associated death. RESULTS: A total of 5,315 patients were eligible for the analysis of incidence, with a total follow-up time of 37,495 patient-years for RA, 19,837 patient-years for axial SpA, and 9,171 patient-years for PsA. The unadjusted incidence rate of MACE per 1,000 patient-years was 2.67 for RA, 1.41 for axial SpA, and 1.42 for PsA. Compared to the unadjusted incidence rate ratios (IRRs) in patients with RA, those in patients with axial SpA were 0.53 (95% confidence interval [95% CI] 0.34 0.80; P = 0.003) and in patients with PsA were 0.53 (95% CI 0.30-0.95; P = 0.03). After adjustment for traditional cardiovascular risk factors, age at disease onset, sex, and disease duration, the difference was not significant between RA and axial SpA (adjusted IRR 0.93 [95% CI 0.51-1.69]; P = 0.80) or between RA and PsA (adjusted IRR 0.56 [95% CI 0.27-1.14]; P = 0.11). We found a similar result with the analysis of prevalence. CONCLUSION: There was no significant difference in the incidence and prevalence of MACE between RA and axial SpA or PsA, suggesting that inflammation, rather than a particular disease, drives the increased risk of cardiovascular disease. PMID- 29609201 TI - Ocular hangover. PMID- 29609202 TI - Wait times are not the problem! Detailed analysis of unsolicited patient complaints from a metropolitan Australian emergency department. AB - OBJECTIVE: To describe characteristics of ED admissions that resulted in unsolicited complaints and compare with overall ED admissions. The site utilised is an inner city tertiary hospital, with 630 beds, with approximately 82 600 annual presentations, where 32.5% were children. METHODS: Complaints between the dates of 27 November 2012 and 10 March 2016 were reviewed. Performance indicators and the distribution of presentations by diagnostic code were reviewed. RESULTS: A total of 572 different complaint reasons were found and grouped into 12 categories. The most common reasons for complaints were treatment (33.2%) and communication (28.3%), and most complaints concerned medical staff. Other variables including wait times have no effect on patient complaints. Utilising aggregate numbers, the overall paediatric complaint ratio was 0.98:1000 presentations, and the total adult department complaints were 1.78:1000 presentations. CONCLUSION: As seen in this study the vast majority of patient complaints were associated with treatment and communication issues and skewed towards doctors. It may be feasible for medical staff to undertake communication training as clinician-patient communication in the ED is an important aspect in the improvement of patient satisfaction and in decreasing patient complaints as waiting times and triage categories had no major influence on patient complaints. PMID- 29609203 TI - Review article: A primer for clinical researchers in the emergency department: Part 6. Measuring what matters: Core outcome sets in emergency medicine research. AB - In this series we address important topics for clinicians who participate in research as part of their work in the ED. The overarching goal of clinical research is to improve care and determine which treatment is best. Yet, defining and measuring outcomes - what is 'best' - can be one of the most difficult steps in the design of a study, in particular when answers to research questions cannot be captured in simple binary results. This article addresses how to choose outcome measures and highlights the increasingly important concept of core outcome sets. PMID- 29609204 TI - Aerobic Exercise and Fatigue in Rheumatoid Arthritis Participants: A Meta Analysis Using the Minimal Important Difference Approach. AB - OBJECTIVE: To use the minimal important difference (MID) versus the standardized mean difference (SMD) approach in order to provide more robust and clinically relevant information regarding the association between land-based aerobic exercise and changes in self-reported fatigue among adults with rheumatoid arthritis (RA). METHODS: Data from a previous meta-analysis of 5 randomized controlled trials that represented up to 298 participants per study were utilized to calculate 9 effect sizes, using the MID approach. Data used to obtain the MID were derived from previously reported anchor-based values specific to each fatigue instrument in adults with RA. Results were pooled using a random-effects model. RESULTS: Aerobic exercise resulted in statistically significant reductions in self-reported fatigue (MID effect size -0.34 [95% confidence interval (95% CI) -0.58, -0.10]; P = 0.006). Results were similar when effect sizes were collapsed so that only 1 effect size represented each study (MID effect size -0.39 [95% CI 0.76, -0.03]; P = 0.04). CONCLUSION: Land-based aerobic exercise is associated with statistically significant reductions in fatigue; however, based on previous cut points, it may be unlikely that a substantial number of participants with RA could obtain clinically relevant reductions in fatigue. Additional studies are needed, especially in those individuals with RA who have elevated levels of fatigue. PMID- 29609205 TI - Cost-Utility Analysis of Routine Anxiety and Depression Screening in Patients Consulting for Osteoarthritis: Results From a Clinical, Randomized Controlled Trial. AB - OBJECTIVE: To investigate the cost-effectiveness (cost-utility) of introducing general practitioner screening for anxiety and depression in patients consulting for osteoarthritis (OA). METHODS: A cluster-randomized trial-based economic evaluation to assess general practitioners screening for anxiety and depression symptoms in patients consulting for OA compared to usual care (screening for pain intensity) was undertaken over a 12-month period from a UK National Health Service and societal perspective. Patient-level mean costs and mean quality adjusted life years (QALYs) were estimated, and cost-effectiveness acceptability curves controlling for cluster-level data were constructed. The base-case analysis used the net benefit regressions approach. The 2-stage nonparametric sampling technique was explored in a sensitivity analysis. RESULTS: The base-case analysis demonstrated that the intervention was as costly as, and less effective than, the control (QALY differential -0.029 [95% confidence interval -0.062, 0.003]). In the base-case analyses, general practitioner screening for anxiety and depression was unlikely to be a cost-effective option (probability <5% at L20,000/QALY). Similar results were observed in all sensitivity analyses. CONCLUSION: Prompting general practitioners to routinely screen and manage comorbid anxiety and depression in patients presenting with OA is unlikely to be cost-effective. Further research is needed to explore clinically effective and cost-effective models of managing anxiety and depression in patients presenting with clinical OA. PMID- 29609206 TI - Relationship between Roe and Metz simulation model for multireader diagnostic data and Obuchowski-Rockette model parameters. AB - For the typical diagnostic radiology study design, each case (ie, patient) undergoes several diagnostic tests (or modalities) and the resulting images are interpreted by several readers. Often, each reader is asked to assign a confidence-of-disease rating to each case for each test, and the diagnostic tests are compared with respect to reader-performance outcomes that are functions of the reader receiver operating characteristic (ROC) curves, such as the area under the ROC curve. These reader-performance outcomes are frequently analyzed using the Obuchowski and Rockette method, which allows conclusions to generalize to both the reader and case populations. The simulation model proposed by Roe and Metz (RM) in 1997 emulates confidence-of-disease data collected from such studies and has been an important tool for empirically evaluating various reader performance analysis methods. However, because the RM model parameters are expressed in terms of a continuous decision variable rather than in terms of reader-performance outcomes, it has not been possible to evaluate the realism of the RM model. I derive the relationships between the RM and Obuchowski-Rockette model parameters for the empirical area under the ROC curve reader-performance outcome. These relationships make it possible to evaluate the realism of the RM parameter models and to assess the performance of Obuchowski-Rockette parameter estimates. An example illustrates the application of the relationships for assessing the performance of a proposed upper one-sided confidence bound for the Obuchowski-Rockette test-by-reader variance component, which is useful for sample size estimation. PMID- 29609207 TI - Open-Label, Non-Mandatory Transitioning From Originator Etanercept to Biosimilar SB4: Six-Month Results From a Controlled Cohort Study. AB - OBJECTIVE: To evaluate the effects of non-mandatory transitioning from the originator biologic drug etanercept (ETN) to its biosimilar, SB4, on drug survival and effectiveness in a controlled cohort study of patients with an inflammatory rheumatic disease. METHODS: In 2016, 642 patients were asked to transition their treatment from originator ETN to biosimilar SB4 by a structured communication strategy with opt-out option. Patients who consented to switch to SB4 were considered eligible for inclusion in the transition cohort, while patients being treated with originator ETN in 2014 were recruited as the historical cohort. Drug survival was compared between the 2 cohorts using Cox regression analyses, which were adjusted for age, sex, diagnosis, ETN treatment duration, ETN dose interval, conventional synthetic disease-modifying antirheumatic drug usage, and C-reactive protein (CRP) level, with a robust variance estimator applied to account for repeated subjects (i.e., patients who were included in both the transition cohort and the historical cohort). Adjusted differences in the 6-month change in CRP level, Disease Activity Score in 28 joints using CRP level (DAS28-CRP), and Bath Ankylosing Spondylitis Disease Activity Index were also assessed. RESULTS: Of the 642 ETN-treated patients, 635 (99%) agreed to transition from originator ETN to biosimilar SB4, of whom 625 patients (433 with rheumatoid arthritis, 128 with psoriatic arthritis, and 64 with ankylosing spondylitis) were included in the transition cohort, and 600 ETN treated patients from 2014 were included in the historical cohort. The crude treatment persistence rate for biosimilar SB4 over 6 months was 90% (95% confidence interval [95% CI] 88-93%), compared to a 6-month treatment persistence rate of 92% (95% CI 90-94%) for originator ETN. Patients in the transition cohort, compared to the historical cohort, had a statistically significantly higher relative risk of treatment discontinuation (adjusted hazard ratio 1.57, 95% CI 1.05-2.36) and showed smaller decreases in the CRP level (adjusted difference 1.8, 95% CI 0.3-3.2) and DAS28-CRP (adjusted difference 0.15, 95% CI 0.05-0.25) over 6 months. CONCLUSION: Non-mandatory transitioning from originator ETN to biosimilar SB4 using a specifically designed communication strategy resulted in a slightly lower 6-month treatment persistence rate and smaller decreases in disease activity in the transition cohort compared to the historical cohort, but these differences were not considered clinically relevant. PMID- 29609208 TI - Qualitative evaluation of evidence-based online decision aid and resources for osteoarthritis management: Understanding patient perspectives. AB - OBJECTIVE: To qualitatively examine the experiences with, and impact of, evidence based online resources in self-management among Australians with osteoarthritis. METHODS: Telephone interviews were conducted with 36 users of a novel osteoarthritis resource, the "OA awareness hub." Rogers' five attributes of innovation, Relative advantage, Compatibility, Complexity, Trialability and Observability, and outcomes, guided the semi-structured interview and analysis. Maximum variation sampling was used and data saturation occurred after 33 interviews. A coding scheme was agreed upon by the first two authors and all interview data were entered into NVivo for qualitative content analysis. RESULTS: Study participants had high levels of literacy and 'health literacy'. For adoption and implementation of an innovation, the participants' narratives confirmed and underscored that it was important that it come from an authoritative and trusting voice and that its perceived benefits align with their values and existing practices (Relative Advantage and Compatibility). The participants also valued seeing the practical benefits of the innovation, such as its capacity to impart quality and balanced new insights and information, and to maintain and monitor their personal progress. Notably, many participants spoke about the mental and physical health benefits that they derived from engagement with the online resources. CONCLUSION: Our study findings confirm that web-based tools can be a useful adjunct to patients adopting self-management strategies. Rogers' theory provides a framework for a deeper appreciation of the how, why and what questions concerning the adoption and implementation processes especially among people with good technology and health literacy. This article is protected by copyright. All rights reserved. PMID- 29609200 TI - IL1RN Variation Influences Both Disease Susceptibility and Response to Recombinant Human Interleukin-1 Receptor Antagonist Therapy in Systemic Juvenile Idiopathic Arthritis. AB - OBJECTIVE: To determine whether systemic juvenile idiopathic arthritis (JIA) susceptibility loci that were identified by candidate gene studies demonstrate association with systemic JIA in the largest study population assembled to date. METHODS: Single-nucleotide polymorphisms (SNPs) from 11 previously reported systemic JIA risk loci were examined for association in 9 populations, including 770 patients with systemic JIA and 6,947 controls. The effect of systemic JIA associated SNPs on gene expression was evaluated in silico in paired whole genome and RNA sequencing data from the lymphoblastoid cell lines (LCLs) of 373 European subjects from the 1000 Genomes Project. Responses of systemic JIA-associated SNPs to anakinra treatment were evaluated in 38 US patients for whom treatment response data were available. RESULTS: We found no association between the previously reported 26 SNPs and systemic JIA. Expanded analysis of the regions containing the 26 SNPs revealed only 1 significant association: the promoter region of IL1RN (P < 1 * 10-4 ). Systemic JIA-associated SNPs correlated with IL1RN expression in LCLs, with an inverse correlation between systemic JIA risk and IL1RN expression. The presence of homozygous IL1RN high expression alleles correlated strongly with a lack of response to anakinra therapy (odds ratio 28.7 [95% confidence interval 3.2-255.8]). CONCLUSION: In our study, IL1RN was the only candidate locus associated with systemic JIA. The implicated SNPs are among the strongest known determinants of IL1RN and interleukin-1 receptor antagonist levels, linking low expression with increased systemic JIA risk. Homozygous high expression alleles predicted nonresponsiveness to anakinra therapy, making them ideal candidate biomarkers to guide systemic JIA treatment. This study is an important first step toward the personalized treatment of systemic JIA. PMID- 29609211 TI - Barriers to Shared Use of Indoor and Outdoor Facilities at US Elementary Schools. AB - BACKGROUND: School policies and practices, such as the sharing of school facilities with the surrounding community, support physical activity among students and community members, but are often underutilized. This study examined variations in shared use practices, and associations with perceived barriers. METHODS: Surveys were completed by a nationally representative sample of 640 public elementary schools across the United States. Administrators reported on their school's practices related to the shared use of indoor and outdoor facilities, and perceived barriers to sharing. Multivariate logistic regression models were used to examine associations between barriers and practices. RESULTS: Liability or legal concerns, staffing expenses, and facility operation costs were most frequently reported as barriers, while lack of adequate facilities and perceived lack of community interest were less common. Cost concerns and perceived lack of community interest were most strongly associated with lack of sharing. CONCLUSIONS: Although liability or legal concerns are common, such concerns are not necessarily associated with less sharing when other factors are taken into account. Administrators' perceptions about lack of community interest were associated with less sharing, but these perceptions may not accurately reflect the community's perspective. Active development of partnerships could increase access to school facilities. PMID- 29609210 TI - Does Systemic Lupus Erythematosus Care Provided in a Lupus Clinic Result in Higher Quality of Care Than That Provided in a General Rheumatology Clinic? AB - OBJECTIVE: To compare the quality of care received by patients with systemic lupus erythematosus (SLE) in 2 settings within the academic institution (a dedicated lupus clinic and a general rheumatology clinic) using validated SLE quality measures. METHODS: One hundred fifty consenting, consecutive SLE patients receiving longitudinal care at the Rush University general rheumatology clinic (n = 73) or the subspecialty lupus clinic (n = 77) were recruited. An updated quality measure survey and retrospective medical chart review were used to evaluate each quality measure (n = 20). The overall and individual quality measure performance was calculated and compared between the 2 groups. Data on the number of SLE patients seen by each rheumatologist were collected to assess the relationship between SLE patient volume and quality measures. RESULTS: Overall quality measure performance was significantly better in SLE patients receiving care at the lupus clinic (85.8% versus 70.2% of patients receiving care at the general rheumatology clinic; P = 0.001). Differences between the 2 groups were observed for sunscreen counseling (98.7% and 83.6%, respectively; P = 0.001), antiphospholipid antibody testing (71.4% and 37%, respectively; P < 0.001), pneumococcal vaccination (84.8% and 48.8%, respectively; P < 0.001), bone mineral density testing (94.2% and 54.5%, respectively; P < 0.001), drug counseling (92.2% and 80.8%, respectively; P = 0.04), use of a steroid-sparing agent (100% and 82%, respectively; P < 0.007), use of an angiotensin-converting enzyme inhibitor (94.4% and 58.3%, respectively; P = 0.03), and cardiovascular disease risk assessment (40.3% and 15.1%, respectively; P = 0.01). There was a moderate correlation between physician volume and quality measure performance (rho = 0.48, P < 0.001). CONCLUSION: Compared with the general rheumatology clinic, the dedicated lupus clinic had better quality measure performance in this cross sectional single-center study. In our health care system, we also observed indicators suggesting that rheumatologists with a higher volume of SLE patients provide higher quality of care. PMID- 29609209 TI - Review: Unmet Needs and the Path Forward in Joint Disease Associated With Calcium Pyrophosphate Crystal Deposition. AB - Calcium pyrophosphate (CPP) crystal deposition (CPPD) is prevalent and can be associated with synovitis and joint damage. The population of elderly persons predominantly affected by CPPD is growing rapidly. Since shortfalls exist in many aspects of CPPD, we conducted an anonymous survey of CPPD unmet needs, prioritized by experts from the Gout, Hyperuricemia and Crystal-Associated Disease Network. We provide our perspectives on the survey results, and we propose several CPPD basic and clinical translational research pathways. Chondrocyte and cartilage culture systems for generating CPP crystals in vitro and transgenic small animal CPPD models are needed to better define CPPD mechanism paradigms and help guide new therapies. CPPD recognition, clinical research, and care would be improved by international consensus on CPPD nomenclature and disease phenotype classification, better exploitation of advanced imaging, and pragmatic new point-of-care crystal analytic approaches for detecting CPP crystals. Clinical impacts of CPP crystals in osteoarthritis and in asymptomatic joints in elderly persons remain major unanswered questions that are rendered more difficult by current inability to therapeutically limit or dissolve the crystal deposits and assess the consequent clinical outcome. Going forward, CPPD clinical research studies should define clinical settings in which articular CPPD does substantial harm and should include analyses of diverse clinical phenotypes and populations. Clinical trials should identify the best therapeutic targets to limit CPP crystal deposition and associated inflammation and should include assessment of intraarticular agents. Our perspective is that such advances in basic and clinical science in CPPD are now within reach and can lead to better treatments for this disorder. PMID- 29609212 TI - From Tactics to Strategy: Creating and Sustaining Social Conditions That Demand and Deliver Effective School Health Programs. PMID- 29609213 TI - The Utility of Measuring Intentions to Use Best Practices: A Longitudinal Study Among Teachers Supporting Students With Autism. AB - BACKGROUND: School-based interventions can result in profound social, behavioral, and academic improvement for students with autism, but teachers rarely implement them. It is important to understand why this occurs and use this information to increase the use of evidence-based practices. Toward this goal, 2 proof-of construct studies demonstrate the theoretical and methodological advantages of measuring behavioral intentions to use specific practices. METHODS: Two observational studies enrolled public school teachers who work with students with autism. The studies measure the strength of teachers' intentions to use each of 4 different evidence-based practices, assess variability in intentions, and test whether intentions predict future teacher behavior. RESULTS: In adjusted analyses, intentions to use a specific evidence-based practice were strongly associated with subsequent use (adjusted odds ratio = 5.2). The proportion of teachers who reported strong intentions varied from a low of 33% to a high of 66%, depending on the practice. CONCLUSIONS: The findings illustrate that the strength of intentions, which varies depending on the specific practice, can predict implementation. More generally, the studies demonstrate how measures of intention can aid efforts to identify implementation barriers. The approach taken can be applied to study implementation of any practices designed to improve student health. PMID- 29609214 TI - Barriers to the Administration of Epinephrine in Schools. AB - BACKGROUND: Anaphylaxis is a serious and growing concern in the school setting as the prevalence of food allergies and food-induced severe allergic reactions continues to increase. METHODS: A cross-sectional, web-based survey was conducted regarding anaphylactic events that occurred during the 2014-2015 school year. Eligible schools were enrolled in the EPIPEN4SCHOOLS(r) program (Mylan Specialty L.P., Canonsburg, PA), which provides free epinephrine auto-injectors to qualifying US schools. Participating schools completed a 29-item survey on anaphylactic event occurrence and treatment, epinephrine stock, school policies regarding anaphylaxis, school staff training, and school nursing coverage. RESULTS: Responses were provided by 12,275 schools. Epinephrine was administered on school property for 63.7% of reported anaphylactic events (1272/1998). In 38.5% (235/610) of events for which epinephrine was not used, antihistamines were cited as the reason. Only 59.4% of schools cited epinephrine as their standard first-line therapy for anaphylaxis. School nurses were most likely to be trained in anaphylaxis recognition and permitted to administer epinephrine; however, just 53.6% of schools had a full-time nurse on staff. CONCLUSIONS: Process-related barriers to the appropriate use of epinephrine go beyond access to medication. Widespread staff training and review of school policies are needed to ensure that anaphylaxis is appropriately managed in schools. PMID- 29609215 TI - The Opioid Crisis and Schools-A Commentary. PMID- 29609216 TI - Navigating the Health Care System: An Adolescent Health Literacy Unit for High Schools. AB - BACKGROUND: Currently, no intervention concerning transition of health care responsibilities from parents to teens exists for adolescents in the general population. The purpose of this intervention was to evaluate teacher satisfaction and student knowledge gain of a health unit developed for adolescents on becoming their own health care advocates. METHODS: Throughout the 2014-2015 school year, 13 health and career technical education teachers in 11 Delaware high schools taught the unit to 948 students in 2 90-minute classes in 35 classrooms. Assessments included teacher reflections and student pre- and posttests to measure knowledge transfer and gain and gather feedback. RESULTS: Teacher and student feedback indicated the materials were appropriate and useful in teaching students to navigate the health care system. Student knowledge increased from pretest (64%) to posttest (82%), (p < .001). The educational background of the teacher did not influence this outcome. Students reported they will know what to do better at their next doctor's appointment because of this unit and indicated support for peers to learn this information. CONCLUSIONS: The unit resulted in content knowledge increase for students. It was consistently effective throughout all schools regardless of social and demographic characteristics, teacher type, or experience teaching the unit. PMID- 29609217 TI - Later Start, Longer Sleep: Implications of Middle School Start Times. AB - BACKGROUND: Although adolescents generally get less than the recommended 9 hours of sleep per night, research and effort to delay school start times have generally focused on high schools. This study assesses the relation between school start times and sleep in middle school students while accounting for potentially confounding demographic variables. METHODS: Seventh and eighth grade students attending 8 late starting schools (~8:00 am, n = 630) and 3 early starting schools (~7:23 am, n = 343) from a diverse suburban school district completed online surveys about their sleep behaviors. Doubly robust inverse probability of treatment weighted regression estimates of the effects of later school start time on student bedtimes, sleep duration, and daytime sleepiness were generated. RESULTS: Attending a school starting 37 minutes later was associated with an average of 17 additional minutes of sleep per weeknight, despite an average bedtime 15 minutes later. Students attending late starting schools were less sleepy than their counterparts in early starting schools, and more likely to be wide awake. CONCLUSIONS: Later school start times were significantly associated with improved sleep outcomes for early adolescents, providing support for the movement to delay school start times for middle schools. PMID- 29609218 TI - Health Literacy Teaching Beliefs, Attitudes, Efficacy, and Intentions of Middle School Health and Physical Education Teachers. AB - BACKGROUND: Health education (HE) courses in schools are vital paths for improving teenagers' health literacy. HE and physical education (PE) teachers lead HE courses, and their teaching intentions and competency influence the effectiveness of the courses and the ability to promote students' health literacy. This study attempted to understand HE and PE teachers' health literacy teaching intentions and professional competency and to investigate their relationships. METHODS: This study adopted a cross-sectional design. A questionnaire survey was administered to 906 middle school HE and PE teachers in Taiwan by mail, and 545 provided valid data with consent. RESULTS: Participants had a favorable health literacy (47.78/50), positive health literacy teaching beliefs and attitudes, and acceptable efficacy. They intended to implement health literacy instruction within the subsequent year. Teaching beliefs, attitudes, and efficacy were all positively correlated with intentions (all p < .001). Demographic variables, health literacy, and teaching beliefs, attitudes, and efficacy explained 33.5% of the variance of teaching intentions. CONCLUSION: Teaching beliefs, attitudes, and efficacy were crucial predictors of health literacy teaching intentions. To improve students' health literacy, educational authorities and schools should pay attention to HE and PE teachers' intentions and vital factors, thereby enhancing teachers' willingness to perform health literacy instruction. PMID- 29609219 TI - Assessing School Wellness Policies and Identifying Priorities for Action: Results of a Bi-State Evaluation. AB - BACKGROUND: Obesity is a complex health problem affecting more than one-third of school-aged youth. The increasing obesity rates in Kansas and Missouri has been particularly concerning, with efforts being made to improve student health through the implementation of school wellness policies (SWPs). The primary purpose of this study was to conduct a rigorous assessment of SWPs in the bi state region. METHODS: SWPs were collected from 46 school districts. The Wellness School Assessment Tool (WellSAT) was used to assess comprehensiveness and strength. Additionally, focus group discussions and an online survey were conducted with school personnel to identify barriers and supports needed. RESULTS: Assessment of the SWPs indicated that most school districts failed to provide strong and specific language. Due to these deficiencies, districts reported lack of enforcement of policies. Several barriers to implementing the policies were reported by school personnel; supports needed for effective implementation were identified. CONCLUSIONS: To promote a healthful school environment, significant improvements are warranted in the strength and comprehensiveness of the SWPs. The focus group discussions provided insight as to where we need to bridge the gap between the current state of policies and the desired beneficial practices to support a healthy school environment. PMID- 29609220 TI - Burden of Psoriatic Arthritis According to Different Definitions of Disease Activity: Comparing Minimal Disease Activity and the Disease Activity Index for Psoriatic Arthritis. AB - OBJECTIVE: Treat-to-target strategies have improved outcomes in rheumatic diseases. In psoriatic arthritis (PsA), the proposed targets are the multidimensional target minimal disease activity (MDA) and the articular target Disease Activity index for PsA (DAPSA). The aim of this study was to compare the disease burden of PsA in patients with low disease activity according to the 2 definitions, MDA and DAPSA low disease activity (DAPSA-LDA), 1 year after diagnosis. METHODS: We obtained data on MDA, DAPSA-LDA and disease burden 1 year after diagnosis for patients included in the Dutch southwest early PsA cohort. Disease burden was assessed in 2 domains: "Body functions," including the Short Form 36 bodily pain (SF-36 BP) measure, and "Activity," including the Health Assessment Questionnaire (HAQ). RESULTS: Among the 292 patients included, 48% achieved MDA and 74% achieved DAPSA-LDA. Average scores for Body functions and Activity were better in patients who achieved MDA and those who achieved DAPSA LDA. The scores were significantly better in the 46% of patients who achieved both MDA and DAPSA-LDA than in the 29% of patients who achieved only DAPSA-LDA. The average SF-36 BP score was higher in patients achieving both targets (73.8; 95% confidence interval [95% CI] 71.1-76.5) than in patients achieving only DAPSA LDA (57.6; 95% CI 54.5-60.8). Similarly, mean HAQ scores measuring Activity were 0.21 (95% CI 0.15-0.26) and 0.63 (95% CI 0.53-0.72), respectively. CONCLUSION: Among patients with newly diagnosed PsA, 48% achieved MDA and 74% achieved DAPSA LDA after 1 year of receiving usual care. The average disease burden was better in patients who achieved MDA and those who achieved DAPSA-LDA. Also, patients who achieved only DAPSA-LDA reported worse outcomes than those who also achieved MDA. PMID- 29609221 TI - Accuracy of medication information sources compared to the best possible medication history for patients presenting to the emergency department. AB - OBJECTIVE: To assess the accuracy of medication information sources available for adult patients presenting to the ED, compared to a best possible medication history (BPMH). METHODS: This prospective observational study was undertaken in the ED of a major tertiary-referral teaching hospital. A convenience sample of consecutive adult patients taking one or more regular medications was included. A BPMH was ascertained using patient/carer interviews, where available, and confirmed with one or more other sources. For residential care facility (RCF) patients, the RCF medication chart and at least one other source were used. Information sources compared with the BPMH were community pharmacy dispensing history, patient's own medications, patient's medication list, general practitioner letter, medications stored in and labelled on dose administration aids (DAAs) and the RCF chart. Number of discrepancies per patient for each source was determined by comparing medications and dose regimens to those documented in the BPMH. RESULTS: A total of 455 patients (median age 71 years) took a median of six 'regular' and two 'as required' medications. The median number (range) of discrepancies per patient for regular medication names and dosages were RCF chart 0 (0-3), DAA contents 2.0 (0-9), patient's medication list 2.5 (0-16), DAA medications label 3.0 (0-7), community pharmacy history 3.0 (0 19), general practitioner letter 3.0 (0-18) and patient's own medications 4.0 (0 16). Overall, 40.4% of discrepancies were deemed 'moderate' or 'high' clinical significance. Omission errors accounted for 55.6% of discrepancies. CONCLUSIONS: A combination of sources is essential to determine the BPMH. RCF charts provided the most accurate information. Other sources had two to four regular medication related discrepancies per patient. PMID- 29609222 TI - Response to the Letter to the Editor by Khullar and colleagues about our manuscript. AB - Cardiovascular involvement is measured by three items in the BILD index, so clearly it can play a role in overall levels of damage accumulation. However, efforts to unravel the impact of traditional versus SLE-specific risk factors remain challenging, and we are unable to examine these relationships with our current data. Moreover, we do not believe that the understanding of what drives cardiovascular disease in persons with SLE has progressed to the point to make this distinction more generally. This article is protected by copyright. All rights reserved. PMID- 29609223 TI - Utility of community-acquired pneumonia severity scores in guiding disposition from the emergency department: Intensive care or short-stay unit? AB - OBJECTIVE: To assess community-acquired pneumonia severity scores from two perspectives: (i) prediction of ICU admission or mortality; and (ii) utility of low scores for prediction of discharge within 48 h, potentially indicating suitability for short-stay unit admission. METHODS: Patients with community acquired pneumonia were identified from a prospective database of emergency patients admitted with infection. Pneumonia severity index (PSI), CURB-65, CORB, CURXO, SMARTCOP scores and the Infectious Diseases Society of America/American Thoracic Society (IDSA/ATS) minor criteria were calculated. Diagnostic accuracy statistics (sensitivity, specificity, predictive values, likelihood ratios and area under receiver operating characteristic curves [AUROC]) were determined for both end-points. RESULTS: Of 618 patients admitted with community-acquired pneumonia judged eligible for invasive therapies, 75 (12.1%) were admitted to ICU or deceased at 30 days, and 87 (14.1%) were discharged within 48 h. All scores effectively stratified patients into categories of risk. For prediction of severe pneumonia, SMARTCOP, CURXO and IDSA/ATS discriminated well (AUROC 0.84-0.87). SMARTCOP and CURXO showed optimal sensitivity (85% [95% confidence interval (CI) 75-92]), while specificity was highest for CORB and CURB-65 (93% and 94%, respectively). Using lowest risk categories for prediction of discharge within 48 h, only SMARTCOP and CURXO showed specificity >80%. PSI demonstrated highest positive predictive value (31% [95% CI 24-39]) and AUROC (0.74 [95% CI 0.69 0.79]). CONCLUSIONS: Community-acquired pneumonia severity scores had different strengths; SMARTCOP and CURXO were sensitive with potential to rule out severe disease, while the high specificity of CORB and CURB-65 facilitated identification of patients at high risk of requirement for ICU. Low severity scores were not useful to identify patients suitable for admission to short-stay units. PMID- 29609224 TI - Emerging Treatment Models in Rheumatology: Challenges for Osteoarthritis Trials. AB - At a time when advancing understanding of osteoarthritis (OA) has created opportunities for new treatments, development of treatments has remained considerably behind advances in other rheumatic diseases. We describe elements of trial design and measurements that have inhibited success and offer suggestions that may help break the log jam. Among the problems with trials that include pain as an outcome measure are reliance on a single, non-optimal pain outcome, overestimation of likely effects of treatments on pain, and failure to identify patient subgroups most likely to respond to specific treatments. With regard to the use of structure modification as an outcome measure, demonstrating structure modification is often highly challenging, even with the use of magnetic resonance imaging. Many OA patients have advanced disease that is unlikely to respond to treatments that prevent cartilage loss. Further, prevention of cartilage loss and reduction of pain correlate weakly at best, and in at least some patients, reduction in pain may actually increase joint damage, making it impossible to demonstrate dual treatment effects on structure and pain in such scenarios. For structure outcomes, treatment effects on pain-sensitive structures such as bone and synovium may be more achievable than preventing cartilage loss. We suggest that changes in trial design related to some of these issues may increase the chances that new exciting and effective OA treatments will become available. PMID- 29609225 TI - Social determinants of mortality in U.S. lupus patients. AB - We read with interest the study by Yelin et al.1 that poverty results in higher mortality in lupus patients by increasing disease damage accumulation. We suggest some alternative mechanisms for the contribution of poverty to higher mortality. First, cardiovascular disease (CVD) is the leading cause of death in lupus patients, and lupus itself is an independent CVD risk factor.2 Risk of CVD specific death has declined and is projected to continue declining due to better control of risk factors such as hypertension and diabetes.3 Second, according to recent guidelines of American College of Cardiology/American Heart Association (ACC/AHA)4 , health insurance is a key enabling factor promoting CVD risk factor management and in turn reducing the likelihood of life-threatening CV conditions (e.g., acute coronary syndrome). This article is protected by copyright. All rights reserved. PMID- 29609226 TI - [Chinese experts consensus on management of artifical graft complications in pelvic reconstrctive surgery]. PMID- 29609227 TI - [Characteristics and prognosis of interrupted inferior vena cava with azygous continuation]. AB - Objective: To explore the clinical characteristics of interrupted of the inferior vena cava with azygous continuation and the prognosis. Methods: Retrospective analysis of 21 fetuses diagnosed with interrupted inferior vena cava with azygous continuation among 28 567 pregnant women who underwent routine ultrasound scan. The clinical data, ultrasonographic features, genetic information and prognosis were collected. Results: Interrupted of the inferior vena cava with azygous continuation occurred in 21(0.07%, 21/28 567) of 28 567 patients. Three fetuses (14%, 3/21) complicated with heart and extracardiac malformations, including endocardiac cushion defect, single atrium and single ventricle, double superior vena cava, dextrocardia, asplenia syndrome, visceral heterotaxy, duodenal atresia; six fetuses (29%, 6/21) were associated with cardiac anomalies, such as hypoplastic left heart syndrome, double outlet right ventricle, pulmonary stenosis, ventricular septal defect, persistent left superior vena cava, endocardiac cushion defect and transposition of the great arteries; six cases (29%, 6/21) were only combined with extracardiac malformations, includingasplenia syndrome, visceral heterotaxy, duodenal atresia. Three fetuses (14%, 3/21) were nonorganic abnormalities included thickening of the right ventricle wall, fetal bradycardia, pericardial effusion, hydrops abdominis, increased peak systolic velocity/end diastolic velocity and single umbilical artery. Three fetuses (14%, 3/21) were isolated interrupted inferior vena cava with azygous continuation, but without other anomalies and 2 of them had normal fetal karyotype. Five cases (24%, 5/21) were successfully vaginal delivery, 1 case (5%, 1/21) had cesarean section. After 12-40 months follow-up, we didn't obeserve obviously abnormality, nor any chromosomal abnormality. Ten patients (48%, 10/21) opted for termination of the pregnancy and the autopsies were not done. Five cases (24%, 5/21) were lost to follow up. Conclusions: Interrupted inferior vena cava with azygous continuation are associated with cardiovascular and extracardiac anomalies, cardiac malformation and visceral heterotaxy are the most common anomalies. Visceral heterotaxy should be considered and fetal karyotype should be suggested. In the cases of isolated interrupted inferior vena cava with azygous continuation and normal karyotype, the outcome is favorable. PMID- 29609228 TI - [Prenatal diagnosis of women with an adverse reproductive history using both traditional karyotyping and SNP-array]. AB - Objective: To explore the occurrence of fetal chromosomal abnormalities among pregnant women with an adverse reproductive history using traditional karyotyping and single nucleotide polymorphism microarray (SNP-array) technology. Methods: Totally 94 in 2 163 (4.35%) cases of singleton pregnant women with an adverse reproductive history were performed amniocentesis in Jinhua Maternal and Child Health Care Hospital from June 2015 to June 2017. Traditional karyotyping and SNP array were employed simultaneously for prenatal diagnosis, and the detection rates of the two methods were compared. Results: All of the 94 specimens were successfully analyzed, 11 cases were found with chromosomal anomaly, the overall detection rate was 11.7%(11/94). Seven (7.4%,7/94) abnormalities cases were detected by karyotyping, and 7(7.4%) by SNP-array. The karyotyping results of trisomy 21, and 45,X and the deletion of chromosome 13 were consistent with SNP array. Only 3 (3.2%, 3/94) microdeletion/duplications (the sizes of duplications and deletions were between 422.4-1 708.4 kb) and 1 (1/4) loss of heterozygosity were detected by SNP-array, but were missed by karyotyping. Furthermore, 2 cases' copy number variation were found pathogenic gene related, while the other 2 were considered benign or variant of uncertain significance. Four cases (4/7) of abnormalities were detected by karyotyping, while confirmed balanced translocation and inversion by SNP-array. All patients were informed and chosen to continue the pregnancy. Conclusions: The rate of abnormal fetal chromosomes in pregnant women with an adverse reproductive history is still high. SNP-array is a new molecular genetic technique, and combined with use of traditional karyotyping, it could improve the detection rate of fetal chromosomal abnormalities and reduce abortion rate, thus providing a basis for genetic counseling and prenatal diagnosis. PMID- 29609229 TI - [Cumulative live birth rates per oocytes retrieved cycle: evaluation of clinical outcomes of IVF/ICSI]. AB - Objective: Using of cumulative live birth rate (CLBR) per oocytes retrieved cycle, to assess the clinical outcomes of in vitro fertilization or intracytoplasmic sperm injection (IVF/ICSI) , and to explore impact factors on CLBR following utilization of all fresh and frozen embryos in one complete IVF/ICSI cycle using gonadotropin-releasing hormone (GnRH) agonist, GnRH antagonist and clomiphene mild stimulation protocols. Methods: Of the patients who underwent IVF/ICSI from January 1st, 2014 to December 31st, 2015 in the First Affiliated Hospital, Nanjing Medical University, a total of 6 142 oocytes retrieved cycles were included. The clinical and laboratory parameters of different ovarian stimulation protocols, and the effects of the age, number of oocytes retrieved and number of embryos available on the CLBR of each oocytes retrieved cycle were analyzed. Results: The CLBR was 69.0% (2 004/2 906) in the GnRH-agonist protocol versus 67.4% (644/955) in the GnRH-antagonist protocol (P>0.05); the CLBR of clomiphene mild stimulation protocol was 53.2% (1 215/2 281) , significantly lower than those of the other two protocols (all P<0.05). The CLBR significantly decreased with age increased. When divided into four groups according to the patients' age, we found that CLBR were not statistically significant using three different protocols in the 20-25 years old group (all P>0.05). There was a strong association between the number of oocytes retrieved and embryos available on CLBR. CLBR rose significantly with an increasing number of oocytes up to 6, then the rising trend slowed down. Patients were categorized into four groups according to the number of oocytes retrieved, CLBR was significantly higher using GnRH-antagonist protocol (50.0%) than mild stimulation protocol (37.0%) in low ovarian responder (0-4 oocytes) group (P<0.05) . The CLBR were no significant difference among three protocols in normal (10-15 oocytes) and high responders (>=15 oocytes) group (all P>0.05) . The incidence rate of ovarian hyperstimulation syndrome in GnRH-agonist protocols (5.2%, 152/2 906) were significantly higher than those of GnRH-antagonist (4.4%, 42/955) and clomiphene mild stimulation protocols (1.5%, 34/2 281; all P<0.05) . Conclusions: CLBR is an important index to assess the clinical outcomes of IVF/ICSI. Age, number of oocytes retrieved and embryos available could affect CLBR obviously. According to the different age and ovarian response of patients, we should design ovarian stimulation protocols based on target oocytes number in order to get higher CLBR and reduce complications. PMID- 29609230 TI - [Role and clinical significance of coagulation and inflammatory factors in moderate and severe ovarian endometriosis]. AB - Objective: To determine the levels of coagulation and inflammatory factors in women with moderate and severe ovarian endometriosis so as to investigate the possible role of coagulation and inflammatory factors in the pathogenesis, diagnosis and treatment of this disease. Methods: From June 2015 and June 2017, clinical data of 366 patients with pathologically diagnosed moderate and severe ovarian endometriosis (case group) and 244 patients with pathologically diagnosed benign ovarian cysts (control group) in Women's Hospital of Zhejiang University School of Medicine were retrospectively analyzed. The levels of coagulation indicators, inflammatory factors and serum tumor markers were measured. Then, the values of these indicators in diagnosis of endometriosis were analyzed. Results: (1) The levels of plasma prothrombin time (PT) and thrombin time (TT) in patients with ovarian endometriosis [median: 12.8 s (range: 12.4-13.2 s) and 15.5 s (range: 15.1-15.9 s), respectively] were significantly shorter than those with benign ovarian cysts [median: 13.0 s (range: 12.5-13.4 s) and 15.7 s (range: 15.3 16.1 s), respectively; allP<0.01]. The levels of plasma fibrinogen (FIB) and D dimer [D-D; median: 3.1 g/L (range: 2.8-3.5 g/L) and 0.9 mg/L (range: 0.6-2.1 mg/L) , respectively] in patients with ovarian endometriosis were significantly higher than those with benign ovarian cysts [median: 2.8 g/L (range: 2.6-3.2 g/L) and 0.6 mg/L (range: 0.4-1.2 mg/L), respectively; P=0.000]. Moreover, neutrophil to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio [PLR; median: 2.3 (range: 1.8-3.1) and 144 (range: 113-179), respectively] in patients with ovarian endometriosis were significantly higher than those with benign ovarian cysts [median: 2.1 (range: 1.6-2.8) and 128 (range: 104-165), respectively; P<0.01]. Furthermore, in patients with ovarian endometriosis, the levels of PT were significantly shorter in stage IV endometriosis than that in stage III endometriosis (P<0.05). The levels of FIB and PLR in patients with stage IV endometriosis were significantly higher than those in patients with stage III endometriosis (P<0.01) . (2) The cut-off value of CA(125) was 27.2 kU/L with a sensitivity of 83.6%, the cut-off value of FIB was 3.1 g/L with a sensitivity of 53.2%, while the sensitivity of combination index (FIB*CA(125)) was 84.9%. Conclusion: The abnormality of coagulation and inflammatory factors may be involved in the pathogenesis of moderate and severe ovarian endometriosis, and the detection of coagulation and inflammatory factors may be have important clinical significance for the diagnosis and treatment of moderate and severe ovarian endometriosis. PMID- 29609231 TI - [Characteristics of invisible cervical intraepithelial neoplasia III under colposcopy]. AB - Objective: To explore the human papilomavirus (HPV) genotypes and epithelial thickness of invisible cervical intraepithelial neoplasia III (CIN III) under colposcopy. Methods: One hundred and sixty-nine biopsies from 93 patients with a final diagnosis of CIN III were extracted from the Shenzhen cervical cancer screening trial II (SHENCCAST II) . The SHENCCAST II was conducted from 2009 to 2010. All the cervical blocks from these patients were re-cut and placed on 6 slides, i.e. sandwich model, with the top and bottom sections being stained with HE, the top second be processed for other studies, 3 sections for HPV genotypes by matrix-assisted laser desorption ionization-time of flight-mass spectrometry (MALDI-TOF-MS) assay. The thickness of squamous epithelium of CIN III was measured by a microscope (*10) after re-cut. Colposcope directed CIN III biopsies positively was defined as visible CIN III, while random CIN III biopsies positively was defined as invisible CIN III. Results: HPV16 positivity was 37.2% (16/43) and 55.6% (70/126) between invisible and visible CIN III biopsies, respectively (chi(2)=4.318, P=0.038) . Forty-nine cases of the 93 CIN III patients were HPV16 positive, while 44 of them non-HPV16 positive. The proportion of patients with >=45 years of age for other non-HPV16 positive 40.9% (18/44) was significantly higher than that HPV16 positive 20.4% (10/49; chi(2)=4.630, P=0.031) . Patients with HPV16 positive were more likely to have lesions >=1 quadrant (chi(2)=7.786, P=0.005) than other non-HPV16 positive. Compared the average epithelium thickness of invisible CIN III tissue (140+/-12) MUm, the average epithelium thickness of visible CIN III tissue (161+/-9) MUm was thicker. There was statistical difference between two groups (t=4.383, P=0.038). The mean average epithelial thickness of CIN III with HPV16 positive (172+/-11) MUm was thicker than that the mean average epithelial thickness of CIN III with non-HPV16 positive (130+/-10) MUm (t=4.784, P=0.031) . Conclusions: Invisible lesions is difficult to identify under colposcopy and is related to non-HPV16 positive, small lesion size and thinner squamous epithelium. For non-HPV16 positive or older women should be performed colposcope directed biopsies and randomly multi sites biopsies by colopscopy, which may be helpful to improve the detection of CIN III and to reduce miss diagnosis. PMID- 29609232 TI - [Clinical significance of loop electrosurgical excisional procedure in diagnosis and treatment of cervical adenocarcinoma in situ and invasive cervical adenocarcinoma]. AB - Objective: To evaluate the accuracy of colposcopic biopsy on diagnosis of cervical adenocarcinoma in situ (AIS) and the clinical significance of loop electrosurgical excisional procedure (LEEP) on diagnosis and treatment of AIS and invasive adenocarcinoma. Methods: All medical records of 193 patients diagnosed as AIS by colposcopic biopsy and (or) AIS or invasive adenocarcinoma diagnosed by LEEP conization from Jan. 2015 to Dec. 2016 in Obstetrics and Gynecology Hospital of Fudan University were retrospectively reviewed. The final diagnosis was based on colposcopic biopsy or LEEP or the highest grade of pathological diagnosis after hysterectomy. Results: In the 193 patients, 155 cases were finally diagnosed as AIS and 38 cases as invasive adenocarcinoma by histopathologic examination. Among the 155 AIS patients, 21.9% (34/155) had positive cone margins, in which 26 patients had hysterectomy, 30.8% (8/26) had residual disease in hysterectomy specimens; 78.1% (121/155) had negative cone margins, 68 patients with negative margins had hysterectomy and 5.9% (4/68) had residual disease, which was significantly lower than that with positive margins (chi(2)=10.46, P=0.001) . One hundred and twenty from one hundred ninty-three (62.3%, 120/193) with AIS were detected by colposcopy. Pathological diagnosis of 50.8% (98/193) cases were upgraded after LEEP conization. Conclusions: Colposcopy is indispensable for the diagnosis of AIS, but accurate diagnosis should be made by LEEP. LEEP is capable of detecting AIS or cervical adenocarcinoma that was misdiagnosed by colposcopy, which is a pivotal method for accurate diagnosis. The margin status of LEEP is important for patients in choosing further hysterectomy, but the presence of cervical adenocarcinoma should always be aware of. PMID- 29609233 TI - [Regulation of pravastatin on long-chain fatty acid oxidative enzyme in pre eclampsia-like mouse model]. AB - Objective: To investigate the modulation of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) expression by pravastatin in pre-eclampsia-like mouse model. Methods: C57BL/6J mice were randomly injected with N-nitro-L-arginine methyl ester (L-NAME) as pre-eclampsia-like model group (PE) or saline as normal pregnancy control group (Con) respectively, from gestational the 7th to 18th day. For each group, pravastatin (PE+Pra, Con+Pra group) or saline (PE+N, Con+N Group) was given from the 8th to 18th day of gestation, respectively. Liver and placenta of pregnant mice were collected on gestational day 18. The LCHAD protein expression and mRNA levels of liver and placenta were detected through western blot, immunohistochemistry and real-time quantitative PCR. Results: (1) The average arterial pressure of pregnant mice increased gradually from the 8th to 18th day in PE+N group, but decreased in PE+Pra group from gestational 10th day, 24 hour urinary protein levels in PE+N group [(1 494 +/- 201) MUg] were significantly higher than that in Con+N group [(935+/-128) MUg, P<0.01], and also higher than that in PE+Pra group [(981+/-116) MUg, P<0.01].(2) The results of western blot: the expression of LCHAD was significantly lower in PE+N group (liver: 0.64+/-0.11, placenta: 0.48+/-0.06) than that in Con+N group (liver: 1.06+/-0.10, placenta: 0.60+/-0.10), and lower than that in PE+Pra group (liver: 0.99+/-0.04, placenta: 0.60+/-0.08; all P<0.01).(3)The results of real-time quantitative PCR: the levels of LCHAD mRNA in liver and placenta in PE+N group (liver: 0.621+/-0.128, placenta: 0.646+/-0.129) were significantly decreased compared with Con+N group (liver: 1.007+/-0.130, placenta: 1.004+/-0.103; all P<0.01), but there was no significant difference between PE+Pra group (liver: 0.693+/-0.678, placenta: 0.662+/-0.183; P>0.05). (4) LCHAD protein was expressed widely and evenly in liver. The expression in placental cytotrophoblast and syncytial trophoblast cells located in outer layer of villous in labyrinth layer was the most. The expression of LCHAD was significantly lower in PE+N group (liver: 0.062+/-0.016, placenta: 0.147+/-0.018) than that in Con+N group (liver: 0.126+/-0.013, placenta: 0.183+/-0.024), and lower than that in PE+Pra group (liver: 0.111+/-0.017, placenta: 0.174+/-0.027; all P<0.05). Conclusion: Pravastatin could upregulate the LCHAD protein expression of liver and placenta in the pre-eclampsia-like mouse, which may be a mechanism to improve the clinical manifestations of pre-eclampsia. PMID- 29609234 TI - [Healthy aging and the progress in the research of geriatric epidemiology]. AB - In recent years, great effort has been made in the promotion of healthy aging in China. The core indicator of a country's healthy aging is the level of body health, mental health, social adaptation and quality of life (QOL) of the elderly. This paper summarizes the concept and the progress in the research of healthy ageing and the leading role of geriatric epidemiology. Articles on column "Pay attention to function and health of elderly" analyze the basic conditions affecting the QOL of the elderly, such as disability, comorbidity and Alzheimer disease prevalence, in the elderly in China and related risk factors to describe the severity of different health problems affecting the QOL of the elderly in different areas of China and provide essential data for developing effective health approaches and conducting targeted intervention foe healthy aging. PMID- 29609235 TI - [Incidence of fall related injury in people aged 50 and above and risk factors in 8 provinces in China: a cross-sectional study]. AB - Objective: To estimate the incidence and distribution characteristics of fall related injury in people aged >=50 years in 8 provinces in China and related physiological, psychological and social risk factors. Methods: Cross-sectional data were collected from adults aged >=50 years participating in the World Health Organization (WHO) study on global ageing and adult health (SAGE) round 1 in China. Two-level hierarchical logistic model was used to identify the related factors for fall-related injury. All the models were stratified by living area (urban/rural). Results: Estimated incidence of fall related injury (road traffic injury was not included) was 3.2%. Ageing and multiple chronic conditions (OR=2.55, 95%CI: 1.41-4.64) was significantly associated with the incidence of fall related injury in urban area. In rural area, depression (OR=4.33, 95% CI: 2.52-7.42) and multiple chronic conditions (OR=2.46, 95%CI: 1.37-4.41) were associated with the incidence of fall related injury. Conclusions: This study estimated the incidence of fall related injury in adults aged >=50 years in 8 provinces in China. A significant association between multiple chronic conditions and fall related injury were found in both urban and rural residents. Targeted measures should be taken for the prevention and control of chronic diseases in elderly population. PMID- 29609236 TI - [Study on self-rated health and related factors in centenarians in Hainan province]. AB - Objective: To investigate the self-rated health and related factors in centenarians in Hainan province. Methods: A cross-sectional study in centenarians from 18 cities and counties was carried out in Hainan between June 2014 and December 2016. They data about their demographics, chronic diseases, ability of daily life, mental health and sleep quality were collected in a household interview. Self-rated health status was classified into 5 degrees according to the subjective assessment by centenarians. Results: Of 991 centenarians in this study, 157 (15.8%) were in good self-rated health and 228 (23.0%) were in poor self-rated health. Multivariate logistic regression analysis showed that chronic pain, visual impairment, depression, limited ability of daily life and poor sleep quality were the factors associated with poor self-rated health in centenarians in Hainan (P<0.05). Conclusion: The proportion of centenarians in good self-rated health was low in Hainan, the influencing factors included chronic pain, visual impairment, depression, poor sleep quality and limited ability of daily life. It is necessary to conduct targeted intervention in centenarians in Hainan. PMID- 29609237 TI - [Evaluation of activities of daily living and related factors in community elderly people in urban and rural areas of Beijing]. AB - Objective: To evaluate the activities of daily living (ADL) and related factors in community elderly people in urban and rural areas of Beijing. Methods: A population-based cross-sectional study was conducted in Haidian and Miyun districts of Beijing using two-stage random cluster sampling method between 2011 and 2014. Results: A total of 4 499 community elderly people (1 815 males, 2 684 females) aged 60-95 years were included in the study. The mean age was (70.3+/ 6.7) years. Compared with the participants from urban area, the participants from rural area had lower education level (85.2% had education level primary school), but higher level of smoking (22.8%) and drinking (43.1%). The ADL disability rate was higher in rural area than in urban area (12.4% vs. 11.8%, P=0.039). And it increased significantly with age (P<0.05). Multivariate logistic regression showed besides urban-rural difference (P=0.031), age (P=0.013), education level (P=0.015), physical activity (P=0.001) and stroke (P<0.001) were related factors influencing ADL disability. Conclusions: The ADL disability was relatively low in the community elderly people in Beijing, and there was significant difference between rural area and urban area. Older age, lower education level and physical inactivity and stroke were related factors. PMID- 29609238 TI - [Associations of obesity and physical activity with cognition in people aged 50 and above in Shanghai]. AB - Objective: To investigate the associations of obesity and physical activity with cognition in the elderly. Methods: A cross-sectional survey was conducted from October 2009 to June 2010 among people aged >=50 years selected through multistage random cluster sampling in Shanghai. The subjects' body weight, body height, waist circumference and hip circumference were measured to calculate body mass index (BMI) and waist-hip ratio (WHR), and the data on self-reported physical activity level were collected through questionnaire survey. A comprehensive battery of cognitive tests was conducted to assess subjects' cognitive functions, including verbal recall, forward digit span (FDS), backward digit span (BDS), and verbal fluency (VF). General linear model was used to examine the associations of BMI, WHR and physical activity with cognition. Results: A total of 7 913 participants were included, with a median age of 60 years. Age, sex, education level, income level, BMI, WHR and physical activity level were significantly associated with cognitive scores in univariate analysis. After adjusted for age, sex, education level and income level, BMI was no longer significantly associated with cognitive scores in all cognitive functions (all P>0.01). WHR was significantly associated with VF score (P<0.01). Abdominally obese participants had lower VF score than non-abdominally obese participants (P<0.01). Physical activity level was significantly associated with all cognitive functions (P<0.01). Compared with participants with moderate physical activity level, participants with low physical activity level had lower scores in all cognitive functions (P<0.01). Conclusion: Abdominal obesity and low physical activity level were negatively associated with cognition level in the elderly, suggesting that waist circumference control and physical activity might help maintain cognition in the elderly. PMID- 29609239 TI - [Prevalence of alcohol drinking in males aged 20-79 years in China, 2012]. AB - Objective: To understand the prevalence of alcohol drinking in 20-79 years old males with different educational backgrounds and smoking behaviors in different areas of China. Methods: A multi-stage cluster random sampling survey was conducted in 150 surveillance sites in 2010-2012 Chinese nutrition and health surveillance in China. At least 1 000 subjects were selected in each surveillance site. Alcohol drinking prevalence and pattern information were collected by using personal health and food frequency questionnaire in face to face interviews. Results: A total of 60 791 males aged 20-79 years were surveyed. The prevalence of alcohol drinking was 57.8% (58.3% in rural area, 57.3% in urban area). The mean daily alcohol intake level was 32.7 g (33.3 g in rural area, 32.1 g in urban area). The rate of almost drinking every day and daily alcohol intake level were highest among males aged 50-59 years. Mean daily alcohol intake level, rate of almost drinking every day and excessive drinking decreased with the increase of education level. Non-smokers had higher rate of never drinking and lower prevalence of drinking and excessive drinking, lower mean daily alcohol intake level, and lower rate of almost drinking every day compared with current and past smokers. Conclusions: Alcohol drinking was common in males aged 20-79 years in China, and, the difference was not obvious between rural residents and urban residents. The differences in daily intake level of different alcohol drinks among males with different characteristics had certain significance. Significant difference in excessive drinking was found among different age groups, those with different education levels and those with different smoking history. PMID- 29609240 TI - [Prevalence of hyperuricemia in the elderly in 7 areas of China]. AB - Objective: To investigate the prevalence of hyperuricemia (HUA) in the elderly in China. Methods: A randomized stratified cluster sampling survey was conducted. And 5 376 residents aged >=60 year in 7 Beijing, Xi'an and Harbin in northern China and Chengdu, Chongqing, Changsha and Shanghai in southern China were surveyed. A unified questionnaire was used to collect their basic information, and blood samples were taken from them to detect the level of plasma uric acid (UA). The differences in hyperuricemia prevalence among different groups were compared with chi(2) test. Results: The mean concentration of plasma UA was 302.8 MUmol/L in the elderly surveyed, 329.5 MUmol/L in males and 282.7 MUmol/L in females, 272.4 MUmol/L in rural residents and 315.5 MUmol/L in urban residents. Our study showed the prevalence of hyperuricemia was 13.1% in the elderly surveyed. The prevalence of hyperuricemia in women (14.1%) was higher than that in men (12.0%) (P<0.05); and the prevalence of hyperuricemia was higher in urban residents (15.8%) than in rural residents (6.9%) (P<0.01); in southern area (16.0%) than in northern area (11.6%) (P<0.01). Both the plasma UA level and the prevalence of hyperuricemia increased with age in those aged >=60 years. The average prevalence of hyperuricemia were 9.5%, 11.9%, 14.5%, 16.4% and 21.9% and the plasma UA levels were 287.7, 295.9, 308.1, 311.6 and 323.3 MUmol/L respectively in age group >=60, 65, 70, 75 and 80 years (P<0.01). Conclusion: The result showed that mean concentration of plasma UA was 302.8 MUmol/L and the overall prevalence of hyperuricemia was 13.1% in the elderly surveyed in China. The prevalence of hyperuricemia in females was higher than in males, in urban residents than in rural residents and in southern area than in northern area. Both the UA level and prevalence of hyperuricemia increased with age. PMID- 29609241 TI - [Potential demand on cancer screening service in urban populations in China: a cross-sectional survey]. AB - Objective: To understand the acceptance and personal demand for cancer screening service among the urban residents who had never been involved in any national level cancer screening programs in China and identify the key factors influencing the sustainability of cancer screening. Methods: A questionnaire survey was conducted among the local people aged 40-69 years selected through convenience sampling in 16 provinces of China to collect the general information about their demands for the screening service and others. Results: A total of 16 394 qualified questionnaires were completed. The average age of the people surveyed was (53.8+/-8.0) years, and men accounted for 44.6%. Without concerning the cost, 4 831 people (29.5%) had no demands for cancer screening services, the reasons are as follow: they would like to go to see doctors only when they were ill (61.8%); they had already received similar medical examinations (36.8%) and they would like to receive cancer screening directly without pre-health risk assessment (33.0%). Among the people surveyed, 10 795 (65.8%) had demands for cancer screening services, but they had choice on the screening settings, 43.7% wanted to receive the service in a general hospitals, while 36.5% would like to go to cancer-specialized hospitals. As for the level of medical institutes providing cancer screening service, 61.4% of the people surveyed would choose a higher level one, while 36.4% would choose an ordinary one. On screening procedures, 61.5% of the people surveyed would accept the mode of "clinical examination after questionnaire-assessment" . Conclusion: Most people surveyed had demands for cancer screening services and they would like to receive the screening services in higher level medical institutes. It is suggested to spread cancer screening know ledge, and strengthen the capability building of screening in grass root medical institutes to attract more people to receive cancer screening. PMID- 29609243 TI - [Study on prevalence of physical activity in rural residents in four counties (districts) of Shanxi and Chongqing]. AB - Objective: To investigate the prevalence of physical activity and its influencing factors in rural residents in Shanxi and Chongqing. Methods: In four counties (districts) of Shanxi and Chongqing, local residents aged >=18 who lived there for more than one year and had no plan to migrate to other areas in 2 years were surveyed through face to face questionnaire interviews to collect the information about their daily physical activity time, sedentary time, related knowledge and attitude, and others. Results: The physical inactivity rate of the residents was 14.9%, and 88.7% of residents never took daily physical activity. The average sedentary time was (3.91+/-2.06) hours. The results of multivariate analysis showed that education level, per capita monthly income and activity degree were the factors influencing physical inactivity. Conclusion: The proportion of people who never took daily physical activity in the survey area was higher than the average level in rural areas in China, so measures should be taken to improve the overall rate of physical activity. For people who have exercise willingness, but have no practice, and those who have already increased their physical activities, targeted guidance is needed on the basis of strengthened health education. PMID- 29609242 TI - [Constituent and workload of service providers engaged in cancer screening: findings and suggestions from a multi-center survey in China]. AB - Objective: To understand the constituent and workload of service providers engaged in cancer screening in China and provide evidence for the assessment of the sustainability of national cancer screening project. Methods: Using either questionnaire or online approach, the survey was conducted in 16 provinces, where Cancer Screening Program in Urban China (CanSPUC) was conducted, from 2014 to 2015. The medical institutes surveyed included hospitals [71.1% were class III(A) hospitals], centers for disease control and prevention (CDCs) and community centers where cancer screening was undertaken during 2013-2015. The questionnaire survey was conducted among the staffs responsible for the overall coordination, management and implementation of the screening project to collect the information about the allocation, workload and compensation of the service providers from different specialties. Results: A total of 4 626 staffs were surveyed in this study, their average age was (37.7+/-9.5) years, and males accounted for 31.0%. Human resources allocated differed with province. The number of senior staff ranged from 6 (Chongqing) to 43 (Beijing) among the 8 comparable provinces. Among the staffs surveyed, 2 192 were from hospitals, 431 were from CDCs and 1 990 were from community centers, and the staffs who complained heavy workload accounted for 19.9%, 24.6% and 34.1% respectively (P<0.001). Among 227 staffs for overall coordination, 376 management staffs and 3 908 staffs for implementation, those who complained heavy workload accounted for 23.6%, 22.3% and 28.2% respectively (P<0.001). A total of 3 244 staffs (73.8%) got compensations for heavy workload. The compensation types were manly labor fee linked with workload (67.5%) and labor fee regardless workload (26.6%). Conclusion: The province specific differences in human resources allocation indicated the differences in screening project's organizing pattern and capability. It is suggested to conduct routine cancer screening (using specialized staffs), reduce the workload of the first line and community staffs and increase the compensation for the service providers for the sustainability of cancer screening project in China. PMID- 29609244 TI - [Relationship between fall and frailty index in elderly adults of urban community in Beijing]. AB - Objective: To evaluate the frailty status and understand the relationship between the incidence of fall and frailty status in the elderly in Beijing. Methods: A cross-sectional study was conducted in old people aged >=60 years in Longtan community of Dongcheng district in Beijing from November 2015 to January 2016. The information about any fall during the past year and frailty status of the elderly were collected with a standardized structured questionnaire in face-to face interviews. The frailty status of elderly people was assessed with frailty index (FI) method. Logistic regression analysis was used to explore the relationship between fall and frailty status among the elderly. Results: Among 1 557 old people surveyed, the incidence of fall was 17.8% (277/1 557) during the past year. The incidence of fall in women (21.0%, 192/277) was statistically higher than that in men (13.3%, 85/277) (chi(2)=15.288, P=0.000). The median (quartile) value of FI of the elderly surveyed was 0.09 (0.08); and women had a higher FI median value than men [0.10 (0.08) versus 0.08 (0.07)](Z=5.376, P=0.000). The median FI value (quartile range) of 277 old people with history of fall in previous year was 0.12 (0.11), which was higher than the median FI value of 0.08 (0.07) of 1 280 old people without fall history (Z=7.501, P=0.000). Logistic regression analysis showed that higher FI value was associated with more risks for fall; and FI value showed the greatest impact on the incidence and frequency of fall (OR=1.093, 2.234) compared with other related factors of fall, such as age and gender. Conclusion: Frailty status has a greater impact on both incidence and frequency of fall compared with other factors in elderly people in Beijing; more attention should be paid to weak and old adults in the prevention of fall. PMID- 29609245 TI - [Association between maternal body height and risk of preterm birth]. AB - Objective: To investigate the association between maternal body height and risk of preterm birth. Methods: A total of 11 311 pregnant women who gave birth of live singletons were recruited from the Healthy Baby Cohort Study in Hubei province, China from September 2012 to October 2014. Finally 11 070 pregnant women were selected as study subjects. Data were collected by using questionnaires, their prenatal care records and medical records. The women were divided into 4 groups according to the quartiles distribution (<158 cm, 158- cm, 160- cm, and >164 cm). Gestational age was estimated according to maternal last menstrual time. Preterm birth was defined as delivering a live singleton infant at 28-37 weeks' gestational age. Logistic regression was used to calculate the odds ratios (OR) and 95% confidence intervals (CI) for the association between body height and preterm birth. Results: Among the 11 070 pregnant women, the incidence of preterm birth was 5.9%. Logistic regression analysis indicated that women in group with body height <158 cm had 46% (OR=1.46, 95%CI: 1.16-1.83) higher risk of giving preterm birth than those in group with body height >164 cm after adjustment for potential confounders. Every 1- cm increase in body height was associated with 3% lower risk of preterm birth (OR=0.97, 95%CI: 0.95-0.99). Conclusion: Shorter body height was a risk factor for preterm birth. It is necessary to strengthen the monitoring in pregnant women with short body height to reduce the risk of preterm birth. PMID- 29609246 TI - [Effect of interpregnancy interval of childbearing aged women on birth weight of single live birth neonates]. AB - Objective: To understand the effect of interpregnancy interval (IPI) of childbearing aged women on the birth weight of single live birth neonates in Shaanxi province. Methods: A questionnaire survey was conducted among the childbearing aged women selected through multistage stratified random sampling in Shaanxi during 20l0-2013, all the childbearing aged women had definite pregnancy outcomes. The interpregnancy interval of the childbearing aged women and the birth weight of the newborns were used as the independent variables and dependent variables respectively in multiple linear regression model and quantile regression model, and confounding factors were controlled. Results: A total of 13 063 women at childbearing age and their infants were investigated. The incidence of low birth weight and macrosomia was 3.54% and 7.62% respectively. Multiple linear regression analysis showed that there was no significant difference in birth weight among different IPI group and control group. Quantile regression analysis showed when birth weight was at 5 percentiles, the difference in birth weight between newborns whose mothers had short interpregnancy interval (<12 months) and those in control group was significant, when the birth weight was >=90 percentiles, the birth weights of newborns whose mothers had long interpregnancy interval (60-119 months) were higher than those in control group, the difference was significant. As the increase of the percentiles of birth weight, the extent of changes gradually increased. Conclusion: The analysis indicated that both short (<12 months) and long (60-119 months) interpregnancy interval would had negative effects on birth weights of newborns. Therefore, planning for pregnancy is important for having a good perinatal outcome. PMID- 29609247 TI - [Stratified sampling survey of major human parasitic diseases in Henan province]. AB - Objective: To understand the prevalence of major human parasitic diseases and related factors in Henan province. Methods: This stratified sampling survey was carried out according to the requirement of national survey protocol of major human parasitic diseases, 2014-2015. The prevalence of soil-transmitted helminths infection, taeniasis and intestinal protozoiasis were surveyed in 104 sites selected from 35 counties (districts) and the prevalence of clonorchiasis was surveyed in 62 sites selected from 37 townships. In each survey spot, 250 persons were surveyed. A total of 26 866 persons and 15 893 persons were surveyed. Modified Kato-Katz thick smear was used to detect the eggs of intestinal helminthes. Tube fecal culture was used to identify the species of hookworm. The Enterobius eggs were detected in children aged 3 to 6 years by using adhesive tape. The cyst and trophozoite of intestinal protozoa were examined with physiological saline direct smear method and iodine stain method. Results: The overall infestation rate of intestinal parasites was2.02% in Henan, and the worm infection rate was higher than protozoa infection rate. Fourteen kinds of intestinal parasites were found, including nematode (5 species), trematode (2 species), and protozoan (7 species). The infection rate of Enterobius vermicularis was highest, and Qinba Mountain ecological area had the highest infestation rate of intestinal parasites in 4 ecological areas of Henan. There was no significant difference in intestinal parasite infection rate between males and females (chi(2)=3.630, P=0.057), and the differences in intestinal parasite infection rate among different age groups had significance (chi(2)=124.783, P=0.000 1). The infection rate reached the peak in age group <=9 years and the major parasite was Enterobius vermicularis. Furthermore the overall human infection rate of parasite showed a downward trend with the increase of educational level of the people (chi(2)=70.969, P=0.000 1), the differences had significance (chi(2)=120.118, P=0.000 1). For different populations, the infection rate of intestinal parasites was highest among preschool children. The infection of intestinal helminth was mainly mild, only 2 severe cases were detected. The infection rate of Clonorchis sinensis in urban residents was only 0.006%. Logistic regression analysis showed that being preschool children (chi(2)=15.765, P=0.000 1) and drinking well water (chi(2)=45.589, P=0.000 1) were the risk factors for intestinal parasite infection, and annual income per capita of farmers was the protective factor against intestinal parasite infection. The infection rates of protozoa and intestinal parasites decreased sharply compared with the results of previous two surveys, and the rate of intestinal helminth infection also dropped sharply compared with the second survey. The numbers of protozoa, helminth and intestinal parasites detected in this survey were all less than the numbers found in the previous two surveys. Conclusions: Compared the results of three surveys in Henan, the infection rate of protozoa and intestinal parasites showed a downward trend. The prevention and treatment of Enterobius vermicularis infection in children should be the key point of parasitic disease control in the future. PMID- 29609248 TI - [Prevalence of HIV infection and syphilis and related behaviors in clients in Ya'an of Sichuan province]. AB - Objective: To understand the prevalence of HIV infection and syphilis in clients in Ya'an of Sichuan province. Methods: A survey was conducted in clients recruited through snowball method in Ya'an of Sichuan from April 2014 to December 2015. The information of the clients, including basic demography characteristics, AIDS knowledge awareness, high-risk behaviors and others, were collected through face-to-face interviews. Blood sample (5 ml) was taken from each client to test antibodies against HIV and syphilis. Statistical software SPSS 18.0 was used for data analysis. Results: Among the 708 clients, the constituent ratio of those aged >=50 years was 51.27% (363/708), those in Han ethnic group was 99.72% (706/708), those with junior high school educational level or below was 90.11% (638/708), those who got married or cohabitated with others was 74.15% (525/708), and those who used condoms at each sex was 27.40% (194/708). Seven HIV positive cases were detected and 4 cases were aged >=50 years. Seven syphilis cases were detected and all the cases were aged >=50 year. No HIV-syphilis co-infection case was detected. The prevalence of HIV infection and syphilis were all 0.99% (95%CI: 0.30%-1.70%). Results from the multivariate logistic regression analysis showed that the clients who had their first commercial sex behavior at age <30 years (OR=6.61, 95%CI: 1.09-40.18) would have higher HIV positive rate. Conclusion: The rate of condom use was low in the clients in Ya'an and they didn't pay enough attention to their self-protection in sexual activities. Especially the clients aged >=50 years were with low educational level and had high risk commercial sexual behaviors for HIV infection and syphilis. Close attention needs to be paid to them. PMID- 29609249 TI - [Investigation of a measles outbreak caused by genotype D8 virus in Pinghu city of Zhejiang province, 2017]. AB - Objective: To investigate the epidemiological characteristics of measles outbreak caused by genotype D8 virus in Pinghu city of Zhejiang province, and provide evidence for the control of the outbreak. Methods: The measles outbreak data were collected through National Measles Surveillance System. The outpatient records and admission records were checked, field investigation and outbreak response were conducted. Blood samples in acute phase and swab specimens were collected from the patients for laboratory testing, including serology test, RNA extraction and amplification, measles virus isolation and genotype identification. Software SPSS 17.0 and Excel 2016 were used for data analysis. Results: A total of 10 confirmed measles cases were reported in Pinghu city, and 8 cases were aged >40 years. Six blood samples were collected, in which 5 were measles D8 virus positive and 1 was negative in measles virus detection. There were epidemiological links among 10 cases which occurred in a factory, a hospital and a family at the same time. There was no statistical difference in symptoms among cases caused by D8 virus and H1a virus. After the emergent measles vaccination, the measles outbreak was effectively controlled. Conclusion: Untimely response due to the uneasy detection of measles cases in the early stage, nosocomial infection and weak barrier of measles immunity in adults might be the main reasons for this outbreak. Measles vaccination is effective in the prevention of measles D8 virus infection. It is necessary to strengthen measles genotype monitoring for the tracing of infection source and control of outbreaks. PMID- 29609250 TI - [Epidemiological characteristics and molecular typing of typhoid and paratyphoid in China, 2009-2013]. AB - Objective: To understand the epidemiological and molecular characteristics of typhoid and paratyphoid in China from 2009 to 2013, and provide evidence for the prevention and control of typhoid and paratyphoid, the development and improvement of surveillance strategies. Methods: Epidemiological analysis was conducted on the incidence data of typhoid and paratyphoid, and related public health emergencies in China during 2009-2013. Pathogen isolation and culture, serologic test were conducted for the typhoid and paratyphoid cases from 13 national surveillance sites. The isolates were subjected to antimicrobial susceptibility testing. Pulsed-field gel electrophoresis (PFGE) was performed for the molecular typing of these isolates. Results: The average incidence of typhoid and paratyphoid in China during this period was 1.03/100 000. The reported case number and incidence decreased with year. The provinces reporting high case numbers were Yunnan, Guizhou, Guangxi, Hunan, Zhejiang, Guangdong and Xinjiang. The incidence of age group 0-4 years was highest. The proportion of farmers and children outside child care settings showed an increasing tendency over time. The annual incidence peak was during July-August. Twenty five outbreaks occurred during 2009-2013. The results of pathogen isolation and culture showed that the positive rate was 3.00% (940/31 322), among the positive isolates, the proportion of Salmonella paratyphi A accounted for higher proportion (68.19%, 641/940) compared with Salmonella typhi (31.60%, 297/940). The drug resistances of Salmonella typhi and Salmonella paratyphi varied, but their resistances to nalidixic acid were highest (50.22% and 85.33%) respectively. A certain amount of Salmonella typhi isolates showed the resistance to the 3rd generation cephalosporins. PFGE analysis showed divergent patterns of Salmonella typhi compared with limited patterns of Salmonella paratyphi A. Conclusion: The epidemic level of typhoid and paratyphoid in China was relatively low, but the outbreak occurred occasionally. It is necessary to enhance the laboratory-based surveillance, particularly the capability of etiological diagnosis, outbreak investigation, response and antibiotic resistance monitoring, and conduct risk factor investigation in provinces with high incidences in recent years. PMID- 29609251 TI - [Epidemiological characteristics of Coxsackie virus A16 caused hand foot and mouth disease cases in Guangdong province, 2012-2016]. AB - Objective: To analyze the epidemiological characteristics of hand foot and mouth disease (HFMD) cases caused by Coxsackie virus A16 (Cox A16) in Guangdong province from 2012 to 2016. Methods: The data of mild HFMD cases caused by Cox A16 were collected from 8 sentinel hospitals in 8 prefecture-level cities in Guangdong to estimate Cox A16 infection status and its population and time distribution characteristics. Results: (1) The highest estimated incidence of Cox A16 infection was in 2014 (113.0/100 000), followed by 2016 (86.4/100 000) and 2012 (79.1/100 000), while the estimated incidence was lower in 2015 (29.0/100 000) and 2013 (28.8/100 000). (2) Cox A16 was confirmed to be the predominant pathogen causing HFMD outbreaks (54.6%, 89/163). The number of outbreaks in the year with high incidence (28 outbreaks) was 11.2 times higher than that in the year with low incidence (2.5 outbreaks). (3) Across all age groups, the annual estimated incidence of Cox A16 infection decreased with age (trend chi(2)=853 905.63, P<0.01). The incidence was highest in age group 1 year (1 449.2/100 000), followed by that in age group 3 years (1 097.0/100 000), in age group 2 years (1 083.5/100 000), in age group 4 years (687.8/100 000) and in age group 0 year (604.9/100 000). Among the age groups <12 months, the estimated incidence increased with age (trend chi(2)=5 541.77, P<0.01), which was highest in age group 11-months (2 105.1/100 000), followed by that in age groups 10-months (1 448.6/100 000), 9-months (938.3/100 000), 8-months (703.3/100 000) and 6-months (664.6/100 000). (4) The annual incidence peak was during May (143.9/100 000) June (131.5/100 000). Conclusion: The prevalence of Cox A16 infection differed with year in Guangdong during 2012-2016. When the incidence of Cox A16 infection was high, more outbreaks occurred. The prevalence occurred mainly in nurseries and kindergartens from May to June each year. Children aged 0-4 years were the high risk group for Cox A16 infection, children aged 6-11 months were at high risk for Cox A16 infection. PMID- 29609252 TI - [Spatial distribution characteristics of tuberculosis and its visualization in Qinghai province, 2014-2016]. AB - Objective: To analyze the spatial distribution of tuberculosis (TB) and identify the clustering areas in Qinghai province from 2014 to 2016, and provide evidence for the prevention and control of TB. Methods: The data of pulmonary TB cases confirmed by clinical and laboratory diagnosis in Qinghai during this period were collected from National Disease Reporting Information System. The visualization of annual reported incidence, three-dimensional trend analysis and local Getis Ord G(i)(*) spatial autocorrelation analysis of TB were performed by using software ArcGIS 10.2.2, and global Moran's I spatial autocorrelation analysis were analyzed by using software OpenGeoDa 1.2.0 to describe and analyze the spatial distribution characteristics and high incidence areas of TB in Qinghai from 2014 to 2016. Results: A total of 20 609 pulmonary TB cases were reported in Qinghai during this period. The reported incidences were 101.16/100 000, 123.26/100 000 and 128.70/100 000 respectively, an increasing trend with year was observed (trend chi(2)=187.21, P<0.001). The three-dimensional trend analysis showed that the TB incidence increased from northern area to southern area, and up-arch trend from the east to the west. Global Moran's I spatial autocorrelation analysis showed that annual reported TB incidence in different areas had moderate spatial clustering (Moran's I values were 0.631 3, 0.605 4, and 0.587 3, P<0.001). And local G(i)(*) analysis showed that there were some areas with high TB incidences, such as 10 counties of Yushu and Guoluo prefectures (Gande, Banma and Dari counties, etc., located in the southwest of Qinghai), and some areas with low TB incidences, such as Huangzhong county, Chengdong district and Chengbei district of Xining city and Dachaidan county of Haixi prefecture, and the reported TB incidences in the remaining areas were moderate. Conclusion: The annual reported TB incidence increased year by year in Qinghai from 2014 to 2016. The distribution of TB cases showed obvious spatial clustering, and Yushu and Guoluo prefectures were the key areas in TB prevention and control. In addition, the spatial clustering analysis could provide the important evidence for the development of TB prevention and control measures in Qinghai. PMID- 29609253 TI - [Study on early warning threshold values for 7 common communicable diseases in Gansu province, 2016]. AB - Objective: To optimize the warning threshold values of common communicable diseases in Gansu province, and improve the early warning effect. Method: An early warning model was set up for influenza, scarlet fever, other infectious diarrheal diseases, dysentery, typhoid and paratyphoid, viral hepatitis type E and hand foot and mouth disease (HFMD) respectively in Gansu by using the moving percentile method and cumulative sum method. By calculating the sensitivity, specificity, predictive value of positive test, predictive value of negative test, Youden' index and receiver-operating characteristic curve, the optimum early warning threshold values for communicable diseases in Gansu were selected. Results: The optimum early warning boundary values of influenza, scarlet fever, other infectious diarrheal diseases, dysentery, typhoid and paratyphoid, and viral hepatitis type E were P(90), P(80), P(95), P(90), P(80) and P(90) respectively. The optimum early warning parameters of HFMD were k=1.2, H=5sigma. Under the optimum early warning boundary values/parameters, the early warning sensitivities of influenza, scarlet fever, other infectious diarrheal diseases, dysentery, typhoid and paratyphoid, viral hepatitis type E and HFMD were 86.67%, 100.00%, 91.67%, 100.00%, 100.00%, 100.00% and 100.00%, the specificities were 86.49%, 62.22%, 75.00%, 100.00%, 97.92%, 89.13% and 74.47%. The predictive values of positive test were 72.22%, 29.17%, 52.38%, 100.00%, 80.00%, 54.55% and 29.41%, and the predictive values of negative test were 94.12%, 100.00%, 96.77%, 100.00%, 100.00%, 100.00% and 100.00%, and the Youden' indexes were 0.73, 0.62, 0.67, 1.00, 0.98,0.89 and 0.74. Receiver-operating characteristic curve showed that the values/parameters of this warning boundary were the points closest to the upper left of the coordinate diagram. Conclusion: The early warning thresholds of influenza, other infectious diarrheal diseases, dysentery and hepatitis E in Gansu may be raised appropriately and the early warning parameters of HFMD need to be adjusted to improve the effectiveness of early warning. PMID- 29609254 TI - [Effect of health literacy and exercise-focused interventions on glycemic control in patients with type 2 diabetes in China]. AB - Objective: To evaluate the effect of health literacy and exercise-focused interventions on glycemic control in patients with type 2 diabetes (T2DM) in China. Methods: In this cluster randomized controlled trial, a total of 799 T2DM patients with most recent hemoglobin A1c (HbA1c) >= 7.5% (or fasting plasma glucose level >=10 mmol/L) were recruited from 8 communities in Minhang and Changning districts of Shanghai, and randomized into a health literacy intervention group, an exercise intervention group, a comprehensive intervention group and a control group. After baseline survey and examination, a one-year intervention and 3 times (at 3(rd), 6(th), and 12(th) month) follow-up surveys were conducted. Results: The follow-up rates for all the subjects were 99.4%, 98.4% and 95.2%, respectively, at 3(rd), 6(th) and 12(th) month. Patients in intervention groups were more likely to achieve a goal HbA1c level (HbA1c <7.0%) than those in control group, with the highest glycemic control rate (25.3%) observed in comprehensive intervention group at 3(rd) month and then in exercise intervention group (25.3% and 34.6%) respectively, at 6(th) month and 12(th) month. The average levels of HbA1c in three intervention groups were lower at each follow-up time point than those at baseline survey. However, the decreases in HbA1c were obvious only at 6(th) month (P<0.001), with ls-mean (95%CI) of 0.48% (-0.71%, -0.25%), -0.33% (-0.55%, -0.11%) and -0.70% (-0.92%, -0.48%), respectively, in comprehensive, health literacy and exercise intervention groups, but it increased slightly by 0.03% (-0.19%, 0.25%) in control group. Compared with control group, the interventions were significantly associated with the decrease of HbA1c level, with the most improvement observed in comprehensive group (beta=-0.47, 95% CI: -0.73, -0.20) at 3(rd) month, and in exercise intervention group at 6(th) month (beta=-0.73, 95%CI: -0.98, -0.47) and at 12(th) month (beta=-0.75, 95%CI: -1.05, -0.45) of follow-up. Stratified analyses showed that patients with lower health literacy level could benefit from any intervention, while those with higher numeracy skill benefited more from exercise intervention. Conclusion: Both health literacy and exercise-focused interventions may decrease HbA1c level in patients with T2DM, which would be helpful in reducing the risks of complications and deaths in diabetes patients. PMID- 29609255 TI - [Trends in 30-day case fatality rate in patients hospitalized due to acute myocardial infarction in Beijing, 2007-2012]. AB - Objective: To understand the distribution and trends in 30-day coronary heart disease (CHD) case fatality rate in patients hospitalized due to acute myocardial infarction (AMI) in Beijing during 2007-2012. Methods: The clinical data of patients hospitalized due to AMI in Beijing from 1 January 2007 to 31 December 2012 were collected from "The Cardiovascular Disease Surveillance System in Beijing" . A total of 77 943 local patients aged >=25 years were hospitalized due to AMI in Beijing during the this period. After excluding duplicate records and validation for the completeness and accuracy of the records, the clinical characteristics of the patients and 30-day CHD case fatality rate in the patients were analyzed. Trends in 30-day CHD case fatality rate in the patients were analyzed with Poisson regression models. Results: The age-standardized average 30 day CHD case fatality rate was 9.7% in the 77 943 patients. During this period, a decreasing trend was observed in 30-day CHD case fatality rate after adjusting for age and gender (P<0.001). The age-standardized 30-day CHD case fatality rate decreased by 16.0%, from 10.8% in 2007 to 9.0% in 2012. The decreases of 30-day CHD case fatality rates were noted in both men and women, whereas 30-day CHD case fatality rate was higher in women (14.1%) than in men (7.6%) after adjusting for age. During this period, the proportion of ST-segment elevation myocardial infarction (STEMI) decreased, while the proportion of non-ST-segment elevation myocardial infarction (NSTEMI) increased with year. A significant decline (20.1%) in 30-day case fatality rate of STEMI was found, but no decline was found for 30 day mortality rate of NSTEMI. Conclusion: A decreasing trend in 30-day CHD case fatality rate was observed in the patients aged >=25 years and hospitalized due to AMI in Beijing during 2007-2012, indicating the improvement in short-term prognosis of patients hospitalized due to AMI. Our findings highlight the urgent need to improve the treatment for woman and NSTEMI patients. PMID- 29609256 TI - [Application of generalized estimation equations to establish prediction equation for tuberculosis drug resistance in Zhejiang province]. AB - Objective: Drug-resistant tuberculosis (TB) may be resistant to one or multiple anti-TB drugs. We used generalized estimation equations to analysis the risk factors of drug-resistant TB and provide information for the establishment of a warning model for these non-independent data. Methods: The drug susceptibility test and questionnaire survey were performed in sputum positive TB patients from 30 anti TB drug-resistance surveillance sites in Zhejiang province. The generalized estimation model was established by the GENMOD module of SAS, with resistance to 13 kinds of anti-TB drugs as dependent variables and possible influencing factors, such as age, having insurance, HBV infection status, and history of anti-TB drug intake, as independent variables. Results: In this study, the probability of drug resistance at baseline level was 20.26%. Age, insurance, whether being co-infected with HBV, and treatment history or treatment withdrawal were statistically significantly correlated with anti-TB drug resistance. The prediction equation was established according to the influence degree of the factors mentioned above on drug resistance. Conclusion: The generalized estimation equations can effectively and robustly analyze the correlated binary outcomes, and thus provide more comprehensive information for drug resistance risk factor evaluation and warning model establishment. PMID- 29609257 TI - [Series of risk of bias assessment (5): Risk Of Bias In Non-randomized Studies-of Interventions (ROBINS-I)]. AB - This paper summaries the Risk Of Bias In Non-randomized Studies-of Interventions (ROBINS-I), a tool for evaluating risk of bias about Non-randomized Studies-of Interventions (NRSI), and introduces the application of ROBINS-I in a published NRSI. According to the characteristics of NRSI, evaluation field and signaling question were designed in ROBINS-I to provide essential information about risk of bias for NRSI included in systematic reviews. ROBINS-I is the tool in assessment of risk of bias in observational studies and quasi-randomised studies. Although the tool has been used in practice to some extent, but it still needs further improvement. Attention should be paid to its update and progress. PMID- 29609258 TI - [Progress in research of human microbiota for upper gastrointestinal tumors and precancerous lesions]. AB - With the widely application of the metagenomics, the relationship between microbiota and disease has become a hot research topic. Understanding the potential association between upper gastrointestinal cancer or precancerous lesions and microbiota may play an important role in the early detection, clinical diagnosis and treatment, and prognostic evaluation of upper gastrointestinal cancer. Therefore, a literature retrieval was conducted by using PubMed, Embase and wanfang databases to summarize the latest research progress in the microbiota of upper gastrointestinal cancer, including oral, esophageal, gastric cancer and precancerous lesions. Lower microbial diversity or richness in esophageal cancer and precancerous lesions and specific prognostic biomarkers for esophageal cancer were found. Lactobacillus richness showed an increase trend during the process from gastritis to gastric cancer. This paper summarizes the progress in the research of potential biological etiology of upper gastrointestinal cancer from the perspective of metagenomics in order to provide evidence on the, prevention and control of upper gastrointestinal cancer. PMID- 29609259 TI - [Progress in next-generation sequencing research of non-syndromic oral clefts]. AB - Non-syndromic oral clefts (NSOC) are among the most common birth defects. The prevalence of NSOC is 1.13-1.30 per 1 000 live births in China, which is higher than those in other major ethnic groups. The etiology of NSOC is complex and heterogeneous, which involves both genetic and environmental risk factors. Although genome-wide association studies have identified a number of risk loci, these loci can only account for a small proportion of the heritability of NSOC. The next-generation sequencing research provides new ideas for further exploring the genetic risk factors of NSOC. This paper summaries the progress in the next generation sequencing research of NSOC. PMID- 29609260 TI - [The controversy of synthetic mesh in pelvic floor reconstruction]. PMID- 29609261 TI - [Reliability and validity of the simplified Chinese version of the fecal incontinence quality of life questionnaire in the patients with fecal incontinence]. AB - Objective: To develop the Chinese version of the fecal incontinence quality of life (FIQL) questionnaire, and to validate them in Chinese population. Methods: Our study included 52 cases recruiting from outpatients diagnosed with fecal incontinence in Peking Union Medical College Hospital, fecal incontinence in Beijing City nursing homes for the elderly, and patients received perineal repair surgeries who suffered from perineal laceration and laceration in in Peking Union Medical College Hospital from October 2013 to 2016 December.The Original English Fecal Incontinence Quality of Life scale questionnaires were translated into Chinese and they were linguistically validated following the Cross-cultural adaptation of health-related quality of life measures.The reliability and validity of the Chinese version of FIQL questionnaires in Chinese population were evaluated. Results: Fifty-two patients completed the FIQL and the SF-12 questionnaires, as well as Cleveland Clinic Incontinence Score.The Cronbach's alpha of FIQL was 0.949, test-retest reliability ICC was 0.437-0.866. FIQL scores were positively correlated with SF-12 (Spearman correlation coefficient was 0.588, P<0.01) and negatively correlated with Cleveland Clinic Incontinence Score (Spearman correlation coefficient was -0.617, P<0.01). Factor analysis showed that there were 6 common factors in FIQL. Conclusions: Chinese version of FIQL have high reliability and validity in Chinese population, there fore it is suitable for clinic and research. PMID- 29609262 TI - [Multiple factors analysis of early postpartum pelvic floor muscles injury in regenerated parturients]. AB - Objective: To investigate the risk factors for multiparous pelvic floor muscles injury during 6-8 weeks after delivery. Method: From June 2015 to April 2017, 1917 women (1 523 primigravidas and 294 multiparas) were accepted postpartum pelvic floor function screening during 6-8 weeks after delivery in Beijing Hospital.Pelvic examination and pelvic floor muscle strength testing were carried out in these women.All the data were analyzed with multivariate logistic regression method to explore the related factors for postpartum pelvic floor muscle injury. Result: The incidence of muscle strength grades less than third grade was 63.60 % (type I muscle fiber) and 24.83 % (type II muscle fiber). Multivariate analysis showed that time interval, between two deliveries, less than 3 years (OR=2.16, 95%CI 1.21-3.86), and maternal BMI<18.5 (OR=3.04, 95%CI 1.10-9.30) and BMI>=28 (OR=3.04, 95%CI 1.10-9.30) before pregnancy were risk factors for postpartum injury of type I muscle fiber. Gestational age more than 40 weeks increased the risk of damaging type II muscle fiber (OR=2.79, 95%CI 1.156-6.76). Compared with cesarean section, vaginal delivery significantly increased the risk of injury of type I and II pelvic floor muscle fibers (P<0.05). Conclusion: The incidence of multiparous pelvic floor muscle injury was high in early postpartum period.Several factors are related to the pelvic floor muscle injury.Pelvic floor rehabilitation in early postpartum and maternal education may be helpful to reduce the radio of injury. PMID- 29609263 TI - [Evaluation of pelvic floor function of postpartum pelvic floor ultrasound in pregnant women with multiple pregnancies]. AB - Objective: To probe the effect of multiple pregnancy on pelvic floor function of pregnant women, Pelvic floor ultrasonography was performed on the 42 day postpartum women.And the bladder neck mobility, bladder and urethral posterior angle and pelvic diaphragmatic hiatus area were measured. Methods: Collect 200 cases 42 day postpartum women who visited the second hospital of Jilin University from July 2015 to June 2017, of which 100 cases of primipara belong to group A, 100 cases of multiple pregnancy belong to group B, and 100 cases without maternal at the same age belong to the control group, ultrasound measurement of the bladder neck mobility, bladder and urethral posterior angle and pelvic diaphragmatic hiatus area were measured.t test were proformed respectively between the three groups, P<0.05 was considered statistically significant difference. Results: In the control group, the bladder neck mobility is (2.59+/ 0.51) cm , the bladder neck mobility in A group is (2.99+/-0.69) cm, the bladder neck mobility in B group is (3.36+/-0.71) cm; the bladder and urethral posterior angle in the control group is (112.56+/-13.61) degrees , the bladder and urethral posterior angle in the control group after Valsalva action angle is(135.37+/ 12.17) degrees , the bladder and urethral posterior angle in A group is(119.26+/ 15.80) degrees , the bladder and urethral posterior angle in group A after Valsalva action is(141.79+/-12.08) degrees , the bladder and urethral posterior angle in B group is(123.62+/-16.20) degrees , the bladder and urethral posterior angle in group B after Valsalva action is (148.92+/-13.60) degrees ; the pelvic diaphragmatic hiatus area in the control group is (13.35+/-2.86) cm(2,) the pelvic diaphragmatic hiatus area in the control group after Valsalva action is(15.28+/-3.15) cm(2,) the pelvic diaphragmatic hiatus area in A group is(17.52+/-3.19) cm(2,) the pelvic diaphragmatic hiatus area in A group ater Valsalva action is (18.06+/-5.13_the pelvic diaphragmatic hiatus area) cm(2,) the pelvic diaphragmatic hiatus area in B group is (18.26+/-4.18) cm(2,) the pelvic diaphragmatic hiatus area in B group after Valsalva action is (20.3+/-3.53) cm(2).In group A, group B and the control group, the measured value of the bladder neck mobility, bladder and urethral posterior angle and pelvic diaphragmatic hiatus area were examined by t test, and P<0.05, which means the difference was statistically significant. Conclusion: Pregnancy can affect the function of female pelvic floor, and the effect of parturient is more significant than that of the primipara. PMID- 29609264 TI - [Long-term prognosis of coronary artery disease with atrial fibrillation after percutaneous coronary intervention]. AB - Objective: To investigate the long-term prognosis of coronary artery disease with atrial fibrillation (AF) after percutaneous coronary intervention (PCI). Methods: A total of 10 724 patients with PCI were enrolled in 2013, and 2-year clinical outcomes in patients with AF (AF group) and without AF (non-AF group) were compared. Results: A total of 113 patients were with AF (1.1%), and 8 out of them were on triple antithrombotic therapy (9.5%), and AF group patients were with more complications. The 2-year follow-up results showed that the all-cause mortality in AF group was significantly higher than that in non-AF group (9.7% vs 1.1%; P<0.001). The incidence of cardiac death, stent thrombosis and stroke was also significantly higher in patients with AF. The incidence of major adverse cardiac and cerebrovascular events (MACCE) was also significantly higher in AF group compared with non-AF group (17.7% vs 8.8%; P<0.001), whereas the incidence of revascularization was significantly lower in the AF group than in the non-AF group (2.7% vs 8.7%; P=0.023). The incidence of myocardial infarction and bleeding had no significant difference between the two groups, and the adverse events between the two groups had no significant difference after propensity score (PS) either. Conclusions: The 2-year clinical follow-up of single-center, large-sample PCI patients shows poor prognosis in patients with AF compared with the non-AF patients. But there is no difference in the prognosis between the two groups after PS, however, this conclusion still needs to be confirmed by randomized controlled studies. PMID- 29609265 TI - [Relationships between percentage of skeletal muscle mass and cardiorespiratory fitness in elderly patients with coronary heart disease]. AB - Objective: To determine the relative percentage of skeletal muscle mass (SMM) in elderly patients with coronary heart disease, analyse the relationship between percentage of SMM and cardiorespiratory fitness (CRF), predict exercise capacity and cardiac reserve. Methods: Patients aged 65 years and over after PCI, receiving cardiopulmonary exercise testing (CPET) during February 2014 to December 2016 in Department of Cardiology at Peking University Third Hospital were enrolled.All patients' basic data, percentage of SMM and CPET related parameters, including peak oxygen uptake (VO(2)peak), oxygen pulse (VO(2)/HR), oxygen uptake efficiency slope (OUES) and other cardiorespiratory endurance indicators were collected, to do correlation analysis. Results: There were 402 patients enrolled, with average age (71+/-5) years, including 283 cases of male (70.40%) and 119 cases of female patients (29.60%). There were 62 patients with acute myocardial infarction (15.42%), 113 patients with old myocardial infarction (28.11%), and 227 patients diagnosed with angina pectoris (56.47%). The percentage of SMM was correlated to CRF.The percentage of SMM[97.00 (92.05, 102.10)%] and VO(2)/HR (r=0.231, P<0.001) and OUES (r=0.264, P<0.001) were positively correlated.Body mass index was negatively correlated with VO(2)peak(r= 0.162, P=0.001). Visceral fat area (VFA) was also negatively correlated with VO(2)peak(r=-0.126, P=0.016). Multiple linear regression analysis showed that Body mass index and VFA were negatively correlated with VO(2)peak (r=-0.204, P=0.014; r=-0.031, P=0.013). The percentage of SMM was positively independently correlated with OUES(r=11.020, P<0.001). Conclusions: Muscle content is positively correlated with exercise capacity of patients.The percentage of skeletal muscle mass determines the core index of cardiorespiratory fitness, such as the slope of oxygen pulse and oxygen uptake efficiency.These indexes can be used as an important criterion for predicting and guiding rehabilitation exercise in patients with coronary heart disease. PMID- 29609266 TI - [Biomechanical behaviors of cervical spinal cord injury related to various bone fragment impact velocities: a finite element study]. AB - Objective: To establish a three-dimensional (3D) finite element (FE) model of the whole cervical spinal cord (WSCS) and explore the biomechanical behaviors of cervical spinal cord injury related to different bone fragment impact velocities by FE analysis. Methods: A 3D FE model of WCSC was established based on the morphologic data of each segment of the human cervical cord. The reconstruction structures, which included the dura mater, the cerebrospinal fluid, the gray and white matter in the C(2) to C(7) cervical vertebrae, were validated.On the validated WCSC model, three kinds of pellets with same mass (7 g) but different impact areas (314, 157 and 78.5 mm(2)) were created to represent the bone fragments.These were positioned in the middle of the spinal cord to impact at various initial velocities.The maximum of von Mises stress and the reduction of the cross-sectional area (CSA) of the spinal cord were measured from each impact. Results: The compression of WCSC (percentage) and the time to reach maximum compression were similar with the results reported in literatures, indicating the validity of the model.Regardless of the impact areas of the pellet, the maximum of von Mises stress and the reduction of CSA of the spinal cord increased with the increased velocity.The maximum of von Mises stress was 5.0-7.0 kPa at a pellet velocity of 1.5 m/s, and the reduction of CSA was 9.3%-12.3%.At a velocity of 3.5 m/s, the maximum of von Mises stress was 42-54 kPa and the reduction of CSA was over 30%.The stress of the spinal cord significantly increased when pellet velocity exceeded 3.5 m/s, and the fastest increase was recorded at 4.5 m/s.The von Mises stress of the spinal cord ranged between 240 and 320 kPa at a velocity of 6.0 m/s, and CSA decreased by more than 50%. Conclusion: The 3D FE model of WSCS could provide more insights on the biomechanical mechanisms of spinal cord injury through various bone fragment impacts in burst fracture.When the impact velocity of the bone fragment exceeds 3.5 m/s, the maximum stress significantly increases and the reduction of CSA of the spinal cord is over 30%, and this could possibly lead to the contusion injury of the spinal cord. PMID- 29609267 TI - [Effects of sural nerve nutrition vess els-supported flap for reconstruction of distal lower leg and ankle soft tissue defects]. AB - Objective: To observe the effects of sural nerve nutrition vessels-supported flap for reconstruction of distal lower leg and ankle soft tissue defects. Methods: From June 2014 to June 2017, 37 patients with calf distal and ankle soft tissue defect were repaired with sural nerve nutrition vessels-supported flap, of them 12 cases with calf distal soft tissue defect wounds and 25 cases with ankle soft tissue defect wounds.The scope of flaps was 9 cm*4 cm to 18 cm*9 cm, anti infection, anti-freezing and dressing treatments were carried out after operation.The results of two-point discrimination among reexamination were recorded. Results: All the flaps survived without ulcer and effusion, only 1 flap for reconstruction of medial malleolus swelled and deactivated at the beginning while it recovered with proper dressings.During the follow-up periods, all the flaps kept favorable feelings, aspects and functions, and the two-point discrimination was 5 to 15 mm [averaged (11.2+/-1.7) mm]. Conclusion: Sural nerve nutrition vessels-supported flap brings significant effects with excellent safety and reliability in repairing calf and ankle soft tissue defects. PMID- 29609268 TI - [Expressions and clinicopathologic significance of Id2 and NF-kappaB/P65 in gastric cancer]. AB - Objective: To investigate the expressions and clinicopathologic significance of Id2 and NF-kappaB/P65 in gastric cancer. Methods: Immunohistochemistry was used to detect Id2 and NF-kappaB/P65 expressions in gastric cancer tissues of 336 cases and paraneoplastic normal mucosa tissues of 60 cases.The expressions of Id2 and NF-kappaB/P65 in gastric cancer were significantly higher than those in normal mucosa tissues (chi(2)=44.631, P<0.001; chi(2)=34.650, P<0.001). Results: The positive expression rates of Id2 and NF-kappaB/P65 were 71.4% (240/336) and 56.3% (189/336) in cancer tissues, and 26.7%(16/60) and 15.0%(9/60)in normal tissues, respectively.Id2 and NF-kappaB/P65 were all related to tumor size, differentiation degree, infiltrative depth, lymphatic invasion, distant metastasis and clinical TNM stage (P<0.05). The 5-year survival rate of the patients with Id2 or NF-kappaB/P65 expression was lower than that of patients with negative Id2 or NF-kappaB/P65 expression (chi(2)=52.329, P<0.001; chi(2)=20.525, P<0.001). Id2 expression in gastric cancer was positively correlated with the NF-kappaB/P65 expression (r=0.292, P<0.001). And the NF kappaB/P65 expression in the Id2 positive group is significantly higher than that in the group with negative Id2 (chi(2)=28.681, P<0.001). The final multivariate Cox regression model indicated that Id2 expression was an independent prognostic factor for overall survival after operation (HR=2.327, 95%CI 1.622-3.337, P<0.001). Conclusions: Id2 and NF-kappaB/P65 may synergistically promote the generation and evolution of gastric cancer, and their co-detection can be of great importance for clinical assessment of tumor biological behavior and prognosis in patients with gastric cancer. PMID- 29609269 TI - [Network correlation of circRNA-miRNA and the possible regulatory mechanism in acute myocardial infarction]. AB - Objective: Using microarray technology, to research characteristic circRNA and miRNA expression profile of acute myocardial infarction (AMI), and then explore the role of these circRNA and miRNA in gene regulation. The aim is to explore the mechanism of development of AMI. Methods: The patients hospitalized in the Cardiovascular Research Center of the First Affiliated Hospital of Xinxiang Medical University between November 2016 and January 2017 were included and divided into control group and AMI group according to diagnostic criteria. We collected their whole blood and extracted the total RNA, and the expression profiles of circRNA and microRNA genes in peripheral blood of AMI were analyzed by gene chip. We predicted circRNA which was possible to combine with miRNA, and drew a network diagram, and the differentially expressed circRNA was analyzed by GO and Pathway. Results: There was difference in circRNA expression profile between the control group and the AMI group. The results showed: (1) a total of 1 670 circRNA had differential expressions, and in the analysis of miRNA expression, 13 miRNA had differential expressions (P<0.05, fc>=2); (2) multiple circRNAs-miRNAs were involved in the occurrence of AMI; (3) the analysis of GO and Pathway for differentially expressed circRNAs showed that many pathways, disease and function participated in it. Conclusion: CircRNA, as an important post transcriptional regulator, is closely related to the development of AMI with miRNA. PMID- 29609270 TI - [Effect of alpha7nAChR mediated cholinergic anti-inflammatory pathway on inhibition of atrial fibrillation by low-level vagus nerve stimulation]. AB - Objective: To investigate the effect of alpha7nAChR mediated cholinergic anti inflammatory pathway on inhibition of atrial fibrillation by low-level vagus nerve stimulation(LL-VNS). Methods: Eighteen beagles were randomized into control group (n=6), LL-VNS group (n=6) and methyllycaconitine (MLA) + LL-VNS group (n=6). All the beagles were subjected to rapid atrial pacing at 800 beats/min for 6 hours.And the effective refractory period (ERP) of atriums and pulmonary veins and induced atrial fibrillation (AF) were measured hourly during non-pacing.After cessation of pacing for 3 hours, the beagles in control group were injected with saline into four ganglionated plexis (GPs), the beagles in LL-VNS group were given LL-VNS and saline injected into four GPs, and the beagles in MLA+ LL-VNS group were injected with MLA into four GPs combined with LL-VNS.And the levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and acetylcholine (ACh) in the plasma at baseline condition, 3 h and 6 h were measured.At the end of this experiment, atrial tissues were collected to examine the levels of TNF alpha, IL-6, ACh, NF-kappaBp65 and STAT3 proteins. Results: During the right atrium pacing for the first 3 hours, the ERPs were gradually decreased while AF inducibility were gradually increased in all groups. At the end of this experiment, compared with the control group and MLA+ LL-VNS group, the ERPs in LL VNS group were increased, and the induced times and duration of AF were significantly decreased. The levels of TNF-alpha and IL-6 in plasma were all significantly decreased in LL-VNS group and MLA+ LL-VNS group when compared with the control group(pg/ml) [IL-6: (101+/-6) vs (119+/-7), P<0.05; (102+/-5) vs (119+/-7), P<0.05; TNF-alpha: (17.8+/-1.7) vs (22.1+/-2.0), P<0.05; (17.9+/-2.2) vs (22.1+/-2.0), P<0.05]. And the levels of ACh were higher than in the control group(MUg/ml)[(151+/-13) vs (123+/-10), P<0.05; (145+/-5) vs (123+/-10), P<0.05]. After cessation of pacing for 6 hours, compared with the control groupand MLA+ LL VNS group, the tissue levels of TNF-alpha and IL-6 were significantly decreased in LL-VNS group (P<0.05). The concentrations of NF-kappaBp65 proteins in atrial tissues were lower in the LL-VNS group (P<0.05), and the levels of STAT3 proteins in those tissues were higher in the LL-VNS group than in thein the two other groups (P<0.05). Conclusion: LL-VNS could inhibit the atrial electrical remodeling and atrial fibrillation induction; cholinergic anti-inflammatory pathway mediated by alpha7nAChR may be the important mechanism in vagal nerve regulated AF. PMID- 29609271 TI - [Killing effect of Robo1 targeted Chimeric Antigen Receptor modified NK92 cells against glioma and neuroblastoma cells]. AB - Objective: To study the cytotoxicity of Robo1-CAR-NK92 cells against U87-MG and SH-SY5Y cells, to explore the effects of IL-15, IL-21 and dexamethasone on the proliferation, survival and cytotoxicity of Robo1-CAR-NK92 cells and to optimize the culture protocol. Methods: Robo1-CAR-NK92 cells were constructed by lentivirus transfection.The Robo1 car positive cells were sorted, expanded and detected by flow cytometry.The levels of Robo1 expression in SH-SY5Y and U87-MG cells were examined by flow cytometry.The cytotoxicity of Robo1-CAR-NK92 or NK92 cells against target cells was tested by CCK-8 and live cell imaging. The levels of cytokines in the supernatant of cultured cells during the cytotoxicity assay were quantified by the multiplex bead-array assay.NK92 and Robo1-CAR-NK92 cells (4*10(4)/ml) were treated with 25 ng/ml of IL-15, 25 ng/ml of IL-21 and/or 50 nmol/L dexamethasone for 3 days and were stained with trypan blue to acquire the viable cell numbers and survival rates. Results: Robo1-CAR-NK92 cells were constructed and tested 98.89% positive after sorting and expansion. While 88.14% of U87-MG cells were Robo1 positive, there were 99.75% of Robo1 positive SH-SY5Y cells.The specific lysis of Robo1-CAR-NK92 cells against target cells was significantly higher than that of NK92 cells (P<0.05). Robo1-CAR-NK92 cells obviously secreted more cytokines including IL-6, IL-10, TNF-alpha and IFN-gamma than parental NK92 cells during cytotoxic activity against U87-MG cells (P<0.05). IL-15 significantly increased the proliferation and survival of Robo1-CAR-NK92 cells, but IL-21 played the opposite role.Remarkably, IL-21 and IL-15+ IL-21 enhanced the cytotoxicity of NK92 and Robo1-CAR-NK92 cells.The combination of dexamethasone and interleukins dramatically promoted the proliferation and survival but obviously impaired the cytotoxicity of NK92 and Robo1-CAR-NK92 cells (except that IL+ 15 and dexamethasone have no effect on the cytotoxicity of Robo1 CAR-NK92 cells). Conclusions: Compared to parental NK92 cells, Robo1-CAR-NK92 cells exhibited more potent targeted killing against glioma and neuroblastoma cells.Collectively, treatment of IL-15 and dexamethasone was the optimized protocol for culture of Robo1 CAR NK cells during our experimental time. PMID- 29609272 TI - [Discipline construction is the theme of the development of burn surgery]. AB - Discipline construction is the core element of department development, including discipline structure setting, scale, equipment, medical workers structure, clinical feature and advantage, talent training, teaching level, scientific research level, management system, and cultural construction of department. As leader and engine of discipline construction, directors' ability is an important factor for discipline construction. Clinical characteristic is the basis of discipline construction; innovation actuation is the essence of discipline construction; talents training is the guarantee of discipline construction; scientific research is the wing of discipline construction; cultural construction is the hot spring of discipline construction. Discipline construction is the theme of the development of burn surgery. PMID- 29609273 TI - [Talking about the discipline construction and development of burn from five ideas]. AB - Discipline construction is an important aspect of hospital modernization management and construction. The level of medical treatment, education, and scientific research could be assured and improved through discipline construction, which could speed up the talent training, promote science and technology innovation, and realize the sustainable development of hospital. At present, most of the hospital management models adopt the two ranks of the hospital and department. The manager of a department must grasp medical treatment, education, scientific research, and discipline construction steadily. The author talks about the discipline construction and development of burn from " five ideas" for the readers. PMID- 29609274 TI - [Practice and thinking about the establishment and management of burn intensive care unit]. AB - The treatment of critically burned patients has benefited from the development of knowledge and technologies that we got in critical care medicine of our country in the past ten years. The close-ended management model of general intensive care unit (ICU) and the idea of general ICU doctors who treat the monitoring of organ function and alternative therapy of organs as their primary tasks would affect the treatments for special critical patients hospitalized in general ICU, especially for those patients who were severely burned. If the burn wounds of patients are not treated timely, properly or in effective manner, the final treatment outcome would be affected. Therefore, the establishment of burn ICU is necessary. The development and close-ended management of burn specialty ICU has significantly improved the success rates, reduced complications, shortened hospitalization time, and increased the quality of wound healing of severe burn patients in the past more than 10 years in our unit. With the reducing of burn, especially severe burn accidents, the construction of regional burn center and burn specialty ICU locating in burn center is necessary. It can not only reduce the waste of medical resource, but also ensure timely and professional treatments for the patients in sudden fire accidents. At present, there is no consensus on the establishment and management model of burn specialty ICU, and further discussion is needed in practice. PMID- 29609275 TI - [Innovation drive is the original motive force of discipline construction: the developing road of Department of Burns and Plastic Surgery in the 309th Hospital of PLA]. AB - Discipline construction is a systematic project, covering clinic, teaching, scientific research, management, and humanity. Based on the perspective of innovation drive, from the aspects of discipline structure setting, specialized laboratory construction, sub-specialty formation, clinical characteristic and advantage formation, and management concept update, this article summarizes the growth process of Department of Burns and Plastic Surgery in the 309th Hospital of PLA. PMID- 29609276 TI - [Influence of three-level collaboration network of pediatric burns treatment in Anhui province on treatment effects of burn children]. AB - Objective: To explore the influence of three-level collaboration network of pediatric burns in Anhui province on treatment effects of burn children. Methods: The data of medical records of pediatric burn children transferred from Lu'an People's Hospital and Fuyang People's Hospital to the First Affiliated Hospital of Anhui Medical University from January 2014 to December 2015 and January 2016 to September 2017 (before and after establishing three-level collaboration network of pediatric burns treatment) were analyzed: percentage of transferred burn children to hospitalized burn children in corresponding period, gender, age, burn degree, treatment method, treatment result, occurrence and treatment result of shock, and operative and non-operative treatment time and cost. Rehabilitation result of burn children transferred back to local hospitals in 2016 and 2017. Data were processed with t test, chi-square test, Mann-Whitney U test, and Fisher's exact test. Results: (1) Percentage of burn children transferred from January 2014 to December 2015 was 34.3% (291/848) of the total number of hospitalized burn children in the same period of time, which was close to 30.4% (210/691) of burn children transferred from January 2016 to September 2017 (chi(2)=2.672, P>0.05). (2) Gender, age, burn degree, and treatment method of burn children transferred from the two periods of time were close (chi(2)=3.382, Z=-1.917, -1.911, chi(2)=3.133, P>0.05). (3) Cure rates of children with mild, moderate, and severe burns transferred from January 2016 to September 2017 were significantly higher than those of burn children transferred from January 2014 to December 2015 (chi(2)=11.777, 6.948, 4.310, P<0.05). Cure rates of children with extremely severe burns transferred from the two periods of time were close (chi(2)=1.181, P>0.05). (4) Children with mild and moderate burns transferred from the two periods of time were with no shock. The incidence of shock of children with severe burns transferred from January 2014 to December 2015 was 6.0% (4/67), and 3 children among them were cured. The incidence of shock of children with severe burns transferred from January 2016 to September 2017 was 3.9% (2/51), and both children were cured. The incidences and cures of shock of children with severe burns transferred from the two periods of time were close (chi(2)=0.006, P>0.05). Incidence of shock of children with extremely severe burns transferred from January 2014 to December 2015 was 57.1% (32/56), significantly higher than that of burn children transferred from January 2016 to September 2017 [34.5% (10/29), chi(2)=3.925, P<0.05]. Shock of 25 children with extremely severe burns transferred from January 2014 to December 2015 were cured, and shock of 9 children with extremely severe burns transferred from January 2016 to September 2017 were cured. The cures of shock of children with extremely severe burns transferred from the two periods of time were close ( chi(2)=0.139, P>0.05). (5) Time of operative treatment of children with moderate, severe, and extremely severe burns transferred from January 2014 to December 2015 was obviously longer than that of burn children transferred from January 2016 to September 2017 (t=2.335, 2.065, 2.310, P<0.05). Time of operative treatment of children with mild burns transferred from the two periods of time was close (Z= 0.417, P>0.05). Costs of operative treatment of children with moderate and severe burns transferred from January 2014 to December 2015 were significantly more than those of burn children transferred from January 2016 to September 2017 (Z=-3.324, t=2.167, P<0.05). Costs of operative treatment of children with mild and extremely severe burns transferred from the two periods of time were close (t=0.627, 0.808, P>0.05). (6)Time of non-operative treatment of children with mild, moderate, and severe burns transferred from January 2014 to December 2015 was obviously longer than that of burn children transferred from January 2016 to September 2017 (t=2.335, Z=-2.095, t=2.152, P<0.05). Time of non-operative treatment of children with extremely severe burns transferred from the two periods of time was close (t=0.450, P>0.05). Costs of non-operative treatment of children with moderate and severe burns transferred from January 2014 to December 2015 were obviously higher than those of burn children transferred from January 2016 to September 2017 (Z=-2.164, t=2.040, P<0.05). Costs of non-operative treatment of children with mild and extremely severe burns transferred from the two periods of time were close (t=0.146, 1.235, P>0.05). (7) Sixty-seven burn children transferred from January 2016 to September 2017 were transferred back to local hospitals for rehabilitation under the guidance of experts of the First Affiliated Hospital of Anhui Medical University, with 25 patients in 2016 and 42 patients in 2017. Effective rehabilitation rates of burn children transferred back to local hospitals for rehabilitation in 2016 and 2017 were both 100%. Conclusions: The three-level collaboration network of pediatric burns treatment in Anhui province can effectively increase cure rate of children with mild, moderate, and severe burns, reduce incidence of shock of children with extremely severe burns, shorten time of operative treatment of burn children with moderate, severe, and extremely severe burns, and time of non-operative treatment of children with mild, moderate, and severe burns, reduce treatment costs of children with moderate and severe burns, and improve rehabilitation effectiveness of children transferred from Lu'an People's Hospital and Fuyang People's Hospital to the the First Affiliated Hospital of Anhui Medical University. PMID- 29609277 TI - [Analysis of distribution and drug resistance of pathogens of burn patients during 9 years]. AB - Objective: To investigate distribution and drug resistance of pathogens of burn patients. Methods: A total of 3 357 strains were cultured and isolated from 25 286 specimens of wounds excretion, deep venous catheters, venous blood, stool, mid-stream urine, sputum, puncture fluid, and throat swab of 11 510 burn patients hospitalized in our burn wards from January 2007 to December 2015. After being identified by API bacteria identification panels and automatically bacteria identification equipment, drug-resistances of Staphylococcus aureus, Pseudomonas aeruginosa, Acinetobacter baumannii, and Klebsiella pneumoniae to 28 common antibiotics were tested by drug sensitivity test with K-B paper disk diffusion method. The WHONET 5.6 software was used to analyze constituent ratio of gram negative bacteria and gram-positive bacteria in each year, distribution of pathogens in each year, and drug resistance of the above-mentioned 4 pathogens in 9 years to 28 common antibiotics. Data were analyzed by the linear model curve fitting. Results: (1) From 2007 to 2015, constituent ratios of gram-negative bacteria were respectively 41.22% (101/245), 41.88% (165/394), 45.92% (169/368), 42.54% (208/489), 52.35% (267/510), 56.89% (194/341), 58.99% (210/356), 56.95% (172/302), and 50.28% (177/352), with significantly increasing trend (R(2)=0.625, P<0.05); constituent ratios of gram-positive bacteria were respectively 58.78% (144/245), 58.12% (229/394), 54.08% (199/368), 57.46% (281/489), 47.65% (243/510), 43.11% (147/341), 41.01% (146/356), 43.05% (130/302), 49.72% (175/352), with significantly decreasing trend (R(2)=0.625, P<0.05). In 9 years, constituent ratio of Staphylococcus aureus ranked the first in all bacteria, and constituent ratios of Pseudomonas aeruginosa and Klebsiella pneumoniae were with significantly increasing trend (R(2)=0.811, 0.778, P<0.01). (2) In 9 years, drug resistant rates of Staphylococcus aureus to gentamycin and rifampicin were with significantly decreasing trend (R(2)=0.727, 0.766, P<0.01); drug-resistant rates of Staphylococcus aureus to phosphonomycin were always in lower levels of 4.6% to 19.5%. In 9 years, drug-resistant rates of Pseudomonas aeruginosa to ceftazidime and ciprofloxacin had no significant change in trend (R(2)=0.023, <0.001, P>0.05), while drug-resistant rates of Pseudomonas aeruginosa to other 10 common antibiotics were with significantly increasing trend (R(2)=0.764, 0.793, 0.785, 0.768, 0.752, 0.749, 0.789, 0.786, 0.706, 0.629, P<0.01). In 9 years, drug resistant rate of Acinetobacter baumannii to ampicillin/sulbactam was with significantly decreasing trend (R(2)=0.652, P<0.01), and drug-resistant rate of Acinetobacter baumannii to amikacin was with significantly increasing trend ( R(2)=0.531, P<0.05). In 9 years, drug-resistant rates of Klebsiella pneumoniae to piperacillin, ampicillin/sulbactam, cefuroxime, ceftazidime, cefotaxime, cefepime, imipenem, meropenem, amikacin, and gentamicin were with obviously increasing trend (R(2)=0.481, 0.672, 0.694, 0.532, 0.810, 0.641, 0.809, 0.709, 0.579, 0.810, P<0.05 or P<0.01). Conclusions: Constituent ratios of gram-positive bacteria of Pseudomonas aeruginosa and Klebsiella pneumoniae of burn patients hospitalized in our burn wards from 2007 to 2015 were significantly increased, while constituent ratios of Staphylococcus aureus of those children always ranked the first. Drug-resistence of bacteria of those children in our burn wards was serious. Drug-resistant rate of Staphylococcus aureus only to phosphonomycin was always in lower level. Drug-resistant rates of Pseudomonas aeruginosa to 10 common antibiotics except ceftazidime and ciprofloxacin were significantly increased. Drug-resistant rate of Acinetobacter baumannii only to ampicillin/sulbactam was significantly decreased. Drug-resistant rates of Klebsiella pneumoniae to most common antibiotics were significantly increased. PMID- 29609278 TI - [Influence of WeChat platform on the compliance of continuous treatment of scar in adult burn patients]. AB - Objective: To explore influence of the WeChat platform on the compliance of continuous treatment of scar in adult burn patients. Methods: A total of 124 adult burn patients, conforming to the study criteria, admitted in the Department of Burns of our hospital from January 2015 to January 2016 were divided into WeChat group (n=63) and control group (n=61) according to the random number table. Patients in control group only received regular discharging rehabilitation guide, while patients in WeChat group received regular discharging rehabilitation guide and joined WeChat platform after being discharged from hospital. Through pushing rehabilitation plan and rehabilitation related knowledge, organizing support discussion of burn patients, answering the patients' questions, members of WeChat platform intervention group conducted continuous treatment for 6 months on patients of WeChat group. The compliance of functional exercise of patients in two groups in one week before discharge and 3 and 6 months after discharge was evaluated by using the self-made functional exercise compliance log sheet. The compliance of using anti-scar drug and appliance of patients in two groups in 3 and 6 months after discharge was evaluated by using self-made anti-scar drug and appliance usage log sheets. Data were processed with chi-square test, independent sample t test, non-parametric rank sum test of independent sample, and Wilcoxon rank sum test. Results: (1) The compliance ratio of functional exercise of patients in WeChat group (95.24%, 60/63) was close to 93.44% (57/61) in control group in one week before discharge (chi(2)=0.188, P>0.05). The compliance ratios of functional exercise of patients in WeChat group were respectively 93.65% (59/63) and 87.30% (55/63) in 3 and 6 months after discharge, which were higher than 68.85% (42/61) and 65.57% (40/61) in control group (chi(2)=12.615, 8.166, P<0.01). (2) The compliance of using anti-scar drug of patients in WeChat group was significantly better than that in control group in 3 and 6 months after discharge (Z=-4.150, -4.563, P<0.01). (3) The compliance of using anti-scar appliance of patients in WeChat group in 3 and 6 months after discharge was obviously better than that in control group (Z=-4.242, -4.301, P<0.01). Conclusions: By using WeChat platform to provide guide for scar rehabilitation continuous treatment, adult burn patients have better compliance to functional exercise and usage of anti-scar drug and appliance. PMID- 29609279 TI - [Qualitative research on pain experiences of adult burn patients]. AB - Objective: To explore the pain experiences of adult burn patients so as to lay foundation for practical analgesic measures. Methods: Using phenomenological method in qualitative research, semi-structured interviews were conducted on 12 adult burn patients hospitalized in our burn units from May to November 2015, aiming at pain experiences from immediately after burns to 3 to 7 months after being discharged from hospital. Then the Colaizzi's analysis method was applied to analyze, induce, and refine themes of interview data. Results: After analysis, pain experiences of adult burn patients were generalized into 6 themes: deep pain experiences, heavy psychological burden, limited daily life, poor assessment and treatment of pain, different attributions of pain, and different ways of coping of pain. Conclusions: Burn pain brings harm to the patients' physiology, mentality, and daily life. Nevertheless, pain processing modes of medical staff and patients themselves are the key factors affecting patients' pain experiences. Therefore, according to the deficiency of current situation of pain management, the targeted analgesic intervention measures should be carried out from the perspectives of medical staff and patients. PMID- 29609280 TI - [Advances in the research of relationship between brown or beige fat and hypermetabolism after severe burn]. AB - Hypermetabolism is one of the remarkable characteristics of burn injury. Prolonged hypermetabolism causes insufficient energy supply, which leads to delayed wound healing, immune system dysfunction, increased infection rate, and multi-organ failure. In recent years, it is concerned that the activation of brown or beige adipose tissue may be related to hypermetabolism in severe burn patients. Brown or beige adipose tissue could be regulated by stress hormones and some cytokines which increase and persist in high level for several months after severe burn. This paper reviews the current knowledge of brown or beige adipocytes developmental lineages, molecular regulation mechanism, and regulation of brown or beige adipocytes activation after severe burn. PMID- 29609281 TI - [Advances in the research of antibacterial properties of silver ion and its application in wound treatment]. AB - Nowadays, antibacterial products containing silver ion are widely used in clinical wound treatment. The concentration of silver ion in products, pH value, and other factors may affect the release of silver ion and its antibacterial effects. In the treatment of clinical wound, silver ion product plays a good role in anti-infection, promoting healing and reducing medical expenses. In this paper, the related applications of silver ion products in wound surface are analyzed, and the antibacterial properties of silver ion and its therapeutic effects in wound treatment are summarized. PMID- 29609282 TI - [Advances in the research of dermabrasion in burn wounds]. AB - The process of burn wounds healing includes the removal of necrotic tissue, the hyperplasia of granulation tissue and epithelialization. The removal of necrotic tissue is the first step in dealing with burn wounds. Although there are a variety of adjuvant drugs for removing necrotic tissue, surgical debridement is still the main way of debridement of burn wounds. Surgical debridement of burn wounds includes escharectomy, tangential excision and dermabrasion. Escharectomy and tangential excision have been widely used in clinical practice, while dermabrasion has not been known to the majority of burns colleagues. This article summarizes the clinical application and progress of dermabrasion in burn wounds. PMID- 29609283 TI - [Wet cement skin burns]. AB - Under certain condition, wet cement can cause skin chemical burns, which belongs to alkaline burns. As the symptoms are insidious in onset, the patients may be initially unaware of the injury until several hours later. It often causes full thickness burns especially in knees, the lower limbs, and ankles. The prevalence of wet cement burns may be hugely underestimated. This article reviews the definition, occurrence, progress of injury and pathogenesis, clinical characteristics and diagnosis, and treatment and prevention of wet cement skin burns, in order to promote its prevention. PMID- 29609284 TI - Semipolar InGaN quantum-well laser diode with integrated amplifier for visible light communications. AB - GaN-based semiconductor optical amplifier (SOA) and its integration with laser diode (LD) is an essential building block yet to be demonstrated for III-nitride photonic integrated circuits (PICs) at visible wavelength. This paper presents the InGaN/GaN quantum well (QW) based dual-section LD consisting of integrated amplifier and laser gain regions fabricated on a semipolar GaN substrate. The threshold current in the laser gain region was favorably reduced from 229mA to 135mA at SOA driving voltages, VSOA, of 0V and 6.25V, respectively. The amplification effect was measured based on a large gain of 5.7 dB at VSOA = 6.25V from the increased optical output power of 8.2 mW to 30.5 mW. Such integrated amplifier can be modulated to achieve Gbps data communication using on-off keying technique. The monolithically integrated amplifier-LD paves the way towards the III-nitride on-chip photonic system, providing a compact, low-cost, and multi functional solution for applications such as smart lighting and visible light communications. PMID- 29609285 TI - Linear self-focusing of continuous UV laser beam in photo-thermo-refractive glasses. AB - The experimental and theoretical study of continuous UV laser beam propagation through thick silver-containing photo-thermo-refractive glass is presented. It is shown for the first time that self-action of UV Gaussian beam in glass results in its self-focusing. The observed linear effect is non-reversible and is caused by the transformation of subnanosized charged silver molecular clusters to neutral state under UV laser radiation. Such transformation is accompanied by the increase of molecular clusters polarizability and the refractive index increase in irradiated area. As a result, an extended positive lens is formed in glass bulk. In a theoretical study of linear self-focusing effect, the "aberration free" approximation was used, taking into account spatial distribution of induced absorption. PMID- 29609286 TI - Comparison of metal/polymer back reflectors with half-sphere, blazed, and pyramid gratings for light trapping in III-V solar cells. AB - We report on the fabrication of diffraction gratings for application as back contact reflectors. The gratings are designed for thin-film solar cells incorporating absorbers with bandgap slightly lower than GaAs, i.e. InAs quantum dot or GaInNAs solar cells. Light trapping in the solar cells enables the increase of the absorption leading to higher short circuit current densities and higher efficiencies. We study metal/polymer back reflectors with half-sphere, blazed, and pyramid gratings, which were fabricated either by photolithography or by nanoimprint lithography. The gratings are compared in terms of the total and the specular reflectance, which determine their diffraction capabilities, i.e. the feature responsible for increasing the absorption. The pyramid grating showed the highest diffuse reflection of light compared to the half-sphere structure and the blazed grating. The diffraction efficiency measurements were in agreement with the numerical simulations. The validated model enables designing such metal/polymer back reflectors for other type of solar cells by refining the optimal dimensions of the gratings for different wavelength ranges. PMID- 29609287 TI - Experimental demonstration of multi-Gbps multi sub-bands FBMC transmission in mm wave radio over a fiber system. AB - The filter bank multicarrier (FBMC) modulation format is considered as a potential candidate for future wireless 5G due to its feature of high suppression for out-of-band emissions, which allows combining multiple sub-bands with very narrow band-gaps, and hence increases the overall wireless transmission capacity. In this paper, we experimentally demonstrate the generation of multi sub-bands FBMC signals at millimeter-wave (mm-wave) for radio-over-fiber (RoF) systems. The designed multi sub-bands FBMC system consists of 5 sub-bands of 800 MHz with inter sub-band gaps of 781.25 kHz. The composite 5 sub-bands FBMC signal is generated with no band-gap between dc to the first sub-band to preserve the bandwidth of the system. Each FBMC sub-band consists of 1024 sub-carriers and is modulated with uncorrelated data sequences. The aggregate FBMC signal is carried optically by externally modulating a free running laser and is converted to millimeter waves (mm-waves) by photomixing with another free running laser at a frequency offset of 53 GHz. At the receiver, the received electrical mm-wave signal is down-converted to an intermediate frequency (IF) and then post processed using digital signal processing (DSP) techniques. With the use of the simple recursive least square (RLS) equalizer in the DSP receiver, the achieved aggregate data rate is 8 Gbps and 12 Gbps for 16 quadrature amplitude modulation (QAM), and 64 QAM, respectively with a total bandwidth of 4.2 GHz. The system performance is evaluated by measuring error vector magnitude (EVM) and bit error rate (BER) calculations. PMID- 29609288 TI - High power single-mode delivery of mid-infrared sources through chalcogenide fiber. AB - Mechanically robust and low loss single-mode arsenic sulfide fibers are used to deliver high power mid-infrared sources. Anti-reflection coatings were deposited on the fiber facets, enabling 90% transmission through 20 cm length fibers. 10.3 W was transmitted through an anti-reflection coated fiber at 2053 nm, and uncoated fibers sustained 12 MW/cm2 intensities on the facet without failure. A Cr:ZnSe laser transmitted >1 W at 2520 nm, and a Fe:ZnSe laser transmitted 0.5 W at 4102 nm. These results indicate that by improving the anti-reflection coatings and using a high beam quality mid-infrared source, chalcogenide fibers can reliably deliver >=10 W in a single mode, potentially out to 6.5 um. PMID- 29609289 TI - Interplay between topological phase and self-acceleration in a vortex symmetric Airy beam. AB - Photons in an optical vortex usually carry orbital angular momentum, which boosts the application of the micro-rotation of absorbing particles and quantum information encoding. Such photons propagate along a straight line in free space or follow a curved trace once guided by an optical fiber. Teleportation of an optical vortex using a beam with non-diffraction and self-healing is quite challenging. We demonstrate the manipulation of the propagation trace of an optical vortex with a symmetric Airy beam (SAB) and found that the SAB experiences self-rotation with the implementation of a topological phase structure of coaxial vortex. Slight misalignment of the vortex and the SAB enables the guiding of the vortex into one of the self-accelerating channels. Multiple off-axis vortices embedded in SAB are also demonstrated to follow the trajectory of the major lobe for the SAB beam. The Poynting vector for the beams proves the direction of the energy flow corresponding to the intensity distribution. Hence, we anticipate that the proposed vortex symmetric Airy beam (VSAB) will provide new possibilities for optical manipulation and optical communication. PMID- 29609290 TI - All-optical and broadband microwave fundamental/sub-harmonic I/Q down-converters. AB - Microwave I/Q down-converters are frequently used in image-reject super heterodyne receivers, zero intermediate frequency (zero-IF) receivers, and phase/frequency discriminators. However, due to the electronic bottleneck, conventional microwave I/Q mixers face a serious bandwidth limitation, I/Q imbalance, and even-order distortion. In this paper, photonic microwave fundamental and sub-harmonic I/Q down-converters are presented using a polarization division multiplexing dual-parallel Mach-Zehnder modulator (PDM DPMZM). Thanks to all-optical manipulation, the proposed system features an ultra wide operating band (7-40 GHz in the fundamental I/Q down-converter, and 10-40 GHz in the sub-harmonic I/Q down-converter) and an excellent I/Q balance (maximum 0.7 dB power imbalance and 1 degree phase imbalance). The conversion gain, noise figure (NF), even-order distortion, and spurious free dynamic range (SFDR) are also improved by LO power optimization and balanced detection. Using the proposed system, a high image rejection ratio is demonstrated for a super heterodyne receiver, and good EVMs over a wide RF power range is demonstrated for a zero-IF receiver. The proposed broadband photonic microwave fundamental and sub-harmonic I/Q down-converters may find potential applications in multi-band satellite, ultra-wideband radar and frequency-agile electronic warfare systems. PMID- 29609291 TI - 450 nm (Al,In)GaN optical amplifier with double 'j-shape' waveguide for master oscillator power amplifier systems. AB - In this paper we demonstrate 450 nm (Al,In)GaN graded index separate confinement heterostructure travelling wave optical amplifier with a double 'j-shape' waveguide. The length of the amplifier is 2.5 mm and the width of the ridge is 2.5 um. The active region consists of three 3.5 nm thick quantum wells. The measured optical gain under CW operation in room temperature exceeded 29 dB for low power input signals. The saturation output power was 21 dBm for 400 mA driving current. The demonstrated amplifier, provides a good solution for the blue light, all nitrides, and master oscillator power amplifier systems. PMID- 29609292 TI - Low-energy high-speed plasmonic enhanced modulator using graphene. AB - Graphene, as a type of flexible and electrically adjustable two-dimensional material, has exceptional optical and electrical properties that make it possible to be used in modulators. However, the poor interaction between optical fields and a single atom graphene layer prevents the easy implementation of graphene modulators. Currently available devices often require a larger overlap area of graphene to obtain the desired phase or amplitude modulation, which results in a rather large footprint and high capacitance and consequently increases the energy consumption and reduces the modulation speed. In this paper, a localized plasmonic-enhanced waveguide modulator with high-speed tunability using graphene is proposed for telecommunication applications. Strong modulation of the transmission takes place due to the enhanced interaction between the ultrathin plasmon patches and the graphene, when the plasmons are tuned on- and off resonance by the gate-tunable graphene. A 400 GHz modulation rate using low gated voltages with an active device area of 0.2 MUm2 and a low consumption of only 0.5 fJ/bit is achieved, which paves the way for ultrafast low-energy optical waveguide modulation and switching. PMID- 29609293 TI - Plasmonic circuit for second-order spatial differentiation at the subwavelength scale. AB - We suggest a plasmonic nanodevice for performing the second-order spatial derivative of light fields. The device consists of five gold nanorods arranged to evanescently couple to each other so that emit cross-polarized output proportional to the second-order differentiation of the incident wave. A theoretical model based on the electrostatic eigenmode analysis is derived and numerical simulations using the finite-difference time-domain methods are provided as supporting evidence. It is shown in both the analytic and numerical methods that the proposed plasmonic circuit performs second-order differentiation of the phase of the incident light field in transmission mode with a subwavelength planar resolution. The resolution of 0.29 lambda-1 is numerically demonstrated for a 20 nm thick circuit at the wavelength of 700 nm. The suggested plasmonic device has potential application in miniaturized systems for all optical computation. PMID- 29609294 TI - Coherence scanning and phase imaging optical interference microscopy at the lateral resolution limit. AB - To get physical insight into the 3D transfer characteristics of interference microscopy at high numerical apertures we study reflecting rectangular grating structures. In general, the height obtained from phase information seems to be reduced, whereas height values resulting from coherence scanning sometimes seem to be systematically overestimated. Increasing the numerical aperture of an interference microscope broadens the spectra of the resulting interference signals, thus offering a broad variety of wavelength contributions to be analyzed. If phase analysis of a measured far-field interference wavefront is performed at very short wavelengths the periodical profiles obtained from coherence scanning and phase shifting analysis differ only by the measured amplitude. However, at longer wavelength there is a 180 degrees phase shift of the measured profiles obtained from phase analysis compared to coherence peak analysis. Increasing the evaluation wavelength improves the lateral resolution since the long wavelength contributions are related to electromagnetic waves of high angles of incidence. This behavior is to the best of our knowledge not documented in literature so far. It was first observed experimentally and could be confirmed by simulation results obtained from either Kirchhoff diffraction theory or an extended Richards-Wolf model developed in our group. Compared to original input profiles used for the simulation the profiles obtained from phase evaluation correspond quite well at longer wavelength, whereas the results obtained from coherence peak analysis are typically inverted with respect to height. PMID- 29609295 TI - Sensor performance requirements for atmospheric correction of satellite ocean color remote sensing. AB - We analyze the effects of the sensor signal-to-noise ratio (SNR) requirements for atmospheric correction of satellite ocean color remote sensing using the near infrared (NIR) and shortwave infrared (SWIR) bands. Using the Gaussian noise model for the sensor noise distribution in the NIR and SWIR bands, some extensive simulations have been carried out to evaluate and assess the effects of sensor NIR and SWIR SNR values on the retrieved normalized water-leaving reflectance spectra rhowN(lambda), which are used to derive all ocean or inland water biological and biogeochemical property data. The standard atmospheric correction algorithm for global oceans and inland waters using the two NIR bands, i.e., Gordon and Wang (1994) [Appl. Opt.33, 443 (1994)Appl. Opt.46, 1535 (2007)], is assumed in the evaluation. Specifically, the minimum and goal SNR requirements for the NIR and SWIR bands for atmospheric correction are estimated. The minimum SNR values are those with which sufficiently accurate rhowN(lambda) can be derived, while the goal SNR requirements are those with which the atmospheric correction algorithms reach to their corresponding inherent limitations (or inherent errors), i.e., no gains can be achieved with further increase of SNR values in the NIR and SWIR bands. Evaluation results show that the minimum SNR requirement for the two NIR bands is ~200-300, while the minimum SNR requirement for the three SWIR bands is ~100. For the goal SNR requirements, the recommendations are SNR's of ~600 and ~200 for the two NIR bands and three SWIR bands, respectively. PMID- 29609296 TI - Performance metrics for the assessment of satellite data products: an ocean color case study. AB - Performance assessment of ocean color satellite data has generally relied on statistical metrics chosen for their common usage and the rationale for selecting certain metrics is infrequently explained. Commonly reported statistics based on mean squared errors, such as the coefficient of determination (r2), root mean square error, and regression slopes, are most appropriate for Gaussian distributions without outliers and, therefore, are often not ideal for ocean color algorithm performance assessment, which is often limited by sample availability. In contrast, metrics based on simple deviations, such as bias and mean absolute error, as well as pair-wise comparisons, often provide more robust and straightforward quantities for evaluating ocean color algorithms with non Gaussian distributions and outliers. This study uses a SeaWiFS chlorophyll-a validation data set to demonstrate a framework for satellite data product assessment and recommends a multi-metric and user-dependent approach that can be applied within science, modeling, and resource management communities. PMID- 29609297 TI - Small-scale Scheimpflug lidar for aerosol extinction coefficient and vertical atmospheric transmittance detection. AB - In this paper, a new prototypical Scheimpflug lidar capable of detecting the aerosol extinction coefficient and vertical atmospheric transmittance at 1 km above the ground is described. The lidar system operates at 532 nm and can be used to detect aerosol extinction coefficients throughout an entire day. Then, the vertical atmospheric transmittance can be determined from the extinction coefficients with the equation of numerical integration in this area. CCD flat fielding of the image data is used to mitigate the effects of pixel sensitivity variation. An efficient method of two-dimensional wavelet transform according to a local threshold value has been proposed to reduce the Gaussian white noise in the lidar signal. Furthermore, a new iteration method of backscattering ratio based on genetic algorithm is presented to calculate the aerosol extinction coefficient and vertical atmospheric transmittance. Some simulations are performed to reduce the different levels of noise in the simulated signal in order to test the precision of the de-noising method and inversion algorithm. The simulation result shows that the root-mean-square errors of extinction coefficients are all less than 0.02 km-1, and that the relative errors of the atmospheric transmittance between the model and inversion data are below 0.56% for all cases. The feasibility of the instrument and the inversion algorithm have also been verified by an optical experiment. The average relative errors of aerosol extinction coefficients between the Scheimpflug lidar and the conventional backscattering elastic lidar are 3.54% and 2.79% in the full overlap heights of two time points, respectively. This work opens up new possibilities of using a small-scale Scheimpflug lidar system for the remote sensing of atmospheric aerosols. PMID- 29609298 TI - Near-field spectroscopy and tuning of sub-surface modes in plasmonic terahertz resonators. AB - Highly confined modes in THz plasmonic resonators comprising two metallic elements can enhance light-matter interaction for efficient THz optoelectronic devices. We demonstrate that sub-surface modes in such double-metal resonators can be revealed with an aperture-type near-field probe and THz time-domain spectroscopy despite strong mode confinement in the dielectric spacer. The sub surface modes couple a fraction of their energy to the resonator surface via surface waves, which we detected with the near-field probe. We investigated two resonator geometries: a lambda/2 double-metal patch antenna with a 2 MUm thick dielectric spacer, and a three-dimensional meta-atom resonator. THz time-domain spectroscopy analysis of the fields at the resonator surface displays spectral signatures of sub-surface modes. Investigations of strong light-matter coupling in resonators with sub-surface modes therefore can be assisted by the aperture type THz near-field probes. Furthermore, near-field interaction of the probe with the resonator enables tuning of the resonance frequency for the spacer mode in the antenna geometry from 1.6 to 1.9 THz (~15%). PMID- 29609299 TI - Numerical realization of the variational method for generating self-trapped beams. AB - We introduce a numerical variational method based on the Rayleigh-Ritz optimization principle for predicting two-dimensional self-trapped beams in nonlinear media. This technique overcomes the limitation of the traditional variational approximation in performing analytical Lagrangian integration and differentiation. Approximate soliton solutions of a generalized nonlinear Schrodinger equation are obtained, demonstrating robustness of the beams of various types (fundamental, vortices, multipoles, azimuthons) in the course of their propagation. The algorithm offers possibilities to produce more sophisticated soliton profiles in general nonlinear models. PMID- 29609300 TI - Pulse energy dependence of refractive index change in lithium niobium silicate glass during femtosecond laser direct writing. AB - Femtosecond laser-induced refractive index changes in lithium niobium silicate glass were explored at high repetition rate (300 fs, 500 kHz) by polarized light microscopy, full-wave retardation plate, quantitative birefringence microscopy, and digital holographic microscopy. We found three regimes on energy increase. The first one corresponds to isotropic negative refractive index change (for pulse energy ranging 0.4-0.8 MUJ/pulse, 0.6 NA, 5MUm/s, 650MUm focusing depth in the glass). The second one (0.8-1.2 MUJ/pulse) corresponds to birefringence with well-defined slow axis orientation. The third one (above 1.2 MUJ/pulse) is related to birefringence direction fluctuation. Interestingly, these regimes are consistent with crystallization ones. In addition, an asymmetric orientational writing effect has been detected on birefringence. These topics extend the possibility of controlling refractive index change in multi-component glasses. PMID- 29609301 TI - New on-orbit geometric interior parameters self-calibration approach based on three-view stereoscopic images from high-resolution multi-TDI-CCD optical satellites. AB - To increase the field of view (FOV), combining multiple time-delayed and integrated charge-coupled devices (TDI-CCD) into the camera and the pushbroom imaging modality are traditionally used with high-resolution optical satellites. It is becoming increasingly labor- and cost-intensive to build and maintain a calibration field with high resolution and broad coverage. This paper introduces a simple and feasible on-orbit geometric self-calibration approach for high resolution multi-TDI-CCD optical satellites based on three-view stereoscopic images. With the aid of the a priori geometric constraint of tie points in the triple-overlap regions of stereoscopic images, as well as tie points between adjacent single TDI-CCD images (STIs), high accuracy calibration of all TDI-CCD detectors can be achieved using a small number of absolute ground control points (GCPs) covering the selected primary STI. This method greatly reduces the demand on the calibration field and thus is more time-, effort- and cost-effective. Experimental results indicated that the proposed self-calibration approach is effective for increasing the relative internal accuracy without the limitations associated with using a traditional reference calibration field, which could have great significance for future super-high-resolution optical satellites. PMID- 29609303 TI - Large-area broadband optical absorber fabricated by shadowing sphere lithography. AB - We report a large-area broadband optical absorber consisting of Ag/SiO2 stacked plasmonic layers fabricated on a self-assembly polystyrene sphere monolayer using the glancing angle deposition. Such an absorber can absorb more than 90% of light in the spectral range of 350 - 850 nm when the polystyrene spheres have a diameter of 750 nm. The broadband absorption is due to the overlap of localized plasmonic resonance wavelengths resulting from different patchy sizes and shapes of Ag coating on polystyrene spheres. Such a simple, flexible and large-area absorber has potential applications in light cloaking and energy conversion. PMID- 29609302 TI - Real-time free spectral range measurement based on optical single-sideband technique. AB - We demonstrate a real-time scheme for measuring the free spectral range (FSR) of a high-aspect-ratio Si3N4 waveguide ring resonator with a fiber-based hybrid unbalanced Mach-Zehnder modulator (MZM) using an optical single-sideband technique. Resonance-tracking loops were established with the Pound-Drever-Hall technique for locking resonance modes. A relative precision of 3.25 * 10-6 was achieved for a 35-mm waveguide ring resonator with FSR = 1,844,628 kHz and Q = 3.211 * 106. Furthermore, the Si3N4 resonator FSR coefficient of thermal expansion was measured as -16.735+/-0.002 kHz/ degrees C. This method will provide a flexible photonic interface for realizing advanced photonic systems. PMID- 29609304 TI - Paths to light trapping in thin film GaAs solar cells. AB - It is now well established that light trapping is an essential element of thin film solar cell design. Numerous light trapping geometries have already been applied to thin film cells, especially to silicon-based devices. Less attention has been paid to light trapping in GaAs thin film cells, mainly because light trapping is considered less attractive due to the material's direct bandgap and the fact that GaAs suffers from strong surface recombination, which particularly affects etched nanostructures. Here, we study light trapping structures that are implemented in a high-bandgap material on the back of the GaAs active layer, thereby not perturbing the integrity of the GaAs active layer. We study photonic crystal and quasi-random nanostructures both by simulation and by experiment and find that the photonic crystal structures are superior because they exhibit fewer but stronger resonances that are better matched to the narrow wavelength range where GaAs benefits from light trapping. In fact, we show that a 1500 nm thick cell with photonic crystals achieves the same short circuit current as an unpatterned 4000 nm thick cell. These findings are significant because they afford a sizeable reduction in active layer thickness, and therefore a reduction in expensive epitaxial growth time and cost, yet without compromising performance. PMID- 29609305 TI - Guided-mode resonance gratings for enhanced mid-infrared absorption in quantum dot intermediate-band solar cells. AB - Achieving strong absorption of low-energy photons is one of the key issues to demonstrate quantum dot solar cells working in the intermediate band regime at practical concentration factors and operating temperatures. Guided-mode resonance effects may enable large enhancement of quantum dot intraband optical transitions. We propose quantum dot thin-film cells designed to have significant field waveguiding in the quantum dot stack region and patterned at the rear-side with a sub-wavelength diffraction grating. Remarkable increase of the optical path length at mid-infrared wavelengths is shown owing to guided-mode resonances. Design guidelines are presented for energy and strength of the second-photon absorption for III-V quantum dots, such as InAs/GaAs and GaSb/GaAs, whose intraband and intersubband transitions roughly extends over the 2 - 8 um range. The proposed design can also be applied to quantum dot infrared detectors. Angle selectivity is discussed in view of applications in concentrator photovoltaic systems and infrared imaging systems. PMID- 29609306 TI - Highly efficient, cascaded extraction optical parametric amplifier. AB - The scheme of cascaded extraction optical parametric amplifier (CE-OPA) has been proposed as a final amplifier for high peak power laser systems. 4D numerical simulations show that conversion efficiency of a CE-OPA system pumped with a temporal Gaussian pump pulse is as close to the theoretical limit of quantum efficiency as a conventional OPA pumped with temporal flat-top pump pulse. The CE OPA system is also similar to the conventional scheme in output energy stability and alignment sensitivity of the phase-matching angles, too. However, with the use of the CE-OPA scheme, the requirement of pump pulse shaping can be relaxed, leading to an overall higher plug in efficiency as well as compact design. PMID- 29609307 TI - Resolution limits of quantum ghost imaging. AB - Quantum ghost imaging uses photon pairs produced from parametric downconversion to enable an alternative method of image acquisition. Information from either one of the photons does not yield an image, but an image can be obtained by harnessing the correlations between them. Here we present an examination of the resolution limits of such ghost imaging systems. In both conventional imaging and quantum ghost imaging the resolution of the image is limited by the point-spread function of the optics associated with the spatially resolving detector. However, whereas in conventional imaging systems the resolution is limited only by this point spread function, in ghost imaging we show that the resolution can be further degraded by reducing the strength of the spatial correlations inherent in the downconversion process. PMID- 29609308 TI - Enhanced upconversion in one-dimensional photonic crystals: a simulation-based assessment within realistic material and fabrication constraints. AB - This paper presents a simulation-based assessment of the potential for improving the upconversion efficiency of beta-NaYF4:Er3+ by embedding the upconverter in a one-dimensional photonic crystal. The considered family of structures consists of alternating quarter-wave layers of the upconverter material and a spacer material with a higher refractive index. The two photonic effects of the structures, a modified local energy density and a modified local density of optical states, are considered within a rate-equation-modeling framework, which describes the internal dynamics of the upconversion process. Optimal designs are identified, while taking into account production tolerances via Monte Carlo simulations. To determine the maximum upconversion efficiency across all realistically attainable structures, the refractive index of the spacer material is varied within the range of existing materials. Assuming a production tolerance of sigma = 1 nm, the optimized structures enable more than 300-fold upconversion photoluminescence enhancements under one sun and upconversion quantum yields exceeding 15% under 30 suns concentration. PMID- 29609309 TI - All-optical 10Gb/s ternary-CAM cell for routing look-up table applications. AB - We experimentally demonstrate the first all-optical Ternary-Content Addressable Memory (T-CAM) cell that operates at 10Gb/s and comprises two monolithically integrated InP Flip-Flops (FF) and a SOA-MZI optical XOR gate. The two FFs are responsible for storing the data bit and the ternary state 'X', respectively, with the XOR gate used for comparing the stored FF-data and the search bit. The experimental results reveal error-free operation at 10Gb/s for both Write and Ternary Content Addressing of the T-CAM cell, indicating that the proposed optical T-CAM cell could in principle lead to all-optical T-CAM-based Address Look-up memory architectures for high-end routing applications. PMID- 29609310 TI - Computational localization microscopy with extended axial range. AB - A new single-aperture 3D particle-localization and tracking technique is presented that demonstrates an increase in depth range by more than an order of magnitude without compromising optical resolution and throughput. We exploit the extended depth range and depth-dependent translation of an Airy-beam PSF for 3D localization over an extended volume in a single snapshot. The technique is applicable to all bright-field and fluorescence modalities for particle localization and tracking, ranging from super-resolution microscopy through to the tracking of fluorescent beads and endogenous particles within cells. We demonstrate and validate its application to real-time 3D velocity imaging of fluid flow in capillaries using fluorescent tracer beads. An axial localization precision of 50 nm was obtained over a depth range of 120MUm using a 0.4NA, 20* microscope objective. We believe this to be the highest ratio of axial range-to precision reported to date. PMID- 29609311 TI - Refractive index measurements in absorbing media with white light spectral interferometry. AB - White light spectral interferometry is applied to measure the refractive index in absorbing liquids in the spectral range of 400-1000 nm. We analyze the influence of absorption on the visibility of interferometric fringes and, accordingly, on the measurement of the refractive index. Further, we show that the refractive index in the absorption band can be retrieved by a two-step process. The procedure requires the use of two samples of different thickness, the thicker one to retrieve the refractive index in the transparent region and the thinnest to obtain the data in the absorption region. First, the refractive index values are retrieved with good accuracy in the transparent region of the material for 1-mm thick samples. Second, these refractive index values serve also to precisely calculate the thickness of a thinner sample (~150 um) since the accuracy of the methods depends strongly on the thickness of the sample. Finally, the refractive index is recovered for the entire spectral range. PMID- 29609312 TI - Controllable optical rogue waves via nonlinearity management. AB - Using a similarity transformation, we obtain analytical solutions to a class of nonlinear Schrodinger (NLS) equations with variable coefficients in inhomogeneous Kerr media, which are related to the optical rogue waves of the standard NLS equation. We discuss the dynamics of such optical rogue waves via nonlinearity management, i.e., by selecting the appropriate nonlinearity coefficients and integration constants, and presenting the solutions. In addition, we investigate higher-order rogue waves by suitably adjusting the nonlinearity coefficient and the rogue wave parameters, which could help in realizing complex but controllable optical rogue waves in properly engineered fibers and other photonic materials. PMID- 29609313 TI - Ray calibration and phase mapping for structured-light-field 3D reconstruction. AB - In previous work, we presented a structured light field (SLF) method combining light field imaging with structured illumination to perform multi-view depth measurement. However, the previous work just accomplishes depth rather than 3D reconstruction. In this paper, we propose a novel active method involving ray calibration and phase mapping, to achieve SLF 3D reconstruction. We performed the ray calibration for the first time to determine each light field ray with metric spatio-angular parameters, making the SLF realize multi-view 3D reconstruction. Based on the ray parametric equation, we further derived the phase mapping in the SLF that spatial coordinates can be directly mapped from phase. A flexible calibration strategy was correspondently designed to determine mapping coefficients for each light field ray, achieving high-efficiency SLF 3D reconstruction. Experimental results demonstrated that the proposed method was suitable for high-efficiency multi-view 3D reconstruction in the SLF. PMID- 29609314 TI - Thermal analysis of Yb-doped high-power fiber amplifiers with Al:P co-doped cores. AB - It has been recently shown that photodarkening can significantly reduce the mode instability threshold in high power Yb-doped fiber amplifiers, thus resulting in an even more severe limitation to the scaling of the output average power of these systems. Therefore, an efficient reduction of photodarkening in an Yb-doped active fiber will lead to very significant gains in the output average power delivered by such systems. In this context, it has been reported that photodarkening can be significantly mitigated when co-doping a fiber core with Al and P, which makes this approach potentially appealing to increase the TMI threshold. Unfortunately co-doping the fiber core with Al and P also alters the effective cross-sections of the fiber, which has repercussion in the amplification efficiency. Thus, a fiber with a higher P concentration will exhibit lower cross-sections, therefore requiring a higher Yb-ion concentration to reach a certain desired amplification efficiency. However, increasing the Yb ion concentration leads to higher photodarkening losses, which might potentially counteract the benefits of using P co-doping. In this paper we present a comparative analysis of the expected performance of different fiber amplifiers for a given constant average heat-load and amplification efficiency as a function of the ratio of Al:P concentration in the fiber core. This study indicates which core compositions are more beneficial for increasing the mode instability threshold in Yb-doped high-power fiber amplifier systems. PMID- 29609315 TI - Integrated manufacture of a freeform off-axis multi-reflective imaging system without optical alignment. AB - Multi-reflective imaging systems find wide applications in optical imaging and space detection. However, it is faced with difficulties in adjusting the freeform mirrors with high accuracy to guarantee the optical function. Motivated by this, an alignment-free manufacture approach is proposed to machine the optical system. The direct optical performance-guided manufacture route is established without measuring the form error of freeform optics. An analytical model is established to investigate the effects of machine errors to serve the error identification and compensation in machining. Based on the integrated manufactured system, an ingenious self-designed testing configuration is constructed to evaluate the optical performance by directly measuring the wavefront aberration. Experiments are carried out to manufacture a three-mirror anastigmat, surface topographical details and optical performance shows agreement to the designed expectation. The final system works as an off-axis infrared imaging system. Results validate the feasibility of the proposed method to achieve excellent optical application. PMID- 29609316 TI - Demonstration of coherent stealthy and encrypted transmission for data center interconnection. AB - We show in an experiment a covert transmission of QPSK and 64-QAM over up to 100km of SSMF, digitally encrypted with spectral phase mask, buried under ASE noise with negative -15 dB/0.1nm OSNR. We record a post-FEC error free BER for a stealthy channel, at 16 Gbps on a single polarization. PMID- 29609317 TI - Measuring the Kerr nonlinearity via seeded Kerr instability amplification: conceptual analysis. AB - Whereas the Kerr nonlinearity is well understood in the perturbative limit of nonlinear optics, there is considerable discussion about its functional form and magnitude at extreme intensities, at which point matter starts to ionize. Here, we introduce a concept to answer this question and theoretically analyze its feasibility. We demonstrate that seeded Kerr instability amplification provides clear signatures from which functional form and magnitude of the Kerr nonlinearity can be extracted in the non-perturbative limit of nonlinear optics. PMID- 29609318 TI - Inverse scattering with a non self-adjoint variational formulation. AB - The weak scattering approximation is used when designing optical media that couple fields together, but to account for the interactions of multiple fields in a volume or to achieve the best efficiency, the solution must be consistent with Maxwell's equations. We describe a method based on the variational formulation of Maxwell's equations typically employed in the finite element method (FEM) that finds both the fields and the medium that couples incident and scattered fields together, and so can be considered an extension of the FEM when both the field and the medium are allowed to vary. The method iteratively updates estimates of the field and the medium and can be readily implemented. We demonstrate designs of diffractive and refractive elements that couple fields together using an iteratively updated finite-difference-frequency-domain (FDFD) solution. Such methods that are fully consistent with Maxwell's equations are needed to design metamaterials that fully exploit strongly interacting metamaterial elements. PMID- 29609319 TI - InGaN/GaN micro mirror with electrostatic comb drive actuation integrated on a patterned silicon-on-insulator wafer. AB - A double-sided mask process is used to define the micro actuators on a silicon-on insulator (SOI) wafer. Then, an InGaN/GaN multilayer film was deposited on the surface of the above patterned SOI substrate by employed MBE technology. Thus, the final device consisting of comb-drive actuators, springs and micro-mirror is implemented to obtain the two-dimensional (2D) tuning effect of the mirror. The displacement response is characterized by applying voltage to the micro actuators. It shows an approximation linear relationship between the displacement and the square of applied voltage. And the influences of the cross-axis coupling effect are also measured and evaluated. Moreover, the luminous performances of the InGaN/GaN multiquantum well films were also studied by analyzing temperature dependent and laser intensity-dependent PL spectra. The authors observed the localized state effect and/or band-gap narrowing effect which results in an S shaped behavior with increasing temperature. The PL intensity and wavelength are also significantly affected by the excitation energy of laser. PMID- 29609320 TI - Photoalignment-induced two-dimensional liquid crystal polarization structure via multi-beam polarization interferometry. AB - A two-dimensional (2D) pure polarization pattern via four-beam polarization interferometry of circularly polarized beams is demonstrated both theoretically and experimentally. The polarization orientation of the interference pattern is recorded by an azobenzene photoalignment layer and transferred to liquid crystal (LC), enabling the fabrication of a 2D liquid crystal (LC) chiral structure. This structure behaves as a 2D LC polarization grating (LCPG) that can generate multiple polarization-selective diffraction beams of orthogonal polarization states with high efficiency. This 2D LCPG provides an effective way to distribute an optical signal into multiple receivers by both incidence polarization control and external electric field, therefore offering potential applications on multi channel optical communication and information processing. PMID- 29609321 TI - Generation of focal pattern with controllable polarization and intensity for laser beam passing through a multi-mode fiber. AB - Similar to coherent light passing through a scattering medium, the propagation of coherent light through a multi-mode fiber (MMF) will result in a random speckle field. For a non-polarization maintaining MMF, the randomization can be observed not only in the intensity distribution, but also in the polarization state. In this paper, we propose a new technique known as phase combination to control the optical field for the light passing through the MMF. We show that, based on this new technique, the random speckle pattern can be modulated into an intensity distribution of two bright focal spots with mutually perpendicular polarization by only one polarizer. In particular, the intensity distribution of these two focal spots can be quantitatively controlled. This technique may find applications in medical imaging, nonlinear optics and optical communication etc. PMID- 29609322 TI - Measurements of polarization-dependent angle-resolved light scattering from individual microscopic samples using Fourier transform light scattering. AB - We present a method to measure the vector-field light scattering of individual microscopic objects. The polarization-dependent optical field images are measured with quantitative phase imaging at the sample plane, and then numerically propagated to the far-field plane. This approach allows the two-dimensional polarization-dependent angle-resolved light scattered patterns from individual object to be obtained with high precision and sensitivity. Using this method, we present the measurements of the polarization-dependent light scattering of a liquid crystal droplet and individual silver nanowires over scattering angles of 50 degrees . In addition, the spectroscopic extension of the polarization dependent angle-resolved light scattering is demonstrated using wavelength scanning illumination. PMID- 29609323 TI - Oxide composition and period variation of thermochemical LIPSS on chromium films with different thickness. AB - In this paper, we present the results of thermochemical LIPSS formation on a chromium film with a thickness in the range of 28-350 nm induced by femtosecond laser radiation (lambda = 1026 nm, nu = 200 kHz, tau = 232 fs). The period, height, morphology and chemical composition of TLIPSS as a function of the metal film thickness and focusing configuration are investigated. The growth of TLIPSS period from 678 nm to 950 nm with increasing thickness of the film has been explained by a formation of oxides with different stoichiometry composition. So, the CrO2 oxide prevails in the composition for the case of TLIPSS formed on thin films which have the minimal period, whereas Cr2O3 oxide is dominant in the case of TLIPSS formed on thick chromium films which have the maximal period value. The results obtained are in agreement with numerical modeling of a period defined by the interference between an incident radiation and a scattered one from a single oxide ridge with a different chemical composition. PMID- 29609324 TI - Study of chromatic adaptation via neutral white matches on different viewing media. AB - Two experiments were carried out to study the neutral white and the chromatic adaptation in human vision and color science. After matching neutral whites under different illuminants using both surface and self-luminous colors, the result were used to verify the previous study about the chromatic adaptation. Not all the white illuminants were found neutral even the adaptation time is long. The baseline illuminant of the two-step chromatic adaptation transform was found as the illuminant with the same chromaticity of the neutral white under it and depended on viewing medium in the present study. The results were also used as corresponding colors to derive models of the effective degree of chromatic adaptation, which were found highly associated with the chromaticity of the adapting illuminant. PMID- 29609325 TI - Tolerable performance of silicon photonic optical-serial-to-parallel converter with variable power splitter. AB - We have proposed and investigated the tolerable performance of an optical serial to-parallel converter with phase operation (OSPC) with lower power consumption than the conventional scheme for the purpose of achieving reduction of both the processing load and the processing latency of the high-speed packet switching systems in the data center. The target OSPC consists of Mach-Zehnder delay interferometers (MZDIs) and balanced photodetectors with silicon (Si) photonic technology. However, we have confirmed that the performance becomes degraded due to optical propagation losses of the delay lines in MZDIs. To solve this issue, unbalanced splitting ratio of a multi-mode interferometer (MMI)-type couplers in the MZDIs has been investigated, but we have found the necessity of improving the tolerance of the splitting ratio deviation. In this paper, we will analytically and experimentally demonstrate the improvement of the characteristics by using an OSPC with variable splitting ratio optical coupler (VSOC) consisting of a symmetric Mach-Zehnder interferometer (MZI). By observing the transmission spectra of the device with various applied voltage to the heater, controllability of peak-to-valley ratios of transmission spectra was observed. In addition, splitting ratio of the output symmetric MMI almost matches well with that of the optimized peak-to-valley ratios of transmission spectra by using short-optical pulse injection. We have confirmed the tolerable performance of the Si-photonic OSPC by using VSOC with the symmetric MZI. PMID- 29609326 TI - Aberration analysis for freeform surface terms overlay on general decentered and tilted optical surfaces. AB - Aberration theory helps designers to better understand the nature of imaging systems. However, the existing aberration theory of freeform surfaces has many limitations. For example, it only works in the special case when the central area of the freeform surface is used. In addition, the light footprint is limited to a circle, which does not match the case of an elliptical footprint for general systems. In this paper, aberrations generated by freeform surface term overlay on general decentered and tilted optical surfaces are analyzed. For the case when the off-axis section of a freeform surface is used, the aberration equation for using stop and nonstop surfaces is discussed, and the aberrations generated by Zernike terms up to Z17/18 are analyzed in detail. To solve the problem of the elliptical light footprint for tilted freeform surfaces, the scaled pupil vector is used in the aberration analysis. The mechanism of aberration transformation is discovered, and the aberrations generated by different Zernike terms in this case are calculated. Finally we proposed aberration equations for freeform terms on general decentered and tilted freeform surfaces. The research result given in this paper offers an important reference for optical designers and engineers, and it is of great importance in developing analytical methods for general freeform system design, tolerance analysis, and system assembly. PMID- 29609327 TI - Temperature effects on tunable cw Alexandrite lasers under diode end-pumping. AB - Diode pumped Alexandrite is a promising route to high power, efficient and inexpensive lasers with a broad (701 nm to 858 nm) gain bandwidth; however, there are challenges with its complex laser dynamics. We present an analytical model applied to experimental red diode end-pumped Alexandrite lasers, which enabled a record 54 % slope efficiency with an output power of 1.2 W. A record lowest lasing wavelength (714 nm) and record tuning range (104 nm) was obtained by optimising the crystal temperature between 8 degrees C and 105 degrees C in the vibronic mode. The properties of Alexandrite and the analytical model were examined to understand and give general rules in optimising Alexandrite lasers, along with their fundamental efficiency limits. It was found that the lowest threshold laser wavelength was not necessarily the most efficient, and that higher and lower temperatures were optimal for longer and shorter laser wavelengths, respectively. The pump excited to ground state absorption ratio was measured to decrease from 0.8 to 0.7 by changing the crystal temperature from 10 degrees C to 90 degrees C. PMID- 29609328 TI - Analysis and design of fibers for pure-quartic solitons. AB - The recently discovered pure-quartic solitons, arising from the interaction of quartic dispersion and Kerr nonlinearity, open the door to unexplored soliton regimes and ultrafast laser science. Here, we report a general analysis of the dispersion and nonlinear properties necessary to observe pure-quartic solitons in optical platforms. We apply this analysis, in combination with numerical calculations, to the design of pure-quartic soliton supporting microstructured optical fibers. The designs presented here, which have realistic fabrication tolerances, support unperturbed pure-quartic soliton propagation providing access to an unmatched platform to study novel soliton physics. PMID- 29609329 TI - Edge optical scattering of two-dimensional materials. AB - Rayleigh scattering has shown powerful abilities to study electron resonances of nanomaterials regardless of the specific shapes. In analogy to Rayleigh scattering, here we demonstrate that edge optical scattering from two dimensional(2D) materials also has the similar advantage. Our result shows that, in visible spectral range, as long as the lateral size of a 2D sample is larger than 2 MUm, the edge scattering intensity distribution of the high-angle scattering in k space is nearly independent of the lateral size and the shape of the 2D samples. The high-angle edge scattering spectra are purely determined by the intrinsic dielectric properties of the 2D materials. As an example, we experimentally verify this feature in single-layer MoS2, in which A and B excitons are clearly detected in the edge scattering spectra, and the scattering images in k space and real space are consistent with our theoretical model. This study shows that the edge scattering is a highly practical and efficient method for optical studies of various 2D materials as well as thin films with clear edges. PMID- 29609330 TI - TuLUMIS - a tunable LED-based underwater multispectral imaging system. AB - Multispectral imaging (MSI) is widely used in terrestrial applications to help increase the discriminability between objects of interest. While MSI has shown potential for underwater geological and biological surveys, it is thus far rarely applied underwater. This is primarily due to the fact light propagation in water is subject to wavelength dependent attenuation and tough working conditions in the deep ocean. In this paper, a novel underwater MSI system based on a tunable light source is presented which employs a monochrome still image camera with flashing, pressure neutral color LEDs. Laboratory experiments and field tests were performed. Results from the lab experiments show an improvement of 76.66% on discriminating colors on a checkerboard by using the proposed imaging system over the use of an RGB camera. The field tests provided in situ MSI observations of pelagic fauna, and showed the first evidence that the system is capable of acquiring useful imagery under real marine conditions. PMID- 29609331 TI - Photonic microwave waveforms generation based on two cascaded single-drive Mach Zehnder modulators. AB - A new photonic scheme for various waveforms generation has been proposed and demonstrated. In the scheme, two cascaded single-drive LiNbO3 Mach-Zehnder modulators serve as pulse shaper and the polarization-dependent character of the modulators is fully exploited and utilized. By arranging the polarization states of the incident light, two different spectra are achieved on two orthogonal polarization components respectively. Finally, the desired waveforms can be obtained by superimposing the photocurrents of the two orthogonal signals on a photodetector. The detailed theoretical analyses and simulations are given. In the experiment, square-shaped waveform, triangular waveform and sawtooth (or reversed-sawtooth) waveform are obtained successfully. Furthermore, an approach to smoothing the sawtooth waveform with fewer harmonics is suggested and verified. PMID- 29609332 TI - Optical tuning of dielectric properties of La0.7Sr0.3MnO3/SrTiO3 superlattices in the terahertz range. AB - Two (La0.7Sr0.3MnO3)n/(SrTiO3)m superlattices with different superlattice period but the same total thickness were deposited on LaAlO3 substrates by pulsed laser deposition. Dielectric properties of these samples were investigated by means of terahertz time-domain spectroscopy (THz-TDS) under external continuous wave green laser excitation and optical-pump terahertz-probe spectroscopy (OPTP) at room temperature. Experimental results show that the real part of the permittivity for both superlattices increases significantly with increasing green laser pump power, which indicates the decrease of the plasma frequency, along with the increase of the electron scattering rate, soft mode eigenfrequency and oscillator strength in the Drude-Lorentz model. Furthermore, it's observed that the insulating superlattice exhibits a more significant dielectric tunability than the metallic superlattice. Besides, the carrier lifetime of superlattices is much shorter than the La0.7Sr0.3MnO3 thin film in the OPTP measurements, indicating that the electrons excited in the La0.7Sr0.3MnO3 layers may be trapped by the defects located in the interfaces of La0.7Sr0.3MnO3 and SrTiO3 or the SrTiO3 layers. With the optical field-induced tunability of dielectric properties, (La0.7Sr0.3MnO3)n/(SrTiO3)m superlattices show great potential in the actively tunable devices in the THz range. PMID- 29609333 TI - Spatial light modulator based laser microfabrication of volume optics inside solar modules. AB - Ultrashort pulse laser systems enable new approaches of material processing and manufacturing with enhanced precision and productivity. Time- and cost effectiveness in the context of the industrialization of ultrashort laser pulse processes require an improvement of processing speed, which is of key importance for strengthening industrial photonics based manufacturing and extending its field of applications. This article presents results on improving the speed of a laser process by parallelization for creating light deflecting volume optics. Diffractive optical elements are fabricated directly inside the encapsulant of solar modules by utilizing a spatial light modulator based parallel laser microfabrication method. The fabricated volume optical elements effectively deflect light away from front side electrodes and significantly reduce the corresponding optical losses. PMID- 29609334 TI - Optical enhancement of a printed organic tandem solar cell using diffractive nanostructures. AB - Solution processable organic tandem solar cells offer a promising approach to achieve cost-effective, lightweight and flexible photovoltaics. In order to further enhance the efficiency of optimized organic tandem cells, diffractive light-management nanostructures were designed for an optimal redistribution of the light as function of both wavelength and propagation angles in both sub cells. As the fabrication of these optical structures is compatible with roll-to roll production techniques such as hot-embossing or UV NIL imprinting, they present an optimal cost-effective solution for printed photovoltaics. Tandem cells with power conversion efficiencies of 8-10% were fabricated in the ambient atmosphere by doctor blade coating, selected to approximate the conditions during roll-to-roll manufacturing. Application of the light management structure onto an 8.7% efficient encapsulated tandem cell boosted the conversion efficiency of the cell to 9.5%. PMID- 29609335 TI - On-line analysis of algae in water by discrete three-dimensional fluorescence spectroscopy. AB - In view of the problem of the on-line measurement of algae classification, a method of algae classification and concentration determination based on the discrete three-dimensional fluorescence spectra was studied in this work. The discrete three-dimensional fluorescence spectra of twelve common species of algae belonging to five categories were analyzed, the discrete three-dimensional standard spectra of five categories were built, and the recognition, classification and concentration prediction of algae categories were realized by the discrete three-dimensional fluorescence spectra coupled with non-negative weighted least squares linear regression analysis. The results show that similarities between discrete three-dimensional standard spectra of different categories were reduced and the accuracies of recognition, classification and concentration prediction of the algae categories were significantly improved. By comparing with that of the chlorophyll a fluorescence excitation spectra method, the recognition accuracy rate in pure samples by discrete three-dimensional fluorescence spectra is improved 1.38%, and the recovery rate and classification accuracy in pure diatom samples 34.1% and 46.8%, respectively; the recognition accuracy rate of mixed samples by discrete-three dimensional fluorescence spectra is enhanced by 26.1%, the recovery rate of mixed samples with Chlorophyta 37.8%, and the classification accuracy of mixed samples with diatoms 54.6%. PMID- 29609336 TI - Characterising energy transfer upconversion in Nd-doped vanadates at elevated temperatures. AB - The Energy Transfer Upconversion (ETU) macroparameter is measured for Nd-doped GdVO4 and YVO4 samples at temperatures ranging from Room Temperature (RT) to 450K, by means of a simple and automated z-scan technique. Furthermore, the ground state absorption cross section into the 2H9/2 +4F5/2 energy levels is characterised for both crystals over the same range of temperatures. The 808 nm pi-polarisation absorption cross section is found to decrease from (58.6 +/- 0.2) pm2 to (30.9 +/- 0.6) pm2 for Nd:YVO4 and (54.0 +/- 0.3) pm2 to (25.7 +/- 0.5) pm2 for Nd:GdVO4, from RT to 450K. Over the same range the ETU coefficient decreases from (3.2 +/- 0.7) 10-16cm3/s to (1.8 +/- 0.4 10-16cm3/s and (5.0 +/- 0.5) 10-16cm3/s to (3.4+/-0.2) 10-16cm3/s for 0.6 at. % and 1 at. % Nd:YVO4 respectively, and (3.3 +/- 0.5) 10-16cm3/s to (0.8 +/- 0.2) 10-16cm3/s and (5.5 +/- 0.5) 10-16cm3/s to (3.1 +/- 0.3) 10-16cm3/s for 0.5 at.% and 1.1 at.% Nd:GdVO4. PMID- 29609337 TI - 295-kW peak power picosecond pulses from a thulium-doped-fiber MOPA and the generation of watt-level >2.5-octave supercontinuum extending up to 5 MUm. AB - We report a gain-switched diode-seeded thulium doped fiber master oscillator power amplifier (MOPA) producing up to 295-kW picosecond pulses (35 ps) at a repetition rate of 1 MHz with a good beam quality (M2 ~1.3). A narrow-band, grating-based filter was incorporated within the amplifier chain to restrict the accumulation of nonlinear spectral broadening and counter-pumping of a short length of large-mode-area (LMA) fiber was used in the final stage amplifier to further reduce nonlinear effects. Finally, we generated watt-level >2.5-octave supercontinuum spanning from 750 nm to 5000 nm by using the MOPA output to pump an indium fluoride fiber. PMID- 29609338 TI - Transverse optical forces and sideways deflections in subwavelength-diameter optical fibers. AB - We investigate transverse optical forces exerted on the endface of subwavelength diameter (SD) optical fiber by using a finite-difference time-domain (FDTD) method. Detailed spatial distributions of transverse optical force along the fiber axis can now be accessible, based on which the dependence of transverse optical force on transverse cross sections, oblique-cut endfaces and high-order mode are carefully studied. Our numerical results demonstrate that either asymmetric cross section or oblique-cut endface would dominantly contribute to the transverse optical force and the corresponding sideways deflection of SD fiber, which is in good agreement with previous experimental observations. The novel behavior of transverse optical force by the high-order mode would give rise to new guidelines for constructing high-performance optomechanical devices. PMID- 29609339 TI - Enhanced Raman scattering in porous silicon grating. AB - The enhancement of Raman signal on monocrystalline silicon gratings with varying groove depths and on porous silicon grating were studied for a highly sensitive surface enhanced Raman scattering (SERS) response. In the experiment conducted, porous silicon gratings were fabricated. Silver nanoparticles (Ag NPs) were then deposited on the porous silicon grating to enhance the Raman signal of the detective objects. Results show that the enhancement of Raman signal on silicon grating improved when groove depth increased. The enhanced performance of Raman signal on porous silicon grating was also further improved. The Rhodamine SERS response based on Ag NPs/ porous silicon grating substrates was enhanced relative to the SERS response on Ag NPs/ porous silicon substrates. Ag NPs / porous silicon grating SERS substrate system achieved a highly sensitive SERS response due to the coupling of various Raman enhancement factors. PMID- 29609340 TI - Single-shot photonic time-stretch digitizer using a dissipative soliton-based passively mode-locked fiber laser. AB - We demonstrate a single-shot photonic time-stretch digitizer using a dissipative soliton-based passively mode-locked fiber laser. The theoretical analysis and simulation results indicate that the dissipative soliton-based optical source with a flat spectrum relieves the envelope-induced signal distortion, and its high energy spectral density helps to improve the signal-to-noise ratio, both of which are favorable for simplifying the optical front-end architecture of a photonic time-stretch digitizer. By employing a homemade dissipative soliton based passively mode-locked erbium-doped fiber laser in a single-shot photonic time-stretch digitizer, an effective number of bits of 4.11 bits under an effective sampling rate of 100 GS/s is experimentally obtained without optical amplification in the link and pulse envelope removing process. PMID- 29609341 TI - Dielectrophoresis-actuated in-plane optofluidic lens with tunability of focal length from negative to positive. AB - This paper reports a tunable in-plane optofluidic lens by continuously tuning a silicone oil-air interface from concave to convex using the dielectrophoresis (DEP) force. Two parallel glasses are bonded firmly on two sides by NOA 81(Norland Optical Adhesive 81) spacers, forming an open microfluidic channel. An ITO (indium tin oxide) strip and another unpatterned ITO layer are deposited on two glasses as the top and bottom electrodes. Initially, a capillary concave liquid-air interface is formed at the end of the open channel. Then the DEP force is enabled to continuously deform the interface (lens) from concave to convex. In the experiment, the focal length gradually decreases from about -1 mm to infinite and then from infinite to around + 1 mm when the driving voltage is increased from 0 V to 260 V. Particularly, the longitudinal spherical aberration (LSA) is effectively suppressed to have LSA < 0.04 when the lens is operated in the focusing state. This work is the first study of in-plane tunable lenses using the DEP force and possesses special merits as compared to the other reported tunable lenses that are formed by pumping different liquids or by temperature gradient, such as wide tunability, no need for continuous supply of liquids, low power consumption (~81 nJ per switching) due to the capacitor-type driving, and the use of only one type of liquid. Besides, its low aberration makes it favorable for light manipulation in microfluidic networks. PMID- 29609342 TI - Application of optical single-sideband laser in Raman atom interferometry. AB - A frequency doubled I/Q modulator based optical single-sideband (OSSB) laser system is demonstrated for atomic physics research, specifically for atom interferometry where the presence of additional sidebands causes parasitic transitions. The performance of the OSSB technique and the spectrum after second harmonic generation are measured and analyzed. The additional sidebands are removed with better than 20 dB suppression, and the influence of parasitic transitions upon stimulated Raman transitions at varying spatial positions is shown to be removed beneath experimental noise. This technique will facilitate the development of compact atom interferometry based sensors with improved accuracy and reduced complexity. PMID- 29609343 TI - 5.6 kW peak power, nanosecond pulses at 274 nm from a frequency quadrupled Yb doped fiber MOPA. AB - A 2 W deep-ultraviolet (DUV) source at 274 nm with 5.6 kW peak power is demonstrated by frequency quadrupling a diode-seeded, polarization-maintaining (PM), Yb-doped fiber master oscillator power amplifier (MOPA) system delivering 1.8 ns pulses at a repetition rate of 200 kHz. The second harmonic generation (SHG) and the fourth harmonic generation (FHG) are achieved by using Lithium Triborate (LBO) crystal and beta-BaB2O4 (BBO) crystal in sequence, with an IR-to green and green-to-UV conversion efficiency of up to 65% and 26%, respectively. This is the first kW peak power pulsed UV system reported at 274 nm which has great potential for machining insulators, 2D materials, isotopic separation of Calcium-48, and fluorescence analysis of biological molecules. PMID- 29609344 TI - High-repetition-rate, high-pulse-energy, and high-beam-quality laser system using an ultraclean closed-type SBS-PCM. AB - We present a high-repetition-rate, high-pulse-energy, high-beam-quality, and high average-power laser system using an ultraclean closed-type stimulated-Brillouin scattering phase-conjugate mirror (SBS-PCM). By controlling microparticles of SBS PCM down to 40 nm, thermal load capacity of such closed-type SBS-PCM was greatly improved, which presented the best reported cleanliness. The closed-type SBS-PCM, lacking scanning wedge plates, achieved reflectivity as high as 92% and showed no optical breakdown phenomena or obvious thermal effects at a 500 Hz pulse repetition frequency (PRF). Operation at 550 W output power, approximately 1.1 J pulse energy, and beam quality M2 of approximately 2 represents, to our knowledge, the best reported performance. Thermal phase distortion was compensated, and the maximum-output-power pulse-width compression improved from 30 ns to approximately 10 ns. PMID- 29609345 TI - Time resolved Fabry-Perot measurements of cavity temperature in pulsed QCLs. AB - Temperature rise during operation is a central concern of semiconductor lasers and especially difficult to measure during a pulsed operation. We present a technique for in situ time-resolved temperature measurement of quantum cascade lasers operating in a pulsed mode at ~9.25 MUm emission wavelength. Using a step scan approach with 5 ns resolution, we measure the temporal evolution of the spectral density, observing longitudinal Fabry-Perot modes that correspond to different transverse modes. Considering the multiple thin layers that make up the active layer and the associated Kapitza resistance, thermal properties of QCLs are significantly different than bulk-like laser diodes where this approach was successfully used. Compounded by the lattice expansion and refractive index changes due to time-dependent temperature rise, Fabry-Perot modes were observed and analyzed from the time-resolved emission spectra of quantum cascade lasers to deduce the cavity temperature. Temperature rise of a QCL in a pulsed mode operation between -160 degrees C to -80 degrees C was measured as a function of time. Using the temporal temperature variations, a thermal model was constructed that led to the extraction of cavity thermal conductivity in agreement with previous results. Critical in maximizing pulsed output power, the effect of the duty cycle on the evolution of laser heating was studied in situ, leading to a heat map to guide the operation of pulsed lasers. PMID- 29609346 TI - Ultra-large core birefringent Yb-doped tapered double clad fiber for high power amplifiers. AB - We present a birefringent Yb-doped tapered double-clad fiber with a record core diameter of 96 um. An impressive gain of over 38 dB was demonstrated for linearly polarized CW and pulsed sources at a wavelength of 1040 nm. For the CW regime the output power was70 W. For a mode-locked fiber laser a pulse energy of 28 uJ with 292 kW peak power was reached at an average output power of 28 W for a 1 MHz repetition rate. The tapered double-clad fiber has a high value of polarization extinction ratio at 30 dB and is capable of delivering the linearly polarized diffraction-limited beam (M2 = 1.09). PMID- 29609347 TI - Chirality induced asymmetric spin splitting of light beams reflected from an air chiral interface. AB - The spin Hall effect (SHE) of light beams reflected from an air-chiral interface are investigated systematically. Due to the intrinsic chiral asymmetry of the medium, a horizontally polarized incident Gaussian beam will undergo asymmetric spin splitting, i.e., both the displacements and energies of two spin components of the reflected beam are different. One spin component can undergo large displacement near points of |rpp| = |rsp| (rpp and rsp are the Fresnel reflection coefficients), where the reflected beams are almost in circular polarization states. Moreover, for an incident beam carrying orbital angular momentum (OAM), the two spin components acquire additional OAM dependent shifts, which attribute to the asymmetric spin splitting. Thus, the asymmetric spin splitting of the reflected beam will vary with the incident OAM. These findings provide a deeper insight into the SHE of light, and they may have potential application in precision metrology. PMID- 29609348 TI - Statistical analysis of nonlinear coupling in a WDM system over a two mode fiber. AB - We study the effect of nonlinear coupling in a WDM configuration over a two-mode fiber. A statistical analysis is presented that takes into account the effect of the random phase-sensitive amplification or depletion. Our results show high nonlinear coupling between the modes. We have quantified the channel power fluctuations, due to the wave phase random variations, at the output of the fiber. We also investigate the effect of random linear mode coupling on the nonlinear mode coupling. PMID- 29609349 TI - Free-space optical channel characterization and experimental validation in a coastal environment. AB - Over the years, free-space optical (FSO) communication has attracted considerable research interest owing to its high transmission rates via the unbounded and unlicensed bandwidths. Nevertheless, various weather conditions lead to significant deterioration of the FSO link capabilities. In this context, we report on the modelling of the channel attenuation coefficient (beta) for a coastal environment and related ambient, considering the effect of coastal air temperature (T), relative humidity (RH) and dew point (TD) by employing a mobile FSO communication system capable of achieving a transmission rate of 1 Gbps at an outdoor distance of 70 m for optical beam wavelengths of 1310 nm and 1550 nm. For further validation of the proposed models, an indoor measurement over a 1.5 m distance utilizing 1310 nm, 1550 nm, and 1064 nm lasers was also performed. The first model provides a general link between T and beta, while the second model provides a relation between beta, RH as well as TD. By validating our attenuation coefficient model with actual outdoor and indoor experiments, we obtained a scaling parameter x and decaying parameter c values of 19.94, 40.02, 45.82 and 0.03015, 0.04096, 0.0428 for wavelengths of 1550, 1310, 1064 nm, respectively. The proposed models are well validated over the large variation of temperature and humidity over the FSO link in a coastal region and emulated indoor environment. PMID- 29609350 TI - Optical single side-band Nyquist PAM-4 transmission using dual-drive MZM modulation and direct detection. AB - We present the design and optimization of the optical single side-band (SSB) Nyquist four-level pulse amplitude modulation (PAM-4) transmission using dual drive Mach-Zehnder modulator (DDMZM)modulation and direct detection (DD), aiming at the C-band cost-effective, high-speed and long-distance transmission. At the transmitter, the laser line width should be small to avoid the phase noise to amplitude noise conversion and equalization-enhanced phase noise due to the large chromatic dispersion (CD). The optical SSB signal is generated after optimizing the optical modulation index (OMI) and hence the minimum phase condition which is required by the Kramers-Kronig (KK) receiver can also be satisfied. At the receiver, a simple AC-coupled photodiode (PD) is used and a virtual carrier is added for the KK operation to alleviate the signal-to-signal beating interference (SSBI).A Volterra filter (VF) is cascaded for remaining nonlinearities mitigation. When the fiber nonlinearity becomes significant, we elect to use an optical band-pass filter with offset filtering. It can suppress the simulated Brillouin scattering and the conjugated distortion by filtering out the imaging frequency components. With our design and optimization, we achieve single channel, single polarization 102.4-Gb/s Nyquist PAM-4 over 800-km standard single mode fiber (SSMF). PMID- 29609351 TI - Laser acceleration of absorbing particles. AB - A Yb-doped fiber laser is used to accelerate and evaporate absorbing particles in air. Optical intensities of 1MW/cm2 and 2MW/cm2 illuminate stainless steel particles. These particles are accelerated to velocities of tens of meters per second before evaporating within a few tenths of a millisecond. Position measurements are made using direct imaging with a high-speed camera. A fundamental system of coupled differential equations to track particle momentum, velocity, mass, radius, temperature, vapor opacity, and temperature distribution is developed and shown to accurately model the trajectories and lifetimes of laser heated particles. Atoms evaporating from the particle impart momentum to the larger particle, which accelerates until it is slowed by drag forces. Heat transfer within the evaporating particles is dominated by radiation diffusion, a process that usually only dominates in astrophysical objects, for example in the photospheres of stars. PMID- 29609352 TI - Marangoni force-driven manipulation of photothermally-induced microbubbles. AB - The generation and manipulation of microbubbles by means of temperature gradients induced by low power laser radiation is presented. A laser beam (lambda = 1064 nm) is divided into two equal parts and coupled to two multimode optical fibers. The opposite ends of each fiber are aligned and separated a distance D within an ethanol solution. Previously, silver nanoparticles were photo deposited on the optical fibers ends. Light absorption at the nanoparticles produces a thermal gradient capable of generating a microbubble at the optical fibers end in non absorbent liquids. The theoretical and experimental studies carried out showed that by switching the thermal gradients, it is possible to generate forces in opposite directions, causing the migration of microbubbles from one fiber optic tip to another. Marangoni force induced by surface tension gradients in the bubble wall is the driving force behind the manipulation of microbubbles. We estimated a maximum Marangoni force of 400nN for a microbubble with a radius of 110 MUm. PMID- 29609353 TI - High-speed Si/GeSi hetero-structure Electro Absorption Modulator. AB - The ever-increasing demand for integrated, low power interconnect systems is pushing the bandwidth density of CMOS photonic devices. Taking advantage of the strong Franz-Keldysh effect in the C and L communication bands, electro absorption modulators in Ge and GeSi are setting a new standard in terms of device footprint and power consumption for next generation photonics interconnect arrays. In this paper, we present a compact, low power electro-absorption modulator (EAM) Si/GeSi hetero-structure based on an 800 nm SOI overlayer with a modulation bandwidth of 56 GHz. The device design and fabrication tolerant process are presented, followed by the measurement analysis. Eye diagram measurements show a dynamic ER of 5.2 dB at a data rate of 56 Gb/s at 1566 nm, and calculated modulator power is 44 fJ/bit. PMID- 29609354 TI - Explanation of the distorted spectrum in a spectral hole burning RF spectrum analyzer using Bloch equations. AB - A readout using a frequency-chirped laser is investigated in a spectrum analyzer with spectral-hole-burning (SHB). An analysis based on the Bloch equations is presented for the spectral distortion due to a fast readout, and a recovery algorithm is developed for the distortion. The experiment of a SHB spectrum analyzer is executed to demonstrate the optical spectral distortion due to fast readout. The experimental spectral distortion is recovered by the recovery algorithm developed from the Bloch equations. PMID- 29609355 TI - Evolution properties of polarization states of far-zone electromagnetic field scattered from an anisotropic medium. AB - Within the accuracy of the first-order Born approximation, expressions are derived for the cross-spectral density matrix of the electromagnetic field scattered from a three-dimensional (3D), spatially anisotropic medium. By using the analytical forms of the spectral degree of polarization (SDOP), semi-major axis, semi-minor axis, and orientation angle of the polarization ellipse, we illustrate the evolution properties of the polarization states of the far-zone scattered field. Dependences of the polarization ellipses on different combinations of correlation lengths of the medium and polarization of incident plane wave are also revealed through numerical simulations. It is shown that the polarization ellipse of the scattered field can be either stretched or squeezed along certain scattering angles, strongly depending on the anisotropic statistics of medium and polarization of incident plane wave. Our results substantially enrich the study on the reciprocal relations between the far-zone scattered properties and correlation statistics of a spatially anisotropic medium. PMID- 29609356 TI - Doppler-free spectroscopy with a terahertz quantum-cascade laser. AB - We report on the Doppler-free saturation spectroscopy of a molecular transition at 3.3 THz based on a quantum-cascade laser and an absorption cell in a collinear pump-probe configuration. A Lamb dip with a sub-Doppler linewidth of 170 kHz is observed for a rotational transition of HDO. We found that a certain level of external optical feedback is tolerable as long as the free spectral range of the external cavity is large compared to the width of the absorption line. PMID- 29609357 TI - Implementation of a violet Scheimpflug lidar system for atmospheric aerosol studies. AB - A violet Scheimpflug lidar system employing a 1-W 407-nm multimode laser diode is developed for remote sensing of atmospheric aerosols. The laser beam of the laser diode that is transmitted into atmosphere has been investigated in detail and a cylindrical lens pair is designed to improve the geometrical transmission efficiency. A measurement scheme with automatic exposure as well as a generalized signal processing method are established to optimize the signal-to-noise ratio of lidar signals. The performance of the violet Scheimpflug lidar system has been evaluated during a six-day continuous measurement campaign on a near horizontal path. The maximum measurement distance can reach up to 7 km in sunny clean weathers and to about 2 km during haze with an aerosol extinction coefficient of about 0.9 km. The aerosol extinction coefficient retrieved by the Fernald method is promising and shows good correlation with particle concentrations measured by a local national pollution monitoring station. This work promotes the development of all-time Scheimpflug lidar systems operating at other wavelengths or multiple wavelengths for various atmospheric applications. PMID- 29609358 TI - Mesoscale trumps nanoscale: metallic mesoscale contact morphology for improved light trapping, optical absorption and grid conductance in silicon solar cells. AB - We report on a computational study exploring the design of mesoscale metallic front contacts for solar cells. We investigated silver contact structures with circle, triangle and square cross-sections for various length scales and surface coverages. We found that for 'nanoscale' contacts with widths between 10 nm and 1000 nm, resonant coupling actually impairs light absorption in the semiconductor. Conversely, for 'mesoscale' contact widths > 1000 nm, the light interaction is determined by the geometric shadowing. We find that mesoscale silver contacts with triangular cross-section outperform other nanostructure morphologies in reducing shadow losses and yield contact transparency of >99% percent with sheet resistance <0.2 Omega/sq. Surprisingly, very densely spaced mesoscale silver triangular cross-section contacts can enhance the absorption of thin silicon/silver structures by up to 15% at a front contact coverage of 83%, due to light trapping by the front contact. Such structures can also maintain up to 100% absorption within the silicon, at a front contact coverage of 50%, relative to the same structure without metal. PMID- 29609359 TI - Improving the optical performance of multi-chip LEDs by using patterned phosphor configurations. AB - In order to improve the color uniformity of multi-chip LEDs, a patterned phosphor configuration has been proposed by using pulsing spray process. The patterned phosphor has detached yellow and red phosphor regions matching every single LED chip. Optical performances of different phosphor parameters are experimentally investigated. The results show that the yellow central coating (YCC) configuration produces outstanding performance not only in chromatic uniformity but also in luminous. In comparison with the conventional phosphor coating, the YCC patterned phosphor LED can improve the luminous flux by 20.6%, and decrease the difference of the correlated color temperature (CCT) distribution from 1362K to 489K. We believe that the patterned phosphor configuration can be used for improving optical properties of multi-chip LEDs. PMID- 29609360 TI - Shift of zero-dispersion wavelength in bent optical fibers. AB - The understanding of how bending modifies the dispersion of optical fibers, in particular, the zero-dispersion wavelength (lambda0), is essential in the development of compact nonlinear optical devices such as parametric amplifiers, wavelength converters, soliton lasers and frequency comb generators. Typically, substantial variations in the parametric gain and/or conversion efficiency are significant for changes in lambda0 of ~0.1 nm, which occur for variations on the bending radius (Rb) of 1 cm or less. Measuring lambda0 as a function of bending radius (Rb) is challenging, as it requires detecting changes < 0.1 nm and in short fibers. By using a method based on four-wave mixing (FWM) generated by an incoherent-pump with relatively broad spectrum and a weak laser, we report measurements of lambda0 as a function of Rb in a dispersion-shifted fiber with <0.1 nm accuracy on lambda0. This method is sensitive enough to measure small variations in lambda0 of ~0.04 nm in very short fibers (~20 m). We observe that lambda0 increases by 12 nm when Rb is decreased from 10 cm to 1 cm, and a change of 1 nm is obtained for Rb = 3 cm. We also present numerical simulations of the bent fiber that are in good agreement with our measurements, and help us to explain the observations and to predict how high-order dispersion is modified with bending. This study can provide insights for dispersion engineering, in which bending could be used as a tuning, equalization, or tailoring mechanism for lambda0, which can be used in the development of compact nonlinear optical devices based on fibers or other bent-waveguide structures. PMID- 29609361 TI - Coherent beam combination of four holmium amplifiers with phase control via a direct digital synthesizer chip. AB - We present the coherent beam combination of four 2100 nm holmium amplifiers with their phase controlled through acousto-optic modulators driven by the RF output of direct digital synthesizer chips. Phase alignment was achieved through the use of a field programmable gate array based stochastic parallel gradient descent algorithm. PMID- 29609362 TI - Gradient phase partially reflecting surfaces for beam steering in microwave antennas. AB - A metal-dielectric-metal gradient phase partially reflecting surface based on the combination of a gradient index dielectric substrate with an inductive and a capacitive grids, is designed at microwave frequencies for antenna applications. The gradient index is obtained by realizing air holes of different dimensions in a dielectric host material. A prototype of the gradient index dielectric substrate is fabricated through three-dimensional printing, an additive fabrication technology. It is then associated to two patterned metallic grids to realize a partially reflecting surface with a gradient phase behavior. For experimental validation, the partially reflective surface is used as reflector in a low-profile Fabry-Perot cavity antenna. An angular enhancement of the emitted beam in a desired direction is reported by further engineering the phase introduced by the inductive and the capacitive grids. Far-field measurements are performed on fabricated antenna prototypes to validate the concept. Such gradient phase reflective surface paves the way to low-cost easy-made microwave metal dielectric surfaces incorporating functionalities such as beam control, forming and collimation. PMID- 29609363 TI - VSPIN: a new model relying on the vectorial description of the laser field for predicting the polarization dynamics of spin-injected V(e)CSELs. AB - A new vectorial model (VSPIN) based on the Jones formalism is proposed to describe the polarization dynamics of spin injected V(e)CSELs. This general modelling framework accounts for spin injection effects as a gain circular dichroism in the active medium and provides guidelines for developing functional spin-controlled lasers. We investigate the detrimental role of phase anisotropy on polarization switching and show that it can be overcome by preparing the laser cavity to achieve efficient polarization switching under low effective spin injection. The VSPIN model predictions have been confirmed experimentally and explain the polarization behavior of spin-VCSELs reported in the literature. PMID- 29609364 TI - Digital-to-analog converters for high-speed optical communications using frequency interleaving: impairments and characteristics. AB - Digital-to-analog converters (DACs) for high-speed optical communication systems based on CMOS technology have bandwidths lower than nowadays electro-optic components. A promising concept to circumvent this bottleneck is the frequency interleaved DAC (FI-DAC) concept. In this paper, experimental results for the application of a 180 GS/s FI-DAC with 40 GHz analog bandwidth based on two DACs in a high-speed optical link are discussed and compared with simulation results. Thereby, phase and power mismatches, spectral overlap, clipping and the required DAC resolution are investigated. Signal-to-noise ratio (SNR) estimations based on a discrete multi-tone (DMT) signal show the influence of the individual analog components on the signal quality. PMID- 29609365 TI - Few-femtosecond extreme-ultraviolet pulses fully reconstructed by a ptychographic technique. AB - Sub-10-fs pulses tunable in the extreme-ultraviolet (XUV) spectral region are particularly important in many research fields: from atomic and molecular spectroscopy to the study of relaxation processes in solids and transition phase processes, from holography to free-electron laser injection. A crucial prerequisite for all applications is the accurate measurement of the temporal characteristics of these pulses. To fulfill this purpose, many phase retrieval algorithms have been successfully applied to reconstruct XUV attosecond pulses. Nevertheless, their extension to XUV femtosecond pulses is not trivial and has never been investigated/reported so far. We demonstrate that ultrashort XUV pulses, produced by high-order harmonic generation, spectrally filtered by a time delay compensated monochromator, can be fully characterized, in terms of temporal intensity and phase, by employing the ptychographic reconstruction technique while other common reconstruction algorithms fail. This allows us to report on the generation and complete temporal characterization of XUV pulses with duration down to 5 fs, which constitute the shortest XUV pulse ever achieved via a time delay compensated monochromator. PMID- 29609366 TI - Effect of backscattering in phase contrast imaging of the retina. AB - The observation of retinal cellular structures is fundamental to the understanding of eye pathologies. However, except for rods and cones, most of the retinal microstructures are weakly reflective and thus difficult to image with state of the art reflective optical imaging techniques such as optical coherence tomography. Recently, we demonstrated the possibility of obtaining the phase contrast of retinal cells in the eye using oblique illumination of the retina. Indeed, by illuminating the eye with incoherent oblique illumination, we obtain a secondary oblique illumination from the backscattered light which can then be used to obtain phase contrast in an effective transmission-like configuration. In this technique, a weak phase signal is modulated over an intense background. Maximizing this phase contrast is thus crucial for the image quality. Here, we investigate the parameters that affect phase contrast by modelling image formation with the backscattered light. We find that the key parameter for maximizing contrast is the intensity profile of the backscattered light. Specifically, the gradient of the profile is found to be proportional to the phase contrast. We validate the model by comparing simulations with experimental results on ex-vivo retina samples. PMID- 29609367 TI - Development of a TiO2/SiO2 waveguide-mode chip for an ultraviolet near-field fluorescence sensor. AB - Aimed at detecting fluorescent-labeled biological substances sensitively, a sensor that utilizes near-field light has attracted much attention. According to our calculations, a planar structure composed of two dielectric layers can enhance the electric field of UV near-field light effectively by inducing waveguide-mode (WM) resonance. The fluorescence intensity obtainable by a WM chip with an optimized structure is 5.5 times that obtainable by an optimized surface plasmon resonance chip. We confirmed the above by making a WM chip consisting of TiO2 and SiO2 layers on a silica glass substrate and by measuring the fluorescence intensity of a solution of quantum dots dropped on the chip. PMID- 29609368 TI - Polarimetric lidar measurements of aquatic turbulence - laboratory experiment. AB - Lidar is one of few remote sensing methods available to researchers to sense below the oceanic air-surface. We present polarimetric lidar measurements of turbulence in a laboratory generated turbulent flow. We found that the nearforward light depolarization characterized by the depolarization rate gamma(z), varies with the turbulent flow parameter: chi(z)?(z)1/4, where chi(z) and ?(z) are the respective depth dependent, temperature variance, and turbulent kinetic energy dissipation rates. The presence of particles in the flow modifies the values of gamma in such a way that the ratio gamma(z)/alpha(z) becomes independent of the particle concentration and depends only on chi(z)?(z)1/4. We posit that the mechanism of light depolarization in turbulent flow with particles is forward scattered light interaction between turbulent refractive index inhomogeneities and flow particles. Such interactions result so that the observed depolarization rate, gamma(z), is much larger than expected from 'pure' turbulent flow. Our observations open up the fascinating possibility of using lidar for turbulence measurements of aquatic flows. PMID- 29609369 TI - High-efficiency sub-watt in-band-pumped single-frequency DBR Tm3+-doped germanate fiber laser at 1950 nm. AB - Based on a 1.8-cm-long heavily Tm3+-doped germanate fiber and being in-band pumped by a 1610 nm single-mode laser, a high-efficiency and high-power single frequency distribute Bragg reflector (DBR) fiber laser emitting at 1950 nm is demonstrated. The DBR fiber laser has a maximum output power of ~617 mW and a slope efficiency for the absorbed pump power reaches to more than 42.2%. A stable single-longitudinal-mode laser output with a signal-to-noise ratio of greater than 63 dB is realized. The measured relative intensity-noise of the fiber laser reaches to around -150 dB/Hz at frequencies of over 8.4 MHz. It is beneficial to exploit the sub-watt and high-efficiency single-frequency laser from fiber oscillators directly, especially in the application of multiple paths coherent beam combination and optical medical technology. PMID- 29609370 TI - Ultrafast diode-pumped Ti:sapphire laser with broad tunability. AB - We report a broadly wavelength-tunable femtosecond diode-pumped Ti:sapphire laser, passively mode-locked using both semiconductor saturable absorber mirror (SESAM) and Kerr-lens mode-locking (KLM) techniques. Using two pump laser diodes (operating at 450 nm), an average output power as high as 433 mW is generated during mode-locking with the SESAM. A tunability range of 37 nm (788-825 nm) was achieved with the shortest pulse duration of 62 fs at 812 nm. In the KLM regime, an average output power as high as 382 mW, pulses as short as 54 fs, and a tunability of 120 nm (755-875 nm) are demonstrated. PMID- 29609371 TI - Ground-based synchronous optical instrument for measuring atmospheric visibility and turbulence intensity: theories, design and experiments. AB - Atmospheric visibility and turbulence are important meteorological factors in light propagation and optical communication, air quality prediction, and climate environment model. They are often measured separately by the conventional instruments, but the interaction between aerosol (closely relate to visibility) and turbulence may potentially influence their measurement accuracy. In this paper, a novel instrument, the atmospheric visibility and turbulence optical meter (AVTOM), is developed to synchronously measure atmospheric visibility and turbulence intensity through a transmission method. The atmospheric visibility is measured by the extinction principle whereas the turbulence intensity is measured by the light intensity flicker principle. We validated the measurement results by comparing them to other two conventional instruments in July 2017, at Nanjing, in southeast China. They agree well with the relative differences of 4.7% for the visibility and 3.5% for the turbulence intensity, respectively. We further demonstrated their dynamic changes under the different weather or aerosol loadings through the synchronous measurements, which may be associated with the aerosol-turbulence-interaction. Finally, we proposed a calibration method and discussed the measurement errors. PMID- 29609372 TI - Husimi functions at gradient index cavities designed by conformal transformation optics. AB - Dielectric cavity systems, which have been studied extensively so far, have uniform refractive indices of their cavities, and Husimi functions, the most widely used phase space representation of optical modes formed in the cavities, accordingly were derived only for these homogeneous index cavities. For the case of the recently proposed gradient index dielectric cavities (called as transformation cavities) designed by optical conformal mapping, we show that the phase space structure of resonant modes can be revealed through the conventional Husimi functions by constructing a reciprocal virtual space. As examples, the Husimi plots were obtained for an anisotropic whispering gallery mode (WGM) and a short-lived mode supported in a limacon-shaped transformation cavity. The phase space description of the corresponding modes in the reciprocal virtual space is compatible with the far-field directionality of the resonant modes in the physical space. PMID- 29609373 TI - Spectrally resolved single-shot wavefront sensing of broadband high-harmonic sources. AB - Wavefront sensors are an important tool to characterize coherent beams of extreme ultraviolet radiation. However, conventional Hartmann-type sensors do not allow for independent wavefront characterization of different spectral components that may be present in a beam, which limits their applicability for intrinsically broadband high-harmonic generation (HHG) sources. Here we introduce a wavefront sensor that measures the wavefronts of all the harmonics in a HHG beam in a single camera exposure. By replacing the mask apertures with transmission gratings at different orientations, we simultaneously detect harmonic wavefronts and spectra, and obtain sensitivity to spatiotemporal structure such as pulse front tilt as well. We demonstrate the capabilities of the sensor through a parallel measurement of the wavefronts of 9 harmonics in a wavelength range between 25 and 49 nm, with up to lambda/32 precision. PMID- 29609374 TI - Programmable passive Talbot optical waveform amplifier. AB - We introduce and experimentally demonstrate a new design for passive Talbot amplification of repetitive optical waveforms, in which the gain factor can be electrically reconfigurable. The amplifier setup is composed of an electro-optic phase modulator followed by an optical dispersive medium. In contrast to conventional Talbot amplification, here we achieve different amplification factors by using combinations of fixed dispersion and programmable temporal phase modulation. To validate the new design, we experimentally show tunable, passive amplification of picosecond optical pulses with gain factors from m = 2 to 30 using a fixed dispersive line (a linearly chirped fiber Bragg grating). PMID- 29609375 TI - Efficient higher-order nonlinear optical effects in CdSe nanowaveguides. AB - Stimulating higher-order nonlinear optical (HO-NLO) response from individual semiconductor nanostructures is challenging due to the low nonlinear coefficients and the small number of molecules within the nanostructures. In this work, we demonstrate efficient third harmonic generation and multi-photon luminescence in CdSe nanowaveguides by means of evanescent wave coupling technique. Under appropriate conditions, a coupling efficiency of 70% can be achieved from an optical microfiber to a single CdSe nanowaveguide, leading to the enhanced HO-NLO effects. Provided a high signal-to-noise ratio, we thus observe a fourth order excitation power dependence of 3-photon luminescence, and we attribute it to surface defect mechanism based on the recombination of free carriers. This work provides an alternative for efficient excitation for HO-NLO, which also makes these hard-to-produce signals more feasible in the applications of nonlinear optical devices. PMID- 29609376 TI - Enhanced secure 4-D modulation space optical multi-carrier system based on joint constellation and Stokes vector scrambling. AB - This paper proposes and demonstrates an enhanced secure 4-D modulation optical generalized filter bank multi-carrier (GFBMC) system based on joint constellation and Stokes vector scrambling. The constellation and Stokes vectors are scrambled by using different scrambling parameters. A multi-scroll Chua's circuit map is adopted as the chaotic model. Large secure key space can be obtained due to the multi-scroll attractors and independent operability of subcarriers. A 40.32Gb/s encrypted optical GFBMC signal with 128 parallel subcarriers is successfully demonstrated in the experiment. The results show good resistance against the illegal receiver and indicate a potential way for the future optical multi carrier system. PMID- 29609377 TI - Spectral and angular shaping of infrared radiation in a polymer resonator with molecular vibrational modes. AB - We present a comprehensive approach for tailoring the spectral and angular properties of infrared thermal radiation by using a polymer resonator with molecular vibrational modes, consisting of a polymer thin film on a back reflective substrate. To precisely design the resonator, we derived the infrared dielectric function of a poly(methyl methacrylate) (PMMA) thin film from the measured reflectance spectrum by fitting it with a Gaussian-convoluted Drude Lorentz model while accounting for the inhomogeneous broadening caused by the disordered structure of polymers. Our experimental and numerical characterization confirms that the polymer resonator exhibits spectral shaping from quasi broadband to narrowband due to the intrinsic molecular vibrational absorption of the polymer. The frequency-isolated and strong molecular vibrational absorption of the carbonyl stretching mode at 1730 cm-1 enables the narrowband shaping of the PMMA resonator. In addition, we confirm that the angular-shaping characteristics of this polymer resonator can be tuned, from omnidirectional to strongly angular selective, by changing its polymer film thickness. Modal dispersion analysis reveals that the angle-selectivity of the polymer resonator at an angle of incidence of 80 degrees comes from coupling between the molecular vibrational mode and leaky mode. The proposed infrared radiation management strategy based on molecular vibrational modes of polymers is cost-effective, scalable, and works well with terrestrial matter, including organic compounds and gas molecules, showing promise for applications such as optical gas sensing and radiative thermal management. PMID- 29609378 TI - Dynamic strain measurement with kHz-level repetition rate and centimeter-level spatial resolution based on Brillouin optical correlation domain analysis. AB - In this paper, we propose and demonstrate an ultrahigh-speed Brillouin optical correlation domain analysis (BOCDA) with a single-position sampling rate of 200 kS/s and a spatial resolution of 8 cm. The Brillouin gain spectrum (BGS) is obtained by using a data subtraction scheme rather than the conventional lock-in amplifier (LIA) detection configuration, thus removing the limitation of measurement speed imposed by the LIA. Meanwhile, a voltage controlled oscillator (VCO) is used to sweep the frequency interval between the pump and the probe rapidly. As a proof of concept, we implement measurements of various dynamic strains with frequencies up to 20 kHz at arbitrary position. Moreover, to implement high-speed distributed measurements of Brillouin frequency shift (BFS) along the whole fiber under test (FUT), we propose a novel measuring method which moves the correlation peak and sweeps the pump-probe frequency interval simultaneously. A repetition rate of 1 kHz is verified by measuring dynamic strains with frequencies up to 200 Hz, for distributed measurements performed with 200 points. PMID- 29609379 TI - Doubling the pixel count limitation of single-pixel imaging via sinusoidal amplitude modulation. AB - We demonstrate a single-pixel imaging (SPI) method that can achieve pixel resolution beyond the physical limitation of the spatial light modulator (SLM), by adopting sinusoidal amplitude modulation and frequency filtering. Through light field analysis, we observe that the induced intensity with a squared value of the amplitude contains higher frequency components. By filtering out the zero frequency of the sinusoidal amplitude in the Fourier domain, we can separate out the higher frequency components, which enables SPI with higher resolving ability and thus beyond the limitation of the SLM. Further, to address the speed issue in grayscale spatial light modulation, we propose a fast implementation scheme with tens-of-kilohertz refresh rate. Specifically, we use a digital micromirror device (DMD) working at the full frame rate to conduct binarized sinusoidal patterning in the spatial domain and pinhole filtering eliminating the binarization error in the Fourier domain. For experimental validation, we build a single-pixel microscope to retrieve 1200 * 1200-pixel images via a sub-megapixel DMD, and the setup achieves comparable performance to array sensor microscopy and provides additional sectioning ability. PMID- 29609380 TI - Real-time transmission of 16 Tb/s over 1020km using 200Gb/s CFP2-DCO. AB - We demonstrate real-time transmission of 16 Tb/s (80x200Gb/s) over 1020km TeraWave ULL fiber with 170km span length using the world's first 200Gb/s CFP2 DCO module with a record low power consumption less than 0.1W/Gbps. PMID- 29609381 TI - Symmetric and asymmetric solitons supported by a ????-symmetric potential with saturable nonlinearity: bifurcation, stability and dynamics. AB - The symmetry breaking bifurcation of solitons in an optical waveguide with focusing saturable nonlinearity and parity-time (????)-symmetric complex-valued external potentials is investigated. As the soliton power increases, it is found that the branches of asymmetric solitons split off from the base branches of ???? symmetric fundamental soliton. The bifurcation diagrams, consisting essentially of the propagation constants of optical solitons, indicate that symmetric fundamental and multipole solitons, as well as asymmetric solitons can exist. The stabilities and the dynamics characteristics of solitons are comprehensively investigated. We find the different instability scenarios of the symmetric solitons, but the symmetry breaking bifurcation is caused only by the onset of instability of the symmetric fundamental solitons. This result is further confirmed by the numerical examples with the different saturable nonlinearity parameters. In particular, we find that the soliton power and the stability of soliton at the bifurcation points are significantly changed by varying the strength of the saturable nonlinearities. These results provide additional way to control symmetry breaking bifurcations in ????-symmetric optical waveguide. PMID- 29609382 TI - Brillouin optical correlation domain analysis based on chaotic laser with suppressed time delay signature. AB - A new technology for Brillouin optical correlation domain analysis (BOCDA) based on chaotic laser is proposed, analyzed and demonstrated. The numerical simulation shows that the stimulated acoustic field has the secondary spurious peaks, which are the result of a weak amplitude autocorrelation of the chaotic signal occurring at the delay time of the external cavity, i.e., time delay signature (TDS). These secondary spurious peaks deteriorate the Brillouin gain spectrum and decrease the performance of the chaotic BOCDA system. The effect of the injection current and feedback strength on the TDS suppression is theoretically analyzed. By optimizing the two free parameters, chaotic laser sources operate in a TDS suppression region. Ultimately, a 3.2 km long single-mode fiber with a spatial resolution of 7.4 cm is experimentally demonstrated. The uncertainty of the local Brillouin frequency shift is +/- 1.2 MHz. PMID- 29609383 TI - Mid-frequency MTF compensation of optical sparse aperture system. AB - Optical sparse aperture (OSA) can greatly improve the spatial resolution of optical system. However, because of its aperture dispersion and sparse, its mid frequency modulation transfer function (MTF) are significantly lower than that of a single aperture system. The main focus of this paper is on the mid-frequency MTF compensation of the optical sparse aperture system. Firstly, the principle of the mid-frequency MTF decreasing and missing of optical sparse aperture are analyzed. This paper takes the filling factor as a clue. The method of processing the mid-frequency MTF decreasing with large filling factor and method of compensation mid-frequency MTF with small filling factor are given respectively. For the MTF mid-frequency decreasing, the image spatial-variant restoration method is proposed to restore the mid-frequency information in the image; for the mid-frequency MTF missing, two images obtained by two system respectively are fused to compensate the mid-frequency information in optical sparse aperture image. The feasibility of the two method are analyzed in this paper. The numerical simulation of the system and algorithm of the two cases are presented using Zemax and Matlab. The results demonstrate that by these two methods the mid frequency MTF of OSA system can be compensated effectively. PMID- 29609384 TI - Improvement of ultrafast holographic performance in silver nanoprisms dispersed photopolymer. AB - This work demonstrates the grating formation of bulk nanoparticle polymer composites through an improved interference optical system under ultrafast nanoseconds exposure of a silver nanoprisms (NPs) dispersed photo-polymerizable mixture in the case of 532 nm wavelength. The polymerizable mixture is composed of phenathrenequinone (PQ) (photoinitiator) and methyl methacrylate (MMA) (monomer). The mechanism in this bulk nanoparticle polymer composite is analyzed by mixing nonlocal polymerization driven diffusion (NPDD) model and absorption modulation caused by the spatial concentration distribution difference of silver NPs. We find that the attenuation of diffraction efficiency under pulsed exposure is due to the reciprocity law failure. This work presents an analysis of the cause of reciprocity failure and improvement in holographic properties by doping silver NPs. The optimized photopolymer presents diffraction efficiencies as high as 51.4% with 1.8 MUs cumulative pulsed exposure. Cumulative gratings strength is also enhanced by 70% while doping silver NPs under 1.5 MUs cumulative pulsed exposure. PMID- 29609385 TI - Design and fabrication of a heterostructured cladding solid-core photonic bandgap fiber for construction of Mach-Zehnder interferometer and high sensitive curvature sensor. AB - A heterostructured cladding solid-core photonic bandgap fiber (HCSC-PBGF) is designed and fabricated which supports strong core mode and cladding mode transmission in a wide bandgap. An in-line Mach-Zehnder interferometer (MZI) curvature sensor is constructed by splicing single mode fibers at both ends of a HCSC-PBGF. Theoretical analysis of this heterostructured cladding design has been implemented, and the simulation results are consistent with experiment results. Benefiting from the heterostructured cladding design, an enhanced curvature sensing sensitivity of 24.3 nm/m-1 in the range of 0-1.75 m-1 and a high quality interference spectrum with 20 dB fringe visibility are achieved. In order to eliminate the interference of longitudinal strain and transverse torsion on the result of the curvature sensing experiment, we measure the longitudinal strain and transverse torsion sensing properties of HCSC-PBGF, and the results show that the impact is negligible. It is obvious that this high-sensitivity and cost effective all fiber sensor with a compact structure will have a promising application in fiber sensing. PMID- 29609386 TI - LP01-LP11a mode converters based on long-period fiber gratings in a two-mode polarization-maintaining photonic crystal fiber. AB - A long-period fiber grating (LPFG) mode converter based on a two-mode polarization-maintaining photonic crystal fiber (PM-PCF) is proposed and demonstrated. The mode converters realize conversions between the LP01 modes and LP11a modes with parallel polarization directions. Different from typical conventional mode converters, the PM-PCF-LPFG mode converters most notably can separate out two linearly polarized LP11a modes at different wavelengths. The highest mode-conversion efficiency is more than 99%. In addition, the bandwidth of the mode converter is adjustable by changing the grating number of the LPFG. PMID- 29609387 TI - Directly modulated 1.3 MUm quantum dot lasers epitaxially grown on silicon. AB - We report the first demonstration of direct modulation of InAs/GaAs quantum dot (QD) lasers grown on on-axis (001) Si substrate. A low threading dislocation density GaAs buffer layer enables us to grow a high quality 5-layered QD active region on on-axis Si substrate. The active layer has p-modulation doped GaAs barrier layers with a hole concentration of 5 * 1017 cm-3to suppress gain saturation. Small-signal measurement on a 3 * 580 MUm2 Fabry-Perot laser showed a 3dB bandwidth of 6.5 GHz at a bias current of 116 mA. A 12.5 Gbit/s non-return-to zero signal modulation was achieved by directly probing the chip. Open eyes with an extinction ration of 3.3dB was observed at room temperature. The bit-error rate (BER) curve showed no error-floor up to BER of 1 * 10-13. 12 km single-mode fiber transmission experiments using the QD laser on Si showed a low power penalty of 1 dB at 5Gbit/s. These results demonstrate the potential for QD lasers epitaxially grown on Si to be used as a low-cost light source for optical communication systems. PMID- 29609388 TI - Phytoplankton photosynthetic rate measurement using tunable pulsed light induced fluorescence kinetics. AB - The photosynthetic process of phytoplankton is the basis of the material circulation and energy flow of the ecosystem. The rapid and accurate measurement of phytoplankton photosynthesis rate is of great significance to water ecological environment monitoring, marine resource assessment and global climate change prediction. On the basis of "Bio-Optical" model, a photosynthetic rate measurement method based on tunable pulsed light induced fluorescence kinetics was put forward in this paper. The chlorophyll fluorescence was used as the probe of photosynthesis process, and the phytoplankton photosynthetic rate was evaluated by the photosynthetic electron transport rate. Comparative experiment results showed that the photosynthetic electron transport rate measured by fluorescence kinetic method under different conditions of DCMU, culture light and nutrients (nitrogen) were consistent with the photosynthetic oxygen evolution rate measured by oxygen evolution method, and the correlation coefficient R2 were 0.934, 0.957 and 0.955 respectively. PMID- 29609389 TI - Direct measurement of the quantum state of photons in a cavity. AB - We propose a scheme to measure the quantum state of photons in a cavity. The proposal is based on the concept of quantum weak values and applies equally well to both the solid-state circuit and atomic cavity quantum electrodynamics (QED) systems. The proposed scheme allows us to access directly the superposition components in Fock state basis, rather than the Wigner function as usual in phase space. Moreover, the separate access feature held in the direct scheme does not require a global reconstruction for the quantum state, which provides a particular advantage beyond the conventional method of quantum state tomography. PMID- 29609390 TI - Compressive hyperspectral imaging recovery by spatial-spectral non-local means regularization. AB - Hyperspectral imaging systems can benefit from compressed sensing to reduce data acquisition demands. We present a new reconstruction algorithm to recover the hyperspectral datacube from limited optically compressed measurements, exploiting the inherent spatial and spectral correlations through non-local means regularization. The reconstruction process is solved with the help of split Bregman optimization techniques, including penalty functions defined according to the spatial and spectral properties of the scene and noise sources. For validation purposes, we also implemented a compressive hyperspectral imaging system that relies on a digital micromirror device and a near-infrared spectrometer, where we obtained enhanced and promising reconstruction results when using our proposed technique in contrast with traditional compressive image reconstruction. PMID- 29609391 TI - Robust, tunable, and high purity triggered single photon source at room temperature using a nitrogen-vacancy defect in diamond in an open microcavity. AB - We report progress in the development of tunable room temperature triggered single photon sources based on single nitrogen-vacancy (NV) centres in nanodiamond coupled to open access optical micro-cavities. The feeding of fluorescence from an NV centre into the cavity mode increases the spectral density of the emission and results in an output stream of triggered single photons with spectral line width of order 1 nm, tunable in the range 640 - 700 nm. We record single photon purities exceeding 96% and estimated device efficiencies up to 3%. We compare performance using plano-concave microcavities with radii of curvature from 25 MUm to 4 MUm and show that up to 17% of the total emission is fed into the TEM00 mode. Pulsed Hanbury-Brown Twiss (HBT) interferometry shows that an improvement in single photon purity is facilitated due to the increased spectral density. PMID- 29609392 TI - Metasurface with multi-sized structure for multi-band coherent perfect absorption. AB - We demonstrate that multi-band coherent perfect absorption can be achieved at infrared frequencies by a metasurface in which four-sized columnar metal patches are separated by a dielectric layer in a unit cell. The absorption bandwidth is enhanced by three times compared with single-band absorption while high absorbance is maintained. The coherent perfect absorption is polarization independent and can be independently modulated at each resonant frequency by tuning the phase difference of two coherent incident beams. Moreover, the resonant frequency is sensitive to the radius of the columnar patch, and thus a wide coherent perfect absorption frequency range can be obtained by adjusting the radius. Through optimizing the structural parameters, nearly perfect absorption at oblique incidence for both TE and TM polarizations are achieved. The optimized metasurface can be used as a beamsplitter at oblique incidence. PMID- 29609393 TI - Non-flickering 100 m RGB visible light communication transmission based on a CMOS image sensor. AB - We demonstrate a non-flickering 100 m long-distance RGB visible light communication (VLC) transmission based on a complementary-metal-oxide semiconductor (CMOS) camera. Experimental bit-error rate (BER) measurements under different camera ISO values and different transmission distances are evaluated. Here, we also experimentally reveal that the rolling shutter effect- (RSE) based VLC system cannot work at long distance transmission, and the under-sampled modulation- (USM) based VLC system is a good choice. PMID- 29609394 TI - Augmenting mask-based lithography with direct laser writing to increase resolution and speed. AB - A new method of hybrid photolithography, Laser Augmented Microlithographic Patterning (LAMP), is described in which direct laser writing is used to define additional features to those made with an inexpensive transparency mask. LAMP was demonstrated with both positive- and negative-tone photoresists, S1813 and SU-8, respectively. The laser written features, which can have sub-micron linewidths, can be registered to within 2.2 um of the mask created features. Two example structures, an interdigitated electrode and a microfluidic device that can capture an array of dozens of silica beads or living cells, are described. This combination of direct laser writing and conventional UV lithography compensates for the drawbacks of each method, and enables high resolution prototypes to be created, tested, and modified quickly. PMID- 29609395 TI - Low transmission penalty dual-stage broadband discrete Raman amplifier. AB - We present a broadband (>70nm), dual stage, discrete Raman amplifier designed with small and standard core fibres to maximize gain and minimize nonlinearity. The amplifier provides ~19.5dB net gain, 22.5dBm saturation output power and a noise figure of <7.2dB. 120Gb/s DP-QPSK transmission over 38x80km at a pre-FEC BER <3.8x10-3 is demonstrated. PMID- 29609396 TI - Control of the coherence behavior in a SFG interferometer through the multipump phases command. AB - In this paper, we report on a novel method to control the coherence behavior in a sum frequency generation interferometer powered by two independent pump lines. At the output of the interferometer, the two incoherent fringe patterns must be superimposed to maximize the contrast. The first step consists in canceling the differential group delay. The second one uses the phase control on one pump to synchronize the fringe patterns. This innovative method is experimentally demonstrated with a setup involving a 1544 nm signal and two pump lines around 1064 nm leading to a converted signal around 630 nm. It can be easily extended to a greater number of pump lines. PMID- 29609397 TI - Highly efficient generation of 0.2 mJ terahertz pulses in lithium niobate at room temperature with sub-50 fs chirped Ti:sapphire laser pulses. AB - We demonstrate generation of 0.2 mJ terahertz (THz) pulses in lithium niobate driven by Ti:sapphire laser pulses at room temperature. Employing tilted pulse front technique, the 800 nm-to-THz energy conversion efficiency has been optimized to 0.3% through chirping the sub-50 fs pump laser pulses to overcome multi-photon absorption and to extend effective interaction length for phase matching. Our approach paves the way for mJ-level THz generation via optical rectification using existing Ti:sapphire laser systems which can deliver Joule level pulse energy with sub-50 fs pulse duration. PMID- 29609398 TI - 3D shape measurement in the presence of strong interreflections by epipolar imaging and regional fringe projection. AB - A 3D shape measurement method in the presence of strong interreflections is presented. Traditional optical 3D shape measurement methods such as fringe projection profilometry (FPP) cannot measure regions that contain strong interreflections, which result in 3D shape measurement failure. In the proposed method, epipolar imaging with speckle patterns is utilized to eliminate the effects of interreflections and obtain the initial 3D shape measurement result. Regional fringe projection based on the initial measurement result is further applied to achieve high-accuracy measurement. Experimental results show that the proposed method can measure the regions that contain strong interreflections at a high accuracy. PMID- 29609399 TI - Size and edge dependence of two-photon absorption in rectangular graphene quantum dots. AB - The size and edge-dependence of two-photon absorption (TPA) for rectangular graphene quantum dots (GQDs) is investigated theoretically in the framework of Dirac equation under hard wall boundary conditions. The TPA cross section associated with interband transitions around K point is derived and the transition selection rules are obtained. Results reveal that when the size of zigzag-edge M = 3M0 +/- 1 (M0 is an integer), the GQD exhibits a semiconductor while for M = 3M0 it is metallic. For semiconducting rectangular GQDs, TPA is tuned by the sizes of both edges in GQDs and the armchair-edge dimension contributes more to TPA. While for metallic rectangular GQDs, zigzag-edge dimension affects TPA little and the position of absorption peak and the magnitude of the TPA coefficient are determined by the size of armchair-edge and the resonant enhancement occurs. PMID- 29609400 TI - Organic-inorganic hybrid microdisk laser with dye and silica mixed doping prepared by ink-jet printing method. AB - We developed an ink-jet printing method for fabricating inorganic microdisks at room temperature, which is much lower than the melting point of solid-state inorganic oxide, and have fabricated an organic-inorganic hybrid microdisk laser. Silica was used as the inorganic disk material, and microdisk-shaped aggregates were formed by the ink-jet printing method using a solution in which nanosilica particles were dispersed in propylene glycol monomethylether (PGME) solvent. Then, a microdisk capable of laser oscillation was also prepared by preliminarily adding the laser dye rhodamine 6G to the ink to form a mixed organic material. The structural evaluation of the printed microdisk was first conducted using an optical microscope, a scanning electron microscope (SEM), and an atomic force microscope (AFM). The results of laser oscillation evaluation by optical excitation showed that the printed microdisk sufficiently functions as an optical resonator with a low optical loss. In these evaluations, excellent values such as a surface roughness of 5.83 nm from root mean square (R. M. S.) which is one forth smaller than the particle diameter, and a laser oscillation threshold of 4.76 uJ/mm2 at a wavelength of 601.4 nm were obtained. To the best of our knowledge, this is the first time that an inorganic microdisk has been fabricated at room temperature to realize an organic-inorganic hybrid microdisk laser. PMID- 29609401 TI - Broadband tunable terahertz absorber based on vanadium dioxide metamaterials. AB - An active absorption device is proposed based on vanadium dioxide metamaterials. By controlling the conductivity of vanadium dioxide, resonant absorbers are designed to work at wide range of terahertz frequencies. Numerical results show that a broadband terahertz absorber with nearly 100% absorptance can be achieved, and its normalized bandwidth of 90% absorptance is 60% under normal incidence for both transverse-electric and transverse-magnetic polarizations when the conductivity of vanadium dioxide is equal to 2000 Omega-1cm-1. Absorptance at peak frequencies can be continuously tuned from 30% to 100% by changing the conductivity from 10 Omega-1cm-1 to 2000 Omega-1cm-1. Absorptance spectra analysis shows a clear independence of polarization and incident angle. The presented results may have tunable spectral applications in sensor, detector, and thermophotovoltaic device working at terahertz frequency bands. PMID- 29609402 TI - 1.6 MUm dissipative soliton fiber laser mode-locked by cesium lead halide perovskite quantum dots. AB - We demonstrate a stable, picosecond fiber laser mode-locked by cesium lead halide perovskite quantum dots (CsPbBr3-QDs). The saturable absorber is produced by depositing the CsPbBr3-QDs nanocrystals onto the endface of a fiber ferrule through light pressure. A balanced two-detector measurement shows that it has a modulation depth of 2.5% and a saturation power of 17.29 MW/cm2. After incorporating the fabricated device into an Er3+-doped fiber ring cavity with a net normal dispersion of 0.238 ps2, we obtain stable dissipative soliton with a pulse duration of 14.4 ps and a center wavelength at 1600 nm together with an edge-to-dege bandwidth of 4.5 nm. The linear chirped phase can be compensated by 25 m single mode fiber, resulting into a compressed pulse duration of 1.046 ps. This experimental works proves that such CsPbBr3-QDs materials are effective choice for ultrafast laser operating with devious mode-locking states. PMID- 29609403 TI - Single-chip source-free terahertz spectroscope across 0.04-0.99 THz: combining sub-wavelength near-field sensing and regression analysis. AB - This paper demonstrates a methodology to miniaturize THz spectroscopes into a single silicon chip by eliminating traditional solid-state architectural components such as complex tunable THz and optical sources, nonlinear mixing and amplifiers. The proposed method achieves this by extracting incident THz spectral signatures from the surface of an on-chip antenna itself. The information is sensed through the spectrally-sensitive 2D distribution of the impressed current surface under the THz incident field. By converting the antenna from a single port to a massively multi-port architecture with integrated electronics and deep subwavelength sensing, THz spectral estimation is converted into a linear estimation problem. We employ rigorous regression techniques and analysis to demonstrate a single silicon chip system operating at room temperature across 0.04-0.99 THz with 10 MHz accuracy in spectrum estimation of THz tones across the entire spectrum. PMID- 29609404 TI - Dynamics characteristics of highly-charged ions in laser-produced SiC plasmas. AB - The radiation and dynamic properties of C VI, C V, Si VI and Si V ions from laser produced SiC plasmas in a vacuum are studied both experimentally and theoretically. The EUV emission spectra of SiC plasmas are measured using the spatio-temporally resolved laser-produced plasma spectroscopy technique. To explore the dynamic evolution of highly-charged ions in such plasmas, an extended radiation hydrodynamics model is developed. The comparison of theoretical and experimental time-space evolved spectral profiles provides the temporal evolution of plasma temperature and electron density, the distribution of various transient ions and their velocities. The results show that the present radiation hydrodynamics model for a multi-element target reflects the dynamic evolution processes of their laser-produced plasmas, which make it an effective tool for plasma diagnostics. PMID- 29609405 TI - Velocimetry of fast microscopic liquid jets by nanosecond dual-pulse laser illumination for megahertz X-ray free-electron lasers. AB - To conduct X-ray Free-Electron Laser (XFEL) measurements at megahertz (MHz) repetition rates, sample solution must be delivered in a micron-sized liquid free jet moving at up to 100 m/s. This exceeds by over a factor of two the jet speeds measurable with current high-speed camera techniques. Accordingly we have developed and describe herein an alternative jet velocimetry based on dual-pulse nanosecond laser illumination. Three separate implementations are described, including a small laser-diode system that is inexpensive and highly portable. We have also developed and describe analysis techniques to automatically and rapidly extract jet speed from dual-pulse images. PMID- 29609406 TI - Ultraviolet light-induced terahertz modulation of an indium oxide film. AB - Active ultraviolet light-induced terahertz modulation of an indium oxide film is investigated. A large absorption modulation of ~66% is achieved upon illumination with a low intensity UV laser (11 mW/cm2). The interaction between indium oxide and a flexible metamaterial structure is investigated owing to the large UV induced enhancement of photo carriers observed in an indium oxide film. We are able to realize absorption peak shifts of 37 GHz by changing the UV excitation light intensity. We also propose a multi-frequency switch by building a circular metallic split ring resonator whose gaps are filled with silicon, germanium, and indium oxide. In future, a photo-excited tunable multi-frequency metamaterial switch can be realized by irradiating the structure with multi-wavelength laser beam. PMID- 29609407 TI - Window-split structured frequency domain Kalman equalization scheme for large PMD and ultra-fast RSOP in an optical coherent PDM-QPSK system. AB - A window-split frequency domain Kalman scheme is proposed in this paper for the equalization of large polarization mode dispersion (PMD) and ultra-fast rotation of state-of-polarization (RSOP) which is an extreme environment due to the Kerr effect and the Faraday effect under the lightning strike near the fiber cables. In order to carry out the proposed Kalman scheme, we give a simplified and equivalent fiber channel model as a replacement for the general model of the polarization effect of the co-existence of PMD and RSOP. With this fiber channel model, we can conduct compensation for PMD in the frequency domain and tracking RSOP in time domain. A half analytical and half empirical theory for the initialization of the process and measurement noise covariance is also presented in theory and verified by the numerical simulation. The performance of the proposed Kalman scheme is checked in the 28Gbaud PDM-QPSK coherent system built on both simulation and experiment platforms. The simulation and experiment results confirm that compared with the generally used constant modulus algorithm (CMA), the proposed scheme provides excellent performance and stability to cope with large range DGD from 20ps to 200ps and RSOP from 200krad/s to 2Mrad/s, with less computational complexity. PMID- 29609408 TI - Integration of an InSb photodetector on Si via heteroepitaxy for the mid-infrared wavelength region. AB - In this study, InSb p-i-n photodetectors with In0.82Al0.18Sb barrier layers were grown on a (100) 6 degrees offcut Si substrate by heteroepitaxy via an AlSb/GaSb buffer. Based on an interfacial misfit array growth mode, the dislocations at the GaSb/Si and InSb/AlSb interfaces accommodated the lattice mismatch. The In0.82Al0.18Sb barrier layer increased the 77 K R0A of the detector. From 180 K to 300 K, the generation-recombination mechanism dominated the dark current generation in the detector and surface leakage became dominant below 120 K. The detector exhibited a 77 K responsivity of 0.475 A/W and a Johnson-noise-limited detectivity of 3.08 * 109 cmHz1/2W-1 at 5.3 um. PMID- 29609409 TI - Polarization management based on dipolar interferences and lattice couplings. AB - We have achieved efficient polarization manipulations based on dipolar interferences and lattice couplings in one-dimensional cylindrical metalattices. First, we employ the scattering asymmetry factor g to quantify the directional scattering ability and find the maximum |g|max=1/2 for a cylinder with effective excitations of electric and magnetic dipoles simultaneously. Further, the strong negative-g (gp = -0.38) for p-polarization and positive-g (gs = 0.68) for s polarization are obtained within a narrow visible band using c-Si with experimental data. Inspired by the polarization-dependent phenomena, we design a metalattice-based linear polarizer considering lattice effects with an optimal particle arrangement. The metalattice performs near-perfect reflection for p polarized waves but with zero reflection for s-polarized waves with large extinction ratios for transmission (17 dB) and reflection (24 dB). The perfect functionalities can be attributed to the near-field lattice couplings with dipolar interferences. And, we reveal that the polarization-dependent scattering coefficients, which are sensitive to the lattice period, can be largely tuned owing to lattice effects, therefore contributing to modifying far-field scattering patterns. More specifically, the proposed linear polarizers also show robust and reliable functionalities when considering lattice imperfections, the effects of system sizes, oblique incident angles, and the tunbility for different working wavelengths. The present study paves a way to stimulate many advanced practical implements based on multipolar interferences and lattice couplings. PMID- 29609410 TI - Physical model for multiple scattered space-borne lidar returns from clouds. AB - A practical model for determining the time-dependent lidar attenuated backscattering coefficient beta was developed for application to global lidar data. An analytical expression for the high-order phase function was introduced to reduce computational cost for simulating the angular distribution of the multiple scattering irradiance. The decay rate of the multiple scattering backscattered irradiance was expressed by incorporating the dependence on the scattering angle and the scattering order based on the path integral approach. The estimated beta over time and the actual range showed good agreement with Monte Carlo simulations for vertically homogeneous and inhomogeneous cloud profiles, resulting in about 15% mean relative error corresponding to 4 times improved accuracy against the Ornstein-Furth Gaussian approximation method. PMID- 29609411 TI - Theoretical study of pyramid sizes and scattering effects in silicon photovoltaic module stacks. AB - Front side pyramids are the industrial standard for wafer based monocrystalline silicon solar cells. These pyramids fulfill two tasks: They act as anti reflective structure on the one hand and as a light-trapping structure on the other hand. In recent development smaller pyramids with sizes below 1 um attract more and more interest. In this paper an optical analysis of periodically arranged front side pyramids is performed. The impact on the reflectance as well as on the useful absorption within the solar cell is investigated depending on the pyramids size, the amount of additional scattering in the system and the quality of the rear side reflector. In contrast to other investigations not only the solar cell, but the full photovoltaic (PV) module stack is considered. This can strongly influence results, as we show in this paper. The results indicate that in a PV module stack with realistic assumptions for the amount of scattering as well as for the rear side reflectance only small differences for pyramids with sizes above 600 nm occur. Preliminary conclusions for random pyramids deduced from these results for periodically arranged pyramids indicate that these differences could become even smaller. PMID- 29609412 TI - Characterization of spectral-domain OCT with autocorrelation interference response for axial resolution performance. AB - We present a class of novel system characterization methods for spectral-domain optical coherence tomography (SD-OCT) particularly on getting optimized axial resolution performance. Our schemes uniquely utilize the autocorrelation interference response, also known as the self-interference product, which is generated by the optical fields from the imaging sample in automatic interferences. In our methods, an autocorrelation-inducing calibration sample was prepared which was made by sandwiching glass plates. OCT images of the calibration sample were captured by an SD-OCT system under testing. And the image data were processed to find various system characteristics based on the unique properties of autocorrelation interferograms, free of dispersion- and polarization-involved modulations. First, we could analyze the sampling characteristic of the SD-OCT's spectrometer for spectral calibration that enables accurate linear-k resampling of detected spectral fringes. Second, we could obtain the systematic polarization properties for quantifying their impact on the achieved axial resolutions. We found that our methods based on the autocorrelation response provide an easy way of self-characterization and self validation that is useful in optimizing and maintaining axial resolution performances. It was found very attractive that a variety of system characteristics can be obtained in a single-shot measurement without any increased system complexity. PMID- 29609413 TI - Point-spread function manipulation of the swept-source optical coherence tomography through temporal phase modulation. AB - Recent breakthroughs in microscopy have surpassed Abbe's spatial diffraction limit, especially in the regime of fluorescence imaging. Microcopy's depth imaging relative tomography is, however, still confined to basic imaging quality, which is limited by the Fourier bandwidth. In this paper, we explore the analogy between spatial microscopy and temporal tomography based on the space-time duality, and hence enlighten the advancement of tomography. As a proof-of principle demonstration, an all-optical manipulation of the point-spread function (PSF) of a swept-source optical coherence tomography (OCT) is performed based on temporal phase modulation. Although the axial resolving power remains the same, much sharper sketch lines can be obtained from the specimen. In addition, the imaging quality is also improved with suppressed ghost fringes and better sensitivity. PMID- 29609414 TI - Optical amplification of Airy beams by photorefractive two-wave mixing. AB - We propose and demonstrate nonlinear amplifications of self-accelerating Airy beams by two-wave mixing in photorefractive crystals both numerically and experimentally. By employing a broad Gaussian beam as the pump beam, we show that weak signal Airy beams can be significantly amplified under both diffusion and drift mechanisms. It is revealed that not only higher optical gains but also faster response time can be achieved in the presence of an external electric field, where the drift mechanism dominates. We verify that the self-accelerating and self-healing characteristics of the Airy beams are well preserved during the nonlinear amplification. PMID- 29609415 TI - Modulation format identification enabled by the digital frequency-offset loading technique for hitless coherent transceiver. AB - We propose a blind and fast modulation format identification (MFI) enabled by the digital frequency-offset (FO) loading technique for hitless coherent transceiver. Since modulation format information is encoded to the FO distribution during digital signal processing (DSP) at the transmitter side (Tx), we can use the fast Fourier transformation based FO estimation (FFT-FOE) method to obtain the FO distribution of individual data block after constant modulus algorithm (CMA) pre equalization at the receiver side, in order to realize non-data-aided (NDA) and fast MFI. The obtained FO can be also used for subsequent FO compensation (FOC), without additional complexity. We numerically investigate and experimentally verify the proposed MFI with high accuracy and fast format switching among 28 Gbaud dual-polarization (DP)-4/8/16/64QAM, time domain hybrid-4/16QAM, and set partitioning (SP)-128QAM. In particular, the proposed MFI brings no performance degradation, in term of tolerance of amplified spontaneous emission (ASE) noise, laser linewidth, and fiber nonlinearity. Finally, a hitless coherent transceiver enabled by the proposed MFI with switching-block of only 2048 symbols is demonstrated over 1500 km standard single mode fiber (SSMF) transmission. PMID- 29609416 TI - Importance of Central Regulation for Lower Urinary Tract Functions. PMID- 29609417 TI - Response to Current Pharmacologic Approaches in Painful Bladder Research: An Update. PMID- 29609418 TI - Central Regulation of Micturition and Its Association With Epilepsy. AB - Micturition is a complex process involving the bladder, spinal cord, and the brain. Highly sophisticated central neural program controls bladder function by utilizing multiple brain regions, including pons and suprapontine structures. Periaqueductal grey, insula, anterior cingulate cortex, and medial prefrontal cortex are components of suprapontine micturition centers. Under pathologic conditions such as epilepsy, urinary dysfunction is a frequent symptom and it seems to be associated with increased suprapontine cortical activity. Interestingly, micturition can also trigger seizures known as reflex epilepsy. During voiding behavior, frontotemporal cortical activation has been reported and it may induce reflex seizures. As current researches are only limited to present clinical cases, more rigorous investigations are needed to elucidate biological mechanisms of micturition to advance our knowledge on the process of micturition in physiology and pathology. PMID- 29609419 TI - Add-on Therapy With the alpha-Blockers Tamsulosin and Naftopidil Improves Voiding Function by Enhancing Neuronal Activity in Prostatic Hyperplasia Rats. AB - PURPOSE: Benign prostatic hyperplasia (BPH) impacts quality of life in men by causing lower urinary tract symptoms. alpha1-Adrenoceptor (alpha1-AR) blockers improve lower urinary tract symptoms. We investigated the efficacy of add-on therapy with alpha1-AR blockers on BPH rats. METHODS: Rats in the drug-treated groups were orally administered each drug once a day for 30 days after orchiectomy. To induce BPH, rats were castrated and testosterone (20 mg/kg) was injected subcutaneously once per day for 30 days. Cystometry was conducted to measure voiding contraction pressure and the interval contraction time, immunohistochemistry was performed to measure c-Fos and nerve growth factor (NGF) expression in the neuronal voiding centers, and nicotinamide adenine dinucleotide phosphate-diaphorase histochemistry was used to measure nitric oxide synthase (NOS) expression. RESULTS: Orchiectomy and testosterone injection decreased voiding contraction pressure and the interval contraction time, suggesting BPH symptoms. Voiding contraction pressure and the interval contraction time were greater in the group that received the combination treatment (tamsulosin with naftopidil) than in the tamsulosin monotherapy or naftopidil monotherapy groups. c-Fos, NGF, and NOS expression in the neuronal voiding centers was enhanced by BPH induction. c-Fos, NGF, and NOS expression was suppressed by the combination treatment (tamsulosin with naftopidil) to a greater extent than was the case for tamsulosin monotherapy or naftopidil monotherapy. CONCLUSIONS: Combination therapy of tamsulosin and naftopidil showed greater efficacy for the treatment of BPH than tamsulosin monotherapy or naftopidil monotherapy; therefore, combination therapy can be considered as a novel therapeutic method for BPH. PMID- 29609420 TI - Efficacy of an Alpha-Blocker for the Treatment of Nonneurogenic Voiding Dysfunction in Women: An 8-Week, Randomized, Double-Blind, Placebo-Controlled Trial. AB - PURPOSE: To evaluate the efficacy of an alpha-1 adrenergic receptor (alpha1-AR) blocker for the treatment of female voiding dysfunction (FVD) through a pressure flow study. METHODS: This was a randomized, double-blind, placebo-controlled trial. Women aged >=18 years with voiding symptoms, as defined by an American Urological Association symptom score (AUA-SS) >=15 and a maximum flow rate (Qmax) <15 mL/sec with a voided volume of >100 mL and/or a postvoid residual (PVR) volume >150 mL, were randomly allocated to either the alfuzosin or placebo group. After 8 weeks of treatment, changes in the AUA-SS, Bristol female lower urinary tract symptoms (BFLUTS) questionnaire, Qmax/PVR, and voiding diary were compared between groups. Patients' satisfaction with the treatment was compared. Patients were categorized into 3 groups according to the Blaivas-Groutz bladder outlet obstruction (BOO) nomogram: none, mild, and moderate to severe. Subgroup comparisons were also made. RESULTS: Of a total of 187 women, 154 (79 alfuzosin, 75 placebo) were included in the analysis. After 8 weeks of treatment, the AUA-SS decreased by 7.0 in the alfuzosin group and by 8.0 in the placebo group. Changes in AUA-SS subscores, BFLUTS (except the I-sum), the voiding diary, and Qmax/PVR were not significantly different between groups. Approximately 54% of the alfuzosin group and 62% of the placebo group were satisfied with the treatment. No significant difference was observed between groups according to the presence or grade of BOO. CONCLUSIONS: Alfuzosin might not be more effective than placebo for treating FVD. The presence or the grade of BOO did not affect the results. A further study with sufficient power is needed to determine the efficacy of alpha1 AR blockers for the treatment of FVD. PMID- 29609421 TI - Clinical Efficacy of Solifenacin in the Management of Diabetes Mellitus Associated Versus Idiopathic Overactive Bladder Symptoms: A Multicenter Prospective Study. AB - PURPOSE: To compare the clinical efficacy of anticholinergics for managing diabetes mellitus-associated overactive bladder (DM OAB) versus idiopathic overactive bladder (OAB) in Korean women. METHODS: We conducted a multicenter, prospective, parallel-group, open-label, 12-week study. Women (20-65 years old) with OAB symptoms for over 3 months were assigned to the DM OAB and idiopathic OAB groups. Changes in the Overactive Bladder Symptom Score (OABSS), urgency, urinary urgency incontinence, nocturia, daytime frequency according to a voiding diary, uroflowmetry, and postvoid residual urine volume (PVR) at the first visit (V1), week 4 (V2), and week 12 (V3) were compared. RESULTS: No significant difference was found between the baseline patient characteristics of the DM OAB and idiopathic OAB groups. Treatment with solifenacin was associated with improvements in urgency, urinary urgency incontinence, nocturia, frequency according to a voiding diary, and the total OABSS between V1 and V2 and between V1 and V3. Moreover, a significant improvement in urgency and urge incontinence was found between V2 and V3 in the DM OAB group. However, no significant changes were found in any other parameters. There were no significant differences between the DM OAB group and the idiopathic OAB group except for urgency and urge incontinence at V2 (3.71 vs. 2.28 and 0.47 vs. 0.32, respectively). CONCLUSIONS: The patients who received solifenacin demonstrated improved urgency, urinary urgency incontinence, nocturia, frequency according to a voiding diary, and total OABSS. Management with solifenacin was equally effective for both DM-related OAB and idiopathic OAB. PMID- 29609422 TI - Influence of the Short-term Intake of High Doses of Solifenacin and Trospium on Cognitive Function and Health-Related Quality of Life in Older Women With Urinary Incontinence. AB - PURPOSE: The aim of this study was to investigate the safety and the effects of elevated doses of solifenacin and trospium on cognitive function and health related quality of life (HRQoL) in elderly women receiving treatment for urinary incontinence. METHODS: The study included 312 women aged 60-83 years (mean age, 69.4 years). All participants had scored at least 24 points on the Mini-Mental State Examination (MMSE) scale, and all of them had been diagnosed with urge urinary incontinence (UUI) or mixed urinary incontinence (MUI). The women were randomly assigned to 3 groups: group A, individuals who were simultaneously administered solifenacin at a high dosage of 20 mg per day and trospium at a high dosage of 60 mg per day; group B, persons taking solifenacin and trospium at the usual dosage of 10 and 30 mg per day, respectively; and group C, persons who received a placebo. Participants' cognitive status was assessed by the MMSE, Controlled Oral Word Association Test, Wechsler Adult Intelligence Scale-Revised, Wechsler Memory Scale III, Colour Trails Test, and California Verbal Learning Test scales. The HRQoL assessment was performed using the Medical Outcomes Study 36-Item Health Survey. RESULTS: The cognitive function parameters did not differ at the start and end of the study across the groups (P>0.05). Additionally, the cognitive function parameters did not differ significantly within each group between the start and end of the study (P>0.05). The values of most HRQoL parameters regarding the functional state of the lower urinary tract (LUT) after the termination of treatment significantly improved in groups A and B (P<0.05). A significant correlation between cognitive status and HRQoL or LUT parameters was absent (r<0.3), while the correlations between HRQoL and LUT parameters were r=0.31-0.83, P<0.05. CONCLUSIONS: The use of elevated doses of solifenacin and trospium did not increase the risk of cognitive impairment in women with UUI and MUI. The combination of solifenacin and trospium at a double dosage may be recommended to elderly women with treatment-resistant symptoms of UUI and MUI. However, the safety of combining antimuscarinic drugs in women with an increased volume of residual urine requires further study. PMID- 29609423 TI - Intermittent Self-catheterization in Older Adults: Predictors of Success for Technique Learning. AB - PURPOSE: The main goal of this retrospective study is to explore the predictors of success in learning clean intermittent self-catheterization (CISC) in patients over 65 years of age. The secondary goal is to assess whether in this population, the risk of failure to perform CISC is greater, compared with patients under 65 with similar pathologies. METHODS: All patients older than 65 consulting between January 2011 and January 2016 for learning CISC were included. A control population younger than 65 matching with sex, body mass index, and pathology was selected. RESULTS: One hundred sixty-nine of the 202 patients (83.7%) over 65 succeeded in learning CISC. Obesity (P<0.05), low pencil and paper test (PP test) (P<0.01) and low functional independence measure (FIM) (P<0.01) scores were risk factors of failure. No significant differences were found with sex or pathology. In multivariate analysis, low PP test perineum access (odds ratio [95% confidence interval], 2.30 [1.32-4.42]), low FIM motor (1.04 [1.01-1.08]), and FIM cognition (1.18 [1.03-1.37]) scores were independent factors of learning failure. Compared to control group, age over 65 was not predictive of failure (P=0.15). CONCLUSIONS: Our study shows that success in learning CISC does not depend on age but on difficulties in mobility, access to perineum and probably cognitive disorders. PMID- 29609424 TI - Synergistic Activities of Abdominal Muscles Are Required for Efficient Micturition in Anesthetized Female Mice. AB - PURPOSE: To characterize the electromyographic activity of abdominal striated muscles during micturition in urethane-anesthetized female mice, and to quantitatively evaluate the contribution of abdominal responses to efficient voiding. METHODS: Cystometric and multichannel electromyographic recordings were integrated to enable a comprehensive evaluation during micturition in urethane anesthetized female mice. Four major abdominal muscle domains were evaluated: the external oblique, internal oblique, and superior and inferior rectus abdominis. To further characterize the functionality of the abdominal muscles, pancuronium bromide (25 MUg/mL or 50 MUg/mL, abdominal surface) was applied as a blocking agent of neuromuscular junctions. RESULTS: We observed a robust activation of the abdominal muscles during voiding, with a consistent onset/offset concomitant with the bladder pressure threshold. Pancuronium was effective, in a dose-dependent fashion, for partial and complete blockage of abdominal activity. Electromyographic discharges during voiding were significantly inhibited by applying pancuronium. Decreased cystometric parameters were recorded, including the peak pressure, pressure threshold, intercontractile interval, and voiding duration, suggesting that the voiding efficiency was significantly compromised by abdominal muscle relaxation. CONCLUSIONS: The relevance of the abdominal striated musculature for micturition has remained a topic of debate in human physiology. Although the study was performed on anesthetized mice, these results support the existence of synergistic abdominal electromyographic activity facilitating voiding in anesthetized mice. Further, our study presents a rodent model that can be used for future investigations into micturition-related abdominal activity. PMID- 29609425 TI - Lower Urinary Tract Symptoms in Elderly Population With Multiple Sclerosis. AB - PURPOSE: The aim of this study is to compare the clinical and urodynamic characteristics of urinary disorders in multiple sclerosis (MS) patients in a geriatric population with a nongeriatric population. METHODS: This study was conducted retrospectively between 2010 and 2016. Each patient with MS aged 65 and older was matched with 2 patients with MS aged less than 65 in sex, form of MS, and Expended Disability Status Scale (EDSS). Demographic data, urinary symptoms, treatment, quality of life, repercussion of lower urinary tract symptoms on daily life activities and psychological state and urodynamic parameters were collected. Differences between the 2 populations were evaluated using Student test, chi square, or Fischer tests. RESULTS: Twenty-four patients with MS aged 65 and older (mean age, 69.8 years) were matched with 48 patients aged less than 65 years (mean age, 49.4 years). Maximum urethral closure pressure was lower in the elderly population than in the nongeriatric population (mean+/-standard deviation [SD]: 35.6+/-18.5 cm H2O vs. 78.2+/-52.3 cm H2O, P<0.001). In the male population, there was no statistical difference in any other clinical or urodynamic endpoints. In the female population, voiding symptoms was more described in the nongeriatric population (Urinary Symptom Profile low stream: 3.4+/-3.5 vs. 1.7+/-2.4, P=0.04), geriatric population had less urinary treatment (P=0.05). LUTS had less impact on quality of life (Qualiveen: 1.4+/-1.0 vs. 2.1+/ 0.9, P=0.02) on the geriatric population than in the nongeriatric of female MS patients. CONCLUSIONS: Geriatric population of MS has few differences of urinary disorders compared to a nongeriatric population with EDSS, sex, and MS form equal. However, the psychological impact of these urinary disorders is less important in female geriatric population. PMID- 29609426 TI - Panfacial bone fracture: cephalic to caudal. AB - Theoretically, panfacial bone fractures involve all three areas of the face: frontal bone, midface, and mandible. In practice, when two out of these three areas are involved, the term "panfacial bone fracture" has been applied. We can use physical examination, simple radiologic examination, and computed tomography study for diagnosis. Linear fracture are treated by conservative treatment. But, most of panfacial bone fracture patients need to be treated by open reduction and internal fixation. Facial width is most important thing that we need to care during operation. There are many ways about sequence like "top to bottom," "bottom to top," "outside to inside," or "inside to outside" and the authors prefer "top to bottom" and "outside to inside" ways. The authors apply arch bar from the first of surgery and then, set frontal bone fracture, midface fracture and mandible fracture in sequence. Usually, we remove the stitches for 5 days after surgery and the intraoral stitch removed after 2 weeks. Usually arch bar is going to be removed 4 weeks after surgery. We could get acceptable results with the above way. PMID- 29609427 TI - Personal technique for definite repair of complete unilateral cleft lip: modified Millard technique. AB - BACKGROUND: Millard's rotation-advancement repair, which is used by many surgeons, can make a natural philtral column, but most surgeons use a modification of the rotation-advancement flap. The purpose of this article is to introduce a modification utilized by the authors and to provide detailed surgical procedure. METHODS: We retrospectively reviewed 82 patients' medical records and presented surgical technique and outcomes. The main features of the authors' strategy are emphasizing horizontal length of the lip, orbicularis oris muscle duplication for improving the definition of the philtral column, overcorrection of domal portion than the non-cleft side in order to compensate for the recurrence during growth. Two judges rated two times the appearance of the patients' nose and lip using Asher-McDade aesthetic index. Intra- and interobserver reliabilities were determined using Cohen's kappa statistics. RESULTS: All patients recovered eventually after surgery; however, two patients have a minor complications (wound infection in one patient, wound disruption due to trauma in the other patient). The improvement of the aesthetic results can be achieved with this modified Millard technique. Total mean scores of the Asher McDade index was 2.08, fair to good appearance. The intraobserver reliabilities were substantial to almost perfect agreement and the interobserver reliabilities were moderate to almost perfect agreement. CONCLUSION: We modified Millard method for repair of complete unilateral cleft lip. The surgical outcomes were favorable in long-term follow-up. We hope our technique will serve as a guide for those new to the procedure. PMID- 29609428 TI - Modified Abbe flap for reconstruction of Cupid's bow and vermilion tubercle in secondary cleft lip deformity. AB - BACKGROUND: Abbe flap technique is one of the most challenging operations to correct horizontal deficiencies in secondary cleft lip deformity. Since its first introduction, the operative method was dynamically modified from simple variation to complete conceptual change, but conventional Abbe flap has many drawbacks in esthetic and functional aspect. Our purpose was reconstructing the symmetry of Cupid's bow and central vermilion tubercle with minimal sequalae. METHODS: From 2008 to 2016, this technique was applied to 16 secondary cleft lip patients who had total or more than 60% of unilateral deficiency of Cupid's bow and central lip or tubercle pouting deficiency. A quadrangular-shaped flap was transferred from vermilion including skin and white line of central or contralateral lower lip. Pedicle division and insetting were made at 9 (unilateral) or 10 (bilateral) days after transfer. Secondary lip revision was done with open rhinoplasty after wound maturation. RESULTS: Overall satisfaction was high with modified technique. Scar was minimally noticeable on both upper and lower lip especially. Balanced Cupid's bow and symmetric vermilion tubercle were made with relatively small size of flap compared to conventional Abbe flap. An accompanying benefit was reduced ectropion of lower lip, which made balanced upper and lower lip protrusion with more favorable profile. CONCLUSION: A new modified Abbe flap technique showed great satisfaction. It is worth considering in secondary cleft lip patient who has central lip shortage and asymmetry of upper lip vermilion border line. Our technique is one of the substitutes for correction of horizontal and central lip deficiency with asymmetric Cupid's bow. PMID- 29609430 TI - The treatment of post-traumatic facial skin defect with artificial dermis. AB - BACKGROUND: When a skin defect occurs, clinicians must work to restore the original skin quality as soon as possible. Accordingly, an artificial dermis can be used to supplement the wound and prevent severe scar contracture formation. The Terudermis is an artificial dermis that is simple and easy to use. We investigated the effectiveness of the Terudermis in the treatment of facial skin defects by analyzing previous relevant cases treated in our institution. METHODS: We retrospectively examined 143 patients who were treated with the Terudermis graft in facial skin defect at Dong Kang General Hospital in 2015 and 2016. The patients' age, sex and location, wound size, complications were analyzed. In addition, the patients were asked to complete a self-satisfaction questionnaire after 18 months from the completion of treatment. The results were compared with that of autologous full-thickness skin graft (FTSG) and split-thickness skin graft (STSG) patients in same period. RESULTS: The mean self-satisfaction scores evaluated by patients were 4.1+/-1.0, 4.0+/-1.3 and 3.5+/-1.8 for the Terudermis graft, FTSG and STSG patients, respectively. With respect to complications, there were fewer incidences of hematoma, partial skin loss and complete skin loss in the Terudermis graft patients. CONCLUSION: In the present study, the Terudermis, when used to treat post-traumatic facial skin defects, is a good alternative option to obtain satisfactory aesthetic outcomes. Also, the Terudermis grafting is a simple and easy treatment method to perform. PMID- 29609429 TI - Comparison of wound healing effects between Oncorhynchus keta-derived polydeoxyribonucleotide (PDRN) and Oncorhynchus mykiss-derived PDRN. AB - BACKGROUND: Polydeoxyribonucleotide (PDRN) influencing cellular growth and differentiation is recognized to promote wound healing by stimulating tissue repair. Although PDRN can be extracted from human placentas, PDRN medications have recently been extracted from the semen of trout (Oncorhynchus mykiss) and salmon (Oncorhynchus keta). The present study was designed to evaluate the wound healing effects of O. keta-derived PDRN for injection (Rejuvenex) and PDRN cream (Rejuvenex Cream) in comparison with those of O. mykiss-derived PDRN injection (Placentex). METHODS: Full-thickness skin defects were made on the back of mice (n=60). The mice were divided into the following four groups according to the dressing used for the wounds: O. mykiss-derived PDRN injection group, O. keta derived PDRN injection group, O. keta-derived PDRN cream group, and normal saline soaked dressing group (control group). We analyzed the gross findings, wound sizes, histological findings, immunohistochemistry and enzyme-linked immunosorbent assays for the groups immediately after the treatment, and again after 4, 7, and 10 days of treatment. RESULTS: The wound healing effects were the greatest in the O. keta-derived PDRN injection and O. mykiss-derived PDRN injection groups, which showed similar scores, followed by the O. keta-derived cream and normal saline soaked dressing groups. CONCLUSION: The injection of PDRN extracted from O. keta was found to be as effective at healing full-thickness skin defects as the O. mykiss-derived PDRN injection, which is currently used in the clinic. Moreover, the O. keta-derived PDRN injection was also found to reduce the time required for wound healing. PMID- 29609431 TI - The efficacy of mobile application use on recall of surgical risks in nasal bone fracture reduction surgery. AB - BACKGROUND: The number of surgical risks recalled by a patient after surgery can be used as a parameter for assessing how well the patient has understood the informed consent process. No study has investigated the usefulness of a self developed mobile application in the traditional informed consent process in patients with a nasal bone fracture. This study aimed to investigate whether delivery of information, such as surgical risks, through a mobile application is more effective than delivery of information through only verbal means and a paper. METHODS: This prospective, randomized study included 60 patients with a nasal bone fracture. The experimental group (n=30) received preoperative explanation with the traditional informed consent process in addition to a mobile application, while the control group (n=30) received preoperative explanation with only the traditional informed consent process. Four weeks after surgery, the number of recalled surgical risks was compared for analysis. The following six surgical risks were explained: pain, bleeding, nasal deformity, numbness, nasal obstruction, and nasal cartilage necrosis. RESULTS: The mean number of recalled surgical risks among all patients was 1.58+/-0.56. The most frequently recalled surgical risk was nasal deformity in both groups. The mean number of recalled surgical risks was 1.72+/-0.52 in the experimental group and 1.49+/-0.57 in the control group. There was a significant association between mobile application use and the mean number of recalled surgical risks (p=0.047). Age, sex, and the level of education were not significantly associated with the mean number of recalled surgical risks. CONCLUSION: This study found that a mobile application could contribute to the efficient delivery of information during the informed consent process. With further improvement, it could be used in other plastic surgeries and other surgeries, and such an application can potentially be used for explaining risks as well as delivering other types of information. PMID- 29609433 TI - Correction of a post-traumatic scar fold in the lateral canthus using modified Z plasty. AB - Post-traumatic scar deformations are common in many skin injury cases. These are usually aesthetic problems, but if these deformations impair mobility and the patient feels uncomfortable, we must resolve them. In a patient with a lateral post-traumatic scar fold in the lateral canthus that shortened the horizontal orbital fissure and created traction on eye opening, we performed modified classic Z-plasty, resulting in aesthetic and functional improvements without recurrence. PMID- 29609432 TI - Upper lip tie wrapping into the hard palate and anterior premaxilla causing alveolar hypoplasia. AB - Bony anomaly caused by lip tie is not many reported yet. There was a case of upper lip tie wrapping into the anterior premaxilla. We represent a case of severe upper lip tie of limited lip motion, upper lips curling inside, and alveolar hypoplasia. Male patient was born on June 3, 2016. He had a deep philtral sulcus, low vermilion border and deep cupid's bow of upper lip due to tension of short, stout and very tight frenulum. His upper lip motion was severely restricted in particular lip eversion. There was anterior alveolar hypoplasia with deep sulcus in anterior maxilla. Resection of frenulum cord with Z-plasty was performed at anterior premaxilla and upper lip sulcus. Frenulum was tightly attached to gingiva through gum and into hard palate. Width of frenulum cord was about 1 cm, and length was about 3 cm. He gained upper lip contour including cupid's bow and normal vermilion border after the surgery. This case is severe upper lip tie showing the premaxillary hypoplasia, abnormal lip motion and contour for child. Although there is mild limitation of feeding with upper lip tie child, early detection and treatment are needed to correct bony growth. PMID- 29609434 TI - Primary extracranial meningioma presenting as a forehead mass. AB - Meningioma originates from arachnoid cap cells and is the second most common intracranial tumor; however, it can also be found in an extracranial location. A very rare primary extracranial meningioma without the presence of an intracranial component has also been reported. Primary extracranial meningiomas have been found in the skin, scalp, middle ear, and nasal cavity. A computerized tomography or magnetic resonance imaging scan is necessary to determine the presence or absence of an intracranial meningioma, and a biopsy is essential for diagnosis. We report a case of primary extracranial meningioma located in the forehead skin of a 51-year-old male. PMID- 29609435 TI - Retained large glass fragments for over 40 years in the maxillofacial region. AB - Foreign body (FB) impaction in the maxillofacial area could be caused by knives, glass fragments, and vegetative materials. We present the rare case of a 62-year old man with a large glass FB in the left cheek retained for over 40 years. He had traffic accident over 40 years ago and glass fragments impacted on his left cheek. Glass fragments were retained around the zygomatic arch with dimpled scar and unclear serous discharge, but other facial motor or sensory dysfunction was not observed. We confirmed three glass fragments with radiologic examination including plain radiograph and computed tomographic image. Under general anesthesia, impacted glass fragments were removed through the direct incision on the dimpled scar and the additional incision on the left lateral canthal area. Remnant FBs were not seen on an intraoperative C-arm radiograph. After 2 days of irrigation for inflammation control, the dimpled wound was sutured. The wound was healed without major complication and the original dimpled scar was much improved. PMID- 29609436 TI - Forehead reconstruction using modified double-opposing rotation-advancement flaps for severe skin necrosis after filler injection. AB - Varying degrees of complications can occur after hyaluronic acid filler injections. Tissue necrosis due to interruption of the vascular supply is an early complication that can be severe. If the site of tissue necrosis due to the filler injection is the forehead, successfully reconstructing the region without distorting the key landmarks is challenging. We describe the case of a 50-year old man who experienced widespread forehead skin necrosis after hyaluronic acid filler injection in the glabellar area. We successfully covered the forehead area with a 3*4-cm2 midline necrotic tissue using the modified double-opposing rotation-advancement flap method. Although modified double-opposing rotation advancement flap closure has the disadvantage of leaving a longer scar compared to conventional double-opposing rotation-advancement flap closure, the additional incision line made along the superior border of the eyebrow aids in camouflaging the scar and decreases eyebrow distortion. Therefore, it is believed that the modified double-opposing rotation-advancement flap technique is an excellent tool for providing adequate soft tissue coverage and minimal free margin distortion when reconstructing widespread skin necrosis in the central mid-lower forehead that can occur after filler injection in the glabellar area. PMID- 29609437 TI - Intraosseous hemangioma of the orbit. AB - Intraosseous hemangioma is an extremely rare tumor that accounts for 1% or fewer of all osseous tumors. The most common sites of its occurrence are the vertebral column and calvaria. Occurrence in a facial bone is very rare. The authors aim to report a case of the surgical treatment of intraosseous hemangioma occurring in the periorbital region, which is a very rare site of occurrence and to introduce our own experiences with the diagnosis and treatment of this condition along with a literature review. A 73-year-old male patient visited our hospital with the chief complaint of a mass touching the left orbital rim. A biopsy was performed by applying a direct incision after local anesthesia. Eventually, intraosseous hemangioma was diagnosed histologically. To fully resect the mass, the orbital floor and zygoma were exposed through a subciliary incision under general anesthesia, and then the tumor was completely eliminated. Bony defect was reconstructed by performing a seventh rib bone graft. Follow-up observation has so far been conducted for 10 months after surgery without recurrence or symptoms. PMID- 29609438 TI - Rare experience of keloidal dermatofibroma of forehead. AB - Dermatofibromas most commonly occur on limbs and rarely occur on the face. Dermatofibroma occurring on the face is associated with unusual clinicopathologic features and a more aggressive clinical course in comparison to typical cases. Additionally, the most common subtype found in previous studies was benign fibrous histiocytoma, with the keloid type being very rare (about 1% of reported cases). The aim of this study was to present our experience with a keloidal dermatofibroma of the face, which is usually missed clinically, and to discuss the treatment of a keloidal dermatofibroma in this location. PMID- 29609439 TI - A better facial contour accomplished by parotid duct preserving superficial parotidectomy. AB - Depression of facial contour after parotidectomy is still challenging to many of surgeons. A 68-year-old man presented with a 4-month history of a painless swelling in both parotid area. The mass was multiple and fixed at the parotid region. We conducted a parotid duct preserving bilateral superficial parotidectomy by one-stage operation to remove the multiple tumors. A lazy S incision was made in both preauricular area and the peripheral branches of the facial nerve were identified using surgical landmark. After dissecting the branches of the facial nerve and parotid duct, main parotid duct was preserved but only small fine ductules from the superficial lobe were ligated. Parotid gland was excised from its anterior aspect with about 1 cm of normal parotid tissue margin. The patient was followed up for 6 years to evaluate postoperative parotid gland function and the computed tomography (CT) was taken. Patient was satisfied with no significant complication such as sunken changes in facial contour, facial nerve function. As far as we know, it is the first study to compare long-term soft tissue contours of soft tissue of duct preserving superficial parotidectomy with duct sacrificing superficial parotidectomy by means of CT findings. PMID- 29609440 TI - Tragus formation during concha-type microtia repair using a chondrocutaneous island flap. AB - Formation of an ideally-shaped tragus remains one of the most challenging issues during staged tragus reconstruction in microtia patients. The authors describe a new method used to treat a unique case of concha-type microtia in which the 10 year-old male patient had only a portion of pre-existing cartilage at the tragus site. An anomalous skin lump was also present. During the initial stages of the reconstruction, the two-stage Nagata method was used for surgical correction of the microtia. An autologous rib cartilage graft was used to form the ear framework. A temporoparietal fascia flap was also constructed. Remnant skin tags and anomalous cartilage that accompany microtia are usually removed during microtia repair. However, the cartilage and skin lump were preserved during the reconstruction. The skin lump was later used to form a vascularized chondrocutaneous island flap that supplemented the portion of cartilage during tragus formation. The result was a new tragus that was satisfactorily improved in both size and shape. Patients with concha-type microtia may benefit from the use of this new method for tragus formation. PMID- 29609441 TI - Longitudinal follow-up to near final height of auxological changes in girls with idiopathic central precocious puberty treated with gonadotropin-releasing hormone analog and grouped by pretreatment body mass index level. AB - PURPOSE: Reported changes in body mass index (BMI) in central precocious puberty (CPP) during and after gonadotropin-releasing hormone analog (GnRHa) treatment are inconsistent. We, therefore, investigated auxological parameters in GnRHa treated girls with idiopathic CPP (ICPP) until attainment of near final height (NFH). METHODS: From the medical records of 59 ICPP girls who attained NFH after GnRHa therapy, auxological changes were compared between overweight (BMI>=85th percentile) and normal-weight (BMI<85th percentile) groups. BMIs were changed into standard deviation scores (BMISDSs) for subject chronologic age (BMISDS-CA) and bone age (BMISDS-BA). RESULTS: The incidence of overweight including obesity was high at the start of therapy (35.6%). The predicted adult height (PAH) at start of therapy was significantly shorter than the midparental height (MPH), whereas PAH at end of therapy approached MPH, and NFH was greater than MPH. Height velocity (HV) in the overweight group was higher during GnRHa therapy than that in the normal-weight group, but those in the two groups were not different after therapy until NFH. Both BMISDS-CA and BMISDS-BA increased significantly during therapy, but both BMISDSs decreased significantly after therapy until NFH. At NFH, neither BMISDS was different from that at baseline. In the normal-weight group, both BMISDSs increased during therapy and were maintained until NFH. In the overweight group, neither BMISDS changed during therapy, but there was a decrease after therapy until NFH. CONCLUSIONS: The different patterns of BMISDS change during and after GnRHa therapy until NFH between the 2 groups were related to the different HV during GnRHa therapy. PMID- 29609442 TI - Adherence of the Annals of Pediatric Endocrinology & Metabolism to the Principles of Transparency and Best Practice in Scholarly Publishing. PMID- 29609443 TI - Small for gestational age and obesity related comorbidities. AB - Infant born small for gestational age (SGA) are at increased risk of perinatal morbidity, persistent short stature and metabolic alterations in later life. The result of SGA followed by rapid weight gain during early postnatal life has been associated with increased long-term risks for central obesity, insulin resistance, impaired glucose tolerance, type 2 diabetes, hypertension, increased fat mass, and cardiovascular disease. We should carefully monitor their weight during infancy and childhood to prevent excessive rates of weight gain. 'Healthy catch up growth' may decreased the risk of obesity-related comorbidities in SGA. Establishing the optimal growth patterns in SGA to minimize short- and long-term risks is important, and further studies will be needed. This review discusses recent studies concentrating on obesity-related morbidities in SGA infants that may provide insight into growth monitoring. PMID- 29609444 TI - Small for gestational age and obesity: epidemiology and general risks. AB - Children born small for gestational age (SGA) have several life-long consequences. Previous epidemiological studies investigated from childhood to adulthood reported that a number of chronic diseases originate in the prenatal period. With the emerging era of obesity epidemic, more concerns are related to being obese than being short-statured in SGA children. The exact mechanisms are uncertain; however, growth hormone-insulin-like growth factor axis disturbance by fetal programming and accelerated postnatal weight gain contributed to central adiposity in SGA children. In this review, we summarized the definitions and prevalence of SGA, epidemiology, and general risks of obesity in SGA children. Early interventions, before and after birth, are needed for healthy catch-up growth to prevent later obesity and related complications. PMID- 29609445 TI - Low levels of 25-hydroxyvitamin D in children and adolescents with type 1 diabetes mellitus: a single center experience. AB - PURPOSE: Low vitamin D level is common in adults with diabetes mellitus (DM). We assessed vitamin D level and its associated factors in Korean youth with type 1 DM. METHODS: Type 1 DM cases (n=85) and healthy controls (n=518) aged <20 years were included and grouped into 3 categories according to vitamin D level: deficiency (<20 ng/mL), insufficiency (20-30 ng/mL), or sufficiency (>=30 ng/mL). RESULTS: The mean serum vitamin D level was significantly lower (21.6+/-8.5 ng/mL vs. 28.0+/-12.0 ng/mL, P<0.001) and vitamin D deficiency prevalence was significantly higher (48% vs. 26%, P<0.001) in type 1 DM cases than in healthy controls. Logistic regression analysis revealed that type 1 DM cases were more likely to have vitamin D deficiency (P=0.004), independent of sex, age, and body mass index. Type 1 DM cases with vitamin D deficiency/insufficiency were mainly diagnosed in winter (November to April) (P=0.005), and the duration of diabetes was longer than in those with vitamin D sufficiency (P=0.046). However, season of diagnosis, duration of diabetes, prescribed daily insulin dose, and glycosylated hemoglobin and C-peptide levels were not associated with 25-hydroxyvitamin D (25(OH)D) level in type 1 DM cases after adjustment for other factors. CONCLUSIONS: We recommend assessment of serum 25(OH)D level in type 1 DM cases and to treatment if findings indicate insufficiency. Further studies investigating the mechanisms underlying vitamin D deficiency in youth with type 1 DM are needed. PMID- 29609446 TI - Near final height in Korean children referred for evaluation of short stature: clinical utility and analytical validity of height prediction methods. AB - PURPOSE: Predicted adult height (PAH) is often crucial to decision-making about treatment with human growth hormone (GH) or gonadotropin-releasing hormone agonist in children with short stature. This study compares final adult height (FAH) with different methods used to determine PAH and assesses the clinical utility and analytical validity of height prediction for children not treated with GH. METHODS: Clinical findings were retrospectively analyzed, and the heights of 44 children (22 males and 22 females) who visited our clinic between August 2006 and June 2017 and reached near final adult height (NFAH) were evaluated. Children treated with GH were excluded. We compared measured NFAH to PAH using the Bayley-Pinneau (BP), Tanner-Whitehouse Mark 2, and Roche-Wainer Thissen (RWT) methods. RESULTS: Pearson correlation between all 3 prediction methods and NFAH showed high positive correlations in males and females (P<0.05). The average difference between PAH and NFAH for the BP method (0.4+/-3.9 cm) was significantly lower than those for the RWT and TW 2 methods in females (P=0.000, analysis of variance). Furthermore, only PAH by the BP method in females was very close to measured NFAH (paired t-test). A Bland-Altman plot verified that 95% of the differences between the PAH and NFAH exist between limits of agreement (mean+/-1.96 standard deviation). CONCLUSIONS: The BP method is more useful to predict NFAH in females than other methods. Careful attention is still required when using such tools because PAH can be inaccurate. Therefore, a more accurate FAH prediction model for Korean children is needed. PMID- 29609448 TI - The relationship between subclinical hypothyroidism and serum levels of uric acid and creatinine in children aged 2-14 years. AB - PURPOSE: Hypothyroidism is a clinical syndrome that can lead to elevated levels of serum creatinine and uric acid by causing impaired renal function. Although many studies have been carried out on the relationship between overt hypothyroidism and renal function, few studies have been conducted on subclinical hypothyroidism and renal function, especially in pediatric patients. For this reason, we studied this issue in children, so as to provide a background for more useful research and future education. METHODS: This case-control study was performed on 107 children aged 2-14 years, 56 children with subclinical hypothyroidism in the case group, and 51 healthy children in the control group presenting to Ayatollah Mousavi Hospital in Zanjan and private clinics of Zanjan city. Thyroid stimulating hormone, triiodothyronine, thyroxine, creatinine, and uric acid were measured in both groups of children after obtaining the necessary criteria for entering the study. RESULTS: Compared to the control group, subjects with subclinical hypothyroidism had higher levels of creatinine (P=0.003), while serum uric acid levels in subclinical hypothyroid children was not significantly different from those in the control group (P=0.200). CONCLUSIONS: In subclinical hypothyroidism in children, creatinine was higher than in euthyroid patients, but uric acid was not different. PMID- 29609447 TI - Prevalence of autoimmune thyroiditis in patients with type 1 diabetes: a long term follow-up study. AB - PURPOSE: Type 1 diabetes mellitus (DM) is associated with autoimmune diseases such as thyroiditis. Therefore, we aimed to investigate the prevalence of autoimmune thyroiditis in patients with type 1 DM. METHODS: A total of 102 patients who were diagnosed and followed up (mean age, 8.1+/-4.0 years) in Ajou University Hospital were enrolled in this study. All the patients were evaluated for beta cell autoimmunity, including insulin autoantibody, glutamic acid decarboxylase antibodies (GADA), and islet cell antibody. Moreover, autoantibodies to thyroid peroxidase and thyroglobulin were assessed at initial diagnosis and annually thereafter. RESULTS: The mean patient age (49 men and 53 women) was 19.2+/-4.8 years. The prevalence of at least one thyroid antibody was 30.4%. Patients with thyroid anti-bodies had a significantly higher frequency of GADA at the time of the diagnosis. Autoimmune thyroiditis was more prevalent in the older age group. GADA was a significant risk factor for development of thyroid autoantibodies after diagnosis of type 1 DM (odds ratio, 4.45; 95% confidence interval, 1.399-14.153). CONCLUSIONS: In patients with type 1 DM, the prevalence of autoimmune thyroiditis was higher than in the general population. Moreover, GADA positivity at diagnosis was associated with thyroid autoimmunity. PMID- 29609449 TI - Design of the long-term observational cohort study with recombinant human growth hormone in Korean children: LG Growth Study. AB - PURPOSE: Regarding recombinant human growth hormone (rhGH) use in the pediatric population, no long-term follow-up data are available for Korean patients. To fill in the gap of knowledge, a registry study (LG Growth Study) was initiated to assess the safety and effectiveness of four types of rhGH products in real-life settings. METHODS: A total of 4,000 children will be registered and prospectively followed up at 6-month intervals until 2 years after epiphyseal closure to collect data on treatment and adverse events, with primary interest in malignancies and growth outcomes. RESULTS: As of 22 March 2017, approximately 50% (2,024) of the target number of patients have been included in the analysis set: growth hormone deficiency, 1,297 (64.1%); idiopathic short stature, 315 (15.6%); small for gestational age, 206 (10.2%); Turner syndrome, 197 (9.7%); and chronic renal failure, 9 (0.4%). At baseline, median age (years) was 8 (interquartile range [IQR], 5-11); 52% (1,048) were boys; and the majority were at Tanner stage I (83% based on breast/external genitalia, 97% on pubic hair). Median height standard deviation score was -2.26 (IQR, -2.69 to -2.0), and median bone age delay (years) was -1.46 (IQR, -2.26 to -0.78). CONCLUSIONS: This registry study will provide the opportunity to assess the risk of malignancies as well as the general safety data in Korean pediatric patients receiving rhGH. In addition, the long-term effectiveness of rhGH and comparative data between different disease entities will provide practical insight on the standard rhGH treatment. PMID- 29609451 TI - Erratum: The effect of first nocturnal ejaculation timing on risk and sexual behaviors of Korean male adolescents. AB - [This corrects the article on p. 43 in vol. 22.]. PMID- 29609450 TI - Hepatopulmonary syndrome caused by hypothalamic obesity and nonalcoholic fatty liver disease after surgery for craniopharyngioma: a case report. AB - Hypothalamic obesity is often complicated in patients with craniopharyngioma due to hypothalamic damage by the tumor itself, treatment modalities, and associated multiple pituitary hormone deficiency. Hypothalamic obesity causes secondary diseases such as nonalcoholic fatty liver disease (NAFLD) and diabetes mellitus (DM). We report a 19-year-old female who was diagnosed with craniopharyngioma, developed hypothalamic obesity after tumor resection, and progressed to hepatopulmonary syndrome. She manifested NAFLD 1 year after tumor resection. Two years later, the craniopharyngioma recurred, and she underwent a second resection. Three years after her second operation, she was diagnosed with type 2 DM, after which she did not visit the outpatient clinic for 2 years and then suddenly reappeared with a weight loss of 25.8 kg that had occurred over 21 months. One month later, she presented to the Emergency Department with dyspnea. Laboratory findings revealed liver dysfunction and hypoxia with increased alveolar artery oxygen gradient. Liver biopsy showed portal hypertension and micronodular cirrhosis. Echocardiography and a lung perfusion scan demonstrated a right to left shunt. She was finally diagnosed with hepatopulmonary syndrome and is currently awaiting a donor for liver transplantation. Patients surviving craniopharyngioma need to be followed up carefully to detect signs of hypothalamic obesity and monitored for the development of other comorbidities such as DM, NAFLD, and hepatopulmonary syndrome. PMID- 29609452 TI - Experiences of magnetic resonance imaging scanning in patients with pacemakers or implantable cardioverter-defibrillators. AB - Background/Aims: Despite the U.S. Food and Drug Adminstration approving a magnetic resonance imaging (MRI)-conditional pacemaker system in 2011, many physicians remain reluctant to perform MRI scanning in patients with cardiac implantable electronic devices. Herein, we aimed to evaluate the real-world safety of MRI in these patients. Methods: This single-center retrospective study examined the interrogation data and outcomes of patients with pacemakers or implantable cardioverter defibrillators who underwent MRI. MRI interrogation data were collected pre- and post-MRI and after 1 month of follow-up; these included the lead impedance, measured P- and R-wave amplitudes, and capture threshold. We compared these results between the magnetic resonance (MR)-conditional and conventional groups. Results: From September 2013 to December 2015, 35 patients with cardiac implantable electronic devices underwent 43 MRI scans, with a mean follow-up of 5 months. Among these 35 patients, 14 (40%) had MR-conditional devices and 21 (60%) had conventional devices. Seven patients had high voltage devices, which were all the conventional type. There were no adverse events associated with MRI during the follow-up period, and there were no significant differences in the interrogation data changes between the conventional and MR conditional groups. Conclusions: This single-center retrospective study found that MRI can be performed safely in patients with pacemakers or implantable cardioverter defibrillators, regardless of the MRI support, as long as appropriate precautions are taken. PMID- 29609453 TI - Korean physicians' policies for postoperative surveillance of colorectal cancer. AB - Background/Aims: We explored Korean physicians' policies for surveillance of colorectal cancer (CRC) after curative surgery. METHODS: Web-based self-report questionnaires were developed. Invitations to participate were emailed to physicians who diagnosed and treated CRC from October 1 to November 15, 2015. The questionnaire consisted of the role doctors played in the surveillance, examination of surveillance, and duration of postoperative surveillance according to CRC stage or primary site of the cancer. RESULTS: Ninety-one physicians participated in the online survey, and 78 completed the survey. Sixty-seven participants (13%) answered "up to 5 years" for stage I surveillance duration; and 11 (13%) responded with a duration of > 5 years for stage I. A total of 61 (75%) responded with a surveillance duration of up to 5 years for stage II; and 19 (24%) responded with a duration of > 5 years for stage II. Sixty-seven (97%) and 61 (91%) physicians monitored patients with stage II/III every 3 or 6 months by laboratory examination and by abdominopelvic computed tomography scan for the first year, respectively. A total of 43 (53%) responded with a surveillance duration of up to 5 years for stage IV; and 46 (46%) responded with a duration of > 5 years for stage IV after curative resection. Conclusions: Korean physicians mostly followed up CRC using intensive postoperative surveillance. In preference to monitoring over a comparatively shorter period of time, the physicians tended to prefer monitoring patients post-operatively over a > 5 year period, particularly in cases of advanced-stage CRC. PMID- 29609454 TI - Pt-like Hydrogen Evolution Electrocatalysis on PANI/CoP Hybrid Nanowires by Weakening the Shackles of Hydrogen Ions on the Surfaces of Catalysts. AB - The search for high active, stable, and cost-efficient hydrogen evolution reaction (HER) electrocatalysts for water electrolysis has attracted great interest. The coordinated water molecules in the hydronium ions will obviously reduce the positive charge density of H+ and hamper the ability of H+ to receive electrons from the cathode, leading to large overpotential of HER on nonprecious metal catalysts. Here we realize Pt-like hydrogen evolution electrocatalysis on polyaniline (PANI) nanodots (NDs)-decorated CoP hybrid nanowires (HNWs) supported on carbon fibers (CFs) (PANI/CoP HNWs-CFs) as PANI can effectively capture H+ from hydronium ions to form protonated amine groups that have higher positive charge density than those of hydronium ions and can be electro-reduced easily. The PANI/CoP HNWs-CFs as low-cost electrocatalysts show excellent catalytic performance toward HER in acidic solution, such as super high catalytic activity, small Tafel slope, and superior stability. PMID- 29609455 TI - First Clear-Cut Experimental Evidence of a Glass Transition in a Polymer with Intrinsic Microporosity: PIM-1. AB - Polymers with intrinsic microporosity (PIMs) represent a novel, innovative class of materials with great potential in various applications from high-performance gas-separation membranes to electronic devices. Here, for the first time, for PIM 1, as the archetypal PIM, fast scanning calorimetry provides definitive evidence of a glass transition ( Tg = 715 K, heating rate 3 * 104 K/s) by decoupling the time scales responsible for glass transition and decomposition. Because the rigid molecular structure of PIM-1 prevents any conformational changes, small-scale bend and flex fluctuations must be considered the origin of its glass transition. This result has strong implications for the fundamental understanding of the glass transition and for the physical aging of PIMs and other complex polymers, both topical problems of materials science. PMID- 29609456 TI - Retraction of "Excavating the Role of Aloe Vera Wrapped Mesoporous Hydroxyapatite Frame Ornamentation in Newly Architectured Polyurethane Scaffolds for Osteogenesis and Guided Bone Regeneration with Microbial Protection". PMID- 29609457 TI - Integrating T7 RNA Polymerase and Its Cognate Transcriptional Units for a Host Independent and Stable Expression System in Single Plasmid. AB - Metabolic engineering and synthetic biology usually require universal expression systems for stable and efficient gene expression in various organisms. In this study, a host-independent and stable T7 expression system had been developed by integrating T7 RNA polymerase and its cognate transcriptional units in single plasmid. The expression of T7 RNA polymerase was restricted below its lethal threshold using a T7 RNA polymerase antisense gene cassette, which allowed long periods of cultivation and protein production. In addition, by designing ribosome binding sites, we further tuned the expression capacity of this novel T7 system within a wide range. This host-independent expression system efficiently expressed genes in five different Gram-negative strains and one Gram-positive strain and was also shown to be applicable in a real industrial d- p hydroxyphenylglycine production system. PMID- 29609458 TI - Kinetics of First-Row Transition Metal Cations (V+, Fe+, Co+) with OCS at Thermal Energies. AB - The temperature-dependent kinetics for reactions of V+, Fe+, and Co+ with OCS are measured using a selected ion flow tube apparatus heated to 300-600 K. All three reactions proceed solely by C-S activation at thermal energies, resulting in metal sulfide cation formation. Previously calculated reaction pathways were employed to inform statistical modeling of these reactions for comparison to the data. As surmised previously, all three reactions at thermal energies require spin crossing, with the Fe+ reaction crossing once circumventing a prohibitive transition state, before crossing again to form ground state products. The Fe+ and Co+ reaction efficiencies increase with energy. For the Co+ reaction, and to a lesser extent the Fe+ reaction, the apparent activation energies are less than the reaction endothermicities, possibly indicating increasing diabatic behavior of the spin crossings with energy. The V+ reaction was well modeled assuming an entirely adiabatic spin crossing, such that the resultant avoided crossing behaves similarly to a tight transition state. The subsequent reaction of VS+ with OCS producing VS2+ is also investigated; the rate-limiting transition state energy derived from statistical modeling is poorly reproduced by quantum calculations using a variety of methods, highlighting the large (1-2 eV) uncertainty in calculated energetics of transition-metal containing species. PMID- 29609460 TI - Retraction of "On-Demand Guided Bone Regeneration with Microbial Protection of Ornamented SPU Scaffold with Bismuth-Doped Single Crystalline Hydroxyapatite: Augmentation and Cartilage Formation". PMID- 29609459 TI - Modulating Antibody Structure and Function through Directed Mutations and Chemical Rescue. AB - Monoclonal antibody therapeutics have revolutionized the treatment of diseases such as cancer and autoimmune disorders, and also serve as research reagents for diverse and unparalleled applications. To extend their utility in both contexts, we have begun development of tunable antibodies, whose activity can be controlled by addition of a small molecule. Conceptually, we envision that incorporating cavity-forming mutations into an antibody can disrupt its structure, thereby reducing its affinity for antigen; addition of a small molecule may then restore the active structure, and thus rescue antigen binding. As a first proof of concept toward implementing this strategy, we have incorporated individual tryptophan to glycine mutations into FITC-E2, an anti-fluorescein single-chain variable fragment (scFv). We find that these can disrupt the protein structure and diminish antigen binding, and further that both structure and function can be rescued by addition of indole to complement the deleted side chain. While the magnitude of the affinity difference triggered by indole is modest in this first model system, it nonetheless provides a framework for future mutation/ligand pairs that may induce more dramatic responses. Disrupting and subsequently rescuing antibody activity, as exemplified by this first example, may represent a new approach to "design in" fine-tuned control of antibody activity for a variety of future applications. PMID- 29609461 TI - Asymmetric Cu-Catalyzed 1,4-Dearomatization of Pyridines and Pyridazines without Preactivation of the Heterocycle or Nucleophile. AB - We show that a chiral copper hydride (CuH) complex catalyzes C-C bond-forming dearomatization of pyridines and pyridazines at room temperature. The catalytic reaction operates directly on free heterocycles and generates the nucleophiles in situ, eliminating the need for stoichiometric preactivation of either reaction partner; further, it is one of very few methods available for the enantioselective 1,4-dearomatization of heteroarenes. Combining the dearomatization with facile derivatization steps enables one-pot syntheses of enantioenriched pyridines and piperidines. PMID- 29609462 TI - Metastable Superconductivity in Two-Dimensional IrTe2 Crystals. AB - Two-dimensional (2D) materials exhibit unusual physical and chemical properties that are attributed to the thinning-induced modification of their electronic band structure. Recently, reduced thickness was found to dramatically impact not only the static electronic structure, but also the dynamic ordering kinetics. The ordering kinetics of first-order phase transitions becomes significantly slowed with decreasing thickness, and metastable supercooled states can be realized by thinning alone. We therefore focus on layered iridium ditelluride (IrTe2), a charge-ordering system that is transformed into a superconductor by suppressing its first-order transition. Here, we discovered a persistent superconducting zero resistance state in mechanically exfoliated IrTe2 thin flakes. The maximum superconducting critical temperature ( Tc) was identical to that which is chemically optimized, and the emergent superconductivity was revealed to have a metastable nature. The discovered robust metastable superconductivity suggests that 2D material is a new platform to induce, control, and functionalize metastable electronic states that are inaccessible in bulk crystals. PMID- 29609463 TI - STM Imaging of Localized Surface Plasmons on Individual Gold Nanoislands. AB - An optically modulated scanning tunneling microscopy technique developed for measurement of single-molecule optical absorption is used here to image the light absorption by individual Au nanoislands and Au nanostructures. The technique is shown to spatially map, with nanometer resolution, localized surface plasmons (LSPs) excited within the nanoislands. Electrodynamic simulations demonstrate the correspondence of the measured images to plasmonic near-field intensity maps. The optical STM imaging technique captures the wavelength, polarization, and geometry dependence of the LSP resonances and their corresponding near-fields. Thus, we introduce a tool for real-space, nanometer-scale visualization of optical energy absorption, transport, and dissipation in complex plasmonic nanostructures. PMID- 29609464 TI - Structural Basis for Superoxide Activation of Flavobacterium johnsoniae Class I Ribonucleotide Reductase and for Radical Initiation by Its Dimanganese Cofactor. AB - A ribonucleotide reductase (RNR) from Flavobacterium johnsoniae ( Fj) differs fundamentally from known (subclass a-c) class I RNRs, warranting its assignment to a new subclass, Id. Its beta subunit shares with Ib counterparts the requirements for manganese(II) and superoxide (O2-) for activation, but it does not require the O2--supplying flavoprotein (NrdI) needed in Ib systems, instead scavenging the oxidant from solution. Although Fj beta has tyrosine at the appropriate sequence position (Tyr 104), this residue is not oxidized to a radical upon activation, as occurs in the Ia/b proteins. Rather, Fj beta directly deploys an oxidized dimanganese cofactor for radical initiation. In treatment with one-electron reductants, the cofactor can undergo cooperative three-electron reduction to the II/II state, in contrast to the quantitative univalent reduction to inactive "met" (III/III) forms seen with I(a-c) betas. This tendency makes Fj beta unusually robust, as the II/II form can readily be reactivated. The structure of the protein rationalizes its distinctive traits. A distortion in a core helix of the ferritin-like architecture renders the active site unusually open, introduces a cavity near the cofactor, and positions a subclass-d-specific Lys residue to shepherd O2- to the Mn2II/II cluster. Relative to the positions of the radical tyrosines in the Ia/b proteins, the unreactive Tyr 104 of Fj beta is held away from the cofactor by a hydrogen bond with a subclass-d-specific Thr residue. Structural comparisons, considered with its uniquely simple mode of activation, suggest that the Id protein might most closely resemble the primordial RNR-beta. PMID- 29609466 TI - ES&T's Best Papers of 2017. PMID- 29609465 TI - Evaporative Crystallization in Drops on Superhydrophobic and Liquid-Impregnated Surfaces. AB - Mineral-fouling induced corrosion and deterioration of marine vessels, aircraft, and coastal structures is due in part from structural intrusion of crystals grown from ocean-generated saline drops. As such, much work has explored surface treatments that induce hydrophobicity or introduce barriers for antifouling and corrosion prevention; however, the efficacy of these strategies will be altered by the underlying substrate texture. Here, we study the behavior of evaporating saline drops on superhydrophobic and liquid-impregnated surfaces as a function of surface texture. On superhydrophobic surfaces, four disparate regimes (which are not observed for particle-laden drops) emerge as a function of the substrate solid fraction: Cassie-pinning, Cassie-gliding, Cassie-Wenzel transition, and Wenzel. These regimes control the morphology of the resultant crystal deposits. In contrast to the superhydrophobic surfaces, spreading liquid-impregnated surfaces demonstrate minimal influence of solid fraction on evaporative crystallization. The area, area localization, timescale of evaporation, and deposit morphology are all normalized by the presence of the lubricating layer, thus introducing an efficient method of eliminating crystal "coffee rings" as well as reducing the potential for fouling and corrosion. PMID- 29609467 TI - Analytical Technologies to Improve Human Health. PMID- 29609468 TI - Femtosecond laser desorption ionization mass spectrometry imaging and multivariate analysis of lipids in pancreatic tissue. AB - Femtosecond laser desorption ionization mass spectrometry was used to obtain mass spectrometric (MS) images of lipids in human pancreatic tissue. The resulting MS images were analyzed using multivariate analysis, specifically principal component analysis and maximum a posteriori (MAP) reconstruction. Both analysis methods showed that the MS images can be separated into lipid and non-lipid areas. MAP analysis further indicated that the lipid areas are composed of phosphatidylcholines and fatty acids. However, definitive identification of the lipids cannot be made because none of the intact parent ions of phosphatidylcholine, sphingomyelins, and/or other lipids were observed. The MAP analysis also revealed that the non-lipid areas could be separated into components that are due to the sample chemical treatment and topography. PMID- 29609470 TI - Relationships Between Glycemic Control and Cardiovascular Fitness. AB - INTRODUCTION: Diabetes is a serious health problem affecting approximately 29.1 million individuals in the United States. Another 86 million have prediabetes. The development and implementation of lifestyle modifications such as physical activity for these persons are among the most effective methods for prevention and treatment. OBJECTIVE: The aim of this study was to examine relationships between glycemic control (HbA1c) and cardiovascular fitness (peak maximal oxygen uptake [VO2 peak] and ventilatory threshold [VT]) in overweight/obese subjects with and without type 2 diabetes (T2DM). In addition, the influences of body mass index (BMI) and insulin sensitivity (homeostasis model assessment [HOMA %S]) on the relationship between glycemic control and cardiovascular fitness were explored. METHOD: Data were abstracted from a completed study that included 51 overweight or obese subjects with T2DM ( n = 18), impaired glucose tolerance ( n = 8), or normal glucose tolerance ( n = 25). Relationships between glycemic control (HbA1c) and cardiovascular fitness (VO2 peak and VT) were determined using correlational analysis and multiple linear regression analyses. RESULTS: A statistically significant relationship was observed between HbA1c and cardiovascular fitness. However, BMI and HOMA %S did not influence the relationship between glycemic control and cardiovascular fitness. DISCUSSION: HbA1c contributes to VO2 peak and VT in obese and overweight subjects across glucose tolerance categories. Significant results were achieved despite the fact that there was a limited range of HbA1c based on the study inclusion criteria. This finding suggests that even a mild decrease in glycemic control can negatively influence cardiovascular fitness. PMID- 29609471 TI - Victor W. Sidel (7 July 1931-30 January 2018). PMID- 29609469 TI - Bereaved Family Members' Perceptions of the Distressing Symptoms of Terminal Patients With Cancer. AB - BACKGROUND: Few data are available on bereaved family members' perspective on the frequency of symptoms and degree of distress among terminal patients with cancer. METHODS: We sent a questionnaire to 1472 bereaved family members of terminal patients with cancer in 20 general hospitals. The questionnaire asked them (1) to indicate which symptoms the patients had, (2) to rate on a 4-point scale the extent to which the symptom was distressing, as follows: 1 = not distressing, 2 = slightly distressing, 3 = quite distressing, and 4 = very distressing at the point of 2 weeks before the patient had died. RESULTS: We analyzed 805 questionnaires for this study. Anorexia was the commonest symptom among terminal patients with cancer experienced by bereaved family members, followed by somnolence, weight loss, fatigue, and pain. Anorexia was the most distressing symptom among terminal patients with cancer experienced by bereaved family members, followed by weight loss, pain, edema, and dyspnea. CONCLUSIONS: Anorexia and weight loss were frequent symptoms and bereaved family members felt very distressing. Furthermore, there are not means of effective treatment now. Thus, we think that further study in this field is necessary. PMID- 29609472 TI - Perceived confidence, competence and training in evidence-based treatments for eating disorders: a survey of clinicians in an Australian regional health service. AB - OBJECTIVES: Eating disorders (EDs) are challenging to treat and contribute to considerable morbidity and mortality. This study sought to identify the educational preparedness, competence and confidence of clinicians to work with people with EDs; and to identify how services might be improved. METHODS: Clinicians who worked in the emergency department, medical, paediatric wards and mental health services were invited to complete an online survey. RESULTS: From the 136 surveys returned, 73% of respondents reported little or no confidence working with EDs. There was a strong linear correlation between perceived confidence and competence and hours of education. Those with 70 or more hours of self-reported training were 2.7 times more likely to rate themselves as both confident and competent. Improving services for people with eating disorders included the provision of appropriate training, improving access to services including psychotherapy, and facilitating consistency in and continuity of care. CONCLUSIONS: To increase the confidence and competence of the workforce, regular training around EDs should be undertaken. The establishment of a specialist team to provide services across the continuum of care for people with severe or complex EDs appears warranted in a regional health service. PMID- 29609473 TI - Nutrition and husbandry conditions of Palearctic tortoises (Testudo spp.) in captivity. AB - Mediterranean and Russian tortoises (Testudo spp.) are popular companion animals (pets), despite ongoing controversy concerning privately keeping reptiles. The arguments used during these controversial discussions have often been based on outdated facts. Therefore, a survey was developed to evaluate the current population structure, husbandry conditions, diet regime, and health status of Testudo species in captivity. More than 75% of the 1075 respondents housed their tortoises in an outdoor enclosure containing a greenhouse or cold frame, which is considered the most species-appropriate way of husbandry. Of the respondents, 67.7% fed their tortoises with the optimum diet of more than 80% grasses and weeds during the summer vegetation period. Only 8.2% of respondents owned a tortoise with a diagnosed disease. According to the results, the likelihood of tortoises developing pyramidal growth syndrome, which can be used as an indicator of the quality of tortoise husbandry, was high in tortoises kept in a terrarium and/or fed a diet of less than 80% grasses and weeds in summer. This likelihood varied among species, with a higher incidence in Hermann's tortoises (Testudo hermanni). PMID- 29609474 TI - A comparison between Right Unilateral Ultrabrief electroconvulsive therapy and bilateral electroconvulsive therapy in the elderly: a pilot naturalistic observational study. AB - OBJECTIVES: To compare clinical outcomes and adverse effects between Bitemporal (BT) and Right Unilateral Ultrabrief (RUL(UB)) electroconvulsive therapy (ECT) in an elderly population. METHODS: Patients over the age of 65 years admitted to a tertiary referral hospital over a seven month period requiring ECT received RUL(UB) ECT. They were compared with those who received BT ECT over these and the preceding seven months. RESULTS: Twenty-three patients entered the study. No significant differences was observed between the groups in demographic and clinical characteristics or clinical improvement. However, patients who received BT ECT were significantly more likely to be confused post treatment compared with the RUL(UB) group. CONCLUSIONS: This pilot study found RUL(UB) ECT to be an effective treatment in elderly patients. These patients also suffered significantly less confusion than patients who received BT ECT. PMID- 29609475 TI - Effectiveness of a smartphone-based worry-reduction training for stress reduction: A randomized-controlled trial. AB - OBJECTIVE: Perseverative cognition (e.g. worry) and unconscious stress are suggested to be important mediators in the relation between stressors and physiological health. We examined whether a smartphone-based worry-reduction training improved a physiological marker of stress (i.e. increased heart rate variability [HRV]) and unconscious stress. DESIGN: Randomised-controlled trial was conducted with individuals reporting work stress (n = 136). Participants were randomised to the experimental, control or waitlist condition (resp. EC, CC, WL). The EC and CC registered emotions five times daily for four weeks. The EC additionally received a worry-reduction training with mindfulness exercises. MAIN OUTCOME MEASURES: Primary outcome was 24-h assessments of HRV measured at pre-, mid- and post-intervention. Secondary outcomes were implicit affect and stress. Effects on heart rate and other psychological outcomes were explored. RESULTS: A total of 118 participants completed the study. No change from pre- to post intervention was observed for the primary or secondary outcomes. The change over time was not different between conditions. CONCLUSION: Findings suggest that the training was ineffective for improving HRV or psychological stress. Future studies may focus on alternative smartphone-based stress interventions, as stress levels are high in society. There is need for easy interventions and smartphones offer possibilities for this. PMID- 29609476 TI - Understanding the social and community support networks of American Indian women cancer survivors. AB - OBJECTIVE: Cancer is the leading cause of death among American Indian and Alaska Native (AI/AN) women, and although cancer disparities among AI women are alarming, there is little research focused on the topic of social support and cancer treatment and outcomes. DESIGN: A community advisory board was used to develop and administer the project, and a qualitative descriptive study methodology was used. This research was conducted in partnership with two community-based hospitals in the Northern Plains. The sample included 43 AI female cancer survivors who were interviewed with a semi-structured interview guide. The data were analyzed using content analysis. RESULTS: Emergent themes revealed that AI cancer survivors' non-familial support systems included friends (n = 12), support groups (n = 6), churches (n = 10), co-workers (n = 5), communities (n = 4), support from health practitioners (n = 3) and additional forms of support. CONCLUSION: Results indicate that survivors' networks are diverse, and support broad prevention programs that reach out to churches, community groups, and online forums. These sources of supports can be enhanced through sustainable community-based infrastructures. PMID- 29609477 TI - Virtual study groups and online Observed Structured Clinical Examinations practices - enabling trainees to enable themselves. AB - OBJECTIVES: To explore online study groups as augmentation tools in preparing for the Royal Australian and New Zealand College of Psychiatrists Observed Structured Clinical Examinations (OSCE) for fellowship. METHODS: An online survey of New Zealand trainees was carried out to assess exam preparedness and openness to virtual study groups and results analysed. Relevant material around virtual study groups for fellowship examinations was reviewed and used to inform a pilot virtual study group. Four New Zealand trainees took part in the pilot project, looking at using a virtual platform to augment OSCE preparation. RESULTS: Of the 50 respondents 36% felt adequately prepared for the OSCE. Sixty-four per cent were interested in using a virtual platform to augment their study. Virtual study groups were noted to be especially important for rural trainees, none of whom felt able to form study groups for themselves. The pilot virtual study group was trialled successfully. All four trainees reported the experience as subjectively beneficial to their examination preparation. CONCLUSIONS: Virtual platforms hold promise as an augmentation strategy for exam preparation, especially for rural trainees who are more geographically isolated and less likely to have peers preparing for the same examinations. PMID- 29609478 TI - Visual outcomes of pediatric traumatic cataracts. AB - INTRODUCTION: To report visual outcomes and risk factors of pediatric traumatic cataracts in a tertiary care referral center in northern India. METHODS: We analyzed medical records of traumatic cataracts in the pediatric age group (1-15 years) operated for cataract surgery with or without posterior chamber intraocular lens implantation with or without primary posterior capsulotomy with anterior vitrectomy between 2004 and 2012. Causative agents, types of trauma, demographic factors, surgical interventions, complications, and visual acuity were recorded and compared among different groups. RESULTS: A total of 147 children were documented to have undergone cataract surgery for traumatic cataract in the study period, male-to-female ratio being approximately 5:1. Mean age was 7.67 +/- 3.30 years (range, 1-15 years). Type of primary insult was penetrating injury in 100 (68%) patients and blunt trauma in 47 (32%) patients. Mean interval between injury and cataract surgery in penetrating injury cases was 3.84 +/- 7.05 months and in the blunt injury cases was 6.28 +/- 11.13 months. Preoperatively, only 110 patients were cooperative for visual acuity. Out of them, none had vision better than 6/18 and only 21 patients (19.9%) had vision of >=6/60. Visual acuity of 6/18 or better (was considered good visual outcome) was achieved by 87.9%, 97.3%, and 97.9% at 1, 6, and 36 months, postoperatively. Eyes which underwent primary posterior capsulotomy and anterior vitrectomy during cataract surgery showed statistically better visual outcome than those without it. CONCLUSION: Phacoaspiration with posterior chamber intraocular lens implantation along with primary posterior capsulotomy and anterior vitrectomy and timely introduction of amblyopia therapy helped in gaining good visual outcome in pediatric traumatic cataract patients irrespective of the age of presentation and the type of injury. PMID- 29609479 TI - Improvement in Quality of Life Following Operative Correction of Midtarsal Charcot Foot Deformity. AB - BACKGROUND: Patients with Charcot foot arthropathy report a poor quality of life following the development of deformity. Their quality of life is often not improved with "successful" historic accommodative treatment. There is increased current interest in operative correction of the acquired deformity with the stated goals of achieving both the traditional goals of resolution of infection and limb salvage as well as the desire to improve quality of life. The Short Musculoskeletal Functional Assessment (SMFA) outcomes instrument appears to be a valid tool for evaluating this complex patient population. METHODS: Twenty-five consecutive patients undergoing operative reconstruction for nonplantigrade midtarsal Charcot foot arthropathy completed the SMFA patient-reported outcomes instrument prior to surgery, with 24 completing it at 1 year following the surgery. One patient died during the year following surgery from unrelated causes. RESULTS: There was an 11.5-point (95% confidence interval [CI]: -19.7 to 3.2) decrease in the standardized functional index ( P = .01). Similarly, there was a 12.4-point (95% CI: -22.5 to -2.3) decrease in the standardized bother index ( P = .02). The standardized daily activity index demonstrated a 19.6-point decrease (95% CI: -30.5 to -8.6, P = .002), and there was a 14.7-point (95% CI: 24.1 to -5.3) decrease in the standardized emotion index ( P = .004). There was no meaningful change in the standardized arm/hand index ( P = .81). CONCLUSION: The results of this investigation demonstrate that successful operative reconstruction of midtarsal Charcot foot arthropathy improved quality of life. This supports the modern paradigm shift from immobilization during the active phase of the disease process followed by simple accommodation of the acquired deformity to the modern interest in operative correction to allow the use of commercially available therapeutic footwear. LEVEL OF EVIDENCE: Level IV, case series. PMID- 29609480 TI - Adherence and retention of African Americans in a randomized controlled trial with a yoga-based intervention: the effects of health promoting programs on cardiovascular disease risk study. AB - OBJECTIVES: Sedentary lifestyle is a risk factor for cardiovascular disease (CVD). Few alternative lifestyle interventions, such as yoga practice, focus on African Americans (AA), the population most vulnerable to CVD. Our objective is to compare the retention and adherence rates between yoga, walking, and health education interventions while providing information about the acceptance of various yoga regimens. DESIGN: Three hundred seventy-five AA participants were recruited exclusively from an active cohort study and randomized into a 48-week study (24 weeks intervention, 24 weeks follow-up) with 5 health promotion interventions: high frequency yoga, moderate frequency yoga, low frequency yoga, guided walking, and health education. In addition to examining the separate yoga interventions, a pooled yoga intervention is considered for comparison to guided walking and health education. Participant retention, adherence, and vitals were monitored at each intervention session. Participants were also scheduled for four clinic visits throughout the study where blood panels, health behavior, and medication surveys were administered. RESULTS: Of the 375 participants recruited, 31.7% did not complete the study. At baseline, in both the guided walking group and the high frequency yoga group, there were significant differences between those who completed the study and those who did not. Although intervention retention in the pooled yoga program (78.3%) was higher compared to the walking (60%) and education programs (74.3%) (p = 0.007), differences in post intervention retention was not significant. Median adherence rates for the pooled yoga program exceeded rates for guided walking and education with moderate frequency yoga out performing high and low frequency yoga. CONCLUSION: Study defined retention success rates were not reached by all health promotion programs. However, retention and adherence rates for the pooled yoga program show that older African Americans are receptive to participating in yoga-based health promotion practices. PMID- 29609481 TI - Why is ethnicity important in cardiovascular care? PMID- 29609482 TI - HeartBeat. PMID- 29609483 TI - A method for estimating fetal weight based on body composition. AB - Fetal weight is an important factor to determine the delivery mode of pregnant women. The change of fetal weight is significant, according to regular health monitoring of pregnant women. Conventional methods of fetal weight estimation, namely those based on B-ultrasound, are very complicated and the costs are high. In this paper, we propose a new method based on body composition. An abdominal four-segment impedance model is first established upon pregnant women, as well as the method of calculation. A body composition based method is then given to estimate the fetal weight, with the solution given explicitly. Analyses of clinical data reveal the smallness of the error between the estimated value and the actual value. The error between B-ultrasound and the present method is less than 15%. PMID- 29609484 TI - Correctional Policy and Attempted Suicide Among Transgender Individuals. AB - Little research has examined the link between incarceration and suicide among transgender individuals. Transgender inmates face unique circumstances within the correctional setting that expose them to potentially harmful conditions, including correctional policies that limit access to proper medical care and expose them to threats of harassment and violence. Using data from the 2011 National Transgender Discrimination Survey, this article examines the link between incarceration and suicide among transgender individuals by focusing on the link between correctional policies and attempted suicide among transgender individuals who have been incarcerated. Multivariate results suggest that correctional policies regarding health care and housing may deleteriously impact transgender inmates. PMID- 29609486 TI - You Can't Fool the Children of the Revolution. PMID- 29609485 TI - Treatment for occult hepatocellular carcinoma: does it offer survival advantages over symptom-driven treatment? AB - OBJECTIVE: In order to claim a benefit of screen-based diagnosis for asymptomatic individuals, treatment of occult disease needs to offer survival advantages compared to the treatment of symptomatic disease, yet information on this issue is scarce with regard to hepatocellular carcinoma (HCC) screening. METHODS: A total of 3353 treatment-naive, consecutive, newly diagnosed HCC patients [age: 57.9 +/- 10.3, male: 2,689 (80.2%), hepatitis B virus: 2555 (76.2%)], diagnosed between 2010 and 2013 were analyzed. Data on the mode of detection was prospectively collected at the time of HCC diagnosis and was used to group patients into occult or symptomatic cases. RESULTS: Overall, 643 (19.2%) patients were symptomatic cases. The proportion of patients undergoing resection, radiofrequency ablation or transplantation were lower in symptomatic cases than occult cases (20.8 vs. 56.2%, p < .001). Survival was better in occult cases than symptomatic cases (71.2 vs. 30.4% at three-years, p < .001), with a multivariable adjusted hazard ratio of 1.40 (95% confidence interval (CI), 1.24-1.58). When stratified by tumor stage, a survival benefit was not observed for patients diagnosed at modified International Union Against Cancer (mUICC) stage I, but presenting symptoms were diverse and nonspecific. In a statistical model adjusting for potential lead-time bias, the association between overall survival and the mode of detection was markedly attenuated and was no longer significant when the treatment modality was included in the model (hazard ratio, 0.94; 95% CI, 0.82-1.07). CONCLUSION: Treatment of occult disease offered a survival benefit to patients over symptomatic cases. These data support screening practices for asymptomatic individuals to diagnose occult HCC. PMID- 29609487 TI - 3D printing processes for photocurable polymeric materials: technologies, materials, and future trends. AB - The aim of this review is a faithful report of the panorama of solutions adopted to fabricate a component using vat photopolymerization (VP) processes. A general overview on additive manufacturing and on the different technologies available for polymers is given. A comparison between stereolithography and digital light processing is also presented, with attention to different aspects and to the advantages and limitations of both technologies. Afterward, a quick overview of the process parameters is given, with an emphasis on the necessities and the issues associated with the VP process. The materials are then explored, starting from base matrix materials to composites and nanocomposites, with attention to examples of applications and explanations of the main factors involved. PMID- 29609488 TI - Telomeres as a molecular marker of male infertility. AB - In recent years, male infertility has become a growing social problem. Standard diagnostic procedures, based on assessing seminological parameters, are often insufficient to explain the causes of male infertility. Because of this, new markers with better clinical application are being sought. One of the promising markers seems to be an assessment of telomere length of sperm. Sperm telomeres, in contrast to somatic cells, are elongated as men age. The results of some studies suggest that telomere length may be relevant in the case of fertilization and normal embryo development. Literature reports indicate that there is a correlation between telomere length of sperm and abnormal sperm parameters. The measurement of telomere length using the method of quantitative PCR could become a new marker of spermatogenesis, which can be useful for evaluating male reproductive age. PMID- 29609490 TI - Colostrum and mature breast milk analysis of serum irisin and sterol regulatory element-binding proteins-1c in gestational diabetes mellitus. AB - BACKGROUND: We aimed to evaluate irisin and SREBP-1c levels in serum, colostrum and mature breast milk in women with and without gestational diabetes (GDM); and to relate them with maternal glucose, lipid profile and weight status of babies. METHODS: GDM positive women (n = 33) and normal glucose tolerant women (NGT) (n = 33) were recruited. Maternal blood samples were collected at 28th week of gestation and later at 6-week post-partum while breast milk samples of the lactating mothers were collected within 72 hours of birth (colostrum) and at 6 weeks post-partum (mature milk). Irisin and SREBP-1c levels were analyzed by commercially available ELISA kits for all maternal samples. RESULTS: Lower levels of irisin were seen in serum, colostrum and mature breast milk of GDM females (p < .01). SREBP-1c profile showed a similar trend of low serum levels in GDM, however, they were undetectable in colostrum and mature breast milk. Weak to moderate correlations of serum irisin with BMI (r = 0.439; p < .001), GTT 0 hours (r = 0.403; p = .01), HbA1c (r = -0.312; p = .011), Fasting blood glucose (r = 0.992; p = .008), and baby weight at birth (r = 0.486; p < .001). Colostrum and mature breast milk irisin showed positive associations with baby weight at 6 weeks (r = 0.325; p = .017; r = 0.296; p = .022, respectively). Serum SREBP-1c at 6 weeks correlated with random blood glucose (r = 0.318; p = .009), and HbA1c (r= -0.292; p = .011). All correlations were lost once we adjusted for maternal BMI. CONCLUSIONS: Low irisin and SREBP1-c levels may favor development of GDM in pregnant subjects. Further, low mature breast milk levels may act as a continued stressor from fetal to infant life as long as breast-feeding is continued. Further studies are required to identify the mechanistic relationship between these biomarkers and GDM. PMID- 29609489 TI - Long-term sequelae of acute respiratory distress syndrome caused by severe community-acquired pneumonia: Delirium-associated cognitive impairment and post traumatic stress disorder. AB - Objective Delirium in critically ill patients is considered a risk factor for various long-term consequences. We evaluated delirium and associated long-term outcomes in patients with acute respiratory distress syndrome with non-H1N1 and H1N1- associated severe community-acquired pneumonia (sCAP) who had been recommended to take antiviral drugs associated with delirious symptoms as adverse effects. Methods Of 64 patients, 42 survivors (H1N1, 15; non-H1N1, 27) were analyzed regarding the relationship between medication and the duration of delirium in the intensive care unit. During follow-up (n = 23), we assessed cognitive abilities, post-traumatic stress disorder (PTSD), physical capacity, and health-related quality of life (HRQoL). Results The incidence of delirium was 88%. There was no difference in the incidence and duration of delirium between patients with H1N1 and non-H1N1 infection. The haloperidol and opioid doses were associated with a longer delirium duration. The delirium duration was correlated with reduced cognitive performance in motor skills, memory function, and learning efficiency. Patients with PTSD (16%) had a significantly longer delirium duration and low mental HRQoL. Conclusions H1N1 infection and corresponding antiviral medication had no impact on delirium. The duration of delirium in these patients was associated with impairments in various outcome parameters, illustrating the burden of sCAP. PMID- 29609491 TI - Covalent immobilization of coagulation factor VIII on magnetic nanoparticles for aptamer development. AB - INTRODUCTION: Magnetic nanoparticles (MNPs) are one of the most useful particulate systems in analytical applications such as specific aptamer selection. Proteins are the most noted targets of aptamer selection. Generally, covalently immobilized protein coated MNPs are more stable structures. METHODS: In this study, coagulation factor VIII (FVIII) was immobilized on MNPs. A silica coating provided isocyanate functional groups was considered to interact covalently with reactive groups of the protein, resulting in a stable protein immobilization. The reactions was run in dried toluene. At end, these MNPs were applied for affinity determination of a previously selected FVIII specific aptamers. RESULTS: Immobilization of 1 mg FVIII (~ 3 nmol) on 5 mg particles was achieved with no significant particle aggregation. Using a fluorescence-based method, affinity measurement resulted in a calculated dissociation constant of 120 +/- 5.6 nM for the FVIII-specific aptamer to the FVIII-coated MNPs. CONCLUSION: The final product could be a suitable protein-coated solid support for magnetic-based aptamer selection processes. PMID- 29609492 TI - Cancer cells growing on perfused 3D collagen model produced higher reactive oxygen species level and were more resistant to cisplatin compared to the 2D model. AB - INTRODUCTION: Three-dimensional (3D) collagen scaffold models, due to their ability to mimic the tissue and organ structure in vivo, have received increasing interest in drug discovery and toxicity evaluation. METHODS: In this study, we developed a perfused 3D model and studied cellular response to cytotoxic drugs in comparison with traditional 2D cell cultures as evaluated by cancer drug cisplatin. RESULTS: Cancer cells grown in perfused 3D environments showed increased levels of reactive oxygen species (ROS) production compared to the 2D culture. As determined by growth analysis, cells in the 3D culture, after forming a spheroid, were more resistant to the cancer drug cisplatin compared to that of the 2D cell culture. In addition, 3D culturing cells showed elevated level of ROS, indicating a physiological change or the formation of a microenvironment that resembles tumor cells in vivo. CONCLUSIONS: These data revealed that cellular response to drugs for cells growing in 3D environments are dramatically different from that of 2D cultured cells. Thus, the perfused 3D collagen scaffold model we report here might be a potentially very useful tool for drug analysis. PMID- 29609493 TI - A rare and dangerous hand infection caused by Francisella tularensis after a mouse bite. PMID- 29609494 TI - Oxidative damage mediated iNOS and UCP-2 upregulation in rat brain after sub acute cyanide exposure: dose and time-dependent effects. AB - Cyanide-induced chemical hypoxia is responsible for pronounced oxidative damage in the central nervous system. The disruption of mitochondrial oxidative metabolism has been associated with upregulation of uncoupling proteins (UCPs). The present study addresses the dose- and time-dependent effect of sub-acute cyanide exposure on various non-enzymatic and enzymatic oxidative stress markers and their correlation with inducible-nitric oxide synthase (iNOS) and uncoupling protein-2 (UCP-2) expression. Animals received (oral) triple distilled water (vehicle control), 0.25 LD50 potassium cyanide (KCN) or 0.50 LD50 KCN daily for 21 d. Animals were sacrificed on 7, 14 and 21 d post-exposure to measure serum cyanide and nitrite, and brain malondialdehyde (MDA), reduced glutathione (GSH), glutathione disulfide (GSSG), cytochrome c oxidase (CCO), superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GR) and catalase (CA) levels, together with iNOS and UCP-2 expression, and DNA damage. The study revealed that a dose- and time-dependent increase in cyanide concentration was accompanied by corresponding CCO inhibition and elevated MDA levels. Decrease in GSH levels was not followed by reciprocal change in GSSG levels. Diminution of SOD, GPx, GR and CA activity was congruent with elevated nitrite levels and upregulation of iNOS and UCP-2 expression, without any DNA damage. It was concluded that long-term cyanide exposure caused oxidative stress, accompanied by upregulation of iNOS. The upregulation of UCP-2 further sensitized the cells to cyanide and accentuated the oxidative stress, which was independent of DNA damage. PMID- 29609495 TI - Is fatigue after work a barrier for leisure-time physical activity? Cross sectional study among 10,000 adults from the general working population. AB - AIM: In spite of the many health-related benefits of regular physical activity, fatiguing work may be a barrier to performing leisure-time physical activity. This study investigates the association between work-related fatigue and the duration of low- and high-intensity leisure-time physical activity in workers with sedentary and physically demanding jobs. METHODS: From the 2010 round of the Danish Work Environment Cohort Study, currently employed wage earners from the general working population ( N=10,427) replied to questions about work-related fatigue (predictor) and duration of low- and high-intensity leisure-time physical activity (outcome). Associations were modelled using general linear models controlling for various confounders. RESULTS: Among workers with physically demanding jobs, higher levels of work-related fatigue were associated with gradually lower levels of leisure-time physical activity - for low, moderate and high levels of work-related fatigue the duration of high-intensity leisure-time physical activity was 133 (95% confidence interval (CI) 127-178), 134 (95% CI 109 160) and 113 (95% CI 86-140) min per week, respectively (trend test p<0.001). The duration of high-intensity leisure-time physical activity was lower among older workers (>=50 years) compared to younger workers (<50 years) (132 +/- 126 vs 168 +/- 150 min per week) ( p<0.0001). CONCLUSIONS: The duration of high-intensity leisure-time physical activity gradually decreases with increased work-related fatigue in workers with physically demanding jobs. Older workers perform less high-intensity physical activity than younger workers. Workplaces should consider initiatives to allow workers with physically demanding jobs and older workers to perform physical exercise during working hours and thereby increase physical capacity to meet the job demands. PMID- 29609497 TI - A novel D90_K91insN mutation in exon 4 of the SOD1 gene caused familial amyotrophic lateral sclerosis in a Chinese pedigree. AB - We reported a novel heterozygous duplication mutation (c.272_274dupACA, D90_K91insN) in exon 4 of the SOD1 gene in a Chinese pedigree. This pedigree demonstrates an autosomal dominant pattern of inheritance, with potentially reduced penetrance. The clinical phenotype was rather uniform with a distal lower extremity onset, predominant involvement of lower motor neurons (LMNs), and a relatively short survival time (mean 2.6 years) compared with other mutations in the loop V structure of SOD1. We also detected that the average SOD1 activity in D90_K91insN mutation carriers is 68.5% of wild-type controls. In conclusion, we identified the first non-frameshift duplication mutation in loop V of the human SOD1 in the Chinese population, suggesting the importance of the loop V structure in the pathogenicity of FALS. PMID- 29609498 TI - Trends in intentional abuse or misuse of benzodiazepines and opioid analgesics and the associated mortality reported to poison centers across the United States from 2000 to 2014. AB - CONTEXT: Prior works demonstrates an increased risk of death when opioid analgesics and benzodiazepines are used concomitantly to gain a high. Using poison center data, we described trends in abuse or misuse of benzodiazepines and opioid analgesics. We quantified mortality risk associated with abuse or misuse of benzodiazepines, opioid analgesics and the combination of opioid analgesics and benzodiazepines. METHODS: This was a retrospective chart review of data from the National Poison Data System which collects information from 55 poison centers located across the United States. We identified reported cases of "intentional abuse or misuse" of benzodiazepine and/or opioid analgesic exposures. Poisson regression was used to compare the number of cases from each year between 2001 and 2014 to the year 2000. Logistic regression was used to determine whether cases exposed to both benzodiazepines and opioids had greater odds of death relative to cases exposed to opioid analgesics alone. RESULTS: From 2000 to 2014, there were 125,485 benzodiazepine exposures and 84,627 opioid exposures among "intentional abuse or misuse" cases. Of the benzodiazepine exposures, 17.3% (n = 21,660) also involved an opioid. In 2010, exposures involving both opioids and benzodiazepines were 4.26-fold (95% CI: 3.87-4.70; p < .001) higher than in 2000. The risk of death was 1.55 (95% CI: 1.01-2.37; p = .04) times greater among those who used both an opioid and a benzodiazepine compared to opioids alone. This association held after adjusting for gender and age. CONCLUSION: Intentional abuse or misuse of benzodiazepines and opioids in combination increased significantly from 2000 to 2014. Benzodiazepine abuse or misuse far exceeded cases of opioid abuse or misuse. Death was greater with co-abuse or misuse of benzodiazepines and opioids. Population-level campaigns to inform the public about the risk of death with co-abuse or misuse of benzodiazepines and opioids are urgently needed to address this overdose epidemic. PMID- 29609496 TI - Music and Speech Perception in Children Using Sung Speech. AB - This study examined music and speech perception in normal-hearing children with some or no musical training. Thirty children (mean age = 11.3 years), 15 with and 15 without formal music training participated in the study. Music perception was measured using a melodic contour identification (MCI) task; stimuli were a piano sample or sung speech with a fixed timbre (same word for each note) or a mixed timbre (different words for each note). Speech perception was measured in quiet and in steady noise using a matrix-styled sentence recognition task; stimuli were naturally intonated speech or sung speech with a fixed pitch (same note for each word) or a mixed pitch (different notes for each word). Significant musician advantages were observed for MCI and speech in noise but not for speech in quiet. MCI performance was significantly poorer with the mixed timbre stimuli. Speech performance in noise was significantly poorer with the fixed or mixed pitch stimuli than with spoken speech. Across all subjects, age at testing and MCI performance were significantly correlated with speech performance in noise. MCI and speech performance in quiet was significantly poorer for children than for adults from a related study using the same stimuli and tasks; speech performance in noise was significantly poorer for young than for older children. Long-term music training appeared to benefit melodic pitch perception and speech understanding in noise in these pediatric listeners. PMID- 29609499 TI - Excessive sedentary time during in-patient stroke rehabilitation. AB - Background and Purpose Previous research suggests that patients receiving inpatient stroke rehabilitation are sedentary although there is little data to confirm this supposition within the Canadian healthcare system. The purpose of this cross-sectional study was to observe two weeks of inpatient rehabilitation in a tertiary stroke center to determine patients' activity levels and sedentary time. Methods Heart rate (HR) and accelerometer data were measured using an Actiheart monitor for seven consecutive days, 24 h/day, on the second week and the last week of admission. Participants or their proxies completed a daily logbook. Metabolic equivalent (MET) values were calculated and time with MET < 1.5 was considered sedentary. The relationship between patient factors (disability, mood, and social support) and activity levels and sedentary time were analyzed. Results Participants (n = 19; 12 males) spent 10 h sleeping and 4 h resting each day, with 86.9% of their waking hours sedentary. They received on average 8.5 task-specific therapy sessions; substantially lower than the 15 h/week recommended in best practice guidelines. During therapy, 61.6% of physical therapy and 76.8% of occupational therapy was spent sedentary. Participants increased their HR about 15 beats from baseline during physical therapy and 8 beats during occupational therapy. There was no relationship between sedentary time or activity levels and patient factors. Discussion Despite calls for highly intensive stroke rehabilitation, there was excessive sedentary time and therapy sessions were less frequent and of lower intensity than recommended levels. Conclusions In this sample of people attending inpatient stroke rehabilitation, institutional structure of rehabilitation rather than patient-related factors contributed to sedentary time. PMID- 29609500 TI - An unusual hazard of menopause in the workplace: a case report. AB - Untreated vasomotor symptoms of the menopause can have a major impact on women at work. Recent recommendations advocate modification of the working environment, including adequate air-conditioning, to help relieve these symptoms. However, this may cause discomfort for work colleagues. We report the case of a 40-year old woman with cold urticaria. Cold urticaria is a serious, potentially life threatening condition. Our patient's symptoms were exacerbated when her postmenopausal work colleagues turned the air-conditioner temperature down to relieve their vasomotor symptoms. PMID- 29609501 TI - The relationship between obesity and the severity of non-alcoholic fatty liver disease: systematic review and meta-analysis. AB - INTRODUCTION: A number of researches have explored the association between obesity and nonalcoholic fatty liver disease (NAFLD) liver function, histopathology, complications, genetic factors and prognosis, but the results were conflicting and inconclusive. Areas covered: In this meta-analysis, the liver function, histopathology, metabolic complications, patatin-like phospholipase domain-containing protein 3 (PNPLA3) genetic polymorphism and prognosis were compared between non-obese and obese NAFLD. Pubmed, EMBASE, Cochrane databases were searched to identify eligible studies. The odds ratio (OR) or standardized mean difference (SMD) with 95% confidence intervals (CI) were pooled using fixed- or random-effects models. Expert commentary: This meta analysis indicated that for NAFLD patients, obesity (according to ethnic-specific BMI cut-off points to define obesity) could predict a worse long-term prognosis. However, obesity may not be an independent factor for the development of NASH or advanced fibrosis in NAFLD patients and NAFLD should be considered as potential population for pharmacologic treatment regardless of obesity. In addition, PNPLA3 rs738409 may be more relevant to the progression of non-obese NAFLD when compared to obese NAFLD. Importantly, large-sample, long-term follow-up cohort studies based on liver biopsy are highly needed due to limited liver pathology and long term follow-up data at present. PMID- 29609502 TI - Fluid shear stress promotes osteoblast proliferation through the NFATc1-ERK5 pathway. AB - PURPOSE: Extracellular-regulated kinase 5 (ERK5) is thought to regulate osteoblast proliferation. To further understand how ERK5 signaling regulates osteoblast proliferation induced by fluid shear stress (FSS), we examined some potential signaling targets associated with ERK5 in MC3T3-E1 cells. METHODS: MC3T3-E1 cells were treated with XMD8-92 (an ERK5 inhibitor) or Cyclosporin A (CsA, a nuclear factor of activated T cells (NFAT) c1 inhibitor) and/or exposed to 12 dyn/cm2 FSS. Phosphorylated-ERK5 (p-ERK5) and expression levels of NFATc1, ERK5, E2F2, and cyclin E1 were analyzed by western blot. The mRNA levels of genes associated with cell proliferation were analyzed by Polymerase Chain Reaction (PCR) array. Subcellular localization of p-ERK5 and NFATc1 were determined by immunofluorescence. Cell proliferation was evaluated by MTT assay. RESULTS: NFATc1 expression was up-regulated by FSS. XMD8-92 only blocked ERK5 activation; however, CsA decreased NFATc1 and p-ERK5 levels, including after FSS stimulation. Exposure to NFATc1 inhibitor or ERK5 inhibitor resulted in decreased E2F2 and cyclin E1 expression and proliferation by proliferative MC3T3-E1 cells. Furthermore, immunofluorescence results illustrated that NFATc1 induced ERK5 phosphorylation, resulting in p-ERK5 translocation to the nucleus. CONCLUSIONS: Our results reveal that NFATc1 acts as an intermediate to promote the phosphorylation of ERK5 induced by FSS. Moreover, activated NFATc1-ERK5 signaling up-regulates the expression of E2F2 and cyclin E1, which promote osteoblast proliferation. PMID- 29609503 TI - Postmenopausal endometriosis: drawing a clearer clinical picture. AB - This review aims to draw a clearer clinical picture of postmenopausal endometriosis. Based on limited literature, postmenopausal endometriosis emerges as an infrequent entity but with a clinical picture significantly unlike that of premenopausal endometriosis. In contrast to the premenopausal disease, postmenopausal endometriosis occurs in a state of ovarian estrogen deficiency, appears to have a greater predisposition to malignant change, may have a greater tendency to spread to extragonadal organs and develop into constrictive and/or obstructive lesions, and is preferably treated surgically. The need to use hormone therapy for the management of menopausal symptoms that may concomitantly affect women with postmenopausal endometriosis is an unresolved therapeutic dilemma. This is mainly because the relationships of menopausal hormone therapy to recurrence of endometriosis and, more importantly, to increased risk of malignant degeneration, remain unclear. PMID- 29609504 TI - Modified Approach to Stroke Rehabilitation (MAStR): feasibility study of a method to apply procedural memory concepts to transfer training. AB - OBJECTIVE: Training and implementation for a multidisciplinary stroke rehabilitation method emphasizing procedural memory. BACKGROUND: Current practice in stroke rehabilitation relies on explicit memory, often compromised by stroke, failing to capitalize on better-preserved procedural memory skills. Recruitment of procedural memory requires consistency and practice, characteristics difficulty to promote on inpatient rehabilitation units. We designed a method Modified Approach to Stroke Rehabilitation (MAStR) to maximize consistency and practice for transfer training with stroke patients. DESIGN: Phase I, single group study. MAStR has two innovations: (1) simplification of instructions to only three words, other direction provided non-verbally; (2) having all rehabilitation staff apply the same approach for transfers. Staff training in MAStR included review of written material describing the rationale for MAStR and demonstration of a transfer using MAStR. Enrolled patients completed each transfer with MAStR in addition to standard rehabilitation therapy. RESULTS: The MAStR method was taught to a large, multidisciplinary rehabilitation staff (n = 31). Training and certification required 15 min per staff member. Five stroke patients were enrolled. No transfers with MAStR resulted in injury, no negative feedback was received from staff or patients. Staff reported satisfaction with the brief MAStR training and reported transfers were easier to complete with the MAStR method. CONCLUSIONS: Feasibility was demonstrated for an innovative application of procedural memory concepts to stroke rehabilitation. All rehabilitation disciplines were successfully trained. MAStR was well-tolerated and liked by rehabilitation staff and patients. These results support pursuit of a Phase II pilot study. PMID- 29609505 TI - Radiosensitivity enhancement of Fe3O4@Ag nanoparticles on human glioblastoma cells. AB - Radiotherapy is one of the main therapeutic methods for cancers, but radiation resistance of cancer cells still remains a serious concern. Searching for radiosensitizers to overcome such resistance is therefore urgently required. The goal of this study is to evaluate and compare the radiosensitizing efficacy of Fe3O4-OA, Ag and Fe3O4@Ag nanoparticles on U251 cells. The results show that Fe3O4@Ag nanoparticles have the highest ability of radiosensitization among the three nanoparticles. The underlying mechanism of Fe3O4@Ag nanoparticles' radiosensitivity enhancement is through decrease of the cytoprotective autophagy at the early stage, and increase of the calcium-dependent apoptosis at the later stage. These findings suggest the potential application of Fe3O4@Ag nanoparticles as a highly effective nano-radiosensitizer for the treatment of glioblastoma cells. PMID- 29609506 TI - Ublituximab for the treatment of CD20 positive B-cell malignancies. AB - INTRODUCTION: Non-Hodgkin lymphoma (NHL) is the most common adult hematologic malignancy. Conventional methods of treatment are chemotherapy and radiation, which were associated with toxicities and lack of specificity. Potential cell surface targets for treatment of B-cell NHL (B-NHL) include CD19, CD20, and CD22 which are highly expressed on malignant B-cells. The development of monoclonal antibody (mAb) therapy directed against CD20 had the most clinical impact in the treatment of B-NHL. Early clinical trials with rituximab (RTX), the first chimeric mAb against CD20, showed efficacy and minimal toxicities. RTX was later approved as first line in combination with CHOP chemotherapy for Diffuse Large B NHL (DLBCL). The emergence of resistance to RTX prompted the development of the next-generation of mAbs targeting CD20 (e.g. obinituzumab, ofatumumab), and includes ublituximab (Ub), with higher complement-dependent cytotoxicity (CDC) and antibody-dependent cellular cytotoxicity (ADCC) against malignant B-cells. Areas covered: Herein, we discuss clinical trials of Ub, highlighting efficacy, tolerability and an expert opinion on drug development in B-NHL. A pubmed search was conducted to evaluate all Ub clinical trials. Expert opinion: Ub demonstrated efficacy in patients with high-risk CLL and B-NHL in both first line, subsequent lines, and in rituximab refractory patients. PMID- 29609507 TI - Biomechanical characterization of the Junzuki karate punch: indexes of performance. AB - The aims of this study were: (i) to determine kinematic, kinetic, and electromyographic characteristics of Junzuki karate punch in professional karate athletes; (ii) to identify biomechanical parameters that correlate with punch force and lead to a higher punching performance; (iii) to verify the presence of muscle co-activation in the upper limb, trunk, and lower limb muscles. Data were collected from nine experienced karatekas from the Accademia Italiana Karate e Arti Marziali during the execution of the specific punch. Mean punch forces (181.2 N) delivered to the target, the range of motion of both right and left knees (1.13 and 0.82 rad) and right elbow (1.49 rad) joints, and the angles at impact (knee: 0.81 and 0.91 rad; elbow: 1.19 rad) in the sagittal plane were computed. Furthermore, the trunk rotational angular acceleration (63.1 rad s-2), force related to the lower limbs (550.2 and 425.1 N), and co-activation index for the upper limb (36.1% and 34.7%), trunk (24.5% and 16%), and lower limbs (16.0% and 16.1%) muscles were evaluated bilaterally. Significant positive correlations were found between the punch force and both right and left knee flexion at the instant of impact and right and left leg force. Significant negative correlation was found between the punch force and maximum trunk angular acceleration. Significant differences (p = .03) in the co-activation index among the upper limb, trunk, and lower limbs muscles highlighted a rostro-caudal gradient on both body sides. This research could be of use to performers and coaches when considering training preparations. PMID- 29609508 TI - Dynamical release nanospheres containing cell growth factor from biopolymer hydrogel via reversible covalent conjugation. AB - For practical adipose regeneration, the challenge is to dynamically deliver the key adipogenic insulin-like growth factors in hydrogels to induce adipogenesis. In order to achieve dynamic release, smart hydrogels to sense the change in the blood glucose concentration is required when glucose concentration increases. In this study, a heparin-based hydrogel has been developed for use in dynamic delivery of heparin nanospheres containing insulin-like growth factor. The gel scaffold was facilely prepared in physiological conditions by the formation of boronate-maltose ester cross-links between boronate and maltose groups of heparin derivatives. Due to its intrinsic glucose-sensitivity, the exposure of gel scaffold to glucose induces maltose functionalized nanospheres dissociation off hydrogel network and thereby could dynamically move into the microenvironment. The potential of the hydrogel as a cell scaffold was demonstrated by encapsulation of human adipose-derived stem cells (ASCs) within the gel matrix in vitro. Cell culture showed that this dynamic hydrogel could support survival and proliferation of ASCs. This biocompatible coupling chemistry has the advantage that it introduces no potentially cytotoxic groups into injectable gel scaffolds formed and can create a more biomimetic microenvironment for drug and cell delivery, rendering them more suitable for potential in vivo biomedical applications. All these results indicate that this biocompatible gel scaffold can render the formulation of a therapeutically effective platform for diabetes treatment and adipose regeneration. PMID- 29609509 TI - Bowel cancer screening for women at midlife. AB - In Australia one in 15 women will be diagnosed with colorectal cancer in their lifetime because of the high incidences of lifestyle risk factors. The risk could be reduced by taking aspirin. Evidence-based Clinical Practice Guidelines for the prevention, early detection and management of colorectal cancer produced by Cancer Council Australia and approved by the National Health and Medical Research Council recommended that 'population screening in Australia, directed at those at average risk of colorectal cancer and without relevant symptoms, is immunochemical fecal occult blood testing every 2 years, starting at age 50 years and continuing to age 74 years.' Women at high risk because of family history will need more intense screening. At the current 40% participation rate, it is estimated that biennial screening with fecal immunohistochemical tests (FIT) reduces colorectal cancer incidence by 23% and mortality by 36%. The major adverse effects of screening are the psychological impact of a positive FIT that does not prove to be cancer, or adenomas on colonoscopy (47.7%), and the rare side-effects of colonoscopy of hemorrhage, bleeding or even death. A range of factors that could increase a woman's participation rate includes advice to screen from her general practitioner and more information about the nature of the screening tests. PMID- 29609510 TI - Immunohistochemical expression of TLR-4 in temporomandibular joint dysfunction. AB - Objective Toll-like receptor 4 (TLR-4) is a transmembrane protein involved in the innate immune system and has been implicated in the pathogenesis of temporomandibular joint dysfunction (TMD). The purpose of this study was to histologically examine the level of expression of TLR-4 relative to severity of TMD. Methods Thirty-one human TMJ disc samples were immunostained for TLR-4 and evaluated for intensity of stain. Among the samples, 8 were control samples, 16 were from patients with anterior disc displacement with reduction (ADDwR), and 7 were from patients with anterior disc displacement without reduction (ADDwoR). Results There was no statistically significant difference in intensity of stain between groupings (p = 0.673). Conclusions The results indicate a negative correlation between TMD and the expression of TLR-4. PMID- 29609511 TI - Extended-release oral treprostinil in the management of pulmonary arterial hypertension: clinical evidence and experience. AB - Treprostinil diolamine is the first oral prostacyclin approved for the treatment of pulmonary arterial hypertension (PAH) to improve exercise capacity. Clinical studies have demonstrated modest benefit as monotherapy, whereas no difference in exercise capacity was observed with combination therapy. However, these trials were limited by subtherapeutic dosing owing to intolerable adverse effects. Prostacyclin-related adverse effects, such as nausea, diarrhea, headache, flushing, and jaw pain, are prevalent. More recent pharmacokinetic and clinical studies illustrate the dose-response relationship and the importance of achieving clinically effective doses. Therefore, efforts to improve tolerability are paramount. Oral treprostinil is recommended to be administered three times daily in order to facilitate more rapid titration, higher doses achieved, and improved tolerability. Oral treprostinil has also been studied in carefully selected, stable patients that transitioned from parenteral or inhaled therapy with close monitoring for late deterioration. Ongoing clinical trials will determine the long-term effects of higher doses of oral treprostinil on clinical outcomes. This review describes the clinical evidence and practical experience with the use of oral treprostinil for PAH. PMID- 29609512 TI - Longitudinal Performance of Plasma Neurofilament Light and Tau in Professional Fighters: The Professional Fighters Brain Health Study. AB - The aim of this study is to evaluate longitudinal change in plasma neurofilament light (NF-L) and tau levels in relationship to clinical and radiological measures in professional fighters. Participants (active and retired professional fighters and control group) underwent annual blood sampling, 3-Tesla magnetic resonance imaging (MRI) brain imaging, computerized cognitive testing, and assessment of exposure to traumatic brain injury. Plasma tau and NF-L concentrations were measured using Simoa assays. Multiple linear regression models were used to compare the difference across groups in regard to baseline measurements, whereas mixed linear models was used for the longitudinal data with multiple measurements for each participant. Plasma samples were available on 471 participants. Baseline NF-L measures differed across groups (F3,393 = 6.99; p = 0.0001), with the active boxers having the highest levels. Higher NF-L levels at baseline were correlated with lower baseline MRI regional volumes and lower cognitive scores. The number of sparring rounds completed by the active fighters was correlated with NF-L (95% confidence interval, 0.0116-0.4053; p = 0.0381), but not tau, levels. Among 126 subjects having multiple yearly samples, there was a significant difference in average yearly percentage change in tau across groups (F3,83 = 3.87; p = 0.0121). We conclude that plasma NF-L and tau behave differently in a group of active and retired fighters; NF-L better reflects acute exposure whereas the role of plasma tau levels in signifying chronic change in brain structure over time requires further study. PMID- 29609513 TI - Extubation Reflectivity. AB - The purpose of this article is to share a recovery room practitioner's experience using reflection and to explore the issues surrounding extubation in the post anaesthetic care unit (PACU). Currently there are no national standards of practice for practitioners' learning and safe practice of extubation techniques within the PACU. Therefore, the possibility of an adverse incident is significantly increased, potentially causing harm to the patient and damage to any hospital's reputation as well as the practitioners' profession. The authors wish to identify the concerns by citing a clinical incident that lead to reflection and sharing of the experience through this article. PMID- 29609514 TI - Superior Cavopulmonary Anastomosis in Patients With Bilateral Superior Caval Veins: Use of a Rolled Pericardial Graft to Create a Single Caval Vein. AB - We propose a new surgical technique for superior cavopulmonary anastomosis in patients with functionally univentricular heart and bilateral superior caval veins. One of the reasons for failure of bidirectional Glenn shunts in patients with bilateral superior caval veins is the small caliber of one or both veins, with limited flow through each cavopulmonary anastomosis that can easily result in torsion, blockage, or clot formation. The conversion of two small superior caval veins into a single confluence which is large enough to connect with the pulmonary artery (PA) can resolve this problem. We present our experience with two cases in which a rolled pericardial graft was used to create a single caval vein to provide balanced pulmonary blood flow and yield growth of the central PA as well as reducing the likelihood of thrombus formation. PMID- 29609515 TI - Jaw Opening Decreases Window to the Deep Parotid Lobe. AB - To describe the relationship between jaw opening and access to the deep parotid window, we identified the following distances in 10 human skulls: symphysis to angle of mandible, mastoid tip to angle of mandible, angle of mandible to condylar process, and mastoid tip to condylar process. With the jaw closed and open, these distances were measured with 1 to 3 wooden blocks, each measuring 1 cm, between the upper and lower incisors. The triangular deep parotid area formed by the last 3 distances was calculated. A repeated measures analysis of variance showed a significant decrease in the deep parotid area with increasing interincisal distance ( P < .01). A generalized estimating equation model demonstrated a statistically significant decreasing area of the deep parotid window with increasing interincisal distance. These results suggest that nasal intubation may improve access to the parotid window. PMID- 29609516 TI - A Systematic Review of Positron Emission Tomography of Tau, Amyloid Beta, and Neuroinflammation in Chronic Traumatic Encephalopathy: The Evidence To Date. AB - Chronic traumatic encephalopathy (CTE) is associated with pathological changes, yet detecting these changes during life has proven elusive. Positron emission tomography (PET) offers the potential for identifying such pathology. Few studies have been completed to date and their approaches and results have been diverse. It was the objective of this review to systematically examine relevant research using ligands for PET that bind to identified pathology in CTE. We focused on identification of patterns of binding and addressing gaps in knowledge of PET imaging for CTE. A comprehensive literature search was conducted. Data used were published on or before May 22, 2017. As the extant literature is limited, any peer-reviewed article assessing military, contact sports athletes, or professional fighters was considered for inclusion. The main outcomes were regional binding to brain regions identified through control comparisons or through clinical metrics (e.g., standardized uptake volume ratios). A total of 1207 papers were identified for review, of which six met inclusion criteria. Meta analyses were planned but were deemed inappropriate given the small number of studies identified. Methodological concerns in these initial papers included small sample sizes, lack of a control comparison, use of nonstandard statistical procedures to quantify data, and interpretation of potentially off-target binding areas. Across studies, the hippocampi, amygdalae, and midbrain had reasonably consistent increased uptake. Evidence for increased uptake in cortical regions was less consistent. The evidence suggests that the field of PET imaging in those at risk for CTE remains nascent. As the field evolves to include more stringent studies, ligands for PET may prove an important tool in identifying CTE in vivo. PMID- 29609517 TI - PD-1 Inhibition Minimally Affects Cisplatin-Induced Toxicities in a Murine Model. AB - Immune checkpoint inhibition used in combination with standard cisplatin-based chemotherapy regimens is currently under evaluation in clinical trials for head and neck squamous cell carcinoma (HNSCC). The impact of anti-PD-1 therapy on cisplatin-induced ototoxicity and nephrotoxicity has not been established. Here we use a murine model of cisplatin-induced hearing loss to investigate the impact of anti-PD-1 immunotherapy on auditory brainstem responses (ABRs), distortion product otoacoustic emissions (DPOAEs), serum creatinine, and hair cell and renal histology. We demonstrate only mild worsening of DPOAEs at 14.4 and 16 kHz as well as a mild increase in serum creatinine. Renal and hair cell histology as well as ABR measures were unchanged by PD-1 inhibition. Thus, our data suggest that the use of PD-1 inhibition in conjunction with cisplatin results in toxicities that are similar to those of cisplatin alone. PMID- 29609518 TI - Vascular Abnormalities within Normal Appearing Tissue in Chronic Traumatic Brain Injury. AB - Magnetic resonance imaging (MRI) is a powerful tool for visualizing traumatic brain injury(TBI)-related lesions. Trauma-induced encephalomalacia is frequently identified by its hyperintense appearance on fluid-attenuated inversion recovery (FLAIR) sequences. In addition to parenchymal lesions, TBI commonly results in cerebral microvascular injury, but its anatomical relationship to parenchymal encephalomalacia is not well characterized. The current study utilized a multi modal MRI protocol to assess microstructural tissue integrity (by mean diffusivity [MD] and fractional aniosotropy [FA]) and altered vascular function (by cerebral blood flow [CBF] and cerebral vascular reactivity [CVR]) within regions of visible encephalomalacia and normal appearing tissue in 27 chronic TBI (minimum 6 months post-injury) subjects. Fifteen subjects had visible encephalomalacias whereas 12 did not have evident lesions on MRI. Imaging from 14 age-matched healthy volunteers were used as controls. CBF was assessed by arterial spin labeling (ASL) and CVR by measuring the change in blood-oxygen level-dependent (BOLD) MRI during a hypercapnia challenge. There was a significant reduction in FA, CBF, and CVR with a complementary increase in MD within regions of FLAIR-visible encephalomalacia (p < 0.05 for all comparisons). In normal-appearing brain regions, only CVR was significantly reduced relative to controls (p < 0.05). These findings indicate that vascular dysfunction represents a TBI endophenotype that is distinct from structural injury detected using conventional MRI, may be present even in the absence of visible structural injury, and persists long after trauma. CVR may serve as a useful diagnostic and pharmacodynamic imaging biomarker of traumatic microvascular injury. PMID- 29609519 TI - A review of prospective memory in individuals with acquired brain injury. AB - OBJECTIVE: Prospective memory (PM) deficits have emerged as an important predictor of difficulty in daily life for individuals with acquired brain injury (BI). This review examines the variables that have been found to influence PM performance in this population. In addition, current methods of assessment are reviewed with a focus on clinical measures. Finally, cognitive rehabilitation therapies are reviewed, including compensatory, restorative and metacognitive approaches. METHOD: Preferred reporting items for systematic reviews and meta analyses guidelines were used to identify studies. Studies were added that were identified from the reference lists of these. RESULTS: Research has begun to elucidate the contributing variables to PM deficits after BI, such as attention, executive function and retrospective memory components. Imaging studies have identified prefrontal deficits, especially in the region of BA10 as contributing to these deficits. There are now several clinical measures available with good psychometric properties. Rehabilitation techniques have mostly focused on compensatory strategies, but, in addition, some restorative and metacognitive approaches have shown preliminary promise. CONCLUSIONS: PM deficits are a common and important deficit after BI. Clinical evaluation is recommended and further understanding of rehabilitation techniques is needed. PMID- 29609520 TI - Diathermy smoke shown to be hazardous, so why are we not protecting ourselves? AB - Diathermy smoke has been studied for over three decades and data has been collected to establish its composition. Although its full structure has not been established, the compounds confirmed pose a health hazard to all exposed. Recommendations suggest that theatre staff need to protect themselves using smoke evacuating systems and masks. This review looks at the compliance of theatre staff within these guidelines and the reasons behind noncompliance. PMID- 29609521 TI - Extended operating times are more efficient, save money and maintain a high staff and patient satisfaction. AB - Current public sector austerity measures necessitate efficiency savings throughout the NHS. Performance targets have resulted in activity being performed in the private sector, waiting list initiative lists and requests for staff to work overtime. This has resulted in staff fatigue and additional agency costs. Adoption of extended operating theatre times (0800-1800 hours) may improve productivity and efficiency, with potentially significant financial savings; however, implementation may adversely affect staff morale and patient compliance. A pilot period of four months of extended operating times (4.5 hour sessions) was completed and included all theatre surgical specialties. Outcome measures included: the number of cases completed, late starts, early finishes, cancelled operations, theatre overruns, preoperative assessment and 18-week targets. The outcomes were then compared to pre-existing normal working day operating lists (0900-1700). Theatre staff, patient and surgical trainee satisfaction with the system were also considered by use of an anonymous questionnaire. The study showed that in-session utilisation time was unchanged by extended operating hours 88.7% (vs 89.2%). The service was rated as 'good' or 'excellent' by 87.5% of patients. Over L345,000 was saved by reducing premium payments. Savings of L225,000 were made by reducing privately outsourced operation and a further L63,000 by reviewing staff hours. Day case procedures increased from 2.8 to 3.2 cases/day with extended operating. There was no significant increase in late starts (5.1% vs 6.8%) or cancellation rates (0.75% vs 1.02%). Theatre over-runs reduced from 5% to 3.4%. The 18 weeks target for surgery was achieved in 93.7% of cases (vs 88.3%). The number of elective procedures increased from 4.1 to 4.89 cases/day. Only 13.33% of trainees (n = 33) surveyed felt that extended operating had a negative impact on training. The study concludes that extended operating increased productivity from 2.8 patients per session to 3.2 patients per session with potential savings of just over L2.4 million per financial year. Extrapolating this to the other 155 trusts in England could be a potential saving of L372 million per year. Staff, trainee and patient satisfaction was unaffected. An improved 18 weeks target position was achieved with a significant reduction in private sector work. However, some staff had difficulty with arranging childcare and taking public transport and this may prevent full implementation. PMID- 29609522 TI - Quantifying effects of cyclic stretch on cell-collagen substrate adhesiveness of vascular endothelial cells. AB - Vascular endothelium is continuously subjected to mechanical stimulation in the form of shear forces due to blood flow as well as tensile forces as a consequence of blood pressure. Such stimuli influence endothelial behavior and regulate cell tissue interaction for an optimized functionality. This study aimed to quantify influence of cyclic stretch on the adhesive property and stiffness of endothelial cells. The 10% cyclic stretch with frequency of 1 Hz was applied to a layer of endothelial cells cultured on a polydimethylsiloxane substrate. Cell-substrate adhesion of endothelial cells was examined by the novel approach of atomic force microscope-based single-cell force spectroscopy and cell stiffness was measured by atomic force microscopy. Furthermore, the adhesive molecular bonds were evaluated using modified Hertz contact theory. Our results show that overall adhesion of endothelial cells with substrate decreased after cyclic stretch while they became stiffer. Based on the experimental results and theoretical modeling, the decrease in the number of molecular bonds after cyclic stretch was quantified. In conclusion, in vitro cyclic stretch caused alterations in both adhesive capacity and elastic modulus of endothelial cells through mechanotransductive pathways as two major determinants of the function of these cells within the cardiovascular system. PMID- 29609523 TI - Contribution of Fibrinogen to Inflammation and Neuronal Density in Human Traumatic Brain Injury. AB - Traumatic brain injury (TBI) is a leading cause of death and disability, particularly among the young. Despite this, no disease-specific treatments exist. Recently, blood-brain barrier disruption and parenchymal fibrinogen deposition have been reported in acute traumatic brain injury and in long-term survival; however, their contribution to the neuropathology of TBI remains unknown. The presence of fibrinogen-a well-documented activator of microglia/macrophages-may be associated with neuroinflammation, and neuronal/axonal injury. To test this hypothesis, cases of human TBI with survival times ranging from 12 h to 13 years (survival <2 months, n = 15; survival >1 year, n = 6) were compared with uninjured controls (n = 15). Tissue was selected from the frontal lobe, temporal lobe, corpus callosum, cingulate gyrus, and brainstem, and the extent of plasma protein (fibrinogen and immunoglobulin G [IgG]) deposition, microglial/macrophage activation (CD68 and ionized calcium-binding adapter molecule 1 [Iba-1] immunoreactivity), neuronal density, and axonal transport impairment (beta amyloid precursor protein [betaAPP] immunoreactivity) were assessed. Quantitative analysis revealed a significant increase in parenchymal fibrinogen and IgG deposition following acute TBI compared with long-term survival and control. Fibrinogen, but not IgG, was associated with microglial/macrophage activation and a significant reduction in neuronal density. Perivascular fibrinogen deposition also was associated with microglial/macrophage clustering and accrual of betaAPP in axonal spheroids, albeit rarely. These findings mandate the future exploration of causal relationships between fibrinogen deposition, microglia/macrophage activation, and potential neuronal loss in acute TBI. PMID- 29609524 TI - Editor's Note. PMID- 29609525 TI - Balint 2.0: A virtual Balint group for doctors around the world. AB - Objective Balint groups have shown promise in addressing clinician-patient relationships, clinician burnout, referral practices, and psychological mindedness. However, their traditional format of in-person sessions limits their ability to meet the needs of clinicians practicing in locations without trained Balint leaders. We report on a pilot of an international, internet-based Balint group in collaboration between the World Organization of Family Doctors regional Young Doctors Movements and the International Balint Federation. Method Balint 2.0 arose through interest of the Young Doctors Movements leadership, who approached the International Balint Federation for assistance. Initial discussions and some trialing of videoconference platforms led to monthly group meetings over the internet. Surveys evaluated each individual session as well as quarterly progress of the group. Survey items were borrowed from existing surveys in use by the American and German Balint Societies. Results Session surveys demonstrated the effectiveness of the videoconferencing platform for convening a Balint group, with a majority of participants expressing agreement with survey items evaluating each session. Quarterly survey responses were more positive reflecting agreement with outcomes seen from in-person Balint groups. Conclusions The Balint 2.0 pilot has demonstrated the ability of a Balint group to successfully convene over the internet and reach the common outcomes of a Balint group meeting in-person. The Young Doctors Movements and International Balint Federation plan to expand this work based on this successful pilot. We hope that others may also be able to build on this success with the result that Balint groups are available to clinicians in areas where they might not otherwise be accessible. PMID- 29609526 TI - Stromal and Hematopoietic Progenitors from C57/BI/6N Murine Bone Marrow After 30 Day "BION-M1" Spaceflight. AB - Elucidation of the spaceflight (SF) effects on the adult stem and progenitor cells is an important goal in space biology and medicine. A unique opportunity for this was provided by project "BION-M1". The purpose of this study was to evaluate the effects of 30-day SF on biosatellite, 7-day recovery (SFR), and subsequent ground control (GC) experiment on the mononuclear cells (MNCs) from C57/BI/6N murine tibia bone marrow. Also, hematopoietic and stromal precursor functions were characterized ex vivo. There was no significant difference in the total MNC number between experimental groups. After SF, immunophenotyping revealed an increase of large-sized CD45+MNCs corresponded to committed hematopoietic progenitors. The total hematopoietic colony-forming unit (CFU) number decreased after SF and did not restore after 7 day of recovery due to predominant reduction of bi- and multipotent CFUs and primitive burst-forming units in favor of unipotent CFUs. Functional activity of stromal precursors in vitro was only slightly altered. SF cells displayed the enhanced expression of alkaline phosphatase. The data of the GC experiment demonstrated the preservation of the functional activity of progenitor cells from mice bone marrow. The activation of erythropoiesis in expense of burst-forming units of erythrocytes elevation was detected. After 7 days of recovery, the number of colony-forming units of fibroblast (CFUs-f) was similar to the vivarium control, while the proliferative activity of bone marrow stromal precursors decreased. The present study demonstrated that certain hematopoietic progenitors are susceptible to SF factors, while the stromal precursors displayed a certain degree of resistance. These data indicate mild and reversible alterations of bone marrow progenitors after SF. PMID- 29609527 TI - The differentially expressed circular ribonucleic acids of primary hepatic carcinoma following liver transplantation as new diagnostic biomarkers for primary hepatic carcinoma. AB - Recent studies have shown that circular ribonucleic acids have differential expression in some diseases. This study compared the expression levels of five circular ribonucleic acids between patients of primary hepatic carcinoma following liver transplantation and healthy individuals for searching a new diagnostic biomarker about primary hepatic carcinoma. We chose differentially expressed targeted circular ribonucleic acids according to fold change >=2.0 or <=-2.0 between circular ribonucleic acids microarray of perioperative liver transplantation and normal controls. Then we used the Arraystar home-made micro ribonucleic acid target prediction software based on TargetScan and miRanda to predict circular ribonucleic acid/micro-ribonucleic acid interactions. And we assess the expression levels of hsa_circ_100571, hsa_circ_400031, hsa_circ_102032, hsa_circ_103096, and hsa_circ_102347 in the peripheral blood of normal controls and liver transplantation patients before transplantation and on the first, third, and seventh days after transplantation by real-time quantitative polymerase chain reaction. We chose five circular ribonucleic acids, two of which have been correlated with micro-ribonucleic acid-related carcinoma recurrence after liver transplantation, hepatocellular carcinoma and analyzed their expression with 2-??Ct method. The expression level of hsa_circ_100571 and hsa_circ_400031 on day 1 after liver transplantation was higher than pre transplantation (p < 0.01), and these levels showed a declining trend on post transplantation. The expression level of hsa_circ_102032 and hsa_circ_103096 on day 1 after liver transplantation was lower than pre-transplantation (p < 0.01) and decreased on post-transplantation. There were the significantly different expressions between the post-transplantation day 7 and normal control (p < 0.01). The expression level of hsa_circ_102347 on day 1 after liver transplantation was lower than pre-transplantation (p < 0.01). This expression showed a declining trend on post-transplantation, and the postoperative day 7 level was similar to normal control (p > 0.05). Five types of circular ribonucleic acid-related micro ribonucleic acids had varying degrees of upregulation and downregulation between perioperative transplantation of primary hepatic carcinoma patients and normal controls; the hsa_circ_102347 is most likely to have association with primary hepatic carcinoma. PMID- 29609529 TI - Video-recording consultations for educational purposes in out-of-hours primary care: patients and physicians are willing to participate. AB - Background Video-recordings of consultations are used by general practitioner (GP) trainees to enable reflection on aspects of knowledge, skills and attitudes. Typically, these recordings are made during office hours in general practice, but little is known about using video-recording during out of hours (OOH) care, which is an important and distinct part of a GP's work. To be able to record consultations during OOH care (i.e. at the emergency department (ED) and at the General Practitioner Cooperative (GPC)), patients must be willing to cooperate and give informed consent. Therefore, it was of interest to investigate potential barriers in these OOH settings. Methods A questionnaire on demographics and attitudes regarding consent was administered to patients and physicians at the ED and at the GPC in Sint-Niklaas, Belgium. Results A total of 346 questionnaires were completed, 23 by physicians and 323 by patients. A majority of the patients (225/286 (79%)) would consent to video-recording the consultation, without physical examination. Almost all physicians (21/23) would agree to participate. Overall, 85% (260/323) of the patients agree when only the doctor was being recorded. Patients were neutral in recording in 79% (88/224) at the GPC and 57% (56/99) at the ED. Shyness or embarrassment was present in 32% (71/224), and 28% (28/99) at the GPC and ED, respectively. We did not find any significant differences in giving consent or feelings between patients at the GPC and ED. Conclusion A vast majority of both patients and physicians would consent to video recording their consultation in OOH primary care settings (GPC and ED), with possible concerns about privacy, shame and discomfort. PMID- 29609530 TI - High frequency of M. leprae DNA detection in asymptomatic household contacts. AB - BACKGROUND: Characterization of the Mycobacterium leprae genome has made possible the development of Polymerase Chain Reaction (PCR) systems that can amplify different genomic regions. Increased reliability and technical efficiency of quantitative PCR (qPCR) makes it a promising tool for early diagnosis of leprosy. Index cases that are multibacillary spread the bacillus silently, even before they are clinically diagnosed. Early detection and treatment could prevent transmission in endemic areas. METHODS: In this study, the qPCR technique is used to detect DNA of M. leprae in samples of slit skin smears (SSS) of the ear lobe and blood of leprosy patients and their asymptomatic household contacts residing in Governador Valadares, MG, Brazil, a hyperendemic area for leprosy. A total of 164 subjects participated in the study: 43 index cases, 113 household contacts, and, as negative controls, 8 individuals who reported no contact with patients nor history of leprosy in the family. The qPCR was performed to amplify 16S rRNA fragments and was specifically designed for M. leprae. RESULTS: Of asymptomatic household contacts, 23.89% showed bacillary DNA by qPCR in samples of SSS and blood. Also, 48.84% of patients diagnosed with leprosy were positive for qPCR while the bacillary load was positive in only 30.23% of patients. It is important to note that most patients were already receiving treatment when the collection of biological material for qPCR was performed. The level of bacillary DNA from household contacts was similar to the DNA levels detected in the group of paucibacillary patients. CONCLUSION: Considering that household contacts comprise a recognizable group of individuals with a high risk of disease, as they live in close proximity to a source of infection, qPCR can be used to estimate the risk of progress towards leprosy among household contacts and as a routine screening method for a chemoprophylactic protocol. PMID- 29609531 TI - Metformin associated lactic acidosis: a case series of 28 patients treated with sustained low-efficiency dialysis (SLED) and long-term follow-up. AB - BACKGROUND: Metformin associated lactic acidosis (MALA) is a well-known serious side effect of biguanides. However, the best treatment strategy remains a matter of debate. In the last 14 years, we observed a significant increase in hospitalizations for MALA to our Center. We report the outcomes of our clinical and therapeutic approach. METHODS: This is a single-center case series. Twenty eight patients affected with MALA and acute kidney failure admitted between January 2000 and September 2014 were included. We analyzed comorbidities, laboratory tests and clinical parameters at admission, at 36 h and at discharge. All patients were treated with sustained low-efficiency dialysis (SLED) until normalization of serum lactate (<= 3 mmol/L), bicarbonate (between 20 and 25 mmol/L) and potassium (between 4.0 and 5.1 mmol/L). RESULTS: The mortality rate was 21.4%, with all of the events occurring within 24 h from admission, and before or during the first hemodialysis treatment. Precipitating causes included; acute dehydration (86.4%), systemic inflammatory response syndrome (SIRS) (57.1%), sepsis (10.7%), nephrolithiasis (14.6%) and exposure to iodinated contrast (7.1%). No further episodes of lactic acidosis were described after discontinuing the drug over a mean follow-up of 27.2 months. Furthermore, while in 2010, we had a peak incidence of MALA of 76.8 cases per 100,000 patients on metformin, this rate fell after an education campaign conducted by specialists on the proper usage of metformin in patients at risk of MALA. Although the fall in incidence after the educational program was not necessarily causal, in 2014 the incidence was 32.9/100,000. CONCLUSIONS: We report an improved mortality rate in patients affected with MALA and acute kidney injury treated with SLED compared with other series published in literature. Rapid introduction of effective hemodialysis is critical in improving outcomes. PMID- 29609532 TI - Design and rationale for the life after stopping tyrosine kinase inhibitors (LAST) study, a prospective, single-group longitudinal study in patients with chronic myeloid leukemia. AB - BACKGROUND: Treatment of chronic myeloid leukemia with a tyrosine kinase inhibitor (TKI) offers significant improvements over previous treatments in terms of survival and toxicity yet nevertheless is associated with reduced health related quality of life and very high cost. Several small studies from Europe and Australia suggested that discontinuing TKIs with regular monitoring was safe. METHODS: The Life After Stopping TKIs (LAST) study is a large, U.S.-based study that aims to improve the evidence for clinical decision making regarding TKI discontinuation with monitoring in patients with chronic myeloid leukemia who have a deep molecular response to TKI therapy. The LAST study is a non randomized, prospective, single-group longitudinal study of 173 patients. The co primary objectives are to determine the proportion of patients who develop molecular recurrence (> 0.1% BCR-ABLIS) after discontinuing one of four TKIs (imatinib, dasatinib, nilotinib, or bosutinib) and to compare the patient reported health status of patients before and after stopping TKIs. Outcomes are assessed at baseline and throughout the 36-month study follow-up period with a central laboratory used for blood samples. All samples with undetectable BCR-ABL are also examined using digital polymerase chain reaction, which is a more sensitive nanofluidic polymerase chain reaction system. DISCUSSION: Because of their high cost and side effects, discontinuation of TKIs for patients with chronic myeloid leukemia who have a deep molecular response to TKI therapy is a promising approach to treatment. The LAST study is the largest U.S.-based TKI discontinuation study. It is the first to allow participation from patients on any of 4 first- and second-generation TKIs, includes a robust approach to measurement of clinical and patient-reported outcomes, and is using digital polymerase chain reaction to explore better prediction of safe discontinuation. TRIAL REGISTRATION: This study was registered prospectively on October 21, 2014 and assigned trial number NCT02269267 . PMID- 29609534 TI - Negative cancer beliefs, recognition of cancer symptoms and anticipated time to help-seeking: an international cancer benchmarking partnership (ICBP) study. AB - BACKGROUND: Understanding what influences people to seek help can inform interventions to promote earlier diagnosis of cancer, and ultimately better cancer survival. We aimed to examine relationships between negative cancer beliefs, recognition of cancer symptoms and how long people think they would take to go to the doctor with possible cancer symptoms (anticipated patient intervals). METHODS: Telephone interviews of 20,814 individuals (50+) in the United Kingdom, Australia, Canada, Denmark, Norway and Sweden were carried out using the Awareness and Beliefs about Cancer Measure (ABC). ABC included items on cancer beliefs, recognition of cancer symptoms and anticipated time to help seeking for cough and rectal bleeding. The anticipated time to help-seeking was dichotomised as over one month for persistent cough and over one week for rectal bleeding. RESULTS: Not recognising persistent cough/hoarseness and unexplained bleeding as cancer symptoms increased the likelihood of a longer anticipated patient interval for persistent cough (OR = 1.66; 95%CI = 1.47-1.87) and rectal bleeding (OR = 1.90; 95%CI = 1.58-2.30), respectively. Endorsing four or more out of six negative beliefs about cancer increased the likelihood of longer anticipated patient intervals for persistent cough and rectal bleeding (OR = 2.18; 95%CI = 1.71-2.78 and OR = 1.97; 95%CI = 1.51-2.57). Many negative beliefs about cancer moderated the relationship between not recognising unexplained bleeding as a cancer symptom and longer anticipated patient interval for rectal bleeding (p = 0.005). CONCLUSIONS: Intervention studies should address both negative beliefs about cancer and knowledge of symptoms to optimise the effect. PMID- 29609533 TI - Prolonged persistence of IgM against dengue virus detected by commonly used commercial assays. AB - BACKGROUND: Initial symptoms of dengue fever are non-specific, and thus definite diagnosis requires laboratory confirmation. Detection of IgM against dengue virus (DENV) has become widely used for dengue diagnosis. Understanding the persistence of anti-DENV IgM in subjects after acute infection is essential in order to interpret test results correctly. Although the longevity of anti-DENV IgM has been vehemently investigated in symptomatic children, anti-DENV IgM persistence in adults and in asymptomatically infected people have seldom been reported. METHODS: We prospectively investigated 44 adults with detectable anti-DENV IgM in a serosurvey conducted in the 2015 dengue epidemic in Tainan, Taiwan. Among subjects within the cohort, 17 were classified to be symptomatic and 27 were asymptomatic. The enzyme-linked immunosorbent assay (ELISA) from Standard Diagnostic (SD) and Focus Diagnostic were used to detect anti-DENV IgM for specimens collected initially, at 6 and 12 months. Regression analyses were used to estimate the duration of anti-DENV IgM fell below the detectable level. Rapid dengue tests from Standard Diagnostics had been widely adopted to detect anti DENV IgM in Taiwan during the 2015 dengue outbreak. As such, collected specimens were also evaluated with the SD rapid dengue test in parallel. RESULTS: Anti-DENV IgM was detectable in 70.5 and 46.2% of the 44 subjects at 6 months and 12 months by the SD ELISA, respectively, while 13.6 and 7.7%, respectively, by the Focus ELISA. There was no significant difference in anti-DENV IgM detection for the follow-up specimens between subjects with symptomatic and asymptomatic infections. The regression analysis estimated that anti-DENV IgM persistence fell to the undetectable level at 338.3 days (95% CI 279.7-446.9) by SD ELISA, while at 175.7 days (95% CI 121.9-221.1) by Focus ELISA. The detectable frequency of anti-DENV IgM by rapid tests was 86.4%, 68.2 and 35.9% at initial, 6 and 12 months, respectively. CONCLUSION: Anti-DENV IgM was found to persist much longer than previously thought, suggesting a necessity of re-evaluation of the use of anti-DENV IgM for both the diagnosis of dengue and serological surveillance, especially when large outbreaks have occurred in the preceding year. PMID- 29609535 TI - Prevalence and correlates of central venous catheter use among haemodialysis patients in the Irish health system - a national study. AB - BACKGROUND: Central venous catheters (CVC) are associated with substantial morbidity and mortality among patients undergoing haemodialysis (HD), yet they are frequently used as the primary vascular access for many patients on HD. The goal of this study was to determine the prevalence and variation in CVC use across centres in the Irish health system. METHODS: Data from the National Kidney Disease Clinical Patient Management System (KDCPMS) was used to determine CVC use and patterns across centres. Data on demographic characteristics, primary cause of end-stage kidney disease (ESKD), comorbid conditions, laboratory values and centre affiliation were extracted for adult HD patients (n = 1, 196) who were on dialysis for at least three months up to end of December 2016. Correlates of CVC use were explored using multivariable logistic regression. RESULTS: Overall prevalence of CVC use was 54% and varied significantly across clinical sites from 43% to 73%, P < 0.001. In multivariate analysis, the likelihood of CVC use was lower with increasing dialysis vintage, OR 0.40 (0.26-0.60) for 4 years vs 1 year vintage, rising serum albumin, OR 0.73 (0.59-0.90) per 5 g/L), and with cystic disease as a cause of ESKD, OR 0.38 (95% CI 0.21-0.6). In contrast, catheter use was greater for women than men, OR 1.77 (1.34-2.34) and for 2 out of 10 regional dialysis centres, OR 1.98 (1.02-3.84) and OR 2.86 (1.67-4.90) respectively compared to referent group). CONCLUSIONS: Catheters are the predominant type of vascular access in patients undergoing HD in the Irish health system. Substantial centre variation exists which is not explained by patient-level characteristics. PMID- 29609536 TI - Effects of dialysate to serum sodium (Na+) alignment in chronic hemodialysis (HD) patients: retrospective cohort study from a quality improvement project. AB - BACKGROUND: Evidence indicates favorable effects of dialysate (DNa+) to serum sodium concentration (SNa+) alignment, however, results from larger sample populations are needed. For this reason, we conducted a retrospective propensity score-matched cohort study from a quality improvement project to investigate the effects of alignment on population of maintenance hemodialysis patients. METHODS: At 4 participating hemodialysis (HD) clinics, patients with SNa+ lower than the standard DNa+ of 137 mEq/L who received HD with DNa+ aligned to the average of the last 4 SNa+ measurements were evaluated (clinicaltrials.gov # NCT01825590 ). In this retrospective data analysis, an intention-to-treat (primary) and an as treated "intervention" (secondary) cohort were created. "Aligned" patients from both cohorts (N = 163 for the primary and N = 137 for the secondary) were then propensity-score matched in a 1:1 fashion to "unaligned" patients from the Renal Research Institute database. The propensity score was generated based on age, gender, white race, Hispanic ethnicity, absence or presence of diabetes, hemodialysis vintage, interdialytic weight gain (IDWG; as a percentage of postdialysis body weight), catheter as primary dialysis access, predialysis systolic blood pressure, serum sodium concentration, hospitalization count during baseline. T-Test was employed for group comparisons of changes to the primary (volume-related and hemodynamic parameters) and tertiary outcomes. All-cause and fluid overload-related hospitalization admission rates were compared using Wilcoxon Rank Sum test and Cox regression analysis for repeated events. RESULTS: In the primary analysis, aligned and unaligned subjects showed comparable demographics at baseline. Treatment effects were significant for IDWG [-0.12 (95% CI -0.24 to 0) L] and showed decreasing non-significant trends for pre-dialysis hemodynamic parameters. Count comparison and Cox regression analysis showed no clear advantage of alignment in terms of all-cause and fluid overload-related hospitalization. CONCLUSIONS: Results from the largest sodium alignment program to date suggest positive treatment effects on volume-related and hemodynamic parameters, but no clear effect on risk of hospitalization. Well-matched control patients minimized confounding effects. Small effects and lack of significant differences may be explained by a low baseline DNa+ limiting the interventional change. PMID- 29609537 TI - No difference in renal injury and fibrosis between wild-type and NOD1/NOD2 double knockout mice with chronic kidney disease induced by ureteral obstruction. AB - BACKGROUND: Chronic kidney disease (CKD) is characterized by sustained tissue damage and ongoing tubulo-interstitial inflammation and fibrosis. Pattern recognition receptors (PRRs) including Toll-like receptors (TLRs) and NOD-like receptors (NLRs) can sense endogenous ligands released upon tissue damage, leading to sterile inflammation and eventually irreversible kidney disease. It is known that NOD1 and NOD2 contribute to the pathogenesis of various inflammatory diseases, including acute kidney injury. However their role in chronic kidney disease is largely unknown. The aim of this study was therefore to investigate the contribution of NOD1 and NOD2 in renal interstitial fibrosis and obstructive nephropathy. METHODS: To do so, we performed unilateral ureteral obstruction (UUO) in wild type (WT) and NOD1/NOD2 double deficient (DKO) mice and analysed renal damage, fibrosis and inflammation. Data were analysed using the non parametric Mann-Whitney U-test. RESULTS: Minor changes in inflammatory response were observed in NOD1/2 DKO mice, while no effects were observed on renal injury and the development of fibrosis. CONCLUSION: No difference in renal injury and fibrosis between WT and NOD1/NOD2 DKO mice following obstructive nephropathy induced by ureteral obstruction. PMID- 29609538 TI - Significance of CD133 positive cells in four novel HPV-16 positive cervical cancer-derived cell lines and biopsies of invasive cervical cancer. AB - BACKGROUND: Cervical cancer is a major cause of cancer-related mortality in women in the developing world. Cancer Stem cells (CSC) have been implicated in treatment resistance and metastases development; hence understanding their significance is important. METHODS: Primary culture from tissue biopsies of invasive cervical cancer and serial passaging was performed for establishing cell lines. Variable Number Tandem Repeat (VNTR) assay was performed for comparison of cell lines with their parental tissue. Tumorsphere and Aldefluor assays enabled isolation of cancer stem cells (CSC); immunofluorescence and flow cytometry were performed for their surface phenotypic expression in cell lines and in 28 tissue samples. Quantitative real-time PCR for stemness and epithelial-mesenchymal transition (EMT) markers, MTT cytotoxicity assay, cell cycle analysis and cell kinetic studies were performed. RESULTS: Four low-passage novel cell lines designated RSBS-9, - 14 and - 23 from squamous cell carcinoma and RSBS-43 from adenocarcinoma of the uterine cervix were established. All were HPV16+. VNTR assay confirmed their uniqueness and derivation from respective parental tissue. CSC isolated from these cell lines showed CD133+ phenotype. In tissue samples of untreated invasive cervical cancer, CD133+ CSCs ranged from 1.3-23% of the total population which increased 2.8-fold in radiation-resistant cases. Comparison of CD133+ with CD133- bulk population cells revealed increased tumorsphere formation and upregulation of stemness and epithelial-mesenchymal transition (EMT) markers with no significant difference in cisplatin sensitivity. CONCLUSION: Low-passage cell lines developed would serve as models for studying tumor biology. Cancer Stem Cells in cervical cancer display CD133+ phenotype and are increased in relapsed cases and hence should be targeted for achieving remission. PMID- 29609539 TI - Association of polymorphism rs1053005 in STAT3 with chronic hepatitis B virus infection in Han Chinese population. AB - BACKGROUND: Signal transducer and activator of transcription 3 (STAT3) is involved in hepatitis B virus (HBV) infection and HBV-related hepatocellular carcinoma (HCC). The association between polymorphism rs1053005 and haplotypes formed by rs1053004 and rs1053005 in the 3'UTR of STAT3 and chronic HBV infection has yet to be investigated. METHODS: This study included 567 patients with chronic HBV infection (239 chronic hepatitis, 141 liver cirrhosis and 187 HCC), 98 HBV infection resolvers, and 169 healthy controls. STAT3 rs1053004 and rs1053005 polymorphisms were genotyped by TaqMan SNP Genotyping Assays. RESULTS: The rs1053004 genotype CC [P value by Bonferroni correction (P c ) = 0.002] and allele C (P c = 0.019) were more frequent in patients with chronic HBV infection than in healthy controls. The rs1053005 genotype GG was also more frequent in patients with chronic HBV infection than in healthy controls (P c = 0.046). The rs1053004-rs1053005 haplotype T-G was less frequent in patients with chronic HBV infection than in healthy controls (Pc < 0.001). Haplotype C-A was more frequent in patients with liver cirrhosis than in patients with HCC (P c = 0.042). The rs1053004 genotype TC, rs1053005 genotype AG and rs1053004-rs1053005 haplotype T A were associated with higher HBV DNA levels. CONCLUSIONS: STAT3 rs1053004 and rs1053005 polymorphisms and haplotypes formed by rs1053004 and rs1053005 are associated with chronic HBV infection and the haplotypes appear to be also associated with the development of liver disease. Studies in large sample sizes of patients and control populations are required to verify and extend these findings. PMID- 29609540 TI - Cost-benefit analysis of antibiofilm microbiological techniques for peri prosthetic joint infection diagnosis. AB - BACKGROUND: Implant-related infections, including those of peri-prosthetic joint (PJIs), osteosynthesis and other biomaterials, are biofilm-related. Pathogen identification is considered the diagnostic benchmark; however, the presence of bacterial biofilms makes pathogen detection with traditional microbiological techniques only partially effective. To improve microbiological diagnostic accuracy, some biofilm debonding techniques have been recently proposed. Aim of this health economics assessment study was to evaluate their economic impact on hospital costs. METHODS: Direct and indirect hospital costs connected with the routine introduction of sonication and dithiothreitol treatment applied to hip and knee PJIs and of tissue cultures were examined. In particular the consequences of diagnostic inaccuracy, the opportunities, costs, and risks of each technique were calculated. RESULTS: Considering an average of five samples per patient, processed separately with traditional tissue culture with or without sonication of prosthetic components, or pooled together using the MicroDTTect device (a close system for sample collection, transport and treatment with Dithiothreitol for microbial release from biofilm), the overall mean direct cost per patient was ? 397 and ? 393 for sonication or MicroDTTect, respectively, compared to ? 308 for traditional tissue cultures. In terms of opportunity costs, MicroDTTect was the most effective technique, allowing for a 35% or 55% reduction in time required for sample treatment, compared to tissue cultures combined or not with sonication, respectively. Pooling together direct and indirect costs associated with false positive and negative results of the different diagnostic techniques, unnecessary medical treatments and possible medical claims, MicroDTTect or sonication become increasingly cost-effective when the extra costs, generated by diagnostic inaccuracy of traditional tissue culture, took place, respectively, in 2% or 20% or more of the patients. CONCLUSIONS: This is the first study specifically focused on the economic impact of the routine clinical use of microbiological antibiofilm sampling and processing techniques in orthopaedics. Although our results may suffer from a potential country and hospital bias, as the data collection process for direct and indirect costs is specific to each institution and country, this analysis highlights the potential economic advantage to hospitals associated with the routine introduction of antibiofilm techniques for microbiological diagnosis of PJI. PMID- 29609541 TI - Earliest ontogeny of early Cambrian acrotretoid brachiopods - first evidence for metamorphosis and its implications. AB - BACKGROUND: Our understanding of the ontogeny of Palaeozoic brachiopods has changed significantly during the last two decades. However, the micromorphic acrotretoids have received relatively little attention, resulting in a poor knowledge of their ontogeny, origin and earliest evolution. The uniquely well preserved early Cambrian fossil records in South China provide a great new opportunity to investigate the phylogenetically important ontogeny of the earliest acrotretoid brachiopods, and give new details of the dramatic changes in anatomy of acrotretoid brachiopods during the transition from planktotrophic larvae to filter feeding sedentary juveniles. RESULTS: Well preserved specimens of the earliest Cambrian acrotretoid brachiopods Eohadrotreta zhenbaensis and Eohadrotreta? zhujiahensis (Cambrian Series 2, Shuijingtuo Formation, Three Gorges area, South China) provide new insights into early acrotretoid ontogeny, and have significance for elucidating the poorly understood early phylogeny of the linguliform brachiopods. A more comprehensive understanding of the applied terminology based on new observation, especially in definition of the major growth stages (embryo, planktotrophic larva, post-metamorphically sessile juvenile and adult), is established. The so-called acrotretoid "larval shell" of both valves of Eohadrotreta demonstrates evidence for metamorphosis (shedding of the larval setae and transitions of shell secretion), during the planktotrophic stage. Therefore, it is here termed the metamorphic shell. The inferred early acrotretoid larval body plan included a bivalved protegulum, secreted at the beginning of the pelagic stage, which later developed two pairs of larval dorsal setal sacs and anterior-posterior alignment of the gut during metamorphosis. CONCLUSION: The primary larval body plan of acrotretoid Eohadrotreta is now known to have been shared with most early linguliforms and their relatives (including paterinates, siphonotretoids, early linguloids, the problematic mickwitziids, as well as many early rhynchonelliforms). It is suggested that this type of earliest ontogeny can be considered as plesiomorphic for the Brachiopoda and probably first evolved in stem group brachiopods with subsequent heterochronic changes. PMID- 29609542 TI - Gastrointestinal microbial community changes in Atlantic cod (Gadus morhua) exposed to crude oil. AB - BACKGROUND: The expansion of offshore oil exploration increases the risk of marine species being exposed to oil pollution in currently pristine areas. The adverse effects of oil exposure through toxic properties of polycyclic aromatic hydrocarbons (PAHs) have been well studied in Atlantic cod (Gadus morhua). Nevertheless, the fate of conjugated metabolites in the intestinal tract and their effect on the diversity of intestinal microbial community in fish is less understood. Here, we investigated the intestinal microbial community composition of Atlantic cod after 28 days of exposure to crude oil (concentration range 0.0 0.1 mg/L). RESULTS: Analysis of PAH metabolites in bile samples confirmed that uptake and biotransformation of oil compounds occurred as a result of the exposure. Various evidence for altered microbial communities was found in fish exposed to high (0.1 mg/L) and medium (0.05 mg/L) concentrations of oil when compared to fish exposed to low oil concentration (0.01 mg/L) or no oil (control). First, altered banding patterns were observed on denaturing gradient gel electrophoresis for samples pooled from each treatment group. Secondly, based on 16S rRNA sequences, higher levels of oil exposure were associated with a loss of overall diversity of the gut microbial communities. Furthermore, 8 operational taxonomic units (OTUs) were found to have significantly different relative abundances in samples from fishes exposed to high and medium oil concentrations when compared to samples from the control group and low oil concentration. Among these, only one OTU, a Deferribacterales, had increased relative abundance in samples from fish exposed to high oil concentration. CONCLUSIONS: The results presented herein contribute to a better understanding of the effects of oil contamination on the gut microbial community changes in fish and highlight the importance of further studies into the area. Our findings suggest that increased relative abundance of bacteria belonging to the order Deferribacterales may be indicative of exposure to oil at concentrations higher than 0.05 mg/L. PMID- 29609543 TI - RNA-seq analysis of lncRNA-controlled developmental gene expression during puberty in goat & rat. AB - BACKGROUND: Puberty is a pivotal stage in female animal development, and marks the onset of reproductive capability. However, little is known about the function of lncRNAs (long noncoding RNAs) in puberty. Therefore, RNA-seq analysis were performed between goats and rats to clarify the roles of lncRNAs and mRNAs in the onset of puberty. RESULTS: In the present study, the length of lncRNAs, the length of the open reading frame and the exon count were compared between the two species. Furthermore, functional annotation analysis based on Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) analysis of lncRNAs target genes and differentially expressed mRNA demonstrated the significantly enriched terms, such as AMPK signaling pathway, oxytocin signaling pathway, insulin secretion as well as pheromone receptor activity, and some other signaling pathways which were involved in the regulation of female puberty. Moreover, our results of siRNA interference in vitro showed the candidate lncRNA XLOC_446331 may play a crucial role in regulating female puberty. CONCLUSION: In conclusion, the RNA-seq analysis between goat and rat provide novel candidate regulators for genetic and molecular studies on female puberty. PMID- 29609544 TI - Detection of CTX-M-15 harboring Escherichia coli isolated from wild birds in Tunisia. AB - BACKGROUND: The spreading of antibiotic resistant bacteria is becoming nowadays an alarming threat to human and animal health. There is increasing evidence showing that wild birds could significantly contribute to the transmission and spreading of drug-resistant bacteria. However, data for antimicrobial resistance in wild birds remain scarce, especially throughout Africa. The aims of this investigation were to analyze the prevalence of ESBL-producing E. coli in faecal samples of wild birds in Tunisia and to characterize the recovered isolates. RESULTS: One hundred and eleven samples were inoculated on MacConkey agar plates supplemented with cefotaxime (2 MUg/ml). ESBL-producing E. coli isolates were detected in 12 of 111 faecal samples (10.81%) and one isolate per sample was further characterized. beta-lactamase detected genes were as follows: blaCTX-M-15 (8 isolates), blaCTX-M-15 + blaTEM-1b (4 isolates). The ISEcp1 and orf477 sequences were found respectively in the regions upstream and downstream of all blaCTX-M-15 genes. Seven different plasmid profiles were observed among the isolates. IncF (FII, FIA, FIB) and IncW replicons were identified in 11 CTX-M-15 producing isolates, and mostly, other replicons were also identified: IncHI2, IncA/C, IncP, IncI1 and IncX. All ESBL-producing E. coli isolates were integron positive and possessed "empty" integron structures with no inserted region of DNA. The following detected virulence genes were: (number of isolates in parentheses): fimA (ten); papC (seven); aer (five); eae (one); and papGIII, hly, cnf, and bfp (none). Molecular typing using pulsed-field gel electrophoresis and multilocus sequence typing showed a low genetic heterogeneity among the 12 ESBL producing strains with five unrelated PFGE types and five different sequence types (STs) respectively. CTX-M-15-producing isolates were ascribed to phylogroup A (eleven isolates) and B2 (one isolate). CONCLUSION: To our knowledge, this study provides the first insight into the contribution of wild birds to the dynamics of ESBL-producing E. coli in Tunisia. PMID- 29609545 TI - Relationship of cardiovascular disease risk factors and noncoding RNAs with hypertension: a case-control study. AB - BACKGROUND: The present study sought to explore the relationship of common cardiovascular disease risk factors and noncoding RNAs with essential hypertension (EH). METHODS: A total of 402 EH patients and 402 gender- and age frequency matched healthy controls were enrolled in this study. Each participant received a questionnaire survey, physical examination and laboratory tests. Quantitative real-time polymerase chain reaction (qPCR) was performed to assess relative expression levels of six noncoding RNAs (NR_027032, NR_034083, NR_104181, miR-126, miR-143 and miR-145) in peripheral blood leucocytes. Multiple logistic regression analysis was used to estimate the risk of having EH between hypertensive and non-hypertensive patients. RESULTS: Analysis showed that participants with anxiety, high body mass index, abdominal obesity and family history of hypertension had higher risk for EH, whereas those with bland diet and occupational physical activities had lower risk for EH. qPCR assays showed that NR_027032 (P = 0.015) and NR_034083 (P = 0.004) were significantly reduced in EH patients compared with controls, whereas NR_104181 (P = 0.007), miR-143 (P = 0.005) and miR-145 (P = 0.015) were significantly elevated. After controlling the cardiovascular risk factors, multivariate analysis showed that lower expression levels of NR_034083 and higher expression levels of NR_104181 and miR-143 were risk factors for EH. CONCLUSIONS: EH is a result of environmental and epigenetic factors. Strikingly, NR_034083, NR_104181 and miR-143 may be correlated with the risk for EH development; therefore, epigenetic markers could be used to measure hypertension levels to help elucidate the pathogenesis of EH. PMID- 29609546 TI - High-frequency power of heart rate variability can predict the outcome of thoracic surgical patients with acute respiratory distress syndrome on admission to the intensive care unit: a prospective, single-centric, case-controlled study. AB - BACKGROUND: The morbidity and mortality of acute respiratory distress syndrome (ARDS) remains high, and the strategic focus of ARDS research has shifted toward identifying patients at high risk of mortality early in the course of illness. This study intended to identify the heart rate variability (HRV) measure that can predict the outcome of patients with ARDS on admission to the surgical intensive care unit (SICU). METHODS: Patients who had lung or esophageal cancer surgery were included either in the ARDS group (n = 21) if they developed ARDS after surgery or in the control group (n = 11) if they did not. The ARDS patients were further stratified into survivors and non-survivors subgroups according to their outcomes. HRV measures of the patients were used for statistical analysis. RESULTS: The mean RR interval (mRRI), high-frequency power (HFP) and product of low-/high-frequency power ratio tidal volume and tidal volume (LHR*VT) were significantly lower (p < 0.05), while the normalized HFP to VT ratio (nHFP/VT) was significantly higher in the ARDS patients (p = 0.011). The total power (TP), low-frequency power (LFP), HFP and HFP/VT were all significantly higher in the non-survived ARDS patients, whereas Richmond Agitation-Sedation Scale (RASS) was significantly lower in the non-survived ARDS patients. After adjustment for RASS, age and gender, firth logistic regression analysis identified the HFP, TP as the significant independent predictors of mortality for ARDS patients. CONCLUSIONS: The vagal modulation of thoracic surgical patients with ARDS was enhanced as compared to that of non-ARDS patients, and the non-survived ARDS patients had higher vagal activity than those of survived ARDS patients. The vagal modulation related parameters such as TP and HFP were independent predictors of mortality in patients with ARDS on admission to the SICU, and the HFP was found to be the best predictor of mortality for those ARDS patients. Increased vagal modulation might be an indicator for poor prognosis in critically ill patients following thoracic surgery. PMID- 29609547 TI - Health professional perceptions regarding screening tools for developmental surveillance for children in a multicultural part of Sydney, Australia. AB - BACKGROUND: Encouraging early child development and the early identification of developmental difficulties is a priority. The Ministry of Health in the Australian State of New South Wales (NSW), has recommended a program of developmental surveillance using validated screening questionnaires, namely, the Parents' Evaluation of Development Status (PEDS) and Ages and Stages Questionnaire (ASQs), however, the use of these tools has remained sub-optimal. A longitudinal prospective birth cohort "Watch Me grow" study was carried out in the South Western Sydney (SW) region of NSW to ascertain the uptake as well as the strategies and the resources required to maximise engagement in the surveillance program. This paper reports on a qualitative component of the study examining the attitudes, enablers and barriers to the current developmental surveillance practices, with reference to screening tools, amongst health professionals. METHODS: Qualitative data from 37 primary health care providers in a region of relative disadvantage in Sydney was analysed. RESULTS: The major themes that emerged from the data were the "difficulties/problems" and "positives/benefits" of surveillance in general, and "specificity" of the tools which were employed. Barriers of time, tool awareness, knowledge and access of referral pathways, and services were important for the physician providers, while the choice of screening tools and access to these tools in other languages were raised as important issues by Child and Family Health Nurses (CFHN). The use of these tools by health professionals was also influenced by what the professionals perceived as the parents' understanding of their child's development. While the PEDS and ASQs was utilised by CFHNs, both General Practitioners (GPs) and paediatricians commented that they lacked awareness of developmental screening tools and highlighted further training needs. CONCLUSIONS: The results highlight the practical challenges to, and limited knowledge and uptake of, the use of recommended screening tools as part of developmental surveillance. There is a need for further research regarding the most effective integrated models of care which will allow for a better collaboration between parents and service providers and improve information sharing between different professionals such as CFHNs GPs, Practices nurses and Paediatricians involved in screening and surveillance programs. PMID- 29609548 TI - Effectiveness of 13-pneumococcal conjugate vaccine (PCV13) against invasive pneumococcal disease in children in the Dominican Republic. AB - BACKGROUND: Limited data are available on the effectiveness of 13-valent pneumococcal conjugate vaccine (PCV13) in resource-poor settings and PCV naive populations. The Dominican Republic introduced PCV13 in September 2013 using a 2 + 1 schedule (2, 4, and 12 months) without a catch-up campaign. We evaluated PCV13 effectiveness against vaccine-type (VT) invasive pneumococcal disease (IPD) among children in the Dominican Republic. METHODS: We conducted a matched case control study. A case-patient was defined as VT-IPD identified by culture or polymerase chain reaction (PCR) from a normally sterile-site in a hospitalized child who was age-eligible to have received >=1 PCV13 dose. Four age- and neighborhood-matched controls were enrolled for each case-patient. We collected demographic, vaccination history, and risk factor data. Conditional logistic regression was performed. Vaccine effectiveness was calculated as (1- adjusted matched odds ratio for vaccination) X 100%. RESULTS: We enrolled 39 case-patients and 149 matched-controls. Most case-patients had pneumonia with pleural effusion (64%), followed by meningitis (28%) and septicemia (13%). The most common pneumococcal serotypes identified included 14 (18%), 3 (13%), 19A (10%), and 1 (8%). Fewer case-patients had >=1 PCV13 dose as compared to controls (61.5% vs. 80.0%; p = 0.006). Adjusting for malnutrition and socioeconomic status, VE of >=1 PCV13 dose compared to no doses was 67.2% (95% CI: 2.3% to 90.0%). Only 44% of controls were up-to-date for PCV13, suggesting low vaccine coverage in the population. CONCLUSIONS: We found that PCV13 provided individual protection against VT-IPD in this resource-poor setting with a PCV-naive population, despite low PCV13 coverage. Expanding vaccination coverage might increase PCV13 impact. PMID- 29609549 TI - A statistical approach to identify, monitor, and manage incomplete curated data sets. AB - BACKGROUND: Many biological knowledge bases gather data through expert curation of published literature. High data volume, selective partial curation, delays in access, and publication of data prior to the ability to curate it can result in incomplete curation of published data. Knowing which data sets are incomplete and how incomplete they are remains a challenge. Awareness that a data set may be incomplete is important for proper interpretation, to avoiding flawed hypothesis generation, and can justify further exploration of published literature for additional relevant data. Computational methods to assess data set completeness are needed. One such method is presented here. RESULTS: In this work, a multivariate linear regression model was used to identify genes in the Zebrafish Information Network (ZFIN) Database having incomplete curated gene expression data sets. Starting with 36,655 gene records from ZFIN, data aggregation, cleansing, and filtering reduced the set to 9870 gene records suitable for training and testing the model to predict the number of expression experiments per gene. Feature engineering and selection identified the following predictive variables: the number of journal publications; the number of journal publications already attributed for gene expression annotation; the percent of journal publications already attributed for expression data; the gene symbol; and the number of transgenic constructs associated with each gene. Twenty-five percent of the gene records (2483 genes) were used to train the model. The remaining 7387 genes were used to test the model. One hundred and twenty-two and 165 of the 7387 tested genes were identified as missing expression annotations based on their residuals being outside the model lower or upper 95% confidence interval respectively. The model had precision of 0.97 and recall of 0.71 at the negative 95% confidence interval and precision of 0.76 and recall of 0.73 at the positive 95% confidence interval. CONCLUSIONS: This method can be used to identify data sets that are incompletely curated, as demonstrated using the gene expression data set from ZFIN. This information can help both database resources and data consumers gauge when it may be useful to look further for published data to augment the existing expertly curated information. PMID- 29609550 TI - Perceptions of self-rated health among stroke survivors: a qualitative study in the United Kingdom. AB - BACKGROUND: Self-rated health predicts health outcomes independently of levels of disability or mood. Little is known about what influences the subjective health experience of stroke survivors. Our aim was to investigate stroke survivors' perceptions of self-rated health, with the intention of informing the design of interventions that may improve their subjective health experience. METHODS: We conducted semi-structured interviews with a purposive sample of 28 stroke survivors recruited from a stroke unit and follow-up outpatient clinic, 4-6 months after stroke, to explore what factors are perceived to be part of self rated health in the early stages of recovery. Qualitative data were analysed using a thematic analysis approach to identify underlying themes. RESULTS: Participants' accounts show that stroke survivors' perceptions of self-rated health are multifactorial, comprising physical, psychological and social components. Views on future recovery after stroke play a role in present health experience and are shaped by psychosocial resources that are influenced by past experiences of ill-health, dispositional outlook such as degree of optimism, a sense of control and views on ageing. CONCLUSIONS: Severity of physical limitations alone does not influence perceptions of self-rated health among stroke survivors. Self-rated health in stroke survivors is a multidimensional construct shaped by changes in health status occurring after the stroke, individual characteristics and social context. Understanding the factors stroke survivors themselves associate with better health will inform the development of effective approaches to improve rehabilitation and recovery after stroke. PMID- 29609551 TI - A high-resolution genetic linkage map and QTL fine mapping for growth-related traits and sex in the Yangtze River common carp (Cyprinus carpio haematopterus). AB - BACKGROUND: A high-density genetic linkage map is essential for QTL fine mapping, comparative genome analysis, identification of candidate genes and marker assisted selection for economic traits in aquaculture species. The Yangtze River common carp (Cyprinus carpio haematopterus) is one of the most important aquacultured strains in China. However, quite limited genetics and genomics resources have been developed for genetic improvement of economic traits in such strain. RESULTS: A high-resolution genetic linkage map was constructed by using 7820 2b-RAD (2b-restriction site-associated DNA) and 295 microsatellite markers in a F2 family of the Yangtze River common carp (C. c. haematopterus). The length of the map was 4586.56 cM with an average marker interval of 0.57 cM. Comparative genome mapping revealed that a high proportion (70%) of markers with disagreed chromosome location was observed between C. c. haematopterus and another common carp strain (subspecies) C. c. carpio. A clear 2:1 relationship was observed between C. c. haematopterus linkage groups (LGs) and zebrafish (Danio rerio) chromosomes. Based on the genetic map, 21 QTLs for growth-related traits were detected on 12 LGs, and contributed values of phenotypic variance explained (PVE) ranging from 16.3 to 38.6%, with LOD scores ranging from 4.02 to 11.13. A genome wide significant QTL (LOD = 10.83) and three chromosome-wide significant QTLs (mean LOD = 4.84) for sex were mapped on LG50 and LG24, respectively. A 1.4 cM confidence interval of QTL for all growth-related traits showed conserved synteny with a 2.06 M segment on chromosome 14 of D. rerio. Five potential candidate genes were identified by blast search in this genomic region, including a well studied multi-functional growth related gene, Apelin. CONCLUSIONS: We mapped a set of suggestive and significant QTLs for growth-related traits and sex based on a high-density genetic linkage map using SNP and microsatellite markers for Yangtze River common carp. Several candidate growth genes were also identified from the QTL regions by comparative mapping. This genetic map would provide a basis for genome assembly and comparative genomics studies, and those QTL-derived candidate genes and genetic markers are useful genomic resources for marker assisted selection (MAS) of growth-related traits in the Yangtze River common carp. PMID- 29609552 TI - Experiences of liver health related uncertainty and self-reported stress among people who inject drugs living with hepatitis C virus: a qualitative study. AB - BACKGROUND: People who inject drugs (PWID) are most at risk of hepatitis C virus infection in Australia. The introduction of transient elastography (TE) (measuring hepatitis fibrosis) and direct acting antiviral medications will likely alter the experience of living with hepatitis C. We aimed to explore positive and negative influences on wellbeing and stress among PWID with hepatitis C. METHODS: The Treatment and Prevention (TAP) study examines the feasibility of treating hepatitis C mono-infected PWID in community settings. Semi-structured interviews were conducted with 16 purposively recruited TAP participants. Participants were aware of their hepatitis C seropositive status and had received fibrosis assessment (measured by TE) prior to interview. Questions were open-ended, focusing on the impact of health status on wellbeing and self-reported stress. Interviews were voice recorded, transcribed verbatim and thematically analysed, guided by Mishel's (1988) theory of Uncertainty in Illness. RESULTS: In line with Mishel's theory of Uncertainty in Illness all participants reported hepatitis C-related uncertainty, particularly mis information or a lack of knowledge surrounding liver health and the meaning of TE results. Those with greater fibrosis experienced an extra layer of prognostic uncertainty. Experiences of uncertainty were a key motivation to seek treatment, which was seen as a way to regain some stability in life. Treatment completion alleviated hepatitis C-related stress, and promoted feelings of empowerment and confidence in addressing other life challenges. CONCLUSION: TE scores seemingly provide some certainty. However, when paired with limited knowledge, particularly among people with severe fibrosis, TE may be a source of uncertainty and increased personal stress. This suggests the need for simple education programs and resources on liver health to minimise stress. PMID- 29609553 TI - Utility of posaconazole therapeutic drug monitoring and assessment of plasma concentration threshold for effective prophylaxis of invasive fungal infections: a meta-analysis with trial sequential analysis. AB - BACKGROUND: Posaconazole therapeutic drug monitoring (TDM) is increasingly used in clinical practice. However, the utility of posaconazole TDM and the target of posaconazole plasma concentration for clinical successful prophylaxis remain uncertain and controversial. The aim of this study was to evaluate posaconazole exposure-response relationship and determine an optimum posaconazole concentration for prophylaxis against invasive fungal infections (IFIs). METHODS: Bibliographic databases were searched (from inception to September 2017) to select studies including the clinical outcomes below and above concentration cut off value of 0.5 mg/L and 0.7 mg/L. The reliability of the results were evaluated with trial sequential analysis (TSA). RESULTS: Twenty-eight studies with 1930 patients included were analyzed. The results of our pooled analysis demonstrated that patients with posaconazole plasma concentrations over 0.5 mg/L were twice more likely to achieve successful responses compared with those with lower concentrations (odds ratio, OR = 1.98, 95% confidence interval, CI 1.09-3.58, P = 0.02) while the threshold, 0.7 mg/L showed no significant difference (OR = 1.84, 95% CI 0.94-3.63, P = 0.08). The TSA results showed that there was sufficient information to support these findings. CONCLUSIONS: An optimal posaconazole concentration target of 0.5 mg/L is suggested to ensure the clinical prophylactic efficacy and may help reduce the dosage and dose-dependent toxicity comparing with the target of 0.7 mg/L. PMID- 29609554 TI - Internet-based self-help smoking cessation and alcohol moderation interventions for cancer survivors: a study protocol of two RCTs. AB - BACKGROUND: Brief interventions for smoking cessation and alcohol moderation may contribute considerably to the prevention of cancer among populations at risk, such as cancer survivors, in addition to improving their general wellbeing. There is accumulating evidence for the effectiveness of internet-based brief health behaviour interventions. The objective of this study is to assess the effectiveness, patient-level cost-effectiveness and cost-utility of two new online theory-based self-help interventions among adult cancer survivors in the Netherlands. One of the interventions focuses on alcohol moderation, the other on smoking cessation. Both interventions are tailored to cancer survivors. METHODS: Effectiveness will be assessed in two separate, nearly identical 2-armed RCTs: alcohol moderation (AM RCT) and smoking cessation (SC RCT). Participants are randomly allocated to either the intervention groups or the control groups. In the intervention groups, participants have access to one of the newly developed interventions. In the control groups, participants receive an online static information brochure on alcohol (AM RCT) or smoking (SC RCT). Main study outcome parameters are the number of drinks post-randomisation (AM RCT) and tobacco abstinence (SC RCT). In addition, cost-data and possible effect moderators and mediators will be assessed. Both treatments are internet-based minimally guided self-help interventions: MyCourse - Moderate Drinking (in Dutch: MijnKoers - Minderen met Drinken) and MyCourse - Quit Smoking (MijnKoers - Stoppen met Roken). They are based on cognitive behaviour therapy (CBT), motivational interviewing (MI) and acceptance and commitment therapy (ACT). Both interventions are optimized in collaboration with the target population of cancer survivors in focus groups and interviews, and in collaboration with several experts on eHealth, smoking cessation, alcohol misuse and cancer survivorship. DISCUSSION: The present study will add to scientific knowledge on the (cost-)effectiveness of internet-based self-help interventions to aid in smoking cessation or alcohol moderation, working mechanisms and impact on quality of life of cancer survivors. If found effective, these interventions can contribute to providing evidence based psychosocial oncology care to a growing population of cancer survivors. TRIAL REGISTRATION: Trials are prospectively registered in The Netherlands Trial Register (NTR): NTR6011 (SC RCT), NTR6010 (AM RCT) on 1 September 2016. PMID- 29609555 TI - Long-term effects on cardiovascular risk of a structured multidisciplinary lifestyle program in clinical practice. AB - BACKGROUND: Cardiovascular disease is still the leading cause of premature death world-wide with factors like abdominal obesity, hypertension and dyslipidemia being central risk factors in the etiology. The aim of the present study was to investigate the effects on cardiovascular risk factors and cardiovascular risk after 6 months and 1 year, in individuals with increased cardiovascular risk enrolled in a lifestyle multidisciplinary program in a clinical setting. METHOD: Individuals with increased cardiovascular risk were referred from primary health care and hospitals to a program at an outpatient clinic at a department of cardiology. The program consisted of three individual visits including a health check-up with a physical examination and blood sampling, and a person-centered dialogue for support in behavioural change of unhealthy lifestyle habits (at baseline, 6 months and 1 year). Furthermore, five educational group sessions were given at baseline. Cardiovascular risk was assessed according to Framingham cardiovascular risk predicting model. RESULTS: One hundred individuals (mean age 59 years, 64% women) enrolled between 2008 and 2014 were included in the study. Waist circumference, systolic and diastolic blood pressure and total cholesterol decreased significantly over 1 year. In parallel, cardiovascular risk according to the cardiovascular risk profile based on Framingham 10-year risk prediction model, decreased with 15%. The risk reduction was seen in both men and women, and in participants with or without previous cardiovascular disease. CONCLUSION: Participating in a structured lifestyle program over a year was associated with significant improvement in multiple cardiovascular risk factors and decreased overall cardiovascular risk. TRIAL REGISTRATION: The study is registered at www.clinicaltrials.gov (ClinicalTrial.gov ID: NCT02744157 ). PMID- 29609556 TI - The Warburg effect in human pancreatic cancer cells triggers cachexia in athymic mice carrying the cancer cells. AB - BACKGROUND: Cancer cachexia is a cancer-induced metabolic disorder and a major cause of cancer-induced death. The constituents of cancer cachexia include an increase in energy expenditure, hepatic gluconeogenesis, fat lipolysis, and skeletal-muscle proteolysis and a decrease in body weight. The aetiology of cancer cachexia is unclear and may involve cancer-cell metabolism and secretion. In this study, we investigated whether the high glycolysis in cancer cells (the Warburg effect) triggers cachexia in athymic mice carrying pancreatic cancer cells. METHODS: First, we examined five human pancreatic cancer cell lines for glycolysis and cachectic-cytokine secretion. Consequently, MiaPaCa2 and AsPC1 cells were selected for the present study, because the glycolysis in MiaPaCa2 cells was typically high and that in AsPC1 cells was exceptionally low. In addition, both MiaPaCa2 and AsPC1 cells were competent in the secretion of examined cytokines. Next, we transplanted MiaPaCa2 and AsPC1 cells subcutaneously in different athymic mice for 8 weeks, using intact athymic mice for control. In another experiment, we treated normal mice with the supernatants of MiaPaCa2 or AsPC1 cells for 7 days, using vehicle-treated mice for control. In both models, we measured food intake and body weight, assayed plasma glucose, triglycerides, and TNF-alpha and used Western blot to determine the proteins that regulated hepatic gluconeogenesis, fat lipolysis, and skeletal-muscle proteolysis in the corresponding tissues. We also studied the effect of MiaPaCa2-cell supernatants on the proteolysis of C2C12 skeletal-muscle cells in vitro. RESULTS: The athymic mice carrying high-glycolytic MiaPaCa2 cells had anorexia and also showed evidence for cachexia, including increased hepatic gluconeogenesis, fat lipolysis and skeletal-muscle proteolysis and decreased body weight. The athymic mice carrying low-glycolytic AsPC1 cells had anorexia but did not show the above mentioned evidence for cachexia. When normal mice were treated with the supernatants of MiaPaCa2 or AsPC1 cells, their energy homeostasis was largely normal. Thus, the cachexia in the athymic mice carrying MiaPaCa2 cells may not result from humeral factors released by the cancer cells. In vitro, MiaPaCa2-cell supernatants did not induce proteolysis in C2C12 cells. CONCLUSION: The Warburg effect in pancreatic cancer cells is an independent aetiological factor for pancreatic cancer-induced cachexia. PMID- 29609557 TI - A study on volatile organic compounds emitted by in-vitro lung cancer cultured cells using gas sensor array and SPME-GCMS. AB - BACKGROUND: Volatile organic compounds (VOCs) emitted from exhaled breath from human bodies have been proven to be a useful source of information for early lung cancer diagnosis. To date, there are still arguable information on the production and origin of significant VOCs of cancer cells. Thus, this study aims to conduct in-vitro experiments involving related cell lines to verify the capability of VOCs in providing information of the cells. METHOD: The performances of e-nose technology with different statistical methods to determine the best classifier were conducted and discussed. The gas sensor study has been complemented using solid phase micro-extraction-gas chromatography mass spectrometry. For this purpose, the lung cancer cells (A549 and Calu-3) and control cell lines, breast cancer cell (MCF7) and non-cancerous lung cell (WI38VA13) were cultured in growth medium. RESULTS: This study successfully provided a list of possible volatile organic compounds that can be specific biomarkers for lung cancer, even at the 24th hour of cell growth. Also, the Linear Discriminant Analysis-based One versus All-Support Vector Machine classifier, is able to produce high performance in distinguishing lung cancer from breast cancer cells and normal lung cells. CONCLUSION: The findings in this work conclude that the specific VOC released from the cancer cells can act as the odour signature and potentially to be used as non-invasive screening of lung cancer using gas array sensor devices. PMID- 29609559 TI - Irinotecan-containing doublet treatment versus irinotecan monotherapy as second line choice for advanced gastric cancer. AB - BACKGROUND: For patients with advanced gastric cancer (AGC), second-line chemotherapy regimen remains controversial. The efficacy and safety of irinotecan containing doublet treatment and irinotecan monotherapy were compared in this systematic analysis. METHODS: A search was conducted on EMBASE and Medline databases. All articles compared irinotecan-containing doublet to irinotecan as second-line chemotherapy for AGC. STATA statistical software (Version 12.0) was used to analyze the data. RESULTS: Seven studies, including 905 cases, were included in the analysis. Irinotecan-containing doublet treatment significantly prolonged progression-free survival compared to irinotecan monotherapy (HR = 0.82, 95% CI: 0.70-0.95). However, doublet treatment neither significantly prolong overall survival compared to monotherapy (HR = 0.94, 95% CI: 0.81-1.10), nor did it significantly increase the overall response rates and disease control rates, when compared to monotherapy. In addition, the irinotecan-containing doublet group had an increase in incidences of >= Grade 3 neutropenia (RR = 1.23, 95% CI: 1.01-1.51) and anemia (RR = 2.00, 95% CI: 1.37-2.92). CONCLUSIONS: When compared to irinotecan monotherapy, irinotecan-containing doublet treatment increased progression free survival and was tolerable as a second- line chemotherapy for AGC. PMID- 29609558 TI - Epigenetics and early domestication: differences in hypothalamic DNA methylation between red junglefowl divergently selected for high or low fear of humans. AB - BACKGROUND: Domestication of animals leads to large phenotypic alterations within a short evolutionary time-period. Such alterations are caused by genomic variations, yet the prevalence of modified traits is higher than expected if they were caused only by classical genetics and mutations. Epigenetic mechanisms may also be important in driving domesticated phenotypes such as behavior traits. Gene expression can be modulated epigenetically by mechanisms such as DNA methylation, resulting in modifications that are not only variable and susceptible to environmental stimuli, but also sometimes transgenerationally stable. To study such mechanisms in early domestication, we used as model two selected lines of red junglefowl (ancestors of modern chickens) that were bred for either high or low fear of humans over five generations, and investigated differences in hypothalamic DNA methylation between the two populations. RESULTS: Twenty-two 1-kb windows were differentially methylated between the two selected lines at p < 0.05 after false discovery rate correction. The annotated functions of the genes within these windows indicated epigenetic regulation of metabolic and signaling pathways, which agrees with the changes in gene expression that were previously reported for the same tissue and animals. CONCLUSIONS: Our results show that selection for an important domestication-related behavioral trait such as tameness can cause divergent epigenetic patterns within only five generations, and that these changes could have an important role in chicken domestication. PMID- 29609561 TI - Knowledge and attitude of emergency physician about the emergency management of tooth avulsion. AB - BACKGROUND: The aim of the study was to evaluate the knowledge of ER physicians with different specialties, experience and hospital sectors for the management of avulsed teeth in the emergency rooms of eight major hospitals in Jeddah, Saudi Arabia. It also covers their attitude towards receiving further education on tooth avulsion management. METHODS: A cross-sectional survey was conducted at the emergency rooms of eight hospitals in Jeddah from August to December 2015. A self administered questionnaire consisting of 31 multiple choice questions assessing both knowledge and attitude was distributed to 150 physicians who were working in the ER departments. RESULTS: Response rate was 81.33%. Data revealed that 45.9% of the respondents did not have prior knowledge about avulsion. Physicians working in military hospitals had better knowledge about the ER management of avulsion cases than physicians of public hospitals. 80.3% of participants showed willingness to replant the tooth, however, 65.3% would not do it by themselves. 42.6% of the physicians did not know the importance of extra-oral time. Milk was selected as the best transport media for avulsed tooth by 31.1% of the participants. Regarding physicians' attitude, 95.1% showed interest in receiving information about the subject. CONCLUSION: This study revealed that the majority of ER physicians lack the knowledge needed to manage avulsions cases. Hence, educational programs are necessary for ER physicians to provide proper management for those cases. PMID- 29609560 TI - Differences in opinions of occupational physicians on the required competencies by field of practice: results of an international Delphi study. AB - BACKGROUND: The activities and work demands of medical professionals, including occupational physicians (OPs), fall into three categories: clinical, academic, and administrative. Work demands of an OP consist of these three categories and additional specialty specific roles and competencies. Research on the core competencies and skills required for OPs have identified high levels of consensus amongst OPs internationally, however these opinions have not been examined between areas of practice specific groups. Furthermore, it has been identified that to a large extent academics are often the group who define the skills required of OPs. The aim of this study is to compare the opinions of OPs grouped by field of practice on the common core competencies required for occupational health (OH) practice using results from an international survey. METHODS: An international modified Delphi study conducted among OPs, completed in two rounds (Rating-Round 1; Ranking-Round 2) using developed questionnaires based on the specialist training syllabus of a number of countries and expert discussions. Respondents were categorised as Physician, Manager/Physician, and Academic/Physician, based on self-reported job titles and place of work. RESULTS: There was good agreement between the Physician and Manager/Physician groups, with the Academic/Physician group deviating the most. The top three and bottom three principle domains (PDs) were in good agreement across all groups. The top three were clinically based and would be considered core OH activities. The PDs with considerable intergroup variance were Environmental Issues Related to Work Practice and Communication Skills, categories which may reflect direct relevance and relative importance to the job tasks of respective groups. CONCLUSION: This study demonstrated general agreement between the three occupational groups. Academic/Physician opinions deviate the most, while good agreement is depicted between the Physician and Manager/Physician groups. The findings of this study can help identify potential gaps in training requirements for OPs and be used as a stepping stone to developing training programmes that are reflective of practice and tailored for those predominantly undertaking these specific roles. PMID- 29609562 TI - Including gene networks to predict calving difficulty in Holstein, Brown Swiss and Jersey cattle. AB - BACKGROUND: Calving difficulty or dystocia has a great economic impact in the US dairy industry. Reported risk factors associated with calving difficulty are feto pelvic disproportion, gestation length and conformation. Different dairy cattle breeds have different incidence of calving difficulty, with Holstein having the highest dystocia rates and Jersey the lowest. Genomic selection becomes important especially for complex traits with low heritability, where the accuracy of conventional selection is lower. However, for complex traits where a large number of genes influence the phenotype, genome-wide association studies showed limitations. Biological networks could overcome some of these limitations and better capture the genetic architecture of complex traits. In this paper, we characterize Holstein, Brown Swiss and Jersey breed-specific dystocia networks and employ them in genomic predictions. RESULTS: Marker association analysis identified single nucleotide polymorphisms explaining the largest average proportion of genetic variance on BTA18 in Holstein, BTA25 in Brown Swiss, and BTA15 in Jersey. Gene networks derived from the genome-wide association included 1272 genes in Holstein, 1454 genes in Brown Swiss, and 1455 genes in Jersey. Furthermore, 256 genes in Holstein network, 275 genes in the Brown Swiss network, and 253 genes in the Jersey network were within previously reported dystocia quantitative trait loci. The across-breed network included 80 genes, with 9 genes being within previously reported dystocia quantitative trait loci. The gene-gene interactions in this network differed in the different breeds. Gene ontology enrichment analysis of genes in the networks showed Regulation of ARF GTPase was very significant (FDR <= 0.0098) on Holstein. Neuron morphogenesis and differentiation was the term most enriched (FDR <= 0.0539) on the across-breed network. Genomic prediction models enriched with network-derived relationship matrices did not outperform regular GBLUP models. CONCLUSIONS: Regions identified in the genome were in the proximity of previously described quantitative trait loci that would most likely affect calving difficulty by altering the feto-pelvic proportion. Inclusion of identified networks did not increase prediction accuracy. The approach used in this paper could be extended to any instance with asymmetric distribution of phenotypes, for example, resistance to disease data. PMID- 29609563 TI - The association between circulating adiponectin levels, lung function and adiposity in subjects from the general population; data from the Akershus Sleep Apnea Project. AB - BACKGROUND: Circulating adiponectin (ADPN) levels are inversely associated with disease severity in patients with chronic obstructive pulmonary disease (COPD), while studies assessing the relationship between ADPN and lung function in subjects from the general population have shown diverging results. Accordingly, we hypothesized that ADPN would be associated with lung function in a population based sample and tested how abdominal adiposity, metabolic syndrome, and systemic inflammation influenced this association. METHODS: We measured total ADPN in serum, forced vital capacity (FVC) and forced expiratory volume during the 1st second (FEV1) in 529 participants (median 50 years, 54.6% males) recruited from the general population. We assessed the association between ADPN and lung function by multivariate linear regression analyses and adjusted for age, gender, height, smoking habits, weight, body mass index, waist-hip ratio, metabolic syndrome, obstructive sleep apnoea (OSA) and C-reactive protein. RESULTS: The median (interquartile range) level of serum ADPN was 7.6 (5.4-10.4) mg/L. ADPN levels were positively associated with FVC % of predicted (beta 3.4 per SD adiponectin, p < 0.001)) in univariate linear regression analysis, but the association was attenuated in multivariate analysis (standardized beta 0.03, p = 0.573)). Among co-variates only WHR significantly attenuated the relationship. ADPN levels were also associated with FEV1% of predicted in bivariate analysis that adjusted for smoking (beta 1.4, p = 0.042)), but this association was attenuated and no longer significant in multivariate analysis (standardized beta 0.06, p = 0.254)). CONCLUSION: In this population-based sample no association between ADPN and lung function was evident after adjustment for covariates related to adiposity. PMID- 29609565 TI - The clinical relevance of the presence of bridging syndesmophytes on kyphosis correction and maintenance following pedicle subtraction osteotomy for thoracolumbar kyphotic deformity in ankylosing spondylitis: a comparative cohort study. AB - BACKGROUND: The presence of bridging syndesmophytes (BS) in spinal osteotomy region serves traditionally as one critical determinant for selection of osteotomy techniques. While nowadays the proportion of kyphotic ankylosing spondylitis (AS) patients receiving pedicle subtraction osteotomy (PSO) with yet mobile neighboring disc has seen a substantial increase. Literatures investigating the clinical relevance of the presence of BS on kyphosis correction and maintenance following PSO are scarce. METHODS: A total of 71 thoracolumbar kyphotic AS patients treated with single-level PSO at our hospital between September 2010 and August 2014 were retrospectively reviewed, 32 of whom were stratified into the BS group (BG). The operative corrections of multiple spino pelvic sagittal parameters were assessed. Comparison of the contribution of adjacent disc wedging to total correction per PSO segment was made between the BS and non-BS groups (NBG). The correction loss were also evaluated and compared with a minimum 2-year follow-up. RESULTS: A significantly younger age (30.97 +/- 8.28 vs. 40.31 +/- 8.44 yrs., p < 0.001), smaller pelvic incidence (PI) (43.03 +/ 10.60 vs. 49.36 +/- 9.75 degrees , p = 0.011), greater wedging index of osteotomized vertebra (1.17 +/- 0.16 vs. 1.09 +/- 0.08, p = 0.011) and larger local kyphosis (19.59 +/- 10.84 vs. 13.56 +/- 8.50 degrees , p = 0.013) was observed in NBG preoperatively. Patients in BG and NBG accomplished comparable amount of kyphosis correction per PSO segment (40.22 +/- 7.09 vs. 43.85 +/- 8.71 degrees , p = 0.062). However, the contribution of adjacent disc wedging to total correction per PSO was significantly larger in NBG [8.10 +/- 6.19 (18.5%) vs. 1.09 +/- 2.88 degrees (2.7%), p < 0.001]. By ultimate follow-up, the global kyphosis (18.26 +/- 10.97 vs. 21.51 +/- 10.89 degrees , p < 0.05) and thoracic kyphosis (37.95 +/- 11.87 vs. 42.87 +/- 11.56 degrees , p < 0.05) deteriorated significantly in the NBG but not BG, so was further pelvic retroversion as represented by increased pelvic tilt (19.46 +/- 8.13 vs. 23.44 +/- 8.19 degrees , p < 0.05) and decreased sacral slope (23.02 +/- 9.12 vs. 18.62 +/- 10.10 degrees , p < 0.05). Loss of corrections concerning contribution of adjacent disc wedging was also larger in NBG (1.41 +/- 3.27 vs. 0.22 +/- 1.49 degrees , p < 0.05). CONCLUSIONS: Our study might suggest that the evaluation and treatment methods of kyphotic AS patients needed to be fine-tuned with appropriate subgrouping by the presence of syndesmophytes with bamboo sign as they were potentially distinct groups with different PI, contributor of lordosing capability and prognosis that might require separate analysis. PMID- 29609564 TI - Apical periodontitis: preliminary assessment of microbiota by 16S rRNA high throughput amplicon target sequencing. AB - BACKGROUND: Apical periodontitis includes periapical granulomas and radicular cysts, which are histologically distinguished by the absence and the presence of an epithelial lining, respectively. The main cause of apical periodontitis is the bacterial colonization of the root canal space. This research aimed at assessing whether and how periapical granulomas and radicular cysts differ in terms of microbiota using high throughput amplicon target sequencing (HTS) techniques. METHODS: This study included 5 cases of Periapical Granulomas (PGs) and 5 cases of Radicular Cysts (RCs) selected on the base of histology out of 37 patients from January 2015 to February 2016. Complete medical history, panoramic radiograms (OPTs) and histologic records of each patient were assessed. Only lesions greater than 1 cm in diameter and developed in proximity to teeth with bad prognosis were included. The microbiota present in periapical granulomas and radicular cysts thus retrieved was finely characterized by pyrosequencing of the 16S rRNA genes. RESULTS: The core of OTUs shared between periapical granulomas and radicular cysts was dominated by the presence of facultative anaerobes taxa such as: Lactococcus lactis, Propionibacterium acnes, Staphylococcus warneri, Acinetobacter johnsonii and Gemellales. L. lactis, the main OTUs of the entire datasets, was associated with periapical granuloma samples. Consistently with literature, the anaerobic taxa detected were most abundant in radicular cyst samples. Indeed, a higher abundance of presumptive predicted metabolic pathways related to Lipopolysaccharide biosynthesis was found in radicular cyst samples. CONCLUSIONS: The present pilot study confirmed the different microbial characterization of the two main apical periodontitis types and shade light on the possible role of L. lactis in periapical granulomas. PMID- 29609566 TI - Pulsatile dry cupping in chronic low back pain - a randomized three-armed controlled clinical trial. AB - BACKGROUND: We aimed to investigate the effectiveness of two different forms of dry pulsatile cupping in patients with chronic low back pain (cLBP) compared to medication on demand only in a three-armed randomized trial. METHODS: 110 cLBP patients were randomized to regular pulsatile cupping with 8 treatments plus paracetamol on demand (n = 37), minimal cupping with 8 treatments plus paracetamol on demand (n = 36) or the control group with paracetamol on demand only (n = 37). Primary outcome was the pain intensity on a visual analogue scale (VAS, 0-100 mm) after 4 weeks, secondary outcome parameter included VAS pain intensity after 12 weeks, back function as measured with the 'Funktionsfragebogen Hannover Rucken' (FFbH-R) and health related quality of life questionnaire Short form 36 (SF-36) after 4 and 12 weeks. RESULTS: The mean baseline-adjusted VAS after 4 weeks was 34.9 mm (95% CI: 28.7; 41.2) for pulsatile cupping, 40.4 (34.2; 46.7) for minimal cupping and 56.1 (49.8; 62.4) for control group, resulting in statistically significant differences between pulsatile cupping vs. control (21.2 (12.2; 30.1); p < 0.001) and minimal cupping vs. control (15.7 (6.9; 24.4); p = 0.001). After 12 weeks, mean adjusted VAS difference between pulsatile cupping vs. control was 15.1 ((3.1; 27.1); p = 0.014), and between minimal cupping vs. control 11.5 ((- 0.44; 23.4); p = 0.059). Differences of VAS between pulsatile cupping and minimal cupping showed no significant differences after 4 or 12 weeks. Pulsatile cupping was also better (- 5.8 (- 11.5;-0.1); p = 0.045) compared to control for back function after 4 weeks, but not after 12 weeks (- 5.4 (- 11.7;0.8); p = 0.088), pulsatile cupping also showed better improvements on SF-36 physical component scale compared to control at 4 and 12 weeks (- 5.6 (- 9.3;-2.0); p = 0.003; - 6.1 (- 9.9;-2.4); p = 0.002). For back function and quality of life minimal cupping group was not statistically different to control after 4 and 12 weeks. Paracetamol intake did not differ between the groups (cupping vs. control (7.3 (- 0.4;15.0); p = 0.063); minimal cupping vs. control (6.3 (- 2.0;14.5); p = 0.133). CONCLUSIONS: Both forms of cupping were effective in cLBP without showing significant differences in direct comparison after four weeks, only pulsatile cupping showed effects compared to control after 12 weeks. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov (identifier: NCT02090686 ). PMID- 29609567 TI - Community influences on modern contraceptive use among young women in low and middle-income countries: a cross-sectional multi-country analysis. AB - BACKGROUND: Despite investment in family planning programs and education, unmet need for family planning remains high among young women (aged 15-24) in low and middle-income countries, increasing the risk for unwanted pregnancies and adverse social and reproductive health outcomes. There is a dearth of cross-national research that identifies the differential impact of community level factors among youth in low and middle-income countries (LMICs), which is imperative for the design of structural level interventions aimed at increasing family planning use. METHODS: Grounded in the socio-ecological framework, this paper utilizes Demographic and Health Survey (DHS) from 52 LMICs to examine the influence of community level reproductive, gender, fertility, literacy and economic indicators on modern contraceptive use among female youth. Analyses are conducted using multi-level logistic regressions with random community-level effects. RESULTS: Our findings highlight the positive influence of community level education attainment and negative influence of gender and fertility related norms on young women's contraceptive use. Additionally, increased exposure to mass media did not positively influence young women's uptake of modern contraceptive methods. CONCLUSIONS: Taken together, findings indicate that young women's contraceptive decision-making is greatly shaped by their social contexts. The commonalities and regional variations in community level influences provide support for both structural level interventions and tailored regional approaches to family planning interventions. PMID- 29609568 TI - A cluster randomized controlled trial to assess the impact on intimate partner violence of a 10-session participatory gender training curriculum delivered to women taking part in a group-based microfinance loan scheme in Tanzania (MAISHA CRT01): study protocol. AB - BACKGROUND: Worldwide, almost one third (30%) of women who have been in a relationship have experienced physical and/or sexual violence from an intimate partner. Given the considerable negative impacts of intimate partner violence (IPV) on women's physical health and well-being, there is an urgent need for rigorous evidence on violence prevention interventions. METHODS: The study, comprising a cluster randomized controlled trial (RCT) and in-depth qualitative study, will assess the impact on women's past year experience of physical and/or sexual IPV of a participatory gender training curriculum (MAISHA curriculum) delivered to women participating in group-based microfinance in Tanzania. More broadly, the study aims to learn more about the factors that contribute to women's vulnerability to violence and understand how the intervention impacts on the lives of women and their families. Sixty-six eligible microfinance loan groups are enrolled and randomly allocated to: the 10-session MAISHA curriculum, delivered over 20 weeks (n = 33); or, to no intervention (n = 33). Study participants are interviewed at baseline and at 24 months post-intervention about their: household; partner; income; health; attitudes and social norms; relationship (including experiences of different forms of violence); childhood; and community. For the qualitative study and process evaluation, focus group discussions are being conducted with study participants and MAISHA curriculum facilitators. In-depth interviews are being conducted with a purposive sample of 18 participants. The primary outcome, assessed at 24 months post-intervention, is a composite of women's reported experience of physical and/or sexual IPV during the past 12 months. Secondary outcomes include: reported experience of physical, sexual and emotional/psychological IPV during the past 12 months, attitudes towards IPV and reported disclosure of IPV to others. DISCUSSION: The study forms part of a wider programme of research (MAISHA) that includes: a complementary cluster RCT evaluating the impact of delivering the MAISHA curriculum to women not receiving formal group-based microfinance; an economic evaluation; and a cross-sectional survey of men to explore male risk factors associated with IPV. MAISHA will generate rigorous evidence on violence prevention interventions, as well as further insights into the different forms and consequences of violence and drivers of violence perpetration. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02592252 , registered retrospectively on 13 August 2015. PMID- 29609569 TI - The alterations of cytokeratin and vimentin protein expressions in primary esophageal spindle cell carcinoma. AB - BACKGROUND: The accumulated evidence has indicated the diagnostic role of cytokeratin (CK) and vimentin protein immunoassay in primary esophageal spindle cell carcinoma (PESC), which is a rare malignant tumor with epithelial and spindle components. However, it is largely unknown for the expression of CK and vimentin in pathological changes and prognosis of PESC. METHODS: Eighty-two PESC patients were identified from the esophageal and gastric cardia cancer database established by Henan Key Laboratory for Esophageal Cancer Research of Zhengzhou University. We retrospectively evaluated CK and vimentin protein expressions in PESC. Clinicopathological features were examined by means of univariate and multivariate survival analyses. Furthermore, the co-expression value of cytokeratin and vimentin was analyzed by receiver operating characteristic (ROC) curve. RESULTS: The positive pan-cytokeratins AE1/AE3 (AE1/AE3 for short) staining was chiefly observed in cytoplasm of epithelial component tumor cells, with a positive detection rate of 85.4% (70/82). Interestingly, 19 cases showed AE1/AE3 positive staining both in epithelial and spindle components (23.2%). However, AE1/AE3 expression was not observed with any significant association with age, gender, tumor location, gross appearance, lymph node metastasis and TNM stage. Furthermore, AE1/AE3 protein expression does not show any effect on survival. Similar results were observed for vimentin immunoassay. However, in comparison with a single protein, the predictive power of AE1/AE3 and vimentin proteins signature was increased apparently than with single signature [0.75 (95% CI = 0.68-0.82) with single protein v.s. 0.89 (95% CI = 0.85-0.94) with AE1/AE3 and vimentin proteins]. The 1-, 3-, 5- and 7-year survival rates for PESC patients in this study were 79.3%, 46.3%, 28.0% and 15.9%, respectively. Multivariate analysis demonstrated age and TNM stage were independent prognostic factors for overall survival (P = 0.036 and 0.003, respectively). It is noteworthy that only 17.1% patients had a PESC accurate diagnosis by biopsy pathology before surgery (14/82). 72.4% PESC patients with biopsy pathology before surgery had been diagnosed as squamous cell carcinoma. CONCLUSION: The present study demonstrates that cytokeratin and vimentin protein immunoassay is a useful biomarker for PESC accurate diagnosis, but not prognosis. The co expression of cytokeratin and vimentin in both epithelial and spindle components suggest the possibility of single clone origination for PESC. PMID- 29609570 TI - A school-based intervention program in promoting leisure-time physical activity: trial protocol. AB - BACKGROUND: Regular participation in moderate-to-vigorous physical activity (MVPA) is important to manage obesity. Physical education (PE) is considered to play an important role in promoting lifelong participation in physical activity (PA) because it provides an existing network where cost-effective interventions can be implemented to produce sustainable change in health behavior. However, the association between compulsory school PA (e.g., PE lessons) and body composition levels has received mixed support in the literature. Therefore, the present study aimed to investigate whether a school-based intervention targeting salient PA benefits and barriers grounded on the theory of planned behavior would promote young people's participation in MVPA during leisure time and reduce body mass index (BMI) of overweight students. METHODS/DESIGN: A total of 171 students from 3 secondary schools in Singapore underwent the control condition followed by the intervention condition. Both the conditions consisted of PE lessons twice per week over 4 weeks. In the control condition, PE teachers encouraged students to participate in PA during leisure time without providing persuasive message. While in the intervention condition, PE teachers delivered persuasive messages that targeted the salient benefits and barriers associated with PA to the students at the last 5 to 10 min of each PE lesson. PA levels over a week were measured objectively with wrist-mounted GENEActiv Original accelerometers and subjectively with self-reporting questionnaires three times (Baseline, Post 1, and Post 2) in each condition. Student's self-reported PA level was measured using the Leisure Time Physical Activity Participation Questionnaire and the International Physical Activity Questionnaire, and their attitudes, intentions, subjective norms and perceived behavior control towards leisure-time PA were measured with a questionnaire based on the theory of planned behavior. Furthermore, students' intention, determination and willingness to engage in leisure-time PA were compared with the other activity (e.g., doing homework, shopping). DISCUSSION: This study will provide the evidence on the effectiveness of a cost-effective school-based intervention on reducing BMI of overweight students through promoting sustained participation in leisure-time PA. It will also address methodological issues on the gaps between objective and subjective measures of PA. TRIAL REGISTRATION: This trial is registered with the ISRCTN registry (ISRCTN73786157, 26/10/2017, retrospectively registered). PMID- 29609571 TI - Under-estimation of maternal and perinatal mortality revealed by an enhanced surveillance system: enumerating all births and deaths in Pakistan. AB - BACKGROUND: Reliable and timely data on maternal and neonatal mortality is required to implement health interventions, monitor progress, and evaluate health programs at national and sub-national levels. In most South Asian countries, including Pakistan, vital civil registration and health information systems are inadequate. The aim of this study is to determine accurate maternal and perinatal mortality through enhanced surveillance of births and deaths, compared with prior routinely collected data. METHODS: An enhanced surveillance system was established that measured maternal, perinatal and neonatal mortality rates through more complete enumeration of births and deaths in a rural district of Pakistan. Data were collected over a period of 1 year (2015/16) from augmentation of the existing health information system covering public healthcare facilities (n = 19), and the community through 273 existing Lady Health Workers; and with the addition of private healthcare facilities (n = 10), and 73 additional Community Health Workers to cover a total study population of 368,454 consisting of 51,690 eligible women aged 18 to 49 years with 7580 pregnancies and 7273 live births over 1 year. Maternal, neonatal, perinatal and stillbirth rates and ratios were calculated, with comparisons to routine reporting from the previous period (2014-15). RESULTS: Higher maternal mortality, perinatal mortality and neonatal mortality rates were observed through enhanced surveillance compared to mortality rates in the previous 1.5 years from the routine monitoring system from increased completeness and coverage. Maternal mortality was 247 compared to 180 per 100, 000 live births (p = 0.36), neonatal mortality 40 compared to 20 per 1, 000 live births (p < 0.001), and perinatal mortality 60 compared to 47 per 1000 live births (p < 0.001). All the mortality rates were higher than provincial and national estimates proffered by international agencies based on successive Pakistan Demographic and Health Surveys and projections. CONCLUSION: Extension of coverage and improvement in completeness through reconciliation of data from health information systems is possible and required to obtain accurate maternal, perinatal and neonatal mortality for assessment of health service interventions at a local level. PMID- 29609572 TI - Clinical and radiographic evaluation of biodentine versus calcium hydroxide in primary teeth pulpotomies: a retrospective study. AB - BACKGROUND: Pulpotomy is the surgical removal of the entire coronal pulp with preservation of the radicular pulp vitality. The purpose of this retrospective study was to evaluate the clinical and radiographic success of pulpotomy of primary molars using two materials, biodentine and calcium hydroxide. METHODS: Records of 400 primary molars in 360 paediatric participants (mean age: 7.5 +/- 1.6 years, ranging from 5 to 9 years) with dental caries who required pulp therapy were included in this study. Biodentine was used on 200 teeth, and calcium hydroxide (CH) was used on another 200 teeth, as a pulpotomy material. Clinical and radiographic evaluation was performed after 9 and 18 months. Statistical analysis was evaluated with the chi-squared test, and the level of significance was set at p < 0.05. RESULTS: The treatment success with CH was 85.5% after 9 months and 79.5% after 18 months, while the success rate of biodentine was 94% after 9 months and 89.5% after 18 months. The statistical analysis with the Chi-squared test showed that the clinical and radiographic success rate with biodentine was significantly higher than CH (p < 0.05). CONCLUSIONS: Biodentine exhibited a higher clinical and radiographic success rate compared to CH. However, besides the clinical results, biodentine has some disadvantages, such as higher costs, compared to CH. PMID- 29609573 TI - Adequacy of public health communications on H7N9 and MERS in Singapore: insights from a community based cross-sectional study. AB - BACKGROUND: Singapore remains vulnerable to worldwide epidemics due to high air traffic with other countries This study aims to measure the public's awareness of the Middle East Respiratory Syndrome (MERS) and Avian Influenza A (H7N9), identify population groups who are uninformed or misinformed about the diseases, understand their choice of outbreak information source, and assess the effectiveness of communication channels in Singapore. METHODS: A cross-sectional study, comprising of face-to-face interviews, was conducted between June and December 2013 to assess the public's awareness and knowledge of MERS and H7N9, including their choice of information source. Respondents were randomly selected and recruited from 3 existing cohort studies. An opportunistic sampling approach was also used to recruit new participants or members in the same household through referrals from existing participants. RESULTS: Out of 2969 participants, 53.2% and 79.4% were not aware of H7N9 and MERS respectively. Participants who were older and better educated were most likely to hear about the diseases. The mean total knowledge score was 9.2 (S.D +/- 2.3) out of 20, and 5.9 (S.D +/- 1.2) out of 10 for H7N9 and MERS respectively. Participants who were Chinese, more educated and older had better knowledge of the diseases. Television and radio were the primary sources of outbreak information regardless of socio-demographic factors. CONCLUSION: Heightening education of infectious outbreaks through appropriate media to the young and less educated could increase awareness. PMID- 29609574 TI - Utility of serum IGF-1 for diagnosis of growth hormone deficiency following traumatic brain injury and sport-related concussion. AB - BACKGROUND: Growth hormone deficiency (GHD) is a potential consequence of traumatic brain injury (TBI), including sport-related concussion (SRC). GH stimulation testing is required for definitive diagnosis; however, this is resource intensive and can be associated with adverse symptoms or risks. Measurement of serum IGF-1 is more practical and accessible, and pituitary tumour patients with hypopituitarism and low serum IGF-1 have been shown to have a high probability of GHD. We aimed to evaluate IGF-1 measurement for diagnosing GHD in our local TBI population. METHODS: We conducted a retrospective chart review of patients evaluated for GHD at the TBI clinic and referred for GH stimulation testing with insulin tolerance test (ITT) or glucagon stimulation test (GST) since December 2013. We obtained demographics, TBI severity, IGF-1, data pertaining to pituitary function, and GH stimulation results. IGF-1 values were used to calculate z-scores per age and gender specific reference ranges. Receiver operator curve analysis was performed to evaluate diagnostic threshold of IGF-1 z score for determining GHD by GST or ITT. RESULTS: Sixty four patient charts were reviewed. 48 patients had mild, six had moderate, eight had severe TBI, and two had non-traumatic brain injuries. 47 patients underwent ITT or GST. 27 were confirmed to have GHD (peak hGH < 5 MUg/L). IGF-1 level was within the age and gender specific reference range for all patients with confirmed GHD following GH stimulation testing. Only one patient had a baseline IGF-1 level below the age and gender specific reference range; this patient had a normal response to GH stimulation testing. ROC analysis showed IGF-1 z-score AUC f, confirming lack of diagnostic utility. CONCLUSION: Baseline IGF-1 is not a useful predictor of GHD in our local TBI population, and therefore has no value as a screening tool. TBI patients undergoing pituitary evaluation will require a dynamic test of GH reserve. PMID- 29609575 TI - Influence of iRoot SP and mineral trioxide aggregate on the activation and polarization of macrophages induced by lipopolysaccharide. AB - BACKGROUND: Biomaterials could affect the inflammation reaction and wound healing via the activation and polarization of macrophages. However, the influence of iRoot SP and mineral trioxide aggregate (MTA) on macrophage polarization under inflammatory conditions was not reported although these two root filling materials have been applied extensively in patients undergoing endodontic treatment. Therefore, the present study aimed to explore the mechanism how iRoot SP and MTA affect the cell behavior of RAW 264.7 macrophages when stimulated by lipopolysaccharide (LPS) in vitro. METHODS: The gene expression of three main related pro-inflammatory cytokines (IL-1beta, TNF-alpha, IL-6) was examined by quantitative real-time polymerase chain reaction (qRT-PCR) in RAW 264.7 macrophages when stimulated by iRoot SP and MTA in the presence of LPS. The protein expression of the M1 and M2 phenotype specific markers, CD11c and CD206, was assessed by immunofluorescence and flow cytometry in RAW 264.7 macrophages. RESULTS: LPS promoted the expression of IL-1beta, TNF-alpha, and IL-6 in RAW 264.7 macrophages as compared to the control group. Both iRoot SP and MTA were significantly able to enhance the expression of IL-1beta, TNF-alpha, and IL-6 in RAW 264.7 macrophages as compared to LPS group. LPS could increase the expression of CD11c as compared to the control group while iRoot SP and MTA were able to enhance the expression of both CD11c and CD206 as compared to LPS group. CONCLUSIONS: iRoot SP and MTA could potentially promote the release of pro inflammatory cytokines in RAW 264.7 macrophages and induce into M1/M2 phenotype when cultured with LPS. PMID- 29609576 TI - Photovoice and empowerment: evaluating the transformative potential of a participatory action research project. AB - BACKGROUND: Photovoice is a visual research methodology with the intention to foster social change. Photovoice has been used to investigate change in empowerment in vulnerable communities, However, the individual experience of participants involved in Photovoice projects is seldom scrutinized. Our aim was to explore and describe the individual experiences of the female individuals who participated in a previous Photovoice project. We analyzed a change in the women's empowerment in terms of: 1) gain in knowledge and skills, 2) change in self-perception, and 3) access to and use of resources. METHODS: This qualitative study took place in the low-income District of Villaverde (Madrid, Spain), from January-June 2016. We conducted 10 semi-structured interviews with the female residents who had participated in the previous Photovoice project. We also collected field notes. We analyzed these data through a direct qualitative content analysis. The three outlined dimensions of empowerment provided guidance for the analysis of the results. RESULTS: We found positive changes in the three dimensions of empowerment: 1) participants acquired new knowledge and developed critical awareness of their community; 2) the social recognition participants received transformed their self-perception; and 3) the project allowed them to expand their social networks and to build new links with different actors (research partners, local decision makers, media and the wider public). CONCLUSIONS: Photovoice projects entail the opportunity for empowering participants. Future research using Photovoice should assess the influence it has on participants' empowerment changes and how to sustain these individual and social changes. PMID- 29609577 TI - Handgrip force steadiness in young and older adults: a reproducibility study. AB - BACKGROUND: Force steadiness is a quantitative measure of the ability to control muscle tonus. It is an independent predictor of functional performance and has shown to correlate well with different degrees of motor impairment following stroke. Despite being clinically relevant, few studies have assessed the validity of measuring force steadiness. The aim of this study was to explore the reproducibility of handgrip force steadiness, and to assess age difference in steadiness. METHOD: Intrarater reproducibility (the degree to which a rating gives consistent result on separate occasions) was investigated in a test-retest design with seven days between sessions. Ten young and thirty older adults were recruited and handgrip steadiness was tested at 5%, 10% and 25% of maximum voluntary contraction (MVC) using Nintendo Wii Balance Board (WBB). Coefficients of variation were calculated from the mean force produced (CVM) and the target force (CVT). Area between the force curve and the target force line (Area) was also calculated. For the older adults we explored reliability using intraclass correlation coefficient (ICC) and agreement using standard error of measurement (SEM), limits of agreement (LOA) and smallest real difference (SRD). RESULTS: A systematic improvement in handgrip steadiness was found between sessions for all measures (CVM, CVT, Area). CVM and CVT at 5% of MVC showed good to high reliability, while Area had poor reliability for all percentages of MVC. Averaged ICC for CVM, CVT and Area was 0.815, 0.806 and 0.464, respectively. Averaged ICC on 5%, 10%, and 25% of MVC was 0.751, 0.667 and 0.668, respectively. Measures of agreement showed similar trends with better results for CVM and CVT than for Area. Young adults had better handgrip steadiness than older adults across all measures. CONCLUSION: The CVM and CVT measures demonstrated good reproducibility at lower percentages of MVC using the WBB, and could become relevant measures in the clinical setting. The Area measure had poor reproducibility. Young adults have better handgrip steadiness than old adults. PMID- 29609578 TI - The identification of H3F3A mutation in giant cell tumour of the clivus and the histological diagnostic algorithm of other clival lesions permit the differential diagnosis in this location. AB - BACKGROUND: Giant Cell Tumour of Bone (GCT) is a locally aggressive primary bone tumour that usually occurs at the epiphyses of the long bones of the appendicular skeleton with a tendency to recurrence. Recurrent somatic H3F3A mutations have been described in 92% of GCT cases. GCTs involving the Clivus are extremely rare lesions and less than 15 cases are described in the literature. They represent a surgery challenge and are easily misdiagnosed. Our aim was to reveal if the genetic bases underlying Clival GCTs were the same of GCTs of long bones to improve the diagnosis and treatment. METHODS: The targeted somatic sequencing of GCT-related genes (H3F3A, H3F3B, IDH1, IDH2 and ZNF687) was performed on Clival GCT biopsies of two different cases. Histological analyses on the same tissues were used to detect the neoplastic population and its expression profile. RESULTS: Sanger sequencing revealed that both patients were positive for the p.Gly34Trp mutation in the H3F3A gene. Immunofluorescence assay using monoclonal antibody, specifically detecting the mutant H3.3, highlighted that the mutation only involved the mononuclear cell population and not the multinucleated giant cells. Moreover, immunohistochemistry assay showed that RANKL was highly expressed by the stromal cells within Clival GCT, mimicking what happens in GCT of the long bones. In addition, systematic literature review allowed us to generate a histology-based diagnostic algorithm of the most common clival lesions. CONCLUSIONS: We conclude that the Clival GCT is genetically defined by somatic mutation in the H3F3A gene, linking it to the GCT of long bones. The similarity with GCTs of long bones let us to hypothesize the utility of Denosumab therapy (already effective for GCTs) in these surgically challenging cases. Moreover, H3F3A genetic screening can be combined to the histological analysis to differentiate GCTs from morphologically similar giant cell-rich sarcomas, while the histological diagnostic algorithm could help the differential diagnosis of other clival lesions. PMID- 29609579 TI - Euterpe oleracea extract inhibits tumorigenesis effect of the chemical carcinogen DMBA in breast experimental cancer. AB - BACKGROUND: Among the processes involved in the breast tumor microenvironment, angiogenesis and inflammation play a central role, and the main factors of these processes are the vascular endothelial growth factor (VEGF), cyclooxygenase 2 (COX-2) and macrophages. Recently, the extract of Euterpe oleracea (acai), a fruit that is widely found in the Amazon region, already showed antitumorigenic effects in vitro in human breast cancer cell lines. The present study aimed to investigate the effect of acai on breast cancer using a chemically DMBA (7,12 dimethylbenzanthracene) experimental model. METHODS: One day after initiation of treatment with acai, mammary carcinogenesis was induced in female Wistar rats using a subcutaneous injection of 25 mg/kg of DMBA in the mammary gland. Forty rats were randomized into two groups: treated with 200 mg/kg of either acai extract or vehicle, via gastric tube for 16 consecutive weeks. After treatment, the tumor was collected for macroscopic, histological and immunohistochemical (VEGF, vascular endothelial growth factor receptor 2 -VEGFR-2, COX-2 and matrix metalloproteinase -MMP-9) analyses; peritoneal fluid was subjected to flow cytometry (F4-80/MAC-2+) and ELISA immunoassay (VEGF, prostaglandin E2 -PGE2 and interleukin-10 -IL-10). Heart, liver and kidney samples were collected for histological analysis. RESULTS: After 16 weeks of induction, the mammary carcinoma was confirmed by macroscopic and histological evaluation. Survival analysis indicates that acai increased the survival (P = .0002, long-rank test) and reduced the deaths number (P = .0036, Chi-square test). Acai treatment decreased the number of inflammatory cells and macrophage positive cells (Mac-2 + F4-80+), as well as promoting a reduction in immunostaining of VEGF, VEGFR-2 and COX-2. The acai group also exhibited lower concentrations of PGE2, VEGF and IL-10 compared to the control. The histopathological results of the liver and kidneys showed protective effect of acai, since in the control group, there was an increase in fibrosis, atypical cells and hemorrhagic microenvironment. CONCLUSION: The results of this study demonstrated the antiangiogenic and anti inflammatory potential of acai, like due to the decreases of the number of activated macrophages, resulting in the inhibition of DMBA carcinogenicity in breast cancer. PMID- 29609580 TI - Prevalence of and factors associated with utilization of herbal medicines among outpatients in primary health centers in Cambodia. AB - BACKGROUND: Traditional, complementary and alternative medicine (TCAM) is seen as a way to provide healthcare in both developed and developing countries across the world. In Cambodia, there is a long tradition of using TCAM. However, scant studies have been conducted on the extent of Cambodian TCAM use and how it interacts with allopathic health care to date. In this study, we examined the prevalence of and factors associated with utilization of herbal medicines among patients with chronic diseases in primary health care settings in Cambodia. METHODS: A cross-sectional survey was conducted in 2015 with outpatients receiving treatment and care for chronic diseases in two urban and two rural primary health centers purposively selected from Phnom Penh, Kampong Cham and Siem Reap. Every eligible patient was randomly selected at the health centers using a systematic sampling procedure. I-CAM-Q was used to measure TCAM use. A multivariate logistic regression model was constructed to identify factors associated with herbal medicine use. RESULTS: In total, 1602 patients were included in this study, of whom 77.7% were female, and 51.2% were recruited from urban primary health centers with a mean age of 46.5 years (SD = 15.2). Of total, 27.0% reported at least one consultation with a TCAM provider in the past 12 months. The most common modality of TCAM used was herbal medicine (89%). Herbs were obtained at drug or folk stores (36.9%), from herbalists directly (28.5%) or from their own gardens (18.6%). Of herb users, 55.2% reported that herbs were somewhat helpful. After adjustment, herb users were significantly more likely to be female (AOR = 1.42, 95% CI = 1.12-2.67), have completed less schooling (AOR = 0.66, 95% CI = 0.45-0.96), were unemployed or homemakers (AOR = 0.23, 95% CI = 0.13-0.52) and have a gastrointestinal illness (AOR = 0.49, 95% CI = 0.39-0.62). CONCLUSIONS: Herbal medicines are broadly used among chronic disease patients in Cambodia. Understanding TCAM use in the general population will support health care practitioners and policy makers to make informed decisions about the use of TCAM. Integration of TCAM into the primary health system should be further explored. PMID- 29609581 TI - Mild (not severe) disc degeneration is implicated in the progression of bilateral L5 spondylolysis to spondylolisthesis. AB - BACKGROUND: Spondylolytic (or lytic) spondylolisthesis is often associated with disc degeneration at the index-level; however, it is not clear if disc degeneration is the cause or the consequence of lytic spondylolisthesis. The main objective of this computed tomography based finite element modelling study was to examine the role of different grades of disc degeneration in the progression of a bilateral L5-lytic defect to spondylolisthesis. METHODS: High-resolution computed tomography data of the lumbosacral spine from an anonymised healthy male subject (26 years old) were segmented to build a 3D-computational model of an INTACT L1 S1 spine. The INTACT model was manipulated to generate four more models representing a bilateral L5-lytic defect and the following states of the L5-S1 disc: nil degeneration (NOR LYTIC), mild degeneration (M-DEG LYTIC), mild degeneration with 50% disc height collapse (M-DEG-COL LYTIC), and severe degeneration with 50% disc height collapse(S-COL LYTIC). The models were imported into a finite element modelling software for pre-processing, running nonlinear static solves, and post-processing of the results. RESULTS: Compared with the baseline INTACT model, M-DEG LYTIC model experienced the greatest increase in kinematics (Fx range of motion: 73% ?, Fx intervertebral translation: 53%?), shear stresses in the annulus (Fx anteroposterior: 163%?, Fx posteroanterior: 31%?), and strain in the iliolumbar ligament (Fx: 90%?). The S-COL LYTIC model experienced a decrease in mobility (Fx range of motion: 48%?, Fx intervertebral translation: 69%?) and an increase in normal stresses in the annulus (Fx Tensile: 170%?; Fx Compressive: 397%?). No significant difference in results was noted between M-DEG-COL LYTIC and S-COL LYTIC models. CONCLUSIONS: In the presence of a bilateral L5 spondylolytic defect, a mildly degenerate index-level disc experienced greater intervertebral motions and shear stresses compared with a severely degenerate index-level disc in flexion and extension bending motions. Disc height collapse, with or without degenerative changes in the stiffness properties of the disc, is one of the plausible re-stabilisation mechanisms available to the L5-S1 motion segment to mitigate increased intervertebral motions and shear stresses due to a bilateral L5 lytic defect. PMID- 29609582 TI - EX-MET study: exercise in prevention on of metabolic syndrome - a randomized multicenter trial: rational and design. AB - BACKGROUND: Metabolic syndrome substantially increases risk of cardiovascular events. It is therefore imperative to develop or optimize ways to prevent or attenuate this condition. Exercise training has been long recognized as a corner stone therapy for reducing individual cardiovascular risk factors constituting the metabolic syndrome. However, the optimal exercise dose and its feasibility in a real world setting has yet to be established. The primary objective of this randomized trial is to investigate the effects of different volumes of aerobic interval training (AIT) compared to the current exercise guideline of moderate intensity continuous training (MICT) on the composite number of cardiovascular disease risk factors constituting the metabolic syndrome after a 16 week, 1-year, and 3-year follow-up. METHODS: This is a randomized international multi-center trial including men and women aged >=30 years diagnosed with the metabolic syndrome according to the International Diabetes Federation criteria. Recruitment began in August 2012 and concluded in December 2016. This trial consists of supervised and unsupervised phases to evaluate the efficacy and feasibility of different exercise doses on the metabolic syndrome in a real world setting. This study aims to include and randomize 465 participants to 3 years of one of the following training groups: i) 3 times/week of 4 * 4 min AIT at 85-95% peak heart rate (HRpeak); ii) 3 times/week of 1 * 4 min AIT at 85-95% HRpeak; or iii) 5-7 times/week of >=30 min MICT at 60-70% HRpeak. Clinical examinations, physical tests and questionnaires are administered to all participants during all testing time points (baseline, 16 weeks and after 1-, and 3-years). DISCUSSION: This multi-center international trial indeed aims to ease the burden in healthcare/economic cost arising from treating end-stage CVD related conditions such as stroke and myocardial infarction, that could eventually emerge from the metabolic syndrome condition. TRIAL REGISTRATION: Clinical registration number: NCT01676870 , ClinicalTrials.gov (August 31, 2012). PMID- 29609583 TI - Risk factors for neonatal early-onset group B streptococcus-related diseases after the implementation of a universal screening program in Taiwan. AB - BACKGROUND: We examined the risk for Group B streptococcus (GBS)-related diseases in newborns born to mothers who participated in a universal GBS screening program and to determine whether differences are observed in factors affecting the morbidity for neonatal early-onset GBS-related diseases. METHODS: This is a retrospective study and the study subjects were women who had undergone GBS screening and who gave birth naturally and their newborns between April 15, 2012 and December 31, 2013. Data from the GBS screening system database and the National Health Insurance database were collected to calculate the GBS prevalence in pregnant women and morbidity of newborns with early-onset GBS-related diseases. RESULTS: The GBS prevalence in pregnant women who gave birth naturally was 19.58%. The rate of early-onset infection caused by GBS in newborns decreased from the original 0.1% to 0.02%, a decrease of as high as 80%. After the implementation of the universal GBS screening program, only three factors, including positive GBS screening result (OR = 2.84), CCI (OR = 2.45), and preterm birth (OR = 4.81) affected the morbidity for neonatal early-onset GBS-related diseases, whereas other factors had no significant impact. CONCLUSION: The implementation of the universal GBS screening program decreased the infection rate of neonatal early-onset GBS diseases. The effects of socioeconomic factors and high-risk pregnancy on early-onset GBS infections were weakened. PMID- 29609584 TI - Total Saikosaponins of Bupleurum yinchowense reduces depressive, anxiety-like behavior and increases synaptic proteins expression in chronic corticosterine treated mice. AB - BACKGROUND: Bupleurum yinchowense Shan et Y. Li is widely used to treat depressive and anxiety disorders for hundreds of years in China. Total saikosaponins (TSS) is the major ingredient of Bupleurum yinchowense. A-amino-3 hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and subsequent mammalian target of rapamycin (mTOR) signaling is responsible for synaptic maturation and may contribution to the synaptic alteration underlying depression. The aim of the study was to investigate the antidepressant-like and anxiolytic effect of TSS in chronic corticosterone-treated mice. The effect of TSS on synaptic proteins expression and AMPA receptor-mTOR signaling pathway alteration was also evaluated. METHODS: Dose-response effect of TSS (12.5, 25, 50 mg/kg) was investigated in forced swim test (FST) in ICR male mice. In the chronic corticosterine-treated model, TSS was given intragastrically once a day for 2 weeks and continued through the behavior testing period. Behavior tests and AMPA receptor related signaling pathway were investigated. RESULTS: TSS (25 and 50 mg/kg) decreased the immobility time in the FST when compared with the control group. TSS (25 mg/kg) showed antidepressant-like and anxiolytic effects in the chronic corticosterone treatment model in mice. TSS increased hippocampal synaptic proteins (synapsin-1 and postsynaptic density protein 95) expression. Immunohistochemistry analysis showed that TSS significantly increased the synapsin-1 expression in CA3 of hippocampus. TSS also increased hippocampal phosphorylation expression of GluR1 Ser 845 (AMPA receptor subunit) and its downstream regulators extracellular signaling-regulated kinase (ERK), protein kinase B (Akt) and mTOR. CONCLUSION: TSS produces antidepressant-like and anxiolytic effects and increases synaptic proteins expression which may be mediated by induction of AMPA receptor and subsequent mTOR signaling pathway. PMID- 29609585 TI - The association between balance and free-living physical activity in an older community-dwelling adult population: a systematic review and meta-analysis. AB - BACKGROUND: Poor balance is associated with an increased risk of falling, disability and death in older populations. To better inform policies and help reduce the human and economic cost of falls, this novel review explores the effects of free-living physical activity on balance in older (50 years and over) healthy community-dwelling adults. METHODS: Search methods: CENTRAL, Bone, Joint and Muscle Trauma Group Specialised register and CDSR in the Cochrane Library, MEDLINE, EMBASE, CINAHL, PsychINFO, and AMED were searched from inception to 7th June 2016. SELECTION CRITERIA: Intervention and observational studies investigating the effects of free-living PA on balance in healthy community dwelling adults (50 years and older). DATA EXTRACTION AND ANALYSIS: Thirty studies were eligible for inclusion. Data extraction and risk of bias assessment were independently carried out by two review authors. Due to the variety of outcome measures used in studies, balance outcomes from observational studies were pooled as standardised mean differences or mean difference where appropriate and 95% confidence intervals, and outcomes from RCTs were synthesised using a best evidence approach. RESULTS: Limited evidence provided by a small number of RCTs, and evidence from observational studies of moderate methodological quality, suggest that free-living PA of between one and 21 years' duration improves measures of balance in older healthy community-dwelling adults. Statistical analysis of observational studies found significant effects in favour of more active groups for neuromuscular measures such as gait speed; functionality using Timed Up and Go, Single Leg Stance, and Activities of Balance Confidence Scale; flexibility using the forward reach test; and strength using the isometric knee extension test and ultrasound. A significant effect was also observed for less active groups on a single sensory measure of balance, the knee joint repositioning test. CONCLUSION: There is some evidence that free-living PA is effective in improving balance outcomes in older healthy adults, but future research should include higher quality studies that focus on a consensus of balance measures that are clinically relevant and explore the effects of free living PA on balance over the longer-term. PMID- 29609586 TI - Fructus Ligustri Lucidi modulates estrogen receptor expression with no uterotrophic effect in ovariectomized rats. AB - BACKGROUND: Accumulating evidence suggests that Fructus Ligustri Lucidi (FLL) plays a beneficial role in preventing the development of osteoporosis. However, the effects of FLL on estrogen receptor (ER) alpha and ERbeta expressions remain unknown. Therefore, in the current study we attempted to probe into the effects of FLL on ERalpha and ERbeta expressions in femurs, tibias and uteri of ovariectomized (OVX) rats. METHODS: The OVX rats were orally administrated with FLL water extract (3.5 g/kg/day) for 12 weeks. The uteri, femurs, tibias and serum were harvested from rats. The serum levels of estrogen (E2), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were determined by ELISA. The expressions of ERalpha and ERbeta in the femurs and tibias as well as uteri were analysed by western blot and immunohistochemical staining. RESULTS: FLL treatment did not increase uterus relative weight in OVX rats. Further, FLL treatment increased ERalpha expression in the femurs and tibias, and enhanced ERbeta expression in the uteri of OVX rats. However, the resulted expression of ERalpha was stronger than that of ERbeta in OVX rats in response to FLL treatment. Meanwhile, administration with FLL to OVX rats increased FSH and LH but did not increase E2 level in the serum. CONCLUSION: FLL treatment shows tissue selection on ERalpha and ERbeta expressions in the femurs and tibias as well as uteri of OVX rats without uterotrophic effect, which may offer the scientific evidence of the efficiency and safety of its clinical application. PMID- 29609587 TI - New indexes of body fat distribution and sex-specific risk of total and cause specific mortality: a prospective cohort study. AB - BACKGROUND: A number of prior studies have examined the association between anthropometric measures and mortality, but studies investigating the sex-specific predictive value of novel anthropometric measures on mortality are scarce so far. Therefore, we investigated the sex-specific relevance of the new anthropometric measures body adiposity index (BAI) and waist to height ratio (WHtR) as well as the common measures body mass index (BMI), waist circumference (WC), and waist to hip ratio (WHR) for cause-specific mortality risk. METHODS: The analysis was based on data from the German population based KORA (Cooperative Health Research in the Region of Augsburg) Augsburg cohort study. A total of 6670 men and 6637 women aged 25 to 74 years at baseline examination were included. During a mean follow-up period of 15.4 years, 2409 persons died. Via Cox proportional hazard regression, the associations between the different anthropometric measures and all cause-, cardiovascular disease (CVD)- and cancer mortality were assessed. RESULTS: BMI, WC, and WHR were significantly associated with all-cause and CVD mortality in both sexes. WC and WHR were particularly associated with higher all cause and CVD-mortality risk in women, while in men especially WHtR and BAI were strongly related to these outcomes. Females with WC, WHtR, and WHR measures in the 4th quartile compared with women in the 2nd quartile had a higher risk of death from cancer. Contrary, men in the lowest quartile of WC and WHtR in comparison to men in the 2nd quartile had a significantly elevated cancer mortality risk. BAI was no risk predictor for all-cause and cause-specific mortality in women. CONCLUSIONS: Central obesity reflects higher all-cause and CVD-mortality risk particularly in women. BAI and WHtR seem to be valid as risk predictors for all-cause and especially CVD mortality in men but not women. There are marked sex-differences regarding cancer mortality risk for the different anthropometric measures. PMID- 29609588 TI - Subclinical atherosclerosis, cardiovascular health, and disease risk: is there a case for the Cardiovascular Health Index in the primary prevention population? AB - BACKGROUND: Current primary prevention guidelines for cardiovascular disease (CVD) prioritize risk identification, risk stratification using clinical and risk scores, and risk reduction with lifestyle interventions and pharmacotherapy. Subclinical atherosclerosis is an early indicator of atherosclerotic burden and its timely recognition can slow or prevent progression to CVD. Thus, individuals with subclinical atherosclerosis are a priority for primary prevention. This study takes a practical approach to answering a challenge commonly faced by primary care practitioners: in patients with no known CVD, how can individuals likely to have subclinical atherosclerosis be easily identified using existing clinical data and/or information provided by the patient? METHODS: Using NHANES (1999-2004), 6091 men and women aged >=40 years without any CVD comprised the primary prevention population for this study. Subclinical atherosclerosis was determined via ankle-brachial index (ABI) using established cutoffs (subclinical atherosclerosis defined as ABI (0.91-0.99); normal defined as ABI (1.00-1.30)). Three common scores were calculated: the Framingham Risk Score (FRS), the Metabolic Syndrome (MetS), and the Cardiovascular Health Index (CVHI). Logistic regression analysis assessed the association between these scores and subclinical atherosclerosis. The sensitively and specificity of these scores in identifying subclinical atherosclerosis was determined. RESULTS: In eligible participants, 3.8% had subclinical atherosclerosis. Optimum and average CVHI was associated with decreased odds for subclinical atherosclerosis. High, but not intermediate risk, FRS was associated with increased odds for subclinical atherosclerosis. MetS was not associated with subclinical atherosclerosis. Of the 3 scores, CVHI was the most sensitive in identifying subclinical atherosclerosis and had the lowest number of missed cases. The FRS was the most specific but least sensitive of the 3 scores, and had almost 10-fold more missed cases vs. the CVHI. The MetS had "middle" sensitivity and specificity, and 10-fold more missed cases vs. the CVHI. CONCLUSIONS: Results from this study suggest that routine administration of the CVHI in a primary prevention population would yield the benefits of identifying patients with existing subclinical CVD not identified through traditional CVD risk factors or scores, and bring physical activity and nutrition to the forefront of provider-patient discussions about lifestyle factors critical to maintaining and prolonging cardiovascular health. PMID- 29609589 TI - Food beliefs and practices in urban poor communities in Accra: implications for health interventions. AB - BACKGROUND: Poor communities in low and middle income countries are reported to experience a higher burden of chronic non-communicable diseases (NCDs) and nutrition-related NCDs. Interventions that build on lay perspectives of risk are recommended. The objective of this study was to examine lay understanding of healthy and unhealthy food practices, factors that influence food choices and the implications for developing population health interventions in three urban poor communities in Accra, Ghana. METHODS: Thirty lay adults were recruited and interviewed in two poor urban communities in Accra. The interviews were audio taped, transcribed and analysed thematically. The analysis was guided by the socio-ecological model which focuses on the intrapersonal, interpersonal, community, structural and policy levels of social organisation. RESULTS: Food was perceived as an edible natural resource, and healthy in its raw state. A food item retained its natural, healthy properties or became unhealthy depending on how it was prepared (e.g. frying vs boiling) and consumed (e.g. early or late in the day). These food beliefs reflected broader social food norms in the community and incorporated ideas aligned with standard expert dietary guidelines. Healthy cooking was perceived as the ability to select good ingredients, use appropriate cooking methods, and maintain food hygiene. Healthy eating was defined in three ways: 1) eating the right meals; 2) eating the right quantity; and 3) eating at the right time. Factors that influenced food choice included finances, physical and psychological state, significant others and community resources. CONCLUSIONS: The findings suggest that beliefs about healthy and unhealthy food practices are rooted in multi-level factors, including individual experience, family dynamics and community factors. The factors influencing food choices are also multilevel. The implications of the findings for the design and content of dietary and health interventions are discussed. PMID- 29609590 TI - Oxidative stress enhances tumorigenicity and stem-like features via the activation of the Wnt/beta-catenin/MYC/Sox2 axis in ALK-positive anaplastic large cell lymphoma. AB - BACKGROUND: The phenomenon that malignant cells can acquire stemness under specific stimuli, encompassed under the concept of cancer cell plasticity, has been well-described in epithelial malignancies. To our knowledge, cancer cell plasticity has not yet been described in hematopoietic cancers. To illustrate and study cancer cell plasticity in hematopoietic cancers, we employed an in-vitro experimental model of ALK-positive anaplastic large-cell lymphoma (ALK+ALCL) that is based on the phenotypic and functional dichotomy of these cells, with cells responsive to a Sox2 reporter (i.e. RR cells) being significantly more stem-like than those unresponsive to the reporter (i.e. RU cells). METHODS: H2O2 was employed to trigger oxidative stress. GFP expression and luciferase activity, readouts of the Sox2 reporter activity, were quantified by using flow cytometry and luciferase activity assay, respectively. Doxorubicin-resistance and clonogenicity were assessed by using the MTS, methylcellulose colony formation and limiting dilution assays. Western blotting and quantitative PCR were used to assess the expression of various members of the Wnt/beta-catenin pathway. Pull down studies using a Sox2 binding consensus sequence were used to assess Sox2-DNA binding. Quercetin and 10074-G5 were used to inhibit beta-catenin and MYC, respectively. siRNA was used to downregulate Sox2. RESULTS: Under H2O2-induced oxidative stress, a substantial fraction of RU cells was found to convert to RR cells, as evidenced by their acquisition of GFP expression and luciferase activity. Compared to the native RU cells, converted RR cells had significantly higher levels of doxorubicin-resistance, clonogenicity and sphere formation. Converted RR cells were characterized by an upregulation of the Wnt/beta catenin/MYC/Sox2 signaling axis, previously found to be the key regulator of the RU/RR dichotomy in ALK+ALCL. Furthermore, Sox2 was found to bind to DNA efficiently in converted RR cells but not RU cells, and this finding correlated with significant elevations of several Sox2 downstream targets such as WNT2B and BCL9. Lastly, inhibition of beta-catenin, MYC or Sox2 in RU cells significantly abrogated the H2O2-induced RU/RR conversion. CONCLUSIONS: We have demonstrated that cancer cell plasticity exists in ALK+ALCL, a type of hematopoietic cancer. In this cancer type, the Wnt/beta-catenin/MYC/Sox2 axis is an important regulator of cancer cell plasticity. PMID- 29609591 TI - Who's cooking? Trends in US home food preparation by gender, education, and race/ethnicity from 2003 to 2016. AB - BACKGROUND: While US home cooking declined in the late twentieth century, it is unclear whether the trend has continued. This study examines home cooking from 2003 to 2016 by gender, educational attainment, and race/ethnicity. METHODS: Nationally representative data from the American Time Use Study from 2003 to 2016 and linear regression models were used to examine changes in the percent of adults aged 18-65 years who cook and their time spent cooking, with interactions to test for differential changes by demographic variables of gender, education, and race/ethnicity. RESULTS: Cooking increased overall from 2003 to 2016. The percent of college-educated men cooking increased from 37.9% in 2003 to 51.9% in 2016, but men with less than high school education who cook did not change (33.2% in 2016) (p < 0.05). College-educated women who cook increased from 64.7% in 2003 to 68.7% in 2016, while women with less than high school education had no change (72.3% in 2016) (p < 0.05). Women with less education spent more time cooking per day than high-educated women, but the reverse was true for men. Among men, the percent who cook increased for all race/ethnic groups except non-Hispanic blacks. Among women, only non-Hispanic whites increased in percent who cook. Among both men and women, non-Hispanic blacks had the lowest percentage who cooked, and non Hispanic others spent the greatest amount of time cooking. CONCLUSIONS: Home cooking in the United States is increasing, especially among men, though women still cook much more than men. Further research is needed to understand whether the heterogeneity in home cooking by educational attainment and race/ethnicity observed here contributes to diet-related disparities in the United States. PMID- 29609592 TI - A systematic review of health status, health seeking behaviour and healthcare utilisation of low socioeconomic status populations in urban Singapore. AB - INTRODUCTION: It is well-established that low socioeconomic status (SES) influences one's health status, morbidity and mortality. Housing type has been used as an indicator of SES and social determinant of health in some studies. In Singapore, home ownership is among the highest in the world. Citizens who have no other housing options are offered heavily subsidised rental housings. Residents staying in such rental housings are characterised by low socioeconomic status. Our aim is to review studies on the association between staying in public rental housing in Singapore and health status. METHODS: A PubMed and Scopus search was conducted in January 2017 to identify suitable articles published from 1 January 2000 to 31 January 2017. Only studies that were done on Singapore public rental housing communities were included for review. A total of 14 articles including 4 prospective studies, 8 cross-sectional studies and 2 retrospective cohort studies were obtained for the review. Topics addressed by these studies included: (1) Health status; (2) Health seeking behaviour; (3) Healthcare utilisation. RESULTS: Staying in public rental housing was found to be associated with poorer health status and outcomes. They had lower participation in health screening, preferred alternative medicine practitioners to western-trained doctors for primary care, and had increased hospital utilisation. Several studies performed qualitative interviews to explore the causes of disparity and concern about cost was one of the common cited reason. CONCLUSION: Staying in public rental housing appears to be a risk marker of poorer health and this may have important public health implications. Understanding the causes of disparity will require more qualitative studies which in turn will guide interventions and the evaluation of their effectiveness in improving health outcome of this sub-population of patients. PMID- 29609593 TI - Electrical performance of PEDOT:PSS-based textile electrodes for wearable ECG monitoring: a comparative study. AB - BACKGROUND: Wearable textile electrodes for the detection of biopotentials are a promising tool for the monitoring and early diagnosis of chronic diseases. We present a comparative study of the electrical characteristics of four textile electrodes manufactured from common fabrics treated with a conductive polymer, a commercial fabric, and disposable Ag/AgCl electrodes. These characteristics will allow identifying the performance of the materials when used as ECG electrodes. The electrodes were subjected to different electrical tests, and complemented with conductivity calculations and microscopic images to determine their feasibility in the detection of ECG signals. METHODS: We evaluated four electrical characteristics: contact impedance, electrode polarization, noise, and long-term performance. We analyzed PEDOT:PSS treated fabrics based on cotton, cotton-polyester, lycra and polyester; also a commercial fabric made of silver plated nylon Shielde(r) Med-Tex P130, and commercial Ag/AgCl electrodes. We calculated conductivity from the surface resistance and, analyzed their surface at a microscopic level. Rwizard was used in the statistical analysis. RESULTS: The results showed that textile electrodes treated with PEDOT:PSS are suitable for the detection of ECG signals. The error detecting features of the ECG signal was lower than 2% and the electrodes kept working properly after 36 h of continuous use. Even though the contact impedance and the polarization level in textile electrodes were greater than in commercial electrodes, these parameters did not affect the acquisition of the ECG signals. Fabrics conductivity calculations were consistent to the contact impedance. PMID- 29609594 TI - Cluster randomized controlled trial of a multilevel physical activity intervention for older adults. AB - BACKGROUND: Older adults are the least active population group. Interventions in residential settings may support a multi-level approach to behavior change. METHODS: In a cluster randomized control trial, 11 San Diego retirement communities were assigned to a physical activity (PA) intervention or a healthy aging attention control condition. Participants were 307 adults over 65 years old. The multilevel PA intervention was delivered with the assistance of peer leaders, who were trained older adult from the retirement communities. Intervention components included individual counseling & self-monitoring with pedometers, group education sessions, group walks, community advocacy and pedestrian community change projects. Intervention condition by time interactions were tested using generalized mixed effects regressions. The primary outcomes was accelerometer measured physical activity. Secondary outcomes were blood pressure and objectively measured physical functioning. RESULTS: Over 70% of the sample were 80 years or older. PA significantly increased in the intervention condition (56 min of moderate-vigorous PA per week; 119 min of light PA) compared with the control condition and remained significantly higher across the 12 month study. Men and participants under 84 years old benefited most from the intervention. There was a significant decrease in systolic (p < .007) and diastolic (p < .02) blood pressure at 6 months. Physical functioning improved but the changes were not statistically significant. CONCLUSIONS: Intervention fidelity was high demonstrating feasibility. Changes in PA and blood pressure achieved were comparable to other studies with much younger participants. Men, in particular, avoided a year-long decline in PA. TRIAL REGISTRATION: clincialtrials.gov Identifier: NCT01155011 . PMID- 29609595 TI - Capture of intraocular lens optic by residual capsular opening in secondary implantation: long-term follow-up. AB - BACKGROUND: To introduce a novel surgical technique for optic capture by residual capsular opening in secondary intraocular lens (IOL) implantation and to report the outcomes of a long follow-up. METHODS: Twenty patients (20 eyes) who had received secondary IOL implantation with the optic capture technique were retrospectively reviewed. We used the residual capsular opening for capturing the optic and inserted the haptics in the sulcus during surgery. Baseline clinical characteristics and surgical outcomes, including best-corrected visual acuity (BCVA), refractive status, and IOL position were recorded. The postoperative location and stability of IOL were evaluated using the ultrasound biomicroscopy. RESULTS: Optic capture technique was successfully performed in all cases, including 5 cases with large area of posterior capsular opacity, 6 cases with posterior capsular tear or rupture,and 9 cases with adhesive capsules. BCVA improved from 0.60 logMAR at baseline to 0.36 logMAR at the last follow-up (P < 0.001). Spherical equivalent changed from 10.67 +/- 4.59 D at baseline to 0.12 +/ 1.35 D at 6 months postoperatively (P < 0.001). Centered IOLs were observed in all cases and remained captured through residual capsular opening in 19 (95%) eyes at the last follow-up. In one case, the captured optic of IOL slid into ciliary sulcus at 7 months postoperatively. No other postoperative complications were observed in any cases. CONCLUSIONS: This optic capture technique by using residual capsule opening is an efficacious and safe technique and can achieve IOL stability in the long follow-up. PMID- 29609596 TI - Training community healthcare workers on the use of information and communication technologies: a randomised controlled trial of traditional versus blended learning in Malawi, Africa. AB - BACKGROUND: Despite the increasing uptake of information and communication technologies (ICT) within healthcare services across developing countries, community healthcare workers (CHWs) have limited knowledge to fully utilise computerised clinical systems and mobile apps. The 'Introduction to Information and Communication Technology and eHealth' course was developed with the aim to provide CHWs in Malawi, Africa, with basic knowledge and computer skills to use digital solutions in healthcare delivery. The course was delivered using a traditional and a blended learning approach. METHODS: Two questionnaires were developed and tested for face validity and reliability in a pilot course with 20 CHWs. Those were designed to measure CHWs' knowledge of and attitudes towards the use of ICT, before and after each course, as well as their satisfaction with each learning approach. Following validation, a randomised controlled trial was conducted to assess the effectiveness of the two learning approaches. A total of 40 CHWs were recruited, stratified by position, gender and computer experience, and allocated to the traditional or blended learning group using block randomisation. Participants completed the baseline and follow-up questionnaires before and after each course to assess the impact of each learning approach on their knowledge, attitudes, and satisfaction. Per-item, pre-post and between group, mean differences for each approach were calculated using paired and unpaired t-tests, respectively. Per-item, between-group, satisfaction scores were compared using unpaired t-tests. RESULTS: Scores across all scales improved after attending the traditional and blended learning courses. Self-rated ICT knowledge was significantly improved in both groups with significant differences between groups in seven domains. However, actual ICT knowledge scores were similar across groups. There were no significant differences between groups in attitudinal gains. Satisfaction with the course was generally high in both groups. However, participants in the blended learning group found it more difficult to follow the content of the course. CONCLUSIONS: This study shows that there is no difference between blended and traditional learning in the acquisition of actual ICT knowledge among community healthcare workers in developing countries. Given the human resource constraints in remote resource-poor areas, the blended learning approach may present an advantageous alternative to traditional learning. PMID- 29609598 TI - Modelling the persistence of mosquito vectors of malaria in Burkina Faso. AB - BACKGROUND: Populations of the Anopheles gambiae complex are found during the rainy season throughout West Africa, even in arid areas with long dry seasons during which mosquitoes appear to be absent. Several hypotheses have been proposed to explain this apparent paradox, including aestivation, dispersal between neighbouring settlements, and long distance migration using high-altitude wind currents. METHODS: An individual-based, spatially explicit model of mosquito populations was developed for a region of West Africa centred on, and including all of, Burkina Faso. Populations associated with human settlements were linked by dispersal and the model incorporated geospatial data on the distribution of settlements, water bodies and rainfall. RESULTS: Local dispersal (at rates consistent with experimental data) was necessary to explain observed patterns of rainy season populations across all of the simulation area, but by itself failed to account for the presence of populations in the arid North (the Sahel). The presence of rare dry-season larval sites could explain these northern populations, but seems inconsistent with field surveys. Aestivation by female mosquitoes explained rainy-season populations in all but the very sparsest and driest areas of human habitation, while long-distance migration based on annual wind patterns could account for all observed populations. CONCLUSIONS: Modelling studies such as this can help assess the potential validity of different hypotheses and suggest priority areas for experimental study. In particular, the results highlight a shortage of empirical research on mosquito dispersal between neighbouring settlements, which may be critically important to the continued presence of many mosquito populations in West Africa. Further research that establishes the extent to which mosquitoes aestivate, and migrate using high altitude winds, is also much needed to understand Sahelian mosquito populations. PMID- 29609597 TI - Targeted application of an organophosphate-based paint applied on windows and doors against Anopheles coluzzii resistant to pyrethroids under real life conditions in Vallee du Kou, Burkina Faso (West Africa). AB - BACKGROUND: A novel strategy applying an organophosphate-based insecticide paint on doors and windows in combination with long-lasting insecticide-treated nets (LLINs) was tested for the control of pyrethroid-resistant malaria vectors in a village setting in Vallee du Kou, a rice-growing area west of Burkina Faso. METHODS: Insecticide Paint Inesfly 5A IGRTM, comprised of two organophosphates and an insect growth regulator, was applied to doors and windows and tested in combination with pyrethroid-treated LLINs. The killing effect was monitored for 5 months by early morning collections of anophelines and other culicids. The residual efficacy was evaluated monthly by WHO bioassays using Anopheles gambiae 'Kisumu' and local populations of Anopheles coluzzii resistant to pyrethroids. The spatial mortality efficacy (SME) at distances of 1 m was also assessed against pyrethroid-susceptible and -resistant malaria vectors. The frequency of L1014F kdr and Ace-1 R G119S mutations was, respectively, reported throughout the study. The Insecticide Paint Inesfly 5A IGR had been tested in past studies yielding a long-term mortality rate of 80% over 12 months against An. coluzzii, the local pyrethroid-resistant malaria vector. The purpose of the present study is to test if treating smaller, targeted surfaces (e.g. doors and windows) was also efficient in killing malaria vectors. RESULTS: Treating windows and doors alone yielded a killing efficacy of 100% for 1 month against An. coluzzii resistant to pyrethroids, but efficacy reduced quickly afterwards. Likewise, WHO cone bioassays yielded mortalities of 80-100% for 2 months but declined to 90 and 40% 2 and 3 months after treatment, respectively. Mosquitoes exposed to insecticide paint-treated surfaces at distances of 1 m, yielded mortality rates of about 90-80% against local pyrethroids-resistant An. coluzzii during the first 2 months, but decreased to 30% afterwards. Anopheles coluzzii was reported to be exclusively the local malaria vector and resistant to pyrethroids with high L1014 kdr frequency. CONCLUSION: The combination of insecticide paint on doors and windows with LLINs yielded high mortality rates in the short term against wild pyrethroid-resistant malaria vector populations. A high SME was observed against laboratory strains of pyrethroid-resistant malaria vectors placed for 30 min at 1 m from the treated/control walls. The application of the insecticide paint on doors and windows led to high but short-lasting mortality rates. The strategy may be an option in a context where low cost, rapid responses need to be implemented in areas where malaria vectors are resistant to pyrethroids. PMID- 29609599 TI - Time motion study using mixed methods to assess service delivery by frontline health workers from South India: methods. AB - BACKGROUND: In India, amidst the increasing number of health programmes, there are concerns about the performance of frontline health workers (FLHW). We assessed the time utilisation and factors affecting the work of frontline health workers from South India. METHODS: This is a mixed methods study using time and motion (TAM) direct observations and qualitative enquiry among frontline/community health workers. These included 43 female and 6 male multipurpose health workers (namely, auxiliary nurse midwives (ANMs) and male MPHWs), 12 nutrition and health workers (Anganwadi workers, AWWs) and 53 incentive-based community health workers (accredited social health activists, ASHAs). We conducted the study in two phases. In the formative phase, we conducted an in-depth inductive investigation to develop observation checklists and qualitative tools. The main study involved deductive approach for TAM observations. This enabled us to observe a larger sample to capture variations across non-tribal and tribal regions and different health cadres. For the main study, we developed GPRS-enabled android-based application to precisely record time, multi-tasking and field movement. We conducted non-participatory direct observations (home to home) for consecutively 6 days for each participant. We conducted in-depth interviews with all the participants and 33 of their supervisors and relevant officials. We conducted six focus group discussions (FGDs) with ASHAs and one FGD with ANMs to validate preliminary findings. We established a mechanism for quality assurance of data collection and analysis. We analysed the data separately for each cadre and stratified for non-tribal and tribal regions. RESULTS: On any working day, the ANMs spent median 7:04 h, male MPHWs spent median 5:44 h and AWWs spent median 6:50 h on the job. The time spent on the job was less among the FLHWs from tribal areas as compared to those from non-tribal areas. ANMs and AWWs prioritised maternal and child health, while male MPHWs were involved in seasonal diseases and school health. ASHAs visited homes to provide maternal health, basic curative care, and follow-up of tuberculosis patients. The results describe issues related with work planning, time management and several systemic, community-based and personnel factors affecting work of FLHWs. CONCLUSION: TAM study with mixed methods can help researchers as well as managers to periodically review work patterns, devise appropriate job responsibilities and improve the efficiency of health workers. PMID- 29609600 TI - Screening for caregivers at risk: Extended validation of the short version of the Burden Scale for Family Caregivers (BSFC-s) with a valid classification system for caregivers caring for an older person at home. AB - BACKGROUND: Informal caregivers' (CGs') subjective burden is an important aspect of the care situation because it is linked to various outcomes such as health, mortality risk, institutionalization, and caregiving style. The aims of this study were a) to examine the convergent and discriminant validity of the 10-item short version of the Burden Scale for Family Caregivers (BSFC-s) and b) to develop a valid classification system for interpreting BSFC-s scores. METHODS: In this cross-sectional study, we analyzed data obtained from 386 informal CGs who applied for an initial grade or upgrade of the care level for the care recipient at the Medical Service of Compulsory Health Insurance Funds of Bavaria (Germany). To validate the BSFC-s, we analyzed the reliability and the convergent/discriminant validity. We calculated correlations with the short form of the Giessen Symptom Complaints List (GBB-24), the Caregiver Strain Index (CSI), the personal further development sub-scale of the Berlin Inventory of Caregivers' Burden with Dementia Patients (BIZA-D), and other scales for establishing informal CGs' situations. To develop the classification system, we compared the percentile ranks of the GBB-24 with the respective BSFC-s sum scores and their distributions and derived three classification categories. RESULTS: Results confirmed the convergent and discriminant validity of the BSFC-s (GBB-24: r = 0.68; CSI: r = 0.70; BIZA-D: r = 0.16; p < 0.001). For informal CGs with low subjective burden, the risk of physical psychosomatic complaints was elevated to a less than average level (BSFC-s scores of 0-4). In those with a moderate subjective burden (BSFC-s scores of 5-14), the risk was elevated. In those with a high burden (BSFC-s scores of 15-30), the risk was substantially elevated. CONCLUSIONS: The BSFC-s is a valid scale for measuring subjective burden in informal CGs. The risk of physical psychosomatic complaints, which is a consequence of subjective CG burden, can be determined by using the valid classification system to deduce the necessity for action and to give concrete recommendations for interventions. The BSFC-s should therefore be employed as a screening instrument in medical contexts and in counseling services for informal CGs. PMID- 29609601 TI - Geographical heterogeneity and inequality of access to improved drinking water supply and sanitation in Nepal. AB - BACKGROUND: Per United Nations' Sustainable Development Goals, Nepal is aspiring to achieve universal and equitable access to safe and affordable drinking water and provide access to adequate and equitable sanitation for all by 2030. For these goals to be accomplished, it is important to understand the country's geographical heterogeneity and inequality of access to its drinking-water supply and sanitation (WSS) so that resource allocation and disease control can be optimized. We aimed 1) to estimate spatial heterogeneity of access to improved WSS among the overall Nepalese population at a high resolution; 2) to explore inequality within and between relevant Nepalese administrative levels; and 3) to identify the specific administrative areas in greatest need of policy attention. METHODS: We extracted cluster-sample data on the use of the water supply and sanitation that included 10,826 surveyed households from the 2011 Nepal Demographic and Health Survey, then used a Gaussian kernel density estimation with adaptive bandwidths to estimate the distribution of access to improved WSS conditions over a grid at 1 * 1 km. The Gini coefficient was calculated for the measurement of inequality in the distribution of improved WSS; the Theil L measure and Theil T index were applied to account for the decomposition of inequality. RESULTS: 57% of Nepalese had access to improved sanitation (range: 18.1% in Mahottari to 100% in Kathmandu) and 92% to drinking-water (range: 41.7% in Doti to 100% in Bara). The most unequal districts in Gini coefficient among improved sanitation were Saptari, Sindhuli, Banke, Bajura and Achham (range: 0.276 to 0.316); and Sankhuwasabha, Arghakhanchi, Gulmi, Bhojpur, Kathmandu (range: 0.110 to 0.137) among improved drinking-water. Both the Theil L and Theil T showed that within-province inequality was substantially greater than between province inequality; while within-district inequality was less than between district inequality. The inequality of several districts was higher than what is calculated by regression of the Gini coefficient and our estimates. CONCLUSIONS: This study showed considerable geographical heterogeneity and inequality not evidenced in previous national statistics. Our findings may be useful in prioritizing resources to reduce inequality and expand the coverage of improved water supply and sanitation in Nepal. PMID- 29609602 TI - Streamlined, PCR-based testing for pfhrp2- and pfhrp3-negative Plasmodium falciparum. AB - BACKGROUND: Rapid diagnostic tests (RDTs) that detect histidine-rich protein 2 (PfHRP2) are used throughout Africa for the diagnosis of Plasmodium falciparum malaria. However, recent reports indicate that parasites lacking the pfhrp2 and/or histidine-rich protein 3 (pfhrp3) genes, which produce antigens detected by these RDTs, are common in select regions of South America, Asia, and Africa. Proving the absence of a gene is challenging, and multiple PCR assays targeting these genes have been described. A detailed characterization and comparison of published assays is needed to facilitate robust and streamlined testing approaches. RESULTS: Among six pfhrp2 and pfhrp3 PCR assays tested, the lower limit of detection ranged from 0.01 pg/uL to 0.1 ng/uL of P. falciparum 3D7 strain DNA, or approximately 0.4-4000 parasite genomes/uL. By lowering the elongation temperature to 60 degrees C, a tenfold improvement in the limit of detection and/or darker bands for all exon 1 targets and for the first-round reaction of a single exon 2 target was achieved. Additionally, assays targeting exon 1 of either gene yielded spurious amplification of the paralogous gene. Using these data, an optimized testing algorithm for the detection of pfhrp2- and pfhrp3-negative P. falciparum is proposed. CONCLUSIONS: Surveillance of pfhrp2- and pfhrp3-negative P. falciparum requires careful laboratory workflows. PCR based testing methods coupled with microscopy and/or antigen testing serve as useful tools to support policy development. Standardized approaches to the detection of pfhrp2- and pfhrp3-negative P. falciparum should inform efforts to define the impact of these parasites. PMID- 29609603 TI - Pharmacists in general practice: a qualitative interview case study of stakeholders' experiences in a West London GP federation. AB - BACKGROUND: Increased patient demand for healthcare services coupled with a shortage of general practitioners necessitates changes in professional roles and service delivery. In 2016, NHS England began a 3-year- pilot study of pharmacists in general practice, however, this is not an entirely new initiative. There is limited, current, evidence-based, UK research to inform the pilot so studies of pre-existing services must suffice until findings from a formal national evaluation are available. METHODS: The aim of this exploratory, descriptive interview study was to explore the experiences of stakeholders in eight general practices in the Ealing GP Federation, West London, where pharmacy services have been provided for several years. Forty-seven participants, including pharmacy team members (pre-registration and clinical pharmacists, independent prescribers and pharmacy technicians), general practitioners, patients, practice managers, practice nurses and receptionists took part in semi-structured, audio-recorded qualitative interviews which were transcribed verbatim, coded and analysed thematically to extract the issues raised by participants and the practicalities of providing pharmacy services in general practice. RESULTS: Findings are reported under the themes of Complementarity (incorporating roles, skills, education and workloads); Integration (incorporating relationships, trust and communication) and Practicalities (incorporating location and space, access, and costs). Participants reported the need for time to develop and understand the various roles, develop communication processes and build inter-professional trust. Once these were established, however, experiences were positive and included decreased workloads, increased patient safety, improved job satisfaction, improved patient relationships, and enhanced cost savings. Areas for improvement included patients' awareness of services; pharmacists' training; and regular, onsite access for practice staff to the pharmacy team. CONCLUSIONS: Recommendations are made for the development of clear role definitions, identification of training needs, dedication of time for team building, production of educational materials for practice staff members and patients, and provision of on-site, full-time pharmacy services. Future work should focus on evaluation of various models of employing pharmacy teams in general practice; integration of pharmacists and pharmacy technicians into multidisciplinary general practice teams; relationships between local community pharmacy and general practice personnel; and patients' service and information needs. A formal national evaluation of the pilot scheme is overdue. PMID- 29609605 TI - Severe Plasmodium ovale malaria complicated by acute respiratory distress syndrome in a young Caucasian man. AB - BACKGROUND: Although Plasmodium ovale is considered the cause of only mild malaria, a case of severe malaria due to P. ovale with acute respiratory distress syndrome is reported. CASE PRESENTATION: A 37-year old Caucasian man returning home from Angola was admitted for ovale malaria to the National Institute for Infectious Diseases Lazzaro Spallanzani in Rome, Italy. Two days after initiation of oral chloroquine treatment, an acute respiratory distress syndrome was diagnosed through chest X-ray and chest CT scan with intravenous contrast. Intravenous artesunate and oral doxycycline were started and he made a full recovery. CONCLUSION: Ovale malaria is usually considered a tropical infectious disease associated with low morbidity and mortality. However, severe disease and death have occasionally been reported. In this case clinical failure of oral chloroquine treatment with clinical progression towards acute respiratory distress syndrome is described. PMID- 29609604 TI - Airway disease phenotypes in animal models of cystic fibrosis. AB - In humans, cystic fibrosis (CF) lung disease is characterised by chronic infection, inflammation, airway remodelling, and mucus obstruction. A lack of pulmonary manifestations in CF mouse models has hindered investigations of airway disease pathogenesis, as well as the development and testing of potential therapeutics. However, recently generated CF animal models including rat, ferret and pig models demonstrate a range of well characterised lung disease phenotypes with varying degrees of severity. This review discusses the airway phenotypes of currently available CF animal models and presents potential applications of each model in airway-related CF research. PMID- 29609606 TI - Spatio-temporal dynamic of malaria in Ouagadougou, Burkina Faso, 2011-2015. AB - BACKGROUND: Given the scarcity of resources in developing countries, malaria treatment requires new strategies that target specific populations, time periods and geographical areas. While the spatial pattern of malaria transmission is known to vary depending on local conditions, its temporal evolution has yet to be evaluated. The aim of this study was to determine the spatio-temporal dynamic of malaria in the central region of Burkina Faso, taking into account meteorological factors. METHODS: Drawing on national databases, 101 health areas were studied from 2011 to 2015, together with weekly meteorological data (temperature, number of rain events, rainfall, humidity, wind speed). Meteorological factors were investigated using a principal component analysis (PCA) to reduce dimensions and avoid collinearities. The Box-Jenkins ARIMA model was used to test the stationarity of the time series. The impact of meteorological factors on malaria incidence was measured with a general additive model. A change-point analysis was performed to detect malaria transmission periods. For each transmission period, malaria incidence was mapped and hotspots were identified using spatial cluster detection. RESULTS: Malaria incidence never went below 13.7 cases/10,000 person weeks. The first and second PCA components (constituted by rain/humidity and temperatures, respectively) were correlated with malaria incidence with a lag of 2 weeks. The impact of temperature was significantly non-linear: malaria incidence increased with temperature but declined sharply with high temperature. A significant positive linear trend was found for the entire time period. Three transmission periods were detected: low (16.8-29.9 cases/10,000 person-weeks), high (51.7-84.8 cases/10,000 person-weeks), and intermediate (26.7-32.2 cases/10,000 person-weeks). The location of clusters identified as high risk varied little across transmission periods. CONCLUSION: This study highlighted the spatial variability and relative temporal stability of malaria incidence around the capital Ouagadougou, in the central region of Burkina Faso. Despite increasing efforts in fighting the disease, malaria incidence remained high and increased over the period of study. Hotspots, particularly those detected for low transmission periods, should be investigated further to uncover the local environmental and behavioural factors of transmission, and hence to allow for the development of better targeted control strategies. PMID- 29609607 TI - The integrated stress response regulates BMP signalling through effects on translation. AB - BACKGROUND: Developmental pathways must be responsive to the environment. Phosphorylation of eIF2alpha enables a family of stress-sensing kinases to trigger the integrated stress response (ISR), which has pro-survival and developmental consequences. Bone morphogenetic proteins (BMPs) regulate multiple developmental processes in organisms from insects to mammals. RESULTS: Here we show in Drosophila that GCN2 antagonises BMP signalling through direct effects on translation and indirectly via the transcription factor crc (dATF4). Expression of a constitutively active GCN2 or loss of the eIF2alpha phosphatase dPPP1R15 impairs developmental BMP signalling in flies. In cells, inhibition of translation by GCN2 blocks downstream BMP signalling. Moreover, loss of d4E-BP, a target of crc, augments BMP signalling in vitro and rescues tissue development in vivo. CONCLUSION: These results identify a novel mechanism by which the ISR modulates BMP signalling during development. PMID- 29609608 TI - Methamphetamine-type stimulant use in Lao PDR: qualitative findings from users aged 15-25 years in Vientiane Capital and Vientiane Province. AB - BACKGROUND: Methamphetamine is one of the most widely used illicit drugs in several Southeast Asian countries, including the Lao People's Democratic Republic (PDR). The purpose of this study was to examine the socio-cultural context of its use in Lao PDR. METHODS: We conducted a cross-sectional qualitative survey among young people, aged 15-24 years, who use methamphetamine (or Yaba as it is commonly known in the region) in Vientiane Capital and Vientiane Province, Lao PDR. In total, we conducted 21 in-depth interviews (6 female, 13 males and 2 transgender) and 8 focus group discussions with 47 participants (10 female, 29 male and 8 transgender). The data analysis drew on the theory and insights of the social theorist Pierre Bourdieu (1990, 1997) to understand the Yaba consumption practices among young Laotians. RESULTS: Yaba consumption among young people in this study was used to enhance both productivity and pleasure. Its pleasure producing affects were often linked to core Laotian notions of having fun, partying and being together. Its increased productivity effects on the other hand, were used to pursue goals related to self-betterment within an emerging market economy. CONCLUSIONS: This study highlights the complex interaction between agency and identity, structure, context and practices. In terms of public health policy and programme responses, developing proper interventions implies a good understanding of how young people interpret Yaba consumption, its dynamics and the relationships and resources that mediate the behaviours. PMID- 29609609 TI - Free text adversity statements as part of a contextualised admissions process: a qualitative analysis. AB - BACKGROUND: Medical schools globally are encouraged to widen access and participation for students from less privileged backgrounds. Many strategies have been implemented to address this inequality, but much still needs to be done to ensure fair access for all. In the literature, adverse circumstances include financial issues, poor educational experience and lack of professional-status parents. In order to take account of adverse circumstances faced by applicants, The University of Dundee School of Medicine offers applicants the opportunity to report circumstances which may have resulted in disadvantage. Applicants do this by completing a free text statement, known as an 'adversity statement', in addition to the other application information. This study analysed adversity statements submitted by applicants during two admissions cycles. Analysis of content and theme was done to identify the information applicants wished to be taken into consideration, and what range of adverse circumstances individuals reported. METHODS: This study used a qualitative approach with thematic analysis to categorise the adversity statements. The data was initially analysed to create a coding framework which was then applied to the whole data set. Each coded segment was then analysed for heterogeneity and homogeneity, segments merged into generated themes, or to create sub-themes. RESULTS: The data set comprised a total of 384 adversity statements. These showed a wide range of detail involving family, personal health, education and living circumstances. Some circumstances, such as geographical location, have been identified and explored in previous research, while others, such as long term health conditions, have had less attention in the literature. The degree of impact, the length of statement and degree of detail, demonstrated wide variation between submissions. CONCLUSIONS: This study adds to the debate on best practice in contextual admissions and raises awareness of the range of circumstances and impact applicants wish to be considered. The themes which emerged from the data included family, school, personal health, and geographical location issues. Descriptions of the degree of impact that an adverse circumstance had on educational or other attainment was found to vary substantially from statements indicating minor, impact through to circumstances stated as causing major impact. PMID- 29609610 TI - Robotic sleeve resection for pulmonary disease. AB - BACKGROUND: Few studies have described robotic sleeve resection with pulmonary resection. Here, we report the successful implementation of a completely portal robotic sleeve resection with or without pulmonary resection using a modified suture mode. METHODS: In total, 339 patients underwent curative robotic pulmonary surgery at Ruijin Hospital between May 2015 and September 2017. Three of these patients underwent robotic sleeve resection (right upper lobe, one; left upper lobe, one; and lingular segmental bronchus, one). Five port incisions were utilized, and a simple continuous running suture combined with two interrupted sutures of the membranous and cartilaginous junction portion was preferred for the anastomosis. RESULTS: The postoperative course was uneventful for two patients with squamous cell carcinoma. The lingular segmental bronchus patient without pulmonary resection (a salivary gland tumor) underwent short-term atelectasis. The median operation time was 155 (range 132-230) minutes. The median anastomosis time was 25 (range 23-32) minutes. The median length of postoperative hospital stay was 7 (range 6-10) days. There was no mortality or conversion to thoracotomy for any of the patients. All patients were followed for 3-6 months, and there is no tumour recurrence. CONCLUSIONS: Our limited experience suggested that robotic sleeve resection for pulmonary disease with or without pulmonary resection may be safe and effective. The anastomosis time can be shortened with more robotic surgery experiences and the modified suture mode. PMID- 29609611 TI - Association between industry payments and prescribing costly medications: an observational study using open payments and medicare part D data. AB - BACKGROUND: While many new medications may offer advantages over existing drugs, some newer drugs are reformulations of existing products that provide little innovation or incremental benefit while driving up drug costs. Despite the lack of benefit of these medications, prescribers may be motivated by payments made by the pharmaceutical industry. The objective of the study was to determine the association between payments made to physicians by the pharmaceutical industry and prescriptions for certain selected costly brand name drugs. METHODS: This was a cross-sectional, retrospective study linking the Open Payments Database and Medicare Part D Prescriber Public Use File for 2014, including 667,278 physicians who prescribed one of 6 brand-name drugs with less costly but similarly effective alternatives: lovastatin ER, almotriptan, amlodipine+olmesartan, ibuprofen+famotidine, saxagliptin+metformin and naproxen+esomeprazole. The primary outcome was the odds of a physician prescribing one of the selected drugs, and the primary predictor was the receipt of any payment from the pharmaceutical industry. RESULTS: The odds of prescribing 3 of the 6 drugs were increased among physicians who received industry payment, compared to those without payment: amlodipine+olmesartan, aOR 1.42, (95% CI 1.36-1.49); saxagliptin+metformin, aOR 1.50, (95% CI 1.42-1.59); and naproxen+esomeprazole, aOR 1.45, (95% CI 1.25-1.68). Payment from the manufacturer of the specific drug, compared to not receiving payment from the drug's manufacturer, was associated with increased odds of prescribing 4 of the 6 drugs: amlodipine+olmesartan, aOR 2.40, (95% CI 2.29-2.52), ibuprofen+famotidine, aOR 8.06, (95% CI 5.42-12.00), saxagliptin+metformin, aOR 2.21, (95% CI 2.10-2.34) and naproxen+esomeprazole, aOR 5.96, (95% CI 5.08-7.00). CONCLUSIONS: A physician-industry financial relationship was associated with increased odds of prescribing costly brand-name drugs of uncertain medical benefit. Patients, as healthcare consumers, should demand transparency from their physicians about payment from the pharmaceutical industry to increase shared decision-making. Physician and policy makers need increased awareness and reflection on how industry payment influences their prescribing practices. PMID- 29609612 TI - Association between age and outpatient clinic arrival time: myth or reality? AB - BACKGROUND: Non-attendance and late arrivals diminish patient flow in outpatient clinics. On the other hand, patient earliness may also be undesirable. Physicians often experience that older patients are more punctual than younger patients, and often they come excessively early. The aim of this study was to determine whether an association between age and outpatient clinic arrival time could be established or not, i.e. to find out if it is a myth or a reality. METHODS: Prospective descriptive study performed at a neurological outpatient clinic. Data were collected from all scheduled appointments during an eight-week period. Variables included were age, gender, appointment time, arrival time, no-shows, appointment type, need for assistance and if it was an early or late appointment. Outcomes were unpunctuality (early and late arrivals) and non-attendance. RESULTS: Of 1353 appointments, non-attendance rate was 9.5 and 5.1% were late arrivals. Median age increased with increased patient earliness (p < 0.001). Younger age (p = 0.007) and new referrals (p = 0.025) were associated with non attendance. CONCLUSIONS: The intuition of an association between age and outpatient clinic arrival time was confirmed, thus it is a reality that older patients attend their appointments more frequently and have better punctuality than younger adults. This age effect in outpatient clinics should be considered when developing future simulation models and intervention studies. PMID- 29609613 TI - Use of analgesics in France, following dextropropoxyphene withdrawal. AB - BACKGROUND: In 2009, the European Medicines Agency recommended withdrawal of dextropropoxyphene (DXP); in March 2011 it was withdrawn from the market in France. Up until that time the combination dextropropoxyphene-paracetamol (DXP/PC) was widely used for analgesia. At withdrawal, French regulators recommended that DXP/PC be replaced by other step 2 analgesics, i.e. tramadol, codeine, or opium-containing drugs, or by PC for a weak level of pain. To investigate prescribing behaviours after DXP/PC withdrawal, dispensations of analgesics before and after withdrawal were analysed. METHODS: Aggregated dispensation data of analgesics prescribed between January 2009 and December 2012 in the Rhone-Alpes region were obtained from the general health insurance claims data; changes in analgesic dispensation over time were analysed with the ATC/DDD methodology. Pre (Jan-June 2009) and post-withdrawal (Jan-June 2012) changes of DDDs where computed for each analgesic step. RESULTS: The dispensations of DXP/PC experienced a two-step decrease until 2011. Over the withdrawal period 2009-2012, there was a 14% decrease in the overall use of analgesic (from 109 to 94 DDDs), while the use of step 2 analgesics declined by 46% (- 22 DDDs, from 47 to 25 DDDs). This latter decline included a cessation of use of DXP/PC (29 DDDs in 2009) that were only in part (+ 7 DDDs, from 18 to 25 DDDs) compensated by increased use of codeine, tramadol and opium, in monotherapy or combined with PC. For step 1 analgesics, use increased with 9%, mostly PC (+ 8 DDDs, from 31 to 39 DDDs). Step 3 analgesics dispensations remained largely unchanged over this period (around 3 DDDs). CONCLUSIONS: In the Rhone-Alpes region, DXP/PC withdrawal was accompanied in part by an increased use of same level analgesics, and in part by an increased use of PC in monotherapy. The extent of DXP/PC use before withdrawal, and the increased use of PC after DXP withdrawal, underline the complexity of pain management. PMID- 29609614 TI - Health workforce cultural competency interventions: a systematic scoping review. AB - BACKGROUND: Addressing health workforce cultural competence is a common approach to improving health service quality for culturally and ethnically diverse groups. Research evidence in this area is primarily focused on cultural competency training and its effects on practitioners' knowledge, attitudes, skills and behaviour. While improvements in measures of healthcare practitioner cultural competency and other healthcare outcomes have been reported, there are concerns around evidence strength and quality. This scoping review reports on the intervention strategies, outcomes, and measures of included studies with the purpose of informing the implementation and evaluation of future interventions to improve health workforce cultural competence. METHODS: This systematic scoping review was completed as part of a larger systematic literature search conducted on cultural competence intervention evaluations in health care in Canada, the United States, Australia and New Zealand published from 2006 to 2015. Overall, 64 studies on cultural competency interventions were found, with 16 aimed directly at the health workforce. RESULTS: There was significant heterogeneity in workforce intervention strategies, measures and outcomes reported across studies making comparisons of intervention effects difficult. The two main workforce intervention strategies identified were cultural competency training and other professional development interventions including other training and mentoring. Positive outcomes were commonly reported for improved practitioner knowledge (9/16), skills (7/16), and attitudes/beliefs (5/16). Although health care (6/16) and health (2/16) outcomes were reported in some studies there was very limited evidence of positive intervention impacts. Only four studies utilised existing validated measurement tools to assess intervention outcomes. CONCLUSION: Training and development of the health workforce remain a principle strategy towards the goal of improved cultural competence in health services and systems. Diverse approaches are available to increase health workforce cultural competence. However, the effects of interventions beyond practitioner knowledge and attitudes remains unclear. Assessment of practitioner behavioural outcomes as well as measures of intervention impact on healthcare and health outcomes are needed to build a stronger evidence base. PMID- 29609615 TI - Metabolic syndrome in hypertensive women in the age of menopause: a case study on data from general practice electronic health records. AB - BACKGROUND: There is potential for medical research on the basis of routine data used from general practice electronic health records (GP eHRs), even in areas where there is no common GP research platform. We present a case study on menopausal women with hypertension and metabolic syndrome (MS). The aims were to explore the appropriateness of the standard definition of MS to apply to this specific, narrowly defined population group and to improve recognition of women at high CV risk. METHODS: We investigated the possible uses offered by available data from GP eHRs, completed with patients interview, in goal of the study, using a combination of methods. For the sample of 202 hypertensive women, 47-59 years old, a data set was performed, consisted of a total number of 62 parameters, 50 parameters used from GP eHRs. It was analysed by using a mixture of methods: analysis of differences, cutoff values, graphical presentations, logistic regression and decision trees. RESULTS: The age range found to best match the emergency of MS was 51-55 years. Deviations from the definition of MS were identified: a larger cut-off value of the waist circumference measure (89 vs 80 cm) and parameters BMI and total serum cholesterol perform better as components of MS than the standard parameters waist circumference and HDL-cholesterol. The threshold value of BMI at which it is expected that most of hypertensive menopausal women have MS, was found to be 25.5. The other best means for recognision of women with MS include triglycerides above the threshold of 1.7 mmol/L and information on statins use. Prevention of CVD should focus on women with a new onset diabetes and comorbidities of a long-term hypertension with anxiety/depression. CONCLUSIONS: The added value of this study goes beyond the current paradigm on MS. Results indicate characteristics of MS in a narrowly defined, specific population group. A comprehensive view has been enabled by using heterogenoeus data and a smart combination of various methods for data analysis. The paper shows the feasibility of this research approach in routine practice, to make use of data which would otherwise not be used for research. PMID- 29609616 TI - Palmitate-induced Slc2a4/GLUT4 downregulation in L6 muscle cells: evidence of inflammatory and endoplasmic reticulum stress involvement. AB - BACKGROUND: Obesity is strongly associated to insulin resistance, inflammation, and elevated plasma free fatty acids, but the mechanisms behind this association are not fully comprehended. Evidences suggest that endoplasmic reticulum (ER) stress may play a role in this complex pathophysiology. The aim of the present study was to investigate the involvement of inflammation and ER stress in the modulation of glucose transporter GLUT4, encoded by Slc2a4 gene, in L6 skeletal muscle cells. METHODS: L6 cells were acutely (2 h) and chronically (6 and 12 h) exposed to palmitate, and the expression of several proteins involved in insulin resistance, ER stress and inflammation were analyzed. RESULTS: Chronic and acute palmitate exposure significantly reduced GLUT4 protein (~ 39%, P < 0.01) and its mRNA (18%, P < 0.01) expression. Only acute palmitate treatment increased GRP78 (28%, P < 0.05), PERK (98%, P < 0.01), eIF-2A (35%, P < 0.01), IRE1a (60%, P < 0.05) and TRAF2 (23%, P < 0.05) protein content, and PERK phosphorylation (106%, P < 0.001), but did not elicit eIF-2A, IKK phosphorylation or increased XBP1 nuclear content. Additionally, acute and chronic palmitate increased NFKB p65 nuclear content (~ 30%, P < 0.05) and NFKB binding activity to Slc2a4 gene promoter (~ 45%, P < 0.05). CONCLUSION: Different pathways are activated in acute and chronic palmitate induced-repression of Slc2a4/GLUT4 expression. This regulation involves activation of initial component of ER stress, such as the formation of a IRE1a-TRAF2-IKK complex, and converges to NFKB-induced repression of Slc2a4/GLUT4. These results link ER stress, inflammation and insulin resistance in L6 cells. PMID- 29609617 TI - Genome-wide analysis of gene regulation mechanisms during Drosophila spermatogenesis. AB - BACKGROUND: During Drosophila spermatogenesis, testis-specific meiotic arrest complex (tMAC) and testis-specific TBP-associated factors (tTAF) contribute to activation of hundreds of genes required for meiosis and spermiogenesis. Intriguingly, tMAC is paralogous to the broadly expressed complex Myb-MuvB (MMB)/dREAM and Mip40 protein is shared by both complexes. tMAC acts as a gene activator in spermatocytes, while MMB/dREAM was shown to repress gene activity in many cell types. RESULTS: Our study addresses the intricate interplay between tMAC, tTAF, and MMB/dREAM during spermatogenesis. We used cell type-specific DamID to build the DNA-binding profiles of Cookie monster (tMAC), Cannonball (tTAF), and Mip40 (MMB/dREAM and tMAC) proteins in male germline cells. Incorporating the whole transcriptome analysis, we characterized the regulatory effects of these proteins and identified their gene targets. This analysis revealed that tTAFs complex is involved in activation of achi, vis, and topi meiosis arrest genes, implying that tTAFs may indirectly contribute to the regulation of Achi, Vis, and Topi targets. To understand the relationship between tMAC and MMB/dREAM, we performed Mip40 DamID in tTAF- and tMAC-deficient mutants demonstrating meiosis arrest phenotype. DamID profiles of Mip40 were highly dynamic across the stages of spermatogenesis and demonstrated a strong dependence on tMAC in spermatocytes. Integrative analysis of our data indicated that MMB/dREAM represses genes that are not expressed in spermatogenesis, whereas tMAC recruits Mip40 for subsequent gene activation in spermatocytes. CONCLUSIONS: Discovered interdependencies allow to formulate a renewed model for tMAC and tTAFs action in Drosophila spermatogenesis demonstrating how tissue-specific genes are regulated. PMID- 29609618 TI - What should the African health workforce know about disasters? Proposed competencies for strengthening public health disaster risk management education in Africa. AB - BACKGROUND: As part of efforts to implement the human resources capacity building component of the African Regional Strategy on Disaster Risk Management (DRM) for the health sector, the African Regional Office of the World Health Organization, in collaboration with selected African public health training institutions, followed a multistage process to develop core competencies and curricula for training the African health workforce in public health DRM. In this article, we describe the methods used to develop the competencies, present the identified competencies and training curricula, and propose recommendations for their integration into the public health education curricula of African member states. METHODS: We conducted a pilot research using mixed methods approaches to develop and test the applicability and feasibility of a public health disaster risk management curriculum for training the African health workforce. RESULTS: We identified 14 core competencies and 45 sub-competencies/training units grouped into six thematic areas: 1) introduction to DRM; 2) operational effectiveness; 3) effective leadership; 4) preparedness and risk reduction; 5) emergency response and 6) post-disaster health system recovery. These were defined as the skills and knowledge that African health care workers should possess to effectively participate in health DRM activities. To suit the needs of various categories of African health care workers, three levels of training courses are proposed: basic, intermediate, and advanced. The pilot test of the basic course among a cohort of public health practitioners in South Africa demonstrated their relevance. CONCLUSIONS: These competencies compare favourably to the findings of other studies that have assessed public health DRM competencies. They could provide a framework for scaling up the capacity development of African healthcare workers in the area of public health DRM; however further validation of the competencies is required through additional pilot courses and follow up of the trainees to demonstrate outcome and impact of the competencies and curriculum. PMID- 29609619 TI - Pre-exposure prophylaxis (PrEP) in an era of stalled HIV prevention: Can it change the game? AB - Pre-exposure prophylaxis (PrEP) for HIV prevention has evolved significantly over the years where clinical trials have now demonstrated the efficacy of oral PrEP, and the field is scaling-up implementation. The WHO and UNAIDS have made PrEP implementation a priority for populations at highest risk, and several countries have developed guidelines and national plans accordingly, largely based on evidence generated by demonstration projects. PrEP presents the opportunity to change the face of HIV prevention by offering a new option for protection against HIV and disrupting current HIV prevention systems. Nevertheless, as with all new technologies, both practical and social requirements for implementation must be taken into account if there is to be sustained and widespread adoption, which will also apply to forthcoming prevention technologies. Defining and building success for PrEP within the scope of scale-up requires careful consideration. This review summarises where the PrEP field is today, lessons learned from the past, the philosophy and practicalities of how successful programming may be defined, and provides perspectives of costs and affordability. We argue that a successful PrEP programme is about effective intervention integration and ultimately keeping people HIV negative. PMID- 29609620 TI - High mitochondrial sequence divergence in synanthropic flea species (Insecta: Siphonaptera) from Europe and the Mediterranean. AB - BACKGROUND: Adult fleas are haematophagous ectoparasites of warm-blooded vertebrates, particularly mammals. Among them, the cat flea (Ctenocephalides felis) and the human flea (Pulex irritans) have high veterinary-medical significance, owing to their cosmopolitan distribution and role in the transmission of important vector-borne pathogens. While the taxonomy of Ct. felis has been investigated on a morphological basis during the past decades, its molecular-phylogenetic analyses have been only recently conducted. This study expands the knowledge on Ct. felis from hitherto less studied geographical regions, and includes representatives from additional flea families, less investigated with molecular approaches. METHODS: Fleas were collected in four countries of the Mediterranean Basin (Croatia, Italy, Malta and Israel), as well as in Hungary, from domestic and wild carnivores, rodents and humans. The DNA extracts of representative fleas (n = 148), belonging to ten species of eight genera, were used for PCR amplification of part of their cytochrome c oxidase subunits 1, 2 (cox1, cox2) and 18S rRNA genes, followed by sequencing and phylogenetic analyses. RESULTS: The majority (65.6%) of Ct. felis felis cox2 sequences showed 99.4-100% similarity to each other (haplogroup A), whereas those from Malta and Israel had 98.1-98.7% sequence similarity (haplogroup B), and a third sequence from Israel (haplotype C) had as low as 96.3% sequence similarity in comparison with a reference sequence from group "A". Except for the shape of the head, no consistent morphological differences (e.g. in chaetotaxy) were found between haplogroups "A" and "C". Haplotypes of Ct. canis were genetically more homogenous, with 99.6-100% sequence similarity to each other. However, when P. irritans collected from humans was compared to those from three species of wild carnivores, these only had 96.6% cox2 similarity. The mouse flea, Leptopsylla segnis and the northern rat flea, Nosopsyllus fasciatus were both shown to have haplotypes with low intraspecific cox2 similarities (96.2 and 94.4%, respectively). Taken together, differences between mitochondrial lineages within four flea species exceeded that observed between two Chaetopsylla spp. (which had 97.3% cox2 similarity). The topologies of cox1 and cox2 phylogenetic trees were in line with relevant sequence comparisons. Conversely, 18S rRNA gene analyses only resolved differences above the species level. CONCLUSIONS: Ctenocephalides felis felis, P. irritans, L. segnis and N. fasciatus were shown to have such a high level of mitochondrial gene heterogeneity, that the uniformity of these flea taxa should be reconsidered. Although the present results are limited (especially in the case of L. segnis and N. fasciatus), there appears to be no geographical or host restriction, which could explain the divergence of these genetic lineages. PMID- 29609622 TI - 16p11.2 microdeletion syndrome: a case report. AB - BACKGROUND: The recurrent ~ 600 kb 16p11.2 microdeletion is among the most commonly known genetic etiologies of autism spectrum disorder, overweightness, and related neurodevelopmental disorders. CASE PRESENTATION: Our patient is a 2 year-old white girl from the first pregnancy of a non-consanguineous healthy young white couple (father 33-years old and mother 29-years old). Our patient and her parents' DNA were analyzed by comparative genomic hybridization-array platform. Comparative genomic hybridization-array analysis highlighted a ~ 600 kb deletion in 16p11.2 region. It has a segregant nature, since it was found in the mother and in her 2-year-old daughter. The microdeletion was confirmed by fluorescence in situ hybridization analysis. CONCLUSIONS: The presented clinical case is worthy of note since the observed microdeletion is often associated with a clinical phenotype tending to overweightness, but the proband (female) was hospitalized due to poor height and weight development, and anorexia. Moreover, the segregant nature of the observed genomic abnormality has to be noted, as well as the phenotypic variability between the mother and daughter. The case described here enriches the phenotypical spectrum linked to the 16p11.2 microdeletion. For these reasons, in the presence of a suspected genetic pathology it is fundamental to study the proband from the clinical point of view, to extend the clinical observation to the parents, and to provide a good family anamnesis. In this way, it is possible to reveal the presence of a familial genetic pathology whose phenotypical outcomes can be highly variable among the members of a family. PMID- 29609621 TI - A qualitative exploration of contextual factors that influence dissemination and implementation of evidence-based chronic disease prevention across four countries. AB - BACKGROUND: Little is known about the contextual factors affecting the uptake of evidence-based chronic disease interventions in the United States and in other countries. This study sought to better understand the contextual similarities and differences influencing the dissemination and implementation of evidence-based chronic disease prevention (EBCDP) in Australia, Brazil, China, and the United States. METHODS: Between February and July 2015, investigators in each country conducted qualitative, semi-structured interviews (total N = 50) with chronic disease prevention practitioners, using interview guides that covered multiple domains (e.g., use of and access to EBCDP interventions, barriers and facilitators to the implementation of EBCDP interventions). RESULTS: Practitioners across the four countries reported only a few programmatic areas in which repositories of EBCDP interventions were used within their workplace. Across countries, academic journals were the most frequently cited channels for accessing EBCDP interventions, though peers were commonly cited as the most useful. Lack of time and heavy workload were salient personal barriers among practitioners in Australia and the United States, while lack of expertise in developing and implementing EBCDP interventions was more pertinent among practitioners from Brazil and China. Practitioners in all four countries described an organizational culture that was unsupportive of EBCDP. Practitioners in Brazil, China and the United States cited an inadequate number of staff support to implement EBCDP interventions. A few practitioners in Australia and China cited lack of access to evidence. Partnerships were emphasized as key facilitators to implementing EBCDP interventions across all countries. CONCLUSIONS: This study is novel in its cross-country qualitative exploration of multilevel constructs of EBCDP dissemination and implementation. The interviews produced rich findings about many contextual similarities and differences with EBCDP that can inform both cross-country and country-specific research and practice to address barriers and improve EBCDP implementation among the four countries long-term. PMID- 29609623 TI - Cross sectional study on prevalence of sickle cell alleles S and C among patients with mild malaria in Ivory Coast. AB - OBJECTIVES: Sickle cell anemia is due to a mutations on the betaglobin gene, inducing abnormal hemoglobin. In West Africa the main mutations lead to S or C types of hemoglobin. Patients with homozygote mutations seem protected against severe malaria, but not against mild disease. The prevalence of abnormal hemoglobin among patients attending dispensaries for mild malaria is thus unknown. A retrospective study was conducted to update data on the prevalence of S and C hemoglobin among patients attending dispensaries with mild malaria. Enrolment of patients was conducted during in vivo malaria treatment efficacy survey following the 42 days WHO protocol. A group of non-infected pregnant women and a group of patients with fever different from malaria, were also recruited in the same dispensaries. RESULTS: 794 blood samples were included. S and C genotypes were found in all the regions of Ivory Coast with the highest prevalence in the Northern region (S and C genotypes, 27%). In non-infected patients, prevalence of mutations was higher than in malaria patients. CONCLUSION: A high proportion of patients with mild malaria carried genetic hemoglobin disorder. This population of high risk must be better investigated to control treatment efficacy and to manage complications. PMID- 29609624 TI - Can education improve clinical practice concerning delirium in older hospitalised patients? Results of a pre-test post-test study on an educational intervention for nursing staff. AB - BACKGROUND: Delirium is a common and serious complication of hospitalisation in older adults. It can lead to prolonged hospital stay, institutionalisation, and even death. However, it often remains unrecognised or is not managed adequately. The aim of this study was to evaluate the effects of an educational intervention for nursing staff on three aspects of clinical practice concerning delirium in older hospitalised patients: the frequency and correctness of screening for delirium using the 13-item Delirium Observation Screening score (DOS), and the frequency of geriatric consultations requested for older patients. The a priori expectations were that there would be an increase in all three of these outcomes. METHODS: We designed an educational intervention and implemented this on two inpatient hospital units. Before providing the educational session, the nursing staff was asked to fill out two questionnaires about delirium in older hospitalised patients. The educational session was then tailored to each unit based on the results of these questionnaires. Additionally, posters and flyers with information on the screening and management of delirium were provided and participants were shown where to find additional information. Relevant data (outcomes, demographics and background patient data) were collected retrospectively from digital medical files. Data was retrospectively collected for four different time points: three pre-test and one post-test. RESULTS: There was a significant increase in frequency of delirium screening (P = 0.001), and both units showed an increase in the correctness of the screening. No significant effect of the educational intervention was found for the proportion of patients who received a geriatric consultation (P = 0.083). CONCLUSION: The educational intervention was fairly successful in making positive changes in clinical practice: after the educational session an improvement in the frequency and correctness of screening for delirium was observed. A trend, though not significant, towards an increase in the proportion of geriatric consultations for older hospitalised patients was also observed. PMID- 29609625 TI - PfCap380 as a marker for Plasmodium falciparum oocyst development in vivo and in vitro. AB - BACKGROUND: Despite the importance of the Plasmodium berghei oocyst capsule protein (PbCap380) in parasite survival, very little is known about the orthologous Plasmodium falciparum capsule protein (PfCap380). The goal of this work was to study the growth of P. falciparum oocysts using PfCap380 as a developmental marker. METHODS: To study P. falciparum oocyst development using both in vivo (mosquito-derived) and in vitro (culture-derived) growth conditions, antibodies (polyclonal antisera) were raised against PfCap380. For studies on in vivo oocysts, mature P. falciparum gametocytes were fed to Anopheles stephensi mosquitoes. For studies on in vitro parasites, P. falciparum gametocytes were induced and matured for subsequent ookinete production. Ookinetes were purified and then tested for binding affinity to basal lamina components and transformation into early oocysts, which were grown on reconstituted basal lamia coated wells with novel oocyst media. To monitor in vivo oocyst development, immunofluorescence assays (IFA) were performed using anti-PfCap380 antisera on Pf infected mosquito midguts. IFA were also performed on culture-derived oocysts to follow in vitro oocyst development. RESULTS: The anti-PfCap380 antisera allowed detection of early midgut oocysts starting at 2 days after gametocyte infection, while circumsporozoite protein was definitively observed on day 6. For in vitro culture, significant transformation of gametocytes to ookinetes (24%) and of ookinetes to early oocysts (85%) was observed. After screening several basal lamina components, collagen IV provided greatest binding of ookinetes and transformation into early oocysts. Finally, PfCap380 expression was observed on the surface of culture-derived oocysts but not on gametocytes or ookinetes. CONCLUSIONS: This study presents developmental monitoring of P. falciparum oocysts produced in vivo and in vitro. The anti-PfCap380 antisera serves as an important reagent for developmental studies of oocysts from the mosquito midgut and also from oocyst culture using in vitro methodology. The present data demonstrate that PfCap380 is a useful marker to follow the development and maturation of in vivo and in vitro produced oocysts as early as 2 days after zygote formation. Further in vitro studies focused on oocyst and sporozoite maturation will support the manufacturing of whole sporozoites for malaria vaccines. PMID- 29609626 TI - CHRNA5 and CHRNA3 polymorphism and lung cancer susceptibility in Palestinian population. AB - OBJECTIVE: The genetic polymorphism (rs16969968 in CHRNA5, and rs1051730 in CHRNA3 genes) were recently shown to be associated with risk of LC. The aim of this study is to elucidate whether they predispose Palestinian individuals to lung cancer, and how is this related to smoking. RESULTS: Frequency of the rs16969968-A allele was significantly higher in the case group (36.7%) than in normal controls (17.5%; P = 0.022; OR = 6.83 for AA and 2.81 for AG genotypes). The frequency of rs1051730-T allele was also significantly higher in the case group (46.7%) than in the control group (22.5%; P = 0.001; OR = 2.20 for TC and 13.22 for TT genotypes). Frequency of rs16969968-A allele was higher in smokers (29.1%) than nonsmokers (15.7%) regardless of lung cancer; similarly, frequency of rs1051730-T allele was also higher in smokers than in smokers (46.7% vs 22.5%, respectively). The higher the proportion of the risk allele (rs16969968-A and rs1051730-T), the higher the mean number of daily consumed cigarettes (P = 0.006). Carrying rs16969968-A and/or rs1051730-T alleles results in an increased risk to lung cancer probably by increasing the individual's tendency for heavy smoking. The allelic frequency of the rs16969968-A and rs1051730-T alleles among normal Palestinian controls is similar to different populations worldwide. PMID- 29609627 TI - Trends in spatio-temporal dynamics of visceral leishmaniasis cases in a highly endemic focus of Bihar, India: an investigation based on GIS tools. AB - BACKGROUND: Visceral leishmaniasis (VL) in Bihar State (India) continues to be endemic, despite the existence of effective treatment and a vector control program to control disease morbidity. A clear understanding of spatio-temporal distribution of VL may improve surveillance and control implementation. This study explored the trends in spatio-temporal dynamics of VL endemicity at a meso scale level in Vaishali District, based on geographical information systems (GIS) tools and spatial statistical analysis. METHODS: A GIS database was used to integrate the VL case data from the study area between 2009 and 2014. All cases were spatially linked at a meso-scale level. Geospatial techniques, such as GIS layer overlaying and mapping, were employed to visualize and detect the spatio temporal patterns of a VL endemic outbreak across the district. The spatial statistic Moran's I Index (Moran's I) was used to simultaneously evaluate spatial correlation between endemic villages and the spatial distribution patterns based on both the village location and the case incidence rate (CIR). Descriptive statistics such as mean, standard error, confidence intervals and percentages were used to summarize the VL case data. RESULTS: There were 624 endemic villages with 2719 (average 906 cases/year) VL cases during 2012-2014. The Moran's I revealed a cluster pattern (P < 0.05) of CIR distribution at the meso-scale level. On average, 68 villages were newly-endemic each year. Of which 93.1% of villages' endemicity were found to have occurred on the peripheries of the previous year endemic villages. The mean CIR of the endemic villages that were peripheral to the following year newly-endemic villages, compared to all endemic villages of the same year, was higher (P < 0.05). CONCLUSION: The results show that the VL endemicity of new villages tends to occur on the periphery of villages endemic in the previous year. High-CIR plays a major role in the spatial dispersion of the VL cases between non-endemic and endemic villages. This information can help achieve VL elimination throughout the Indian subcontinent by improving vector control design and implementation in highly-endemic district. PMID- 29609628 TI - Reconsideration of the nomadic condition of the southernmost Guachichiles based on the relationship with their environment. AB - BACKGROUND: The Guachichiles were a group of Chichimeca people that inhabited the southern and central parts of the Mexican Plateau. In the southern area of their distribution, they occupied and used the tunales, extensive forests of arborescent nopales (Opuntia spp.). Their pre-Columbian distribution was dissected by the Royal Silver Road established by the Spaniards, and this lead to them being main protagonists in the so-called Chichimeca War, during the sixteenth century. With very little first-hand documentation, the Guachichiles were described as savage, warring, primitive, hunting nomads, but little efforts have been done to understand their daily life habits. Based on the relationship of pre-Columbian southern Guachichiles with their environment, we re-valuate whether they were nomads, as the Chichimecas collectively have been labeled, or whether those living in tunales could live year-round in this habitat. As part of our analysis, we propose the primary plant and animal species that integrated their diet. METHODS: We draw information from a review of bibliographic sources, complemented with extensive searches in all pertinent Mexican archives. We carried out field work to define the geographical extent of the pre-Columbian territory of the southernmost Guachichiles, based on the Spanish Chronicles, remnant fragments of vegetation, landscape characteristics, and geographic names related with nopales. Using approaches from wildlife ecology, historical sciences and ethnobiological information on wild resources currently or recently used in the area, we proposed which resources were available to the southernmost Guachichiles, and how their primary diet might have been. RESULTS: The habitat of the southern Guachichiles, the tunal forest, was exuberant and rich in resources, having provided numerous plant products, of which tunas (prickly pears) and mesquite pods were of uttermost importance. At least 10 plant foods were available within the tunales. They would have consumed at least seven birds (including their eggs), six mammals, four reptiles, grubs, and honey, in addition to at least six vertebrate species hunted at the edges of the tunal with grasslands and shrublands or in more open patches of tunal. In addition to food, they prepared at least three alcoholic beverages, had access to two species of probable psychoactive beehive cacti and to one hallucinogenic mushroom species, and might have traded peyote from the north with outside-tunal Guachichiles. CONCLUSIONS: The rich habitat in which southern Guachichiles lived allowed them to be largely sedentary, but this required that they prevented other groups from gathering and hunting in their habitat. As a result of them living in and defending the tunales, the Guachichiles could have been divided into two or three habitat-driven groups: Tunal Guachichiles, and grassland and, or shrubland Guachichiles. PMID- 29609629 TI - SGK1 inhibition-induced autophagy impairs prostate cancer metastasis by reversing EMT. AB - BACKGROUND: Despite SGK1 has been identified and characterized as a tumor promoting gene, the functions and underlying mechanisms of SGK1 involved in metastasis regulation have not yet been investigated in cancer. METHODS: We investigated the cellular responses to GSK650394 treatment and SGK1 silencing (or overexpression) in human prostate cancer (PCa) cell lines and PC3 xenografts by wound healing assay, migration and invasion assay, western blotting, immunofluorescence and immunohistochemistry. RESULTS: In the present study, we found that SGK1 expression positively correlates with human prostate cancer (PCa) progression and metastasis. We show that SGK1 inhibition significantly attenuates EMT and metastasis both in vitro and in vivo, whereas overexpression of SGK1 dramaticlly promoted the invasion and migration of PCa cells. Our further results suggest that SGK1 inhibition induced antimetastatic effects, at least partially via autophagy-mediated repression of EMT through the downregulation of Snail. Moreover, ectopic expression of SGK1 obviously attenuated the GSK650394-induced autophagy and antimetastatic effects. What's more, dual inhibition of mTOR and SGK1 enhances autophagy and leads to synergistic antimetastatic effects on PCa cells. CONCLUSIONS: Taken together, this study unveils a novel mechanism in which SGK1 functions as a tumor metastasis-promoting gene and highlights how co targeting SGK1 and autophagy restrains cancer progression due to the amplified antimetastatic effects. PMID- 29609630 TI - Rationale and design for cognitive behavioral therapy for anxiety disorders in children with autism spectrum disorder: a study protocol of a randomized controlled trial. AB - BACKGROUND: Autism spectrum disorder (ASD) is found in approximately 1% of the population and includes core symptoms that affect general and social development. Beside these core symptoms, it is suggested that up to 60% of children with ASD suffer from comorbid anxiety disorders which may further affect educational, social and general development as well as quality of life. The main goal of this study is to examine the effectiveness of a manualized cognitive behavioral therapy (CBT) anxiety program adapted for children with ASD. METHODS: This study is a randomized controlled trial (RCT). Fifty children with ASD and anxiety, aged 7 to 13 years, will be randomly assigned to group CBT or a wait-list control (WL) condition. The design will follow a two (CBT and WL) by two (pre-post assessment) mixed between-within design. The control group will receive intervention after the waitlist period of 13 weeks. Primary outcomes are diagnostic status and severity of the anxiety disorders, measured with The Anxiety Disorder Interview Schedule for DSM-IV, Parent and Child Versions. Secondary outcomes are parent and child ratings on questionnaires on the child's level of anxiety and impact on everyday life. Additional outcomes entail information gathered from parents, child and teachers on the child's behavior and negative self-statements, together with social and adaptive skills. Follow-up data will be collected 3 months after intervention. DISCUSSION: This study aims to evaluate the effectiveness of a manualized CBT program in Danish children with ASD and anxiety within a mental health clinic setting. The hypothesis is that training anxiety reduction skills will decrease anxiety in children, as well as ensure better psychosocial development for the child in general. TRIAL REGISTRATION: https://ClinicalTrials.gov ( NCT02908321 ). Registered 19th of September 2016. PMID- 29609631 TI - Quantitative analysis of respiration-induced motion of each liver segment with helical computed tomography and 4-dimensional computed tomography. AB - BACKGROUND: To analyze the respiratory-induced motion of each liver segment using helical computed tomography (helical CT) and 4-dimensional computed tomography (4DCT), and to establish the individual segment expansion margin of internal target volume (ITV) to facilitate target delineation of tumors in different liver segments. METHODS: Twenty patients who received radiotherapy with CT-simulation scanning of the whole liver in both helical CT and 10-phase-gated 4DCT were investigated, including 2 patients with esophagus cancer, 4 with lung cancer, 10 with breast cancer, 2 with liver cancer, 1 with thymoma, and 1 with gastric diffuse large B-cell lymphoma (DLBCL). For each patient, 9 representative points were drawn on the helical CT images of liver segments 1, 2, 3, 4a, 4b, 5, 6, 7, and 8, respectively, and adaptively deformed to 2 phases of the 4DCT images at the end of inspiration (phase 0 CT) and expiration (phase 50 CT) in the treatment planning system. Using the amplitude of each point between phase 0 CT and phase 50 CT, we established quantitative data for the respiration-induced motion of each liver segment in 3-dimensional directions. Moreover, using the amplitude between the original helical CT and both 4DCT images, we rendered the individual segment expansion margin of ITV for hepatic target delineation to cover more than 95% of each tumor. RESULTS: The average amplitude (mean +/- standard deviation) was 0.6 +/- 3.0 mm in the left-right (LR) direction, 2.3 +/- 2.4 mm in the anterior-posterior (AP) direction, and 5.7 +/- 3.4 mm in the superior-inferior (SI) direction, respectively. All of the segments moved posteriorly and superiorly during expiration. Segment 7 had the largest amplitude in the SI direction, at 8.6 +/- 3.4 mm. Otherwise, the segments over the lateral side, including segments 2, 3, 6, and 7, had greater excursion in the SI direction compared to the medial segments. To cover more than 95% of each tumor, the required expansion margin of ITV in the LR, AP, and SI directions were at least 2.5 mm, 2.5 mm, and 5.0 mm on average, respectively, with variations between different segments. CONCLUSIONS: The greatest excursion occurred in liver segment 7, followed by the segments over the lateral side in the SI direction. The individual segment expansion margin of ITV is required to delineate targets for each segment and direction. PMID- 29609632 TI - Naming is not explaining: future directions for the "cognitive reserve" and "brain maintenance" theories. AB - Contemporary imaging measures of the human brain explain less than half of the differences in cognitive functioning and change among older adults. Researchers have advanced several theories and concepts to guide research that aims to better explain these individual differences in cognitive aging. Taking the fundamental measurement model in the empirical sciences as a starting point, we here scrutinize two such complementary theories, brain maintenance and cognitive reserve, in an attempt to clarify these theories, gauge their usefulness, and identify ways in which they can be further developed. We demonstrate that, although both theories are highly useful for spawning theorizing and empirical work, they can be further developed by detailing the theoretical and operational definitions of the concepts that they propose. We propose a few ways forward in these directions. PMID- 29609633 TI - Online immunocapture ICP-MS for the determination of the metalloprotein ceruloplasmin in human serum. AB - OBJECTIVE: The human copper-protein ceruloplasmin (Cp) is the major copper containing protein in the human body. The accurate determination of Cp is mandatory for the reliable diagnosis of several diseases. However, the analysis of Cp has proven to be difficult. The aim of our work was a proof of concept for the determination of a metalloprotein-based on online immunocapture ICP-MS. The immuno-affinity step is responsible for the enrichment and isolation of the analyte from serum, whereas the compound-independent quantitation with ICP-MS delivers the sensitivity, precision, and large dynamic range. Off-line ELISA (enzyme-linked immunosorbent assay) was used in parallel to confirm the elution profile of the analyte with a structure-selective method. The total protein elution was observed with the 32S mass trace. The ICP-MS signals were normalized on a 59Co signal. RESULTS: The human copper-protein Cp could be selectively determined. This was shown with pure Cp and with a sample of human serum. The good correlation with off-line ELISA shows that Cp could be captured and eluted selectively from the anti-Cp affinity column and subsequently determined by the copper signal of ICP-MS. PMID- 29609634 TI - Evaluation of three cryoprotectants used with bovine milk affected with Mycoplasma bovis in different freezing conditions. AB - OBJECTIVES: Currently, there is no consensus protocols regarding the combination of glycerol (GLY), gelatin or foetal bovine serum (FBS) with dimethyl sulphoxide (DMSO) as cryoprotectants for Mycoplasma bovis in bovine milk samples. This study aimed to compare different cryopreservation compounds and storage temperatures for M. bovis. RESULTS: There were significant differences in the survival of M. bovis on different media. Differences were also observed between different storage conditions. All additives improved the survival of M. bovis in comparison to control (CON). The combination of GLY and DMSO was shown to be significantly different to CON with 57.1% (95% CI = 21.43-133.34) and 19.1% (95% CI = 11.73 60.27), respectively at week 16, and its use should be encouraged as a cryoprotectant for M. bovis at - 20 and - 80 degrees C. GEL/DMSO showed the highest survival rate for M. bovis with 57.14% (95% CI = 21.43-133.34) at 4 degrees C in comparison with CON 14.29% (95% CI = 9.60-50.39). FBS/DMSO showed the highest survival rate for the short-term preservation similarly to other additives. The evaluated cryopreservative compounds would improve survivability of M. bovis in milk for both transport and long-term storage. Hence, it is recommended to use the mentioned methods for routine transportation or storage purposes for suspicious M. bovis milk samples. PMID- 29609636 TI - A perspective on "cure" for Rett syndrome. AB - The reversal of the Rett syndrome disease process in the Mecp2 mouse model of Guy et al. (2007) has motivated families and researchers to work on this condition. The reversibility in adult mice suggests that there is potentially much to be gained from rational treatments applied to patients of any age. However, it may be difficult to strike the right balance between enthusiasm on the one hand and realism on the other. One effect of this has been a fragmentation of the "Rett syndrome community" with some groups giving priority to work aimed at a cure while fewer resources are devoted to medical or therapy-based interventions to enhance the quality of life of affected patients or provide support for their families.Several possible therapeutic approaches are under development that, it is claimed and hoped, may lead to a "cure" for patients with Rett syndrome. While all have a rationale, there are potential obstacles to each being both safe and effective. Furthermore, any strategy that succeeded in restoring normal levels of MECP2 gene expression throughout the brain carries potential pitfalls, so that it will be of crucial importance to introduce any clinical trials of such therapies with great care.Expectations of families for a radical, rational treatment should not be inflated beyond a cautious optimism. This is particularly because affected patients with us now may not be able to reap the full benefits of a "cure". Thus, interventions aimed at enhancing the quality of life of affected patients should not be forgone and their importance should not be minimised. PMID- 29609635 TI - Why was PERV not transmitted during preclinical and clinical xenotransplantation trials and after inoculation of animals? AB - Porcine endogenous retroviruses (PERVs) are present in the genome of all pigs, they infect certain human cells and therefore pose a special risk for xenotransplantation using pig cells, tissues and organs. Xenotransplantation is being developed in order to alleviate the reduced availability of human organs. Despite the fact that PERVs are able to infect certain human cells and cells from other species, transmission of PERVs has not been observed when animals (including non-human primates) were inoculated with PERV preparations or during preclinical xenotransplantations. The data indicate that PERVs were not transmitted because they were not released from the transplant or were inhibited by intracellular restriction factors and innate immunity in the recipient. In a single study in guinea pigs, a transient PERV infection and anti-PERV antibodies were described, indicating that in this case at least, the immune system may also have been involved. PMID- 29609637 TI - Primary total knee arthroplasty using constrained condylar knee design for severe deformity and stiffness of knee secondary to post-traumatic arthritis. AB - BACKGROUND: Key to a successful outcome of total knee arthroplasty (TKA) is to attain optimum alignment, adequate balance, and deformity correction. In primary TKA, this can be achieved efficiently by posterior stabilized (PS) design with or without the sub-periosteal release. However, certain circumstances such as post traumatic arthritis are often associated with severe deformities with a significant bone defect, stiffness, and instability. Such deformities are extremely difficult to balance with soft tissue release only and require additionally constrained prostheses even in primary TKA. In such situation, constrained condylar knee (CCK) design is the ultimate choice. This study primarily aimed to report on clinical outcome, regain of function, and complication of patients who underwent primary CCK-TKA for severe deformity of the knee secondary to post-traumatic arthritis. The secondary aim was to find out the mid-term prostheses survival. METHODS: Between February 2007 and November 2013, 38 consecutive patients with post-traumatic arthritis of the knee received cemented primary CCK-TKA. Thirty-four patients (21 men and 13 women) who had a minimum of 3 years follow-up were included in this retrospective study. We used Knee Society Score (KSS), Hospital for Special Surgery (HSS) score, and roentgenographic evaluation form to assess the patients. Prostheses survival was assessed using Kaplan-Meier's survival analysis. RESULTS: Patients were followed up for an average duration of 6.47 years. KSS knee score improved from 44 points (23-68) pre-operatively to 91 points (76-100) post-operatively [P < 0.001]. The average KSS functional score improved from 49 points (20-75) pre-operatively to 91 points (65-100) post-operatively [P < 0.001]. The average HSS score improved from 51 points (27-83) pre-operatively to 91 points (75-100) post-operatively [P < 0.001]. Similarly, the average ROM improved from 68.09 degrees +/- 35.99 degrees (0 degrees -120 degrees ) to 113.68 degrees +/- 8.90 degrees (100 degrees -130 degrees ) post-operatively [P < 0.001]. The average hip-knee-ankle (HKA) angle was 176.88 degrees +/- 14.48 degrees (135 degrees -199 degrees ) pre-operatively and 180.24 degrees +/- 1.77 degrees (175 degrees -184 degrees ) post-operatively. Radiolucencies were evident in 13 knees, mostly on the tibial side. Prostheses survival was 94.7% at a mean follow-up of 6.47 years. CONCLUSION: Despite severe deformity, instability, and stiffness at a relatively young age, mid-term follow-up of primary CCK-TKA in post-traumatic arthritis provides satisfactory clinical and functional outcomes with 94.7% prostheses survival. However, it is not without complication. PMID- 29609638 TI - The truncated mutant HBsAg expression increases the tumorigenesis of hepatitis B virus by regulating TGF-beta/Smad signaling pathway. AB - BACKGROUND: It has been reported that the emergence of HBV rtA181T/sW172* mutant could result in a dominant secretion defect of HBsAg and increase the risk of HCC development. This study was designed to reveal the role and possible pathogenic mechanism of truncated mutant HBsAg in tumorigenesis of HBV rtA181T/sW172* mutant. RESULTS: As compared to wide type or substituted mutant HBsAg, the ratio of cell clones was significant higher in L02 cells stable expressing truncated mutant HBsAg. Injection of L02 cells stable expressing truncated mutant HBsAg into the dorsal skin fold of nude mice resulted in increased primary tumor growth compared to L02 cells stable expressing wide-type and substituted mutant HBsAg. In HBV replication L02 cell lines, the key molecular involved in TGF-beta/Smad pathway was also investigated. We found that the mRNA and protein levels of Smad3/2, CREB and CyclinD1 were significantly higher and TGFBI level was significantly lower in cells stably expressing truncated mutant HBsAg as compared to cells stably expressing wide-type and substituted mutant HBsAg. Additionally, after administration of TGF-beta1 (increasing TGFBI level), the volume of tumor is obviously reduced in nude mice with injection of L02 cells stable expressing truncated HBsAg. CONCLUSIONS: The emergence of sW172* mutant may increase the tumorigenesis of HBV, and its mechanism may be associated with down-regulated expression of TGFBI in TGF-beta/Smad signaling pathway. PMID- 29609639 TI - The best method for evaluating anteversion of the acetabular component after total hip arthroplasty on plain radiographs. AB - BACKGROUND: Several radiological methods for measuring the anteversion of the acetabular component after total hip arthroplasty (THA) exist, and no single standardized method has been established. We evaluated the reliability and accuracy of six widely utilized methods (Liaw et al., Lewinnek et al., Widmer, Hassan et al., Ackland et al., and Woo and Morrey) for measuring anteversion on plain radiographs, using a reference standard in the same definition obtained from the PolyWare programme. METHODS: We reviewed 71 patients who underwent primary unilateral THA. The anteversion of the acetabular component was measured on pelvis AP radiographs using five different methods (Liaw et al., Lewinnek et al., Widmer, Hassan et al., and Ackland et al.) and on cross-table lateral radiographs using the method of Woo and Morrey. The values obtained using the PolyWare programme, which determines the anteversion of the acetabular component by edge detection, were regarded as the reference standard. RESULTS: Intra- and inter-observer reliabilities were excellent for all methods using plain radiographs, including the PolyWare programme. The method of Liaw et al. obtained values similar to those obtained using the PolyWare programme and was thus considered accurate (P = 0.447). However, values obtained using the other five methods significantly differed from those obtained using the PolyWare programme and were thus considered less accurate (P < 0.001, P < 0.001, P < 0.001, P = 0.007, and P < 0.001, respectively). CONCLUSION: The method of Liaw et al. is more accurate than other methods using plain radiographs for the measurement of the anteversion of the acetabular component after THA, with reference to the anteversion obtained from the PolyWare programme. PMID- 29609640 TI - Is there an association between the use of complementary medicine and vaccine uptake: results of a pilot study. AB - OBJECTIVE: Despite the incredible success of paediatric immunisation, support is not universal. It has been suggested that complementary medicine practitioners enable vaccine rejection and his study aims to explore the relationship between complementary medicine use and paediatric vaccination. A total of 149 Australian parents were recruited via a parenting website and Facebook groups to complete an online questionnaire. RESULTS: The majority of parents (66.4%) stated that their children's vaccination status was up-to-date. Vaccination status was associated with parental education, area of residence, income, private health insurance, and having a Health Care Card (p < 0.05). Children's vaccinations were more likely to be up-to-date if they had consulted a general practitioner in the previous 12 months (OR 21.75; p < 0.001), and less likely to be up-to-date if they had consulted a complementary medicine practitioner (OR 0.10; p < 0.001) in the same period. Concerns about vaccine safety and efficacy were the most common reasons for a child's immunisation status not being up-to-date. These findings highlight an interface between lower vaccine uptake and visits to complementary medicine practitioners. These results emphasise the need to examine the routine paediatric care practices of complementary medicine practitioners as a crucial piece of the puzzle in understanding vaccine rejection. PMID- 29609641 TI - Enhanced Nogo-P3 amplitudes of mothers compared with non-mother women during an emotional Go/Nogo task. AB - BACKGROUND: It is known that emotion regulatory responses of humans are changed by the experiences they have, but in particular, they are changed by becoming a mother. A recent study has found how a woman's emotion regulatory response to a child's crying changes after becoming a mother. However, mothers' emotion regulatory responses other than those to children and the association between emotion regulatory response and parental stress are still unknown. METHODS: Eighteen healthy Japanese females (nine mothers and nine non-mothers) participated in the experiment. They performed an emotional Go/Nogo task, with facial expressions of others (angry, happy, and neutral faces) used as emotional stimuli. The percentage of correct responses, response time, and event-related potentials (ERPs) during the task was measured. RESULTS: This comparison revealed that the mother group had a larger P3 (Nogo-P3) amplitude than the non-mother group when Nogo trials were held. This indicates that in mothers, there was greater activation of the behavioral inhibition-related brain areas than in non mother women when they inhibited inappropriate behavior following recognition of facial expressions of others. In addition, in the mother group, there was a negative correlation between parental stress levels and Nogo-P3 amplitudes evoked by angry faces. This suggests that there is a relation between the level of parental stress of mothers and their emotion regulatory responses to angry faces. CONCLUSIONS: Our results demonstrate that mothers' emotion regulatory processes may differ from those of non-mothers in response, not only to a child's crying but also to expressions of emotions by others, and also suggest that the inhibitory recognition activity of mothers can be affected by parental stress. PMID- 29609642 TI - A comprehensive characterization of myocardial and vascular phenotype in pediatric chronic kidney disease using cardiovascular magnetic resonance imaging. AB - BACKGROUND: Children with chronic kidney disease (CKD) have increased cardiovascular mortality. Identifying high-risk children who may benefit from further therapeutic intervention is difficult as cardiovascular abnormalities are subtle. Although transthoracic echocardiography may be used to detect sub clinical abnormalities, it has well-known problems with reproducibility that limit its ability to accurately detect these changes. Cardiovascular magnetic resonance (CMR) is the reference standard method for assessing blood flow, cardiac structure and function. Furthermore, recent innovations enable the assessment of radial and longitudinal myocardial velocity, such that detection of sub-clinical changes is now possible. Thus, CMR may be ideal for cardiovascular assessment in pediatric CKD. This study aims to comprehensively assess cardiovascular function in pediatric CKD using CMR and determine its relationship with CKD severity. METHODS: A total of 120 children (40 mild, 40 moderate, 20 severe pre-dialysis CKD subjects and 20 healthy controls) underwent CMR with non invasive blood pressure (BP) measurements. Cardiovascular parameters measured included systemic vascular resistance (SVR), total arterial compliance (TAC), left ventricular (LV) structure, ejection fraction (EF), cardiac timings, radial and longitudinal systolic and diastolic myocardial velocities. Between group comparisons and regression modelling were used to identify abnormalities in CKD and determine the effects of renal severity on myocardial function. RESULTS: The elevation in mean BP in CKD was accompanied by significantly increased afterload (SVR), without evidence of arterial stiffness (TAC) or increased fluid overload. Left ventricular volumes and global function were not abnormal in CKD. However, there was evidence of LV remodelling, prolongation of isovolumic relaxation time and reduced systolic and diastolic myocardial velocities. CONCLUSION: Abnormal cardiovascular function is evident in pre-dialysis pediatric CKD. Novel CMR biomarkers may be useful for the detection of subtle abnormalities in this population. Further studies are needed to determine to prognostic value of these biomarkers. PMID- 29609644 TI - Assessing the effectiveness of Enhanced Psychological Care for patients with depressive symptoms attending cardiac rehabilitation compared with treatment as usual (CADENCE): a pilot cluster randomised controlled trial. AB - BACKGROUND: Around 17% of people attending UK cardiac rehabilitation programmes have depression. Optimising psychological wellbeing is a rehabilitation goal, but provision of psychological care is limited. We developed and piloted an Enhanced Psychological Care (EPC) intervention embedded within cardiac rehabilitation, aiming to test key areas of uncertainty to inform the design of a definitive randomised controlled trial (RCT) and economic evaluation. METHODS: An external pilot randomised controlled trial (RCT) randomised eight cardiac rehabilitation teams (clusters) to either usual care of cardiac rehabilitation provision (UC), or EPC in addition to UC. EPC comprised mental health care coordination and patient-led behavioural activation with nurse support. Adults eligible for cardiac rehabilitation following an acute coronary syndrome and identified with new-onset depressive symptoms during an initial nurse assessment were eligible. Measures were performed at baseline and 5- and 8-month follow-ups and compared between EPC and UC. Team and participant recruitment and retention rates, and participant outcomes (clinical events, depression, anxiety, health-related quality of life, patient experiences, and resource use) were assessed. RESULTS: Eight out of twenty teams were recruited and randomised. Of 614 patients screened, 55 were eligible and 29 took part (5%, 95% CI 3 to 7% of those screened), with 15 patient participants cluster randomised to EPC and 14 to UC. Nurse records revealed that 8/15 participants received the maximum number of EPC sessions offered; and 4/15 received no sessions. Seven out of fifteen EPC participants were referred to another NHS psychological service compared to none in UC. We followed up 27/29 participants at 5 months and 17/21 at 8 months. The mean difference (EPC minus UC) in depressive symptoms (Beck Depression Inventory) at follow-up (adjusting for baseline score) was 1.7 (95% CI - 3.8 to 7.3; N = 26) at 5 months and 4.4 (95% CI - 1.4 to 10.2; N = 17) at 8 months. DISCUSSION: While valued by patients and nurses, organisational and workload constraints are significant barriers to EPC implementation. There remains a need to develop and test new models of psychological care within cardiac rehabilitation. Our study offers important data to inform the design of future trials of similar interventions. TRIAL REGISTRATION: ISRCTN34701576 . Registered on 29 May 2014. Funding details: UK NIHR HTA Programme (project 12/189/09). PMID- 29609643 TI - Clinical features of children with enthesitis-related juvenile idiopathic arthritis / juvenile spondyloarthritis followed in a French tertiary care pediatric rheumatology centre. AB - BACKGROUND: Childhood-onset spondyloarthropathies usually start with enthesitis and peripheral arthritis. However, axial disease may develop afterward. Patients are most often classified, following revised (Edmonton 2011) ILAR criteria, as enthesitis-related arthritis, psoriatic arthritis, or unclassified juvenile idiopathic arthritis, particularly in cases of psoriasis in the patient or a first-degree relative. In adults, peripheral spondyloarthritis is classified by ASAS criteria. METHODS: We retrospectively studied patients with childhood-onset spondyloarthropathies followed for more than one year in our referral centre. We did not exclude patients with a personal or familial history of psoriasis. RESULTS: We included 114 patients followed between January 2008 and December 2015 for a median of 2.5 years (IQR = 2.3). Sixty-nine per-cent of patients fulfilled the revised ILAR classification criteria for enthesitis-related arthritis, and 92% the ASAS criteria for peripheral spondyolarthritis (p < 0.001). Axial disease and sacroiliitis were rare at disease onset. However, they appeared during follow-up in 63% and 47% of cases respectively, after a median disease duration of 2.6 (IC 95% [2.2-4.4]) and 5.3 years (IC 95% [4.1-7.7]), respectively. Multivariable analysis showed that familial history of spondyloarthritis was associated with the presence of sacroiliitis and active disease at the latest follow-up (OR = 3.61 [1.5-8.7], p < 0.01 and 2.98 [1.2 7.3], p = 0.02, respectively). CONCLUSION: Axial involvement developed in most patients within five years. Revised Edmonton criteria were less sensitive than ASAS criteria to classify patients as having childhood-onset spondyloarthropathies. The main risk factor for both sacroiliitis and persistent active disease was a familial history of spondyloarthritis. PMID- 29609645 TI - Host specificity of Enterocytozoon bieneusi genotypes in Bactrian camels (Camelus bactrianus) in China. AB - BACKGROUND: Enterocytozoon bieneusi is an obligate, intracellular fungus and is commonly reported in humans and animals. To date, there have been no reports of E. bieneusi infections in Bactrian camels (Camelus bactrianus). The present study was conducted to understand the occurrence and molecular characteristics of E. bieneusi in Bactrian camels in China. RESULTS: Of 407 individual Bactrian camel fecal specimens, 30.0% (122) were E. bieneusi-positive by nested polymerase chain reaction (PCR) based on internal transcriber spacer (ITS) sequence analysis. A total of 14 distinct E. bieneusi ITS genotypes were obtained: eight known genotypes (genotype EbpC, EbpA, Henan-IV, BEB6, CM8, CHG16, O and WL17), and six novel genotypes (named CAM1 to CAM6). Genotype CAM1 (59.0%, 72/122) was the most predominant genotype in Bactrian camels in Xinjiang, and genotype EbpC (18.9%, 23/122) was the second-most predominant genotype. Phylogenetic analysis revealed that six known genotypes (EbpC, EbpA, WL17, Henan-IV, CM8 and O) and three novel genotypes (CAM3, CAM5 and CAM6) fell into the human-pathogenic group 1. Two known genotypes (CHG16 and BEB6) fell into the cattle host-specific group 2. The novel genotypes CAM1, CAM 2 and CAM4 cluster into group 8. CONCLUSIONS: To our knowledge, this is the first report of E. bieneusi in Bactrian camels. The host specific genotype CAM1 was the predominant genotype, which plays a negligible role in the zoonotic transmission of E. bieneusi. However, the second-most predominant genotype, EbpC, has greater zoonotic potential. PMID- 29609646 TI - Stereotactic body-radiotherapy boost dose of 18 Gy vs 21 Gy in combination with androgen-deprivation therapy and whole-pelvic radiotherapy for intermediate- or high-risk prostate cancer: a study protocol for a randomized controlled, pilot trial. AB - BACKGROUND: Combination therapy using external-beam radiotherapy (EBRT) with a brachytherapy boost has demonstrated superior biochemical control than dose escalated EBRT alone. Whereas brachytherapy is disadvantageous because it is an invasive procedure, stereotactic body-radiotherapy (SBRT) using CyberKnife could emulate the dose distribution of brachytherapy and is a non-invasive and safe modality to control intra-fractional movement. We therefore adopted SBRT using CyberKnife as a boost therapy after whole-pelvic radiotherapy (WPRT). METHODS/DESIGN: In this prospective, randomized, single-center, pilot study for intermediate- and high-risk prostate cancer without nodal or distant metastasis, after androgen-deprivation therapy and WPRT, patients will be randomized to one of two SBRT boost regimens, i.e., 18 or 21 Gy administered in three fractions every other day. DISCUSSION: The aim of this trial is to evaluate acute toxicities using both physician- and patient-reported outcomes and short-term biochemical control with SBRT boost following WPRT. Additionally, chronic toxicities and long-term biochemical control will be evaluated as secondary endpoints in this trial. Based on the generated results, we will plan the full scale phase II study for selecting the SBRT boost dose. TRIAL REGISTRATION: ClinicalTrials.gov, ID; NCT03322020 . Retrospectively registered on 26 October 2017. PMID- 29609647 TI - Higher satisfaction with an alternative collection device for stool sampling in colorectal cancer screening with fecal immunochemical test: a cross-sectional study. AB - BACKGROUND: Identifying preferences for stool collection devices may help increase uptake rates for colorectal cancer screening via fecal immunochemical test (FIT). This study surveyed satisfaction with different devices utilized to collect stool samples for FIT: a conventional container and a sampling bottle (Eiken OC-Sensor). METHODS: This cross-sectional study was conducted at the National Cancer Center, Korea. Participants aged 50-74 years who used either a conventional container or a sampling bottle to collect a stool sample for FIT were asked to complete a questionnaire designed to survey their satisfaction with the stool collection process and their intentions to undergo FIT in subsequent screening rounds. In total, 1657 participants (1224 conventional container, 433 sampling bottle) were included for analysis. RESULTS: Satisfaction with the sampling bottle was higher than that with the conventional container (79.9% vs.73.0%, p = 0.005, respectively; aOR = 1.52, 95% CI: 1.16-2.00). Participants satisfied with the sampling bottle were more likely to be female, be of younger age (50-64 years old), have higher household income, and have prior experience with FIT. Intentions to undergo subsequent screening were stronger among those given the sampling bottle than those given the conventional container (aOR = 1.78, 95% CI: 1.28-2 .48). CONCLUSIONS: Satisfaction with the stool collection process was higher with the sampling bottle. However, additional studies are needed to validate whether the increased satisfaction and stronger intentions to undergo subsequent screening with the sampling bottle could actually lead to increased uptake in subsequent rounds, along with analysis of the device's cost effectiveness. PMID- 29609648 TI - Six-helix bundle completion in the distal C-terminal heptad repeat region of gp41 is required for efficient human immunodeficiency virus type 1 infection. AB - BACKGROUND: The native pre-fusion structure of gp120/gp41 complex of human immunodeficiency virus type 1 was recently revealed. In the model, the helices of gp41 (alpha6, alpha7, alpha8, and alpha9) form a four-helix collar underneath trimeric gp120. Gp41 is a class I fusion protein and mediates membrane fusion by forming a post-fusion structure called the six-helix bundle (6HB). The comparison of the pre- and post-fusion structures revealed the large conformational changes in gp41 during the antiparallel packing of the N- and C-terminal heptad repeats (NHRs and CHRs) in membrane fusion. Several mutagenesis studies of gp41 performed in the past were interpreted based on 6HB, the only available structure at that time. To obtain an insight about the current pre-fusion structural model and conformational changes during membrane fusion, alanine insertion mutagenesis of the NHR, CHR and connecting loop regions of HXB2 gp41 was performed. The effects of mutations on biosynthesis and membrane fusion were analyzed by immunoblotting and fusion assays, respectively. The extent of membrane fusion was evaluated by split luciferase-based pore formation and syncytia formation assays, respectively. RESULTS: Consistent with the current structural model, drastic negative effects of mutations on biosynthesis and membrane fusion were observed for NHR, loop, and proximal regions of CHR (up to amino acid position 643). The insertions in alpha9 after it leaves the four-helix collar were tolerable for biosynthesis. These CHR mutants showed varying effects on membrane fusion. Insertion at position 644 or 645 resulted in poor pore and syncytia formation. Efficient pore and syncytia formation almost similar to that of the wild type was observed for insertion at position 647, 648 or 649. However, recovery of virus infectivity was only observed for the insertions beyond position 648. CONCLUSIONS: The mutagenesis data for HXB2 gp41 is in agreement with the recent pre-fusion structure model. The virus infection data suggested that fusion pores sufficiently large enough for the release of the virus genome complex are formed after the completion of 6HB beyond position 648. PMID- 29609649 TI - Ethnomycological study in the Kilum-Ijim mountain forest, Northwest Region, Cameroon. AB - BACKGROUND: Majority of the people in rural areas depend on traditional fungi based medicines to combat different illnesses. This ethnomycological survey was undertaken to document the traditional knowledge of mushrooms among the communities in the Kilum-Ijim mountain forest reserve. Although macrofungi are exploited for food and medicine, their ethnomycological knowledge has not been documented in this ecosystem. METHODS: A field study was carried out between 2014 and 2015; 14 mushrooms used by the local communities were collected and identified using the polymorphism of the ribosomal ITS1, 5.8S, and ITS2 regions. Semi-structured questionnaires, focus group discussions, and pictorial method were used to collect information on edibility, local names, indigenous knowledge, and the role of macrofungi in ten communities. RESULTS: Ethnomycological findings revealed that mushrooms were used as food and medicine, while the non-edible species were regarded as food from Satan. Eight species, Polyporus tenuiculus, Termitomyces striatus, Termitomyces microcarpus Auricularia polytricha, Laetiporus sulphureus, Termitomyces sp.1, Termitomyces sp.2, and Polyporus dictyopus, were reported as edible and Auricularia polytricha, Daldinia concentrica, Ganoderma applanatum, Lentinus squarrosulus, Polyporus dictyopus, Termitomyces microcarpus, Trametes versicolor, Vascellum pretense and Xylaria sp., were used as medicine in traditional health care. Local names were found to be a very important factor in distinguishing between edible, medicinal, and poisonous mushrooms. Edible mushrooms are called "awo'oh" in Belo and "Kiwoh" in Oku. Poisonous mushrooms were commonly referred to as "awo'oh Satan" in Belo and "Kiwohfiyini" in Oku. Mushrooms were highly valued as a source of protein and as a substitute for meat in their diets. It is worth noting that Polyporus dictyopus was reported here for the first time in literature as an edible mushroom species. CONCLUSION: Local knowledge of medicinal mushrooms in the treatment of different illness still exists in all ten villages surveyed. Elderly men and women appear to play an important role in primary health care services in these communities. This survey underscores the need to preserve and document traditional knowledge of the different medicinal mushrooms used in treating different illnesses and for more future scientific research on the mushrooms to determine their efficacy and their safety. PMID- 29609650 TI - A gel-based PCR method to differentiate sheeppox virus field isolates from vaccine strains. AB - BACKGROUND: Sheeppox (SPP) and goatpox (GTP) caused by sheeppox virus (SPPV) and goatpox virus (GTPV), respectively of the genus Capripoxvirus in the family Poxviridae, are severely afflicting small ruminants' production systems in Africa and Asia. In endemic areas, SPP and GTP are controlled using vaccination with live attenuated vaccines derived from SPPV, GTPV or Lumpy skin disease virus (LSDV). Sometimes outbreaks occur following vaccination. In order to successfully control the spread of the virus, it is essential to identify whether the animals were infected by the field strain and the vaccine did not provide sufficient protection. Alternatively, in some cases the vaccine strain may cause adverse reactions in vaccinated animals or in rare occasions, re-gain virulence. Thus, diagnostic tools for differentiation of virulent strains from attenuated vaccine strains of the virus are needed. The aim of this study was to identify an appropriate diagnostic target region in the capripoxvirus genome by comparing the genomic sequences of SPPV field isolates with those of the most widely used SPP vaccine strains. RESULTS: A unique 84 base pair nucleotide deletion located between the DNA ligase gene and the VARV B22R homologue gene was found only in SPPV vaccines derived from the Romanian and Yugoslavian RM/65 strains and absent in SPPV field isolates originated from various geographical locations of Asia and Africa. In addition, we developed and evaluated a conventional PCR assay, exploiting the targeted intergenic region to differentiate SPPV vaccine virus from field isolates. The assay produced an amplicon size of 218 bp for the vaccine strains, while the SPPV field isolates resulted in a 302 bp PCR fragment. The assay showed good sensitivity and specificity, and the results were in full agreement with the sequencing data of the PCR amplicons. CONCLUSION: The developed assay is an improvement of currently existing diagnostic tools and, when combined with a capripox virus species-specific assay, will enhance SPP and GTP diagnosis and surveillance and facilitate epidemiological investigations in countries using live attenuated SPP vaccines. In addition, for laboratories with limited resources, the assay provides a simple and cost-effective alternative for sequencing. PMID- 29609651 TI - The use of standardized management protocols for critically ill patients with non traumatic subarachnoid hemorrhage: a protocol of a systematic review and meta analysis. AB - BACKGROUND: Caring for patients with subarachnoid hemorrhage (SAH) presents unique challenges, due in part to the severity of the underlying insult, competing systemic injuries, and unpredictable clinical course. Even when management occurs in dedicated critical care settings, treatment uncertainty often persists, and morbidity and mortality from the condition remain high. Complex decisions in SAH care may be simplified with the use of standardized management protocols (SMPs). SMPs incorporate evidence-based guidelines into a practical framework for decision-making, thereby providing clinicians with an algorithm for organizing treatments. But despite these potential advantages, it is currently unknown whether SMPs may improve outcomes in the critical care of patients with SAH. METHODS: We will conduct a systematic review of cohort studies and randomized control trials of adult patients with non-traumatic SAH who received care according to a standardized management protocol. Comprehensive search strategies will be developed for MEDLINE, EMBASE, WoS, CINAHL, and CENTRAL, to identify studies for review. The gray literature will be scanned for further eligible studies. Two reviewers will independently screen the material generated by the search to identify studies for inclusion. A standardized data extraction form will be used to collect information on study design, baseline characteristics, details of the management protocol employed, and primary and secondary outcomes. Where possible, meta-analyses with random-effects models will be used to calculate pooled estimates of effect sizes. Statistical heterogeneity will be evaluated with the I2 statistics, and risk of bias and reporting quality will be assessed independently and in duplicate with standardized scales. DISCUSSION: We anticipate a significant degree of clinical heterogeneity in our review, as protocols will likely vary in their content, implementation, and ICU setting. We will aim to summarize the current literature in this domain to understand if SMPs, as a low-cost process-targeted intervention, improve outcomes for critically ill patients with SAH. Our review will additionally inform future research endeavors to improve the processes of care for this patient population. SYSTEMATIC REVIEW REGISTRATION: CRD42017069173. PMID- 29609652 TI - Protocol for a systematic review of methods and cost-effectiveness findings of economic evaluations of obesity prevention and/or treatment interventions in children and adolescents. AB - BACKGROUND: Childhood obesity is a major global public health problem, with governments increasingly having to undertake various strategies to reduce excess weight in their populations. Considering the increasing number of well-conducted intervention studies in the field of childhood obesity prevention, there are relatively few published economic evaluations. The proposed systematic review will explore the methods of these economic evaluations, examine the limitations and establish the evidence base for cost-effectiveness analyses. METHODS/DESIGN: Systematic review methodology will be applied to identify, select and extract data from published economic evaluation studies (trial-based, non-trial based, simulation-based, decision model and trial based model economic evaluations) of obesity prevention and/or treatment interventions in children and adolescents. A systematic literature search will be conducted using bibliographic databases (MEDLINE, EMBASE, CINAHL, Web of Science, EconLit, PsycINFO, Cochrane Library, Centre for Reviews and Dissemination (CRD) and Cost-Effectiveness Analysis (CEA) Registry). The review will only include full economic evaluations. There will be no restrictions based on language, perspective, follow-up duration, sample size, country or setting. To minimise selection bias, translation of non-English language articles will be undertaken. The quality of included studies will be assessed. Following data extraction, a narrative synthesis of the results from the included studies will be undertaken. Subgroup analysis will be considered where deemed appropriate. DISCUSSION: The findings from this review, which will include primary studies, will provide evidence to assist health policy decision makers interpret economic evaluations in this field. In addition, we will identify gaps in the current literature to inform future-related research. SYSTEMATIC REVIEW REGISTRATION: Prospero CRD42017062236. PMID- 29609653 TI - The active microbial community more accurately reflects the anaerobic digestion process: 16S rRNA (gene) sequencing as a predictive tool. AB - BACKGROUND: Amplicon sequencing methods targeting the 16S rRNA gene have been used extensively to investigate microbial community composition and dynamics in anaerobic digestion. These methods successfully characterize amplicons but do not distinguish micro-organisms that are actually responsible for the process. In this research, the archaeal and bacterial community of 48 full-scale anaerobic digestion plants were evaluated on DNA (total community) and RNA (active community) level via 16S rRNA (gene) amplicon sequencing. RESULTS: A significantly higher diversity on DNA compared with the RNA level was observed for archaea, but not for bacteria. Beta diversity analysis showed a significant difference in community composition between the DNA and RNA of both bacteria and archaea. This related with 25.5 and 42.3% of total OTUs for bacteria and archaea, respectively, that showed a significant difference in their DNA and RNA profiles. Similar operational parameters affected the bacterial and archaeal community, yet the differentiating effect between DNA and RNA was much stronger for archaea. Co occurrence networks and functional prediction profiling confirmed the clear differentiation between DNA and RNA profiles. CONCLUSIONS: In conclusion, a clear difference in active (RNA) and total (DNA) community profiles was observed, implying the need for a combined approach to estimate community stability in anaerobic digestion. PMID- 29609654 TI - Evaluation of a flipped classroom approach to learning introductory epidemiology. AB - BACKGROUND: Although the flipped classroom model has been widely adopted in medical education, reports on its use in graduate-level public health programs are limited. This study describes the design, implementation, and evaluation of a flipped classroom redesign of an introductory epidemiology course and compares it to a traditional model. METHODS: One hundred fifty Masters-level students enrolled in an introductory epidemiology course with a traditional format (in person lecture and discussion section, at-home assignment; 2015, N = 72) and a flipped classroom format (at-home lecture, in-person discussion section and assignment; 2016, N = 78). Using mixed methods, we compared student characteristics, examination scores, and end-of-course evaluations of the 2016 flipped classroom format and the 2015 traditional format. Data on the flipped classroom format, including pre- and post-course surveys, open-ended questions, self-reports of section leader teaching practices, and classroom observations, were evaluated. RESULTS: There were no statistically significant differences in examination scores or students' assessment of the course between 2015 (traditional) and 2016 (flipped). In 2016, 57.1% (36) of respondents to the end of-course evaluation found watching video lectures at home to have a positive impact on their time management. Open-ended survey responses indicated a number of strengths of the flipped classroom approach, including the freedom to watch pre-recorded lectures at any time and the ability of section leaders to clarify targeted concepts. Suggestions for improvement focused on ways to increase regular interaction with lecturers. CONCLUSIONS: There was no significant difference in students' performance on quantitative assessments comparing the traditional format to the flipped classroom format. The flipped format did allow for greater flexibility and applied learning opportunities at home and during discussion sections. PMID- 29609656 TI - Perspectives of primary health care staff on the implementation of a sexual health quality improvement program: a qualitative study in remote aboriginal communities in Australia. AB - BACKGROUND: Young people living in remote Australian Aboriginal communities experience high rates of sexually transmissible infections (STIs). STRIVE (STIs in Remote communities, ImproVed and Enhanced primary care) was a cluster randomised control trial of a sexual health continuous quality improvement (CQI) program. As part of the trial, qualitative research was conducted to explore staff perceptions of the CQI components, their normalisation and integration into routine practice, and the factors which influenced these processes. METHODS: In depth semi-structured interviews were conducted with 41 clinical staff at 22 remote community clinics during 2011-2013. Normalisation process theory was used to frame the analysis of interview data and to provide insights into enablers and barriers to the integration and normalisation of the CQI program and its six specific components. RESULTS: Of the CQI components, participants reported that the clinical data reports had the highest degree of integration and normalisation. Action plan setting, the Systems Assessment Tool, and the STRIVE coordinator role, were perceived as adding value to the program, but were less readily integrated or normalised. The remaining two components (dedicated funding for health promotion and service incentive payments) were seen as least relevant. Our analysis also highlighted factors which enabled greater integration of the CQI components. These included familiarity with CQI tools, increased accountability of health centre staff and the translation of the CQI program into guideline-driven care. The analysis also identified barriers, including high staff turnover, limited time involved in the program and competing clinical demands and programs. CONCLUSIONS: Across all of the CQI components, the clinical data reports had the highest degree of integration and normalisation. The action plans, systems assessment tool and the STRIVE coordinator role all complemented the data reports and allowed these components to be translated directly into clinical activity. To ensure their uptake, CQI programs must acknowledge local clinical guidelines, be compatible with translation into clinical activity and have managerial support. Sexual health CQI needs to align with other CQI activities, engage staff and promote accountability through the provision of clinic specific data and regular face-to-face meetings. TRIAL REGISTRATION: Australian and New Zealand Clinical Trials Registry ACTRN12610000358044 . Registered 6/05/2010. Prospectively Registered. PMID- 29609657 TI - Associations of increases in public transport use with physical activity and adiposity in older adults. AB - BACKGROUND: We investigated predictors of two increases in older people's public transport use: initiating public transport use among non-users; and increasing public transport use amongst users. We also investigated associations of these changes with physical activity, Body Mass Index (BMI) and waist circumference. METHODS: Data come from the 2008 and 2012 English Longitudinal Study of Ageing (ELSA). Logistic regression assessed predictors of increases in public transport use among adults aged >=50 years. Gender-stratified logistic and linear models assessed associations of increases in public transport use with changes in physical activity and adiposity. RESULTS: Those becoming eligible for a free older person's bus pass were more likely to both initiate and increase public transport use (e.g. for initiating public transport use Adjusted Odds Ratio (AORs) 1.77, 95% Confidence Interval 1.35; 2.33). Retiring from paid work was also associated with both initiating and increasing public transport use e.g. AOR 1.57 (1.29; 1.91) for initiating use. Women who increased public transport use had mean BMI 2.03 kg/m2 lower (- 2.84, - 1.21) at follow up than those who did not, although this was attenuated after adjusting for BMI at baseline (- 0.40 kg/m2, - 0.82, 0.01). After adjustment for baseline physical activity those initiating public transport use were more likely to undertake at least some physical activity in 2012 (e.g. AOR for women 1.67, 1.03; 2.72). CONCLUSIONS: Both initiating and increasing public transport use were associated with increased physical activity and may be associated with lower adiposity among women. These findings strengthen the case for considering public transport provision as an effective means of promoting healthier ageing. PMID- 29609655 TI - Host-microbe interactions in octocoral holobionts - recent advances and perspectives. AB - Octocorals are one of the most ubiquitous benthic organisms in marine ecosystems from the shallow tropics to the Antarctic deep sea, providing habitat for numerous organisms as well as ecosystem services for humans. In contrast to the holobionts of reef-building scleractinian corals, the holobionts of octocorals have received relatively little attention, despite the devastating effects of disease outbreaks on many populations. Recent advances have shown that octocorals possess remarkably stable bacterial communities on geographical and temporal scales as well as under environmental stress. This may be the result of their high capacity to regulate their microbiome through the production of antimicrobial and quorum-sensing interfering compounds. Despite decades of research relating to octocoral-microbe interactions, a synthesis of this expanding field has not been conducted to date. We therefore provide an urgently needed review on our current knowledge about octocoral holobionts. Specifically, we briefly introduce the ecological role of octocorals and the concept of holobiont before providing detailed overviews of (I) the symbiosis between octocorals and the algal symbiont Symbiodinium; (II) the main fungal, viral, and bacterial taxa associated with octocorals; (III) the dominance of the microbial assemblages by a few microbial species, the stability of these associations, and their evolutionary history with the host organism; (IV) octocoral diseases; (V) how octocorals use their immune system to fight pathogens; (VI) microbiome regulation by the octocoral and its associated microbes; and (VII) the discovery of natural products with microbiome regulatory activities. Finally, we present our perspectives on how the field of octocoral research should move forward, and the recognition that these organisms may be suitable model organisms to study coral-microbe symbioses. PMID- 29609658 TI - Sulforaphane attenuates pulmonary fibrosis by inhibiting the epithelial mesenchymal transition. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease with no effective treatment. The epithelial-mesenchymal transition (EMT) is a critical stage during the development of fibrosis. To assess the effect of sulforaphane (SFN) on the EMT and fibrosis using an in vitro transforming growth factor (TGF)-beta1-induced model and an in vivo bleomycin (BLM)-induced model. METHODS: In vitro studies, cell viability, and cytotoxicity were measured using a Cell Counting Kit-8. The functional TGF-beta1-induced EMT and fibrosis were assessed using western blotting and a quantitative real-time polymerase chain reaction. The lungs were analyzed histopathologically in vivo using hematoxylin and eosin and Masson's trichrome staining. The BLM-induced fibrosis was characterized by western blotting and immunohistochemical analyses for fibronectin, TGF-beta1, E-cadherin (E-cad), and alpha-smooth muscle actin (SMA) in lung tissues. RESULTS: SFN reversed mesenchymal-like changes induced by TGF beta1 and restored cells to their epithelial-like morphology. The results confirmed that the expression of the epithelial marker, E-cadherin, increased after SFN treatment, while expression of the mesenchymal markers, N-cadherin, vimentin, and alpha-SMA decreased in A549 cells after SFN treatment. In addition, SFN inhibited TGF-beta1-induced mRNA expression of the EMT-related transcription factors, Slug, Snail, and Twist. The SFN treatment attenuated TGF-beta1-induced expression of fibrosis-related proteins, such as fibronection, collagen I, collagen IV, and alpha-SMA in MRC-5 cells. Furthermore, SFN reduced the TGF-beta1 induced phosphorylation of SMAD2/3 protein in A549 cells and MRC-5 cells. BLM induced fibrosis in mouse lungs that was also attenuated by SFN treatment, and SFN treatment decreased BLM-induced fibronectin expression, TGF-beta1 expression, and the levels of collagen I in the lungs of mice. CONCLUSIONS: SFN showed a significant anti-fibrotic effect in TGF-beta-treated cell lines and BLM-induced fibrosis in mice. These findings showed that SFN has anti-fibrotic activity that may be considered in the treatment of IPF. PMID- 29609659 TI - Dengue virus-like particles mimic the antigenic properties of the infectious dengue virus envelope. AB - BACKGROUND: The 4 dengue serotypes (DENV) are mosquito-borne pathogens that are associated with severe hemorrhagic disease. DENV particles have a lipid bilayer envelope that anchors two membrane glycoproteins prM and E. Two E-protein monomers form head-to-tail homodimers and three E-dimers align to form "rafts" that cover the viral surface. Some human antibodies that strongly neutralize DENV bind to quaternary structure epitopes displayed on E protein dimers or higher order structures forming the infectious virus. Expression of prM and E in cell culture leads to the formation of DENV virus-like particles (VLPs) which are smaller than wildtype virus particles and replication defective due to the absence of a viral genome. There is no data available that describes the antigenic landscape on the surface of flavivirus VLPs in comparison to the better studied infectious virion. METHODS: A large panel of well characterized antibodies that recognize epitope of ranging complexity were used in biochemical analytics to obtain a comparative antigenic surface view of VLPs in respect to virus particles. DENV patient serum depletions were performed the show the potential of VLPs in serological diagnostics. RESULTS: VLPs were confirmed to be heterogeneous in size morphology and maturation state. Yet, we show that many highly conformational and quaternary structure-dependent antibody epitopes found on virus particles are efficiently displayed on DENV1-4 VLP surfaces as well. Additionally, DENV VLPs can efficiently be used as antigens to deplete DENV patient sera from serotype specific antibody populations. CONCLUSIONS: This study aids in further understanding epitopic landscape of DENV VLPs and presents a comparative antigenic surface view of VLPs in respect to virus particles. We propose the use VLPs as a safe and practical alternative to infectious virus as a vaccine and diagnostic antigen. PMID- 29609661 TI - All-male hybrids of a tetrapod Pelophylax esculentus share its origin and genetics of maintenance. AB - BACKGROUND: Sexual parasites offer unique insights into the reproduction of unisexual and sexual populations. Because unisexuality is almost exclusively linked to the female sex, most studies addressed host-parasite dynamics in populations where sperm-dependent females dominate. Pelophylax water frogs from Central Europe include hybrids of both sexes, collectively named P. esculentus. They live syntopically with their parental species P. lessonae and/or P. ridibundus. Some hybrid lineages consist of all males providing a chance to understand the origin and perpetuation of a host-parasite (egg-dependent) system compared to sperm-dependent parthenogenesis. METHODS: We focused on P. ridibundus P. esculentus populations where P. ridibundus of both sexes lives together with only diploid P. esculentus males. Based on 17 microsatellite markers and six allozyme loci, we analyzed (i) the variability of individual genomes, (ii) the reproductive mode(s) of all-male hybrids, and (iii) the genealogical relationships between the hybrid and parental genomes. RESULTS: Our microsatellite data revealed that P. esculentus males bear Mendelian-inherited ridibundus genomes while the lessonae genome represents a single clone. Our data indicate that this clone did not recently originate from adjacent P. lessonae populations, suggesting an older in situ or ex situ origin. CONCLUSIONS: Our results confirm that also males can perpetuate over many generations as the unisexual lineage and successfully compete with P. ridibundus males for eggs provided by P. ridibundus females. Natural persistence of such sex-specific hybrid populations allows to studying the similarities and differences between male and female reproductive parasitism in many biological settings. PMID- 29609660 TI - Ginger (Zingiber officinale) phytochemicals-gingerenone-A and shogaol inhibit SaHPPK: molecular docking, molecular dynamics simulations and in vitro approaches. AB - BACKGROUND: Antibiotic resistance is a defense mechanism, harbored by pathogens to survive under unfavorable conditions. Among several antibiotic resistant microbial consortium, Staphylococcus aureus is one of the most havoc microorganisms. Staphylococcus aureus encodes a unique enzyme 6-hydroxymethyl-7,8 dihydropterin pyrophosphokinase (SaHPPK), against which, none of existing antibiotics have been reported. METHODS: Computational approaches have been instrumental in designing and discovering new drugs for several diseases. The present study highlights the impact of ginger phytochemicals on Staphylococcus aureus SaHPPK. Herein, we have retrieved eight ginger phytochemicals from published literature and investigated their inhibitory interactions with SaHPPK. To authenticate our work, the investigation proceeds considering the known antibiotics alongside the phytochemicals. Molecular docking was performed employing GOLD and CDOCKER. The compounds with the highest dock score from both the docking programmes were tested for their inhibitory capability in vitro. The binding conformations that were seated within the binding pocket showing strong interactions with the active sites residues rendered by highest dock score were forwarded towards the molecular dynamic (MD) simulation analysis. RESULTS: Based on molecular dock scores, molecular interaction with catalytic active residues and MD simulations studies, two ginger phytochemicals, gingerenone-A and shogaol have been proposed as candidate inhibitors against Staphylococcus aureus. They have demonstrated higher dock scores than the known antibiotics and have represented interactions with the key residues within the active site. Furthermore, these compounds have rendered considerable inhibitory activity when tested in vitro. Additionally, their superiority was corroborated by stable MD results conducted for 100 ns employing GROMACS package. CONCLUSIONS: Finally, we suggest that gingerenone-A and shogaol may either be potential SaHPPK inhibitors or can be used as fundamental platforms for novel SaHPPK inhibitor development. PMID- 29609663 TI - PERSPECTIVE: SOME CONCLUSIONS FROM MY LIFE IN HEALTH TECHNOLOGY ASSESSMENT. AB - I have worked in health technology assessment (HTA) since 1975, beginning in the United States Congress Office of Technology Assessment (OTA), where we were charged with defining "medical technology assessment". My main concern in HTA has always been efficacy of healthcare interventions. After years in OTA, I was invited to the Netherlands in 1985, where the Dutch government invited me to head a special commission concerning future healthcare technology and HTA. From there, I became involved in over forty countries, beginning in Europe and then throughout the world. My most intense involvements, outside the United States and Europe, have been in Brazil, China, and Malaysia. During these 40-plus years, I have seen HTA grow from its earliest beginnings to a worldwide force for better health care for everyone. I have also had some growing concerns, outlined in this Perspective article. Within HTA, I am most disappointed by a narrow perspective of cost-effective analysis, which tends to ignore considerations of culture, society, ethics, and organizational and legal issues. In the general environment affecting HTA and health care, I am most concerned about the need to protect the independence of HTA activities from influences of the healthcare industries. PMID- 29609664 TI - Prediction of Electroconvulsive Therapy Response and Remission in Major Depression: Meta-analysis - CORRIGENDUM. AB - SummaryThis notice describes a correction to the above mentioned paper. PMID- 29609662 TI - Considerations for expanding community exercise programs incorporating a healthcare-recreation partnership for people with balance and mobility limitations: a mixed methods evaluation. AB - OBJECTIVE: To increase access to safe and appropriate exercise for people with balance and mobility limitations, community organizations have partnered with healthcare providers to deliver an evidence-based, task-oriented group exercise program in community centers in Canada. We aimed to understand challenges and solutions to implementing this program model to inform plans for expansion. RESULTS: At a 1-day meeting, 53 stakeholders (healthcare/recreation personnel, program participants/caregivers, researchers) identified challenges to program implementation that were captured by seven themes: Resources to deliver the exercise class (e.g., difficulty finding instructors with the skills to work with people with mobility limitations); Program marketing (e.g., to foster healthcare referrals); Transportation (e.g., particularly from rural areas); Program access (e.g., program full); Maintaining program integrity; Sustaining partnerships (i.e., with healthcare partners); and Funding (e.g., to deliver program or register). Stakeholders prioritized solutions to form an action plan. A survey of individuals supervising 28 programs revealed that people with stroke, acquired brain injury, multiple sclerosis, and Parkinson's disease register at 95-100% of centers. The most prevalent issues with program fidelity across centers were not requiring a minimum level of walking ability (32%), class sizes exceeding 12 (21%), and instructor-to-participant ratios exceeding 1:4 (19%). Findings provide considerations for program expansion. PMID- 29609666 TI - Research Abstracts Radiography. PMID- 29609665 TI - Do not neglect calcium: a systematic review and meta-analysis (meta-regression) of its digestibility and utilisation in growing and finishing pigs. AB - Ca digestibility and utilisation in growing pigs are not well understood, and are usually neglected in diet formulation. This has implications not only for the accurate determination of its requirements but also for its interactions with other nutrients. A systematic review and meta-analysis (meta-regression) of published trials was carried out to quantify factors affecting Ca absorption and utilisation, and to derive an estimate of Ca endogenous excretion. The analysis was carried out on the data from forty studies, corresponding to 201 treatments performed on 1204 pigs. The results indicated that although Ca absorption and retention (g/kg of body weight per d) increased with increasing Ca intake (P<0.001), non-phytate-P intake (P<0.001) and exogenous phytase supplementation (P<0.001), these values decreased with increasing phytate-P intake (P<0.05). Interactions between exogenous phytase and Ca intake, indicating reduced efficacy of this enzyme (P<0.001), and between phytate-P intake and exogenous phytase, counteracting the direct negative effect of phytate-P (P<0.05) on Ca absorption and retention, were also detected. There were no effects of animal-related characteristics, such as pig genotype in Ca absorption and retention. The large amount of variance explained in Ca absorption (90 %) and retention (91 %) supported our choice of independent variables. Endogenous Ca losses obtained via linear regression were 239 mg/kg of DM intake (95 % CI 114, 364). These outcomes advance the current understanding of Ca digestibility and utilisation, and should contribute towards establishing requirements for digestible Ca. Consequently, pig diets will be more correctly formulated if digestible Ca values are used in estimating requirements for Ca. PMID- 29609667 TI - Cone Beam Computed Tomography (CBCT) in General Dental Practice. AB - Cone beam computed tomography (CBCT) can be a useful adjunct to conventional plain film radiography, but its use must be carefully justified as the radiation dose is generally higher. Factors affecting the dose include the field of view (FOV) size, the exposure factors, the angle of rotation and voxel size. Once justified, the exposure should be fully optimised to ensure the dose to the patient is kept as low as possible while ensuring there is no reduction in the diagnostic yield. The European Commission (EC) and the Faculty of General Dental Practice (FGDP)(UK) have published selection criteria on the use of CBCT in dentistry. This article provides an overview of CBCT and summarises the latest guidance on selection criteria relevant to the general dental practitioner. PMID- 29609668 TI - Radiopacities of the Jaws: Interpretation and Diagnosis. AB - General dental practitioners are less confident at diagnosing radiopaque lesions of the jaws than radiolucent ones, possibly because the incidence of jaw radiopacities is comparatively low. The current review covers the majority of radiopaque lesions that are referred for a specialist opinion, and focuses on those lesions that occur commonly or those that mimic other diagnoses. The majority of radiopaque jaw lesions represent normal anatomy/normal variants or superimposed soft tissue calcifications that are typically of no clinical significance. Common pathological radiopacities of the jaws include sclerosing (condensing) osteitis, a response to low-grade chronic apical infection, and odontomes, a form of odontogenic hamartoma. The typical imaging appearances of these and other jaw radiopacities are discussed. PMID- 29609669 TI - Good Practice in Radiography: Dos and Don'ts. PMID- 29609670 TI - Ransomware and Cyber Security: the King That Did Not Wannacry. PMID- 29609671 TI - Salivary Gland Diseases: Presentation and Investigation. AB - A number of salivary gland diseases may present with a wide variety of symptoms to the general dental practitioner, or may appear as unexpected findings on dental radiographs. Careful clinical examination in combination with appropriate imaging will assist practitioners in identifying whether further investigation or referral is required. This article explores the main types of salivary gland diseases and their potential pathology. PMID- 29609672 TI - Psychometric Properties of the Child-to-Parent Aggression Questionnaire in a Clinical Sample of Adolescents Who Abuse Their Parents: Prevalence and Gender Differences. AB - The main objective of this study was to validate the child-to-parent aggression questionnaire (CPAQ) in a clinical sample of adolescents who aggress against their parents. The second aim was to analyze the child-to-parent violence (CPV) prevalence and gender and age differences among these adolescents. The third aim was to analyze the frequency of CPV against mothers and fathers. The CPAQ was completed by 169 adolescents (49 girls) with a mean age of 16.26 years (SD = 1.56) who had committed CPV. Confirmatory factor analysis indicated a good model fit for four related factors (physical-aggression against mother, physical aggression against father, psychological-aggression against mother, psychological aggression against father). Hierarchical models indicated that these factors could be accounted for by broader dimensions of psychological versus physical aggression, and aggression against mother versus father. PMID- 29609673 TI - The Intersection of Stalking and the Severity of Intimate Partner Abuse. AB - Using data from the Chicago Women's Health Risk Study (N = 464), this study examined the intersection of stalking and the severity of intimate partner abuse while controlling for previously identified risk factors of intimate partner homicide. Findings indicate that (a) victims of life-threatening abuse by an intimate partner were significantly more likely to experience stalking than victims of nonlethal abuse; (b) after controlling for key risk factors, stalking increased the risk of life-threatening abuse; and (c) threats to kill the victim if she left was the only significant stalking-related behavior that increased the risk for life-threatening abuse. In addition, an offender's prior record and a higher number of previous abusive incidents increased the risk of life threatening abuse. Implications for prevention and future directions for research are discussed. PMID- 29609674 TI - Young Adult Victimization and Midlife Consequences: Sensitization or Steeling Effects of Childhood Adversity? AB - The interrelationship between victimization, violence, and substance use/abuse has been well established, yet those who experience victimization do not necessarily respond with violence or substance use or escalate to experiencing substance abuse symptoms. Drawing on literature from both the syndemic research from medical anthropology and the resilience research from psychology, this study examines the interaction between early childhood adversity and young adult violent victimization on later substance use/abuse and violent offending to provide insight into conditional effects. Data are derived from the Woodlawn Study, an African American cohort of men and women from a socioeconomically heterogeneous community in the South Side of Chicago, who were followed from first grade through age 42. Results indicate that those with lower levels of childhood adversity are more likely to suffer the negative consequences of violent victimization than those with higher childhood adversity, providing support for a "steeling" effect. PMID- 29609675 TI - Injury and Psychiatric Disorder in Low-Income Women Experiencing Bidirectional Intimate Partner Violence. AB - This study compared severity of physical violence, intimate partner violence (IPV)-related injury, and lifetime diagnoses of psychiatric disorders among women in relationships with bidirectional, unidirectional, or no IPV. The sample includes 763 low-income women from community-based family planning clinics. Results showed that women in relationships with bidirectional IPV were more likely to experience severe physical violence and severe IPV-related injury compared to women in the unidirectional IPV category. These women were also more likely to be diagnosed with drug abuse and depression than women in relationships without IPV. Similarly, women in the bidirectional IPV category were more likely to be diagnosed with drug abuse when compared to women in the victim-only unidirectional IPV category. Recommendations for health-care providers are discussed. PMID- 29609676 TI - Turkish Version of the Multidimensional Measure of Emotional Abuse: Preliminary Psychometrics in College Students. AB - The aim of the current study was to investigate the basic psychometrics of the Multidimensional Measure of Emotional Abuse (MMEA; Murphy & Hoover, 1999) in a Turkish sample. Two hundred and fifty-four college students participated and completed the Turkish version of the MMEA (MMEA-TR) along with the Physical Assault of Conflict Tactics Scale-Revised, Experiences in Close Relationships Inventory, Relationship Assessment Scale, and Social Desirability Questionnaire. Confirmatory factor analysis supported the four-factor structure of the MMEA-TR for both victimization and perpetration reports. This factor structure was cross validated with an independent older sample of 328 dating college students for perpetration reports. Satisfactory criterion validity and internal consistency reliability results were obtained as well. Based on the preliminary investigation, the MMEA-TR appears to be a psychometrically sound measure of psychological dating aggression perpetration and victimization among college students in Turkey. The results, limitations, and recommendations for future studies were discussed. PMID- 29609677 TI - Relationships Between Shame, Restrictiveness, Authoritativeness, and Coercive Control in Men Mandated to a Domestic Violence Offenders Program. AB - Coercive control, a key element of intimate partner violence (IPV), is defined as an abuse dynamic that intends to strip the target of autonomy and liberty. While coercive control is gaining popularity in the research world, little is known about its correlates and causes. This study sought to examine how shame and men's need for dominance, measured by two trait indexes of dominance, restrictiveness and the need for authority, influence coercive control. The present study used a diverse sample of men (n = 134) who were mandated to attend a domestic violence offenders program. Findings suggest that shame plays a role in the commission of coercively controlling behavior both directly and partially through its influence on authority but not through restrictiveness. Implications for understanding IPV in a domestic violence offenders program are discussed. PMID- 29609678 TI - The Relationship Between Experiences With the Criminal Justice System and Mental Health Outcomes Among Survivors of Homicide. AB - Homicide survivors are at increased risk for mental health disorders, including depression, posttraumatic stress disorder (PTSD), and complicated grief (CG). Accordingly, this survey study examined how satisfaction with the criminal justice system (CJS) was associated with depression, PTSD, and CG among 47 homicide survivors. It also examined how satisfaction with specific aspects of the CJS related to satisfaction with the overall CJS. Satisfaction with the overall CJS was uniquely associated with depression (odds ratio [OR] = 2.32; 95% confidence interval [CI] [1.16, 4.66]) while satisfaction with the police department was uniquely associated with CG (OR = 2.14; 95% CI [1.02, 4.47]). Satisfaction with having input into the CJS process and satisfaction with efforts devoted by the CJS to apprehend the perpetrator were uniquely related to satisfaction with the overall CJS (beta = .49, p = .003 and beta = .40, p = .007, respectively). PMID- 29609679 TI - Hate Crime Victimization Data in Pennsylvania: A Useful Complement to the Uniform Crime Reports. AB - Data on the incidence and prevalence of hate crimes in the United States come primarily from the Uniform Crime Reports (UCR). Although UCR data undercount most crimes, hate crimes are particularly underreported, especially for some groups. We compare 2000-2011 UCR data in Pennsylvania to data from a state agency that came from police, media, and citizen reports. First, we find that the state agency database is generally consistent with the UCR data, in terms of absolute counts, correlations, and predictors. Second, we find that UCR data underestimate hate crime rates by a factor of about 1.6 overall and by a factor of 2.5 for rural areas. Moreover, although UCR data on hate crimes show a decrease in the most recent 5-year period, the state agency data show that hate crime incident counts have not dropped. We suggest that using a broader index that includes both the UCR and a database like that in Pennsylvania will give a more complete picture of hate crime. PMID- 29609680 TI - Intimate Partner Violence Myths in Police Reports: A Directed Content Analysis. AB - Although much has changed in social and criminal justice system responses to intimate partner violence (IPV) since public awareness campaigns began in the 1970s, stigmatization around IPV offense and victimization remains a barrier to victims obtaining available assistance, including those offered by police forces. Unfortunately, stigma is often perpetuated by mythology about the crime, its offenders, its victims, and overarching gender norms. Since IPV cases are managed under the auspices of the criminal justice system, the manner in which the system itself perpetuates IPV myths is worthy of attention. Prior literature suggests that police officers may be vulnerable to this mythology in their decision-making and reporting of IPV calls. This is troubling for IPV victims and offenders alike, since police reports follow them through the criminal justice system and associated IPV intervention programs. A report heavily influenced by IPV mythology is unlikely to serve IPV offenders or victims particularly well. Guided by four popular IPV myths identified in Eigenberg et al.'s (2012) study, the purpose of the present qualitative study of IPV in police reports (N = 58) is to explore the influence of IPV mythology on police officers' decision-making and intervention. One overarching theme emerged after the analysis: undetected coercive control evident in the cases. Implications on improvement in police training are suggested. PMID- 29609681 TI - Exposure to Family Violence and Internalizing and Externalizing Problems Among Spanish Adolescents. AB - Exposure to intimate partner violence (IPV) and child maltreatment may have devastating consequences on children's development. The aim of this research was to examine the predictive associations between exposure to violence at home (witnessing violence against the mother and/or direct victimization by the parents) and adolescent internalizing and externalizing problems. A total of 613 Spanish adolescents (13-18 years) took part in this study. Results indicate that psychological victimization by the parents predicted an increase in anxious/depressive symptoms, aggressive and rule-breaking behavior, and substance abuse at Time 2. In addition, rule-breaking behavior predicted an increase in adolescents' substance abuse at Time 2. Concerning gender, psychological victimization predicted an increase in anxiety/depression, aggressive behavior, rule-breaking behavior, and substance abuse in boys; whereas in girls, psychological victimization only predicted an increase in anxiety/depression. PMID- 29609682 TI - Methodological Considerations for Research With Black Male Victims of Violent Injury in an Urban Trauma Unit. AB - There is a body of research over the last three decades that has focused on the etiology of violence among victims of violent injury. This body of literature indicates that Black men are disproportionately represented among victims of violent injury seen in emergency departments and trauma centers across the country. Despite the disproportionate number of low-income young Black men treated for violent injury in urban trauma units and the growing body of literature accompanying it, little is known about the unique methodological challenges violent injury researchers face when conducting research on this vulnerable population in a clinical setting. This article describes the unique and often nuanced methodological difficulties a research team encountered while conducting a longitudinal qualitative study on risk factors for repeat violent injury among low-income young Black male victims of violent injury treated at a Level II trauma center in the Eastern United States. Four methodological challenges are identified: (a) the identification and screening of participants, (b) recruitment and interviewing, (c) understanding hospital culture, policies, and procedures, and (d) retention and attrition of sample. Recommendations to overcome these challenges are offered. PMID- 29609683 TI - Are GnRH and FSH potentially damaging factors in the cardiovascular system? AB - In the physiological view the human cardiomyocytes express receptors of gonadotropin-releasing hormone and follicle-stimulating hormone. The local effects of these hormones in the heart are related also to some interstitial cells, such as endothelial cells with follicle-stimulating hormone receptors and immune cells with gonadotropin-releasing hormone receptors. The administration of androgen deprivation therapy in patients with prostate cancer is associated with increased incidence of cardiovascular complications. It is suggested that negative action of this therapy on cardiovascular system is due to the loss of testosterone but also levels of gonadotropin-releasing hormone and follicle stimulating hormone are changed by therapy. In this article we review the literature to date with an emphasis on recent investigation focused on potential role of abnormal gonadotropin-releasing hormone and follicle-stimulating hormone levels induced by gonadotropin-releasing hormone agonists on the cardiovascular risk. These facts exacerbate the complexity of specific hormone and cell relationships within heart and vessels. Androgen deprivation therapy reveals the physiological relationships between hormones and specific tissues that are not part of the endocrine system. PMID- 29609684 TI - Synthesis and biological evaluation of novel 2 (4'-hydroxynaphthyl) chromen-4-one as a CK2 inhibitor. AB - Protein kinase CK2 is a potential drug target for many diseases including cancer, inflammatory disorders, Alzheimer's disease, Parkinson's disease and viral infections. Significant efforts have been made for the discovery of potent inhibitors of this enzyme. Herein, we report on the synthesis, characterization, and biological evaluation of novel flavonoid compounds as CK2 inhibitors. The tested compounds were 2 (4'-hydroxynaphthyl) chromen-4-one which is a naphthyl backbone flavonoid with an IC50 value of 0.45+/-0.059 MUM and 2(4-hydroxyphenyl) 4H-chromen-4-one a phenyl based derivative with an IC50 value of 0.33+/-0.048 MUM. Cell viability was tested using MCF-7 cells. Both compounds were able to reduce the cell viability around 50 % in concentration of 100 MUM after 48 h. Molecular modeling studies were performed to understand the binding mode of both compounds. PMID- 29609685 TI - Stability of regularly prescribed oral liquids formulated with SyrSpend(r) SF. AB - The purpose of this research was to evaluate the stability of 12 oral liquid formulations frequently compounded in hospital and community settings formulated in a specific vehicle: SyrSpend(r) SF. The stability of melatonin, glycopyrrolate, ciclosporin, chloral hydrate, flecainide acetate, tiagabine HCl, labetalol HCl, ciprofloxacin HCl, spironolactone/hydrochlorothiazide, hydrocortisone, itraconazole and celecoxib in SyrSpend SF PH4 (liquid) was investigated at 0, 30, 60 and 90 days and stored at both controlled room temperature and refrigerated. Itraconazole samples were also investigated at 15 and 45 days. No change in odor, color or appearance was observed in the formulations during the test period. Based on the results, a beyond-use date of 30 days can be assigned to tiagabine HCl 1.0 mg/ml in SyrSpend SF when stored at controlled room temperature, and 90 days under refrigeration, improving stability data previously published using other vehicles. A beyond-use date of 60 days can be assigned to chloral hydrate 100.0 mg/ml. In this case, stability is not enhanced by refrigeration. With the rest of the formulations, less than 10% API loss occurred over 90 days at either controlled room temperature or under refrigeration. Including for example itraconazole 20.0 mg/ml, thus providing extended stability compared to simple syrup and other oral liquid vehicles. The findings of this study show that SyrSpend SF is an appropriate suspending vehicle to be used for personalized formulations of the APIs studied here. PMID- 29609686 TI - Aberrant histone modifications of global histone and MCP-1 promoter in CD14+ monocytes from patients with coronary artery disease. AB - OBJECTIVES: To investigate whether there are aberrant acetylation modifications in global histone and monocyte chemoattractant protein-1 (MCP-1) promoter in monocytes from patients with coronary artery disease (CAD) and demonstrate the potential mechanisms. METHODS: CD14+ monocytes were isolated from 13 patients with CAD and 18 confirmed non-CAD controls using magnetic beads. Global histone H3/H4 acetylation and H3K4/H3K27 tri-methylation levels were measured with enzyme linked immunosorbent assay. Quantitative real time-PCR was performed to detect the mRNA expression levels of MCP-1 and enzymes involved in histone modification processes. Histone modification levels in MCP-1 promoter were assessed by ChIP qPCR assay. RESULTS: Our results showed a markedly lower global histone H3 acetylation level in monocytes from CAD patients. Global H3K27 tri-methylation level was significantly increased in monocytes from CAD patients. Furthermore, the mRNA expression levels of epigenetic modification enzymes HDAC3, SIRT1, P300, JMJD3 and SUV39H1 were decreased significantly in monocytes from CAD patients, while HDAC7 mRNA expression level was markedly increased. MCP-1 mRNA expression level was increased histone H3/H4 acetylation levels in MCP-1 promoter were markedly increased in monocytes of CAD patients. CONCLUSION: Aberrant histone modifications, including acetylation and tri-methylation, were found both in global histone and specific MCP-1 gene locos in monocytes from patients with CAD. Aberrant epigenetic modification enzymes expressions may be the regulatory mechanism responsible for aberrant histone modifications. PMID- 29609687 TI - Safranal carried by nanostructured lipid vehicles inhibits generalized epilepsy in mice. AB - Safranal, a main component of Crocus sativus, is suggested to have neuroprotective effects. The aim of this study was to investigate the effect of safranal and nanostructured lipid vehicle (NLV) carried safranal in acute and chronic experimental mice models of epilepsy. In PILO acute seizure model, safranal dose-dependently extended latency to generalized seizure, decreased the highest seizure stages and the number of generalized seizures. Moreover, NLV carried safranal further enhanced the anti-seizure effect, which is comparable to the action of sodium valproate. Meanwhile, NLV carried safranal reduced and delayed the electroencephalogram spectra power after pilocarpine injection. In histological aspect, safranal dose-dependently reduced the loss of neurons induced by seizure and NLV system further improved this protection at the same dose. In MES acute model, safranal markedly increased the electroconvulsive threshold, where NLV further improved its effect. In PTZ chronic seizure model, NLV carried safranal significantly delayed the kindling rate of progress and the time it took to reach generalized seizures as compared to NLV control group. In conclusion, this study indicates that safranal inhibits generalized seizure in acute and chronic epilepsy models in mice and NLV can enhance this effect. So, NLV carried safranal may have potential value in treatment of generalized epilepsy. PMID- 29609688 TI - PDX1 transfection induces human adipose derived stem cells differentiation into islet-like cells: what is the benefit for diabetic rats? AB - In this study, we observed the differentiation potential of human ADMSCs (hADMSCs) into functional islet-like cells and the therapeutic effect of hADMSCs transplantation in diabetic rats. Firstly, the PDX1 gene was transfected into hADMSCs by an adenovirus. Cell differentiation and insulin secretion were identified and detected by dithizone staining and ELISA, respectively. Twenty male Sprague-Dawley rats were randomly divided into control group (n=4), diabetes group (n=8) and transplantation group (n=8). Rats in the latter two groups were subjected to making diabetic models by 65 mg/kg streptozotocin injection. Afterwards, rats in the transplantation group were given PDX1 transfected ADMSCs via the tail vein. At 15 days after transfection, the number of insulin positive cells and insulin secretion were both increased significantly (P < 0.05). Fasting glucose levels in the transplantation group decreased significantly (P < 0.05), while the body weight increased significantly (P < 0.05). In the diabetic group, the fasting glucose level still maintained at a high level, and the body weight of rats was significantly decreased. These results implicated that the PDX-1 gene could induce hADMSCs differentiating into functional islet-like cells. PDX-1 transfected ADMSCs transplantation is effective in treating diabetic rats, but the mechanism needs further study. PMID- 29609689 TI - Regorafenib delays the proliferation of hepatocellular carcinoma by inducing autophagy. AB - The aim of the present study was to investigate the effects of regorafenib on hepatocellular carcinoma autophagy, thereby supressing the malignancy of HCC. First, HepG2 and Hep3B cell autophagy was investigated using GFP-LC3 transfection after the treatment of regorafenib. Then, the activation of Akt/mTOR signaling was analyzed using western blot. Our data showed that liver cancer cell autophagy was significantly induced by 20 MUM regorafenib using GFP-LC3 transfection. Meanwhile, regorafenib-induced cell death could largely be abolished by 3-MA or CQ treatment, suggesting that regorafenib-induced HepG2 cell death was partially dependent on autophagy. Moreover, the activation of Akt/mTOR signaling was inhibited by regorafenib pre-incubation. MTT assay showed the combination use of regorafenib and CDDP led to a stronger growth inhibitory effect on HepG2 and Hep3B cells. In summary, regorafenib may acts an adjunctive therapy for liver cancer patients via modulating autophagy-dependent cell death even when apoptosis resistance is induced in cancer cells. PMID- 29609690 TI - Efficacy of entecavir-based rescue therapy in lamivudine-resistant chronic hepatitis B patients in China: a retrospective study. AB - Limited studies have investigated the antiviral efficacy of entecavir (ETV)-based rescue therapy in lamivudine (LAM)-resistant chronic hepatitis B (CHB) patients. We retrospectively analyzed the efficacy of entecavir (ETV) monotherapy versus ETV-tenofovir disoproxil fumarate (TDF) combination therapy in 220 LAM-resistant CHB patients. Among 220 patients, 114 patients were treated with ETV monotherapy and 106 were treated with ETV-TDF combination therapy for at least 24 months. There were no significant differences between the two groups in baseline characteristics. During the follow-up of 24 months, virologic response (VR) occurred in 146 (66.4%) patients (58 patients belonged to the ETV monotherapy group and 88 patients belonged to the ETV-TDF combination group). The VR rates were different between the ETV and ETV-TDF groups (32.5% vs. 57.5% at 6 months, 50.0% vs. 77.4% at 12 months; and 50.9% vs. 83.0% at 24 months, P<0.001). In addition, both groups showed no difference in terms of the biochemical and HBeAg response. The rates of viral breakthrough at 6, 12 and 24 months were significantly different between ETV and ETV-TDF groups (2.63%, 4.39% and 9.65% vs. 0.00%, 0.94% and 1.89% at 6, 12 and 24 months, respectively). The ETV-TDF group was superior to the ETV group in achieving a virologic response. Moreover, the ETV-TDF was lower than the ETV group in achieving the initial viral breakthrough and genotypic mutations. Therefore, ETV-TDF combination therapy might be a better regimen than ETV monotherapy in the subgroup of LAM-resistant Chinese patients with CHB. PMID- 29609691 TI - Chrysophanol ameliorates high-fat diet-induced obesity and inflammation in neonatal rats. AB - Chrysophanol is a member of the anthraquinone family abundant in rhubarb, a widely used herb for obesity treatment in Traditional Chinese Medicine. Though several studies have indicated numerous features of chrysophanol, no study has yet reported the effect of chrysophanol on juvenile obesity. In this study, we tried to identify the anti-obesity effects of chrysophanol by using high-fat diet (HFD)-induced rats as in vivo models. In HFD rats, chrysophanol treatment decreased body weight, blood glucose and the blood level of triglyceride (TG), and enhanced the level of high-density lipoprotein-cholesterol (HDL-C). In addition, chrysophanol markedly reduced lipid accumulation in HFD rats-derived primary hepatocytes. Moreover, chrysophanol effectively relieved HFD-induced inflammation, as demonstrated by the reduction of interleukin (IL)-6 and IL-1beta and the elevation of IL-10. Furthermore, chrysophanol markedly increased the levels of lipolytic genes and decreased the expressions of lipogenic genes in HFD rats, which was probably benefited from the activation of AMP-activated protein kinase (AMPK)/ Sirtuin 1 (SIRT1). Taken together our study has demonstrated that chrysophanol could improve the HFD-induced obesity and provided a molecular basis for chrysophanol potential applications in the treatment of juvenile obesity and other metabolic diseases. PMID- 29609692 TI - Controllable vitamin K deficiency under high-dose oral menatetrenone administration - a case report. AB - Vitamin (V) K deficiency may cause severe bleeding tendencies, which necessitates extreme caution. We report a case of a 30-year-old man diagnosed with VK deficiency of unknown etiology. He was treated with intravenous menatetrenone three times a week in an outpatient setting for about 1 year and 9 months. Eventually, he developed an allergic reaction to intravenous menatetrenone and was under steroid therapy. In order to reduce his hospital visits and discontinue steroid use, the pharmacist proposed to change the method of menatetrenone administration from intravenous to oral (high dose). The change in treatment method has greatly improved the patient's quality of life. PMID- 29609693 TI - A coumarin with an unusual structure from Cuphea ignea, its cytotoxicity and antioxidant activities. AB - Phenolic metabolite profiling using two dimensional paper chromatographic analysis (2 DPC) was used for assaying the complex mixture of phenolics of an aqueous ethanol aerial part extract of Cuphea ignea (Lytheraceae). A coumarin with a rare structure, namely, 7-hydroxy 3-methoxy coumarin 5-O-beta glucopyranoside was isolated from the investigated extract. The structure was elucidated by conventional methods and spectral analysis, including one and two dimensional NMR (1D and 2D NMR), as well as by interpretation of the spectra obtained by high resolution electrospray ionization mass technique (HRESIMS). The rare coumarin significantly inhibited reactive oxygen species production with an ED50 value of 6.31+/-1.64 MUg/ml and 5.78+/-0.66 MUg/ml as determined by the the free radical 2,2-diphenyl-1-picrylhydrazyl (DPPH) and the oxygen radical absorption capacity (ORAC) assay respectively. The isolated coumarin presented a cytotoxic activity assessed by using the neutral red assay (NRU) against lung cancer cell line (H23) with IC50 of 40.38+/-2.75 MUg/ml. PMID- 29609694 TI - Karl Blumenreuter (1881-1969): Himmler's chief pharmacist and medical supply quartermaster of the SS. AB - The present article elucidates the role and function of SS Gruppenfuhrer Karl Blumenreuter (1881-1969), the leading pharmacist of the SS. The aim is to clarify how he participated in the crimes of the Nazi Party and especially the SS during the "Third Reich" and the extent to which he was brought to justice after 1945. Central elements of the study are based on researched archival primary sources. The latter were compared with each other and supplemented with the currently available secondary literature on the subject. It can be established that Blumenreuter was a zealous National Socialist with marked career ambitions who advanced within the SS to the rank of SS Gruppenfuhrer and Lieutenant General of the Waffen SS (Generalleutnant der Waffen SS). He supplied pre-measured phenol ampoules for the murder of prisoners in the concentration camps. Blumenreuter furthermore organised equipment and material supplies for various experiments on humans. After 1945 he succeeded in playing down his participation in the crimes in the time of National Socialism. Blumenreuter died in 1969 without having being brought to justice by the judiciary and without having reflected self-critically on his role in the "Third Reich". PMID- 29609695 TI - A Big Year for Innovation. PMID- 29609696 TI - Safety Challenges with Insulin Delivery. PMID- 29609697 TI - 2018 New Drug Update. AB - Five new drugs marketed within the last year, which are used for medical problems often experienced by the elderly, have been selected for consideration in this review. The uses and most important properties of these agents are discussed, and a rating for each new drug is determined using the New Drug Comparison Rating system developed by the author (DAH). Advantages, disadvantages, and other important information regarding each new drug are identified and used as the basis for determining the rating. The drugs include an anticoagulant, an antiparkinson agent, an agent for tardive dyskinesia, an agent for psoriasis, and an agent for constipation. The drugs reviewed are betrixaban, safinamide mesylate, valbenazine tosylate, guselkumab, and plecanatide. PMID- 29609698 TI - VMAT2 Inhibitors: New Drugs for the Treatment of Tardive Dyskinesia. AB - OBJECTIVE: To provide a review of tardive dyskinesia (TD) symptoms, etiology, pathophysiology, and treatments. DATA SOURCES: PubMed, Web of Science, ClinicalTrials. gov, and Google Scholar were searched for relevant literature using a combination of the following terms: tardive dyskinesia, treatment, management, guidelines, tetrabenazine, deutetrabenazine, and valbenazine. Sources were limited to human data. STUDY SELECTION/DATA EXTRACTION: Articles were reviewed for relevance to TD therapy. Reference lists were manually searched for other relevant articles. Selected literature was published between 1968 and 2017. DATA SYNTHESIS: This article reviews treatment options available for patients with TD. Many agents have been tried off-label to manage symptoms, with limited evidence of benefit. The Food and Drug Administration approved the first drug to treat TD valbenazine on April 11, 2017. CONCLUSION: TD is largely iatrogenic. Valbenazine's approval by the Food and Drug Administration was followed by the approval of deutetrabenazine, a drug with similar mechanism of action. Further data from postmarketing studies will be needed to verify that valbenazine's adverse effect profile is different from the profiles of tetrabenazine and deutetrabenazine. PMID- 29609699 TI - Considerations for Geriatric Patients with COPD. AB - As patients age, they are predisposed to certain disease states such as chronic obstructive pulmonary disease (COPD). Physiologic changes that occur during aging as well as guidelines for treatment must be considered in providing pharmaceutical care for older adults. Preferred treatment options have special considerations in the aging population because of the inability to use certain inhaler devices and medications appropriately. This paper reviews physiologic changes in geriatric adults, COPD treatment, medications that should be avoided in this population, and special considerations for geriatric patients with COPD. PMID- 29609700 TI - Use of Topical Morphine to Relieve Painful Pressure Ulcers. AB - INTRODUCTION: Topical morphine is a potential treatment option for painful pressure ulcers in hospice and palliative care patients who favor avoidance of systemic opioid therapy. CASE: A 65-year-old male African-American veteran with a painful stage 3 sacral pressure injury was hesitant to take systemic opioids to control his pain, as he wished to stay alert for family and friends. Topical morphine was initiated, and within 24 hours the patient reported a significant reduction in pain on the numeric rating scale. DISCUSSION: Palliative pharmacotherapy is focused on reducing the symptoms of disease while avoiding side effects that impair quality of life. Evidence suggests topical morphine can be an effective treatment option for painful pressure ulcers and can reduce the need for systemic opioids in select patients. CONCLUSION: In the palliative care setting, topical morphine may be considered for compassionate use when treatment with systemic analgesics is undesired, inadequate, or poorly tolerated. PMID- 29609701 TI - Evaluation of Pharmacist-Initiated Discharge Medication Reconciliation and Patient Counseling Procedures. AB - OBJECTIVE: To evaluate a recently implemented procedure of discharge medication reconciliation and patient counseling completed by pharmacists at a nursing facility. SETTING: This is a 138-bed nursing facility that houses long-term care residents as well as patients for subacute rehabilitation. PRACTICE DESCRIPTION: Discharge process involves the medical team (geriatrician, medical resident, medical students), social workers, and nurse coordinators. PRACTICE INNOVATION: Pharmacists are incorporated in the discharge process by completing medication reconciliation, patient counseling, and telephone follow-up, to improve patient understanding and satisfaction. MAIN OUTCOME MEASUREMENTS: Medication discrepancies identified by pharmacists via medication reconciliation, number of patients who were counseled by pharmacist, and number of patients encountered for telephone follow-up. RESULTS: Fifty-four patients were discharged during the study period. A total of 200 discrepancies were identified after discharge medication reconciliation by the pharmacist. On average, we found that there were 4 discrepancies per patient (range 0 to 16). Most of the discrepancies that were found were medication additions and omissions. Forty-five patients (83.3%) agreed to counseling and were then counseled by a pharmacist. Patients were often not counseled because of last-minute discharge, and no encounter was made. CONCLUSION: Involving pharmacists in patient transitions of care may be beneficial as previous studies have demonstrated; however, additional studies in a nursing facility setting are needed to validate these benefits. PMID- 29609702 TI - Adapting to a New Regulatory Environment. PMID- 29609703 TI - Diagnostic and Treatment Challenges of Sighted Non-24-Hour Sleep-Wake Disorder. AB - STUDY OBJECTIVES: To report the diagnostic and treatment challenges of sighted non-24-hour sleep-wake disorder (N24SWD). METHODS: We report a series of seven sighted patients with N24SWD clinically evaluated by history and sleep diaries, and when available wrist actigraphy and salivary melatonin levels, and treated with timed melatonin and bright light therapy. RESULTS: Most patients had a history of a delayed sleep-wake pattern prior to developing N24SWD. The typical sleep-wake pattern of N24SWD was seen in the sleep diaries (and in actigraphy when available) in all patients with a daily delay in midpoint of sleep ranging 0.8 to 1.8 hours. Salivary dim light melatonin onset (DLMO) was evaluated in four patients but was missed in one. The estimated phase angle from DLMO to sleep onset ranged from 5.25 to 9 hours. All six patients who attempted timed melatonin and bright light therapy were able to entrain their sleep-wake schedules. Entrainment occurred at a late circadian phase, possibly related to the late timing of melatonin administration, though the patients often preferred late sleep times. Most did not continue treatment and continued to have a non-24-hour sleep-wake pattern. CONCLUSIONS: N24SWD is a chronic debilitating disorder that is often overlooked in sighted people and can be challenging to diagnose and treat. Tools to assess circadian pattern and timing can be effectively applied to aid the diagnosis. The progressive delay of the circadian rhythm poses a challenge for determining the most effective timing for melatonin and bright light therapies. Furthermore, once the circadian sleep-wake rhythm is entrained, long-term effectiveness is limited because of the behavioral and environmental structure that is required to maintain stable entrainment. PMID- 29609704 TI - Role of Positive Airway Pressure Therapy for Obstructive Sleep Apnea in Patients With Stroke: A Randomized Controlled Trial. AB - STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is an independent risk factor for stroke. The objective of this study was to assess the effect of continuous positive airway pressure (CPAP) treatment on prevention of new vascular events among patients with stroke and OSA. METHODS: Consecutive conscious patients presenting with first imaging-confirmed arterial stroke were included, 6 weeks or more after ictus. All patients underwent clinical and polysomnography (PSG) testing. Patients with an apnea-hypopnea index (AHI) of > 15 events/h were randomized to posttitration nightly CPAP treatment and non-CPAP (received best medical treatment) groups. On follow-up at 3, 6, and 12 months from randomization, evaluation was carried out for any new vascular events as the primary outcome measure, and for clinical stroke outcomes (using the Barthel Index and modified Rankin scale) and neuropsychological parameters as the secondary outcome measures. RESULTS: Among the 679 patients with stroke who were screened, 116 reported for PSG, 83 had AHI > 15 events/h, and 70 (34 in CPAP and 36 in non-CPAP) were randomized. Thirteen patients could not be randomized because of a lack of CPAP devices. Four patients crossed over from the CPAP to the non-CPAP group. Age (mean age 53.41 +/- 9.85 in CPAP versus 52.69 +/- 13.23 years in non-CPAP, P = .81) and sex distribution (24 males in CPAP versus 33 males in non-CPAP, P = .79) were similar in both groups. At 12-month follow-up, there was 1 vascular event (3.33%) in the CPAP group and 6 events (15%) in the non-CPAP group (P = .23). Modified Rankin scale score improvement by >= 1 at 12 month follow-up was found in significantly more patients in the CPAP group than in the non-CPAP group (53% versus 27%). CONCLUSIONS: These findings suggest significantly better stroke outcomes and statistically nonsignificant favorable outcomes in terms of recurrence of vascular events for patients with stroke and OSA who use CPAP treatment. CLINICAL TRIAL REGISTRATION: Registry: Clinical Trials Registry - India, CTRI Registration No: CTRI/2016/07.007104, Title: Sleep Disordered Breathing in stroke patients: Effect of treatment trial, URL: http://ctri.nic.in/Clinicaltrials/showallp.php?mid1=8682&EncHid=&userName=sleep%2 disordered%20breathing. PMID- 29609705 TI - Ambulatory Surgery Has Minimal Impact on Sleep Parameters: A Prospective Observational Trial. AB - STUDY OBJECTIVES: The presence of obstructive sleep apnea (OSA) in ambulatory surgical patients causes significant perioperative concern; however, few data exist to guide clinicians' management decisions. The objective of this study was to measure changes in perioperative sleep parameters among an ambulatory surgery population. METHODS: This study is a prospective, observational study of ambulatory patients undergoing orthopedic surgery on an extremity. Study subjects completed three unattended home sleep apnea tests: baseline before surgery, the first night after surgery (N1), and third night after surgery (N3). Anesthesia and surgical teams were blinded to study participation and patients received routine perioperative care. RESULTS: Two hundred three subjects were enrolled and 166 completed the baseline home sleep test. Sixty-six (40.0%) had OSA at baseline, 35 patients received a new diagnosis, and 31 patients had a previous diagnosis of OSA. Of those with a previous diagnosis, 20 (64.5%) were compliant with continuous positive airway pressure therapy. Respiratory event index and SpO2 nadir did not significantly change postoperatively from baseline. Cumulative percentage of time oxygen saturation < 90% significantly increased N1 as compared to baseline for all patients except for those with moderate to severe OSA. CONCLUSIONS: Ambulatory surgery had minimal effect on sleep parameters and there was no increase in adverse events among patients with either treated or untreated OSA. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Title: Evaluation of Sleep Disordered Breathing Following Ambulatory Surgery; Identifier: NCT01851798; URL: https://clinicaltrials.gov/ct2/show/study/NCT01851798. PMID- 29609706 TI - Gestational Obstructive Sleep Apnea: Biomarker Screening Models and Lack of Postpartum Resolution. AB - STUDY OBJECTIVES: To measure prevalence and severity of third trimester obstructive sleep apnea and evaluate postpartum resolution. To assess a novel biomarker for screening for obstructive sleep apnea in pregnancy. METHODS: This prospective observational study was performed at Wake Forest School of Medicine obstetrics clinics between April 2014 and December 2015. Fractional exhaled nitric oxide measurements and sleep studies were obtained and compared at 32 0/7 to 35 6/7 weeks gestation and postpartum. Exhaled nitric oxide and risk factors for the development of gestational sleep apnea were evaluated for predictive ability independently and in screening models. RESULTS: Of 76 women enrolled, 73 performed valid sleep studies in pregnancy and 65 had an additional valid study 6 to 15 weeks postpartum. Twenty-four women (37%) had gestational sleep apnea compared with 23 (35%) with postpartum sleep apnea (P > .99). Eight of 11 women (73%) retested 6 to 8 months postpartum had persistent sleep apnea. Exhaled nitric oxide had moderate discrimination screening for sleep apnea in pregnancy (area under the receiver operating characteristic curve = 0.64). A model utilizing exhaled nitric oxide, pregnancy-specific screening, and Mallampati score improved ability to identify women at risk for gestational sleep apnea (sensitivity = 46%, specificity = 91% and likelihood ratio = 5.11, area under receiver operating characteristic curve = 0.75). CONCLUSIONS: Obstructive sleep apnea is common in the early postpartum period and often persisted at least 6 months. Exhaled nitric oxide as a sole biomarker to screen for sleep apnea in pregnancy has only modest discrimination. Combined with additional parameters sensitivity and specificity improved. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov, Identifier: NCT02100943, Title: Exhaled Nitric Oxide as a Biomarker of Gestational Obstructive Sleep Apnea and Persistence Postpartum, URL: https://clinicaltrials.gov/ct2/show/NCT02100943. PMID- 29609707 TI - The Role of Functional Respiratory Imaging in Treatment Selection of Children With Obstructive Sleep Apnea and Down Syndrome. AB - STUDY OBJECTIVES: The complexity of the pathogenesis of obstructive sleep apnea (OSA) in children with Down syndrome (DS) is illustrated by a prevalence of residual OSA after adenotonsillectomy. The aim of this study was to investigate whether upper airway imaging combined with computation fluid dynamics could characterize treatment outcome after adenotonsillectomy in these children. METHODS: Children with DS and OSA were prospectively included. All children underwent an evaluation of the upper airway and an ultra-low dose computed tomography scan of the upper airway before adenotonsillectomy. The upper airway tract was extracted from the scan and combined with computational fluid dynamics. Results were evaluated using control polysomnography after adenotonsillectomy. RESULTS: Thirty-three children were included: 18 boys, age 4.3 +/- 2.3 years, median body mass index z-score 0.6 (-2.9 to 3.0), and median obstructive apnea hypopnea index was 15.7 (3-70) events/h. The minimal upper airway cross-sectional area was significantly smaller in children with more severe OSA (P = .03). Nineteen children underwent a second polysomnography after adenotonsillectomy. Seventy-nine percent had persistent OSA (obstructive apneahypopnea index > 2 events/h). A greater than 50% decrease in obstructive apnea-hypopnea index was observed in 79% and these children had a significantly higher volume of the regions below the tonsils. CONCLUSIONS: This is the first study to characterize treatment outcome in children with DS and OSA using computed tomography upper airway imaging. At baseline, children with more severe OSA had a smaller upper airway. Children with a less favorable response to adenotonsillectomy had a smaller volume of regions below the tonsils, which could be due to enlargement of the lingual tonsils, glossoptosis, or macroglossia. COMMENTARY: A commentary on this article appears in this issue on page 501. PMID- 29609708 TI - Effects of Bedroom Environmental Conditions on the Severity of Obstructive Sleep Apnea. AB - STUDY OBJECTIVES: Epidemiological associations have demonstrated the effects of long-term air pollution to obstructive sleep apnea (OSA) through a physiological mechanism linking particulate matter exposure to OSA. This study aimed to determine the relationship between bedroom environmental conditions, OSA severity, and sleep quality. METHODS: Sixty-three participants were enrolled for an overnight polysomnography; OSA was diagnosed between May to August 2016. Personal characteristics and sleep quality were obtained by a face-to-face interview. Bedroom environments, including data on particulate matter with an aerodynamic diameter less than 10 MUm (PM10), temperature, and relative humidity, were collected by personal air sampling and a HOBO tempt/RH data logger. RESULTS: Sixty-eight percent of the participants experienced poor sleep. An elevation in 1 year mean PM10 concentration was significantly associated with an increase in apnea-hypopnea index (beta = 1.04, P = .021) and respiratory disturbance index (beta = 1.07, P = .013). An increase of bedroom temperature during sleep was significantly associated with poorer sleep quality (adjusted odds ratio 1.46, 95% confidence interval 1.01-2.10, P = .044). Associations between PM10 concentration and respiratory disturbance index were observed in the dry season (beta = 0.59, P = .040) but not in the wet season (beta = 0.39, P = .215). PM10 was not associated with subjective sleep quality. CONCLUSIONS: Elevation of PM10 concentration is significantly associated with increased OSA severity. Our findings suggest that reduction in exposure to particulate matter and suitable bedroom environments may lessen the severity of OSA and promote good sleep. PMID- 29609709 TI - Integrating the Divided Nasal Cannula Into Routine Polysomnography to Assess Nasal Cycle: Feasibility and Effect on Outcomes. AB - STUDY OBJECTIVES: Patients suspected to have sleep-disordered breathing underwent an overnight polysomnography using a divided nasal cannula to gain additional information about the nasal cycle during sleep. METHODS: This was a prospective, observational cohort study replacing the undivided nasal cannula with a divided nasal cannula during routine polysomnography (n = 28). RESULTS: Integration of the divided nasal cannula pressure transducer system into routine polysomnography was easy and affordable. Most patients (89%) demonstrated nasal cycle changes during the test. Nasal cycle changes tended to occur during body position changes (62%) and transitions from non-rapid eye movement sleep to rapid eye movement sleep (41%). The mean nasal cycle duration was 2.5 +/- 2.1 hours. Other sleep study metrics did not reveal statistically significant findings in relation to the nasal cycle. CONCLUSIONS: Replacing an undivided nasal cannula with a divided nasal cannula is easy to implement, adding another physiologic measure to polysomnography. Although the divided nasal cannula did not significantly affect traditional polysomnographic metrics such as the apnea-hypopnea index or periodic limb movement index based on this small pilot study, we were able to replicate past nasal cycle findings that may be of interest to sleep clinicians and researchers. Given the ease with which the divided nasal cannula can be integrated, we encourage other sleep researchers to investigate the utility of using a divided nasal cannula during polysomnography. PMID- 29609710 TI - Associations Between Neuropsychological, Neurobehavioral and Emotional Functioning and Either Narcolepsy or Idiopathic Hypersomnia in Children and Adolescents. AB - STUDY OBJECTIVES: Narcolepsy and idiopathic hypersomnia are chronic neurological sleep disorders characterized by hypersomnolence or excessive daytime sleepiness. This review aims to systematically examine the scientific literature on the associations between narcolepsy and idiopathic hypersomnia and their effect on intellectual functioning, academic achievement, behavior, and emotion. METHODS: Published studies that examined those associations in children and adolescents were included. Studies in which children or adolescents received a clinical diagnosis, and in which the associated function was measured with at least one objective instrument were included. Twenty studies published between 1968 and 2017 were eligible for inclusion in this review. RESULTS: There does not appear to be a clear association between intellectual functioning and narcolepsy or idiopathic hypersomnia; however, limited research is an obstacle to obtaining generalizability. The variability in results from studies investigating associations between academic achievement and these two hypersomnolence disorders suggests that further research using standardized and validated assessment instruments is required to determine if there is an association. Behavior and emotion appear to be significantly affected by narcolepsy. Only two studies included populations of children and adolescents with idiopathic hypersomnia. CONCLUSIONS: Further research using larger populations of children and adolescents with narcolepsy or idiopathic hypersomnia while utilizing standardized and validated instruments is required, because the effect of these conditions of hypersomnolence varies and is significant for each individual. PMID- 29609711 TI - Melatonin-Responsive Complex Nocturnal Visual Hallucinations. AB - ABSTRACT: Complex nocturnal visual hallucinations are vivid, dramatic, intricate visual hallucinations occurring during sleep onset or awakenings at night, generally lasting for a few minutes at most and disappearing with increased levels of light. They may occur in a number of neurological conditions, as well as in normal individuals. The optimal treatment for this condition remains unclear. We describe three patients with complex nocturnal visual hallucinations in whom melatonin brought about a dramatic improvement in symptoms. Our report suggests that melatonin may be a safe, effective treatment for this rare but often distressing and anxiety-provoking condition. PMID- 29609713 TI - Dissociative Identity Disorder CPAP Adherence: An Uncommon Factor in Obstructive Sleep Apnea. AB - ABSTRACT: We present a case of a patient with dissociative identity disorder and symptomatic sleep apnea who was treated with continuous positive airway pressure (CPAP). CPAP use depended upon which personality the patient exhibited but apnea reduction did not. This case illustrates in one individual how personality can positively or negatively affect CPAP adherence. PMID- 29609712 TI - Evaluation of a Trial Period With a Sleep Position Trainer in Patients With Positional Sleep Apnea. AB - STUDY OBJECTIVES: To assess the overall clinical effectiveness of a sleep position trainer (SPT) in patients with positional obstructive sleep apnea (POSA) and to evaluate how many patients were willing to continue treatment after a 1 month trial period. METHODS: Patients in whom POSA was diagnosed underwent a 1 month trial period with the SPT. Home sleep apnea tests were used to measure baseline data and data following the trial period with the SPT. RESULTS: The 79 patients who completed the study protocol were 81% male, had a mean age of 52 +/- 12 years, and a median baseline respiratory event index (REI) of 11 (8, 16) events/h. A significant reduction in overall REI to 5 (3, 10) events/h was observed with the SPT as compared to baseline (P < .001). The median percentage of sleep time in the supine position decreased significantly from 27 (20, 48) to 7 (2, 20) with the SPT (P < .001). Adherence was found to be 95 +/- 8%. Of the 44 patients who decided to continue treatment, 27 were categorized as responders (having a decrease in REI of at least 50%) and 17 were non-responders. The most important reasons for not purchasing the SPT were poor objective results, intolerance to the vibrations, cost of the device, persistent daytime sleepiness, or patient preference for other treatment options. CONCLUSIONS: Treatment with the SPT came with high adherence rates and was effective in reducing REI and supine sleep position. The trial period is in the patients' best interest, as it may prevent those who will not benefit from positional training from purchasing an SPT. PMID- 29609714 TI - Reliability and Validity of the Functional Outcomes of Sleep Questionnaire - Spanish Short Version (FOSQ-10SV) in Peruvian Patients With Obstructive Sleep Apnea. AB - STUDY OBJECTIVES: The aim of this study was to verify the reliability and validity of the Spanish short version of the Functional Outcomes of Sleep Questionnaire (FOSQ-10SV) in Peruvian patients with obstructive sleep apnea (OSA). METHODS: Participants underwent physical examinations, completed the FOSQ 10SV, and polysomnography tests were carried out. RESULTS: A total of 672 patients were analyzed, 75 females (11%), mean age 50.5 +/- 13.8 years. A total of 563 patients (84%) had OSA. The mean FOSQ-10SV score was 15.96 +/- 3.23. The FOSQ-10SV Cronbach alpha was 0.84 and two significant factors were extracted in the factor analysis-both factors explained a variance of 43% and 14%. A significant correlation was found between the FOSQ-10SV score and the apnea hypopnea index. Patients with more severe disease have a lower FOSQ-10SV score (P = .003). Ninety-nine patients with OSA who started continuous positive airway pressure treatment were followed, and we observed an improvement in the FOSQ-10SV score from pretreatment to posttreatment (P < .001). CONCLUSIONS: The FOSQ-10SV has internal consistency, construct validity, and the sensitivity to change in Peruvian patients with OSA who undergo treatment. PMID- 29609715 TI - Segmental Hair Testing of Triazolam to Unmask a Suspected Case of Idiopathic Recurrent Stupor. AB - ABSTRACT: Stupor is a diagnostic challenge at emergency department. Differential diagnosis includes idiopathic recurrent stupor, formerly attributed to "endozepine-4" accumulation. This condition has been recently questioned because many suspected cases resulted in exogenous benzodiazepine intake that eludes the conventional toxicological assay. In case of unexplained recurrent stupor, to extend the benzodiazepine search in nonconventional matrices can allow unmasking of hidden toxic behavior. PMID- 29609716 TI - Analyses of the Complexity of Patients Undergoing Attended Polysomnography in the Era of Home Sleep Apnea Tests. AB - STUDY OBJECTIVES: Health care complexity includes dimensions of patient comorbidity and the level of services needed to meet patient demands. Home sleep apnea tests (HSAT) are increasingly used to test medically uncomplicated patients suspected of having moderate to severe obstructive sleep apnea (OSA). Patients with significant comorbidities or other sleep disorders are not candidates for HSAT and require attended in-center polysomnography. We hypothesized that this trend would result in increasingly complex patients being studied in sleep centers. METHODS: Our study had two parts. To ascertain trends in sleep patient comorbidity, we used administrative diagnostic codes from patients undergoing polysomnography at the Mayo Clinic Center for Sleep Medicine from 2005 to June 2015 to calculate the Charlson and the Elixhauser comorbidity indices. We measured the level of services provided in two ways: (1) in a subset of patients from the past 2 months of 2015, we evaluated correlation of these morbidity indices with an internally developed Polysomnogram Clinical Index (PSGCI) rating anticipated patient care needs from 0 to 3 and (2) we measured the sleep study complexity based on polysomnography protocol design. RESULTS: In 43,780 patients studied from 2005 to June 2015, the Charlson index increased from a mean of 1.38 to 1.88 (3.1% per year, P < .001) and the mean Elixhauser index increased from 2.61 to 3.35 (2.5% per year, P < .001). Both comorbidity indices were significantly higher at the highest (Level 3) level of the PSGCI (P < .001), and sleep study complexity increased over time. CONCLUSIONS: The complexity of patients undergoing attended polysomnography has increased by 28% to 36% over the past decade as measured by validated comorbidity indices, and these indices correlate with the complexity of rendered care during polysomnography. These findings have implications for increasing requirements for staffing, monitoring capabilities, and facility design of future sleep centers. COMMENTARY: A commentary on this article appears in this issue on page 499. PMID- 29609717 TI - Sleep Disorders and Their Management in Children With Ehlers-Danlos Syndrome Referred to Sleep Clinics. AB - STUDY OBJECTIVES: The nature of sleep disorders in children with Ehlers-Danlos syndrome (EDS) is unknown. We aimed to describe the type, the management, and the short-term outcome of sleep disorders in children with EDS referred to sleep clinics. METHODS: This is a retrospective review of medical records and polysomnography tests of children with EDS younger than 18 years who were referred to the sleep clinic. Demographic information and medical history were collected, and polysomnography tests were reviewed. Questionnaires completed during previous clinic visits, including the Pediatrics Sleep Questionnaire (PSQ), Epworth Sleepiness Scale (ESS), and Pediatric Quality of Life Inventory (PedsQL), were also evaluated. RESULTS: Sixty-five patients with EDS hypermobility type were included. The mean age was 13.15 +/- 3.9 years. There were 68% of patients who were female, and 91% of patients were Caucasian. The mean follow-up period was 1.14 +/- 1.55 years. Common sleep diagnoses included insomnia (n = 14, 22%), obstructive sleep apnea (OSA) (n = 17, 26%), periodic limb movement disorder (PLMD) (n = 11, 17%), and hypersomnia (n = 10, 15%). In addition, 65% required pharmacologic treatment and 29% were referred to behavioral sleep medicine. For OSA, two patients required continuous positive airway pressure. A significant improvement was observed in the PSQ, ESS, and PedsQL scores during follow-up visits after treatment (n = 34; P = .0004, 0.03, and 0.01, respectively). CONCLUSIONS: There is a high prevalence of sleep disorders, including OSA, insomnia, PLMD, and hypersomnia in children with EDS referred to sleep clinics. Specific management can improve quality of life and questionnaire scores of this patient population. Our study emphasizes the importance of screening for sleep disorders in children with EDS. PMID- 29609718 TI - Reference Data for Polysomnography-Measured and Subjective Sleep in Healthy Adults. AB - STUDY OBJECTIVES: Reference data for sleep are needed for the interpretation of clinical sleep parameters. This analysis aimed to provide polysomnography measured, spectral analytic and subjective reference data based on a sample of healthy adults. In addition, effects of age and sex were investigated. METHODS: The sample was selected from the archival database of the Sleep Center at the University Medical Center Freiburg and consisted of 206 healthy adults aged 19 to 73 years. For an adaptation and a second examination night, polysomnography parameters, spectral analytic data, and subjective sleep estimations are presented. RESULTS: With increasing age, sleep became shorter (less total sleep time, more wake time after sleep onset) and lighter (eg, more percentage of stage N1 sleep, increase in fast activity in the beta range). Sleep in females was deeper than sleep in males (eg, higher percentage of stage N3 sleep). Females had higher overall power density than males. Altogether, it is apparent that sleep parameters exhibit high standard deviations, suggesting a high variability within healthy adults and complicating the specification of reference values. CONCLUSIONS: Our data suggest that the informative value of sleep reference data in healthy individuals is limited because of high interindividual and intraindividual variation within sleep variables. More research, preferably in the form of meta-analyses and/or large international databases, is needed to further investigate the relevance of such reference data for mental and physical health. In the absence of such knowledge, giving patients feedback about deviations from the norm in their sleep profile may give rise to ill-founded concerns and worry. PMID- 29609719 TI - The Association Between Vitamin D Level and Restless Legs Syndrome: A Population Based Case-Control Study. AB - STUDY OBJECTIVES: The pathophysiology of restless legs syndrome (RLS) may be related to abnormalities in central dopamine pathways. Vitamin D may play a role in the pathophysiology of RLS by modulating the dopaminergic system. The aim of our study is to examine the possible link between RLS and vitamin D deficiency. METHODS: The total number of subjects enrolled was 201, including 78 patients with RLS based on the International RLS Study Group (IRLSSG) diagnostic criteria and 123 controls. Serum 25-hydroxy vitamin D levels were measured in both groups. RLS severity was assessed in all cases using the IRLSSG symptom severity rating scale. RESULTS: Fifty-nine patients with RLS (75.6%) and 52 controls (42.3%) had a diagnosis of vitamin D deficiency, P < .001. The odds ratio (OR) of the development of RLS was 4.24 for those with a vitamin D level < 50 nmol/L compared to those with a vitamin D level >= 50 nmol/L (P < .001, 95% confidence interval [CI] 2.3-7.9). After adjusting for all other significant factors in the multivariate logistic model, vitamin D was significantly associated with RLS (OR 3.1, P < .002, 95% CI 1.51-6.38). Moreover, a dark or black skin color (OR 3.4, P < .001, 95% CI 1.5-6.3) and working as a teacher (OR 8.8, P < .001, 95% CI 3.4 23.5) were also independently significantly associated with RLS. CONCLUSIONS: Our study identified an association between vitamin D deficiency and RLS. Consequently, vitamin D deficiency should be considered in the management of RLS. However, further studies are needed to evaluate the causality relationship between vitamin D level and RLS. PMID- 29609720 TI - Heart Rate Variability Responses of Individuals With and Without Saline-Induced Obstructive Sleep Apnea. AB - STUDY OBJECTIVES: Postoperative development of obstructive sleep apnea (OSA) has been attributed to the fluid overloaded state of patients during the postoperative period. In this context, alterations in cardiac autonomic regulation caused by OSA may explain the increased postoperative risk for adverse cardiovascular events. This study tests the hypothesis that individuals with fluid overload-induced OSA will experience autonomic dysregulation, compared to those without fluid overload-induced OSA. METHODS: Twenty-one normotensive, nonobese (mean body mass index 24.5 kg/m2) males (mean age 37 years) underwent a sleep study. Participants were randomly assigned to infusion with saline during sleep either at the minimum rate (control) or as a bolus of 22 mL/kg body weight (intervention). Participants were blinded to the intervention and crossed over to the other study arm after 1 week. Measures of heart rate variability were calculated from electrocardiography recordings presaline and postsaline infusion in the intervention arm. Heart rate variability measures computed were: standard deviation of the RR interval; root mean square of successive differences; low frequency, high-frequency, and total power; and the ratio of low-frequency to high-frequency power. RESULTS: Although presaline infusion values were similar, postsaline infusion values of the standard deviation of the RR interval and high frequency power were lower in the group whose apnea-hypopnea index increased in response to saline infusion, compared to the group whose apnea-hypopnea index did not increase in response to saline infusion (P < .05 for both). CONCLUSIONS: Fluid overload-induced OSA is accompanied by a reduction in heart rate variability, consistent with vagal withdrawal. Future work should explore autonomic dysregulation in the postoperative period and its association with adverse events. PMID- 29609721 TI - High Interrater Reliability of Overnight Pulse Oximetry Interpretation Among Inexperienced Physicians Using a Structured Template. AB - STUDY OBJECTIVES: To assess the interrater reliability and accuracy of overnight pulse oximetry (OPO) interpretations by pulmonary fellows using a comprehensive structured template and after a brief educational session. METHODS: Using the template, four pulmonary and critical care (PCC) fellows interpreted OPO saturation waveforms and parameters extracted from 50 adult consecutive in laboratory sleep studies. The template included three saturation parameters (mean saturation, oxygen desaturation index [ODI], and cumulative desaturation time) and description of the saturation waveform. A scoring system was proposed combining waveform characteristics and ODI to determine the suspicion for moderate to severe sleep apnea. Waveform description and mean saturation determined the suspicion for cardiopulmonary disease (CPD). Cumulative desaturation time determined need for oxygen prescription. Apnea-hypopnea index was extracted from the sleep study results. RESULTS: The overall interrater reliability for final recommendations (sleep apnea suspicion, presence of CPD, and oxygen prescription) was high (kappa = .81, 95% confidence interval [CI] .76 .88). Good agreement was noted in CPD evaluation and suspicion of moderate to severe sleep apnea (kappa = .70, 95% CI .46-.86 and kappa = .65, 95% CI .56-.77 respectively). The interrater reliability for oxygen prescription was in an excellent range (kappa = .98, 95% CI .91-1.00). The accuracy of a high sleep apnea suspicion score in detecting apnea-hypopnea index >= 15 events/h ranged from 88.0% to 94.0% (sensitivity 91.3% to 95.7%, specificity 81.5% to 92.6%). Desaturations due to CPD were identified by 75% of the raters as desaturations due to conditions other than sleep apnea. CONCLUSIONS: A structured template for OPO interpretation can produce a high interrater agreement and good accuracy, and make it a reliable clinical tool. COMMENTARY: A commentary on this article appears in this issue on page 497. PMID- 29609722 TI - The Validity of a New Consumer-Targeted Wrist Device in Sleep Measurement: An Overnight Comparison Against Polysomnography in Children and Adolescents. AB - STUDY OBJECTIVES: The validity of consumer-targeted wrist-worn sleep measurement systems has been little studied in children and adolescents. We examined the validity of a new fitness tracker (PFT) manufactured by Polar Electro Oy and the previously validated Actiwatch 2 (AW2) from Philips Respironics against polysomnography (PSG) in children and adolescents. METHODS: Seventeen children (age 11.0 +/- 0.8 years) and 17 adolescents (age 17.8 +/- 1.8 years) wore the PFT and AW2 concurrently with an ambulatory PSG in their own home for 1 night. We compared sleep onset, offset, sleep interval (time from sleep on to offset), actual sleep time (time scored as sleep between sleep on and offset), and wake after sleep onset (WASO) between accelerometers and PSG. Sensitivity, specificity, and accuracy were calculated from the epoch-by-epoch data. RESULTS: Both devices performed adequately against PSG, with excellent sensitivity for both age groups (> 0.91). In terms of specificity, the PFT was adequate in both groups (> 0.77), and AW2 adequate in children (0.68) and poor in adolescents (0.58). In the younger group, the PFT underestimated actual sleep time by 29.9 minutes and AW2 underestimated actual sleep time by 43.6 minutes. Both overestimated WASO, PFT by 24.4 minutes and AW2 by 20.9 minutes. In the older group, both devices underestimated actual sleep time (PFT by 20.6 minutes and AW2 by 26.8 minutes) and overestimated WASO (PFT by 12.5 minutes and AW2 by 14.3 minutes). Both devices were accurate in defining sleep onset. CONCLUSIONS: This study suggests that this consumer-targeted wrist-worn device performs as well as, or even better than, the previously validated AW2 against PSG in children and adolescents. Both devices underestimated sleep but to a lesser extent than seen in many previous validation studies on research-targeted accelerometers. PMID- 29609723 TI - Tooth Movement Associated With CPAP Therapy. AB - ABSTRACT: We report on a rarely documented side effect-tooth movement-associated with positive airway pressure therapy. A 64-year-old woman presented to an orthodontic practice for evaluation of unexplained tooth movement and spaces opening between her anterior teeth. The patient recently received a diagnosis of mild obstructive sleep apnea, for which she had been using continuous positive airway pressure (CPAP) delivered by a nasal pillows interface for the past 18 months. Follow-up questioning revealed that shifting of the teeth was first noticed in the months following the initiation of CPAP and the result of forward thrusting of the tongue during use. Following 12 months of orthodontic treatment, the malocclusion was corrected and teeth returned to their pretreatment positions. Unwanted tooth movement, although a minor sequela, can have a meaningful effect on quality of life. With improved awareness of this issue, the patient experience and ultimately adherence with CPAP treatment can be improved. PMID- 29609724 TI - Did Rene Descartes Have Exploding Head Syndrome? AB - ABSTRACT: Rene Descartes (1596-1650), "the Father of Modern Philosophy" and advocate of mind-body dualism, had three successive dreams on November 10, 1619 that changed the trajectory of his life and the trajectory of human thought. Descartes' influential dreams have been of interest to a number of commentators including the famous neurologist and psychoanalyst Sigmund Freud. Descartes' second dream in particular, in which he heard a loud noise in his head before seeing a bright flash of light upon awakening, has been discussed extensively. Commentators have employed psychoanalytic and medical explanations to account for Descartes' unusual nocturnal experience. In this tradition, I propose that Descartes' second dream was not a dream at all; rather, it was an episode of exploding head syndrome; a benign and relatively common parasomnia. I further suggest that Adrien Baillet's account of Descartes' experience constitutes the earliest description of exploding head syndrome, predating the account described by Silas Weir Mitchell in 1876 by nearly 200 years. PMID- 29609725 TI - Getting Personal with Down Syndrome and Obstructive Sleep Apnea. PMID- 29609726 TI - The Future of the Sleep Lab: It's Complicated. PMID- 29609727 TI - Medical Cannabis and the Treatment of Obstructive Sleep Apnea: An American Academy of Sleep Medicine Position Statement. AB - ABSTRACT: The diagnosis and effective treatment of obstructive sleep apnea (OSA) in adults is an urgent health priority. Positive airway pressure (PAP) therapy remains the most effective treatment for OSA, although other treatment options continue to be explored. Limited evidence citing small pilot or proof of concept studies suggest that the synthetic medical cannabis extract dronabinol may improve respiratory stability and provide benefit to treat OSA. However, side effects such as somnolence related to treatment were reported in most patients, and the long-term effects on other sleep quality measures, tolerability, and safety are still unknown. Dronabinol is not approved by the United States Food and Drug Administration (FDA) for treatment of OSA, and medical cannabis and synthetic extracts other than dronabinol have not been studied in patients with OSA. The composition of cannabinoids within medical cannabis varies significantly and is not regulated. Synthetic medical cannabis may have differential effects, with variable efficacy and side effects in the treatment of OSA. Therefore, it is the position of the American Academy of Sleep Medicine (AASM) that medical cannabis and/or its synthetic extracts should not be used for the treatment of OSA due to unreliable delivery methods and insufficient evidence of effectiveness, tolerability, and safety. OSA should be excluded from the list of chronic medical conditions for state medical cannabis programs, and patients with OSA should discuss their treatment options with a licensed medical provider at an accredited sleep facility. Further research is needed to understand the functionality of medical cannabis extracts before recommending them as a treatment for OSA. PMID- 29609728 TI - The Risk of Fatigue and Sleepiness in the Ridesharing Industry: An American Academy of Sleep Medicine Position Statement. AB - ABSTRACT: The ridesharing-or ride-hailing-industry has grown exponentially in recent years, transforming quickly into a fee-for-service, unregulated taxi industry. While riders are experiencing the benefits of convenience and affordability, two key regulatory and safety issues deserve consideration. First, individuals who work as drivers in the ridesharing industry are often employed in a primary job, and they work as drivers during their "off" time. Such a schedule may lead to driving after extended periods of wakefulness or during nights, both of which are factors that increase the risk of drowsy driving accidents. Second, these drivers are often employed as "independent contractors," and therefore they are not screened for medical problems that can reduce alertness, such as obstructive sleep apnea. Some ridesharing companies now require a rest period after an extended driving shift. This measure is encouraging, but it is insufficient to impact driving safety appreciably, particularly since many of these drivers are already working extended hours and tend to drive at non traditional times when sleepiness may peak. Therefore, it is the position of the American Academy of Sleep Medicine (AASM) that fatigue and sleepiness are inherent safety risks in the ridesharing industry. The AASM calls on ridesharing companies, government officials, medical professionals, and law enforcement officers to work together to address this public safety risk. A collaborative effort is necessary to understand and track the scope of the problem, provide relevant education, and mitigate the risk through thoughtful regulation and effective fatigue risk management systems. PMID- 29609729 TI - Overnight Pulse Oximetry Unwoven. PMID- 29609730 TI - Enhancing general practice referrals for women of refugee background to maternity care. AB - This paper presents the findings from a quality improvement project implemented by a maternity hospital located in a region of high refugee settlement. The project was designed to improve the completeness of general practice referral information to enable triage to maternity care that would best meet the needs of women of refugee background. Referral information included four data items - country of birth, year of arrival in Australia, language spoken and interpreter required - used in combination to provide a proxy measure of refugee background. A communication strategy and professional development activity engaged general practitioners (GPs) in the rationale for collecting the four data items on a new referral form. Audits of referrals to the maternity hospital before, and at two time points following the quality improvement activity, indicated that very few referrals were completed on the new form. There were modest improvements in the recording of two items - country of birth and interpreter required. Overall, two thirds of referrals did not contain information on interpreter requirements. Changing practice will require a more cohesive approach involving GPs in the co design of the form and development of the quality improvement strategy. PMID- 29609732 TI - An expanded model of the moral self: Beyond care and justice. AB - Most research on moral identities conceptualizes morality exclusively in terms of care and justice, but work from across the social sciences indicates that these represent only a corner of the moral landscape. Emphasizing care and justice alone severely restricts the scope of moral identity models, and risks under estimating the influence of moral self-processes. To address this, we develop and validate measures of moral identity focused on group loyalty, authority, and purity, three additional facets of morality highlighted in Moral Foundations Theory. Although the loyalty identity is remarkably similar to the care/justice identity, the authority and purity identities are distinct, and demonstrate adequate convergent, divergent, and nomological validity. These identities also predict a wide range of behaviors that traditional care/justice focused moral identities miss. Taken together, our work indicates that the moral self is more complex - and has a much wider scope of influence - than previously supposed. PMID- 29609733 TI - Girls' self-efficacy in the context of neighborhood gender stratification. AB - Scholars have linked neighborhood characteristics to self-efficacy, but few have considered how gender factors into this association. We integrate literature on neighborhoods, gender stratification, and self-efficacy to examine the association between women's relative resources among neighborhood residents and adolescents' self-efficacy. We hypothesize that girls report more self-efficacy when they reside in neighborhoods where women have more socioeconomic resources relative to men. We test this hypothesis using data from the Project on Human Development in Chicago Neighborhoods and the 1990 Census. Results from multilevel regression models with gender-interacted effects indicate the neighborhood level of women's relative resources was not associated with boys' self-efficacy. However, girls reported higher self-efficacy when women's relative resources in their neighborhoods were greater. This association persisted after including potential individual- and neighborhood-level confounding variables. Our study underscores the importance of attending to gendered processes when understanding how neighborhoods impact youth. PMID- 29609731 TI - Neural retina-specific Aldh1a1 controls dorsal choroidal vascular development via Sox9 expression in retinal pigment epithelial cells. AB - VEGF secreted from retinal pigment epithelial (RPE) cells is responsible for the choroidal vascular development; however, the molecular regulatory mechanism is unclear. We found that Aldh1a1-/- mice showed choroidal hypoplasia with insufficient vascularization in the dorsal region, although Aldh1a1, an enzyme that synthesizes retinoic acids (RAs), is expressed in the dorsal neural retina, not in the RPE/choroid complex. The level of VEGF in the RPE/choroid was significantly decreased in Aldh1a1-/- mice, and RA-dependent enhancement of VEGF was observed in primary RPE cells. An RA-deficient diet resulted in dorsal choroidal hypoplasia, and simple RA treatment of Aldh1a1-/- pregnant females suppressed choroid hypoplasia in their offspring. We also found downregulation of Sox9 in the dorsal neural retina and RPE of Aldh1a1-/- mice and RPE-specific disruption of Sox9 phenocopied Aldh1a1-/- choroidal development. These results suggest that RAs produced by Aldh1a1 in the neural retina directs dorsal choroidal vascular development via Sox9 upregulation in the dorsal RPE cells to enhance RPE-derived VEGF secretion. PMID- 29609734 TI - Gender of the immediate manager and women's wages: The importance of managerial position. AB - One argument for increasing female representation in management is the expectation that female managers will be particularly beneficial for female employees through, e.g., role modeling, mentoring or providing other incentives to enhance female productivity. We explore this issue by analyzing the association between women's wages and the gender of their immediate managers using Swedish matched employee-employer data from 2010. Contrary to the expected positive association, we find that wages are overall 3% lower for female employees with a female instead of male manager. However, dividing the sample by managerial position and controlling for the sorting of employees with respect to, e.g., non-cognitive traits, work tasks, family commitment and establishment gender composition, the negative association is found only for female employees working for lower-level managers, not for women with a manager at the highest rank. One possible explanation could be a difference in decision-making power if lower-level female managers have more limited resources for their subordinates compared to lower-level male managers. PMID- 29609735 TI - Gender, expert advice, and judicial gatekeeping in the United States. AB - This article investigates the role of gender in decision-making by examining trial judges' decisions to admit or exclude expert witness testimony. An analysis of civil rights cases in United States district courts (n = 198) reveals that male judges are substantially more likely than females to exclude expert evidence. Importantly, this pattern cannot be attributed to other characteristics of judges, experts, or courts that may influence judges' rulings. These findings are consistent with theories of gender, organizations, and science that suggest that women are more likely than men to consider expert advice. These results also indicate that the organizational role of trial judge may not be enough to offset the wider effects of the gender system on perceptions of experts. PMID- 29609736 TI - The scarring effect of unemployment on psychological well-being across Europe. AB - Past unemployment may have a pervasive psychological impact that occurs across nations. We investigate the association between unemployment events across working life and subsequent psychological well-being across 14 European countries. Additionally, we consider the influence of between-country differences in labour market institutions and conditions on the cross-country well-being effects of unemployment. Data detailing life-long employment trajectories and contemporary life conditions are drawn from the Survey of Health, Ageing and Retirement in Europe. The well-being impact of unemployment is modeled using linear, multi-level specifications. Each six-month spell of past unemployment is found to predict reduced quality of life and life satisfaction after the age of 50, having adjusted for a broad range of individual and country-specific covariates. In contrast, the impact of past unemployment on depression is explained by individual demographic factors. We identify the first comparative long-term evidence that unemployment welfare scarring may be a broad, international phenomenon. PMID- 29609737 TI - Measures of gender role attitudes under revision: The example of the German General Social Survey. AB - Using the example of the German General Social Survey, this study describes how measures of gender role attitudes can be revised. To date measures have focused on the traditional male breadwinner model. However, social developments in female labor force participation, education, and family structure suggest that a revision and adjustment of existing measures are required. First, these measures need to be supplemented with items that represent more egalitarian models of division of labor and the role of the father in the family. Second, the phrasing of existing items needs to be revised. The results of this study indicate that especially regarding the amount of working hours and the age of children, a specification is needed. This study presents a revised measure, to facilitate analyses over time. This revised measure represents two factors: one referring to traditional and one to modern gender role attitudes. PMID- 29609738 TI - Structural stability, quantitative change: A latent class analysis approach towards gender role attitudes in Germany. AB - Since the 1960s, social science surveys have aimed to assess respondents' attitudes towards gender roles. In this paper, a model-based clustering approach towards gender role attitudes is proposed in contrast to commonly used dimensional methods. Working from a role theory perspective, we expect different profiles in the population when it comes to role expectations. Using data from the German General Social Survey in 1991 and 2012, we identify attitude patterns via multi-group latent class analysis, taking differences between Eastern and Western Germany into account. Five latent classes representing different combinations of role expectations towards couples and parents and varying levels of intensity are distinguished. Attitude change is assessed by comparing latent class prevalence over time, while statistically testing for measurement equivalence. The analysis reveals a regionally variable decrease in traditional role models: Eastern Germany exhibits a faster pace of 'de-traditionalization' and less potential for role conflicts regarding working mothers. PMID- 29609739 TI - Mexican parent's undocumented status and the educational attainment of the children left behind. AB - Research shows that having undocumented parents lowers the educational attainment of children that grew up in the United States, but we know less about how it affects the education of children left behind in their origin countries. We use fixed effects models and data from the Mexican Migration Project to examine this relationship. We find that having both parents documented increases the educational attainment of children left behind by over two years in comparison to similar children with mixed-status, undocumented, and nonimmigrant parents. The effect is especially robust for boys that migrate as teenagers. These findings reveal that US immigration laws that define most Mexican immigrants as undocumented have had a devastating effect on the education of Mexican children left behind. PMID- 29609740 TI - Political regimes, income and health: Evidence from sub-national comparative method. AB - This paper investigates the effect of political regimes on healthcare outcomes with a novel approach. Instead of focusing on cross-country comparisons, like most studies do, we utilize the within-country variation of political regimes across individual regions. We use the case of the Russian Federation, where large sub-national differences exist in both health outcomes and political regimes in different provinces. General differences in sub-national politics in Russia have been subject of investigation of a large literature our paper adds to. The paper shows that the effect of political regimes on health is heterogeneous and depends on the type of health problems more salient for the region. More pluralist and competitive regimes are able to produce better results than the less competitive ones in rich regions, while in poor regions political pluralism and competition have an adverse impact on health. PMID- 29609741 TI - Mothers' work patterns and Children's cognitive achievement: Evidence from the India Human Development survey. AB - As female labor force participation increases globally, the relationship between maternal employment and children's development remains unclear. Using data from the India Human Development Survey (2005), we investigate the link between maternal employment and children's arithmetic and reading achievement. We develop a work pattern typology that goes beyond standard measures of employment and captures work intensity and its compatibility with child-rearing in a transitional economy. We find that the relationship between maternal employment and children's outcomes is not unidimensional. For example, children of self employed mothers are not disadvantaged compared to those with stay-at-home mothers, but maternal employment in salaried jobs or wage work outside the home is negatively associated with cognitive skills in children. However, this negative association is reversed at higher levels of maternal education, suggesting greater access to resources and flexibility associated with better jobs mitigate the negative aspects of maternal employment posed by time constraints. Additionally, maternal employment is associated with maternal involvement in schoolwork and financial investment in academic activities, providing evidence that both time and resources devoted to children's education are significant. PMID- 29609742 TI - Strategic action or self-control? Adolescent information management and delinquency. AB - Recent scholarship has begun to challenge the prevailing view that children are passive recipients of parental socialization, including the common belief that parental disciplinary practices are central to explaining adolescent problem behaviors. This research shows that children exert a significant influence over parents via information management, or the degree to which children disclose information about their behavior to parents. Despite the incorporation of child information management into contemporary models of parenting, significant theoretical and empirical concerns cast doubt on its utility over classic parent centered approaches. The current paper addresses these concerns and adjudicates between disparate definitions of adolescent information management in two ways. First, it provides a theoretically grounded definition of information management as agentic behavior. Second, it specifies a model that tests definitions of secret keeping as agentic against a non-agentic definition of secret keeping supplied by criminological theories of self-control. The model is estimated with three four-wave cross-lagged panel models, which disentangle the interrelationships between parenting, child concealment of information, and child problem behavior in a sample of high risk youth. The results offer support for a definition of concealment as strategic and self-regarding, and have implications for research on delinquency, parent-child interactions, and child agency. PMID- 29609743 TI - The effect of neighborhood context on children's academic achievement in China: Exploring mediating mechanisms. AB - Along with the economic reforms, rapid urbanization, and the growth of a free land market, Chinese cities witness new forms of neighborhood poverty and increasing residential segregation by social class, migration status, and housing tenure. But little is known about the consequences of the growing social-spatial differentiation for children's educational achievement in China. Using national scale survey data from the China Family Panel Studies in 2010, this study examines the relationship between neighborhood socioeconomic status (SES) and children's test scores in urban China, and explores the mechanisms through which neighborhood environment is associated with children's academic achievement. The results show that neighborhood SES is positively associated with children's verbal and math test scores after accounting for myriad individual and family characteristics. The relationship between neighborhood SES and test scores is partially explained by neighborhood educational institutions and collective socialization. Peer contagion, neighborhood social organization, or neighborhood physical environment do not explain this relationship. PMID- 29609744 TI - The persistence of white flight in middle-class suburbia. AB - Scholars have continued to debate the extent to which white flight remains racially motivated or, in contrast, the result of socioeconomic concerns that proxy locations of minority residence. Using 1990-2010 census data, this study contributes to this debate by re-examining white flight in a sample of both poor and middle-class suburban neighborhoods. Findings fail to provide evidence in support of the racial proxy hypothesis. To the contrary, for neighborhoods with a larger non-white presence, white flight is instead more likely in middle-class as opposed to poorer neighborhoods. These results not only confirm the continued salience of race for white flight, but also suggest that racial white flight may be motivated to an even greater extent in middle-class, suburban neighborhoods. Theoretically, these findings point to the decoupling of economic and racial residential integration, as white flight may persist for groups even despite higher levels of socioeconomic attainment. PMID- 29609745 TI - Perceptions as the crucial link? The mediating role of neighborhood perceptions in the relationship between the neighborhood context and neighborhood cohesion. AB - This study examines the effects of neighborhood racial in-group size, economic deprivation and the prevalence of crime on neighborhood cohesion among U.S. whites. We explore to what extent residents' perceptions of their neighborhood mediate these macro-micro relationships. We use a recent individual-level data set, the American Social Fabric Study (2012/2013), enriched with contextual-level data from the U.S. Census Bureau (2010) and employ multi-level structural equation models. We show that the racial in-group size is positively related to neighborhood cohesion and that neighborhood cohesion is lower in communities with a high crime rate. Individuals' perceptions of the racial in-group size partly mediate the relationship between the objective racial in-group size and neighborhood cohesion. Residents' perceptions of unsafety from crime also appear to be a mediating factor, not only for the objective crime rate but also for the objective racial in-group size. This is in line with our idea that racial stereotypes link racial minorities to crime whereby neighborhoods with a large non-white population are perceived to be more unsafe. Residents of the same neighborhood differ in how they perceive the degree of economic decay of the neighborhood and this causes them to evaluate neighborhood cohesion differently, however perceptions of neighborhood economic decay do not explain the link between the objective neighborhood context and neighborhood cohesion. PMID- 29609746 TI - Differential investments and opportunities: How do neighborhood conditions moderate the relationship between perceived housing discrimination and social capital? AB - Though the adverse consequences of perceived housing discrimination have been documented, little is known about whether such experience undermines one's social capital in a neighborhood and even less is about whether and how this relationship is altered by neighborhood features. We proposed a framework that simultaneously considers within-individual and between-neighborhood processes. We applied multilevel structural equation models to data from Philadelphia (n = 9987) and found that (a) perceived housing discrimination was negatively associated with one's social capital even after other confounders were considered, (b) this negative association could be partly explained by the proliferated daily stress and anxiety mechanisms, (c) differential exposures to neighborhood social disadvantage accounted for the variation in social capital across neighborhoods, and (d) the adverse association between perceived housing discrimination and social capital could be attenuated by neighborhood stability. The findings suggested that appropriate interventions should buffer the negative association of perceived housing discrimination with social capital. PMID- 29609747 TI - The American Muslim voter: Community belonging and political participation. AB - The past few election cycles have brought increased attention on voting rates among racial and ethnic minorities in the United States, focusing on African Americans, Asian Americans and Latinos. Building on theories of in-group identity, we assess whether or not American Muslims are similarly mobilized to vote consonant with other ethnic minorities in the U.S. whereby in-group attachment and group-level resources encourage participation. Using a national sample of American Muslims, we find that those who live around more co-ethnics and those who actively engage their religious identity are more likely to report they voted, and more likely to vote Democratic. This research offers the first evidence that American Muslims may follow similar patterns of in-group identity mobilization to other racial and ethnic groups in the United States. PMID- 29609748 TI - Impact of Lipoproteins on Atherobiology: Emerging Insights. AB - Apolipoprotein B-containing lipoproteins and low-density lipoprotein play a key role in atherosclerotic vascular disease. Modified forms of low-density lipoprotein drive inflammation, an integral aspect of plaque progression. High density lipoprotein particles are equipped to protect low-density lipoprotein from enzymatic and nonenzymatic modification. Under normal conditions, high density lipoproteins facilitate cholesterol efflux from tissues, preventing its accumulation with deleterious consequences. However, the high-density lipoprotein particles characteristic of dyslipidemic states associated with premature atherosclerosis are typically dysfunctional as a result of alteration in their metabolism and consequently their structure and composition. Such an effect indirectly enhances low-density lipoprotein atherogenicity. PMID- 29609749 TI - Causal Effect of Lipids and Lipoproteins on Atherosclerosis: Lessons from Genomic Studies. AB - Mendelian randomization studies demonstrate that apolipoprotein B-containing lipoproteins have both causal and cumulative effects on the risk of atherosclerotic cardiovascular disease. The clinical benefit of lipid-lowering therapies depends on both the absolute reduction in circulating apolipoprotein B containing lipoproteins and the total duration of exposure to these particles. Because atherosclerosis seems to be caused by the retention of apolipoprotein B containing lipoproteins rather than by the cholesterol content carried by those lipoproteins, high-density lipoprotein-mediated efflux of cholesterol from the arterial wall may not reduce the risk of atherosclerotic cardiovascular disease. PMID- 29609750 TI - Lipids and Lipoproteins in Risk Prediction. AB - Ischemic heart disease remains the leading cause of death worldwide. Low-density lipoprotein cholesterol (LDL-C) has proved to have a causal relationship with atherosclerotic cardiovascular disease. Lowering LDL-C improves outcomes, although some patients continue to have residual risk of cardiovascular disease. Cardiovascular risk prediction calculators are routinely used in to identify patients most at risk. Research into other lipoprotein factors has suggested that they may have advantages over LDL-C and improve the ability to identify those most at risk. Although some technology is not widely available, there is potential for better risk prediction in specific groups. PMID- 29609751 TI - Optimizing Statins and Ezetimibe in Guideline-Focused Management. AB - Statins are essential medications in the management of patients with clinical atherosclerotic cardiovascular disease, and have been supported by numerous clinical trials. Emerging evidence suggests that adding ezetimibe to statin therapy is associated with a net benefit and improved hard clinical outcomes, particularly in patients with significantly elevated atherosclerotic cardiovascular disease risk and elevated low-density lipoprotein cholesterol levels. PMID- 29609752 TI - Statin Intolerance: Some Practical Hints. AB - Statin intolerance is the inability to tolerate a dose of statin required to sufficiently reduce cardiovascular risk. With the five-step approach, more than 90% of these patients might be treated with statins. The principal approaches are to try not to discontinue statin therapy and to treat these patients as effectively as possible. New therapies with the proprotein convertase subtilisin kexin type 9 inhibitors and bempedoic acid might be an effective response to these needs. In case of lack of achieved goal of the therapy nutraceuticals with confirmed low-density lipoprotein cholesterol reduction properties may be considered as a part of the lipid-lowering combination therapy. PMID- 29609753 TI - Treating Dyslipidemia in Type 2 Diabetes. AB - Type 2 diabetes is associated with elevated levels of triglycerides and small, dense low-density lipoprotein particles, in addition to low levels of high density lipoprotein cholesterol. Clinical trials have demonstrated the clear cardiovascular benefit of use of statin therapy in patients with diabetes. Additional lipid-modifying agents are typically guided by the presence of additional lipid abnormalities. The optimal use of existing lipid agents and the potential for novel therapies in patients with diabetes is reviewed. PMID- 29609754 TI - Proprotein Convertase Subtilisin Kexin 9 Inhibitors. AB - High levels of low-density lipoprotein cholesterol (LDL-C) are directly associated with an increased risk of cardiovascular disease. Reducing LDL-C levels reduces the incidence of cardiovascular events. Several lipid-lowering approaches are available to achieve the LDL-C levels recommended by current guidelines, statins being the first-line therapy. However, many patients cannot achieve the recommended LDL-C levels with current therapies. The discovery of the role of proprotein convertase subtilisin kexin 9 (PCSK9) in the regulation of plasma LDL-C levels suggested it as a potential pharmacologic target and led to the development of PCSK9 inhibitors for the management of LDL-C levels. PMID- 29609755 TI - Bempedoic Acid (ETC-1002): A Current Review. AB - Although statins are first-line therapy for low-density lipoprotein cholesterol (LDL-C) reduction, many individuals on maximally tolerated statin therapy have elevated LDL-C. Bempedoic acid (ETC-1002) is a novel once-daily LDL-C-lowering agent in phase 3 clinical trials. In phase 1 and 2 studies, ETC-1002 was efficacious in lowering LDL-C when used as monotherapy and when added to statin and/or ezetimibe and was well tolerated in patients with statin intolerance. ETC 1002 also improved cardiometabolic risk factors. Ongoing phase 3 studies of ETC 1002 are evaluating its long-term efficacy and safety, and effects on cardiovascular events. This article discusses current evidence and future directions for ETC-1002. PMID- 29609756 TI - Triglyceride-Rich Lipoproteins. AB - Plasma triglyceride levels are causally related to an increased risk of cardiovascular disease. Here, the authors summarize their understanding of triglyceride-rich lipoprotein metabolism, previous and newly identified regulators, and their relevance as candidate targets for therapeutic intervention. PMID- 29609757 TI - Evolution of Omega-3 Fatty Acid Therapy and Current and Future Role in the Management of Dyslipidemia. AB - Omega-3 fatty acids have shown modest benefit in certain subgroups at higher cardiovascular risk. Ongoing trials are investigating cardiovascular event rate reduction with newer, more efficacious formulations with a focus on these higher risk patients. This article focuses on the previously demonstrated benefits of omega-3 fatty acid therapies, currently available formulations, and their current and future role in reducing cardiovascular risk. PMID- 29609758 TI - Is Lipoprotein(a) Ready for Prime-Time Use in the Clinic? AB - Lipoprotein (a) is a low-density lipoprotein-like particle covalently bound to a glycoprotein called apolipoprotein(a) that is under potent genetic control. Plasma levels of lipoprotein (a) vary by up to 1000-fold among individuals, with 1 in 4 having levels that increase the risk of atherosclerotic cardiovascular disease. New evidence supports a causal role for lipoprotein (a) in atherosclerotic cardiovascular disease and aortic valve stenosis. Individuals with elevated lipoprotein (a) have a high life-time burden of atherosclerotic cardiovascular disease. This notion is important for coronary prevention. But is lipoprotein (a) ready for prime-time use in coronary prevention clinics? PMID- 29609759 TI - Cholesteryl Ester Transfer Protein Inhibitors as Agents to Reduce Coronary Heart Disease Risk. AB - Cholesteryl ester transfer protein (CETP) promotes the transfer of cholesteryl esters from the nonatherogenic high density lipoprotein (HDL) fraction to potentially proatherogenic non-HDL fractions. Inhibition of CETP reduces the concentration of non-HDL cholesterol, enhances HDL functionality, and increases the concentration of HDL cholesterol and apoA-I. Despite an absence of benefit in earlier trials of CETP inhibition, the REVEAL trial has shown that treatment with the CETP inhibitor anacetrapib reduces the risk of having a coronary event in high-risk, statin-treated patients. PMID- 29609760 TI - High-Density Lipoprotein Infusions. AB - High-density lipoproteins (HDLs) have presented an attractive target for development of new therapies for cardiovascular prevention on the basis of epidemiology and preclinical studies demonstrating their protective properties. Development of HDL mimetics provides an opportunity to administer functional HDL. However, clinical trials have produced variable results, with no evidence to date that they reduce cardiovascular events. This article reviews development programs of HDL mimetics. PMID- 29609761 TI - High-Density Lipoproteins: Effects on Vascular Function and Role in the Immune Response. AB - The focus in studies of high-density lipoproteins was on their capacity to remove excess cholesterol and deliver it to the liver. Other functions and vascular effects have been described. Clinical trials and translational/genetic studies have led to a refined understanding of the role of high-density lipoprotein; it is likely not a causal cardiovascular risk factor. In healthy subjects, it limits lipid oxidation, protects endothelial cell functions/integrity, and exerts antiinflammatory/antiapoptotic effects. In patients with coronary disease or diabetes, it undergoes modifications/remodeling, resulting in dysfunctional high density lipoprotein. We summarize recent findings about the regulation of its function and discuss the clinical implications. PMID- 29609762 TI - Intravascular Ultrasound Studies of Plaque Progression and Regression: Impact of Lipid-Modifying Therapies. AB - Application of serial intravascular ultrasound imaging within the coronary arteries enables characterization of the factors associated with progression of atherosclerotic plaque. Integration into clinical trials has enabled determination of the impact of medical therapies on coronary disease. These trials have provided important insights into the effects of lipid-modifying agents currently used in clinical practice and of experimental agents at early stages of clinical development. The results of these trials are reviewed. PMID- 29609763 TI - Lipidology. PMID- 29609764 TI - Erratum to: "Efficacy and safety of vaginally administered lyophilized Lactobacillus crispatus IP 174178 in the prevention of bacterial vaginosis recurrence" [J. Gynecol. Obstet. Hum. Reprod. 47 (2018) 81-7]. PMID- 29609765 TI - Origins of mosaicism and criteria for the transfer of mosaic embryos. PMID- 29609766 TI - Dienogest suppresses the activation of primordial follicles and preserves the primordial follicle stockpile for fertility in mice. AB - The aim of the present study was to characterize the effect of long-term usage of dienogest, a fourth-generation progestin that possesses progestogen and anti androgen activities, on the stockpile of oocytes and fertility after administration. Female ICR mice (100 days old) were divided into a dienogest group and a control group. The mice received 16 consecutive subcutaneous injections of 5 mg dienogest dissolved in corn oil or corn oil as a vehicle control every 4 days. The mice treated with dienogest had more total offspring and larger litter sizes after the final administration than the mice treated with the vehicle control. Greater numbers of primordial follicles were detected at both 4 and 80 days after the final administration. No significant differences were found in serum anti-Mullerian hormone concentrations at 4 and 80 days after the final dienogest administration. The ratio of primary to primordial follicles was decreased in 3-day-old newborn ovaries cultured for 4 days with dienogest (10 7, 10-6 and 10-5 mol/l) compared with ovaries cultured without dienogest. The results of the present study indicate that dienogest suppresses the activation of primordial follicles during its administration and preserves the primordial follicle stockpile and subsequent fertility in mice. PMID- 29609767 TI - Patients with a high proportion of immature and meiotically resistant oocytes experience defective nuclear oocyte maturation patterns and impaired pregnancy outcomes. AB - Patients presenting with abnormally high numbers of immature oocytes at retrieval are more likely to exhibit maturation resistant oocytes. However, the clinical relevance of such events remains unknown. We investigated nuclear maturation competence of immature oocytes from patients showing >40% of collected immature oocytes (Study group) and Controls, in which a normal number of mature oocytes (>=60%) was retrieved. Following in-vitro culture, oocytes were classified as maturation resistant or in-vitro matured (IVM). Treatment outcomes were evaluated in Study and Control groups based on presence of maturation resistant oocytes. Overall, similarly high spindle and chromosome abnormality rates were observed in maturation resistant oocytes from both Study and Control groups. IVM oocytes from the Study group revealed significantly higher percentages of misaligned chromosomes compared with Controls (P < 0.05). Remarkably, Study group patients with at least one maturation resistant oocyte showed significantly reduced cumulative pregnancy and live birth rates compared with Control group maturation resistant patients (P < 0.05). When further investigating the aetiology, a maturation resistant mouse model revealed defective Ca2+ signalling of maturation resistant oocytes at germinal vesicular breakdown and parthenogenetic activation. In conclusion, appropriate treatment strategies, including clinical utilization of IVM oocytes from Study group patients, warrant further investigation. PMID- 29609769 TI - Introduction: Multiple Realizability and Levels of Reality. PMID- 29609768 TI - Multiple pregnancies achieved with IVF/ICSI and risk of specific congenital malformations: a meta-analysis of cohort studies. AB - Studies comparing risk of specific congenital malformations (CM) between multiple pregnancies resulting from IVF/intracytoplasmic sperm injection (ICSI) and those conceived naturally report conflicting results; furthermore, there is a lack of a complete overview. This meta-analysis aimed to address which types of CM are increased in IVF/ICSI multiple pregnancies compared with those conceived naturally. All studies testing the association between IVF/ICSI multiple pregnancies and specific CM identified in various databases were considered. The literature search yielded 856 records, of which 21 cohort studies were included for analysis. Overall, multiple pregnancies achieved with IVF/ICSI experienced a significantly higher risk of chromosomal defects (relative risk [RR] = 1.36; 95% confidence interval [CI]: 1.04-1.77), urogenital (RR = 1.18; 95% CI: 1.03-1.36) and circulatory (RR = 1.22; 95% CI: 1.01-1.47) system malformations. However, the remaining specific CM, such as cleft lip and/or palate, eye, ear, face and neck, respiratory, musculoskeletal, nervous and digestive system malformations, were similar in the two groups. No substantial heterogeneity was observed for most outcomes except for digestive (P = 0.094; I2 = 38.3%) and circulatory (P = 0.070; I2 = 35.2%) system malformations. These findings provide additional information on risks of IVF/ICSI for use when counselling patients. PMID- 29609770 TI - Reduction redux. AB - Putnam's criticisms of the identity theory attack a straw man. Fodor's criticisms of reduction attack a straw man. Properly interpreted, Nagel offered a conception of reduction that captures everything a physicalist could want. I update Nagel, introducing the idea of overlap, and show why multiple realization poses no challenge to reduction so construed. PMID- 29609771 TI - Cognition wars. AB - In what kinds of physical systems can cognition be realized? There are currently competing answers among scientists and theorists of cognition. There are many plant scientists who maintain that cognition can be realized in plants. There are biological scientists who maintain that cognition is materially realized in bacteria. In this paper, I will present the basis for such claims and evaluate them and discuss the future for theories of the metaphysical basis of cognition in the cognitive sciences. PMID- 29609772 TI - Multiple realization and multiple "ways" of realization: A progress report. AB - One might have thought that if something has two or more distinct realizations, then that thing is multiply realized. Nevertheless, some philosophers have claimed that two or more distinct realizations do not amount to multiple realization, unless those distinct realizations amount to multiple "ways" of realizing the thing. Corey Maley, Gualtiero Piccinini, Thomas Polger, and Lawrence Shapiro are among these philosophers. Unfortunately, they do not explain why multiple realization requires multiple "ways" of realizing. More significantly, their efforts to articulate multiple "ways" of realizing turn out to be problematic. PMID- 29609773 TI - Physicalism, realization, and structure. AB - In the philosophy of mind and psychology, a central question since the 1960s has been that of how to give a philosophically adequate formulation of mind-body physicalism. A large quantity of work on the topic has been done in the interim. There have been, and continue to be, extensive discussions of the ideas of physicalism, identity, functionalism, realization, and constitution. My aim in this paper is a modest one: it is to get clearer about these ideas and some of their interrelations. After providing some background and history, I shall focus on two related topics: the distinction between a functional property and a structural one and the dispute over whether a realization account of the mental physical relation provides a better physicalist account than a constitutional account. PMID- 29609774 TI - Realizability and the varieties of explanation. AB - What realization is has been convincingly presented in relation to the way we determine what counts as the realizers of realized properties. The way we explain a fact of realization includes a reference to what realization should be; therefore it informs in turn our understanding of the nature of realization. Conceptions of explanation are thereby included in the views of realization as a metaphysical property. Recently, several major views of realization such as Polger and Shapiro's or Gillett and Aizawa's, however competing, have relied on the neo-mechanicist theory of explanations (e.g,. Darden and Caver 2013), currently popular among philosophers of science. However, it has also been increasingly argued that some explanations are not mechanistic (e.g., Batterman 2009). Using an account given in Huneman (2017), I argue that within those explanations the fact that some mathematical properties are instantiated is explanatory, and that this defines a specific explanatory type called "structural explanation", whose subtypes could be: optimality explanations (usually found in economics), topological explanations, etc. This paper thereby argues that all subtypes of structural explanation define several kinds of realizability, which are not equivalent to the usual notion of realization tied to mechanistic explanations, onto which many of the philosophical investigations are focused. Then it draws some consequences concerning the notion of multiple realizability. PMID- 29609775 TI - In defense of interventionist solutions to exclusion. PMID- 29609776 TI - Saving the mutual manipulability account of constitutive relevance. AB - Constitutive mechanistic explanations are said to refer to mechanisms that constitute the phenomenon-to-be-explained. The most prominent approach of how to understand this relation is Carl Craver's mutual manipulability approach (MM) to constitutive relevance. Recently, MM has come under attack (Baumgartner and Casini 2017; Baumgartner and Gebharter 2015; Harinen 2014; Kastner 2017; Leuridan 2012; Romero 2015). It is argued that MM is inconsistent because, roughly, it is spelled out in terms of interventionism (which is an approach to causation), whereas constitutive relevance is said to be a non-causal relation. In this paper, I will discuss a strategy of how to resolve this inconsistency-so-called fat-handedness approaches (Baumgartner and Casini 2017; Baumgartner and Gebharter 2015; Romero 2015). I will argue that these approaches are problematic. I will present a novel suggestion for how to consistently define constitutive relevance in terms of interventionism. My approach is based on a causal interpretation of manipulability in terms of causal relations between the mechanism's components and what I will call temporal EIO-parts of the phenomenon. Still, this interpretation accounts for the fundamental difference between constitutive relevance and causal relevance. PMID- 29609777 TI - Integrating mechanistic explanations through epistemic perspectives. AB - Talk of levels is ubiquitous in philosophy, especially in the context of mechanistic explanations spanning multiple levels. The mechanistic conception of levels, however, does not allow for the kind of integration needed to construct such multi-level mechanistic explanations integrating observations from different scientific domains. To address the issues arising in this context, I build on a certain perspectival aspect inherent in the mechanistic view. Rather than focusing on compositionally related levels of mechanisms, I suggest analyzing the situation in terms of epistemic perspectives researchers take when making scientific observations. Characterizing epistemic perspectives along five dimensions allows for a systematic analysis of the relations the scientific observations made from these different epistemic perspectives. This, in turn, provides a solid foundation for integrating the mechanistic explanations that are based on the scientific observations in question. PMID- 29609780 TI - Editorial. PMID- 29609778 TI - The realizers and vehicles of mental representation. AB - The neural vehicles of mental representation play an explanatory role in cognitive psychology that their realizers do not. Cognitive psychology individuates neural structures as representational vehicles in terms of the specific causal properties to which cognitive mechanisms are sensitive. Explanations that appeal to properties of vehicles can capture generalisations which are not available at the level of their neural realizers. In this paper, I argue that the individuation of realizers as vehicles restricts the sorts of explanations in which they can participate. I illustrate this with reference to Rupert's (2011) claim that representational vehicles can play an explanatory role in psychology in virtue of their quantity or proportion. I propose that such quantity-based explanatory claims can apply only to realizers and not to vehicles, in virtue of the particular causal role that vehicles play in psychological explanations. PMID- 29609781 TI - ? PMID- 29609782 TI - ? PMID- 29609783 TI - [Beating cancer, living with it: success and ethical dilemmas]. AB - Cancers are serious conditions which affect numerous families. The advances made in treatments thanks to research enable a growing number of cancers to be cured. Some cancers which are treated evolve towards a form of chronicity whereby patients have to live with the condition. These varied situations, always sensitive, mobilise and bring together patients, their families, caregivers, researchers and associations. There are many ethical dilemmas facing all those involved in this fight. PMID- 29609784 TI - [The nurse and ethics in a diagnosis of a serious disease]. AB - In the context of the announcement of a diagnosis, a key element of the 2003-2007 cancer plan, nurses spend time with patients to support them and identify their needs. A nurse working in clinical haematology, discusses the specific ethical challenges facing nurses, during these diagnosis consultations and as part of a multidisciplinary team, supporting patients along their care pathway. PMID- 29609785 TI - [The ethical issues of inclusion in clinical trials]. AB - Envisaging the wider ethical issues regarding the inclusion of patients in clinical trials means considering the wider context (regional coverage and patient pathway). It is also necessary to take into account the role of the lead caregivers in maintaining continuity of care for the patients, whether they are included in a clinical trial or given palliative care. PMID- 29609786 TI - [Organising and supporting the end of life when faced with a refusal of care]. AB - Often ethically complex, end-of-life situations can mean nursing teams are confronted with a refusal of care. Through a representative clinical situation, a nurse describes the support provided by a multidisciplinary team, in the home, to comply with the wishes of a person at the end of life, support the family, anticipate possible difficulties and organise adapted care which respects all those concerned. PMID- 29609787 TI - [Ethical issues and limiting of cancer treatments in the advanced stage]. AB - Nurses play a strategic role alongside patients and their families in the process leading to the decision to limit cancer treatments in the advanced phase of the disease. This stage of the patient's care requires support and guidance as part of the palliative approach, which, in addition to the patient and the family, also concerns the oncologist. PMID- 29609788 TI - [Smart health, care relationship and ethics]. AB - A health application is aimed at patients undergoing treatment at home, with chemotherapy or targeted therapy, administered orally. Medical safety, the collaborative approach, data protection and the respect of patients' rights form part of the ethical charter of this innovative project. PMID- 29609789 TI - [Improving communication by adopting a positive relational attitude]. AB - In their daily practice caregivers are in constant communication with patients and families. However, as they deliver the care, are teams always mindful of the issues at stake with regard to the comments they make and the attitudes they adopt? Is the professional language always adapted to the situation? This article attempts to offer solutions by explaining the principles of hypnotic communication which facilitates relationships, including with the teams. PMID- 29609790 TI - [The nurse mobilised in the face of precarity in the rural environment]. AB - In the rural environment, faced with people in situations of precarity, the nurse is an ideal partner for health professionals, as a general practitioner working in a centre for emergency housing and social reintegration explains. PMID- 29609791 TI - [Improving the management of heart failure in the Vendee]. AB - Heart failure is a serious condition which affects mainly elderly people. In the Vendee region, where many people choose to retire, hospital teams have noticed an increase in hospitalisations for heart failure. To optimise the management of these patients, a follow-up service was set up in July 2016 comprising a PRADO programme specifically supporting the return home of patients with heart failure. PMID- 29609793 TI - ? PMID- 29609792 TI - [The nurse and the reconstruction of military casualties through sport]. AB - Soldiers are confronted with physical and mental injuries which constitute a social trauma. The French army has put in place tools, notably sports courses, to favour resilience and the reintegration of casualties. Nurses and nurse assistants working in physical medicine and rehabilitation and psychiatry, play a key role using their skills to support this scheme which runs outside the hospital setting. PMID- 29609794 TI - A nursing consultation for occupational depression in England. AB - Catherine is an advanced nurse practitioner (ANP) and so trained to assess, diagnose and treat patients with undifferentiated conditions. Paul, her patient, is a 50-year old academic working at the university. PMID- 29609795 TI - ? PMID- 29609796 TI - ? PMID- 29609797 TI - ? PMID- 29609798 TI - ? PMID- 29609799 TI - Diagnostic value of screening enzyme immunoassays compared to indirect immunofluorescence for anti-nuclear antibodies in patients with systemic rheumatic diseases: A systematic review and meta-analysis. AB - OBJECTIVE: This study aimed to review and compare the diagnostic accuracy of the screening enzyme immunoassay (SEIA) and indirect immunofluorescence (IIF) as anti nuclear antibody (ANA) screening assays for patients with systemic rheumatic diseases (SRDs), including systemic lupus erythematosus (SLE), Sjogren's syndrome (SS), and systemic sclerosis (SSc). METHODS: A systematic literature search was conducted in the Medline, Embase, Cochrane, Web of Science, and Scopus databases for articles published before August 2017. A bivariate random effects model was used to calculate pooled diagnostic values. RESULTS: Thirty-three studies including 3976 combined SRDs, 2839 SLE, 610 SS, and 1002 SSc patients and 11,716 non-healthy and 8408 healthy controls were available for the meta-analysis. The summary sensitivities of SEIA vs. IIF were 87.4% vs 88.4% for combined SRDs, 89.4% vs. 95.2% for SLE, 88.7% vs. 88.4% for SS, and 85.4% vs. 93.6% for SSc, respectively. Meanwhile, the summary specificities of SEIA vs. IIF were 79.7% vs.78.9% for combined SRDs, 89.1% vs. 83.3% for SLE, 89.9% vs. 86.8% for SS, and 92.8% vs. 84.2% for SSc, respectively. Although the differences in sensitivity and specificity between SEIA and IIF were not significant in most subgroups, the summary sensitivity of SLE presented statistically significant changes. CONCLUSIONS: Our systematic meta-analysis demonstrates that both SEIA and IIF are useful to detect ANAs for SRDs. Between the two assays, IIF is a more sensitive screening assay than SEIA, particularly in patients with SLE. SEIA is comparable to IIF, considering the specificity and standardization. PMID- 29609800 TI - Corrigendum to "A non-invasive methodology for ATAA rupture risk estimation" [J. Biomech. 66 (2018) 119-126]. PMID- 29609801 TI - Electromyogram refinement using muscle synergy based regulation of uncertain information. AB - Electromyogram signal (EMG) measurement frequently experiences uncertainty attributed to issues caused by technical constraints such as cross talk and maximum voluntary contraction. Due to these problems, individual EMGs exhibit uncertainty in representing their corresponding muscle activations. To regulate this uncertainty, we proposed an EMG refinement, which refines EMGs with regulating the contribution redundancy of the signals from EMGs to approximating torques through EMG-driven torque estimation (EDTE) using the muscular skeletal forward dynamic model. To regulate this redundancy, we must consider the synergistic contribution redundancy of muscles, including "unmeasured" muscles, to approximating torques, which primarily causes redundancy of EDTE. To suppress this redundancy, we used the concept of muscle synergy, which is a key concept of analyzing the neurophysiological regulation of contribution redundancy of muscles to exerting torques. Based on this concept, we designed a muscle-synergy-based EDTE as a framework for EMG refinement, which regulates the abovementioned uncertainty of individual EMGs in consideration of unmeasured muscles. In achieving the proposed EMG refinement, the most considerable point is to suppress a large change such as overestimation attributed to enhancement of the contribution of particular muscles to estimating torques. Therefore it is reasonable to refine EMGs by minimizing the change in EMGs. To evaluate this model, we used a Bland-Altman plot, which quantitatively evaluates the proportional bias of refined signals to EMGs. Through this evaluation, we showed that the proposed EDTE minimizes the bias while approximating torques. Therefore this minimization optimally regulates the uncertainty of EMGs and thereby leads to optimal EMG refinement. PMID- 29609802 TI - Tracking control of nonholonomic mobile agents with external disturbances and input delay. AB - This paper investigates the tracking control problem of chained-form nonholonomic multiagent systems (MASs). In contrast to the existing works in which some algorithms have been designed for ideal conditions, the destructive factors including external disturbances and input delay are considered in the dynamics of the agents in this work. Two distributed controllers are proposed such that the states of the controlled agents can track the states of the target in the presence of external disturbances and input delay. For this purpose, a distributed controller is firstly suggested based on a switching method to solve the tracking control problem for nonholonomic MASs with external disturbances. Then, the proposed control law is extended based on a state predictor for the tracking control of agents in the presence of input delay. The stability analysis of the two distributed controllers is also provided. Simulation results show the promising performance of the proposed algorithms. PMID- 29609803 TI - Real-time biscuit tile image segmentation method based on edge detection. AB - In this paper we propose a novel real-time Biscuit Tile Segmentation (BTS) method for images from ceramic tile production line. BTS method is based on signal change detection and contour tracing with a main goal of separating tile pixels from background in images captured on the production line. Usually, human operators are visually inspecting and classifying produced ceramic tiles. Computer vision and image processing techniques can automate visual inspection process if they fulfill real-time requirements. Important step in this process is a real-time tile pixels segmentation. BTS method is implemented for parallel execution on a GPU device to satisfy the real-time constraints of tile production line. BTS method outperforms 2D threshold-based methods, 1D edge detection methods and contour-based methods. Proposed BTS method is in use in the biscuit tile production line. PMID- 29609804 TI - Corrigendum to "Respiration-based monitoring of metabolic rate following cold exposure in two invasive Anoplophora species depending on acclimation regime" [Comp. Biochem. Physiol. A Vol. 216 (2018) 20-27]. PMID- 29609805 TI - Three-dimensional cluster formation and structure in heterogeneous dose distribution of intensity modulated radiation therapy. AB - PURPOSE: To investigate three-dimensional cluster structure and its correlation to clinical endpoint in heterogeneous dose distributions from intensity modulated radiation therapy. METHODS: Twenty-five clinical plans from twenty-one head and neck (HN) patients were used for a phenomenological study of the cluster structure formed from the dose distributions of organs at risks (OARs) close to the planning target volumes (PTVs). Initially, OAR clusters were searched to examine the pattern consistence among ten HN patients and five clinically similar plans from another HN patient. Second, clusters of the esophagus from another ten HN patients were scrutinized to correlate their sizes to radiobiological parameters. Finally, an extensive Monte Carlo (MC) procedure was implemented to gain deeper insights into the behavioral properties of the cluster formation. RESULTS: Clinical studies showed that OAR clusters had drastic differences despite similar PTV coverage among different patients, and the radiobiological parameters failed to positively correlate with the cluster sizes. MC study demonstrated the inverse relationship between the cluster size and the cluster connectivity, and the nonlinear changes in cluster size with dose thresholds. In addition, the clusters were insensitive to the shape of OARs. CONCLUSION: The results demonstrated that the cluster size could serve as an insightful index of normal tissue damage. The clinical outcome of the same dose-volume might be potentially different. PMID- 29609806 TI - The impact of driver distraction in tractor-trailers and motorcoach buses. AB - Driver distraction has become an increasing concern over the last decade as portable technology has emerged and its presence while driving has become more common. Driver distraction occurs when inattention leads to a delay in recognition of information necessary to accomplish the driving task. Two recent studies were conducted using a naturalistic data collection method and analysis of driver distraction. The Commercial Motor Vehicle Driver Distraction study (Olson et al., 2009) was conducted using heavy truck data, and the Distraction and Drowsiness in Motorcoach Drivers study (Hammond et al., 2016) was conducted using motorcoach data. Data were collected continuously every time the instrumented vehicle was turned on and in motion. Data were reduced to identify safety-critical events such as crashes, near-crashes, crash-relevant conflicts, and unintentional lane deviations. Results show that 40% of truck crashes and 56% of motorcoach crashes had some kind of distracting behavior. Odds ratios were calculated on individual secondary tasks and analyses of variance (ANOVAs) were calculated on eye-glance data to determine the effects of eyes off the forward roadway. Fewer distractions were identified in the motorcoach data, most notably the use of handheld cell phones. This suggests that the 2010 ban on handheld phones has had a positive effect on decreasing cell phone use while driving. PMID- 29609807 TI - Nanoscale domain formation of phosphatidylinositol 4-phosphate in the plasma and vacuolar membranes of living yeast cells. AB - In budding yeast Saccharomyces cerevisiae, PtdIns(4)P serves as an essential signalling molecule in the Golgi complex, endosomal system, and plasma membrane, where it is involved in the control of multiple cellular functions via direct interactions with PtdIns(4)P-binding proteins. To analyse the distribution of PtdIns(4)P in yeast cells at a nanoscale level, we employed an electron microscopy technique that specifically labels PtdIns(4)P on the freeze-fracture replica of the yeast membrane. This method minimizes the possibility of artificial perturbation, because molecules in the membrane are physically immobilised in situ. We observed that PtdIns(4)P is localised on the cytoplasmic leaflet, but not the exoplasmic leaflet, of the plasma membrane, Golgi body, vacuole, and vesicular structure membranes. PtdIns(4)P labelling was not observed in the membrane of the endoplasmic reticulum, and in the outer and inner membranes of the nuclear envelope or mitochondria. PtdIns(4)P forms clusters of <100 nm in diameter in the plasma membrane and vacuolar membrane according to point pattern analysis of immunogold labelling. There are three kinds of compartments in the cytoplasmic leaflet of the plasma membrane. In the present study, we showed that PtdIns(4)P is specifically localised in the flat undifferentiated plasma membrane compartment. In the vacuolar membrane, PtdIns(4)P was concentrated in intramembrane particle (IMP)-deficient raft-like domains, which are tightly bound to lipid droplets, but not surrounding IMP-rich non-raft domains in geometrical IMP-distributed patterns in the stationary phase. This is the first report showing microdomain formations of PtdIns(4)P in the plasma membrane and vacuolar membrane of budding yeast cells at a nanoscale level, which will illuminate the functionality of PtdIns(4)P in each membrane. PMID- 29609808 TI - Bi-Atrial Function before and after Percutaneous Closure of Atrial Septum in Patients with and without Paroxysmal Atrial Fibrillation: A 2-D and 3-D Speckle Tracking Echocardiographic Study. AB - Our aim was to analyze atrial function with 2-D (2-D-STE) and 3-D (3-D-STE) speckle tracking echocardiography in patients with atrial septal devices and paroxysmal atrial fibrillation (PAF). One hundred sixteen patients and a subgroup of 22 patients who developed PAF after device insertion were studied. Left atrial and right atrial peak longitudinal strain and standard deviations of time to peak strain (TPS) were calculated using 2-D-STE. The left atrial/right atrial emptying fraction and expansion index were determined using 3-D-STE. By multivariate analysis, pre-closure 3-D right atrial expansion index, left atrial time to peak strain, and 3-D left atrial expansion index were independently associated with PAF. Compared with the other indices, receiver operating characteristic analysis revealed better diagnostic accuracy for the combination of pre-closure time to peak strain and 3-D expansion index in detecting PAF. Patients with atrial septal devices have pre-existing left and right atrial dilation and dysfunction as assessed by 2-D-STE and 3-D-STE that appear sensitive for the stratification of PAF risk in this population. PMID- 29609809 TI - Acoustic Structure Quantification Versus Point Shear Wave Speed Measurement for the Assessment of Liver Fibrosis in Viral Hepatitis B. AB - This study was conducted to evaluate the value of acoustic structure quantification (ASQ) technology versus that of point shear wave speed measurement (PSWSM) imaging technology for the assessment of liver fibrosis stage. A total of 104 patients with chronic hepatitis B (CHB) and 30 healthy control patients underwent ASQ and PSWSM examinations. Seven quantitative parameters were obtained from ASQ, and a principal component analysis was used to establish the integrative indicators. A quantitative parameter, known as the shear wave speed (SWS, m/s), was obtained from the PSWSM. The METAVIR scores for the assessment of pathologic liver fibrosis were used as a benchmark. Liver fibrosis stages exhibited a good correlation with the integrative indicators and SWS (r = 0.682, p <0.001; r = 0.651, p <0.001). The areas under the receiver operating characteristic curves for ASQ and PSWSM were 0.705 and 0.854 for mild liver fibrosis (F >= 1, p = 0.045), 0.813 and 0.743 for significant liver fibrosis (F >= 2, p = 0.115), 0.839 and 0.857 for severe liver fibrosis (F >= 3, p = 0.417) and 0.874 and 0.971 for liver cirrhosis (F = 4, p = 0.016), respectively. In conclusion, both ASQ and PSWSM were promising ultrasonic methods for assessing liver fibrosis in patients with CHB; however, PSWSM was more valuable for identifying mild liver fibrosis (F >= 1) and cirrhosis (F = 4) than ASQ, and the combination of PSWSM and ASQ improved the accuracy of diagnosing severe liver fibrosis (F >= 3). PMID- 29609810 TI - Commissioning and validation of commercial deformable image registration software for adaptive contouring. AB - PURPOSE: To report the commissioning and validation of deformable image registration(DIR) software for adaptive contouring. METHODS: DIR (SmartAdapt(r)v13.6) was validated using two methods namely contour propagation accuracy and landmark tracking, using physical phantoms and clinical images of various disease sites. Five in-house made phantoms with various known deformations and a set of 10 virtual phantoms were used. Displacement in lateral, anterio-posterior (AP) and superior-inferior (SI) direction were evaluated for various organs and compared with the ground truth. Four clinical sites namely, brain (n = 5), HN (n = 9), cervix (n = 18) and prostate (n = 23) were used. Organs were manually delineated by a radiation oncologist, compared with the deformable image registration (DIR) generated contours. 3D slicer v4.5.0.1 was used to analyze Dice Similarity Co-efficient (DSC), shift in centre of mass (COM) and Hausdorff distances Hf95%/avg. RESULTS: Mean (SD) DSC, Hf95% (mm), Hfavg (mm) and COM of all the phantoms 1-5 were 0.84 (0.2) mm, 5.1 (7.4) mm, 1.6 (2.2) mm, and 1.6 (0.2) mm respectively. Phantom-5 had the largest deformation as compared to phantoms 1-4, and hence had suboptimal indices. The virtual phantom resulted in consistent results for all the ROIs investigated. Contours propagated for brain patients were better with a high DSC score (0.91 (0.04)) as compared to other sites (HN: 0.84, prostate: 0.81 and cervix 0.77). A similar trend was seen in other indices too. The accuracy of propagated contours is limited for complex deformations that include large volume and shape change of bladder and rectum respectively. Visual validation of the propagated contours is recommended for clinical implementation. CONCLUSION: The DIR algorithm was commissioned and validated for adaptive contouring. PMID- 29609811 TI - The effect of feature selection on multivariate pattern analysis of structural brain MR images. AB - Clinical predictions performed using structural magnetic resonance (MR) images are crucial in neuroimaging studies and can be used as a successful complementary method for clinical decision making. Multivariate pattern analysis (MVPA) is a significant tool that helps correct predictions by exhibiting a compound relationship between disease-related features. In this study, the effectiveness of determining the most relevant features for MVPA of the brain MR images are examined using ReliefF and minimum Redundancy Maximum Relevance (mRMR) algorithms to predict the Alzheimer's disease (AD), schizophrenia, autism, and attention deficit and hyperactivity disorder (ADHD). Three state-of-the-art MVPA algorithms namely support vector machines (SVM), k-nearest neighbor (kNN) and backpropagation neural network (BP-NN) are employed to analyze the images from five different datasets that include 1390 subjects in total. Feature selection is performed on structural brain features such as volumes and thickness of anatomical structures and selected features are used to compare the effect of feature selection on different MVPA algorithms. Selecting the most relevant features for differentiating images of healthy controls from the diseased subjects using both ReliefF and mRMR methods significantly increased the performance. The most successful MVPA method was SVM for all classification tasks. PMID- 29609812 TI - Correlation between gamma passing rate and complexity of IMRT plan due to MLC position errors. AB - PURPOSE: This study evaluates the correlation between the susceptibility of the gamma passing rate of IMRT plans to the multi-leaf collimator (MLC) position errors and a quantitative plan complexity metric. METHODS: Twenty patients were selected for this study. For each patient, two IMRT plans were generated using sliding window and step-&-shoot techniques, respectively. Modulation complexity score (MCS) was calculated for all IMRT plans, and symmetric MLC leaf bank errors, ranging from 0.3 mm to 1 mm, were introduced. Original and modified plans were delivered using Varian's Clinac iX. The obtained dose distribution using ArcCHECK was then compared with the TPS calculated dose distribution of the original plans. 3D gamma analysis was performed for each verification with passing criteria of 2%/2 mm. The gamma passing rate decreasing gradient were calculated to evaluate relationship between variation of gamma passing rate due to MLC errors and complexity. RESULTS: A linear regression analysis was applied between gamma gradient and complexity, and the results showed a linear correlation (R2 = 0.81 and 0.82 for open and closed MLC error types, respectively) indicating the more complex plans are more susceptible to MLC leaf bank errors. Meanwhile, correlation of re-normalized gamma passing rate and complexity for all errors scenarios also presented a strong correlation (r > 0.75). CONCLUSION: The statistics results revealed variation relationship of dosimetry robust of plans with various complexities to MLC errors. Our results also suggested that the observed susceptibility is independent of the delivery techniques. PMID- 29609813 TI - Metallic nanoparticle radiosensitisation of ion radiotherapy: A review. AB - The use of gold nanoparticle (GNP) and other metal nanoparticle (MNP) radiosensitisers to enhance radiotherapy offers the potential of improved treatment outcomes. Originally intended for use with X-ray therapy, the possibility of enhanced hadron therapy is desirable due to the superior sparing of healthy tissue in hadron therapy compared to conventional X-ray therapy. While MNPs were not expected to be effective radiosensitisers for hadron therapy due to the limited Z dependence of interactions, recent experimental measurements have contradicted this expectation. Key experimental measurements and Monte Carlo simulations of MNP radiosensitisation for hadron irradiation are reviewed in the current work. Numerous experimental measurements have found a large radiosensitisation effect due to MNPs for proton and carbon ion irradiation. Experiments have also indicated that the radiosensitisation is due in large part to enhanced reactive oxygen species (ROS) production. Simulations have found a large radial dose and ROS enhancement on the nanoscale around a single MNP. However, the short range of the dose enhancement is insufficient for a large macroscale dose enhancement or enhanced biological effect in a cell model considering dose to the nucleus from GNPs in the cytoplasm (a distribution observed in most experiments). PMID- 29609814 TI - Characterization of OSL dosimeters for use in dose assessment in Computed Tomography procedures. AB - This study describes the characterization of an Al2O3:C OSLD (Landauer's LuxelTM tape) for dose evaluation in Computed Tomography. The irradiations were conducted using both a constant potential X-ray equipment and a 64-slice clinical CT scanner, and the readouts were performed using a Riso TL/OSL reader. The following aspects were studied: batch homogeneity, energy response, linearity of dose response, reproducibility, reusability, and effect of uncertainties with the normalization of OSL signals per their response to beta radiation. A group of 330 dosimeters from the 452 irradiated with the same dose presented OSL signals within the interval of 4.7% from the average. The dosimeters presented energy dependent response in good agreement with results found in the literature. The air kerma response of the OSL signal showed a linear trend for both the constant potential X-ray device and the clinical CT scanner, with differences in their slopes of approximately 10%. Reproducibility, reusability, and effect of beta normalization were analyzed by separating 72 dosimeters in 3 groups. The results obtained in this study together with those of previous works indicate that this type of dosimeter is adequate for dose evaluation in CT clinical applications. PMID- 29609815 TI - Monte Carlo uncertainty analysis of dose estimates in radiochromic film dosimetry with single-channel and multichannel algorithms. AB - PURPOSE: To provide a multi-stage model to calculate uncertainty in radiochromic film dosimetry with Monte-Carlo techniques. This new approach is applied to single-channel and multichannel algorithms. MATERIAL AND METHODS: Two lots of Gafchromic EBT3 are exposed in two different Varian linacs. They are read with an EPSON V800 flatbed scanner. The Monte-Carlo techniques in uncertainty analysis provide a numerical representation of the probability density functions of the output magnitudes. From this numerical representation, traditional parameters of uncertainty analysis as the standard deviations and bias are calculated. Moreover, these numerical representations are used to investigate the shape of the probability density functions of the output magnitudes. Also, another calibration film is read in four EPSON scanners (two V800 and two 10000XL) and the uncertainty analysis is carried out with the four images. RESULTS: The dose estimates of single-channel and multichannel algorithms show a Gaussian behavior and low bias. The multichannel algorithms lead to less uncertainty in the final dose estimates when the EPSON V800 is employed as reading device. In the case of the EPSON 10000XL, the single-channel algorithms provide less uncertainty in the dose estimates for doses higher than four Gy. CONCLUSION: A multi-stage model has been presented. With the aid of this model and the use of the Monte-Carlo techniques, the uncertainty of dose estimates for single-channel and multichannel algorithms are estimated. The application of the model together with Monte-Carlo techniques leads to a complete characterization of the uncertainties in radiochromic film dosimetry. PMID- 29609816 TI - Detectability comparison of simulated tumors in digital breast tomosynthesis using high-energy X-ray inline phase sensitive and commercial imaging systems. AB - This study compared the detectability of simulated tumors using a high-energy X ray inline phase sensitive digital breast tomosynthesis (DBT) prototype and a commercial attenuation-based DBT system. Each system imaged a 5-cm thick modular breast phantom with 50-50 adipose-glandular percentage density containing contrast-detail (CD) test objects to simulate different tumor sizes. A commercial DBT system acquired 15 projection views over 15 degrees (15d-15p) was used to acquire the attenuation-based projection views and to reconstruct the conventional DBT slices. Attenuation-based projection views were acquired at 32 kV, 46 mAs with a mean glandular dose (Dg) of 1.6 mGy. For acquiring phase sensitive projection views, the prototype utilized two acquisition geometries: 11 projection views were acquired over 15 degrees (15d-11p), and 17 projection views were acquired over 16 degrees (16d-17p) at 120 kV, 5.27 mAs with 1.51 mGy under the magnification (M) of 2. A phase retrieval algorithm based on the phase attenuation duality (PAD) was applied to each projection view, and a modified Feldkamp-Davis-Kress (FDK) algorithm was used to reconstruct the phase sensitive DBT slices. Simulated tumor margins were rated as more conspicuous and better visualized for both phase sensitive acquisition geometries versus conventional DBT imaging. The CD curves confirmed the improvement in both contrast and spatial resolutions with the phase sensitive DBT imaging. The superiority of the phase sensitive DBT imaging was further endorsed by higher contrast to noise ratio (CNR) and figure-of-merit (FOM) values. The CNR improvements provided by the phase sensitive DBT prototype were sufficient to offset the noise reduction provided by the attenuation-based DBT imaging. PMID- 29609817 TI - Comparison of CT-number parameterization models for stoichiometric CT calibration in proton therapy. AB - PURPOSE: This study compares the predictions of three parameterization models used in previously published works, implementing the stoichiometric CT calibration for proton therapy, and a further two alternative parameterizations suggested here. METHODS: Stoichiometric calibrations of patient CT-number to stopping-power ratio (SPR) were performed for four CT protocols using tissue substitutes supplied by CIRS (CIRS Inc., Norfolk, VA, USA). To evaluate robustness of the five models (Sch96/Sch00/Mar12/Karol/Spek), the calibration was repeatedly simulated by randomly perturbing the measured CT-numbers of the tissue substitutes (1sigma:10 HU). The impact of high-Z content was assessed through calibrations where the two substitutes with barium content were replaced by hypothetical materials without barium. RESULTS: The stoichiometric calibrations generally agreed within 1% between the models, for non-bony tissues. For higher CT-numbers, a well-known 2-parameter model (Sch00) generated larger SPRs compared to the other models, with inter-model discrepancies of up to 3%. The 95% coverage interval of the calibrations obtained from the robustness analysis varied substantially. The well-known 2- and 3-parameter models (Sch00/Sch96) had the largest intervals. However, the partly-hypothetical (i.e. no barium) input data generated calibrations that agreed within 1% over the whole CT scale for all models and improved the 95% coverage interval of the well-known models (Sch00/Sch96). CONCLUSION: All parameterization models performed comparably if the scanned materials only contained elements with Z <= 20. However, the two alternative models proposed here (Karol/Spek), together with a previously published 1-parameter model (Mar12), generated robust calibrations in close agreement even when tissue substitutes contain elements with higher atomic number. PMID- 29609818 TI - Reference 3 T MRI parameters of the normal human eye. AB - The purpose of this study is to establish magnetic resonance imaging (MRI) standard normative reference quantitative markers for future possible diagnosis in Ophthalmology based on relaxation times (T1 and T2) and retina/choroid complex (RCC) layer thickness values measured in vivo in normal human eyes. This research followed the tenets of the Declaration of Helsinki and was approved by the local Ethical Committee. 15 healthy subjects volunteered to undergo MRI of both eyes. 3 T MRI was performed using a circular surface detector coil with a 15 min acquisition protocol for each eye. The most important normal human eye structures were visualized and characterized geometrico-physicochemically by the 35 MRI standard normative reference markers (20 RCC thicknesses, 8 T1 and 7 T2) calculated. Future possible pathology management could be based on the relative to-normal differences between the standard normative reference MRI markers calculated in this study and the corresponding MRI markers calculated in the future in disease-suspected eyes. In conclusion, this research demonstrates that ocular MRI at 3 T, performed without contrast agents, brings useful additional multiparametric quantitative information for future possible automated medical diagnosis, staging and evaluation of ocular disease mechanisms. PMID- 29609819 TI - Exradin W1 plastic scintillation detector for in vivo skin dosimetry in passive scattering proton therapy. AB - In vivo skin dosimetry is desirable in passive scattering proton therapy because of the possibility of high entrance dose with a small number of fields. However, suitable detectors are needed to determine skin dose in proton therapy. Plastic scintillation detectors (PSDs) are particularly well suited for applications in proton therapy because of their water equivalence, small size, and ease of use. We investigated the utility of the Exradin W1, a commercially available PSD, for in vivo skin dosimetry during passive scattering proton therapy. We evaluated the accuracy of the Exradin W1 in six patients undergoing proton therapy for prostate cancer, as part of an Institutional Review Board-approved protocol. Over 22 weeks, we compared in vivo PSD measurements with in-phantom ionization chamber measurements and doses from the treatment planning system, resulting in 96 in vivo measurements. Temperature and ionization quenching correction factors were applied on the basis of the dose response of the PSD in a phantom. The calibrated PSD exhibited an average 7.8% under-response (+/-1% standard deviation) owing to ionization quenching. We observed 4% under-response at 37 degrees C relative to the calibration-temperature response. After temperature and quenching corrections were applied, the overall PSD dose response was within +/-1% of the expected dose for all patients. The dose differences between the PSD and ionization chamber measurements for all treatment fields were within +/-2% (standard deviation 0.67%). The PSD was highly accurate for in vivo skin dosimetry in passively scattered proton beams and could be useful in verifying proton therapy delivery. PMID- 29609820 TI - Dosimetry perspectives in radiation synovectomy. AB - Rheumatoid arthritis (RA) is a chronic inflammatory disease that can potentially damage the synovial joints. One of the effective treatment modality for RA is radiation synovectomy (RSV) where properly selected radionuclide is injected into the joint space, enabling controlled destruction of diseased synovial membrane via radiation exposure. Radiation dosimetry in RSV appears challenging due to the heterogeneous nature of synovial membrane, nonuniform distribution and leakage of radionuclide from the synovial cavity. This article reviews the dosimetric perspective pertaining to RSV. Specifically, characteristics of radionuclide for RSV and radiation dose to target and non-target (i.e., articular cartilage, bone, bloodstream, gonads, etc.) tissues of patient have been discussed. The personal dose Hp(0.07) to the hands of medical staff (i.e., radiochemist, therapist physician, nurse) may be considerably high due to handling of high specific activities (~500 MBq/ml for Y-90); such doses are typically measured using thermoluminescence dosimeters (TLD) ring dosimeters and ranges from 1 to 21.5, 0.1 to 40 and 0.1 to 5 uSv/MBq for the radiochemist, therapist physician and the nurse, respectively. Methods to minimize radiation doses to the patient, medical staff and public are elaborated. Contamination risks and precautionary measures are also reported. PMID- 29609821 TI - Bayesian penalized-likelihood reconstruction algorithm suppresses edge artifacts in PET reconstruction based on point-spread-function. AB - PURPOSE: The Bayesian penalized-likelihood reconstruction algorithm (BPL), Q.Clear, uses relative difference penalty as a regularization function to control image noise and the degree of edge-preservation in PET images. The present study aimed to determine the effects of suppression on edge artifacts due to point spread-function (PSF) correction using a Q.Clear. METHODS: Spheres of a cylindrical phantom contained a background of 5.3 kBq/mL of [18F]FDG and sphere to-background ratios (SBR) of 16, 8, 4 and 2. The background also contained water and spheres containing 21.2 kBq/mL of [18F]FDG as non-background. All data were acquired using a Discovery PET/CT 710 and were reconstructed using three dimensional ordered-subset expectation maximization with time-of-flight (TOF) and PSF correction (3D-OSEM), and Q.Clear with TOF (BPL). We investigated beta-values of 200-800 using BPL. The PET images were analyzed using visual assessment and profile curves, edge variability and contrast recovery coefficients were measured. RESULTS: The 38- and 27-mm spheres were surrounded by higher radioactivity concentration when reconstructed with 3D-OSEM as opposed to BPL, which suppressed edge artifacts. Images of 10-mm spheres had sharper overshoot at high SBR and non-background when reconstructed with BPL. Although contrast recovery coefficients of 10-mm spheres in BPL decreased as a function of increasing beta, higher penalty parameter decreased the overshoot. CONCLUSIONS: BPL is a feasible method for the suppression of edge artifacts of PSF correction, although this depends on SBR and sphere size. Overshoot associated with BPL caused overestimation in small spheres at high SBR. Higher penalty parameter in BPL can suppress overshoot more effectively. PMID- 29609822 TI - A framework for alignment of on-board imagers of medical linear accelerators. AB - PURPOSE: To develop an assumption-free methodology for aligning the geometry of on-board imagers with the geometry of medical linear accelerators applied in image-guided radiotherapy (IGRT). MATERIAL: Alignment of the on-board imaging (OBI) system with respect to the accelerator system is achieved using a multi modular phantom described elsewhere (Tabor et al., 2017), enabling the geometry of the linear accelerator to be specified without any pre-assumptions. METHODS: The placement of two isocentres (of the on-board imager and of the therapeutic system) and of three frames of reference (those of the on-board imager, of the therapeutic system, and of the treatment table) is formulated as an optimization problem. It is solved by analysing the images of fiducial points positioned in 3D space in phantom modules attached to the treatment table and to the collimator of the accelerator. Fiducials are projected onto an imaging plane of unknown characteristics from a virtual source of unknown coordinates. CONCLUSIONS: An analytical framework exploiting projection images of the proposed multi-modular phantom has been developed, enabling precise alignment of the reference frame related to the on-board imager with the reference frame related to the therapeutic system. Within the proposed framework, the necessary corrections of treatment table positioning prior to patient irradiation, are delivered in the treatment table coordinates. PMID- 29609823 TI - Evaluation of a LED-based flatbed document scanner for radiochromic film dosimetry in transmission mode. AB - Flatbed scanners are the most frequently used reading instrument for radiochromic film dosimetry because its low cost, high spatial resolution, among other advantages. These scanners use a fluorescent lamp and a CCD array as light source and detector, respectively. Recently, manufacturers of flatbed scanners replaced the fluorescent lamp by light emission diodes (LED) as a light source. The goal of this work is to evaluate the performance of a commercial flatbed scanner with LED based source light for radiochromic film dosimetry. Film read out consistency, response uniformity, film-scanner sensitivity, long term stability and total dose uncertainty was evaluated. In overall, the performance of the LED flatbed scanner is comparable to that of a cold cathode fluorescent lamp (CCFL). There are important spectral differences between LED and CCFL lamps that results in a higher sensitivity of the LED scanner in the green channel. Total dose uncertainty, film response reproducibility and long-term stability of LED scanner are slightly better than those of the CCFL. However, the LED based scanner has a strong non-uniform response, up to 9%, that must be adequately corrected for radiotherapy dosimetry QA. The differences in light emission spectra between LED and CCFL lamps and its potential impact on film-scanner sensitivity suggest that the design of a dedicated flat-bed scanner with LEDs may improve sensitivity and dose uncertainty in radiochromic film dosimetry. PMID- 29609824 TI - IAEA-SSDL bilateral comparisons for diagnostic level air kerma measurement standards. AB - Comparisons of national standard of air kerma for conventional and mammographic diagnostic X-ray radiation qualities were conducted by the IAEA. Eleven secondary standards dosimetry laboratories provided calibration data for Exradin A3 and Radcal RC6M transfer ionization chambers circulated. Each comparison result expressed as the ratio of the participant and IAEA calibration coefficient were within the acceptance limit of +/-2.5%. From the 67 results of 11 participants and 10 available beam qualities, the comparison result was within its standard uncertainty in 63 cases, and within the expanded (k = 2) uncertainty in four cases. Detailed calibration uncertainty budgets from participant laboratories are presented. The relative standard calibration uncertainty of each participant was in the range of 0.5-1.3%. These results indicate that the calibration related uncertainty component is reasonable low for a clinical measurement. In addition to the calibration coefficient, other corrections should be applied for clinical measurement to achieve the recommended accuracy. PMID- 29609825 TI - A patient-centric approach to quality control and dosimetry in CT including CBCT. AB - One measurement and an algebraic formula are used to calculate the incident air kerma (Ka,i) at the skin after any CT examination, including cone-beam CT (CBCT) and multi-slice CT (MSCT). Empty scans were performed with X-ray CBCT systems (dental, C-arm and linac guidance scanners) as well as two MSCT scanners. The accumulated Ka,i at the flat panel (in CBCT) or the maximum incident air kerma at the isocentre (in MSCT) were measured using a solid-state probe. The average Ka,i(skin), at the skin of a hypothetical patient, was calculated using the proposed formula. Additional measurements of dose at the isocentre (DFOV) and kerma-area product (KAP), as well as Ka,i(skin) from thermoluminiscence dosimeters (TLDs) and size-specific dose estimates are presented for comparison. The Ka,i(skin) for the standard head size in the dental scanner, the C-arm (high dose head protocol) and the linac (head protocol) were respectively 3.33 +/- 0.19 mGy, 15.15 +/- 0.76 mGy and 3.23 +/- 0.16 mGy. For the first MSCT, the calculated Ka,i(skin) was 13.1 +/- 0.7 mGy and the TLDs provided a Ka,i(skin) between 10.3 +/- 1.1 mGy and 13.8 +/- 1.4 mGy. Estimation of patient air kerma in tomography with an uncertainty below 7% is thus feasible using an empty scan and conventional measurement tools. The provided equations and website can be applied to a standard size for the sake of quality control or to several sizes for the definition of diagnostic reference levels (DRLs). The obtained incident air kerma can be directly compared to the Ka,i from other X-ray modalities as recommended by ICRU and IAEA. PMID- 29609826 TI - Results of adrenalectomy in lung cancer metastases. AB - BACKGROUND: The aim of this study was to report our centre's experience over the past 15 years with patients with lung carcinoma and adrenal metastases treated sequentially with lung resection and adrenalectomy. PATIENTS AND METHODS: We analysed a retrospective series of 19 patients who underwent adrenalectomy for lung carcinoma metastasis. All patients were operated on at the same centre, between October 2000 and October 2015. We performed a descriptive analysis and an overall survival and disease-free survival analysis. RESULTS: The study included 13 men and 6 women. The most common primary lung tumour was adenocarcinoma, 87.5% of which were G3. In 7 patients, the adrenal metastasis was detected synchronously, and in 12 patients it was detected metachronously. The median size of the metastasis was 63mm. Twenty-one percent of the cases presented local recurrence, and 79% presented distant metastasis. The median DFS was 21.5 months, while the DFS at 5 years was calculated at 58.33%. The median overall survival was 37.3 months, while survival at 5 years was calculated at 42.86%. None of the prognostic factors evaluated were statistically significant. CONCLUSIONS: Adrenalectomy in cases of isolated lung carcinoma metastasis can offer increased overall survival. Age and the degree of differentiation of the primary lung carcinoma are the factors that most influence poorer survival. PMID- 29609827 TI - Development and validation of a training and assessment tool for laparoscopic radical nephrectomy. AB - INTRODUCTION: Laparoscopic radical nephrectomy(LRN) is a cornerstone in managing renal cancer and small renal masses. Twenty-first century surgical training faces challenges, thus must be efficient and safe so surgeons attain relevant skills, protecting patients and operative outcomes. This study aimed to systematically develop a tool for training and assessment in LRN and validate the developed tool for use by trainee urologists. METHODS: This prospective, longitudinal, multi institutional study was undertaken from September 2014 - June 2015. Healthcare Failure Mode and Effect Analysis was utilised for development and followed by validation where the assessment tool was distributed to five specialists to increase content validity. Four experts were observed as a multi-institutional approach. Hand-assisted, transperitoneal and retroperitoneal approaches were considered. RESULTS: The LRN Assessment Tool comprised four phases, 17 processes, 41 sub-processes. Four surgeons and operating teams were observed across four hospitals for 19.5hours (5.75h hand-assisted, 8.75h trans-peritoneal, 5h retro peritoneal). After hazard analysis, three checklists were constructed. Those for hand-assisted LRN and transperitoneal LRN contained four phases, 20 processes, 33 sub-processes and that for retroperitoneal LRN contained four phases, 20 processes, 30 sub-processes. These were merged to form one assessment tool. The final result was a four phase LRN Assessment Tool with 17 processes, 41 sub processes. All participants agreed the final LRN Assessment Tool included pertinent steps. CONCLUSIONS: The LRN Assessment Tool was developed using Healthcare Failure Mode and Effect Analysis risk analysis to ensure hazardous procedural sub-steps were included. Validation ascertained important processes were not overlooked. Full application through a pilot study must be undertaken. PMID- 29609829 TI - Is the Virtual Colonoscopy a Replacement for Optical Colonoscopy? AB - OBJECTIVE: To examine the viability of colon cancer screening with computed tomography colonography, also known as virtual colonoscopy. DATA SOURCES: Clinical guidelines, published medical research. CONCLUSION: Virtual colonoscopy, under the right circumstances, is an accurate viable screening tool for patients who may not otherwise desire to or are not able to participate in traditional colonoscopy. IMPLICATIONS FOR NURSING PRACTICE: Nurses should be aware that routine colon cancer screening is recommended starting at age 50. In addition to the traditional colonoscopy, there are other options if a patient is unwilling or unable to undergo optical colon screening. Nurses should discuss the positive and negative aspects of different types of colon screening and teach proper bowel preparation for colon screening. PMID- 29609830 TI - Safety data and withdrawal of hepatotoxic drugs. AB - BACKGROUND AND AIM: The occurrence of drug induced liver injury (DILI) is the most common reason of post-marketing withdrawals. DILI in humans is difficult to predict using in vitro cytotoxicity screening and animal studies. A review of hepatotoxicity data was performed with the aim of identifying relevant factors that could have predicted the occurrence of serious DILI. METHODS: The drugs withdrawn from the market due to hepatotoxicity in Europe and/or in USA either by marketing authorization holders or by Regulatory agencies from 1997 to 2016 were selected. The liver safety data and the withdrawal decisions were identified from a search within the European medicine agency (EMA) website, the Food and drug administration (FDA) orange book and PubMed(r). RESULTS: From 1997 to 2016, eight drugs were withdrawn from the market for hepatotoxicity reason: tolcapone, troglitazone, trovafloxacin, bromfenac, nefazodone, ximelagatran, lumiracoxib and sitaxentan. The safety data suggest that while liver test abnormalities have been detected during clinical trials, other relevant factors leading to the discontinuation of these drugs have been identified: lack of predictability of animal models, inappropriate liver function test, non-compliance with drug treatment, less attention paid to rare adverse drug reactions, unpredictable occurrence and irreversible outcome of liver toxicity. CONCLUSION: Several relevant factors may contribute to an inadequate risk management leading to the discontinuation of the drugs. Preclinical safety data are not sufficient to allow early prediction of DILI in humans and post-marketing safety monitoring and signal detection still should be used to identify potential serious cases of DILI. However, it seems that changes in Pharmacovigilance legislation with a closer management of drug safety may have contributed to the improvement of the risk minimization. PMID- 29609831 TI - Birth defects in children of men exposed in utero to diethylstilbestrol (DES). AB - OBJECTIVE: Prenatal exposure to diethylstilbestrol (DES) is associated with adverse effects, including genital anomalies and cancers in men and women. Animal studies showed birth defects and tumors in the offspring of mice prenatally exposed to DES. In humans, birth defects, such as hypospadias were observed in children of prenatally exposed women. The aim of this research was to assess the birth defects in children of prenatally exposed men. METHODS: In a retrospective study conceived by a patients' association (Reseau DES France), the reports of men prenatally exposed to DES on adverse health effects in their children were compared with those of unexposed controls and general population. RESULTS: An increased incidence of two genital anomalies, cryptorchidism (OR=5.72; 95% CI 1.51-21.71), and hypoplasia of the penis (OR=22.92; 95% CI 3.81-137.90), was observed in the 209 sons of prenatally exposed men compared with controls, but hypospadias incidence was not increased in comparison with either the controls or the general population. No increase of genital anomalies was observed in daughters. CONCLUSION: With caution due to the methods and to the small numbers of defects observed, this work suggests an increased incidence of two male genital tract defects in sons of men prenatally exposed to DES. This transgenerational effect, already observed in animals and in the offspring of women prenatally exposed to DES, could be the result of epigenetic changes transmitted to the subsequent generation through men. PMID- 29609832 TI - EASL Clinical Practice Guidelines on hepatitis E virus infection. AB - Infection with hepatitis E virus (HEV) is a significant cause of morbidity and mortality, representing an important global health problem. Our understanding of HEV has changed completely over the past decade. Previously, HEV was thought to be limited to certain developing countries. We now know that HEV is endemic in most high-income countries and is largely a zoonotic infection. Given the paradigm shift in our understanding of zoonotic HEV and that locally acquired HEV is now the commonest cause of acute viral hepatitis in many European countries, the focus of these Clinical Practice Guidelines will be on HEV genotype 3 (and 4). PMID- 29609833 TI - Self-care confidence mediates the relationship between type D personality and self-care adherence in chinese heart failure patients. AB - BACKGROUND: Existing theory and evidence suggest that self-care confidence may mediate the relationship between Type D personality and self-care adherence. OBJECTIVES: To assess the mediating role of self-care confidence between Type D personality and self-care adherence in Chinese HF patients. METHODS: This is a secondary analysis of a cross-sectional study. Self-care confidence and self-care adherence (maintenance) were measured by the subscales of the Self-Care of Heart Failure Index (v6). The Type D Scale-14 was administered to assess negative affect (NA), social inhibition (SI), and Type D personality. Mediation analysis based on Baron and Kenny was performed. RESULTS: A total of 127 HF patients were included. Self-care confidence partially mediated the relationship between Type D personality and self-care adherence but completely mediated the relationship between NA/SI and self-care adherence. CONCLUSIONS: Clinicians may effectively improve self-care adherence by enhancing self-care confidence in HF patients with Type D personality. PMID- 29609834 TI - Evaluation of the description of active mobilisation protocols for mechanically ventilated patients in the intensive care unit: A systematic review of randomized controlled trials. AB - BACKGROUND: The complete description of exercise interventions is essential to allow for the replication of clinical trials and to the correct application in clinical practice. OBJECTIVES: The aim of this review was to evaluate of the description of the active mobilisation protocols in patients on invasive mechanical ventilation at intensive care units (ICU). METHODS: Systematic review of randomised controlled trials (RCTs) using the Consensus on Exercise Reporting Template. RESULTS: We identified 16 RCTs (n = 1,850). None sufficiently described the intervention for all items required for replication. The frequency, intensity, time, volume, and progression of active mobilisation as well as other important components of the intervention such as the instructor's qualifications/expertise, the types and incidence of adverse events, and the adherence to the exercise intervention were not adequately reported. CONCLUSION: Active mobilisation interventions were only incompletely described in RCTs, which can compromise replication in both, clinical and research settings. REGISTRATION: PROSPRERO (CRD42017068762). PMID- 29609835 TI - Using a systems approach to evaluate a circulating nurse's work patterns and workflow disruptions. AB - The physical environment affects how work is done in operating rooms (OR). The circulating nurse (CN), in particular, requires access to and interacts with materials, equipment, and technology more than other OR team members. Naturalistic study of CN behavior is therefore valuable in assessing how OR space and physical configuration influences work patterns and disruptions. This study evaluated the CNs' work patterns and flow disruptions (FD) by analyzing 25 surgeries across three different ORs. The OR layouts were divided into transitional and functional zones, and the work of CNs was categorized into patient, equipment, material, and information tasks. The results reveal that information tasks involve less movement than other types of work, while across all ORs, CNs were more likely to be involved in layout and environmental hazard FDs when involved in patient, material, or equipment-related tasks compared to information tasks. Different CN work patterns and flow disruptions between ORs suggest a link between OR layout and a CN's work. Future studies should examine how specific layout elements influence outcomes. PMID- 29609836 TI - Prematurity may negatively impact means-end problem solving across the first two years of life. AB - Preterm infants are at risk for delays in motor, perceptual, and cognitive development. While research has shown preterm infants may exhibit learning delays in the first months of life, these delays are commonly under-diagnosed. The purpose of this study was to longitudinally evaluate behavioral performance and learning in two means-end problem-solving tasks for 30 infants born preterm (PT) and 23 born full-term (FT). Infants were assessed at 6, 9, 12, 18, and 24 months old in tasks that required towel pulling or turntable rotation to obtain a distant object. PT infants performed more non-goal-directed and less goal directed behavior than FT infants throughout the study, resulting in a lower success rate among PT infants. PT infants showed delayed emergence of intentionality (prevalence of goal-directed behaviors) compared to FT infants in both tasks. Amount and variability of behavioral performance significantly correlated with task success differentially across age. The learning differences documented between PT and FT infants suggest means-end problem-solving tasks may be useful for the early detection of learning delays. The identification of behaviors associated with learning and success across age may be used to guide interventions aimed at advancing early learning for infants at risk. PMID- 29609837 TI - Formative research to identify community partnerships and foster relationships for health promotion research in South Mississippi. AB - OBJECTIVES: The purpose of this short communication is to describe the trust building and collaboration, fostering phases of a community-academic partnership between churches and academic researchers using a community-based participatory research approach. STUDY DESIGN AND METHODS: An academic-community partnership with church leaders was initiated using survey administration and was further developed using focus groups. A coalition was developed, and it guided a subsequent focus group with church members. RESULTS: Most churches surveyed did not have a health ministry in place but were agreeable that a variety of health topics were appropriate for the church setting. Church leaders felt that church members were key to engage in health programs in the church, whereas church members viewed pastoral support as important. Church leaders felt that working with a university brings credibility to their own health programs. CONCLUSION: This early work provides a valuable example of how community collaborations may be initiated and developed using formative research methods, serving both community and research agendas. PMID- 29609838 TI - Operationalizing outcome measures of human papillomavirus vaccination among adolescents. AB - OBJECTIVES: When examining vaccination coverage, researchers must make decisions about how to define outcome measures based on many factors, including the timing of doses. Different operationalizations of the same outcome can often lead to different findings and can affect the ability to make comparisons across studies. This methodological article aimed to illustrate the implications of two options for operationalizing human papillomavirus (HPV) vaccination based on timing: initiation of the first dose at any age vs before the 13th birthday (on time). STUDY DESIGN: Cross-sectional observational design. METHODS: The 2014 National Immunization Survey for Teens (N = 16,439 adolescents aged 13-17 years) was analyzed using multivariate logistic regression for each outcome measure and effect modification by gender. RESULTS: Age was positively associated with initiation at any age but negatively associated with on-time initiation. Gender modified the effect of race/ethnicity for both measures of initiation, but the pattern across groups was different for the two outcomes. Gender modified the effect of provider recommendation for initiation at any age, while gender modified the effects of age and region for on-time initiation. CONCLUSION: Decisions of how to operationalize outcomes of HPV vaccine initiation among adolescents can lead to different conclusions about the role of age and gender differences for several predictive variables. To inform the development of public health efforts that promote on-time HPV vaccination among male and female adolescents, researchers should consider the importance of dose timing when operationalizing outcome measures. We recommend including on-time receipt of the HPV vaccine as an outcome measure. PMID- 29609839 TI - Effects of a PRECEDE-PROCEED model based ergonomic risk management programme to reduce musculoskeletal symptoms of ICU nurses. AB - OBJECTIVES: To evaluate effects of a PRECEDE-PROCEED Model based, nurse-delivered Ergonomic Risk Management Program (ERMP) in the aim of reducing musculoskeletal symptoms of intensive care unit (ICU) nurses. METHODS: This pre-test post-test design for non-equivalent control groups study comprised 72 ICU nurses from two hospitals. A randomised sampling was done through the study population. The ERMP was delivered as an intervention including 26weeks of follow-up. Data was collected by "Descriptives of Nurses and Ergonomic Risk Reporting Form", "Rapid Upper Risk Assessment Form (RULA)", "ICU Environment Assessment Form" and "Personal interviews form". RESULTS: There was no difference between sociodemographic characteristics, work and general health conditions within intervention and control group. One month after the intervention, nurses had significant decrease in their total RULA scores during bending down and patient repositioning movements as 1.40 and 0.82, respectively. Six months after the ERMP, the mean total RULA scores of nurses during the patient repositioning was 4.39+/-1.49 which meant "immediate further analyses and modifications recommended". After all, pain intensity scores, medication use due to pain, and RULA ergonomic risk scores were significantly decreased, while exercise frequency was increased. CONCLUSIONS: The ERMP was effective to increase exercise frequency and to decrease musculoskeletal pain and ergonomic risk levels of ICU nurses. PMID- 29609840 TI - [Persistent asthma: Chronic therapy quantitative compliance in daily practice]. AB - INTRODUCTION: The aim of the study was to assess, compliance with maintenance treatment in patients with persistent asthma in clinical practice. METHODS: This observational, cross-sectional, prospective, multicenter study was conducted in metropolitan France on patients with persistent asthma under the care of a representative sample of general practitioners and pneumologists. Compliance was determined via access to the Health Insurance database allowing comparison between the actual consumption of medications and the corresponding theoretical consumption related to prescription. Additional compliance data were obtained using the validated Morisky questionnaire. RESULTS: Eighty one physicians included 488 patients, mean age of 51 years, 55% women. The statement of consumption (SC) was available for 35% of patients however the Morisky questionnaire (present for 85% of patients) showed a similar compliance between patients with or without SC. The good compliance rate (compliance >=80%) was observed in 51% based on the SC and in 38% based on the Morisky questionnaire. Among possible predictive factors, only obesity was associated with a bad compliance (19% vs 7%, P<0.05). Patients with poor compliances displayed more severe symptoms and a higher rate of non-control (21.7% vs 5.7%, P<0.01). CONCLUSIONS: The statement of consumption is a useful tool to provide quantitative measurement of compliance in daily practice. PMID- 29609841 TI - The safety and risk factors of revision adenoidectomy in children and adolescents: A nationwide retrospective population-based cohort study. AB - OBJECTIVE: To investigate the safety of adenoidectomy and risk factors of re adenoidectomy, and intend to provide evidence-based information to clinicians for further consideration. METHODS AND MATERIALS: This study was based on data obtained from Taiwan's National Health Insurance Research Database from the period 2002-2011. We utilized that data from the hospitalization group and collected information regarding those individuals who accepted adenoidectomy with or without tonsillectomy and post-adenoidectomy bleeding. Thereafter, we performed univariate and multi-variate analysis to explore the possible risk factors of re-adenoidectomy. RESULTS: A total of 5435 individuals who accepted a first adenoidectomy with or without tonsillectomy were collected. After further tracing treatment of these individuals, 107 (1.97%) accepted the revision adenoidectomy until 2011. Post-op bleeding was approximately 0.28%. The revision rate associated with patient age showed the following: 0-4 years (0.61%), 4-12 years (2.06%) and 12-18 years (2.56%). The revision rate associated with surgeon age showed: 28-41 years (1.42%), 41-50 years (2.96%), 50-65 years (2.74%); the surgeons' surgery volume showed low (4.34%), medium (0.71%), and higher (1.02%). There are 4 diseases (otitis media with effusion, sinusitis, chronic pharyngitis, and sleep disorder) that showed a significant relationship with the revision rate when subject to univariate and multivariate analysis. The revision rate incorporating hospital locations, volumes and levels revealed no significant difference with each other. CONCLUSIONS: Adenoidectomy is a generally safe surgical procedure, with low complication and low revision rate. Our study indicated that the revision rate of adenoidectomy might be lower when performed by young visiting staff with medium to higher surgical volume in the medium to higher volume hospital. If patients had diseases such as otitis media with effusion, sinusitis, chronic pharyngitis, and sleep disorder, they would be subject to higher rate of re-adenoidectomy. Surgeons should be aware and sufficiently explain this information to the parents before surgery. PMID- 29609842 TI - Akebia saponin D alleviates hepatic steatosis through BNip3 induced mitophagy. AB - Akebia Saponin D (ASD) is the most abundant constituent of the rhizome of Dipsacus asper Wall. The prior studies have shown that ASD alleviates hepatic steatosis targeted at the modulation of autophagy and exerts hepatoprotective effects through mitochondria. However, it is still unclear which signal transduction pathway that ASD increase autophagy and protect the mitochondria. The purpose of this paper was to explore the mechanisms through which ASD alleviates hepatic steatosis. ASD significantly reduced lipid accumulation in BRL cells. Furthermore, ASD significantly increased the mitophagy acting as increase the colocalization between mitochondria and punctate EGFP-LC3. ASD treatment increased the expression of BNip3, phospho-AMPK, prevented oleic acid (OA) induced LC3-II and phospho-mTOR expression. These effects were similar to the effects cotreatment with rapamycin. ASD treatment could not attenuate the expression of BNip3 blocked by chloroquine (CQ) or siRNA-mediated knockdown of BNip3. These results suggest that Akebia saponin D alleviates hepatic steatosis targeted at BNip3 mediated mitophagy. Activation of BNip3 via ASD may offer a new strategy for treating NAFLD. PMID- 29609843 TI - Interdisciplinary treatment algorithm for facial high-flow arteriovenous malformations, and review of the literature. AB - INTRODUCTION: High-flow arteriovenous malformations (HF-AVMs) are congenital vascular malformations. Typical localizations include the face, oral cavity, and extremities. Due to the high recurrence rate of AVM after incomplete resection or embolization, a combination of both therapeutic modalities has become the preferred choice of treatment. Therefore, we have developed an interdisciplinary therapeutic treatment algorithm for facial HF-AVM and performed a systematic review of the literature. PATIENTS AND METHODS: In a retrospective analysis, all patients who were treated using the interdisciplinary therapeutic treatment algorithm for facial HF-AVM between 10/2010 and 09/2014 were included in the study. Small HF-AVMs (n = 2) without prior therapy and with clearly detectable arterial blood supply were treated by surgical monotherapy. Larger, previously unsuccessfully treated HF-AVMs and lesions with complex arterial blood supply were treated using a combined therapy (n = 6). Combined therapy consisted of a preoperative embolization and a subsequent surgical resection 1-2 days later. If an extensive surgical reconstruction became necessary due to the size of the malformation, or the risk of recurrence was high due to the complex vascular anatomical situation, a second postoperative angiogram was performed to safely exclude a residual nidus, using a 'second look' prior to definitive wound closure (n = 3). HF-AVMs that did not allow for curative therapeutic intervention due to their size and localization were treated by interventional monotherapy (n = 1). Patients with suspicion of a primarily hormone-dependent growth during pregnancy were closely followed up clinically, following a 'wait and see' strategy (n = 1). In addition, a systematic literature review was performed to analyze treatment outcomes and current standards. RESULTS: 13 patients with a mean age of 39 years were included in the analysis. Patients were followed up for a mean of 26.8 months (range 12-60 months). Combined treatment (n = 9) was free of recurrence in all cases (100%) after a mean follow up of 30.3 months (range 12-60 months). Surgical monotherapy (n = 2) was also successful in both cases. Non-curative, interventional monotherapy lead to significant decrease in symptoms and did not have to be repeated. A postpartum decrease of the tumor could be observed in the 'wait and see' group. However, at the end of the observational period, a hormone independent growth occurred. Results were supported by findings of the review. CONCLUSION: The treatment of HF-AVMs of the head and neck remains challenging due to high recurrence rates. In our cohort, following the Heidelberg treatment algorithm both surgical monotherapy and combined surgical and interventional therapy had very high success rates. For non-curative, symptomatic therapy, interventional treatment should be discussed in terms of the risk of growth induction of HF-AVMs. Findings from the literature concerning therapeutic strategies and success rates are in line with the developed Heidelberg treatment algorithm. However, a larger sample of patients will be necessary to prove the validity of this algorithm. PMID- 29609844 TI - Does vaccination in solid-organ transplant recipients result in adverse immunologic sequelae? A systematic review and meta-analysis. AB - BACKGROUND: Clinical guidelines recommend vaccinations for solid-organ transplant recipients. However, concern exists that vaccination may stimulate adverse alloimmune responses. METHODS: We systematically reviewed the published literature regarding this aspect of vaccine safety. Electronic databases were searched for interventional and observational studies assessing de novo donor specific antibodies (DSA) and rejection episodes after vaccination against infectious pathogens. Graft loss was also assessed. A meta-analysis was conducted for prospective, controlled studies. PRISMA reporting guidelines were followed. RESULTS: Ninety studies (15,645 vaccinated patients and 42,924 control patients) were included. Twelve studies included control groups. The incidence of de novo DSA (14 studies) was 23 of 1,244 patients (1.85%) at 21 to 94 days. The incidence of rejection (83 studies) was 107 episodes in 5,116 patients (2.1%) at 0.7 to 6 months. Meta-analysis of prospective controlled studies (n = 8) showed no increased rejection risk with vaccination compared with no vaccination (RR 1.12, 95% CI 0.75 to 1.70). This finding was supported by data from 3 registry analyses. CONCLUSIONS: Although the current evidence lacks high-quality, controlled studies, the currently available data provide reassurance that clinicians should recommend appropriate vaccination for their transplant patients as the risk of de novo DSA and rejection is relatively low. PMID- 29609845 TI - Evolution of brachytherapy treatment planning to deterministic radiation transport for calculation of cardiac dose. AB - Brachytherapy was among the first methods of radiotherapy and has steadily continued to evolve. Here we present a brief review of the progression of dose calculation methods in brachytherapy to the current state-of-the art computerized methods for heterogeneity correction. We further review the origin and development of the BrachyVision (Varian Medical Systems, Inc., Palo Alto, CA) treatment planning system and evaluate dosimetric results from 12 patients implanted with the strut-assisted volumetric implant (SAVI) applicator (Cianna Medical, Aliso Viejo, CA) for accelerated partial breast irradiation (APBI). Dosimetric results from plans calculated using homogenous and heterogeneous algorithms have been compared to investigate the impact of heterogeneity corrections. Our study showed large percent difference between mean cardiac doses 11.8 +/- 6.2% (p = 0.0007) calculated with and without heterogeneity corrections. Our findings are consistent with those of others, indicating an overestimation of the distal dose to organs-at-risk by traditional methods, especially at interfaces between air and tissue. PMID- 29609846 TI - Acquired Port-Wine Stain: Not a simple stain! PMID- 29609848 TI - Spinocerebellar ataxias type 3 and 10: Onset and progression of ataxia during pregnancy and puerperium. PMID- 29609847 TI - Angiotensin IV improves subnormothermic machine perfusion preservation of rat liver graft. AB - This study aims to determine whether Angiotensin IV (Ang IV) addition to Celsior preservation solution could improve hepatic endothelium function and provide better liver protection during subnormothermic machine preservation (SMP). Two experimental models were used: In the first part of the study, rings isolated from rat hepatic artery were preserved in Celsior solution (6 h, 20 degrees C) with and without Ang IV (10-9 M), then, endothelium-dependent relaxation (EDR) and the concentration of acetylcholine inducing half-maximal relaxation of pre contracted rings (EC50) were measured. Also, in order to investigate the implication of nitric oxide (NO) on EDR, the rings of hepatic artery were incubated with L-NG-nitroarginine metyl ester (L-NAME). In the second part of the study, rat livers were subjected to SMP with oxygenated Celsior solution (6 h, 20 degrees C), supplemented or not with Ang IV (10-9 M) and then perfused (2 h, 37 degrees C) with Krebs Henseleit solution. We found that Ang IV supplementation to Celsior solution decreased EC50 value and improved EDR of hepatic artery rings, 6h after sub-normothermic preservation. Interestingly, Ang IV amplified the vessel relaxation in a NO-dependent manner. Moreover, liver SMP with Ang IV reduced oxidative stress and cell injury and improved organ function. Ang IV activated pAkt, increased eNOS protein level and decreased apoptosis in the preserved liver grafts. In conclusion, we showed that the use of Ang IV in Celsior solution for sub-normothermic graft preservation insured a better NO dependent relaxation and improved liver functional recovery. PMID- 29609849 TI - Occurrence of serological reactions for serogroup Sejroe (CTG and Prajtino) in female buffalo in the state of Pernambuco, Brazil. AB - The objective of this study was to evaluate the occurrence of anti-Leptospira spp. antibodies in female buffalo in the state of Pernambuco. A total of 123 female buffalo blood samples were collected from five properties distributed in the state of Pernambuco. The microscopic agglutination test was used to study anti-Leptospira spp. antibodies. The occurrence of anti-Leptospira spp. antibodies was 28.5% (35/123; CI 20.7-37.3%) and on different properties, the occurrence ranged from 28.6% to 80.0%, with 100% of the properties showing animals with positive results. The serovars of the serogroup Sejroe with a higher incidence were Hardjoprajtino (CTG strain, 49.1%) and Hardjo (Prajtino genotype, 43.2%), followed by serogroup Grippotyphosa with the Grippotyphosa serovar (3.9%), serogroup Pomona with the Pomona serovar (1.9%), and the Icterohaemorrhagiae serovar Copenhageni (1.9%). This was the first record of the occurrence of anti-Lepstospira spp. antibodies in female buffalo in the state of Pernambuco. Control measures are necessary to prevent health and economic losses, given that the agent involved affects animal reproduction, triggering drops in conception rates or even clinical cases of abortion. PMID- 29609850 TI - Effect of a training programme on blood culture contamination rate in critical care. AB - : Blood culture contamination can occur from extraction to processing; its rate should not exceed 3%. OBJECTIVE: To evaluate the impact of a training programme on the rate of contaminated blood cultures after the implementation of sample extraction recommendations based on the best evidence. METHOD: Prospective before after study in a polyvalent intensive care unit with 18 beds. Two phases were established (January-June 2012, October 2012-October 2015) with a training period between them. Main recommendations: sterile technique, surgical mask, double skin disinfection (70 degrees alcohol and 2% alcoholic chlorhexidine), 70 degrees alcohol disinfection of culture flasks and injection of samples without changing needles. Including all blood cultures of patients with extraction request. VARIABLES: demographic, severity, pathology, reason for admission, stay and results of blood cultures (negative, positive and contaminated). Basic descriptive statistics: mean (standard deviation), median (interquartile range) and percentage (95% confidence interval). Calculated contamination rates per 100 blood cultures extracted. Bivariate analysis between periods. RESULTS: Four hundred and eight patients were included. Eight hundred and forty-one blood cultures were taken, 33 of which were contaminated. In the demographic variables, severity, diagnosis and stay of patients with contaminated samples, no differences were observed from those with uncontaminated samples. Pre-training vs post-training contamination rates: 14 vs 5.6 per 100 blood cultures extracted (P=.00003). CONCLUSION: An evidence-based training programme reduced the contamination of samples. It is necessary to continue working on the planning of activities and care to improve the detection of pollutants and prevent contamination of samples. PMID- 29609851 TI - Critical Care Unit presurgical tour, is it helpful for patients undergoing elective cardiac surgery? PMID- 29609852 TI - Response to the critique of "Effectiveness of a shielded ultraviolet C air disinfection system in an inpatient pharmacy of a tertiary care children's hospital". PMID- 29609853 TI - Risk factors for sepsis morbidity in a rural hospital population: A case-control study. AB - BACKGROUND: The aim of the study was to identify risk factors for sepsis morbidity in a rural hospital population. METHODS: We used a case-control study design. Patients included adult admissions to a rural health system between January 1, 2012, and December 31, 2015. Case selection was by electronic medical record search for codes of the ICD-9-CM. Cases were validated against Quick Sequential Organ Failure Assessment criteria. Multiple logistic regression modeling was performed to determine which predefined variables were significantly associated with sepsis diagnosis. RESULTS: A total of 220 patients were studied (110 cases and 110 controls). Cases had an in-hospital mortality of 20% compared with 0% of the controls. Indwelling medical device use during hospitalization (adjusted odds ratio [OR], 3.02; 95% confidence interval [CI], 1.44-6.30; P = .003), coronary heart disease (adjusted OR, 2.59; 95% CI, 1.13-5.97; P = .03), and type of health insurance (adjusted OR, 2.36; 95% CI, 1.13-4.93; P = .02) were independently associated with sepsis diagnosis after adjusting for potential confounders. CONCLUSIONS: This study underscores the need for implementation and maintenance of infection control measures during management of patients with indwelling medical devices at a rural hospital. PMID- 29609854 TI - Residual moisture and waterborne pathogens inside flexible endoscopes: Evidence from a multisite study of endoscope drying effectiveness. AB - BACKGROUND: Endoscopy-associated infection transmission is frequently linked to inadequate reprocessing. Residual organic material and moisture may foster biofilm development inside endoscopes. This study evaluated the effectiveness of endoscope drying and storage methods and assessed associations between retained moisture and contamination. METHODS: Endoscope reprocessing, drying, and storage practices were assessed at 3 hospitals. Researchers performed visual examinations and tests to detect fluid and contamination on patient-ready endoscopes. RESULTS: Fluid was detected in 22 of 45 (49%) endoscopes. Prevalence of moisture varied significantly by site (5%; 83%; 85%; P < .001). High adenosine triphosphate levels were found in 22% of endoscopes, and microbial growth was detected in 71% of endoscopes. Stenotrophomonas maltophilia, Citrobacter freundii, and Lecanicillium lecanii/Verticillium dahliae were found. Retained fluid was associated with significantly higher adenosine triphosphate levels (P < .01). Reprocessing and drying practices conformed with guidelines at 1 site and were substandard at 2 sites. Damaged endoscopes were in use at all sites. CONCLUSIONS: Inadequate reprocessing and insufficient drying contributed to retained fluid and contamination found during this multisite study. More effective methods of endoscope reprocessing, drying, and maintenance are needed to prevent the retention of fluid, organic material, and bioburden that could cause patient illness or injury. PMID- 29609855 TI - Influenza vaccine availability at urgent care centers in the state of Arizona. AB - We surveyed urgent care centers (UCCs) in the state of Arizona to determine whether they offered the influenza vaccine during the 2016-2017 influenza season. Overall vaccine availability was 80.3% at these facilities. During this season, one-third of the UCCs offered influenza vaccination to children 6 months or older; approximately two-thirds offered influenza vaccination to children and young adults 16 years or older. This is the first study of influenza vaccine availability at UCCs. PMID- 29609856 TI - A polymicrobial fungal outbreak in a regional burn center after Hurricane Sandy. AB - OBJECTIVE: To describe a polymicrobial fungal outbreak after Hurricane Sandy. DESIGN: An observational concurrent outbreak investigation and retrospective descriptive review. SETTING: A regional burn intensive care unit that serves the greater Baltimore area, admitting 350-450 burn patients annually. PATIENTS: Patients with burn injuries and significant dermatologic diseases such as toxic epidermal necrolysis who were admitted to the burn intensive care unit. METHODS: An outbreak investigation and a retrospective review of all patients with non candida fungal isolates from 2009-2016 were performed. RESULTS: A polymicrobial fungal outbreak in burn patients was temporally associated with Hurricane Sandy and associated with air and water permeations in the hospital facility. The outbreak abated after changes to facility design. CONCLUSIONS: Our results suggest a possible association between severe weather events like hurricanes and nosocomial fungal outbreaks. This report adds to the emerging literature on the effect of severe weather on healthcare-associated infections. PMID- 29609857 TI - Sex differences in cholesterol levels from birth to 19 years of age may lead to increased cholesterol burden in females with FH. AB - BACKGROUND: The increased risk of cardiovascular disease in familial hypercholesterolemia (FH) is caused by increased cholesterol burden from birth. Even small elevation in cholesterol level accumulates over time and aggravates atherosclerosis. OBJECTIVES: The aim of the present study was to describe the lipid profile across sex and age in a large cohort of untreated children and adolescents with FH, as this have not clearly been described. METHODS: FH children (438 girls, 452 boys) not receiving lipid-lowering therapy, aged 0 to 19 years were included and divided into 4 age groups (<5, 5-9, 10-14, and 15-19 years). Information was retrieved from the medical records. Total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and non-HDL cholesterol (non-HDL-C) were studied in relation to sex and age by multiple linear regression analysis. RESULTS: Girls with FH as compared to boys had significantly higher TC, LDL-C, and non-HDL-C (P < .001 for all) levels with mean (95% confidence interval) differences of 0.48 mmol/L (0.28, 0.68) (18.6 g/dL), 0.39 mmol/L (0.19, 0.59) (15.08 mg/dL), and 0.42 mmol/L (0.22, 0.63) (16.24 mg/dL), respectively. These estimates did not change after adjustment for age. We also observed sex differences for HDL-C; girls had higher HDL-C in the youngest (<5 years, P = .05) and oldest age groups (15-19 years, P < .001). CONCLUSIONS: FH girls have higher levels of TC, LDL-C, and non-HDL-C levels than boys from birth up to 19 years of age. This may contribute significantly to the total lifelong cholesterol burden in FH women. PMID- 29609858 TI - Undetectable high-density lipoprotein cholesterol in acute malaria. AB - We report the case of a 39-year-old West African man in whom high-density lipoprotein cholesterol (HDL-C) was identified as undetectable at <0.08 mmol/L. Total cholesterol in the same sample was 2.85 mmol/L; triglycerides were only mildly elevated at 2.32 mmol/L. He was admitted with a 2-week history of polydipsia, polyuria, weight loss and hyperpyrexia. Dual malarial infection with Plasmodium ovale and falciparum was identified and attributed to a recent trip to Nigeria without chemoprophylaxis. Also, he was diagnosed with diabetes mellitus with random hyperglycemia of 39 mmol/L but no ketonemia. Subsequent investigation revealed a low apolipoprotein A1 of 0.38 g/L (1.04-2.02), confirming a true HDL-C deficit. On clinical examination, he had neither orange tonsils consistent with Tangier disease nor corneal opacification consistent with lecithin-cholesterol acyltransferase deficiency. The patient was an avid gym goer but denied anabolic steroid abuse, a fact supported by a transient primary testosterone deficiency at presentation (testosterone 6.56 nmol/L, RR 8.6-29; follicle-stimulating hormone high at 9.2 mU/L, luteinising hormone high at 11.9 mU/L). He was treated for malaria and started on metformin for diabetes. At 8-week follow-up, his HDL-C was entirely normal at 1.38 mmol/L. We believe this severe drop in HDL-C level to be due to acute inflammation caused by malaria. As extreme drops in HDL-C have been found to be associated with the poorest prognosis, prospective identification of HDL-C and prompt clinical liaison may be of benefit. PMID- 29609859 TI - Cognitive behavioral therapies and multiple sclerosis fatigue: A review of literature. AB - BACKGROUND: Patients with multiple sclerosis (MS) commonly suffer from fatigue, a multidimensional symptom with physical, cognitive and psychosocial components that can drastically alter the quality of life. Despite its debilitating nature, the current treatment options are limited by their modest efficacy and numerous side effects. Cognitive behavioral therapies (CBT) have been applied in MS patients and might be of help in relieving fatigue. This constitutes the main objective of the current review. METHODS: Computerized databases (Medline/PubMed, Scopus) were consulted till January 2018, and a research was conducted according to PRISMA guidelines in order to identify original research articles published at any time in English and French languages on cognitive behavioral therapies and MS fatigue as a primary outcome. The following key terms were used: ('multiple sclerosis' OR 'MS') AND ('fatigue') AND ('cognitive behavioral therapy' OR 'CBT' OR 'cognitive therapy' OR 'CT' OR 'behavioral therapy' OR 'BT' OR 'psychotherapy'). RESULTS: Fourteen papers matched the above criteria (11 trials, 2 methods and 1 study addressing CBT mechanisms of action). CBT seems to have positive effects on MS fatigue. However, the onset and duration of effects varied across the studies. CONCLUSION: These data highlight the promising effects of CBT in MS fatigue. Admitting the limited number of studies, more protocols are needed before drawing any conclusion. Future works might benefit from combining CBT with emerging therapies such as non-invasive brain stimulation techniques which also yielded promising results in the setting of MS. This may help in long-term maintenance of fatigue relief. PMID- 29609860 TI - Prophylaxis of surgical site infection in adult spine surgery: A systematic review. AB - INTRODUCTION: Surgical site infection (SSI) remains a significant source of morbidity in spine surgery, with reported rates varying from 0.7 to 16%. OBJECTIVE: To systematically review and evaluate the evidence for strategies for prophylaxis of SSI in adult spine surgery in the last twenty years. METHODS: Two independent systematic searches were conducted, at two international spine centers, encompassing PubMed, ClinicalTrials.gov, Cochrane Database, EBSCO Medline, ScienceDirect, Ovid Medline, EMBASE (Ovid), and MEDLINE. References were combined and screened, then distilled to 69 independent studies for final review. RESULTS: 11 randomized controlled trials (RCTs), 51 case-controlled studies (CCS), and 7 case series were identified. Wide variation exists in surgical indications, approaches, procedures, and even definitions of SSI. Intra-wound vancomycin powder was the most widely studied intervention (19 studies, 1 RCT). Multiple studies examined perioperative antibiotic protocols, closed-suction drainage, povidone-iodine solution irrigation, and 2-octyl-cyanoacrylate skin closure. 18 interventions were examined by a single study only. There is limited evidence for the efficacy of intra-wound vancomycin. There is strong evidence that closed-suction drainage does not affect SSI rates, while there is moderate evidence for the efficacy of povidone-iodine irrigation and that single-dose preoperative antibiotics is as effective as multiple doses. Few conclusions can be drawn about other interventions given the paucity and poor quality of studies. CONCLUSIONS: While a small body of evidence underscores a select few interventions for SSI prophylaxis in adult spine surgery, most proposed measures have not been investigated beyond a single study. Further high level evidence is required to justify SSI preventative treatments. PMID- 29609861 TI - Enantioselective determination of aspartate and glutamate in biological samples by ultrasonic-assisted derivatization coupled with capillary electrophoresis and linked to Alzheimer's disease progression. AB - A simple cyclodextrin-mediated capillary zone electrophoresis method equipped with a laser-induced fluorescence detector was developed for chiral analysis of the excitatory amino acids aspartate (Asp) and glutamate (Glu). Plasma and cerebrospinal fluid (CSF) samples were pretreated with centrifugal filter devices before analysis to remove high-molecular-weight proteins (molecular weight cut off: 3000) and then derivatized using 10 mM 6-carboxyfluorescein N hydroxysuccinimide ester in DMSO under sonication at 25 degrees C for 2 h. After the derivatization reaction, reacted samples were diluted 100-fold with 5-([4,6 dichlorotriazin-2-yl]amino)fluorescein hydrochloride (DTAF) solution and then hydrodynamically subjected to capillary electrophoresis (0.5 psi for 5 s, injection volume 8.27 nL). The separation buffer consisted of 50 mM borate buffer (pH 9.0) with 6 mM gamma-CD and 0.1% polyvinylpyrrolidone, and the separation voltage was set at 20 kV. In the linearity calculations for the determination of d/l-Asp and d/l-Glu in plasma and CSF, a standard addition method was utilized to spike solutions with 0-20.0 MUg mL-1l-Glu and 0-2.0 MUg mL-1d-Glu and d/l-Asp to construct calibration curves. Correlation coefficients were above 0.998 for every analyte. The limits of detection (S/N = 3) for d/l-Asp and d/l-Glu standard solutions were 0.85-0.96 MUg mL-1. The proposed method was applied successfully to determine d/l-Asp and d/l-Glu concentrations in the plasma and CSF samples of 26 patients with Alzheimer's disease (AD), and the association between these concentrations and disease severity was investigated. Statistical analysis showed a moderately negative correlation (r = -0.158) between plasma l-Asp concentration and AD severity. PMID- 29609862 TI - O-carboxymethyl chitosan Schiff base complexes as affinity ligands for immobilized metal-ion affinity chromatography of lysozyme. AB - We synthesized Ni2+-attached O-Carboxymethyl chitosan Schiff base complexes embedded composite cryogels (Ni2+-O-CMCS-CCs) by means of polymerization of gel forming precursors at subzero temperatures. Prepared affinity cryogel showed excellent adsorption performance for lysozyme selected as model protein to test adsorption parameters, demonstrating an adsorption capacity of 244.6 mg/g (15.3 mg/g for Ni2+ minus O-CMCS-CCs), with fast adsorption equilibrium within 30 min and good reversibility. The performance of Ni2+-O-CMCS-CCs for lysozyme was also evaluated by SDS-PAGE, and a purification efficiency of 86.9% with 89.5% purification yield was determined. The swelling test, FT-IR, and SEM analysis were carried out for the characterization of Ni2+-O-CMCS-CCs. At the end of 35 adsorption-desorption cycles, there was no significant change in the adsorption capacity. PMID- 29609863 TI - Reply to "Dietary patterns and the risk of coronary heart disease among Jordanians: A case-control study. Statistical and methodological issues". PMID- 29609864 TI - Long-acting insulin analogs and cancer. AB - AIMS: Hyperinsulinemia is a recognized risk factor for cancer and plays a major role for the increased cancer incidence in diabetic patients. Whether insulin analogs, and particularly long-acting analogs, worsen the pro-cancer effect of excess insulin is still controversial. DATA SYNTHESIS: In this paper we summarize the biological bases for the potential detrimental effect of long-acting analogs on cancer cells and review the in vitro and in vivo evidence on this issue. Because of their different molecular structure relative to native insulin, insulin analogs may activate the insulin receptor (IR) and the post receptor pathways differently. Most, but not all, in vitro evidence indicate that long acting analogs may have a stronger mitogenic potency than insulin on cancer cells. Notably insulin glargine, the most studied long-acting analog, also has a higher affinity for the insulin-like growth factor (IGF)-1 receptor, a potent growth mediator. In vitro observations, however, may not reflect what occurs in vivo when analogs are metabolized to derivatives with a different mitogenic activity. Clinical studies, mostly retrospective and predominantly concerning glargine, provide contrasting results. The only perspective trial found no cancer increase in patients treated with glargine. All these studies, however, have severe weaknesses because of the insufficient evaluation of important factors such as dose administered, length of exposure, patient follow-up duration and site-specific cancer investigation. Moreover, whether cancer promotion is a long acting analog class characteristic or a specific effect of a single agent is not clear. CONCLUSIONS: In conclusion the carcinogenic risk of long-acting analogs, and specifically glargine, can be neither confirmed nor excluded. A personalized and shared decision, considering all the individual risk factors (metabolic and non-metabolic), is the suggestion for the clinician. PMID- 29609865 TI - Dairy shows different associations with abdominal and BMI-defined overweight: Cross-sectional analyses exploring a variety of dairy products. AB - BACKGROUND AND AIMS: Previous studies have suggested weight-regulatory properties for several dairy nutrients, but population-based studies on dairy and body weight are inconclusive. We explored cross-sectional associations between dairy consumption and indicators of overweight. METHODS AND RESULTS: We included 114,682 Dutch adults, aged >=18 years. Dairy consumption was quantified by a food frequency questionnaire. Abdominal overweight was defined as waist circumference (WC) >=88 cm (women) or >=102 cm (men) (n = 37,391), overweight as BMI >=25-30 kg/m2 (n = 44,772) and obesity as BMI >=30 kg/m2 (n = 15,339). Associations were quantified by logistic (abdominal overweight, no/yes), multinomial logistic (BMI defined overweight and obesity) and linear regression analyses (continuous measures of WC and BMI), and they were adjusted for relevant covariates. Total dairy showed a positive association with abdominal overweight (OR Q1 ref vs. Q5: 1.09; 95% CI: 1.04-1.14) and with BMI-defined overweight (OR Q5 1.13; 95% CI: 1.08-1.18) and obesity (OR Q5 1.09; 95% CI: 1.02-1.16). Skimmed, semi-skimmed and non-fermented dairy also showed positive associations with overweight categories. Full-fat dairy showed an inverse association with overweight and obesity (OR Q5 for obesity: 0.78; 95% CI: 0.73-0.83). Moreover, inverse associations were observed for yoghurt and custard and positive associations for milk, buttermilk, flavoured yoghurt drinks, cheese and cheese snacks. Fermented dairy, curd cheese and Dutch cheese did not show a consistent association with overweight categories. CONCLUSIONS: Total, skimmed, semi-skimmed and non-fermented dairy; milk; buttermilk; flavoured yoghurt drinks; total cheese and cheese snacks showed a positive association with overweight categories, whereas full-fat dairy, custard and yoghurt showed an inverse association with overweight categories. PMID- 29609866 TI - Biomechanical analysis of bone remodeling following mandibular reconstruction using fibula free flap. AB - Whilst the newly established biomechanical conditions following mandibular reconstruction using fibula free flap can be a critical determinant for achieving favorable bone union, little has been known about their association in a time dependent fashion. This study evaluated the bone healing/remodeling activity in reconstructed mandible and its influence on jaw biomechanics using CT data, and further quantified their correlation with mechanobiological responses through an in-silico approach. A 66-year-old male patient received mandibular reconstruction was studied. Post-operative CT scans were taken at 0, 4, 16 and 28 months. Longitudinal change of bone morphologies and mineral densities were measured at three bone union interfaces (two between the fibula and mandibular bones and one between the osteotomized fibulas) to investigate bone healing/remodeling events. Three-dimensional finite element models were created to quantify mechanobiological responses in the bone at these different time points. Bone mineral density increased rapidly along the bone interfaces over the first four months. Cortical bridging formed at the osteotomized interface earlier than the other two interfaces with larger shape discrepancy between fibula and mandibular bones. Bone morphology significantly affected mechanobiological responses in the osteotomized region (R2 > 0.77). The anatomic position and shape discrepancy at bone union affected the bone healing/remodeling process. PMID- 29609867 TI - Circadian health differs between boys and girls as assessed by non-invasive tools in school-aged children. AB - BACKGROUND & AIMS: Assessment of circadian health is confined to adults. However, understanding circadian status of school-aged children is necessary due to its health implications. The aim was to develop 1) a protocol to assess circadian function in school-aged children by combining the best non-invasive tools previously validated in adults; 2) a score to capture circadian function in children including food timing. This protocol will allow to explore gender differences and to compare the circadian function of school-aged children with adults from the same Mediterranean area. METHODS: Healthy children (8-12 y) from 3 schools in a Mediterranean area of Spain were recruited (n = 248; 125 males and 123 females). Several non-invasive tools were used: a) 7-day-diaries of food timing and food intake, physical-activity and sleep, b) Munich-chronotype-self reported-questionnaire; c) cortisol and melatonin saliva determinations; d) 7-day rhythms of wrist temperature (T), activity (A), position (P) and the integrative variable TAP e) 7-day-light exposure. RESULTS: We have constructed the first school-aged children population for the assessment of circadian function (ONTIME Jr) and a new circadian score has been developed. Among circadian-related measures, TAP was the most suitable and reliable to determine circadian system characteristics. Circadian function was better in girls than in boys [circadian score (AU) Mean +/- SD (girls, 1216 +/- 153 vs. 1159 +/- 173 boys, P = 0.012)], and also in school-aged children than in adults from the same Mediterranean area (Circadian-Function-Index: children 0.47 +/- 0.06 vs. adults 0.45 +/- 0.06 P = 0.001). CONCLUSIONS: A new protocol, including TAP and food timing, demonstrated to be reliable in assessing circadian function in children. These non-invasive techniques provide the wherewithal for paediatricians to assess circadian function in clinical practice. TRIAL REGISTRATION: Chronobiology and childhood obesity (ONTIME-Jr: Obesity, Nutrigenetics, Timing and Mediterranean, Junior). ClinicalTrials.gov ID: NCT02895282, October 2014. PMID- 29609868 TI - Genetic variants in selenoprotein genes modulate biomarkers of selenium status in response to Brazil nut supplementation (the SU.BRA.NUT study). AB - BACKGROUND: The beneficial effects of selenium (Se) to human health are exerted by selenoproteins, which can be quantified in blood and used as biomarkers of Se status. Different responses of Se biomarkers after supplementation with selenomethionine and sodium selenite have been observed and some of them could be due to genetic polymorphisms, mainly single nucleotide polymorphisms (SNPs). Brazil nuts are known to be the richest natural source of Se. OBJECTIVE: Investigate how genetic variations in selenoprotein genes modulate biomarkers of Se status in response to Brazil nut supplementation. METHODS: The SU.BRA.NUT study was a four month interventional trial which involved healthy volunteers of both genders, selected in University of Sao Paulo. The supplementation was done with one Brazil nut a day for 8 weeks, followed by 8 weeks of washout. Blood samples were collected at 5 time points: baseline, 4 and 8 weeks of supplementation and 4 and 8 weeks of washout for analysis of five biomarkers of Se status - erythrocyte GPx1 (Glutathione Peroxidase 1) activity, plasma GPx3 activity, plasma Se, erythrocyte Se, and plasma selenoprotein P. The gene expression of GPX1, SELENOP, SELENOF and SELENOS was done before and after 8 weeks of supplementation. The volunteers were genotyped for SNPs in GPX1 (rs1050450, rs3811699 and rs1800699), GPX4 (rs713041), SELENOP (rs3877899 and rs7579), SELENOF (rs5845) and SELENOS (rs34713741). RESULTS: A total of 130 volunteers finished the protocol. The concentrations of four biomarkers of Se status increased significantly after 4 and 8 weeks of supplementation, being modulated by gender. In addition, erythrocyte GPx1 activity was associated with rs1050450, rs713041 and rs5845. Plasma Se was associated with rs7579 and selenoprotein P with plasma Se at baseline. Nut supplementation significantly increased GPX1 mRNA expression only in subjects with CC genotype at rs1050450. SELENOP mRNA expression was significantly lower in subjects with GG genotype at rs7579 before and after supplementation. CONCLUSION: Genetic variations in GPX1 and SELENOP genes are associated with different responses of molecular and biochemical biomarkers of Se status after Brazil nut supplementation in healthy Brazilians. The SU.BRA.NUT study was registred at www.clinicaltrials.gov as NCT 03111355. PMID- 29609869 TI - Bone status and adipokine levels in children on vegetarian and omnivorous diets. AB - BACKGROUND & AIMS: Measurements of bone mineral density (BMD) reflect bone status but not the dynamics of bone turnover. Biochemical markers, which show global skeletal activity, were validated for the assessment of bone formation and resorption processes. Adipokines also play a significant role in the regulation of bone metabolism. OBJECTIVE: To assess body composition, bone mineral density, bone turnover markers and adipokine levels in relation to vegetarian and omnivorous diets. METHODS: The study included 53 vegetarian and 53 omnivorous prepubertal healthy children matched for age and sex (median age 7.0 years). Body composition and BMD were assessed by dual-energy X-ray absorptiometry. 25 hydroxyvitamin D and parathormone levels were measured by chemiluminescence method. Serum carboxy-terminal propeptide of type I collagen (CICP), total osteocalcin (OC) and its forms carboxylated (c-OC) and undercarboxylated (uc-OC), C-terminal cross-linking telopeptide of collagen type I (CTX), leptin and adiponectin levels were determined using immunoenzymatic assays. RESULTS: Both groups of children were comparable in terms of body composition, except for the percentage of fat mass, which was lower (19.24 vs. 21.77%, p = 0.018) in vegetarians. Mean values of total BMD z-score and lumbar spine BMD z-score were lower (-0.583 vs. -0.194, p = 0.009 and -0.877 vs. -0.496, p = 0.019, respectively) in vegetarians compared with omnivores. Serum leptin level was about 2-fold lower (1.39 vs. 2.94 ng/mL, p < 0.001) in vegetarians, however, adiponectin concentration was similar in both groups. Vegetarians had similar concentration of 25-hydroxyvitamin D, but higher parathormone (40.8 vs. 32.1 pg/mL, p = 0.015) and CTX (1.94 vs. 1.76 ng/mL, p = 0.077) levels than omnivores. Total osteocalcin and CICP concentrations were comparable in both groups, however, c-OC/uc-OC ratio was higher (1.43 vs. 1.04 ng/mL, p < 0.05) in vegetarians. We found positive correlation between c-OC and nutritional parameters adjusted for total energy intake (plant protein, phosphorus, magnesium and fiber intakes) in vegetarian children. CONCLUSIONS: Prepubertal children on a vegetarian diet had significantly lower total and lumbar spine BMD z-scores, but absolute values of bone mineral density did not differ. BMD z-scores did not correlate with bone metabolism markers and nutritional variables, but were positively associated with anthropometric parameters. Lower leptin levels in vegetarian children reflect lower body fat. Longitudinal studies are necessary to evaluate the impact of the observed association on bone health at adulthood. PMID- 29609870 TI - [Prevalence and relations of orthostatic hypotension in patients 80 years old and over from a primary care unit]. AB - OBJECTIVE: To estimate the prevalence of orthostatic hypotension (OH) in patients 80 years old and over attending a primary care unit. To relate OH to the most prevalent pathologies and to the most used drugs. DESIGN: Transversal observational study. LOCATION: Primary care unit, Santiago de Compostela. PARTICIPANTS: Eighty one patients 80 years old or over representative of a primary care unit were recruited. Ten patients were excluded. MAIN MEASUREMENTS: Blood pressure was measured in decubitus and later in erect position first immediately after standing and then after 3 minutes. Diagnoses and active treatments were reviewed in the electronic clinical history and through an interview with the patient and caregiver. RESULTS: In 26.76% of patients the systolic blood pressure fell by 20mmHg or more and/or the diastolic blood pressure fell by 10mmHg in the instant following the postural shift. In 16.90% of patients the drop persisted after 3 minutes of standing from decubitus position. None of the patients was diagnosed with OH. The highest prevalence ratio was observed for diabetes mellitus (1.6; P=.412), not existing differences for arterial hypertension (P=.881). OH related in a statistically meaningful way to the use of renin angiotensin aldosterone system inhibitors (OR: 8.174, CI95%: 1.182-56.536); P=.033] and benzodiazepines (OR: 5.938, CI95%: 1.242-28.397; P=.026)]. CONCLUSION: OH had a prevalence of 16.90% among the elderly patients who had a consultation. Its connection with some drugs (renin angiotensin aldosterone system inhibitors and benzodiazepines) must be considered. PMID- 29609871 TI - [Point of Care Ultrasound in Primary Care. Is it a high resolution tool?] AB - Point-of-Care Ultrasound is a method of performing a rapid clinical ultrasound, with the aim of responding to a clinical question immediately. This is not an ultrasound performed systematically as the radiologists do, nor does it pretend to replace it. It is useful in some kind of screening (abdominal aortic aneurysm) and is of special interest in ultrasound-guided procedures (joint infiltration by injection). It allows to adapt the derivations, minimising the uncertainty, ruling out certain pathologies due to its high diagnostic precision. It can also lead to overdiagnosis, if the examinations carried out are not limited to the organs on which our clinical suspicion is based. Ultrasound is one tool more in the diagnostic process, but its use must be limited to certain clinical situations. Its use in early detection of prevalent diseases in Primary Care should be properly evaluated. On the other hand with more evidence of a high diagnostic accuracy in a large list of pathological conditions. PMID- 29609872 TI - Long-term trends in antithrombotic drug prescriptions among adults aged 80 years and over from primary care: a temporal trends analysis using electronic health records. AB - PURPOSE: This study aimed to estimate trends in antithrombotic prescriptions from 2001 to 2015 among people aged 80 years and over within clinical indications. METHODS: A prospective cohort study with 215,559 participants registered with the UK Clinical Practice Research Datalink from 2001 to 2015 was included in the analyses. The prevalence and incidence of antiplatelet and anticoagulant drugs were estimated for each year and by five clinical indications. RESULTS: The prevalence rate of antithrombotic prescriptions among patients aged over 80 years and diagnosed with atrial fibrillation increased from 53% in 2001 to 77% in 2015 (Ptrend <.001). Anticoagulant prescriptions rates also increased five-fold in older adults with atrial fibrillation from around 10% in 2001 to 46% in 2015 (Ptrend <.001). Clopidogrel-prescribing rates in patients aged over 80 years and with venous thrombosis increased from 0.4% in 2001 to 10% in 2015 (Ptrend <.001). Warfarin-prescribing rates in older patients with venous thrombosis increased from 13% in 2001 to 21% in 2015 (Ptrend <.001). CONCLUSIONS: The use of antithrombotic drugs increased from 2001 to 2015 in people aged 80 years and over across multiple clinical indications. Assessing the benefits and harms of antithrombotic drugs across different clinical indications in older people is a priority. PMID- 29609873 TI - Analogy in causal inference: rethinking Austin Bradford Hill's neglected consideration. AB - The purpose of this article was to rethink and resurrect Austin Bradford Hill's "criterion" of analogy as an important consideration in causal inference. In epidemiology today, analogy is either completely ignored (e.g., in many textbooks), or equated with biologic plausibility or coherence, or aligned with the scientist's imagination. None of these examples, however, captures Hill's description of analogy. His words suggest that there may be something gained by contrasting two bodies of evidence, one from an established causal relationship, the other not. Coupled with developments in the methods of systematic assessments of evidence-including but not limited to meta-analysis-analogy can be restructured as a key component in causal inference. This new approach will require that a collection-a library-of known cases of causal inference (i.e., bodies of evidence involving established causal relationships) be developed. This library would likely include causal assessments by organizations such as the International Agency for Research on Cancer, the National Toxicology Program, and the United States Environmental Protection Agency. In addition, a process for describing key features of a causal relationship would need to be developed along with what will be considered paradigm cases of causation. Finally, it will be important to develop ways to objectively compare a "new" body of evidence with the relevant paradigm case of causation. Analogy, along with all other existing methods and causal considerations, may improve our ability to identify causal relationships. PMID- 29609874 TI - [Detection of chronic kidney disease using estimated glomerular filtration and urine albumin: Are we complying with the recommendations of the guidelines?] PMID- 29609875 TI - SOCS-mediated immunomodulation of natural killer cells. AB - Natural killer (NK) cells are innate immune cells with an intrinsic ability to detect and kill infected and cancerous cells. The success of therapies targeting immune checkpoints on CD8 cells has intensified interest in harnessing the cytolytic effector functions of NK cells for new cancer treatments. NK cell development, survival and effector activity is dependent on exposure to the cytokine interleukin (IL)-15. The suppressor of cytokine (SOCS) proteins (CIS; SOCS1-7) are important negative regulators of cytokine signaling, and both CIS and SOCS2 are reported to have roles in regulating NK cell responses. Their immunomodulatory effects on NK cells suggest that these SOCS proteins are promising targets that can potentially form the basis of novel cancer therapies. Here we discuss the role of NK cells in tumor immunity as well as review the role of the SOCS proteins in regulating IL-15 signaling and NK cell function. PMID- 29609876 TI - Covert atrial fibrillation and atrial high-rate episodes as a potential cause of embolic strokes of undetermined source: Their detection and possible management strategy. AB - Cryptogenic ischemic stroke, defined as stroke of undetermined etiology, accounts for 7-25% of all ischemic strokes. Stroke severity is reported to be less severe than cardioembolic stroke and similar to large-artery atherosclerosis. Because its etiology is believed to be mostly an embolic type, it is often called "embolic strokes of undetermined source" (ESUS). In patients with ESUS, it is of significant importance to seek an embolic source with intensive diagnostic assessment, which mostly originates from the heart. Covert atrial fibrillation (AF) and atrial high-rate episodes (AHRE) detected by cardiac implantable electronic devices are believed to contribute to the pathogenesis of ESUS. AHRE is common not only in device-implanted patients, but also in older patients with cardiovascular risk factors. However, it is unclear whether AHRE is a direct cause or simply a risk marker of stroke. Furthermore, indication of anticoagulation therapy for stroke prevention in patients with AHRE remains undetermined. In this review, we focus on the roles of covert AF and AHRE in the pathogenesis of cryptogenic ischemic stroke or ESUS. Detection of covert AF and AHRE, and possible management strategies are also discussed. PMID- 29609877 TI - Impact of catheter ablation of atrial fibrillation on long-term clinical outcomes in patients with heart failure. AB - BACKGROUND: Heart failure (HF) promotes atrial fibrillation (AF) and AF worsens HF. This study aimed to investigate the long-term clinical outcomes after AF ablation in patients with HF. METHODS AND RESULTS: A total of 106 consecutive HF patients, including 51 (48.1%) with a reduced left ventricular ejection fraction (LVEF) (HFrEF) and 55 (51.9%) with a preserved LVEF (HFpEF), underwent AF ablation. All patients underwent successful pulmonary vein antrum isolation, and substrate modification was added in 38 (35.8%). The mean follow-up period was 32.4+/-18.6 months, and mean number of procedures was 1.4+/-0.5 per patient. Low dose antiarrhythmic drugs were combined in 29 (27.3%) patients. Freedom from recurrent atrial arrhythmias (ATa), HF-related hospitalizations, and the composite endpoint (all-cause death, stroke, HF-related hospitalizations) at 3 years was 88.7%, 97.6%, and 97.6% in HFrEF patients, and 79.3%, 96.2%, and 91.8% in HFpEF patients, respectively. LVEF normalization (>=50%) was observed in 37 (72.5%) HFrEF patients post-ablation, and a smaller LV diastolic diameter (LVDd) was the sole predictor [odds ratio (OR)=0.863; 95% confidence interval (CI)=0.779 0.955, p=0.005]. Shortening of the LVDd (>=5mm) was observed in 16 (29.1%) HFpEF patients post-ablation, and no recurrence after the initial procedure was the sole predictor (OR=6.229; 95% CI=1.524-25.469, p=0.011). CONCLUSIONS: Catheter ablation of AF could be one of the important therapeutic options in the management of patients with HF combined with AF regardless of the type of HF. PMID- 29609878 TI - A New Class of Antiretroviral Enabling Innate Immunity by Protecting APOBEC3 from HIV Vif-Dependent Degradation. AB - The infectivity of HIV depends on overcoming APOBEC3 (A3) innate immunity, predominantly through the expression of the viral protein Vif, which induces A3 degradation in the proteasome. Disruption of the functional interactions of Vif enables A3 mutagenesis of the HIV genome during viral replication, which can result in a broadly neutralizing antiviral effect. Vif function requires self association along with interactions with A3 proteins, protein chaperones, and factors of the ubiquitination machinery and these are described here as a potential platform for novel antiviral drug discovery. This Review will examine the current state of development of Vif inhibitors that we believe to have therapeutic and functional cure potential. PMID- 29609879 TI - Trends in Readmission Rates, Hospital Charges, and Mortality for Patients With Chronic Obstructive Pulmonary Disease (COPD) in Florida From 2009 to 2014. AB - PURPOSE: Chronic obstructive pulmonary disease (COPD) is a leading and costly cause of readmissions to the hospital, with one of the highest rates reported in Florida. From 2009 to 2014, strategies such as readmission reduction programs, as well as updated guidelines for COPD management, were instituted to reduce readmission rates for patients with COPD. Thus, the question has been raised whether COPD-related 30-day hospital readmission rates in Florida have decreased and whether COPD-related readmission costs during this period have changed. In addition, we examined trends in length of stay, hospital charges, and in-hospital mortality associated with COPD, as well as identified patient-level risk factors associated with 30-day readmissions. METHODS: A retrospective analysis of adult patients (>=18 years of age) with COPD was conducted by using the Healthcare Cost and Utilization Project Florida State Inpatient Database, 2009 to 2014. Weighted least squares regression was used to assess trends in the COPD readmission rate on a yearly basis, as well as other outcomes of interest. A multivariable logistic regression was used to identify patient characteristics that were associated with 30-day COPD readmissions. FINDINGS: Overall, 268,084 adults were identified as having COPD. Between 2009 and 2014, more than half of patients aged 65-84 years, most were white, 55% were female, and 73% had Medicare. The unadjusted rate for COPD-related 30-day readmissions did not change (8.04% to 7.85%; P = 0.434). However, the mean total charge for 30-day COPD-related readmissions was significantly higher in 2014 ($40,611) compared with that in 2009 ($36,714) (P = 0.011). The overall unadjusted in-hospital mortality of COPD related hospitalizations significantly decreased from 1.83% in 2009 to 1.34% in 2014 (P < 0.001). In a multivariable logistic regression model, patients with COPD were 2% less likely to be readmitted to the hospital for each additional year (odds ratio [OR], 0.98 [95% confidence interval (CI), 0.97-0.99]). Factors associated with significantly higher odds of COPD-related readmission were: older age (45 <= age <= 64 years; OR, 1.91 [95% CI, 1.70-2.14]), being male (OR, 1.14 [95% CI, 1.10-1.17]), and being a Medicaid beneficiary (OR, 1.28 [95% CI, 1.21 1.35]). IMPLICATIONS: Although the adjusted odds of COPD readmissions slightly decreased, as did the length of stay and all-cause in-patient mortality, the financial burden increased substantially. Future strategies to further reduce readmissions of patients with COPD and curb financial burden in Florida are needed. PMID- 29609880 TI - Progression-free Survival With First-line Endocrine-based Therapies Among Postmenopausal Women With HR+/HER2- Metastatic Breast Cancer:: A Network Meta analysis. AB - PURPOSE: The comparative efficacy of endocrine-based therapies (ETs) for hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC) is not well characterized. This network meta analysis (NMA) synthesized available evidence on progression-free survival (PFS) with first-line ETs for postmenopausal HR+/HER2- mBC. METHODS: A systematic literature review identified randomized controlled trials of first-line ETs. Pairwise hazard ratios and 95% credible intervals (CrIs) were obtained via a Bayesian NMA model. Subgroup NMAs were conducted among late progressors (disease free interval >=12 months from completion of [neo] adjuvant therapy with letrozole or anastrozole at the time of randomization) and de novo patients, defined as patients whose initial BC diagnosis is mBC. FINDINGS: Five trials and 5 regimens (ribociclib + an aromatase inhibitor [AI] [LEE + AI], palbociclib + AI [Pal + AI], fulvestrant 250 mg + AI [Ful250 + AI], fulvestrant 500 mg [Ful500], and AI) were selected. LEE + AI, Pal + AI, Ful250 + AI, and Ful500 had significantly longer PFS versus AI (95% CrI upper-bound <=1). LEE + AI had a 30% and 29%, and Pal + AI had a 31% and 30%, reduced hazard of progression or death versus Ful250 + AI and Ful500 (95% CrI upper-bound <=1), respectively. The probability of being the most efficacious was 46% for LEE + AI and 54% for Pal + AI. In subgroup analyses among late progressors, LEE + AI had a 4% reduced hazard of progression or death versus Pal + AI but was not statistically significant. In the de novo analysis, Pal + AI and LEE + AI had a 29% and 40% reduced hazard of progression or death versus Ful500, respectively, but were not statistically significant. In both subgroup analyses, all therapies had significantly longer PFS compared with AI. IMPLICATIONS: Pal + AI, LEE + AI, Ful250 + AI, or Ful500 as first-line treatment for HR+/HER2- mBC had longer PFS than AI alone. Given the lack of head-to-head clinical trials comparing the efficacy of recently approved first-line ETs for HR+/HER2- mBC, these results have important clinical implications for the treatment of HR+/HER2- mBC in the first-line setting. PMID- 29609881 TI - [Ketamine as an adjunct to bupivacaine in infra-orbital nerve block analgesia after cleft lip repair]. AB - OBJECTIVES: We conducted this study to investigate the safety and analgesic efficacy of the addition of Ketamine to Bupivacaine in bilateral extra-oral infra orbital nerve block in children undergoing cleft lip surgeries. METHODS: Sixty patients were randomly allocated into two groups (n=30), Group B received infra orbital nerve block with 2mL of 0.25% Bupivacaine and Group BK received 0.5mg.kg 1 Ketamine for each side added to 1mL of 0.5% Bupivacaine solution diluted up to 2mL solution to 0.25% Bupivacaine concentration. Assessment parameters included; hemodynamics, recovery time, time to first oral intake, postoperative Faces Legs Activity Cry Consolability (FLACC) scores, Four-point Agitation scores, analgesic consumption and adverse effects. RESULTS: Patients in Group BK showed lower postoperative FLACC scores during all recorded time points (p<0.0001). Two patients in Group BK versus 12 in Group B requested for postoperative rescue analgesia (p<0.001). There were no differences between groups in time, minutes (min), to first request for rescue analgesia. Patients in Group BK reported lower analgesic consumption (366.67+/-45.67 vs. 240.0+/-0.0mg, p<0.04). The time to first oral intake was significantly reduced in Group BK (87.67+/-15.41 vs. 27.33+/-8.68min, p<0.001). Lower postoperative Agitation scores were recorded in Group BK patients that reached a statistical significance at 45min (0.86+/-0.11 vs. 0.46+/-0.16, p<0.04) and in the first hour (h) postoperatively (1.40+/-0.17 vs. 0.67+/-0.14, p<0.003). Higher parent satisfaction scores were recorded in Group BK (p<0.04) without significant adverse effects. CONCLUSIONS: The addition of Ketamine to Bupivacaine has accentuated the analgesic efficacy of infra orbital nerve block in children undergoing cleft lip repair surgeries. PMID- 29609882 TI - [Enhanced recovery after surgery protocol versus conventional perioperative care in colorectal surgery. A single center cohort study]. AB - BACKGROUND: Enhanced recovery after surgery (ERAS) protocols consist of a set of perioperative measures aimed at improving patient recovery and decreasing length of stay and postoperative complications. We assess the implementation and outcomes of an ERAS program for colorectal surgery. METHODS: Single center observational study. Data were collected from consecutive patients undergoing open or laparoscopic colorectal surgery during 2 time periods, 3 years before (Pre-ERAS) and 2 years after (Post-ERAS) the implementation of an ERAS protocol. Baseline characteristics of both groups were compared. The primary outcome was the number of patients with 180 days follow-up with moderate or severe complications; secondary outcomes were postoperative length of stay, and specific complications. Data were extracted from patient records. RESULTS: There were 360 patients in the Pre-ERAS group and 319 patients in the Post-ERAS Group. 214 (59.8%) patients developed at least one complication in the pre ERAS group, versus 163 patients in the Post-ERAS group (51.10%). More patients in the Pre ERAS group developed moderate or severe complications (31.9% vs. 22.26%, p=0.009); and severe complications (15.5% vs. 5.3%; p<0.0001). The median length of stay was 13 (17) days in Pre-ERAS Group and 11 (10) days in the Post-ERAS Group (p=0.034). No differences were found on mortality rates (4.7% vs. 2.5%; p=0.154), or readmission (6.39% vs. 4.39%; p=0.31). Overall ERAS protocol compliance in the Post-ERAS cohort was 88%. CONCLUSIONS: The implementation of ERAS protocol for colorectal surgery was associated with a significantly reduction of postoperative complications and length of stay. PMID- 29609883 TI - Unilateral lung transplantation using intact bilateral upper lobes. PMID- 29609884 TI - Management of bilateral necrotizing bronchial dehiscence after a double lung transplantation. PMID- 29609885 TI - Institution of localized high-frequency electrical stimulation targeting early myocardial infarction: Effects on left ventricle function and geometry. AB - BACKGROUND: Although strategies have focused on myocardial salvage/regeneration in the context of an acute coronary syndrome and a myocardial infarction (MI), interventions targeting the formed MI region and altering the course of the post MI remodeling process have not been as well studied. This study tested the hypothesis that localized high-frequency stimulation instituted within a formed MI region using low-amplitude electrical pulses would favorably change the trajectory of changes in left ventricle geometry and function. METHODS: At 7 days following MI induction, pigs were randomized for localized high-frequency stimulation (n = 5, 240 bpm, 0.8 V, and 0.05 ms pulses) or unstimulated (n = 6). Left ventricle geometry and function were measured at baseline (pre-MI) and at 7, 14, 21, and 28 days post-MI using echocardiography. MI size at 28 days post-MI was determined by histochemical staining and planimetry. RESULTS: At 7 days post MI and before randomization to localized high-frequency stimulation, left ventricular ejection fraction and end-diastolic volume was equivalent. However, when compared with 7-day post-MI values, left ventricle end-diastolic volume increased in a time-dependent manner in the MI unstimulated group, but the relative increase in left ventricle end-diastolic volume was reduced in the MI localized high-frequency stimulation group. For example, by 28 days post-MI, left ventricle end-diastolic volume increased by 32% in the MI unstimulated group but only by 12% in the MI localized high-frequency stimulation group (P < .05). Whereas left ventricular ejection fraction appeared unchanged between MI groups, estimates of pulmonary capillary wedge pressure, a marker of adverse left ventricle performance and progression to failure, increased by 62% in the MI unstimulated group and actually decreased by 17% in the MI localized high frequency stimulation group when compared with 7-day post-MI values (P < .05). MI size was equivalent between the MI groups, indicative of no difference in the extent of absolute myocardial injury. CONCLUSIONS: The unique findings from this study are 2-fold. First, targeting the MI region following the resolution of the acute event using a localized stimulation approach is feasible. Second, localized stimulation modified a key parameter of adverse post-MI remodeling (dilation) and progression to heart failure. These findings demonstrate that the MI region itself is a modifiable tissue and responsive to localized electrical stimulation. PMID- 29609886 TI - Risk factors for reinsertion of urinary catheter after early removal in thoracic surgical patients. AB - OBJECTIVES: To reduce the incidence of urinary tract infection, Surgical Care Improvement Project 9 mandates the removal of urinary catheters within 48 hours postoperatively. In patients with thoracic epidural anesthesia, we sought to determine the rate of catheter reinsertion, the complications of reinsertion, and the factors associated with reinsertion. METHODS: We conducted a prospective observational study of consecutive patients undergoing major pulmonary or esophageal resection with thoracic epidural analgesia over a 2-year period. As per Surgical Care Improvement Project 9, all urinary catheters were removed within 48 hours postoperatively. Excluded were patients with chronic indwelling catheter, patients with urostomy, and patients requiring continued strict urine output monitoring. Multivariable logistic regression analysis was used to identify independent risk factors for urinary catheter reinsertion. RESULTS: Thirteen patients met exclusion criteria. Of the 275 patients evaluated, 60 (21.8%) required reinsertion of urinary catheter. There was no difference in the urinary tract infection rate between patients requiring reinsertion (1/60 [1.7%]) versus patients not requiring reinsertion (1/215 [0.5%], P = .389). Urethral trauma during reinsertion was seen in 1 of 60 patients (1.7%). After reinsertion, discharge with urinary catheter was required in 4 of 60 patients (6.7%). Multivariable logistic regression analysis found esophagectomy, lower body mass index, and benign prostatic hypertrophy to be independent risk factors associated with catheter reinsertion after early removal in the presence of thoracic epidural analgesia. CONCLUSIONS: When applying Surgical Care Improvement Project 9 to patients undergoing thoracic procedures with thoracic epidural analgesia, consideration to delayed removal of urinary catheter may be warranted in patients with multiple risk factors for reinsertion. PMID- 29609887 TI - Extracorporeal membrane oxygenation as a bridge to lung transplantation is about more than just surviving. PMID- 29609889 TI - Graft patency in diabetic patients and the discomfort of thought. PMID- 29609888 TI - Impact of hemodynamics and fluid energetics on liver fibrosis after Fontan operation. AB - OBJECTIVE: The staged Fontan procedure has shown promising short-term outcomes in patients with single ventricles. However, Fontan-associated liver disease is a marked problem as patients age. The purpose of this study is to investigate the relationship between hemodynamics and liver fibrosis in patients undergoing the Fontan. METHODS: A total of 33 patients undergoing the Fontan with liver fibrosis were included in this study. Cardiac magnetic resonance and phase-contrast cardiac magnetic resonance data, as well as catheterization measurements and liver biopsies, were obtained for each patient. Computational fluid dynamic simulations were performed to quantify total cavopulmonary connection hemodynamics using patient-specific anatomies and blood flow waveforms reconstructed from cardiac magnetic resonance data. Collagen deposition (as a measure of liver fibrosis) was quantified by digital image analysis of Sirius Red stained slides. Statistical analyses were performed to investigate potential relationships between liver fibrosis and Fontan hemodynamics. RESULTS: Liver fibrosis was found to be related to global metrics (inferior vena cava flow, ventricle power output) rather than to local total cavopulmonary connection hemodynamics and efficiency. Indexed inferior vena cava flow showed a significant, positive correlation with liver fibrosis (rho = 0.624, P < .001). Upper and lower Sirius Red tertile comparisons showed a significant difference in indexed inferior vena cava flow (P = .008). CONCLUSIONS: Significant increases in inferior vena cava flow consistent with fibrosis induced arterialization and ventricular power output suggest a burden being placed on the single ventricle from liver fibrosis. Local total cavopulmonary connection flow dynamics do not seem to influence the degree of fibrosis. Favorable total cavopulmonary connection hemodynamics may not be enough to overcome the power shortage and elevated venous pressures inherent to a Fontan circulation. PMID- 29609891 TI - Bentall procedure after previous aortic valve or complete root replacement: Usefulness of self-assembled aortic valve conduit. AB - OBJECTIVES: The aim of this study was to evaluate surgical results of complete aortic root replacement using self-assembled valve composite graft in the setting of destroyed aortic annulus after previous valve replacement. METHODS: Aortic root pathology being addressed by complete root replacement was combined with partial or complete absence of annular tissue in 112 consecutive patients. Eighty eight had undergone a previous replacement of the aortic valve and 24 had undergone root replacement with a valved conduit. Altogether, 31 patients (27.7%) presented with acute endocarditis, which was the indication for surgery in 75% of patients with prior root replacement. In all patients, the root replacement or re replacement was performed with a self-assembled valved conduit using mechanical (n = 74) or, in patients with an advanced age, biological (n = 38) valve prostheses. RESULTS: In-hospital mortality was 11.6%, including a 30-day mortality of 6.3%. Resternotomy for bleeding was necessary in 5.4% of patients and about one-quarter did not need any blood transfusion. Estimated survival at 1, 5, and 10 years was 84.8% +/- 3.4%, 75.7% +/- 4.3%, and 57.1% +/- 6.5%, respectively. Freedom from any valve-related events at 10 years was 86.2% +/- 4.1%. During the follow-up time (mean, 63 +/- 47 months), there was only 1 reoperation necessary 9 years after surgery (replacement of deteriorated biological valve prosthesis within the vascular tube leaving the conduit untouched). CONCLUSIONS: A self-assembled composite graft allows safe proximal fixation of the conduit in patients with destroyed aortic annulus, resulting in sufficient proximal anastomosis and a very low incidence of aorta-related reoperations. PMID- 29609890 TI - Increasing circulating sphingosine-1-phosphate attenuates lung injury during ex vivo lung perfusion. AB - BACKGROUND: Sphingosine-1-phosphate regulates endothelial barrier integrity and promotes cell survival and proliferation. We hypothesized that upregulation of sphingosine-1-phosphate during ex vivo lung perfusion would attenuate acute lung injury and improve graft function. METHODS: C57BL/6 mice (n = 4-8/group) were euthanized, followed by 1 hour of warm ischemia and 1 hour of cold preservation in a model of donation after cardiac death. Subsequently, mice underwent 1 hour of ex vivo lung perfusion with 1 of 4 different perfusion solutions: Steen solution (Steen, control arm), Steen with added sphingosine-1-phosphate (Steen + sphingosine-1-phosphate), Steen plus a selective sphingosine kinase 2 inhibitor (Steen + sphingosine kinase inhibitor), or Steen plus both additives (Steen + sphingosine-1-phosphate + sphingosine kinase inhibitor). During ex vivo lung perfusion, lung compliance and pulmonary artery pressure were continuously measured. Pulmonary vascular permeability was assessed with injection of Evans Blue dye. RESULTS: The combination of 1 hour of warm ischemia, followed by 1 hour of cold ischemia created significant lung injury compared with lungs that were immediately harvested after circulatory death and put on ex vivo lung perfusion. Addition of sphingosine-1-phosphate or sphingosine kinase inhibitor alone did not significantly improve lung function during ex vivo lung perfusion compared with Steen without additives. However, group Steen + sphingosine-1-phosphate + sphingosine kinase inhibitor resulted in significantly increased compliance (110% +/- 13.9% vs 57.7% +/- 6.6%, P < .0001) and decreased pulmonary vascular permeability (33.1 +/- 11.9 MUg/g vs 75.8 +/- 11.4 MUg/g tissue, P = .04) compared with Steen alone. CONCLUSIONS: Targeted drug therapy with a combination of sphingosine-1-phosphate + sphingosine kinase inhibitor during ex vivo lung perfusion improves lung function in a murine donation after cardiac death model. Elevation of circulating sphingosine-1-phosphate via specific pharmacologic modalities during ex vivo lung perfusion may provide endothelial protection in marginal donor lungs leading to successful lung rehabilitation for transplantation. PMID- 29609892 TI - Communication Skills Training for Surgical Residents: Learning to Relate to the Needs of Older Adults. AB - BACKGROUND: It is vital for physicians and surgeons to communicate successfully with older adults, who will constitute one-fifth of the US population by 2030. Older adults often perceive themselves as stigmatized and powerless in healthcare settings. Effective communication leads to better patient compliance and satisfaction, which is now a component of Medicare hospital reimbursement and physician and surgeon compensation from hospitals and networks. OBJECTIVE: To increase orthopaedic surgery resident understanding of the unique needs of older adults in order to maintain effective and sensitive communication with this vulnerable population. DESIGN: A two-part training program (ongoing for 8 years) comprised of: 1) small-group interactive didactic sessions on aging issues; and 2) workshop demonstrations given by the residents to a group of older adults, followed by a Question & Answer session. Residents were assessed using a 22-item pre-post questionnaire covering medical knowledge of aging, attitudes toward older adults, and personal anxiety about aging. Older adult participants were surveyed for perceptions of residents' sensitivity toward them. SETTING: Hospital for Special Surgery in New York City, a specialized urban academic center, with a 5-year Orthopedic Surgery Residency program. PARTICIPANTS: 70 PGY3 residents, for whom the program is a requirement, and 711 older adult participants recruited from a community convenience sample. RESULTS: Older adult participants: Of 711 participants, 672 (95%) responded; 96% strongly agreed/agreed that the residents had demonstrated sensitivity toward them. Residents: Of 70 residents, 35 (50%) were assessed. Mean knowledge scores increased significantly (p <= 0.001); five of nine attitude items (p <= 0.05) and one of four anxiety items improved significantly (p <= 0.001). CONCLUSIONS: Significant change was seen in residents' attitudes and anxiety levels toward older adults, attributes that are usually deep seated and hard to change. Residents moved along the Accreditation Council for Graduate Medical Education Milestones continuum for three core competencies. PMID- 29609893 TI - Evaluation of the Characteristics of a Workplace Assessment Form to Assess Entrustable Professional Activities (EPAs) in an Undergraduate Surgery Core Clerkship. AB - OBJECTIVE: Entrustable Professional Activities (EPAs) are explicit, directly observable tasks requiring the demonstration of specific knowledge, skills, and behaviors that learners are expected to perform without direct supervision once they have gained sufficient competence. Undergraduate level implementation of EPAs is relatively new. We examined the characteristics of a workplace assessment form (clinic card) as part of a formative programmatic assessment process of EPAs for a core undergraduate surgery rotation. DESIGN: A clinic card was introduced to assess progression towards EPA achievement in the clerkship curriculum phase. Students completing their core eight (8) week clerkship surgery rotation submitted at least 1 clinic card per week. We compiled assessment scores for the 2015 to 2016 academic year, in which EPAs were introduced, and analyzed relationships between scores and time, EPA, training site, and assessor role. We surveyed preceptors and students, and conducted a focus group with clinical discipline coordinators of all core rotations. SETTING: This study took place at the Faculty of Medicine, Memorial University in St. John's, Newfoundland, Canada. PARTICIPANTS: Third year medical students (n = 79) who completed their core eight (8) week surgery clerkship rotation during the 2015 to 2016 academic year, preceptors, and clinical discipline coordinators participated in this study. RESULTS: EPAs reflecting tasks commonly performed by students were more likely to be assessed. EPAs frequently observed during preceptor-student encounters had higher entrustment ratings. Most EPAs showed increased entrustment scores over time and no significant differences in ratings between teaching sites nor preceptors and residents. Survey and focus group feedback suggest clinic cards fostered direct observation by preceptors and promoted constructive feedback on clinical tasks. A binary rating scale (entrustable/pre-entrustable) was not educationally beneficial. CONCLUSIONS: The findings support the feasibility, utility, catalytic and educational benefits of clinic cards in assessing EPAs in a core surgery rotation in undergraduate medical education. PMID- 29609896 TI - Pediatric case of fatal necrotizing pneumonia due to Panton-Valentine leukocidin positive methicillin-resistant Staphylococcus aureus in Spain. PMID- 29609895 TI - Neonatal Transitions in Social Behavior and Their Implications for Autism. AB - Within the context of early infant-caregiver interaction, we review a series of pivotal transitions that occur within the first 6 months of typical infancy, with emphasis on behavior and brain mechanisms involved in preferential orientation towards, and interaction with, other people. Our goal in reviewing these transitions is to better understand how they may lay a necessary and/or sufficient groundwork for subsequent phases of development, and also to understand how the breakdown thereof, when development is atypical and those transitions become derailed, may instead yield disability. We review these developmental processes in light of recent studies documenting disruptions to early-emerging brain and behavior mechanisms in infants later diagnosed with autism spectrum disorder, shedding light on the brain-behavior pathogenesis of autism. PMID- 29609894 TI - Interpreting and Utilising Intersubject Variability in Brain Function. AB - We consider between-subject variance in brain function as data rather than noise. We describe variability as a natural output of a noisy plastic system (the brain) where each subject embodies a particular parameterisation of that system. In this context, variability becomes an opportunity to: (i) better characterise typical versus atypical brain functions; (ii) reveal the different cognitive strategies and processing networks that can sustain similar tasks; and (iii) predict recovery capacity after brain damage by taking into account both damaged and spared processing pathways. This has many ramifications for understanding individual learning preferences and explaining the wide differences in human abilities and disabilities. Understanding variability boosts the translational potential of neuroimaging findings, in particular in clinical and educational neuroscience. PMID- 29609897 TI - Increased Prostate Cancer Glucose Metabolism Detected by 18F-fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Localised Gleason 8-10 Prostate Cancers Identifies Very High-risk Patients for Early Recurrence and Resistance to Castration. AB - BACKGROUND: The accuracy of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) to stage prostate cancer (PCa) is limited. However, Gleason 8-10 PCa and more aggressive metastatic PCa have been shown to exhibit a higher glycolytic activity. OBJECTIVE: To evaluate the potential of intraprostatic FDG uptake to prognose Gleason 8-10 PCa patients prior to prostatectomy, based on tumour intrinsic biology. DESIGN, SETTING, AND PARTICIPANTS: FDG-PET/CT and a bone scan were performed as a staging procedure prior to prostatectomy in 148 consecutive patients diagnosed with PCa with a Gleason sum of >=8 at biopsy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The FDG-PET/CT images were blind reviewed. Lymph node (LN) metastasis and intraprostatic FDG uptake were systematically recorded, and correlated with the patients' clinicopathological characteristics. RESULTS AND LIMITATIONS: FDG PET/CT detected foci of intraprostatic FDG uptake in 66% of patients. An intraprostatic FDG uptake of maximum intraprostatic standardised uptake value (SUVmax) of >=4.6 was statistically significantly associated with a higher pathological Gleason >=8, extracapsular extension, seminal vesicle invasion, and pathological LN metastasis. In multivariate analysis, an intraprostatic SUVmax of >=4.6 was associated with a two-fold increased risk of biochemical recurrence in the year following surgery. Patients with an intraprostatic SUVmax of >=4.6 had estimated median biochemical recurrence-free survival (BFS) of 11.3mo compared with 49.5mo for those with a lower SUVmax. Finally, high intraprostatic FDG uptake was associated with shorter time to castration resistance following radical prostatectomy (RP). CONCLUSIONS: Preoperative intraprostatic FDG uptake is an integrator of adverse pathological prognostic factors, predicting BFS and castration resistance following RP in patients with a Gleason score >=8 PCa at biopsy. These results support the use of preoperative FDG-PET/CT as a tool to distinguish at diagnosis very high-risk Gleason 8-10 PCa patients in whom novel neoadjuvant or adjuvant therapies should be explored. PATIENT SUMMARY: This study shows that an increased use of glucose by prostate cancer cells detected by 18F fluorodeoxyglucose positron emission tomography molecular imaging can identify aggressive prostate cancers. PMID- 29609898 TI - Real-Time Pathophysiologic Correlates of Left Atrial Appendage Thrombus in Patients Who Underwent Transesophageal-Guided Electrical Cardioversion for Atrial Fibrillation. AB - Although current guidelines advocate using the CHA2DS2-VASc score to assess the risk of stroke in patients with atrial fibrillation (AF), compared with transesophageal echocardiography (TEE), its ability to predict left atrial appendage thrombus (LAAT) is limited. We studied 3,324 consecutive patients with sustained AF from our prospective registry of patients who underwent first-time TEE-guided electrical cardioversion (ECV) from May 2000 through March 2012. The association of CHA2DS2-VASc score or TEE risk factors with the occurrence of LAAT was analyzed. The mean (SD) age was 69 (12.5) years and 67% were men. LAAT was identified in 49 (1.5%) during pre-ECV TEE. Compared with patients without LAAT, those with LAAT had lower peak left atrial appendage emptying velocity (LAAEV) (17.2 +/- 8.5 vs 36.6 +/- 20.8; p <0.001) and left ventricular ejection fraction (LVEF) (39.9 +/- 17.6 vs 51.4 +/- 13.7; p <0.001); their CHA2DS2-VASc score also was higher, but the difference was not statistically significant (3.6 +/- 1.4 vs 3.2 +/- 1.6; p = 0.06). Multivariate logistic regression analysis identified an LVEF <=40% (adjusted odds ratio 2.48, 95% confidence interval 1.38 to 4.46), LAAEV 20.3 to 33.9 cm/s (odds ratio 12.19, 95% confidence interval 1.53 to 96.86), and LAAEV <=20.2 cm/s as independent predictors of LAAT. An LAAEV cut point of 20 cm/s and an LVEF <=40% were optimal for detecting LAAT (sensitivity 75% and 62%; specificity 77% and 75%; area under the curve 0.822 and 0.776, respectively). On follow-up, LAAT was an independent risk factor of subsequent ischemic stroke but did not influence survival. In conclusion, reduced LVEF and reduced LAAEV are important pathophysiologic correlates of left atrial appendage thrombogenesis and subsequent ischemic stroke in patients who underwent TEE guided ECV for AF. PMID- 29609899 TI - Creating a synergy effect: A cluster randomized controlled trial testing the effect of a tailored multimedia intervention on patient outcomes. AB - OBJECTIVE: Improving adherence is a challenge and multiple barriers are likely to explain non-adherence. These barriers differ per patient and over course of the regimen. Hence, personalized interventions tailored to the specific barriers are needed. In a theoretical and evidence-based Tailored Multimedia Intervention, technology (online preparatory assessment, text messaging) was used as an add-on to a tailored counseling session (learned during a communication skills training), with the expectation of synergistic effects. METHODS: A cluster randomized controlled trial was conducted in six hospitals, eight nurses and 160 chronic patients. Patient satisfaction with communication, beliefs about medication, self-efficacy and medication adherence were assessed at initiation of the treatment and after six months. RESULTS: Intervention effects were found for patient satisfaction with nurses' affective communication and self-efficacy at the initiation of treatment. The effect on self-efficacy remained after six months. CONCLUSION: By combining tailored counseling with technology, this intervention resulted in positive changes in important prerequisites of medication adherence. PRACTICAL IMPLICATIONS: Technology can contribute significantly to health care providers' ability to tailor information to the patients' needs. PMID- 29609900 TI - Prevalence of Mental Health Disorders in Geriatric U.S. Military Veterans. PMID- 29609902 TI - Preoperative arterial embolization of endobronchial glomus tumor before endoscopic removal. PMID- 29609901 TI - Perceived Treatment Status of Fluctuations in Parkinson Disease Impacts Suicidality. AB - OBJECTIVE: On/off motor fluctuations in Parkinson disease (PD) can be associated with extreme mood fluctuations and severe dysphoria. The impact of these affective symptoms may be overlooked in the treatment of motor fluctuations. Our goal was to examine the relationship between motor fluctuations, their treatment status, and suicidality in PD participants. METHODS: We analyzed data from the Methods of Optimal Depression Detection in Parkinson's Disease (MOOD-PD) study of 223 individuals with PD. Suicidality was measured using items from four depression scales: Hamilton Depression Rating Scale (HAM-D-17); Montgomery-Asberg Depression Rating Scale (MADRS); Inventory for Depressive Symptomatology (IDS-C); and the self-rated Beck Depression Inventory (BDI). Multivariable Poisson regression analyses tested whether self-reported motor fluctuations and their treatment status were associated with suicidality while controlling for recognized risk factors. RESULTS: Thirty-seven participants (16.6%) self-reported suicidality and 89 (39.5%) self-reported motor fluctuations, of whom 21 (23.6%) perceived their fluctuations as untreated. Participants reporting untreated motor fluctuations more frequently had a current depressive disorder (p < 0.001) and endorsed suicidality (p = 0.006) than participants with treated or no fluctuations. They also had significantly higher total scores on the HAM-D-17, MADRS, IDS-C, and BDI depression scales (p < 0.001 for each). Regression analyses showed significant associations between untreated motor fluctuations and higher scores on suicide questions extracted from the HAM-D-17, MADRS, and IDS-C (p < 0.01 for each). CONCLUSIONS: PD patients with untreated motor fluctuations are at increased risk for suicidal thoughts and should be monitored for mood changes as treatment is adapted. PMID- 29609903 TI - Transarterial chemoembolization (TACE) in the management of hepatocellular carcinoma: Results of a French national survey on current practices. AB - PURPOSE: To report current practices of transarterial chemoembolization (TACE) by interventional radiologists (IR) for hepatocellular carcinoma (HCC) through a French national survey. MATERIALS AND METHODS: An electronic survey was sent by e mail to 232 IRs performing TACE in 32 private or public centers. The survey included 66 items including indications for TACE, technical aspects of TACE, other locally available treatments for HCC, follow-up imaging and general aspects of interventional radiology practices. RESULTS: A total of 64 IRs (64/232; 27%) answered the survey. Each IR performed a mean of 49+/-45 (SD) TACE procedures per year. Marked variations in indications for TACE in HCC were observed. Six percent of IRs (4/64) treated only patients with Barcelona Clinic Liver Cancer (BCLC) stage B HCC. Antibioprophylaxis was not used by 43/64 of IRs (67%). The number of HCC nodules was considered to select conventional TACE versus drug-eluting beadsTACE (DEB-TACE) by 17/49 IRs (35%) followed by patient performance status and Child-Pugh score by 6/49 IRs (12%). Seventy-three percent of IRs (45/62) treated nodules selectively in patients with unilobar disease with cTACE. Thirty three percent of IRs (21/64) planned systematically a second TACE session. Doxorubicin was the most frequently used drug (52/64; 81%) and 15/64 IRs (23%) used gelatine sponge as the only embolic agent. For DEB-TACE, 100-300MUm beads were used by 26/49 IRs (53%) and no additional embolization was performed by 19/48 IRs (39%). Monopolar radiofrequency technique was widely available (59/63; 94%) compared to selective internal radiation therapy (37/64; 58%). Magnetic resonance imaging was used for follow-up by 13/63 IRs (20%). CONCLUSION: Current practices of TACE for HCC varied widely among IRs suggesting a need for more standardized practices. PMID- 29609904 TI - Translation, Adaptation, and Preliminary Validation of Dacakis and Davies' "Transsexual Voice Questionnaire (Male to Female)" in French. AB - : Transgender MtF people (trans women) consult otorhinolaryngologists and vocologists with the aim of feminizing their voice and being consistently perceived as women. Treatment of these trans women always begins with a vocal assessment that is relatively unspecific as it was originally constructed for individuals with dysphonia. OBJECTIVES: This study examines the subjective portion of the assessment and specifically the self-assessment questionnaire. There is no French-language questionnaire designed to identify the issues facing people who want voice feminization and quantify the impact of their voice disorder on their daily lives. We present a translation and adaption into French of the questionnaire developed by Dacakis et al [6]. METHODS: This work follows the World Health Organization recommendations [12] regarding translation. Thirty six Belgian and French trans women took part in this study. RESULTS: The results show excellent repeatability and reliability, while the construct validity measures show that the items correlate with six areas of concern for trans women identified by Davies and Johnson [7] in a previous study. The domains are the following: effect of voice on ease of social interaction, effect of voice on emotions, relationship between voice and gender identity, effort and concentration required to produce voice, physical aspects of voice production, and pitch. Concurrent validity could not be measured owing to lack of sufficiently detailed stories. CONCLUSION: The psychometric properties of the French version of the questionnaire are acceptable. The questionnaire can be used as is in daily clinical practice. PMID- 29609905 TI - Injectable Silk Protein Microparticle-based Fillers: A Novel Material for Potential Use in Glottic Insufficiency. AB - OBJECTIVES AND HYPOTHESIS: A novel, silk protein-based injectable filler was engineered with the intention of vocal fold augmentation as its eventual intended use. This injectable filler leverages the unique properties of silk protein's superior biocompatibility, mechanical tunability, and slow in vivo degradation to one day better serve the needs of otolaryngologists. This paper intends to demonstrate the mechanical properties of the proposed novel injectable and to evaluate its longevity in animal models. MATERIALS AND METHODS: Experimental. The mechanical properties of silk bulking agents were determined to characterize deformation resistance and recovery compared with commercially available calcium hydroxylapatite through rheologic testing. Fresh porcine vocal fold tissue was used for injectable placement to simulate the mechanical outcomes of native tissue after bulking procedures. In vivo subcutaneous rodent implantation examined immune response, particle migration, and volume retention. RESULTS: Porous, elastomeric silk microparticles demonstrate high recovery (>90% original volume) from compressive strain and mimic the native storage modulus of soft tissues (1-3 kPa). Injectable silk causes only a slight increase in porcine vocal fold stiffness immediately after injection (20%), preserving the native mechanics of bulked tissue. In the subcutaneous rat model, silk demonstrated biocompatibility and slow degradation, thus enabling host cell integration and tissue deposition. CONCLUSIONS: The presented novel silk injectable material demonstrates favorable qualities for a vocal fold injection augmentation material. An in vivo long-term canine study is planned. PMID- 29609906 TI - Heterogeneity of PD-L1 Expression Among the Different Histological Components and Metastatic Lymph Nodes in Patients With Resected Lung Adenosquamous Carcinoma. AB - INTRODUCTION: Programmed death-ligand 1 (PD-L1) expression using immunohistochemistry is approved by the US Food and Drug Administration to guide treatment with anti-programmed death-1/PD-L1 monoantibodies. However, intratumoral heterogeneity of PD-L1 expression and the accordance between primary and metastatic lesions remains unresolved. MATERIALS AND METHODS: PD-L1 expression was evaluated in tumor cells and tumor-infiltrating lymphocytes (TILs) of surgically resected lung adenosquamous carcinoma. Discrepancy of PD-L1 expression and cluster of differentiation 8-positive TILs of different histologic components was investigated. PD-L1 expression was also compared between primary tumor and nodal metastases. RESULTS: The study included a total of 72 lung adenosquamous carcinomas. Fifteen patients (20.8%) and 25 patients (34.7%) were positive for PD-L1 expression in adenomatous and squamous components respectively, with a cutoff value of 5%. We found that 57.8% of cases showed consistent PD-L1 expression in tumor cells in the different histological components at a cutoff of 1%, and 48.1% of cases were likewise consistent at a cutoff of 5%. In paired squamous components of metastatic nodes and primary lesions, 90% and 80% of cases of PD-L1 expression were consistent, at cutoffs of 1% and 5%, respectively. For the adenomatous component of tumor/metastasis pairs, 77.8% of cases at the 1% cutoff and 74.1% of cases at the 5% cutoff were consistent, partially attributed to the difference of predominant histologic patterns. CONCLUSION: PD-L1 expression showed discrepancy in different histological components within a tumor and consistency in paired histological type between tumor and metastases. Different pathological features might contribute to the heterogeneous PD-L1 expression in patients with non-small-cell lung cancer. PMID- 29609907 TI - Visual Acuity and the Evolution of Signals. AB - Acuity, the fineness with which sensory systems perceive and parse information, limits the information that organisms can extract from stimuli. Here, we focus on visual acuity (the ability to perceive static spatial detail) to discuss relationships between acuity and signal form and evolution. Research suggests that acuity varies by orders of magnitude across species, and that most animals have much lower acuity than humans. Thus, hypotheses regarding the function of spatial patterns must account for the acuity of relevant viewers. New data quantifying acuity in a range of taxa allow us to examine correlations between acuity and ecology, elucidate the selective forces that receiver acuity places on signal evolution, and examine how signals might appear to viewers with different acuities. PMID- 29609908 TI - Discovery of a quinoline-based phenyl sulfone derivative as an antitrypanosomal agent. AB - A series of natural products-based phenyl sulfone derivative and their property based analogues were investigated as potential growth inhibitors of Trypanosoma brucei. Trypanosoma brucei is a kinetoplastid protozoan parasite that causes trypanosomiasis. In this work, we found that nopol- and quinoline-based phenyl sulfone derivative were the most active and selective for T. brucei, and they were not reactive towards the active thiol of T. brucei's cysteine protease rhodesain. A thiol reactive variant of the quinoline-based phenyl sulfone was subsequently investigated and found to be a moderate inhibitor of rhodesain. The quinoline-based compound that is not reactive towards rhodesain can serve a template for phenotypic-based lead discovery while its thiol-active congener can serve as template for structure-based investigation of new antitrypanosomal agents. PMID- 29609910 TI - Comprehensive Assessment of Women's Sexual Arousal Requires Both Objective and Subjective Measurement. PMID- 29609909 TI - [Why is the morbidly obese patient at high risk of anesthetic complications?] AB - Obesity is often associated with obstructive sleep apnea (OSA), which increases the risk of intraoperative and postoperative complications. The role of preoperative screening of OSA is crucial, with adequate management based on continuous positive pressure before, during and after surgery. The obese patient is at risk of postoperative complications: difficult airway management, acute respiratory failure following extubation due to atelectasis and airway obstruction, added to morphine overdosing. Optimal management of difficult mask ventilation and intubation, protective ventilation, combined to the reduction of sedatives and analgesics and the sitting position as soon as possible with a postoperative monitoring should decrease the occurrence of complications. Cardiovascular risk is also increased in the obese patient. Preoperative screening of cardiovascular complications with appropriate therapy, combined to per- and postoperative hemodynamic optimization with a close monitoring allow to limit the cardiovascular risk. Drug dosing titration is fundamental due to unknown pharmacokinetic and pharmacodynamics properties in obese patients. Neuromuscular monitoring should always be used whenever neuromuscular blocking drugs are used, as depth of anaesthesia monitoring, especially when total intravenous anaesthesia is used in conjunction with neuromuscular blocking drugs. Appropriate prophylaxis against venous thromboembolism (VTE) after assessment of risk benefit ratio and early mobilisation are recommended since the incidence of venous thromboembolism is increased in the obese. PMID- 29609911 TI - Registries and Databases in Sexual Medicine: Utility? PMID- 29609912 TI - PDE5i and Cardiac Health: Why Are We Still Worried After So Many Years? PMID- 29609913 TI - The Effects of Partner Presence and Sexual Stimulation on the Appraisal of Vaginal Pressure and Sexual Arousal. AB - BACKGROUND: Sex research lacks experimental studies in which both partners participate in a laboratory procedure. This is relevant in the context of genital pain because painful vaginal sensations often occur in the presence of the partner. AIM: To examine the effects of partner presence, sexual stimulation, and vaginal pressure on the appraisal of vaginal sensations and sexual arousal, ultimately aiming to increase the ecologic validity of laboratory designs. METHODS: A community sample of 42 women and their male partners watched sexual and neutral films while separated or together. We induced gradually increasing vaginal pressure in the women using an intravaginal inflatable rubber balloon. OUTCOMES: Women reported on pleasant and painful vaginal pressure and perceived genital arousal. Men and women reported on subjective sexual arousal. We also examined whether these appraisals were moderated by relationship satisfaction. RESULTS: The appraisal of vaginal pressure varied as a function of relationship satisfaction. Less satisfied women reported more painful pressure than women who were highly satisfied and highly satisfied women appraised the pressure as more pleasant in the context of a sex film and in the presence (vs absence) of their partner. In men and women, although partner presence had a negative effect on subjective sexual arousal, the presence of the partner did increase women's perception of genital arousal when vaginal pressure was induced during a sex film, particularly when women felt highly satisfied with their relationship. Also, the effects on subjective sexual arousal were moderated by relationship satisfaction. For couples in which the woman was less satisfied, the induction of vaginal pressure resulted in higher subjective sexual arousal when the partner was absent compared with when he was present, whereas when the man felt less satisfied, partner presence had a positive effect on sexual arousal. CLINICAL IMPLICATIONS: Interventions need to focus on the importance of sexual arousal during vaginal pressure stimulation and the way this is shaped by partner and relationship variables. Our results indicate that enhancing the relationship climate is an important target of intervention. STRENGTHS AND LIMITATIONS: We did not include physical indices of genital arousal and did not use a clinical sample of women with genital pain. CONCLUSIONS: The appraisal of vaginal sensations and sexual arousal are context-dependent responses that vary as a function of partner presence and sexual stimulation. Including both partners in the laboratory setting is important to create more valid models on sexual responding. Dewitte M, Schepers J, Melles R. The Effects of Partner Presence and Sexual Stimulation on the Appraisal of Vaginal Pressure and Sexual Arousal. J Sex Med 2018;15:539-549. PMID- 29609914 TI - An Online Cross-Sectional Comparison of Women With Symptoms of Persistent Genital Arousal, Painful Persistent Genital Arousal, and Chronic Vulvar Pain. AB - BACKGROUND: Persistent genital arousal disorder (PGAD) is an understudied condition characterized by unwanted physiologic genital arousal in the absence of subjective sexual arousal. Markos and Dinsmore (Int J STD AIDS 2013;24:852-858) theorized that PGAD shares a number of similarities with vulvodynia (unexplained chronic vulvar pain [CVP]), including symptom characteristics and comorbidities. AIM: To compare medical histories, symptom characteristics, pain characteristics, and daily functioning among women with persistent genital pain (PGA) (n = 42), painful PGA (n = 37), and CVP (n = 42) symptoms. METHODS: An online cross sectional survey was conducted from October 2015 through April 2016. OUTCOMES: Self-report measures of symptoms, diagnosed medical conditions, pain characteristics (McGill Pain Questionnaire), catastrophizing (Pain Catastrophizing Scale), and daily functioning (Functional Status Questionnaire) were collected. RESULTS: All 3 groups reported similar medical diagnoses and high frequencies of other chronic pelvic pain conditions. Women in all 3 groups reported comparable ages at symptom onset and timing of symptom expression (ie, constant vs intermittent). Women in the 2 PGA groups reported significantly greater feelings of helplessness than women in the CVP group. Women in the painful PGA and CVP groups endorsed significantly more sensory terms to describe their symptoms compared with women in the PGA group, whereas women in the painful PGA group reported significantly more affective terms to describe their symptoms compared with women in the CVP group. Women in the 2 PGA groups reported that their symptoms interfered significantly with most areas of daily functioning. CLINICAL IMPLICATIONS: Given the similarities between PGA and CVP symptoms, women with PGA may benefit from similar assessment, treatment, and research approaches. STRENGTHS AND LIMITATIONS: Limitations of the present study include its sole use of self-report measures; the presence of PGA or CVP symptoms was not confirmed by clinical assessment. However, the anonymous design of the online survey could have resulted in a larger and more diverse sample. CONCLUSION: The results of this study provide some initial support for the conceptualization of persistent genital arousal as a subtype of genital paresthesias/discomfort. These results also further highlight the negative impact that PGA symptoms have on many domains of daily living and the need for further research on this distressing condition. Jackowich RA, Pink L, Gordon A, et al. An Online Cross-Sectional Comparison of Women With Symptoms of Persistent Genital Arousal, Painful Persistent Genital Arousal, and Chronic Vulvar Pain. J Sex Med 2018;15:558-567. PMID- 29609915 TI - Erratum. PMID- 29609916 TI - Impact of Marijuana Legalization in Colorado on Adolescent Emergency and Urgent Care Visits. AB - PURPOSE: Approximately 6%-8% of U.S. adolescents are daily/past-month users of marijuana. However, survey data may not reliably reflect the impact of legalization on adolescents. The objective was to evaluate the impact of marijuana legalization on adolescent emergency department and urgent cares visits to a children's hospital in Colorado, a state that has allowed both medical and recreational marijuana. METHODS: Retrospective review of marijuana-related visits by International Classification of Diseases codes and urine drug screens, from 2005 through 2015, for patients >= 13 and < 21 years old. RESULTS: From 2005 to 2015, 4,202 marijuana-related visits were identified. Behavioral health evaluation was obtained for 2,813 (67%); a psychiatric diagnosis was made for the majority (71%) of these visits. Coingestants were common; the most common was ethanol (12%). Marijuana-related visits increased from 1.8 per 1,000 visits in 2009 to 4.9 in 2015. (p = < .0001) CONCLUSIONS: Despite national survey data suggesting no appreciable difference in adolescent marijuana use, our data demonstrate a significant increase in adolescent marijuana-associated emergency department and urgent cares visits in Colorado. PMID- 29609917 TI - Chosen Name Use Is Linked to Reduced Depressive Symptoms, Suicidal Ideation, and Suicidal Behavior Among Transgender Youth. AB - PURPOSE: This study aimed to examine the relation between chosen name use, as a proxy for youths' gender affirmation in various contexts, and mental health among transgender youth. METHODS: Data come from a community cohort sample of 129 transgender and gender nonconforming youth from three U.S. cities. We assessed chosen name use across multiple contexts and examined its association with depression, suicidal ideation, and suicidal behavior. RESULTS: After adjusting for personal characteristics and social support, chosen name use in more contexts was associated with lower depression, suicidal ideation, and suicidal behavior. Depression, suicidal ideation, and suicidal behavior were lowest when chosen names could be used in all four contexts. CONCLUSION: For transgender youth who choose a name different from the one given at birth, use of their chosen name in multiple contexts affirms their gender identity and reduces mental health risks known to be high in this group. PMID- 29609918 TI - Treatment outcomes and predicting factors for diabetic macular edema treated with ranibizumab - One-year real-life results in Taiwan. AB - PURPOSE: To report the one-year outcomes of diabetic macular edema (DME) treated with ranibizumab under a real-life setting in Taiwan, and to identify the prognostic factors. METHODS: Between July 2013 and January 2015, 119 eyes receiving intravitreal ranibizumab for DME were retrospectively recruited. Best corrected visual acuity (BCVA) and central foveal thickness (CFT) measured with optical coherence tomography were collected at baseline and at Month 3, 6, and 12. Linear regression was used to identify the predicting factors for changes in BCVA and CFT at Month 12. RESULTS: The average number of ranibizumab given within one year was 4.36 +/- 1.87. The BCVA (logMAR) improved from 0.74 +/- 0.30 at baseline to 0.64 +/- 0.37 at Month 12 (p = 0.002). A better improvement in BCVA at Month 3 was significantly correlated with a better visual improvement at Month 12 (p < 0.001). The existence of subretinal fluid at baseline (p = 0.02) and a greater reduction in CFT at Month 3 (p < 0.001) were both correlated with a greater reduction in CFT at Month 12. Previous subtenon injection of triamcinolone acetonide was associated with fewer additional IVR after Month 3 (odds ratio = 0.35, 95% CI = 0.14-0.89). CONCLUSION: Compared with existing prospective studies, the one-year real-life data in Taiwan showed fewer ranibizumab injections for DME and a less prominent yet still significant visual improvement. Both visual and anatomical improvements at Month 3 were correlated with the level of improvements at Month 12. Previous subtenon steroid injection might reduce the need of additional ranibizumab injections. PMID- 29609919 TI - Response to three Letters to the Editor regarding: Donahue JG, et al. "Association of spontaneous abortion with receipt of inactivated influenza vaccine containing H1N1pdm09 in 2010-11 and 2011-12". Vaccine 35 (2017) 5314 5322. PMID- 29609920 TI - The effect of self-selected complementary therapies on cancer patients' quality of life and symptom distress: A prospective cohort study in an integrative oncology setting. AB - OBJECTIVE: To examine the effectiveness of a multifaceted complementary therapies intervention, delivered in a systematic manner within an Australian public hospital setting, on quality of life and symptom distress outcomes for cancer patients. METHODS: Adults receiving treatment for any form of cancer were eligible to participate in this study. Self-referred participants were offered a course of six complementary therapy sessions. Measures were administered at baseline, and at the third and sixth visit. The primary outcomes were quality of life and symptom distress. Linear mixed models were used to assess change in the primary outcomes. RESULTS: In total, 1376 cancer patients participated in this study. The linear mixed models demonstrated that there were significant improvements in quality of life and significant reductions in symptom distress over six sessions. Body-based therapies demonstrated significantly superior improvement in quality of life over counselling, but no other differences between therapies were identified. Reduced symptom distress was not significantly associated with any particular type of therapy. CONCLUSION: A self-selected complementary therapies intervention, provided in an Australian public hospital by accredited therapists, for cancer patients significantly mproved quality of life and reduced symptom distress. The effect of this intervention on quality of life has particular salience, since cancer impacts on many areas of people's lives and impairs quality of life. PMID- 29609921 TI - A comparison of the cardiovascular effects of simulated and spontaneous laughter. AB - OBJECTIVES: Laughter has long been regarded as beneficial for health, but the mechanisms are not clearly understood. The current study aimed to compare the acute cardiovascular effects of spontaneous and simulated laughter. DESIGN: A mixed factorial experiment was performed to examine changes in cardiovascular variables in response to experimental tasks across conditions. INTERVENTIONS: A sample of 72 participants were randomised to one of three 6 min interventions. Participants in the simulated laughter condition were asked to generate fake laughter, the spontaneous laughter condition viewed a humorous video, and the control condition watched a non-humorous documentary. This was followed by a laboratory stress task. MAIN OUTCOMES MEASURES: Heart rate and heart rate variability (as indexed by rMSSD) were monitored continuously throughout the experiment using ECG. RESULTS: The simulated laughter condition had a significantly higher heart rate (p < .001, etap2 = .26) and lower rMSSD (p < .001, etap2 = .13) during the laughter task compared to the other two conditions. Follow-up hierarchical regressions indicated that the difference in heart rate was due to the fact that the simulated condition produced more laughter. The difference in rMSSD, however, was unique to the simulated condition even when controlling for the amount of laughter. The simulated laughter condition had a significantly lower mean HR during the stress task but this was not significant after controlling amount of laughter produced. CONCLUSIONS: Laughter leads to increased heart rate and reduced heart rate variability, which is similar to the effects of exercise. This finding is more pronounced in simulated laughter. PMID- 29609922 TI - An investigation into the use of recorded music as a surgical intervention: A systematic, critical review of methodologies used in recent adult controlled trials. AB - CONTEXT: While music is being increasingly used as a surgical intervention, the types of music used and the reasons underlying their selection remain inconsistent. Empirical research into the efficacy of such musical interventions is therefore problematic. OBJECTIVE: To provide clear guidelines for musical selection and employment in surgical interventions, created through a synthesis of the literature. The aim is to examine how music is implemented in surgical situations, and to provide guidance for the selection and composition of music for future interventions. METHODS: English language quantitative surgical intervention studies from Science Direct, ProQuest, and Sage Journals Online, all published within the last 10 years and featuring recorded music, were systematically reviewed. Variables investigated included: the time the intervention was performed, the intervention length, the outcomes targeted, music description (general and specific), theoretical frameworks underlying the selection of the music, whether or not a musical expert was involved, participant music history, and the participants' feedback on the chosen music. RESULTS: Several aspects contribute to the lack of scientific rigour regarding music selection in this field, including the lack of a theoretical framework or frameworks, no involvement of musical experts, failure to list the music tracks used, and the use of vague and subjective terms in general music descriptions. Patients are frequently allowed to select music (risking both choosing music that has an adverse effect and making study replication difficult), and patient music history and listening habits are rarely considered. Crucially, five primary theoretical frameworks underlying the effectiveness of music arose in the literature (distraction, relaxation, emotional shift, entrainment, and endogenous analgesia), however music was rarely selected to enhance any of these mechanisms. CONCLUSIONS: Further research needs to be conducted to ensure that music is selected according to a theoretical framework and more rigorous and replicable methodology. Music interventions can be made more effective at improving psychological states and reducing physiological arousal by selecting music conducive to specific mechanisms, and also by considering at what point during the surgical experience the music would be most effective. Greater involvement of music experts in interventions would help to ensure that the most appropriate music was chosen, and that it is clearly and precisely described. PMID- 29609923 TI - Evaluation on clinical efficacy of Fuzheng Jiedu Huayu Decoction combined with antibiotics in the treatment of pneumonia in the elderly - A multi-center, double blind, parallel, randomized controlled trial. AB - OBJECTIVE: To evaluate the efficacy and safety of Fuzheng Jiedu Huayu Decoction (FJHD) in treating pneumonia in the elderly. METHODS: Adopting a multi-center, double-blind, parallel, randomized controlled trial, 284 elderly pneumonia patients were enrolled and randomly allocated to the standard treatment with FJHD (treatment group, TG) and the standard treatment with placebo group (control group, CG). Efficacy and safety was evaluated through mortality rate, curative rate, symptom improvement, chest X-ray (CXR) lesion absorption, arterial blood gas (ABG), peripheral blood leukocyte count (PBLC) and adverse events. RESULTS: There was no significant difference in mortality rate between both groups (P > 0.05). TG significantly enhanced the curative rate of a 2-week treatment course (P < 0.05). Compared with CG, TG significantly decreased the expectoration score during the first and second week of treatment (P < 0.05). During the first week, improvement in expectoration was conducive to airway patency. During the second week, wheezing, shortness of breath and other symptoms were also significantly improved. During the third week, body temperature was stable. TG improved lesion absorption with Pneumonia Severity Index (PSI) class II (P < 0.05) and SMART-COP score 1 (P < 0.05). TG significantly decreased the arterial carbon dioxide partial pressure after a 1-week treatment. There were no serious adverse events in TG. CONCLUSION: Standard anti-infection treatment with FJHD is a safe and reliable method of treating elderly patients with pneumonia, improving the curative effect after a 2-week treatment course, ameliorating expectoration and promoting the absorption of pneumonia lesions. PMID- 29609924 TI - Medicinal plants for primary dysmenorrhoea: A systematic review. AB - OBJECTIVES: Primary dysmenorrhoea is a common complaint experienced by many females in their reproductive years. The use of medicinal plants in the treatment of various gynaecological conditions is on the increase, despite the limited evidence available regarding efficacy and safety of their use. The aim of this systematic review was to synthesise the most recent evidence relating to the treatment of primary dysmenorrhoea with medicinal plants. METHODOLOGY: A thorough database search was conducted using defined search terms, and randomised controlled trials (RCTs) published in English between 2008 and 2016, pertaining to the use of medicinal plants (single use) for the treatment of primary dysmenorrhoea, were assessed. Studies evaluating dysmenorrhoeal pain and associated symptoms as a primary or secondary outcome were considered and assessed by two reviewers independently of each other, using the JADAD scale and the Cochrane risk of bias tool,. RESULTS: 22 RCTs were included in the review; 9 were placebo-controlled trials and 13 were comparative studies to pharmacological treatment or nutritional supplements. Most of the evaluated medicinal plants showed evidence of efficacy in relieving menstrual pain in at least one RCT. The low or unclear quality of the majority of these studies however warrants caution in interpreting these results. CONCLUSION: This review adds to the knowledge-base on the use of these medicinal plants in the treatment of primary dysmenorrhoea. Further research is needed before definitive conclusions can be made regarding the efficacy and safety of the use of these medicinal plants. PMID- 29609925 TI - Complementary and integrative medicine attitudes and perceived knowledge in a large pediatric residency program. AB - OBJECTIVE: There is limited formal complementary and alternative medicine (CAM)/integrative medicine (IM) training in most US pediatric residency programs. Not surprisingly, the AAP Fellows survey #49 demonstrated that pediatricians in residency training and those younger than 42 years old reported less knowledge of CAM than their counterparts. The purpose of this study was to assess pediatric residents' attitudes toward CAM and IM, personal use of CAM, perceived knowledge gaps, and preferred methods of delivery for IM education in a large pediatric residency program. METHODS: A 20-question anonymous, voluntary electronic survey was sent to all categorical and combined program pediatric residents at a pediatric residency program in Texas. RESULTS: Eighty of 177 pediatric residents completed the survey. Eighty-three percent of respondents reported that patients have asked them about complementary and integrative medicine, and 88% reported that they would like to expand their knowledge on CAM/IM. Lack of knowledge was the top barrier to residents' incorporation of complementary and integrative medicine into their practice. Preferred methods of education delivery were reported as exposure to complementary and integrative medicine providers and noon conference lectures. CONCLUSIONS: Residents in this large pediatric residency program recognize their knowledge gaps and wish to improve their understanding of complementary and integrative medicine. A formal IM curriculum could bridge knowledge gaps and help residents feel more comfortable discussing IM with patients and their families. PMID- 29609926 TI - A randomized controlled dosing study of Iyengar yoga and coherent breathing for the treatment of major depressive disorder: Impact on suicidal ideation and safety findings. AB - BACKGROUND: Yoga interventions offer promise for the treatment of major depressive disorder (MDD), yet their safety and potential impact on suicidal ideation (SI) have not been well documented. This study evaluated the safety of a randomized controlled dose-finding trial of Iyengar yoga plus coherent breathing for individuals with MDD, as well as the potential effects of the intervention on SI without intent. METHODS: Participants with Beck Depression Inventory-II (BDI II) scores >=14 and a diagnosis of MDD (using DSM-IV criteria) were randomized to either a low dose group (LDG) or high dose group (HDG) and received a 12-week manualized intervention. The LDG included two 90-min yoga classes plus three 30 min homework sessions weekly. The HDG offered three 90-min classes plus four 30 min homework sessions weekly. RESULTS: Thirty-two individuals with MDD were randomized, of which 30 completed the protocol. At screening, SI without intent was endorsed on the BDI-II by 9 participants; after completing the intervention, 8 out of 9 reported resolution of SI. There were 17 adverse events possibly related and 15 definitely-related to the intervention. The most common protocol related adverse event was musculoskeletal pain, which resolved over the course of the study. CONCLUSIONS: The Iyengar yoga plus coherent breathing intervention was associated with the resolution of SI in 8 out of 9 participants, with mild side effects that were primarily musculoskeletal in nature. This preliminary evidence suggests that this intervention may reduce SI without intent and be safe for use in those with MDD. PMID- 29609927 TI - Complementary and alternative medicine for rheumatic diseases: A systematic review of randomized controlled trials. AB - OBJECTIVES: To summarize all good quality randomized controlled trials (RCTs) using complementary and alternative medicine (CAM) interventions in patients with rheumatic diseases. METHODS: A systematic literature review guided by the Preferred Reporting Items for Systematic review and Meta-Analysis (PRISMA) was performed. We excluded non-English language articles and abstract-only publications. Due to the large number of RCTs identified, we only include "good quality" RCTs with Jadad score of five. RESULTS: We identified 60 good quality RCTs using CAM as intervention for patients with rheumatic diseases: acupuncture (9), Ayurvedic treatment (3), homeopathic treatment (3), electricity (2), natural products (31), megavitamin therapies (8), chiropractic or osteopathic manipulation (3), and energy healing therapy (1). The studies do not seem to suggest a particular type of CAM is effective for all types for rheumatic diseases. However, some CAM interventions appear to be more effective for certain types of rheumatic diseases. Acupuncture appears to be beneficial for osteoarthritis but not rheumatoid arthritis. For the other therapeutic modalities, the evidence base either contains too few trials or contains trials with contradictory findings which preclude any definitive summary. There were only minor adverse reactions observed for CAM interventions presented. CONCLUSION: We identified 60 good quality RCTs which were heterogenous in terms of interventions, disease, measures used to assess outcomes, and efficacy of CAM interventions. Evidence indicates that some CAM therapies may be useful for rheumatic diseases, such as acupuncture for osteoarthritis. Further research with larger sample size is required for more conclusive evidence regarding efficacy of CAM interventions. PMID- 29609928 TI - Complementary and alternative medicine utilisation for the management of acute respiratory tract infection in children: A systematic review. AB - INTRODUCTION: As many as one in two children across the globe use complementary and alternative medicine (CAM) to manage a health condition. Despite the high prevalence of use, there is still limited information on the types of CAM used in children, particularly for the management of one of the most common childhood health complaints - acute respiratory tract infection (ARTI). This systematic review was undertaken to address this knowledge gap. METHODS: Eligible studies reporting the use of CAM in children with ARTI were identified using a targeted search of seven electronic databases and the grey literature. Data were extracted using a customised data extraction form and appraised using the McMaster critical review forms for quantitative and qualitative studies. Findings were synthesised in narrative form. RESULTS: The search identified 2261 papers, of which 22 studies were eligible for inclusion. The 22 studies reported the use of 118 distinct CAM interventions for the management of ARTI in children. Most (53%, n = 63) of these interventions represented biologically-based therapies, followed by whole medical systems/alternative medical systems (46%, n = 55). No studies reported the use of energy therapies, or manipulative and body-based methods, or mind-body therapies. CONCLUSION: A diverse range of CAM interventions are used in the management of ARTI in children. These interventions largely represent CAM use in the southern region of Asia - India, Pakistan and Bangladesh. Further research is needed to better understand the types of CAM used among children with ARTI in western countries. PMID- 29609929 TI - Red Yeast Rice (RYR) supplementation in patients treated with second-generation antipsychotics. AB - OBJECTIVE: Second-generation antipsychotics (SGAs) have a negative impact on metabolic syndrome (MetS) risk factors for their effects on body weight and on metabolic parameters. Statins are widely used in the treatment of dyslipidemia; less is known on the ability of statins to treat SGAs-induced dyslipidemia, and nutraceutical approaches may represent promising strategies in SGAs-treated patients. Red Yeast Rice (RYR), the fermented product of the Aspergillaceae mold Monascus purpureus (red yeast) grown on white rice, has been shown to have a cholesterol-lowering effect which can be ascribed to monacolin K, although other active compounds may play a role management of hyperlipidemia. The present study was aimed to explore the efficacy and safety of RYR treatment on clinical and metabolic parameters in a sample of subjects receiving SGAs. METHODS: Fifteen outpatients treated with SGAs assumed RYR at the oral daily dose of 200 mg/day (total monacolin K = 11.88 mg) for 30 days. Fasting levels of triglycerides, total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol and glucose were determined. RESULTS: RYR administration resulted in a statistically significant reduction of LDL (p = 0.029), corresponding to 11.0% decrease from baseline mean value. No significant differences in clinical and in other and metabolic parameters were observed. CONCLUSIONS: Our findings suggest that RYR, at the daily dose of 200 mg for 30 days, could be a promising agent to prevent and/or treat SGAs-induced hyperlipidemia. However, future adequately powered and well-designed studies with long-term follow-up should evaluate RYR effectiveness, as an alternative option to statins, on the SGAs-induced metabolic side effects. PMID- 29609930 TI - A pilot study: Horticulture-related activities significantly reduce stress levels and salivary cortisol concentration of maladjusted elementary school children. AB - The effects of three horticulture-related activities (HRAs), including floral arranging, planting, and flower pressing were compared to see if they influenced changes on a stress scale and on salivary cortisol concentrations (SCC) in maladjusted elementary school children. Twenty maladjusted elementary school children were randomly assigned either to an experimental or control group. The control group carried out individual favorite indoor activities under the supervision of a teacher. Simultaneously, the ten children in the experimental group participated in a HRA program consisting of flower arrangement (FA), planting (P), and flower pressing (PF) activities, in which the other ten children in the control group did not take part. During nine sessions, the activities were completed as follows: FA-FA-FA, P-P-P, and PF-PF-PF; each session lasted 40 min and took place once a week. For the quantitative analysis of salivary cortisol, saliva was collected from the experimental group one week before the HRAs and immediately after the activities for 9 consecutive weeks at the same time each session. In the experimental group, stress scores of interpersonal relationship, school life, personal problems, and home life decreased after the HRAs by 1.3, 1.8, 4.2, and 1.3 points, respectively. In particular, the stress score of school life was significantly reduced (P < 0.01). In addition, from the investigation of the SCCs for the children before and after repeating HRAs three times, it was found that flower arrangement, planting, and flower pressing activities reduced the SCCs by >=37% compared to the SCCs prior to taking part in the HRAs. These results indicate that HRAs are associated with a reduction in the stress levels of maladjusted elementary school children. PMID- 29609931 TI - Development and inter-rater reliability of a tool assessing hypnotic communication behaviours adopted by nurses caring for children with cancer: The Sainte-Justine Hypnotic Communication Assessment Scale. AB - BACKGROUND: Several studies in pediatric oncology have shown the successful effects of using hypnotic communication techniques (HCTech) during painful medical procedures. Since no studies assessed the precise use of these techniques with a validated tool, it is unsure that the observed relationships involve the use of HCTech. OBJECTIVES: To develop a scale evaluating healthcare professionals' behaviours when using HCTech and to evaluate its inter-rater reliability. METHODS: This study involved the preliminary steps of the Sainte Justine Hypnotic Communication Assessment Scale (SJ-HCAS) development process. As part of a larger intervention study, the SJ-HCAS was developed in three steps by five experts and four lay raters using an iterative process applied to subsets of video-recorded nurse-patient interactions. The development aimed to maximize clarity and precision of items as well as minimize redundancy amongst items. Inter-rater reliability was assessed in a randomly selected sample of 1/3 of collected video-recorded interactions (n=42). RESULTS: The final version of the scale is composed of 11 items categorized in two domains pertaining to Relationship and Technique. We found excellent inter-rater reliability for both subscores and total score in two independent inter-rater comparisons (median ICC=0.879), with most items showing very good to perfect inter-rater reliability (median Kappa=0.847). CONCLUSIONS: The results support further work with the SJ HCAS. The scale has the potential to help ensure the integrity of hypnotic communication training in children which could ultimately promote the dissemination of the practice of HCTech. PMID- 29609932 TI - Corrigendum to "Short-term effect of add on bell pepper (Capsicum annuum var. grossum) juice with integrated approach of yoga therapy on blood glucose levels and cardiovascular functions in patients with type 2 diabetes mellitus: A randomized controlled study." [Comp. Ther. Med. 34 (2017) 42-45]. PMID- 29609933 TI - Is hypnotherapy an acceptable treatment option for children with habit cough? AB - Habit cough is a chronic, persistent dry cough which occurs in children only when awake. It is considered functional (non-organic) and can have a significant impact on the quality of life of the child and their family. One possible treatment option for habit cough is hypnotherapy. At our centre we offered hypnotherapy sessions to patients diagnosed with habit cough, and conducted telephone interviews with patients' parents to determine the acceptability of this therapy. Nine patients' parents were interviewed, and despite being unsure of what to expect with hypnotherapy, all nine found it an acceptable treatment option. Parents reported that hypnotherapy appeared to result in cough reduction or cessation in 6 out of 9 cases. PMID- 29609934 TI - Developing evaluation scales for horticultural therapy. AB - OBJECTIVES: This study developed evaluation scales for measuring the effects of horticultural therapy in practical settings. DESIGN: Qualitative and quantitative research, including three preliminary studies and a main study, were conducted. SETTING: In the first study, a total of 779 horticultural therapists answered an open-end questionnaire based on 58 items about elements of occupational therapy and seven factors about singularity of horticultural therapy. In the second study, 20 horticultural therapists participated in in-depth interviews. In the third study, a Delphi method was conducted with 24 horticultural therapists to build a model of assessment indexes and ensure the validity. In the final study, the reserve scales were tested by 121 horticultural therapists in their practical settings for 1045 clients, to verify their reliability and validity. MAIN OUTCOME MEASURES: Preliminary questions in the effects area of horticultural therapy were developed in the first study, and validity for the components in the second study. In the third study, an expert Delphi survey was conducted as part of content validity verification of the preliminary tool of horticultural therapy for physical, cognitive, psychological-emotional, and social areas. In the final study, the evaluation tool, which verified the construct, convergence, discriminant, and predictive validity and reliability test, was used to finalise the evaluation tool. RESULTS: The effects of horticultural therapy were classified as four different aspects, namely, physical, cognitive, psycho emotional, and social, based on previous studies on the effects of horticultural therapy. 98 questions in the four aspects were selected as reserve scales. The reliability of each scale was calculated as 0.982 in physical, 0.980 in cognitive, 0.965 in psycho-emotional, and 0.972 in social aspects based on the Cronbach's test of intra-item internal consistency and half reliability of Spearman-Brown. CONCLUSIONS: This study was the first to demonstrate validity and reliability by simultaneously developing four measures of horticultural therapy effectiveness, namely, physical, cognitive, psychological-emotional, and social, both locally and externally. It is especially worthwhile in that it can be applied in common to people. PMID- 29609935 TI - Efficacy and safety of Vernonia cinerea (L.) Less. for smoking cessation: A systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND & OBJECTIVE: Several randomized controlled trials have investigated Vernonia cinerea (L.) Less. for smoking cessation but there remains no critical summary of overall findings. This study uses systematic review and meta-analysis to summarize the efficacy and safety of V. cinerea. METHODS: Nine databases were searched through November 2017. Randomized controlled trials that reported the smoking cessation effect of V. cinerea were included. Data were extracted by two independent researchers. Study quality was assessed using the Cochrane risk of bias and JADAD score. The estimates of pooled effects were calculated as relative risk (RR) with 95% CI using a random-effects model. RESULTS: Five trials with 347 smokers were included. V. cinerea treatment group was significantly associated with cessation rate higher than that in the control group with no evidence of heterogeneity for both continuous abstinence rate (CAR) at week 8 with risk ratio (RR): 1.69, 95% CI [1.00, 2.86]; week 12 RR: 2.18, 95% CI [1.17, 4.04]) and 7-day point prevalence abstinence rate (PAR) (week 8 RR: 1.51, 95% CI [1.01, 2.27]; week 12 RR: 1.93, 95% CI [1.24, 2.99]) at week 8 and 12, respectively. There was no significant difference of all adverse events between the treatment and the control groups. CONCLUSION: Our study demonstrates that V. cinerea has potential efficacy for smoking cessation. Further well-design RCTs of standardized V. cinerea compared with standard treatment should be conducted to strengthen this evidence. PMID- 29609936 TI - Rationale for routine collection of patient reported outcomes during integrative medicine consultation visits. AB - OBJECTIVES: Integrative medicine (IM) is whole-person care utilizing complementary health approaches to address numerous physical or emotional influences that can impact an individual's health. Patient-reported outcomes (PRO) are subjective measures that quantify patients' perception of their quality of life. While PRO measures have been routinely assessed in specific oncology clinics, our objective was to assess the ability and utility of routine collection of PRO measures in an IM clinic. DESIGN/SETTING/MAIN OUTCOME: Patients receiving a clinical consultation in an ambulatory IM clinic completed the PROMIS Global Health Form in the clinic waiting room. RESULTS: From November 2013 through October 2016, the PROMIS Global Health Form (PROMIS-10) was administered during 59% of IM provider consultation visits (7172/12,207), representing 3473 unique patients. Most patients were female (81%), White (93%), middle-aged (49.2; SD 15.4) and had commercial health insurance (66%). Baseline Mental (44.9; SD 9.1) and Physical Health (44.2; SD 8.6) scores were roughly 0.5 standard deviation below the national mean values (50; SD 10). Factors such as age, race and non-commercial insurance were associated with lower PROMIS-10 scores. Patients completing at least two PROMIS-10 questionnaires (n = 1541) exhibited increases of 2.3% and 2.8% from first to last PROMIS-10 assessment in Mental and Physical Heath scores respectively. CONCLUSIONS: It is possible to routinely collect PRO measures in large IM clinic and longitudinal improvements in Mental and Physical Health scores were observed. Future research should focus on understanding how providers can utilize PRO results in real-time to improve patients' clinical outcomes and potentially decrease healthcare utilization. PMID- 29609937 TI - Can Aidi injection improve overall survival in patients with non-small cell lung cancer? A systematic review and meta-analysis of 25 randomized controlled trials. AB - OBJECTIVES: Aidi injection can significantly improve clinical response and reduce radiochemotherapy related toxicity. Can Aidi injection improve the survival in non-small-cell lung cancer (NSCLC)? Therefore, to further reveal it, we systematically evaluated all related studies. METHODS: We collected all studies about Aidi injection for NSCLC in Medline, Embase, Web of Science(ISI), China National Knowledge Infrastructure Database(CNKI), Chinese Scientific Journals Full-Text Database(VIP), Wanfang, China Biological Medicine Database (CBM), Cochrane Central Register of Controlled Trials (CENTRAL), Chinese clinical trial registry (Chi-CTR) and WHO International Clinical Trials Registry Platform (WHO ICTRP), and US-clinical trials (established to June 2016). We evaluated their quality according to the Cochrane evaluation handbook of randomized controlled trials (RCTs) (5.1.0), extracted data following the PICO principles, and synthesized the data by meta-analysis. RESULTS: We included 25 RCTs involving 2662 patients with NSCLC which most studies had unclear risk of bias. The merged risk ratios (RR) values and their 95% CI of meta-analysis for objective response rate (ORR) and disease control rate (DCR) were as following: 1.19(1.09-1.29) and 1.07(1.03-1.11). The merged RR values and their 95% CI of meta-analysis for the 1 , 2- and 3-year overall survival (OS) rate were as following: 1.23(1.14-1.33), 1.46(1.22-1.74) and 1.67(1.04-2.69). All differences were statistically significant. Subgroup analysis showed that Aidi injection plus different therapies had different effects on 1-, 2- and 3-year OS rate. Sensitivity analysis showed that the RR of ORR, DCR, 1- and 2- year OS rate had good stability, and 3-year OS rate had poor stability. CONCLUSIONS: Available evidences indicate that Aidi injection can significantly improve the clinical response and OS rates in patients with NSCLC and especially, the 1- and 2-year OS rate. But, Aidi injection plus different therapies had different effects on overall survival. It is still unclear whether Aidi injection can improve the PFS and HR. PMID- 29609938 TI - How are complementary health professions regulated in Australia? An examination of complementary health professions in the national registration and accreditation scheme. AB - OBJECTIVES: This study aims to provide an empirical examination of how complementary medicine practice in Australia is actually regulated under the current national registration model. METHODS: Data was obtained from Australian Health Practitioner Regulation Agency (AHPRA) Annual Reports for the years 2011/12-2014/15 and supplemented by the Chinese Medical Registration Board of Victoria (CMRBV) Annual Reports in 2011/12 for Chinese Medicine complaints. The data analysed includes complaint statistics, stage of closure of complaints and the outcome of complaints concerning Chinese medicine, chiropractic and osteopathy under the National Law. RESULTS: During 2014-2015 the number of complaints per 100 registrants for was highest for the medical board (4.4), while much lower for the chiropractic (1.5), osteopath (0.7) and Chinese medicine (0.5) boards. For conventional boards, 58% of complaints were closed at the assessment stage, while 57%, 29% and 16% of complaints to the osteopath, Chinese medicine and chiropractic boards respectively were closed at the assessment stage. The decision to suspend or cancel registration of health professionals was 17% from the Chinese medicine board, 14% from the Osteopathy Board, 1.5% from the chiropractor board and 0.6% from the medical board. CONCLUSION: It appears that complementary medicine practitioner regulation works at least as well as conventional regulation, and at most complementary medicine boards take a stricter interpretation of misconduct though more research would need to be undertaken to state this definitively. Our findings indicate that the public are using the statutory complaint mechanisms available to them with respect to the three CM groups. PMID- 29609939 TI - A novel cognitive behavioral treatment for patients with chronic insomnia: A pilot experimental study. AB - OBJECTIVES: Chronic insomnia (CI) is a common sleep disorder linked to stress and various ubiquitous stress-related disorders (e.g. cardiovascular and mental diseases). Previous experimental studies exploring the effects of stress management in CI have confirmed that reducing stress, especially through cognitive methods, could ameliorate symptoms and repercussions of CI. In this 16 week experimental pilot study, we primarily examined the feasibility of a novel method, dubbed Pythagorean Self-Awareness Intervention (PSAI) in 30 CI patients. DESIGN: This is a pilot experimental study. SETTING: Attikon General Hospital, School of Medicine, University of Athens. INTERVENTIONS: PSAI for a period of 8 weeks (8-16 weeks). MAIN OUTCOMES: Feasibility data and efficacy measures for sleep quality, cognitive function, perceived stress and hair cortisol. RESULTS: All eligible patient gave their consent to participate and there were no drop outs or adverse effects. 43.3%, 30% and 26.7% of patients showed high (PSAI twice per day), moderate (at least three times per week) and low (less than three times per week) compliance, respectively. Morning lack of time and evening tiredness were the main reasons for missing home sessions. Significant improvements in sleep quality, cognitive function, hair cortisol and perceived stress were also recorded especially in patients with higher compliance. CONCLUSIONS: PSAI is a feasible and possibly efficacious stress management method. Future randomized controlled studies should explore its efficacy in CI. PMID- 29609940 TI - Functional outcome from sacroiliac joint prolotherapy in patients with sacroiliac joint instability. AB - OBJECTIVES: Examine the effectiveness of sacroiliac (SI) joint prolotherapy for SI joint instability, and characterize the patients most likely to benefit from this treatment. DESIGN: Retrospective cohort study. SETTING: Department of Veterans Affairs outpatient physical medicine clinic. INTERVENTIONS: Patients referred for low back pain and diagnosed with SI joint instability received a series of three SI joint prolotherapy injections (15% dextrose in lidocaine) at approximately a one-month interval. The outcome of those completing treatment was retrospectively examined, and characteristics were compared between those with at least a minimum clinically important improvement and those without improvement. MAIN OUTCOME MEASURES: Patients completed the Oswestry Disability Index (ODI) before treatment was initiated, immediately preceding each prolotherapy injection, and at 3-4 month follow-up. RESULTS: Of 103 treated patients returning for post-treatment follow-up at a median of 117 days, 24 (23%) showed a minimum clinically important improvement despite a median of 2 years with low back pain and a mean (+/-SD) pre-intervention ODI of 54 +/- 15 points. Much of the improvement was evident after the initial prolotherapy injection, and a 15-point improvement in ODI prior to the second prolotherapy injection had a sensitivity of 92% and specificity of 80% for determining which patients would improve. CONCLUSIONS: A satisfactory proportion of patients with symptomatic SI joint instability as an etiology of low back pain can have clinically meaningful functional gains with prolotherapy treatment. The patients who are not likely to improve with prolotherapy are generally evident by lack of improvement following the initial prolotherapy injection. PMID- 29609941 TI - Development and validation of a tool to evaluate Inpatient Beliefs, Expectations and Attitudes toward Reflexology (IBEAR-16). AB - BACKGROUND: The integration of manual therapies, including reflexology, into conventional care settings is growing extensively. Patients' beliefs, attitudes and expectations toward these therapies interact with their outcomes, but currently there are no validated tools to evaluate these factors. We aimed to design and to validate such a tool specifically targeted into reflexology. METHODS: Following input of a multidisciplinary team of experts, the self administered Inpatient Beliefs, Expectations and Attitudes toward Reflexology (IBEAR) questionnaire was constructed, containing 25 items, 8 referring to demographics and 17 specifically addressing reflexology. Cronbach's alpha was computed to evaluate the questionnaire's internal reliability, and factor analysis was used for further validation (232 patients). Pearson coefficient and Kappa tests were used to test and retest (within 48 hours) the questionnaire on a group of 199 patients, to assure clarity and reliability. RESULTS: For the 232 questionnaires collected, the computed Cronbach's alpha coefficient was 0.716 (acceptable reliability). Factor analysis pointed to two content areas separated into four items addressing attitudes and expectations and five items focusing on beliefs and attitudes. In the test-retest stage, 199 participants filled in the questionnaire for a second time. The Pearson coefficient for all questions ranged between 0.73 and 0.94 (good to excellent correlation) and Kappa scores ranged between 0.66 and 1.0 (moderate to high reliability). Consequently, one of the questions was removed from the IBEAR. CONCLUSIONS: The present study provides evidence that the proposed IBEAR questionnaire with 16 items is a valid and reliable tool for evaluation of inpatients' beliefs, expectations and attitudes toward reflexology. PMID- 29609942 TI - Convenient and Live Movement (CALM) for women undergoing breast cancer treatment: Challenges and recommendations for internet-based yoga research. AB - OBJECTIVE: To conduct a pilot trial of internet-based, cancer-adapted yoga for women receiving breast cancer treatment. DESIGN: Women undergoing radiation or chemotherapy for breast cancer were recruited for 12, 75-min, biweekly, cancer adapted yoga classes delivered via internet-based, multipoint videoconferencing. Data were collected on feasibility and acceptability, including qualitative feedback from participants and the yoga instructor. RESULTS: Among 42 women approached, 13 declined eligibility screening, and 23 were ineligible. All 6 women who were eligible provided consent, but 2 withdrew prior to beginning yoga classes. The remaining 4 participants attended 1-11 of 12 online yoga classes. In post-intervention interviews, participants and the instructor agreed that internet-based yoga classes hold great potential for increasing access and improving psychological outcomes in adults with cancer. Qualitative feedback from participants revealed suggestions for future trials of internet-based, cancer adapted yoga classes, including: continued use of group format; offering more varied class times to accommodate patients' demanding schedules and fluctuating symptoms; enrolling patients after they have acclimated to or completed cancer treatment; streamlining the technology interface; and careful attention to participant burden when designing surveys/forms. The instructor recommended closed session courses, as opposed to rolling enrollment; teaching the same modified poses for all participants, rather than individual tailoring; and using a large screen to allow closer monitoring of students' class experience. CONCLUSIONS: Internet delivery may increase patients' access to cancer-adapted yoga classes, but cancer-related and technological barriers remain. This study informs how to optimally design yoga classes, technology, and research procedures to maximize feasibility and acceptability in future trials. PMID- 29609943 TI - The effects of pilates on mental health outcomes: A meta-analysis of controlled trials. AB - OBJECTIVE: This meta-analysis estimated the population effect size for Pilates effects on mental health outcomes. DATA SOURCES: Articles published prior to August 2017 were located with searches of Pubmed, Medline, Cinahl, SportDiscus, Science Direct, PsychINFO, Web of Science, and Cochrane Controlled Trial Register using combinations of: Pilates, Pilates method, mental health, anxiety, and depression. STUDY SELECTION: Eight English-language publications that included allocation to a Pilates intervention or non-active control and a measure of anxiety and/or depressive symptoms at baseline and after the Pilates intervention were selected. DATA EXTRACTION: Participant and intervention characteristics, anxiety and depressive symptoms and other mental health outcomes, including feelings of energy and fatigue and quality of life, were extracted. Hedges' d effect sizes were computed, study quality was assessed, and random effects models estimated sampling error and population variance. DATA SYNTHESIS: Pilates resulted in significant, large, heterogeneous reductions in depressive (Delta = 1.27, 95%CI: 0.44, 2.09; z = 3.02, p <= 0.003; N = 6, n = 261) and anxiety symptoms (Delta = 1.29, 95%CI: 0.24, 2.33; z = 2.40, p <= 0.02; N = 5, n = 231) and feelings of fatigue (Delta = 0.93, 95%CI: 0.21, 1.66; z = 2.52, p <= 0.012; N = 3, n = 161), and increases in feelings of energy (Delta = 1.49, 95%CI: 0.67, 2.30; z = 3.57, p < 0.001; N = 2, n = 116). CONCLUSIONS: Though this review included a small number of controlled trials with small sample sizes and non active control conditions of variable quality, the available evidence reviewed here supports that Pilates improves mental health outcomes. Rigorously designed randomized controlled trials, including those that compare Pilates to other empirically-supported therapies, are needed to better understand Pilates' clinical effectiveness and plausible mechanisms of effects. PMID- 29609944 TI - Movement and manual therapy for adults with arthritis: 2012 National Health Interview Survey. AB - BACKGROUND: The use of manual therapies (chiropractic manipulation, massage) and movement therapies (yoga, tai chi) by people with arthritis may relate to their personal characteristics, and the reported emotional and physical health outcomes may differ by type of therapy. OBJECTIVES: To describe personal characteristics and predictors of manual and movement therapy use for people with arthritis, and to compare the use of manual versus movement therapy to improve physical and emotional health outcomes for people with arthritis. METHODOLOGY: CAM respondents with arthritis were identified from the 2012 National Health Interview Survey (n = 8229). Data were analyzed to determine the overall percentages of CAM users, and to examine the associations between use/nonuse using multivariable linear regressions. RESULTS: White, well-educated, physically active females were more likely to use both types of therapy. Movement therapy users reported positive emotional health outcomes twice as much as manual therapy users and 10% more reported positive physical health outcomes. CONCLUSION: While both movement and manual therapies can have positive effects on people with arthritis, it appears that active therapies are more beneficial than passive therapies. PMID- 29609945 TI - Highlights of the Portuguese Journal of Cardiology in 2017. PMID- 29609946 TI - Exercise-induced cardiac remodeling in athletes and in special forces soldiers. AB - INTRODUCTION: Exercise-induced cardiac remodeling is frequent in athletes. This adaptation is structurally manifested by an increase in cardiac dimensions and mass. Soldiers are also subject to intense physical exercise, although with different characteristics. OBJECTIVE: To compare exercise-induced cardiac remodeling in competitive athletes and in soldiers on a special forces training course. METHODS: We studied 17 soldiers (all male and Caucasian, mean age 21+/-3 years) who completed a special forces course and 17 basketball players (47.3% male, 64.7% Caucasian, mean age 21+/-3 years). Assessment included a transthoracic echocardiogram and analysis of myocardial mechanics. This assessment was performed at the beginning and end of the military course and the sports season, respectively. RESULTS: Cardiac remodeling was observed in both groups. The soldiers presented a predominantly eccentric pattern, with increased left ventricular (LV) size (49.7+/-3.2 vs. 52.8+/-3.4 mm; p<0.01), increased LV mass (93.1+/-7.7 vs. 100.2+/-11.4 g/m2; p<0.01) and decreased relative wall thickness (0.40+/-0.1 vs. 0.36+/-0.1; p=0.05). The basketball players showed a concentric pattern, with decreased LV size (52.0+/-4.7 vs. 50.4+/-4.7 mm; p=0.05), and increased relative wall thickness (0.33+/-0.1 vs. 0.36+/-0.1; p=0.05). Although there was no significant difference in LV myocardial strain in the groups separately, when compared there was a significant decrease (-20.2+/ 1.6% vs. -19.4+/-2.1%; p=0.03). CONCLUSION: Cardiac remodeling was frequent, with an eccentric pattern in soldiers and a concentric pattern in basketball players. Myocardial deformation may represent a physiological adaptation to physical exercise. PMID- 29609947 TI - Atrial tachycardia ablation in surgically treated congenital heart disease. PMID- 29609948 TI - Can the ESC/EAS LDL-cholesterol target in patients with diabetes and high cardiovascular risk be achieved in clinical practice? Results from an ambulatory multidisciplinary diabetes center cohort. PMID- 29609949 TI - Progress toward a reduced phage genetic code. AB - All known living organisms use at least 20 amino acids as the basic building blocks of life. Efforts to reduce the number of building blocks in a replicating system to below the 20 canonical amino acids have not been successful to date. In this work, we use filamentous phage as a model system to investigate the feasibility of removing methionine (Met) from the proteome. We show that all 24 elongation Met sites in the M13 phage genome can be replaced by other canonical amino acids. Most of these changes involve substitution of methionine by leucine (Leu), but in some cases additional compensatory mutations are required. Combining Met substituted sites in the proteome generally led to lower viability/infectivity of the mutant phages, which remains the major challenge in eliminating all methionines from the phage proteome. To date a total of 15 (out of all 24) elongation Mets have been simultaneously deleted from the M13 proteome, providing a useful foundation for future efforts to minimize the genetic code. PMID- 29609950 TI - The effect of fatty acid binding in the acid isomerizations of albumin investigated with a continuous acidification method. AB - The protein Human Serum Albumin (HSA) is known to undergo conformational transitions towards partially unfolded forms triggered by acidification below pH 4.5. The extent of Fatty Acids (FA) binding has been thought to have an impact on the conformational equilibrium between the native and acid forms and to be a possible explanation for the observation of more than one band in early electrophoretic migration experiments at pH 4. We compared the acid-induced unfolding processes of commercial FA-free HSA, commercial "fatted" HSA and FA-HSA complexes, prepared at FA:HSA molar ratios between 1 and 6 by simple mixing and equilibration. We used a method for continuous acidification based on the hydrolysis of glucono-delta-lactone from pH 7 to pH 2.5, and followed the average protein changes by the blue shift of the intrinsic fluorescence emission and by performing a small angle X-ray scattering analysis on selected samples. The method also allowed for continuous monitoring of the increase of turbidity and laser light scattering of the protein samples related to the release of the insoluble ligands with acidification. Our results showed that the presence of FA interacting with albumin, an aspect often neglected in biophysical studies, affects the conformational response of the protein to acidification, and slightly shifts the loss of the native shape from pH 4.2 to pH 3.6. This effect increased with the FA:HSA molar ratio so that with three molar equivalents a saturation was reached, in agreement with the number of high-affinity binding sites reported for the FA. These findings confirm that a non-uniform level of ligand binding in an albumin sample can be an explanation for the early-observed conformational heterogeneity at pH 4. PMID- 29609951 TI - Bone Metastasis in Advanced Breast Cancer: Analysis of Gene Expression Microarray. AB - BACKGROUND: Approximately 30% to 40% of breast cancer recurrences involve bone metastasis (BM). Certain genes have been linked to BM; however, none have been able to predict bone involvement. In this study, we analyzed gene expression profiles in advanced breast cancer patients to elucidate genes that can be used to predict BM. PATIENTS AND METHODS: A total of 92 advanced breast cancer patients, including 46 patients with BM and 46 patients without BM, were identified for this study. Immunohistochemistry and gene expression analysis was performed on 81 formalin-fixed paraffin-embedded samples. Data were collected through medical records, and gene expression of 200 selected genes compiled from 6 previous studies was performed using NanoString nCounter. RESULTS: Genetic expression profiles showed that 22 genes were significantly differentially expressed between breast cancer patients with metastasis in bone and other organs (BM+) and non-BM, whereas subjects with only BM showed 17 significantly differentially expressed genes. The following genes were associated with an increasing incidence of BM in the BM+ group: estrogen receptor 1 (ESR1), GATA binding protein 3 (GATA3), and melanophilin with an area under the curve (AUC) of 0.804. In the BM group, the following genes were associated with an increasing incidence of BM: ESR1, progesterone receptor, B-cell lymphoma 2, Rab escort protein, N-acetyltransferase 1, GATA3, annexin A9, and chromosome 9 open reading frame 116. ESR1 and GATA3 showed an increased strength of association with an AUC of 0.928. CONCLUSION: A combination of the identified 3 genes in BM+ and 8 genes in BM showed better prediction than did each individual gene, and this combination can be used as a training set. PMID- 29609952 TI - Rethinking the PGY-1 Basic Clinical Year: A Canadian National Survey of Its Educational Value for Diagnostic Radiology Residents. AB - RATIONALE AND OBJECTIVES: Recently, the relevance of the postgraduate year 1 (PGY 1) Basic Clinical Year for radiology residents has been questioned. The purpose of this study was to determine the attitude of radiologists and trainees toward this year and which clinical rotations they perceived as most valuable to clinical practice. MATERIALS AND METHODS: Following institutional review board approval, an anonymous online survey was administered to Canadian radiologists and radiology trainees. In addition to reporting demographic information, respondents were asked to rank the usefulness of individual rotations on a five point Likert scale. To assess whether there are differences in the ratings and therefore rankings of the rotations by gender, position, and level of training, the Kruskal-Wallis one-way analysis of variance test was used with significance defined as P < .05. The Schulze method was used to rank the perceived usefulness of clinical rotations considered. RESULTS: Of the 275 respondents, 73.1% were male and 47.3% were trainees. A total of 71.3% of respondents were in favor of the basic clinical year, whereas 16.4% opposed. There was a statistically significant difference between the responses of staff radiologists and trainees, with the staff more strongly favoring the Basic Clinical Year (84.1%) than the trainees (56.9%) (P < .0001). As a whole, the respondents favored general surgery rotations as most relevant to their clinical practice (agreement rate of 48.3%). Interventional radiologists found general and subspecialty surgical rotations to be equally relevant. The rotations deemed to be "essential" were emergency medicine (48.7%) and general surgery (46.6%), and the rotations deemed to be "very useful" were orthopedics (45.8%), trauma (44.4%), neurosurgery (43.3%), neurology (42.2%), and hepatobiliary surgery (38.9%). There was no statistical difference between the respondents' choices based on their level of experience and scope of practice. CONCLUSIONS: Most radiologists and radiology trainees were in favor of completing the PGY-1 Basic Clinical Year. However, programs should maximize the education value of this year by including more of the top-ranked rotations. As the practice of radiology evolves, it is important to ensure that training paradigms continue to prepare residents for independent practice. PMID- 29609953 TI - Determination of Prostate Volume: A Comparison of Contemporary Methods. AB - RATIONALE AND OBJECTIVES: Prostate volume (PV) determination provides important clinical information. We compared PVs determined by digital rectal examination (DRE), transrectal ultrasound (TRUS), magnetic resonance imaging (MRI) with or without three-dimensional (3D) segmentation software, and surgical prostatectomy weight (SPW) and volume (SPV). MATERIALS AND METHODS: This retrospective review from 2010 to 2016 included patients who underwent radical prostatectomy <=1 year after multiparametric prostate MRI. PVs from DRE and TRUS were obtained from urology clinic notes. MRI-based PVs were calculated using bullet and ellipsoid formulas, automated 3D segmentation software (MRI-A3D), manual segmentation by a radiologist (MRI-R3D), and a third-year medical student (MRI-S3D). SPW and SPV were derived from pathology reports. Intraclass correlation coefficients compared the relative accuracy of each volume measurement. RESULTS: Ninety-nine patients were analyzed. Median PVs were DRE 35 mL, TRUS 35 mL, MRI-bullet 49 mL, MRI ellipsoid 39 mL, MRI-A3D 37 mL, MRI-R3D 36 mL, MRI-S3D 36 mL, SPW 54 mL, SPV bullet 47 mL, and SPV-ellipsoid 37 mL. SPW and bullet formulas had consistently large PV, and formula-based PV had a wider spread than PV based on segmentation. Compared to MRI-R3D, the intraclass correlation coefficient was 0.91 for MRI-S3D, 0.90 for MRI-ellipsoid, 0.73 for SPV-ellipsoid, 0.72 for MRI-bullet, 0.71 for TRUS, 0.70 for SPW, 0.66 for SPV-bullet, 0.38 for MRI-A3D, and 0.33 for DRE. CONCLUSIONS: With MRI-R3D measurement as the reference, the most reliable methods for PV estimation were MRI-S3D and MRI-ellipsoid formula. Automated segmentations must be individually assessed for accuracy, as they are not always truly representative of the prostate anatomy. Manual segmentation of the prostate does not require expert training. PMID- 29609954 TI - Differentiation Between Brucellar and Tuberculous Spondylodiscitis in the Acute and Subacute Stages by MRI: A Retrospective Observational Study. AB - RATIONALE AND OBJECTIVES: The aim of this study was to reveal the distinctive features of magnetic resonance imaging (MRI) for distinguishing brucellar spondylodiscitis (BSD) from tuberculous spondylodiscitis (TSD) in the acute and subacute stages. METHODS: This study involved 14 patients with BSD and 18 patients with TSD from May 2011 to January 2015. BSD was diagnosed based on >=1/160 titers of a Brucella agglutination test or isolation of Brucella spp. TSD was diagnosed based on the isolation of tuberculosis bacteria. All patients underwent T1- and T2-weight imaging (T1WI and T2WI) and fat suppression T2WI (FS T2WI). The height and the signal intensity (SI) of the vertebra and intervertebral disc were assessed. The distinctive MRI features were compared using the chi-square test. The SI of the vertebra between BSD and TSD was observed in terms of histogram characteristics of kurtosis, skewness, and percentile (75%-25%) on FS T2WI. RESULTS: Twenty-nine (76.3%) vertebrae of BSD were infected throughout the whole vertebra, and 49 (90.7%) vertebrae of TSD were infected near the osseous end plate (P <.001). Compared to TSD, the vertebral height of BSD was nearly intact (P <.001), owing to the new bone formation in the end plate without vertebral collapse. Furthermore, significant differences in the SI of the vertebra were observed between patients with BSD and TSD in terms of homogeneous characteristics on FS T2WI, that is, kurtosis (BSD vs TSD, 0.107 vs 0.250, P = .023), skewness (BSD vs TSD, -0.021 vs 0.266, P = .017), and percentile (75%-25%) (BSD vs TSD, 54.498 vs 79.399, P = .00049). CONCLUSIONS: The nearly intact vertebra with homogeneous high signal on FS T2WI was an important MRI feature for distinguishing BSD from TSD in the acute and subacute stages. PMID- 29609955 TI - The application effect of percutaneous cryoablation for the stage IIIB/IV advanced non-small-cell lung cancer after the failure of chemoradiotherapy. AB - BACKGROUND/OBJECTIVE: A retrospective review is required to assess the application effect of percutaneous cryoablation on the stage IIIB/IV advanced non small-cell lung cancer (NSCLC) after the failure of chemoradiotherapy. A total of twenty-two cases with stage IIIB/IV advanced NSCLC after failure of chemoradiotherapy were enrolled. METHODS: Computed Tomography (CT) was used for the assessment of tumor response, and Functional Assessment of Cancer Therapy General (FACT-G) was applied for the evaluation of quality of life. After the treatment of cryoablation, we performed a follow-up analysis. RESULTS: The primary technique effectiveness of 100% was observed in the one month of follow up. At three months, local tumor progression was shown in 4 of 31 lesions (13.6%). The one-year survival rate of 81.8% and progression-free rate of 27.8% were obtained. Six patients died 7, 9, 10, 12, 15 and 22 months after treatment, respectively. Decreased scores of total quality of life at one week after cryoablation (P = 0.006), but increased scores at one month after cryoablation (P = 0.024) were observed, compared with pre-cryoablation. CONCLUSION: Cryoablation contributes to the effective local tumor therapy for stage IIIB/IV advanced NSCLC after the failure of chemoradiotherapy. PMID- 29609956 TI - Arcuate uterus: is there an impact on in vitro fertilization outcomes after euploid embryo transfer? AB - OBJECTIVE: To study the impact of the arcuate uterus on euploid blastocyst-stage embryo transfer outcomes after comprehensive chromosomal screening (CCS). DESIGN: Controlled retrospective trial. SETTING: Tertiary care assisted reproduction technology (ART) center. PATIENT(S): Consecutive patients undergoing in vitro fertilization and euploid embryo transfer after CCS during 2014. INTERVENTION(S): Ultrasound examinations and office hysteroscopy; array comparative genomic hybridization to perform CCS after a trophectoderm biopsy. MAIN OUTCOME MEASURE(S): Implantation and live-birth rates. RESULT(S): Patients were divided into two groups based on the presence (group 1) or absence (group 2) of arcuate uterus. Exclusion criteria were donor oocytes, evidence of other endometrial cavitary abnormalities, prior uterine surgery, and arcuate uterus <4 mm. Group 1 included 78 patients with arcuate uterus of mean depth 5.43 +/- 1.81 mm (range: 4 9.5 mm) undergoing 83 transfer cycles. Group 2 included 354 controls undergoing 378 transfer cycles. There were no differences between the groups in baseline characteristics or mean number of euploid embryos transferred. Cycle outcomes were similar between the two groups: rates of implantation (63.7% vs. 65.4%), live birth (68.67% vs. 67.81%), biochemical pregnancy (8.4% vs. 7.65%), and spontaneous abortion (4.8% vs. 4.27%). CONCLUSION(S): Arcuate uterus has no impact on ART outcomes after euploid embryo transfer subsequent to CCS, so arcuate uterus should be considered an incidental finding without an indication for surgical resection. PMID- 29609957 TI - Co-occurrence of chronic pain disorders in adolescents suggests early pain programming and possible timing for intervention. PMID- 29609958 TI - The genus Vietbocap Lourenco & Pham, 2010 in the Thien Duong cave, Vietnam: A possible case of subterranean speciation in scorpions (Scorpiones: Pseudochactidae). AB - Two new species of scorpion belonging to the family Pseudochactidae and to the genus Vietbocap are described based on specimens collected in the Thien Duong cave, which belongs to the Vom cave system, in the Phong Nha-Ke Bang National Park, Quang Binh Province, Vietnam. The previously described species from this cave, Vietbocap thienduongensis Lourenco & Pham, 2012 was collected in the initial section of the cave (1500 to 1800m from the cave entrance) and proved to be a true troglobitic element. The diagnosis of this species, only known from males, is completed based on females collected at 750m from the cave entrance. The two new species described here were collected respectively at 3000 and 5000m from the cave entrance and are also true troglobitic elements, very similar to V. thienduongensis, but showing some clear morphological differences. This observed situation suggests a possible case of speciation within the cave system, the first one ever reported for scorpions. The population found at 5000m from the entrance of the cave is a total new record of distance from a cave entrance for scorpions. PMID- 29609959 TI - Impairment of social cognition in neurological diseases. AB - Social cognition is impaired in a large number of neurological afflictions, including neurodegenerative diseases, neuropsychiatric disorders and neurodevelopmental syndromes, and has become a significant element in differential diagnoses. This report describes the different processes involved in social cognition and the way in which they work together to allow adapted behaviors. This is then followed by the numerous clinical symptoms of social behavioral disturbances and social cognition performance in different neurological afflictions such as frontotemporal lobar degeneration, Alzheimer's disease and schizophrenia. In addition, the available tasks allowing social cognition assessment in routine clinical practice are also presented. PMID- 29609960 TI - Autoimmune encephalitis and psychiatric disorders. AB - Autoimmune encephalitis (AE) refers to a rare, newly described, group of diseases associated with specific circulating autoantibodies directed against neuronal proteins used as biomarkers of the disease. Characterization of the associated autoantibodies present in the patients' cerebrospinal fluid (CSF) and/or sera can differentiate the various AE subgroups, which have specific clinical presentations and prognoses, and is therefore essential for proposing appropriate treatments. As psychiatric symptoms may predominate at the onset or over the course of these diseases, the diagnosis is frequently delayed. Yet, patients' prognoses depend on the speed with which the disease is detected, identified and managed. A wide range of neuropsychiatric symptoms is observed according to the patient's AE subgroup, and some are highly suggestive of an immune origin and should be recognized as such by physicians. Because the presence of pronounced psychiatric symptoms drives patients to psychiatric institutions, which can hinder the diagnosis, physicians need to be aware of AE and propose the detection of autoantibodies as early as possible to provide optimal medical care to such patients. In fact, the description of AE subgroups over the past decade has allowed the present overview of their incidence in psychiatric diseases and some general guidelines for the management of these patients. PMID- 29609961 TI - Motor functional neurological disorders: An update. AB - Motor functional neurological disorders (FNDs) are motor symptoms not explained by a lesion or related to a known dysfunction of the central nervous system, yet functional imaging studies suggest the presence of a genuine brain dysfunction. With this common disabling condition, there is a particular need for collaboration between neurologists and psychiatrists. Neurologists can search for positive clinical signs to make the diagnosis, which can then be followed by an explanation of the disease, whereas psychiatrists can look for psychological factors and psychiatric comorbidities in order to deliver appropriate treatment. Such a multidisciplinary approach is important, particularly with the participation of neurologists, psychiatrists, physiotherapists and psychologists. If necessary, additional treatments such as transcranial magnetic stimulation (TMS), hypnosis and sedation may be proposed. PMID- 29609962 TI - John Gordon-A greatly undervalued complement pioneer. PMID- 29609963 TI - Saccular Aneurysm of the Extracranial Internal Carotid Artery. PMID- 29609964 TI - Use of an Assistant Surgeon Does not Mitigate the Effect of Lead Surgeon Volume on Outcomes Following Open Repair of Intact Abdominal Aortic Aneurysms. AB - OBJECTIVE/BACKGROUND: While higher lead surgeon volume has been associated with lower mortality following open abdominal aortic aneurysm (AAA) repair, little is known about the impact of using an attending surgeon as assistant surgeon. The aim of this study was to determine whether the presence of an assistant surgeon, particularly a high volume assistant, mitigates the relationship between lead surgeon volume and outcomes. METHODS: All Medicare beneficiaries who underwent intact, open AAA repair between 2003 and 2008 were evaluated and nested regression models were constructed to evaluate the relationship between surgeon and assistant volume and peri-operative mortality, adjusting for comorbid conditions and hospital volume. RESULTS: In total 28,590 repairs were studied, of which 19,284 (67.5%) were performed by a single surgeon and 9306 (32.5%) included an assistant surgeon. Of cases with an assistant, 12.3% included a high volume assistant surgeon. Lower volume surgeons more frequently used an assistant (lead surgeon Q1 volume: 40%; Q2: 36%; Q3: 34%; Q4: 29%; Q5: 27% [p < .01]). In cases with no assistant, adjusted peri-operative mortality varied monotonically with surgeon volume (Q1: 4.7%; Q2: 4.4%; Q3: 4.1%; Q4: 3.3%; Q5: 3.2%). However, the use of a high or a low volume assistant surgeon, compared with no attending surgeon as assistant, was not associated with lower peri-operative mortality in any lead surgeon volume quintile, even among those operations performed by the lowest volume lead surgeons. CONCLUSION: Employing an assistant surgeon does not improve outcomes amongst any quintile of volume of the lead surgeon. As surgeons perform fewer open AAA repairs in the modern era, these data imply that even the help of a high volume assistant surgeon may not mitigate the detrimental effect of a lower volume surgeon. PMID- 29609965 TI - BCG vaccine: WHO position paper, February 2018 - Recommendations. AB - This article presented the World Health Organization's (WHO) recommendations on the use of on Bacille Calmette-Guerin (BCG) vaccine excerpted from the BCG vaccines: WHO position paper - February 2018 published in the Weekly Epidemiological Record [1]. This position paper replaces the 2004 WHO position paper on Bacille Calmette-Guerin (BCG) vaccine [2] and the 2007 WHO revised BCG vaccination guidelines for infants at risk for human immunodeficiency virus (HIV) infection [3]. It incorporates recent developments in the tuberculosis (TB) field, provides revised guidance on the immunization of children infected with HIV, and re-emphasizes the importance of the birth dose. This position paper also includes recommendations for the prevention of leprosy. Footnotes to this paper provide a number of core references including references to grading tables that assess the quality of the scientific evidence, and to the evidence-to recommendation tables. In accordance with its mandate to provide guidance to Member States on health policy matters, WHO issues a series of regularly updated position papers on vaccines and combinations of vaccines against diseases that have an international public health impact. These papers are concerned primarily with the use of vaccines in large-scale immunization programmes; they summarize essential background information on diseases and vaccines, and conclude with WHO's current position on the use of vaccines in the global context. Recommendations on the use of cholera vaccines were discussed by the Strategic Advisory Group of Experts (SAGE) in October 2017; evidence presented at these meetings can be accessed at: http://www.who.int/immunization/sage/meetings/2017/october/presentations_backgrou d_docs/en/. PMID- 29609966 TI - African swine fever virus (ASFV) protection mediated by NH/P68 and NH/P68 recombinant live-attenuated viruses. AB - The risk of spread of African swine fever virus (ASFV) from Russia and Caucasian areas to several EU countries has recently emerged, making it imperative to improve our knowledge and defensive tools against this important pathogen. The ASFV genome encodes many genes which are not essential for virus replication but are known to control host immune evasion, such as NFkappaB and the NFAT regulator A238L, the apoptosis inhibitor A224L, the MHC-I antigen presenting modulator EP153R, and the A276R gene, involved in modulating type I IFN. These genes are hypothesized to be involved in virulence of the genotype I parental ASFV NH/P68. We here describe the generation of putative live attenuated vaccines (LAV) prototypes by constructing recombinant NH/P68 viruses lacking these specific genes and containing specific markers. PMID- 29609967 TI - School-age children and adolescents suspected of having been to be infected with pertussis in Japan. AB - Many countries including Japan have adapted acellular pertussis vaccines combined with diphtheria and tetanus toxoids (DTaP). DTaP vaccine coverage is approximately >90%, but pertussis re-emergence has been observed since 2000 in Japan. In the present study, anti-pertussis antibodies were investigated among school-age children and adolescents from 2013 to 2015. The positive rate of anti pertussis toxin (PT) antibodies was higher among children aged 12-13 years (60.0%. 95%CI; 56.0-63.9%) in 2014 and 18-19 years (73.0%. 95%CI; 61.4-82.6%) in 2013, compared with 6-7 years (47.1%. 95%CI; 40.7-53.6%). The mean PT antibody titer was higher among children aged 12-13 years (23.8 EU/ml. 95%CI; 21.9-25.8) in 2014 and 18-19 years (29.3 EU/ml. 95%CI; 23.0-35.6) in 2013, compared with 6-7 years (18.3 EU/ml. 95%CI; 15.5-21.2). Distributions of pertussis antibodies and mean titers at their same grade of school-age were similar from 2013 to 2015. Although school-age children were immunized with 4 doses of DTaP, the data suggested the decay of vaccine-acquired immunity and possibility of asymptomatic infection in school age, indicating the additional DTaP vaccination before the entry of elementary school, preventing household contact. PMID- 29609968 TI - Hepatitis B infection control in Colombian Amazon after 15 years of hepatitis B vaccination. Effectiveness of birth dose and current prevalence. AB - BACKGROUND: Hepatitis B virus (HBV) infection is highly endemic in the Colombian Amazon basin. In Colombia, the universal hepatitis B vaccination in that area has been active since 1993. The program targets children aged under five years. Newborns receive at least three doses, and in 2001, HBV vaccine birth dose was included. This study aimed to evaluate the advances on HBV control in the Colombian Amazon. METHODS: A population-based cross-sectional study was conducted in children less than 11 years old in rural areas of the Colombian Amazon, in order to assess the current levels of HBV prevalence and evaluate the effectiveness of HBV vaccination. Participants were selected from villages scattered along the Amazon, Putumayo and Loretoyaco Rivers. Blood samples were taken from children. All the samples were examined for surface antigen (HBsAg) and IgG antibodies against core antigen (AntiHBc) of HBV. Data on HBV vaccination status and other risk factors were also collected. RESULTS: Blood samples from 1275 children were included in the study. The positivity for IgG AntiHBC and HBsAg was 3.8% and 0.5%, respectively. It was observed that receiving a dose of HBV vaccine within 48 h after birth decreased the risk of HBV infection and carriage by 95%. Being born to an AntiHBc positive mother increased 8 times the risk of HBV infection (OR = 7.8 CI 95% 3.3-10.2) and 7 times the risk of HBsAg carriage (OR = 6.6 CI 95% 2.1-10.1). CONCLUSION: The prevalence of HBV infection and HBsAg carriage continues to decrease among children living in the Colombian Amazon. The high protective effectiveness of an HBV birth does suggest that perinatal transmission is important in endemic areas of Latin America, an aspect that has not been fully studied in the region. PMID- 29609969 TI - Are the current guidelines for surgical delay in hip fractures too rigid? A single center assessment of mortality and economics. AB - PURPOSE: Controversy remains around acceptable surgical delay of acute hip fractures with current guidelines ranging from 24 to 48 h. Increasing healthcare costs force us to consider the economic burden as well. We aimed to evaluate the adjusted effect of surgical delay for hip fracture surgery on early mortality, healthcare costs and readmission rate. We hypothesized that shorter delays resulted in lower early mortality and costs. METHODS: In this retrospective cohort study 2573 consecutive patients aged >=50 years were included, who underwent surgery for acute hip fractures between 2009 and 2017. Main endpoints were thirty- and ninety-day mortality, total cost, and readmission rate. Multivariable regression included sex, age and ASA score as covariates. RESULTS: Thirty-day mortality was 5% (n = 133), ninety-day mortality 12% (n = 304). Average total cost was ?11960, dominated by hospitalization (59%) and honoraria (23%). Per 24 h delay, the adjusted odds ratio was 1.07 (95% CI 0.98-1.18) for thirty-day mortality, 1.12 (95% CI 1.04-1.19) for ninety-day mortality, and 0.99 (95% CI = 0.88-1.12) for readmission. Per 24 h delay, costs increased with 7% (95% CI 6-8%). For mortality, delay was a weaker predictor than sex, age, and ASA score. For costs, delay was the strongest predictor. We did not find clear cut points for surgical delay after which mortality or costs increased abruptly. CONCLUSIONS: Despite only modest associations with mortality, we observed a steady increase in healthcare costs when delaying surgery. Hence, a more pragmatic approach with surgery as soon as medically and organizationally possible seems justifiable over rigorous implementation of the current guidelines. PMID- 29609970 TI - Modified Stoppa approach for operative treatment of acetabular fractures: 10-year experience and mid-term follow-up. AB - INTRODUCTION: The (modified) Stoppa approach for acetabular fracture surgery has gained significant popularity and early results have been encouraging but clinical outcome at extensive follow-up is scarce. The purpose of this study is to provide an update on our experience with this approach for operative treatment of acetabular fractures and to assess clinical outcome at mid-term follow-up. METHODS: In this retrospective study, all patients treated operatively for an acetabular fracture using the Stoppa approach over a 10-year period were included. Surgery details were reviewed and patients were contacted and requested to return for follow-up. Primary outcome was native hip survivorship, secondary outcome measures included; functional outcome (Merle d'Aubigine, Harris hip) scores, health-related quality of life (short-form 36) and radiographic outcome (heterotopic ossification, hip osteoarthritis). RESULTS: Forty-five patients received operative fixation for 47 acetabular fractures using the Stoppa approach. Complications requiring surgical intervention were found in one patient (with a vascular lesion) intra-operatively and 3 patients (with wound infections (2) and diffuse bleeding (1)) post-operatively. Follow-up was 83% and 29/39 (74%) native hips survived at mean 59 months (SD 49) postoperatively. Excellent-good functional scores were found in 88% (Merle d'Aubigine) and 76% (Harris hip) of patients who had retained their native hip. Most (6/8) short-form 36 indices in these patients were comparable to population norms. Of 29 native hips with radiographic follow-up (mean 59 months (SD 49), 4 (86%) had no-minimal radiographic abnormalities. CONCLUSION: This study confirms that the Stoppa approach is a safe and effective technique for acetabular fracture fixation. Moreover, at mid-term follow-up, this approach is associated with satisfactory results in terms of hip survivorship as well as functional and radiographic outcome. As such, our findings reinforce the notion that this less invasive technique presents a valuable alternative to the ilioinguinal approach for the surgical treatment of acetabular fractures. PMID- 29609971 TI - The use of arteriovenous anastomosis for venous drainage during Tamai zone I fingertip replantation. AB - PURPOSE: The purpose of this study was to evaluate outcomes for patients sustaining a distal fingertip amputation who underwent replantation witharteriovenous anastomosis for venous drainage over a one year period at our institution. This technique has been utilized when insufficient veins are identified in the amputated part for standard veno-venous anastomosis. METHODS: A retrospective study was performed on patients presenting from 2013 to 2014. Guillotine, crush, and avulsion/degloving injuries were included if they underwent fingertip (Tamai Zone I) replantation with arterial anastomosis for vascular inflow and arteriovenous anastomosis for venous drainage. The cases were further classified as Ishikawa subzone I and subzone II. RESULTS: Arteriovenous anastomosis for venous drainage during replantation was used in 45 digits in 35 patients. 41 of the 45 digits underwent successful replantation using this technique (91%). The mean active ROM in the DIP joint of the fingers and in the IP joint of thumbs was 65 degrees and 57 degrees , respectively. Sensory evaluation demonstrated a mean of 6.9 mm s2PD in digits where the digital nerves could be repaired. 11 replanted digits without nerve repair regained some sensory recovery with a mean of 9.6 mm s2PD. 91% of patients were highly satisfied with the appearance of the replanted digits based on Tamai criteria. CONCLUSIONS: Arteriovenous anastomosis for venous outflow should be considered during zone I fingertip replantation if sufficient veins are not identified in the amputated part. This technique may allow for more routine and successful distal replantation. PMID- 29609972 TI - Fixed angle plate fixation of comminuted patellar fractures. AB - INTRODUCTION: Comminuted patella fractures are uncommon and difficult fractures to manage. Multiple treatment modalities have been suggested, with little clinical data to support practice. Recent biomechanical and technical investigations have described successful plate fixation of comminuted patella fractures. The purpose of this study was to evaluate radiographic, clinical and functional outcome of comminuted patella fractures treated with a fixed angle locking plates. We believe stable fixation, which results in successful fracture union and functional recovery, can be achieved with this technique. MATERIALS AND METHODS: A retrospective review was performed at a single regional academic Level 1 trauma hospital. All comminuted patella fractures treated with a fixed angle locking plate (AO/OTA 34C2 and C3) over a six-year period were evaluated. Thirty six patients were identified. Average length of follow up was 154 weeks (range 12 297 weeks). Twenty patients were available for functional outcome scoring. Primary outcome measures were: Knee Outcome Score (KOS), Lower Extremity Functional Scale (LES) and goniometer measured knee range of motion. Secondary outcomes evaluated the need for additional screw or cerclage fixation, reoperation for any reason, bothersome hardware, infection and nonunion. RESULTS: Average KOS = 57.2 (20-74), average LES = 58.9 (15-80). Median extension = 0 degrees (full extension), median flexion = 130 degrees . Supplemental screws were used in 17/36 cases; cerclage used in 2/36 cases. Hardware irritation was noted in 4/20 patients, no patient requested elective hardware removal, one patient had failure of fixation and no nonunions were identified. CONCLUSION: Fixed angle plate stabilization of comminuted patella fractures is a viable technique for fracture fixation. Good to excellent return of knee function and low complication rates, including need for hardware removal, can be expected. PMID- 29609973 TI - The burden of gunshot wounding of UK military personnel in Iraq and Afghanistan from 2003-14. AB - INTRODUCTION: Gunshot wounding (GSW) is the second most common mechanism of injury in warfare after explosive injury. The aim of this study was to define the clinical burden of GSW placed on UK forces throughout the recent Iraq and Afghanistan conflicts. METHODS: This study was a retrospective review of data from the UK Military Joint Theatre Trauma Registry (JTTR). A JTTR search identified records within the 12 year period of conflict between 19 Mar 2003 and 27 Oct 2014 of all UK military GSW casualties sustained during the complete timelines of both conflicts. Included cases had their clinical timelines and treatment further examined from time of injury up until discharge from hospital or death. RESULTS: There were 723 casualties identified (177 fatalities, 546 survivors). Median age at the time of injury was 24 years (range 18-46 years), with 99.6% of casualties being male. Most common anatomical locations for injury were the extremities, with 52% of all casualties sustaining extremity GSW, followed by 16% GSW to the head, 15% to the thorax, and 7% to the abdomen. In survivors, the rate of extremity injury was higher at 69%, with head, thorax and abdomen injuries relatively lower at 5%, 11% and 6% respectively. All GSW casualties had a total of 2827 separate injuries catalogued. A total of 545 casualties (523 survivors, 22 fatalities) underwent 2357 recorded surgical procedures, which were carried out over 1455 surgical episodes between admission to a deployed medical facility and subsequent transfer to the Royal Centre for Defence Medicine (RCDM) in the UK. This gave a median of 3 (IQR 2-5) surgical procedures within a median of 2 (IQR 2-3) surgical episodes per casualty. Casualties had a combined length of stay (LoS) of 25 years within a medical facility, with a mean LoS in a deployed facility of 1.9 days and 14 days in RCDM. CONCLUSION: These findings define the massive burden of injury associated with battlefield GSW and underscore the need for further research to both reduce wound incidence and severity of these complex injuries. PMID- 29609974 TI - Policy brief as a knowledge transfer tool: to "make a splash", your policy brief must first be read. PMID- 29609975 TI - In Reply to 'Low Birth Weight: Intrauterine Growth Restriction or Prematurity?' PMID- 29609976 TI - In Reply to 'Artificial Intelligence Can Predict GFR Decline During the Course of ADPKD' and 'Linear and Nonlinear Estimated GFR Slopes in ADPKD Patients Reaching ESRD'. PMID- 29609977 TI - Linear and Nonlinear Estimated GFR Slopes in ADPKD Patients Reaching ESRD. PMID- 29609978 TI - Low Birth Weight: Intrauterine Growth Restriction or Prematurity? PMID- 29609979 TI - Artificial Intelligence Can Predict GFR Decline During the Course of ADPKD. PMID- 29609980 TI - Age- and gender-dependent associations of blood pressure and serum sodium and potassium-renal and extrarenal regulations. AB - Association analyses between blood pressure (BP) and serum sodium and potassium for 14,657 men and 16,977 women between ages 12 and 85 years show that responses of BP to serum sodium and potassium are age and gender dependent. The data were from the National Health and Nutrition Examination Survey between 2003 and 2014. Associations between serum sodium and BP are positive only for advanced age groups and for serum sodium level greater than 139-140 mmol/L in less advanced groups. These positive associations can be explained by traditional renal centered mechanism. Inverse associations between systolic BP and serum sodium exist when sodium is less than ~140 mmol/L in less advanced age groups (<60 for men and <70 for women). These inverse associations can partially be explained by the extrarenal regulatory mechanism in which sodium storage in negatively charged glycosaminoglycans in the interstitium may be involved. Associations of high serum potassium and low BP are consistent and exist in most age groups. Effect of potassium on systolic BP and diastolic BP are more prominent in less advanced age groups. Age-dependent associations between sodium and BP support the theory that sodium homeostasis in the body may not be regulated by renal-centered responses alone. There might be regulation of an extrarenal system in which sodium attraction by negatively charged glycosaminoglycans plays a role. PMID- 29609981 TI - On the enjoyment of violence and aggression in music. Comment on "An integrative review of the enjoyment of sadness associated with music" by Tuomas Eerola et al. PMID- 29609982 TI - Sleep disturbances, posttraumatic stress, and psychological distress among survivors of the 2013 Super Typhoon Haiyan. AB - Sleep disturbances and their relation with posttraumatic stress and general psychological distress were examined after the 2013 Super Typhoon Haiyan. Sleep disturbances were hypothesized to be associated with posttraumatic stress and general psychological distress in two samples of survivors across two time points (N = 361) in the Philippines. Sample 1 (n = 223) and Sample 2 (n = 138) were collected 18 months and 30 months after the storm, respectively. Results from structural regression modeling indicated that insomnia was associated with both posttraumatic stress and general psychological distress. Poor sleep quality was associated with posttraumatic stress but not with general psychological distress. Findings underscore the longer-term relationship between sleep disturbances and overall sleep quality to posttraumatic stress in the context of a natural disaster. Implications for public mental health interventions in disaster settings are discussed. PMID- 29609983 TI - Comment on "Therapeutic effect of sertindole on neurocognitive deficit independently of positive and negative symptoms response: A case report". PMID- 29609984 TI - Evaluating the role of functional impairment in personality psychopathology. AB - DSM-5's Section III Alternative Model for Personality Disorder (AMPD) model states that an individual must show impairment in self and interpersonal functioning for PD diagnosis. The current study investigated dimensional personality trait associations with impairment, including differential patterns of impairment across specific PDs, and whether traits have improved our assessment of functional impairment in PDs. Two-hundred and seventy-seven participants were administered measures of Antisocial PD, Avoidant PD, Borderline PD, Narcissistic PD, Obsessive-Compulsive PD, and Schizotypal PD from the perspectives of Section II (PDQ-4) and Section III (PID-5) PD models, as well as measures of functional impairment in interpersonal and intrapersonal domains. Pearson correlations showed associations between ratings of impairment and most Section II and Section III PDs and trait facets, with the exception of narcissistic PD. Hierarchical regression analyses revealed that Section III PDs added predictive validity beyond Section II PDs in predicting impairment, except narcissistic PD. These findings provide support both for the impairment criterion in the AMPD and for the association between trait-based PDs and impairment, and suggest that this trait-based measurement adds uniquely to the understanding of functional impairment. PMID- 29609985 TI - Family allocentrism and its relation to adjustment among Chinese and Italian adolescents. AB - Family allocentrism is a domain-specific collectivistic attribute referring to the family. This research tested the one-factor structure of the Family Allocentrism Scale (FAS), examined the association between family allocentrism and adjustment outcomes, and compared the factor means and the correlations with adjustment between Chinese and Italian adolescents. To this end, 484 Chinese and 480 Italian adolescents participated in the study by answering a battery of self report measures. The results confirmed the one-factor structure of the FAS. Family allocentrism was related to a number of adjustment outcomes. More importantly, Chinese adolescents reported more family allocentrism than their Italian counterparts did, but the relations between family allocentrism and adjustment outcomes were equivalent in magnitude between the two samples. Collectively, these findings provide crucial evidence for the psychometric properties of the FAS and shed light on the importance of family allocentrism in promoting positive youth development from a cross-cultural perspective. PMID- 29609986 TI - State paranoia and urban cycling. AB - Consistent with a continuum approach to mental health, a growing body of research has established that paranoia occurs in the general population. The stress vulnerability model would predict an association between environments high in threat and the presence of state paranoia, even in those with low dispositional trait paranoia. The present research examines whether urban cycling, a naturalistic environment high in interpersonal threat, is associated with state paranoia - operationalised as an explicit perception that other road users intend the agent harm. 323 members of the general population who regularly cycled in London completed measures of state and trait paranoia, anxiety, depression and stress. The majority of the general population sample (70%) reported experiencing state paranoia during urban cycling, and there was no association between state paranoia and trait paranoia. Reported state paranoia was higher during urban cycling than when using the London underground (a lower threat environment) and reported state paranoia on the underground was associated with trait paranoia. The findings are consistent with the stress-vulnerability model of everyday paranoia. PMID- 29609987 TI - Associations of oxytocin and vasopressin plasma levels with neurocognitive, social cognitive and meta cognitive function in schizophrenia. AB - Many with schizophrenia experiences deficits in social cognition, neurocognition and metacognition. Yet the biological mechanisms which may underpin these cognitive deficits are poorly understood. Two candidate causes of these deficits are disturbances in oxytocin (OT) and vasopressin (VP). To explore this we assessed plasma OT and VP in 34 schizophrenia patients and 31 healthy controls. We also concurrently assessed social cognition using the Reading the Mind from the Eyes test, neurocognition using the Wisconsin Card Sorting Test and metacognition using the Metacognitive Assessment Scale-Abbreviated. Group comparisons revealed lower plasma OT levels in the schizophrenia group. Plasma VP levels did not differ between groups. Correlations revealed that lower levels of OT were associated with poorer levels of metacognitive functioning in the schizophrenia group but not poorer social cognition or neurocognition. In a stepwise multiple regression, plasma OT level, neurocognition and social cognition contributed uniquely to the prediction of metacognition in the schizophrenia group. Results may suggest that disturbance in OT is linked with deficits in metacognition and may interact with other forms of cognitive deficits, interfering with the person's abilities to form a complex and integrated sense of self and others. PMID- 29609988 TI - Internalised stigma in mental health: An investigation of the role of attachment style. AB - Internalised stigma is associated with a range of negative outcomes, yet little is known about what determines the internalisation of stigma. In this study we examined the potential role of adult attachment style in the internalisation process in a transdiagnostic sample of adults with experience of recent mental health service use (n = 122), using an online survey. Associations between internalised stigma and perceived public stigma were tested. We also examined whether anxious and avoidant (insecure) attachment styles were positively associated with a significant amount of variance in internalised stigma when controlling for other variables, and whether the relationship between perceived public stigma and internalised stigma was moderated by anxious and avoidant attachment. We found that internalised stigma, perceived public stigma and insecure attachment were commonly reported and that internalised stigma was positively associated with perceived public stigma. However, neither anxious or avoidant attachment were associated with a significant amount of variance in internalised stigma and we found no moderating effect on the relationship between perceived public stigma and internalised stigma for insecure attachment. Despite mixed results, the strength of association between anxious attachment and internalised stigma suggests further research, which addresses some limitations of the current study, is warranted. PMID- 29609989 TI - Developing a short version of the Toronto Structured Interview for Alexithymia using item response theory. AB - The Toronto Structured Interview for Alexithymia (TSIA) was developed to provide a structured interview method for assessing alexithymia. One drawback of this instrument is the amount of time it takes to administer and score. The current study used item response theory (IRT) methods to analyze data from a large heterogeneous multi-language sample (N = 842) to investigate whether a subset of items could be selected to create a short version of the instrument. Samejima's (1969) graded response model was used to fit the item responses. Items providing maximum information were retained in the short model, resulting in the elimination of 12-items from the original 24-items. Despite the 50% reduction in the number of items, 65.22% of the information was retained. Further studies are needed to validate the short version. A short version of the TSIA is potentially of practical value to clinicians and researchers with time constraints. PMID- 29609990 TI - Behavior Problems Inventory (BPI): Psychometric characteristics of an instrument for routine assessment of persons with psychoses and related disorders. AB - This study explores the psychometric characteristics of the Behavior Problems Inventory (BPI), an instrument for routine clinical assessment of behavior problems in outpatients with psychosis based on information provided by key family informants. Six hundred and twenty-one patients diagnosed with psychosis and bipolar affective disorder (ICD-10 F20-F31) attended at Community Mental Health Units were evaluated in routine reviews using the BPI and the Social Functioning Scale (SFS). Twenty-five subjects were simultaneously administered the Social Behavior Schedule (SBS) and 28 were again administered the BPI eight weeks later. The instrument shows adequate psychometric characteristics with high internal consistency and robust temporal reliability, as well as satisfactory concurrent and construct validity. Factor analysis identified three factors: Underactivity/Social Withdrawal, Active Problems and Lack of Impulse Control, with adequate saturation of the items on each of the factors. The BPI is easy to apply, reliable and valid, takes up little of valuable clinical time, allowing routine assessment in public service contexts for persons diagnosed with psychosis and bipolar affective disorder for whom key family informants are available. PMID- 29609991 TI - Exploring the role of the DSM-5 performance-only specifier in adolescents with social anxiety disorder. AB - The DSM-5 social anxiety disorder section has recently added the performance-only specifier for individuals whose anxiety is limited to speaking or performing in public. The impact of the DSM-5 performance-only specifier remains a neglected area. The sample comprised 44 healthy controls and 50 adolescents with a clinical diagnosis of SAD (20% met criteria for the performance-only specifier). Findings revealed that adolescents with the specifier had a later age of onset; lower levels of depression, social anxiety symptomatology and clinical severity; and a lesser degree of comorbidity relative to adolescents with SAD but excluding the performance-only specifier. Specifiers only evidenced higher (cognitive) social anxiety symptomatology compared to healthy controls. Results of this study also suggested that the performance-only specifier may correspond to a mild form of social anxiety disorder. Data also revealed that SAD exists on a continuum of severity among healthy controls, specifier participants, and those with both interactional and performance fears, which is consistent with a dimensional structure for SAD. Finally, findings suggested a unique comorbid pattern for specifiers and those adolescents with SAD but excluding the performance-only specifier. The implications of these findings for the etiology, assessment, classification, and treatment of social anxiety in youth are discussed. PMID- 29609992 TI - Epileptogenicity and pathology - Under consideration of ablative approaches. AB - Besides resective epilepsy surgery, minimally invasive ablation using new diagnostic and therapeutic techniques recently became available. Optimal diagnostic approaches for these treatment options are discussed. The pathophysiology of epileptogenic networks differs depending on the lesion-types and location, requiring a differential use of non-invasive or invasive functional studies. In addition to the definition of epileptogenic zones, a challenge for pre-surgical investigation is the determination of three-dimensional epileptic networks to be removed. PMID- 29609993 TI - Evidence on selection, optimization, and compensation strategies to optimize aging with multiple chronic conditions: A literature review. AB - The self-regulation strategies of selection, optimization, and compensation (SOC) can be effective in optimizing aging with multiple chronic conditions (MCC). Nineteen articles on the use and effects of SOC among older adults with chronic conditions were reviewed. The studies' quality, evaluated by the Mixed Methods Appraisal Tool, ranged from medium to high (Mean = 0.90, SD = 0.10). SOC were found to improve the symptom experience for older adults, resulting in better health outcomes such as increased daily living activities, subjective well-being, life success, fewer falls/sick days, and use of medication for pain control. For those with MCC, higher degree of disabilities, serious health events, and negative self-perceived aging undermined the relationships between SOC and long term physical functioning, self-rated health, and life satisfaction. Aging can be optimized by identifying and improving older individuals' coping using SOC. Future studies should utilize better MCC measures for comorbidity and chronic disabling symptoms to investigate the influence of SOC on MCC-associated health outcomes. PMID- 29609995 TI - Discussion. PMID- 29609994 TI - Refinement of anatomic indications for the Nellix System for endovascular aneurysm sealing based on 2-year outcomes from the EVAS FORWARD IDE trial. AB - BACKGROUND: The Nellix System (Endologix, Inc, Irvine, Calif) for endovascular aneurysm sealing (EVAS) is a novel approach to abdominal aortic aneurysm treatment and conceptually different from endovascular aneurysm repair, whereby polymer is employed to fill and actively manage the abdominal aortic aneurysm sac. One-year safety and effectiveness results of the Nellix pivotal trial demonstrated encouraging outcomes with very low morbidity and mortality and high procedural and treatment success. Two-year imaging revealed a signal of migration, leading to a field safety notification issued by the manufacturer on October 21, 2016, and a dedicated root cause analysis, resulting in refinements to the instructions for use (IFU). We report the 2-year results of the investigational device exemption pivotal trial stratified according to the new and original criteria for selection of patients. METHODS: Comprehensive engineering evaluations, statistical analyses, and clinical assessments were conducted looking at patients enrolled in the pivotal trial (N = 150), roll-in cohort (N = 29), and continued access program (N = 154). All patients in all cohorts were treated on-IFU at the time of enrollment. Logistic regression models supported the mechanism that migration with Nellix is associated with a small aortic flow lumen relative to a large aneurysm thrombus burden and large aortic neck diameters. Based on these findings, refinements to the IFU criteria were applied, excluding patients with a thrombus index (maximum aneurysm sac/maximum flow lumen diameter) >1.4, aortic neck diameter >28 mm, and aortic neck conicity (>10% diameter change along the infrarenal neck) and requiring a 10-mm distal seal zone in the iliac artery. RESULTS: Freedom from all-cause mortality at 2 years was 94%. Patient outcomes were then stratified on the refined morphologic criteria and analyzed retrospectively. Two-year freedom from composite endoleak was high among both cohorts (95% on-IFU vs 92% off-IFU). Freedom from migration was 97.7% on-IFU vs 93.2% off-IFU (P = .0125). Freedom from aneurysm enlargement was 98.1% on-IFU vs 93.5% off-IFU (P value is not available because of failure of log-rank test assumptions). Composite freedom from migration, type IA endoleak, or aneurysm expansion was 95.9% among the on-IFU cohort vs 85.1% in the off-IFU cohort (P = .0017). CONCLUSIONS: Consistent with the introduction of a novel therapy, the presentation of failure modes of EVAS over time was inevitable. Using detailed imaging as well as engineering and statistical analysis, we were able to understand risk factors for adverse events specific to EVAS and defined those patients best suited for Nellix. With this EVAS-specific approach to defining IFU, on-IFU patients were identified as those with large aneurysms with little thrombus that would be prone to type II endoleaks and sac expansion with traditional devices. When treated with Nellix, these patients were predicted to experience exceptional results, especially with regard to a low composite endoleak rate and low all-cause mortality. PMID- 29609996 TI - Surgical Management of Stage 2 Adult and Pediatric Acquired Flatfoot Without Tendon Transfer or Arthrodesis: A Retrospective Study. AB - Posterior tibial tendon dysfunction (PTTD) is a common pathology of the foot and ankle. Numerous techniques are available to reconstruct the flatfoot. Fusions and tendon transfers are popular methods; however, a wide range of complications have been associated with these procedures. The objective of the present study was to demonstrate the outcomes of reconstructive surgery for flatfoot correction without tendon transfer or arthrodesis. We performed a retrospective study of 43 patients and 56 feet who had undergone flatfoot reconstructive surgery from November 2011 to June 2016, with a mean follow-up period of 60 weeks (range 12 to 60 months). Each patient demonstrated a stage 2 flatfoot deformity classified using the Johnson and Strom classification. Depending on the patient's deformity, the procedures consisted of different variations of gastrocnemius recession, medial displacement calcaneal osteotomy, Evans osteotomy, and Cotton osteotomy. Six different preoperative and postoperative angles were radiographically measured on each foot studied. In all cases, the differences in the preoperative versus postoperative measurements were statistically significant (p < .003). We believe the foot and ankle surgeon can correct flatfoot deformity with the use of extraarticular procedures and create a plantigrade functional foot without fusion or tendon transfer. PMID- 29609997 TI - Dynamic Functional Stiffness Index of the Ankle Joint During Daily Living. AB - Exploring ankle joint physiologic functional stiffness is crucial for improving the design of prosthetic feet that aim to mimic normal gait. We hypothesized that ankle joint stiffness would vary among the different activities of daily living and that the magnitude of the stiffness would indicate the degree of energy storage element sufficiency in terms of harvesting and returning energy. We examined sagittal plane ankle moment versus flexion angle curves from 12 healthy subjects during the daily activities. The slopes of these curves were assessed to find the calculated stiffness during the peak energy return and harvest phases. For the energy return and harvest phases, stiffness varied from 0.016 to 0.283 Nm/kg degrees and 0.025 and 0.858 Nm/kg degrees , respectively. The optimum stiffness during the energy return phase was 0.111 +/- 0.117 Nm/kg degrees and during the energy harvest phase was 0.234 +/- 0.327 Nm/kg degrees . Ankle joint stiffness varied significantly during the activities of daily living, indicating that an energy storage unit with a constant stiffness would not be sufficient in providing energy regenerative gait during all activities. The present study was directed toward the development of a complete data set to determine the torque angle properties of the ankle joint to facilitate a better design process. PMID- 29609998 TI - Arthroscopic isolated capsular release for shoulder contracture after brachial plexus birth palsy: clinical outcomes in a prospective cohort of 28 children with 2 years' follow-up. AB - BACKGROUND: The primary objective of this study was to evaluate improvements in external rotation after isolated arthroscopic capsular release in children with shoulder contracture due to brachial plexus birth palsy. MATERIALS AND METHODS: This study included all children older than 2 years with a range of active external rotation limited to 30 degrees or less and/or active anterior elevation (AE) limited to 90 degrees or less secondary to brachial plexus palsy treated between 2011 and 2015. Passive glenohumeral motion, passive global (glenohumeral plus scapulothoracic) motion, active global motion for external rotation with the elbow at the side (ER1), AE, and internal rotation with the elbow at the side were recorded before and 2 years after surgery. Improvement was evaluated by comparing the preoperative and follow-up values. The operation performed was subscapularis-sparing arthroscopic capsular release. RESULTS: Thirty-five patients were included, and 28 completed 2 years of follow-up. The average changes in active global ER1, passive glenohumeral ER1, and passive global ER1 were +35 degrees (range, -20 degrees to +100 degrees ; P <.0001), +35 degrees (range, +0 degrees to +75 degrees ; P <.0001), and +26 degrees (range, -15 degrees to +60 degrees ; P <.0001), respectively. There were no significant changes in internal rotation with the elbow at the side or AE. The mean improvement in the aggregate Mallet score was 3.9 points (range, -3 to +9 points; P <.0001). CONCLUSIONS: For children with shoulder contracture secondary to brachial plexus palsy, subscapularis-sparing isolated capsular release improves external rotation and functional scores and avoids any loss of active internal rotation but does not improve AE. PMID- 29609999 TI - Topical benzoyl peroxide application on the shoulder reduces Propionibacterium acnes: a randomized study. AB - BACKGROUND: Propionibacterium acnes is a common cause of infection following shoulder surgery. Studies have shown that standard surgical preparation does not eradicate P acnes. The purpose of this study was to examine whether topical application of benzoyl peroxide (BPO) gel could decrease the presence of P acnes compared with today's standard treatment with chlorhexidine soap (CHS). We also investigated and compared the recolonization of the skin after surgical preparation and draping between the BPO- and CHS-treated groups. METHODS: In this single-blinded nonsurgical study, 40 volunteers-24 men and 16 women-were randomized to preoperative topical treatment at home with either 5% BPO or 4% CHS on the left shoulder at the area of a deltopectoral approach. Four skin swabs from the area were taken in a standardized manner at different times: before and after topical treatment, after surgical skin preparation and sterile draping, and 120 minutes after draping. RESULTS: Topical treatment with BPO significantly reduced the presence of P acnes measured as the number of colony-forming units on the skin after surgical preparation. P acnes was found in 1 of 20 subjects in the BPO group and 7 of 20 in the CHS group (P = .044). The results remained after 2 hours (P = .048). CONCLUSION: Topical preparation with BPO before shoulder surgery may be effective in reducing P acnes on the skin and preventing recolonization. PMID- 29610000 TI - Critical period of neuromuscular development: Importance for a new treatment of SMA. AB - Findings from mice that had their Smn gene deleted and some copies of the human SMN2 gene introduced to produce SMN protein are summarized. Symptoms due to this manipulation can be corrected only by restoring the SMN protein expression in neurones and not in muscle. The changes in muscle and neuromuscular junction (NMJ) in these mutant mice are probably due to the malfunction of the neuronal component of the NMJ i.e. the nerve terminal. The reduction of transmitter release by nerve terminals in animals with reduced SMN protein supports this notion. There is a critical period during which the presence of the SMN protein is mandatory for the survival of the motor unit and the individual. This period coincides with the most important events involved in the development of the motor unit. Results from normal genetically unaffected rats and mice show that during a critical period of development the function of the nerve terminal and the release of transmitter play a crucial role in the development of the motor neurone and muscle. The possibility that targeting the function of the nerve terminal to overcome its inability to release transmitter could benefit patients with the deletion of the SMN gene. PMID- 29610001 TI - Opioid-overdose laws association with opioid use and overdose mortality. AB - INTRODUCTION: Since the 1990's, governmental and non-governmental organizations have adopted several measures to increase access to the opioid overdose reversal medication naloxone. These include the implementation of laws that increase layperson naloxone access and overdose-specific Good Samaritan laws that protect those reporting overdoses from criminal sanction. The association of these legal changes with overdose mortality and non-medical opioid use is unknown. We assess the relationship of (1) naloxone access laws and (2) overdose Good Samaritan laws with opioid-overdose mortality and non-medical opioid use in the United States. METHODS: We used 2000-2014 National Vital Statistics System data, 2002-2014 National Survey on Drug Use and Health data, and primary datasets of the location and timing of naloxone access laws and overdose Good Samaritan laws. RESULTS: By 2014, 30 states had a naloxone access and/or Good Samaritan law. States with naloxone access laws or Good Samaritan laws had a 14% (p = 0.033) and 15% (p = 0.050) lower incidence of opioid-overdose mortality, respectively. Both law types exhibit differential association with opioid-overdose mortality by race and age. No significant relationships were observed between any of the examined laws and non-medical opioid use. CONCLUSIONS: Laws designed to increase layperson engagement in opioid-overdose reversal were associated with reduced opioid overdose mortality. We found no evidence that these measures were associated with increased non-medical opioid use. PMID- 29610002 TI - Renal Cell Carcinoma Presenting as Carcinoma of Unknown Primary Site: Recognition of a Treatable Patient Subset. AB - BACKGROUND: Improved diagnostic methods, including gene expression profiling, allow identification of the tissue of origin in most patients with carcinoma of unknown primary site (CUP). Patients with an occult renal cell carcinoma (RCC) are of particular interest, because effective treatment for advanced RCC has no overlap with the empiric chemotherapy used traditionally for CUP. We report the clinical characteristics, pathologic features, and response to RCC-specific treatment in CUP patients identified as RCC using a molecular cancer classifier assay (MCCA). PATIENTS AND METHODS: All CUP patients who had an MCCA performed between 2008 and 2013 at a single institution were reviewed. Patients with an RCC diagnosis using MCCA are reported in this article. RESULTS: Twenty-four of 539 CUP patients (4.4%) were diagnosed with RCC using MCCA. None had suspected renal lesions on computed tomography scan; otherwise, clinical characteristics were typical of advanced RCC. Histology was adenocarcinoma or poorly differentiated carcinoma; only 5 of 24 patients had focal features suggestive of RCC (clear-cell 1, papillary 4). Specific MCCA diagnoses included papillary (11) and clear cell (6). Relatively specific renal immunohistochemistry (IHC) stains, when performed, were compatible with RCC in 9 of 11 tumors. Twenty of 24 patients received RCC specific treatment, and had a median survival of 16 months. CONCLUSIONS: Patients with occult RCC can be identified in the CUP population using MCCA and/or IHC. Papillary carcinoma is more common in this group than in the larger RCC population. Although confirmation from prospective studies is needed, RCC specific treatment should be considered for this group of patients. PMID- 29610003 TI - [Therapeutic strategy for the treatment of non-infectious uveitis proposed by an expert panel]. AB - Conventional immunosuppressive drugs, anti-TNF alpha and other biotherapies used in clinical practice are capable of controlling non-infectious anterior uveitis, posterior uveitis and panuveitis. The present work has been led by a multidisciplinary panel of experts, internists, rheumatologists and ophthalmologists and is based on a review of the literature. In case of corticodependency or sight-threatening disease, conventional immunosuppressive drugs (methotrexate, azathioprine and mycophenolate mofetil) and/or anti-TNF alpha (adalimumab, infliximab) are used to achieve and maintain remission. Interferon is an efficient immunomodulatory treatment, as a second-line therapy, for some therapeutic indications (refractory macular edema, Behcet's vascularitis). Other biologics, especially tocilizumab, are showing promising results. Local treatments (corticosteroids, sirolimus etc.) are adjuvant therapies in case of unilateral inflammatory relapse. Therapeutic response must be evaluated precisely by clinical examination and repeated complementary investigations (laser flare photometry, multimodal imaging, perimetry, electroretinography measures). PMID- 29610004 TI - [Bell's palsy]. AB - Idiopathic peripheral facial palsy, also named Bell's palsy, is the most common cause of peripheral facial palsy in adults. Although it is considered as a benign condition, its social and psychological impact can be dramatic, especially in the case of incomplete recovery. The main pathophysiological hypothesis is the reactivation of HSV 1 virus in the geniculate ganglia, leading to nerve edema and its compression through the petrosal bone. Patients experience an acute (less than 24 hours) motor deficit involving ipsilateral muscles of the upper and lower face and reaching its peak within the first three days. Frequently, symptoms are preceded or accompanied by retro-auricular pain and/or ipsilateral face numbness. Diagnosis is usually clinical but one should look for negative signs to eliminate central facial palsy or peripheral facial palsy secondary to infectious, neoplastic or autoimmune diseases. About 75% of the patients will experience spontaneous full recovery, this rate can be improved with oral corticotherapy when introduced within the first 72 hours. To date, no benefit has been demonstrated by adding an antiviral treatment. Hemifacial spasms (involuntary muscles contractions of the hemiface) or syncinesia (involuntary muscles contractions elicited by voluntary ones, due to aberrant reinnervation) may complicate the disease's course. Electroneuromyography can be useful at different stages: it can first reveal the early conduction bloc, then estimate the axonal loss, then bring evidence of the reinnervation process and, lastly, help for the diagnosis of complications. PMID- 29610005 TI - [Iron deficiency: Recent pathophysiological approach and treatment consequences]. PMID- 29610006 TI - [Type 3 Gaucher disease, also an adult disease?] AB - INTRODUCTION: Gaucher disease is a genetic lysosomal storage disorder due to a glucocerebrosidase deficiency. Type 3, including neurological impairment, may have a specific phenotype in the context of the D409H mutation. OBSERVATION: We report the case of a 22-year-old woman who presented with Gaucher disease. Enzyme replacement therapy by imiglucerase was followed by rapid clinical and biological improvement. However, communication difficulties, which were initially attributed to the language barrier, revealed neurological impairment. After complementary assessment, the diagnosis of type 3 Gaucher disease was suspected. Gene analysis of the glucocerebrosidase showed a homozygous D409H mutation. CONCLUSION: This mutation results in calcified heart valves, corneal opacities, alteration of oculomotricity and hydrocephalus. The mild manifestation at onset and the late neurological involvement in the medical history make the diagnosis more difficult. This particular clinical phenotype deserves to be known in adult medicine departments. PMID- 29610007 TI - Conventional JOA score for cervical myelopathy has a rater's bias -In comparison with JOACMEQ. AB - BACKGROUND: The JOA (Japan Orthopaedic Association) score has been a standard outcome measure to evaluate cervical myelopathy in Japan. Despite its reliability and convenience, there can be a rating bias in the JOA score. The current study was conducted to delineate the rater's bias of the JOA score by comparing it with a new objective outcome measure. METHODS: Two hundred and thirty four operative candidates with cervical myelopathy were included in the study. The patients were divided into four groups according to the surgeon (92 patients in group A, 60 patients in group B, 38 patients in group C and 44 patients in group D). Each patient's preoperative JOA score was exclusively recorded by the surgeon himself, while JOACMEQ (Japanese Orthopaedic Association Cervical Myelopathy Evaluation Questionnaire) was recorded by each patient. Disease severity, the most important prognostic factor, was equalized between patient groups by a special statistical method called inverse-probability weighting (IPW). To define similarity of the two groups, Cohen's d was used. RESULTS: After the adjustment, the differences of the JOA score were only 0.1 between groups A and D and 0 between groups B and C. The values of Cohen's d were also very small both between groups A and D (3%), and between groups B and C (0.3%). The averaged JOA scores of groups A and D were higher by 0.4-0.8 than those of groups B and C, while the averaged JOA scores were almost the same both between groups A and D, and between groups B and C. Surgeons A and D had the same tendency to give higher JOA scores than surgeons B and C did. CONCLUSIONS: The current study confirmed there is a definite rater's bias in the JOA score. JOACMEQ is to be applied as a more reliable outcome measure to evaluate myelopathy patients. PMID- 29610008 TI - Surgical outcomes of spinal cord and cauda equina ependymoma: Postoperative motor status and recurrence for each WHO grade in a multicenter study. AB - BACKGROUND: The goals of the study are to analyze postoperative outcomes and recurrence in cases of spinal cord and cauda equina ependymoma in each World Health Organization (WHO) Grade, and to examine the influence of extent of surgical removal on prognosis. Spinal ependymoma has a relatively high frequency among intramedullary spinal cord tumors. The tumor is classified in WHO guidelines as grades I, II, and III, but few studies have examined postoperative prognosis based on these grades. METHODS: The records of 80 patients undergoing surgery for spinal cord and cauda equina ependymoma were examined in a multicenter study using a retrospective database. Neurological motor status, pathological type, extent of resection, and tumor recurrence were evaluated. RESULTS: The histopathological types were grade I in 23 cases (myxopapillary: 21, subependymoma: 2), grade II in 52 cases, and grade III in 5 cases (including all anaplastic cases). Total resection was performed in 60 cases (83%), and eight cases had recurrence, including 2 in WHO grade I, 2 in grade II, and 4 in grade III. The 5-year recurrence-free survival rates were 90%, 91%, and 20% in grades I, II and III, respectively. Adjuvant radiotherapy for the local site was performed in 8 cases, including 3 in grade I and 5 in grade III; however, 4 of the 5 grade III cases (80%) had recurrence after radiotherapy. Among 59 patients with normal ambulation or independence without external assistance (McCormick Grade I or II), 53 (90%) maintained the same mobility after surgery. In cases that underwent total resection, the recurrence rate was significantly lower (p < 0.01). A good preoperative motor status also resulted in significantly better postoperative recovery of motor status (p < 0.05). CONCLUSIONS: Total resection of spinal cord and cauda equina ependymoma leads to postoperative motor recovery and may reduce tumor recurrence. Therefore, early surgery for this tumor is recommended before aggravation of paralysis. PMID- 29610009 TI - Selected Heat-Sensitive Antibiotics Are Not Inactivated During Polymethylmethacrylate Curing and Can Be Used in Cement Spacers for Periprosthetic Joint Infection. AB - BACKGROUND: Antibiotic use in polymethylmethacrylate (PMMA) spacers has historically been limited to those which are "heat-stable" and thus retain their antimicrobial properties after exposure to the high temperatures which occur during PMMA curing. METHODS: This study examines the requirement of "heat stability" by measuring temperatures of Palacos and Simplex PMMA as they cure inside commercial silicone molds of the distal femur and proximal tibia. Temperature probes attached to thermocouples were placed at various depths inside the molds and temperatures were recorded for 20 minutes after PMMA introduced and a temperature curve for each PMMA product was determined. A "heat-stable" antibiotic, vancomycin, and a "heat-sensitive" antibiotic, ceftazidime, were placed in a programmable thermocycler and exposed to the same profile of PMMA curing temperatures. Antimicrobial activity against Staphylococcus aureus was compared for heat-treated antibiotics vs room temperature controls. RESULTS: Peak PMMA temperatures were significantly higher in tibial (115.2 degrees C) vs femoral (85.1 degrees C; P < .001) spacers. In the hottest spacers, temperatures exceeded 100 degrees C for 3 minutes. Simplex PMMA produced significantly higher temperatures (P < .05) compared with Palacos. Vancomycin bioactivity did not change against S aureus with heat exposure. Ceftazidime bioactivity did not change when exposed to femoral temperature profiles and was reduced only 2-fold with tibial profiles. CONCLUSION: The curing temperatures of PMMA in knee spacers are not high enough or maintained long enough to significantly affect the antimicrobial efficacy of ceftazidime, a known "heat-sensitive" antibiotic. Future studies should investigate if more "heat-sensitive" antibiotics could be used clinically in PMMA spacers. PMID- 29610010 TI - High Rate of Positive Cultures in Patients Referred With Antibiotic Spacers as Part of 2-Stage Exchange. AB - BACKGROUND: Two-stage exchange for periprosthetic joint infection (PJI) in total knee arthroplasty (TKA) remains the gold standard treatment in North America. Occasionally, patients with knee PJI are referred for definitive management after resection and antibiotic spacer placement. Currently, little literature exists to suggest how these patients should be managed. The purpose of this study is to report the clinical outcomes of these patients. METHODS: We retrospectively identified 54 patients (54 knees) from 2000 to 2012 treated for PJI with initial TKA resection and spacer placement performed somewhere other than the definitive treatment center. The mean age at reimplantation was 64 years, with 59% being male. Redebridement and antibiotic spacer exchange was performed for all patients. Mean follow-up was 6.5 years. RESULTS: Of the 54 knees, 22 (41%) grew an organism from a culture taken at the time of redebridement and spacer exchange. The most common organism identified at redebridement was Staphylococcus aureus (41%). Obtaining positive cultures at redebridement was not associated with presenting erythrocyte sedimentation rate (P = .46), C-reactive protein (P = .57), or the presence of retained cement (P = .13). Forty-nine of 54 (91%) knees were ultimately reimplanted. Two-year survivorship free of infection in reimplanted knees was 98%. CONCLUSION: Patients referred with an antibiotic knee spacer for PJI have a high rate of positive cultures at the time of redebridement. Neither the presenting serology nor the identification of retained cement was associated with obtaining positive cultures at the time of redebridement. Nevertheless, this unique cohort of patients has favorable outcomes when redebrided with spacer exchange prior to reimplantation. PMID- 29610011 TI - The Oxford Medial Unicompartmental Knee Arthroplasty: The South African Experience. AB - BACKGROUND: The Oxford unicompartmental knee arthroplasty (OUKA) is a successful treatment for endstage, symptomatic anteromedial osteoarthritis. This study reports the results of a cohort of consecutive cemented and cementless medial OUKAs from an independent center and aims to answer the following questions: what is the survival of OUKA in the hands of a nondesigner surgeon? Are there any differences in the survival of cementless and cemented OUKA? Are the failure modes any different with the cementless and cemented OUKA? METHODS: One thousand one hundred twenty consecutive OUKAs were implanted in a single center for the recommended indications. Patients were prospectively identified and followed up. Survival was calculated with revision as the end point. RESULTS: There were 522 cemented and 598 cementless implants. The mean follow-up was 8.3 years for cemented implants (range 0.5-17, standard deviation [SD] 2.9) and 2.7 years (range 0.5-7, SD 1.8) for cementless implants. The Oxford knee score improved from a preoperative mean of 22 (SD 8.1) to 40 (SD 7.9) at the last follow-up (P < .001). There were 59 failures requiring revision surgery, with a 5.3% cumulative revision rate. The most common reason for failure was progression of osteoarthritis in the lateral compartment, occurred in 26 cases (2.3%). The cumulative 10-year survival was 91% (95% confidence interval 87.3-95.2). CONCLUSION: The results of this prospective, consecutive case series from the African continent demonstrated that excellent results are achievable with the OUKA in independent centers if the correct indications and surgical technique are used. PMID- 29610012 TI - Sexualised drug use among sexual minority young adults in the United States: The P18 cohort study. AB - BACKGROUND: Substance use and condomless sexual behaviours are both well studied in sexual minority men, but few researchers have used event-level data collection to examine sexualised drug use in sexual and gender minority young adults. The aim of this study is to describe the co-occurrence of sex under the influence of substances and condomless sexual behaviours, using nuanced event-level data, in a racially/ethnically and socioeconomically diverse sample in New York City. METHODS: Data from one wave of a cohort of sexual and gender minority young adults who were assigned male at birth (n = 500) were used to characterise co occurrence of sex under the influence of drugs and condomless sexual behaviours (oral receptive, anal insertive, and anal receptive sex), in the last 30 days. Logistic regression models were constructed to assess associations between sex while high and condomless sexual behaviours, controlling for sociodemographic factors. RESULTS: Preliminary analyses indicated significant associations between engaging in sex while high and condomless sexual behaviours. In unadjusted regression models, sexualised and non-sexualised drug use were both significantly associated with increased odds of condomless sexual behaviours. In adjusted models, sexualised drug use remained significantly associated with condomless anal insertive sex (AOR = 3.57) and condomless anal receptive sex (AOR = 4.98). Having multiple sexual partners was also significantly associated with greater odds of condomless sexual activity in all three adjusted models. CONCLUSION: Multivariable analyses indicated that engaging in sex while high on any drug was associated with increased condomless sexual behaviour, but that sexualised drug use was associated with particularly elevated condomless anal sex. These findings provide insight for understanding the co-occurrence of substance use and condomless sex, and suggest a need for HIV/STI risk reduction strategies that address the role of sexualised drug use. PMID- 29610013 TI - Trocar port scar quality in morbidly obese patients after bariatric surgery. AB - BACKGROUND: Patient satisfaction of scar quality and their influence on health related quality of life (HRQoL) have never been investigated in morbidly obese patients. OBJECTIVES: Our objectives were (1) to assess scar quality 1 year post laparoscopic bariatric surgery by means of the Patient and Observer Scar Assessment Scale (POSAS), and (2) to examine the influence of patients' perception of scar quality on patients' HRQoL. SETTING: A large Bariatric Center of Excellence in the Netherlands. METHODS: This was a descriptive pilot study of patients who underwent primary laparoscopic bariatric surgery. One year after surgery, patients and 2 observers completed the POSAS. HRQoL was assessed by using the RAND-36. Agreement of POSAS scores between patients and observers was calculated with intraclass correlation coefficient. Correlations between POSAS scores and HRQoL scores were calculated with Spearman's rho. RESULTS: A total of 50 patients were included. Patients scored their scar quality worse than observers (21 versus 15-16), particularly on visual parameters (4-5 versus 2-3). Patients and observers showed poor agreement on all POSAS items (intraclass correlation coefficient = .16-.32). No significant correlations were detected between POSAS and HRQoL scores. CONCLUSION: While patient scar quality satisfaction was relatively low after bariatric surgery, these outcomes were not correlated with HRQoL. Bariatric surgeons should be aware that patients could have a different view on scar quality compared with them. This realization is important to manage patient expectations regarding scar quality after bariatric surgery. Effective communication may improve patient satisfaction as an outcome. PMID- 29610014 TI - Gain of function mutation and inflammasome driven diseases in human and mouse models. AB - Activation of the NLRP3 inflammasome, a multiprotein complex, leading to caspase activation with production of proinflammatory IL-1beta represents a major pathway of inflammation. Recent, studies in mice and human patients uncovered several gain-of- function (GOF) mutations in inflammasome sensor proteins that allow inflammasome assembly in the absence of cognate ligands to trigger autoinflammatory syndromes. Cryopyrin-associated periodic syndromes (CAPS) are rare autoinflammatory diseases, comprising a broad disease spectrum with varying severity. CAPS are associated with GOF mutations in the NLRP3 inflammasome and activation of IL-1beta leading to episodes of fever, cutaneous, musculoskeletal, articular, ocular, and neurological symptoms. Here, we review current knowledge on different mutations leading to CAPS and related clinical syndromes. Homologous gene mutations in mice provide insights into the regulation and consequences of the activation of different inflammasomes in several autoinflammatory syndrome. In view of the critical role of IL-1beta in the pathogenesis of autoinflammatory GOF mutations such as CAPS, blockade of the action of IL-1beta is critical. Therapeutic administration of recombinant IL-1 receptor antagonists or monoclonal anti-IL-1beta antibody had a beneficial effect. Furthermore, novel inhibitors of inflammasome complex formation such as MCC950 and related compounds attenuate experimental and clinical disease. The discovery of new GOF mutants of inflammasomes leading to further insights in pathomechanisms and the development of novel inhibitors represent a great challenge. PMID- 29610015 TI - Anxiolytic Therapy: A Paradigm of Successful Mitochondrial Pharmacology. AB - The complex biochemistry and dynamic structure of mitochondria have prevented them from being prominent pharmacological targets. New mechanistic understanding of cholesterol transport and associated neurosteroidogenesis is providing evidence on therapeutic outcomes in mental disorders that is achievable via mitochondrial pharmacology. This warrants general attention on mitochondrial pharmacology to inform therapies. PMID- 29610016 TI - TRPV2 channel inhibitors attenuate fibroblast differentiation and contraction mediated by keratinocyte-derived TGF-beta1 in an in vitro wound healing model of rats. AB - BACKGROUND: Keratinocytes release several factors that are involved in wound contracture and scar formation. We previously reported that a three-dimensional reconstruction model derived from rat skin represents a good wound healing model. OBJECTIVE: We characterized the role of transient receptor potential (TRP) channels in the release of transforming growth factor (TGF)-beta1 from keratinocytes and the differentiation of fibroblasts to identify possible promising pharmacological approaches to prevent scar formation and contractures. METHODS: The three-dimensional culture model was made from rat keratinocytes seeded on a collagen gel in which dermal fibroblasts had been embedded. RESULTS: Among the TRP channel inhibitors tested, the TRPV2 inhibitors SKF96365 and tranilast attenuated most potently keratinocyte-dependent and - independent collagen gel contraction due to TGF-beta signaling as well as TGF-beta1 release from keratinocytes and alpha-smooth muscle actin production in myofibroblasts. Besides the low amounts detected in normal dermis, TRPV2 mRNA and protein levels were increased after fibroblasts were embedded in the gel. TRPV2 was also expressed in the epidermis and keratinocyte layers of the model. Both inhibitors and TRPV2 siRNA attenuated the intracellular increase of Ca2+ induced by the TRPV agonist 2-aminoethoxydiphenyl borate in TGF-beta1-pretreated fibroblasts. CONCLUSION: This is the first study to show that compounds targeting TRPV2 channels ameliorate wound contraction through the inhibition of TGF-beta1 release and the differentiation of dermal fibroblasts in a culture model. PMID- 29610018 TI - Study of the standard direct costs of various techniques of advanced endoscopy. Comparison with surgical alternatives. AB - INTRODUCTION: The complexity of endoscopy has carried out an increase in cost that has a direct effect on the healthcare systems. However, few studies have analyzed the cost of advanced endoscopic procedures (AEP). OBJECTIVES: To carry out a calculation of the standard direct costs of AEP, and to make a financial comparison with their surgical alternatives. METHODS: Calculation of the standard direct cost in carrying out each procedure. An endoscopist detailed the time, personnel, materials, consumables, recovery room time, stents, pathology and medication used. The cost of surgical procedures was the average cost recorded in the hospital. RESULTS: Thirty-eight AEP were analyzed. The technique showing lowest cost was gastroscopy + APC (?116.57), while that with greatest cost was ERCP with cholangioscopy + stent placement (?5083.65). Some 34.2% of the procedures registered average costs of ?1000-2000. In 57% of cases, the endoscopic alternative was 2-5 times more cost-efficient than surgery, in 31% of cases indistinguishable or up to 1.4 times more costly. CONCLUSION: Standard direct cost of the majority of AEP is reported using a methodology that enables easy application in other centers. For the most part, endoscopic procedures are more cost-efficient than the corresponding surgical procedure. PMID- 29610017 TI - Epidermal barrier and oxidative stress parameters improve during in 311 nm narrow band UVB phototherapy of plaque type psoriasis. AB - BACKGROUND: Psoriasis is a multi-systemic inflammatory disease that results from dysregulation between epidermal keratinocyte homeostasis and both innate and acquired immunity. Epidermal barrier defect has been described in psoriatic lesions. Furthermore an imbalance between pro-oxidative stress and antioxidant defense mechanisms are known in psoriasis patients. AIM: The aim of this study was to address the link between disease activity, epidermal barrier and systemic oxidative stress in the course of 311 nm narrow band ultraviolet B (NB-UVB) therapy of psoriasis. The dynamic of systemic oxidative stress parameters as well as local transepidermal water loss (TEWL) and stratum corneum hydration (SCH) was characterized before and after 311 nm NB-UVB therapy on the plaques of psoriasis vulgaris in comparison to untreated non-affected volar forearm sites of the same patients. MATERIAL AND METHODS: 22 patients with plaque type psoriasis vulgaris and 25 gender- and age-matched healthy controls were enrolled. We assessed the psoriasis area and severity index (PASI) and the dermatology life quality index (DLQI) for monitoring disease activity, severity and self-perceived DLQI impact as patient related outcome parameter. We measured non-invasively TEWL (Tewameter TM 300) and SCH (Corneometer CM 825) and the end product of lipid peroxidation - malondialdehyde (MDA), Reactive oxygen species (ROS), ascorbyl radicals (Asc) and detoxifying activity of catalase (CAT) were measured in the peripheral blood with spectrophotometric and EPR spectroscopy methods. RESULTS: Disease activity improved in all patients compared to baseline witnessed by significant decrease in PASI; (from 14.1 to 10.4; p < 0.0001) and DLQI (from 11.7 to 8.1; p < 0.0001). At baseline TEWL-values were significantly (p < 0.0001) higher on psoriatic plaques (16.8 g/h/m2) in comparison to uninvolved skin (5.3 g/h/m2); with a decrease at both sites after NB-UVB phototherapy. SCH was significantly lower at psoriatic plaque s (4.7AU) compared to uninvolved sskin (42.4AU) and increased after treatment (8.6AU) (p < 0.0001). Interestingly, SCH decrease slightly during therapy at uninvolved skin (40.6AU). ROS and Asc declined during therapy in parallel to a decrease in MDA. A mild decrease in the antioxidative enzyme CAT activity which did not reach the significance was observed. CONCLUSION: The presented data is shows that a clinical improvement of psoriatic plaques under NB UVB therapy, shown in with a decreased PASI and reflected by an increase in quality of life has beneficial effects on epidermal barrier function, SCH and improvement of systemic oxidative stress parameters (ROS, MDA and Asc). We assume that the general improvement in the oxidative stress parameters along with epidermal barrier parameters reflects mainly the improvement of disease activity which overwrites the possible negative pro-oxidative effects of the UV treatment. PMID- 29610019 TI - Ustekinumab in the management of Crohn's disease: Expert opinion. AB - This expert-opinion paper reviews available evidence for the use of ustekinumab, a human interleukin 12/23 monoclonal antibody, in the treatment of Crohn's disease and discusses its potential role in the current treatment scenario for the condition. Ustekinumab appears to be associated with rapid and sustained clinical effect, as reported from the clinical research program, with additional support for potential mucosal healing. These characteristics are paralleled by a favorable safety profile, lack of immunogenicity and the presence of systemic anti-inflammatory activity. Importantly, ustekinumab requires only one single intravenous administration, while subsequent dosing is administered subcutaneously, with potential advantages for home-based therapy. Lastly, the dosage of ustekinumab is flexible. On the basis of the evidence, ustekinumab has a role in patients with primary failure or secondary loss of response to anti tumor necrosis factor agents, as well as in those who have adverse events on front-line biologics or are reinitiating therapy after a treatment holiday. Current evidence suggests that ustekinumab may be particularly suitable in patients who present extra-intestinal manifestations of the disease or are at risk of infections. Ustekinumab may also be considered in the first-line setting, especially in frail patients, in young subjects or in those who have concomitant immune-mediated diseases. PMID- 29610020 TI - Pharmacological treatment of gastrointestinal bleeding due to angiodysplasias: A position paper of the Italian Society of Gastroenterology (SIGE). AB - Angioectasias (AD) belong to benign vascular malformations of the gastrointestinal tract and are responsible for about 4-7% of upper non variceal bleeding, 30-40% of small bowel occult bleeding and 3-40% of colonic bleeding episodes. Gastrointestinal haemorrhage secondary to AD represents an important diagnostic and therapeutic problem that negatively impacts on the quality of life of patients and heath care costs. Endoscopic interventions are the mainstay in both diagnosis and treatment of vascular malformations. However, in a substantial percentage of the cases, age of the patients, comorbidities, clinical severity of anaemia and blood loss as well as size, site and number of lesions prevent this therapeutic approach. Hormonal therapy, thalidomide and somatostatin analogues have been investigated for their potential role as rescue therapies in controlling AD bleeding although, thus far, no recommendations have been provided on their use in this clinical setting. In order to implement appropriate prescription of pharmacological agents to manage gastrointestinal bleeding due to ADs, the Italian Society of Gastroenterology (SIGE) nominated a panel of experts who reviewed the available clinical literature and produced practical clinical recommendations. PMID- 29610021 TI - Correlation of polymorphisms in long non-coding RNAs with the pathogenesis of inflammatory bowel diseases. PMID- 29610022 TI - Complications and their correlation with prognosis in patients undergoing total gastrectomy with splenectomy for treatment of proximal advanced gastric cancer. AB - INTRODUCTION: Spleen-preserving surgery is a mainstay in the treatment of proximal advanced gastric cancer according to the results of several clinical studies. However, total gastrectomy with splenectomy (TGS) still plays a role in the treatment of aggressive tumors invading the greater curvature line or adjacent structures, in spite of its high morbidity. The aim of this study was to identify the risk factors for morbidity and the association between the occurrence of postoperative complications and long-term outcomes. METHODS: We retrospectively analyzed 430 patients with gastric cancer who underwent curative TGS from 1992 to 2010. In total, 134 patients encountered grade >=III postoperative complications (C group), and risk factors for morbidity were analyzed. Patients in the C group were matched 1:1 with patients selected from among 296 patients without complications (matched non-C group, n = 134) using propensity score estimation, to compare relapse-free survival (RFS) between the two groups. RESULTS: The overall grade >=III complication rate was 31.2%. Multivariable analysis identified pancreatic resection (odds ratio [OR], 5.65), male sex (OR, 1.77), and an operation time of >=240 min (OR, 1.69) as independent predictors of postoperative complications after TGS. The RFS was not significantly different between the C-group and matched non-C group (46.9% vs. 45.0%, respectively; hazard ratio, 0.98). CONCLUSIONS: Pancreatic resection, male sex, and a longer operation time are risk factors for morbidity after TGS, and a precise surgical technique is required for such patients. However, postoperative complications of TGS may have little impact on long-term outcomes. PMID- 29610024 TI - Topography-guided transepithelial photorefractive keratectomy to correct irregular refractive errors after radial keratotomy. AB - PURPOSE: To evaluate the efficacy and safety of topography-guided transepithelial photorefractive keratectomy (PRK) in a group of patients with post-radial keratotomy (RK) showing irregular corneas. SETTING: Feiz University Hospital, Isfahan, Iran. DESIGN: Prospective case series. METHODS: Consecutive patients who had irregular astigmatism after RK with stable refraction and topography for at least 1 year were recruited. All eyes had excimer laser topography-guided single step transepithelial PRK. The efficacy, safety, predictability, and corneal wavefront aberration changes were assessed 6 months after the surgery. Vector analysis was performed using the Alpins method to evaluate the astigmatic treatment. RESULTS: Twenty-two patients (22 eyes) were enrolled. The patients' ages ranged from 37 to 61 years (45.77 years +/- 4.9 [SD]); there were 12 men (54.54%) and 10 women (45.46%). Uncorrected distance visual acuity significantly improved after 6 months of treatment (0.45 +/- 0.19 logarithm of the minimum angle of resolution [logMAR] preoperatively and 0.25 +/- 0.19 logMAR after 6 months) (P < .001). Moreover, the corrected distance visual acuity significantly improved at the end of the study (0.14 +/- 0.13 logMAR preoperatively and 0.09 +/ 0.11 logMAR after 6 months) (P = .01). Furthermore, the aberrometric values were significantly reduced at the 6-month visit (P < .001). The mean of the surgically induced astigmatism was 2.15 +/- 1.44 diopters. No significant complication was observed. CONCLUSION: Topography-guided single-step transepithelial PRK is a safe and effective method for treating the irregular refractive errors in post-RK patients. PMID- 29610023 TI - The number of positive nodes accurately predicts recurrence after pancreaticoduodenectomy for nonfunctioning neuroendocrine neoplasms. AB - BACKGROUND: The most appropriate nodal staging for pancreatic neuroendocrine neoplasms (PanNENs) is unclear. Aim of the study was to evaluate the effect of the number of positive lymph nodes on prognosis after pancreaticoduodenectomy for PanNENs. METHODS: A retrospective analysis of pancreaticoduodenectomies for nonfunctioning PanNENs was performed. PanNENs with nodal metastases (N+) were classified into N1 (1 to 3 positive lymph nodes) and N2 (4 or more positive lymph nodes). Univariate and multivariate analyses of disease-free survival were performed. RESULTS: 157 patients were included. 99 patients (63%) had N0 PanNENs whereas 58 patients (37%) had nodal involvement (N+). Patients with N0 PanNENs had a 3-year disease-free survival rate of 89% compared with 83% and 75% in patients with N1 and N2 PanNENs, respectively (P < 0.0001). Independent predictors of disease-free survival were the presence of necrosis, lymph node ratio and nodal status. Factors positively correlated with the number of positive lymph nodes were the Ki67 value, the T stage and the number of examined lymph nodes. Similar percentage of N0 and N+ PanNENs was demonstrated for a cut-off of 13 examined lymph nodes. CONCLUSIONS: The number of positive lymph nodes is accurate in predicting recurrence for PanNENs. Thirteen examined lymph nodes seems to be the minimum number of lymph nodes to be resected/examined in patients who undergo pancreaticoduodenectomy for PanNENs. PMID- 29610025 TI - Comparative study of 3 intracorneal implant types to manage central keratoconus. AB - PURPOSE: To compare the visual acuity, refraction, corneal topography, and corneal asphericity of intrastromal corneal implantation of Keratacx 160-degree 2 symmetrical ring segment, the Keratacx 320-degree near-total ring, and the Myoring continuous intracorneal ring (ICR) in central keratoconus. SETTING: Ophthalmology Department, Ain Shams University, Cairo, Egypt. DESIGN: Prospective case series. METHODS: Surgeries were performed using a femtosecond laser for tunnel creation for the 160-degree 2-segment device (Group 1) and the 320-degree near-total ring (Group 2), and for pocket creation for the ICR (Group 3). The preoperative and 6-month postoperative uncorrected (UDVA) and corrected (CDVA) distance visual acuities, spherical equivalent (SE), corneal and refractive astigmatism, keratometry (K) readings, and Q value using topography images were acquired. RESULTS: The study included 73 eyes. No statistically significant differences were found in the preoperative parameters between groups (P > .05). The postoperative UDVA, CDVA, SE, corneal and refractive astigmatisms, K readings, and Q value were statistically better than the preoperative parameters in all study groups (P < .01). A statistically significant increase in the median UDVA and CDVA occurred in Group 2 compared with Group 1 (P < .01). Groups 2 and 3 had a more effective reduction in SE (P < .01). No statistically significant difference was found in the postoperative changes in the corneal and refractive cylinders, mean and maximum K readings, and corneal asphericity between the study groups (P > .05). CONCLUSIONS: All devices were effective in improving UDVA, CDVA, refraction, K readings, and corneal asphericity. The 320-degree segment and ICR improved UDVA and SE more than the 2-segment device. PMID- 29610026 TI - Epithelial remodeling after corneal crosslinking using higher fluence and accelerated treatment time. AB - PURPOSE: To evaluate changes in regional corneal epithelial thickness after corneal crosslinking (CXL) using higher fluence (7.2 J/cm2) and accelerated treatment time (4 minutes) in eyes with progressive keratoconus using spectral domain optical coherence tomography (SD-OCT) and to correlate focal epithelial and focal anterior curvature changes. SETTING: Academic medical center in the United States. DESIGN: Prospective case series. METHODS: Patients had anterior segment SD-OCT (RTVue-100) with focal stromal and epithelial measurements and Scheimpflug imaging before and 1, 3, 6, and 12 months after accelerated CXL. RESULTS: Twenty-seven eyes from 20 patients were evaluated. Before the accelerated CXL, the epithelium was thinnest in the inferior inner and outer temporal regions, whereas at 12 months postoperatively, the epithelium was significantly thinned in multiple inferior and nasal regions by 1.1 to 3.2 MUm (P < .05, all measurements), with no significant changes from 6 to 12 months. Epithelial thickness standard deviation across the central 6.0 mm was significantly reduced by 3 months (1.4 MUm, P = .09) and remained stable at 12 months (P = .009). Change in epithelial thickness was poorly correlated to change in anterior curvature (r = -0.035). CONCLUSIONS: Significant epithelial remodeling occurred after accelerated CXL in eyes with progressive keratoconus, with improved regularity across the central 6.0 mm, by 6 months after treatment. There was poor correlation between focal epithelial thickness and anterior curvature changes, with wide variability between patients. Establishing the pattern of epithelial remodeling after CXL might help optimize future custom treatment protocols. PMID- 29610027 TI - [It's either all or nothing: Utilization of care and relief services amongst people with dementia. A cohort study based on administrative data]. AB - OBJECTIVE: Caregiving often is a demanding task for family caregivers of people with dementia. In order to provide relief for caregivers and stabilize informal care, care and relief services for people with dementia and their caregivers were established by the German long-term care insurance ("Pflegeversicherung"). It is unknown how many people with dementia have used the additional care and relief services over the time and which characteristics predict permanent utilization. METHODS: The analysis is based on administrative data. 2,887 people with prevalent dementia were followed from 2012 to 2015. The data was analyzed descriptively and by logistic regression. RESULTS: About a quarter of the observed people with dementia continuously used the additional care and relief services from 2012 to 2015. 22.8% used them since 2013, while nearly a quarter made no use whatsoever of the services during the observation period. The probability of using care and relief services is higher when using an outpatient nursing service in comparison to family care and when the care level has gone up in the year before use. CONCLUSION: Permanent utilization of care and relief services seems to be based on need in most cases. It could also be a learning effect or supplier-induced when simultaneously using an outpatient nursing service. People who discontinued service use or never used it could provide further information in order to adjust the additional care and relief services program. PMID- 29610028 TI - [Factors affecting in-hospital mortality in patients with sepsis: Development of a risk-adjusted model based on administrative data from German hospitals]. AB - BACKGROUND: Inpatient administrative data from hospitals is already used nationally and internationally in many areas of internal and public quality assurance in healthcare. For sepsis as the principal condition, only a few published approaches are available for Germany. The aim of this investigation is to identify factors influencing hospital mortality by employing appropriate analytical methods in order to improve the internal quality management of sepsis. METHODS: The analysis was based on data from 754,727 DRG cases of the CLINOTEL hospital network charged in 2015. The association then included 45 hospitals of all supply levels with the exception of university hospitals (range of beds: 100 to 1,172 per hospital). Cases of sepsis were identified via the ICD codes of their principal diagnosis. Multiple logistic regression analysis was used to determine the factors influencing in-hospital lethality for this population. The model was developed using sociodemographic and other potential variables that could be derived from the DRG data set, and taking into account current literature data. The model obtained was validated with inpatient administrative data of 2016 (51 hospitals, 850,776 DRG cases). RESULTS: Following the definition of the inclusion criteria, 5,608 cases of sepsis (2016: 6,384 cases) were identified in 2015. A total of 12 significant and, over both years, stable factors were identified, including age, severity of sepsis, reason for hospital admission and various comorbidities. The AUC value of the model, as a measure of predictability, is above 0.8 (H-L test p>0.05, R2 value=0.27), which is an excellent result. CONCLUSION: The CLINOTEL model of risk adjustment for in hospital lethality can be used to determine the mortality probability of patients with sepsis as principal diagnosis with a very high degree of accuracy, taking into account the case mix. Further studies are needed to confirm whether the model presented here will prove its value in the internal quality assurance of hospitals. PMID- 29610030 TI - Clinical Implications of Targeting XPO1-mediated Nuclear Export in Multiple Myeloma. AB - Multiple myeloma (MM) is a malignancy of plasma cells that is typically chronic, and relapse is common. Current therapeutic strategies include combination and sequential treatments with corticosteroids, alkylating agents, proteasomal inhibitors, immunomodulators, and monoclonal antibodies. These drugs prolong survival but ultimately become ineffective. Exportin 1 (XPO1), a nuclear export protein, is overexpressed in MM cells, and knockdown studies have suggested that XPO1 is essential for MM cell survival. Selective inhibitor of nuclear export (SINE) compounds are novel, orally bioavailable class of agents that specifically inhibit XPO1. Selinexor (KPT-330) is the first-in-human SINE compound. Early phase clinical trials have established the safety profile of this agent and have shown promising efficacy in combination with low-dose dexamethasone and other anti-MM agents. The combination of selinexor and dexamethasone has demonstrated activity in "penta-refractory" MM, (ie, MM refractory to the 5 most active anti MM agents currently used in treatment). We have reviewed the available data on the molecular implications of XPO1 inhibition in MM. We also reviewed the pertinent early phase clinical data with SINE compounds and discuss management strategies for common toxicities encountered with use of selinexor. PMID- 29610029 TI - Final 3-year Results of the Dasatinib Discontinuation Trial in Patients With Chronic Myeloid Leukemia Who Received Dasatinib as a Second-line Treatment. AB - INTRODUCTION: We previously reported an interim analysis of the DADI (dasatinib discontinuation) trial. The results showed that 48% of patients with chronic myeloid leukemia in the chronic phase who maintained a deep molecular response (DMR) for >= 1 year could discontinue second- or subsequent-line dasatinib treatment safely at a median follow-up of 20 months. However, the results from longer follow-up periods would be much more useful from a clinical perspective. PATIENTS AND METHODS: The DADI trial was a prospective, multicenter trial conducted in Japan. After confirming a stable DMR for >= 1 year, dasatinib treatment subsequent to imatinib or nilotinib was discontinued. After discontinuation, the loss of DMR (even of 1 point) was defined as stringent molecular relapse, thereby triggering therapy resumption. The predictive factors of treatment-free remission (TFR) were analyzed. RESULTS: The median follow-up period was 44.0 months (interquartile range, 40.5-48.0 months). The estimated overall TFR rate at 36 months was 44.4% (95% confidence interval, 32.0%-56.2%). Only 2 patients developed a molecular relapse after the 1-year cutoff point. The presence of imatinib resistance was a significant risk factor for molecular relapse. Moreover, high natural killer cell and low gammadelta+ T-cell and CD4+ regulatory T-cell (CD25+CD127low) counts before discontinuation correlated significantly with successful therapy discontinuation. CONCLUSION: These findings suggest that discontinuation of second- or subsequent-line dasatinib after a sustained DMR of >= 1 year is feasible, especially for patients with no history of imatinib resistance. In addition, the natural killer cell count was associated with the TFR. PMID- 29610031 TI - Quantitative assessment of primary mitral regurgitation using left ventricular volumes obtained with new automated three-dimensional transthoracic echocardiographic software: A comparison with 3-Tesla cardiac magnetic resonance. AB - BACKGROUND: Quantitative assessment of primary mitral regurgitation (MR) using left ventricular (LV) volumes obtained with three-dimensional transthoracic echocardiography (3D TTE) recently showed encouraging results. Nevertheless, 3D TTE is not incorporated into everyday practice, as current LV chamber quantification software products are time consuming. AIMS: To investigate the accuracy and reproducibility of new automated fast 3D TTE software (HeartModelA.I.; Philips Healthcare, Andover, MA, USA) for the quantification of LV volumes and MR severity in patients with isolated degenerative primary MR; and to compare regurgitant volume (RV) obtained with 3D TTE with a cardiac magnetic resonance (CMR) reference. METHODS: Fifty-three patients (37 men; mean age 64+/ 12 years) with at least mild primary isolated MR, and having comprehensive 3D TTE and CMR studies within 24h, were eligible for inclusion. MR RV was calculated using the proximal isovelocity surface area (PISA) method and the volumetric method (total LV stroke volume minus aortic stroke volume) with either CMR or 3D TTE. RESULTS: Inter- and intraobserver reproducibility of 3D TTE was excellent (coefficient of variation<=10%) for LV volumes. MR RV was similar using CMR and 3D TTE (57+/-23mL vs 56+/-28mL; P=0.22), but was significantly higher using the PISA method (69+/-30mL; P<0.05 compared with CMR and 3D TTE). The PISA method consistently overestimated MR RV compared with CMR (bias 12+/-21mL), while no significant bias was found between 3D TTE and CMR (bias 2+/-14mL). Concordance between echocardiography and CMR was higher using 3D TTE MR grading (intraclass correlation coefficient [ICC]=0.89) than with PISA MR grading (ICC=0.78). Complete agreement with CMR grading was more frequent with 3D TTE than with the PISA method (76% vs 63%). CONCLUSION: 3D TTE RV assessment using the new generation of automated software correlates well with CMR in patients with isolated degenerative primary MR. PMID- 29610032 TI - Personalized prevention in high risk individuals: Managing hormones and beyond. AB - Increasing numbers of women are being identified at 'high-risk' of breast cancer, defined by The National Institute of Health and Care Excellence (NICE) as a 10 year risk of >=8%. Classically women have been so identified through family history based risk algorithms or genetic testing of high-risk genes. Recent research has shown that assessment of mammographic density and single nucleotide polymorphisms (SNPs), when combined with established risk factors, trebles the number of women reaching the high risk threshold. The options for risk reduction in such women include endocrine chemoprevention with the selective estrogen receptor modulators tamoxifen and raloxifene or the aromatase inhibitors anastrozole or exemestane. NICE recommends offering anastrozole to postmenopausal women at high-risk of breast cancer as cost effectiveness analysis showed this to be cost saving to the National Health Service. Overall uptake to chemoprevention has been disappointingly low but this may improve with the improved efficacy of aromatase inhibitors, particularly the lack of toxicity to the endometrium and thrombogenic risks. Novel approaches to chemoprevention under investigation include lower dose and topical tamoxifen, denosumab, anti-progestins and metformin. Although oophorectomy is usually only recommended to women at increased risk of ovarian cancer it has been shown in numerous studies to reduce breast cancer risks in the general population and in those with mutations in BRCA1/2. However, recent evidence from studies that have confined analysis to true prospective follow up have cast doubt on the efficacy of oophorectomy to reduce breast cancer risk in BRCA1 mutation carriers, at least in the short-term. PMID- 29610033 TI - Ketogenic Diet Therapy in Infants: Efficacy and Tolerability. AB - PURPOSE: This study evaluated tolerability and efficacy of the ketogenic diet in infants less than 12 months of age. METHODS: Infants less than 12 months of age, commencing the ketogenic diet between September 2007 and July 2016 were identified. Records were reviewed for epilepsy details, diet initiation details, efficacy and tolerability. RESULTS: Twenty-seven infants commenced the ketogenic diet (56% male, median age seven months). Median age at seizure onset was 1.9 months and 92% had daily seizures. An epilepsy syndrome was noted in 19 (West-11, epilepsy in infancy with migrating focal seizures-5, early myoclonic encephalopathy-1, Ohtahara-1, Dravet-1). Infants were on a median of two and had failed a median of one medications for lack of efficacy. All initiated a traditional ketogenic diet at full calories without fasting, and all but one started the diet in hospital. Significant hypoglycemia during initiation was seen in two - both had emesis +/- decreased oral intake. Eighty-eight percent developed urinary ketosis by 48 hours and all were successfully discharged on the diet (median ratio 3:1). Of those continuing dietary therapy, responder rates at one, six and 12 months were 68%, 82% and 91%, with 20%, 29% and 27% achieving seizure freedom. By 12 months, two stopped the diet for serious adverse effects, five discontinued for lack of efficacy, six were lost to follow-up and two died of unrelated causes. CONCLUSIONS: The ketogenic diet is an effective and well tolerated treatment for infants with intractable epilepsy. In-hospital initiation is strongly recommended due to risk of hypoglycemia with emesis or reduced intake. PMID- 29610034 TI - Obituary: Alan Milford Aron, MD (1933 to 2017). PMID- 29610035 TI - Corrigendum to "Targeting NAD+ degradation: The therapeutic potential of flavonoids for Alzheimer's disease and cognitive frailty" [Pharmacol. Res. 128 (February) (2018) 345-358]. PMID- 29610036 TI - Paradoxical Association of Symptomatic Local Vasogenic Edema with Global Cerebral Hypoperfusion after Direct Revascularization Surgery for Adult Moyamoya Disease. AB - BACKGROUND: Superficial temporal artery-middle cerebral artery (STA-MCA) anastomosis is the standard treatment for Moyamoya disease (MMD). Cerebral hyperperfusion syndrome is a potential complication of this procedure and can cause local vasogenic edema and/or delayed intracerebral hemorrhage. Cerebral hypoperfusion is a contradictory postoperative pathophysiological condition implicated in MMD, but its association with symptomatic local vasogenic edema has not been reported. CASE REPORT: A 31-year-old woman with MMD underwent left STA MCA anastomosis 3 months after a minor completed stroke in bilateral hemispheres. Eight hours after the operation, the patient developed neurological deterioration of dysarthria and mono-paresis in her right hand. Magnetic resonance (MR) angiography showed apparently patent STA-MCA bypass, whereas MR imaging of fluid attenuated inversion recovery demonstrated a local high-signal-intensity lesion at the vascular territory supplied by the bypass. The apparent diffusion coefficient value was significantly increased in this lesion, suggesting local vasogenic edema formation. N-isopropyl-p-[123I] iodoamphetamine single-photon emission computed tomography revealed global hypoperfusion in the left hemisphere. The administration of a free-radical scavenger and antiepileptic agent gradually relieved her symptoms, and MR imaging 1 month after surgery confirmed the complete disappearance of local vasogenic edema. CONCLUSIONS: Vasogenic edema may be associated not only with cerebral hyperperfusion but also with hypoperfusion after STA-MCA anastomosis for MMD. Although the exact mechanism of this rare association is unknown, the intrinsic vulnerability of intracranial vascular wall structures and the increased vascular permeability in MMD may partly explain the paradoxical association of hypoperfusion and local vasogenic edema. PMID- 29610037 TI - Cytokine Response, Tract-Specific Fractional Anisotropy, and Brain Morphometry in Post-Stroke Cognitive Impairment. AB - BACKGROUND: Post-stroke cognitive impairment is a clinically heterogeneous condition and its types have a different course and prognosis. The aim of the present study is to address the roles of inflammation, white matter pathology, and brain atrophy in different neuropsychological types of cognitive impairment in the acute period of ischemic stroke. METHODS: In 92 patients, we performed an assessment of the cognitive status and measured concentrations of cytokines (interleukin [IL]-1beta, IL-6, tumor necrosis factor-alpha, IL-10) in liquor and serum, as well as a number of magnetic resonance imaging (MRI) morphometric parameters and fractional anisotropy. The control group consisted of 14 individuals without cerebrovascular disease. RESULTS: All patients had a higher level of IL-10 in serum than the control group. Patients with dysexecutive cognitive impairment had a higher concentration of IL-1beta and IL-10 in liquor, IL-6 level in serum, and a lower fractional anisotropy of the ipsilateral thalamus than patients with normal cognition. Patients with mixed cognitive impairment were characterized by a lower fractional anisotropy of contralateral fronto-occipital fasciculus, compared with patients with dysexecutive cognitive impairment. Patients with both dysexecutive and mixed cognitive deficit had a wide area of leukoaraiosis and a reduced fractional anisotropy of the contralateral cingulum, compared with patients without cognitive impairment. Also, we found numerous correlations between cognitive status and levels of cytokines, MRI morphometric parameters, and fractional anisotropy of certain regions of the brain. CONCLUSIONS: The concentrations of cytokines in serum and cerebrospinal fluid studied in combination with MRI morphometric parameters and fractional anisotropy appear to be informative biomarkers of clinical types of post-stroke cognitive impairment. PMID- 29610038 TI - Impact of General Practitioner Transient Ischemic Attack Training on 90-Day Stroke Outcomes: Secondary Analysis of a Cluster Randomized Controlled Trial. AB - GOALS: Many patients with transient ischemic attack (TIA) receive initial assessments by general practitioners (GPs) who may lack TIA management experience. In a randomized controlled trial (RCT), we showed that electronic decision support for GPs improves patient outcomes and guideline adherence. Some stroke services prefer to improve referrer expertise through TIA/stroke education sessions instead of promoting TIA decision aids or triaging tools. This is a secondary analysis of whether a GP education session influenced TIA management and outcomes. MATERIALS AND METHODS: Post hoc analysis of a multicenter, single blind, parallel group, cluster RCT comparing TIA/stroke electronic decision support guided GP management with usual care to assess whether a pretrial TIA/stroke education session also affected RCT outcomes. FINDINGS: Of 181 participating GPs, 79 (43.7%) attended an education session and 140 of 291 (48.1%) trial patients were managed by these GPs. There were fewer 90-day stroke events and 90-day vascular events or deaths in patients treated by GPs who attended education; 2 of 140 (1.4%) and 10 of 140 (7.1%) respectively, compared with those who did not; 5 of 151 (3.3%), and 14 of 151 (9.3%), respectively. Logistic regression for association between 90-day stroke and 90-day vascular events or death and education, however, was nonsignificant (odds ratio [OR] .42 (.08 to 2.22), P = .29 and .59 (95% confidence interval [CI] .27 to 1.29), P = .18 respectively. Guideline adherence was not improved by the education session: OR .84 (95% CI .49 to 1.45), P = .54. CONCLUSION: In the described setting, a GP TIA/stroke education session did not significantly enhance guideline adherence or reduce 90-day stroke or vascular events following TIA. PMID- 29610039 TI - Botulinum Toxin Type A Treatment Combined with Intensive Rehabilitation for Gait Poststroke: A Preliminary Study. AB - GOAL: To examine the effects of botulinum toxin type A (BoNT-A) treatment combined with intensive rehabilitation for gait compared with intensive rehabilitation alone in patients with chronic stroke. MATERIALS AND METHODS: A comparative case series design was used. Subjects were 19 patients with chronic stroke and spastic hemiplegia. In 9 patients (group I), BoNT-A was injected into spastic muscles of the affected lower limbs, followed by a 4-week inpatient intensive rehabilitation program. In the other 10 patients (group II), a 4-week inpatient intensive rehabilitation program alone was first provided (control period) followed by the same treatment protocol in group I. The Modified Ashworth Scale (MAS) scores, range of motion (ROM), gait speed in the 10-Meter Walking Test, 6-Minute Walking Distance Test (6MD) scores, Timed Up and Go Test (TUG) scores, and Berg Balance Scale scores were evaluated every 4 weeks following baseline assessments. RESULTS: All results except for the MAS score of knee flexor and the ROM of knee flexion improved in group I and the gait speed, 6MD, and TUG scores improved in group II. Intergroup comparisons at week 4 showed significantly greater improvements in the MAS score of ankle plantar flexor, ROM of ankle dorsiflexion, and 6MD in group I than in group II (P = .016, .011, and .009, respectively). CONCLUSIONS: BoNT-A treatment for lower-limb spasticity, combined with intensive rehabilitation, was effective in improving spasticity and the 6MD compared with intensive rehabilitation alone in patients with chronic stroke. PMID- 29610040 TI - Initial Experience with a Flow Redirection Endoluminal Device Stent-A Brazilian Multicenter Study. PMID- 29610041 TI - Fumarate hydratase-specific T cell response in Chinese patients with autoimmune hepatitis. AB - PURPOSE: Fumarate hydratase (FH) is expressed in the serum of patients with autoimmune hepatitis (AIH). The specific involvement of FH-specific T cell response is currently unknown. The aim of the study was to assess the frequency and clinical significance of FH-specific T cell response in AIH. METHODS: This was a prospective study of 42 consecutive patients admitted to the clinical study center of autoimmune liver disease of our Hospital, Capital Medical University (China) between January 2011 and December 2014. PBMCs were collected and the FH specific T cell response was detected by Elispot. Cytokines and antibody responses were assessed. RESULTS: Among the 42 AIH patients, 57.1% showed a positive response to FH peptides. The difference in FH-specific T cell response frequency among AIH patients and control groups was significant (P<0.001). The FH peptides induced the secretion of CD4+ and CD8+ T cells. The FH-specific T cell response in patients with active disease was stronger than in those with remission (P=0.0283). FH-specific T cell response in patients with active disease showed a positive association with ALT (r=0.4712, P=0.0098) and AST (r=0.3924, P=0.0352) levels. The magnitude of the FH-specific T cell response correlated with the HAI score (r=0.7290, P=0.0047) and anti-FH titer (r=0.6457, P=0.0093). CONCLUSION: FH-specific T cell response may be detected in the blood of patients with AIH and seems to be associated with AIH disease progression. FH-specific T cell response could be a pathogenic cause of AIH. PMID- 29610042 TI - Regulatory pathways to enable the licencing of alternatives to antibiotics. AB - Effective alternatives to antibiotics (ATA) such as vaccines, antibodies, phage therapies, prebiotics, probiotics and herbal medicines can be used in place of traditional antibiotics in a way that does not compromise animal health as means of tackling the growing threat to both animal and human health from antimicrobial resistance (AMR). This paper reflects the key points on the approaches that were discussed during the 2nd International Symposium on ATA between regulatory agencies, veterinary product companies representing largely the pharmaceutical and feed-additive sectors, academia and other stakeholders on regulatory pathways to enable the licensing of alternatives to antibiotics for food producing animals. The need to demonstrate compliance with generally accepted standards for quality, safety and efficacy is considered a pre-requisite for all veterinary medicinal products receiving an authorisation including ATA, irrespective of the region in which they are approved. ATA are often based on novel technologies, with complex mechanisms of action; therefore, early and close communication with regulators is encouraged. In addition, strategic use by ATA applicants of all regulatory tools available to support innovation is highly recommended. The veterinary product manufacturers consider that the regulation of veterinary medicines should evolve to accommodate innovative ATA technologies and incentives from regulatory agencies provided to stimulate further ATA development. PMID- 29610043 TI - An algorithm for predicting blood loss and transfusion risk after total hip arthroplasty. AB - INTRODUCTION: Patients receiving blood transfusions after total hip arthroplasty have increased morbidity and longer lengths of stay compared to non-transfused patients. The aim of this study is to create an algorithm in order to identify patients at risk for transfusion after total hip replacement and define a safe point in hemoglobin levels after which the need for blood, transfusion can be excluded. METHODS: This retrospective study analyzed hemoglobin (Hb) levels for 5 days in patients undergoing total hip replacement. An algorithm was implemented to identify the critical trends of Hb levels in the first two postoperative days, trying to identify the patients at high risk of transfusion. Specificity, sensibility and efficiency were calculated in relation to the capability of the algorithm to correctly identify transfused patients. RESULTS: The algorithm found a pre-operative Hb >= 13 g/dl as a cut off between patients at low-risk or high risk for transfusion. When parameters were calculated considering the best efficiency with the least number of false negatives, the algorithm showed a specificity of 84% and a sensitivity of 70% with an efficiency of 80.6%. Hb values >10 g/dl in the first operative day for low-risk patients and Hb level > 11 g/dl the second post-operative day for high-risk patients led to exclusion of the need for transfusion. CONCLUSIONS: The algorithm suggested critical Hb levels to predict transfusion. In association with clinical data, the suggested critical values of Hb may be useful to schedule lab tests and a safe early discharge. PMID- 29610044 TI - Alarmed or unalarmed!! Donor red cell lysis during plateletpheresis procedure. AB - Plateletpheresis procedures are considered safe for donors and very few adverse events are reported. Donor related adverse events include hypo-calcemia due to citrate toxicity, vasovagal reactions, transient post-procedural decline in hemoglobin, hematocrit and platelet count. Kit related adverse events include damage of the kit or rarely mechanical damage of the red cells during procedure. This damage can lead to failure of the rinse-back of the red cells to the donors causing higher red cell loss in such donors. Here, we are reporting a kit related adverse event that led to donor red cell lysis during plateletpheresis procedure. PMID- 29610045 TI - Gait parameters, functional mobility and fall risk in individuals with early to moderate primary open angle glaucoma: a cross-sectional study. AB - OBJECTIVE: This study investigated the influence of early to moderate primary open angle glaucoma on gait, functional mobility and fall risk. METHODS: Thirty three participants in the early and moderate stages of primary open angle glaucoma and 34 asymptomatic controls participated in the study. Spatiotemporal gait data were obtained with the GAITRite system and included: velocity, cadence, step length, base of support, swing, stance and double support times. Functional measures included the Timed Up and Go test, the Five-Repetition Sit-To-Stand test and the Dynamic Gait Index. Fall risk was measured using the Physiological Profile Assessment. RESULTS: The variables contrast sensitivity, proprioception and the Timed Up and Go and Dynamic Gait Index tests were significantly different between groups. In addition, the glaucoma group presented significantly higher risk of falling compared to the control group. Individuals in the early and moderate stages of primary open glaucoma presented mobility and sensory deficits that increase the risk of falling. CONCLUSIONS: The results of this study suggest that adding the Timed Up and Go and Dynamic Gait Index tests to routine physical therapy assessment of individuals with early glaucoma could be useful. Rehabilitation programs should focus on maintaining and/or improving mobility and balance, and prevention of falls in this population. PMID- 29610046 TI - Phylogenetic studies of bacteria (Rickettsia, Coxiella, and Anaplasma) in Amblyomma and Dermacentor ticks in Thailand and their co-infection. AB - In this study, we attempted to detect Rickettsia, Coxiella and Anaplasma bacteria in one hundred and fourteen-Dermacentor and thirty three-Amblyomma unfed adult ticks that were collected from under leaves along animal trails at different places across Thailand. PCR amplification was used to identify bacterial infection with general conserved sequences of bacteria. The results revealed single infection in Amblyomma testudinarium ticks with Rickettsia (24%) and Coxiella (6%). Anaplasma bacteria were often detected in Dermacentor auratus ticks (32%). Coxiella spp. were detected in Dermacentor atrosignatus (6%) and D. auratus ticks (3%) in this study. Moreover, we found co-infection by Coxiella and Rickettsia bacteria (39%) in Am. testudinarium. In contrast, D. atrosignatus ticks were co-infected with Coxiella and Anaplasma bacteria (3%) and Dermacentor compactus ticks were co-infected with Rickettsia and Anaplasma spp. (25%). Interestingly, Am. testudinarium ticks (12%) were found for the first time to exhibit triple infection by these three bacteria. Phylogenetic studies showed the rickettsiae from ticks causing both single and multiple infections had sequence similarity with spotted fever group rickettsial strains, including Rickettsia massilliae, R. raoultii and R. tamurae. In addition, the phylogenetic analysis of the 16S rRNA gene of Coxiella bacteria showed that they were closely grouped with Coxiella endosymbionts in both Dermacentor and Amblyomma. Moreover, the Anaplasma identified in a D. auratus tick was grouped in the same clade with the pathogenic bacterium Anaplasma phagocytophilum. Bacterial co-infections in Dermacentor and Amblyomma ticks may cause co-transmission of some tick-borne microorganisms (pathogen and endosymbiont, whether enhance or reduce) in humans and animals and they could affect medical and veterinary health. PMID- 29610048 TI - Is the renal pyramidal thickness a good predictor for pyeloplasty in postnatal hydronephrosis? AB - OBJECTIVES: We evaluated the feasibility and value of renal pyramidal thickness (PT) as a predictor of pyeloplasty in high-grade postnatal hydronephrosis. PATIENTS AND METHODS: We retrospectively reviewed the charts of patients who presented with postnatal hydronephrosis from 2008 to 2013. Included cases had grade 3 or 4 hydronephrosis. We included only units diagnosed as ureteropelvic junction obstruction. Gender, laterality, hydronephrosis side, renogram data, and follow-up data were recorded. Two investigators reviewed all patients' ultrasounds images. We measured PT and pelvic anteroposterior diameter (APD) in the last ultrasound before surgery. For those managed conservatively, measurements were obtained from the ultrasound with worst hydronephrosis. PT was measured in supine position in the middle third of the sagittal plane (Figure). We assessed the reliability of PT measurement using the intraclass correlation coefficient (ICC). Univariate and multivariate analyses were used to correlate the collected parameters to pyeloplasty incidence. Receiver operating characteristic curve was used to evaluate the cutoff value of PT that predicts pyeloplasty. RESULTS: The total included cases were 155 patients (165 units). One hundred and fourteen units had grade 3 hydronephrosis and 51 units had grade 4 hydronephrosis. Fifty-two cases (55 units) underwent pyeloplasty. The median follow-up period was 37.6 months. PT measurement was reliable (ICC = 0.94). Univariate analysis revealed that SFU grading, APD, PT, T1/2, and MAG-3 curves were associated with surgery. Multivariate analysis showed that PT was a single independent predictor for pyeloplasty. PT <= 3 mm had 98.1% sensitivity and 89.7% specificity in predicting pyeloplasty. DISCUSSION: PT is the first portion of renal parenchyma that is affected in high-grade hydronephrosis. Moreover, it changes little over the first 9 years of life. PT measurement in hydronephrosis was not previously evaluated. We found that PT was easily measured in most kidneys with high negative predictive value. The PT value as an indicator for pyeloplasty should undergo extensive assessment by other institutions with different protocols. CONCLUSION: Being a slowly growing part of the parenchyma, PT can be a good measurable parameter to predict pyeloplasty. Measurement of PT in hydronephrosis is reliable. PT <= 3 mm can predict pyeloplasty with 98.1% sensitivity and 89.7% specificity. PMID- 29610047 TI - Comparison of three commercial IgG and IgM ELISA kits for the detection of tick borne encephalitis virus antibodies. AB - Tick-borne encephalitis (TBE) is endemic in many parts of Europe and Asia. The diagnosis of this disease is essentially based on the demonstration of specific antibodies. For reasons of simplicity, automatization and quick availability of test results, enzyme-linked immunosorbent assays (ELISAs) are the method of choice for serological diagnosis of TBE. Here, we evaluated three commercially available anti-TBEV IgG and IgM ELISAs using 251 serum samples: the SERION ELISA classic FSME Virus/TBE Virus IgG and IgM kit (Virion?Serion), the RIDASCREEN(r) FSME/TBE IgG and IgM kit (R-Biopharm), and the anti-FSME/TBE virus ELISA "Vienna" IgG/anti-FSME/TBE virus ELISA IgM kit (Euroimmun). In total, discrepant test results for IgG and/or IgM were observed for 37/251 (14.7 %) of tested samples; differences were statistically significant. Reference values defined by serum neutralization test (SNT, n = 25) or results provided by EQA organizers (n = 2) were established for a subset of samples. In relation to these values, false positive results were observed mainly for Euroimmun Vienna IgG and RIDASCREEN IgG, whereas false-negative results were primarily observed for Virion?Serion IgG and RIDASCREEN IgM kits. In routine diagnostics, specificity problems are of major relevance and may be addressed by analyzing the respective samples using SNT. PMID- 29610049 TI - The King-Devick test is a valid and reliable tool for assessing sport-related concussion in Australian football: A prospective cohort study. AB - OBJECTIVES: Sport-related concussion (SRC) research has focused on impaired oculomotor function. The King-Devick (K-D) test measures oculomotor performance and is reported to identify suboptimal brain function. The use of the K-D test in Australian football (AF), a sport involving body contact and tackling, has not been documented. Therefore, the objective of this study was to determine the test retest reliability and diagnostic accuracy of the K-D test on a sub-elite AF team. DESIGN: Prospective cohort study METHODS: In total, 22 male players (19.6+2.3 years) were tested and re-tested on the K-D test. Those suspected of having a SRC secondary to a significant head impact were tested. Randomly selected additional players without SRC were assessed for comparison. RESULTS: There were observable learning effects between the first and second baseline testing (48 vs. 46s). The ICC for the first and second baseline tests was 0.91. Post-match test times were longer than the baseline times for players with SRC (n=7) (-1.9s; z=-5.08; p<0.0001). Players tested with no signs of SRC (n=13) had an improvement in time when compared with their baseline score (3.0s; z=-4.38; p<0.0001). The overall sensitivity was 0.98, specificity 0.96, and a kappa of kappa=0.94. The positive likelihood ratio was 11.6 and the positive predictive value was 89.0%. CONCLUSIONS: This study supports the use of the K-D test due to its test-retest reliability, high sensitivity and specificity, and fast and simple use that is ideal for sports medicine professionals to make quick judgement on management and playability. PMID- 29610050 TI - UPMC's blueprint for BuILDing a high-value health care system. AB - National-level demonstration projects and real-world studies continue to inform health care transformation efforts and catalyze implementation of value-based service delivery and payment models, though evidence generation and diffusion of learnings often occurs at a relatively slow pace. Rapid-cycle learning models, however, can help individual organizations to more quickly adapt health care innovations to meet the challenges and demands of a rapidly changing health care landscape. Integrated delivery and financing systems (IDFSs) offer a unique platform for rapid-cycle learning and innovation. Since both the provider and payer benefit from delivering care that enhances the patient experience, improves quality, and reduces cost, incentives are aligned to experiment with value-based models, enhance learning about what works and why, and contribute to solutions that can accelerate transformation. In this article, we describe how the UPMC Insurance Services Division, as part of a large IDFS, uses its Business, Innovation, Learning, and Dissemination (BuILD) model to prioritize, design, test, and refine health care innovations and accelerate learning. We provide examples of how the BuILD model offers an approach for quickly assessing the impact and value of health care transformation efforts. Lessons learned through the BuILD process will offer insights and guidance for a wide range of stakeholders whether an IDFS or independent payer-provider collaborators. PMID- 29610051 TI - Quantity and economic value of unused oral anti-cancer and biological disease modifying anti-rheumatic drugs among outpatient pharmacy patients who discontinue therapy. AB - BACKGROUND: Patients sometimes discontinue the use of expensive oral anti-cancer drug (OACD) or biological disease-modifying anti-rheumatic drug (bDMARD) therapies early, leading to medication waste if the patient has not used all dispensed medication. OBJECTIVE: To determine the proportion of patients who have unused OACDs or bDMARDs after therapy discontinuation, and the quantity and economic value of these unused medications. Furthermore, patients' reasons for therapy discontinuation and their disposal method for unused medications were determined. METHODS: In a retrospective follow-up study using a Dutch outpatient pharmacy database, patients (>=18 years) who did not refill an OACD or bDMARD prescription, dispensed between November 2015 and February 2016, within two weeks of the prescription end date were contacted by phone and asked about their unused medication and reasons thereof. The economic value was calculated using Dutch medication prices. Data were descriptively analyzed in STATA13. RESULTS: The database included 1173 patients, of whom 159 likely had discontinued therapy and were contacted. Of these, 88 patients were excluded (39 refilled, 47 missing, and 2 other). Of the 71 patients who had discontinued therapy, 39 (54.9%) had unused medications, comprising 22 OACD users (mean age 63.0 (SD +/- 15.9) years, 50.0% female) and 17 bDMARD users (mean age 50.7 (SD +/- 13.5) years, 47.1% female). A total of 59 packages were unused, with a total value of ?60,341. Unused OACD packages and bDMARD packages had median values of ?179 (IQR ?24-2487) and ?992 (IQR ?681-1093), respectively. Patients primarily discontinued therapy due to adverse or insufficient effects. CONCLUSIONS: This study illustrates that more than half of patients discontinuing OACD or bDMARD therapies have unused medication. This emphasizes the need for waste-reducing interventions. PMID- 29610052 TI - The pharmacy care plan service: Evaluation and estimate of cost-effectiveness. AB - BACKGROUND: The UK Community Pharmacy Future group developed the Pharmacy Care Plan (PCP) service with a focus on patient activation, goal setting and therapy management. OBJECTIVE: To estimate the effectiveness and cost-effectiveness of the PCP service from a health services perspective. METHODS: Patients over 50 years of age prescribed one or more medicines including at least one for cardiovascular disease or diabetes were eligible. Medication review and person centred consultation resulted in agreed health goals and actions towards achieving them. Clinical, process and cost-effectiveness data were collected at baseline and 12-months between February 2015 and June 2016. Mean differences are reported for clinical and process measures. Costs (NHS) and quality-adjusted life year scores were estimated and compared for 12 months pre- and post-baseline. RESULTS: Seven hundred patients attended the initial consultation and 54% had a complete set of data obtained. There was a significant improvement in patient activation score (mean difference 5.39; 95% CI 3.9-6.9; p < 0.001), systolic (mean difference -2.90 mmHg; 95% CI -4.7 to -1; p = 0.002) and diastolic blood pressure (mean difference -1.81 mmHg; 95% CI -2.8 to -0.8; p < 0.001), adherence (mean difference 0.26; 95% CI 0.1-0.4; p < 0.001) and quality of life (mean difference 0.029; 95% CI 0.015-0.044; p < 0.001). HDL cholesterol reduced significantly and QRisk2 scores increased significantly over the course of the 12 months. The mean incremental cost associated with the intervention was estimated to be L202.91 (95% CI 58.26 to L346.41) and the incremental QALY gain was 0.024 (95% CI 0.014 to 0.034), giving an incremental cost per QALY of L8495. CONCLUSIONS: Enrolment in the PCP service was generally associated with an improvement over 12 months in key clinical and process metrics. Results also suggest that the service would be cost-effective to the health system even when using worst case assumptions. PMID- 29610053 TI - Collaborative study using common samples to evaluate the performance of anti-drug antibody assays constructed by different companies. AB - This study was undertaken to evaluate the performance of anti-drug antibody (ADA) assays constructed by each participating company using common samples including ADA, drug and human serum. The ADA assays constructed by each company showed good sensitivity and precision for evaluation of ADA. Cut points for screening and confirmatory assays and assay selectivity were determined by various calculation methods. In evaluations of blind ADA samples, nearly similar results were obtained by the study companies in determinations of whether samples were positive or negative except at the lowest sample concentration (5 ng/mL). In measurement of drug tolerance, for almost samples containing ADA and drugs, more positive results were obtained in assays using acid dissociation compared to those without acid dissociation. Overall, the performance of ADA assays constructed by the 10 companies participating in this study was acceptable in terms of sensitivity and reproducibility for detection and evaluation of immunogenicity in both patients and healthy subjects. On the other hand, based on results for samples containing ADA and drugs, validity of results for ADA assays conducted without acid dissociation was less meaningful and more difficult to evaluate. Thus, acid dissociation was confirmed to be useful for improving drug tolerance. PMID- 29610054 TI - Comparison of protein expression between human livers and the hepatic cell lines HepG2, Hep3B, and Huh7 using SWATH and MRM-HR proteomics: Focusing on drug metabolizing enzymes. AB - Human hepatic cell lines are widely used as an in vitro model for the study of drug metabolism and liver toxicity. However, the validity of this model is still a subject of debate because the expressions of various proteins in the cell lines, including drug-metabolizing enzymes (DMEs), can differ significantly from those in human livers. In the present study, we first conducted an untargeted proteomics analysis of the microsomes of the cell lines HepG2, Hep3B, and Huh7, and compared them to human livers using a sequential window acquisition of all theoretical mass spectra (SWATH) method. Furthermore, high-resolution multiple reaction monitoring (MRM-HR), a targeted proteomic approach, was utilized to compare the expressions of pre-selected DMEs between human livers and the cell lines. In general, the SWATH quantifications were in good agreement with the MRM HR analysis. Over 3000 protein groups were quantified in the cells and human livers, and the proteome profiles of human livers significantly differed from the cell lines. Among the 101 DMEs quantified with MRM-HR, most were expressed at substantially lower levels in the cell lines. Thus, appropriate caution must be exercised when using these cell lines for the study of hepatic drug metabolism and toxicity. PMID- 29610055 TI - Language function in childhood idiopathic epilepsy syndromes. AB - PURPOSE: To examine the impact of diverse syndromes of focal and generalized epilepsy on language function in children with new and recent onset epilepsy. Of special interest was the degree of shared language abnormality across epilepsy syndromes and the unique effects associated with specific epilepsy syndromes. METHODS: Participants were 136 youth with new or recent-onset (diagnosis within past 12 months) epilepsy and 107 healthy first-degree cousin controls. The participants with epilepsy included 20 with Temporal Lobe Epilepsy (TLE; M age = 12.99 years, SD = 3.11), 41 with Benign Epilepsy with Centrotemporal Spikes (BECTS; M age = 10.32, SD = 1.67), 42 with Juvenile Myoclonic Epilepsy (JME; M age = 14.85, SD = 2.75) and 33 with absence epilepsy (M age = 10.55, SD = 2.76). All children were administered a comprehensive test battery which included multiple measures of language and language-dependent abilities (i.e., verbal intelligence, vocabulary, verbal reasoning, object naming, reception word recognition, word reading, spelling, lexical and semantic fluency, verbal list learning and delayed verbal memory). Test scores were adjusted for age and gender and analyzed via MANCOVA. RESULTS: Language abnormalities were found in all epilepsy patient groups. The most broadly affected children were those with TLE and absence epilepsy, whose performance differed significantly from controls on 8 of 11 and 9 of 11 tests respectively. Although children with JME and BECTS were less affected, significant differences from controls were found on 4 of 11 tests each. While each group had a unique profile of language deficits, commonalities were apparent across both idiopathic generalized and localization-related diagnostic categories. DISCUSSION: The localization related and generalized idiopathic childhood epilepsies examined here were associated with impact on diverse language abilities early in the course of the disorder. PMID- 29610056 TI - Omega-6 fatty acids and inflammation. AB - Inflammation is a normal process that is part of host defence and tissue healing. However, excessive or unresolved inflammation can lead to uncontrolled tissue damage, pathology and disease. In humans on a Western diet, the omega-6 polyunsaturated fatty acid arachidonic acid (ARA) makes a significant contribution to the fatty acids present in the membrane phospholipids of cells involved in inflammation. ARA is a precursor to a number of potent pro inflammatory mediators including well described prostaglandins and leukotrienes, which has led to the development of anti-inflammatory pharmaceuticals that target the ARA pathway to successfully control inflammation. Hence, it is commonly believed that increasing dietary intake of the omega-6 fatty acids ARA or its precursor linoleic acid (LA) will increase inflammation. However, studies in healthy human adults have found that increased intake of ARA or LA does not increase the concentrations of many inflammatory markers. Epidemiological studies have even suggested that ARA and LA may be linked to reduced inflammation. Contrastingly, there is also evidence that a high omega-6 fatty acid diet inhibits the anti-inflammatory and inflammation-resolving effect of the omega-3 fatty acids. Thus, the interaction of omega-3 and omega-6 fatty acids and their lipid mediators in the context of inflammation is complex and still not properly understood. PMID- 29610057 TI - Guidelines for care of the newborn baby at birth knowledge by prehospital emergency physicians. AB - INTRODUCTION: In 2010, the International Liaison Committee On Resuscitation (ILCOR) guidelines for care of the newborn baby immediately after birth were published. MATERIALS AND METHODS: Using a questionnaire that was distributed to a sample of 44 prehospital emergency physicians (April 2014), we assessed knowledge of these guidelines, in particular specificities for newborns as compared to adults. Twenty-five questions, starting with a birth with no problems to one resulting in neonatal distress, were used to profile the practice of the surveyed physicians. RESULTS: Among the solicited physicians, 30 responded to the questionnaire (68%). Priority was given to efficient respiratory resuscitation during the first minutes of extrauterine life and the difficulties of newborn respiratory adaptation are well-known, but their implementation remains imperfectly understood. The assessment showed very mixed results, partly explained by the low frequency of newborn scenarios experienced by the practitioners who responded to the questionnaire. CONCLUSION: To move from guidelines to their practical implementation is always delicate, with room for improvement such as continuing education, knowledge assessment and practice in the context of a quality approach. Well accepted, this evaluation process could be renewed upon publication of the next guidelines on this subject, thus contributing to their knowledge. PMID- 29610058 TI - Impact of cryopreservation on sterlet, Acipenser ruthenus sperm motility and proteome. AB - Fish sperm cryopreservation is a well-established technique allowing for artificial insemination on a commercial scale. The extent of proteome alterations in seminal plasma and sperm due to cryopreservation, however, is not known. This study was conducted to evaluate the effect of cryopreservation on motility variables of sterlet Acipenser ruthenus sperm and to detect the differences in protein profiles of fresh and cryopreserved sterlet sperm and seminal plasma. Fresh sperm had 89 +/- 3% motility and 160 +/- 14 MUm/s curvilinear velocity at 15 s post-activation. The motility rate of cryopreserved sperm (37 +/- 5%) was less at 15 s post-activation. No difference (ANOVA; P > 0.05) in mean curvilinear velocity of fresh and cryopreserved sperm was detected. The protein profiles of seminal plasma and sperm were characterized using comparative proteomics to determine the influence of cryopreservation. Six altered protein spots in seminal plasma and thirteen altered spots in sperm were detected in fresh and thawed sperm. Subsequent protein characterization suggested that the proteins identified were involved in sperm metabolism, cytoskeleton, and stress response. The results broaden the understanding of the effects of cryopreservation and identify the proteins associated with cryo-injury. These data may help to determine the function of altered proteins and provide new insights into improving sperm cryopreservation. PMID- 29610059 TI - Gonadotropin concentrations associated with variations in diameter deviation during follicle selection in Holstein heifers. AB - Diameter deviation or selection of the future dominant follicle (F1) from the future largest subordinate follicle (F2) during a follicular wave occurs when F1 is 8.5 mm (expected deviation, day 0). Deviation has been classified as conventional (F2 >= 7.0 mm), F2-undersized (F2 < 7.0 mm), and F1,F2-switched (F2 larger than F1 on day -1 or 0). Concentrations of gonadotropins were compared within and among deviation classifications in waves 1 and 2 in 48 heifers. A three-way (wave 1 compared with 2, classification, day) analysis indicated no effect of wave 1 compared with 2 on F2 or FSH. An interaction of classification by day for F2 diameter (P < 0.001) and FSH concentration (P < 0.005) was primarily from differences on day -1. Rankings on day -1 from greatest to least for F2 diameter were switched, conventional, and undersized and for FSH concentration were undersized, conventional, and switched. Lower FSH concentration in conventional compared with undersized deviations during the decline in the FSH surge was presumed to represent greater output of FSH inhibitors by larger follicles. The incline in FSH surge 2 began significantly later for undersized than for conventional deviation. Switched deviation was associated significantly with emergence of F2 before F1, lower FSH concentration during the decline in the FSH surge, and earlier occurrence of the post-surge FSH nadir. Results supported the hypothesis that diameter differences among deviation classifications are temporally associated with differences in FSH concentration within each classification. These novel findings may complicate studies on the mechanisms of follicle selection. PMID- 29610060 TI - Comparison of the detectability of UBOs in Neurofibromatosis Type I patients with proton density-weighted and FLAIR sequences in 3T MRI. AB - OBJECTIVE: In NF 1 patients, significant numbers of so-called unidentified bright objects (UBOs) can be found. The aim of the study was to investigate whether the detectability of UBOs increases at 3T by comparing Proton density-weighted images (PDw) with fluid-attenuated inversion recovery (FLAIR) sequences. PATIENTS AND METHODS: A total of 14 NF1 patients (7 male, 7 female, between 8 and 26 years old, mean age 15.4 years) were examined by a 3T magnetic resonance scanner. The presence of UBOs was evaluated on PD-w and FLAIR images by 4 evaluators. Detectability was rated by a three-point scoring system: lesions which were "well defined/detectable", "suspicious" or "detected after a second look". The Wilcoxon signed-rank test was used for comparisons between the raters. The level of significance was P < 0.05. RESULTS: Significantly more lesions were marked as "well defined/detectable" in the PD-w Sequence compared to FLAIR at 3T (P < 0.001 for all four evaluators together, as well as for each evaluator separately). In particular, PD-w proved to be superior for detecting UBOs located in the medulla oblongata, dentate nucleus and hippocampal region, regardless of the level of the raters' experience. CONCLUSION: This is the first study which compares FLAIR and PD-w at 3T for the diagnosis of UBOs in NF1. At this field strength significantly more UBOs were detected in the PD-w compared to FLAIR sequences, especially for the infratentorial regions. As UBOs occur at very early stages of the disease in patients with suspected NF1, PD-w might aid in the early diagnosis when using 3T scanners. PMID- 29610061 TI - Implementation of waste-to-energy options in landfill-dominated countries: Economic evaluation and GHG impact. AB - The economic and environmental impact of several waste-to-energy (WtE) schemes to produce electricity from municipal solid waste (MSW) refuse is evaluated and compared with landfill disposal. Both incineration and gasification alternatives are considered. The gasification option includes three different configurations: (1) a fluidized bed gasifier (FBG) with internal combustion engine (ICE), (2) a FBG with organic Rankine cycle (ORC) and (3) a grate gasifier with steam Rankine cycle (SRC). The study is primarily applied to regions where the management system is based on Mechanical Biological Treatment (MBT) plants, generating a large share of refuse (>70%), which is currently landfilled. The specific case of Andalusia, a region in the south of Spain with 23 MBT plants distributed over a region of 87.000 km2, where about 80% of municipal solid waste (MSW) is currently landfilled, is taken as main reference; thereafter, the study is further extended to preliminary assess other regions of some European landfill-dominated countries with similar characteristics. The results show that both incineration and gasification improve landfill disposal, contributing favorably to greenhouse gas (GHG) reduction and fulfilling EU environmental regulations, although the three gasification options analyzed yield lower GHG emissions than incineration. In addition, gasification enables better integration of WtE into existing MBT plants, especially in the particular case of Andalusia, where MBT plants are widespread on the region, making it a more promising option than incineration, which is mainly based on large centralized plants, and less socially accepted. From the options analyzed, the WtE scheme based on FBG with ICE gives the highest profitability for a given gate fee, due to much higher electrical efficiency. However, FBG with ORC seems to be a better option in the short-term for landfill dominated countries, due to its higher technical reliability and the low gate fee currently available in these countries. PMID- 29610062 TI - Electrophysiological measurements of diabetic peripheral neuropathy: A systematic review. AB - INTRODUCTION: Peripheral neuropathy is one of the main complications of diabetes mellitus. One of the features of diabetic nerve damage is abnormality of sensory and motor nerve conduction study. An electrophysiological examination can be reproduced and is also a non-invasive approach in the assessment of peripheral nerve function. Population-based and clinical studies have been conducted to validate the sensitivity of these methods. When the diagnosis was based on clinical electrophysiological examination, abnormalities were observed in all patients. METHOD: In this research, using a review design, we reviewed the issue of clinical electrophysiological examination of diabetic peripheral neuropathy in articles from 2008 to 2017. For this purpose, PubMed, Scopus and Embase databases of journals were used for searching articles. RESULTS/FINDINGS: The researchers indicated that diabetes (both types) is a very disturbing health issue in the modern world and should be given serious attention. Based on conducted studies, it was demonstrated that there are different procedures for prevention and treatment of diabetes-related health problems such as diabetic polyneuropathy (DPN). The first objective quantitative indication of the peripheral neuropathy is abnormality of sensory and motor nerve conduction tests. Electrophysiology is accurate, reliable and sensitive. It can be reproduced and also is a noninvasive approach in the assessment of peripheral nerve function. CONCLUSION: The methodological review has found that the best method for quantitative indication of the peripheral neuropathy compared with all other methods is clinical electrophysiological examination. For best results, standard protocols such as temperature control and equipment calibration are recommended. PMID- 29610063 TI - Association between free thyroid hormones values and the lipid profile in middle aged women with chronic symptoms. AB - AIMS: To determine the association between the thyroid hormones(FT3, FT4 and TSH) and the lipid profile markers(HDL-c, LDL-c and triglycerides) values in middle aged women with no metabolic disorders and recurrent chronic symptomatology. MATERIALS AND METHODS: We carried out an analytical cross-sectional study in euthyroid women with recurrent chronic symptoms of at least six months with no apparent diagnosis who attended the endocrinological gynaecology outpatient service of a private clinic in Lima-Peru during 2012-2014. Participants who met the eligibility criteria were evaluated according to their thyroid hormones(FT3, FT4 and TSH) and lipid profile markers(HDL-c, LDL-c and triglycerides) values. We elaborated univariate/multivariate linear regression models to evaluate the association between the thyroid markers and the lipid profile levels. The reported association measure was the beta coefficient(beta) with its respective p value. RESULTS: We analyzed 211 participants, the average age was 44.9 +/- 14.0(SD) years, the FT3 and FT4 mean levels were 3.2 +/- 0.4 pg/mL and 1.2 +/- 0.2 ng/dL respectively, while the TSH median was 2.8(IQR:1.9-4.0) MUU/mL. The mean or median levels of LDL-c, HDL-c and triglycerides were of 137.5 +/- 37.9 mg/dL, 54.0 +/- 15.0 mg/dL and 118.5(IQR:79.5-169.5) mg/dL respectively. In the multivariate linear regression model between the FT3 and LDL-c levels, we found that for each increase in a FT3 unit, the LDL-c values decreased on average 30.85 mg/dL(p < 0.01). We found no statistically significant associations in the other multivariate models of linear regression, among the other thyroid hormones and lipid markers. CONCLUSION: We found an inverse association between the FT3 and LDL-c values in women with chronic gynaecological symptoms. PMID- 29610064 TI - Frontoethmoidal encephalocele. Report of a case. AB - Encephaloceles are uncommon in western countries and most cases are located in the occipital bone. Frontal encephaloceles may involve the ethmoid bone, nasal bones and/or the orbits. Surgical repair is complex and usually requires a multidisciplinary approach. The goal of the surgery is to reconstruct the normal anatomy, to achieve a good cosmetic repair and to avoid a cerebrospinal fluid leak. We present a case of a patient with a large congenital frontoethmoidal encephalocele. Autologous calvarian bone grafts were used to repair of encephalocele defect and for the reconstruction of the frontonasal area. The defect closure and the cosmetic result were satisfactory, and the only complication detected was the infection of a previously performed ventriculoperitoneal shunt. A description of the technique and a review of the literature are presented. PMID- 29610065 TI - Correction to "Pysics-based vibrotactile feedback library for collision events". AB - The authors of "A Physics-Based Vibrotactile Feedback Library for Collision Events" which appeared in the July-September 2017 issue of this journal [ibid., vol. 10, no. 3, pp. 325-337, Jul.-Sep. 2017] would like to update their Acknowledgments section to say: The authors thank Jong-Rak Park for his discussion on the physics of multi-body collision and vibration. This work was supported by an MSIP/IITP grant (No. 16ZC1300), an IITP grant (No. 2017-0-00179), and an NRF grant (No. NRF-2017R1A2B4008144), all funded by the Korean government. Seungmoon Choi is the corresponding author. PMID- 29610066 TI - 2.5-D Extended Field-of-View Ultrasound. AB - Recently, the growing emphasis on medical ultrasound (US) has led to a rapid development of US extended field-of-view (EFOV) techniques. US EFOV techniques can be classified into three categories: 2-D US EFOV, 3-D US, and 3-D US EFOV. In this paper, we propose a novel EFOV method called 2.5-D US EFOV that combines both the advantages of the 2-D US EFOV and the 3-D US by generating a panorama on a curved image plane guided by a curved scanning trajectory of the US probe. In 2.5-D US EFOV, the real-time position and orientation of the US image plane can be recorded via an electromagnetic spatial sensor attached to the probe. The scanning direction is not necessarily straight and can be curved according to the regions of interest (ROI). To form the curved panorama, an image cutting method is proposed. Finally, the curved panorama is rendered in a 3-D space using a surface rendering based on a texture mapping technique. This allows 3-D measurements of lines and angles. Phantom experiments demonstrated that 2.5-D US EFOV images could show anatomical structures of ROI accurately and rapidly. The overall average errors for the distance and angle measurements are -0.097 +/- 0.128 cm (-1% +/- 1.2%) and 1.50 degrees +/- 1.60 degrees (1.9% +/- 2%), respectively. A typical extended US image can be reconstructed from 321 B-scans images within 3 s. The satisfying quantitative result on the spinal tissues of a scoliosis subject demonstrates that our system has potential applications in the assessment of musculoskeletal issues. PMID- 29610067 TI - Multi-Scale Modeling and Oxygen Impact on Tumor Temporal Evolution: Application on Rectal Cancer During Radiotherapy. AB - We present a multi-scale approach of tumor modeling in order to predict its evolution during radiotherapy. Within this context we focus on three different scales of tumor modeling: microscopic (individual cells in a voxel), mesoscopic (population of cells in a voxel) and macroscopic (whole tumor), with transition interfaces between these three scales. At the cellular level, the description is based on phase transfer probabilities in the cellular cycle. At the mesoscopic scale we represent populations of cells according to different stages in a cell cycle. Finally, at the macroscopic scale, the tumor description is based on the use of FDG PET image voxels. These three scales exist naturally: biological data are collected at the macroscopic scale, but the pathological behavior of the tumor is based on an abnormal cell-cycle at the microscopic scale. On the other hand, the introduction of a mesoscopic scale is essential in order to reduce the gap between the two extreme, in terms of resolution, description levels. It also reduces the computational burden of simulating a large number of individual cells. As an application of the proposed multi-scale model, we simulate the effect of oxygen on tumor evolution during radiotherapy. Two consecutive FDG PET images of 17 rectal cancer patients undergoing radiotherapy are used to simulate the tumor evolution during treatment. The simulated results are compared with those obtained on a third FDG PET image acquired two weeks after the beginning of the treatment. PMID- 29610068 TI - Estimating Maximum Target Registration Error Under Uniform Restriction of Fiducial Localization Error in Image Guided System. AB - In this paper, we investigate the estimation of the maximum target registration error (TRE) magnitude of the target location while using point-based rigid registration in the image guided system. Under the uniform restriction of fiducial localization error (FLE) magnitude, we explicitly formulate the estimation as an optimization problem. Through analyzing the approximated problem which assumes the rigidity of the fiducial set holds with the perturbation of FLE, we present a strict lower bound for the maximum TRE magnitude. The simulations show that the lower bound is close to the actual maximum TRE magnitude for the target locations lying far away from the fiducial points. Unlike the expected TRE magnitude in which all fiducial points contribute, the lower bound is only related to the fiducial points serving as the vertices of the convex hull of the fiducial set. Our analysis provides a new perspective of investigating the problem of TRE estimation and is helpful for the surgeons to learn about the worst situation during using the image guided system. PMID- 29610069 TI - Sparse Representation-Based Radiomics for the Diagnosis of Brain Tumors. AB - Brain tumors are the most common malignant neurologic tumors with the highest mortality and disability rate. Because of the delicate structure of the brain, the clinical use of several commonly used biopsy diagnosis is limited for brain tumors. Radiomics is an emerging technique for noninvasive diagnosis based on quantitative medical image analyses. However, current radiomics techniques are not standardized regarding feature extraction, feature selection, and decision making. In this paper, we propose a sparse representation-based radiomics (SRR) system for the diagnosis of brain tumors. First, we developed a dictionary learning- and sparse representation-based feature extraction method that exploits the statistical characteristics of the lesion area, leading to fine and more effective feature extraction compared with the traditional explicitly calculation based methods. Then, we set up an iterative sparse representation method to solve the redundancy problem of the extracted features. Finally, we proposed a novel multi-feature collaborative sparse representation classification framework that introduces a new coefficient of regularization term to combine features from multi-modal images at the sparse representation coefficient level. Two clinical problems were used to validate the performance and usefulness of the proposed SRR system. One was the differential diagnosis between primary central nervous system lymphoma (PCNSL) and glioblastoma (GBM), and the other was isocitrate dehydrogenase 1 estimation for gliomas. The SRR system had superior PCNSL and GBM differentiation performance compared with some advanced imaging techniques and yielded 11% better performance for estimating IDH1 compared with the traditional radiomics methods. PMID- 29610070 TI - Ultrafast Ultrasound Imaging With Cascaded Dual-Polarity Waves. AB - Ultrafast ultrasound imaging using plane or diverging waves, instead of focused beams, has advanced greatly the development of novel ultrasound imaging methods for evaluating tissue functions beyond anatomical information. However, the sonographic signal-to-noise ratio (SNR) of ultrafast imaging remains limited due to the lack of transmission focusing, and thus insufficient acoustic energy delivery. We hereby propose a new ultrafast ultrasound imaging methodology with cascaded dual-polarity waves (CDWs), which consists of a pulse train with positive and negative polarities. A new coding scheme and a corresponding linear decoding process were thereby designed to obtain the recovered signals with increased amplitude, thus increasing the SNR without sacrificing the frame rate. The newly designed CDW ultrafast ultrasound imaging technique achieved higher quality B-mode images than coherent plane-wave compounding (CPWC) and multiplane wave (MW) imaging in a calibration phantom, ex vivo pork belly, and in vivo human back muscle. CDW imaging shows a significant improvement in the SNR (10.71 dB versus CPWC and 7.62 dB versus MW), penetration depth (36.94% versus CPWC and 35.14% versus MW), and contrast ratio in deep regions (5.97 dB versus CPWC and 5.05 dB versus MW) without compromising other image quality metrics, such as spatial resolution and frame rate. The enhanced image qualities and ultrafast frame rates offered by CDW imaging beget great potential for various novel imaging applications. PMID- 29610071 TI - Mass Segmentation in Automated 3-D Breast Ultrasound Using Adaptive Region Growing and Supervised Edge-Based Deformable Model. AB - Automated 3-D breast ultrasound has been proposed as a complementary modality to mammography for early detection of breast cancers. To facilitate the interpretation of these images, computer aided detection systems are being developed in which mass segmentation is an essential component for feature extraction and temporal comparisons. However, automated segmentation of masses is challenging because of the large variety in shape, size, and texture of these 3-D objects. In this paper, the authors aim to develop a computerized segmentation system, which uses a seed position as the only priori of the problem. A two-stage segmentation approach has been proposed incorporating shape information of training masses. At the first stage, a new adaptive region growing algorithm is used to give a rough estimation of the mass boundary. The similarity threshold of the proposed algorithm is determined using a Gaussian mixture model based on the volume and circularity of the training masses. In the second stage, a novel geometric edge-based deformable model is introduced using the result of the first stage as the initial contour. In a data set of 50 masses, including 38 malignant and 12 benign lesions, the proposed segmentation method achieved a mean Dice of 0.74 +/- 0.19 which outperformed the adaptive region growing with a mean Dice of 0.65 +/- 0.2 (p-value < 0.02). Moreover, the resulting mean Dice was significantly (p-value < 0.001) better than that of the distance regularized level set evolution method (0.52 +/- 0.27). The supervised method presented in this paper achieved accurate mass segmentation results in terms of Dice measure. The suggested segmentation method can be utilized in two aspects: 1) to automatically measure the change in volume of breast lesions over time and 2) to extract features for a computer aided detection or diagnosis system. PMID- 29610072 TI - Automated Cell Segmentation for Quantitative Phase Microscopy. AB - Automated cell segmentation and tracking is essential for dynamic studies of cellular morphology, movement, and interactions as well as other cellular behaviors. However, accurate, automated, and easy-to-use cell segmentation remains a challenge, especially in cases of high cell densities, where discrete boundaries are not easily discernable. Here, we present a fully automated segmentation algorithm that iteratively segments cells based on the observed distribution of optical cell volumes measured by quantitative phase microscopy. By fitting these distributions to known probability density functions, we are able to converge on volumetric thresholds that enable valid segmentation cuts. Since each threshold is determined from the observed data itself, virtually no input is needed from the user. We demonstrate the effectiveness of this approach over time using six cell types that display a range of morphologies, and evaluate these cultures over a range of confluencies. Facile dynamic measures of cell mobility and function revealed unique cellular behaviors that relate to tissue origins, state of differentiation, and real-time signaling. These will improve our understanding of multicellular communication and organization. PMID- 29610073 TI - A New 4-D Nonlocal Transform-Domain Filter for 3-D Magnetic Resonance Images Denoising. AB - The simultaneous removal of noise and preservation of the integrity of 3-D magnetic resonance (MR) images is a difficult and important task. In this paper, we consider characterizing MR images with 3-D operators, and present a novel 4-D transform-domain method termed 'modified nonlocal tensor-SVD (MNL-tSVD)' for MR image denoising. The proposed method is based on the grouping, hard-thresholding and aggregation paradigms, and can be viewed as a generalized nonlocal extension of tensor-SVD (t-SVD). By keeping MR images in its natural three-dimensional form, and collaboratively filtering similar patches, MNL-tSVD utilizes both the self-similarity property and 3-D structure of MR images to preserve more actual details and minimize the introduction of new artifacts. We show the adaptability of MNL-tSVD by incorporating it into a two-stage denoising strategy with a few adjustments. In addition, analysis of the relationship between MNL-tSVD and current the state-of-the-art 4-D transforms is given. Experimental comparisons over simulated and real brain data sets at different Rician noise levels show that MNL-tSVD can produce competitive performance compared with related approaches. PMID- 29610074 TI - Direct Patlak Reconstruction From Dynamic PET Data Using the Kernel Method With MRI Information Based on Structural Similarity. AB - Positron emission tomography (PET) is a functional imaging modality widely used in oncology, cardiology, and neuroscience. It is highly sensitive, but suffers from relatively poor spatial resolution, as compared with anatomical imaging modalities, such as magnetic resonance imaging (MRI). With the recent development of combined PET/MR systems, we can improve the PET image quality by incorporating MR information into image reconstruction. Previously, kernel learning has been successfully embedded into static and dynamic PET image reconstruction using either PET temporal or MRI information. Here, we combine both PET temporal and MRI information adaptively to improve the quality of direct Patlak reconstruction. We examined different approaches to combine the PET and MRI information in kernel learning to address the issue of potential mismatches between MRI and PET signals. Computer simulations and hybrid real-patient data acquired on a simultaneous PET/MR scanner were used to evaluate the proposed methods. Results show that the method that combines PET temporal information and MRI spatial information adaptively based on the structure similarity index has the best performance in terms of noise reduction and resolution improvement. PMID- 29610076 TI - Predicting CT Image From MRI Data Through Feature Matching With Learned Nonlinear Local Descriptors. AB - Attenuation correction for positron-emission tomography (PET)/magnetic resonance (MR) hybrid imaging systems and dose planning for MR-based radiation therapy remain challenging due to insufficient high-energy photon attenuation information. We present a novel approach that uses the learned nonlinear local descriptors and feature matching to predict pseudo computed tomography (pCT) images from T1-weighted and T2-weighted magnetic resonance imaging (MRI) data. The nonlinear local descriptors are obtained by projecting the linear descriptors into the nonlinear high-dimensional space using an explicit feature map and low rank approximation with supervised manifold regularization. The nearest neighbors of each local descriptor in the input MR images are searched in a constrained spatial range of the MR images among the training dataset. Then the pCT patches are estimated through k-nearest neighbor regression. The proposed method for pCT prediction is quantitatively analyzed on a dataset consisting of paired brain MRI and CT images from 13 subjects. Our method generates pCT images with a mean absolute error (MAE) of 75.25 +/- 18.05 Hounsfield units, a peak signal-to-noise ratio of 30.87 +/- 1.15 dB, a relative MAE of 1.56 +/- 0.5% in PET attenuation correction, and a dose relative structure volume difference of 0.055 +/- 0.107% in , as compared with true CT. The experimental results also show that our method outperforms four state-of-the-art methods. PMID- 29610075 TI - Low-Frequency Conductivity Tensor Imaging of the Human Head In Vivo Using DT MREIT: First Study. AB - We present the first in vivo images of anisotropic conductivity distribution in the human head, measured at a frequency of approximately 10 Hz. We used magnetic resonance electrical impedance tomography techniques to encode phase changes caused by current flow within the head via two independent electrode pairs. These results were then combined with diffusion tensor imaging data to reconstruct full anisotropic conductivity distributions in 5-mm-thick slices of the brains of two participants. Conductivity values recovered in this paper were broadly consistent with literature values. We anticipate that this technique will be of use in many areas of neuroscience, most importantly in functional imaging via inverse electroencephalogram. Future studies will involve pulse sequence acceleration to maximize brain coverage and resolution. PMID- 29610077 TI - Fast Quasi-Newton Algorithms for Penalized Reconstruction in Emission Tomography and Further Improvements via Preconditioning. AB - This paper reports on the feasibility of using a quasi-Newton optimization algorithm, limited-memory Broyden-Fletcher-Goldfarb-Shanno with boundary constraints (L-BFGS-B), for penalized image reconstruction problems in emission tomography (ET). For further acceleration, an additional preconditioning technique based on a diagonal approximation of the Hessian was introduced. The convergence rate of L-BFGS-B and the proposed preconditioned algorithm (L-BFGS-B PC) was evaluated with simulated data with various factors, such as the noise level, penalty type, penalty strength and background level. Data of three 18F-FDG patient acquisitions were also reconstructed. Results showed that the proposed L BFGS-B-PC outperforms L-BFGS-B in convergence rate for all simulated conditions and the patient data. Based on these results, L-BFGS-B-PC shows promise for clinical application. PMID- 29610078 TI - Estimating Dynamic Connectivity States in fMRI Using Regime-Switching Factor Models. AB - We consider the challenges in estimating the state-related changes in brain connectivity networks with a large number of nodes. Existing studies use the sliding-window analysis or time-varying coefficient models, which are unable to capture both smooth and abrupt changes simultaneously, and rely on ad-hoc approaches to the high-dimensional estimation. To overcome these limitations, we propose a Markov-switching dynamic factor model, which allows the dynamic connectivity states in functional magnetic resonance imaging (fMRI) data to be driven by lower-dimensional latent factors. We specify a regime-switching vector autoregressive (SVAR) factor process to quantity the time-varying directed connectivity. The model enables a reliable, data-adaptive estimation of change points of connectivity regimes and the massive dependencies associated with each regime. We develop a three-step estimation procedure: 1) extracting the factors using principal component analysis, 2) identifying connectivity regimes in a low dimensional subspace based on the factor-based SVAR model, and 3) constructing high-dimensional state connectivity metrics based on the subspace estimates. Simulation results show that our estimator outperforms -means clustering of time windowed coefficients, providing more accurate estimate of time-evolving connectivity. It achieves percentage of reduction in mean squared error by 60% when the network dimension is comparable to the sample size. When applied to the resting-state fMRI data, our method successfully identifies modular organization in the resting-statenetworksin consistencywith other studies. It further reveals changes in brain states with variations across subjects and distinct large-scale directed connectivity patterns across states. PMID- 29610079 TI - Macular OCT Classification Using a Multi-Scale Convolutional Neural Network Ensemble. AB - Computer-aided diagnosis (CAD) of retinal pathologies is a current active area in medical image analysis. Due to the increasing use of retinal optical coherence tomography (OCT) imaging technique, a CAD system in retinal OCT is essential to assist ophthalmologist in the early detection of ocular diseases and treatment monitoring. This paper presents a novel CAD system based on a multi-scale convolutional mixture of expert (MCME) ensemble model to identify normal retina, and two common types of macular pathologies, namely, dry age-related macular degeneration, and diabetic macular edema. The proposed MCME modular model is a data-driven neural structure, which employs a new cost function for discriminative and fast learning of image features by applying convolutional neural networks on multiple-scale sub-images. MCME maximizes the likelihood function of the training data set and ground truth by considering a mixture model, which tries also to model the joint interaction between individual experts by using a correlated multivariate component for each expert module instead of only modeling the marginal distributions by independent Gaussian components. Two different macular OCT data sets from Heidelberg devices were considered for the evaluation of the method, i.e., a local data set of OCT images of 148 subjects and a public data set of 45 OCT acquisitions. For comparison purpose, we performed a wide range of classification measures to compare the results with the best configurations of the MCME method. With the MCME model of four scale dependent experts, the precision rate of 98.86%, and the area under the receiver operating characteristic curve (AUC) of 0.9985 were obtained on average. PMID- 29610080 TI - High-Permittivity Pad Design for Dielectric Shimming in Magnetic Resonance Imaging Using Projection-Based Model Reduction and a Nonlinear Optimization Scheme. AB - Inhomogeneities in the transmit radio frequency magnetic field ( ) reduce the quality of magnetic resonance (MR) images. This quality can be improved by using high-permittivity pads that tailor the fields. The design of an optimal pad is application-specific and not straightforward and would therefore benefit from a systematic optimization approach. In this paper, we propose such a method to efficiently design dielectric pads. To this end, a projection-based model order reduction technique is used that significantly decreases the dimension of the design problem. Subsequently, the resulting reduced-order model is incorporated in an optimization method in which a desired field in a region of interest can be set. The method is validated by designing a pad for imaging the cerebellum at 7 T. The optimal pad that is found is used in an MR measurement to demonstrate its effectiveness in improving the image quality. PMID- 29610081 TI - A Skeletal Similarity Metric for Quality Evaluation of Retinal Vessel Segmentation. AB - The most commonly used evaluation metrics for quality assessment of retinal vessel segmentation are sensitivity, specificity, and accuracy, which are based on pixel-to-pixel matching. However, due to the inter-observer problem that vessels annotated by different observers vary in both thickness and location, pixel-to-pixel matching is too restrictive to fairly evaluate the results of vessel segmentation. In this paper, the proposed skeletal similarity metric is constructed by comparing the skeleton maps generated from the reference and the source vessel segmentation maps. To address the inter-observer problem, instead of using a pixel-to-pixel matching strategy, each skeleton segment in the reference skeleton map is adaptively assigned with a searching range whose radius is determined based on its vessel thickness. Pixels in the source skeleton map located within the searching range are then selected for similarity calculation. The skeletal similarity consists of a curve similarity, which measures the structural similarity between the reference and the source skeleton maps and a thickness similarity, which measures the thickness consistency between the reference and the source vessel segmentation maps. In contrast to other metrics that provide a global score for the overall performance, we modify the definitions of true positive, false negative, true negative, and false positive based on the skeletal similarity, based on which sensitivity, specificity, accuracy, and other objective measurements can be constructed. More importantly, the skeletal similarity metric has better potential to be used as a pixelwise loss function for training deep learning models for retinal vessel segmentation. Through comparison of a set of examples, we demonstrate that the redefined metrics based on the skeletal similarity are more effective for quality evaluation, especially with greater tolerance to the inter-observer problem. PMID- 29610082 TI - Online Robust Projective Dictionary Learning: Shape Modeling for MR-TRUS Registration. AB - Robust and effective shape prior modeling from a set of training data remains a challenging task, since the shape variation is complicated, and shape models should preserve local details as well as handle shape noises. To address these challenges, a novel robust projective dictionary learning (RPDL) scheme is proposed in this paper. Specifically, the RPDL method integrates the dimension reduction and dictionary learning into a unified framework for shape prior modeling, which can not only learn a robust and representative dictionary with the energy preservation of the training data, but also reduce the dimensionality and computational cost via the subspace learning. In addition, the proposed RPDL algorithm is regularized by using the norm to handle the outliers and noises, and is embedded in an online framework so that of memory and time efficiency. The proposed method is employed to model prostate shape prior for the application of magnetic resonance transrectal ultrasound registration. The experimental results demonstrate that our method provides more accurate and robust shape modeling than the state-of-the-art methods do. The proposed RPDL method is applicable for modeling other organs, and hence, a general solution for the problem of shape prior modeling. PMID- 29610083 TI - A Spatial Coherence Approach to Minimum Variance Beamforming for Plane-Wave Compounding. AB - A new approach to implement minimum variance distortionless response (MVDR) beamforming is introduced for coherent plane-wave compounding (CPWC). MVDR requires the covariance matrix of the incoming signal to be estimated and a spatial smoothing approximation is usually adopted to prevent this calculation from being underconstrained. In the new approach, we analyze MVDR as a spatial filter that decorrelates signals received at individual channels before summation. Based on the analysis, we develop two MVDR beamformers without using any spatial smoothing. First, MVDR weights are applied to the received signals after accumulating the data over transmits at different angles, while the second involves weighting the data collected in individual transmits and compounding over the transducer elements. In both cases, the covariance matrix is estimated using a set of slightly different combinations of the echo data. We show the sufficient statistic for this estimation that can be described by approximating the correlation among the backscattered ultrasound signals to their spatial coherence. Using the van Cittert-Zernike theorem, their statistical similarity is assessed by relating the spatial coherence to the profile of the source intensity. Both spatial-coherence-based MVDR beamformers are evaluated on data sets acquired from simulation, phantom, and in vivo studies. Imaging results show that they offer improvements over simple coherent compounding in terms of spatial and contrast resolutions. They also outperform other existing MVDR-based methods in the literature that are applied to CPWC. PMID- 29610084 TI - Multiline Transmit Beamforming Combined With Adaptive Apodization. AB - Increased frame rate is of high importance to cardiac diagnostic imaging as it enables examination of fast events during the cardiac cycle and improved quantitative analysis, such as speckle tracking. Multiline transmission (MLT) is one of the methods proposed for this purpose. In contrast to the single-line transmission (SLT), where one focused beam is sent in each direction, MLT beams are simultaneously transmitted and focused in several ( ) directions improving the frame rate accordingly. The simultaneous transmission is known to cause crosstalk artifacts due to the interference between the main lobes and the sidelobes of the transmitted and received beams. Usually, the artifacts are attenuated using a Tukey window apodization, but the lateral resolution is degraded. Several other methods, such as minimum variance beamforming and filtered delay multiply and sum beamforming were proposed to deal with these artifacts. The assumption examined in this paper is that a receive apodization can be chosen adaptively from a number of apodization windows in order to provide better artifact rejection and to increase the spatial resolution. The entire study was performed on an experimental MLT data set including wire and tissue mimicking phantoms, as well as in vivo cardiac data. The results demonstrate that application of a predefined apodization bank outperforms Tukey windowing alone, in terms of both resolution and receive crosstalk artifact rejections. Moreover, the achieved spatial resolution is superior to the nonapodized SLT, as measured from wire phantoms. The proposed method can also be combined with wider transmit beams, suitable for multiline acquisition. PMID- 29610085 TI - Laser Generated Leaky Acoustic Waves for Needle Visualization. AB - Ultrasound (US)-guided needle operation is usually used to visualize both tissue and needle position such as tissue biopsy and localized drug delivery. However, the transducer-needle orientation is limited due to reflection of the acoustic waves. We proposed a leaky acoustic wave method to visualize the needle position and orientation. Laser pulses are emitted on top of the needle to generate acoustic waves; then, these acoustic waves propagate along the needle surface. Leaky wave signals are detected by the US array transducer. The needle position can be calculated by phase velocities of two different wave modes and their corresponding emission angles. In our experiments, a series of needles was inserted into a tissue mimicking phantom and porcine tissue to evaluate the accuracy of the proposed method. The results show that the detection depth is up to 51 mm and the insertion angle is up to 40 degrees with needles of different diameters. It is demonstrated that the proposed approach outperforms the conventional B-mode US-guided needle operation in terms of the detection range while achieving similar accuracy. The proposed method reveals the potentials for further clinical applications. PMID- 29610086 TI - An Adaptive Synthetic Aperture Method Applied to Ultrasound Tissue Harmonic Imaging. AB - In recent years, the minimum variance (MV) beamformer has been highly regarded since it provides high resolution and contrast in B-mode ultrasound imaging compared with nonadaptive delay-and-sum (DAS) beamformer. However, the performance of MV beamformer is degraded in the presence of the noise due to inaccurate estimation of the covariance matrix resulting in low-quality images. The conventional tissue harmonic imaging (THI) offers multiple advantages over conventional pulse-echo ultrasound imaging, including enhanced contrast resolution and improved axial and lateral resolutions, but low signal-to-noise ratio (SNR) is a major problem facing this imaging method, which uses a fixed transmit focus and dynamic receive focusing (DRF). In this paper, a synthetic aperture method based on the virtual source, namely, bidirectional pixel-based focusing (BiPBF), has been combined with the MV beamformer and then applied to second-harmonic ultrasound imaging. The main objective is suppressing the noise level to enhance the performance of the MV beamformer in the harmonic imaging, especially in lower and deeper depths where the SNR is low. In addition, combining the BiPBF and MV weighting results in simultaneous improvement in imaging resolution and contrast, in comparison with the conventional methods: DRF (DAS), BiPBF (DAS), and DRF (MV). The performance of the proposed method is evaluated on simulated and experimental RF data. The THI is achieved using the pulse-inversion technique. The results of the simulated wire phantom demonstrate that the proposed beamformer can achieve the best lateral resolution, along different depths, compared with DRF (DAS), BiPBF (DAS), and DRF (MV) methods. The results of the simulated and experimental cyst phantoms show that the new beamformer improves the contrast ratio (CR) and contrast-to-noise ratio (CNR) of the resulting images. In results of simulated cyst phantom, in average, the new beamformer improves the CR and CNR of the cyst about (7.4 dB, 49%), (3.2 dB, 16%), and (5 dB, 26%) compared with DRF (DAS), BiPBF (DAS), and DRF (MV), respectively. In results of experimental cyst phantom, these relative improvements are about (4.2 dB, 22%), (1.7 dB, 7%), and (2.6 dB, 15%). In addition, BiPBF (MV) method offers improved edge definition of cysts in comparison with the other methods. PMID- 29610087 TI - Acoustic Characterization of a Vessel-on-a-Chip Microfluidic System for Ultrasound-Mediated Drug Delivery. AB - Ultrasound in the presence of gas-filled microbubbles can be used to enhance local uptake of drugs and genes. To study the drug delivery potential and its underlying physical and biological mechanisms, an in vitro vessel model should ideally include 3-D cell culture, perfusion flow, and membrane-free soft boundaries. Here, we propose an organ-on-a-chip microfluidic platform to study ultrasound-mediated drug delivery: the OrganoPlate. The acoustic propagation into the OrganoPlate was determined to assess the feasibility of controlled microbubble actuation, which is required to study the microbubble-cell interaction for drug delivery. The pressure field in the OrganoPlate was characterized non-invasively by studying experimentally the well-known response of microbubbles and by simulating the acoustic wave propagation in the system. Microbubble dynamics in the OrganoPlate were recorded with the Brandaris 128 ultrahigh-speed camera (17 million frames/s) and a control experiment was performed in an OptiCell, an in vitro monolayer cell culture chamber that is conventionally used to study ultrasound-mediated drug delivery. When insonified at frequencies between 1 and 2 MHz, microbubbles in the OrganoPlate experienced larger oscillation amplitudes resulting from higher local pressures. Microbubbles responded similarly in both systems when insonified at frequencies between 2 and 4 MHz. Numerical simulations performed with a 3-D finite-element model of ultrasound propagation into the OrganoPlate and the OptiCell showed the same frequency-dependent behavior. The predictable and homogeneous pressure field in the OrganoPlate demonstrates its potential to develop an in vitro 3-D cell culture model, well suited to study ultrasound-mediated drug delivery. PMID- 29610088 TI - Fabrication and Characterization of Single-Aperture 3.5-MHz BNT-Based Ultrasonic Transducer for Therapeutic Application. AB - This paper discusses the fabrication and characterization of 3.5-MHz single element transducers for therapeutic applications in which the active elements are made of hard lead-free BNT-based and hard commercial PZT (PZT-841) piezoceramics. Composition of (BiNa0.88K0.08Li0.04)0.5(Ti0.985Mn0.015)O3 (BNKLT88-1.5Mn) was used to develop lead-free piezoelectric ceramic. Mn-doped samples exhibited high mechanical quality factor ( ) of 970, thickness coupling coefficient ( ) of 0.48, a dielectric constant ( ) of 310 (at 1 kHz), depolarization temperature ( ) of 200 degrees C, and coercive field ( ) of 52.5 kV/cm. Two different unfocused single-element transducers using BNKLT88-1.5Mn and PZT-841 with the same center frequency of 3.5 MHz and similar aperture size of 10.7 and 10.5 mm were fabricated. Pulse-echo response, acoustic frequency spectrum, acoustic pressure field, and acoustic intensity field of transducers were characterized. The BNT based transducer shows linear response up to the peak-to-peak voltage of 105 V in which the maximum rarefactional acoustic pressure of 1.1 MPa, and acoustic intensity of 43 W/cm2 were achieved. Natural focal point of this transducer was at 60 mm from the surface of the transducer. PMID- 29610089 TI - Design and Simulation of a Ring-Shaped Linear Array for Microultrasound Capsule Endoscopy. AB - Video capsule endoscopy (VCE) has significantly advanced visualization of the gastrointestinal tract since its introduction in the last 20 years. Work is now under way to combine VCE with microultrasound imaging. However, small maximum capsule dimensions, coupled with the electronics required to integrate ultrasound imaging capabilities, pose significant design challenges. This paper describes a simulation process for testing transducer geometries and imaging methodologies to achieve satisfactory imaging performance within the physical limitations of the capsule size and outlines many of the tradeoffs needed in the design of this new class of ultrasound capsule endoscopy (USCE) device. A hybrid MATLAB model is described, incorporating Krimholtz-Leedom-Matthaei circuit elements and digitizing and beamforming elements to render a gray-scale B-mode. This model is combined with a model of acoustic propagation to generate images of point scatterers. The models are used to demonstrate the performance of a USCE transducer configuration comprising a single, unfocused transmit ring of radius 5 mm separated into eight segments for electrical impedance control and a 512 element receive linear array, also formed into a ring. The MATLAB model includes an ultrasonic pulser circuit connected to a piezocrystal composite transmit transducer with a center frequency of 25 MHz. B-scan images are simulated for wire target phantoms, multilayered phantoms, and a gut wall model. To demonstrate the USCE system's ability to image tissue, a digital phantom was created from single-element ultrasonic transducer scans of porcine small bowel ex vivo obtained at a frequency of 45 MHz. PMID- 29610090 TI - Quantification of the Effect of Array Element Pitch on Imaging Performance. AB - This paper investigates how the pitch of elements in periodic ultrasonic arrays is related to their imaging performance, with particular emphasis on imaging artifacts (grating lobes) arising from discrete spatial sampling. Although the classical Nyquist rules for array element pitch are well known, they only provide the limiting condition needed to eliminate grating lobes from an array with an infinitely large aperture at a single frequency. Physical arrays have finite sized apertures and most applications employ broadband pulses. For these reasons, grating lobe artifacts are always present at some level, and practical array design is, therefore, based on suppressing grating lobe artifacts to a level appropriate to a given application. In this paper, a theoretical framework is developed that enables the point spread function of a periodic imaging array to be decomposed into the sum of contributions from a main lobe and different orders of grating lobes, thus allowing grating lobe artifacts to be unambiguously quantified. Numerical simulations are used to analyze the performance of 1-D linear arrays in both far-field (steering only) and near-field (focusing only) scenarios, and design guidelines are deduced. It is shown that in general, the classical Nyquist rules are overly conservative and that the pitch of an array can be increased without significantly compromising image quality, provided that certain constraints on ray angles are implemented in the imaging algorithm. Experimental examples are shown that illustrate the practical application to arrays in two configurations. PMID- 29610091 TI - Performance Evaluation of CMUT-Based Ultrasonic Transformers for Galvanic Isolation. AB - This paper presents the development of a novel acoustic transformer with high galvanic isolation dedicated to power switch triggering. The transformer is based on two capacitive micromachined ultrasonic transducers layered on each side of a silicon substrate; one is the primary circuit, and the other is the secondary circuit. The thickness mode resonance of the substrate is leveraged to transmit the triggering signal. The fabrication and characterization of an initial prototype is presented in this paper. All experimental results are discussed, from the electrical impedance measurements to the power efficiency measurements, for different electrical load conditions. A comparison with a specifically developed finite-element method model is done. Simulations are finally used to identify the optimization rules of this initial prototype. It is shown that the power efficiency can be increased from 35% to 60%, and the transmitted power can be increased from 1.6 to 45 mW/Volt. PMID- 29610092 TI - Method for Designing Multielement Fully Populated Random Phased Arrays for Ultrasound Surgery Applications. AB - Maximizing the power of multielement phased arrays is a critical factor for high intensity focused ultrasound (HIFU) applications such as histotripsy and transcostal sonications. This can be achieved by a tight packing of the array elements. Good electronic focusing capabilities are also required. Currently used quasi-random arrays with a relatively low filling factor of about 60% have this focusing ability. Here, a novel method of designing random HIFU arrays with the maximum possible filling factor (100% if no gaps between elements needed in practice are introduced) and polygonal elements of equal area and slightly different shapes based on the capacity-constrained tessellation is described. The method is validated by comparing designs of two arrays with the same geometric and physical parameters: an existing 256-element array with a compact 16-spirals layout of circular elements and the proposed array with the maximum possible filling factor. Introduction of a 0.5-mm gap between the elements of the new array resulted in a reduction of its filling factor to 86%, as compared with 61% for the spiral array. It is shown that for the same intensity at the elements, the proposed array provides two times higher total power while maintaining the same electronic focusing capabilities as compared to the spiral one. Furthermore, the surface of the capacity-constrained tessellation array, its boundary, and a central opening can have arbitrary shapes. PMID- 29610093 TI - Cryo-Ultrasonic NDE: Ice-Cold Ultrasonic Waves for the Detection of Damage in Complex-Shaped Engineering Components. AB - Recent advances in computational methods, materials science, and new manufacturing processes are resulting in an unprecedented design flexibility which is driving the geometrical complexity of the components found in modern structures and machines. For safety-critical components, the geometrical complexity poses a significant challenge to the sensitivity of the existing nondestructive evaluation (NDE) methods available for the detection of manufacturing defects or damage that develops while a component is in service. Although X-ray computed tomography is the primary NDE method used to test these parts in current industrial practice, it is widely recognized that it has limited sensitivity to critical defects, such as cracks, especially in the presence of large size parts made of dense materials. The lack of sensitive NDE methods represents a major technology gap that could impede the acceptance of rapidly developing technologies, such as 3-D printing, for the production of safety critical components. This paper attempts to bridge this gap by exploring the possibility of inspecting a complex-shaped part with ultrasonic waves after it has been encapsulated in ice, under the paradigm of what can be defined as cryo ultrasonic NDE. The underpinning hypothesis is that through ice encapsulation a complex-shaped part can be transformed into a simple-shaped solid whose volume can be probed with ultrasonic waves, which are known to be highly sensitive to both pores and crack-like defects and over a wide range of material properties. Damage detection is then performed by analyzing cross-sectional images of the ice encapsulated part obtained by applying migration methods to the ultrasonic signals measured by an array of transducers. This paper lays the foundation for cryo-ultrasonic NDE and presents the first experimental results demonstrating the possibility of imaging defects through multiple ice-metal interfaces. This paves the way to the detection of defects in complex-shaped parts containing internal vanes which have so far limited the use of conventional NDE methods. PMID- 29610094 TI - Relative Ability of Wedge-Coupled Piezoelectric and Meander Coil EMAT Probes to Generate Single-Mode Lamb Waves. AB - Ultrasonic guided waves are used extensively when checking for defects in petrochemical and other industries and are mostly generated using piezoelectric transducers on an angled wedge or electromagnetic acoustic transducers (EMATs) in different configurations. Low-frequency inspection allows for long-distance propagation, but it is best suited for detecting relatively large defects, while at higher frequencies, the presence of multiple wave modes limit defect detectability, so achieving practical single Lamb mode excitation via careful transduction is very beneficial. This paper investigates the relative ability of angled piezoelectric and meander coil EMAT probes to produce single-mode transduction in the medium (~1-5 MHz-mm) and high (>5 MHz-mm) frequency-thickness regions of the dispersion curves. The nature of each transducer is studied analytically by simulating the corresponding surface forces, followed by the use of a Fourier transform in time and space (2-D fast Fourier transform) to highlight the excitation region in the wavenumber-frequency space. With angled wedge excitation there is a linear relationship between the excitation frequency and the wavenumber which means that the excitation tends to track typical dispersion curves, allowing for easier pure mode generation. In contrast, the EMAT controls frequency and wavenumber separately which makes it more difficult to generate a pure mode when dispersion curves are close together; however, by narrowing the frequency bandwidth via a large number of cycles in the excitation signal, pure mode generation via an EMAT was shown to be possible even in areas of closely spaced modes. As example cases, analytical results, backed up by experiments, showed that signals dominated by the A0 mode at 1.5 MHz-mm and also the A1 mode at 18 MHz-mm can be generated with both angled piezoelectric and EMAT probes. PMID- 29610095 TI - High-Temperature SAW Resonator Sensors: Electrode Design Specifics. AB - Surface acoustic wave (SAW) sensors are steadily paving the way to wider application areas. Their main benefit consisting in the possibility of wireless interrogation with the radio frequency interrogation signal being the only energy source for the reradiated signal. This feature is getting more and more attractive with the growing demand in monitoring multiple industrial objects difficult to access by wired sensors in harsh environments. Among such wider applications, the possibility of making measurements of temperature, deformation, vibrations, and some other parameters at temperatures in the range of 300 degrees C-1000 degrees C look quite promising. This paper concentrates on specific features of the SAW resonator-based sensors operation at this temperature range. High-temperature influences the material choice and thus the properties of SAW resonators design peculiarities intended for use at high temperature. It is suggested that preferable designs should use synchronous resonators with relatively thick electrodes (10% of wavelength) based on Ir or Pt alloys while benefiting from the possibilities of specific designs that could reduce the negative impact of thick electrodes on the manufacturing in quantity. This solution benefits from lower resonance frequency scatter because of the automatic compensation of SAW velocity decrease due to electrode metallization ratio increase. This compensation originates from the resonance frequency increase that is related to the decrease of the Bragg bandwidth defined by the reflection. It is shown in modeling examples that the value of metallization ratio at which this compensation occurs is close to 65%-70%. PMID- 29610096 TI - A Twofold Approach in Loss Reduction of KTa0.5Nb0.5O3 Ferroelectric Layers for Low-Loss Tunable Devices at Microwaves. AB - Ferroelectric oxide films are attractive to design and fabricate reconfigurable and miniaturized planar devices operating at microwaves due to the large electric field dependence of their dielectric permittivity. In particular, KTa1-xNbxO3 (KTN) ferroelectric material presents a high tunability under moderate dc bias electric field. However, its intrinsic dielectric loss strongly contributes to the global loss of the related devices and limits their application areas at microwaves. In this paper, a twofold approach is investigated to reduce the device loss. The intrinsic loss of KTN is first reduced by doping the ferroelectric material with a low-loss dielectric material, namely, MgO. Second, the doped ferroelectric films are confined using an original laser microetching process. Both routes have been implemented here to provide a synergic effect on the total insertion loss of the microwave test device, namely, a coplanar waveguide stub resonator. The experimental data demonstrate a decrease of the intrinsic loss by a factor of ~2 and a decrease of the global loss by a factor of ~4 with a frequency tunability close to 10% at ~10 GHz under a moderate biasing (80 kV/cm). PMID- 29610097 TI - Modeling the Geometry and Dynamics of the Endoplasmic Reticulum Network. AB - The endoplasmic reticulum (ER) is an intricate network that pervades the entire cortex of plant cells and its geometric shape undergoes drastic changes. This paper proposes a mathematical model to reconstruct geometric network dynamics by combining the node movements within the network and topological changes engendered by these nodes. The network topology in the model is determined by a modified optimization procedure from the work (Lemarchand, et al. 2014) which minimizes the total length taking into account both degree and angle constraints, beyond the conditions of connectedness and planarity. A novel feature for solving our optimization problem is the use of "lifted" angle constraints, which allows one to considerably reduce the solution runtimes. Using this optimization technique and a Langevin approach for the branching node movement, the simulated network dynamics represent the ER network dynamics observed under latrunculin B treated condition and recaptures features such as the appearance/disappearance of loops within the ER under the native condition. The proposed modeling approach allows quantitative comparison of networks between the model and experimental data based on topological changes induced by node dynamics. An increased temporal resolution of experimental data will allow a more detailed comparison of network dynamics using this modeling approach. PMID- 29610098 TI - Examining De Novo Transcriptome Assemblies via a Quality Assessment Pipeline. AB - New de novo transcriptome assembly and annotation methods provide an incredible opportunity to study the transcriptome of organisms that lack an assembled and annotated genome. There are currently a number of de novo transcriptome assembly methods, but it has been difficult to evaluate the quality of these assemblies. In order to assess the quality of the transcriptome assemblies, we composed a workflow of multiple quality check measurements that in combination provide a clear evaluation of the assembly performance. We presented novel transcriptome assemblies and functional annotations for Pacific Whiteleg Shrimp (Litopenaeus vannamei ), a mariculture species with great national and international interest, and no solid transcriptome/genome reference. We examined Pacific Whiteleg transcriptome assemblies via multiple metrics, and provide an improved gene annotation. Our investigations show that assessing the quality of an assembly purely based on the assembler's statistical measurements can be misleading; we propose a hybrid approach that consists of statistical quality checks and further biological-based evaluations. PMID- 29610099 TI - Computational Prediction of Pathogenic Network Modules in Fusarium verticillioides. AB - Fusarium verticillioides is a fungal pathogen that triggers stalk rots and ear rots in maize. In this study, we performed a comparative analysis of wild type and loss-of-virulence mutant F. verticillioides co-expression networks to identify subnetwork modules that are associated with its pathogenicity. We constructed the F. verticillioides co-expression networks from RNA-Seq data and searched through these networks to identify subnetwork modules that are differentially activated between the wild type and mutant F. verticillioides, which considerably differ in terms of pathogenic potentials. A greedy seed-and extend approach was utilized in our search, where we also used an efficient branch-out technique for reliable prediction of functional subnetwork modules in the fungus. Through our analysis, we identified four potential pathogenicity associated subnetwork modules, each of which consists of interacting genes with coordinated expression patterns, but whose activation level is significantly different in the wild type and the mutant. The predicted modules were comprised of functionally coherent genes and topologically cohesive. Furthermore, they contained several orthologs of known pathogenic genes in other fungi, which may play important roles in the fungal pathogenesis. PMID- 29610100 TI - Optimal Fault Detection and Diagnosis in Transcriptional Circuits Using Next Generation Sequencing. AB - We propose a methodology for model-based fault detection and diagnosis for stochastic Boolean dynamical systems indirectly observed through a single time series of transcriptomic measurements using Next Generation Sequencing (NGS) data. The fault detection consists of an innovations filter followed by a fault certification step, and requires no knowledge about the possible system faults. The innovations filter uses the optimal Boolean state estimator, called the Boolean Kalman Filter (BKF). In the presence of knowledge about the possible system faults, we propose an additional step of fault diagnosis based on a multiple model adaptive estimation (MMAE) method consisting of a bank of BKFs running in parallel. Performance is assessed by means of false detection and misdiagnosis rates, as well as average times until correct detection and diagnosis. The efficacy of the proposed methodology is demonstrated via numerical experiments using a p53-MDM2 negative feedback loop Boolean network with stuck-at faults that model molecular events commonly found in cancer. PMID- 29610101 TI - MeTDiff: A Novel Differential RNA Methylation Analysis for MeRIP-Seq Data. AB - N6-Methyladenosine (m6A) transcriptome methylation is an exciting new research area that just captures the attention of research community. We present in this paper, MeTDiff, a novel computational tool for predicting differential m6A methylation sites from Methylated RNA immunoprecipitation sequencing (MeRIP-Seq) data. Compared with the existing algorithm exomePeak, the advantages of MeTDiff are that it explicitly models the reads variation in data and also devices a more power likelihood ratio test for differential methylation site prediction. Comprehensive evaluation of MeTDiff's performance using both simulated and real datasets showed that MeTDiff is much more robust and achieved much higher sensitivity and specificity over exomePeak. The R package "MeTDiff" and additional details are available at: https://github.com/compgenomics/MeTDiff. PMID- 29610102 TI - Bayesian Multiresolution Variable Selection for Ultra-High Dimensional Neuroimaging Data. AB - Ultra-high dimensional variable selection has become increasingly important in analysis of neuroimaging data. For example, in the Autism Brain Imaging Data Exchange (ABIDE) study, neuroscientists are interested in identifying important biomarkers for early detection of the autism spectrum disorder (ASD) using high resolution brain images that include hundreds of thousands voxels. However, most existing methods are not feasible for solving this problem due to their extensive computational costs. In this work, we propose a novel multiresolution variable selection procedure under a Bayesian probit regression framework. It recursively uses posterior samples for coarser-scale variable selection to guide the posterior inference on finer-scale variable selection, leading to very efficient Markov chain Monte Carlo (MCMC) algorithms. The proposed algorithms are computationally feasible for ultra-high dimensional data. Also, our model incorporates two levels of structural information into variable selection using Ising priors: the spatial dependence between voxels and the functional connectivity between anatomical brain regions. Applied to the resting state functional magnetic resonance imaging (R-fMRI) data in the ABIDE study, our methods identify voxel-level imaging biomarkers highly predictive of the ASD, which are biologically meaningful and interpretable. Extensive simulations also show that our methods achieve better performance in variable selection compared to existing methods. PMID- 29610103 TI - Gender Identification of Human Brain Image with A Novel 3D Descriptor. AB - Determining gender by examining the human brain is not a simple task because the spatial structure of the human brain is complex, and no obvious differences can be seen by the naked eyes. In this paper, we propose a novel three-dimensional feature descriptor, the three-dimensional weighted histogram of gradient orientation (3D WHGO) to describe this complex spatial structure. The descriptor combines local information for signal intensity and global three-dimensional spatial information for the whole brain. We also improve a framework to address the classification of three-dimensional images based on MRI. This framework, three-dimensional spatial pyramid, uses additional information regarding the spatial relationship between features. The proposed method can be used to distinguish gender at the individual level. We examine our method by using the gender identification of individual magnetic resonance imaging (MRI) scans of a large sample of healthy adults across four research sites, resulting in up to individual-level accuracies under the optimized parameters for distinguishing between females and males. Compared with previous methods, the proposed method obtains higher accuracy, which suggests that this technology has higher discriminative power. With its improved performance in gender identification, the proposed method may have the potential to inform clinical practice and aid in research on neurological and psychiatric disorders. PMID- 29610104 TI - A Copula-Based Granger Causality Measure for the Analysis of Neural Spike Train Data. AB - In systems neuroscience, it is becoming increasingly common to record the activity of hundreds of neurons simultaneously via electrode arrays. The ability to accurately measure the causal interactions among multiple neurons in the brain is crucial to understanding how neurons work in concert to generate specific brain functions. The development of new statistical methods for assessing causal influence between spike trains is still an active field of neuroscience research. Here, we suggest a copula-based Granger causality measure for the analysis of neural spike train data. This method is built upon our recent work on copula Granger causality for the analysis of continuous-valued time series by extending it to point-process neural spike train data. The proposed method is therefore able to reveal nonlinear and high-order causality in the spike trains while retaining all the computational advantages such as model-free, efficient estimation, and variability assessment of Granger causality. The performance of our algorithm can be further boosted with time-reversed data. Our method performed well on extensive simulations, and was then demonstrated on neural activity simultaneously recorded from primary visual cortex of a monkey performing a contour detection task. PMID- 29610106 TI - Context-Aware Local Binary Feature Learning for Face Recognition. AB - In this paper, we propose a context-aware local binary feature learning (CA-LBFL) method for face recognition. Unlike existing learning-based local face descriptors such as discriminant face descriptor (DFD) and compact binary face descriptor (CBFD) which learn each feature code individually, our CA-LBFL exploits the contextual information of adjacent bits by constraining the number of shifts from different binary bits, so that more robust information can be exploited for face representation. Given a face image, we first extract pixel difference vectors (PDV) in local patches, and learn a discriminative mapping in an unsupervised manner to project each pixel difference vector into a context aware binary vector. Then, we perform clustering on the learned binary codes to construct a codebook, and extract a histogram feature for each face image with the learned codebook as the final representation. In order to exploit local information from different scales, we propose a context-aware local binary multi scale feature learning (CA-LBMFL) method to jointly learn multiple projection matrices for face representation. To make the proposed methods applicable for heterogeneous face recognition, we present a coupled CA-LBFL (C-CA-LBFL) method and a coupled CA-LBMFL (C-CA-LBMFL) method to reduce the modality gap of corresponding heterogeneous faces in the feature level, respectively. Extensive experimental results on four widely used face datasets clearly show that our methods outperform most state-of-the-art face descriptors. PMID- 29610105 TI - Cortical Thinning and Cognitive Impairment in Parkinson's Disease without Dementia. AB - Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized clinically by motor dysfunction (bradykinesia, rigidity, tremor, and postural instability), and pathologically by the loss of dopaminergic neurons in the substantia nigra of the basal ganglia. Growing literature supports that cognitive deficits may also be present in PD, even in non-demented patients. Gray matter (GM) atrophy has been reported in PD and may be related to cognitive decline. This study investigated cortical thickness in non-demented PD subjects and elucidated its relationship to cognitive impairment using high-resolution T1 weighted brain MRI and comprehensive cognitive function scores from 71 non demented PD and 48 control subjects matched for age, gender, and education. Cortical thickness was compared between groups using a flexible hierarchical multivariate Bayesian model, which accounts for correlations between brain regions. Correlation analyses were performed among brain areas and cognitive domains as well, which showed significant group differences in the PD population. Compared to Controls, PD subjects demonstrated significant age-adjusted cortical thinning predominantly in inferior and superior parietal areas and extended to superior frontal, superior temporal, and precuneus areas (posterior probability >0.9). Cortical thinning was also found in the left precentral and lateral occipital, and right postcentral, middle frontal, and fusiform regions (posterior probability >0.9). PD patients showed significantly reduced cognitive performance in executive function, including set shifting (p = 0.005) and spontaneous flexibility (p = 0.02), which were associated with the above cortical thinning regions (p < 0.05). PMID- 29610107 TI - SIFT Meets CNN: A Decade Survey of Instance Retrieval. AB - In the early days, content-based image retrieval (CBIR) was studied with global features. Since 2003, image retrieval based on local descriptors (de facto SIFT) has been extensively studied for over a decade due to the advantage of SIFT in dealing with image transformations. Recently, image representations based on the convolutional neural network (CNN) have attracted increasing interest in the community and demonstrated impressive performance. Given this time of rapid evolution, this article provides a comprehensive survey of instance retrieval over the last decade. Two broad categories, SIFT-based and CNN-based methods, are presented. For the former, according to the codebook size, we organize the literature into using large/medium-sized/small codebooks. For the latter, we discuss three lines of methods, i.e., using pre-trained or fine-tuned CNN models, and hybrid methods. The first two perform a single-pass of an image to the network, while the last category employs a patch-based feature extraction scheme. This survey presents milestones in modern instance retrieval, reviews a broad selection of previous works in different categories, and provides insights on the connection between SIFT and CNN-based methods. After analyzing and comparing retrieval performance of different categories on several datasets, we discuss promising directions towards generic and specialized instance retrieval. PMID- 29610108 TI - Preferences for Web-Based Information Material for Low Back Pain: Qualitative Interview Study on People Consulting a General Practitioner. AB - BACKGROUND: Information on self-management, including addressing people's fears and concerns, are core aspects of managing patients with low back pain (LBP). Web apps with patient information may be used to extend patient-physician consultations and encourage self-management outside of the consultation room. It is, however, important to identify the end users' needs and preferences in order to maximize acceptance. OBJECTIVE: The aim of this study was to identify preferences for the content, design, and functionality of a Web app with evidence based information and advice for people with LBP in Denmark. METHODS: This is a phenomenological qualitative study. Adults who had consulted their general practitioner because of LBP within the past 14 days were included. Each participated in a semistructured interview, which was audiotaped and transcribed for text condensation. Interviews were conducted at the participant's home by 2 interviewers. Participants also completed a questionnaire that requested information on age, gender, internet usage, interest in searching new knowledge, LBP-related function, and pain. RESULTS: Fifteen 45-min interviews were conducted. Participants had a median age of 40 years (range 22-68 years) and reported a median disability of 7 points (range 0-18) using the 23-item Roland Morris Disability Questionnaire. Participants reported that Web-based information should be easy to find and read, easily overviewed, and not be overloaded with information. Subjects found existing Web-based information confusing, often difficult to comprehend, and not relevant for them, and they questioned the motives driving most hosting companies or organizations. The Patient Handbook, a Danish government-funded website that provides information to Danes about health, was mentioned as a trustworthy and preferred site when searching for information and advice regarding LBP. CONCLUSIONS: This study identified important issues to consider when developing and supplementing existing general practice treatment with Web-based information and advice for patients with LBP. Development of a Web app should consider patient input, and developers should carefully address the following domains: readability, customization, design, credibility, and usability. PMID- 29610109 TI - Improvement of Attention-Deficit/Hyperactivity Disorder Symptoms in School-Aged Children, Adolescents, and Young Adults With Autism via a Digital Smartglasses Based Socioemotional Coaching Aid: Short-Term, Uncontrolled Pilot Study. AB - BACKGROUND: People with autism spectrum disorder (ASD) commonly experience symptoms related to attention-deficit/hyperactivity disorder (ADHD), including hyperactivity, inattention, and impulsivity. One-third of ASD cases may be complicated by the presence of ADHD. Individuals with dual diagnoses face greater barriers to accessing treatment for ADHD and respond less positively to primary pharmacologic interventions. Nonpharmacologic technology-aided tools for hyperactivity and inattention in people with ASD are being developed, although research into their efficacy and safety remains limited. OBJECTIVE: The objective of this preliminary study was to describe the changes in ADHD-related symptoms in children, adolescents, and young adults with ASD immediately after use of the Empowered Brain system, a behavioral and social communication aid for ASD running on augmented reality smartglasses. METHODS: We recruited 8 children, adolescents, and young adults with ASD (male to female ratio of 7:1, mean age 15 years, range 11.7-20.5 years) through a Web-based research signup form. The baseline score on the hyperactivity subscale of the Aberrant Behavioral Checklist (ABC-H), a measure of hyperactivity, inattention, and impulsivity, determined their classification into a high ADHD-related symptom group (n=4, ABC-H>=13) and a low ADHD-related symptom group (n=4, ABC-H<13). All participants received an intervention with Empowered Brain, where they used smartglasses-based social communication and behavioral modules while interacting with their caregiver. We then calculated caregiver-reported ABC-H scores at 24 and 48 hours after the session. RESULTS: All 8 participants were able to complete the intervention session. Postintervention ABC-H scores were lower for most participants at 24 hours (n=6, 75%) and for all participants at 48 hours (n=8, 100%). At 24 hours after the session, average participant ABC-H scores decreased by 54.9% in the high ADHD symptom group and by 20% in the low ADHD symptom group. At 48 hours after the session, ABC-H scores compared with baseline decreased by 56.4% in the high ADHD symptom group and by 66.3% in the low ADHD symptom group. CONCLUSIONS: This study provides initial evidence for the possible potential of the Empowered Brain system to reduce ADHD-related symptoms, such as hyperactivity, inattention, and impulsivity, in school-aged children, adolescents, and young adults with ASD. This digital smartglasses intervention can potentially be targeted at a broader array of mental health conditions that exhibit transdiagnostic attentional and social communication deficits, including schizophrenia and bipolar disorder. Further research is required to understand the clinical importance of these observed changes and to conduct longitudinal studies on this intervention with control groups and larger sample sizes. PMID- 29610110 TI - Counting Steps in Activities of Daily Living in People With a Chronic Disease Using Nine Commercially Available Fitness Trackers: Cross-Sectional Validity Study. AB - BACKGROUND: Measuring physical activity with commercially available activity trackers is gaining popularity. People with a chronic disease can especially benefit from knowledge about their physical activity pattern in everyday life since sufficient physical activity can contribute to wellbeing and quality of life. However, no validity data are available for this population during activities of daily living. OBJECTIVE: The aim of this study was to investigate the validity of 9 commercially available activity trackers for measuring step count during activities of daily living in people with a chronic disease receiving physiotherapy. METHODS: The selected activity trackers were Accupedo (Corusen LLC), Activ8 (Remedy Distribution Ltd), Digi-Walker CW-700 (Yamax), Fitbit Flex (Fitbit inc), Lumoback (Lumo Bodytech), Moves (ProtoGeo Oy), Fitbit One (Fitbit inc), UP24 (Jawbone), and Walking Style X (Omron Healthcare Europe BV). In total, 130 persons with chronic diseases performed standardized activity protocols based on activities of daily living that were recorded on video camera and analyzed for step count (gold standard). The validity of the trackers' step count was assessed by correlation coefficients, t tests, scatterplots, and Bland Altman plots. RESULTS: The correlations between the number of steps counted by the activity trackers and the gold standard were low (range: -.02 to .33). For all activity trackers except for Fitbit One, a significant systematic difference with the gold standard was found for step count. Plots showed a wide range in scores for all activity trackers; Activ8 showed an average overestimation and the other 8 trackers showed underestimations. CONCLUSIONS: This study showed that the validity of 9 commercially available activity trackers is low measuring steps while individuals with chronic diseases receiving physiotherapy engage in activities of daily living. PMID- 29610111 TI - Connecting Smartphone and Wearable Fitness Tracker Data with a Nationally Used Electronic Health Record System for Diabetes Education to Facilitate Behavioral Goal Monitoring in Diabetes Care: Protocol for a Pragmatic Multi-Site Randomized Trial. AB - BACKGROUND: Mobile and wearable technology have been shown to be effective in improving diabetes self-management; however, integrating data from these technologies into clinical diabetes care to facilitate behavioral goal monitoring has not been explored. OBJECTIVE: The objective of this paper is to report on a study protocol for a pragmatic multi-site trial along with the intervention components, including the detailed connected health interface. This interface was developed to integrate patient self-monitoring data collected from a wearable fitness tracker and its companion smartphone app to an electronic health record system for diabetes self-management education and support (DSMES) to facilitate behavioral goal monitoring. METHODS: A 3-month multi-site pragmatic clinical trial was conducted with eligible patients with diabetes mellitus from DSMES programs. The Chronicle Diabetes system is currently freely available to diabetes educators through American Diabetes Association-recognized DSMES programs to set patient nutrition and physical activity goals. To integrate the goal-setting and self-monitoring intervention into the DSMES process, a connected interface in the Chronicle Diabetes system was developed. With the connected interface, patient self-monitoring information collected from smartphones and wearable fitness trackers can facilitate educators' monitoring of patients' adherence to their goals. Feasibility outcomes of the 3-month trial included hemoglobin A1c levels, weight, and the usability of the connected system. RESULTS: An interface designed to connect data from a wearable fitness tracker with a companion smartphone app for nutrition and physical activity self-monitoring into a diabetes education electronic health record system was successfully developed to enable diabetes educators to facilitate goal setting and monitoring. A total of 60 eligible patients with type 2 diabetes mellitus were randomized into either group 1) standard diabetes education or 2) standard education enhanced with the connected system. Data collection for the 3-month pragmatic trial is completed. Data analysis is in progress. CONCLUSIONS: If results of the pragmatic multi-site clinical trial show preliminary efficacy and usability of the connected system, a large-scale implementation trial will be conducted. TRIAL REGISTRATION: ClinicalTrials.gov NCT02664233; https://clinicaltrials.gov/ct2/show/NCT02664233 (Archived by WebCite at http://www.webcitation.org/6yDEwXHo5). PMID- 29610112 TI - Contents, Followers, and Retweets of the Centers for Disease Control and Prevention's Office of Advanced Molecular Detection (@CDC_AMD) Twitter Profile: Cross-Sectional Study. AB - BACKGROUND: The Office of Advanced Molecular Detection (OAMD), Centers for Disease Control and Prevention (CDC), manages a Twitter profile (@CDC_AMD). To our knowledge, no prior study has analyzed a CDC Twitter handle's entire contents and all followers. OBJECTIVE: This study aimed to describe the contents and followers of the Twitter profile @CDC_AMD and to assess if attaching photos or videos to tweets posted by @CDC_AMD would increase retweet frequency. METHODS: Data of @CDC_AMD were retrieved on November 21, 2016. All followers (N=809) were manually categorized. All tweets (N=768) were manually coded for contents and whether photos or videos were attached. Retweet count for each tweet was recorded. Negative binomial regression models were applied to both the original and the retweet corpora. RESULTS: Among the 809 followers, 26.0% (210/809) were individual health professionals, 11.6% (94/809) nongovernmental organizations, 3.3% (27/809) government agencies' accounts, 3.3% (27/809) accounts of media organizations and journalists, and 0.9% (7/809) academic journals, with 54.9% (444/809) categorized as miscellaneous. A total of 46.9% (360/768) of @CDC_AMD's tweets referred to the Office's website and their current research; 17.6% (135/768) referred to their scientists' publications. Moreover, 80% (69/86) of tweets retweeted by @CDC_AMD fell into the miscellaneous category. In addition, 43.4% (333/768) of the tweets contained photos or videos, whereas the remaining 56.6% (435/768) did not. Attaching photos or videos to original @CDC_AMD tweets increases the number of retweets by 37% (probability ratio=1.37, 95% CI 1.13 1.67, P=.002). Content topics did not explain or modify this association. CONCLUSIONS: This study confirms CDC health communicators' experience that original tweets created by @CDC_AMD Twitter profile sharing images or videos (or their links) received more retweets. The current policy of attaching images to tweets should be encouraged. PMID- 29610114 TI - Two cases of unidentified acute compartment syndrome. AB - Acute compartment syndrome (ACS) is a surgical emergency that requires urgent fasciotomy to prevent irreversible sequelae. We report two cases of unidentified ACS, which did not result from traumatic injuries such as fractures or crush injury, iatrogenic injury or diseases such as haematological malignancies. Both patients complained of severe pain and swelling of their extremity. No bite marks, blisters or skin necrosis was noted. They also complained of marked symptoms of third cranial nerve injury, including divergent squint and diplopia. The diagnosis of ACS was made following continuous intracompartmental pressure measurement, and both patients underwent urgent fasciotomy with partial incision. Considering the season and location of the injuries, together with the rapid progression of signs and symptoms that included thrombocytopaenia, acute renal failure, rhabdomyolysis and especially that of third cranial nerve injury, we postulate that these two cases may have developed following mamushi (Gloydiusblomhoffii) bites. PMID- 29610113 TI - The Association Between Technology Use and Health Status in a Chronic Obstructive Pulmonary Disease Cohort: Multi-Method Study. AB - BACKGROUND: Telemedicine and electronic health (eHealth) interventions have been proposed to improve management of chronic obstructive pulmonary disease (COPD) for patients between traditional clinic and hospital visits to reduce complications. However, the effectiveness of such interventions may depend on patients' comfort with technology. OBJECTIVE: The aim was to describe the relationship between patient demographics and COPD disease severity and the use of communication-related technology. METHODS: We administered a structured survey about the use of communication technologies to a cohort of persons in the COPDGene study at one midwestern hospital in the United States. Survey results were combined with clinical and demographic data previously collected as part of the cohort study. A subsample of patients also completed eHealth simulation tasks. We used logistic or linear regression to determine the relationship between patient demographics and COPD disease severity and reported use of communication-related technology and the results from our simulated eHealth related tasks. RESULTS: A total of 686 patients completed the survey and 100 participated in the eHealth simulation. Overall, those who reported using communication technology were younger (P=.005) and had higher incomes (P=.03). Men appeared less likely to engage in text messaging (P<.001) than women. Patients who spent more time on tasks in the eHealth simulation had greater odds of a COPD Assessment Test score >10 (P=.02) and walked shorter distances in their 6-minute walk tests (P=.003) than those who took less time. CONCLUSIONS: Older patients, patients with lower incomes, and less healthy patients were less likely to report using communication technology, and they did not perform as well on our simulated eHealth tasks. Thus, eHealth-based interventions may not be as effective in these populations, and additional training in communication technology may be needed. PMID- 29610115 TI - A phase 1 study of lenalidomide and ibrutinib in combination with rituximab in relapsed and refractory CLL. AB - Attempts to improve upon the activity of ibrutinib in chronic lymphocytic leukemia (CLL) include the addition of targeted therapies. The combination of lenalidomide and rituximab demonstrated an overall response rate (ORR) of 66% with a complete response (CR) of 12% in the relapsed/refractory setting. Based on these data, we conducted a phase 1 study of rituximab (R), lenalidomide (L), and ibrutinib (I) in relapsed/refractory CLL. Patients received R 375 mg/m2 cycles 1 to 6 day 1, L on cycles 1 to 12 days 1 to 21, and I until disease progression. Dose escalation used a standard 3+3 design from a dose level (DL) of L 5 mg (DL1) and increasing to 15 mg (DL3) for a total of 3 dose levels. Twelve patients were enrolled; there were 2 dose-limiting toxicities of grade 4 neutropenia at DL3; thus, DL2 was the recommended phase 2 dose. A high incidence of sustained grade 4 neutropenia occurred at all dose levels, prompting study withdrawal in 5 patients, despite growth factor support. The ORR was 67%; ORR at the RP2D was 100% (1 CR). The 12-month progression-free survival at the RP2D was 83%. Preliminary efficacy data with the triplet did not appear superior to prior reports of the rituximab-lenalidomide doublet or single-agent ibrutinib. Given these findings and the sustained neutropenia, this regimen was not pursued. The study was registered at www.clinicaltrials.gov as #NCT02200848. PMID- 29610116 TI - Network Modeling of microRNA-mRNA Interactions in Neuroblastoma Tumorigenesis Identifies miR-204 as a Direct Inhibitor of MYCN. AB - Neuroblastoma is a pediatric cancer of the sympathetic nervous system where MYCN amplification is a key indicator of poor prognosis. However, mechanisms by which MYCN promotes neuroblastoma tumorigenesis are not fully understood. In this study, we analyzed global miRNA and mRNA expression profiles of tissues at different stages of tumorigenesis from TH-MYCN transgenic mice, a model of MYCN driven neuroblastoma. On the basis of a Bayesian learning network model in which we compared pretumor ganglia from TH-MYCN+/+ mice to age-matched wild-type controls, we devised a predicted miRNA-mRNA interaction network. Among the miRNA mRNA interactions operating during human neuroblastoma tumorigenesis, we identified miR-204 as a tumor suppressor miRNA that inhibited a subnetwork of oncogenes strongly associated with MYCN-amplified neuroblastoma and poor patient outcome. MYCN bound to the miR-204 promoter and repressed miR-204 transcription. Conversely, miR-204 directly bound MYCN mRNA and repressed MYCN expression. miR 204 overexpression significantly inhibited neuroblastoma cell proliferation in vitro and tumorigenesis in vivo Together, these findings identify novel tumorigenic miRNA gene networks and miR-204 as a tumor suppressor that regulates MYCN expression in neuroblastoma tumorigenesis.Significance: Network modeling of miRNA-mRNA regulatory interactions in a mouse model of neuroblastoma identifies miR-204 as a tumor suppressor and negative regulator of MYCN. Cancer Res; 78(12); 3122-34. (c)2018 AACR. PMID- 29610117 TI - CD163 Is Required for Protumoral Activation of Macrophages in Human and Murine Sarcoma. AB - Recent findings have shown the significance of CD163-positive macrophages in tumor progression, yet there have been few studies on the function of CD163 in macrophages. Here, we uncover the role of CD163 in macrophage activation using CD163-deficient mice and human samples. We detected CD163 in 62 undifferentiated pleomorphic sarcoma samples, in which a high percentage of CD163-positive macrophages was associated with decreased overall survival and higher histologic grade. We observed macrophage-induced tumor cell proliferation in cocultures of human monocyte-derived macrophages and leiomyosarcoma (TYLMS-1) and myxofibrosarcoma (NMFH-1) cell lines, which was abrogated by silencing of CD163. Tumor development of sarcoma (MCA205 and LM8) cells in CD163-deficient mice was significantly abrogated in comparison with wild-type (WT) mice. Coculture with WT peritoneal macrophages significantly increased proliferation of MCA205 cells but decreased in the presence of CD163-deficient macrophages. Production of IL6 and CXCL2 in CD163-deficient macrophages was suppressed in comparison with WT macrophages, and overexpression of CD163 in CD163-deficient macrophages induced production of IL6 and CXCL2. Silencing of IL6 but not CXCL2 abrogated macrophage induced proliferation of MCA205 cells. Taken together, our results show that CD163 is involved in protumoral activation of macrophages and subsequent development and progression of tumors in mice and humans.Significance: Macrophage CD163-mediated induction of IL6 promotes tumor development and progression in murine and human malignant tumors. Cancer Res; 78(12); 3255-66. (c)2018 AACR. PMID- 29610118 TI - Behcet's Disease: Pulmonary Aneurysm Resolution with Oral Therapy and HLA B72 Allele Association. AB - We report the case of a woman who was diagnosed with a pulmonary artery aneurysm that was caused by Behcet's disease. The patient was initially diagnosed with community-acquired pneumonia and then pulmonary thromboembolism and aneurysm of the right pulmonary artery segmental branch was confirmed. The initial treatment consisted of anticoagulant drugs. After analysis of the family history and a positive pathergy test, the patient was diagnosed with Behcet's disease. Oral pharmacological treatment began with corticosteroids, cyclophosphamide, and anticoagulant suspension. The HLA B72 allele was identified in the patient and her two sisters, demonstrating the familial characteristic of the disease and the presence of this allele in a female patient with Behcet's disease. After 12 months of treatment, the clinical condition completely resolved. PMID- 29610119 TI - Biologic Agent-Associated Cutaneous Adverse Events: A Single Center Experience. AB - Biologic agents are regarded as an effective treatment for a variety of autoimmune diseases. These drugs have an acceptable safety and tolerability profile, although an increasing number of autoimmune conditions have been reported with their use. Additionally, a variety of cutaneous diseases have been associated with their use. Here we report our experience of adverse cutaneous events with the use of biologic agents. An alternative explanation for patients presenting with adverse cutaneous events including drug interactions must be carefully investigated. PMID- 29610121 TI - Response to ERBB3-Directed Targeted Therapy in NRG1-Rearranged Cancers. AB - NRG1 rearrangements are oncogenic drivers that are enriched in invasive mucinous adenocarcinomas (IMA) of the lung. The oncoprotein binds ERBB3-ERBB2 heterodimers and activates downstream signaling, supporting a therapeutic paradigm of ERBB3/ERBB2 inhibition. As proof of concept, a durable response was achieved with anti-ERBB3 mAb therapy (GSK2849330) in an exceptional responder with an NRG1 rearranged IMA on a phase I trial (NCT01966445). In contrast, response was not achieved with anti-ERBB2 therapy (afatinib) in four patients with NRG1-rearranged IMA (including the index patient post-GSK2849330). Although in vitro data supported the use of either ERBB3 or ERBB2 inhibition, these clinical results were consistent with more profound antitumor activity and downstream signaling inhibition with anti-ERBB3 versus anti-ERBB2 therapy in an NRG1-rearranged patient-derived xenograft model. Analysis of 8,984 and 17,485 tumors in The Cancer Genome Atlas and MSK-IMPACT datasets, respectively, identified NRG1 rearrangements with novel fusion partners in multiple histologies, including breast, head and neck, renal, lung, ovarian, pancreatic, prostate, and uterine cancers.Significance: This series highlights the utility of ERBB3 inhibition as a novel treatment paradigm for NRG1-rearranged cancers. In addition, it provides preliminary evidence that ERBB3 inhibition may be more optimal than ERBB2 inhibition. The identification of NRG1 rearrangements across various solid tumors supports a basket trial approach to drug development. Cancer Discov; 8(6); 686 95. (c)2018 AACR.See related commentary by Wilson and Politi, p. 676This article is highlighted in the In This Issue feature, p. 663. PMID- 29610122 TI - In search of a physiological function of lipoprotein(a): causality of elevated Lp(a) levels and reduced incidence of type 2 diabetes. PMID- 29610124 TI - Is There Really a Benefit to Net Clinical Benefit in Testing Antithrombotics? PMID- 29610123 TI - Probing de novo sphingolipid metabolism in mammalian cells utilizing mass spectrometry. AB - Sphingolipids constitute a dynamic metabolic network that interconnects several bioactive molecules, including ceramide (Cer), sphingosine (Sph), Sph 1 phosphate, and Cer 1-phosphate. The interconversion of these metabolites is controlled by a cohort of at least 40 enzymes, many of which respond to endogenous or exogenous stimuli. Typical probing of the sphingolipid pathway relies on sphingolipid mass levels or determination of the activity of individual enzymes. Either approach is unable to provide a complete analysis of flux through sphingolipid metabolism, which, given the interconnectivity of the sphingolipid pathway, is critical information to identify nodes of regulation. Here, we present a one-step in situ assay that comprehensively probes the flux through de novo sphingolipid synthesis, post serine palmitoyltransferase, by monitoring the incorporation and metabolism of the 17 carbon dihydrosphingosine precursor with LC/MS. Pulse labeling and analysis of precursor metabolism identified sequential well-defined phases of sphingolipid synthesis, corresponding to the activity of different enzymes in the pathway, further confirmed by the use of specific inhibitors and modulators of sphingolipid metabolism. This work establishes precursor pulse labeling as a practical tool for comprehensively studying metabolic flux through de novo sphingolipid synthesis and complex sphingolipid generation. PMID- 29610120 TI - Translation Elongation and Recoding in Eukaryotes. AB - In this review, we highlight the current understanding of translation elongation and recoding in eukaryotes. In addition to providing an overview of the process, recent advances in our understanding of the role of the factor eIF5A in both translation elongation and termination are discussed. We also highlight mechanisms of translation recoding with a focus on ribosomal frameshifting during elongation. We see that the balance between the basic steps in elongation and the less common recoding events is determined by the kinetics of the different processes as well as by specific sequence determinants. PMID- 29610125 TI - Reduced Mortality With Sodium-Glucose Cotransporter-2 Inhibitors in Observational Studies: Avoiding Immortal Time Bias. PMID- 29610126 TI - Statins in Peripheral Artery Disease: What Are We Waiting For? PMID- 29610127 TI - Sodium Glucose Cotransporter 2 Inhibitors and Amputation Risk: Achilles' Heel or Opportunity for Discovery? PMID- 29610128 TI - Renin-Angiotensin-Aldosterone System Inhibitors for Right Ventricular Dysfunction in Tetralogy of Fallot: Quo Vadis? PMID- 29610129 TI - Ultrasound for Lower Extremity Deep Venous Thrombosis: Multidisciplinary Recommendations From the Society of Radiologists in Ultrasound Consensus Conference. AB - Venous ultrasound is the standard imaging test for patients suspected of having acute deep venous thrombosis (DVT). There is variability and disagreement among authoritative groups regarding the necessary components of the test. Some protocols include scanning the entire lower extremity, whereas others recommend scans limited to the thigh and knee supplemented with serial testing. Some protocols use gray-scale ultrasound alone, whereas others include Doppler interrogation. Point-of-care ultrasound is recommended in some settings, and there is heterogeneity of these protocols as well. Heterogeneity of recommendations can lead to errors including incorrect application of guidelines, confusion among requesting physicians, and incorrect follow-up. In October 2016, the Society of Radiologists in Ultrasound convened a multidisciplinary panel of experts to evaluate the current evidence to develop recommendations regarding ultrasound protocols for DVT and the terminology used to communicate results to clinicians. Recommendations were made after open discussion and by unanimous consensus.The panel recommends a comprehensive duplex ultrasound protocol from thigh to ankle with Doppler at selected sites rather than a limited or complete compression-only examination. This protocol is currently performed in many facilities and is achievable with standard ultrasound equipment and personnel. The use of these recommendations will increase the diagnosis of calf DVT and provide better data to explain the presenting symptoms. The panel recommends a single point-of-care protocol that minimizes underdiagnoses of proximal DVT.The panel recommends the term chronic postthrombotic change to describe the residual material that persists after the acute presentation of DVT to avoid potential overtreatment of prior thrombus.Adoption of a single standardized comprehensive duplex ultrasound and a single point-of-care examination will enhance patient safety and clinicians' confidence. PMID- 29610130 TI - Pollution Exposure Counteracts Exercise Benefits: Exercise in Green Spaces, Pollution Reductions Recommended. PMID- 29610131 TI - Highlights From the Circulation Family of Journals. PMID- 29610132 TI - Letter by Spartalis et al Regarding Article, "Modifiable Risk Factors and Atrial Fibrillation". PMID- 29610133 TI - Letter by Zei Regarding Article, "Modifiable Risk Factors and Atrial Fibrillation". PMID- 29610134 TI - Letter by Borghi and Cicero Regarding Article, "Modifiable Risk Factors and Atrial Fibrillation". PMID- 29610135 TI - Response by Lau et al to Letters Regarding Article, "Modifiable Risk Factors and Atrial Fibrillation". PMID- 29610136 TI - Letter by Graudal and Mente Regarding Article, "Use of a Single Baseline Versus Multiyear 24-Hour Urine Collection for Estimation of Long-Term Sodium Intake and Associated Cardiovascular and Renal Risk". PMID- 29610137 TI - Response by Olde Engberink et al to Letter Regarding Article, "Use of a Single Baseline Versus Multiyear 24-Hour Urine Collection for Estimation of Long-Term Sodium Intake and Associated Cardiovascular and Renal Risk". PMID- 29610138 TI - Letter by Jin-shan and Xue-bin Regarding Article, "Worsening Conduction Delay in Hypertrophic Cardiomyopathy: What Drug Is Responsible?" PMID- 29610139 TI - Response by Garcia-Granja et al to Letter Regarding Article, "Worsening Conduction Delay in Hypertrophic Cardiomyopathy: What Drug Is Responsible?" PMID- 29610141 TI - Altered Ratio of T Follicular Helper Cells to T Follicular Regulatory Cells Correlates with Autoreactive Antibody Response in Simian Immunodeficiency Virus Infected Rhesus Macaques. AB - Individuals with chronic HIV-1 infection have an increased prevalence of autoreactive Abs. Many of the isolated HIV broadly neutralizing Abs from these individuals are also autoreactive. However, the underlying mechanism(s) that produce these autoreactive broadly neutralizing Abs remains largely unknown. The highly regulated coordination among B cells, T follicular helper (TFH) cells, and T follicular regulatory (TFR) cells in germinal centers (GCs) of peripheral lymphatic tissues (LTs) is essential for defense against pathogens while also restricting autoreactive responses. We hypothesized that an altered ratio of TFH/TFR cells in the GC contributes to the increased prevalence of autoreactive Abs in chronic HIV infection. We tested this hypothesis using a rhesus macaque (RM) SIV model. We measured the frequency of TFH cells, TFR cells, and GC B cells in LTs and anti-dsDNA and anti-phospholipid Abs from Indian RMs, with and without SIV infection. We found that the frequency of anti-dsDNA and anti-phospholipid Abs was much higher in chronically infected RMs (83.3% [5/6] and 66.7% [4/6]) than in acutely infected RMs (33.3% [2/6] and 18.6% [1/6]) and uninfected RMs (0% [0/6] and 18.6% [1/6]). The increased ratio of TFH/TFR cells in SIV infection correlated with anti-dsDNA and anti-phospholipid autoreactive Ab levels, whereas the frequency of TFR cells alone did not correlate with the levels of autoreactive Abs. Our results provide direct evidence that the ratio of TFH/TFR cells in LTs is critical for regulating autoreactive Ab production in chronic SIV infection and possibly, by extension, in chronic HIV-1 infection. PMID- 29610140 TI - Mycobacterium tuberculosis Transfer RNA Induces IL-12p70 via Synergistic Activation of Pattern Recognition Receptors within a Cell Network. AB - Upon recognition of a microbial pathogen, the innate and adaptive immune systems are linked to generate a cell-mediated immune response against the foreign invader. The culture filtrate of Mycobacterium tuberculosis contains ligands, such as M. tuberculosis tRNA, that activate the innate immune response and secreted Ags recognized by T cells to drive adaptive immune responses. In this study, bioinformatics analysis of gene-expression profiles derived from human PBMCs treated with distinct microbial ligands identified a mycobacterial tRNA induced innate immune network resulting in the robust production of IL-12p70, a cytokine required to instruct an adaptive Th1 response for host defense against intracellular bacteria. As validated by functional studies, this pathway contained a feed-forward loop, whereby the early production of IL-18, type I IFNs, and IL-12p70 primed NK cells to respond to IL-18 and produce IFN-gamma, enhancing further production of IL-12p70. Mechanistically, tRNA activates TLR3 and TLR8, and this synergistic induction of IL-12p70 was recapitulated by the addition of a specific TLR8 agonist with a TLR3 ligand to PBMCs. These data indicate that M. tuberculosis tRNA activates a gene network involving the integration of multiple innate signals, including types I and II IFNs, as well as distinct cell types to induce IL-12p70. PMID- 29610142 TI - Inflammasome-Independent Leukotriene B4 Production Drives Crystalline Silica Induced Sterile Inflammation. AB - Silicosis is a lung inflammatory disease caused by chronic exposure to crystalline silica (CS). Leukotriene B4 (LTB4) plays an important role in neutrophilic inflammation, which drives silicosis and promotes lung cancer. In this study, we examined the mechanisms involved in CS-induced inflammatory pathways. Phagocytosis of CS particles is essential for the production of LTB4 and IL-1beta in mouse macrophages, mast cells, and neutrophils. Phagosomes enclosing CS particles trigger the assembly of lipidosome in the cytoplasm, which is likely the primary source of CS-induced LTB4 production. Activation of the JNK pathway is essential for both CS-induced LTB4 and IL-1beta production. Studies with bafilomycin-A1- and NLRP3-deficient mice revealed that LTB4 synthesis in the lipidosome is independent of inflammasome activation. Small interfering RNA knockdown and confocal microscopy studies showed that GTPases Rab5c, Rab40c along with JNK1 are essential for lipidosome formation and LTB4 production. BI-78D3, a JNK inhibitor, abrogated CS-induced neutrophilic inflammation in vivo in an air pouch model. These results highlight an inflammasome-independent and JNK activation-dependent lipidosome pathway as a regulator of LTB4 synthesis and CS induced sterile inflammation. PMID- 29610145 TI - Autologous Hematopoietic Stem Cell Transplantation in the Treatment of Multiple Sclerosis. AB - Multiple sclerosis (MS) is an autoimmune disorder that typically affects young people during their most productive years, causing irreversible damage and accumulation of disability. Treatments over time have had modest effects at completely controlling or suppressing disease activity, but are generally aimed at controlling early dominating inflammation that, over time, accumulates damage and leads to progressive disability. Some unfortunate patients are destined to deteriorate despite even newer and more effective agents because of the inability of these drugs to fully curb the inflammatory component of the disease. These patients require something more that might be capable of halting the disease process. Using high-intensity myeloablative chemotherapeutic agents, it is now possible to completely remove the peripheral immune system and replace it anew from autologous bone marrow-derived hematopoietic stem cells, purged of disease causing MS cells. This procedure, referred to as hematopoietic stem cell transplantation (HSCT), produces a new immune system that appears tolerant and no longer attacks the central nervous system (CNS). PMID- 29610146 TI - Evolutionary Origins of Enteric Hepatitis Viruses. AB - The enterically transmitted hepatitis A (HAV) and hepatitis E viruses (HEV) are the leading causes of acute viral hepatitis in humans. Despite the discovery of HAV and HEV 40-50 years ago, their evolutionary origins remain unclear. Recent discoveries of numerous nonprimate hepatoviruses and hepeviruses allow revisiting the evolutionary history of these viruses. In this review, we provide detailed phylogenomic analyses of primate and nonprimate hepatoviruses and hepeviruses. We identify conserved and divergent genomic properties and corroborate historical interspecies transmissions by phylogenetic comparisons and recombination analyses. We discuss the likely non-recent origins of human HAV and HEV precursors carried by mammals other than primates, and detail current zoonotic HEV infections. The novel nonprimate hepatoviruses and hepeviruses offer exciting new possibilities for future research focusing on host range and the unique biological properties of HAV and HEV. PMID- 29610143 TI - Characterization of the Antigenic Heterogeneity of Lipoarabinomannan, the Major Surface Glycolipid of Mycobacterium tuberculosis, and Complexity of Antibody Specificities toward This Antigen. AB - Lipoarabinomannan (LAM), the major antigenic glycolipid of Mycobacterium tuberculosis, is an important immunodiagnostic target for detecting tuberculosis (TB) infection in HIV-1-coinfected patients, and is believed to mediate a number of functions that promote infection and disease development. To probe the human humoral response against LAM during TB infection, several novel LAM-specific human mAbs were molecularly cloned from memory B cells isolated from infected patients and grown in vitro. The fine epitope specificities of these Abs, along with those of a panel of previously described murine and phage-derived LAM specific mAbs, were mapped using binding assays against LAM Ags from several mycobacterial species and a panel of synthetic glycans and glycoconjugates that represented diverse carbohydrate structures present in LAM. Multiple reactivity patterns were seen that differed in their specificity for LAM from different species, as well as in their dependence on arabinofuranoside branching and nature of capping at the nonreducing termini. Competition studies with mAbs and soluble glycans further defined these epitope specificities and guided the design of highly sensitive immunodetection assays capable of detecting LAM in urine of TB patients, even in the absence of HIV-1 coinfection. These results highlighted the complexity of the antigenic structure of LAM and the diversity of the natural Ab response against this target. The information and novel reagents described in this study will allow further optimization of diagnostic assays for LAM and may facilitate the development of potential immunotherapeutic approaches to inhibit the functional activities of specific structural motifs in LAM. PMID- 29610147 TI - Hepatitis A Virus Genome Organization and Replication Strategy. AB - Hepatitis A virus (HAV) is a positive-strand RNA virus classified in the genus Hepatovirus of the family Picornaviridae It is an ancient virus with a long evolutionary history and multiple features of its capsid structure, genome organization, and replication cycle that distinguish it from other mammalian picornaviruses. HAV proteins are produced by cap-independent translation of a single, long open reading frame under direction of an inefficient, upstream internal ribosome entry site (IRES). Genome replication occurs slowly and is noncytopathic, with transcription likely primed by a uridylated protein primer as in other picornaviruses. Newly produced quasi-enveloped virions (eHAV) are released from cells in a nonlytic fashion in a unique process mediated by interactions of capsid proteins with components of the host cell endosomal sorting complexes required for transport (ESCRT) system. PMID- 29610148 TI - The Interdependent Activation of Son-of-Sevenless and Ras. AB - The guanine-nucleotide exchange factor (GEF) Son-of-Sevenless (SOS) plays a critical role in metazoan signaling by converting Ras*GDP (guanosine diphosphate) to Ras*GTP (guanosine triphosphate) in response to tyrosine kinase activation. Structural studies have shown that SOS differs from other Ras-specific GEFs in that SOS is itself activated by Ras*GTP binding to an allosteric site, distal to the site of nucleotide exchange. The activation of SOS involves membrane recruitment and conformational changes, triggered by lipid binding, that open the allosteric binding site for Ras*GTP. This is in contrast to other Ras-specific GEFs, which are activated by second messengers that more directly affect the active site. Allosteric Ras*GTP binding stabilizes SOS at the membrane, where it can turn over other Ras molecules processively, leading to an ultrasensitive response that is distinct from that of other Ras-specific GEFs. PMID- 29610149 TI - Mechanism of Bone Mineralization. AB - Mineralized "hard" tissues of the skeleton possess unique biomechanical properties to support the body weight and movement and act as a source of essential minerals required for critical body functions. For a long time, extracellular matrix (ECM) mineralization in the vertebrate skeleton was considered as a passive process. However, the explosion of genetic studies during the past decades has established that this process is essentially controlled by multiple genetic pathways. These pathways regulate the homeostasis of ionic calcium and inorganic phosphate-two mineral components required for bone mineral formation, the synthesis of mineral scaffolding ECM, and the maintainence of the levels of the inhibitory organic and inorganic molecules controlling the process of mineral crystal formation and its growth. More recently, intracellular enzyme regulators of skeletal tissue mineralization have been identified. The current review will discuss the key determinants of ECM mineralization in bone and propose a unified model explaining this process. PMID- 29610150 TI - Osteoimmunology. AB - Bone is a crucial element of the skeletal-locomotor system, but also functions as an immunological organ that harbors hematopoietic stem cells (HSCs) and immune progenitor cells. Additionally, the skeletal and immune systems share a number of regulatory molecules, including cytokines and signaling molecules. Osteoimmunology was created as an interdisciplinary field to explore the shared molecules and interactions between the skeletal and immune systems. In particular, the importance of an inseparable link between the two systems has been highlighted by studies on the pathogenesis of rheumatoid arthritis (RA), in which pathogenic helper T cells induce the progressive destruction of multiple joints through aberrant expression of receptor activator of nuclear factor (NF) kappaB ligand (RANKL). The conceptual bridge of osteoimmunology provides not only a novel framework for understanding these biological systems but also a molecular basis for the development of therapeutic approaches for diseases of bone and/or the immune system. PMID- 29610152 TI - NTH1 Is a New Target for Ubiquitylation-Dependent Regulation by TRIM26 Required for the Cellular Response to Oxidative Stress. AB - Endonuclease III-like protein 1 (NTH1) is a DNA glycosylase required for the repair of oxidized bases, such as thymine glycol, within the base excision repair pathway. We examined regulation of NTH1 protein by the ubiquitin proteasome pathway and identified the E3 ubiquitin ligase tripartite motif 26 (TRIM26) as the major enzyme targeting NTH1 for polyubiquitylation. We demonstrate that TRIM26 catalyzes ubiquitylation of NTH1 predominantly on lysine 67 present within the N terminus of the protein in vitro In addition, the stability of a ubiquitylation-deficient protein mutant of NTH1 (lysine to arginine) at this specific residue was significantly increased in comparison to the wild-type protein when transiently expressed in cultured cells. We also demonstrate that cellular NTH1 protein is induced in response to oxidative stress following hydrogen peroxide treatment of cells and that accumulation of NTH1 on chromatin is exacerbated in the absence of TRIM26 through small interfering RNA (siRNA) depletion. Stabilization of NTH1 following TRIM26 siRNA also causes significant acceleration in the kinetics of DNA damage repair and cellular resistance to oxidative stress, which can be recapitulated by moderate overexpression of NTH1. This demonstrates the importance of TRIM26 in regulating the cellular levels of NTH1, particularly under conditions of oxidative stress. PMID- 29610151 TI - Multilevel Differential Control of Hormone Gene Expression Programs by hnRNP L and LL in Pituitary Cells. AB - The pituitary-derived somatolactotrophe GH3 cells secrete both growth hormone (GH) and prolactin (PRL). We have found that the hnRNP L and L-like (LL) paralogs differentially regulate alternative splicing of genes in these cells. Here, we show that hnRNP L is essential for PRL only, but LL is essential for both PRL and GH production. Transcriptome-wide RNA sequencing (RNA-Seq) analysis indicates that they differentially control groups of hormone or hormone-related genes involved in hormone production/regulation at total transcript and alternative exon levels. Interestingly, hnRNP L also specifically binds and prevents the aberrant usage of a nonconserved CA-rich intron piece of Prl pre-mRNA transcripts, and many others involved in endocrine functions, to prevent mostly cryptic last exons and mRNA truncation. Essential for the full hnRNP L effect on specific exons is a proline-rich region that emerged during evolution in vertebrate hnRNP L only but not LL. Together, our data demonstrate that the hnRNP L and its paralog, LL, differentially control hormone gene expression programs at multiple levels, and hnRNP L in particular is critical for protecting the transcriptome from aberrant usage of intronic sequences. The multilevel differential control by hnRNPs likely tailors the transcriptome to help refine and safeguard the different gene expression programs for different hormones. PMID- 29610155 TI - The Case for the Case Report. PMID- 29610156 TI - Successful Liver Transplants for Liver Failure Associated With Pyruvate Kinase Deficiency. AB - Pyruvate kinase deficiency (PKD) is the most common cause of congenital nonspherocytic chronic hemolytic anemia, and patients normally present with mild to severe anemia, unconjugated hyperbilirubinemia, and splenomegaly. Only a few reports of PKD have documented its association with severe, progressive liver failure. In all those cases, the patients died before liver transplant (LT) or immediately after transplant. We report 2 case patients with liver failure associated with PKD who successfully underwent LT and splenectomy: an infant who presented with neonatal cholestasis and a young adult with a severe form of PKD and having been transfusion dependent during childhood. After transplant, both patients have normal liver function test results and have considerably decreased their need for blood transfusion despite ongoing, mild hemolysis. We suggest that PKD can lead to severe liver dysfunction and that LT and splenectomy can be life saving procedures in such cases. PMID- 29610157 TI - Clinical Benefit of NMDA Receptor Antagonists in a Patient With ATP1A2 Gene Mutation. AB - Mutations in the ATP1A2 gene cause familial hemiplegic migraine type 2, alternating hemiplegia of childhood, and cerebellar function deficits, epilepsy, and mental retardation. These symptoms are likely related to glutamatergic hyperexcitability. Our patient is a 12-year-old boy with a history of complex partial seizures, attention-deficit/hyperactivity disorder, and fine motor difficulty. During early childhood, he had episodes of a self-resolving right sided hemiparesis and focal epilepsy. His seizures did not respond to several antiepileptic medications but stopped after he received valproate. His intermittent episodes of hemiplegia persisted. Additionally, he had pronounced bilateral fine motor impairment and significant executive deficits that gradually worsened. The whole exome sequencing revealed a de novo missense mutation in the ATP1A2 gene and a maternally inherited POLG gene mutation of unknown clinical significance. We hypothesized that glutamatergic excitotoxicity due to the ATP1A2 mutation contributed to the pathogenesis of our patient's condition. He was started on N-methyl-D-aspartate receptor antagonists (memantine and dextromethorphan), as well as coenzyme Q10 One year later, he showed significant improvement in sustained attention, learning efficiency, general cognitive efficiency, and fine motor dexterity. We postulate that N-methyl-D-aspartate receptor antagonists were effective for behavioral, cognitive, and cerebellar symptoms in our patient with ATP1A2 gene mutation. PMID- 29610158 TI - Lung Volume Reduction Surgery for Respiratory Failure in Infants With Bronchopulmonary Dysplasia. AB - Lung volume reduction surgery (LVRS) can be performed in patients with severe emphysematous disease. However, LVRS in pediatric patients has not yet been reported. Here, we report our experience with 2 cases of pediatric LVRS. The first patient was a preterm infant girl with severe bronchopulmonary dysplasia, pulmonary hypertension, and hypothyroidism. The emphysematous portion of the right lung was removed via sternotomy and right hemiclamshell incision. The patient was discharged on full-time home ventilator support for 3 months after the surgery. Since then, her respiratory function has improved continuously. She no longer needs oxygen supplementation or ventilator care. Her T-cannula was removed recently. The second patient was also a preterm infant girl with bronchopulmonary dysplasia. She was born with pulmonary hypertension and multiple congenital anomalies, including an atrial septal defect. Despite receiving the best supportive care, she could not be taken off the mechanical ventilator because of severe hypercapnia. We performed LVRS on the right lung via thoracotomy. She was successfully weaned off the mechanical ventilator 1 month after the surgery. She was discharged without severe complications at 3 months after the operation. At present, she is growing well with the help of intermittent home ventilator support. She can now tolerate an oral diet. Our experience shows that LVRS can be considered as a treatment option for pediatric patients with severe emphysematous lung. It is especially helpful for discontinuing prolonged mechanical ventilator care for patients with respiratory failure. PMID- 29610159 TI - Use of Insulin Glargine in the Management of Neonatal Hyperglycemia in an ELBW Infant. AB - Neonatal hyperglycemia is common in extremely low birth weight (ELBW) infants because of physiologic stress, exogenous glucose infusion, and postnatal corticosteroid therapy for hypotension, adrenal insufficiency, and pulmonary immaturity. The use of long-acting insulin glargine has been described in the treatment of transient neonatal diabetes in the premature infant, but in these reports is a lack of regard to its use in the treatment of iatrogenic neonatal hyperglycemia. We present the case of an ELBW infant with significant hyperglycemia that was refractory to usual treatment but demonstrated a favorable response to long-acting subcutaneous insulin glargine. The pharmacokinetics on regular insulin and long-acting insulin are different. Regular insulin is broken down into biologically active monomers after subcutaneous injection, and long acting insulin forms microprecipitates and is gradually released to the body at a neutral physiologic pH after subcutaneous injection. Pharmacokinetics of both regular insulin and long-acting insulin are not clear in ELBW infants. However, with further research on long-acting insulin, it can be used safely to achieve consistent euglycemia with once-daily administration in neonatal hyperglycemia. PMID- 29610160 TI - The Use of Pyridostigmine in a Child With Chronic Intestinal Pseudo-Obstruction. AB - Chronic intestinal pseudo-obstruction is a rare disorder that affects the motility of the gastrointestinal tract. It results in acute or subacute intestinal obstruction symptoms in the absence of mechanical lesion. It can lead to intestinal failure in children with significant strain on nutrition, growth, and development. There is no universally agreed protocol for management of chronic intestinal pseudo-obstruction in children, and there is wide variation in clinical practice. PMID- 29610161 TI - Topical Hypochlorite and Skin Acidification Improves Erythroderma of Omenn Syndrome. AB - We describe a case of Omenn syndrome displaying exudative erythroderma and other characteristic features, including alopecia, absent B and naive T cells, hyper immunoglobulin E levels, and eosinophilia. A pathogenic recombination-activating RAG1 homozygous genetic mutation confirmed the diagnosis. She required frequent antibiotics at both treatment and prophylactic doses, which alone did not control her erythroderma, but her high risk of infection precluded the use of systemic agents such as cyclosporine, which would further suppress her already severely compromised immune system. Thrice-weekly topical dilute hypochlorite compresses, combined with skin acidification with a low pH emollient, were initiated to control inflammation and for cutaneous bacterial prophylaxis. She demonstrated a marked improvement in her erythroderma within days after treatment initiation. Further improvement continued with the addition of systemic corticosteroids, with resolution of erythroderma after her first dose. This case reveals for the first time that dilute topical hypochlorite and skin pH restoration holds promise to control severe dermatitis associated with immunodeficiency and inflammatory syndromes with minimal side effects. PMID- 29610162 TI - Vagal Termination of Ventricular Tachycardia in a Pediatric Patient. AB - Ventricular tachycardia is a rare clinical entity in pediatric patients and typically requires chemical and/or electrical intervention to convert into a sustained sinus rhythm. However, for certain forms originating from the right ventricular outflow tract, conversion with adenosine and vagal maneuvers has been demonstrated in adult patients. In this case, we suggest that pediatric patients with right ventricular outflow tract ventricular tachycardia who are hemodynamically stable may benefit from a trial of vagal maneuvers. PMID- 29610153 TI - Signaling Pathways Involved in the Regulation of mRNA Translation. AB - Translation is a key step in the regulation of gene expression and one of the most energy-consuming processes in the cell. In response to various stimuli, multiple signaling pathways converge on the translational machinery to regulate its function. To date, the roles of phosphoinositide 3-kinase (PI3K)/AKT and the mitogen-activated protein kinase (MAPK) pathways in the regulation of translation are among the best understood. Both pathways engage the mechanistic target of rapamycin (mTOR) to regulate a variety of components of the translational machinery. While these pathways regulate protein synthesis in homeostasis, their dysregulation results in aberrant translation leading to human diseases, including diabetes, neurological disorders, and cancer. Here we review the roles of the PI3K/AKT and MAPK pathways in the regulation of mRNA translation. We also highlight additional signaling mechanisms that have recently emerged as regulators of the translational apparatus. PMID- 29610163 TI - Recanalization of Occluded Central Veins in a Parenteral Nutrition-Dependent Child With No Access. AB - Central venous thromboses are common and pose challenges in the care of chronically ill pediatric patients. Among patients with intestinal failure (most commonly because of short bowel syndrome) who depend on parenteral nutrition, progressive loss of central venous access sites is a potentially fatal complication. We present the case of a 5-year-old girl with parenteral nutrition dependent short bowel syndrome and no remaining standard central venous access sites despite medical anticoagulation, in whom angioplasty and stent implantations were used to reconstruct chronically occluded central veins. The patient presented with a bloodstream infection necessitating tunneled central venous line removal from the left internal jugular vein. All other standard access sites had known occlusions. The right iliofemoral vein (RIFV) and infrarenal inferior vena cava were recanalized and dilated with high-pressure balloons. The left internal jugular line was removed and a line was placed in the now-patent RIFV for antimicrobial therapy. After treatment, the RIFV line was removed and the vessels were stented open for future access. The occluded left innominate vein was recanalized and dilated to allow a new tunneled line to be placed. At 10 months, the line was functional and uninfected and the RIFV and inferior vena cava stents were patent without in-stent restenosis. We propose a new paradigm that uses these techniques to prevent access site exhaustion in patients who do not respond to anticoagulation therapy. This approach may reduce morbidity and mortality in patients with chronic access needs and the need for intestinal transplantation in patients with intestinal failure. PMID- 29610164 TI - Pneumocystis Jirovecii Pneumonia During Sirolimus Therapy for Kaposiform Hemangioendothelioma. AB - Sirolimus is an effective therapy for children with kaposiform hemangioendothelioma with or without the Kasabach-Merritt phenomenon. We report the case of a child with kaposiform hemangioendothelioma and the Kasabach-Merritt phenomenon who developed Pneumocystis carinii pneumonia (PCP) while on sirolimus and a prednisolone taper, after lack of adequate response to prednisolone, propranolol, and vincristine. He had a prompt positive clinical and laboratory response to sirolimus, but 4 weeks after starting it, at the age of 4 months, he developed PCP. This led to respiratory failure, which required extracorporeal membrane oxygenation. Sirolimus was temporarily discontinued, and he was successfully treated for PCP with sulfamethoxazole-trimethoprim and methylprednisolone. He was restarted on sirolimus 3 weeks after discharge and given sulfamethoxazole-trimethoprim prophylaxis. At the age of 22 months, while still on sirolimus, the lesion continued to improve with test results revealing stable hemoglobin and platelet counts. PCP is a rare but life-threatening side effect of sirolimus therapy, especially in the setting of concurrent steroid treatment. Pneumocystis prophylaxis should be considered for patients receiving sirolimus. PMID- 29610165 TI - A Case Report of 2 Sirolimus-Related Deaths Among Infants With Kaposiform Hemangioendotheliomas. AB - Kaposiform hemangioendothelioma (KHE) is a rare infiltrative vascular tumor that is potentially life-threatening when presenting with Kasabach-Merritt phenomenon (KMP). KMP is clinically characterized as severe thrombocytopenia and hypofibrinogenemia and therefore is associated with a high mortality rate. There is no standard of cure for KHE currently. Potential medications, including corticosteroids, propranolol, and chemotherapy drugs such as sirolimus, are often used for alleviating KHE symptoms. Although some case reports of sirolimus treatment have shown promising results with recovered coagulant parameters, the off-target effects may cause severe problems. Here we describe 2 cases of infant patients with KHE and KMP who were scheduled to receive sirolimus on a long-term basis. However, both patients developed paroxysmal cough and tachypnea shortly after the onset of sirolimus treatment and succumbed to infection thereafter. This report reveals a potential risk of infection in sirolimus-treated infant patients. The fatal complication highlights the importance of antibiotic prophylaxis and serum sirolimus level monitoring to ensure the safe use of sirolimus in the treatment of infant patients with KHE. PMID- 29610166 TI - B6 and Bleeding: A Case Report of a Novel Vitamin Toxicity. AB - Pyridox(am)ine-5-phosphate oxidase deficiency is an inborn error of vitamin B6 metabolism that is characterized by neonatal seizures, requiring lifelong therapy with pyridoxal-5-phosphate. We present the first case of a patient with pyridox(am)ine-5-phosphate oxidase deficiency and mild hemophilia A, whose bleeding symptoms were exacerbated by the vitamin B6 therapy essential for his epileptic disorder. This report expands the spectrum of known vitamin B6 toxicity and demonstrates a need for vigilance in monitoring for bleeding symptoms in patients requiring pyridoxine or pyridoxal-5-phosphate supplementation. PMID- 29610167 TI - HLA-A*31:01 and Oxcarbazepine-Induced DRESS in a Patient With Seizures and Complete DCX Deletion. AB - Oxcarbazepine is an antiepileptic drug (AED) commonly used as a first-line treatment option for focal epilepsy. Several AEDs, including carbamazepine, oxcarbazepine, and phenytoin are associated with various delayed-hypersensitivity reactions such as drug reaction with eosinophilia and systemic symptoms, Stevens Johnson syndrome, or toxic epidermal necrolysis. The Food and Drug Administration approved label for oxcarbazepine currently presents information regarding a pharmacogenomic association with the HLA antigen allele HLA-B*15:02 and hypersensitivity reactions in certain ancestry groups with a high incidence of this allele. However, unlike carbamazepine, screening for the presence of this allele is not routinely recommended before administration of oxcarbazepine. In practice, even with carbamazepine, HLA antigen testing is not always performed before initiating treatment because of lack of physician awareness of the recommendations and because of the desire to initiate treatment without delay. We present the clinical course of a pediatric patient with focal epilepsy refractory to several AEDs who developed drug reaction with eosinophilia and systemic symptoms after oxcarbazepine administration. The pharmacogenomic testing for various HLA antigen alleles was performed post hoc, and results were evaluated for structural similarities between AEDs and their molecular associations with HLA antigen proteins. In addition, we review the population-wide prevalence of various hypersensitivity reactions to AEDs and associated HLA antigen alleles. Finally, we discuss the potential utility of preemptive pharmacogenomic screening of patients before pharmacological treatment of epilepsy to assess the risk of developing hypersensitivity reactions. PMID- 29610168 TI - Vitamin A Deficiency Due to Selective Eating as a Cause of Blindness in a High Income Setting. AB - Vitamin A is a fat-soluble micronutrient involved in the regulation of several physiologic functions, such as visual acuity, epithelial tissue integrity, immune response, and gene expression, thus playing a crucial role in childhood growth and development. Although vitamin A deficiency (VAD) in resource-limited settings is still an actual issue and represents the leading cause of preventable childhood blindness, its occurrence in high-income countries is rare, although possibly underdiagnosed because of its nonspecific early manifestations. A good awareness of VAD symptoms and risk factors could aid its early diagnosis, which is fundamental to undertake a prompt treatment and to prevent ocular complications. Nevertheless, the role of restrictive dietary habits, increasingly common in developed countries, is often overlooked in infants and children. We present a case of VAD with permanent ocular sequelae in a 5-year-old girl from a high-income country. In the case described, VAD ensued from a highly restricted diet, mainly limited to oat milk, which had been followed for more than 2 years. This child presented with ocular symptoms, opportunistic infection, anemia, poor growth, and a diffuse squamous metaplasia of the bladder; after commencing retinol supplementation, a gradual healing of clinical VAD manifestations occurred, with the exception of the ocular sequelae, which resulted in irreversible visual loss. PMID- 29610169 TI - Erythropoietic Protoporphyria: Initial Diagnosis With Cholestatic Liver Disease. AB - The porphyrias are a group of rare metabolic disorders that result from defects in heme biosynthesis. Erythropoietic protoporphyria (EPP) is the most common inherited porphyria in children and is diagnosed in most individuals after the onset of cutaneous manifestations. Hepatobiliary disease affects the minority of individuals with EPP and usually manifests in patients with an established diagnosis of EPP. We report on a classic but rare case of EPP that masqueraded as cholestasis. An 8-year-old boy was referred to the Hepatology Clinic after an abrupt onset of jaundice with a longstanding history of dermatitis. The diagnosis of EPP was established with liver biopsy, which revealed dense, dark-brown pigment in hepatocytes and Kupffer cells that, on polarization, displayed bright red birefringence and centrally located Maltese crosses. Plasma total porphyrins and erythrocyte protoporphyrin were elevated and confirmed a diagnosis of EPP. We hope to raise awareness of this diagnosis among pediatricians, hepatologists, and pathologists and increase the consideration of EPP in patients with cholestatic liver disease and chronic dermatitis. PMID- 29610170 TI - Some Limitations for Early Diagnosis of Congenital Chagas Infection by PCR. AB - Trypanosoma cruzi, the causing agent of Chagas disease, can be transmitted to the offspring of infected pregnant women, thus being an epidemiologically important way of parasite transmission in humans. In addition, the migration of infected women from endemic areas to nonendemic countries may export this parasite infection. The diagnosis of congenital Chagas disease relies on the detection of the parasite because maternal antibodies are passively transferred to infants during pregnancy. The diagnosis of congenital infection can also be confirmed by detection of infant-specific anti-T cruzi antibodies at 10 months after delivery. Because early detection of T cruzi infection in newborns allows an efficient trypanocidal treatment and cure, more sensitive molecular techniques such as DNA amplification are being used for a prompt parasitological diagnosis of children born to seropositive mothers. In this report, we describe a diagnosis case of a child congenitally infected with T cruzi who tested negative for parasite detection both by microscopic observation and DNA amplification at 20 days and 6 months after delivery. However, at 7 months of age, a hemoculture was made from the infant's blood, and the infective parasite was finally isolated and classified as T cruzi discrete typing unit I. In a retrospective study, real-time polymerase chain reaction also allowed detecting the parasite but failed to detect any parasite load in earlier control samples. This case report stresses that even when molecular techniques are negative, a long-term follow-up is necessary for the diagnosis of infants congenitally infected with T cruzi. PMID- 29610171 TI - Autoimmune Pancreatitis and Ulcerative Rectocolitis in an Adolescent. AB - Autoimmune pancreatitis (AIP) is rare in teenagers and difficult to diagnose. There are no clear and established diagnostic criteria in the pediatric population to distinguish subtype 1 and subtype 2. Here, we report the case of a 16-year-old white French teenager admitted to the pediatric emergency service with more than 1 year's history of pain originating from the epigastric and the right hypochondriac regions, with bloody diarrhea. After exclusion of pancreatic cancer and other common causes of acute pancreatitis, the diagnosis of AIP was suspected. Biological analyses revealed acute pancreatitis with severe cholestasis and an elevated level of serum immunoglobulin G4. Magnetic resonance cholangiography revealed a voluminous pancreas presenting a typical "sausage like" aspect. Anatomopathological analyses of the liver biopsy specimen revealed a biliary obstruction due to pancreatic involvement without the typical aspect of chronic destructive cholangitis. Corticotherapy and immunosuppressive treatment proved effective after 1 week of treatment. Without a pancreatic biopsy specimen, the distinction between AIP type 1 and 2 could not be made clearly in this case. The succession of clinical observations could allow clinicians to recognize, treat, and manage AIP in children. PMID- 29610172 TI - Histoplasmosis Myocarditis in an Immunocompetent Host After a Recreational Mud Run. AB - Mud runs are an increasingly popular recreational fitness activity across the United States, combining a running race through an obstacle course with submersion in mud. Recent reports estimate 4 million people have participated in these types of events over the last 5 years. We describe an atypical case of myocarditis and multiorgan failure from disseminated histoplasmosis in a previously healthy pediatric patient, likely acquired during participation in a mud run. Although cases of histoplasmosis-associated endocarditis and pericarditis have been reported in the literature, cases of histoplasmosis myocarditis are rare. PMID- 29610173 TI - Sternoclavicular Arthritis as a Clinical Presentation for Lyme Disease. AB - Lyme disease is caused by Borrelia burgdorferi and can lead to dermatologic, neurologic, cardiac, and musculoskeletal manifestations. The arthritis of Lyme disease is typically monoarticular, with the knee being most commonly involved. Lyme arthritis of small joints has not previously been well described. We report 3 children who presented with sternoclavicular joint swelling and who were found to have Lyme disease based on enzyme-linked immunosorbent assay and Western blot. This description of sternoclavicular Lyme arthritis highlights the importance of considering Lyme disease in the differential and diagnostic workup of new onset, small joint arthritis in patients presenting from or with travel to Lyme endemic regions. PMID- 29610174 TI - Recalcitrant Atopic Keratoconjunctivitis in Children: A Case Report and Literature Review. AB - Atopic keratoconjunctivitis (AKC) is the most severe type of allergic conjunctivitis and may eventually lead to blindness. Although AKC is reported to be more prevalent in adults, we report a child with AKC whose clinical characteristics were not inconsistent with those typically seen in adult patients with AKC, and who was refractory to traditional topical anti-inflammatory and immunosuppressant therapies. An 11-year-old boy presented with a 3-month history of ocular redness and itching and decreased vision for a week in both eyes. Slit lamp examination revealed typical signs of vernal keratoconjunctivitis, including cobblestone papillae in both upper conjunctiva, superficial punctate keratopathy on the right cornea, and a sterile shield-shaped ulcer on the left cornea. Physical examination revealed eczematous lid changes and a generalized body rash, particularly on the face, neck, and flexor surfaces of the limbs. He was diagnosed to have AKC in both eyes and atopic dermatitis. The patient did not respond well to conventional topical antihistamine, mast cell stabilizers, corticosteroids, or tacrolimus, even in combination with amniotic membrane transplant. After using systemic immunosuppressants, the symptoms were relieved; the inflammation on the skin and ocular surface subsided, the cobblestone papillae disappeared, and the corneal ulcer healed gradually within 8 weeks. This case reveals that pediatric AKC should be differentiated from vernal keratoconjunctivitis because both disorders include upper cobblestone papillae, but the former is accompanied by atopic dermatitis. Pediatric AKC requires appropriate and aggressive treatment to prevent sight-threatening corneal complications. Systemic immunosuppressant should be considered when traditional topical anti-inflammatory therapies have failed. PMID- 29610175 TI - Neonatal Adenovirus Infection Complicated by Hemophagocytic Lymphohistiocytosis Syndrome. AB - Two infants with disseminated adenoviral infections are described. Both these infants had a similar clinical course and were also diagnosed with secondary hemophagocytic lymphohistiocytosis (HLH). Previous reports of immunocompromised adults with adenovirus-associated HLH are in the literature; however, this is the first report that we are aware of with this pathology occurring in infants. These cases are used to demonstrate the importance of thinking about HLH in patients who are diagnosed with adenovirus and exhibit prolonged fevers that are unresponsive to antimicrobial agents with hepatosplenomegaly and cytopenias. PMID- 29610176 TI - Pediatric Malignant Atrophic Papulosis. AB - Malignant atrophic papulosis (MAP), also known as Degos disease, is an extremely rare disease that is characterized by its unique skin presentation (namely, central, porcelain-white atrophic lesions with a telangiectatic rim). MAP has the following 2 variants: cutaneous MAP is manifested in the skin alone, whereas systemic MAP affects the gastrointestinal tract, central nervous system, lungs, and other internal organs. Some patients who presented with only cutaneous symptoms at first may develop systemic symptoms several years later. Although the exact pathologic mechanisms are unclear, Magro et al suggested in a recent study that MAP is a vascular injury syndrome that involves complement component C5b-9 complex deposition and high expression of interferon-alpha. The prognosis of systemic MAP is poor and typically fatal within a few years. Nonetheless, because the C5b-9 complex is detected in MAP, some researchers have suggested combined treatment with eculizumab (a humanized monoclonal antibody against C5) and treprostinil (a prostacyclin analog). Here, we report on a girl with systemic MAP who had severe central nervous system involvement and responded to eculizumab. PMID- 29610177 TI - NALCN Dysfunction as a Cause of Disordered Respiratory Rhythm With Central Apnea. AB - The sodium leak channel nonselective protein (NALCN) is a regulator of the pacemaker neurons that are responsible for rhythmic behavior (including respiration), maintaining the resting membrane potential, and are required for action potential production. NALCN-null mice show early death associated with disrupted respiratory rhythms, characterized by frequent and profound apneas. We report 3 children (2 siblings) with compound heterozygous mutations in NALCN associated with developmental impairment, hypotonia, and central sleep-disordered breathing causing apneas. Supplemental oxygen normalized the respiratory rhythm. NALCN mutations have been previously reported to cause severe hypotonia, speech impairment, and cognitive delay as well as infantile neuroaxonal dystrophy and facial dysmorphism. Nonsynonymous changes in the 2 affected extracellular loops may be responsible for the deleterious effect on the stability of the respiratory rhythm. Although oxygen is known to be a stabilizer of respiratory rhythm in central apnea in children, its role in NALCN dysfunction requires further investigation. PMID- 29610178 TI - Proximal Hypospadias and a Novel WT1 Variant: When Should Genetic Testing Be Considered? AB - We present a case of an infant with proximal hypospadias, penoscrotal transposition, and bilaterally descended testes found to have a clinically significant WT1 gene alteration on a customized disorder of sex development genetic panel in which 62 genes associated with 46, XY disorders of sex development were evaluated. This diagnosis led to early screening for and diagnosis and treatment of Wilms tumor. Patients with proximal hypospadias are not routinely evaluated by genetic testing, and when initial hormonal analyses are within normal ranges for a typical male patient, the genital atypia is usually attributed to an isolated anatomic abnormality. There is no consensus among urologists, endocrinologists, or geneticists regarding when genetic testing is warranted in these patients or the extent of genetic testing that should be pursued. However, given advances in genetic testing and the discovery of more genetic variants, the genetic evaluation of infants with proximal hypospadias should be considered on an individual patient basis. Only with continued evaluation and the identification of further genetic variants can we establish future parameters for genetic evaluation in patients with proximal hypospadias and more appropriately counsel patients and their families regarding the implications of these variants. PMID- 29610179 TI - Inherited Immunodeficiency: A New Association With Early-Onset Childhood Panniculitis. AB - We report on 4 children who presented with aseptic panniculitis associated with inherited immunodeficiency. Three patients had a B-cell immunodeficiency resulting from mutations in the TRNT1 and NF-kappab2 genes (no mutation was found in the third patient), and 1 had a T-cell deficiency (mutation in the LCK gene). Panniculitis occurred before the age of 2 years in the 4 patients and preceded the onset of recurrent infections because of immunodeficiency in 2. It presented either as nodules, which resolved spontaneously within 1 to 2 weeks (3 patients), or chronic ulcerative lesions (1 patient) associated with unexplained fever and elevated acute phase reactants, without evidence of infection or high-titer autoantibodies. Febrile nodules relapsed in 2 patients, and recurrent attacks of unexplained fever (without relapse of panniculitis) occurred in the third. Skin biopsy revealed predominantly lympho-histiocytic or septal neutrophilic panniculitis in 1 and 3 patients, respectively. Panniculitis was associated with dermal involvement in the 4 patients. Patients with B-cell deficiency received monthly intravenous immunoglobulin replacement. Two patients who underwent bone marrow transplant died of bone marrow transplant-related complications. The 2 remaining patients had persistent, mild autoinflammatory disease, which did not require specific treatment. In these cases, the need for careful immunologic evaluation of patients who present with unexplained panniculitis, especially early-onset panniculitis before the age of 2 years, is highlighted. PMID- 29610180 TI - Blue Diaper Syndrome and PCSK1 Mutations. AB - Blue diaper syndrome (BDS) (Online Mendelian Inheritance in Man number 211000) is an extremely rare disorder that was first described in 1964. The characteristic finding is a bluish discoloration of urine spots in the diapers of affected infants. Additional clinical features of the first described patients included diarrhea, inadequate weight gain, hypercalcemia, and nephrocalcinosis. An intestinal defect of tryptophan absorption was postulated as the underlying pathology. However, functional evidence for this theory is lacking. No genetic cause has been identified so far. Here, we report on a boy who presented with neonatal-onset diarrhea, metabolic acidosis, transient hepatopathy, recurrent hypoglycemia, and blue-stained urine spots in his diapers. An ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry analysis of urine samples at different time points demonstrated the constant presence of indigo derivatives, thereby confirming the diagnosis of BDS. Of note, the visibility of indigo derivatives in the urine was highly dependent on the urine's pH. To identify the underlying genetic cause of the disease, whole-exome sequencing was performed, leading to the identification of a homozygous frameshift mutation in proprotein convertase subtilisin/kexin type 1 (PCSK1; NM_000439.4: c.679del, p.[Val227Leufs*12]). PCSK1 encodes prohormone convertase 1/3, and mutations within this gene have been reported as a rare cause of early onset malabsorptive diarrhea and multiple endocrine dysfunction. In our report, we suggest that BDS can be caused by PCSK1 mutations. PMID- 29610181 TI - Neonatal Alloimmune Thrombocytopenia With Amegakaryocytosis, B Lymphopenia, and Villitis. AB - Neonatal alloimmune thrombocytopenia (NAIT) is a common but significant challenge for neonatologists and a potentially devastating disease that may lead to intracranial bleeding. The underlying mechanism of thrombocytopenia is expected to be mediated by accelerated clearance of antibody-opsonized fetal platelets. We report severe recurrent NAIT related to human platelet antigen (HPA)-15 systems in 2 consecutive siblings. The first child presented with intracranial hemorrhage at birth and subsequently died. The diagnosis of NAIT, although initially suspected, was ruled out after negative investigation of only HPA-1, HPA-3, and HPA-5 systems. The second child experienced a clinically milder presentation but a profound thrombocytopenia. In both siblings, NAIT was unexpectedly associated with amegakaryocytosis, suggesting that alloimmunization could extend at the megakaryocyte level. In addition, both siblings presented with drastic abnormalities in the B-cell compartment, which led to broad investigations for an immune-deficiency syndrome and provided a novel pathophysiologic hypothesis. Both placental examinations revealed major lymphoid infiltration involving the villous placenta, which is consistent with the diagnosis of villitis of unknown etiology. Severe thrombocytopenia in an otherwise healthy newborn should raise high the suspicion of NAIT. The diagnosis of NAIT should not be ruled out until extensive human platelet antigen systems have been investigated to screen for fetal maternal antigen incompatibility. This is crucial not only for the newborn to allow optimal lifesaving treatments but also for effective management of future pregnancies. Interestingly, antibodies to HPA-15 have previously been reported with severe NAIT-related thrombocytopenia, but we are the first to report associated in vivo amegakaryocytosis. PMID- 29610182 TI - Unusual Presentations of Dystrophinopathies in Childhood. AB - X-linked recessive mutations in the dystrophin gene are one of the most common causes of inherited neuromuscular disorders in humans. Duchenne muscular dystrophy, the most common phenotype, and Becker muscular dystrophy are often recognizable by certain clinical features; however, less frequent presentations require a higher degree of suspicion. In this article, we describe a series of 6 children (4 boys, 2 girls) referred to a tertiary pediatric neuromuscular clinic for isolated elevated creatine kinase levels (range: 720-7000 IU/L) identified on initial assessment for otherwise unexplained transaminase elevations (n = 2), a social communication disorder (n = 3), and exertional myalgia and/or rhabdomyolysis (n = 1). There was no preceding family history of neuromuscular disease. One boy had an additional history of severe cerebral palsy and cyclical vomiting, and 1 girl had a history of maternal hepatitis C. There was no significant weakness at presentation, and the majority remained stable over a prolonged period of follow-up (age range at last follow-up: 9-16 years). All 6 children were found to carry dystrophin gene mutations resulting in milder phenotypes. This series highlights that dystrophinopathies may not uncommonly present with features distinct from the classic Duchenne muscular dystrophy and Becker muscular dystrophy phenotypes in both boys and girls. Pediatricians should be aware of such atypical presentations to initiate a timely and adequate diagnostic process. Establishing the correct genetic diagnosis of a dystrophinopathy is important to allow appropriate genetic counseling, to implement relevant surveillance and management strategies, and to avoid unnecessary investigations in search of an incorrect alternative diagnosis. PMID- 29610183 TI - Craniosynostosis as the Presenting Feature of X-linked Hypophosphatemic Rickets. AB - Craniosynostosis is the premature closure of cranial sutures. Primary, or congenital, craniosynostosis is often sporadic but may be associated with genetic or chromosomal abnormalities. Secondary craniosynostosis presents after gestation, and can occur in metabolic bone diseases, including rickets. We describe the first reported cases of primary craniosynostosis in 2 unrelated, term infants with X-linked hypophosphatemic rickets (XLH). The diagnosis of XLH in both patients was confirmed by genetic testing. At the time craniosynostosis was detected, the patient in the first case did not have any other clinical features of XLH. The second patient developed clinical findings of craniosynostosis, followed by rickets. These are the earliest reported cases of craniosynostosis in XLH and demonstrate that craniosynostosis may be a presenting feature of this disease. PMID- 29610184 TI - A Novel Presentation of Littoral Cell Angioma and Lymphatic Malformations in a Neonate. AB - This case report describes a novel presentation of littoral cell angioma (LCA) and lymphatic malformations involving the omentum and mesentery. To our knowledge, these 2 entities have not been reported in the same patient. A 1-month term infant male presented with chylous ascites. During his workup, imaging detected splenic nodules. Biopsies revealed that the nodules were LCA and the chylous ascites was secondary to microscopic mesenteric and omental lymphatic malformations. Evaluation for a secondary malignancy, an underlying immunologic defect, and genetic causes were unrevealing. The presence of LCA and lymphatic malformations in the same patient suggests a genetic link between these 2 rare vascular disorders and may help elucidate the etiopathogenesis of these 2 poorly understood anomalies. PMID- 29610185 TI - Appropriateness of Pediatrics Case Reports Citations. AB - BACKGROUND: We determined types of peer-reviewed articles that cited Pediatrics case reports and whether citations were "appropriate" or "inappropriate." METHODS: The 20 most highly cited Pediatrics case reports published between January 2011 and April 2016 were identified. All articles referencing these 20 case reports were analyzed for appropriateness of the citation. Appropriate citations referred to the original article specifically as a case report or cited the case report in support of general knowledge. Inappropriate citations used case reports to infer causation, support proof of mechanism, or were deemed irrelevant to claims being supported. Two authors independently coded all citations. RESULTS: These 20 case reports were cited in 479 articles (median: 24 citations per case report). In most articles (83.6%, n = 367), case reports were cited appropriately; in 53.4% (n = 196) of articles, a case report was specifically referred to, and in 46.6% (n = 171) of articles, the case report was used to support general knowledge. For inappropriate citations, in 63.3% (n = 50) of articles, case reports were used to infer causation; in 15.2% (n = 12) of articles, they were used as proof of mechanism of pathogenesis or treatment; and in 21.5% (n = 17) of articles, they were irrelevant. Case reports were most commonly cited in review articles (38.7%, n = 170) and original studies (31%, n = 136). "Original studies" were articles in which authors reported original data, excluding case reports. CONCLUSIONS: These results reveal that most citations of Pediatrics case reports are appropriate. PMID- 29610187 TI - Nuclear Medicine Procedure Performance and Cataracts. PMID- 29610186 TI - Erratum. PMID- 29610188 TI - Domestic Non-Uranium-Based 99mTc Production System Approved. PMID- 29610189 TI - NAD+ Supplementation in Mouse AD Model. PMID- 29610190 TI - SNMMI Leadership Update: The SNMMI Annual Meeting: Making History in Philadelphia. PMID- 29610193 TI - FDA Approves Lutathera for GEP NET Therapy. PMID- 29610194 TI - The Combination of Daptomycin and Fosfomycin Has Synergistic, Potent, and Rapid Bactericidal Activity against Methicillin-Resistant Staphylococcus aureus in a Rabbit Model of Experimental Endocarditis. AB - We investigated whether the addition of fosfomycin or cloxacillin to daptomycin provides better outcomes in the treatment of methicillin-resistant Staphylococcus aureus (MRSA) experimental aortic endocarditis in rabbits. Five MRSA strains were used to perform in vitro time-kill studies using standard (106) and high (108) inocula. Combined therapy was compared to daptomycin monotherapy treatment in the MRSA experimental endocarditis model. A human-like pharmacokinetics model was applied, and the equivalents of cloxacillin at 2 g/4 h, fosfomycin at 2 g/6 h, and daptomycin at 6 to 10 mg/kg/day were administered intravenously. A combination of daptomycin and either fosfomycin or cloxacillin was synergistic in the five strains tested at both inocula. A bactericidal effect was detected in four of five strains tested with both combinations. The MRSA-277 strain (vancomycin MIC, 2 MUg/ml) was used for the experimental endocarditis model. Daptomycin plus fosfomycin significantly improved the efficacy of daptomycin monotherapy at 6 mg/kg/day in terms of both the proportion of sterile vegetations (100% versus 72%, P = 0.046) and the decrease in the density of bacteria within the vegetations (P = 0.025). Daptomycin plus fosfomycin was as effective as daptomycin monotherapy at 10 mg/kg/day (100% versus 93%, P = 1.00) and had activity similar to that of daptomycin plus cloxacillin when daptomycin was administered at 6 mg/kg/day (100% versus 88%, P = 0.48). Daptomycin nonsusceptibility was not detected in any of the isolates recovered from vegetations. In conclusion, for the treatment of MRSA experimental endocarditis, the combination of daptomycin plus fosfomycin showed synergistic and bactericidal activity. PMID- 29610195 TI - Overexpression of the Efflux Pumps SmeVWX and SmeDEF Is a Major Cause of Resistance to Co-trimoxazole in Stenotrophomonas maltophilia. AB - Co-trimoxazole is one of the antimicrobials of choice for treating Stenotrophomonas maltophilia infections. Most works on the molecular epidemiology of the resistance to this drug combination are based on the analysis of sul genes. Nevertheless, the existence of clinical co-trimoxazole-resistant S. maltophilia isolates that do not harbor sul genes has been reported. To investigate potential mutations that can reduce the susceptibility of S. maltophilia to co-trimoxazole, spontaneous S. maltophilia co-trimoxazole resistant mutants isolated under different co-trimoxazole concentrations were studied. All mutants presented phenotypes compatible with the overexpression of either SmeVWX (94.6%) or SmeDEF (5.4%). Indeed, the analysis of a selected set of strains showed that the overexpression of either of these efflux pumps, which was due to mutations in their regulators smeRv and smeT, respectively, was the cause of co-trimoxazole resistance. No other efflux pump was overexpressed in any of the studied mutants, indicating that they do not participate in the observed resistance phenotype. The analysis of mutants overexpressing or lacking SmeDEF or SmeVWX shows that SmeDEF contributes to the intrinsic and acquired resistance to co-trimoxazole in S. maltophilia, whereas SmeVWX only contributes to acquired resistance. It is important to highlight that all mutants were less susceptible to other antibiotics, including chloramphenicol and quinolones. Since both SmeVWX and SmeDEF are major determinants of quinolone resistance, the potential cross selection of resistance to co-trimoxazole and quinolones, when either of the antimicrobials is used, is of particular concern for the treatment of S. maltophilia infections. PMID- 29610196 TI - Fungicidal Potency and Mechanisms of theta-Defensins against Multidrug-Resistant Candida Species. AB - Systemic candidiasis is a growing health care concern that is becoming even more challenging due to the growing frequency of infections caused by multidrug resistant (MDR) Candida species. Thus, there is an urgent need for new therapeutic approaches to candidiasis, including strategies bioinspired by insights into natural host defense against fungal pathogens. The antifungal properties of theta-defensins, macrocyclic peptides expressed in tissues of Old World monkeys, were investigated against a panel of drug-sensitive and drug resistant clinical isolates of Candida albicans and non-albicans Candida species. Rhesus theta-defensin 1 (RTD-1), the prototype theta-defensin, was rapidly and potently fungicidal against drug-sensitive and MDR C. albicans strains. Fungal killing occurred by cell permeabilization that was temporally correlated with ATP release and intracellular accumulation of reactive oxygen species (ROS). Killing by RTD-1 was compared with that by histatin 5 (Hst 5), an extensively characterized anticandidal peptide expressed in human saliva. RTD-1 killed C. albicans much more rapidly and at a >200-fold lower concentration than that of Hst 5. Unlike Hst 5, the anticandidal activity of RTD-1 was independent of mitochondrial ATP production. Moreover, RTD-1 was completely resistant to Candida proteases for 2 h under conditions that rapidly and completely degraded Hst 5. MICs and minimum fungicidal concentrations (MFCs) of 14 natural theta-defensins isoforms against drug-resistant C. albicans isolates identified peptides that are more active than amphotericin B and/or caspofungin against fluconazole-resistant organisms, including MDR Candida auris. These results point to the potential of macrocyclic theta-defensins as structural templates for the design of antifungal therapeutics. PMID- 29610197 TI - Mechanistic Basis of pH-Dependent 5-Flucytosine Resistance in Aspergillus fumigatus. AB - The antifungal drug 5-flucytosine (5FC), a derivative of the nucleobase cytosine, is licensed for the treatment of fungal diseases; however, it is rarely used as a monotherapeutic to treat Aspergillus infection. Despite being potent against other fungal pathogens, 5FC has limited activity against Aspergillus fumigatus when standard in vitro assays are used to determine susceptibility. However, in modified in vitro assays where the pH is set to pH 5, the activity of 5FC increases significantly. Here we provide evidence that fcyB, a gene that encodes a purine-cytosine permease orthologous to known 5FC importers, is downregulated at pH 7 and is the primary factor responsible for the low efficacy of 5FC at pH 7. We also uncover two transcriptional regulators that are responsible for the repression of fcyB and, consequently, mediators of 5FC resistance, the CCAAT binding complex (CBC) and the pH regulatory protein PacC. We propose that the activity of 5FC might be enhanced by the perturbation of factors that repress fcyB expression, such as PacC or other components of the pH-sensing machinery. PMID- 29610198 TI - Pharmacokinetics of Daptomycin in Critically Ill Pediatric Patients. AB - The pharmacokinetics of daptomycin (10 mg/kg once daily) was studied in 4 critically ill pediatric patients aged 8 to 14 yrs. The area under the concentration-time curve from time zero to infinity (AUC0-infinity) of plasma concentrations on day 1 ranged between 123.8 to 663.9 MUg . h/ml, with lower values observed in septic and burn patients; clearance ranged from 15.1 to 80.7 ml/h/kg. Higher-than-recommended doses of daptomycin may be needed in septic children to ensure optimal drug exposure. Interpatient variability may suggest a role for therapeutic drug monitoring. PMID- 29610199 TI - Absence of Azole or Echinocandin Resistance in Candida glabrata Isolates in India despite Background Prevalence of Strains with Defects in the DNA Mismatch Repair Pathway. AB - Candida glabrata infections are increasing worldwide and exhibit greater rates of antifungal resistance than those with other species. DNA mismatch repair (MMR) gene deletions, such as msh2Delta, in C. glabrata resulting in a mutator phenotype have recently been reported to facilitate rapid acquisition of antifungal resistance. This study determined the antifungal susceptibility profiles of 210 C. glabrata isolates in 10 hospitals in India and investigated the impact of novel MSH2 polymorphisms on mutation potential. No echinocandin- or azole-resistant strains and no mutations in FKS hot spot regions were detected among the C. glabrata isolates, supporting our in vitro susceptibility testing results. CLSI antifungal susceptibility data showed that the MICs of anidulafungin (geometric mean [GM], 0.12 MUg/ml) and micafungin (GM, 0.01 MUg/ml) were lower and below the susceptibility breakpoint compared to that of caspofungin (CAS) (GM, 1.31 MUg/ml). Interestingly, 69% of the C. glabrata strains sequenced contained six nonsynonymous mutations in MSH2, i.e., V239L and the novel mutations E459K, R847C, Q386K, T772S, and V239/D946E. Functional analysis of MSH2 mutations revealed that 49% of the tested strains (40/81) contained a partial loss-of-function MSH2 mutation. The novel MSH2 substitution Q386K produced higher frequencies of CAS-resistant colonies upon expression in the msh2Delta mutant. However, expression of two other novel MSH2 alleles, i.e., E459K or R847C, did not confer selection of resistant colonies, confirming that not all mutations in the MSH2 MMR pathway affect its function or generate a phenotype of resistance to antifungal drugs. The lack of drug resistance prevented any correlations from being drawn with respect to MSH2 genotype. PMID- 29610200 TI - EfrEF and the Transcription Regulator ChlR Are Required for Chlorhexidine Stress Response in Enterococcus faecalis V583. AB - Enterococcus faecalis is an opportunistic pathogen and leading cause of health care-associated infections. Daily chlorhexidine gluconate (CHG) bathing of patients is generally regarded as an effective strategy to reduce the occurrence of health care-associated infections. It is likely that E. faecalis is frequently exposed to inhibitory and subinhibitory concentrations of CHG in clinical settings. The goal of this study was to investigate how the vancomycin-resistant strain E. faecalis V583 transcriptionally responds to and tolerates stress from CHG. We used transcriptome (microarray) analysis to identify genes upregulated by E. faecalis V583 in response to CHG. The genes efrE (EF2226) and efrF (EF2227), encoding a heterodimeric ABC transport system, were the most highly upregulated genes. efrEF expression was induced by CHG at concentrations several 2-fold dilutions below the MIC. Deletion of efrEF increased E. faecalis V583 susceptibility to CHG. We found that ChlR, a MerR-like regulator encoded by a sequence upstream of efrEF, mediated the CHG-dependent upregulation of efrEF, and deletion of chlR also increased chlorhexidine susceptibility. Overall, our study gives insight into E. faecalis stress responses to a commonly used antiseptic. PMID- 29610201 TI - Tomatidine Is a Lead Antibiotic Molecule That Targets Staphylococcus aureus ATP Synthase Subunit C. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of deadly hospital-acquired infections. The discovery of anti-Staphylococcus antibiotics and new classes of drugs not susceptible to the mechanisms of resistance shared among bacteria is imperative. We recently showed that tomatidine (TO), a steroidal alkaloid from solanaceous plants, possesses potent antibacterial activity against S. aureus small-colony variants (SCVs), the notoriously persistent form of this bacterium that has been associated with recurrence of infections. Here, using genomic analysis of in vitro-generated TO-resistant S. aureus strains to identify mutations in genes involved in resistance, we identified the bacterial ATP synthase as the cellular target. Sequence alignments were performed to highlight the modified sequences, and the structural consequences of the mutations were evaluated in structural models. Overexpression of the atpE gene in S. aureus SCVs or introducing the mutation found in the atpE gene of one of the high-level TO-resistant S. aureus mutants into the Bacillus subtilis atpE gene provided resistance to TO and further validated the identity of the cellular target. FC04-100, a TO derivative which also possesses activity against non-SCV strains, prevents high-level resistance development in prototypic strains and limits the level of resistance observed in SCVs. An ATP synthesis assay allowed the observation of a correlation between antibiotic potency and ATP synthase inhibition. The selectivity index (inhibition of ATP production by mitochondria versus that of bacterial ATP synthase) is estimated to be >105-fold for FC04-100. PMID- 29610202 TI - In Vitro and In Vivo Activities of DS-2969b, a Novel GyrB Inhibitor, and Its Water-Soluble Prodrug, DS11960558, against Methicillin-Resistant Staphylococcus aureus. AB - DS-2969b is a novel GyrB inhibitor under clinical development. In this study, the in vitro activity of DS-2969b and the in vivo activities of DS-2969b and its water-soluble prodrug, DS11960558, against methicillin-resistant Staphylococcus aureus (MRSA) were evaluated. DS-2969b inhibited the supercoiling activity of S. aureus DNA gyrase and the decatenation activity of its topoisomerase IV. DS-2969b showed antibacterial activity against Gram-positive aerobes but not against Gram negative aerobes, except for Moraxella catarrhalis and Haemophilus influenzae DS 2969b was active against MRSA with an MIC90 of 0.25 MUg/ml, which was 8-fold lower than that of linezolid. The presence of a pulmonary surfactant did not affect the MIC of DS-2969b. DS-2969b showed time-dependent slow killing against MRSA. The frequency of spontaneous resistance development was less than 6.2 * 10 10 in all four S. aureus isolates at 4* MIC of DS-2969b. In a neutropenic MRSA induced murine muscle infection model, DS-2969b was more efficacious than linezolid by both the subcutaneous and oral routes. DS-2969b and DS11960558 showed efficacy in a neutropenic murine MRSA lung infection model. The pharmacokinetics and pharmacodynamics of DS-2969b and DS11960558 against MRSA were characterized in a neutropenic murine thigh infection model; the percentage of time during the dosing period in which the free drug concentration exceeded the MIC (fTMIC) correlated best with in vivo efficacy, and the static percent fTMIC was 43 to 49%. A sufficient fTMIC was observed in a phase 1 multiple ascending-dose study of DS-2969b given orally at 400 mg once a day. These results suggest that DS11960558 and DS-2969b have potential for use as intravenous-to oral step-down therapy for treating MRSA infections with a higher efficacy than linezolid. PMID- 29610203 TI - Pyocyanin Inhibits Chlamydia Infection by Disabling Infectivity of the Elementary Body and Disrupting Intracellular Growth. AB - The obligate intracellular bacterium Chlamydia is a widespread human pathogen that causes serious problems, including (but not limited to) infertility and blindness. Our search for novel antichlamydial metabolites from marine-derived microorganisms led to the isolation of pyocyanin, a small compound from Pseudomonas aeruginosa Pyocyanin is an effective antichlamydial for all three Chlamydia spp. tested. It has a 50% inhibitory concentration (IC50) of 0.019 to 0.028 MUM, which is comparable to the IC50 of tetracycline. At concentrations as low as 0.0039 MUM, pyocyanin disables infectivity of the chlamydial elementary body (EB). At 0.5 MUM or higher concentrations, the continuous presence of pyocyanin also inhibits chlamydial growth in the inclusion during later stages of the developmental cycle. Oxidative stress, a major known antimicrobial mechanism of pyocyanin, appears to be responsible only for the inhibition of bacterial growth and not for the disinfection of EBs. Pyocyanin is well-tolerated by probiotic vaginal Lactobacillus spp. Our findings suggest that pyocyanin is of therapeutic value for chlamydial infections and can serve as a valuable chemical probe for studying chlamydial biology. PMID- 29610204 TI - Evaluation of the Antifungal Activity of the Novel Oral Glucan Synthase Inhibitor SCY-078, Singly and in Combination, for the Treatment of Invasive Aspergillosis. AB - Invasive aspergillosis remains a major cause of death among the immunocompromised population and those receiving long-term immunosuppressive therapy. In light of increased azole resistance, variable outcomes with existing echinocandin monotherapy and combination therapy, and persistent high mortality rates, new antifungal agents for the treatment of invasive aspergillosis are clearly needed. SCY-078 is the first-in-class triterpenoid antifungal, a novel class of glucan synthase inhibitors with broad in vitro and in vivo activity against a broad spectrum of Candida and Aspergillus species. In vitro testing of clinical strains of Aspergillus fumigatus and non-fumigatus Aspergillus strains showed that SCY 078 had potent fungistatic activity (minimum effective concentration for 90% of strains tested = 0.125 MUg/ml) compared with the activities of amphotericin B (MIC90 = 8 MUg/ml) and voriconazole (MIC90 = 2 MUg/ml). Testing of SCY-078 in combination with isavuconazole or voriconazole demonstrated synergistic activity against the majority of the azole-susceptible strains tested, and SCY-078 in combination with amphotericin B was synergistic against the azole-susceptible strains, as well as one known resistant cyp51A mutant. SCY-078 may be an important additional antifungal for first-line or salvage monotherapy or combination treatment of invasive aspergillosis. PMID- 29610205 TI - Relebactam Is a Potent Inhibitor of the KPC-2 beta-Lactamase and Restores Imipenem Susceptibility in KPC-Producing Enterobacteriaceae. AB - The imipenem-relebactam combination is in development as a potential treatment regimen for infections caused by Enterobacteriaceae possessing complex beta lactamase backgrounds. Relebactam is a beta-lactamase inhibitor that possesses the diazabicyclooctane core, as in avibactam; however, the R1 side chain of relebactam also includes a piperidine ring, whereas that of avibactam is a carboxyamide. Here, we investigated the inactivation of the Klebsiella pneumoniae carbapenemase KPC-2, the most widespread class A carbapenemase, by relebactam and performed susceptibility testing with imipenem-relebactam using KPC-producing clinical isolates of Enterobacteriaceae MIC measurements using agar dilution methods revealed that all 101 clinical isolates of KPC-producing Enterobacteriaceae (K. pneumoniae, Klebsiella oxytoca, Enterobacter cloacae, Enterobacter aerogenes, Citrobacter freundii, Citrobacter koseri, and Escherichia coli) were highly susceptible to imipenem-relebactam (MICs <= 2 mg/liter). Relebactam inhibited KPC-2 with a second-order onset of acylation rate constant (k2/K) value of 24,750 M-1 s-1 and demonstrated a slow off-rate constant (koff) of 0.0002 s-1 Biochemical analysis using time-based mass spectrometry to map intermediates revealed that the KPC-2-relebactam acyl-enzyme complex was stable for up to 24 h. Importantly, desulfation of relebactam was not observed using mass spectrometry. Desulfation and subsequent deacylation have been observed during the reaction of KPC-2 with avibactam. Upon molecular dynamics simulations of relebactam in the KPC-2 active site, we found that the positioning of active site water molecules is less favorable for desulfation in the KPC-2 active site than it is in the KPC-2-avibactam complex. In the acyl complexes, the water molecules are within 2.5 to 3 A of the avibactam sulfate; however, they are more than 5 to 6 A from the relebactam sulfate. As a result, we propose that the KPC-2 relebactam acyl complex is more stable than the KPC-2-avibactam complex. The clinical implications of this difference are not currently known. PMID- 29610206 TI - Sequence Type 273 Carbapenem-Resistant Klebsiella pneumoniae Carrying blaNDM-1 and blaIMP-4. AB - A carbapenem-resistant Klebsiella pneumoniae isolate was recovered from human blood. Its whole-genome sequence was obtained using Illumina and long-read MinION sequencing. The strain belongs to sequence type 273 (ST273), which was found recently and caused an outbreak in Southeast Asia. It has two carbapenemase genes, blaNDM-1 (carried by an ST7 IncN self-transmissible plasmid) and blaIMP-4 (located on a self-transmissible IncHI5 plasmid). Non-KPC-producing ST237 may represent a lineage of carbapenem-resistant K. pneumoniae, which warrants further monitoring. PMID- 29610207 TI - Systematic Review, Meta-analysis, and Network Meta-analysis of the Cardiovascular Safety of Macrolides. AB - Studies reporting an increased risk for cardiac toxicities with macrolide antibiotics have raised concern regarding their cardiovascular safety. We sought to assess the cardiac safety of macrolide antibiotics as a class and of the individual agents by conducting a systematic review and network meta-analysis. Medline, Embase, and the Cochrane Library were searched up to February 2018 for studies reporting on cardiovascular outcomes with macrolides. We followed the PRISMA 2009 guidelines for data selection and extraction. Outcomes were pooled using random-effects models and odds ratios (OR), and 95% confidence intervals (CI) were calculated for arrhythmia, cardiovascular death, and myocardial infarction (MI). A total of 33 studies and data on 22,601,032 subjects were retrieved and included in the current meta-analyses. Macrolide use was not associated with the risk of arrhythmia or cardiovascular mortality. In the primary analysis, macrolide use was associated with a small but statistically significant 15% increase in risk for MI (OR = 1.15 [95% CI, 1.01 to 1.30]). In indirect network meta-analysis, erythromycin and clarithromycin were ranked considerably more likely to be associated with a higher risk for MI and significantly associated with increased risk of MI compared to azithromycin (OR = 1.58 [95% CI, 1.18 to 2.11] and OR = 1.41 [95% CI, 1.11 to 1.81], respectively). Our findings indicate that macrolide antibiotics as a group are associated with a significant risk for MI but not for arrhythmia and cardiovascular mortality. Among the macrolides, erythromycin and clarithromycin were associated with a greater risk of MI. However, it is possible that the association between macrolide use and risk of MI is the result of residual confounding. PMID- 29610208 TI - Avibactam Pharmacokinetic/Pharmacodynamic Targets. AB - Avibactam is a novel non-beta-lactam beta-lactamase inhibitor that has been approved in the United States and Europe for use in combination with ceftazidime. Combinations of avibactam with aztreonam or ceftaroline fosamil have also been clinically evaluated. Until recently, there has been very little precedence of which pharmacokinetic/pharmacodynamic (PK/PD) indices and magnitudes are appropriate to use for beta-lactamase inhibitors in population PK modeling for analyzing potential doses and susceptibility breakpoints. For avibactam, several preclinical studies using different in vitro and in vivo models have been conducted to identify the PK/PD index of avibactam and the magnitude of exposure necessary for effect in combination with ceftazidime, aztreonam, or ceftaroline fosamil. The PD driver of avibactam critical for restoring the activity of all three partner beta-lactams was found to be time dependent rather than concentration dependent and was defined as the time that the concentration of avibactam exceeded a critical concentration threshold (%fT>CT). The magnitude of the CT and the time that this threshold needed to be exceeded to elicit particular PD endpoints varied depending on the model and the partner beta lactam. This review describes the preclinical studies used to determine the avibactam PK/PD target in combination with its beta-lactam partners. PMID- 29610209 TI - An SPX-RLI1 Module Regulates Leaf Inclination in Response to Phosphate Availability in Rice. AB - Leaf erectness is one of the key traits of plant architecture; in grains, plants with upright leaves can be planted close together, thus benefiting yield/unit area. Many factors, such as hormones, affect leaf inclination; however, how nutrition status, in particular phosphate (Pi) availability, affects leaf inclination remains largely unexplained. Here, we show that in rice (Oryza sativa), Pi deficiency stress inhibits lamina joint cell elongation, thus restricting lamina joint size and inducing leaf erectness in rice. The Pi starvation-induced proteins SPX1 (for Syg1/Pho81/XPR1) and SPX2 play a negative role in the regulation of leaf inclination. We further identified an SPX1 interacting protein, REGULATOR OF LEAF INCLINATION1 (RLI1), which positively regulates leaf inclination by affecting lamina joint cell elongation in rice. The rli1 mutants showed reduced leaf inclination and the RLI1 overexpressors showed increased leaf inclination. RLI1 directly activates the downstream genes BRASSINOSTEROID UPREGULATED1 (BU1) and BU1-LIKE 1 COMPLEX1 to control elongation of the lamina joint cells, therefore enhancing leaf inclination. We also found that Pi deficiency repressed the expression of RLI1 SPX1 protein interacts directly with RLI1, which could prevent RLI1 binding to the promoters of downstream genes. Therefore, SPX and RLI1 form a module to regulate leaf inclination in response to external Pi availability in rice. PMID- 29610210 TI - OsALMT7 Maintains Panicle Size and Grain Yield in Rice by Mediating Malate Transport. AB - Panicle size is a critical determinant of grain yield in rice (Oryza sativa) and other grain crops. During rice growth and development, spikelet abortion often occurs at either the top or the basal part of the panicle under unfavorable conditions, causing a reduction in fertile spikelet number and thus grain yield. In this study, we report the isolation and functional characterization of a panicle abortion mutant named panicle apical abortion1-1 (paab1-1). paab1-1 exhibits degeneration of spikelets on the apical portion of panicles during late stage of panicle development. Cellular and physiological analyses revealed that the apical spikelets in the paab1-1 mutant undergo programmed cell death, accompanied by nuclear DNA fragmentation and accumulation of higher levels of H2O2 and malondialdehyde. Molecular cloning revealed that paab1-1 harbors a mutation in OsALMT7, which encodes a putative aluminum-activated malate transporter (OsALMT7) localized to the plasma membrane, and is preferentially expressed in the vascular tissues of developing panicles. Consistent with a function for OsALMT7 as a malate transporter, the panicle of the paab1-1 mutant contained less malate than the wild type, particularly at the apical portions, and injection of malate into the paab1-1 panicle could alleviate the spikelet degeneration phenotype. Together, these results suggest that OsALMT7-mediated transport of malate into the apical portion of panicle is required for normal panicle development, thus highlighting a key role of malate in maintaining the sink size and grain yield in rice and probably other grain crops. PMID- 29610212 TI - Cyclic di-GMP Positively Regulates DNA Repair in Vibrio cholerae. AB - In Vibrio cholerae, high intracellular cyclic di-GMP (c-di-GMP) concentration are associated with a biofilm lifestyle, while low intracellular c-di-GMP concentrations are associated with a motile lifestyle. c-di-GMP also regulates other behaviors, such as acetoin production and type II secretion; however, the extent of phenotypes regulated by c-di-GMP is not fully understood. We recently determined that the sequence upstream of the DNA repair gene encoding 3 methyladenine glycosylase (tag) was positively induced by c-di-GMP, suggesting that this signaling system might impact DNA repair pathways. We identified a DNA region upstream of tag that is required for transcriptional induction by c-di GMP. We further showed that c-di-GMP induction of tag expression was dependent on the c-di-GMP-dependent biofilm regulators VpsT and VpsR. In vitro binding assays and heterologous host expression studies show that VpsT acts directly at the tag promoter in response to c-di-GMP to induce tag expression. Last, we determined that strains with high c-di-GMP concentrations are more tolerant of the DNA damaging agent methyl methanesulfonate. Our results indicate that the regulatory network of c-di-GMP in V. cholerae extends beyond biofilm formation and motility to regulate DNA repair through the VpsR/VpsT c-di-GMP-dependent cascade.IMPORTANCEVibrio cholerae is a prominent human pathogen that is currently causing a pandemic outbreak in Haiti, Yemen, and Ethiopia. The second messenger molecule cyclic di-GMP (c-di-GMP) mediates the transitions in V. cholerae between a sessile biofilm-forming state and a motile lifestyle, both of which are important during V. cholerae environmental persistence and human infections. Here, we report that in V. cholerae c-di-GMP also controls DNA repair. We elucidate the regulatory pathway by which c-di-GMP increases DNA repair, allowing this bacterium to tolerate high concentrations of mutagens at high intracellular levels of c-di-GMP. Our work suggests that DNA repair and biofilm formation may be linked in V. cholerae. PMID- 29610213 TI - Coping with an Essential Poison: a Genetic Suppressor Analysis Corroborates a Key Function of c-di-AMP in Controlling Potassium Ion Homeostasis in Gram-Positive Bacteria. AB - Cyclic di-AMP (c-di-AMP) is an important second messenger in bacteria. In most Firmicutes, the molecule is required for growth in complex media but also toxic upon accumulation. In an article on their current study, Zarrella and coworkers present a suppressor analysis of a Streptococcus pneumoniae strain that is unable to degrade c-di-AMP (T. M. Zarrella, D. W. Metzger, and G. Bai, J Bacteriol 200:e00045-18, 2018, https://doi.org/10.1128/JB.00045-18). Their study identifies new links between c-di-AMP and potassium homeostasis and supports the hypothesis that c-di-AMP serves as a second messenger to report about the intracellular potassium concentrations. PMID- 29610211 TI - Chloroplast Translation: Structural and Functional Organization, Operational Control, and Regulation. AB - Chloroplast translation is essential for cellular viability and plant development. Its positioning at the intersection of organellar RNA and protein metabolism makes it a unique point for the regulation of gene expression in response to internal and external cues. Recently obtained high-resolution structures of plastid ribosomes, the development of approaches allowing genome wide analyses of chloroplast translation (i.e., ribosome profiling), and the discovery of RNA binding proteins involved in the control of translational activity have greatly increased our understanding of the chloroplast translation process and its regulation. In this review, we provide an overview of the current knowledge of the chloroplast translation machinery, its structure, organization, and function. In addition, we summarize the techniques that are currently available to study chloroplast translation and describe how translational activity is controlled and which cis-elements and trans-factors are involved. Finally, we discuss how translational control contributes to the regulation of chloroplast gene expression in response to developmental, environmental, and physiological cues. We also illustrate the commonalities and the differences between the chloroplast and bacterial translation machineries and the mechanisms of protein biosynthesis in these two prokaryotic systems. PMID- 29610214 TI - Two-Component Flavin-Dependent Riboflavin Monooxygenase Degrades Riboflavin in Devosia riboflavina. AB - The actinobacterium Microbacterium maritypicum splits riboflavin (vitamin B2) into lumichrome and d-ribose. However, such degradation by other bacteria and the involvement of a two-component flavin-dependent monooxygenase (FMO) in the reaction remain unknown. Here we investigated the mechanism of riboflavin degradation by the riboflavin-assimilating alphaproteobacterium Devosia riboflavina (formerly Pseudomonas riboflavina). We found that adding riboflavin to bacterial cultures induced riboflavin-degrading activity and a protein of the FMO family that had 67% amino acid identity with the predicted riboflavin hydrolase (RcaE) of M. maritypicum MF109. The D. riboflavina genome clustered genes encoding the predicted FMO, flavin reductase (FR), ribokinase, and flavokinase, and riboflavin induced their expression. This finding suggests that these genes constitute a mechanism for utilizing riboflavin as a carbon source. Recombinant FMO (rFMO) protein of D. riboflavina oxidized riboflavin in the presence of reduced flavin mononucleotide (FMN) provided by recombinant FR (rFR), oxidized FMN and NADH, and produced stoichiometric amounts of lumichrome and d ribose. Further investigation of the enzymatic properties of D. riboflavina rFMO indicated that rFMO-rFR coupling accompanied O2 consumption and the generation of enzyme-bound hydroperoxy-FMN, which are characteristic of two-component FMOs. These results suggest that D. riboflavina FMO is involved in hydroperoxy-FMN dependent mechanisms to oxygenize riboflavin and a riboflavin monooxygenase is necessary for the initial step of riboflavin degradation.IMPORTANCE Whether bacteria utilize either a monooxygenase or a hydrolase for riboflavin degradation has remained obscure. The present study found that a novel riboflavin monooxygenase, not riboflavin hydrolase, facilitated this process in D. riboflavina The riboflavin monooxygenase gene was clustered with flavin reductase, flavokinase, and ribokinase genes, and riboflavin induced their expression and riboflavin-degrading activity. The gene cluster is uniquely distributed in Devosia species and actinobacteria, which have exploited an environmental niche by developing adaptive mechanisms for riboflavin utilization. PMID- 29610215 TI - Genetic Control of Genomic Alterations Induced in Yeast by Interstitial Telomeric Sequences. AB - In many organisms, telomeric sequences can be located internally on the chromosome in addition to their usual positions at the ends of the chromosome. In humans, such interstitial telomeric sequences (ITSs) are nonrandomly associated with translocation breakpoints in tumor cells and with chromosome fragile sites (regions of the chromosome that break in response to perturbed DNA replication). We previously showed that ITSs in yeast generated several different types of instability, including terminal inversions (recombination between the ITS and the "true" chromosome telomere) and point mutations in DNA sequences adjacent to the ITS. In the current study, we examine the genetic control of these events. We show that the terminal inversions occur by the single-strand annealing pathway of DNA repair following the formation of a double-stranded DNA break within the ITS. The point mutations induced by the ITS require the error-prone DNA polymerase zeta. Unlike the terminal inversions, these events are not initiated by a double stranded DNA break, but likely result from the error-prone repair of a single stranded DNA gap or recruitment of DNA polymerase zeta in the absence of DNA damage. PMID- 29610216 TI - Hybrid Sterility in Fish Caused by Mitotic Arrest of Primordial Germ Cells. AB - Sterility in hybrid animals is widely known to be due to a cytological mechanism of aberrant homologous chromosome pairing during meiosis in hybrid germ cells. In this study, the gametes of four marine fish species belonging to the Sciaenid family were artificially fertilized, and germ cell development was examined at the cellular and molecular levels. One of the intergeneric hybrids had gonads that were testis-like in structure, small in size, and lacked germ cells. Specification of primordial germ cells (PGCs) and their migration toward genital ridges occurred normally in hybrid embryos, but these PGCs did not proliferate in the hybrid gonads. By germ cell transplantation assay, we showed that the gonadal microenvironment in hybrid recipients produced functional donor-derived gametes, suggesting that the germ cell-less phenotype was caused by cell autonomous proliferative defects of hybrid PGCs. This is the first evidence of mitotic arrest of germ cells causing hybrid sterility in animals. PMID- 29610218 TI - April 2nd Question. PMID- 29610217 TI - Sequence-Based Analysis of Lipid-Related Metabolites in a Multiethnic Study. AB - Small molecule lipid-related metabolites are important components of fatty acid and steroid metabolism-two important contributors to human health. This study investigated the extent to which rare and common genetic variants spanning the human genome influence the lipid-related metabolome. Sequence data from 1552 European-Americans (EA) and 1872 African-Americans (AA) were analyzed to examine the impact of common and rare variants on the levels of 102 circulating lipid related metabolites measured by a combination of chromatography and mass spectroscopy. We conducted single variant tests [minor allele frequency (MAF) > 5%, statistical significance P-value <= 2.45 * 10-10] and tests aggregating rare variants (MAF <= 5%) across multiple genomic motifs, such as coding regions and regulatory domains, and sliding windows. Multiethnic meta-analyses detected 53 lipid-related metabolites-locus pairs, which were inspected for evidence of consistent signal between the two ethnic groups. Thirty-eight lipid-related metabolite-genomic region associations were consistent across ethnicities, among which seven were novel. The regions contain genes that are related to metabolite transport (SLC10A1) and metabolism (SCD, FDX1, UGT2B15, and FADS2). Six of the seven novel findings lie in expression quantitative trait loci affecting the expression levels of 14 surrounding genes in multiple tissues. Imputed expression levels of 10 of the affected genes were associated with four corresponding lipid related traits in at least one tissue. Our findings offer valuable insight into circulating lipid-related metabolite regulation in a multiethnic population. PMID- 29610219 TI - Volume of Light Versus Moderate-to-Vigorous Physical Activity: Similar Benefits for All-Cause Mortality? AB - BACKGROUND: It is unclear whether the greater benefits of moderate-to-vigorous physical activity (PA) over light PA are attributed to the higher-intensity PA or simply the greater volume of PA accumulated per unit time for moderate-to vigorous PA. We examined this question using estimates of the volume of light and moderate-to-vigorous PA in relation to all-cause mortality. METHODS AND RESULTS: We used National Health and Nutrition Examination Survey 2003-2006 accelerometer records in adults (>=40 years; n=4840) and mortality data collected through 2011 (n=700 deaths). We estimated intensity-specific PA volume using activity counts (AC) accumulated in light (100-759 AC/min), moderate-to-vigorous PA (>=760 AC/min), and total PA (>=100 AC/min). We examined quartiles of each exposure using Cox proportional hazard models (hazard ratios [95% confidence interval) adjusted for demographic and behavioral risk factors, health status, and body mass index. Mortality risk was less across increasing quartiles of light PA volume (AC*1000) when compared with the least quartile (AC <=61.8); the least risk occurred in the upper quartile of light PA, AC >98.5 (hazard ratios=0.69, 95% confidence interval: 0.47, 1.00, P trend <=0.05). The benefits for mortality risk were greater across quartiles of moderate-to-vigorous PA and reached a hazard ratio of 0.28 (95% confidence interval: 0.17, 0.46, P trend <=0.05) for AC >187.9, when compared with the referent group (AC <=50.8). Results examining various combinations of light and moderate-to-vigorous intensity-specific volumes demonstrated the strong influence of total activity on mortality risk. CONCLUSIONS: In this population, increasing light PA was associated with less mortality, but at an approximately equal volume of PA, moderate-to-vigorous PA appeared to have greater benefits. PMID- 29610221 TI - Comparative analysis of large macular hole surgeries using an internal limiting membrane: insertion technique versus inverted flap technique. AB - BACKGROUND: To determine whether the internal limiting membrane (ILM) insertion technique is as effective as the inverted ILM flap technique for the initial surgical treatment of eyes with large idiopathic macular holes (MHs). METHODS: This retrospective, non-randomised, comparative clinical study included 41 eyes with large MHs (minimum diameter >500 um) that were treated using the ILM insertion technique or the inverted ILM flap technique. The hole closure rate, postoperative best corrected visual acuity (BCVA) and swept source optical coherence tomography findings were analysed at 6 months after surgery. RESULTS: There were 15 and 26 eyes in the insertion and inverted flap groups, respectively. Hole closure was achieved in all eyes. The mean final BCVA was better in the inverted flap group than in the insertion group (0.527 vs 0.773, p=0.006), although significant postoperative improvements were observed in both groups (p<0.001). Postoperative foveal discolouration was more common in the insertion group than in the inverted flap group (86.7% vs 7.7%, p<0.001). Complete resolution of ellipsoid zone and external limiting membrane defects was observed in 7 and 18 eyes, respectively, in the inverted flap group; in contrast, complete resolution was not observed in any of the eyes in the insertion group (p=0.035 and p<0.001, respectively). CONCLUSION: The ILM insertion technique may be as effective as the inverted ILM flap technique for the closure of large MHs. However, the latter technique results in better recovery of photoreceptor layers and, consequently, better postoperative visual acuity. PMID- 29610222 TI - Two-year follow-up of corneal cross-linking and refractive surface ablation in patients with asymmetric corneal topography. AB - AIMS: To evaluate the safety and efficacy of corneal cross-linking (CXL) followed by photorefractive keratectomy (PRK) for refractive correction in patients with bilateral asymmetric topography. METHODS: Forty-four patients (88 eyes) were enrolled in this prospective randomised clinical trial. CXL with subsequent PRK after 6 months was performed in one eye (study group), and PRK alone was performed in contralateral eyes (control group). Patients were followed for 24 months after PRK. Outcome measures investigated included visual acuity (VA), refraction, aberrometry, topography, pachymetry and endothelial cell count. Groups were compared with linear mixed regression and repeated measures logistic regression. Multiple comparison adjustment with the Holm procedure was performed. RESULTS: At baseline, the logMAR VA (best spectacle corrected) in study and control groups was 0.12+/-0.13 (mean+/-SD) and 0.08D+/-0.14, respectively, and axial inferior-superior index (IS) (topographic IS) in study and control groups were 0.59D+/-0.31D and 0.58D+/-0.32D, respectively. After 24 months, a mean under correction of -0.50D was observed in both groups. Change from baseline in logMAR VA in study and control groups was 0.00D+/-0.08D and -0.02D+/-0.10D, respectively. Frequency of haze at 30 months in study and control group eyes was, respectively, 18.2% and 4.6% (p=0.05). There was no statistical difference between groups in spherical aberration and coma after adjustment for multiple comparisons. CONCLUSIONS: Non-simultaneous CXL followed by PRK may be performed safely, and refractive results over a 2-year follow-up are highly similar in virgin and previously cross-linked corneas. Despite using mitomycin C, corneal haze can be significantly higher in the first year after PRK in eyes pretreated with CXL. PMID- 29610223 TI - What's happening in Neurology(r). PMID- 29610224 TI - What's happening in Neurology(r)Clinical Practice. PMID- 29610225 TI - What's happening in Neurology(r)Genetics. PMID- 29610226 TI - What's happening in Neurology(r)Neuroimmunology & Neuroinflammation. PMID- 29610227 TI - What's happening in Innovations in Care Delivery. PMID- 29610228 TI - Video NeuroImages: Paraneoplastic spinal myoclonus associated with Caspr2 antibodies. PMID- 29610229 TI - International Issues: A guide to US academic global health programs in neurology. PMID- 29610230 TI - Editors' note: Magnesium, hemostasis, and outcomes in patients with intracerebral hemorrhage. PMID- 29610231 TI - Reader response: Magnesium, hemostasis, and outcomes in patients with intracerebral hemorrhage. PMID- 29610232 TI - Author response: Magnesium, hemostasis, and outcomes in patients with intracerebral hemorrhage. PMID- 29610233 TI - Editors' note: 25-Hydroxyvitamin D deficiency and risk of MS among women in the Finnish Maternity Cohort. PMID- 29610234 TI - Reader response: 25-Hydroxyvitamin D deficiency and risk of MS among women in the Finnish Maternity Cohort. PMID- 29610236 TI - Randomized dose-escalation trial of elamipretide in adults with primary mitochondrial myopathy. PMID- 29610235 TI - Author response: 25-Hydroxyvitamin D deficiency and risk of MS among women in the Finnish Maternity Cohort. PMID- 29610237 TI - Clinical Reasoning: A 53-year-old woman with headache and altered mental status. PMID- 29610238 TI - Teaching NeuroImages: Autosomal recessive spastic ataxia of Charlevoix-Saguenay: Typical MRI findings. PMID- 29610239 TI - Teaching Video NeuroImages: Sustained clonus of the upper extremity. PMID- 29610241 TI - A Conversation with Steve Henikoff. PMID- 29610240 TI - A Conversation with Daniel Durocher. PMID- 29610242 TI - A Conversation with Ian Hickson. PMID- 29610244 TI - A Conversation with Bernard de Massy. PMID- 29610243 TI - Impact of Centrosome Aberrations on Chromosome Segregation and Tissue Architecture in Cancer. AB - Centrosomes determine the disposition of microtubule networks and thereby contribute to regulate cell shape, polarity, and motility, as well as chromosome segregation during cell division. Additionally, centrioles, the core components of centrosomes, are required for the formation of cilia and flagella. Mutations in genes coding for centrosomal and centriolar proteins are responsible for several human diseases, foremost ciliopathies and developmental disorders resulting in small brains (primary microcephaly) or small body size (dwarfism). Moreover, a long-standing postulate implicates numerical and/or structural centrosome aberrations in the etiology of cancer. In this review, we will discuss recent work on the role of centrosome aberrations in the promotion of genome instability and the disruption of tissue architecture, two hallmarks of human cancers. We will emphasize recent studies on the impact of centrosome aberrations on the polarity of epithelial cells cultured in three-dimensional spheroid models. Collectively, the results from these in vitro systems suggest that different types of centrosome aberrations can promote invasive behavior through different pathways. Particularly exciting is recent evidence indicating that centrosome aberrations may trigger the dissemination of potentially metastatic cells through a non-cell-autonomous mechanism. PMID- 29610245 TI - Function of Junk: Pericentromeric Satellite DNA in Chromosome Maintenance. AB - Satellite DNAs are simple tandem repeats that exist at centromeric and pericentromeric regions on eukaryotic chromosomes. Unlike the centromeric satellite DNA that comprises the vast majority of natural centromeres, function(s) for the much more abundant pericentromeric satellite repeats are poorly understood. In fact, the lack of coding potential allied with rapid divergence of repeat sequences across eukaryotes has led to their dismissal as "junk DNA" or "selfish parasites." Although implicated in various biological processes, a conserved function for pericentromeric satellite DNA remains unidentified. We have addressed the role of satellite DNA through studying chromocenters, a cytological aggregation of pericentromeric satellite DNA from multiple chromosomes into DNA-dense nuclear foci. We have shown that multivalent satellite DNA-binding proteins cross-link pericentromeric satellite DNA on chromosomes into chromocenters. Disruption of chromocenters results in the formation of micronuclei, which arise by budding off the nucleus during interphase. We propose a model that satellite DNAs are critical chromosome elements that are recognized by satellite DNA-binding proteins and incorporated into chromocenters. We suggest that chromocenters function to preserve the entire chromosomal complement in a single nucleus, a fundamental and unquestioned feature of eukaryotic genomes. We speculate that the rapid divergence of satellite DNA sequences between closely related species results in discordant chromocenter function and may underlie speciation and hybrid incompatibility. PMID- 29610246 TI - Substantial Evidence for Auxin Secretory Vesicles. PMID- 29610247 TI - MicroProteins as the First Step toward a Master Key for Posttranslational Regulation. PMID- 29610248 TI - Correction to: Moving the Goalposts Into Unblinded Territory: The Larger Lessons of DEFER and FAME 2 and Their Implications for Shifting End Points in ISCHEMIA ['Faith Healing' and 'Subtraction Anxiety' in Unblinded Trials of Procedures: Lessons from DEFER and FAME-2 for End Points in the ISCHEMIA Trial]. PMID- 29610249 TI - The Ultimate Goal Post. PMID- 29610251 TI - Corrigendum: Transcription rate strongly affects splicing fidelity and cotranscriptionality in budding yeast. PMID- 29610250 TI - Corrigendum: Direct determination of diploid genome sequences. PMID- 29610252 TI - Enhancing Postdischarge Asthma Care by Using Pharmacy Claims and Telephone Follow up. AB - BACKGROUND AND OBJECTIVES: Asthma is a common reason for hospital readmission. The majority of children are not receiving adequate preventive care after discharge. Our objective is to decrease return visits to the emergency department (ED) or hospital for asthma through a series of interventions (eg, access to real time claims data and structured follow-up phone calls) designed to increase preventive care. METHODS: We performed a single-site quality improvement project for children 2 to 17 years old discharged with asthma from January 2010 to March 2014. We compared a baseline period and a stepwise intervention period including the following: brief follow-up phone calls to families, access to medication claims data, and structured phone calls. The primary outcome of return visits to the ED or hospital and preventive care outcomes (controller refills and ambulatory visits) up to 90 days were assessed using state all-payer and Medicaid data sets. Interrupted time series analysis was used to investigate secular trends. RESULTS: Six hundred and seventy-seven asthma discharges were analyzed. The majority of children were 2 to 7 years old, African American, and insured by Medicaid. Successful phone contact occurred in 57% of encounters. Ninety-day revisits to the ED or hospital demonstrated a significant decline (15% to 8%; P < .05), but preventive care measures did not improve. CONCLUSIONS: A process to improve transitions for children who are hospitalized with an asthma exacerbation that includes follow-up phone calls was associated with a decrease in ED or hospital revisits. The lack of a detectable increase in preventive care warrants further exploration. PMID- 29610253 TI - Deconstructing Pneumococcal Progression from Colonization to Disease. AB - Despite advances in treatment and prevention, the pneumococcus continues to be a dominant cause of severe pneumonia and sepsis and of otitis media, sinusitis, and nonbacteremic pneumonia. Lewnard and colleagues (Infect Immun 86:e00727-17, 2018, https://doi.org/10.1128/IAI.00727-17) used a unique data set of nasopharyngeal and middle ear fluid samples to provide further insight into the progression of nasopharyngeal pneumococcal colonization to disease. They report the comparative rate of progression from colonization to otitis media by serotype, providing insight into how conjugate vaccines that do not reduce the overall prevalence of pneumococci in the nasopharynx dramatically impact the incidence of acute and complex otitis media. PMID- 29610254 TI - Hypervirulent Group A Streptococcus of Genotype emm3 Invades the Vascular System in Pulmonary Infection of Mice. AB - Natural mutations of the two-component regulatory system CovRS are frequently associated with invasive group A Streptococcus (GAS) isolates and lead to the enhancement of virulence gene expression, innate immune evasion, systemic dissemination, and virulence. How CovRS mutations enhance systemic dissemination is not well understood. A hypervirulent GAS isolate of the emm3 genotype, MGAS315, was characterized using a mouse model of pulmonary infection to understand systemic dissemination. This strain has a G1370T mutation in the sensor kinase covS gene of CovRS. Intratracheal inoculation of MGAS315 led to the lung infection that displayed extensive Gram staining at the alveolar ducts, alveoli, and peribronchovascular and perivascular interstitium. The correction of the covS mutation did not alter the infection at the alveolar ducts and alveoli but prevented GAS invasion of the peribronchovascular and perivascular interstitium. Furthermore, the covS mutation allowed MGAS315 to disrupt and degrade the smooth muscle and endothelial layers of the blood vessels, directly contributing to systemic dissemination. It is concluded that hypervirulent emm3 GAS covS mutants can invade the perivascular interstitium and directly attack the vascular system for systemic dissemination. PMID- 29610255 TI - PDL-1 Blockade Prevents T Cell Exhaustion, Inhibits Autophagy, and Promotes Clearance of Leishmania donovani. AB - Leishmania donovani is a causative pathogen of potentially fatal visceral leishmaniasis (VL). Therapeutic agents are available; however, their use is limited because of high cost, serious side effects, and development of antimicrobial resistance. Protective immunity against VL depends on CD4+ Th1 cell mediated immunity. Studies have shown that progression of VL is due to exhaustion of T cells; however, the mechanism involved is not clearly understood. Here, we examined the role of PD1/PDL-1 in the pathogenesis of VL by using a murine model of VL. Our data indicate that L. donovani is able to elicit initial expansion of gamma interferon-producing CD4+ Th1 and CD8+ T cells at day 7 postinfection (p.i.); however, the frequency of those cells and inflammatory response decreased at day 21 p.i., despite persistence of parasites. Persistent infection-induced expansion of interleukin-10+ FOXP3+ Treg and CD4+ and CD8+ T cells expressing PD1. Blocking of PDL-1 signaling in vivo resulted in restoration of protective type 1 responses by both CD4+ and CD8+ T cells, which resulted in a significant decrease in the parasite burden. Mechanistically, PDL-1 blocking inhibited autophagy, a cellular degradation process hijacked by Leishmania to acquire host cell nutrients for their survival. Inhibition of autophagy was marked by decreased lipidation of microtubule-associated protein 1 light chain 3, a marker of autophagosome formation, and P62 accumulation. Together, our findings show for the first time that anti-PDL-1 antibody is an effective therapeutic approach for restoration of effector arms of protective immunity against VL and subsequent parasite clearance. PMID- 29610256 TI - Myeloid differentiation factor 88 (MyD88) and IL-1R1 signaling contribute to resistance to Coccidioides immitis. AB - Rodents are a natural host for the dimorphic pathogenic fungi Coccidioides immitis and posadasii, and mice are a good model for human infection. Humans and rodents both express Dectin-1 and TLR2 on myeloid cells and those receptors collaborate to maximize the cytokine/chemokine responses to spherules (the tissue form of the fungi), and to formalin killed spherules (FKS). We showed that Dectin 1 is necessary for resistance to pulmonary coccidioidomycosis, but the importance of TLR2 in vivo is uncertain. MyD88 is the adapter protein for TLR2 and 4, and IL 1R1 and IL-18R1. MyD88/TRIF -/-and MyD88 -/- mice were equally susceptible to C. immitis infection, compared to C57BL/6 (B6) controls. Of the four surface receptors, only IL-1R1 was required for resistance to C. immitis, partially explaining the susceptibility of MyD88 -/- mice. We also found that FKS stimulated production of IL-1Ra by BMDC, independent of MyD88 and Dectin-1. There also was a very high concentration of IL-1Ra in the lungs of infected B6 mice, supporting the potential importance of this regulatory IL-1 family protein in the largely ineffective response of B6 mice to coccidioidomycosis. These results suggest that IL-1R1 signaling is important for defense against C. immitis infection. PMID- 29610257 TI - Comparison of Immunogenicity and Protection of Two Pneumococcal Protein Vaccines Based on PsaA and PspA. AB - Streptococcus pneumoniae is a major cause of invasive pneumococcal disease, septicemia, and meningitis that can result in high morbidity rates in children under 5 years old. The current polysaccharide-based vaccines can provide type specific immunity, but a broad-spectrum vaccine would provide greater coverage. Therefore, developing pneumococcal-protein-based vaccines that can extend to more serum types is highly important. In this study, we vaccinated mice via the subcutaneous (s.c.) route with a systemic vaccine that is a mixture of fusion protein PsaA-PspA23 and a single protein, PspA4, with aluminum hydroxide as an adjuvant. As a comparison, mice were immunized intranasally with a mucosal vaccine that is a mixture of PspA2-PA-BLP (where PA is protein anchor and BLP is bacterium-like particle) and PspA4-PA-BLP, via the intranasal (i.n.) route. The two immunization processes were followed by challenge with Streptococcus pneumoniae bacteria from two different PspA families. Specific IgG titers in the serum and specific IgA titers in the mucosa were determined following immunizations. Bacterial loads and survival rates after challenge were compared. Both the systemic vaccine and the mucosal vaccine induced a significant increase of IgG against PspAs. Only the mucosal vaccine also induced specific IgA in the mucosa. The two vaccines provided protection, but each vaccine showed an advantage. The systemic vaccine induced higher levels of serum antibodies, whereas the mucosal vaccine limited the bacterial load in the lung and blood. Therefore, coimmunizations with the two types of vaccines may be implemented in the future. PMID- 29610258 TI - Certhrax Is an Antivirulence Factor for the Anthrax-Like Organism Bacillus cereus Strain G9241. AB - Bacillus cereus G9241 caused a life-threatening anthrax-like lung infection in a previously healthy human. This strain harbors two large virulence plasmids, pBCXO1 and pBC210, that are absent from typical B. cereus isolates. The pBCXO1 plasmid is nearly identical to pXO1 from Bacillus anthracis and carries genes (pagA1, lef, and cya) for anthrax toxin components (protective antigen [called PA1 in G9241], lethal factor [LF], and edema factor [EF], respectively). The plasmid also has an intact hyaluronic acid capsule locus. The pBC210 plasmid has a tetrasaccharide capsule locus, a gene for a PA1 homolog called PA2 (pagA2), and a gene (cer) for Certhrax, an ADP-ribosyltransferase toxin that inactivates vinculin. LF, EF, and Certhrax require PA for entry into cells. In this study, we asked what role PA1, PA2, LF, and Certhrax play in the pathogenicity of G9241. To answer this, we generated isogenic deletion mutations in the targeted toxin gene components and then assessed the strains for virulence in highly G9241 susceptible (A/J) and moderately G9241-sensitive (C57BL/6) mice. We found that full virulence of G9241 required PA1 and LF, while PA2 contributed minimally to pathogenesis of G9241 but could not functionally replace PA1 as a toxin-binding subunit in vivo Surprisingly, we discovered that Certhrax attenuated the virulence of G9241; i.e., a Deltacer Deltalef mutant strain was more virulent than a Deltalef mutant strain following subcutaneous inoculation of A/J mice. Moreover, the enzymatic activity of Certhrax contributed to this phenotype. We concluded that Certhrax acts as an antivirulence factor in the anthrax-like organism B. cereus G9241. PMID- 29610259 TI - The Host Antimicrobial Protein Calgranulin C Participates in the Control of Campylobacter jejuni Growth via Zinc Sequestration. AB - Campylobacter jejuni is a leading cause of bacterially derived gastroenteritis worldwide. Campylobacter is most commonly acquired through the consumption of undercooked poultry meat or through drinking contaminated water. Following ingestion, Campylobacter adheres to the intestinal epithelium and mucus layer, causing toxin-mediated inflammation and inhibition of fluid reabsorption. Currently, the human response to infection is relatively unknown, and animal hosts that model these responses are rare. As such, we examined patient fecal samples for the accumulation of the neutrophil protein calgranulin C during infection with Campylobacter jejuni In response to infection, calgranulin C was significantly increased in the feces of humans. To determine whether calgranulin C accumulation occurs in an animal model, we examined disease in ferrets. Ferrets were effectively infected by C. jejuni, with peak fecal loads observed at day 3 postinfection and full resolution by day 12. Serum levels of interleukin-10 (IL 10) and tumor necrosis factor alpha (TNF-alpha) significantly increased in response to infection, which resulted in leukocyte trafficking to the colon. As a result, calgranulin C increased in the feces of ferrets at the time when C. jejuni loads decreased. Further, the addition of purified calgranulin C to C. jejuni cultures was found to inhibit growth in a zinc-dependent manner. These results suggest that upon infection with C. jejuni, leukocytes trafficked to the intestine release calgranulin C as a mechanism for inhibiting C. jejuni growth. PMID- 29610260 TI - Protein Acetylation Mediated by YfiQ and CobB Is Involved in the Virulence and Stress Response of Yersinia pestis. AB - Recent studies revealed that acetylation is a widely used protein modification in prokaryotic organisms. The major protein acetylation acetyltransferase YfiQ and the sirtuin-like deacetylase CobB have been found to be involved in basic physiological processes, such as primary metabolism, chemotaxis, and stress responses, in Escherichia coli and Salmonella However, little is known about protein acetylation modifications in Yersinia pestis, a lethal pathogen responsible for millions of human deaths in three worldwide pandemics. Here we found that Yp_0659 and Yp_1760 of Y. pestis encode the major protein acetylation acetyltransferase YfiQ and the sirtuin-like deacetylase CobB, respectively, which can acetylate and deacetylate PhoP enzymatically in vitro Protein acetylation impairment in cobB and yfiQ mutants greatly decreased bacterial tolerance to cold, hot, high-salt, and acidic environments. Our comparative transcriptomic data revealed that the strongly decreased tolerance to stress stimuli was probably related to downregulation of the genes encoding the heat shock proteins (HtpG, HslV, HslR, and IbpA), cold shock proteins (CspC and CspA1), and acid resistance proteins (HdeB and AdiA). We found that the reversible acetylation mediated by CobB and YfiQ conferred attenuation of virulence, probably partially due to the decreased expression of the psaABCDEF operon, which encodes Psa fimbriae that play a key role in virulence of Y. pestis This is the first report, to our knowledge, on the roles of protein acetylation modification in stress responses, biofilm formation, and virulence of Y. pestis. PMID- 29610261 TI - Association of Cancer Cell Type and Extracellular Vesicles With Coagulopathy in Patients With Lung Cancer and Stroke. AB - BACKGROUND AND PURPOSE: Coagulopathy is an important cause of stroke in cancer patients. However, underlying mechanisms and clinical factors related to coagulopathy remain unclear. We hypothesized that certain characteristics of cancer affect coagulopathy in patients with lung cancer and ischemic stroke. METHODS: Consecutive patients with active lung cancer and acute ischemic stroke were prospectively studied. Volume and pattern of acute brain infarcts and plasma levels of circulating tumor extracellular vesicles (EVs) were measured using flow cytometry. In vitro experiments investigated the pathophysiological mechanisms underlying cancer-associated coagulopathy. RESULTS: Of 114 patients, 95 (83.3%) had an adenocarcinoma cell type and 95 (83.3%) had distant metastasis. Acute brain infarct volumes were larger and circulating EV levels were higher in patients with an adenocarcinoma cell type than in those with other cell types. The presence of metastasis was not associated with infarct volume or circulating EV levels. Coagulation assays demonstrated dose-dependent shorter clotting times after treatment with EVs from adenocarcinoma cell lines than with the use of EVs from squamous cell carcinoma. These findings were confirmed by coagulation assays using circulating EVs from patients with adenocarcinoma and stroke and from those with conventional stroke mechanisms. CONCLUSIONS: Our findings indicate that cancer cell type is associated with circulating EV levels and coagulopathy in patients with lung cancer and stroke. PMID- 29610262 TI - Long-Term Risk of Cardiovascular Disease in Women Who Have Had Infants With Heart Defects. AB - BACKGROUND: The possibility that congenital heart defects signal a familial predisposition to cardiovascular disease has not been investigated. We aimed to determine whether the risk of cardiovascular disorders later in life was higher for women who have had newborns with congenital heart defects. METHODS: We studied a cohort of 1 084 251 women who had delivered infants between 1989 and 2013 in Quebec, Canada. We identified women whose infants had critical, noncritical, or no heart defects, and tracked the women over time for future hospitalizations for cardiovascular disease, with follow-up extending up to 25 years past pregnancy. We calculated the incidence of cardiovascular hospitalization per 1000 person-years, and used Cox proportional hazards regression to estimate hazard ratios and 95% confidence intervals (CIs) for the association between infant heart defects and risk of maternal cardiovascular hospitalization. Models were adjusted for age, parity, preeclampsia, comorbidity, material deprivation, and time period. RESULTS: Women whose infants had heart defects had a higher overall incidence of cardiovascular hospitalization. There were 3.38 cardiovascular hospitalizations per 1000 person-years for those with critical defects (95% CI, 2.67-4.27), 3.19 for noncritical defects (95% CI, 2.96 3.45), and 2.42 for no heart defects (95% CI, 2.39-2.44). In comparison with no heart defects, women whose infants had critical defects had a hazard ratio of 1.43 (95% CI, 1.13-1.82) for any cardiovascular hospitalization, and women whose infants had noncritical defects had a hazard ratio of 1.24 (95% CI, 1.15-1.34), in adjusted models. Risks of specific causes of cardiovascular hospitalization, including myocardial infarction, heart failure, and other atherosclerotic disorders, were also greater for mothers of infants with congenital heart defects than with no defects. CONCLUSIONS: Women whose infants have congenital heart defects have a greater risk of cardiovascular hospitalization later in life. Congenital heart defects in offspring may be an early marker of predisposition to cardiovascular disease. PMID- 29610264 TI - Relevant Fetal Epigenetic Modifications Result From a Diabetic Intrauterine Environment: Healthy Aging Starts With a Healthy Pregnancy. PMID- 29610263 TI - Cardiac Dysfunction and Metabolic Inflexibility in a Mouse Model of Diabetes Without Dyslipidemia. AB - Diabetes is a well-established risk factor for heart disease, leading to impaired cardiac function and a metabolic switch toward fatty acid usage. In this study, we investigated if hyperglycemia/hypoinsulinemia in the absence of dyslipidemia is sufficient to drive these changes and if they can be reversed by restoring euglycemia. Using the betaV59M mouse model, in which diabetes can be rapidly induced and reversed, we show that stroke volume and cardiac output were reduced within 2 weeks of diabetes induction. Flux through pyruvate dehydrogenase was decreased, as measured in vivo by hyperpolarized [1-13C]pyruvate MRS. Metabolomics showed accumulation of pyruvate, lactate, alanine, tricarboxyclic acid cycle metabolites, and branched-chain amino acids. Myristic and palmitoleic acid were decreased. Proteomics revealed proteins involved in fatty acid metabolism were increased, whereas those involved in glucose metabolism decreased. Western blotting showed enhanced pyruvate dehydrogenase kinase 4 (PDK4) and uncoupling protein 3 (UCP3) expression. Elevated PDK4 and UCP3 and reduced pyruvate usage were present 24 h after diabetes induction. The observed effects were independent of dyslipidemia, as mice showed no evidence of elevated serum triglycerides or lipid accumulation in peripheral organs (including the heart). The effects of diabetes were reversible, as glibenclamide therapy restored euglycemia, cardiac metabolism and function, and PDK4/UCP3 levels. PMID- 29610265 TI - Preconception Blood Pressure Levels and Reproductive Outcomes in a Prospective Cohort of Women Attempting Pregnancy. AB - : Elevated blood pressure in young adulthood is an early risk marker for cardiovascular disease. Despite a strong biological rationale, little research has evaluated whether incremental increases in preconception blood pressure have early consequences for reproductive health. We evaluated preconception blood pressure and fecundability, pregnancy loss, and live birth in the EAGeR trial (Effects of Aspirin on Gestational and Reproduction; 2007-2011), a randomized clinical trial of aspirin and reproductive outcomes among 1228 women attempting pregnancy with a history of pregnancy loss. Systolic and diastolic blood pressure were measured during preconception in the first observed menstrual cycle and in early pregnancy and used to derive mean arterial pressure. Fecundability was assessed as number of menstrual cycles until pregnancy, determined through human chorionic gonadotropin testing. Pregnancy loss included both human chorionic gonadotropin-detected and clinical losses. Analyses adjusted for treatment assignment, age, body mass index, race, marital status, smoking, parity, and time since last loss. Mean preconception systolic and diastolic blood pressure were 111.6 mm Hg (SD, 12.1) and 72.5 (SD, 9.4) mm Hg. Risk of pregnancy loss increased 18% per 10 mm Hg increase in diastolic blood pressure (95% confidence interval, 1.03-1.36) and 17% per 10 mm Hg increase in mean arterial pressure (95% confidence interval, 1.02-1.35) in adjusted analyses. Findings were similar for early pregnancy blood pressure. Preconception blood pressure was not related to fecundability or live birth in adjusted analyses. Findings suggest that preconception blood pressure among healthy women is associated with pregnancy loss, and lifestyle interventions targeting blood pressure among young women may favorably impact reproductive health. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00467363. PMID- 29610267 TI - Case of Severe Hypertension and Nephrotic Range Proteinuria. PMID- 29610266 TI - Causative Effects of Genetically Determined High Maternal/Fetal Endothelin-1 on Preeclampsia-Like Conditions in Mice. AB - Endothelin-1 (ET-1) is implicated in the pathophysiology of preeclampsia. An association between an EDN1 gene polymorphism with high ET-1 and preeclampsia was reported in humans, but their cause and effect relationships have not been defined. We examined the pregnancy effects in mice with a modified Edn1 allele that increases mRNA stability and thus ET-1 production. Heterozygous Edn1H/+ females showed no obvious abnormalities before pregnancy, but when mated with wild-type (WT) males developed a full spectrum of preeclampsia-like phenotypes, including increased systolic blood pressure, proteinuria, glomerular endotheliosis, and intrauterine fetal growth restriction. At 7.5 days post coitus, the embryos from Edn1H/+ dams, regardless of their Edn1 genotype, lagged 12 hours in development compared with embryos from WT dams, had disoriented ectoplacental cones, and retained high E-cadherin expression. In contrast, WT females mated with Edn1H/+ males, which also carried half of the fetuses with Edn1H/+ genotype, showed a mild systolic blood pressure increase only. These WT dams had 2* higher plasma soluble fms-like tyrosine kinase-1 than WT dams mated with WT males. In human first trimester trophoblast cells, pharmacological doses of ET-1 increased the cellular sFlt1 transcripts and protein secretion via both type A and B ET-1 receptors. Our data demonstrate that high maternal ET-1 production causes preeclampsia-like phenotypes during pregnancy, affecting both initial stage of trophoblast differentiation/invasion and maternal peripheral vasculature during late gestation. High fetal ET-1 production, however, could cause increased soluble fms-like tyrosine kinase-1 in the maternal circulation and contribute to blood pressure elevation. PMID- 29610268 TI - Diabetes Mellitus in Pregnancy Leads to Growth Restriction and Epigenetic Modification of the Srebf2 Gene in Rat Fetuses. AB - Diabetic pregnancy is correlated with increased risk of metabolic and neurological disorders in the offspring putatively mediated epigenetically. Little is known about epigenetic changes already present in fetuses of diabetic pregnancies. We aimed at characterizing the perinatal environment after preexisting maternal diabetes mellitus and at identifying relevant epigenetic changes in the fetus. We focused on the transcription factor Srebf2 (sterol regulatory element binding transcription factor 2), a master gene in regulation of cholesterol metabolism. We tested whether diabetic pregnancy induces epigenetic changes in the Srebf2 promoter and if they become manifest in altered Srebf2 gene expression. We worked with a transgenic rat model of type 2 diabetes mellitus (Tet29) in which the insulin receptor is knocked down by doxycycline induced RNA interference. Doxycycline was administered preconceptionally to Tet29 and wild-type control rats. Only Tet29 doxycycline dams were hyperglycemic, hyperinsulinemic, and hyperlipidemic. Gene expression was analyzed with quantitative real-time reverse transcriptase polymerase chain reaction and CpG promoter methylation with pyrosequencing. Immunohistochemistry was performed on fetal brains. Fetuses from diabetic Tet29 dams were hyperglycemic and growth restricted at the end of pregnancy. They further displayed decreased liver and brain weight with concomitant decreased microglial activation in the hippocampus in comparison to fetuses of normoglycemic mothers. Importantly, diabetic pregnancy induced CpG hypermethylation of the Srebf2 promoter in the fetal liver and brain, which was associated with decreased Srebf2 gene expression. In conclusion, diabetic and hyperlipidemic pregnancy induces neurological, metabolic, and epigenetic alterations in the rat fetus. Srebf2 is a potential candidate mediating intrauterine environment-driven epigenetic changes and later diabetic offspring health. PMID- 29610269 TI - Resistant Hypertension: Trials and Tribulations. PMID- 29610270 TI - Targeted Proteomics Guided by Label-free Quantitative Proteome Analysis in Saliva Reveal Transition Signatures from Health to Periodontal Disease. AB - Periodontal diseases are among the most prevalent worldwide, but largely silent, chronic diseases. They affect the tooth-supporting tissues with multiple ramifications on life quality. Their early diagnosis is still challenging, due to lack of appropriate molecular diagnostic methods. Saliva offers a non-invasively collectable reservoir of clinically relevant biomarkers, which, if utilized efficiently, could facilitate early diagnosis and monitoring of ongoing disease. Despite several novel protein markers being recently enlisted by discovery proteomics, their routine diagnostic application is hampered by the lack of validation platforms that allow for rapid, accurate and simultaneous quantification of multiple proteins in large cohorts. Here we carried out a pipeline of two proteomic platforms; firstly, we applied open ended label-free quantitative (LFQ) proteomics for discovery in saliva (n = 67, including individuals with health, gingivitis, and periodontitis), followed by selected reaction monitoring (SRM)-targeted proteomics for validation in an independent cohort (n = 82). The LFQ platform led to the discovery of 119 proteins with at least 2-fold significant difference between health and disease. The 65 proteins chosen for the subsequent SRM platform included 50 functionally related proteins derived from the significantly enriched processes of the LFQ data, 11 from literature-mining, and four house-keeping ones. Among those, 60 were reproducibly quantifiable proteins (92% success rate), represented by a total of 143 peptides. Machine-learning modeling led to a narrowed-down panel of five proteins of high predictive value for periodontal diseases with maximum area under the receiver operating curve >0.97 (higher in disease: Matrix metalloproteinase-9, Ras-related protein-1, Actin-related protein 2/3 complex subunit 5; lower in disease: Clusterin, Deleted in Malignant Brain Tumors 1). This panel enriches the pool of credible clinical biomarker candidates for diagnostic assay development. Yet, the quantum leap brought into the field of periodontal diagnostics by this study is the application of the biomarker discovery-through-verification pipeline, which can be used for validation in further cohorts. PMID- 29610271 TI - Mining the Human Tissue Proteome for Protein Citrullination. AB - Citrullination is a posttranslational modification of arginine catalyzed by five peptidylarginine deiminases (PADs) in humans. The loss of a positive charge may cause structural or functional alterations, and while the modification has been linked to several diseases, including rheumatoid arthritis (RA) and cancer, its physiological or pathophysiological roles remain largely unclear. In part, this is owing to limitations in available methodology to robustly enrich, detect, and localize the modification. As a result, only a few citrullination sites have been identified on human proteins with high confidence. In this study, we mined data from mass-spectrometry-based deep proteomic profiling of 30 human tissues to identify citrullination sites on endogenous proteins. Database searching of ~70 million tandem mass spectra yielded ~13,000 candidate spectra, which were further triaged by spectrum quality metrics and the detection of the specific neutral loss of isocyanic acid from citrullinated peptides to reduce false positives. Because citrullination is easily confused with deamidation, we synthetized ~2,200 citrullinated and 1,300 deamidated peptides to build a library of reference spectra. This led to the validation of 375 citrullination sites on 209 human proteins. Further analysis showed that >80% of the identified modifications sites were new, and for 56% of the proteins, citrullination was detected for the first time. Sequence motif analysis revealed a strong preference for Asp and Gly, residues around the citrullination site. Interestingly, while the modification was detected in 26 human tissues with the highest levels found in the brain and lung, citrullination levels did not correlate well with protein expression of the PAD enzymes. Even though the current work represents the largest survey of protein citrullination to date, the modification was mostly detected on high abundant proteins, arguing that the development of specific enrichment methods would be required in order to study the full extent of cellular protein citrullination. PMID- 29610272 TI - AGE Content of a Protein Load Is Responsible for Renal Performances: A Pilot Study. AB - OBJECTIVE: Chronic kidney disease is associated with higher morbidity and mortality in patients with diabetes. A low-protein diet is recommended to slow diabetic nephropathy progression because each protein load leads to renal hemodynamic variations. The aim of our study was to evaluate whether the advanced glycation end products (AGE) content of a protein load is responsible for the protein-induced renal hemodynamic variations in humans. RESEARCH DESIGN AND METHODS: Ten healthy subjects were assigned to a high-protein (1 g/kg) low-AGE (3,000 kU AGE) versus high-AGE (30,000 kU AGE) meal. Renal perfusion, oxygen consumption, and oxygen content were measured before and 120 min after each meal. RESULTS: Renal perfusion (3.2 +/- 0.5 vs. 3.8 +/- 0.4 mL/min/g; P = 0.0002) and oxygen consumption (0.3 +/- 0.04 vs. 0.4 +/- 0.08 min-1; P = 0.005) increased significantly after the high-AGE meal compared with the low-AGE meal. CONCLUSIONS: Our results suggest that the AGE content of a protein load is responsible for renal hemodynamic modifications. Therefore, prevention of diabetic nephropathy progression could aim predominantly at reducing food AGE content. PMID- 29610273 TI - Subcellular compartmentalization of proximal Galphaq-receptor signaling produces unique hypertrophic phenotypes in adult cardiac myocytes. AB - G protein-coupled receptors that signal through Galphaq (Gq receptors), such as alpha1-adrenergic receptors (alpha1-ARs) or angiotensin receptors, share a common proximal signaling pathway that activates phospholipase Cbeta1 (PLCbeta1), which cleaves phosphatidylinositol 4,5-bisphosphate (PIP2) to produce inositol 1,4,5 trisphosphate (IP3) and diacylglycerol. Despite these common proximal signaling mechanisms, Gq receptors produce distinct physiological responses, yet the mechanistic basis for this remains unclear. In the heart, Gq receptors are thought to induce myocyte hypertrophy through a mechanism termed excitation transcription coupling, which provides a mechanistic basis for compartmentalization of calcium required for contraction versus IP3-dependent intranuclear calcium required for hypertrophy. Here, we identified subcellular compartmentalization of Gq-receptor signaling as a mechanistic basis for unique Gq receptor-induced hypertrophic phenotypes in cardiac myocytes. We show that alpha1-ARs co-localize with PLCbeta1 and PIP2 at the nuclear membrane. Further, nuclear alpha1-ARs induced intranuclear PLCbeta1 activity, leading to histone deacetylase 5 (HDAC5) export and a robust transcriptional response (i.e. significant up- or down-regulation of 806 genes). Conversely, we found that angiotensin receptors localize to the sarcolemma and induce sarcolemmal PLCbeta1 activity, but fail to promote HDAC5 nuclear export, while producing a transcriptional response that is mostly a subset of alpha1-AR-induced transcription. In summary, these results link Gq-receptor compartmentalization in cardiac myocytes to unique hypertrophic transcription. They suggest a new model of excitation-transcription coupling in adult cardiac myocytes that accounts for differential Gq-receptor localization and better explains distinct physiological functions of Gq receptors. PMID- 29610274 TI - The Salmonella effectors SseF and SseG inhibit Rab1A-mediated autophagy to facilitate intracellular bacterial survival and replication. AB - In mammalian cells, autophagy plays crucial roles in restricting further spread of invading bacterial pathogens. Previous studies have established that the Salmonella virulence factors SseF and SseG are required for intracellular bacterial survival and replication. However, the underlying mechanism by which these two effectors facilitate bacterial infection remains elusive. Here, we report that SseF and SseG secreted by Salmonella Typhimurium (S. Typhimurium) inhibit autophagy in host cells and thereby establish a replicative niche for the bacteria in the cytosol. Mechanistically, SseF and SseG impaired autophagy initiation by directly interacting with the small GTPase Rab1A in the host cell. This interaction abolished Rab1A activation by disrupting the interaction with its guanine nucleotide exchange factor (GEF), the TRAPPIII (transport protein particle III) complex. This disruption of Rab1A signaling blocked the recruitment and activation of Unc-51-like autophagy-activating kinase 1 (ULK1) and decreased phosphatidylinositol 3-phosphate biogenesis, which ultimately impeded autophagosome formation. Furthermore, SseF- or SseG-deficient bacterial strains exhibited reduced survival and growth in both mammalian cell lines and mouse infection models, and Rab1A depletion could rescue these defects. These results reveal that virulence factor-dependent inactivation of the small GTPase Rab1A represents a previously unrecognized strategy of S Typhimurium to evade autophagy and the host defense system. PMID- 29610275 TI - Inflammation-induced iron transport and metabolism by brain microglia. AB - Microglia are immune cells of the central nervous system and are implicated in brain inflammation. However, how brain microglia modulate transport and metabolism of the essential metal iron in response to pro- and anti-inflammatory environmental cues is unclear. Here, we characterized uptake of transferrin (Tf) bound iron (TBI) and non-Tf-bound iron (NTBI) by immortalized microglial (IMG) cells. We found that these cells preferentially take up NTBI in response to the proinflammatory stimulus lipopolysaccharide (LPS) or beta-amyloid (Abeta). In contrast, the anti-inflammatory cytokine interleukin 4 (IL-4) promoted TBI uptake. Concordant with these functional data, levels of the Tf receptor (TfR) in IMG cells were up-regulated in response to IL-4, whereas divalent metal transporter-1 (DMT1) and ferritin levels increased in response to LPS or Abeta. Similar changes in expression were confirmed in isolated primary adult mouse microglia treated with pro- or anti-inflammatory inducers. LPS-induced changes in IMG cell iron metabolism were accompanied by notable metabolic changes, including increased glycolysis and decreased oxidative respiration. Under these conditions, the extracellular acidification rate was increased, compatible with changes in the cellular microenvironment that would support the pH-dependent function of DMT1. Moreover, LPS increased heme oxygenase-1 (HO1) expression in IMG cells, and iron released because of HO1 activity increased the intracellular labile free iron pool. Together, this evidence indicates that brain microglia preferentially acquire iron from Tf or from non-Tf sources, depending on their polarization state; that NTBI uptake is enhanced by the proinflammatory response; and that under these conditions microglia sequester both extra- and intracellular iron. PMID- 29610276 TI - The transcriptional regulator CCCTC-binding factor limits oxidative stress in endothelial cells. AB - The CCCTC-binding factor (CTCF) is a versatile transcriptional regulator required for embryogenesis, but its function in vascular development or in diseases with a vascular component is poorly understood. Here, we found that endothelial Ctcf is essential for mouse vascular development and limits accumulation of reactive oxygen species (ROS). Conditional knockout of Ctcf in endothelial progenitors and their descendants affected embryonic growth, and caused lethality at embryonic day 10.5 because of defective yolk sac and placental vascular development. Analysis of global gene expression revealed Frataxin (Fxn), the gene mutated in Friedreich's ataxia (FRDA), as the most strongly down-regulated gene in Ctcf deficient placental endothelial cells. Moreover, in vitro reporter assays showed that Ctcf activates the Fxn promoter in endothelial cells. ROS are known to accumulate in the endothelium of FRDA patients. Importantly, Ctcf deficiency induced ROS-mediated DNA damage in endothelial cells in vitro, and in placental endothelium in vivo Taken together, our findings indicate that Ctcf promotes vascular development and limits oxidative stress in endothelial cells. These results reveal a function for Ctcf in vascular development, and suggest a potential mechanism for endothelial dysfunction in FRDA. PMID- 29610277 TI - The cell division protein MinD from Pseudomonas aeruginosa dominates the assembly of the MinC-MinD copolymers. AB - Cell division of rod-shaped bacteria requires the Z ring, a ring of FtsZ filaments associated with the inner-membrane wall. The MinCDE proteins help localize the Z ring to the center of the Escherichia coli cell. MinC, which inhibits Z-ring assembly, is a passenger on MinD. Previous studies have shown that MinC-MinD from E. coli and Aquifex aeolicus assemble in vitro into extended filaments with a 1:1 stoichiometry. However, a recent study has raised questions about the function of the MinC-MinD copolymer in vivo, because its assembly appears to require a high concentration of these two proteins and has a long lag time, and its blockade does not affect in vivo activities. Here, we found that MinC and MinD from Pseudomonas aeruginosa coassemble into filaments with a 1:1 stoichiometry. We also found that the minimal concentration of ~4 MUm required for assembly applies only to MinD because above 4 MUm MinD, even very low MinC concentrations sustained coassembly. As previously reported, the MinC-MinD coassembly exhibited a long lag of ~100 s when initiated by ATP. Premixing MinD with ATP eliminated this lag, suggesting that it may be due to slow MinD dimerization following ATP activation. We also discovered that MinC-MinD copolymers quickly bound FtsZ filaments and formed huge bundles. Our results resolve previous questions about the low concentration of MinC and the lag time, insights that may inform future investigations into the exact role of the MinC MinD copolymer in vivo. PMID- 29610281 TI - Adaptive Resistance to Chemotherapy, A Multi-FAK-torial Linkage. AB - Oncogenes provide tumor cells with a growth and survival advantage. Directed therapies targeted to oncogenic mutations (such as BRAF V600E) are part of effective late-stage melanoma treatment. However, tumors with BRAF V600E mutations, in approximately 10% of colorectal cancer, are generally treatment insensitive. Research has identified various "feedback" mechanisms that result in BRAF signal pathway reactivation in response to BRAF inhibition. Herein, we highlight key findings from Chen and colleagues (this issue) showing that integrin-associated focal adhesion kinase (FAK) activation selectively occurs in BRAF V600E-mutant colorectal cancer cells in response to pharmacological BRAF inhibition. FAK activation results in elevated beta-catenin protein levels, beta catenin nuclear localization, and increased gene transcription. Small-molecule inhibitors of beta-catenin or FAK synergize with vemurafenib BRAF inhibitor to prevent BRAF V600E colorectal cancer cell proliferation in vitro and xenograft tumor growth in mice. This study complements findings linking FAK to beta-catenin in intestinal tumorigenesis, resistance to radiotherapy, and cancer stem cell survival. Thus, FAK activation may occur as a frequent tumor cell "adaptive resistance" mechanism. Although FAK (PTK2) is not mutated in most cancers, targeting FAK activity in combinational approaches may limit tumor cell escape mechanisms and enhance durable responses to treatment. Mol Cancer Ther; 17(4); 719-23. (c)2018 AACR. PMID- 29610278 TI - The unassembled flavoprotein subunits of human and bacterial complex II have impaired catalytic activity and generate only minor amounts of ROS. AB - Complex II (SdhABCD) is a membrane-bound component of mitochondrial and bacterial electron transport chains, as well as of the TCA cycle. In this capacity, it catalyzes the reversible oxidation of succinate. SdhABCD contains the SDHA protein harboring a covalently bound FAD redox center and the iron-sulfur protein SDHB, containing three distinct iron-sulfur centers. When assembly of this complex is compromised, the flavoprotein SDHA may accumulate in the mitochondrial matrix or bacterial cytoplasm. Whether the unassembled SDHA has any catalytic activity, for example in succinate oxidation, fumarate reduction, reactive oxygen species (ROS) generation, or other off-pathway reactions, is not known. Therefore, here we investigated whether unassembled Escherichia coli SdhA flavoprotein, its homolog fumarate reductase (FrdA), and the human SDHA protein have succinate oxidase or fumarate reductase activity and can produce ROS. Using recombinant expression in E. coli, we found that the free flavoproteins from these divergent biological sources have inherently low catalytic activity and generate little ROS. These results suggest that the iron-sulfur protein SDHB in complex II is necessary for robust catalytic activity. Our findings are consistent with those reported for single-subunit flavoprotein homologs that are not associated with iron-sulfur or heme partner proteins. PMID- 29610282 TI - SKLB-23bb, A HDAC6-Selective Inhibitor, Exhibits Superior and Broad-Spectrum Antitumor Activity via Additionally Targeting Microtubules. AB - Our previous study reported that SKLB-23bb, an orally bioavailable HDAC6 selective inhibitor, exhibited superior antitumor efficiency both in vitro and in vivo in comparison with ACY1215, a HDAC6-selective inhibitor recently in phase II clinical trial. This study focused on the mechanism related to the activity of SKLB-23bb. We discovered that despite having HDAC6-selective inhibition equal to ACY1215, SKLB-23bb showed cytotoxic effects against a panel of solid and hematologic tumor cell lines at the low submicromolar level. Interestingly, in contrast to the reported HDAC6-selective inhibitors, SKLB-23bb was more efficient against solid tumor cells. Utilizing HDAC6 stably knockout cell lines constructed by CRISPR-Cas9 gene editing, we illustrated that SKLB-23bb could remain cytotoxic independent of HDAC6 status. Investigation of the mechanism confirmed that SKLB 23bb exerted its cytotoxic activity by additionally targeting microtubules. SKLB 23bb could bind to the colchicine site in beta-tubulin and act as a microtubule polymerization inhibitor. Consistent with its microtubule-disrupting ability, SKLB-23bb also blocked tumor cell cycle at G2-M phase and triggered cellular apoptosis. In solid tumor xenografts, oral administration of SKLB-23bb efficiently inhibited tumor growth. These results suggested that SKLB-23bb was an orally bioavailable HDAC6 and microtubule dual targeting agent. The microtubule targeting profile enhanced the antitumor activity and expanded the antitumor spectrum of SKLB-23bb, thus breaking through the limitation of HDAC6 inhibitors. Mol Cancer Ther; 17(4); 763-75. (c)2018 AACR. PMID- 29610284 TI - By the Numbers: Novel Drugs Approved by the FDA, 2011-2017. AB - In 2017, the FDA approved 12 novel cancer drugs. The agency also approved two chimeric antigen receptor T-cell therapies for blood cancers. PMID- 29610279 TI - H3K36me3-mediated mismatch repair preferentially protects actively transcribed genes from mutation. AB - Histone H3 trimethylation at lysine 36 (H3K36me3) is an important histone mark involved in both transcription elongation and DNA mismatch repair (MMR). It is known that H3K36me3 recruits the mismatch-recognition protein MutSalpha to replicating chromatin via its physical interaction with MutSalpha's PWWP domain, but the exact role of H3K36me3 in transcription is undefined. Using ChIP combined with whole-genome DNA sequencing analysis, we demonstrate here that H3K36me3, together with MutSalpha, is involved in protecting against mutation, preferentially in actively transcribed genomic regions. We found that H3K36me3 and MutSalpha are much more co-enriched in exons and actively transcribed regions than in introns and nontranscribed regions. The H3K36me3-MutSalpha co-enrichment correlated with a much lower mutation frequency in exons and actively transcribed regions than in introns and nontranscribed regions. Correspondingly, depleting H3K36me3 or disrupting the H3K36me3-MutSalpha interaction elevated the spontaneous mutation frequency in actively transcribed genes, but it had little influence on the mutation frequency in nontranscribed or transcriptionally inactive regions. Similarly, H2O2-induced mutations, which mainly cause base oxidations, preferentially occurred in actively transcribed genes in MMR deficient cells. The data presented here suggest that H3K36me3-mediated MMR preferentially safeguards actively transcribed genes not only during replication by efficiently correcting mispairs in early replicating chromatin but also during transcription by directly or indirectly removing DNA lesions associated with a persistently open chromatin structure. PMID- 29610286 TI - Immunotherapy for Pancreatic Cancer: More Than Just a Gut Feeling. AB - Development of pancreatic cancer in spontaneous murine models is associated with enrichment of specific strains of gut and intratumoral bacteria that induce a tolerogenic immunosuppressive microenvironment favoring cancer progression and resistance to immunotherapies. Ablation of the microbiome with antibiotics reshapes the tumor microenvironment, inducing T-cell activation, improving immune surveillance, and increasing sensitivity to immunotherapy in established tumors. Cancer Discov; 8(4); 386-8. (c)2018 AACR.See related article by Pushalkar et al., p. 403. PMID- 29610287 TI - Advances on the BRAF Front in Colorectal Cancer. AB - Colorectal cancer with BRAFV600E mutation can be effectively treated with combination approaches involving inhibition of BRAF, MEK, and EGFR proteins. However, activation of the MAPK pathway, often due to emergence of previously undetected molecular alterations, ultimately leads to adaptive therapeutic resistance. Novel combination strategies combining inhibition of BRAF, ERK, and EGFR can be used to prevent MAPK pathway-driven resistance and warrant further investigation. Cancer Discov; 8(4); 389-91. (c)2018 AACRSee related article by Corcoran et al., p. 428See related article by Hazar-Rethinam et al., p. 417. PMID- 29610288 TI - Plasma DNA and Metastatic Castration-Resistant Prostate Cancer: The Odyssey to a Clinical Biomarker Test. AB - Comprehensive plasma DNA analysis identifies clinically actionable genomic aberrations. Cancers harboring disruption of TP53 or BRCA2 or ATM detected in plasma have significantly worse outcomes on novel AR targeting. Cancer Discov; 8(4); 392-4. (c)2018 AACR.See related article by Annala et al., p. 444. PMID- 29610289 TI - E-Cadherin/ROS1 Inhibitor Synthetic Lethality in Breast Cancer. AB - The cell adhesion glycoprotein E-cadherin (CDH1) is commonly inactivated in breast tumors. Precision medicine approaches that exploit this characteristic are not available. Using perturbation screens in breast tumor cells with CRISPR/Cas9 engineered CDH1 mutations, we identified synthetic lethality between E-cadherin deficiency and inhibition of the tyrosine kinase ROS1. Data from large-scale genetic screens in molecularly diverse breast tumor cell lines established that the E-cadherin/ROS1 synthetic lethality was not only robust in the face of considerable molecular heterogeneity but was also elicited with clinical ROS1 inhibitors, including foretinib and crizotinib. ROS1 inhibitors induced mitotic abnormalities and multinucleation in E-cadherin-defective cells, phenotypes associated with a defect in cytokinesis and aberrant p120 catenin phosphorylation and localization. In vivo, ROS1 inhibitors produced profound antitumor effects in multiple models of E-cadherin-defective breast cancer. These data therefore provide the preclinical rationale for assessing ROS1 inhibitors, such as the licensed drug crizotinib, in appropriately stratified patients.Significance: E cadherin defects are common in breast cancer but are currently not targeted with a precision medicine approach. Our preclinical data indicate that licensed ROS1 inhibitors, including crizotinib, should be repurposed to target E-cadherin defective breast cancers, thus providing the rationale for the assessment of these agents in molecularly stratified phase II clinical trials. Cancer Discov; 8(4); 498-515. (c)2018 AACR.This article is highlighted in the In This Issue feature, p. 371. PMID- 29610290 TI - Implementation and quality assessment of a pharmacy services call center for outpatient pharmacies and specialty pharmacy services in an academic health system. AB - PURPOSE: The implementation and quality assessment of a pharmacy services call center (PSCC) for outpatient pharmacies and specialty pharmacy services within an academic health system are described. SUMMARY: Prolonged wait times in outpatient pharmacies or hold times on the phone affect the ability of pharmacies to capture and retain prescriptions. To support outpatient pharmacy operations and improve quality, a PSCC was developed to centralize handling of all outpatient and specialty pharmacy calls. The purpose of the PSCC was to improve the quality of pharmacy telephone services by (1) decreasing the call abandonment rate, (2) improving the speed of answer, (3) increasing first-call resolution, (4) centralizing all specialty pharmacy and prior authorization calls, (5) increasing labor efficiency and pharmacy capacities, (6) implementing a quality evaluation program, and (7) improving workplace satisfaction and retention of outpatient pharmacy staff. The PSCC centralized pharmacy calls from 9 pharmacy locations, 2 outpatient clinics, and a specialty pharmacy. Since implementation, the PSCC has achieved and maintained program goals, including improved abandonment rate, speed of answer, and first-call resolution. A centralized 24-7 support line for specialty pharmacy patients was also successfully established. A quality calibration program was implemented to ensure service quality and excellent patient experience. Additional ongoing evaluations measure the impact of the PSCC on improving workplace satisfaction and retention of outpatient pharmacy staff. CONCLUSION: The design and implementation of the PSCC have significantly improved the health system's patient experiences, efficiency, and quality. PMID- 29610291 TI - The Need for Neddylation: A Key to Achieving NED in Uveal Melanoma. AB - The ability of uveal melanoma cells to enter and exit dormancy plays a fundamental role in the development of metastatic disease. Neddylation blockade is a promising strategy to prolong tumor dormancy via impaired angiogenesis and prevent the establishment of metastases via elimination of cancer stem-like cells. Clin Cancer Res; 24(15); 3477-9. (c)2018 AACRSee related article by Jin et al., p. 3741. PMID- 29610292 TI - Renin-Angiotensin System Inhibitors to Mitigate Cancer Treatment-Related Adverse Events. AB - Treatment-related side effects are a major clinical problem in cancer treatment. They lead to reduced compliance to therapy as well as increased morbidity and mortality. Well-known are the sequelae of chemotherapy on the heart, especially in childhood cancer survivors. Therefore, measures to mitigate the adverse events of cancer therapy may improve health and quality of life in patients with cancer, both in the short and long term. The renin-angiotensin system (RAS) affects all hallmarks of cancer, and blockage of the RAS is associated with an improved outcome in several cancer types. There is also increasing evidence that inhibition of the RAS might be able to alleviate or even prevent certain types of cancer treatment-related adverse effects. In this review, we summarize the potential of RAS inhibitors to mitigate cancer treatment-related adverse events, with a special emphasis on chemotherapy-induced cardiotoxicity, radiation injury, and arterial hypertension. Clin Cancer Res; 24(16); 3803-12. (c)2018 AACR. PMID- 29610293 TI - Critical impact of vegetation physiology on the continental hydrologic cycle in response to increasing CO2. AB - Predicting how increasing atmospheric CO2 will affect the hydrologic cycle is of utmost importance for a range of applications ranging from ecological services to human life and activities. A typical perspective is that hydrologic change is driven by precipitation and radiation changes due to climate change, and that the land surface will adjust. Using Earth system models with decoupled surface (vegetation physiology) and atmospheric (radiative) CO2 responses, we here show that the CO2 physiological response has a dominant role in evapotranspiration and evaporative fraction changes and has a major effect on long-term runoff compared with radiative or precipitation changes due to increased atmospheric CO2 This major effect is true for most hydrological stress variables over the largest fraction of the globe, except for soil moisture, which exhibits a more nonlinear response. This highlights the key role of vegetation in controlling future terrestrial hydrologic response and emphasizes that the carbon and water cycles are intimately coupled over land. PMID- 29610294 TI - Learned immunosuppressive placebo responses in renal transplant patients. AB - Patients after organ transplantation or with chronic, inflammatory autoimmune diseases require lifelong treatment with immunosuppressive drugs, which have toxic adverse effects. Recent insight into the neurobiology of placebo responses shows that associative conditioning procedures can be employed as placebo-induced dose reduction strategies in an immunopharmacological regimen. However, it is unclear whether learned immune responses can be produced in patient populations already receiving an immunosuppressive regimen. Thus, 30 renal transplant patients underwent a taste-immune conditioning paradigm, in which immunosuppressive drugs (unconditioned stimulus) were paired with a gustatory stimulus [conditioned stimulus (CS)] during the learning phase. During evocation phase, after patients were reexposed to the CS, T cell proliferative capacity was significantly reduced in comparison with the baseline kinetics of T cell functions under routine drug intake (np2 = 0.34). These data demonstrate, proof of-concept, that learned immunosuppressive placebo responses can be used as a supportive, placebo-based, dose-reduction strategy to improve treatment efficacy in an ongoing immunopharmacological regimen. PMID- 29610295 TI - SAMHD1 suppresses innate immune responses to viral infections and inflammatory stimuli by inhibiting the NF-kappaB and interferon pathways. AB - Sterile alpha motif and HD-domain-containing protein 1 (SAMHD1) blocks replication of retroviruses and certain DNA viruses by reducing the intracellular dNTP pool. SAMHD1 has been suggested to down-regulate IFN and inflammatory responses to viral infections, although the functions and mechanisms of SAMHD1 in modulating innate immunity remain unclear. Here, we show that SAMHD1 suppresses the innate immune responses to viral infections and inflammatory stimuli by inhibiting nuclear factor-kappaB (NF-kappaB) activation and type I interferon (IFN-I) induction. Compared with control cells, infection of SAMHD1-silenced human monocytic cells or primary macrophages with Sendai virus (SeV) or HIV-1, or treatment with inflammatory stimuli, induces significantly higher levels of NF kappaB activation and IFN-I induction. Exogenous SAMHD1 expression in cells or SAMHD1 reconstitution in knockout cells suppresses NF-kappaB activation and IFN-I induction by SeV infection or inflammatory stimuli. Mechanistically, SAMHD1 inhibits NF-kappaB activation by interacting with NF-kappaB1/2 and reducing phosphorylation of the NF-kappaB inhibitory protein IkappaBalpha. SAMHD1 also interacts with the inhibitor-kappaB kinase epsilon (IKKepsilon) and IFN regulatory factor 7 (IRF7), leading to the suppression of the IFN-I induction pathway by reducing IKKepsilon-mediated IRF7 phosphorylation. Interactions of endogenous SAMHD1 with NF-kappaB and IFN-I pathway proteins were validated in human monocytic cells and primary macrophages. Comparing splenocytes from SAMHD1 knockout and heterozygous mice, we further confirmed SAMHD1-mediated suppression of NF-kappaB activation, suggesting an evolutionarily conserved property of SAMHD1. Our findings reveal functions of SAMHD1 in down-regulating innate immune responses to viral infections and inflammatory stimuli, highlighting the importance of SAMHD1 in modulating antiviral immunity. PMID- 29610296 TI - Distinct MHC class I-like interacting invariant T cell lineage at the forefront of mycobacterial immunity uncovered in Xenopus. AB - The amphibian Xenopus laevis is to date the only species outside of mammals where a MHC class I-like (MHC-like) restricted innate-like (i) T cell subset (iValpha6 T cells) reminiscent of CD1d-restricted iNKT cells has been identified and functionally characterized. This provides an attractive in vivo model to study the biological analogies and differences between mammalian iT cells and the evolutionarily antecedent Xenopus iT cell defense system. Here, we report the identification of a unique iT cell subset (Valpha45-Jalpha1.14) requiring a distinct MHC-like molecule (mhc1b4.L or XNC4) for its development and function. We used two complementary reverse genetic approaches: RNA interference by transgenesis to impair expression of either XNC4 or the Valpha45-Jalpha1.14 rearrangement, and CRISPR/Cas9-mediated disruption of the Jalpha1.14 gene segment. Both XNC4 deficiency that ablates iValpha45T cell development and the direct disruption of the iValpha45-Jalpha1.14 T cell receptor dramatically impairs tadpole resistance to Mycobacterium marinum (Mm) infection. The higher mortality of Mm-infected tadpoles deficient for iValpha45T cells correlates with dysregulated expression responses of several immune genes. In contrast, iValpha45 Jalpha1.14-deficient tadpoles remain fully competent against infection by the ranavirus FV3, which indicates a specialization of this unique iT cell subset toward mycobacterial rather than viral pathogens that involve iValpha6 T cells. These data suggest that amphibians, which are evolutionarily separated from mammals by more than 350 My, have independently diversified a prominent and convergent immune surveillance system based on MHC-like interacting innate-like T cells. PMID- 29610297 TI - Intron retention induced by microsatellite expansions as a disease biomarker. AB - Expansions of simple sequence repeats, or microsatellites, have been linked to ~30 neurological-neuromuscular diseases. While these expansions occur in coding and noncoding regions, microsatellite sequence and repeat length diversity is more prominent in introns with eight different trinucleotide to hexanucleotide repeats, causing hereditary diseases such as myotonic dystrophy type 2 (DM2), Fuchs endothelial corneal dystrophy (FECD), and C9orf72 amyotrophic lateral sclerosis and frontotemporal dementia (C9-ALS/FTD). Here, we test the hypothesis that these GC-rich intronic microsatellite expansions selectively trigger host intron retention (IR). Using DM2, FECD, and C9-ALS/FTD as examples, we demonstrate that retention is readily detectable in affected tissues and peripheral blood lymphocytes and conclude that IR screening constitutes a rapid and inexpensive biomarker for intronic repeat expansion disease. PMID- 29610298 TI - Mechanosensitivity of Jagged-Notch signaling can induce a switch-type behavior in vascular homeostasis. AB - Hemodynamic forces and Notch signaling are both known as key regulators of arterial remodeling and homeostasis. However, how these two factors integrate in vascular morphogenesis and homeostasis is unclear. Here, we combined experiments and modeling to evaluate the impact of the integration of mechanics and Notch signaling on vascular homeostasis. Vascular smooth muscle cells (VSMCs) were cyclically stretched on flexible membranes, as quantified via video tracking, demonstrating that the expression of Jagged1, Notch3, and target genes was down regulated with strain. The data were incorporated in a computational framework of Notch signaling in the vascular wall, where the mechanical load was defined by the vascular geometry and blood pressure. Upon increasing wall thickness, the model predicted a switch-type behavior of the Notch signaling state with a steep transition of synthetic toward contractile VSMCs at a certain transition thickness. These thicknesses varied per investigated arterial location and were in good agreement with human anatomical data, thereby suggesting that the Notch response to hemodynamics plays an important role in the establishment of vascular homeostasis. PMID- 29610299 TI - Second-order spinal cord pathway contributes to cortical responses after long recoveries from dorsal column injury in squirrel monkeys. AB - Months after the occurrence of spinal cord dorsal column lesions (DCLs) at the cervical level, neural responses in the hand representation of somatosensory area 3b hand cortex recover, along with hand use. To examine whether the second-order spinal cord pathway contributes to this functional recovery, we injected cholera toxin subunit B (CTB) into the hand representation in the cuneate nucleus (Cu) to label the spinal cord neurons, and related results to cortical reactivation in four squirrel monkeys (Saimiri boliviensis) at least 7 months after DCL. In two monkeys with complete DCLs, few CTB-labeled neurons were present below the lesion, and few neurons in the affected hand region in area 3b responded to touch on the hand. In two other cases with large but incomplete DCLs, CTB-labeled neurons were abundant below the lesion, and the area 3b hand cortex responded well to tactile stimulation in a roughly somatotopic organization. The proportions of labeled neurons in the spinal cord hand region reflected the extent of cortical reactivation to the hand. Comparing monkeys with short and long recovery times suggests that the numbers of labeled neurons below the lesion increase with time following incomplete DCLs (<95%) but decrease with time after nearly complete DCLs (>=95%). Taken together, these results suggest that the second-order spinal cord pathway facilitates cortical reactivation, likely through the potentiation of persisting tactile inputs from the hand to the Cu over months of postlesion recovery. PMID- 29610300 TI - Correction for Bevan et al., Holocene fluctuations in human population demonstrate repeated links to food production and climate. PMID- 29610301 TI - China, the United States, and competition for resources that enable emerging technologies. AB - Historically, resource conflicts have often centered on fuel minerals (particularly oil). Future resource conflicts may, however, focus more on competition for nonfuel minerals that enable emerging technologies. Whether it is rhenium in jet engines, indium in flat panel displays, or gallium in smart phones, obscure elements empower smarter, smaller, and faster technologies, and nations seek stable supplies of these and other nonfuel minerals for their industries. No nation has all of the resources it needs domestically. International trade may lead to international competition for these resources if supplies are deemed at risk or insufficient to satisfy growing demand, especially for minerals used in technologies important to economic development and national security. Here, we compare the net import reliance of China and the United States to inform mineral resource competition and foreign supply risk. Our analysis indicates that China relies on imports for over half of its consumption for 19 of 42 nonfuel minerals, compared with 24 for the United States-11 of which are common to both. It is for these 11 nonfuel minerals that competition between the United States and China may become the most contentious, especially for those with highly concentrated production that prove irreplaceable in pivotal emerging technologies. PMID- 29610302 TI - Identification of long-lived synaptic proteins by proteomic analysis of synaptosome protein turnover. AB - Memory formation is believed to result from changes in synapse strength and structure. While memories may persist for the lifetime of an organism, the proteins and lipids that make up synapses undergo constant turnover with lifetimes from minutes to days. The molecular basis for memory maintenance may rely on a subset of long-lived proteins (LLPs). While it is known that LLPs exist, whether such proteins are present at synapses is unknown. We performed an unbiased screen using metabolic pulse-chase labeling in vivo in mice and in vitro in cultured neurons combined with quantitative proteomics. We identified synaptic LLPs with half-lives of several months or longer. Proteins in synaptic fractions generally exhibited longer lifetimes than proteins in cytosolic fractions. Protein turnover was sensitive to pharmacological manipulations of activity in neuronal cultures or in mice exposed to an enriched environment. We show that synapses contain LLPs that may underlie stabile long-lasting changes in synaptic structure and function. PMID- 29610303 TI - Dramatic pressure-sensitive ion conduction in conical nanopores. AB - Ion transporters in Nature exhibit a wealth of complex transport properties such as voltage gating, activation, and mechanosensitive behavior. When combined, such processes result in advanced ionic machines achieving active ion transport, high selectivity, or signal processing. On the artificial side, there has been much recent progress in the design and study of transport in ionic channels, but mimicking the advanced functionalities of ion transporters remains as yet out of reach. A prerequisite is the development of ionic responses sensitive to external stimuli. In the present work, we report a counterintuitive and highly nonlinear coupling between electric and pressure-driven transport in a conical nanopore, manifesting as a strong pressure dependence of the ionic conductance. This result is at odds with standard linear response theory and is akin to a mechanical transistor functionality. We fully rationalize this behavior on the basis of the coupled electrohydrodynamics in the conical pore by extending the Poisson-Nernst Planck-Stokes framework. The model is shown to capture the subtle mechanical balance occurring within an extended spatially charged zone in the nanopore. The pronounced sensitivity to mechanical forcing offers leads in tuning ion transport by mechanical stimuli. The results presented here provide a promising avenue for the design of tailored membrane functionalities. PMID- 29610304 TI - Structural characterization of a non-heme iron active site in zeolites that hydroxylates methane. AB - Iron-containing zeolites exhibit unprecedented reactivity in the low-temperature hydroxylation of methane to form methanol. Reactivity occurs at a mononuclear ferrous active site, alpha-Fe(II), that is activated by N2O to form the reactive intermediate alpha-O. This has been defined as an Fe(IV)=O species. Using nuclear resonance vibrational spectroscopy coupled to X-ray absorption spectroscopy, we probe the bonding interaction between the iron center, its zeolite lattice derived ligands, and the reactive oxygen. alpha-O is found to contain an unusually strong Fe(IV)=O bond resulting from a constrained coordination geometry enforced by the zeolite lattice. Density functional theory calculations clarify how the experimentally determined geometric structure of the active site leads to an electronic structure that is highly activated to perform H-atom abstraction. PMID- 29610305 TI - Structural dynamics is a determinant of the functional significance of missense variants. AB - Accurate evaluation of the effect of point mutations on protein function is essential to assessing the genesis and prognosis of many inherited diseases and cancer types. Currently, a wealth of computational tools has been developed for pathogenicity prediction. Two major types of data are used to this aim: sequence conservation/evolution and structural properties. Here, we demonstrate in a systematic way that another determinant of the functional impact of missense variants is the protein's structural dynamics. Measurable improvement is shown in pathogenicity prediction by taking into consideration the dynamical context and implications of the mutation. Our study suggests that the class of dynamics descriptors introduced here may be used in conjunction with existing features to not only increase the prediction accuracy of the impact of variants on biological function, but also gain insight into the physical basis of the effect of missense variants. PMID- 29610307 TI - Complete biosynthesis of noscapine and halogenated alkaloids in yeast. AB - Microbial biosynthesis of plant natural products from simple building blocks is a promising approach toward scalable production and modification of high-value compounds. The pathway for biosynthesis of noscapine, a potential anticancer compound, from canadine was recently elucidated as a 10-gene cluster from opium poppy. Here we demonstrate the de novo production of noscapine in Saccharomyces cerevisiae, through the reconstruction of a biosynthetic pathway comprising over 30 enzymes from plants, bacteria, mammals, and yeast itself, including 7 plant endoplasmic reticulum (ER)-localized enzymes. Optimization directed to tuning expression of pathway enzymes, host endogenous metabolic pathways, and fermentation conditions led to an over 18,000-fold improvement from initial noscapine titers to ~2.2 mg/L. By feeding modified tyrosine derivatives to the optimized noscapine-producing strain we further demonstrated microbial production of halogenated benzylisoquinoline alkaloids. This work highlights the potential for microbial biosynthetic platforms to support the synthesis of valuable and novel alkaloid compounds, which can advance alkaloid-based drug discovery and development. PMID- 29610306 TI - Autochthonous tumors driven by Rb1 loss have an ongoing requirement for the RBP2 histone demethylase. AB - Inactivation of the retinoblastoma gene (RB1) product, pRB, is common in many human cancers. Targeting downstream effectors of pRB that are central to tumorigenesis is a promising strategy to block the growth of tumors harboring loss-of-function RB1 mutations. One such effector is retinoblastoma-binding protein 2 (RBP2, also called JARID1A or KDM5A), which encodes an H3K4 demethylase. Binding of pRB to RBP2 has been linked to the ability of pRB to promote senescence and differentiation. Importantly, genetic ablation of RBP2 is sufficient to phenocopy pRB's ability to induce these cellular changes in cell culture experiments. Moreover, germline Rbp2 deletion significantly impedes tumorigenesis in Rb1+/- mice. The value of RBP2 as a therapeutic target in cancer, however, hinges on whether loss of RBP2 could block the growth of established tumors as opposed to simply delaying their onset. Here we show that conditional, systemic ablation of RBP2 in tumor-bearing Rb1+/- mice is sufficient to slow tumor growth and significantly extend survival without causing obvious toxicity to the host. These findings show that established Rb1-null tumors require RBP2 for growth and further credential RBP2 as a therapeutic target in human cancers driven by RB1 inactivation. PMID- 29610308 TI - Increased autophagy blocks HER2-mediated breast tumorigenesis. AB - Allelic loss of the autophagy gene, beclin 1/BECN1, increases the risk of patients developing aggressive, including human epidermal growth factor receptor 2 (HER2)-positive, breast cancers; however, it is not known whether autophagy induction may be beneficial in preventing HER2-positive breast tumor growth. We explored the regulation of autophagy in breast cancer cells by HER2 in vitro and the effects of genetic and pharmacological strategies to increase autophagy on HER2-driven breast cancer growth in vivo. Our findings demonstrate that HER2 interacts with Beclin 1 in breast cancer cells and inhibits autophagy. Mice with increased basal autophagy due to a genetically engineered mutation in Becn1 are protected from HER2-driven mammary tumorigenesis, and HER2 fails to inhibit autophagy in primary cells derived from these mice. Moreover, treatment of mice with HER2-positive human breast cancer xenografts with the Tat-Beclin 1 autophagy inducing peptide inhibits tumor growth as effectively as a clinically used HER2 tyrosine kinase inhibitor (TKI). This inhibition of tumor growth is associated with a robust induction of autophagy, a disruption of HER2/Beclin 1 binding, and a transcriptional signature in the tumors distinct from that observed with HER2 TKI treatment. Taken together, these findings indicate that the HER2-mediated inhibition of Beclin 1 and autophagy likely contributes to HER2-mediated tumorigenesis and that strategies to block HER2/Beclin 1 binding and/or increase autophagy may represent a new therapeutic approach for HER2-positive breast cancers. PMID- 29610309 TI - Hip extensor mechanics and the evolution of walking and climbing capabilities in humans, apes, and fossil hominins. AB - The evolutionary emergence of humans' remarkably economical walking gait remains a focus of research and debate, but experimentally validated approaches linking locomotor capability to postcranial anatomy are limited. In this study, we integrated 3D morphometrics of hominoid pelvic shape with experimental measurements of hip kinematics and kinetics during walking and climbing, hamstring activity, and passive range of hip extension in humans, apes, and other primates to assess arboreal-terrestrial trade-offs in ischium morphology among living taxa. We show that hamstring-powered hip extension during habitual walking and climbing in living apes and humans is strongly predicted, and likely constrained, by the relative length and orientation of the ischium. Ape pelves permit greater extensor moments at the hip, enhancing climbing capability, but limit their range of hip extension, resulting in a crouched gait. Human pelves reduce hip extensor moments but permit a greater degree of hip extension, which greatly improves walking economy (i.e., distance traveled/energy consumed). Applying these results to fossil pelves suggests that early hominins differed from both humans and extant apes in having an economical walking gait without sacrificing climbing capability. Ardipithecus was capable of nearly human-like hip extension during bipedal walking, but retained the capacity for powerful, ape like hip extension during vertical climbing. Hip extension capability was essentially human-like in Australopithecus afarensis and Australopithecus africanus, suggesting an economical walking gait but reduced mechanical advantage for powered hip extension during climbing. PMID- 29610311 TI - Correction for Jiang et al., Proteins induced by telomere dysfunction and DNA damage represent biomarkers of human aging and disease. PMID- 29610310 TI - Microbes vs. chemistry in the origin of the anaerobic gut lumen. AB - The succession from aerobic and facultative anaerobic bacteria to obligate anaerobes in the infant gut along with the differences between the compositions of the mucosally adherent vs. luminal microbiota suggests that the gut microbes consume oxygen, which diffuses into the lumen from the intestinal tissue, maintaining the lumen in a deeply anaerobic state. Remarkably, measurements of luminal oxygen levels show nearly identical pO2 (partial pressure of oxygen) profiles in conventional and germ-free mice, pointing to the existence of oxygen consumption mechanisms other than microbial respiration. In vitro experiments confirmed that the luminal contents of germ-free mice are able to chemically consume oxygen (e.g., via lipid oxidation reactions), although at rates significantly lower than those observed in the case of conventionally housed mice. For conventional mice, we also show that the taxonomic composition of the gut microbiota adherent to the gut mucosa and in the lumen throughout the length of the gut correlates with oxygen levels. At the same time, an increase in the biomass of the gut microbiota provides an explanation for the reduction of luminal oxygen in the distal vs. proximal gut. These results demonstrate how oxygen from the mammalian host is used by the gut microbiota, while both the microbes and the oxidative chemical reactions regulate luminal oxygen levels, shaping the composition of the microbial community throughout different regions of the gut. PMID- 29610313 TI - Constraining the climate and ocean pH of the early Earth with a geological carbon cycle model. AB - The early Earth's environment is controversial. Climatic estimates range from hot to glacial, and inferred marine pH spans strongly alkaline to acidic. Better understanding of early climate and ocean chemistry would improve our knowledge of the origin of life and its coevolution with the environment. Here, we use a geological carbon cycle model with ocean chemistry to calculate self-consistent histories of climate and ocean pH. Our carbon cycle model includes an empirically justified temperature and pH dependence of seafloor weathering, allowing the relative importance of continental and seafloor weathering to be evaluated. We find that the Archean climate was likely temperate (0-50 degrees C) due to the combined negative feedbacks of continental and seafloor weathering. Ocean pH evolves monotonically from [Formula: see text] (2sigma) at 4.0 Ga to [Formula: see text] (2sigma) at the Archean-Proterozoic boundary, and to [Formula: see text] (2sigma) at the Proterozoic-Phanerozoic boundary. This evolution is driven by the secular decline of pCO2, which in turn is a consequence of increasing solar luminosity, but is moderated by carbonate alkalinity delivered from continental and seafloor weathering. Archean seafloor weathering may have been a comparable carbon sink to continental weathering, but is less dominant than previously assumed, and would not have induced global glaciation. We show how these conclusions are robust to a wide range of scenarios for continental growth, internal heat flow evolution and outgassing history, greenhouse gas abundances, and changes in the biotic enhancement of weathering. PMID- 29610312 TI - Robust, linear correlations between growth rates and beta-lactam-mediated lysis rates. AB - It is widely acknowledged that faster-growing bacteria are killed faster by beta lactam antibiotics. This notion serves as the foundation for the concept of bacterial persistence: dormant bacterial cells that do not grow are phenotypically tolerant against beta-lactam treatment. Such correlation has often been invoked in the mathematical modeling of bacterial responses to antibiotics. Due to the lack of thorough quantification, however, it is unclear whether and to what extent the bacterial growth rate can predict the lysis rate upon beta-lactam treatment under diverse conditions. Enabled by experimental automation, here we measured >1,000 growth/killing curves for eight combinations of antibiotics and bacterial species and strains, including clinical isolates of bacterial pathogens. We found that the lysis rate of a bacterial population linearly depends on the instantaneous growth rate of the population, regardless of how the latter is modulated. We further demonstrate that this predictive power at the population level can be explained by accounting for bacterial responses to the antibiotic treatment by single cells. This linear dependence of the lysis rate on the growth rate represents a dynamic signature associated with each bacterium antibiotic pair and serves as the quantitative foundation for designing combination antibiotic therapy and predicting the population-structure change in a population with mixed phenotypes. PMID- 29610315 TI - Correction for Ramus et al,. An invasive foundation species enhances multifunctionality in a coastal ecosystem. PMID- 29610314 TI - Role of metabolic spatiotemporal dynamics in regulating biofilm colony expansion. AB - Cell fate determination is typically regulated by biological networks, yet increasing evidences suggest that cell-cell communication and environmental stresses play crucial roles in the behavior of a cell population. A recent microfluidic experiment showed that the metabolic codependence of two cell populations generates a collective oscillatory dynamic during the expansion of a Bacillus subtilis biofilm. We develop a modeling framework for the spatiotemporal dynamics of the associated metabolic circuit for cells in a colony. We elucidate the role of metabolite diffusion and the need of two distinct cell populations to observe oscillations. Uniquely, this description captures the onset and thereafter stable oscillatory dynamics during expansion and predicts the existence of damping oscillations under various environmental conditions. This modeling scheme provides insights to understand how cells integrate the information from external signaling and cell-cell communication to determine the optimal survival strategy and/or maximize cell fitness in a multicellular system. PMID- 29610316 TI - Long-term in vivo recording of circadian rhythms in brains of freely moving mice. AB - Endogenous circadian clocks control 24-h physiological and behavioral rhythms in mammals. Here, we report a real-time in vivo fluorescence recording system that enables long-term monitoring of circadian rhythms in the brains of freely moving mice. With a designed reporter of circadian clock gene expression, we tracked robust Cry1 transcription reporter rhythms in the suprachiasmatic nucleus (SCN) of WT, Cry1-/- , and Cry2-/- mice in LD (12 h light, 12 h dark) and DD (constant darkness) conditions and verified that signals remained stable for over 6 mo. Further, we recorded Cry1 transcriptional rhythms in the subparaventricular zone (SPZ) and hippocampal CA1/2 regions of WT mice housed under LD and DD conditions. By using a Cre-loxP system, we recorded Per2 and Cry1 transcription rhythms specifically in vasoactive intestinal peptide (VIP) neurons of the SCN. Finally, we demonstrated the dynamics of Per2 and Cry1 transcriptional rhythms in SCN VIP neurons following an 8-h phase advance in the light/dark cycle. PMID- 29610319 TI - Effects of iron on the lattice thermal conductivity of Earth's deep mantle and implications for mantle dynamics. AB - Iron may critically influence the physical properties and thermochemical structures of Earth's lower mantle. Its effects on thermal conductivity, with possible consequences on heat transfer and mantle dynamics, however, remain largely unknown. We measured the lattice thermal conductivity of lower-mantle ferropericlase to 120 GPa using the ultrafast optical pump-probe technique in a diamond anvil cell. The thermal conductivity of ferropericlase with 56% iron significantly drops by a factor of 1.8 across the spin transition around 53 GPa, while that with 8-10% iron increases monotonically with pressure, causing an enhanced iron substitution effect in the low-spin state. Combined with bridgmanite data, modeling of our results provides a self-consistent radial profile of lower-mantle thermal conductivity, which is dominated by pressure, temperature, and iron effects, and shows a twofold increase from top to bottom of the lower mantle. Such increase in thermal conductivity may delay the cooling of the core, while its decrease with iron content may enhance the dynamics of large low shear-wave velocity provinces. Our findings further show that, if hot and strongly enriched in iron, the seismic ultralow velocity zones have exceptionally low conductivity, thus delaying their cooling. PMID- 29610318 TI - Ablation of insulin receptor substrates 1 and 2 suppresses Kras-driven lung tumorigenesis. AB - Non-small-cell lung cancer (NSCLC) is a leading cause of cancer death worldwide, with 25% of cases harboring oncogenic Kirsten rat sarcoma (KRAS). Although KRAS direct binding to and activation of PI3K is required for KRAS-driven lung tumorigenesis, the contribution of insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF1R) in the context of mutant KRAS remains controversial. Here, we provide genetic evidence that lung-specific dual ablation of insulin receptor substrates 1/2 (Irs1/Irs2), which mediate insulin and IGF1 signaling, strongly suppresses tumor initiation and dramatically extends the survival of a mouse model of lung cancer with Kras activation and p53 loss. Mice with Irs1/Irs2 loss eventually succumb to tumor burden, with tumor cells displaying suppressed Akt activation and strikingly diminished intracellular levels of essential amino acids. Acute loss of IRS1/IRS2 or inhibition of IR/IGF1R in KRAS-mutant human NSCLC cells decreases the uptake and lowers the intracellular levels of amino acids, while enhancing basal autophagy and sensitivity to autophagy and proteasome inhibitors. These findings demonstrate that insulin/IGF1 signaling is required for KRAS-mutant lung cancer initiation, and identify decreased amino acid levels as a metabolic vulnerability in tumor cells with IR/IGF1R inhibition. Consequently, combinatorial targeting of IR/IGF1R with autophagy or proteasome inhibitors may represent an effective therapeutic strategy in KRAS-mutant NSCLC. PMID- 29610321 TI - Correction for Chen et al., B7-H1 maintains the polyclonal T cell response by protecting dendritic cells from cytotoxic T lymphocyte destruction. PMID- 29610317 TI - Plasticity in early immune evasion strategies of a bacterial pathogen. AB - Borrelia burgdorferi is one of the few extracellular pathogens capable of establishing persistent infection in mammals. The mechanisms that sustain long term survival of this bacterium are largely unknown. Here we report a unique innate immune evasion strategy of B. burgdorferi, orchestrated by a surface protein annotated as BBA57, through its modulation of multiple spirochete virulent determinants. BBA57 function is critical for early infection but largely redundant for later stages of spirochetal persistence, either in mammals or in ticks. The protein influences host IFN responses as well as suppresses multiple host microbicidal activities involving serum complement, neutrophils, and antimicrobial peptides. We also discovered a remarkable plasticity in BBA57 mediated spirochete immune evasion strategy because its loss, although resulting in near clearance of pathogens at the inoculum site, triggers nonheritable adaptive changes that exclude detectable nucleotide alterations in the genome but incorporate transcriptional reprograming events. Understanding the malleability in spirochetal immune evasion mechanisms that ensures their host persistence is critical for the development of novel therapeutic and preventive approaches to combat long-term infections like Lyme borreliosis. PMID- 29610320 TI - Label-free and charge-sensitive dynamic imaging of lipid membrane hydration on millisecond time scales. AB - Biological membranes are highly dynamic and complex lipid bilayers, responsible for the fate of living cells. To achieve this function, the hydrating environment is crucial. However, membrane imaging typically neglects water, focusing on the insertion of probes, resonant responses of lipids, or the hydrophobic core. Owing to a recent improvement of second-harmonic (SH) imaging throughput by three orders of magnitude, we show here that we can use SH microscopy to follow membrane hydration of freestanding lipid bilayers on millisecond time scales. Instead of using the UV/VIS resonant response of specific membrane-inserted fluorophores to record static SH images over time scales of >1,000 s, we SH imaged symmetric and asymmetric lipid membranes, while varying the ionic strength and pH of the adjacent solutions. We show that the nonresonant SH response of water molecules aligned by charge-dipole interactions with charged lipids can be used as a label-free probe of membrane structure and dynamics. Lipid domain diffusion is imaged label-free by means of the hydration of charged domains. The orientational ordering of water is used to construct electrostatic membrane potential maps. The average membrane potential depends quadratically on an applied external bias, which is modeled by nonlinear optical theory. Spatiotemporal fluctuations on the order of 100-mV changes in the membrane potential are seen. These changes imply that membranes are very dynamic, not only in their structure but also in their membrane potential landscape. This may have important consequences for membrane function, mechanical stability, and protein/pore distributions. PMID- 29610322 TI - Hominin skeletal part abundances and claims of deliberate disposal of corpses in the Middle Pleistocene. AB - Humans are set apart from other organisms by the realization of their own mortality. Thus, determining the prehistoric emergence of this capacity is of significant interest to understanding the uniqueness of the human animal. Tracing that capacity chronologically is possible through archaeological investigations that focus on physical markers that reflect "mortality salience." Among these markers is the deliberate and culturally mediated disposal of corpses. Some Neandertal bone assemblages are among the earliest reasonable claims for the deliberate disposal of hominins, but even these are vigorously debated. More dramatic assertions center on the Middle Pleistocene sites of Sima de los Huesos (SH, Spain) and the Dinaledi Chamber (DC, South Africa), where the remains of multiple hominin individuals were found in deep caves, and under reported taphonomic circumstances that seem to discount the possibility that nonhominin actors and processes contributed to their formation. These claims, with significant implications for charting the evolution of the "human condition," deserve scrutiny. We test these assertions through machine-learning analyses of hominin skeletal part representation in the SH and DC assemblages. Our results indicate that nonanthropogenic agents and abiotic processes cannot yet be ruled out as significant contributors to the ultimate condition of both collections. This finding does not falsify hypotheses of deliberate disposal for the SH and DC corpses, but does indicate that the data also support partially or completely nonanthropogenic formational histories. PMID- 29610323 TI - Correction for Itkin et al., The biosynthetic pathway of the nonsugar, high intensity sweetener mogroside V from Siraitia grosvenorii. PMID- 29610324 TI - Direct electrochemical observation of glucosidase activity in isolated single lysosomes from a living cell. AB - The protein activity in individual intracellular compartments in single living cells must be analyzed to obtain an understanding of protein function at subcellular locations. The current methodology for probing activity is often not resolved to the level of an individual compartment, and the results provide an extent of reaction that is averaged from a group of compartments. To address this technological limitation, a single lysosome is sorted from a living cell via electrophoresis into a nanocapillary designed to electrochemically analyze internal solution. The activity of a protein specific to lysosomes, beta glucosidase, is determined by the electrochemical quantification of hydrogen peroxide generated from the reaction with its substrate and the associated enzymes preloaded in the nanocapillary. Sorting and assaying multiple lysosomes from the same cell shows the relative homogeneity of protein activity between different lysosomes, whereas the protein activity in single lysosomes from different cells of the same type is heterogeneous. Thus, this study for the analysis of protein activity within targeted cellular compartments allows direct study of protein function at subcellular resolution and provides unprecedented information about the homogeneity within the lysosomal population of a single cell. PMID- 29610326 TI - Correction for Li et al., Regulator of G protein signaling 5 protects against cardiac hypertrophy and fibrosis during biomechanical stress of pressure overload. PMID- 29610325 TI - A small-molecule fragment that emulates binding of receptor and broadly neutralizing antibodies to influenza A hemagglutinin. AB - The influenza virus hemagglutinin (HA) glycoprotein mediates receptor binding and membrane fusion during viral entry in host cells. Blocking these key steps in viral infection has applications for development of novel antiinfluenza therapeutics as well as vaccines. However, the lack of structural information on how small molecules can gain a foothold in the small, shallow receptor-binding site (RBS) has hindered drug design against this important target on the viral pathogen. Here, we report on the serendipitous crystallization-based discovery of a small-molecule N-cyclohexyltaurine, commonly known as the buffering agent CHES, that is able to bind to both group-1 and group-2 HAs of influenza A viruses. X ray structural characterization of group-1 H5N1 A/Vietnam/1203/2004 (H5/Viet) and group-2 H3N2 A/Hong Kong/1/1968 (H3/HK68) HAs at 2.0-A and 2.57-A resolution, respectively, revealed that N-cyclohexyltaurine binds to the heart of the conserved HA RBS. N-cyclohexyltaurine mimics the binding mode of the natural receptor sialic acid and RBS-targeting bnAbs through formation of similar hydrogen bonds and CH-pi interactions with the HA. In H3/HK68, N cyclohexyltaurine also binds to a conserved pocket in the stem region, thereby exhibiting a dual-binding mode in group-2 HAs. These long-awaited structural insights into RBS recognition by a noncarbohydrate-based small molecule enhance our knowledge of how to target this important functional site and can serve as a template to guide the development of novel broad-spectrum small-molecule therapeutics against influenza virus. PMID- 29610327 TI - Precise characterization of KRAS4b proteoforms in human colorectal cells and tumors reveals mutation/modification cross-talk. AB - Mutations of the KRAS gene are found in human cancers with high frequency and result in the constitutive activation of its protein products. This leads to aberrant regulation of downstream pathways, promoting cell survival, proliferation, and tumorigenesis that drive cancer progression and negatively affect treatment outcomes. Here, we describe a workflow that can detect and quantify mutation-specific consequences of KRAS biochemistry, namely linked changes in posttranslational modifications (PTMs). We combined immunoaffinity enrichment with detection by top-down mass spectrometry to discover and quantify proteoforms with or without the Gly13Asp mutation (G13D) specifically in the KRAS4b isoform. The workflow was applied first to isogenic KRAS colorectal cancer (CRC) cell lines and then to patient CRC tumors with matching KRAS genotypes. In two cellular models, a direct link between the knockout of the mutant G13D allele and the complete nitrosylation of cysteine 118 of the remaining WT KRAS4b was observed. Analysis of tumor samples quantified the percentage of mutant KRAS4b actually present in cancer tissue and identified major differences in the levels of C-terminal carboxymethylation, a modification critical for membrane association. These data from CRC cells and human tumors suggest mechanisms of posttranslational regulation that are highly context-dependent and which lead to preferential production of specific KRAS4b proteoforms. PMID- 29610328 TI - Ectopic neurogenesis induced by prenatal antiepileptic drug exposure augments seizure susceptibility in adult mice. AB - Epilepsy is a neurological disorder often associated with seizure that affects ~0.7% of pregnant women. During pregnancy, most epileptic patients are prescribed antiepileptic drugs (AEDs) such as valproic acid (VPA) to control seizure activity. Here, we show that prenatal exposure to VPA in mice increases seizure susceptibility in adult offspring through mislocalization of newborn neurons in the hippocampus. We confirmed that neurons newly generated from neural stem/progenitor cells (NS/PCs) are integrated into the granular cell layer in the adult hippocampus; however, prenatal VPA treatment altered the expression in NS/PCs of genes associated with cell migration, including CXC motif chemokine receptor 4 (Cxcr4), consequently increasing the ectopic localization of newborn neurons in the hilus. We also found that voluntary exercise in a running wheel suppressed this ectopic neurogenesis and countered the enhanced seizure susceptibility caused by prenatal VPA exposure, probably by normalizing the VPA disrupted expression of multiple genes including Cxcr4 in adult NS/PCs. Replenishing Cxcr4 expression alone in NS/PCs was sufficient to overcome the aberrant migration of newborn neurons and increased seizure susceptibility in VPA exposed mice. Thus, prenatal exposure to an AED, VPA, has a long-term effect on the behavior of NS/PCs in offspring, but this effect can be counteracted by a simple physical activity. Our findings offer a step to developing strategies for managing detrimental effects in offspring exposed to VPA in utero. PMID- 29610329 TI - Hybridization and gene flow in the mega-pest lineage of moth, Helicoverpa. AB - Within the mega-pest lineage of heliothine moths are a number of polyphagous, highly mobile species for which the exchange of adaptive traits through hybridization would affect their properties as pests. The recent invasion of South America by one of the most significant agricultural pests, Helicoverpa armigera, raises concerns for the formation of novel combinations of adaptive genes following hybridization with the closely related Helicoverpa zea To investigate the propensity for hybridization within the genus Helicoverpa, we carried out whole-genome resequencing of samples from six species, focusing in particular upon H. armigera population structure and its relationship with H. zea We show that both H. armigera subspecies have greater genetic diversity and effective population sizes than do the other species. We find no signals for gene flow among the six species, other than between H. armigera and H. zea, with nine Brazilian individuals proving to be hybrids of those two species. Eight had largely H. armigera genomes with some introgressed DNA from H. zea scattered throughout. The ninth resembled an F1 hybrid but with stretches of homozygosity for each parental species that reflect previous hybridization. Regions homozygous for H. armigera-derived DNA in this individual included one containing a gustatory receptor and esterase genes previously associated with host range, while another encoded a cytochrome P450 that confers insecticide resistance. Our data point toward the emergence of novel hybrid ecotypes and highlight the importance of monitoring H. armigera genotypes as they spread through the Americas. PMID- 29610330 TI - Seagrass habitat metabolism increases short-term extremes and long-term offset of CO2 under future ocean acidification. AB - The role of rising atmospheric CO2 in modulating estuarine carbonate system dynamics remains poorly characterized, likely due to myriad processes driving the complex chemistry in these habitats. We reconstructed the full carbonate system of an estuarine seagrass habitat for a summer period of 2.5 months utilizing a combination of time-series observations and mechanistic modeling, and quantified the roles of aerobic metabolism, mixing, and gas exchange in the observed dynamics. The anthropogenic CO2 burden in the habitat was estimated for the years 1765-2100 to quantify changes in observed high-frequency carbonate chemistry dynamics. The addition of anthropogenic CO2 alters the thermodynamic buffer factors (e.g., the Revelle factor) of the carbonate system, decreasing the seagrass habitat's ability to buffer natural carbonate system fluctuations. As a result, the most harmful carbonate system indices for many estuarine organisms [minimum pHT, minimum Omegaarag, and maximum pCO2(s.w.)] change up to 1.8*, 2.3*, and 1.5* more rapidly than the medians for each parameter, respectively. In this system, the relative benefits of the seagrass habitat in locally mitigating ocean acidification increase with the higher atmospheric CO2 levels predicted toward 2100. Presently, however, these mitigating effects are mixed due to intense diel cycling of CO2 driven by aerobic metabolism. This study provides estimates of how high-frequency pHT, Omegaarag, and pCO2(s.w.) dynamics are altered by rising atmospheric CO2 in an estuarine habitat, and highlights nonlinear responses of coastal carbonate parameters to ocean acidification relevant for water quality management. PMID- 29610331 TI - Evolutionary emergence of the rac3b/rfng/sgca regulatory cluster refined mechanisms for hindbrain boundaries formation. AB - Developmental programs often rely on parallel morphogenetic mechanisms that guarantee precise tissue architecture. While redundancy constitutes an obvious selective advantage, little is known on how novel morphogenetic mechanisms emerge during evolution. In zebrafish, rhombomeric boundaries behave as an elastic barrier, preventing cell intermingling between adjacent compartments. Here, we identify the fundamental role of the small-GTPase Rac3b in actomyosin cable assembly at hindbrain boundaries. We show that the novel rac3b/rfng/sgca regulatory cluster, which is specifically expressed at the boundaries, emerged in the Ostariophysi superorder by chromosomal rearrangement that generated new cis regulatory interactions. By combining 4C-seq, ATAC-seq, transgenesis, and CRISPR induced deletions, we characterized this regulatory domain, identifying hindbrain boundary-specific cis-regulatory elements. Our results suggest that the capacity of boundaries to act as an elastic mesh for segregating rhombomeric cells evolved by cooption of critical genes to a novel regulatory block, refining the mechanisms for hindbrain segmentation. PMID- 29610332 TI - Accurate and sensitive quantification of protein-DNA binding affinity. AB - Transcription factors (TFs) control gene expression by binding to genomic DNA in a sequence-specific manner. Mutations in TF binding sites are increasingly found to be associated with human disease, yet we currently lack robust methods to predict these sites. Here, we developed a versatile maximum likelihood framework named No Read Left Behind (NRLB) that infers a biophysical model of protein-DNA recognition across the full affinity range from a library of in vitro selected DNA binding sites. NRLB predicts human Max homodimer binding in near-perfect agreement with existing low-throughput measurements. It can capture the specificity of the p53 tetramer and distinguish multiple binding modes within a single sample. Additionally, we confirm that newly identified low-affinity enhancer binding sites are functional in vivo, and that their contribution to gene expression matches their predicted affinity. Our results establish a powerful paradigm for identifying protein binding sites and interpreting gene regulatory sequences in eukaryotic genomes. PMID- 29610333 TI - High-accuracy lagging-strand DNA replication mediated by DNA polymerase dissociation. AB - The fidelity of DNA replication is a critical factor in the rate at which cells incur mutations. Due to the antiparallel orientation of the two chromosomal DNA strands, one strand (leading strand) is replicated in a mostly processive manner, while the other (lagging strand) is synthesized in short sections called Okazaki fragments. A fundamental question that remains to be answered is whether the two strands are copied with the same intrinsic fidelity. In most experimental systems, this question is difficult to answer, as the replication complex contains a different DNA polymerase for each strand, such as, for example, DNA polymerases delta and epsilon in eukaryotes. Here we have investigated this question in the bacterium Escherichia coli, in which the replicase (DNA polymerase III holoenzyme) contains two copies of the same polymerase (Pol III, the dnaE gene product), and hence the two strands are copied by the same polymerase. Our in vivo mutagenesis data indicate that the two DNA strands are not copied with the same accuracy, and that, remarkably, the lagging strand has the highest fidelity. We postulate that this effect results from the greater dissociative character of the lagging-strand polymerase, which provides additional options for error removal. Our conclusion is strongly supported by results with dnaE antimutator polymerases characterized by increased dissociation rates. PMID- 29610334 TI - Impact of the tree prior on estimating clock rates during epidemic outbreaks. AB - Bayesian phylogenetics aims at estimating phylogenetic trees together with evolutionary and population dynamic parameters based on genetic sequences. It has been noted that the clock rate, one of the evolutionary parameters, decreases with an increase in the sampling period of sequences. In particular, clock rates of epidemic outbreaks are often estimated to be higher compared with the long term clock rate. Purifying selection has been suggested as a biological factor that contributes to this phenomenon, since it purges slightly deleterious mutations from a population over time. However, other factors such as methodological biases may also play a role and make a biological interpretation of results difficult. In this paper, we identify methodological biases originating from the choice of tree prior, that is, the model specifying epidemiological dynamics. With a simulation study we demonstrate that a misspecification of the tree prior can upwardly bias the inferred clock rate and that the interplay of the different models involved in the inference can be complex and nonintuitive. We also show that the choice of tree prior can influence the inference of clock rate on real-world Ebola virus (EBOV) datasets. While commonly used tree priors result in very high clock-rate estimates for sequences from the initial phase of the epidemic in Sierra Leone, tree priors allowing for population structure lead to estimates agreeing with the long-term rate for EBOV. PMID- 29610335 TI - Negative regulator of E2F transcription factors links cell cycle checkpoint and DNA damage repair. AB - DNA damage poses a serious threat to genome integrity and greatly affects growth and development. To maintain genome stability, all organisms have evolved elaborate DNA damage response mechanisms including activation of cell cycle checkpoints and DNA repair. Here, we show that the DNA repair protein SNI1, a subunit of the evolutionally conserved SMC5/6 complex, directly links these two processes in Arabidopsis SNI1 binds to the activation domains of E2F transcription factors, the key regulators of cell cycle progression, and represses their transcriptional activities. In turn, E2Fs activate the expression of SNI1, suggesting that E2Fs and SNI1 form a negative feedback loop. Genetically, overexpression of SNI1 suppresses the phenotypes of E2F overexpressing plants, and loss of E2F function fully suppresses the sni1 mutant, indicating that SNI1 is necessary and sufficient to inhibit E2Fs. Altogether, our study revealed that SNI1 is a negative regulator of E2Fs and plays dual roles in DNA damage responses by linking cell cycle checkpoint and DNA repair. PMID- 29610336 TI - Origins and spread of fluted-point technology in the Canadian Ice-Free Corridor and eastern Beringia. AB - Fluted projectile points have long been recognized as the archaeological signature of early humans dispersing throughout the Western Hemisphere; however, we still lack a clear understanding of their appearance in the interior "Ice-Free Corridor" of western Canada and eastern Beringia. To solve this problem, we conducted a geometric morphometric shape analysis and a phylogenetic analysis of technological traits on fluted points from the archaeological records of northern Alaska and Yukon, in combination with artifacts from further south in Canada, the Great Plains, and eastern United States to investigate the plausibility of historical relatedness and evolutionary patterns in the spread of fluted-point technology in the latest Pleistocene and earliest Holocene. Results link morphologies and technologies of Clovis, certain western Canadian, and northern fluted points, suggesting that fluting technology arrived in the Arctic from a proximate source in the interior Ice-Free Corridor and ultimately from the earliest populations in temperate North America, complementing new genomic models explaining the peopling of the Americas. PMID- 29610338 TI - Good news and bad news of blue carbon. PMID- 29610337 TI - Human bony labyrinth is an indicator of population history and dispersal from Africa. AB - The dispersal of modern humans from Africa is now well documented with genetic data that track population history, as well as gene flow between populations. Phenetic skeletal data, such as cranial and pelvic morphologies, also exhibit a dispersal-from-Africa signal, which, however, tends to be blurred by the effects of local adaptation and in vivo phenotypic plasticity, and that is often deteriorated by postmortem damage to skeletal remains. These complexities raise the question of which skeletal structures most effectively track neutral population history. The cavity system of the inner ear (the so-called bony labyrinth) is a good candidate structure for such analyses. It is already fully formed by birth, which minimizes postnatal phenotypic plasticity, and it is generally well preserved in archaeological samples. Here we use morphometric data of the bony labyrinth to show that it is a surprisingly good marker of the global dispersal of modern humans from Africa. Labyrinthine morphology tracks genetic distances and geography in accordance with an isolation-by-distance model with dispersal from Africa. Our data further indicate that the neutral-like pattern of variation is compatible with stabilizing selection on labyrinth morphology. Given the increasingly important role of the petrous bone for ancient DNA recovery from archaeological specimens, we encourage researchers to acquire 3D morphological data of the inner ear structures before any invasive sampling. Such data will constitute an important archive of phenotypic variation in present and past populations, and will permit individual-based genotype-phenotype comparisons. PMID- 29610339 TI - The Vibrio cholerae type VI secretion system can modulate host intestinal mechanics to displace gut bacterial symbionts. AB - Host-associated microbiota help defend against bacterial pathogens; however, the mechanisms by which pathogens overcome this defense remain largely unknown. We developed a zebrafish model and used live imaging to directly study how the human pathogen Vibrio cholerae invades the intestine. The gut microbiota of fish monocolonized by symbiotic strain Aeromonas veronii was displaced by V. cholerae expressing its type VI secretion system (T6SS), a syringe-like apparatus that deploys effector proteins into target cells. Surprisingly, displacement was independent of T6SS-mediated killing of A. veronii, driven instead by T6SS induced enhancement of zebrafish intestinal movements that led to expulsion of the resident microbiota by the host. Deleting an actin cross-linking domain from the T6SS apparatus returned intestinal motility to normal and thwarted expulsion, without weakening V. cholerae's ability to kill A. veronii in vitro. Our finding that bacteria can manipulate host physiology to influence intermicrobial competition has implications for both pathogenesis and microbiome engineering. PMID- 29610340 TI - Fluctuations uncover a distinct class of traveling waves. AB - Epidemics, flame propagation, and cardiac rhythms are classic examples of reaction-diffusion waves that describe a switch from one alternative state to another. Only two types of waves are known: pulled, driven by the leading edge, and pushed, driven by the bulk of the wave. Here, we report a distinct class of semipushed waves for which both the bulk and the leading edge contribute to the dynamics. These hybrid waves have the kinetics of pushed waves, but exhibit giant fluctuations similar to pulled waves. The transitions between pulled, semipushed, and fully pushed waves occur at universal ratios of the wave velocity to the Fisher velocity. We derive these results in the context of a species invading a new habitat by examining front diffusion, rate of diversity loss, and fluctuation induced corrections to the expansion velocity. All three quantities decrease as a power law of the population density with the same exponent. We analytically calculate this exponent, taking into account the fluctuations in the shape of the wave front. For fully pushed waves, the exponent is -1, consistent with the central limit theorem. In semipushed waves, however, the fluctuations average out much more slowly, and the exponent approaches 0 toward the transition to pulled waves. As a result, a rapid loss of genetic diversity and large fluctuations in the position of the front occur, even for populations with cooperative growth and other forms of an Allee effect. The evolutionary outcome of spatial spreading in such populations could therefore be less predictable than previously thought. PMID- 29610341 TI - Multiple nuclear-replicating viruses require the stress-induced protein ZC3H11A for efficient growth. AB - The zinc finger CCCH-type containing 11A (ZC3H11A) gene encodes a well-conserved zinc finger protein that may function in mRNA export as it has been shown to associate with the transcription export (TREX) complex in proteomic screens. Here, we report that ZC3H11A is a stress-induced nuclear protein with RNA-binding capacity that localizes to nuclear splicing speckles. During an adenovirus infection, the ZC3H11A protein and splicing factor SRSF2 relocalize to nuclear regions where viral DNA replication and transcription take place. Knockout (KO) of ZC3H11A in HeLa cells demonstrated that several nuclear-replicating viruses are dependent on ZC3H11A for efficient growth (HIV, influenza virus, herpes simplex virus, and adenovirus), whereas cytoplasmic replicating viruses are not (vaccinia virus and Semliki Forest virus). High-throughput sequencing of ZC3H11A cross-linked RNA showed that ZC3H11A binds to short purine-rich ribonucleotide stretches in cellular and adenoviral transcripts. We show that the RNA-binding property of ZC3H11A is crucial for its function and localization. In ZC3H11A KO cells, the adenovirus fiber mRNA accumulates in the cell nucleus. Our results suggest that ZC3H11A is important for maintaining nuclear export of mRNAs during stress and that several nuclear-replicating viruses take advantage of this mechanism to facilitate their replication. PMID- 29610342 TI - Transcriptional mutagenesis mediated by 8-oxoG induces translational errors in mammalian cells. AB - Reactive oxygen species formed within the mammalian cell can produce 8-oxo-7,8 dihydroguanine (8-oxoG) in mRNA, which can cause base mispairing during gene expression. Here we found that administration of 8-oxoGTP in MTH1-knockdown cells results in increased 8-oxoG content in mRNA. Under this condition, an amber mutation of the reporter luciferase is suppressed. Using second-generation sequencing techniques, we found that U-to-G changes at preassigned sites of the luciferase transcript increased when 8-oxoGTP was supplied. In addition, an increased level of 8-oxoG content in RNA induced the accumulation of aggregable amyloid beta peptides in cells expressing amyloid precursor protein. Our findings indicate that 8-oxoG accumulation in mRNA can alter protein synthesis in mammalian cells. Further work is required to assess the significance of these findings under normal physiological conditions. PMID- 29610344 TI - Multiscale mixing patterns in networks. AB - Assortative mixing in networks is the tendency for nodes with the same attributes, or metadata, to link to each other. It is a property often found in social networks, manifesting as a higher tendency of links occurring between people of the same age, race, or political belief. Quantifying the level of assortativity or disassortativity (the preference of linking to nodes with different attributes) can shed light on the organization of complex networks. It is common practice to measure the level of assortativity according to the assortativity coefficient, or modularity in the case of categorical metadata. This global value is the average level of assortativity across the network and may not be a representative statistic when mixing patterns are heterogeneous. For example, a social network spanning the globe may exhibit local differences in mixing patterns as a consequence of differences in cultural norms. Here, we introduce an approach to localize this global measure so that we can describe the assortativity, across multiple scales, at the node level. Consequently, we are able to capture and qualitatively evaluate the distribution of mixing patterns in the network. We find that, for many real-world networks, the distribution of assortativity is skewed, overdispersed, and multimodal. Our method provides a clearer lens through which we can more closely examine mixing patterns in networks. PMID- 29610343 TI - Transient fibrosis resolves via fibroblast inactivation in the regenerating zebrafish heart. AB - In the zebrafish (Danio rerio), regeneration and fibrosis after cardiac injury are not mutually exclusive responses. Upon cardiac cryoinjury, collagen and other extracellular matrix (ECM) proteins accumulate at the injury site. However, in contrast to the situation in mammals, fibrosis is transient in zebrafish and its regression is concomitant with regrowth of the myocardial wall. Little is known about the cells producing this fibrotic tissue or how it resolves. Using novel genetic tools to mark periostin b- and collagen 1alpha2 (col1a2)-expressing cells in combination with transcriptome analysis, we explored the sources of activated fibroblasts and traced their fate. We describe that during fibrosis regression, fibroblasts are not fully eliminated but become inactivated. Unexpectedly, limiting the fibrotic response by genetic ablation of col1a2-expressing cells impaired cardiomyocyte proliferation. We conclude that ECM-producing cells are key players in the regenerative process and suggest that antifibrotic therapies might be less efficient than strategies targeting fibroblast inactivation. PMID- 29610345 TI - Molecular excitonic seesaws. AB - The breaking of molecular symmetry through photoexcitation is a ubiquitous but rather elusive process, which, for example, controls the microscopic efficiency of light harvesting in molecular aggregates. A molecular excitation within a pi conjugated segment will self-localize due to strong coupling to molecular vibrations, locally changing bond alternation in a process which is fundamentally nondeterministic. Probing such symmetry breaking usually relies on polarization resolved fluorescence, which is most powerful on the level of single molecules. Here, we explore symmetry breaking by designing a large, asymmetric acceptor donor-acceptor (A1-D-A2) complex 10 nm in length, where excitation energy can flow from the donor, a pi-conjugated oligomer, to either one of the two boron dipyrromethene (bodipy) dye acceptors of different color. Fluorescence correlation spectroscopy (FCS) reveals a nondeterministic switching between the energy-transfer pathways from the oligomer to the two acceptor groups on the submillisecond timescale. We conclude that excitation energy transfer, and light harvesting in general, are fundamentally nondeterministic processes, which can be strongly perturbed by external stimuli. A simple demonstration of the relation between exciton localization within the extended pi-system and energy transfer to the endcap is given by considering the selectivity of endcap emission through the polarization of the excitation light in triads with bent oligomer backbones. Bending leads to increased localization so that the molecule acquires bichromophoric characteristics in terms of its fluorescence photon statistics. PMID- 29610347 TI - Thermodynamic limits of energy harvesting from outgoing thermal radiation. AB - We derive the thermodynamic limits of harvesting power from the outgoing thermal radiation from the ambient to the cold outer space. The derivations are based on a duality relation between thermal engines that harvest solar radiation and those that harvest outgoing thermal radiation. In particular, we derive the ultimate limit for harvesting outgoing thermal radiation, which is analogous to the Landsberg limit for solar energy harvesting, and show that the ultimate limit far exceeds what was previously thought to be possible. As an extension of our work, we also derive the ultimate limit of efficiency of thermophotovoltaic systems. PMID- 29610346 TI - Flavivirus internalization is regulated by a size-dependent endocytic pathway. AB - Flaviviruses enter host cells through the process of clathrin-mediated endocytosis, and the spectrum of host factors required for this process are incompletely understood. Here we found that lymphocyte antigen 6 locus E (LY6E) promotes the internalization of multiple flaviviruses, including West Nile virus, Zika virus, and dengue virus. Perhaps surprisingly, LY6E is dispensable for the internalization of the endogenous cargo transferrin, which is also dependent on clathrin-mediated endocytosis for uptake. Since viruses are substantially larger than transferrin, we reasoned that LY6E may be required for uptake of larger cargoes and tested this using transferrin-coated beads of similar size as flaviviruses. LY6E was indeed required for the internalization of transferrin coated beads, suggesting that LY6E is selectively required for large cargo. Cell biological studies found that LY6E forms tubules upon viral infection and bead internalization, and we found that tubule formation was dependent on RNASEK, which is also required for flavivirus internalization, but not transferrin uptake. Indeed, we found that RNASEK is also required for the internalization of transferrin-coated beads, suggesting it functions upstream of LY6E. These LY6E tubules resembled microtubules, and we found that microtubule assembly was required for their formation and flavivirus uptake. Since microtubule end-binding proteins link microtubules to downstream activities, we screened the three end binding proteins and found that EB3 promotes virus uptake and LY6E tubularization. Taken together, these results highlight a specialized pathway required for the uptake of large clathrin-dependent endocytosis cargoes, including flaviviruses. PMID- 29610348 TI - Activation of AMPK by metformin improves withdrawal signs precipitated by nicotine withdrawal. AB - Cigarette smoking is the leading cause of preventable disease and death in the United States, with more persons dying from nicotine addiction than any other preventable cause of death. Even though smoking cessation incurs multiple health benefits, the abstinence rate remains low with current medications. Here we show that the AMP-activated protein kinase (AMPK) pathway in the hippocampus is activated following chronic nicotine use, an effect that is rapidly reversed by nicotine withdrawal. Increasing pAMPK levels and, consequently, downstream AMPK signaling pharmacologically attenuate anxiety-like behavior following nicotine withdrawal. We show that metformin, a known AMPK activator in the periphery, reduces withdrawal symptoms through a mechanism dependent on the presence of the AMPKalpha subunits within the hippocampus. This study provides evidence of a direct effect of AMPK modulation on nicotine withdrawal symptoms and suggests central AMPK activation as a therapeutic target for smoking cessation. PMID- 29610349 TI - Soft self-assembly of Weyl materials for light and sound. AB - Soft materials can self-assemble into highly structured phases that replicate at the mesoscopic scale the symmetry of atomic crystals. As such, they offer an unparalleled platform to design mesostructured materials for light and sound. Here, we present a bottom-up approach based on self-assembly to engineer 3D photonic and phononic crystals with topologically protected Weyl points. In addition to angular and frequency selectivity of their bulk optical response, Weyl materials are endowed with topological surface states, which allow for the existence of one-way channels, even in the presence of time-reversal invariance. Using a combination of group-theoretical methods and numerical simulations, we identify the general symmetry constraints that a self-assembled structure has to satisfy to host Weyl points and describe how to achieve such constraints using a symmetry-driven pipeline for self-assembled material design and discovery. We illustrate our general approach using block copolymer self-assembly as a model system. PMID- 29610351 TI - Topological order in the pseudogap metal. AB - We compute the electronic Green's function of the topologically ordered Higgs phase of a SU(2) gauge theory of fluctuating antiferromagnetism on the square lattice. The results are compared with cluster extensions of dynamical mean field theory, and quantum Monte Carlo calculations, on the pseudogap phase of the strongly interacting hole-doped Hubbard model. Good agreement is found in the momentum, frequency, hopping, and doping dependencies of the spectral function and electronic self-energy. We show that lines of (approximate) zeros of the zero frequency electronic Green's function are signs of the underlying topological order of the gauge theory and describe how these lines of zeros appear in our theory of the Hubbard model. We also derive a modified, nonperturbative version of the Luttinger theorem that holds in the Higgs phase. PMID- 29610350 TI - Myosin IIA interacts with the spectrin-actin membrane skeleton to control red blood cell membrane curvature and deformability. AB - The biconcave disk shape and deformability of mammalian RBCs rely on the membrane skeleton, a viscoelastic network of short, membrane-associated actin filaments (F actin) cross-linked by long, flexible spectrin tetramers. Nonmuscle myosin II (NMII) motors exert force on diverse F-actin networks to control cell shapes, but a function for NMII contractility in the 2D spectrin-F-actin network of RBCs has not been tested. Here, we show that RBCs contain membrane skeleton-associated NMIIA puncta, identified as bipolar filaments by superresolution fluorescence microscopy. MgATP disrupts NMIIA association with the membrane skeleton, consistent with NMIIA motor domains binding to membrane skeleton F-actin and contributing to membrane mechanical properties. In addition, the phosphorylation of the RBC NMIIA heavy and light chains in vivo indicates active regulation of NMIIA motor activity and filament assembly, while reduced heavy chain phosphorylation of membrane skeleton-associated NMIIA indicates assembly of stable filaments at the membrane. Treatment of RBCs with blebbistatin, an inhibitor of NMII motor activity, decreases the number of NMIIA filaments associated with the membrane and enhances local, nanoscale membrane oscillations, suggesting decreased membrane tension. Blebbistatin-treated RBCs also exhibit elongated shapes, loss of membrane curvature, and enhanced deformability, indicating a role for NMIIA contractility in promoting membrane stiffness and maintaining RBC biconcave disk cell shape. As structures similar to the RBC membrane skeleton exist in many metazoan cell types, these data demonstrate a general function for NMII in controlling specialized membrane morphology and mechanical properties through contractile interactions with short F-actin in spectrin-F-actin networks. PMID- 29610354 TI - Observation of acetyl phosphate formation in mammalian mitochondria using real time in-organelle NMR metabolomics. AB - Recent studies point out the link between altered mitochondrial metabolism and cancer, and detailed understanding of mitochondrial metabolism requires real-time detection of its metabolites. Employing heteronuclear 2D NMR spectroscopy and 13C3-pyruvate, we propose in-organelle metabolomics that allows for the monitoring of mitochondrial metabolic changes in real time. The approach identified acetyl phosphate from human mitochondria, whose production has been largely neglected in eukaryotic metabolism since its first description about 70 years ago in bacteria. The kinetic profile of acetyl phosphate formation was biphasic, and its transient nature suggested its role as a metabolic intermediate. The method also allowed for the estimation of pyruvate dehydrogenase (PDH) enzyme activity through monitoring of the acetyl-CoA formation, independent of competing cytosolic metabolism. The results confirmed the positive regulation of mitochondrial PDH activity by p53, a well-known tumor suppressor. Our approach can easily be applied to other organelle-specific metabolic studies. PMID- 29610352 TI - Spatial organization and dynamics of RNase E and ribosomes in Caulobacter crescentus. AB - We report the dynamic spatial organization of Caulobacter crescentus RNase E (RNA degradosome) and ribosomal protein L1 (ribosome) using 3D single-particle tracking and superresolution microscopy. RNase E formed clusters along the central axis of the cell, while weak clusters of ribosomal protein L1 were deployed throughout the cytoplasm. These results contrast with RNase E and ribosome distribution in Escherichia coli, where RNase E colocalizes with the cytoplasmic membrane and ribosomes accumulate in polar nucleoid-free zones. For both RNase E and ribosomes in Caulobacter, we observed a decrease in confinement and clustering upon transcription inhibition and subsequent depletion of nascent RNA, suggesting that RNA substrate availability for processing, degradation, and translation facilitates confinement and clustering. Importantly, RNase E cluster positions correlated with the subcellular location of chromosomal loci of two highly transcribed rRNA genes, suggesting that RNase E's function in rRNA processing occurs at the site of rRNA synthesis. Thus, components of the RNA degradosome and ribosome assembly are spatiotemporally organized in Caulobacter, with chromosomal readout serving as the template for this organization. PMID- 29610353 TI - Superresolution microscopy reveals structural mechanisms driving the nanoarchitecture of a viral chromatin tether. AB - By tethering their circular genomes (episomes) to host chromatin, DNA tumor viruses ensure retention and segregation of their genetic material during cell divisions. Despite functional genetic and crystallographic studies, there is little information addressing the 3D structure of these tethers in cells, issues critical for understanding persistent infection by these viruses. Here, we have applied direct stochastic optical reconstruction microscopy (dSTORM) to establish the nanoarchitecture of tethers within cells latently infected with the oncogenic human pathogen, Kaposi's sarcoma-associated herpesvirus (KSHV). Each KSHV tether comprises a series of homodimers of the latency-associated nuclear antigen (LANA) that bind with their C termini to the tandem array of episomal terminal repeats (TRs) and with their N termini to host chromatin. Superresolution imaging revealed that individual KSHV tethers possess similar overall dimensions and, in aggregate, fold to occupy the volume of a prolate ellipsoid. Using plasmids with increasing numbers of TRs, we found that tethers display polymer power law scaling behavior with a scaling exponent characteristic of active chromatin. For plasmids containing a two-TR tether, we determined the size, separation, and relative orientation of two distinct clusters of bound LANA, each corresponding to a single TR. From these data, we have generated a 3D model of the episomal half of the tether that integrates and extends previously established findings from epifluorescent, crystallographic, and epigenetic approaches. Our findings also validate the use of dSTORM in establishing novel structural insights into the physical basis of molecular connections linking host and pathogen genomes. PMID- 29610357 TI - Formaldehyde Cross-Linking. AB - Formaldehyde cross-linking of DNA to associated proteins is a relatively straightforward method, but it is also the most critical step in the chromatin immunoprecipitation (ChIP) and 3C analyses. Although formaldehyde is a highly permeable cross-linker, its maximum cross-linking efficiencies are estimated to be at ~1% for mammalian cells because reactivity is limited to amines. Therefore, a relatively large number of cells are required for 3C and ChIP-based assays. Five hundred million cross-linked diploid cells are equivalent to ~1.66 fmol of the genome. Thus, only ~100 amol of genomic copies is analyzed for one ChIP assay. Because the quality of cross-linked chromatin can vary, even when generated under near-identical conditions, it is preferable to generate multiple large batches. This protocol describes growing and cross-linking IMR90 primary human fibroblast cells for ChIP analysis. For other cell types, some modification of the protocol is necessary. PMID- 29610358 TI - Preparation of Cross-Linked Chromatin for ChIP. AB - After living cells have been treated with formaldehyde to lock proteins to their DNA substrates, the DNA-protein complexes must be extracted and fragmented as described here. For ChIP-chip, it is not essential that a majority of chromatin fragments are ~500 bp; an average fragment size ranging 1-2 kb is sufficient. However, for ChIP-seq, the average chromatin fragment should be <500 bp. PMID- 29610355 TI - The computational form of craving is a selective multiplication of economic value. AB - Craving is thought to be a specific desire state that biases choice toward the desired object, be it chocolate or drugs. A vast majority of people report having experienced craving of some kind. In its pathological form craving contributes to health outcomes in addiction and obesity. Yet despite its ubiquity and clinical relevance we still lack a basic neurocomputational understanding of craving. Here, using an instantaneous measure of subjective valuation and selective cue exposure, we identify a behavioral signature of a food craving-like state and advance a computational framework for understanding how this state might transform valuation to bias choice. We find desire induced by exposure to a specific high-calorie, high-fat/sugar snack good is expressed in subjects' momentary willingness to pay for this good. This effect is selective but not exclusive to the exposed good; rather, we find it generalizes to nonexposed goods in proportion to their subjective attribute similarity to the exposed ones. A second manipulation of reward size (number of snack units available for purchase) further suggested that a multiplicative gain mechanism supports the transformation of valuation during laboratory craving. These findings help explain how real-world food craving can result in behaviors inconsistent with preferences expressed in the absence of craving and open a path for the computational modeling of craving-like phenomena using a simple and repeatable experimental tool for assessing subjective states in economic terms. PMID- 29610359 TI - ChIP. AB - ChIP is a powerful method for analyzing protein-DNA interactions that occur in vivo. A basic protocol involves immunoprecipitation of the cross-linked nucleoprotein complex and isolating and analyzing the DNA that is associated with the protein of interest. The antibody and chromatin amounts indicated here are for ChIP-chip and ChIP-seq and are ~10-fold higher than for a standard ChIP assay. PMID- 29610356 TI - Spatial eye-hand coordination during bimanual reaching is not systematically coded in either LIP or PRR. AB - We often orient to where we are about to reach. Spatial and temporal correlations in eye and arm movements may depend on the posterior parietal cortex (PPC). Spatial representations of saccade and reach goals preferentially activate cells in the lateral intraparietal area (LIP) and the parietal reach region (PRR), respectively. With unimanual reaches, eye and arm movement patterns are highly stereotyped. This makes it difficult to study the neural circuits involved in coordination. Here, we employ bimanual reaching to two different targets. Animals naturally make a saccade first to one target and then the other, resulting in different patterns of limb-gaze coordination on different trials. Remarkably, neither LIP nor PRR cells code which target the eyes will move to first. These results suggest that the parietal cortex plays at best only a permissive role in some aspects of eye-hand coordination and makes the role of LIP in saccade generation unclear. PMID- 29610360 TI - Isolation of High-Molecular-Weight DNA from Suspension Cultures of Mammalian Cells Using Proteinase K and Phenol. AB - This procedure is the method of choice for purification of mammalian genomic DNA from suspension cultures when large amounts of DNA are required, for example, for Southern blotting. Approximately 200 ug of mammalian DNA, 100-150 kb in length, is obtained from 5 * 107 cultured aneuploid cells (e.g., HeLa cells). PMID- 29610361 TI - Subcutaneous Injection of Pluripotent Stem Cells in Mice. AB - This protocol describes the production of teratomas and teratocarcinomas used to determine the in vivo developmental potential of adult or embryonic tissues, including early-stage embryos, somites, and tail bud, as well as embryonic and other pluripotent stem cells. Resulting tumors are screened by histology and markers to assess differentiation of the tissues. Methods and sites may vary, depending on cell and tissue type. Subcutaneous injections are easy to perform and do not need surgical manipulations. Suspension of cells in Matrigel Basement Membrane (BD Biosciences) promotes their anatomical localization and is a commonly used, efficient, and reproducible approach. PMID- 29610362 TI - Production of High-Titer Retrovirus and Lentivirus Vectors. AB - The most commonly used method for production of retrovirus and lentivirus vectors in research laboratories is of transient transfection of 293T cells with a lentivirus vector plasmid, packaging genome plasmid(s), and an envelope expression plasmid. High-titer stocks are obtained by concentration of vector supernatants by ultracentrifugation. PMID- 29610363 TI - Titration of Lentivirus Vectors. AB - The titer of a lentivirus vector is often expressed in transducing units per milliliter. This is a functional titer that reflects the lentivirus' ability to transduce a particular cell line under specific conditions. Transduction of other cell lines is likely to be different and will require optimization. 293T cells are used for production of lentivirus stocks, and they can be easily transduced with vesicular stomatitis virus glycoprotein (VSV-G) pseudotyped lentivirus vectors. Consequently, this cell line is commonly used to determine the functional titer of lentivirus vector stocks produced with this envelope. For lentivirus vectors encoding fluorescent proteins under the control of promoters functional in these cells, titration can be performed using the limiting dilution method or a flow cytometry-based method. For lentivirus vectors lacking a fluorescent marker, or for those carrying promoters that may not be functional in 293T cells, titer can be determined either by real-time polymerase chain reaction (PCR) quantification of viral genomes in genomic DNA from transduced cells or a p24 ELISA-based assay. PMID- 29610364 TI - Monitoring Lentivirus Vector Stocks for Replication-Competent Viruses. AB - The potential emergence of replication-competent lentiviruses (RCLs) during vector production and the significant biosafety risk that this represents has led to the development of lentivirus vector production systems to minimize the risk of generating RCLs. Second- and third-generation lentivirus vector production systems appear to be safe, because there are no reports of RCL generation in either system. Screening of lentivirus vector stocks for RCLs involves serial passaging of transduced cells for 30 d with weekly monitoring of p24 levels in supernatants using an ELISA Kit. PMID- 29610365 TI - Chemiluminescence. AB - Radioactive reagents have been gradually replaced by nonisotopic reagents for some tasks in molecular biology. Concern over laboratory safety and the economic and environmental aspects of radioactive waste disposal have been key factors in this change. Generally, the new nonisotopic systems have improved in terms of analytical sensitivity and the time required to obtain a result. The most prominent nonisotopic analytical methods exploit chemiluminescence, described here. This technique has been particularly effective when used in combination with an enzyme label, so that the amplifying properties of an enzyme label and the high sensitivity of a chemiluminescent detection reaction are combined to produce an ultrasensitive assay (e.g., chemiluminescent detection of peroxidase- and alkaline phosphatase-labeled proteins and nucleic acid probes). In all of the commonly used applications in molecular biology, the analytical performance of the chemiluminescent systems approaches that of 125I- or 32P-based systems. Chemiluminescent systems also avoid the lengthy signal detection times required with 32P-based methods, yielding results in minutes rather than days. In addition, chemiluminescent probes can be easily stripped from membranes, allowing the membranes to be reprobed many times without significant loss of resolution. Experimental protocols for directly attaching nonisotopic labels to nucleic acids and indirect labeling methods based on biotin, fluorescein, and digoxigenin labels are now well established. The ancillary reagents (e.g., avidin, streptavidin, antidigoxigenin, and antifluorescein enzyme conjugates) required for the indirect methods are widely available. PMID- 29610367 TI - Pathways limiting warming to 1.5 degrees C: a tale of turning around in no time? AB - We explore the feasibility of limiting global warming to 1.5 degrees C without overshoot and without the deployment of carbon dioxide removal (CDR) technologies. For this purpose, we perform a sensitivity analysis of four generic emissions reduction measures to identify a lower bound on future CO2 emissions from fossil fuel combustion and industrial processes. Final energy demand reductions and electrification of energy end uses as well as decarbonization of electricity and non-electric energy supply are all considered. We find the lower bound of cumulative fossil fuel and industry CO2 emissions to be 570 GtCO2 for the period 2016-2100, around 250 GtCO2 lower than the lower end of available 1.5 degrees C mitigation pathways generated with integrated assessment models. Estimates of 1.5 degrees C-consistent CO2 budgets are highly uncertain and range between 100 and 900 GtCO2 from 2016 onwards. Based on our sensitivity analysis, limiting warming to 1.5 degrees C will require CDR or terrestrial net carbon uptake if 1.5 degrees C-consistent budgets are smaller than 650 GtCO2 The earlier CDR is deployed, the more it neutralizes post-2020 emissions rather than producing net negative emissions. Nevertheless, if the 1.5 degrees C budget is smaller than 550 GtCO2, temporary overshoot of the 1.5 degrees C limit becomes unavoidable if CDR cannot be ramped up faster than to 4 GtCO2 in 2040 and 10 GtCO2 in 2050.This article is part of the theme issue 'The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5 degrees C above pre-industrial levels'. PMID- 29610368 TI - The legal character and operational relevance of the Paris Agreement's temperature goal. AB - This article assesses the legal character and operational relevance of the Paris Agreement's 1.5 degrees C temperature goal. This article begins with a textual analysis of the 1.5 degrees C goal. It considers whether the goal creates individual or collective obligations for Parties, and whether it is sufficiently specific to enable the tracking of individual or collective performance. Next, it assesses the operational relevance of the 1.5 degrees C temperature goal, by considering the role it will play in the Paris Agreement's institutions and procedures. To the extent that the goal plays a role, and implies global limits on greenhouse gas emissions, this article observes that it could have implications for the sharing of the effort between Parties. Thus, this article considers the relevance of equity and the principle of common but differentiated responsibilities and respective capabilities, in the light of different national circumstances, to understanding how the 1.5 degrees C goal could be reached. In this context, this article explores whether the 1.5 degrees C goal could play a role in the Paris Agreement's 'ambition cycle'. Finally, this article asks whether there are any legal or political implications, individually or collectively under the Paris Agreement, should the Parties fail to achieve the 1.5 degrees C goal.This article is part of the theme issue 'The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5 degrees C above pre-industrial levels'. PMID- 29610366 TI - Exome chip analyses identify genes affecting mortality after HLA-matched unrelated-donor blood and marrow transplantation. AB - Although survival outcomes have significantly improved, up to 40% of patients die within 1 year of HLA-matched unrelated-donor blood and marrow transplantation (BMT). To identify non-HLA genetic contributors to mortality after BMT, we performed the first exome-wide association study in the DISCOVeRY-BMT cohorts using the Illumina HumanExome BeadChip. This study includes 2473 patients with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome and 2221 10/10 HLA-matched donors treated from 2000 to 2011. Single-variant and gene-level analyses were performed on overall survival (OS), transplantation related mortality (TRM), and disease-related mortality (DRM). Genotype mismatches between recipients and donors in a rare nonsynonymous variant of testis-expressed gene TEX38 significantly increased risk of TRM, which was more dramatic when either the recipient or donor was female. Using the SKAT-O test to evaluate gene level effects, variant genotypes of OR51D1 in recipients were significantly associated with OS and TRM. In donors, 4 (ALPP, EMID1, SLC44A5, LRP1), 1 (HHAT), and 2 genes (LYZL4, NT5E) were significantly associated with OS, TRM, and DRM, respectively. Inspection of NT5E crystal structures showed 4 of the associated variants affected the enzyme structure and likely decreased the catalytic efficiency of the enzyme. Further confirmation of these findings and additional functional studies may provide individualized risk prediction and prognosis, as well as alternative donor selection strategies. PMID- 29610369 TI - Towards legitimacy of the solar geoengineering research enterprise. AB - Mounting evidence that even aggressive reductions in net emissions of greenhouse gases will be insufficient to limit global climate risks is increasing calls for atmospheric experiments to better understand the risks and implications of also deploying solar geoengineering technologies to reflect sunlight and rapidly lower surface temperatures. But solar geoengineering research itself poses significant environmental and geopolitical risks. Given limited societal awareness and public dialogue about this climate response option, conducting such experiments without meaningful societal engagement could galvanize opposition to solar geoengineering research from civil society, including the most climate vulnerable communities who are among its intended beneficiaries. Here, we explore whether and how a solar geoengineering research enterprise might be developed in a way that promotes legitimacy as well as scientific credibility and policy relevance. We highlight the distinctive responsibilities of researchers and research funders to ensure that solar geoengineering research proposals are subject to legitimate societal review and scrutiny, recommend steps they can take to strive towards legitimacy and call on them to be explicitly open to multiple potential outcomes, including the societal rejection or considerable alteration of the solar geoengineering research enterprise.This article is part of the theme issue 'The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5 degrees C above pre-industrial levels'. PMID- 29610370 TI - Uncertain impacts on economic growth when stabilizing global temperatures at 1.5 degrees C or 2 degrees C warming. AB - Empirical evidence suggests that variations in climate affect economic growth across countries over time. However, little is known about the relative impacts of climate change on economic outcomes when global mean surface temperature (GMST) is stabilized at 1.5 degrees C or 2 degrees C warming relative to pre industrial levels. Here we use a new set of climate simulations under 1.5 degrees C and 2 degrees C warming from the 'Half a degree Additional warming, Prognosis and Projected Impacts' (HAPPI) project to assess changes in economic growth using empirical estimates of climate impacts in a global panel dataset. Panel estimation results that are robust to outliers and breaks suggest that within year variability of monthly temperatures and precipitation has little effect on economic growth beyond global nonlinear temperature effects. While expected temperature changes under a GMST increase of 1.5 degrees C lead to proportionally higher warming in the Northern Hemisphere, the projected impact on economic growth is larger in the Tropics and Southern Hemisphere. Accounting for econometric estimation and climate uncertainty, the projected impacts on economic growth of 1.5 degrees C warming are close to indistinguishable from current climate conditions, while 2 degrees C warming suggests statistically lower economic growth for a large set of countries (median projected annual growth up to 2% lower). Level projections of gross domestic product (GDP) per capita exhibit high uncertainties, with median projected global average GDP per capita approximately 5% lower at the end of the century under 2 degrees C warming relative to 1.5 degrees C. The correlation between climate-induced reductions in per capita GDP growth and national income levels is significant at the p < 0.001 level, with lower-income countries experiencing greater losses, which may increase economic inequality between countries and is relevant to discussions of loss and damage under the United Nations Framework Convention on Climate Change.This article is part of the theme issue 'The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5 degrees C above pre-industrial levels'. PMID- 29610371 TI - Building equity in: strategies for integrating equity into modelling for a 1.5 degrees C world. AB - Emission pathways consistent with limiting temperature increase to 1.5 degrees C raise pressing questions from an equity perspective. These pathways would limit impacts and benefit vulnerable communities but also present trade-offs that could increase inequality. Meanwhile, rapid mitigation could exacerbate political debates in which equity has played a central role. In this paper, we first develop a set of elements we suggest are essential for evaluating the equity implications of policy actions consistent with 1.5 degrees C. These elements include (i) assess climate impacts, adaptation, loss and damage; (ii) be sensitive to context; (iii) compare costs of mitigation and adaptation policy action; (iv) incorporate human development and poverty; (v) integrate inequality dynamics; and (vi) be clear about normative assumptions and responsive to users. We then assess the ability of current modelling practices to address each element, focusing on global integrated assessment models augmented by national modelling and scenarios. We find current practices face serious limitations across all six dimensions although the severity of these varies. Finally, based on our assessment we identify strategies that may be best suited for enabling us to generate insights into each of the six elements in the context of assessing pathways for a 1.5 degrees C world.This article is part of the theme issue 'The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5 degrees C above pre-industrial levels'. PMID- 29610372 TI - Reaching a 1.5 degrees C target: socio-technical challenges for a rapid transition to low-carbon electricity systems. AB - A 1.5 degrees C global average target implies that we should no longer focus on merely incremental emissions reductions from the electricity system, but rather on fundamentally re-envisaging a system that, sooner rather than later, becomes carbon free. Many low-carbon technologies are surpassing mainstream predictions for both uptake and cost reduction. Their deployment is beginning to be disruptive within established systems. 'Smart technologies' are being developed to address emerging challenges of system integration, but their rates of future deployment remain uncertain. We argue that transition towards a system that can fully displace carbon generation sources will require expanding the focus of our efforts beyond technical solutions. Recognizing that change has social and technical dimensions, and that these interact strongly, we set out a socio technical review that covers electricity infrastructure, citizens, business models and governance. It describes some of the socio-technical challenges that need to be addressed for the successful transition of the existing electricity systems. We conclude that a socio-technical understanding of electricity system transitions offers new and better insights into the potential and challenges for rapid decarbonization.This article is part of the theme issue 'The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5 degrees C above pre-industrial levels'. PMID- 29610373 TI - Can 'loss and damage' carry the load? AB - Even assuming a heroic rush towards carbon reduction and adaptation, some regions of the world will be hammered hard by climate impacts. Thus, a global consensus now sees the need for a supplemental plan to deal with the kind of harms that cannot be avoided-what Parties call 'loss and damage'. For a loss-and-damage plan to work, it must be capable of carrying the load, the load being whatever minimal standards that morality and political consensus require. But if residual risk climbs too high, it will fall short of even the most basic expectations. The Paris Agreement calls for holding the rise in global average temperature to 'well below 2 degrees C above pre-industrial levels', while working to limit the increase to 1.5 degrees C. How much difference is in that half-degree? From the point of view of residual risk, quite a lot. According to a 2016 study published by the European Geosciences Union, a jump from 1.5 degrees C to 2 degrees C could produce outsize impacts, particularly in tropical latitudes. That difference could mark the line between a plan that is politically and morally defensible and one that is not. At the very least, the difference is enough to inform the design and expectations of any future plan.This article is part of the theme issue 'The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5 degrees C above pre-industrial levels'. PMID- 29610374 TI - Mitigation gambles: uncertainty, urgency and the last gamble possible. AB - A rejection by current generations of more ambitious mitigation of carbon emissions inflicts on future generations inherently objectionable risks about which they have no choice. Any gains through savings from less ambitious mitigation, which are relatively minor, would accrue to current generations, and all losses, which are relatively major, would fall on future generations. This mitigation gamble is especially unjustifiable because it imposes a risk of unlimited losses until carbon emissions cease. Ultimate physical collapses remain possible. Much more ominous is prior social collapse from political struggles over conflicting responses to threatened physical collapse. The two most plausible objections to the thesis that less ambitious mitigation is unjustifiable rely, respectively, on the claim that negative emissions will allow a later recovery from a temporary overshoot in emissions and on the claim that ambitious mitigation is incompatible with poverty alleviation that depends on inexpensive fossil fuels. Neither objection stands up. Reliance on negative emissions later instead of ambitious mitigation now permits the passing of tipping points for irreversible change meanwhile, and non-carbon energy is rapidly becoming price competitive in developing countries like India that are committed to poverty alleviation.This article is part of the themed issue 'The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5 degrees C above pre-industrial levels'. PMID- 29610375 TI - The impact of Earth system feedbacks on carbon budgets and climate response. AB - A number of studies have examined the size of the allowable global cumulative carbon budget compatible with limiting twenty-first century global average temperature rise to below 2 degrees C and below 1.5 degrees C relative to pre industrial levels. These estimates of cumulative emissions have a number of uncertainties including those associated with the climate sensitivity and the global carbon cycle. Although the IPCC fifth assessment report contained information on a range of Earth system feedbacks, such as carbon released by thawing of permafrost or methane production by wetlands as a result of climate change, the impact of many of these Earth system processes on the allowable carbon budgets remains to be quantified. Here, we make initial estimates to show that the combined impact from typically unrepresented Earth system processes may be important for the achievability of limiting warming to 1.5 degrees C or 2 degrees C above pre-industrial levels. The size of the effects range up to around a 350 GtCO2 budget reduction for a 1.5 degrees C warming limit and around a 500 GtCO2 reduction for achieving a warming limit of 2 degrees C. Median estimates for the extra Earth system forcing lead to around 100 GtCO2 and 150 GtCO2, respectively, for the two warming limits. Our estimates are equivalent to several years of anthropogenic carbon dioxide emissions at present rates. In addition to the likely reduction of the allowable global carbon budgets, the extra feedbacks also bring forward the date at which a given warming threshold is likely to be exceeded for a particular emission pathway.This article is part of the theme issue 'The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5 degrees C above pre-industrial levels'. PMID- 29610376 TI - The myriad challenges of the Paris Agreement. AB - The much awaited and intensely negotiated Paris Agreement was adopted on 12 December 2015 by the Parties to the United Nations Framework Convention on Climate Change. The agreement set out a more ambitious long-term temperature goal than many had anticipated, implying more stringent emissions reductions that have been under-explored by the research community. By its very nature a multidisciplinary challenge, filling the knowledge gap requires not only climate scientists, but the whole Earth system science community, as well as economists, engineers, lawyers, philosophers, politicians, emergency planners and others to step up. To kick start cross-disciplinary discussions, the University of Oxford's Environmental Change Institute focused its 25th anniversary conference upon meeting the challenges of the Paris Agreement for science and society. This theme issue consists of review papers, opinion pieces and original research from some of the presentations within that meeting, covering a wide range of issues underpinning the Paris Agreement.This article is part of the theme issue 'The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5 degrees C above pre-industrial levels'. PMID- 29610377 TI - Climate and development: enhancing impact through stronger linkages in the implementation of the Paris Agreement and the Sustainable Development Goals (SDGs). AB - One of the greatest achievements in the global negotiations of 2015 that delivered the 2030 Agenda for Sustainable Development or Sustainable Development Goals (SDGs) and the Paris Agreement on climate change is that, for the first time, the linkages between climate and development were enshrined in each of the documents. This was done in recognition that climate change and development need to be addressed together in order not only to avoid harmful trade-offs and high costs, particularly for poorer countries, but also to exploit the benefits that come from strengthening these linkages. This review presents some of the latest data that argue for stronger linkages as well as the challenges of implementation which are not only politically and economically related but also include issues such as knowledge gaps, finance and governance. Finally, the review also presents a glimpse at the pathways that will be required to reach the ambitious global temperature targets of the Paris Agreement of less than 2 degrees C above pre industrial levels with efforts to limit temperature rise even further to 1.5 degrees C. This provides the context for some conclusions and recommendations for policy-makers, including on methodologies for assessing linkages and leveraging them for greater benefit.This article is part of the theme issue 'The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5 degrees C above pre-industrial levels'. PMID- 29610378 TI - Implications of possible interpretations of 'greenhouse gas balance' in the Paris Agreement. AB - The main goal of the Paris Agreement as stated in Article 2 is 'holding the increase in the global average temperature to well below 2 degrees C above pre industrial levels and pursuing efforts to limit the temperature increase to 1.5 degrees C'. Article 4 points to this long-term goal and the need to achieve 'balance between anthropogenic emissions by sources and removals by sinks of greenhouse gases'. This statement on 'greenhouse gas balance' is subject to interpretation, and clarifications are needed to make it operational for national and international climate policies. We study possible interpretations from a scientific perspective and analyse their climatic implications. We clarify how the implications for individual gases depend on the metrics used to relate them. We show that the way in which balance is interpreted, achieved and maintained influences temperature outcomes. Achieving and maintaining net-zero CO2 equivalent emissions conventionally calculated using GWP100 (100-year global warming potential) and including substantial positive contributions from short lived climate-forcing agents such as methane would result in a sustained decline in global temperature. A modified approach to the use of GWP100 (that equates constant emissions of short-lived climate forcers with zero sustained emission of CO2) results in global temperatures remaining approximately constant once net zero CO2-equivalent emissions are achieved and maintained. Our paper provides policymakers with an overview of issues and choices that are important to determine which approach is most appropriate in the context of the Paris Agreement.This article is part of the theme issue 'The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5 degrees C above pre-industrial levels'. PMID- 29610379 TI - Negative emissions technologies and carbon capture and storage to achieve the Paris Agreement commitments. AB - How will the global atmosphere and climate be protected? Achieving net-zero CO2 emissions will require carbon capture and storage (CCS) to reduce current GHG emission rates, and negative emissions technology (NET) to recapture previously emitted greenhouse gases. Delivering NET requires radical cost and regulatory innovation to impact on climate mitigation. Present NET exemplars are few, are at small-scale and not deployable within a decade, with the exception of rock weathering, or direct injection of CO2 into selected ocean water masses. To keep warming less than 2 degrees C, bioenergy with CCS (BECCS) has been modelled but does not yet exist at industrial scale. CCS already exists in many forms and at low cost. However, CCS has no political drivers to enforce its deployment. We make a new analysis of all global CCS projects and model the build rate out to 2050, deducing this is 100 times too slow. Our projection to 2050 captures just 700 Mt CO2 yr-1, not the minimum 6000 Mt CO2 yr-1 required to meet the 2 degrees C target. Hence new policies are needed to incentivize commercial CCS. A first urgent action for all countries is to commercially assess their CO2 storage. A second simple action is to assign a Certificate of CO2 Storage onto producers of fossil carbon, mandating a progressively increasing proportion of CO2 to be stored. No CCS means no 2 degrees C.This article is part of the theme issue 'The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5 degrees C above pre-industrial levels'. PMID- 29610380 TI - Stabilization of global temperature at 1.5 degrees C and 2.0 degrees C: implications for coastal areas. AB - The effectiveness of stringent climate stabilization scenarios for coastal areas in terms of reduction of impacts/adaptation needs and wider policy implications has received little attention. Here we use the Warming Acidification and Sea Level Projector Earth systems model to calculate large ensembles of global sea level rise (SLR) and ocean pH projections to 2300 for 1.5 degrees C and 2.0 degrees C stabilization scenarios, and a reference unmitigated RCP8.5 scenario. The potential consequences of these projections are then considered for global coastal flooding, small islands, deltas, coastal cities and coastal ecology. Under both stabilization scenarios, global mean ocean pH (and temperature) stabilize within a century. This implies significant ecosystem impacts are avoided, but detailed quantification is lacking, reflecting scientific uncertainty. By contrast, SLR is only slowed and continues to 2300 (and beyond). Hence, while coastal impacts due to SLR are reduced significantly by climate stabilization, especially after 2100, potential impacts continue to grow for centuries. SLR in 2300 under both stabilization scenarios exceeds unmitigated SLR in 2100. Therefore, adaptation remains essential in densely populated and economically important coastal areas under climate stabilization. Given the multiple adaptation steps that this will require, an adaptation pathways approach has merits for coastal areas.This article is part of the theme issue 'The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5 degrees C above pre-industrial levels'. PMID- 29610381 TI - The utility of the historical record for assessing the transient climate response to cumulative emissions. AB - The historical observational record offers a way to constrain the relationship between cumulative carbon dioxide emissions and global mean warming. We use a standard detection and attribution technique, along with observational uncertainties to estimate the all-forcing or 'effective' transient climate response to cumulative emissions (TCRE) from the observational record. Accounting for observational uncertainty and uncertainty in historical non-CO2 radiative forcing gives a best-estimate from the historical record of 1.84 degrees C/TtC (1.43-2.37 degrees C/TtC 5-95% uncertainty) for the effective TCRE and 1.31 degrees C/TtC (0.88-2.60 degrees C/TtC 5-95% uncertainty) for the CO2-only TCRE. While the best-estimate TCRE lies in the lower half of the IPCC likely range, the high upper bound is associated with the not-ruled-out possibility of a strongly negative aerosol forcing. Earth System Models have a higher effective TCRE range when compared like-for-like with the observations over the historical period, associated in part with a slight underestimate of diagnosed cumulative emissions relative to the observational best-estimate, a larger ensemble mean-simulated CO2 induced warming, and rapid post-2000 non-CO2 warming in some ensemble members.This article is part of the theme issue 'The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5 degrees C above pre-industrial levels'. PMID- 29610382 TI - Climate extremes, land-climate feedbacks and land-use forcing at 1.5 degrees C. AB - This article investigates projected changes in temperature and water cycle extremes at 1.5 degrees C of global warming, and highlights the role of land processes and land-use changes (LUCs) for these projections. We provide new comparisons of changes in climate at 1.5 degrees C versus 2 degrees C based on empirical sampling analyses of transient simulations versus simulations from the 'Half a degree Additional warming, Prognosis and Projected Impacts' (HAPPI) multi model experiment. The two approaches yield similar overall results regarding changes in climate extremes on land, and reveal a substantial difference in the occurrence of regional extremes at 1.5 degrees C versus 2 degrees C. Land processes mediated through soil moisture feedbacks and land-use forcing play a major role for projected changes in extremes at 1.5 degrees C in most mid latitude regions, including densely populated areas in North America, Europe and Asia. This has important implications for low-emissions scenarios derived from integrated assessment models (IAMs), which include major LUCs in ambitious mitigation pathways (e.g. associated with increased bioenergy use), but are also shown to differ in the simulated LUC patterns. Biogeophysical effects from LUCs are not considered in the development of IAM scenarios, but play an important role for projected regional changes in climate extremes, and are thus of high relevance for sustainable development pathways.This article is part of the theme issue 'The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5 degrees C above pre-industrial levels'. PMID- 29610383 TI - Changes in climate extremes, fresh water availability and vulnerability to food insecurity projected at 1.5 degrees C and 2 degrees C global warming with a higher-resolution global climate model. AB - We projected changes in weather extremes, hydrological impacts and vulnerability to food insecurity at global warming of 1.5 degrees C and 2 degrees C relative to pre-industrial, using a new global atmospheric general circulation model HadGEM3A GA3.0 driven by patterns of sea-surface temperatures and sea ice from selected members of the 5th Coupled Model Intercomparison Project (CMIP5) ensemble, forced with the RCP8.5 concentration scenario. To provide more detailed representations of climate processes and impacts, the spatial resolution was N216 (approx. 60 km grid length in mid-latitudes), a higher resolution than the CMIP5 models. We used a set of impacts-relevant indices and a global land surface model to examine the projected changes in weather extremes and their implications for freshwater availability and vulnerability to food insecurity. Uncertainties in regional climate responses are assessed, examining ranges of outcomes in impacts to inform risk assessments. Despite some degree of inconsistency between components of the study due to the need to correct for systematic biases in some aspects, the outcomes from different ensemble members could be compared for several different indicators. The projections for weather extremes indices and biophysical impacts quantities support expectations that the magnitude of change is generally larger for 2 degrees C global warming than 1.5 degrees C. Hot extremes become even hotter, with increases being more intense than seen in CMIP5 projections. Precipitation-related extremes show more geographical variation with some increases and some decreases in both heavy precipitation and drought. There are substantial regional uncertainties in hydrological impacts at local scales due to different climate models producing different outcomes. Nevertheless, hydrological impacts generally point towards wetter conditions on average, with increased mean river flows, longer heavy rainfall events, particularly in South and East Asia with the most extreme projections suggesting more than a doubling of flows in the Ganges at 2 degrees C global warming. Some areas are projected to experience shorter meteorological drought events and less severe low flows, although longer droughts and/or decreases in low flows are projected in many other areas, particularly southern Africa and South America. Flows in the Amazon are projected to decline by up to 25%. Increases in either heavy rainfall or drought events imply increased vulnerability to food insecurity, but if global warming is limited to 1.5 degrees C, this vulnerability is projected to remain smaller than at 2 degrees C global warming in approximately 76% of developing countries. At 2 degrees C, four countries are projected to reach unprecedented levels of vulnerability to food insecurity.This article is part of the theme issue 'The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5 degrees C above pre-industrial levels'. PMID- 29610384 TI - Solar geoengineering as part of an overall strategy for meeting the 1.5 degrees C Paris target. AB - Solar geoengineering refers to deliberately reducing net radiative forcing by reflecting some sunlight back to space, in order to reduce anthropogenic climate changes; a possible such approach would be adding aerosols to the stratosphere. If future mitigation proves insufficient to limit the rise in global mean temperature to less than 1.5 degrees C above preindustrial, it is plausible that some additional and limited deployment of solar geoengineering could reduce climate damages. That is, these approaches could eventually be considered as part of an overall strategy to manage the risks of climate change, combining emissions reduction, net-negative emissions technologies and solar geoengineering to meet climate goals. We first provide a physical-science review of current research, research trends and some of the key gaps in knowledge that would need to be addressed to support informed decisions. Next, since few climate model simulations have considered these limited-deployment scenarios, we synthesize prior results to assess the projected response if solar geoengineering were used to limit global mean temperature to 1.5 degrees C above preindustrial in an overshoot scenario that would otherwise peak near 3 degrees C. While there are some important differences, the resulting climate is closer in many respects to a climate where the 1.5 degrees C target is achieved through mitigation alone than either is to the 3 degrees C climate with no geoengineering. This holds for both regional temperature and precipitation changes; indeed, there are no regions where a majority of models project that this moderate level of geoengineering would produce a statistically significant shift in precipitation further away from preindustrial levels.This article is part of the theme issue 'The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5 degrees C above pre-industrial levels'. PMID- 29610385 TI - Coordinating AgMIP data and models across global and regional scales for 1.5 degrees C and 2.0 degrees C assessments. AB - The Agricultural Model Intercomparison and Improvement Project (AgMIP) has developed novel methods for Coordinated Global and Regional Assessments (CGRA) of agriculture and food security in a changing world. The present study aims to perform a proof of concept of the CGRA to demonstrate advantages and challenges of the proposed framework. This effort responds to the request by the UN Framework Convention on Climate Change (UNFCCC) for the implications of limiting global temperature increases to 1.5 degrees C and 2.0 degrees C above pre industrial conditions. The protocols for the 1.5 degrees C/2.0 degrees C assessment establish explicit and testable linkages across disciplines and scales, connecting outputs and inputs from the Shared Socio-economic Pathways (SSPs), Representative Agricultural Pathways (RAPs), Half a degree Additional warming, Prognosis and Projected Impacts (HAPPI) and Coupled Model Intercomparison Project Phase 5 (CMIP5) ensemble scenarios, global gridded crop models, global agricultural economics models, site-based crop models and within country regional economics models. The CGRA consistently links disciplines, models and scales in order to track the complex chain of climate impacts and identify key vulnerabilities, feedbacks and uncertainties in managing future risk. CGRA proof-of-concept results show that, at the global scale, there are mixed areas of positive and negative simulated wheat and maize yield changes, with declines in some breadbasket regions, at both 1.5 degrees C and 2.0 degrees C. Declines are especially evident in simulations that do not take into account direct CO2 effects on crops. These projected global yield changes mostly resulted in increases in prices and areas of wheat and maize in two global economics models. Regional simulations for 1.5 degrees C and 2.0 degrees C using site-based crop models had mixed results depending on the region and the crop. In conjunction with price changes from the global economics models, productivity declines in the Punjab, Pakistan, resulted in an increase in vulnerable households and the poverty rate.This article is part of the theme issue 'The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5 degrees C above pre-industrial levels'. PMID- 29610386 TI - Impacts on terrestrial biodiversity of moving from a 2 degrees C to a 1.5 degrees C target. AB - We applied a recently developed tool to examine the reduction in climate risk to biodiversity in moving from a 2 degrees C to a 1.5 degrees C target. We then reviewed the recent literature examining the impact of (a) land-based mitigation options and (b) land-based greenhouse gas removal options on biodiversity. We show that holding warming to 1.5 degrees C versus 2 degrees C can significantly reduce the number of species facing a potential loss of 50% of their climatic range. Further, there would be an increase of 5.5-14% of the globe that could potentially act as climatic refugia for plants and animals, an area equivalent to the current global protected area network. Efforts to meet the 1.5 degrees C target through mitigation could largely be consistent with biodiversity protection/enhancement. For impacts of land-based greenhouse gas removal technologies on biodiversity, some (e.g. soil carbon sequestration) could be neutral or positive, others (e.g. bioenergy with carbon capture and storage) are likely to lead to conflicts, while still others (e.g. afforestation/reforestation) are context-specific, when applied at scales necessary for meaningful greenhouse gas removal. Additional effort to meet the 1.5 degrees C target presents some risks, particularly if inappropriately managed, but it also presents opportunities.This article is part of the theme issue 'The Paris Agreement: understanding the physical and social challenges for a warming world of 1.5 degrees C above pre-industrial levels'. PMID- 29610387 TI - Exceptional response to everolimus in a novel tuberous sclerosis complex-2 mutation-associated metastatic renal-cell carcinoma. AB - Everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR) pathway, is currently approved for treatment of advanced renal-cell carcinoma (RCC) after failure of initial treatment with the tyrosine kinase inhibitors. Patients with tuberous sclerosis complex (TSC) syndrome can also develop RCC primarily mediated through mTOR signaling. However, the efficacy and duration of response of mTOR inhibition in patients with TSC-associated RCC is not well known. Herein, we describe a case of a patient with TSC2-associated metastatic RCC with mutations H1620R and Y1650C who has had an exceptional response to everolimus in the frontline setting and continues to derive benefit from mTOR inhibition 2 yr into therapy. Furthermore, the alteration H1620R in exon 37 resulting in a missense mutation is likely deleterious given our findings and previous analyses of the TSC2 gene. Further studies of somatic mutations in extended responders to mTOR inhibitors will help personalize therapy for these patients. It also emphasizes the value of targeted therapies based on genomic analyses. PMID- 29610389 TI - FGFR1 tyrosine kinase domain duplication in pilocytic astrocytoma with anaplasia. AB - We report the case of a 27-yr-old male with visual field loss who had a 4.9-cm complex cystic mass in the right occipital lobe. Histologic examination showed pilocytic astrocytoma (PA) with anaplasia, and molecular characterization revealed FGFR1 duplication with additional variants of unknown significance in several genes (ARID1A, ARID1B, CHEK2, EPHA5, and MLL2). This is one of only a very few reported cases of anaplastic PA with characterization of molecular alterations. PMID- 29610388 TI - Clinically actionable mutation profiles in patients with cancer identified by whole-genome sequencing. AB - Next-generation sequencing (NGS) efforts have established catalogs of mutations relevant to cancer development. However, the clinical utility of this information remains largely unexplored. Here, we present the results of the first eight patients recruited into a clinical whole-genome sequencing (WGS) program in the United Kingdom. We performed PCR-free WGS of fresh frozen tumors and germline DNA at 75* and 30*, respectively, using the HiSeq2500 HTv4. Subtracted tumor VCFs and paired germlines were subjected to comprehensive analysis of coding and noncoding regions, integration of germline with somatically acquired variants, and global mutation signatures and pathway analyses. Results were classified into tiers and presented to a multidisciplinary tumor board. WGS results helped to clarify an uncertain histopathological diagnosis in one case, led to informed or supported prognosis in two cases, leading to de-escalation of therapy in one, and indicated potential treatments in all eight. Overall 26 different tier 1 potentially clinically actionable findings were identified using WGS compared with six SNVs/indels using routine targeted NGS. These initial results demonstrate the potential of WGS to inform future diagnosis, prognosis, and treatment choice in cancer and justify the systematic evaluation of the clinical utility of WGS in larger cohorts of patients with cancer. PMID- 29610390 TI - Genomic profiling of dedifferentiated liposarcoma compared to matched well differentiated liposarcoma reveals higher genomic complexity and a common origin. AB - Well-differentiated (WD) liposarcoma is a low-grade mesenchymal tumor with features of mature adipocytes and high propensity for local recurrence. Often, WD patients present with or later progress to a higher-grade nonlipogenic form known as dedifferentiated (DD) liposarcoma. These DD tumors behave more aggressively and can metastasize. Both WD and DD liposarcomas harbor neochromosomes formed from amplifications and rearrangements of Chr 12q that encode oncogenes (MDM2, CDK4, and YEATS2) and adipocytic differentiation factors (HMGA2 and CPM) However, genomic changes associated with progression from WD to DD have not been well defined. Therefore, we selected patients with matched WD and DD tumors for extensive genomic profiling in order to understand their clonal relationships and to delineate any defining alterations for each entity. Exome and transcriptomic sequencing was performed for 17 patients with both WD and DD diagnoses. Somatic point and copy-number alterations were integrated with transcriptional analyses to determine subtype-associated genomic features and pathways. The results were, on average, that only 8.3% of somatic mutations in WD liposarcoma were shared with their cognate DD component. DD tumors had higher numbers of somatic copy number losses, amplifications involving Chr 12q, and fusion transcripts than WD tumors. HMGA2 and CPM rearrangements occur more frequently in DD components. The shared somatic mutations indicate a clonal origin for matched WD and DD tumors and show early divergence with ongoing genomic instability due to continual generation and selection of neochromosomes. Stochastic generation and subsequent expression of fusion transcripts from the neochromosome that involve adipogenesis genes such as HMGA2 and CPM may influence the differentiation state of the subsequent tumor. PMID- 29610391 TI - Application of genomics to identify therapeutic targets in recurrent pediatric papillary thyroid carcinoma. AB - Children with papillary thyroid carcinoma (PTC) may relapse despite response to radioactive iodine (RAI). Two children with multiply relapsed PTC underwent whole genome and transcriptome sequencing. A TPM3-NTRK1 fusion was identified in one tumor, with outlier NTRK1 expression compared to the TCGA thyroid cancer compendium and to Illumina BodyMap normal thyroid. This patient demonstrated resolution of multiple pulmonary nodules without toxicity on oral TRK inhibitor therapy. A RET fusion was identified in the second tumor, another potentially actionable finding. Identification of oncogenic drivers in recurrent pediatric PTC may facilitate targeted therapy while avoiding repeated RAI. PMID- 29610393 TI - Journey from oncologist to cancer survivor and patient advocate in the era of precision medicine. AB - In 2013, the American Association for Cancer Research (AACR) introduced the "Precision Medicine Series" of symposia. The goal of these conferences is to "highlight the incredible technology and advances in cancer research that together are enabling treatments that are precisely targeted to the unique molecular and genetic characteristics of an individual's cancer." This new series of AACR conferences reflects how patient treatment has evolved and continues to progress toward personalized treatments/medicine. It was in May of 2013 that I was diagnosed with a rare form of bladder cancer, plasmacytoid variant, for which survival statistics were grim, and the only genomic information available was the frequent somatic CDH1 loss-of-function mutation consistent with aggressive clinical behavior. The CDH1 gene encodes for E-cadherin, which plays a role in cell-cell adhesions and acts as a tumor suppressor when expressed normally. This information was subsequently published, but not until April 2016 (Al-Ahmadie et al. 2017. Nat Genet48: 356-358). At the time, I was a practicing medical oncologist and, ironically, urologic cancers had been my area of interest, dating back to my fellowship at Memorial Sloan Kettering Cancer Center (MSKCC) in 1981. I decided to return to MSKCC for treatment based on their experience with rare urologic cancers as well as my own personal connection. PMID- 29610392 TI - Personalized oncogenomic analysis of metastatic adenoid cystic carcinoma: using whole-genome sequencing to inform clinical decision-making. AB - Metastatic adenoid cystic carcinomas (ACCs) can cause significant morbidity and mortality. Because of their slow growth and relative rarity, there is limited evidence for systemic therapy regimens. Recently, molecular profiling studies have begun to reveal the genetic landscape of these poorly understood cancers, and new treatment possibilities are beginning to emerge. The objective is to use whole-genome and transcriptome sequencing and analysis to better understand the genetic alterations underlying the pathology of metastatic and rare ACCs and determine potentially actionable therapeutic targets. We report five cases of metastatic ACC, not originating in the salivary glands, in patients enrolled in the Personalized Oncogenomics (POG) Program at the BC Cancer Agency. Genomic workup included whole-genome and transcriptome sequencing, detailed analysis of tumor alterations, and integration with existing knowledge of drug-target combinations to identify potential therapeutic targets. Analysis reveals low mutational burden in these five ACC cases, and mutation signatures that are commonly observed in multiple cancer types. Notably, the only recurrent structural aberration identified was the well-described MYB-NFIB fusion that was present in four of five cases, and one case exhibited a closely related MYBL1 NFIB fusion. Recurrent mutations were also identified in BAP1 and BCOR, with additional mutations in individual samples affecting NOTCH1 and the epigenetic regulators ARID2, SMARCA2, and SMARCB1. Copy changes were rare, and they included amplification of MYC and homozygous loss of CDKN2A in individual samples. Genomic analysis revealed therapeutic targets in all five cases and served to inform a therapeutic choice in three of the cases to date. PMID- 29610394 TI - Bloom syndrome: research and data priorities for the development of precision medicine as identified by some affected families. AB - Bloom syndrome (BS) is a rare, autosomal recessive genetic disorder characterized by short stature, a skin rash associated with sun exposure, and an elevated likelihood of developing cancers of essentially all types, beginning at an early age. Cancer is the leading cause of death for persons with BS, and its early onset results in a reported median lifespan of <30 years. With fewer than 300 documented cases since BS was first described in 1954, its rarity has challenged progress in advancing both the care of and the cure for persons with BS. Presently, there are no known clinically actionable targets specific to persons with this cancer predisposition syndrome, despite the fact that standard cancer treatments are often contraindicated or must be substantially modified for persons with BS. Herein, Zachary Rogers recounts his experience as a cancer patient with BS contemplating a substantially customized chemotherapy regimen that highlights the need for development of individualized treatments in the BS community. We also outline a patient-centered research and community action road map with the goal of improving and prolonging the lives of persons with Bloom syndrome, including the facilitation of precision medicine development specific to this condition. PMID- 29610395 TI - The future of cancer treatment using precision oncogenomics. AB - Clinicians should soon have the opportunity to use precision oncogenomics to tailor the optimal cancer treatment to a specific patient. Precision oncogenomics will incorporate different sequencing platforms depending on the goal of the sequencing result. For example, the sequencing strategy used in immuno-oncology for the design of a tumor-specific vaccine may be different than that used by oncologists following a patient for clearance of mutations from circulating tumor DNA in the peripheral blood. I will provide a broad overview of several of the ways that precision oncogenomics is likely to influence the field of oncology over the next several years building off the experience at the Genomics Tumor Board at Washington University in St. Louis and a case of small-cell neuroendocrine carcinoma of the endometrium as examples. PMID- 29610396 TI - Precision oncogenomics in pediatrics: a personal reflection. AB - Cindy Campbell, a bereaved parent who lost her son to a rare pediatric brain tumor, shares her experience and frustration over the lack of treatment options and minimal research funding in pediatric oncology. She invites Dr. Jeffrey P. Greenfield to reflect on the situation and share his professional experiences pertaining to advances in oncogenomics and pediatric brain tumors. They share a passion for making this technology available to all pediatric brain tumor patients in the future and using data to inform treatment protocols and improve outcomes. PMID- 29610397 TI - The era of precision oncogenomics. PMID- 29610399 TI - Tribute to the 2017 Reviewers. PMID- 29610398 TI - Types I and II Keratin Intermediate Filaments. AB - SummaryKeratins-types I and II-are the intermediate-filament-forming proteins expressed in epithelial cells. They are encoded by 54 evolutionarily conserved genes (28 type I, 26 type II) and regulated in a pairwise and tissue type-, differentiation-, and context-dependent manner. Here, we review how keratins serve multiple homeostatic and stress-triggered mechanical and nonmechanical functions, including maintenance of cellular integrity, regulation of cell growth and migration, and protection from apoptosis. These functions are tightly regulated by posttranslational modifications and keratin-associated proteins. Genetically determined alterations in keratin-coding sequences underlie highly penetrant and rare disorders whose pathophysiology reflects cell fragility or altered tissue homeostasis. Furthermore, keratin mutation or misregulation represents risk factors or genetic modifiers for several additional acute and chronic diseases. PMID- 29610401 TI - Safety and Immunogenicity of a Recombinant Influenza Vaccine: A Randomized Trial. AB - OBJECTIVES: The recombinant influenza vaccine is well established in adults >=18 years of age for preventing seasonal influenza disease. In this randomized controlled trial, we compared the safety and immunogenicity of the quadrivalent, recombinant influenza vaccine (RIV4) versus the inactivated influenza vaccine in children and adolescents 6 to 17 years of age. METHODS: Two age cohorts were enrolled sequentially: 159 subjects aged 9 to 17 years and, after reviewing for safety, 60 children aged 6 to 8 years. Enrollment of the younger children was halted prematurely at the onset of the influenza season. Subjects in each cohort were randomly assigned 1:1 to the RIV4 or inactivated vaccine. Hemagglutination inhibition antibody titers were obtained before and 28 days after vaccination. Tolerability and safety were monitored for 7 days and 6 months after vaccination, respectively. RESULTS: Both vaccines were well tolerated in both age groups, and long-term follow-up revealed no vaccine-related adverse events. Overall, immunogenicity (geometric mean titers and seroconversion rate differences) provided comparable antibody responses to most antigens in both vaccines in the older subjects. Low responses to the influenza B Victoria lineage in both vaccines made interpretation difficult. Immunogenicity in younger children was similar, but the truncated sample size was insufficient to support noninferiority comparisons. CONCLUSIONS: Despite low responses to influenza B lineages in both vaccines, the RIV4 provided safety and immunogenicity that were comparable to those of the licensed inactivated vaccine in pediatric subjects, which was most convincing in those aged 9 to 17 years. Future confirmatory clinical efficacy trials may be used to support the recombinant influenza vaccine as an alternative for the pediatric age group of >=6 years. PMID- 29610400 TI - Poverty, Transportation Access, and Medication Nonadherence. AB - BACKGROUND AND OBJECTIVES: Variability in primary medication nonadherence (PMN), or failure to fill a new prescription, influences disparities and widens equity gaps. This study sought to evaluate PMN across 1 metropolitan area and assess relationships with underlying zip code-level measures. METHODS: This was a retrospective observational study using data extracted from 1 regional community pharmacy market-share leader (October 2016-April 2017). Data included patient age, sex, payer, medication type, and home zip code. This zip code was connected to US census measures enumerating poverty and vehicle access, which were treated as continuous variables and within quintiles. The prescription-level outcome was whether prescriptions were not filled within 30 days of reaching the pharmacy. The ecological-level outcome was PMN calculated for each zip code (numerator, unfilled prescriptions; denominator, received prescriptions). RESULTS: There were 213 719 prescriptions received by 54 included pharmacies; 12.2% were unfilled. Older children, boys, and those with public insurance were more likely to have prescriptions not filled. Prescriptions originating from the highest poverty quintile were significantly more likely to not be filled than those from the lowest poverty quintile (adjusted odds ratio 1.60; 95% confidence interval 1.52 1.69); a similar pattern was noted for vehicle access (adjusted odds ratio 1.77; 95% confidence interval 1.68-1.87). At the ecological level, there were significant, graded relationships between PMN rates and poverty and vehicle access (both P < .0001); these gradients extended across all medication classes. CONCLUSIONS: Poverty and vehicle access are related to significant differences in prescription- and ecological-level PMN across 1 metropolitan area. Pharmacists and pharmacies can be key partners in population health efforts. PMID- 29610402 TI - "A Guide to Gutsy Living": Patient-Driven Development of a Pediatric Ostomy Toolkit. PMID- 29610406 TI - Introduction to Transitions in the Life Course of Autism and Other Developmental Disabilities. AB - The Health Care Transitions Research Network for Autism Spectrum Disorder and other Developmental Disabilities and the Life Course Research Network, both funded by the Maternal and Child Health Bureau, invited articles for this Supplement. Our goal in this Supplement is to highlight and explore developmental and transition-related challenges over the life course of individuals on the autism spectrum and other neurodevelopmental disabilities, discuss the clinical and practice implications of these issues, highlight gaps in knowledge, and identify directions for future research. PMID- 29610404 TI - Ischemia-Induced DNA Hypermethylation during Kidney Transplant Predicts Chronic Allograft Injury. AB - Background Ischemia during kidney transplant causes chronic allograft injury and adversely affects outcome, but the underlying mechanisms are incompletely understood. In tumors, oxygen shortage reduces the DNA demethylating activity of the ten-11 translocation (TET) enzymes, yielding hypermethylated genomes that promote tumor progression. We investigated whether ischemia similarly induces DNA hypermethylation in kidney transplants and contributes to chronic injury.Methods We profiled genome-wide DNA methylation in three cohorts of brain-dead donor kidney allograft biopsy specimens: a longitudinal cohort with paired biopsy specimens obtained at allograft procurement (preischemia; n=13), after implantation and reperfusion (postischemia; n=13), and at 3 or 12 months after transplant (n=5 each); a cross-sectional cohort with preimplantation biopsy specimens (n=82); and a cross-sectional cohort with postreperfusion biopsy specimens (n=46).Results Analysis of the paired preischemia and postischemia specimens revealed that methylation increased drastically in all allografts on ischemia. Hypermethylation was caused by loss of 5-hydroxymethylcytosine, the product of TET activity, and it was stable 1 year after transplant. In the preimplantation cohort, CpG hypermethylation directly correlated with ischemia time and for some CpGs, increased 2.6% per additional hour of ischemia. Hypermethylation preferentially affected and reduced the expression of genes involved in suppressing kidney injury and fibrosis. Moreover, CpG hypermethylation in preimplantation specimens predicted chronic injury, particularly fibrosis and glomerulosclerosis, 1 year after transplant. This finding was validated in the independent postreperfusion cohort, in which hypermethylation also predicted reduced allograft function 1 year after transplant, outperforming established clinical variables.Conclusions We highlight a novel epigenetic basis for ischemia-induced chronic allograft injury with biomarker potential. PMID- 29610403 TI - Cooperation of Antiporter LAT2/CD98hc with Uniporter TAT1 for Renal Reabsorption of Neutral Amino Acids. AB - Background Reabsorption of amino acids (AAs) across the renal proximal tubule is crucial for intracellular and whole organism AA homeostasis. Although the luminal transport step is well understood, with several diseases caused by dysregulation of this process, the basolateral transport step is not understood. In humans, only cationic aminoaciduria due to malfunction of the basolateral transporter y+LAT1/CD98hc (SLC7A7/SLC3A2), which mediates the export of cationic AAs, has been described. Thus, the physiologic roles of basolateral transporters of neutral AAs, such as the antiporter LAT2/CD98hc (SLC7A8/SLC3A2), a heterodimer that exports most neutral AAs, and the uniporter TAT1 (SLC16A10), which exports only aromatic AAs, remain unclear. Functional cooperation between TAT1 and LAT2/CD98hc has been suggested by in vitro studies but has not been evaluated in vivoMethods To study the functional relationship of TAT1 and LAT2/CD98hc in vivo, we generated a double-knockout mouse model lacking TAT1 and LAT2, the catalytic subunit of LAT2/CD98hc (dKO LAT2-TAT1 mice).Results Compared with mice lacking only TAT1 or LAT2, dKO LAT2-TAT1 mice lost larger amounts of aromatic and other neutral AAs in their urine due to a tubular reabsorption defect. Notably, dKO mice also displayed decreased tubular reabsorption of cationic AAs and increased expression of y+LAT1/CD98hc.Conclusions The LAT2/CD98hc and TAT1 transporters functionally cooperate in vivo, and y+LAT1/CD98hc may compensate for the loss of LAT2/CD98hc and TAT1, functioning as a neutral AA exporter at the expense of some urinary loss of cationic AAs. Cooperative and compensatory mechanisms of AA transporters may explain the lack of basolateral neutral aminoacidurias in humans. PMID- 29610407 TI - The Diagnostic Odyssey of Autism Spectrum Disorder. AB - OBJECTIVES: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by challenges in social communication and interaction and restricted or repetitive behavior, interests, or activities. Although ASD symptoms generally manifest in early childhood, many individuals experience delays accessing an autism diagnosis and related services. In this study, we identify the individual, social, and structural factors that influence parents' experiences of children's ASD diagnosis. METHODS: Parents of 25 children with autism participated in 60- to 90-minute semistructured in-person interviews. Interviews were recorded and transcribed verbatim. Transcripts were analyzed using the method of grounded theory. This inductive method allowed analysts to identify key themes related to participants' experiences of children's ASD diagnosis. RESULTS: The process of ASD diagnosis reflects an odyssey that includes 3 key phases: the prediagnosis phase, in which "Making Sense of Child Difference" is a primary characteristic of participants' experiences; the during diagnosis phase, when "Navigating Diagnosis" suggests systematic barriers that influence the timing of ASD diagnosis; and the postdiagnosis phase, when participants' experiences of "Connecting to Services" point to the important role that personal efforts play in gaining access to care. CONCLUSIONS: In this study, we highlight individual, social, and structural factors that influence parent experiences before, during, and after their child's autism diagnosis. Our findings indicate the need for more consistent and continuous support for autistic individuals and their families during the diagnostic odyssey, as well as resources that better represent the diversity of experiences and symptoms associated with autism across the life course. PMID- 29610408 TI - Family Characteristics and Children's Receipt of Autism Services in Low-Resourced Families. AB - OBJECTIVES: Parents of children with autism spectrum disorder (ASD) face competing demands when caring for their child and fulfilling family commitments. It remains unknown whether family obligations and parental stress might decrease the use of intervention services for young children with ASD. METHODS: The current study is a secondary analysis of baseline date from a published randomized control trial with 147 low-resourced caregiver-child dyads. Demographic information, data on service use, maternal employment, parent's perception of their child's development, and parental stress were collected for primary caregivers of 2- to 5-year-old children with ASD from 5 sites. Multiple logistic regressions of accessing any intervention services or more than 1 services on familial characteristics were performed, controlling for demographic and contextual variables. RESULTS: Twenty-five percent of children were receiving no intervention service; 26% were receiving 1 service; and 49% were receiving 2 or more services. Perceived developmental delay and not having a sibling in the home were associated with higher odds of receiving intervention services. Children were more likely to receive more than 1 service if their parents had at least a college education and low levels of stress. CONCLUSIONS: Factors including perceived developmental level, parental stress, and caring for siblings may play a role in accessing services for children with ASD. Results reveal that competing family needs may be barriers to service use. Mothers of children with ASD with multiple children in the home, low levels of education, and high levels of stress may need additional supports or alternative service delivery models. PMID- 29610409 TI - Network Measures of Collaborative Support for Young Adults With Autism. AB - OBJECTIVES: The treatment of autism requires complex, multimodal interventions, provided by parents and providers across settings. As young adults with autism spectrum disorder (ASD) transition into adulthood, new stakeholders are added to support planning for postsecondary employment. In this article, we investigate the use of dynamic social network measures that describe the resources of young adults throughout transition. METHODS: A longitudinal, dynamic social network survey (Social Dynamics of Intervention [SoDI]) was conceptualized, designed, and conducted as a feasibility test, measuring changes in collaboration among parents and school staff members who provided interventions for children with ASD in 2 urban public schools. Using the SoDI, we tracked the following over time: the team who provided interventions, their locations, the interventions they provided, the autism trainings they attended, and the density of the team's problem-solving network for the child. RESULTS: Using the SoDI, we successfully identified stakeholders across settings who provided interventions for each child. Results indicated variation in the density of problem-solving and trust related to ASD intervention across teams as well as variation in intervention and autism knowledge networks during the school year. Adaptations of the SoDI for mapping pre- and posttransition resources and social connectivity across stakeholders for young adults with ASD are proposed in the Discussion section. CONCLUSIONS: Dynamic social network approaches can be used to capture changes in intervention, autism knowledge, and social connectivity, providing informative descriptive data about how vocational rehabilitation policies might increase employment supports during the transition process for young adults with ASD. PMID- 29610410 TI - Stakeholder Perspectives on Research and Practice in Autism and Transition. AB - OBJECTIVES: Individuals with autism spectrum disorder (ASD) are reported to experience significant challenges during the transition to adulthood. Although recent evidence indicates that individuals with ASD experience poor outcomes in adulthood, little is understood about the contributing factors. In this qualitative study, we investigated the barriers to and needs in research and practice in the transition to adulthood among individuals with ASD. METHODS: Thirteen researchers, including service providers, family members, and an individual with ASD participated in 30- to 60-minute, semistructured, open-ended telephone interviews. Interviews were transcribed, and data were analyzed by using an inductive approach to identify themes related to barriers to and needs in the transition to adulthood for youth with ASD. RESULTS: Stakeholders identified the need for transition planning and preparation to begin earlier and for systems to better accommodate the interests and varying abilities of individuals with ASD. Stakeholders also felt that parent and service provider expectations and perceptions influence early opportunities and experiences offered throughout the transition process. CONCLUSIONS: This study reveals the multilevel barriers to and needs in the transition to adulthood and the need for interagency and multidisciplinary collaboration and research to address the varying levels of needs, abilities, and multisector challenges. PMID- 29610411 TI - Barriers to Receipt of Services for Young Adults With Autism. AB - OBJECTIVES: In this study, we examine experiences of families of young adults (YAs) on the autism spectrum to better understand dynamics leading to poor YA outcomes. METHODS: Twenty parents of YAs with autism spectrum disorder (ASD) who had completed high school in the past 15 years took part in a 90-minute interview. They described their YA's experiences at the transition from high school and current status with regards to services or postsecondary education. Qualitative interviews were digitally recorded, transcribed, and analyzed by using the constant comparative method associated with a grounded theory approach. RESULTS: Few adults with ASD were receiving autism-specific assistance no matter their level of cognitive functioning. Existing systems, such as service agencies and college disability support offices, had seldom been designed to meet their needs. Some families gave up on services, some used self-directed services they had to manage themselves, and others paid out of pocket for services they could access no other way. Inadequate services often led to YA failure and worsening of symptoms. The majority of families bore the financial and emotional brunt of finding or creating services and community experiences to meet their adult child's needs. CONCLUSIONS: Parent narratives highlight the difficulties that are faced as families attempt to access appropriate services for YAs on the autism spectrum at all levels of functioning. These insights can help pediatricians understand family concerns and develop anticipatory guidance strategies. More research is needed to identify potential solutions to challenges faced by specific subgroups of YAs with ASD. PMID- 29610412 TI - Social-Ecological Correlates in Adult Autism Outcome Studies: A Scoping Review. AB - The transition into adulthood is a critical period in the life course that shapes later outcomes. Many adults on the autism spectrum fare poorly across a wide range of quality of life indicators. Understanding the multilevel factors that influence transition outcomes is necessary to develop strategies that promote better outcomes. In this scoping review, we characterize the use of social ecological factors in adult autism outcome studies, identify understudied areas of research, and provide recommendations for future research. We conducted a literature search for studies in which the relationship between social-ecological factors and transition outcomes among transition-age youth with autism was assessed. We organized variables used in studies across 5 levels of influence: family-, interpersonal-, institutional-, community-, and policy-level factors. Our findings reveal that both breadth and depth of social-ecological factors usage in autism outcomes studies is limited because of the narrow inclusion of variables across social-ecological levels, the overreliance on a limited number of national data sets, and the overall lack of variation in research design. We propose 9 recommendations to inform the development of multilevel studies. PMID- 29610413 TI - Transition of Individuals With Autism to Adulthood: A Review of Qualitative Studies. AB - Many young adults with autism spectrum disorder experience poor transition outcomes in key areas, including postsecondary employment, higher education, health care, social connectedness, and independent living, yet we lack a clear understanding of the specific factors that impact these outcomes. We reviewed qualitative research in which the perspectives of youth and young adults with autism spectrum disorder, parents, services providers, and other stakeholders were gathered to identify barriers and facilitators to optimal outcomes. Findings revealed that poor transition outcomes are influenced by several factors, including poor person-environment fit, uncertainty about the roles of parents, and the lack of comprehensive or integrated services. These findings also revealed the aspects of familial, organizational, and policy contexts that may be targeted for interventions. Finally, stakeholders emphasized that supports should be individualized and focused on the changing aspects of the young adult's social and physical environment rather than behavior change. We discuss implications for policy and practice and provide recommendations for further research. PMID- 29610414 TI - The Medical Home and Health Care Transition for Youth With Autism. AB - BACKGROUND: Our objective in this study was to describe the association between the receipt of health care transition services (HCTS) and having a medical home in youth with autism spectrum disorder (ASD). Youth with ASD receive HCTS less often than other youth with special health care needs but are in particular need of continuous, comprehensive health care. METHODS: We used the National Survey of Children with Special Health Care Needs to describe the receipt of HCTS in youth with ASD and its association with presence of a medical home. Descriptive statistics are presented, and logistic regression is used to assess the association between medical home and HCTS. RESULTS: Twenty-one percent of youth with ASD met the criteria for receiving HCTS. Youth with ASD and a medical home were almost 3 times as likely to receive HCTS as youth without a medical home, and youth who received family-centered care and have adequate care coordination within the medical home were more than twice as likely to receive HCTS as those who did not. CONCLUSIONS: Youth with ASD are not receiving HCTS at the same rate as their peers. Increasing provider awareness of autism, the components of a medical home, and of the importance of HCTS could greatly help increase the percentage of youth who receive effective HCTS. PMID- 29610415 TI - Psychiatric and Medical Conditions in Transition-Aged Individuals With ASD. AB - BACKGROUND AND OBJECTIVES: Children with autism spectrum disorder (ASD) have a variety of medical and psychiatric conditions and an increased use of health care services. There is limited information about the prevalence of psychiatric and medical conditions in adolescents and young adults with ASD. Our objective was to describe the frequency of medical and psychiatric conditions in a large population of diverse, insured transition-aged individuals with ASD. METHODS: Participants included Kaiser Permanente Northern California members who were enrolled from 2013 to 2015 and who were 14 to 25 years old. Individuals with ASD (n = 4123) were compared with peers with attention-deficit/hyperactivity disorder (n = 20 615), diabetes mellitus (n = 2156), and typical controls with neither condition (n = 20 615). RESULTS: Over one-third (34%) of individuals with ASD had a co-occurring psychiatric condition; the most commonly reported medical conditions included infections (42%), obesity (25%), neurologic conditions (18%), allergy and/or immunologic conditions (16%), musculoskeletal conditions (15%), and gastrointestinal (11%) conditions. After controlling for sex, age, race, and duration of Kaiser Permanente Northern California membership, most psychiatric conditions were significantly more common in the ASD group than in each comparison group, and most medical conditions were significantly more common in the ASD group than in the attention-deficit/hyperactivity disorder and typical control groups but were similar to or significantly less common than the diabetes mellitus group. CONCLUSIONS: Although more research is needed to identify factors contributing to this excess burden of disease, there is a pressing need for all clinicians to approach ASD as a chronic health condition requiring regular follow up and routine screening and treatment of medical and psychiatric issues. PMID- 29610416 TI - A Health Care Transition Curriculum for Primary Care Residents: Identifying Goals and Objectives. AB - BACKGROUND AND OBJECTIVES: The transition from pediatric to adult health care is a vulnerable period for youth with special health care needs. Although successful transitions are recognized as critical for improving adult outcomes and reducing health care utilization and cost, an educational gap in health care transitions for physicians persists. Our aim with this project was to develop a national health care transition residency curriculum for primary care physicians, using an expert-based, consensus-building process. METHODS: Medical professionals with expertise in health care transition were recruited to participate in a survey to assist in the development of a health care transition curriculum for primary care physicians. By using a modified Delphi process, curricular goals and objectives were drafted, and participants rated the importance of each objective, feasibility of developing activities for objectives, and appropriateness of objectives for specified learners. Mean and SDs for each response and percent rating for the appropriateness of each objective were calculated. RESULTS: Fifty six of 246 possible respondents participated in round 1 of ratings and 36 (64%) participated in the second round. Five goals with 32 associated objectives were identified. Twenty-five of the 32 objectives (78%) were rated as being appropriate for "proficient" learners, with 7 objectives rated as "expert." Three objectives were added to map onto the Got Transition guidelines. CONCLUSIONS: The identified goals and objectives provide the foundation and structure for future curriculum development, facilitating the sharing of curricular activities and evaluation tools across programs by faculty with a range of expertise. PMID- 29610417 TI - A National Research Agenda for the Transition of Youth With Autism. AB - In this article, we outline a national research agenda to improve the transition to adulthood among youth with autism. We synthesized the results from 5 interconnected sets of activities: (1) a scoping review of published autism research and research priority statements, (2) a series of key informant interviews with stakeholders, (3) a 2-day National Research Agenda meeting, (4) a modified Delphi survey of stakeholders, and (5) 2 formal reviews of published literature on autism and transition. We identified 2 overarching priorities to advance research about autism and transition: (1) increased focus on community- and systems-level factors that influence outcomes with population-level approaches to measuring outcomes and (2) greater involvement of people with autism in establishing research priorities, designing research studies, and producing study findings and recommendations. We discuss how the life course framework can guide future inquiry that addresses gaps in extant research. PMID- 29610418 TI - Social Support, Well-being, and Quality of Life Among Individuals on the Autism Spectrum. PMID- 29610419 TI - The Autism Spectrum: Human Rights Perspectives. PMID- 29610420 TI - Essential Self-Advocacy and Transition. PMID- 29610421 TI - What We're Reading: Article Recommendations from Our Deputy and Senior Editors. PMID- 29610422 TI - Re(de)fining Innate Lymphocyte Lineages in the Face of Cancer. AB - Innate lymphocytes play critical roles in maintaining tissue homeostasis and integrity of the host at steady state and during pathogenic insults. The successive identification of new innate lymphocyte subsets has revealed an incredible diversity within the family. While this heterogeneous population can be grouped based on their cytotoxic potential into exclusively cytokine-producing helpers and cytolytic killers, the exact developmental relationships between the subsets are not fully understood. The former group is enriched at mucosal surfaces, whereas innate lymphocytes with cytotoxic potential can be identified in a wider array of tissues, including tumors. Although their cytotoxicity suggests an antitumor role, the nature of tumor-elicited innate lymphocyte responses has only begun to be investigated, and the identities of participating subsets still remain contentious. In this review, we provide a brief overview of innate lymphocyte biology, review the current knowledge on their ontogeny, and discuss their roles in tumor immunosurveillance. Cancer Immunol Res; 6(4); 372-7. (c)2018 AACR. PMID- 29610423 TI - Neurotoxicity Associated with a High-Affinity GD2 CAR-Letter. PMID- 29610424 TI - Neurotoxicity Associated with a High-Affinity GD2 CAR-Response. PMID- 29610425 TI - Vitamin Excess and Deficiency. AB - The published literature supports the high prevalence of supplement use in children and adolescents in the United States. Pediatricians today are faced with questions from parents and patients about the benefits, safety, efficacy, and correct dose of vitamins and minerals. In this article, we review 7 vitamins with the most clinical relevance as judged by abundance in food, risks and symptoms of deficiency, and potential for toxicity. Specifically, we focus on possible clinical scenarios that can be indicative of nutritional deficiency. We synthesize and summarize guidelines from nutrition experts, various medical societies, the World Health Organization, and the American Academy of Pediatrics. PMID- 29610426 TI - Atopic Dermatitis. PMID- 29610427 TI - Clinical Presentation, Evaluation, and Management of Neuroblastoma. PMID- 29610428 TI - Back to Basics: Red Blood Cell Distribution Width: Clinical Use beyond Hematology. PMID- 29610429 TI - Case 1: Eye Discharge in a 10-day-old Neonate Born by Cesarean Delivery. PMID- 29610430 TI - Case 2: Jaw Pain, Pain on Deep Inspiration, and Severe Odynophagia in an 18-year old Boy. PMID- 29610431 TI - Case 3: Persistent Pharyngitis in a 14-year-old Girl. PMID- 29610432 TI - Case 4: Diffuse Rash in a 2-month-old Girl. PMID- 29610433 TI - Case 5: Ulcerated, Painful Genital and Perianal Rash in a 1-year-old Girl. PMID- 29610434 TI - Case 6: 17-year-old Girl with a Skin Reaction from a Home Remedy. PMID- 29610435 TI - Toxic Ingestions: Initial Management. PMID- 29610437 TI - Correction. PMID- 29610436 TI - Brucellosis. PMID- 29610438 TI - Visual Diagnosis: 7-year-old Girl with a Facial Rash. PMID- 29610440 TI - Sustained Expression of Negative Regulators of Myelination Protects Schwann Cells from Dysmyelination in a Charcot-Marie-Tooth 1B Mouse Model. AB - Schwann cell differentiation and myelination in the PNS are the result of fine tuning of positive and negative transcriptional regulators. As myelination starts, negative regulators are downregulated, whereas positive ones are upregulated. Fully differentiated Schwann cells maintain an extraordinary plasticity and can transdifferentiate into "repair" Schwann cells after nerve injury. Reactivation of negative regulators of myelination is essential to generate repair Schwann cells. Negative regulators have also been implicated in demyelinating neuropathies, although their role in disease remains elusive. Here, we used a mouse model of Charcot-Marie-Tooth neuropathy type 1B (CMT1B), the P0S63del mouse characterized by ER stress and the activation of the unfolded protein response, to show that adult Schwann cells are in a partial differentiation state because they overexpress transcription factors that are normally expressed only before myelination. We provide evidence that two of these factors, Sox2 and Id2, act as negative regulators of myelination in vivo However, their sustained expression in neuropathy is protective because ablation of Sox2 or/and Id2 from S63del mice of both sexes results in worsening of the dysmyelinating phenotype. This is accompanied by increased levels of mutant P0 expression and exacerbation of ER stress, suggesting that limited differentiation may represent a novel adaptive mechanism through which Schwann cells counter the toxic effect of a mutant terminal differentiation protein.SIGNIFICANCE STATEMENT In many neuropathies, Schwann cells express high levels of early differentiation genes, but the significance of these altered expression remained unclear. Because many of these factors may act as negative regulators of myelination, it was suggested that their misexpression could contribute to dysmyelination. Here, we show that the transcription factors Sox2 and Id2 act as negative regulators of myelination in vivo, but that their sustained expression in Charcot-Marie-Tooth type 1B (CMT1B) represents an adaptive response activated by the Schwann cells to reduce mutant protein toxicity and prevent demyelination. PMID- 29610441 TI - Modified Origins of Cortical Projections to the Superior Colliculus in the Deaf: Dispersion of Auditory Efferents. AB - Following the loss of a sensory modality, such as deafness or blindness, crossmodal plasticity is commonly identified in regions of the cerebrum that normally process the deprived modality. It has been hypothesized that significant changes in the patterns of cortical afferent and efferent projections may underlie these functional crossmodal changes. However, studies of thalamocortical and corticocortical connections have refuted this hypothesis, instead revealing a profound resilience of cortical afferent projections following deafness and blindness. This report is the first study of cortical outputs following sensory deprivation, characterizing cortical projections to the superior colliculus in mature cats (N = 5, 3 female) with perinatal-onset deafness. The superior colliculus was exposed to a retrograde pathway tracer, and subsequently labeled cells throughout the cerebrum were identified and quantified. Overall, the percentage of cortical projections arising from auditory cortex was substantially increased, not decreased, in early-deaf cats compared with intact animals. Furthermore, the distribution of labeled cortical neurons was no longer localized to a particular cortical subregion of auditory cortex but dispersed across auditory cortical regions. Collectively, these results demonstrate that, although patterns of cortical afferents are stable following perinatal deafness, the patterns of cortical efferents to the superior colliculus are highly mutable.SIGNIFICANCE STATEMENT When a sense is lost, the remaining senses are functionally enhanced through compensatory crossmodal plasticity. In deafness, brain regions that normally process sound contribute to enhanced visual and somatosensory perception. We demonstrate that hearing loss alters connectivity between sensory cortex and the superior colliculus, a midbrain region that integrates sensory representations to guide orientation behavior. Contrasting expectation, the proportion of projections from auditory cortex increased in deaf animals compared with normal hearing, with a broad distribution across auditory fields. This is the first description of changes in cortical efferents following sensory loss and provides support for models predicting an inability to form a coherent, multisensory percept of the environment following periods of abnormal development. PMID- 29610439 TI - Soluble TNFalpha Signaling within the Spinal Cord Contributes to the Development of Autonomic Dysreflexia and Ensuing Vascular and Immune Dysfunction after Spinal Cord Injury. AB - Cardiovascular disease and susceptibility to infection are leading causes of morbidity and mortality for individuals with spinal cord injury (SCI). A major contributor to these is autonomic dysreflexia (AD), an amplified reaction of the autonomic nervous system (hallmarked by severe hypertension) in response to sensory stimuli below the injury. Maladaptive plasticity of the spinal sympathetic reflex circuit below the SCI results in AD intensification over time. Mechanisms underlying this maladaptive plasticity are poorly understood, restricting the identification of treatments. Thus, no preventative treatments are currently available. Neuroinflammation has been implicated in other pathologies associated with hyperexcitable neural circuits. Specifically, the soluble form of TNFalpha (sTNFalpha) is known to play a role in neuroplasticity. We hypothesize that persistent expression of sTNFalpha in spinal cord underlies AD exacerbation. To test this, we intrathecally administered XPro1595, a biologic that renders sTNFalpha nonfunctional, after complete, high-level SCI in female rats. This dramatically attenuated the intensification of colorectal distension induced and naturally occurring AD events. This improvement is mediated via decreased sprouting of nociceptive primary afferents and activation of the spinal sympathetic reflex circuit. We also examined peripheral vascular function using ex vivo pressurized arterial preparations and immune function via flow cytometric analysis of splenocytes. Diminishing AD via pharmacological inhibition of sTNFalpha mitigated ensuing vascular hypersensitivity and immune dysfunction. This is the first demonstration that neuroinflammation-induced sTNFalpha is critical for altering the spinal sympathetic reflex circuit, elucidating a novel mechanism for AD. Importantly, we identify the first potential pharmacological, prophylactic treatment for this life-threatening syndrome.SIGNIFICANCE STATEMENT Autonomic dysreflexia (AD), a disorder that develops after spinal cord injury (SCI) and is hallmarked by sudden, extreme hypertension, contributes to cardiovascular disease and susceptibility to infection, respectively, two leading causes of mortality and morbidity in SCI patients. We demonstrate that neuroinflammation-induced expression of soluble TNFalpha plays a critical role in AD, elucidating a novel underlying mechanism. We found that intrathecal administration after SCI of a biologic that inhibits soluble TNFalpha signaling dramatically attenuates AD and significantly reduces AD-associated peripheral vascular and immune dysfunction. We identified mechanisms behind diminished plasticity of neuronal populations within the spinal sympathetic reflex circuit. This study is the first to pinpoint a potential pharmacological, prophylactic strategy to attenuate AD and ensuing cardiovascular and immune dysfunction. PMID- 29610442 TI - Multicenter Registry of Real-World Patients With Severely Calcified Coronary Lesions Undergoing Orbital Atherectomy: 1-Year Outcomes. AB - OBJECTIVES: We report the 1-year outcomes of real-world patients with severely calcified coronary arteries who underwent orbital atherectomy. BACKGROUND: Percutaneous coronary intervention of heavily calcified lesions is technically challenging and associated with worse clinical outcomes. Modification of severely calcified coronary lesions with orbital atherectomy facilitates stent delivery and expansion. Although we previously reported the safety of orbital atherectomy at 30 days in all comers with severely calcified coronary lesions, including patients who were excluded from the ORBIT II trial, longer-term follow-up is unknown. METHODS: We retrospectively analyzed 458 all-comer patients who underwent orbital atherectomy followed by stenting from October 2013 to December 2015 at three centers. The primary endpoint was the 1-year major adverse cardiac and cerebrovascular event (MACCE) rate, defined as the composite of death, myocardial infarction, target-vessel revascularization, and stroke. RESULTS: One year data were available for 453/457 patients (98.9%). At 1-year follow-up, the MACCE rate was 12.6%, death rate was 4.0%, myocardial infarction rate was 1.8%, target-vessel revascularization rate was 7.5%, stroke rate was 1.3%, and stent thrombosis rate was 1.3%. CONCLUSION: Orbital atherectomy is a valuable option for the treatment of severely calcified coronary arteries, including patients with very complex coronary anatomy and severe underlying comorbid conditions. Orbital atherectomy provided acceptable outcomes at 1 year and compared favorably to historical controls. A randomized trial with longer follow-up is needed to determine the optimal treatment strategy for patients with severely calcified coronary lesions. PMID- 29610443 TI - One-Year Clinical Outcomes of Forty-Eight Millimeter Everolimus-Eluting Stent Implanted in Very Long Lesions: A Propensity-Matched Comparison (The FREIUS Study). AB - BACKGROUND: Long coronary lesions still remain a challenge, with poor immediate results and suboptimal outcomes when compared to class A/B1 lesions. The presence of overlapped segments of metal struts and polymer might trigger an abnormal inflammatory reaction, resulting in a higher restenosis rate. The aim of our study was to evaluate the safety, feasibility, and cost effectiveness of a 48 mm everolimus-eluting stent (EES) during treatment of very long coronary lesions. METHODS AND RESULTS: The FREIUS study is a prospective data collection of consecutive patients undergoing 48 mm EES implantation in six high-volume European centers. Each patient was matched through a propensity score to a comparable patient treated with two or more second-generation overlapped drug eluting stents. The primary endpoint was the combined incidence of cardiac death, target-vessel myocardial infarction, and target-lesion revascularization (device oriented composite endpoint [DOCE]). The secondary endpoints were all-cause death, each individual component of the primary endpoint, and definite/probable stent thrombosis. From January 2014 to April 2015, a total of 218 patients were treated with at least one 48 mm EES and were compared with 218 matched controls. Overall, 9% of patients reached the primary endpoint. Cumulative survival free from DOCE incidence did not differ between the two groups (7% in the cases vs 10.5% in the controls; P=.10). After multivariable analysis, only clinical presentation with myocardial infarction (hazard ratio [HR], 1.8; 95% confidence interval [CI], 1.5-2.1; P=.01) and stent number (HR, 1.4; 95% CI, 1.1-1.8; P=.02) emerged as independent predictors of DOCE. CONCLUSION: The use of 48 mm EES offers a safe and effective strategy for the treatment of very long coronary lesions. PMID- 29610444 TI - Hemodynamic Effects of Valve Asymmetry in Sapien 3 Transcatheter Aortic Valves. AB - BACKGROUND: Eccentric valve deployment after transcatheter aortic valve replacement (TAVR) has been associated with abnormal leaflet shear stresses that may accelerate structural valve deterioration (SVD). This phenomenon has not been studied in patients receiving Sapien 3 prostheses (Edwards Lifesciences). METHODS: A retrospective cohort analysis of 100 patients who received Sapien 3 valves between 2013 and 2015 at a single institution was performed. Axial fluoroscopic images from the co-planar view were used to assess TAVR asymmetry, which was defined as a ratio of left-to-right valve heights <=0.9 or >=1.1. Transthoracic echocardiograms (TTEs) were obtained at follow-up to analyze peak and mean aortic valve (AV) gradients, paravalvular leak (PVL), and aortic insufficiency (AI). RESULTS: Overall, 26 mm and 29 mm valves had greater asymmetry (45.2% and 46.9%) compared to 23 mm valves (21.2%; P=.06). There was no relationship between pre-TAVR eccentricity and post-TAVR asymmetry, but greater annular calcification was associated with a higher incidence of TAVR asymmetry. Although asymmetry was associated with higher mean and peak AV gradients among 23 mm and 26 mm valves at both 1-year and 2-year follow-up exams, these results did not reach significance. There were no significant differences in PVL or AI severity between asymmetric and symmetric valves. CONCLUSIONS: Asymmetric deployment of Sapien 3 valves is common, particularly among 26 mm and 29 mm prostheses. Overall, we detected a small increase in gradients in smaller prostheses, which could reflect early subclinical SVD. Longer follow-up will be necessary to determine the extent to which eccentricity is associated with clinically significant SVD. PMID- 29610445 TI - Dissections in Peripheral Vascular Interventions: A Proposed Classification Using Intravascular Ultrasound. AB - Dissections following interventions in the infrainguinal arteries occur very frequently and are mostly under-appreciated on angiographic imaging. Media and external elastic lamina injury can contribute to loss of patency, and intravascular ultrasound (IVUS) can identify this type of injury. The circumference of injury also has been proposed to be a predictor of outcome. We therefore propose a classification combining depth of injury from intima to adventitia with circumference of dissection. This classification exhibits six dissection grades (A1, A2, B1, B2, C1, and C2) as seen on IVUS (the "iDissection" classification). PMID- 29610446 TI - Mechanisms of Lead Failure by Recall Status and Manufacturer: Results From the Pacemaker and Implantable Defibrillator Leads Survival Study ("PAIDLESS"). AB - OBJECTIVES: The aim of this study was to determine the differences in lead failure mechanisms across the major United States implantable defibrillator lead manufacturers (Boston Scientific, Medtronic, and St. Jude Medical), between all non-recalled and recalled leads, and between two recalled lead families (Medtronic Sprint Fidelis and the St. Jude Medical Riata and Riata ST). METHODS: This was a single-center, non-randomized, retrospective study analyzing 3802 patients with 4078 leads who underwent implantable defibrillator lead implantation between February 1, 1996 and December 31, 2011. Lead failure mechanisms were defined as lead fracture, insulation defect, and other. RESULTS: A total of 153 leads (3.8%) failed during the trial period. Failed Medtronic and St. Jude Medical leads presented predominantly as lead fractures (75.8% and 52.8%, respectively). Failed Boston Scientific leads displayed greater variability, although many also failed by fracture (44.4%). The majority of failed non-recalled and recalled leads presented as fractures (50.7% and 82.9%, respectively). The recalled Medtronic Sprint Fidelis and St. Jude Medical Riata/Riata ST leads primarily presented as fractures (89.3% and 65.0%, respectively). Patients whose lead failed via an insulation defect or other mechanism appeared to have a faster time to mortality following lead failure than patients whose lead failed via fracture (P<.01 and P=.02, respectively). CONCLUSIONS: Lead fracture is the most common form of lead failure regardless of the failure points previously identified in these leads. Patients who experienced a lead failure as a result of an insulation defect or other mechanism appeared to die faster than patients whose lead failed via fracture. PMID- 29610447 TI - Very Late Migration of Balloon-Expandable Transcatheter Aortic Valve. AB - Color-flow Doppler transesophageal echocardiography during valve-in-valve TAVR illustrates the placement of a 23 mm Edwards Sapien 3 valve carefully positioned within a displaced 23 mm Edwards Sapien XT valve. PMID- 29610448 TI - Rotational Atherectomy and Simultaneous Temporary Transvenous Pacing Through a Forearm Approach. AB - This is the first reported rotational atherectomy procedure with transvenous pacing utilizing a complete forearm approach. An imaging series illustrates the feasibility of this procedure and its advantages for the patient. PMID- 29610449 TI - Rupture of a Non-Obstructive Plaque. AB - An invasive and non-invasive imaging series representing a classic rupture of a non-obstructive plaque with thin-cap fibroatheroma. PMID- 29610450 TI - Atherosclerosis of the Internal Mammary Artery: Intravascular Ultrasound and Virtual Histology Imaging. AB - Atherosclerotic disease of the shaft of the internal mammary artery (IMA) is rare. This imaging series demonstrates that angiography or arterial duplex ultrasound before bypass surgery of the IMA should be performed even when considering the patient for an emergent bypass surgery. PMID- 29610451 TI - Association of Slow Graft Function with Long-Term Outcomes in Kidney Transplant Recipients. AB - BACKGROUND Whether slow graft function (SGF) represents an intermediate phenotype between immediate graft function (IGF) and delayed graft function (DGF) in kidney transplant recipients is unknown. MATERIAL AND METHODS In a retrospective cohort analysis of 1,222 kidney transplant recipients, we classified patients as having IGF, SGF, and DGF using two different schemas. SGF was defined as serum creatinine (Cr) >=3.0 mg/dL by postoperative day 5 in Schema 1, and in Schema 2, SGF was defined as Cr >1.5 mg/dL plus a creatinine reduction ratio <20% between postoperative days 1 and 3. A complementary log-log model was used to examine the association of graft function with graft survival and patient survival. RESULTS Mean age of study patients was 51.5+/-13.3 years, 59.9% were male, and 66.7% were white. In Schema 1, SGF and DGF were associated with comparable increases in risk of graft failure compared to IGF (hazard ratio (HR) 1.46, 95% confidence intervals (CI) 1.02-2.10 for SGF and HR 1.56, CI 1.11-2.22 for IGF); estimates were similar for Schema 2 (HR 1.52, CI 1.05-2.20 for SGF and HR 1.54, CI 1.10 2.17 for IGF). However, for mortality, outcomes for SGF were similarly to IGF, both SGF and IGF were associated with lower risk relative to DGF (HR 0.54, CI 0.36-0.80 for SGF in Schema 1; HR 0.58, CI 0.39-0.85 for SGF in Schema 2). CONCLUSIONS These findings suggest that SGF may be a marker for graft failure but not for mortality, and SGF may therefore represent a phenotype separate from IGF and DGF. PMID- 29610452 TI - Baicalin Inhibits Human Cervical Cancer Cells by Suppressing Protein Kinase C/Signal Transducer and Activator of Transcription (PKC/STAT3) Signaling Pathway. AB - BACKGROUND Like other human cancers, the malignancy of cervical cancer is also characterized by abilities of proliferation, migration, and invasion. Protein kinase C-zeta (PKCzeta) has been highly correlated with several human cancers. Baicalin was proven to regulate PKC. This study aimed to investigate the anti cancer effect and involved molecular mechanisms of baicalin on human cervical cancer. MATERIAL AND METHODS Baicalin at various concentrations was used to treat 2 human cervical cancer cell lines HeLa and SiHa. The proliferation was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenylterazolium bromide (MTT) assay. The apoptosis was detected by terminal transferase UTP nick end labeling (TUNEL) assay. Wound healing assay and Transwell assay were used to evaluate the migration and invasion respectively. Western blotting was performed to assess the protein expression levels. RESULTS Baicalin administration significantly reduced the viability by facilitating the apoptosis in HeLa and SiHa cells. Baicalin treatment also significantly reduced the wound closure and cell amount invaded as measured by Transwell assay. The expression levels of PKCzeta, survivin, matrix metalloproteinase (MMP)2, MMP9 as well as the phosphorylation of signal transducer and activator of transcription (STAT) 3 were reduced in baicalin administrated cervical cancer cells. CONCLUSIONS Baicalin exerted anti-cancer effects on human cervical cancer cells by targeting STAT3 regulated signaling pathways. PMID- 29610453 TI - Sjogren's Syndrome Associated with Fanconi's Syndrome and Osteomalacia. AB - BACKGROUND Sjogren's syndrome is a chronic inflammatory autoimmune disease, which is also known as sicca syndrome, due to the symptoms of dry eyes and dry mouth, and is associated with other connective tissue diseases and autoimmune diseases. Sjogren's syndrome can also be associated with renal involvement. Fanconi's syndrome is associated with impaired reabsorption in the proximal renal tubule associated with tubulointerstitial nephritis and is associated with renal tubular acidosis and hypophosphatemia. Osteomalacia is a rare association with Sjogren's syndrome, which may result from renal disease. CASE REPORT We report the case of a 34-year-old woman who presented with xerostomia, xerophthalmia, bone fractures, and osteomuscular pain. A Schirmer test showed reduced tear production, and a biopsy of a minor salivary gland of the lip, with high titers of antinuclear antibodies (ANA), and positive anti-SSA/Ro and anti-SSB/La antibodies confirmed the diagnosis of Sjogren's syndrome. Serum and urinary laboratories tests and clinical manifestations confirmed Fanconi's syndrome associated with osteomalacia. The patient was treated with potassium supplements, 25 hydroxyvitamin D (25(OH)D), hydroxychloroquine, mycophenolate mofetil, and prednisone, with a favorable response. CONCLUSIONS This case is of a rare association between Sjogren's syndrome, Fanconi's syndrome, and osteomalacia. Even though these are rare clinical associations, early detection can improve the quality of life and prevent further complications. PMID- 29610455 TI - Velocity correlated crack front and surface marks in single crystalline silicon. AB - Single crystalline silicon fractures on low-energy cleavage planes such as (111) and (110). The crack propagation cannot accurately be predicted by linear elastic fracture mechanics since it does not account for small scale and inelastic phenomena such as atomic lattice trapping. Here we show that, under pure bending load, (110) cleavage in silicon single crystal rapidly accelerates to 3700 m/s without crack path deviation or crack branching, contrasting previous observations. We highlight that the crack front shape involves strong velocity dependence and presents a curvature jump during very high-speed crack growth. In addition, we observe special marks-a kind of periodic surface undulation-that exclusively arise on the rapid fracture surfaces, and we suggest that they are front wave traces resulting from an intrinsic local velocity fluctuation. This finding gives insight to the wavy nature of the crack front in the absence of material asperity. PMID- 29610454 TI - Designer exosomes produced by implanted cells intracerebrally deliver therapeutic cargo for Parkinson's disease treatment. AB - Exosomes are cell-derived nanovesicles (50-150 nm), which mediate intercellular communication, and are candidate therapeutic agents. However, inefficiency of exosomal message transfer, such as mRNA, and lack of methods to create designer exosomes have hampered their development into therapeutic interventions. Here, we report a set of EXOsomal transfer into cells (EXOtic) devices that enable efficient, customizable production of designer exosomes in engineered mammalian cells. These genetically encoded devices in exosome producer cells enhance exosome production, specific mRNA packaging, and delivery of the mRNA into the cytosol of target cells, enabling efficient cell-to-cell communication without the need to concentrate exosomes. Further, engineered producer cells implanted in living mice could consistently deliver cargo mRNA to the brain. Therapeutic catalase mRNA delivery by designer exosomes attenuated neurotoxicity and neuroinflammation in in vitro and in vivo models of Parkinson's disease, indicating the potential usefulness of the EXOtic devices for RNA delivery-based therapeutic applications. PMID- 29610456 TI - Potential of quantitative SEPT9 and SHOX2 methylation in plasmatic circulating cell-free DNA as auxiliary staging parameter in colorectal cancer: a prospective observational cohort study. AB - BACKGROUND: Septin 9 (SEPT9) and short stature homeobox 2 (SHOX2) methylation in circulating cell-free DNA (ccfDNA) are powerful biomarkers for colorectal cancer (CRC) screening, as well as head and neck squamous cell carcinoma staging and monitoring. In the present study, we investigated SEPT9 and SHOX2 ccfDNA methylation as auxiliary pre and post-therapeutic staging parameters in CRC patients. METHODS: ccfDNA methylation was quantified in 184 prospectively enrolled patients prior to and 3-10 days after surgery, and biomarker levels were associated with clinico-pathological parameters. RESULTS: Pre-therapeutic levels of SHOX2 and SEPT9 ccfDNA methylation were strongly associated with Union for International Cancer Control (UICC) stages, tumour (T), nodal (N), and metastasis (M) categories, and histological grade (all P <= 0.001), as well as lymphatic invasion and extracapsular lymph node extension (all P< 0.05). Post-therapeutic SHOX2 and SEPT9 ccfDNA methylation levels correlated with UICC stage (all P <0.01). SEPT9 ccfDNA methylation further allowed for an accurate pre- and post therapeutic detection of distant metastases (AUCpre-therapeutic = 0.79 (95%CI 0.69-0.89), AUCpost-therapeutic = 0.93 (95% CI 0.79-1.0)). CONCLUSIONS: DNA methylation analysis in plasma is a powerful pre and post-therapeutic diagnostic tool for CRC and may add valuable information to current TNM staging, thereby holding the potential to assist in the development of individually tailored treatment protocols. PMID- 29610459 TI - Impact of evolving greenhouse gas forcing on the warming signal in regional climate model experiments. AB - Variations in the atmospheric concentrations of greenhouse gases (GHG) may not be included as external forcing when running regional climate models (RCMs); at least, this is a non-regulated, non-documented practice. Here we investigate the so far unexplored impact of considering the rising evolution of the CO2, CH4, and N2O atmospheric concentrations on near-surface air temperature (TAS) trends, for both the recent past and the near future, as simulated by a state-of-the-art RCM over Europe. The results show that the TAS trends are significantly affected by 1 2 K century-1, which under 1.5 degrees C global warming translates into a non negligible impact of up to 1 K in the regional projections of TAS, similarly affecting projections for maximum and minimum temperatures. In some cases, these differences involve a doubling signal, laying further claim to careful reconsideration of the RCM setups with regard to the inclusion of GHG concentrations as an evolving external forcing which, for the sake of research reproducibility and reliability, should be clearly documented in the literature. PMID- 29610457 TI - CNTNAP2 stabilizes interneuron dendritic arbors through CASK. AB - Contactin associated protein-like 2 (CNTNAP2) has emerged as a prominent susceptibility gene implicated in multiple complex neurodevelopmental disorders, including autism spectrum disorders (ASD), intellectual disability (ID), and schizophrenia (SCZ). The presence of seizure comorbidity in many of these cases, as well as inhibitory neuron dysfunction in Cntnap2 knockout (KO) mice, suggests CNTNAP2 may be crucial for proper inhibitory network function. However, underlying cellular mechanisms are unclear. Here we show that cultured Cntnap2 KO mouse neurons exhibit an inhibitory neuron-specific simplification of the dendritic tree. These alterations can be replicated by acute knockdown of CNTNAP2 in mature wild-type (WT) neurons and are caused by faulty dendrite stabilization rather than outgrowth. Using structured illumination microscopy (SIM) and stimulated-emission depletion microscopy (STED), two super-resolution imaging techniques, we uncovered relationships between nanoscale CNTNAP2 protein localization and dendrite arborization patterns. Employing yeast two-hybrid screening, biochemical analysis, in situ proximity ligation assay (PLA), SIM, and phenotype rescue, we show that these effects are mediated at the membrane by the interaction of CNTNAP2's C-terminus with calcium/calmodulin-dependent serine protein kinase (CASK), another ASD/ID risk gene. Finally, we show that adult Cntnap2 KO mice have reduced interneuron dendritic length and branching in particular cortical regions, as well as decreased CASK levels in the cortical membrane fraction. Taken together, our data reveal an interneuron-specific mechanism for dendrite stabilization that may provide a cellular mechanism for inhibitory circuit dysfunction in CNTNAP2-related disorders. PMID- 29610460 TI - An artificial interphase enables reversible magnesium chemistry in carbonate electrolytes. AB - Magnesium-based batteries possess potential advantages over their lithium counterparts. However, reversible Mg chemistry requires a thermodynamically stable electrolyte at low potential, which is usually achieved with corrosive components and at the expense of stability against oxidation. In lithium-ion batteries the conflict between the cathodic and anodic stabilities of the electrolytes is resolved by forming an anode interphase that shields the electrolyte from being reduced. This strategy cannot be applied to Mg batteries because divalent Mg2+ cannot penetrate such interphases. Here, we engineer an artificial Mg2+-conductive interphase on the Mg anode surface, which successfully decouples the anodic and cathodic requirements for electrolytes and demonstrate highly reversible Mg chemistry in oxidation-resistant electrolytes. The artificial interphase enables the reversible cycling of a Mg/V2O5 full-cell in the water-containing, carbonate-based electrolyte. This approach provides a new avenue not only for Mg but also for other multivalent-cation batteries facing the same problems, taking a step towards their use in energy-storage applications. PMID- 29610461 TI - High phase-purity 1T'-MoS2- and 1T'-MoSe2-layered crystals. AB - Phase control plays an important role in the precise synthesis of inorganic materials, as the phase structure has a profound influence on properties such as conductivity and chemical stability. Phase-controlled preparation has been challenging for the metallic-phase group-VI transition metal dichalcogenides (the transition metals are Mo and W, and the chalcogens are S, Se and Te), which show better performance in electrocatalysis than their semiconducting counterparts. Here, we report the large-scale preparation of micrometre-sized metallic-phase 1T'-MoX2 (X = S, Se)-layered bulk crystals in high purity. We reveal that 1T' MoS2 crystals feature a distorted octahedral coordination structure and are convertible to 2H-MoS2 following thermal annealing or laser irradiation. Electrochemical measurements show that the basal plane of 1T'-MoS2 is much more active than that of 2H-MoS2 for the electrocatalytic hydrogen evolution reaction in an acidic medium. PMID- 29610462 TI - Second-generation DNA-templated macrocycle libraries for the discovery of bioactive small molecules. AB - DNA-encoded libraries have emerged as a widely used resource for the discovery of bioactive small molecules, and offer substantial advantages compared with conventional small-molecule libraries. Here, we have developed and streamlined multiple fundamental aspects of DNA-encoded and DNA-templated library synthesis methodology, including computational identification and experimental validation of a 20 * 20 * 20 * 80 set of orthogonal codons, chemical and computational tools for enhancing the structural diversity and drug-likeness of library members, a highly efficient polymerase-mediated template library assembly strategy, and library isolation and purification methods. We have integrated these improved methods to produce a second-generation DNA-templated library of 256,000 small molecule macrocycles with improved drug-like physical properties. In vitro selection of this library for insulin-degrading enzyme affinity resulted in novel insulin-degrading enzyme inhibitors, including one of unusual potency and novel macrocycle stereochemistry (IC50 = 40 nM). Collectively, these developments enable DNA-templated small-molecule libraries to serve as more powerful, accessible, streamlined and cost-effective tools for bioactive small-molecule discovery. PMID- 29610463 TI - Single-cell mRNA cytometry via sequence-specific nanoparticle clustering and trapping. AB - Cell-to-cell variation in gene expression creates a need for techniques that can characterize expression at the level of individual cells. This is particularly true for rare circulating tumour cells, in which subtyping and drug resistance are of intense interest. Here we describe a method for cell analysis-single-cell mRNA cytometry-that enables the isolation of rare cells from whole blood as a function of target mRNA sequences. This approach uses two classes of magnetic particles that are labelled to selectively hybridize with different regions of the target mRNA. Hybridization leads to the formation of large magnetic clusters that remain localized within the cells of interest, thereby enabling the cells to be magnetically separated. Targeting specific intracellular mRNAs enablescirculating tumour cells to be distinguished from normal haematopoietic cells. No polymerase chain reaction amplification is required to determine RNA expression levels and genotype at the single-cell level, and minimal cell manipulation is required. To demonstrate this approach we use single-cell mRNA cytometry to detect clinically important sequences in prostate cancer specimens. PMID- 29610464 TI - Single helically folded aromatic oligoamides that mimic the charge surface of double-stranded B-DNA. AB - Numerous essential biomolecular processes require the recognition of DNA surface features by proteins. Molecules mimicking these features could potentially act as decoys and interfere with pharmacologically or therapeutically relevant protein DNA interactions. Although naturally occurring DNA-mimicking proteins have been described, synthetic tunable molecules that mimic the charge surface of double stranded DNA are not known. Here, we report the design, synthesis and structural characterization of aromatic oligoamides that fold into single helical conformations and display a double helical array of negatively charged residues in positions that match the phosphate moieties in B-DNA. These molecules were able to inhibit several enzymes possessing non-sequence-selective DNA-binding properties, including topoisomerase 1 and HIV-1 integrase, presumably through specific foldamer-protein interactions, whereas sequence-selective enzymes were not inhibited. Such modular and synthetically accessible DNA mimics provide a versatile platform to design novel inhibitors of protein-DNA interactions. PMID- 29610465 TI - A general strategy for synthesis of cyclophane-braced peptide macrocycles via palladium-catalysed intramolecular sp3 C-H arylation. AB - New methods capable of effecting cyclization, and forming novel three-dimensional structures while maintaining favourable physicochemical properties are needed to facilitate the development of cyclic peptide-based drugs that can engage challenging biological targets, such as protein-protein interactions. Here, we report a highly efficient and generally applicable strategy for constructing new types of peptide macrocycles using palladium-catalysed intramolecular C(sp3)-H arylation reactions. Easily accessible linear peptide precursors of simple and versatile design can be selectively cyclized at the side chains of either aromatic or modified non-aromatic amino acid units to form various cyclophane braced peptide cycles. This strategy provides a powerful tool to address the long standing challenge of size- and composition-dependence in peptide macrocyclization, and generates novel peptide macrocycles with uniquely buttressed backbones and distinct loop-type three-dimensional structures. Preliminary cell proliferation screening of the pilot library revealed a potent lead compound with selective cytotoxicity toward proliferative Myc-dependent cancer cell lines. PMID- 29610466 TI - Horizontal gene transfer constrains the timing of methanogen evolution. AB - Microbial methanogenesis may have been a major component of Earth's carbon cycle during the Archaean eon, generating a methane greenhouse that increased global temperatures enough for a liquid hydrosphere, despite the Sun's lower luminosity at the time. Evaluation of potential solutions to the 'faint young Sun' hypothesis by determining the age of microbial methanogenesis has been limited by ambiguous geochemical evidence and the absence of a diagnostic fossil record. To overcome these challenges, we use a temporal constraint: a horizontal gene transfer event from within archaeal methanogens to the ancestor of Cyanobacteria, one of the few microbial clades with recognized crown-group fossils. Results of molecular clock analyses calibrated by this horizontal-gene-transfer-propagated constraint show methanogens diverging within Euryarchaeota no later than 3.51 billion years ago, with methanogenesis itself probably evolving earlier. This timing provides independent support for scenarios wherein microbial methane production was important in maintaining temperatures on the early Earth. PMID- 29610467 TI - Human footprint restricts ranges. PMID- 29610469 TI - Scales of data. PMID- 29610468 TI - Hagfish and lamprey Hox genes reveal conservation of temporal colinearity in vertebrates. AB - Hox genes exert fundamental roles for proper regional specification along the main rostro-caudal axis of animal embryos. They are generally expressed in restricted spatial domains according to their position in the cluster (spatial colinearity)-a feature that is conserved across bilaterians. In jawed vertebrates (gnathostomes), the position in the cluster also determines the onset of expression of Hox genes (a feature known as whole-cluster temporal colinearity (WTC)), while in invertebrates this phenomenon is displayed as a subcluster-level temporal colinearity. However, little is known about the expression profile of Hox genes in jawless vertebrates (cyclostomes); therefore, the evolutionary origin of WTC, as seen in gnathostomes, remains a mystery. Here, we show that Hox genes in cyclostomes are expressed according to WTC during development. We investigated the Hox repertoire and Hox gene expression profiles in three different species-a hagfish, a lamprey and a shark-encompassing the two major groups of vertebrates, and found that these are expressed following a whole cluster, temporally staggered pattern, indicating that WTC has been conserved during the past 500 million years despite drastically different genome evolution and morphological outputs between jawless and jawed vertebrates. PMID- 29610470 TI - Fossil-free dating. PMID- 29610471 TI - Gene transfers can date the tree of life. AB - Biodiversity has always been predominantly microbial, and the scarcity of fossils from bacteria, archaea and microbial eukaryotes has prevented a comprehensive dating of the tree of life. Here, we show that patterns of lateral gene transfer deduced from an analysis of modern genomes encode a novel and abundant source of information about the temporal coexistence of lineages throughout the history of life. We use state-of-the-art species tree-aware phylogenetic methods to reconstruct the history of thousands of gene families and demonstrate that dates implied by gene transfers are consistent with estimates from relaxed molecular clocks in Bacteria, Archaea and Eukarya. We present the order of speciations according to lateral gene transfer data calibrated to geological time for three datasets comprising 40 genomes for Cyanobacteria, 60 genomes for Archaea and 60 genomes for Fungi. An inspection of discrepancies between transfers and clocks and a comparison with mammalian fossils show that gene transfer in microbes is potentially as informative for dating the tree of life as the geological record in macroorganisms. PMID- 29610472 TI - The spatial and temporal domains of modern ecology. AB - To understand ecological phenomena, it is necessary to observe their behaviour across multiple spatial and temporal scales. Since this need was first highlighted in the 1980s, technology has opened previously inaccessible scales to observation. To help to determine whether there have been corresponding changes in the scales observed by modern ecologists, we analysed the resolution, extent, interval and duration of observations (excluding experiments) in 348 studies that have been published between 2004 and 2014. We found that observational scales were generally narrow, because ecologists still primarily use conventional field techniques. In the spatial domain, most observations had resolutions <=1 m2 and extents <=10,000 ha. In the temporal domain, most observations were either unreplicated or infrequently repeated (>1 month interval) and <=1 year in duration. Compared with studies conducted before 2004, observational durations and resolutions appear largely unchanged, but intervals have become finer and extents larger. We also found a large gulf between the scales at which phenomena are actually observed and the scales those observations ostensibly represent, raising concerns about observational comprehensiveness. Furthermore, most studies did not clearly report scale, suggesting that it remains a minor concern. Ecologists can better understand the scales represented by observations by incorporating autocorrelation measures, while journals can promote attentiveness to scale by implementing scale-reporting standards. PMID- 29610473 TI - Microinfarcts and blood pressure trajectories: response to Dr Niu et al. PMID- 29610474 TI - Association between microinfarcts and blood pressure trajectories. PMID- 29610477 TI - Switching from fetal to adult hemoglobin. PMID- 29610476 TI - Mapping the in vivo fitness landscape of lung adenocarcinoma tumor suppression in mice. AB - The functional impact of most genomic alterations found in cancer, alone or in combination, remains largely unknown. Here we integrate tumor barcoding, CRISPR/Cas9-mediated genome editing and ultra-deep barcode sequencing to interrogate pairwise combinations of tumor suppressor alterations in autochthonous mouse models of human lung adenocarcinoma. We map the tumor suppressive effects of 31 common lung adenocarcinoma genotypes and identify a landscape of context dependence and differential effect strengths. PMID- 29610478 TI - Natural regulatory mutations elevate the fetal globin gene via disruption of BCL11A or ZBTB7A binding. AB - beta-hemoglobinopathies such as sickle cell disease (SCD) and beta-thalassemia result from mutations in the adult HBB (beta-globin) gene. Reactivating the developmentally silenced fetal HBG1 and HBG2 (gamma-globin) genes is a therapeutic goal for treating SCD and beta-thalassemia 1 . Some forms of hereditary persistence of fetal hemoglobin (HPFH), a rare benign condition in which individuals express the gamma-globin gene throughout adulthood, are caused by point mutations in the gamma-globin gene promoter at regions residing ~115 and 200 bp upstream of the transcription start site. We found that the major fetal globin gene repressors BCL11A and ZBTB7A (also known as LRF) directly bound to the sites at -115 and -200 bp, respectively. Furthermore, introduction of naturally occurring HPFH-associated mutations into erythroid cells by CRISPR-Cas9 disrupted repressor binding and raised gamma-globin gene expression. These findings clarify how these HPFH-associated mutations operate and demonstrate that BCL11A and ZBTB7A are major direct repressors of the fetal globin gene. PMID- 29610475 TI - The long tail of oncogenic drivers in prostate cancer. AB - Comprehensive genomic characterization of prostate cancer has identified recurrent alterations in genes involved in androgen signaling, DNA repair, and PI3K signaling, among others. However, larger and uniform genomic analysis may identify additional recurrently mutated genes at lower frequencies. Here we aggregate and uniformly analyze exome sequencing data from 1,013 prostate cancers. We identify and validate a new class of E26 transformation-specific (ETS)-fusion-negative tumors defined by mutations in epigenetic regulators, as well as alterations in pathways not previously implicated in prostate cancer, such as the spliceosome pathway. We find that the incidence of significantly mutated genes (SMGs) follows a long-tail distribution, with many genes mutated in less than 3% of cases. We identify a total of 97 SMGs, including 70 not previously implicated in prostate cancer, such as the ubiquitin ligase CUL3 and the transcription factor SPEN. Finally, comparing primary and metastatic prostate cancer identifies a set of genomic markers that may inform risk stratification. PMID- 29610479 TI - Single-cell RNA sequencing identifies celltype-specific cis-eQTLs and co expression QTLs. AB - Genome-wide association studies have identified thousands of genetic variants that are associated with disease 1 . Most of these variants have small effect sizes, but their downstream expression effects, so-called expression quantitative trait loci (eQTLs), are often large 2 and celltype-specific3-5. To identify these celltype-specific eQTLs using an unbiased approach, we used single-cell RNA sequencing to generate expression profiles of ~25,000 peripheral blood mononuclear cells from 45 donors. We identified previously reported cis-eQTLs, but also identified new celltype-specific cis-eQTLs. Finally, we generated personalized co-expression networks and identified genetic variants that significantly alter co-expression relationships (which we termed 'co-expression QTLs'). Single-cell eQTL analysis thus allows for the identification of genetic variants that impact regulatory networks. PMID- 29610482 TI - The gastroesophageal cancer drug market. PMID- 29610480 TI - DNA methylation loss in late-replicating domains is linked to mitotic cell division. AB - DNA methylation loss occurs frequently in cancer genomes, primarily within lamina associated, late-replicating regions termed partially methylated domains (PMDs). We profiled 39 diverse primary tumors and 8 matched adjacent tissues using whole genome bisulfite sequencing (WGBS) and analyzed them alongside 343 additional human and 206 mouse WGBS datasets. We identified a local CpG sequence context associated with preferential hypomethylation in PMDs. Analysis of CpGs in this context ('solo-WCGWs') identified previously undetected PMD hypomethylation in almost all healthy tissue types. PMD hypomethylation increased with age, beginning during fetal development, and appeared to track the accumulation of cell divisions. In cancer, PMD hypomethylation depth correlated with somatic mutation density and cell cycle gene expression, consistent with its reflection of mitotic history and suggesting its application as a mitotic clock. We propose that late replication leads to lifelong progressive methylation loss, which acts as a biomarker for cellular aging and which may contribute to oncogenesis. PMID- 29610481 TI - A global transcriptional network connecting noncoding mutations to changes in tumor gene expression. AB - Although cancer genomes are replete with noncoding mutations, the effects of these mutations remain poorly characterized. Here we perform an integrative analysis of 930 tumor whole genomes and matched transcriptomes, identifying a network of 193 noncoding loci in which mutations disrupt target gene expression. These 'somatic eQTLs' (expression quantitative trait loci) are frequently mutated in specific cancer tissues, and the majority can be validated in an independent cohort of 3,382 tumors. Among these, we find that the effects of noncoding mutations on DAAM1, MTG2 and HYI transcription are recapitulated in multiple cancer cell lines and that increasing DAAM1 expression leads to invasive cell migration. Collectively, the noncoding loci converge on a set of core pathways, permitting a classification of tumors into pathway-based subtypes. The somatic eQTL network is disrupted in 88% of tumors, suggesting widespread impact of noncoding mutations in cancer. PMID- 29610483 TI - Author Correction: Mitochondrial DNA repair and replication proteins revealed by targeted chemical probes. AB - In the version of this article initially published, Sanduni Liyanage and Aaron Schimmer were not properly acknowledged as co-authors. Both authors have now been included in the current author list, and their contributions are now specified in the author contributions statement. The error has been corrected in the PDF and HTML versions of this article. PMID- 29610485 TI - Super-long single-molecule tracking reveals dynamic-anchorage-induced integrin function. AB - Single-fluorescent-molecule imaging tracking (SMT) is becoming an important tool to study living cells. However, photobleaching and photoblinking (hereafter referred to as photobleaching/photoblinking) of the probe molecules strongly hamper SMT studies of living cells, making it difficult to observe in vivo molecular events and to evaluate their lifetimes (e.g., off rates). The methods used to suppress photobleaching/photoblinking in vitro are difficult to apply to living cells because of their toxicities. Here using 13 organic fluorophores we found that, by combining low concentrations of dissolved oxygen with a reducing plus-oxidizing system, photobleaching/photoblinking could be strongly suppressed with only minor effects on cells, which enabled SMT for as long as 12,000 frames (~7 min at video rate, as compared to the general 10-s-order durations) with ~22 nm single-molecule localization precisions. SMT of integrins revealed that they underwent temporary (<80-s) immobilizations within the focal adhesion region, which were responsible for the mechanical linkage of the actin cytoskeleton to the extracellular matrix. PMID- 29610484 TI - FINO2 initiates ferroptosis through GPX4 inactivation and iron oxidation. AB - Ferroptosis is a non-apoptotic form of regulated cell death caused by the failure of the glutathione-dependent lipid-peroxide-scavenging network. FINO2 is an endoperoxide-containing 1,2-dioxolane that can initiate ferroptosis selectively in engineered cancer cells. We investigated the mechanism and structural features necessary for ferroptosis initiation by FINO2. We found that FINO2 requires both an endoperoxide moiety and a nearby hydroxyl head group to initiate ferroptosis. In contrast to previously described ferroptosis inducers, FINO2 does not inhibit system xc- or directly target the reducing enzyme GPX4, as do erastin and RSL3, respectively, nor does it deplete GPX4 protein, as does FIN56. Instead, FINO2 both indirectly inhibits GPX4 enzymatic function and directly oxidizes iron, ultimately causing widespread lipid peroxidation. These findings suggest that endoperoxides such as FINO2 can initiate a multipronged mechanism of ferroptosis. PMID- 29610486 TI - The structural organization of substrate loading in iterative polyketide synthases. AB - Polyketide synthases (PKSs) are microbial multienzymes for the biosynthesis of biologically potent secondary metabolites. Polyketide production is initiated by the loading of a starter unit onto an integral acyl carrier protein (ACP) and its subsequent transfer to the ketosynthase (KS). Initial substrate loading is achieved either by multidomain loading modules or by the integration of designated loading domains, such as starter unit acyltransferases (SAT), whose structural integration into PKS remains unresolved. A crystal structure of the loading/condensing region of the nonreducing PKS CTB1 demonstrates the ordered insertion of a pseudodimeric SAT into the condensing region, which is aided by the SAT-KS linker. Cryo-electron microscopy of the post-loading state trapped by mechanism-based crosslinking of ACP to KS reveals asymmetry across the CTB1 loading/-condensing region, in accord with preferential 1:2 binding stoichiometry. These results are critical for re-engineering the loading step in polyketide biosynthesis and support functional relevance of asymmetric conformations of PKSs. PMID- 29610487 TI - Collapse of superconductivity in cuprates via ultrafast quenching of phase coherence. AB - The possibility of driving phase transitions in low-density condensates through the loss of phase coherence alone has far-reaching implications for the study of quantum phases of matter. This has inspired the development of tools to control and explore the collective properties of condensate phases via phase fluctuations. Electrically gated oxide interfaces1,2, ultracold Fermi atoms3,4 and cuprate superconductors5,6, which are characterized by an intrinsically small phase stiffness, are paradigmatic examples where these tools are having a dramatic impact. Here we use light pulses shorter than the internal thermalization time to drive and probe the phase fragility of the Bi2Sr2CaCu2O8+delta cuprate superconductor, completely melting the superconducting condensate without affecting the pairing strength. The resulting ultrafast dynamics of phase fluctuations and charge excitations are captured and disentangled by time-resolved photoemission spectroscopy. This work demonstrates the dominant role of phase coherence in the superconductor-to-normal state phase transition and offers a benchmark for non-equilibrium spectroscopic investigations of the cuprate phase diagram. PMID- 29610488 TI - Pancreatic cancer: The COMPASS shows the way. PMID- 29610489 TI - Leukaemia: Powers of prediction. PMID- 29610490 TI - Breast cancer: Obesity - tipping the scales of resistance. PMID- 29610491 TI - Breast cancer: External communication. PMID- 29610492 TI - Gunter Blobel 1936-2018. PMID- 29610493 TI - Atomic structures of FUS LC domain segments reveal bases for reversible amyloid fibril formation. AB - Thermostable cross-beta structures are characteristic of pathological amyloid fibrils, but these structures cannot explain the reversible nature of fibrils formed by RNA-binding proteins such as fused in sarcoma (FUS), involved in RNA granule assembly. Here, we find that two tandem (S/G)Y(S/G) motifs of the human FUS low-complexity domain (FUS LC) form reversible fibrils in a temperature- and phosphorylation-dependent manner. We named these motifs reversible amyloid cores, or RAC1 and RAC2, and determined their atomic structures in fibrillar forms, using microelectron and X-ray diffraction techniques. The RAC1 structure features an ordered-coil fibril spine rather than the extended beta-strand typical of amyloids. Ser42, a phosphorylation site of FUS, is critical in the maintenance of the ordered-coil structure, which explains how phosphorylation controls fibril formation. The RAC2 structure shows a labile fibril spine with a wet interface. These structures illuminate the mechanism of reversible fibril formation and dynamic assembly of RNA granules. PMID- 29610494 TI - Structural basis of small-molecule inhibition of human multidrug transporter ABCG2. AB - ABCG2 is an ATP-binding cassette (ABC) transporter that protects tissues against xenobiotics, affects the pharmacokinetics of drugs and contributes to multidrug resistance. Although many inhibitors and modulators of ABCG2 have been developed, understanding their structure-activity relationship requires high-resolution structural insight. Here, we present cryo-EM structures of human ABCG2 bound to synthetic derivatives of the fumitremorgin C-related inhibitor Ko143 or the multidrug resistance modulator tariquidar. Both compounds are bound to the central, inward-facing cavity of ABCG2, blocking access for substrates and preventing conformational changes required for ATP hydrolysis. The high resolutions allowed for de novo building of the entire transporter and also revealed tightly bound phospholipids and cholesterol interacting with the lipid exposed surface of the transmembrane domains (TMDs). Extensive chemical modifications of the Ko143 scaffold combined with in vitro functional analyses revealed the details of ABCG2 interactions with this compound family and provide a basis for the design of novel inhibitors and modulators. PMID- 29610495 TI - Genetic Testing in Young Adult Patients With Idiopathic Acute Pancreatitis. PMID- 29610496 TI - Pembrolizumab-Induced Microscopic Colitis. PMID- 29610497 TI - Use of a Laparoscopic Bag for the Endoscopic Retrieval of a Large Gastric Tumor After Endoscopic Submucosal Dissection. PMID- 29610498 TI - An Unexpected Cause of Acute Enteritis in a Patient with Pure Red Cell Aplasia Parvovirus B19-Associated Acute Enteritis. PMID- 29610499 TI - Phenotypic Variability of MUTYH-Associated Polyposis in Monozygotic Twins and Endoscopic Resection of A Giant Polyp in Pregnancy. PMID- 29610500 TI - Editorial: The Risky Business of Fungal Infections in Patients with Cirrhosis. AB - Hospitalized patients with cirrhosis have a high rate of mortality. In the report by Bajaj et al., the negative impact of fungal infections (FI) on outcomes in a large US cohort of hospitalized cirrhotics is highlighted. Risk factors for FI are identified. Increasing awareness of FI along with the application of new diagnostic tools in species identification will provide the opportunity to improve patient outcomes. PMID- 29610502 TI - Gingival Hyperplasia as a Presenting Symptom of Crohn's Disease in a Teenager. PMID- 29610504 TI - Continuing Medical Education Questions: April 2018: ACG Clinical Guideline: Management of Crohn's Disease in Adults. PMID- 29610503 TI - Gastric Inverted Hyperplastic Polyp Mimicking a Papilla. PMID- 29610505 TI - Spanish Women Hepatologists: Breaking The Glass Ceiling? PMID- 29610506 TI - Comment on ACG and CAG Clinical Guidelines for Management of Dyspesia. PMID- 29610507 TI - Vedolizumab as a Novel Treatment for Refractory Collagenous Colitis: A Case Report. PMID- 29610510 TI - Pathophysiology of the Appendix in Ulcerative Colitis. PMID- 29610509 TI - Ileocecal Anastomosis Type Significantly Influences Long-Term Functional Status, Quality of Life, and Healthcare Utilization in Postoperative Crohn's Disease Patients Independent of Inflammation Recurrence. AB - OBJECTIVES: Anastomotic reconstruction following intestinal resection in Crohn's disease (CD) may employ side-to-side anastomosis (STSA; anti-peristaltic orientation) or end-to-end anastomosis (ETEA). Our aim was to determine the impact of these two anastomotic techniques on long-term clinical status in postoperative CD patients. METHODS: We performed a comparative effectiveness study of prospectively collected observational data from consented CD patients undergoing their first or second ileocolonic bowel resection and re-anastomosis between 2008 and 2012, in order to assess the association between anastomosis type and 2-year postoperative quality of life (QoL), healthcare utilization, disease clinical or endoscopic recurrence, use of medications, and need for repeat resection. RESULTS: One hundred and twenty eight postoperative CD patients (60 STSA and 68 ETEA) were evaluated. At 2 years postoperatively, STSA patients had higher rates of emergency department visits (33.3% vs. 14.7%; P=0.01), hospitalizations (30% vs. 11.8%; P=0.01), and abdominal computed tomography scans (50% vs. 13.2%; P<0.001) with lower QoL (mean short inflammatory bowel disease questionnaire 47.9 vs. 53.4; P=0.007). There was no difference among the two groups in the 30 day surgical complications and 2-year patterns of disease activity, CD medication requirement, endoscopic recurrence, and need for new surgical management (all P > 0.05). CONCLUSIONS: At 2 years postoperatively, CD patients with ETEA demonstrated better QoL and less healthcare utilization compared with STSA, despite having similar patterns of disease recurrence and CD treatment. These findings suggest that surgical reconstruction of the bowel as an intact tube (ETEA) contribute to improved functional and clinical status in patients with CD. PMID- 29610511 TI - Response to Culetto et al. PMID- 29610512 TI - Risk of Interval Cancer in Fecal Immunochemical Test Screening Significantly Higher During the Summer Months: Results from the National Cancer Screening Program in Korea. AB - OBJECTIVES: This study aimed to evaluate the impact of seasonal variations in climate on the performance of the fecal immunochemical test (FIT) in screening for colorectal cancer in the National Cancer Screening Program in Korea. METHODS: Data were extracted from the National Cancer Screening Program databases for participants who underwent FIT between 2009 and 2010. We compared positivity rates, cancer detection rates, interval cancer rates, positive predictive value, sensitivity, and specificity for FIT during the spring, summer, fall, and winter seasons in Korea. RESULTS: In total, 4,788,104 FIT results were analyzed. FIT positivity rate was lowest during the summer months. In the summer, the positive predictive value of FIT was about 1.1 times (adjusted odds ratio (aOR) 1.08, 95% confidence interval (CI) 1.00-1.16) higher in the overall FIT group and about 1.3 times (aOR 1.29, 95% CI 1.10-1.50) higher in the quantitative FIT group, compared to those in the other seasons. Cancer detection rates, however, were similar regardless of season. Interval cancer risk was significantly higher in the summer for both the overall FIT group (aOR 1.16, 95% CI 1.07-1.27) and the quantitative FIT group (aOR 1.31, 95% CI 1.12-1.52). In addition, interval cancers in the rectum and distal colon were more frequently detected in the summer and autumn than in the winter. CONCLUSIONS: The positivity rate of FIT was lower in the summer, and the performance of the FIT screening program was influenced by seasonal variations in Korea. These results suggest that more efforts to reduce interval cancer during the summer are needed in population-based screening programs using FIT, particularly in countries with high ambient temperatures. PMID- 29610514 TI - Continuing Medical Education Questions: April 2018: ACG Clinical Guideline: Diagnosis and Management of Pancreatic Cysts. PMID- 29610513 TI - Effects of Saline Irrigation of the Bile Duct to Reduce the Rate of Residual Common Bile Duct Stones: A Multicenter, Prospective, Randomized Study. AB - OBJECTIVES: In clinical practice, recurrent cholangitis due to residual common bile duct (CBD) stone occurs frequently even after endoscopic stone removal. This study aimed to determine whether preventive saline irrigation of the bile duct (PSIB) after endoscopic removal of CBD stones would decrease the residual CBD stones. METHODS: In this multicenter, prospective, randomized study, patients who received endoscopic retrograde cholangiopancreatography for removal of CBD stone were randomized to either receiving PSIB after stone removal (PSIB group) or not receiving PSIB (non-PSIB group). Patients were prospectively followed up and the presence of residual CBD stones was evaluated within 6 months after endoscopic stone removal. RESULTS: A total of 148 patients were enrolled and completed follow-up (73 in PSIB group and 75 in non-PSIB group). The two groups were similar with regard to baseline characteristics. Residual CBD stones were detected in 22 patients (14.9%). The incidences of residual CBD stones were 6.8% in PSIB group and 22.7% in non-PSIB group (P=0.010). Multivariate analysis revealed that the performance of PSIB and the presence of only a single-CBD stone were the significant factors for the decrease of the occurrence of the residual CBD stones. Although, procedure time was slightly longer in PSIB group (22.0 vs 19.2 min, P=0.037), no significant difference was observed in the procedure related complications between the two groups. CONCLUSIONS: PSIB could reduce the residual CBD stones without increasing complications. Considering the efficacy and safety, routine PSIB after endoscopic CBD stone removal seems to be preferred (ClinicalTrials.gov identifier: NCT01425177). PMID- 29610508 TI - ACG Clinical Guideline: Management of Crohn's Disease in Adults. AB - Crohn's disease is an idiopathic inflammatory disorder of unknown etiology with genetic, immunologic, and environmental influences. The incidence of Crohn's disease has steadily increased over the past several decades. The diagnosis and treatment of patients with Crohn's disease has evolved since the last practice guideline was published. These guidelines represent the official practice recommendations of the American College of Gastroenterology and were developed under the auspices of the Practice Parameters Committee for the management of adult patients with Crohn's disease. These guidelines are established for clinical practice with the intent of suggesting preferable approaches to particular medical problems as established by interpretation and collation of scientifically valid research, derived from extensive review of published literature. When exercising clinical judgment, health-care providers should incorporate this guideline along with patient's needs, desires, and their values in order to fully and appropriately care for patients with Crohn's disease. This guideline is intended to be flexible, not necessarily indicating the only acceptable approach, and should be distinguished from standards of care that are inflexible and rarely violated. To evaluate the level of evidence and strength of recommendations, we used the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) system. The Committee reviews guidelines in depth, with participation from experienced clinicians and others in related fields. The final recommendations are based on the data available at the time of the production of the document and may be updated with pertinent scientific developments at a later time. PMID- 29610515 TI - Demographic and Dietary Associations of Chronic Diarrhea in a Representative Sample of Adults in the United States. AB - OBJECTIVES: No studies to date estimate the prevalence of chronic diarrhea in the United States using the Bristol stool form scale (BSFS). This study aims to report the prevalence and associated factors of chronic diarrhea using BSFS scores in a nationally representative sample of US adults. METHODS: We identified 5,246 adult participants (age >=20 years) who completed the bowel health questionnaire in the National Health and Nutrition Examination Survey 2009-2010 data set. Chronic diarrhea was defined as type 6 or 7 rating on the BSFS (mushy or liquid consistency) as the "usual or the most common stool type." Co-variables included age, race, education, poverty income ratio, body mass index, number of medications, feeling depressed, physical activity, and dietary intake. Prevalence estimates and prevalence odds ratios (PORs) were analyzed in adjusted multivariable models using appropriate sampling weights. RESULTS: We found a prevalence of chronic diarrhea of 6.6% (95% confidence interval (CI) 5.8, 7.4) in the nationally representative data set. High daily carbohydrate intake (POR 1.56, 95% CI 1.02, 2.40), obesity (POR 2.04, 95% CI 1.44, 2.89), feeling depressed (POR 1.84, 95% CI 1.21, 2.80), older age (POR 1.02, 95% CI 1.01, 1.02), and female sex (POR 1.68, 95% CI 1.28, 2.21) were positively correlated with chronic diarrhea. Non-Hispanic White race (POR 0.49, 95% CI 0.29, 0.81) and higher education (POR 0.60, 95% CI 0.43, 0.83) were negatively correlated with chronic diarrhea. CONCLUSIONS: In a nationally representative sample of the US adults, the prevalence of chronic diarrhea was 6.6%. We identified demographic, lifestyle, and dietary factors associated with chronic diarrhea. PMID- 29610516 TI - Ustekinumab IV 6 mg/kg Loading Dose Re-induction Improves Clinical and Endoscopic Response in Crohn's disease: A Case Series. PMID- 29610517 TI - Differential bacterial capture and transport preferences facilitate co-growth on dietary xylan in the human gut. AB - Metabolism of dietary glycans is pivotal in shaping the human gut microbiota. However, the mechanisms that promote competition for glycans among gut commensals remain unclear. Roseburia intestinalis, an abundant butyrate-producing Firmicute, is a key degrader of the major dietary fibre xylan. Despite the association of this taxon to a healthy microbiota, insight is lacking into its glycan utilization machinery. Here, we investigate the apparatus that confers R. intestinalis growth on different xylans. R. intestinalis displays a large cell attached modular xylanase that promotes multivalent and dynamic association to xylan via four xylan-binding modules. This xylanase operates in concert with an ATP-binding cassette transporter to mediate breakdown and selective internalization of xylan fragments. The transport protein of R. intestinalis prefers oligomers of 4-5 xylosyl units, whereas the counterpart from a model xylan-degrading Bacteroides commensal targets larger ligands. Although R. intestinalis and the Bacteroides competitor co-grew in a mixed culture on xylan, R. intestinalis dominated on the preferred transport substrate xylotetraose. These findings highlight the differentiation of capture and transport preferences as a possible strategy to facilitate co-growth on abundant dietary fibres and may offer a unique route to manipulate the microbiota based on glycan transport preferences in therapeutic interventions to boost distinct taxa. PMID- 29610518 TI - The beta secretase BACE1 regulates the expression of insulin receptor in the liver. AB - Insulin receptor (IR) plays a key role in the control of glucose homeostasis; however, the regulation of its cellular expression remains poorly understood. Here we show that the amount of biologically active IR is regulated by the cleavage of its ectodomain, by the beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), in a glucose concentration-dependent manner. In vivo studies demonstrate that BACE1 regulates the amount of IR and insulin signaling in the liver. During diabetes, BACE1-dependent cleavage of IR is increased and the amount of IR in the liver is reduced, whereas infusion of a BACE1 inhibitor partially restores liver IR. We suggest the potential use of BACE1 inhibitors to enhance insulin signaling during diabetes. Additionally, we show that plasma levels of cleaved IR reflect IR isoform A expression levels in liver tumors, which prompts us to propose that the measurement of circulating cleaved IR may assist hepatic cancer detection and management. PMID- 29610519 TI - Porous translucent electrodes enhance current generation from photosynthetic biofilms. AB - Some photosynthetically active bacteria transfer electrons across their membranes, generating electrical photocurrents in biofilms. Devices harvesting solar energy by this mechanism are currently limited by the charge transfer to the electrode. Here, we report the enhancement of bioelectrochemical photocurrent harvesting using electrodes with porosities on the nanometre and micrometre length scale. For the cyanobacteria Nostoc punctiforme and Synechocystis sp. PCC6803 on structured indium-tin-oxide electrodes, an increase in current generation by two orders of magnitude is observed compared to a non-porous electrode. In addition, the photo response is substantially faster compared to non-porous anodes. Electrodes with large enough mesopores for the cells to inhabit show only a small advantage over purely nanoporous electrode morphologies, suggesting the prevalence of a redox shuttle mechanism in the electron transfer from the bacteria to the electrode over a direct conduction mechanism. Our results highlight the importance of electrode nanoporosity in the design of electrochemical bio-interfaces. PMID- 29610520 TI - Comment on: 'An international comparison of retinopathy of prematurity grading performance within the Benefits of Oxygen Saturation Targeting II trials'. PMID- 29610521 TI - A 10-year analysis of microbiological profiles of microbial keratitis: the North East England Study. PMID- 29610522 TI - Response to: A 10-year analysis of microbiological profiles of microbial keratitis: the North East England study. PMID- 29610523 TI - Physical activity, visual impairment, and eye disease. AB - Numerous studies have demonstrated physical activity is a strong factor in overall health and well-being, and a growing body of literature, reviewed herein, suggests that several eye conditions, including glaucoma, age-related macular degeneration, and diabetic retinopathy, are associated with lower activity levels. Likewise, physical activity levels are lower in persons with worse vision. Research in this area has utilized both self-reported physical activity measures as well as objective measures of activity (i.e., accelerometers), each of which have their own strengths and limitations. Putative mechanisms explaining the association of various eye conditions with physical activity are discussed. It is possible that activity restriction occurs as a downstream consequence of eye disease/visual impairment, that activity restriction causes eye disease/visual impairment, or that causality is bidirectional; evidence supporting each of these theories is put forth. An improved understanding of the relationship between physical activity and eye disease will highlight potential secondary health risks resulting from eye disease, and can help determine whether activity might serve as a readily available preventative measure to prevent specific eye conditions. PMID- 29610524 TI - A lever-like transduction pathway for long-distance chemical- and mechano-gating of the mechanosensitive Piezo1 channel. AB - Piezo1 represents a prototype of eukaryotic mechanotransduction channels. The full-length 2547-residue mouse Piezo1 possesses a unique 38-transmembrane-helix (TM) topology and is organized into a three-bladed, propeller-shaped architecture, comprising a central ion-conducting pore, three peripheral blade like structures, and three 90-A-long intracellular beam-resembling structures that bridge the blades to the pore. However, how mechanical force and chemicals activate the gigantic Piezo1 machinery remains elusive. Here we identify a novel set of Piezo1 chemical activators, termed Jedi, which activates Piezo1 through the extracellular side of the blade instead of the C-terminal extracellular domain of the pore, indicating long-range allosteric gating. Remarkably, Jedi induced activation of Piezo1 requires the key mechanotransduction components, including the two extracellular loops in the distal blade and the two leucine residues in the proximal end of the beam. Thus, Piezo1 employs the peripheral blade-beam-constituted lever-like apparatus as a designated transduction pathway for long-distance mechano- and chemical-gating of the pore. PMID- 29610525 TI - CDH4 is a novel determinant of osteosarcoma tumorigenesis and metastasis. AB - The era of cancer genomics now provides an opportunity to discover novel determinants of osteosarcoma (OS), the most common primary bone cancer in children and adolescents known for its poor prognosis due to lung metastasis. Here, we identify CDH4 amplification in 43.6% of human osteosarcoma using array CGH and demonstrate its critical role in osteosarcoma development and progression. Gain or loss-of-function of CDH4, which encodes R-cadherin, causally impacts multiple features of human OS cells including cell migration and invasion, osteogenic differentiation, and stemness. CDH4 overexpression activates c-Jun via the JNK pathway, while CDH4 knockdown suppresses both tumor xenograft growth and lung colonization. In OS patient specimens, high CDH4 expression associates with lung metastases and poor prognosis. Collectively, our bioinformatics, functional, molecular, and clinical analyses uncover an oncogenic function of CDH4 in osteosarcoma and its relationship with patient outcome. PMID- 29610526 TI - Zinc-finger protein 471 suppresses gastric cancer through transcriptionally repressing downstream oncogenic PLS3 and TFAP2A. AB - Zinc-finger protein 471 (ZNF471) was preferentially methylated in gastric cancer using promoter methylation array. The role of ZNF471 in human cancer is unclear. Here we elucidated the functional significance, molecular mechanisms and clinical impact of ZNF471 in gastric cancer. ZNF471 mRNA was silenced in 15 out of 16 gastric cancer cell lines due to promoter hypermethylation. Significantly higher ZNF471 promoter methylation was also observed in primary gastric cancers compared to their adjacent normal tissues (P < 0.001). ZNF471 promoter CpG-site hypermethylation correlated with poor survival of gastric cancer patients (n = 120, P = 0.001). Ectopic expression of ZNF471 in gastric cancer cell lines (AGS, BGC823, and MKN74) significantly suppressed cell proliferation, migration, and invasion, while it induced apoptosis in vitro and inhibited xenograft tumorigenesis in nude mice. Transcription factor AP-2 Alpha (TFAP2A) and plastin3 (PLS3) were two crucial downstream targets of ZNF471 demonstrated by bioinformatics modeling and ChIP-PCR assays. ZNF471 directly bound to the promoter of TFAP2A and PLS3 and transcriptionally inhibited their expression. TFAP2A and PLS3 showed oncogenic functions in gastric cancer cell lines. Moreover, ZNF471 recruited KAP1 to the promoter of the target genes, thereby inducing H3K9me3 enrichment for transcriptional repression and inhibition of oncogenic TFAP2A and PLS3. In conclusion, ZNF471 acts as a tumor suppressor in gastric cancer by transcriptionally inhibiting downstream targets TFAP2A and PLS3. KAP1 is a co-repressor of ZNF471 at the promoter of the target genes. The promoter CpG-site methylation is an independent prognostic factor for overall survival of gastric cancer patients. PMID- 29610527 TI - Superparamagnetic nickel colloidal nanocrystal clusters with antibacterial activity and bacteria binding ability. AB - Recent progress in synthetic nanotechnology and the ancient use of metals in food preservation and the antibacterial treatment of wounds have prompted the development of nanometallic materials for antimicrobial applications1-4. However, the materials designed so far do not simultaneously display antimicrobial activity and the capability of binding and capturing bacteria and spores. Here, we develop a one-step pyrolysis procedure to synthesize monodisperse superparamagnetic nickel colloidal nanocrystal clusters (SNCNCs), which show both antibacterial activity and the ability to bind Gram-positive (Bacillus subtilis) and Gram-negative (Escherichia coli) bacteria, as well as bacterial spores. The SNCNCs are formed from a rapid burst of nickel nanoparticles, which self-assemble slowly into clusters. The clusters can magnetically extract 99.99% of bacteria and spores and provide a promising approach for the removal of microbes, including hard-to-treat microorganisms. We believe that our work illustrates the exciting opportunities that nanotechnology offers for alternative antimicrobial strategies and other applications in microbiology. PMID- 29610528 TI - Highly efficient solar vapour generation via hierarchically nanostructured gels. AB - Solar vapour generation is an efficient way of harvesting solar energy for the purification of polluted or saline water. However, water evaporation suffers from either inefficient utilization of solar energy or relies on complex and expensive light-concentration accessories. Here, we demonstrate a hierarchically nanostructured gel (HNG) based on polyvinyl alcohol (PVA) and polypyrrole (PPy) that serves as an independent solar vapour generator. The converted energy can be utilized in situ to power the vaporization of water contained in the molecular meshes of the PVA network, where water evaporation is facilitated by the skeleton of the hydrogel. A floating HNG sample evaporated water with a record high rate of 3.2 kg m-2 h-1 via 94% solar energy from 1 sun irradiation, and 18-23 litres of water per square metre of HNG was delivered daily when purifying brine water. These values were achievable due to the reduced latent heat of water evaporation in the molecular mesh under natural sunlight. PMID- 29610529 TI - An artificial molecular machine that builds an asymmetric catalyst. AB - Biomolecular machines perform types of complex molecular-level tasks that artificial molecular machines can aspire to. The ribosome, for example, translates information from the polymer track it traverses (messenger RNA) to the new polymer it constructs (a polypeptide) 1 . The sequence and number of codons read determines the sequence and number of building blocks incorporated into the biomachine-synthesized polymer. However, neither control of sequence2,3 nor the transfer of length information from one polymer to another (which to date has only been accomplished in man-made systems through template synthesis) 4 is easily achieved in the synthesis of artificial macromolecules. Rotaxane-based molecular machines5-7 have been developed that successively add amino acids8-10 (including beta-amino acids 10 ) to a growing peptide chain by the action of a macrocycle moving along a mono-dispersed oligomeric track derivatized with amino acid phenol esters. The threaded macrocycle picks up groups that block its path and links them through successive native chemical ligation reactions 11 to form a peptide sequence corresponding to the order of the building blocks on the track. Here, we show that as an alternative to translating sequence information, a rotaxane molecular machine can transfer the narrow polydispersity of a leucine ester-derivatized polystyrene chain synthesized by atom transfer radical polymerization 12 to a molecular-machine-made homo-leucine oligomer. The resulting narrow-molecular-weight oligomer folds to an alpha-helical secondary structure 13 that acts as an asymmetric catalyst for the Julia-Colonna epoxidation14,15 of chalcones. PMID- 29610530 TI - Nanoparticle-induced neuronal toxicity across placental barriers is mediated by autophagy and dependent on astrocytes. AB - The potential for maternal nanoparticle (NP) exposures to cause developmental toxicity in the fetus without the direct passage of NPs has previously been shown, but the mechanism remained elusive. We now demonstrate that exposure of cobalt and chromium NPs to BeWo cell barriers, an in vitro model of the human placenta, triggers impairment of the autophagic flux and release of interleukin 6. This contributes to the altered differentiation of human neural progenitor cells and DNA damage in the derived neurons and astrocytes. Crucially, neuronal DNA damage is mediated by astrocytes. Inhibiting the autophagic degradation in the BeWo barrier by overexpression of the dominant-negative human ATG4BC74A significantly reduces the levels of DNA damage in astrocytes. In vivo, indirect NP toxicity in mice results in neurodevelopmental abnormalities with reactive astrogliosis and increased DNA damage in the fetal hippocampus. Our results demonstrate the potential importance of autophagy to elicit NP toxicity and the risk of indirect developmental neurotoxicity after maternal NP exposure. PMID- 29610532 TI - A seesaw between Pi and Zn. PMID- 29610531 TI - Small molecules promote CRISPR-Cpf1-mediated genome editing in human pluripotent stem cells. AB - Human pluripotent stem cells (hPSCs) have potential applications in biological studies and regenerative medicine. However, precise genome editing in hPSCs remains time-consuming and labor-intensive. Here we demonstrate that the recently identified CRISPR-Cpf1 can be used to efficiently generate knockout and knockin hPSC lines. The unique properties of CRISPR-Cpf1, including shorter crRNA length and low off-target activity, are very attractive for many applications. In particular, we develop an unbiased drug-selection-based platform feasible for high-throughput screening in hPSCs and this screening system enables us to identify small molecules VE-822 and AZD-7762 that can promote CRISPR-Cpf1 mediated precise genome editing. Significantly, the combination of CRISPR-Cpf1 and small molecules provides a simple and efficient strategy for precise genome engineering. PMID- 29610533 TI - Translating photosynthesis. PMID- 29610534 TI - To list or not to list? The value and detriment of freelisting in ethnobotanical studies. AB - Although freelisting and semi-structured interviews are widespread methods in ethnobotany, few studies quantitatively examine how these methods may bias results. Using a comprehensive ethnobotanical inventory of palm species, uses and names in the Chacobo tribe of Bolivia, we show that interviews elicit more items than freelists, but the effect is sensitive to sample size, item type and data categorization. This implies that even subtle methodological choices may greatly affect reported results. PMID- 29610535 TI - Dynamic feedback of the photosystem II reaction centre on photoprotection in plants. AB - Photosystem II of higher plants is protected against light damage by thermal dissipation of excess excitation energy, a process that can be monitored through non-photochemical quenching of chlorophyll fluorescence. When the light intensity is lowered, non-photochemical quenching largely disappears on a time scale ranging from tens of seconds to many minutes. With the use of picosecond fluorescence spectroscopy, we demonstrate that one of the underlying mechanisms is only functional when the reaction centre of photosystem II is closed, that is when electron transfer is blocked and the risk of photodamage is high. This is accompanied by the appearance of a long-wavelength fluorescence band. As soon as the reaction centre reopens, this quenching, together with the long-wavelength fluorescence, disappears instantaneously. This allows plants to maintain a high level of photosynthetic efficiency even in dangerous high-light conditions. PMID- 29610536 TI - Structure of the chloroplast ribosome with chl-RRF and hibernation-promoting factor. AB - Oxygenic photosynthesis produces oxygen and builds a variety of organic compounds, changing the chemistry of the air, the sea and fuelling the food chain on our planet. The photochemical reactions underpinning this process in plants take place in the chloroplast. Chloroplasts evolved ~1.2 billion years ago from an engulfed primordial diazotrophic cyanobacterium, and chlororibosomes are responsible for synthesis of the core proteins driving photochemical reactions. Chlororibosomal activity is spatiotemporally coupled to the synthesis and incorporation of functionally essential co-factors, implying the presence of chloroplast-specific regulatory mechanisms and structural adaptation of the chlororibosome1,2. Despite recent structural information3-6, some of these aspects remained elusive. To provide new insights into the structural specialities and evolution, we report a comprehensive analysis of the 2.9-3.1 A resolution electron cryo-microscopy structure of the spinach chlororibosome in complex with its recycling factor and hibernation-promoting factor. The model reveals a prominent channel extending from the exit tunnel to the chlororibosome exterior, structural re-arrangements that lead to increased surface area for translocon binding, and experimental evidence for parallel and convergent evolution of chloro- and mitoribosomes. PMID- 29610537 TI - X-ray structure of an asymmetrical trimeric ferredoxin-photosystem I complex. AB - Photosystem I (PSI), a large protein complex located in the thylakoid membrane, mediates the final step in light-driven electron transfer to the stromal electron carrier protein ferredoxin (Fd). Here, we report the first structural description of the PSI-Fd complex from Thermosynechococcus elongatus. The trimeric PSI complex binds three Fds in a non-equivalent manner. While each is recognized by a PSI protomer in a similar orientation, the distances between Fds and the PSI redox centres differ. Fd binding thus entails loss of the exact three-fold symmetry of the PSI's soluble subunits, inducing structural perturbations which are transferred to the lumen through PsaF. Affinity chromatography and nuclear magnetic resonance analyses of PSI-Fd complexes support the existence of two different Fd-binding states, with one Fd being more tightly bound than the others. We propose a dynamic structural basis for productive complex formation, which supports fast electron transfer between PSI and Fd. PMID- 29610538 TI - New Approaches in Cancer Biology Can Inform the Biology Curriculum. AB - Students tend to be very interested in medical issues that affect them and their friends and family. Using cancer as a hook, the ART of Reproductive Medicine: Oncofertility curriculum (free, online, and NIH sponsored) has been developed to supplement the teaching of basic biological concepts and to connect biology and biomedical research. This approach allows integration of up-to-date information on cancer and cancer treatment, cell division, male and female reproductive anatomy and physiology, cryopreservation, fertility preservation, stem cells, ethics, and epigenetics into an existing biology curriculum. Many of the topics covered in the curriculum relate to other scientific disciplines, such as the latest developments in stem cell research including tissue bioengineering and gene therapy for inherited mitochondrial disease, how epigenetics occurs chemically to affect gene expression or suppression and how it can be passed down through the generations, and the variety of biomedical careers students could pursue. The labs are designed to be open-ended and inquiry-based, and extensions to the experiments are provided so that students can explore questions further. Case studies and ethical dilemmas are provided to encourage thoughtful discussion. In addition, each chapter of the curriculum includes links to scientific papers, additional resources on each topic, and NGSS alignment. PMID- 29610539 TI - Chimpanzees gesture to humans in mirrors: using reflection to dissociate seeing from line of gaze. AB - There is much experimental evidence suggesting that chimpanzees understand that others see. However, previous research has never experimentally ruled out the alternative explanation that chimpanzees are just responding to the geometric cue of 'direct line of gaze', the observable correlate of seeing in others. Here, we sought to resolve this ambiguity by dissociating seeing from direct line of gaze using a mirror. We investigated the frequency of chimpanzees' visual gestures towards a human experimenter who could see them (as a result of looking into a mirror) but who lacked a direct line of gaze to them (as a result of having his/her head turned away). Chimpanzees produced significantly more visual gestures when the experimenter could see them than when he/she could not, even when the experimenter did not have a direct line of gaze to them. Results suggest that chimpanzees, through a possible process of experience projection based on their own prior experience with mirrors, infer that an experimenter looking at the mirror can see them. We discuss our results in relation to the theory of mind hypothesis that chimpanzees understand seeing in others, and we evaluate possible alternative low-level explanations. PMID- 29610540 TI - Determinants of Pseudogymnoascus destructans within bat hibernacula: implications for surveillance and management of white-nose syndrome. AB - 1. Fungal diseases are an emerging global problem affecting human health, food security and biodiversity. Ability of many fungal pathogens to persist within environmental reservoirs can increase extinction risks for host species and presents challenges for disease control. Understanding factors that regulate pathogen spread and persistence in these reservoirs is critical for effective disease management. 2. White-nose syndrome (WNS) is a disease of hibernating bats caused by Pseudogymnoascus destructans (Pd), a fungus that establishes persistent environmental reservoirs within bat hibernacula, which contribute to seasonal disease transmission dynamics in bats. However, host and environmental factors influencing distribution of Pd within these reservoirs are unknown. 3. We used model selection on longitudinally collected field data to test multiple hypotheses describing presence-absence and abundance of Pd in environmental substrates and on bats within hibernacula at different stages of WNS. 4. First detection of Pd in the environment lagged up to one year after first detection on bats within that hibernaculum. Once detected, the probability of detecting Pd within environmental samples from a hibernaculum increased over time and was higher in sediment compared to wall surfaces. Temperature had marginal effects on the distribution of Pd. For bats, prevalence and abundance of Pd were highest on Myotis lucifugus and on bats with visible signs of WNS. 5. Synthesis and applications. Our results indicate that distribution of Pseudogymnoascus destructans (Pd) within a hibernaculum is driven primarily by bats with delayed establishment of environmental reservoirs. Thus, collection of samples from Myotis lucifugus, or from sediment if bats cannot be sampled, should be prioritized to improve detection probabilities for Pd surveillance. Long-term persistence of Pd in sediment suggests that disease management for white-nose syndrome should address risks of sustained transmission from environmental reservoirs. PMID- 29610541 TI - Synthesis of a novel fused pyrrolodiazepine-based library with anti-cancer activity. AB - Development of drugs for new and persistent diseases will increasingly rely on the expansion of accessible chemical space to allow exploration of novel molecular targets. Here we report the synthesis of a library of novel fused heterobicyclic small molecules based on the 1,4-diazepine and 2,4 pyrrolidinedione scaffolds. Key chemical transformations included a Mannich-type condensation and chemoselective N-acylation reactions. Screening shows anti cancer activity of several library compounds which suggests translational potential of this novel chemical scaffold. PMID- 29610542 TI - Who Receives Medicaid in Old Age? Rules and Reality. AB - Medicaid is a government programme that also provides health insurance to the elderly who have few assets and either low income or catastrophic health care expenses. We ask how the Medicaid rules map into the reality of Medicaid recipiency, and we ask what other observable characteristics are important to determine who ends up on Medicaid. The data show that both singles and couples with high retirement income can end up on Medicaid at very advanced ages. We find that, conditioning on a large number of observable characteristics, including those that directly relate to Medicaid eligibility criteria, single women are more likely to end up on Medicaid - so are non-white people, but, surprisingly, their higher recipiency is concentrated in the higher income percentiles. We also find that people with low incomes who have a high-school diploma or higher degree are much less likely to end up receiving Medicaid than their less-educated counterparts. All of these effects are large and depend on retirement income in a very non-linear way. PMID- 29610543 TI - The potential impacts of 21st century climatic and population changes on human exposure to the virus vector mosquito Aedes aegypti. AB - The mosquito Aedes (Ae). aegypti transmits the viruses that cause dengue and chikungunya, two globally-important vector-borne diseases. We investigate how choosing alternate emissions and/or socioeconomic pathways may modulate future human exposure to Ae. aegypti. Occurrence patterns for Ae. aegypti for 2061-2080 are mapped globally using empirically downscaled air temperature and precipitation projections from the Community Earth System Model, for the Representative Concentration Pathway (RCP) 4.5 and 8.5 scenarios. Population growth is quantified using gridded global population projections consistent with two Shared Socioeconomic Pathways (SSPs), SSP3 and SSP5. Change scenarios are compared to a 1950-2000 reference period. A global land area of 56.9 M km2 is climatically suitable for Ae. aegypti during the reference period, and is projected to increase by 8% (RCP4.5) to 13% (RCP8.5) by 2061-2080. The annual average number of people exposed globally to Ae. aegypti for the reference period is 3794 M, a value projected to statistically significantly increase by 298-460 M (8-12%) by 2061-2080 if only climate change is considered, and by 4805-5084 M (127-134%) for SSP3 and 2232-2483 M (59-65%) for SSP5 considering both climate and population change (lower and upper values of each range represent RCP4.5 and RCP8.5 respectively). Thus, taking the lower-emissions RCP4.5 pathway instead of RCP8.5 may mitigate future human exposure to Ae. aegypti globally, but the effect of population growth on exposure will likely be larger. Regionally, Australia, Europe and North America are projected to have the largest percentage increases in human exposure to Ae. aegypti considering only climate change. PMID- 29610544 TI - Predictors of Parental Use of Corporal Punishment in Ukraine. AB - Despite a great deal of evidence that corporal punishment is harmful, corporal punishment is still very prevalent worldwide. We examine predictors of different types of corporal punishment among Ukrainian mothers in 12 communities across Ukraine. Findings suggest that maternal spirituality, maternal coping styles, family communication, and some demographic characteristics are predictive of mothers' use of corporal punishment. PMID- 29610545 TI - Neuroticism, rumination, negative affect, and sleep: Examining between- and within-person associations. PMID- 29610546 TI - Modulated release from implantable ocular silicone oil tamponade drug reservoirs. AB - Complicated cases of retinal detachment can be treated with silicone oil tamponades. There is the potential for silicone oil tamponades to have adjunctive drug releasing behaviour within the eye, however the lipophilic nature of silicone oil limits the number of drugs that are suitable, and drug release from the hydrophobic reservoir is uncontrolled. Here, a radiometric technique was developed to accurately measure drug solubility in silicone oil and measure release into culture media. All-trans retinoic acid (atRA), a lipophilic drug known to act as an anti-proliferative within the eye, was used throughout this work. Chain-end modification of polydimethylsiloxane with atRA produced a polydimethylsiloxane retinoate (PDMS-atRA), which was used as an additive to silicone oil to modify the solvent environment within the silicone oil and the distribution coefficient. Blends of PDMS-atRA and silicone oil containing different concentrations of free atRA were produced. The presence of PDMS-atRA in silicone oil had a positive effect on atRA solubility and the longevity of release in vitro. The drug release period was independent of atRA starting concentration and dependent on the PDMS-atRA concentration in the blend. A clinically relevant release period of atRA over 7 weeks from a silicone oil blend with PDMS-atRA was observed. (c) 2018 The Authors. Journal of Polymer Science Part A: Polymer Chemistry Published by Wiley Periodicals, Inc. J. Polym. Sci., Part A: Polym. Chem. 2018, 56, 938-946. PMID- 29610547 TI - Training self-assessment and task-selection skills to foster self-regulated learning: Do trained skills transfer across domains? AB - Students' ability to accurately self-assess their performance and select a suitable subsequent learning task in response is imperative for effective self regulated learning. Video modeling examples have proven effective for training self-assessment and task-selection skills, and-importantly-such training fostered self-regulated learning outcomes. It is unclear, however, whether trained skills would transfer across domains. We investigated whether skills acquired from training with either a specific, algorithmic task-selection rule or a more general heuristic task-selection rule in biology would transfer to self-regulated learning in math. A manipulation check performed after the training confirmed that both algorithmic and heuristic training improved task-selection skills on the biology problems compared with the control condition. However, we found no evidence that students subsequently applied the acquired skills during self regulated learning in math. Future research should investigate how to support transfer of task-selection skills across domains. PMID- 29610548 TI - Personality and Neural Correlates of Mentalizing Ability. AB - Theory of mind, or mentalizing, defined as the ability to reason about another's mental states, is a crucial psychological function that is disrupted in some forms of psychopathology, but little is known about how individual differences in this ability relate to personality or brain function. One previous study linked mentalizing ability to individual differences in the personality trait Agreeableness. Agreeableness encompasses two major subdimensions: Compassion reflects tendencies toward empathy, prosocial behavior, and interpersonal concern, whereas Politeness captures tendencies to suppress aggressive and exploitative impulses. We hypothesized that Compassion but not Politeness would be associated with better mentalizing ability. This hypothesis was confirmed in Study 1 (N = 329) using a theory of mind task that required reasoning about the beliefs of fictional characters. Post hoc analyses indicated that the honesty facet of Agreeableness was negatively associated with mentalizing. In Study 2 (N = 217), we examined whether individual differences in mentalizing and related traits were associated with patterns of resting-state functional connectivity in the brain. Performance on the theory of mind task was significantly associated with patterns of connectivity between the dorsal medial and core subsystems of the default network, consistent with evidence implicating these regions in mentalization. PMID- 29610549 TI - Biochemical properties of cholesterol aldehyde secosterol and its derivatives. AB - Elevated levels of cholesterol aldehyde, 3beta-hydroxy-5-oxo-5,6-secocholestan-6 al (secosterol-A, also called 5,6-secosterol), and its aldolization product (secosterol-B) have been detected in human atherosclerotic plaques and tissues samples of brains affected by neurodegeneration, such as Alzheimer's disease and Lewy body dementia suggesting that increased formation of these compounds may be associated with inflammation-related diseases. Secosterol-A and secosterol-B, and also further oxidized products seco-A-COOH and seco-B-COOH induce several pro inflammatory activities in vitro. Accumulating evidences demonstrate that the covalent bindings of these secosterols to target proteins seem to be critical to trigger their pro-inflammatory activities. One of the molecular mechanisms of protein adduct formations is that aldehydic function of secosterol-A and secosterol-B is reactive and form Schiff bases with epsilon- or N-terminal amino groups of proteins. In other cases, it is recently suggested that Michael acceptor moiety formed by the dehydration of not only secosterol-A and secosterol B but also seco-A-COOH may react with nucleophilic site on target proteins. In this review, I summarize and provide an overview of formation mechanism of secosterols in in vitro and in vivo, patho- or physiological concentrations in biological and clinical samples, and molecular mechanisms of pro-inflammatory activities of secosterols. PMID- 29610550 TI - Non-specific protein modifications may be novel mechanism underlying bioactive phytochemicals. AB - In a variety of experimental models, dietary phytochemicals have been demonstrated to exhibit pronounced and versatile bioactivities. Importantly, the possibility of such phytochemicals for human application has been supported in part by epidemiological surveys, which have demonstrated that frequent ingestion of vegetables and fruits containing abundant phytochemicals lowers the risk of onset of various diseases. However, the action mechanisms underlying those dietary phytochemical activities remain to be fully elucidated. For example, even though the anti-oxidant effects of natural polyphenols have long received widespread attention from food scientists, their roles in and contribution to those bioactivities remain controversial because of their poor bioavailability, resulting in extremely low concentrations in the bloodstream. Meanwhile, another important question is why phytochemicals have beneficial effects for animals, including humans, since they are biosynthesized by plants as compounds necessary for adaptation to environmental stress. In regard to that fundamental question, we recently reported novel and unique mechanisms of action of zerumbone, a sesquiterpene with anti-inflammatory and chemopreventive properties. This agent was found to partially exhibit bioactivity through its non-specific interactions with cellular proteins. More strikingly, a non-specific protein binding action of zerumbone was revealed to partially contribute to its anti-inflammatory functions via activation of heat shock factor 1. The present review article highlights and introduces our recent findings regarding the proteo-stress-mediated mechanisms of this phytochemical, along with the concept of hormesis. PMID- 29610551 TI - Numerical analyses of intestinal microbiota by data mining. AB - The human intestinal microbiota has a close relationship with health control and causes of diseases, and a vast number of scientific papers on this topic have been published recently. Some progress has been made in identifying the causes or species of related microbiota, and successful results of data mining are reviewed here. Humans who are targets of a disease have their own individual characteristics, including various types of noise because of their individual life style and history. The quantitatively dominant bacterial species are not always deeply connected with a target disease. Instead of conventional simple comparisons of the statistical record, here the Gini-coefficient (i.e., evaluation of the uniformity of a group) was applied to minimize the effects of various types of noise in the data. A series of results were reviewed comparatively for normal daily life, disease and technical aspects of data mining. Some representative cases (i.e., heavy smokers, Crohn's disease, coronary artery disease and prediction accuracy of diagnosis) are discussed in detail. In conclusion, data mining is useful for general diagnostic applications with reasonable cost and reproducibility. PMID- 29610552 TI - Antioxidant nitroxides protect hepatic cells from oxidative stress-induced cell death. AB - Oxidative stress causes cell death and induces many kinds of disease, including liver disease. Nitroxides are known to react catalytically with free radicals. In this study, the cell protective activities of nitroxides were compared with those of other antioxidants. Nitroxides showed much greater inhibition of hydrogen peroxide-induced cell death than other antioxidants in a hepatic cell line and in primary hepatocytes. The intracellular oxidative stress level at 24 h after hydrogen peroxide stimulation was significantly decreased by nitroxides, but not by other antioxidants. To clarify the mechanism of cell protection by nitroxides, we investigated whether nitroxides inhibited DNA damage and mitogen-activated protein kinase pathway activation. We found that nitroxides reduced caspase-3 activation and may have ultimately inhibited cell death. In conclusion, nitroxides are very useful for attenuating cell damage due to oxidative stress. Nitroxides are thus a potential therapeutic agent for oxidative stress-related diseases. PMID- 29610553 TI - Preventive effect of Dioscorea japonica on squamous cell carcinoma of mouse skin involving down-regulation of prostaglandin E2 synthetic pathway. AB - Hyperproduced prostaglandin E2 by cyclooxygenase-2 and microsomal prostaglandin E synthase-1 evokes several pathophysiological responses such as inflammation and carcinogenesis. Our recent study demonstrated that Dioscorea japonica extract suppressed the expression of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 and induced apoptosis in lung carcinoma A549 cells. In the present study, we investigated the effects of Dioscorea japonica on squamous cell carcinoma of mouse skin. Dioscorea japonica feeding and Dioscorea japonica extract topical application suppressed the expression of cyclooxygenase-2, microsomal prostaglandin E synthase-1, interleukin-1beta and interleukin-6 and inhibited tumor formation, hyperplasia and inflammatory cell infiltration. Immunohistochemical analyses showed the immunoreactivities of cyclooxygenase-2 and microsomal prostaglandin E synthase-1 in tumor keratinocytes and stronger immunoreactivities of cyclooxygenase-2 and hematopoietic prostaglandin D synthase in epidermal dendritic cells (Langerhans cells). Treatment with Dioscorea japonica decreased the immunoreactivity of cyclooxygenase-2 and microsomal prostaglandin E synthase-1. These results indicate that Dioscorea japonica may have inhibitory effects on inflammation and carcinogenesis via suppression of the prostaglandin E2 synthetic pathway. PMID- 29610554 TI - Hypoglycemic property of soy isoflavones from hypocotyl in Goto-Kakizaki diabetic rats. AB - The present study was carried out to investigate the hypoglycemic effect of soy isoflavones from hypocotyl in GK diabetic rats. A single administration and long term administration tests were conducted in GK diabetic rats to test the hypoglycemic effect of soy isoflavones. At the end of long-term administration trial, blood protein, cholesterol, triglyceride, glycosylated serum protein, C reactive protein, insulin, aminotransferase, lipid peroxide, interleukin-6, tumor necrosis factor-alpha were estimated. Inhibition of soy isoflavones against alpha amylase and alpha-glucosidase, as well as on glucose uptake into brush border membrane vesicles or Caco-2 cells were determined in vitro. In single administration experiment, soy isoflavones reduced postprandial blood glucose levels in GK rats. In long-term administration, hypoglycemic effect of soy isoflavones was first observed at week 12 and maintained till week 16. A significant reduction in fasting blood glucose, C-reactive protein, and lipid peroxide was noted at week 16. However, there was no significant treatment effect on blood insulin. Furthermore, soy isoflavone administration resulted in significant decreases in glycosylated serum protein, tumor necrosis factor-alpha, and interleukin-6. Other biochemical parameters, such as protein, cholesterol, triglyceride and aminotransferases were not modified, however. The results in vitro showed that soy isoflavones showed a potent inhibitory effect on intestinal alpha-glucosidase, but not on pancreatic alpha-amylase. Soy isoflavones also decreased glucose transport potency into brush border membrane vesicles or Caco-2 cells. It is concluded that soy isoflavones from hypocotyl, performs hypoglycemic function in GK rats with type 2 diabetes, maybe via suppression of carbohydrate digestion and glucose uptake in small intestine. PMID- 29610555 TI - Effect of prenatal administration of low dose antibiotics on gut microbiota and body fat composition of newborn mice. AB - Several environmental factors during the prenatal period transgenerationally affect the health of newborns in later life. Because low-dose antibiotics have been used for promoting the growth of crops and livestock in agriculture, humans may have ingested residual antibiotics for several decades. However, the effect of prenatal administration of low-dose antibiotics on newborns' health in later life is unclear. In the present study, we found that prenatal treatment of murine mothers with low-dose antibiotics increased the abundance of bacteria of the phylum Firmicutes and the genera Clostridium IV and XIVa in feces from pups. In addition, the body fat percentage of mice in the antibiotic-treated group was higher than those in the control group at 12 weeks of age even though all pups were fed a standard diet. The body fat percentage of all mice was correlated with the abundance of fecal bacteria of Clostridium IV and XIVa. These results predict that low-dose antibiotic administration during the prenatal period affects the gut microbiota of newborns and possibly their health in later life. PMID- 29610556 TI - Comparison of the effect of non-esterified and esterified astaxanthins on endurance performance in mice. AB - Astaxanthin, a natural antioxidant, exists in non-esterified and esterified forms. Although it is known that astaxanthin can improve exercise endurance and cause metabolic improvement in skeletal muscle, the effects of the two different forms are unclear. We investigated the effects of the different forms of astaxanthin on endurance in mice. Eight-week-old ICR mice were divided into four groups: control; astaxanthin extracted from Haematococcus pluvialis in an esterified form; astaxanthin extracted from Phaffia rhodozyma in a non-esterified form; and astaxanthin synthesized chemically in a non-esterified form. After 5 weeks of treatment, each group was divided into sedentary and exercise groups. In the group fed astaxanthin from Haematococcus, the running time to exhaustion was longest, and the plasma and tissue concentrations of astaxanthin were significantly higher than those in the other groups. Astaxanthin from Haematococcus increased 5'-adenosine monophosphate-activated protein kinase levels in the skeletal muscle. Although the mice in the Haematococcus group ran for longer, hexanoyl lysine adduct levels in the skeletal muscle mitochondria were similar in the control and Haematococcus groups. Our results suggested that esterified astaxanthin promoted energy production and protected tissues from oxidative damage during exercise owing to its favorable absorption properties, leading to a longer running time. PMID- 29610557 TI - Dietary intake of inorganic phosphorus has a stronger influence on vascular endothelium function than organic phosphorus. AB - Phosphorus management through dietetic therapy is vital for the prevention of cardiovascular disease in chronic kidney disease patients. There are two main sources of phosphorus in the diet, organic phosphorus from protein and inorganic phosphorus from food additives. The adverse effects of high phosphorus intake on vascular-endothelium function have been reported; however, the differences in the effects of organic phosphorus versus inorganic phosphorus are not clear. In this study, we examined an acute effect of these high phosphorus meals intake on vascular-endothelium function. This was a randomized, double-blind, cross-over test study design targeting healthy young men. We conducted a food intake test using two test meals, one high in organic phosphorus from organic food sources, and one high in inorganic phosphorus from food additives. Endothelium-dependent vasodilation, phosphorus and calcium in the urine and blood, and phosphorus related hormones were measured preprandial to 120 min postprandial. The results showed higher serum and urine phosphorus values after the high inorganic phosphorus meal, and a significant reduction in endothelium-dependent vasodilation at 30 min postprandial. These findings are evidence that inorganic phosphorus has a stronger influence on vascular-endothelium function than organic phosphorus. PMID- 29610558 TI - Effect of egualen sodium hydrate on small-intestinal mucosal damage induced by low-dose aspirin: a prospective randomized clinical trial. AB - Low-dose aspirin, which is widely used to reduce the risk of cardio- and cerebrovascular thrombosis, often induces gastroenteropathy by increasing the permeability of the mucosa. However, therapeutic strategies for patients with low dose aspirin-induced small intestinal injury have not been determined. We evaluated the preventative effect of egualen sodium hydrate, a gastro-protective agent that suppresses indomethacin-induced small-intestinal damage in rats, against small-intestinal mucosal damage induced by low-dose aspirin in healthy adult male volunteers. Participants were randomly allocated to receive aspirin 100 mg/kg daily (control group, n = 10) or aspirin 100 mg/kg plus egualen sodium 30 mg daily (egualen sodium group, n = 10). Small intestinal mucosal injury was evaluated by capsule endoscopy two weeks after initiation of drug administration. Fecal analyses (occult blood test, immunochemical test, transferrin measurement and calprotectin measurement) were carried out before and after treatment. Egualen sodium significantly suppressed the total number of small intestinal injuries detected by capsule endoscopy and the positive ratio for the fecal occult blood test. Daily use of 30 mg of egualen sodium showed a preventative effect on low-dose aspirin-induced small intestinal injury. Since acid suppression therapy was reported to exacerbate NSAIDs-induced enteropathy via dysbiosis, egualen sodium may be useful for patients treated with low-dose aspirin. PMID- 29610559 TI - A double blind, placebo-controlled, randomized clinical trial that breast milk derived-Lactobacillus gasseri BNR17 mitigated diarrhea-dominant irritable bowel syndrome. AB - The exact pathogenesis of diarrhea-dominant irritable bowel syndrome (IBS) is not known, but the abnormal microbiota of the gastrointestinal tract is considered to be one of the important contributing factors as in other gastrointestinal diseases such as inflammatory bowel disease, antibiotic-associated diarrhea, and colorectal cancer as well as systemic diseases. Though diverse trials of probiotics had been continued in the treatment of diarrhea-IBS, only a few proved by randomized clinical trial. To prove the efficacy of Lactobacillus gasseri BNR17 isolated from breast milk in patients with diarrhea-IBS, prospective, randomized, placebo controlled clinical trial was done including health related quality of life analysis, colon transit time, and the changes of fecal microbiota. BNR17 significantly improved the symptoms of diarrhea compared to control group. Health related-QOL analysis showed significant improvement of abdominal pain, distension, disturbed daily life, and mean defecation frequency with BNR17. On comparative CTT before and after BNR17, 6 out of 24 subjects showed significant correction of rapid colon transit pattern, while only 2 out of 24 in placebo (p<0.01). Upon fecal microbiota analysis, BNR17 significantly increased B. fecalis, E. rectale, C. aerofaciens, F. prausnitzil and B. steroris. Conclusively, Lactobacillus gasseri BNR17 can be a potential probiotics to ameliorate diarrhea-IBS. PMID- 29610560 TI - Early diagnosis of type 2 diabetes based on multiple biomarkers and non-invasive indices. AB - We previously reported that type 2 diabetes risk, early impaired glucose tolerance and insulin resistance can be predicted by measuring the fasting levels of certain biomarkers. Here we validated these findings in randomly recruited healthy volunteers (n = 101) based on biomarker expression as well as various non invasive indices. Weight, body mass index, waist circumference and visceral fat differed between individuals with impaired fasting glucose and/or impaired glucose tolerance, and normal subjects. Fasting plasma levels of glycated hemoglobin, leptin, pro-insulin and retinol binding protein 4 differed between impaired fasting glucose/impaired glucose tolerance and normal subjects group and between newly detected diabetes and normal subjects group. Insulin resistance was correlated with fasting levels of insulin and leptin/adiponectin (r = 0.913); of insulin, retinol binding protein 4 and leptin/adiponectin (r = 0.903); and of insulin, glycated albumin, and leptin/adiponectin (r = 0.913). Type 2 diabetes risk, early impaired glucose tolerance and insulin resistance were predicted with >98% specificity and sensitivity by comparing fasting glucose levels to the estimated Matsuda Index based on fasting levels of insulin, adiponectin and leptin with or without oxidative lineolate metabolites. Non-invasive indices are slightly correlated with glucose tolerance and insulin resistance but do not increase the accuracy of predicting type 2 diabetes risk. PMID- 29610561 TI - Effect of astaxanthin-rich extract derived from Paracoccus carotinifaciens on cognitive function in middle-aged and older individuals. AB - This study was conducted to investigate the effect of dietary supplement containing astaxanthin-rich extract derived from Paracoccus carotinifaciens (astaxanthin supplement) on cognitive function of subjects aged 45-64 years. Cognitive functions of 28 subjects orally administered 8 mg astaxanthin/day of astaxanthin supplement for 8 weeks (astaxanthin group) and 26 subjects given a placebo (placebo group) were compared by word memory test, verbal fluency test, and Stroop test. The astaxanthin group experienced significantly larger increase in blood astaxanthin level than the placebo group. However, there were no significant intergroup differences in the results of the tests. A subgroup analysis was performed after dividing subjects into the <55 years old and >=55 years old age groups. The result of "words recalled after 5 minutes" in word memory test in <55 years old subjects showed significant improvement in the astaxanthin group than in the placebo group, which was not found in >=55 years old subjects. Our results indicate that people aged 45-54 years may experience improved cognitive function after ingesting astaxanthin supplement for 8 weeks. On the basis of the parameters tested, administration of astaxanthin supplement was not associated with any problems related to safety. PMID- 29610562 TI - African American Adolescent-Caregiver Relationships in a Weight Loss Trial. PMID- 29610564 TI - Effects of secreted frizzled-related protein 1 on proliferation, migration, invasion, and apoptosis of colorectal cancer cells. AB - Background: Secreted frizzled-related protein 1 (SFRP1) is a member of the SFRPs family that modulates the Wnt signal transduction pathway. Recent studies have showed down-regulation of SFRP1 expression in colorectal cancer (CRC). We aimed to evaluate the effect of SFRP1 on the proliferation, migration, invasion and apoptosis of CRC cells in vitro. Materials and methods: We used real-time fluorescence quantification (RT-PCR) and Western blotting to detect SFRP1 expression in CRC, pericarcinomatous tissues and CRC cell lines. We assessed the influence of overexpression and knockdown of SFRP1 on CRC cell proliferation, migration, invasion, and apoptosis, Western blotting was used to evaluate protein levels of Wnt, beta-catenin, and apoptosis-related proteins. Results: The expression of SFRP1 was significantly decreased in CRC tissues. Among the six CRC cell lines (sw-480, sw1116, caco-2, ht-29, colo-205, and hct-116), RT-PCR revealed that sw1116 cells had the lowest expression of SFRP1, while caco-2 cells had the highest SFRP1 expression. SFRP1 overexpression in sw1116 cells significantly suppressed cell proliferation while SFRP1 knockdown in caco-2 cells significantly increase the cell proliferation. In addition, overexpression of SFRP1 in sw1116 cells remarkedly suppressed cell migration and invasion, whereas knockdown of SFRP1 in caco-2 cells resulted in significant enhancement of migration and invasion. Furthermore, SFRP1 overexpression in sw1116 cells promoted cell apoptosis. Western blotting showed that SFRP1 overexpression significantly decreased the protein levels of Wnt, beta-catenin and apoptosis related proteins, including MMP2, MMP9, Twist, CDK1, TGF, and Bcl2. Conclusion: Our results demonstrate that SFRP1 suppresses cell proliferation, migration and invasion, and promotes apoptosis in CRC cells. PMID- 29610563 TI - Aerosol Gemcitabine after Amputation Inhibits Osteosarcoma Lung Metastases but Not Wound Healing. AB - Background: In newly diagnosed osteosarcoma (OS) patients, the time between surgery and resumption of chemotherapy is 2-7 weeks. Delays > 16 days are associated with increased risk of relapse and decreased overall survival. Identifying an effective therapy that can be used postoperatively may prevent relapse. We investigated whether aerosol gemcitabine (GCB) initiated after tumor resection inhibited the growth of OS lung metastases without affecting the wound healing process. Methods: Mice were injected intratibially with OS cells. Amputation was performed when the tumor reached 1.5 cm. Full-thickness excisional wounds were also made on the dorsal skin and tail. Aerosol GCB or PBS was initiated 48 hours after amputation (3 times/week for 3 weeks). Wound sections were evaluated by immunohistochemistry for Ki-67 (proliferation), CD31 (vessels), VEGF, IL-10, bFGF, mast cells, macrophages, and M1/M2 macrophage ratios. The lungs were analyzed for macro- and micrometastases. Results: Aerosol GCB inhibited the growth of the lung metastases but had no effect on the 3 phases of wound healing in the dorsal skin, tail, or bone. Production of cytokines at the wound sites was the same. Conclusion: These data indicate that initiating aerosol GCB postoperatively may kill residual lung metastases thereby preventing relapse and improve survival. PMID- 29610565 TI - The Price Elasticity of Specialty Drug Use: Evidence from Cancer Patients in Medicare Part D. AB - Specialty drugs can bring substantial benefits to patients with debilitating conditions, such as cancer, but their costs are very high. Insurers/payers have increased patient cost-sharing for specialty drugs to manage specialty drug spending. We utilized Medicare Part D plan formulary data to create the initial price (cost-sharing in the initial coverage phase in Part D), and estimated the total demand (both on- and off-label uses) for specialty cancer drugs among elderly Medicare Part D enrollees with no low-income subsidies (non-LIS) as a function of the initial price. We corrected for potential endogeneity associated with plan choice by instrumenting the initial price of specialty cancer drugs with the initial prices of specialty drugs in unrelated classes. We report three findings. First, we found that elderly non-LIS beneficiaries with cancer were less likely to use a Part D specialty cancer drug when the initial price was high: the overall price elasticity of specialty cancer drug spending ranged between -0.72 and -0.75. Second, the price effect in Part D specialty cancer drug use was not significant among newly diagnosed patients. Finally, we found that use of Part B-covered cancer drugs was not responsive to the Part D specialty cancer drug price. As the demand for costly specialty drugs grows, it will be important to identify clinical circumstances where specialty drugs can be valuable and ensure access to high-value treatments. PMID- 29610566 TI - A modified 384-well-device for versatile use in 3D cancer cell (co-)cultivation and screening for investigations of tumor biology in vitro. AB - Pancreatic cancer exhibits a worst prognosis owed to an aggressive tumor progression i.a. driven by chemoresistance or tumor-stroma-interactions. The identification of candidate genes, which promote this progression, can lead to new therapeutic targets and might improve patient's outcome. The identification of these candidates in a plethora of genes requires suitable screening protocols. The aim of the present study was to establish a universally usable device which ensures versatile cultivation, screening and handling protocols of cancer cells with the 3D spheroid model, an approved model to study tumor biology. By surface modification and alternative handling of a commercial 384-well plate, a modified device enabling (i) 3D cultivation either by liquid overlay or by a modified hanging drop method for (ii) screening of substances as well as for tumor-stroma interactions (iii) either with manual or automated handling was established. The here presented preliminary results of cell line dependent dose-response-relations and a stromal-induced spheroid-formation of the pancreatic cancer cells demonstrate the proof-of-principle of the versatile functionality of this device. By adapting the protocols to automation, a higher reproducibility and the ability for high-throughput analyses were ensured. PMID- 29610567 TI - Influence of cavitation and high shear stress on HSA aggregation behavior. AB - Neither the influence of high shear rates nor the impact of cavitation on protein aggregation is fully understood. The effect of cavitation bubble collapse-derived hydroxyl radicals on the aggregation behavior of human serum albumin (HSA) was investigated. Radicals were generated by pumping through a micro-orifice, ultra sonication, or chemically by Fenton's reaction. The amount of radicals produced by the two mechanical methods (0.12 and 11.25 nmol/(L min)) was not enough to change the protein integrity. In contrast, Fenton's reaction resulted in 382 nmol/(L min) of radicals, inducing protein aggregation. However, the micro orifice promoted the formation of soluble dimeric HSA aggregates. A validated computational fluid dynamic model of the orifice revealed a maximum and average shear rate on the order of 108 s-1 and 1.2 * 106 s-1, respectively. Although these values are among the highest ever reported in the literature, dimer formation did not occur when we used the same flow rate but suppressed cavitation. Therefore, aggregation is most likely caused by the increased surface area due to cavitation-mediated bubble growth, not by hydroxyl radical release or shear stress as often reported. PMID- 29610568 TI - Longer TA repeat but not V89L polymorphisms in the SRD5A2 gene may confer acne risk in the Chinese population. AB - Introduction: Several studies have reported that the V89L and TA repeat polymorphisms [(TA)n] of the SRD5A2 gene were associated with SRD5A2 activity. The activity of dihydrotestosterone, which is converted from testosterone by SRD5A2, is responsible for sebum secretion and the formation of acne. We hypothesized that abnormalities in SRD5A2 action could contribute to the formation of acne. Aim: To study whether the structural change of the SRD5A2 gene may affect the risk of acne in patients with normal serum testosterone levels. Material and methods: Genotyping of rs523349 and (TA)n of SRD5A2 was performed in 49 Chinese acne patients with significant improvements with SRD5A2 inhibitor finasteride but normal serum testosterone levels, and in 50 healthy Chinese age matched controls without acne. Results: There was no significant difference between the two groups in the frequencies of V and L alleles and VV, VL, and LL genotypes of V89L (chi2 test, p > 0.5). (TA)n polymorphic repeat sites are 5 alleles (TA0, TA3, TA6, TA9, TA12) in our population. The differences in S and L allele frequencies between the two groups were statistically significant (p < 0.005). People with a longer (n >= 6) allele of the (TA)n repeat polymorphism had a higher risk of having acne than those with a shorter (n < 6) allele (OR = 3.52, 95% CI: 1.73-7.16). Conclusions: This study suggests that SRD5A2 polymorphisms might be associated with acne risk. This is the first report focusing on the Chinese population according to our knowledge. Further large sample studies may be required to confirm the association and to assess any interactions with environmental factors. PMID- 29610569 TI - Respiratory Motion Correction for Compressively Sampled Free Breathing Cardiac MRI Using Smooth l1-Norm Approximation. AB - Transformed domain sparsity of Magnetic Resonance Imaging (MRI) has recently been used to reduce the acquisition time in conjunction with compressed sensing (CS) theory. Respiratory motion during MR scan results in strong blurring and ghosting artifacts in recovered MR images. To improve the quality of the recovered images, motion needs to be estimated and corrected. In this article, a two-step approach is proposed for the recovery of cardiac MR images in the presence of free breathing motion. In the first step, compressively sampled MR images are recovered by solving an optimization problem using gradient descent algorithm. The L1-norm based regularizer, used in optimization problem, is approximated by a hyperbolic tangent function. In the second step, a block matching algorithm, known as Adaptive Rood Pattern Search (ARPS), is exploited to estimate and correct respiratory motion among the recovered images. The framework is tested for free breathing simulated and in vivo 2D cardiac cine MRI data. Simulation results show improved structural similarity index (SSIM), peak signal-to-noise ratio (PSNR), and mean square error (MSE) with different acceleration factors for the proposed method. Experimental results also provide a comparison between k-t FOCUSS with MEMC and the proposed method. PMID- 29610570 TI - Characterizing the Use of Telepsychiatry for Patients with Opioid Use Disorder and Cooccurring Mental Health Disorders in Ontario, Canada. AB - Rural patients with opioid use disorder (OUD) face a variety of barriers when accessing opioid agonist therapy (OAT) and psychiatric services, due to the limited supply of physicians and the vast geographic area. The telemedicine allows for contact between patients and their physician-regardless of physical distance. Objective. We characterize the usage of telemedicine to deliver psychiatric services to patients with OUD in Ontario, as well as traits of treatment-seeking patients with opioid dependence and concurrent psychiatric disorders. Methodology. A retrospective cohort study was conducted using an administrative database for patients who received psychiatric services via telemedicine between 2008 and 2014 and who also had OUD. Results. We identified 9,077 patients with concurrent opioid use and other mental health disorders who had received psychiatric services via telemedicine from 2008 to 2014; 7,109 (78.3%) patients lived in Southern Ontario and 1,968 (21.7%) in Northern Ontario. Telemedicine was used more frequently to provide mental health services to patients residing in Northern Ontario than Southern Ontario. Conclusion. Telemedicine is increasingly being utilized throughout Ontario for delivering mental health treatment. There is an opportunity to increase access to psychiatric services for patients with opioid dependence and concurrent psychiatric disorders through the use of the telemedicine. PMID- 29610571 TI - Efficacy of Bilateral Transversus Abdominis Plane and Ilioinguinal Iliohypogastric Nerve Blocks for Postcaesarean Delivery Pain Relief under Spinal Anesthesia. AB - Background: Caesarean delivery can be associated with considerable postoperative pain. While the benefits of transversus abdominis plane (TAP) and ilioinguinal iliohypogastric (II-IH) nerve blocks on pain after caesarean delivery via Pfannenstiel incision have been demonstrated, no enough investigations on the comparison of these blocks on pain after caesarean delivery have been conducted in our setup. Method: An institutional-based prospective observational cohort study was conducted to compare the analgesic efficacy of those blocks. We observed 102 postoperative parturients. The outcome measure was the severity of pain measured using a numeric rating scale. Result: Twenty-four hours after surgery, the NRS score at rest was (0.90 +/- 0.80) versus (0.67 +/- 0.58) and at movement (1.2 +/- 1.07) versus (0.88 +/- 0.76) for the TAP and II-IH groups, respectively. Twenty-four hours after surgery, the mean tramadol consumption was (55.45 +/- 30.51) versus (37.27 +/- 27.09) mg in TAP and II-IH groups, respectively (p = 0.009). The mean first analgesic requirement time was also prolonged in the II-IH group. Conclusion and Recommendations: There was no statically significant difference between TAP and II-IH blocks regarding postoperative pain score, but the II-IH block significantly reduced the total tramadol consumption and prolonged the time to first analgesic request than TAP. Thus, we recommend the II-IH nerve block. PMID- 29610572 TI - Effectiveness of Bilateral Superficial Cervical Plexus Block as Part of Postoperative Analgesia for Patients Undergoing Thyroidectomy in Empress Zewditu Memorial Hospital, Addis Ababa, Ethiopia. AB - Introduction: The pain after thyroid surgery is considered of moderate intensity and short duration. Most trials showed significant reduction in pain intensity and severity of pain in patients for whom bilateral superficial cervical plexus block (BSCPB) was done. Objective: To assess the postoperative analgesic effect of BSCPB for thyroid surgery. Methods: Sixty six euthyroid patients were recruited and assigned to two groups (33 patients each). Group 1 BSCPB and Group 2 standard analgesia. The unpaired Student's t-test and Mann-Whitney test were used for comparison. Statistical significance was stated at p value < 0.05. Results: The median postoperative pain score (NRS) was 3 in the BSCPB group and 5 in the control group (p=0.002). There was also statistically significant difference at 6th, 12th, and 24th hour showing a lower median pain score in the BSCPB group compared to the control group. The median time was (360 minutes) in the treatment group and (180 minutes) in the control group (p=0.0006). The median tramadol consumption within 24 hours is 0 mg in the BSCPB group compared to 100 mg in the control group (p=0.001). Conclusion and Recommendation: BSCPB done for thyroidectomy under general anesthesia decreases the postoperative pain score, total analgesia consumption, and time to first analgesia request. PMID- 29610573 TI - A Toxicological Evaluation of a Standardized Hydrogenated Extract of Curcumin (CuroWhiteTM). AB - A series of toxicological investigations were conducted in order to evaluate the genotoxic potential and repeated-dose oral toxicity of CuroWhite, a proprietary extract of curcumin that has been hydrogenated and standardized to not less than 25% hydrogenated curcuminoid content. All tests were conducted in general accordance with internationally accepted standards. The test item was not mutagenic in the bacterial reverse mutation test or in vitro mammalian chromosomal aberration test, and no in vivo genotoxic activity was observed in rat bone marrow in the micronucleus test. A 90-day repeated-dose study was conducted in male and female Sprague-Dawley rats. Two mortalities occurred in the main and satellite high-dose groups and were determined due to gavage error. No organ specific or other toxic effects of the test item were observed up to the maximum dose of 800 mg/kg bw/day, administered by gavage. NOAEL was, therefore, estimated as 800 mg/kg bw/day. PMID- 29610574 TI - Impact of Age on Outcomes in Hospitalized Patients with Hereditary Hemorrhagic Telangiectasia. AB - Background: There is little published literature regarding the impact of age on outcomes amongst hospitalized HHT (hereditary hemorrhagic telangiectasia) patients. Methods: The Nationwide Inpatient Sample (NIS) was used to obtain data on all hospital discharges occurring in HHT patients from 2000 to 2012. The association between admission age and HHT-related complications and outcomes were studied. Results: 10293 hospitalizations in HHT patients from 2000 to 2012 were included. Patients > 50 accounted for 77% of all admissions with 30% of admissions occurring in the 51-65 age group. Bleeding related complications were the most frequent (62.7%, n = 6455 hospitalizations), followed by cardiovascular (41%, n = 4216), neurological (12.4%, n = 1276), and hepatobiliary (6.4%, n = 660) complications. Patients older than 50 accounted for 83% of bleeding events, 90% of cardiovascular events, 58% of neurologic events, and 81% of hepatobiliary events. The vast majority (83%) of medical and surgical procedures were performed in those older than 50 years of age. Older patients also experienced higher rates of death. Conclusion: Aging has significant adverse impacts on rates of hospitalization, complications, and outcomes amongst HHT patients in the United States. Except for neurologic complications, the vast majority of this disease burden is borne by patients older than 50 years. PMID- 29610576 TI - Comparison of three PCR-based assays for SNP genotyping in plants. AB - Background: PCR allelic discrimination technologies have broad applications in the detection of single nucleotide polymorphisms (SNPs) in genetics and genomics. The use of fluorescence-tagged probes is the leading method for targeted SNP detection, but assay costs and error rates could be improved to increase genotyping efficiency. A new assay, rhAmp, based on RNase H2-dependent PCR (rhPCR) combined with a universal reporter system attempts to reduce error rates from primer/primer and primer/probe dimers while lowering costs compared to existing technologies. Before rhAmp can be widely adopted, more experimentation is required to validate its effectiveness versus established methods. Results: The aim of this study was to compare the accuracy, sensitivity and costs of TaqMan, KASP, and rhAmp SNP genotyping methods in sugar beet (Beta vulgaris L.). For each approach, assays were designed to genotype 33 SNPs in a set of 96 sugar beet individuals obtained from 12 parental lines. The assay sensitivity was tested using a series of dilutions from 100 to 0.1 ng per PCR reaction. PCR was carried out on the QuantStudio 12K Flex Real-Time PCR System (Thermo Fisher Scientific, USA). The call-rate, defined as the percentage of genotype calls relative to the possible number of calls, was 97.0, 97.6, and 98.1% for TaqMan, KASP, and rhAmp, respectively. For rhAmp SNP, 24 of the 33 SNPs demonstrated 100% concordance with other two technologies. The genotype concordance with either technologies for the other 9 targets was above 99% (99.34-99.89%). Conclusion: The sensitivity test demonstrated that TaqMan and rhAmp were able to successfully determine SNP genotypes using as little as 0.2 ng DNA per reaction, while the KASP was unable to ascertain SNP states below 0.9 ng of DNA per reaction. Comparative cost per reaction was also analyzed with rhAmp SNP offering the lowest cost per reaction. In conclusion, rhAmp produced more calls than either TaqMan or KASP, higher signal to NTC data while offering the lowest cost per reaction. PMID- 29610575 TI - Arsenic trioxide induces apoptosis and the formation of reactive oxygen species in rat glioma cells. AB - Background: Arsenic trioxide (As2O3) has a dramatic therapeutic effect on acute promyelocytic leukemia (APL) patients. It can also cause apoptosis in various tumor cells. This study investigated whether As2O3 has an antitumor effect on glioma and explored the underlying mechanism. Results: MTT and trypan blue assays showed that As2O3 remarkably inhibited growth of C6 and 9 L glioma cells. Cell viability decreased in glioma cells to a greater extent than in normal glia cells. The annexin V-FITC/PI and Hoechest/PI staining assays revealed a significant increase in apoptosis that correlated with the duration of As2O3 treatment and occurred in glioma cells to a greater extent than in normal glial cells. As2O3 treatment induced reactive oxygen species (ROS) production in C6 and 9 L cells in a time-dependent manner. Cells pretreated with the antioxidant N acetylcysteine (NAC) showed significantly lower As2O3-induced ROS generation. As2O3 significantly inhibited the expression of the anti-apoptotic gene Bcl-2, and upregulated the proapoptotic gene Bax in both C6 and 9 L glioma cells in a time-dependent manner. Conclusions: As2O3 can significantly inhibit the growth of glioma cells and it can induce cell apoptosis in a time- and concentration dependent manner. ROS were found to be responsible for apoptosis in glioma cells induced by As2O3. These results suggest As2O3 is a promising agent for the treatment of glioma. PMID- 29610577 TI - Profiling and quantification of grain anthocyanins in purple pericarp * blue aleurone wheat crosses by high-performance thin-layer chromatography and densitometry. AB - Background: Anthocyanins are abundant secondary metabolites responsible for most blue to blue-black, and red to purple colors of various plant organs. In wheat grains, anthocyanins are accumulated in the pericarp and/or aleurone layer. Anthocyanin pigmented wheat grains can be processed into functional foods with potential health benefits due to the antioxidant properties of the anthocyanins. The grain anthocyanin content can be increased by pyramidizing the different genes responsible for the accumulation of anthocyanins in the different grain layers. Our objective was to develop a high-performance thin-layer chromatography (HPTLC) method that allows the determination of both the anthocyanin profile and the total pigment concentration. Thereby, selection of breeding lines with significantly higher grain anthocyanin content from purple pericarp * blue aleurone wheat crosses should become more efficient than selection based on only visual scoring of grain color and the unspecific determination of anthocyanin concentration by UV/Vis spectroscopy. Results: A wide variability in the grain anthocyanin content was observed in breeding lines and check varieties. The highest concentration of anthocyanins was observed in deep purple (i.e. combination of the purple pericarp and blue aleurone genetics) grained breeding lines, followed by blue aleurone and purple pericarp genotypes. Determination of the total anthocyanin content was included into the chromatographic analysis, rendering an additional photometric analysis unnecessary. Ten target zones were identified in anthocyanin pigmented wheat grains; four of these zones were typically for blue aleurone types, five for purple pericarp types, and one (i.e. kuromanin glucoside) was characteristic for both. Chemometrics applied to the anthocyanin profile recorded by scanning densitometry revealed that peak heights and peak areas are highly correlated and that seven out of the ten target zones were responsible for about 90% of the total variation in the germplasm. Multivariate analysis of these seven target zones allowed not only a separation of the genetic material into purple, blue and deep purple grained genotypes, but also the identification of genotypes with a specific anthocyanin pattern. Thereby, the original classification by visual scoring was overruled in about one third of the breeding lines. Conclusions: The presented HPTLC method with a cote calibration allowed the profiling of the pigments and quantification of wheat grain anthocyanin content in a single analysis, replacing UV/Vis spectroscopy with subsequent HPLC analysis. Moreover, no sample preparation apart from extraction and filtration is required, and more than 15 samples can be evaluated in one analysis run, corresponding to several dozens of samples per day. Hence, the method fulfills the requirements for screening methods in early generations of a plant breeding program such as high-throughput, small sample size, high repeatability, fast determination, and reasonable costs per sample. Combined with multivariate statistical analysis, the anthocyanin pattern allowed the validation of the genetic background in the offspring of purple * blue wheat crosses and, therefore, the efficient selection of genotypes exhibiting both the cyanidin and delphinidin aglycon. PMID- 29610578 TI - Techno-economic analysis of the industrial production of a low-cost enzyme using E. coli: the case of recombinant beta-glucosidase. AB - Background: The enzymatic conversion of lignocellulosic biomass into fermentable sugars is a promising approach for producing renewable fuels and chemicals. However, the cost and efficiency of the fungal enzyme cocktails that are normally employed in these processes remain a significant bottleneck. A potential route to increase hydrolysis yields and thereby reduce the hydrolysis costs would be to supplement the fungal enzymes with their lacking enzymatic activities, such as beta-glucosidase. In this context, it is not clear from the literature whether recombinant E. coli could be a cost-effective platform for the production of some of these low-value enzymes, especially in the case of on-site production. Here, we present a conceptual design and techno-economic evaluation of the production of a low-cost industrial enzyme using recombinant E. coli. Results: In a simulated baseline scenario for beta-glucosidase demand in a hypothetical second generation ethanol (2G) plant in Brazil, we found that the production cost (316 US$/kg) was higher than what is commonly assumed in the literature for fungal enzymes, owing especially to the facility-dependent costs (45%) and to consumables (23%) and raw materials (25%). Sensitivity analyses of process scale, inoculation volume, and volumetric productivity indicated that optimized conditions may promote a dramatic reduction in enzyme cost and also revealed the most relevant factors affecting production costs. Conclusions: Despite the considerable technical and economic uncertainties that surround 2G ethanol and the large-scale production of low-cost recombinant enzymes, this work sheds light on some relevant questions and supports future studies in this field. In particular, we conclude that process optimization, on many fronts, may strongly reduce the costs of E. coli recombinant enzymes, in the context of tailor-made enzymatic cocktails for 2G ethanol production. PMID- 29610579 TI - Pairwise gene GO-based measures for biclustering of high-dimensional expression data. AB - Background: Biclustering algorithms search for groups of genes that share the same behavior under a subset of samples in gene expression data. Nowadays, the biological knowledge available in public repositories can be used to drive these algorithms to find biclusters composed of groups of genes functionally coherent. On the other hand, a distance among genes can be defined according to their information stored in Gene Ontology (GO). Gene pairwise GO semantic similarity measures report a value for each pair of genes which establishes their functional similarity. A scatter search-based algorithm that optimizes a merit function that integrates GO information is studied in this paper. This merit function uses a term that addresses the information through a GO measure. Results: The effect of two possible different gene pairwise GO measures on the performance of the algorithm is analyzed. Firstly, three well known yeast datasets with approximately one thousand of genes are studied. Secondly, a group of human datasets related to clinical data of cancer is also explored by the algorithm. Most of these data are high-dimensional datasets composed of a huge number of genes. The resultant biclusters reveal groups of genes linked by a same functionality when the search procedure is driven by one of the proposed GO measures. Furthermore, a qualitative biological study of a group of biclusters show their relevance from a cancer disease perspective. Conclusions: It can be concluded that the integration of biological information improves the performance of the biclustering process. The two different GO measures studied show an improvement in the results obtained for the yeast dataset. However, if datasets are composed of a huge number of genes, only one of them really improves the algorithm performance. This second case constitutes a clear option to explore interesting datasets from a clinical point of view. PMID- 29610580 TI - Infectious bursal disease virus inoculation infection modifies Campylobacter jejuni-host interaction in broilers. AB - Background: Campylobacter jejuni is considered as a chicken commensal. The gut microbiota and the immune status of the host may affect its colonization. Infectious bursal disease virus (IBDV) is an immunosuppressive virus of chickens, which allows secondary pathogens to invade or exacerbates their pathogenesis. To investigate the effect of IBDV-induced immunosuppression on the pathogenesis of C. jejuni, broiler chickens were inoculated with a very virulent (vv) strain of IBDV at 14 days post hatch followed by C. jejuni inoculation at 7 (Experiment A) or 9 (Experiment B) days post virus (IBDV) inoculation. Results: vvIBDV-infection led to a depression in caecal lamina propria B lymphocytes and the anti-C. jejuni antibody response starting at 14 days post C. jejuni inoculation (pbi). The C. jejuni-colonization pattern was comparable between mono-inoculated groups of both experiments, but it varied for vvIBDV + C. jejuni co-inoculated groups. In Experiment A significant higher numbers of colony forming units (CFU) of C. jejuni were detected in the caecum of co-inoculated birds compared to C. jejuni mono-inoculated birds in the early phase after C. jejuni-inoculation. In Experiment B the clearance phase was affected in the co-inoculated group with significantly higher CFU at 21 days pbi compared to the mono-inoculated group (P < 0.05). No major differences were seen in numbers local lamina propria T lymphocyte populations between C. jejuni-inoculated groups with or without vvIBDV infection. Interestingly, both pathogens affected the microbiota composition. The consequences of these microflora changes for the host have to be elucidated further. Conclusion: Our data suggests that the timing between viral and bacterial infection might affect the outcome of C. jejuni colonization differently. Our results confirm previous studies that anti-Campylobacter antibodies may specifically be important for the clearance phase of the bacteria. Therefore, as vvIBDV is widely distributed in the field, it may have a significant impact on the colonization and shedding rate of C. jejuni in commercial poultry flocks. Subsequently, successful IBDV-control strategies may indirectly also benefit the gut-health of chickens. PMID- 29610581 TI - Bridging glycated hemoglobin with quality of life and health state; a randomized case-control study among type 2 diabetes patients. AB - Background: The aim of this study was to explore the predictors of QOL and health state and examine the relationship with glycemic control among type 2 diabetes mellitus (T2DM) patients. Methods: A randomized cross-sectional case-control study was conducted among n = 600 T2DM patients of Malaysia. Study population was distributed into three groups as: controls: patients with HbA1c <= 7 (n = 199), cases arm 1: with HbA1c 7-7.9 (n = 204) and cases arm 2 (n = 197): with HbA1c >= 8 consecutively last 3 times. Results: Participants with diabetes history > 10 years exhibits higher mean QOL score among all the three groups. In contrast mean health status score significantly (p < 0.001) reduced with the exposure duration of diabetes both within and intergroup assessment that participants with poor glycemic control (arm 2) had significantly higher mean QOL score with knowledge and self-care dimensions as compared to others, however mean health state scores were significantly (p < 0.001) lower in all assessment dimensions as compared to controls. The F test of significance showed that demographic and clinical parameters were strong predictors of QOL, whereas self-care activities, comorbidities, ability of positive management and BMI were significant predictors to health state for consistent glycemic control (controls) as compared to poor glycemic control (arm 2) participants. Conclusion: This study suggested that poor glycemic index reported low self-care behavior, increase barriers to daily living activities and poor ability to manage diabetes positively, which cause poor QOL and decrease health state. PMID- 29610582 TI - The SAMHD1-mediated block of LINE-1 retroelements is regulated by phosphorylation. AB - Background: The restriction factor SAMHD1 regulates intracellular nucleotide level by degrading dNTPs and blocks the replication of retroviruses and DNA viruses in non-cycling cells, like macrophages or dendritic cells. In patients, inactivating mutations in samhd1 are associated with the autoimmune disease Aicardi-Goutieres Syndrome (AGS). The accumulation of intracellular nucleic acids derived from endogenous retroelements thriving in the absence of SAMHD1 has been discussed as potential trigger of the autoimmune reaction. In vitro, SAMHD1 has been found to restrict endogenous retroelements, like LINE-1 elements (L1). The mechanism, however, by which SAMHD1 blocks endogenous retroelements, is still unclear. Results: Here, we show that SAMHD1 inhibits the replication of L1 and other endogenous retroelements in cycling cells. By applying GFP- and neomycin based reporter assays we found that the anti-L1 activity of SAMHD1 is regulated by phosphorylation at threonine 592 (T592). Similar to the block of HIV, the cofactor binding site and the enzymatic active HD domain of SAMHD1 proofed to be essential for restriction of L1 elements. However, phosphorylation at T592 did not correlate with the dNTP hydrolase activity of SAMHD1 in cycling 293T cells suggesting an alternative mechanism of regulation. Interestingly, we found that SAMHD1 binds to ORF2 protein of L1 and that this interaction is regulated by T592 phosphorylation. Together with the finding that the block is also active in cycling cells, our results suggest that the SAMHD1-mediated inhibition of L1 is similar but not identical to HIV restriction. Conclusion: Our findings show conclusively that SAMHD1 restricts the replication of endogenous retroelements in vitro. The results suggest that SAMHD1 is important for maintaining genome integrity and support the idea of an enhanced replication of endogenous retroelements in the absence of SAMHD1 in vivo, potentially triggering autoimmune diseases like AGS. Our analysis also contributes to the better understanding of the activities of SAMHD1 in antiviral defense and nucleotide metabolism. The finding that the phosphorylation of SAMHD1 at T592 regulates its activity against retroelements but not necessarily intracellular dNTP level suggests that the dNTP hydrolase activity might not be the only function of SAMHD1 important for its antiviral activity and for controlling autoimmunity. PMID- 29610584 TI - Justice Came to Hypertension Or Did It? PMID- 29610585 TI - Pulmonary Diffusion Capacity for Carbon Monoxide (DLCO) in Indonesian Patients with End-stage Renal Disease. AB - Objectives: End-stage renal disease affects all systems in human including the respiratory system. This study aimed to discover the lung diffusion capacity of carbon monoxide (DLCO) in chronic hemodialysis patients and to establish its relation to several demographic and clinical factors as well as spirometry parameters. Material and Methods: This was a cross-sectional study among chronic hemodialysis patients aged .18 years, clinically stable in the last four weeks, without prior history of lung and cardiac disorder. Spirometry and DLCO examination were performed in the span of 24 hours after hemodialysis. Outcomes: There were 40 subjects analyzed. Majority of them were males (67.5%), non-smokers (55%), with a median age of 51 years, a mean body mass index of 22.6+/-3.9 kg/m2, a hemoglobin level of 9.5+/-1.3 g/dL, a median dialysis adequacy of 1.62 and a hemodialysis duration of 31.5 months. Hypertension was the most common underlying disease. About 20% of subjects had varying degrees of dyspnea. Prevalence of DLCO reduction was 52.5% with mild to moderate degree. Restrictive spirometry pattern was evident in 47.5% of subjects and obstructive pattern in 5%. There was a significant relation between DLCO reduction with smoking history (OR 4.52 [95% CI 1.04-19.6]) and also with restrictive disorder [OR 5.5 (95% CI 1.29-23.8)]. We suspected a lung parenchymal disorder as the cause of lung restriction and diffusion inhibition. Conclusions: Reduction of lung diffusion capacity in chronic dialysis patients is common, although not accompanied by dyspnea. Risk factors for DLCO reduction are smoking history and restrictive disorder in spirometry. PMID- 29610583 TI - Contrasted patterns of evolution of the LINE-1 retrotransposon in perissodactyls: the history of a LINE-1 extinction. AB - Background: LINE-1 (L1) is the dominant autonomously replicating non-LTR retrotransposon in mammals. Although our knowledge of L1 evolution across the tree of life has considerably improved in recent years, what we know of L1 evolution in mammals is biased and comes mostly from studies in primates (mostly human) and rodents (mostly mouse). It is unclear if patterns of evolution that are shared between those two groups apply to other mammalian orders. Here we performed a detailed study on the evolution of L1 in perissodactyls by making use of the complete genome of the domestic horse and of the white rhinoceros. This mammalian order offers an excellent model to study the extinction of L1 since the rhinoceros is one of the few mammalian species to have lost active L1. Results: We found that multiple L1 lineages, carrying different 5'UTRs, have been simultaneously active during the evolution of perissodactyls. We also found that L1 has continuously amplified and diversified in horse. In rhinoceros, L1 was very prolific early on. Two successful families were simultaneously active until ~20my ago but became extinct suddenly at exactly the same time. Conclusions: The general pattern of L1 evolution in perissodactyls is very similar to what was previously described in mouse and human, suggesting some commonalities in the way mammalian genomes interact with L1. We confirmed the extinction of L1 in rhinoceros and we discuss several possible mechanisms. PMID- 29610586 TI - Analysis of Interleukin-17 mRNA Level in the Urinary Cells of Kidney Transplant Recipients with Stable Function. AB - Objectives: Kidney transplantation supports patients with end-stage kidney diseases. Many factors control the allograft function in kidney transplant recipients. Interleukin-17 (IL-17) can be used as a non-invasive diagnostic biomarker of rejection. The aim of this study was to evaluate the expression of IL-17 mRNA in urinary cells of kidney transplant recipients with stable function. Material and Methods: A total of 40 renal transplant recipients who were admitted for surgery and 30 healthy controls were enrolled in the study. From each patient, 30 mL urine samples were collected in 50 mL tubes on days 3 and 5 after renal transplantation; also, 30 mL urine samples were obtained from controls. Quantitative Real-Time PCR (qRT-PCR) technique was used for analysis of IL-17 mRNA level in the tested groups; 2-AACT method was performed for determining the relative gene expression between tested groups. Results: The mRNA expression mean +/- SE of fold in patients and controls were 3.58+/-1.61 fold and 2.85+/-1.37 fold, respectively. The mRNA expression mean of IL-17 (fold) was not statistically different in tested groups (P-value = 0.63). Conclusions: In kidney transplant recipients, urinary IL-17 expression provides informative data in relation to the allograft function regardless of allograft pathology. PMID- 29610587 TI - High Resolution Melting Curve Analysis for Rapid Detection of Streptomycin and Ethambutol Resistance in Mycobacterium tuberculosis. AB - Objectives: Development of molecular techniques for rapid detection of drug resistant tuberculosis allows for the prompt initiation of appropriate anti-TB treatment. We aimed to assess high-resolution melting (HRM) analysis for the detection of rpsL, rrs and embB mutations to identify streptomycin and ethambutol resistance in Mycobacterium tuberculosis. Material and Methods: A total of 76 clinical isolates of M. tuberculosis including 25 SM-R, 21 EB-R and 30 drug susceptible - determined by the proportion method of drug susceptibility testing (DST) - were analyzed by HRM analysis, and the results were confirmed using DNA sequencing. Results: The sensitivity and specificity of the HRMA compared to phenotypic DST were 88% and 100.0%, respectively for the detection of streptomycin resistance (SM-R), and 90.4% and 96.6%, respectively for ethambutol resistance (EB-R). Three SM-R and two EB-R isolates had no mutations in the studied regions of rpsL, rrs and embB genes determined by DNA sequencing and therefore were not identified as resistant by HRM assay. Interestingly, one phenotypic EM-S isolate was found by sequencing to have a mutation at codon 423 (Met->Ilu) of embB gene and was clustered as resistant by HRM as well. Conclusions: The sensitivity and specificity of HRM curve assay was consistent with DNA sequencing, which is the gold standard method for genotypic DST. This assay can be utilized as a screening method for detection of drug-resistant tuberculosis, offering the advantages of a high throughput, single step, cost effectiveness, and rapid work flow method. PMID- 29610588 TI - Plasma Prolactin and Total Lipid Levels and Subsequent Risk of Breast Cancer in Pre- and Postmenopausal Women: Experience from an Indian Rural Centre. AB - Aims and objectives: 1) To analyze serum lipid and prolactin levels in breast cancer patients and normal subjects; 2) to correlate those levels with risk and prognostic factors. Material and Methods: The present study was performed in the Department of Surgery, MMIMSR, Mullana, Ambala, from 2013 to 2014, at a rural centre. The study group comprised 40 patients with carcinoma of the breast who underwent surgery and the control group included 10 patients who underwent surgery for reasons other than carcinoma of the breast. Apart from routine tests, special investigations like estimation of serum lipids and prolactin levels were carried out in each patient to assess the general health status and detect any potential evidence of distance metastasis. Results: Most patients were in the fourth and fifth decade of life. The mean value of serum total cholesterol in the study group (190.77 mg/dL) was higher than that of the control group (166.22 mg/dL), which was statistically significant. The mean value of LDL in the study group was 153.8 mg/dL, as compared to 118.4 mg/dL in the control group; therefore, the difference in LDL cholesterol levels between the two groups was statistically significant. The VLDL level was also higher in breast cancer patients, with a mean value of 35.25 mg/dL, as compared to 22.6 mg/dL in the control group. Serum triglycerides showed higher trends in the study group than in controls. The correlation coefficient of total lipids and prolactin was 0.428, which was significant (p value 0.002), and pointed to a positive relation between prolactin and total lipids, meaning that an elevation in total lipids would lead to an increase in prolactin levels. Conclusions: It was observed that significantly increased prolactin levels were found among patients with breast cancer. Serum lipids in carcinoma of the breast had higher levels of VLDL and LDL cholesterol and elevated triglyceride concentrations. Serum prolactin showed a statistically significant elevation in premenopausal patients as compared to postmenopausal subjects with breast cancer. Prolactin level may be also one of the risk factors for breast cancer, which points to its diagnostic significance. PMID- 29610589 TI - A Statistical Assessment of Information, Knowledge and Attitudes of Medical Students Regarding Contraception Use. AB - Objective: To evaluate how contraception use is linked to information, knowledge and attitudes towards family planning and contraception of medical students. Methods: This is a voluntary cross-sectional study using an anonymous questionnaire applied to 62 medical students. The questionnaire had the following main structure: characteristics of the studied population, information on contraception, knowledge about contraception methods, attitudes regarding family planning and contraception, and contraception use. Statistical analysis was performed using STATISTICA 8.0 software and statistical significance of the data was verified using the t-statistic test. Results: The survey had a 95% response rate. Seventy seven percent of the studied population consisted of females aged between 20-40 years, with 85.50% of them being 20-25 years old. The overwhelming majority of respondents believed it was important to be informed on the subject and considered themselves to be well informed on contraception. The internet and courses are the main sources of information. Of all respondents, 75.41% had routine discussions with their partners regarding contraception, 53.23% talked about it with family members and 46.77% with their physician; 90.16% had at least one gynecological examination and 47.54% got themselves tested for sexually transmitted diseases. The condom and the contraceptive pill were the main contraceptive methods for the respondents. Conclusions: Romanian medical students share similar features to their peers in European developed countries. We used a statistical analysis to demonstrate that information, knowledge and attitudes on contraception are closely linked to contraceptive choice. PMID- 29610590 TI - Effects of Appropriate Nutrition Training in Small Groups on Laboratory Parameters in Hemodialysis Patients from Iran. AB - Introduction: Adherence to appropriate nutrition and fluid intake is one of the essential parts of chronic renal failure treatment for achieving the desirable results among the patients with hemodialysis. Among various training methods, the "small groups' method", as an advanced method, can be performed by nurses in achieving desirable therapeutic results. The present study was aimed to investigate the effect of appropriate nutrition training in small groups on laboratory parameters in hemodialysis patients. Material and Methods: In this clinical trial, 64 patients who met the inclusion criteria were randomly selected and divided into an intervention group and a control group. Subsequently, an appropriate nutritional training program, including lectures along with appropriate nutrition pamphlets in three one hour question and answer sessions were performed. Thirty two patients in each group were assigned to intervention groups of five. Then, the laboratory indicators for each patient were measured in each group one month after training. Thereafter, data analysis was performed using descriptive and analytical statistics (statistical tests including independent t-test, paired t-test, repeated measures, and ANOVA) in SPSS V.16 software. Results: The mean age of the patients was 50.1 +/- 13.1 years; 47.5% of them had undergone dialysis due to hypertension and 55.7% had a history of 1-5 years of hemodialysis. There was a significant difference in post-intervention levels of urea, creatinine, sodium, potassium, calcium, and phosphorus between the two groups. Conclusions: Appropriate nutrition training via small-group method for patients on hemodialysis can impose positive effects on laboratory parameters. PMID- 29610591 TI - Does Phantom Tumor Really Exist?! AB - Localized interlobar effusion in congestive heart failure (known as phantom tumor or vanishing tumor of the lung) is an uncommon entity. We report a case of a 61 year-old man who presented to the Emergency Departament with a two week history of dyspnoea, palpitations, dry cough and intermitent anterior chest pain. A posteroanterior chest radiography showed a nodular mass in the medium third of the right hemithorax suggestive of a pulmonary tumor. With this supposition of diagnosis, the patient was admitted to the Pneumology Departament for further investigations. Left ventricular systolic dysfunction was identified on the echocardiographic examination, in the presence of atrial flutter with 2 to 1 block. Lateral chest X-ray confirmed the presence of a pleural effusion with complete regression of "the lung tumor" after ten days of congestive heart failure treatment, avoiding other expensive and unnecessary investigations. PMID- 29610592 TI - Predominant Upper Limb Chronic Demyelinating Polyneuropathy Associated with HBV Infection. AB - Chronic inflammatory demyelinating polyneuropathy is an acquired, presumably immune-mediated peripheral neuropathy, characterized by symmetric sensory-motor involvement. Although most often idiopathic, it has been described in association with several disorders, sometimes improving under treatment. We present the case of a 57-year-old male who was admitted to hospital for paresthesias and muscle weakness affecting both upper limbs, initially only the hands, but with worsening and ascending progression during the last three years. The lower limbs were also involved but to a lesser extent. Electromyography indicated multifocal chronic demyelinating polyneuropathy with predominant upper limb involvement. Lumbar puncture showed a raised cerebrospinal fluid protein level. Laboratory samples revealed positive serology for HBV. Based on these, the diagnosis of chronic inflammatory demyelinating polyneuropathy with chronic hepatitis B was made. The patient received IVIG therapy and has since been coming periodically for IVIG sessions, with clinical and electromyographic improvement. PMID- 29610593 TI - Immunological Evaluation of Surgical Stress in Liver Resections. AB - Surgery has its origins in caring for patients suffering from injury or infection. In the last decade, a huge amount of published data has been describing a wide range of conditions resulting from trauma or infection, from minor, local reactions to a surgical operation and leading to a systemic stress response, systemic inflammatory response and finally to multiple organ failure. Our aim was to highlight the main immunological aspects of liver resections. There are many types of liver resections, ranging from small, isolated resections for benign diseases (e.g., small cysts or angyoma) to segmentectomies, bi- or trisegmentectomies to hepatectomies in the end. Patients undergoing such resections are subjected to a large amount of surgical stress and in some cases, postoperative complications ranging from light to severe. The main links between immunology and liver resections is surgical stress that can be evaluated through various immunological methods, which will be presented in this article. PMID- 29610594 TI - Tyrosine-kinase Inhibitors Treatment in Advanced Malignant Melanoma. AB - Objective: To put in perspective recent advances in the treatment of malignant melanoma with novel tyrosine-kinase inhibitors. Methods: We reviewed the largest trials that support the treatment with tyrosine-kinase inhibitors (TKIs) in cutaneous malignant melanoma, the base of the current guideline recommendations. Conclusions: Mitogen-activated protein-kinase (MAPK) pathway inhibition via modern TKIs is a major breakthrough in the treatment of melanoma, with a very high benefit for patients with disease harboring BRAF-gene mutations, in terms of rates of response and survival. PMID- 29610595 TI - The Basic Steps of Evolution of Brain Surgery. AB - Objective and conclusion: Neurosurgery is probably the most constantly developing specialty of all times. Its dimension is enormous and its history, Ancient. The evolution of neurosurgery from the Mayan and Egyptian periods to the Renaissance and the 21st century was the result of many physicians and patients whose experiences lead to the revolution of modernization. Today, the field of neurosurgery is continuously expanding, aiming to introduce knowledge and technologies that could provide a new futuristic wave of medicine. Methods: Given this background, our team selected relevant data from Medline published between 1936 and 2017. Results: We included 91 articles on this topic, all of them providing enough information about the revolution and progress of brain surgery through the centuries as well as its potential expansion in the future. PMID- 29610596 TI - Catecholaminergic Polymorphic Ventricular Tachycardia - Looking to the Future. AB - Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare inheritable cardiac disorder, characterized by polymorphic ventricular tachycardia (PVT) or bidirectional ventricular tachycardia, triggered by adrenergic stress, and manifested most frequently as syncope or sudden cardiac death. The disease has a heterogeneous genetic basis, with mutations in the genes encoding the ryanodine and calsequestrin channels accounting for the majority of cases. The diagnosis of CPVT is established in individuals with polymorphic ventricular premature beats, PVT or bidirectional ventricular tachycardia documented during exercise or adrenergic stress, who have a structurally normal heart and normal resting ECG. Genetic testing completes the diagnosis, but is limited by the fact that, to date, about one third of cases are genotype-unknown. Treatment strategies have improved as the knowledge of the disease has evolved, and several therapeutic options are now available. They include pharmacologic measures (especially non-selective beta-blockers and flecainide), but also more complex interventions, such implantation of internal cardiac defibrillators and left cardiac sympathetic denervation. There are many unknowns to CPVT, but one that is essential to clinical practice is risk stratification, which will aid in a more targeted treatment of these patients. This goal is to be achieved by creating large patient registries and bio-banks, and ultimately by incorporating both clinical and genetic data into a risk stratification score. PMID- 29610597 TI - Immunohistochemical Expression of TGF-Beta1, SMAD4, SMAD7, TGFbetaRII and CD68 Positive TAM Densities in Papillary Thyroid Cancer. AB - BACKGROUND: Papillary thyroid carcinoma (PTC) accounts for 80% of the thyroid malignancies that are characterised by slow growth and an excellent prognosis. Over-expression of SMAD4 protein restores TGF-beta signalling, determines a strong increase in anti-proliferative effect and reduces invasive potential of tumour cells expressing it. AIM: The study aimed to analyse the immunohistochemical expression of TGF-beta1 and its downstream phosphorylated SMAD4, element and of the inhibitory SMAD7 PTC variants and their association with the localisation of TAMs within the tumour microenvironment. METHODS: For this retrospective study we investigated 69 patients immunohistochemistry with antibodies against TGF-beta, TGF - beta-RII, SMAD4, SMAD7, CD68+ macrophages. RESULTS: Patients with low infiltration with CD68+ cells in tumour stroma has significantly shorter survival (median of 129.267 months) compared to those with high CD68+ cells infiltration (p = 0.034). From the analysis of CD68+ cells in tumour border and tumour stroma correlated with expression of TGF-beta1 / SMAD proteins, we observed that the positive expression of TGF-beta1 in tumour cytoplasm, significantly correlated with increased number of CD68+ cells in tumour border (X2 = 5,945; p = 0.015). CONCLUSION: TGF-beta enhances motility and stimulates recruitment of monocytes, macrophages and other immune cells while directly inhibiting their anti-tumour effector functions. PMID- 29610598 TI - Proton Pump Inhibitors Intake and Iron and Vitamin B12 Status: A Prospective Comparative Study with a Follow up of 12 Months. AB - BACKGROUND: Proton pump inhibitors (PPIs) represent the most widely prescribed antisecretory agents, but their prolonged use, may influence iron and vitamin B12 status, which could have important implications for clinical practice. AIM: We undertook this study aiming to investigate the association between PPIs use for 12 months and potential changes in iron and vitamin B12 status, as well as whether this potential association varies among four specific PPI drugs used in the study. METHODS: A total of 250 adult subjects were recruited into this study, of which 200 subjects were PPIs users while 50 subjects belonged to the control group. Serum iron, ferritin, vitamin B12, and homocysteine (Hcy) levels were measured before the start of the study and after 12 months. Mann - Whitney U test and Kruskal - Wallis test was used to compare the baseline characteristics of the study groups, while Wilcoxon test was used to analyse post - pre differences. RESULTS: Statistical analysis showed significant changes within PPIs group and specific PPIs subgroups between the two-time points in serum ferritin and vitamin B12 levels, respectively, while no significant changes in serum iron and homocysteine levels were shown. However, subsequent diagnosis of hypoferremia and hypovitaminosis B12 in the whole study sample at 12 months was established in only 3.8% and 2.9% of the subjects, respectively. CONCLUSION: PPIs use for 12 months did not result in clinically significant iron and/or vitamin B12 deficiency; thus, these findings argue routine screening under normal circumstances, although monitoring in elderly and malnourished may be of precious value. PMID- 29610599 TI - Is the rs1801282 (G/C) Polymorphism of PPAR - Gamma Gene Associated with T2DM in Iraqi People? AB - BACKGROUND: Pro12Ala (rs1801282) is a common polymorphism of the human PPAR-gamma gene. Studies have demonstrated conflicting results about its association with T2DM worldwide. There are no reports about such possible association among Iraqi people. OBJECTIVES: This study aims at finding out whether having the mutant allele (Ala12) might be associated with T2DM among Iraqi people. METHODS: One hundred and ninety-two Arabic Iraqi adult subjects (97 with T2DM and 95 controls) were genotyped using PCR- RFLP. Clinical, anthropometrical and biochemical variables were compared regarding the Pro12Ala genotypes. RESULTS: About 5.67% of people with diabetes were carriers of the (Ala12) allele versus 9.47% of controls. Allelic and genotypic frequencies were not statistically different among diabetics and controls [(chi2= 1.99, p= 0.16) and (chi2= 2.17, p= 0.14)]. Age, BMI and smoking- but not Pro12Ala - were independent risk factors for T2DM in our subjects. Pro12Ala was not associated with T2DM (Odd's ratio 0.55, 95% CI 0.23- 1.32, p= 0.14). CONCLUSIONS: Our study revealed a relatively high frequency of the Ala12 allele among Arabic Iraqis. These frequencies did not significantly differ between diabetics and controls indicating the absence of association of Pro12Ala with T2DM among Iraqis. PMID- 29610600 TI - Eosinophil Cationic Protein Concentrations among Crop and Dairy Farmers with Asthma. AB - OBJECTIVE: To assess the mean serum eosinophil cationic protein (s-ECP) concentrations among crop and dairy farmers and office controls, and further examine its relation to exposure duration, smoking habit, as well as presence or absence of asthma. METHODS: A cross-sectional survey was performed including examined group (EG), composed by agricultural workers (87 crop - EG1 and 83 dairy farmers - EG2), and control group (CG) composed by 80 office workers within the same enterprise. We have used a questionnaire to record the chronic respiratory symptoms, detailed work history, specific farming activities and tasks performed and smoking history. Evaluation of examined subjects also included lung function tests, diagnosis of asthma, and measurement of s-ECP as a marker of inflammation. RESULTS: The main finding of the present study is that s-ECP concentrations were raised in subjects with asthma independent of the smoking habit. The mean s-ECP concentrations were higher in subjects of EG1 and EG2 compared with those in CG, but without reaching statistical significance. Mean s-ECP concentrations were significantly higher among subjects in EG1 exposed more than 20 years, while mean s-ECP concentrations were non-significantly higher in subjects of EG2 exposed more than 20 years, compared to those exposed less than 20 years. Mean s-ECP concentrations were higher among smokers within all three groups, but without reaching statistical significance between smokers and non-smokers. Mean s-ECP concentrations were significantly higher in subjects with asthma within EG1 (P = 0.049) and EG2 (P = 0.040), but also within those in CG (P = 0.046). CONCLUSION: Data obtained suggest that airway inflammation is present in farmers with asthma, and s-ECP is an important biomarker in means of reflecting disease severity and prognosis among exposed workers. PMID- 29610601 TI - Carotid Endarterectomy in Women versus Man: Patient Characteristics and Perioperative Complication (<30 Day). AB - AIM: Compare the basic characteristics of patients and to examine the existence of higher rates of perioperative complications (0 - 30 days) in women versus men after carotid endarterectomy (CEA). METHODS: This is a retrospective-prospective study included 270 patients with significant stenosis of carotid in whom CEA was performed, during the period from 2012 to 2017. Patients they were divided: group 1 - 100 female patients, group 2 - 170 male patients. RESULTS: No statistically significant age difference was observed between the two groups, group 1 - 66.01 years (SD 8.42, 46 to 86 years), group 2 - 66.46 years (SD 8.03, 47 to 85 years) (p = 0.659). Risk factors represent a greater prevalence in group 2, but the observed difference is not statistically significant. The average duration of surgery and the time of carotid artery clamping time were longer in group 1: (p = 0.002; p = 0.005). The number of classic endarterectomy with the patch was higher in women (41 (41%) versus 31 (18. 2%), p = 0.005), while the number of bilateral CEAs was not statistically significant. CONCLUSION: The results of this study of this study did not indicate a greater presence of perioperative complications (< 30 days) in women versus male patients after CEA. PMID- 29610602 TI - The Effect of Technological Devices on Cervical Lordosis. AB - PURPOSE: There is a need for cervical flexion and even cervical hyperflexion for the use of technological devices, especially mobile phones. We investigated the effect of this use on the cervical lordosis angle. MATERIAL AND METHODS: A group of 156 patients who applied with only neck pain between 2013-2016 and had no additional problems were included. Patients are specifically questioned about mobile phone, tablet, and other devices usage. The value obtained by multiplying the year of usage and the average usage (hour) in daily life was determined as the total usage value (an average hour per day x year: hy). Cervical lordosis angles were statistically compared with the total time of use. RESULTS: In the general ROC analysis, the cut-off value was found to be 20.5 hy. When the cut-off value is tested, the overall accuracy is very good with 72.4%. The true estimate of true risk and non-risk is quite high. The ROC analysis is statistically significant. CONCLUSION: The use of computing devices, especially mobile telephones, and the increase in the flexion of the cervical spine indicate that cervical vertebral problems will increase even in younger people in future. Also, to using with attention at this point, ergonomic devices must also be developed. PMID- 29610603 TI - Myasthenia Gravis and Associated Diseases. AB - BACKGROUND: Myasthenia gravis (MG) is an autoimmune disease caused by the action of specific antibodies to the postsynaptic membrane of the neuromuscular junction, leading to impaired neuromuscular transmission. Patients with MG have an increased incidence of other autoimmune diseases. AIM: to determine the presence of other associated diseases in patients with MG. METHOD: A group of 127 patients with MG followed in 10 years period, in which the presence of other associated diseases has been analysed. RESULTS: The sex ratio is in favour of the female sex, the average age of the initial manifestation of the disease is less than 50 years, 65.4% of the patients with MG have another disease. 15.0% patients have associated another autoimmune disease. Thyroid disease is the most common associated with MG, rarely rheumatoid arthritis (RA), systemic lupus erythematosus (SLE) and other autoimmune diseases. Other diseases include hypertension, heart disease, diabetes, respiratory diseases, dyslipidemia. 10.2% of the patients are diagnosed with extrathymic tumours of various origins. CONCLUSION: Associated diseases are common in patients with MG, drawing attention to the possible common basis for their coexistence, as well as their impact on the intensity and treatment of the disease. PMID- 29610604 TI - Correlation of Procalcitonin and C-Reactive Protein with Intra-Abdominal Hypertension in Intra-Abdominal Infections: Their Predictive Role in the Progress of the Disease. AB - AIM: To analyse the correlation of procalcitonin (PCT) and C-reactive protein (CRP) values with increased intra-abdominal pressure and to evaluate their predictive role in the progression of Intra-abdominal infections. MATERIALS AND METHODS: A non-randomized prospective study conducted in the group of 80 patients. We have measured the PCT, CRP and intra-abdominal pressure (IAP). RESULTS: According to IAH grades (G), there was a significant difference of PCT values: G I 3.6 +/- 5.1 ng/ml, G II 10.9 +/- 22.6 ng/ml, G III 15.2 +/- 30.2 ng/ml (p = 0.045) until: CRP values were increased in all IAH groups but without distinction between the groups: GI 183 +/- 64.5, GII 196 +/- 90.2, GIII 224 +/- 96.3 (p = 0.17). According to the severity of the infection, we yielded increased values of PCT, IAP and CRP in septic shock, severe sepsis and SIRS/sepsis resulting in significant differences of PCT and IAP. CONCLUSION: Based on the results of our research, we conclude that the correlation of PCT values with IAH grades is quite significant while the CRP results remain high in IAH but without significant difference between the different grades of IAH. PMID- 29610605 TI - A Study of Selenium in Leprosy. AB - INTRODUCTION: Leprosy is a chronic infection caused by Mycobacterium leprae. Selenium, on the other hand, is a substance, which is needed for its protective role against microorganism infection. AIM: This study aims to know the association between selenium serum levels with bacteriological index. METHODS: This is an analytical cross-sectional study model. Sampling was done with consecutive sampling method in Pirngadi General Hospital, Lau Simomo Leprosy Hospital and H. Adam Malik General Hospital. Samples were taken from patients' venous blood serum then selenium levels were measured. RESULTS: This study found 30 leprosy patients consisted of 19 patients with paucibacillary (PB) leprosy and 11 patients with multibacillary (MB) leprosy. Selenium serum levels of patients with PB leprosy (mean = 97.16 ug/dL) were found to be significantly higher than MB leprosy (mean = 77.27 ug/dL) with p = 0.008 using t-test. The negative correlation between selenium serum levels with bacterial index in patients with leprosy was also found in this study using Spearman's rho test (r = - 0.499, p = 0.005). CONCLUSIONS: Selenium serum levels of patients with PB leprosy are higher than patients with MB leprosy, and high bacteriological index in patients with leprosy were correlated with low selenium serum levels. PMID- 29610606 TI - Thyroid Function and 25 (OH) Vitamin D Level among Sudanese Women in Early Pregnancy. AB - AIM: A cross-sectional study was conducted at Saad Abualila Hospital (Khartoum, Sudan) to evaluate the vitamin D levels and thyroid function among pregnant Sudanese women (132) in early pregnancy. METHODS: A cross-sectional study was conducted at Saad Abualila hospital (Khartoum, Sudan) during the period from March to July 2015. Women who were in early pregnancy with a singleton pregnancy were approached to participate in the study after signing informed consent. A sample size of 132 participants was calculated guided by the normal interval of thyroid function in Sudanese women in the first trimester and not the level of 25(OH) vitamin D. The 25 - hydroxyvitamin D (25 (OH) vitamins levels were measured using an electrochemiluminescence immunoassay on an Elecsys 2010 Analyzer (Roche Diagnostics, Mannheim, Germany). RESULTS: The mean (SD) of age, gravidity and gestational age was 27.6 (5.5) years, 2.2 (1.6) and 10.4 (2.2) weeks, respectively. The mean (SD) of the body mass index (BMI) and haemoglobin was 27.1 (5.2) kg/m2 and 10.8 (1.1) g/dl, respectively. Median (interquartile) values of TSH, FT3, and FT4 were 1.164 IU/ml (0.079 -2.177 IU/ml), 4.639 nmol/l (3.843 - 6.562 nmol/l), and 16.86 pmol/l (13.02 - 31.48 pmol/l), respectively. There was no significant correlation between vitamin D levels and TSH, FT3 and FT4. CONCLUSION: There is no correlation between 25 (OH) vitamin D levels and thyroid function during early pregnancy among Sudanese pregnant women, despite prevalent vitamin D deficiency among these women. PMID- 29610607 TI - Physiotherapy Effects in Gait Speed in Patients with Knee Osteoarthritis. AB - BACKGROUND: Knee osteoarthritis is a chronic degenerative disease, known as the most common cause of difficulty walking in older adults and subsequently is associated with slow walking. Also one of the main symptoms is a degenerative and mechanics type of pain. Pain is very noticeable while walking in rugged terrain, during ascent and descent of stairs, when changing from sitting to standing position as well as staying in one position for a long time. Many studies have shown that the strength of the quadriceps femoris muscle can affect gait, by improving or weakening it. Kinesio Tape is a physiotherapeutic technique, which reduces pain and increases muscular strength by irritating the skin receptors. AIM: The aims of this study was first to verify if the application of Kinesio Tape on quadriceps femoris muscle increases gait speed in patients with knee osteoarthritis and secondly if applying Kinesio Tape on quadriceps femoris muscle reduces pain while walking. METHOD: Seventy-four patients with primary knee osteoarthritis, aged 50 - 73 years, participated in this study. Firstly we observed the change of gait speed, while walking for 10 meters at normal speed for each patient, before, one day and three days after the application of Kinesio Tape on quadriceps femoris muscle, with the help of the 10 - meter walk test. Secondly, we observed the change of pain, while walking for 10 meters at normal speed for each patient, before, one day and three days after the application, with the help of Numerical Pain Rating Scale - NRS. RESULTS: Our results indicated that there was a significant increase in gait speed while walking for 10 meters one day and also three days after application of Kinesio Tape on quadriceps femoris muscle. Also, there was a significant reduction of pain level 1 and 3 days after application of Kinesio Tape, compared to the level of pain before its application. CONCLUSIONS: Our results indicated that there was a significant decrease in pain and increase of gait speed while walking for 10 meters. Kinesio Tape can be used in patients with knee osteoarthritis, especially when changing walking stereotypes is a long-term goal of the treatment. PMID- 29610609 TI - The Outcome of Using a Jamshidi Biopsy Trocar Needle in a Novel Technique for Bone Grafting in Percutaneous Internal Fixation of Scaphoid Non-Union. AB - INTRODUCTION: We report the outcome of using a novel technique of minimally invasive internal fixation and distal radius bone grafting using the Jamishidi Trephine needle and biopsy/graft capture device. METHODS: The technique utilises a 8 mm incision at the distal pole of the scaphoid. The non-union is excavated using the standard Acutrak drill. An 8 gauge Jamshidi trephine needle is used to harvest bone graft from the distal radius which is impacted into the scaphoid and fixed with an Acutrak screw. Fifteen patients were available for retrospective review, 14 male, age mean 29.5 (15-56). Average time from injury to surgery was 167 days (45-72). Fractures classified according to Herbert giving 7 D1 and 8 D2 fractures, 14 waist and 1 proximal pole fractures, all of which had no humpback deformity. RESULTS: Sixty-six percentages of the fractures went onto unite, 4/7 D1 and 6/8 D2 united (p > 0.05). Seventy-five percentages of fracture that had surgery in less than 3 months from time of injury went onto unite, whereas only 63% united in patients who had surgery later than 3 months (p > 0.05). DASH outcome for all patients improved from 86 down to 32 (p < 0.05). With those that united going down from 90 to 6. Those that did not unite went from 81 to 61. CONCLUSION: The Jamshidi bone grafting technique shows comparable results (union rate 66%) to other techniques published in the literature (27-100%) providing the surgeon with an alternative and less demanding procedure than open scaphoid non union surgery. PMID- 29610608 TI - Pharmacotherapy Evaluation and Utilization in Coronary Artery Bypass Grafting Patients in Kosovo during the Period 2016-2017. AB - BACKGROUND: Coronary Artery Bypass Grafting (CABG) is realised in patients with critical or advanced disease of coronary arteries. There are different pharmacotherapeutic approaches which are used as management, treatment and preventive therapy in cardiovascular disease or related comorbidities. Performing a successful surgery, pharmacotherapy, and increase of bypass patency rate remains a serious challenge. AIM: This study aims to analyse the patient characteristics undergoing CABG and evaluation of their drug utilisation rate and daily dosages in the perioperative period. MATERIAL AND METHODS: Data were collected from 102 patients in the period 2016-2017 and detailed therapeutic prescription and dosages, patient characteristics were analysed before the operation, after the operation and visit after operation in the Clinic of Cardiac surgery-University Clinical Center of Kosovo. RESULTS: Our findings had shown that patients provided to have normal biochemical parameters in the clinic before the operation, and were related to cardiovascular diseases and comorbidities and risk factors with mainly elective intervention. The, however, higher utilisation of cardiovascular drugs such as beta blockers, diuretics, anticoagulants, statins and lower calcium blockers, ACEi, ARBs, hydrochlorothiazide, amiodarone were founded. ARBs, beta blockers, statins, nitrates and nadroparin utilisation decreased after operation and visit after the operation, whereas amiodarone only in the visit after the operation. Diuretics are increased after the operation which decreases in the visit after the operation. Regarding the daily dosage, only metoprolol was increased in the visit after operation (P < 0.001) and visit after operation (P < 0.05) whereas losartan and furosemide were increased (P < 0.01) and (P < 0.05) respectively. CONCLUSION: The study showed that beta blockers, statins, aspirin, nitrates (before the operation), furosemide and spironolactone are the most utilised drugs. However, we found low utilisation rate for ACEi, ARBs, clopidogrel, nadroparin, warfarin, xanthines, amiodarone, calcium blockers. Daily dosages were different compared to before CABG only in metoprolol, losartan, and furosemide. PMID- 29610610 TI - Metabolic Profiles in Obese Children and Adolescents with Insulin Resistance. AB - BACKGROUND: In the past several decades, the increasing frequency of overweight and obese children and adolescents in the world has become a public health problem. It has contributed significantly to the already high tide of diabetes, cardiovascular and cerebrovascular diseases. AIM: To investigate the frequency of insulin resistance and to evaluate the metabolic profile of insulin resistant and non-insulin resistant obese children and adolescents. SUBJECTS AND METHODS: The study included 96 (45 boys, 51 girls) obese children and adolescents aged 4-17 years old (10.50 +/- 2.87 years). Only participants with Body Mass Index >= 95 percentile were included. We analysed sera for fasting insulin levels (FI), fasting serum triglycerides (TG), total serum cholesterol (TC), fasting plasma glucose (FPG) and plasma glucose 2 hours after the performance of the oral glucose tolerance test (2-h G). Homeostatic model assessment for insulin resistance (HOMA-IR) index was calculated as fasting insulin concentration (microunits per millilitre) x fasting glucose concentration (millimolar)/22.5. The value of HOMA-IR above 3.16 was used as a cut-off value for both genders. RESULTS: Insulin resistance was determined in 58.33% of study participants. Insulin resistant participants had significantly higher level of 2-h G (p = 0.02), FI level (p = 0.000) as well as TG levels (p = 0.01), compared to non insulin resistant group. Strikingly, 70.73% of the pubertal adolescents were insulin resistant in comparison to 49.09% of the preadolescents (p = 0.03). Significantly higher percentage of insulin-resistant participants were girls (p = 0.009). Moreover, a higher percentage of the girls (70.59%) than boys (44.44%) had HOMA-IR above 3.16 and had elevated FI levels (70.59% vs 48.89%). The difference in the frequency of insulin resistance among obese versus severely obese children and adolescents was not significant (p = 0.73, p > 0.05). Our study results also showed positive, but weak, correlation of HOMA-IR with age, FPG, TG and BMI of the participants (p < 0.05). CONCLUSION: Higher percentage of insulin-resistant participants was of female gender and was adolescents. In general, insulin resistant obese children and adolescents tend to have a worse metabolic profile in comparison to individuals without insulin resistance. It is of note that the highest insulin resistance was also linked with the highest concentrations of triglycerides. PMID- 29610611 TI - Acupuncture Treatment of Subfertility and Ovarian Endometrioma. AB - BACKGROUND: Ovarian endometriotic cysts, also known as 'chocolate' cysts or ovarian endometriomas, appear as endometrial tissue outside the uterine cavity which grows inside ovaries. Endometriotic cysts can cause chronic pelvic pain, dysmenorrhea, dyspareunia, impairment of ovarian function in regards to subfertility, etc. Traditional Chinese Medicine (TCM) is effectively treating subfertility associated with endometriosis for years, and the treatment gives positive results in achieving pregnancy. With the acupuncture treatment, blood circulation is promoted, external physical factors - eliminated, the stasis is dissolved, the menstrual cycle is regulated, and inflammation is diminished. CASE REPORT: Our treated patient is 29-year-old woman diagnosed with ovarian endometrioma, slightly - elevated prolactin levels and inability to get pregnant after trying for two years. Ningteen acupuncture treatments were done on the meridians of Pericardium, Spleen, Stomach, Liver, Ren Mai, Kidney, Large intestine, Du Mai and Bladder. After the acupuncture treatments, the endometrioma was decreased in size and the patient got pregnant spontaneously in a short period. CONCLUSION: Acupuncture, as part of the TCM, gives positive results and can successfully add up to variety of non - surgical infertility treatment options in women with endometrioma(s). PMID- 29610612 TI - The Effectiveness of Radial Extracorporeal Shock Wave Therapy for Chronic Achilles Tendinopathy: A Case Report with 18 Months Follow-Up. AB - BACKGROUND: Achilles tendinopathy (AT) is a pathological state resulting from repetitive loading or stress on the tendon. The article aims to evaluate the effects of the low - energy radial extracorporeal shockwave therapy (RESWT) in the treatment of the adult with chronic insertional Achilles tendinopathy (AT) after the unsuccessful conservative treatment, with 18 months follow - up evaluation. CASE REPORT: We report the case of a 55 years - old male suffering from severe right posterior heel pain for 4 months. For his chronic insertional Achilles tendinopathy on the right heel, he received conservative treatment in the Institute of Physical Medicine and Rehabilitation. For outcome assessment, Numerical Rating Scale (NRS) for pain, the range of motion in the ankle, and Roles-Maudsley Score (RMS) for assessment of function were used. At the baseline the pain was severe, and he received physical therapy treatment. After unsuccessful conservative treatment, he underwent RESWT treatment. Numeric Rating Scale was significantly decreased at immediate, short-term and long-term follow up. After the last treatment, the patient had no pain, and function assessed by Roles-Maudsley Score was excellent. At the follow-up check-up at 3, 6, 12 and 18 months the patient had no pain and excellent functional results. CONCLUSION: Radial ESWT is a safe and effective treatment even for a longer period for patients with chronic insertional Achilles tendinopathy. PMID- 29610613 TI - Microperforated Hymen Presenting Spontaneous Pregnancy with Cesarean Delivery and Hymenotomy Surgery: A Case Report. AB - BACKGROUND: Female genital tract anomalies including imperforate hymen affect sexual life and fertility. CASE PRESENTATION: In the present case, we describe a pregnant woman diagnosed with imperforate hymen which never had penetrative vaginal sex. A 27-year-old married patient with 2 months of amenorrhea presented in a clinic without any other complications. Her history of difficult intercourse and prolonged menstrual flow were reported, and subsequent vaginal examination confirmed the diagnosis of imperforate hymen even though she claims to made pinhole surgery in hymen during puberty. Her urine pregnancy test was positive, and an ultrasound examination revealed 8.3 weeks pregnant. The pregnancy was followed up to 39.5 weeks when she entered in cesarean delivery in urgency. Due to perioperative complications in our study, a concomitant hymenotomy was successfully performed. The patient was discharged with the baby, and vaginal anatomy was restored. CONCLUSIONS: This case study suggests that even though as microperforated hymen surgery in puberty can permit pregnancy and intervention with cesarean section and hymenotomy is a good option to reduce the resulting perioperative complications which indirectly affect the increase of the fertilisation and improvement of later sexual life. PMID- 29610614 TI - Topical Imiquimod 5% as a Treatment Option in Solitary Facial Keratoacanthoma. AB - BACKGROUND: Keratoacanthoma (KA) is a rapidly growing epithelial tumour with histopathologic and clinical features similar to squamous cell carcinoma (SCC) and a certain tendency toward spontaneous regression. CASE PRESENTATION: This article presents a unique and rare case of keratoacanthoma arising from the upper lip of a young male patient. These two features are in contrast to most of the reported cases in elder male individuals and on the lower lip. Relevant management protocol of the case has also been discussed. CONCLUSION: The article emphasises the significance of discerning such lesions from squamous cell carcinoma thus carrying diagnostic and therapeutic implications. However, in case of the dilemma it is prudent to assume that the lesion is SCC unless proved otherwise clinically and histologically. PMID- 29610615 TI - Surgical Management of Facial Features of Robinow Syndrome: A Case Report. AB - BACKGROUND: Robinow Syndrome is an extremely rare genetic disorder characterised by abnormalities in head, face and external genitalia. This disorder exists in dominant pattern with moderate symptoms and recessive pattern with more physical and skeletal abnormalities. It was first introduced by Menihard Robinow in 1969. It was related to chromosome 9q22 ROR2 gene related to bone and cartilage growth aspects. CASE PRESENTATION: A 17-year-old Egyptian male presented to National Research Centre Orodental genetics Clinic with typical features of short stature and facial dysmorphism weighted 50 Kg and measured 150 cm height complaining of facial dis figurement. There was no significant prenatal history, and family history was negative for congenital disabilities and genetic disorders. Clinical examination revealed macrocephaly and special facial features as prominent forehead, deformed ear pinna, hypertelorism, flat nasal tongue tie, deficient malar bone, bow-shaped upper and lower lips and dimpled chin. Orally the patient suffered from tonetie, gingival hypertrophy and dental malalignment. The orthopantomogram showed multiple impacted teeth. The physical examination revealed that the patient had deformed spine, short limbs with ectrodactyly, micropenis & hypospadias. Surgical management included correction of midface deficiency with zygomatic augmentation, closed rhinoplasty for the broad nose, lips muscles release and tongue tie relief. The patient is currently undergoing orthodontic treatment for his teeth. CONCLUSION: Improvement of facial features and a good psychological impact on the patient and his family. PMID- 29610616 TI - Ovarian Strumal Carcinoid Tumour: Case Report. AB - BACKGROUND: Ovarian strumal carcinoid is a germ cell tumour characterised by a mixture of thyroid tissue and carcinoid. Ovarian struma is a very rare occurrence with 0.3-1% incidence of all ovarian tumours and 3% of mature teratomas. Primary carcinoid ovarian tumours are still uncommon as a part of mature teratoma or mucinous cystadenoma. There are four major variants of a carcinoid tumour: insular, trabecular, strumal and mucinous. A strumal carcinoid is an unusual form of ovarian teratoma composed of an intimate admixture of thyroid/carcinoid tissues. CASE REPORT: This is a case report of a 59-year old woman with a 5-year clinical history of perimenopausal uterine bleeding and three explorative curettages. Gynaecological and ultrasound examinations revealed ovarian enlargement with a diameter of 50 mm with hypoechoic zones suspected of benign teratoma. The diagnostic test such as Ca-125, AFP, free-T4 and TSH was in normal range. A smooth, solid right ovarian 50 an mm-size tumour, as well as small amount of fluid in the Douglas pouch, was found during the total abdominal hysterectomy, bilateral salpingo-oophorectomy and staging biopsy. The histopathology revealed teratoma with strumal carcinoid tumour IA stage according to AJCC 2010 of the right ovary and negative cytopathology of the fluid from the Douglas pouch. On the postoperative 2-year control, the patient was tumour free, and Ca-125, free-T4 and TSH were in normal range. CONCLUSION: We would like to point out those specific diagnostic tools, such as ultrasound and Ca-125 have low specificity and sensitivity in detection of this rare ovarian malignancy. PMID- 29610617 TI - Rathke's Cleft Cyst or Pituitary Apoplexy: A Case Report and Literature Review. AB - BACKGROUND: During the examination of the sellar region by magnetic resonance imaging, hyperintensity in T1 weighted is a common finding. This signal intensity has different sources, and its significance depends on the clinical context. Pathologic variations in T1 signal hyperintensity may be related to clotting of blood (pituitary apoplexy) or the presence of a high concentration of protein (Rathke cleft cyst). The purpose of this study is to describe the significance of intracystic nodule, a diagnostic characteristic found in Rathke's cleft cyst, on MRI. CASE REPORT: We will present the case of a 20-year-old girl which referral to our hospital for head examination with magnetic resonance imaging because she has a post-traumatic headache. Pathological findings presented in T1-weighted hyperintensity intrasellar which persist even in T1 weighted-Fat suppression. These changes signal the presence of methemoglobin imposes. The patient is a referral to laboratory tests which result in rate except for slight value increase of prolactin. Recommended controller examination after a month but finding the same results which exclude the presence of methemoglobin. CONCLUSION: Morphological characteristics and signal intensity can impose the presence of high concentration of protein (Rathke cleft cyst). PMID- 29610618 TI - Effect of Luting Cements On the Bond Strength to Turkom-Cera All-Ceramic Material. AB - BACKGROUND: The selection of the appropriate luting cement is a key factor for achieving a strong bond between prepared teeth and dental restorations. AIM: To evaluate the shear bond strength of Zinc phosphate cement Elite, glass ionomer cement Fuji I, resin-modified glass ionomer cement Fuji Plus and resin luting cement Panavia-F to Turkom-Cera all-ceramic material. MATERIALS AND METHODS: Turkom-Cera was used to form discs 10mm in diameter and 3 mm in thickness (n = 40). The ceramic discs were wet ground, air - particle abraded with 50 - MUm aluminium oxide particles and randomly divided into four groups (n = 10). The luting cement was bonded to Turkom-Cera discs as per manufacturer instructions. The shear bond strengths were determined using the universal testing machine at a crosshead speed of 0.5 mm/min. The data were analysed using the tests One Way ANOVA, the nonparametric Kruskal - Wallis test and Mann - Whitney Post hoc test. RESULTS: The shear bond strength of the Elite, Fuji I, Fuji Plus and Panavia F groups were: 0.92 +/- 0.42, 2.04 +/- 0.78, 4.37 +/- 1.18, and 16.42 +/- 3.38 MPa, respectively. There was the statistically significant difference between the four luting cement tested (p < 0.05). CONCLUSION: the phosphate-containing resin cement Panavia-F exhibited shear bond strength value significantly higher than all materials tested. PMID- 29610619 TI - Prevalence of Plaque-Induced Gingivitis in a Sample of the Adult Egyptian Population. AB - AIM: The aim of this cross-sectional study is recording the prevalence and evaluation of the severity of plaque-induced gingival inflammation among a sample of the adult Egyptian population. PATIENTS AND METHODS: Four hundred and twenty five subjects in this contemplate were seen from patients visiting the diagnostic clinic at the Faculty of Dentistry, Cairo University. The gingival and plaque indices for each patient diagnosed as having plaque-induced gingivitis were recorded. The pocket depth was also measured. RESULTS: The incidence of gingivitis was 100% amid adult subjects with an age range between 18-45 years. The average plaque index (PI) was 1.05 +/- 0.43, which reflects relatively superior plaque control of the participants. The mean gingival index (GI) was 1.66 +/- 0.40, which reflects the presence of moderate gingival inflammation. PD mean values confirmed limitation of inflammation to the gingiva. The sex was correlated to the condition of the inflamed gingiva (p = 0.014) and the quantity of biofilm build-up (p = 0.003). Females were less affected than males (p = 0.005). CONCLUSION: The outcomes of this contemplate demonstrated that biofilm build-up is stoutly accompanied with elevated incidence of modest to rigorous gingivitis amid adult Egyptian individuals. PMID- 29610620 TI - Evaluation of Maximum Bite Force in Patients with Complete Dentures. AB - OBJECTIVE: This study aimed to evaluate maximum bite forces (mBF) in dominant (DS) and non-dominant sides (NDS) at certain time periods after the insertion of new complete dentures based on prior experience and gender. MATERIALS AND METHODS: A total of 88 patients, complete denture wearers (CDWs), were examined. The maximum bite force at the intercuspal position between the first molars in 3 seconds was registered and recorded with piezoelectric gnathodynamometer. The procedure was repeated 3 times in identical conditions, with relaxation intervals of 1 minute between repeats and the limiting factor was the subjective feeling of pain. Testing of parametric data was performed with One Way Repeated Measurement of ANOVA test. RESULTS: The average mBF values increased during the observational period, both on the DS and NDS, with significant difference in DS, which was greater. The analysis of one-factor variance showed that there were differences of average mBF values in DS and NDS during six consecutive measurements (mBF-DS = 11.3, p = 0.0001, and mBF-NDS = 2.26, p = 0.047). Significant changes in the masticatory force (mBF) on the DS and NDS is explained by different measurement times and with the prior experience with complete dentures, BF-DS = 11.76, p = 0.0000; mBF-NDS = 2.42, p = 0.0351; mBFe-DS = 40.48; P = 0.0000 mBFe-NDS = 39.93, p = 0.0000. CONCLUSION: mBF represents a significant discriminating variable of the level of functional adaptation of new complete denture wearers (nCDWs) about the initial measurements. PMID- 29610621 TI - Therapeutic Challenge in a Severely Atrophic Mandible. AB - BACKGROUND: After tooth loss, however, severely atrophic residual alveolar ridges are fairly common, especially in patients who have been edentulous for a long period. Anterior area of the mandible is areas where clinicians have greater anatomical limitations. Reduced alveolar bone height very often represents a contraindication to implant therapy, unless a procedure such as a ridge augmentation is performed. CASE REPORT: This study aims to present two separate cases in highly selected edentulous anterior mandibular sites, where one stage, mini implants were used to support total prostheses. Small diameter implants have been used for retention of complete removable mandibular overdentures. This is an excellent option for those who suffer from the inconvenience and embarrassment of loose lower dentures and are tired of having to use sticky pastes and creams to make their dentures stay in place. CONCLUSION: Small diameter implants, when used multiples may offer adequate support for a removable prosthesis and overcome this problem. PMID- 29610622 TI - Acid Etching as Surface Treatment Method for Luting of Glass-Ceramic Restorations, part 1: Acids, Application Protocol and Etching Effectiveness. AB - AIM: The purpose of this review is to represent acids that can be used as surface etchant before adhesive luting of ceramic restorations, placement of orthodontic brackets or repair of chipped porcelain restorations. Chemical reactions, application protocol, and etching effect are presented as well. STUDY SELECTION: Available scientific articles published in PubMed and Scopus literature databases, scientific reports and manufacturers' instructions and product information from internet websites, written in English, using following search terms: "acid etching, ceramic surface treatment, hydrofluoric acid, acidulated phosphate fluoride, ammonium hydrogen bifluoride", have been reviewed. RESULTS: There are several acids with fluoride ion in their composition that can be used as ceramic surface etchants. The etching effect depends on the acid type and its concentration, etching time, as well as ceramic type. The most effective etching pattern is achieved when using hydrofluoric acid; the numerous micropores and channels of different sizes, honeycomb-like appearance, extruded crystals or scattered irregular ceramic particles, depending on the ceramic type, have been detected on the etched surfaces. CONCLUSION: Acid etching of the bonding surface of glass - ceramic restorations is considered as the most effective treatment method that provides a reliable bond with composite cement. Selective removing of the glassy matrix of silicate ceramics results in a micromorphological three dimensional porous surface that allows micromechanical interlocking of the luting composite. PMID- 29610623 TI - Diabetics Retinopathy Knowledge and Awareness Assessment among the Type 2 Diabetics. AB - INTRODUCTION: Diabetic retinopathy (DR) is a leading cause of blindness worldwide. In Saudi Arabia and other Arab countries, several studies estimated the prevalence of DR ranging from 30 - 40%. AIM: To assess the DR knowledge and its association with diabetes control among Type 2 diabetic patients. METHODS: A cross-sectional study of patients with Type II diabetes (T2D) who had a routine visit to the endocrine clinic to assess the DR knowledge and its relation to the glycemic control. We used a questionnaire that was used in previously published studies, and the reliability was assessed using the alpha Cronbach coefficient. Patients who answered correctly > 60% were considered to have good knowledge about DR. RESULTS: Total of 253 patients participated, 43.4% has diabetes > 10 years and 30.7% have it for 5 - 10 years, 36.4% did college degree or higher, 40.8% considered having low income. 37.7% of participants were not screened for the DR in the past year. 28.4% of participants think that seeing optometrist is enough for DR diagnosis. Diabetics with good knowledge who have T2D > 10 years were 46.3% compared to 38.6% (p = 0.04). Diabetics with good knowledge have mean A1c of 8.55 vs. 8.59 (p = 0.32), mean BMI 30.4 vs. 30.2 (p = 0.46), mean diastolic pressure was 77.12% vs. 79.48% (p = 0.03). CONCLUSION: Almost two thirds of screened T2D were considered to have good knowledge about DR. The good knowledge group tends to have a longer duration of T2D, more likely to have a college degree, and tend to have non -significantly better A1c control. PMID- 29610624 TI - Dyspnea in Children as a Symptom of Acute Respiratory Tract Infections and Antibiotic Prescribing. AB - BACKGROUND: Dyspnea is an unpleasant feeling of breathing difficulty, shortness of breath and inability to satisfy the hunger for air. The role of family physicians is to be prepared to recognise dyspnea as a symptom of acute respiratory infections (ARI), to perform triage and managing of children with acute dyspnea and make continuous education of parents. In the treatment of acute dyspnea more important is to treat dyspnea as a symptom than the prescribing of antibiotics (AB). Nowadays, even more often large amount of children, because of the noncompliance in the treatment and the pressure from the parents, unnecessary is hospitalised and frequently used antibiotics: According to the guidelines, a small percentage of children with ARI should be treated with AB. The rate of antibiotic prescription should be around 15-20% and lower. AIM: To assess doctor's AB prescriptions in Primary care practices in Macedonia, for ARI and dyspnea in children we use the data from a National project about antibiotic prescribing for acute respiratory tract infections, which has been run in 2014 November as a part of E - quality program. METHODS: Eighty-six general practitioners from Macedonia have taken participation in it. The group of 3026 children, from 0-5 years of age, with symptoms of dyspnea, was analysed. We have found a rate of 54.6% antibiotic prescriptions (AB). From 3026 children with dyspnea, AB got 1519 children, 852 of which were prescribed by a specialist. RESULTS: The children were mostly diagnosed with upper ARI, in 57.7%. The most used AB is amoxicillin + clavulonic acid. We concluded that there was an increased and inappropriate prescribing of antibiotics in children with ARI, presented with dyspnea in Macedonia. CONCLUSION: Perceptions and the parent's attitudes do not correlate with the severity of clinical picture of the disease in children and lack of use Evidence-based medicine (EBM), insecurity, fear, loss of patients effect on antibiotic prescribing of the doctors. PMID- 29610625 TI - Body Weight Concern and Belief among Adolescent Egyptian Girls. AB - BACKGROUND: Body weight concern and belief in adolescent females are of great importance. They are the keys to successful dietary interventions including dietary habits' modifications to practice a healthy diet. This critical phase of transition from childhood to adulthood is the most sensitive stage of behavioural rectification. AIM: This study was conducted with the aim to figure out the prevalence of body image dissatisfaction and the association of body image satisfaction and believe with body mass index in adolescent girls aged 16-18 years. MATERIAL AND METHODS: Two hundred and three Egyptian adolescent females were enrolled in this cross-sectional study. Their mean age was (17.4 +/- 0.64) years old. Self-administered questionnaires about the students' body satisfaction and weight belief were answered by the candidates. Their body mass index was calculated. Also, sociodemographic data were collected. Data were analysed using SPSS software version 16.0. Chi-square test was conducted for the variables. RESULTS: Sixty-eight percent of the students were within normal weight, 3.3% were underweight, while 18.2% and 10.5% were overweight and obese respectively. Body dissatisfaction was prevalent among 37.4%. The prevalence of body dissatisfaction was higher in both obese and underweight candidates reaching (93.8% and 80%) respectively. This reflects students' awareness of their body shape. CONCLUSION: More than one-third of adolescent females were dissatisfied with their body image. The subjective belief about self-body image matched the objective Body Mass Index measurements. PMID- 29610626 TI - Knowledge and Awareness of Medical Practitioners of Jazan City towards Oral and Maxillofacial Surgery as a Specialty. AB - BACKGROUND: In many health services communities the scope of oral and maxillofacial surgery (OMFS) as a discipline is frequently not probably understood. Good awareness towards OMFS among different branches of health services providers is essential for better referral strategies and will be for the benefit of the patient. MATERIALS AND METHODS: The cross-sectional study was done using a specially prepared questionnaire distributed randomly to 125 general medical practitioners working in Jazan province. In this questionnaire, there were also some close-ended questions to evaluate awareness regarding a variety of conditions treated by the oral and maxillofacial surgeons. RESULTS: Out of 125 participants, 105 (84%) were aware of the oral and maxillofacial surgery as a speciality branch of dentistry. Only 52 (41.6%) participants were aware of the different treatment modalities coming under the scope of oral and maxillofacial surgery. Also in the referral of cases to the oral and maxillofacial surgeon, 50 (40%) participants referred their oral and maxillofacial region cases to OMS. Tooth removal was the only procedure where most of the medical practitioners knew it is a speciality procedure of the oral and maxillofacial surgeon. For facial fractures, 76 medical practitioners believe it comes under the scope of the orthopaedic surgeon. Similarly, for facial abscesses, 81 and 36 practitioners responded that it is a job of a general surgeon and OMS respectively. CONCLUSION: There is low awareness toward the scope of oral and maxillofacial surgery in the medical community. Knowledge and awareness of the scope of oral and maxillofacial surgery can improve the success and promptness of delivery of health services. PMID- 29610627 TI - Colloidal Au Catalyst Preparation: Selective Removal of Polyvinylpyrrolidone from Active Au Sites. AB - Colloids with controlled dimensions, morphology and composition can be used to obtain supported metal catalysts with desired characteristics. Yet, removal of capping agents which block active metal sites in such catalysts can be challenging: mild methods often result in incomplete removal of capping agents, whereas harsher methods can cause change in particle size or morphology or cause metal segregation for bimetallic particles. Here we provide evidence that polyvinylpyrrolidone used as a stabilizing agent for gold colloids is present both on the metal and the support surface after colloid deposition on the TiO2 support. The polymer adsorbed on Au sites blocks their catalytic activity if it cannot be desorbed/decomposed under reaction conditions. Polyvinylpyrrolidone can be removed completely from the active gold surface of Au/TiO2 without particle growth using a number of mild treatment methods described in this work, despite only partial removal (~45 %) of the stabilizer from the bulk of Au/TiO2 can be achieved. The remaining >50 % of polyvinylpyrrolidone resides exclusively on the TiO2 support and has no effect on the optical properties and catalytic activity of gold nanoparticles. The treated catalysts demonstrate catalytic activity and selectivity similar to those of a catalyst prepared by impregnation. These findings are important for further advancing the preparation of well-defined supported catalysts using metal colloids. PMID- 29610628 TI - Selective Catalytic Oxidation of Cyclohexene with Molecular Oxygen: Radical Versus Nonradical Pathways. AB - We study the allylic oxidation of cyclohexene with O2 under mild conditions in the presence of transition-metal catalysts. The catalysts comprise nanometric metal oxide particles supported on porous N-doped carbons (M/N:C, M=V, Cr, Fe, Co, Ni, Cu, Nb, Mo, W). Most of these metal oxides give only moderate conversions, and the majority of the products are over-oxidation products. Co/N:C and Cu/N:C, however, give 70-80 % conversion and 40-50 % selectivity to the ketone product, cyclohexene-2-one. Control experiments in which we used free radical scavengers show that the oxidation follows the expected free-radical pathway in almost all cases. Surprisingly, the catalytic cycle in the presence of Cu/N:C does not involve free-radical species in solution. Optimisation of this catalyst gives >85 % conversion with >60 % selectivity to the allylic ketone at 70 degrees C and 10 bar O2. We used SEM, X-ray photoelectron spectroscopy and XRD to show that the active particles have a cupric oxide/cuprous oxide core shell structure, giving a high turnover frequency of approximately 1500 h-1. We attribute the high performance of this Cu/N:C catalyst to a facile surface reaction between adsorbed cyclohexenyl hydroperoxide molecules and activated oxygen species. PMID- 29610629 TI - Digital Clubbing Is Associated with Higher Serum KL-6 Levels and Lower Pulmonary Function in Patients with Interstitial Lung Disease. AB - Background: Although digital clubbing is a common presentation in patients with interstitial lung disease (ILD), little has been reported regarding its role in assessing patients with ILD. This study evaluated patients with ILD for the presence of clubbing and investigated its association with clinical data. Methods: We evaluated patients with ILD who visited the teaching hospital at which the study was conducted, between October 2014 and January 2015. Clubbing, evaluated using a Vernier caliper for individual patients, was defined as a phalangeal depth ratio > 1. We examined the association of clubbing with clinical data. Results: Of 102 patients with ILD, we identified 17 (16.7%) with clubbing. The partial pressure of oxygen in arterial blood was lower (65.2 +/- 5.9 mmHg versus 80.2 +/- 3.1 mmHg; p=0.03), serum Krebs von den Lugen-6 (KL-6) levels were higher (1495.0 +/- 277.4 U/mL versus 839.1 +/- 70.2 U/mL; p=0.001), and the percent predicted diffusing capacity of carbon monoxide was lower (50.0 +/- 6.0 versus 73.5 +/- 3.1; p=0.002) in these patients with clubbing. Conclusions: Patients with clubbing had lower oxygen levels, higher serum KL-6 levels, and lower pulmonary function than those without clubbing. PMID- 29610630 TI - Feasibility and Safety of Pleuroscopic Cryobiopsy of the Pleura: A Prospective Study. AB - Background: The aim of this study was thus to evaluate the feasibility and safety of taking biopsy specimens by cryoprobe from the parietal pleura during semirigid pleuroscope. Methods: In a single-center, observational, prospective study, patients with exudative pleural effusion (EPE) were evaluated with a semirigid pleuroscope between January 2015 and July 2017. Each patient underwent pleural biopsy using flexible forceps and flexible cryoprobe through pleuroscope following diagnostic thoracentesis and closed pleural biopsy (CPB). Results: A total of 92 patients (median age 64 years) were included in the study, most of whom were men (65.2%). Cytological cell block (CCB) and CPB made definitive diagnoses in 32/92 (34.8%) and 25/92 (27.5%), respectively; flexible forceps biopsy (FFB) and cryoprobe biopsy (CB) established definitive diagnoses in 84/92 (91.3%) and 91/92 (98.9%), respectively. The sample obtained by CB (9.4 +/- 4.9 mm) was significantly larger than the other two methods: FFB (4.2 +/- 2.3 mm) or CPB (1.9 +/- 1.0 mm) (P < 0.0001). The immunohistochemical (IHC) staining was more easily performed with CB (98.9%) compared to either FFB (87.0%) or CPB (13.0%). There were no significant complications or procedure-related deaths. Conclusions: Based on these results, CB during semirigid pleuroscope has a high diagnostic yield, differentiating EPE of unknown etiology with satisfactory effectiveness and safety. PMID- 29610631 TI - The Effect of Propofol on Chronic Headaches in Patients Undergoing Endoscopy. AB - Objective: This study determined acute and long-term effects of propofol administration in patients with severe headaches undergoing endoscopic procedures. Background: Approximately 13% of the US population is affected by migraines or severe headaches. The effect of propofol on headaches more than a few days after the intervention has not been explored. Methods: We employed a nonrandomized, prospective observational study that recruited patients with chronic headaches who received propofol from an outpatient endoscopy center for either upper or lower endoscopies. Patients completed the six-item Headache Impact Test (HIT-6) questionnaire prior to the procedure and 30 days after endoscopy. Additionally, the patients' response to propofol two days after endoscopy was assessed via phone. Results: The age of the participants (n=31) ranged from 20 to 70 years. The mean HIT-6 composite scores were significantly lower (p < 0.05) 30 days after propofol administration when compared to baseline scores. Upon stratification, 23 patients indicated an improved condition, 7 a worsened outcome, and 1 showed no change. Furthermore, mean scores were significantly lower (p < 0.05) in three HIT-6 questions pertaining to the severity of pain, daily activity, and frequency of lying down. Finally, the mean pain score obtained was significantly lower (p < 0.05) two days after procedure. Conclusions: The results of this suggest that propofol administration should be considered in treating chronic headaches. Double-blind studies are necessary to confirm these results. PMID- 29610632 TI - [Retroperitoneal fibrosis: about 12 cases]. AB - Retroperitoneal fibrosis (RPF) is rare. It is characterized by the gradual transformation of retroperitoneal adipose tissue into a fibrous mass surrounding the aorta, the inferior vena cava and the urinary tract responsible for progressive alteration in the renal function. It usually manifests as lumbar pain associated with renal failure and biologic inflammatory syndrome. We report 12 cases of retroperitoneal fibrosis in order to determine its clinical, radiological and therapeutic features. We conducted a retrospective study of 12 patients with retroperitoneal fibrosis whose medical data were collected in the Departement of Urology at the University Hospital Hassan II, Fes over a period of 9 years (2005-2013). The study involved ten men and two women. Clinical symptomatology was very variable, dominated by lumbar pain in all patients and hydrocele in 1 patient. Laboratory tests showed renal failure in all patients and inflammatory syndrome in 10 patients. The diagnosis of retroperitoneal fibrosis was suspected in all patients on ultrasound showing obstruction of the upper urinary tract without visible obstacle. The diagnosis was confirmed by abdominal CT scan without contrast that objectified a retroperitoneal tissue lesion enveloping the vessels and the urinary tract. Nine patients had idiopathic retroperitoneal fibrosis. Two patients had perianeurysmal fibrosis and one patient had post-radiation fibrosis. All patients underwent urinary drainage by double J. ureteral catheter. Seven patients underwent corticosteroid therapy. Six patients had an improvement of clinical and laboratory test outcome with disappearance of pain and improvement of the general condition. This study confirms the rarity of retroperitoneal fibrosis, the difficulty of diagnosis, pain associated with inflammatory syndrome and renal failure as common manifestations. Abdominal CT scan without contrast is the gold standard for definitive diagnosis. Urinary drainage is essential in most cases as well as regular monitoring of patients. PMID- 29610633 TI - Neglected tumor in a female with albinism. PMID- 29610634 TI - Giant solitary primary intracranial lymphoma masquerading as meningioma: a case and review of literature. AB - Non-Hodgkin's lymphomas (NHL) with intracranial origin are very rare and constitutes about 1-2% of primary central nervous system lymphomas (PCNSL). Diffuse large B cell lymphoma (DLBCL) is the most common subtype of NHL and mostly seen in immunocompromised patients. Therefore, the occurrence of giant solitary DLBCL in an immunocompetent patient is puzzling. We present a case of 68 year-old man who was admitted at our facility with a history of "hypomnesia of two (2) months" duration. Magnetic resonance imaging (MRI) revealed a space occupying lesion in the bilateral frontal lobe and corpus callosum measuring about 5.4cm * 4.6cm * 3.8cm with mixed signal intensities and vasogenic edema around the mass. Radiological, this mass was mistaken for meningioma until histopathological studies revealed DLBCL. Giant solitary primary intracranial lymphomas are very rare and can be mistake for meningioma even with very experience radiologist or neurosurgeon since the radiological features of PCNSL can be very unspecific. We achieved to total resection because of the giant and solitary nature of our case. The prognosis of PCNSL is general very poor when the patient is immunocompromised. In immunocompetent patients, who are well managed with surgery and chemotherapy, the overall survival and quality of life can very encouraging. PMID- 29610635 TI - Factors associated with tuberculosis treatment outcomes among tuberculosis patients attending tuberculosis treatment centres in 2016-2017 in Mogadishu, Somalia. AB - Introduction: World Health Organization (WHO) reported that tuberculosis (TB) was a major health problem and the second leading cause of mortality globally. An estimated 1.8 million TB deaths were reported in 2015. In Somalia, the average TB incidence was 274 cases per 100,000 people in 2014; prevalence was 513 per 100,000 population; and mortality rate excluding human immune deficiency virus (HIV)/TB co-infection was 64/100,000. In addition, the prevalence rates of multi drug resistant (MDR)-TB are still high, 5.2% among new cases and 40.7% for retreatment cases. The objective of this study was to determine individual and institutional level factors associated with TB treatment outcomes (TB-TOs) among patients attending TBTCs in Mogadishu. Methods: The study design was cross sectional, using quantitative and qualitative methods. Data was collected using interviewer administered semi-structured questionnaires and key in-depth interviews in 2016/2017. Qualitative data was coded using NVIVO8 and quantitative data analyzed using descriptive and inferential statistics at 95% confidence interval using SPSS20 software. Results: The study used a sample of 385 TB patients. There were 315(81.8%) successful TB-TOs. Individual level factors marital status, education level, HIV status, treatment category and knowledge on TB influenced TB-TOs (p-value < 0.05). Being married, educated, HIV-negative, new treatment case and knowledgeable on TB increased odds of successful TB-TOs (OR > 0, p value < 0.05) compared to other patients. TBTCs factors did not influence TB TOs (p-value > 0.05). Conclusion: TB-TOs were mainly affected by patient individual factors. There was need for patient education on TB management and treatment; and improved patient-health provider relationship. PMID- 29610636 TI - [Pneumoblastoma in adults: a new case report and literature review]. AB - Pulmonary blastoma is a rare tumor which has been mainly reported in children. It accounts for 0.25-0.5% of all pulmonary tumors, with a very serious prognosis. Histologically, it is a tumor composed of two components: an epithelial component and a mesenchymal component. Clinically, it usually manifests as chest pain, cough, hemoptysis and dyspnea, but it is asymptomatic in approximately 40% of cases. We report the case of a 25 year old woman, with no previous medical history, who complained of dyspnoea, cough and left basithoracic pain. Radiological evaluation showed large basithoracic mass in the left lung. A biopsy was performed which only showed necrotic material. The surgical specimen was largely necrotic. The viable tissue was examined with the miroscope which showed biphasic pattern composed of malignant epithelial tissue associated with malignant mesenchymal tissue, typical of biphasic pneumoblastoma. The patient underwent chemotherapy and radiation therapy. Follow-up examination showed a recurrence, thus the patient underwent second line chemotherapy. PMID- 29610637 TI - Evaluation of drug-drug interactions among patients with chronic kidney disease in a South-Eastern Nigeria tertiary hospital: a retrospective study. AB - Introduction: The risk of drug-drug interactions (DDIs) is high in patients with chronic kidney disease (CKD) necessitating dose adjustments or the avoidance of drug combinations. This study aimed to evaluate DDIs among patients with CKD in the University of Nigeria Teaching Hospital (UNTH), Enugu, South-East Nigeria. Methods: This study was a retrospective review of patients with CKD who received treatment at the nephrology unit of UNTH between January 2004 and December 2014. The drug-drug interactions (DDIs) of the prescribed drugs were classified using the RxList interaction checker. The IBM SPSS Version 21.0 was utilized for statistical analysis with P-value <= 0.05, considered statistically significant. Results: A total of 749 DDIs were identified from the folders of the 169 patients with CKD that were eligible. Majority were above 50 years old and in stage 4 or 5 CKD. Furosemide, lisinopril and amlodipine were the most frequently prescribed drugs and had the greatest likelihood for nephrotoxicity. The number of medications and hypertension (as co-morbidity) were significant and independent predictors of DDIs among the patients. About 70% of the drug combinations required monitoring as they fell within the "significant category" of the RxList interaction checker. The most common interactions were between lisinopril and furosemide; furosemide and calcium carbonate; lisinopril and calcium carbonate. Conclusion: The prevalence of DDIs was high among the CKD patients. Prescribers and pharmacists in Nigerian hospitals may need to pay close attention to prescriptions of patients with CKD to identify, prevent and resolve undesirable DDIs. PMID- 29610638 TI - Ethics approval: responsibilities of journal editors, authors and research ethics committees. AB - Meaningful progress of medicine depends on research that must ultimately involve human subjects. Obtaining ethical approval therefore, especially in medical sciences, should be a moral reflex for researchers. This unfortunately is not the case, with numerous researchers bypassing the ethics approval procedure, or simply unaware of its importance. Good research involves risks taken by research participants and uses tax payers' money in the process. These mandates the research endeavor to aim at attaining the highest degree of respect for the sacrifices made by others for science. Most researchers mistake scientific clearance or approval, for ethics approval. For a study to be ethical sound, it must be scientifically sound. This is only one of the activities carried out during protocol review. It is not uncommon for sensitive ethical concerns, especially in the social sciences to be overlooked and considered not to be accompanied by any serious risks for the research participants.The researcher has the responsibility of systematically consulting the competent ethics committee for advice and consequent approvals or ethical waivers. Journal editors and reviewers have the duty to systematically evaluate the ethical soundness of manuscripts submitted for review. Capacity building in research ethics and institutional support for Research Ethics Committees to speed up protocol review could reduce the incentive of carrying out research in human subjects without ethics approvals. It is hypocritical and idle to continue to expect optimal reviews on time and of good quality, from ethics committees functioning purely on altruistic grounds. Capacity building for researchers in research ethics, and institutional reforms and support for Research Ethics Committees appear not to have received the attention they truly deserve. PMID- 29610639 TI - Sero-epidemiology of human immunodeficiency virus, hepatitis B virus and hepatitis C virus: a cross-sectional survey in a rural setting of the West region of Cameroon. AB - Introduction: Human immunodeficiency Virus (HIV), hepatitis B virus (HBV), and hepatitis C virus (HCV) are the three most common chronic viral infections worldwide, specifically in sub-Saharan Africa (SSA). This study aimed to determine the sero-epidemiology of HIV, HBV and HCV infections in a rural setting of the West region of Cameroon, a SSA country. Methods: We conducted a cross sectional study from August 2 to 5, 2014 in the three health districts of the Menoua Division, West region of Cameroon. Sixteen villages were randomly selected. Participants were currently living in the Division at the time of the survey, and enrolled after they had provided a signed consent form. HIV screening used the "determine test" followed by Hexagon HIV for positive cases to the first assay. HBV and HCV were detected using DIASpot HBsAg and DIASpot HCV-Ab, respectively. Results: On the whole, 612 subjects consented to take part in this study, of whom 71.1% were females. Mean age of the study population was 45.3 +/- 17.9 years. The seroprevalences of HIV, HBV and HCV infections were 1.0% (6/582), 4.5% (20/443) and 6.3% (23/365), respectively. The 41-50 years age group was the most represented among HIV-positive subjects. HBV prevalence was higher in the 21 30 years age group (13.4%), followed by the 51-60 years age group (7.8%), with a significant difference of prevalences among age groups (p = 0.002). All HCV positive cases were above 40 years of age with a higher prevalence in the > 70 years age group (33.3%) followed by the 61-70 years age group (14.5%); there was a significant difference between the age groups (p = 0.001). Conclusion: The seroprevalences of HIV, HBV and HCV infections in the Menoua Division of the West region of Cameroon were 1.0%, 4.5% and 6.3%, respectively. Preventive measures against these health threats need to be reinforced in this setting. PMID- 29610640 TI - [Isolated male epispadias]. AB - Epispadias is a rare urogenital malformation characterized by more or less complete aplasia of the upper part of the urethra. It is commonly associated with bladder exstrophy. Isolated epispadias occurs in 10% of cases. Continent and incontinent epispadias may be distinguished. We report the case of a 29-year old patient presenting with dysuria associated with the impossibility of having sexual intercourses. Physical examination of the external genitalia showed slit like abnormal urethral opening on the distal half of the dorsal side of the penis. Patient's penis didn't have dorsal curvature (chordee), the corpus cavernosum was palpated and slightly lateralized. The abdominal wall was without abnormalities. The remainder of the clinical examination was normal. Given this anomaly, the diagnosis of balano-pubic continent epispadias was retained. Ultrasound of the urinary tract was normal and pelvis X-ray without preparation showed interpubic diastasis. The patient underwent single-stage surgery using Cantwell-Young technique. Immediate postoperative outcome was without abnormalities; the urethral probe was removed 21 days later, after wound healing. Functional and aesthetics outcome evaluated at three and six months was satisfactory without penis shortness. PMID- 29610641 TI - [Pancreatic mucinous cystadenoma doubly complicated by acute pancreatitis and retroperitoneal rupture]. AB - Mucinous cystadenomas are benign tumors with malignant potential. They are often revealed by non-specific abdominal pain, jaundice or an episode of acute pancreatitis. We here report an exceptional case of mucinous cystadenoma doubly complicated by acute pancreatitis and retroperitoneal rupture. The study involved a 30-year old non-weighted female patient, presenting with epigastric pain associated with left hypochondrium evolving over the last three months and which had intensified without fever or jaundice in the last 3 days. Clinical examination showed impingement on palpation of the epigastrium and of the left hypochondrium. There was no palpable mass. Laboratory tests were without abnormalities, except for lipasemia that was 8-times the upper normal. Abdominal CT scan showed bi-loculated cystic mass in the pancreas tail, measuring 111 mm * 73 mm, with a thin wall and a fluid content, associated with an infiltration of the left perirenal fascia. MRI (Panel A) showed mucinous cystadenoma with retroperitoneal rupture. The caudal portion of the main pancreatic duct was slightly dilated and communicated with the pancreatic cyst. The patient underwent surgery via bi-sub-costal approach. A cystic mass in the pancreas tail with retroperitoneal rupture associated with acute pancreatitis (outflow of necrotic content from left anterior prerenal space) was found. Caudal splenopancreatectomy was performed (Panel B). The postoperative course was uneventful. The anatomo pathological examination of the surgical specimen showed pancreatic mucinous cystadenoma with low-grade dysplasia. PMID- 29610642 TI - Dyslipidemia in people living with HIV-AIDS in a tertiary hospital in South-East Nigeria. AB - Introduction: Across the globe, human immunodeficiency virus (HIV) infection is a healthcare problem. Dyslipidemia, a cardiovascular risk factor, is known to occur with the progression of HIV infection. The factors which influence dyslipidemia in HIV subjects have not been completely identified. The aim of this study was to evaluate serum lipids and identify the factors which might influence dyslipidemia in treatment-naive HIV subjects in Owerri, Nigeria. Methods: This was a cross sectional study of treatment-naive HIV subjects. Anthropometric and demographic data were collected. Serum LDL serum cholesterol, serum high density lipoprotein cholesterol, serum triglyceride, spot urine creatinine, spot urine osmolality, spot urine protein, serum creatinine, 24-hour urine protein, 24-hour urine osmolality, 24-hour urine creatinine, creatinine clearance and hemoglobin were conducted. The variables were compared between those who have dyslipidemia and those who have no dyslipidemia. Results: The mean age of the subjects was 39 +/- 11 years. Females constituted 72.0% and males 28.0%. Elevated serum LDL was present in 17.6%, elevated serum total cholesterol in 11.4%, elevated serum triglyceride in 9.9% and low serum HDL in 34.4% of the subjects. There was significant association between dyslipidemia and CD4 cells count, as well as anemia. There was no significant association between dyslipidemia and urine protein, urine creatinine, urine osmolality, creatinine clearance, as well as 24 hour urine volume. Conclusion: The prevalence of dyslipidemia was high in the study subjects. Abnormal CD4 cells count and anemia were common in treatment naive HIV subjects who have dyslipidemia. PMID- 29610643 TI - Spontaneous subserosal venous rupture overlying a uterine leiomyoma in a young woman. AB - Uterine leiomyomas are very common tumors found in women. Rupture of veins on the surface of uterine leiomyoma is an unusual source of hemoperitoneum. It is an extremely uncommon gynaecological cause of hemoperitoneum. It is a life threatening emergency. We report a case of massive intraperitoneal hemorrhage due to rupture of vessels on the surface of subserous leiomyoma. A differential diagnosis of rupture of leiomyoma'ssurface vessel should be considered, while dealing with a case of hemoperitoneum with pelvic mass. PMID- 29610644 TI - [Difficulties in the management of cerebral venous thrombosis (CVT) complicated by subarachnoid hemorrhage (SAH) in infants: about a case]. AB - CVT is generally rare, particularly among infants. The occurrence of a SAH associated with CVT is very uncommon and only a few cases have been reported in the literature. Symptoms are variable and often misleading. Outcome can be lethal or it can cause potentially severe sequelae if it is not treated or treated late. We report the case of a 22-month old infant examined for convulsions with Stage II coma, intracranial hypertension syndrome and infectious syndrome. Laboratory tests showed pseudomonas spp sepsis and cerebral CT scan allowed the diagnosis. Treatment was based on antibiotic therapy but mainly on anticoagulation therapy. The patient had a significant clinical improvement and follow-up cerebral CT scan showed disappearance of thrombosis with sequellar right hemoragic images. CVT is a severe disease, usually of infectious origin. Anticoagulant therapy is controversial, in particular in patients with associated hemorrhage, but clinical experience supports the effectiveness and safety of this treatment. PMID- 29610645 TI - ? PMID- 29610646 TI - [Epidemiological, clinical and hematological profiles of homozygous sickle cell disease during the intercritical period among children in Ziguinchor, Senegal]. AB - Sickle cell disease poses a public health problem in Senegal. It mainly affects children and adolescents. This study aimed to determine the epidemiological, clinical and hematological profiles of homozygous (SS) sickle cell disease in a cohort of children followed-up at the Peace Hospital in Ziguinchor. We conducted a retrospective study of the medical records from children with sickle cell disease. All patients aged between 2 months and 21 years with sickle cell disease SS during the intercritical period, hospitalized during the study period from 1st January 2015 to 31 August 2017 were included in our study. Compound heterozygous patients (SC, S Beta Thalassemia) were not included. We collected 46 medical records of patients with sickle cell disease SS (20 girls and 26 boys). The average age of children was 8,0 years [11 months-21 years]. Approximately 1/3 of children (39.1%) had an age less than or equal to 5 years. There was an ethnic diversity showing a predominance of the Diola (30.2%) followed by the Mandinga (27.9%) and the Poular (25.6%). The average age of children with first crisis was 35,5 months [7-192 months]. More than 1/3 of children (41.3%) had had first crisis before their second anniversary. In the child, first crisis was dominated by vaso-occlusive crisis (32.6%) followed by hand-foot syndrome (30.4%). Clinical signs during the intercritical period were pallor 95.6%), jaundice (36.9%) and splenomegaly (21.7%). Mean white blood cell count was 12465 leucocytes/mm3 [5340 26900]. Hyperleukocytosis greater than 10 000 leucocytes/mm3was found in 34 patients (73.9%). All patients had anemia with an average hemoglobin of 08,6 g/dl [05,7-11,8]. Hemoglobin S rate ranged between 54.6 and 98.4%. Diagnosis and medical management of sickle cell disease SS are delayed in Ziguinchor. Neonatal screening may lead to improve early management of patients in the region. PMID- 29610647 TI - Improving the efficiency and standards of a National Immunization Program Review: lessons learnt from United Republic of Tanzania. AB - A National Immunization Program Review (NIP Review) is a comprehensive external assessment of the performance of a country's immunization programme. The number of recommended special-topic NIP assessments, such as those for vaccine introduction or vaccine management, has increased. These assessments often have substantial overlap with NIP reviews, raising concern about duplication. Innovative technical and management approaches, including integrating several assessments into one, were applied in the United Republic of Tanzania's 2015 NIP Review. These approaches and processes were documented and a post-Review survey and group discussion. The Tanzania Review found that integrating assessments so they can be conducted at one time was feasible and efficient. There are concrete approaches for successfully managing a Review that can be shared and practiced including having a well-planned desk review and nominating topic-leads. The use of tablets for data entry has the potential to improve Review data quality and timely analysis; however, careful team training is needed. A key area to improve was to better coordinate and link findings from the national-level and field teams. PMID- 29610648 TI - Pyloric atresia: a challenge in an underdeveloped country. AB - Pyloric atresia is a rare congenital malformation. We report a case in a 5-day newborn with pyloric atresia type C. Authors emphasize the diagnostic difficulties and therapeutic challenges in a resource-limited country. PMID- 29610649 TI - Riedel's lobe of the liver. PMID- 29610650 TI - ? PMID- 29610651 TI - An unusual presentation of neurosarcoidosis with progressive hearing loss. AB - Sarcoidosis is a granulomatous disease of unknown etiology that can involve several organ system. Neurological manifestations are not common and mostly include cranial neuropathies. However, auricular disorders are rare and exceptionally inaugural. We describe the case of a 46-year-old lady presented with hearing loss as the initial manifestation of sarcoidosis, and aim to raise awareness of this condition, that is often associated with significant morbidity. PMID- 29610652 TI - Antibiotic prescription pattern in a Ghanaian primary health care facility. AB - Introduction: A major challenge to the provision of health care worldwide is the irrational use of antibiotics. To help promote rational use of drugs, standard treatment guidelines (STG) and essential medicine lists and facility-specific formularies have been developed to be used by clinicians. This study assessed the prescription pattern of antibiotics and explored the use of STG by clinicians. Methods: A prospective cross sectional study that made use of seven core drug use indicators was conducted from February, 2017 to July, 2017. Prescribing indicators were assessed using 388 prescriptions that were submitted for filling and dispensing at the pharmacy unit of the hospital. Clinicians were interviewed to assess their use of STG. Data were analyzed using SPSS version 20.0 with a p value of < 0.05 considered as statistically significant. Results: A total of 1351 drugs were prescribed for 388 patients. The average number of medicines per prescription was 3.5. Of the 388 prescriptions, 55.2% bore antibiotics, with amoxicillin (22.5%) and ciprofloxacin (18.4%) being the most prescribed antibiotics. Patients' knowledge about their medications was found to be significantly associated with the number of drugs per prescription (p = 0.001), age (p = 0.015) and educational level (p = 0.001). Only 41.7% of prescribers had copies of STG and used them. Conclusion: The prescribing and dispensing practices in the hospital were generally not satisfactory with a low patronage of STG among prescribers. In order to improve the situation, clinicians should practice evidence based medicine rather than empirical treatment of conditions as well as use the STG in practice. PMID- 29610653 TI - Risk factors for hematemesis in Hoima and Buliisa Districts, Western Uganda, September-October 2015. AB - Introduction: On 17 September 2015, Buliisa District Health Office reported multiple deaths due to haemorrhage to the Uganda Ministry of Health. We conducted an investigation to verify the existence of an outbreak and to identify the disease nature, mode of transmission and risk factors. Methods: We defined a suspected case as onset of hematemesis between 1 June 2015 and 15 October 2015 in a resident of Hoima, Buliisa or neighbouring districts. We identified cases by reviewing medical records and actively searching in the community. We interviewed case-patients and health-care workers and performed descriptive epidemiology to generate hypotheses on possible exposures. In a case-control study we compared exposures between 21 cases and 81 controls, matched by age (+/- 10 years), sex and village of residence. We collected 22 biological specimens from 19 case patients to test for Viral Haemorrhagic Fevers (VHF). We analysed the data using the Mantel-Haenszel method to account for the matched study design. Results: We identified 56 cases with onset from June to October (attack rate 15/100,000 in Buliisa District and 5.2/100,000 in Hoima District). The age-specific attack rate was highest in persons aged 31-60 years (15/100,000 in Hoima and 47/100,000 in Buliisa); no persons below 15 years of age had the illness. In the case-control study, 42% (5/12) of cases vs. 0.0% (0/77) of controls had liver disease (ORM-H = infinity; 95%CI = 3.7-infinity); 71% (10/14) of cases vs. 35% (28/81) of controls had ulcer disease (ORM-H = 13; 95% CI = 1.6-98); 27% (3/11) of cases vs. 14% (11/81) of controls used indomethacin prior to disease onset (ORM-H = 6.0; 95% CI = 1.0-36). None of the blood samples were positive for any of the VHFs. Conclusion: This reported cluster of hematemesis illness was due to predisposing conditions and use of Non-Steroidal Anti-inflammatory Drugs (NSAID). Health education should be conducted on the danger of NSAIDs misuse, especially in persons with pre-disposing conditions. PMID- 29610654 TI - Dynamic Analysis of the Abnormal Isometric Strength Movement Pattern between Shoulder and Elbow Joint in Patients with Hemiplegia. AB - Patients with hemiplegia usually have weak muscle selectivity and usually perform strength at a secondary joint (secondary strength) during performing a strength at one joint (primary strength). The abnormal strength pattern between shoulder and elbow joint has been analyzed by the maximum value while the performing process with strength changing from 0 to maximum then to 0 was a dynamic process. The objective of this study was to develop a method to dynamically analyze the strength changing process. Ten patients were asked to perform four group asks (maximum and 50% maximum voluntary strength in shoulder abduction, shoulder adduction, elbow flexion, and elbow extension). Strength and activities from seven muscles were measured. The changes of secondary strength had significant correlation with those of primary strength in all tasks (R > 0.76, p < 0.01). The antagonistic muscles were moderately influenced by the primary strength (R > 0.4, p < 0.01). Deltoid muscles, biceps brachii, triceps brachii, and brachioradialis had significant influences on the abnormal strength pattern (all p < 0.01). The dynamic method was proved to be efficient to analyze the different influences of muscles on the abnormal strength pattern. The muscles, deltoid muscles, biceps brachii, triceps brachii, and brachioradialis, much influenced the stereotyped movement pattern between shoulder and elbow joint. PMID- 29610656 TI - Noninvasive Estimation of Joint Moments with Inertial Sensor System for Analysis of STS Rehabilitation Training. AB - An original approach for noninvasive estimation of lower limb joint moments for analysis of STS rehabilitation training with only inertial measurement units was presented based on a piecewise three-segment STS biomechanical model and a double sensor difference based algorithm. Joint kinematic and kinetic analysis using a customized wearable sensor system composed of accelerometers and gyroscopes were presented and evaluated compared with a referenced camera system by five healthy subjects and five patients in rehabilitation. Since there is no integration of angular acceleration or angular velocity, the result is not distorted without offset and drift. Besides, since there are no physical sensors implanted in the lower limb joints based on the algorithm, it is feasible to noninvasively analyze STS kinematics and kinetics with less numbers and types of inertial sensors than those mentioned in other methods. Compared with the results from the reference system, the developed wearable sensor system is available to do spatiotemporal analysis of STS task with fewer sensors and high degree of accuracy, to apply guidance and reference for rehabilitation training or desired feedback for the control of powered exoskeleton system. PMID- 29610655 TI - Corneal Vibrations during Intraocular Pressure Measurement with an Air-Puff Method. AB - Introduction: The paper presents a commentary on the method of analysis of corneal vibrations occurring during eye pressure measurements with air-puff tonometers, for example, Corvis. The presented definition and measurement method allow for the analysis of image sequences of eye responses-cornea deformation. In particular, the outer corneal contour and sclera fragments are analysed, and 3D reconstruction is performed. Methods: On this basis, well-known parameters such as eyeball reaction or corneal response are determined. The next steps of analysis allow for automatic and reproducible separation of four different corneal vibrations. These vibrations are associated with (1) the location of the maximum of cornea deformation; (2) the cutoff area measured in relation to the cornea in a steady state; (3) the maximum of peaks occurring between applanations; and (4) the other characteristic points of the corneal contour. Results: The results obtained enable (1) automatic determination of the amplitude of vibrations; (2) determination of the frequency of vibrations; and (3) determination of the correlation between the selected types of vibrations. Conclusions: These are diagnostic features that can be directly applied clinically for new and archived data. PMID- 29610657 TI - Sleep disturbances are associated with specific sensory sensitivities in children with autism. AB - Background: Sensory abnormalities and sleep disturbances are highly prevalent in children with autism, but the potential relationship between these two domains has rarely been explored. Understanding such relationships is important for identifying children with autism who exhibit more homogeneous symptoms. Methods: Here, we examined this relationship using the Caregiver Sensory Profile and the Children's Sleep Habits Questionnaire, which were completed by parents of 69 children with autism and 62 age-matched controls. Results: In line with previous studies, children with autism exhibited more severe sensory abnormalities and sleep disturbances than age-matched controls. The sleep disturbance scores were moderately associated with touch and oral sensitivities in the autism group and with touch and vestibular sensitivities in the control group. Hypersensitivity towards touch, in particular, exhibited the strongest relationship with sleep disturbances in the autism group and single-handedly explained 24% of the variance in total sleep disturbance scores. In contrast, sensitivity in other sensory domains such as vision and audition was not associated with sleep quality in either group. Conclusions: While it is often assumed that sensitivities in all sensory domains are similarly associated with sleep problems, our results suggest that hypersensitivity towards touch exhibits the strongest relationship with sleep disturbances when examining children autism. We speculate that hypersensitivity towards touch interferes with sleep onset and maintenance in a considerable number of children with autism who exhibit severe sleep disturbances. This may indicate the existence of a specific sleep disturbance mechanism that is associated with sensitivity to touch, which may be important to consider in future scientific and clinical studies. PMID- 29610658 TI - Characterization of the bHLH family of transcriptional regulators in the acoel S. roscoffensis and their putative role in neurogenesis. AB - Background: The basic helix-loop-helix (bHLH) family of transcription factors is one of the largest superfamilies of regulatory transcription factors and is widely used in eukaryotic organisms. They play an essential role in a range of metabolic, physiological, and developmental processes, including the development of the nervous system (NS). These transcription factors have been studied in many metazoans, especially in vertebrates but also in early branching metazoan clades such as the cnidarians and sponges. However, currently very little is known about their expression in the most basally branching bilaterian group, the xenacoelomorphs. Recently, our laboratory has characterized the full complement of bHLH in the genome of two members of the Xenacoelomorpha, the xenoturbellid Xenoturbella bocki and the acoel Symsagittifera roscoffensis. Understanding the patterns of bHLH gene expression in members of this phylum (in space and time) provides critical new insights into the conserved roles of the bHLH and their putative specificities in this group. Our focus is on deciphering the specific roles that these genes have in the process of neurogenesis. Results: Here, we analyze the developmental expression of the whole complement of bHLH genes identified in the acoel S. roscoffensis. Based on their expression patterns, several members of bHLH class A appear to have specific conserved roles in neurogenesis, while other class A genes (as well as members of other classes) have likely taken on more generalized functions. All gene expression patterns are described in embryos and early juveniles. Conclusion: Our results suggest that the main roles of the bHLH genes of S. roscoffensis are evolutionarily conserved, with a specific subset dedicated to patterning the nervous system: SrAscA, SrAscB, SrHes/Hey, SrNscl, SrSrebp, SrE12/E47 and SrOlig. PMID- 29610659 TI - Survival is influenced by approaches to local treatment of Ewing sarcoma within an international randomised controlled trial: analysis of EICESS-92. AB - Background: Two national clinical trial groups, United Kingdom Children's Cancer and Leukaemia Group (CCLG) and the German Paediatric Oncology and Haematology Group (GPOH) together undertook a randomised trial, EICESS-92, which addressed chemotherapy options for Ewing's sarcoma. We sought the causes of unexpected survival differences between the study groups. Methods: 647 patients were randomised. Cox regression analyses were used to compare event-free survival (EFS) and overall survival (OS) between the two study groups. Results: 5-year EFS rates were 43% (95% CI 36-50%) and 57% (95% CI 52-62) in the CCLG and GPOH patients, respectively; corresponding 5-year OS rates were 52% (95% CI 45-59%) and 66% (95% CI 61-71). CCLG patients were less likely to have both surgery and radiotherapy (18 vs. 59%), and more likely to have a single local therapy modality compared to the GPOH patients (72 vs. 35%). Forty-five percent of GPOH patients had pre-operative radiotherapy compared to 3% of CCLG patients. In the CCLG group local recurrence (either with or without metastases) was the first event in 22% of patients compared with 7% in the GPOH group. After allowing for the effects of age, metastases, primary site, histology and local treatment modality, the risk of an EFS event was 44% greater in the CCLG cohort (95% CI 10 89%, p = 0.009), and the risk of dying was 30% greater, but not statistically significant (95% CI 3-74%, p = 0.08). Conclusions: Unexpected differences in EFS and OS occurred between two patient cohorts recruited within an international randomised trial. Failure to select or deliver appropriate local treatment modalities for Ewing's sarcoma may compromise chances of cure.Trial registration Supported by Deutsche Krebshilfe (Grants No. DKH M43/92/Ju2 and DKH 70-2551 Ju3), and European Union Biomedicine and Health Programme (Grants No. BMH1-CT92-1341 and BMH4-983956), and Cancer Research United Kingdom. Clinical trial information can be found for the following: NCT0000251. PMID- 29610660 TI - Estimating active layer thickness and volumetric water content from ground penetrating radar measurements in Barrow, Alaska. AB - Ground penetrating radar (GPR) has emerged as an effective tool for estimating active layer thickness (ALT) and volumetric water content (VWC) within the active layer. In August 2013, we conducted a series of GPR and probing surveys using a 500 MHz antenna and metallic probe around Barrow, Alaska. We collected about 15 km of GPR data and 1.5 km of probing data. Here, we describe the GPR data processing workflow from raw GPR data to the estimated ALT and VWC. We include the corresponding uncertainties for each measured and estimated parameter. The estimated average GPR-derived ALT was 41 cm, with a standard deviation of 9 cm. The average probed ALT was 40 cm, with a standard deviation of 12 cm. The average GPR-derived VWC was 0.65, with a standard deviation of 0.14. PMID- 29610661 TI - Regulatory T-cell heterogeneity. PMID- 29610662 TI - A feasibility study: association between gut microbiota enterotype and antibody response to seasonal trivalent influenza vaccine in adults. AB - Objective: We investigated the potential feasibility of a randomized controlled trial of a nutritional intervention that may alter human gut microbiota and support immune defence against respiratory tract infection in adults (Proposed Study). Methods: In total, 125 healthy adults aged 18-64 participated in a 6 month study that measured antibody response to the seasonal trivalent influenza vaccine. We assessed completion rates, procedure adherence rates and the influence of possible exclusion criteria on potential recruitment into the Proposed Study. We examined whether the gut microbiota could be categorised into enterotypes, and whether there was an association between enterotypes and the antibody response to the influenza vaccine. Results: The participant completion rate was 97.6% (95% CI 93.1-99.5%). The proportions (95% CI) of participants who may be excluded for antibiotic or corticosteroid use in the 30 days prior to the study, or due to receiving the influenza vaccine in the previous two years were 9.6% (5.1-16.2), 8.0% (3.9-14.2) and 61.6% (52.5-70.2), respectively. All participants were stratified into four gut microbiota enterotypes. There was no association between these enterotypes and the antibody response to the influenza vaccine, although the study was not powered for this outcome. Conclusion: This study design is suitable for the Proposed Study. The completion rate is likely to be high, although exclusion criteria should be selected with care. Further analyses of gut microbiota composition or function in association with antibody and immune responses are warranted to explore the role of host-microbiota interactions on protective immunity. PMID- 29610663 TI - Seasonal micro-migration in a farm-island population of striated caracaras (Phalcoboenus australis) in the Falkland Islands. AB - Background: The extent to which seasonal changes in food availability affect small-scale movements in free-ranging populations of birds of prey is relatively little studied. Here we describe a seasonal "micro-migration" of a farm-island population of striated caracaras (Phalcoboenus australis) in the Falkland Islands in response to seasonal changes in the availability of seabird carcasses. We banded more than 450 individuals on Saunders Island, deployed archival and satellite GPS data loggers on 17 individuals, and monitored movements within and between two feeding areas on Saunders Island, a "marine-subsidized" site near seabird colonies and an anthropogenic "human-subsidized" farm site 16 km to the southeast. Results: During 67 observation days between 2010 and 2015, resightings of 312 banded caracaras were greater at the marine-subsidized site during austral summer than winter, and the total daily resightings varied significantly between spring versus summer, summer versus winter, autumn versus spring, and autumn versus winter. Resightings were higher at the human-subsidized site in austral winter than summer and the total daily resightings varied significantly across all bi-seasonal comparisons. Resightings indicated that at least 12 of 197 birds (6.1%) moved between the human- and marine-subsidized sites at least once during the same winter, 15 of 335 birds (4.5%) did so in spring, none of 164 birds did so in summer, and 16 of 297 birds (5.4%) did so in autumn. Individuals fitted with archival GPS data loggers at the marine-subsidized site in summer maintained highly localized 95% kernel core areas (0.55 +/- 0.12 km2 [mean +/- SD]), whereas those at the human-subsidized site in winter maintained larger 95% kernel core areas (3.8 +/- 4.6 km2). Two of 6 satellite-tagged individuals that summered at known caracara breeding colonies 80 km WNW of Saunders Island were subsequently resighted in winter at the human-subsidized site. Conclusion: Our results suggest that seasonal shifts in food resource availability drive seasonal micro migrations in a farm-island population of striated caracaras, and that farm sites can be critical in providing nutritional resources for caracaras when naturally occurring marine-subsidized resources become less available. Our results have important implications for striated caracara spatial ecology and conservation, as increased winter survival could improve the status of this globally Near Threatened population. PMID- 29610664 TI - Hypomagnesemia in critically ill patients. AB - Background: Magnesium (Mg) is essential for life and plays a crucial role in several biochemical and physiological processes in the human body. Hypomagnesemia is common in all hospitalized patients, especially in critically ill patients with coexisting electrolyte abnormalities. Hypomagnesemia may cause severe and potential fatal complications if not timely diagnosed and properly treated, and associate with increased mortality. Main body: Mg deficiency in critically ill patients is mainly caused by gastrointestinal and/or renal disorders and may lead to secondary hypokalemia and hypocalcemia, and severe neuromuscular and cardiovascular clinical manifestations. Because of the physical distribution of Mg, there are no readily or easy methods to assess Mg status. However, serum Mg and the Mg tolerance test are most widely used. There are limited studies to guide intermittent therapy of Mg deficiency in critically ill patients, but some empirical guidelines exist. Further clinical trials and critical evaluation of empiric Mg replacement strategies is needed. Conclusion: Patients at risk of Mg deficiency, with typical biochemical findings or clinical symptoms of hypomagnesemia, should be considered for treatment even with serum Mg within the normal range. PMID- 29610665 TI - Rifampin modulation of xeno- and endobiotic conjugating enzyme mRNA expression and associated microRNAs in human hepatocytes. AB - Rifampin is a pleiotropic inducer of multiple drug metabolizing enzymes and transporters. This work utilized a global approach to evaluate rifampin effects on conjugating enzyme gene expression with relevance to human xeno- and endo biotic metabolism. Primary human hepatocytes from 7 subjects were treated with rifampin (10 MUmol/L, 24 hours). Standard methods for RNA-seq library construction, EZBead preparation, and NextGen sequencing were used to measure UDP glucuronosyl transferase UGT, sulfonyltransferase SULT, N acetyltransferase NAT, and glutathione-S-transferase GST mRNA expression compared to vehicle control (0.01% MeOH). Rifampin-induced (>1.25-fold) mRNA expression of 13 clinically important phase II drug metabolizing genes and repressed (>1.25-fold) the expression of 3 genes (P < .05). Rifampin-induced miRNA expression changes correlated with mRNA changes and miRNAs were identified that may modulate conjugating enzyme expression. NAT2 gene expression was most strongly repressed (1.3-fold) by rifampin while UGT1A4 and UGT1A1 genes were most strongly induced (7.9- and 4.8-fold, respectively). Physiologically based pharmacokinetic modeling (PBPK) was used to simulate the clinical consequences of rifampin induction of CYP3A4- and UGT1A4-mediated midazolam metabolism. Simulations evaluating isolated UGT1A4 induction predicted increased midazolam N-glucuronide exposure (~4-fold) with minimal reductions in parent midazolam exposure (~10%). Simulations accounting for simultaneous induction of both CYP3A4 and UGT1A4 predicted a ~10 fold decrease in parent midazolam exposure with only a ~2-fold decrease in midazolam N-glucuronide metabolite exposure. These data reveal differential effects of rifampin on the human conjugating enzyme transcriptome and potential associations with miRNAs that form the basis for future mechanistic studies to elucidate the interplay of conjugating enzyme regulatory elements. PMID- 29610666 TI - Revisiting the putative role of heme as a trigger of inflammation. AB - Activation of the innate immune system by free heme has been proposed as one of the principal consequences of cell-free hemoglobin (Hb) exposure. Nonetheless, in the absence of infection, heme exposures within a hematoma, during hemolysis, or upon systemic administration of Hb (eg, as a Hb-based oxygen carrier) are typically not accompanied by uncontrolled inflammation, challenging the assumption that heme is a major proinflammatory mediator in vivo. Because of its hydrophobic nature, heme liberated from oxidized hemoglobin is rapidly transferred to alternative protein-binding sites (eg, albumin) or to hydrophobic lipid compartments minimizing protein-free heme under in vivo equilibrium conditions. We demonstrate that the capacity of heme to activate human neutrophil granulocytes strictly depends on the availability of non protein-associated heme. In human endothelial cells as well as in mouse macrophage cell cultures and in mouse models of local and systemic heme exposure, protein-associated heme or Hb do not induce inflammatory gene expression over a broad range of exposure conditions. Only experiments in protein-free culture medium demonstrated a weak capacity of heme-solutions to induce toll-like receptor-(TLR4) dependent TNF alpha expression in macrophages. Our data suggests that the equilibrium-state of free and protein-associated heme critically determines the proinflammatory capacity of the metallo-porphyrin. Based on these data it appears unlikely that inflammation-promoting equilibrium conditions could ever occur in vivo. PMID- 29610667 TI - A survey of knowledge, attitude, and practices of private retail pharmacies staff in tuberculosis care: study from Dera Ismail Khan City, Pakistan. AB - Background: In order to engage pharmacies in tuberculosis (TB) care, a survey was conducted in the Dera Ismail (DI) Khan City of the Khyber Pakhtoon Khwa province, Pakistan. The objectives were to; 1) characterize the retail pharmacies; 2) determine knowledge of the staff on various aspects of pulmonary TB; 3) determine practices related to the sale of anti-TB drugs, and referrals of presumptive TB patient, and willingness to participate in the National Tuberculosis Control Programme's (NTP) Directly Observed Treatment Short-Course (DOTS) strategy. Methods: A cross-sectional survey was conducted by using a structured questionnaire to collect data from pharmacy staff at all the private retail pharmacies of the DI khan city. Results: All the interviewed staff (n = 82) were males, only 38% had formal training as pharmacist (5%) or as a pharmacy assistant (33%). Pharmacies established for a longer period were better staffed and had high customer load. About 92% of the interviewed staff knew that persistent cough is a symptom for TB, 82% knew that TB is diagnosed by examination of sputum. Almost 66% of the pharmacy staff did not know multi-drug resistance TB as a consequence of improper treatment. Those with formal training and longer experience in retail pharmacy had better knowledge of various aspects of TB as compared to the staff with no formal pharmacy training and lesser experience (p < 0.01). Only 57% were aware of NTP while only 30% had heard of the DOTS strategy. All reported sale of first-line TB drugs as fixed dose combinations. The majority (80%) referred presumptive TB patients to chest physicians and no patient was referred to the NTP. Nearly 83% of the interviewed staff was willing to be involved in TB control efforts by getting training and referring patients to the DOTS facility. Conclusion: There was shortage of professionally qualified and female staff in private retail pharmacies. Knowledge of professionally qualified staff about TB seemed sufficient to identify presumptive TB patients; however, their knowledge about NTP and DOTS was poor, and referral practices to NTP and DOTS centers were suboptimal. Majority of staff was willing to be involved in TB control efforts. PMID- 29610668 TI - HCFC-123-induced toxic hepatitis and death at a Korean fire extinguisher manufacturing facility: a case series. AB - Background: Exposure to sustained high concentrations of HCFC-123 is known to be hepatotoxic. We report two simultaneous cases of toxic hepatitis related to exposure to 2,2-dichloro-1,1,1-trifluoroethane (HCFC-123), a common refrigerant, at a Korean fire extinguisher manufacturing facility. Case presentation: Patients A and B were men aged 21 and 22 years, respectively, with no notable medical histories. They had recently started working for a manufacturer of fire extinguishers. During the third week of their employment, they visited the emergency center of a general hospital due to fever, lack of appetite, and general weakness. At the time of their visit, they were suspected as having hepatitis due to elevated aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), and total bilirubin levels and were hospitalized. However, as their condition did not improve, they were moved to a tertiary general hospital. After conservative treatment, one patient improved but the other died from acute hepatic failure. Assessments of the work environment showed that the short-term exposure levels of HCFC-123 for valve assembly processes were as high as 193.4 ppm. A transjugular liver biopsy was performed in patient A; the results indicated drug/toxin-induced liver injury (DILI). Given the lack of a medical history and the occupational exposure to high levels of HCFC-123, a hepatotoxic agent, the toxic hepatitis of the workers was likely related to HCFC-123 exposure. Conclusions: Work environment assessments have not included this agent. To the best of our knowledge, we are the first to report a case of death related to HCFC-123-induced liver damage. Our findings suggest that exposure standards and limits for HCFC-123 must be developed in Korea; work environments will have to be improved based on such standards. PMID- 29610669 TI - Nationwide genetic testing towards eliminating Lafora disease from Miniature Wirehaired Dachshunds in the United Kingdom. AB - Background: Canine DNA-testing has become an important tool in purebred dog breeding and many breeders use genetic testing results when planning their breeding strategies. In addition, information obtained from testing of hundreds dogs in one breed gives valuable information about the breed-wide genotype frequency of disease associated allele. Lafora disease is a late onset, recessively inherited genetic disease which is diagnosed in Miniature Wirehaired Dachshunds (MWHD). It is one of the most severe forms of canine epilepsy leading to neurodegeneration and, frequently euthanasia within a few years of diagnosis. Canine Lafora disease is caused by a dodecamer repeat expansion mutation in the NHLRC1 gene and a DNA test is available to identify homozygous dogs at risk, carriers and dogs free of the mutation. Results: Blood samples were collected from 733 MWHDs worldwide, mostly of UK origin, for canine Lafora disease testing. Among the tested MWHD population 7.0% were homozygous for the mutation and at risk for Lafora disease. In addition, 234 dogs were heterozygous, indicating a carrier frequency of 31.9% in the tested population. Among the tested MWHDs, the mutant allele frequency was 0.2. In addition, data from the tested dogs over 6 years (2012-2017) indicated that the frequency of the homozygous and carrier dogs has decreased from 10.4% to 2.7% and 41.5% to 25.7%, respectively among MWHDs tested. As a consequence, the frequency of dogs free of the mutation has increased from 48.1% to 71.6%. Conclusions: This study provides valuable data for the MWHD community and shows that the DNA test is a useful tool for the breeders to prevent occurrence of Lafora disease in MWHDs. DNA testing has, over 6 years, helped to decrease the frequency of carriers and dogs at risk. Additionally, the DNA test can continue to be used to slowly eradicate the disease-causing mutation in the breed. However, this should be done carefully, over time, to avoid further compromising the genetic diversity of the breed. The DNA test also provides a diagnostic tool for veterinarians if they are presented with a dog that shows clinical signs associated with canine Lafora disease. PMID- 29610670 TI - Community-based childhood obesity prevention intervention for parents improves health behaviors and food parenting practices among Hispanic, low-income parents. AB - Background: Given the current prevalence of childhood obesity among Hispanic populations, and the importance of parental feeding behaviors, we aimed to assess the impact of the evidence-based Healthy Children, Healthy Families (HCHF) intervention on responsive food parenting practices (FPPs) in a low-income Hispanic population. Methods: This community-based pilot study used a non experimental pre/post within-subjects design. Parents (n = 94) of children aged 3 11 years old were recruited to participate in an 8-week, weekly group-based intervention. The intervention was delivered to nine groups of parents by trained paraprofessional educators over a two-year period. Children participated in a separate curriculum that covered topics similar to those covered in the parent intervention. Parents completed self-administered pre/post surveys, which included demographic questions, seven subscales from the Comprehensive Feeding Practices Questionnaire, and the 16-item HCHF Behavior Checklist. Descriptive statistics and paired samples t-tests were used to analyze data from parents that completed the intervention. Results: Fifty-two, primarily Hispanic (93%) parents completed the intervention (39% attrition rate). For parents who completed the intervention, there was a significant increase in one of the feeding practice subscales: encouragement of balance and variety (p = 0.01). There were significant improvements in several parent and child diet and activity outcomes (p <= 0.01). Conclusions: Although attrition rates were high, parents completing the study reported enjoying and being satisfied with the intervention. For parents who completed the intervention, reported 'encouragement of balance and variety', in addition to several health behaviors significantly improved. Larger studies utilizing an experimental design, should further explore the impact of the HCHF curriculum on improving certain FPPs and health behaviors that contribute to obesity. PMID- 29610672 TI - Work-Hour Trajectories and Depressive Symptoms among Midlife and Older Married Couples. AB - Life course theories highlight the importance of understanding psychological health of aging individuals in context. Work and marriage are influential contexts in later life that are increasingly relevant because both spouses of many households work and individuals are delaying retirement. Although there is extensive literature on predictors of depressive symptoms, incorporating life course histories of work and social contexts has been a critical omission in the aging and health field. This study identifies couples' work trajectories as a function of husband's and wife's weekly work hours and examines the link between couple work-hour trajectory membership and individual depressive symptoms. Data are from 1641 married couples who participated in the 1998-2012 waves (ages 51 89) of the Health and Retirement Study (HRS). Findings revealed six distinct subgroups of work-hour trajectories among couples and that membership in these subgroups was associated with depressive symptoms. Retiring husbands with wives who continued to work and wives who worked minimally throughout the years (regardless of whether their husbands worked or retired) reported more depressive symptoms than other subgroups. These results suggest that work trajectories themselves, beyond current health status, may carry differential psychological health risk. Moreover, several sociodemographic and life course factors in 1998 were significant predictors of trajectory membership. These findings provide insight into midlife factors that may influence work trajectories (and the potential health risk) through to older adulthood. They suggest that a life course examination of work and social contexts is needed for a greater understanding of individual and couple health development. PMID- 29610671 TI - The mystery of the cerebellum: clues from experimental and clinical observations. AB - The cerebellum has a striking homogeneous cytoarchitecture and participates in both motor and non-motor domains. Indeed, a wealth of evidence from neuroanatomical, electrophysiological, neuroimaging and clinical studies has substantially modified our traditional view on the cerebellum as a sole calibrator of sensorimotor functions. Despite the major advances of the last four decades of cerebellar research, outstanding questions remain regarding the mechanisms and functions of the cerebellar circuitry. We discuss major clues from both experimental and clinical studies, with a focus on rodent models in fear behaviour, on the role of the cerebellum in motor control, on cerebellar contributions to timing and our appraisal of the pathogenesis of cerebellar tremor. The cerebellum occupies a central position to optimize behaviour, motor control, timing procedures and to prevent body oscillations. More than ever, the cerebellum is now considered as a major actor on the scene of disorders affecting the CNS, extending from motor disorders to cognitive and affective disorders. However, the respective roles of the mossy fibres, the climbing fibres, cerebellar cortex and cerebellar nuclei remains unknown or partially known at best in most cases. Research is now moving towards a better definition of the roles of cerebellar modules and microzones. This will impact on the management of cerebellar disorders. PMID- 29610673 TI - Physicochemical properties of M. longissimus dorsi of Korean native pigs. AB - Background: The meat quality of Korean native pigs (KNP) and crossbred pigs (LYD; Landrace * Yorkshire * Duroc) was examined to generate data useful for selecting native pigs for improved pork production. Methods: Fifty Korean native pigs (KNP) and 50 crossbred pigs (LYD) were tested. Loin samples (M. longissimus dorsi) of the two breeds were analyzed to determine meat quality and sensory properties. Result: KNP had a higher moisture content than LYD (p < 0.05); however, it had significantly lower crude fat and ash content than that of LYD (p < 0.001). KNP had significantly higher shear force than LYD (p < 0.01). KNP also showed significantly higher cooking loss than LYD (p < 0.05). KNP had a lower L* value than LYD (p < 0.05); however, it had a markedly higher a* and b* value than LYD (p < 0.001). KNP showed significantly higher linoleic acid, linolenic acid, and arachidonic acid content than LYD (p < 0.05). Although KNP had significantly better flavor and overall palatability than LYD, it was less tender than LYD (p < 0.01). Conclusion: KNP had a markedly higher a* value than LYD. KNP had significantly higher shear force than LYD. The total unsaturated fatty acid content was higher in KNP than in LYD. PMID- 29610674 TI - Passive surveillance of Leptospira infection in swine in Germany. AB - Background: As no current data are available on the prevalence of leptospiral infection in swine in Germany, we analysed laboratory data from diagnostic examinations carried out on samples from swine all over Germany from January 2011 to September 2016. A total of 29,829 swine sera were tested by microscopic agglutination test (MAT) for antibodies against strains of eleven Leptospira serovars. Results: Overall, 20.2% (6025) of the total sample collection tested positive for leptospiral infection. Seropositivity ranged between 16.3% (964) in 2011 and 30.9% (941) in 2016 (January to September only). Of all samples, 11.6% (57.3% of the positives) reacted with only one Leptospira serovar, and only 8.6% (42.7% of the positives) reacted simultaneously with two or more serovars. The most frequently detected serovar was Bratislava, which was found in 11.6% (3448) of all samples, followed by the serovars Australis in 7.3% (2185), Icterohaemorrhagiae in 4.0% (1191), Copenhageni in 4.0% (1182), Autumnalis in 3.7% (1054), Canicola in 2.0% (585), and Pomona in 1.2% (368). Modelling shows that both the year and the reason for testing at the laboratory had statistically strong effects on the test results; however, no interactions were determined between those factors. The results support the suggestion that the seropositivities found may be considered to indicate the state of leptospiral infections in the German swine population. Conclusion: Although data from passive surveillance are prone to selection bias, stratified analysis by initial reason for examination and analyses by model approaches may correct for biases. A prevalence of about 20% for a leptospiral infection is most probable for sows with reproductive problems in Germany, with an increasing trend. Swine in Germany are probably a reservoir host for serovar Bratislava, but in contrast to other studies not for Pomona and Tarassovi. PMID- 29610675 TI - HABIT-an early phase study to explore an oral health intervention delivered by health visitors to parents with young children aged 9-12 months: study protocol. AB - Background: Parental supervised brushing (PSB) when initiated in infancy can lead to long-term protective home-based oral health habits thereby reducing the risk of dental caries. However, PSB is a complex behaviour with many barriers reported by parents hindering its effective implementation. Within the UK, oral health advice is delivered universally to parents by health visitors and their wider teams when children are aged between 9 and 12 months. Nevertheless, there is no standardised intervention or training upon which health visitors can base this advice, and they often lack the specialised knowledge needed to help parents overcome barriers to performing PSB and limiting sugary foods and drinks.Working with health visitors and parents of children aged 9-24 months, we have co designed oral health training and resources (Health Visitors delivering Advice in Britain on Infant Toothbrushing (HABIT) intervention) to be used by health visitors and their wider teams when providing parents of children aged 9-12 months with oral health advice.The aim of the study is to explore the acceptability of the HABIT intervention to parents and health visitors, to examine the mechanism of action and develop suitable objective measures of PSB. Methods/design: Six health visitors working in a deprived city in the UK will be provided with training on how to use the HABIT intervention. Health visitors will then each deliver the intervention to five parents of children aged 9-12 months. The research team will collect measures of PSB and dietary behaviours before and at 2 weeks and 3 months after the HABIT intervention. Acceptability of the HABIT intervention to health visitors will be explored through semi-structured diaries completed after each visit and a focus group discussion after delivery to all parents. Acceptability of the HABIT intervention and mechanism of action will be explored briefly during each home visit with parents and in greater details in 20 25 qualitative interviews after the completion of data collection. The utility of three objective measures of PSB will be compared with each other and with parental-self reports. Discussion: This study will provide essential information to inform the design of a definitive cluster randomised controlled trial. Trial registration: There is no database for early phase studies such as ours. PMID- 29610676 TI - Pregnant or recently pregnant opioid users: contraception decisions, perceptions and preferences. AB - Background: Multiple factors are linked to extremely high unintended pregnancy rates among women who use opioids, including various barriers to contraception adherence. These include patient level barriers such as lack of knowledge and education about highly effective contraception, and potential provider barriers. Using a mixed-methods framework to examine the contraception-related perceptions and preferences of opioid using women is a necessary next step to understanding this phenomenon. Methods: A mixed-method study was conducted which included both self-report questionnaires along with a semi-structured qualitative interview of opioid-using pregnant or recently pregnant women in two drug treatment facilities in Ohio. Results: Forty-two women completed the study. The majority of recent (75%) and total pregnancies were unintended. Male condoms were reported as the highest form of lifetime contraception used within the present sample (69%). Participants reported low lifetime use of long acting reversible contraception (LARC) (ranging from 5 to 12%). Participants preferred hormonal injections first (40%), followed by IUDs (17%). Reasons for preferences of injections and LARC were similar: not needing to remember, side effects, and long-term effectiveness. Conclusions: Most of the study population participants stated they would utilize contraception, particularly Tier 1 LARC methods, if freely available; however, high rates of unintended pregnancy were observed in this sample. This indicates the need for contraception education, and addressing the procedural, logistical and economic barriers that may be preventing the use of LARC among this population. PMID- 29610678 TI - Increased mtDNA copy number promotes cancer progression by enhancing mitochondrial oxidative phosphorylation in microsatellite-stable colorectal cancer. AB - Colorectal cancer is one of the leading causes of cancer death worldwide. According to global genomic status, colorectal cancer can be classified into two main types: microsatellite-stable and microsatellite-instable tumors. Moreover, the two subtypes also exhibit different responses to chemotherapeutic agents through distinctive molecular mechanisms. Recently, mitochondrial DNA depletion has been shown to induce apoptotic resistance in microsatellite-instable colorectal cancer. However, the effects of altered mitochondrial DNA copy number on the progression of microsatellite-stable colorectal cancer, which accounts for the majority of colorectal cancer, remain unclear. In this study, we systematically investigated the functional role of altered mitochondrial DNA copy number in the survival and metastasis of microsatellite-stable colorectal cancer cells. Moreover, the underlying molecular mechanisms were also explored. Our results demonstrated that increased mitochondrial DNA copy number by forced mitochondrial transcription factor A expression significantly facilitated cell proliferation and inhibited apoptosis of microsatellite-stable colorectal cancer cells both in vitro and in vivo. Moreover, we demonstrated that increased mitochondrial DNA copy number enhanced the metastasis of microsatellite-stable colorectal cancer cells. Mechanistically, the survival advantage conferred by increased mitochondrial DNA copy number was caused in large part by elevated mitochondrial oxidative phosphorylation. Furthermore, treatment with oligomycin significantly suppressed the survival and metastasis of microsatellite-stable colorectal cancer cells with increased mitochondrial DNA copy number. Our study provides evidence supporting a possible tumor-promoting role for mitochondrial DNA and uncovers the underlying mechanism, which suggests a potential novel therapeutic target for microsatellite-stable colorectal cancer. PMID- 29610677 TI - Potential association of LMNA-associated generalized lipodystrophy with juvenile dermatomyositis. AB - Background: Juvenile dermatomyositis (JDM) is an auto-immune muscle disease which presents with skin manifestations and muscle weakness. At least 10% of the patients with JDM present with acquired lipodystrophy. Laminopathies are caused by mutations in the lamin genes and cover a wide spectrum of diseases including muscular dystrophies and lipodystrophy. The p.T10I LMNA variant is associated with a phenotype of generalized lipodystrophy that has also been called atypical progeroid syndrome. Case presentation: A previously healthy female presented with bilateral proximal lower extremity muscle weakness at age 4. She was diagnosed with JDM based on her clinical presentation, laboratory tests and magnetic resonance imaging (MRI). She had subcutaneous fat loss which started in her extremities and progressed to her whole body. At age 7, she had diabetes, hypertriglyceridemia, low leptin levels and low body fat on dual energy X-ray absorptiometry (DEXA) scan, and was diagnosed with acquired generalized lipodystrophy (AGL). Whole exome sequencing (WES) revealed a heterozygous c.29C > T; p.T10I missense pathogenic variant in LMNA, which encodes lamins A and C. Muscle biopsy confirmed JDM rather than muscular dystrophy, showing perifascicular atrophy and perivascular mononuclear cell infiltration. Immunofluroscence of skin fibroblasts confirmed nuclear atypia and fragmentation. Conclusions: This is a unique case with p.T10I LMNA variant displaying concurrent JDM and AGL. This co-occurrence raises the intriguing possibility that LMNA, and possibly p.T10I, may have a pathogenic role in not only the occurrence of generalized lipodystrophy, but also juvenile dermatomyositis. Careful phenotypic characterization of additional patients with laminopathies as well as individuals with JDM is warranted. PMID- 29610679 TI - Low IL-6, IL-10, and TNF-alpha and High IL-13 Cytokine Levels Are Associated with Severe Hepatic Fibrosis in Schistosoma mansoni Chronically Exposed Individuals. AB - Several studies have attributed the etiopathogenesis of chronic Schistosoma mansoni related hepatic fibrosis to unregulated immune responses against trapped parasite ova in the host. However, there is limited data on immune profiles associated with varying degrees of the disease in a population under chronic exposure to the parasite. We therefore investigated the role of selected T-helper (Th)1, Th2, and Th17 cytokines in relation to hepatic fibrosis severity among individuals resident in a hyper-Schistosoma mansoni endemic region of Western Zambia. Two hundred and forty-four S. mansoni infected individuals with and without fibrosis were analysed for cytokine profiles. Based on hepatic fibrosis stage as determined by ultrasound, participants were categorized into Group 0, Group I, Group II, and Group III. Cytokines were measured in S. mansoni egg stimulated whole blood culture supernatants using the BD Cytometric Bead Array kits. Compared to the nonfibrotic group, participants in the severe hepatic fibrotic group produced less interleukin- (IL-) 6, IL-10, and tumour necrosis factor-alpha (TNF-alpha). On the other hand, IL-13 was significantly elevated in this group compared to the nonfibrotic group (p < 0.001). Our results suggest that low IL-6, IL-10, and TNF-alpha and high IL-13 levels may influence S. mansoni disease progression. PMID- 29610680 TI - Association between CD4 Cell Count and Blood Pressure and Its Variation with Body Mass Index Categories in HIV-Infected Patients. AB - The aim of this study was to establish whether an independent relationship exists between CD4 count and hypertension and if this relationship is modified or confounded by the body mass index (BMI). Methods. A secondary data analysis of a cross-sectional study on 200 HIV/AIDS patients at a referral hospital in Cameroon was conducted. Linear and logistic regression models were used as appropriate to explore the association between the variables of interest. Results. There was no linear association between log CD4 count and both systolic (p = 0.200; r = 0.12) and diastolic blood pressures (p = 0.123; r = 0.14), respectively. After adjusting for BMI, patients with CD4 count >= 350 cells/MUl were more likely to have hypertension than those with CD4 count < 350 cells/MUl (AOR: 2.50, 95% CI: 1.05-5.93, and p = 0.032). There was no effect modification from BMI (test of homogeneity, p = 0.721). There was no independent relationship between CD4 count and hypertension after controlling for age, sex, family history of hypertension, BMI-defined overweight, HAART use, and duration of HIV infection (AOR: 1.66, 95% CI: 0.48-5.71, and p = 0.419). Conclusion. This study did not identify any independent relationship between CD4 count and hypertension. Large prospective studies are recommended to better explore this relationship between hypertension and CD4 count. PMID- 29610681 TI - Hypertension and Associated Factors in Rural and Urban Areas Mali: Data from the STEP 2013 Survey. AB - Background: Our study aims to estimate hypertension (HTN) prevalence and its predictors in rural and urban area. Methods: We conducted a cross-sectional population-based study involving subjects aged 15 to 65 years. Collected data (sociodemographic, blood pressure, weight, height, and blood glucose) were analyzed using SPSS version 20. A logistic regression was conducted to look for factors associated with HTN. Results: Mean was 47 years. High blood pressure (HBP) prevalence was 21.1 and 24.7%, respectively, in rural and urban setting. In rural area age group significantly predicted hypertension with age of 60 years having more-than-4-times risk of hypertension, whereas, in urban area age group, sex and body mass index were predictors with OR: HTN raising from 2.06 [1.24 3.43] for 30-44 years old to 7.25 [4.00-13.13] for 60 years and more using <30 years as reference. Female sex was protective with OR of 0.45 [0.29-0.71] and using normal weight as reference OR for overweight was 1.54 [1.04-2.27] and 2.67 [1.64-4.36] for obesity. Conclusion: Hypertension prevalence is high and associated factors were age group in rural area and age group, female sex, and body mass index in urban area. PMID- 29610682 TI - Association of Dietary Habits and Interest for Food and Science versus Weight Status in Children Aged 8 to 18 Years. AB - Introduction: This study aims to describe the association between dietary habits and weight status and the interest in food and science. Methods: We examined in a cross-sectional study 525 children aged between 8 and 18 years, who attended the Brussels Food Fair or the Belgian Science Day in 2013. They were divided into three groups: special interest in science, special interest in food, and a general control group. They completed a questionnaire, and body parameters were measured. The weight status of the children was identified using the growth charts and the calculated BMI. Results: In total, 525 children were included: 290 children in the reference group, 194 in the food group, and 41 in the science group. The prevalence of overweight and obesity was 28% in the general control group, 14% in the food group, and 15% in the science group. Breakfast and dinner were skipped more often by children with overweight or obesity. Children from the food and science groups had more sweets and meat, had less fruit, and skipped less meals. Conclusion: In our study, 28% of the reference group had overweight or obesity. The children with special interest in food or science differed from the control group. PMID- 29610683 TI - Assigning Clinical Significance and Symptom Severity Using the Zung Scales: Levels of Misclassification Arising from Confusion between Index and Raw Scores. AB - Background: The Zung Self-Rating Depression Scale (SDS) and Self-Rating Anxiety Scale (SAS) are two norm-referenced scales commonly used to identify the presence of depression and anxiety in clinical research. Unfortunately, several researchers have mistakenly applied index score criteria to raw scores when assigning clinical significance and symptom severity ratings. This study examined the extent of this problem. Method: 102 papers published over the six-year period from 2010 to 2015 were used to establish two convenience samples of 60 usages of each Zung scale. Results: In those papers where cut-off scores were used (i.e., 45/60 for SDS and 40/60 for SAS), up to 51% of SDS and 45% of SAS papers involved the incorrect application of index score criteria to raw scores. Inconsistencies were also noted in the severity ranges and cut-off scores used. Conclusions: A large percentage of publications involving the Zung SDS and SAS scales are using incorrect criteria for the classification of clinically significant symptoms of depression and anxiety. The most common error-applying index score criteria to raw scores-produces a substantial elevation of the cut-off points for significance. Given the continuing usage of these scales, it is important that these inconsistencies be highlighted and resolved. PMID- 29610684 TI - Immune Toxicity with Checkpoint Inhibition for Metastatic Melanoma: Case Series and Clinical Management. AB - Immune checkpoint inhibitors (anti-PD-1 and anti-CTLA-4 antibodies) are a standard of care for advanced melanoma. Novel toxicities comprise immune-related adverse events (irAE). With increasing use, irAE require recognition, practical management strategies, and multidisciplinary care. We retrospectively evaluated the incidence, kinetics, and management of irAE in 41 patients receiving anti-PD 1 antibody therapy (pembrolizumab) for advanced melanoma. 63% received prior anti CTLA-4 antibody therapy (ipilimumab). IrAE occurred in 54%, most commonly dermatological (24%), rheumatological (22%), and thyroid dysfunction (12%). Thyroiditis was characterised by a brief asymptomatic hyperthyroid phase followed by a symptomatic hypothyroid phase requiring thyroxine replacement. Transplant rejection doses of methylprednisolone were necessary to manage refractory hepatotoxicity. A bullous pemphigoid-like skin reaction with refractory pruritus responded to corticosteroids and neuropathic analgesia. Disabling grade 3-4 oligoarthritis required sulfasalazine therapy in combination with steroids. The median interval between the last dose of anti-CTLA-4 antibody and the first dose of anti-PD-1 therapy was 2.0 months (range: 0.4 to 22.4). Toxicities may occur late; this requires vigilance and multidisciplinary management which may allow effective anticancer therapy to continue. Management algorithms for thyroiditis, hypophysitis, arthralgia/arthritis, colitis, steroid-refractory hepatitis, and skin toxicity are discussed. PMID- 29610686 TI - Comparison of Oil Content and Fatty Acids Profile of Western Schley, Wichita, and Native Pecan Nuts Cultured in Chihuahua, Mexico. AB - Two different extraction processes, Soxhlet and ultrasound, were used to obtain the oil extracts of Western Schley, Wichita, and Native pecan nuts cultured in Chihuahua, Mexico. The aspects evaluated in this study were the extraction yield of the processes and fatty acids' profile of the resulting extracts. Gas chromatography coupled with mass spectrometry (GC-MS) was used to identify and determine the composition percentage of fatty acids present in pecan nuts oils extracted. The results obtained show that higher oil extraction yields were obtained by Soxhlet method with hexane (69.90%) in Wichita varieties. Wichita, Western Schley, and Native pecan nuts from Chihuahua are rich in PUFA (polyunsaturated fatty acids) and MUFA (monounsaturated fatty acids) and have low levels of SFA (saturated fatty acids). The predominant fatty acid present in all pecan nuts oils was linoleic acid followed by oleic acid. Myristic acid, palmitic acid, and linolenic acid were also identified in representative quantities. The results from this study suggest that there are statistically significant differences in the chemical composition of the pecan nuts oils extracted from the varieties cultured in Chihuahua, Mexico, and those cultivated in other regions of the world. PMID- 29610687 TI - Potential Applications of Some Indigenous Bacteria Isolated from Polluted Areas in the Treatment of Brewery Effluents. AB - Biological wastewater treatment is economically feasible and ecofriendly. This study was aimed at isolating bacteria from brewery wastes and evaluating their bioremediation potential as individual isolate and/or their consortium in reducing the pollutants of brewery effluents. A total of 40 bacterial isolates were recovered and of these the three best isolates were selected. The selected bacteria were identified to genus level by using morphological and biochemical characteristics. Accordingly, the isolates were identified as Aeromonas sp., Pseudomonas sp., and Bacillus sp. After 12 days of incubation, the removal efficiency of these three isolates and their combinations for biological oxygen demand and chemical oxygen demand varied from 73.55% to 94.85% and 76.78% to 93.25%, respectively. Total nitrogen and phosphorus removal was within the range of 54.43% to 77.21% and 41.80% to 78.18%, respectively. Total suspended solid, total solid, and total dissolved solids removal ranged from 66.74% to 90.3%, 54.69% to 88.5%, and 53.02% to 88.2%, respectively. The pH and electrical conductivity values ranged from 6.81 to 8.65 and 3.31 mS/cm to 3.67 mS/cm, respectively. The treated effluent increased Beta vulgaris seeds germination from 80% to 100%, with mean germination time of 3.1 to 5.2 days and seedlings length of 2.3 cm to 6.3 cm. Therefore, the development of this finding into a large scale offers an attractive technology for brewery waste treatment. PMID- 29610685 TI - Ceramide and Ischemia/Reperfusion Injury. AB - Ceramide, a bioactive membrane sphingolipid, functions as an important second messenger in apoptosis and cell signaling. In response to stresses, it may be generated by de novo synthesis, sphingomyelin hydrolysis, and/or recycling of complex sphingolipids. It is cleared from cells through the activity of ceramidases, phosphorylation to ceramide-1-phosphate, or resynthesis into more complex sphingolipids. Ischemia/reperfusion (IR) injury occurs when oxygen/nutrition is rapidly reintroduced into ischemic tissue, resulting in cell death and tissue damage, and is a major concern in diverse clinical settings, including organ resection and transplantation. Numerous reports show that ceramide levels are markedly elevated during IR. Mitochondria are major sites of reactive oxygen species (ROS) production and play a key role in IR-induced and ceramide-mediated cell death and tissue damage. During the development of IR injury, the initial response of ROS and TNF-alpha production activates two major ceramide generating pathways (sphingomyelin hydrolysis and de novo ceramide synthesis). The increased ceramide has broad effects depending on the IR phases, including both pro- and antiapoptotic effects. Therefore, strategies that reduce the levels of ceramide, for example, by modulation of ceramidase and/or sphingomyelinases activities, may represent novel and promising therapeutic approaches to prevent or treat IR injury in diverse clinical settings. PMID- 29610688 TI - Prenatal Identification and Molecular Characterization of Two Simultaneous De Novo Interstitial Duplications of Chromosomal Regions 7p22.1p21.1 and 15q24.1. AB - The occurrence of simultaneous de novo chromosomal aberrations is extremely rare. Here, we describe two, previously unreported, simultaneous de novo interstitial duplications of chromosomes 7p and 15q. Amniocentesis was completed for a healthy gravida 4 para 3 woman due to her advanced maternal age and concurrent ultrasound findings of partial vermian agenesis, choroid-plexus cysts, and hypoplastic nasal bone. Cytogenetic analysis of cultured amniocytes by conventional chromosome analysis, comparative genomic hybridization, and fluorescence in situ hybridization revealed two interstitial duplications of the chromosomal regions 7p22.1p21.1 and 15q24.1, leading to partial trisomy of 7p and 15q and karyotype 46,XY,dup(7)(p22.1-p21.1),dup (15)(q24.1). Parental chromosomal analysis did not identify any heritable changes, suggesting both mutations were de novo in nature. Postnatal examination of the neonate was significant for low set ears, thick helices, flat nasal bridge, ankyloglossia, and aberrant head shape and size concerning for craniosynostosis. Postnatal MRI was consistent with Dandy-Walker variant showing hypogenesis of the inferior cerebellar vermis. To our knowledge, there are no prenatal or postnatal reports of comparable duplications involving these two regions simultaneously. Continued observation of the neonate may reveal further phenotypic consequences of these two simultaneous de novo interstitial duplications. PMID- 29610689 TI - Acquired Perforating Dermatosis in a Patient on Peritoneal Dialysis: A Case Report and Review of the Literature. AB - Acquired perforating dermatosis (APD) is a debilitating and itchy skin disease. Its diagnosis is based on biopsy and the treatment is not very clear. It is not well established as to how wide spread it is in patients on peritoneal dialysis (PD) and its implications in this population have not been well studied. Here we present a case of APD that developed in a patient on PD. Its pathology and treatment options are reviewed. More studies are needed to assess the prevalence of APD in PD population. PMID- 29610690 TI - Comorbid Normal Pressure Hydrocephalus with Parkinsonism: A Clinical Challenge and Call for Awareness. AB - Idiopathic normal pressure hydrocephalus (iNPH) is the most common cause of hydrocephalus in adults. The diagnosis may be challenging, requiring collaborative efforts between different specialists. According to the International Society for Hydrocephalus and Cerebrospinal Fluid Disorders, iNPH should be considered in the differential of any unexplained gait failure with insidious onset. Recognizing iNPH can be even more difficult in the presence of comorbid neurologic disorders. Among these, idiopathic Parkinson's disease (PD) is one of the major neurologic causes of gait dysfunction in the elderly. Both conditions have their peak prevalence between the 6th and the 7th decade. Importantly, postural instability and gait dysfunction are core clinical features in both iNPH and PD. Therefore, diagnosing iNPH where diagnostic criteria of PD have been met represents an additional clinical challenge. Here, we report a patient with parkinsonism initially consistent with PD who subsequently displayed rapidly progressive postural instability and gait dysfunction leading to the diagnosis of concomitant iNPH. In the following sections, we will review the clinical features of iNPH, as well as the overlapping and discriminating features when degenerative parkinsonism is in the differential diagnosis. Understanding and recognizing the potential for concomitant disease are critical when treating both conditions. PMID- 29610691 TI - Cerebral Venous Sinus Thrombosis in a Patient with Ulcerative Colitis Flare. AB - Inflammatory bowel disease is characterized by a chronic inflammatory state and is therefore associated with abnormalities in coagulation and a hypercoagulable state. Cerebral venous sinus thrombosis is a rare complication of inflammatory bowel disease yet contributes significant morbidity and mortality to those affected. Early diagnosis is critical, as a delay in diagnosis portends a worse prognosis. This paper seeks to highlight the increased risk of venous sinus thrombosis in patients with inflammatory bowel disease. We start by discussing the case of a seventeen-year-old female who presented with ulcerative colitis flare and developed new-onset seizures, found to be caused by a large venous sinus thrombosis. PMID- 29610692 TI - Successful Complete Response of Tumor Thrombus after Combined with Chemotherapy and Irradiation for Ewing Sarcoma. AB - Pelvic Ewing sarcoma is associated with a worse prognosis. Thromboembolic events are relatively common in pediatric patients with cancers including sarcomas. We have presented a case of Ewing sarcoma arising from the left iliac bone with tumor thrombus of inferior vena cava (IVC) which was obtained complete response by both chemotherapy and irradiation. Magnetic resonance imaging (MRI) scan demonstrated that the tumor arising from the left iliac bone extended into the left side of sacral bone, suggesting the difficulty of surgical resection. Computed tomography (CT) revealed the existence of the tumor thrombus of IVC. We performed irradiation (31.2 Gy) and chemotherapy (combination of VCR, Act-D, IFM, and ADR). The tumor was controlled successfully, and the tumor thrombus of IVC has completely vanished. Four years after the treatment, coin lesion in the left upper lung appeared. Suspected of metastasis, segmental resection of the left upper lung was performed. Fourteen years after the surgery, the patient has been remained free of recurrence. It is clinically significant for surgeons to treat pelvic Ewing sarcoma with tumor thrombus. PMID- 29610694 TI - Diabetic Neuropathic Arthropathy of the Knee: Two Case Reports and a Review of the Literature. AB - Diabetic neuroarthropathy of the knee or Charcot knee (CK) is a lesser-known complication of diabetes mellitus, with a limited number of case reports and small case series published in the literature. The majority of these reports describe the complexities and challenges that arise in these patients undergoing knee arthroplasty procedures. We present two cases of CK, including a rare case of concurrent bilateral disease, and also a review of the current literature. PMID- 29610693 TI - Total Hip Arthroplasty in a Patient with Oto-Spondylo-Megaepiphyseal Dysplasia Planned by Three-Dimensional Motion Analyses and Full-Scale Three-Dimensional Plaster Model of Bones. AB - We present the case of a 28-year-old woman with oto-spondylo-megaepiphyseal dysplasia, which is a rare skeletal disorder, who underwent bilateral total hip arthroplasty. Full-scale three-dimensional plaster model of the acetabulum and the femur provided us with a feasible preoperative plan. Pre- and postoperative three-dimensional motion analyses proved a significant improvement in her ambulation and confirmed the efficacy of total hip arthroplasty. In conclusion, full-scale three-dimensional plaster models of the bone and three-dimensional motion analyses were useful for total hip arthroplasty in patients with skeletal dysplasia. PMID- 29610695 TI - An Unusual Case of Pinna Squamous Cell Carcinoma Arising Shortly after Resection of Atypical Fibroxanthoma. AB - Objective: To report a unique case of pinna squamous cell carcinoma (SCC) arising shortly after resection of atypical fibroxanthoma (AFX) at the same site. Case report: An 81-year-old gentleman presented with a nodular right pinna lesion. This was excised, and histology confirmed AFX. Ten weeks later, an ulcerative lesion appeared at the resection site. This was confirmed to be SCC. Comparative analysis revealed no morphological resemblance between the initial AFX and new SCC lesion, and there was no evidence of initial misdiagnosis. Conclusion: SCC is the most common cancer involving the pinna. Whilst prolonged sun exposure is an important risk factor for SCC, chronic inflammation and wounds are other potential sources. We postulate whether SCC could have arisen from the previous scar tissue in a manner similar to Marjolin's ulcer. This would be a highly unusual finding in the pinna and to our knowledge unprecedented in the English literature. PMID- 29610696 TI - A Rare Cause of a Fluctuating Cystic Lesion in the External Auditory Canal. AB - Temporomandibular joint (TMJ) ganglionic cyst is an uncommon entity and only a few have been reported in the literature. TMJ ganglion within the external auditory canal presenting clinically as a fluctuating cystic lesion has never been reported. Here, we present a unique case of such a lesion together with otoscopic and radiological images as well as provide a descriptive review of TMJ ganglionic cysts. PMID- 29610697 TI - A Case of Spondyloarthritis in Patient Affected by Unicentric Castleman's Disease Effectively Managed with Surgery Resection and Tocilizumab Treatment. AB - A 38-year-old woman was referred to our hospital for rheumatologic manifestations (migrant arthritis and tenosynovitis), without psoriasis or family history of psoriasis, gastroenteric manifestations, or recent genitourinary infections. The instrumental and laboratory tests have suggested a diagnosis of undifferentiated seronegative HLA-B27-positive spondyloarthritis with predominantly peripheral involvement. The symptoms were very severe and resistant to anti-inflammatory drugs and steroids. She had a history of hyaline-vascular unicentric Castleman's disease (HBV, HIV, and HHV-8 negative) treated with surgery resection. After a first pharmacological attempt with sulfasalazine (suspended for urticarial rash), we managed the patient with monotherapy tocilizumab 8 mg/kg, with full response of rheumatologic manifestations. The efficacy of tocilizumab was confirmed even after a follow-up of three years. Our experience seems to describe a new late onset autoimmune disease (only 21 cases described in literature) potentially related to Castleman's disease. The patient experienced marked improvement from IL-6-based therapy (tocilizumab). PMID- 29610698 TI - Three Case Reports of Rhupus Syndrome: An Overlap Syndrome of Rheumatoid Arthritis and Systemic Lupus Erythematosus. AB - We present the clinical and serological characteristics of three patients with rhupus. The 3 patients with rhupus presented ACR criteria for SLE as well as for RA, ANA positive with a titer of 1/100 in all patients, and positive anti-DNA in 2 of the 3 patients, with the predominance of symmetrical polyarthritis. We found anti-CCP positivity and rheumatoid factor positivity and high titers in all patients, positive anti- anti-SSA in one patient, and positive anti- anti-Sm in one patient. Renal and liver function tests were normal in all patients. The 3 patients achieved clinical remission with DMARD treatment. PMID- 29610699 TI - Hemorrhagic Tamponade as Initial Manifestation of Systemic Lupus with Subsequent Refractory and Progressive Lupus Myocarditis Resulting in Cardiomyopathy and Mitral Regurgitation. AB - Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease with a wide range of clinical and serological manifestations. Cardiac disease among patients with SLE is common and can involve the pericardium, myocardium, valves, conduction system, and coronary arteries. We are reporting a case of SLE in a young woman that is unique is unique in that initial symptoms consisted of pericarditis and hemorrhagic tamponade which remained progressive and resistant to aggressive immunosuppressive treatment and led to severe cardiomyopathy (ejection fraction of 25%) and severe (+4) mitral regurgitation. Her immunosuppressive treatment included hydroxychloroquine, high-dose steroids, intravenous immunoglobulins, azathioprine, and mycophenolate mofetil. Her disease progression was felt to be due to underlying uncontrolled SLE because the complement levels remained persistently low throughout the entire course and PET Myocardial Perfusion and Viability study showed stable persistent active inflammation. Eventually, she was treated with cyclophosphamide which led to improvement in ejection fraction to 55% with only mild mitral regurgitation. PMID- 29610700 TI - Pulmonary Sarcoidosis following Etanercept Treatment for Ankylosing Spondylitis: A Case Report and Review of the Literature. AB - Antitumor necrosis factor therapies have revolutionized the treatment of some inflammatory diseases. However, the use of these agents is associated with the development of many paradoxical autoimmune diseases. Less well-recognized is the association with sarcoidosis. We report a 55-year-old female with long-standing ankylosing spondylitis who developed persistent dry cough and dyspnea while receiving etanercept therapy. High-resolution computed tomography scanning showed mediastinal lymphadenopathy and multiple nodules in both lung fields developed two months after the administration of etanercept. Lymph node biopsy was not practicable. Histopathological examination of minor salivary gland biopsy revealed noncaseating granulomata, and the serum angiotensin-converting enzyme was very elevated. All infectious studies were negative. Etanercept was discontinued plus a course of corticosteroids with a clinical improvement, and a follow-up high-resolution computed tomography scanning 4 months later showed evident regression of mediastinal lymph nodes and pulmonary nodules. Potential pathogenic mechanisms of this paradoxical effect of tumor necrosis factor-alpha blocking agents are discussed. PMID- 29610701 TI - What Makes Super-Aged Nations Happier? Exploring Critical Factors of Happiness Among Middle-Aged Men and Women in Japan. AB - This study aimed to examine multiple factors associated with happiness from the perspective of gender difference among a middle-aged Japanese population. A total of 865 participants (male = 344, female = 521) aged 40-64 years were divided into two groups (high and low) by their self-reported level of happiness. Logistic regression analysis by gender was carried out. In men, high levels of happiness were significantly correlated with living with spouse, occupation, enough sleep, leading a normal life, and regular checkups; while low levels of happiness were significantly correlated with smoking and having two or more diseases. In women, low levels of happiness were significantly correlated with caring for a family member. Our data suggested that the factors relevant to happiness levels might vary between men and women among middle-aged people in Japan. To increase the nation's level of happiness, the Japanese government must implement extended social services and policymaking, to alleviate caregivers' burdens, especially among Japanese women. PMID- 29610703 TI - Glycaemic control in type 2 diabetic patients with chronic kidney disease: the impacts on enzymatic antioxidants and soluble RAGE. AB - Background: Chronic kidney disease (CKD) is characterised by long-term kidney damage and renal function decline. Diabetic CKD is the principal subtype of kidney disease in Malaysia and is associated with oxidative stress which plays an important role in development and progression of the disease. Glycaemic control slows down the progression of diabetic complications, including diabetic CKD. However, the implication of glycaemic control on enzymatic antioxidants and soluble RAGE (sRAGE) in CKD patients remains elusive. The aim of this study was to investigate the effect of glycaemic control on the levels or activities of glutathione peroxidase (GPx), superoxide dismutase (SOD) and sRAGE in CKD patients. Methods: A total of 150 CKD patients and 64 non-CKD patients were enrolled. The type 2 diabetic patients in the recruited study participants were categorised based on their glycaemic control; poor glycaemic control (GC) with haemoglobin A1c (HbA1c) > 7% and good GC with HbA1c <= 7%. The levels or activities of GPx, SOD and sRAGE in plasma were measured. These biochemical parameters were analysed using Mann-Whitney U test and two-way analysis of variance (ANOVA). Results: The activities of GPx and SOD as well as plasma level of sRAGE were not significantly different among the CKD patients with varying glycaemic control status. Irrespective of diabetes status and glycaemic control status, CKD patients also exhibited lower plasma SOD activities compared with non CKD patients. Among the non-CKD patients, SOD activities were significantly higher in diabetic patients with good GC than diabetic patients with poor GC. Two way ANOVA revealed that both CKD status and glycaemic control had an interaction effect on SOD activities in diabetic subjects with and without CKD. Follow-up analysis showed that SOD activities were significantly higher in non-CKD patients with good GC. There were no overall significant differences in GPx activities among the study participants. Furthermore, plasma sRAGE levels were higher in diabetic patients with CKD than those without CKD, regardless of glycaemic control status. There were no interaction effects between CKD status and glycaemic control status on GPx and sRAGE. Instead, CKD status showed significant main effects on these parameters, indicating significant differences between diabetic subjects with CKD and diabetic subjects without CKD. Conclusion: Glycaemic control did not quantitatively alter GPx, SOD and sRAGE in diabetic CKD patients. Despite the advantages of good glycaemic control, a well-controlled diabetes in CKD did not modulate the activities of enzymatic antioxidants and sRAGE levels, therefore may not be the primary mechanism to handle oxidative stress. PMID- 29610704 TI - The importance of sponges and mangroves in supporting fish communities on degraded coral reefs in Caribbean Panama. AB - Fish communities associated with coral reefs worldwide are threatened by habitat degradation and overexploitation. We assessed coral reefs, mangrove fringes, and seagrass meadows on the Caribbean coast of Panama to explore the influences of their proximity to one another, habitat cover, and environmental characteristics in sustaining biomass, species richness and trophic structure of fish communities in a degraded tropical ecosystem. We found 94% of all fish across all habitat types were of small body size (<=10 cm), with communities dominated by fishes that usually live in habitats of low complexity, such as Pomacentridae (damselfishes) and Gobiidae (gobies). Total fish biomass was very low, with the trend of small fishes from low trophic levels over-represented, and top predators under-represented, relative to coral reefs elsewhere in the Caribbean. For example, herbivorous fishes comprised 27% of total fish biomass in Panama relative to 10% in the wider Caribbean, and the small parrotfish Scarus iseri comprised 72% of the parrotfish biomass. We found evidence that non-coral biogenic habitats support reef-associated fish communities. In particular, the abundance of sponges on a given reef and proximity of mangroves were found to be important positive correlates of reef fish species richness, biomass, abundance and trophic structure. Our study indicates that a diverse fish community can persist on degraded coral reefs, and that the availability and arrangement within the seascape of other habitat-forming organisms, including sponges and mangroves, is critical to the maintenance of functional processes in such ecosystems. PMID- 29610702 TI - Acidification increases abundances of Vibrionales and Planctomycetia associated to a seaweed-grazer system: potential consequences for disease and prey digestion efficiency. AB - Ocean acidification significantly affects marine organisms in several ways, with complex interactions. Seaweeds might benefit from rising CO2 through increased photosynthesis and carbon acquisition, with subsequent higher growth rates. However, changes in seaweed chemistry due to increased CO2 may change the nutritional quality of tissue for grazers. In addition, organisms live in close association with a diverse microbiota, which can also be influenced by environmental changes, with feedback effects. As gut microbiomes are often linked to diet, changes in seaweed characteristics and associated microbiome can affect the gut microbiome of the grazer, with possible fitness consequences. In this study, we experimentally investigated the effects of acidification on the microbiome of the invasive brown seaweed Sargassum muticum and a native isopod consumer Synisoma nadejda. Both were exposed to ambient CO2 conditions (380 ppm, pH 8.16) and an acidification treatment (1,000 ppm, pH 7.86) for three weeks. Microbiome diversity and composition were determined using high-throughput sequencing of the variable regions V5-7 of 16S rRNA. We anticipated that as a result of acidification, the seaweed-associated bacterial community would change, leading to further changes in the gut microbiome of grazers. However, no significant effects of elevated CO2 on the overall bacterial community structure and composition were revealed in the seaweed. In contrast, significant changes were observed in the bacterial community of the grazer gut. Although the bacterial community of S. muticum as whole did not change, Oceanospirillales and Vibrionales (mainly Pseudoalteromonas) significantly increased their abundance in acidified conditions. The former, which uses organic matter compounds as its main source, may have opportunistically taken advantage of the possible increase of the C/N ratio in the seaweed under acidified conditions. Pseudoalteromonas, commonly associated to diseased seaweeds, suggesting that acidification may facilitate opportunistic/pathogenic bacteria. In the gut of S. nadejda, the bacterial genus Planctomycetia increased abundance under elevated CO2. This shift might be associated to changes in food (S. muticum) quality under acidification. Planctomycetia are slow-acting decomposers of algal polymers that could be providing the isopod with an elevated algal digestion and availability of inorganic compounds to compensate the shifted C/N ratio under acidification in their food. In conclusion, our results indicate that even after only three weeks of acidified conditions, bacterial communities associated to ungrazed seaweed and to an isopod grazer show specific, differential shifts in associated bacterial community. These have potential consequences for seaweed health (as shown in corals) and isopod food digestion. The observed changes in the gut microbiome of the grazer seem to reflect changes in the seaweed chemistry rather than its microbial composition. PMID- 29610705 TI - Osteology of Batrachuperus londongensis (Urodela, Hynobiidae): study of bony anatomy of a facultatively neotenic salamander from Mount Emei, Sichuan Province, China. AB - The Longdong Stream Salamander Batrachuperus londongensis, living in a mountain stream environment at Mt. Emei in Sichuan Province, China, represents a rare species that is facultatively neotenic in the family Hynobiidae. Although the species has been known to science for some 40 years since its initial discovery in the late 1970s, anatomical details of its osteology remain poorly understood and developmental information is still lacking for the species. This study (1) provides a detailed osteological account of B. londongensis based on micro-CT scanning and clearing and staining of multiple specimens from the type locality; (2) provides a discussion of intraspecific variation related to life-history differences; and (3) presents a discussion on limb features related to morphological evolution of limb patterns correlative with ecological adaptation to mountain stream environments. Osteological comparisons with congeneric species has led to recognition of several diagnostic features that are unique to B. londongensis, including: vomers widely separated from one another, lacking a midline contact; presence of uncommon perichondral ossification of the ascending process of the palatoquadrate as part of the suspensorium; and presence of a prominent posterodorsal process of the scapular blade, which serves as a ligamentous insertion of the levator muscle of the scapula. In addition, some but not all neotenic individuals retain the palatine as a discrete element, indicative of its delayed absorption after sexual maturity. Postmetamorphic and neotenic individuals are strikingly different in the complexity of hyobranchial structures. Neotenes display a high degree of ossification of hyobranchial elements, tend to increase ossification of both hypobranchial I and ceratobranchial I during aging, and retain fully ossified ceratobranchial III and IV; in contrast, these elements remain entirely cartilaginous or are totally lost by resorption in postmetamorphic individuals. In addition, all postmetamorphic forms display an inverted "T"-shaped basibranchial II, whereas neotenes show transformation from a "fork"-shaped to the "T"-shaped configuration after sexual maturity. B. londongensis displays a mosaic of apomorphic and plesiomorphic states in its limb ossifications: presence of a single centrale element in both the manus and pes is a derived condition in Hynobiidae and other families as well, whereas retention of a postminimus in the pes is obviously plesiomorphic within Urodela. Reduction in number of digits from five to four in the pes and possession of a cornified sheath covering the terminal phalanges are also derived features shared with some but not all mountain stream salamanders that are adapted to a similar type of environment. PMID- 29610706 TI - The value of citizen science for ecological monitoring of mammals. AB - Citizen science approaches are of great interest for their potential to efficiently and sustainably monitor wildlife populations on both public and private lands. Here we present two studies that worked with volunteers to set camera traps for ecological surveys. The photographs recorded by these citizen scientists were archived and verified using the eMammal software platform, providing a professional grade, vouchered database of biodiversity records. Motivated by managers' concern with perceived high bear activity, our first example enlisted the help of homeowners in a short-term study to compare black bear activity inside a National Historic Site with surrounding private land. We found similar levels of bear activity inside and outside the NHS, and regional comparisons suggest the bear population is typical. Participants benefited from knowing their local bear population was normal and managers refocused bear management given this new information. Our second example is a continuous survey of wildlife using the grounds of a nature education center that actively manages habitat to maintain a grassland prairie. Center staff incorporated the camera traps into educational programs, involving visitors with camera setup and picture review. Over two years and 5,968 camera-nights this survey has collected 41,393 detections of 14 wildlife species. Detection rates and occupancy were higher in open habitats compared to forest, suggesting that the maintenance of prairie habitat is beneficial to some species. Over 500 volunteers of all ages participated in this project over two years. Some of the greatest benefits have been to high school students, exemplified by a student with autism who increased his communication and comfort level with others through field work with the cameras. These examples show how, with the right tools, training and survey design protocols, citizen science can be used to answer a variety of applied management questions while connecting participants with their secretive mammal neighbors. PMID- 29610708 TI - Limb-use by foraging marine turtles, an evolutionary perspective. AB - The use of limbs for foraging is documented in both marine and terrestrial tetrapods. These behaviors were once believed to be less likely in marine tetrapods due to the physical constraints of body plans adapted to locomotion in a fluid environment. Despite these obstacles, ten distinct types of limb-use while foraging have been previously reported in nine marine tetrapod families. Here, we expand the types of limb-use documented in marine turtles and put it in context with the diversity of marine tetrapods currently known to use limbs for foraging. Additionally, we suggest that such behaviors could have occurred in ancestral turtles, and thus, possibly extend the evolutionary timeline of limb use behavior in marine tetrapods back approximately 70 million years. Through direct observation in situ and crowd-sourcing, we document the range of behaviors across habitats and prey types, suggesting its widespread occurrence. We argue the presence of these behaviors among marine tetrapods may be limited by limb mobility and evolutionary history, rather than foraging ecology or social learning. These behaviors may also be remnant of ancestral forelimb-use that have been maintained due to a semi-aquatic life history. PMID- 29610707 TI - Comparative genome analysis of 24 bovine-associated Staphylococcus isolates with special focus on the putative virulence genes. AB - Non-aureus staphylococci (NAS) are most commonly isolated from subclinical mastitis. Different NAS species may, however, have diverse effects on the inflammatory response in the udder. We determined the genome sequences of 20 staphylococcal isolates from clinical or subclinical bovine mastitis, belonging to the NAS species Staphylococcus agnetis, S. chromogenes, and S. simulans, and focused on the putative virulence factor genes present in the genomes. For comparison we used our previously published genome sequences of four S. aureus isolates from bovine mastitis. The pan-genome and core genomes of the non-aureus isolates were characterized. After that, putative virulence factor orthologues were searched in silico. We compared the presence of putative virulence factors in the NAS species and S. aureus and evaluated the potential association between bacterial genotype and type of mastitis (clinical vs. subclinical). The NAS isolates had much less virulence gene orthologues than the S. aureus isolates. One third of the virulence genes were detected only in S. aureus. About 100 virulence genes were present in all S. aureus isolates, compared to about 40 to 50 in each NAS isolate. S. simulans differed the most. Several of the virulence genes detected among NAS were harbored only by S. simulans, but it also lacked a number of genes present both in S. agnetis and S. chromogenes. The type of mastitis was not associated with any specific virulence gene profile. It seems that the virulence gene profiles or cumulative number of different virulence genes are not directly associated with the type of mastitis (clinical or subclinical), indicating that host derived factors such as the immune status play a pivotal role in the manifestation of mastitis. PMID- 29610709 TI - Simulated Disperser Analysis: determining the number of loci required to genetically identify dispersers. AB - Empirical genetic datasets used for estimating contemporary dispersal in wild populations and to correctly identify dispersers are rarely tested to determine if they are capable of providing accurate results. Here we test whether a genetic dataset provides sufficient information to accurately identify first-generation dispersers. Using microsatellite data from three wild populations of common starlings (Sturnus vulgaris), we artificially simulated dispersal of a subset of individuals; we term this 'Simulated Disperser Analysis'. We then ran analyses for diminishing numbers of loci, to assess at which point simulated dispersers could no longer be correctly identified. Not surprisingly, the correct identification of dispersers varied significantly depending on the individual chosen to 'disperse', the number of loci used, whether loci had high or low Polymorphic Information Content and the location to which the dispersers were moved. A review of the literature revealed that studies that have implemented first-generation migrant detection to date have used on average 10 microsatellite loci. Our results suggest at least 27 loci are required to accurately identify dispersers in the study system evaluated here. We suggest that future studies use the approach we describe to determine the appropriate number of markers needed to accurately identify dispersers in their study system; the unique nature of natural systems means that the number of markers required for each study system will vary. Future studies can use Simulated Disperser Analysis on pilot data to test marker panels for robustness to contemporary dispersal identification, providing a powerful tool in the efficient and accurate design of studies using genetic data to estimate dispersal. PMID- 29610710 TI - A revision of Haematodes Laporte and Weiserianum Bernhauer (Coleoptera: Staphylinidae: Staphylininae: Xanthopygina). AB - The species of poorly known but charismatic genera Haematodes Laporte, 1835 and Weiserianum Bernhauer, 1927 are revised. Weiserianumsyn. nov. is considered a junior synonym of Haematodes, with Haematodes kuntzeni (Scheerpeltz, 1936) comb. nov.Weiserianum woltersi Bernhauer, 1927 syn. nov. is treated as a synonym of Haematodes tenuipes Kraatz, 1858. Haematodes myterossp. nov., is described from Paraguay and Brazil. As the type series of Haematodes bicolor Laporte, 1835 is considered lost, a neotype, selected from the original type locality is designated. We also designate a lectotype for H. tenuipes Kraatz, 1858 to stabilize nomenclature for this species, which is similar to H. myteros. As far as known, Haematodes is restricted to the southern Neotropical region and may be nest parasites within Acromyrmex and Atta ant nests as are species of the related genus Scariphaeus, but no direct observations are yet available. We provide a key to the four known species of Haematodes and illustrate their diagnostic features. PMID- 29610711 TI - Determining the numbers of a landscape architect species (Tapirus terrestris), using footprints. AB - Background: As a landscape architect and a major seed disperser, the lowland tapir (Tapirus terrestris) is an important indicator of the ecological health of certain habitats. Therefore, reliable data regarding tapir populations are fundamental in understanding ecosystem dynamics, including those associated with the Atlantic Forest in Brazil. Currently, many population monitoring studies use invasive tagging with radio or satellite/Global Positioning System (GPS) collars. These techniques can be costly and unreliable, and the immobilization required carries physiological risks that are undesirable particularly for threatened and elusive species such as the lowland tapir. Methods: We collected data from one of the last regions with a viable population of lowland tapir in the south-eastern Atlantic Forest, Brazil, using a new non-invasive method for identifying species, the footprint identification technique (FIT). Results: We identified the minimum number of tapirs in the study area and, in addition, we observed that they have overlapping ranges. Four hundred and forty footprints from 46 trails collected from six locations in the study area in a landscape known to contain tapir were analyzed, and 29 individuals were identified from these footprints. Discussion: We demonstrate a practical application of FIT for lowland tapir censusing. Our study shows that FIT is an effective method for the identification of individuals of a threatened species, even when they lack visible natural markings on their bodies. FIT offers several benefits over other methods, especially for tapir management. As a non-invasive method, it can be used to census or monitor species, giving rapid feedback to managers of protected areas. PMID- 29610712 TI - Identification of three classes of acute respiratory distress syndrome using latent class analysis. AB - Acute respiratory distress syndrome (ARDS) is a highly heterogeneous syndrome that can exhibit significant differences in the underlying causes, leading to different responses to treatment. It is required to identify subtypes of ARDS to guideline clinical treatment and trial design. The study aimed to identify subtypes of ARDS using latent class analysis (LCA). The study was a secondary analysis of the EDEN study, which was a randomized, controlled, multicenter trial conducted from January 2, 2008 to April 12, 2011. The primary study endpoint was death through 90-day follow up. LCA was performed incorporating variables on day 0 before randomization. The number of classes was chosen by a bootstrapped likelihood ratio test, Bayesian information criterion and the number of patients in each class. A total of 943 patients were enrolled in the study, including 219 (23.2%) non-survivors and 724 (76.8%) survivors. The LCA identified three classes of ARDS. Class 1 (hemodynamically unstable type) had significantly higher mortality rate (p = 0.003) than class 2 (intermediate type) and 3 (stable type) through 90 days follow up. There was significant interaction between cumulative fluid balance and the class (p = 0.02). While more fluid balance was beneficial for class 1, it was harmful for class 2 and 3. In conclusion, the study identified three classes of ARDS, which showed different clinical presentations, responses to fluid therapy and prognosis. The classification system used simple clinical variables and could help to design ARDS trials in the future. PMID- 29610713 TI - Ultrasound for Volume Assessment in Patients with Shock: Effectiveness of an Educational Intervention for Fourth-year Medical Students. AB - Objective Shock is a common emergency condition with high morbidity and mortality, and judicious fluid resuscitation can significantly affect outcomes. The use of a bedside echocardiogram and evaluation of the inferior vena cava (IVC) via ultrasound (US) for collapsibility can predict volume status. Additionally, the Association of American Medical Colleges (AAMC) Entrustable Professional Activities (EPA) 10 states that residents need to be able to address a patient with a critical illness, including hypotension, on Day 1 of residency. Existing literature revealed no published curriculum to teach medical students these skills. We aimed to determine the effectiveness of an educational intervention to teach fourth-year medical students how to utilize IVC US measurement and echocardiography to assist in volume assessment of patients presenting with shock. Methods Students participated in an hour session on the first day of the emergency medicine (EM) clerkship. Didactic effectiveness was evaluated by comparing results on a pre-test and post-test. The test was administered to residents and attendings during the first week of the academic year to gain evidence for content validity. Students also responded to a survey to evaluate learner satisfaction. Results The average score on the validation test was 68.4% (standard deviation (SD): 21.6%, number (n) = 38) for residents and attendings, and 47.4% (SD: 19.4, n = 13) for interns. Students scored an average of 45.6% (SD: 23.6, n = 83) on the pre-test and 66.4% (SD: 22.1 n = 72) on the post-test, p < 0.01 (degrees of freedom (df) = 153, t = 5.7), Cohen's d = 0.92. The satisfaction survey showed 97.6% of students felt the session was worthwhile, 96.4% would recommend it to other students, and 83.1% felt it taught new information. Conclusion These results show that the educational intervention provides a significant increase in knowledge regarding volume assessment and the use of echocardiogram and IVC US. Additionally, students rated the course highly and felt that it provided information not otherwise taught in medical school. This curriculum addresses the AAMC EPA 10, as it increases students' readiness to address hypotension and could add significant value to the medical school curriculum. PMID- 29610714 TI - Visual and Refractive Outcomes of Topography-guided Laser-assisted In Situ Keratomileusis in Virgin Eyes. AB - Introduction We wanted to assess the efficacy, predictability, and stability of topography-guided, laser-assisted in situ keratomileusis (TGL) on normal untreated eyes with a preoperative best corrected visual acuity (BCVA) of 20/20. Methods This was a retrospective, non-randomized, and single arm study evaluating the outcomes of TGL in eyes with a preoperative BCVA of 20/20. We included 50 eyes of 50 patients who presented to the Hashmanis Hospital, Pakistan and were followed for six months postoperatively. All eyes underwent treatment using the Alcon Wavelight Allegro Topolyzer (Alcon Laboratories, Inc., TX, USA). Results The mean preoperative sphere, cylinder, and spherical equivalent (SE) values were -4.3 +/- 1.6 dioptres (D), -1.0 +/- 0.8 D, and -4.8 +/- 1.8 D. On day one these values were 0.2 +/- 0.8 D, -0.5 +/- 0.3, and 0.3 +/- 0.8, respectively, and on month six they were -0.1 +/- 0.6, -0.5 +/- 0.3, and -0.4 +/- 0.6 D, respectively. On postoperative day one and month six, 86% and 94% of eyes had a UCVA of 20/20 or better, respectively. Two eyes (4%) had an SE change of greater than 0.5 D from three to six months. Conclusion Our study demonstrates good efficacy, predictability, and stability of eyes undergoing TGL with a follow-up of six months. PMID- 29610715 TI - Complications of Subcutaneous Contraception: A Review. AB - Over 62 million women in the United States are of childbearing age and 60% of them use contraception. Subcutaneous contraceptives include implantable contraceptives and subcutaneous injections. Implantable contraception involves subdermal time-release of synthetic progestin, which allows for several years of continuous, highly effective contraception. Its main effects are inhibition of ovulation and thickening of the cervical mucus. Many complications have been associated with subcutaneous contraception, including menstrual disturbances, headache, weight gain, acne, dizziness, mood disturbances, nausea, lower abdominal pain, hair loss, loss of libido, pain at the implant site, neuropathy, and follicular cysts. Using standard search engines, the complications of subcutaneous contraception are reviewed. Patients should be adequately counseled on the possible complications and side effects of subcutaneous contraception to help them make an informed decision when choosing the right contraceptive to meet their needs. PMID- 29610716 TI - Orthognathic Relevant Scales of FACE-Q: Translation and Validation for Hong Kong Chinese Patients. AB - Background: A validated questionnaire is needed to study a more holistic outcome assessment including postsurgical aesthetic satisfaction and psychosocial changes in orthognathic patients. The aim of this study was to determine the reliability and validity of 9 orthognathically relevant translated FACE-Q scales among Hong Kong Chinese orthognathic patients. Methods: Two hundred fifty adult Cantonese speaking patients of 18 years or older who underwent orthognathic treatment were recruited in the Prince Philip Dental Hospital of Hong Kong. Nine of an overall of 40 independent FACE-Q scales were selected and translated into Hong Kong Chinese. The reliability, validity, and test-retest reliability were examined using Cronbach's alpha, paired t test and Pearson's correlation coefficients. Results: The Hong Kong Chinese version of the 9 FACE-Q scales was obtained by forward-backward translation. One hundred eight male (mean age, 25.57 +/- 4.49) and 142 female (mean age, 24.61 +/- 4.54) patients were recruited for the reliability and validation process. The internal consistency (0.89-0.97) and the test-retest reliability (0.73-0.90) were found to be high. The validity of the translated questionnaires was comparable with that of the original FACE-Q. Conclusion: The results presented here prove that the 9 translated FACE-Q scales are reliable and valid instruments for research and clinical purposes in Hong Kong Chinese orthognathic patients. PMID- 29610717 TI - Direct Detection of the Ion Pair to Free Ions Transformation upon Complexation with an Ion Receptor in Non-Polar Solvents by using Conductometry. AB - In this study, we performed conductometry in various organic solvents to directly detect the transformation from tetrabutylammonium chloride (TBACl) ion-pair salt to the free ions through complexation with meso-octamethylcalix[4]pyrrole (CP), which is a well-known receptor for chloride anions. In the presence of CP, the conductivity of TBACl increases in various non-polar solvents, indicating that complexation with CP enhances the ionic dissociation of TBACl in such non-polar solvents. In other words, CP recognizes chloride as an ion-paired salt as well as a free anion in non-polar solvents. Additionally, the TBA(CP-Cl) complex exhibited a considerably lower ion-pairing constant (Kip) than TBACl in non-polar solvents, resulting in enhanced conductivity. Based on these findings, we can conclude that complexation of an anion with a hydrophobic anion receptor will be useful for creating functional and stimuli-responsive soft materials in organic solvents using coulombic forces. PMID- 29610718 TI - Alkali Metal Doping for Improved CH3NH3PbI3 Perovskite Solar Cells. AB - Organic-inorganic hybrid halide perovskites are proven to be a promising semiconductor material as the absorber layer of solar cells. However, the perovskite films always suffer from nonuniform coverage or high trap state density due to the polycrystalline characteristics, which degrade the photoelectric properties of thin films. Herein, the alkali metal ions which are stable against oxidation and reduction are used in the perovskite precursor solution to induce the process of crystallization and nucleation, then affect the properties of the perovskite film. It is found that the addition of the alkali metal ions clearly improves the quality of perovskite film: enlarges the grain sizes, reduces the defect state density, passivates the grain boundaries, increases the built-in potential (Vbi), resulting to the enhancement in the power conversion efficiency of perovskite thin film solar cell. PMID- 29610719 TI - Lead-Free Hybrid Perovskite Absorbers for Viable Application: Can We Eat the Cake and Have It too? AB - Many years since the booming of research on perovskite solar cells (PSCs), the hybrid perovskite materials developed for photovoltaic application form three main categories since 2009: (i) high-performance unstable lead-containing perovskites, (ii) low-performance lead-free perovskites, and (iii) moderate performance and stable lead-containing perovskites. The search for alternative materials to replace lead leads to the second group of perovskite materials. To date, a number of these compounds have been synthesized and applied in photovoltaic devices. Here, lead-free hybrid light absorbers used in PV devices are focused and their recent developments in related solar cell applications are reviewed comprehensively. In the first part, group 14 metals (Sn and Ge)-based perovskites are introduced with more emphasis on the optimization of Sn-based PSCs. Then concerns on halide hybrids of group 15 metals (Bi and Sb) are raised, which are mainly perovskite derivatives. At the same time, transition metal Cu based perovskites are also referred. In the end, an outlook is given on the design strategy of lead-free halide hybrid absorbers for photovoltaic applications. It is believed that this timely review can represent our unique view of the field and shed some light on the direction of development of such promising materials. PMID- 29610720 TI - Radiation-Sensitive Dendrimer-Based Drug Delivery System. AB - Combination of chemotherapy and radiotherapy is used to enhance local drug delivery while reducing off-target tissue effects. Anticancer drug doxorubicin (DOX) is loaded into l-cysteine modified G4.5 dendrimer (GC/DOX) and released at different pH values in the presence and absence of gamma-radiation. Presence of gamma-radiation significantly improves DOX release from the GC/DOX under acidic pH conditions, suggesting that GC dendrimer is a radiation-sensitive drug delivery system. GC/DOX is further evaluated by determining cytotoxicity in uterine cervical carcinoma HeLa cells. GC/DOX shows high affinity for cancer cells and effective drug release following an external stimulus (radiation exposure), whereas an in vivo zebrafish study confirms that l-cysteine acts as a radiosensitizer. GC/DOX treatment combined with radiotherapy synergistically and successfully inhibits cancer cell growth. PMID- 29610721 TI - Electrochemically Synthesis of Nickel Cobalt Sulfide for High-Performance Flexible Asymmetric Supercapacitors. AB - A lightweight, flexible, and highly efficient energy management strategy is highly desirable for flexible electronic devices to meet a rapidly growing demand. Herein, Ni-Co-S nanosheet array is successfully deposited on graphene foam (Ni-Co-S/GF) by a one-step electrochemical method. The Ni-Co-S/GF composed of Ni-Co-S nanosheet array which is vertically aligned to GF and provides a large interfacial area for redox reactions with optimum interstitials facilitates the ions diffusion. The Ni-Co-S/GF electrodes have high specific capacitance values of 2918 and 2364 F g-1 at current densities of 1 and 20 A g-1, respectively. Using such hierarchical Ni-Co-S/GF as the cathode, a flexible asymmetric supercapacitor (ASC) is further fabricated with polypyrrple(PPy)/GF as the anode. The flexible asymmetric supercapacitors have maximum operation potential window of 1.65 V, and energy densities of 79.3 and 37.7 Wh kg-1 when the power densities are 825.0 and 16100 W kg-1, respectively. It's worth nothing that the ASC cells have robust flexibility with performance well maintained when the devices were bent to different angles from 180 degrees to 15 degrees at a duration of 5 min. The efficient electrochemical deposition method of Ni-Co-S with a preferred orientation of nanosheet arrays is applicable for the flexible energy storage devices. PMID- 29610722 TI - Electrocatalysts for Hydrogen Evolution in Alkaline Electrolytes: Mechanisms, Challenges, and Prospective Solutions. AB - Hydrogen evolution reaction (HER) in alkaline medium is currently a point of focus for sustainable development of hydrogen as an alternative clean fuel for various energy systems, but suffers from sluggish reaction kinetics due to additional water dissociation step. So, the state-of-the-art catalysts performing well in acidic media lose considerable catalytic performance in alkaline media. This review summarizes the recent developments to overcome the kinetics issues of alkaline HER, synthesis of materials with modified morphologies, and electronic structures to tune the active sites and their applications as efficient catalysts for HER. It first explains the fundamentals and electrochemistry of HER and then outlines the requirements for an efficient and stable catalyst in alkaline medium. The challenges with alkaline HER and limitation with the electrocatalysts along with prospective solutions are then highlighted. It further describes the synthesis methods of advanced nanostructures based on carbon, noble, and inexpensive metals and their heterogeneous structures. These heterogeneous structures provide some ideal systems for analyzing the role of structure and synergy on alkaline HER catalysis. At the end, it provides the concluding remarks and future perspectives that can be helpful for tuning the catalysts active-sites with improved electrochemical efficiencies in future. PMID- 29610723 TI - Increasing Photovoltaic Performance of an Organic Cationic Chromophore by Anion Exchange. AB - A symmetrical cyanine dye chromophore is modified with different counteranions to study the effect on crystal packing, polarizability, thermal stability, optical properties, light absorbing layer morphology, and organic photovoltaic (OPV) device parameters. Four sulfonate-based anions and the bulky bistriflylimide anion are introduced to the 2-[5-(1,3-dihydro-1,3,3-trimethyl-2H-indol-2-ylidene) 1,3-pentadien-1-yl]-1,3,3-trimethyl-3H-indolium chromophore using an Amberlyst A26 (OH- form) anion exchanger. Anionic charge distribution clearly correlates with device performance, whereby an average efficiency of 2% was reached in a standard bilayer organic solar. Evidence is given that the negative charge of the anion distributed over a large number of atoms is significantly more important than the size of the organic moieties of the sulfonate charge carrying group. This provides a clear strategy for future design of more efficient cyanine dyes for OPV applications. PMID- 29610724 TI - High Discharge Energy Density at Low Electric Field Using an Aligned Titanium Dioxide/Lead Zirconate Titanate Nanowire Array. AB - Polymer-based capacitors with high energy density have attracted significant attention in recent years due to their wide range of potential applications in electronic devices. However, the obtained high energy density is predominantly dependent on high applied electric field, e.g., 400-600 kV mm-1, which may bring more challenges relating to the failure probability. Here, a simple two-step method for synthesizing titanium dioxide/lead zirconate titanate nanowire arrays is exploited and a demonstration of their ability to achieve high discharge energy density capacitors for low operating voltage applications is provided. A high discharge energy density of 6.9 J cm-3 is achieved at low electric fields, i.e., 143 kV mm-1, which is attributed to the high relative permittivity of 218.9 at 1 kHz and high polarization of 23.35 uC cm-2 at this electric field. The discharge energy density obtained in this work is the highest known for a ceramic/polymer nanocomposite at such a low electric field. The novel nanowire arrays used in this work are applicable to a wide range of fields, such as energy harvesting, energy storage, and photocatalysis. PMID- 29610725 TI - Guidance and Self-Sorting of Active Swimmers: 3D Periodic Arrays Increase Persistence Length of Human Sperm Selecting for the Fittest. AB - Male infertility is a reproductive disease, and existing clinical solutions for this condition often involve long and cumbersome sperm sorting methods, including preprocessing and centrifugation-based steps. These methods also fall short when sorting for sperm free of reactive oxygen species, DNA damage, and epigenetic aberrations. Although several microfluidic platforms exist, they suffer from structural complexities, i.e., pumps or chemoattractants, setting insurmountable barriers to clinical adoption. Inspired by the natural filter-like capabilities of the female reproductive tract for sperm selection, a model-driven design, featuring pillar arrays that efficiently and noninvasively isolate highly motile and morphologically normal sperm, with lower epigenetic global methylation, from raw semen, is presented. The Simple Periodic ARray for Trapping And isolatioN (SPARTAN) created here modulates the directional persistence of sperm, increasing the spatial separation between progressive and nonprogressive motile sperm populations within an unprecedentedly short 10 min assay time. With over 99% motility of sorted sperm, a 5-fold improvement in morphology, 3-fold increase in nuclear maturity, and 2-4-fold enhancement in DNA integrity, SPARTAN offers to standardize sperm selection while eliminating operator-to-operator variations, centrifugation, and flow. SPARTAN can also be applied in other areas, including conservation ecology, breeding of farm animals, and design of flagellar microrobots for diagnostics. PMID- 29610726 TI - Electroplex as a New Concept of Universal Host for Improved Efficiency and Lifetime in Red, Yellow, Green, and Blue Phosphorescent Organic Light-Emitting Diodes. AB - A new concept of host, electroplex host, is developed for high efficiency and long lifetime phosphorescent organic light-emitting diodes by mixing two host materials generating an electroplex under an electric field. A carbazole-type host and a triazine-type host are selected as the host materials to form the electroplex host. The electroplex host is found to induce light emission through an energy transfer process rather than charge trapping, and universally improves the lifetime of red, yellow, green, and blue phosphorescent organic light emitting diodes by more than four times. Furthermore, the electroplex host shows much longer lifetime than a common exciplex host. This is the first demonstration of using the electroplex as the host of high efficiency and long lifetime phosphorescent organic light-emitting diodes. PMID- 29610727 TI - Modified Back Contact Interface of CZTSe Thin Film Solar Cells: Elimination of Double Layer Distribution in Absorber Layer. AB - Double layer distribution exists in Cu2SnZnSe4 (CZTSe) thin films prepared by selenizing the metallic precursors, which will degrade the back contact of Mo substrate to absorber layer and thus suppressing the performance of solar cell. In this work, the double-layer distribution of CZTSe film is eliminated entirely and the formation of MoSe2 interfacial layer is inhibited successfully. CZTSe film is prepared by selenizing the precursor deposited by electrodeposition method under Se and SnSe x mixed atmosphere. It is found that the insufficient reaction between ZnSe and Cu-Sn-Se phases in the bottom of the film is the reason why the double layer distribution of CZTSe film is formed. By increasing Sn content in the metallic precursor, thus making up the loss of Sn because of the decomposition of CZTSe and facilitate the diffusion of liquid Cu2Se, the double layer distribution is eliminated entirely. The crystallization of the formed thin film is dense and the grains go through the entire film without voids. And there is no obvious MoSe2 layer formed between CZTSe and Mo. As a consequence, the series resistance of the solar cell reduces significantly to 0.14 Omega cm2 and a CZTSe solar cell with efficiency of 7.2% is fabricated. PMID- 29610728 TI - Formation and Diffusion of Metal Impurities in Perovskite Solar Cell Material CH3NH3PbI3: Implications on Solar Cell Degradation and Choice of Electrode. AB - Solar cells based on methylammonium lead triiodide (MAPbI3) have shown remarkable progress in recent years and have demonstrated efficiencies greater than 20%. However, the long-term stability of MAPbI3-based solar cells has yet to be achieved. Besides the well-known chemical and thermal instabilities, significant native ion migration in lead halide perovskites leads to current-voltage hysteresis and photoinduced phase segregation. Recently, it is further revealed that, despite having excellent chemical stability, the Au electrode can cause serious solar cell degradation due to Au diffusion into MAPbI3. In addition to Au, many other metals have been used as electrodes in MAPbI3 solar cells. However, how the external metal impurities introduced by electrodes affect the long-term stability of MAPbI3 solar cells has rarely been studied. A comprehensive study of formation energetics and diffusion dynamics of a number of noble and transition metal impurities (Au, Ag, Cu, Cr, Mo, W, Co, Ni, Pd) in MAPbI3 based on first-principles calculations is reported herein. The results uncover important general trends of impurity formation and diffusion in MAPbI3 and provide useful guidance for identifying the optimal metal electrodes that do not introduce electrically active impurity defects in MAPbI3 while having low resistivities and suitable work functions for carrier extraction. PMID- 29610730 TI - Comparison of the efficacy of dispensing granules with traditional decoction: a systematic review and meta-analysis. AB - Background: Dispensing granules have been developed for about 20 years. However, whether they are as effective as the traditional decoction kept unclear. This systematic review and meta-analysis was made to assess the efficacy of dispensing granules compared with traditional decoction. Methods: We searched four databases since their inception to 9th September in 2016. Two authors independently identified trials, extracted data and assessed risk of bias with Cochrane Reviewer's Handbook 5.0. We conducted meta-analysis with RevMan 5.1.0 software for eligible and appropriate trials. Results: In the end, 7,035 participants from 51 randomized controlled trials (RCTs) which compared dispensing granules with traditional decoction were included in this systematic review. There were 33 different kinds of diseases for investigation, of which 8 RCTs observed common cold, 4 RCTs observed migraine. For rheumatoid arthritis, insomnia and hypertension, there were 3 RCTs reported respectively. The last RCTs reported different kinds of diseases in one or two trials. The majority of trials were in low methodological quality. Thirty-eight (74.5%) RCTs showed that the efficacy of dispensing granules were similar with traditional decoction, 6 (11.8%) RCTs reported that the therapeutic efficacy of dispensing granules were significantly better than traditional decoction. We conducted meta-analysis for 4 trials investigating patients with migraine. The results showed that dispensing granules reduced headache frequency by about 1.03 attacks per month as compared to traditional decoction. No evidence was found in terms of migraine intensity and duration. Conclusions: The low quality of RCTs and conflicting results made it difficult to draw a definite conclusion. In the future, it needs much more evidence to explore the efficacy and safety of dispensing granules. N-of-1 trials and fuzzy comprehensive evaluation methods may be better choices for assessing the efficacy of them than RCTs. PMID- 29610729 TI - Valence State Manipulation of Cerium Oxide Nanoparticles on a Titanium Surface for Modulating Cell Fate and Bone Formation. AB - Understanding cell-biomaterial interactions is critical for the control of cell fate for tissue engineering and regenerative medicine. Here, cerium oxide nanoparticles (CeONPs) are applied at different Ce4+/Ce3+ ratios (i.e., 0.46, 1.23, and 3.23) to titanium substrate surfaces by magnetron sputtering and vacuum annealing. Evaluation of the cytotoxicity of the modified surface to cultured rat bone marrow mesenchymal stem cells (BMSCs) reveals that the cytocompatibility and cell proliferation are proportional to the increases in Ce4+/Ce3+ ratio on titanium surface. The bone formation capability induced by these surface modified titanium alloys is evaluated by implanting various CeONP samples into the intramedullary cavity of rat femur for 8 weeks. New bone formation adjacent to the implant shows a close relationship to the surface Ce4+/Ce3+ ratio; higher Ce4+/Ce3+ ratio achieves better osseointegration. The mechanism of this in vivo outcome is explored by culturing rat BMSCs and RAW264.7 murine macrophages on CeONP samples for different durations. The improvement in osteogenic differentiation capability of BMSCs is directly proportional to the increased Ce4+/Ce3+ ratio on the titanium surface. Increases in the Ce4+/Ce3+ ratio also elevate the polarization of the M2 phenotype of RAW264.7 murine macrophages, particularly with respect to the healing-associated M2 percentage and anti inflammatory cytokine secretion. The manipulation of valence states of CeONPs appears to provide an effective modulation of the osteogenic capability of stem cells and the M2 polarization of macrophages, resulting in favorable outcomes of new bone formation and osseointegration. PMID- 29610731 TI - Microscopic colitis-microbiome, barrier function and associated diseases. AB - Microscopic colitis (MC) is a chronic inflammatory bowel disease (IBD) with little in terms of endoscopic abnormalities and is frequently associated with other autoimmune diseases. The peak incidence of the disease is in middle aged or older populations, mostly females. The pathogenesis of MC is complex, multifactorial and poorly understood. Current concepts revolve around innate immunity or microbiome alterations as well as gut barrier dysfunction, all of which lead to the development of subtle inflammatory lesions in gut mucosa. The results of numerous basic and clinical studies involving molecular techniques as well as advanced endoscopic imaging revealed the important role of both intrinsic (e.g., hormonal) as well as extrinsic (e.g., NSAIDs and PPIs) factors in the modulation of gastrointestinal microbiome and MC pathogenesis. Capsule endoscopy as well confocal endomicroscopy imaging, alongside standard endoscopic techniques offer new tools in the evaluation of MC patients and allow their better stratification for novel treatment protocols based on modulation of gut microbiome and barrier function. PMID- 29610732 TI - Thoracic perforations-surgical techniques. AB - Esophageal perforation may occur spontaneously, iatrogenically or in connection with traumas. Sepsis may develop in connection with mediastinal and pleural exposure in a very short time as a consequence of disintegration of the esophagus. Esophageal perforation is an emergency accompanied with a high level of mortality and morbidity. Rate of mortality for the perforations in the thoracic region is higher than that in the cervical and abdominal regions. Delay in diagnosis and treatment is the most important factor to affect the mortality. A quick and true diagnosis of esophageal perforation is prerequisite for a successful treatment. There is no certain consensus in relation with the optimal treatment of that life-threatening condition. However, in the event that perforation is detected early in a healthy esophagus, then primary repair is recommended. When it is detected late, nonoperative conservative treatment would be appropriate. The rates of mortality for the operations following a period of 24 h after rupture formation are higher than 50%. Esophagectomy is a type of an operation that is to be considered in the event of an end stage benign esophageal disease or of a large esophageal damage that does not allow primary repair. Significant decrease has been observed in the morbidity and mortality of esophageal perforation due to the improvements in the endoscopical techniques today. Minimally invasive techniques, in which drug eluting stents come first, will become an important step for the treatment of esophageal perforations in the forthcoming years. PMID- 29610733 TI - Peculiarities of intra-thoracic colon interposition-eso-coloplasty: indications, surgical management and outcomes. AB - Stomach is the usual organ of choice for oesophageal replacement. Gastric pull-up is a standardized, fast and secure procedure, requiring only one anastomosis and usually performed with mini-invasive techniques. Colon is used when the stomach is not available, for tumours of the upper oesophagus or the hypopharynx, for benign or paediatric diseases. It is a complex surgery requiring a specific pre operative management, three or four anastomoses, and a careful choice of the route of reconstruction. Early post-operative complications, such as anastomotic leakage, are frequent. Long-term outcomes are marked by strictures of the anastomosis and redundancy, but the reported quality of life of the patients is good. Eso-coloplasty remains a safe and feasible alternative to gastric pull-up for oesophageal replacement, for specific indications. PMID- 29610734 TI - Extracting and utilizing electronic health data from Epic for research. AB - Many institutions would like to harness their electronic health record (EHR) data for research. However, with many EHR systems, this process is remarkably difficult. We have been using our vast EHR system for research very effectively, with substantial research support and many publications. Herein we share our process and provide recommendations for others wanting to utilize their EHR data for research. PMID- 29610735 TI - Hypertension, aortic stenosis, and aortic regurgitation. PMID- 29610736 TI - Initiation of antihypertensive therapy. PMID- 29610737 TI - Variable selection in Logistic regression model with genetic algorithm. AB - Variable or feature selection is one of the most important steps in model specification. Especially in the case of medical-decision making, the direct use of a medical database, without a previous analysis and preprocessing step, is often counterproductive. In this way, the variable selection represents the method of choosing the most relevant attributes from the database in order to build a robust learning models and, thus, to improve the performance of the models used in the decision process. In biomedical research, the purpose of variable selection is to select clinically important and statistically significant variables, while excluding unrelated or noise variables. A variety of methods exist for variable selection, but none of them is without limitations. For example, the stepwise approach, which is highly used, adds the best variable in each cycle generally producing an acceptable set of variables. Nevertheless, it is limited by the fact that it commonly trapped in local optima. The best subset approach can systematically search the entire covariate pattern space, but the solution pool can be extremely large with tens to hundreds of variables, which is the case in nowadays clinical data. Genetic algorithms (GA) are heuristic optimization approaches and can be used for variable selection in multivariable regression models. This tutorial paper aims to provide a step-by step approach to the use of GA in variable selection. The R code provided in the text can be extended and adapted to other data analysis needs. PMID- 29610738 TI - Tutorial: development of an online risk calculator platform. AB - Risk calculators are online tools developed for use by physicians in clinical settings to predict the risk of a clinical event, and as an aid in personalizing medical decision-making. Cleveland Clinic prediction models are listed at http://rcalc.ccf.org. We illustrate how we used R to create a risk calculator, and demonstrate the ease of using R, RStudio, and a Shiny package. PMID- 29610739 TI - Dr. Howard West: lung cancer research, a field of great optimism. PMID- 29610740 TI - Interview with Prof. Katsushi Tokunaga during the APCHG 2017. PMID- 29610741 TI - Dr. Stephen T. S. Lam: clinical genetic services in the private sector could use expansion. PMID- 29610742 TI - Dr. Le Nguyen Uyen Chi: surgical education with ASOHNS. PMID- 29610743 TI - Prof. Stuart MacKay: advances in sleep surgery in Australia. PMID- 29610744 TI - Secondary analysis of electronic health records in critical care medicine. PMID- 29610745 TI - LAMP assay for specific detection of Asian and African lineage Zika virus: will it meet the expectations? PMID- 29610746 TI - CMTM6 stabilizes PD-L1 expression and refines its prognostic value in tumors. PMID- 29610747 TI - Sodium-glucose cotransporter-2 inhibitors and cardiovascular outcomes: insights from the CVD-REAL study. PMID- 29610748 TI - Protease activated receptor 4: a backup receptor or a dark horse as a target in antiplatelet therapy? PMID- 29610749 TI - New insight into type 1 diabetes development: resolving early diabetogenic CD4+ T cell responses that precede seroconversion. PMID- 29610750 TI - Geospatial mapping to identify feasible HIV prevention and treatment strategies that target specific settings. PMID- 29610751 TI - Lowering low-density lipoprotein cholesterol by PCSK9 inhibition in patients with diabetes on insulin therapy: is it efficacious and safe? PMID- 29610752 TI - First-line osimertinib in patients with EGFR-mutated advanced non-small cell lung cancer. PMID- 29610753 TI - Insulin degludec U100 is associated with lower risk for severe and symptomatic hypoglycemia as compared with insulin glargine U100 in subjects with type 1 diabetes. PMID- 29610754 TI - MucoJet: a novel noninvasive buccal mucosa immunization strategy. PMID- 29610755 TI - Treatment of thoracic aortic aneurysm. PMID- 29610756 TI - How do I peer-review a scientific article?-a personal perspective. AB - Peer-review is an essential activity for the vast majority of credited scientific journals and represents the cornerstone for assessing the quality of potential publications, since it is substantially aimed to identify drawbacks or inaccuracies that may flaw the outcome or the presentation of scientific research. Since the importance of this activity is seldom underestimated by some referees, the purpose of this article is to present a personal and arbitrary perspective on how a scientific article should be peer-reviewed, offering a tentative checklist aimed to describe the most important criteria that should be considered. These basically include accepting the assignment only when the topic is in accordance with referee's background, disclosing potential conflicts of interest, checking availability and time according to size and complexity of the article, identifying the innovative value of the manuscript, providing exhaustive and clear comments, expressing disagreement with a fair and balanced approach, weighting revisions according to the importance of the journal, summarizing recommendations according to previous comments, maintaining confidentiality throughout and after the peer-review process. I really hope that some notions reported in this dissertation may be a guide or a help, especially for young scientists, who are willing to be engaged in peer-review activity for scientific journals. PMID- 29610757 TI - The subtypes of microscopic colitis from a pathologist's perspective: past, present and future. AB - Microscopic colitis (MC) is a chronic inflammatory bowel disease, encompassing a triad of chronic diarrhea, normal endoscopy and characteristic histological findings. MC embraces two histological subtypes described as lymphocytic colitis (LC) and collagenous colitis (CC). The diagnostic criteria of MC were established several years ago and the histological description of LC and CC was based almost exclusively on heamatoxylin-eosin (HE) stained sections. Since the establishment of the diagnostic criteria, important changes have occurred in the concept and diagnostic methods of MC: the emergence of the entity "microscopic colitis incomplete" (MCi), comprising collagenous colitis incomplete (CCi) and lymphocytic colitis incomplete (LCi) and pathologists' increasing use of special stains in everyday diagnostics. The diagnostic challenges of today are threefold: which stains to apply to properly distinguish between MC, MCi and slight inflammatory changes, how to handle cases of diagnostic uncertainty and how to minimize inter observer variability. The views of this article are from the pathologist's perspective. We describe the changes in criteria and diagnostic methods of MC occurring over time, discus pathologists' diagnostic challenges and suggest how these can be met: by automated image analysis of tissue sections and by international collaboration under auspices of the PRO-MC collaboration, a European collaboration on the disease course of MC. PMID- 29610758 TI - On- vs. off-pump coronary artery bypass grafting in a heterogeneous patient population. PMID- 29610759 TI - Molecular signature of the imprintosome complex at the mating-type locus in fission yeast. AB - Genetic and molecular studies have indicated that an epigenetic imprint at mat1, the sexual locus of fission yeast, initiates mating type switching. The polar DNA replication of mat1 generates an imprint on the Watson strand. The process by which the imprint is formed and maintained through the cell cycle remains unclear. To understand better the mechanism of imprint formation and stability, we characterized the recruitment of early players of mating type switching at the mat1 region. We found that the switch activating protein 1 (Sap1) is preferentially recruited inside the mat1M allele on a sequence (SS13) that enhances the imprint. The lysine specific demethylases, Lsd1/2, that control the replication fork pause at MPS1 and the formation of the imprint are specifically drafted inside of mat1, regardless of the allele. The CENP-B homolog, Abp1, is highly enriched next to mat1 but it is not required in the process. Additionally, we established the computational signature of the imprint. Using this signature, we show that both sides of the imprinted molecule are bound by Lsd1/2 and Sap1, suggesting a nucleoprotein protective structure defined as imprintosome. PMID- 29610760 TI - Non-canonical regulation of glutathione and trehalose biosynthesis characterizes non-Saccharomyces wine yeasts with poor performance in active dry yeast production. AB - Several yeast species, belonging to Saccharomyces and non-Saccharomyces genera, play fundamental roles during spontaneous must grape fermentation, and recent studies have shown that mixed fermentations, co-inoculated with S. cerevisiae and non-Saccharomyces strains, can improve wine organoleptic properties. During active dry yeast (ADY) production, antioxidant systems play an essential role in yeast survival and vitality as both biomass propagation and dehydration cause cellular oxidative stress and negatively affect technological performance. Mechanisms for adaptation and resistance to desiccation have been described for S. cerevisiae, but no data are available on the physiology and oxidative stress response of non-Saccharomyces wine yeasts and their potential impact on ADY production. In this study we analyzed the oxidative stress response in several non-Saccharomyces yeast species by measuring the activity of reactive oxygen species (ROS) scavenging enzymes, e.g., catalase and glutathione reductase, accumulation of protective metabolites, e.g., trehalose and reduced glutathione (GSH), and lipid and protein oxidation levels. Our data suggest that non canonical regulation of glutathione and trehalose biosynthesis could cause poor fermentative performance after ADY production, as it corroborates the corrective effect of antioxidant treatments, during biomass propagation, with both pure chemicals and food-grade argan oil. PMID- 29610761 TI - Impact of F1Fo-ATP-synthase dimer assembly factors on mitochondrial function and organismic aging. AB - In aerobic organisms, mitochondrial F1Fo-ATP-synthase is the major site of ATP production. Beside this fundamental role, the protein complex is involved in shaping and maintenance of cristae. Previous electron microscopic studies identified the dissociation of F1Fo-ATP-synthase dimers and oligomers during organismic aging correlating with a massive remodeling of the mitochondrial inner membrane. Here we report results aimed to experimentally proof this impact and to obtain further insights into the control of these processes. We focused on the role of the two dimer assembly factors PaATPE and PaATPG of the aging model Podospora anserina. Ablation of either protein strongly affects mitochondrial function and leads to an accumulation of senescence markers demonstrating that the inhibition of dimer formation negatively influences vital functions and accelerates organismic aging. Our data validate a model that links mitochondrial membrane remodeling to aging and identify specific molecular components triggering this process. PMID- 29610763 TI - Internalized Stigma among Patients with Mental Illness Attending Psychiatric Follow-Up at Dilla University Referral Hospital, Southern Ethiopia. AB - Background: This study tried to reflect evidences regarding internalized stigma and assessed risk factors of internalized stigma. Objective: It aims to assess the magnitude, domains, and covariates of internalized stigma among patients with mental illness in southern Ethiopia. Methods: The study was carried out by using a cross-sectional study design at Dilla University Referral Hospital (DURH). A total of 317 patients with mental illness were involved. Internalized stigma was measured using Internalized Stigma of Mental Illness (ISMI) scale. Data analysis was done using SPSS version 20. Descriptive statistics and logistic regression were done. Result: The prevalence of internalized stigma was 32.1% among people living with mental illness in Dilla University Referral Hospital. Being female, medication nonadherence, and lack of family support were factors independently associated with internalized stigma. Conclusion: The results of this study found an intermediate prevalence of internalized stigma among people living with mental illness in Dilla University Referral Hospital (DURH). It revealed how much antistigma campaigns are so much important to tackle internalized stigma among people living with mental illness. Incorporating counseling and structured therapy played an important role in maximizing their quality of life. PMID- 29610762 TI - Hippocampal Pathophysiology: Commonality Shared by Temporal Lobe Epilepsy and Psychiatric Disorders. AB - Accumulating evidence points to the association of epilepsy, particularly, temporal lobe epilepsy (TLE), with psychiatric disorders, such as schizophrenia. Among these illnesses, the hippocampus is considered the regional focal point of the brain, playing an important role in cognition, psychosis, and seizure activity and potentially suggesting common etiologies and pathophysiology of TLE and schizophrenia. In the present review, we overview abnormal network connectivity between the dentate gyrus (DG) and the Cornus Ammonis area 3 (CA3) subregions of the hippocampus relative to the induction of epilepsy and schizophrenia. In light of our recent finding on the misguidance of hippocampal mossy fiber projection in the rodent model of schizophrenia, we discuss whether ectopic mossy fiber projection is a commonality in order to evoke TLE as well as symptoms related to schizophrenia. PMID- 29610764 TI - Dysmenorrhea among University Health Science Students, Northern Ethiopia: Impact and Associated Factors. AB - Background: It is estimated that more than half of all women in adolescence age suffer from dysmenorrhea and it often interferes with their daily physical and emotional aspects. It is the leading cause of short-term school absenteeism and is associated with a negative impact on academic and daily activities. Objectives: To investigate impacts of dysmenorrhea, factors associated with it, and its self-management strategies used by health science students. Methods: A cross-sectional institution based study was conducted among 246 Mekelle University health science students selected by stratified random sampling technique. Data were collected using self-administered semistructured questionnaire. Data were analyzed using SPSS 16. Results: The prevalence of dysmenorrhea was 71.8%. Participants who had long menstrual cycle interval, long menses flows, and positive family history and who were alcohol users were more likely to had dysmenorrhea. Participants reported that 28.6% feel depressed, 16.2% are absent from class, and 22.9% had poor personal relationship due to dysmenorrhea and 78.2% of them practiced self-medication. Conclusion: Dysmenorrhea is common among Mekelle University health science students and it is major problem representing the cause of feeling depressed, poor personal relationship, and class absenteeism. Majority of the study participants used self medication to treat dysmenorrhea. PMID- 29610765 TI - Does Oral Implant Design Affect Marginal Bone Loss? Results of a Parallel-Group Randomized Controlled Equivalence Trial. AB - Objective: To test whether or not the modified design of the test implant (intended to increase primary stability) has an equivalent effect on MBL compared to the control. Methods: Forty patients were randomly assigned to receive test or control implants to be installed in identically dimensioned bony beds. Implants were radiographically monitored at installation, at prosthetic delivery, and after one year. Treatments were considered equivalent if the 90% confidence interval (CI) for the mean difference (MD) in MBL was in between -0.25 and 0.25 mm. Additionally, several soft tissue parameters and patient-reported outcome measures (PROMs) were evaluated. Linear mixed models were fitted for each patient to assess time effects on response variables. Results: Thirty-three patients (21 males, 12 females; 58.2 +/- 15.2 years old) with 81 implants (47 test, 34 control) were available for analysis after a mean observation period of 13.9 +/- 4.5 months (3 dropouts, 3 missed appointments, and 1 missing file). The adjusted MD in MBL after one year was -0.13 mm (90% CI: -0.46-0.19; test group: -0.49; control group: -0.36; p = 0.507). Conclusion: Both implant systems can be considered successful after one year of observation. Concerning MBL in the presented setup, equivalence of the treatments cannot be concluded. Registration: This trial is registered with the German Clinical Trials Register (ID: DRKS00007877). PMID- 29610766 TI - Checking procalcitonin suitability for prognosis and antimicrobial therapy monitoring in burn patients. AB - Background: Due to greater infection susceptibility, sepsis is the main cause of death in burn patients. Quick diagnosis and patient stratification, early and appropriated antimicrobial therapy, and focus control are crucial for patients' survival. On the other hand, superfluous extension of therapy is associated with adverse events and arousal of microbial resistance. The use of biomarkers, necessarily coupled with close clinical examination, may predict outcomes, stratifying patients who need more intensive care, and monitor the efficacy of antimicrobial therapy, allowing faster de-escalation or stop, reducing the development of resistance and possibly the financial burden, without increasing mortality. The aim of this work is to check the suitability of procalcitonin (PCT) to fulfill these goals in a large sample of septic burn patients. Methods: One hundred and one patients, with 15% or more of total body surface area (TBSA) burned, admitted from January 2011 to December 2014 at Coimbra Burns Unit (CBU), in Portugal were included in the sample. All patients had a diagnosis of sepsis, according to the American Burn Association (ABA) criteria. The sample was factored by survival (68 survivors and 33 non-survivors). The maximum value of PCT in each day was used for statistical analysis. Data were summarized by location measures (mean, median, minimum, maximum, quartiles) and dispersion measures (standard error and range measures). Statistical analysis was performed with SPSS(c) 23.0 IBM(c) for Windows(c). Results: There were statistically significant differences between PCT levels of patients from the survivor and non survivor groups during the first and the last weeks of hospitalization as well as during the first week after sepsis suspicion, being slightly higher during this period. During the first 7 days of antimicrobial therapy, PCT was always higher in the non-survivor, still without reaching statistical significance, but when the analysis was extended till the 15th day, PCT increased significantly, rapidly, and steadily, denouncing therapy failure. Conclusion: Despite being not an ideal biomarker, PCT proved to have good prognostic power in septic burn patients, paralleling the evolution of the infectious process and reflecting the efficacy of antimicrobial therapy, and the inclusion of its serial dosing may be advised to reinforce antimicrobial stewardship programs at burn units; meanwhile, more accurate approaches are not available. PMID- 29610767 TI - Brain's functional network clustering coefficient changes in response to instruction (RTI) in students with and without reading disabilities: Multi leveled reading brain's RTI. AB - In students in grades 4 to 9 (22 males, 20 females), two reading disability groups-dyslexia (n = 20) or oral and written language learning disability (OWL LD) (n = 6)-were compared to each other and two kinds of control groups-typical readers (n = 6) or dysgraphia (n = 10) on word reading/spelling skills and fMRI imaging before and after completing 18 computerized reading lessons. Mixed ANOVAs showed significant time effects on repeated measures within participants and between groups effects on three behavioral markers of reading disabilities-word reading/spelling: All groups improved on the three behavioral measures, but those without disabilities remained higher than those with reading disabilities. On fMRI reading tasks, analyzed for graph theory derived clustering coefficients within a neural network involved in cognitive control functions, on a word level task the time * group interaction was significant in right medial cingulate; on a syntax level task the time * group interaction was significant in left superior frontal and left inferior frontal gyri; and on a multi-sentence text level task the time * group interaction was significant in right middle frontal gyrus. Three white matter-gray matter correlations became significant only after reading instruction: axial diffusivity in left superior frontal region with right inferior frontal gyrus during word reading judgments; mean diffusivity in left superior corona radiata with left middle frontal gyrus during sentence reading judgments; and mean diffusivity in left anterior corona radiata with right middle frontal gyrus during multi-sentence reading judgments. Significance of results for behavioral and brain response to reading instruction (RTI) is discussed. PMID- 29610768 TI - Sensorimotor Representation of Speech Perception. Cross-Decoding of Place of Articulation Features during Selective Attention to Syllables in 7T fMRI. AB - Sensorimotor integration, the translation between acoustic signals and motoric programs, may constitute a crucial mechanism for speech. During speech perception, the acoustic-motoric translations include the recruitment of cortical areas for the representation of speech articulatory features, such as place of articulation. Selective attention can shape the processing and performance of speech perception tasks. Whether and where sensorimotor integration takes place during attentive speech perception remains to be explored. Here, we investigate articulatory feature representations of spoken consonant-vowel (CV) syllables during two distinct tasks. Fourteen healthy humans attended to either the vowel or the consonant within a syllable in separate delayed-match-to-sample tasks. Single-trial fMRI blood oxygenation level-dependent (BOLD) responses from perception periods were analyzed using multivariate pattern classification and a searchlight approach to reveal neural activation patterns sensitive to the processing of place of articulation (i.e., bilabial/labiodental vs. alveolar). To isolate place of articulation representation from acoustic covariation, we applied a cross-decoding (generalization) procedure across distinct features of manner of articulation (i.e., stop, fricative, and nasal). We found evidence for the representation of place of articulation across tasks and in both tasks separately: for attention to vowels, generalization maps included bilateral clusters of superior and posterior temporal, insular, and frontal regions; for attention to consonants, generalization maps encompassed clusters in temporoparietal, insular, and frontal regions within the right hemisphere only. Our results specify the cortical representation of place of articulation features generalized across manner of articulation during attentive syllable perception, thus supporting sensorimotor integration during attentive speech perception and demonstrating the value of generalization. PMID- 29610769 TI - Improving driving advice provided to cardiology patients on discharge. AB - Certain cardiac conditions can limit patients' ability to drive. It remains the doctors' responsibility to advise patients of any driving restrictions and is particularly important after certain diagnoses or procedures. We identified that the quality of documented advice was variable and frequently no written driving advice was recorded on discharge. It was apparent that there was a lack of awareness and knowledge of the current Driving and Vehicle Licensing Agency (DVLA) guidance among junior doctors. We therefore designed a quality improvement project using Plan-Do-Study-Act (PDSA) methodology to improve the provision of driving advice on discharge from a cardiology ward by focusing on staff education. After collecting baseline data, we created a template with cardiology specific DVLA advice. During the second PDSA cycle, we improved the electronic template and also introduced a hard copy on the ward. During the third PDSA cycle, we incorporated information on DVLA guidance in the specialty induction session. We also evaluated junior doctors' confidence of providing driving advice before and after this intervention. Baseline measurements showed that 10% (9/92) of all discharge summaries included driving advice. This improved to 49% (34/69) after the third PDSA cycle. Importantly, after receiving information on driving advice in the induction, junior doctors felt more confident in providing driving advice to cardiology patients on discharge. In conclusion, the provision of driving advice on discharge is an important element of patient safety. However, clinicians' knowledge and awareness of current DVLA guidance is often limited. We demonstrated a significant increase in the provision of driving advice by introducing a standardised template. PMID- 29610770 TI - Reducing the number of invalid surgical consents in the day surgery unit. AB - Aim: To reduce the number of invalid surgical consents in the Singapore National Eye Centre Day Surgery Unit over a period of 6 months. Methodology: A multidisciplinary team involving doctors, nurses, day surgery unit, operating theatre, listing and clinical audit staff looked into the listing process and the root causes of the high number of invalid consents. A Pareto chart detailing the top causes of invalid consents was drawn, and with a prioritisation matrix, feasible yet effective changes were identified and effected. Plan-Do-Study-Act (PDSA) cycles included moving consent checks upstream, getting invalid consents amended on the same day, sending emails to raise awareness on invalid consents and posters in clinics to emphasise the correct way to fill up consent forms. Result: There has been a progressive downtrend in the monthly mean percentage of invalid consents since the introduction of PDSA cycles. There was a significant reduction in the mean rate of rejected consents from the preintervention phase of 15.2% to the postintervention phase of 11.3%, shown with a Z score of 6.56 (P<0.05). Sustainability was also demonstrated with multiple consecutive points below the median of 14.5% on the postimplementation phase of the run chart, with estimated time-efficiency savings of USD$19 738.50 annually. Conclusion: Errors in the workplace can be reduced with a concerted effort from multiple stakeholders. It is important to have a thorough look at processes with concerned parties, so that different perspectives and skill sets can be harnessed to determine and implement feasible and effective interventions. PMID- 29610771 TI - Enhancing the performance of gastrointestinal tumour board by improving documentation. AB - Tumour board contributes to providing better patient care by using a multidisciplinary team approach. In the efforts of evaluating the performance of the gastrointestinal tumour board at our institution, it was difficult to assess past performance due to lack of proper use of standardised documentation tool. This project aimed at improving adherence to the documentation tool and its recommendations in order to obtain performance measures for the tumour board. A multidisciplinary team and a plan were developed to improve documentation. Four rapid improvement cycles, Plan-Do-Study-Act (PDSA) cycles, were conducted. The first cycle focused on updating the case discussion summary form (CDSF) based on experts' input and previous identified deficiencies to enhance documentation and improve performance. The second PDSA cycle aimed at incorporating the CDSF into the electronic medical records system and assessing its functionality. The third cycle was to orient and train staff on using the form and launching it. The fourth PDSA cycle aimed at assessing the ability to obtain tumour board performance measures. Adherence to completion of the CDSF improved from 82% (baseline) to 94% after the fourth PDSA cycle. Over 104 consecutive cases discussed in the tumour board between January and July 2016 and 76 cases discussed in 2015, results were as follows: adherence to National Comprehensive Cancer Network guidelines in 2016 was observed in 141 (95%) recommendations, while it was observed in 90 (92%) recommendations in 2015. Changes in the management plans were observed in 37 (36%) cases in 2016 and in 6 (8%) cases in 2015. Regarding tumour board recommendations, 87% were done within 3 months of tumour board discussion in 2016, while 69% were done in 2015. Implementing electronic standardised documentation tool improved communication among the team and enabled getting accurate data about performance measures of the tumour board with positive impact on healthcare process and outcomes. PMID- 29610772 TI - Improving routine outpatient monitoring for patients with sickle-cell disease on hydroxyurea. AB - Hydroxyurea is the gold standard treatment for prevention of vaso-occlusive crises in patients with sickle-cell anaemia. It has a narrow therapeutic index and dangerous side effects including cytopenias. There is high variation in dose response across the population. Therefore, a robust outpatient monitoring programme is crucial to ensure efficacy and safety of treatment. However, there has historically been difficulty engaging the target population in regular laboratory test monitoring programmes. This project aimed to ensure that all patients on hydroxyurea had routine blood tests at least once every 2 months which were reviewed and acted upon within the 3-year project life cycle. A specialist haematology nurse prescriber clinic service was introduced, first informally, and then formally to take blood tests, alter medication dosing, prescribe it and then write a clinic letter. The mean number of tests per patient per year rose from 0.21 at baseline to 9.05 after 2 years of the formal nurse prescriber clinic. This led to an associated increase in dose changes from 0.23 to 1.45 per patient per year. This improved the number of patients on the optimum dose of hydroxyurea. Furthermore, due to increased confidence in the outpatient monitoring, the total number of people being prescribed hydroxyurea increased from 26 to 42. Restriction of prescriptions to only those enrolled in the service has prevented unmonitored patients being at risk of the potential toxicities associated with doses that are too high. The introduction of a formal nurse-led clinic has improved the safety, efficacy and compliance and increased the number of patients on the gold standard preventative treatment for vaso-occlusive crises in sickle-cell anaemia. PMID- 29610773 TI - Are they high on steroids? Tailored interventions help improve screening for steroid-induced hyperglycaemia in hospitalised patients. AB - Steroid-induced hyperglycaemia (SIH) is a common adverse effect in patients both with and without diabetes. This project aimed to improve the screening and diagnosis of SIH by improving the knowledge of healthcare professionals who contribute to the management of SIH in hospitalised patients. Monitoring and diagnosis of SIH were measured in areas of high steroid use in our hospital from May 2016 to January 2017. Several interventions were implemented to improve knowledge and screening for SIH including a staff education programme for nurses, healthcare assistants and doctors. The Trust guidelines for SIH management were updated based on feedback from staff. The changes to the guideline included shortening the document from 14 to 4 pages, incorporating a flowchart summarising the management of SIH and publishing the guideline on the Trust intranet. A questionnaire based on the recommendations of the Joint British Diabetes Societies for SIH was used to assess the change in knowledge pre-intervention and post-intervention. Results showed an increase in junior doctors' knowledge of this topic. Although there was an initial improvement in screening for SIH, this returned to near baseline by the end of the study. This study highlights that screening for SIH can be improved by increasing the knowledge of healthcare staff. However, there is a need for ongoing interventions to sustain this change. PMID- 29610775 TI - Editorial: Digital complete dentures - quo vadis? PMID- 29610774 TI - Implementation of Failure Mode and Effects Analysis to the specimens flow in a population-based colorectal cancer screening programme using immunochemical faecal occult blood tests: a quality improvement project in the Milan colorectal cancer screening programme. AB - Background: A multidisciplinary working group applied the Healthcare Failure Mode and Effects Analysis (HFMEA) approach to the flow of kits and specimens for the first-level test of a colorectal cancer screening programme using immunochemical faecal occult blood tests. Methods: HFMEA comprised four steps: (1) identification and mapping of the process steps (subprocesses); (2) analysis of failure modes and calculation of the risk priority numbers (RPNs); (3) identification of corrective actions; and (4) follow-up and evaluation of corrective actions. Results: The team identified 9 main failure modes, 12 effects and 34 associated causes. RPN scores ranged from 2 to 96. Failure modes within the first five positions in the ranking list ordered by RPN concerned: 'degraded haemoglobin in the specimen', 'mixed-up kits' and 'anonymous specimen'. All of these could lead to false-negative results and/or subjects with positive tests not being recalled for assessment. The team planned corrective actions for those failure modes. As a result, the follow-up of corrective actions showed a significant decrease in the proportion of anonymous kits from 11.6 to 4.8 per 1000 (relative reduction of 59%). The HFMEA exercise led to a reduction in: missed positive tests; missed cancer and high-risk adenomas; complaints about the communication of test results to a person who never did the test; and false negative results due either to haemoglobin degradation or an expired sampling tube. Conclusions: HFMEA is a useful tool for reducing errors in colorectal cancer screening programmes using faecal occult blood tests and is characterised by a straightforward interpretation of results and ease of communication to healthcare managers and decision makers. PMID- 29610776 TI - Occlusion of artificial teeth in complete dentures: population-based analysis. AB - : Occlusion is a central aspect of all prosthetic restorations, including complete dentures. Within the follow-up (SHIP 1) of the regional population-based "Study of Health in Pomerania" (SHIP), a number of 3300 study participants were examined concerning the occlusion of artificial teeth in purely mucosa and non implant-borne complete dentures. These subjects were representative of the population. Therefore, occlusal bite registrations obtained in habitual intercuspation (IP) were made and were digitally evaluated with the Greifswald Digital Analyzing System (GEDAS) software based on transparent contact areas. A total of 495 subjects wore such complete dentures, of whom 438 wore maxillary dentures (217 men, 71.3 +/- 9.2 years; 221 women, 68.9 +/- 9.1 years), and 278 wore mandibular dentures (141 men, 70.4 +/- 8.5 years; 137 women, 70.4 +/- 8.5 years). The mean number of denture teeth was 13.4 +/- 0.89 in the maxilla (of which 6.8 +/- 2.77 were in occlusal contact), and 13.3 +/- 0.91 in the mandible (of which 6.8 +/- 2.97 were in occlusal contact). In general, the premolars (maxilla: 2.8 +/- 1.31; mandible: 2.6 +/- 1.29 teeth) had more occlusal contact than the molars (maxilla: 2.2 +/- 1.24; mandible: 2.3 +/- 1.23 teeth). The differences were highly significant, with P < 0.01 in the Wilcoxon test for paired samples. Furthermore, there were distinctions between both sides, with the right side having more posterior teeth in contact than the left side (maxillary right: 2.6 +/- 1.18; maxillary left: 2.5 +/- 1.14; mandibular right: 2.5 +/- 1.13; mandibular left: 2.4 +/- 1.13), each significant for the maxilla at P = 0.022 (Wilcoxon test). Here, the number of denture teeth played a role. In dentures with exactly 14 denture teeth (maxillary: n = 301; mandibular: n = 179), there were significantly more molars than premolars in contact in the mandible (premolars: 2.4 +/- 1.37; molars: 2.7 +/- 1.27; P = 0.026), whereas in the maxilla the ratio of premolars to molars in contact was reversed (premolars: 2.8 +/- 1.36; molars: 2.6 +/- 1.25); however, the latter difference proved barely significant at just P = 0.099. Women tended to have slightly fewer contact bearing teeth than men (posteriors in men: 5.1 +/- 2.04; in women: 4.9 +/- 2.03); the differences were not significant. Nor were there any significant differences between the groups < 70 years (maxillary: n = 189; mandibular: n = 101), and >= 70 years (maxillary: n = 249; mandibular: n = 177). The presence of dysfunction of the masticatory system was determined using the Helkimo Index (HI). A value of HI >= 2 was regarded as dysfunctional. The groups with and without dysfunctions differed significantly for the number of posterior teeth on the right side of the maxilla (HI >= 2: 2.2 +/- 1.34; HI < 2: 2.6 +/- 1.6; P = 0.041) in the Mann Whitney U test. The difference in the groups according to HI was found to be slightly significant regarding the number of posteriors (HI >= 2: 4.5 +/- 2.28; HI < 2: 5.1 +/- 2.00; P = 0.063) and molars (HI >= 2: 1.9 +/- 1.34; HI < 2: 2.3 +/- 1.22; P = 0.092) with occlusal contacts. The differences for the mandibular premolars and for the maxillary left posterior teeth were not significant. CONCLUSION: With regard to masticatory system dysfunctions, it makes sense to ensure that there are molar contacts, especially in the maxilla. A tendency to "premolarize" contacts should be counteracted by appropriate measures. PMID- 29610777 TI - Effects of occlusal modifications on the muscular activity of the masseter and anterior temporalis muscles. AB - The aim of this study was to analyze the effect of occlusal modifications on the muscular activity of the masseter and anterior temporalis muscles. The study included 41 healthy dentate subjects who were examined in relation to the muscle activity of the masseter and anterior temporalis muscles recorded by surface electromyography (EMG) bilaterally in two different sessions. Occlusal plastic strips (thickness: 0.4 or 0.8 mm) were placed on different mandibular teeth to simulate different bite constellations (unilateral, bilateral transversal, and bilateral diagonal). Controlled by visual feedback, the subjects performed submaximum occlusion at 10% and 35% of maximum voluntary contraction (MVC). The activity ratios of the muscles were analyzed by two-way repeated measurement analysis of variance (ANOVA), and the reliability of muscle activity data was determined by intraclass correlation coefficient (ICC) analysis. The activity ratios of the masseter muscles were not significantly different under various biting conditions. In contrast, the anterior temporalis muscles showed significant differences (P < 0.001) between unilateral configurations and the other biting conditions (bilateral transversal or diagonal), in particular during biting at 10% MVC. In general, ICC values revealed low to moderate reliability of the measurements of muscle activity. Under controlled submaximum occlusal loading, the activity behavior of the masseter muscles remained stable, whereas the anterior temporalis muscles reacted differently to distinct occlusal biting configurations. The results support the assumption that the anterior temporalis muscles might operate as fine-tuning muscles when asymmetric bite force distributions occur, for instance during chewing, caused by food fragments between the teeth. PMID- 29610778 TI - Testing occlusal performance by using chewing simulation with virtually designed substrate. AB - Physically accurate deformable models based on the finite element method (FEM) are being used for a wide range of applications, from entertainment to medicine. This article describes how we applied this method in the CAD/CAM area that is concerned with reconstructing 3D models of teeth. We simulated the process of mastication by employing a deformable model that represented the substrate, and a rigid model that represented the teeth. We extended a recent approach for substrate deformation by also modelling the fracture of the substrate by the mastication process. Although including fracturing into the process allowed us to assess a mastication result, it posed new technical challenges such as defining the start of fracturing, propagating fracture through the substrate, detecting collisions between substrate pieces after fracturing, and resolving such collisions. We developed an approach that solved these challenges. The resulting simulation allowed us to compare the functionality of different occlusal designs in a mastication process. We are convinced that these simulations are an interesting tool that could be used to improve occlusal performance, especially in complete dentures, which are nowadays being more and more digitally designed. PMID- 29610779 TI - Evaluation of flexural strength and surface properties of prepolymerized CAD/CAM PMMA-based polymers used for digital 3D complete dentures. AB - PURPOSE: The objectives of this in vitro study were to evaluate the flexural strength (FS), surface roughness (Ra), and hydrophobicity of polymethylmethacrylate (PMMA)-based computer-aided design/computer-aided manufacturing (CAD/CAM) polymers and to compare the properties of different CAD/CAM PMMA-based polymers with conventional heat-polymerized PMMA following thermal cycling. MATERIALS AND METHODS: Twenty rectangular-shaped specimens (64 * 10 * 3.3 mm) were fabricated from three CAD/CAM PMMA-based polymers (M-PM Disc [M], AvaDent Puck Disc [A], and Pink CAD/CAM Disc Polident [P], and one conventional heat-polymerized PMMA (Promolux [C]), according to ISO 20795-1:2013 standards. The specimens were divided into two subgroups (n = 10), a control and a thermocycled group. The specimens in the thermocycled group were subjected to 5000 thermal cycling procedures (5 to 55 degrees C; 30 s dwell times). The Ra value was measured using a profilometer. Contact angle (CA) was assessed using the sessile drop method to evaluate surface hydrophobicity. In addition, the FS of the specimens was tested in a universal testing machine at a crosshead speed of 1.0 mm/min. Surface texture of the materials was assessed using scanning electron microscope (SEM). The data were analyzed using two-way analysis of variance (ANOVA), followed by Tukey's HSD post-hoc test (alpha < 0.05). RESULTS: CAD/CAM PMMA-based polymers showed significantly higher FS than conventional heat polymerized PMMA for each group (P < 0.001). CAD/CAM PMMA-based polymer [P] showed the highest FS, whereas conventional PMMA [C] showed the lowest FS before and after thermal cycling (P < 0.001). There were no significant differences among the Ra values of the tested denture base polymers in the control group (P > 0.05). In the thermocycled group, the lowest Ra value was observed for CAD/CAM PMMA-based polymer [M] (P < 0.001), whereas CAD/CAM PMMA-based polymers [A] and [P], and conventional PMMA [C] had similar Ra values (P > 0.05). Conventional PMMA [C] had a significantly lower CA and consequently lower hydrophobicity compared to the CAD/CAM polymers in the control group (P < 0.001). In the thermocycled group, CAD/CAM PMMA-based polymer [A] and conventional PMMA [C] had significantly higher CA, and consequently higher hydrophobicity when compared to CAD/CAM polymers [M] and [P] (P < 0.001). However, no significant differences were found among the other materials (P > 0.05). CONCLUSIONS: The FS and hydrophobicity of the CAD/CAM PMMA-based polymers were higher than the conventional heat-polymerized PMMA, whereas the CAD/CAM PMMA-based polymers had similar Ra values to the conventional PMMA. Thermocycling had a significant effect on FS and hydrophobicity except for the Ra of denture base materials. PMID- 29610780 TI - Systematics and concepts for the digital production of complete dentures: risks and opportunities. AB - The rehabilitation of the edentulous patient with complete dentures is still an essential aspect of dental prosthetics. Modern digital manufacturing technologies have made it possible to produce even complete dentures digitally. This has several advantages, especially regarding the properties of the denture material. In addition, the use of digital technology facilitates new treatment concepts and procedures that reduce the number of appointments needed at the dental office. PMID- 29610781 TI - Three-dimensional registration of real jaw motion tracking data and its therapeutic consequences. AB - When determined by conventional jaw relation recording methods, the real position of the condyle remains largely unclear because the geometric relationship between the reference point and the position of the condyle is unknown. Sicat Function combines cone beam computed tomography (CBCT) data with digital jaw motion tracking (JMT) data and digital intraoral surface data. It is thus capable of measuring and visualizing patient-specific jaw movements. The corresponding patient-specific treatment position can be defined and integrated in various therapeutic appliances, eg, repositioning splints designed to increase the vertical dimension of occlusion (VDO). PMID- 29610782 TI - Local structure and hydrogen bond characteristics of imidazole molecules for proton conduction in acid and base proton-conducting composite materials. AB - Composite materials of acidic polymers and basic molecules have high proton conductivity. Understanding the proton conduction mechanism of the composite materials, which depends on hydrogen bond characteristics, is an important task for developing materials with high proton-conductivity. This work is focused on poly(vinylphosphonic acid)-imidazole and alginic acid-imidazole as examples of composite materials of acidic polymers and basic molecules and examines the local structure and hydrogen bond characteristics of imidazole (Im) molecules in composite materials using density functional theory. The results show that Im molecules interact strongly with polymeric acids in these composite materials and that the interaction energy increases with the increase in the number of Im molecules. The rotational motion of Im molecules occurs in the segment where only Im molecules without excess protons are hydrogen-bonded to each other. The calculation results for the various segments, which depend on the hydrogen bonding environment, show that the proton conduction process in composite materials consists of the following steps: proton transfer in the segment where Im molecules interact with polymeric acids, proton transfer in the segment where Im molecules are affected by excess protons, and Grotthuss diffusion with reorientation of Im molecules in the segment where only Im molecules without excess protons are bonded to each other. PMID- 29610783 TI - When is electronic friction reliable for dynamics at a molecule-metal interface? AB - We investigate rates of electron transfer for generalized Anderson-Holstein models in the limit of weak molecule-metal coupling, using both surface hopping and electronic friction dynamics in one and two dimensions. Overall, provided there is an external source of friction, electronic friction can sometimes perform well even in the limit of small metal-molecule coupling and capture nonadiabatic effects. However, we show that electronic friction dynamics is likely to fail if there is a competition between nonequivalent pathways. Our conclusions provide further insight into the recent observation by Ouyang et al., [J. Chem. Theory Comput., 2016, 12, 4178] regarding the applicability of Kramer's theory in the adiabatic limit to recover Marcus theory in the nonadiabatic limit. PMID- 29610784 TI - InSe: a two-dimensional material with strong interlayer coupling. AB - Atomically thin, two-dimensional (2D) indium selenide (InSe) has attracted considerable attention due to the large tunability in the band gap (from 1.4 to 2.6 eV) and high carrier mobility. The intriguingly high dependence of the band gap on layer thickness may lead to novel device applications, although its origin remains poorly understood, and is generally attributed to the quantum confinement effect. In this work, we demonstrate via first-principles calculations that strong interlayer coupling may be mainly responsible for this phenomenon, especially in the fewer-layer region, and it could also be an essential factor influencing other material properties of beta-InSe and gamma-InSe. The existence of strong interlayer coupling manifests itself in three aspects: (i) indirect-to direct band gap transitions with increasing layer thickness; (ii) fan-like frequency diagrams of the shear and breathing modes of few-layer flakes; and (iii) strong layer-dependent carrier mobilities. Our results indicate that multiple-layer InSe may be deserving of attention from FET-based technologies and may also be an ideal system to study interlayer coupling, possibly inherent in other 2D materials. PMID- 29610785 TI - Solid-state NMR of quadrupolar nuclei for investigations into supported organometallic catalysts: scope and frontiers. AB - The rational development of heterogeneous catalysts is a prerequisite for improving current catalytic technologies. One of the most successful approaches to achieve this goal is the grafting of organometallic complexes onto a given support, via surface organometallic chemistry (SOMC). In such cases, the immobilization of (transition) metal centres onto an inorganic support affords single-site catalysts with precise tuning of the coordination sphere and thus target-specific catalytic reactivity. In this context, the precise characterization of the surface sites by several spectroscopic techniques in parallel is of paramount importance. Solid-state NMR, in particular for half integer quadrupolar nuclei, is a method that has increased its scope in the field of catalysis, especially due to recent methodological breakthroughs, occasionally combined with DFT calculations. In this tutorial review, we provide an overview of the most robust and efficient NMR experiments for half-integer quadrupolar nuclei, from simple one-dimensional acquisition under static and MAS conditions up to high-resolution and heteronuclear correlation two-dimensional spectra, as illustrated by selected examples. PMID- 29610786 TI - MnWO4 nanoparticles as advanced anodes for lithium-ion batteries: F-doped enhanced lithiation/delithiation reversibility and Li-storage properties. AB - F-Doped MnWO4 nano-particles were synthesized by a one-pot hydrothermal reaction. When evaluated as an electrode material for a Li ion battery, the F-doped nano MnWO4 delivers a theoretical capacity of 708 mA h g-1 and a long cycle life, as demonstrated by more than 85% capacity retention when cycled for 150 cycles. PMID- 29610787 TI - The pure rotational spectrum of the T-shaped AlC2 radical (X[combining tilde]2A1). AB - The pure rotational spectrum of the AlC2 radical (X[combining tilde]2A1) has been measured using Fourier transform microwave/millimeter-wave (FTMmmW) techniques in the frequency range 21-65 GHz. This study is the first high-resolution spectroscopic investigation of this molecule. AlC2 was created in a supersonic jet from the reaction of aluminum, generated by laser ablation, with a mixture of CH4 or HCCH, diluted in argon, in the presence of a DC discharge. Three transitions (NKa,Kc = 101 -> 000, 202 -> 101, and 303 -> 202) were measured, each consisting of multiple fine/hyperfine components, resulting from the unpaired electron in the species and the aluminum-27 nuclear spin (I = 5/2). The data were analyzed using an asymmetric top Hamiltonian and rotational, fine structure, and hyperfine constants determined. These parameters agree well with those derived from previous theoretical calculations and optical spectra. An r0 structure of AlC2 was determined with r(Al-C) = 1.924 A, r(C-C) = 1.260 A, and theta(C-Al-C) = 38.2 degrees . The Al-C bond was found to be significantly shorter than in other small, Al-bearing species. The Fermi contact term established in this work indicates that the unpaired electron in the valence orbital has considerable 3pza1 character, suggesting polarization towards the C2 moiety. A high degree of ionic character in the molecule is also evident from the quadrupole coupling constant. These results are consistent with a T-shaped geometry and an Al+C2- bonding scheme. AlC2 is a possible interstellar molecule that may be present in the circumstellar envelopes of carbon-rich AGB stars. PMID- 29610788 TI - A 3D interconnected NH4Fe0.6V2.4O7.4@C nanocomposite with superior sodium storage properties. AB - A novel 3D interconnected NH4Fe0.6V2.4O7.4@C nanocomposite was in situ synthesized through a facile hydrothermal reaction at low temperature (98 degrees C), and its electrochemical performance as a cathode for sodium-ion batteries (SIBs) was investigated for the first time. Under the intercalation of Fe3+ and carbon-coating, as-prepared samples turned to 3D interconnected structures, which were composed of NH4Fe0.6V2.4O7.4 nanoparticles and carbon chains. The 3D interconnected NH4Fe0.6V2.4O7.4@0.5 wt%C nanocomposite exhibits a high discharge specific capacity of 306 mA h g-1 at a current density of 20 mA g 1 and a high-rate capacity of 130 mA h g-1 at 0.4 A g-1. The results of EIS and ex situ SEM indicated that the 3D interconnected NH4Fe0.6V2.4O7.4@0.5 wt%C nanocomposite possesses good electrical conductivity and structural stability. The ex situ XRD results suggest that NH4Fe0.6V2.4O7.4@0.5 wt%C undergoes a reversible insertion/de-insertion mechanism during a charge/discharge process. Our work demonstrates that the 3D interconnected NH4Fe0.6V2.4O7.4@C nanocomposite material could be considered as a potential cathode for sodium ion batteries. PMID- 29610789 TI - Generation of sulfonated 1-isoindolinones through a multicomponent reaction with the insertion of sulfur dioxide. AB - A four-component reaction of 2-vinylbenzoic acids, aryldiazonium tetrafluoroborates, the sulfur dioxide surrogate DABCO.(SO2)2, and nitriles under photocatalysis in the presence of visible light is developed. This multicomponent reaction works efficiently, promoted by BF3.OEt2 with the insertion of sulfur dioxide under mild conditions, leading to sulfonated 1-isoindolinones in moderate to good yields. This route is highly selective, and several competitive pathways are not observed under these conditions. A possible mechanism involving photocatalysis and a Lewis acid is proposed. PMID- 29610790 TI - Photochemically deoxygenating solvents for triplet-triplet annihilation photon upconversion operating in air. AB - Sulfoxides and cyclic ureas are photochemically deoxygenating solvents in which the oxidative stress could be released and efficient triplet-triplet annihilation photon upconversion (TTA-UC) can operate in air. Such solvents can be practically screened out by harnessing the property of photo-activated phosphorescence. PMID- 29610792 TI - Highly enantioselective transfer hydrogenation of racemic alpha-substituted beta keto sulfonamides via dynamic kinetic resolution. AB - Highly enantioselective transfer hydrogenation of beta-keto sulfonamides was developed via dynamic kinetic resolution using a chiral Ru(ii) catalyst with an azeotropic solution of HCO2H/Et3N as a hydrogen donor, affording alpha substituted beta-hydroxyl sulfonamides in good yields with excellent diastereo- and enantioselectivities. This method is featured with mild conditions, easy operation, and a broad substrate scope, which make it possible to find wide applications in the synthesis of natural products and biologically active compounds containing the alpha-substituted beta-hydroxyl sulfonamide core. PMID- 29610793 TI - beta-Bi2O3 reduction by laser irradiation in a liquid environment. AB - This study reports the structural and stoichiometric modifications of bismuth oxide nanoparticles in the beta phase (beta-Bi2O3) by UV pulsed laser irradiation in water or ethanol solutions. Scanning electron microscopy, X-ray diffraction, X ray photoelectron spectroscopy, UV-vis diffuse reflectance and high-resolution transmission electron microscopy were used to characterize the synthesized nanomaterials. The various analyses demonstrate that the laser irradiation of beta-Bi2O3 nanospheres is a green, fast and effective method to produce Bi2O2CO3 nanosheets or metallic Bi nanoparticles depending on the liquid environment used. Bi subcarbonate is obtained by laser irradiation in water, whereas metallic Bi is produced by laser irradiation in ethanol, and in particular the relative amount of metallic Bi is found to depend on the laser fluence. These typologies of materials find application in several fields, such as photocatalytic processes, light filters and environmental sensors. PMID- 29610795 TI - Designing lateral spintronic devices with giant tunnel magnetoresistance and perfect spin injection efficiency based on transition metal dichalcogenides. AB - Giant tunnel magnetoresistance (TMR) and perfect spin-injection efficiency (SIE) are extremely significant for modern spintronic devices. Quantum transport properties in a two-dimensional (2D) VS2/MoS2/VS2 magnetic tunneling junction (MTJ) are investigated theoretically within the framework of density functional theory combining with the non-equilibrium Green's functions (DFT-NEGF) method. Our results indicate that the designed MTJ exhibits a TMR with a value up to 4 * 103, which can be used as a switch of spin-electron devices. And due to the huge barrier for spin-down transport, the spin-down electrons could hardly cross the central scattering region, thus achieving a perfect SIE. Furthermore, we also explore for the effect of bias voltage on the TMR and SIE. We find that the TMR increases with the increasing bias voltage, and the SIE is robust against either bias or gate voltage in MTJs, which can serve as effective spin filter devices. Our results can not only give fresh impetus to the research community to build MTJs but also provide potential materials for spintronic devices. PMID- 29610796 TI - Mechanism of ionic-liquid-based acidic aqueous biphasic system formation. AB - Ionic-liquid-based acidic aqueous biphasic systems (IL-based AcABS) represent a promising alternative to the solvent extraction process for the recovery of critical metals, in which the substitution of the inorganic salt by an acid allows for a 'one-pot' approach to the leaching and separation of metals. However, a more fundamental understanding of AcABS formation remains wanting. In this work, the formation mechanisms of AcABS are elucidated through a comparison with traditional aqueous biphasic systems (ABS). A large screening of AcABS formation with a wide range of IL identifies the charge shielding of the cation as the primary structural driver for the applicability of an IL in AcABS. Through a systematic study of tributyltetradecylphosphonium chloride ([P44414]Cl) with various chloride salts and acids, we observed the first significant deviation to the cationic Hofmeister series reported for IL-based ABS. Furthermore, the weaker than expected salting-out ability of H3O+ compared to Na+ is attributed to the greater interaction of H3O+ with the [P44414]+ micelle surface. Finally, the remarkable thermomorphic properties of [P44414]Cl based systems are investigated with a significant increase in the biphasic region induced by the increase in the temperature from 298 K to 323 K. These finding allows for the extension of ABS to new acidic systems and highlights their versatility and tunability. PMID- 29610797 TI - Double spin transition in a two dimensional Fe(ii) coordination network. AB - In the two dimensional network [Fe(ebbtr)2(CH3CN)2](ClO4)2.4CH3CN a sequence of LS -> HS -> LS -> HS transitions occurs as the exclusive result of the change in temperature. This property results from the extraordinary flexibility/elasticity manifested in the hierarchical arrangement of structural events involving the reorientation of coordinated/noncoordinated molecules as well as with the deformation and the mutual shift of the polymeric units. PMID- 29610799 TI - Heteroporous MoS2/Ni3S2 towards superior electrocatalytic overall urea splitting. AB - The heteroporous MoS2/Ni3S2 catalyst exhibits excellent electrocatalytic activity for the overall urea splitting with only a cell voltage of 1.45 V at 20 mA cm-2 in 1 M KOH with 0.33 M urea. This value is the best of all the bifunctional urea splitting electrocatalysts, including Pt, reported to date. PMID- 29610800 TI - On the making of aromatic organometallic superalkali complexes. AB - Superalkalis are complexes that have a lower ionization energy than that of the corresponding alkali and alkaline earth metals. Based on First Principles calculations, the plausible existence of a superalkali complex consisting of an all-metal aromatic trigonal Au3 core coupled with pyridine (Py) and imidazole (IMD) ligands is suggested. The calculated ionization energy (IE) values of the subsequent organometallic complexes, Au3(Py)3 and Au3(IMD)3, are low, thereby mimicking the usual behavior of a superalkali. First order hyperpolarizability calculations show the existence of non-linear optical properties in some of the complexes, which is also on par with the properties of a superalkali. PMID- 29610801 TI - Density functional study on the high catalytic performance of single metal atoms on the NbC(001) surface. AB - The adsorption and activation of O2 is regarded as the first critical step for the oxygen reduction reaction (ORR), and catalysts with a high performance toward O2 adsorption and activation would provide a theoretical foundation for further investigations. Here, we have studied the adsorption and electronic properties as well as the catalytic activities of group 9-11 single metal atoms deposited on NbC(001), denoted M/NbC(001). According to the location of the d-band centers and the frontier molecular orbital analysis, single metals of Co, Rh, Ir and Ni on NbC(001) exhibit higher activities than other metals (Pd, Pt, Cu, Ag and Au). The quite different catalytic activities of M/NbC(001) may be attributed to the differences in their electro-negativities and work-functions. Meanwhile, the reasonable stabilities of Co, Rh, Ir and Ni on NbC(001) were clarified by investigating the agglomeration resistance and oxidation resistance, and the results indicate that Co and Ni have poor oxidative stability, and Rh and Ir are antioxidants on NbC(001). Further research into the adsorption and activation of O2 confirmed the outstanding properties of Rh/NbC(001) and Ir/NbC(001), which may provide great opportunities to find alternative catalysts. PMID- 29610802 TI - Metal-free alpha-alkylation of alcohols with para-quinone methides. AB - A metal-free alpha-alkylation of alcohols with para-quinone methides (p-QMs) for accessing alcohol-containing phenols and dihydroisocoumarins has been developed. The alcohols were converted to alpha-oxy radicals in the presence of di-tert butyl peroxide (DTBP), which were added to p-QMs for aromatization and C(sp3) C(sp3) bond formation. PMID- 29610803 TI - Probing the temperature-dependent changes of the interfacial hydration and viscosity of Tween20 : cholesterol (1 : 1) niosome membrane using fisetin as a fluorescent molecular probe. AB - A detailed photophysical study of fisetin in a Tween20 : cholesterol (1 : 1) niosome membrane has been carried out. Fisetin is found to partition well into the Tween20 : cholesterol (1 : 1) niosome membrane at low temperature (Kp = 2.7 * 104 M-1 at 10 degrees C). Cetylpyridinium chloride quenching study confirms the location of fisetin molecules in the interfacial domain of Tween20 : cholesterol (1 : 1) niosome membrane. The emission from the prototropic forms of fisetin (neutral form, excited state anion, ground state anion and phototautomer form) is found to sensitively reflect the local heterogeneities in Tween20 : cholesterol (1 : 1) niosome membrane. The shift in anionic emission maximum with variation in temperature shows the sensitivity of fisetin towards water accessibility at the interfacial domain of Tween20 : cholesterol (1 : 1) niosome membrane. Zeta potential value confirms that there is no role of surface charge in the multiple prototropism of fisetin in Tween20 : cholesterol (1 : 1) niosome membrane. The microviscosity changes with temperature, as reflected in fluorescence anisotropy values of fisetin phototautomeric species FT*, give information about the temperature-induced changes in the motional resistance offered by the interfacial domain of the niosomal membrane to small molecules. A temperature-dependent fluorescence lifetime study confirms the distribution of FT* in the two different sites of niosomal interfacial domain, i.e. water-deficient inner site and water accessible outer site. This heterogeneity in distribution of FT* is further confirmed through time-resolved fluorescence anisotropy decay resulting in two different rotational time constants (faster component of ~1.04 ns originates from water-accessible outer site and slower component of ~16.50 ns originates from water-deficient inner site). The interfacial location of fisetin in Tween20 : cholesterol (1 : 1) niosome membrane has an important implication with regards to antioxidant activity as confirmed from a DPPH radical scavenging study. PMID- 29610805 TI - Nanoscale mapping of catalytic hotspots on Fe, N-modified HOPG by scanning electrochemical microscopy-atomic force microscopy. AB - The scanning electrochemical microscopy-atomic force microscopy (SECM-AFM) technique is used to map catalytic currents post Fe and N surface modification of graphitic carbon with an ultra-high resolution of 50 nm. The oxidation current of the partial reduction product, hydrogen peroxide, was also mapped in the same location in the graphitic carbon. The current mapping and ex situ spectroscopic evidence revealed that Fe-coordinated nitrogen sites formed both in the edge and basal planes of highly ordered pyrolytic graphite (HOPG) constitute the primary oxygen reduction catalytic sites in acid solutions of this important yet insufficiently understood class of catalysts. PMID- 29610806 TI - First-order wedge wetting revisited. AB - We consider a fluid adsorbed in a wedge made from walls that exhibit a first order wetting transition and revisit the argument as to why and how the pre filling and pre-wetting coexistence lines merge when the opening angle is increased approaching the planar geometry. We clarify the nature of the possible surface phase diagrams, pointing out the connection with complete pre-wetting, and show that the merging of the coexistence lines lead to new interfacial transitions. These occur along the side walls and are associated with the unbinding of the thin-thick interface, rather than the liquid-gas interface (meniscus), from the wedge apex. When fluctuation effects, together with the influence of dispersion forces are included, these transitions display strong non universal critical singularities that depend on the opening angle itself. Similar phenomena are also shown to occur for adsorption near an apex tip. PMID- 29610807 TI - Shape evolution and splitting of ferrofluid droplets on a hydrophobic surface in the presence of a magnetic field. AB - We elucidate the phenomena of dynamic wetting, shape evolution and splitting of ferrofluid (FF) droplets on a hydrophobic surface under the influence of a magnetic field. In the case of a FF droplet interacting with a magnetic field, both surface energy and magnetic energy contribute to the total Gibb's free energy and hence the wetting phenomena. The nanoparticles in the FF droplet migrate and get accumulated at the apex of the droplet which enhances the magnetic interaction causing large deformation of the droplet. The FF droplet deformation and subsequent splitting are governed by the interplay between the magnetic Fm and surface tension Fs forces. The ratio of the forces km = (Fm/Fs) was found to be a function of the magnetic Bond number Bom and non-dimensional gap g* as km ~ (Bom)0.3(g*)-0.86. Splitting of the FF droplets was observed for km > 1 and for km < 1, an equilibrium droplet shape was observed. The wetting behavior of the FF droplets was found to be strongly dependent on the FF concentration c - concentrated (c = 1.2%) FF droplets exhibit contact line (CL) pinning and decrease in contact angle (CA) theta with time throughout, while diluted (c = 0.6%) FF droplets show a mixed mode (CL pinning followed by constant CA). In splitting of FF droplets, the ratio of the volume of the daughter droplet to that of the parent droplet i.e. (Vd/Vp), was found to decrease with an increase in the parent droplet size Vp. PMID- 29610808 TI - Nearly suppressed photoluminescence blinking of small-sized, blue-green-orange red emitting single CdSe-based core/gradient alloy shell/shell quantum dots: correlation between truncation time and photoluminescence quantum yield. AB - CdSe-based core/gradient alloy shell/shell semiconductor quantum dots (CGASS QDs) have been shown to be optically quite superior compared to core-shell QDs. However, very little is known about CGASS QDs at the single particle level. Photoluminescence blinking dynamics of four differently emitting (blue (lambdaem = 510), green (lambdaem = 532), orange (lambdaem = 591), and red (lambdaem = 619)) single CGASS QDs having average sizes <~7 nm have been probed in our home built total internal reflection fluorescence (TIRF) microscope. All four samples possess an average ON-fraction of 0.70-0.85, which hints towards nearly suppressed PL blinking in these gradiently alloyed systems. Suppression of blinking has been so far achieved with QDs having sizes greater than 10 nm and mostly emitting in the red region (lambdaem > 600 nm). In this manuscript, we report nearly suppressed PL blinking behaviour of CGASS QDs with average sizes <~7 nm and emitting in the entire range of the visible spectrum, i.e. from blue to green to orange to red. The probability density distribution of both ON- and OFF-event durations for all of these CGASS QDs could be fitted well with a modified inverse truncated power law with an additional exponential model equation. It has been found that unlike most of the literature reports, the power law exponent for OFF-event durations is greater than the power law exponent for ON-event durations for all four samples. This suggests that relatively large ON event durations are interrupted by comparatively small OFF-event durations. This in turn is indicative of a suppressed non-radiative Auger recombination process for these CGASS systems. However, in these four different samples the ON-event truncation time varies inversely with the OFF-event truncation time, which hints that both the ON- and OFF-event truncation processes are dictated by some common factor. We have employed 2D joint probability distribution analysis to probe the correlation between the event durations and found that residual memory exists in both the ON- and OFF-event durations. Positively correlated successive ON-ON and OFF-OFF event durations and negatively correlated (anti-correlated) ON-OFF event durations perhaps suggest the involvement of more than one type of trapping process within the blinking framework. The timescale corresponding to the additional exponential term has been assigned to hole trapping for ON-event duration statistics. Similarly, for OFF-event duration statistics, this component suggests hole detrapping. We found that the average duration of the exponential process for the ON-event durations is an order of magnitude higher than that of the OFF-event durations. This indicates that the holes are trapped for a significantly long time. When electron trapping is followed by such a hole trapping, long ON-event durations result. We have observed long ON-event durations, as high as 50 s. The competing charge tunnelling model has been used to account for the observed blinking behaviour in these CGASS QDs. Quite interestingly, the PLQY of all of these differently emitting QDs (an ensemble level property) could be correlated with the truncation time (a property at the single particle level). A respective concomitant increase-decrease of ON-OFF event truncation times with increasing PLQY is also indicative of a varying degree of suppression of the Auger recombination processes in these four different CGASS QDs. PMID- 29610809 TI - In-plane stress development in mesoporous thin films. AB - Ordered mesoporous thin films of TiO2 and CexZr1-xO2 (x = 0, 0.5, 1) were prepared via an evaporation-induced self-assembly (EISA) process and subsequently investigated in terms of the developing intrinsic and residual in-plane stress. These mechanical properties were determined by the curvature method, which is based on the determination of the deflection of light due to concave or convex bending of the films on a substrate. The films were investigated with regard to the intrinsic stress during heat treatment up to 500 degrees C and to the residual stress at room temperature for several annealing temperatures. Following this strategy, the influence of the decomposition of a block copolymer template on the intrinsic stress as well as the pore collapsing on the residual stress was analyzed. Nanoporous TiO2 thin films were prepared using two different block copolymers (PIB50-b-PEO45 and Pluronic(r) F127). A comparison between the templated and non-templated TiO2 films showed the lowest intrinsic and residual stress for the ordered mesoporous material prepared with PIB50-b-PEO45 indicating that the distributed polymer and the corresponding mesopores act as relaxing agents for the system. This was verified by mesoporous CexZr1-xO2 (x = 0, 0.5, 1) thin films showing a comparable behavior in terms of the experienced intrinsic stress. This work reveals an increase in the residual in-plane stress during pore collapse, which lays the foundation for further understanding of the stress related mechanical properties of mesoporous thin films. PMID- 29610810 TI - An organocatalytic enantioselective direct alpha-heteroarylation of aldehydes with isoquinoline N-oxides. AB - A new protocol for the enantioselective direct alpha-heteroarylation of aldehydes with isoquinoline N-oxides, via chiral enamine catalysis, has been successfully developed. High enantiomeric excesses and moderate to good yields were achieved for a variety of alpha-heteroarylated aldehydes. PMID- 29610812 TI - Multiple conical intersections in small linear parameter Jahn-Teller systems: the DMBE potential energy surface of ground-state C3 revisited. AB - A new single-sheeted DMBE potential energy surface for ground-state C3 is reported. The novel analytical form accurately describes the three symmetry equivalent C2v disjoint seams, in addition to the symmetry-required D3h one, over the entire configuration space. The present formalism warrants by built-in construction the confluence of the above crossings, and the rotation-in-plane of the C2v seams when the perimeter of the molecule fluctuates. Up to 1050 ab initio energies have been employed in the calibration procedure, of which 421 map the loci of intersection. The calculated energies have been scaled to account for the incompleteness of the basis set and truncation of the MRCI expansion, and fitted analytically with chemical accuracy. The novel form is shown to accurately mimic the region defined by the 4 conical intersections, while exhibiting similar attributes to the previously reported one [J. Chem. Phys., 2015, 143, 074302] at the regions of configuration space away from the crossing seams. Despite being mainly addressed to C3, the present approach should be applicable to adiabatic PESs of any X3 system experiencing similar topological attributes, in particular the small-linear-parameter Jahn-Teller molecules. PMID- 29610813 TI - Copper-mediated regioselective C-H etherification of naphthylamides with arylboronic acids using water as an oxygen source. AB - The copper-mediated regioselective C-H activation and C-O bond formation of naphthylamides with arylboronic acids has been developed using water as an oxygen source. The kinetic isotope study suggests that C-H bond activation is the rate determining step. The H2O18 labelling experiment reveals the incorporation of oxygen from water. The substrate scope, functional group diversity and post synthetic utilities are the important practical features. PMID- 29610814 TI - An intramolecular antiparallel G-quadruplex formed by human telomere RNA. AB - Until now, RNA G-quadruplexes were believed to only adopt a parallel G-quadruplex structure. In this study, we describe the first observation of an antiparallel RNA G-quadruplex formed by human telomere RNA. This newly described topology is of great interest as it shows that RNA G-quadruplexes can also be polymorphic and adopt structures that are different from the parallel configuration. PMID- 29610815 TI - Vapor-deposited organic glasses exhibit enhanced stability against photodegradation. AB - Photochemically stable solids are in demand for applications in organic electronics. Previous work has established the importance of the molecular packing environment by demonstrating that different crystal polymorphs of the same compound react at different rates when illuminated. Here we show, for the first time, that different amorphous packing arrangements of the same compound photodegrade at different rates. For these experiments, we utilize the ability of physical vapor deposition to prepare glasses with an unprecedented range of densities and kinetic stabilities. Indomethacin, a pharmaceutical molecule that can undergo photodecarboxylation when irradiated by UV light, is studied as a model system. Photodegradation is assessed through light-induced changes in the mass of glassy thin films due to the loss of CO2, as measured by a quartz crystal microbalance (QCM). Glasses prepared by physical vapor deposition degraded more slowly under UV illumination than did the liquid-cooled glass, with the difference as large as a factor of 2. Resistance to photodegradation correlated with glass density, with the vapor-deposited glasses being up to 1.3% more dense than the liquid-cooled glass. High density glasses apparently limit the local structural changes required for photodegradation. PMID- 29610816 TI - An I2-mediated aerobic oxidative annulation of amidines with tertiary amines via C-H amination/C-N cleavage for the synthesis of 2,4-disubstituted 1,3,5 triazines. AB - An iodine-mediated formal oxidative cycloaddition of amidines with tertiary amines was first demonstrated in air. Both symmetrical and unsymmetrical 2,4 disubstituted 1,3,5-triazines were obtained in up to 85% yields. It is noted that a tertiary amine was employed as a one carbon synthon of 1,3,5-triazines and two C-N bonds were formed in one pot. Control experiments revealed that the reaction underwent a radical pathway promoted by I+. The method is transition-metal-free, peroxide-free, and operationally simple to implement with a wide scope of substrates. PMID- 29610817 TI - On-surface synthesis of a 2D boroxine framework: a route to a novel 2D material? AB - The synthesis and preliminary characterization of a boron-based 2D framework are presented. The peculiar electronic and morphological properties of this compound, together with its facile formation process, enable it to be used as a novel smart material for the design of electronic devices. PMID- 29610818 TI - A high-affinity subtype-selective fluorescent probe for estrogen receptor beta imaging in living cells. AB - Estrogen receptor beta (ERbeta) has recently been identified as a pharmaceutical target in hormone replacement therapy for breast cancers. However, the biological function of ERbeta in disease progression remains unclear. A highly ERbeta selective fluorescent probe (FPNM) was discovered exhibiting nanomolar affinity for ERbeta with an ERbeta/ERalpha selectivity as high as 80, which allowed specific labeling of intracellular ERbeta. Moreover, distinct ERbeta dynamics in various cellular bio-settings such as prostate cancer (DU-145) or triple-negative breast cancer (MDA-MB-231) cells were directly observed for the first time viaFPNM staining. PMID- 29610819 TI - Regioselectivity inversion tuned by iron(iii) salts in palladium-catalyzed carbonylations. AB - Impactful regioselectivity control is crucial for cost-effective chemical synthesis. By using cheap and abundant iron(iii) salts, the hydroxycarbonylations of both aromatic and aliphatic alkenes were significantly enhanced in both reactivity and selectivity (iso/n or n/iso up to >99 : 1). Moreover, Pd-catalyzed carbonylation selectivity can be switched from branched to linear by using different Fe(iii) salts. In addition, similar results were obtained for the carbonylation of secondary alcohols. PMID- 29610821 TI - The enzyme-like catalytic activity of cerium oxide nanoparticles and its dependency on Ce3+ surface area concentration. AB - Cerium oxide nanoparticles are known to catalyze the decomposition of reactive oxygen species such as the superoxide radical and hydrogen peroxide. Herein, we examine the superoxide dismutase (SOD) and catalase (CAT) mimetic catalytic activities of nanoceria and demonstrate the existence of generic behaviors. For particles of sizes 4.5, 7.8, 23 and 28 nm, the SOD and CAT catalytic activities exhibit the characteristic shape of a Langmuir isotherm as a function of cerium concentration. The results show that the catalytic effects are enhanced for smaller particles and for the particles with the largest Ce3+ fraction. The SOD like activity obtained from the different samples is found to superimpose on a single master curve using the Ce3+ surface area concentration as a new variable, indicating the existence of particle independent redox mechanisms. For the CAT assays, the adsorption of H2O2 molecules at the particle surface modulates the efficacy of the decomposition process and must be taken into account. We design an amperometry-based experiment to evaluate the H2O2 adsorption at nanoceria surfaces, leading to the renormalization of the particle specific area. Depending on the particle type the amount of adsorbed H2O2 molecules varies from 2 to 20 nm 2. The proposed scalings are predictive and allow the determination of the SOD and CAT catalytic properties of cerium oxide solely from physicochemical features. PMID- 29610822 TI - Polydopamine nanoparticles for the treatment of acute inflammation-induced injury. AB - Nanotechnology-mediated anti-inflammatory therapy is emerging as a novel strategy for the treatment of inflammation-induced injury. However, one of the main hurdles for these anti-inflammatory nano-drugs is their potential toxic side effects in vivo. Herein, we uncovered that polydopamine (PDA) nanoparticles with their structure and chemical properties similar to melanin, a natural bio polymer, displayed a significant anti-inflammation therapeutic effect on acute inflammation-induced injury. PDA with enriched phenol groups functioned as a radical scavenger to eliminate reactive oxygen species (ROS) generated during inflammatory responses. As revealed by in vivo photoacoustic imaging with a H2O2 specific nanoprobe, PDA nanoparticles remarkably reduced intracellular ROS levels in murine macrophages challenged with either H2O2 or lipopolysaccharide (LPS). The anti-inflammatory capacity of PDA nanoparticles was further demonstrated in murine models of both acute peritonitis and acute lung injury (ALI), where diminished ROS generation, reduced proinflammatory cytokines, attenuated neutrophil infiltration, and alleviated lung tissue damage were observed in PDA treated mice after a single dose of PDA treatment. Our work therefore presents the great promise of PDA nanoparticles as a biocompatible nano-drug for anti inflammation therapy to treat acute inflammation-induced injury. PMID- 29610823 TI - Tunable electronic properties of partially edge-hydrogenated armchair boron nitrogen-carbon nanoribbons. AB - We employ a first-principles calculations based density-functional-theory (DFT) approach to study the electronic properties of partially and fully edge hydrogenated armchair boron-nitrogen-carbon (BNC) nanoribbons (ABNCNRs), with widths between 0.85 nm to 2.3 nm. Due to the partial passivation of edges, the electrons, which do not participate in the bonding, form new energy states located near the Fermi-level. Because of these additional bands, some ABNCNRs exhibit metallic behavior, which is quite uncommon in armchair nanoribbons. Our calculations reveal that metallic behavior is observed for the following passivation patterns: (i) when the B atom from one edge and the N atom from another edge are unpassivated. (ii) when the N atoms from both the edges are unpassivated. (iii) when the C atom from one edge and the N atom from another edge are unpassivated. Furthermore, spin-polarization is also observed for certain passivation schemes, which is also quite uncommon for armchair nanoribbons. Thus, our results suggest that the ABNCNRs exhibit a wide range of electronic and magnetic properties in that the fully edge-hydrogenated ABNCNRs are direct band gap semiconductors, while the partially edge-hydrogenated ones are either semiconducting, or metallic, while simultaneously exhibiting spin polarization, based on the nature of passivation. We also find that the ribbons with larger widths are more stable as compared to the narrower ones. PMID- 29610824 TI - A three-dimensional cubic halogen-bonded network. AB - The rational, deliberate design of supramolecular architectures is of great importance for the discovery of complex materials. A three-dimensional cubic halogen-bonded network has been prepared by combination of an octahedral metal containing halogen bond acceptor and a linear ditopic donor. This material displays alpha-Po pcu topology and is seven-fold interpenetrated. This is the first neutral, metal-containing three-dimensional halogen-bonded network to be reported. PMID- 29610825 TI - Effects of gold nanoparticles on the photophysical and photosynthetic parameters of leaves and chloroplasts. AB - Effects of gold nanoparticles (average diameter: 10-14 nm) on leaves and chloroplasts have been studied. Gold nanoparticles (AuNPs) quenched significantly chlorophyll fluorescence when introduced both in intact leaves and isolated chloroplasts. Additionally, the fluorescence spectra corrected for light re absorption processes showed a net decrease in the fluorescence ratio calculated as the quotient between the maximum fluorescence at 680 and 735 nm. This fact gave evidence for a reduction in the fluorescence emission of the PSII relative to that of the PSI. Strikingly, the photosynthetic parameters derived from the analysis of the slow phase of Kautsky's kinetics, the rate of oxygen evolution and the rate of photo-reduction of 2,6-dichlorophenolindophenol were increased in the presence of AuNPs indicating an apparent greater photosynthetic capacity. The observed results were consistent with an electron transfer process from the excited PSII, which was thermodynamically possible, and which competed with both the electron transport process that initiated photosynthesis and the deactivation of the excited PSII by fluorescence emission. Additionally, it is here explained, in terms of a completely rational kinetic scheme and their corresponding algebraic expressions, why the photosynthetic parameters and the variable and non variable fluorescence of chlorophyll are modified in a photosynthetic tissue containing gold nanoparticles. PMID- 29610826 TI - A Child With a Blistering Rash. PMID- 29610827 TI - Association of Medical and Adult-Use Marijuana Laws With Opioid Prescribing for Medicaid Enrollees. AB - Importance: Overprescribing of opioids is considered a major driving force behind the opioid epidemic in the United States. Marijuana is one of the potential nonopioid alternatives that can relieve pain at a relatively lower risk of addiction and virtually no risk of overdose. Marijuana liberalization, including medical and adult-use marijuana laws, has made marijuana available to more Americans. Objective: To examine the association of state implementation of medical and adult-use marijuana laws with opioid prescribing rates and spending among Medicaid enrollees. Design, Setting, and Participants: This cross-sectional study used a quasi-experimental difference-in-differences design comparing opioid prescribing trends between states that started to implement medical and adult-use marijuana laws between 2011 and 2016 and the remaining states. This population based study across the United States included all Medicaid fee-for-service and managed care enrollees, a high-risk population for chronic pain, opioid use disorder, and opioid overdose. Exposures: State implementation of medical and adult-use marijuana laws from 2011 to 2016. Main Outcomes and Measures: Opioid prescribing rate, measured as the number of opioid prescriptions covered by Medicaid on a quarterly, per-1000-Medicaid-enrollee basis. Results: State implementation of medical marijuana laws was associated with a 5.88% lower rate of opioid prescribing (95% CI, -11.55% to approximately -0.21%). Moreover, the implementation of adult-use marijuana laws, which all occurred in states with existing medical marijuana laws, was associated with a 6.38% lower rate of opioid prescribing (95% CI, -12.20% to approximately -0.56%). Conclusions and Relevance: The potential of marijuana liberalization to reduce the use and consequences of prescription opioids among Medicaid enrollees deserves consideration during the policy discussions about marijuana reform and the opioid epidemic. PMID- 29610828 TI - Interactions Between Physicians and Skilled Home Health Care Agencies in the Certification of Medicare Beneficiaries' Plans of Care: Results of a Nationally Representative Survey. AB - Background: Physicians are required to certify a plan of care for patients who receive Medicare skilled home health care (SHHC) services. The Centers for Medicare & Medicaid Services form 485 (CMS-485) is typically used for certification of SHHC plans of care and for interactions between SHHC agencies and physicians. Little is known about how physicians use the CMS-485 or their perceptions of its usefulness with respect to coordinating care with SHHC agencies. Objective: To determine how physicians interact with SHHC agencies and use the CMS-485 in care coordination for patients receiving SHHC services. Design: Mailed survey. Setting: Nationally representative random sample. Participants: Physicians from the American Medical Association Physician Masterfile specializing in family or general medicine (excluding adolescent and sports medicine), geriatrics, geriatric psychiatry, internal medicine, or hospice and palliative medicine. Measurements: Time spent reviewing the plan of care and experiences with making changes and communicating with SHHC clinicians. Results: The response rate after 3 mailings was 53% (1044 of 1968). Of 1005 respondents who provided patient care, 72% had certified at least 1 plan of care in the past year. Nearly half (47%) reported spending less than 1 minute reviewing the CMS 485 before certification, whereas 21% reported spending at least 2 minutes. Physicians typically interacted with multiple SHHC agencies by fax or mail. Approximately 80% rarely or never changed an order on the CMS-485, and 78.3% rarely or never contacted SHHC clinicians with questions about information. The mean reported ease of contacting the SHHC agency was 4.7 (SD, 2.3) on a scale of 1 (easy) to 10 (difficult). Limitation: Self-reported data and 53% response rate. Conclusion: The CMS-485 does not meaningfully engage physicians. Physicians spend little time reviewing or acting on the SHHC plan of care. Strategies to enhance meaningful communication between SHHC agencies and physicians are needed. Primary Funding Source: National Institute on Aging and National Institute of Mental Health. PMID- 29610829 TI - Association of Histologic Chorioamnionitis With Perinatal Brain Injury and Early Childhood Neurodevelopmental Outcomes Among Preterm Neonates. AB - Importance: Understanding the role of chorioamnionitis, a major factor leading to preterm birth, in the pathogenesis of neonatal brain injury and adverse neurodevelopmental outcomes may help in identifying potentially modifiable perinatal variables affecting brain health and outcomes among children born preterm. Objective: To evaluate whether histologic chorioamnionitis among neonates born very preterm is associated with intraventricular hemorrhage (IVH) and punctate white matter injury (WMI) or with adverse neurodevelopmental outcomes during early childhood. Design, Setting, and Participants: Prospective cohort study conducted across 3 academic centers (from April 2006 to September 2013 in Canada, from March 2007 to March 2013 in the Netherlands, and from January 2004 to August 2011 in the United States). Children who were born preterm (24-32 weeks' gestation) and who had undergone a placental pathologic evaluation, magnetic resonance imaging as soon as clinically stable, and Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III) assessments between 18 and 24 months' corrected age (CA) were included. Magnetic resonance imaging scans were assessed for grade of IVH and volume of punctate WMI. Data analysis occurred between December 2016 and January 2018. Final multivariable analyses examining the association of chorioamnionitis with motor and cognitive outcomes accounted for academic center and perinatal and postnatal factors. Main Outcomes and Measures: Punctate WMI volume and IVH detected on neonatal magnetic resonance imaging scans; motor and cognitive outcomes defined using Bayley-III assessments conducted among these children between 18 and 24 months' CA. Results: Of 350 neonates (182 male) in the final cohort, 145 (41.4%) had histologic chorioamnionitis. Gestational age was significantly lower among those with chorioamnionitis (median, 26.4 weeks; interquartile range [IQR], 25.6-27.7 weeks) than among those without chorioamnionitis (median, 28.0 weeks; IQR, 27.0-29.7 weeks). Chorioamnionitis was not associated with IVH or WMI, nor was it associated with worse motor outcomes in univariable or multivariable analyses (adjusted Bayley-III motor score, -2.2; 95% CI, -5.6 to 1.3). Cognitive scores were marginally yet statistically significantly lower among children with chorioamnionitis (median, 105; IQR, 95-110) than among those without chorioamnionitis (median, 105; IQR, 100-115) in the univariable model. This difference was attenuated in the multivariable model (adjusted Bayley-III cognitive score, -3.0; 95% CI, -6.4 to 0.4). Conclusions and Relevance: Histologic chorioamnionitis was not associated with IVH or WMI near birth or with worse cognitive or motor outcomes from 18 to 24 months' CA after accounting for perinatal factors. Postnatal factors attenuated the association between chorioamnionitis and neurodevelopmental outcomes, highlighting the importance of preventing postnatal illness, such as infection, to promote optimal outcomes among children born preterm. PMID- 29610832 TI - Effect of Money-Back Guarantees on the Cost-Effectiveness of Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors. PMID- 29610831 TI - Association of HLA-A*31:01 Screening With the Incidence of Carbamazepine-Induced Cutaneous Adverse Reactions in a Japanese Population. AB - Importance: Carbamazepine, a commonly used antiepileptic drug, is one of the most common causes of cutaneous adverse drug reactions (cADRs) worldwide. The allele HLA-A*31:01 is reportedly associated with carbamazepine-induced cADRs in Japanese and European populations; however, the clinical utility of HLA-A*31:01 has not been evaluated. Objective: To assess the use of HLA-A*31:01 genetic screening to identify Japanese individuals at risk of carbamazepine-induced cADRs. Design, Setting, and Participants: This cohort study was conducted across 36 hospitals in Japan from January 2012 to November 2014 among 1202 patients who had been deemed suitable to start treatment with carbamazepine. Preemptive HLA-A*31:01 genetic screening was performed for 1187 participants. Patients who did not start treatment with carbamazepine or alternative drugs were excluded. Participants were interviewed once weekly for 8 weeks to monitor the development of cADRs. Data analysis was performed from June 8, 2015, to December 27, 2016. Exposures: Neuropsychiatrists were asked to prescribe carbamazepine for patients who tested negative for HLA-A*31:01 and alternative drugs for those who tested positive for HLA-A*31:01. Main Outcomes and Measures: Incidence of carbamazepine-induced cADRs. Results: Of the 1130 included patients who were prescribed carbamazepine or alternative drugs, the mean (range) age was 37.4 (0-95) years, 614 (54.3%) were men, and 198 (17.5%) were positive for HLA-A*31:01. Expert dermatologists identified 23 patients (2.0%) who had carbamazepine-induced cADRs, of which 4 patients required hospitalization. Drug-induced hypersensitivity syndrome was observed for 3 patients, maculopapular eruption for 9 patients, erythema multiforme for 5 patients, and an undetermined type of cADR for 6 patients. No patient developed Stevens-Johnson syndrome or toxic epidermal necrolysis. Compared with historical controls, the incidence of carbamazepine-induced cADRs was significantly decreased (for BioBank Japan data: incidence, 3.4%; odds ratio, 0.60; 95% CI, 0.36-1.00; P = .048; for the Japan Medical Data Centre claims database: incidence, 5.1%; odds ratio, 0.39; 95% CI, 0.26-0.59; P < .001). Conclusions and Relevance: Preemptive HLA-A*31:01 genetic screening significantly decreased the incidence of carbamazepine-induced cADRs among Japanese patients, which suggests that it may be warranted in routine clinical practice. PMID- 29610833 TI - ST-Segment Elevation in Lead aVR: A Visual Reminder of Potential Catastrophe. PMID- 29610834 TI - Closing the Sex Divide in the Emerging Field of Neurology. PMID- 29610830 TI - Association Between Early Caffeine Citrate Administration and Risk of Acute Kidney Injury in Preterm Neonates: Results From the AWAKEN Study. AB - Importance: Acute kidney injury (AKI) occurs commonly in preterm neonates and is associated with increased morbidity and mortality. Objectives: To examine the association between caffeine citrate administration and AKI in preterm neonates in the first 7 days after birth and to test the hypothesis that caffeine administration would be associated with reduced incidence and severity of AKI. Design, Setting, and Participants: This study was a secondary analysis of the Assessment of Worldwide Acute Kidney Injury Epidemiology in Neonates (AWAKEN) study, a retrospective observational cohort that enrolled neonates born from January 1 to March 31, 2014. The dates of analysis were October 2016 to December 2017. The setting was an international, multicenter cohort study of neonates admitted to 24 participating level III or IV neonatal intensive care units. Participants met the original inclusion and exclusion criteria of the AWAKEN study. Additional exclusion criteria for this study included participants greater than or equal to 33 weeks' gestation at birth, admission after age 7 days, use of theophylline in the neonatal intensive care unit, or lack of data to define AKI. There were 675 preterm neonates available for analysis. Exposure: Administration of caffeine in the first 7 days after birth. Main Outcomes and Measures: The primary outcome was the incidence of AKI (based on the modified neonatal Kidney Disease: Improving Global Outcomes [KDIGO] definition) in the first 7 days after birth. The hypothesis that caffeine administration would be associated with reduced AKI incidence was formulated before data analysis. Results: The study cohort (n = 675) was 55.4% (n = 374) male, with a mean (SD) gestational age of 28.9 (2.8) weeks and a mean (SD) birth weight of 1285 (477) g. Acute kidney injury occurred in 122 neonates (18.1%) in the first 7 days after birth. Acute kidney injury occurred less frequently among neonates who received caffeine than among those who did not (50 of 447 [11.2%] vs 72 of 228 [31.6%], P < .01). After multivariable adjustment, administration of caffeine remained associated with reduced odds of developing AKI (adjusted odds ratio, 0.20; 95% CI, 0.11-0.34), indicating that for every 4.3 neonates exposed to caffeine one case of AKI was prevented. Among neonates with early AKI, those receiving caffeine were less likely to develop stage 2 or 3 AKI (adjusted odds ratio, 0.20; 95% CI, 0.12 0.34). Conclusions and Relevance: Caffeine administration in preterm neonates is associated with reduced incidence and severity of AKI. Further studies should focus on the timing and dosage of caffeine to optimize the prevention of AKI. PMID- 29610835 TI - Building on #MeToo to Enhance the Learning Environment for US Medical Schools. PMID- 29610836 TI - The Role of Cannabis Legalization in the Opioid Crisis. PMID- 29610837 TI - Cardiovascular Disease and Risk Management: Review of the American Diabetes Association Standards of Medical Care in Diabetes 2018. AB - Description: The American Diabetes Association (ADA) annually updates its Standards of Medical Care in Diabetes to provide clinicians, patients, researchers, payers, and other interested parties with evidence-based recommendations for the diagnosis and management of patients with diabetes. Methods: For the 2018 standards, the ADA Professional Practice Committee searched MEDLINE through November 2017 to add, clarify, or revise recommendations on the basis of new evidence. The committee rated the recommendations as A, B, or C depending on the quality of evidence or E for expert consensus or clinical experience. The standards were reviewed and approved by the Executive Committee of the ADA Board of Directors, which includes health care professionals, scientists, and laypersons. Feedback from the larger clinical community informed revisions. Recommendations: This synopsis focuses on guidance relating to cardiovascular disease and risk management in nonpregnant adults with diabetes. Recommendations address diagnosis and treatment of cardiovascular risk factors (hypertension and dyslipidemia), aspirin use, screening for and treatment of coronary heart disease, and lifestyle interventions. PMID- 29610838 TI - Money-Back Guarantees for Expensive Drugs: Wolf's Clothing but a Sheep Underneath. PMID- 29610839 TI - Explaining Discrepancies Between the Digit Triplet Speech-in-Noise Test Score and Self-Reported Hearing Problems in Older Adults. AB - Purpose: The purpose of this study is to determine which demographic, health related, mood, personality, or social factors predict discrepancies between older adults' functional speech-in-noise test result and their self-reported hearing problems. Method: Data of 1,061 respondents from the Longitudinal Aging Study Amsterdam were used (ages ranged from 57 to 95 years). Functional hearing problems were measured using a digit triplet speech-in-noise test. Five questions were used to assess self-reported hearing problems. Scores of both hearing measures were dichotomized. Two discrepancy outcomes were created: (a) being unaware: those with functional but without self-reported problems (reference is aware: those with functional and self-reported problems); (b) reporting false complaints: those without functional but with self-reported problems (reference is well: those without functional and self-reported hearing problems). Two multivariable prediction models (logistic regression) were built with 19 candidate predictors. The speech reception threshold in noise was kept (forced) as a predictor in both models. Results: Persons with higher self-efficacy (to initiate behavior) and higher self-esteem had a higher odds to being unaware than persons with lower self-efficacy scores (odds ratio [OR] = 1.13 and 1.11, respectively). Women had a higher odds than men (OR = 1.47). Persons with more chronic diseases and persons with worse (i.e., higher) speech-in-noise reception thresholds in noise had a lower odds to being unaware (OR = 0.85 and 0.91, respectively) than persons with less diseases and better thresholds, respectively. A higher odds to reporting false complaints was predicted by more depressive symptoms (OR = 1.06), more chronic diseases (OR = 1.21), and a larger social network (OR = 1.02). Persons with higher self-efficacy (to complete behavior) had a lower odds (OR = 0.86), whereas persons with higher self-esteem had a higher odds to report false complaints (OR = 1.21). The explained variance of both prediction models was small (Nagelkerke R2 = .11 for the unaware model, and .10 for the false complaints model). Conclusions: The findings suggest that a small proportion of the discrepancies between older individuals' results on a speech-in-noise screening test and their self-reports of hearing problems can be explained by the unique context of these individuals. The likelihood of discrepancies partly depends on a person's health (chronic diseases), demographics (gender), personality (self-efficacy to initiate behavior and to persist in adversity, self-esteem), mood (depressive symptoms), and social situation (social network size). Implications are discussed. PMID- 29610840 TI - It Is Time for Women (and Men) to Be Brave: A Consequence of the #MeToo Movement. PMID- 29610841 TI - Growing Symbiotic Local Partnerships to Nurture Quality Pediatric Hospice Care in Rural Regions: Companion Planting. PMID- 29610842 TI - Clinical Usefulness of Imaging and Blood Cultures in Cellulitis Evaluation. PMID- 29610843 TI - Listeria monocytogenes-Induced Rhombencephalitis in a Patient With Multiple Sclerosis Treated With Dimethyl Fumarate. PMID- 29610844 TI - Multispectral Pattern Recognition Reveals a Diversity of Clinical Signs in Intermediate Age-Related Macular Degeneration. AB - Purpose: To develop a proof-of-concept, computational method for the quantification and classification of fundus images in intermediate age-related macular degeneration (AMD). Methods: Multispectral, unsupervised pattern recognition was applied to 184 fundus images from 10 normal and 36 intermediate AMD eyes. The imaging results of preprocessed, grayscale images from three modalities (infrared, green, and fundus autofluorescence scanning laser ophthalmoscopy) were automatically classified into various clusters sharing a common spectral signature, using a k-means clustering algorithm. Class separability was calculated by using transformed divergence (DT). The classification results for large drusen, pigmentary abnormalities, and areas unaffected by AMD were compared against three expert observers for concordance, and to calculate sensitivity and specificity. Results: Multispectral, unsupervised pattern recognition successfully identified a finite number of AMD specific, statistically separable signatures in eyes with intermediate AMD. By using a correct classification criterion of >83% for identical clusters and a total of 1693 expert annotations, the sensitivity and specificity of multispectral pattern recognition for the detection of AMD lesions was 74% and 98%, respectively. Large drusen and pigmentary abnormalities were correctly classified in 75% and 68% of instances, respectively. Conclusions: We describe herein a novel approach for the classification of multispectral images in intermediate AMD. Automated classification of intermediate AMD, using multispectral pattern recognition, has moderate sensitivity and high specificity, when compared against clinical experts. The methods described may have a future role in AMD screening or monitoring. PMID- 29610845 TI - Erratum-title alt-title-type="runhead" />. PMID- 29610846 TI - Erratum-title alt-title-type="runhead" />. PMID- 29610847 TI - The Imbalance of Lymphocyte Subsets and Cytokines: Potential Immunologic Insights Into the Pathogenesis of Chronic Dacryocystitis. AB - Purpose: To explore the quantitative distributions of different lymphocyte subsets in the lacrimal sac mucosa and identify changes of Th1- and Th2 associated cytokines in the tears of patients with chronic dacryocystitis. Methods: Lacrimal sac mucosal specimens from patients with chronic dacryocystitis were analyzed. Hematoxylin-eosin staining and Masson staining were performed for pathologic analysis, and immunohistochemical staining was performed for the detection of CD3+, CD4+, CD8+, CD20+, Th1, and Th2 lymphocytes. Quantitative real time PCR was performed to analyze IFN-gamma and IL-4 mRNA expression. In addition, tear samples from patients with chronic dacryocystitis and healthy volunteers were collected and analyzed with an antibody array system for Th1- and Th2-associated cytokines and chemokines. Results: Different distribution patterns of lymphocyte subsets were observed in the lacrimal sac walls. Both CD20+ B lymphocytes and CD3+ T lymphocytes accumulated in organized lymphoid follicles, and CD3+ T cells were also distributed in a diffuse manner. Among the two subsets of T cells, CD4+ T cells were more abundant than CD8+ T cells. Both the immunohistochemical staining and real-time PCR results revealed significantly higher expression levels of IFN-gamma than those of IL-4. The levels of Th1- and Th2-related cytokines and chemokines measured were significantly higher in the tears of patients than in those of controls. Conclusions: The different distribution patterns of lymphocyte subsets provide insight into a potential immunologic mechanism for dacryocystitis. The cytokines secreted by Th1 or Th2 cells may play a major role in the pathogenesis of dacryocystitis and could be explored as therapeutic targets. PMID- 29610848 TI - Photoreceptor Cell-Derived CAPN5 Regulates Retinal Pigment Epithelium Cell Proliferation Through Direct Regulation of SLIT2 Cleavage. AB - Purpose: To identify the causative gene and investigate the corresponding mechanisms for an autosomal dominant neovascular inflammatory vitreoretinopathy (ADNIV) family. Methods: Clinical examination and genetic analysis were performed in a Chinese ADNIV family. To dissect the molecular consequence, we used gene targeting to knock-in a patient's specific mutation in the mouse genome. Immunostaining and immunoprecipitation were harnessed to analyze the colocalization and interaction of CAPN5 with SLIT2 in photoreceptors. The purified SLIT2-N, SLIT2-C fragments, and the conditioned medium from 661W cells with the overexpression of CAPN5 were treated on ARPE-19 cells. The viability of ARPE-19 cells was determined by MTT assays. The activation of protein kinase A (PKA) was analyzed by immunofluorescence and Western blotting in 661W and ARPE-19 cells as well as in frozen retina tissue from wildtype (WT) and knock-in mice. Results: We identified a novel CAPN5 mutation (p.R289W) in a Chinese family and generated the knock-in CAPN5R289W mouse. This mutation caused abnormal proliferative RPE in both humans and mice. CAPN5 directly cleaved WT SLIT2 in vitro, but not the mutant SLIT2 (p.R1113I). CAPN5 interacted with the SLIT2 in mouse retinal photoreceptors (661W cells) and increased cleavage and secretion of the SLIT2 fragments (SLIT2-N and SLIT2-C). Conditioned medium induced higher levels of secreted SLIT2 fragments, which promoted PKA activation and promoted proliferation of ARPE-19 cells. Conclusions: The novel CAPN5 mutation (p.R289W) is responsible for the present ADNIV family. The mutant CAPN5 stimulated secretion and cleavage of SLIT2 fragments that may act as a bystander to regulate abnormal RPE cell proliferation for ADNIV. PMID- 29610849 TI - Temporary Piggyback Intraocular Lens Implantation Versus Single Intraocular Lens Implantation in Congenital Cataracts: Long-Term Clinical Outcomes. AB - Purpose: To report the long-term results of temporary piggyback IOL implantation in congenital cataract and to compare the clinical outcomes of temporary piggyback IOL with those of single IOL implantation. Methods: This is a retrospective, comparative, interventional study. The medical records of all consecutive patients who underwent cataract extraction and single or temporary piggyback IOL implantation within the first 3 years of life from 1999 to 2013 at Samsung Medical Center were reviewed. Twenty-eight eyes from 18 patients underwent single IOL implantation (monopseudophakia group), and 32 eyes of 20 patients underwent temporary piggyback IOL implantation in congenital cataract surgery (polypseudophakia group). Results: The mean age at initial cataract surgery was 15.8 months in the monopseudophakia group and 11.1 months in the polypseudophakia group (P = 0.144). The average follow-up duration was 133 months in the monopseudophakia group and 120 months in the polypseudophakia group (P = 0.391). The best-corrected visual acuity at the last visit was 0.36 logMAR in the monopseudophakia group and 0.55 logMAR in the polypseudophakia group (P = 0.044). Four (14%) and 14 (44%) reoperations for complications within the anterior segment were performed in the monopseudophakia group and polypseudophakia group, respectively (P = 0.042). Four cases (14.3%) in the monopseudophakia group and 13 cases (40.6%) in the polypseudophakia group had a glaucoma-related adverse event (P = 0.086). Conclusions: Compared with primary single IOL implantation in congenital cataract, temporary piggyback IOL implantation produced worse visual acuity, higher reoperation rate, and higher risk of secondary glaucoma. Temporary piggyback IOL implantation does not have benefit in congenital cataract. PMID- 29610850 TI - Plasma Concentrations of Lutein and Zeaxanthin, Macular Pigment Optical Density, and Their Associations With Cognitive Performances Among Older Adults. AB - Purpose: We investigated the cross-sectional associations between macular pigment optical density (MPOD), plasma lutein (L), and zeaxanthin (Z) concentrations and cognitive function in 184 older adults of the 3-City-Bordeaux cohort. Methods: MPOD was measured using the two-wavelength autofluorescence method with a modified scanning laser ophthalmoscope. Plasma L and Z (L+Z) concentrations were determined by high-performance liquid chromatography and were considered either crude or expressed as a ratio of the concentration of plasma lipids (total cholesterol [TC] + triglycerides [TG]). Cognitive performances were assessed using the following four separate neuropsychological tests: the Mini-Mental State Examination (MMSE), the Isaacs Set Test (IST), the Benton Visual Retention Test (BVRT), and the sum of the three free recalls of the Free and Cued Selective Reminding Test (FCSRT). These test results were summarized by a composite global cognitive z-score. Results: Higher MPOD at 0.5 degrees was significantly associated with a higher composite z-score (beta = 0.15, 95% confidence interval [CI] 0.04-0.26), higher BVRT (beta = 0.39, 95%CI 0.08-0.70), and higher IST (beta = 1.16, 95%CI 0.11-2.22) performances. Higher plasma L+Z concentrations were significantly associated with higher IST scores (beta = 0.97, 95%CI 0.01-1.94). Furthermore, a higher L+Z/TC+TG ratio was associated with a higher composite z score (beta = 0.12, 95%CI 0.01-0.23), along with higher IST (beta = 1.02, 95%CI 0.002-2.04) and FCSRT (beta = 1.55, 95%CI 0.41-2.69) performances. Conclusions: This analysis suggested that both higher MPOD and L+Z concentrations were significantly associated with higher cognitive performances. However, MPOD measurements have the advantage of being a fast and representative measure of long-term carotenoid intake. PMID- 29610851 TI - Refractive Correction and Biomechanical Strength Following SMILE With a 110- or 160-MUm Cap Thickness, Evaluated Ex Vivo by Inflation Test. AB - Purpose: To examine the refractive correction and corneal biomechanical strength after small incision lenticule extraction (SMILE) by using a 110- or 160-MUm cap thickness. Methods: Thirty-two human donor corneas were allocated into 4 groups, combining one of two cap thicknesses (110 and 160 MUm) with one of two spherical corrections (-4 D and -8 D). Each cornea was mounted on an artificial anterior chamber. The chamber pressure was adjusted by an attached 8% dextran media column. The anterior and posterior sagittal 3-mm-diameter curvature (rsag3mm) and the total corneal refractive power (TCRP4mm,apex,zone) were obtained before and after SMILE at a chamber pressure of 15 or 40 mm Hg. The average changes after surgery (Delta = postoperative - preoperative) and at increased chamber pressure (delta = 40 mm Hg - 15 mm Hg) were compared. Results: A 110-MUm cap thickness caused more anterior flattening (Deltar15,-8D, 1.02 +/- 0.08 mm versus 0.60 +/- 0.17 mm), less posterior steepening (Deltar15,-8D, -0.19 +/- 0.11 mm versus -0.45 +/- 0.20 mm), and more myopic correction (DeltaTCRP15,-8D, -6.30 +/- 0.96 D versus -4.55 +/- 1.66 D) than a 160-MUm cap thickness for -8 D SMILE (P < 0.034), but not for -4 D SMILE (DeltaTCRP15,-4D,110MUm, -3.86 +/- 1.31 D versus DeltaTCRP15,-4D,160MUm, -3.57 +/- 1.27 D, P = 0.718). After SMILE, increased chamber pressure caused anterior steepening (P < 0.014), which was similar at cap thicknesses of 110 and 160 MUm (deltar-4D, -0.13 +/- 0.14 mm versus -0.09 +/- 0.05mm, P = 0.431). Conclusions: For high myopic corrections, a 160-MUm cap caused less anterior curvature flattening and more posterior steepening than a 110-MUm cap, and consequently less myopic correction. The inflation test revealed a reduction in the biomechanical strength after SMILE; this was similar when using a 110- or 160-MUm cap thickness. PMID- 29610852 TI - Consistency of Structure-Function Correlation Between Spatially Scaled Visual Field Stimuli and In Vivo OCT Ganglion Cell Counts. AB - Purpose: To investigate the effect of stimulus size and disease status on the structure-function relationship within the central retina, we correlated the differential light sensitivity (DLS) with Goldmann stimulus size I to V (GI-V) and optical coherence tomography (OCT) derived in vivo ganglion cell count per stimulus area (GCc) within the macular area in normal subjects and patients with early glaucoma. Methods: Humphrey Field Analyzer 10-2 visual field data with GI through V and Spectralis OCT macular ganglion cell layer (GCL) thickness measurements were collected from normal and early glaucoma cohorts including 25 subjects each. GCc was calculated from GCL thickness data and correlated with DLSs for different stimulus sizes. Results: Correlation coefficients attained with smaller stimulus size were higher compared to larger stimulus sizes in both normal (GI-GII: R2 = 0.41-0.43, GIII-GV: R2 = 0.16-0.41) and diseased cohorts (GI GII: R2 = 0.33-0.41, GIII-GV: R2 = 0.19-0.36). Quadratic regression curves for combined GI to V data demonstrated high correlation (R2= 0.82-0.90) and differed less than 1 dB of visual sensitivity within the GCc range between cohorts. The established structure-function relationship was compatible with a histologically derived model correlation spanning the range predicted by stimulus sizes GI to GIII. Conclusions: Stimulus sizes within critical spatial summation area (GI-II) improved structure-function correlations in the central visual field. The structure-function relationship was identical in both normal and diseased cohort when GI to GV data were combined. Congruency of GI and GII structure-function correlation with those previously derived with GIII from more peripheral locations further suggests that the structure-function relationship is governed by the number of ganglion cell per stimulus area. PMID- 29610853 TI - A Novel Selective Soluble Guanylate Cyclase Activator, MGV354, Lowers Intraocular Pressure in Preclinical Models, Following Topical Ocular Dosing. AB - Purpose: The nitric oxide/soluble guanylate cyclase/protein kinase G (NO/sGC/PKG) is known to be involved in the regulation of intraocular pressure (IOP) and may be dysregulated in glaucoma. The purpose is to demonstrate that the sGC activator MGV354 lowers IOP in a monkey model of glaucoma and could be considered as a possible new clinical drug candidate. Methods: Changes to cGMP were assessed in primary human trabecular meshwork (hNTM) cells and binding studies were conducted using human sGC full-length protein. Ocular safety tolerability, exposure, and efficacy studies were conducted in rabbit and monkey models following topical ocular dosing of MGV354. Results: sGC was highly expressed in the human and cynomolgus monkey outflow pathways. MGV354 had a 7-fold greater Bmax to oxidized sGC compared to that of reduced sGC and generated an 8- to 10-fold greater cGMP compared to that of a reduced condition in hTM cells. A single topical ocular dose with MGV354 caused a significant dose-dependent reduction of 20% to 40% (versus vehicle), lasting up to 6 hours in pigmented rabbits and 24 hours postdose in a cynomolgus monkey model of glaucoma. The MGV354-induced IOP lowering was sustained up to 7 days following once-daily dosing in a monkey model of glaucoma and was greater in magnitude compared to Travatan (travoprost) induced IOP reduction. Mild to moderate ocular hyperemia was the main adverse effect noted. Conclusions: MGV354 represents a novel class of sGC activators that can lower IOP in preclinical models of glaucoma. The potential for sGC activators to be used as effective IOP-lowering drugs in glaucoma patients could be further determined in clinical studies. PMID- 29610854 TI - The First Histologic Evidence of a Paravascular Pathway Within the Optic Nerve. PMID- 29610855 TI - Author Response: The First Histologic Evidence of a Paravascular Pathway Within the Optic Nerve. PMID- 29610856 TI - Natural Killer Cell Inhibition by HLA-E Molecules on Induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelial Cells. AB - Purpose: To determine whether human induced pluripotent stem (iPS) cell-derived retinal pigment epithelial (RPE) cells (iPS-RPE) can suppress natural killer (NK) cell activation. Methods: iPS-RPE cells were cocultured with peripheral blood mononuclear cells (PBMCs) or purified NK cells from healthy donors after stimulation with cytokines. To confirm expression of NK cell-specific markers, flow cytometry and quantitative RT-PCR (qRT-PCR) were performed. NK cells (or PBMCs) cocultured with iPS-RPE cells were assessed for proliferation by Ki-67 expression with flow cytometry, and NK suppression by RPE cells was assessed for granzyme B production with ELISA. Human leukocyte antigen (HLA) expression including HLA-E on iPS-RPE cells was evaluated with flow cytometry and qRT-PCR. The effect of HLA-E downregulation was also investigated using small interfering RNA (siRNA) systems. Following iPS-RPE cell transplantation in vivo, we evaluated NK cell invasion in the retina with immunohistochemistry. Results: Activated NK cells expressed NK-related markers such as CD16, CD56, and CD11b, and NK cells produced cytotoxic agents such as granzyme B, perforin, and TNF-alpha. Human iPS RPE cells inhibited cell proliferation and production of these cytotoxic agents by activated NK cells in vitro. iPS-RPE cells constitutively expressed HLA-E and suppressed NK cell activation through an interaction between HLA-E and CD94/NKG2A. Moreover, immunohistochemical evaluation of monkey RPE transplantation into in vivo immune rejection models showed no NK cell invasion in the retina in allografts or xenografts except for one xenografted eye. Conclusions: Cultured iPS cell-derived RPE cells greatly suppress NK cell activation. Thus, NK cells might be inactivated when exposed to this type of retinal cell. PMID- 29610857 TI - Mast Cells Initiate the Recruitment of Neutrophils Following Ocular Surface Injury. AB - Purpose: The purpose of this study was to investigate the contribution of mast cells to early neutrophil recruitment during ocular inflammation. Methods: In a murine model of corneal injury, the epithelium and anterior stroma were removed using a handheld motor brush. Cromolyn sodium (2% in PBS) eye drops were administered topically for mast cell inhibition. In vitro, bone marrow-derived mast cells were cultured alone or with corneal tissue. The frequencies of CD45+ inflammatory cells, CD11b+Ly6G+ neutrophils, and ckit+FcepsilonR1+ mast cells in the cornea were assessed by flow cytometry. mRNA expression of CXCL2 was evaluated by real-time PCR and protein expression by ELISA. beta-Hexosaminidase assays were performed to gauge mast cell activation. Results: Neutrophil infiltration of the cornea was observed within 1 hour of injury, with neutrophil frequencies increasing over subsequent hours. Concurrent expansion of mast cell frequencies at the cornea were observed, with mast cell activation (assessed by beta-hexosaminidase levels) peaking at 6 hours after injury. Evaluation of CXCL2 mRNA and protein expression levels demonstrated augmented expression by injured corneal tissue relative to naive corneal tissue. Mast cells were observed to constitutively express CXCL2, with significantly higher expression of CXCL2 protein compared with naive corneal tissue. Culture with harvested injured corneas further amplified CXCL2 expression by mast cells. In vivo, mast cell inhibition was observed to decrease CXCL2 expression, limit early neutrophil infiltration, and reduce inflammatory cytokine expression by the cornea. Conclusions: Our data suggest that mast cell activation after corneal injury amplifies their secretion of CXCL2 and promotes the initiation of early neutrophil recruitment. PMID- 29610858 TI - High-Mobility Group Box 1 in Dry Eye Inflammation. AB - Purpose: To determine high-mobility group box 1 (HMGB1) expression during experimental dry eye (EDE) and dry eye-like culture conditions and elucidate its role in corneal dry eye-related inflammation. Methods: EDE was induced in 8- to 12-week-old C57BL/6 mice. Corneal tissue sections and lysates from EDE and untreated mice were evaluated for HMGB1 expression by immunostaining and quantitative real-time PCR (qPCR). For in vitro studies, human corneal epithelial cells (HCEC) were treated with hyperosmolar media, toll-like receptor (TLR) agonists, or proinflammatory cytokines to determine HMGB1 expression. HCEC were also treated with human recombinant HMGB1 (hrHMGB1) alone or in combination with inflammatory stimuli, and TNFalpha, IL-6, and IL-8 expression evaluated by qPCR and ELISA. Nuclear factor-kappaB (NF-kappaB) p65 nuclear translocation was determined by immunostaining. Results: EDE mice had higher corneal HMGB1 RNA and protein expression compared to untreated animals. In HCEC, hyperosmolar stress and TNFalpha treatment stimulated HMGB1 production and secretion into culture supernatants. However, in vitro stimulation with hrHMGB1 did not induce secretion of TNFalpha, IL-6, or IL-8 or NF-kappaB p65 nuclear translocation. In addition, the inflammatory response elicited by TLR agonists fibroblast-stimulating lipopeptide-1 and lipopolysaccharide was not enhanced by hrHMGB1 treatment. Conclusions: HMGB1 expression was enhanced by dry eye conditions in vivo as well as in vitro, during hyperosmolar stress and cytokine exposure, suggesting an important role for HMGB1 in dry eye disease. However, no direct inflammatory effect was observed with HMGB1 treatment. Therefore, under these conditions, HMGB1 does not contribute directly to dry eye-induced inflammation and its function at the ocular surface needs to be explored further. PMID- 29610860 TI - Fundus Autofluorescence Lifetime Patterns in Retinitis Pigmentosa. AB - Purpose: We investigated whether fundus autofluorescence (FAF) lifetimes in patients with retinitis pigmentosa display a disease-specific lifetime pattern. Methods: Fundus autofluorescence lifetime imaging ophthalmoscopy (FLIO) was performed in two spectral channels (498-560 and 560-720 nm) after excitation with a 473 nm pulsed laser in patients with retinitis pigmentosa and compared to healthy controls of a similar age range. Corresponding FAF intensity and spectral domain optical coherence tomography (OCT) data, as well as best corrected visual acuity (BCVA) were acquired and compared to fluorescence lifetime data. Results: We investigated 43 eyes from 43 patients with retinitis pigmentosa (mean age 45 +/- 15 years) and compared them to eyes of 13 age-matched healthy participants. Mean FAF lifetimes were prolonged in areas of photoreceptor atrophy with preserved retinal pigment epithelium (RPE) (P = 0.0036) and even longer in areas with total atrophy of photoreceptors and RPE (P = 0.0002). The prevalence of perifoveal ring structures characterized by prolonged fluorescence lifetimes in FLIO was higher (63% vs. 49%) and the rings were wider compared to the hyperautofluorescent rings in qualitative fundus autofluorescence intensity images. In the central fovea with intact retinal layer structure identified by OCT, fluorescence lifetimes were slightly prolonged compared to those of age matched healthy controls (short spectral channel [SSC], P = 0.0044; long spectral channel [LSC], P = 0.0128). Short lifetimes within the macular center were negatively correlated with BCVA (R2 = 0.33, P < 0.0001) as well as the greatest diameter of the ellipsoid band in OCT. Conclusions: FLIO in retinitis pigmentosa reveals characteristic patterns that allow identification of areas of photoreceptor atrophy, RPE atrophy, and remaining photoreceptor segments in areas of RPE atrophy. Fluorescence lifetimes can be used to identify ellipsoid zone loss that correlates with functional parameters. PMID- 29610861 TI - Integrin-Linked Kinase Controls Choroidal Neovascularization by Recruitment of Endothelial Progenitor Cells. AB - Purpose: Vasculogenesis has been shown to contribute to the formation of choroidal neovascularization (CNV). However, the mechanism behind the recruitment of endothelial progenitor cells (EPC) to CNV is not well understood. Therefore, we were interested to know whether integrin-linked kinase (ILK) plays a role in recruiting EPC to CNV, and its possible mechanism. Methods: We investigated the effect of hypoxia on retinal pigment epithelium (RPE) cells expressing ILK, hypoxia-inducible factor 1alpha (HIF-1alpha), stromal-derived factor-1 (SDF-1), and vascular endothelial growth factor (VEGF), and we further examined the effect of ILK small interfering RNA (siRNA) on their expression. The function of ILK expressed by RPE on EPC in vitro with regard to angiogenic effect was also studied. In vivo, we determined the expression levels of the above factors in CNV. We also examined the role of ILK on their expression, on EPC recruiting, and on the growth of CNV. Results: We found that hypoxia strongly induced the expression of ILK, HIF-1alpha, SDF-1, and VEGF. Moreover, the silencing of ILK attenuated their expression. It also decreased the phosphorylation of protein kinase B (PKB/AKT) and extracellular regulated protein kinases (ERK) and nearly abolished the proliferation, migration, and adhesion of EPC to RPE cells. In vivo, we showed that these factors were upregulated in CNV. Inhibiting the expression of ILK prohibited the "homing" of EPC to CNV lesions and attenuated the growth of CNV. Conclusions: We demonstrate that ILK controls the development of CNV by regulating the recruitment of EPC to CNV lesions, possibly through ILK dependent expression of SDF-1 and VEGF in RPE. PMID- 29610859 TI - The MT-CO1 V83I Polymorphism is a Risk Factor for Primary Open-Angle Glaucoma in African American Men. AB - Purpose: We investigate the function of the V83I polymorphism (m.6150G>A, rs879053914) in the mitochondrial cytochrome c oxidase subunit 1 (MT-CO1) gene and its role in African American (AA) primary open-angle glaucoma (POAG). Methods: This study used Sanger sequencing (1339 cases, 850 controls), phenotypic characterization of Primary Open-Angle African American Glaucoma Genetics study (POAAGG) cases, a masked chart review of CO1 missense cases (V83I plus M117T, n = 29) versus wild type cases (n = 29), a yeast 2-hybrid (Y2H) cDNA library screen, and quantification of protein-protein interactions by Y2H and ELISA. Results: The association of V83I with POAG in AA was highly significant for men (odds ratio [OR] 6.5; 95% confidence interval [CI] 2.0-21.3, P = 0.0001), but not for women (OR 1.1; 95% CI, 0.62-2.00, P = 0.78). POAG cases having CO1 double missense mutation (V83I + M117T, L1c2 haplogroup) had a higher cup-to-disc ratio (0.77 vs. 0.71, P = 0.04) and significantly worse visual function (average pattern standard deviation, 6.5 vs. 4.3, P = 0.009; average mean deviation -10.4 vs. -4.5, P = 0.006) when compared to matched wild type cases (L1b haplogroup). Interaction of the V83I region of CO1 with amyloid beta peptide (Abeta) was confirmed by ELISA assay, and this interaction was abrogated by V83I. A Y2H screen of an adult human brain cDNA library with the V83 region of CO1 as bait retrieved the UBQLN1 gene. Conclusions: The V83I polymorphism was associated strongly with POAG in AA men and disrupts Abeta-binding to CO1. This region also interacts with a neuroprotective protein, UBQLN1. PMID- 29610862 TI - Reliability and Validity of Gaze-Dependent Functional Vision Space: A Novel Metric Quantifying Visual Function in Infantile Nystagmus Syndrome. AB - Purpose: This study presents test-retest reliability of optotype visual acuity (OVA) across 60 degrees of horizontal gaze position in patients with infantile nystagmus syndrome (INS). Also, the validity of the metric gaze-dependent functional vision space (GDFVS) is shown in patients with INS. Methods: In experiment 1, OVA was measured twice in seven horizontal gaze positions from 30 degrees left to right in 10 degrees steps in 20 subjects with INS and 14 without INS. Test-retest reliability was assessed using intraclass correlation coefficient (ICC) in each gaze. OVA area under the curve (AUC) was calculated with horizontal eye position on the x-axis, and logMAR visual acuity on the y axis and then converted to GDFVS. In experiment 2, validity of GDFVS was determined over 40 degrees horizontal gaze by applying the 95% limits of agreement from experiment 1 to pre- and post-treatment GDFVS values from 85 patients with INS. Results: In experiment 1, test-retest reliability for OVA was high (ICC >= 0.88) as the difference in test-retest was on average less than 0.1 logMAR in each gaze position. In experiment 2, as a group, INS subjects had a significant increase (P < 0.001) in the size of their GDFVS that exceeded the 95% limits of agreement found during test-retest. Conclusions: OVA is a reliable measure in INS patients across 60 degrees of horizontal gaze position. GDFVS is a valid clinical method to be used to quantify OVA as a function of eye position in INS patients. This method captures the dynamic nature of OVA in INS patients and may be a valuable measure to quantify visual function patients with INS, particularly in quantifying change as part of clinical studies. PMID- 29610867 TI - Golden Hour, Great Lawn, Central Park. PMID- 29610868 TI - Uses of H.P. Acthar Gel in the Clinical Setting. PMID- 29610863 TI - Evaluating Vaccination Strategies for Zika Virus in the Americas. AB - Background: Mosquito-borne and sexually transmitted Zika virus has become widespread across Central and South America and the Caribbean. Many Zika vaccine candidates are under active development. Objective: To quantify the effect of Zika vaccine prioritization of females aged 9 to 49 years, followed by males aged 9 to 49 years, on incidence of prenatal Zika infections. Design: A compartmental model of Zika transmission between mosquitoes and humans was developed and calibrated to empirical estimates of country-specific mosquito density. Mosquitoes were stratified into susceptible, exposed, and infected groups; humans were stratified into susceptible, exposed, infected, recovered, and vaccinated groups. Age-specific fertility rates, Zika sexual transmission, and country specific demographics were incorporated. Setting: 34 countries and territories in the Americas with documented Zika outbreaks. Target Population: Males and females aged 9 to 49 years. Intervention: Age- and sex-targeted immunization using a Zika vaccine with 75% efficacy. Measurements: Annual prenatal Zika infections. Results: For a base-case vaccine efficacy of 75% and vaccination coverage of 90%, immunizing females aged 9 to 49 years (the World Health Organization target population) would reduce the incidence of prenatal infections by at least 94%, depending on the country-specific Zika attack rate. In regions where an outbreak is not expected for at least 10 years, vaccination of women aged 15 to 29 years is more efficient than that of women aged 30 years or older. Limitation: Population-level modeling may not capture all local and neighborhood-level heterogeneity in mosquito abundance or Zika incidence. Conclusion: A Zika vaccine of moderate to high efficacy may virtually eliminate prenatal infections through a combination of direct protection and transmission reduction. Efficiency of age specific targeting of Zika vaccination depends on the timing of future outbreaks. Primary Funding Source: National Institutes of Health. PMID- 29610864 TI - Association Between Use of Acid-Suppressive Medications and Antibiotics During Infancy and Allergic Diseases in Early Childhood. AB - Importance: Allergic diseases are prevalent in childhood. Early exposure to medications that can alter the microbiome, including acid-suppressive medications and antibiotics, may influence the likelihood of allergy. Objective: To determine whether there is an association between the use of acid-suppressive medications or antibiotics in the first 6 months of infancy and development of allergic diseases in early childhood. Design, Setting, and Participants: A retrospective cohort study was conducted in 792 130 children who were Department of Defense TRICARE beneficiaries with a birth medical record in the Military Health System database between October 1, 2001, and September 30, 2013, with continued enrollment from within 35 days of birth until at least age 1 year. Children who had an initial birth stay of greater than 7 days or were diagnosed with any of the outcome allergic conditions within the first 6 months of life were excluded from the study. Data analysis was performed from April 15, 2015, to January 4, 2018. Exposures: Exposures were defined as having any dispensed prescription for a histamine-2 receptor antagonist (H2RA), proton pump inhibitor (PPI), or antibiotic. Main Outcomes and Measures: The main outcome was allergic disease, defined as the presence of food allergy, anaphylaxis, asthma, atopic dermatitis, allergic rhinitis, allergic conjunctivitis, urticaria, contact dermatitis, medication allergy, or other allergy. Results: Of 792 130 children (395 215 [49.9%] girls) included for analysis, 60 209 (7.6%) were prescribed an H2RA, 13 687 (1.7%) were prescribed a PPI, and 131 708 (16.6%) were prescribed an antibiotic during the first 6 months of life. Data for each child were available for a median of 4.6 years. Adjusted hazard ratios (aHRs) in children prescribed H2RAs and PPIs, respectively, were 2.18 (95% CI, 2.04-2.33) and 2.59 (95% CI, 2.25-3.00) for food allergy, 1.70 (95% CI, 1.60-1.80) and 1.84 (95% CI, 1.56 2.17) for medication allergy, 1.51 (95% CI, 1.38-1.66) and 1.45 (95% CI, 1.22 1.73) for anaphylaxis, 1.50 (95% CI, 1.46-1.54) and 1.44 (95% CI, 1.36-1.52) for allergic rhinitis, and 1.25 (95% CI, 1.21-1.29) and 1.41 (95% CI, 1.31-1.52) for asthma. The aHRs after antibiotic prescription in the first 6 months of life were 2.09 (95% CI, 2.05-2.13) for asthma, 1.75 (95% CI, 1.72-1.78) for allergic rhinitis, 1.51 (95% CI, 1.38-1.66) for anaphylaxis, and 1.42 (95% CI, 1.34-1.50) for allergic conjunctivitis. Conclusions and Relevance: This study found associations between the use of acid-suppressive medications and antibiotics during the first 6 months of infancy and subsequent development of allergic disease. Acid-suppressive medications and antibiotics should be used during infancy only in situations of clear clinical benefit. PMID- 29610869 TI - Assessing Pharmaceutical Research and Development Costs. PMID- 29610871 TI - Questionable Conclusions Regarding Blood Pressure End Points. PMID- 29610870 TI - Assessing Pharmaceutical Research and Development Costs. PMID- 29610872 TI - Evidence-Based Rationale for Use of Inferior Vena Cava Filters. PMID- 29610873 TI - Methods Used to Assess Pharmaceutical Research and Development Costs. PMID- 29610874 TI - Physician Burnout-Overdiagnosis and Unproven Interventions. PMID- 29610875 TI - What Patients Expect and Deserve. PMID- 29610876 TI - Concerns Regarding Resource Use and Outcomes in Subsets of Clinicians. PMID- 29610877 TI - Concerns Regarding Resource Use and Outcomes in Subsets of Clinicians. PMID- 29610878 TI - Concerns Regarding Resource Use and Outcomes in Subsets of Clinicians. PMID- 29610879 TI - Incorrect Conclusions of a Secondary Analysis. PMID- 29610880 TI - Questionable Conclusions Regarding Blood Pressure End Points. PMID- 29610881 TI - Lower Cancer Incidence-Warfarin Effect or Immortal Time Bias? PMID- 29610882 TI - Lower Cancer Incidence-Warfarin Effect or Immortal Time Bias? PMID- 29610883 TI - Further Questions Regarding Electrocardiogram Prior to Liver Transplant. PMID- 29610884 TI - Uses of H.P. Acthar Gel in the Clinical Setting-Reply. PMID- 29610885 TI - Assessing Pharmaceutical Research and Development Costs-Reply. PMID- 29610887 TI - Evidence-Based Rationale for Use of Inferior Vena Cava Filters-Reply. PMID- 29610886 TI - Questionable Conclusions Regarding Blood Pressure End Points-Reply. PMID- 29610888 TI - What Patients Expect and Deserve-Reply. PMID- 29610889 TI - Physician Burnout-Overdiagnosis and Unproven Interventions-Reply. PMID- 29610890 TI - Concerns Regarding Resource Use and Outcomes in Subsets of Clinicians-Reply. PMID- 29610891 TI - Incorrect Conclusions of a Secondary Analysis-Reply. PMID- 29610892 TI - Incorrect Conclusions of a Secondary Analysis-Reply. PMID- 29610893 TI - Lower Cancer Incidence-Warfarin Effect or Immortal Time Bias?-Reply. PMID- 29610894 TI - Further Questions Regarding Electrocardiogram Prior to Liver Transplant-Reply. PMID- 29610896 TI - Avoidance of Severe Cutaneous Adverse Drug Events as a First Step in Precision Neurology. PMID- 29610897 TI - Association Between US State Medical Cannabis Laws and Opioid Prescribing in the Medicare Part D Population. AB - Importance: Opioid-related mortality increased by 15.6% from 2014 to 2015 and increased almost 320% between 2000 and 2015. Recent research finds that the use of all pain medications (opioid and nonopioid collectively) decreases in Medicare Part D and Medicaid populations when states approve medical cannabis laws (MCLs). The association between MCLs and opioid prescriptions is not well understood. Objective: To examine the association between prescribing patterns for opioids in Medicare Part D and the implementation of state MCLs. Design, Setting, and Participants: Longitudinal analysis of the daily doses of opioids filled in Medicare Part D for all opioids as a group and for categories of opioids by state and state-level MCLs from 2010 through 2015. Separate models were estimated first for whether the state had implemented any MCL and second for whether a state had implemented either a dispensary-based or a home cultivation only-based MCL. Main Outcomes and Measures: The primary outcome measure was the total number of daily opioid doses prescribed (in millions) in each US state for all opioids. The secondary analysis examined the association between MCLs separately by opioid class. Results: From 2010 to 2015 there were 23.08 million daily doses of any opioid dispensed per year in the average state under Medicare Part D. Multiple regression analysis results found that patients filled fewer daily doses of any opioid in states with an MCL. The associations between MCLs and any opioid prescribing were statistically significant when we took the type of MCL into account: states with active dispensaries saw 3.742 million fewer daily doses filled (95% CI, -6.289 to -1.194); states with home cultivation only MCLs saw 1.792 million fewer filled daily doses (95% CI, -3.532 to -0.052). Results varied by type of opioid, with statistically significant estimated negative associations observed for hydrocodone and morphine. Hydrocodone use decreased by 2.320 million daily doses (or 17.4%) filled with dispensary-based MCLs (95% CI, -3.782 to 0.859; P = .002) and decreased by 1.256 million daily doses (or 9.4%) filled with home-cultivation-only-based MCLs (95% CI, -2.319 to -0.193; P = .02). Morphine use decreased by 0.361 million daily doses (or 20.7%) filled with dispensary based MCLs (95% CI, -0.718 to -0.005; P = .047). Conclusions and Relevance: Medical cannabis laws are associated with significant reductions in opioid prescribing in the Medicare Part D population. This finding was particularly strong in states that permit dispensaries, and for reductions in hydrocodone and morphine prescriptions. PMID- 29610898 TI - "To Be Quite Honest, If It Wasn't for Videogames I Wouldn't Have a Social Life at All": Motivations of Young Adults With Autism Spectrum Disorder for Playing Videogames as Leisure. AB - Purpose: Leisure activities are underutilized as a context for intervention in the field of speech-language pathology despite the fact that leisure can be an important context for skill development. The current study investigated the perceptions of individuals with autism spectrum disorder (ASD) who play videogames as their primary leisure activity regarding the role of videogames in their lives and their motivations for playing videogames. Method: Qualitative interview methodology was used to investigate the experiences of 10 18-24-year olds with ASD. Information was collected about the role of videogames in the lives of adolescents and young adults with ASD and the perceived benefits of playing videogames. Results: Results indicated the participants perceived playing videogames to have a positive impact on their lives and their development. The motivations for playing videogames described are similar to those reported by typically developing populations. Conclusions: Videogaming is a popular leisure pursuit for adolescents and young adults with and without ASD. Speech-language pathologists should consider how videogame play may be a useful context for teaching new communication, social, and language. PMID- 29610899 TI - Sex Differences in Academic Rank and Publication Rate at Top-Ranked US Neurology Programs. AB - Importance: Women are underrepresented in academic neurology, and the reasons for the underrepresentation are unclear. Objective: To explore potential sex differences in top-ranked academic neurology programs by comparing the number of men and women at each academic faculty rank and how many articles each group has published. Design, Setting, and Participants: Twenty-nine top-ranked neurology programs were identified by combining the top 20 programs listed on either the 2016 or 2017 Doximity Residency Navigator tool with the top 20 programs listed in the US News and World Report ranking of Best Graduate Schools. An internet search of the departmental websites was performed between December 1, 2015, and April 30, 2016. For each faculty member on a program site, the following biographical information was obtained: first name, last name, academic institution, sex, academic faculty rank, educational leadership (clerkship, fellowship, or residency director/assistant director), and year of medical school graduation. Main Outcomes and Measures: To compare the distribution of men vs women and the number of publications for men vs women at each academic faculty rank. Secondary analyses included Scopus h-index, book authorship, educational leadership (clerkship, residency, or fellowship director/assistant director), and clinical activity as inferred through Medicare claims data in men vs women after controlling for years since medical school graduation. Results: Of 1712 academic neurologists in our sample, 528 (30.8%) were women and 1184 (69.2%) were men (P < .001). Men outnumbered women at all academic faculty ranks, and the difference increased with advancing rank (instructor/lecturer, 59.4% vs 40.5%; assistant professor, 56.7% vs 43.3%; associate professor, 69.8% vs 30.2%; and professor, 86.2% vs 13.8%). After controlling for clustering and years since medical school graduation, men were twice as likely as women to be full professors (odds ratio [OR], 2.06; 95% CI, 1.40-3.01), whereas men and women had the same odds of being associate professors (OR, 1.04; 95% CI, 0.82-1.32). Men had more publications than women at all academic ranks, but the disparity in publication number decreased with advancing rank (men vs women after adjusting for years since medical school graduation: assistant professor [exponentiated coefficient, 1.85; 95% CI, 1.57-2.12]; associate professor [1.53; 95% CI, 1.22-1.91]; and full professor [1.36; 95% CI, 1.09-1.69]). Men had a higher log Scopus h-index than women after adjustment (linear coefficient, 0.44; 95% CI, 0.34-0.55). There was no significant association between sex and clinical activity (linear coefficient, 0.02; 95% CI, -0.10 to 0.13), educational leadership (OR, 1.09; 95% CI, 0.85 1.40), or book authorship (OR, 2.75; 95% CI, 0.82-9.29) after adjusting for years since medical school graduation. Conclusions and Relevance: Men outnumber women at all faculty ranks in top-ranked academic neurology programs, and the discrepancy increases with advancing rank. Men have more publications than women at all ranks, but the gap narrows with advancing rank. Other measures of academic productivity do not appear to differ between men and women. PMID- 29610901 TI - A Call for Open-Source Cost-Effectiveness Analysis. PMID- 29610902 TI - A Call for Open-Source Cost-Effectiveness Analysis. PMID- 29610900 TI - Web Exclusives. Annals Graphic Medicine - The Cure Is at Hand. PMID- 29610903 TI - A Call for Open-Source Cost-Effectiveness Analysis. PMID- 29610904 TI - Continuous Glucose Monitoring Versus Usual Care in Patients With Type 2 Diabetes Receiving Multiple Daily Insulin Injections. PMID- 29610905 TI - Continuous Glucose Monitoring Versus Usual Care in Patients With Type 2 Diabetes Receiving Multiple Daily Insulin Injections. PMID- 29610906 TI - Holding Providers Accountable for Health Care Outcomes. PMID- 29610907 TI - Holding Providers Accountable for Health Care Outcomes. PMID- 29610908 TI - Continuous Glucose Monitoring in Patients With Type 2 Diabetes Receiving Insulin Injections. PMID- 29610909 TI - The Effects of Cannabis Among Adults With Chronic Pain. PMID- 29610910 TI - The Effects of Cannabis Among Adults With Chronic Pain. PMID- 29610911 TI - Correction: Pharmacologic Treatment of Hypertension in Adults Aged 60 Years or Older to Higher Versus Lower Blood Pressure Targets. PMID- 29610912 TI - Correction: Benefits and Harms of Intensive Blood Pressure Treatment in Adults Aged 60 Years or Older. PMID- 29610913 TI - Provisions. PMID- 29610914 TI - Politics in the Exam Room. PMID- 29610915 TI - On Seeing Your Obituary in the Newspaper. PMID- 29610916 TI - Should This Patient Receive Prophylactic Medication to Prevent Delirium?: Grand Rounds Discussion From Beth Israel Deaconess Medical Center. AB - In 2015, the American Geriatrics Society released recommendations for prevention and management of postoperative delirium, based on a systematic literature review and evaluation of nonpharmacologic and pharmacologic approaches by an expert panel. The guidelines recommend an interdisciplinary focus on nonpharmacologic measures (reorientation, medication management, early mobility, nutrition, and gastointestinal motility) for prevention and consideration of this strategy for acute management. They also recommend optimizing nonopioid medication as a means to manage pain and avoiding benzodiazepines other than to treat substance withdrawal. The authors concluded that evidence to recommend antipsychotics for prevention of delirium is insufficient but that these drugs may be considered for short-term treatment in the setting of imminent harm to the patient or caregivers or severe distress due to agitation. Patients should be given the lowest possible dose for the shortest duration when other nonpharmacologic measures have failed. In this Beyond the Guidelines, a psychiatrist and a geriatrician debate whether Mr. W, a 79-year-old man at high risk for postoperative delirium, should receive prophylactic antipsychotics with his next surgery. They review risk factors, appropriate evaluation, and potential benefits and harms of the various medications often used in this setting. PMID- 29610917 TI - Web Exclusives. Annals Story Slam - Despair to Hope. PMID- 29610918 TI - Web Exclusives. Annals Story Slam - Teamwork Is the Real Lesson. PMID- 29610919 TI - Web Exclusives. Annals Story Slam - To Save One Life Is to Save the World. PMID- 29610920 TI - Web Exclusives. Annals Story Slam - Just Another Day in the Emergency Department. PMID- 29610921 TI - Web Exclusives. Annals Story Slam - Lessons From Crying. PMID- 29610922 TI - Web Exclusives. Annals Story Slam - Escape From Iraq: A Refugee Family's Story of Resilience and Hope. PMID- 29610923 TI - Psoriasis. AB - Psoriasis, an inherited disorder of the immune system, presents most commonly in the skin and joints but is also associated with cardiovascular, metabolic, and neuropsychiatric effects. Treatments include topical therapy for mild disease; phototherapy and oral therapy, such as retinoids and immunomodulating agents; and targeted biologic therapies that have revolutionized treatment of psoriasis and psoriatic arthritis. Primary care physicians should be aware of the systemic associations of psoriasis and the treatments available for this disorder. PMID- 29610924 TI - Annals for Educators - 3 April 2018. PMID- 29610928 TI - Brain drains: new insights into brain clearance pathways from lymphatic biology. AB - The lymphatic vasculature act as the drainage system for most of our tissues and organs, clearing interstitial fluid and waste and returning them to the blood circulation. This is not the case for the central nervous system (CNS), which is devoid of parenchymal lymphatic vessels. Nevertheless, the brain is responsible for 25% of the body's metabolism and only compromises 2% of the body's mass. This high metabolic load requires an efficient system to remove waste products and maintain homeostasis. Well-described mechanisms of waste clearance include phagocytic immune cell functions as well as perivascular fluid flow; however, the need for active drainage of waste from the brain is becoming increasingly appreciated. Recent developments in lymphatic vascular biology challenge the proposition that the brain lacks lymphatic drainage or an equivalent. In this review, we describe the roles of the glymphatic system (a key drainage mechanism in the absence of lymphatics), the recently characterized meningeal lymphatic vessels, and explore an enigmatic cell population found in zebrafish called mural lymphatic endothelial cells. These systems may play important individual and collective roles in draining and clearing wastes from the brain. PMID- 29610927 TI - Distress and burnout in young medical researchers before and during the Greek austerity measures: forerunner of a greater crisis? AB - PURPOSE: Distress and burnout are strongly correlated with austerity and financial recessions. Aim of this study was to assess distress and burnout among young medical researchers (YMR) in Greece before and during the financial crisis. METHODS: In total 2050 YMR affiliated in all the nursing and medical departments of Greece were enrolled (1025 in Period A: 2008 and 1025 in Period B: 2017). Distress and burnout were measured via DASS-21 and Maslach Burnout Inventory (MBI) questionnaires. RESULTS: Before the crisis, prevalence of distress and burnout among young medical researchers was 24 and 20%, respectively. During the financial crisis distress prevalence increased significantly (56%), while there has also been a tremendous increase in burnout occurrence (60%). Specific sociodemographic characteristics presented significantly increased rate of change (females, singles and divorced/widowers, living with family members, volunteers, smokers and heavy alcohol consumers). Distress and burnout scales were positively correlated (Spearman's r = 0.81; p = 0.01). Depression scores shifted from normal to moderate (rate of change = 13.1%), anxiety levels increased from normal to severe (rate of change = 14.3%) and tension/stress scores elevated from normal to severe (rate of change = 20.2%). CONCLUSIONS: It is evident that the current financial crisis and working conditions have a strong impact on health status of young medical researchers in Greece. The observed increased trends and the identified predictors could guide targeted and comprehensive interventions towards tackling distress among the medical researchers not only in Greece but also in other countries suffering from financial crisis. PMID- 29610929 TI - COMP-angiopoietin-1 ameliorates inflammation-induced lymphangiogenesis in dextran sulfate sodium (DSS)-induced colitis model. AB - : Alterations in the intestinal lymphatic network are pathological processes as related to inflammatory bowel disease (IBD). In this study, we demonstrated that reduction in inflammation-induced lymphangiogenesis ameliorates experimental acute colitis. A soluble and stable angiopoietin-1 (Ang1) variant, COMP-Ang1, possesses anti-inflammatory and angiogenic effects. We investigated the effects of COMP-Ang1 on an experimental colonic inflammation model. Experimental colitis was induced in mice by administering 3% dextran sulfate sodium (DSS) via drinking water. We determined body weight, disease activity indices, histopathological scores, lymphatic density, anti-ER-HR3 staining, and the expression of members of the vascular endothelial growth factor (VEGF) family and various inflammatory cytokines in the mice. The density of lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1) and VEGFR-3-positive lymphatic vessels increased in mice with DSS-induced colitis. We observed that COMP-Ang1-treated mice showed less weight loss, fewer clinical signs of colitis, and longer colons than Ade-DSS-treated mice. COMP-Ang1 also significantly reduced the density of LYVE-1-positive lymphatic vessels and the disruption of colonic architecture that is normally associated with colitis and repressed the immunoregulatory response. Further, COMP-Ang1 treatment reduced both M1 and M2 macrophage infiltration into the inflamed colon, which involved inhibition of VEGF-C and D expression. Thus, COMP Ang1, which acts by reducing inflammation-induced lymphangiogenesis, may be used as a novel therapeutic for the treatment of IBD and other inflammatory diseases. KEY MESSAGES: COMP-Ang1 decreases inflammatory-induced lymphangiogenesis in experimental acute colitis. COMP-Ang1 improves the symptom of DSS-induced inflammatory response. COMP-Ang1 reduces the expression of pro-inflammatory cytokines in inflamed colon. COMP-Ang1 reduces the expression of VEGFs in inflamed colon. COMP-Ang1 prevents infiltration of macrophages in a DSS-induced colitis model. PMID- 29610931 TI - Optimal Surgery for Mid-Transverse Colon Cancer: Laparoscopic Extended Right Hemicolectomy Versus Laparoscopic Transverse Colectomy. AB - BACKGROUND: Although the feasibility and safety of laparoscopic surgery for transverse colon cancer have been shown by the recent studies, the optimal laparoscopic approach for mid-transverse colon cancer is controversial. METHODS: We retrospectively analyzed the data of patients with the mid-transverse colon cancer at our institutions between January 2007 and April 2017. Thirty-eight and 34 patients who received extended right hemicolectomy and transverse colectomy, respectively, were enrolled. RESULTS: There were no significant differences in operating time, blood loss, and hospital stay between the two groups. Postoperative complications developed in 10 of 34 patients (29.4%; wound infection: 2 cases, anastomotic leakage: 2 cases, bowel obstruction: 1 case, incisional hernia: 2 cases, others: 3 cases) for the transverse colectomy group and in 4 of 38 patients (10.5%; wound infection: 1 case, anastomotic leakage: 0 case, bowel obstruction: 2 cases, incisional hernia: 0 case, others: 1 case) for the extended right hemicolectomy group (P = 0.014). Although the median number of harvested #221 and #222 LNs was similar between the two groups (6 vs. 8, P = 0.710, and 3 vs. 2, P = 0.256, respectively), that of #223 was significantly larger in extended right hemicolectomy than in transverse colectomy (3 vs. 1, P = 0.038). The 5-year disease-free and overall survival rates were 92.4 and 90.3% for the extended right hemicolectomy group, and 95.7 and 79.6% for the transverse colectomy group (P = 0.593 and P = 0.638, respectively). CONCLUSIONS: Laparoscopic extended right hemicolectomy and laparoscopic transverse colectomy offer similar oncological outcomes for mid-transverse colon cancer. Laparoscopic extended right hemicolectomy might be associated with fewer postoperative complications. PMID- 29610930 TI - Analysis of Early and Long-Term Oncologic Outcomes After Converted Laparoscopic Resection Compared to Primary Open Surgery for Rectal Cancer. AB - BACKGROUND: Laparoscopic rectal resection (LRR) for cancer is a challenging procedure, with conversion to open surgery being reported in up to 30% of cases. Since only a few studies with short follow-up have compared converted LRR and open RR (ORR), it is unclear if conversion to open surgery should be prevented by preferring an open approach in those patients with preoperatively known risk factors for conversion. The aim of this study was to compare early postoperative outcomes and long-term survival after completed LRR, converted LRR or ORR for non metastatic rectal cancer. METHODS: A prospective database of consecutive curative LRRs and ORRs for rectal cancer was reviewed. Patients undergoing LRR who required conversion (CONV group) were compared with those who had primary open rectal surgery (OPEN group) and completed LRR (LAP group). A multivariate analysis was performed to identify predictors of poor survival. RESULTS: A total of 537 patients were included in the study: 272 in the LAP group, 49 in the CONV group and 216 in the OPEN group. There were no significant differences in perioperative morbidity, mortality and length of hospital stay between the three groups. Five-year overall survival and disease-free survival rates did not significantly differ between LAP, CONV and OPEN patients: 83.9 versus 77.8 versus 81% (P = 0.398) and 74.5 versus 62.9 versus 72.7% (P = 0.145), respectively. Similar 5-year OS and DFS rates were observed between patients who had converted LRR for locally advanced tumor or for non-tumor-related reasons: 81.2 versus 80.8% (P = 0.839) and 62.5 versus 63.7% (P = 0.970), respectively. Poor grade of tumor differentiation, lymphovascular invasion and a lymph node ratio of 0.25 or greater, but not conversion, were independently associated with poorer survival. CONCLUSION: Conversion to open surgery does not impair short-term outcomes and does not jeopardize 5-year survival in patients with rectal cancer when compared to primary open surgery. PMID- 29610932 TI - EML4-ALK rearrangement in squamous cell carcinoma shows significant response to anti-ALK inhibitor drugs crizotinib and alectinib. AB - EML4-ALK alterations are more common in adenocarcinomas and are rarely found in squamous cell histology. In documented cases, the majority of EML4-ALK translocations are identified in squamous cell histology and occur in patients with no or light smoking history. We report an EML4-ALK4 translocation in a 50 year-old patient with squamous cell carcinoma and an 18 pack-year smoking history. The patient had a near complete response in the CNS to alectinib treatment. Our observation suggests that EML4-ALK genomic testing may be clinically useful in patients with heavy smoking history. PMID- 29610933 TI - Treadmill locomotion of the mouse lemur (Microcebus murinus); kinematic parameters during symmetrical and asymmetrical gaits. AB - The gaits of the adult grey mouse lemur Microcebus murinus were studied during treadmill locomotion over a large range of velocities. The locomotion sequences were analysed to determine the gait and the various spatiotemporal gait parameters of the limbs. We found that velocity adjustments are accounted for differently by stride frequency and stride length depending on whether the animal showed a symmetrical or an asymmetrical gait. When using symmetrical gaits the increase in velocity is associated with a constant contribution of the stride length and stride frequency; the increase of the stride frequency being always lower. When using asymmetrical gaits, the increase in velocity is mainly assured by an increase in the stride length which tends to decrease with increasing velocity. A reduction in both stance time and swing time contributed to the increase in stride frequency for both gaits, though with a major contribution from the decrease in stance time. The pattern of locomotion obtained in a normal young adult mouse lemurs can be used as a template for studying locomotor control deficits during aging or in different environments such as arboreal ones which likely modify the kinematics of locomotion. PMID- 29610934 TI - IL-33 attenuates mortality by promoting IFN-gamma production in sepsis. AB - OBJECTIVE AND DESIGN: Sepsis remains a major clinical problem with high morbidity and mortality. Interleukin (IL)-33 is a recently described member of the IL-1 family that is widely expressed and functions as a new inflammatory mediator. IL 33 has been reported to protect sepsis, but the underlying mechanisms are not well-elucidated. MATERIALS AND METHODS: We measured the interferon gamma (IFN gamma) production in septic mice after IL-33 treatment. RESULTS: IL-33 treatment enhanced the IFN-gamma level in blood and promoted mice's survival, so the protective effects of IL-33 depend on IFN-gamma. The IL-33 treatment also promoted both gammadelta T cells and NK cells in septic mice. CONCLUSION: Our data showed that IL-33 attenuates mortality by promoting IFN-gamma production in sepsis. PMID- 29610935 TI - Correction to: Feasibility and Validity of Printing 3D Heart Models from Rotational Angiography. AB - The original version of this article unfortunately contained a mistake. PMID- 29610936 TI - Impact of intravascular thrombosis on failure of radial arterial catheters in critically ill patients: a nested case-control study. AB - PURPOSE: The patency of arterial catheters is essential for reliable invasive blood pressure monitoring. We sought to determine whether radial catheter failures were associated with intravascular thrombosis in critically ill adult patients. METHODS: This unmatched case-control study was conducted within a prospective cohort of patients admitted to an intensive care unit. The arterial catheter failure was the main outcome, which identified cases. Controls were patients with patent catheter until removal or 28 days of follow-up. The prevalence of intravascular thrombosis in cases and controls was determined by ultrasonography of the cannulated radial artery. Assessors were blinded to clinical findings. Failing catheters were removed and examined microscopically. RESULTS: Catheter failures occurred in 25.5% of 200 patients during 584 catheter days (incidence rate, 87/1000 catheter-days). The median patency duration was 13.1 days. An intravascular thrombosis located in front of the catheter tip was diagnosed in 42 of 50 cases (84.0%) and 24 of 139 controls (17.3%). In multivariable logistic regression analysis, the probability of catheter failure was higher in patients with intravascular thrombosis [odds ratio (OR), 36.52; 95% confidence interval (CI), 12.86-103.74] and females (OR, 3.45; 95% CI 1.32-9.05), increased proportionally to arterial blood sampling frequency (OR, 1.20; 95% CI 1.04-1.38), and decreased in thrombocytopenia (OR, 0.28; 95% CI 0.10-0.78). After removal, 15.7% of failing catheters had some luminal fibrin deposits, but none were occluded. CONCLUSIONS: Most failing radial arterial catheters had no luminal obstruction, but were associated with an intravascular thrombosis. Among predictive factors, arterial blood sampling frequency is the most susceptible to intervention. PMID- 29610937 TI - Paediatric musculoskeletal disease in Kumi District, Uganda: a cross-sectional survey. AB - PURPOSE: The purpose of this study is to estimate the burden of musculoskeletal disease among children treated in Kumi District, Uganda, to inform training, capacity-building efforts, and resource allocation. METHODS: We conducted a retrospective cohort study by reviewing the musculoskeletal (MSK) clinic and community outreach logs for children (age < 18 years) seen at Kumi Hospital in Kumi, Uganda, between January 2013 and December 2015. For each patient, we recorded the age, sex, diagnosis, and treatment recommendation. RESULTS: Of the 4852 children, the most common diagnoses were gluteal and quadriceps contractures (29.4% (95% CI 28.1-30.7%), 96% of which were gluteal fibrosis), post-injection paralysis (12.7% (95% CI 11.8-13.6%)), infection (10.5% (95% CI 9.7-11.4%)), trauma (6.9% (95% CI 6.2-7.6%)), cerebral palsy (6.9% (95% CI 6.2-7.7%)), and clubfoot (4.3% (95% CI 3.8-4.9%)). Gluteal fibrosis, musculoskeletal infections, and angular knee deformities create a large surgical burden with 88.1%, 59.1%, and 54.1% of patients seen with these diagnoses referred for surgery, respectively. Post-injection paralysis, clubfoot, and cerebral palsy were treated non-operatively in over 75% of cases. CONCLUSION: While population-based estimates of disease burden and resource utilization are needed, this data offers insight into burden of musculoskeletal disease for this region of Sub-Saharan Africa. We estimate that 50% of the surgical conditions could be prevented with policy changes and education regarding injection practices and early care for traumatic injuries, clubfeet, and infection. This study highlights a need to increase capacity to care for specific musculoskeletal conditions, including gluteal fibrosis, post-injection paralysis, infection, and trauma in the paediatric population of Uganda. PMID- 29610938 TI - The diversity of sulfate-reducing bacteria in the seven bioreactors. AB - Anaerobic technology has a wide scope of application in different areas such as manufacturing, food industry, and agriculture. Nowadays, it is mainly used to produce electrical and thermal energy from crop processing, solid waste treatment or wastewater treatment. More intensively, trend nowadays is usage of this technology biodegradable and biomass waste processing and biomethane or hydrogen production. In this paper, the diversities of sulfate-reducing bacteria (SRB) under different imputed raw material to the bioreactors were characterized. These diversities at the beginning of sampling and after cultivation were compared. Desulfovibrio, Desulfobulbus, and Desulfomicrobium genus as dominant among sulfate reducers in the bioreactors were detected. The Desulfobulbus species were dominant among other SRB genera before cultivation, but these bacteria were detected only in three out of the seven bioreactors after cultivation dominant. PMID- 29610939 TI - Antibacterial potential of secondary metabolites produced by Aspergillus sp., an endophyte of Mitrephora wangii. AB - Mitrephora wangii, an ethnomedicinal plant, has been used as a natural antibiotic and immunity booster in Thailand. A total of 22 fungi were isolated from M. wangii flowers. The fungal isolates were categorized into six genera including Agrocybe, Aspergillus, Colletotrichum, Nigrospora, Puccinia and Ustilago. Most extracts exhibited antibacterial activity against at least one of the test bacteria. Aspergillus sp. MFLUCC16-0845 was identified as the most bioactive fungus. Chemical composition of Aspergillus sp. MFLUCC16-0845 investigated using gas chromatography-mass spectrometry indicated that the major antibacterial compound was beta-thujaplicin. Moreover, the newly isolated Aspergillus sp. MFLUCC16-0845 could be exploited as a potential source of bioactive compounds and plant defense activators. In addition, it is the first time that strain of Aspergillus sp. isolated and cultured from M. wangii flowers could produce beta thujaplicin at high yield with strong antimicrobial spectrum, which may lead to wide utilization in producing cosmetics and clinical products. PMID- 29610940 TI - FPMRSChallenges on behalf of the Collaborative Research in Pelvic Surgery Consortium (CoRPS): managing complicated cases : Series 1: Adverse events after a sacrocolpopexy: management and recommendations on treatment of a vesicovaginal fistula. PMID- 29610941 TI - Pilot in vitro and in vivo study on a mouse model to evaluate the safety of transcutaneous low-frequency electrical nerve stimulation on cervical cancer patients. AB - INTRODUCTION AND HYPOTHESIS: To clarify whether the pulse electrical field (PEF) caused by transcutaneous low-frequency nerve electrical stimulation (TENS) enhances the proliferation of cervical cancer cells, leading to recurrence and metastasis, and the effect of such a PEF on a cervical cancer mouse model. METHODS: 1. In vitro experiment: SiHa cervical cancer cells treated with one session of microsecond PEFs for 30 min were divided into four groups: three experimental groups and the control group. Cell proliferation and migration were determined by CCK-8 proliferation and Transwell chamber Matrigel migration assay. 2. In vivo experiment: A mouse cancer model was established by subcutaneous implantation of SiHa cells that were then were randomly divided into the TENS group and control group. The former group received one session of TENS treatment and the control group received a sham pulse. The growth trend and tumor volume of each group were compared 28 days after PEF treatment. The proliferation and apoptosis of the tumor were determined by an immunohistochemical method. RESULTS: (1) The CCK-8 proliferation assay and cell migration ability showed no difference after PEF stimulation treatment (F = 2.478, P = 0.136 > 0.05 and F = 0.364, P = 0.779). (2) Tumor growth, size and weight showed no significant difference between the two groups. (3) Expression of VEGF, CD34, caspase-3 and Ki-67 in the tumor tissue showed no significant difference between the two groups. CONCLUSIONS: In vitro and in vivo experiments (mice) showed that the PEF created by TENS had no effect on the proliferation and migration of SiHa cervical cancer cells and also had no effect on the tumor growth, tumor cell apoptosis and proliferation. PMID- 29610942 TI - Cross-Reactivity of Prokaryotic 16S rDNA-Specific Primers to Eukaryotic DNA: Mistaken Microbial Community Profiling in Environmental Samples. AB - 16S ribosomal RNA gene sequences are characteristically used as gold-standard genetic marker for the determination of bacterial and/or archaeal biodiversity, and community profiling of environmental samples. The 16S rRNA amplicon analysis till-date is taken as a standard method for investigation and identification of uncultivable bacteria in microbial diversity studies. The accuracy of these analyses strongly depends upon the choice of primers. It is presumed that these primers do not participate in non-specific amplifications. In the present study, by in silico, PCR and denaturing gradient gel electrophoresis (DGGE) analysis, we have shown that primers do cross-react with eukaryotic DNAs as well, eventually leading to overestimation of microbial biodiversity. We further demonstrated that the overestimation is not only due to cross-reaction with eukaryotic mitochondrial or plastid DNA, but also with eukaryotic chromosomal DNA, that is ubiquitous in environmental samples. We tried to establish methanogenic diversity in municipal solid waste (MSW) leachates and cow dung samples before and after enrichment of the prokaryotic DNA from eukaryotic ones. Results revealed that bands disappeared/get lightened in bacterial 16S rRNA-based DGGE community profiles, after prokaryotic DNA enrichment, but not in mcrA-based community profiles. PMID- 29610943 TI - Restless legs syndrome is a relevant comorbidity in patients with inflammatory bowel disease. AB - BACKGROUND AND AIMS: In patients with inflammatory bowel disease (IBD), restless legs syndrome (RLS) may occur as an extraintestinal disease manifestation. Iron deficiency (ID) or folate deficiency/vitamin B12 deficiency (FD/VB12D) has previously been described to cause RLS. Here, we determined the prevalence and severity of RLS in IBD patients and evaluated the effect of iron and/or folic acid/vitamin B12 supplementation. METHODS: Patients were screened for ID and RLS by a gastroenterologist. If RLS was suspected, a neurologist was consulted for definitive diagnosis and severity. Patients with RLS and ID, FD, or VB12D received supplementation and were followed-up at weeks 4 and 11 after starting supplementation. RESULTS: A total of 353 IBD patients were included. Prevalence for RLS was 9.4% in Crohn's disease (CD) and 8% in ulcerative colitis (UC). Prevalence for the subgroup of clinically relevant RLS (symptoms >= twice/week with at least moderate distress) was 7.1% (n = 16) for CD and 4.8% (n = 6) for UC. 38.7% of RLS patients presented with ID, FD, and/or VB12D. Most frequently ID was seen (25.8%; n = 8). Iron supplementation resulted in RLS improvement (p = 0.029) at week 4 in seven out of eight patients. CONCLUSION: Although the overall prevalence of RLS in IBD did not differ to the general population, clinically relevant RLS was more frequent in IBD patients and, therefore, it is important for clinicians to be aware of RLS symptoms. Though for definite diagnosis and proper treatment of RLS, a neurologist must be consulted. Additionally, iron supplementation of IBD patients with ID can improve RLS symptoms. TRIAL REGISTRATION: ClinicalTrials.gov No. NCT03457571. PMID- 29610944 TI - Imaging the dynamics of transcription loops in living chromosomes. AB - When in the lampbrush configuration, chromosomes display thousands of visible DNA loops that are transcribed at exceptionally high rates by RNA polymerase II (pol II). These transcription loops provide unique opportunities to investigate not only the detailed architecture of pol II transcription sites but also the structural dynamics of chromosome looping, which is receiving fresh attention as the organizational principle underpinning the higher-order structure of all chromosome states. The approach described here allows for extended imaging of individual transcription loops and transcription units under conditions in which loop RNA synthesis continues. In intact nuclei from lampbrush-stage Xenopus oocytes isolated under mineral oil, highly specific targeting of fluorescent fusions of the RNA-binding protein CELF1 to nascent transcripts allowed functional transcription loops to be observed and their longevity assessed over time. Some individual loops remained extended and essentially static structures over time courses of up to an hour. However, others were less stable and shrank markedly over periods of 30-60 min in a manner that suggested that loop extension requires continued dense coverage with nascent transcripts. In stable loops and loop-derived structures, the molecular dynamics of the visible nascent RNP component were addressed using photokinetic approaches. The results suggested that CELF1 exchanges freely between the accumulated nascent RNP and the surrounding nucleoplasm, and that it exits RNP with similar kinetics to its entrance. Overall, it appears that on transcription loops, nascent transcripts contribute to a dynamic self-organizing structure that exemplifies a phase separated nuclear compartment. PMID- 29610945 TI - Effect of maternal obesity on labor induction in postdate pregnancy. AB - OBJECTIVE: To test the hypothesis that there is a higher rate of unsuccessful induction of labor (IOL) in post-term obese pregnant women compared to non-obese ones. METHODS: In this prospective cohort study, 144 obese (BMI > 30) and 144 non obese (BMI < 29.9) post-term (> 41 weeks) pregnant women were recruited. IOL was done by misoprostol or amniotomy and oxytocin infusion according to the Bishop score. Comparison of percentage of failed IOL in both groups (primary outcome) was performed by the Chi-test. Logistic regression and multivariable regression were performed to assess the odds ratio (OR) of cesarean section (CS) and coefficient of delay in labor till vaginal delivery (VD) in obese versus (vs) non obese groups. Adjustment for gestational age, parity, Bishop Score, membrane rupture and amniotic fluid index was done in both regression analyses. RESULTS: CS rate was significantly higher in obese group [26.4 vs 15.9%; difference in proportion (95% CI) 0.1 (0.01, 0.19); P value 0.02]. 106 (73.6%) obese women and 121 (84.1%) non-obese women delivered vaginally. In addition, the duration till VD was significantly higher in obese group (22 vs 19 h, P value 0.01). After adjustment for possible confounding factors, the CS was still higher in the obese group in comparison to non-obese group (OR 2.02; 95% CI 1.1, 3.7; P value 0.02). This finding suggested that obesity was an independent factor for failure of IOL. In addition, after adjustment for these confounders, obesity had the risk of increasing labor duration by 2.3 h (95% CI 0.1, 4.5) in cases that ended in VD. CONCLUSION: Based on our results, we conclude that there is a higher risk of CS in obese postdate pregnant women undergoing IOL in comparison to non-obese counterparts. Therefore, obstetricians should pay more attention to advising pregnant women about optimal weight gain during pregnancy and counseling about the chances of VD in cases of IOL. CLINCALTRIAL. GOV ID: NCT02788305. PMID- 29610946 TI - Increased ZNF84 expression in cervical cancer. AB - PURPOSE: Little is known about ZNF84 gene. This study aims to investigate ZNF84 expression in cervical cancer (CC) and the effects of ZNF84 on CC. MATERIALS AND METHODS: Cervical cancer tissue specimens were collected from The First People's Hospital of Foshan. ZNF84 and Akt expression were detected by immunohistochemistry. The influence of ZNF84 on cell proliferation was detected by CCK-8 kits. The effects of ZNF84 on Akt protein and mRNA expression were detected by western blotting and qPCR, respectively. RESULTS: High expression of ZNF84 protein (80.0%) was detected within CC tissues while negative expression was found in normal cervical tissues. ZNF84 was specifically associated with tumor size (p = 0.018) and negatively associated with other indicators. Further, in squamous cell carcinoma, ZNF84 was associated with both TNM staging (p = 0.041) and tumor size (p = 0.041). In vitro, we used shZNF84 to inhibit the mRNA and protein expression of ZNF84, and showed marked inhibition of cancer cell proliferation by shZNF84. Furthermore, inhibition of ZNF84 down-regulated Akt. Ly294002 (an Akt inhibitor) decreased the cell inhibition ability of shZNF84, indicating the involvement of Akt. Finally, the relationship between ZNF84 and Akt in vivo showed positive correlation (p = 0.023). CONCLUSION: ZNF84 expression was increased in CC tissues and associated with tumor size. ZNF84 promoted cell proliferation which might involve Akt signal. PMID- 29610947 TI - Effect of 5-trans Isomer of Arachidonic Acid on Model Liposomal Membranes Studied by a Combined Simulation and Experimental Approach. AB - Unsaturated fatty acids are found in humans predominantly in the cis configuration. Fatty acids in the trans configuration are primarily the result of human processing (trans fats), but can also be formed endogenously by radical stress. The cis-trans isomerization of fatty acids by free radicals could be connected to several pathologies. Trans fats have been linked to an increased risk of coronary artery disease; however, the reasons for the resulting pathogenesis remain unclear. Here, we investigate the effect of a mono-trans isomer of arachidonic acid (C20:4-5trans, 8cis, 11cis, 14cis) produced by free radicals in physiological concentration on a model erythrocyte membrane using a combined experimental and theoretical approach. Molecular Dynamics (MD) simulations of two model lipid bilayers containing arachidonic acid and its 5 trans isomer in 3 mol% were carried out for this purpose. The 5-trans isomer formation in the phospholipids was catalyzed by HOCH2CH2S. radicals, generated from the corresponding thiol by gamma-irradiation, in multilamellar vesicles of SAPC. Large unilamellar vesicles were made by the extrusion method (LUVET) as a biomimetic model for cis-trans isomerization. Atomic Force Microscopy and Dynamic Light Scattering were used to measure the average size, morphology, and the z potential of the liposomes. Both results from MD simulations and experiments are in agreement and indicate that the two model membranes display different physicochemical properties in that the bilayers containing the trans fatty acids were more ordered and more rigid than those containing solely the cis arachidonic acid. Correspondingly, the average size of the liposomes containing trans isomers was smaller than the ones without. PMID- 29610948 TI - Adaptive threshold hunting for the effects of transcranial direct current stimulation on primary motor cortex inhibition. AB - Primary motor cortex excitability can be modulated by anodal and cathodal transcranial direct current stimulation (tDCS). These neuromodulatory effects may, in part, be dependent on modulation within gamma-aminobutyric acid (GABA) mediated inhibitory networks. GABAergic function can be quantified non-invasively using adaptive threshold hunting paired-pulse transcranial magnetic stimulation (TMS). The previous studies have used TMS with posterior-anterior (PA) induced current to assess tDCS effects on inhibition. However, TMS with anterior posterior (AP) induced current in the brain provides a more robust measure of GABA-mediated inhibition. The aim of the present study was to assess the modulation of corticomotor excitability and inhibition after anodal and cathodal tDCS using TMS with PA- and AP-induced current. In 16 young adults (26 +/- 1 years), we investigated the response to anodal, cathodal, and sham tDCS in a repeated-measures double-blinded crossover design. Adaptive threshold hunting paired-pulse TMS with PA- and AP-induced current was used to examine separate interneuronal populations within M1 and their influence on corticomotor excitability and short- and long-interval inhibition (SICI and LICI) for up to 60 min after tDCS. Unexpectedly, cathodal tDCS increased corticomotor excitability assessed with AP (P = 0.047) but not PA stimulation (P = 0.74). SICIAP was reduced after anodal tDCS compared with sham (P = 0.040). Pearson's correlations indicated that SICIAP and LICIAP modulation was associated with corticomotor excitability after anodal (P = 0.027) and cathodal tDCS (P = 0.042). The after effects of tDCS on corticomotor excitability may depend on the direction of the TMS-induced current used to make assessments, and on modulation within GABA mediated inhibitory circuits. PMID- 29610949 TI - Task-relevant cognitive and motor functions are prioritized during prolonged speed-accuracy motor task performance. AB - This study aimed to explore the effect of prolonged speed-accuracy motor task on the indicators of psychological, cognitive, psychomotor and motor function. Ten young men aged 21.1 +/- 1.0 years performed a fast- and accurate-reaching movement task and a control task. Both tasks were performed for 2 h. Despite decreased motivation, and increased perception of effort as well as subjective feeling of fatigue, speed-accuracy motor task performance improved during the whole period of task execution. After the motor task, the increased working memory function and prefrontal cortex oxygenation at rest and during conflict detection, and the decreased efficiency of incorrect response inhibition and visuomotor tracking were observed. The speed-accuracy motor task increased the amplitude of motor-evoked potentials, while grip strength was not affected. These findings demonstrate that to sustain the performance of 2-h speed-accuracy task under conditions of self-reported fatigue, task-relevant functions are maintained or even improved, whereas less critical functions are impaired. PMID- 29610951 TI - Correction to: Randomized Controlled Study Comparing Disposable Negative-Pressure Wound Therapy with Standard Care in Bilateral Breast Reduction Mammoplasty Evaluating Surgical Site Complications and Scar Quality. AB - The second to last sentence in the Results section of the Abstract should be corrected to, "At 180-days follow-up, there was a significant improvement in total VAS scores." PMID- 29610950 TI - Neural encoding of choice during a delayed response task in primate striatum and orbitofrontal cortex. AB - Reward outcomes are available in many diverse situations and all involve choice. If there are multiple outcomes each rewarding, then decisions regarding relative value lead to choosing one over another. Important factors related to choice context should be encoded and utilized for this form of adaptive choosing. These factors can include the number of alternatives, the pacing of choice behavior and the possibility to reverse one's choice. An essential step in understanding if the context of choice is encoded is to directly compare choice with a context in which choice is absent. Neural activity in orbitofrontal cortex and striatum encodes potential value parameters related to reward quality and quantity as well as relative preference. We examined how neural activations in these brain regions are sensitive to choice situations and potentially involved in a prediction for the upcoming outcome selection. Neural activity was recorded and compared between a two-choice spatial delayed response task and an imperative 'one-option' task. Neural activity was obtained that extended from the instruction cue to the movement similar to previous work utilizing the identical imperative task. Orbitofrontal and striatal neural responses depended upon the decision about the choice of which reward to collect. Moreover, signals to predictive instruction cues that precede choice were selective for the choice situation. These neural responses could reflect chosen value with greater information on relative value of individual options as well as encode choice context itself embedded in the task as a part of the post-decision variable. PMID- 29610952 TI - Epicanthal Restoration Surgery with Scar Excision in Severe Epicanthal Scar. AB - BACKGROUND: Medial epicanthoplasty is a common aesthetic surgery in Asia to remove the epicanthal fold. With increasing use of this surgery, unsatisfactory results have grown. Several methods have been developed to correct it. However, there are limitations in restoration if the patient has a severe scar or does not have enough skin for reconstruction. By aggressively removing scar tissue, the authors present a better reverse redraping epicanthoplasty. METHODS: The procedure was performed on 512 patients who had complications of medial epicanthoplasty from May 2011 to October 2015. The mean age was 31.3 years. Those who had already undergone reconstruction were 15.4% (n = 79). Of these, 68 patients received a V-Y flap and the rest had V-Y modification surgery. After the design, the skin-muscle flap was dissected and elevated. The upper and lower eyelid skin was pulled medially. The previous scar tissue was widely excised while removing skin excess, and the new epicanthal fold was created without a rectangular shape. RESULTS: The mean interepicanthal distance has been increased from 32.8 to 36.6 mm. The mean lengthening effect is 3.8 mm. Lacrimal lake exposure, fierce and narrow appearance, and incomplete medial eyelid closure were improved. CONCLUSIONS: Medial epicanthoplasty is a common cosmetic surgery in the Asian population. A demand for an effective reconstructive method has grown in association with higher complication rates. The authors have better results to make a natural epicanthal fold through aggressive scar removal in the reverse redraping epicanthoplasty. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29610953 TI - Judicial Precedent-Based Clinical Practice Guidelines of Propofol in Sedative Esthetic Surgery. AB - BACKGROUND: Propofol is has been widely used for sedation in the field of esthetic surgery because of its favorable pharmacokinetic profile. Propofol sedation-induced side effects are rare. However, when present, they can be serious. The number of malpractice claims associated with propofol sedation has increased in recent years. This study aims to show which procedures lead to the most claims in the field of esthetic surgery through a review of Korean precedents. METHODS: Thirteen precedent cases of propofol sedation in the field of esthetic surgery were collected between 2000 and 2016. We analyzed the type of procedure, administration route, anesthesia provider, complications, timing of damaging events, average indemnification, plaintiff's (patients) winning rate, ratio and the reason of limitation of liability and the key factors affecting the judgement in these cases. RESULTS: Most plaintiffs were women, and in most cases (11/13, 73.3%), the times of the damaging events were in maintenance and the anesthesia provider was the surgeon. The most common complication related to propofol sedation was hypoxic brain damage. Among the 13 cases, 12 were won by the plaintiff. The mean claim settlement was 339,455,814 KRW (USD 301,792.15). The key factors affecting the judgement were administration method and staff, monitoring method, preparation of emergency kit, response to emergencies, transfer to a higher-level hospital, detailed medical recording about event and informed consent. CONCLUSION: The number of claims owing to propofol sedation after esthetic surgery is increasing. Close monitoring during the operation, immediate reaction to an event and thorough medical records were main key factors that influenced the judgement. Preoperative explanation about the possibility of complications was important. The findings will help surgeons achieve high patient satisfaction and reduce liability concerns. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29610954 TI - Buttock Lifting Using Elastic Thread (Elasticum(r)) with a New Classification of Gluteal Ptosis. AB - PURPOSE: Conventional buttock lifting is invasive, so it is difficult to recommend it to patients especially to those who do not have severe gluteal ptosis. In addition, the gluteal area is a large area change among the joints. Therefore, this surgery can cause pain during hip flexion after lifting using a conventional thread. The authors report on buttock lifting using an elastic thread with high satisfaction from patients. METHODS: From July 2016 to June 2017, 60 patients were enrolled in this study. The degree of gluteal ptosis was graded from Grade 0 to Grade 6. All patients underwent lifting of both buttocks using Elasticum(r). We drew a circle along the outer edge of the buttock and another small circle inside the first circle. A stab incision was done at 5 points (A, B, C, C', and D), and then according to the circle, lifting was done. Postoperative grade changes and complications were evaluated. RESULT: Grades 2-5 were lifted to at least Grade 2 after surgery, but Grade 6 was at most Grade 3 (14.2%), with 85.8% of these to either Grade 5 or Grade 6. Seven patients (11.67%) complained of postoperative pain, and 6 patients (10.00%) showed skin dimpling or creases 10 days after surgery, all of which disappeared at 1 month after surgery. CONCLUSION: Buttock lifting with elastic thread is effective in pre-ptosis to moderate gluteal ptosis. Because of the elasticity of the thread, postoperative pain is low on hip flexion, so the lifting is done naturally. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29610956 TI - Prognostic role of serial quantitative evaluation of 18F-fluorodeoxyglucose uptake by PET/CT in patients with cardiac sarcoidosis presenting with ventricular tachycardia. AB - BACKGROUND: Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) has shown to be useful in diagnosis, staging and monitoring of cardiac sarcoidosis (CS) but its interpretation is not standardized. OBJECTIVES: We sought to investigate the clinical impact of serial quantitative FDG uptake analysis in patients with CS presenting with ventricular tachycardia (VT) treated by catheter ablation (CA). METHODS: We followed 20 patients (51 +/- 9 years, 70% males) with CS and VT who underwent CA, with 92 serial FDG-PET scans (3-10 per patient). Myocardial FDG-avid lesions were quantified using three parameters: maximum standardized uptake value (SUVmax), partial-volume corrected mean standardized uptake value (SUVmean) and partial-volume corrected volume-intensity product [lesion metabolic activity (LMA)]. The volume-intensity product of the entire heart [global cardiac metabolic activity (gCMA)] and the background cardiac metabolic activity (bCMA: difference between gCMA and LMA) were also calculated. The primary end-point was the occurrence of major adverse cardiac events (MACE), including death, heart transplant, hospitalization for heart failure and implantable cardioverter defibrillator (ICD) appropriate interventions. Evolution of echocardiographic parameters over follow-up was also assessed. RESULTS: During a median follow-up of 35 (20-66) months, 18 MACE (1 death, 2 heart transplants, 12 ICD appropriate interventions, 3 hospitalizations) occurred in 12 (60%) patients. At univariable analysis, lack of PET improvement (defined by decrease in LMA of at least 25%) was the only variable associated with cardiac events during follow-up. In particular, non-responders had a 20-fold higher risk of MACE at follow-up (HR 18.96, 95% CI 2.26-159.27; p = 0.007). Moreover, a significant linear inverse relationship was observed between changes in LMA and changes in left ventricular ejection fraction over follow-up (beta = 20.11; p = 0.003). CONCLUSIONS: In patients with CS and VT, temporal change in FDG uptake evaluated by a quantitative approach is associated with parallel change in systolic function. Moreover, reduction in FDG uptake is strongly associated with fewer MACE at long-term follow-up. PMID- 29610955 TI - Prognostic value of [18F]FDG-PET/CT in multiple myeloma patients before and after allogeneic hematopoietic cell transplantation. AB - PURPOSE: Despite improved treatment options, multiple myeloma (MM) remains an incurable disease. The aim of this study was to investigate the prognostic value of positron emission tomography/computed tomography (PET/CT) using 18F-2'-deoxy 2'-fluorodeoxyglucose ([18F]FDG) in MM patients shortly before and ~100 days after allogeneic hematopoietic cell transplantation (allo-HCT). METHODS: In this retrospective analysis, we evaluated [18F]FDG-PET/CT-scans of 45 heavily pre treated MM patients before and 27 patients after scheduled allo-HCT. All scans were qualitatively and semi-quantitatively assessed for the presence of active disease. Serological response was recorded according to International Myeloma Working Group (IMWG) criteria. Progression-free (PFS) and overall survival (OS) were correlated with different PET/CT-derived parameters, such as presence, number and maximum standardized uptake value (SUVmax) of focal myeloma lesions. The impact of extramedullary disease on patient outcome was also assessed. RESULTS: PET/CT negativity -prior to or following allo-HCT- was a favorable prognostic factor for progression-free and overall survival (both, PFS and OS: pre-HSCT p < 0.001, post-HCT p < 0.005). High FDG-uptake (SUVmax > 6.5) revealed a significantly shortened survival compared to patients with a lower SUVmax (<6.5) (OS, 5.0 +/- 1.1 m vs. not reached - longest 122.0 m; p < 0.001). Moreover, our data prove that a higher number (>3) of focal lesions (pre-HCT: both PFS and OS: p < 0.001; post-HCT PFS: p < 0.001, OS: p = 0.139) as well as the presence of extramedullary disease serve as adverse prognostic factors prior to and after allo-HCT. At response assessment after allo-HCT, [18F]FDG-PET/CT had a complementary value in prognostication in addition to IMWG criteria alone. CONCLUSION: [18F]FDG-PET/CT before and shortly after allogeneic HCT is a powerful predictor for progression-free and overall survival in MM patients. PMID- 29610957 TI - Organ preservation surgery for patients with T4a laryngeal cancer. AB - PURPOSE: Surgical preservation of laryngeal function is very challenging in patients with advanced SCCL, especially those of stage T4a. The purpose of this study was to assess the feasibility of organ preservation surgery for patients with T4a squamous cell carcinoma of the larynx (SCCL). METHODS: We enrolled 32 patients with T4a SCCL and performed organ preservation surgery on them. Surgical details and perioperative morbidity were described, functional and oncologic outcomes were also evaluated. RESULTS: All patients underwent supracricoid subtotal laryngectomy with unilateral or bilateral neck dissection, restoring laryngeal function via direct anastomosis of the cricoid cartilage and tongue base. The patients recovered well and exhibited relatively acceptable survival duration, with a 5-year overall survival rate of 62.5%. Most patients commenced oral intake within 2 weeks, and aspiration was commonly observed. Subjective functional outcomes indicated a relatively acceptable swallowing function and voice quality. CONCLUSION: Our retrospective analysis of 32 patients with T4a SCCL showed that successful organ preservation surgery is safe and reliable, and associated with a relatively acceptable disease-free survival, normal swallowing function, and acceptable voice quality. More patients with T4a SCCL who wish to preserve the larynx should be considered for organ preservation surgery. PMID- 29610958 TI - Potassium titanyl phosphate laser-induced inflammatory response and extracellular matrix turnover in rabbit vocal fold scar. AB - PURPOSE: The objectives of this study were to observe the regulating effect of KTP laser and Nd:YAG laser in the repair of vocal fold scars. METHODS: All rabbits were injured in the muscular layer with a sharp instrument, and then the vocal folds were treated with a KTP laser and a Nd:YAG laser at a power of 2, 4, 6 and 8 W 1 month after the injury. One month after treatment, the rabbits were killed and the throats were removed to detect changes in histology and gene expression of the vocal fold scar after laser therapy. RESULTS: The best efficacy of all KTP laser treatment groups was the KTP laser 6 W group. Regarding the detection of gene expression, in the KTP laser 6 W and Nd:YAG laser 6 W groups, col-3A1 was decreased compared to the scar group (P < 0.05), and col-1A1 was decreased only in the KTP laser 6 W group (P < 0.05). TGF-beta1 levels in the two groups were lower than in the scar group. There were also significant differences in the levels of IL-1beta, COX-2 and TNF-alpha in the two laser groups compared with the scar group (P < 0.05). CONCLUSION: KTP laser and Nd:YAG laser treatments for vocal fold scars have particular therapeutic effects. The KTP laser may be better than the Nd:YAG laser for the regulation of vocal fold scars. LEVEL OF EVIDENCE: NA. PMID- 29610959 TI - Poor oral intake causes enteral nutrition dependency after concomitant chemoradiotherapy for pharyngeal cancers. AB - PURPOSE: To identify precipitating factors responsible for enteral nutrition (EN) dependency after concomitant chemoradiotherapy (CCRT) of head and neck cancers and to examine their statistical correlations. METHODS: Factors related to feeding condition, nutritional status, disease, and treatment of 26 oropharyngeal and hypopharyngeal cancer patients who received definitive CCRT were retrospectively investigated by examining their medical records. The days of no oral intake (NOI) during hospitalization and the months using enteral nutrition after CCRT were counted as representing the feeding condition, and the changes in body weight (BW) were examined as reflecting nutritional status. The factors related to EN dependency after CCRT were analyzed. RESULTS: Long duration of total NOI (>= 30 days) and maximum NOI >= 14 days were significant predictors of EN dependency. Decreased BW (>= 7.5 kg) was the next predictor identified, but it was not significant. Multivariate analysis showed that the total duration of NOI was more correlated with EN dependency than changes in BW. CONCLUSIONS: A long duration of NOI was more strongly related to EN dependency than nutritional factors. PMID- 29610960 TI - Imaging evaluation of electrode placement and effect on electrode discrimination on different cochlear implant electrode arrays. AB - OBJECTIVE: The aim of the present study is to evaluate the effect of electrode discrimination based on electrode to modiolus distance in different cochlear implant models, using image information to estimate the outcomes after an implantation on electrode discrimination METHODS: A descriptive prospective randomized study performed during 16 months. A psychoacoustic platform was used to evaluate patients' electrode discrimination capabilities of patients. For the acquisition of the images, a cone beam computed tomography was used to assess postcochlear implantation of electrodes' position. We considered two other new measurements: the intracochlear position index, which indicates how far is the electrode from the modiolar wall, and the homogeneity factor (HF), which provides us with information about the distance between the electrodes and the modiolus RESULTS: 21 postlingually deaf adults showing different CI models [CI522 (n = 7), CI512 (n = 7), and CI532 (n = 7)] that corresponded to the lateral and perimodiolar array electrodes. The average success rate of the CI522 group was 47%, of the CI512 group was 48%, and of the CI532 group was 77%. There is statistically significant difference between groups CI532-CI522 (p = 0.0033) and CI532-CI512 (p = 0.0027) CONCLUSION: The Nucleus CI532 offers a better perimodiolar placement. HF and IPI measurements provide information about the electrodes location inside the cochlea, being related to electrode discrimination. PMID- 29610962 TI - Are clinical guidelines designed according to guidelines? Cross-sectional assessment of quality and transparency of clinical guidelines in urology. AB - PURPOSE: Guidelines and recommendations become increasingly important in clinical urologic practice. This study aims to inform clinicians using guidelines on how to evaluate the quality of the methodology and transparency of these documents. METHODS: The guidelines on management of castration-resistant prostate cancer of the American Urology Association, European Association of Urology, National Comprehensive Cancer Network, National Institute for Health and Care Excellence, European Society of Medical Oncology were reviewed using the AGREE-II tool (Appraisal of Guidelines for Research and Evaluation). We reported and compared the domain scores for the domains 1 scope and purpose, 2 stakeholder involvement, 3 rigor of development, 4 clarity of presentation, 5 applicability, and 6 editorial independence (100% indicates highest-best quality score). RESULTS: The domains evaluated highest and with lowest variability were 'editorial independence' (92% {88-95%}) and 'clarity of presentation' (83% {72-90%}), while the domains with the lowest scores and most variability were 'stakeholder involvement' (56% {36-79%}) and 'applicability' (40% {30-63%}). Length and extent of detail of guidelines vary considerably, each with its own strengths and limitations and adapted to target users. Standard external review using AGREE criteria may be preferable. A formal search strategy was not performed. Findings may be outdated by guidelines' updates. CONCLUSIONS: Clinicians using practice guidelines need to be aware of the different domains of methodology and transparency used to assess the quality of guidelines contents and recommendations. Urologists increasingly use guidelines for support in evidence based recommendations in clinical practice. It is very important to know how to assess these documents. This study applies standard criteria to compare the design and background of different available guidelines on prostate cancer no longer responding to hormonal treatment. PMID- 29610961 TI - Surgical perspectives regarding application of biomaterials for the management of large congenital diaphragmatic hernia defects. AB - This review focuses on the surgical viewpoints on patch repairs in neonates with large congenital diaphragmatic hernia defects. The main focus is on the various biomaterials that have been employed to date with regard to their source of origins, degradation properties as well as tissue integration characteristics. Further focus is on the present knowledge on patch integration when biomaterials are placed in the diaphragmatic defect. The review will also look at the present evidence on the biomechanical characteristics of the most commonly used biomaterials and compares these materials to diaphragmatic tissue to offer more insight on the present practice of patch repairs in large defects. Since tissue engineering and regenerative medicine has offered another dimension to diaphragmatic replacement, a detailed overview of this technology will be undertaken with regard to cell sourcing, scaffolds, in vitro versus in vivo implants as well as quality of tissue produced, to explore the limitations and the feasibility facing the scientific community in its clinical implementation of skeletal muscle-engineered tissue beyond laboratory research for diaphragmatic replacement. PMID- 29610963 TI - Diagnostic value of urinary survivin as a biomarker for bladder cancer: a systematic review and meta-analysis of published studies. AB - OBJECTIVE: This study is a meta-analysis and aims to determine the value of urinary survivin for detecting bladder cancer (BC) on the basis of preceding statistical performance and to compare their diagnostic value. MATERIALS AND METHODS: Considering that the urinary survivin data were from both RNA and protein levels, the key words "bladder cancer" AND "survivin" and "bladder cancer" AND "survivin RNA" were used; and PubMed, Web of Science, and Cochrane Library were systematically searched to identify relevant articles. The methodological quality of each study was assessed by QUADAS-2. Data were analyzed by STATA 12.0 and Meta-disc v.1.4 software package. A random-effects model was used and subgroup analysis was carried out to identify possible sources of heterogeneity. RESULTS: Nine articles for survivin protein test with 789 patients and 684 controls, and 12 articles for survivin RNA test with 880 patients and 922 controls were identified. The results showed that the pooled sensitivity was 0.79 (95% CI 0.73, 0.84), specificity was 0.87 (95% CI 0.79, 0.92) of the survivin protein test for bladder cancer, and the sensitivity and specificity was 0.84 (95% CI 0.79, 0.88) and 0.94 (95% CI 0.89, 0.97) of the survivin RNA test. The AUC of the two approaches was 0.89 (95% CI 0.86, 0.91) and 0.94 (95% CI 0.92, 0.96), respectively. CONCLUSIONS: The survivin protein and survivin RNA both had great potential as biomarkers for BC detection, and survivin RNA showed higher accuracy than survivin protein on BC diagnosis. PMID- 29610965 TI - Boxwood blight: an ongoing threat to ornamental and native boxwood. AB - Boxwood blight is an emerging disease of ornamental and native boxwood plants in the family Buxaceae. First documented in the 1990s at a single location in England, the disease is now reported throughout Europe, Asia, New Zealand, and North America. To address the growing concern over boxwood blight, ongoing research focuses on multiple biological and genetic aspects of the causal pathogens and susceptible host plants. Characterization of genetic variation among the Calonectria fungi that cause boxwood blight shows that two unique sister species with different geographic distributions incite the disease. Studies of the pathogen life cycle show the formation of long-lived survival structures and that host infection is dependent on inoculum density, temperature, and humidity. Host range investigations detail high levels of susceptibility among boxwood as well as the potential for asymptomatic boxwood infection and for other plants in the family Buxaceae to serve as additional hosts. Multiple DNA based diagnostic assays are available, ranging from probe-based quantitative PCR assays to the use of comparative genomics to develop robust diagnostic markers or provide whole genome-scale identifications. Though many questions remain, the research that continues to address boxwood blight demonstrates the importance of applying a multidisciplinary approach to understand and control emerging plant diseases. PMID- 29610964 TI - Epidemiology and screening for renal cancer. AB - PURPOSE: The widespread use of abdominal imaging has affected the epidemiology of renal cell carcinoma (RCC). Despite this, over 25% of individuals with RCC have evidence of metastases at presentation. Screening for RCC has the potential to downstage the disease. METHODS: We performed a literature review on the epidemiology of RCC and evidence base regarding screening. Furthermore, contemporary RCC epidemiology data was obtained for the United Kingdom and trends in age-standardised rates of incidence and mortality were analysed by annual percentage change statistics and joinpoint regression. RESULTS: The incidence of RCC in the UK increased by 3.1% annually from 1993 through 2014. Urinary dipstick is an inadequate screening tool due to low sensitivity and specificity. It is unlikely that CT would be recommended for population screening due to cost, radiation dose and increased potential for other incidental findings. Screening ultrasound has a sensitivity and specificity of 82-83% and 98-99%, respectively; however, accuracy is dependent on tumour size. No clinically validated urinary nor serum biomarkers have been identified. Major barriers to population screening include the relatively low prevalence of the disease, the potential for false positives and over-diagnosis of slow-growing RCCs. Individual patient risk stratification based on a combination of risk factors may improve screening efficiency and minimise harms by identifying a group at high risk of RCC. CONCLUSION: The incidence of RCC is increasing. The optimal screening modality and target population remain to be elucidated. An analysis of the benefits and harms of screening for patients and society is warranted. PMID- 29610966 TI - Identification and characterization of a chondroitin synthase from Avibacterium paragallinarum. AB - Avibacterium paragallinarum is a Gram-negative bacterium that causes infectious coryza in chicken. It was reported that the capsule polysaccharides extracted from Av. paragallinarum genotype A contained chondroitin. Chondroitin synthase of Av. paragallinarum (ApCS) encoded by one gene within the presumed capsule biosynthesis gene cluster exhibited considerable homology to identified bacterial chondroitin synthases. Herein, we report the identification and characterization of ApCS. This enzyme indeed displays chondroitin synthase activity involved in the biosynthesis of the capsule. ApCS is a bifunctional protein catalyzing the elongation of the chondroitin chain by alternatively transferring the glucuronic acid (GlcA) and N-acetyl-D-galactosamine (GalNAc) residues from their nucleotide forms to the non-reducing ends of the saccharide chains. GlcA with a para nitrophenyl group (pNP) could serve as the acceptor for ApCS; this enzyme shows a stringent donor tolerance when the acceptor is as small as this monosaccharide. Then, UDP-GalNAc and GlcA-pNP were injected sequentially through the chip immobilized chondroitin synthases, and the surface plasmon resonance data demonstrated that the up-regulated extent caused by the binding of the donor is one possibly essential factor in successful polymerization reaction. This conclusion will, therefore, enhance the understanding of the mode of action of glycosyltransferase. Surprisingly, high activity at near-zero temperature as well as weak temperature dependence of this novel bacterial chondroitin synthase indicate that ApCS was a cold-active enzyme. From all accounts, ApCS becomes the fourth known bacterial chondroitin synthase, and the potential applications in artificial chondroitin sulfate and glycosaminoglycan synthetic approaches make it an attractive glycosyltransferase for further investigation. PMID- 29610967 TI - Early analysis of operative management of Chiari I malformation in pediatric cystic fibrosis patients. AB - INTRODUCTION: Chiari I malformation, defined as herniation of the cerebellar tonsils at least 5 mm below the foramen magnum, can result from congenital or acquired pathology. While the mechanism is not well understood, an association between Chiari I and cystic fibrosis has been described in the literature. The lifelong respiratory status management necessitated by cystic fibrosis creates a greater risk of Chiari symptomatology as well as post-operative CSF-related complications in the setting of duraplasty secondary to recurrent transient increases in intracranial pressure. We will review the literature, describe our experience with these patients, and propose bony decompression as an approach to treatment. METHODS: A retrospective review of pediatric patients treated at our institution with both cystic fibrosis and Chiari I was performed. Since our first case in 2016, our department has evaluated four patients carrying that dual diagnosis. All four underwent posterior fossa decompression surgery. Two patients had incidental pathology. Two symptomatic patients exhibited headaches and/or coordination difficulty. Half of the patients had associated syringomyelia. All patients were offered posterior fossa decompression utilizing intraoperative ultrasound. RESULTS: All four patients underwent posterior fossa decompression without duraplasty. Average operative time was 128 min. There were no complications post-operatively. Average hospital stay was 3.8 days. Average surgical length of stay was 2.3 days. Morbidity and mortality were 0%. The longest follow-up to date is 20 months. The two asymptomatic patients remained so post-operatively. The child with headaches and imbalance had complete resolution of his symptoms after surgery, as did the toddler with headaches. Both patients with syringomyelia demonstrated significant decrease in the size of their syrinxes on imaging performed at least 3 months post-operatively. CONCLUSION: Based on the literature and our experience, we recommend considering posterior fossa decompression without duraplasty as treatment for pediatric cystic fibrosis patients with Chiari I malformation. This approach can be effective for symptomatic and prophylactic cases in this particular patient demographic because their comorbidities predispose them to Chiari pathology and symptomatology as well as certain post-operative complications. PMID- 29610968 TI - Impact of hematopoietic stem cell transplantation in patients with relapsed or refractory mantle cell lymphoma. AB - Rituximab has been shown to improve outcomes in patients with B-cell lymphoma. However, patients with relapsed or refractory (R/R) mantle cell lymphoma (MCL) still have a poor prognosis, and the choice between high-dose therapy with autologous hematopoietic cell transplantation (HCT) and allogeneic HCT remains controversial in these patients. We retrospectively analyzed the risk factors for outcomes in 162 R/R MCL patients who received autologous (n = 111) or allogeneic (n = 51) HCT between 2004 and 2014. The median overall survival (OS) rates were 48 and 65 months in the autologous and allogeneic HCT groups, respectively (P = 0.20). Significant risk factors for overall survival in R/R MCL patients after autologous HCT were > 60 years of age at HCT (P = 0.017), higher score of HCT specific comorbidity index at HCT (P = 0.033), and receiving MCEC (ranimustine + carboplatin + etoposide + cyclophosphamide) regimen (P = 0.017), while higher performance status at HCT (P = 0.011) and longer interval from diagnosis to HCT (P = 0.0054) were risk factors after allogeneic HCT. Strategies that carefully select R/R MCL patients for autologous HCT may allow the identification of individuals suitable for allogeneic HCT. PMID- 29610969 TI - Bendamustine and rituximab (BR) versus dexamethasone, rituximab, and cyclophosphamide (DRC) in patients with Waldenstrom macroglobulinemia. AB - The treatment approaches for Waldenstrom macroglobulinemia (WM) are largely based upon information from single-arm phase II trials, without comparative data. We compared the efficacy of two commonly used regimens in routine practice (bendamustine-rituximab (BR) and dexamethasone, rituximab plus cyclophosphamide (DRC)) and evaluated their activity with respect to the patients' MYD88L265P mutation status. Of 160 consecutive patients, 60 received BR (43 with relapsed/refractory WM) and 100 received DRC (50 had relapsed/refractory WM). In the treatment-naive setting, overall response rate (ORR) was 93% with BR versus 96% with DRC (p = 0.55). Two-year progression-free survival (PFS) with BR and DRC was 88 and 61%, respectively (p = 0.07). In salvage setting, ORR was 95% with BR versus 87% with DRC, p = 0.45; median PFS with BR was 58 versus 32 months with DRC (2-year PFS was 66 versus 53%; p = 0.08). Median disease-specific survival was not reached with BR versus 166 months with DRC (p = 0.51). The time-to-event endpoints and depth of response were independent of the MYD88 mutation status. Grade >= 3 adverse events of both regimens were comparable. A trend for longer PFS was observed with BR although the regimens have comparable toxicities. The activity of BR and DRC appears to be unaffected by patients' MYD88 mutation status. PMID- 29610970 TI - Male gender and age range 20-29 years are the most important non-modifiable risk factors for recurrence after primary post-traumatic shoulder dislocation. AB - PURPOSE: The aim of the study was to identify and analyze non-modifiable risk factors for recurrence after a first-time post-traumatic dislocation of the shoulder in the entire Polish population. METHODS: The entire Polish population was included in a cohort study. Patients diagnosed with primary post-traumatic dislocation of the shoulder between January 1st, 2010 and December 31st, 2011 were identified and followed up from January 1st, 2010 to December 31st, 2014. Incidence and recurrence rates and odds ratios (OR) were calculated. Demographic data were obtained from Poland's Central Statistical Office. Data on the number of patients with primary post-traumatic shoulder dislocation were drawn from the National Health Fund database. RESULTS: A total of 21,739 patients (14,466 males and 7273 females) with a primary shoulder dislocation in Poland were identified in 2010 and 2011. There were 3341 (15.4%) recurrences. Increased risk of recurrence was associated with male gender (OR = 1.92, 95% CI 1.76-2.09, p < 10 10) in the age range of 20-29 years (OR = 2.59, 95% CI 2.38-2.83, p < 10-10). The highest risk of first-time shoulder dislocation was revealed among females in the age group >= 80 years (OR = 24.1, 95% CI 22.6-25.7, p < 10-10). The risk of recurrence in the same group was significantly decreased (OR = 0.41, 95% CI 0.32 0.51, p < 10-10). CONCLUSION: Male gender and age range 20-29 years are highest population risk factors for recurrence after primary shoulder dislocation. Female gender and age >= 80 years are highest risk factors for the first-time post traumatic dislocation of the shoulder joint and protective factors for recurrences after the first-time shoulder dislocation. LEVEL OF EVIDENCE: III. PMID- 29610971 TI - No neurovascular damage after creation of an accessory anteromedial portal for arthroscopic reduction and fixation of coronoid fractures. AB - PURPOSE: Arthroscopic reduction and internal fixation for coronoid process fractures has been proposed to overcome limitations of open approaches. Currently, arthroscopy is most frequently used to assist insertion of a retrograde guide wire for a retrograde cannulated screw. The present anatomical study presents an innovative arthroscopic technique to introduce an antegrade guide wire from an accessory anteromedial portal and evaluates its safety and reproducibility. METHODS: Six fresh-frozen cadaver specimens were obtained and prepared to mimic an arthroscopic setting. The coronoid process was localized and a 0.9 mm Kirschner wire was introduced from an accessory anteromedial portal, located 2 cm proximal to the standard anteromedial portal. At the end of the procedure, a lateral radiograph was taken to verify the Kirschner wire position and open dissection was conducted to evaluate possible damage to neurovascular structures. RESULTS: The Kirschner wire was drilled without complications in the coronoid process of all six specimens. Damage of the brachial artery, the median nerve, and the ulnar nerve did not occur in any specimen. A corridor between the brachialis muscle, the median intermuscular septum, and the pronator teres could be identified as suitable for the wire passage. CONCLUSION: This study presents a safe and reproducible technique combining the possibility to introduce a guide wire from the anteromedial part of the coronoid, under direct visual control, with a completely arthroscopic approach. This wire can guide the introduction of a retrograde cannulated screw from the dorsolateral ulna to the tip of the coronoid. This new arthroscopic approach permits to obtain improved visual control over coronoid process fixation, without endangering neurovascular structures. PMID- 29610972 TI - Combined reconstruction of the anterolateral ligament in chronic ACL injuries leads to better clinical outcomes than isolated ACL reconstruction. AB - PURPOSE: To evaluate the results of combined anterior cruciate ligament (ACL) and anterolateral ligament (ALL) reconstruction in patients with chronic ACL injury. It was hypothesized that patients who underwent combined ACL and ALL reconstruction would exhibit less residual laxity and better clinical outcomes. METHODS: Two groups of patients were evaluated and compared retrospectively. Both groups consisted only of patients with chronic (more than 12 months) ACL injuries. Patients in group 1 underwent anatomical intra-articular reconstruction of the ACL and patients in group 2 underwent anatomic intra-articular ACL reconstruction combined with ALL reconstruction. The presence of associated meniscal injury, the subjective International Knee Documentation Committee (IKDC) and Lysholm functional outcome scores in the postoperative period, KT-1000 evaluation, the presence of residual pivot shift and graft rupture rate were evaluated. RESULTS: One hundred and one patients who underwent reconstruction of chronic ACL injuries were evaluated. The median follow-up was 26 (24-29) months for group 1 and 25 (24-28) months for group 2. There were no significant differences between groups regarding gender, age, duration of injury until reconstruction, follow-up time or presence of associated meniscal injuries in the preoperative period. Regarding functional outcome scores, patients in group 2 presented better results on both the IKDC (p = 0.0013) and the Lysholm (p < 0.0001) evaluations. In addition, patients in group 2 had better KT-1000 evaluation (p = 0.048) and a lower pivot shift rate at physical examination, presenting only 9.1% positivity versus 35.3% in the isolated ACL reconstruction (p = 0.011). Regarding re-ruptures, group 1 presented 5 (7.3%) cases, and group 2 presented no cases. CONCLUSION: The combined ACL and ALL reconstruction in patients with chronic ACL injury is an effective and safety solution and leads to good functional outcomes with no increase in complication rate. The clinical relevance of this finding is the possibility to indicate this type of procedure when patients present with more than 12 months after injury for surgery. LEVEL OF EVIDENCE: Level III. PMID- 29610973 TI - Subspinal impingement: clinical outcomes of arthroscopic decompression with one year minimum follow up. AB - PURPOSE: This study was designed to (1) evaluate the clinical outcomes after arthroscopic subspinal decompression in patients with hip impingement symptoms and low AIIS, and to (2) assess the presence of low anterior inferior iliac spine on the pre-operative radiographs of patients with established subspinal impingement diagnosed intra-operatively. METHODS: Retrospective analysis of patients who underwent arthroscopic subspinal decompression has been performed. The indications for surgery were femoroacetabular impingement (FAI), or subspinal impingement. Pre-operative radiographs were assessed for anterior inferior iliac spine type. Intra-operative diagnosis of low anterior inferior iliac spine was based on the level of anterior inferior iliac spine extension relative to the acetabulum and the presence of reciprocal labral and chondral lesions. In patients where low anterior inferior iliac spine was not diagnosed on pre operative radiographs, the pre-operative radiographs were re-read retrospectively to assess missed signs of low anterior inferior iliac spine. RESULTS: Thirty-four patients underwent arthroscopic subspinal decompression between 2012 and 2015. The patients were followed for a median of 25 months (13-37 months). Intra operatively, grade 2 anterior inferior iliac spine was found in 27 patients and grade 3 anterior inferior iliac spine was found in 7 patients. MHHS, HOS, and HOSS scores increased from median (range) pre-operative scores of 55 (11-90), 48 (20-91) and 20 (0-80) to 95 (27-100), 94 (30-100) and 91 (5-100), respectively (p < 0.0001, p = 0.001, p < 0.0001, respectively). Pre-operative diagnosis of low AIIS was made in 6/34 patients via AP radiographs. On retrospective analysis of pre-operative radiographs, signs of low AIIS were still not observed in 21/34 (61.8%) patients. CONCLUSIONS: Arthroscopic subspinal decompression of low AIIS yielded significantly improved outcome measures and high patient satisfaction at a minimum of 13 months follow-up. Low AIIS is often under-diagnosed on AP pelvis and lateral frog radiographs and if left untreated, may result in unresolved symptoms and failed procedure. LEVEL OF EVIDENCE: IV. PMID- 29610975 TI - Prognostic factors for long-term survival after adult liver transplantation. AB - PURPOSE: Prognostic factors for survival >= 15 years and life years lost after liver transplantation are largely unknown. METHODS: One thousand six hundred thirty primary adult liver transplants between 1983 and 2014 were analyzed. Risk factors for survival were identified with multivariable Cox regression and subsequently tested for their relevance as prognostic factors for observed 15 year survival using multivariable logistic regression and c statistics. The difference of life expectancy between a matched national reference population and survival in patients with post-transplant survival >= 15 years was calculated. RESULTS: Survival of >= 15 years was observed in 361 patients (22%). Sixty-nine adults died after more than 15 years losing a median of 15 years of life expectancy. One of those patients lived longer while 292 patients still have the chance to survive longer than their normal life expectancy. The indication primary sclerosing cholangitis (PSC) and later eras of transplantation were identified as significant independent protective factors while recipient age > 36.8 years, graft loss due to initial non-function or thrombosis, the indications hepatocellular carcinoma (HCC), hepatitis-C-virus-related cirrhosis (HCV cirrhosis) and all other indications, donor age > 53 years, the number of surgical complications, and operative durations > 4.5 h were identified as significant independent risk factors limiting survival. All of these factors except the duration of operation had also a significant independent influence on observed 15-year survival (AUROC = 0.739). CONCLUSIONS: Recipients can exceptionally live longer than their normal life expectancy. Older recipients and patients with the indications HCC, HCV-cirrhosis, or other indications except PSC, should be transplanted with younger donor organs. PMID- 29610976 TI - Truly sedentary? The multi-range tactic as a response to resource heterogeneity and unpredictability in a large herbivore. AB - Much research on large herbivore movement has focused on the annual scale to distinguish between resident and migratory tactics, commonly assuming that individuals are sedentary at the within-season scale. However, apparently sedentary animals may occupy a number of sub-seasonal functional home ranges (sfHR), particularly when the environment is spatially heterogeneous and/or temporally unpredictable. The roe deer (Capreolus capreolus) experiences sharply contrasting environmental conditions due to its widespread distribution, but appears markedly sedentary over much of its range. Using GPS monitoring from 15 populations across Europe, we evaluated the propensity of this large herbivore to be truly sedentary at the seasonal scale in relation to variation in environmental conditions. We studied movement using net square displacement to identify the possible use of sfHR. We expected that roe deer should be less sedentary within seasons in heterogeneous and unpredictable environments, while migratory individuals should be seasonally more sedentary than residents. Our analyses revealed that, across the 15 populations, all individuals adopted a multi-range tactic, occupying between two and nine sfHR during a given season. In addition, we showed that (i) the number of sfHR was only marginally influenced by variation in resource distribution, but decreased with increasing sfHR size; and (ii) the distance between sfHR increased with increasing heterogeneity and predictability in resource distribution, as well as with increasing sfHR size. We suggest that the multi-range tactic is likely widespread among large herbivores, allowing animals to track spatio-temporal variation in resource distribution and, thereby, to cope with changes in their local environment. PMID- 29610977 TI - A multifunctional probe based on the use of labeled aptamer and magnetic nanoparticles for fluorometric determination of adenosine 5'-triphosphate. AB - A multifunctional fluorescent probe is synthesized for the determination of adenosine 5'-triphosphate (ATP). The 6-carboxyfluorescein-labeled aptamer (FAM aptamer) was bound to the surface of magnetite nanoparticles coated with polydopamine (Fe3O4@PDA) by pi-pi stacking interaction to form the multifunctional probe. The probe has three functions including recognition, magnetic separation, and yielding a fluorescent signal. In the presence of ATP, FAM-aptamer on the surface of the probe binds to ATP and returns to the solution. Thus, the fluorescence of the supernatant is enhanced and can be related to the concentration of ATP. Fluorescence intensities were measured at excitation/emission wavelengths of 494/526 nm. Response is linear in the 0.1-100 MUM ATP concentration range, and the detection limit is 89 nM. The probe was applied to the quantitation of ATP in spiked human urine and serum samples, with recoveries ranging between 94.8 and 102%. Graphical abstract A multifunctional fluorescent probe based on the use of FAM-aptamer and Fe3O4@PDA is described for the determination of ATP in spiked human urine and serum samples. FAM-aptamer: 6 carboxyfluorescein-labeled aptamer; Fe3O4@PDA: magnetite nanoparticles coated with polydopamine. ATP: adenosine 5'-triphosphate. PMID- 29610978 TI - The relationship between the thickness of glomerular basement membrane and renal outcomes in patients with diabetic nephropathy. AB - AIMS: Glomerular basement membrane (GBM) thickening is considered as one of the earliest detectable pathological features of diabetic nephropathy (DN). However, whether the thickness of GBM will impact the prognosis of DN remains largely unknown. Our aim was to explore the relationship between thickness of GBM and DN progression in patients with type 2 diabetes mellitus (T2DM). METHODS: A total of 118 patients with T2DM and biopsy-proven DN who received follow-up for at least 1 year were recruited. The patients were divided into two groups according to the median (787 nm) of the GBM thickness: Group 1: GBM thickness < 787 nm (n = 59), and Group 2: GBM thickness >= 787 nm (n = 59). The GBM width was estimated by the direct GBM measurements as recently modified by Haas. Renal outcomes were defined by progression to ESRD and/or doubling of serum creatinine (D-Cr). The influence of GBM thickness on renal outcomes was assessed using Cox regression. RESULTS: Compared with the Group 1, patients in Group 2 had more serious renal insufficiency and glomerular lesions. During the follow-up, ESRD occurred in 39.8% of patients, and 8.5% of patients progressed to D-Cr. The univariate analysis indicated the greater width of GBM the higher risk of renal outcomes in T2DM patients with DN (HR [95% CI] = 2.180 [1.246-3.814], p = 0.006). However, the multivariate COX analysis demonstrated that the GBM thickness was not an independent risk factor for progression to ESRD or D-Cr (HR [95% CI] = 0.825 [0.404-1.685], p = 0.597) when adjusting for important clinical variables and pathological findings. CONCLUSIONS: In conclusion, the DN patients with greater width of GBM had relatively poorer renal prognosis, although it did not emerge as an independent indicator of disease progression. PMID- 29610979 TI - Behavioral Modeling for Mental Health using Machine Learning Algorithms. AB - Mental health is an indicator of emotional, psychological and social well-being of an individual. It determines how an individual thinks, feels and handle situations. Positive mental health helps one to work productively and realize their full potential. Mental health is important at every stage of life, from childhood and adolescence through adulthood. Many factors contribute to mental health problems which lead to mental illness like stress, social anxiety, depression, obsessive compulsive disorder, drug addiction, and personality disorders. It is becoming increasingly important to determine the onset of the mental illness to maintain proper life balance. The nature of machine learning algorithms and Artificial Intelligence (AI) can be fully harnessed for predicting the onset of mental illness. Such applications when implemented in real time will benefit the society by serving as a monitoring tool for individuals with deviant behavior. This research work proposes to apply various machine learning algorithms such as support vector machines, decision trees, naive bayes classifier, K-nearest neighbor classifier and logistic regression to identify state of mental health in a target group. The responses obtained from the target group for the designed questionnaire were first subject to unsupervised learning techniques. The labels obtained as a result of clustering were validated by computing the Mean Opinion Score. These cluster labels were then used to build classifiers to predict the mental health of an individual. Population from various groups like high school students, college students and working professionals were considered as target groups. The research presents an analysis of applying the aforementioned machine learning algorithms on the target groups and also suggests directions for future work. PMID- 29610980 TI - The role of the action context in object affordance. AB - Behavioral and neuroscience studies have shown that observation of objects automatically evokes potential actions to interact with those objects. In this study, the left and right hand key presses were facilitated when they corresponded with the task-irrelevant handle orientation of household objects, which is termed the affordance effect. The present study investigated how the affordance effect is affected by the action context when other agents are observed acting on a neutral or dangerous object. Participants were shown a series of pictures in which an actor grasped a neutral or dangerous object and moved it away from or toward the participant. The participants were required to press different keys to identify a symbol which was presented above the last picture. The results showed that affordance effect of a neutral object was modulated by the direction of object movement. When the neutral object moved away from the participant, an affordance effect was observed if the perceived action was congruent with handle orientation, whereas the affordance effect emerged if the perceived action was incongruent with handle orientation when the object was moved toward the participant. However, for the dangerous object, the affordance effect was obtained regardless of object movement direction or congruency between perceived action and handle orientation. This result suggests that the processing of objects involves a sophisticated integration of body behavior with the object. PMID- 29610974 TI - The role of pollutants in type 2 diabetes mellitus (T2DM) and their prospective impact on phytomedicinal treatment strategies. AB - Type 2 diabetes mellitus (T2DM) is the most common form of diabetes and it is characterized by high blood sugar and abnormal sera lipid levels. Although the specific reasons for the development of these abnormalities are still not well understood, traditionally, genetic and lifestyle behavior have been reported as the leading causes of this disease. In the last three decades, the number of diabetic patients has drastically increased worldwide, with current statistics suggesting the number is to double in the next two decades. To combat this incurable ailment, orthodox medicines, to which economically disadvantaged patients have minimal access to, have been used. Thus, a considerable amalgamation of medicinal plants has recently been proven to possess therapeutic capabilities to manage T2DM, and this has prompted studies primarily focusing on the healing aspect of these plants, and ultimately, their commercialization. Hence, this review aims to highlight the potential threat of pollutants, i.e., polyfluoroalkyl compounds (PFCs), endocrine disrupting chemicals (EDCs) and heavy metals, to medicinal plants, and their prospective impact on the phytomedicinal therapy strategies for T2DM. It is further suggested that auxiliary research be undertaken to better comprehend the factors that influence the uptake of these compounds by these plants. This should include a comprehensive risk assessment of phytomedicinal products destined for the treatment of T2DM. Regulations that control the use of PFC-precursors in certain developing countries are also long overdue. PMID- 29610981 TI - Speech Recognition for Medical Dictation: Overview in Quebec and Systematic Review. AB - Speech recognition is increasingly used in medical reporting. The aim of this article is to identify in the literature the strengths and weaknesses of this technology, as well as barriers to and facilitators of its implementation. A systematic review of systematic reviews was performed using PubMed, Scopus, the Cochrane Library and the Center for Reviews and Dissemination through August 2017. The gray literature has also been consulted. The quality of systematic reviews has been assessed with the AMSTAR checklist. The main inclusion criterion was use of speech recognition for medical reporting (front-end or back-end). A survey has also been conducted in Quebec, Canada, to identify the dissemination of this technology in this province, as well as the factors leading to the success or failure of its implementation. Five systematic reviews were identified. These reviews indicated a high level of heterogeneity across studies. The quality of the studies reported was generally poor. Speech recognition is not as accurate as human transcription, but it can dramatically reduce turnaround times for reporting. In front-end use, medical doctors need to spend more time on dictation and correction than required with human transcription. With speech recognition, major errors occur up to three times more frequently. In back-end use, a potential increase in productivity of transcriptionists was noted. In conclusion, speech recognition offers several advantages for medical reporting. However, these advantages are countered by an increased burden on medical doctors and by risks of additional errors in medical reports. It is also hard to identify for which medical specialties and which clinical activities the use of speech recognition will be the most beneficial. PMID- 29610982 TI - Fluoride varnish versus glutaraldehyde for hypersensitive teeth: a randomized controlled trial, meta-analysis and trial sequential analysis. AB - OBJECTIVE: Reports indicate Gluma and Duraphat are commonly used in-office agents to treat hypersensitive teeth. Considering this, the aim of this paper is to compare Gluma and Duraphat using a randomized controlled trial, meta-analysis collating evidences from previous studies and trial sequential analysis. MATERIALS AND METHODS: Thirty-eight participants were randomized. Hypersensitivity and visual analog scale (VAS) scores were recorded at baseline, 5 min and 7 days. Oral health-related quality of life (OHIP) questionnaire was administered at baseline and 7 days. Statistical analysis was performed to identify significant differences between the variables. For the meta-analysis, electronic data bases were searched and eligible data was extracted and analysed using RevMan 5.0. Trial sequential analysis was performed using O'Brien-Fleming boundary approach for the primary outcome. RESULTS: Both agents caused significant reduction in hypersensitivity and VAS score at 5 min and 7 days in the randomized trial with no superiority. The quality of life significantly improved in patients treated with both the agents. Four studies including the present trial in meta-analysis and trial sequential analysis indicated that Gluma produced significant reduction in VAS scores at 7 days. CONCLUSION: Gluma produces significant reduction in hypersensitivity at 7 days post treatment compared with Duraphat. There is definite lack of evidence on the long-term effect of these agents. CLINICAL RELEVANCE: This paper provides strong evidence on the use of Gluma for hypersensitive teeth. This also is a way forward to future research on long-term effects, adverse effects and cost-effectiveness studies. PMID- 29610983 TI - A nanoporous palladium(II) bridged coordination polymer acting as a peroxidase mimic in a method for visual detection of glucose in tear and saliva. AB - A nanoporous coordination polymer (NPCP) was prepared from palladium(II) chloride and 4-amino-3-hydrazino-5-mercapto-1,2,4-triazole and is shown to act as a peroxidase mimetic. It can catalyze the oxidation of 3,3',5,5' tetramethylbenzidine (TMB) by H2O2 which is formed on enzymatic oxidation of glucose by glucose oxidase. Based on these findings, a sensitive glucose test was worked out at 652 nm where the intensity if the greenish-blue product is related to the actual concentration of glucose. Figures of merit include (a) rather low Km value (30 MUM) which evidences the strong binding affinity of the NPCP toward glucose, (b) a high v(max) (8.5 M.s-1), (c) a 47 nM detection limit, (d) a lifetime of a month, (e) a wide working pH range (2-10), and (f) a 25-80 degrees C temperature range. The assay was applied to non-invasive determination of glucose assay in tear, saliva where the detection limits are found to be 61 and 91 nM, respectively. Graphical abstract DSchematic of the mechanism of the peroxidase like catalytic activity of AHMT-Pd NPCP that was applied in a selective colorimetric method for glucose detection based on TMB oxidation in the presence of enzymatically generated H2O2. PMID- 29610984 TI - Fruit traits and temporal abundance shape plant-frugivore interaction networks in a seasonal tropical forest. AB - Interactions between fleshy fruited plants and frugivores are crucial for the structuring and functioning of biotic communities, particularly in tropical forests where both groups are diverse and play different roles in network organization. However, it remains poorly understood how different groups of frugivore species and fruit traits contribute to network structure. We recorded interactions among 28 plant species and three groups of frugivores (birds, bats, and non-flying mammals) in a seasonal forest in Mexico to determine which species contribute more to network structure and evaluate the importance of each species. We also determined whether fruit abundance, water content, morphology traits, and fruiting phenology are related to network parameters: the number of interactions, species contribution to nestedness, and species strength. We found that plants did not depend on a single group of frugivores, but rather on one species of each group: the bird Pitangus sulphuratus, the bat Sturnira parvidens, and the non flying mammal Procyon lotor. The abundance, size, and water content of the fruits were significantly related to the contribution to nestedness, number of interactions, and species strength index of plant species. Tree species and birds contributed mainly to the nested structure of the network. We show that the structure of plant-frugivore networks in this seasonal forest is non-random and that fruit traits (i.e., abundance, phenology, size, and water content) are important factors shaping plant-frugivore networks. Identification of the key species and their traits that maintain the complex structure of species interactions is therefore fundamental for the integral conservation of tropical forests. PMID- 29610985 TI - Human-APOBEC3G-dependent restriction of porcine endogenous retrovirus replication is mediated by cytidine deamination and inhibition of DNA strand transfer during reverse transcription. AB - Although human apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3G (APOBEC3G, hA3G)-mediated deamination is the major mechanism used to restrict the infectivity of a broad range of retroviruses, it is unclear whether porcine endogenous retrovirus (PERV) is affected by hA3G or porcine A3F (poA3F). To determine whether DNA deamination is required for hA3G- and poA3F-dependent inhibition of PERV transmission, we developed VSV-pseudotype PERV-B expressing hA3G, mutant hA3G-E67Q (encapsidation and RNA binding activity-deficient), mutant hA3G-E259Q (deaminase-deficient), or poA3F. hA3G-E67Q decreased virus infectivity by ~ 93% compared to the ~ 99% decrease of viral infectivity by wild-type hA3G, while hA3G-E259Q decreased the infectivity of PERV-B by ~ 35%. These data suggest that cytidine deamination activity is crucial for efficient restriction of PERV by hA3G, but cytidine deamination cannot fully explain the inactivation of PERV by hA3G. Furthermore, differential DNA denaturation PCR (3D-PCR) products from 293T cells infected with PERV-B expressing hA3G mutants were sequenced. G-to-A hypermutation was detected at a frequency of 4.1% for hA3G, 3.4% for hA3G-E67Q, and 4.7% for poA3F. These results also suggest that hA3G and poA3F inhibit PERV by a deamination-dependent mechanism. To examine the effect of hA3G on the production of PERV DNA, genomic DNA was extracted from 293T cells 12 h after infection with PERV expressing hA3G, and this DNA was used as template for real time PCR. A 50% decrease in minus strand strong stop (-sss) DNA synthesis/transfer was observed in the presence of hA3G. Based on these results, we conclude that hA3G may restrict PERV by both deamination-dependent mechanisms and inhibition of DNA strand transfer during PERV reverse transcription. PMID- 29610987 TI - Comparison of the capture efficiency, prey processing, and nutrient extraction in a generalist and a specialist spider predator. AB - Predators are traditionally classified as generalists and specialists based on the presence of adaptations that increase efficiency of prey capture and consumption and selection of particular prey types. Nevertheless, empirical evidence comparing foraging efficiency between generalist and specialist carnivores is scarce. We compared the prey-capture and feeding efficiency in a generalist and a specialist (araneophagous) spider predator. By using two related species, the generalist Harpactea rubicunda (Dysderidae) and the specialist Nops cf. variabilis (Caponiidae), we evaluated their fundamental trophic niche by studying the acceptance of different prey. Then, we compared their predatory behavior, efficiency in capturing prey of varying sizes, feeding efficiency, and nutrient extraction. Nops accepted only spiders as prey, while Harpactea accepted all offered prey, confirming that Nops is stenophagous, while Harpactea is euryphagous. Further, Nops displayed more specialized (stereotyped) capture behavior than Harpactea, suggesting that Nops is a specialist, while Harpactea is a generalist. The specialist immobilized prey faster, overcame much larger prey, and gained more mass (due to feeding on larger prey) than the generalist. Both the specialist and the generalist spider extracted more proteins than lipids, but the extraction of macronutrients in the specialist was achieved mainly by consuming the prosoma of the focal prey. We show that the specialist has more efficient foraging strategy than the generalist. PMID- 29610986 TI - Soluble mucus component CLCA1 modulates expression of leukotactic cytokines and BPIFA1 in murine alveolar macrophages but not in bone marrow-derived macrophages. AB - The secreted airway mucus cell protein chloride channel regulator, calcium activated 1, CLCA1, plays a role in inflammatory respiratory diseases via as yet unidentified pathways. For example, deficiency of CLCA1 in a mouse model of acute pneumonia resulted in reduced cytokine expression with less leukocyte recruitment and the human CLCA1 was shown to be capable of activating macrophages in vitro. Translation of experimental data between human and mouse models has proven problematic due to several CLCA species-specific differences. We therefore characterized activation of macrophages by CLCA1 in detail in solely murine ex vivo and in vitro models. Only alveolar but not bone marrow-derived macrophages freshly isolated from C57BL6/J mice increased their expression levels of several pro-inflammatory and leukotactic cytokines upon CLCA1 stimulation. Among the most strongly regulated genes, we identified the host-protective and immunomodulatory airway mucus component BPIFA1, previously unknown to be expressed by airway macrophages. Furthermore, evidence from an in vivo Staphylococcus aureus pneumonia mouse model suggests that CLCA1 may also modify BPIFA1 expression in airway epithelial cells. Our data underscore and specify the role of mouse CLCA1 in inflammatory airway disease to activate airway macrophages. In addition to its ability to upregulate cytokine expression which explains previous observations in the Clca1-deficient S. aureus pneumonia mouse model, modulation of BPIFA1 expression expands the role of CLCA1 in airway disease to involvement in more complex downstream pathways, possibly including liquid homeostasis, airway protection, and antimicrobial defense. PMID- 29610988 TI - Operating force information on-line acquisition of a novel slave manipulator for vascular interventional surgery. AB - Vascular interventional surgery has its advantages compared to traditional operation. Master-slave robotic technology can further improve the operation accuracy, efficiency and safety of this complicated and high risk surgery. However, on-line acquisition of operating force information of catheter and guidewire remains to be a significant obstacle on the path to enhancing robotic surgery safety. Thus, a novel slave manipulator is proposed in this paper to realize on-line sensing of guidewire torsional operating torque and axial operation force during robotic assisted operations. A strain sensor is specially designed to detect the small scale torsional operation torque with low rotational frequency. Additionally, the axial operating force is detected via a load cell, which is incorporated into a sliding mechanism to eliminate the influence of friction. For validation, calibration and performance evaluation experiments are conducted. The results indicate that the proposed operation torque and force detection device is effective. Thus, it can provide the foundation for enabling accurate haptic feedback to the surgeon to improve surgical safety. PMID- 29610989 TI - The use of gait analysis in the assessment of patients afflicted with spinal disorders. AB - PURPOSE: Use gait analysis to establish and detail the clinically relevant components of normal human gait, analyze the gait characteristics for those afflicted with spinal pathology, and identify those aspects of human gait that correlate with pre- and postoperative patient function and outcomes. METHODS: Twenty patients with adult degenerative scoliosis (ADS), 20 patients with cervical spondylotic myelopathy (CSM), and 15 healthy volunteers performed over ground gait trials with a comfortable self-selected speed using video cameras to measure patient motion, surface electromyography (EMG) to record muscle activity, and force plates to record ground reaction force (GRF). Gait distance and temporal parameters, ankle, knee, hip, pelvic, and trunk range of motion (ROM), duration of lower extremity EMG activity and peak vertical GRF were measured. RESULTS: Patients with ADS and CSM exhibited a significantly slower gait speed, decrease in step length, cadence, longer stride time, stance time, double support time, and an increase in step width compared to those in the control group. These patients also exhibited a significantly different ankle, knee, pelvic, and trunk ROM. Moreover, spinal disorder patients exhibited a significantly longer duration of rectus femoris, semitendinosus, tibialis anterior and medial gastrocnemius muscle activity along with an altered vertical GRF pattern. CONCLUSIONS: Gait analysis provides an objective measure of functional gait in healthy controls as well as those with ADS and CSM. This study established and detailed some of the important kinematic and kinetic variables of gait in patients with spinal disorders. We recommend that spine care providers use gait analysis as part of their clinical evaluation to provide an objective measure of function. These slides can be retrieved under Electronic Supplementary Material. PMID- 29610990 TI - Psychometric validation of the cross-culturally adapted traditional Chinese version of the Back Beliefs Questionnaire (BBQ) and Fear-Avoidance Beliefs Questionnaire (FABQ). AB - PURPOSE: To translate and cross-culturally adapt the Back Beliefs Questionnaire (BBQ) and Fear-Avoidance Beliefs Questionnaire (FABQ) into traditional Chinese for their use in patients experiencing low back pain (LBP). METHODS: This was a prospective questionnaire translation and psychometric validation of the BBQ and FABQ in Chinese patients with back pain. Patients also completed the Traditional Chinese (Hong Kong) versions of the Oswestry Disability Index (ODI), the Short Form-12 version 2 (SF-12v2) questionnaires and the visual analogue scale (VAS) for LBP. Construct validity was assessed using Spearman's correlation test against the subscales and domains with similar constructs. Internal consistency was assessed by Cronbach's alpha (alpha). Sensitivity was determined by known group comparisons. RESULTS: A total of 100 patients were recruited. Both BBQ (alpha = 0.810) and FABQ (alpha = 0.859) demonstrated excellent overall internal consistency. BBQ scores significantly correlated with ODI scores, VAS-LBP and all domains of SF-12v2 (p < 0.01-0.05), whereas only FABQ Work subscale correlated with ODI scores (p < 0.01) and VAS-LBP (p < 0.05). Both FABQ subscales correlated with only specific domains of SF-12v2 (p < 0.01-0.05). FABQ-W was sensitive to difference between patients with acute versus chronic back pain. CONCLUSIONS: Both the adapted BBQ and FABQ (Traditional Chinese-Hong Kong) were demonstrated to have satisfactory psychometric properties, with adequate internal consistencies, construct validity and sensitivity to certain clinical parameters. Our findings were based on a clinically relevant patient group and provides insight into patients' own perception of back pain which may often be different from that of surgeons. This is a platform for future cross-cultural comparisons. LEVEL OF EVIDENCE: 2. These slides can be retrieved under Electronic Supplementary Material. PMID- 29610991 TI - The viability of probiotics in water, breast milk, and infant formula. AB - : The aim of this study was to determine bacteriological stability of a probiotic mixture dispersed in various diluents. The commercially available probiotic (Infloran(r)), containing Bifidobacterium bifidum (109 CFU/250 mg tablet) and Lactobacillus acidophilus (109 CFU/250 mg tablet), was dispersed within expressed breast milk, sterile water, and infant formula and examined at temperatures of 4 and 21 degrees C. When stored at 4 degrees C, significant decreases (P < 0.05) in the level of L. acidophilus and B. bifidum were observed in expressed breast milk and sterile water after a 6-h period. However, when stored in infant formula, both strains remained stable over a 12-h period. When stored at 21 degrees C, a significant decrease (P < 0.05) was observed in the level of L. acidophilus in sterile water, expressed breast milk and infant formula throughout a 12-h period. However, no significant decrease was observed overtime in B. bifidum in all three diluents at this temperature. CONCLUSION: Our findings suggest that, when stored at 4 degrees C, this probiotic product can remain at a stable condition for 6 h in sterile water and infant formula; however, the viability of the probiotic decreases significantly after this period of time. Administration of this probiotic in sterile water can be an acceptable alternative to dispersion and administration in expressed breast milk. What is Known: * Administration of probiotics containing lactobacilli and bifidobacteria has become more widespread in neonatology, mainly as prophylaxis for the prevention of necrotising entercolitis in preterm infants. * Probiotic reconstitution, from its powder base, is not standardized and various diluents, including sterile water, breast milk, and infant formula, have been used. What is New: * When stored at 4 degrees C, a probiotic containing lactobacilli and bifidobacteria remains at a stable microbological condition for up to 6 h in sterile water. * Administration of this probiotic dispersed in sterile water, followed by an EBM feed, can be an acceptable alternative to dispersion and administration in EBM. PMID- 29610992 TI - Silver microspheres coated with a molecularly imprinted polymer as a SERS substrate for sensitive detection of bisphenol A. AB - An efficient approach is demonstrated for preparing particles consisting of a silver core and a shell of molecularly imprinted polymer (Ag@MIP). The MIP is prepared by using bisphenol A (BPA) as the template and 4-vinylpyridine as the functional monomer. The Ag@MIP fulfills a dual function in that the silver core acts as a SERS substrate, while the MIP allows for selective recognition of BPA. The Ag@MIP is characterized by scanning electron microscopy, transmission electron microscopy, X-ray powder diffraction, thermogravimetric analysis and Raman spectroscopy. The Raman intensity of Ag@MIP is higher than that of bare silver microspheres. The detection limit for BPA is as low as 10-9 mol.L-1. Graphical abstract Schematic illustration of the preparation of silver microspheres coated with a molecularly imprinted polymer (Ag@MIPs) for detecting bisphenol A (BPA) by surface enhanced Raman scattering (SERS). PMID- 29610993 TI - MnO nanoparticles with unique excitation-dependent fluorescence for multicolor cellular imaging and MR imaging of brain glioma. AB - The authors describe MnO nanoparticles (NPs) with unique excitation-dependent fluorescence across the entire visible spectrum. These NPs are shown to be efficient optical nanoprobe for multicolor cellular imaging. Synthesis of the NPs is accomplished by a thermal decomposition method. The MnO NPs exhibit a high r1 relaxivity of 4.68 mM-1 s-1 and therefore give an enhanced contrast effect in magnetic resonance (MR) studies of brain glioma. The cytotoxicity assay, hemolysis analysis, and hematoxylin and eosin (H&E) staining tests verify that the MnO NPs are biocompatible. In the authors' perception, the simultaneous attributes of multicolor fluorescence and excellent MR functionality make this material a promising dual-modal nanoprobe for use in bio-imaging. Graphical abstract A direct method to synthesize fluorescent MnO NPs is reported. The NPs are biocompatible and have been successfully applied for multicolor cellular imaging and MR detection of brain glioma. PMID- 29610994 TI - Morphological regulation of Aspergillus niger to improve citric acid production by chsC gene silencing. AB - The mycelial morphology of Aspergillus niger, a major filamentous fungus used for citric acid production, is important for citric acid synthesis during submerged fermentation. To investigate the involvement of the chitin synthase gene, chsC, in morphogenesis and citric acid production in A. niger, an RNAi system was constructed to silence chsC and the morphological mutants were screened after transformation. The compactness of the mycelial pellets was obviously reduced in the morphological mutants, with lower proportion of dispersed mycelia. These morphological changes have caused a decrease in viscosity and subsequent improvement in oxygen and mass transfer efficiency, which may be conducive for citric acid accumulation. All the transformants exhibited improvements in citric acid production; in particular, chsC-3 showed 42.6% higher production than the original strain in the shake flask. Moreover, the high-yield strain chsC-3 exhibited excellent citric acid production potential in the scale-up process.The citric acid yield and the conversion rate of glucose of chsC-3 were both improved by 3.6%, when compared with that of the original strain in the stirred tank bioreactor. PMID- 29610995 TI - Extra-Renal manifestations of atypical hemolytic uremic syndrome in children. AB - BACKGROUND: Atypical hemolytic uremic syndrome (aHUS) is a chronic disease characterized by thrombotic microangiopathy and a high risk of end-stage kidney disease. Dysregulation and/or excessive activation of the complement system results in thrombotic microangiopathy. Interest in extrarenal manifestations of aHUS is increasing. This study aimed to determine the clinical characteristics of patients with extrarenal manifestations of aHUS in childhood. METHODS: This study included 70 children with extrarenal manifestations of HUS from the national Turkish aHUS Registry. The demographics, clinical characteristics, genetic test results, all treatments, and renal/hematologic status of aHUS patients with extrarenal involvement were recorded. RESULTS: The most common extrarenal manifestation was neurological system involvement (n = 46 [27.2%]), followed by gastrointestinal (n = 20 [11.8%]), cardiovascular (n = 12 [7%]), and respiratory (n = 12 [7%]) involvement. The patients with neurological involvement had a higher mortality rate and a lower estimated glomerular filtration rate (eGFR) than the other patients at last follow-up. Eculizumab (with or without plasma exchange/plasma infusion) treatment increased the renal and hematologic recovery rates. CONCLUSIONS: The most common and serious extrarenal manifestation of aHUS is neurological involvement and treatment outcome findings presented herein are important to all relevant clinicians. PMID- 29610996 TI - Multi-speed sedimentation velocity implementation in UltraScan-III. AB - A framework for the global analysis of multi-speed analytical ultracentrifugation sedimentation velocity experiments is presented. We discuss extensions to the adaptive space-time finite element fitting methods implemented in UltraScan-III to model sedimentation velocity experiments where a single run is performed at multiple rotor speeds, and describe extensions in the optimization routines used for fitting experimental data collected at arbitrary multi-speed profiles. Our implementation considers factors such as speed dependent rotor stretching, the resulting radial shifting of the finite element solution's boundary conditions, and changes in the associated time-invariant noise. We also address the calculation of acceleration rates and acceleration zones from existing radial acceleration and time records, as well as utilization of the time state object available at high temporal resolution from the new Beckman Optima AUC instrument. Analysis methods in UltraScan-III support unconstrained models that extract reliable information for both the sedimentation and the diffusion coefficients. These methods do not rely on any assumptions and allow for arbitrary variations in both sedimentation and diffusion transport. We have adapted these routines for the multi-speed case, and developed optimized and general grid based fitting methods to handle changes in the information content of the simulation matrix for different speed steps. New graphical simulation tools are presented that assist the investigator to estimate suitable grid metrics and evaluate information content based on edit profiles for individual experiments. PMID- 29610997 TI - Rechallenge treatment with a platinum-based regimen in patients with sensitive relapsed small-cell lung cancer. AB - Among patients with relapsed small-cell lung cancer (SCLC), those who relapse > 90 days after first-line chemotherapy are classified sensitive relapse. Rechallenge with a first-line platinum-based regimen has been used in sensitive relapsed SCLC patients, but its importance is not known. We evaluated the outcome of rechallenge with platinum-based chemotherapy for sensitive relapse patients. We reviewed consecutive patients with sensitive relapsed SCLC who received second line chemotherapy between January 1999 and December 2016. We evaluated the treatment outcomes of platinum-based rechallenge and non-rechallenge regimens for second-line chemotherapy in sensitive relapse patients. Of 245 patients, 81 sensitive relapse patients received second-line chemotherapy. Sixty-seven patients (82.7%) were treated with rechallenging platinum-based regimens ("rechallenge group") and 14 patients (17.3%) were treated with other regimens ("non-rechallenge group") as second-line chemotherapy. Median progression-free survival (PFS) was 5.1 months in the rechallenge group and 3.5 months in the non rechallenge group, and median survival time was 10.8 and 8.2 months, respectively. There were no significant differences in PFS or overall survival (OS) between the two groups. Sub-analyses of patients who received chemotherapy alone as first-line treatment showed that the rechallenge group had longer PFS than that of the non-rechallenge group (median 5.4 vs. 3.6 months, p = 0.0038), and the rechallenge group had a tendency to have longer OS than non-rechallenge group. These data suggest that rechallenge treatment with a platinum-based regimen could be second-line chemotherapy in patients with sensitive relapsed SCLC, especially those treated with chemotherapy alone as first-line therapy. PMID- 29610998 TI - A modified method for genomic DNA extraction from the fish intestinal microflora. AB - A modified genomic DNA extraction method named the combination of lysozyme and ultrasonic lysis (CLU) method was used to analyze the fish intestinal microflora. In this method, the physical disruption and chemical lysis steps were combined, and some parameters in the key steps were adjusted. In addition, the results obtained by this method were compared with the results obtained by the Zirmil beating cell disruption method and the QIAamp Fast DNA Stool Mini Kit. The OD260/OD280 ratio and concentration of the DNA extracted using the CLU method were 2.02 and 282.8 ug/uL, respectively; when the incubation temperatures for lysozyme and RNase were adjusted to 37 degrees C, those values were 2.08 and 309.8 ug/uL, respectively. On the agarose gel, a major high-intensity, discrete band of more than 10 kb was found for the CLU method. However, the smearing intensity of degraded DNA was lower when the incubation temperatures were 60 degrees C for lysozyme and 30 degrees C for RNase than when incubation temperatures of 37 degrees C for lysozyme and 37 degrees C for RNase were used. The V3 variable region of the prokaryotic 16S rDNA was amplified, and an approximately 600-bp fragment was observed when the DNA extracted using the CLU method was used as a template. The CLU method is simple and cost effective, and it yields high-quality, unsheared, high-molecular-weight DNA, which is comparable to that obtained with a commercially available kit. The extracted DNA has potential for applications in critical molecular biology techniques. PMID- 29611000 TI - Design, characterization and in vivo functioning of a light-dependent histidine protein kinase in the yeast Saccharomyces cerevisiae. AB - Helical alignment of the alpha-helical linker of the LOV (light-oxygen-voltage) domain of YtvA from Bacillus subtilis with the alpha-helical linker of the histidine-protein kinase domain of the Sln1 kinase of the phospho-relay system for osmoregulation of Saccharomyces cerevisiae has been used to construct a light modulatable histidine protein kinase. In vitro, illumination with blue light inhibits both the ATP-dependent phosphorylation of this hybrid kinase, as well as the phosphoryl transfer to Ypd1, the phosphoryl transfer domain of the Sln1 system. The helical alignment was carried out with conservation of the complete Jalpha helix of YtvA, as well as of the phosphorylatable histidine residue of the Sln1 kinase, with conservation of the hepta-helical motive of coiled-coil structures, recognizable in the helices of the two separate, constituent, proteins. Introduction of the gene encoding this hybrid histidine protein kinase into cells of S. cerevisiae in which the endogenous Sln1 kinase had been deleted, allowed us to modulate gene expression in the yeast cells with (blue) light. This was first demonstrated via the light-induced alteration of the expression level of the mannosyl-transferase OCH1, via a translational-fusion approach. As expected, illumination decreased the expression level of OCH1; the steady state decrease in saturating levels of blue light was about 40%. To visualize the in vivo functionality of this light-dependent regulation system, we fused the green fluorescent protein (GFP) to another regulatory protein, HOG1, which is also responsive to the Sln1 kinase. HOG1 is phosphorylated by the MAP-kinase-kinase Pbs2, which in turn is under control of the Sln1 kinase, via the phosphoryl transfer domain Ypd1. Fluorescence microscopy was used to show that illumination of cells that contained the combination of the hybrid kinase and the HOG1::GFP fusion protein, led to a persistent increase in the level of nuclear accumulation of HOG1, in contrast to salt stress, which-as expected-showed the well characterized transient response. The system described in this study will be valuable in future studies on the role of cytoplasmic diffusion in signal transduction in eukaryotic cells. PMID- 29610999 TI - Quantifying the Effects of Different Treadmill Training Speeds and Durations on the Health of Rat Knee Joints. AB - BACKGROUND: Walking and running provide cyclical loading to the knee which is thought essential for joint health within a physiological window. However, exercising outside the physiological window, e.g. excessive cyclical loading, may produce loading conditions that could be detrimental to joint health and lead to injury and, ultimately, osteoarthritis. The purpose of this study was to assess the effects of a stepwise increase in speed and duration of treadmill training on knee joint integrity and to identify the potential threshold for joint damage. METHODS: Twenty-four Sprague-Dawley rats were randomized into four groups: no exercise, moderate duration, high duration, and extra high duration treadmill exercise. The treadmill training consisted of a 12-week progressive program. Following the intervention period, histologic serial sections of the left knee were graded using a modified Mankin Histology Scoring System. Mechanical testing of the tibial plateau cartilage and RT-qPCR analysis of mRNA from the fat pad, patellar tendon, and synovium were performed for the right knee. Kruskal-Wallis testing was used to assess differences between groups for all variables. RESULTS: There were no differences in cartilage integrity or mechanical properties between groups and no differences in mRNA from the fat pad and patellar tendon. However, COX-2 mRNA levels in the synovium were lower for all animals in the exercise intervention groups compared to those in the no exercise group. CONCLUSIONS: Therefore, these exercise protocols did not exceed the joint physiological window and can likely be used safely in aerobic exercise intervention studies without affecting knee joint health. PMID- 29611001 TI - Eosinophilic Granulomatosis With Polyangiitis: Newer Therapies. AB - PURPOSE OF REVIEW: Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic disseminated vasculitis associated with extravascular granulomas in patients suffering from asthma and tissue eosinophilia. Current therapies to achieve remission and prevent relapse include glucocorticoids and immunosuppressants like cyclophosphamide. RECENT FINDINGS: With the right treatment, clinical prognosis is favorable, so concerted efforts have been made in recent years to find new alternatives for treating severe EGPA. Monoclonal antibodies such as omalizumab, rituximab, and mepolizumab are among these new options. This review summarizes the pathogenesis and clinical manifestations of EGPA and critically examines current and emerging therapies. PMID- 29611002 TI - Current and Emerging Therapeutic Targets for Metastatic Renal Cell Carcinoma. AB - PURPOSE OF REVIEW: The treatment of advanced renal cell carcinoma has evolved dramatically over recent years. In this review, we will summarize current and emerging therapies based on molecular targets and provide insight into treatment strategy for metastatic renal cell carcinoma. RECENT FINDINGS: We have witnessed a paradigm shift in the therapeutic landscape as treatment was formerly reliant on cytokine-based agents which have now been replaced with therapies targeting angiogenesis, mammalian target of rapamycin pathways, and immune responses. These dramatic changes are primarily due to our improved understanding of the underlying mutations and molecular mechanisms leading to tumorigenesis and progression. We now have targeted agents in the form of small-molecule tyrosine kinase inhibitors, monoclonal antibodies, and mTOR inhibitors. Moreover, immunotherapy-targeting checkpoints of T-lymphocyte activity has provided increased overall survival and a new class of agents with potential to radically change the treatment options. With these agents and their combination, durable responses are increasingly seen even though treatment resistance remains a huge challenge. New treatment strategies are rapidly developing and the therapeutic landscape is expected for further evolution. PMID- 29611003 TI - Metatranscriptomics analysis of mangroves habitats around Mauritius. AB - Mangroves are unique but endangered coastal ecosystems that play a vital role in the tropical and subtropical environments. Mauritius has two species of mangroves, Bruguiera gymnorrhiza (L.) Lam. and Rhizophora mucronata Lam., growing along its coast. The mangrove rhizosphere harbours a diverse microbial community and the use of RNA-sequencing can reveal both the taxonomic composition and active biochemical functions of the complex microbial community. Metatranscriptomic study was carried out by comparing the microbial community of rhizosphere microbiomes sediments from the two mangroves species. The study also included a comparison between a natural and a man grown mangrove microbiome. Overall, samples showed predominance by Proteobacteria, Bacteroidetes and Firmicutes, with high abundance of sulphate reducers, nitrogen reducers and methanogens. Significant difference was, however, noted at both taxonomic and functional levels among the mangroves species. The data also indicate that the microbial core involved in methane, nitrogen, and sulphur metabolism consisted mainly of Burkholderiaceae, Planctomycetaceae, Rhodobacteraceae, and Desulfobacteraceae. Also, genes encoding enzymes involved in carbon cycling, the metabolism of nitrogen, methane and sulphur were dominant in the rhizosphere of the natural mangrove ecosystem. To our knowledge, this is a first metatranscriptomic study on the microbiome of mangroves in the Mauritius, and our results provide the first insights in the range of functions and microbial diversity of the local mangrove species. PMID- 29611004 TI - Eugenol derivatives: synthesis, characterization, and evaluation of antibacterial and antioxidant activities. AB - Eugenol is the major component of clove essential oil and has demonstrated relevant biological potential with well-known antimicrobial and antioxidant action. Therefore, this work carried out the synthesis, purification, characterization, and evaluation of the antioxidant and antibacterial potential of 19 eugenol derivatives. The derivatives were produced by esterification reactions in the hydroxyl group (-OH) of eugenol with different carboxylic acids and also by addition reactions in the double bond of the allyl group. The derivatives had a promising antibacterial potential, including a lower minimum inhibitory concentration of 500 MUg/mL than eugenol (1000 MUg/mL). In addition, the derivatives were active against bacterial strains (Escherichia coli, Staphylococcus aureus) that eugenol itself showed no activity, thus increasing the spectrum of antibacterial action. As for the antioxidant activity, it was observed that the derivatives that involved esterification reactions in the hydroxyl group (-OH) of the eugenol molecule's phenol resulted in a significant reduction of the antioxidant action (IC50 > 100 MUg/mL) when compared with the eugenol precursor molecule (IC50 = 4.38 MUg/mL). On the other hand, the structural changes located in the double bond affected much more smoothly the capacity of capturing radicals than the starting molecule, also being obtained derivatives with proximal antioxidant capacity (IC50 = 19.30 MUg/mL) to commercial standards such as Trolox (IC50 = 16.00 MUg/mL). PMID- 29611005 TI - Recent Advances in Giant Cell Arteritis. AB - PURPOSE OF REVIEW: Giant cell arteritis (GCA) is the most common systemic vasculitis. GCA is categorized as a granulomatous vasculitis of large and medium size vessels. Majority of the symptoms and signs of GCA result from involvement of the aorta and its branches intra- and extracranial. Temporal artery biopsy continues to be the cardinal diagnostic procedure despite new imaging modalities for diagnosing GCA with cranial involvement. Great advances in awareness have led to improvement in preventing irreversible vision loss due to early diagnosis. RECENT FINDINGS: The cause of GCA has not been elucidated but major progress has been made in the knowledge of its pathogenesis leading to new therapeutic targets, particularly inhibition of interleukin 6. IL 6 plays a key role in the regulation of TH17/Tregs imbalance in GCA and appears to correlate with clinical disease activity in GCA. All of this has led to the first FDA (food and drug administration) approved treatment for GCA, Tocilizumab. Abatacept and Ustekinumab are promising targets for therapy in LVV but still need further research. This paper is a review of the recent progress in the understanding of GCA pathogenesis, diagnosis, treatment, and prognosis. PMID- 29611006 TI - Review of interactions between phosphorus and arsenic in soils from four case studies. AB - Arsenic is a non-essential element that poses risks in many environments, including soil, groundwater, and surface water. Insights into the environmental biogeochemistry of As can be gained by comparing As and P reaction processes. Arsenic and P are chemical analogues, and it is proposed that they have similar chemical behaviors in environmental systems. However some chemical properties of As and P are distinct, such as redox reactions, causing the biogeochemical behavior of the two elements to differ. In the environment, As occurs as either As(V) or As(III) oxyanions (e.g., AsO43- or AsO33-). In contrast, P occurs predominantly as oxidation state five plus; most commonly as the orthophosphate ion (PO43-). In this paper, data from four published case studies are presented with a focus on P and As distribution and speciation in soil. The goal is show how analyzing P chemistry in soils can provide greater insights into As reaction processes in soils. The case studies discussed include: (1) soil developed from shale parent material, (2) mine-waste impacted wetland soils, (3) phosphate amended contaminated soil, and (4) plants grown in biochar-amended, mine contaminated soil. Data show that while P and As have competitive reactions in soils, in most natural systems they have distinct biogeochemical processes that create differing mobility and bioavailability. These processes include redox reactions and rhizosphere processes that affect As bioavailability. Results from these case studies are used as examples to illustrate how studying P and As together allows for enhanced interpretation of As biogeochemical processes in soils. PMID- 29611007 TI - Femoral tunnel widening is associated with tunnel malposition but not with clinical failure after medial patellofemoral ligament reconstruction with a free gracilis tendon graft. AB - INTRODUCTION: MPFL reconstruction is widely and successfully used for treating patella instability, either as a standalone procedure or in combination. Although different techniques allow for MPFL reconstruction, the use of a free tendon graft is one of the most commonly used. The phenomenon of tunnel widening or tunnel enlargement is well described in ACL reconstruction, but so far only little effort has been put into evaluating this phenomenon after MPFL reconstruction. MATERIALS AND METHODS: Patients who received an MPFL reconstruction with a free gracilis tendon graft were identified by review of patient files. Additional clinical examination and magnetic resonance imaging were performed to assess tunnel enlargement and clinical outcome. RESULTS: Fifty one knees of 49 patients (34 female, 17 male) with a mean follow-up of 3.0 +/- 1.4 years were included in this study. Mean age at the time of surgery was 22.6 +/- 8.5 years. Mean Tegner score decreased from preoperative 5.3 +/- 2.0 to 4.0 +/- 1.4 postoperative. Postoperative IKDC and Kujala scores were 74 +/- 16 and 80 +/- 15, respectively. Twenty-three patients showed a tunnel enlargement at follow up examination. Of these 23 patients, 20 showed a tunnel that was positioned too proximal, whereas only 13 of the 28 patients showing no enlargement had a tunnel that was positioned too proximal (p = 0.0033). Interestingly, patients showing a tunnel enlargement at follow-up examination also showed significantly better Kujala (84 +/- 12 vs. 75 +/- 16; p = 0.03) and IKDC scores (80 +/- 7 vs. 70 +/- 19; p = 0.02) when compared to the non-enlarged group. CONCLUSION: Tunnel enlargement after MPFL reconstruction with a free gracilis tendon graft seems to be connected to mechanical overload due to a proximal malposition of the femoral tunnel. Interestingly, this did not influence clinical outcome as patients with tunnel enlargement showed better Kujala and IKDC scores. PMID- 29611009 TI - Development of Electrospun Chitosan-Polyethylene Oxide/Fibrinogen Biocomposite for Potential Wound Healing Applications. AB - Normal wound healing is a highly complex process that requires the interplay of various growth factors and cell types. Despite advancements in biomaterials, only a few bioactive wound dressings reach the clinical setting. The purpose of this research was to explore the feasibility of electrospinning a novel nanofibrous chitosan (CS)-fibrinogen (Fb) scaffold capable of sustained release of platelet derived growth factor (PDGF) for the promotion of fibroblast migration and wound healing. CS-Fb scaffolds were successfully electrospun using a dual-spinneret electrospinner and directly evaluated for their physical, chemical, and biological characteristics. CS-polyethylene/Fb scaffolds exhibited thinner fiber diameters than nanofibers electrospun from the individual components while demonstrating adequate mechanical properties and homogeneous polymer distribution. In addition, the scaffold demonstrated acceptable water transfer rates for wound healing applications. PDGF was successfully incorporated in the scaffold and maintained functional activity throughout the electrospinning process. Furthermore, released PDGF was effective at promoting fibroblast migration equivalent to a single 50 ng/mL dose of PDGF. The current study demonstrates that PDGF-loaded CS-Fb nanofibrous scaffolds possess characteristics that would be highly beneficial as novel bioactive dressings for enhancement of wound healing. PMID- 29611008 TI - Characteristics of menstrual versus non-menstrual migraine during pregnancy: a longitudinal population-based study. AB - BACKGROUND: Migraine is a common headache disorder that affects mostly women. In half of these, migraine is menstrually associated, and ranges from completely asymptomatic to frequent pain throughout pregnancy. METHODS: The aim of the study was to define the pattern (frequency, intensity, analgesics use) of migrainous headaches among women with and without menstural migraine (MM) during pregnancy, and define how hormonally-related factors affect its intensity. RESULTS: The analysis was based upon data from 280 women, 18.6% of them having a self-reported MM. Women with MM described a higher headache intensity during early pregnancy and postpartum compared those without MM, but both groups showed improvement during the second half of pregnancy and directly after delivery. Hormonal factors and pre-menstrual syndrome had no effect upon headache frequency, but may affect headache intensity. CONCLUSIONS: Individual treatment plan is necessary for women with migrainous headaches during pregnancy, especially for those suffering highest symptoms load. PMID- 29611010 TI - Expanded algorithm for managing patients with acute decompensated heart failure. AB - Heart failure is a complex disease process, the manifestation of various cardiac and noncardiac abnormalities. General treatment approaches for heart failure have remained the same over the past decades despite the advent of novel therapies and monitoring modalities. In the same vein, the readmission rates for heart failure patients remain high and portend a poor prognosis for morbidity and mortality. In this context, development and implementation of improved algorithms for assessing and treating HF patients during hospitalization remains an unmet need. We propose an expanded algorithm for both monitoring and treating patients admitted for acute decompensated heart failure with the goal to improve post-discharge outcomes and decrease rates of rehospitalizations. PMID- 29611011 TI - Reply to the letter to the editor: Lymph node metastasis of adenocarcinoma and different definitions of sm1 cancer in the esophagus. PMID- 29611012 TI - Lymph node metastasis of adenocarcinoma and different definitions of sm1 cancer in the esophagus. PMID- 29611013 TI - Correction to: Nebulization of RNS60, a Physically-Modified Saline, Attenuates the Adoptive Transfer of Experimental Allergic Encephalomyelitis in Mice: Implications for Multiple Sclerosis Therapy. AB - The original version of this article unfortunately contained a mistake. The Figure 3, 4, 5 legends have been misplaced. The updated legends along with the figures are corrected with this erratum. PMID- 29611014 TI - Cost-effectiveness of novel treatment of hepatitis C virus in Lebanese patients. AB - Background Limited data is available on Hepatitis C disease prevalence, treatment initiation and its cost-effectiveness in Lebanon and the whole Middle East. Objective The aim of the study is to assess whether initiation of novel Direct Acting Antiviral agents (DAAs) at early stage of hepatitis C is cost-effective in Lebanese patients. Setting Lebanon. Methods This modeling study was conducted from the perspective of Lebanese third party payers, where existing practice is based on international guidelines for the diagnosis and treatment of diseases. The model assessed cost-effectiveness of early versus delayed DAAs treatment in a standard patient upon HCV diagnosis. Medical costs were valued using in-house database. Main outcome measures Incremental Cost-Effectiveness Ratio (ICER) per QALY and per life-year extended. Results Treatment at early HCV disease stage has led to an ICER of 587 euro per QALY gained throughout the course of the disease. Outcomes of early treatment with DAAs upon HCV diagnosis led to an incremental cost of 27,268 euro per QALY gained at first year of treatment, and of 1527 euro per additional life-year extended. Sensitivity analysis showed that a 25% decrease in the cost of dual drug option resulted in a decrease of incremental cost to 16,982 euro per QALY gained at first year of treatment with DAAs upon early HCV diagnosis. Conclusion Decision makers are encouraged to reinforce the need to screen for HCV and initiate novel treatment at early disease stage in the Lebanese healthcare system. PMID- 29611015 TI - Epidemiology of drug hypersensitivity reactions using 6-year national health insurance claim data from Korea. AB - Background Drug hypersensitivity reactions (DHRs) constitute a large portion of adverse drug reactions (ADRs), but studies for DHR incidence based on national data are scarce. Objective This study aimed to estimate the incidence and patterns of DHRs in a Korean population and the associated utilization of medical resources using the national claims data. Setting The retrospective cohort study performed using the national insurance claim database of the Health Insurance Review and Assessment (HIRA) in Korea. Methods The International Classification of Disease 10th revision code was used to identify DHRs with 20 drug induced DHR codes. The claim data with a diagnosis of DHR in the 2009-2014 periods were analyzed. Main outcome and measure The annual incidence and the 6-year incidence rates were calculated. Incidence rate coefficients were analyzed by sex, age, and year. DHRs following with visits of emergency department (ED) or intensive care unit (ICU) were assessed for utilization of medical resources and risk of ER or ICU visits by sex and age Results A total of 535,049 patients with 1,083,507 claims were assessed in the HIRA database for 6 years. DHR incidence was high in the elderly. The risk of ED and ICU visit with DHR was also higher in the elderly than in the young [highest relative risk, RR of ED 2.59 (1.65-4.07), ICU 5.04 (2.50-10.18)]. DHRs related to blood were high in the young age. Conclusion Incidence of DHRs in the real-world clinical practice was higher in the elderly and female. Clinical consequence was more severe in the elderly. PMID- 29611016 TI - Geniposide Attenuates LPS-Induced Injury via Up-Regulation of miR-145 in H9c2 Cells. AB - Myocarditis is a cardiomyopathy associated with inflammatory response. It has been reported that geniposide (GEN), a traditional Chinese herb extract from Gardenia jasminoides Ellis, possesses an anti-inflammatory effect and a protective effect on cardiomyocytes. The present study aimed to explore the protective role of GEN and the underlying mechanism in LPS-injured H9c2 cells. H9c2 cells were treated with LPS to induce cell injury and then we investigated the effect of GEN. miR-145 expression was inhibited by transfection with miR-145 inhibitor and its expression was measured by RT-PCR. Cell viability and apoptotic cells were measured by CCK-8 assay and flow cytometry analysis. The levels of pro inflammatory factors (IL-6, TNF-alpha, and MCP-1) were assessed by western blot and RT-PCR. Western blot was performed to detect the expression of the MEK/ERK pathway-related factors. LPS exposure reduced cell viability, increased apoptotic cells, and promoted the expression of pro-inflammatory factors in H9c2 cells. However, GEN pretreatment significantly reduced LPS-induced cell injury, as increased cell viability, reduced apoptotic cells, and inhibited the expression of pro-inflammatory factors. Moreover, we found that miR-145 expression was down regulated by LPS exposure but was up-regulated by GEN pretreatment. The protective effect of GEN on LPS-injured H9c2 cells was blocked by miR-145 inhibitor. In addition, GEN inhibited the MEK/ERK pathway through up-regulating miR-145. Our results suggested that GEN exerted a protective role in LPS-injured H9c2 cells. The GEN-associated regulation might be related to its regulation on miR-145 and the MEK/ERK signaling pathway. PMID- 29611017 TI - Prevalence of Nutritional Deficiencies Among Populations of Newly Arriving Government Assisted Refugee Children to Kitchener/Waterloo, Ontario, Canada. AB - This study examined the variation among ethnic populations in prevalence of anemia, vitamin D and B12 deficiencies among refugee children. A retrospective chart review of 388 government assisted refugee children <= 16 years of age, seen at the Refugee Health Clinic in Kitchener, Canada from January 2009 to December 2014 was conducted. Vitamin D levels were only collected until December 1st 2010 (116 children). 15.7% were anemic (25% < 5 years, 8.7% 5-11 years, and 18.3% 12 16 years old) with Somali children having the lowest hemoglobin levels compared to those from Iraq, Afghanistan and Myanmar. 53.5% were vitamin D deficient (25(OH)D < 50 nmol/L), seen most commonly in Iraqis and Afghans. 11.2% had vitamin B12 levels < 150 pmol/L. Providers' knowledge of prevalence of nutritional deficiencies related to region of origin, can guide appropriate screening and treatment options to promote longer term cognitive, physical and developmental health. PMID- 29611018 TI - The Who, What, Why and When of Gynaecological Referrals for Refugee Women. AB - Refugees have health needs relating to unstable living situations and poor access to care. We examined the nature of health problems requiring gynaecological referrals for refugee women in Toronto. A retrospective cohort design was used to examine gynaecologic referrals of women at a refugee clinic between December, 2011 and June, 2016. The primary outcome measure was the indications for gynaecological referral. 125 out of 1040 women received a gynaecologic referral for 131 unique concerns. The most common referrals were for abnormal uterine bleeding and cervical dysplasia. Fibroids were prevalent amongst African patients, while referrals for LARCs/sterilization were absent from Middle Eastern patients. 26% of patients referred had a sexual violence history. Refugee women exhibit gynaecologic needs similar to the broader population. Needs vary by geographic origins. As global conflicts shift, so too will this population's needs. High rates of sexual violence history reflect the need for further understanding and intervention. PMID- 29611019 TI - Intergenerational Mobility and Goal-Striving Stress Among Black Americans: The Roles of Ethnicity and Nativity Status. AB - Goal-striving stress refers to the psychological consequences of seeking but failing to reach upward mobility and is more common among low-income and people of color. Intergenerational mobility-or improved socioeconomic standing relative to one's parents-may be an important predictor of goal-striving stress for Blacks. We used the National Survey of American Life to investigate the association between intergenerational mobility and goal-striving stress among U.S.-born African Americans, U.S.-born Caribbean Blacks, and foreign-born Caribbean Blacks. Intergenerational mobility was associated with lower goal striving stress and U.S.-born African Americans and Caribbean Blacks reported lower goal-striving stress than foreign-born Caribbean Blacks. Goal-striving stress was relatively high among foreign-born Blacks, regardless of level of intergenerational mobility attained. Goal-striving is an important stressor for foreign-born Caribbean Blacks, regardless of their level of educational success. Given increasing Black migration, future studies should disaggregate the Black racial category based on ethnicity and nativity. PMID- 29611021 TI - Development and Validation of a Brief Version of the Anti-Bisexual Experiences Scale. AB - Experiencing anti-bisexual discrimination has been linked with numerous negative consequences, such as internalized stigma and symptoms of anxiety and depression. A commonly used measure of anti-bisexual discrimination in research is the Anti Bisexual Experiences Scale (ABES). While this scale has been instrumental in advancing knowledge about discrimination against bisexual individuals, its length presents challenges to widespread use and it remains unknown if its psychometric properties are consistent across diverse genders and non-monosexual identities. To address these limitations, the current study developed and validated a brief version of the ABES. Using confirmatory factor analysis, we reduced the number of items by more than half, while retaining the full measure's associations with other stigma- and identity-related constructs as well as mental health. Invariance testing indicated that the Brief ABES functioned similarly across diverse genders (i.e., cisgender men, cisgender women, and gender minorities) and sexual identities (i.e., bisexual and other non-monosexual identities). These findings provide initial validation of the Brief ABES and demonstrate that it can be used with bisexual and other non-monosexual (e.g., pansexual, queer) individuals, including cisgender and gender minority individuals. PMID- 29611020 TI - Probing the opportunities for designing anthelmintic leads by sub-structural topology-based QSAR modelling. AB - A quantitative structure-activity (QSAR) model has been developed for enriched tubulin inhibitors, which were retrieved from sequence similarity searches and applicability domain analysis. Using partial least square (PLS) method and leave one-out (LOO) validation approach, the model was generated with the correlation statistics of [Formula: see text] and [Formula: see text] of 0.68 and 0.69, respectively. The present study indicates that topological descriptors, viz. BIC, CH_3_C, IC, JX and Kappa_2 correlate well with biological activity. ADME and toxicity (or ADME/T) assessment showed that out of 260 molecules, 255 molecules successfully passed the ADME/T assessment test, wherein the drug-likeness attributes were exhibited. These results showed that topological indices and the colchicine binding domain directly influence the aetiology of helminthic infections. Further, we anticipate that our model can be applied for guiding and designing potential anthelmintic inhibitors. PMID- 29611022 TI - A phase I, open-label, two-stage study to investigate the safety, tolerability, pharmacokinetics, and pharmacodynamics of the oral AKT inhibitor GSK2141795 in patients with solid tumors. AB - Background We sought to determine the recommended phase II dose (RP2D) and schedule of GSK2141795, an oral pan-AKT kinase inhibitor. Patients and Methods Patients with solid tumors were enrolled in the dose-escalation phase. Pharmacokinetic (PK) analysis after a single dose (Cycle 0) informed dose escalation using accelerated dose titration. Once one grade 2 toxicity or dose limiting toxicity was observed in Cycle 1, the accelerated dose titration was terminated and a 3 + 3 dose escalation was started. Continuous daily dosing was evaluated along with two intermittent regimens (7 days on/7 days off and 3 times per week). In the expansion phase at RP2D, patients with endometrial or prostate cancer, as well as those with select tumor types with a PIK3CA mutation, AKT mutation or PTEN loss, were enrolled. Patients were evaluated for adverse events (AEs), PK parameters, blood glucose and insulin levels, and tumor response. Results The RP2D of GSK2141795 for once-daily dosing is 75 mg. The most common (>10%) treatment-related AEs included diarrhea, fatigue, vomiting, and decreased appetite. Most AEs were low grade. The frequency of hyperglycemia increased with dose; however, at the RP2D, grade 3 hyperglycemia was only reported in 4% of patients and no grade 4 events were observed. PK characteristics were favorable, with a prolonged half-life and low peak-to-trough ratio. There were two partial responses at the RP2D in patients with either a PIK3CA mutation or PTEN loss. Conclusion GSK2141795 was safe and well-tolerated, with clinical activity seen as monotherapy at the RP2D of 75 mg daily. NCT00920257. PMID- 29611023 TI - Fast Decomposition of Three-Component Spectra of Fluorescence Quenching by White and Grey Methods of Data Modeling. AB - 'White' and 'grey' methods of data modeling have been employed to resolve the heterogeneous fluorescence from a fluorophore mixture of 9-cyanoanthracene (CNA), 10-chloro-9-cyanoanthracene (ClCNA) and 9,10-dicyanoanthracene (DCNA) into component individual fluorescence spectra. The three-component spectra of fluorescence quenching in methanol were recorded for increasing amounts of lithium bromide used as a quencher. The associated intensity decay profiles of differentially quenched fluorescence of single components were modeled on the basis of a linear Stern-Volmer plot. These profiles are necessary to initiate the fitting procedure in both 'white' and 'grey' modeling of the original data matrices. 'White' methods of data modeling, called also 'hard' methods, are based on chemical/physical laws expressed in terms of some well-known or generally accepted mathematical equations. The parameters of these models are not known and they are estimated by least squares curve fitting. 'Grey' approaches to data modeling, also known as hard-soft modeling techniques, make use of both hard model and soft-model parts. In practice, the difference between 'white' and 'grey' methods lies in the way in which the 'crude' fluorescence intensity decays of the mixture components are estimated. In the former case they are given in a functional form while in the latter as digitized curves which, in general, can only be obtained by using dedicated techniques of factor analysis. In the paper, the initial values of the Stern-Volmer constants of pure components were evaluated by both 'point-by-point' and 'matrix' versions of the method making use of the concept of wavelength dependent intensity fractions as well as by the rank annihilation factor analysis applied to the data matrices of the difference fluorescence spectra constructed in two ways: from the spectra recorded for a few excitation lines at the same concentration of a fluorescence quencher or classically from a series of the spectra measured for one selected excitation line but for increasing concentration of the quencher. The results of multiple curve resolution obtained by all types of the applied methods have been scrutinized and compared. In addition, the effect of inadequacy of sample preparation and increasing instrumental noise on the shape of the resolved spectral profiles has been studied on several datasets mimicking the measured data matrices. Graphical Abstract ?. PMID- 29611024 TI - Anticancer effect of fermented Insampaedok-san in human colon cancer cells: a pilot study. AB - Insampaedok-san (IPS) is one of the East Asian traditional medicines which have been prescribed for hundreds of years to treat common cold and headache. Although many herbs and prescriptions are known to have significant activities against diseases, only a limited number of reports and scientific evidences on their efficacies are available. To identify anticancer effect against colon cancer, traditional prescription IPS and its fermented IPS (FIPS) were examined by in vitro molecular biological analysis. IPS water extract was fermented, lyophilized, and examined by cytotoxicity, cell cycle, and western blot assays, using cancer cell lines. Resultantly, FIPS showed significant cytotoxicities inducing caspase dependent apoptosis and activation of caspase-3 (CASP3) and poly (ADP-ribose) polymerase (PARP) cleavage in colon cancer cell line SW620. These findings can be useful for development of anticancer functional food or complementary and alternative medicine, with remaining in-depth molecular functional studies. PMID- 29611025 TI - Expressions of some antioxidant genes in SH-SY5Y cells treated with beta lapachone, morphine and electromagnetic field. AB - beta-Lapachone (beta-Lap), morphine (Mor), and electromagnetic field (EMF) generate reactive oxygen species. The goal of the present study was to examine the effects of Mor and EMF, in combination with beta-Lap on the cell growth inhibition and expression of several antioxidant genes. The 0.50 mT intensity of 50 Hz EMF and two exposure conditions ("15 min field-on/15 min field-off" and "30 min field-on continuously") on SH-SY5Y cells were used. The effects of Mor and EMF, in combination with beta-Lap on cell growth inhibition and the expression levels of several antioxidant genes (NQO1, NQO2, SOD1, SOD2, CAT, GSTO1, GSTM2, GSTM3, GSTP1, MGST1, MGST3) in SH-SY5Y cells were measured. The relative mRNA levels were calculated according to the [Formula: see text]. Whereas NQO1 mRNA level decreased in the "15 min field-on/15 min field-off" condition, the expression level of NQO2 was increased. Both NQO1 and NQO2 expressions increased in Mor treated cells. IC50 values of beta-Lap in combination with Mor, EMF, and "Mor + EMF" were higher than cells treated only with beta-Lap. The NQO1 expression level in the cells treated with beta-Lap was higher than the other treatments, indicating that beta-Lap induces the expression of NQO1. Moreover, multiple linear regression analysis indicated that NQO1 mRNA levels were associated positively with beta-Lap and negatively with EMF. At least in part, the mRNA levels of NQO1 were associated with IC50 values of beta-Lap in designed treatments. There is a negative association between mRNA levels of NQO1 and IC50 values of beta-Lap but not NQO2. PMID- 29611026 TI - The spatiotemporal inhomogeneity of pollutant concentrations and its dependence on regional weather conditions in a coastal city of China. AB - Hourly data for sulfur dioxide (SO2), nitrogen oxides (NOx), and inhalable particulate matter (PM10) over a 33-month period from a network of air quality monitoring stations across Qingdao, a major coastal city in eastern China, along with surface and upper-air meteorological data, are used to characterize the spatiotemporal variability of these pollutants in the region and the role of meteorological conditions play in pollution episodes. Large differences in the concentrations of all three pollutants are found between densely populated or industrial areas and suburban commercial or residential or coastal tourist areas, but the differences are relatively small between older and newer parts of the residential-commercial areas and between old and newly developed industrial areas. Wavelet analyses revealed a strong seasonal cycle for all three pollutants, introseasonal variability with a periodicity depending on pollutant and location, and diurnal and a semi-diurnal variability with season-dependent amplitude and phase. Low wind speed is found to be the leading factor for pollution buildup in the region. These results may prove useful for urban planning and development and implementation of effective air pollution control strategies for other coastal regions with economic development similar to Qingdao. PMID- 29611027 TI - Prevalence and Prognostic Significance of Extramural Venous Invasion in Patients with Locally Advanced Esophageal Cancer. AB - BACKGROUND: Extramural venous invasion (EMVI) is a known adverse prognostic factor in patients with colorectal carcinoma. The prevalence and significance of EMVI in esophageal cancer (EC) patients is still unclear. METHODS: From a prospectively maintained database, we retrospectively reviewed the resection specimens of patients with pathologic locally advanced (pT3/T4/N0-3) EC who were treated with curative intent between 2000 and 2015. Patients with previous malignancies and gastroesophageal junction (type II/III) tumors were excluded. Included were 81 patients who underwent surgery alone and 37 patients who underwent neoadjuvant chemoradiotherapy (nCRT). EMVI was assessed on hematoxylin and eosin slides and confirmed or excluded by additional Elastica van Gieson staining. Survival was analyzed using a multivariable Cox regression. RESULTS: EMVI was present in 23.5% (n = 19) of patients in the surgery-alone group and 21.6% (n = 8) of patients in the nCRT group. The prevalence of EMVI after surgery alone was significantly high in squamous cell carcinomas and among tumors located in the mid-esophagus, as well as those with lymphovascular invasion (p < 0.05). After nCRT, the presence of EMVI was significantly high in tumors with lymphovascular and perineural tumor growth (p = 0.034). EMVI status was an independent adverse prognostic factor for disease-free survival [hazard ratio (HR) 7.0, 95% confidence interval (CI) 2.3-21.8; p =0.001] and overall survival (HR 6.5, 95% CI 2.2-19.1; p = 0.001) in the surgery-alone group for node-positive tumors. CONCLUSIONS: In this study of locally advanced > pT3/N0-3 EC patients, EMVI was present in 23.5% of patients in the surgery-alone group and in 21.6% of patients after nCRT. EMVI was an independent adverse prognostic factor in patients after surgery alone. PMID- 29611028 TI - Comparison of Immunohistochemistry and Direct Sequencing Methods for Identification of the BRAFV600E Mutation in Papillary Thyroid Carcinoma. AB - BACKGROUND: BRAFV600E mutation is the most common somatic variant in papillary thyroid carcinoma (PTC) and is associated with aggressive prognostic factors. The conventional detection method for BRAF mutations is polymerase chain reaction followed by Sanger sequencing. Recently, an immunohistochemistry (IHC) method using a BRAFV600E-specific antibody (VE1) has been developed and widely adopted in the clinics; however, there is a lack of evidence regarding the comparability of the IHC and Sanger sequencing methods. METHODS: Our institution began using the BRAFV600E IHC test in January 2013. We retrospectively analyzed 697 samples that were tested using both the IHC and sequencing methods, and evaluated their concordance. RESULTS: BRAF mutation was detected in 90.0% (627/697) of samples using IHC and 83.4% (581/697) of samples using direct sequencing. The diagnostic parameters of IHC compared with Sanger sequencing were as follows: 100% sensitivity (581/581), 60.3% specificity (70/116), 92.7% positive predictive value (581/627), and 100% negative predictive value (70/70). No false negative results were recorded using IHC. The overall concordance rate between the two methods was 93.4% (651/697). Discordant results were found in 46 samples (6.6%), 29 of which were from cases with small tumors (< 6 mm), 8 were from cases with low tumor cellularity, and 9 were specimens yielding low-quality DNA. CONCLUSIONS: IHC using the VE1 antibody is a reliable and highly sensitive method for detecting the BRAFV600E mutation in classic PTC. PMID- 29611029 TI - Randomized trial of proactive rapid genetic counseling versus usual care for newly diagnosed breast cancer patients. AB - PURPOSE: Breast cancer patients who carry BRCA1/BRCA2 gene mutations may consider bilateral mastectomy. Having bilateral mastectomy at the time of diagnosis not only reduces risk of a contralateral breast cancer, but can eliminate the need for radiation therapy and yield improved reconstruction options. However, most patients do not receive genetic counseling or testing at the time of their diagnosis. In this trial, we tested proactive rapid genetic counseling and testing (RGCT) in newly diagnosed breast cancer patients in order to facilitate pre-surgical genetic counseling and testing. METHODS: We recruited newly diagnosed breast cancer patients at increased risk for carrying a BRCA1/2 mutation. Of 379 eligible patients who completed a baseline survey, 330 agreed to randomization in a 2:1 ratio to RGCT (n = 220) versus UC (n = 108). Primary outcomes were genetic counseling and testing uptake and breast cancer surgical decisions. RESULTS: RGCT led to higher overall (83.8% vs. 54.6%; p < 0.0001) and pre-surgical (57.8% vs. 38.7%; p = 0.001) genetic counseling uptake compared to UC. Despite higher rates of genetic counseling, RGCT did not differ from UC in overall (54.1% vs. 49.1%, p > 0.10) or pre-surgical (30.6% vs. 27.4%, p > 0.10) receipt of genetic test results nor did they differ in uptake of bilateral mastectomy (26.6% vs. 21.8%, p > 0.10). CONCLUSIONS: Although RGCT yielded increased genetic counseling participation, this did not result in increased rates of pre-surgical genetic testing or impact surgical decisions. These data suggest that those patients most likely to opt for genetic testing at the time of diagnosis are being effectively identified by their surgeons. PMID- 29611030 TI - Exploring conformational states and helical packings in the P2X receptor transmembrane domain by molecular dynamics simulation. AB - The P2X receptor is a trimeric transmembrane protein that acts as an ATP-gated ion channel. Its transmembrane domain (TMD) contains only six helices and three of them, the M2 helices, line the ion conduction pathway. Here, using molecular dynamics simulation, I identify four conformational states of the TMD that are associated with four types of packing between M2 helices. Packing in the extracellular half of the M2 helix produces closed conformations, while packing in the intracellular half produces both open and closed conformations. State transition is observed and supports a mechanism where iris-like twisting of the M2 helices switches the location of helical packing between the extracellular and the intracellular halves of the helices. In addition, this twisting motion alters the position and orientation of residue side-chains relative to the pore and therefore influences the pore geometry and possibly ion permeation. Helical packing, on the other hand, may restrict the twisting motion and generate discrete conformational states. PMID- 29611032 TI - Thoracoabdominal aortic replacement in patients aged 50 and younger. AB - OBJECTIVE: Open repair of a thoracoabdominal aortic aneurysm (TAAA) has been regarded as one of the most invasive procedures in cardiovascular surgery. Conversely, endovascular technology currently enables the repair of the thoracoabdominal aorta, and this approach is less invasive. However, the long term durability of this method of endovascular repair remains unknown. This investigation retrospectively analyzed the long-term durability of thoracoabdominal aorta repair in patients aged 50 and younger. PATIENTS AND METHODS: Since 1995, 100 patients aged 50 and younger underwent thoracoabdominal aortic replacement at our institution. There were 63 males, and the average age was 38 +/- 7. Ninety-six had aortic dissection as an aortic pathology. Marfan syndrome was found in 61 patients, Loeys-Dietz in 10, Acta 2 mutations in 4, aortitis in 2, and Ehlers-Danlos syndrome in 1. There were 2 patients with a type I TAAA, 56 with a type II, 33 with a type III, and 9 with a type IV. RESULTS: There were 3 hospital deaths (3%), of which 2 were emergent cases. Spinal cord injury occurred in 1 patient (1%). Two patients (2%) had wound complications. Three patients suffered cerebral hemorrhage and 1 had an intramedullary infection, of which all were associated with cerebrospinal fluid drainage. The 3 year survival rate after the operation was 94%, that of 5 years was 94%, and that of 10 years was 91%. CONCLUSIONS: Results of thoracoabdominal aortic replacement in patients aged 50 and younger were favorable. While spinal cord complications were rare, cerebrospinal drainage revealed several complications in this series. Evolving endovascular repair needs to be compared with these results, especially in patients aged 50 and younger. PMID- 29611031 TI - Metabolomics Study of Immune Responses of New Zealand GreenshellTM Mussels (Perna canaliculus) Infected with Pathogenic Vibrio sp. AB - Vibrio coralliilyticus is a bacterial pathogen which can affect a range of marine organisms, such as corals, fish and shellfish, with sometimes devastating consequences. However, little is known about the mechanisms involved in the host pathogen interaction, especially within molluscan models. We applied gas chromatography-mass spectrometry (GC-MS)-based metabolomics to characterize the physiological responses in haemolymph of New Zealand GreenshellTM mussels (Perna canaliculus) injected with Vibrio sp. DO1 (V. coralliilyticus/neptunius-like isolate). Univariate data analyses of metabolite profiles in Vibrio-exposed mussels revealed significant changes in 22 metabolites at 6 h post-infection, compared to non-exposed mussels. Among them, 10 metabolites were up-regulated, while 12 metabolites were down-regulated in infected mussels. Multivariate analyses showed a clear distinction between infected and non-infected mussels. In addition, secondary pathway analyses indicated perturbations of the host innate immune system following infection, including oxidative stress, inflammation and disruption of the TCA cycle, change in amino acid metabolism and protein synthesis. These findings provide new insights into the pathogenic mechanisms of Vibrio infection of mussels and demonstrate our ability to detect detailed and rapid host responses from haemolymph samples using a metabolomics approach. PMID- 29611034 TI - Finding cancer driver mutations in the era of big data research. AB - In the last decade, the costs of genome sequencing have decreased considerably. The commencement of large-scale cancer sequencing projects has enabled cancer genomics to join the big data revolution. One of the challenges still facing cancer genomics research is determining which are the driver mutations in an individual cancer, as these contribute only a small subset of the overall mutation profile of a tumour. Focusing primarily on somatic single nucleotide mutations in this review, we consider both coding and non-coding driver mutations, and discuss how such mutations might be identified from cancer sequencing datasets. We describe some of the tools and database that are available for the annotation of somatic variants and the identification of cancer driver genes. We also address the use of genome-wide variation in mutation load to establish background mutation rates from which to identify driver mutations under positive selection. Finally, we describe the ways in which mutational signatures can act as clues for the identification of cancer drivers, as these mutations may cause, or arise from, certain mutational processes. By defining the molecular changes responsible for driving cancer development, new cancer treatment strategies may be developed or novel preventative measures proposed. PMID- 29611033 TI - Aqueous ionic liquids in comparison with standard co-solutes : Differences and common principles in their interaction with protein and DNA structures. AB - Ionic liquids (ILs) are versatile solvents for a broad range of biotechnological applications. Recent experimental and simulation results highlight the potential benefits of dilute ILs in aqueous solution (aqueous ILs) in order to modify protein and DNA structures systematically. In contrast to a limited number of standard co-solutes like urea, ectoine, trimethylamine-N-oxide (TMAO), or guanidinium chloride, the large amount of possible cation and anion combinations in aqueous ILs can be used to develop tailor-made stabilizers or destabilizers for specific purposes. In this review article, we highlight common principles and differences between aqueous ILs and standard co-solutes with a specific focus on their underlying macromolecular stabilization or destabilization behavior. In combination with statistical thermodynamics theories, we present an efficient framework, which is used to classify structure modification effects consistently. The crucial importance of enthalpic and entropic contributions to the free energy change upon IL-assisted macromolecular unfolding in combination with a complex destabilization mechanism is described in detail. A special focus is also set on aqueous IL-DNA interactions, for which experimental and simulation outcomes are summarized and discussed in the context of previous findings. PMID- 29611036 TI - Metastatic Hepatocellular Carcinoma into the Transverse Colon. PMID- 29611035 TI - ZNF804A Variation May Affect Hippocampal-Prefrontal Resting-State Functional Connectivity in Schizophrenic and Healthy Individuals. AB - The ZNF804A variant rs1344706 has consistently been associated with schizophrenia and plays a role in hippocampal-prefrontal functional connectivity during working memory. Whether the effect exists in the resting state and in patients with schizophrenia remains unclear. In this study, we investigated the ZNF804A polymorphism at rs1344706 in 92 schizophrenic patients and 99 healthy controls of Han Chinese descent, and used resting-state functional magnetic resonance imaging to explore the functional connectivity in the participants. We found a significant main effect of genotype on the resting-state functional connectivity (RSFC) between the hippocampus and the dorsolateral prefrontal cortex (DLPFC) in both schizophrenic patients and healthy controls. The homozygous ZNF804A rs1344706 genotype (AA) conferred a high risk of schizophrenia, and also exhibited significantly decreased resting functional coupling between the left hippocampus and right DLPFC (F(2,165) = 13.43, P < 0.001). The RSFC strength was also correlated with cognitive performance and the severity of psychosis in schizophrenia. The current findings identified the neural impact of the ZNF804A rs1344706 on hippocampal-prefrontal RSFC associated with schizophrenia. PMID- 29611037 TI - The Role of Matrix Composition in the Mechanical Behavior of Bone. AB - PURPOSE OF REVIEW: While thinning of the cortices or trabeculae weakens bone, age related changes in matrix composition also lower fracture resistance. This review summarizes how the organic matrix, mineral phase, and water compartments influence the mechanical behavior of bone, thereby identifying characteristics important to fracture risk. RECENT FINDINGS: In the synthesis of the organic matrix, tropocollagen experiences various post-translational modifications that facilitate a highly organized fibril of collagen I with a preferred orientation giving bone extensibility and several toughening mechanisms. Being a ceramic, mineral is brittle but increases the strength of bone as its content within the organic matrix increases. With time, hydroxyapatite-like crystals experience carbonate substitutions, the consequence of which remains to be understood. Water participates in hydrogen bonding with organic matrix and in electrostatic attractions with mineral phase, thereby providing stability to collagen-mineral interface and ductility to bone. Clinical tools sensitive to age- and disease related changes in matrix composition that the affect mechanical behavior of bone could potentially improve fracture risk assessment. PMID- 29611038 TI - Tumor necrosis factor gene polymorphisms are associated with systemic lupus erythematosus susceptibility or lupus nephritis in Mexican patients. AB - The TNF -238G/A (rs361525) and -308G/A (rs1800629) polymorphisms have consistently been associated with systemic lupus erythematosus (SLE) in several populations; however, these findings have not been verified in all populations. Here, we aimed to examine whether the TNF -238G/A, -308G/A, -376G/A (rs1800750), and -1031T/C (rs1799964) polymorphisms confer SLE or lupus nephritis (LN) susceptibility in a Mexican population. Our study included 442 patients with SLE and 495 controls. For genotyping, we used the TaqMan 5' allele discrimination assay. The TNF -238G/A and -1031T/C polymorphisms were associated with SLE susceptibility (odds ratio (OR) 2.1, p = 0.0005 and OR 1.4, p = 0.003, respectively). Gender stratification showed a strong association between TNF 238G/A and SLE in women (OR 2.2, p = 0.00006), while TNF -1031T/C had an OR of 1.5 (p = 0.007). With regard to the TNF -376G/A polymorphism, this also showed association with SLE susceptibility (OR 1.95, p = 0.036) and LN (OR 3.5, p = 0.01). In conclusion, our study provides the first demonstration of association between the TNF -376G/A polymorphism and SLE and LN susceptibility. In addition, our study is the second documenting an association of TNF -1031T/C with SLE susceptibility. We also observed a strong association between TNF -238G/A and SLE susceptibility. The TNF 308G/A polymorphism was not associated with SLE or LN. PMID- 29611039 TI - Analysis of computed tomography density of liver before and after amiodarone administration. AB - PURPOSE: To evaluate CT density of liver changes between before and after amiodarone administration. MATERIALS AND METHODS: Twenty-five patients underwent non-enhanced CT including the liver before and after amiodarone administration. We set regions of interest (ROIs) at liver S8, spleen, paraspinal muscle, and calculated average CT density in these ROIs, then compared CT density between liver and other organs. Statistical differences between CT density of liver and various ratios before and after administration were determined, along with correlations between cumulative dose of amiodarone and liver density after administration, density change of liver, and various ratios after administration. RESULTS: Liver density, liver-to-spleen ratio, and liver-to-paraspinal muscle ratio differed significantly between before and after amiodarone administration. No significant correlations were found between cumulative doses of amiodarone and any of liver density after administration, density change of liver, or various ratios after administration. CONCLUSION: CT density of liver after amiodarone administration was significantly higher than that before administration. No correlations were identified between cumulative dose of amiodarone and either liver density after administration or density change of liver. Amiodarone usage should be checked when radiologists identify high density of the liver on CT. PMID- 29611040 TI - Cloning and expression of a novel alpha-1,3-arabinofuranosidase from Penicillium oxalicum sp. 68. AB - The discovery and creation of biocatalysts for plant biomass conversion are essential for industrial demand and scientific research of the plant cell wall. alpha-1,2 and alpha-1,3-L-arabinofuranosidases are debranching enzymes that catalyzing hydrolytic release of alpha-L-arabinofuranosyl residues in plant cell wall. Gene database analyses shows that GH62 family only contains specific alpha L-arabinofuranosidases that play an important role in the degradation and structure of the plant cell wall. At present, there are only 22 enzymes in this group has been characterized. In this study, we cloned a novel alpha-1,3 arabinofuranosidase gene (poabf62a) belonging to glycoside hydrolase family 62 from Penicillium oxalicum sp. 68 and expressed it in Pichia pastoris. The molecular mass of recombinant PoAbf62A was estimated to be 32.9 kDa. Using p nitrophenyl-alpha-l-arabinofuranoside (pNPalphaAbf) as substrate, purified PoAbf62A exhibited an optimal pH of 4.5 and temperature of 35 degrees C. Results of methylation and 13C NMR analyses showed that PoAbf62A was exclusively alpha 1,3-arabinofuranosidase, specific for cleavage of alpha-1,3-arabinofuranosyl residues, and with the absence of activity towards alpha-1,2-arabinofuranose and alpha-1,5-arabinofuranose. Therefore, PoAbf62A exhibits high activity on sugar beet arabinan and wheat arabinoxylan, because their branched side chain are decorated with alpha-1,3-arabinofuranose. On the other hand, there is a lack of activity with linear-alpha-L-1,5-arabinan and xylan that only contained alpha-L 1,5-arabinofuranose or beta-1,4-xylose. The alpha-1,3-arabinofuranosidase activity identified here provides a new biocatalytic tool to degrade hemicellulose and analyze the structure of plant cell walls. PMID- 29611042 TI - Dysfunction of Mesenchymal Stem Cells Isolated from Metabolic Syndrome and Type 2 Diabetic Patients as Result of Oxidative Stress and Autophagy may Limit Their Potential Therapeutic Use. AB - Mesenchymal stem cells (MSC) have become a promising tool for therapeutic intervention. Their unique features, including self-renewal, multipotency and immunomodulatory properties draw the worldwide attention of researchers and physicians with respect to their application in disease treatment. However, the environment (so-called niche) from which MSCs are isolated may determine their usefulness. Many studies indicated the involvement of MSCs in ageing and disease. In this review, we have focused on how type 2 diabetes (T2D) and metabolic syndrome (MS) affect MSC properties, and thus limit their therapeutic potential. Herein, we mainly focus on apoptosis, autophagy and mitochondria deterioration processes that indirectly affect MSC fate. Based on the data presented, special attention should be paid when considering autologous MSC therapy in T2D or MS treatments, as their therapeutic potential may be restricted. PMID- 29611043 TI - The relationship between physician and cancer patient when initiating adjuvant treatment and its association with sociodemographic and clinical variables. AB - PURPOSE: The aim of this study was to analyze differences in physician and patient satisfaction in shared decision-making (SDM); patients' emotional distress, and coping in subjects with resected, non-metastatic cancer. METHODS: 602 patients from 14 hospitals in Spain were surveyed. Information was collected regarding physician and patient satisfaction with SDM, participants' emotional distress and coping, as well as patient sociodemographic and clinical characteristics by means of specific, validated questionnaires. RESULTS: Overall, 11% of physicians and 19% of patients were dissatisfied with SDM; 22% of patients presented hopelessness or anxious preoccupation as coping strategies, and 56% presented emotional distress. By gender, female patients showed a higher prevalence of dissatisfaction with SDM (23 vs 14%), anxious preoccupation (26 vs 17%), and emotional distress (63 vs 44%) than males. Hopelessness was more prevalent in individuals with stage III disease than those with stages I-II (28 vs 18%). CONCLUSION: Physicians must be mindful of the importance of emotional support and individual characteristics when communicating treatment options, benefits, and adverse effects of each alternative to oncological patients. PMID- 29611041 TI - Time of exposure to night work and carotid atherosclerosis: a structural equation modeling approach using baseline data from ELSA-Brasil. AB - PURPOSE: The study of cardiovascular diseases (CVD) associated with night work is difficult due to the long period required for conditions to manifest and the healthy-worker effect. Analyzing asymptomatic pre-clinical changes in the atherosclerotic process is a way to assess the pathways between exposure to night work and CVD. AIM: To evaluate the associations between night work and subclinical atherosclerosis measured by carotid intima-media thickness (CIMT) using baseline data from the Brazilian Longitudinal Study of Adult Health (ELSA Brasil). METHODS: We conducted cross-sectional analyses using baseline data (2008 2010) from 9785 civil servants, aged 35-74 years. The associations between time of exposure to night work and mean CIMT were examined using a structural equation model. RESULTS: The sample included 4259 men and 5526 women, mean age of 51.6 years. A total of 1778 (18.2%) individuals were exposed to night work (594 current and 1184 former night workers), and the mean years of night work exposed was 11.47 (SD = 9.45) years. On average, mean CIMT was 0.606 (SD = 0.130) mm. Among men, the increase in exposure to night work was significantly associated with an increase in BMI and CIMT. Among women, night work was not associated with increased CIMT. In relation to the indirect associations, results suggest a possible mediation by BMI, diabetes and hypertension on the association between the years of night work and mean CIMT only among men. CONCLUSION: Night work was associated with increased CIMT only among men. These findings add to the knowledge of the possible pathways that link night work and carotid atherosclerosis. Additionally, these results contribute to the recognition of work schedules as a public health problem that should be addressed by the medical community and policy makers. PMID- 29611044 TI - Long-term oncologic outcomes after laparoscopic versus open rectal cancer resection: a high-quality population-based analysis in a Southern German district. AB - BACKGROUND: An increasing number of rectal carcinoma resections in Germany and worldwide are performed laparoscopically. The recently published COLOR II trial demonstrated the oncologic safety of this surgical approach. It remains unclear whether these findings can be transferred to clinical practice. PATIENTS AND METHODS: This population-based retrospective cohort study aimed to evaluate 5 year overall, relative, disease-free, and local recurrence-free survival of rectal cancer patients treated by open surgery and laparoscopy. Data from a southern German region of 1.1 million inhabitants were collected by an official clinical cancer registry. All primary non-metastatic rectal adenocarcinoma cases with surgery between 2004 and 2013 were eligible for inclusion. To compare survival rates, Kaplan-Meier analyses, relative survival models, and multivariate Cox regression were applied; a sensitivity analysis assessed bias by exclusion. RESULTS: Finally, 1507 patients with a median follow-up time of 7.1 years were included. Of these patients, 28.4% underwent laparoscopic procedures, with an increasing rate over time. Patients with tumors of the upper or middle rectum, younger patients, and patients of specialized colorectal cancer centers were more likely to undergo laparoscopy. After 5 years, 80.4% of laparoscopy patients were still alive, compared to 68.6% in the open group (p < 0.001). Moreover, laparoscopy was associated with superior local recurrence-free survival rates. This advantage was also significant in multivariate analysis (HR 0.70, 95% CI 0.52-0.92). CONCLUSION: Laparoscopic rectal cancer surgery can be considered safe in daily clinical practice. This should be confirmed by future studies outside the setting of randomized trials. PMID- 29611045 TI - SAGES Mini Med School: inspiring high school students through exposure to the field of surgery. AB - OBJECTIVE: The SAGES Mini Med School (SMMS) was designed to expose high school students to the field of surgery through mentoring, knowledge transfer, and hands on experience with simulation. The objective of this paper is to profile the evolutionary development, performance metrics, and satisfaction queries of this innovative effort. METHODS: Sixty-one high school students, grades 9-12, took part in the (SMMS) program during the 2015 SAGES Annual Congress. The students completed a surgical skills lab session where they attempted tasks associated with the development of open surgical and laparoscopic skills. The lab included a warm-up with the validated Super Monkey Ball video game, Top Gun Pea Drop task, FLS Peg Transfer task, open knot tying station, and open instrument tie station. RESULTS: The following are the results of the surgical skills lab. For the Super Monkey Ball task, 60 students participated with an average score of 73.0 s (SD = 53.9; range 59.1-87.0; median = 74). Sixty students participated in the Surgeons Knot and Pea Drop tasks with average times of 26.6 s (SD = 19.3; range 21.7-31.6; median = 21.0) and 113.8 s (SD = 65.9; range 96.6-131.0; median = 101.0), respectively. Sixty students participated in the Instrument Tie and 56 students participated in the Peg Transfer stations with average times of 51.7 s (SD = 34.5; range 42.8-60.6; median = 39.5) and 173.1 s (SD = 25.0; range 166.4-179.8; median = 180.0), respectively. 51 (83.6%) agreed that the Mini Med School made them more likely to consider a career in medicine. When asked if the program made them more likely to consider a career in surgery 42 (68.8%) agreed. All 61 respondents (100%) said that they would recommend the program to others. CONCLUSIONS: The SMMS program showed that the students had an excellent aptitude for the performance of validated surgical subtasks with high satisfaction, and increased consideration of a career in medicine/surgery. Long-term studies are needed to evaluate the impact on workforce recruitment. PMID- 29611046 TI - Feasibility of adapting the fundamentals of laparoscopic surgery trainer box to endoscopic skills training tool. AB - BACKGROUND: The fundamentals of laparoscopic surgery (FLS) training box is a validated tool, already accessible to surgical trainees to hone their laparoscopic skills. We aim to investigate the feasibility of adapting the FLS box for the practice and assessment of endoscopic skills. This would allow for a highly available, reusable, low-cost, mechanical trainer. METHODS: The design and development process was based on a user-centered design, which is a combination of the design thinking method and cognitive task analysis. The process comprises four phases: empathy, cognitive, prototyping/adaptation, and end user testing. The underlying idea was to utilize as many of the existing components of FLS training to maintain simplicity and cost effectiveness while allowing for the practice of clinically relevant endoscopic skills. A sample size of 18 participants was calculated to be sufficient to detect performance differences between experts and trainees using a two tailed t test with alpha set at 0.05, standard deviation of 5.5, and a power of 80%. RESULTS: Adaptation to the FLS box included two fundamental attachments: a front panel with an insertion point for an endoscope and a shaft which provides additional support and limits movement of the scope. The panel also allows for mounting of retroflexion tasks. Six endoscopic tasks inspired by FLS were designed (two of which utilize existing FLS components). Pilot testing with 38 participants showed high user's satisfaction and demonstrated that the trainer was robust and reliable. Task performance times was able to discriminate between trainees and experts for all six tasks. CONCLUSIONS: A mechanical, reusable, low-cost adaptation of the FLS training box for endoscopic skills is feasible and has high user satisfaction. Preliminary testing shows that the simulator is able to discriminate between trainees and experts. Following further validation, this adaptation may act as a supplement to the FES program. PMID- 29611047 TI - Economic Studies on Non-Communicable Diseases and Injuries in India: A Systematic Review. AB - BACKGROUND: The burden from non-communicable diseases and injuries (NCDI) in India is increasing rapidly. With low public sector investment in the health sector generally, and a high financial burden on households for treatment, it is important that economic evidence is used to set priorities in the context of NCDI. OBJECTIVE: Our objective was to understand the extent to which economic analysis has been used in India to (1) analyze the impact of NCDI and (2) evaluate prevention and treatment interventions. Specifically, this analysis focused on the type of economic analysis used, disease categories, funding patterns, authorship, and author characteristics. METHODS: We conducted a systematic review based on economic keywords to identify studies on NCDI in India published in English between January 2006 and November 2016. In all, 96 studies were included in the review. The analysis used descriptive statistics, including frequencies and percentages. RESULTS: A majority of the studies were economic impact studies, followed by economic evaluation studies, especially cost effectiveness analysis. In the costing/partial economic evaluation category, most were cost-description and cost-analysis studies. Under the economic impact/economic burden category, most studies investigated out-of-pocket spending. The studies were mostly on cardiovascular disease, diabetes, and neoplasms. Slightly over half of the studies were funded, with funding coming mainly from outside of India. Half of the studies were led by domestic authors. In most of the studies, the lead author was a clinician or a public health professional; however, most of the economist-led studies were by authors from outside India. CONCLUSIONS: The results indicate the lack of engagement of economists generally and health economists in particular in research on NCDI in India. Demand from health policy makers for evidence-based decision making appears to be lacking, which in turn solidifies the divergence between economics and health policy, and highlights the need to prioritize scarce resources based on evidence regarding what works. Capacity building in health economics needs focus, and the government's support in this is recommended. PMID- 29611048 TI - Use of speckle tracking in the evaluation of late subclinical myocardial damage in survivors of childhood acute leukaemia. AB - Heart disease is the leading cause of non-cancer death in childhood cancer survivors. to determine the prevalence of subclinical cardiac dysfunction using speckle tracking and compare its results with those obtained by classical methods of assessing left ventricular function and its relationship with different factors to identify the population at higher risk. Echocardiographic assessment of left ventricular function included ejection fraction, tissue Doppler, longitudinal/circumferential strains and biochemical parameters (troponin-T and Pro-BNP) in a cohort of 57 survivors of childhood acute leukaemia with at least 10 years since diagnosis. Ventricular dysfunction was found in 5.2% of patients in M-mode (ejection fraction-EF < 53% with a reduction in the EF >= 10%) and in 7% of patients with Simpson's method, compared with 21.05 and 8.8% with suboptimal global longitudinal strain (GLS) and global circumferential strain, respectively. The GLS alteration was significantly correlated with lower values of left ventricular systolic function and was associated with high tumour risk (odds ratio [OR] 13.8), cumulative doses of anthracyclines >= 250 mg/m2 (OR 7.6) and radiotherapy (OR 7.19). Biomarkers were not useful for the diagnosis of subclinical cardiomyopathy. Good reproducibility was obtained, with an intraobserver correlation of 93.6% and an interobserver correlation of 89.2% in the GLS. The alteration of the GLS was more prevalent than the alteration in the EF and was associated with the treatment received and high tumour risk. strain imaging seems to be a powerful tool to identify an increased number of survivor with an early myocardial injury. PMID- 29611049 TI - Pembrolizumab for primary malignant melanoma of the central nervous system. PMID- 29611050 TI - Correction to: Radioiodine ablation with 1,850 MBq in association with rhTSH in patients with differentiated thyroid cancer. AB - Unfortunately, the fourth author's middle name was missed out in the original publication of this article. The complete correct name should read as follows. PMID- 29611051 TI - IgA Vasculitis: Genetics and Clinical and Therapeutic Management. AB - PURPOSE OF REVIEW: The purpose of the study is to perform an update on the current knowledge on genetics, clinical manifestations, and therapy in immunoglobulin A vasculitis (IgAV) (Henoch-Schonlein purpura). RECENT FINDINGS: A strong genetic predisposition in individuals with IgAV was confirmed. It was due to the association with the HLA class II region that in people of European background is mainly related to HLA-DRB1*01 allele. Recent reports support the claim that kidney disease is more common in adults than in children with IgAV. The clinical spectrum and outcome of adults with IgAV depends on the age of onset. Relapses are not uncommon in IgAV. The presence of renal impairment or proteinuria excretion exceeding 1 g/24 h at the time of disease diagnosis and the degree of renal damage on the kidney biopsy are the best predictors of end-stage renal failure in adults with IgAV. The levels of urinary IgA at the onset of the disease may predict a poor renal outcome. The use of prednisone does not seem to prevent persistent kidney disease in children with IgAV. No additional benefit of adding cyclophosphamide to glucocorticoids in adults with IgAV was found. Rituximab seems to be a promising therapy in the management of adults with IgAV. In this overview, we focus on the genetics, clinical manifestations, and therapy of IgA vasculitis, emphasizing the main differences in the clinical expression of the disease between children and adults. PMID- 29611052 TI - Gastric cancer in India: epidemiology and standard of treatment. AB - India has a low incidence of gastric cancer. It ranks among the top five most common cancers. Regional diversity of incidence is of importance. It is the second most common cause of cancer related deaths among Indian men and women in the age between 15 and 44. Helicobacter pylori carcinogenesis is low in India. Advanced stage at presentation is a cause of concern. Basic and clinical research in India reveals a globally comparable standard of care and outcome. The large population, sociodemographic profile and challenges in health expenditure, however, remain a major challenge for health care policy managers. The newer formation of National Cancer Grid, integration of national databases and the creation of social identification database Aadhaar by The Unique Identification Authority of India are set to enhance the health care provision and optimal outcome. PMID- 29611053 TI - Extra-osseous Ewing sarcoma of the pancreas: case report with radiologic, pathologic, and molecular correlation, and brief review of the literature. AB - In 2002, due to extensive histomorphologic, immunohistochemical, and cytogenetic similarities, the World Health Organization unified undifferentiated small round blue cell neoplasms of soft tissue and bone (previously segregated as Ewing sarcoma or Primitive Neuroectodermal tumor) into one category: Ewing family of tumors (EFT). Osseous EFT are more common, and while extra-osseous EFT can occur anywhere in the body, those of the pancreas are rare and likely to be seen in the second decade of life in the head of the pancreas. We report the case of a 39 year-old Caucasian male with a large heterogeneously enhancing mass in the pancreatic body. Pathologic examination showed a malignant round blue cell tumor diffusely positive for CD99, chromogranin, and synaptophysin; Ki-67 proliferation index was greater than 80%. FISH showed EWSR1 gene rearrangement in 90% of cells and Archer FusionPlexTM-targeted RNA sequencing analysis identified the EWSR1 FLI1 fusion transcript. The diagnosis of EFT of the pancreas was rendered. Unfortunately, the patient had minimal improvement and was transitioned to oral pain medications to continue care at a different institution. PMID- 29611054 TI - Molecular evidence of JAK2 p.V617F mutated pure erythroid leukemia arising from polycythemia vera. PMID- 29611055 TI - The more the micropapillary pattern in stage I lung adenocarcinoma, the worse the prognosis-a retrospective study on digitalized slides. AB - Although the majority of lung adenocarcinomas show mixed pattern, only the predominant component is taken into account according to the novel classification. We evaluated the proportion of different patterns and their impact on overall survival (OS) and disease-free survival (DFS). Patterns were recorded according to predominance and their proportions were rated and calculated by objective area measuring on digitalized, annotated slides of resected stage I lung adenocarcinomas. Spearman's rank correlation, Kaplan-Meier models and the log rank test were used for statistical evaluation. Two hundred forty-three stage I adenocarcinoma were included. Lepidic pattern is more frequent in tumours without recurrence (20 vs. 8%), and lepidic predominant tumours have favourable prognosis (OS 90.5%, DFS 89.4%), but proportions above 25% are not associated with improving outcome. Solid and micropapillary patterns are more frequent in patients with recurrence (48 vs. 5% and 13 vs. 4%) and predominance of each one is associated with unfavourable prognosis (OS 64.1%, DFS 56.3% and OS 28.1%, DFS 28.1%, respectively). Above 25%, a growing proportion of solid or micropapillary pattern is not associated with worsening prognosis. In contrast, tumours having micropapillary pattern as secondly predominant form a different intermediate group (OS 51.1%, DFS 57.8%). Our study was based on measured area of each growth pattern on all available slides digitalized. This is the most precise way of determining the size of each component from the material available. We propose using predominant and secondly predominant patterns for prognostic purposes, particularly in tumours having solid or micropapillary patterns. PMID- 29611056 TI - Cis-regulated additively expressed genes play a fundamental role in the formation of triploid loquat (Eriobotrya japonica (Thunb.) Lindl.) Heterosis. AB - Triploid loquat (Eriobotrya japonica (Thunb.) Lindl.) has greater vigor than their respective diploid and tetraploid parents, but the molecular basis of this triploid heterosis remains unclear. Recent studies have suggested that DNA methylation is involved in heterosis, which is a recognized method of suppressing gene expression. However, our previous studies revealed a trend of increased DNA methylation in triploid loquat hybrids compared to their parents. To elucidate the mechanism of triploid loquat heterosis, we investigated the levels and regulation of relative gene expression between hybrid and parental lines using RNA-Seq technology. We found that gene expression in the hybrid lines was down regulated and gene expression analysis revealed that approximately 94.56 and 86.97% were expressed additively in triploid-A and triploid-B, respectively. Analyses of the allele-specific gene expression in the hybrids revealed significantly more Longquan-1 alleles were preferentially expressed in the two hybrid lines. Further analysis of cis- and trans-regulatory effects showed that gene expression variation between parental alleles is largely attributable to cis regulatory variation in triploid loquat and analyses of genes belonging to cis regulatory variation showed that 88-90% of cis genes contributed to an additive expression pattern. Taken together, our results suggest that gene expression variation in triploid loquat fundamentally cis-regulated may play a dominant role in triploid loquat heterosis. PMID- 29611057 TI - A discrepancy between prothrombin time and Normotest (Hepaplastintest) results is useful for diagnosis of acquired factor V inhibitors. AB - Acquired coagulation factor inhibitors are rare. Among them, coagulation factor V (FV) inhibitor is particularly uncommon and presents with variable clinical manifestations. Certain acquired FV inhibitor patients have only mild bleeding or, in select cases, no symptoms at all, leading to spontaneous recovery. Others have life-threatening bleeding that requires medical attention. Thus, a prompt decision regarding diagnosis and clinical intervention is crucial for such patients. In five acquired FV inhibitor cases treated in our facility, each patient had a malignancy as an underlying disease and all unexpectedly showed prolongation of both prothrombin time (PT) and activated partial thromboplastin time (APTT). They all also displayed a discrepancy between PT and Normotest (Hepaplastintest, HPT) results. All but one patient experienced no bleeding at the time of diagnosis and achieved spontaneous recovery in 1-3 weeks. The patient with bleeding symptoms received plasma exchanges and a platelet transfusion. Useful markers in diagnosing the presence of an acquired FV inhibitor were a sudden prolongation of PT and APTT, and a discrepancy between the PT/APTT and HPT assays. Spontaneous recovery can be expected for patients with only minor bleeding. PMID- 29611058 TI - Anti-inflammatory intravenous immunoglobulin (IVIg) suppresses homeostatic proliferation of B cells. AB - An intravenous injection of plasma-derived immunoglobulins is used for the treatment of severe infectious and autoimmune disorders. Despite of its clinical efficacy, precise mechanisms by which intravenous immunoglobulin (IVIg) suppresses proinflammatory immune response are still enigmatic. Here, we provide in vitro evidence that IVIg inhibits homeostatic proliferation of B cells accompanied by induction of their cell aggregation. The IVIg-driven suppression of B cell proliferation and induction of cell aggregation are both unaffected by treatment with a neutralizing antibody against low-affinity Fc receptors for IgG (CD16/FcgammaRIII and CD32/FcgammaRII), known cell surface ligands for IVIg. Our observations propose a new immunosuppressive action of IVIg, which directly acts on steady-state B cells to suppress their homeostatic expansion. PMID- 29611059 TI - New Developments in the Genetics of Inclusion Body Myositis. AB - PURPOSE OF REVIEW: Our goal is to review the recent literature pertaining to the genetics of sporadic inclusion body myositis (IBM). RECENT FINDINGS: In a study of 252 IBM patients, the class II MHC allele HLA-DRB1*03:01 showed the most significant association with IBM, and that risk could be largely attributed to amino acids within the peptide-binding pocket. Candidate gene sequencing identified rare missense variants in proteins regulating protein homeostasis including VCP and SQSTM1. An unbiased approach employing exome sequencing of genes encoding rimmed vacuole proteins identified FYCO1 variants in IBM. Ongoing GWAS approaches may shed new light on genetic risk factors for IBM. Many variants have been reported at an increased frequency in IBM in small studies; however, only HLA association has shown genome-wide significance. Future studies are needed to validate variants in larger cohorts and to understand the molecular roles these risk factors play in IBM. PMID- 29611060 TI - Targeted Agents in Cervical Cancer: Beyond Bevacizumab. AB - Cervical cancer constitutes a leading cause of morbidity and cancer deaths in women throughout the world. Approximately two thirds of the patients are diagnosed with locally advanced cervical cancer, showing disappointing survival rates despite correct multidisciplinary management. Metastatic disease implies a poor prognosis itself since diagnosis. Platinum-based chemotherapy has been the backbone treatment of metastatic cervical cancer for years with no major outstanding improvements on survival. The addition of new molecules, such as antiangiogenic agents, dramatically changed the treatment of this disease. Bevacizumab, an antiangiogenic agent that targets vascular endothelial growth factor 2 (VEGF-2), added to standard chemotherapy in cervical cancer showed significant improvement on survival; therefore, the combination of carboplatin, paclitaxel, and bevacizumab is currently the standard frontline treatment in cervical cancer. Other antiangiogenic agents have been tested in this disease with no further development nor approvals. New compounds are currently being under development with promising results in this disease as well as a number of new strategies that could potentially fulfill the unmet need of establishing effective therapeutic approaches in cervical cancer. PMID- 29611061 TI - Enhancing Initial Parental Engagement in Interventions for Parents of Young Children: A Systematic Review of Experimental Studies. AB - Low rates of participation in parenting interventions may undermine their effectiveness. Although a wide range of strategies to engage parents in interventions are described in the literature, little is known about which engagement strategies are most effective in enhancing parental engagement. This systematic review explores effective engagement strategies to encourage initial parental engagement (recruitment, enrolment, and first attendance) in parenting interventions for parents of children aged 2-8 years old. This review was conducted based on the guidelines of the Cochrane Handbook for Systematic Reviews of Interventions (Higgins and Green 2011) and the Preferred Reporting Items for Systematic Review and Meta-Analysis (Moher et al. 2009). Electronic systematic searches from January 1996 to August 2017 were conducted in PsycINFO, Scopus, ProQuest Social Sciences Journals, CINAHL, and PubMed databases. Eight studies met the inclusion criteria representing 1952 parents from four different countries. Of the engagement strategies tested in included studies (monetary incentive, setting, testimonial, advertisement, and engagement package), three strategies (advertisement, incentive, and engagement package) showed a significant effect on a stage of engagement, but none across stages. The low methodological quality of the selected studies limits their generalisability and thus provides limited evidence regarding effective engagement strategies to increase recruitment, enrolment, and first attendance rates in parenting interventions. There is a need for further, more methodologically rigorous, research evidence regarding how to engage parents more effectively in the early stages of parenting interventions. PMID- 29611063 TI - Physical properties of hydrogel wound dressing and its use in low-level laser therapy (LLLT). AB - Hydrogel dressings are routinely used in the treatment of superficial skin wounds. Due to their excellent transparency, we decided to evaluate their usefulness in laser-based medical procedures. We focused on assessing selected physical properties of HydroAid hydrogel wound dressing, used for low-level laser therapy (LLLT) aka laser biostimulation procedures. For the two wavelengths of 660 and 808 nm used in the biostimulation laser POLARIS 2, a dressing transmittance of 92 and 98%, respectively, was determined. Using a FLIR i7 thermal imaging camera, the changes in temperature distribution across the surface of the dressing were assessed, during a 3-h period following its unpacking and placing on the skin of a patient or leaving it at the ambient temperature. The results of the thermal imaging, as well as temperature measurements using a digital thermometer, showed that the cooling properties of a hydrogel dressing were maintained throughout the entire experiment and that it was capable to keep the temperature at least 5 degrees below the skin/ambient (room) temperature. During the 6-h observation using the holographic microscope, which provided indirect insight into the processes occurring within the hydrogel, only minimum topographical changes (observable at a micrometre scale) were recorded, although dressing thickness and its flexibility decreased significantly with time. Additionally, the possibility to regenerate the hydrogel dressing by treating it with distilled water or a physiological salt solution was tested. PMID- 29611062 TI - Psychological Treatments for Mental Disorders in Children and Adolescents: A Review of the Evidence of Leading International Organizations. AB - In recent decades, the evidence on psychological treatments for children and adolescents has increased considerably. Several organizations have proposed different criteria to evaluate the evidence of psychological treatment in this age group. The aim of this study was to analyze evidence-based treatments drawn from RCTs, reviews, meta-analyses, guides and lists provided by four leading international organizations. The institutions reviewed were the National Institute for Health and Care Excellence, the Society of Clinical Child and Adolescent Psychology (Division 53) of the American Psychological Association, Cochrane Collaboration and the Australian Psychological Society in relation to mental disorders in children and adolescents. A total of 137 treatments were analyzed for 17 mental disorders and compared to determine the level of agreement among the organizations. The results indicate that, in most cases, there is little agreement among organizations and that there are several discrepancies within certain disorders. These results require reflection on the meaning attributed to evidence-based treatments with regard to psychological treatments in children and adolescents. The possible reasons for these differences could be explained by a combination of different issues: the procedures or committees may be biased, different studies were reviewed, different criteria are used by the organizations or the reviews of existing evidence were conducted in different time periods. PMID- 29611064 TI - Comparative effect of photobiomodulation associated with dexamethasone after sciatic nerve injury model. AB - To analyze the effect of photobiomodulation and dexamethasone on nerve regeneration after a sciatic nerve crushing model. Twenty-six Swiss mice were divided into the following groups: naive; sham; injured, low-level laser therapy (LLLT) (660 nm, 10 J/cm2, 0.6 J, 16.8 J total energy emitted during the 28 days of radiation, 20 s, for 28 days); dexamethasone (Dex) (local injection of 2 mg/kg for 10 consecutive days); and LLLT group associated with Dex (LLLT/Dex), with the same parameters of the other groups. For nerve injury, a portable adjustable pinch was used. The animals were evaluated using the Sciatic Functional Index (SFI) and Sciatic Static Index (SSI). The results obtained were evaluated with Image JTM and KinoveaTM. Data and images were obtained at baseline and after 7, 14, 21, and 28 days after surgery. The evaluation of hyperalgesia, using Hargreaves, and behavior through the open field was also performed. In functional and static analysis, all groups presented significant differences when compared to the injured group. In the analysis of the SSI results, the group treated with both LLLT and dexamethasone was more effective in improving the values of this parameter, and in the SFI, the laser-treated group obtained better results. In the evaluation through the open field and the Hargreaves, there was no difference. The application of LLLT and dexamethasone was effective in nerve regeneration according to the results and was more effective when LLLT was associated with dexamethasone than in LLLT alone for the SSI. PMID- 29611066 TI - Application of wavelet analysis to detect dysfunction in cerebral blood flow autoregulation during experimental hyperhomocysteinaemia. AB - The purpose of the present study was to investigate the use of laser Doppler flowmetry (LDF) signals coupled with spectral wavelet analysis to detect endothelial link dysfunction in the autoregulation of cerebral blood flow in the setting of hyperhomocysteinaemia (HHcy). Fifty-one rats were assigned to three groups (intact, control, and HHcy) according to the results of biochemical assays of homocysteine level in blood plasma. LDF signals on the rat brain were recorded by LAKK-02 device to measure the microcirculatory blood flow. The laser operating wavelength and output power density were1064 nm and 0.051 W/mm2, respectively. A Morlet mother wavelet transform was applied to the measured 8-min LDF signals, and periodic oscillations with five frequency intervals were identified (0.01 0.04 Hz, 0.04-0.15 Hz, 0.15-0.4 Hz, 0.4-2 Hz, and 2-5 Hz) corresponding to endothelial, neurogenic, myogenic, respiratory, and cardiac origins, respectively. In initial state, the amplitude of the oscillations decreased by 38% (P < 0.05) in the endothelial range in HHcy rats than in control rats. Cerebral autoregulation was challenged by hemorrhagic hypotension. The lower limit of autoregulation raised in a rat model of chronic HHcy (71.5 +/- 0.7 mmHg in HHcy vs. 62.3 +/- 0.5 mmHg in control). The data obtained indicate that the laser Doppler method and wavelet analysis may be successfully applied to detect the dysfunction of the endothelial link in cerebral vessel tone and to reveal the pathological shift of lower limit of autoregulation. PMID- 29611065 TI - ROS-induced autophagy reduces B16F10 melanoma cell proliferative activity. AB - Cancer is a pathology characterized by increased cell progression and/or reduced programmed cell death. Melanoma shows a rapid increase in cell progression and its resistance to chemotherapy is associated with uncontrolled apoptosis and to mechanisms that increase the flow of the drug out of the cell. The objective of this study was to evaluate the effects of photodynamic therapy (PDT) on the cell proliferation and cellular alterations in B16F10 murine melanoma. For that, four experimental groups were evaluated: the control group; laser group (y = 660 etam, 40 mW, 2.4 J/cm2); photosensitizer group (solution containing methylene blue and toluidine blue 1:1-12.5 MUg/mL); PDT group. The incubation time was 30 min. Fluorescence microscopy assays were performed without fixation with the DAPI, monodansylcadaverine (MDC), and dihydroethidium (DHE) probes. Cell proliferation was also determined at 24-h time. The tests were performed in triplicate and the statistical test used was ANOVA with Tukey post-test. The results demonstrate that the plasma membrane of the cells of all the experimental groups remained intact, ROS production and autophagy significantly increased (p < 0.0005 and p < 0.0071, respectively) only in the PDT group. The cell proliferation essay showed a reduction of 74.2% on the PDT group in relation to the control group. The present study demonstrated that oxidative stress promoted by photodynamic therapy may induce autophagy and consequently reduce cell proliferation in B16F10 melanoma. PMID- 29611067 TI - ReToAd: simple method for the rapid replacement of promoters to improve protein production. AB - OBJECTIVE: To develop a method for fast replacement of promoters to improve protein production. RESULTS: A method (entitled retreat to advance or "ReToAd"), which includes a deleting PCR and a touchdown PCR, was validated by replacing seven IPTG-inducible promoters with enhanced green fluorescent protein (eGFP). The seven promoters were fully recovered by sequencing only 30 clones. The activity of E. coli harboring omega-transaminase (omega-TA) was increased from 112 U/mg cells (T7 promoter) to 147 U/mg cells (Trc promoter) by combining ReToAd and screening experiments. After screening a library comprising glutamate dehydrogenase (GDH) expressed by different promoters, the activity of E. coli cell harboring Trc-promoter-expressed GDH was ~31-fold higher than that of T7 promoter-expressed GDH. CONCLUSIONS: The "ReToAd" for in situ rapid replacement of promoters was developed and optimized, and one round of "ReToAd" can be completed within 3 days. PMID- 29611068 TI - Global budgets in Maryland: early evidence on revenues, expenses, and margins in regulated and unregulated services. AB - Maryland implemented one of the most aggressive payment innovations the nation has seen in several decades when it introduced global budgets in all its acute care hospitals in 2014. Prior to this, a pilot program, total patient revenue (TPR), was established for 8 rural hospitals in 2010. Using financial hospital report data from the Health Services Cost Review Commission from 2007 to 2013, we examined the hospitals' financial results including revenue, costs, and profit/loss margins to explore the impact of the adoption of the TPR pilot global budget program relative to the remaining hospitals in the state. We analyze financial results for both regulated (included in the global budget and subject to rate-setting) and unregulated services in order to capture a holistic image of the hospitals' actual revenue, cost and margin structures. Common size and difference-in-differences analyses of the data suggest that regulated profit ratios for treatment hospitals increased (from 5% in 2007 to 8% in 2013) and regulated expense-to-gross patient revenue ratios decreased (75% in 2007 and 68% in 2013) relative to the controls. Simultaneously, the profit margins for treatment hospitals' unregulated services decreased (- 12% in 2007 and - 17% in 2013), which reduced the overall margin significantly. This analysis therefore indicates cost shifting and less profit gain from the program than identified by solely focusing on the regulated margins. PMID- 29611069 TI - Influence of the erineum strain of Colomerus vitis (Acari: Eriophyidae) on grape (Vitis vinifera) defense mechanisms. AB - Grape (Vitis vinifera) is commonly affected by the erineum strain of Colomerus vitis (GEM) in Iran and the susceptibility of grape cultivars to GEM is poorly understood. In order to evaluate the impact of GEM on grape and its defense mechanisms against the mite, an exploratory study was carried out on 19 cultivars (18 Iranian and the non-native Muscat Gordo). The differential susceptibility of cultivars to GEM was compared on the basis of the area of leaf damage induced by GEM. The cultivars White Thompson seedless of Bovanat, Atabaki Zarghan, Koladari Ghoochan and Sahebi Uroomie were less susceptible to GEM, whereas Ghalati Dodaj, Rishbaba, Muscat Gordo and Neyshaboori Birjand appeared to be the most affected by the mite. In a no-choice setup, plants of selected cultivars of these two groups were infested by GEM and assayed for 10 biomarkers usually related to plant stress mechanisms against plant feeders: the activity of defense enzymes peroxidase (POX), polyphenol oxidase (PPO), superoxide dismutase (SOD), phenylalanine ammonia-lyase (PAL), catalase (CAT), the amount of total polyphenolics, total flavonoids, total soluble carbohydrates, hydrogen peroxide (H2O2), and malondialdehyde (MDA) expressing lipid peroxidation. The biomarkers were assessed in grape leaves 7 days before releasing the mites, as well as 7, 14 and 28 days after infestation (DAI). The activity of the enzymes and the amount of the compounds usually increased in percentage after mite infestation. A significant negative correlation was found between the area of leaf damage and PPO, POX, SOD, MDA and H2O2 for all sampling dates. The area of leaf damage showed a significant positive correlation with total soluble carbohydrates at 28 DAI, and significant negative correlations with CAT (at 14 and 28 DAI), PAL and total flavonoids (at 7 DAI). No correlation was observed between area of leaf damage and total polyphenolics. The biomarkers PPO, SOD, CAT activity and H2O2 provided the best explanation for the response of grape cultivars to GEM infestation. PMID- 29611070 TI - Pathogenic differences of the entomopathogenic fungus Isaria cateniannulata to the spider mite Tetranychus urticae (Trombidiformes: Tetranychidae) and its predator Euseius nicholsi (Mesostigmata: Phytoseiidae). AB - Isaria cateniannulata and Euseius nicholsi are two important biological control agents currently being used in many areas of China to control a variety of pests. In order to determine the possibility of a concomitant application with the two agents in a biocontrol program involving the two-spotted spider mite, Tetranychus urticae, we quantified the pathogenicity of a strain of I. cateniannulata (08XS 1) against females of both T. urticae and E. nicholsi. We observed the infection process using scanning electron microscopy and fluorescence microscopy to distinguish differences in fungal performance. The female mites were infected by I. cateniannulata at 2 * 107 conidia/ml. The mortality of T. urticae was 100% when treated with submerged conidia and 92% when treated with aerial conidia (spray), and that of E. nicholsi was 4.2 and 6.7%, correspondingly. Following infection with aerial or submerged conidia, mated E. nicholsi females displayed no significant differences between treatments and control, indicating the fungus had no obvious effect on their vitality and fertility. This demonstrates that I. cateniannulata is safe to E. nicholsi when used to control T. urticae. The two types of propagules of I. cateniannulata are readily produced by common culture, and the submerged conidia, because of their substantially higher mortality, are preferable to the aerial conidia. Our results indicate that I. cateniannulata and E. nicholsi are viable candidates to be concomitantly applied in the biocontrol programs of T. urticae. PMID- 29611071 TI - Study of defense-related gene expression in grapevine infested by Colomerus vitis (Acari: Eriophyidae). AB - Real-time quantitative polymerase chain reaction was used to study the expression of some marker genes involved in the interaction between grape (Vitis vinifera L.) and the erineum mite Colomerus vitis Pagenstecher (Acari: Eriophyidae). Potted vines of cultivars Atabaki (resistant to C. vitis), Ghalati (susceptible to C. vitis) and Muscat Gordo (moderately resistant to C. vitis) were infested at the six-leaf stage. The expression of protease inhibitor (PIN), beta-1,3 glucanase (GLU), polygalacturonase inhibitor (PGIP), Vitis vinifera proline-rich protein 1 (PRP1), stilbene synthase (STS), and lipoxygenase (LOX) genes was assessed on young leaves collected 96, 120 and 144 h after mite infestation (hami). As a control, non-infested leaves collected 24 h before mite infestations were used. Differences were detected in expression of the selected genes during the C. vitis-grapevine interaction. The resistant cultivar Atabaki increased the expression of LOX, STS, GLU, PGIP and PRP1 genes during the first 120 hami. On the contrary, in the susceptible Ghalati, all selected genes showed an expression level similar or lower than non-infested leaves. Muscat Gordo increased the expression of all selected genes in comparison with non-infested leaves, but it was lower than in Atabaki. Significant transcript accumulation of PIN gene was detected for Muscat Gordo whereas it was slightly up-regulated in Ghalati and Atabaki. LOX, STS, PIN, GLU, PGIP and PRP1 genes were clearly expressed in response to C. vitis infestation. We therefore infer that expression of PGIP, PIN and PRP1 genes could represent a defense strategy against C. vitis infestations in grapevine leaves. PMID- 29611072 TI - Differential Pheromone Sampling of the Gland of Female Heliothis Virescens Moths Reveals Glandular Differences in Composition and Quantity. AB - By differentially sampling the pheromone gland of females of the moth Heliothis virescens, we explored differences in pheromone on the surface, or outer distal layer(s) of the gland, and that located more proximally. For this, we used two sampling approaches, (i) a solid phase microextraction fiber rub followed by solvent extraction of residual pheromone (SPME rub/extract), and (ii) rapid solvent rinsing followed by solvent extraction of residual pheromone (rinse/extract). The SPME rub showed differences in component ratio between the dorsal and ventral gland surfaces. The rinse sampled a greater amount of pheromone than the SPME rub, sampling the whole gland surface as well as likely deeper into the gland. Compared to the other samplings, pheromone in the rinse was depleted in the minor component; consequently, the corresponding residual extract was highly enriched in the minor component. Further rinses of the gland yielded only small amounts of pheromone, with a similar component ratio as the first rinse, suggesting that the residual pheromone was less accessible and required extraction in solvent to be liberated. Sampling over the photoperiod showed that the more volatile minor component was depleted (relative to the major component) on the surface/outer cuticle over the period when females called. Together, these data suggest that the pheromone is stored, at least in part, on and in the gland cuticle and that distinct pools may be transported to different topographic regions. Females fed with a stable isotope tracer, incorporated label into pheromone in the gland very rapidly, with the labeled pheromone appearing on the gland surface ca. 1 min later. PMID- 29611073 TI - The Scent of the Fly. AB - (Z)-4-undecenal (Z4-11Al) is the volatile pheromone produced by females of the vinegar fly Drosophila melanogaster. Female flies emit Z4-11Al for species specific communication and mate-finding. A sensory panel finds that synthetic Z4 11Al has a characteristic flavour, which can be perceived even at the small amounts produced by a single female fly. Since only females produce Z4-11Al, and not males, we can reliably distinguish between single D. melanogaster males and females, according to their scent. Females release Z4-11Al at 2.4 ng/h and we readily sense 1 ng synthetic Z4-11Al in a glass of wine (0.03 nmol/L), while a tenfold concentration is perceived as a loud off-flavour. This corroborates the observation that a glass of wine is spoilt by a single D. melanogaster fly falling into it, which we here show is caused by Z4-11Al. The biological role of Z4-11Al or structurally related aldehydes in humans and the basis for this semiochemical convergence remains yet unclear. PMID- 29611074 TI - Intrathalline Metabolite Profiles in the Lichen Argopsis friesiana Shape Gastropod Grazing Patterns. AB - Lichen-gastropod interactions generally focus on the potential deterrent or toxic role of secondary metabolites. To better understand lichen-gastropod interactions, a controlled feeding experiment was designed to identify the parts of the lichen Argopsis friesiana consumed by the Subantarctic land snail Notodiscus hookeri. Besides profiling secondary metabolites in various lichen parts (apothecia, cephalodia, phyllocladia and fungal axis of the pseudopodetium), we investigated potentially beneficial resources that snails can utilize from the lichen (carbohydrates, amino acids, fatty acids, polysaccharides and total nitrogen). Notodiscus hookeri preferred cephalodia and algal layers, which had high contents of carbohydrates, nitrogen, or both. Apothecia were avoided, perhaps due to their low contents of sugars and polyols. Although pseudopodetia were characterized by high content of arabitol, they were also rich in medullary secondary compounds, which may explain why they were not consumed. Thus, the balance between nutrients (particularly nitrogen and polyols) and secondary metabolites appears to play a key role in the feeding preferences of this snail. PMID- 29611075 TI - Presurgical localization and spatial shift of resting state networks in patients with brain metastases. AB - Brain metastases are the most prevalent cerebral tumors. Resting state networks (RSNs) are involved in multiple perceptual and cognitive functions. Therefore, precisely localizing multiple RSNs may be extremely valuable before surgical resection of metastases, to minimize neurocognitive impairments. Here we aimed to investigate the reliability of independent component analysis (ICA) for localizing multiple RSNs from resting-state functional MRI (rs-fMRI) data in individual patients, and further evaluate lesion-related spatial shifts of the RSNs. Twelve patients with brain metastases and 14 healthy controls were recruited. Using an improved automatic component identification method, we successfully identified seven common RSNs, including: the default mode network (DMN), executive control network (ECN), dorsal attention network (DAN), language network (LN), sensorimotor network (SMN), auditory network (AN) and visual network (VN), in both individual patients and controls. Moreover, the RSNs in the patients showed a visible spatial shift compared to those in the controls, and the spatial shift of some regions was related to the tumor location, which may reflect a complicated functional mechanism - functional disruptions and reorganizations - caused by metastases. Besides, higher cognitive networks (DMN, ECN, DAN and LN) showed significantly larger spatial shifts than perceptual networks (SMN, AN and VN), supporting a functional dichotomy between the two network groups even in pathologic alterations associated with metastases. Overall, our findings provide evidence that ICA is a promising approach for presurgical localization of multiple RSNs from rs-fMRI data in individual patients. More attention should be paid to the spatial shifts of the RSNs before surgical resection. PMID- 29611076 TI - Assessing Adherence and Barriers to Long-Term Elimination Diet Therapy in Adults with Eosinophilic Esophagitis. AB - BACKGROUND: The six-food elimination diet (SFED) is an effective treatment approach for eosinophilic esophagitis (EoE), but it can be challenging and affect patients' quality of life. AIM: Assess patients' long-term adherence to SFED and potential factors influencing adherence. METHODS: EoE patients were recruited online via multiple platforms. Patients were classified as reaching the maintenance stage if they responded to SFED and identified specific trigger foods by reintroduction. Maintenance stage patients were categorized into those actively following the elimination diet (ACTIVE) and those no longer on their prescribed diet (FORMER). Participants completed a study-specific questionnaire assessing patient experiences related to SFED use. RESULTS: Forty-two participants were identified as having reached the SFED's maintenance stage. 57% (24/42) of the maintenance stage patients were ACTIVE users. FORMER users rated the SFED's effectiveness at treating symptoms (5.45 +/- 3.96, 10 max.) lower than ACTIVE users (8.29 +/- 2.76, p = .02). A greater percentage of FORMER users (100%) agreed social situations create challenges in following the diet compared to ACTIVE users (67%, p < .05). Anxiety related to SFED was also higher among FORMER users (64%) compared to ACTIVE users (21%, p < .01). Both ACTIVE (95.8%) and FORMER (81.8%, NSS) users would recommend the elimination diet to other EoE patients. CONCLUSIONS: Understanding SFED adherence is multifactorial and complex. Factors influencing SFED adherence during long-term maintenance with diet therapy include diet effectiveness, social situations, and diet-related anxiety. Despite a lower than expected long-term adherence to maintenance of an elimination diet, the majority would recommend diet therapy as a treatment to other EoE patients. PMID- 29611077 TI - Immunephenotype Predicts Response to Vedolizumab: Integrating Clinical and Biochemical Biomarkers in the Treatment of Inflammatory Bowel Diseases. PMID- 29611078 TI - Colonic Crohn's Disease Is Associated with Less Aggressive Disease Course Than Ileal or Ileocolonic Disease. AB - BACKGROUND: The literature on disease characteristics of colonic Crohn's disease (CD) is sparse, especially from Asia, where the burden of inflammatory bowel disease is on the rise. The present study aims to describe the disease characteristics of colonic CD, and compare it with that of ileal/ileocolonic disease. METHODS: This retrospective study included adult patients of CD (diagnosed by standard criteria, follow-up duration > 6 months) on follow-up between August 2004 and January 2016. The disease location was classified by Montreal classification. The data were recorded on demographic characteristics, smoking status, disease phenotype, disease course, treatment received, hospitalization and surgeries. RESULTS: Of 406 CD patients, 123 had colonic [mean age (at onset) 30.4 +/- 13.2 years, 59.3% males] and 265 had ileal/ileocolonic disease [mean age (at onset) 32.9 +/- 13.8 years, 61.5% males] while 18 patients had isolated upper GI disease. The frequency of inflammatory behavior (B1 phenotype; 61.8 vs. 46.4%, p = 0.003), perianal disease (23.6 vs. 4.5%, p < 0.001), and extra-intestinal manifestation (42.3 vs. 30.2%, p = 0.019) was higher in colonic than ileal/ileocolonic CD. Though not statistically significant, requirement of atleast one course of steroid was lower in colonic CD (72.7 vs. 84.2%, p = 0.098). Although there was no difference in the frequency of hospitalization (30.1 vs. 27.1%, p = 0.45), the overall requirement for surgery was significantly lower in colonic CD (17.1 vs. 26.1%, p = 0.032) and patients with colonic disease had a lower cumulative probability of first surgery in the first 10 years of follow-up [Hazard ratio 0.556 (95% CI 0.313-0.985), p = 0.045]. CONCLUSION: Colonic CD was associated with less aggressive disease behavior and lower requirement of surgery as compared to ileal/ileocolonic CD. PMID- 29611080 TI - Correction to: Relationship Between Abdominal Symptoms and Fructose Ingestion in Children with Chronic Abdominal Pain. AB - The original version of this article unfortunately contained an error in a couple of reference citation in Discussion Section, paragraph 6. The reference citation number should be changed from [6] to [9] in the below sentences so that it reads. PMID- 29611079 TI - Waitlist Outcomes in Liver Transplant Candidates with High MELD and Severe Hepatic Encephalopathy. AB - BACKGROUND: Organ Procurement and Transplantation Network and United Network for Organ Sharing (OPTN/UNOS) implemented the Share 35 policy in June 2013 to prioritize the sickest patients awaiting liver transplantation (LT). However, Model for End-Stage Liver Disease (MELD) score does not incorporate hepatic encephalopathy (HE), an independent predictor of waitlist mortality. AIM: To evaluate the impact of severe HE (grade 3-4) on waitlist outcomes in MELD >= 30 patients. METHODS: Using the OPTN/UNOS database, we evaluated LT waitlist registrants from 2005-2014. Demographics, comorbidities, and waitlist survival were compared between four cohorts: MELD 30-34 with severe HE, MELD 30-34 without severe HE, MELD >= 35 with severe HE, and MELD >= 35 without severe HE. RESULTS: Among 10,003 waitlist registrants studied, 41.6% had MELD score 30-34 and 58.4% had MELD >= 35. Patients with severe HE had a higher 90-day waitlist mortality in both MELD 30-34 (severe HE 71.1% vs. no HE 56.6%; p < 0.001) and MELD >= 35 subgroups (severe HE 85% versus no HE 74.2%; p < 0.001). MELD 30-34 patients with severe HE had similar 90-day waitlist mortality as MELD >= 35 patients without severe HE (71.1 vs. 74.2%, respectively; p = 0.35). On multivariate Cox proportional hazards modeling, MELD >= 30 patients had 58% greater risk of 90-day waitlist mortality than those without severe HE (HR 1.58, 95% CI 1.53-1.62; p < 0.001). CONCLUSION: Patients awaiting LT with MELD score of 30-34 and severe HE should receive priority status for organ allocation with exception MELD >= 35. PMID- 29611081 TI - Impact of robot-assisted spine surgery on health care quality and neurosurgical economics: A systemic review. AB - Whenever any new technology is introduced into the healthcare system, it should satisfy all three pillars of the iron triangle of health care, which are quality, cost-effectiveness, and accessibility. There has been quite advancement in the field of spine surgery in the last two decades with introduction of new technological modalities such as CAN and surgical robotic devices. MAZOR SpineAssist/Renaissance was the first robotic system to be approved for the use in spine surgeries in the USA in 2004. In this review, the authors sought to determine if the current literature supports this technology to be cost effective, accessible, and improve the quality of care for individuals and populations by increasing the likelihood of desired health outcomes. Robotic assisted surgery seems to provide perfection in surgical ergonomics and surgical dexterity, consequently improving patient outcomes. A lot of data is present on the accuracy, effectiveness, and safety of the robotic-guided technology which reflects remarkable improvements in quality of care, making its utility convincingly undisputable. The technology has been claimed to be cost-effective but there seems to be lack of data in the literature on this topic to validate this claim. Apart from just the outcome parameters, there is an immense need of studies on real-time cost-efficacy, patient perspective, surgeon and resident learning curve, and their experience with this new technology. Furthermore, new studies looking into increased utilities of this technology, such as brain and spine tumor resection, deep brain stimulation procedures, and osteotomies in deformity surgery, might authenticate the cost of the equipment. PMID- 29611082 TI - Comparative analysis of transcriptomic responses to sub-lethal levels of six environmentally relevant pesticides in Saccharomyces cerevisiae. AB - Accidental spills and misuse of pesticides may lead to current and/or legacy environmental contamination and may pose concerns regarding possible risks towards non-target microbes and higher eukaryotes in ecosystems. The present study was aimed at comparing transcriptomic responses to effects of sub-lethal levels of six environmentally relevant pesticide active substances in the Saccharomyces cerevisiae eukaryotic model. The insecticide carbofuran, the fungicide pyrimethanil and the herbicides alachlor, S-metolachlor, diuron and methyl(4-chloro-2-methylphenoxy)acetate were studied. Some are currently used agricultural pesticides, while others are under restricted utilization or banned in Europe and/or North America albeit being used in other geographical locations. In the present work transcriptional profiles representing genome-wide responses in a standardized yeast population upon 2 h of exposure to concentrations of each compound exerting equivalent toxic effects, i.e., inhibition of growth by 20% relative to the untreated control cells, were examined. Hierarchical clustering and Venn analyses of the datasets of differentially expressed genes pointed out transcriptional patterns distinguishable between the six active substances. Functional enrichment analyses allowed predicting mechanisms of pesticide toxicity and response to pesticide stress in the yeast model. In general, variations in transcript numbers of selected genes assessed by Real-Time quantitative reverse transcription polymerase chain reaction confirmed microarray data and correlated well with growth inhibitory effects. A possible biological relevance of mechanistic predictions arising from these comparative transcriptomic analyses is discussed in the context of better understanding potential modes of action and adverse side-effects of pesticides. PMID- 29611083 TI - Regional differences in baseline disease activity and remission rates following golimumab treatment for RA: results from the GO-MORE trial. AB - GO-MORE (NCT00975130) was a large open-label, multinational, multicenter, prospective phase 3 trial evaluating add-on therapy with golimumab in biologic naive patients with active rheumatoid arthritis (RA). The objective of this post hoc analysis was to examine regional differences in baseline disease activity and remission rates following golimumab treatment for RA. This was a planned, descriptive post hoc analysis of data from the GO-MORE trial. Baseline disease activity and remission were defined as moderate or severe based on EULAR criteria. This analysis included 3280 participants from the GO-MORE trial. All participants included in this analysis had high or moderate disease activity at baseline. At baseline, high disease activity was least common in Europe (71.0%), Canada (77.0%), and the Middle East (78.2%) and most common in Latin America (90.7%), South Africa (91.5%), and Asia (92.5%). Month 6 remission rates were highest in South Africa (29.1%), Europe (27.9%), and the Middle East (27.3%) and lowest in Canada (19.7%), Latin America (17.2%), and Asia (15.0%). Higher rates of remission in each geographical region generally corresponded with lower baseline disease activity. We suspect that access to care and implementation of the treat-to-target strategy were the most important determinants, but this apparent relationship needs to be confirmed in further studies that include a statistical analysis of prognostic indicators. PMID- 29611084 TI - The association between the Mediterranean diet and magnetic resonance parameters for knee osteoarthritis: data from the Osteoarthritis Initiative. AB - The Mediterranean diet appears to be beneficial for osteoarthritis (OA), but the few data available regarding the association between the diet and the condition are limited to X-ray and clinical findings. The current study aimed to investigate the association between adherence to the Mediterranean diet and knee cartilage morphology, assessed using magnetic resonance (MRI) in a cohort of North American participants. Seven hundred eighty-three participants in the Osteoarthritis Initiative (59.8% females; mean age 62.3 years) in possession of a MRI assessment (a coronal 3D FLASH with Water Excitation MR sequence of the right knee) were enrolled in our cross-sectional study. Adherence to the Mediterranean diet was evaluated using a validated Mediterranean diet score (aMED). The strength of the association between aMED and knee MRI parameters was gauged using an adjusted linear regression analysis, expressed as standardized betas with 95% confidence intervals (CIs). Using an adjusted linear regression analysis, each increase of one standard deviation (SD) in the aMED corresponded to a significant increase in the central medial femoral cartilage volume (beta = 0.12; 95%CI 0.09 to 0.15), in the mean central medial femoral cartilage thickness (beta = 0.13; 95%CI 0.01 to 0.17), in the cartilage thickness of the mean central medial tibiofemoral compartment (beta = 0.12; 95%CI 0.09 to 0.15), and in the cartilage volume of the medial tibiofemoral compartment (beta = 0.09; 95%CI 0.06 to 0.12). Higher adherence to a Mediterranean diet was found to be associated with a significant improvement in knee cartilage as assessed by MRI, even after adjusting for potential confounding factors. PMID- 29611085 TI - Paradoxical skin lesions induced by anti-TNF-alpha agents in SAPHO syndrome. AB - The objectives of the study were to characterize the clinical picture of paradoxical skin lesions in SAPHO patients treated with anti-TNF-alpha agents and to explore its pathogenesis. Patients treated with anti-TNF-alpha therapy were identified from a cohort of 164 SAPHO patients. The clinical data and skin biopsies were collected. The usage, efficacy, and side effects of anti-TNF-alpha therapy were recorded. Forty-one (25.0%) patients received anti-TNF-alpha therapy, of which seven (17.1%) developed paradoxical skin lesions after 1 to 14 infusions. Patients with such lesions were older at onset of skin lesions than those without (p = 0.034). Expression of TNF-alpha in palmoplantar pustulosis increased after anti-TNF-alpha therapy in the two examined patients with exacerbated skin lesions. Anti-TNF-alpha therapy induces paradoxical skin lesions in 17.1% SAPHO patients. Late onset of skin manifestations is associated with an increased risk of such lesions. The paradoxical elevation of TNF-alpha expression in lesions may contribute to this phenomenon. PMID- 29611086 TI - Resveratrol as an effective adjuvant therapy in the management of rheumatoid arthritis: a clinical study. AB - Resveratrol (RSV), a naturally occurring polyphenol, has been found to have potent antioxidant, anti-inflammatory, and anticancer effects. Recently, RSV was reported as a new potential agent to suppress inflammation of collagen-induced arthritis in a mouse model. Nevertheless, the clinical benefits of RSV in the management of rheumatoid arthritis (RA) were not studied. This randomized controlled clinical trial aims to shed some light on the therapeutic benefits of RSV in the treatment of RA in patients with different stages of the disease activity. In this randomized controlled clinical trial, 100 RA patients (68 female, 32 male) were enrolled randomly and divided into two groups, each of 50 patients: an RSV-treated group that received a daily RSV capsule of 1 g with the conventional treatment for 3 months and a control group that just received the regular treatment. The clinical and biochemical markers of RA in both groups were assessed. It was found that the clinical markers (i.e., the 28-joint count for swelling and tenderness) and the disease activity score assessment for 28 joints were significantly lowered in the RSV-treated group. Moreover, serum levels of certain biochemical markers (i.e., C-reactive protein, erythrocyte sedimentation rate, undercarboxylated osteocalcin, matrix metalloproteinase-3, tumor necrosis factor alpha, and interleukin-6) were also significantly decreased in RSV-treated patients. The current study suggests the addition of RSV as an adjuvant to the conventional antirheumatic drugs. PMID- 29611087 TI - Long-term retention rates of adalimumab and infliximab in non-infectious intermediate, posterior, and panuveitis. AB - The aim of the present study was to compare long-term adalimumab (ADA) and infliximab (IFX) retention rates in patients with intermediate, posterior, or panuveitis. Additional aims are as follows: (i) to identify any difference in the causes of treatment discontinuation between patients treated with ADA and IFX; (ii) to assess any impact of demographic features, concomitant treatments, and different lines of biologic therapy on ADA and IFX retention rates; and (iii) to identify any correlation between ADA and IFX treatment duration and the age at uveitis onset, the age at onset of the associated systemic diseases, and the age at the start of treatment. Clinical, therapeutic, and demographic data from patients with non-infectious intermediate, posterior, or panuveitis treated with ADA or IFX were retrospectively collected. Kaplan-Meier plot and log-rank (Mantel Cox) test were used to assess survival curves. One hundred eight patients (188 eyes) were enrolled; in 87 (80.6%) patients, uveitis was associated with a systemic disease. ADA and IFX were administered in 62 and 46 patients, respectively. No statistically significant differences were identified between ADA and IFX retention rates (p value = 0.22). Similarly, no differences were identified between ADA and IFX retention rates in relation to gender (p value = 0.61 for males, p value = 0.09 for females), monotherapy (p value = 0.08), combination therapy with conventional disease-modifying antirheumatic drugs (log rank p value = 0.63), and different lines of biologic therapy (p value = 0.79 for biologic-naive patients; p value = 0.81 for subjects previously treated with other biologics). In conclusion, ADA and IFX have similar long-term retention rates in patients with non-infectious intermediate, posterior, and panuveitis. Demographic, clinical, and therapeutic features do not affect their long-term effectiveness. PMID- 29611088 TI - The Impact of Care Specialty on Survival-Adjusted Medical Costs of COPD Patients After a Hospitalization: a longitudinal analysis. AB - BACKGROUND: Little is known about the impact of care provider's specialty on the medical costs of COPD patients over time. OBJECTIVE: To compare the long-term medical costs between newly hospitalized COPD patients whose post-discharge care was initiated by a pulmonary specialist versus by a general practitioner. DESIGN: Retrospective matched cohort study. PARTICIPANTS: We identified patients with an incident COPD-related hospitalization from the administrative health database (January 1, 1996, to December 31, 2012) of British Columbia, Canada. MAIN MEASURES: Patients were categorized as receiving specialist care or primary care within the first 90 days after discharge from an incident COPD-related hospitalization. Using propensity scores, we matched each patient who initially received specialist care to a patient who received primary care based on demographics, COPD severity, comorbidity, and admission time. A survival adjusted, multi-part generalized linear model was used to estimate direct medical costs (in 2015 Canadian dollars, [$], including inpatient, outpatient, pharmacy, and community care costs) as overall and as COPD-specific and comorbidity-related costs over the following 5 years. KEY RESULTS: The sample included 7710 patients under each group. The initial specialist-care recipients had a modestly higher 5 year survival than the generalist-care recipients (0.564 [95% CI 0.535, 0.634] vs 0.555 [95% CI 0.525, 0.625]; P < .001). Meanwhile, the former incurred $2809 higher all-cause medical costs over 5 years compared to the latter (95% CI $2343, $2913; P < .001), mainly driven by higher medication costs (difference $1782 [95% CI $1658, $1830]; P < .001) particularly related to COPD medications ($1170 [95% CI $1043, $1225]; P < .001). Specialist care recipients also incurred higher costs of COPD-related hospitalization ($1144 [95% CI $650, $1221]; P < .001). CONCLUSIONS: Compared to generalist care, specialist care following COPD hospitalization is slightly more expensive, mainly driven by medication costs especially COPD-specific medications. Future studies should compare differences in health-related quality of life and COPD functional status. PMID- 29611090 TI - Chronic Abdominal Pain from Disseminated Splenosis. PMID- 29611089 TI - Impact of Patient-Centered Medical Home Implementation on Diabetes Control in the Veterans Health Administration. AB - BACKGROUND: Given its widespread dissemination across primary care, the Veterans Health Administration (VA) is an ideal setting to examine the impact of the patient-centered medical home (PCMH) on diabetes outcomes. OBJECTIVE: To assess the impact of PCMH implementation on diabetes outcomes among patients receiving care in the Veterans Health Administration. DESIGN: Retrospective cohort analysis and multilevel logistic regression. PATIENTS: Twenty thousand eight hundred fifty eight patients in one Midwest VA network who had a diabetes diagnosis in both 2009 and 2012 and who received primary care between October 1, 2008 and September 30, 2009. MAIN MEASURES: Glycemic and lipid control using VA quality indicators [hemoglobin (Hb) A1c < 9%, low-density lipoprotein cholesterol (LDL-C) < 100 mg/dL]. KEY RESULTS: Odds of glycemic control were lower in 2012 than 2009 (OR = 0.72, 95% CI = 0.67-0.77, p < 0.001), and this change in control over time varied by race (OR of the interaction between time and race = 1.18, 95% CI = 1.02 1.36, p = 0.028). While the disparity in glycemic control between white and black patients persisted post-PCMH, the magnitude of the disparity was smaller in 2012 compared to 2009 (2012: OR = 1.32, 95% CI = 1.18-1.47, p < 0.0001 and 2009: OR = 1.59, 95% CI = 1.39-1.82, p < 0.0001). Odds of lipid control did not significantly change between 2009 and 2012 and change did not vary by race and/or gender. CONCLUSIONS: Although there were no significant improvements in odds of lipid control, and odds of glycemic control decreased following PCMH implementation, there was evidence of reduced racial disparities in glycemic control post-PCMH implementation. PMID- 29611091 TI - Risk Factors for Weight Loss 1 Year After Esophagectomy and Gastric Pull-up for Esophageal Cancer. AB - BACKGROUND: Loss of body weight is regarded as a marker of malnutrition after esophagectomy. This study investigated changes in body weight and risk factors for weight loss after esophagectomy for esophageal cancer. METHODS: We retrospectively reviewed records of 181 patients who underwent esophagectomy and gastric pull-up from 2012 to June 2016. Patients with operative mortality and recurrences were excluded. Percent change in body weight was defined as change in body weight (%) = (1-year body weight - preoperative body weight) * 100/preoperative body weight. RESULTS: Mean age of patients was 62.98 +/- 8.23 years with 164 men (90.6%). Mean preoperative body weight was 63.12 +/- 9.42 kg, and body weight at 1 year was 56.04 +/- 8.59 kg. Mean change in body weight was - 10.95 +/- 7.50%, and 98 (54.1%) patients showed weight loss more than 10% compared to initial body weight. Univariable analysis showed that initial body weight, narrow gastric tube, thoracotomy, laparotomy, and postoperative vocal cord palsy (VCP) were related to more than 10% weight loss. Multivariable analysis showed that initial body weight (odds ratio [OR] = 1.041, p = 0.031) and postoperative VCP (OR = 2.772, p = 0.025) were adverse risk factors for weight loss 1 year after esophagectomy, whereas conduit type, route of reconstruction, postoperative complications, anastomotic complications, minimally invasive esophagectomy, and adjuvant therapy were not. CONCLUSIONS: Initial body weight and postoperative VCP were related to weight loss. Patients with VCP need additional nutritional monitoring and support. PMID- 29611092 TI - Usefulness of the Ligamentum Venosum as an Anatomical Landmark for Safe Laparoscopic Left Hepatectomy (How I Do It). AB - Anatomical landmarks are commonly utilized in surgical practice to help surgeons to maintain an anatomical orientation. The ligamentum venosum (LV) is an anatomical landmark that is utilized during left hepatectomy via both the open and the laparoscopic approaches. We describe the usefulness of the LV as an anatomical landmark in performing a safe laparoscopic left hepatectomy. The key characteristic of our technique is that the LV is divided at the end of the surgery. Our technique involves identification and dissection of the LV, but we do not divide it during liver mobilization. The LV marks the boundary for safe vascular inflow control of the left hemiliver. Following exposure of the middle hepatic vein, hepatic parenchymal transection is curved toward the LV, which serves as a landmark to guide surgeons to achieve an optimal plane of transection in the late stages. A suitable transection point of the left bile duct is determined based on the location of the LV. Between February 2013 and September 2017, 21 consecutive patients underwent pure laparoscopic left hepatectomy. The median operation time was 240 min (range 180-350 min), and the median intraoperative estimated blood loss was 200 ml (range 80-600 ml). Major postoperative complications occurred in one patient (4.8%). The median postoperative hospital stay was 8 days (range 5-15 days). This systematic approach using the LV as an anatomical landmark may serve as a safe and effective technique to perform a laparoscopic left hepatectomy. PMID- 29611093 TI - Nonlinear Predictive Models for Multiple Mediation Analysis: With an Application to Explore Ethnic Disparities in Anxiety and Depression Among Cancer Survivors. AB - Mediation analysis allows the examination of effects of a third variable (mediator/confounder) in the causal pathway between an exposure and an outcome. The general multiple mediation analysis method (MMA), proposed by Yu et al., improves traditional methods (e.g., estimation of natural and controlled direct effects) to enable consideration of multiple mediators/confounders simultaneously and the use of linear and nonlinear predictive models for estimating mediation/confounding effects. Previous studies find that compared with non Hispanic cancer survivors, Hispanic survivors are more likely to endure anxiety and depression after cancer diagnoses. In this paper, we applied MMA on MY-Health study to identify mediators/confounders and quantify the indirect effect of each identified mediator/confounder in explaining ethnic disparities in anxiety and depression among cancer survivors who enrolled in the study. We considered a number of socio-demographic variables, tumor characteristics, and treatment factors as potential mediators/confounders and found that most of the ethnic differences in anxiety or depression between Hispanic and non-Hispanic white cancer survivors were explained by younger diagnosis age, lower education level, lower proportions of employment, less likely of being born in the USA, less insurance, and less social support among Hispanic patients. PMID- 29611094 TI - Past Care Predicts Future Care in Out-of-Care People Living with HIV: Results of a Clinic-Based Retention-in-Care Intervention in North Carolina. AB - Poor retention in care is associated with higher viral load (VL) results and decreased rates of viral load suppression (VS) in people living with HIV (PLWH). Therefore, improving retention in HIV care is a priority of national significance. The NC-LINK Retention Project utilized a systematic approach to identify, locate, and attempt to return to care patients who did not attend a clinic appointment for 6-9 months. Clinical and surveillance data were used to evaluate associations between patient characteristics and VL outcomes. Between January 1, 2013 and December 31, 2014, 1118 patients at participating clinics were identified as out-of-care and referred to retention staff. Of these, 712 (64%) were located in North Carolina. Patients with recent prior medical care (aPR 1.43, 95% CI 1.25, 1.66) and recent VS (aPR 1.28, 95% CI 1.16, 1.41) were more likely to be located. Of located patients, 58% re-engaged in care within 90 days of retention referral. Patients who achieved VS within 180 days were more likely to be 40-49 years (aPR 1.19 95% CI 1.01-1.40; compared with 18-29 age group), had insurance at their last visit (aPR 1.19 95% CI 1.01-1.77), had a care visit in the prior year (aPR 1.37 95% CI 1.05-1.77), and had VS at the prior care visit (aPR 2.54 95% CI 1.98-3.25). Clinic-based retention efforts may be effective at helping PLWH decrease out-of-care periods, but prior patterns of care usage persist. PMID- 29611095 TI - An End-User Participatory Approach to Collaboratively Refine HIV Care Data, The New York State Experience. AB - Existing data dissemination structures primarily rely on top-down approaches. Unless designed with the end user in mind, this may impair data-driven clinical improvements to Human Immunodeficiency Virus (HIV) prevention and care. In this study, we implemented a data visualization activity to create region-specific data presentations collaboratively with HIV providers, consumers of HIV care, and New York State (NYS) Department of Health AIDS Institute staff for use in local HIV care decision-making. Data from the NYS HIV Surveillance Registry (2009-2013) and HIV care facilities (2010-2015) participating in a Health Resources and Services Administration (HRSA) Systems Linkages and Access to Care project were used. Each data package incorporated visuals for: linkage to HIV care, retention in care and HIV viral suppression. End-users were vocal about their data needs and their capacity to interpret public health data. This experience suggests that data dissemination strategies should incorporate input from the end user to improve comprehension and optimize HIV care. PMID- 29611097 TI - Increased cortisol metabolism in women with pregnancy-related hypertension. AB - PURPOSE: The diminished function of 11beta-hydroxysteroid dehydrogenase 2 (11beta HSD2) was found in placentae from preeclamptic pregnancies. Here, we examine the overall maternal glucocorticoid balance in pregnancy-related hypertension. We aim to answer the question if the functions of primary enzymes involved in cortisol metabolism: 11beta-HSD1 and 11beta-HSD2 and 5-reductases (both 5alpha- and 5beta) are altered in the course of hypertensive pregnancy. METHODS: We determined plasma and urinary cortisol and cortisone as well as their urinary tetrahydro- and allo-tetrahydrometabolites, both in free and conjugated forms in samples obtained from 181 Polish women in the third trimester of pregnancy. We compared steroid profiles in women with preeclampsia (PE), gestational hypertension (GH), chronic hypertension (CH) and in normotensives (controls). RESULTS: We found significant differences in glucocorticoid balance in pregnancy-related hypertension. Plasma cortisol to cortisone was significantly lower in PE than in controls (3.00 vs. 4.79; p < 0.001). Increased function of renal 11beta-HSD2 in PE and GH was manifested by significantly lower urinary free cortisol to cortisone ratio (0.169 and 0.206 vs. 0.277 in controls; p < 0.005). Markedly enhanced metabolism of cortisol was observed in pregnancy-related hypertension, with no significant alterations in CH, and the changes were more clearly expressed in PE than in GH. CONCLUSIONS: The glucocorticoid balance in PE and GH is shifted towards decreasing cortisol concentration either due to intensified conversion to cortisone or enhanced production of tetrahydro and allo tetrahydrometabolites. PMID- 29611096 TI - Experimental validation of robot-assisted cardiovascular catheterization: model based versus model-free control. AB - PURPOSE: In cardiac electrophysiology, a long and flexible catheter is delivered to a cardiac chamber for the treatment of arrhythmias. Although several robot assisted platforms have been commercialized, the disorientation in tele-operation is still not well solved. We propose a validation platform for robot-assisted cardiac EP catheterization, integrating a customized MR Safe robot, a standard clinically used EP catheter, and a human-robot interface. Both model-based and model-free control methods are implemented in the platform for quantitative evaluation and comparison. METHODS: The model-based and model-free control methods were validated by subject test (ten participants), in which the subjects have to perform a simulated radiofrequency ablation task using both methods. A virtual endoscopic view of the catheter is also provided to enhance hand-to-eye coordination. Assessment indices for targeting accuracy and efficiency were acquired for the evaluation. RESULTS: (1) Accuracy: The average distance measured from catheter tip to the closest lesion target during ablation of model-free method was 19.1% shorter than that of model-based control. (2) Efficiency: The model-free control reduced the total missed targets by 35.8% and the maximum continuously missed targets by 46.2%, both indices corresponded to a low p value ([Formula: see text]). CONCLUSION: The model-free method performed better in terms of both accuracy and efficiency, indicating the model-free control could adapt to soft interaction with environment, as compared with the model-based control that does not consider contacts. PMID- 29611098 TI - The inter-tester repeatability of a model for analysing elbow flexion-extension during overhead sporting movements. AB - This study investigates the inter-tester repeatability of an upper limb direct kinematic (ULDK) model specifically for the reporting of elbow flexion-extension (FE) during overhead sporting movements, such as cricket bowling. The ULDK model consists of an upper arm and a forearm connected with a 6 degrees of freedom elbow joint. The ULDK model was assessed for inter-tester repeatability by calculating elbow FE during cricket bowling in two sessions, with unique testers applying the kinematic marker set in each session. Analysis of both elbow FE time varying waveforms (statistical parametric mapping = 0% time different) and extracted discrete events (no statistical differences, strong correlations > 0.9) support that this model is inter-tester repeatable at assessing elbow FE within the context of cricket bowling. This model is recommended as a framework in future studies for measuring elbow kinematics during other overhead sporting tasks, with recommendations for further participant-specific considerations. Graphical abstract ?. PMID- 29611099 TI - Correction to: The Small GTPase RAC1/CED-10 Is Essential in Maintaining Dopaminergic Neuron Function and Survival Against alpha-Synuclein-Induced Toxicity. AB - With the author(s)' decision to opt for Open Choice the copyright of the article changed on March 2018 to PMID- 29611100 TI - Resveratrol Acts Anti-Inflammatory and Neuroprotective in an Infant Rat Model of Pneumococcal Meningitis by Modulating the Hippocampal miRNome. AB - Resveratrol (RSV) is anti-inflammatory and neuroprotective, cross the blood-brain barrier (BBB) and has a safe profile. Besides, RSV modulates the expression of some miRNAs related to neurological disorders. Thus, we hypothesized that RSV can be neuroprotective in pneumococcal meningitis by modulating the global microRNA expression profile (miRNome). Eleven-day old rats were intracysternally infected with S. pneumoniae (~ 2 * 106 c.f.u.) and were orally administered with RSV (50 mg/kg) or vehicle in pre-treatment (before infection) or post-treatment schedules (3 and 18 h p.i.). At 24 h p.i., animals were euthanized and apoptotic cells were counted in the hippocampal dentate gyrus of the right brain hemispheres. The hippocampi from left hemispheres were used for cytokines and chemokines multiplex assay and miRNome profiling with TaqMan OpenArray Rodent MicroRNA. Infected rats treated with RSV had lower apoptotic scores and IL-1beta, CCL2, and CCL3 levels when compared to the infected group receiving placebo. Seven miRNAs were down regulated, and 18 were up regulated by pneumococcal acute meningitis. Thirty seven miRNAs were down regulated, and three were up regulated (hsa-miR-15b-5p, hsa-miR-25-3p, hsa-miR-125b-5p) by the interaction between meningitis and RSV. Pathway enriched analysis revealed that meningitis and RSV modulate the expression of miRNAs targeting critical pathways related to the pathophysiology of bacterial meningitis. Nevertheless, hsa-miR-25-3p and hsa-miR-125b-5p target the transcription factor TEF-1, for which there are binding sites in Il-1beta, Ccl2, and Ccl3 genes. RSV is anti-inflammatory and neuroprotective in an infant rat model of pneumococcal meningitis and these positive effects involve the modulation of the hippocampal miRNome. PMID- 29611102 TI - 11beta-HSD1 Inhibition by RL-118 Promotes Autophagy and Correlates with Reduced Oxidative Stress and Inflammation, Enhancing Cognitive Performance in SAMP8 Mouse Model. AB - Elevated glucocorticoid (GC) exposure is widely accepted as a key factor in the age-related cognitive decline in rodents and humans. 11beta-HSD1 is a key enzyme in the GCs pathway, catalyzing the conversion of 11beta-dehydrocorticosterone to corticosterone in mice, with possible implications in neurodegenerative processes and cognitive impairment. Here, we determined the effect of a new 11beta-HSD1 inhibitor, RL-118, administered to 12-month-old senescence-accelerated mouse prone 8 (SAMP8) mice with neuropathological AD-like hallmarks and widely used as a rodent model of cognitive dysfunction. Behavioral tests (open field and object location) and neurodegeneration molecular markers were studied. After RL-118 treatment, increased locomotor activity and cognitive performance were found. Likewise, we found changes in hippocampal autophagy markers such as Beclin1, LC3B, AMPKalpha, and mTOR, indicating a progression in the autophagy process. In line with autophagy increase, a diminution in phosphorylated tau species (Ser 396 and Ser 404) jointly with an increase in ADAM10 and sAPPalpha indicated that an improvement in removing the abnormal proteins by autophagy might be implicated in the neuroprotective role of the 11beta-HSD1 inhibitor. In addition, gene expression of oxidative stress (OS) and inflammatory markers, such as Hmox1, Aldh2, Il-1beta, and Ccl3, were reduced in old treated mice in comparison to that of the control group. Consistent with this, we further demonstrate a significant correlation with autophagy markers and cognitive improvement and significant inverse correlation with autophagy, OS, and neuroinflammation markers. We concluded that inhibition of 11beta-HSD1 by RL-118 prevented neurodegenerative processes and cognitive decline, acting on autophagy process, being an additional neuroprotective mechanism not described previously. PMID- 29611101 TI - The Compensatory Immune-Regulatory Reflex System (CIRS) in Depression and Bipolar Disorder. AB - Here, we review a novel concept namely the compensatory immune-regulatory reflex system (CIRS) as applied to the pathophysiology of major depressive disorder (MDD) and bipolar disorder (BD). There is evidence that a substantial subset of individuals with MDD and BD exhibit an activation of the immune-inflammatory response system (IRS), as indicated by an increased production of macrophagic M1 and T helper (Th)-1 pro-inflammatory cytokines, interleukin (IL)-6 trans signaling, positive acute phase proteins (APPs), and complement factors. These immune aberrations appear to be evident during the course of major affective episodes of either depressive or (hypo) manic polarity. Here, we review (a) the current state of the art of CIRS functions in both mood disorders and (b) the possible role of CIRS-related biomarkers for the understanding of affective disorders within the framework of precision psychiatry that could also provide novel drug targets for both MDD and BD. CIRS-related abnormalities in mood disorders include elevated Th-2 and T regulatory (Treg) activities with increased IL-4 and IL-10 production, classical IL-6 signaling, increased levels of sIL-1R antagonist (sIL-1RA), soluble IL-2 (sIL-2R) and tumor necrosis factor-alpha- receptors, and positive APPs, including haptoglobin, hemopexin, alpha1-acid glycoprotein, alpha1-antitrypsin, and ceruloplasmin. It is concluded that CIRS is involved in MDD and BD by regulating the primary immune-inflammatory response, thereby contributing to spontaneous and antidepressant-promoted recovery from the acute phase of illness. Signs of activated IRS and CIRS pathways are observed in the remitted phases of both disorders indicating that there is no return to the original homeostasis after an acute episode, while later episodes of mood disorders are characterized by sensitized IRS and CIRS responses. New z-unit weighted composite biomarker scores are proposed, which reflect different aspects of IRS versus CIRS activation and may be used to estimate different IRS/CIRS activity ratios in mood and other neuroimmune disorders. PMID- 29611104 TI - Fixed-dose 4-factor prothrombin complex concentrate: we don't know where we're going if we don't know how to get there. AB - 4-Factor Prothrombin Complex Concentrate (4F-PCC) is the standard-of-care intervention in patients with major bleeding taking oral vitamin K antagonists. Despite growing clinical experience with 4-FPCC, the optimal dosing strategy remains unclear. In balancing efficacy, safety, and cost of this treatment, many institutions have adopted a low, fixed-dose regimen, with average doses lower than that in the package insert. The fixed-dose 4F-PCC strategy is supported by the available observational studies and case reports; however, the current body of literature is highly heterogenous. The purpose of this narrative review is to address the advantages and shortcomings with clinical use of fixed-dose 4F-PCC, as well as limitations of the available literature. The heterogeneity of the current literature should guide future studies to support or refute this potentially life-saving intervention. PMID- 29611103 TI - Evidence for Compromised Insulin Signaling and Neuronal Vulnerability in Experimental Model of Sporadic Alzheimer's Disease. AB - Evidence from animal studies categorizes sporadic Alzheimer's disease (sAD) as a metabolic syndrome with accompanying cognitive deficits. Given that glial cells act as "silent partners" to neurons by providing trophic support and defense, the present study investigated the role of glia in sAD pathology. A streptozotocin (STZ)-induced glial-neuronal co-culture model of sAD was used to study the metabolic status of the two cell types. Real time RT-PCR and Western blotting results indicated that amyloid precursor protein (APP) and beta-secretase (BACE1) were highly expressed in co-cultured neurons than in monocultures. Increased amyloidogenesis was accompanied by decreased expression of mediators in insulin signaling pathway that included insulin receptor (IR), insulin receptor substrate 2 (IRS2), insulin-like growth factor 2 (IGF2), insulin-like growth factor 1 receptor (IGF1R), total-glycogen synthase kinase 3beta (t-GSK3beta), and phosphorylated-GSK3betaser9 (p-GSK3betaser9), suggesting that neuronal cells are more prone to metabolic variability when cultured in the presence of glial cells. Findings from the sAD model induced by intracerebroventricular (ICV) injection of STZ revealed that increased amyloid beta (Abeta) load in the hippocampus was potentially responsible for the hyperphosphorylation of tau at ser396. Furthermore, impaired cognitive functions and decreased dendritic spine density and axonal thinning in CA1 region of hippocampus were associated with decreased IR and p-GSK3betaser9/t-GSK3beta expression. Taken together, the present study provides evidence that glia mediated response and insulin signaling defects drive pathological changes in sAD and represent potential targets for delaying sAD progression. PMID- 29611105 TI - Quality of direct oral anticoagulant prescribing in elderly patients with non valvular atrial fibrillation: results from a large urban health system. AB - Non-valvular atrial fibrillation (NVAF) is common in older adults. Oral anticoagulation is indicated to reduce the risk of stroke and systemic embolism, but it also poses a risk of bleeding, particularly in the elderly. Direct oral anticoagulants (DOACs) provide an alternative to warfarin and their use in the treatment of AF is growing. We conducted a retrospective cohort study to assess the quality of DOAC prescribing in elderly patients with NVAF in a large academic health system and to compare practice with consensus best practice recommendations. We searched the electronic medical record for patients >= 65 years of age who were newly initiated on a DOAC for AF from January 2013 through December 2015. Patient and provider characteristics, baseline laboratory investigations, concomitant medications, and interval to first follow-up were recorded. 192 patients met eligibility criteria. The most commonly prescribed DOACs were rivaroxaban (65%) and apixaban (26%). Despite consensus recommendations that patients have a baseline creatinine, complete blood cell count, and coagulation studies prior to DOAC initiation, these tests were not performed in 18, 31, and 67% of patients, respectively. Consensus recommendations also suggest a follow-up visit within 1 month of DOAC initiation. However, only 39% of patients had a return visit within 6 weeks and 43% did not have follow-up within 12 weeks. DOAC prescribing in elderly patients with NVAF frequently fell short of quality standards. Interventions to enhance the quality of DOAC prescribing in this high-risk population are needed. PMID- 29611108 TI - Forecasting and Uncertainty Quantification Using a Hybrid of Mechanistic and Non mechanistic Models for an Age-Structured Population Model. AB - In this paper, we present a new method for the prediction and uncertainty quantification of data-driven multivariate systems. Traditionally, either mechanistic or non-mechanistic modeling methodologies have been used for prediction; however, it is uncommon for the two to be incorporated together. We compare the forecast accuracy of mechanistic modeling, using Bayesian inference, a non-mechanistic modeling approach based on state space reconstruction, and a novel hybrid methodology composed of the two for an age-structured population data set. The data come from cannibalistic flour beetles, in which it is observed that the adults preying on the eggs and pupae result in non-equilibrium population dynamics. Uncertainty quantification methods for the hybrid models are outlined and illustrated for these data. We perform an analysis of the results from Bayesian inference for the mechanistic model and hybrid models to suggest reasons why hybrid modeling methodology may enable more accurate forecasts of multivariate systems than traditional approaches. PMID- 29611106 TI - Direct-acting antiviral drugs for chronic hepatitis C and risk of major vascular events: a systematic review. AB - Direct-acting antiviral drugs (DAAs) were recently approved for treating hepatitis C virus-related chronic hepatitis. As advanced chronic liver disease may predispose patients to thrombotic events, it is still uncertain whether DAAs may influence the actual risk of major arterial and venous thrombotic events. We performed a systematic review to assess the incidence of major vascular events in patients receiving DAAs for HCV chronic hepatitis during phase-III randomized controlled trials (RCTs). Two reviewers identified studies through Pubmed database until October 2015. Reporting and incidence of any vascular events were compared with reporting and incidence of major bleeding, anemia (a prespecified safety outcome) and headache (a common non-prespecified safety outcome). 33 RCTs, encompassing 14,764 patients, were included. Only 13 (39%) and 4 (12%) RCTs provide data on any arterial or venous events, respectively. Occurrence of anemia and headache is reported in all studies. Crude unweighted rate of major arterial events is 0.16% (95% CI 0.10-0.24) of the total included population and 0.47% in those 13 RCTs reporting data. Crude unweighted rate of major venous events is 0.03% of the total included population (95% CI 0.01-0.08) and 0.22% in those four RCTs reporting data. Crude unweighted rate of major bleeding is 0.07% (95% CI 0.03-0.1). Incidence of thrombotic events in HCV patients receiving DAAs may be low, but an incorrect estimation cannot be excluded. PMID- 29611107 TI - Long-Term Relationship Between Tobacco Use and Weight Loss after Sleeve Gastrectomy. AB - BACKGROUND: Smoking cessation had been typically associated with weight gain. We have reported that there is no relationship between tobacco use and weight loss after bariatric surgery in the short term. The objective of this study was to establish the relationship between weight loss and the smoking habit in patients undergoing bariatric surgery and to analyze weight loss on severe smokers and on those patients who stopped smoking during the long-term postoperative period. METHODS: One hundred eighty-four patients included in our previous study were contacted by phone at 7 years after sleeve gastrectomy. They were again divided into three groups: (A) smokers, (B) ex-smokers, and (C) non-smokers. Demographics and weight loss at 6, 12, 24, and 7 years were analyzed. Smokers were subdivided for further analysis into the following: group A1: heavy smokers, group A2: non heavy smokers, group A3: active smokers after surgery, and group A4: quitters after surgery. Student test was used for statistics. RESULTS: One hundred two patients were included. The follow-up was 80.74 +/- 7.25 month. Group A: 29 patients, group B: 34 patients, and group C: 39 patients. Mean BMI was 34.35 +/- 8.44 kg/m2 and the %EWL was 56.95 +/- 27. The subgroup analysis showed the following composition: group A1: 6 patients, group A2: 23 patients, group A3: 23 patients, and group A4: 6 patients. Weight loss difference among groups and subgroups was statistically non-significant. CONCLUSIONS: This study reaffirms the hypothesis that weight loss among bariatric patients is independent from smoking habit even at long-term follow-up and regardless from cessation. PMID- 29611109 TI - Stochastic Sensitivity Analysis of Noise-Induced Extinction in the Ricker Model with Delay and Allee Effect. AB - A susceptibility of population systems to the random noise is studied on the base of the conceptual Ricker-type model taking into account the delay and Allee effect. This two-dimensional discrete model exhibits the persistence in the form of equilibria, discrete cycles, closed invariant curves, and chaotic attractors. It is shown how the Allee effect constrains the persistence zones with borders defined by crisis bifurcations. We study the role of random noise on the contraction and destruction of these zones. This phenomenon of the noise-induced extinction is investigated with the help of direct numerical simulations and semi analytical approach based on the stochastic sensitivity functions. Stochastic transitions from the persistence regimes to the extinction are studied by the analysis of the mutual arrangement of the basins of attraction and confidence domains. PMID- 29611110 TI - Asymptotic Behavior of Eigen's Quasispecies Model. AB - We study Eigen's quasispecies model in the asymptotic regime where the length of the genotypes goes to [Formula: see text] and the mutation probability goes to 0. A limiting infinite system of differential equations is obtained. We prove convergence of trajectories, as well as convergence of the equilibrium solutions. We give analogous results for a discrete-time version of Eigen's model, which coincides with a model proposed by Moran. PMID- 29611111 TI - Caspase-1-associated immune activation in an accelerated SIV-infected rhesus macaque model. AB - In the antiretroviral therapy (ART) era, chronic HIV infection is primarily associated with chronic inflammation driving comorbidities such as cardiovascular disease and neurocognitive impairment. Caspase-1 activation in leukocytes has been documented in HIV infection; however, whether caspase-1 activation and the downstream pro-inflammatory cytokines interleukin-1beta (IL-1beta) and interleukin-18 (IL-18) contribute to chronic inflammation in HIV comorbidities remains undetermined. The relationship between the caspase-1 cascade and persistent inflammation in HIV has not been investigated. Here, we used an accelerated simian immunodeficiency virus (SIV)-infected rhesus macaque model with or without ART to investigate the dynamics of caspase-1 and immune cell activation before infection, 21 days post infection (dpi), and necropsy. Caspase 1, IL-18, IL-1beta, and immune markers were measured both in the circulation and lymphoid tissues. We found a significant increase in caspase-1 and IL-18 in SIV infection that positively correlated with inflammatory monocytes and negatively correlated with CD4+ T cell counts. ART attenuated these effects at necropsy in the circulation. Further, lymph nodes from SIV+ or SIV+ART animals had increased activation of caspase-1 and potential upstream priming of the NF-kappaB pathway, indicating that tissue-specific immune activation persists with ART. Together, these results shed light on the interconnectedness of the caspase-1 pathway and peripheral immune activation and further indicate that ART is not sufficient for suppressing inflammation. The caspase-1 pathway may provide novel therapeutic targets to improve HIV-associated comorbidities and health outcomes in the context of viral suppression. PMID- 29611112 TI - Sedation practices in gastrointestinal endoscopy-A survey from southern India. AB - Gastrointestinal endoscopies can cause an unpleasant experience for the patient. In India, most endoscopists follow a common institutional policy for sedation. The aim of this study was to analyze the sedation practices in various endoscopy centers across southern India. Data were collected with the help of a structured questionnaire given to a senior endoscopist of the center. Data from the completed questionnaire were later analyzed. Data were obtained from 19 centers across southern India. All endoscopy suites had central oxygen supply and emergency cart. A defibrillator was available in 12 centers (63.2%). Common criteria followed for administering sedation included therapeutic procedures (84.2%), patients who requested sedation (63.2%), children (63.2%), high-risk procedures (57.9%), and uncooperative patients (57.9%). Monitoring methods included pulse oximetry alone in six centers (31.6%), pulse oximetry with blood pressure monitoring in five centers (26.3%), and pulse oximetry, blood pressure, and electrocardiography (ECG) monitoring in eight centers (42.1%). For advanced procedures like endoscopic ultrasonography (EUS) and endoscopic retrograde cholangiopancreatography (ERCP), sedation was universally used. An anesthesiologist was available in the endoscopy suite in eight centers (42.1%). Five endoscopists administered propofol sedation without anesthesiologist's presence (26.3%). Thirteen centers had a written protocol for pre-procedure risk assessment (68.4%). A dedicated post-procedure observation area was available in seventeen centers (89.5%). Seven centers followed a written post-sedation discharge protocol (36.8%). Significant variations exist in the practice of sedation among endoscopists in southern India. There is an urgent need to formulate guidelines by endoscopy societies for ensuring better patient outcomes in endoscopy. PMID- 29611113 TI - Natural and synthetic polymer-based smart biomaterials for management of ulcerative colitis: a review of recent developments and future prospects. AB - Ulcerative colitis (UC) is an inflammatory disease of the colon that severely affects the quality of life of patients and usually responds well to anti inflammatory agents for symptomatic relief; however, many patients need colectomy, a surgical procedure to remove whole or part of the colon. Though various types of pharmacological agents have been employed for the management of UC, the lack of effectiveness is usually predisposed to various reasons including lack of target-specific delivery of drugs and insufficient drug accumulation at the target site. To overcome these glitches, many researchers have designed and characterized various types of versatile polymeric biomaterials to achieve target specific delivery of drugs via oral route to optimize their targeting efficiency to the colon, to improve drug accumulation at the target site, as well as to ameliorate off-target effects of chemotherapy. Therefore, the aim of this review was to summarize and critically discuss the pharmaceutical significance and therapeutic feasibility of a wide range of natural and synthetic biomaterials for efficient drug targeting to colon and rationalized treatment of UC. Among various types of biomaterials, natural and synthetic polymer-based hydrogels have shown promising targeting potential due to their innate pH responsiveness, sustained and controlled release characteristics, and microbial degradation in the colon to release the encapsulated drug moieties. These characteristic features make natural and synthetic polymer-based hydrogels superior to conventional pharmacological strategies for the management of UC. PMID- 29611115 TI - C. elegans-based screen identifies lysosome-damaging alkaloids that induce STAT3 dependent lysosomal cell death. AB - Lysosomes are degradation and signaling centers within the cell, and their dysfunction impairs a wide variety of cellular processes. To understand the cellular effect of lysosome damage, we screened natural small-molecule compounds that induce lysosomal abnormality using Caenorhabditis elegans (C. elegans) as a model system. A group of vobasinyl-ibogan type bisindole alkaloids (ervachinines A-D) were identified that caused lysosome enlargement in C. elegans macrophage like cells. Intriguingly, these compounds triggered cell death in the germ line independently of the canonical apoptosis pathway. In mammalian cells, ervachinines A-D induced lysosomal enlargement and damage, leading to leakage of cathepsin proteases, inhibition of autophagosome degradation and necrotic cell death. Further analysis revealed that this ervachinine-induced lysosome damage and lysosomal cell death depended on STAT3 signaling, but not RIP1 or RIP3 signaling. These findings suggest that lysosome-damaging compounds are promising reagents for dissecting signaling mechanisms underlying lysosome homeostasis and lysosome-related human disorders. PMID- 29611114 TI - Of genes and microbes: solving the intricacies in host genomes. AB - Microbiome research is a quickly developing field in biomedical research, and we have witnessed its potential in understanding the physiology, metabolism and immunology, its critical role in understanding the health and disease of the host, and its vast capacity in disease prediction, intervention and treatment. However, many of the fundamental questions still need to be addressed, including the shaping forces of microbial diversity between individuals and across time. Microbiome research falls into the classical nature vs. nurture scenario, such that host genetics shape part of the microbiome, while environmental influences change the original course of microbiome development. In this review, we focus on the nature, i.e., the genetic part of the equation, and summarize the recent efforts in understanding which parts of the genome, especially the human and mouse genome, play important roles in determining the composition and functions of microbial communities, primarily in the gut but also on the skin. We aim to present an overview of different approaches in studying the intricate relationships between host genetic variations and microbes, its underlying philosophy and methodology, and we aim to highlight a few key discoveries along this exploration, as well as current pitfalls. More evidence and results will surely appear in upcoming studies, and the accumulating knowledge will lead to a deeper understanding of what we could finally term a "hologenome", that is, the organized, closely interacting genome of the host and the microbiome. PMID- 29611116 TI - The Methods and Mechanisms to Differentiate Endothelial-Like Cells and Smooth Muscle Cells from Mesenchymal Stem Cells for Vascularization in Vaginal Reconstruction. AB - Endothelial cells and smooth muscle cells (SMCs) are important aspects of vascularization in vaginal reconstruction. Research has confirmed that mesenchymal stem cells could differentiate into endothelial-like cells and SMCs. But the methods were more complicated and the mechanism was unknown. In the current study, we induced the bone mesenchymal stem cells (BMSCs) to differentiate into endothelial-like cells and SMCs in vitro by differentiation medium and investigated the effect of Wnt/beta-catenin signaling on the differentiation process of BMSCs. Results showed that the hypoxic environment combined with VEGF and bFGF could induce increased expression of endothelial-like cells markers VEGFR1, VEGFR2, and vWF. The SMCs derived from BMSCs induced by TGF beta1 and PDGF-AB significantly expressed SMC markers SMMHC11 and alpha-SMA. The data also showed that activation of Wnt/beta-catenin signaling could promote the differentiation of BMSCs into endothelial-like cells and SMCs. Thus, we established endothelial-like cells and SMCs in vitro by more simple methods, presented the important role of hypoxic environment on the differentiation of BMSCs into endothelial-like cells, and confirmed that the Wnt/beta-catenin signaling pathway has a positive impact on the differentiation of BMSCs into endothelial-like cells and SMCs. This is important for vascular reconstruction. PMID- 29611119 TI - Benefits of recording images during video laryngoscopy for early detection of oropharyngeal and laryngeal lesions: implications for "inattentional blindness". PMID- 29611117 TI - Intestinal perforation by a peritoneal dialysis catheter in which fungal peritonitis led to diagnosis: a rare case report. AB - Intestinal perforation by a peritoneal catheter is an uncommon, but serious, complication that has a high mortality rate. Intestinal perforation in peritoneal dialysis (PD) patients is difficult to diagnose using symptoms and radiological findings, which may result in a delay in diagnosis. Moreover, intestinal perforation complicated with fungal peritonitis is reportedly a severe condition with a poor prognosis. Herein, we report the case of a 78-year-old man on PD, whose diagnosis of perforative peritonitis was difficult to diagnose preoperatively. He was transferred to our hospital complaining of relapsing PD related peritonitis due to Klebsiella oxytoca infection 2 months after the insertion of the PD catheter. He had been treated with various antibiotics in the previous hospital. Over the course of treatment, he complained of diarrhea, which was diagnosed as acute enteritis. Upon admission to our hospital, he had no abnormal clinical signs except for a cloudy PD effluent. Blood examination showed a high C-reactive protein level (8.41 mg/dL), a white blood cell count in the PD fluid of 367 cell/uL (neutrophils 55.1%), and the presence of Candida parapsilosis. We initiated antifungal therapy and, during catheter removal, found evidence of intestine perforations by the PD catheter, which were successfully repaired. After catheter removal and intestine repair, he recovered and was discharged to continue undergoing hemodialysis. Based on our case, we recommend that intestine perforations should be considered as a cause of relapsing PD related peritonitis with abdominal symptoms, particularly watery diarrhea. Furthermore, catheter removal and antifungal administration should be initiated earlier after the diagnosis of fungal peritonitis. PMID- 29611120 TI - Morphological and functional responses of a metal-tolerant sunflower mutant line to a copper-contaminated soil series. AB - The potential use of a metal-tolerant sunflower mutant line for biomonitoring Cu phytoavailability, Cu-induced soil phytotoxicity, and Cu phytoextraction was assessed on a Cu-contaminated soil series (13-1020 mg Cu kg-1) obtained by fading a sandy topsoil from a wood preservation site with a similar uncontaminated soil. Morphological and functional plant responses as well as shoot, leaf, and root ionomes were measured after a 1-month pot experiment. Hypocotyl length, shoot and root dry weight (DW) yields, and leaf area gradually decreased as soil Cu exposure rose. Their dose-response curves (DRC) plotted against indicators of Cu exposure were generally well fitted by sigmoidal curves. The half-maximal effective concentration (EC50) of morphological parameters ranged between 203 and 333 mg Cu kg-1 soil, corresponding to 290-430 MUg Cu L-1 in the soil pore water, and 20 +/- 5 mg Cu kg-1 DW in the shoots. The EC10 for shoot Cu concentration (13 15 mg Cu kg-1 DW) coincided to 166 mg Cu kg-1 soil. Total chlorophyll content and total antioxidant capacity (TAC) were early biomarkers (EC10: 23 and 51 mg Cu kg 1 soil). Their DRC displayed a biphasic response. Photosynthetic pigment contents, e.g., carotenoids, correlated with TAC. Ionome was changed in Cu stressed roots, shoots, and leaves. Shoot Cu removal peaked roughly at 280 MUg Cu L-1 in the soil pore water. PMID- 29611121 TI - Controls on the spatial distribution of iodine in groundwater in the Hebei Plain, China. AB - In the Hebei Plain of North China, 70% of the inhabitants depend on groundwater for drinking water. Little is known regarding high-iodine concentrations in groundwater because there have been few systematic studies on high levels of iodine in groundwater in this region. To help identify the mechanisms that control the spatial distribution of iodine in groundwater, 61 samples of shallow groundwater and 161 samples of deep groundwater were collected along a sample section from Taihang Mountain to the Bo Sea. There were four pockets of high iodine concentrations along the sample section. As the groundwater depth increased, the ratio of undetected iodine decreased, and the ratio of high-iodine concentrations increased. The high-iodine concentrations in the groundwater reflect the geological and sedimentary settings, and were mainly controlled by pH and Eh. Iodine concentrations were particularly high when the pH was between 7.3 and 8.5, and there was an inflection point at 150 MUg/L in the curve of the relationship between iodine concentrations and Eh. PMID- 29611122 TI - A comprehensive air quality investigation at an aquatic centre: Indoor/outdoor comparisons. AB - Air quality and comfort parameters in a naturally ventilated aquatic centre were studied in relation to the outdoor pollution levels. Simultaneous measurements of PM 2.5, as well as of volatile organic compounds, were carried out for the indoor and outdoor environment of the aquatic centre. The chemical analysis of ionic species and trace elements associated with particulate matter was also performed. In addition, automated analyzer for NO2 and O3 was used in order to record the indoor and outdoor levels of these pollutants. Analysis of diurnal variation of the pollutants' concentration was applied to the collected data, allowing the identification of potential variation on the sources affecting the indoor air quality. PM 2.5 concentration was almost two times higher indoors than outdoors with average values of 13.96 and 6.78 MUg/m3, respectively. Concerning the ion fraction of PM 2.5, SO42- and Ca2+ were the ions with higher concentration indoors with values of 1.06 and 0.93 MUg/m3, respectively, while the percentage of Cl- to the PM 2.5 fraction of the indoor atmosphere (9%) was too high than outdoor ones (1%). These results showed that indoor air of swimming pool concerning PM 2.5 and ionic species is mainly affected by the chlorination process along with the comfort conditions (high relative humidity) created during the operation of the facility. The common volatile organic compound concentrations at indoor air are generally in higher levels, compared to the outdoor air with p,m-xylene and toluene to be the substances with the higher concentration for indoor and outdoor area, respectively (7.80 and 1.57 MUg/m3); nevertheless, values were rather low compared with the findings of other studies. Also, they clearly demonstrate a diurnal variation as a result of poor ventilation during night. As it was expected, chloroform showed the highest concentration compared to the other volatile organic compounds with values ranging from 3.35 to 135.89 MUg/m3, with an average of 54.50 MUg/m3. Concerning the NO2 concentration, indoor levels showed an increased pattern when the swimming pool was fully occupied, a fact that reveals a possible correlation. As an overall conclusion, the natural ventilation and the disinfection process seem to play a key role to the air quality of the indoor air of the aquatic centre. PMID- 29611123 TI - Immunocompetence analysis of the aquatic snail Lymnaea stagnalis exposed to urban wastewaters. AB - Wastewater treatment plant effluents from urban area are a well-known source of chronic multiple micropollution to the downstream living organisms. In this study, ecologically relevant laboratory-bred freshwater gastropods, Lymnaea stagnalis, were exposed for 29 days to raw effluents of a wastewater treatment plant in Lyon area (France). A time-course analysis of individual markers of immunocompetence (hemocyte density and viability, hemocyte NADPH activity, phenol oxidase activity, and capacity of phagocytosis) has shown slight trends of inflammatory-like responses induced by the 100% effluents. So far, no short-term hazard for L. stagnalis can be revealed. However, over the long term, such environmental stress-stimulating immune responses could provoke deleterious life history trade-offs because the immune system is known to be highly energy consuming. PMID- 29611124 TI - UVAlpha pre-irradiation to P25 titanium dioxide nanoparticles enhanced its toxicity towards freshwater algae Scenedesmus obliquus. AB - There has recently been an increase in the usage of TiO2 nanoparticles (NPs). P25 TiO2 NPs, a mixture of anatase and rutile phase in 3:1 ratio, are generally used for photocatalytic applications because both phases exhibit a synergistic effect on the photocatalytic activity of the TiO2 NPs. In the present study, increased toxicity of UVA-pre-irradiated P25 TiO2 NPs on freshwater algae Scenedesmus obliquus was assessed under visible light and dark exposure conditions at actual low concentrations (0.3, 3 and 35 MUM of Ti). Photocatalytic property of P25 TiO2 NPs caused disaggregation of UVA-pre-irradiated NPs, thus significantly decreasing the mean hydrodynamic diameter (MHD) (188.74 +/- 0.54 nm) than that of non-irradiated NPs (232.26 +/- 0.44). This decrease in diameter of UVA-pre irradiated NPs may increase its biological activity towards algal samples. All concentrations of pre-irradiated NPs, under both light and dark conditions, showed a significantly lesser cell viability (p < 0.001) when compared with non irradiated NPs. Increased production of ROS, antioxidant enzymes and lipid peroxidation supported the viability data. Higher exopolysaccharide production and more nuclear damage were observed for pre-irradiated NPs. NP uptake was also more for the pre-irradiated NPs on treated samples when compared with non irradiated NPs on treated samples, which, in turn, established the higher toxic potential of UVA-pre-irradiated TiO2 NPs. This study improves our understanding of the toxic effects of UVA-pre-irradiated TiO2 NPs on freshwater algae, thereby emphasising the need for ecological risk assessments of metal oxide nanoparticles in a natural experimental medium. PMID- 29611125 TI - Experimental assessment and validation of quantification methods for cellulose content in municipal wastewater and sludge. AB - Cellulose, mostly in the form of toilet paper, forms a major component of the particulates in raw municipal wastewater, which could lead to significant consequences due to the potential accumulation of cellulosic fibers and slow biodegradability. Despite the sparse reports on cellulose content and degradation in wastewater and sludge, an accurate and validated method for its quantification in such matrices does not exist. In this paper, four different methods were compared including dilute acid hydrolysis, concentrated acid hydrolysis, enzymatic hydrolysis, and the Schweitzer reagent method. The Schweitzer reagent method, applied to municipal wastewater and sludge, was found to be a very robust and reliable quantification method in light of its reproducibility, accuracy, and ideal (100%) recovery. The determination of cellulose content is critical to understand its fate in wastewater treatment plants as well as improve sludge management and enhance resource recovery. PMID- 29611126 TI - Mode of action of nanoparticles against insects. AB - The employment of nanoparticles obtained through various synthesis routes as novel pesticides recently attracted high research attention. An impressive number of studies have been conducted to test their toxic potential against a wide number of arthropod pests and vectors, with major emphasis on mosquitoes and ticks. However, precise information on the mechanisms of action of nanoparticles against insects and mites are limited, with the noteworthy exception of silica, alumina, silver, and graphene oxide nanoparticles on insects, while no information is available for mites. Here, I summarize current knowledge about the mechanisms of action of nanoparticles against insects. Both silver and graphene oxide nanoparticles have a significant impact on insect antioxidant and detoxifying enzymes, leading to oxidative stress and cell death. Ag nanoparticles also reduced acetylcholinesterase activity, while polystyrene nanoparticles inhibited CYP450 isoenzymes. Au nanoparticles can act as trypsin inhibitors and disrupt development and reproduction. Metal nanoparticles can bind to S and P in proteins and nucleic acids, respectively, leading to a decrease in membrane permeability, therefore to organelle and enzyme denaturation, followed by cell death. Besides, Ag nanoparticles up- and downregulate key insect genes, reducing protein synthesis and gonadotrophin release, leading to developmental damages and reproductive failure. The toxicity of SiO2 and Al2O3 nanoparticles is due to their binding to the insect cuticle, followed by physico-sorption of waxes and lipids, leading to insect dehydration. In the final section, insect nanotoxicology research trends are critically discussed, outlining major challenges to predict the ecotoxicological consequences arising from the real world use of nanoparticles as pesticides. PMID- 29611127 TI - The levels of polycyclic aromatic hydrocarbons (PAHs) in human milk and exposure risk to breastfed infants in petrochemical industrialized Lanzhou Valley, Northwest China. AB - We investigated in this paper the presence of PAHs in human milk from lactating women residing in Lanzhou, a petrochemical industrialized valley city in Northwest China. The PAH concentration levels in human milk samples from 98 healthy women were determined by gas chromatography/mass spectrometry (GC/MS). The associations between the lifestyle factors and the PAHs levels of human milk were analyzed. Moreover, we applied principal component analysis (PCA) method to gain a better insight into the similarities or dissimilarities of the human milk PAH loads and different pathways of source exposure. In addition, the exposure risks of breastfed infants due to PAH ingestion via breast milk were assessed and the relative breast-feeding risk to the total intake dose of infants was addressed. The results showed that the average fat-normalized human milk ?15PAHs concentrations for the lactating women residing in four districts of Lanzhou, namely, Xigu, Anning, Qilihe, and Chengguan were 320.40, 270.36, 374.04, and 259.84 ng/g of fat, respectively. The ?15PAHs of human milk from the lactating women of Qilihe District exhibited the highest concentration level, while the concentration level for women from Xigu District is the second highest for the observed human milk ?15PAHs. And the corresponding BaPeq concentrations for women in Xigu, Anning, Qilihe, and Chengguan districts were 58.29, 47.95, 65.13, and 45.60 ng/g of fat, respectively. A significant correlation was only found between human milk and living district environment (p < 0.05). Although the Spearman correlation analysis showed that there were no significant correlation existing between other lifestyle and human milk PAHs, we confirmed that consuming barbecue food could elevate PAHs levels in human milk: the barbecue intake frequency caused 10% fluctuation of ?15PAHs concentration between high frequency and low frequency group in our study. Furthermore, the exposure to second-hand smoke can also increase the ?15PAHs levels in human milk by 4 to 11% here. Ingestion doses of PAHs by infants (19.37-77.75 ng kg-1 day-1) were much higher than the inhalation doses (2.83-16.48 ng kg-1 day-1), which indicated that the ingestion is the main exposure risk pathway for infants. Since there are limited guidelines and standards for PAHs ingestion dose in human milk by infant, we compared the ingestion dose of BaP with the upper bound estimates of BaP dietary exposure of 108 ng kg-1 day-1 for toddlers of ages between 1.5 and 2.5 years of age in the UK reported by Committee on Toxicity of Chemicals in Food (COT) and the data we obtained were lower than this upper bound. However, the estimated margin of exposure (MOE) values of BaP-MOE, PAH2-MOE, PAH4-MOE, and PAH8-MOE were smaller than 10,000 which indicated that there are potential hazard for breastfed infants consuming these human milk samples. PMID- 29611128 TI - Identification and quantitation of semi-crystalline microplastics using image analysis and differential scanning calorimetry. AB - There are several techniques used to analyze microplastics. These are often based on a combination of visual and spectroscopic techniques. Here we introduce an alternative workflow for identification and mass quantitation through a combination of optical microscopy with image analysis (IA) and differential scanning calorimetry (DSC). We studied four synthetic polymers with environmental concern: low and high density polyethylene (LDPE and HDPE, respectively), polypropylene (PP), and polyethylene terephthalate (PET). Selected experiments were conducted to investigate (i) particle characterization and counting procedures based on image analysis with open-source software, (ii) chemical identification of microplastics based on DSC signal processing, (iii) dependence of particle size on DSC signal, and (iv) quantitation of microplastics mass based on DSC signal. We describe the potential and limitations of these techniques to increase reliability for microplastic analysis. Particle size demonstrated to have particular incidence in the qualitative and quantitative performance of DSC signals. Both, identification (based on characteristic onset temperature) and mass quantitation (based on heat flow) showed to be affected by particle size. As a result, a proper sample treatment which includes sieving of suspended particles is particularly required for this analytical approach. PMID- 29611129 TI - Does the application of silicon and Moringa seed extract reduce heavy metals toxicity in potato tubers treated with phosphate fertilizers? AB - Two field trials were carried out in two successive agricultural seasons to study the possibility of using silicon (Si) and Moringa seed extract (MSE) for reducing heavy metal contamination resulting from phosphate fertilizers addition to potato tubers. A randomized complete block design experiment was performed using three replicates. Various sources of phosphate fertilizers as ordinary super phosphate and rock phosphate were added at rate of 100 kg P ha-1 prior sowing. Silicon was added as potassium silicate (20% SiO2) at rate of 6 L ha-1, and MSE was also added at rate of 150 L ha-1 in three equal doses with the 2nd, 4th, and 6th irrigations during the last 10 min of drip irrigation. Results indicated that the addition of phosphate fertilizers increased fresh tuber yield, dry weight yield, NPK uptake, catalase, peroxidase, superoxide dismutase, and glutathione reductase of potato either alone or combined with silicon and MSE. The accumulation rate of Cu, Cd, and Ni in potato was higher with the single addition of rock phosphate fertilizer compared with single addition of super phosphate fertilizer. The highest reduction (P < 0.05) in heavy metal accumulation in potato leaves and tubers as well as soil was found with MSE treatment plus super phosphate fertilizer. It is recommended to add MSE at a rate of 150 L ha-1 along with fertilizing the potato crop with ordinary super phosphate fertilizer. PMID- 29611130 TI - Understanding the Disease Course and Therapeutic Benefit of Tafamidis Across Real World Studies of Hereditary Transthyretin Amyloidosis with Polyneuropathy: A Proof of Concept for Integrative Data Analytic Approaches. AB - INTRODUCTION: Hereditary transthyretin (TTR) amyloidosis with polyneuropathy (hATTR-PN) is a rare, autosomal dominant amyloidosis characterized primarily by progressive ascending sensorimotor neuropathy often associated with autonomic involvement. hATTR-PN is caused by a mutation in the TTR gene leading to protein misfolding and amyloid accumulation in peripheral nerves and vital organs. The latest global prevalence estimates point to 10,000 cases worldwide, with an upper end of about 40,000. Tafamidis has been approved in over 40 countries for delaying neurologic disease progression in early-stage hATTR-PN. Multiple observational studies have examined clinical outcomes in hATTR-PN patients treated with tafamidis in the routine clinical setting. Integrative data analysis (IDA) is a technique for optimally constructing synthetic treatment and control cohorts from multiple independent studies, which allows meta-analysis of patient level data. Herein, we provide a proof of concept for the application of IDA to real-world and natural history hATTR-PN data. IDA permits increased understanding of outcomes in tafamidis-treated and untreated persons with hATTR-PN by optimally pooling all available information. METHODS: Summary statistics corresponding to the Neuropathy Impairment Score-Lower Limb (NIS-LL) from five published studies were pooled, converted to change from baseline means and variances, and analyzed using IDA. IDA-based synthetic cohorts were generated by averaging across studies stratified on treatment versus control cohort. Trends in change from baseline in each study and the corresponding synthetic cohorts were plotted. Patient-level data were simulated from the synthetic cohort trends in a Monte Carlo simulation to highlight the ability to contrast synthetic cohort trends using the mixed model for repeated measures (MMRM). RESULTS: The average sample size among the five studies was 71 (37-128) patients. The average NIS-LL trends indicated that tafamidis-treated patients experienced slower progression in neuropathy compared to untreated patients. Synthetic cohort trends reflected the trends observed in the contributing studies, while simultaneously shrinking the width of corresponding confidence bands. Monte Carlo simulation results demonstrated precise recovery of the synthetic cohort and time-dependent simulated NIS-LL means by the MMRM. DISCUSSION: This proof of concept demonstrates the utility of IDA-based synthetic cohorts for increased precision in characterizing and testing hypotheses about treatment outcomes and prognosis in hATTR-PN. FUNDING: Pfizer. Plain language summary available for this article. PMID- 29611131 TI - The Rare Disease Bank of Japan: establishment, current status and future challenges. AB - Research on rare diseases cannot be performed without appropriate samples from patients with such diseases. Due to the limited number of such patients, securing biosamples of sufficient quality for extensive research is a challenge and represents an important barrier to the advancement of research on rare diseases. To tackle this problem, the Rare Disease Bank (RDB) was established in 2009 at the National Institute of Biomedical Innovation (NIBIO; currently, the National Institutes of Biomedical Innovation, Health and Nutrition in Japan). Since then, the RDB has focused on three objectives: (1) emphasizing the importance of collecting biosamples from patients with rare diseases, together with appropriate clinical information, from various medical facilities nationwide; (2) maintaining strict high-quality sample management standards; and (3) sharing biosamples with research scientists across Japan for the advancement of research on rare diseases. As of August 2017, the bank has collected 4147 biosamples from patients with rare diseases, including DNA, serum, plasma, and cell samples from various university hospitals and other medical institutions across the country, and provided various research institutions with 13,686 biosample aliquots from 2850 cases. In addition, the management committee has successfully established a bank system that provides high-quality biosamples together with the results of human leukocyte antigen analysis. It is anticipated that the RDB, through the collection and sharing of biosamples with the medical research community, will enhance the understanding, prevention, and treatment of rare diseases in Japan and the world at large. PMID- 29611133 TI - Satisfactory arterial healing after second-generation drug-eluting stent implantation for segmental stenosis in a patient with Kawasaki disease. PMID- 29611132 TI - Modulation of diabetes-related liver injury by the HMGB1/TLR4 inflammatory pathway. AB - Chronic inflammation plays an essential role in the development of diabetic complications. Understanding the molecular mechanisms that support inflammation is a prerequisite for the design of novel anti-inflammatory therapies. These would take into consideration circulating levels of cytokines and damage associated molecular patterns (DAMPs) that include the high mobility group box 1 (HMGB1) protein which, in part, promotes the inflammatory response through TLR4 signaling. The liver, as the source of circulating cytokines and acute-phase proteins, contributes to the control of systemic inflammation. We previously found that liver injury in streptozotocin-induced diabetic rats correlated with the level of oxidative stress, increased expression of HMGB1, and with the activation of TLR4-mediated cell death pathways. In the present work, we examined the effects of ethyl pyruvate (EP), an inhibitor of HMGB1 release/expression, on the modulation of activation of the HMGB1/TLR4 inflammatory cascade in diabetic liver. We observed that increased expression of inflammatory markers, TNF-alpha, IL-6, and haptoglobin in diabetic liver was associated with increased HMGB1/TLR4 interaction, activation of MAPK (p38, ERK, JNK)/NF-kappaB p65 and JAK1/STAT3 signaling pathways, and with decreased expression of Nrf2-regulated antioxidative enzymes. The reduction in HMGB1 expression as the result of EP administration reduced the pro-inflammatory activity of HMGB1 and exerted a protective effect on diabetic liver, which was observed as improved liver histology and antioxidant and inflammatory statuses. Our results suggest that prevention of HMGB1 release and blockage of the HMGB/TLR4 axis represents a potentially effective therapeutic strategy aimed at ameliorating diabetes-induced inflammation and ensuing liver injury. PMID- 29611134 TI - An Overview of the Genetics of Plant Response to Salt Stress: Present Status and the Way Forward. AB - Salinity is one of the major threats faced by the modern agriculture today. It causes multidimensional effects on plants. These effects depend upon the plant growth stage, intensity, and duration of the stress. All these lead to stunted growth and reduced yield, ultimately inducing economic loss to the farming community in particular and to the country in general. The soil conditions of agricultural land are deteriorating at an alarming rate. Plants assess the stress conditions, transmit the specific stress signals, and then initiate the response against that stress. A more complete understanding of plant response mechanisms and their practical incorporation in crop improvement is an essential step towards achieving the goal of sustainable agricultural development. Literature survey shows that investigations of plant stresses response mechanism are the focus area of research for plant scientists. Although these efforts lead to reveal different plant response mechanisms against salt stress, yet many questions still need to be answered to get a clear picture of plant strategy to cope with salt stress. Moreover, these studies have indicated the presence of a complicated network of different integrated pathways. In order to work in a progressive way, a review of current knowledge is critical. Therefore, this review aims to provide an overview of our understanding of plant response to salt stress and to indicate some important yet unexplored dynamics to improve our knowledge that could ultimately lead towards crop improvement. PMID- 29611135 TI - A Chimeric Two-Component Regulatory System-Based Escherichia coli Biosensor Engineered to Detect Glutamate. AB - In this study, we constructed amino acid biosensors that can be used as a high throughput system to screen microorganisms that produce glutamate. The biosensors are based on two-component regulatory systems (TCRSs) combined with green fluorescent protein (GFP) as a reporter. A chimeric DegS/EnvZ (DegSZ) TCRS was constructed by fusing the N-terminal domain of the sensor kinase DegS from Planococcus sp. PAMC21323 with the catalytic domain of the osmosensor EnvZ from Escherichia coli to control expression of gfp in response to glutamate. gfp was controlled by the ompC promoter through the activated response regulator OmpR-P. The chimeric TCRS-based biosensors showed a 4-fold increase in the fluorescent signal after adding glutamate. A linear correlation was observed between fluorescence intensity and exogenously added glutamate concentration. The chimeric TCRS-based biosensor was used to determine glutamate concentration at the single-cell level by fluorescence-activated cell sorting. Therefore, this biosensor can be used to isolate novel gene products and optimize pathways involved in amino acid production. PMID- 29611136 TI - Cytotoxicity of Silica Nanoparticles with Transcaucasian Nose-Horned Viper, Vipera ammodytes transcaucasiana, Venom on U87MG and SHSY5Y Neuronal Cancer Cells. AB - Highly bioactive compounds of the snake venom make them particular sources for anticancer agent development. They contain very rich peptide-protein structures. Therefore, they are very susceptible to environmental conditions such as temperature, pH, and light. In this study, Vipera ammodytes transcaucasiana venom was encapsulated in PAMAM-G4 dendrimer by sol-gel method in order to prevent degradation of venom contents from the environmental conditions. For this purpose, nanoparticles were prepared by sol-gel methodology and SEM analyses were performed. U87MG and SHSY5Y neuronal cancer cell lines were treated with different concentrations of venom-containing nanoparticles and cytotoxicity was determined by MTT assay. IC50 values of nanoparticles with snake venom were calculated as 37.24 and 44.64 MUg/ml for U87MG and SHSY5Y cells, respectively. The IC50 values of nanoparticles with snake venom were calculated as 10.07 and 7.9 MUg/ml for U87MG and SHSY5Y cells, respectively. As a result, nanoparticles with V. a. transcaucasiana venom showed remarkably high cytotoxicity. Encapsulation efficiency of nanoparticles with 1 mg/ml snake venom was determined as %67 via BCATM protein analysis. In conclusion, this method is found to be convenient and useful for encapsulating snake venom as well as being suitable for drug delivery systems. PMID- 29611137 TI - Taxonomic description and genome sequence of Halobacillus marinus sp. nov., a novel strain isolated from Chilika Lake, India. AB - moderately halophilic spore forming, motile, Gram-positive, rod-shaped bacterial strain designated as KGW1T was isolated from water sample of Chilika Lake and characterized taxonomically using polyphasic approach. The strain grew in the presence of 0-25% (w/v) NaCl in marine salt agar media, hydrolyzes casein, and gelatin and shows presence of alkaline proteases. The major cell wall menaquinone was MK7 and major cellular fatty acids were anteiso-C15:0 (44.89%), anteiso-C17:0 (6.18%), isoC15:0 (19.38%), and iso-C16:0 (7.39%). Several chemotaxonomic features conform the isolate be a member of genus Halobacillus. The isolate KGW1T contained A1gamma meso-Dpm-direct type of peptidoglycan which is different from its phylogenetically closest neighbours. The 16S rRNA gene sequence based phylogenetic analysis also revealed the strain KGW1T was affiliated to the genus Halobacillus and sequence similarity between the isolated strain and the type strains of Halobacillus species were found closest to, H. dabanensis D-8 DSM 18199T (99.08%) and H. faecis IGA7-4 DSM 21559T (99.01%), H. trueperi SL-5 DSM 10404T (98.94%). The in silico DDH showed that the values in a range of 14.2 17.5% with the most closest strain H. dabanensis D-8 DSM 18199T and other type strains of the genus Halobacillus for which whole genome sequence is reported. DNA-DNA relatedness between strain KGW1T and the closest type strain Halobacillus trueperi DSM 10404T was 11.75% (+/- 1.15). The draft genome sequence includes 3,683,819 bases and comprises of 3898 predicted coding sequences with a G + C content of 46.98%. Thus, the significant distinctiveness supported by phenotypic and genotypic data with its closest neighbors and other closely related species confirm the strain KGW1T to be classified as a novel species within the genus Halobacillus, for which the name Halobacillus marinus sp. nov. is proposed. The type strain is KGW1T (= DSM 29522 = JCM 30443). PMID- 29611138 TI - Hymenobacter terrigena sp. nov., isolated from soil. AB - A Gram-stain-negative, non-motile, non-spore-forming, rodshaped, aerobic bacterial strain, designated S1-2-2-5T, was isolated from the Jeollabuk-do province, Republic of Korea, and was characterized taxonomically using a polyphasic approach. Comparative 16S rRNA gene sequence analysis showed that strain S1-2-2-5T belonged to the family Cytophagaceae in phylum Bacteroidetes, and was most closely related to Hymenobacter terrae DG7AT (98.2%), Hymenobacter rubidus DG7BT (98.0%), Hymenobacter soli PB17T (97.7%), Hymenobacter daeguensis 16F3Y-2T (97.2%) and Hymenobacter saemangeumensis GSR0100T (97.0%). The G + C content of the genomic DNA of strain S1-2-2-5T was 59.4 mol%. The detection of menaquinone MK-7 as the predominant respiratory quinone, a fatty acid profile with summed feature 3 (C16:1omega7c/C16:1omega6c; 32.0%), C15:0 iso (19.0%), and C15:0 anteiso (15.0%) as the major components, and a polar lipid profile with phosphatidylethanolamine as the major component supported the affiliation of strain S1-2-2-5T to the genus Hymenobacter. The DNA-DNA relatedness between strain S1-2-2-5T and H. terrae KCTC 32554T, H. rubidus KCTC 32553T, H. soli KCTC 12607T, H. daeguensis KCTC 52537T, and H. saemangeumensis KACC 16452T were 49.5, 48.2, 34.1, 28.1, and 31.8% respectively, clearly showing that the isolate is not related to them at the species level. Strain S1-2-2-5T could be clearly differentiated from its closest neighbors on the basis of its phenotypic, genotypic and chemotaxonomic features. Therefore, strain S1-2-2-5T represents a novel species of the genus Hymenobacter, for which the name Hymenobacter terrigena sp. nov. is proposed. The type strain is S1-2-2-5T (= KCTC 52737T = JCM 32195T). PMID- 29611139 TI - Identification of a novel phospholipase D gene and effects of carbon sources on its expression in Bacillus cereus ZY12. AB - In the present study, a new strain, Bacillus cereus ZY12, producing phospholipase D (PLD) was identified. The expression of PLD in this strain was found to be induced by its substrate, phosphatidylcholine (PC), and completely silenced by other carbon sources, such as glucose, fructose, and maltose, which are generally used in microbial growth cultures, thus presenting a unique expression pattern different from other PLD-producing microorganisms. This study is the first to report on the ability of B. cereus to produce PLD, and successfully clone its PLD coding gene and identify its function, extending the knowledge on PLD distribution and evolution in microorganisms. PMID- 29611140 TI - A murine colitis model developed using a combination of dextran sulfate sodium and Citrobacter rodentium. AB - Adult mice were treated with dextran sulfate sodium (DSS) and infected with Citrobacter rodentium for developing a novel murine colitis model. C57BL/6N mice (7-week-old) were divided into four groups. Each group composed of control, dextran sodium sulfate-treated (DSS), C. rodentium-infected (CT), and DSS-treated and C. rodentium-infected (DSS-CT) mice. The DSS group was administered 1% DSS in drinking water for 7 days. The CT group was supplied with normal drinking water for 7 days and subsequently infected with C. rodentium via oral gavage. The DSS CT group was supplied with 1% DSS in drinking water for 7 days and subsequently infected with C. rodentium via oral gavage. The mice were sacrificed 10 days after the induction of C. rodentium infection. The DSS-CT group displayed significantly shorter colon length, higher spleen to body weight ratio, and higher histopathological score compared to the other three groups. The mRNA expression levels of tumor necrosis factor (TNF)-alpha and interferon (INF)-gamma were significantly upregulated; however, those of interleukin (IL)-6 and IL-10 were significantly downregulated in the DSS-CT group than in the control group. These results demonstrated that a combination of low DSS concentration (1%) and C. rodentium infection could effectively induce inflammatory bowel disease (IBD) in mice. This may potentially be used as a novel IBD model, in which colitis is induced in mice by the combination of a chemical and a pathogen. PMID- 29611141 TI - The influence of making judgments of learning on memory performance: Positive, negative, or both? AB - A common measure of memory monitoring--judgments of learning (JOLs)--has recently been shown to have reactive effects on learning. When participants study a list of related and unrelated word pairs, they recall more related than unrelated pairs. This relatedness effect is larger when people make JOLs than when they do not make them. Evidence is mixed concerning whether this increased relatedness effect arises because JOLs help memory for related pairs, hurt it for unrelated pairs, or do both. In three experiments, we investigated (1) the nature of the increased relatedness effect (i.e., does it arise from positive reactivity for related pairs, negative reactivity for unrelated pairs, or both?) and (2) the mechanisms underlying the effect. Participants studied cue-target word pairs and either did (or did not) make immediate JOLs and then completed a cued-recall test. When participants studied a mixed list consisting of related and unrelated pairs, the increased relatedness effect was largely driven by positive reactivity. When participants studied pure lists consisting solely of related or unrelated word pairs (Experiment 2 only), the increased relatedness effect was minimized. These and other findings suggest that making JOLs helps learning more than hurts it, and that this reactive effect partly occurs because making JOLs changes people's learning goals. PMID- 29611142 TI - Combined Transcranial Direct Current Stimulation and Virtual Reality-Based Paradigm for Upper Limb Rehabilitation in Individuals with Restricted Movements. A Feasibility Study with a Chronic Stroke Survivor with Severe Hemiparesis. AB - Impairments of the upper limb function are a major cause of disability and rehabilitation. Most of the available therapeutic options are based on active exercises and on motor and attentional inclusion of the affected arm in task oriented movements. However, active movements may not be possible after severe impairment of the upper limbs. Different techniques, such as mirror therapy, motor imagery, and non-invasive brain stimulation have been shown to elicit cortical activity in absence of movements, which could be used to preserve the available neural circuits and promote motor learning. We present a virtual reality-based paradigm for upper limb rehabilitation that allows for interaction of individuals with restricted movements from active responses triggered when they attempt to perform a movement. The experimental system also provides multisensory stimulation in the visual, auditory, and tactile channels, and transcranial direct current stimulation coherent to the observed movements. A feasibility study with a chronic stroke survivor with severe hemiparesis who seemed to reach a rehabilitation plateau after two years of its inclusion in a physical therapy program showed clinically meaningful improvement of the upper limb function after the experimental intervention and maintenance of gains in both the body function and activity. The experimental intervention also was reported to be usable and motivating. Although very preliminary, these results could highlight the potential of this intervention to promote functional recovery in severe impairments of the upper limb. PMID- 29611143 TI - Biospecimen Education Among Pacific Islanders in Southern California. AB - Despite increasing rates of cancer, biospecimen donations for cancer research remains low among Pacific Islanders (PIs). To address this disparity, researchers partnered with PI community organizations to develop and test a theory-based culturally tailored educational intervention designed to raise awareness about the issues surrounding biospecimen research. A total of 219 self-identified PI adults in Southern California were recruited to participate in a one-group pre post design study. Participants completed questionnaires that assessed their knowledge and attitude regarding biospecimen research before and after viewing an educational video and receiving print materials. Results showed that participants' overall knowledge and attitude increased significantly from pre test to post-test (p < .0001). Over 98% of participants also reported that they would be willing to donate at least one type of biospecimen sample. Efforts such as these that utilize culturally tailored education interventions may be instrumental in improving biospecimen donation rates in the PI community as well as other minority populations. PMID- 29611144 TI - Treatment dose and the elimination rates of electrolytes, vitamins, and trace elements during continuous veno-venous hemodialysis (CVVHD). AB - INTRODUCTION: During continuous renal replacement therapy, achievement of recommended treatment dose is important. However, relevant substrate loss may occur and recommended nutrition during critical illness could not be sufficient for higher dialysis doses. We investigated the correlation of dialysis dose and substrate loss for a broad range of dialysis doses. METHODS: Forty critically ill patients with acute kidney injury undergoing citrate CVVHD were included in this prospective study. Three different corresponding blood flow (BF) and dialysate flow (DF) rates were applied (BF/DF: 100 ml/min, 2000 ml/h; 80 ml/min, 1500 ml/h; 120 ml/min, 2500 ml/h). Delivered effluent flow rate (DEFR) was calculated and correlated with losses of vitamins, electrolytes, and trace elements during recommended nutritional supplementation. RESULTS: For folic acid, vitamin B12, zinc, inorganic phosphate, and magnesium, no correlation of losses and DEFR was detected. For ionized calcium, a correlation was observed and additional substitution was required. CONCLUSION: Clinically relevant loss of folic acid, vitamin B12, zinc, inorganic phosphate, and magnesium was not observed for differently used dialysis doses of CVVHD, and the loss was covered sufficiently by daily recommended nutritional supplementation. Increased loss of ionized calcium for higher dialysis doses occurred during citrate CVVHD. Therefore, a strict protocol must maintain calcium homeostasis to avoid calcium depletion. PMID- 29611145 TI - Elevated visceral obesity quantified by CT is associated with adverse postoperative outcome of laparoscopic radical nephrectomy for renal clear cell carcinoma patients. AB - PURPOSE: To examine the association between CT measures of visceral obesity and short-term postoperative outcomes in renal clear cell carcinoma (RCCC) patients. METHODS: In this retrospective study, 76 patients treated with unilateral laparoscopic radical nephrectomy for stage I-III renal cancer were classified as obese or non-obese by preoperative CT-based measures of adiposity [obese: visceral fat area (VFA) > 100 cm2, BMI >= 28 kg/m2]. Clinical variables, Fuhrman grade, operation time, estimated blood loss (EBL), postoperative complications, postoperative stay, drainage time and hospitalization expenses were compared between the two groups. RESULTS: Viscerally obese patients significantly had higher Fuhrman grade than the non-obese (p = 0.018). The operation time of obese patients by VFA or BMI was more than the non-obese (171.6 +/- 68.9 vs. 140.8 +/- 35.5 min, p = 0.012 and 197.2 +/- 67.2 vs. 153.2 +/- 57.7 min, p = 0.013, respectively). And obese patients by VFA or BMI tended to have more EBL than non obese (132.0 +/- 120.7 vs. 83.8 +/- 53.4 ml, p = 0.018 and 215.3 +/- 165.0 vs. 92.5 +/- 68.8 ml, p = 0.013, respectively). Viscerally obese patients by VFA (not BMI) were more likely to develop postoperative complications as compared to patients classified as non-obese: VFA (26.9 vs. 4.2%, p = 0.045) and BMI (33.3 vs. 16.4%, p =0.265). Furthermore, obese patients by VFA (not BMI) were more likely to have longer postoperative stay: VFA (8.7 +/- 2.5 vs. 7.5 +/- 1.4 dollars, p = 0.013) and BMI (9.1 +/- 2.9 vs. 8.1 +/- 2.1 dollars, p = 0.209). Obese patients expensed more than non-obese: VFA (7570.9 +/- 2674.3 vs. 6368.8 +/ 1289.8 dollars, p = 0.040) and BMI (8390.8 +/- 2929.7 vs. 6896.3 +/- 2159.1 dollars, p = 0.029). CONCLUSIONS: Elevated visceral obesity by VFA is associated with increased surgical complexity, postoperative morbidity, postoperative stay and hospitalization expenses for RCCC patients and may be superior to BMI for renal cancer outcome assessment. VFA may be a useful index for the evaluation and calculation of RCCC aggressiveness. PMID- 29611146 TI - A care bundle to improve perioperative mitomycin use in non-muscle-invasive bladder cancer. AB - PURPOSE: Intravesical chemotherapy administered within 24 h of the first resection of non-muscle-invasive bladder cancer (NMIBC) reduces recurrence rates and prolongs recurrence-free intervals. However, there is considerable variation in the use of intravesical chemotherapy amongst urologists. In our hospital, we use mitomycin C (MMC), and our usage was inconsistent. Therefore, we devised a care bundle to improve MMC usage. The objective of this study was to evaluate the effectiveness of the care bundle on postoperative MMC use. METHODS: We measured baseline postoperative MMC use during the first quarter of 2013. In 2014, we implemented a care bundle by changing MMC delivery, through computer-based clinical information systems and repeated training of key stakeholders. We studied the performance of the bundle through snapshot audits in the last quarter of 2014, a 6-month period in the middle of 2015 and again in the final quarter of 2016. RESULTS: We observed an increase in intravesical chemotherapy usage after implementing the care bundle. Instillation rates in our samples increased from 46% (6/13), in 2013 to 89% (8/9), in 2014, 90% (9/10), in 2015 and 100% (12/12), in 2016. CONCLUSION: Compliance rates of intravesical chemotherapy in NMIBC can improve by devising care bundles to modify team behaviour. PMID- 29611147 TI - Effect of improved navigation performance on the accuracy of implant placement in total hip arthroplasty with a CT-based navigation system. AB - A computed tomography (CT)-based navigation system is one of the support tools to place implant with appropriate alignment and position in total hip arthroplasty (THA). To determine whether the higher performance of the navigation would further improve the accuracy of implant placement in the clinical setting, we retrospectively compared the navigation accuracy of two different versions of a navigation system. The newer version of the navigation system had an upgraded optical sensor with superior positional accuracy. Navigation accuracy, defined as differences between postoperative measurements on CT images and intraoperative records on the navigation system, of 49 THAs performed with the newer version of the navigation system was compared with that of 49 THAs performed with the older version. With the newer version, the mean absolute accuracy (95% limits of agreement) of implant alignment was 1.2 degrees (+/- 3.3 degrees ) for cup inclination, 1.0 degrees (+/- 2.4 degrees ) for cup anteversion, 2.0 degrees (+/- 4.9 degrees ) for stem anteversion, and 1.1 degrees (+/- 2.4 degrees ) for stem valgus angle. The accuracy of the implant position was 1.5 mm (+/- 3.1 mm), 1.3 mm (+/- 3.0 mm), and 1.5 mm (+/- 3.1 mm) for cup x-, y-, and z-axes, respectively, 1.6 mm (+/- 3.2 mm), 1.4 mm (+/- 2.9 mm), and 1.5 mm (+/- 2.7 mm) for stem x-, y-, and z-axes, respectively, and 2.4 mm (+/- 4.5 mm) for leg length discrepancy. The values for the newer version were significantly more accurate with less variation compared to those of the older version. With upgraded navigation performance, more accurate implant placement was demonstrated in the clinical setting. PMID- 29611149 TI - Effect of ambient temperature on the proliferation of brown adipocyte progenitors and endothelial cells during postnatal BAT development in Syrian hamsters. AB - In Syrian hamsters, brown adipose tissue (BAT) develops postnatally through the proliferation and differentiation of brown adipocyte progenitors. In the study reported here, we investigated how ambient temperature influenced BAT formation in neonatal hamsters. In both hamsters raised at 23 or 30 degrees C, the interscapular fat changed from white to brown coloration in an age-dependent manner and acquired the typical morphological features of BAT by day 16. However, the expression of uncoupling protein 1, a brown adipocyte marker, and of vascular endothelial growth factor alpha were lower in the group raised at 30 degrees C than in that raised at 23 degrees C. Immunofluorescent staining revealed that the proportion of Ki67-expressing progenitors and endothelial cells was lower in the 30 degrees C group than in the 23 degrees C group. These results indicate that warm ambient temperature suppresses the proliferation of brown adipocyte progenitors and endothelial cells and negatively affects the postnatal development of BAT in Syrian hamsters. PMID- 29611148 TI - What is the current evidence of the impact on quality of life whilst waiting for management/treatment of orthopaedic/musculoskeletal complaints? A systematic scoping review. AB - PURPOSE: To describe quality of life (QoL) outcome measures that are reported in the literature in patients waiting for outpatient orthopaedic/musculoskeletal specialist care and how waiting impacts on QoL in these terms. METHODS: A subset of studies reporting on QoL outcome measures were extracted from literature identified in a recent scoping search of Medline, Embase, Pubmed, NHS Economic Evaluation Database (Prospero registration CRD42016047332). The systematic scoping search examined impacts on patients waiting for orthopaedic specialist care. Two independent reviewers ranked study design using the National Health and Medical Research Council aetiology evidence hierarchy, and appraised study quality using Critical Appraisal Skills Programme tools. QoL measures were mapped against waiting period timepoints. RESULTS: The scoping search yielded 142 articles, of which 18 reported on impact on QoL. These studies reported only on patients waiting for hip and/or knee replacement surgery. The most recent study reported on data collected in 2006/7. The Western Ontario and McMaster Universities Arthritis Index and the SF-36 were the most commonly reported QoL measures. QoL was measured at variable timepoints in the waiting period (from a few weeks to greater than 12 months). The impact of waiting on QoL was inconsistent. CONCLUSION: The evidence base was over 10 years old, reported only on patients with hip and knee problems, and on limited QoL outcome measures, and with inconsistent findings. A better understanding of the impact on QoL for patients waiting for specialist care could be gained by using standard timepoints in the waiting period, patients with other orthopaedic conditions, comprehensive QoL measures, as well as expectations, choices and perspectives of patients waiting for specialist care. PMID- 29611150 TI - Nociceptive Response to L-DOPA-Induced Dyskinesia in Hemiparkinsonian Rats. AB - Non-motor symptoms are increasingly identified to present clinical and diagnostic importance for Parkinson's disease (PD). The multifactorial origin of pain in PD makes this symptom of great complexity. The dopamine precursor, L-DOPA (L-3,4 dihydroxyphenylalanine), the classic therapy for PD, seems to be effective in pain threshold; however, there are no studies correlating L-DOPA-induced dyskinesia (LID) and nociception development in experimental Parkinsonism. Here, we first investigated nociceptive responses in a 6-hydroxydopamine (6-OHDA) lesioned rat model of Parkinson's disease to a hind paw-induced persistent inflammation. Further, the effect of L-DOPA on nociception behavior at different times of treatment was investigated. Pain threshold was determined using von Frey and Hot Plate/Tail Flick tests. Dyskinesia was measured by abnormal involuntary movements (AIMs) induced by L-DOPA administration. This data is consistent to show that 6-OHDA-lesioned rats had reduced nociceptive thresholds compared to non lesioned rats. Additionally, when these rats were exposed to a persistent inflammatory challenge, we observed increased hypernociceptive responses, namely hyperalgesia. L-DOPA treatment alleviated pain responses on days 1 and 7 of treatment, but not on day 15. During that period, we observed an inverse relationship between LID and nociception threshold in these rats, with a high LID rate corresponding to a reduced nociception threshold. Interestingly, pain responses resulting from CFA-induced inflammation were significantly enhanced during established dyskinesia. These data suggest a pro-algesic effect of L-DOPA induced dyskinesia, which is confirmed by the correlation founded here between AIMs and nociceptive indexes. In conclusion, our results are consistent with the notion that central dopaminergic mechanism is directly involved in nociceptive responses in Parkinsonism condition. PMID- 29611152 TI - [Evaluation of intra- and interobserver agreement of Technetium-99m-sestamibi imaging in cold thyroid nodules]. AB - AIM: A supplementary diagnostic tool in the assessment of cold thyroid nodules is scintigraphic imaging with99mTc-MIBI. Aim of this study was to investigate the validity of this tool by determining the intra- and interobserver agreement in the assessment of cold thyroid nodules in Tc-MIBI scintigrams. METHODS: A retrospective study with 284 patients (16-85 years of age, 194 women, 90 men) was performed. They had at least one cold nodule and from each of whom were available at least one99mTc-MIBI and the Tc- pertechnetate image. Eight physicians, active in nuclear medicine, reviewed the sctinti- grams twice in a random order. They were asked if they considered the combination a match, a mismatch, or inconclusive, and if the early or delayed image was more significant or if there was no difference. RESULTS: Intraobserver agreement ranged from kappa = 0.56 (moderate) to kappa = 0.78 (substantial). Interobserver agreement ranged from kappa = 0.44 to kappa = 0.53 (moderate). Interobserver agreement for observers with more than 5 years of work experience in nuclear medicine ranged from kappa=0.61 to kappa = 0.70 (substantial), for observers with 2-5 years from kappa = 0.53 (moderate) to kappa = 0.61 (substantial) and for observers with < 2 years from kappa = 0.47 to kappa = 0.61. "No difference" was chosen in 70 resp. 77 % of all cases in session 1 resp. 2. The early image was preferred in 26 resp. 20 %, and the delayed one in 3 resp. 4 % of all cases. CONCLUSION: The values of interobserver agreement of all eight observers show that the assessment of Tc MIBI scintigrams is subject to a certain variance. Hence, they ought to be finally assessed by observers with at least 5 years of work experience. PMID- 29611153 TI - Indocyanine Green (Icg)-Enhanced Fluorescence for Intraoperative Assessment of Bowel Microperfusion During Laparoscopic and Robotic Colorectal Surgery: The Quest for Evidence-Based Results. AB - Anastomotic leakage is a severe complication after colonic/rectal surgery. One of the most important causes of anastomotic leakage is poor vascular supply. However, microvascular impairment at the anastomotic site is very often not detected intraoperatively by observation under white light. Indocyanine green (ICG)-enhanced fluorescence is a technology that may be useful for detecting microvascular alterations and potentially preventing anastomotic leakage. The aim of this Editorial-Minireview is to briefly and critically assess the literature evidence regarding the feasibility of using an ICG ?uorescent tracer for detecting microvascular changes in the perianastomotic tissue and its potential role in preventing anastomotic leakage. We focused on minimally invasive (robotic and laparoscopic) colorectal surgery. Intraoperative ICG angiography and the quantification of ICG kinetics can be used to intraoperatively reveal the tissue perfusion status during colorectal surgery. This may be useful for intraoperatively changing a previously planned resection/anastomotic level, and conceivably decreasing the degree of anastomotic leakage. At this stage, even though ICG technology appears to be very promising and some preliminary clinical studies have suggested that certain ICG pharmacokinetic parameters may be used to predict leakage, more reliable scoring and grading tools are needed. Furthermore, in minimally invasive colorectal surgery, more randomized prospective well powered trials are needed to properly standardize this surgical technology. PMID- 29611151 TI - Perinatal Glyphosate-Based Herbicide Exposure in Rats Alters Brain Antioxidant Status, Glutamate and Acetylcholine Metabolism and Affects Recognition Memory. AB - Glyphosate-based herbicides (Gly-BHs) lead the world pesticide market. Although are frequently promoted as safe and of low toxicity, several investigations question its innocuousness. Previously, we described that oral exposure of rats to a Gly-BH during pregnancy and lactation decreased locomotor activity and anxiety in the offspring. The aim of the present study was to evaluate the mechanisms of neurotoxicity of this herbicide. Pregnant Wistar rats were supplied orally with 0.2 and 0.4% of Gly-BH (corresponding to 0.65 and 1.30 g/l of pure Gly, respectively) from gestational day (GD) 0, until weaning (postnatal day, PND, 21). Oxidative stress markers were determined in whole brain homogenates of PND90 offspring. The activity of acetylcholinesterase (AChE), transaminases, and alkaline phosphatase (AP) were assessed in prefrontal cortex (PFC), striatum, and hippocampus. Recognition memory was evaluated by the novel object recognition test. Brain antioxidant status was altered in Gly-BH-exposed rats. Moreover, AChE and transaminases activities were decreased and AP activity was increased in PFC, striatum and hippocampus by Gly-BH treatment. In addition, the recognition memory after 24 h was impaired in adult offspring perinatally exposed to Gly-BH. The present study reveals that exposure to a Gly-BH during early stages of rat development affects brain oxidative stress markers as well as the activity of enzymes involved in the glutamatergic and cholinergic systems. These alterations could contribute to the neurobehavioral variations reported previously by us, and to the impairment in recognition memory described in the present work. PMID- 29611154 TI - Intracorporeal Ileocolic Anastomosis in Laparoscopic Right Colectomy: A New Way to Make it Simple? AB - Although there has been a recent increase in the use of laparoscopy in colorectal surgery, the percentage of patients who undergo surgery using entirely minimally invasive techniques is still quite low, and there are substantial differences among centers. It has been argued that the limiting factor in the use of laparoscopic procedures is not the tumor or patient characteristics, but rather the number of surgeons with adequate skills to perform an entirely laparoscopic colectomy. To address this issue, we report here our totally laparoscopic right colectomy technique, with particular focus on a new way to perform the enterotomy closure, which may simplify ileocolic anastomosis. PMID- 29611155 TI - Managing the Diabetic Foot Ulcer: How Best Practices Fit the Real 2018 United States. AB - Diabetes Mellitus is a serious systemic illness that has an epidemic-like increasing prevalence in the United States, as well as the rest of the world. With the increasing number of people with diabetes comes the higher incidence of diabetes-related complications. One of these known complications, diabetic foot ulcers (DFU), has an estimated lifetime incidence of 15% in diabetics. Having a DFU increases the risk of infection, amputation, and even death, which is why prompt treatment and surveillance of such ulcers is imperative. Multiple organizations and journals have recently published best practices to heal and close DFU. Despite these guidelines, it is estimated that only 50% of all diabetic foot ulcers close within one year in the United States. To further confuse this picture, many trials include postoperative wounds that behave in a very different way than chronic wounds. The management of diabetic ulcers requires an understanding of not only the pathophysiology along with a multi modal approach involving local wound care, pressure prevention, infection control, and, in some, revascularization, but also how care is delivered in the United States presently. In this review, we hope to elucidate the current knowledge and modalities used in ulcer management and to focus on key areas and best practices to inform the clinician, both in what they should do and what they can do. PMID- 29611156 TI - Practical Application of Granulocyte-Macrophage Colony-Stimulating Factor (GM CSF) in Patients with Wounds. AB - Rapidly evolving advances in wound-care technologies and treatment modalities, including locally injectable granulocyte-macrophage colony-stimulating factor (GM CSF), are increasingly being used. Based on its role in the stimulation and recruitment of key contributors to wound healing, such as keratinocytes, macrophages, and fibroblasts, GM-CSF is considered to play an essential role in the wound-healing cascade. Synthetic GM-CSF has been shown to have a positive effect on the healing of chronic wounds when given as a local injection in a small number of patients. Subsequent randomized, controlled trials demonstrated that GM-CSF accelerated the healing of chronic wounds. This paper reviews the proposed mechanism of action of GM-CSF in wound healing. We also describe its method of application in the operating room at a tertiary care center for patients with wounds. Key Messages: Many types of chronic wounds have an altered keratinocyte and macrophage function that can be potentially assuaged by the addition of locally injected growth factor therapy to standard-of-care treatment. Granulocyte-macrophage colony-stimulating factor (GM-CSF) has been shown to be beneficial for the treatment of chronic, non-healing wounds. This article reviews the data on GM-CSF, reports a proposed mechanism of action, and describes its use by a team of wound surgeons. PMID- 29611157 TI - Robotic-Assisted and Computer-Navigated Unicompartmental Knee Arthroplasties: A Systematic Review. AB - INTRODUCTION: Unicompartmental knee arthroplasty (UKA) effectively improves pain and function associated with isolated compartmental knee arthritis. The developments of computer-navigated and robotic-assisted UKA are among the most significant changes that have improved patient outcomes. This study aimed to systematically review the literature to identify differences between computer navigated and robotic-assisted UKAs. MATERIALS AND METHODS: Twenty total articles were identified. Data pertaining to demographics, outcomes, and complications/failures were extracted from each study. Reoperation/revision rates, indications for reoperation/revision, type of procedure, and number of patients who underwent conversion to TKA (when available) were recorded. RESULTS: Nine studies reported 451 computer-navigated medial UKAs, with 19 (3.9%) reportedly requiring reoperation: primary revision (n=8; 42.1%), conversion to TKA (n=6), and manipulation under anesthesia (n=5). Eleven studies reported 2,311 robotic-assisted UKAs (74 lateral UKAs), with 106 (5.0%) requiring reoperation: conversion to TKA (n=46; 43.4%), primary revision (n=43), reoperations without component-removal (n=15), subchondroplasty, and partial meniscectomy/synovectomy (both n=1). Reoperation rate discrepancy between computer-navigated and robotic assisted UKA was not statistically significant (p=0.495); age and BMI differed between both groups (p<0.0001). DISCUSSION: This study represents the first known comparison of revision rates of computer-navigated and robotic-assisted UKA, suggesting that these methods can benefit orthopaedic surgeons, especially those new to UKA or in a low-volume practice. PMID- 29611158 TI - Decreased Time to Return to Work Using Robotic-Assisted Unicompartmental Knee Arthroplasty Compared to Conventional Techniques. AB - INTRODUCTION: Unicompartmental knee arthroplasty (UKA) is a commonly used procedure for patients suffering from debilitating unicompartmental knee arthritis. For UKA recipients, robotic-assisted surgery has served as an aid in improving surgical accuracy and precision. While studies exist detailing outcomes of robotic UKA, to our knowledge, there are no studies assessing time to return to work using robotic-assisted UKA. Thus, the purpose of this study was to prospectively assess the time to return to work and to achieve the level of work activity following robotic-assisted UKA to create recommendations for patients preoperatively. We hypothesized that the return to work time would be shorter for robotic-assisted UKAs compared with TKAs and manual UKAs, due to more accurate ligament balancing and precise implementation of the operative plan. MATERIALS AND METHODS: Thirty consecutive patients scheduled to undergo a robotic-assisted UKA at an academic teaching hospital were prospectively enrolled in the study. Inclusion criteria included employment at the time of surgery, with the intent on returning to the same occupation following surgery and having end-stage knee degenerative joint disease (DJD) limited to the medial compartment. Patients were contacted via email, letter, or phone at two, four, six, and 12 weeks following surgery until they returned to work. The Baecke physical activity questionnaire (BQ) was administered to assess patients' level of activity at work pre- and postoperatively. Statistical analysis was performed using SAS Enterprise Guide (SAS Institute Inc., Cary, North Carolina) and Excel(r) (Microsoft Corporation, Redmond, Washington). Descriptive statistics were calculated to assess the demographics of the patient population. Boxplots were generated using an Excel(r) spreadsheet to visualize the BQ scores and a two-tailed t-test was used to assess for differences between pre- and postoperative scores with alpha 0.05. RESULTS: The mean time to return to work was 6.4 weeks (SD=3.4, range 2-12 weeks), with a median time of six weeks. There was no difference seen in the mean pre- and postoperative BQ scores (2.70 vs. 2.69, respectively; p=0.87). CONCLUSION: The findings of the current study suggest that most patients can return to work six weeks following robotic-assisted UKA which appears to be shorter than conventional UKA and TKA. Future level I studies are needed to verify our study findings. PMID- 29611159 TI - Perioperative Outcomes and Short-Term Complications Following Total Knee Arthroplasty in Chronically, Immunosuppressed Patients. AB - BACKGROUND: Although there are studies regarding immunosuppressed patients undergoing total knee arthroplasty (TKA) for inflammatory arthritis or osteonecrosis, there is a paucity of studies evaluating immunosuppressed patients undergoing TKA for diagnoses other than these. MATERIALS AND METHODS: We identified all patients undergoing primary TKA for osteoarthritis from 2008-2014 in the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database. Overall, 111,624 patients were included. The immunosuppressed group consisted of 3,466 patients, and the control group included 108,158. Outcomes measured included operative time, lengths-of-stay, discharge destination, and 30-day complication rates. Univariate analysis was used to compare the outcomes. Multivariate regression analysis was then applied to determine if immunosuppression was an independent risk factor for differences in outcomes. RESULTS: Immunosuppressant use did not change operative time, lengths-of-stay, or discharge disposition. Immunosuppressed patients were at higher risks of developing the following surgical and medical complications: organ/space surgical site infection (SSI), wound dehiscence, deep venous thrombosis (DVT), pneumonia, urinary tract infection (UTI), and systemic sepsis. Return to the operating room and 30-day readmission were also significantly higher in the immunosuppressed group. CONCLUSIONS: Patients taking chronic immunosuppressants and undergoing TKA for osteoarthritis are at higher risk of specific surgical and medical complications. These complications include organ/space SSI, wound dehiscence, DVT, pneumonia, UTI, and systemic sepsis. In addition, these patients were at increased odds of returning to the operating room and being readmitted. PMID- 29611160 TI - Stress-induced changes in the aged-rat adrenal cortex. Histological and histomorphometric study. AB - BACKGROUND: Stress exposure exerts direct effects on the morphology and functionality of the adrenal cortex. In addition, aging effects growth, differentiation, apoptosis and cellularity of the cortex. The missing data is the combined effect of stress and aging on the adrenal cortex. The aim of this study was to demonstrate the structural changes in the adrenal cortex following the exposure to stress in the adult and aged albino rats. MATERIAL AND METHODS: 40 rats were divided into groups I, II (adult and senile). Each group was further subdivided into subgroups a, b (control and stressed). Light and electron microscopic studies were done. Area percent of collagen fibers (Masson's trichrome-stained sections), number of proliferating cells (optical density immunoreactivity in the Ki 67 stained sections) and thickness of the three adrenal zones were also measured. RESULTS: Lamellar separation of the capsule with subcapsular spindle cell hyperplasia and areas of ghost cells were observed in ZG and ZF in group I-b. Separation and indentation of the capsule with its lamellar separation were observed in group II-a with the existence of multiple scattered degenerative foci in ZF and ZR. Similarly and aggressively was the architectural pattern of ZF in group II-b with the presence of areas of homogenous degeneration. The nuclei of ZG had marginated chromatin in group I-b and were pyknotic with deformed irregular outlines in group II-b. Multiple lysosomes and vacuolar degeneration mitochondria were also seen in group I-b. The nuclei of ZF were irregular with condensed marginated heterochromatin in group I b, irregular with scattered chromatin in group II-a and indented with areas of chromatin destruction in group II-b. Mitochondria with disrupted cristae and cristolysis were also detected in group I-b. Numerous lipofuscin granules and dilated SER were realized in group II-b. The mean collagen fiber area percent and the mean number of the proliferating cells in group II-b were 39% and 23 % significantly higher. The thickness of ZG decreased 20% significantly in group I b. Contrary, the thickness of both ZF and ZR increased 10 % significantly in group I-b. CONCLUSION: Histological alterations occurred in the adrenal cortex in response to stress, especially when coupled with the advancement of age. This was accompanied by increase in the area percent of collagen fibers and increase in the mean number of the proliferating cells in the adrenal cortex. PMID- 29611161 TI - The triticeous cartilage: redefining of morphology, prevalence and function. AB - Triticeous cartilage is a small cartilaginous component of the laryngeal skeleton. This cartilage, located in posterior end of the thyrohyoid ligament, presents in different shapes. Radiological studies indicate clinical and anatomical importance of the triticeous cartilage but these studies have limited information due to inadequate inspection method. Computed tomographic angiography is able to evaluate the triticeous cartilage with using 3 dimensional images in more detail. The aim of this study is describing prevalence and morphological properties of the triticeous cartilage. We examined computed tomographic angiography images of 746 patients (368 women, 378 men) retrospectively. Shapes, calcification degrees, volumes, lengths and wideness of the triticeous cartilage were evaluated by OsiriX-Lite software. According to our results, triticeous cartilage presents common in population (68.1%). Prevalence of the triticeous cartilage was higher in men than women. We also found that degree of calcification was not related with age and gender. Clinical importance of the triticeous cartilage is that it could be misdiagnosed with atherosclerosis in common carotid artery because the location of the triticeous cartilage is almost at same level with bifurcation of the common carotid artery. Therefore, clinicians should be aware about the triticeous cartilage. PMID- 29611162 TI - The superficial palmar branch of the radial artery, a corrosion cast study. AB - BACKGROUND: Surgical procedures such as thenar flaps and radial artery (RA) harvesting call for an elaborate anatomical study of the RA's superficial palmar branch (SPB). The aim of this study was to describe the branching pattern of this vessel related to the morphometric characteristics and variations of this artery. MATERIALS AND METHODS: Twenty 4% formalin solution injected hands were dissected. For the morphometric study we used another group of thirty five human hands of adult persons, injected with methylmethacrylate fluid into the ulnar and radial arteries. As soon as polymerization was completed, a 40% solution of potassium hydroxide was applied for corrosion. The vascular arterial casts were examined under the stereoscopic microscope and precise drawings of each specimen were made. RESULTS: In the majority of cases (75%) SPB passed superficially, over the abductor pollicis brevis muscle. The mean diameter of the SPB, very variable depending on its length and field of supply, was 1.52+/-0.49 mm, ranging from 0.8 to 2.7 mm. Developed SPB type, was present in 31.4% of hands, with the diameter of 1.7 mm and larger (mean 1.95 mm), continuing distally to become the radialis indicis artery (RIA), with an average caliber of 1.2 mm, and with important branches to the thumb. In most hands, (68.6%), the hypoplastic SPB, was present, with a mean diameter of 1.17 mm, and the field of supply within the thenar area. CONCLUSIONS: Knowledge of the SPB dominance, and existence of anastomotic vessels in its field of supply are of importance to avoid the risk of possible ischemic sequelae in the hand associated with harvesting the RA. PMID- 29611163 TI - Cadaveric-Biomechanical study on medial retinaculum: Its stabilising role for the patella against lateral dislocation. AB - BACKGROUND: The aim of this study was to analyse the biomechanical role of medial retinaculum, as a stabilising factor against lateral patellar dislocation. MATERIALS AND METHODS: This cadaveric-biomechanical study included the patellae of ten cadaveric knees, which were surgically exposed and the medial retinaculum of each one was located. A stable 24.51N force was applied to the four parts of the quadriceps, and an increasing lateral displacing force was applied to the patella, up to 5mm dislocation. The study was repeated for 00, 450, and 900 of knee flexion, with the medial retinaculum intact and dissected. The Wilcoxon signed rank test was used for data analysis. A p value <0.05 was considered as statistical significant. RESULTS: After the dissection of medial retinaculum, the lateral displacement force was lower at every angle of knee flexion (p=0.005, p=0.007, p=0.005 respectively). The lateral displacement force increased as the flexion angle increased (p=0.005), regardless of medial retinaculum integrity. CONCLUSIONS: Medial retinaculum acts as a stabilising factor for the patella, against its lateral dislocation in lower flexion angles. Therefore, methods of surgical reinforcement or repair of medial retinaculum could provide protection against recurrent patellar dislocation. PMID- 29611164 TI - Thermic sealing in femoral catheterisation: First experience with the Secure Device. AB - BACKGROUND: Devices currently used to achieve hemostasis of the femoral artery following percutaneous cardiac catheterization are associated with vascular complications and remnants of artificial materials are retained at the puncture site. The SECURE arterial closure device induces hemostasis by utilizing thermal energy, which causes collagen shrinking and swelling. In comparison to established devices, it has the advantage of leaving no foreign material in the body following closing. This study was designed to evaluate the efficacy and safety of the SECURE device to close the puncture site following percutaneous cardiac catheterization. METHODS: The SECURE device was evaluated in a prospective non-randomized single-centre trial with patients undergoing 6 F invasive cardiac procedures. A total of 67 patients were enrolled and the device was utilized in 63 patients. 50 diagnostic and 13 interventional cases were evaluated. Femoral artery puncture closure was performed immediately after completion of the procedure. Time to hemostasis (TTH), time to ambulation (TTA) and data regarding short-term and 30-day clinical follow-up were recorded. RESULTS: Mean TTH was 4:30 +/- 2:15 min in the overall observational group. A subpopulation of patients receiving anticoagulants had a TTH of 4:53 +/- 1:43 min. There were two access site complications (hematoma > 5 cm). No major adverse events were identified during hospitalization or at the 30 day follow-up. CONCLUSIONS: The new SECURE device demonstrates that it is feasible in diagnostic and interventional cardiac catheterization. With respect to safety, the SECURE device was non-inferior to other closure devices as tested in the ISAR closure trial. PMID- 29611165 TI - Invasive reperfusion after 12 hours of the symptom onset remains beneficial in patients with ST-segment elevation myocardial infarction: Evidence from a meta analysis of published data. AB - BACKGROUND: Early myocardial reperfusion therapy ( < 12 h) in patients with acute myocardial infarction (AMI) can significantly improve their prognosis. However, the effect of late reperfusion ( > 12 h) remains controversial. In this study, the effects of late reperfusion versus standard drug therapy on the outcomes of patients with AMI were evaluated by systematic review and meta-analysis. METHODS: PubMed, Embase, Medline, Cochrane, Wanfang, and CNKI databases were searched for eligible studies for the present study. Meta-analysis was performed using RevMan 5.3.3 software. Relative risk (RR) and the 95% confidence interval (CI) were used to compare the outcomes between the two groups. The main outcome measures were major adverse cardiac events (MACEs), all-cause mortality, recurrent myocardial infarction (MI), and heart failure. RESULTS: Eighteen studies were identified including 14,677 patients, of whom 5157 received late reperfusion with percutaneous coronary intervention (PCI) and 9520 received medication therapy (MT). Compared to MT, late PCI was associated with decreased all-cause mortality (RR 0.60, 95% CI 0.44-0.83; p = 0.002), MACEs (RR 0.67; 95% CI 0.50-0.89; p < 0.001), and heart failure (RR 0.76; 95% CI 0.60-0.97; p = 0.03), while there was also a trend toward decreased recurrent MI (RR 0.70; 95% CI 0.47-1.05; p = 0.08). However, subgroup analysis according to time to PCI showed that the clinical benefit was only from PCI after 12 h but not from 2 to 60 days of the onset of symptoms. CONCLUSIONS: The present meta-analysis suggested that PCI performed > 12 h but not 2-60 days after AMI is associated with significant improvement in clinical outcomes. However, these results need further rigorously designed large sample size clinical trials to be validated. PMID- 29611166 TI - Diagnostic and prognostic value of QRS duration and QTc interval in patients with suspected myocardial infarction. AB - BACKGROUND: While prolongation of QRS duration and QTc interval during acute myocardial infarction (AMI) has been reported in animals, limited data is available for these readily available electrocardiography (ECG) markers in humans. METHODS: Diagnostic and prognostic value of QRS duration and QTc interval in patients with suspected AMI in a prospective diagnostic multicentre study were prospectively assessed. Digital 12-lead ECGs were recorded at presentation. QRS duration and QTc interval were automatically calculated in a blinded fashion. Final diagnosis was adjudicated by two independent cardiologists. The prognostic endpoint was all-cause mortality during 24 months of follow-up. RESULTS: Among 4042 patients, AMI was the final diagnosis in 19% of patients. Median QRS duration and median QTc interval were significantly greater in patients with AMI compared to those with other final diagnoses (98 ms [IQR 88-108] vs. 94 ms [IQR 86-102] and 436 ms [IQR 414-462] vs. 425 ms [IQR 407-445], p < 0.001 for both comparisons). The diagnostic value of both ECG signatures however was only modest (AUC 0.56 and 0.60). Cumulative mortality rates after 2 years were 15.9% vs. 5.6% in patients with a QRS > 120 ms compared to a QRS duration <= 120 ms (p < 0.001), and 11.4% vs. 4.3% in patients with a QTc > 440 ms compared to a QRS duration <= 440 ms (p < 0.001). After adjustment for age and important ECG and clinical parameters, the QTc interval but not QRS duration remained an independent predictor of mortality. CONCLUSIONS: Prolongation of QRS duration > 120 ms and QTc interval > 440 ms predict mortality in patients with suspected AMI, but do not add diagnostic value. PMID- 29611167 TI - Proteomics study of serum exosomes in Kawasaki disease patients with coronary artery aneurysms. AB - BACKGROUND: To study the protein profile of the serum exosomes of patients with coronary artery aneurysms (CAA) caused by Kawasaki disease (KD). METHODS: Two dimensional electrophoresis (2-DE) was used to identify proteins from the exosomes of serum obtained from children with CAA caused by KD, as well as healthy controls. Differentially expressed proteins were identified using matrix assisted laser desorption/ionization time-of-flight/time-of-flight mass spectrometry (MALDI-TOF/TOF MS) analysis. RESULTS: 32 differentially expressed proteins were identified (18 up-regulated and 14 down-regulated) from serum exosomes of children with CAA and were compared to healthy controls. The expression levels of 4 proteins (TN, RBP4, LRG1, and APOA4) were validated using western blotting. Classification analysis and protein-protein network analysis showed that they are associated with multiple functional groups, including host immune response, inflammation, apoptotic process, developmental process, and biological adhesion process. CONCLUSIONS: These findings establish a comprehensive proteomic profile of serum exosomes from children with CAA caused by KD, and provide additional insights into the mechanisms of CAA caused by KD. PMID- 29611168 TI - The impact of renal function on the prognostic value of N-terminal B-type natriuretic peptide in patients with coronary artery disease. AB - BACKGROUND: The impact of renal function on the prognostic value of N-terminal B type natriuretic peptide (NT-proBNP) remains unclear in coronary artery disease (CAD). This study sought to investigate the value of using NT-proBNP level to predict prognoses of CAD patients with different estimated glomerular filtration rates (eGFRs). METHODS: A retrospective analysis was conducted from a single registered database. 2087 consecutive patients with CAD confirmed by coronary angiography were enrolled. The primary endpoint was all-cause mortality. RESULTS: The mean follow-up time was 26.4 +/- 11.9 months and death events occurred in 197 cases. The NT-proBNP levels increased with the deterioration of renal function, as well as the optimal cut-off values based on eGFR stratification to predict endpoint outcome (179.4 pg/mL, 1443.0 pg/mL, 3478.0 pg/mL, for eGFR >= 90, 60 to 90 and < 60 mL/min/1.73 m2, respectively). Compared with the routine cut-off value or overall optimal one, stratified optimal ones had superior predictive ability for endpoint in each eGFR group (all with the highest Youden's J statistics). And the prognostic value became weaker as eGFR level decreased (eGFR >= 90 vs. 60-90 vs. < 60 mL/min/1.73 m2, odds ratio [OR] 7.7; confidence interval [CI] 1.7-33.9 vs. OR 4.8 CI 2.7-8.5 vs. OR 3.0 CI 1.5-6.2). CONCLUSIONS: This study demonstrated that NT-proBNP exhibits different predictive values for prognosis for CAD patients with different levels of renal function. Among the assessed values, the NT-proBNP cut-off value determined using renal function improve the accuracy of the prognosis prediction of CAD. Moreover, lower eGFR is associated with a higher NT-proBNP cut-off value for prognostic prediction. PMID- 29611169 TI - Increased plasma cathepsin S and trombospondin-1 in patients with acute ST segment elevation myocardial infarction. AB - BACKGROUND: The role of cathepsins in the pathological progression of atherosclerotic lesions in ischemic heart disease have been defined in detail more than numerous times. This investigation examined the platelet-specific biomarker trombospondin-1 (TSP-1) and platelet function ex vivo, and compared this with cathepsin S (Cat-S; a biomarker unrelated to platelet activation but also associated this with increased mortality risk) in patients with ST segment elevation myocardial infarction (STEMI). METHODS: The STEMI patients were divided into two groups depending on the degree of coronary vessel occlusion: those with closed (n = 90) and open culprit vessel (n = 40). Cat-S and TSP-1 were analyzed before, 1-3 days after and 3 months after percutanous coronary intervention (PCI). RESULTS: During acute STEMI, plasma TSP-1 was significantly elevated in patients with closed culprit lesions, but rapidly declined after PCI. In fact, TSP-1 after PCI was significantly lower inpatient samples compared to healthy individuals. In comparison, plasma Cat-S was significantly elevated both before and after PCI. In patients with closed culprit lesions, Cat-S was significantly higher compared to patients with open culprit lesions 3 months after PCI. Although troponin-I were higher (p < 0.01) in patients with closed culprit lesion, there was no correlation with Cat-S and TSP-1. CONCLUSIONS: Cat-S but not TSP-1 may be a useful risk biomarker in relation to the severity of STEMI. However, the causality of Cat-S as a predictor for long-term mortality in STEMI remains to be ascertained in future studies. PMID- 29611170 TI - Feasibility of zero or near zero fluoroscopy during catheter ablation procedures. AB - BACKGROUND: Awareness of risks associated with radiation exposure to patients and medical staff has significantly increased. It has been reported before that the use of advanced three-dimensional electro-anatomical mapping (EAM) system significantly reduces fluoroscopy time, however this study aimed for zero or near zero fluoroscopy ablation to assess its feasibility and safety in ablation of atrial fibrillation (AF) and other tachyarrhythmias in a "real world" experience of a single tertiary care center. METHODS: This was a single-center study where ablation procedures were attempted without fluoroscopy in 34 consecutive patients with different tachyarrhythmias under the support of EAM system. When transseptal puncture (TSP) was needed, it was attempted under the guidance of intracardiac echocardiography (ICE). RESULTS: Among 34 patients consecutively enrolled in this study, 28 (82.4%) patients were referred for radiofrequency ablation (RFA) of AF, 3 (8.8%) patients for ablation of right ventricular outflow tract (RVOT) ventricular extrasystole (VES), 1 (2.9%) patient for ablation of atrioventricular nodal reentry tachycardia (AVNRT), 2 (5.9%) patients for typical atrial flutter ablation. In 21 (62%) patients the entire procedure was carried out without the use of fluoroscopy. Among 28 AF patients, 15 (54%) patients underwent ablation without the use of fluoroscopy and among these 15 patients, 10 (67%) patients required TSP under ICE guidance while 5 (33%) patients the catheters were introduced to left atrium through a patent foramen ovale. In 13 AF patients, fluoroscopy was only required for double TSP. The total procedure time of AF ablation was 130 +/- 50 min. All patients referred for atrial flutter, AVNRT, and VES of the RVOT ablation did not require any fluoroscopy. CONCLUSIONS: This study demonstrates the feasibility of zero or near zero fluoroscopy procedure including TSP with the support of EAM and ICE guidance in a "real world" experience of a single tertiary care center. When fluoroscopy was required, it was limited to TSP hence keeping the radiation dose very low. . PMID- 29611171 TI - Percutaneous renal artery denervation in patients with chronic systolic heart failure: a randomized controlled trial. AB - : B: ACKGROUND: Renal denervation (RDN) is as an effective treatment for heart failure, but its effects on cardiac function of patients with heart failure (HF) are not well documented. Here, the aim was to investigate RDN's effect on patients with chronic systolic HF, by conducting a single-center, prospective, randomized, and controlled study. M: ETHODS: Sixty patients with chronic systolic HF were randomly assigned to the RDN or control groups, receiving percutaneous catheter-based RDN with radiofrequency ablation and drug treatment respectively. All patients performed a 6-minute walk test, echocardiography, blood pressure measurement, and biochemical test, at both baseline and in a 6-month follow up. R: ESULTS: Over 6-month follow up, patients in RDN group showed a decrease in NT proBNP (440.1 +/- 226.5 pg/mL vs. 790.8 +/- 287.0 pg/mL, p < 0.001, Cohen's d = 1.14), an increase in left ventricular ejection fraction (39.1 +/- 7.3% vs. 35.6 +/- 3.3%, p = 0.017, Cohen's d = 0.61), improved NYHA class assessment (p = 0.01, Cohen's d = 0.66), and decreased blood pressures (p < 0.001, Cohen's d = 0.91), without reporting hypotension and syncope amaurosis. No significant between-group difference was observed for glomerular filtration rate and heart rate. CONCLUSIONS: Renal denervation which effectively and safely improves patient's cardiac function as well as exercise tolerance, could be considered as an effective treatment for chronic systolic heart failure. PMID- 29611172 TI - Prevention of in-stent restenosis with endothelial progenitor cell (EPC) capture stent placement combined with regional EPC transplantation: An atherosclerotic rabbit model. AB - BACKGROUND: Even with drug-eluting stents, the risk of in-stent restenosis (ISR) remains high. The goal of this study was to investigate the use of an endothelial progenitor cell (EPC) capture stent plus regional EPC transplantation to reduce the ISR rate. METHODS: Endothelial progenitor cell capture stents were fabricated using fibrin gel and anti-CD34 plus anti-VEGFR-2 dual antibodies. Twenty male New Zealand white rabbits established as an atherosclerotic model were randomly divided into two groups: group 1 (n = 10), in which EPC capture stents were deployed into the right iliac artery; and group 2 (n = 10), in which sirolimus eluting stents were placed. In both groups, EPCs were transplanted into target vessels beyond the stents, with outflow blocked. Radiologic-pathologic correlation outcomes were reviewed after 2 months. RESULTS: The technical success rate of EPC capture stent placement plus EPC transplantation was 100%. The ISR rate in group 1 was lower than in group 2 (1/10 vs. 4/10; p > 0.05). Minimal luminal diameters were larger in group 1 than in group 2 (computed tomographic angiography, 1.85 +/- 0.15 mm vs. 1.50 +/- 0.20 mm; duplex ultrasound, 1.90 +/- 0.10 mm vs. 1.70 +/- 0.30 mm; p > 0.05). Transplanted EPCs were tracked positively only in group 1. Pathologic analysis demonstrated neointimal hyperplasia thickness of 0.21 +/- 0.09 mm in group 1 vs. 0.11 +/- 0.07 mm in group 2 (p < 0.05). CONCLUSION: Endothelial progenitor cell capture stent placement plus local EPC transplant decreases the ISR rate through thrombosis reduction rather than through neointimal hyperplasia inhibition. PMID- 29611173 TI - The relationship between pulse waveform analysis indices, endothelial function and clinical outcomes in patients with peripheral artery disease treated using percutaneous transluminal angioplasty during a one-year follow-up period. AB - BACKGROUND: The aim of the current study was to assess the relationship between potential predictors of clinical outcomes after percutaneous transluminal angioplasty (PTA) of peripheral arteries during a one-year follow-up. Indices of endothelial function (EF), arterial pulse waveform analysis (aPWA) and markers of peripheral arteries ischemia were among those mostly examined. METHODS: The study comprised of 72 individuals with PAD who underwent PTA of the peripheral arteries. During the first visit and 1 and 6 months after PTA, endothelial function and aPWA measurements were performed. Ankle-brachial index (ABI), toe brachial index (TBI) and physical evaluation of the limbs took place during the first visit and 1, 6 and 12 months after the PTA. The study endpoints included myocardial infarction, amputation, death, stroke and reintervention. All subjects included into the study were observed for 386 days after the PTA. RESULTS: We noticed significant improvement in walking distance after PTA, as well as transient improvement of ABI and flow-mediated dilatation (FMD), and no significant changes in aPWA indices or reactive-hyperemia index (RHI). There were 25 study endpoints which occurred in 16 patients during the follow-up period (22.2%). Patients with CLI, hypercholesterolemia, lower diastolic blood pressure, higher subendocardial viability ratio, greater number of pack-years and lower TBI at baseline presented significantly poorer clinical outcomes in terms of endpoint events. CONCLUSIONS: Endothelial function assessed as FMD and RH-PAT before PTA in patients with advanced PAD does not predict clinical outcomes during the one year follow-up. < p > < /p >. PMID- 29611174 TI - Epidemiology and chronobiology of out-of-hospital cardiac arrest in a subpopulation of southern Poland: A two-year observation. AB - BACKGROUND: Although recent studies indicate temporal variations in the incidence of out-of-hospital cardiac arrest (OHCA), the Polish experience in this research is scarce to date. Epidemiology of OHCA and circadian is evaluated herein, weekly and seasonal variations of OHCA frequency among the adult population of the Opole district, Poland. METHODS: The retrospective analysis of 815 OHCA cases with presumed cardiac etiology was made based on dispatch cards from the Emergency Medical Center in Opole registered during a 2 year period (2006-2007). RESULTS: The incidence of OHCA in the studied population was 1.56/1000 inhabitants per year. Mean age of the group was 69.2 +/- 14.2 years, with the majority of men (63%), younger than women (66.1 vs. 74 years, p = 0.0001). The OHCA occurrence increased with age reaching a peak between 71 and 75 years. The incidence of OHCA stayed stable low levels between 22:00 and 4:59 and started to increase at 5:00, with trimodal peaks: 8:00-10:59, 14:00-15:59 and 18.00-21.59. The lowest number of OHCA occurred from 00:00 to 5:59, the highest from 6:00 to 11:59 (13% vs. 32.4%, p < 0.001). The day with the lowest occurrence of OHCA was Friday, the highest Saturday (10.9% vs. 16%, p = 0.01). Summer was the season of the lowest incidence of OHCA, while winter - the highest (22.6% vs. 26%, p = 0.04). These seasons were the warmest and the coldest one, respectively (average temperature 18.5o vs. 0oC, p < 0.001). CONCLUSIONS: It was confirmed that circadian and less marked, weekly variability in OHCA occurrence. Existing seasonal differences may be affected by temperature. This is the first Polish analysis of a large subpopulation, which also includes seasonal temperature data. PMID- 29611175 TI - Initial experience with the subcutaneous implantable cardioverter-defibrillator with the real costs of hospitalization analysis in a single Polish center. AB - BACKGROUND: The recent introduction of an entirely subcutaneous implantable cardioverter-defibrillator (S-ICD) represents an important progress in the defibrillation technology towards a less invasive approach. This is a single center observational study of S-ICD implantations in Poland. METHODS: The S-ICD was implanted in 11 patients with standard indications for an ICD. Patients in whom the device was implanted were evaluated for adverse events and device function at hospital discharge. All hospitalization costs were calculated and summed up for all patients. Costs were divided into following categories: medical materials, pharmaceuticals, operating theatre staff, cardiology department staff, laboratory tests, non-laboratory tests and additional non-medical costs. RESULTS: The mean age of patients was 51.6 +/- 16.4 years, 9 were men and 2 were women. Four patients had atrial fibrillation as the basal rhythm, 1 patient had atrial flutter and 6 patients had sinus rhythm. All patients had at least one condition that precluded the use of a traditional ICD system or the S-ICD was preferred due to other conditions, i.e. a history complicated transvenous ICD therapy (18%), anticipated higher risk of infection (27%), lack or difficult vascular access (18%), young age and anticipated high cumulated risk of lifetime device therapy (36%). The mean duration of the implantation procedure was 2 h. One patient developed a postoperative pocket hematoma. Mean total time of hospitalization was 28 (6-92) days. Average cost of hospitalization per patient was 21,014.29 EUR (minimal = 19,332.71 EUR and maximal = 24,824.14 EUR). CONCLUSIONS: S-ICD implantation appears to provide a viable alternative to transvenous ICD, especially for patients without pacing requirements. PMID- 29611176 TI - The epidemiology of rasburicase use in paediatric patients with acute lymphoblastic leukaemia and non-Hodgkin lymphoma. PMID- 29611177 TI - Second-line and subsequent therapy and outcomes for follicular lymphoma in the United States: data from the observational National LymphoCare Study. PMID- 29611178 TI - A rare contemporary record of the Critically Endangered Ganges shark Glyphis gangeticus. AB - The first record of the Ganges shark Glyphis gangeticus from anywhere in its range in over a decade is reported from the Arabian Sea. One female specimen was recorded at Sassoon Docks in Mumbai, India in February 2016, measuring 266 cm total length. In light of the Critically Endangered status of this species and its rarity, urgent management actions are needed to determine population size and trends in abundance in combination with fisher education and awareness campaigns. PMID- 29611179 TI - Anti-alphaIIb beta3 immunization in Glanzmann thrombasthenia: review of literature and treatment recommendations. AB - Glanzmann thrombasthenia (GT) is caused by inherited defects of the alphaIIb beta3 platelet glycoprotein. This bleeding disorder can be treated with platelet transfusion therapy, but some patients will be immunized and begin to form anti human leucocyte antigen (HLA) and/or anti-alphaIIb beta3 antibodies. These antibodies can bind and interfere with the function of the transfused platelets, rendering treatment ineffective. However, platelet transfusion refractoriness attributable to HLA antibodies may be managed by the selection of compatible donors, although they are not always readily available, particularly in an emergency. Thus, anti-alphaIIb beta3 antibodies represent one of the most severe complications in GT. Both genetic and environmental factors may contribute to the risk of anti-alphaIIb beta3 development, but the underlying pathogenic mechanisms are still unknown. This review will summarize the current knowledge of the risk factors for development of anti-alphaIIb beta3 antibodies in patients with GT and discuss how these findings may influence the clinical management of patients. PMID- 29611181 TI - Incidence and outcomes of rare paediatric non-hodgkin lymphomas. PMID- 29611180 TI - Antimicrobial lock solutions for preventing catheter-related infections in haemodialysis. AB - BACKGROUND: Patients undergoing haemodialysis (HD) through a central venous catheter (CVC) are exposed to several risks, being a catheter-related infection (CRI) and a CVC lumen thrombosis among the most serious. Standard of care regarding CVCs includes their sealing with heparin lock solutions to prevent catheter lumen thrombosis. Other lock solutions to prevent CRI, such as antimicrobial lock solutions, have proven useful with antibiotics solutions, but not as yet for non-antibiotic antimicrobial solutions. Furthermore, it is uncertain if these solutions have a negative effect on thrombosis incidence. OBJECTIVES: To assess the efficacy and safety of antimicrobial (antibiotic, non antibiotic, or both) catheter lock solutions for preventing CRI in participants undergoing HD with a CVC. SEARCH METHODS: We searched the Cochrane Kidney and Transplant Specialised Register up to 18 December 2017 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal, and ClinicalTrials.gov. SELECTION CRITERIA: We included all randomised or quasi-randomised control trials (RCTs) comparing antimicrobial (antibiotic and non-antibiotic) lock solutions to standard lock solutions, in participants using a CVC for HD, without language restriction. DATA COLLECTION AND ANALYSIS: Two authors independently assessed studies for eligibility, and two additional authors assessed for risk of bias and extracted data. We expressed results as rate ratios (RR) per 1000 catheter-days or 1000 dialysis sessions with 95% confidence intervals (CI). Statistical analyses were performed using the random effects model. MAIN RESULTS: Thirty-nine studies, enrolling 4216 participants, were included in this review, however only 30 studies, involving 3392 participants, contained enough data to be meta-analysed. Risk of bias was low or unclear for most domains in the majority of the included studies.Studies compared antimicrobial lock solutions (antibiotic and non-antibiotic) to standard sealing solutions (usually heparin) of the CVC for HD. Fifteen studies used antibiotic lock solutions, 21 used non-antibiotic antimicrobial lock solutions, and 4 used both (antibiotic and non-antibiotic) lock solutions. Studies reported the incidence of CRI, catheter thrombosis, or both.Antimicrobial lock solutions probably reduces CRI per 1000 catheter-days (27 studies: RR 0.38, 95% CI 0.27 to 0.53; I2 = 54%; low certainty evidence), however antimicrobial lock solutions probably makes little or no difference to the risk of thrombosis per 1000 catheter days (14 studies: RR 0.79, 95% CI 0.52 to 1.22; I2 = 83%; very low certainty evidence). Subgroup analysis of antibiotic and the combination of both lock solutions showed that both probably reduced CRI per 1000 catheter-days (13 studies: RR 0.30, 95% CI: 0.22 to 0.42; I2 = 47%) and risk of thrombosis per 1000 catheter-days (4 studies: RR 0.26, 95% CI: 0.14 to 0.49; I2 = 0%), respectively. Non-antibiotic antimicrobial lock solutions probably reduced CRI per 1000 catheter-days for tunnelled CVC (9 studies: RR 0.60, 95% CI 0.40 to 0.91) but probably made little or no difference with non-tunnelled CVC (4 studies: RR 0.93, 95% CI 0.48 to 1.81). Subgroup analyses showed that antibiotic (5 studies: RR 0.76, 95% CI 0.42 to 1.38), non-antibiotic (8 studies: RR 0.85, 95% CI 0.44 to 1.66), and the combination of both lock solutions (3 studies: RR 0.63, 95% CI 0.22 to 1.81) made little or no difference to thrombosis per 1000 catheter-days compared to control lock solutions. AUTHORS' CONCLUSIONS: Antibiotic antimicrobial and combined (antibiotic-non antibiotic) lock solutions decreased the incidence of CRI compared to control lock solutions, whereas non-antibiotic lock solutions reduce CRI only for tunnelled CVC. The effect on thrombosis incidence is uncertain for all antimicrobial lock solutions. Our confidence in the evidence is low and very low; therefore, better-designed studies are needed to confirm the efficacy and safety of antimicrobial lock solutions. PMID- 29611182 TI - Factor (F)VIII/VIIa enhances global haemostatic function in the co-presence of bypassing agents and FVIII among patients with haemophilia A with inhibitor. AB - Bypassing therapy is essential for the haemostatic management of patients with haemophilia A with inhibitor (PWHA-inh), but the therapeutic effects are inconsistent. We previously reported that activated prothrombin complex concentrates (aPCC) activated factor (F)VIIIin vitro, and was mediated mainly by the activated FVII (FVIIa) contained in aPCC. We have extended those studies to assess global coagulation in whole blood from 18 PWHA-inh in the co-presence of aPCC and FVIII using Ca2+ -triggered rotational thromboelastometry. The clot times (CTs) in the presence of both aPCC (0.05 iu/ml) and recombinant (r)FVIII (1 iu/ml) ex vivo were shortened compared to the aPCC alone (P < 0.01). These enhancing effects of rFVIII were observed, irrespective of recognizing inhibitor epitopes; however, the clot formation time and 'alpha'-angle were not significantly different. In samples from 7 PWHA-inh post-infusion of aPCC (70-80 iu/kg), only the CTs were shortened in the presence of rFVIIIex vivo compared to its absence (P < 0.05), indicating that the enhanced activity centred on the initiation phase of coagulation. Furthermore, experiments in the co-presence of rFVIIa and rFVIII demonstrated that FVIII accelerated only the CTs. We concluded that FVIII/FVIIa-related coagulation mechanism enhanced global haemostatic function by the co-presence of bypassing agents and FVIII in PWHA-inh. PMID- 29611183 TI - Maternal environment and craniofacial growth: geometric morphometric analysis of mandibular shape changes with in utero thyroxine overexposure in mice. AB - An estimated 3% of US pregnancies are affected by maternal thyroid dysfunction, with between one and three of every 1000 pregnancies being complicated by overactive maternal thyroid levels. Excess thyroid hormones are linked to neurological impairment and excessive craniofacial variation, affecting both endochondral and intramembranous bone. Using a geometric morphometric approach, this study evaluates the role of in utero thyroxine overexposure on the growth of offspring mandibles in a sample of 241 mice. Canonical variate analysis utilized 16 unilateral mandibular landmarks obtained from 3D micro-computed tomography to assess shape changes between unexposed controls (n = 63) and exposed mice (n = 178). By evaluating shape changes in the mandible among three age groups (15, 20 and 25 days postnatal) and different dosage levels (low, medium and high), this study found that excess maternal thyroxine alters offspring mandibular shape in both age- and dosage-dependent manners. Group differences in overall shape were significant (P < 0.001), and showed major changes in regions of the mandible associated with muscle attachment (coronoid process, gonial angle) and regions of growth largely governed by articulation with the cranial base (condyle) and occlusion (alveolus). These results compliment recent studies demonstrating that maternal thyroxine levels can alter the cranial base and cranial vault of offspring, contributing to a better understanding of both normal and abnormal mandibular development, as well as the medical implications of craniofacial growth and development. PMID- 29611184 TI - Trabectedin is a novel chemotherapy agent for diffuse large B cell lymphoma. PMID- 29611185 TI - Reducing the need for diagnostic imaging in suspected cases of deep vein thrombosis. PMID- 29611186 TI - No effect of intraspecific relatedness on public goods cooperation in a complex community. AB - Many organisms-notably microbes-are embedded within complex communities where cooperative behaviors in the form of excreted public goods can benefit other species. Under such circumstances, intraspecific interactions are likely to be less important in driving the evolution of cooperation. We first illustrate this idea with a simple theoretical model, showing that relatedness-the extent to which individuals with the same cooperative alleles interact with each other-has a reduced impact on the evolution of cooperation when public goods are shared between species. We test this empirically using strain of Pseudomonas aeruginosa that vary in their production of metal-chelating siderophores in copper contaminated compost (an interspecific public good). We show that nonsiderophore producers grow poorly relative to producers under high relatedness, but this cost can be alleviated by the presence of the isogenic producer (low relatedness) and/or the compost microbial community. Hence, relatedness can become unimportant when public goods provide interspecific benefits. PMID- 29611188 TI - Gene-Gene Interactions Implicated in Vascular Endothelial Function in Migraine. PMID- 29611187 TI - Tandem haematopoietic stem cell transplantation for High Risk relapsed/refractory Hodgkin Lymphoma: a LYSA study. AB - Tandem stem cell transplantation (SCT) is an option for high-risk relapsed/refractory Hodgkin Lymphoma (HL) patients. We evaluated the tolerance/efficacy of double autologous or autologous SCT (ASCT) followed by allogenic SCT (alloSCT) in 120 HL patients prospectively registered on a French nationwide database. Median age was 26 (14-56) years. Complete remission rate was 60%, including 33% after a single line, and another 27% after two or more salvage regimens. Partial response rate was 32%, and 8% suffered treatment failure. Overall, 115 (96%) patients underwent a first ASCT, and 73 (61%) had a tandem SCT, including alloSCT in 44 (60%) and ASCT in 29 (40%). The median follow-up was 43 months (4.8-73.7 months). The two-year progression-free survival rate for the whole population and for patients receiving tandem transplant was 56% (95% confidence interval [CI]: 46-65%) and 71% (95% CI: 49-84%), respectively. Among tandem transplants, we observed 20 deaths (17%), 10 of which were transplant related (6 alloSCT and 4 ASCT). We suggest that tandem SCT is efficient in high risk relapsed/refractory HL patients, although transplant-related mortality remains high. The benefit of tandem SCT should be balanced with the efficacy of Brentuximab vedotin-based post-transplant consolidative strategies in high-risk relapsed/refractory HL patients. PMID- 29611189 TI - Editorial: Understanding Menstrual Migraine. PMID- 29611190 TI - A Case of Vestibular Migraine Resolving on Warfarin and Topiramate. PMID- 29611191 TI - Erratum. PMID- 29611193 TI - New Editorial Board Appointment. PMID- 29611192 TI - A Proposal for Acronyms for Anti-Calcitonin Gene-Related Peptide Antibodies. PMID- 29611195 TI - In chronic lymphocytic leukaemia with complex karyotype, major structural abnormalities identify a subset of patients with inferior outcome and distinct biological characteristics. AB - Complex karyotype (CK) is a negative prognostic factor in chronic lymphocytic leukaemia (CLL). However, CK is a heterogeneous cytogenetic category. Unbalanced rearrangements were present in 73.3% of 90 CLL patients with CK (i.e. >=3 chromosome aberrations in the same clone), and were associated with a shorter overall survival (P = 0.025) and a shorter time to first treatment (P = 0.043) by multivariate analysis. Patients with unbalanced rearrangements presented a distinct mRNA expression profile. In conclusion, CLL patients with unbalanced rearrangements might represent a subset of very high-risk CLL patients with distinct clinical and biological characteristics. PMID- 29611194 TI - Recognition of early melanoma: a monocentric dermoscopy follow-up study comparing de novo melanoma with nevus-associated melanoma. AB - BACKGROUND: The earlier detection of melanomas occurring within preexisting nevi is theoretically possible using sequential dermoscopy. Characterizing the early follow-up changes of nevus-associated melanomas (NAMs) and differentiating them from those observed in de novo melanomas (DNMs) may help the earlier recognition of NAMs. METHODS: Using descriptive dermoscopic features to detect focal changes, we blindly evaluated retrospectively the baseline and follow-up images of 32 melanomas that were subsequently classified as histopathologically defined NAMs or DNMs. RESULTS: Correlates of growth, as structureless brown-black areas or clods, complemented each other for the identification of DNMs at baseline (structureless brown-black areas: 66.7% DNMs, 15% NAMs, P < 0.01; combined with clods, one or the other being present: 100% DNMs, 30% NAMs, P < 0.01) and when considering their baseline presence or their appearance at follow-up (100% DNMs, 35% NAMs, P < 0.01). Correlates of fibrosis, as white lines, when considering their baseline presence or their appearance at follow-up, were associated with NAMs (60%, 16.7% DNMs, P = 0.027). CONCLUSION: Significant differences, distinguishing NAMs from DNMs, were detected particularly when considering both baseline signs and follow-up changes. Earlier identification of NAMs and their subsequent improved histological characterization will help define the subgroup of high-risk patients, for whom comprehensive image monitoring may be beneficial. PMID- 29611196 TI - Azacitidine improves outcome in higher-risk MDS patients with chromosome 7 abnormalities: a retrospective comparison of GESMD and GFM registries. AB - Treatment with azacitidine (AZA) has been suggested to be of benefit for higher risk myelodysplastic syndrome (HR-MDS) patients with chromosome 7 abnormalities (Abn 7). This retrospective study of 235 HR-MDS patients with Abn 7 treated with AZA (n = 115) versus best supportive care (BSC; n = 120), assessed AZA treatment as a time-varying variable in multivariable analysis. A Cox Regression model with time-interaction terms of overall survival (OS) at different time points confirmed that, while chromosome 7 cytogenetic categories (complex karyotype [CK] versus non-CK) and International Prognostic Scoring System risk (high versus intermediate-2) retained poor prognosis over time, AZA treatment had a favourable impact on OS during the first 3 years of treatment compared to BSC (Hazard ratio [HR] 0.5 P < 0.001 at 1 year, 0.7 P = 0.019 at 2 years; 0.73 P = 0.029 at 3 years). This benefit was present in all chromosome 7 categories, but tended to be greater in patients with CK (risk reduction of 82%, 68% and 53% at 1, 3 and 6 months in CK patients; 79% at 1 month in non-CK patients, P < 0.05 for all). AZA also significantly improved progression-free survival (P < 0.01). This study confirms a time-dependent benefit of AZA on outcome in patients with HR-MDS and cytogenetic abnormalities involving chromosome 7, especially for those with CK. PMID- 29611197 TI - DCEUS-based multiparametric perfusion imaging using pulse-inversion Bubblet decorrelation. AB - PURPOSE: This study aimed to clarify the influences of composite dynamic contrast enhanced ultrasound (DCEUS) on multiparametric perfusion imaging (PPI) and to develop a novel PPI scheme through pulse-inversion Bubblet decorrelation (PIBD) to improve its contrast and detailed discriminability. METHOD: In in vivo perfusion experiments on rabbit kidneys, a pair of phase-inverted "Bubblets" was constructed. Phase-inverted raw radiofrequency echoes were reconstructed by using the maximum coefficients obtained from Bubblet decorrelation analysis and summed to form DCEUS loops. Nine perfusion parameters were estimated from these loops and color coded to create the corresponding PIBD-based PPIs. RESULTS: In addition to time-related PPIs, the contrast and detailed discriminability quantified by the average contrast and information entropy of intensity- and ratio-related PPIs were proportional to the microbubble detection sensitivity and microvascular discriminability evaluated by CTR in DCEUS techniques. Compared with the second harmonic, the CTR of DCEUS and the average contrast and information entropy of PPI were significantly improved by 9.03 +/- 5.39 dB (P < 0.01), 6.39 +/- 1.38 dB (P < 0.01), and 0.57 +/- 0.15 (P < 0.05) in PIBD technique, respectively. CONCLUSIONS: As a multiparametric functional imaging technique, these improvements in the proposed scheme can be beneficial to accurately quantify and depict the hemodynamic perfusion features and details of tumor angiogenesis, and further can also assist clinicians in making a confirmed diagnosis. PMID- 29611199 TI - Preliminary study of protein changes in trisomy 21 fetus by proteomics analysis in amniocyte. AB - OBJECTIVE: To discover the candidate biomarker proteins of trisomy 21 (T21) in amniocytes. METHODS: Amniocentesis was performed to collect amniotic fluid from women who underwent prenatal diagnosis due to high risk of T21 at 18th to 22nd week of gestation. Amniocyte samples were collected, and karyotyping analysis was used to confirm the chromosomal status (18 samples of T21 amniocytes and 20 samples of chromosomally normal ones). Then, backup samples for cytogenetic test were used in this study. Two-dimensional gel electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry were employed for proteomic analysis. Subsequently, western blotting and biological informatic analysis were utilized to validate the identified proteins and their functions. RESULTS: Six proteins were found to be significantly up regulated in T21 amniocytes, and they were calumenin, nucleophosmin, elongation factor 1-beta, cathepsin D, platelet-activating factor acetylhydrolase IB subunit beta, and 14-3 3 protein beta/alpha identified by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. Western blotting analysis confirmed the alterations of nucleophosmin and cathepsin D. CONCLUSION: These proteins may be involved in the pathogenesis of T21. Further studies exploring the exact role of these proteins were essential. PMID- 29611198 TI - Is primary sidedness a prognostic factor in patients with resected colon cancer liver metastases (CLM)? AB - BACKGROUND AND OBJECTIVES: Recent studies have suggested that sidedness of origin from colorectal adenocarcinomas is a predictor of survival, however the impact of this factor in patients with resected colon cancer liver metastases (CLM) is not clear. So, in this study, we compared clinic and pathologic characteristics and long-term survival of patients with resected CLM according to the primary tumor location. METHODS: This is a retrospective analyzes of a prospective database. Patients with resected CLM from 1998 to 2012 were included. Right colon included tumors from cecum to middle transverse colon, and left colon included tumors from splenic flexure to sigmoid. RESULTS: One hundred fifty-one patients were included, 27 right colon and 124 left colon. In the latter group, there were more patients with synchronous disease (67.7 * 6.2%, P = 0.026) and a higher CEA (22.0 * 11.7 ng/mL, P = 0.001). However, K-Ras mutation was more frequent in right sided tumors (75.0 * 24.1%, P = 0.001). There was no difference in long term survival in both groups in this series even when adjusted for the confounding variables. CONCLUSION: Sidedness do not seem to be a predictor of long term survival in patients with resected colon cancer liver metastases. PMID- 29611200 TI - Assessment of pre-operative maropitant citrate use in macaque (Macaca fasicularis & Macaca mulatta) neurosurgical procedures. AB - BACKGROUND: Retrospective analysis of post-operative vomiting (POV) in non-human primates at our institution was 11%. Based on this additional risk factor for post-operative complications, we aimed to eliminate or decrease POV by adding an antiemetic, maropitant citrate, to the pre-medication protocol. METHODS: Retrospective and prospective data were collected over a 5-year period from 46 macaques of two species during 155 procedures. Additionally, blood was collected from five Macaca mulatta to perform a pharmacokinetic analysis. RESULTS: A 1 mg/kg subcutaneous dose of maropitant given pre-operatively significantly decreased POV. Findings indicated post-neurosurgical emesis in Macaca fasicularis was significantly greater than in Macaca mulatta. Pharmacokinetic analysis of maropitant in Macaca mulatta determined the mean maximum plasma concentration to be 113 ng/mL. CONCLUSIONS: Maropitant administration prior to anesthesia for neurosurgeries decreased our incidence of POV to 1%. The plasma concentration reaches the proposed plasma level for clinical efficacy approximately 20 minutes after administration. PMID- 29611201 TI - A practical toxicity bioassay for vicine and convicine levels in faba bean (Vicia faba). AB - BACKGROUND: Faba bean (Vicia faba) vicine and convicine (V-C) aglycones (divicine and isouramil respectively) provoke an acute hemolytic anemia called favism in individuals with a glucose-6-phosphate dehydrogenase (G6PD) enzyme defect in their red blood cells. Geneticists/plant breeders are working with faba bean to decrease V-C levels to improve public acceptance of this high-protein pulse crop. Here, we present a fast and simple ex vivo in vitro bioassay for V-C toxicity testing of faba bean or faba bean food products. RESULTS: We have shown that 1,3 bis (2-chloroethyl)-1-nitrosourea (BCNU)-treated (i.e., sensitized) normal red blood cells, like G6PD-defective blood, displayed (i) continuous glutathione (GSH) depletion with no regeneration as incubation time and the dose of aglycones increased, (ii) progressive accumulation of denatured hemoglobin products into high molecular weight (HMW) proteins with increased aglycone dose, (iii) both band 3 membrane proteins and hemichromes, in HMW protein aggregates. We have also demonstrated that sensitized red blood cells can effectively differentiate various levels of toxicity among faba bean varieties through the two hemolysis biomarkers: GSH depletion and HMW clumping. CONCLUSION: BCNU-sensitized red blood cells provide an ideal model for favism blood, to assess and compare the toxicity of faba bean varieties and their food products. (c) 2018 Society of Chemical Industry. PMID- 29611202 TI - Joint analysis of left-censored longitudinal biomarker and binary outcome via latent class modeling. AB - Joint latent class modeling is an appealing approach for evaluating the association between a longitudinal biomarker and clinical outcome when the study population is heterogeneous. The link between the biomarker trajectory and the risk of event is reflected by the latent classes, which accommodate the underlying population heterogeneity. The estimation of joint latent class models may be complicated by the censored data in the biomarker measurements due to detection limits. We propose a modified likelihood function under the parametric assumption of biomarker distribution and develop a Monte Carlo expectation maximization algorithm for joint analysis of a biomarker and a binary outcome. We conduct simulation studies to demonstrate the satisfactory performance of our Monte Carlo expectation-maximization algorithm and the superiority of our method to the naive imputation method for handling censored biomarker data. In addition, we apply our method to the Genetic and Inflammatory Markers of Sepsis study to investigate the role of inflammatory biomarker profile in predicting 90-day mortality for patients hospitalized with community-acquired pneumonia. PMID- 29611203 TI - Stabilisation of acute-on-chronic liver failure patients before liver transplantation predicts post-transplant survival. AB - BACKGROUND: Acute-on-chronic liver failure (ACLF) is a severe complication of liver cirrhosis associated with excess short-term mortality rates. Orthotopic liver transplantation (OLT) is a potentially life-saving therapeutic modality for acute-on-chronic liver failure patients, but selection of transplant candidates with an acceptable post-transplant outcome is difficult. AIM: To assess the risk of liver transplantation in patients with ACLF, and to determine parameters that predict post-transplant survival in this patient cohort. METHODS: We retrospectively analysed all 250 patients with cirrhosis who underwent their first liver transplantation between 2009 and 2014 at our institution, and assessed post-transplant outcomes. RESULTS: Of 250 cirrhotic liver transplant recipients, 98 patients fulfilled the diagnostic criteria for acute-on-chronic liver failure in the 3-month pre-transplant period. Compared to non-ACLF patients, ACLF was associated with significantly higher short-term morbidity and mortality after liver transplantation (90-day patient survival 96.1% non-ACLF vs 72.4% ACLF patients, P < 0.0001). Clinical improvement in the pre-transplant period, as defined by recovery of at least one previously failed organ system, was observed in 37 of 98 acute-on-chronic liver failure patients, mostly within several days after diagnosis. Most notably, clinical improvement prior to liver transplantation was associated with excellent post-transplant survival rates that approximated non-ACLF transplant recipients. Following the 90-day post-transplant period, patient survival and long-term graft functions were comparable between ACLF and non-ACLF liver transplant recipients for up to 5 years. CONCLUSIONS: Acute-on-chronic liver failure predicts adverse outcome after orthotopic liver transplantation. Given the dismal prognosis without transplantation, however, our results indicate that ACLF patients can be transplanted with comparably good outcomes, in particular patients who improve under conservative therapeutic measures. PMID- 29611204 TI - Evidence for the anti-inflammatory activity of Bupleurum marginatum (Apiaceae) extracts using in vitro and in vivo experiments supported by virtual screening. AB - OBJECTIVES: To explore the potential anti-inflammatory activity of Bupleurum marginatum extracts using in vitro and in vivo studies supported by virtual screening. METHODS: Antioxidant activity was assessed using the DPPH and inhibition of 2-deoxyribose degradation assays. Anti-inflammatory activity was determined in vitro by measuring the suppression of prostaglandin E2 release (PGE2 ) in pancreatic cancer cells (MIA-PaCa-2) and the inhibition of 5 lipoxygenase whereas the rat paw oedema was used in vivo. The major constituents were docked in 5-lipoxygenase and cyclooxygenase-II active sites. KEY FINDINGS: Methanol and dichloromethane (DCM) extracts showed IC50 of 46.99 and 162.99 MUg/ml in the DPPH, 1.52 and 2.12 MUg/ml in inhibition of 2-deoxyribose degradation assays, respectively. They reduced PGE2 release by 41.33 and 52.85% at 25 MUg/ml and inhibited 5-lipoxygenase with IC50 of 45.28 and 25.92 MUg/ml, respectively. 50 and 70% reduction in the diameter of the carrageenan-induced rat paws with methanol and DCM extracts, respectively, with a marked decline in the inflammation score was observed. Rutin, a predominating compound, showed a strong interaction with the key amino acids in 5-LOX active site with interaction energy of -74.59 kcal/mol. CONCLUSIONS: Our study provides evidence for an interesting anti-inflammatory activity of B. marginatum aerial parts offering a natural anti inflammatory agent. PMID- 29611205 TI - On the use of the not-at-random fully conditional specification (NARFCS) procedure in practice. AB - The not-at-random fully conditional specification (NARFCS) procedure provides a flexible means for the imputation of multivariable missing data under missing-not at-random conditions. Recent work has outlined difficulties with eliciting the sensitivity parameters of the procedure from expert opinion due to their conditional nature. Failure to adequately account for this conditioning will generate imputations that are inconsistent with the assumptions of the user. In this paper, we clarify the importance of correct conditioning of NARFCS sensitivity parameters and develop procedures to calibrate these sensitivity parameters by relating them to more easily elicited quantities, in particular, the sensitivity parameters from simpler pattern mixture models. Additionally, we consider how to include the missingness indicators as part of the imputation models of NARFCS, recommending including all of them in each model as default practice. Algorithms are developed to perform the calibration procedure and demonstrated on data from the Avon Longitudinal Study of Parents and Children, as well as with simulation studies. PMID- 29611206 TI - New insights into the cellular mechanisms of plant growth at elevated atmospheric carbon dioxide concentrations. AB - Rising atmospheric carbon dioxide concentration ([CO2 ]) significantly influences plant growth, development, and biomass. Increased photosynthesis rate, together with lower stomatal conductance, has been identified as the key factors that stimulate plant growth at elevated [CO2 ] (e[CO2 ]). However, variations in photosynthesis and stomatal conductance alone cannot fully explain the dynamic changes in plant growth. Stimulation of photosynthesis at e[CO2 ] is always associated with post-photosynthetic secondary metabolic processes that include carbon and nitrogen metabolism, cell cycle functions, and hormonal regulation. Most studies have focused on photosynthesis and stomatal conductance in response to e[CO2 ], despite the emerging evidence of e[CO2 ]'s role in moderating secondary metabolism in plants. In this review, we briefly discuss the effects of e[CO2 ] on photosynthesis and stomatal conductance and then focus on the changes in other cellular mechanisms and growth processes at e[CO2 ] in relation to plant growth and development. Finally, knowledge gaps in understanding plant growth responses to e[CO2 ] have been identified with the aim of improving crop productivity under a CO2 rich atmosphere. PMID- 29611208 TI - The Effect of On-Line Hemodiafiltration, Vegetarian Diet, and Urine Volume on Advanced Glycosylation End Products Measured by Changes in Skin Auto Fluorescence. AB - Increasing urea clearance by hemodialysis (HD) has not improved patient survival. Hemodiafiltration (HDF) has been reported to reduce cardiovascular mortality. HDF increases middle sized solute clearances. Advanced glycosylation end products (AGEs) are associated with increased cardiovascular mortality. We wished to determine whether HDF reduces AGEs. Skin auto-fluorescence (SAF) measures circulating AGEs deposited in the skin. We compared SAF measurements 12 months apart in high flux HD and HDF patients. At enrollment SAF was not different (HD 3.34 +/- 0.71 vs. HDF 3.48 +/- 1.05 AU). At seven months after completion of SAF measurement, one hemodiafiltration center returned to hemodialysis, and one hemodialysis center converted to hemodiafiltration. In the 66 patients treated solely by high flux HD, SAF increased (3.36 +/- 0.71 to 3.82 +/- 0.88 AU, P < 0.001), whereas there was no change for 47 exclusively treated by HDF (3.45 +/- 1.13 to 3.44 +/- 0.85 AU, P > 0.9). SAF increased in 34 patients switching from HDF to high flux HD (3.52 +/- 0.94 vs. 3.88 +/- 1.05, P < 0.05), with no significant change for 33 patients converting from high flux HD to HDF (3.32 +/- 0.72 to 3.48 +/- 1.07 AU, P > 0.3). On multivariate analysis, SAF was associated with older age (beta coefficient 0.013, P = 0.002), prescription of insulin (beta 0.29, P = 0.016), lanthanum (beta 0.36, P = 0.004), and warfarin (beta 0.62, P = 0.012), whereas vegetarian diet and > 250 mL/day residual urine volume were negatively associated with SAF (beta -0.58, P = 0.002 and beta -0.26, P = 0.033 respectively). Residual urine output and vegetarian diet were associated with lower AGE deposition. Whereas SAF increased over time in patients treated with high flux HD, there was no statistical change in SAF in those exclusively treated by HDF. PMID- 29611207 TI - Immunological and hematological effects of IL-5(Ralpha)-targeted therapy: An overview. AB - IL-5 is an important cytokine for priming and survival of mature eosinophils and for proliferation and maturation of their progenitors. Hence, IL-5(Ralpha) targeting will be increasingly used in diseases where eosinophils are the key immune effector cells such as eosinophilic asthma (EA), hypereosinophilic syndrome (HES), eosinophilic esophagitis (EE), and eosinophilic granulomatosis with polyangiitis (EGPA). Therefore, several neutralizing monoclonal antibodies directed against IL-5 (mepolizumab and reslizumab) and its receptor IL-5Ralpha (benralizumab) have found or will find their way to the clinic. While the clinical effect of these drugs has been extensively investigated and reviewed, the understanding of the underlying immunological and hematological mechanisms remains less clear. This review will discuss the translational outcomes of treatment with these monoclonal antibodies in humans to shed light on the mechanisms underlying the main immunological and hematological findings from these clinical trials in humans. PMID- 29611209 TI - Intensity of surveillance for hepatocellular carcinoma determines survival in patients at risk in a hepatitis B-endemic area. AB - BACKGROUND: Data are insufficient regarding the survival benefit of surveillance for hepatocellular carcinoma (HCC). AIM: To investigate the effectiveness of HCC surveillance in a hepatitis B-endemic population. METHODS: This retrospective cohort study included 1402 consecutive patients who were newly diagnosed with HCC between 2005 and 2012 at a single tertiary hospital in Korea. The primary endpoint was overall survival. Lead-time and length-time biases were adjusted (sojourn time = 140 days) and sensitivity analyses were performed. RESULTS: The most common aetiology was hepatitis B (80.4%). Cirrhosis was present in 78.2%. HCC was diagnosed during regular surveillance (defined as mean interval of ultrasonography <8 months, n = 834), irregular surveillance (n = 104) or nonsurveillance (n = 464). Patients in the regular surveillance group were diagnosed at earlier stages ([very] early stage, 64.4%) than the irregular surveillance (40.4%) or nonsurveillance (26.9%) groups and had more chance for curative treatments (52.4%) than the irregular surveillance (39.4%) or nonsurveillance (23.3%) groups (all P < 0.001). Mortality risk was significantly lower in the regular surveillance group (adjusted hazard ratio [aHR], 0.69; 95% [CI], 0.57-0.83) but not in the irregular surveillance group (aHR, 0.94; 95% CI, 0.69-1.28) compared with the nonsurveillance group after adjusting for confounding factors and lead-time. When the subjects were restricted to cirrhotic patients or Child-Pugh class A/B patients, similar results were obtained for mortality risk reduction between groups. CONCLUSIONS: HCC surveillance was associated with longer survival owing to earlier diagnosis and curative treatment. Survival advantage was significant with regular surveillance but not with irregular surveillance. PMID- 29611210 TI - Interplay effect on a 6-MV flattening-filter-free linear accelerator with high dose rate and fast multi-leaf collimator motion treating breast and lung phantoms. AB - PURPOSE: Using a new linear accelerator with high dose rate (800 MU/min), fast MLC motions (5.0 cm/s), fast gantry rotation (15 s/rotation), and 1 cm wide MLCs, we aimed to quantify the effects of complexity, arc number, and fractionation on interplay for breast and lung treatments under target motion. METHODS: To study lung interplay, eight VMAT plans (1-6 arcs) and four-nine-field sliding-window IMRT plans varying in complexity were created. For the breast plans, four-four field sliding-window IMRT plans were created. Using the Halcyon 1.0 linear accelerator, each plan was delivered five times each under sinusoidal breathing motion to a phantom with 20 implanted MOSFET detectors; MOSFET dose (cGy), delivery time, and MU/cGy values were recorded. Maximum and mean dose deviations were calculated from MOSFET data. The number of MOSFETs with at least 19 of 20 detectors agreeing with their expected dose within 5% per fraction was calculated across 106 iterations to model dose deviation as function of fraction number for all plan variants. To put interplay plans into clinical context, additional IMRT and VMAT plans were created and delivered for the sites of head and neck, prostate, whole brain, breast, pelvis, and lung. Average modulation and interplay effect were compared to those from conventional linear accelerators, as reported from previous studies. RESULTS: The mean beam modulation for plans created for the Halcyon 1.0 linear accelerator was 2.9 MU/cGy (two- to four-field IMRT breast plans), 6.2 MU/cGy (at least five-field IMRT), and 3.6 MU/cGy (four-arc VMAT). To achieve treatment plan objectives, Halcyon 1.0 VMAT plans require more arcs and modulation than VMAT on conventional linear accelerators. Maximum and mean dose deviations increased with increasing plan complexity under tumor motion for breast and lung treatments. Concerning VMAT plans under motion, maximum, and mean dose deviations were higher for one arc than for two arcs regardless of plan complexity. For plan variants with maximum dose deviations greater than 3.7%, dose deviation as a function of fraction number was protracted. CONCLUSION: For treatments on the Halcyon 1.0 linear accelerator, the convergence of dose deviation with fraction number happened more slowly than reported for conventional linear accelerators. However, if plan complexity is reduced for IMRT and if tumor motion is less than ~10-mm, interplay is greatly reduced. To minimize dose deviations across multiple fractions for dynamic targets, we recommend limiting treatment plan complexity and avoiding one-arc VMAT on the Halcyon 1.0 linear accelerator when interplay is a concern. PMID- 29611211 TI - A predictive probability interim design for phase II clinical trials with continuous endpoints. AB - Molecular targeted therapies come often with lower toxicity profiles than traditional cytotoxic treatments, thus shifting drug development paradigm into establishing evidence of biological activity, target modulation, and pharmacodynamics effects of these therapies in early phase trials. Therefore, these trials need to address simultaneous evaluation of safety, proof-of-concept biological marker activity, or changes in continuous tumor size instead of binary response rate. Interim analyses are typically incorporated in the trial due to concerns regarding excessive toxicity and ineffective new treatment. There is a lack of interim strategies developed to monitor futility and/or efficacy for these types of continuous outcomes, especially in single-arm phase II trials. We propose a 2-stage design based on predictive probability to accommodate continuous endpoints, assuming a normal distribution with known variance. Simulation results and case study demonstrated that the proposed design can incorporate an interim stop for futility as well as for efficacy while maintaining desirable design properties. As expected, using continuous tumor size resulted in reduced sample sizes for both optimal and minimax designs. A limited exploration of various priors was performed and shown to be robust. As research rapidly moves to incorporate more molecular targeted therapies, it will accommodate new types of outcomes while allowing for flexible stopping rules to continue optimizing trial resources and prioritize agents with compelling early phase data. PMID- 29611212 TI - Design of Bioartificial Pancreases From the Standpoint of Oxygen Supply. AB - A bioartificial pancreas (BAP), in which islets of Langerhans (islets) are enclosed in a semipermeable membrane, has been developed to realize islet transplantation without the use of immunosuppressive drugs. Although recent progress in induced pluripotent stem (iPS) and embryonic stem (ES) cells has attracted attention owing to the potential applications of these cells as insulin releasing cells, concerns about the safety of implantation of these cells remain. The use of the BAP has the advantage of easy removal if insulin-releasing cells derived from iPS/ES cells undesirably proliferate and form tumors in the BAP. Oxygen supply is a crucial issue for cell survival in BAPs as insufficient oxygen supply causes central necrosis of cell aggregates. In this study, we derived several simple equations considering oxygen supply in BAPs in order to provide insights into the rational design of three different types of BAPs (spherical microcapsules, cylindrical capsules, and planar capsules). The equations give (i) the thickness of a capsule membrane leading to no central necrosis of encapsulated cell aggregates as a function of the original size of the cell aggregate; (ii) the oxygen concentration profiles in BAPs; (iii) the effects of encapsulation of a cell aggregate on insulin release; (iv) the amount of encapsulated cells required to normalize blood glucose levels of a patient; and (v) the total volumes and sizes of BAPs. As an example, we used the equations in order to design three different types of BAPs for subcutaneous implantation. PMID- 29611213 TI - Efficiently train and validate a RapidPlan model through APQM scoring. AB - PURPOSE: The aim of this study was to propose and validate an intuitive method for training and to validate knowledge-based planning (KBP) systems based on a patient-specific plan quality scoring. METHODS: A sample of 80 clinical plans of prostate cancer patients were ranked on the basis of the Adjusted Plan Quality Metric (APQM%). This quality metric was computed normalizing the Plan Quality Metric (PQM%) score to the best possible OAR sparing estimated by the Feasibility DVH (FDVH) algorithm. Two different plan libraries were created, purging all the plans below the first quartile or below the median the APQM% distribution. These libraries were used to populate and train two RapidPlan models: respectively, the APMQ25% and the APMQ50% models. No further refinements or actions were undertaken on these two models. Their performances were benchmarked against another two RapidPlan models. An Uncleaned model, which was populated and trained with the initial sample of 80 plans, and a Cleaned model, obtained through the standard iterative cleaning and refinement process suggested by the vendor and in literature. The outcomes of a planning test based on 20 patients within the training library (closed loop) and 20 patients outside of the training library (open-loop) were compared through various DVH metrics and the PQM% score. RESULTS: The selection through APQM% thresholding roughly preserves the geometric variety of the Cleaned model; only the APMQ50% model showed a modest broadness reduction. The models generated through APQM% thresholding showed target coverage and OARs sparing equal or superior to the Uncleaned and Cleaned models both for the closed- and the open-loop tests. No significant differences were found between the four models. PQM% analysis ranked the overall plan quality as: 86.5 +/- 6.5% APQM50% , 83.1 +/- 5.9% APQM25% , 80.39 +/- 10.6% Cleaned and 79.4 +/- 8.5% Uncleaned in the closed-loop test; 84.9 +/- 7.6% APQM50% , 82.6 +/- 7.9% APQM25% , 80.39 +/- 10.6% Cleaned and 79.4 +/- 8.5% Uncleaned in the open-loop test. CONCLUSIONS: Forward feeding a RapidPlan model through a thresholding selection based on APQM% is proven to produce equal or better results than a model based on a manually and iteratively refined population. A tighter APQM% threshold turns approximately into a higher average quality of plans generated with RapidPlan. A trade-off must be found between the mean quality of the KBP library and its numerosity. The proposed KBP feeding method helps the KBP user, because it makes the model refinement more intuitive and less time consuming. PMID- 29611214 TI - Hydrogen Gas Does Not Ameliorate Renal Ischemia Reperfusion Injury in a Preclinical Model. AB - In renal transplantation, ischemia reperfusion injury impairs early graft function and can reduce long term graft survival. Hydrogen has antioxidant and anti-inflammatory properties that can reduce the effects of ischemic injury. The aim of this study was to examine the effects of hydrogen gas administered during reperfusion in a preclinical model of kidney ischemia reperfusion injury. Porcine kidneys underwent 15 min of warm ischemia followed by 22 h of cold ischemia. They were then reperfused for 6 h with whole autologous blood on an ex vivo reperfusion circuit. Paired kidneys were randomized to control (n = 6) (25% oxygen, 5% carbon dioxide, 70% nitrogen) or hydrogen (n = 6) (2% hydrogen, 25% oxygen, 5% carbon dioxide, 68% nitrogen) groups. Tissue, urine, and blood samples were collected at baseline and hourly throughout the reperfusion period. Baseline measurements were similar across groups. Following perfusion, there was no significant difference between control and hydrogen groups in urine output (693 mL vs. 608 mL, P = 0.86), renal blood flow (105.9 vs. 108 mL/min/100g, P = 0.89), acid-base homeostasis, or creatinine clearance. There was a significant increase in cytokine levels from baseline to 6 h in both groups (IL-1beta P = 0.002; IL-6 P = 0.004; IL-8 P = 0.002). However, there were no significant differences in levels of inflammatory cytokines (IL1beta, IL-6, and IL-8) between the groups. The administration of hydrogen gas did not improve renal function, reduce oxidative damage, or inflammation during the reperfusion of ischemically damaged kidneys. PMID- 29611215 TI - Improving Occupational Health Disparity Research: Testing a method to estimate race and ethnicity in a working population. AB - BACKGROUND: Race and ethnicity data are often absent from administrative and health insurance databases. Indirect estimation methods to assign probability scores for race and ethnicity to insurance records may help identify occupational health inequities. METHODS: We compared race and ethnicity estimates from the Bayesian Improved Surname Geocoding (BISG) formula to self-reported race and ethnicity from 1132 workers. RESULTS: The accuracy of the BISG using gender stratified regression models adjusted for worker age and industry were excellent for White and Latino males and Latino females, good for Black and Asian Pacific Islander males and White and Asian Pacific Islander females. American Indian/Alaskan Native and those who indicated they were "Other" or "More than one race" were poorly identified. CONCLUSION: The BISG estimation method was accurate for White, Black, Latino, and Asian Pacific Islanders in a sample of workers. Using the BISG in administrative datasets will expand research into occupational health disparities. PMID- 29611217 TI - Transcatheter aortic valve-in-valve implantation for early failure of sutureless aortic bioprosthesis. AB - We report a case of early failure of a Perceval sutureless aortic bioprosthesis (LivaNova, London, UK) which was treated with a transcatheter valve-in-valve implantation with an Edwards 3 bioprosthesis (Edwards Lifesciences, Irvine, CA). PMID- 29611216 TI - A semiautomatic segmentation method for prostate in CT images using local texture classification and statistical shape modeling. AB - PURPOSE: Prostate segmentation in computed tomography (CT) images is useful for treatment planning and procedure guidance such as external beam radiotherapy and brachytherapy. However, because of the low, soft tissue contrast of CT images, manual segmentation of the prostate is a time-consuming task with high interobserver variation. In this study, we proposed a semiautomated, three dimensional (3D) segmentation for prostate CT images using shape and texture analysis and we evaluated the method against manual reference segmentations. METHODS: The prostate gland usually has a globular shape with a smoothly curved surface, and its shape could be accurately modeled or reconstructed having a limited number of well-distributed surface points. In a training dataset, using the prostate gland centroid point as the origin of a coordination system, we defined an intersubject correspondence between the prostate surface points based on the spherical coordinates. We applied this correspondence to generate a point distribution model for prostate shape using principal component analysis and to study the local texture difference between prostate and nonprostate tissue close to the different prostate surface subregions. We used the learned shape and texture characteristics of the prostate in CT images and then combined them with user inputs to segment a new image. We trained our segmentation algorithm using 23 CT images and tested the algorithm on two sets of 10 nonbrachytherapy and 37 postlow dose rate brachytherapy CT images. We used a set of error metrics to evaluate the segmentation results using two experts' manual reference segmentations. RESULTS: For both nonbrachytherapy and post-brachytherapy image sets, the average measured Dice similarity coefficient (DSC) was 88% and the average mean absolute distance (MAD) was 1.9 mm. The average measured differences between the two experts on both datasets were 92% (DSC) and 1.1 mm (MAD). CONCLUSIONS: The proposed, semiautomatic segmentation algorithm showed a fast, robust, and accurate performance for 3D prostate segmentation of CT images, specifically when no previous, intrapatient information, that is, previously segmented images, was available. The accuracy of the algorithm is comparable to the best performance results reported in the literature and approaches the interexpert variability observed in manual segmentation. PMID- 29611218 TI - Validation of multivariable models for predicting tooth loss in periodontitis patients. AB - OBJECTIVES: A large number of multivariable models which associate independent variables with the outcome tooth loss exist. Directly or indirectly, these make predictions as to the relative risk of tooth loss. We aimed to validate six of these prediction models. METHODS: We applied each model, if needed after adaptions, in a cohort of 301 compliant periodontitis patients who had been under supportive periodontal treatment (SPT) in a university setting over 21.7 +/- 5.6 years. The models employed a range of tooth-level and patient-level parameters. Model accuracy, that is, the ability to rightly predict tooth loss during SPT using baseline parameters, was investigated by the area under the receiver operating-characteristics curve (AUC). RESULTS: Most models showed low accuracy (AUC ranged between 0.52 and 0.67). The classification model from Avila et al. (2009) Journal of Periodontology, 80, 476-491, expressing the risk of tooth loss in five grades, was most accurate (mean AUC: 0.67, 95%CI: 0.65/0.69). When applying this model, the risk of false-positively predicting tooth loss was high, except when the highest grade (i.e. a tooth being considered as having a hopeless prognosis) was used. In this case, the specificity was 84% and the sensitivity 46%. CONCLUSIONS: Predicting tooth loss in this specific cohort of periodontitis patients was only limitedly possible. PMID- 29611219 TI - Association between periodontal disease and gestational diabetes mellitus-A prospective cohort study. AB - AIM: This study aimed to determine the association between periodontal disease and gestational diabetes mellitus (GDM) and the effect of this association on pregnancy outcome in North Indian population. MATERIALS AND METHODS: A total of 584 primigravidae were recruited at 12-14 weeks of gestation. Their periodontal examination was carried out along with 75 g oral glucose load test at the time of recruitment. GDM was diagnosed as per the DIPSI (The Diabetes in Pregnancy Study group India) guidelines (>=140 mg/dl). Women with normal plasma glucose values underwent a repeat 75 g oral glucose load test at 24-28 weeks of gestation. All patients were followed up for pregnancy outcomes. RESULTS: Of 584 primigravida, 184 (31.5%) had gingivitis and 148 (25.3%) had periodontitis. Overall, 332 (56.8%) pregnant women had periodontal disease. It was associated with GDM with adjusted hazard ratio (aHR) of 2.85 (95%CI = 1.47-5.53). The occurrence of pre eclampsia was associated with periodontal disease with aHR of 2.20 (95%CI = 0.86 5.60). If primigravidae had periodontal disease along with GDM, the risk of pre eclampsia had shown increased aHR of 18.79 (95% CI = 7.45-47.40). CONCLUSIONS: The study shows a significant association of periodontal disease with GDM and an increased risk of developing pre-eclampsia due to this association. PMID- 29611220 TI - Cardiovascular disease after transplantation: an emerging role of the immune system. AB - Cardiovascular disease (CVD) after transplantation remains a major concern. Little is known about what drives the increased cardiovascular risk in transplant recipients apart from traditional risk factors. The immune system is involved in the pathogenesis of hypertension, atherosclerosis, and coronary artery disease in the general population. Recently, inhibition of interleukin 1 - beta by canakinumab versus placebo decreased the incidence of cardiovascular events. Emerging evidence points to a role of adaptive cellular immunity in the development of CVD. Especially, expansion of pro-inflammatory and antiapoptotic cytotoxic CD4+ CD28null T cells is closely associated with incident CVD in various study populations including transplant recipients. The association of cytomegalovirus exposure with increased cardiovascular mortality might be explained by its capacity to upregulate these cytotoxic cells. Also, humoral immunity seems to be relevant for cardiovascular outcome in transplant recipients. Panel-reactive antibodies at baseline and donor-specific antibodies are independently associated with poor cardiovascular outcome after kidney transplantation. Cardiovascular effects of immunosuppressive drugs and statins do not only imply indirect positive or negative effects on traditional cardiovascular risk factors but also intrinsic immunological effects. How immunosuppressive drugs modify atherosclerosis largely remains elusive. PMID- 29611221 TI - A 5-year randomized clinical trial comparing minimally with moderately rough implants in patients with severe periodontitis. AB - AIM: To compare the clinical and microbiological performance of minimally and moderately rough implants in patients with a history of severe periodontitis. MATERIAL AND METHODS: Forty-eight minimally (Turned surface [Tur]) and moderately (TiUnite surface [TiU]) rough implants were placed in eighteen patients according to a split-mouth protocol. Marginal bone loss, probing pocket depth (PPD), clinical attachment level (CAL), and bleeding on probing (BoP) were recorded, and microbial samples were analysed by means of quantitative PCR. RESULTS: The amount of bone loss over the 5-year period tended to be lower along Tur when compared with that of TiU surfaces (1.0 versus 1.7 mm, p = .06). Although the clinical outcomes tended to be better for Tur surfaces, there were no significant differences between both surfaces in mean PPD (Tur: 3.1 versus TiU: 4.2 mm, p = .09) or CAL (Tur: 0.5 versus TiU: 1.7 mm, p = .06). More bone loss and deeper pockets were recorded for partially than for fully edentulous patients. The cumulative survival rate at 5-year follow-up was 95.8% for Tur, and 100% for TiU surface implants. No significant differences were found between the surfaces in counts for key pathogens. CONCLUSION: In patients with a history of severe periodontitis minimally rough implants showed more favourable clinical parameters after 5 years of loading, when compared with moderately rough implants. PMID- 29611222 TI - Few-Layer GeAs Field-Effect Transistors and Infrared Photodetectors. AB - The family of 2D semiconductors (2DSCs) has grown rapidly since the first isolation of graphene. The emergence of each 2DSC material brings considerable excitement for its unique electrical, optical, and mechanical properties, which are often highly distinct from their 3D counterparts. To date, studies of 2DSC are majorly focused on group IV (e.g., graphene, silicene), group V (e.g., phosphorene), or group VIB compounds (transition metal dichalcogenides, TMD), and have inspired considerable effort in searching for novel 2DSCs. Here, the first electrical characterization of group IV-V compounds is presented by investigating few-layer GeAs field-effect transistors. With back-gate device geometry, p-type behaviors are observed at room temperature. Importantly, the hole carrier mobility is found to approach 100 cm2 V-1 s-1 with ON-OFF ratio over 105 , comparable well with state-of-the-art TMD devices. With the unique crystal structure the few-layer GeAs show highly anisotropic optical and electronic properties (anisotropic mobility ratio of 4.8). Furthermore, GeAs based transistor shows prominent and rapid photoresponse to 1.6 um radiation with a photoresponsivity of 6 A W-1 and a rise and fall time of ~3 ms. This study of group IV-V 2DSC materials greatly expands the 2D family, and can enable new opportunities in functional electronics and optoelectronics based on 2DSCs. PMID- 29611223 TI - Chirality Dependent Charge Transfer Rate in Oligopeptides. AB - It is shown that "spontaneous magnetization" occurs when chiral oligopeptides are attached to ferrocene and are self-assembled on a gold substrate. As a result, the electron transfer, measured by electrochemistry, shows asymmetry in the reduction and oxidation rate constants; this asymmetry is reversed between the two enantiomers. The results can be explained by the chiral induced spin selectivity of the electron transfer. The measured magnetization shows high anisotropy and the "easy axis" of magnetization is along the molecular axis. PMID- 29611224 TI - Self-report assessment of severe periodontitis: Periodontal screening score development. AB - AIM: To derive from a validated questionnaire a periodontal screening score (PESS), intended as a user-friendly tool to identify individuals at risk of periodontitis in epidemiological studies. METHODS: A French 12-item self-reported questionnaire was developed by translating English questions previously used for periodontitis screening and surveillance. After a cognitive evaluation, the questionnaire was validated in a sample of 232 individuals (mean age: 46.1 +/- 12.6 years) receiving full-mouth periodontal examination, including probing pocket depth and clinical attachment level recordings. Case definition was based on the American Academy of Periodontology/Centers for Disease Control and Prevention criteria. Logistic regression analyses and C-statistics were used to assess the validity and accuracy of the questionnaire and to develop the PESS. RESULTS: The sample was constituted of 109 individuals with severe periodontitis, who were compared with 123 individuals with no/moderate periodontitis. The questionnaire had moderate-to-high accuracy in identifying severe cases; the PESS (calculated on five self-report items, age, and smoking) showed a sensitivity of 78.9% and a specificity of 74.8%, with an area under the receiver operating characteristics curve of 0.821. CONCLUSION: The PESS represents a valuable and accurate tool to screen for severe periodontitis at the population level. PMID- 29611226 TI - Susceptibility of A. fumigatus-specific T-cell assays to pre-analytic blood storage and PBMC cryopreservation greatly depends on readout platform and analytes. AB - Mould-specific T cells detectable by flow cytometry or ELISPOT were proposed as a novel biomarker in invasive aspergillosis. To define protocols facilitating sample shipment and longitudinal analysis, this study evaluated the susceptibility of different functional assays for A. fumigatus-specific T-cell quantification and characterisation to pre-analytic delays. PBMCs from 6 healthy donors were analysed after immediate isolation, after 6 hours whole blood storage or after cryopreservation using 3 different common media. Functional responses to A. fumigatus lysate stimulation were comparatively assessed by flow cytometry, ELISPOT and 14-plex cytokine assay. After 6 hours pre-analytic storage, all functional assays showed reduced detection rates, higher coefficients of variation (CV) and widely varying individual recovery indices of specific T-cell response. While cryopreservation resulted in sufficient yields and largely unaltered cellular composition, outcomes of functional readouts significantly differed from freshly processed samples. For CD154-based flow cytometry, only cryopreservation in RPMI supplemented with autologous serum resulted in satisfactory detection rates and CVs. For ELISPOT and cytokine secretion assays, none of the cryopreservation protocols provided sufficient concordance with immediately processed samples. Even using the same readout platform, individual analytes widely varied in their susceptibility to cryopreservation, highlighting that distinct optimisation is required depending on the downstream assay. PMID- 29611227 TI - Isavuconazole for treatment of invasive fungal diseases caused by more than one fungal species. AB - The optimal approach to treat invasive fungal disease (IFD) caused by more than one fungal species is unknown. We documented the efficacy and safety of isavuconazole for treatment of IFDs caused by more than one fungal species. VITAL was a single-arm, international, open-label study evaluating the efficacy and safety of isavuconazole (200 mg orally or intravenously every 8 hours for 48 hours, then once daily) for treatment of rare IFDs. The primary outcome was the overall response at Day 42; key secondary outcomes were overall responses at Day 84 and end of treatment (EOT), mortality at Days 42 and 84, and safety. This analysis includes patients with IFD caused by multiple fungal species. Fifteen patients were included in this analysis (including Aspergillus spp., n = 11; without Aspergillus spp., n = 4); median treatment duration was 97 days [range, 6 544] days). Overall treatment success was observed in 2/15 patients (13.3%) at Days 42 and 84, and 2/14 (14.3%) at EOT. All-cause mortality was 2/15 (13.3%) at Day 42 and 4/15 (26.7%) at Day 84. All patients had >=1 treatment-emergent adverse event (TEAE); 12 patients (80.0%) had serious TEAEs; TEAEs led to discontinuation of isavuconazole in two patients (13.3%). Isavuconazole may be useful to treat some IFDs caused by multiple fungal species. PMID- 29611225 TI - Optimizing the use of topical retinoids in Asian acne patients. AB - Acne vulgaris is a common disease among people in Asia. International guidelines and treatment recommendations emphasize the central role of topical retinoids in the management of acne. However, topical retinoids remain underutilized in clinical practise, which may be in part due to fear of retinoid-associated dermatitis/lack of experience, particularly in Asian patients. There is a perception that Asian skin has a greater tendency toward sensitivity compared with Caucasian skin. In our clinical experience, topical retinoid therapy can be used with excellent effect to treat Asians with acne. This article discusses available published work regarding the use of topical retinoids in Asian populations, and presents tips for utilizing these important agents in daily practise. Optimizing use of topical retinoids may improve adherence and, in turn, therapeutic outcomes and patient satisfaction. PMID- 29611228 TI - Pigmented dermatofibrosarcoma protuberans associated with dermal melanocytosis. PMID- 29611229 TI - Relationship between environmental factors, age of onset and familial history in Japanese patients with psoriasis. AB - Psoriasis is a chronic inflammatory disease that often involves the skin and joints. Psoriasis develops at any age and the distribution of age of onset of psoriasis is bimodal in Japan. Also, male predominance is distinct in Japanese psoriatic patients. To clarify the relationship between sex difference and habitual/environmental status, age and incidence of familial psoriasis, we analyzed data from the Fukuoka University Psoriasis Registry. A total of 1120 Japanese patients (751 men, 369 women) were analyzed. The male/female ratio was 2.03:1. Smoking and drinking habit, known as risk factors of psoriasis, were significantly more prevalent in men. Age-specific psoriasis-onset rate standardized by population showed bimodal distribution in both men and women; the younger peak was in their 30s for men and 10s in women; the second peak was in the 50s for both sexes. A familial history of psoriasis was seen in 6.3% of patients overall; however, female patients showed a significantly higher rate (8.7%) compared with men (5.1%, P = 0.024). When stratified by age of onset, the frequency of familial history was much higher among women with onset at less than 30 years (15.4%), compared with 30 years or more (5.3%, P = 0.0026). Our data suggest that genetic factors have a stronger influence in young women who experience fewer environmental factors such as smoking and drinking. This is the first study to show that there is a difference in the incidence of familial psoriasis depending on age of onset of psoriasis in Japan. PMID- 29611230 TI - In vitro activities of antifungal drugs against environmental Exophiala isolates and review of the literature. AB - Exophiala is a genus of black fungi isolated worldwide from environmental and clinical specimens. Data on antifungal susceptibility of Exophiala isolates are limited and the methodology on susceptibility testing is not yet standardised. In this study, we investigated in vitro antifungal susceptibilities of environmental Exophiala isolates. A total of 87 Exophiala isolated from dishwashers or railway ties were included. A CLSI M38-A2 microdilution method with modifications was used to determine antifungal susceptibility for fluconazole, voriconazole, posaconazole, itraconazole, amphotericin B and terbinafine. Minimum inhibitory concentration (MIC) values were determined visually at 48 hours, 72 hours and 96 hours. MIC-0 endpoint (complete inhibition of growth) was used for amphotericin B and azoles, except fluconazole, for which MIC-2 endpoint (~50% inhibition compared to growth control) was used. Both MIC-0 and MIC-1 (~80% inhibition compared to growth control) results were analysed for terbinafine to enable comparison with previous studies. Fungal growth was sufficient for determination of MICs at 48 hours for all isolates except two Exophiala dermatitidis strains. At 72 hours, most active antifungal agents according to GM MIC were voriconazole and terbinafine, followed by posaconazole, itraconazole and amphotericin B in rank order of decreasing activity. While amphotericin B displayed adequate in vitro activity despite relatively high MICs, fluconazole showed no meaningful antifungal activity against Exophiala. PMID- 29611231 TI - In Situ Encapsulating alpha-MnS into N,S-Codoped Nanotube-Like Carbon as Advanced Anode Material: alpha -> beta Phase Transition Promoted Cycling Stability and Superior Li/Na-Storage Performance in Half/Full Cells. AB - Incorporation of N,S-codoped nanotube-like carbon (N,S-NTC) can endow electrode materials with superior electrochemical properties owing to the unique nanoarchitecture and improved kinetics. Herein, alpha-MnS nanoparticles (NPs) are in situ encapsulated into N,S-NTC, preparing an advanced anode material (alpha MnS@N,S-NTC) for lithium-ion/sodium-ion batteries (LIBs/SIBs). It is for the first time revealed that electrochemical alpha -> beta phase transition of MnS NPs during the 1st cycle effectively promotes Li-storage properties, which is deduced by the studies of ex situ X-ray diffraction/high-resolution transmission electron microscopy and electrode kinetics. As a result, the optimized alpha MnS@N,S-NTC electrode delivers a high Li-storage capacity (1415 mA h g-1 at 50 mA g-1 ), excellent rate capability (430 mA h g-1 at 10 A g-1 ), and long-term cycling stability (no obvious capacity decay over 5000 cycles at 1 A g-1 ) with retained morphology. In addition, the N,S-NTC-based encapsulation plays the key roles on enhancing the electrochemical properties due to its high conductivity and unique 1D nanoarchitecture with excellent protective effects to active MnS NPs. Furthermore, alpha-MnS@N,S-NTC also delivers high Na-storage capacity (536 mA h g-1 at 50 mA g-1 ) without the occurrence of such alpha -> beta phase transition and excellent full-cell performances as coupling with commercial LiFePO4 and LiNi0.6 Co0.2 Mn0.2 O2 cathodes in LIBs as well as Na3 V2 (PO4 )2 O2 F cathode in SIBs. PMID- 29611233 TI - Herpes vegetans accompanied by Good's syndrome. PMID- 29611232 TI - Serodiagnosis of aspergillosis in falcons (Falco spp.) by an Afmp1p-based enzyme linked immunosorbent assay. AB - Aspergillosis in falcons may be associated with high mortality and difficulties in clinical and laboratory diagnosis. We previously cloned an immunogenic protein, Afmp1p, in Aspergillus fumigatus and showed that anti-Afmp1p antibodies were present in human patients with A. fumigatus infections. In this study, we hypothesise that a similar Afmp1p-based enzyme-linked immunosorbent assay (ELISA) could be applied to serodiagnose falcon aspergillosis. A specific polyclonal antibody was first generated to detect falcon serum IgY. Horseradish peroxidase conjugate of this antibody was then used to measure anti-Afmp1p antibodies in sera collected from falcons experimentally infected with A. fumigatus, and the performance of the Afmp1p-based ELISA was evaluated using sera from healthy falcons and falcons with documented A. fumigatus infections. All four experimentally infected falcons developed culture- and histology-proven invasive aspergillosis. Anti-Afmp1p antibodies were detected in their sera. For the Afmp1p based ELISA, the mean +/- SD OD450 nm using sera from 129 healthy falcons was 0.186 +/- 0.073. Receiver operating characteristics curve analysis showed an absorbance cut-off value of 0.407. One negative serum gave an absorbance outside the normal range, giving a specificity of 99.2%. For the 12 sera from falcons with confirmed aspergillosis, nine gave absorbance values >= cut-off, giving a sensitivity of 75%. The Afmp1p-based ELISA is useful for serodiagnosis of falcons with aspergillosis. PMID- 29611234 TI - Versatility of Carbon Enables All Carbon Based Perovskite Solar Cells to Achieve High Efficiency and High Stability. AB - Carbon-based perovskite solar cells (PVSCs) without hole transport materials are promising for their high stability and low cost, but the electron transporting layer (ETL) of TiO2 is notorious for inflicting hysteresis and instability. In view of its electron accepting ability, C60 is used to replace TiO2 for the ETL, forming a so-called all carbon based PVSC. With a device structure of fluorine doped tin oxide (FTO)/C60 /methylammonium lead iodide (MAPbI3 )/carbon, a power conversion efficiency (PCE) is attained up to 15.38% without hysteresis, much higher than that of the TiO2 ones (12.06% with obvious hysteresis). The C60 ETL is found to effectively improve electron extraction, suppress charge recombination, and reduce the sub-bandgap states at the interface with MAPbI3 . Moreover, the all carbon based PVSCs are shown to resist moisture and ion migration, leading to a much higher operational stability under ambient, humid, and light-soaking conditions. To make it an even more genuine all carbon based PVSC, it is further attempted to use graphene as the transparent conductive electrode, reaping a PCE of 13.93%. The high performance of all carbon based PVSCs stems from the bonding flexibility and electronic versatility of carbon, promising commercial developments on account of their favorable balance of cost, efficiency, and stability. PMID- 29611235 TI - Site-Controlled Single-Photon Emitters Fabricated by Near-Field Illumination. AB - Many of the most advanced applications of semiconductor quantum dots (QDs) in quantum information technology require a fine control of the QDs' position and confinement potential, which cannot be achieved with conventional growth techniques. Here, a novel and versatile approach for the fabrication of site controlled QDs is presented. Hydrogen incorporation in GaAsN results in the formation of N-2H and N-2H-H complexes, which neutralize all the effects of N on GaAs, including the N-induced large reduction of the bandgap energy. Starting from a fully hydrogenated GaAs/GaAsN:H/GaAs quantum well, the N?H bonds located within the light spot generated by a scanning near-field optical microscope tip are broken, thus obtaining site-controlled GaAsN QDs surrounded by a barrier of GaAsN:H (laterally) and GaAs (above and below). By adjusting the laser power density and exposure time, the optical properties of the QDs can be finely controlled and optimized, tuning the quantum confinement energy over more than 100 meV and resulting in the observation of single-photon emission from both the exciton and biexciton recombinations. This novel fabrication technique reaches a position accuracy <100 nm and it can easily be applied to the realization of more complex nanostructures. PMID- 29611236 TI - IFNbeta inhibits the development of allergen tolerance and is conducive to the development of asthma on subsequent allergen exposure. AB - Asthma is a chronic disease affecting up to 10% of the Australian population for which medical treatment is solely aimed at relief of symptoms rather than prevention of disease. Evidence from animal and human studies demonstrates a strong link between viral respiratory infections, atopy and the development of asthma. Type I IFNs include IFNalpha and IFNbeta, with subtype expression tailored toward the specific viral infection. We hypothesized that exposure to type I IFNs and allergen may interfere with the healthy response to innocuous airway antigen exposure. In this study, we use an ovalbumin (OVA)-induced BALB/c model of experimental allergic airways disease, where pre-exposure of the airways to OVA is protective against allergen sensitization, leading to allergen tolerance. We investigated airways pre-exposure with OVA and type I IFNs on development of allergic airways disease. We demonstrate restoration of allergic airways disease on pre-exposure with allergen and IFNbeta, and not IFNalpha. Dysfunction in tolerance led to changes in dendritic cell antigen capture/traffic, T-cell and B-cell responses. Furthermore, exposure to IFNbeta with ongoing allergen exposure led to the development of hallmark asthma features, including OVA-specific IgE and airways eosinophilia. Data indicate a role for IFNbeta in linking viral infection and allergy. PMID- 29611237 TI - Oxidized Laser-Induced Graphene for Efficient Oxygen Electrocatalysis. AB - An efficient metal-free catalyst is presented for oxygen evolution and reduction based on oxidized laser-induced graphene (LIG-O). The oxidation of LIG by O2 plasma to form LIG-O boosts its performance in the oxygen evolution reaction (OER), exhibiting a low onset potential of 260 mV with a low Tafel slope of 49 mV dec-1 , as well as an increased activity for the oxygen reduction reaction. Additionally, LIG-O shows unexpectedly high activity in catalyzing Li2 O2 decomposition in Li-O2 batteries. The overpotential upon charging is decreased from 1.01 V in LIG to 0.63 V in LIG-O. The oxygen-containing groups make essential contributions, not only by providing the active sites, but also by facilitating the adsorption of OER intermediates and lowering the activation energy. PMID- 29611238 TI - Glassomer-Processing Fused Silica Glass Like a Polymer. AB - Fused silica glass is one of the most important high-performance materials for scientific research, industry, and society. However due to its high chemical and thermal resistance as well as high hardness, fused silica glass is notoriously difficult to structure. This work introduces Glassomer, a solid nanocomposite, which can be structured using polymer molding and subtractive technologies at submicrometer resolution. After polymer processing Glassomer is turned into optical grade fused silica glass during a final heat treatment. The resulting glass has the same optical transparency as commercial fused silica and a smooth surface with a roughness of a few nanometers. This work makes high-performance fused silica glass components accessible to high-throughput fabrication technologies and will enable numerous optical, photonic and medical applications in science and industry. PMID- 29611239 TI - Directed Nanoscale Self-Assembly of Low Molecular Weight Hydrogelators Using Catalytic Nanoparticles. AB - The work presented here shows that the growth of supramolecular hydrogel fibers can be spatially directed at the nanoscale by catalytic negatively charged nanoparticles (NCNPs). The NCNPs with surfaces grafted with negatively charged polymer chains create a local proton gradient that facilitates an acid-catalyzed formation of hydrogelators in the vicinity of NCNPs, ultimately leading to the selective formation of gel fibers around NCNPs. The presence of NCNPs has a dominant effect on the properties of the resulting gels, including gelation time, mechanical properties, and network morphology. Interestingly, local fiber formation can selectively entrap and precipitate out NCNPs from a mixture of different nanoparticles. These findings show a new possibility to use directed molecular self-assembly to selectively trap target nano-objects, which may find applications in therapy, such as virus infection prevention, or engineering applications, like water treatment and nanoparticle separation. PMID- 29611240 TI - Phase Transition Control for High Performance Ruddlesden-Popper Perovskite Solar Cells. AB - Ruddlesden-Popper reduced-dimensional hybrid perovskite (RDP) semiconductors have attracted significant attention recently due to their promising stability and excellent optoelectronic properties. Here, the RDP crystallization mechanism in real time from liquid precursors to the solid film is investigated, and how the phase transition kinetics influences phase purity, quantum well orientation, and photovoltaic performance is revealed. An important template-induced nucleation and growth of the desired (BA)2 (MA)3 Pb4 I13 phase, which is achieved only via direct crystallization without formation of intermediate phases, is observed. As such, the thermodynamically preferred perpendicular crystal orientation and high phase purity are obtained. At low temperature, the formation of intermediate phases, including PbI2 crystals and solvate complexes, slows down intercalation of ions and increases nucleation barrier, leading to formation of multiple RDP phases and orientation randomness. These insights enable to obtain high quality (BA)2 (MA)3 Pb4 I13 films with preferentially perpendicular quantum well orientation, high phase purity, smooth film surface, and improved optoelectronic properties. The resulting devices exhibit high power conversion efficiency of 12.17%. This work should help guide the perovskite community to better control Ruddlesden-Popper perovskite structure and further improve optoelectronic and solar cell devices. PMID- 29611241 TI - The interactive effect of advanced cancer patient and caregiver prognostic understanding on patients' completion of Do Not Resuscitate orders. AB - OBJECTIVE: Advanced cancer patients' prognostic understanding is associated with completion of Do Not Resuscitate (DNR) orders, which often represent engagement in advance care planning (ACP). Given caregivers' critical roles in patient decision-making about ACP and end-of-life care, caregivers' prognostic understanding may have a large additive effect. The present study examined the association between the main and interactive effects of advanced cancer patient and caregiver prognostic understanding on DNR order completion. METHODS: Data were analyzed from a combined dataset of 2 sequential multi-institutional, longitudinal cohort studies of patients with advanced cancer and their informal caregivers (n = 279 dyads) from 2002 to 2008 (Coping with Cancer 1) and 2010 to 2015 (Coping with Cancer 2). Patients' and caregivers' prognostic understanding regarding life-expectancy (<= 12 months [prognostic understanding], >12 months [lack of prognostic understanding]) was assessed. DNR order completion was assessed through self-report and confirmed through cross-checking with medical records. RESULTS: Multivariable modeling of the main and interactive effects revealed the interactive effect, but not the individual effects, of patients' and caregivers' prognostic understanding was significantly associated with higher odds of patients' DNR order completion, adjusting for potential confounds (AOR = 5.89, P = 0.04). For dyads in which both the patient and caregiver had prognostic understanding regarding life expectancy of <=12 months, 70.7% of patients had completed DNR orders compared with 31.6% to 38.9% in which 1 or both lacked prognostic understanding. CONCLUSIONS: Findings highlight the need for ensuring accurate patient and caregiver prognostic understanding in increasing DNR order completion, which may provide a framework for improving engagement in ACP more broadly. PMID- 29611242 TI - Porous Graphene Films with Unprecedented Elastomeric Scaffold-Like Folding Behavior for Foldable Energy Storage Devices. AB - The development of fully foldable energy storage devices is a major science and engineering challenge, but one that must be overcome if next-generation foldable or wearable electronic devices are to be realized. To overcome this challenge, it is necessary to develop new electrically conductive materials that exhibit superflexibility and can be folded or crumpled without plastic deformation or damage. Herein, a graphene film with engineered microvoids is prepared by reduction (under confinement) of its precursor graphene oxide film. The resultant porous graphene film can be single folded, double folded, and even crumpled, but springs back to its original shape without yielding or plastic deformation akin to an elastomeric scaffold after the applied stress is removed. Even after thermal annealing at ~1300 degrees C, the folding performance of the porous graphene film is not compromised and the thermally annealed film exhibits complete foldability even in liquid nitrogen. A solid-state foldable supercapacitor is demonstrated with the porous graphene film as the device electrode. The capacitance performance is nearly identical after 2000 cycles of single-folding followed by another 2000 cycles of double folding. PMID- 29611243 TI - Morphological Redescription of Opalina undulata Nie 1932 from Fejervarya limnocharis with Molecular Phylogenetic Study of Opalinids (Heterokonta, Opalinea). AB - The redescription of Opalina undulata Nie 1932, collected from the rectum of the frog Fejervarya limnocharis, is presented in this paper based on detailed morphological information and molecular data. Our results revealed that specimens collected from Diaocha Lake in late August were larger and had more nuclei than those collected from the same site in early May. We sequenced their SSU rDNA-ITS1 5.8S rDNA-ITS2-LSU rDNA (5' end) and found that they were completely identical, which means that the two populations belonged to the same species. These facts gave us a hint that body dimension and number of nuclei are not reliable taxonomic parameters for opalinids during their life cycle. Therefore, we recommended that the specific identification of opalinids based on morphological features should be carried out during seasons except spring. Meanwhile, our molecular phylogenetic analysis confirmed the monophyly of Opalinata. Within Opalinata, Opalinea were monophyletic with all opalinid species grouping together. Karotomorpha and Proteromonas did not group together confirming the paraphyly of Proteromonadea. PMID- 29611245 TI - Simple structural elucidation of ostreocin-B, a new palytoxin congener isolated from the marine dinoflagellate Ostreopsis siamensis, using complementary positive and negative ion liquid chromatography/quadrupole time-of-flight mass spectrometry. AB - RATIONALE: Ostreocin-B is a new palytoxin congener of comparable complexity. Elucidation of the chemical structure by nuclear magnetic resonance has been hampered due to limited sample availability. More importantly, the dihedral angles of protons at the base of the hydroxyl groups on the ring structures are predicted to produce little couplings and thus disrupt connectivity. The present investigation solved the problem through mass spectrometry. METHODS: Structural elucidation was performed by high-performance liquid chromatograph coupled to a quadrupole time-of-flight mass spectrometer equipped with an electrospray ionization source operated in positive and negative ion mode. Measurement parameters were optimized to achieve high sensitivity and a high ratio of singly charged ions. Ostreocin-D (C127 H219 N3 O53 ), another palytoxin congener possessing an unambiguously determined structure, was used as a template. RESULTS: The molecular formula of ostreocin-B, C127 H219 N3 O54 , indicates that it has one more oxygen atom than ostreocin-D. Comparison of the product ion spectra in negative ion mode indicates the occurrence of hydroxyl substitution at C44 in ostreocin-B, unlike in ostreocin-D. Positive ion spectra also support the 44-OH substructure by producing conjugated polyenes ascribable to the sequential loss of hydroxyls on the cyclic hemiacetal. CONCLUSIONS: The planar structure of ostreocin-B is assigned to 42-hydroxy-3,26-didemethyl-19-deoxypalytoxin (=44 hydroxyostreocin-D). The method used in this study is an excellent tool to obtain structural information on interspecies and intrastrain variation of palytoxin congeners in marine organisms. PMID- 29611244 TI - S100A12 as a marker of worse cardiac output and mortality in pulmonary hypertension. AB - BACKGROUND AND OBJECTIVE: Molecular biomarkers are needed to refine prognostication and phenotyping of pulmonary hypertension (PH) patients. S100A12 is an emerging biomarker of various inflammatory diseases. This study aims to determine the prognostic value of S100A12 in PH. METHODS: Exploratory microarray analysis performed on peripheral blood mononuclear cells (PBMC) collected from idiopathic pulmonary fibrosis (IPF) patients suggested an association between S100A12 and both PH and mortality. So the current study was designed to evaluate for an association between S100A12 in peripheral blood collected from two well phenotyped PH cohorts in two other centres to derive and validate an association between S100A12 protein serum concentrations and mortality. RESULTS: The majority of the patients in the discovery and validation cohorts were either World Health Organization (WHO) group 1 (pulmonary arterial hypertension (PAH)) or 3 (lung disease-associated) PH. In the discovery PH cohort, S100A12 was significantly increased in patients with PH (n = 51) compared to controls (n = 22) (29.8 vs 15.7 ng/mL, P < 0.001) and negatively correlated with cardiac output (r = -0.58, P < 0.001) in PH patients. When S100A12 data were pooled from both cohorts, PAH and non-PAH PH patients had higher S100A12 compared to healthy external controls (32.6, 30.9, 15.7 ng/mL; P < 0.001). S100A12 was associated with an increased risk in overall mortality in PH patients in both the discovery (n = 51; P = 0.008) and validation (n = 40; P < 0.001) cohorts. CONCLUSION: S100A12 levels are increased in PH patients and are associated with increased mortality. PMID- 29611246 TI - Isavuconazole for treatment of rare invasive fungal diseases. AB - Data regarding treatment of rare invasive fungal diseases (IFDs) are scarce. We documented the efficacy and safety of isavuconazole for treatment of uncommonly diagnosed IFDs. VITAL was a single-arm, international, open-label study evaluating the efficacy and safety of isavuconazole (200 mg orally or intravenously every 8 hours for 48 hours, then once daily). The primary outcome was overall response at Day 42; key secondary outcomes were overall responses at Day 84 and end of treatment (EOT), mortality at Days 42 and 84, and safety. This analysis includes patients with IFD caused by rare or unidentified pathogens. Twenty-six patients with IFDs caused by rare moulds (n = 17), non-Candida yeasts (n = 2), or unidentified moulds (n = 7) were enrolled (median treatment duration [range], 114.5 [1-496]) days. Overall treatment success was observed in 11/26 (42.3%), 10/26 (38.5%), and 15/26 (57.7%) patients at Days 42, 84, and EOT, respectively. All-cause mortality rates were 2/26 patients (7.7%) at Day 42 and 4/26 patients (15.4%) at Day 84; another two patients died after Day 84. All patients had >=1 treatment-emergent adverse event (TEAE); 15 patients (57.7%) had serious TEAEs, and TEAEs led to discontinuation of isavuconazole in four patients (15.4%). Isavuconazole may be efficacious for treatment of a range of rare IFDs. PMID- 29611247 TI - Precursor-Based Synthesis of Porous Colloidal Particles towards Highly Efficient Catalysts. AB - In recent years, porous colloidal particles have found promising applications in catalytic fields, such as photocatalysis, electrocatalysis, industrial and automotive byproducts removal, as well as biomass upgrading. These applications are critical for alleviating the energy crisis and environmental pollution. Porous colloidal particles have remarkable specific areas and abundant reactive sites, which can significantly improve the mass/charge transport and reaction rate in catalysis. Precursor-based synthesis is among the most facile and widely adopted methods to achieve monodisperse and homogeneous porous colloidal particles. In the current review, we briefly introduce the general catalytic applications of porous colloidal particles. The conventional precursor-based methods are reviewed to design state-of-the-art porous colloidal particles as highly efficient catalysts. The recent development of porous colloidal particles derived from metal-organic frameworks (MOFs), glycerates, carbonate precursors, and ion exchange methods are reviewed. In the end, the current concerns and future development of porous colloidal particles are outlined. PMID- 29611248 TI - Alexithymia and perception of illness in patients with cancer. AB - This study aimed to determine how alexithymia affects the perception of illness in patients with cancer. This was a descriptive study conducted at the Ataturk University Health, Research and Practice Hospital and the Erzurum Regional Training and Research Hospital's Medical Oncology Clinic and Chemotherapy Unit. The study data were collected between July 2013 and January 2014. In total, data were collected from 283 patients with cancer. The data were collected using questionnaires enquiring about demographic and medical information: the IPQ and TAS-20. The study concluded that 50.5% of the participating patients had alexithymia. It was found that the alexithymic patients with cancer perceived the negative outcomes of their illness more strongly, and their negative feelings about the illness were more intense. This study suggests that further research should be carried out on alexithymia in patients with cancer and that their positive beliefs about the illness could be enhanced using psychosocial interventions. PMID- 29611249 TI - Association rules method and big data: Evaluating frequent medication combinations associated with fractures in older adults. AB - BACKGROUND: The association rules method is a novel methodology to ascertain patterns of medication use and combinations associated with adverse drug events. OBJECTIVES: The aim of this case-crossover study was to apply the association rules method to ascertain medication combinations contributing to the risk of fractures in older adults. METHODS: A nationwide representative sample of New Zealanders aged >=65 years was sourced from the pharmaceutical collection. The first-time coded diagnosis of fracture was extracted from the National Minimum Dataset. Association rule method is a data mining technique that can be used to quickly traverse big datasets to identify a combination of items that co-occur. The association rules method were applied to identify frequent 11 medication combinations in the case and the control periods (1-14 days as hazard period, with 35-day washout period), and the association of fractures with each frequent medication combination were tested by computing a matched odd ratio (OR) and its 95% CI. RESULTS: We identified a total of 72 184 individuals (mean age 81.5 years) from 2005 to 2014 with incident fracture and exposed to at least 1 medication of interest. The association rules method revealed codeine phosphate (aOR = 11.50, 95% CI, 7.09-15.20, concomitantly with ibuprofen), zopiclone (aOR = 2.34, 95% CI, 1.49-3.67, concomitantly with morphine) and quetiapine (OR = 1.95, 95% CI, 1.28-2.98, concomitantly with zopiclone) were associated with fractures. CONCLUSION: The association rules method identified medication exposure combinations containing psychotropic medications and codeine are frequently associated with fractures. This novel methodology applied to big data can be an important tool to ascertain medication combinations associated with adverse drug events. PMID- 29611250 TI - Differences in the prevalence of sarcopenia in haemodialysis patients: the effects of gender and ethnicity. AB - BACKGROUND: There is no universal consensus definition of sarcopenia, although there is agreement that sarcopenia is a risk factor for mortality in haemodialysis (HD) patients. We aimed to determine the effect of using different operational definitions in a multiracial group of HD patients. METHODS: We measured hand grip strength (HGS) and appendicular lean mass (ALM) by segmental bioimpedance using the Foundation for the National Institutes of Health Sarcopenia Project (FNIH), European Working Group on Sarcopenia (EWGS) and Asian Working Group on Sarcopenia definitions for HGS weakness and loss of appendicular lean mass. RESULTS: In total, there were 600 HD patients: 373 men (62.2%), mean (SD) age 66.3 (14.7) years, 45.6% diabetic, ethnicity: 281 (48.5%) White, 167 (27.8%) Asian and 149 (24.8%) Black. On HGS criteria, 90.5% of Asian women and 88.5% of Asian men were weak according to EWGS compared to 62.3% of Black women and 52.5% of Black men and 64.5% of White women and 69.1% of White men by FNIH criteria (P < 0.001). On adding appendicular lean mass, the prevalence of sarcopenia was 68.3% for Asian, 27.1% for Black and 36.6% for White women by FNIH and 59.6% Asian, 21.3% Black and 39.9% White men by EWGS criteria. CONCLUSIONS: Current definitions of sarcopenia report a greater prevalence of muscle weakness compared to appendicular muscle loss in female compared to male HD patients and this is greater for Asian compared to Black and White patients. Because HGS weakness is a greater risk for death, definitions of sarcopenia may underestimate risk in HD patients. PMID- 29611251 TI - Ultrasonographic estimation of fetal weight: development of new model and assessment of performance of previous models. AB - OBJECTIVES: To develop a new formula for ultrasonographic estimation of fetal weight and evaluate the accuracy of this and all previous formulae in the prediction of birth weight. METHODS: The study population consisted of 5163 singleton pregnancies with fetal biometry at 22-43 weeks' gestation and live birth of a phenotypically normal neonate within 2 days of the ultrasound examination. Multivariable fractional polynomial analysis was used to determine the combination of variables that provided the best-fitting models for estimated fetal weight (EFW). A systematic review was also carried out of articles reporting formulae for EFW and comparing EFW to actual birth weight. The accuracy of each model for EFW was assessed by comparing mean percentage error, absolute mean error (AE), proportion of pregnancies with AE <= 10% and Euclidean distance. RESULTS: The most accurate models, with the lowest Euclidean distance and highest proportion of AE <= 10%, were provided by the formulae incorporating >= 3 rather than < 3 biometrical measurements. The systematic review identified 45 studies describing a total of 70 models for EFW by various combinations of measurements of fetal head circumference (HC), biparietal diameter, femur length (FL) and abdominal circumference (AC). The most accurate model with the lowest Euclidean distance and highest proportion of AE <= 10% was provided by the formula of Hadlock et al., published in 1985, which incorporated measurements of HC, AC and FL; there was a highly significant linear association between EFW and birth weight (r = 0.959; P < 0.0001), and EFW was within 10% of birth weight in 80% of cases. The performance of the best model developed in this study, utilizing HC, AC and FL, was very similar to that of Hadlock et al. CONCLUSION: Despite many efforts to develop new models for EFW, the one reported in 1985 by Hadlock et al., from measurements of HC, AC and FL, provides the most accurate prediction of birth weight and can be used for assessment of all babies, including those suspected to be either small or large. Copyright (c) 2018 ISUOG. Published by John Wiley & Sons Ltd. PMID- 29611252 TI - Significant differences in maternal child-feeding style between ethnic groups in the UK: the role of deprivation and parenting styles. AB - BACKGROUND: Nonresponsive maternal child-feeding interactions, such as restricting, pressurising and emotional feeding, can affect the ability of a child to self-regulate intake and increase the risk of becoming overweight. However, despite findings that South Asian and Black children living in the UK are more likely to be overweight, UK research has not considered how maternal child-feeding style might differ between ethnic groups. The present study aimed to explore variations in maternal child-feeding style between ethnic groups in the UK, taking into account associated factors such as deprivation and parenting style. METHODS: Six hundred and fifty-nine UK mothers with a child who was aged 5 11 years old completed a questionnaire. Items included ethnicity and demographic data, as well as copies of the Child Feeding Questionnaire, Parental Feeding Styles Questionnaire and Parenting Styles and Dimensions Questionnaire. RESULTS: Significant differences in perceived responsibility (P = 0.002), restriction (P = 0.026), pressure to eat (P = 0.045), instrumental feeding (P = 0.000) and emotional feeding (P = 0.000) were found between the groups. Mothers from South Asian backgrounds reported higher levels of pressure to eat, emotional feeding and indulgent feeding styles, whereas mothers from Chinese backgrounds reported greater perceived responsibility and restriction. Mothers from Black and White British backgrounds were not significantly higher with respect to any behaviour. Maternal child-feeding style was also associated with deprivation and parenting style, although these did not fully explain the data. CONCLUSIONS: Understanding cultural factors behind maternal child-feeding style, particularly around pressurising and indulgent feeding behaviours, may play an important part in reducing levels of children who are overweight and obese in the UK. PMID- 29611253 TI - Responsive Block Copolymer Photonic Microspheres. AB - Responsive photonic crystals (PCs) have attracted much attention due to their broad applications in the field of chemical and physical sensing through varying optical properties when exposed to external stimuli. In particular, assembly of block copolymers (BCPs) has proven to be a robust platform for constructing PCs in the form of films or bulk. Here, the generation of BCPs photonic microspheres is presented with 3D periodical concentric lamellar structures through confined self-assembly. The structural color of the spherical PCs can be tuned by selective swelling of one block, yielding large change of optical property through varying both layer thickness and refraction index of the domains. The as formed spherical PCs demonstrate large reflection wavelength shift (~400-700 nm) under organic solvent permeation and pH adjustment. Spherical shape and structural symmetry endow the formed spherical PCs with rotation independence and monochrome, which is potentially useful in the fields of displays, sensing, and diagnostics. PMID- 29611254 TI - Oxytocin levels in saliva correlate better than plasma levels with concentrations in the cerebrospinal fluid of patients in neurocritical care. AB - In the converging fields of neuroendocrinology and behavioural neuroscience, the interaction between peripheral secretion and central release of oxytocin in humans has not yet been comprehensively assessed. As the human brain is not directly accessible and as the collection of human cerebrospinal fluid (CSF) usually requires invasive procedures, easier accessible compartments such as blood or saliva attract increasing attention. In this study, we prospectively determined oxytocin concentrations in the three compartments plasma, CSF and saliva of fifty critically ill patients with neurological and neurosurgical diseases. All samples per patient were collected concomitantly. Oxytocin was measured by a highly sensitive and specific radioimmunoassay. Strength of correlation was assessed by the Spearman rank correlation coefficient. Correlation analyses revealed modest to strong correlations for oxytocin between the saliva and CSF compartments while predominantly weak correlations were found between the CSF and plasma as well as between the plasma and saliva compartments. In conclusion, we demonstrated modest to strong correlations between the saliva and CSF compartment suggesting that saliva oxytocin may help to assess CSF oxytocin levels. In contrast, plasma oxytocin failed to correspond well with CSF oxytocin levels as predominantly weak correlations were found between the CSF and plasma as well as between the plasma and saliva compartments which are unlikely to have a biological relevance. Further research is needed to clarify to what extent saliva oxytocin may serve as a biomarker reflecting brain oxytocin activity. This article is protected by copyright. All rights reserved. PMID- 29611255 TI - Translational validity of PASAT and the effect of fatigue and mood in patients with relapsing remitting MS: A functional MRI study. AB - RATIONALE, AIMS, AND OBJECTIVES: Paced Auditory Serial Addition Test (PASAT) is used for assessment of information processing speed, attention, and working memory, which are the most frequently affected cognitive domains in multiple sclerosis (MS) patients, and may be significantly affected by fatigue. However, the effect of fatigue and mood on the PASAT performance in MS patients translationally validated by fMRI has not been studied yet. The aim of this study is to investigate the translational validity of the PASAT, using fMRI during a paced visual serial addition test (PVSAT) paradigm in patients with relapsing remitting MS (RRMS) and to assess the impact of fatigue and mood on test performance. METHODS: Fourteen patients with RRMS in remission and 14 healthy controls, matched by sex, age, and educational status, were enrolled in the study. The subjects underwent a standard neurological examination, neuropsychological evaluation with the PASAT 3', fMRI scanning with a PVSAT paradigm, and Beck Depression Inventory. All patients were assessed by the Modified Fatigue Impact Scale. RESULTS: Paced Auditory Serial Addition Test score was lower in patients (41.4 +/- 15.5 vs 51.6 +/- 7.5, P = .035). A moderate negative correlation (P = -0.563, P = 0.036) was found between PASAT and MIFS scores. The fMRI scanning showed significant activations in several clusters that differed between patients and controls. The patient group presented wider cluster activation; Brodmann area (BA) 6-bilaterally; left BA7, 8, and 9; and right BA40, while controls presented with activations in left BA6 and BA44. Significant negative correlations between PASAT score and cortical activations in left BA23, right BA32, and left BA7 were observed in patients only. CONCLUSION: Our results show that poorer performance on the PASAT is associated with higher activation in areas connected with working memory, attention, and emotional processes during the fMRI assessment with PVSAT paradigm, which provides evidence for the translational validity of the PASAT in patients with RRMS. PMID- 29611257 TI - Self-Assembled Semiconducting Polymer Nanoparticles for Ultrasensitive Near Infrared Afterglow Imaging of Metastatic Tumors. AB - Detection of metastatic tumor tissues is crucial for cancer therapy; however, fluorescence agents that allow to do share the disadvantage of low signal-to background ratio due to tissue autofluorescence. The development of amphiphilic poly(p-phenylenevinylene) derivatives that can self-assemble into the nanoagent (SPPVN) in biological solutions and emit near-infrared afterglow luminescence after cessation of light irradiation for ultrasensitive imaging of metastatic tumors in living mice is herein reported. As compared with the counterpart nanoparticle (PPVP) prepared from the hydrophobic PPV derivate, SPPVN has smaller size, higher energy transfer efficiency, and brighter afterglow luminescence. Moreover, due to the higher PEG density of SPPVN relative to PPVP poly(ethylene glycol), SPPVN has a better accumulation in tumor. Such a high sensitivity and ideal biodistribution allow SPPVN to rapidly detect xenograft tumors with the size as small as 1 mm3 and tiny peritoneal metastatic tumors that are almost invisible to naked eye, which is not possible for PPVP. Moreover, the oxygen sensitive afterglow makes SPPVN potentially useful for in vivo imaging of oxygen levels. By virtue of enzymatic biodegradability and ideal in vivo clearance, these organic agents can serve as a platform for the construction of advanced afterglow imaging tools. PMID- 29611258 TI - Reversible Immobilization of Proteins in Sensors and Solid-State Nanopores. AB - The controlled functionalization of surfaces with proteins is crucial for many analytical methods in life science research and biomedical applications. Here, a coating for silica-based surfaces is established which enables stable and selective immobilization of proteins with controlled orientation and tunable surface density. The coating is reusable, retains functionality upon long-term storage in air, and is applicable to surfaces of complex geometry. The protein anchoring method is validated on planar surfaces, and then a method is developed to measure the anchoring process in real time using silicon nitride solid-state nanopores. For surface attachment, polyhistidine tags that are site specifically introduced into recombinant proteins are exploited, and the yeast nucleoporin Nsp1 is used as model protein. Contrary to the commonly used covalent thiol chemistry, the anchoring of proteins via polyhistidine tag is reversible, permitting to take proteins off and replace them by other ones. Such switching in real time in experiments on individual nanopores is monitored using ion conductivity. Finally, it is demonstrated that silica and gold surfaces can be orthogonally functionalized to accommodate polyhistidine-tagged proteins on silica but prevent protein binding to gold, which extends the applicability of this surface functionalization method to even more complex sensor devices. PMID- 29611256 TI - An fMRI study of finger tapping in children and adults. AB - Functional brain imaging studies have characterized the neural bases of voluntary movement for finger tapping in adults, but equivalent information for children is lacking. When contrasted to adults, one would expect children to have relatively greater activation, reflecting compensation for an underdeveloped motor system combined with less experience in the execution of voluntary movement. To test this hypothesis, we acquired functional magnetic resonance imaging (fMRI) data on 17 healthy right-handed children (7.48 +/- 0.66 years) and 15 adults (24.9 +/- 2.9 years) while they performed an irregularly paced finger-tapping task in response to a visual cue (left- and right-hand examined separately). Whole-brain within-group analyses revealed that finger tapping in either age group and for either hand activated contralateral SM1, SMA, ipsilateral anterior cerebellum, and occipital cortices. We used an ANOVA factorial design to test for main effects of Age Group (children vs adults), Hand (left vs. right), and their interactions. For main effects of Age Group, children showed relatively greater activity in left SM1 (extending into bilateral SMA), and, surprisingly, adults exhibited relatively greater activity in right pre-SMA/SMA (extending into left pre-SMA/SMA), right lateral globus pallidus, left putamen, and right anterior cerebellum. The interaction of Age Group * Hand revealed that while both groups activated right SM1 during left finger tapping and exhibited signal decreases (i.e., below fixation baseline) during right finger tapping, both these responses were attenuated in children relative to adults. These data provide an important foundation by which to study children with motor disorders. PMID- 29611259 TI - The sea as deathtrap: comment on a paper by miller and wiens. AB - Miller & Wiens (2017) claim that low marine as compared with terrestrial diversity results from more frequent extinctions and insufficient time for diversification in marine clades. Their data on marine amniotes are unrepresentative of marine diversity, their analysis of clade dynamics is flawed, and they ignore previously proposed explanations for the diversity difference. PMID- 29611260 TI - Noncontinuous Super-Diffusive Dynamics of a Light-Activated Nanobottle Motor. AB - We report a carbonaceous nanobottle (CNB) motor for near infrared (NIR) light driven jet propulsion. The bottle structure of the CNB motor is fabricated by soft-template-based polymerization. Upon illumination with NIR light, the photothermal effect of the CNB motor carbon shell causes a rapid increase in the temperature of the water inside the nanobottle and thus the ejection of the heated fluid from the open neck, which propels the CNB motor. The occurrence of an explosion, the on/off motion, and the swing behavior of the CNB motor can be modulated by adjusting the NIR light source. Moreover, we simulated the physical field distribution (temperature, fluid velocity, and pressure) of the CNB motor to demonstrate the mechanism of NIR light-driven jet propulsion. This NIR light powered CNB motor exhibits fuel-free propulsion and control of the swimming velocity by external light and has great potential for future biomedical applications. PMID- 29611261 TI - Stomata-Inspired Photomechanical Ion Nanochannels Modified by Azobenzene Composites. AB - A low-powered and highly selective photomechanical sensor system mimicking stomata in the epidermis of leaves harvested from nature is demonstrated. This device uses a light-responsive composite consisting of 4-amino-1,1'-azobenzene 3,4'-disulfonic acid monosodium salt (AZO) and poly(diallyldimethylammonium chloride) (PDDA) coated on a membrane with tens of nanometer-size pores. The ionic current change through the pore channels as a function of pore size variation is then measured. The tran-cis isomerism of AZO-PDDA during light irradiation and the operation mechanism of photomechanical ion channel sensor are discussed and analyzed using UV-vis spectroscopy and atomic force microscopy analysis. It presents the discriminative current levels to the different light wavelengths. The response time of the photoreceptor is about 0.2 s and it consumes very low operating power (~15 nW) at 0.1 V bias. In addition, it is found that the change of the pore diameter during the light irradiation is due to the photomechanical effect, which is capable of distinguishing light intensity and wavelength. PMID- 29611262 TI - Contact sensitization to lanolin alcohols and Amerchol(r) L101 - analysis of IVDK data. PMID- 29611263 TI - Allergic contact dermatitis caused by hypersensitivity to gold - description of a clinical case. PMID- 29611264 TI - Allergic contact dermatitis from formaldehyde mimicking impetigo and initiating rosacea. PMID- 29611265 TI - Allergic contact dermatitis secondary to the use of aluminium Finn Chambers(r). PMID- 29611266 TI - Cobalt not detected in contemporary US consumer paint colorants by cobalt indicator solution or X-ray fluorescence spectroscopy. PMID- 29611267 TI - Delayed-type drug hypersensitivity caused by paracetamol in a 2-year-old boy, confirmed by a positive patch test reaction and oral provocation. PMID- 29611268 TI - Nickel and cobalt release from fidget spinners on the Danish market. PMID- 29611270 TI - Corrigendum. PMID- 29611269 TI - The energetics of fish growth and how it constrains food-web trophic structure. AB - The allocation of metabolic energy to growth fundamentally influences all levels of biological organisation. Here we use a first-principles theoretical model to characterise the energetics of fish growth at distinct ontogenetic stages and in distinct thermal regimes. Empirically, we show that the mass scaling of growth rates follows that of metabolic rate, and is somewhat steeper at earlier ontogenetic stages. We also demonstrate that the cost of growth, Em , varies substantially among fishes, and that it may increase with temperature, trophic level and level of activity. Theoretically, we show that Em is a primary determinant of the efficiency of energy transfer across trophic levels, and that energy is transferred more efficiently between trophic levels if the prey are young and sedentary. Overall, our study demonstrates the importance of characterising the energetics of individual growth in order to understand constraints on the structure of food webs and ecosystems. PMID- 29611271 TI - Comparison of DSM-IV and DSM-5 dementia criteria among older people living in a community sample. PMID- 29611272 TI - La maladie du petit papier: A sign of functional cognitive disorder? PMID- 29611273 TI - A Jacksonian approach to BPSD. PMID- 29611274 TI - To give or to receive: Relationship between social support giving/receiving and psychometrics in a large-scale survey. PMID- 29611276 TI - Demystifying the marine-terrestrial biodiversity gradient: response to Vermeij et al. AB - We respond to seven criticisms made by Vermeij et al. () regarding Miller & Wiens (). Their criticisms generally reflect misunderstandings, unsupported speculations, and topics that were explicitly addressed in our paper. PMID- 29611275 TI - Clinical and prognostic significance of changes in haemoglobin concentration during 1 year of androgen-deprivation therapy for hormone-naive bone-metastatic prostate cancer. AB - OBJECTIVE: To estimate the strength of change in haemoglobin (Hb) concentrations during 1 year of androgen-deprivation therapy (ADT) as a predictor of survival in hormone-naive patients with bone-metastatic (Stage M1b) prostate cancer. PATIENTS AND METHODS: The patients included in this study were taken from the randomised trial (number 5) carried out by the Scandinavian Prostate Cancer Group (SPCG), comparing parenteral oestrogen with total androgen blockade (TAB) in hormone naive M1b prostate cancer. We identified 597 men where Hb measurements were made at enrolment, as well as at 3, 6 and 12 months of ADT. The time-dependent impact of Hb concentration changes on overall survival (OS) was analysed using multivariate Cox proportional hazards analysis. The 10-year OS according to increase/decrease in Hb concentration for the three treatment periods was demonstrated using Kaplan-Meier curves. RESULTS: Multivariate analysis of changes in Hb concentration between baseline and 3 months showed better survival in patients with a decrease in Hb concentration (hazard ratio [HR] 1.42, 95% confidence interval [CI] 1.11-1.80) compared to those with an increase, whilst there was no difference in survival associated with a change in Hb concentration between 3 and 6 months (HR 0.93, 95% CI 0.76-1.12). Contrary to the first 3 months, poorer survival was seen in patients with a decrease in Hb concentration between 6 and 12 months (HR 0.76, 95% CI 0.62-0.92) compared to those with an increase. CONCLUSIONS: In a large cohort of Scandinavian men with hormone-naive M1b prostate cancer, an increase in Hb concentration between baseline and 3 months of ADT was associated with significantly poorer survival, whereas an increase between 6 and 12 months was associated with better survival. These findings provide new information about patterns of change in Hb concentrations during 12 months of ADT for M1b prostate cancer, and survival. Clinicians should be aware of the prognostic value of Hb concentration changes during ADT in M1b prostate cancer. PMID- 29611277 TI - Renal transplantation outcome and social deprivation in the French healthcare system: a cohort study using the European Deprivation Index. AB - The study objective was to estimate the effect of social deprivation estimated by the European Deprivation Index (EDI) on the risk of death and graft failure on renal transplantation in France. EDI was calculated for 8701 of 9205 patients receiving a first renal transplantation between 2010 and 2014. Patients were separated in EDI quintiles of the general population. A Cox model (cs-HR: cause specific hazard ratio of death or graft failure) and a Fine and Gray model (sd HR: subdistribution hazard ratio of death and graft failure) were used for the analysis. The 5th quintile group (most deprived) accounted for 32% of patients [2818 of 8701]. In the multivariate analysis, compared with quintile 1, the risk of death was higher for the 5th quintile group in the complete cohort [cs-HR: 1.31, 95% CI: (1.01-1.70), sd-HR: 1.29, 95% CI: (1.00-1.68)], in the deceased donor group [cs-HR: 1.31, 95% CI: (1.00-1.71), sd-HR: 1.30, 95% CI: (1.00-1.70)] but not in living donor transplant patients. There was no association between the EDI groups and the risk of transplant failure. Social deprivation estimated by the EDI is associated with an increased risk of death in transplantation in France but not with the chance of allograft loss. PMID- 29611278 TI - How ecology shapes exploitation: a framework to predict the behavioural response of human and animal foragers along exploration-exploitation trade-offs. AB - Understanding how humans and other animals behave in response to changes in their environments is vital for predicting population dynamics and the trajectory of coupled social-ecological systems. Here, we present a novel framework for identifying emergent social behaviours in foragers (including humans engaged in fishing or hunting) in predator-prey contexts based on the exploration difficulty and exploitation potential of a renewable natural resource. A qualitative framework is introduced that predicts when foragers should behave territorially, search collectively, act independently or switch among these states. To validate it, we derived quantitative predictions from two models of different structure: a generic mathematical model, and a lattice-based evolutionary model emphasising exploitation and exclusion costs. These models independently identified that the exploration difficulty and exploitation potential of the natural resource controls the social behaviour of resource exploiters. Our theoretical predictions were finally compared to a diverse set of empirical cases focusing on fisheries and aquatic organisms across a range of taxa, substantiating the framework's predictions. Understanding social behaviour for given social-ecological characteristics has important implications, particularly for the design of governance structures and regulations to move exploited systems, such as fisheries, towards sustainability. Our framework provides concrete steps in this direction. PMID- 29611279 TI - Cobalt Sulfide Nanowires Core Encapsulated by a N, S Codoped Graphitic Carbon Shell for Efficient Oxygen Reduction Reaction. AB - Exploration of economical electrocatalysts for highly efficient and stable oxygen reduction reaction (ORR) is believed to be essential for diverse future renewable energy applications. Herein, cobalt sulfide nanowire core encapsulated in a N, S codoped graphitic carbon shell (CoS NWs@NSC) is successfully fabricated via the calcination of polydopamine-coated Co(CO3 )0.5 (OH)0.11 H2 O NWs with sulfur powder under argon atmosphere. The uniform encapsulation of CoS core by N, S codoped graphitic carbon shell favors the interaction of the core-shell structure for generating stable and numerous ORR active sites homogeneously dispersed throughout the materials. Meanwhile, the wire-like CoS NWs@NSC stacks to form 3D mesoporous conductive networks, which improves the mass and charge transport capability of catalyst. Accordingly, the resultant CoS NWs@NSC electrocatalysts possess excellent ORR activity through the four-electron pathway with superior stability and methanol tolerance over the Pt/C in 0.1 m KOH. This strategy can offer inspiration for designing and fabricating novel core-shell-structured nanomaterials with active sites derived from uniform morphology as potential electrocatalysts for various vital renewable energy devices. PMID- 29611280 TI - Controlled Homoepitaxial Growth of Hybrid Perovskites. AB - Organic-inorganic hybrid perovskites have demonstrated tremendous potential for the next-generation electronic and optoelectronic devices due to their remarkable carrier dynamics. Current studies are focusing on polycrystals, since controlled growth of device compatible single crystals is extremely challenging. Here, the first chemical epitaxial growth of single crystal CH3 NH3 PbBr3 with controlled locations, morphologies, and orientations, using combined strategies of advanced microfabrication, homoepitaxy, and low temperature solution method is reported. The growth is found to follow a layer-by-layer model. A light emitting diode array, with each CH3 NH3 PbBr3 crystal as a single pixel, with enhanced quantum efficiencies than its polycrystalline counterparts is demonstrated. PMID- 29611282 TI - Feeding environment and other traits shape species' roles in marine food webs. AB - Food webs and meso-scale motifs allow us to understand the structure of ecological communities and define species' roles within them. This species-level perspective on networks permits tests for relationships between species' traits and their patterns of direct and indirect interactions. Such relationships could allow us to predict food-web structure based on more easily obtained trait information. Here, we calculated the roles of species (as vectors of motif position frequencies) in six well-resolved marine food webs and identified the motif positions associated with the greatest variation in species' roles. We then tested whether the frequencies of these positions varied with species' traits. Despite the coarse-grained traits we used, our approach identified several strong associations between traits and motifs. Feeding environment was a key trait in our models and may shape species' roles by affecting encounter probabilities. Incorporating environment into future food-web models may improve predictions of an unknown network structure. PMID- 29611281 TI - Pyrolytic Carbon Nanosheets for Ultrafast and Ultrastable Sodium-Ion Storage. AB - Na-ion cointercalation in the graphite host structure in a glyme-based electrolyte represents a new possibility for using carbon-based materials (CMs) as anodes for Na-ion storage. However, local microstructures and nanoscale morphological features in CMs affect their electrochemical performances; they require intensive studies to achieve high levels of Na-ion storage performances. Here, pyrolytic carbon nanosheets (PCNs) composed of multitudinous graphitic nanocrystals are prepared from renewable bioresources by heating. In particular, PCN-2800 prepared by heating at 2800 degrees C has a distinctive sp2 carbon bonding nature, crystalline domain size of ~44.2 A, and high electrical conductivity of ~320 S cm-1 , presenting significantly high rate capability at 600 C (60 A g-1 ) and stable cycling behaviors over 40 000 cycles as an anode for Na-ion storage. The results of this study show the unusual graphitization behaviors of a char-type carbon precursor and exceptionally high rate and cycling performances of the resulting graphitic material, PCN-2800, even surpassing those of supercapacitors. PMID- 29611284 TI - A Novel Zr-MOF as Fluorescence Turn-On Probe for Real-Time Detecting H2 S Gas and Fingerprint Identification. AB - The development of fluorescence turn-on probes for selectively sensing toxic gases and visualization identification of fingerprints is significantly important for society security and human health. Here, Zr is used as the metal center and 1,3,6,8-tetra (4-carboxylphenyl) pyrene (TBAPy) and tetrakis(4 carboxyphenyl)porphyrin (TCPP) as double linkers to synthesize a novel Zr(TBAPy)5 (TCPP) material. Results indicate that Zr(TBAPy)5 (TCPP) can be used as a fluorescence turn-on probe for highly selective and sensitive detection of H2 S gas and its derivatives S2- in aqueous solutions with an extremely low concentration (~1 ppb) and fast response time (<10 s). Moreover, by tailoring the particle size of samples, it is found that Zr(TBAPy)5 (TCPP) can efficiently achieve the visualization identification of fingerprints due to the fluorescence turn-on effect. All the results indicate that the Zr(TBAPy)5 (TCPP) is a promising multifunctional fluorescence turn-on probe. PMID- 29611283 TI - In Situ Electrochemically Derived Amorphous-Li2 S for High Performance Li2 S/Graphite Full Cell. AB - High-capacity Li2 S cathode (1166 mAh g-1 ) is regarded as a promising candidate for the next-generation lithium ion batteries. However, its high potential barrier upon the initial activation process leads to a low utilization of Li2 S. In this work, a Li2 S/graphite full cell with the zero activation potential barrier is achieved through an in situ electrochemical conversion of Li2 S8 catholyte into the amorphous Li2 S. Theoretical calculations indicate that the zero activation potential for amorphous Li2 S can be ascribed to its lower Li extraction energy than that of the crystalline Li2 S. The constructed Li2 S/graphite full cell delivers a high discharge capacity of 1006 mAh g-1 , indicating a high utilization of the amorphous Li2 S as a cathode. Moreover, a long cycle life with 500 cycles for this Li2 S/graphite full cell is realized. This in situ electrochemical conversion strategy designed here is inspired for developing high energy Li2 S-based full cells in future. PMID- 29611285 TI - Tailoring Structure, Composition, and Energy Storage Properties of MXenes from Selective Etching of In-Plane, Chemically Ordered MAX Phases. AB - The exploration of 2D solids is one of our time's generators of materials discoveries. A recent addition to the 2D world is MXenes that possses a rich chemistry due to the large parent family of MAX phases. Recently, a new type of atomic laminated phases (coined i-MAX) is reported, in which two different transition metal atoms are ordered in the basal planes. Herein, these i-MAX phases are used in a new route for tailoriong the MXene structure and composition. By employing different etching protocols to the parent i-MAX phase (Mo2/3 Y1/3 )2 AlC, the resulting MXene can be either: i) (Mo2/3 Y1/3 )2 C with in-plane elemental order through selective removal of Al atoms or ii) Mo1.33 C with ordered vacancies through selective removal of both Al and Y atoms. When (Mo2/3 Y1/3 )2 C (ideal stoichiometry) is used as an electrode in a supercapacitor-with KOH electrolyte-a volumetric capacitance exceeding 1500 F cm 3 is obtained, which is 40% higher than that of its Mo1.33 C counterpart. With H2 SO4 , the trend is reversed, with the latter exhibiting the higher capacitance (~1200 F cm-3 ). This additional ability for structural tailoring will indubitably prove to be a powerful tool in property-tailoring of 2D materials, as exemplified here for supercapacitors. PMID- 29611286 TI - High-Responsivity Photodetection by a Self-Catalyzed Phase-Pure p-GaAs Nanowire. AB - Defects are detrimental for optoelectronics devices, such as stacking faults can form carrier-transportation barriers, and foreign impurities (Au) with deep energy levels can form carrier traps and nonradiative recombination centers. Here, self-catalyzed p-type GaAs nanowires (NWs) with a pure zinc blende (ZB) structure are first developed, and then a photodetector made from these NWs is fabricated. Due to the absence of stacking faults and suppression of large amount of defects with deep energy levels, the photodetector exhibits room-temperature high photoresponsivity of 1.45 * 105 A W-1 and excellent specific detectivity (D*) up to 1.48 * 1014 Jones for a low-intensity light signal of wavelength 632.8 nm, which outperforms previously reported NW-based photodetectors. These results demonstrate these self-catalyzed pure-ZB GaAs NWs to be promising candidates for optoelectronics applications. PMID- 29611287 TI - Effect of tumor necrosis factor alpha inhibitors on spinal radiographic progression in patients with ankylosing spondylitis. AB - AIM: To evaluate the effect of tumor necrosis factor alpha inhibitors (TNFi) on spinal radiographic progression in patients with ankylosing spondylitis (AS). METHODS: Subjects were selected from patients at a single tertiary hospital between 1995 and 2014. Patients who used TNFi with baseline and paired follow-up radiographic data with a minimum interval of 2 years were included. Time to start TNFi was defined as the time from symptom onset to the start of TNFi use. TNFi index was defined as the ratio of the period of TNFi use to the entire period of disease. Radiographic damage was assessed by the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS). Univariable and multivariable linear regression analyses were used to identify factors associated with radiographic progression. RESULTS: A total of 151 patients were included in the analysis. Seventeen (11.3%) patients were female and mean DeltamSASSS/year was 1.01 units/year. Mean X-ray follow-up duration was 102.9 +/- 54.9 months. Mean time from symptom onset to start of TNFi use was 104.8 +/- 83.6 months (median 84 months) and mean TNFi index was 42.9 +/- 23.8% (median 40.9%). In multivariable analysis, initial mSASSS, initial C-reactive protein, body mass index, current smoker, and delayed start of TNFi use were associated with radiographic progression. Presence of peripheral arthritis and the TNFi index were negatively associated with radiographic progression. CONCLUSIONS: A delay in starting TNFi use and low TNFi index were associated with radiographic progression. Early and long-term use of TNFi appear to reduce spinal radiographic progression in patients with AS. PMID- 29611288 TI - Metabolic syndrome in patients with systemic lupus erythematosus: Association with disease activity, disease damage and age. AB - AIM: Systemic lupus erythematosus (SLE) is associated with an increased risk of cardiovascular involvement. Metabolic syndrome (MetS) includes a group of classic cardiovascular risk factors with probably proinflammatory conditions. The aim of the present study was to evaluate the frequency of MetS in SLE patients. METHODS: Demographic, clinical and laboratory features of 73 SLE patients were compared with 73 age-sex matched controls using SLE Disease Activity Index (SLEDAI), Systemic Lupus Damage Index (SDI) and Health Assessment Questionnaire (HAQ). MetS was diagnosed according to the definitions of the 2005 National Cholesterol Education Program (NCEP/ATP III) and International Diabetes Federation (IDF). The frequency of MetS was compared in SLE patients and controls, and then patients were investigated for MetS and major organ involvement. Statistical analysis was performed in SPSS version 19, and results were considered significant at P < 0.05. RESULTS: The mean age of SLE patients was 40.97 +/- 12.2 years, and 95.8% were female. MetS according to NCEP/ATP III and IDF criteria was present in 33 (45.2%) and 34 (46.6%) SLE patients versus 27 (37%) and 29 (39.7%) controls (P > 0.05). Lupus patients were more likely to have hypertension (P = 0.038). SLE patients with MetS had higher HAQ scores (P = 0.029). In patients with major organ involvement, age and disease duration were significantly higher in the MetS subgroup (P < 0.05). CONCLUSION: The frequency of MetS was not significantly different from that of the control group, but almost half of the patients were found with this syndrome. This calls for further follow up and appropriate treatment of patients with MetS. PMID- 29611289 TI - A Novel Thermoresponsive Catalytic Membrane with Multiscale Pores Prepared via Vapor-Induced Phase Separation. AB - A novel thermoresponsive catalytic polyethersulfone membrane with multiscale pores is developed by constructing silver nanoparticles (Ag NPs) loaded poly(N isopropylacrylamide) (PNIPAM) nanogels on pore walls of cellular pores as thermoresponsive gates and catalysts via vapor-induced phase separation. The Ag NPs are stably immobilized on the PNIPAM nanogels by an in situ reduction method based on the versatile adhesion and reduction properties of polydopamine. The micrometer cellular pores decorated with Ag NPs loaded PNIPAM nanogels are formed throughout the membrane and act as numerous microreactors with a large pore surface. The proposed membrane exhibits both satisfactory thermoresponsive characteristics and stable catalytic properties. The effects of operation temperature and reactant concentration of feed solution on the catalytic properties are investigated systematically. The results show that the apparent kinetic rate constant of catalytic reduction of 4-nitrophenol (4-NP) in water by reductant sodium borohydride (NaBH4 ), is ranging from 3.7 to 37.9 min-1 at temperatures from 20 to 45 oC and the molar ratio of NaBH4 to 4-NP from 100:1 to 500:1. When the reactant concentration in feed solution fluctuates, the permeability or throughput of the membrane is simply adjusted by virtue of the thermoresponsive characteristics of membranes to achieve high catalytic conversion of reactant. PMID- 29611290 TI - Organic Dye Based Nanoparticles for Cancer Phototheranostics. AB - Phototheranostics, which simultaneously combines photodynamic and/or photothermal therapy with deep-tissue diagnostic imaging, is a promising strategy for the diagnosis and treatment of cancers. Organic dyes with the merits of strong near infrared absorbance, high photo-to-radical and/or photothermal conversion efficiency, great biocompatibility, ready chemical structure fine-tuning capability, and easy metabolism, have been demonstrated as attractive candidates for clinical phototheranostics. These organic dyes can be further designed and fabricated into nanoparticles (NPs) using various strategies. Compared to free molecules, these NPs can be equipped with multiple synergistic functions and show longer lifetime in blood circulation and passive tumor-targeting property via the enhanced permeability and retention effect. In this article, the recent progress of organic dye-based NPs for cancer phototheranostic applications is summarized, which extends the anticancer arsenal and holds promise for clinical uses in the near future. PMID- 29611291 TI - Multistimuli Responsive Core-Shell Nanoplatform Constructed from Fe3 O4 @MOF Equipped with Pillar[6]arene Nanovalves. AB - An intelligent theranostic nanoplatform based on nanovalve operated metal-organic framework (MOF) core-shell hybrids, incorporating tumorous microenvironment triggered drug release, magnetic resonance imaging (MRI) guidance, sustained release, and effective chemotherapy in one pot is reported. The core-shell hybrids are constructed by an in situ growth method, in which Fe3 O4 particles with superior abilities of MRI and magnetic separation form the core and UiO-66 MOF with high loading capacity compose the shell, and then are surface-installed with pillararene-based pseudorotaxanes as tightness-adjustable nanovalves. This strategy endows the system with the ability of targeted, multistimuli responsive drug release in response to pH changes, temperature variations, and competitive agents. Water-soluble carboxylatopillar[6]arene system achieved sustained drug release over 7 days due to stronger host-guest binding, suggesting that the nanovalve tightness further reinforces the desirable release of anticancer agent over a prolonged time at the lesion site. PMID- 29611293 TI - Can 'omics' studies provide evidence for causal effects of coffee consumption on risk of type 2 diabetes? PMID- 29611292 TI - Vitamin D deficiency is associated with ethnicity and knee pain in a multi-ethnic South-East Asian nation: Results from Malaysian Elders Longitudinal Research (MELoR). AB - AIM: To determine the association between vitamin D and knee pain among participants of the Malaysian Elders Longitudinal Research (MELoR) study. METHOD: This was a cross-sectional study from the MELoR study consisting of a representative group of 1011 community-dwelling older persons (57% female), mean age 86.5 (54-94) years; 313 were Malays, 367 Chinese and 330 Indians. Participants were asked if they had knee pain. Levels of serum 25-hydroxy cholecalciferol (25-[OH]D), an indicator of vitamin D status, were measured using routine laboratory techniques. RESULTS: In unadjusted analysis, presence of knee pain was significantly associated with vitamin D deficiency (odds ratio [OR] 1.42; 95% confidence interval (CI) 1.08-1.85, P 0.011). Vitamin D levels were significantly associated with ethnicity differences where Malays (OR 7.08; 95% CI 4.94-10.15) and Indians (OR 6.10; 95% CI 4.28-9.71) have lower levels of vitamin D compared to Chinese. Subsequent multivariate analysis revealed that the association between vitamin D deficiency and knee pain was confounded by ethnic differences. CONCLUSION: A previous study suggested that vitamin D deficiency was associated with knee pain. This relationship was reproduced in our study, but we further established that the association was explained by ethnic variations. As vitamin D status is dependent on skin tone, diet and sunlight exposure, which are all effected by ethnicity, future studies are now required to determine whether a true relationship exists between vitamin D and knee pain. PMID- 29611294 TI - Novel Kdr mutations (K964R and A943V) in pyrethroid-resistant populations of Triatoma mazzottii and Triatoma longipennis from Mexico and detoxifying enzymes. AB - Although having five different ways of transmission the vector-borne is the principal way of transmission of Chagas disease, which involves insects of the subfamily Triatominae (Hemiptera: Reduviidae). Nineteen of the 31 species that occur in Mexico are associated with humans, and all are capable of transmitting the disease. Pyrethroids are the insecticides recommended for the control of these vectors in Mexico. We determined the susceptibility to the pyrethroids deltamethrin and permethrin of peridomestic populations of Triatoma mazzottii Usinger and two populations of Triatoma longipennis Usinger in comparison with a reference strain for each species. Bioassays were performed for the determination of the LD50 for both field populations and reference strains. A maximum of 27 fold resistance to deltamethrin was observed in T. mazzottii, meanwhile, for permethrin, T. longipennis from Jalisco show the highest value of 3.19 fold. There was significantly increased activity of esterases in field populations in comparison with their corresponding reference strain. The results of the search of kdr mutations related to the resistance to deltamethrin and permethrin in the evaluated species show the presence of mutations in the field populations, as is the case with individuals of T. mazzottii, for which the mutation was found A943V, and for the two populations of T. longipennis included in this study, we report the presence of the kdr mutation K964R. Evaluation of the various mechanisms involved in resistance to pyrethroids in triatomines from Mexico could guide us to the real justification for insecticide resistance monitoring. PMID- 29611295 TI - Cutis laxa in a patient with 1p36 deletion syndrome. AB - Chromosome 1p36 deletion is the most common subtelomeric deletion syndrome characterized by variable features including unique facial appearance, intellectual disability, developmental delay, cardiac defects, seizures and hypotonia. Here, we report a patient with developmental delay, dilated cardiomyopathy, seizures, hirsutism and cutis laxa who was diagnosed with 1p36 deletion syndrome by chromosome microarray analysis. This patient is the first reported case of 1p36 deletion syndrome associated with cutis laxa and our results suggest that the 1p36 region contains one or more genes relevant to cutis laxa. This case also indicates the importance of considering chromosome abnormalities (microdeletion/microduplication syndromes) in patients presenting skin disorders combined with unexplained developmental delay, intellectual disability or multiple congenital abnormalities. PMID- 29611296 TI - Magnetically Powered Annelid-Worm-Like Microswimmers. AB - A bioinspired magnetically powered microswimmer is designed and experimentally demonstrated by mimicking the morphology of annelid worms. The structural parameters of the microswimmer, such as the surface wrinkling, can be controlled by applying prestrain on substrate for the precise fabrication and consistent performance of the microswimmers. The resulting annelid-worm-like microswimmers display efficient propulsion under an oscillating magnetic field, reaching a peak speed of ~100 um s-1 . The speed and directionality of the microswimmer can be readily controlled by changing the parameters of the field inputs. Additionally, it is demonstrated that the microswimmers are able to transport microparticles toward a predefined destination, although the translation velocity is inevitably reduced due to the additional hydrodynamic resistance of the microparticles. These annelid-worm-like microswimmers have excellent mobility, good maneuverability, and strong transport capacity, and they hold considerable promise for diverse biomedical, chemical sensing, and environmental applications. PMID- 29611297 TI - Relations between structural and EEG-based graph metrics in healthy controls and schizophrenia patients. AB - Our aim was to assess structural and functional networks in schizophrenia patients; and the possible prediction of the latter based on the former. The possible dependence of functional network properties on structural alterations has not been analyzed in schizophrenia. We applied averaged path-length (PL), clustering coefficient, and density (D) measurements to data from diffusion magnetic resonance and electroencephalography in 39 schizophrenia patients and 79 controls. Functional data were collected for the global and theta frequency bands during an odd-ball task, prior to stimulus delivery and at the corresponding processing window. Connectivity matrices were constructed from tractography and registered cortical segmentations (structural) and phase-locking values (functional). Both groups showed a significant electroencephalographic task related modulation (change between prestimulus and response windows) in the global and theta bands. Patients showed larger structural PL and prestimulus density in the global and theta bands, and lower PL task-related modulation in the theta band. Structural network values predicted prestimulus global band values in controls and global band task-related modulation in patients. Abnormal functional values found in patients (prestimulus density in the global and theta bands and task-related modulation in the theta band) were not predicted by structural data in this group. Structural and functional network abnormalities respectively predicted cognitive performance and positive symptoms in patients. Taken together, the alterations in the structural and functional theta networks in the patients and the lack of significant relations between these alterations, suggest that these types of network abnormalities exist in different groups of schizophrenia patients. PMID- 29611298 TI - In vitro evaluation of 225 Ac-DOTA-substance P for targeted alpha therapy of glioblastoma multiforme. AB - Glioblastoma multiforme (GBM) is the most malignant form of brain tumors with dismal prognosis despite treatment by surgery combined with radiotherapy and chemotherapy. The neuropeptide Substance P (SP) is the physiological ligand of the neurokinin-1 receptor, which is highly expressed in glioblastoma cells. Thus, SP represents a potential ligand for targeted alpha therapy. In this study, a protocol for the synthesis of SP labeled with the alpha emitter 225 Ac was developed and binding affinity properties were determined. The effects of 225 Ac DOTA-SP were investigated on human glioblastoma cell lines (T98G, U87MG, U138MG) as well as GBM stem cells. A significant dose-dependent reduction in cell viability was detected up to 6 days after treatment. Also, colony-forming capacity was inhibited at the lower doses tested. In comparison, treatment with the conventional agent temozolomide showed higher cell viability and colony forming capacity. 225 Ac-DOTA-SP treatment caused induction of late apoptosis pathways. Cells were arrested to G2/M-phase upon treatment. Increasing doses and treatment time caused additional S-phase arrest. Similar results were obtained using human glioblastoma stem cells, known to show radioresistance. Our data suggest that 225 Ac-DOTA-SP is a promising compound for treatment of GBM. PMID- 29611299 TI - Pseudocapacitance of TiO2-x /CNT Anodes for High-Performance Quasi-Solid-State Li Ion and Na-Ion Capacitors. AB - It is challenging for flexible solid-state hybrid capacitors to achieve high energy-high-power densities in both Li-ion and Na-ion systems, and the kinetics discrepancy between the sluggish faradaic anode and the rapid capacitive cathode is the most critical issue needs to be addressed. To improve Li-ion/Na-ion diffusion kinetics, flexible oxygen-deficient TiO2-x /CNT composite film with ultrafast electron/ion transport network is constructed as self-supported and light-weight anode for a quasi-solid-state hybrid capacitor. It is found that the designed porous yolk-shell structure endows large surface area and provides short diffusion length, the oxygen-deficient composite film can improve electrical conductivity, and enhance ion diffusion kinetic by introducing intercalation pseudocapacitance, therefore resulting in advance electrochemical properties. It exhibits high capacity, excellent rate performance, and long cycle life when utilized as self-supported anodes for Li-ion and Na-ion batteries. When assembled with activated carbon/carbon nanotube (AC/CNT) flexible cathode, using ion conducting gel polymer as the electrolyte, high energy densities of 104 and 109 Wh kg-1 are achieved at 250 W kg-1 in quasi-solid-state Li-ion and Na-ion capacitors (LICs and SICs), respectively. Still, energy densities of 32 and 36 Wh kg-1 can be maintained at high power densities of 5000 W kg-1 in LICs and SICs. PMID- 29611300 TI - Recent advances in pediatric rheumatology: October - December 2017. PMID- 29611301 TI - Understanding lymphocyte metabolism for use in cancer immunotherapy. AB - Like all dividing cells, naive T cells undergo a predictable sequence of events to enter the cell cycle starting from G0 and progressing to G1 , S and finally G2 /M. This methodical series of steps ensures fidelity in the generation of two identical T cells during a single round of division. To achieve this, T cells must activate or inactivate metabolic pathways at discrete times during each phase of the cell cycle. This permits the generation of substrates to support biosynthesis, bioenergetics and the epigenetic changes required for proper differentiation and function. The precursors that feed into these pathways are often shared, highlighting the complex relationship between metabolism and cellular processes that are essential to lymphocytes. It is therefore not surprising that different T cell subtypes exhibit unique metabolic dependencies that change as they mature and go through specialized differentiation programmes. The importance of the influence of metabolism on T cells is underscored by the emerging field of cancer immunotherapy, where autologous T cells can be manufactured ex vivo then infused as a form of curative treatment for human cancers. This review will highlight some of the recent knowledge on T lymphocyte metabolism and give a perspective on the practical implications for cellular based immunotherapy. PMID- 29611302 TI - Recent advances in pediatric rheumatology: July to September 2017. PMID- 29611303 TI - Different attention bias patterns in anorexia nervosa restricting and binge/purge types. AB - Patients with anorexia nervosa (AN) have been shown to display both elevated anxiety and attentional biases in threat processing. In this study, we compared threat-related attention patterns of patients with AN restricting type (AN-R; n = 32), AN binge/purge type (AN-B/P; n = 23), and healthy controls (n = 19). A dot probe task with either eating disorder-related or general and social anxiety related words was used to measure attention patterns. Severity of eating disorder symptoms, depression, anxiety, and stress were also assessed. Patients with AN-R showed vigilance to both types of threat words, whereas patients with AN-B/P showed avoidance of both threat types. Healthy control participants did not show any attention bias. Attention bias was not associated with any of the demographic, clinical, and psychometric parameters introduced. These findings suggest that there are differential patterns of attention allocation in patients with AN-R and AN-B/P. More research is needed to identify what causes/underlies these differential patterns. PMID- 29611304 TI - Tuning Surface Electronic Configuration of NiFe LDHs Nanosheets by Introducing Cation Vacancies (Fe or Ni) as Highly Efficient Electrocatalysts for Oxygen Evolution Reaction. AB - Intrinsically inferior electrocatalytic activity of NiFe layered double hydroxides (LDHs) nanosheets is considered as a limiting factor to inhibit the electrocatalytic properties for oxygen evolution reaction (OER). Proper defect engineering to tune the surface electronic configuration of electrocatalysts may significantly improve the intrinsic activity. In this work, the selective formation of cation vacancies in NiFe LDHs nanosheets is successfully realized. The as-synthesized NiFe LDHs-VFe and NiFe LDHs-VNi electrocatalysts show excellent activity for OER, mainly attributed to the introduction of rich iron or nickel vacancies in NiFe LDHs nanosheets, which efficiently tune the surface electronic structure increasing the adsorbing capacity of OER intermediates. Density functional theory (DFT) computational results also further indicate that the OER catalytic performance of NiFe LDHs can be pronouncedly improved by introducing Fe or Ni vacancies. PMID- 29611305 TI - A Highly Solvent-Stable Metal-Organic Framework Nanosheet: Morphology Control, Exfoliation, and Luminescent Property. AB - Compared to bulk metal-organic framework (MOF), 2D MOF nanosheets have gained intensive research attention due to their ultrathin thickness and large surface area with highly accessible active sites. However, structural deterioration and morphological damage have impeded producing high-quality MOF nanosheets during exfoliation. Here, first a new layered bulk MOF ZSB-1 is synthesized and several solvents such as isopropanol, methanol, n-hexyl alcohol, and N,N dimethylformamide are surveyed to examine their performance for the exfoliation of layered ZSB-1. As a result, a highly solvent-stable metal-organic framework rectangular nanosheet retaining undamaged morphology is obtained by the soft physical method in n-hexyl alcohol. Theoretical simulations reveal that the strong interaction energy between n-hexyl alcohol and MOF layers is responsible for the best exfoliation performance of making the bulk MOF into nanosheets. In addition, ZSB-1 shows a tunable fluorescence peak position, fluorescent lifetime, and quantum yield by simply changing the solvent and morphology. Besides, the ZSB 1 was selected as a fluorescence sensor to detect metal ions, and ZSB-1 nanosheet exhibits excellent sensing ability for Fe3+ . It is worth noting that the ZSB-1 nanosheet has better detection limit performance of 0.054 * 10-6 m than that of its bulk counterpart. PMID- 29611306 TI - Two optical coherence tomography systems detect topical gold nanoshells in hair follicles, sweat ducts and measure epidermis. AB - Optical coherence tomography (OCT) is an established imaging technology for in vivo skin investigation. Topical application of gold nanoshells (GNS) provides contrast enhancement in OCT by generating a strong hyperreflective signal from hair follicles and sweat glands, which are the natural skin openings. This study explores the utility of 150 nm diameter GNS as contrast agent for OCT imaging. GNS was massaged into skin and examined in four skin areas of 11 healthy volunteers. A commercial OCT system and a prototype with 3 MUm resolution (UHR OCT) were employed to detect potential benefits of increased resolution and variability in intensity generated by the GNS. In both OCT-systems GNS enhanced contrast from hair follicles and sweat ducts. Highest average penetration depth of GNS was in armpit 0.64 mm +/- SD 0.17, maximum penetration depth was 1.20 mm in hair follicles and 15 to 40 MUm in sweat ducts. Pixel intensity generated from GNS in hair follicles was significantly higher in UHR-OCT images (P = .002) and epidermal thickness significantly lower 0.14 vs 0.16 mm (P = .027). This study suggests that GNSs are interesting candidates for increasing sensitivity in OCT diagnosis of hair and sweat gland disorders and demonstrates that choice of OCT systems influences results. PMID- 29611307 TI - A Novel High-Capacity Anode Material Derived from Aromatic Imides for Lithium-Ion Batteries. AB - A novel anode material for lithium-ion batteries derived from aromatic imides with multicarbonyl group conjugated with aromatic core structure is reported, benzophenolne-3,3',4,4'-tetracarboxylimide oligomer (BTO). It could deliver a reversible capacity of 829 mA h g-1 at 42 mA g-1 for 50 cycles with a stable discharge plateaus ranging from 0.05-0.19 V versus Li+ /Li. At higher rates of 420 and 840 mA g-1 , it can still exhibit excellent cycling stability with a capacity retention of 88% and 72% after 1000 cycles, delivering capacity of 559 and 224 mA h g-1 . In addition, a rational prediction of the maximum amount of lithium intercalation is proposed and explored its possible lithium storage mechanism. PMID- 29611308 TI - Factors impacting couples' decision-making between vasectomy reversal versus sperm retrieval/in vitro fertilization/intracytoplasmic sperm injection. AB - The purpose of this study was to identify factors which impact a couples' decision-making between the options of vasectomy reversal vs. sperm retrieval/in vitro fertilization/intracytoplasmic sperm injection when counseled both by a reproductive urologist and a reproductive endocrinologist. A retrospective chart review was performed of couples who wish to achieve a pregnancy with a male partner with a history of prior vasectomy, in a couples' private fertility center. Of patients presenting for fertility options with a history of vasectomy, 175 couples elected to be counseled by both a reproductive urologist and a reproductive endocrinologist on the options between vasectomy reversal and sperm retrieval/in vitro fertilization/intracytoplasmic sperm injection, with 78.3% of the couples opting for vasectomy reversal and 21.7% opting for sperm retrieval/in vitro fertilization/intracytoplasmic sperm injection. The overall mean age of the male partners was 40.5 years of age, and the mean age of the female partners was 33. The mean obstructed interval was 9.7 years. Twenty-three percent of the female partners in couples selecting vasectomy reversal had diminished ovarian reserve, and 31.6% of couples selecting sperm retrieval/in vitro fertilization/intracytoplasmic sperm injection had female partners with diminished ovarian reserve, two of which elected to have donor oocyte in vitro fertilization/intracytoplasmic sperm injection. Male age, female age, and ovarian reserve status did not have significant roles in this decision-making (p value 0.3578, 0.1185, and 0.3041, respectively); however, a longer obstructed interval since vasectomy was a significant factor associated with couples opting for sperm retrieval/in vitro fertilization/intracytoplasmic sperm injection (0.0238). In this study, the majority of couples who were counseled on vasectomy reversal vs. sperm retrieval/in vitro fertilization/intracytoplasmic sperm injection by a reproductive urologist and reproductive endocrinologist chose vasectomy reversal. Neither male partner age, female partner age, nor ovarian reserve status seemed to impact the decision; however, a longer obstructed interval was a significant factor that was associated with the decision of couples toward sperm retrieval/in vitro fertilization/intracytoplasmic sperm injection rather than vasectomy reversal. PMID- 29611309 TI - Recurrent erythema and hyperpigmentation. PMID- 29611310 TI - Recurrent erythema and hyperpigmentation. PMID- 29611311 TI - Clostridium Cadaveris Splenic Abscess in an Adolescent. PMID- 29611313 TI - Antibiotic use is not a cause of childhood obesity. PMID- 29611312 TI - A ventilated newborn with respiratory distress, abdominal distension and scrotal swelling. PMID- 29611314 TI - A ventilated newborn with respiratory distress, abdominal distension and scrotal swelling. PMID- 29611315 TI - Congenital Cytomegalovirus Infection Presenting with Isolated Secretory Diarrhoea Mimicking a Congenital Diarrhoeal Disorder. PMID- 29611316 TI - The effect of medical clowns on performance of spirometry among preschool aged children. AB - INTRODUCTION: Medical clowns (MCs) are known to assist in reducing pain and alleviating anxiety. The objective of this study is to evaluate the ability of MCs to assist preschoolers in performing spirometry. METHODS: A prospective, randomized controlled trial. Children aged 3-6 years participated. After a first spirometry, children were divided into two groups: the first performed a second spirometry with an MC. The second repeated spirometry with the technician. Primary outcome was second spirometry values compared between the groups. Secondary outcome were change in spirometry values within groups, and difference between the groups. RESULTS: A total of 140 children participated. The groups did not differ in age, sex, mother tongue, or weight. Nor in mean FVC (MC 89.2% +/- 16.7, control 89.5% +/- 16.3) mean FEV1 (MC 91.3% +/- 15.6, control 94.2% +/- 16.8), and expiratory time (MC 1.58 +/- 0.43, control 1.7 +/- 0.44) in first spirometry. In second spirometry the control group had a similar FVC, FEV1, and expiratory time. The MC group had a significant improvement in all parameters: FVC: MC 95.3% +/- 15.5, control 89.3% +/- 19.1, FEV1: MC 98.0% +/- 15.6, control 91.8% +/- 19.3, and expiratory time MC 1.96 +/- 0.55, control 1.84 +/- 0.52. The differences between the groups between first and second attempt were significant (P-value FVC 0.000, FEV1 0.000, expiratory time 0.003). DISCUSSION: MCs improved performance of spirometry among preschoolers. It is possible that laughter and relief of stress had a physiological effect. Further studies are required to better establish the ability of MCs to improve active participation and to better understand whether the mechanism of the improvement is better cooperation or true physiological change. PMID- 29611317 TI - Comparison of Urine and Plasma Peptidome Indicates Selectivity in Renal Peptide Handling. AB - PURPOSE: Urine is considered to be produced predominantly as a result of plasma filtration in the kidney. However, the origin of the native peptides present in urine has never been investigated in detail. Therefore, the authors aimed to obtain a first insight into the origin of urinary peptides based on a side-by side comprehensive analysis of the plasma and urine peptidome. METHODS: Twenty two matched urine and plasma samples are analyzed for their peptidome using capillary electrophoresis coupled to mass spectrometry (CE-MS; for relative quantification) and CE or LC coupled to tandem mass spectrometry (CE- or LC MS/MS; for peptide identification). The overlap and association of abundance of the different peptides present in these two body fluids are evaluated. RESULTS: The authors are able to identify 561 plasma and 1461 urinary endogenous peptides. Only 90 peptides are detectable in both urine and plasma. No significant correlation is found when comparing the abundance of these common peptides, with the exception of collagen fragments. This observation is also supported when comparing published peptidome data from both plasma and urine. CONCLUSIONS AND CLINICAL RELEVANCE: Most of the plasma peptides are not detectable in urine, possibly due to tubular reabsorption. The majority of urinary peptides may in fact originate in the kidney. The notable exception is collagen fragments, which indicates potential selective exclusion of these peptides from tubular reabsorption. Experimental verification of this hypothesis is warranted. PMID- 29611318 TI - A vision for a 'microbcentric' future. AB - Microbes are the most abundant lifeforms on the planet and perform functions critical for all other life to exist. Environmental 'omic' technologies provide the capacity to discover the 'what, how and why' of indigenous species. However, in order to accurately interpret this data, sound conceptual frameworks are required. Here I argue that our understanding of microbes will advance much more effectively if we adopt a microbcentric, and not anthropocentric view of the world. PMID- 29611319 TI - Fecal Enterobacteriales enrichment is associated with increased in vivo intestinal permeability in humans. AB - Type 2 diabetes (T2D) has been linked with increased intestinal permeability, but the clinical significance of this phenomenon remains unknown. The objective of this study was to investigate the potential link between glucose control, intestinal permeability, diet and intestinal microbiota in patients with T2D. Thirty-two males with well-controlled T2D and 30 age-matched male controls without diabetes were enrolled in a case-control study. Metabolic parameters, inflammatory markers, endotoxemia, and intestinal microbiota in individuals subdivided into high (HP) and normal (LP) colonic permeability groups, were the main outcomes. In T2D, the HP group had significantly higher fasting glucose (P = 0.034) and plasma nonesterified fatty acid levels (P = 0.049) compared with the LP group. Increased colonic permeability was also linked with altered abundances of selected microbial taxa. The microbiota of both T2D and control HP groups was enriched with Enterobacteriales. In conclusion, high intestinal permeability was associated with poorer fasting glucose control in T2D patients and changes in some microbial taxa in both T2D patients and nondiabetic controls. Therefore, enrichment in the gram-negative order Enterobacteriales may characterize impaired colonic permeability prior to/independently from a disruption in glucose tolerance. PMID- 29611320 TI - High Fibroblast Growth Factor 23 concentrations in experimental renal failure impair calcium handling in cardiomyocytes. AB - The overwhelming majority of patients with chronic kidney disease (CKD) die prematurely before reaching end-stage renal disease, mainly due to cardiovascular causes, of which heart failure is the predominant clinical presentation. We hypothesized that CKD-induced increases of plasma FGF23 impair cardiac diastolic and systolic function. To test this, mice were subjected to 5/6 nephrectomy (5/6Nx) or were injected with FGF23 for seven consecutive days. Six weeks after surgery, plasma FGF23 was higher in 5/6Nx mice compared to sham mice (720 +/- 31 vs. 256 +/- 3 pg/mL, respectively, P = 0.034). In cardiomyocytes isolated from both 5/6Nx and FGF23 injected animals the rise of cytosolic calcium during systole was slowed (-13% and -19%, respectively) as was the decay of cytosolic calcium during diastole (-15% and -21%, respectively) compared to controls. Furthermore, both groups had similarly decreased peak cytosolic calcium content during systole. Despite lower cytosolic calcium contents in CKD or FGF23 pretreated animals, no changes were observed in contractile parameters of cardiomyocytes between the groups. Expression of calcium handling proteins and cardiac troponin I phosphorylation were similar between groups. Blood pressure, the heart weight:tibia length ratio, alpha-MHC/beta-MHC ratio and ANF mRNA expression, and systolic and diastolic function as measured by MRI did not differ between groups. In conclusion, the rapid, CKD-induced rise in plasma FGF23 and the similar decrease in cardiomyocyte calcium transients in modeled kidney disease and following 1-week treatment with FGF23 indicate that FGF23 partly mediates cardiomyocyte dysfunction in CKD. PMID- 29611321 TI - Symmetric assembly and disassembly processes in an ecological network. AB - The processes whereby ecological networks emerge, persist and decay throughout ecosystem development are largely unknown. Here we study networks of plant and arbuscular mycorrhizal fungal (AMF) communities along a 120 000 year soil chronosequence, as they undergo assembly (progression) and then disassembly (retrogression). We found that network assembly and disassembly were symmetrical, self-reinforcing processes that together were capable of generating key attributes of network architecture. Plant and AMF species that had short indirect paths to others in the community (i.e. high centrality), rather than many direct interaction partners (i.e. high degree), were best able to attract new interaction partners and, in the case of AMF species, also to retain existing interactions with plants during retrogression. We then show using simulations that these non-random patterns of attachment and detachment promote nestedness of the network. These results have implications for predicting extinction sequences, identifying focal points for invasions and suggesting trajectories for restoration. PMID- 29611322 TI - Small non-coding RNAs are altered by short-term sprint interval training in men. AB - Small non-coding RNAs (ncRNAs) are emerging as important molecules for normal biological processes and are deregulated in disease. Exercise training is a powerful therapeutic strategy that prevents cardiometabolic disease and improves cardiorespiratory fitness and performance. Despite the known systemic health benefits of exercise training, the underlying molecular mechanisms are incompletely understood. Recent evidence suggests a role for epigenetic mechanisms, such as microRNAs, but whether other small ncRNAs are modulated by chronic exercise training is unknown. Here, we used small RNA sequencing to explore whether sprint interval training (SIT) controls the abundance of circulating small ncRNAs in human whole blood samples. Ten healthy men performed SIT three times a week for 6 weeks. After training, subjects showed marked improvements in maximal oxygen consumption and cycling performance with concurrent changes to the abundance of diverse species of circulating small ncRNAs (n = 1266 small ncRNAs, n = 13 microRNAs, q < 0.05). Twelve microRNAs altered by 6 weeks of SIT were ubiquitously expressed microRNAs and two regulated important signaling pathways, including p53, thyroid hormone and cell cycle signaling. MicroRNAs altered by 6 weeks of SIT were unchanged after a single session of SIT (n = 24, all P > 0.05). Relative to older individuals, younger subjects exhibited an increased acute SIT-induced fold change in miR-1301-3p (P = 0.02) - a microRNA predicted to target mRNAs involved in alternative splicing, phosphoprotein and chromosomal rearrangement processes (all P < 0.001). Our findings indicate many species of circulating small ncRNAs are modulated by exercise training and that they could control signaling pathways responsible for health benefits achieved from exercise. PMID- 29611324 TI - Validation of a novel wearable, wireless technology to estimate oxygen levels and lactate threshold power in the exercising muscle. AB - There is a growing interest in monitoring muscle oxygen saturation (SmO2 ), which is a localized measure of muscle oxidative metabolism and can be acquired continuously and noninvasively using near-infrared spectroscopy (NIRS) methods. Most NIRS systems are cumbersome, expensive, fiber coupled devices, with use limited to lab settings. A novel, low cost, wireless, wearable has been developed for use in athletic training. In this study, we evaluate the advantages and limitations of this new simple continuous-wave (CW) NIRS device with respect to a benchtop, frequency-domain near-infrared spectroscopy (FDNIRS) system. Oxygen saturation and hemoglobin/myoglobin concentration in the exercising muscles of 17 athletic individuals were measured simultaneously with the two systems, while subjects performed an incremental test on a stationary cycle ergometer. In addition, blood lactate concentration was measured at the end of each increment with a lactate analyzer. During exercise, the correlation coefficients of the SmO2 and hemoglobin/myoglobin concentrations between the two systems were over 0.70. We also found both systems were insensitive to the presence of thin layers of varying absorption, mimicking different skin colors. Neither system was able to predict the athletes' lactate threshold power accurately by simply using SmO2 thresholds. Instead, the proprietary software of the wearable device was able to predict the athletes' lactate threshold power within half of one power increment of the cycling test. These results indicate this novel wearable device may provide a physiological indicator of athlete's exertion. PMID- 29611323 TI - Leptin attenuates D2 receptor-mediated inhibition of putative ventral tegmental area dopaminergic neurons. AB - Obesity causes hyperleptinemia. We have previously shown that D2 receptor mediated inhibition of ventral tegmental area (VTA) dopaminergic neurons is attenuated in diet-induced mice with obesity. Consequently, we hypothesized that high concentrations of serum leptin during obesity might modulate D2 receptor mediated effects on VTA dopaminergic neurons. To investigate our hypothesis, we examined leptin effects on D2 receptor-mediated inhibition of putative VTA dopaminergic neurons from lean mice using electrophysiological techniques. Leptin (100 nmol/L) directly inhibited spontaneous firing in 71% of putative VTA dopaminergic neurons (leptin-responsive), whereas the remaining 29% of neurons were leptin-nonresponsive. In 41% of leptin-responsive neurons, leptin attenuated the reduced firing rate produced by quinpirole (100 nmol/L), whereas the remaining 59% of neurons exhibited no effect of leptin. In leptin-nonresponsive neurons, no significant leptin-induced effect was observed on reduced firing rate produced by quinpirole. In leptin-responsive neurons with positive leptin-induced attenuation of quinpirole effects, leptin-induced attenuation persisted for >20 min, whereas no such persistent attenuation was observed in other types of neurons. In conclusion, leptin attenuates D2 receptor-mediated inhibition in a subpopulation of putative VTA dopaminergic neurons. We suggest that leptin directly decreases, and indirectly increases, excitability of VTA dopaminergic neurons. In turn, this may contribute to a change in feeding behavior through the mesolimbic dopaminergic system during the development of obesity. PMID- 29611325 TI - Modulation of the sympathetic nervous system in youngsters by vitamin-D supplementation. AB - The level of circulating vitamin D is known to be associated with the ejection fraction in heart failure patients and studies in rats have shown that vitamin D depletion leads to increased levels of circulating norepinephrine and decreased atrial contractility. We elucidated the effects of vitamin D supplementation on the autonomous nervous system in healthy youngsters. Thirty healthy subjects aged 18-25 years were recruited based on their serum 25-hydroxyvitamin D (25[OH]D): 15 vitamin D insufficient (25[OH]D < 50 nmol/L) and 15 vitamin D sufficient (25[OH]D > 80 nmol/L) subjects. Both groups had vitamin D supplementation (30 microg/day) and were tested at baseline and after 30, 90, and 180 days. At each visit the serum 25-hydroxyvitamin D was measured and the head-up tilt test performed. Serum 25[OH]D remained stable in the vitamin D sufficient group, while the insufficient group had a significant increase (32.0-64.5 nmol/L), P < 0.0001. Despite the increase, the insufficient group did not reach the level of the vitamin D sufficient group within the 6 months observational period (96.1 vs 64.5 nmol/L), P < 0.01. Serum norepinephrine at baseline was higher in the insufficient group (mean = 1.61 nmol/L) than in the vitamin D sufficient group (mean = 0.94 nmol/L), P < 0.01, whereas the response to tilt was lower in the insufficient group (mean = 0.69 nmol/L) compared to the sufficient group (mean = 1.17 nmol/L), P < 0.01. The heart rate at rest was higher in the insufficient group (mean = 67.7 bpm) than in the vitamin D sufficient group (mean = 56.6 bpm), P < 0.01, for the three first visits. At the last visit no difference was found. The systolic and diastolic blood pressure differed between the groups after a month, with higher pressures in the insufficient group than in the sufficient group. Vitamin D supplementation modulates the sympathetic nervous system in healthy youngsters with low serum vitamin D. The observation might lead to a greater focus on possible prevention of cardiac disease later on in life by vitamin D supplementation early in life. PMID- 29611326 TI - Inhibitory effect of Thai propolis on human osteoclastogenesis. AB - BACKGROUND/AIM: Avulsed teeth should be immediately replanted into the socket or otherwise kept in a physiologic storage medium to maintain periodontal ligament cell viability. A previous study has demonstrated that Thai propolis extract can maintain viability of human periodontal ligament cells. However, root resorption by osteoclasts often occurs when the avulsed teeth are replanted. The aim of this study was to determine the inhibitory effect of Thai propolis extract on human osteoclastogenesis in vitro. MATERIALS AND METHODS: Human peripheral blood mononuclear cells were isolated for osteoclast precursors and cultured in the presence or absence of various non-toxic concentrations of propolis extract, as determined by the alamarBlue(r) assay, during in vitro induction of osteoclastogenesis. Osteoclast formation was examined by tartrate-resistant acid phosphatase staining, actin ring formation, and real-time polymerase chain reaction. The resorption pit assay was performed to determine osteoclast function. RESULTS: Non-toxic concentrations of propolis extract suppressed osteoclast formation by significantly decreasing the percentages of tartrate resistant acid phosphatase-positive multinuclear cells and the ratios of cells with F-actin ring formation (P < .01) in a dose-dependent fashion. Expression of several osteoclast-specific genes was significantly downregulated by propolis in a dose-dependent manner (P < .05). The percentages of resorption areas on dentin slices were significantly decreased by propolis (P < .05). CONCLUSIONS: Thai propolis can inhibit human osteoclast formation and function, which may be beneficial for prevention of root resorption following replantation of avulsed teeth. PMID- 29611327 TI - Fecal imaging demonstrates that low-methoxyl pectin supplementation normalizes gastro-intestinal transit in mice given a liquid diet. AB - This study has the following aims: (1) to confirm a methodology for a fecal indocyanine green (ICG) imaging test for measuring gastro-intestinal transit time (GITT); and (2) to compare GITT in mice given a liquid diet in which viscosity increases under acidic conditions to that in mice given stable liquid diets with comparable viscosity or regular chow. To address Aim 1, mice received ICG orally along with intraperitoneal injection of atropine in Study 1, and mice were given ICG orally with concurrent carmine red for Study 2. Fluorescence imaging of feces collected for 8 h thereafter was used to detect the first feces with fluorescence and thereby determine GITT. To address Aim 2, mice were fed ad libitum for 1 week with either liquid diet or regular chow for Study 3, or with liquid diet containing low-methoxyl (LM) pectin or high-methoxyl (HM) pectin, or regular chow for Study 4. GITT was then determined by fecal ICG imaging. Atropine delayed GITT in a dose-dependent manner. The GITT of ICG completely corresponded to that of carmine red (correlation coefficient, 1.00). The first ICG excretion in the loose/some diarrheal feces of mice given a liquid diet was seen at 170 min. Feces of mice given liquid diet were loose with LM pectin and loose/some diarrhea with HM pectin. GITT of mice given liquid diet with HM pectin was significantly delayed (280 min) compared to that of mice given liquid diet with LM pectin (111 min) or regular chow (130 min). Fecal imaging of ICG enables measurements of GITT. LM pectin supplementation in a liquid diet may normalize GITT in mice to that of a normal meal and may be associated with changes in fecal properties. PMID- 29611332 TI - An aggressive physician and a conservative surgeon: the ideal combination for the management of IBD in the age of biologics? PMID- 29611333 TI - Real-Time Imaging of Dynamic Cell Reprogramming with Nanosensors. AB - Cellular reprogramming, the process by which somatic cells regain pluripotency, is relevant in many disease modeling, therapeutic, and drug discovery applications. Molecular evaluation of reprogramming (e.g., polymerase chain reaction, immunostaining) is typically disruptive, and only provides snapshots of phenotypic traits. Gene reporter constructs facilitate live-cell evaluation but is labor intensive and may risk insertional mutagenesis during viral transfection. Herein, the utilization of a non-integrative nanosensor is demonstrated to visualize key reprogramming events in situ within live cells. Principally based on sustained intracellular release of encapsulated molecular probes, nanosensors successfully monitored mesenchymal-epithelial transition, pluripotency acquisition, and transdifferentiation events. Tracking the dynamic expression of four pivotal biomarkers (i.e., THY1, E-CADHERIN, OCT4, and GATA4 mRNA), nanosensor signal showed great agreement with polymerase chain reaction and gene reporter imaging (R2 > 0.9). Overall, such facile, versatile nanosensor enables real-time monitoring of low-frequency reprogramming events, thereby useful for high-throughput assessment, optimization, and biomarker-specific cell enrichment. PMID- 29611334 TI - Conditional ablation of the prorenin receptor in nephron progenitor cells results in developmental programming of hypertension. AB - Nephron induction during kidney development is driven by reciprocal interactions between progenitor cells (NPCs) of the cap mesenchyme (CM) and the ureteric bud (UB). The prorenin receptor (PRR) is a receptor for renin and prorenin, and an accessory subunit of the vacuolar proton pump V-ATPase. Previously, we demonstrated that conditional ablation of the PRR in Six2+ NPCs in mice (Six2PRR /- ) causes early neonatal death. Here, we identified genes that are regulated by PRR in Six2+ NPCs FACS-isolated from Six2PRR-/- and control kidneys on embryonic day E15.5 using whole-genome expression analysis. Seven genes with expression in CM cells previously shown to direct kidney development, including Notch1, beta catenin, Lef1, Lhx1, Jag1, and p53, were downregulated. The functional groups within the downregulated gene set included genes involved in embryonic and cellular development, renal regeneration, cellular assembly and organization, cell morphology, death and survival. Double-transgenic Six2PRR-/- /BatGal+ mice, a reporter strain for beta-catenin transcriptional activity, showed decreased beta-catenin activity in the UB in vivo. Reduced PRR gene dosage in heterozygous Six2PRR+/- mice was associated with decreased glomerular number, segmental thickening of the glomerular basement membrane with focal podocyte foot process effacement, development of hypertension and increased soluble PRR (sPRR) levels in the urine at 2 months of age. Together, these data demonstrate that NPC PRR performs essential functions during nephrogenesis via control of hierarchy of genes that regulate critical cellular processes. Both reduced nephron endowment and augmented urine sPRR likely contribute to programming of hypertension in Six2PRR+/- mice. PMID- 29611335 TI - The prevalence of comorbid alcohol use disorder in the presence of personality disorder: Systematic review and explanatory modelling. AB - Comorbid personality disorder (PD) worsens outcome in mental state disorders; however, the proportion of people with PD who have an alcohol use disorder (AUD) is poorly described. A systematic review of the literature for studies reporting on AUD in those with PD was completed. Lifetime prevalence figures were meta analysed using multilevel models, accounting for type of PD and population examined. Sixteen unique studies contributed data to the analysis. PD type accounted for most of the heterogeneity in lifetime AUD prevalence. People with antisocial PD had the highest lifetime AUD prevalence, at 76.7%, followed by those with borderline PD at 52.2%, while those with other forms of PD, or undifferentiated PD, had a prevalence of 38.9%. Lifetime AUD prevalence was not significantly higher in clinical compared with population samples. The majority of people with PD experience an AUD at some time in the life course. This has clinical screening and management implications. Copyright (c) 2018 John Wiley & Sons, Ltd. PMID- 29611336 TI - The association between locus of control, emotion regulation and borderline personality disorder features. AB - BACKGROUND: Locus of control (LOC) represents individuals' beliefs about how much control they have over outcomes in their life. Previous research has found an association between external LOC and psychopathology. Borderline personality disorder (BPD) is characterized by mood instability, identity disturbance and difficulties in impulse control. AIMS: The aims of this study are to evaluate the relationship between BPD features and LOC in a non-clinical sample and to assess whether external LOC is associated with BPD features after controlling for symptoms of depression and anxiety. METHODS: In a cross-sectional study of 328 university students, we assessed LOC, BPD features, depression and anxiety, as well as difficulties in emotion regulation and cognitive emotion regulation as potential mediators. RESULTS: We found an association between external LOC and BPD features after controlling for symptoms of depression, anxiety and demographic covariates. Assessing for indirect effects through potential mediators, we found that difficulties in emotion regulation, but not cognitive emotion regulation, partially mediated the relationship between external LOC and BPD features. CONCLUSIONS: Findings provide support for a unique association between external LOC and BPD features and suggest a role for external LOC in related emotion regulation problems. Future investigations using experimental designs should examine potential causal associations and the effect of changing LOC on emotion regulation and features of BPD. Copyright (c) 2018 John Wiley & Sons, Ltd. PMID- 29611337 TI - The Flexibility of an Amorphous Cobalt Hydroxide Nanomaterial Promotes the Electrocatalysis of Oxygen Evolution Reaction. AB - Structural flexibility can be a desirable trait of an operating catalyst because it adapts itself to a given catalytic process for enhanced activity. Here, amorphous cobalt hydroxide nanocages are demonstrated to be a promising electrocatalyst with an overpotential of 0.28 V at 10 mA cm-2 , far outperforming the crystalline counterparts and being in the top rank of the catalysts of their kind, under the condition of electrocatalytic oxygen evolution reaction. From the direct experimental in situ and ex situ results, this enhanced activity is attributed to its high structural flexibility in terms of 1) facile and holistic transformation into catalytic active phase; 2) hosting oxygen vacancies; and 3) structure self-regulation in a real-time process. Significantly, based on plausible catalytic mechanism and computational simulation results, it is disclosed how this structural flexibility facilitates the kinetics of oxygen evolution reaction. This work deepens the understanding of the structure-activity relationship of the Co-based catalysts in electrochemical catalysis, and it inspires more applications that require flexible structures enabled by such amorphous nanomaterials. PMID- 29611338 TI - Ultrathin Planar Cavity Metasurfaces. AB - An ultrathin planar cavity metasurface is proposed based on ultrathin film interference and its practicability for light manipulation in visible region is experimentally demonstrated. Phase of reflected light is modulated by finely adjusting the thickness of amorphous silicon (a-Si) by a few nanometers on an aluminum (Al) substrate via nontrivial phase shifts at the interfaces and interference of multireflections generated from the planar cavity. A phase shift of pi, the basic requirement for two-level phase metasurface systems, can be accomplished with an 8 nm thick difference. For proof of concept, gradient metasurfaces for beam deflection, Fresnel zone plate metalens for light focusing, and metaholograms for image reconstruction are presented, demonstrating polarization-independent and broadband characteristics. This novel mechanism for phase modulation with ultrathin planar cavity provides diverse routes to construct advanced flat optical devices with versatile applications. PMID- 29611339 TI - Vertical ZnO Nanotube Transistor on a Graphene Film for Flexible Inorganic Electronics. AB - The bottom-up integration of a 1D-2D hybrid semiconductor nanostructure into a vertical field-effect transistor (VFET) for use in flexible inorganic electronics is reported. Zinc oxide (ZnO) nanotubes on graphene film is used as an example. The VFET is fabricated by growing position- and dimension-controlled single crystal ZnO nanotubes vertically on a large graphene film. The graphene film, which acts as the substrate, provides a bottom electrical contact to the nanotubes. Due to the high quality of the single crystal ZnO nanotubes and the unique 1D device structure, the fabricated VFET exhibits excellent electrical characteristics. For example, it has a small subthreshold swing of 110 mV dec-1 , a high Imax /Imin ratio of 106 , and a transconductance of 170 nS um-1 . The electrical characteristics of the nanotube VFETs are validated using 3D transport simulations. Furthermore, the nanotube VFETs fabricated on graphene films can be easily transferred onto flexible plastic substrates. The resulting components are reliable, exhibit high performance, and do not degrade significantly during testing. PMID- 29611340 TI - The targeted anti-oxidant MitoQ causes mitochondrial swelling and depolarization in kidney tissue. AB - Kidney proximal tubules (PTs) contain a high density of mitochondria, which are required to generate ATP to power solute transport. Mitochondrial dysfunction is implicated in the pathogenesis of numerous kidney diseases. Damaged mitochondria are thought to produce excess reactive oxygen species (ROS), which can lead to oxidative stress and activation of cell death pathways. MitoQ is a mitochondrial targeted anti-oxidant that has shown promise in preclinical models of renal diseases. However, recent studies in nonkidney cells have suggested that MitoQ might also have adverse effects. Here, using a live imaging approach, and both in vitro and ex vivo models, we show that MitoQ induces rapid swelling and depolarization of mitochondria in PT cells, but these effects were not observed with SS-31, another targeted anti-oxidant. MitoQ consists of a lipophilic cation (Tetraphenylphosphonium [TPP]) joined to an anti-oxidant component (quinone) by a 10-carbon alkyl chain, which is thought to insert into the inner mitochondrial membrane (IMM). We found that mitochondrial swelling and depolarization was also induced by dodecyltriphenylphosphomium (DTPP), which consists of TPP and the alkyl chain, but not by TPP alone. Surprisingly, MitoQ-induced mitochondrial swelling occurred in the absence of a decrease in oxygen consumption rate. We also found that DTPP directly increased the permeability of artificial liposomes with a cardiolipin content similar to that of the IMM. In summary, MitoQ causes mitochondrial swelling and depolarization in PT cells by a mechanism unrelated to anti-oxidant activity, most likely because of increased IMM permeability due to insertion of the alkyl chain. PMID- 29611341 TI - Outcome and predictors of renal survival in patients with lupus nephritis: Comparison between cyclophosphamide and mycophenolate mofetil. AB - AIM: To compare renal outcomes between cyclophosphamide (CYC) and mycophenolate mofetil (MMF), and attempt to identify a predictor of renal survival. METHODS: A total of 99 patients with class III-V lupus nephritis (LN) and treated with CYC or MMF were enrolled. The remission rate and predictors of poor renal outcomes in LN were assessed. RESULTS: The mean age at LN diagnosis was 31.7 years. The baseline characteristics of the two groups were similar except for the chronicity index (3.1 +/- 2.4 and 2.3 +/- 0.8 for CYC and MMF, respectively, P = 0.007). The overall remission rate was 76.8% and 77.7% after 6 and 12 months, respectively, with no significant difference between the two groups at these time points. After a median follow-up of 36 months (interquartile range 12-60), eight (8.1%) patients had chronic kidney disease, four (4.1%) were dialyzed permanently, and seven (7.1%) suffered a relapse, with no significant difference in these final outcomes between the two groups. Adverse events included infection (CYC group), and rash and neutropenia (MMF group), with no significant difference in frequency between the two groups. Failure of induction therapy (hazards ratio [HR] = 10.626, P = 0.022) and the creatinine level at diagnosis of LN (HR = 8.397, P = 0.007) were significantly associated with renal survival adjusted for age at LN diagnosis, disease duration and proteinuria. CONCLUSION: Response to current induction therapy for LN was favorable, and 6 months response following induction therapy was the most important predictor for renal survival. PMID- 29611342 TI - The economic impacts of using adalimumab (Humira(r) ) for reducing pain in people with ankylosing spondylitis: A microsimulation study for Australia. AB - AIM: The onset and progression of ankylosing spondylitis (AS) usually occurs during the life stage when individuals are more likely to be working and receiving an income, but little is known about the effects of interventions that reduce pain and improve the economic circumstances of patients out of the labour force due to AS. This study evaluates the economic benefits of pain reduction among people aged 19-64 with AS using adalimumab (Humira(r) ) from the patient and governmental perspectives. METHODS: We estimated the benefits of adalimumab for reducing pain in people aged 19-64 with AS in terms of labor force participation and earnings, and to the Australian Government in terms of income tax revenue and welfare payments using economic simulation. The simulation model integrated data from the Adalimumab Trial Evaluating Long-Term Safety and Efficacy for Ankylosing Spondylitis (ATLAS), the Household Income and Labour Dynamics in Australia (HILDA) Survey - Wave 10, and Static Incomes Model (STINMOD). All benefits are expressed in 2014 real Australian dollars. RESULTS: We estimated an additional 131 people aged 19-64 with AS (111 males, 20 females) would be in the labour force after using adalimumab for 24 weeks. National benefits consisted of an increase in annual earnings of AU$7.4 million for patients through increased labour force participation, savings of $2 million in annual welfare payments, and an increase of $1.3 million in income tax revenue in 2014 (after 24 weeks). CONCLUSION: Adalimumab therapy generates substantial economic benefits in addition to health benefits for individuals, and savings for government. PMID- 29611343 TI - Work disability in Argentinian patients with systemic lupus erythematosus is prevalent and it is due to ethnic, socioeconomic and disease-related factors. AB - OBJECTIVE: To study the prevalence and the associated factors of work disability (WD) in systemic lupus erythematosus (SLE) patients. METHODS: A sample of 419 SLE patients from an observational cross-sectional multicenter study was included. Sociodemographic features, disease characteristics, comorbidities, quality of life, unhealthy behaviors, and work-related factors were measured in a standardized interview. Work disability was defined by patient self-report of not being able to work because of SLE. To identify variables associated with work disability, two different multivariate regression models using a stepwise backward method were performed. RESULTS: Prevalence of WD due to SLE was 24.3%. Eighty-nine percent were female and 51% were Caucasians. Mean disease duration was 8.9 +/- 7.2 years, and median System Lupus International Collaborating Clinics/American College of Rheumatology damage index SLICC-SDI was 1.5 (range 0 17). In stepwise multivariate logistic regression, living below the poverty line (odds ratio [OR] = 4.65), less than 12 years of education (OR = 2.84), Mestizo ethnicity (OR = 1.94) and SLICC-SDI (OR = 1.25) were predictors of WD. A second model was performed including patient-derived measures; in this model sedentary lifestyle (OR = 2.69) and lower emotional health domain score of the Lupus Quality of Life (LupusQoL) questionnaire (OR = 1.03) were found to be associated to WD and a higher score in LupusQoL physical health domain (OR = 0.93) was protective. CONCLUSION: The prevalence of WD in Argentinian SLE patients was 24.3%. WD was associated with ethnic (Mestizo), socioeconomic (poverty) and disease-related factors. Patient-related outcomes such us sedentary lifestyle and poor emotional quality of life were also associated with WD. PMID- 29611345 TI - Are PR3 positive and MPO positive GPA the same disease? PMID- 29611344 TI - Characterization of Heterobasidion occidentale transcriptomes reveals candidate genes and DNA polymorphisms for virulence variations. AB - Characterization of genes involved in differentiation of pathogen species and isolates with variations of virulence traits provides valuable information to control tree diseases for meeting the challenges of sustainable forest health and phytosanitary trade issues. Lack of genetic knowledge and genomic resources hinders novel gene discovery, molecular mechanism studies and development of diagnostic tools in the management of forest pathogens. Here, we report on transcriptome profiling of Heterobasidion occidentale isolates with contrasting virulence levels. Comparative transcriptomic analysis identified orthologous groups exclusive to H. occidentale and its isolates, revealing biological processes involved in the differentiation of isolates. Further bioinformatics analyses identified an H. occidentale secretome, CYPome and other candidate effectors, from which genes with species- and isolate-specific expression were characterized. A large proportion of differentially expressed genes were revealed to have putative activities as cell wall modification enzymes and transcription factors, suggesting their potential roles in virulence and fungal pathogenesis. Next, large numbers of simple sequence repeats (SSRs) and single nucleotide polymorphisms (SNPs) were detected, including more than 14 000 interisolate non synonymous SNPs. These polymorphic loci and species/isolate-specific genes may contribute to virulence variations and provide ideal DNA markers for development of diagnostic tools and investigation of genetic diversity. PMID- 29611346 TI - Links between depression and openness and its facets. AB - Most studies on depression and personality have focused on the role of Neuroticism and Extraversion. Openness is a much less studied trait in this literature, as past studies investigating Openness and depression often have found non-significant correlations between them. However, past studies mostly have investigated Openness and depression at the domain level and used non clinical samples. In the present study, the relationship between depression and Openness at the domain and facet levels was examined in a sample of 266 participants recruited from outpatient psychiatric settings. Findings showed that although the Openness domain was significantly related to depression, it did not account for a significant proportion of unique variance for depression. However, Openness did account for a significant proportion of unique variance for depression at the facet level, even after accounting for sex, age, Neuroticism and Extraversion. Specifically, unique effects emerged for the facets of Aesthetics positively predicting Depression and Values negatively predicting Depression and Anhedonia. Clinical and theoretical implications are discussed. Copyright (c) 2018 John Wiley & Sons, Ltd. PMID- 29611347 TI - Activation of the sympathetic nervous system suppresses mouse white adipose tissue hyperplasia through the beta1 adrenergic receptor. AB - Adipose tissue (AT) expands via both hypertrophy and hyperplasia during the development of obesity. While AT hypertrophy involves the increase in size of existing adipocytes, hyperplasia is the process of creating new adipocytes from the pool of adipocyte precursor cells (APCs), which includes adipocyte progenitor cells and preadipocytes. Prior studies have implicated a role of the sympathetic nervous system (SNS) in regulation of hyperplasia in white adipose tissue (WAT). Here, we aimed to determine the mechanisms underlying SNS regulation of APC proliferation in mouse WAT. Using flow cytometry with antibodies against various cell surface markers, along with an intracellular marker of proliferation (Ki67), we quantitated the percentages and proliferative status of adipocyte progenitor cells and preadipocytes in the stromal vascular fraction (SVF) of WAT. In vivo SNS activation through cold exposure, as well as in vitro adrenergic stimulation via exposure to the canonical SNS neurotransmitter norepinephrine (NE), inhibited preadipocyte proliferation. Pretreatment with propranolol, a beta1- and beta2 adrenergic receptor (AR) antagonist, trended toward rescuing the inhibitory effects of NE in primary cell culture. The selective beta1-AR agonist dobutamine diminished preadipocyte proliferation both in vivo and in vitro, whereas the selective beta2-AR agonist, salbutamol, promoted proliferation in vitro, suggesting that the beta1-AR may mediate the inhibitory effect of NE on preadipocyte proliferation. Taken together, we conclude that SNS activation suppresses preadipocyte proliferation via activation of the beta1 AR in WAT. PMID- 29611348 TI - High frequency oscillatory ventilation in a cohort of children with respiratory failure. AB - OBJECTIVES: Our objective was to determine survival and variables associated with poor outcomes for patients requiring high frequency oscillatory ventilator (HFOV) support. We tested the ability of markers of oxygenation to predict outcome, specifically, the oxygenation index (OI), both prior to and after initiation of HFOV. We also aimed to examine the effect of immunocompromised condition (IC), and specifically stem cell transplant (SCT), on outcome. DESIGN: A retrospective, observational study was performed at two pediatric intensive care units (ICU) and included patients treated with HFOV over a 5 year time period. Oxygenation index and PF ratios were calculated for all patients prior to and at 24 h of HFOV support. RESULTS: Of the 134 patients meeting inclusion criteria, mortality was 42% with a higher rate of mortality (P < 0.001) for both immunocompromised (66%) and SCT patients (83%). Survivors had improved markers of oxygenation at 24 h as compared to non-survivors (P < 0.001). IC and SCT were the variables most closely associated with mortality. Survivors were placed on HFOV earlier than non survivors. The OI at 24 h of HFOV support was the best predictor of mortality among markers of oxygenation. CONCLUSIONS: In this cohort of patients, use of HFOV for pediatric respiratory failure demonstrated a mortality rate in keeping with published data. The presence of an immunocompromised condition was a risk factor for mortality in severe respiratory failure with SCT recipients having the lowest survival rate. The OI at 24 h was the best predictor of mortality, especially in immunocompromised and SCT patients. PMID- 29611349 TI - Gender differences in retention rate of tumor necrosis factor alpha inhibitor treatment in ankylosing spondylitis: a retrospective cohort study in daily practice. AB - AIM: To assess gender differences in ankylosing spondylitis (AS) patients in relation to tumor necrosis factor alpha inhibitor (TNFi) drug survival and occurrence of adverse events in daily practice in a large peripheral hospital. METHOD: Retrospective data were collected from AS patients treated with etanercept, infliximab and adalimumab between January 2004 and January 2014. Kaplan-Meier survival curves were conducted to describe the drug survival and occurrence of adverse events in time. RESULTS: Overall, 122 AS patients (60.7% male) were included over a 10-year time period, with a mean treatment period of 51 months (1-127 months). In total, 21 (17.2%) patients stopped the TNFi, mainly due to inefficacy (52.4%). Female patients showed a significant shorter treatment period compared to males (33.4 vs. 44.9 months). In addition, female patients switched more between TNFi compared to males (26.9% vs. 16.3%) and had a significantly higher risk at developing infections compared to male patients (26% vs.19%). CONCLUSION: Females stayed on the same TNFi for a significantly shorter period compared to males (33.4 vs. 44.9 months) and the most important reason to stop or switch the drug was inefficacy. Moreover, females seemed to be more prone to infections during TNFi treatment than males. PMID- 29611351 TI - Effects of sildenafil, metformin, and simvastatin on ADH-independent urine concentration in healthy volunteers. AB - Nephrogenic diabetes insipidus (NDI) is a rare disorder characterized by resistance of the kidney to the action of antidiuretic hormone (ADH), resulting in a decrease in the capacity of the kidney to concentrate the urine. NDI can be inherited or acquired due to, for example, chronic lithium therapy. Current treatment options are limited to attempts to lower urine output by a low-solute diet and the use of diuretics or anti-inflammatory drugs. These measures are only partially effective. Recent reports suggested that sildenafil, metformin, and simvastatin might improve ADH-independent urine concentration. If confirmed, this would provide interesting additional therapeutic options for patients with NDI. We, therefore, tested the effect of these drugs on ADH-independent urine concentrating capacity in healthy volunteers. We included 36 healthy volunteers who received sildenafil 20 mg thrice daily, metformin 500 mg thrice daily or simvastatin 40 mg once daily during 1 week. At baseline and at the end of treatment, a water loading test was performed. No significant increase in lowest urine osmolality was seen after the use of metformin or sildenafil (P = 0.66 and P = 0.09 respectively). Lowest urine osmolality increased modestly but significantly after the use of simvastatin (70 mOsm/kg to 85 mOsm/kg, P = 0.05). Our data suggest that only simvastatin has an effect on urine osmolality in healthy volunteers. Validation studies are needed and, most importantly, these drugs should be tested in patients with NDI. PMID- 29611352 TI - Impact of social complexity on outcomes in cystic fibrosis after transfer to adult care. AB - OBJECTIVE: This study evaluates the roles of medical and social complexity in health care use outcomes in cystic fibrosis (CF) after transfer from pediatric to adult care. METHODS: Retrospective cohort design included patients with CF who were transitioned into adult care at Indiana University from 2005 to 2015. Predictor variables included demographic and comorbidity data, age at transition, treatment complexity score (TCS), and an objective scoring measure of their social complexity (Bob's Level of Social Support, BLSS). Outcome variables included outpatient visit rates and hospitalization rates. Pearson's correlations and linear regression were used to analyze the data. RESULTS: The median age of the patients (N = 133) at the time of transition was 20 (IQR 19-23) years. The mean FEV1 % predicted at transition was 69 +/- 24%. TCS correlated with outpatient visit rates (r = 0.3, P = 0.003), as well as hospitalization rates (r = 0.4, P < 0.001); while the BLSS only correlated with hospitalization rates (r = 0.7, P < 0.001). After adjusting for covariates, the strongest predictors of post transfer hospitalizations are BLSS (P < 0.0001) and pre-transfer hospitalization rate (P < 0.0001). CONCLUSION: Greater treatment complexity is associated with greater healthcare utilization overall, while greater social complexity is associated with increased hospitalizations (but not outpatient visits). Screening young adults for social complexity may identify high-risk subpopulations and allow for patient centered interventions to support them and prevent avoidable health care use. PMID- 29611350 TI - Oxidative stress and antioxidant treatment in patients with peripheral artery disease. AB - Peripheral artery disease is an atherosclerotic disease of arterial vessels that mostly affects arteries of lower extremities. Effort induced cycles of ischemia and reperfusion lead to increased reactive oxygen species production by mitochondria. Therefore, the pathophysiology of peripheral artery disease is a consequence of metabolic myopathy, and oxidative stress is the putative major operating mechanism behind the structural and metabolic changes that occur in muscle. In this review, we discuss the evidence for oxidative damage in peripheral artery disease and discuss management strategies related to antioxidant supplementation. We also highlight the major pathways governing oxidative stress in the disease and discuss their implications in disease progression. Potential therapeutic targets and diagnostic methods related to these mechanisms are explored, with an emphasis on the Nrf2 pathway. PMID- 29611354 TI - Corrigendum. PMID- 29611353 TI - Intra-individual biological variation in sweat chloride concentrations in CF, CFTR dysfunction, and healthy pediatric subjects. AB - BACKGROUND: The sweat test is one of the main diagnostic tools used in newborn screening programs and as a confirmatory test, in case of suspect of Cystic Fibrosis (CF). Since sweat chloride (Cl) concentration is also considered an appropriate parameter to explore the efficacy of CFTR modulators in clinical trials, it is crucial to evaluate the biological variability of this test in healthy and pathological conditions. The aim of this pilot study was to determine the intra-individual biological variability of sweat Cl, both in healthy individuals and CF patients and to assess its correlation with diet, season, and menstrual cycle. METHODS: Thirty-five out of 36 selected subjects (6-18 years) were enrolled by 2 CF care centers and assigned to 3 cohorts: CF, CFTR-related disorder (CFTR-RD) and healthy volunteers. Each participant was subjected to eight sweat tests in different conditions and time of the year. Data were analyzed using linear mixed effects models for repeated measures, taking also into account intra-individual correlations. RESULTS: We observed a high intra individual variability of sweat Cl, with the lowest mean CV% values among CF patients (20.21 in CF, 29.74 in CFTR-RD, and 31.15 in healthy subjects). Gender and diet had no influence on sweat Cl variability, nor had pubertal age and menstrual phase. CONCLUSION: Results of this pilot study confirmed that sweat Cl variability is high in CF patients, although non-CF individuals displayed even higher mean CV% values. Season significantly influenced sweat test values only in CF patients, likely due to changes in their hydration status. PMID- 29611355 TI - Operating room culture affects patient outcomes, and we should operate accordingly. PMID- 29611356 TI - A retroperitoneal mass needs respect. PMID- 29611357 TI - Medicine in small doses. PMID- 29611358 TI - Timely commencement of bisphosphonates post-fragility fractures. PMID- 29611359 TI - Anal tone may predict recurrence after botulinum toxin for chronic anal fissure. PMID- 29611360 TI - The conundrum of quality in colonoscopy. PMID- 29611361 TI - Age is not a predictor of prognosis in metastatic cutaneous squamous cell carcinoma of the head and neck. AB - BACKGROUND: Metastatic cutaneous squamous cell carcinoma of the head and neck (cHNSCC) is more common in older patients. It is postulated that the age-related decline in immunity plays a role in cancer predisposition and prognosis. We aimed to investigate the effect of age on outcomes in cHNSCC and compare these with the outcomes of patients with cHNSCC and known immunosuppression. METHODS: Patients with metastatic cHNSCC treated with curative intent were identified from a prospectively collated database of head and neck cancers at the Sydney Head and Neck Cancer Institute. Patients with cHNSCC with known immunosuppression provided a comparison group for analysis of disease-specific outcomes. RESULTS: The study cohort includes 418 immunocompetent patients with metastatic cHNSCC (median age: 73 years (interquartile range: 65-81 years)) and the control cohort includes 24 patients with metastatic cHNSCC and immunosuppression (median age: 51 years (interquartile range: 42-62 years)). Increasing age was not associated with poorer disease-free or disease-specific survival. Patients in older age groups (70 years and over) had better disease-specific outcomes than patients with long term immunosuppression. Patterns of disease failure did not differ between different age groups. The number of positive nodes and extra-capsular spread were the only significant prognostic variables in multivariable analysis. CONCLUSION: In the context of metastatic cHNSCC, age should not be considered as a marker of poor prognosis. Age should not be considered a surrogate marker of immune function considering the poorer outcomes seen in patients with immunosuppression. Older patients with metastatic cHNSCC should be considered candidates for standard treatment if otherwise medically fit. PMID- 29611362 TI - Surgeons: cause for complaint. PMID- 29611363 TI - Re: Free-flap salvage: muscle only versus skin paddle - an Australian experience. PMID- 29611364 TI - When the benefits outweigh the risks: preventing colorectal cancer. PMID- 29611365 TI - Response to Re: Recurrent sigmoid volvulus in pregnancy. PMID- 29611366 TI - Novel use of Patent Blue V dye to facilitate repair of lymph leak after groin debridement. PMID- 29611367 TI - 25, 50 & 75 years ago. PMID- 29611368 TI - Multilayer Graphene-GeSn Quantum Well Heterostructure SWIR Light Source. AB - The problem of light source always prevents silicon-based photonics from achieving a final integration. Although some optical pump lasers have been reported in recent years, an electrical pumping laser is considered as the ultimate solution. To fabricate a Si-based laser, there are some crucial obstacles that need to be solved such as difficulties in material epitaxy, light absorption by metal electrodes, and compatibility with the existing complementary metal-oxide-semiconductor transistor process. Here, a multilayer graphene and GeSn/Ge quantum well (QW) heterostructure is designed and fabricated as a Si based light source. Specially designed Ge0.9 Sn0.1 /Ge QWs are used as active layer, which achieves a photoluminescence (PL) peak at 2050 nm. Graphene, which has a high transmittance for all bands of light, lessens the burden of growing thick cladding layer and perfectly breaks the deadlock of light disappearance in metal contacts. The electroluminescence (EL) spectrum of the device is achieved at a peak of 2100 nm under an injection current density of 100 A cm-2 . Both the PL and EL measurements show the heterostructure has good performance as a short wave infrared (SWIR) light source. Therefore, the results provides a good alternative for the light source in silicon-based photonics. PMID- 29611369 TI - The role of neutrophil-to-lymphocyte ratio in men with erectile dysfunction preliminary findings of a real-life cross-sectional study. AB - The aim of this study was to investigate the role of systemic inflammation by means of the neutrophil-to-lymphocyte ratio (NLR) in men with erectile dysfunction (ED). Complete demographic, clinical, and laboratory data from 279 consecutive men with newly diagnosed ED were analyzed. Health-significant comorbidities were scored with the Charlson Comorbidity Index (CCI). A complete blood count was requested for every man, and the NLR was calculated for every individual. Patients were invited to complete the IIEF questionnaire. Logistic regression models tested the odds (OR, 95% CI) of severe ED (defined as IIEF-EF <11, according to Cappelleri's criteria) after adjusting for age, BMI, comorbidities (CCI >0), metabolic syndrome, NLR, cigarette smoking, and color duplex Doppler ultrasound parameters. Likewise, LNR values were also dichotomized according to the most informative cutoff predicting severe ED using the minimum p value approach. Median [IQR] age of included men was 51 [40-64] years. Of all, 87 (31%) men had severe ED. Men with severe ED were older (median [IQR] age: 61 [47 67] vs. 49 [39-58] years) and had a higher rate of CCI>0 [46/87 (53%) vs. 44/192 (23%) patients]. Thereof, NLR was dichotomized according to the most informative cutoff (NLR>3); patients with severe ED more frequently had NLR>3 as compared to all other ED patients [namely, 18/87 (21%) vs. 13/192 (7%)]. At multivariable logistic regression analysis, NLR>3.0 emerged as an independent predictor (OR [CI] 2.43 [1.06; 5.63]) of severe ED, after accounting for other clinical variables. A NLR>3 increased the risk of having severe ED in our cohort, boosting the already existing evidence linking systemic inflammation to ED. Moreover, this easily obtainable index can be clinically useful in better risk-stratifying patients with ED. PMID- 29611371 TI - Visual Recovery after Macular Hole Surgery and Related Prognostic Factors. AB - PURPOSE: To describe the visual recovery and prognostic factors after macular hole surgery. METHODS: A retrospective chart review was conducted. Charts of patients with idiopathic macular holes who underwent surgery by a single surgeon at Severance Hospital between January 1, 2013 and July 31, 2015 were reviewed. The best-corrected visual acuity (BCVA) score was recorded preoperatively and at 1 day and 1, 3, 6, 9, and 12 months after surgery. The variables of age, sex, macular hole size, basal hole diameter, choroidal thickness, and axial length were also noted. RESULTS: Twenty-six eyes of 26 patients were evaluated. Twenty five patients (96.2%) showed successful macular hole closure after the primary operation. The BCVA stabilized 6 months postoperatively. A large basal hole diameter (p = 0.006) and thin choroid (p = 0.005) were related to poor visual outcomes. Poor preoperative BCVA (p < 0.001) and a thick choroid (p = 0.020) were associated with greater improvement in BCVA after surgery. CONCLUSIONS: Visual acuity stabilized by 6 months after macular hole surgery. Choroidal thickness was a protective factor for final BCVA and visual improvement after the operation. PMID- 29611370 TI - Influence of Sodium Hyaluronate Concentration on Corneal Aberrations in Soft Contact Lens Wearers. AB - PURPOSE: This study aimed to evaluate the influence of varying concentrations of sodium hyaluronate (SH) eye drops on corneal aberrations in normal individuals wearing silicone hydrogel contact lenses. METHODS: Normal individuals wearing silicone hydrogel contact lenses were enrolled in this study. Subjects were classified into two groups depending on the concentration of the preservative free SH used (group 1, 0.1% SH; group 2, 0.3% SH). All subjects were asked to blink five times after instillation of the SH eye drop and before the Galilei measurements. Corneal aberrations were measured over the contact lenses before and after SH eye drop instillation. Visual acuity (VA) over the contact lenses was also measured both before instillation of the SH eye drop and after the subjects completed the five blinks. RESULTS: There was no change in VA after SH instillation in group 1; however, group 2's VA significantly deteriorated after SH instillation. Changes in VA after SH instillation compared to baseline were significantly higher in group 2 than in group 1. Similarly, the increase in corneal aberrations after SH instillation was significant in group 2 but not significant in group 1. Among the significantly increased corneal aberration parameters, defocus was the main type in group 2. Changes in corneal aberrations after SH instillation compared to baseline were significantly higher in group 2 than in group 1. CONCLUSIONS: A 0.3%-concentration of SH increases corneal aberration and decreases VA in soft contact lens wearers. Defocus is the main type of aberration that increased in the 0.3% SH instillation group. PMID- 29611372 TI - Scleral Buckling under a Slit-lamp Illumination System with a Contact Wide-angle Viewing Lens Compared with an Indirect Ophthalmoscope. AB - PURPOSE: To investigate the outcomes of scleral buckling surgery performed under a slit-lamp illumination system (Visulux) with a contact wide-angle viewing lens (Mini Quad) in patients with rhegmatogenous retinal detachment (RRD) and to compare these outcomes with those of surgery performed under an indirect ophthalmoscope. METHODS: By retrospective review of electronic medical records, patients with RRD who had undergone scleral buckling surgery were identified. Scleral buckling surgeries were performed with two illumination instruments, a slit-lamp (SL group) and an indirect ophthalmoscope (IO group). Subretinal fluid drainage, cryopexy, and intravitreal gas injection were performed optionally. At 6 months after surgery, anatomical and functional outcomes were evaluated and compared between the two groups. Operation time was also compared between the two groups. RESULTS: Of the 45 total patients (45 eyes), 28 were included in the SL group, and 17 were included in the IO group. In the SL and IO groups, the primary anatomical success rate was 89.3% and 88.2%, respectively (p = 0.92). The logarithm of the minimal angle of resolution change, which reflects improvement in best-corrected visual acuity after surgery, was -0.19 +/- 0.38 in the SL group and -0.21 +/- 0.63 in the IO group; this difference was not statistically significant (p = 0.91). The mean operation time was significantly shorter in the SL group (78.9 +/- 11.8 minutes) than in the IO group (100.0 +/- 13.9 minutes, p < 0.001), especially for patients who underwent additional procedures such as subretinal fluid drainage and cryopexy (81.4 +/- 12.9 and 103.5 +/- 12.3 minutes, respectively, p < 0.001). CONCLUSIONS: Scleral buckling surgery performed under a slit-lamp illumination system yielded a similar anatomical success rate and similar functional improvement in RRD compared with surgery performed under an indirect ophthalmoscope. The slit-lamp system could save time, especially in bullous RRD, which requires additional subretinal fluid drainage. PMID- 29611373 TI - Lamina Cribrosa Changes after Laser In Situ Keratomileusis in Myopic Eyes. AB - PURPOSE: To determine deep optic nerve head structure changes after transient intraocular pressure elevation during laser in situ keratomileusis (LASIK) for myopia. METHODS: Enhanced depth imaging-optical coherence tomography was performed in each myopic eye that underwent LASIK surgery. Enhanced depth imaging optical coherence tomography images were created at postoperative 1 day, 1 week, 2 weeks, and 1 month. Lamina cribrosa (LC) thickness, LC depth and prelaminar thickness at the superior, middle and inferior portions of the optic nerve head were measured by two investigators. RESULTS: Forty eyes in 40 patients were included in the present study. During follow-up, there were no significant differences in prelaminar thickness or LC depth. The LC demonstrated increased thickness at postoperative 1 day at all three locations (superior, middle, and inferior) (p < 0.001, p < 0.001, p < 0.001, respectively). However, no significant changes were observed at postoperative 1 week, 2 weeks, and 1 month. CONCLUSIONS: The LC thickness could increase at 1 day after LASIK surgery. However, the thickness will gradually return to baseline morphology. Temporary intraocular pressure increase during LASIK does not appear to induce irreversible LC thickness changes. PMID- 29611374 TI - Recurrent Endophthalmitis Caused by Achromobacter xylosoxidans: Importance of Aggressive Surgical Removal of Capsular Bag. PMID- 29611375 TI - Congenital Bilateral Inferior Rectus Muscle Absence with A-type Exotropia. PMID- 29611376 TI - Orbital Cellulitis from an Orbital Compressed Air and Diesel Explosion Injury. PMID- 29611377 TI - Mac-2 Binding Protein Glycosylation Isomer: Emerging Non-Invasive Serum Marker for Liver Fibrosis. PMID- 29611378 TI - Principles of Genetic Counseling in the Era of Next-Generation Sequencing. AB - Traditional genetic counseling has focused on the target gene and its natural progress with respect to disease risk. Next-generation sequencing (NGS) can produce information on several genetic variants simultaneously, with different functions and consequences for each. Accordingly, determining the status of the patient or consultant and interpreting sequencing results from many genes can largely increase the complexity of genetic counseling. Moreover, the current environment of big data that can be readily shared via the internet and a ubiquitous network provides many different avenues for which a consultant must handle the traditional principle of genetic counseling in different ways. Thus, further consideration and rethinking of genetic counseling principles are necessary in the era of NGS. In this review, we discuss several aspects of genetic counseling that one can encounter when faced with NGS data. PMID- 29611379 TI - GATA1 Expression in BCR/ABL1-negative Myeloproliferative Neoplasms. AB - BACKGROUND: This study aimed to determine GATA1 expression levels to better characterize subgroups in BCR/ABL1-negative myeloproliferative neoplasms (MPNs). METHODS: This study enrolled 49 patients diagnosed as having BCR/ABL1-negative MPN on the basis of the 2016 World Health Organization classification : nine polycythemia vera (PV), 17 essential thrombocythemia (ET), 12 prefibrotic primary myelofibrosis (prePMF), and 11 overt primary myelofibrosis (PMF). Relevant clinical and laboratory data were retrieved from the medical records. The molecular analysis of CALR and MPL mutations and quantification of JAK2 V617F allele burden were performed. GATA1 expression was assessed by an immunohistochemical assay on bone marrow biopsy. GATA1 expression was analyzed serially in 18 patients. RESULTS: GATA1 expression decreased significantly in PMF compared with that in other subtypes, while no statistical difference was identified between ET and prePMF. GATA1 expression did not differ according to the mutation profiles or the allele burden of JAK2 V617F, but it decreased significantly in patients with overt fibrosis or leukemic transformation. CONCLUSIONS: Our results suggest that GATA1 expression is significantly low in PMF and decreases with progressive fibrosis and possibly with leukemic transformation, although our attempt to accurately distinguish between subgroups using GATA1 immunohistochemical approach did not achieve statistical significance. A large patient cohort with long term follow-up is required to evaluate the prognostic value of GATA1 expression. PMID- 29611380 TI - Galectin-3 Reflects the Echocardiographic Grades of Left Ventricular Diastolic Dysfunction. AB - BACKGROUND: The level of Galectin-3 (Gal-3) protein purportedly reflects an ongoing cardiac fibrotic process and has been associated with ventricular remodeling, which is instrumental in the development of heart failure with preserved ejection fraction (HFpEF) syndrome. The aim of this study was to investigate the potential use of Gal-3 in improved characterization of the grades of diastolic dysfunction as defined by echocardiography. METHODS: Seventy HFpEF patients undergoing routine echocardiography were prospectively enrolled in the present monocentric study. Blood samples for measurements of Gal-3 and amino terminal pro-brain natriuretic peptide (NT-proBNP) were collected within 24 hours pre- or post-echocardiographic examination. The classification of patients into subgroups based on diastolic dysfunction grade permitted detailed statistical analyses of the derived data. RESULTS: The Gal-3 serum levels of all patients corresponded to echocardiographic indices, suggesting HFpEF (E/A, P=0.03 and E/E', P=0.02). Gal-3 was also associated with progressive diastolic dysfunction, and increased levels corresponded to the course of disease (P=0.012). Detailed analyses of ROC curves suggested that Gal-3 levels could discriminate patients with grade III diastolic dysfunction (area under the curve [AUC]=0.770, P=0.005). CONCLUSIONS: Gal-3 demonstrates remarkable effectiveness in the diagnosis of patients suffering from severe grade diastolic dysfunction. Increasing levels of Gal-3 possibly reflect the progressive course of HFpEF, as classified by the echocardiographic grades of diastolic dysfunction. PMID- 29611381 TI - Determining Genotypic Drug Resistance by Ion Semiconductor Sequencing With the Ion AmpliSeqTM TB Panel in Multidrug-Resistant Mycobacterium tuberculosis Isolates. AB - BACKGROUND: We examined the feasibility of a full-length gene analysis for the drug resistance-related genes inhA, katG, rpoB, pncA, rpsL, embB, eis, and gyrA using ion semiconductor next-generation sequencing (NGS) and compared the results with those obtained from conventional phenotypic drug susceptibility testing (DST) in multidrug-resistant Mycobacterium tuberculosis (MDR-TB) isolates. METHODS: We extracted genomic DNA from 30 pure MDR-TB isolates with antibiotic susceptibility profiles confirmed by phenotypic DST for isoniazid (INH), rifampin (RIF), ethambutol (EMB), pyrazinamide (PZA), amikacin (AMK), kanamycin (KM), streptomycin (SM), and fluoroquinolones (FQs) including ofloxacin, moxifloxacin, and levofloxacin. Enriched ion spheres were loaded onto Ion PI Chip v3, with 30 samples on a chip per sequencing run, and Ion Torrent sequencing was conducted using the Ion AmpliSeq TB panel (Life Technologies, USA). RESULTS: The genotypic DST results revealed good agreement with the phenotypic DST results for EMB (Kappa 0.8), PZA (0.734), SM (0.769), and FQ (0.783). Agreements for INH, RIF, and AMK+KM were not estimated because all isolates were phenotypically resistant to INH and RIF, and all isolates were phenotypically and genotypically susceptible to AMK+KM. Moreover, 17 novel variants were identified: six (p.Gly169Ser, p.Ala256Thr, p.Ser383Pro, p.Gln439Arg, p.Tyr597Cys, p.Thr625Ala) in katG, one (p.Tyr113Phe) in inhA, five (p.Val170Phe, p.Thr400Ala, p.Met434Val, p.Glu812Gly, p.Phe971Leu) in rpoB, two (p.Tyr319Asp and p.His1002Arg) in embB, and three (p.Cys14Gly, p.Asp63Ala, p.Gly162Ser) in pncA. CONCLUSIONS: Ion semiconductor NGS could detect reported and novel amino acid changes in full coding regions of eight drug resistance-related genes. However, genotypic DST should be complemented and validated by phenotypic DSTs. PMID- 29611382 TI - Recent Increase in the Incidence of TEM-135 beta-Lactamase-harboring Neisseria gonorrhoeae in Korea. AB - BACKGROUND: We investigated the molecular epidemiological characteristics and antimicrobial susceptibility pattern of penicillinase-producing Neisseria gonorrhoeae (PPNG) isolates to monitor the change in distribution of bla(TEM) in Korea. METHODS: We collected 804 PPNG isolates from diverse hospitals and clinics mainly located in Seoul, Korea, over a period of 11 years (2005-2015). Isolate susceptibility to seven antimicrobials was determined using the agar dilution test. The molecular epidemiological characteristics of the isolates were determined by Sanger sequencing of bla(TEM), N. gonorrhoeae multiantigen sequence typing (NG-MAST) and plasmid typing. RESULTS: Among 72 fully sequenced PPNG isolates, sixteen (22.2%) possessed TEM-135. All TEM-135 isolates had a common silent mutation (c.18C>T), which was previously unreported. We observed a pattern of continuous increase in the number of TEM-135 isolates since 2012. The median and 90% minimum inhibitory concentration of azithromycin were substantially lower in the TEM-135 group than in the non-PPNG and TEM-1 groups. All TEM-135 isolates showed different NG-MAST types and predominantly harbored Toronto/Rio (75%) plasmids. A comprehensive comparative analysis of PPNG with TEM-135 according to NG-MAST, plasmid type, and year of isolation revealed a wide distribution. CONCLUSIONS: The proportion of TEM-135 PPNG has continuously increased since 2012, in association with clonal spread. The difference at position 18 of the TEM 135 sequence can be interpreted as the existence of multiple clonal complexes. The possibility that TEM-135 was acquired via foreign plasmids requires careful follow-up and continuous monitoring of TEM-135 to ascertain whether it constitutes a step towards evolutionary change. PMID- 29611383 TI - Usefulness of Enhanced Liver Fibrosis, Glycosylation Isomer of Mac-2 Binding Protein, Galectin-3, and Soluble Suppression of Tumorigenicity 2 for Assessing Liver Fibrosis in Chronic Liver Diseases. AB - BACKGROUND: Liver biopsies have been partially replaced by noninvasive methods for assessing liver fibrosis. We explored the usefulness of four novel biomarkers, enhanced liver fibrosis (ELF), glycosylation isomer of Mac-2 binding protein (M2BPGi), galectin-3, and soluble suppression of tumorigenicity 2 (sST2), in association with liver fibrosis. METHODS: ELF, M2BPGi, galectin-3, and sST2 were assayed in 173 patients with chronic liver diseases. The results were analyzed according to fibrosis grade (F0/1, F2, and F3/4) by transient elastography (TE). RESULTS: ELF, M2BPGi, galectin-3, and sST2 values differed significantly according to TE grade; ELF and M2BPGi values were higher in F2 and F3/4 than in F0/1 (P<=0.001, all), sST2 values were higher in F3/4 than in F0/1 and F2 (P<0.05), and galectin-3 values were higher in F3/4 than in F0/1 (P=0.0036). ELF and M2BPGi showed good TE fibrosis detection performance (area under the curves [AUC], 0.841 and 0.833 for >=F2; and 0.837 and 0.808 for >=F3). The sensitivity and specificity for predicting TE grade F>=2 were 84.1% and 76.7% for ELF and 63.6% and 91.5% for M2BPGi. CONCLUSIONS: This is the first study to compare the liver fibrosis assessment of four novel biomarkers: ELF, M2BPGi, galectin-3, and sST2. The biomarkers varied significantly according to TE grade, and each biomarker showed a different trend. ELF and M2BPGi seem to have comparable good performance for detecting liver fibrosis. PMID- 29611384 TI - Allergen Microarrays for In Vitro Diagnostics of Allergies: Comparison with ImmunoCAP and AdvanSure. AB - BACKGROUND: In vitro detection of the allergen-specific IgE antibody (sIgE) is a useful tool for the diagnosis and treatment of allergies. Although multiple simultaneous allergen tests offer simple and low-cost screening methods, these platforms also have limitations with respect to multiplexibility and analytical performance. As an alternative assay platform, we developed and validated a microarray using allergen extracts that we termed "GOLD" chip. METHODS: Serum samples of 150 allergic rhinitis patients were used in the study, and the diagnostic performance of the microarray was compared with that of AdvanSure (LG Life Sciences, Daejun, Korea) and ImmunoCAP (Phadia, Uppsala, Sweden). Standard IgE samples were used for the quantitative measurement of sIgEs. RESULTS: The microarray-based assay showed excellent performance in the quantitative measurement of sIgEs, demonstrating a linear correlation within the range of sIgE concentrations tested. The limit of detection (LOD) was lower than 0.35 IU/mL, which is the current standard for the LOD cut-off. The assay also provided highly reproducible sets of data. The total agreement percentage of positive and negative calls was 92.2% compared with ImmunoCAP. Moreover, an outstanding correlation was observed between the microarray and the ImmunoCAP results, with Cohen's kappa and Pearson correlation coefficient values of 0.80 and 0.79, respectively. CONCLUSIONS: The microarray-based in vitro diagnostic platform offers a sensitive, reproducible, and highly quantitative method to detect sIgEs. The results showed strong correlations with that of ImmunoCAP. These results suggest that the new allergen microarray can serve as a useful alternative to current screening platforms, ultimately becoming a first-line screening method. PMID- 29611385 TI - Diagnosis of Liver Fibrosis With Wisteria floribunda Agglutinin-Positive Mac-2 Binding Protein (WFA-M2BP) Among Chronic Hepatitis B Patients. AB - BACKGROUND: Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA M2BP) is a protein with altered glycosylation that reacts with lectin, and was recently identified as a useful non-invasive biomarker for the diagnosis of liver fibrosis in patients with hepatitis C virus infection.This study aimed to evaluate the diagnostic efficacy of WFA-M2BP for liver fibrosis in the context of hepatitis B virus (HBV). METHODS: We enrolled 151 patients infected with HBV. Liver biopsy and elastography (Fibroscan) were performed during the initial visit. Fibrosis was graded according to the Knodell histologic activity index (F0 3). WFA-M2BP levels were determined with an automated immunoassay analyzer (M2BPGi, HISCL-5000, Sysmex, Japan). The diagnostic efficacy of WFA-M2BP was compared with those of various conventional or composite biomarkers, including enhanced liver fibrosis (ELF) score, Fibroscan, aspartate transaminase (AST)-to platelet ratio index (APRI), and FIB-4, based on the area under the ROC curve (AUC) value. RESULTS: The majority of patients were at fibrosis stages F1 and F2. The F2 and F3 AUC values for WFA-M2BP were similar to those for FIB-4, APRI, ELF, and Fibroscan, although the latter showed the best diagnostic efficacy. The diagnostic accuracy of all tested biomarkers for F2 and F3 was 60-70%. In multivariate analysis, WFA-M2BP, ELF, and platelet count significantly predicted stage >=F2, whereas only platelet count significantly predicted F3. CONCLUSIONS: WFA-M2BP can support a diagnosis of liver fibrosis with similar diagnostic efficacy to other biomarkers, and predicted liver fibrosis stage >=2 among patients with chronic hepatitis B. PMID- 29611386 TI - Comparison of Four Automated Carcinoembryonic Antigen Immunoassays: ADVIA Centaur XP, ARCHITECT I2000sr, Elecsys E170, and Unicel Dxi800. AB - BACKGROUND: Carcinoembryonic antigen (CEA) is one of the tumor markers available for evaluating disease progression status after initial therapy and monitoring subsequent treatment modalities in colorectal, gastrointestinal, lung, and breast carcinoma. We evaluated the correlations and differences between widely used, automated CEA immunoassays at four different medical laboratories. METHODS: In total, 393 serum samples with CEA ranging from 3.0 to 1,000 ng/mL were analyzed on ADVIA Centaur XP (Siemens Diagnostics, Tarrytown, NY, USA), ARCHITECT i2000sr (Abbott Diagnostics, Abbott Park, IL, USA), Elecsys E170 (Roche Diagnostics, Indianapolis, IN, USA), and Unicel DxI800 (Beckman Coulter, Fullerton, CA, USA), and the results were compared. Deming regression, Passing-Bablok regression, and Bland-Altman analyses were performed to evaluate the data correlation and % differences among these assays. RESULTS: Deming regression analysis of data from Elecsys E170 and UniCel DxI800 showed good correlation (y=3.1615+0.8970x). According to Bland-Altman plot, no statistically significant bias (-1.78 ng/mL [95% confidence interval: -4.02 to 0.46]) was observed between Elecsys E170 and UniCel DxI800. However, the relative differences of CEA concentrations between assays exceeded the acceptable limit of 30%. Regarding the agreement of positivity with cut-off value 5.0 ng/mL, ARCHITECT i2000sr and Elecsys E170 showed the highest agreement (95.2%), whereas ADVIA Centaur XP and ARCHITECT i2000sr showed the lowest agreement (70.7%). CONCLUSIONS: Agreements between automated CEA immunoassays are variable, and individual CEA concentrations may differ significantly between assays. Standardization of serum CEA concentrations and further harmonization are needed. PMID- 29611387 TI - Flow-Cytometric Analysis of HNA-2 Expression and Phenotypes Among Thai Blood Donors. AB - BACKGROUND: Antibodies specific to human neutrophil antigen (HNA), especially HNA 2, are implicated in various conditions, including neonatal alloimmune neutropenia, febrile non-hemolytic transfusion reactions, and transfusion-related acute lung injury. The distribution of the HNA-2 phenotype frequencies in the Thai population remains unknown. This study aimed to investigate HNA-2 phenotype frequencies in Thai blood donors and to compare the relationships of sex and age with HNA-2 expression. METHODS: EDTA blood samples were collected from 220 unrelated healthy Thai blood donors, including 150 males and 70 females, with ages ranging from 20 to 57 years. Polymorphonuclear cells were isolated and stained with monoclonal antibodies clone MEM-166 and clone 2D1, which are specific to human CD177 (HNA-2) and CD45, respectively. HNA-2 expression according to sex and age was analyzed by flow cytometry. RESULTS: Among the 220 donors, HNA-2-positive and HNA-2-null-phenotype frequencies were 0.995 and 0.005, respectively. Mean antigen expression was significantly higher in women (71.01+/ 15.46%) than in men (64.59+/-18.85%; P <0.05). No significant differences in HNA 2 expression were found between different age groups. HNA-2 phenotype frequencies were similar to those in Asian, African, American, and Brazilian populations, but were significantly different from those in eastern Japanese, Korean, and French populations (P <0.001). CONCLUSIONS: This is the first report of HNA-2 phenotype frequencies in a Thai population, and the data will be helpful in predicting the risk of HNA-2 alloimmunization and in recruiting granulocyte panel donors. PMID- 29611388 TI - Phenotypic and Genomic Characterization of AmpC-Producing Klebsiella pneumoniae From Korea. AB - The prevalence of multidrug-resistant gram-negative bacteria has continuously increased over the past few years; bacterial strains producing AmpC beta lactamases and/or extended-spectrum beta-lactamases (ESBLs) are of particular concern. We combined high-resolution whole genome sequencing and phenotypic data to elucidate the mechanisms of resistance to cephamycin and beta-lactamase in Korean Klebsiella pneumoniae strains, in which no AmpC-encoding genes were detected by PCR. We identified several genes that alone or in combination can potentially explain the resistance phenotype. We showed that different mechanisms could explain the resistance phenotype, emphasizing the limitations of the PCR and the importance of distinguishing closely-related gene variants. PMID- 29611389 TI - Effects of Cold Agglutinin on the Accuracy of Complete Blood Count Results and Optimal Sample Pretreatment Protocols for Eliminating Such Effects. PMID- 29611390 TI - Necessity of Reticulocyte Calibration for More Accurate and Precise Results. PMID- 29611391 TI - Rapid Identification of bla(IMP-1) and bla(IMP-6) by Multiplex Amplification Refractory Mutation System PCR. PMID- 29611392 TI - Multiple Intraabdominal Abscesses Caused by Mycoplasma hominis Infection Following Simultaneous Pancreas-Kidney Transplantation. PMID- 29611393 TI - Prevalence of Plasmid-Mediated Quinolone Resistance Genes Among Escherichia coli in the Gut of Healthy People in Fuzhou, China. PMID- 29611394 TI - Extended Red Blood Cell Genotyping to Investigate Immunohematology Problems. PMID- 29611395 TI - Mutation Analysis of X-linked Sideroblastic Anemia in a 12-Month-Old Boy by Massively Parallel Sequencing. PMID- 29611396 TI - An Emerging Role for Circular RNAs in Osteoarthritis. AB - Circular RNAs (circRNAs) are currently classed as non-coding RNAs that, unlike the better known canonical linear RNAs, form a covalently closed continuous loop without 5' or 3' polarities. With the development of high throughput sequencing technology, a large number of circRNAs have been discovered in many species. More importantly, growing evidence suggests that circRNAs are abundant, evolutionally conserved, and relatively stable in cells and tissues. Strikingly, recent studies have discovered that circRNAs can serve as microRNA sponges, interact with RNA binding protein, and regulate gene transcription, as well as protein translation. Osteoarthritis (OA) is the most common chronic degenerative joint disease. CircRNAs are differentially expressed in OA cartilage. Moreover, some circRNAs are involved in multiple pathological processes during OA, mainly extracellular matrix degradation, inflammation, and apoptosis. In this review, we briefly delineate the biogenesis, characteristics, and biofunctions of circRNAs, and then, focus on the role of circRNAs in the occurrence and progression OA. PMID- 29611397 TI - Trends in Blood Pressure and Prevalence of Hypertension in Korean Adults Based on the 1998-2014 KNHANES. AB - PURPOSE: To investigate trends in blood pressure (BP) and hypertension prevalence in Korea. MATERIALS AND METHODS: Based on the Korean National Health and Nutrition Examination Survey (KNHANES) I (1998), II (2001), III (2005), IV (2007 2009), V (2010-2012), and VI (2013-2014), 56077 participants (23974 men and 32103 women) were included. RESULTS: Mean systolic BP (SBP) and diastolic BP (DBP) decreased in both sexes (male SBP: 128.1 to 120.2 mm Hg, male DBP: 82.0 to 78.5 mm Hg; female SBP: 125.7 to 116.0 mm Hg and female DBP: 77.4 to 73.2 mm Hg from the KNHANES I-VI). The age-standardized prevalence of hypertension was significantly decreased in both sexes (male; 33.3% to 30.3%, female; 28.7% to 22.7%, all p for trend <0.001). Regardless of taking anti-hypertensive medication or not, SBP and DBP declined universally in both sexes. Compared to the KNHANES I, the odds ratios (95% confidence intervals) of the KNHANES II to VI for less than-normotensive and less-than-hypertensive BP increased in both sexes. CONCLUSION: Mean BP levels in both sexes and hypertension prevalence showed downward trends during the 16-year period. PMID- 29611398 TI - Arginase Inhibition Suppresses Native Low-Density Lipoprotein-Stimulated Vascular Smooth Muscle Cell Proliferation by NADPH Oxidase Inactivation. AB - PURPOSE: Vascular smooth muscle cell (VSMC) proliferation induced by native low density lipoprotein (nLDL) stimulation is dependent on superoxide production from activated NADPH oxidase. The present study aimed to investigate whether the novel arginase inhibitor limonin could suppress nLDL-induced VSMC proliferation and to examine related mechanisms. MATERIALS AND METHODS: Isolated VSMCs from rat aortas were treated with nLDL, and cell proliferation was measured by WST-1 and BrdU assays. NADPH oxidase activation was evaluated by lucigenin-induced chemiluminescence, and phosphorylation of protein kinase C (PKC) betaII and extracellular signal-regulated kinase (ERK) 1/2 was determined by western blot analysis. Mitochondrial reactive oxygen species (ROS) generation was assessed using MitoSOX-red, and intracellular L-arginine concentrations were determined by high-performance liquid chromatography (HPLC) in the presence or absence of limonin. RESULTS: Limonin inhibited arginase I and II activity in the uncompetitive mode, and prevented nLDL-induced VSMC proliferation in a p21Waf1/Cip1-dependent manner without affecting arginase protein levels. Limonin blocked PKCbetaII phosphorylation, but not ERK1/2 phosphorylation, and translocation of p47phox to the membrane was decreased, as was superoxide production in nLDL-stimulated VSMCs. Moreover, mitochondrial ROS generation was increased by nLDL stimulation and blocked by preincubation with limonin. Mitochondrial ROS production was responsible for the phosphorylation of PKCbetaII. HPLC analysis showed that arginase inhibition with limonin increases intracellular L-arginine concentrations, but decreases polyamine concentrations. L-Arginine treatment prevented PKCbetaII phosphorylation without affecting ERK1/2 phosphorylation. CONCLUSION: Increased L-arginine levels following limonin dependent arginase inhibition prohibited NADPH oxidase activation in a PKCbetaII dependent manner, and blocked nLDL-stimulated VSMC proliferation. PMID- 29611399 TI - Effect of Central Line Bundle Compliance on Central Line-Associated Bloodstream Infections. AB - PURPOSE: The present study aimed to evaluate the effect of central line (CL) bundle compliance on central line-associated bloodstream infections (CLABSIs) in different departments of the same hospital, including the intensive care unit (ICU) and other departments. MATERIALS AND METHODS: The four components of the CL bundle were hand hygiene, use of maximal sterile barrier precautions, chlorhexidine use, and selection of an appropriate site for venous access. Compliance of the CL bundle and CLABSIs were measured for every department [emergency room (ER), ICU, general ward (GW), and operating room (OR)]. A total of 1672 patients were included over 3 years (August 2013 through July 2016). RESULTS: A total of 29 CLABSI episodes (1.73%) were identified, and only 53.7% of the patients completed CL bundles. The performance rates of all components of the CL bundle were 22.3%, 28.5%, 36.5%, and 84.6% for the ER, ICU, GW, and OR, respectively. The highest CLABSI rate was observed in patients of the ICU, for whom all components were not performed perfectly. Conversely, the lowest CLABSI rate was observed for patients of GWs, for whom all components were performed. Among individual components, femoral insertion site [relative risk (RR), 2.26; 95% confidence interval (CI), 1.09-4.68], not using a full body drape (RR, 3.55; 95% CI, 1.44-8.71), and not performing all CL bundle components (RR, 2.79; 95% CI, 1.19-6.54) were significant variables associated with CLABSIs. CONCLUSION: This study provides direct evidence that completing all CL bundle components perfectly is essential for preventing CLABSIs. Customized education should be provided, according to specific weaknesses of bundle performance. PMID- 29611400 TI - Real World Experience of Telbivudine Versus Entecavir in Patients with Chronic Hepatitis B, Including Long-Term Outcomes after Treatment Modification. AB - PURPOSE: To estimate long-term outcomes after treatment modification in patients with chronic hepatitis B (CHB) treated with entecavir (ETV) and telbivudine (LdT). MATERIALS AND METHODS: The study enrolled 131 nucleos(t)ide analogue (NA) naive CHB patients treated with ETV or LdT. During the 3-year study, NA treatment history including the incidence, the type of treatment modification, reasons for the modification, and overall complete virologic response (CVR) rate were retrospectively evaluated using the patients' medical records. RESULTS: Among the 131 patients, 84 and 47 were initially treated with ETV and LdT, respectively. During the course of 3-year study, 82 patients in the ETV group (97.6%) maintained initial treatment whereas only 19 in the LdT group (40.4%). In the LdT group, 26 patients (92.9%) switched to another NA and another NA was added in 2 (7.1%) patients. An assessment of the CVR rate at 3 years, including treatment modification, showed that 89.3% and 95.7% of patients in the ETV and LdT groups, respectively, had undetectable serum hepatitis B virus DNA levels (p=0.329). Among LdT patients with treatment modification, the cumulative incidence rate of a CVR for rescue therapy was significantly higher in the tenofovir than in the ETV group (p=0.009). CONCLUSION: During the 3-year study, there were no significant differences in the CVR between the ETV and LdT groups if appropriate rescue therapy was considered. PMID- 29611401 TI - Low-Dose Unenhanced Computed Tomography with Iterative Reconstruction for Diagnosis of Ureter Stones. AB - PURPOSE: To study the clinical application of low-dose unenhanced computed tomography with iterative reconstruction technique (LDCT-IR) on renal colic in the emergency department. MATERIALS AND METHODS: We conducted a prospective, single-blinded, randomized, and non-inferiority study. From March 2014 to August 2015, 112 patients with renal colic were included, and were randomized to either LDCT-IR (n=46) or standard-dose unenhanced CT (SDCT) (n=66) groups. The accuracy of urolithiasis diagnosis was the primary endpoint of this study. Radiation dose, size and location of the stone, hydronephrosis, other diseases except urolithiasis, and results of treatment were analyzed between the two groups. RESULTS: The average effective dose radiation of SDCT was approximately four times higher than that of LDCT-IR (6.52 mSv vs. 1.63 mSv, p<0.001). There was no significant difference in the accuracy of ureteral stone diagnosis between the two groups (LDCT-IR group: 96.97% vs. SDCT group: 98.96%, p=0.392). No significant difference was observed regarding the size and location of a stone, hydronephrosis, and diagnosis of other diseases, except urolithiasis. False negative results were found in two LDCT-IR patients and in one SDCT patient. In these patients, stones were misread as vascular calcification, and were difficult to diagnose because evidence of hydronephrosis and ureteral dilatation was not found. CONCLUSION: LDCT-IR, as a first-line imaging test, was non-inferior to SDCT with respect to diagnosis of ureter stones, and was clinically available for the evaluation of renal colic. PMID- 29611402 TI - Delta Neutrophil Index Is Associated with Vasculitis Activity and Risk of Relapse in ANCA-Associated Vasculitis. AB - PURPOSE: Delta neutrophil index (DNI) represents the immature granulocytes count associated with neutrophil-consumption. We investigated whether DNI might be associated with Birmingham vasculitis activity score (BVAS) at diagnosis and could predict relapse during the follow-up in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). MATERIALS AND METHODS: We reviewed the medical records of 97 patients having DNI results. Twenty patients had granulomatosis with polyangiitis (GPA), 58 had microscopic polyangiitis (MPA), and 19 had eosinophilic GPA (EGPA). We collected clinical and laboratory data including BVAS, five factor score (FFS), and DNI. The correlation coefficient and cumulative relapse free survival rate were obtained. The optimal cut-off of DNI was extrapolated by calculating the area under the receiver operator characteristic curve. RESULTS: DNI was significantly related to cross sectional BVAS. Furthermore, among continuous variables, only DNI could reflect BVAS of GPA and MPA, but not EGPA. Severe AAV was defined as BVAS >=20 (the highest quartile). At diagnosis, patients having DNI >=0.65% had a significantly higher risk of severe GPA and MPA than those having not (relative risk 4.255) at diagnosis. During the follow-up, DNI >=0.65% could predict the higher relapse rate. CONCLUSION: DNI could reflect BVAS at diagnosis and furthermore, DNI >=0.65% could not only identify severe AAV at diagnosis, but also predict relapse during the follow-up in patients with GPA and MPA. PMID- 29611404 TI - MiR-212 Attenuates MPP+-Induced Neuronal Damage by Targeting KLF4 in SH-SY5Y Cells. AB - PURPOSE: Parkinson's disease (PD) is a common age-dependent neurodegenerative disease. MiR-212 has been demonstrated to exert protective effects in several neurological disorders. The present study aimed to investigate the role and underlying molecular mechanism of miR-212 in PD. MATERIALS AND METHODS: 1-methyl 4-phenylpyridinium (MPP+)-induced SH-SY5Y cells were applied as a PD model in vitro. RT-qPCR was used to measure the expression of miR-212 and Kruppel-like factor 4 (KLF4) mRNA. Western blot analysis was performed to detect the protein levels of KLF4, Notch1 and Jagged1. Cell viability and apoptosis were determined by the Cell Counting Kit-8 and flow cytometry, respectively. Quantitative analysis of caspase-3 activity, lactate dehydrogenase (LDH), reactive oxygen species (ROS), superoxide dismutase (SOD), tumor necrosis factor-alpha (TNF alpha), and interleukin-1 beta (IL-1beta) was conducted with corresponding ELISA kits. Dual-luciferase reporter assay was employed to evaluate the relationship between miR-212 and KLF4. RESULTS: MiR-212 was downregulated in MPP+-induced SH SY5Y cells. Also, miR-212 alleviated MPP+-induced SH-SY5Y cell damage, embodied by increased cell viability, decreased caspase-3 activity, LDH release, ROS production, TNF-alpha, and IL-1beta expression, as well as elevated SOD levels. KLF4 was a direct target of miR-212, and miR-212 repressed KLF4 expression in a post-transcriptional manner. Moreover, miR-212-mediated protection effects were abated following KLF4 expression restoration in MPP+-induced SH-SY5Y cells, represented as lowered cell viability and enhanced apoptotic rate. Furthermore, Notch signaling was involved in the regulation of miR-212/KLF4 axis in MPP+ induced SH-SY5Y cells. CONCLUSION: miR-212 might attenuate MPP+-induced neuronal damage by regulating KLF4/Notch signaling pathway in SH-SY5Y cells, a promising target for PD therapy. PMID- 29611403 TI - Effect of Placenta-Derived Mesenchymal Stem Cells in a Dementia Rat Model via Microglial Mediation: a Comparison between Stem Cell Transplant Methods. AB - PURPOSE: Loss of cholinergic neurons in the hippocampus is a hallmark of many dementias. Administration of stem cells as a therapeutic intervention for patients is under active investigation, but the optimal stem cell type and transplantation modality has not yet been established. In this study, we studied the therapeutic effects of human placenta-derived mesenchymal stem cells (pMSCs) in dementia rat model using either intracerebroventricular (ICV) or intravenous (IV) injections and analyzed their mechanisms of therapeutic action. MATERIALS AND METHODS: Dementia modeling was established by intraventricular injection of 192 IgG-saporin, which causes lesion of cholinergic neurons. Sixty-five male Sprague-Dawley rats were divided into five groups: control, lesion, lesion+ICV injection of pMSCs, lesion+IV injection of pMSCs, and lesion+donepezil. Rats were subjected to the Morris water maze and subsequent immunostaining analyses. RESULTS: Both ICV and IV pMSC administrations allowed significant cognitive recovery compared to the lesioned rats. Acetylcholinesterase activity was significantly rescued in the hippocampus of rats injected with pMSCs post-lesion. Choline acetyltransferase did not co-localize with pMSCs, showing that pMSCs did not directly differentiate into cholinergic cells. Number of microglial cells increased in lesioned rats and significantly decreased back to normal levels with pMSC injection. CONCLUSION: Our results suggest that ICV and IV injections of pMSCs facilitate the recovery of cholinergic neuronal populations and cognitive behavior. This recovery likely occurs through paracrine effects that resemble microglia function rather than direct differentiation of injected pMSCs into cholinergic neurons. PMID- 29611405 TI - Vocalization of Emotional and Social Expressions in Korean-Speaking Toddlers with Autism Spectrum Disorder and Those with Developmental Delay. AB - PURPOSE: This study aimed to examine the development of socializing and emotional expressions through vocalizations and joint attention (JA) behaviors in Korean speaking children with autism spectrum disorder (ASD), compared to those with developmental delay (DD). MATERIALS AND METHODS: Video samples were collected from 28 toddlers with ASD and 18 age-matched toddlers with DD, and vocalizations were each coded in detail for the purpose of this retrospective research. In addition to some statistical analysis, Computerized Language Analysis was conducted to obtain the final results. RESULTS: Although they produced a higher number of vocalizations than the DD group, the ASD group did not engage in emotional or social interactions with their caretakers, whereas the DD group did. The children with ASD used more atypical vocalizations and socially unengaged vocalizations than the children with DD did. JA using vocalizations in the ASD group, in particular, was largely dyadic, with triadic types occurring at a significantly lower frequency than those in the DD group. CONCLUSION: Results from this study indicate the importance of assessing early vocalizations in toddlers with ASD, suggesting that some common symptoms of ASD, such as lack of typical, emotional, and social functions in early vocalizations, could be used to develop screening and intervention programs related to ASD. PMID- 29611406 TI - Phenotypic Analysis of Korean Patients with Abnormal Chromosomal Microarray in Patients with Unexplained Developmental Delay/Intellectual Disability. AB - PURPOSE: The present study aimed to investigate chromosomal microarray (CMA) and clinical data in patients with unexplained developmental delay/intellectual disability (DD/ID) accompanying dysmorphism, congenital anomalies, or epilepsy. We also aimed to evaluate phenotypic clues in patients with pathogenic copy number variants (CNVs). MATERIALS AND METHODS: We collected clinical and CMA data from patients at Konyang University Hospital between September 2013 and October 2014. We included patients who had taken the CMA test to evaluate the etiology of unexplained DD/ID. RESULTS: All of the 50 patients identified had DD/ID. Thirty nine patients had dysmorphism, 19 patients suffered from epilepsy, and 12 patients had congenital anomalies. Twenty-nine of the 50 patients (58%) showed abnormal results. Eighteen (36%) were considered to have pathogenic CNVs. Dysmorphism (p=0.028) was significantly higher in patients with pathogenic CNVs than in those with normal CMA. Two or more clinical features were presented by 61.9% (13/21) of the patients with normal CMA and by 83.3% (15/18) of the patients with pathogenic CMA. CONCLUSION: Dysmorphism can be a phenotypic clue to pathogenic CNVs. Furthermore, pathogenic CNV might be more frequently found if patients have two or more clinical features in addition to DD/ID. PMID- 29611407 TI - Radiographic and Clinical Outcomes of Robot-Assisted Posterior Pedicle Screw Fixation: Two-Year Results from a Randomized Controlled Trial. AB - PURPOSE: We prospectively assessed the early radiographic and clinical outcomes (minimum follow-up of 2 years) of robot-assisted pedicle screw fixation (Robot PSF) and conventional freehand pedicle screw fixation (Conv-PSF). MATERIALS AND METHODS: Patients were randomly assigned to Robot-PSF (37 patients) or Conv-PSF (41 patients) for posterior interbody fusion surgery. The Robot-PSF group underwent minimally invasive pedicle screw fixation using a pre-planned robot guided screw trajectory. The Conv-PSF underwent screw fixation using the freehand technique. Radiographic adjacent segment degeneration (ASD) was measured on plain radiographs, and clinical outcomes were measured using visual analogue scale (VAS) and Oswestry disability index (ODI) scores regularly after surgery. RESULTS: The two groups had similar values for radiographic ASD, including University California at Los Angeles grade, vertebral translation, angular motion, and loss of disc height (p=0.320). At final follow-up, both groups had experienced significant improvements in back VAS, leg VAS, and ODI scores after surgery (p<0.001), although inter-group differences were not significant for back VAS (p=0.876), leg VAS (p=0.429), and ODI scores (p=0.952). In the Conv-PSF group, revision surgery was required for two of the 25 patients (8%), compared to no patients in the Robot-PSF group. CONCLUSION: There were no significant differences in radiographic ASD and clinical outcomes between Robot-PSF and Conv PSF. Thus, the advantages of robot-assisted surgery (accurate pedicle screw insertion and minimal facet joint violation) do not appear to be clinically significant. PMID- 29611408 TI - The Effect of Mental Rotation on Surgical Pathological Diagnosis. AB - PURPOSE: Pathological diagnosis involves very delicate and complex consequent processing that is conducted by a pathologist. The recognition of false patterns might be an important cause of misdiagnosis in the field of surgical pathology. In this study, we evaluated the influence of visual and cognitive bias in surgical pathologic diagnosis, focusing on the influence of "mental rotation." MATERIALS AND METHODS: We designed three sets of the same images of uterine cervix biopsied specimens (original, left to right mirror images, and 180-degree rotated images), and recruited 32 pathologists to diagnose the 3 set items individually. RESULTS: First, the items found to be adequate for analysis by classical test theory, Generalizability theory, and item response theory. The results showed statistically no differences in difficulty, discrimination indices, and response duration time between the image sets. CONCLUSION: Mental rotation did not influence the pathologists' diagnosis in practice. Interestingly, outliers were more frequent in rotated image sets, suggesting that the mental rotation process may influence the pathological diagnoses of a few individual pathologists. PMID- 29611409 TI - Safety of Tocilizumab in Rheumatoid Arthritis Patients with Resolved Hepatitis B Virus Infection: Data from Real-World Experience. AB - To investigate whether the use of IL-6 receptor antagonist (tocilizumab) might be associated with hepatitis B virus (HBV) reactivation in rheumatoid arthritis (RA) patients, particularly in those with resolved HBV infection [HBV surface antigen (HBsAg) negative and antibody to HBV core antigen (anti-HBc) positive, serologically]. HBsAg, anti-HBc, antibody to HBsAg (anti-HBs), and HBV DNA titers were measured in RA patients who had continuously received tocilizumab for more than 3 months. Patients were divided into two groups according to the presence of anti-HBc. Clinical and laboratory data, in addition to medications administered along with tocilizumab during the treatment duration with tocilizumab, were compared between the two groups. HBV reactivation was defined as the presence of HBV DNA in sera, and alterations in HBsAg, anti-HBc, and anti-HBs titers according to the use of tocilizumab were also evaluated. Fifteen of 39 patients (38.5%) had anti-HBc positivity, while 24 patients (61.5%) did not. There were no differences in demographic data, serologic classification, and variables related to tocilizumab between the anti-HBc-positive and -negative groups. Comparison of the medications administered along with tocilizumab treatment revealed no meaningful differences. None of the patients experienced reactivation of HBV. In addition, in 15 patients with resolved HBV infection, no alterations in HBsAg, anti-HBc, and anti-HBs titers were observed with the use of tocilizumab. Tocilizumab may be applied to RA patients safely with few concerns for HBV reactivation, particularly in those with resolved HBV infection. PMID- 29611411 TI - Erratum to "Pathologic Impact of Insulin Resistance and Sensitivity on the Severity of Liver Histopathology in Pediatric Non-Alcoholic Steatohepatitis" by Park BH, et al. (Yonsei Med J 2017;58:756-762.). AB - This corrects the article on p. 756 in vol. 58, PMID: 28540988. PMID- 29611410 TI - Total Transcanal Endoscopic Facial Nerve Decompression for Traumatic Facial Nerve Palsy. AB - A few approaches can be used to decompress traumatic facial nerve paralysis including the middle cranial fossa approach or transmastoid approach depending on the site of injury. In some specific situation of treating traumatic facial nerve palsy whose injured site was confined from the geniculate ganglion to the second genu, transcanal endoscopic approach for facial nerve decompression can be used. We performed two cases of total endoscopic transcanal facial nerve decompression in patients with traumatic facial nerve palsy. After a six month follow-up, both patients showed improvement in facial function by 2 grades according to House Brackmann grade system. In terms of treatment outcomes, total transcanal endoscopic facial nerve decompression for traumatic facial nerve palsy is an alternative for lesions limited to the tympanic segment I, and has an advantages of being minimally invasive and is cosmetically acceptable without an external scar or bony depression due to drilling. PMID- 29611413 TI - Enhanced Photocatalytic Performance through Magnetic Field Boosting Carrier Transport. AB - The promotion of magnetic field on catalytic performance has attracted extensive attention for a long time, and substantial improvements have been achieved in some catalysis fields. However, because the Zeeman energy is several orders of magnitude weaker, magnetic field seems unable to alter the band structure and has a negligible effect on semiconductor photocatalytic performance, which makes this task a great challenge. On the other hand, the spin-related behavior usually plays an important role in determining catalytic performance. For example, in some molecular catalysis, such as photosystem II, ferromagnetic alignment of the active material results in spin-oriented electrons, which are selected and accumulated at the interface, leading to great promotion of the oxygen evolution reaction activity. Here, we propose a magnetoresistance-related strategy to boost the carrier transfer efficiency and apply it in alpha-Fe2O3/reduced graphene oxide hybrid nanostructures (alpha-Fe2O3/rGO) to improve the photocatalytic performance under magnetic field. We show that both the degradation rate constant and photocurrent density of alpha-Fe2O3/rGO can be dramatically enhanced with the application of magnetic field, indicating the promotion of the photocatalytic performance. PMID- 29611414 TI - Synthesis of Oxygen-Free [2]Rotaxanes: Recognition of Diarylguanidinium Ions by Tetraazacyclophanes. AB - Simple cyclophanes containing four distant amino N atoms or ether O atoms behave as hosts for the threading of guest diarylguanidinium ions. The recognition system exhibits high synthetic flexibility, allowing unique O-free [2]rotaxanes to be synthesized efficiently (yields of up to 80%) through both "threading followed-by-stoppering" and "clipping" approaches. PMID- 29611415 TI - Gauging the Nanotoxicity of h2D-C2N toward Single-Stranded DNA: An in Silico Molecular Simulation Approach. AB - Recent toxicological assessments of graphene, graphene oxides, and some other two dimensional (2D) materials have shown them to be substantially toxic at the nanoscale, where they inhibit and eventually disrupt biological processes. These shortfalls of graphene and analogs have resulted in a quest for novel biocompatible 2D materials with minimum cytotoxicity. In this article, we demonstrate C2N (h2D-C2N), a newly synthesized 2D porous graphene analog, to be non-nanotoxic toward genetic materials from an "in-silico" point of view through sequence-dependent binding of different polynucleotide single-stranded DNA (ssDNA) onto it. The calculated binding energy of nucleobases and the free energy of binding of polynucleotides follow the common trait, cytosine > guanine > adenine > thymine, and are well within the limits of physisorption. Ab-initio simulations completely exclude the possibility of any chemical reaction, demonstrating purely noncovalent binding of nucleobases with C2N through a crucial interplay between hydrogen bonding and pi-stacking interactions with the surface. Further, we show that the extent of distortion inflicted upon ssDNA by C2N is negligible. Analysis of the density of states of the nucleobase-C2N hybrids confirms minimum electronic perturbation of the bases after adsorption. Most importantly, we demonstrate the potency of C2N in nucleic acid transportation via reversible binding of ssDNA. The plausible use of C2N as a template for DNA repair is illustrated through an example of C2N-assisted complementary ssDNA winding. PMID- 29611416 TI - On the Generalized Thermal Conductance Characterizations of Mixed One-Dimensional Two-Dimensional van der Waals Heterostructures and Their Implication for Pressure Sensors. AB - The emergence of ever-growing two-dimensional (2D) materials has made revolutionary innovations on van der Waals (vdW) heterostructural designs by integrating them with other low-dimensional materials to achieve unprecedented and/or multiple functionalities that are beyond individual components. Guided by full-scale molecular dynamics simulations, we present a mixed-dimensional heterostructure by vertically stacking one-dimensional (1D) and 2D materials through noncovalent vdW interactions and demonstrate that the thermal conductance can be generalized into a unified model by incorporating their mechanical properties and geometric features. Simulation analyses further reveal the strong dependence of thermal conductance on the location and magnitude of an external pressure loading applied to the local vdW heterojunctions. The underlying thermal transport mechanism is uncovered through the elucidation of the mechanical deformation, curvature morphology, and density of atomic interactions at the heterojunctions. A proof-of-conceptual design of such a heterostructure-enabled pressure sensor is explored by utilizing the unique response of thermal transport to mechanical deformation at heterojunctions. These designs and models are expected to broaden the applications and functionalities of mixed-dimensional heterostructures and will also offer an alternative strategy to leverage thermal transport mechanisms in the design of high-performance vdW heterostructure enabled sensors. PMID- 29611417 TI - Absorption and Reflection Contributions to the High Performance of Electromagnetic Waves Shielding Materials Fabricated by Compositing Leather Matrix with Metal Nanoparticles. AB - Leather matrix (LM), a natural dielectric material, features a hierarchically suprafibrillar structure and abundant dipoles, which provides the possibility to dissipate electromagnetic waves (EW) energy via dipole relaxation combined with multiple diffuse reflections. Conventionally, metal-based materials are used as EW shielding materials due to that their high conductivity can reflect EW effectively. Herein, a lightweight and high-performance EW shielding composite with both absorption and reflection ability to EW was developed by coating metal nanoparticles (MNPs) onto LM. The as-prepared metal/LM membrane with only 4.58 wt % of coated MNPs showed excellent EW shielding effectiveness of ~76.0 dB and specific shielding effectiveness of ~200.0 dB cm3 g-1 in the frequency range of 0.01-3.0 GHz, implying that more than 99.98% of EW was shielded. Further investigations indicated that the high shielding performances of the metal/LM membrane were attributed to the cooperative shielding mechanism between LM and the coating of MNPs. PMID- 29611418 TI - Photochemical Vapor Generation of Tellurium: Synergistic Effect from Ferric Ion and Nano-TiO2. AB - Photochemical vapor generation (PVG) is emerging as a promising analytical tool for Te determination, thanks to its efficient matrix separation, and simple and green procedure. However, the low PVG generation efficiency of Te is the bottleneck for its wide application in environmental samples containing trace Te. Herein, we reported a high efficient PVG for Te determination by synergistic effect of ferric ion and nano-TiO2. The analytical sensitivity was enhanced approximately 15-fold for Te(IV) in the presence of both ferric ions and nano TiO2, comparing to conventional PVG. Besides, the use of nano-TiO2 can provide Te(VI) and Te(IV) an equal and high PVG efficiency in the presence of ferric ions, owned to the high photocatalytic performance of TiO2 under short-wavelength UV irradiation (254 and 185 nm). Under the optimized experimental conditions, a detection limit of 1.0 ng L-1 was obtained. The precision of replicate measurements was 2.3% (RSD, n = 7) at 0.5 MUg L-1 for Te(IV). The methodology was validated by successful determination of Te in surface waters and two standard reference sediment samples. To our best knowledge, this is the first report of the synergistic enhancement of transitional metal ions and nano-TiO2 in PVG, which possesses potential for highly sensitive determination of vapor-forming elements. PMID- 29611419 TI - In Silico Enhancing M. tuberculosis Protein Interaction Networks in STRING To Predict Drug-Resistance Pathways and Pharmacological Risks. AB - Bacterial protein-protein interaction (PPI) networks are significant to reveal the machinery of signal transduction and drug resistance within bacterial cells. The database STRING has collected a large number of bacterial pathogen PPI networks, but most of the data are of low quality without being experimentally or computationally validated, thus restricting its further biomedical applications. We exploit the experimental data via four solutions to enhance the quality of M. tuberculosis H37Rv (MTB) PPI networks in STRING. Computational results show that the experimental data derived jointly by two-hybrid and copurification approaches are the most reliable to train an L2-regularized logistic regression model for MTB PPI network validation. On the basis of the validated MTB PPI networks, we further study the three problems via breadth-first graph search algorithm: (1) discovery of MTB drug-resistance pathways through searching for the paths between known drug-target genes and drug-resistance genes, (2) choosing potential cotarget genes via searching for the critical genes located on multiple pathways, and (3) choosing essential drug-target genes via analysis of network degree distribution. In addition, we further combine the validated MTB PPI networks with human PPI networks to analyze the potential pharmacological risks of known and candidate drug-target genes from the point of view of system pharmacology. The evidence from protein structure alignment demonstrates that the drugs that act on MTB target genes could also adversely act on human signaling pathways. PMID- 29611420 TI - One- and Two-Photon Uncaging: Carbazole Fused o-Hydroxycinnamate Platform for Dual Release of Alcohols (Same or Different) with Real-Time Monitoring. AB - A one- and two-photon activated photoremovable protecting group (PRPG) was designed based on a carbazole fused o-hydroxycinnamate platform for the dual (same or different) release of alcohols. The mechanism for the dual release proceeds through a stepwise pathway and also monitors the first and second photorelease in real time by an increase in fluorescence intensity and color change, respectively. Further, its application in staining live neurons and ex vivo imaging with two-photon excitation is shown. PMID- 29611421 TI - Cd2+-Doped Amorphous TiO2 Hollow Spheres for Robust and Ultrasensitive Photoelectrochemical Sensing of Hydrogen Sulfide. AB - Hydrogen sulfide is a highly toxic molecule to human health, but high-performance detection of it remains a challenge. Herein, we report an ultrasensitive photoelectrochemical (PEC) sensor for H2S by modifying indium tin oxide (ITO) electrodes with Cd2+-doped amorphous TiO2 hollow spheres, which are prepared by templating against colloidal silica particles followed by a cadmium-sodium cation exchange reaction. The amorphous TiO2 hollow spheres act as both the probing cation carrier and the photoelectric beacon. Upon exposure to sulfide ions, the photocurrent of the functionalized photoanode proportionately decreases in response to the formation of CdS nanoparticles. The decreased photocurrent could be attributed to the mismatching bandgap between the amorphous TiO2 and CdS nanoparticles: the photoexcited electrons and holes from amorphous TiO2 are transferred to the conduction band and valence band of CdS, respectively, and then recombined. The decrease in photocurrent is linear with the concentration of sulfide ions in the range from 1 to 10 000 pmol L-1 with a detection limit of 0.36 pmol L-1. Enabled by a unique sensitization mechanism, this PEC sensor features excellent performance in a wide linear range, high selectivity and sensitivity, high stability, and low fabrication cost. PMID- 29611422 TI - Distinct Proteome Remodeling of Industrial Saccharomyces cerevisiae in Response to Prolonged Thermal Stress or Transient Heat Shock. AB - To gain a deep understanding of yeast-cell response to heat stress, multiple laboratory strains have been intensively studied via genome-wide expression analysis for the mechanistic dissection of classical heat-shock response (HSR). However, robust industrial strains of Saccharomyces cerevisiae have hardly been explored in global analysis for elucidation of the mechanism of thermotolerant response (TR) during fermentation. Herein, we employed data-independent acquisition and sequential window acquisition of all theoretical mass spectra based proteomic workflows to characterize proteome remodeling of an industrial strain, ScY01, responding to prolonged thermal stress or transient heat shock. By comparing the proteomic signatures of ScY01 in TR versus HSR as well as the HSR of the industrial strain versus a laboratory strain, our study revealed disparate response mechanisms of ScY01 during thermotolerant growth or under heat shock. In addition, through proteomics data-mining for decoding transcription factor interaction networks followed by validation experiments, we uncovered the functions of two novel transcription factors, Mig1 and Srb2, in enhancing the thermotolerance of the industrial strain. This study has demonstrated that accurate and high-throughput quantitative proteomics not only provides new insights into the molecular basis for complex microbial phenotypes but also pinpoints upstream regulators that can be targeted for improving the desired traits of industrial microorganisms. PMID- 29611423 TI - Synthesis of Self-Assembled Porphyrin Nanoparticle Photosensitizers. AB - The use of nanoparticles as a potential building block for photosensitizers has recently become a focus of interest in the field of photocatalysis and photodynamic therapy. Porphyrins and their derivatives are effective photosensitizers due to extended pi-conjugated electronic structure, high molar absorption from visible to near-infrared spectrum, and high singlet oxygen quantum yields as well as chemical versatility. In this paper, we report a synthesis of self-assembled porphyrin nanoparticle photosensitizers using zinc meso-tetra(4-pyridyl)porphyrin (ZnTPyP) through a confined noncovalent self assembly process. Scanning electron microscopy reveals formation of monodisperse cubic nanoparticles. UV-vis characterizations reveal that optical absorption of the nanoparticles exhibits a red shift due to noncovalent self-assembly of porphyrins, which not only effectively increase intensity of light absorption but also extend light absorption broadly covering visible light for enhanced photodynamic therapy. Electron spin-resonance spectroscopy (ESR) studies show the resultant porphyrin nanoparticles release a high yield of singlet oxygen. Nitric oxide (NO) coordinates to central metal Zn ions to form stabilized ZnTPyP@NO nanoparticles. We show that under light irradiation ZnTPyP@NO nanoparticles release highly reactive peroxynitrite molecules that exhibit enhanced antibacterial photodynamic therapy (APDT) activity. The ease of the synthesis of self-assembled porphyrin nanoparticles and light-triggered release of highly reactive moieties represent a completely different photosensitizer system for APDT application. PMID- 29611424 TI - Probing the Differential Tissue Distribution and Bioaccumulation Behavior of Per- and Polyfluoroalkyl Substances of Varying Chain-Lengths, Isomeric Structures and Functional Groups in Crucian Carp. AB - Understanding the bioaccumulation mechanisms of per- and polyfluoroalkyl substances (PFASs) across different chain-lengths, isomers and functional groups represents a monumental scientific challenge with implications for chemical regulation. Here, we investigate how the differential tissue distribution and bioaccumulation behavior of 25 PFASs in crucian carp from two field sites impacted by point sources can provide information about the processes governing uptake, distribution and elimination of PFASs. Median tissue/blood ratios (TBRs) were consistently <1 for all PFASs and tissues except bile which displayed a distinct distribution pattern and enrichment of several perfluoroalkyl sulfonic acids. Transformation of concentration data into relative body burdens (RBBs) demonstrated that blood, gonads, and muscle together accounted for >90% of the amount of PFASs in the organism. Principal component analyses of TBRs and RBBs showed that the functional group was a relatively more important predictor of internal distribution than chain-length for PFASs. Whole body bioaccumulation factors (BAFs) for short-chain PFASs deviated from the positive relationship with hydrophobicity observed for longer-chain homologues. Overall, our results suggest that TBR, RBB, and BAF patterns were most consistent with protein binding mechanisms although partitioning to phospholipids may contribute to the accumulation of long-chain PFASs in specific tissues. PMID- 29611425 TI - Biomimetic Interfacial Electron-Induced Electrochemiluminesence. AB - We provide here, for the first time, a new interfacial electron-induced electrochemiluminescence (IEIECL) system, realizing bionic construction of bioluminescence (BL) by exploiting electrochemiluminescence (ECL) and ITIES (the interface between two immiscible electrolyte solutions). Significantly, the superiority of the IEIECL system is embodied with the solution of the two bottlenecks encountered in the conventional ECL innovation: that are (a) the applications of hydrophobic luminophores in more commonly used aqueous solution are inhibited tremendously due to the poor inherent solubility and the instability of radicals and (b) the analytes, insoluble in water, are hard to be discovered in an aqueous system because of too little content. More productive IEIECL radiation, analogous to BL, originates from the triplet excited state porphyrin in comparison to the homogeneous ECL. The mechanism of IEIECL, as well as the interaction mechanism between IEIECL and charge transfer (comprising electron transfer (ET), ion transfer (IT), and facilitated ion transfer (FIT)) at the ITIES, are explored in detail. Finally, we emphasize the actual application potential of the IEIECL system with the detection of cytochrome c (Cyt c); it is a key biomolecule in the electron transport chain in the process of biological oxidation and is also an intermediate species in apoptosis. Potentially, the IEIECL system permits ones to explore the lifetime and diffusion path of free radicals, as well as imparting a possibility for the construction of a bionic sensor. PMID- 29611426 TI - Micellar Mimicry of Intermetallic C14 and C15 Laves Phases by Aqueous Lyotropic Self-Assembly. AB - Concentration-dependent supramolecular self-assembly of amphiphilic molecules in water furnishes a variety of nanostructured lyotropic liquid crystals (LLCs), which typically display high symmetry bicontinuous network and discontinuous micellar morphologies. Aqueous dispersions of soft spherical micelles derived from small molecule amphiphile hydration typically pack into exemplary body centered cubic and closest-packed LLCs. However, investigations of hydrated mixtures of the ionic surfactant tetramethylammonium decanoate loaded with 40 wt % n-decane (TMADec-40) revealed the formation of a high symmetry bicontinuous double diamond LLC, as well as cubic C15 and hexagonal C14 Laves LLC phases that mirror the MgCu2 and MgZn2 intermetallic structure types, respectively. Detailed small-angle X-ray scattering analyses demonstrate that the complex C15 and C14 LLCs exhibit large unit cells, in which 12 or more ~3-4 nm diameter micelles of multiple discrete sizes arrange into tetrahedral close packing arrangements with exceptional long-range translational order. The symmetry breaking that drives self-assembly into these low-symmetry LLC phases is rationalized in terms of a frustrated balance between maximizing counterion-mediated micellar cohesion within the ensemble of oil-swollen particles, while simultaneously optimizing local spherical particle symmetry to minimize molecular-level variations in surfactant solvation. PMID- 29611427 TI - Impact of known or new-onset atrial fibrillation on 2-year cardiovascular event rate in patients with acute coronary syndromes: results from the prospective EPICOR Registry. AB - BACKGROUND: Atrial fibrillation (AF) is associated with increased morbidity in acute coronary syndrome patients, but impact on outcomes beyond 1 year is unclear. METHODS: This was a post-hoc analysis from the long-tErm follow-uP of antithrombotic management patterns In acute CORonary syndrome patients (EPICOR) registry (NCT01171404), a prospective, observational study conducted in Europe and Latin America, which enrolled acute coronary syndrome survivors at discharge. Antithrombotic management patterns, mortality, a composite endpoint of death/new non-fatal myocardial infarction/stroke and bleeding events were assessed after 2 years of follow-up in patients with or without AF. RESULTS: Of 10,568 patients enrolled, 397 (4.7%) had prior AF and 382 (3.6%) new-onset AF during index hospitalisation. Fewer patients with AF underwent percutaneous coronary intervention (52.1% vs. 66.6%; P<0.0001). At discharge, fewer AF patients received dual antiplatelet therapy (71.6% vs. 89.5%; P<0.0001); oral anticoagulant use was higher in AF patients but was still infrequent (35.0% vs. 2.5%; P<0.0001). Use of dual antiplatelet therapy and oral anticoagulants declined over follow-up with over 50% of all AF/no AF patients remaining on dual antiplatelet therapy (55.6% vs. 60.6%), and 23.3% (new-onset AF) to 42.1% (prior AF) on oral anticoagulants at 2 years. At 2 years, mortality, composite endpoint and bleeding rates were higher in AF patients (all P<0.0001) compared to patients without AF. On multivariable analysis, the risk of mortality or the composite endpoint was significant for prior AF ( P=0.003, P=0.001) but not new-onset AF ( P=0.88, P=0.92). CONCLUSIONS: Acute coronary syndrome patients with AF represent a high-risk group with increased event rates during long-term follow-up. Prior AF is an independent predictor of mortality and/or ischaemic events at 2 years. Use of anticoagulants in AF after acute coronary syndrome is still suboptimal. PMID- 29611428 TI - Engineering a yeast double-molecule carrier for drug screening. AB - With the advantages of unicellular eukaryotic structure and easy manipulation, yeast becomes a popular tool for biochemical, genetic and medicinal studies. In order to construct an efficient anti-inflammatory drug screening platform, we engineered yeast as a double-molecule carrier, of which an inserted domain (I domain) of lymphocyte function-associated antigen 1 was displayed on yeast surface and a green fluorescent protein (GFP) was expressed inside cytosol. The I domain specifically targeted a surface marker of mammalian cells, intercellular adhesion molecule 1, whose number is correlated with the level of cellular inflammation. Examination of GFP intensity enables swift quantification of the yeast-mammalian cell binding and thus it reflects inflammatory potency, herein the inflammatory index, of a chemical imposed to cells. The inflammatory potency of a total of 1340 chemicals was indexed. Among them, 1 inflammation-inducing and 1 inflammation-reducing compounds were verified both in vitro and in vivo. Our method demonstrated a swift, facile and high-throughput screening platform at the protein level for inflammation and related diseases drug discovery without using sophisticated instruments. PMID- 29611430 TI - Diagnostic Accuracy Of The Electrocardiographic Decision Support - Myocardial Ischaemia (EDS-MI) Algorithm In Detection Of Acute Coronary Occlusion. AB - Electrocardiographic Decision Support - Myocardial Ischaemia (EDS-MI) is a graphical decision support for detection and localization of acute transmural ischaemia. A recent study indicated that EDS-MI performs well for detection of acute transmural ischaemia. However, its performance has not been tested in patients with non-ischaemic ST-deviation. We aimed to optimize the diagnostic accuracy of EDS-MI in patients with verified acute coronary occlusion as well as patients with non-ischaemic ST deviation and compare its performance with STEMI criteria. We studied 135 patients with non-ischaemic ST deviation (perimyocarditis, left ventricular hypertrophy, takotsubo cardiomyopathy and early repolarization) and 117 patients with acute coronary occlusion. In 63 ischaemic patients, the extent and location of the ischaemic area (myocardium at risk) was assessed by both cardiovascular magnetic resonance imaging and EDS-MI. Sensitivity and specificity of ST elevation myocardial infarction criteria were 85% (95% confidence interval (CI) 77, 90) and 44% (95% CI 36, 53) respectively. Using EDS-MI, sensitivity and specificity increased to 92% (95% CI 85, 95) and 81% (95% CI 74, 87) respectively (p=0.035 and p<0.001). Agreement was strong (83%) between cardiovascular magnetic resonance imaging and EDS-MI in localization of ischaemia. Mean myocardium at risk was 32% (+/- 10) by cardiovascular magnetic resonance imaging and 33% (+/- 11) by EDS-MI when the estimated infarcted area according to Selvester QRS scoring was included in myocardium at risk estimation. In conclusion, EDS-MI increases diagnostic accuracy and may serve as an automatic decision support in the early management of patients with suspected acute coronary syndrome. The added clinical benefit in a non-selected clinical chest pain population needs to be assessed. PMID- 29611429 TI - Evaluating the Contribution of EEG Power Profiles to Characterize and Discriminate Posttraumatic Stress Symptom Factors in a Combat-Exposed Population. AB - This study investigated the use of resting-state electroencephalography (EEG) data to help differentiate posttraumatic stress disorder (PTSD) symptom factors. The sample, 147 combat-exposed OIF/OEF (Operation Iraqi Freedom/Operation Enduring Freedom) Veterans and service members, was a polytrauma population with variable PTSD and mild traumatic brain injury (mTBI) diagnoses. Participants completed the PTSD Checklist (PCL) and resting-state EEG was assessed for 10 minutes, with eyes closed. Regional averages of absolute power in alpha, beta, delta, and theta frequency bands were computed to estimate a single EEG common factor per band. An oblique 4 common-factor model was then fit to the 17 PCL items that included a residual EEG factor as an exogenous predictor with the group mean effect of mTBI on the EEG factor removed. Separate comparative model testing sequences for the alpha, beta, delta, and theta EEG factor frequency bands were conducted. An inverse relationship of delta and theta frequency bands on avoidance and numbing symptom factors (but not re-experiencing and hyperarousal) was found. Results provide evidence for possible neurobiological basis for the 4 PTSD symptom factors. PMID- 29611431 TI - Chromosome identification in Cucumis anguria revealed by cross-species single copy gene FISH. AB - Cucumis anguria is a potential genetic resource for improving crops of the genus Cucumis, owing to its broad-spectrum resistance. However, few cytogenetic studies on C. anguria have been reported because of its small metaphase chromosomes and the scarcity of distinguished chromosomal landmarks. In this study, 14 single copy genes from cucumber and rDNAs were used as probes for FISH to identify the individual chromosomes of C. anguria. The distinctive signal distribution patterns of the probes allowed us to distinguish each chromosome of C. anguria (A01-A12). Further, detailed chromosome characteristics were obtained through pachytene chromosome FISH. The lengths of pachytene chromosomes varied from 54.80 to 143.41 MUm. The proportion of heterochromatin regions varied from 13.56% to 63.86%. Finally, the chromosomal homeologous relationship between C. anguria and cucumber (C1-C7) was analyzed. The results showed that A06 + A09, A03 + A12, A02 + A04, and A01 + A11 were homeologs of C1, C2, C3, and C6, respectively. Furthemore, chromosomes A08, A10, and A05 were homeologs of C4, C5, and C7, respectively. Chromosome identification and homeologous relationship analysis between C. anguria and cucumber lay the foundation for further research of genome structure evolution in species of Cucumis. PMID- 29611432 TI - Advancing Public Health Policy in Louisiana Through Evidence-Based Strategies: Successes and Opportunities. AB - In 2013, a team of public health professionals at Tulane University launched a project to explore strategies for shaping a healthier Louisiana. The team investigated methods for improving diet and physical activity behaviors in early childhood, school, and community settings that could be translated into specific policies. Through key informant interviews and scans of academic journals and reports issued by public health agencies, the team generated a set of actionable steps that could increase healthful behaviors. Previous efforts to address similar topics in Louisiana and other states, and their reception from policy makers, were also considered during analysis. Subsequently, a state legislator used the team's work to introduce public health legislation in 2014. The legislation led to a number of incremental changes in state policy and resolutions for additional policy-relevant studies. This case study summarizes the promising physical activity and nutrition strategies that were considered by the Tulane team, how the team's work product was integrated into state legislation, the outcomes of the legislation, and a set of recommendations for how Louisiana can expand on this work. This article demonstrates how the work of public health professionals can have a positive influence on the policy-making process through research and education. PMID- 29611433 TI - A Real-World Community Health Worker Care Coordination Model for High-Risk Children. AB - Health care systems across the United States are considering community health worker (CHW) services for high-risk patients, despite limited data on how to build and sustain effective CHW programs. We describe the process of providing CHW services to 5,289 at-risk patients within a state-run health system. The program includes 30 CHWs, six care coordinators, the Director of Care Coordination, the Medical Director, a registered nurse, mental health specialists, and legal specialists. CHWs are organized into geographic and specialized teams. All CHWs receive basic training that includes oral and mental health; some receive additional disease-specific training. CHWs develop individualized care coordination plans with patients. The implementation of these plans involves delivery of a wide range of social service and coordination support. The number of CHW contacts is determined by patient risk. CHWs spend about 60% of their time in an office setting. To deliver the program optimally, we had to develop multiple CHW job categories that allow for CHW specialization. We created new technology systems to manage operations. Field issues resulted in program changes to improve service delivery and ensure safety. Our experience serves as a model for how to integrate CHWs into clinical and community systems. PMID- 29611434 TI - Post-transcriptional suppression of TIMP-1 in epithelial-differentiated adipose derived stem cells seeded bladder acellular matrix grafts reduces urethral scar formation. AB - Prevention of fibrosis and urethral scar formation is critical for a successful urethral reconstruction. We have previously shown that epithelial-differentiated adipose-derived stem cells (EASC) seeded bladder acellular matrix grafts (BAMG) can be used for urethral reconstruction. We have also shown that suppression of tissue inhibitor of metalloproteinases-1 (TIMP-1) reduces epithelial-mesenchymal transition in urethral fibroblasts in vitro and in vivo. However, it is unknown whether suppression of TIMP-1 in EASC seeded BAMG may benefit urethral reconstruction through inhibition of fibrosis. Here, we addressed this question. In a rabbit substitution urethroplasty model, we found that E-cadherin + EASC resulted in wider urethral caliber and formation of less urethral scar tissue, compared to non-purified EASC. Bioinformatics study showed that among all TIMP-1 targeting microRNAs (miRNAs), miR-365 is a conserved one in rabbits and humans, and functionally inhibits TIMP-1 protein translation. MiR-365-transduced E cadherin + EASC seeded BAMG further reduced fibrosis and increased urethral caliber width during urethral reconstruction in rabbits, compared to E-cadherin + EASC seeded BAMG. Together, these data suggest that EASC seeded BAMG method for urethral reconstruction could be further improved through purification of EASC by E-cadherin and through post-transcriptional inhibition of TIMP-1 via miR-365 in EASC. PMID- 29611435 TI - Chemical composition and in vitro antibacterial and antiproliferative activities of the essential oil from the leaves of Psidium myrtoides O. Berg (Myrtaceae). AB - In this study, the chemical composition and antibacterial and antiproliferative potential of the essential oil obtained from fresh leaves of Psidium myrtoides (PM-EO) against oral pathogens and human tumour cell lines were investigated for the first time. GC-FID and GC-MS analyses showed that trans-beta-caryophyllene (30.9%), alpha-humulene (15.9%), alpha-copaene (7.8%), caryophyllene oxide (7.3%) and alpha-bisabolol (5.3%) are the major constituents of PM-EO. The antibacterial activity of PM-EO against a panel of oral pathogens was investigated in terms of their minimal inhibitory concentrations (MIC) using the broth microdilution method. PM-EO displayed moderate activity against Streptococcus mitis (MIC = 100 MUg/mL), S. sanguinis (MIC = 100 MUg/mL), S. sobrinus (MIC = 250 MUg/mL), and S. salivarius (MIC = 250 MUg/mL), and strong activity against S. mutans (MIC = 62.5 MUg/mL). The antiproliferative activity in normal (GM07492A, lung fibroblasts) and tumour cell lines (MCF-7, HeLa, and M059 J) was performed using the XTT assay. PM-EO showed 50% inhibition of normal cell growth at 359.8 +/- 6.3 MUg/mL. Antiproliferative activity was observed against human tumour cell lines, with IC50 values significantly lower than that obtained for the normal cell line, demonstrating IC50 values for MCF-7 cells (254.5 +/- 1.6 MUg/mL), HeLa cells (324.2 +/- 41.4 MUg/mL) and M059 J cells (289.3 +/- 10.9 MUg/mL). Therefore, the cytotoxicity of PM-EO had little influence on the antibacterial effect, since it showed antibacterial activity at lower concentrations. Our results suggest that PM-EO is a promising source of new antibacterial and antitumour agents. PMID- 29611436 TI - When BAX doesn't kill. PMID- 29611437 TI - Book of Abstracts: The 15th Congress of the European Society of Contraception and Reproductive Health. PMID- 29611438 TI - An Exploratory Analysis of Violent Offending and the Acquired Capability for Suicide in Male Prisoners. AB - Recently, the Interpersonal Theory of Suicide has offered some understanding as to why inmates are at a disproportionately high risk to die by suicide. The present study was designed to investigate how one aspect of the theory, the acquired capability for suicide, may differ between prison inmates with violent offenses versus those without. Data from 343 male prisoners within the Mississippi Department of Corrections were used to examine potential differences between these two groups on scales of the Acquired Capability for Suicide Scale. Contrary to the hypothesis that violent offenders would evidence higher levels of acquired capability, only the Spectator Enjoyment of Violence subscale was significantly different between the two groups, with nonviolent offenders producing higher scores. Potential explanations for these findings and implications for correctional mental health care providers are discussed. PMID- 29611439 TI - Response to: Pneumococcal conjugate vaccines in Latin America: are PCV10 and PCV13 similar in terms of protection against serotype 19A? PMID- 29611440 TI - New biologics for allergic diseases. AB - INTRODUCTION: Allergic conditions such as asthma and atopic dermatitis have a high prevalence but represent a heterogeneous group of diseases despite similar clinical presentation and underlying pathophysiology. A better understanding of the phenotypes and endotypes of these diseases has driven rapid development of biologic medications targeting many steps of the inflammatory pathways. Areas covered: There are 2 major inflammatory pathways that drive allergic diseases: Type-2 (Th-2) inflammation and non-type 2 inflammation. All of the biologic medications currently approved for use, and most of the biologic medications under development for allergic diseases have focused on the Th-2 inflammatory pathway. Biologic targets along this pathway include Anti-Immunoglobulin E (IgE), Anti-Interleukin 5 (IL-5), Anti-IL 4, and Anti-IL 13. Although the most study has been done in the realm of severe asthma, biologic targets for other allergic diseases including atopic dermatitis, chronic rhinosinusitis with nasal polyposis, chronic idiopathic urticaria, eosinophilic esophagitis, and eosinophilic granulomatosis with polyangiitis are also discussed. Expert commentary: Novel biologic therapies have emerged over the last several years that have revolutionized the management of patients with refractory allergic disease. PMID- 29611441 TI - Juvenile cerebral ischemia reveals age-dependent BDNF-TrkB signaling changes: Novel mechanism of recovery and therapeutic intervention. AB - Global ischemia in childhood often leads to poor neurologic outcomes, including learning and memory deficits. Using our novel model of childhood cardiac arrest/cardiopulmonary resuscitation (CA/CPR), we investigate the mechanism of ischemia-induced cognitive deficits and recovery. Memory is impaired seven days after juvenile CA/CPR and completely recovers by 30 days. Consistent with this remarkable recovery not observed in adults, hippocampal long-term potentiation (LTP) is impaired 7-14 days after CA/CPR, recovering by 30 days. This recovery is not due to the replacement of dead neurons (neurogenesis), but rather correlates with brain-derived neurotrophic factor (BDNF) expression, implicating BDNF as the molecular mechanism underlying impairment and recovery. Importantly, delayed activation of TrkB receptor signaling reverses CA/CPR-induced LTP deficits and memory impairments. These data provide two new insights (1) endogenous recovery of memory and LTP through development may contribute to improved neurological outcome in children compared to adults and (2) BDNF-enhancing drugs speed recovery from pediatric cardiac arrest during the critical school ages. PMID- 29611442 TI - Changes in activity and structure of lysosomes from liver of mouse irradiated in vivo. AB - PURPOSE: Lysosomes may have an important role in response to ionizing radiation. Moreover, radiation could affect autophagy, which process involves the activity of lysosomal enzymes. In the present study, the effect of ionizing radiation on the lysosomal compartment of mouse liver was investigated after in vivo exposure. MATERIALS AND METHODS: Morphology and ultrastructure of hepatocytes were assessed by light and electron microscopy, and activities of selected lysosomal enzymes were assessed in 12, 36 and 120 h after exposure to the mean dose of 1 Gy. The levels of autophagy-related proteins LC3-II and p62 were compared by Western blotting between untreated and irradiated animals (120 h after exposure). RESULTS: Increased number of autophagic vacuoles in hepatocytes from exposed animals was documented in the ultrastructural study; destroyed mitochondria were the dominant component of such vacuoles. Moreover, an increased activity of lysosomal hydrolases was observed after exposure. However, levels of autophagy substrates LC3-II and p62 were barely affected in exposed animals 120 h after irradiation when the accumulation of autophagic vacuoles was observed. CONCLUSION: Effects of irradiation included an increased number of autophagic vacuoles, especially of autophagosomes, and increased activity of lysosomal enzymes. However, putative markers of autophagic flux were not observed, which suggested suppression of the completion of the radiation-mediated autophagy pathway. PMID- 29611443 TI - Nano titanium exposure induces dose- and size-dependent cytotoxicity on human epithelial lung and colon cells. AB - The productions as well as use of Titanium dioxide nanoparticles (TNPs) were rapidly increasing in the present nano-world. The TNP becomes an inevitable part our daily life in the form of cosmeceutical, bio-medical, and nano-pharmaceutical applications. The TNPs are either inhaled or ingested into the human body through common routes of exposure like the lungs and the oral-gastrointestinal tract (GIT). Human lung and colon were exposed to test particles, TNP 18 nm (TNP 18), TNP 30 nm (TNP 30), and TNP 87 nm (TNP 87) with a dose range 0.1-100 ug/ml. The effect of exposure was determined using MTT, LDH, and DCFH-DA methods. The TNP 18, TNP 30, and TNP 87 significantly (p < 0.001) reduced cell viability in a dose and a size-dependent manner in 60 and 100 ug/ml. The lowest IC50 values 21.80 and 24.83 ug/ml were observed in A549 and Caco-2 for the smallest size, TNP 18. Further, for TNP 30, IC50 values were 23.30 and 28.59 ug/ml compared to Nano QTZ 43.82 and 45.86 ug/ml. The EC25 values of LDH leakage were 5.83 and 9.50 ug/ml for TNP 18 in lung and colon cells. Besides, ROS levels increased significantly at doses 60 (p < 0.01) and 100 (p < 0.001) ug/ml in two cells. The smaller size particle, TNP 18 has produced a significant (p < 0.05) toxic effect at the lowest dose i.e., 10 ug/ml. Therefore, we conclude that TNP 18, TNP 30, and TNP 87 induced a dose- and size-dependent cytotoxicity via decreased cell viability, increased LDH and ROS levels by in vitro methods. PMID- 29611444 TI - Combination oral antithrombotic therapy for the treatment of myocardial infarction: recent developments. AB - INTRODUCTION: There have been significant new developments in the treatment of patients with myocardial infarction with respect to oral antithrombotic agents over the past decade. Recent studies have explored the potential utility of targeting the dual pathway inhibition of platelet function with single or dual antiplatelet agents and the thrombin pathway with direct thrombin inhibitors or factor Xa inhibitors. Areas covered: In this review, the authors focus on the recent developments of oral antithrombotic agents including antiplatelet and antithrombin agents. It is based on literature covering: aspirin, P2Y12 receptor blockers, PAR-1 inhibitors, direct thrombin inhibitors and factor Xa inhibitors from PubMed since 2008. Expert opinion: Since thrombus formation involves multiple pathways including platelet activation and aggregation and coagulation, simultaneous and optimal blockade of these pathways is essential to prevent thrombotic complications and to avoid excessive bleeding in the myocardial infraction setting. Despite an improved anti-ischemic effect associated with potent P2Y12 inhibitors plus aspirin, the degree of adverse event reduction compared to clopidogrel therapy in large scale trials is modest along with significantly greater bleeding. Recent studies suggest that targeting the thrombin pathway in addition to antiplatelet agents in high risk patients may further mitigate the risk of ischemic event occurrences with improved safety profiles. PMID- 29611445 TI - Chromosomal damage at bone-marrow cells is induced by exposure of rats to waterpipe water filtrate. AB - Waterpipe smoking is continuing to spread globally. The aim of this study is to investigate the effect of waterpipe water filtrate on chromosomal integrity in the bone-marrow cells of rats. Chromosomal damage was examined using in vivo chromosomal aberrations (CAs) and SCEs assays. Young Wistar male rats were exposed to WWF via drinking water. Chromosomal damage was measured in bone marrow cells after 6 weeks of treatment using fluorescent-plus-Giemsa staining. Treatment of rats with waterpipe water filtrate for 6 weeks did not affect food/liquid consumption and gain in body weight. The results showed that waterpipe water filtrate increased the frequencies of chromosomal breaks and exchanges by more than 30% (p < 0.01). In addition, waterpipe water filtrate significantly increased SCEs in the bone-marrow cells of rats. In conclusion, waterpipe water filtrate contains genotoxic compounds providing additional evidence for genotoxicity of waterpipe smoke. PMID- 29611446 TI - Costs and disease activity in early rheumatoid arthritis in 1996-2000 and 2006 2011, improved outcome and shift in distribution of costs: a two-year follow-up. AB - OBJECTIVE: To evaluate changes in healthcare utilization, costs, and disease activity from 1996 to 2011 for patients with early rheumatoid arthritis (RA). METHOD: Two cohorts of patients with early RA, included in 1996-1998 (T1) and 2006-2009 (T2), were followed regularly. Healthcare utilization, costs, and disease activity were compared between cohorts during 2 years after diagnosis. RESULTS: Disease activity was significantly improved in T2 vs T1. Drug costs increased in T2 vs T1 (EUR 911 vs EUR 535, respectively; p = 0.017), and costs for RA-related hospitalization decreased. More than 90% in T2 were prescribed disease-modifying anti-rheumatic drugs (DMARDs) at inclusion compared to 50% in T1. At 2 year follow-up, levels were still > 90% in T2, while corresponding values in T1 were just above 70%. Comparing T2 to T1, total direct costs were slightly higher in T2 (EUR 3941 vs EUR 3364, respectively; ns), sick leave decreased (EUR 3511 vs EUR 5672; p = 0.025), while disability pension increased slightly (EUR 4889 vs EUR 4244; ns), but total indirect costs remained unchanged (EUR 8400 vs EUR 9916; ns). Total direct and indirect costs did not differ between the cohorts (EUR 12 342 in T2 vs EUR 13 280 in T1; ns), and loss of productivity still represented the largest component of total costs. CONCLUSION: T2 patients were prescribed DMARDs earlier and more aggressively than T1 patients. Stable and better improvements in disease activity, function, and quality of life were achieved in T2 compared to T1. There was a shift within the components in direct costs and indirect costs, but total costs remained essentially unchanged. PMID- 29611447 TI - Investigational drugs for the treatment of infections caused by multidrug resistant Gram-negative bacteria. AB - INTRODUCTION: Infections caused by multidrug-resistant Gram-negative bacteria (MDR-GNB) are associated with significant mortality and costs. New drugs in development to combat these difficult-to-treat infections primarily target carbapenem-resistant Enterobacteriaceae, MDR Pseudomonas aeruginosa, and MDR Acinetobacter baumannii. Areas covered: The authors summarize in vitro and in vivo efficacy studies, as well as available clinical trial findings, for new agents in development for treatment of infection caused by MDR-GNB. Information regarding dosage regimens utilized in clinical trials and key pharmacokinetic and pharmacodynamic considerations are provided if available. A summary of recently approved agents, delafloxacin and meropenem/vaborbactam, is also included. Expert opinion: The development of multiple novel agents to fight MDR-GNB is promising to help save the lives of patients who acquire infection, and judicious use of these agents is imperative once they come to market to prevent the development of resistance. The other component paramount to this field of research is implementation of effective infection control policies and carbapenem-resistant Enterobacteriaceae (CRE) carrier screening protocols to mitigate the worldwide spread of MDR-GNB. Further investigation of anti-infective synergistic combinations will also be important, as well as support for economic research to reveal the true cost-benefit of utilization of the new agents discussed herein. PMID- 29611448 TI - Predictors of Death Penalty Views in China: An Empirical Comparison Between College Students and Citizens. AB - China's current Criminal Law has 46 death-eligible offenses, and China executes more people than any other country in the world. However, there is a lack of study of attitudes toward capital punishment for specific offenses, and no death penalty view comparison between college students and regular citizens in China was found. This study was taken to address these limitations. Using a sample of 401 respondents from Zhejiang, China, in 2016, the present study found that more than 72% of respondents favored the death penalty without any specification of crime types. Level of death penalty support differed by various specific crimes. As expected, relative to college students, general population citizens were more likely to support capital punishment. Both groups had the highest death penalty support for murder. The study also revealed similar and different reasons behind death penalty attitudes between college students and regular citizens. PMID- 29611449 TI - Splenic tyrosine kinase (SYK) inhibitors and their possible use in acute myeloid leukemia. AB - INTRODUCTION: Splenic tyrosine kinase (SYK) is a non-receptor tyrosine kinase. It is important for downstream signaling from several cell surface receptors, including Fc receptors, complement receptors and integrins. SYK can have either oncogenic or tumor suppressor activity in human malignancies. Recent studies suggest that SYK inhibition may have an antileukemic effect in human acute myeloid leukemia (AML). Areas covered: Relevant publications were identified through literature searches in the PubMed database. We searched for (i) original articles describing the results from clinical studies of SYK inhibition; (ii) published articles describing the importance of SYK in human malignancies, especially AML. Expert opinion: SYK is important for the downstream signaling from several cell surface receptors. There is also a crosstalk between SYK and signaling initiated through ligation of Toll like receptors, and SYK is thereby linked with the NFkappaB mediated transcriptional regulation. SYK activation will also influence PI3K-Akt-mTOR signaling. Several of these signaling events are important for survival and proliferation of primary human AML cells. In the present review we describe and discuss the role of SYK in human AML, and these data suggest that SYK inhibition is a possible therapeutic strategy in human AML. PMID- 29611450 TI - Elevated serum vascular endothelial growth factor in treatment-resistant schizophrenia treated with electroconvulsive therapy: Positive association with therapeutic effects. AB - OBJECTIVES: As the name implies, vascular endothelial growth factor (VEGF) enhances angiogenesis, promotes vascular permeability, and stimulates neurogenesis in the adult brain. Furthermore, animal model studies have shown that electroconvulsive therapy (ECT), which is primarily utilised in cases of treatment-resistant schizophrenia (TRS), regulates the expression of VEGF. The current study focuses largely on the effect of ECT on VEGF serum concentration, and the relationship between VEGF and therapeutic effects in patients diagnosed with TRS. METHODS: Participants comprised 40 TRS patients and 43 healthy controls. Clinical severity was assessed (i.e. 1 day before commencement of ECT and 1 day following ECT) using the positive and negative syndrome scale (PANSS). Blood samples were also collected for VEGF measurements at corresponding time points. RESULTS: Pre-treatment serum VEGF levels were significantly lower in TRS patients compared to healthy controls. VEGF concentrations increased significantly following ECT, whereas no difference was found in controls. Moreover, there was a positive correlation between the change in VEGF and therapeutic effects. CONCLUSIONS: Elevated serum VEGF in TRS treated with ECT is positively associated with therapeutic effects, suggesting that alterations in VEGF levels may constitute an index by which to evaluate the improvement in clinical condition. PMID- 29611451 TI - Permeability imaging as a predictor of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage. AB - Blood-brain barrier (BBB) dysfunction has been implicated in ischemic risk following aneurysmal subarachnoid hemorrhage (aSAH), but never directly imaged. We prospectively examined whether post-bleed day 4 dynamic contrast-enhanced magnetic resonance (DCE-MR) BBB permeability imaging could predict development of delayed cerebral ischemia (DCI). Global MR-derived BBB permeability ( Ktrans) was significantly higher in aSAH patients who subsequently developed DCI (five patients; 2.28 +/- 0.09 * 10-3 min-1) compared to those who experienced radiographic vasospasm only (three patients; 1.85 +/- 0.12 * 10-3 min-1; p < 0.05), or no vasospasm/ischemia (eight patients; 1.74 +/- 0.07 * 10-3 min-1; p < 0.01). Ktrans > 2 * 10-3 min-1 predicted development of DCI (AUC = 0.98, 95% CI: 0.93-1). Global BBB dysfunction following aSAH is detectable with DCE-MR and predictive of ischemic risk. PMID- 29611452 TI - The use of human albumin in patients with cirrhosis: a European survey. AB - BACKGROUND: The administration of human albumin (HA) in patients with decompensated cirrhosis is still debated. The European Foundation for the Study of Chronic Liver Failure (EF-CLIF) promoted an online survey to assess its use across Europe. METHODS: Hepatologists were invited to participate to an electronic questionnaire based on multiple-choice questions divided in 6 different areas. A descriptive statistical analysis was performed to analyze the responses. RESULTS: One hundred-one hepatologists (36% non-EF-CLIF member), belonging to 86 centers (25% non-academic hospitals) completed the survey. The vast majority of participants prescribe HA for the evidence-based indications supported by international guidelines, while a proportion of them consider HA administration useful for other complications currently not supported by solid scientific evidence. Participants show a good level of knowledge about the non oncotic properties of the molecule, while HA prescription does not appear to be restricted by health authorities in most centers, at least for the evidence-based indications. CONCLUSIONS: The present survey indicates that hepatologists across Europe present adherence to international guidelines and highlights the areas where solid scientific data are awaited to achieve a more appropriate HA prescription in patients with decompensated cirrhosis. PMID- 29611453 TI - Trends in Pediatric Otolaryngology Disparities Research. AB - Objectives To describe trends in disparities research within pediatric otolaryngology as evidenced by major meeting presentations and to compare observed trends with those in the realm of patient safety and quality improvement (PSQI). Study Design Retrospective review of presentations at national otolaryngology meetings. Setting Online review of meeting programs. Subjects and Methods Meeting programs from the American Society of Pediatric Otolaryngology, Triological Society, American Academy of Otolaryngology-Head and Neck Surgery Foundation, and Society for Ear, Nose and Throat Advances in Children from 2003 to 2016 were manually searched for pediatric oral and poster presentations addressing disparities and socioeconomic determinants of health, as well as PSQI. Presentation frequency was compared between categories and within each category over time. Results Of 11,311 total presentations, 3078 were related to the pediatric population, and 1945 (63.2%) of those were oral presentations. Disparities-related presentations increased from 0 in 2003 to 17 in 2016. From 2003 to 2009, 9 of 656 (1.4%) presentations involved disparities, as opposed to 70 of 2422 (2.9%) from 2010 to 2016 ( P = .03). The proportion of presentations regarding PSQI also increased: from 42 of 656 (6.4%) in 2003-2009 to 221 of 2422 (9.1%) in 2010-2016 ( P = .01). PSQI presentations remain more common than disparities presentations (9.1% vs 2.9%, P < .001). Conclusion Health care disparities are increasingly addressed in pediatric otolaryngology meeting presentations. Compared with the well-established realm of PSQI, disparities research remains nascent but is gaining attention. Health care reform and quality improvement efforts should recognize the role of socioeconomic factors and include strategies for addressing disparities. PMID- 29611454 TI - Commentary: Vaccines-Protecting Health and Saving Lives. PMID- 29611455 TI - Increasing Vaccination: Putting Psychological Science Into Action. AB - Vaccination is one of the great achievements of the 20th century, yet persistent public-health problems include inadequate, delayed, and unstable vaccination uptake. Psychology offers three general propositions for understanding and intervening to increase uptake where vaccines are available and affordable. The first proposition is that thoughts and feelings can motivate getting vaccinated. Hundreds of studies have shown that risk beliefs and anticipated regret about infectious disease correlate reliably with getting vaccinated; low confidence in vaccine effectiveness and concern about safety correlate reliably with not getting vaccinated. We were surprised to find that few randomized trials have successfully changed what people think and feel about vaccines, and those few that succeeded were minimally effective in increasing uptake. The second proposition is that social processes can motivate getting vaccinated. Substantial research has shown that social norms are associated with vaccination, but few interventions examined whether normative messages increase vaccination uptake. Many experimental studies have relied on hypothetical scenarios to demonstrate that altruism and free riding (i.e., taking advantage of the protection provided by others) can affect intended behavior, but few randomized trials have tested strategies to change social processes to increase vaccination uptake. The third proposition is that interventions can facilitate vaccination directly by leveraging, but not trying to change, what people think and feel. These interventions are by far the most plentiful and effective in the literature. To increase vaccine uptake, these interventions build on existing favorable intentions by facilitating action (through reminders, prompts, and primes) and reducing barriers (through logistics and healthy defaults); these interventions also shape behavior (through incentives, sanctions, and requirements). Although identification of principles for changing thoughts and feelings to motivate vaccination is a work in progress, psychological principles can now inform the design of systems and policies to directly facilitate action. PMID- 29611457 TI - Medicare Bundled Payments for Post-Acute Care: Characteristics and Baseline Performance of Participating Skilled Nursing Facilities. AB - Medicare bundled payment models have focused on post-acute care as a key component of improving the efficiency and quality of health care. This study investigated the characteristics and baseline performance of skilled nursing facilities (SNFs) that participated in Medicare Bundled Payments for Care Improvement Initiative Model 3. As of July 2016, 657 SNFs participated in 7,932 episodes in risk-bearing phase. Our retrospective analyses found that larger facilities, higher occupancy rate, chain affiliation, better five-star overall rating, and higher market competition for SNF care were associated with increased likelihood of enrolling in clinical episodes in Model 3, whereas not-for-profit ownership, higher adjusted staffing levels, higher percentage of Medicaid residents, and rural location were associated with reduced likelihood of participation in Bundled Payments for Care Improvement. Policy makers should consider approaches to encourage participation of post-acute care providers in this voluntary program and evaluate its impact on patient selection, cost of care, and health outcomes. PMID- 29611458 TI - A Personalized Approach of Patient-Health Care Provider Communication Regarding Colorectal Cancer Screening Options. AB - BACKGROUND: Current colorectal cancer screening guidelines by the US Preventive Services Task Force endorse multiple options for average-risk patients and recommend that screening choices should be guided by individual patient preferences. Implementing these recommendations in practice is challenging because they depend on accurate and efficient elicitation and assessment of preferences from patients who are facing a novel task. OBJECTIVE: To present a methodology for analyzing the sensitivity and stability of a patient's preferences regarding colorectal cancer screening options and to provide a starting point for a personalized discussion between the patient and the health care provider about the selection of the appropriate screening option. METHODS: This research is a secondary analysis of patient preference data collected as part of a previous study. We propose new measures of preference sensitivity and stability that can be used to determine if additional information provided would result in a change to the initially most preferred colorectal cancer screening option. RESULTS: Illustrative results of applying the methodology to the preferences of 2 patients, of different ages, are provided. The results show that different combinations of screening options are viable for each patient and that the health care provider should emphasize different information during the medical decision-making process. CONCLUSION: Sensitivity and stability analysis can supply health care providers with key topics to focus on when communicating with a patient and the degree of emphasis to place on each of them to accomplish specific goals. The insights provided by the analysis can be used by health care providers to approach communication with patients in a more personalized way, by taking into consideration patients' preferences before adding their own expertise to the discussion. PMID- 29611459 TI - Physician-Specific Maximum Acceptable Risk in Personalized Medicine: Implications for Medical Decision Making. AB - BACKGROUND: In discrete-choice experiments (DCEs), respondents are presented with a series of scenarios and asked to select their preferred choice. In clinical decision making, DCEs allow one to calculate the maximum acceptable risk (MAR) that a respondent is willing to accept for a one-unit increase in treatment efficacy. Most published studies report the average MAR for the whole sample, without conveying any information about heterogeneity. For a sample of psychiatrists prescribing drugs for a series of hypothetical patients with schizophrenia, this article demonstrates how heterogeneity accounted for in the DCE modeling can be incorporated in the derivation of the MAR. METHODS: Psychiatrists were given information about a group of patients' responses to treatment on the Positive and Negative Syndrome Scale (PANSS) and the weight gain associated with the treatment observed in a series of 26 vignettes. We estimated a random parameters logit (RPL) model with treatment choice as the dependent variable. RESULTS: Results from the RPL were used to compute the MAR for the overall sample. This was found to be equal to 4%, implying that, overall, psychiatrists were willing to accept a 4% increase in the risk of an adverse event to obtain a one-unit improvement of symptoms - measured on the PANSS. Heterogeneity was then incorporated in the MAR calculation, finding that MARs ranged between 0.5 and 9.5 across the sample of psychiatrists. LIMITATIONS: We provided psychiatrists with hypothetical scenarios, and their MAR may change when making decisions for actual patients. CONCLUSIONS: This analysis aimed to show how it is possible to calculate physician-specific MARs and to discuss how MAR heterogeneity could have implications for medical practice. PMID- 29611460 TI - Conference Report: 6th Annual International Symposium on Regenerative Rehabilitation. AB - The 6th International Symposium on Regenerative Rehabilitation, hosted by the Alliance for Regenerative Rehabilitation Research and Training (AR3T), included a preconference meeting of institutional representatives of the International Consortium of Regenerative Rehabilitation, keynote talks from distinguished scientists, platform and poster presentations from experts and trainees, panel discussions and postconference workshops. The following priorities were identified: increasing rigor in basic, preclinical and clinical studies, especially the use of better controls; developing better outcome measures for preclinical and clinical trials; focusing on developing more tissue-based interventions versus cell-based interventions; including regenerative rehabilitation in curricula of professional programs like occupational and physical therapy; and developing better instruments to quantify rehabilitative interventions. PMID- 29611461 TI - Poly(ethylene glycol)/chitosan/sodium glycerophosphate gel replaced the joint capsule with slow-release lubricant after joint surgery. AB - Body fluid is normally the only lubricant after joint replacement surgery, but wear problems have occurred because body fluid has poor lubrication ability. However, traditional lubricant would be diluted by body fluids and then absorbed by the human body. Therefore, an injectable gel with the ability to slow-release lubricant was designed to replace the joint capsule. The proposed gel, poly(ethylene glycol)/chitosan/sodium glycerophosphate (PEG/CS/GP) composite gel was then tested. The tribology results showed that the PEG/CS/GP gel had excellent slow-release properties, especially under pressure, and the PEG played an important role in improving the gel's rheological and mechanical properties. Moreover, this study revealed that the release solution had a good lubrication effect because the PEG and GP could crosslink via the hydrogen bond effect. PMID- 29611462 TI - Diagnostic Performance of Narrow Band Imaging for Nasopharyngeal Cancer: A Systematic Review and Meta-analysis. AB - Objective The purposes of this study were to verify the effectiveness of the narrow band imaging (NBI) system in diagnosing nasopharyngeal cancer (NPC) as compared with white light endoscopy. Data Sources PubMed, Cochrane Library, EMBASE, CNKI, and Wan Fang databases. Review Methods Data analyses were performed with Meta-Disc. The updated Quality Assessment of Diagnostic Accuracy Studies-2 tool was used to assess study quality and potential bias. Publication bias was assessed with a Deeks asymmetry test. The registry number of the protocol published on PROSPERO is CRD42015026244. Results This meta-analysis included 10 studies of 1337 lesions. For NBI diagnosis of NPC, the pooled values were as follows: sensitivity, 0.83 (95% CI, 0.80-0.86); specificity, 0.91 (95% CI, 0.89 0.93); positive likelihood ratio, 8.82 (95% CI, 5.12-15.21); negative likelihood ratio, 0.18 (95% CI, 0.12-0.27); and diagnostic odds ratio, 65.73 (95% CI, 36.74 117.60). The area under the curve was 0.9549. For white light endoscopy in diagnosing NPC, the pooled values were as follows: sensitivity, 0.79 (95% CI, 0.75-0.83); specificity, 0.87 (95% CI, 0.84-0.90); positive likelihood ratio, 5.02 (95% CI, 1.99-12.65); negative likelihood ratio, 0.34 (95% CI, 0.24-0.49); and diagnostic odds ratio, 16.89 (95% CI, 5.98-47.66). The area under the curve was 0.8627. The evaluation of heterogeneity, calculated per the diagnostic odds ratio, gave an I2 of 0.326. No marked publication bias ( P = .68) existed in this meta-analysis. Conclusion The sensitivity and specificity of NBI for the diagnosis of NPC are similar to those of white light endoscopy, and the potential value of NBI for the diagnosis of NPC needs to be validated further. PMID- 29611463 TI - A dual-targeting strategy for enhanced drug delivery and synergistic therapy based on thermosensitive nanoparticles. AB - The functionalized nanoparticles have been widely studied and reported as carriers of drug transport recently. Furthermore, many groups have focused more on developing novel and efficient treatment methods, such as photodynamic therapy and photothermal therapy, since both therapies have shown inspiring potential in the application of antitumor. The mentioned treatments exhibited the superiority of cooperative manner and showed the ability to compensate for the adverse effects caused by conventional monotherapy in proposed strategies. In view of the above descriptions, we formulated a thermosensitive drug delivery system, which achieved the enhanced delivery of cisplatin and two photosensitizers (ICG and Ce6) by dual-targeting traction. Drawing on the thin film hydration method, cisplatin and photosensitizers were encapsulated inside nanoparticles. Meanwhile, the targeting peptide cRGD and targeting molecule folate can be modified on the surface of nanoparticles to realize the active identification of tumor cells. The measurements of dynamic light scattering showed that the prepared nanoparticles had an ideal dispersibility and uniform particle size of 102.6 nm. On the basis of the results observed from confocal laser scanning microscope, the modified nanoparticles were more efficient endocytosed by MCF-7 cells as a contrast to SGC 7901 cells. Photothermal conversion-triggered drug release and photo-therapies produced a significant apoptosis rate of 85.9% on MCF-7 cells. The distinguished results made it believed that the formulated delivery system had conducted great efforts and innovations for the realization of concise collaboration and provided a promising strategy for the treatment of breast cancer. PMID- 29611465 TI - ? PMID- 29611464 TI - Evaluation of functional outcomes in traumatic spinal cord injury with rehabilitation-acquired urinary tract infections: A retrospective study. AB - Objective The objective of this study was to evaluate the impact of urinary tract infections (UTIs) acquired during acute inpatient traumatic Spinal Cord Injury (tSCI) rehabilitation on Functional Independence Measure (FIM) gains. Design Retrospective chart review of consecutive patients with tSCI admitted to an acute rehabilitation facility from 2007-2012. The primary outcome was FIM scores and the association with UTI. Results The sample included 110 patients and 70 acquired UTIs. No demographic differences were observed between groups with and without UTI. Those with UTIs had significantly lower FIM motor scores, on admission, discharge, and gain, as well as lower FIM efficiency and longer lengths of stay compared to those without a UTI. Recurrence of UTI was associated with increased length of stay, but did not impact FIM motor gains. Conclusions There was a statistically significant correlation between acquired UTIs and lower FIM motor scores on admission, gain, and discharge in tSCI rehabilitation. The correlation of UTI and decreased FIM gains are similar to other neurorehabilitation populations with UTI occurrence. UTIs are an important negative variable when measuring functional outcomes in rehabilitation. Further prospective studies should be performed to investigate this correlation. PMID- 29611467 TI - ? PMID- 29611466 TI - Climate migrants and health promotion. PMID- 29611468 TI - ? PMID- 29611469 TI - ? PMID- 29611471 TI - Peroxisome Proliferated Activated Receptors (PPARs): Opportunities and Challenges for Ocular Therapy. AB - Peroxisome proliferator-activated receptors (PPARs) are nuclear transcription factors. They exist in three isoforms (PPAR-alpha, PPAR-beta/delta, and PPAR Upsilon) in humans, but mainly PPAR-Upsilon, and they are expressed in retinal epithelial pigment. PPARs are involved in mediating numerous pathological implications in eye such as diabetic retinopathy (DR), choroidal neovascularization (CNV), glaucoma, diabetic macular edema, and other retinal diseases. Peroxisome proliferator-activated receptors are key players in various biological pathways like lipid degeneration, immune regulation, and reactive oxygen species regulation, regulation of vascular endothelial growth factor, matrixmetalloproteinase-9, and docosahexaenoic acid pathway. Based on evidence from clinical investigations, the drugs meant for PPARs could be promising candidates for intraocular therapy. Anti-VEGF therapy, including bevacizumab, ranibizumab, and aptamers (pegaptanib), has been approved for wet age-related macular degeneration (ARMD). Recently, researchers have explored the role of PPAR gamma in ocular pathophysiological processes and PPAR-gamma agonists as novel adjuvants in the treatment of eye diseases. PPAR-gamma exhibits potential benefits to improve or prevent various vision-threatening eye diseases such as age-related macular degeneration (ARMD), diabetic retinopathy (DR), keratitis, and optic neuropathy. However, PPAR-gamma presents challenges and offers opportunities for ocular scientists to bring better outcomes. PMID- 29611470 TI - Polymeric Immunonanoparticles Mediated Cancer Therapy: Versatile Nanocarriers for Cell-Specific Cargo Delivery. AB - The major drawback with conventional therapeutic approaches for cancer therapy is decreased efficacy and redundant therapy associated toxicity and side effects causing increased patient discomfort. With the aim of minimizing these limitations, a vast amount of attention has been given to targeted nanocarrier based drug delivery systems that possess a several-fold advantage over conventional therapy. Increased research in targeted nanoparticulate systems has led to the development of immunonanoparticles with enhanced efficacy and targeting efficiency along with decreased drug-resistant cancer- and dose-related toxicity. These immunonanoparticle- based therapies, which can be extended to immunotherapy, have gained wide attention, but few formulations will be approved by regulatory agencies in the near future. This review details the various immunonanoparticle systems explored in cancer therapy, with particular emphasis on polymeric nanoparticles. This review describes the mechanisms of immunotherapy and the pathways for targeting dendritic cells for immunotherapy. It also focuses on present status of clinical trials of immunonanoparticles and related patents, as well as various FDA-approved monoclonal antibodies (mAbs) for immunotherapy. Toxicity issues related to immunonanoparticles along with regulatory guidelines for these therapeutic nanoparticles are also discussed. PMID- 29611472 TI - Inhibitors of Selected Bacterial Metalloenzymes. AB - The utilization of bacterial metalloenzymes, especially ones not having mammalian (human) counterparts, has drawn attention to develop novel antibacterial agents to overcome drug resistance and especially multidrug resistance. In this review, we focus on the recent achievements on the development of inhibitors of bacterial enzymes peptide deformylase (PDF), metallo-beta-lactamase (MBL), methionine aminopeptidase (MetAP) and UDP-3-O-acyl-N-acetylglucosamine deacetylase (LpxC). The state of the art of the design and investigation of inhibitors of bacterial metalloenzymes is presented, and challenges are outlined and discussed. PMID- 29611473 TI - Tacrine-Natural-Product Hybrids for Alzheimer's Disease Therapy. AB - Alzheimer's disease (AD) is a complex, neurodegenerative pathology showing, among others, high cholinergic and neurotransmitter deficits, oxidative stress, inflammation, A?-aggregation resulting in senile plaques formation, and hyperphosphorylation of tau-protein leading to neurofibrillary tangles. Due to its multifactorial and complex nature, multitarget directed small-molecules able to simultaneously inhibit or bind diverse biological targets involved in the progress and development of AD are considered now the best therapeutic strategy to design new compounds for AD therapy. Among them, tacrine is a very well known standard-gold ligand, and natural products have been a traditional source of new agents for diverse therapeutic treatments. In this review we will update recent developments of multitarget tacrine-natural products hybrids for AD therapy. PMID- 29611474 TI - Glycosides from Medicinal Plants as Potential Anticancer Agents: Emerging Trends towards Future Drugs. AB - BACKGROUND: Cancer continues to be a global burden, despite the advancement of various technological and pharmaceutical improvements over the past two decades. Methods for treating cancer include surgery, radiotherapy and chemotherapy in addition to other specialized techniques. On the other hand, medicinal plants have been traditionally employed either as the complementary medicine or dietary agents in the treatment and management of cancer. Medicinal plants are a rich source of secondary metabolites with interesting biological and pharmacological activities. Among these metabolites, glycosides are naturally occurring substances and have outstanding therapeutic potential and clinical utility. METHODS: Different medical research engines such GoogleScholar, PubMed, SpringerLink, ScienceDirect were used to collect related literature on the subject matter. In this regard, only peer reviewed journals were considered. RESULTS: Emerging results showed that numerous glycosides isolated from various plants possessed marked anticancer activity against a variety of cancer cell lines. Accordingly, the aim of the present review is to shed light on the anticancer effects of glycosides, analyze possible mechanisms of action, and highlight the role of these natural agents as complementary and alternative medicine in combating and managing cancer. CONCLUSIONS: The glycosides isolated from different plants demonstrated potent cytotoxic effects against various cancer cell lines in initial preclinical studies. The anticancer effect was mediated through multiple mechanisms; however further detail studies are needed to understand the full potential of glycosides for clinical utility. PMID- 29611475 TI - Gene silencing strategies in cancer therapy: An update for drug resistance. AB - RNAi, post-transcriptional gene silencing mechanism, could be considered as one of the most important breakthroughs and rapidly growing fields in science. Researchers are trying to use this discovery in the treatment of various diseases and cancer is one of them. Multiple treatment procedures for treatments resistance cancers remain as unsolvable problem yet. The current review summarizes both transcriptional and post-transcriptional gene silencing mechanisms, and highlights mechanisms leading to drug-resistance such as, drug efflux, drug inactivation, drug target alteration, DNA damages repair, and the epithelial-mesenchymal transition, as well as the role of tumor cell heterogeneity and tumor microenvironment, involved genes in these processes. It ultimately points out to obstacles of RNAi application for in vivo treatment of diseases and progressions has been achieved in this field. PMID- 29611476 TI - Antimicrobial Peptides: Phylogenic Sources and Biological Activities. First of Two Parts. AB - Antimicrobial peptides (AMPs) are phylogenetically ancient substances released by living organisms for self protection against a broad variety of microbes. Moreover, AMPs are endowed with immune modulatory activities, linking innate and adaptive immunity together. Lantibiotics are AMPs of bacterial origin currently investigated for the generation of a new class of anti-infective compounds, owing to the phenomenon of antibiotic resistance against a broad variety of bacteria. Also, plants and marine AMPs are screened as novel drugs against human pathogens. Human AMPs encompass defensins and cathelicidins produced by various cell types mostly at mucosal sites. Besides their antimicrobial activity, both AMPs have been shown to trigger either inflammatory or anti-inflammatory pathways. Food derived AMPs are mostly represented by lactoferrin and lysozyme both present in secretions, e.g., milk, and appear to be very exploitable for the generation of functional foods. Finally, the role of natural products ingested with food or administered as supplements on induction and production of AMPs will be discussed. PMID- 29611477 TI - The Role of Formyl Peptide Receptors for Immunomodulatory Activities of Antimicrobial Peptides and Peptidomimetics. AB - In recent years, the therapeutic potential of antimicrobial peptides (AMPs) as immunomodulators has become generally accepted. Nevertheless, only very few AMP based compounds have progressed into clinical trials. This paradox may be explained by the fact, that some of the intrinsic properties of natural peptides, such as proteolytic and oxidative instability, render them inconvenient as therapeutics. Therefore, substantial research efforts have been dedicated to mimic the physico-chemical properties as well as biological activities of AMPs by designing and identifying more stable peptidomimetics displaying analogous immunomodulatory activity profiles. Neutrophils play key roles in host defense as major effector cells in clearance of pathogens by phagocytosis and by regulating other processes of innate immunity as well as by promoting resolution of inflammation. Several aspects of these effects are correlated to their expression of formyl peptide receptors (FPRs) that have been shown to be targets of both natural and synthetic antimicrobial peptides. In the present review recent findings highlighting the role of FPRs in mediating immunomodulatory activities of natural and synthetic AMPs as well as of stabilized peptidomimetics are discussed, and prospects for future development of immunomodulatory therapeutics are presented. PMID- 29611478 TI - Virtual Screening Studies for Discovery of Novel Inhibitors of Inflammatory Process Targets. AB - Inflammation has been very evident in infectious diseases, but in recent times research has increasingly shown that a range of non-infectious diseases may present with inflammatory conditions. This fact becomes important as new anti inflammatory drugs emerge with different targets for treatment of diseases. Virtual screening (VS) involves applying computational methods to discover new ligands for biological structures from the formation of large libraries composed of a large number of compounds. This review aims to report several studies employing a variety of VS: ligand-based and structure-based VS are being used more frequently in combination to decrease the probability of choosing false positive candidates. There are also studies that use only one approach. Docking is widely employed as structure-based VS methodology, however pharmacophore models based on the structure are becoming more prevalent. Molecular dynamics simulations, despite their computational cost, are still utilized to validate docking scores and analyze the stability of the complex ligand-structure. It is important to note that several studies employed several drug-like rules to screen structures, as well, decoys and PAINS to validate the models. Natural product databases, despite the lower number of the compounds compared to other databases that are available, are commonly referred to as a source of drug-like molecules. There is a literal explosion of software being released for a variety of purposes and several of them are free tools and/or web tools. Overall, VS studies are nowadays a normal part of medicinal chemistry to determine novel potential inhibitors for targets of inflammatory diseases. PMID- 29611479 TI - Recent Findings in Molecular Basis of Inflammation and Anti-inflammatory Plants. AB - Inflammation is one of the most important body responses provided by the immune system since it ensures survival when tissues are affected by injuries or infections. The inflammatory response is an important process for maintenance of normal tissue homeostasis. In contrast to acute inflammation, chronic inflammation does not have a useful impact. Prevention and suppression of inflammation are necessary to reduce patient suffering and to preserve the integrity of multiple organs. Unfortunately, commercial available anti inflammatory drugs are not free from side effects. Hence, there is an urgent need for introducing potent, nontoxic or less toxic antiinflammatory drugs. Recently, substantial progress has been made in the understanding of inflammatory mechanisms which may open new avenues for the preparation of novel anti inflammatory drugs. Medicinal plants are also promising sources for preparation of such novel drugs. Taking into consideration the anti-inflammatory activities of a large group of medicinal plants, this article, in addition to describing recent advances in progress in understanding the molecular basis of inflammation, presents the most important medicinal plants with antiinflammatory activity. PMID- 29611480 TI - Systematic Development and Optimization of an in-situ Gelling System for Moxifloxacin Ocular Nanosuspension using High-pressure Homogenization with an Improved Encapsulation Efficiency. AB - BACKGROUND: The objective of this study was to apply Quality by Design (QbD) principles on process parameter optimization for the development of hybrid delivery system (combination of (SLNs) and In-situ gelling system) for hydrophilic drug Moxifloxacin Hydrochloride (MOX) to achieve its controlled delivery, which otherwise may not be possible through single type of technology. METHODS: Risk assessment studies were carried out to identify probable risks influencing CQAs on the product. In design of experiments (DoE), the process parameters (independent variables) i.e., chiller temperature X1, High Pressure Homogenization (HPH) pressure X2, and HPH cycles X3 were optimized using a three factor two level face-centered central composite design to streamline the influence on three responses, namely encapsulation efficiency Y1, particle size Y2 and outlet temperature Y3. Independent and dependent variables were analyzed to establish a full-model second-order polynomial equation. F value is used to confirm the omission of insignificant parameters/interactions to derive a reduced model polynomial equation to predict the Y1, Y2 and Y3 for optimized moxifloxacin in situ gelled nanosuspension. RESULTS: Desirability plots showed the effects of X1, X2, and X3 on Y1, Y2 and Y3, respectively. The design space is generated to obtain optimized process parameters viz. chiller temperature (-5 degrees C), HPH pressure 800 - 900 bar and 8 cycles that resulted in nanosuspension with ~ 500 nm size, encapsulation efficiency >65% and final formulation temperature <23 degrees C that were necessary to maintain the formulation in a liquid state. CONCLUSION: Quality by Design (QbD) approach is recently been encouraged by regulatory bodies to improve the quality of the finished product. This approach proved to be a useful tool in the development of robust nanosuspension of highly hydrophilic drugs with improved efficiency. Results indicate that such hybrid gel systems can be used to control the release of SLNs from application site and prolong their action in a sustained manner. PMID- 29611481 TI - Human Oral Defensins Antimicrobial Peptides: A Future Promising Antimicrobial Drug. AB - The nature and structural composition of antimicrobial peptides are derived from their innate immune response and they are active against various bacteria, fungi and other microorganisms. The aim of this paper was to pool up the literature on the features of human oral defensins antimicrobial peptides. The defensins showed antimicrobial activity against Gram-positive and Gram-negative bacteria and various fungi and viruses. As with their other properties like antiviral, antifungal and antibacterial, human defensins peptides are thought to have a unique amino acid-based structure with Disulphide Bridge which makes them synthesize chemically or naturally with the help of these bacteria. The data contributing in this study was gathered from the research papers published in English language in the last twenty-five years. This literature mainly elaborates the general and analytical characteristics of antimicrobial peptides in the human oral cavity; focusing on the types, biochemistry, and mechanism of action of defensins with its clinical importance. PMID- 29611482 TI - Potential Use of Nanomedicine for the Anti-inflammatory Treatment of Neurodegenerative Diseases. AB - Neurodegenerative diseases, like Alzheimer's and Parkinson's disease, are a group of disorders that have in common their increasingly high prevalence along with the shortage of effective treatments. In addition, the scientific community faces the challenge of getting the drugs used in these treatments to cross the blood brain barrier (BBB) and reach the brain in sufficient concentration to be able to exert its effect. Hence, researchers across multiple disciplines are working together in order to improve the ability of therapeutics to penetrate the BBB. In this sense, the use of nanomedicine, nanoscale structures for drug delivery, exhibits a really high therapeutic potential in the field of neurodegenerative diseases therapy. Since there is new evidence that neuroinflammation produced by reactive microglia contributes to the activation and pathogenesis of neurological disorders, many investigations focus on the identification of new targets whose inhibition can reduce, totally or partially, microglial activation. This review analyzes a wide variety of compounds as possible candidates to achieve this target, from compounds with a natural origin to anti-diabetics, antidepressants, antibiotics and hormones. We also discuss the different strategies to enhance the capacity of these compounds to cross the BBB. Although this review focuses on PLGA nanoparticles as one of the most versatile drug delivery nanosystems, we also describe other strategies, such as direct intranasal administration (nose tobrain), novel viral vectors and novel implanted catheters. PMID- 29611483 TI - Management of Antithrombotic Therapy in Patients with Coronary Artery Disease or Atrial Fibrillation who Underwent Abdominal Surgical Operations. AB - BACKGROUND: Patients treated with antithrombotic therapy that require abdominal surgical procedures have progressively increased over time. The management of antithrombotics during both the peri- and postoperative period is of crucial importance. METHODS: The goal of this review is to present current data concerning the management of antiplatelets in patients with coronary artery disease and of anticoagulants in patients with atrial fibrillation who had to undergo abdominal surgical operations. For this purpose, the incidence of major adverse cardiovascular events (MACE) and risk of antithrombotic use during surgical procedures, as well as the recommendations based on recent guidelines were reported. A thorough search of PubMed, Scopus and the Cochrane Databases was conducted to identify randomized controlled trials, observational studies, novel current reviews, as well as ESC and ACC/AHA guidelines on the subject. RESULTS: Antithrombotic use in daily clinical practice leads to two different pathways: reduction of thromboembolic risk, but a simultaneous increase of bleeding risk. This may cause a therapeutic dilemma during the perioperative period. Nevertheless, careless cessation of antithrombotics can increase MACE and thromboembolic events. However, maintenance of antithrombotic therapy may increase bleeding complications. Studies and current guidelines can help clinicians in making decisions for the treatment of patients that undergo abdominal surgical operations while on antithrombotic therapy. Aspirin should not be stopped perioperatively in the majority of surgical operations. Determining whether to discontinue the use of anticoagulants before surgery depends on the surgical procedure. In surgical operations with a low risk for bleeding, oral anticoagulants should not be discontinued. Bridging therapy should only be considered in patients with a high risk of thromboembolism. Finally, in patients with an intermediate risk for thromboembolism, management should be individualized according to patient's thrombotic and bleeding risk. CONCLUSION: Management of antithrombotics therapy during the perioperative period in patients undergoing abdominal surgery should follow a patient-centered approach according to a patient's medical history and thrombotic risk weighted for bleeding risk. PMID- 29611484 TI - Synthesis of some Novel Imidazoles Catalyzed by Co3O4 Nanoparticles and Evaluation of their Antibacterial Activities. AB - AIM AND OBJECTIVE: The multi-component condensation of benzil, primary amines, ammonium acetate and various aldehydes was efficiently catalyzed using cobalt oxide nanoparticles under ultrasonic irradiation. This approach describes an effective and facile method for the synthesis of some novel 1,2,4,5 tetrasubstituted imidazole derivatives with several advantages such as high yields and short reaction times and reusability of the catalyst. Moreover, the prepared heterocyclic compounds showed high antibacterial activity against some pathogenic strains. MATERIALS AND METHOD: The facile and efficient approaches for the preparation of Co3O4 nanoparticles were carried out by one step method. The synthesized heterogeneous nanocatalyst was characterized by spectroscopic analysis including EDX, FE-SEM, VSM, XRD and FT-IR analysis. The as-synthesized cobalt oxide nanoparticles showed paramagnetic behaviour in magnetic field. In addition, the catalytic influence of the nanocatalyst was examined in the one-pot reaction of primary amines, benzil, ammonium acetate and diverse aromatic aldehydes under ultrasonic irradiation. All of the 1,2,4,5-tetrasubstituted imidazoles were investigated and checked with m.p., 1H NMR, 13C NMR and FT-IR spectroscopy techniques. The antibacterial properties of the heterocycles were evaluated in vitro by the disk diffusion against pathogenic strains such as Escherichia coli (EC), Bacillus subtillis (BS), Staphylococcus aureus (SA), Salmonellatyphi (ST) and Shigella dysentrae (SD) species. RESULTS: In this research cobalt oxide nanostructure was used as a robust and green catalyst in the some novel imidazoles. The average particle size measured from the FE-SEM image is found to be 20-30 nm which confirmed to the obtained results from XRD pattern. Various electron-donating and electron-withdrawing aryl aldehydes were efficiently reacted in the presence of Co3O4 nanoparticles. The role of the catalyst as a Lewis acid is promoting the reactions with the increase in the electrophilicity of the carbonyl and double band groups. To investigate the reusability of the catalyst, the model study was repeated using recovered cobalt oxide nanoparticles. The results showed that the nanocatalyst could be reused for five times with a minimal loss of its activity. CONCLUSION: We have developed an efficient and environmentally friendly method for the synthesis of some tetrasubstituted imidazoles via three-component reaction of benzil, primary amines, ammonium acetate and various aldehydes using Co3O4 NPs. The present approach suggests different benefits such as: excellent yields, short reaction times, simple workup procedure and recyclability of the magnetic nanocatalyst. The prepared 1,2,4,5-tetrasubstituted imidazoles revealed high antibacterial activities and can be useful in many biomedical applications. PMID- 29611485 TI - Diversity Oriented Synthesis of 4H-Pyrimido[2,1-b]benzothiazole Derivatives via Biginellis Reaction: A Review. AB - BACKGROUND: Heterocycles have extended into widespread use for generating large collection of molecules in multi-component reactions. The development of new strategies for fused pyrimidobenzothiazole system has remained a highly attractive but challenging proposition for scientists working all around. OBJECTIVE: The main objective of this work is to explore the utility of different catalysts as an ecofriendly reaction medium for green Biginellis reaction. METHOD: A detailed study of Biginellis reactions using various catalysts was done using different research tools. The methods involved reaction of equimolar mixture of benzothiazole, 1,3-diketone and aldehyde as reactants by conventional and greener pathways via Knoevenagal condensation. RESULTS: The present review has several significant advantages for the scientists regarding green synthesis viz. green conditions, short reaction times, high yields, clean reaction conditions, easy isolation of products, simple work-up procedure and mild reaction conditions. CONCLUSION: Our report gives an overview of the combinatorial libraries for fused benzothiazole entities using metal catalyst, acid catalyst, ionic liquids, phase transfer catalyst, nano catalyst, etc. PMID- 29611486 TI - Why Methylene Blue Have to Be Always Present in the Stocking of Emergency Antidotes. AB - Evidence-based review of the existing literature ultimately recommends stocking of Methylene Blue (MB) as an emergency antidote in the United States. The same is reported around the world in Japan, Greece, Italy and Canada. The observation that MB is always present as the main antidote required in emergency and critical care units calls for a revisit on its effects on the NO/cGMP system to reemphasize its multisystem actions. Therefore, the present review aimed to display the role of MB in emergency units, concerning: 1) Polytrauma and circulatory shock; 2) Neuroprotection, 3) Anaphylaxis and, 4) Overdose and poisoning. PMID- 29611487 TI - Complexation of Bioelements and Toxic Metals by Polyphenolic Compounds - Implications for Health. AB - Nowadays, growing interest in the possibility of prophylactic and therapeutic use of plant products rich in biologically active compounds has been observed. Among them, special interest has been focused on polyphenol-rich products. Owing to the multidirectional favourable action of polyphenols, products rich in these compounds are recommended as functional food in the case of civilization diseases. Moreover, data from studies in animal models show that polyphenols may be a promising preventive/therapeutic strategy for xenobiotics, including toxic heavy metals. The protective impact of polyphenols against metal toxicity may be explained by the presence of many hydroxyl groups in the structure of these compounds, which are capable of forming complexes with metals preventing as a result from their gastrointestinal absorption and accelerating their elimination from the body with urine. However, it should be taken into account that polyphenols may bind not only ions of toxic metals, but also bioelements, what makes a risk of their shortage in the organism. This review provides an overview of implications for humans' and animals' health of complexation of bioelements and toxic metals by polyphenols present in the popular foodstuffs, including phenolic acids, cyanidin derivatives, delphinidin, quercetin, kaempferol, morin, epigallocatechin-3-gallate, and curcumin. Polyphenolic compounds capable of binding both necessary and toxic metals occur in commonly consumed products such as green tea, and some fruit and vegetables, including chokeberries, bilberries, and black currant fruit, grapes, and apples, as well as onion. The mechanisms of complexation of essential and toxic metals by polyphenols and possible implications of these for health are discussed. PMID- 29611488 TI - Lupus Nephritis: A Treatment Update. AB - BACKGROUND: Lupus nephritis (LN) is a common complication in many patients with systemic lupus erythematosus, although renal-limited lupus nephritis has been reported as well. Early diagnosis of lupus nephritis is critical as early detection and effective treatment can improve renal outcomes in such patients. OBJECTIVE: The treatment of lupus nephritis is largely determined based on the histological class present on the renal biopsy specimen. In most cases, Class I and II of lupus nephritis do not require any specific treatment, but class III and IV lupus nephritis require immunosuppressive therapy. Treatment of Class V and VI remains controversial. In 2012, six guidelines were introduced for the management of lupus nephritis. These guidelines offer comprehensive treatment plans for each class of Lupus nephritis but differ from each other in many aspects. The purpose of this article is to review the current literature of the available pharmacological treatments used in the six classes of lupus nephritis as well as resistant lupus nephritis, strategies to address the problems of inadequate therapeutic response, medication related side effects, relapses of lupus nephritis, and some future treatment options. METHODS: We reviewed the available literature and treatment guidelines on lupus nephritis in detail to present a comprehensive review of the available treatment options for different classes of lupus nephritis. CONCLUSION: Lupus nephritis which does not respond to initial treatment is associated with worse renal outcomes. Several therapeutic approaches are available for the induction and maintenance immunosuppression of the different classes of LN. Management of LN should be individualized for each patient based on their risk-benefit profile. PMID- 29611489 TI - Nanocarriers for the Effective Treatment of Cervical Cancer: Research Advancements and Patent Analysis. AB - BACKGROUND: Cervical cancer being the cancer of cervix is caused by an aberrant cell growth that acquires an ability to spread/ invade to other body parts. It has also been reported to be the second most common cause of death and cancer among women. Based on the severity of the disease, treatment aspects need to be explored more in order to overcome the limitations acquired by the conventional treatment. Recently, nanocarriers based drug delivery systems including liposomes, nanofibres, metallic NPs, polymeric NPs, dendrimers, polymeric micelles, antibody-drug conjugates, etc. have been explored to target and treat cervical cancer. OBJECTIVE: This review highlights numerous recent research and patent reports as well on nanocarriers based systems. METHODS: Patents viz US, EP and WIPO have been retrieved using sites www.uspto.gov/patft and www.freepatentsonline.com to collect literature on nanocarriers. RESULTS: Various research reports and patents revealed nanocarriers to be effective in treating cervical cancer and these carriers are observed to be safer than the conventional treatment. CONCLUSION: Nanocarriers result in transforming drug distribution that can overpower drug resistance. Further, nanocarriers based drug delivery systems can particularly target drugs to cellular, subcellular and tissue sites. By enhancing the drug's bioavailability at the desired site, these systems result in therapeutic benefits like enhanced safety and efficacy. Also, in combination with other treatment approaches like radiation, photothermal and gene therapy, nanocarriers are reported to be quite effective and can define novel strategies to combat cervical cancer. PMID- 29611490 TI - Higher agrobiodiversity is associated with improved dietary diversity, but not child anthropometric status, of Mayan Achi people of Guatemala. AB - OBJECTIVE: Child undernutrition remains one of the greatest challenges for public health nutrition in rural areas in developing countries. Interventions aiming to increase and conserve agrobiodiversity seem to be promising alternatives to improve child nutrition. However, the existing literature on these interventions is not conclusive about their effectiveness in combating child undernutrition. We tested the hypothesis that 'higher agrobiodiversity is associated with greater dietary diversity and better anthropometric status' in rural Guatemala.Design/Setting/SubjectsIn the summer of 2016, we conducted a cross sectional study with a sample of 154 children (6-60 months). We conducted dietary recalls and structured interviews, measured children's weight and height, and visited food production systems (Milpas, home gardens, coffee plantations). Crop species richness, nutritional functional diversity, dietary diversity scores and anthropometric status were calculated. RESULTS: Higher food self-sufficiency, nutritional functional diversity and dietary diversity scores were positively correlated with higher crop and animal species richness. Contrarily, remoteness to the local market was negatively correlated with dietary diversity scores. However, higher dietary diversity scores were not correlated with better child anthropometric status. Better child anthropometric status was positively correlated with improved sanitary conditions and maternal education; and negatively correlated with large household size and frequent child morbidity. CONCLUSIONS: Agricultural diversification could diversify diets, increase nutrient availability and improve child anthropometry. However, these interventions need to be accompanied by sanitation improvements, family planning, nutritional education and women's empowerment to strengthen their positive effect on diet and nutrition. PMID- 29611491 TI - Defining the Role of the Environment in the Emergence and Persistence of vanA Vancomycin-Resistant Enterococcus (VRE) in an Intensive Care Unit: A Molecular Epidemiological Study. AB - OBJECTIVETo describe the transmission dynamics of the emergence and persistence of vanA vancomycin-resistant enterococcus (VRE) in an intensive care unit (ICU) using whole-genome sequencing of patient and environmental isolates.DESIGNRetrospective cohort study.SETTINGICU in a tertiary referral center.PARTICIPANTSPatients admitted to the ICU over an 11-month period.METHODS VanA VRE isolated from patients (n=31) were sequenced using the Illumina MiSeq platform. Environmental samples from bed spaces, equipment, and waste rooms were collected. All vanA VRE-positive environmental samples (n=14) were also sequenced. Data were collected regarding patient ward and bed movements.RESULTSThe 31 patient vanA VRE isolates were from screening (n=19), urine (n=4), bloodstream (n=3), skin/wound (n=3), and intra-abdominal (n=2) sources. The phylogeny from sequencing data confirmed several VRE clusters, with 1 group accounting for 38 of 45 isolates (84%). Within this cluster, cross transmission was extensive and complex across the ICU. Directionality indicated that colonized patients contaminated environmental sites. Similarly, environmental sources not only led to patient colonization but also to infection. Notably, shared equipment acted as a conduit for transmission between different ICU areas. Infected patients, however, were not linked to further VRE transmission.CONCLUSIONSGenomic sequencing confirmed a predominantly clonal outbreak of VRE with complex transmission dynamics. The environmental reservoir, particularly from shared equipment, played a key role in ongoing VRE spread. This study provides evidence to support the use of multifaceted strategies, with an emphasis on measures to reduce bacterial burden in the environment, for successful VRE control.Infect Control Hosp Epidemiol 2018;39:668-675. PMID- 29611492 TI - Occurrence and Recovery of Different Neglect-Related Symptoms in Right Hemisphere Infarct Patients during a 1-Year Follow-Up. AB - OBJECTIVES: To examine the occurrence of and recovery from visual neglect-related symptoms with the focus on neglect laterality, ipsilateral orienting bias, and slowed processing speed in right hemisphere (RH) infarct patients during a 1-year follow-up. Furthermore, to propose guidelines for assessing processing speed alongside the Behavioural Inattention Test (BIT). METHODS: We studied three RH patient groups: neglect (N+), mild left inattention (MLI+), and non-neglect (N-) patients, and healthy controls. The BIT with some additional analyses was conducted at the acute phase and at 6 and 12 months. RESULTS: The N+ group's BIT score increased and originally lateralized omissions became more evenly distributed during the follow-up. The N+ and MLI+ groups' starting points were more rightward located than the healthy group's at the acute phase and at 6, and partly at 12 months. Patient groups were slower than the controls in performing cancellation tests at the acute phase. The N+ and MLI+ groups remained slower than the controls throughout the follow-up. CONCLUSIONS: During the first year after RH infarct, originally left-sided manifestation of neglect shifted toward milder non-lateralized attentional deficit. Ipsilateral orienting bias and slowed processing speed appeared to be rather persistent neglect-related symptoms both in neglect patients and patients with initially milder inattention. We propose some effortless, tentative ways of examining processing speed and ipsilateral orienting bias alongside the BIT to better recognize these neglect-related symptoms, and highlight the need to assess and treat patients with initially milder inattention, who have been under-recognized and under-treated in clinical work. (JINS, 2018, 24, 617-628). PMID- 29611493 TI - Nosocomial Outbreak of Upper Respiratory Tract Infection With beta-Lactamase Negative Ampicillin-Resistant Nontypeable Haemophilus influenzae. AB - OBJECTIVETo describe the epidemiologic features of an outbreak of an acute respiratory tract infection (ARI) caused by beta-lactamase-negative ampicillin resistant (BLNAR) nontypeable Haemophilus influenzae (NTHi) in an acute-care ward.DESIGNCross-sectional case-control study.SETTINGAn acute-care ward (ward A) in a general hospital of Kochi in western Japan.METHODSPatients who shared a room with an index patient and all staff in ward A were screened and followed from July 1 to August 31, 2015. Sputum or throat swab samples were collected from participants and tested by culture and polymerase chain reaction (PCR). The association between detected pathogens and ARI development among all participants was examined. A case-control study was conducted to identify risk factors for disease.RESULTSIn total, 78 participants, including the index patient, were enrolled. Of all participants, 27 (34.6%) developed mild respiratory symptoms during a 3-week period: 24 were diagnosed as upper respiratory tract infections, and 3 were diagnosed as lower respiratory tract infections. The presence of BLNAR NTHi was confirmed in 13 participants, and multilocus sequence typing demonstrated that these isolates belonged to sequence type 159. All isolates showed identical pulsed-field gel electrophoresis patterns. The presence of BLNAR NTHi was strongly associated with ARI development, whereas viruses were not associated with the disease. Multivariate analyses demonstrated that a history of contact with the index patient was independently associated with ARI caused by BLNAR NTHi.CONCLUSIONSBLNAR NTHi has the potential to cause upper respiratory tract infections among adults and to spread rapidly in hospital settings.Infect Control Hosp Epidemiol 2018;39:652-659. PMID- 29611494 TI - Reducing Clostridium difficile Colitis Rates Via Cost-Saving Diagnostic Stewardship. AB - We conducted a quality improvement project at a large public tertiary-care academic hospital to reduce reported hospital-acquired Clostridium difficile infection (CDI) rates. We introduced diagnostic stewardship and provider education, resulting in a 2-fold reduction in C. difficile nucleic acid amplification test (NAAT) orders and markedly lower hospital CDI rate.Infect Control Hosp Epidemiol 2018;39:734-736. PMID- 29611495 TI - Clinical and Neurophysiological Features of Leprosy Patients with Neuropathic Pain. AB - Neural pain is a frequent symptom in leprosy disease. There is a paucity of data regarding neural pain diagnostics resulting in common prescriptive errors when neuritis is confused with neuropathic or mixed nociceptive-neuropathic pain. The present study identified important demographic, clinical, and neurophysiological features of 42 leprosy neuropathy patients presenting neuropathic pain (NP). During routine evaluations, patients were selected asking if they had ever experienced neural pain. Data analyses of their pain characteristics, clinical examination results, and both the Douleur Neuropathique 4 Questionnaire and Hamilton Depression Scale scores were used to classify these patients. The most common word they used to describe the sensation of pain for 25 (60%) of these patients was "burning." In the early stages of the disease and before leprosy diagnosis, 19 (45%) had already complained about NP and leprosy treatment was unable to prevent its occurrence in 15 (36%). Leprosy reactions, considered NP risk factors, occurred in 32 (76%) cases. Knowledge of typical NP characteristics could be used to develop more effective therapeutic approaches for a notoriously difficult-to-treat pain condition. PMID- 29611496 TI - Case Report: Role of Interventional Radiology in the Management of Patients with Alveolar Echinococcus: Successful Management of Three Cases. AB - Alveolar echinococcus (AE) is an infestation by Echinococcus multilocularis. Partial hepatectomy or liver transplantation is the first choice of treatment. However, the disease is usually diagnosed at an unresectable stage. In those cases, invasion of the bile ducts and vessels, and necrosis in the center of the lesion lead to severe complications, such as cholangitis and liver abscesses. Palliative surgery has been reported to not offer advantages in management, and percutaneous and endoscopic interventions have become more prominent in management. In this case series, outcomes in three cases with unresectable AE were reported. In one of the cases, interventional procedures were used to manage the complications after surgery. In the second case, the cystic component was aspirated to decrease the size before the surgery and in the third case, it was used to drain biliary tree and no surgery was done. PMID- 29611497 TI - Validity of Time to Sputum Culture Conversion to Predict Cure in Patients with Multidrug-Resistant Tuberculosis: A Retrospective Single-Center Study. AB - To evaluate the predictive value of time to sputum culture conversion (SCC) in predicting cure and factors associated with time to SCC and cure in multidrug resistant tuberculosis (MDR-TB) patients, a retrospective study was conducted at programmatic management unit of drug resistant tuberculosis (TB), Peshawar. A total of 428 pulmonary MDR-TB patients enrolled at the study site from January 1, 2012 to August 31, 2014 were followed until treatment outcome was recorded. Survival analysis using Cox proportional hazards model and multivariate binary logistic regression were, respectively, used to identify factors associated with time to SCC and cure. A P value < 0.05 was considered statistically significant. Overall, 90.9% patients achieved SCC, and 76.9% were cured. Previous use of second-line drugs (SLDs) (hazard ratio [HR] = 0.637; 95% confidence interval [CI] = 0.429-0.947), ofloxacin resistance (HR = 0.656; 95% CI = 0.522-0.825) and lung cavitation (HR = 0.744; 95% CI = 0.595-0.931) were significantly associated with time to SCC. In predicting cure, sensitivities of SCC at 2, 4, and 6 months were 64.1% (95% CI = 58.69-69.32), 93.0% (95% CI = 89.69-95.52), and 97.6% (95% CI = 95.27-98.94), respectively, whereas specificities were 67.7% (95% CI = 57.53 76.73), 51.5% (95% CI = 41.25-61.68), and 44.4% (95% CI = 34.45-54.78), respectively. Furthermore, patients' age of 41-60 (odds ratio [OR] = 0.202; 95% CI = 0.067-0.605) and > 60 years (OR = 0.051; 95% CI = 0.011-0.224), body weight > 40 kg (OR = 2.950; 95% CI = 1.462-5.952), previous SLD use (OR = 0.277; 95% CI = 0.097-0.789), lung cavitation (OR = 0.196; 95% CI = 0.103-0.371) and ofloxacin resistance (OR = 0.386; 95% CI = 0.198-0.749) were significantly associated with cure. Association of SCC with cure was substantially stronger at 6 months (OR = 32.10; 95% CI = 14.34-71.85) than at 4 months (OR = 14.13; 95% CI = 7.92-25.21). However in predicting treatment outcomes, the combined sensitivity and specificity of SCC at 4 months was comparable to SCC at 6 months. Patients with risk factors for delayed SCC were also at high risk of unsuccessful outcomes. PMID- 29611498 TI - Survey to Identify Substandard and Falsified Tablets in Several Asian Countries with Pharmacopeial Quality Control Tests and Principal Component Analysis of Handheld Raman Spectroscopy. AB - The World Health Organization has warned that substandard and falsified medical products (SFs) can harm patients and fail to treat the diseases for which they were intended, and they affect every region of the world, leading to loss of confidence in medicines, health-care providers, and health systems. Therefore, development of analytical procedures to detect SFs is extremely important. In this study, we investigated the quality of pharmaceutical tablets containing the antihypertensive candesartan cilexetil, collected in China, Indonesia, Japan, and Myanmar, using the Japanese pharmacopeial analytical procedures for quality control, together with principal component analysis (PCA) of Raman spectrum obtained with handheld Raman spectrometer. Some samples showed delayed dissolution and failed to meet the pharmacopeial specification, whereas others failed the assay test. These products appeared to be substandard. Principal component analysis showed that all Raman spectra could be explained in terms of two components: the amount of the active pharmaceutical ingredient and the kinds of excipients. Principal component analysis score plot indicated one substandard, and the falsified tablets have similar principal components in Raman spectra, in contrast to authentic products. The locations of samples within the PCA score plot varied according to the source country, suggesting that manufacturers in different countries use different excipients. Our results indicate that the handheld Raman device will be useful for detection of SFs in the field. Principal component analysis of that Raman data clarify the difference in chemical properties between good quality products and SFs that circulate in the Asian market. PMID- 29611499 TI - Case Report: Paederus Dermatitis in the Returning Traveler. AB - Rash in the returned traveler can provide a diagnostic dilemma for clinicians, but a detailed history including epidemiologic exposures can allow prompt diagnosis of etiologies uncommon in the United States. One such disease is Paederus dermatitis, an irritant contact dermatitis related to exposure to the rove beetle characterized by bullous lesions with surrounding erythema. Although cases and outbreaks have commonly been reported throughout the world, they are rarely reported in travelers returning to the United States. Here, we describe a patient who presented to an academic medical center in Virginia after travel to Sierra Leone with clinical presentation including exposure history and histopathology consistent with Paederus dermatitis. Our patient's clinic course is described in detail including treatment. Usual treatment includes antihistamines, topical steroids, and oral antibiotics, particularly with antimicrobials with activity against Pseudomonas sp. In addition, this case suggests a potential role for oral steroids in the treatment of this condition but further investigation is required. This case demonstrates the importance of considering a patient's travel and exposure history, as well as having familiarity with disease processes common in other parts of the world that are rarely seen in the United States. PMID- 29611500 TI - A Randomized Controlled Trial to Assess the Impact of Ceramic Water Filters on Prevention of Diarrhea and Cryptosporidiosis in Infants and Young Children Western Kenya, 2013. AB - Cryptosporidium is a leading cause of diarrhea among Kenyan infants. Ceramic water filters (CWFs) are used for household water treatment. We assessed the impact of CWFs on diarrhea, cryptosporidiosis prevention, and water quality in rural western Kenya. A randomized, controlled intervention trial was conducted in 240 households with infants 4-10 months old. Twenty-six weekly household surveys assessed infant diarrhea and health facility visits. Stool specimens from infants with diarrhea were examined for Cryptosporidium. Source water, filtered water, and filter retentate were tested for Cryptosporidium and/or microbial indicators. To estimate the effect of CWFs on health outcomes, logistic regression models using generalized estimating equations were performed; odds ratios (ORs) and 95% confidence intervals (CIs) are reported. Households reported using surface water (36%), public taps (29%), or rainwater (17%) as their primary drinking water sources, with no differences in treatment groups. Intervention households reported less diarrhea (7.6% versus 8.9%; OR: 0.86 [0.64-1.16]) and significantly fewer health facility visits for diarrhea (1.0% versus 1.9%; OR: 0.50 [0.30 0.83]). In total, 15% of intervention and 12% of control stools yielded Cryptosporidium (P = 0.26). Escherichia coli was detected in 93% of source water samples; 71% of filtered water samples met World Health Organization recommendations of < 1 E. coli/100 mL. Cryptosporidium was not detected in source water and was detected in just 2% of filter rinses following passage of large volumes of source water. Water quality was improved among CWF users; however, the short study duration and small sample size limited our ability to observe reductions in cryptosporidiosis. PMID- 29611501 TI - Comparison of PCR Methods for Onchocerca volvulus Detection in Skin Snip Biopsies from the Tshopo Province, Democratic Republic of the Congo. AB - Defining the optimal diagnostic tools for evaluating onchocerciasis elimination efforts in areas co-endemic for other filarial nematodes is imperative. This study compared three published polymerase chain reaction (PCR) methods: the Onchocerca volvulus-specific qPCR-O150, the pan-filarial qPCR melt curve analysis (MCA), and the O150-PCR enzyme-linked immunosorbent assay (ELISA) currently used for vector surveillance in skin snip biopsies (skin snips) collected from the Democratic Republic of the Congo. The pan-filarial qPCR-MCA was compared with species-specific qPCRs for Loa loa and Mansonella perstans. Among the 471 skin snips, 47.5%, 43.5%, and 27.0% were O. volvulus positive by qPCR-O150, qPCR-MCA, and O150-PCR ELISA, respectively. Using qPCR-O150 as the comparator, the sensitivity and specificity of qPCR-MCA were 89.3% and 98.0%, respectively, whereas for O150-PCR ELISA, they were 56.7% and 100%, respectively. Although qPCR MCA identified the presence of L. loa and Mansonella spp. in skin snips, species specific qPCRs had greater sensitivity and were needed to identify M. perstans. Most of the qPCR-MCA misclassifications occurred in mixed infections. The reduced sensitivity of O150-PCR ELISA was associated with lower microfilaria burden and with lower amounts of O. volvulus DNA. Although qPCR-MCA identified most of the O. volvulus-positive skin snips, it is not sufficiently robust to be used for stop-mass drug administration (MDA) evaluations in areas co-endemic for other filariae. Because O150-PCR ELISA missed 43.3% of qPCR-O150-positive skin snips, the qPCR-O150 assay is more appropriate for evaluating skin snips of OV-16 + children in stop-MDA assessments. Although improving the sensitivity of the O150 PCR ELISA as an alternative to qPCR might be possible, qPCR-O150 offers distinct advantages aside from increased sensitivity. PMID- 29611502 TI - Empowering Girls and Women through Hookworm Prevention. PMID- 29611503 TI - Accuracy of the Lee-White Clotting Time Performed in the Hospital Routine to Detect Coagulopathy in Bothrops atrox Envenomation. AB - Snake envenomation is a major public health problem in Brazil. Systemic complications that may arise from snakebites are mainly related to coagulopathy. The Lee-White clotting time (LWCT) is a simple and inexpensive test and available even in remote health facilities. However, the diagnostic value of such test needs to be evaluated to accurately diagnose coagulopathy in the clinical practice. This study aimed to assess the reliability of the LWCT performed in hospital routine to diagnose venom-induced coagulopathy. We studied 186 patients admitted at the Tropical Medicine Foundation Dr. Heitor Vieira Dourado in Manaus, Amazonas, Brazil, with Bothrops envenomation diagnosis. At admission, blood samples were collected for performing LWCT and the concentration of fibrinogen. Sensitivity, specificity, positive predictive value, negative predictive value, likelihood ratios, diagnostic odds ratio, and accuracy were calculated with 95% confidence intervals. From the total, 85.5% had hypofibrinogenemia. The sensitivity of the LWCT to the diagnosis of hypofibrinogenemia was 78.0% and the specificity 40.7%. The accuracy of the test was 72.6%, and patients with a prolonged LWCT had 2.4 higher odds of developing hypofibrinogenemia. In addition, the LWCT was also compared with venom antigen levels and systemic hemorrhage. The LWCT showed moderate sensitivity to detect consumption coagulopathy and constitutes a valuable tool for the diagnosis of Bothrops snake envenomation and indication of antivenom therapy. PMID- 29611504 TI - Albendazole Treatment Improves Work Capacity in Women Smallholder Farmers Infected with Hookworm: A Double-Blind Randomized Control Trial. AB - An estimated 4.7 billion people live in regions exposed to soil-transmitted helminths, intestinal parasites that have significant impacts on the health of women smallholder farmers. The goal of this trial was to determine whether treatment with albendazole impacts the work capacity of these farmers. This is a prospective double-blind, randomized effectiveness trial. Participants (N = 250) were randomly selected from safe motherhood groups in the Democratic Republic of Congo. Prevalence/intensity of hookworm infection, hemoglobin, and demographics was obtained. At study (Time = 0), participants were randomized into treatment (albendazole 400 mg) and placebo (similar placebo tablet) groups. A step test was administered as a proxy metric for work capacity. Work capacity was defined as ?heart rate before and after 3 minutes of step testing, in beats per minute. At study (time = 7 months), the step test was repeated and work capacity remeasured. The ?work capacity (time = 0 minus time = 7 months) was the primary outcome. Investigators/field assistants were blinded to who was enrolled in groups, hookworm status, and step test results. Regression showed highly significant interactive effects of hookworm status and treatment group relative to ?work capacity after controlling for resting pulse rate and age (P < 0.002). Estimated marginal means for work capacity (WC) for each of four groups (hookworm positive plus placebo, hookworm positive plus treatment, hookworm negative plus placebo, and hookworm negative plus treatment) showed women who were hookworm positive and received treatment decreased heart rate by 9.744 (95% confidence interval [CI]: 6.42, 13.07) beats per minute (increased WC), whereas women who were hookworm positive and received placebo saw a nonsignificant decrease of 0.034 (95% CI: 3.16, 3.84) beats per minute. Treatment with albendazole was associated with improved aerobic work capacity posttreatment. Given modest costs of drug distributions, risk benefits of periodic deworming warrants further study in larger controlled trials. PMID- 29611505 TI - Hospitalized Bacteremic Melioidosis in Rural Thailand: 2009-2013. AB - Melioidosis incidence and mortality have reportedly been increasing in endemic areas of Thailand, but little population-based data on culture-confirmed Burkholderia pseudomallei infections exist. We provide updated estimates of melioidosis bacteremia incidence and in-hospital mortality rate using integration of two population-based surveillance databases in Nakhon Phanom, Thailand, since automated blood culture became available in 2005. From 2009 to 2013, 564 hospitalized bacteremic melioidosis patients were identified. The annual incidence of bacteremic melioidosis ranged from 14 to 17 per 100,000 persons, and average population mortality rate was 2 per 100,000 persons per year. In-hospital mortality rate declined nonsignificantly from 15% (15/102) to 13% (15/118). Of 313 (56%) bacteremic melioidosis patients who met criteria for acute lower respiratory infection and were included in the hospital-based pneumonia surveillance system, 65% (202/313) had a chest radiograph performed within 48 hours of admission; 46% (92/202) showed radiographic evidence of pneumonia. Annual incidence of bacteremic melioidosis with pneumonia was 2.4 per 100,000 persons (95% confidence intervals; 1.9-2.9). In-hospital death was more likely among bacteremic melioidosis patients with pneumonia (34%; 20/59) compared with non-pneumonia patients (18%; 59/321) (P-value = 0.007). The overall mortality could have been as high as 46% (257/564) if patients with poor clinical condition at the time of discharge had died. The continued high incidence of bacteremic melioidosis, pneumonia, and deaths in an endemic area highlights the need for early diagnosis and treatment and additional interventions for the prevention and control for melioidosis. PMID- 29611506 TI - Epidemiological and Clinical Features of Melioidosis: A Report of Seven Cases from Southern Inland China. AB - Some subtropical regions with similar climatic conditions to melioidosis-endemic areas, such as southern Guangxi, may be new endemic zones for melioidosis. We retrospectively reviewed seven culture-proven melioidosis patients from October 2006 to March 2015. Their clinical characteristics, diagnosis, and treatment, and the geographical and environmental factors were analyzed. Seven male patients lived at latitudes of 21-23 degrees N in Beihai, Nanning, Chongzuo City of the Guangxi Province. Symptom onset occurred during the rainy season. All patients had pneumonia, six patients had diabetes, five patients had a history of wounds or exposure to soil or water, and two patients had liver and spleen abscesses. Most patients were misdiagnosed before the confirmatory laboratory testing. The final diagnosis was confirmed as melioidosis by isolation of Burkholderia pseudomallei in a culture of blood or pus. The 6- to 17-month treatment included carbapenems, ceftazidime, or other antibiotics active against the organism in vitro. All patients initially appeared cured, but two subsequently had recurrent melioidosis. In non-highly endemic areas, there is often a lack of awareness of melioidosis, and this leads to misdiagnoses. Other subtropical regions with climatic conditions similar to the highly melioidosis-endemic areas such as southern Guangxi may also be melioidosis endemic. PMID- 29611507 TI - Environmental Enteropathy in Undernourished Pakistani Children: Clinical and Histomorphometric Analyses. AB - Despite nutrition interventions, stunting thought to be secondary to underlying environmental enteropathy (EE) remains pervasive among infants residing in resource-poor countries and remains poorly characterized. From a birth cohort of 380 children, 65 malnourished infants received 12 weeks of nutritional supplementation with ready-to-use therapeutic food (RUTF). Eleven children with insufficient response to RUTF underwent upper endoscopy with duodenal biopsies, which were compared with U.S., age-matched specimens for healthy, celiac disease, non-celiac villous atrophy, non-celiac intraepithelial lymphocytosis, and graft versus-host disease patients. Of the 11 children biopsied, EE was found in 10 (91%) with one subject with celiac disease. Morphometry demonstrated decreased villus-to-crypt (V:C) ratios in EE relative to healthy and non-celiac lymphocytosis patients. Environmental enteropathy villus volumes were significantly decreased relative to healthy controls. In EE, average CD3+ cells per 100 epithelial cells and per 1,000 um2 of lamina propria and the number of lamina propria CD20+ B-cell aggregates were increased relative to all other groups. Our results indicate that V:C ratios are reduced in EE but are less severe than in celiac disease. Environmental enteropathy intraepithelial and lamina propria T lymphocytosis is of greater magnitude than that in celiac disease. The increases in lamina propria B and T lymphocytes suggest that non cytolytic lymphocytic activation may be a more prominent feature of EE relative to celiac disease. These results provide new insights into shared yet distinct histological and immunological features of EE and celiac disease in children. PMID- 29611508 TI - Real-Time Modeling Should Be Routinely Integrated into Outbreak Response. PMID- 29611509 TI - Internally Controlled, Multiplex Real-Time Reverse Transcription PCR for Dengue Virus and Yellow Fever Virus Detection. AB - The differential diagnosis of dengue virus (DENV) and yellow fever virus (YFV) infections in endemic areas is complicated by nonspecific early clinical manifestations. In this study, we describe an internally controlled, multiplex real-time reverse transcription polymerase chain reaction (rRT-PCR) for the detection of DENV and YFV. The DENV-YFV assay demonstrated specific detection and had a dynamic range of 2.0-8.0 log10 copies/MUL of eluate for each DENV serotype and YFV. Clinical performance was similar to a published pan-DENV assay: 48/48 acute-phase samples from dengue cases were detected in both assays. For YFV detection, mock samples were prepared with nine geographically diverse YFV isolates over a range of concentrations. The DENV-YFV assay detected 62/65 replicates, whereas 54/65 were detected using a reference YFV rRT-PCR. Given the reemergence of DENV and YFV in areas around the world, the DENV-YFV assay should be a useful tool to narrow the differential diagnosis and provide early case detection. PMID- 29611510 TI - Trends in Public and Global Health Education among Nationally Recognized Undergraduate Liberal Arts Colleges in the United States. AB - The prevalence of public health and global health (PH/GH) curricular offerings appear to be increasing in terms of undergraduate curricula and in the context of liberal arts education in the United States. Liberal arts colleges (LACs) represent stand-alone institutions, which exclusively focus on undergraduate education. The objective of this study was to assess the prevalence of PH/GH study pathways and PH/GH course offerings among LACs. All LACs identified through the US News and World Report (USNWR) college rankings were contacted with a survey about the following: formal majors, minors, or concentrations in PH/GH; independent study (IS) pathways for PH/GH; specific PH/GH courses offered; and the number of students graduating in 2016, 2017, and 2018 with formal and IS degrees in PH/GH. Demographic characteristics of the colleges came from the USNWR database. Almost half (43%) of all LACs in our sample offer a PH/GH major, minor, concentration, or IS pathway. Almost all (90%) colleges offer at least one course in PH/GH. Approximately 2,000 students attending these LACs pursued or are pursuing graduation with majors, minors, or concentrations in PH/GH for the years 2016-2018. The number of students pursuing formal PH/GH programs has increased by 25% from 2016 to 2018. Student interest in public health is rising in U.S. LACs, with more students seeking formal curricular or IS PH degree pathways. Public health messages are prevalent even among institutions without formal programs. Colleges without programs should consider integrating public health into their curriculum. PMID- 29611512 TI - New interventions offer prostate cancer hope. PMID- 29611511 TI - Use of TaqMan Array Cards to Screen Outbreak Specimens for Causes of Febrile Illness in Tanzania. AB - We describe the deployment of a custom-designed molecular diagnostic TaqMan Array Card (TAC) to screen for 31 bacterial, protozoal, and viral etiologies in blood from outbreaks of acute febrile illness in Tanzania during 2015-2017. On outbreaks notified to the Tanzanian Ministry of Health, epidemiologists were dispatched and specimens were collected, transported to a central national laboratory, and tested by TAC within 2 days. This algorithm streamlined investigation, diagnosed a typhoid outbreak, and excluded dozens of other etiologies. This method is usable in-country and may be incorporated into algorithms for diagnosing outbreaks. PMID- 29611513 TI - Adjuvant therapy in colon cancer: less is more. PMID- 29611514 TI - The NHS and migrant patients with cancer. PMID- 29611515 TI - Guidelines for sub-Saharan Africa: a call for evidence. PMID- 29611516 TI - Slogans and donor pages of cancer centres: do they convey discordant messages? PMID- 29611517 TI - Opportunities for improving oncology care. PMID- 29611519 TI - Genetic testing for young women with breast cancer. PMID- 29611518 TI - 3 versus 6 months of adjuvant oxaliplatin-fluoropyrimidine combination therapy for colorectal cancer (SCOT): an international, randomised, phase 3, non inferiority trial. AB - BACKGROUND: 6 months of oxaliplatin-containing chemotherapy is usually given as adjuvant treatment for stage 3 colorectal cancer. We investigated whether 3 months of oxaliplatin-containing chemotherapy would be non-inferior to the usual 6 months of treatment. METHODS: The SCOT study was an international, randomised, phase 3, non-inferiority trial done at 244 centres. Patients aged 18 years or older with high-risk stage II and stage III colorectal cancer underwent central randomisation with minimisation for centre, choice of regimen, sex, disease site, N stage, T stage, and the starting dose of capecitabine. Patients were assigned (1:1) to receive 3 months or 6 months of adjuvant oxaliplatin-containing chemotherapy. The chemotherapy regimens could consist of CAPOX (capecitabine and oxaliplatin) or FOLFOX (bolus and infused fluorouracil with oxaliplatin). The regimen was selected before randomisation in accordance with choices of the patient and treating physician. The primary study endpoint was disease-free survival and the non-inferiority margin was a hazard ratio of 1.13. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who started study treatment. This trial is registered with ISRCTN, number ISRCTN59757862, and follow-up is continuing. FINDINGS: 6088 patients underwent randomisation between March 27, 2008, and Nov 29, 2013. The intended treatment was FOLFOX in 1981 patients and CAPOX in 4107 patients. 3044 patients were assigned to 3 month group and 3044 were assigned to 6 month group. Nine patients in the 3 month group and 14 patients in the 6 month group did not consent for their data to be used, leaving 3035 patients in the 3 month group and 3030 patients in the 6 month group for the intention-to-treat analyses. At the cutoff date for analysis, there had been 1482 disease-free survival events, with 740 in the 3 month group and 742 in the 6 month group. 3 year disease-free survival was 76.7% (95% CI 75.1-78.2) for the 3 month group and 77.1% (75.6-78.6) for the 6 month group, giving a hazard ratio of 1.006 (0.909-1.114, test for non inferiority p=0.012), significantly below the non-inferiority margin. Peripheral neuropathy of grade 2 or worse was more common in the 6 month group (237 [58%] of 409 patients for the subset with safety data) than in the 3 month group (103 [25%] of 420) and was long-lasting and associated with worse quality of life. 1098 serious adverse events were reported (492 reports in the 3 month group and 606 reports in the 6 month group) and 32 treatment-related deaths occurred (16 in each group). INTERPRETATION: In the whole study population, 3 months of oxaliplatin-containing adjuvant chemotherapy was non-inferior to 6 months of the same therapy for patients with high-risk stage II and stage III colorectal cancer and was associated with reduced toxicity and improved quality of life. Despite the fact the study was underpowered, these data suggest that a shorter duration leads to similar survival outcomes with better quality of life and thus might represent a new standard of care. FUNDING: Medical Research Council, Swedish Cancer Society, NETSCC, and Cancer Research UK. PMID- 29611520 TI - Genetic testing for young women with breast cancer - Authors' reply. PMID- 29611521 TI - Correction to Lancet Oncol 2018; 19: 474-85. PMID- 29611522 TI - Correction to Lancet Oncol 2013; 14: 1067-76. PMID- 29611523 TI - Correction to Lancet Oncol 2018; 19: 434-36. PMID- 29611524 TI - Correction to Lancet Oncol 2017; 18: 1221-37. PMID- 29611525 TI - Correction to Lancet Oncol 2018; 19: 510-20. PMID- 29611526 TI - Correction to Lancet Oncol 2018; 19: 295-309. PMID- 29611527 TI - Chemotherapy medication errors. AB - Although chemotherapy is a well established treatment modality, chemotherapy errors represent a potentially serious risk of patient harm. We reviewed published research from 1980 to 2017 to understand the extent and nature of medication errors in cancer chemotherapy, and to identify effective interventions to help prevent mistakes. Chemotherapy errors occur at a rate of about one to four per 1000 orders, affect at least 1-3% of adult and paediatric oncology patients, and occur at all stages of the medication use process. Oral chemotherapy use is a particular area of growing risk. Our knowledge of chemotherapy errors is drawn primarily from single-institution studies at university hospitals and referral centres, with a particular focus on prescription orders and pharmacy practices. Although the heterogeneity of research methods and measures used in these studies limits our understanding of this issue, the rate of chemotherapy error-related injuries is generally lower than those seen in comparable studies of general medical patients. Although many interventions show promise in reducing chemotherapy errors, most have little empirical support. Additional research is needed to understand and to mitigate the risk of chemotherapy medication errors. PMID- 29611529 TI - Oncology drugs in the crosshairs of pharmaceutical crime. AB - Oncology drugs clearly have become a target for pharmaceutical crime. In 2016, falsified oncology drugs ranked fifth in the most commonly falsified drug category among the reports received by the Pharmaceutical Security Institute. Although the prevalence of illicit oncology drugs in the legal supply chains appears to be small, these drugs are difficult to detect, particularly in clinical practice. Forthcoming countermeasures to detect illicit drugs in high income countries include compulsory antitampering devices and product verification technology for a risk-based selection of medicines. Health-care professionals must implement these new procedures into their workflow and remain vigilant about those medicines that are not selected. Although countermeasures should firmly tighten supply chain security, there are concerns about how quickly pharmaceutical crime will adapt to these protections. Because patients and health care professionals have shown a lenient attitude towards purchasing medicines from unreliable sources, measures against the highly accessible illegal medicine supply chain remain necessary. To improve detectability in clinical practice, reporting of ineffectiveness and unusual drug effects as adverse events or adverse drug reactions is essential. PMID- 29611530 TI - Periosteal aneurysmal bone cyst. PMID- 29611528 TI - Medication overuse in oncology: current trends and future implications for patients and society. AB - The high cost of cancer care worldwide is largely attributable to rising drugs prices. Despite their high costs and potential toxic effects, anticancer treatments could be subject to overuse, which is defined as the provision of medical services that are more likely to harm than to benefit a patient. We found 30 studies documenting medication overuse in cancer, which included 16 examples of supportive medication overuse and 17 examples of antineoplastic medication overuse in oncology. Few specific agents have been assessed, and no studies investigated overuse of the most toxic or expensive medications currently used in cancer treatment. Although financial, psychological, or physical harms of medication overuse in cancer could be substantial, there is little published evidence addressing these harms, so their magnitude is unclear. Further research is needed to better quantify medication overuse, understand its implications, and help protect patients and the health-care system from overuse. PMID- 29611531 TI - Erratum to: Iuchi T, Hatano K, Uchino Y, et al. Methionine uptake and required radiation dose to control glioblastoma. Int J Radiat Oncol Biol Phys 2015;93:133 140. PMID- 29611532 TI - A disease-causing novel missense mutation in the ST14 gene underlies autosomal recessive ichthyosis with hypotrichosis syndrome in a consanguineous family. AB - Autosomal recessive ichthyosis with hypotrichosis (ARIH; MIM 602400) syndrome is characterized by diffused congenital ichthyosis and generalized non-scarring hypotrichosis. The underlying genetic cause of ARIH syndrome has been associated with sequence variants of the gene ST14, encoding type II transmembrane serine protease matriptase, which maps to chromosome 11q24.3. The current report aimed to investigate the clinical features and genetic cause of ARIH syndrome in a large consanguineous family of Pakistani origin. The technique of homozygosity mapping with highly polymorphic microsatellite markers was employed to establish linkage within the family. Sanger sequencing of exons and intron-exon boundaries of ST14 was performed to identify the potential pathogenic sequence variants, followed by structural analysis of the mutated protein. Linkage was established to chromosome 11q24.3, comprising the gene ST14. Sequence analysis led to the identification of a novel homozygous missense variant (c.1315G>A, p.Gly439Ser) in the ST14 gene that co-segregated with the disease phenotype in all affected members. Homology modelling and molecular docking analysis of ST14 with wild-type TMEFF1 protein was performed which revealed that glycine at position 439 is crucial for maintaining normal structural confirmation and interaction with the EGF domain of TMEFF1 protein. Taken together, the data strongly advocate this ST14 variant as the underlying genetic cause of ARIH syndrome in this first reported affected family from Pakistan. Moreover, the present study adds to the spectrum of mutations in the ST14 gene, implicating them in the pathogenesis of ARIH syndrome. PMID- 29611533 TI - New information on morphology and molecular data of camallanid nematodes parasitising Xenopus laevis (Anura: Pipidae) in South Africa. AB - Three species of nematodes from the Camallanidae that are known to infect Xenopus laevis Daudin (Anura: Pipidae) were collected from several localities across South Africa. New data on morphology, partial 28S and cox1 genes, infection levels and distribution are presented herein. The most common species, Batrachocamallanus slomei Southwell et Kirshner, 1937, from the stomach and less often oesophagus, was found in eight localities. Camallanus kaapstaadi Southwell et Kirshner, 1937, also from the oesophagus, was found in two localities and C. xenopodis Jackson et Tinsley, 1995, from the intestine, at a single locality. New localities for both C. kaapstaadi and C. xenopodis provide a geographical range extension. Males of C. xenopodis are described for the first time herein. The existence of a left spicule in the males of both the species of Camallanus Railliet and Henry, 1915 is confirmed and measurements are provided. Although C. xenopodis is distinguished from C. mazabukae Kung, 1948 in the present study, we suggest greater sampling effort in other African amphibians to confirm the species status of the latter taxon. Finally, the new molecular data showed distant relationships between collected species of Camallanus and species parasitising fish and freshwater turtles. PMID- 29611535 TI - Microscopic study of thermoelectric In-doped SnTe. AB - SnTe is a p-type thermoelectric material that is isostructural with PbTe, for which it is a potential environmentally friendly replacement. By doping the SnTe lattice with In, the thermal conductivity of SnTe can be significantly reduced and the thermoelectric conversion efficiency improved. A large number of precipitates were present in the In-doped SnTe samples; based on atomic resolution high-angle annular dark-field images and electron energy loss spectra, these precipitates were identified as the zinc-blende phase of In2Te3. Through geometry phase analysis, a new phonon scattering mechanism is discussed. PMID- 29611537 TI - Stroke: An alarmin' inflammatory response after stroke. PMID- 29611536 TI - Therapeutic Effect of Medical Ozone on Lumbar Disc Herniation. AB - BACKGROUND This study aimed to investigate the therapeutic effect of low, medium, and high concentrations of medical ozone on trauma-induced lumbar disc herniation. MATERIAL AND METHODS A total of 80 patients were included and were grouped into a control group, a low medical ozone (20 MUg/ml) group, a medium medical ozone (40 MUg/ml) group, and a high medical ozone (60 MUg/ml) group. The CT scan and enzyme-linked immunosorbent assay (ELISA) were used to detect IL-6 level, SOD activity, IgM, and IgG levels upon admission and at 6 and 12 months after follow-up. The area under the ROC curve (AUC) was calculated for visual analogue scale (VAS) and efficiency rate. RESULTS All patients showed disc retraction at 6- and 12-month follow-up; while patients in the medium medical ozone (40 MUg/ml) group showed the greatest disc retraction rate. The IL-6, IgM, IgG, and VAS levels significantly decreased while SOD activity increased among all groups over time (p<0.05). The AUCIL-6, AUCIgG, AUCIgM, and AUCSOD was closest to 1 in the medium medical ozone (40 MUg/ml) group compared with other groups (p<0.01), with the highest efficacy at 6 (35%) and 12 (85%) months during follow-up. CONCLUSIONS Low concentrations of medical ozone (20 MUg/ml and 40 MUg/ml) reduced the serum IL-6, IgG, and IgM expression, presenting as analgesic and anti-inflammatory effects, while high concentrations of medical ozone (60 MUg/ml) increased the serum IL-6, IgG, IgM expression, presenting as pain and pro inflammatory effects. The medical ozone concentration of 40 MUg/ml showed the optimal treatment efficacy. PMID- 29611534 TI - Calcium as a signal integrator in developing epithelial tissues. AB - Decoding how tissue properties emerge across multiple spatial and temporal scales from the integration of local signals is a grand challenge in quantitative biology. For example, the collective behavior of epithelial cells is critical for shaping developing embryos. Understanding how epithelial cells interpret a diverse range of local signals to coordinate tissue-level processes requires a systems-level understanding of development. Integration of multiple signaling pathways that specify cell signaling information requires second messengers such as calcium ions. Increasingly, specific roles have been uncovered for calcium signaling throughout development. Calcium signaling regulates many processes including division, migration, death, and differentiation. However, the pleiotropic and ubiquitous nature of calcium signaling implies that many additional functions remain to be discovered. Here we review a selection of recent studies to highlight important insights into how multiple signals are transduced by calcium transients in developing epithelial tissues. Quantitative imaging and computational modeling have provided important insights into how calcium signaling integration occurs. Reverse-engineering the conserved features of signal integration mediated by calcium signaling will enable novel approaches in regenerative medicine and synthetic control of morphogenesis. PMID- 29611538 TI - Neuroimmunology: Are naturally occurring anti-NMDAR autoantibodies pathogenic? PMID- 29611539 TI - PET imaging of the neurovascular interface in cerebrovascular disease. AB - This corrects the article DOI: 10.1038/nrneurol.2017.129. PMID- 29611540 TI - Obesity: ANGPTL4 - the link binding obesity and glucose intolerance. PMID- 29611541 TI - Nanocurcumin-pyrroloquinoline formulation prevents hypertrophy-induced pathological damage by relieving mitochondrial stress in cardiomyocytes under hypoxic conditions. AB - This study investigates the therapeutic effect of a nanocurcumin formulation (NCF) containing nanocurcumin (NC) and pyrroloquinoline quinone (PQQ) on ameliorating hypoxia-induced stress in hypertrophied primary human ventricular cardiomyocytes (HVCM) under hypoxic conditions, as validated in a Sprague-Dawley rat model of chronic hypobaric hypoxia (cHH)-induced right ventricular hypertrophy (RVH). Based on our previous findings, here, we analyzed the improvement in the protective efficacy of NCF against mitochondrial damage. The electron transport chain Complexes' activities were analyzed as a chief operational center for mitochondrial homeostasis, along with key gene and protein markers for mitochondrial biogenesis, redox function, fatty acid oxidation, bio energetic deficit and cell survival. NCF supplementation imparts cyto-protection from hypoxia-induced hypertrophy and damage in both in vitro and in vivo models while maintaining mitochondrial homeostasis better than NC and PQQ alone. This study proposes the use of NCF as a potential candidate molecule for imparting protection from high altitude-induced maladies in ascendants. PMID- 29611544 TI - Findings of Research Misconduct. PMID- 29611545 TI - Correction to: The common use of improper control diets in diet-induced metabolic disease research confounds data interpretation: the fiber factor. AB - [This corrects the article DOI: 10.1186/s12986-018-0243-5.]. PMID- 29611543 TI - Intracellular trafficking of TREM2 is regulated by presenilin 1. AB - Genetic mutations in triggering receptor expressed on myeloid cells 2 (TREM2) have been linked to a variety of neurodegenerative diseases including Alzheimer's disease, amyotrophic lateral sclerosis, frontotemporal dementia and Parkinson's disease. In the brain, TREM2 is highly expressed on the cell surface of microglia, where it can transduce signals to regulate microglial functions such as phagocytosis. To date, mechanisms underlying intracellular trafficking of TREM2 remain elusive. Mutations in the presenilin 1 (PS1) catalytic subunit of the gamma-secretase complex have been associated with increased generation of the amyloidogenic Abeta (amyloid-beta) 42 peptide through cleavage of the Abeta precursor amyloid precursor protein. Here we found that TREM2 interacts with PS1 in a manner independent of gamma-secretase activity. Mutations in TREM2 alter its subcellular localization and affects its interaction with PS1. Upregulation of PS1 reduces, whereas downregulation of PS1 increases, steady-state levels of cell surface TREM2. Furthermore, PS1 overexpression results in attenuated phagocytic uptake of Abeta by microglia, which is reversed by TREM2 overexpression. Our data indicate a novel role for PS1 in regulating TREM2 intracellular trafficking and pathophysiological function. PMID- 29611542 TI - Complex roles of the stroma in the intrinsic resistance to gemcitabine in pancreatic cancer: where we are and where we are going. AB - Pancreatic ductal adenocarcinoma (PDAC) is among the most devastating human malignancies. The poor clinical outcome in PDAC is partly attributed to a growth permissive tumor microenvironment. In the PDAC microenvironment, the stroma is characterized by the development of extensive fibrosis, with stromal components outnumbering pancreatic cancer cells. Each of the components within the stroma has a distinct role in conferring chemoresistance to PDAC, and intrinsic chemoresistance has further worsened this pessimistic prognosis. The nucleoside analog gemcitabine (GEM) is usually the recommended first-line chemotherapeutic agent for PDAC patients and is given alone or in combination with other agents. The mechanisms of intrinsic resistance to GEM are an active area of ongoing research. This review highlights the important role the complex structure of stroma in PDAC plays in the intrinsic resistance to GEM and discusses whether antistroma therapy improves the efficacy of GEM. The addition of antistroma therapy combined with GEM is expected to be a novel therapeutic strategy with significant survival benefits for PDAC patients. PMID- 29611546 TI - Osimertinib in first-line treatment-is a comparison not proof? PMID- 29611547 TI - Corrigendum: Reciprocal Interactions between Cadmium-Induced Cell Wall Responses and Oxidative Stress in Plants. AB - [This corrects the article on p. 1867 in vol. 8, PMID: 29163592.]. PMID- 29611548 TI - Osimertinib, the winner, but cannot yet take it all. PMID- 29611549 TI - Correction to: Aspergillus niger is a superior expression host for the production of bioactive fungal cyclodepsipeptides. AB - [This corrects the article DOI: 10.1186/s40694-018-0048-3.]. PMID- 29611550 TI - Erratum to semaglutide seems to be more effective the other GLP-1Ras. AB - [This corrects the article on p. 505 in vol. 5, PMID: 29299466.]. PMID- 29611551 TI - The impact of thoracic endovascular aortic repair on long-term survival in type B aortic dissection: response to editorial. PMID- 29611552 TI - On the article "Drugs targeting protease-activated receptor-4 improve the anti thrombotic therapeutic window". PMID- 29611553 TI - Connectivity as a multiple: In, with and as "nature". AB - Connectivity is a central concept in contemporary geographies of nature, but the concept is often understood and utilised in plural ways. This is problematic because of the separation, rather than the confusion, of these different approaches. While the various understandings of connectivity are rarely considered as working together, the connections between them have significant implications. This paper thus proposes re-thinking connectivity as a "multiple". It develops a taxonomy of existing connectivity concepts from the fields of biogeography and landscape ecology, conservation biology, socio-economic systems theory, political ecology and more-than-human geography. It then considers how these various understandings might be re-thought not as separate concerns, but (following Annemarie Mol) as "more than one, but less than many". The implications of using the connectivity multiple as an analytic for understanding conservation practices are demonstrated through considering the creation of wildlife corridors in conservation practice. The multiple does not just serve to highlight the practical and theoretical linkages between ecological theories, social inequities and affectual relationships in more-than-human worlds. It is also suggestive of a normative approach to environmental management that does not give temporal priority to biological theories, but considers these as always already situated in these social, often unequal, always more-than-human ecologies. PMID- 29611554 TI - Corrigendum: Novel Variant of New Delhi Metallo-beta-lactamase, NDM-20, in Escherichia coli. AB - [This corrects the article on p. 248 in vol. 9, PMID: 29515538.]. PMID- 29611555 TI - Endolysosomal pathway activity protects cells from neurotoxic TDP-43. AB - The accumulation of protein aggregates in neurons is a typical pathological hallmark of the motor neuron disease amyotrophic lateral sclerosis (ALS) and of frontotemporal dementia (FTD). In many cases, these aggregates are composed of the 43 kDa TAR DNA-binding protein (TDP 43). Using a yeast model for TDP 43 proteinopathies, we observed that the vacuole (the yeast equivalent of lysosomes) markedly contributed to the degradation of TDP 43. This clearance occurred via TDP 43-containing vesicles fusing with the vacuole through the concerted action of the endosomal-vacuolar (or endolysosomal) pathway and autophagy. In line with its dominant role in the clearance of TDP 43, endosomal-vacuolar pathway activity protected cells from the detrimental effects of TDP 43. In contrast, enhanced autophagy contributed to TDP 43 cytotoxicity, despite being involved in TDP 43 degradation. TDP 43's interference with endosomal-vacuolar pathway activity may have two deleterious consequences. First, it interferes with its own degradation via this pathway, resulting in TDP 43 accumulation. Second, it affects vacuolar proteolytic activity, which requires endosomal-vacuolar trafficking. We speculate that the latter contributes to aberrant autophagy. In sum, we propose that ameliorating endolysosomal pathway activity enhances cell survival in TDP 43 associated diseases. PMID- 29611556 TI - Helicobacter hepaticus polysaccharide induces an anti-inflammatory response in intestinal macrophages. AB - A high density of microbes inhabits the intestine, helping with food digestion, vitamin synthesis, xenobiotic detoxification, pathogen resistance and immune system maturation. Crucial for human health, communities of commensal bacteria (collectively termed microbiota) benefit in return from a nutrient-rich environment. Host-microbiota mutualism results from a long-term co-adaptation. At barrier surfaces, immune cells distinguish harmful from commensal bacteria and tolerate non-self organisms at close proximity to the mucosa; gut inhabitants have developed strategies to ensure beneficial conditions in their preferred niche. So far, the complex dialogue of host-microbial mutualism is poorly understood. Helicobacter hepaticus is a member of the mouse microbiota that colonizes the lower intestine without inducing immune pathology. However, when there is a host maladaptation such as the absence of the anti-inflammatory cytokine interleukin 10 (IL-10) or its receptor IL-10R, H. hepaticus triggers aberrant IL-23-driven intestinal inflammation. This response results in major changes in the intestinal innate cell compartment, with the accumulation of inflammatory macrophages. Relying both on a bacterial trigger and on an immune defect, H. hepaticus-induced colitis in the context of IL-10/IL-10R axis deficiency shares many features of human inflammatory bowel diseases (IBD). In our study [Danne et al, Cell Host Microbe 22(6):733-745], we questioned the interactions between H. hepaticus and intestinal macrophages that promote mutualism. Our results show that H. hepaticus produces a large polysaccharide that triggers IL-10 production without a corresponding inflammatory response in macrophages. Moreover, H. hepaticus polysaccharide specifically induces an anti inflammatory gene signature in vitro and in vivo, including transcriptional factors known as repressors of immune activation. This anti-inflammatory program depends on the TLR2/MSK/CREB pathway, which might be crucial to maintain mutualistic relationships at the intestinal interface. PMID- 29611557 TI - Risk models to select high risk candidates for lung cancer screening. PMID- 29611558 TI - The intranuclear length of the electrode trajectory according to the 'port' model for deep brain stimulation of the nucleus accumbens. PMID- 29611559 TI - Ultrafast dynamics in co-sensitized photocatalysts under visible and NIR light irradiation. AB - Co-sensitization to achieve a broad absorption window is a widely accepted technique in light harvesting nanohybrid synthesis. Protoporphyrin (PPIX) and squaraine (SQ2) are two organic sensitizers absorbing in the visible and NIR wavelength regions of the solar spectrum, respectively. In the present study, we have sensitized zinc oxide (ZnO) nanoparticles using PPIX and SQ2 simultaneously for their potential use in broad-band solar light harvesting in photocatalysis. Forster resonance energy transfer (FRET) from PPIX to SQ2 in close proximity to the ZnO surface has been found to enhance visible light photocatalysis. In order to confirm the effect of intermolecular FRET in photocatalysis, the excited state lifetime of the energy donor dye PPIX has been modulated by inserting d10 (ZnII) and d7 (CoII) metal ions in the central position of the dye (PP(Zn) and PP(Co)). In the case of PP(Co)-SQ2, extensive photo-induced ligand to metal charge transfer counteracts the FRET efficiency while efficient FRET has been observed for the PP(Zn)-SQ2 pair. This observation has been justified by the comparison of the visible light photocatalysis of the respective nanohybrids with several control studies. We have also investigated the NIR photocatalysis of the co sensitized nanohybrids which reveals that reduced aggregation of SQ2 due to co sensitization of PPIX increases the NIR photocatalysis. However, core-metalation of PPIX reduces the NIR photocatalytic efficacy, most probably due to excited state charge transfer from SQ2 to the metal centre of PP(Co)/PP(Zn) through the conduction band of the host ZnO nanoparticles. PMID- 29611560 TI - Cationic ionene as an n-dopant agent of poly(3,4-ethylenedioxythiophene). AB - We report the reduction of poly(3,4-ethylenedioxythiophene) (PEDOT) films with a cationic 1,4-diazabicyclo[2.2.2]octane-based ionene bearing N,N'-(meta phenylene)dibenzamide linkages (mPI). Our main goal is to obtain n-doped PEDOT using a polymeric dopant agent rather than small conventional tetramethylammonium (TMA), as is usual. This has been achieved using a three-step process, which has been individually optimized: (1) preparation of p-doped (oxidized) PEDOT at a constant potential of +1.40 V in acetonitrile with LiClO4 as the electrolyte; (2) dedoping of oxidized PEDOT using a fixed potential of -1.30 V in water; and (3) redoping of dedoped PEDOT applying a reduction potential of -1.10 V in water with mPI. The resulting films display the globular appearance typically observed for PEDOT, with mPI being structured in separated phases forming nanospheres or ultrathin sheets. This organization, which has been supported by atomistic molecular dynamics simulations, resembles the nanosegregated phase distribution observed for PEDOT p-doped with poly(styrenesulfonate). Furthermore, the doping level achieved using mPI as the doping agent is comparable to that achieved using TMA, even though ionene provides distinctive properties to the conducting polymer. For example, films redoped with mPI exhibit much more hydrophilicity than the oxidized ones, whereas films redoped with TMA are hydrophobic. Similarly, films redoped with mPI exhibit the highest thermal stability, while those redoped with TMA show thermal stability that is intermediate between those of the latter and the dedoped PEDOT. Overall, the incorporation of an mPI polycation as the n-dopant into PEDOT has important advantages for modulating the properties of this emblematic conducting polymer. PMID- 29611561 TI - Phase diversity in an adsorption model of an additive binary gas mixture for all sets of lateral interactions. AB - Complete analysis of phase behavior of an adsorption model of a binary gas mixture on a square lattice was carried out for all possible sets of lateral interactions between nearest adsorbed molecules of the same type and no interaction between adsorbed molecules of different types. The model was completely investigated in the ground state, and it was shown that the phase behavior of the system is conserved at finite temperatures by means of a transfer matrix method. PMID- 29611562 TI - Room-temperature ferromagnetism in Ni(ii)-chromia based core-shell nanoparticles: experiment and first principles calculations. AB - We have synthesized bimagnetic core-shell nanoparticles containing a first-of-its kind Ni(ii)-chromia nanophase shell and a well-defined, epitaxial core-shell interface. Magnetic measurements reveal a substantial coercivity of the nanoparticles and a significant exchange bias effect between the antiferromagnetic chromia core and the ferromagnetic Ni(ii)-chromia shell at low temperatures. The ferromagnetism and a weak exchange bias effect are found to persist to room temperature in the core-shell nanoparticles of ~57 nm average size. Our first principles Density Functional Theory (DFT) calculations confirm that the novel corundum-structured Ni(ii)-chromia phase has an equilibrium cluster-localized ferromagnetic spin configuration. In addition, the DFT-based calculations show that the Ni(ii)-chromia phase is a Mott-Hubbard insulator, with a narrowed energy band gap and increased covalent bonding due to strong hybridization between Ni 3d and O 2p levels in the upper portion of the valence band and within the band gap region. The antiferromagnetic, ferromagnetic and magnetoelectric properties of our core-shell nanoparticles make these well suited for patterned recording media and biomedical applications. PMID- 29611564 TI - Metastable electronic states in uranium tetrafluoride. AB - The DFT+U approach, where U is the Hubbard-like on-site Coulomb interaction, has successfully been used to improve the description of transition metal oxides and other highly correlated systems, including actinides. The secret of the DFT+U approach is the breaking of d or f shell orbital degeneracy and adding an additional energetic penalty to non-integer occupation of orbitals. A prototypical test case, UO2, benefits from the +U approach whereby the bare LDA method predicts UO2 to be a ferromagnetic metal, whereas LDA+U correctly predicts UO2 to be insulating. However, the concavity of the energetic penalty in the DFT+U approach can lead to a number of convergent "metastable" electronic configurations residing above the ground state. Uranium tetrafluoride (UF4) represents a more complex analogy to UO2 in that the crystal field has lower symmetry and the unit cell contains two symmetrically distinct U atoms. We explore the metastable states in UF4 using several different methods of selecting initial orbital occupations. Two methods, a "pre-relaxation" method wherein an initial set of orbital eigenvectors is selected via the self-consistency procedure and a crystal rotation method wherein the x, y, z axes are brought into alignment with the crystal field, are explored. We show that in the case of UF4, which has non-collinearity between its crystal axes and the U atoms' crystal field potentials, the orbital occupation matrices are much more complex and should be analyzed using a novel approach. In addition to demonstrating a complex landscape of metastable electronic states, UF4 also shows significant hybridization in U-F bonding, which involves non-trivial contributions from s, p, d, and f orbitals. PMID- 29611563 TI - Liquid metals: fundamentals and applications in chemistry. AB - Post-transition elements, together with zinc-group metals and their alloys belong to an emerging class of materials with fascinating characteristics originating from their simultaneous metallic and liquid natures. These metals and alloys are characterised by having low melting points (i.e. between room temperature and 300 degrees C), making their liquid state accessible to practical applications in various fields of physical chemistry and synthesis. These materials can offer extraordinary capabilities in the synthesis of new materials, catalysis and can also enable novel applications including microfluidics, flexible electronics and drug delivery. However, surprisingly liquid metals have been somewhat neglected by the wider research community. In this review, we provide a comprehensive overview of the fundamentals underlying liquid metal research, including liquid metal synthesis, surface functionalisation and liquid metal enabled chemistry. Furthermore, we discuss phenomena that warrant further investigations in relevant fields and outline how liquid metals can contribute to exciting future applications. PMID- 29611565 TI - Silica-supported isolated molybdenum di-oxo species: formation and activation with organosilicon agent for olefin metathesis. AB - A well-defined silica-supported molybdenum dioxo species, ([triple bond, length as m-dash]SiO)2Mo(O)2, is prepared by grafting Mo(O)2[OSi(OtBu)3]2 on partially dehydroxylated silica SiO2-700, followed by thermal treatment under high-vaccum and calcination. Activated by an organosilicon agent the resulting material is active for olefin metathesis at 30 degrees C. PMID- 29611566 TI - Nanoemulsions stabilized by non-ionic surfactants: stability and degradation mechanisms. AB - The prevailing opinion in the literature is that the main mechanism of O/W nanoemulsion degradation is Ostwald ripening. Nevertheless, the experimental rates of Ostwald ripening are usually several orders of magnitude higher than the theoretical values. This suggests that other mechanisms, such as coalescence, flocculation and subsequent creaming, significantly influence nanoemulsion breakdown. We investigated O/W nanoemulsions stabilized by Brij 30 or by a mixture of Tween 80 and Span 80 and with liquid paraffin as a dispersed phase. The results indicate that Ostwald ripening is the main process leading to nanoemulsion coarsening only in nanoemulsions with low oil phase fractions of up to 0.05. For quasi-steady state conditions the rates of Ostwald ripening are equal to (1.5 +/- 0.3) * 10-29 and (1.1 +/- 0.3) * 10-29 m3 s-1 in nanoemulsions with Brij 30 and Tween 80 & Span 80, respectively. In nanoemulsions with oil phase fractions of 0.15-0.45, different mechanisms are identified. Flocculation prevails over other processes during the first days in nanoemulsions stabilized by Brij 30. Coalescence is the main mechanism of nanoemulsion degradation for long times. An increase in droplet size 5-10 days after nanoemulsion preparation due to Ostwald ripening takes place in the case of nanoemulsion stabilization by Tween 80 and Span 80. The stability behavior of these nanoemulsions at later stages is distinctly affected by coalescence and flocculation. PMID- 29611567 TI - Axial modification inhibited H-aggregation of phthalocyanines in polymeric micelles for enhanced PDT efficacy. AB - Axial modified phthalocyanine (BtPc), aiming at avoiding H-aggregation and utilizing long wavelength light, was designed and synthesized. With the aid of polymer nanotechnology, BtPc loaded polymeric micelles with strong singlet oxygen generating ability and enhanced photodynamic therapy efficiency were developed. Optical characterizations and in vitro evaluations proved that the BtPc loaded polymeric micelles hold great potential for photodynamic therapy. PMID- 29611569 TI - Colloidal probe dynamics in gelatin solution during the sol-gel transition. AB - The dynamics of the colloidal probes in a gelatin solution during the time dependent sol-gel transition was investigated by multi-particle tracking. The relationship between the relaxation of the medium at the critical gel point and the mean square displacement of the probes was elucidated. Based on this understanding, the critical gel point of gelatin and the corresponding critical exponent n were unambiguously determined by the loss angle criterion and the time cure superposition. The shift factors of the latter are further used to estimate the time/length-scale evolution of the gelatin during the sol-gel transition. The growth of the medium length scale crossed with the two measuring length scales successively at the pre-gel regime. Coinciding with the length-scale crossovers, the probability density function (PDF) of the probe displacements displayed two transient peaks of non-Gaussianity. In the post-gel regime, the third peak of Gaussianity suggested inhomogeneity in the gel network. The non-Gaussianity results from the bifurcation of diffusivity. The present work showed that the non Gaussian dynamics of the probes are not the direct equivalence of that of the medium, but an effect of length-scale coupling. PMID- 29611570 TI - Rapid colorimetric sensing of gadolinium by EGCG-derived AgNPs: the development of a nanohybrid bioimaging probe. AB - Polyphenol functionalized silver nanoparticles (AgNPs) have been developed and demonstrated as colorimetric sensors for the selective detection of gadolinium. The newly obtained AgNP-Gd3+ conjugates exhibit high aqueous dispersibility and excitation dependent fluorescence emission. The conjugates offer multicolor bioimaging potential owing to their excellent luminescence properties. PMID- 29611571 TI - Crystal structure resolution of an insulator due to the cooperative Jahn-Teller effect through Bader's theory: the challenging case of cobaltite oxide Y114. AB - Cobaltite YBaCo4O7, abbreviated as Y114, is one of the most thoroughly investigated perovskites, owing largely to its interesting magnetic properties. Y114 is an insulator as a result of the cooperative Jahn-Teller effect, where one electron jumps quickly from one cobalt site to another, making it impossible to experimentally assign the correct oxidation state for each of the two cobalt sites. The present study solved the ambiguity by means of state-of-the-art DFT calculations. The two cobalt sites were differentiated through an analysis of charge density within the framework of the quantum theory of atoms in molecules. PMID- 29611572 TI - A new approach to access difluoroalkylated diarylmethanes via visible-light photocatalytic cross-coupling reactions. AB - Difluoroalkylated diarylmethanes with biological and pharmacological potentials were synthesized from para-quinone methides (p-QMs) and difluoroalkylating reagents via a visible light photocatalysis strategy. Mechanism studies showed that the excited photocatalyst, *fac-Ir(ppy)3, was primarily quenched by p-QMs and the generated diarylmethane radical intermediates then underwent a radical radical cross-coupling reaction with difluoroalkyl radicals. This reaction features mild conditions, high efficiency and wide functional group compatibility. PMID- 29611574 TI - Soft modes and strain redistribution in continuous models of amorphous plasticity: the Eshelby paradigm, and beyond? AB - The deformation of disordered solids relies on swift and localised rearrangements of particles. The inspection of soft vibrational modes can help predict the locations of these rearrangements, while the strain that they actually redistribute mediates collective effects. Here, we study soft modes and strain redistribution in a two-dimensional continuous mesoscopic model based on a Ginzburg-Landau free energy for perfect solids, supplemented with a plastic disorder potential that accounts for shear softening and rearrangements. Regardless of the disorder strength, our numerical simulations show soft modes that are always sharply peaked at the softest point of the material (unlike what happens for the depinning of an elastic interface). Contrary to widespread views, the deformation halo around this peak does not always have a quadrupolar (Eshelby like) shape. Instead, for finite and narrowly-distributed disorder, it looks like a fracture, with a strain field that concentrates along some easy directions. These findings are rationalised with analytical calculations in the case where the plastic disorder is confined to a point-like 'impurity'. In this case, we unveil a continuous family of elastic propagators, which are identical for the soft modes and for the equilibrium configurations. This family interpolates between the standard quadrupolar propagator and the fracture-like one as the anisotropy of the elastic medium is increased. Therefore, we expect to see a fracture-like propagator when extended regions on the brink of failure have already softened along the shear direction and thus rendered the material anisotropic, but not failed yet. We speculate that this might be the case in carefully aged glasses just before macroscopic failure. PMID- 29611575 TI - A microfluidic photoreactor enables 2-methylbenzophenone light-driven reactions with superior performance. AB - Light-driven reactions of 2-methylbenzophenones (2-MBPs) occur with improved yields (up to >98%) and reaction rates (up to 0.240 mmol h-1) by using a tailored microfluidic photoreactor (MFP). For the first time, coumarins were converted into 4-benzylated chromanones in high yields (50-93%) and diastereoselectivity (up to >20 : 1 dr), thus by-passing their photo-dimerisation end-reaction. PMID- 29611576 TI - A symmetrical method to obtain shear moduli from microrheology. AB - Passive microrheology typically deduces shear elastic loss and storage moduli from displacement time series or mean-squared displacements (MSD) of thermally fluctuating probe particles in equilibrium materials. Common data analysis methods use either Kramers-Kronig (KK) transformation or functional fitting to calculate frequency-dependent loss and storage moduli. We propose a new analysis method for passive microrheology that avoids the limitations of both of these approaches. In this method, we determine both real and imaginary components of the complex, frequency-dependent response function chi(omega) = chi'(omega) + ichi''(omega) as direct integral transforms of the MSD of thermal particle motion. This procedure significantly improves the high-frequency fidelity of chi(omega) relative to the use of KK transformation, which has been shown to lead to artifacts in chi'(omega). We test our method on both model and experimental data. Experiments were performed on solutions of worm-like micelles and dilute collagen solutions. While the present method agrees well with established KK based methods at low frequencies, we demonstrate significant improvement at high frequencies using our symmetric analysis method, up to almost the fundamental Nyquist limit. PMID- 29611578 TI - Cascade sensitization of triplet-triplet annihilation based photon upconversion at sub-solar irradiance. AB - In triplet-triplet annihilation based upconversion, high-energy photons are generated through the annihilation of fluorophore triplets, populated via energy transfer from a light-harvesting sensitizer. However, the absorption band of common sensitizers is narrow, limiting the fraction of recoverable photons. We overcome this issue using a third chromophore as an additional light-harvester in the transparency window between the upconverted luminescence and the sensitizer absorption. The third component transfers the extra-collected energy to sensitizers, realizing a cascade-sensitized upconversion that shows a 20% increment of the high-energy photon output and a conversion yield of 10% at solar irradiance. PMID- 29611579 TI - DNA metallization: principles, methods, structures, and applications. AB - DNA metallization has witnessed tremendous growth and development, from the initial simple synthesis aimed at manufacturing conductive metal nanowires to the current fabrication of various nanostructures for applications in areas as diverse as nanolithography, energy conversion and storage, catalysis, sensing, and biomedical engineering. To this, our aim here was to present a comprehensive review to summarize the research activities on DNA metallization that have appeared since the concept was first proposed in 1998. We start with a brief presentation of the basic knowledge of DNA and its unique advantages in the template-directed growth of metal nanomaterials, followed by providing a systematic summary of the various synthetic methods developed to date to deposit metals on DNA scaffolds. Then, the leverage of DNAs with different sequences, conformations, and structures for tuning the synthesis of feature-rich metal nanostructures is discussed. Afterwards, the discussion is divided around the applications of these metal nanomaterials in the fields mentioned above, wherein the key role DNA metallization plays in enabling high performance is emphasized. Finally, the current status and some future prospects and challenges in this field are summarized. As such, this review would be of great interest to promote the further development of DNA metallization by attracting researchers from various communities, including chemistry, biology, physiology, material science, and nanotechnology as well as other disciplines. PMID- 29611580 TI - Theoretical studies on the synergistic extraction of Am3+ and Eu3+ with CMPO HDEHP and CMPO-HEH[EHP] systems. AB - In recent years, there has been a trend to use synergistic systems of neutral and acidic extractants into a single-solvent formulation to achieve Ln3+/An3+ extraction and separation via simplified processing schemes. In this study, geometrical structures, bonding nature, and thermodynamic stabilities of a series of possible extraction complexes of Am3+ and Eu3+ with two neutral-acid synergistic systems (CMPO-HDEHP and CMPO-HEH[EHP]) were theoretically studied using scalar-relativistic density functional theory (DFT). It is found that hydrogen bonds between neutral and acid ligands may greatly influence the Eu3+/Am3+ extraction and separation performance of the two synergistic systems. According to natural bond orbital (NBO) and energy decomposition analyses (EDA), the phosphoryl oxygen atoms of HDEHP or HEH[EHP] have higher affinity for Eu3+ and Am3+ than those of the CMPO ligand. Since weak but different extents of covalency exist in Eu- and Am-complexes, Eu3+/Am3+ separation via these two systems may be attributed to the different compositions of interactions between the metal ions and ligands. Thermodynamic analysis shows that the neutral complexes ML(NO3)2 (M = Eu and Am; L = [CMPO-DEHP]- and [CMPO-EH[EHP]]-) appear to be the most probable species in the complexation process. PMID- 29611582 TI - The theory of thermally activated delayed fluorescence for organic light emitting diodes. AB - The interest in organic molecules exhibiting thermally activated delayed fluorescence (TADF) has been reinvigorated in recent years owing to their potential to be exploited as emitters in highly efficient purely organic light emitting diodes (OLEDs). However, designing new molecules that exhibit efficient TADF is a non-trivial task because they would appear to require the optimisation of a number of contrasting properties. For example these molecules must exhibit rapid conversion between the singlet and triplet manifolds without the use of heavy elements to enhance spin-orbit coupling. They should also display a large fluorescence rate, but simultaneously a small energy gap between low lying singlet and triplet states. Consequently to achieve systematic material design, a detailed understanding of the fundamental factors influencing the photophysical behaviour of TADF emitters is essential. Towards achieving this goal, theory and computation is playing a crucial role. In this feature article the recent progress in the theory of organic TADF molecules in the context of OLEDs is presented, with a view of achieving a deeper understanding of these molecules and driving systematic material design. PMID- 29611584 TI - Lanthanide-based near-infrared emitting metal-organic frameworks with tunable excitation wavelengths and high quantum yields. AB - We report here two isoreticular ytterbium (Yb) 2D metal-organic frameworks (MOFs) emitting near-infrared (NIR) luminescence with 1.26(2)% quantum yield values, which are among the highest values reported to date for MOFs incorporating NIR emitting lanthanide cations. The excitation wavelength of the YbIII MOFs can be red-shifted to the visible range by introducing an amino group to the organic chromophore. Density functional theory (DFT) calculations were performed to gain insights into the photophysical properties of this new family of MOFs. PMID- 29611585 TI - Growth-modulating agents for the synthesis of Al-MOF-type materials based on assembled 1D structural subdomains. AB - Novel aluminium MOF-type materials structured by 1D subdomains, such as organic inorganic nanoribbons, were synthesized by modifying the conditions of solvothermal synthesis and the nature of the solvents in the presence of aryl monocarboxylate linkers with long alkyl chains, which acted as growth-modulating agents. Specifically, three different families of materials were prepared with various morphological characteristics: (i) isoreticular MIL-53(Al)-type materials, (ii) mesoscopic metalorganic structures and (iii) lamellar aluminium MOFs. The length of the alkyl chain in the aryl linker and the hydrophobic/hydrophilic nature of the solvothermal synthesis media determined the structuration level that was achieved. The derived Al-MOFs are active and stable catalysts for the synthesis of fine chemicals. This was illustrated by the efficient synthesis of 2,3-dihydro-2,2,4-trimethyl-1H-1,5-benzodiazepine. PMID- 29611586 TI - Ultrasonicated Lespedeza cuneata extract prevents TNF-alpha-induced early atherosclerosis in vitro and in vivo. AB - This study evaluated the use of ultrasonication to extract Lespedeza cuneata as a potential nutraceutical for preventing vascular inflammation. Ultrasonicated L. cuneata extract (ULCE) was prepared using 20% ethanol and 2 h of ultrasonication at room temperature, and its effects were investigated using relevant in vitro and in vivo models. ULCE suppressed tumor necrosis factor-alpha (TNF-alpha) induced adhesion capacity, vascular cell adhesion protein 1 (VCAM-1) expression, and nuclear factor kappa-B (NF-kappaB) activity in human umbilical vein endothelial cells (HUVECs). ULCE also suppressed TNF-alpha-induced NF-kappaB signaling pathways and p65 translocation from the cytosol to the nucleus, as well as the mRNA expression of IL-1beta, IL-6, and TNF-alpha in HUVECs. Oral administration of ULCE suppressed TNF-alpha-induced monocyte infiltration into the intima and VCAM-1 expression, as well as the IL-1beta, IL-6, TNF-alpha, and monocyte chemoattractant protein-1 (MCP-1) mRNA expression in the main artery in mice. Among the compounds identified in the hydrolyzed ULCE, quercetin exhibited the strongest inhibitory effect against TNF-alpha-induced cell adhesion capacity. These results demonstrate that ULCE contains potent preventive factors against early atherosclerosis, which act by suppressing the NF-kappaB and VCAM-1 signaling axis. PMID- 29611587 TI - Discrete element simulation studies of angles of repose and shear flow of wet, flexible fibers. AB - A discrete element method (DEM) model is developed to simulate the dynamics of wet, flexible fibers. The angles of repose of dry and wet fibers are simulated, and the simulation results are in good agreement with experimental results, validating the wet, flexible fiber model. To study wet fiber flow behavior, the model is used to simulate shear flows of wet fibers in a periodic domain under Lees-Edwards boundary conditions. Significant agglomeration is observed in dilute shear flows of wet fibers. The size of the largest agglomerate in the flow is found to depend on a Bond number, which is proportional to liquid surface tension and inversely proportional to the square of the shear strain rate. This Bond number reflects the relative importance of the liquid-bridge force to the particle's inertial force, with a larger Bond number leading to a larger agglomerate. As the fiber aspect ratio (AR) increases, the size of the largest agglomerate increases, while the coordination number in the largest agglomerate initially decreases and then increases when the AR is greater than four. A larger agglomerate with a larger coordination number is more likely to form for more flexible fibers with a smaller bond elastic modulus due to better connectivity between the more flexible fibers. Liquid viscous force resists pulling of liquid bridges and separation of contacting fibers, and therefore it facilitates larger agglomerate formation. The effect of liquid viscous force is more significant at larger shear strain rates. The solid-phase shear stress is increased due to the presence of liquid bridges in moderately dense flows. As the solid volume fraction increases, the effect of fiber-fiber friction coefficient increases sharply. When the solid volume fraction approaches the maximum packing density, the fiber-fiber friction coefficient can be a more dominant factor than the liquid bridge force in determining the solid-phase shear stress. PMID- 29611588 TI - Capillary assembly as a tool for the heterogeneous integration of micro- and nanoscale objects. AB - During the past decade, capillary assembly in topographical templates has evolved into an efficient method for the heterogeneous integration of micro- and nano scale objects on a variety of surfaces. This assembly route has been applied to a large spectrum of materials of micrometer to nanometer dimensions, supplied in the form of aqueous colloidal suspensions. Using systems produced via bulk synthesis affords a huge flexibility in the choice of materials, holding promise for the realization of novel superior devices in the fields of optics, electronics and health, if they can be integrated into surface structures in a fast, simple, and reliable way. In this review, the working principles of capillary assembly and its fundamental process parameters are first presented and discussed. We then examine the latest developments in template design and tool optimization to perform capillary assembly in more robust and efficient ways. This is followed by a focus on the broad range of functional materials that have been realized using capillary assembly, from single components to large-scale heterogeneous multi-component assemblies. We then review current applications of capillary assembly, especially in optics, electronics, and in biomaterials. We conclude with a short summary and an outlook for future developments. PMID- 29611592 TI - Reduction of ormaplatin by an extended series of thiols unravels a remarkable correlation. AB - Ormaplatin ([Pt(dach)Cl4]) represents one of the three primary structural prototypes of Pt(iv) anticancer-active prodrugs. The reduction of ormaplatin by an extended series of thiols has been studied kinetically in a broad pH range. A novel and remarkable correlation between log kRS- and the thiol dissociation constants pKRSH is disclosed: log kRS- = (0.50 +/- 0.02)pKRSH + (0.68 +/- 0.13), where kRS- denotes the second-order rate constant of each thiolate towards the reduction of ormaplatin. PMID- 29611590 TI - Effects of room airflow on accurate determination of PUF-PAS sampling rates in the indoor environment. AB - Accurate and precise interpretation of concentrations from polyurethane passive samplers (PUF-PAS) is important as more studies show elevated concentrations of PCBs and other semivolatile air toxics in indoor air of schools and homes. If sufficiently reliable, these samplers may be used to identify local sources and human health risks. Here we report indoor air sampling rates (Rs) for polychlorinated biphenyl congeners (PCBs) predicted for a frequently used double dome and a half-dome PUF-PAS design. Both our experimentally calibrated (1.10 +/- 0.23 m3 d-1) and modeled (1.08 +/- 0.04 m3 d-1) Rs for the double-dome samplers compare well with literature reports for similar rooms. We determined that variability of wind speeds throughout the room significantly (P < 0.001) effected uptake rates. We examined this effect using computational fluid dynamics modeling and 3-D sonic anemometer measurements and found the airflow dynamics to have a significant but small impact on the precision of calculated airborne concentrations. The PUF-PAS concentration measurements were within 27% and 10% of the active sampling concentration measurements for the double-dome and half-dome designs, respectively. While the half-dome samplers produced more consistent concentration measurements, we find both designs to perform well indoors. PMID- 29611595 TI - Quantum-size effects in visible defect photoluminescence of colloidal ZnO quantum dots: a theoretical analysis. AB - ZnO has been known for a long time to be a highly efficient luminescent material. In the last few years, the experimental investigation of the luminescent properties of colloidal ZnO nanocrystals in the nanometer range of sizes has attracted a lot of interest for their potential applications in light-emitting diodes and other optical devices and in this work we approach the problem from a theoretical perspective. Here, we develop a simple theory for the green photoluminescence of ZnO quantum dots (QDs) that allows us to understand and rationalize several experimental findings on fundamental grounds. We study the spectrum of light emitted in the radiative recombination of a conduction band electron with a deeply trapped hole and find that the experimental behavior of this emission band with particle size can be understood in terms of quantum size effects of the electronic states and their overlap with the deep hole. We focus the comparison of our results on detailed experiments performed for colloidal ZnO nanoparticles in ethanol and find that the experimental evolution of the luminescent signal with particle size at room temperature can be better reproduced by assuming the deep hole to be localized near the surface of the nanoparticles. However, the experimental behavior of the intensity and the decay time of the signal with temperature can be rationalized in terms of holes predominantly trapped near the center of the nanoparticles at low temperatures being transferred to surface defects at room temperature. Furthermore, the calculated values of the radiative lifetimes are comparable to the experimental values of the decay time of the visible emission signal. We also study the visible emission band as a function of the number of electrons in the conduction band of the nanoparticle, finding a pronounced dependence of the radiative lifetime but a weak dependence of the energetic position of the maximum intensity. PMID- 29611596 TI - Correction: Isostructural lanthanide-based metal-organic frameworks: structure, photoluminescence and magnetic properties. AB - Correction for 'Isostructural lanthanide-based metal-organic frameworks: structure, photoluminescence and magnetic properties' by Li-Lin Luo et al., Dalton Trans., 2018, 47, 925-934. PMID- 29611597 TI - On the structural stability of guanosine-based supramolecular hydrogels. AB - Supramolecular hydrogels formed from the self-assembly of low molecular weight derivatives are very attractive systems, because of their potential applications in nano- and bio-technology. In this paper, the stable and transparent hydrogels observed in binary mixtures of guanosine derivatives (G), namely guanosine 5' monophosphate (GMP) and guanosine (Gua), dissolved in water (at volume fractions larger than 0.95), were investigated by microscopy techniques and Small Angle X ray Scattering (SAXS). The results confirm the presence of G-quadruplexes, chiral cylindrical rods obtained by the regular stacking of self-assembled planar cyclic guanosine quartets. However, the addition of Gua determines the formation of very stable hydrogels able to trap large amounts of water (up to a volume fraction of 0.99) and characterised by an unusual anisotropic order. A modified lateral helix to-helix interaction pattern, tuned by Gua, is suggested to be responsible for the supramolecular gelation and the stability of the hydrogels during swelling. PMID- 29611598 TI - A temperature-responsive supramolecular hydrogel: preparation, gel-gel transition and molecular aggregation. AB - In this study, a novel supramolecular hydrogel, abbreviated as AGC16/NTS, was designed and constructed by the molecular self-assembly of a cationic gemini surfactant, 1,3-bis(N,N-dimethyl-N-cetylammonium)-2-propylacrylatedibromide (AGC16), and an anionic aromatic gelator, trisodium 1,3,6-naphthalenetrisulfonate (NTS). The AGC16/NTS hydrogel was able to form in a mass ratio range of AGC16 and NTS from 20 : 1 to 10 : 1. It was interestingly found that AGC16/NTS exhibited two phase transitions (gel-to-gel and gel-to-sol) observed by visual and rheological measurements during the heating process, which is rarely reported in the previous literature reports of hydrogels prepared using low molecular weight gelators. Cryogenic scanning electron microscopy (cryo-SEM), fluorescence emission spectroscopy and X-ray diffraction (XRD) were used to investigate the temperature-responsive properties and molecular self-assembly mechanism of the hydrogel AGC16/NTS. During the gel-to-gel transition process, the temperature responsive changes in the visual appearance of AGC16/NTS (turbid to transparent) were clearly observed. Compared with the transparent gel, the turbid gel possesses higher mechanical strength and a much more compact network mophology due to stronger intermolecular hydrophobic association beetween gelators. The molecular self-assembly modes for the two different hydrogel states (turbid and transparent gel) were proposed, helping to further understand the hydrogel transition mechanisms at a molecular level. PMID- 29611599 TI - Phenanthroline polyazamacrocycles as G-quadruplex DNA binders. AB - Targeting quadruplex DNA structures with small molecules is a promising strategy for anti-cancer drug design. Four phenanthroline polyazamacrocycles were studied for their binding affinity, thermal stabilization, inhibitory effect on the activity of helicase towards human telomeric 22AG and oncogene promoter c-MYC G quadruplexes (G4s), and their ability to inhibit Taq polymerase-mediated DNA extension. The fluorescence resonance energy transfer (FRET) melting assay indicates that the melting temperature increases (DeltaTm values) of c-MYC and 22AG G4s are 17.2 and 20.3 degrees C, respectively, for the ligand [32]phen2N4 followed by [16]phenN4 (11.3 and 15.0 degrees C, for c-MYC and 22AG, respectively). Competitive FRET assays show that [32]phen2N4 and [16]phenN4 exhibit G4 selectivity over duplex DNA. Different G4s were compared; no considerable selectivity of the ligands for a specific G4 was found. Circular dichroism (CD) confirms the formation of G4 structures and the melting experiments show that [16]phenN4 and [32]phen2N4 are the most stabilizing ligands with a DeltaTm of 19.3 degrees C and 15.1 degrees C, respectively, at 5 molar equivalents for the c-MYC G4. The fluorescent intercalator displacement (FID) assay also demonstrates that ligand [32]phen2N4 furnishes very low DC50 values (0.87-1.24 MUM), indicating high stabilization of c-MYC and 22AG G4s. These results suggest that the hexyl chain in these compounds plays an important role in regulating the stabilization of these G4s. Binding constants, determined by fluorescence titrations, indicate a moderate ligand-G4 binding with KSV between 105 and 106 M-1 in which [16]phenN4 has a slightly higher apparent binding constant for telomeric 22AG G4 than that for the c-MYC G4. The ligand's ability to inhibit Taq polymerase confirms the biological activity of [16]phenN4 and [32]phen2N4 against the c-MYC G4. In addition, ligands [32]phen2N4 and [16]phenN4 affect the unwinding activity of Pif1 in the presence of DNA systems harboring c MYC and telomeric G4 motifs. PMID- 29611600 TI - Direct dihalo-alkoxylation of nitroalkenes leading to beta,beta-dihalo-beta nitroethyl alkyl ethers. AB - A highly efficient one-pot synthesis of beta,beta-dihalo-beta-nitroethyl alkyl ethers is achieved by the treatment of nitroalkenes with alcohols and N halosuccinimides in the presence of sodium hydride. The notable advantages of this protocol are that it involves simple experimental manipulations and tolerates a wide range of functional groups. Further transformations of the obtained ethers, such as allylation and conversion to beta,beta-dihalogenated vinyl ethers, are also investigated. PMID- 29611601 TI - Annulation of beta-naphthols and 4-hydroxycoumarins with vinylsulfonium salts: synthesis of dihydrofuran derivatives. AB - A new synthetic approach to dihydrofuran derivatives via the annulation reaction of beta-naphthols and 4-hydroxycoumarins with vinylsulfonium salts has been developed. A variety of dihydrofuran derivatives were prepared in moderate to good yields under mild conditions. The products could be readily transformed to the corresponding furans via the dehydrogenation with DDQ. PMID- 29611602 TI - Understanding and modulating the high-energy properties of noble-gas hydrides from their long-bonding: an NBO/NRT investigation on HNgCO+/CS+/OSi+ and HNgCN/NC (Ng = He, Ar, Kr, Xe, Rn) molecules. AB - The noble-gas hydrides, HNgX (X is an electronegative atom or fragment), represent potential high-energy materials because their two-body decomposition process, HNgX -> Ng + HX, is strongly exoergic. Our previous studies have shown that each member of the HNgX (X = halogen atom or CN/NC fragment) molecules is composed of three leading resonance structures: two omega-bonding structures (H Ng+ :X- and H:- Ng+-X) and one long-bonding structure (H?X). The last one paints a novel [small sigma, Greek, circumflex]-type long-bonding picture. The present study focuses on the relationship between this novel bonding motif and the unusual energetic properties. We chose HNgCO+/CS+/OSi+/CN/NC, with the formula HNgAB (Ng = He, Ar, Kr, Xe, Rn; AB = CO+/CS+/OSi+/CN/NC) as the research system. We first investigated the bonding of HNgCO+ and its analogous HNgCS+/OSi+ species using NBO/NRT methods, and quantitatively compared the bonding with that in HNgCN/NC molecules. NBO/NRT results showed that each of the HNgCO+/CS+/OSi+ molecules could be better represented as a resonance hybrid of omega-bonding and long-bonding structures, but the long-bonding is much weaker than that in HNgCN/NC molecules. Furthermore, we introduced the long-bonding concept into the rationalization of the high-energy properties, and found a good correlation between the highly exothermic two-body dissociation channel and the long-bond order, bH-A. We also found that the long-bond order is highly tunable for these noble-gas hydrides due to its dependence on the nature of the electronegative AB fragments or the central noble-gas atoms, Ng. On the basis of these results, we could optimize the energetic properties by changing the long-bonding motif of our studied molecules. Overall, this study shows that the long-bonding model provides an easy way to rationalize and modulate the unusual energy properties of noble gas hydrides, and that it is helpful to predict some noble-gas hydrides as potential energetic materials. PMID- 29611603 TI - Metathesis of Mg2FeH6 and LiNH2 leading to hydrogen production at low temperatures. AB - Mg2FeH6 with a purity of up to 94.5 wt% was synthesized and its interaction with LiNH2 was investigated in this study. It was found that Li4FeH6, normally synthesized by hydriding a mixture of LiH and Fe at 700 degrees C and 5.5 GPa H2 pressure, can be formed via ball-milling Mg2FeH6 and LiNH2 under ambient conditions following the reaction of Mg2FeH6 + 4LiNH2 -> Li4FeH6 + 2Mg(NH2)2, DeltaH = -92.8 kJ mol-1. The formation of Li4FeH6 was confirmed by XRD, FTIR and Mossbauer spectroscopic characterization. Li4FeH6 further reacts with 2Mg(NH2)2 releasing ca. 4.8 wt% H2 at 225 degrees C and reabsorbing 3.7 wt% H2 at 200 degrees C and 50 bar H2 pressure. Mg(NH2)2, LiH and Fe are the hydrogenated products. PMID- 29611604 TI - Theoretical insights into the effective hydrogen evolution on Cu3P and its evident improvement by surface-doped Ni atoms. AB - On the basis of the first-principles DFT computations, we have systematically investigated the structures and hydrogen evolution reaction (HER) catalytic activities for pristine and Ni-doped Cu3P systems. It was revealed that the (11[combining macron]0) surface could be the one with the most exposure for the Cu3P structure. The calculated free energy values of H* (DeltaGH*) are in the range from 0.012 to 0.320 eV, reflecting the HER activity on the (11[combining macron]0) surface, which is consistent with the experimentally reported results. Our computed results also reveal that the top sites over P atoms as well as the bridge and hollow sites composed of Cu atoms can make the main contribution to the HER activity on the (11[combining macron]0) surface, and the hollow sites (DeltaGH* ~ 0 eV) can serve as the most active sites due to the considerably flexible structural features. Furthermore, we have proposed an effective strategy through doping Ni to significantly improve the HER catalytic activity on the (11[combining macron]0) surface by effectively optimizing the adsorption state of H* based on the case that Ni and Cu have the opposite ability to bind with H. All these doped systems can uniformly possess high HER activity, and particularly some doped structures with the appropriate Ni-atom number can even exhibit considerably high HER activity over a wide range of H coverage, indicating the more excellent catalytic performance. It is worth mentioning that the surface metal-atoms for these Ni-doped systems can still exhibit flexible behavior, which can also be beneficial for realizing high HER activity. These fascinating theoretical insights at the atomic level can be advantageous for achieving highly efficient non-precious HER electrocatalysts based on copper phosphide and even other transition metal phosphides in the near future. PMID- 29611605 TI - Direct Au-C contacts based on biphenylene for single molecule circuits. AB - We propose a novel platform for stable and highly conducting single molecule electronics and characterize its mechanical, electronic and conducting properties using ab initio simulations. We study a biphenylene-based molecular architecture on gold and consider that the antiaromatic instability of biphenylene leads to the breaking of internal carbon-carbon bonds and subsequent formation of Au-C covalent bonds with the substrate. In the resulting conformation the conjugated rings have a large twist angle and stand almost upright on the surface. The top contact is realized by functionalizing one end of the biphenylene unit with a chemical linker group, which in the adsorbed geometry is positioned far from the surface. We consider several linker terminations for this top contact, which is approached in our simulations by a gold tip. Using Density-Functional Theory (DFT) and Non-Equilibrium Green's Function (NEGF) methods, we quantify the mechanical and electron transport properties of the molecular junction and discuss their relationship with the nature of the linker group. Our results show that this biphenylene-based platform is very stable and provides high electronic transparency to current flow, demonstrating its potential in single molecule conductance studies. PMID- 29611606 TI - Liquid-liquid phase coexistence in lipid membranes observed by natural abundance 1H-13C solid-state NMR. AB - We demonstrate that 1H-13C solid-state MAS NMR is suitable to detect liquid disordered/liquid ordered phase coexistence in a DOPC/DPPC/cholesterol mixture with natural abundance of isotopes as an alternative to 2H NMR. Such methodology is potentially applicable to study lipid phase coexistence phenomena in biological matter with high lipid content, e.g. lung surfactant or myelin, for which isotopic labeling is not possible. PMID- 29611608 TI - The status of the doctor and variations in the percentage of unfit declarations in medical examinations of shipping and offshore employees in the Netherlands. AB - BACKGROUND: Both shipping medical examinations in 2012-2013 and 2015 and oil and gas offshore medical examinations in 2009-2011 in the Netherlands show a decline in the percentage of declarations of unfitness as the number of examinations performed annually by each physician increases. MATERIALS AND METHODS: The data from the electronic databases for shipping employees 2012-2013 and 2015 and the data collected from doctors examining offshore workers from 2009 to 2011 (based on data from a voluntary questionnaire) were subject to a statistical analysis to be able to assess which variables affect the rate of unfitness declaration. RESULTS: Both shipping and offshore data show a decline in the percentage of declarations of unfitness as the number of examinations performed annually by each physician increases. The shipping examination data suggests that neither the type of physician (family physician, company's physician or other physician) nor the number of years of experience correlates with any trend in the percentage of such declarations. However shipping physicians working as employees had half the percentage of declaration of unfitness when compared to the self-employed physicians. The self-employed physicians, who performed the largest number of examinations per year, had an almost three times lower percentage of declaration of unfitness than the self-employed physicians, who performed few examinations. The percentages of declarations of medical unfitness by physicians working as employees are constant whether they perform many or few examinations per year. PMID- 29611607 TI - The epidemiology of operations performed by the National Sea Rescue Institute of South Africa over a 5-year period. AB - BACKGROUND: Injuries remain a major contributor of morbidity and mortality worldwide, with drowning accounting for 7% of all injury-related deaths with rates of between 4 and 8 per 100,000. The African region has death rates comparable to most low-income countries. Non-fatal drowning in Africa remains unquantified but it is estimated to be ten times higher than the fatal drowning rate. Timely search and rescue, initial resuscitation and rapid transportation to definitive care play a crucial role in preventing injury- related morbidity and mortality. The National Sea Rescue Institute (NSRI) of South Africa is a non profit organisation responsible for ~97% of maritime search and rescue operations in South Africa (including inland navigable waters). The aim of the study was to describe the epidemiology of operations performed by the NSRI of South Africa over a 5-year period. MATERIALS AND METHODS: The NSRI operational database was analysed from 1 January 2010 to 31 December 2014. Summary statistics are presented. RESULTS: The NSRI launched 3281 operations over the study period. Marked seasonal variation were noticeable with peak periods in December and January, corresponding to the South African summer holiday season. Water-based operations (67.6%) were the most frequent operation performed. The NSRI assisted 3399 individuals of which 77% were male. The mean age of rescued persons was 42 years. Eight hundred and thirty-six (25%) individuals had non-fatal injuries or illnesses requiring medical assistance. Medical emergencies (35%), traumatic injuries (32.8%), and non-fatal drownings (23%) were the most common types of injury and illness. The majority of the 184 (18%) deaths recorded were due to drowning (75%). CONCLUSIONS: Injury and illness, specifically drowning utilise a large proportion of search and rescue services. The results suggest further preventative measures and public health strategies be implemented to minimise traumatic and medical incident severity and subsequent casualties at sea. PMID- 29611609 TI - Prevalence of chronic obstructive respiratory diseases amongst fishermen. AB - BACKGROUND: The objective was to screen and evaluate the prevalence of respiratory diseases and obstructive ventilatory defects among fishermen in Morocco. MATERIALS AND METHODS: This observational and cross-sectional epidemiological study involved 924 men over 20 years old and with at least two years of seniority. It included a questionnaire and a spirometry. The questionnaire is composed of four sections: sociodemographic and occupational characteristics, toxic habits, medical history and respiratory clinical symptoms. RESULTS: The prevalence of symptoms of tracheobronchial irritation was 9.2% for cough, 8.2% for sputum 7.8% for dyspnoea and chest wheezing 8.1%. The frequency of rhinitis was 17.1%, asthma 6.8%, chronic bronchitis 5.6% and chronic obstructive pulmonary disease (COPD) 4.1% (5.4% for current and former smokers versus 1.1% for non-smokers). The prevalence was reaching 6.8% among those who smoked more than 10 pack-years and 17.9% among those who smoked more than 20 pack years. Among subjects over 40 years old who had smoked more than 10 pack-years, the prevalence of COPD was 8.1%. The comorbidities were frequent. CONCLUSIONS: Smoking was very common among fishermen. Symptoms and respiratory diseases remain underdiagnosed and undertreated. Prevention and early detection must be a priority in this sector. PMID- 29611610 TI - Prevalence of skin diseases amongst Moroccan fishermen. AB - BACKGROUND: The main objective was to evaluate the prevalence of skin diseases amongst fishermen, to specify the different clinical forms, associations and most frequent localisations, and to identify potential aetiological factors. The secondary objectives were to assess the knowledge, attitudes and practices of seafarers regarding occupational dermatoses to conduct information, awareness and education campaigns on risk factors and behaviours and to propose adapted prevention. MATERIALS AND METHODS: This cross-sectional survey involved 1102 artisanal fishermen who attended the annual legal medical consultation at the occupational health service. All participants were men and had a regular activity for at least 2 years. It included an individual questionnaire, a clinical examination and a technical visit to the workplace Results: The skin disorders were palmar hyperkeratosis in 67.1% of fishermen, plantar hyperkeratosis in 59.4%, scares in 52.2%, facial wrinkling in 32%, and marine stings in 11.2%. The skin infections were fungal (44.4%), bacterial (8.3%), viral (5.5%) and scabies (1%). Only 192 (17.4%) fishermen did not have any dermatologic disease, 43% had one type of dermatologic diseases, 27.2% two types, 9.5% three types and 2.5% four types. Concerning personal protective equipment, only 87.4% wore protective clothing, 12.8% high visibility clothing, 52.6% safety shoes, 30.1% protective gloves, and 63.5% protective caps or hats. Only, 12% knew that mycosis were infectious origin and were contagious. Eighty-two per cent ignored the mode of contamination, 78% the means of prevention and 91% the existence of a medical treatment. Ninety-five per cent thought that pityriasis versicolor was due to sunrays especially in summer and not to fungus. CONCLUSIONS: The elaboration of the prevention approach needs a cooperative spirit; it will be more accepted and applied by all fishermen, if their representatives are involved in its preparation. The realisation of information and sensitization campaigns about the skin health must be based on the results of prevalence surveys. PMID- 29611611 TI - Benzodiazepine prescriptions on merchant ships without a doctor on board: analysis from medical records of Centro Internazionale Radio Medico (CIRM). AB - BACKGROUND: Benzodiazepines are drugs widely used for the treatment of anxiety and insomnia. The present study has analysed the prescriptions of this class of drugs among sailing seafarers, to evaluate the appropriateness of prescribed therapies. MATERIALS AND METHODS: This study assessed the benzodiazepine prescriptions made by Centro Internazionale Radio Medico (CIRM) doctors from 2011 to 2015. A total of 17,844 medical records were examined. Analysis considered the prescriptions of benzodiazepines in monotherapy, or in association with other drugs. Diagnoses of pathologies for which benzodiazepines were prescribed were made according to the ICD-10 classification system proposed by the World Health Organisation. RESULTS: Among medical records analysed, benzodiazepines were prescribed in 765 cases (3.29% of total cases assisted by CIRM). Benzodiazepines were prescribed as a single-drug treatment in 626 (81.83%) cases, whereas in 139 cases they were associated with other classes of drugs. In case of opioids prescribed in association with benzodiazepines, the drug used was codeine. This therapeutic association was prescribed in cases of severe pain. CONCLUSIONS: Although the "off label" use of benzodiazepines is not uncommon in medical practice, clear evidence indicates their potential side effects for human health. In this respect, medical professionals should comply with international guidelines on the use of benzodiazepines, both when prescribed as a single drug or in combination with other classes of drugs. These recommendations should be considered seriously in case of limited medical facilities such as on board of sailing ships. PMID- 29611612 TI - Maritime environment health risks related to pathogenic microorganisms in seawater. PMID- 29611613 TI - An outbreak of gastroenteritis on board an oil drilling rig in Ghana. AB - The article describes an outbreak of gastroenteritis which occurred on an oil drilling rig which operated in the Jubilee fields of Ghana (offshore Takoradi) between May 2011 and December 2013. An outbreak occurred on board approximately 10 h following a Christmas day buffet. Various Ghanaian and continental dishes were served during the occasion. Over a 3 day period, a total of 33 cases were recorded at the rig's sick bay. In order to describe the outbreak and determine its possible association with the meals served at the buffet, this case control study was conducted. A short questionnaire was used for data collection and a line list prepared for summarising data of cases. Samples of food could not be taken but water samples from multiple points of the rig's pipe water system were collected and cultured for coliforms. Data was analysed using Epi info version 7. Six foods appeared to be associated with the outbreak with odds ratios ranging from 1.2 to 2.7. The epidemic curve showed a propagated fashion of transmission and the outbreak was brought under control with public education on hand washing and disinfection of surfaces and door handles. The conclusion was that food items served at the buffet were not associated with the outbreak. Instead, a possible contamination of surfaces and door handles probably caused it. To prevent future occurrences, routine and regular hand washing and disinfection of surfaces and door handles is recommended. PMID- 29611614 TI - Occupational lung cancer among fisherman: a triple case report. AB - BACKGROUND: The World Health Organisation places lung cancer as the leading cause of cancer mortality in the world. The fishermen are one of the most important consumers of tobacco, which remains the main risk factor for lung cancer. However, there are no epidemiological data on the role of other causes, particularly occupational ones, in genesis of this disease. The objective of our work is to expose medical and occupational data of 3 fishermen with lung cancer and discuss a possible occupational origin of their pathology. CASE PRESENTATION: This is a case report where we describe medical and occupational data of 3 fishermen working in the port of Tangier (Morocco) who have lung cancer. The first one is an ordinary fisherman, the second is a mechanic on board and the third is an ordinary fisherman but who worked 21 years ago aboard deep-sea fishing ships as a helper in the mechanic room. All fishermen were in the fifties; the third one never smoked while the other two were described as heavy smokers. All of them were exposed during their daily work to some chemicals liable to cause lung cancer. The anatomopathological types found were 2 cases of adenocarcinoma which is the histopathological variant often found in cases of occupational origin and one case of squamous cell carcinoma. CONCLUSIONS: The results obtained after studying these 3 cases suggest the possibility of occupational origin in the genesis of lung cancer among fishermen; however, the increased smoking rate in this population remains the most probable factor and helps the preventive approach to be adopted. More detailed epidemiological studies would highlight the possible role of occupational causes in the carcinogenesis of this pathology. PMID- 29611615 TI - Health effects of hyperbaric exposure on chamber attendants: a literature review. AB - BACKGROUND: Inside attendants working in hyperbaric chambers are exposed to risks related to the hyperbaric environment, handling and care. The aim of this study is to review the literature focusing on the impact of this activity on health. MATERIALS AND METHODS: This is a literature review using the Medline database. RESULTS: Eight articles studied decompression illness (DCI). The incidence of DCI ranged from 0 to 37 per 100,000 sessions in hyperbaric chambers (SHC). The incidence of injuries ranged from 0 to 412 per 100,000 SHC. The most prevalent cause of accidental death was fire: 77 deaths (patients and attendants) between 1923 and 1996. Dysbaric osteonecrosis has been reported in one study only. CONCLUSIONS: Inside attendants face risks in the chamber, even if serious health effects seems rare compared to the total number of SHC. PMID- 29611616 TI - The pregnant traveller. AB - Travelling during pregnancy has become increasingly common. Many pregnant women travel for pleasureand recreation and a lot of them continue to work and therefore often travel on business, sometimes to areas with poor standards of sanitation and limited access to health care providers. During pregnancy, it is extremely important that a woman has a regular access to maternal health care, also in temporary destinations, especially in areas characterised by harsh environmental conditions, and places where the prevalence of infectious diseases is high. It must be remembered that the course of contagious or parasitic illnesses, such as hepatitis E and malaria, is generally more severe in pregnant travellers, due to pregnancy-related immunosuppression. The assessment of indications and contraindications for the use of mandatory/recommended vaccinations and antimalarial drugs is also very important in pregnant travellers. When pregnant women travel for long term, it is absolutely necessary that they receive prenatal care in a new place of residence. Scheduled maternity care usually begins in week 10-12 of pregnancy, and continues once a month until the 7 month of pregnancy, next every second week until week 36 and then once a week until the delivery. PMID- 29611617 TI - The paediatric traveller. AB - International travel with children, which is the opportunity for the family to see the world together, has become commonplace. If you are travelling with children the journey needs to be carefully planned, especially in cases of visiting a region with harsh environment or poor sanitation. It is particularly important in terms of thermoregulation (hot climate) and the immune system (protection against pathogens causing infectious and invasive diseases) as these are not fully developed in small children. In addition, it is important to maintain appropriate safety and security measures in the destination area (e.g. using child car seats during drive, supervising children during recreational activities in water and on land, avoiding contact with undomesticated animals). Moreover, it is essential to prepare a travel health kit containing drugs appropriate for young travellers - matched for their age and body weight, and to purchase personal prevention products for everyday use (sunscreen with a high sun protection factor, insect repellents, etc.). PMID- 29611618 TI - Perceived emotion suppression and culture: Effects on psychological well-being. AB - Whether the negative effects of emotion suppression on psychological well-being are applicable cross-culturally is a long-debated topic. The present study attempted to shed light on this debate, focusing on the effects of perceived emotion suppression and examining the psychological processes leading from perceived emotion suppression to lower psychological well-being. We used a scale manipulation to lead 196 American and 213 Chinese participants to perceive themselves as having suppressed their emotions to a greater or lesser extent and then measured their life satisfaction. As expected, both the American and Chinese participants reported lower life satisfaction in the high-suppression condition than in the low-suppression condition; this negative effect was mediated by positive affect and moderated by self-esteem. Specifically, perceived high emotion suppression decreased positive affect, which in turn led to lower well being. This effect was observed only for those with low self-esteem, but the patterns and mechanisms were consistent cross-culturally. PMID- 29611619 TI - Sequential mediating effects of provided and received social support on trait emotional intelligence and subjective happiness: A longitudinal examination in Hong Kong Chinese university students. AB - Past research has often focused on the effects of emotional intelligence and received social support on subjective well-being yet paid limited attention to the effects of provided social support. This study adopted a longitudinal design to examine the sequential mediating effects of provided and received social support on the relationship between trait emotional intelligence and subjective happiness. A total of 214 Hong Kong Chinese undergraduates were asked to complete two assessments with a 6-month interval in between. The results of the sequential mediation analysis indicated that the trait emotional intelligence measured in Time 1 indirectly influenced the level of subjective happiness in Time 2 through a sequential pathway of social support provided for others in Time 1 and social support received from others in Time 2. These findings highlight the importance of trait emotional intelligence and the reciprocal exchanges of social support in the subjective well-being of university students. PMID- 29611620 TI - Synthesis and biological evaluation of potential acetylcholinesterase inhibitors based on a benzoxazine core. AB - With the purpose of expanding the structural variety of chemical compounds available as pharmacological tools for the treatment of Alzheimer's disease, we synthesized and evaluated a novel series of indole-benzoxazinones (Family I) and benzoxazine-arylpiperazine derivatives (Family II) for potential human acetylcholinesterase (hAChE) inhibitory properties. The most active compounds 7a and 7d demonstrated effective inhibitory profiles with Ki values of 20.3 +/- 0.9 MUM and 20.2 +/- 0.9 MUM, respectively. Kinetic inhibition assays showed non competitive inhibition of AChE by the tested compounds. According to our docking studies, the most active compounds from both series (Families I and II) showed a binding mode similar to donepezil and interact with the same residues. PMID- 29611621 TI - Perception, attitude, and satisfaction of paediatric physicians and nurses towards clinical practice guidelines at a university teaching hospital. AB - RATIONALE, AIMS, AND OBJECTIVES: To explore perception, attitude, and satisfaction of paediatric clinicians, trainees, and nurses at King Khalid University Hospital towards clinical practice guidelines (CPGs) including the locally adapted diabetic ketoacidosis CPG (DKA-CPG). METHODS: A cross-sectional survey was distributed to 260 doctors and nurses working in the paediatrics department. RESULTS: The response rate was 95.4%. The respondents had a positive perception and attitude towards general CPGs and specifically for the DKA-CPG; 98.7% thought CPGs were useful sources of advice, improved safety, and decreased risk, and reduced variation in practice. A total of 99.2% thought CPGs were good clinical tools, 98.3% satisfied with, had confidence in well-developed CPGs, and would recommend them to their colleagues to use, and 94.6% agreed they were cost effective. The preferred format for CPGs was paper (46.6%) and electronic (42.9%). The DKA-CPG helped in managing patients and respondents were all satisfied and had confidence with it (100%). The rationale and objectives of the DKA-CPG were clear for 99.25%; 98.5% thought the layout was clear and well organized and user-friendly (96.2%). Compared with nurses, physicians had a higher perception towards CPGs in general (P < .05) and the DKA-CPG (P < .05). CONCLUSIONS: The paediatric doctors, and nurses have a great perception and satisfaction and positive attitude towards CPGs in general, towards the paediatric diabetic ketoacidosis CPG in particular, which in turn had a positive impact on the acceptability and implementation of the CPGs. These findings could help in sustaining a safe and high-quality health care environment through implementation of evidence-based CPGs. PMID- 29611622 TI - Controllable Synthesis of [11-2-2] Faceted InN Nanopyramids on ZnO for Photoelectrochemical Water Splitting. AB - Indium nitride (InN) is one of the promising narrow band gap semiconductors for utilizing solar energy in photoelectrochemical (PEC) water splitting. However, its widespread application is still hindered by the difficulties in growing high quality InN samples. Here, high-quality InN nanopyramid arrays are synthesized via epitaxial growth on ZnO single-crystals. The as-prepared InN nanopyramids have well-defined exposed facets of [0001], [11-2-2], [1-212], and [-2112], which provide a possible routine for understanding water oxidation processes on the different facets of nanostructures in nanoscale. First-principles density functional calculations reveal that the nonpolar [11-2-2] face has the highest catalytic activity for water oxidation. PEC investigations demonstrate that the band positions of the InN nanopyramids are strongly altered by the ZnO substrate and a heterogeneous n-n junction is naturally formed at the InN/ZnO interface. The formation of the n-n junction and the built-in electric field is ascribed to the efficient separation of the photogenerated electron-hole pairs and the good PEC performance of the InN/ZnO. The InN/ZnO shows good photostability and the hydrogen evolution is about 0.56 umol cm-2 h-1 , which is about 30 times higher than that of the ZnO substrate. This study demonstrates the potential application of the InN/ZnO photoanodes for PEC water splitting. PMID- 29611623 TI - Evaluating facts and facting evaluations: On the fact-value relationship in HTA. AB - Health technology assessment (HTA) is an evaluation of health technologies in terms of facts and evidence. However, the relationship between facts and values is still not clear in HTA. This is problematic in an era of "fake facts" and "truth production." Accordingly, the objective of this study is to clarify the relationship between facts and values in HTA. We start with the perspectives of the traditional positivist account of "evaluating facts" and the social constructivist account of "facting values." Our analysis reveals diverse relationships between facts and a spectrum of values, ranging from basic human values, to the values of health professionals, and values of and in HTA, as well as for decision making. We argue for sensitivity to the relationship between facts and values on all levels of HTA, for being open and transparent about the values guiding the production of facts, and for a primacy for the values close to the principal goals of health care, ie, relieving suffering. We maintain that philosophy (in particular ethics) may have an important role in addressing the relationship between facts and values in HTA. Philosophy may help us to avoid fallacies of inferring values from facts; to disentangle the normative assumptions in the production or presentation of facts and to tease out implicit value judgements in HTA; to analyse evaluative argumentation relating to facts about technologies; to address conceptual issues of normative importance; and to promote reflection on HTA's own value system. In this we argue for a(n Aristotelian) middle way between the traditional positivist account of "evaluating facts" and the social-constructivist account of "facting values," which we call "factuation." We conclude that HTA is unique in bringing together facts and values and that being conscious and explicit about this "factuation" is key to making HTA valuable to both individual decision makers and society as a whole. PMID- 29611624 TI - Design, synthesis, biological evaluations, molecular docking, and in vivo studies of novel phthalimide analogs. AB - A series of novel phthalimide analogs containing an indole or brominated indole moiety were synthesized and their antimicrobial activity was evaluated. Compound 8 showed a broad spectrum activity, revealing 53-67% of erythromycin activity on the tested bacteria and 60-70% of miconazole activity on the tested fungi. Anticancer activity was evaluated on the cell lines HepG2, MCF-7, A549, H1299, and Caco2. The results revealed that the new phthalimide analog 8 has broad spectrum anticancer activity toward all the tested cancer cell lines, followed by compound 11, which showed good activity toward all the tested cell lines except for MCF-7. The ability of the promising analogs 5, 8, and 11 to bind to topoisomerase II DNA gyrase was investigated. Caspase-3 activation and Bcl-2 assay of the best active derivatives 8, 11 in addition to compound 5 were evaluated. The antifibrotic activity was studied in an in vivo model and the histopathological studies revealed that treatment with the new compound 8 improved the fibrotic liver tissues to normality. PMID- 29611625 TI - Echocardiography and cardiovascular MRI entwined within the imaging domain; uniting the two. A compendium for the echocardiographer. AB - A review of the unique and complementary roles echocardiography and cardiovascular MRI provide to the clinician. A focus on the physics of each modality as well as imaging of the left ventricle. PMID- 29611626 TI - Quinoxaline and quinoxaline-1,4-di-N-oxides: An emerging class of antimycobacterials. AB - Tuberculosis (TB) is a highly dreaded, infectious, chronic, airborne disease affecting more than two million people all around the world, with more than eight million cases every calendar year. TB is the second leading infectious cause of death after HIV/AIDS. Over the past few decades, numerous efforts have been undertaken to develop new anti-TB agents. The current frontline therapy for TB consists of administering three or more different drugs (usually isoniazid, rifampin, pyrazinamide, and ethambutol) over an extended period of time. But these drugs will take 6-12 months to cure TB, along with many side effects; hence, there is an urgent need to explore new anti-TB agents. Quinoxaline derivatives are a class of compounds that show a spectrum of biological properties and the interest in these compounds is exponentially growing within the field of medicinal chemistry. Quinoxaline-1,4-di-N-oxide derivatives have shown to improve the biological results and are endowed with anti-viral, anti cancer, anti-bacterial, and anti-protozoal activities with application in many other therapeutic areas. Since quinoxaline derivatives are regarded as a new class of effective anti-TB candidates, their 1,4-di-N-oxide analogues may show promising in vitro and in vivo anti-TB activities and might be able to prevent the drug resistance to a certain extent. Therefore, the main aim of this review is to focus on important quinoxaline and quinoxaline-1,4-di-N-oxide analogues that have shown anti-TB activities, and their structure-activity relationships for designing anti-TB agents with better efficacies. The present review will be helpful in providing insights for rational designs of more active and less toxic quinoxaline-based anti-TB prodrugs. PMID- 29611627 TI - Simultaneous confidence sets for several effective doses. AB - Construction of simultaneous confidence sets for several effective doses currently relies on inverting the Scheffe type simultaneous confidence band, which is known to be conservative. We develop novel methodology to make the simultaneous coverage closer to its nominal level, for both two-sided and one sided simultaneous confidence sets. Our approach is shown to be considerably less conservative than the current method, and is illustrated with an example on modeling the effect of smoking status and serum triglyceride level on the probability of the recurrence of a myocardial infarction. PMID- 29611628 TI - Influence of large joint involvement on patient-physician discordance in global assessment of rheumatoid arthritis disease activity analyzed by a novel joint index. AB - OBJECTIVES: The discordance between patient global assessment (PGA) and physician global assessment (PhGA) of rheumatoid arthritis (RA) disease activity may be problematic in clinical practice. The aim of this study was to identify determinants of this discordance using a nationwide RA database in Japan (NinJa) with special attention to large joint involvement. METHODS: We investigated 12 043 adults with RA and used a discordance cutoff of 3 cm. Large joint involvement was investigated using novel joint indices (x, y, z), where x and y were the indices for upper and lower joints, respectively, and z was for large joint predominance. Predictors of PGA-PhGA discordance and determinants of PGA and PhGA were analyzed by multivariate logistic and linear regression models, respectively. RESULTS: Multivariate logistic regression identified age, pain and high modified Health Assessment Questionnaire score as predictors of positive discordance (PGA >= PhGA), whereas parameters of disease activity in RA (C reactive protein, x and y), class 3-4 functional status, and z were found to predict against positive discordance. Linear regression analysis revealed that PGA was mainly determined by pain, whereas PhGA was determined by various other factors. CONCLUSIONS: RA care providers should focus on pain and functional disability to decrease PGA-PhGA discordance. High disease activity and large joint involvement decreased PGA-PhGA discordance, indicating that the number and distribution of affected joints influenced the perception of disease activity by patients with RA and their physicians. PMID- 29611629 TI - Chemometric Strategies for Peak Detection and Profiling from Multidimensional Chromatography. AB - The increasing complexity of omics research has encouraged the development of new instrumental technologies able to deal with these challenging samples. In this way, the rise of multidimensional separations should be highlighted due to the massive amounts of information that provide with an enhanced analyte determination. Both proteomics and metabolomics benefit from this higher separation capacity achieved when different chromatographic dimensions are combined, either in LC or GC. However, this vast quantity of experimental information requires the application of chemometric data analysis strategies to retrieve this hidden knowledge, especially in the case of nontargeted studies. In this work, the most common chemometric tools and approaches for the analysis of this multidimensional chromatographic data are reviewed. First, different options for data preprocessing and enhancement of the instrumental signal are introduced. Next, the most used chemometric methods for the detection of chromatographic peaks and the resolution of chromatographic and spectral contributions (profiling) are presented. The description of these data analysis approaches is complemented with enlightening examples from omics fields that demonstrate the exceptional potential of the combination of multidimensional separation techniques and chemometric tools of data analysis. PMID- 29611630 TI - Large-brained frogs mature later and live longer. AB - Brain sizes vary substantially across vertebrate taxa, yet, the evolution of brain size appears tightly linked to the evolution of life histories. For example, larger brained species generally live longer than smaller brained species. A larger brain requires more time to grow and develop at a cost of exceeded gestation period and delayed weaning age. The cost of slower development may be compensated by better homeostasis control and increased cognitive abilities, both of which should increase survival probabilities and hence life span. To date, this relationship between life span and brain size seems well established in homoeothermic animals, especially in mammals. Whether this pattern occurs also in other clades of vertebrates remains enigmatic. Here, we undertake the first comparative test of the relationship between life span and brain size in an ectothermic vertebrate group, the anuran amphibians. After controlling for the effects of shared ancestry and body size, we find a positive correlation between brain size, age at sexual maturation, and life span across 40 species of frogs. Moreover, we also find that the ventral brain regions, including the olfactory bulbs, are larger in long-lived species. Our results indicate that the relationship between life history and brain evolution follows a general pattern across vertebrate clades. PMID- 29611631 TI - The Integrative Review. PMID- 29611632 TI - Gold Nanoplate-Enhanced Chemiluminescence and Macromolecular Shielding for Rapid Microbial Diagnostics. AB - With the global rise of antimicrobial resistance, rapid screening and identification of low concentrations of microorganisms in less than 1 h becomes an urgent technological need for evidence-based antibiotic therapy. Although many commercially available techniques are labeled for rapid microbial detection, they often require 24-48 h of cell enrichment to reach detectable levels. Here, it is shown that the widely used reducing agent tris(2-carboxyethyl)phosphine (TCEP) can also act as a powerful oxidant on gold nanoplates and subsequently lead to a strong catalysis of luminol chemiluminescence. The catalytic reaction results in up to 100-fold signal enhancement and unprecedented stable luminescence for up to 10 min. However, when TCEP is exposed to microorganisms, it is oxidized by the microbial surface proteins and loses its catalytic properties, leading to a decrease in chemiluminescence. The competitive interaction of TCEP with Au nanoplates and microorganisms is used to introduce a homogenous rapid detection method that allows microbial screening in less than 10 min with a limit of detection down to 100 cfu mL-1 . Furthermore, the concept of microbial macromolecular shielding using antibody-conjugated polymers is introduced. The combination of TCEP redox activity and macromolecular shielding enables specific microbial identification within 1 h, without preconcentration, cell enrichment, or heavy equipment other than a hand-held luminometer. The technique is demonstrated by specific detection of methicillin-resistant Staphylococcus aureus in environmental and urine samples containing a mixture of microorganisms. PMID- 29611633 TI - Deoxynivalenol as potential modulator of human steroidogenesis. AB - Deoxynivalenol (DON) is a type B trichothecene, produced by the Fusarium species. Exposure to DON might cause disruptive effects such as reduced weight gain, neuroendocrine changes and immune modulation in animals (rats, dogs, pigs). There is huge concern that similar effects can be observed in humans. DON is a potential regulator of intracellular steroidogenesis. It is also possible that DON will be involved in the regulation of miRNAs connected with steroidogenesis. This review summarizes the latest knowledge about the influence of DON on steroidogenesis and human hormonal balance. PMID- 29611634 TI - Ubiquitylation Pathways In Insulin Signaling and Organismal Homeostasis. AB - The insulin/insulin-like growth factor-1 (IGF-1) signaling (IIS) pathway is a pivotal genetic program regulating cell growth, tissue development, metabolic physiology, and longevity of multicellular organisms. IIS integrates a fine-tuned cascade of signaling events induced by insulin/IGF-1, which is precisely controlled by post-translational modifications. The ubiquitin/proteasome-system (UPS) influences the functionality of IIS through inducible ubiquitylation pathways that regulate internalization of the insulin/IGF-1 receptor, the stability of downstream insulin/IGF-1 signaling targets, and activity of nuclear receptors for control of gene expression. An age-related decline in UPS activity is often associated with an impairment of IIS, contributing to pathologies such as cancer, diabetes, cardiovascular, and neurodegenerative disorders. Recent findings identified a key role of diverse ubiquitin modifications in insulin signaling decisions, which governs dynamic adaption upon environmental and physiological changes. In this review, we discuss the mutual crosstalk between ubiquitin and insulin signaling pathways in the context of cellular and organismal homeostasis. PMID- 29611635 TI - Molecular cloning, expression, purification and osteoblasts proliferation activity of sika deer thymosin beta10. AB - Thymosin beta 10 (Tbeta10) is a member of the beta-thymosin family. As an actin binding peptide, thymosin beta10 is involved in many important biological activities. Transcriptome sequencing results suggest that Tbeta10 may play important roles in the growth of deer antler. In this study, Tbeta10 cDNA was isolated from sika deer, and complete open reading frame consisting of 129 nucleotides was obtained by PCR amplification. The predicted peptide was 42 amino acids in length. The sdTbeta10 cDNA was cloned and expressed in Escherichia coli resulting in a 6 kDa recombinant-His tagged protein. The recombinant, non glycosylated peptide was overexpressed in a soluble form and purified by immobilized metal ion affinity chromatography. Functional studies revealed that recombinant Tbeta10 stimulated osteoblasts proliferation. This study provides the first evidence that recombinant sika deer Tbeta10 promotes proliferation in an osteoblasts cell model. PMID- 29611636 TI - Serum paraoxonase 1 activity and lipid metabolism parameter changes in Dachshunds with chronic mitral valve disease. Assessment of its diagnostic usefulness. AB - Chronic mitral valve disease, which is frequently diagnosed in Dachshunds, leads to structural, hemodynamic and redox state changes in dogs. The aim of this study was to investigate serum paraoxonase 1 (PON1) activity and lipid metabolism in different disease stages. Standardized PON1 activity (PON1/HDL ratio) was lower in asymptomatic dogs, B1 and B2 Stages when compared to healthy ones and symptomatic Dachshunds in Stage C (ACVIM classfication). PON1 paraoxonase activity was elevated in Stage C dogs, with no changes found in PON1 activity towards phenyl acetate. Dachshunds in Stage B2 and C showed increased triglyceride levels, with no changes in cholesterol and lipoprotein concentration in comparison to healthy ones. Our data suggest that standardized PON1 activity changes could be used in laboratory diagnostics to differentiate the CMVD of affected asymptomatic (Stage B1 and B2) dogs from healthy (Stage A) and clinically affected (Stage C) dogs. Also, a standardized PON1 activity increase might be a prognostic progression signal of the disease to Stage C. PMID- 29611637 TI - Temporospatial study of hexose transporters and mucin in the epithelial cells of chicken (Gallus gallus domesticus) small intestine. AB - The temporospatial patterns in the localization of hexose transporters as well as in the quantitative and qualitative differences of glycoprotein mucin produced by the goblet cells of broiler chicken (Gallus gallus domesticus) small intestine during their first postnatal month were studied. The integral membrane proteins glucose transporter-2 and -5 (GLUT-2 and GLUT-5) that facilitate the transport of hexoses across epithelial cell layers that separate distinct compartments in organism were detected in the chicken intestinal epithelial cells using immunohistochemical labeling with polyclonal primary antibodies Rabbit anti-GLUT 2 and Rabbit anti-GLUT-5 (IHC kit, Abcam, UK). The chemical composition of mucin (neutral, acid) was carried out by applying the histochemical reactions by Alcian Blue and periodic acid-Schiff methods. The results revealed presence of the hexose transporters GLUT-2 and -5, immunolocalized in the enterocytes of broiler's small intestine and the temporospatial pattern of the density of goblet cells of intestinal mucosa as well as the chemical composition of mucin produced by the goblet cells in chicken immediately after hatching and in 30-days-old chicken's. Simultanously, when goblet cells remained unstained with both antibodies in intestinal epithelium in chicken of both ages or some moderate staining was noticed in 30-days-old chickens' ileal epithelium, the increase of neutral and acid mucin- containing cells per area unit in both segments of the small intestine was detected from the first day after hatching to 30 day of life and the densilty of goblet cells was found to be higher in ileal than in duodenal region. PMID- 29611638 TI - The macrostructure and microstructure of the urinary bladder and urethral mucosa in dogs with lower urinary tract diseases. AB - The aim of the study was to assess the macrostructure and the microstructure of the bladder and urethral mucosa in dogs with lower urinary tract disease as well as to evaluate the usefulness of the WHO/ISUP grading of invasive and non invasive tumours of the bladder and urethral mucosa. The study was carried out on 37 dogs of different breeds and of both sexes, from 9 months to 15 years old. An urethrocystoscopy and a histopathological evaluation of mucosal biopsies were carried out in all the studied dogs. Cystitis was the most common disease noted during urethrocystoscopy. Chronic active inflammation of the bladder was the most common inflammatory lesion diagnosed in the histopathological examination, while the transitional cell carcinoma was the most common tumour of the bladder. Urethrocystoscopy proved to be a very useful tool in the assessment of macroscopic lesions in the bladder and urethral mucosa in dogs. We also evaluated the type and extent of microscopic inflammatory lesions in the bladder and urethral mucosa using the modified Sydney scale. The WHO/ISUP scale is very helpful in the histopathological classification of canine invasive and non invasive proliferative lesions in the bladder and urethra. PMID- 29611639 TI - Validation of relationship between milk resistance and daily yield of dairy cows. AB - Purpose: The reduced value of resistance (R) of milk (<167Omega) or increased conductivity (EC) >6.0 mS/cm indicate the growing number of ions in milk during the initial phase of mastitis. The aim of this study is to demonstrate a linear (verified by a validation procedure) dependency between R and mean daily yield (MDY), which could be used for current monitoring and forecasting of milk yield in dairy cow herds. Although the topic has frequently been examined, a validated model for prediction of MDY based on R has still not been presented. Methods: Data from 118 dairy cows were analyzed in the study. The validation of model dependency R<->MDY was performed by the live-one-out method (LOO). Results: The minimum geometrical/arithmetical mean of R milk was observed during the 1st month of lactation and was 53.40/254.86 Omega. However, the maximum geometrical/arithmetical mean of R milk was observed during the 7th month of lactation and has 189.62/574.51 Omega. The final model was described by the curve equation MDY = -04461 * R% + 51.58 where R% - percentage share of cows in a herd whose R oscillated within the limits 49.38-154.32 Omega. Conclusions: Complete predictivity of the model within the above mentioned limits ("prognostic range") was confirmed by the results of validation of the model. The developed model enables the efficiency of a herd at specified percentage share of cows of defined milk R value to be determined. PMID- 29611640 TI - Influence of simvastatin on red blood cell line in porcine bone marrow. AB - Simvastatin is a drug commonly used to reduce the cholesterol level. 32 clinically healthy female pigs with a bodyweight of 35-40 kg, kept in standard laboratory conditions were chosen for the experiment and divided into 2 groups (control and experimental) consisting of 16 animals. The experimental group received simvastatin orally at a dose of 40 mg (one tablet once a day) for 56 days, and at the same time the control group received placebo (empty gelatin capsules). Bone marrow smears and peripheral blood samples were evaluated. The obtained results indicate that simvastatin may inhibit erythropoiesis even after a relatively short period of administration, and observed changes can be the cause of some symptoms (for example anemia) occurring during statin therapy. PMID- 29611641 TI - Significant expression of Foxp3 in murine extrathymic CD4+CD8+ double positive T cells. AB - Forkhead box protein 3 (Foxp3) is a specific marker and the key factor in the development and function of regulatory T (Treg) cells. The present study investigates Foxp3 expression in murine head and neck lymph node (HNLN) and peripheral blood (PB) CD4+CD8+ double positive (DP) T cells and compares it with that in CD4+ or CD8+ single positive (SP) T cells. Here we provide evidence that murine extrathymic DP cells express Foxp3. We determined that the mean percentage of Foxp3-expressing cells within HNLN and PB DP cells was, respectively, 22.4 and 16.2. The obtained results clearly indicate that DP cells are very similar to CD4+ SP cells in respect of Foxp3 expression, and thus considerably deviate from CD8+ SP cells. It was found that Foxp3 expression in DP cells is positively correleted with CD25 expression. These results suggest that murine extrathymic Foxp3+ DP T cells may represent a unique regulatory T cell subset. PMID- 29611642 TI - The effect of budesonide on the expression of Ki-67 and PCNA and the apoptotic index in dogs with inflammatory bowel disease. AB - The aim of this study was to determine the effect of budesonide on the expression of Ki-67 and PCNA proliferative antigens and the apoptotic index in the course of inflammatory bowel disease (IBD) and to evaluate the applicability of these markers in monitoring IBD treatment in dogs. The experiment was performed on 28 dogs of different breeds and both sexes, with body weight of 6 to 20 kg, aged 6 to 10 years. The animals diagnosed with IBD were divided into four groups of 7 dogs each, including three experimental groups characterized by various severity of IBD and a control group. The dogs from the experimental groups were administered budesonide (Entocort, Astra-Zeneca, Sweden) in daily doses depending on body weight of animal - 1.0 mg (6-10 kg), 1.5 mg (11-15 kg) or 2.0 mg (16-20 kg) and control group dogs were orally administered empty gelatin capsules (placebo) for 30 days. The expression of Ki-67 and PCNA antigens was determined immunohistochemically, and the apoptotic index was expressed as the number of TUNEL-positive lamina propria cells in duodenal, jejunal and colonic mucosa before and after 30 days of budesonide therapy. The results of the study point to the limited applicability of Ki-67 and PCNA proliferation markers and high applicability of the apoptotic index in monitoring IBD progression and treatment in dogs. Budesonide exerted significant anti-apoptotic effects in canine patients with various severity of IBD, which indicates that next-generation glucocorticosteroids can be effectively used in the treatment of gastrointestinal diseases characterized by high values of the apoptotic index, including IBD. PMID- 29611643 TI - Immunophenotypic characteristics and karyotype analysis of bone marrow-derived mesenchymal stem cells of rabbits during in vitro cultivation. AB - The aim of this study was to establish the immunophenotypic profile and karyotypic stability of bone marrow mesenchymal stem cells (MSCs) of rabbits at the early passages in vitro following the application of different methods of dissociation of cellular material. MSCs were obtained from the femur bone marrow of three clinically healthy rabbits under general anaesthesia. Bone marrow aspirate was seeded in Petri dishes and cultured in a CO2 incubator with 5% CO2 at 37.0oC using a standard procedure. Immunohistochemical detection of nuclear proteins, cytoskeletal proteins and cell adhesion were performed by immunohistochemical analysis and karyotype analysis of MSCs following the enzyme and chelating methods of dissociation of the cell monolayer. The results of the immunophenotypic analysis of rabbit bone marrow MSCs showed that at the first, seventh, twelfth, and eighteenth passages these cells express markers of mesenchymal, muscle, epithelial and nerve cells. The choice of the enzyme or chelating method of dissociation of a culture of rabbit mesenchymal stem cells affects their cytogenetic variability. Dissociation of the MSCs monolayer with ethylenediaminetetraacetic acid produces a cell culture with fewer quantitative and qualitative changes in the chromosome apparatus as compared to the enzyme method. Rabbit MSCs express markers of mesenchymal (vimentin, actin), muscle, epithelial and nerve (E-cadherin, N-cadherin) cells that are essential for differentiation of these cells. The chelating method of dissociation of a culture of rabbit mesenchymal stem cells, using ethylenediaminetetraacetic acid during cultivation, is more advantageous than the enzyme method of dissociation because it leads to less cytogenetic variability. PMID- 29611644 TI - Metastatic lymphadenomegaly in dogs - cytological study. AB - Enlarged lymph nodes are frequently examined cytologically in dogs and metastatic lymphadenomegaly of various origin is a common cytological finding in these cases. In this study we aimed to examine epidemiological data, and to determine factors affecting the location of neoplastic metastases in the lymph nodes. Samples for cytological examination were obtained by fine-needle biopsy (FNB) of enlarged lymph nodes and stained with Giemsa solution. Cases meeting the following criteria were enrolled in the study: lymphadenomegaly detected in clinical examination, presence of primary mass confirmed by cytopathology or histopathology as a solid malignant tumour, and cytological diagnosis of metastatic tumour. Cytological pattern of lymph node involvement was classified as low, medium and massive. During study period 125 dogs met the eligibility criteria, with age ranged from 1.8 to 19 years. No sex predisposition to particular types of tumors was observed, except for adenocarcinoma which was diagnosed in females more often. Metastatic tumors were various in origin, with predominance of mast cell tumors, adenocarcinomas, and melanomas. Massive involvement predominated in all lymph nodes affected. Neoplastic lymphadenomegally is recognized usually in older dogs, with female predisposition related to dissemination of mammary cancers. Mast cell tumor, adenocarcinoma and melanoma are the most common causes of metastatic lymphadenomegaly, and in the vast majority of the cases massive lymph node involvement is observed. PMID- 29611645 TI - Expression of follicle-stimulating hormone receptor (FSHR), protein kinase B-2 (AKT2) and adapter protein with PH domain, PTB domain, and leucine zipper (APPL1) in pig ovaries. AB - Follicle-stimulating hormone (FSH) regulates oogenesis and spermatogenesis by binding to its receptor (FSHR) on target cells in the ovary and testis, respectively. The signaling cascades activated after ligand binding are extremely complex and have been shown to include protein kinase A and phosphatidylinositol 3-kinase/protein kinase. The adapter protein APPL1 (adapter protein with PH domain, PTB domain, and leucine zipper), which is an assortment of other signaling proteins, was previously identified to interact with the FSH receptor (FSHR) and the protein kinase B (AKT) pathway. APPL1 plays an important role in promoting cell survival within the preovulatory follicle granulosa layer. Here, we aimed to evaluate the FSHR, AKT2, and APPL1 gene and protein expression levels in the ovaries of different prolific porcine breeds (Wannan Black [WB] and Large White [LW] pigs) using immunohistochemistry and qRT-PCR, respectively. Our results showed that FSHR, AKT2, and APPL1 mRNA levels were significantly higher (P < 0.05) in the ovaries of WB pigs than in the ovaries of LW pigs. Additionally, the FSHR, AKT2, and APPL1 proteins were mainly found distributed in the granulosa cells and oocytes. This study showed that high levels of FSHR, AKT2, and APPL1 were expressed in the ovaries of high prolific breed pigs. PMID- 29611646 TI - Application of NucleoCounter for the comprehensive assessment of murine cultured neurons during infection with Equine Herpesvirus type 1 (EHV-1). AB - The NucleoCounter NC-3000, a portable high-speed cell counting device based on the principle of fluorescence microscopy, provides the alternative method for standard flow cytometry. The main objective of the study was to apply an efficient technique for the assessment of the primary murine neurons culture infected with either neuropathogenic or non-neuropathogenic strains of Equine Herpesvirus type 1 (EHV-1). Using the NucleoCounter NC-3000 we have observed a decrease in mitochondrial potential and reduction in cells viability but we have not observed changes in the cell cycle of cultured neurons infected with all EHV 1 strains. PMID- 29611647 TI - Determination of polymorphism of IS-1311 sequence in Mycobacterium avium subspecies paratuberculosis strains isolated from milk samples. AB - The study was aimed at the genetic typing of Mycobacterium avium subspecies paratuberculosis (MAP) with PCR-REA method based on the polymorphism of IS-1311 sequence. MAP strains were isolated from milk samples collected from cows free of disease symptoms and anti-MAP antibodies. Samples of udder milk were collected from 310 cows originating from the herd with a low seroprevalence of paratuberculosis; every 5 samples were pooled. The polymorphism typing of the IS 1311 sequence of the isolated strains demonstrated the presence of two types of the mycobacterium: sheep and cattle ones, of which the bovine type constituted 98.5%. PMID- 29611648 TI - Phenotypic characteristics of feline adipose-derived stem cells affected by cell passage number. AB - In this study we evaluated the influence of passage number on the phenotypic characteristics of feline adipose-derived stem cells (ASCs) in order to develop a broader understanding of their dynamics. Feline ASCs were individually isolated from five domestic cats and subjected to proliferative culture at passage (P) 2, 6 and 10. The cells at each sub-passage were examined in regard to their phenotypic properties associated with multipotent mesenchymal stem cells (MSCs), such as morphology, proliferation kinetics, self-renewal, and expression of MSCs specific surface markers. The differentiation capacity into adipocytes and osteoblasts was also identified. Feline ASCs appeared with a fibroblast-like morphology with minimal alteration through P10. The rate of cell proliferation gradually decreased, while cell doubling time gradually increased with each passage. A significant decrease in CFU-F efficiency was observed with increasing cell passage number. The ASC population uniformly expressed their characteristic markers CD44 and CD90, but did not express the hematopoietic marker CD45. However, MSC markers gradually decreased in the later passage stages. Feline ASCs were capable of undergoing both adipogenesis and osteogenesis at P2. These findings suggested that the phenotypic characteristics of feline ASCs could be affected by long-term passages, which is potentially very important in regard to their therapeutic application. PMID- 29611649 TI - Bovine tuberculosis outbreak in farmed American bison (Bison bison) in Poland. AB - Poland has been an officially bovine tuberculosis (bTB) free country for the last seven years. The problem currently observed is the increasing number of new cases of bTB in wild species, kept in a farmed herd and free-living herd: European bison (Bison bonasus), wild boar (Sus scrofa), wolves (Canis lupus) and red deer (Cervus elaphus). This article presents the case of Mycobacterium caprae transmission to an American bison (Bison bison) herd kept on a private farm in Eastern Poland. PMID- 29611650 TI - Comparison of biofilm formation by Staphylococcus aureus and Staphylococcus epidermidis strains isolated from sheep milk using three diagnostic methods. AB - In this study we investigated 24 strains of Staphylococcus aureus and 33 strains of Staphylococcus epidermidis isolated from milk of sheep with clinical mastitis, for their ability to form biofilms. Three methods for the determination of a biofilm were used. When evaluating the growth on Congo Red agar (CRA), 79.2% S. aureus strains and 72.7% S. epidermidis strains were positive for biofilm formation. The quantitative method of biofilm detection on a Microtitre Plate (MTP) revealed positive results for 75.0% of S. aureus samples and 75.8% for S. epidermidis samples. Using PCR method for determination of the presence of genes that affect formation of biofilms, the most frequently determined genes were eno in both S. aureus (18/24; 75.0%) and S. epidermidis strains (20/33; 60.6%). The genes icaAB and ebpS were detected in both S. aureus and S. epidermidis strains, and similarity between these strains was 12.5% - 15.1% and 4.2% - 6.0%, respectively. The bap was recorded only in S. epidermidis (3.0%). Statistical comparison of the level of biofilm formation was performed using Chi square test. There were no statistically significant differences in the amount of biofilm formation between two methods for detection of biofilm CRA and MTP (p>0.05). Comparison of all six monitored parameters showed no dependence of characteristics of the tested strains S. aureus and S. epidermidis at significance level alpha = 0.05. Biofilm formation by the bacteria isolated from 57 cases of clinical mastitis in sheep was confirmed. Sensitivity and specificity of the CRA method for S. aureus were 94.44% and 66.66%, respectively, and for S. epidermidis 92.0% and 87.5%, respectively. Both CRA and MTP methods can be recommended for the detection of biofilm production by S. aureus and S. epidermidis strains isolated from milk of sheep with clinical mastitis. PMID- 29611651 TI - LBP gene methylation involved in mRNA expression and resistance to E. coli F18 in weaned piglets. AB - Lipopolysaccharide binding protein (LBP) plays an important role in recognizing and regulating endotoxin. In this study, we aimed at clarifying the relationship between the methylation of LBP gene and it's expression, to identify mechanisms involved in resistance to E. coli F18 in Sutai weaned piglets. LBP expression was detected by real-time PCR in duodenum and jejunum tissues from E. coli F18 sensitive or -resistant piglets. The LBP methylation status of the regions with many CG sites upstream of the transcription start site was analyzed by Bbisulfite Sequencing PCR (BSP) +Miseq in jejunum and duodenum tissue. The results showed that LBP expression was significantly higher in the sensitive group than the resistant group in duodenum tissue (p<0.05). There was a negative correlation between the methylation of CpG islands upstream of the LBP transcription start site and its expression; the methylation at two CpG sites in particular was significantly correlated with reduced LBP expression (CpG-1 and CpG-2; p<0.05 and p<0.01, respectively). These indicated that the methylation of CpG-1 and CpG-2 sites in the LBP region is involved in the regulation of LBP expression, and may provide key contributions to resisting E. coli F18 in Sutai weaned piglets. PMID- 29611652 TI - The stress response of Ragusano donkey (Equus asinus) to different semen collection techniques. AB - The aim of the present study was to characterize the stress response of donkeys to different semen collection techniques, comparing the physiological patterns of hormonal (adrenocorticotropic hormone: ACTH, cortisol) and biochemical variables (creatinine, total protein, urea, aspartate aminotransferase: AST, alanine aminotransferase: ALT), and routine seminal parameters and sexual behaviour. Twenty two healthy Ragusano donkeys were used and were randomly assigned to one of 2 groups based on different semen collection techniques. Group A was designated as the experimental group and included 16 donkeys submitted to semen collection by an artificial vagina (AV) "on the ground"; group B was designated as the control group, and included 6 donkeys submitted to semen collection by AV during the mount. The semen collection was performed in October, once a day for 10 consecutive days. Blood samples were collected in baseline conditions, before the onset of the treatments and within 30 min after, from the jugular vein of each subject. Two-way ANOVA showed a significant effect of semen collection technique and time points in group A for ACTH (p=0.0084), cortisol (p=0.0004) and creatinine (p=0.0131), with lower values after semen collection than before. A significant effect of semen collection technique and time points in group B for ACTH (p<0.0001) and cortisol (p<0.0001) was observed, with higher values after semen collection than before. The comparison between groups A and B values over different time points showed a significant effect after semen collection for ACTH (p<0.0001), cortisol (p<0.0001) and creatinine (p<0.0001), with the highest values in group B. This study provides the physiological evidence that semen collection on the ground in healthy donkeys could be used as an alternative strategy to induce a positive animal approach and economical advantages. PMID- 29611653 TI - The evaluation of blood concentrations of testosterone, 17beta-oestradiol and anti-Mullerian hormone in dogs with cryptorchidism and testicular tumours. AB - Cryptorchidism and testicular tumours are very common disorders in dogs genitalia. The aim of the present study was o obtain an overview of serum 17beta oestradiol, anti-Muellerian hormone (AMH) and testosterone levels in intact dogs compared to dogs with different testicular tumours and dogs with cryptorchidism. Testosterone, AMH and 17beta-oestradiol concentrations were measured in peripheral and local spermatic venous blood in dogs with unilateral cryptorchidism (n=8), dogs with neoplastic testicular diseases (n=8) and in a control group of mature intact dogs (n=8). Results confirmed significantly higher concentrations of testosterone in local venous blood (control group: right testicle (RT) 46.23 +/- 40.88 ng/ml and left testicle (LT) 50.76 +/- 43.76 ng/ml; cryptorchid group: RT 23.91 +/- 22.79 ng/ml and LT 10.52 +/- 7.37 ng/ml; tumour group: RT 37.26 +/- 25.26 ng/ml and LT 44.86 +/- 19.03 ng/ml) (p<0.05) compared to their concentrations in peripheral blood (PB) in a control (4.92 +/- 3.3 ng/ml) and in a cryptorchid group (0.89 +/- 0.78 ng/ml), but not in the tumour group (11.37 +/- 10.86 ng/ml). However, we have found increased level of testosterone in PB in the tumour group compared to its PB concentrations in the control or the cryptorchid group. Concentrations of AMH in PB observed in the cryptorchid group was 54.98 +/- 30.07 MUg/ml and in the control group was 6.49 +/ 3.24 MUg/ml (p<0.05). The same was observed in the case of local blood concentrations, which were significantly higher in the cryptorchid group (RT 51.92 +/- 30.59 MUg/ml; LT 46.33 +/- 34.86 MUg/ml) (p<0.05). We also observed high oestradiol concentrations in the cryptorchid group in both peripheral and local blood (PB: 30.86 +/- 20.28 pg/ml; RT: 55.71 +/- 34.7 pg/ml; LT: 78.99 +/- 47.72 pg/ml), and even higher in the tumour group (PB: 52.46 +/- 34.02 pg/ml; RT: 188.16 +/- 132.67 pg/ml; LT: 297.14 +/- 245.56 pg/ml). AMH has been shown to be a specific biomarker of gonadal tumours originated in Sertoli cells. It is also useful marker for confirmation of the existence of a functional cryptorchid testis. According to us, the scientific work dealing with a disorder of testicular descent in dogs, regarding the evaluation of sex hormones levels and the formation of the testes using modern diagnostic methods, significantly contribute to the clarification of some processes, leading to pathophysiological disturbances during this process. PMID- 29611654 TI - Influence of Trendelenburg position and pneumoperitoneum treatment on gastroesophageal reflux in dogs. AB - Gastroesophageal reflux is a latent factor that may cause esophagitis, esophageal stenosis, and aspiration pneumonia through the regurgitation of the gastric fluid contents. For laparoscopic surgery, posture-changing and pneumoperitoneum operations are conducted to develop the visual field. However, few studies have examined the influence of these operations on gastroesophageal reflux. In this experiment using 10 Beagles, 10 mL of contrast medium was administered into the stomach, and the dogs were placed in the Trendelenburg position with 10-degree tilting. Pneumoperitoneum treatment with carbon dioxide was performed, with an intraperitoneal pressure of 10 mmHg. The presence or absence of gastroesophageal reflux was evaluated using computed tomography (CT). In horizontal and Trendelenburg positions, there was no reflux of Contrast medium. However, reflux was observed in the Trendelenburg position under pneumoperitoneum (p<0.05). These results suggest that the risk of gastroesophageal reflux increases during laparoscopic surgery in the Trendelenburg position with 10-degree tilting under an intraperitoneal pressure of 10 mmHg. PMID- 29611655 TI - Emerging of canine kobuvirus in dogs in China, 2015. AB - Canine kobuvirus (CaKoV) is a newly emerging virus in dogs, which relates to the diarrhea of dogs. To investigate the CaKoV infection in dog population, fecal samples of dogs were collected from three provinces of China in 2015. The results of genetic analysis based on the complete VP1 gene showed that six CaKoVs isolates in this study were closely related with the Chinese canine originated isolate CH1 (90.6%-91.9% nucleotide identities). The phylogenetic analysis demonstrated that the Chinese isolates clustered into a unique branch compared with isolates from other countries. The present study suggested that the CaKoVs had established infection in Chinese dog population. The systematic epidemiological investigation should be further carried out to evaluate the prevalence of the CaKoV infection in China. PMID- 29611656 TI - The effect of acetylosalicylic acid and berberis on ascites syndrome parameters in broiler chickens. AB - One-hundred and thirty day-old broiler chickens were kept for 6 days and on the seventh day, 120 chickens were selected and randomly divided into 5 groups with 2 replicates. To cause ascites, an amount of 0.12% sodium was added to the drinking water of 4 groups of chickens. On the fourteenth day, the amount of sodium was increased to 0.24% and at the same time, treatment with acetylosalicylic acid and berberis was started. At the age of 14 and 21 days, random sample chickens from each replicate were necropsied and were examined in terms of the factors associated with ascites. The results showed that the ratio of the weight of the right ventricle (RV) to the weight of the total ventricles (TV) and all other factors on 14th day revealed no significant difference between the groups (p>0.05). On 21st day, the RV/TV ratio in the ascites control group was significantly higher than that in the control group (p<0.05). The RV/TV ratio in the groups receiving acetylosalicylic acid and berberis were lower than those in the ascites control group; however, this reduction was not significant (p>0.05). The rate of mortality in the groups receiving acetylosalicylic acid and berberis was lower than that in ascites control group. Considering the results obtained, it can be suggested that the treatment with acetylosalicylic acid and berberis is effective to prevent ascites. PMID- 29611657 TI - A strain of pathogenic Bacillus subtilis results in brain damage in ducklings when co-infected with Riemerella anatipestifer. AB - Bacillus subtilis is a Gram-positive bacterium widely used in medicine and agriculture. So far, little is known about its pathogenicity in animals. In this study, a strain of Bacillus subtilis, HFBF-B11 isolated from brain tissue of ducklings co-infected with Riemerella anatipestifer was characterized. The strain demonstrated consistent characteristics of B. subtilis in staining and morphological, biochemical and physiological analyses. Moreover, its DNA sequence, which was obtained via PCR sequencing of 16S rRNA, exhibited 99% homology with the B. subtilis reference strain. In in vitro cultures HFBF-B11 exhibited beta-hemolysis. The results of experiments showed that a single infection of HFBF-B11 in 9-day-old ducklings did not result in clear clinical symptoms. However, following co-infection with HFBF-B11 and R. anatipestifer, the animals demonstrated liver injury and blood-brain barrier disruption leading to infection and brain damage with a mortality rate of 100%. These results suggest that the HFBF-B11 strain of B. subtilis is an opportunistic pathogen of ducklings. This is the first report about the isolation of a B. subtilis strain with pathogenicity in ducklings. PMID- 29611658 TI - Antimicrobial activity of some plant extracts against bacterial pathogens isolated from faeces of red deer (Cervus elaphus). AB - Antibacterial activity is the most widely studied aspect of plant extracts. Antibiotics extensively produced and consumed in large quantities, have proved to be problematic due to various types of adverse effects. The development of bacterial resistance to currently available antibiotics has necessitated the search for new antibacterial agents. One of the alternative strategies for fighting antibiotic- resistant bacteria is the use of natural antimicrobial substances such as plant extracts. We tested the antimicrobial activity of nine extracts from different plants against pathogenic bacteria isolated from the faeces of red deer (Cervus elaphus). Selected bacteria commonly contaminated the natural environment and constitute a source of infection in other animals and humans. Extracts obtained from the following plants were tested: Hypericum perforatum L., Chamomilla recutita L., Achillea millefolium L., Salvia officinalis L., Thymus vulgaris L., Pinus sylvestris L., Mentha x piperita L., Valeriana officinalis L. and Foeniculum vulgare Mill. The highest degree of antibacterial properties was observed for Mentha x piperita L., narrower spectrum of activity possessed Hypericum perforatum L. Extracts of Achillea millefolium L. had the lowest spectrum of antibacterial activity. Our study confirms that many plant extracts shows in vitro antibacterial activity. PMID- 29611659 TI - Comparison of serum concentrations of environmental allergen-specific IgE in atopic and healthy (nonatopic) horses. AB - Allergic responses in humans, horses and other species are mediated by immunoglobulin E (IgE) antibodies. Serum testing to detect allergen-specific IgE antibodies has been developed for dogs, cats and horses; this allows for the identification of allergens and determination of appropriate allergen- specific immunotherapies. This study compared serum allergen-specific IgE concentrations in atopic and healthy horses. The study was performed on Malopolski breed atopic (n=21) and nonatopic (n=21) clinically healthy horses. Allergen-specific IgE serum concentrations were measured in summer seasons of 2008-2015 using a monoclonal anti-IgE antibody. A Northern and Central European allergen panel containing mite, insect, mould and plant pollen allergens, including 15 tests of individual allergens and 5 tests of allergen mixtures was used. The mean allergen specific IgE concentrations in the atopic and normal horse populations were compared. Among the atopic horses, the strongest positive reactions occurred against the storage mites Tyrophagus putrescentiae and the domestic mite Dermatophagoides farinae. The atopic horses also demonstrated high IgE concentrations against insects, particularly Tabanus sp., the plant pollens colza, cultivated rye and the mould pollen mixture Aspergillus/Penicillium. No horses in the atopic group were IgE-negative. Among all mite, insect, mould and some plant allergen groups the differences in mean specific IgE concentrations between allergic and healthy horses were significant. The mean IgE concentrations for most allergen groups were significantly higher in the atopic horses than in the healthy animals. However, a high incidence of positive reactions was observed in both healthy and allergic horses. Our results showed a high frequency of polysensitization in atopic horses. PMID- 29611660 TI - Tooth development disorders in infants of rat dams exposed to 2,3,7,8 tetrachlorodibenzo-p-dioxin and protective role of tocopherol and acetylsalicylic acid. AB - Aryl hybrocardon receptor (AhR) activation plays a key role in the pathomechanism of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced defective spatial structure of teeth caused by disordered collagen synthesis. The aim of this study was to identify the influence of dioxins present in female Buffalo rats on the dental structure of their offspring's in the neonatal period and the potential of alpha tocopherol and acetylsalicylic acid in curbing post-dioxin hard tissue defects. Research material consisted of molar teeth (n=40) of rat pups which had been given a single dose of TCDD and were then treated with tocopherol or acetylsalicylic acid for 3 weeks. In the offspring of rat dams exposed to TCDD, ameloblasts and odontoblasts were less developed in comparison with the control group and less dynamic angiogenesis in the area of dental papilla was observed. In the pups of TCDD-exposed mothers, a smaller number of AhR was found in amelogenic and odontoblastic cells, whereas in the pups of mothers exposed to TCDD followed by tocopherol and acetylsalicylic acid treatment, the expression of AhR in ameloblasts and odontoblasts increased. We conclude that tocopherol and acetylsalicylic acid treatment exerts a protective effect on the TCDD-induced structural defects of tooth tissue. PMID- 29611661 TI - Evaluation of luteinizing hormone regulation of maturation and apoptosis, expression of LHR and FSHR in cumulus-oocyte complexes in Lanzhou fat-tailed sheep. AB - The present study aimed to assess LH effects on in vitro maturation (IVM) and apoptosis and also to explore the gene expressions of LHR and FSHR in cumulus oocyte complexes (COCs) of the sheep. COCs were in vitro matured 24h in the IVM medium supplemented with varying concentrations of LH (0, 5, 10, 20 and 30 MUg/mL). They were allocated into LH-1 (control group), LH-2, LH-3, LH-4 and LH-5 groups, respectively. FSH (10 IU/mL) addition was as a positive control (FSH group). COCs apoptosis was assessed by TUNEL. The qPCR and Western blotting were utilized to detect mRNA and protein expressions of FSHR and LHR, respectively. The results showed maturation rates of oocytes improved as LH concentration increased from 0 to 10 MUg/mL (IU/mL), reaching a peak value of 44.3% in the LH-3 group. Maturation rate of LH-5 group was lower than that of LH-3 and FSH-treated groups. The lowest apoptosis rate was found in LH-3 group. The germinal vesicle break down (GVBD) rates of LH-2, LH-3 and LH-4 groups were also increased in comparison with that found in LH-1 group (control group). GVBD rate of LH-5 was lower than that in LH-3 group. The germinal vesicle (GV) rates in LH-3 and LH-4 groups were lower than those in LH-1 and LH-5 groups (p<0.05, or p<0.01). The lowest GV rate was found in LH-3 group. GV rates in LH-2, LH-4 and LH-5 groups were higher than that in FSH group (p<0.05). At hours 20, 22 and 24 after oocytes IVM, caspase-3 concentrations in four LH-treated groups were decreased in comparison with that in LH-1 group. At 24h, caspase-3 concentrations of LH-2 and LH-3 groups were lower than that in LH-1 group (p<0.05). Expression levels of FSHR and LHR mRNAs rose when LH concentrations in IVM medium increased. The greatest expressions of FSHR and LHR mRNAs were found in LH-5 and LH-3 groups (p<0.01) in comparison with those in the control group (LH-1). Meanwhile, FSHR mRNA expressions in LH-2, LH-3 and LH-4 groups were lower than that in FSH group (p<0.01 or p<0.05). Expression levels of FSHR proteins revealed no significant differences among all groups. Expression levels in LHR proteins were increased. LHR protein level in LH-2 group was higher than that in LH-1 group. In conclusion, LH treatment could promote the maturation rate and GVBD rate. LH reduced apoptosis rate, GV rate of sheep oocytes, and caspase-3 concentrations in IVM medium fluids and additionally enhanced expressions of FSHR and LHR mRNAs of sheep COCs. PMID- 29611662 TI - Adrenal gland tumors in dairy cattle from Northern Italy: morphological and phenotypical characterization in comparison with human pathology. AB - Bovine adrenal gland tumours are considered relatively common, although scarce data are available about their real incidence, pathological characterization, classification criteria and immunohistochemical profile. This study describes the morphological and immunophenotypical characteristics of 35 dairy cattle adrenal gland tumors from Northern Italy and compare them with human pathology. Macroscopical, histological, histochemical and immunohistochemical investigations were performed. Microscopically proliferative lesions were classified as focal hyperplasia (8/35), primary cortical tumors (15/35) , primary medullary tumors (12/35). The cortical tumors showed a highly heterogeneous spectrum of morphological aspects not matching the two major diagnostic categories of adenoma and carcinoma in either cattle or humans. The medullary tumors (7 neuroblastomas and 5 pheochromocytomas) showed morphological and immunophenotypical features largely overlapping with human counterparts. Although limited by the small number of neoplasms and the lack of evidence of metastases precluding a clear distinction between benign and malignant lesions, this study represents the first attempt to compare the bovine and the human pathology. The present data support the concept that adrenal tumors in cattle have distinctive features that deserve a species- specific classification. PMID- 29611663 TI - Antimicrobial susceptibility of Salmonella spp. strains isolated from free-living birds. AB - Salmonella is one of the most common causes of food poisoning in the European Union and the United States of America. Free-living birds are known as a reservoir for the different serovars of Salmonella, including S. Typhimurium, S. Enteritidis, S. Infantis, S. Newport and S. Hadar, which may play an important role in the epidemiology of salmonellosis in farm animals, particularly poultry. Also, the antibiotic resistance of Salmonella spp. is a growing, public health emergency. In the present study, the authors examined 36 Salmonella spp. strains, which belonged to 3 subspecies; enterica, salamae and houtenae. All of them were obtained from 13 species of free-living birds in Poland. The antimicrobial susceptibility of these Salmonella strains was determined, using commercial SensititreTM Salmonella, MIC plates, for fourteen antimicrobials, from nine antimicrobial groups: sulfonamides, aminoglycosides, fluorochinolones, cephalosporines, beta-lactams, tetracyclines, phenicols, polymyxins and trimethoprim. The prevalence of selected genes which determine antimicrobial resistance; i.e. aadB, aacC, blaTEM, blaPSE-1, blaOXA, tetA, tetB, tetC, tetG, cat1, cat2, cat3 and floR was also tested. Among all of the examined strains, no resistance was detected in relation to gentamicin, cefotaxime and ceftazidime, while most strains (94.5%) were resistant to sulfamethoxazol. Among the 36 examined bacteria isolates, twenty were resistant to more than one antimicrobial agent. The antimicrobial resistant gene, floR was most frequently detected among all examined strains (50%). PMID- 29611664 TI - Retraction for Pfeffer et al., P0 of Beet Western Yellows Virus Is a Suppressor of Posttranscriptional Gene Silencing PMID- 29611665 TI - [Charles Meniere (1816-1887) : pharmacist and historian of the pharmacists who were in practice in the town of Angers]. AB - Charles Meniere (1816-1887) was the young brother of the doctor Prosper Meniere (1799-1862), who was the obstetrician of the Duchess of Berry, the doctor in chief of the deaf-mute Institution and an erudite ear specialist. Charles learned pharmacy in Paris. Coming back to Angers he bought a chemist's shop. In 1871 he became the chief pharmacist of the Hotel-Dieu. In 1857 he joined the Academic Society of Angers and presented many consequent papers between them one can find notes concerning the history of the Angers's pharmacists. Its researches relate to pharmacology, mineralogy, hydrology and even philology. PMID- 29611666 TI - [The pharmacist and deputy Henri Schmidt, the law voted in 1913 and said "for three years" and the position of mobilized pharmacists at the beginning of First World War]. AB - Henri Schmidt was, with his fellow the senator Paul Cazeneuve, the main defender of the mention of pharmacists and pharmacy students in the articles of the law voted in 1913 for the recruitment of the army. After the description of their interventions to attain this end, and a short biography of these two politicians, the paper explains the activities of the pharmaceutical parliamentary group, during the early years of the war, in view to obtain the admittance in the medical corps of the pharmacists and students unprovided of rank, for the new creation of "auxiliary pharmacists", for the appointment as soon as possible of the maximum number of colleagues at this rank, and then for their promotion to the rank of "aide-major", resolution that appeared more difficult to obtain. PMID- 29611667 TI - MSD: Making Strides to Make Your Life Easier. PMID- 29611668 TI - [Two books printed in Strasburg during the 16th century present in the inventory of the Paris College of Pharmacy Library]. AB - The catalogue of the College of Pharmacy Library, written in 1780, mentioned two books printed in Strasburg during the 16th century. The first one was a Latin edition of PPiepsilonrhoiota Upsilonlambdaetasigma Iotaalphataurhoiotachietasigma of Dioscorides. The drop caps are enriched by the figuration of episodes from the Bible. The principal interest of this book comes from the identity of his donator, Ioannes Du Boys, apothecary of the Duke of Alencon, the brother of King Henry III. This apothecary was also the author of a pharmacopoeia entitled Methodus Miscendorum Medicamentorum. The second one was a compendium of various titles, which had, most of them, in common to have been written by Valerius Cordus. It contains many illustrations and some of them are especially expressive. Its main interest is nevertheless to be a part of a gift made by a group of Parisian apothecaries, in 1570. This gift is considered as the birth of apothecaries' library, the direct ancestor of actual "BIU Sante pole Pharmacy". The presence of these two books in the library constitutes a testimony of the importance of printers from Strasburg in history. PMID- 29611669 TI - [The history of Pharmacy in Portugal (1900-1950) : pharmaceutical industry and community pharmacy ]. AB - The aim of this article is to present the history of pharmacy in Portugal during the first half of the twentieth century, considering two contemporary issues : the industrialization of medicines in Portugal, with regard to law and regulation of medicines and professional activity (emphasizing community pharmacy) and other relevant issues concerning pharmacy and public health. PMID- 29611670 TI - [The Journal de chimie medicale (Journal of Medical Chemistry) : a major innovation on French public health during the 19th century ]. AB - JBA Chevallier is first known for his publication in 1850 of his book on falsifications. But he had also a major role for the opening of the pharmacy world to toxicological and Public Health issues, through the founding in 1825, and the management for more than 50 years, of the Journal de chimie medicale, de pharmacie et de toxicologie (Journal of Medical Chemistry, of Pharmacy and of Toxicology). The purpose of the present study has been to look at the evolution of that publication over the years and to compare its content with the reference pharmaceutical journal at that time : the Journal de pharmacie et de chimie (Journal of Pharmacy and Chemistry). One can observe that the editorial lines of both journals will progressively diverge from each other, but Chevallier remained strongly connected with pharmacy, his journal merging finally in 1876 with the Repertoire de pharmacie (Index of Pharmacy). PMID- 29611671 TI - Stump Appendicitis. AB - Stump appendicitis is a delayed complication of appendectomy. Patients present with symptoms similar to an initial presentation for appendicitis. Diagnosis is often delayed as history of appendectomy often precludes focused workup for an appendiceal source of infection. A 39-year-old female presented to our emergency department with worsening abdominal pain and fever. Se had a past surgical history of a laparoscopic appendectomy approximately 14 months prior to presentation. During her admission, she was diagnosed with ruptured stump appendicitis by computerized tomography (CT) imaging. A percutaneous drain was placed and the patient was discharged with antibiotics. Follow up evaluation revealed clinical improvement, with resolution of peri-appendiceal stump inflammation and subsequent percutaneous drain removal. Completion appendectomy is tentatively scheduled. This case highlights awareness of stump appendicitis as a differential diagnosis for patients with previous appendectomy who present with acute abdominal pain. PMID- 29611672 TI - [Mysteries of a medicine chest ]. AB - This article retraces the history of an old medicine chest, used at the beginning of the 19th century, but probably designed earlier. Possibly made in A ustria, with a two-headed eagle lining the bottom of the lid, this first-aid kit belongs to a small group of related chests. It should be noted that these chests were used for a wide variety of different purposes over time. Also named a "droguier" in French, this light chest, made of walnut, and, according to family lore, found in Normandy, would have belonged to a doctor, as confirmed by a short invoice found among numerous documents. The identity of the supplier of numerous old medicines is shown on the labels on the flasks (many of which are intact) and other boxes (containing, in particular, herbal drugs) : "Clement, Apothicaire. Rue St Onge N degrees . 42. pres le Bd. du Temple A Paris", whose history is recounted here step by step. PMID- 29611673 TI - Non-conservative management of simple renal cysts in adults: a comprehensive review of literature. AB - INTRODUCTION: Renal cysts are common findings in nearly 10% of general population. According to Bosniak classification, they are classified into simple and complex renal cysts based on their CT characteristics. The majority of simple renal cysts are asymptomatic and require no intervention. Once they become symptomatic or complicated, a non-conservative management should be considered. EVIDENCE ACQUISITION: This paper is a narrative review of existing manuscripts regarding the non-conservative management of renal cysts. To perform it a search through PubMed was carried out in January 2017. The search was conducted using the following key words: "simple renal cysts," "non-conservative management," "treatment outcomes comparison" etc. EVIDENCE SYNTHESIS: We found 1880 publications that were reviewed by 2 of our authors, and only 46 manuscripts were considered for this review. The most common treatment were investigated and compared to understand the best treatment modality in accordance with patients' and cysts' characteristics. Different treatment modalities are available for the management of simple renal cysts. Surgical exploration is a historical procedure that is no longer used. Simple aspiration without sclerotherapy has high recurrence rate (20-80%), so sclerosants agents are recommended. Ethanol is the most commonly used sclerosing agent with high efficacy up to 97%. Laparoscopy is the gold standard for management in large cysts especially in younger patients. Other techniques are described for parapelvic renal cysts like percutaneous endoscopic ablation and ureteroscopic marsupialization. CONCLUSIONS: Different factors affect the treatment decision including natural history of the cyst, presence of symptoms and/or complications and patients' choice. This literature overview shows that ethanol percutaneous sclerotherapy and laparoscopy are the most commonly reported treatment modality for simple renal cysts. PMID- 29611674 TI - Augmented reality during robot-assisted radical prostatectomy: expert robotic surgeons' on-the-spot insights after live surgery. AB - 3D reconstruction of the standard two-dimension cross-sectional imaging has known increasing diffusion. It may represent one of the key points for a tailored treatment planning. Along these lines, we used a novel software for augmented reality robot-assisted radical prostatectomy (AR-RARP) at our Institution. 3D virtual models of the prostate and the prostate cancer were reconstructed from high resolution (1-mm slices) multi-parametric Magnetic Resonance Imaging (mp MRI) by M3dics (Turin, Italy). The innovation in the study is represented by the software-based integration of the virtual model inside the Da Vinci (Intuitive, Sunnyvale, CA, USA) robotic console during robotic prostatectomy. In January 2018, the above-described AR-RARP technique has been used during the live surgery sessions of the 6th Techno-Urology Meeting held at San Luigi Gonzaga Hospital (Orbassano, Turin, Italy). During this meeting, 6 experienced robotic surgeons (who have already performed more than 1000 RARP) used the software during nerve sparing prostatectomy. The use of the technology was standardized to four key steps during the procedure: 1) bladder neck dissection; 2) nerve-sparing technique; 3) apex dissection; and 4) tailoring of eventual selective biopsies of prostatic lodge after prostatectomy). A Face Validity questionnaire was purpose built aimed to collect the expert surgeons' insights about the eventual help of the technology in guiding the surgeon during the above-described AR-RARP steps. It was administered at the end of the surgeries to the respective surgeons. The questionnaire was made of open-ended questions of ordinal ten-point rating Likert Scale (where 1 corresponded to a strongly negative opinion and 10 to a strongly positive opinion). The median value of Likert scale from the evaluation of each of the aforementioned steps of AR-RARP was 9, (IQR 9-10). These findings are a confirmation of the increasing interest for a new-generation of image-guided surgery. Particularly, AR-RARP seems to be a step in the direction of "precision" surgery. PMID- 29611675 TI - [Henri-Aime Lotar (1836-1898) and the Museum of Faculty of pharmaceutical and biological sciences at the University of Lille]. AB - Dispensing pharmacist (settled down at n degrees 27 of Roubaix street in Lille, in the ancient pharmacy of his father Henri Lucien Joseph Lotar), Henri-Aime L otar was also assistant professor since 1865, then first pharmacy titular professor at the University of Lille (from the creation of the chair of pharmacy in 1881 to his death in 1898), hospital chief pharmacist, pharmacy inspector, member of Hygiene Council and representative of pharmacy at the Academic Council. He gave his name to the Museum Lotar, which is situated on the ground floor of the Faculty of pharmaceutical and biological sciences at the University of Lille and where his portrait - in official costume of professor - takes place within a rebuild pharmacy in "19th century" style. This museum besides includes ancient pharmacopoeias, numerous books (among which the monumental Herbarium of Charles Fourcade) and old registers of prescription - we made an inventory of those - as well as pharmacy pots, specimens of herbal drugs, patent medicines, medical devices, several objects for pharmaceutical use, laboratory instruments and a professor dress which belonged to Professor Morvillez, third successor of Lotar at the chair of Pharmacy. PMID- 29611676 TI - Examination of Preliminary Cancer Surveillance Data from the National Program of Cancer Registries, Diagnosis Year 2012. PMID- 29611677 TI - [Nicolas Lemery, a pluridisciplinary Scientist]. AB - Nicolas Lemery was born in Rouen, on November 17th 1645. He entered into an apprenticeship in order to become an apothecary in Rouen, and then he went to Paris in King's Gardens where he became a pupil of Christopher Glaser. He went then to Montpellier where Matte La Faveur was demonstrator in chemistry. When he came back to Paris, he bought an apothecary office and delivered courses of chemistry, in his laboratory, rue Galande. He redacted in 1675 the first version of his Course of Chemistry, which was many times republished and translated in various languages. He developed especially his theories of the reaction between acids and alkalis. He was a Protestant and had to withdraw his office and choose to become a Physician, but when the Edit of Nantes was abrogated, he was converted to Catholicism. In 1697, he published the first edition of his Universal Pharmacopoeia, followed by his Universal Treatise on Simple Drugs in 1698. These two books were both republished and translated many times. His Treatise on Antimony was published in 1707. He became associate chemist at the Royal Academy of Sciences in 1699, and full member in 1700. He died in 1715. He played a very important role in the evolution of sciences. PMID- 29611678 TI - [Nicolas Lemery, student apothecary in Montpellier (1668-1671)]. AB - The stay of Lemery in Montpellier as a companion-apothecary from 1668 until 1671 was attested, especially by his registration to the book of rolls. What he has done there is rather a matter of the oral tradition. But the atmosphere of rivalry and fuss between the followers of the Catholicism and those of the Protestantism was tangible through the trials, the rulings or the namings. Even unsaid things, for example in the books of chemistry published then, tell a lot on the atmosphere of the city during the three years of the stay of Lemery in Montpellier. PMID- 29611679 TI - [The Nicolas Lemery's mechanistic approach to chemistry]. AB - Nicolas Lemery was the first chemist to have a mechanistic approach to chemistry. Starting from the acids-bases theory in which two chemicals react with each other in a battle between the pointed acids and the porous bases, he expands his vision to the chemical reaction, which is for him the merging and the transformation of two protagonists into a new identity, resulting in a relationship between the microscopic and the macroscopic. PMID- 29611680 TI - [[Medicinal broths in the books by Nicolas Lemery, a reflection of scientific developments?] AB - From Ancient times, medicinal broths have been an integral part of the diet fed to patients and convalescents. At the end of 17th century, medical and pharmaceutical knowledge and practices were to enter a period of major upheavals. Although also hitherto discredited, chemical drugs became all the rage, work in chemistry boomed and broths benefited. Do the first editions of the works of Nicolas Lemery reflect the knowledge of his time ? Do last editions - revised, corrected, annotated and completed - really reflect transformations in scientific disciplines, technological developments, and scientific advances, particularly in chemistry? PMID- 29611681 TI - [Editorial relationships between Nicolas Lemery and the d'Houry family (1649 1790)]. AB - This article deals with the relationships between Nicolas Lemery and a family of publishers, named d'Houry, during the 17th and the 18th centuries. How did Lemery negociate the contract for the publication of his Pharmacopee Universelle and of his Traite des Drogues Simples ? How much did these two books cost? PMID- 29611682 TI - [About a quarrel concerning the artificial production of iron. The differences between Nicolas Lemery and his son, Louis]. AB - In the early eighteenth century, a quarrel developed between the chemists at the Academie royale des sciences. They discussed the question if it were possible or not to make artificially some iron from the combustion of vegetal organisms. Etienne-Francois Geoffroy defended the thesis resting on certain alchemical texts, but Louis Lemery, Nicolas' son, refused it in the name of a mechanistic conception of chemical operations. Louis Lemery also had to oppose the hypothesis emitted by his father who preferred to admit that the test of the magnet, which was used to reveal the presence of fragments of iron into the ashes, was not convincing. He thought that other substances than iron could be attracted by the magnet. Louis thus had to reject the positions of his father, the latter did not seem for him to have a rather vigorous position against the allusions to alchemical writings and in favour of the strictly mechanistic theories. PMID- 29611683 TI - Immunomodulatory Therapy and an Insidious Presentation of a Large Intra-Abdominal Abscess. AB - Crohn's disease is a disorder characterized by transmural inflammation which can potentially affect any part of the gastrointestinal tract from the mouth to the perianal area. Cohn's disease is a systemic disease characterized by a relapsing remitting course, with variable intestinal and extra-intestinal complications. Abdominal and pelvic abscesses are not an uncommon complication of Crohn's disease occurring in 10-30 percent of all patients. We present the case of a 21 year-old male with Crohn's disease presenting with a massive abdominal abscess, whose diagnosis was delayed given lack of typical symptoms. Shortly after initiating therapy with Prednisone and Adalimumab he presented with worsening abdominal distention. Cross sectional imaging of the abdomen with IV contrast (Figure 1) demonstrated a 34cm x 23 cm x 11 cm rim-enhancing fluid collections in the abdomen and pelvis consistent with a large intra-abdominal abscess. He underwent an exploratory laparotomy, abdominal washout, and wound vacuum placement. Five liters of purulent fluid were aspirated and cultures grew citrobacter, veillonella and candida glabrata.A bowel perforation was suspected as the etiology for abscess formation; however magnetic resonance heterography (Figure2) was unremarkable. He was treated with appropriate antibiotics, antifungal agents, and was started on Aprisa. His course was complicated with recurrence of intra-abdominal abscesses and a colocutaneous fistula for which he underwent an open sigmoidectomy with a diverting loop colostomy. After condirmation of healing with repeat imaging, he was an uneventful postoperative course. He followed as an outpatient and continues to do well on Infliximab.Most abscesses are picked up in their early stages given characteristic symptoms; however in presence of immunosuppressive therapy the host immune system can be suppressed leading to delayed diagnosis. The presence of a massive intra abdominal purulent fluid collection of this size has not been described on our review of the literature. Furthermore, despite the abscess taking up most of the abdominal cavity, the fairly limited symptom burden highlights the importance of having high degree of clinical suspicion for infectious compications in Crohn's disease patients even when classical symptoms are not present. PMID- 29611684 TI - [The chemists at the Paris Royal Academy of Sciences in the time of the Lemerys (1699-1743)]. AB - Who were the chemists at the Paris Royal Academy of Sciences in the time of the Lemerys ? From the nomination of Nicolas Lemery, in 1699, until his death, in 1715, thirteen members of the Academy belonged to the section of Chemistry, and twenty-four until the death of Louis Lemery in 1743. In total, some thirty members made contributions dealing with chemistry, either famous like Reaumur and Buffon, or as obscure as Deschiens de Ressons, who opposed Louis Lemery. On the institutional level, most members of the chemical were promoted up to the coveted seats of senior members (pensionnaires) and several sat among the chief officiers (directeur, sous-directeur). The others were already too old when they entered or died too early : they merely stayed in the low rank of junior fellows (eleve, then adjoint), or in the middle rank of associate (associe). A feature of their academic career was the porosity between the sections : a few members made it through the grades of both the section of chemistry and another among those of the " physical sciences" (anatomy and botany). Many also had other positions, including in education : most of them had chairs or were deputy professors at the Jardin du Roi or the College royal, even more than at the Faculty of Medicine. On the sociological level, family recruitment was more important within the group of chemists than among the other members : in Nicolas Lemery's time, nearly two thirds of them belonged to a sibling or dynasty. They usually had learnt chemistry at Faculty of Medicine or practiced it in their apothecary laboratory. The apothecaries were more numerous than ever : on the fourteen of them who belonged to the Royal Academy between 1666 and 1793, seven sat next to Nicolas Lemery. Nevertheless, a higher consideration was attached to the physicians, and apothecaries such as Lemery himself became medical doctors and started lineages of physicians. Lastly, on the scientific level, there was an important porosity among the research fields : non only members of the " mathematical sciences" sometime also published on chemistry, but the chemist Du Fay did publish in the six fields related to the six sections of the Academy during his fifteen year career. Inversely, the works of several members of the chemical section were merely devoted to medicine or botany. Lastly, on the scientific level, there was an important porosity among the research fields : non only members of the " mathematical sciences" sometime also published on chemistry, but the chemist Du Fay did publish in the six fields related to the six sections of the Academy during his fifteen year career. Inversely, the works of several members of the chemical section were merely devoted to medicine or botany. PMID- 29611685 TI - [Moyse Charas, a typical master apothecary and physician for his time (1619 1698)]. AB - The life of Moyse Charas has been very stormy, especially after 1680. One can consider three main periods in his carrier : a first one from his birth in Uzes (France), in 1619, to 1680 ; his exile from 1680 to 1689 in various European countries ; and finally, his return to Paris in 1690 until his death in 1698. He decided his return to Paris and confirmed his conversion to Catholicism the 1st of July 1691, being received by Louis XIV and elected as a member of the French Academy of Sciences in 1692. Charas dictated his one's will the 12th of January 1698, a few days before his death. All along his very active life, Charas was noteworthy by two major achievements : his interest and works on viper and, as a consequence, on theriac ; and his book that became a reference for all apothecaries and physicians at the time, the Pharmacopee Royale galenique et chimique (the Galenic and Chemical Royal Pharmacopoeia). The present study examines specifically the influence of Charas' pharmacopoeia to the Universal Pharmacopeia of Lemery, and the conceptual visible differences between the two authors. He decided his return to Paris and confirmed his conversion to Catholicism the 1st of July 1691, being received by Louis XIV and elected as a member of the French Academy of Sciences in 1692. Charas dictated his one's will the 12th of January 1698, a few days before his death. All along his very active life, Charas was noteworthy by two major achievements : his interest and works on viper and, as a consequence, on theriac ; and his book that became a reference for all apothecaries and physicians at the time, the Pharmacopee Royale galenique et chimique (the Galenic and Chemical Royal Pharmacopoeia). The present study examines specifically the influence of Charas' pharmacopoeia to the Universal Pharmacopeia of Lemery, and the conceptual visible differences between the two authors. PMID- 29611686 TI - [Christophle Glaser, one of Lemery's]. AB - Christophle Glaser was born in Basel in Switzerland. He was apothecary of the King's brother and became demonstrator of chemistry at the King's Gardens in Paris. He had a bad reputation reported by Fontenelle or by the Marchioness of Sevigne. He had also been suspected during the inquiry concerning the Brinvilliers' murders. He was also known as the author of a book of chemistry, entitled Traite de la Chymie, that had been translated into German or English. He received Lemery in his laboratory. Fontenelle reported that Lemery left Glaser very quickly to go to Montpellier, but he is supposed to have stayed for a longer time with him. Lemery and Glaser had the same opinion on many subjects and their books were similar on many points. It is then established that Glaser was really one of Lemery's master. PMID- 29611687 TI - Pilot and feasibility studies come of age! AB - This editorial introduces the new, online, open-access journal Pilot and Feasibility Studies. The journal considers manuscripts on any aspect of the design and analysis of pilot and feasibility studies, as well as protocols for pilot and feasibility studies, and discussions and reviews of methodological issues around the planning and reporting of such studies. These studies are generally carried out in preparation for future large-scale definitive randomised controlled trials or observational studies and address key issues of uncertainty. Objectives for conducting pilot and feasibility studies therefore differ from those of the future large-scale study and should be clearly expressed. The journal provides a dedicated place for publication of this important work as well as a forum for discussion of methodological issues that will lead to increased scientific rigour in this area. PMID- 29611688 TI - An Innovative Approach to Improve Completeness of Treatment and Other Key Data Elements in a Population-Based Cancer Registry: A15-Month Data Submission. AB - BACKGROUND: In order to comply with the Louisiana legislative obligation and meet funding agencies' requirementof case completeness for 12-month data submission, hospital cancer registries are mandated to submit cancer incidencedata to the Louisiana Tumor Registry (LTR) within 6 months of diagnosis. However, enforcing compliance withtimely reporting may result in incomplete data on adjuvant treatment received by the LTR. Although additional treatmentinformation can be obtained via retransmission of the North American Association of Central Cancer Registries(NAACCR)-modified abstracts, consolidating multiple NAACCR-modified abstracts for the same case is extremely timeconsuming. To avoid a huge amount of work while obtaining timely and complete data, the LTR has requested hospitalcancer registries resubmit their data 15 months after the close of the diagnosis year. The purpose of this report is to assessthe improvement in the completeness of data items related to treatment, staging and site specific factors. METHODS: TheLTR requested that hospital cancer registries resubmit 15 month data between April 1, 2016 and April 15, 2016 for casesdiagnosed in 2014. Microsoft Visual Studio Visual Basic script was used to link and compare resubmitted data with existingdata in the LTR database. Data elements used for matching same patient/tumor were name, Social Security number, dateof birth, primary site, laterality, and hospital identifier number. Treatment data items were compared as known vs none/unknown and known vs known with different code. Matched records with updated information were imported into theLTR database and flagged as modified abstract records for manual consolidation. Nonmatched records were also loaded inthe LTR database as potential new cases for further investigation. RESULTS: A total of 25,207 resubmitted NAACCR abstractswere received from 38 hospitals and freestanding radiation centers. About 11.1% had at least 1 update related to treatmentand/or other data item; an average of 3.3 updates per updated abstract. The majority of the updates (45.7%) for treatmentwere changes from none/unknown to known value and 42.6% of the updates were related to radiation treatment fields. Inaddition, 172 potential new cases were identified. Approximately 10.5% (18 cases) of these new cases were confirmed to betruly missed cases after investigation. CONCLUSION: The 15-month data resubmission is a cost-effective approach to obtaining complete information on treatment and other key data items from reporting facilities and can also be used to identify potential missed cases. PMID- 29611689 TI - Address at Diagnosis: Place Matters. AB - Cancer risk varies by geography. Epidemiologists can apply a spatial approach to recognize geographic patternsand test associations in order to postulate about community health and etiologic pathways, and to determine public healthaction. Geospatial applications are valuable tools to evaluate geographic differences, which are often drive by social disparities. However, relevant conclusions hinge on data limitations, including data quality.Recording address is critical for a geographic information system (GIS) and geospatial studies of cancer surveillance data.Address is used to geocode cases, as well as to append census and other data to a cancer case. New North AmericanAssociation of Central Cancer Registries (NAACCR) tract-level codes are derived based on the geocoded address at diagnosis(Address at DX) and have enabled significant national-level research on the association of cancer and socioeconomicstatus. PMID- 29611690 TI - ATP-Ask the Pathologist: A Valuable Resource for Cancer Registrar and the College of American Pathologists Cancer Protocols. PMID- 29611692 TI - Follow-up: A CTR's Perspective. PMID- 29611691 TI - The Early Bird Doesn't Always Get the Worm: Evaluation of 15-Month Resubmission of Abstracts to Utah Cancer Registry. PMID- 29611693 TI - Lipid-Modified Graphene-Transistor Biosensor for Monitoring Amyloid-beta Aggregation. AB - A graphene field-effect transistor (G-FET) with the spacious planar graphene surface can provide a large-area interface with cell membranes to serve as a platform for the study of cell membrane-related protein interactions. In this study, a G-FET device paved with a supported lipid bilayer (referred to as SLB/G FET) was first used to monitor the catalytic hydrolysis of the SLB by phospholipase D. With excellent detection sensitivity, this G-FET was also modified with a ganglioside GM1-enriched SLB (GM1-SLB/G-FET) to detect cholera toxin B. Finally, the GM1-SLB/G-FET was employed to monitor amyloid-beta 40 (Abeta40) aggregation. In the early nucleation stage of Abeta40 aggregation, while no fluorescence was detectable with traditional thioflavin T (ThT) assay, the prominent electrical signals probed by GM1-SLB/G-FET demonstrate that the G FET detection is more sensitive than the ThT assay. The comprehensive kinetic information during the Abeta40 aggregation could be collected with a GM1-SLB/G FET, especially covering the kinetics involved in the early stage of Abeta40 aggregation. These experimental results suggest that SLB/G-FETs hold great potential as a powerful biomimetic sensor for versatile investigations of membrane-related protein functions and interaction kinetics. PMID- 29611694 TI - Molecular Engineering of Quinoxaline-Based D-A-pi-A Organic Sensitizers: Taking the Merits of a Large and Rigid Auxiliary Acceptor. AB - The continuing efforts of creating novel D-A-pi-A structured organic sensitizers with excellent optoelectronic properties have resulted in substantial improvement of power conversion efficiency (PCE) as well as stability of dye-sensitized solar cells (DSSCs). Here, we report a new molecular engineering strategy for enhancing optical gain and improving excited-state features in D-A-pi-A structured organic sensitizers by improving the conjugation size and rigidity of the auxiliary acceptor functional group. A series of phenanthrene-fused-quinoxaline (PFQ)-based D-A-pi-A organic sensitizers (WS-82, WS-83, and WS-84) are designed and synthesized for applications in DSSCs. Compared to 2,3-diphenylquinoxaline (DPQ) based dye IQ-4, PFQ dyes show extended absorption spectra and improved open circuit voltage performance. Upon a systematical engineering of alkyl chains and pi-spacer structure, the unfavorable issues of PFQ dyes including low solubility and high energy barrier in intramolecular charge transition are successfully eliminated. When applied in iodine electrolyte-based DSSCs, the best performing PFQ dye WS-84 shows a PCE of 10.11%, which is much higher than that of our previous champion DPQ dye IQ-4 under the same conditions. PMID- 29611695 TI - A VTVH MCD and EPR Spectroscopic Study of the Maturation of the "Second" Nitrogenase P-Cluster. AB - The P-cluster of the nitrogenase MoFe protein is a [ Fe8 S7] cluster that mediates efficient transfer of electrons to the active site for substrate reduction. Arguably the most complex homometallic FeS cluster found in nature, the biosynthetic mechanism of the P-cluster is of considerable theoretical and synthetic interest to chemists and biochemists alike. Previous studies have revealed a biphasic assembly mechanism of the two P-clusters in the MoFe protein upon incubation with Fe protein and ATP, in which the first P-cluster is formed through fast fusion of a pair of [ Fe4 S4]+ clusters within 5 min and the second P-cluster is formed through slow fusion of the second pair of [ Fe4 S4]+ clusters in a period of 2 h. Here we report a VTVH MCD and EPR spectroscopic study of the biosynthesis of the slow-forming, second P-cluster within the MoFe protein. Our results show that the first major step in the formation of the second P-cluster is the conversion of one of the precursor [ Fe4 S4]+ clusters into the integer spin cluster [ Fe4 S3-4]alpha, a process aided by the assembly protein NifZ, whereas the second major biosynthetic step appears to be the formation of a diamagnetic cluster with a possible structure of [ Fe8 S7-8]beta, which is eventually converted into the P-cluster. PMID- 29611696 TI - Methyl-cyclopentadienyl Ruthenium Compounds with 2,2'-Bipyridine Derivatives Display Strong Anticancer Activity and Multidrug Resistance Potential. AB - New ruthenium methyl-cyclopentadienyl compounds bearing bipyridine derivatives with the general formula [Ru(eta5-MeCp)(PPh3)(4,4'-R-2,2'-bpy)]+ (Ru1, R = H; Ru2, R = CH3; and Ru3, R = CH2OH) have been synthesized and characterized by spectroscopic and analytical techniques. Ru1 crystallized in the monoclinic P21/ c, Ru2 in the triclinic P1, and Ru3 in the monoclinic P21/ n space group. In all molecular structures, the ruthenium center adopts a "piano stool" distribution. Density functional theory calculations were performed for all complexes, and the results support spectroscopic data. Ru1 and Ru3 were poor substrates of the main multidrug resistance human pumps, ABCB1, ABCG2, ABCC1, and ABCC2, while Ru2 displayed inhibitory properties of ABCC1 and ABCC2 pumps. Importantly, all compounds displayed a very high cytotoxic profile for ovarian cancer cells (sensitive and resistant) that was much more pronounced than that observed with cisplatin, making them very promising anticancer agents. PMID- 29611697 TI - High-Throughput Screening and Quantitative Chemical Ranking for Sodium-Iodide Symporter Inhibitors in ToxCast Phase I Chemical Library. AB - Thyroid uptake of iodide via the sodium-iodide symporter (NIS) is the first step in the biosynthesis of thyroid hormones that are critical for health and development in humans and wildlife. Despite having long been a known target of endocrine disrupting chemicals such as perchlorate, information regarding NIS inhibition activity is still unavailable for the vast majority of environmental chemicals. This study applied a previously validated high-throughput approach to screen for NIS inhibitors in the ToxCast phase I library, representing 293 important environmental chemicals. Here 310 blinded samples were screened in a tiered-approach using an initial single-concentration (100 MUM) radioactive iodide uptake (RAIU) assay, followed by 169 samples further evaluated in multi concentration (0.001 MUM-100 MUM) testing in parallel RAIU and cell viability assays. A novel chemical ranking system that incorporates multi-concentration RAIU and cytotoxicity responses was also developed as a standardized method for chemical prioritization in current and future screenings. Representative chemical responses and thyroid effects of high-ranking chemicals are further discussed. This study significantly expands current knowledge of NIS inhibition potential in environmental chemicals and provides critical support to U.S. EPA's Endocrine Disruptor Screening Program (EDSP) initiative to expand coverage of thyroid molecular targets, as well as the development of thyroid adverse outcome pathways (AOPs). PMID- 29611698 TI - Ascorbate Oxidation by Cu(Amyloid-beta) Complexes: Determination of the Intrinsic Rate as a Function of Alterations in the Peptide Sequence Revealing Key Residues for Reactive Oxygen Species Production. AB - Along with aggregation of the amyloid-beta (Abeta) peptide and subsequent deposit of amyloid plaques, oxidative stress is an important feature in Alzheimer's disease. Cu bound to Abeta is able to produce reactive oxygen species (ROS) by the successive reductions of molecular dioxygen, and the ROS produced contribute to oxidative stress. In vitro, ascorbate consumption parallels ROS production, where ascorbate is the reductant that fuels the reactions. Because the affinity of Cu for Abeta is moderate compared to other biomolecules, the rate of ascorbate consumption is a combination of two contributions. The first one is due to peptide-unbound Cu and the second one to peptide-bound Cu complexes. In the present Article, we aim to determine the amounts of the second contribution in the global ascorbate consumption process. It is defined as the intrinsic rate of ascorbate oxidation, which mathematically corresponds to the rate at an infinite peptide to Cu ratio, i.e., without any contribution from peptide-unbound Cu. We show that, for the wild-type Cu(Abeta) complex, this value equals 10% of the value obtained for peptide-unbound Cu and that this value is strongly dependent on peptide alterations. By examination of the dependence of the intrinsic rate of ascorbate oxidation, followed by UV-vis spectroscopy, for several altered peptides, we determine some of the key residues that influence ROS production. PMID- 29611699 TI - First Measurements of Organic Triplet Excited States in Atmospheric Waters. AB - Photooxidants chemically transform organic compounds in atmospheric drops and particles. Photooxidants such as hydroxyl radical (*OH) and singlet molecular oxygen (1O2*) have been characterized in cloud and fog drops, but there are no measurements of the triplet excited states of organic matter (3C*). These "triplets", which are formed from excitation of chromophoric dissolved organic matter (CDOM), i.e., brown carbon, are difficult to measure because they are a mixture of species instead of a single entity. Here, we use a two-probe technique to measure the steady-state concentrations, rates of photoformation, and quantum yields of oxidizing triplet states during simulated-sunlight illumination of bulk fog waters. Concentrations of 3C* are (0.70-15) * 10-14 M with an average (+/ sigma) value of 5.0 (+/-5.1) * 10-14 M. The average 3C* photoformation rate is 130 (+/-130) MUM h-1, while the average quantum yield is 3.7 (+/-4.5)%. Based on our previous measurements of *OH and 1O2* in the same fog samples, the ratio of the steady-state concentrations for 1O2*:3C*:*OH is approximately 3:1:0.04, respectively. At our measured concentrations, triplet excited states can be the dominant aqueous oxidants for organic compounds such as phenols from biomass combustion. PMID- 29611700 TI - 96X Screen-Printed Gold Electrode Platform to Evaluate Electroactive Polymers as Marine Antifouling Coatings. AB - Several alternatives are currently investigated to prevent and control the natural process of colonization of any seawater submerged surfaces by marine organisms. Since few years we develop an approach based on addressable electroactive coatings containing conducting polymers or polymers with lateral redox groups. In this article we describe the use of a screen-printed plate formed by 96 three-electrode electrochemical cells to assess the potential of these electroactive coatings to prevent the adhesion of marine bacteria. This novel platform is intended to control and record the redox properties of the electroactive coating in each well during the bioassay (15 h) and to allow screening its antiadhesion activity with enough replicates to support significant conclusions. Validation of this platform was carried out with poly(ethylenedioxythiophene) (PEDOT) as electroactive coating obtained by electropolymerization of EDOT monomer in artificial seawater electrolyte on the working electrode of each electrochemical cell of the 96-well microplate. PMID- 29611701 TI - Bimetal Zeolitic Imidazolite Framework-Derived Iron-, Cobalt- and Nitrogen Codoped Carbon Nanopolyhedra Electrocatalyst for Efficient Oxygen Reduction. AB - Replacing precious metal electrocatalysts with high-performance and low-cost nonprecious metal electrocatalysts (NPMCs) is crucial for the commercialization of fuel cell technologies. Herein, we present a novel and facile route for synthesis of iron-, cobalt-, and nitrogen-codoped carbon nanopolyhedra electrocatalysts (Fe,Co,N-CNP) by one-step pyrolysis of a new type of Fe/Co bimetal zeolitic imidazolate framework (Fe,Co-ZIF) crystals that were self assembled by oxygen-free solvothermal reaction of Fe2+ and Co2+ with 2 methylimidazole. During the pyrolysis process, the Fe2+ ions in Fe,Co-ZIF not only effectively inhibit the aggregation of Co nanoparticles but also increase the specific surface area (SSA) and N content of the resultant electrocatalysts. The optimized Fe,Co,N-CNP(0.3) (Fe/Co molar ratio of 0.3 in Fe,Co-ZIF) electrocatalyst exhibited a highly promising activity for oxygen reduction reaction (ORR) with a positive half-wave potential ( E1/2) of 0.875 V (29 mV higher than that of the commercial Pt/C), excellent methanol tolerance, and electrochemical stability in the alkaline electrolyte. Also, Fe,Co,N-CNP(0.3) presents comparable ORR catalytic activity as Pt/C in the acidic electrolyte with E1/2 of 0.764 V and superior methanol tolerance and electrochemical stability. The outstanding ORR performance of Fe,Co,N-CNP(0.3) is ascribed to the synergistic contribution of homogeneous Fe, Co, and N codoping structure, high SSA, and hierarchically porous structure for rapid mass transport. This novel and rational methodology for controlled synthesis of ZIFs-derived nitrogen-doped porous carbon nanopolyhedras offers new prospects in developing highly efficient NPMCs for ORR. PMID- 29611702 TI - Nonlinear Variation in the Composition and Optical Band Gap of an Alloyed Cluster Based Open-Framework Metal Chalcogenide. AB - Unexpected nonlinear variation in the composition and optical band gap was observed in an alloyed open-framework metal chalcogenide composed of supertetrahedral clusters. A tentative hypothesis was proposed to explain how the title compound [In28Se54(H2O)4].24H+-PR. nH2O (PR = piperidine) exhibits a limitation in the S-alloying level and a large variation in the optical band gap. PMID- 29611703 TI - Stereospecific Synthesis of Tris-heteroleptic Tris-cyclometalated Iridium(III) Complexes via Different Heteroleptic Halogen-Bridged Iridium(III) Dimers and Their Photophysical Properties. AB - Herein, we report on the stereospecific synthesis of two single isomers of tris heteroleptic tris-cyclometalated iridium(III) (Ir(III)) complexes composed of three different nonsymmetric cyclometalating ligands via heteroleptic halogen bridged Ir dimers [Ir(tpy)(F2ppy)(MU-Br)]2 17b and [Ir(mpiq)(F2ppy)(MU-Br)]2 27b (tpyH: (2-(4'-tolyl)pyridine) and F2ppyH: (2-(4',6'-difluorophenyl)pyridine), and mpiqH: (1-(4'-methylphenyl)isoquinoline)) prepared by Zn2+-promoted degradation of Ir(tpy)2(F2ppy) 21 and Ir(mpiq)2(F2ppy) 26, as reported by us. Subsequently, 17b and 27b were converted to the tris-heteroleptic tris-cyclometalated Ir complexes Ir(tpy)(F2ppy)(mpiq) 25 consisting of tpy, F2ppy, and mpiq, as confirmed by spectroscopic data and X-ray crystal structure analysis. The first important point in this work is the selective synthesis of specific isomers among eight possible stereoisomers of Ir complexes having the same combination of three cyclometalating ligands. Namely, two meridional forms of 25 were synthesized and isolated. The second finding is that the different stereoisomers of 25 have different stability. Finally, different stereoisomers exhibit different emission spectra. Namely, one of its stereoisomers 25a exhibits a single broad emission from ca. 550 nm to ca. 650 nm (orange emission), while stereoisomer 25c emits dual emission at ca. 509 nm and ca. 600 nm (pale pink emission), as supported by time-dependent density functional theory calculation. To the best of our knowledge, this is the first report of the selective and efficient synthesis of different stereoisomers of tris-heteroleptic tris-cyclometalated Ir(III) complexes that have different stabilities and different photophysical properties. PMID- 29611704 TI - Palladium-Catalyzed Cyanothiolation of Internal Alkynes Using Organic Disulfides and tert-Butyl Isocyanide. AB - Despite the availability of selective synthetic approaches to multifunctionalized substituted olefins, the cyanothiolation of internal alkynes has been much less explored. Herein, we show that nonactivated internal alkynes can be successfully cyanothiolated with diaryl disulfides and tert-butyl isocyanide in the presence of a Pd catalyst (e.g., Pd(PPh3)4) with the release of isobutene and arenethiol to afford beta-thiolated alkenyl cyanides in yields of 34-89%. PMID- 29611705 TI - Electronic and Magnetic Properties of 5d1, 5d2, and 5d3 Double Perovskites Ba2MOsO6 (M = K, Ca, and Sc): Ab Initio Study. AB - We perform detailed investigations on the electronic and magnetic properties in double perovskites Ba2MOsO6 (M = K, Ca, and Sc), with formal valences of Os7+ (5d1), Os6+ (5d2), and Os5+ (5d3), respectively, using first-principles calculations. To understand the effects of Coulomb interaction ( U), spin-orbit coupling (SOC), and magnetic order, we carry out different calculations within density functional theory. It is shown that SOC and U energy not only provide the magneto crystalline anisotropies but also significantly affect the size of the local moments and the magnetic structures in these compounds. The electronic configuration of 5d1 and 5d2 of Os in Ba2MOsO6 (M = K and Ca) have the metal insulator transition (MIT) as the direction of the local moment changes, while the electronic structure of half-filled 5d3 orbitals of Os in Ba2ScOsO6 is insulator, independent of the local moment direction. Our results indicate that both SOC and U interactions are necessary in enlarging the band gaps and putting these compounds into the MIT correlated insulators. PMID- 29611706 TI - Bioinspired Ultralight Inorganic Aerogel for Highly Efficient Air Filtration and Oil-Water Separation. AB - Inorganic aerogels have been attracting great interest owing to their distinctive structures and properties. However, the practical applications of inorganic aerogels are greatly restricted by their high brittleness and high fabrication cost. Herein, inspired by the cancellous bone, we have developed a novel kind of hydroxyapatite (HAP) nanowire-based inorganic aerogel with excellent elasticity, which is highly porous (porosity ~ 99.7%), ultralight (density 8.54 mg/cm3, which is about 0.854% of water density), and highly adiabatic (thermal conductivity 0.0387 W/m.K). Significantly, the as-prepared HAP nanowire aerogel can be used as the highly efficient air filter with high PM2.5 filtration efficiency. In addition, the HAP nanowire aerogel is also an ideal candidate for continuous oil water separation, which can be used as a smart switch to separate oil from water continuously. Compared with organic aerogels, the as-prepared HAP nanowire aerogel is biocompatible, environmentally friendly, and low-cost. Moreover, the synthetic method reported in this work can be scaled up for large-scale production of HAP nanowires, free from the use of organic solvents. Therefore, the as-prepared new kind of HAP nanowire aerogel is promising for the applications in various fields. PMID- 29611707 TI - Correction to Current-Induced Magnetic Polarons in a Colloidal Quantum-Dot Device. PMID- 29611708 TI - Stratification of Colloidal Particles on a Surface: Study by a Colloidal Probe Atomic Force Microscopy Combined with a Transform Theory. AB - Colloidal probe atomic force microscopy (CP-AFM) can be used for measuring force curves between the colloidal probe and the substrate in a colloidal suspension. In the experiment, an oscillatory force curve reflecting the layer structure of the colloidal particles on the substrate is usually obtained. However, the force curve is not equivalent to the interfacial structure of the colloidal particles. In this paper, the force curve is transformed into the number density distribution of the colloidal particles as a function of the distance from the substrate surface using our newly developed transform theory. It is found by the transform theory that the interfacial stratification is enhanced by an increase in an absolute value of the surface potential of the colloidal particle, despite a simultaneous increase in a repulsive electrostatic interaction between the substrate and the colloidal particle. To elucidate the mechanism of the stratification, an integral equation theory is employed. It is found that crowding of the colloidal particles in the bulk due to the increase in the absolute value of the surface potential of the colloidal particle leads to pushing out some colloidal particles to the wall. The combined method of CP-AFM and the transform theory (the experimental-theoretical study of the interfacial stratification) is related to colloidal crystallization, glass transition, and aggregation on a surface. Thus, the combined method is important for developments of colloidal nanotechnologies. PMID- 29611709 TI - Phenomenological Study of Confined Criticality: Insights from the Capillary Condensation of Propane, n-Butane, and n-Pentane in Nanopores. AB - We use the comparison of experimentally measured isotherms for propane, n-butane, and n-pentane in 2.90, 4.19, and 8.08 nm MCM-41 to show that the current model for the progression of capillary condensation may not hold true for chain molecules, such as normal alkanes. Until now, the capillary condensation of gases in unconnected, uniformly sized and shaped nanopores has been shown to progress in two distinct stages before ending in supercriticality of the confined fluid. First, at relatively low temperatures in isothermal measurements, the phase change is accompanied by hysteresis of adsorption and desorption. Second, as temperature increases, the hysteresis critical temperature is surpassed, and the phase change occurs reversibly. Although propane followed this progression, we observed a new progression for n-butane and n-pentane, in which hysteresis continues into the supercritical region of the confined fluid. We attribute this behavior to the molecular chain lengths of the adsorbates. Through further comparison of the adsorption, desorption, and critical properties of the adsorbates, we discovered new pressure phenomena of the confined supercritical fluids. PMID- 29611710 TI - Influence of Ion Solvation on the Properties of Electrolyte Solutions. AB - It is widely appreciated that the addition of salts to water leads to significant changes in the thermodynamic and dynamic properties of these aqueous solutions that have great significance in biology and manufacturing applications. However, no theoretical framework currently exists that describes these property changes in an internally consistent fashion. In previous work, we developed a coarse grained model of electrolyte solutions capable of reproducing basic trends on how salts influence the viscosity and water diffusion coefficient. The present work explores the predictions of this model for basic thermodynamic properties of electrolyte solutions, namely, the density, isothermal compressibility, and surface tension. On the basis of our model, we find that ion-specific effects on thermodynamics properties, and by extension the dynamics of electrolyte solutions, derive primarily from ion solvation. PMID- 29611711 TI - An IRT Analysis of the Reading the Mind in the Eyes Test. AB - The Reading the Mind in the Eyes Test (RMET; Baron-Cohen, Wheelwright, Hill, Raste, & Plumb, 2001 ), originally designed for use in clinical populations, has been used with increasing frequency as a measure of advanced social cognition in nonclinical samples (e.g., Domes, Heinriches, Michel, Berger, & Herpertz, 2007 ; Kidd & Castano, 2013 ; Mar, Oatley, Hirsh, de la Paz, & Peterson, 2006 ). The purpose of this research was to use item response theory to assess the ability of the RMET to detect differences at the high levels of theory of mind to be expected in neurotypical adults. Results indicate that the RMET is an easy test that fails to discriminate between individuals exhibiting high ability. As such, it is unlikely that it could adequately or reliably capture the expected effects of manipulations designed to boost ability in samples of neurotypical populations. Reported effects and noneffects from such manipulations might reflect noise introduced by inaccurate measurement; a more sensitive instrument is needed to verify the effects of manipulations to enhance theory of mind. PMID- 29611712 TI - Recruitment and enrollment of African Americans into health promoting programs: the effects of health promoting programs on cardiovascular disease risk study. AB - OBJECTIVES: Randomized controlled trials (RCT) often employ multiple recruitment methods to attract participants, however, special care must be taken to be inclusive of under-represented populations. We examine how recruiting from an existing observational study affected the recruitment of African Americans into a RCT that included yoga-based interventions. In particular, we report the recruitment success of The Effects of Health Promoting Programs (HPP) on Cardiovascular Disease Risk (NCT02019953), the first yoga-based clinical trial to focus only on African Americans. DESIGN: To recruit participants, a multifaceted recruitment strategy was implemented exclusively in the Jackson Heart Study (JHS) cohort. The HPP recruited from the JHS cohort using direct mailings, signs and flyers placed around JHS study facilities, and through JHS annual follow-up interviews. RESULTS: Enrollment into HPP was open to all active JHS participants that were eligible to return for the third clinic exam (n = 4644). The target sample size was 375 JHS participants over a 24 month recruitment and enrollment period. From the active members of the JHS cohort, 503 were pre-screened for eligibility in HPP. More than 90% of those pre-screened were provisionally eligible for the study. The enrollment goal of 375 was completed after a 16-month enrollment period with over 25% (n = 97) of the required sample size enrolling during the second month of recruitment. CONCLUSIONS: The findings show that participants in observational studies can be successfully recruited into RCT. Observational studies provide researchers with a well-defined population that may be of interest when designing clinical trials. This is particularly useful in the recruitment of a high-risk, traditionally underrepresented populations for non pharmacological clinical trials where traditional recruitment methods may prolong enrollment periods and extend study budgets. PMID- 29611713 TI - Effects of thymoquinone on liver miRNAs and oxidative stress in Ehrlich acid mouse solid tumor model. AB - We investigated the effects of thymoquinone (TQ) on the expression of liver microRNAs (miRNAs), liver histopathology and oxidative stress in Ehrlich acid solid tumor model induced mice. We used 24 male BALB/c mice divided randomly into three groups. Control (C) group mice were injected intraperitoneally (i.p.) with 0.5 ml saline for four weeks. Tumor (T) group mice were injected i.p. with 0.5 ml saline for four weeks, then Ehrlich acid tumor cells were injected subcutaneously into the neck to induce solid tumor formation. TQ (T + Tq) group mice injected i.p. with 10 mg/kg TQ for four weeks, then Ehrlich acid tumor cells were injected subcutaneously into the neck of the mice in this group to induce solid tumor formation. At the end of the study, liver from all groups were removed for histopathological and miRNAs analysis, and oxidative stress measurement. We found that the expression of miR-206b-3p was up-regulated and the oxidative stress and necrosis increased in the liver tissue of mice with Ehrlich acid solid tumor. TQ application decreased the oxidative stress, prevented necrosis, increased regeneration and down-regulated the expression of miR-206b-3p in the liver tissue. PMID- 29611714 TI - Chemical composition of the essential oils from the aerial parts of two Malagasy endemic species (Apiaceae): Billburttia capensoides Sales & Hedge and Billburttia vaginoides Sales & Hedge. AB - The chemical composition of twenty-five essential oil samples from the aerial parts of two Malagasy endemic species Billburttia capensoides Sales & Hedge and B. vaginoides Sales & Hedge, were investigated for the first time. Based on chromatographic profiles, three selected samples were investigated using GC(RI), GC-MS and 13C NMR. The content of the main components varied drastically from sample to sample: p-mentha-1,3,8-triene (0.2-52.7%), terpinolene (2.8-40.7%) and dill apiole (0.0-22.2%). Statistical analysis of the 25 oil compositions allowed the distinction of two well-differentiated groups. Samples of group I contained mainly p-mentha-1,3,8-triene while the Group II was dominated by terpinolene and dill apiole. PMID- 29611715 TI - Validation of rapid descriptive sensory methods against conventional descriptive analyses: A systematic review. AB - A major drawback of conventional descriptive profile (CDP) in sensory evaluation is the long time spent in panel training. Rapid descriptive methods (RDM) have increased significantly. Some of them have been compared with CDP for validation. In Health Sciences, systematic reviews (SR) are performed to evaluate validation of diagnostic tests in relation to a gold standard method. SR present a well defined protocol to summarize research evidence and to evaluate the quality of the studies with determined criteria. We adapted SR protocol to evaluate the validation of RDM against CDP as satisfactory procedures to obtain food characterization. We used "Population Intervention Comparison Outcome Study - PICOS" framework to design the research in which "Population" was food/ beverages; "intervention" were RDM, "Comparison" was CDP as gold standard, "Outcome" was the ability of RDM to generate similar descriptive profiles in comparison with CDP and "Studies" was sensory descriptive analyses. The proportion of studies concluding for similarity of the RDM with CDP ranged from 0% to 100%. Low and moderate risk of bias were reached by 87% and 13% of the studies, respectively, supporting the conclusions of SR. RDM with semi-trained assessors and evaluation of individual attributes presented higher percentages of concordance with CDP. PMID- 29611716 TI - Effects of iron supplementation versus dietary iron on the nutritional iron status: Systematic review with meta-analysis of randomized controlled trials. AB - This meta-analysis compared the effects of dietary intervention versus iron supplementation on biochemical parameters related to the iron nutritional status in humans. The PubMed, CENTRAL, LILACS, SCIELO, OPENGREY.EU and ClinicalTrials.gov databases were searched for randomized clinical trials that assigned individuals to a dietary intervention or to an iron supplementation regimen, for 12 weeks or more. The primary outcome was the hemoglobin concentration, and secondary outcomes were ferritin, RDW, mean corpuscular volume, soluble transferrin receptor, total iron binding capacity, serum iron, and transferrin saturation. From the 6095 records identified, twelve studies were included, six with children, five with adolescents/adults, and one with pregnant women. In the subgroup of studies that included anemic/iron deficient children, supplementation significantly increased the hemoglobin concentration (weighted mean difference (WMD): 3.19 g/L [95% CI: 1.31, 5.07]) and induced a significantly greater reduction of the soluble transferrin receptor (WMD: -0.46 mg/L [95% CI: 0.70, -0, 21]), when compared to dietary intervention. It also induced a greater reduction of the total binding capacity of iron in adolescents/adults (WMD: -6.96 MUmol/L [95% CI: -12.70, -1.21]). Supplementation showed a better effect on hemoglobin recovery in anemic/iron deficient children, while no differences were observed between supplementation and dietary intervention in treating adolescents/adults. PMID- 29611717 TI - Therapeutic Assessment With Child Inpatients. AB - Growing evidence supports Therapeutic Assessment (TA), a collaborative and therapeutic approach to psychological assessment, as an effective method for enhancing motivation for and engagement with psychotherapy across a variety of clinical populations and treatment settings. However, to date there are no known studies assessing the use of TA in child psychiatric inpatient settings. This article briefly reviews the structure of child and family TA, enumerates the challenges and risks associated with short-term inpatient stays, and proposes a path for integrating TA into these units as a way to enhance the quality of care and reduce the risk of rapid rehospitalization. The authors provide three case examples from a child psychiatric inpatient unit, each using a modified version of TA and each integrating assessments into brief family interventions. The authors conclude with suggestions for best practice for child psychiatric inpatient TAs. PMID- 29611718 TI - Antimicrobial activity-guided identification of compounds from the deciduous leaves of Malus doumeri by HPLC-ESI-QTOF-MS/MS. AB - This paper intends to identify the antimicrobial activity compounds from the deciduous leaves of Malus doumeri (Dong Li Tea) by HPLC-ESI-QTOF-MS/MS. The ethanol extracts of Malus doumeri were partitioned into petroleum ether, dichloromethane, ethyl acetate, n-butanol and water fraction, respectively. The antimicrobial screening experiments showed that ethyl acetate fraction has a certain antibacterial activity by inhibition zone method in vitro. And then we used the HPLC-ESI-QTOF-MS/MS method to verify the identities of bioactive compounds. Finally, 41 compounds were determined and 11 of which were firstly reported in this plant. Notably, compounds (32, 34, 38) are new dihydrochalcones, and three chlorogenic acid analogues (10, 13, 17) may be potential antimicrobial active ingredient. Which is of great significance to the isolation of novel compounds and the discovery of new natural preservative candidates from the deciduous leaves of Malus doumeri. PMID- 29611720 TI - Staining for viability testing, germination and maturation of Sambucus nigra L. pollen in vitro. AB - Freshly released pollen of black elderberry (Sambucus nigra L.) was incubated under various culture conditions until germination was achieved. Optimal conditions for germination were determined and used for maturation of unicellular microspores in vitro. Staining with 5-diphenyltetrazolium bromide, propidium iodide and iodine potassium iodide was used to assess pollen viability, nuclear phase and maturation, respectively. The germination rate was highest when fresh pollen was agitated at 40 rpm in Petri dishes containing a liquid medium consisting of Brewbaker and Kwack salts, 15% (w/v) sucrose, 500 mg/l MES sodium salt, at pH 5.0; germination reached nearly 70% after only 1 h in culture. Under these conditions, and with addition of 200 mg/l glutamine, 260 mg/l cytidine and 500 mg/l uridine, uninucleate microspores developed into mature pollen at a 12% germination rate. Our report is the first demonstration of maturation of S. nigra microspores in vitro. PMID- 29611719 TI - Early Hospital Readmissions after an Acute Exacerbation of Chronic Obstructive Pulmonary Disease in the Nationwide Readmissions Database. AB - RATIONALE: Understanding the causes and factors related to readmission for an acute exacerbation of chronic obstructive pulmonary disease (AECOPD) within a nationwide database including all payers and ages can provide valuable input for the development of generalizable readmission reduction strategies. OBJECTIVES: To determine the rates, causes, and predictors for early (3-, 7-, and 30-d) readmission in patients hospitalized with AECOPD in the United States using the Nationwide Readmission Database after the initiation of the Hospital Readmissions Reduction Program, but before its expansion to COPD. METHODS: We conducted an analysis of the Nationwide Readmission Database from 2013 to 2014. Index admissions and readmissions for an AECOPD were defined consistent with Hospital Readmissions Reduction Program guidelines. We investigated the percentage of 30 day readmissions occurring each day after discharge and the most common readmission diagnoses at different time periods after hospitalization. The relationship between predictors (categorized as patient, clinical, and hospital factors) and early readmission were evaluated using a hierarchical two-level logistic model. To examine covariate effects on early-day readmission, predictors for 3-, 7-, and 30-day readmissions were modeled separately. RESULTS: There were 202,300 30-day readmissions after 1,055,830 index AECOPD admissions, a rate of 19.2%. The highest readmission rates (4.2-5.5%) were within the first 72 hours of discharge, and 58% of readmissions were within the first 15 days. Respiratory based diseases were the most common reasons for readmission (52.4%), and COPD was the most common diagnosis (28.4%). Readmission diagnoses were similar at different time periods after discharge. Early readmission was associated with patient (Medicaid payer status, lower household income, and higher comorbidity burden) and clinical factors (longer length of stay and discharge to a skilled nursing facility). Predictors did not vary substantially by time of readmission after discharge within the 30-day window. CONCLUSIONS: Thirty-day readmissions after an AECOPD remain a major healthcare burden, and are characterized by a similar spectrum of readmission diagnoses. Predictors associated with readmission include both patient and clinical factors. Development of a COPD-specific risk stratification algorithm based on these factors may be necessary to better predict patients with AECOPD at high risk of early readmission. PMID- 29611721 TI - Food insecurity and healthcare decision making among mobile food pantry clients in Tampa Bay. AB - This article examines the relationship between food insecurity and health-care decision-making among mobile food pantry clients in Tampa Bay, Florida. Results show a high rate of food insecurity, high stress levels, and chronic health conditions among mobile pantry clients, many of whom are long-term users of food pantry services. The fruits and vegetables supplied by the pantry allow clients to manage chronic health conditions and mitigate some of the financial burden of health-care costs. Research was conducted in cooperation with the Anthropology Department at the University of South Florida, Feeding Tampa Bay, and WellCare . PMID- 29611722 TI - Single-Nucleotide Polymorphisms of FAS and FASL Genes and Risk of Idiopathic Aplastic Anemia. AB - FAS/FASL signaling system plays a vital role in the regulation of apoptosis, envisaged as a death process required for immune surveillance to prevent autoimmunity and tumorigenesis along with several other biological activities. Several single-nucleotide polymorphisms (SNPs) of FAS/FASL system can result in aberrant apoptosis, which can cause different cancers and autoimmune diseases. Aplastic anemia (AA) is an autoimmune dysfunction characterized by peripheral blood pancytopenia associated with hypoplasia of bone marrow. The aim of this study was to screen Pakistani AA patients and controls for two Fas SNPs rs2234767 and rs1800682 and two FASLG SNPs rs763110 and rs5030772. Genotyping of 392 DNA samples was done by Tetra-ARMS polymerase chain reaction. Genotypic frequencies of Fas rs1800682 and FASLG rs5030772 showed significance difference in their distribution in both controls and patients, while Fas rs2234767 and FASLG rs763110 SNPs had no such difference. Carriers of rs1800682 AG+GG had a very odd ratio of 4.63, with 95% confidence interval (CI) of 3.01-7.11, while individuals with FASLG rs5030772 AG+GG were more common in controls than patients with OR 0.53 and 95% CI of 0.34-0.83. Cumulative effects of these SNPs were analyzed, and they showed almost similar trends; however, Fas rs2234767 and FASLG rs763110 genotypes in combination with Fas rs1800682 and FASLG rs5030772 demonstrated significant association. This study provided information that endorsed the involvement of FAS/FASL system SNPs in the pathogenesis of AA; further studies should be designed to understand the exact role of SNPs that can help in early diagnosis and treatment. PMID- 29611723 TI - Activation of tumor cell integrin alphavbeta3 by radiation and reversal of activation by chemically modified tetraiodothyroacetic acid (tetrac). AB - PURPOSE: Integrin alphavbeta3 is an important structural and signaling protein of the plasma membrane of cancer cells and dividing blood vessel cells. The plastic extracellular domain of the protein binds to extracellular matrix proteins and plasma membrane proteins, changing cell-cell interactions and generating intracellular signals that influence cell behavior. alphavbeta3 also contains a receptor for thyroid hormone and derivatives, including tetraiodothyroacetic acid (tetrac). MATERIALS AND METHODS: Human prostate cancer (PC3) cells were engrafted in the chicken chorioallantoic membrane model. The well-vascularized spheroidal xenografts were exposed to X-radiation in varying dosages (1-10 Gy) and in the presence and absence of an antibody that recognizes unliganded human beta3 integrin monomer in the extended or open (activated) configuration. RESULTS: Radiation significantly increased activated beta3 within 1 h (P < .001), a radiation response not previously reported. Incubation of cells with unmodified tetrac or tetrac covalently linked to a nanoparticle (Nanotetrac, NDAT) did not change basal activation state of the integrin monomer, but prevented radiation induced activation of beta3. CONCLUSIONS: Activation of the integrin in response to radiation is interpreted as a defensive response, perhaps leading to increased intercellular affinity and inhibition of cell division, a radioresistant state. Action of NDAT indicates that pharmacologic interventions in the radiation response of integrin beta3 monomer and therefore of alphavbeta3 are feasible. PMID- 29611724 TI - Velocity vector imaging for the assessment of segmental ventricular function in children with a single right ventricle after cavopulmonary anastomosis. AB - OBJECTIVE: Ventricular function assessment is very important for the treatment and prognostic classification of children with a single right ventricle (SRV) after cavopulmonary anastomosis (CPA). However, unusual ventricular shapes can result in inaccurate measurements. The aim of this study was to evaluate velocity vector imaging (VVI) for assessing segmental ventricular function in children with SRV after CPA. METHODS: Twenty-one children with SRV after CPA and 21 age- and sex-matched children with normal biventricular anatomy and function were included. The longitudinal velocity, displacement, strain and strain rate were measured in the two groups in six segments by VVI. The velocity, displacement, strain and strain rate of the SRVs were compared with max(dp/dt) measured during simultaneous cardiac catheterization in the SRV subjects. RESULTS: The control group consisted of 13 males and 8 females (69% males) with a mean age of 6.7 +/- 3.5 years and mean weight of 20.5 +/- 6.5 kg, and the study group consisted of 13 males and 8 females with a mean age 6.7 +/- 3.7 years and mean weight of 20.6 +/- 6.8 kg. Age, weight and sex distribution were similar between the groups (all, p > .05). Strain and strain rate values in all six segments were significantly lower in the study group than in the control group (all, p < .05). The max(dp/dt) of the SRV was 522.84 +/- 158.32 mmHg/s, and the strain rate of the basal segment at the rudimentary chamber correlated best with max(dp/dt) (r = 0.74, p < .01). CONCLUSIONS: Segmental ventricular dysfunction was present in children with SRV after CPA, and it could be assessed using VVI. PMID- 29611725 TI - Isoflurane post-conditioning influences myocardial infarct healing in rats. AB - Isoflurane post-conditioning causes an early increase in cardiac progenitor cells; however, during the chronic phase of infarct healing, the number was smaller compared to control, which suggests a positive effect on infarct scar maturity. Myofibroblasts participate in early phase infarct contraction, but their number is small in a mature scar. We investigated whether isoflurane post conditioning stimulates differentiation of progenitor cells to myofibroblasts and to verify our hypothesis that isoflurane post-conditioning improves maturation of a myocardial scar. Ischemia was induced for 30 min in female rats. From the last 5 min of ischemia until 10 min into reperfusion, the isoflurane group received 1.5% isoflurane, while the control group received only an air-oxygen mixture. Infarct area was analyzed using immunohistochemistry. During the subacute phase of infarct healing, the number of myofibroblasts was greater in isoflurane treated animals than in the control group. During the chronic phase of infarct healing, post-conditioned animals exhibited fewer myofibroblasts compared to control animals, even those derived from progenitor cells, i.e., alpha-smooth actin-nestin positive cells. In addition, isoflurane post-conditioning resulted in higher percentage of mature blood vessels compared to control animals. The myocardium of the isoflurane treated animals exhibited more myofibroblasts in granulation tissue compared to control animals. The smaller number of myofibroblasts together with the greater number of mature blood vessels during the chronic phase of healing demonstrated faster healing of the infarct area of isoflurane-treated animals compared to control animals. PMID- 29611726 TI - Increased circulating endothelial microparticles in children with FMF. AB - OBJECTIVE: Endothelial microparticles (EMPs) are considered as markers of endothelial dysfunction. In this study, we aimed to examine whether there is endothelial dysfunction in children with familial Mediterranean fever (FMF), hypothesizing that endothelial dysfunction would be present especially with acute phase response in the active period of the disease. METHODS: This cross-sectional study included 65 FMF patients (41 attack free, 24 attack period) and 35 healthy controls. Circulating EMPs, serum amyloid A (SAA), and other inflammation markers were measured in all groups. Circulating EMPs were measured using flow cytometry. Study groups were compared for circulating EMP and inflammatory markers. The relationship between EMPs and the activation of the disease was evaluated. RESULTS: The levels of CD144+ and CD146+ EMPs in the FMF attack period group were significantly higher than those of the control group (p < 0.05). The levels of inflammation markers in the attack period group were significantly higher than those of the control and attack-free groups (p < 0.05). In the FMF attack group, the CD144+ and CD146+ EMP were significantly correlated with CRP. CONCLUSIONS: Our results suggest that endothelial damage is present especially in the active period of the disease in children with FMF. The endothelial dysfunction becomes an overt parallel with inflammation. PMID- 29611727 TI - Dose adjustment of metformin and dipeptidyl-peptidase IV inhibitors in diabetic patients with renal dysfunction. AB - OBJECTIVES: This analysis of real-world data aimed to (a) determine the proportion of Type II diabetes (T2DM) patients treated with metformin or dipeptidyl peptidase-4 inhibitors (DPP-4i) that require dose adjustment or therapy discontinuation due to chronic kidney disease (CKD), and (b) to assess the time required to dose adjustment from the time of worsening of CKD. METHODS: In this retrospective study, two study populations were defined in a large healthcare organization. In the cross-sectional analysis, the distribution of CKD stages and the appropriate dosage of metformin and DPP-4i in 2013 was examined according to renal function among T2DM patients. In the longitudinal analysis, a cohort was defined to assess the time elapsed from first indication worsening of CKD to dose adjustment, among patients treated with those medications during years 2006-2013. RESULTS: Among patients treated with metformin or DPP-4i, one third of patients with CKD failed to adjust the dosage or to discontinue metformin or DPP-4i as indicated. Median time for dose adjustment or discontinuation was significantly longer for DPP-4i than for metformin (9.8 compared to 16.8 months for metformin and DPP-4i, respectively; p-value <.001). CONCLUSIONS: This real-world data analysis showed that adjustment of dose or discontinuation of metformin or DPP-4i in patients with worsening CKD occurred less often in DPP-4i users than metformin users and took a longer time. PMID- 29611728 TI - A review of the mechanism and prophylaxis of acetyl salicylic acid-induced injury of the small intestine. AB - Besides the preventive effect of aspirin on cerebrocardiovascular diseases, aspirin has adverse effects, especially on the gastrointestinal system and kidneys. Especially, a recent advancement in endoscopy revealed that aspirin induced small intestinal mucosal injury is considerably higher than previously believed. However, the mechanism of this phenomenon is not clear yet. Moreover, effective prophylaxis does not exist. First, we investigated the cytotoxic effect of aspirin on the intestinal epithelial cell line in rats at a high concentration, and found that aspirin significantly decreased heat shock protein 70 expression, increased reactive oxygen species production, and increased epithelial cell apoptosis. These phenomena were prevented by the increment of heat shock protein 70 expression. Next, we investigated the effect of a lower concentration of aspirin on epithelial cell permeability, and found that aspirin significantly increased reactive oxygen species production, decreased tight junction protein expression, and increased epithelial permeability. These phenomena were suppressed by an antioxidant. Finally, we investigated the role of intestinal mucus on aspirin-induced mucosal damage using an in vivo model, and found that mucus prevented a high concentration of aspirin-induced mucosal damage. The investigation of chronic users of aspirin revealed that mucus increasing therapy might be useful for preventing aspirin-induced small intestinal mucosal injury. PMID- 29611729 TI - Evaluation of a Method for Rapid Detection of Listeria monocytogenes in Dry-Cured Ham Based on Impedanciometry Combined with Chromogenic Agar. AB - The food industry is in need of rapid, reliable methodologies for the detection of Listeria monocytogenes in ready-to-eat products, as an alternative to the International Organization of Standardization (ISO) 11290-1 reference method. The aim of this study was to evaluate impedanciometry combined with chromogenic agar culture for the detection of L. monocytogenes in dry-cured ham. The experimental setup consisted in assaying four strains of L. monocytogenes and two strains of Listeria innocua in pure culture. The method was evaluated according to the ISO 16140:2003 standard through a comparative study with the ISO reference method with 119 samples of dry-cured ham. Significant determination coefficients ( R2 of up to 0.99) for all strains assayed in pure culture were obtained. The comparative study results had 100% accuracy, 100% specificity, and 100% sensitivity. Impedanciometry followed by chromogenic agar culture was capable of detecting 1 CFU/25 g of food. L. monocytogenes was not detected in the 65 commercial samples tested. The method evaluated herein represents a promising alternative for the food industry in its efforts to control L. monocytogenes. Overall analysis time is shorter and the method permits a straightforward analysis of a large number of samples with reliable results. PMID- 29611730 TI - Prevalence of Human Noroviruses in Commercial Food Establishment Bathrooms. AB - Although transmission of human norovirus in food establishments is commonly attributed to consumption of contaminated food, transmission via contaminated environmental surfaces, such as those in bathrooms, may also play a role. Our aim was to determine the prevalence of human norovirus on bathroom surfaces in commercial food establishments in New Jersey, Ohio, and South Carolina under nonoutbreak conditions and to determine characteristics associated with the presence of human norovirus. Food establishments (751) were randomly selected from nine counties in each state. Four surfaces (underside of toilet seat, flush handle of toilet, inner door handle of stall or outer door, and sink faucet handle) were swabbed in male and female bathrooms using premoistened macrofoam swabs. A checklist was used to collect information about the characteristics, materials, and mechanisms of objects in bathrooms. In total, 61 (1.5%) of 4,163 swabs tested were presumptively positive for human norovirus, 9 of which were confirmed by sequencing. Some factors associated with the presence of human norovirus included being from South Carolina (odd ratio [OR], 2.4; 95% confidence interval [CI], 1.2 to 4.9; P < 0.05) or New Jersey (OR, 1.7; 95% CI, 0.9 to 3.3; 0.05 < P < 0.10), being a chain establishment (OR, 1.9; 95% CI, 1.1 to 3.3; P < 0.05), being a unisex bathroom (versus male: OR, 2.0; 95% CI, 0.9 to 4.1; 0.05 < P < 0.10; versus female: OR, 2.6; 95% CI, 1.2 to 5.7; P < 0.05), having a touchless outer door handle (OR, 3.3; 95% CI, 0.79 to 13.63; 0.05 < P < 0.10), and having an automatic flush toilet (OR, 2.5, 95% CI, 1.1 to 5.3; 0.05 < P < 0.10). Our findings confirm that the presence of human norovirus on bathroom surfaces in commercial food establishments under nonoutbreak conditions is a rare event. Therefore, routine environmental monitoring for human norovirus contamination during nonoutbreak periods is not an efficient method of monitoring norovirus infection risk. PMID- 29611731 TI - Rapid Detection of Escherichia coli O157:H7 in Fresh Lettuce Based on Localized Surface Plasmon Resonance Combined with Immunomagnetic Separation. AB - This study presents a method for rapid detection of Escherichia coli O157:H7 in fresh lettuce based on the properties of target separation and localized surface plasmon resonance of immunomagnetic nanoparticles. The multifunctional immunomagnetic nanoparticles enabling simultaneous separation and detection were prepared by synthesizing magnetic nanoparticles (ca. 10 nm in diameter) composed of an iron oxide (Fe3O4) core and gold shell and then conjugating these nanoparticles with the anti- E. coli O157:H7 antibodies. The application of multifunctional immunomagnetic nanoparticles for detecting E. coli O157:H7 in a lettuce matrix allowed detection of the presence of <1 log CFU mL-1 without prior enrichment. In contrast, the detection limit of the conventional plating method was 2.74 log CFU mL-1. The method, which requires no preenrichment, provides an alternative to conventional microbiological detection methods and can be used as a rapid screening tool for a large number of food samples. PMID- 29611732 TI - Development of a Novel Hygiene Monitoring System Based on the Detection of Total Adenylate (ATP+ADP+AMP). AB - ATP is the universal energy molecule found in animals, plants, and microorganisms. ATP rapid hygiene monitoring tests have been employed in the food industry to ensure that adequate cleanliness is being maintained. However, because ATP is hydrolyzed to ADP and AMP by metabolic processes, by heat treatment, or under acidic or alkaline conditions, total adenylate (ATP+ADP+AMP [A3]) could be a more reliable sanitation indicator of food residues that may cause biofilm formation and allergen contamination. Therefore, a novel hygiene monitoring system to measure A3 was developed based on the luciferin-luciferase assay with the combination of two enzymes, pyruvate kinase and pyruvate phosphate dikinase, that can convert ADP into ATP and recycle AMP into ATP, respectively. The newly developed A3 assay system afforded stable bioluminescence signals and equivalent linear calibration curves between relative light units (RLU) and the amounts of ATP, ADP, and AMP, respectively. To verify the significance of the A3 method, the ratios of ATP, ADP, and AMP in various food samples were determined; large amounts of ADP and AMP were found in a variety of foods, such as meat, seafood, dairy, nuts, fruits, vegetables, and fermented foods. Sanitation monitoring of stainless steel exposed to raw meat was also examined, and the A3 method achieved a 200-RLU level, the typical benchmark value, after complete washing with detergent and rinsing. In contrast, a conventional ATP method showed less than 200 RLU after only a light cold and hot water rinse. In conclusion, the A3 assay appeared to be suitable for detection of adenylates from food residues that are not detected by the conventional ATP assay. PMID- 29611733 TI - From the President. PMID- 29611734 TI - Three actions to reduce suicide deaths and attempts. PMID- 29611736 TI - Winner of 2017 PIF essay competition: 'Doctors' mental health is more important now than it has ever been'. PMID- 29611740 TI - Therapeutic nihilism and youth suicide. PMID- 29611739 TI - Talking with Dr Huu Kim Le. PMID- 29611742 TI - Open discussion of suicide. PMID- 29611743 TI - Vehicular suicides resulting in the deaths of others. PMID- 29611745 TI - Suicidality and family violence in Australian immigrant women presenting to out patient mental health settings. PMID- 29611748 TI - "Whales can be deadly too". PMID- 29611749 TI - [The possible role of the timing of the first oncological treatment on the survival rate of cancer diseases. A literature overview]. AB - The aim of this study was to survey the effects of the waiting time for the first oncology treatment in cancer diseases. By the analysis of 67 retrospective studies and reviews the numerical effects of treatment initiation time on survival were assessed. The "time factor" has a leading role on cancer types with aggressive biological behaviour, like breast cancer in younger age, testicular cancers, or head and neck tumours. However, a few days and reasonable delay to the first oncology intervention has no negative impact in numerous cancer diseases. The course of the primary check-up could be modified by several medical and psychosocial factors, and many times the treatment of the most advanced cancers are privileged causing an inverse survival effect. The effectiveness of the cancer therapies is determined by the optimal treatment decision, however, further research is necessary for the determination of the exact role of the "time factor" in oncology. Orv Hetil. 2018; 159(14): 535-546. PMID- 29611751 TI - [The pathogenetic role and expression profile of microRNAs in preeclampsia]. AB - Preeclampsia is the leading cause of maternal and fetal morbidity and mortality that affects 3-8% of pregnancies worldwide. Its main symptoms include new onset of high blood pressure and proteinuria after 20 weeks of pregnancy. The cause of the disease is still debated. microRNAs are short, non-coding RNA molecules that play a pivotal part in the posttranscriptional regulation of eukaryotic genes. They are involved in fine-tuning of vital physiological processes such as cell cycle, proliferation, differentiation and cell death. In genomic studies, hundreds of microRNAs were detected in the placenta, which are supposed to regulate placental development and contribute to uncomplicated pregnancy. Several studies have reported changes in the expression of microRNAs in pregnancy. Abnormal microRNA expression may have a role in the development of preeclampsia as it affects the proliferation, migration, and invasion of the trophoblast cells, spiral artery remodeling, and angiogenesis. Some placental microRNAs (e.g., the C19MC microRNA cluster) are able to reach the maternal circulation through their release via exosomes from the trophoblast layer. These 'circulating' microRNA molecules can be applied as biomarkers for the detection of various placental disorders owing to their stability and specificity. Orv Hetil. 2018; 159(14): 547-556. PMID- 29611753 TI - [Predictive factors for treatment failure of post-sternotomy wound infections]. AB - INTRODUCTION AND AIM: Post-sternotomy wound infection is still a major concern and it affects morbidity, mortality, and hospital costs. Reconstruction failure may further increase these risks with significant financial implications. METHOD: Here, we attempted to verify some factors that may significantly influence the success of the surgical treatment. We performed a single-center retrospective analysis of data from 3177 consecutive patients who underwent midline sternotomy. The diagnostic signs of post-sternotomy wound infections were observed in 60 patients (1.9%). These data were thoroughly analyzed. RESULTS: Beside late diagnosis, the positive microbiological culture of the wounds, radical surgical intervention and peripheral vascular disease were found to significantly contribute to the development of surgical reconstruction failure. Radical surgical reconstruction was associated with a higher success rate (81.8 vs. 11.1%), p<0.001. CONCLUSION: Identification of the predictive factors that may lead to treatment failure can assist in developing treatment algorithms and improving the success rates of surgical reconstructions. Orv Hetil. 2018; 159(14): 566-570. PMID- 29611752 TI - [Effect of smoking on survival after myocardial infarction - smoker's paradox in Hungary?] AB - INTRODUCTION: The strong, positive relationship between smoking and myocardial infarction was proven in the 1960s and 1970s. The prognostic significance of smoking in the acute phase of the infarction, and later in patients who survive the acute phase is, however, not clear. Numerous international studies focus on the phenomenon called the "smoker's paradox", which means that smokers have a lower mortality rate after suffering myocardial infarction than non-smokers. Although in many cases smoking does not have a positive effect on survival after controlling for confounders, an international consensus has not been reached regarding this issue. AIM: The aim of this paper was to investigate whether the paradox effect exists in the case of Hungarian patients after controlling for the patients' risk profiles. METHOD: The database used for the research was based on the 2014-2016 data of the Hungarian Myocardial Infarction Registry (n = 20 811) supervised by the Gottsegen Gyorgy National Institute of Cardiology. The present analysis uses multivariate methodology to adjust for confounding: logistic regression is used for the short-term survival and survival analysis - with Cox proportional hazards model and Accelerated Failure Time models - is used for the long-term survival. Age, sex, performing of PCI, type of infarction (ST-elevation or not), creatinine abnormality, need for prehospital reanimation, cardiogenic shock and the presence of several comorbidities and medical history data were controlled for in the multivariate analysis. RESULTS: Both the short term - 30 day - mortality (OR = 1.517, 99% confidence interval: 1.229-1.872) and the long term mortality (HR = 1.395, 99% confidence interval: 1.232-1.579) were worse for smokers than non-smokers after adjusting for the abovementioned factors. CONCLUSION: The "smoker's paradox" cannot be observed in the case of Hungarian patients, moreover smoking in itself is associated with worse prognosis. Orv Hetil. 2018; 159(14): 557-565. PMID- 29611754 TI - Experience with eribulin in triple-negative metastatic breast cancer: case studies. AB - Triple-negative breast cancers are defined as tumors negative for estrogen receptors, progesterone receptors and human EGFR2. These tumors exhibit diverse biological behavior and have a poor prognosis; chemotherapy is the mainstay of treatment. The first case involves a young woman with cerebral and cerebellar metastases who achieved a persistent objective response to fourth-line eribulin. In the second case, a woman who became metastatic during adjuvant therapy with anthracyclines and taxanes, and was refractory to capecitabine + bevacizumab, achieved a partial response and local symptom improvement with eribulin + bevacizumab. Last, a poly-treated patient demonstrated reasonable response and longer progression-free interval on third-line eribulin relative to previous lines of chemotherapy which is unusual in this clinical setting. PMID- 29611755 TI - Experience with eribulin in HR+/HER2- metastatic breast cancer, including a male. AB - Numerous patient- and disease-related factors must be considered when deciding a treatment approach for hormone receptor-positive (HR+) and human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer. Hormone therapy (HT) is generally the first option in the absence of compelling reasons for chemotherapy (e.g., rapidly progressive visceral disease). After failure of first choice HT, alternative HT options are usually attempted until hormone resistance occurs and chemotherapy becomes the treatment of choice. The first two patients presented herein experienced prolonged disease control with third-line eribulin after two lines of HT. The third report involves a case of male breast cancer which typically presents as the HR+/HER2- phenotype. Eribulin in the second line provided prolonged clinical improvement and was well tolerated. PMID- 29611757 TI - Experience with eribulin in patients with metastatic breast cancer and associated hepatic impairment: case studies. AB - Hepatic impairment in breast cancer arises from metastatic spread of tumor cells to the liver and signals a poor prognosis. Systemic therapy is the mainstay of treatment. Three women with hepatic dysfunction secondary to breast cancer who were treated with eribulin are presented herein. In the first case, third-line eribulin at the time of acute liver failure due to metastases maintained response for up to 9 months with good tolerability. In the second case, a woman with secondary bone and liver disease had progression-free survival of 5 months to third-line eribulin and, upon rechallenge after a drug holiday, had almost four more months of stable disease. Last, a heavily pretreated patient with secondary bone and hepatic involvement showed a response to fourth-line eribulin. PMID- 29611758 TI - Experience with eribulin in the treatment of elderly women with metastatic breast cancer: case studies. AB - Although advancing age can greatly increase the complexities of treating metastatic breast cancer, chronological age alone is insufficient to determine the type or intensity of treatment. Older patients require an individualized approach that takes into account the patient's physical ability, social circumstances and mental capacity to tolerate treatment. This section features three older women treated with eribulin for metastatic breast cancer. In the first case, a 70-year-old woman maintained stable disease into her 34th month of treatment with third-line eribulin. In the remaining cases, two heavily pretreated women (80 and 90 years, respectively) with metastatic disease and liver involvement presented objective radiological benefit to later-line eribulin along with prolonged clinical improvement and good tolerability. PMID- 29611759 TI - Experience with eribulin in patients with breast cancer and cutaneous metastases: case studies. AB - Skin localization occurs in about 25% of women with metastatic breast cancer and represents a major therapeutic challenge. Although clinical literature on response of cutaneous metastases to chemotherapy is scarce, good response to eribulin has been reported. Herein, the clinical courses of three women with skin lesions secondary to metastatic breast cancer are described. The first patient achieved a complete clinical response in skin metastases with good tolerability to fourth-line eribulin (progression-free survival [PFS]: 8.5 months). In the second case, eribulin administered as fifth-line chemotherapy produced an objective response and PFS of 6 months with good tolerability. The third patient also received eribulin in the fifth line and had a visible skin response from the first administration (PFS: 5 months). PMID- 29611761 TI - Safety and effectiveness of iguratimod in patients with rheumatoid arthritis: Final report of a 52-week, multicenter postmarketing surveillance study. AB - OBJECTIVES: We evaluated the long-term (52 weeks) safety and effectiveness of iguratimod (IGU) in patients with rheumatoid arthritis (RA). METHODS: This multicenter, prospective, observational study included all evaluable RA patients who received IGU since its market launch in 2012. We evaluated adverse events (AEs); adverse drug reactions (ADRs); ADRs of special interest, including liver and renal dysfunctions, interstitial lung disease, gastrointestinal and blood disorders, and infection; and change in Disease Activity Score 28-C-reactive protein (DAS28-CRP) at week 52. RESULTS: Safety and effectiveness were analyzed in 2666 and 1614 patients, respectively. The incidences of AEs, serious AEs, ADRs, and serious ADRs were 46.92, 7.35, 38.26, and 4.58%, respectively. The incidence of ADRs peaked at approximately 4 weeks of treatment. Subsequently, the ADR incidence did not increase over time. Improvement of RA activity was shown up to week 52. CONCLUSION: Long-term treatment with IGU in patients with RA resulted in a tolerable safety profile and an improvement in RA activity. IGU could be considered a useful treatment option for patients with RA. PMID- 29611762 TI - (-)-Guaiol regulates autophagic cell death depending on mTOR signaling in NSCLC. AB - (-)-Guaiol, a sesquiterpene alcohol with the guaiane skeleton, has been found in many Chinese medicinal plants and been reported to comprise various guaiane natural products that are well known for their antibacterial activities. Previously, we have shown its antitumor activity by inducing autophagy in NSCLC cells. However, its potential mechanism in inducing autophagy is still under our investigation. Here, data from our western blotting assays showed that, in NSCLC cells, (-)-Guaiol significantly blocked the mTORC2-AKT signaling by suppressing mTOR phosphorylation at serine 2481 (S2481) to induce autophagy, illustrated by the increasing ratio of LC3II/I. Besides, it impaired the mTORC1 signaling by inhibiting the activity of its downstream factors, such as 4E-BP1 and p70 S6K, all of which could obviously rescued by the mTOR activator MHY1485. Afterwards, results from biofunctional assays, including cell survival analysis, colony formation assays and flow cytometry assays, suggested that (-)-Guaiol triggered autophagic cell death by targeting both mTORC1 and mTORC2 signaling pathways. In summary, our studies showed that (-)-Guaiol inhibited the proliferation of NSCLC cells by specifically targeting mTOR signaling pathways, including both mTORC1 and mTORC2 signaling, providing a better therapeutic option for substituting rapamycin in treating NSCLC patients. PMID- 29611763 TI - Comparison of immediate implant placement in infected and non-infected extraction sockets: a systematic review and meta-analysis. AB - OBJECTIVE: This review aimed to investigate the feasibility of immediate implant placement in infected extraction sockets. MATERIAL AND METHODS: We performed electronic and manual searches up to March 2017 to obtain data from randomized controlled trials (RCTs) and nonrandomized controlled clinical trials (CCTs). Using a fixed-effects model to assess the difference in survival rate (primary outcome), we evaluated the risk difference for immediate implant placement in infected and non-infected sites. We estimated the weighted mean differences (WMDs) of the change in marginal bone loss (MBL), probing depth (PD), modified bleeding index (mBI), marginal gingival level (MGL) and width of keratinized gingiva (WKG) at baseline and latest follow-up. RESULTS: In total, five studies (0 RCT, five CCTs) were included in the systematic review and three studies were included in the meta-analysis. The risk difference for immediate implant placement in an infected extraction socket compared with that in a non-infected socket was -0.02. WMDs for MBL, PD, mBI, MGL and WKG between the two groups were 0.32, 0.12, 0.07, -0.06, 0.20 and 0.51, respectively. No statistical differences were observed between the two groups, except for the change in WKG. CONCLUSIONS: Implants can be placed in infected extraction sockets after thorough socket debridement. For aesthetics, WKG should be considered when performing immediate implant placement in infected sites. PMID- 29611764 TI - Lenalidomide combined with R-GDP in a patient with refractory CD5-positive diffuse large B-cell lymphoma: A promising response and review. AB - CD5-positive (CD5+) diffuse large B-cell lymphoma (DLBCL) is associated with poor survival compared with CD5-negative DLBCL. The clinical characteristics of CD5+ DLBCL are different from both CD5-negative DLBCL and other CD5+ B cell lymphomas. There is currently no promising chemotherapy for CD5+ DLBCL. Herein, we report a 49-year-old Asian male with refractory CD5+ DLBCL. He complained of aggravated abdominal pain and weight loss. Computed tomography scan revealed abdominal masses, widespread lymphadenopathy, splenomegaly, and intussusception of the ileocecal junction with bowel wall thickening. Core needle aspiration biopsy of an abdominal mass was performed and immunohistochemistry revealed DLBCL of nongerminal center type. In this report, the dose-intensified R-Hyper CVAD (A) regimen as salvage therapy was introduced but failed to result in substantial improvement over the initially standard R-CHOP regimen. Next, the R-GDP regimen was administered as second-line treatment, but only resulted in a partial response. However, the addition of lenalidomide to R-GDP (R2-GDP) resulted in complete remission. The clinical features, pathogenesis, and possible mechanism of action of lenalidomide in CD5+ DLBCL have been described in the literature. The results of the present case report and literature searches indicate that CD5+ DLBCL may share a common pathway with activated B-cell like (ABC) DLBCL as determined by gene expression profiling. Lenalidomide is expected to induce favorable responses in patients with CD5+ DLBCL. PMID- 29611765 TI - The Potential Role of PTPN-22 C1858T Gene Polymorphism in the Pathogenesis of Type 1 Diabetes in Saudi Population. AB - BACKGROUND: Recent investigations have reported an association between protein tyrosine phosphatase non-receptor type-22 (PTPN-22) gene polymorphism and susceptibility to the development of type 1 diabetes (T1D) in some populations and not in others. In this study, we aimed to investigate the association of PTPN 22 C1858T polymorphism with T1D in Saudi children. METHODS: A cohort of 372 type 1 diabetic children and 372 diabetes-free subjects was enrolled in the current investigation. The PTPN-22 C1858T polymorphism was identified using the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. RESULTS: Our data showed that the frequency of CT and TT genotypes of PTPN-22 C1858T was higher in T1D children (17.7% and 4.3%, respectively) compared to healthy controls (4.8% and 1.6%, respectively), and both genotypes were statistically associated with T1D patients (OR = 4.4, 95% CI: 2.55-7.58, p < 0.001; and OR = 3.2, 95% CI: 1.23-8.28, p = 0.017, respectively). Moreover, the 1858T allele was significantly associated with T1D patients compared to the C allele (OR = 3.2, 95% CI: 1.59-6.88, p < 0.001). In addition, the T allele was significantly associated with elevated levels of HbA1c, anti-GAD, and anti insulin antibodies (p < 0.001) and a lower concentration of C-peptide (p < 0.001) in T1D children. CONCLUSION: The data presented here suggests that the T allele of PTPN-22 C1858T polymorphism might be a risk factor for T1D development in Saudi children. PMID- 29611766 TI - Anti-nerve growth factor antibody improves airway hyperresponsiveness by down regulating RhoA. AB - BACKGROUND: The pathogenesis of asthma is complex and continues to be considered as a challenging subject. Some studies have shown that nerve growth factor (NGF) participates in the pathogenesis of asthma, but the mechanism of airway contraction caused by NGF is still unclear. OBJECTIVE: Our aim was to discuss the effect of anti-NGF antibody on RhoA expression, and further explore the role of NGF in airway hyperresponsiveness (AHR). METHODS: Thirty female BALB/c mice were divided into three groups randomly: control group (group C, n = 10), asthma group (group A, n = 10) and anti-NGF antibody intervention group (group N, n = 10). The asthmatic mice were stimulated by OVA suspension, the intervention mice were given nasal instillation of anti-NGF antibody before the stimulation. Airway responsiveness, eosinophils, IL-13, IFN-gamma were measured. The protein expression and mRNA level of NGF and RhoA were detected by immunohistochemical and Real Time-PCR (RT-PCR) analyses. RESULTS: Airway responsiveness, eosinophils and IL-13 levels in group A were significantly increased compare with the other groups, and significantly decreased in group N than those in group A. IFN-gamma level was significantly reduced in group A and increased in group N. Immunohistochemistry and RT-PCR analyses showed that the protein expression and mRNA level of NGF and RhoA were significantly increased in group A and significantly decreased in group N. CONCLUSION: NGF participates in the pathogenesis of asthma in mice. Anti-NGF antibody can inhibit airway inflammation and alleviate AHR by down-regulating the protein expression and mRNA level of RhoA. PMID- 29611767 TI - Impulse oscillometry and nitrogen washout test in the assessment of small airway dysfunction in asthma: Correlation with quantitative computed tomography. AB - OBJECTIVE: Small airway dysfunction (SAD) and airway remodeling influence the disease control and progression in asthma. We investigated whether impulse oscillometry (IOS) and single breath nitrogen washout (SBN2W) could be reliable tests in evaluating SAD and airway remodeling by correlating their data with radiological parameters derived from quantitative chest multidetector computed tomography (MDCT) imaging. METHODS: Lung function tests were performed before and after bronchodilator. The MDCT lung scans were acquired at full inspiration and expiration using a portable spirometer to control the respiratory manoeuvres. Symptom control was assessed using the Asthma Control Test (ACT) questionnaire. RESULTS: Twenty six patients were enrolled. The bronchial lumen area (LA) measured with MDCT lung scan, correlated inversely with airway resistance (Raw, p < 0.001) and with total and large airway oscillometric resistance (R5, p = 0.002 and R20, p = 0.006, respectively). However these two last correlations became non significant after Bonferroni correction for multiple comparisons. The radiological quantification of air trapping correlated with Raw (p < 0.001), residual volume (RV, p < 0.001), and the slope of phase III of SBN2W (DeltaN2, p < 0.001) whereas the correlation with small airway oscillometric resistance (R5 20) was non-significant after Bonferroni adjustment. Finally, air trapping was significantly higher in patients with a fixed bronchial obstruction in comparison to patients with reversible obstruction. CONCLUSIONS: Plethysmographic method remains the main tool to investigate SAD and airway remodeling in asthmatic patients. The integration with the SBN2W test proved useful to better evaluate the small airway involvement whereas IOS showed a weaker correlation with both radiological and clinical data. PMID- 29611768 TI - Patient perspectives on compensation for biospecimen donation. AB - BACKGROUND: The purpose of this study was to determine whether biospecimen donors believe they should receive compensation. This is the first study to report biospecimen donors' views on compensation and can potentially improve informed consent and recruitment practices. METHODS: Researchers asked patients undergoing surgical removal of tissue to donate biological materials to a biobank; the request was made at their presurgical appointment or in the preoperative clinic of the Emory University Hospital. We interviewed 126 biospecimen donors within 30 days post surgery regarding their perspective on compensation for biospecimen donation. RESULTS: In response to the question "Should you be paid for your participation in the tissue bank?," 95 (95/126, 75%) participants answered "No." Of these, 55 (55/95, 58%) indicated that donating biological materials should be about altruism, not gaining a monetary reward. Only 11 (11/126, 9%) participants unequivocally believed they should receive compensation, while 14 (14/126, 11%) felt entitled to compensation only under specific circumstances. Eleven (11/14) "Depends" participants indicated that donors should only be compensated when researchers perform for-profit research. Responses varied by race and income level, with whites more likely to not feel entitled to compensation and higher income participants more likely to respond "Depends." CONCLUSIONS: The majority of biospecimen donors stated they should not be paid for tissue bank participation. However, a minority believe they should be paid for donating tissue if the tissue is used in revenue-generating projects. These results provide some support for the current biobanking practice of not providing compensation. PMID- 29611769 TI - Predictors of Complications in Patients Receiving Head and Neck Free Flap Reconstructive Procedures. AB - Objective To (1) determine the overall complication rate, wound healing, and wound infection complications and (2) identify preoperative, intraoperative, and postoperative predictors of these complications. Study Design Case series with chart review. Setting Tertiary academic cancer hospital. Subjects and Methods All head and neck free flap patients at The Ohio State University (2006-2012) were assessed. Multivariable logistic regression assessed the impact of patient factors, flap and wound factors, and intraoperative factors on the aforementioned quality metric outcomes. Results Of the 515 patients identified, 54% had a complication predicted by longer operating room (OR) time, higher comorbidity index, and oral cavity and pharyngeal tumor sites. Predictors of wound-healing complications (15%) were longer OR time, volume of crystalloid given intraoperatively, and oral cavity and pharyngeal tumor sites. Predictors of wound infection (12%) were younger age, diabetes mellitus, and malnutrition. Conclusions Wound healing and infectious complications account for most complications in patients with head and neck cancer undergoing free flap reconstruction. Clean contaminated wounds are a significant predictor of wound complications. Advanced OR time, advanced age, and comorbidity status, including diabetes mellitus and malnutrition, are other important predictors. Crystalloid administration is also an important predictor of wound-healing complications, and this warrants further study. PMID- 29611770 TI - Impact of HPV Status on the Prognostic Potential of the AJCC Staging System for Larynx Cancer. AB - Objective We evaluated the ability of the American Joint Committee on Cancer (AJCC) seventh edition staging system to prognosticate the overall survival of patients with human papillomavirus (HPV)-positive laryngeal squamous cell carcinoma. Study Design Retrospective analysis. Setting National Cancer Database. Subjects and Methods Patients diagnosed with laryngeal squamous cell carcinoma who were treated with curative intent were identified in the National Cancer Database. Multivariate analysis was utilized to determine factors correlated with overall survival in the HPV-negative and HPV-positive cohorts. Unadjusted and propensity score-weighted Kaplan-Meier estimation was used to determine overall survival of HPV-negative and HPV-positive patients across AJCC stage groupings. Results We identified 3238 patients with laryngeal squamous cell carcinoma, of which 2812 were HPV negative and 426 were HPV positive. Overall survival adjusted for age, sex, and comorbidity status confirmed significant differences among all consecutive stage groupings (I vs II, P < .001; II vs III, P < .05; III vs IVA, P < .001; IVA vs IVB, P < .05) in the HPV-negative cohort, whereas only stages IVAs and IVB ( P < .01) exhibited a significant difference in overall survival for HPV positive patients. Conclusion The current AJCC staging system does not accurately distinguish risk of mortality for patients with HPV-positive disease. These data support the consideration of HPV status in estimating prognosis as well as clinical trial design and clinical decision making for patients with laryngeal squamous cell carcinoma. PMID- 29611772 TI - Corrigendum. PMID- 29611771 TI - The effects of maturation on jumping ability and sprint adaptations to plyometric training in youth soccer players. AB - The aim of this study was to investigate the effects of maturation on power and sprint performance adaptations following 6 weeks of plyometric training in youth soccer players during pre-season. Sixty male soccer players were categorized into 3 maturity groups (Pre, Mid and Post peak height velocity [PHV]) and then randomly assigned to plyometric group and control group. Vertical jump, standing long jump, and 20-m sprint (with and without ball) tests were collected before- and after-intervention. After the intervention, the Pre, Mid and Post-PHV groups showed significant (P <= 0.05) and small to moderate effect size (ES) improvement in vertical jump (ES = 0.48; 0.57; 0.73), peak power output (E = 0.60; 0.64; 0.76), standing long jump (ES = 0.62; 0.65; 0.7), 20-m sprint (ES = -0.58; 0.66), and 20-m sprint with ball (ES = -0.44; -0.8; -0.55) performances. The Post PHV soccer players indicated greater gains than Pre-PHV in vertical jump and sprint performance after training (P <= 0.05). Short-term plyometric training had positive effects on sprinting and jumping-power which are important determinants of match-winning actions in soccer. These results indicate that a sixty foot contact, twice per week program, seems effective in improving power and sprint performance in youth soccer players. PMID- 29611773 TI - Effect of Surgical Adhesive on the Uterus of Rabbits Following Occlusion. AB - : Purpose/Aim of the Study: The present study investigated the effect of surgical adhesives on the uterus of rabbits and the histomorphology alterations following occlusion, to improve the clinical treatment of abnormal fallopian tube with surgical adhesives for in vitro fertilization and embryo transfer (IVF-ET). MATERIALS AND METHODS: The experimental rabbits received laparotomy and occlusion of the uterus by surgical adhesive adjacent to the two fallopian tubes, while the control rabbits only received laparotomy. The body weight, hysterosalpingography, and histomorphology were measured to evaluate the uterine occlusion at 1 and 6 months after surgery. RESULTS: There was no significant difference in the mortality rate or body weight between the experimental and control groups. In the experimental group, 38 uterine cavities were identified in 19 rabbits, of which 97.37% were occluded, with expanded uterine cavity and tissue oppression at 1 month after surgery. In total, 33 uterine cavities out of the 36 in the control group were occluded, with proliferation of new stratified epithelial cells observed at 6 months after surgery. In the control group, 20 uterine cavities of 10 rabbits were observed to be absent of occlusion at 1 month after surgery, while 18 uterine cavities in the remaining 9 rabbits were also absent of occlusion at 6 months after the surgery. CONCLUSION: Surgical adhesives are effective in occluding the uterus of rabbits without adverse effects, supporting their potential clinical use to treat the occlusion in abnormal fallopian tubes prior to IVF-ET. PMID- 29611774 TI - Examining physiotherapist use of structured aerobic exercise testing to decrease barriers to aerobic exercise. AB - OBJECTIVE: To determine the frequency of physiotherapist-administered aerobic exercise testing/training, the proportion of physiotherapists who administer this testing/training, and the barriers that currently exist across different practice environments. A secondary objective is to identify the learning needs of physiotherapists for the development of an education curriculum in aerobic exercise testing and training with electrocardiograph (ECG) administration and interpretation. DESIGN: National, cross-sectional survey. PARTICIPANTS: Registered physiotherapists practicing in Canada. RESULTS: Out of 137 participants, most (75%) physiotherapists prescribed aerobic exercise on a regular basis (weekly); however, 65% had never conducted an aerobic exercise test. There were no significant differences in frequency of aerobic exercise testing across different practice environments or across years of physiotherapy experience. Physiotherapists perceived the main barriers to aerobic exercise testing as being a lack of equipment/space (78%), time (65%), and knowledge (56%). Although most (82%) were uncomfortable administering 12-lead ECG-monitored aerobic exercise tests, 60% stated they would be interested in learning more about ECG interpretation. CONCLUSION: This study found that physiotherapists are regularly implementing aerobic exercise. This exercise was infrequently guided by formal aerobic exercise testing, which could increase access to safe and effective exercise within the optimal aerobic training zone. As well, this could facilitate training in patients with cardiovascular diagnoses that require additional testing for medical clearance. Increased ECG training and access to equipment for physiotherapists may augment pre-screening aerobic exercise testing. This training should include learning the key arrhythmias for aerobic exercise test termination as defined by the American College of Sports Medicine. PMID- 29611776 TI - Last station in the eosinophilic asthma with chronic rhinosinusitis and/or nasal polyposis march: Eosinophilic asthma with radiological findings associated with blood eosinophilia. AB - OBJECTIVE: Eosinophilic asthma with chronic rhinosinusitis and/or nasal polyposis (EA-CRS/NP) is a subphenotype of adult-onset eosinophilic asthma. Blood eosinophil levels are shown to be highly elevated in patients with EA-CRS/NP and have potential for tissue infiltration. We aimed to demonstrate the clinical features of the patients who have a blood eosinophil level above 10% and have thorax computed tomography findings due to blood eosinophilia. METHODS: Patients who were followed up in our clinic between 2012 and 2017 were retrospectively evaluated. Inclusion criteria were as follows: 1) Eosinophilic severe asthma, 2) eosinophilia >10%, 3) chronic sinusitis and/or nasal polyps, 4) patients with pathologic findings on thorax computed tomography, 5) regular follow-up for at least 1 year. RESULTS: We identified 36 patients who met the above criteria. We defined this group as "Eosinophilic Asthma with chronic Rhinosinusitis and/or nasal polyposis with Radiological findings related to blood eosinophilia" (EARR). The mean age was 44.9 +/- 11 years and 64% were females. Nasal polyps, aspirin exacerbated respiratory disease, and atopy, were present in 81%, 47%, and 25% of the patients, respectively. The mean blood eosinophil count was 1828.6 cells/mm3 (19%). The majority of EARR patients had upper lobe dominant ground-glass opacities. The mean follow-up period was 3.2 +/- 2.5 years. EARR patients did not evolve into eosinophilic granulomatous polyangiitis in the follow-up. CONCLUSIONS: This phenotype is the first eosinophilic asthma sub-phenotype reported in the literature. EARR is the final stage of the allergic march of EA CRS/NP. PMID- 29611775 TI - Upregulated IL-1 Receptor-associated Kinase 1 (IRAK1) in Systemic Lupus Erythematosus: IRAK1 Inhibition Represses Th17 Differentiation with Therapeutic Potential. AB - Systemic lupus erythematosus (SLE) is a typical autoimmune disease. Genome-wide analyses have revealed that interleukin-1 receptor-associated kinase 1 (IRAK1) is associated with susceptibility to SLE. Our previous study investigated the role of IRAK1 in nuclear factor-kappaB (NF-kappaB)-related pathways in a mouse model of lupus. In this study, we aimed to further explore the etiological role of IRAK1. The gene expression and phosphorylation of IRAK1 in CD4+ T cells from lupus patients and healthy controls were examined by quantitative reverse transcription-polymerase chain reaction and western blotting, respectively. The percentage of circulating Th17 cells and plasma IL-17A levels were evaluated by flow cytometry and enzyme-linked immunosorbent assay, respectively. The influence of IRAK1 suppression on Th17 development was assessed using an IRAK1 inhibitor and small interfering RNA. We found that IRAK1 transcript levels in CD4+ T cells were significantly upregulated in SLE patients in comparison to controls and were positively correlated with disease activity. In vitro experiments showed that lupus CD4+ T cells had more pronounced IRAK1 phosphorylation at threonine-209 upon IL-1beta stimulation than did control cells. Moreover, IRAK1 expression was positively associated with Th17/IL-17A in patients. When naive CD4+ T cells were polarized toward the Th17 subset, IRAK1 inhibition significantly repressed IL-17A production and the gene expression of Th17 markers, namely, retinoic acid receptor-related orphan receptor c, IL-23 receptor and IL-17A. In summary, IRAK1 is overexpressed and hyperactivated in CD4+ T cells from SLE patients. IRAK1 inhibition attenuates Th17 differentiation in the context of human SLE, suggesting a therapeutic opportunity. PMID- 29611777 TI - Generating Expectations: What Pediatric Rehabilitation Can Learn From Mental Health Literature. AB - Family-Centered Care (FCC) represents the ideal service delivery approach in pediatric rehabilitation. Nonetheless, implementing FCC as intended in clinical settings continues to be hindered by knowledge gaps. One overlooked gap is our understanding of clients' therapy expectations. This perspective article synthesizes knowledge from the mental health services literature on strategies recommended to service providers for generating transparent and congruent therapy expectations with clients, and applies this knowledge to the pediatric rehabilitation literature, where this topic has been researched significantly less, for the purpose of improving FCC implementation. Dimensions of the Measure of Processes of Care, an assessment tool that measures clients' perceptions of the extent a service is family-centered, inform the organization of therapy expectation-generating strategies: (1) Providing Respectful and Supportive Care (assessing and validating clients' expectations); (2) General and Specific Information (foreshadowing therapy journeys, explaining treatment rationale, and conveying service provider qualifications); (3) Coordinated and Comprehensive Care (socializing clients to roles and reflecting on past socialization); and (4) Enabling and Partnership (applying a negotiation framework and fostering spaces safe to critique). Strategies can help pediatric rehabilitation service providers work with families to reframe unrealistic expectations, establish congruent beliefs supporting effective partnerships, and prevent possible disillusionment with therapy over time. PMID- 29611778 TI - Before and After "I Do": Marriage Processes for Mid-Life Gay and Lesbian Married Couples. AB - This qualitative study examines how mid-life gay and lesbian married individuals articulate their decision to marry. Using 2013 data from 30 mid-life couples in Massachusetts, this study challenges previous literature that conceptualized marriage as entirely positive or negative for same-sex individuals. Mid-life individuals' unique social and historical context influence their experiences of marriage, as mid-life individuals have witnessed the rise and feasibility of marriage equality, have formed relationships outside of the bounds of marriage, and have been in committed relationships long before they married. Using the framework of ambivalence, our findings provide three main contributions to the literature. First, we show that marital ambivalence is a common experience in our sample. Second, we detail how marital ambivalence is indicative of the age, life course stage, and length of relationship for mid-life lesbian and gay individuals. Third, we explore ambivalence at the level of the relationship, not just as an individual experience. This study provides new insight into how sexuality shapes both intimate relationship dynamics as well as the effect of same-sex marriage on LGBT communities and identities. PMID- 29611780 TI - Editorial: reflecting on trafficking research. PMID- 29611779 TI - The association of metacognitive beliefs with emotional distress and trauma symptoms in adolescent and young adult survivors of cancer. AB - PURPOSE/OBJECTIVES: Adolescent and young adults who have survived cancer are at an increased risk of psychological distress. This study investigated whether metacognitive beliefs are associated with emotional distress and trauma symptoms in adolescent and young adult (AYA) survivors of cancer independent of known covariates, including current physical health difficulties. DESIGN: Cross sectional survey using multiple self-report measures. SAMPLE AND METHODS: Eighty seven AYA survivors of cancer were recruited from follow-up appointments at an oncology unit and completed self-report questionnaires measuring emotional distress, posttraumatic stress symptoms, metacognitive beliefs, demographic information, and current physical health difficulties. Data were analysed using correlational and hierarchical multiple regression analyses. FINDINGS: Metacognitive beliefs explained an additional 50% and 41% of the variance in emotional distress and posttraumatic stress symptoms, respectively, after controlling for known covariate effects, including current physical health difficulties. Conclusions/Implications for Psychosocial Providers or Policy: The metacognitive model of psychopathology is potentially applicable to AYA survivors of cancer who present with elevated general distress and/or posttraumatic stress symptoms. Prospective studies are required to determine whether metacognitive beliefs and processes have a causal role in distress in AYA survivors of cancer. PMID- 29611781 TI - STARS experiential group intervention: a complex trauma treatment approach for survivors of human trafficking. AB - This is the abstract that was submitted online with the paper: Despite the fact that many survivors of human trafficking have experienced complex trauma, there are no established interventions designed to specifically address these impacts. Leaders in the field of complex trauma have advocated for the need for somatic approaches to intervention. This paper presents STARS Experiential Group treatment, the first structured bodybased group intervention that has been designed to address complex trauma in survivors of human trafficking. Three pilot groups were run in residential settings with adolescent and adult survivors of sex trafficking. Two adaptations were utilized, with one focusing on application of expressive arts modalities and the other incorporating theater games. Qualitative results, using thematic analysis, identified several themes related to challenges and potential benefits of these groups. Potential benefits of the STARS groups were found in the areas of Interpersonal Relationships, Regulation, and Self/ Identity, with fourteen sub-themes further describing positive impacts. Challenges within these areas are explored, to inform the development of group interventions for trafficking survivors. The results of this paper suggest that experiential, somatically-oriented group treatment shows promise as an important element of holistic intervention with trafficking survivors. PMID- 29611782 TI - A Bibliometric History of the Journal of Psychology Between 1936 and 2015. AB - The Journal of Psychology: Interdisciplinary and Applied is a leading international journal in psychology dating back to 1935. This study examines its publications since its creation utilizing a bibliometric analysis. The primary objective is to provide a complete overview of the key factors affecting the journal. This analysis includes such key issues as the publication and citation structure of the journal, its most cited articles, and the leading authors, institutions, and countries referenced in the journal. The work uses the Scopus database to classify the bibliographic material. Additionally, the analysis provides a graphical mapping of the bibliographic data by using visualization of similarities viewer software. This software uses several bibliometric techniques including co-citation, bibliographic coupling and co-occurrence of keywords. The Journal of Psychology is strongly connected to most of the current leading journals in psychology, and currently has a 5-year impact factor of 1.77 (Thomson Reuters, 2015 Journal Citation Reports). PMID- 29611783 TI - Interindividual Variability in Use-Dependent Plasticity Following Visuomotor Learning: The Effect of Handedness and Muscle Trained. AB - Motor learning has been linked with increases in corticospinal excitability (CSE). However, the robustness of this link is unclear. In this study, changes in CSE associated with learning a visuomotor tracking task were mapped using transcranial magnetic stimulation (TMS). TMS maps were obtained before and after training with the first dorsal interosseous (FDI) of the dominant and nondominant hand, and for a distal (FDI) and proximal (biceps brachii) muscle. Tracking performance improved following 20 min of visuomotor training, while map area was unaffected. Large individual differences were observed with 18%-36% of the participants revealing an increase in TMS map area. This result highlights the complex relationship between motor learning and use-dependent plasticity of the motor cortex. PMID- 29611784 TI - Adult Mental Health Outcomes of Preterm Survivors Experiencing Suicidal Ideation in Adolescence. AB - The aim of this study was to examine the link between suicidal ideation in adolescence (age 12-16) and symptoms of psychopathology in adulthood (age 22-26) in a birth cohort of extremely low birth weight (ELBW; <1000g) survivors and matched normal birth weight (NBW; >2500 g) control participants. This study utilized data from a longitudinally followed cohort of 129 ELBW survivors and 116 NBW individuals born in Ontario, Canada between the years 1977 and 1982. Participants self-reported suicidal ideation via questionnaire during adolescence (age 12-16). The depression, anxiety, inattention, and antisocial behavior subscales of the Young Adult Self Report (YASR) were used to assess symptoms of psychopathology during adulthood (age 22-26). Associations were examined in each birth weight group separately prior to and after adjustment for covariates. Before and after adjustment for covariates, suicidal ideation in NBW adolescents predicted symptoms of depression, anxiety, inattention, and antisociality in adulthood. Suicidal ideation among ELBW adolescents predicted inattentive and depressive symptoms, and antisocial behavior only before adjustment. Adolescents born at NBW who endorse suicidal ideation are at elevated risk for developing symptoms of anxiety, depression, inattention, and antisocial problems in adulthood even after adjustment. Among ELBW survivors, the risks were lower and appear to be due to confounding factors. PMID- 29611785 TI - Successful aging: Asian perspectives. PMID- 29611786 TI - Extravasation injury leading to acute compartment syndrome in a child: The vital role of pulse oximetry in early detection and management. AB - Acute compartment syndrome as a result of an extravasation injury is rare. The perioperative environment presents a unique risk that may contribute to more serious patient outcomes. Using a case study approach we report that the placement of a pulse oximeter on the cannulated limb can provide the first sign of vascular compromise. PMID- 29611788 TI - C-MAC(c) videolaryngoscopy: The anaesthetic assistant's view. AB - Although videolaryngoscopy plays a major role in the 2015 Difficult Airway Society guidelines, the impact on anaesthetic assistant working practices and training has not previously been reported. We surveyed anaesthetic assistants in our hospital to document their experience with using the C-MAC(c) videolaryngoscope (48 practitioners, 100% response rate). Improvements in the following were reported: patient safety 100%; ability to see whether laryngoscopy is difficult 98%; ability to anticipate the 'next step' 98%; team-working and human factors 96%; ability to call a senior anaesthetist more quickly 94%; assessment or adjustment of cricoid force application 92%, understanding of laryngeal anatomy 92%; training in intubation 98%; training in cricoid force application 87%. Concerns were primarily about local issues such as decontamination and blade availability. Ninety percent reported that the clinical benefit outweighed any additional workload. In conclusion, the C-MAC(c) videolaryngoscope is judged by anaesthetic assistants to confer numerous advantages for their working practice and training. PMID- 29611790 TI - Factors that affect scrub practitioner non-technical skills: A literature review. AB - Non-technical skills are the cognitive and interpersonal behaviours that compliment clinical competence in surgery. Effective use of non-technical skills is essential for scrub practice, because they facilitate anticipation of the surgeon's requirements and promote appropriate communication behaviours. This literature review analyses the factors that may influence a scrub practitioner's use of non-technical skills during surgery. Recommendations are made that are intended to improve their use by reducing behavioural variations during surgery. PMID- 29611789 TI - Superficial branch of the radial nerve injury: A case for conscious perioperative arterial cannulation. AB - We present a case of an injury to the superficial branch of the radial nerve following unconscious radial artery cannulation in a 57-year-old gentleman for revision of lumbar spinal fusion. Nerve damage is a rare complication of this commonly used technique; whilst usually self-limiting, it can lead to a significant under-reported burden of morbidity on our patients. We discuss current norms of practice, questioning the safety of unconscious arterial cannulation, and suggest that, where possible, it should be performed in the conscious patient to minimise the risk of this rare complication. PMID- 29611791 TI - You have a voice: We have a voice! PMID- 29611792 TI - Hypertonic salt solution for perioperative fluid management. PMID- 29611793 TI - Hemidiaphragmatic paralysis: A case report. AB - Hemidiaphragmatic paralysis is initially recognised as postoperative respiratory distress. The subsequent sequential management of the patient following arthroscopic shoulder surgery under interscalene block is described. Ultrasound guided technique is considered to be the safest for interscalene block. Reducing the volume of anaesthetic used reduces its spread to the phrenic nerve and thus reduces the incidence of hemidiaphragmatic paralysis. Furthermore, a reduction in anaesthetic volume has equivalent analgesic efficacy. PMID- 29611794 TI - News Update. PMID- 29611795 TI - # hello my name is.... PMID- 29611796 TI - Theory of mind and the Ultimatum Game in healthy adult aging. AB - BACKGROUND: The Ultimatum Game assesses decision-making involved in cooperative interactions with others. However, little is known about the role that the ability to understand other people's intentions plays in these interactions. METHODS: This study examined performance on the Ultimatum Game and theory of mind (ToM) tasks in younger and older adults. RESULTS: Age differences were not found on the ToM tasks, and a lack of variability in performance prevented analyses of the relationships between performance on the Ultimatum Game and ToM. However, age differences were found on the Ultimatum Game, with older adults accepting more unfair offers. Yet, the two age groups did not differ in their appreciation of fairness, as assessed using subjective fairness ratings. CONCLUSIONS: These findings suggest that older adults are more rational in their behavior, accepting unfair offers even when they know they are unfair, as it is in their self interest to accept small monetary values rather than nothing at all. PMID- 29611797 TI - Editorial: Premature Cardiovascular Disease - Expanding the Role of Primary Care. PMID- 29611798 TI - Notification that new names of prokaryotes, new combinations, and new taxonomic opinions have appeared in volume 68, part 1, of the IJSEM. PMID- 29611799 TI - ICTV Virus Taxonomy Profile: Plasmaviridae. AB - The family Plasmaviridae includes bacterial viruses with slightly pleomorphic, enveloped virions with a diameter of 50-125 nm. Virions contain infectious, circular, supercoiled dsDNA molecule(s) of approximately 12 kbp. Plasmaviruses infect Acholeplasma species, wall-less bacteria of the class Mollicutes, and are released by budding through the cell membrane without causing host cell lysis. Although the temperate bacteriophage Acholeplasma virus L2 of Acholeplasma laidlawii is currently the only classified plasmavirus, related prophages reside in the genomes of different Acholeplasma species, where they are integrated into tRNA genes. This is a summary of the International Committee on Taxonomy of Viruses (ICTV) Report on the taxonomy of the Plasmaviridae, which is available at www.ictv.global/report/plasmaviridae. PMID- 29611800 TI - Hepatitis B virus X protein activates proteasomal activator 28 gamma expression via upregulation of p53 levels to stimulate virus replication. AB - Proteasomal activator gamma (PA28gamma), frequently overexpressed in hepatocellular carcinoma, is believed to play important roles in tumourigenesis. However, the underlying mechanism of PA28gamma overexpression and its possible roles in hepatitis B virus (HBV) replication are largely unknown. In the present study, we found that hepatitis B virus X protein (HBx) activates PA28gamma expression by upregulating p53 levels in human hepatoma cells. The elevated PA28gamma levels in turn repressed seven in absentia homologue 1 expression via downregulation of p53 levels, thereby inhibiting ubiquitin-dependent proteasomal degradation of HBx, which ultimately led to upregulation of HBx levels. The correlation among HBx, p53 and PA28gamma was exactly reproduced in a 1.2-mer HBV replicon system, mimicking the natural course of HBV infection. In particular, knockdown of either p53 or PA28gamma in HepG2 cells downregulated HBx levels and thereby inhibited HBV replication, whereas overexpression of p53 or PA28gamma in Hep3B cells upregulated HBx levels, which stimulated HBV replication, indicating that p53 and PA28gamma act as activators of HBV replication. In conclusion, HBx levels are upregulated via a positive feedback loop involving p53 and PA28gamma to stimulate HBV propagation. PMID- 29611801 TI - A naturally occurring feline APOBEC3 variant that loses anti-lentiviral activity by lacking two amino acid residues. AB - Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) is a mammalian protein that restricts lentiviral replication. Various polymorphisms of mammalian APOBEC3 genes have been observed in humans, Old World monkeys and domestic cats; however, the genetic diversity of APOBEC3 genes in other mammals remains unaddressed. Here we identify a novel haplotype of the feline APOBEC3Z3 gene, an APOBEC3 gene that restricts feline immunodeficiency virus (FIV) replication, in a Eurasian lynx (Lynx lynx). Compared to the previously identified lynx APOBEC3Z3 (haplotype I), the new sequence (haplotype II) harbours two amino acid deletions (Q16 and H17) and a nonsynonymous substitution (R68Q). Interestingly, lynx APOBEC3Z3 haplotype II does not suppress FIV infectivity, whereas haplotype I does. Mutagenesis experiments further revealed that deleting two amino acids (Q16 and H17) causes anti-FIV activity loss. This report demonstrates that a naturally occurring APOBEC3 variant loses anti-lentiviral activity through the deletion of two amino acid residues. PMID- 29611802 TI - Gracilimonas amylolytica sp. nov., isolated from deep-sea sediment. AB - A Gram-stain-negative, aerobic, non-motile and rod-shaped bacterium, designated LA399T, was isolated from deep-sea sediment collected from the Pacific Ocean. Cells of strain LA399T grew in the medium containing 0-10.0 % of NaCl (w/v; optimum 3.0-5.0 %), pH 6.5-8.0 (optimum 7.0) and 20-40 degrees C (optimum 37 degrees C). Aesculin, gelatin, starch and Tween 80 were hydrolysed. Strain LA399T was closely related to Gracilimonas halophila WDS2C40T (97.0 % sequence similarity), Gracilimonas mengyeensis YIM J14T (96.4 %), Gracilimonas rosea CL KR2T (96.4 %) and Gracilimonas tropica DSM 19535T (96.0 %), and exhibited equal or less than 96.0 % sequence similarity to other type strains of species with validly published names. Phylogenetic analyses revealed that strain LA399T clustered with the clade comprising the Gracilimonas species and formed an independent lineage. Strain LA399T contained menaquinone 7 as the sole isoprenoid quinone and iso-C15 : 0, anteiso-C15 : 0, summed feature 3 (C16 : 1omega7c/C16 : 1omega6c) and summed feature 9 (iso-C17 : 1omega9c/10-methyl C16 : 0) as the predominant cellular fatty acids. The major polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, one unidentified phospholipid and three unidentified glycolipids. The DNA G+C content was 45.3 mol%. According to the phylogenetic, chemotaxonomic and phenotypic data, it represents a novel species of the genus Gracilimonas, for which the name Gracilimonas amylolytica is proposed. The type strain is LA399T (=CGMCC 1.16248T=KCTC 52885T). PMID- 29611803 TI - Corrigendum: Myrmecridium hiemale sp. nov. from snow-covered alpine soil is the first eurypsychrophile in this genus of anamorphic fungi. PMID- 29611804 TI - Fast and accurate edge orientation processing during object manipulation. AB - Quickly and accurately extracting information about a touched object's orientation is a critical aspect of dexterous object manipulation. However, the speed and acuity of tactile edge orientation processing with respect to the fingertips as reported in previous perceptual studies appear inadequate in these respects. Here we directly establish the tactile system's capacity to process edge-orientation information during dexterous manipulation. Participants extracted tactile information about edge orientation very quickly, using it within 200 ms of first touching the object. Participants were also strikingly accurate. With edges spanning the entire fingertip, edge-orientation resolution was better than 3 degrees in our object manipulation task, which is several times better than reported in previous perceptual studies. Performance remained impressive even with edges as short as 2 mm, consistent with our ability to precisely manipulate very small objects. Taken together, our results radically redefine the spatial processing capacity of the tactile system. PMID- 29611805 TI - Functional roles of Mg2+ binding sites in ion-dependent gating of a Mg2+ channel, MgtE, revealed by solution NMR. AB - Magnesium ions (Mg2+) are divalent cations essential for various cellular functions. Mg2+ homeostasis is maintained through Mg2+ channels such as MgtE, a prokaryotic Mg2+ channel whose gating is regulated by intracellular Mg2+ levels. Our previous crystal structure of MgtE in the Mg2+-bound, closed state revealed the existence of seven crystallographically-independent Mg2+-binding sites, Mg1 Mg7. The role of Mg2+-binding to each site in channel closure remains unknown. Here, we investigated Mg2+-dependent changes in the structure and dynamics of MgtE using nuclear magnetic resonance spectroscopy. Mg2+-titration experiments, using wild-type and mutant forms of MgtE, revealed that the Mg2+ binding sites Mg1, Mg2, Mg3, and Mg6, exhibited cooperativity and a higher affinity for Mg2+, enabling the remaining Mg2+ binding sites, Mg4, Mg5, and Mg7, to play important roles in channel closure. This study revealed the role of each Mg2+-binding site in MgtE gating, underlying the mechanism of cellular Mg2+ homeostasis. PMID- 29611807 TI - CK1/Doubletime activity delays transcription activation in the circadian clock. AB - In the Drosophila circadian clock, Period (PER) and Timeless (TIM) proteins inhibit Clock-mediated transcription of per and tim genes until PER is degraded by Doubletime/CK1 (DBT)-mediated phosphorylation, establishing a negative feedback loop. Multiple regulatory delays within this feedback loop ensure ~24 hr periodicity. Of these delays, the mechanisms that regulate delayed PER degradation (and Clock reactivation) remain unclear. Here we show that phosphorylation of certain DBT target sites within a central region of PER affect PER inhibition of Clock and the stability of the PER/TIM complex. Our results indicate that phosphorylation of PER residue S589 stabilizes and activates PER inhibitory function in the presence of TIM, but promotes PER degradation in its absence. The role of DBT in regulating PER activity, stabilization and degradation ensures that these events are chronologically and biochemically linked, and contributes to the timing of an essential delay that influences the period of the circadian clock. PMID- 29611806 TI - MCM2-7-dependent cohesin loading during S phase promotes sister-chromatid cohesion. AB - DNA replication transforms cohesin rings dynamically associated with chromatin into the cohesive form to establish sister-chromatid cohesion. Here, we show that, in human cells, cohesin loading onto chromosomes during early S phase requires the replicative helicase MCM2-7 and the kinase DDK. Cohesin and its loader SCC2/4 (NIPBL/MAU2 in humans) associate with DDK and phosphorylated MCM2 7. This binding does not require MCM2-7 activation by CDC45 and GINS, but its persistence on activated MCM2-7 requires fork-stabilizing replisome components. Inactivation of these replisome components impairs cohesin loading and causes interphase cohesion defects. Interfering with Okazaki fragment processing or nucleosome assembly does not impact cohesion. Therefore, MCM2-7-coupled cohesin loading promotes cohesion establishment, which occurs without Okazaki fragment maturation. We propose that the cohesin-loader complex bound to MCM2-7 is mobilized upon helicase activation, transiently held by the replisome, and deposited behind the replication fork to encircle sister chromatids and establish cohesion. PMID- 29611809 TI - Electro-Active Polymer Based Soft Tactile Interface for Wearable Devices. AB - This paper reports soft actuator based tactile stimulation interfaces applicable to wearable devices. The soft actuator is prepared by multi-layered accumulation of thin electro-active polymer (EAP) films. The multi-layered actuator is designed to produce electrically-induced convex protrusive deformation, which can be dynamically programmable for wide range of tactile stimuli. The maximum vertical protrusion is and the output force is up to 255 mN. The soft actuators are embedded into the fingertip part of a glove and front part of a forearm band, respectively. We have conducted two kinds of experiments with 15 subjects. Perceived magnitudes of actuator's protrusion and vibrotactile intensity were measured with frequency of 1 Hz and 191 Hz, respectively. Analysis of the user tests shows participants perceive variation of protrusion height at the finger pad and modulation of vibration intensity through the proposed soft actuator based tactile interface. PMID- 29611810 TI - An Enhanced Soft Vibrotactile Actuator Based on ePVC Gel with Silicon Dioxide Nanoparticles. AB - In this paper, we propose a soft vibrotactile actuator made by mixing silicon dioxide nanoparticles and plasticized PVC gel. The effect of the silicon dioxide nanoparticles in the plasticized PVC gel for the haptic performance is investigated in terms of electric, dielectric, and mechanical properties. Furthermore, eight soft vibrotactile actuators are prepared as a function of the content. Experiments are conducted to examine the haptic performance of the prepared eight soft vibrotactile actuators and to find the best weight ratio of the plasticized PVC gel to the nanoparticles. The experiments should show that the plasticized PVC gel with silicon dioxide nanoparticles improves the haptic performance of the plasticized PVC gel-based vibrotactile actuator, and the proposed vibrotactile actuator can create a variety of haptic sensations in a wide frequency range. PMID- 29611811 TI - Understanding Graphics on a Scalable Latching Assistive Haptic Display Using a Shape Memory Polymer Membrane. AB - We present a fully latching and scalable 4 * 4 haptic display with 4 mm pitch, 5 s refresh time, 400 mN holding force, and 650 MUm displacement per taxel. The display serves to convey dynamic graphical information to blind and visually impaired users. Combining significant holding force with high taxel density and large amplitude motion in a very compact overall form factor was made possible by exploiting the reversible, fast, hundred-fold change in the stiffness of a thin shape memory polymer (SMP) membrane when heated above its glass transition temperature. Local heating is produced using an addressable array of 3 mm in diameter stretchable microheaters patterned on the SMP. Each taxel is selectively and independently actuated by synchronizing the local Joule heating with a single pressure supply. Switching off the heating locks each taxel into its position (up or down), enabling holding any array configuration with zero power consumption. A 3D-printed pin array is mounted over the SMP membrane, providing the user with a smooth and room temperature array of movable pins to explore by touch. Perception tests were carried out with 24 blind users resulting in 70 percent correct pattern recognition over a 12-word tactile dictionary. PMID- 29611808 TI - Formation of retinal direction-selective circuitry initiated by starburst amacrine cell homotypic contact. AB - A common strategy by which developing neurons locate their synaptic partners is through projections to circuit-specific neuropil sublayers. Once established, sublayers serve as a substrate for selective synapse formation, but how sublayers arise during neurodevelopment remains unknown. Here, we identify the earliest events that initiate formation of the direction-selective circuit in the inner plexiform layer of mouse retina. We demonstrate that radially migrating newborn starburst amacrine cells establish homotypic contacts on arrival at the inner retina. These contacts, mediated by the cell-surface protein MEGF10, trigger neuropil innervation resulting in generation of two sublayers comprising starburst-cell dendrites. This dendritic scaffold then recruits projections from circuit partners. Abolishing MEGF10-mediated contacts profoundly delays and ultimately disrupts sublayer formation, leading to broader direction tuning and weaker direction-selectivity in retinal ganglion cells. Our findings reveal a mechanism by which differentiating neurons transition from migratory to mature morphology, and highlight this mechanism's importance in forming circuit-specific sublayers. PMID- 29611812 TI - Haptic Rendering of 3D Geometry on 2D Touch Surface Based on Mechanical Rotation. AB - In this paper, we present a robotic surface display that physically imitates the orientation of virtual 3D geometry touched through a 2D flat screen. The proposed approach renders the surface orientation of 3D geometry such that users can tactually obtain relative geometric information, which plays a significant role in the process of real-world haptic object perception. Taking advantage of the planar aspect of touch surfaces, the system constructs a rotation matrix to control the pose of a surface with minimal mechanical movements with given partial geometric information (i.e., normal vector at the point of touch). To evaluate the proposed rendering scheme, we conducted a geometric task (two alternative forced choices) with a set of hand-sized cylindrically curved geometries in which participants were asked to identify which of the two surfaces they perceived as being more curved. Curvatures with the same polarities (i.e., convex-convex and concave-concave) were employed in the study and psychometric curves estimated to obtain the threshold of the curvature difference and to validate the proposed rendering scheme. Possible applications of the proposed system and its limitations are also presented. PMID- 29611813 TI - Structure of the Pacinian Corpuscle: Insights Provided by Improved Mechanical Modeling. AB - An improved model of the Pacinian corpuscle includes corrections for lamellar curvature. Results suggest that outer-zone lamellae produce a focusing effect whereby stimuli are channeled radially inwards. The requirements for this effect (large outer-surface area and thin, closely spaced lamellae) provide a rationale for the complexity of the outer-zone structure. PMID- 29611814 TI - Energy shifts in photoemission lines during the tetragonal- to cubic-phase transition in BaTiO3 single crystals and systems with CoFe2O4 and NiFe2O4 overlayers. AB - In BaTiO3 the phase transition from tetragonal to cubic is connected with the disappearance of the ferroelectric polarization. In photoelectron spectroscopy huge transient shifts in the binding energies of all core-level photoemission lines have been observed while heating and cooling through the Curie temperature. Excitation energies from 2 keV to 6 keV have been used to show this to be a bulk effect and not a surface effect alone. These observations are discussed in terms of charging, which results from the disappearance of the ferroelectric polarization. This mechanism has previously been proposed as the origin of electron emission in ferroelectric materials. Besides the jump-like shifts, additional permanent shifts in binding energies have been observed for the tetragonal and the cubic phase. These experimental shifts have been related to theoretical ones from ab initio calculations. In addition to BaTiO3 single crystals, systems with CoFe2O4 and NiFe2O4 overlayers on BaTiO3 have been investigated. The low conductivity of these layers sets them apart from metallic overlayers like Fe or Co, where the shifts are suppressed. This difference adds further support for charging as the origin of the effect. PMID- 29611816 TI - Tri-metallic PtPdAu mesoporous nanoelectrocatalysts. AB - The design of mesoporous materials with multi-metallic compositions is highly important for various electrocatalytic applications. In this paper, we demonstrate an efficient method to directly fabricate tri-metallic PtPdAu mesoporous nanoparticles (PtPdAu MNs) in a high yield, which is simply performed by heating treatment of the reaction mixture aqueous solution at 40 degrees C for 4 h. Profiting from its mesoporous structure and multi-metallic components, the as-prepared PtPdAu MNs exhibit enhanced electrocatalytic activities toward both methanol oxidation reaction and oxygen reduction reaction in comparison with bi-metallic PtPd MNs and commercial Pt/C catalyst. PMID- 29611815 TI - The effects of hydroxyapatite nanoparticles embedded in a MMP-sensitive photoclickable PEG hydrogel on encapsulated MC3T3-E1 pre-osteoblasts. AB - This study investigated the effects of introducing hydroxyapatite nanoparticles into a matrix metalloproteinase (MMP) sensitive poly(ethylene glycol) (PEG) hydrogel containing cell adhesion peptides of RGD for bone tissue engineering. MC3T3-E1 pre-osteoblasts were encapsulated in the biomimetic PEG hydrogel, which was formed from the photoclick thiol-norbornene reaction system, cultured for up to 28 d in growth medium or osteogenic differentiation medium, and evaluated by cellular morphology and differentiation by alkaline phosphatase (ALP) activity and bone-like extracellular matrix deposition for mineral and collagen. Hydroxyapatite nanoparticles were incorporated during hydrogel formation and cell encapsulation at 0%, 0.1% or 1% (w/w). Incorporation of hydroxyapatite nanoparticles did not affect the hydrogel properties as measured by compressive modulus and equilibrium swelling. In growth medium, encapsulated MC3T3-E1 cells remained largely round regardless of hydroxyapatite concentration. ALP activity increased by 25% at day 14 and total collagen content increased by 55% at day 28 with increasing hydroxyapatite concentration from 0% to 1%. In differentiation medium, cell spreading was evident regardless of hydroxyapatite indicating that the MC3T3-E1 cells were able to degrade the hydrogel. For the 1% hydroxyapatite condition, ALP activity was 27% higher at day 14 and total collagen content was 22% higher at day 28 in differentiation medium when compared to growth medium. Mineral deposits were more abundant and spatial elaboration of collagen type I was more evident in the 1% (w/w) hydroxyapatite condition with differentiation medium when compared to all other conditions. Overall, osteogenesis was observed in the hydrogels with hydroxyapatite nanoparticles in growth medium but was enhanced in differentiation medium. In summary, a biomimetic hydrogel comprised of MMP-sensitive crosslinks, RGD cell adhesion peptides, and 1% (w/w) hydroxyapatite nanoparticles is promising for bone tissue engineering. PMID- 29611817 TI - Surface functionalisation with viscosity-sensitive BODIPY molecular rotor. AB - Surface functionalisation with viscosity sensitive dyes termed 'molecular rotors' can potentially open up new opportunities in sensing, for example for non invasive biological viscosity imaging, in studying the effect of shear stress on lipid membranes and in cells, and in imaging contacts between surfaces upon applied pressure. We have functionalised microscope slides with BODIPY-based molecular rotor capable of viscosity sensing via its fluorescence lifetime. We have optimised functionalisation conditions and prepared the slides with the BODIPY rotor attached directly to the surface of glass slides and through polymer linkers of 5 kDa and 40 kDa in mass. The slides were characterised for their sensitivity to viscosity, and used to measure viscosity of supported lipid bilayers during photooxidation, and of giant unilamellar vesicles lying on the surface of the slide. We conclude that our functionalised slides show promise for a variety of viscosity sensing applications. PMID- 29611818 TI - Two-dimensional Cu2Si sheet: a promising electrode material for nanoscale electronics. AB - Building electronic devices on top of two-dimensional (2D) materials has recently become one of most interesting topics in nanoelectronics. Finding high performance 2D electrode materials is one central issue in 2D nanoelectronics. In the current study, based on first-principles calculations, we compare the electronic and transport properties of two nanoscale devices. One device consists of two single-atom-thick planar Cu2Si electrodes, and a nickel phthalocyanine (NiPc) molecule in the middle. The other device is made of often-used graphene electrodes and a NiPc molecule. Planer Cu2Si is a new type of 2D material that was recently predicted to exist and be stable under room temperature [11]. We found that at low bias voltages, the electric current through the Cu2Si-NiPc Cu2Si junction is about three orders higher than that through graphene-NiPc graphene. Detailed analysis shows that the surprisingly high conductivity of Cu2Si-NiPc-Cu2Si originates from the mixing of the Cu2Si state near Fermi energy and the highest occupied molecular orbital of NiPc. These results suggest that 2D Cu2Si may be an excellent candidate for electrode materials for future nanoscale devices. PMID- 29611819 TI - Protoporphyrin-IX conjugated cellulose nanofibers that exhibit high antibacterial photodynamic inactivation efficacy. AB - Towards the development of anti-infective nanoscale materials employing a photodynamic mechanism of action, we report the synthesis, physical properties (SEM, mechanical strength, water contact angle), spectroscopic characterization (infrared, Raman, DRUV), and evaluation of antibacterial efficacy of porphyrin conjugated regenerated cellulose nanofibers, termed RC-TETA-PPIX-Zn. Cellulose acetate was electrospun to produce nanofibers, thermally treated to enhance mechanical strength, and finally hydrolyzed to produce regenerated cellulose (RC) nanofibers that possessed a high surface area and nanofibrous structure. Covalent grafting of a protoporphyrin IX (PPIX) photosensitizer using epichlorohydrin/triethylenetetramine (TETA), followed by zinc chelation, afforded RC-TETA-PPIX-Zn. The high surface area afforded by the nanofibers and efficient photosensitizer conjugation led to a very high loading of 412 nmol PPIX/mg material, corresponding to a degree of substitution of 0.1. Antibacterial efficacy was evaluated against Staphylococcus aureus (ATCC-6538) and Escherichia coli (ATCC-8099), with our best results achieving detection limit inactivation (99.999+%) of both bacteria after only 20 min illumination (Xe lamp, lambda >= 420 nm). No statistically significant loss in antibacterial activity was observed when using nanofibers that had been 'photo-aged' with 5 h of pre-illumination to simulate the effects of photobleaching. Post aPDI, scanning electron microscopy revealed that the bacteria had undergone cell membrane leakage, consistent with oxidative damage caused by photo-generated reactive oxygen species. Taken together, the conjugation strategy employed here provides a scalable, facile and efficient route to creating nanofibrous materials from natural polymers with a high photosensitizer loading, enabling the use of commercially-available neutral porphyrin photosensitizers, such as PPIX, in the design and synthesis of potent anti-infective nanomaterials. PMID- 29611820 TI - Pressure-induced photoluminescence of MgO. AB - It is reported in this paper that pressure can promote strong photoluminescence (PL) in MgO. The PL measurements of MgO indicate that it has no obvious luminescence at pressures lower than 13 GPa. PL starts to appear upon further compression and reaches a maximum intensity at about 35 GPa. The center of the emission band shows a red shift at lower pressures and turns to a blue shift as pressure exceeds 25 GPa. The PL is preserved upon complete decompression. The defects and micro-strain due to the plastic deformation of MgO are likely responsible for the origin of the luminescence. PMID- 29611821 TI - Galectin-9 inhibits TLR7-mediated autoimmunity in murine lupus models. AB - Uncontrolled secretion of type I IFN, as the result of endosomal TLR (i.e., TLR7 and TLR9) signaling in plasmacytoid DCs (pDCs), and abnormal production of autoantibodies by B cells are critical for systemic lupus erythematosus (SLE) pathogenesis. The importance of galectin-9 (Gal-9) in regulating various autoimmune diseases, including lupus, has been demonstrated. However, the precise mechanism by which Gal-9 mediates this effect remains unclear. Here, using spontaneous murine models of lupus (i.e., BXSB/MpJ and NZB/W F1 mice), we demonstrate that administration of Gal-9 results in reduced TLR7-mediated autoimmune manifestations. While investigating the mechanism underlying this phenomenon, we observed that Gal-9 inhibits the phenotypic maturation of pDCs and B cells and abrogates their ability to mount cytokine responses to TLR7/TLR9 ligands. Importantly, immunocomplex-mediated (IC-mediated) and neutrophil extracellular trap-mediated (NET-mediated) pDC activation was inhibited by Gal-9. Additionally, the mTOR/p70S6K pathway, which is recruited by both pDCs and B cells for TLR-mediated IFN secretion and autoantibody generation, respectively, was attenuated. Gal-9 was found to exert its inhibitory effect on both the cells by interacting with CD44. PMID- 29611823 TI - Blunt Traumatic Injury to the Aortic Root and Aortic Valve. PMID- 29611824 TI - Transesophageal Echocardiographic-Guided Transapical Neochord Implantation. PMID- 29611825 TI - Percutaneous Closure of Complex Membranous Ventricular Septal Defect Under Transesophageal Echocardiographic Guidance. PMID- 29611822 TI - Autoinhibitory regulation of S100A8/S100A9 alarmin activity locally restricts sterile inflammation. AB - Autoimmune diseases, such as psoriasis and arthritis, show a patchy distribution of inflammation despite systemic dysregulation of adaptive immunity. Thus, additional tissue-derived signals, such as danger-associated molecular patterns (DAMPs), are indispensable for manifestation of local inflammation. S100A8/S100A9 complexes are the most abundant DAMPs in many autoimmune diseases. However, regulatory mechanisms locally restricting DAMP activities are barely understood. We now unravel for the first time, to our knowledge, a mechanism of autoinhibition in mice and humans restricting S100-DAMP activity to local sites of inflammation. Combining protease degradation, pull-down assays, mass spectrometry, and targeted mutations, we identified specific peptide sequences within the second calcium-binding EF-hands triggering TLR4/MD2-dependent inflammation. These binding sites are free when S100A8/S100A9 heterodimers are released at sites of inflammation. Subsequently, S100A8/S100A9 activities are locally restricted by calcium-induced (S100A8/S100A9)2 tetramer formation hiding the TLR4/MD2-binding site within the tetramer interphase, thus preventing undesirable systemic effects. Loss of this autoinhibitory mechanism in vivo results in TNF-alpha-driven fatal inflammation, as shown by lack of tetramer formation in crossing S100A9-/- mice with 2 independent TNF-alpha-transgene mouse strains. Since S100A8/S100A9 is the most abundant DAMP in many inflammatory diseases, specifically blocking the TLR4-binding site of active S100 dimers may represent a promising approach for local suppression of inflammatory diseases, avoiding systemic side effects. PMID- 29611826 TI - Use of 3D Transesophageal Echocardiography and the Clock-Face Model to Localize and Facilitate Closure of a Mitral Paravalvular Defect. PMID- 29611827 TI - Evaluation of Pulmonary Artery Pressure Measurements in Severe Pulmonic Valve Insufficiency in the Absence of Tricuspid Regurgitation. PMID- 29611828 TI - Tricuspid Regurgitation Due to Absent Tricuspid Valve Leaflet: Utility of Three Dimensional Echocardiography. PMID- 29611829 TI - A Left Ventricle to Left Atrial Appendage Fistula After Mitral Valve Replacement. PMID- 29611830 TI - Cervicogenic Dizziness Successfully Treated With Upper Cervical Medial Branch Nerve Radiofrequency Ablation: A Case Report. AB - Cervicogenic dizziness is a sensation of disequilibrium caused by abnormal afferent activity from the neck. Its diagnosis and treatment are challenging. In a case of cervicogenic dizziness, we performed diagnostic upper cervical medial branch nerve blocks with near complete symptomatic relief for around 20 hours. Radiofrequency ablation of these nerves resulted in near complete relief for 7 months. Subsequent repeat ablations provided the same relief lasting for 6-10 months. This case suggests that upper cervical medial branch block can serve as a diagnostic test for cervicogenic dizziness, and radiofrequency ablation of these nerves might be an effective treatment. PMID- 29611831 TI - Anesthetic Management for Concomitant Correction of Congenital Cardiac Defects and Long "O" Ring Tracheal Stenosis: A Role for Heliox?: Report of 2 Cases. AB - We present 2 infants with the rare association of long congenital tracheal stenosis, ventricular septal defect, and pulmonary hypertension. We describe a step-by-step assessment of the patients and the necessary procedures for a successful concomitant repair of both cardiac and tracheal malformations. The use of a helium-oxygen mixture (heliox) for the induction of anesthesia and pre cardiopulmonary bypass is discussed. PMID- 29611832 TI - The Therapeutic Activity Goal for Acute Postoperative Pain Management. AB - Acute pain intensity has conventionally been assessed with a patient self reported, unidimensional pain scale. This approach can inadvertently underestimate analgesia and result in large cumulative opioid doses and greater dose-dependent side effects and complications. We have thus created the Therapeutic Activity Goal (TAG) as an alternate, more comprehensive way to assess acute postoperative pain, and even more so, to define and determine adequate postoperative analgesia. The TAG comprises the level of acceptable pain intensity, the level and types of desired activities, and accomplishing other patient-centered functional goals. The TAG evolves throughout the patient's hospitalization to promote timely discharge. PMID- 29611833 TI - Quality of low-cost drugs: the frailty of costs savings. PMID- 29611834 TI - Blood pressure targets in the elderly. PMID- 29611835 TI - Essential role for smooth muscle cell stromal interaction molecule-1 in myocardial infarction. AB - OBJECTIVES: Stromal interacting molecule-1 (STIM1) plays a role in coordinating calcium signaling in different cell types. The increase or deletion of STIM1 expression in cardiomyocyte causes cardiac complication. Moreover, the deletion of STIM1 in endothelial cell causes vascular endothelial dysfunction. However, the disruption of STIM1 in smooth muscle cells (SMC) has no effect on endothelial function but protects vascular function when mice are infused with angiotensin II. Nevertheless, the role of SMC-STIM1 in acute and chronic myocardial infarction (MI) induced by acute ischemia-reperfusion injury and permanent coronary artery occlusion is unknown. METHODS AND RESULTS: Stim1 were generated and crossed into the SM22alpha-Cre backgrounds. SM22alpha-Cre causes deletion of STIM1 floxed genes in adult SMC (Stim1). Control and Stim1 mice were subjected to acute ischemia-reperfusion injury. Hearts were then harvested and incubated with triphenyltetrazolium chloride to determine the infarct size. In control mice which are subjected to ischemia-reperfusion, the heart developed a significant infarct associated with an increase in STIM1 expression. Interestingly, the infarct size was substantially reduced in Stim1 mice. The protection in Stim1 mice against ischemia-reperfusion injury involves the modulation of endoplasmic reticulum stress, apoptosis, oxidative stress, protein kinase B, and mitogen activated protein (MAP) kinase (ERK1/2 and p38) signaling, and inflammation. Furthermore, in another model of chronic MI induced by permanent coronary artery occlusion, SMC-STIM1 disruption significantly reduced myocardial infarct size and improved cardiac function. CONCLUSION: Our results provide new evidence that SMC STIM1 disruption is a novel mechanism that protects the heart from MI through reduction of endoplasmic reticulum stress, oxidative stress, MAP-Kinase, apoptosis, and inflammation. PMID- 29611836 TI - Plasma renin activity to plasma aldosterone concentration ratio for the assessment of essential hypertensive patients in real-life clinical practice. PMID- 29611837 TI - Reply. PMID- 29611838 TI - White-coat UnControlled Hypertension, Masked UnControlled Hypertension, and True UnControlled Hypertension, phonetic and mnemonic terms for treated hypertension phenotypes. PMID- 29611839 TI - False reassurance about the consequences of withdrawing antihypertensive drug therapy. PMID- 29611840 TI - Quality of care for patients with diabetes done by family medicine team during the period 2013-2016. AB - Aim To assess whether the quality of diabetes care provided by a family medicine team changed over the course of four years and to identify potential gaps in our practice in order to improve it in the future. Methods An audit was carried out for randomly selected 120 medical records (MC) from the Diabetes Registry of patients with type 1 or 2 diabetes mellitus treated by one family medicine team for four consecutive years, from 2013 to 2016. We examined demographic data (gender, age, diabetes type, family history), annual examinations (glycated haemoglobin, blood glucose, lipid profile, neurological examination, urinalysis, foot care, ocular fundus and body mass index), prescribed insulin or other drugs and patients' education. Results Over the years females dominated with the maximum of 63% in 2013. In most years type 2 diabetes occurred in 93% of patients. The acceptable level of monitoring included examination of ocular fundus, lipid profile or total cholesterol, blood pressure, fasting and postprandial blood glucose with more than 80% annually. A low level of monitoring complications of diabetes was found on monofilament test, 26% in 2016, urinalysis, 20% in 2016 and examination of feet with the maximum of 46% in 2013. Outcome measurement showed satisfactory levels of glycated haemoglobin of 60% in 2014, blood pressure 76% in 2014, fast 56% and postprandial blood glucose of 73% in 2013. Conclusion We still need to find effective interventions that will lead to improvement of care for patients with diabetes in family medicine. PMID- 29611841 TI - Significance of diffusion weighted imaging (DWI) as an improving factor in contrast enhanced magnetic resonance imaging (MRI) enterography in evaluation of patients with Crohn's disease. AB - Aim To determine capabilities and potential of contrast enhanced magnetic resonance imaging (MRI) enterography in order to establish the diagnosis and to evaluate severity and activity of intestinal inflammation. Methods Fifty-five patients with suspicion for presence of Crohn's disease were evaluated. All patients underwent contrast enhanced MRI enterography and diffusion weighted imaging (DWI), and subsequently endoscopic examination or surgical treatment. Four parameters were analysed: thickening of the bowel wall, and presence of abscess, fistula and lymphadenopathy. Results Comparing results of DWI and contrast enhanced MRI enterography a significant difference between results given through diffusion and histopathological test was found, e.g. a significant difference between results obtained through diffusion and MRI enterography was found. MRI enterography sensitiveness for bowel wall thickening was 97.7% and specificity 70%, whilst DWI sensitivity for bowel wall thickening was 84% and specificity 100%. The diagnostics of abscess and fistula showed no significant difference between DWI and MRI, while in lymphadenopathy significant difference between contrast enhanced MRI enterography and DWI was found. Conclusion Contrast enhanced MRI enterography in combination with DWI allows for excellent evaluation of disease activity, but also problems or complications following it. The examination can be repeated, controlled, and it can contribute to monitoring of patients with this disease. PMID- 29611842 TI - An open experimental database for exploring inorganic materials. AB - The use of advanced machine learning algorithms in experimental materials science is limited by the lack of sufficiently large and diverse datasets amenable to data mining. If publicly open, such data resources would also enable materials research by scientists without access to expensive experimental equipment. Here, we report on our progress towards a publicly open High Throughput Experimental Materials (HTEM) Database (htem.nrel.gov). This database currently contains 140,000 sample entries, characterized by structural (100,000), synthetic (80,000), chemical (70,000), and optoelectronic (50,000) properties of inorganic thin film materials, grouped in >4,000 sample entries across >100 materials systems; more than a half of these data are publicly available. This article shows how the HTEM database may enable scientists to explore materials by browsing web-based user interface and an application programming interface. This paper also describes a HTE approach to generating materials data, and discusses the laboratory information management system (LIMS), that underpin HTEM database. Finally, this manuscript illustrates how advanced machine learning algorithms can be adopted to materials science problems using this open data resource. PMID- 29611843 TI - Spatial distribution of arable and abandoned land across former Soviet Union countries. AB - Knowledge of the spatial distribution of agricultural abandonment following the collapse of the Soviet Union is highly uncertain. To help improve this situation, we have developed a new map of arable and abandoned land for 2010 at a 10 arc second resolution. We have fused together existing land cover and land use maps at different temporal and spatial scales for the former Soviet Union (fSU) using a training data set collected from visual interpretation of very high resolution (VHR) imagery. We have also collected an independent validation data set to assess the map accuracy. The overall accuracies of the map by region and country, i.e. Caucasus, Belarus, Kazakhstan, Republic of Moldova, Russian Federation and Ukraine, are 90+/-2%, 84+/-2%, 92+/-1%, 78+/-3%, 95+/-1%, 83+/-2%, respectively. This new product can be used for numerous applications including the modelling of biogeochemical cycles, land-use modelling, the assessment of trade-offs between ecosystem services and land-use potentials (e.g., agricultural production), among others. PMID- 29611844 TI - The natural variance of the Arabidopsis floral secondary metabolites. AB - Application of mass spectrometry-based metabolomics enables the detection of genotype-related natural variance in metabolism. Differences in secondary metabolite composition of flowers of 64 Arabidopsis thaliana (Arabidopsis) natural accessions, representing a considerable portion of the natural variation in this species are presented. The raw metabolomic data of the accessions and reference extracts derived from flavonoid knockout mutants have been deposited in the MetaboLights database. Additionally, summary tables of floral secondary metabolite data are presented in this article to enable efficient re-use of the dataset either in metabolomics cross-study comparisons or correlation-based integrative analysis of other metabolomic and phenotypic features such as transcripts, proteins and growth and flowering related phenotypes. PMID- 29611845 TI - Dual Radial Styloid and Volar Plating for Unstable Fractures of the Distal Radius. AB - As the operative management of displaced distal radius fractures evolves, intraoperative techniques and fixation strategies evolve as well. Achieving and maintaining an acceptable reduction is paramount but can be difficult with particular fracture patterns. In this article, we describe the use of a radial column plate as a reduction tool in the management of unstable distal radius fractures, along with clinical and radiographic clinical outcomes. This technique can be useful in situations where multiplanar instability exists, or simply when intraoperative assistance is limited. Surgeons can expect acceptable radiographic and clinical outcomes when using this technique, although effects on scar formation and wrist range of motion are currently not known. PMID- 29611846 TI - Implant Survivorship and Complication Rates After Total Knee Arthroplasty With a Third-Generation Cemented System: 15-Year Follow-Up. AB - This work is a retrospective cohort study evaluating patients who had undergone third-generation cemented total knee arthroplasty (TKA) with prostheses (NexGen, Zimmer Biomet) utilizing posterior-stabilized (PS) and cruciate-retaining (CR) designs at a single center at their 15-year follow-up. The purpose of this study is to determine the functional knee scores, reoperations, and long-term survivorship for patients with the NexGen Zimmer Biomet Knee system at the 15 year follow-up. In total, 99 patients who had undergone primary TKA were followed for 15 years. At the 15-year follow-up, survivorship in both study groups was similar: 98% for PS TKAs and 100% for CR TKAs. The 2 groups also showed similar functionality: 80% of the PS implants and 89% of the CR implants were associated with no or mild pain (P = .40). Reoperation rates were 2% for the PS group and 0% for the CR group (P = .38). No differences in any of the outcomes analyzed were observed between patients who had CR TKA and those who had undergone PS TKA. Our study found no significant differences in functional outcomes between PS and CR NexGen knee implants. Patients treated by both methods showed excellent longevity and survivorship at the 15-year follow-up. PMID- 29611847 TI - The Prevention and Treatment of Femoral Trial Head Loss in Total Hip Arthroplasty. AB - This article aims to provide the information necessary to prevent femoral trial head loss and to offer information regarding retrieval of the trial head if it is lost within the surgical field. These techniques can be used to help guide practice in the future. A review of the literature was conducted using a computerized search of PubMed in regard to this issue to investigate how such an occurrence can be prevented and what steps can be taken if preventative measures fail. PMID- 29611848 TI - Special Considerations for Pediatric Patellar Instability. AB - Patellar instability in children and adolescents is a challenging subset to treat. Varied forms of instability, ranging from episodic dislocation to fixed dislocation, have been recognized. It is of utmost importance for the treating physician to recognize these different patterns of instability and their associated risk factors, as more complex patterns of instability would require more extensive surgical procedures. Medial patellofemoral ligament (MPFL) reconstruction, by itself, may not suffice or may not be appropriate for the more complex instability patterns. Appropriate and early treatment of such instability in children would allow for functional progression and possible remodeling of the trochlea. However, early treatment has the associated risk of growth disturbances when surgical procedures are performed around open physis or if adult-type bony procedures are performed in children. Recent knowledge about the relationship between trochlea, MPFL femoral attachment, and distal femoral physis could help to advance safe surgical care for these patients. This article reviews the pathophysiology, risk factors, and the existing classification systems for patellar instability in children and adolescents. It focuses on varied surgical techniques, which are unique to the pediatric population, and summarizes the outcomes of these surgical techniques. PMID- 29611849 TI - Glenoid Bone Loss in Reverse Shoulder Arthroplasty Treated with Bone Graft Techniques. AB - The reverse shoulder arthroplasty facilitates surgical treatment of primary and revision shoulder with rotator cuff and bone deficiencies. Wear pattern classifications and a logical treatment approach for glenoid bone loss enable the surgeon to address a difficult series of problems in the reconstructions where the glenoid might not otherwise be able to support the implants. Bone grafting using the native humeral head in primary cases, and in revision cases, iliac crest are the most reliable sources for structural grafts for the worn or deficient glenoid vault. PMID- 29611850 TI - Prevalence and Impact of Self-Citation in Academic Orthopedic Surgery. AB - The h-index is a commonly utilized metric for academic productivity. Previous studies have proposed that self-citation may limit the utility of the h-index. The purpose of this study is to evaluate the impact of self-citation on the h index among orthopedic investigators. The study cohort consisted of program directors, chairpersons, and faculty at orthopedic surgery residency programs in the United States. The Scopus database was used to determine the h-index and number of citations +/- self-citations. The total number of publications was correlated with the change in the h-index via self-citation. A total of 463 researchers were included (198 National Institutes of Health-funded faculty, 147 chairpersons, 118 program directors). Of these researchers, 83.8% cited previous work at least once (mean, 123.9 +/- 277.6). Self-citations accounted for 5.8% of all citations. Including these citations increased the author h-index from 18.5 +/- 14.9 to 19.2 +/- 15.6 (P < .001). A minority of researchers (36.3%, P < .001) had increased their h-index via self-citation (range, 0-11). The proportional increase in the h-index via self-citation was positively related to the number of publications (P < .001). While the practice of self-citation is prevalent in orthopedics, its impact on the h-index is minimal for most researchers. With more publications, researchers can increase their h-index to a greater degree via self citation. PMID- 29611851 TI - Managing Glenoid Bone Deficiency-The Augment Experience in Anatomic and Reverse Shoulder Arthroplasty. AB - Glenoid bone deficiency in the setting of shoulder replacement surgery is far more common than originally reported. The frequency and severity of the glenoid defects are noted to be more common and severe with the advent of computer assisted surgery. The results of an anatomic total shoulder arthroplasty (aTSA) with glenoid deficiency have been reported to be inferior to aTSA patients without a glenoid deficiency. Options for treating the glenoid deficiency include eccentric reaming, bone grafting, and the use of augmented glenoid components. The purpose of this article is to present the indications, technique, and results of augmented glenoids for both aTSA and reverse TSA (RTSA). Augments for both aTSA and RTSA are viable options. They preserve subchondral bone at the same time as optimizing the joint line without the need for bone grafts. Complications, revisions and results are as good as compared to shoulder arthroplasties without glenoid wear. PMID- 29611853 TI - Stoichiometrically controlled chirality inversion in zinc bisporphyrinate monoamine complexes. AB - We have designed and synthesized a novel amide-linked bisporphyrin with a 2 naphthalenecarboxamide substituent on the linker. The chirality sensing ability of this zinc porphyrinate towards chiral monoamines has been examined. Circular dichroism studies indicate chirality transfer from chiral monoamines to the corresponding host-guest complexes. Interestingly, when optically pure 1-(1 naphthyl)ethylamine is used as a guest, stoichiometrically controlled chirality inversion occurs in the formation of the corresponding zinc bisporphyrinate monoamine complexes. Both CD and NMR spectra indicate that 1 : 1 and 1 : 2 complexes are formed in solution. DFT calculations suggest that steric interactions between the substituent of the linker and the guest in the 1 : 2 complex are responsible for this unprecedented observation. Our studies provide a unique bisporphyrin system for demonstrating that chirality transfer to the host can be tuned by changing the substituent of the linker. PMID- 29611852 TI - Studies of black silicon and black diamond as materials for antibacterial surfaces. AB - 'Black silicon' (bSi) samples with surfaces covered in nanoneedles of varying length, areal density and sharpness, have been fabricated using a plasma etching process. These nanostructures were then coated with a conformal uniform layer of diamond using hot filament chemical vapour deposition to produce 'black diamond' (bD) surfaces. The effectiveness of these bSi and bD surfaces in killing Gram negative (E. coli) and Gram-positive (S. gordonii) bacteria was investigated by culturing the bacteria on the surfaces for a set time and then measuring the live to-dead ratio. All the nanostructured surfaces killed E. coli at a significantly higher rate than the respective flat Si or diamond control samples. The length of the needles was found to be less important than their separation, i.e. areal density. This is consistent with a model for mechanical bacteria death based on the stretching and disruption of the cell membrane, enhanced by the cells motility on the surfaces. In contrast, S. gordonii were unaffected by the nanostructured surfaces, possibly due to their smaller size, thicker cell membrane and/or their lack of motility. PMID- 29611854 TI - Failure mechanisms of 2D silicon film anodes: in situ observations and simulations on crack evolution. AB - An in situ optical system was used to observe the failure processes of two dimensional silicon film anodes, suggesting a new debonding mode based on crack crushing. The stress evolution upon lithiation was quantitatively analyzed via fully coupled finite element simulations, confirming the crack crushing induced failure mechanisms in 2D silicon anodes. PMID- 29611855 TI - Direct oxidative C-H alkynylation of N-carbamoyl tetrahydroisoquinolines and dihydroisoquinolines. AB - An efficient oxidative C-H alkynylation of N-carbamoyl tetrahydroisoquinolines mediated by a TEMPO oxoammonium salt has been established. A variety of electronically varied N-carbamoyl tetrahydroisoquinolines reacted with a range of alkynyl potassium trifluoroborates smoothly under mild metal-free conditions. Dihydroisoquinolines were also suitable components for the reaction. The synthetic applicability of the method for facile access to structurally diverse bioactive molecules was further demonstrated. PMID- 29611856 TI - On the ozonolysis of unsaturated tosylhydrazones as a direct approach to diazocarbonyl compounds. AB - The scope and limitations are described of reacting unsaturated tosylhydrazones with O3 followed by Et3N for the generation of 1,4- and 1,5-diazocarbonyl systems. Tosylhydrazones, from tosylhydrazide condensation with readily available delta- and epsilon-unsaturated alpha-ketoesters, led in the former case to a 2 pyrazoline whereas the latter cases led to alpha-diazo-epsilon-ketoesters, although a terminal alkene produced a tetrahydropyridazinol. Using the ozonolysis Et3N strategy, tosylhydrazones from cyclic enones give 2,5- and 2,6-diazoketones with aldehyde or ester functionality at the 1-position; the alpha-diazoaldehydes prefer the s-trans conformation, with a rotation barrier of 74 kJ mol-1 at 25 degrees C determined by NMR. This one-pot ozonolysis/Bamford-Stevens chemistry demonstrates both the tolerance of tosylhydrazones to ozone, and the subsequently added amine playing a dual role to directly transform the intermediate tosylhydrazone ozonides into products containing reactive diazo and ketone functionalities; such adducts are of particular value as precursors to cyclic carbonyl ylides for 1,3-dipolar cycloadditions. PMID- 29611857 TI - Carbonylative coupling of N-chloroamines with alcohols: synthesis of esterification reagents. AB - Herein we report a new method for the carbonylative synthesis of carbamates. Starting from N-chloroamines and alcohols, with copper or Pd/C as the catalyst, the corresponding carbamates were produced in moderate to good yields. No additional oxidant or base is needed in this system. Notably, the produced benzotriazole-carboxylates can be used as esterification reagents. PMID- 29611858 TI - Multimetallic nanosheets: synthesis and applications in fuel cells. AB - Two-dimensional nanomaterials, particularly multimetallic nanosheets with single or few atoms thickness, are attracting extensive research attention because they display remarkable advantages over their bulk counterparts, including high electron mobility, unsaturated surface coordination, a high aspect ratio, and distinctive physical, chemical, and electronic properties. In particular, their ultrathin thickness endows them with ultrahigh specific surface areas and a relatively high surface energy, making them highly favorable for surface active applications; for example, they have great potential for a broad range of fuel cell applications. First, the state-of-the-art research on the synthesis of nanosheets with a controlled size, thickness, shape, and composition is described and special emphasis is placed on the rational design of multimetallic nanosheets. Then, a correlation is performed with the performance of multimetallic nanosheets with modified and improved electrochemical properties and high stability, including for the oxygen reduction reaction (ORR), hydrogen evolution reaction (HER), formic acid oxidation (FAO), methanol oxidation reaction (MOR), ethanol oxidation reaction (EOR), and methanol tolerance are outlined. Finally, some perspectives and advantages offered by this class of materials are highlighted for the development of highly efficient fuel cell electrocatalysts, featuring low cost, enhanced performance, and high stability, which are the key factors for accelerating the commercialization of future promising fuel cells. PMID- 29611859 TI - Precise tuning of single molecule conductance in an electrochemical environment. AB - Tuning of molecular conductance in a liquid environment is a hot topic in molecular electronics. In this article, we explore a new concept where the Fermi level positions of the metallic ends are varied simply by modifying the electroactive salt concentration in solution. We rely on the electrochemical scanning tunneling microscope break junction method that allows the construction in solution of copper atomic contacts that can be then bridged by single molecules. The experimental conductance evolution is first confronted with an analytical formulation that allows the deduction of the molecule's LUMO position and electronic coupling factors. These parameters are in close agreement with those obtained by independent DFT calculations. PMID- 29611860 TI - Highly efficient hydroboration of carbonyl compounds catalyzed by tris(methylcyclopentadienyl)lanthanide complexes. AB - Homoleptic lanthanide complexes coordinated by a Me-substituted Cp ligand [(MeCp)3Ln] demonstrate unprecedentedly high efficiency in catalyzing the hydroboration of aldehydes and ketones with pinacolborane. This protocol is also applicable for the hydroboration of aryl-substituted imines. In addition, broad functional group compatibility and excellent chemoselectivity is also achieved. DFT calculations are employed to shed light on the reaction mechanism. PMID- 29611861 TI - Wearable and flexible electronics for continuous molecular monitoring. AB - Wearable biosensors have received tremendous attention over the past decade owing to their great potential in predictive analytics and treatment toward personalized medicine. Flexible electronics could serve as an ideal platform for personalized wearable devices because of their unique properties such as light weight, low cost, high flexibility and great conformability. Unlike most reported flexible sensors that mainly track physical activities and vital signs, the new generation of wearable and flexible chemical sensors enables real-time, continuous and fast detection of accessible biomarkers from the human body, and allows for the collection of large-scale information about the individual's dynamic health status at the molecular level. In this article, we review and highlight recent advances in wearable and flexible sensors toward continuous and non-invasive molecular analysis in sweat, tears, saliva, interstitial fluid, blood, wound exudate as well as exhaled breath. The flexible platforms, sensing mechanisms, and device and system configurations employed for continuous monitoring are summarized. We also discuss the key challenges and opportunities of the wearable and flexible chemical sensors that lie ahead. PMID- 29611862 TI - Accessing benzooxadiazepines via formal [4 + 3] cycloadditions of aza-o-quinone methides with nitrones. AB - An unprecedented and efficient [4 + 3] cycloaddition of N-(ortho chloromethyl)aryl amides with nitrones has been developed. This approach provides easy access to a series of seven-membered benzooxadiazepine derivatives in good to excellent yields (up to 99% yield) under mild reaction conditions. PMID- 29611863 TI - [When and how to step down asthma treatment]. AB - Swedish asthma guidelines recommend treating asthma with the lowest effective dose possible. These recommendations are both hard to follow and seldom considered enough in asthma care today. As an example, combination therapy with inhaled corticosteroids (ICS) and long acting beta agonists (LABA) should only be considered if asthma control is not achieved with low to medium dose ICS daily. However, the Swedish National Board of Health and Welfare estimates that 120 000 asthma patients are overmedicated with combination therapy. Guidelines are clear in instructions of when and how to step up asthma treatment, while instructions for stepping down are not that obvious. In this article, we present an asthma treatment algorithm for step 1-3 in adults for use in clinical practice (Fig. 1), where stepping down asthma treatment is considered as an alternative. Included are also instructions of how to step down asthma treatment (Fig. 2). We conclude that stepping down is possible to do in a safe way in certain patient groups while maintaining asthma control. If possible risks are taken into consideration, stepping down asthma treatment can be done in every clinical setting. PMID- 29611864 TI - ? PMID- 29611865 TI - Patient experience in primary care: association with patient, physician and practice characteristics in a fee-for-service system. AB - INTRODUCTION: Nowadays we typically use patient experience as a quality of care indicator, although this has some limitations. The aim of this study was to investigate to what extent patient, physician and practice characteristics were associated with patient-reported experience of care in the major dimensions in family medicine in a fee-for-service system. METHODS: The data came from the Swiss part of the Quality and Costs of Primary Care (QUALICOPC) study, an international cross-sectional survey. A random sample of 194 Swiss family physicians and 1540 of their patients were included in this analysis. We assessed patient experience using three scores characterising access, communication and continuity-coordination. Multilevel statistical methods were used to analyse these scores based on patient-level, physician-level and practice-level factors. RESULTS: Poor experience of access was associated with poor health (incidence rate ratio [IRR] 1.91, 95% confidence interval [CI] 1.54-2.55) but was lower among older patients (IRR 0.75, 95% CI 0.63-0.88). Experience of access was also reported as poorer in urban areas and in practices including other paramedical professionals (besides medical assistants) (IRR 1.27, 95% CI 1.06-1.51). Communication was reported as poorer in practices where physicians achieve greater daily face-to-face consultations (IRR 1.16, 95% CI 1.08-1.25) and in patients reporting higher incomes (IRR 1.24, 95% CI 1.01-1.52). Additionally, younger patients reported poorer continuity-coordination experience. In the continuity-coordination domain, patient experience appeared better in group practices (including other family physicians) and in those of physicians with a greater weekly workload in terms of hours. Finally, we found experience of communication and continuity better in the French-speaking area than German speaking area of Switzerland. CONCLUSIONS: In this study, we found that patient experience in family medicine in Switzerland was very good for all domains studied; access, family physician-patient communication and continuity coordination of care. Most often, predictive factors of care experience relate to the patient's characteristics, such as age and health status. However, several practice characteristics such as size, composition and functioning (in particular, time spent with the patient) represent potential levers for improving patient-reported experience. The variations observed between the three linguistic areas in Switzerland are also interesting, since they raise the issue of the role of sociocultural factors in this field. PMID- 29611866 TI - Gamma knife radiosurgery for arteriovenous malformations: general principles and preliminary results in a Swiss cohort. AB - INTRODUCTION: Arteriovenous malformations (AVMs) are a type of vascular malformation characterised by an abnormal connection between arteries and veins, bypassing the capillary system. This absence of capillaries generates an elevated pressure (hyperdebit), in both the AVM and the venous drainage, increasing the risk of rupture. Management modalities are: observation, microsurgical clipping, endovascular treatment and radiosurgery. The former can be used alone or in the frame of a multidisciplinary approach. We review our single-institution experience with gamma knife radiosurgery (GKR) over a period of 5 years. MATERIALS AND METHODS: The study was open-label, prospective and nonrandomised. Fifty-seven consecutive patients, benefitting from 64 GKR treatments, were included. All were treated with Leksell Gamma Knife Perfexion (Elekta Instruments, AB, Sweden) between July 2010 and August 2015. All underwent stereotactic multimodal imaging: standard digital subtraction angiography, magnetic resonance imaging and computed tomography angiography. We report obliteration rates, radiation-induced complications and haemorrhages during follow-up course. RESULTS: The mean age was 46 years (range 13-79 years). The mean follow-up period was 36.4 months (median 38, range 12-75 months). Most common pretherapeutic clinical presentation was haemorrhage (50%). The most common Pollock-Flickinger score was between 1.01 and 1.5 (46%) and Spetzler Martin grade III (46%). In 39 (60.1%) of cases, GKR was performed as upfront therapeutic option. The mean gross target volume (GTV) was 2.3 ml (median 1.2, range 0.03-11.3 ml). Mean marginal dose was 22.4 Gy (median 24, range 18-24 Gy). The mean prescription isodose volume (PIV) was 2.9 ml (median 1.8, range 0.065 14.6 ml). The overall obliteration rates (all treatments combined) at 12, 24, 36, 48 and 60 months were 4.8, 16.9%, 37.4, 63.6 and 78.4%, respectively. The main predictive factors for complete obliteration were: higher mean marginal dose (23.3 vs 21.0 Gy), lower GTV (mean 1.5 vs 3.5 ml) and absence of previous embolisation (at 60 months 61.8% prior embolisation compared with 82.4% without prior embolisation) (for all p <0.05). Eight (14%) patients experienced complications after GKR. Overall definitive morbidity rate was 3.1%. No patient died from causes related to GKR. However, during the obliteration period, one case of extremely rare fatal haemorrhage occurred. CONCLUSION: Radiosurgery is a safe and effective treatment modality for intracranial AVMs in selected cases. It can be used as upfront therapy or in the frame of a combined management. Obliteration rates are high, with minimal morbidity. The treatment effect is progressive and subsequent and regular clinical and radiological follow-up is needed to evaluate this effect. PMID- 29611867 TI - Maternal Behavior and Socioeconomic Status Predict Longitudinal Changes in Error Related Negativity in Preschoolers. AB - The development self-regulation has been called a primary task of childhood. One system of self-regulation, self-monitoring, is indexed at the level of neural activity as early as preschool as the error-related negativity (ERN). However, how context elicits developmental changes in neural processes of self-monitoring like the ERN is not well understood. Here, socioeconomic status (SES) and parenting were tested as environmental influences on ERN development between ages 3 and 4 (N = 119). Results showed the expected increases in ERN between ages 3 and 4 only when both maternal sensitivity and SES were high. This work demonstrates the importance of considering the early environment in order to understand the development of a neural process supporting self-regulation in young children. PMID- 29611868 TI - Health-related quality of life and peer relationships in adolescents with developmental coordination disorder and attention-deficit-hyperactivity disorder. AB - AIM: Health-related quality of life (HRQoL) and peer relationships were investigated in adolescents with developmental coordination disorder (DCD) and attention-deficit-hyperactivity disorder (ADHD). METHOD: Adolescents with DCD (n=9), ADHD (n=9), DCD and ADHD (n=10), and typically developing adolescents (n=16) completed the following questionnaires: KIDSCREEN-52 Health-Related Quality of Life Questionnaire and Peer Relations Questionnaire for Children. Twenty-five participants took part in semi-structured interviews. RESULTS: Adolescents with DCD and ADHD had lower HRQoL on the mood and emotions, school environment, and financial resources scales of the KIDSCREEN-52 than adolescents in the DCD and typically developing groups (all p<0.05). On the Peer Relations Questionnaire for Children, the DCD and ADHD group reported significantly higher victimization compared with those in the typically developing (p=0.030) and DCD (p=0.010) groups. Qualitative interviews among young people with DCD and ADHD revealed feelings of marginalization and victimization. Descriptors such as 'misfits', 'oddballs', 'weird', and 'the rejects' were used to describe themselves. INTERPRETATION: HRQoL and peer relationships are negatively affected in adolescents with DCD and ADHD. WHAT THIS PAPER ADDS?: Children with developmental coordination disorder (DCD) do not display poorer overall health related quality of life (HRQoL) versus typically developing controls. Having DCD and attention-deficit-hyperactivity disorder (ADHD) was associated with poorer HRQoL. Adolescents with DCD and ADHD experience significantly higher levels of peer victimization than typically developing adolescents. HRQoL and peer relationships are significantly associated in adolescent respondents. PMID- 29611869 TI - Contracting out to improve the use of clinical health services and health outcomes in low- and middle-income countries. AB - BACKGROUND: Contracting out of governmental health services is a financing strategy that governs the way in which public sector funds are used to have services delivered by non-governmental health service providers (NGPs). It represents a contract between the government and an NGP, detailing the mechanisms and conditions by which the latter should provide health care on behalf of the government. Contracting out is intended to improve the delivery and use of healthcare services. This Review updates a Cochrane Review first published in 2009. OBJECTIVES: To assess effects of contracting out governmental clinical health services to non-governmental service provider/s, on (i) utilisation of clinical health services; (ii) improvement in population health outcomes; (iii) improvement in equity of utilisation of these services; (iv) costs and cost effectiveness of delivering the services; and (v) improvement in health systems performance. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, NHS Economic Evaluation Database, EconLit, ProQuest, and Global Health on 07 April 2017, along with two trials registers - ClinicalTrials.gov and the International Clinical Trials Registry Platform - on 17 November 2017. SELECTION CRITERIA: Individually randomised and cluster-randomised trials, controlled before-after studies, interrupted time series, and repeated measures studies, comparing government delivered clinical health services versus those contracted out to NGPs, or comparing different models of non-governmental-delivered clinical health services. DATA COLLECTION AND ANALYSIS: Two authors independently screened all records, extracted data from the included studies and assessed the risk of bias. We calculated the net effect for all outcomes. A positive value favours the intervention whilst a negative value favours the control. Effect estimates are presented with 95% confidence intervals. We used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the certainty of the evidence and we prepared a Summary of Findings table. MAIN RESULTS: We included two studies, a cluster-randomised trial conducted in Cambodia, and a controlled before-after study conducted in Guatemala. Both studies reported that contracting out over 12 months probably makes little or no difference in (i) immunisation uptake of children 12 to 24 months old (moderate-certainty evidence), (ii) the number of women who had more than two antenatal care visits (moderate-certainty evidence), and (iii) female use of contraceptives (moderate certainty evidence).The Cambodia trial reported that contracting out may make little or no difference in the mortality over 12 months of children younger than one year of age (net effect = -4.3%, intervention effect P = 0.36, clustered standard error (SE) = 3.0%; low-certainty evidence), nor to the incidence of childhood diarrhoea (net effect = -16.2%, intervention effect P = 0.07, clustered SE = 19.0%; low-certainty evidence). The Cambodia study found that contracting out probably reduces individual out-of-pocket spending over 12 months on curative care (net effect = $ -19.25 (2003 USD), intervention effect P = 0.01, clustered SE = $ 5.12; moderate-certainty evidence). The included studies did not report equity in the use of clinical health services and in adverse effects. AUTHORS' CONCLUSIONS: This update confirms the findings of the original review. Contracting out probably reduces individual out-of-pocket spending on curative care (moderate-certainty evidence), but probably makes little or no difference in other health utilisation or service delivery outcomes (moderate- to low-certainty evidence). Therefore, contracting out programmes may be no better or worse than government-provided services, although additional rigorously designed studies may change this result. The literature provides many examples of contracting out programmes, which implies that this is a feasible response when governments fail to provide good clinical health care. Future contracting out programmes should be framed within a rigorous study design to allow valid and reliable measures of their effects. Such studies should include qualitative research that assesses the views of programme implementers and beneficiaries, and records implementation mechanisms. This approach may reveal enablers for, and barriers to, successful implementation of such programmes. PMID- 29611870 TI - Initial severity of major depression and efficacy of new generation antidepressants: individual participant data meta-analysis. AB - OBJECTIVE: The role of baseline severity as effect modifier in various psychiatric disorders is a topic of controversy and of clinical import. This study aims to examine whether baseline severity modifies the efficacy of various antidepressants for major depression through individual participant data (IPD) meta-analysis. METHOD: We identified all placebo-controlled, double-blind randomised trials of new generation antidepressants in the acute phase treatment of major depression conducted in Japan and requested their IPD through the public private partnerships (PPPs) between the relevant academic societies and the pharmaceutical companies. The effect modification by baseline depression severity was examined through six increasingly complex competing mixed-effects models for repeated measures. RESULTS: We identified eleven eligible trials and obtained IPD from six, which compared duloxetine, escitalopram, mirtazapine, paroxetine or bupropion against placebo (total n = 2464). The best-fitting model revealed that the interaction between baseline severity and treatment was not statistically significant (coefficient = -0.04, 95% confidence interval: -0.16 to 0.08, P = 0.49). Several sensitivity analyses confirmed the robustness of the findings. CONCLUSION: We may expect as much benefit from antidepressant treatments for mild, moderate or severe major depression. Clinical practice guidelines will need to take these findings into consideration. PMID- 29611871 TI - SIP1 participates in regulation of flowering time in rice by recruiting OsTrx1 to Ehd1. AB - Flowering time (heading date) in rice (Oryza sativa) is an important agronomic trait that determines yield. The levels of histone H3 lysine 4 trimethylation (H3K4me3) modulated by TRITHORAX-like proteins regulate gene transcription, flowering time and environmental stress responses. However, plant TRITHORAX-like proteins have no known DNA-binding domain, and therefore the mechanism that gives sequence specificity to these proteins remains unclear. Here, we show that the rice TRITHORAX-like protein OsTrx1 is recruited to its target, Early heading date 1 (Ehd1), by the C2H2 zinc finger protein SDG723/OsTrx1/OsSET33 Interaction Protein 1 (SIP1). SIP1 binds to the promoter of Ehd1 and interacts with OsTrx1. Mutations in SIP1 led to a late heading date under long-day and short-day conditions. Defects in OsTrx1 or SIP1 led to reduced H3K4me3 levels at Ehd1, thus reducing Ehd1 expression. Together, our results show that the transcription factor SIP1 interacts with OxTrx1, allowing OsTrx1 to specifically target Ehd1, altering H3K4me3 levels, increasing Ehd1 expression and thereby promoting flowering. PMID- 29611872 TI - The Dresden Burnout Study: Protocol of a prospective cohort study for the bio psychological investigation of burnout. AB - OBJECTIVES: The Dresden Burnout Study (DBS) is a 12-year longitudinal cohort study that aims to provide a description of the burnout syndrome on the basis of time and symptom criteria with a special focus on the search for biomarkers. Biological and psychosocial approaches are applied to examine the long-term course and consequences of burnout within a population-based German-speaking sample aged 18 to 68 years. METHODS: Demographics and psychosocial data are generated by online assessments, including demographics and questionnaires on burnout, burnout-related constructs, work-environment, and health-related factors. The lab-based biomarker assessment includes endocrine, physiological, immunological, and epigenetic markers obtained from blood and hair samples. In addition, heart rate variability is also measured repeatedly. Within the first 2 years, the DBS collected psychosocial data from over 7,600 participants with biological data obtained from more than 800 individuals. During the following 10 years, detailed assessments of biomarkers and psychosocial factors will be collected in annual study waves. RESULTS: Results will be generated during the following decade. CONCLUSION: The findings of the DBS are expected to pave the road for an in-depth biopsychosocial characterization of burnout and to give insight into the long-term course and potential mental and physical health consequences of the burnout syndrome. PMID- 29611873 TI - The role of IDO, IL-10, and TGF-beta in the HCV-associated chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. AB - Indoleamine-2,3-dioxygenase (IDO) is an enzyme that catalyzes tryptophan to kynurenine and studies have revealed that IDO play a vital role in regulation of liver immunity and inflammation activities. This study investigated the association between plasma IDO and disease severity and the possible marker role of IDO in the inflammatory process of hepatitis C. In this study, 80 individuals with HCV infection were retrospectively selected. Plasma levels of IDO, IL-10, and TGF-beta were assayed by ELISA. Clinical characteristics of patients, including the levels of ALT, AST, and total bilirubin (TBil) were collected from clinical databases. HCV-related liver cirrhosis (HC-Cirr) and HCV-related Hepatocellular carcinoma (HCV-HCC) had significantly high plasma levels of IDO compared to other patient groups and healthy controls. Plasma IL-10 level were significantly greater in all chronic liver disease groups and with respect to TGF beta, the level was high in all the selected patients with HCV infection compare with controls. Moreover, HCV-HCC patients showed highest values for both IL-10 and TGF-beta, with significant difference compared with other groups. In addition, plasma IDO was positively correlated with TGF-beta among all patients with HCV infection (r = 0.4509, P < 0.0001), with IL-10 in CHC patients (r = 0.4787, P = 0.0047), with TBil in HCV-Cirr patients (r = 0.4671; P = 0.0093). High level of IDO and TGF-beta is associated with hepatocyte necrosis and intrahepatic inflammation, and may be used as an index of disease progression for patients with chronic HCV infection. PMID- 29611874 TI - Intra- and Interindividual Variability in the Behavioral, Affective, and Perceptual Effects of Alcohol Consumption in a Social Context. AB - BACKGROUND: We examined the influence of interindividual differences in alcohol use on the intraindividual associations of drinking occurrence with interpersonal behaviors, affect, and perceptions of others during naturally occurring social interactions. METHODS: For 14 consecutive days, 219 psychology freshmen (55% female; Mage = 20.7 years, SD = 2.18) recorded their behaviors, affect, and perceptions in social interactions soon after an interpersonal event occurred. Interpersonal behaviors and perceptions were assessed in terms of dominance submissiveness and agreeableness-quarrelsomeness. Participants also reported the number of alcoholic drinks consumed within 3 hours of each interaction. We considered the intraindividual associations of (i) having a drinking episode and (ii) the number of drinks during an episode with behaviors, affect, and perceptions and examined interindividual differences in drinking frequency and intensity during social interactions as potential moderators of these associations. RESULTS: Social drinking frequency and intensity moderated the associations between drinking episode and behaviors, affect, and perceptions in social interactions. During a drinking episode, more frequent social drinkers perceived others as more dominant than less frequent social drinkers. During a drinking episode in which more alcohol was consumed than usual, more frequent social drinkers also reported behaving more dominantly and experiencing less pleasant affect. CONCLUSIONS: As more frequent social drinkers had different interpersonal responses to drinking than less frequent social drinkers, including when they had consumed larger amounts of alcohol than usual, our results suggest a differential susceptibility to the effects of alcohol during naturally occurring social interactions among drinkers with varying drinking frequency. PMID- 29611875 TI - A molecular framework to study periderm formation in Arabidopsis. AB - During secondary growth in most eudicots and gymnosperms, the periderm replaces the epidermis as the frontier tissue protecting the vasculature from biotic and abiotic stresses. Despite its importance, the mechanisms underlying periderm establishment and formation are largely unknown. The herbaceous Arabidopsis thaliana undergoes secondary growth, including periderm formation in the root and hypocotyl. Thus, we focused on these two organs to establish a framework to study periderm development in a model organism. We identified a set of characteristic developmental stages describing periderm growth from the first cell division in the pericycle to the shedding of the cortex and epidermis. We highlight that two independent mechanisms are involved in the loosening of the outer tissues as the endodermis undergoes programmed cell death, whereas the epidermis and the cortex are abscised. Moreover, the phellem of Arabidopsis, as in trees, is suberized, lignified and peels off. In addition, putative regulators from oak and potato are also expressed in the Arabidopsis periderm. Collectively, the periderm of Arabidopsis shares many characteristics/features of woody and tuberous periderms, rendering Arabidopsis thaliana an attractive model for cork biology. PMID- 29611876 TI - Screening for oropharyngeal dysphagia in older adults: A systematic review of self-reported questionnaires. AB - BACKGROUND: Oropharyngeal dysphagia is a swallowing disorder with signs and symptoms which may be present in older adults, but they are rarely noticed as a health concern by older people. The earliest possible identification of this clinical condition is needed by self-reported population-based screening questionnaire, which are valid and reliable for preventing risks to nutritional status, increased morbidity and mortality. OBJECTIVE: The aim of this systematic review was to identify self-reported screening questionnaires for oropharyngeal dysphagia in older adults to evaluate their methodological quality for population based studies. METHODS: An extensive search of electronic databases (PubMed (MEDLINE), Ovid MEDLINE(R), Scopus, Cochrane Library, CINAHL, Web of Science (WOS), PsycINFO (APA), Lilacs and Scielo) was conducted in the period from April to May 2017 using previously established search strategies by the two evaluators. The methodological quality and the psychometric properties of the included studies were evaluated by the COSMIN (Consensus based Standards for the selection of health Measurement Instruments) checklist and the quality criteria of Terwee and colleagues, respectively. RESULTS: The analysed information was extracted from three articles which had conducted studies on the prevalence of oropharyngeal dysphagia by self-reported screening questionnaires, showing poor methodological quality and flaws in the methodological description to demonstrate its psychometric properties. CONCLUSION: This study did not find any self reported screening questionnaires for oropharyngeal dysphagia with suitable methodological quality and appropriate evidence in its psychometric properties for elders. Therefore, the self-reported questionnaires within the diagnostic proposal require greater details in its process for obtaining valid and reliable evidence. PMID- 29611878 TI - Prospective Assessment of Peristomal Infections Using Objective Criteria. AB - BACKGROUND: Enteral nutrition (EN) is a safe and cost-effective intervention with significant morbidity and mortality benefit that can also be associated with complications. Peristomal infections can occur in 5%-30% of cases after percutaneous endoscopic gastrostomy placement. Despite this common occurrence, widespread use of objective diagnostic criteria is not prevalent, possibly leading to overuse of antibiotics. METHODS: All patients who were reporting symptoms consistent with peristomal infection were evaluated. Criteria based on erythema, induration, and exudates were applied with cumulative score >=8 indicating peristomal infection. All patients were followed, with additional factors being collected if available. RESULTS: Forty-three patients noted complaints consistent with peristomal infection. In patients with a score <8 (n = 16), only 2 required antibiotics (12.5%) and 1 patient was hospitalized (6.3%). In patients with a score >=8 (n = 27), 16 had a score of 8 or 9; all patients responded to antibiotics (100%), and 1 was hospitalized (6.3%). In patients with a score >=10, all (100%) were treated with antibiotics. Five of 11 (45%) patients were hospitalized, with the most common diagnosis being sepsis. Of the baseline variables analyzed, higher body mass index correlated with score >=10 (26.36 +/- 2.94 vs 22.91 +/- 4.35 in score <9, P = .0128). CONCLUSIONS: Objective criteria were effective in risk stratifying patients who presented with reports of peristomal infection. Patients with a score <8 tended to be at low risk, scores of 8-9 were of moderate risk, and patients with a score >=10 were at high risk and required very close monitoring or hospitalization. PMID- 29611877 TI - Kinetics Are Crucial When Targeting Copper Ions to Fight Alzheimer's Disease: An Illustration with Azamacrocyclic Ligands. AB - Targeting copper ions to either remove or redistribute them is currently viewed as a possible therapeutic strategy in the context of Alzheimer's disease (AD). Thermodynamic parameters, as for instance the copper(II) affinity of the drug candidate or the copper(II) over zinc(II) selectivity, are considered in the design of the drug candidate. In contrast, kinetic factors have been overlooked despite their probable high importance. In the present article, we use a series of azamacrocyclic ligands to demonstrate that kinetic issues must be taken into account when designing copper-targeting drug candidates in the context of AD. PMID- 29611879 TI - Changes in the total knee joint moment in patients with medial compartment knee osteoarthritis over 5 years. AB - Progression of medial compartment knee osteoarthritis (OA) has been associated with repetitive mechanical loading during walking, often characterized by the peak knee adduction (KAM) and knee flexion moments (KFM). However, the relative contributions of these components to the knee total joint moment (TJM) can change as the disease progresses since KAM and KFM are influenced by different factors that change over time. This study tested the hypothesis that the relative contributions of KAM, KFM, and the rotational moment (KRM) to the TJM change over time in subjects with medial compartment knee OA. Patients with medial compartment knee OA (n = 19) were tested walking at their self-selected speed at baseline and a 5-year follow-up. For each frame during stance, the TJM was calculated using the KAM, KFM, and KRM. The peaks of the TJM and the relative contributions of the moment components at the time of the peaks of the TJM were tested for changes between baseline and follow-up. The percent contribution of KFM to the first peak of the TJM (TJM1) significantly decreased (p < 0.001) and the percent contribution of KAM to TJM1 significantly increased (p < 0.001), while the magnitude of the TJM1 did not significantly change over the 5-year follow-up. These gait changes with disease progression appear to maintain a constant TJM1, but the transition from a KFM to a KAM dominance appears to reflect gait changes associated with progressing OA and pain. Thus, the TJM and its component analysis captures a comprehensive metric for total loading on the knee over time. Published 2018. This article is a U.S. Government work and is in the public domain in the USA. 36:2373-2379, 2018. PMID- 29611880 TI - Significance of detectable HCV RNA below the limit of quantification in patients treated with DAAs using standard and ultrasensitive protocols. AB - Predictive factors of HCV relapse after treatment with DAAs are poorly understood. In this study, we aimed to assess whether the residual viral load positivity observed during or at the end of treatment (EOT) has an impact on viral outcome. Blood samples were collected from 337 patients with genotypes (GT) 1a, 1b, 2, 3, and 4 HCV chronic infection, treated with DAAs to determine HCV RNA load by the Abbott RealTime HCV (ART) assay at treatment week (W) 4, at EOT, and 4, 12, 24 weeks after discontinuation. EOT and other samples with "detected <12/mL" (DNQ) were retested by an ultrasensitive protocol (USP) to confirm the result. Frequency of DNQ was analyzed in subgroups of patients and clinical conditions to assess potential correlations. At W4, 22% and 30.9% of the samples were undetectable and DNQ by ART assay, respectively, but no correlation for achieving SVR was found. In contrast, an HCV RNA cut-off of >=50/mL at W4 was a significant predictor of therapy failure (P = 0.036, univariate analysis). At EOT, DNQ was associated to 12W treatment duration (P < 0.001) and GT1a infection (P = 0.036). Overall, 20/41 (48.8%) of DNQ samples at EOT or post-treatment W4, were confirmed by USP but only in a single case the patient experienced viral relapse. HCV RNA at W4 can predict SVR, irrespective to genotype or DAA regimen. HCV RNA DNQ at EOT is associated to shorter treatment duration and to GT1a, but is not a predictor of therapy failure. PMID- 29611881 TI - Asymmetry between the superior and inferior endplates is a risk factor for lumbar disc degeneration. AB - Endplate pathology plays an important role in the development of lumbar disc degeneration. Previous research paid little attention to differences between the superior and inferior endplates as a possible risk factor for disc degeneration. The purpose of this study was to test the hypothesis that asymmetry between the superior and inferior endplates is a risk factor for the development of lumbar disc degeneration. A total of 134 patients with lumbar disc herniation (LDH) and 100 healthy adults ("Controls") underwent magnetic resonance imaging scans. Each disc was categorized as non-degenerated (Pfirrmann grades I-II) or degenerated (Pfirrmann grades III-V) and get the following three groups: "Degenerated LDH" discs (n = 145), "Non-degenerated LDH" discs (n = 525) and "Non-degenerated Control" discs (n = 500). On mid-sagittal image, the lumbar endplate morphology could be categorized into three types: Flat, concave, and irregular. Superior and inferior endplates of a given disc were "symmetric" if both were of the same type, and "asymmetric" if they were of different types. The proportion of asymmetric endplates at L4-5 was higher in the "Degenerated LDH" discs group (47%) than in the "Non-degenerated LDH" discs group (21%) or "Non-degenerated Control" discs group (7%) (p < 0.05). At L5-S1 the proportions were 73%, 55%, and 38% (p < 0.05). Asymmetry of superior and inferior endplates in the mid-sagittal plane is a risk factor for lumbar disc degeneration. (c) 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2469-2475, 2018. PMID- 29611882 TI - Functional diversity. PMID- 29611883 TI - Synthesis, p38alpha MAP kinase inhibition, anti-inflammatory activity, and molecular docking studies of 1,2,4-triazole-based benzothiazole-2-amines. AB - Recent studies have demonstrated that inhibition of p38alpha MAP kinase could effectively inhibit pro-inflammatory cytokines including TNF-alpha and interleukins. Thus, inhibition of this enzyme can prove greatly beneficial in the therapy of chronic inflammatory diseases. A new series of N-[3-(substituted-4H 1,2,4-triazol-4-yl)]-benzo[d]thiazol-2-amines (4a-n) were synthesized and subjected to in vitro evaluation for anti-inflammatory activity (BSA anti denaturation assay) and p38alpha MAPK inhibition. Among the compounds selected for in vivo screening of anti-inflammatory activity (4b, 4c, 4f, 4g, 4j, 4m, and 4n), compound 4f was found to be the most active with an in vivo anti inflammatory efficacy of 85.31% when compared to diclofenac sodium (83.68%). It was also found to have a low ulcerogenic risk and a protective effect on lipid peroxidation. The p38alpha MAP kinase inhibition of this compound (IC50 = 0.036 +/- 0.12 MUM) was also found to be superior to the standard SB203580 (IC50 = 0.043 +/- 0.27 MUM). Furthermore, the in silico binding mode of the compound on docking against p38alpha MAP kinase exemplified stronger interactions than those of SB203580. PMID- 29611884 TI - Fast Sodium-Ion Conductivity in Supertetrahedral Phosphidosilicates. AB - Fast sodium-ion conductors are key components of Na-based all-solid-state batteries which hold promise for large-scale storage of electrical power. We report the synthesis, crystal-structure determination, and Na+ -ion conductivities of six new Na-ion conductors, the phosphidosilicates Na19 Si13 P25 , Na23 Si19 P33 , Na23 Si28 P45 , Na23 Si37 P57 , LT-NaSi2 P3 and HT-NaSi2 P3 , based entirely on earth-abundant elements. They have SiP4 tetrahedra assembled interpenetrating networks of T3 to T5 supertetrahedral clusters and can be hierarchically assigned to sphalerite- or diamond-type structures. 23 Na solid state NMR spectra and geometrical pathway analysis show Na+ -ion mobility between the supertetrahedral cluster networks. Electrochemical impedance spectroscopy shows Na+ -ion conductivities up to sigma (Na+ )=4*10-4 S cm-1 . The conductivities increase with the size of the supertetrahedral clusters through dilution of Na+ -ions as the charge density of the anionic networks decreases. PMID- 29611885 TI - Pregnancy planning and outcomes in patients with multiple sclerosis after mitoxantrone therapy: a monocentre assessment. AB - BACKGROUND AND PURPOSE: Patients with multiple sclerosis (MS) have many pregnancy related doubts and fears. Careful counselling is thus important. Mitoxantrone (MITO) is used in patients with aggressive MS and may affect reproductive capacity. The aim of this study was to investigate pregnancy planning and outcomes in patients with MS treated with MITO, both before and after the treatment. METHODS: Patients with MS previously treated with MITO were recruited. Clinical, demographic and treatment data were recorded. A questionnaire regarding the planning and outcomes of all pregnancies was administered. Parametric and non parametric tests were performed using SPSS 22 software. RESULTS: A total of 238 patients (female/male, 158/80) were included; 106 subjects planned a pregnancy before MITO and 40 after MITO. Of these, respectively, 102 (97%) and 35 (85%) resulted in conception, 19 (19%) and 7 (18%) in miscarriage, 6 (6%) and 1 (3%) in abortion and 98 (96%) and 32 (91%) were full-term pregnancies. A total of 96 patients (40%) planned a pregnancy only before MITO (and not after), whereas 30 (13%) planned a pregnancy only after MITO (and not before) (P < 0.01). A total of 103 patients did not plan a pregnancy before MITO and 198 did not plan a pregnancy after MITO. The reasons included lack of interest or a partner, fear of MS and infertility. All of the babies born were healthy until the end of follow up. CONCLUSIONS: Mitoxantrone does not affect the ability to conceive or pregnancy outcomes. We found no differences in pregnancies, abortions or miscarriages before and after MITO. The tendency to plan pregnancies decreased significantly after MITO. Our findings may be useful for improving the quality of life of patients and the approach taken by neurologists. PMID- 29611886 TI - Dose optimization of tacrolimus with therapeutic drug monitoring and CYP3A5 polymorphism in patients with myasthenia gravis. AB - BACKGROUND AND PURPOSE: Tacrolimus is beneficial for treatment of myasthenia gravis (MG) and has a narrow therapeutic range. Therefore, therapeutic drug monitoring is essential for tacrolimus to optimize dosage and prevent adverse reactions. However, no studies have explored the factors influencing tacrolimus blood concentration in patients with MG. Thus, we aimed to analyze these factors and discuss how to optimize tacrolimus dosage for MG treatment. METHODS: Data regarding clinical characteristics, therapeutic drugs and adverse reactions of patients with MG who received tacrolimus were collected from 2013 to 2015 at Beijing Hospital. Tacrolimus whole-blood concentrations were measured by chemiluminescent microparticle immunoassay and CYP3A5*3 gene polymorphism was detected by digital fluorescence molecule hybridization fluorescence. Regression analysis was applied to analyze the factors influencing blood concentrations and adverse reactions. RESULTS: It was shown that there was a correlation between concentration and dosage. Furthermore, co-administration of proton pump inhibitor and clarithromycin and CYP3A5*3 gene polymorphism could significantly increase the tacrolimus whole-blood levels. Adverse reactions were related to blood concentration, CYP3A5 genetic polymorphisms and combined medication though logistic regression analysis. CONCLUSIONS: The concentration of tacrolimus is affected by many factors. Therapeutic drug monitoring and detection of CYP3A5 gene polymorphism was essential for dosage optimization in patients with MG. PMID- 29611887 TI - Metal-Free Fluorine-Doped Carbon Electrocatalyst for CO2 Reduction Outcompeting Hydrogen Evolution. AB - The electrochemical CO2 reduction (ECDRR), as a key reaction in artificial photosynthesis to implement renewable energy conversion/storage, has been inhibited by the low efficiency and high costs of the electrocatalysts. Herein, we synthesize a fluorine-doped carbon (FC) catalyst by pyrolyzing commercial BP 2000 with a fluorine source, enabling a highly selective CO2 -to-CO conversion with a maximum Faradaic efficiency of 90 % at a low overpotential of 510 mV and a small Tafel slope of 81 mV dec-1 , outcompeting current metal-free catalysts. Moreover, the higher partial current density of CO and lower partial current density of H2 on FC relative to pristine carbon suggest an enhanced inherent activity towards ECDRR as well as a suppressed hydrogen evolution by fluorine doping. Fluorine doping activates the neighbor carbon atoms and facilitates the stabilization of the key intermediate COOH* on the fluorine-doped carbon material, which are also blocked for competing hydrogen evolution, resulting in superior CO2 -to-CO conversion. PMID- 29611888 TI - Decreasing the risk of sudden unexpected death in epilepsy: structured communication of risk factors for premature mortality in people with epilepsy. AB - BACKGROUND AND PURPOSE: Good practice guidelines highlight the importance of making people with epilepsy aware of the risk of premature mortality in epilepsy particularly due to sudden unexpected death in epilepsy (SUDEP). The SUDEP and Seizure Safety Checklist ('Checklist') is a structured risk communication tool used in UK clinics. It is not known if sharing structured information on risk factors allows individuals to reduce SUDEP and premature mortality risks. The aim of this study was to ascertain if the introduction of the Checklist in epilepsy clinics led to individual risk reduction. METHODS: The Checklist was administered to 130 consecutive people with epilepsy attending a specialized epilepsy neurology clinic and 129 attending an epilepsy intellectual disability (ID) clinic within a 4-month period. At baseline, no attendees at the neurology clinic had received formal risk advice, whereas all those attending the ID clinic had received formal risk advice on multiple occasions for 6 years. The Checklist was readministered 1 year later to each group and scores were compared with baseline and between groups. RESULTS: Of 12 risk factors considered, there was an overall reduction in mean risk score for the general (P = 0.0049) but not for the ID (P = 0.322) population. Subanalysis of the 25% of people at most risk in both populations showed that both sets had a significant reduction in risk scores (P < 0.001). CONCLUSION: Structured discussion results in behavioural change that reduces individual risk factors. This impact seems to be higher in those who are at current higher risk. It is important that clinicians share risk information with individuals as a matter of public health and health promotion. PMID- 29611889 TI - Mandibular mesial root canal morphology using micro-computed tomography in a Brazilian population. AB - To assess the root canal system morphology of mandibular molars by means of micro computed tomography, one hundred and four mandibular first molars were investigated and the following were evaluated: Vertucci's classification, the presence of lateral canals and the number of apical foramina. Mesial root canal surface area and volume were obtained by the CTAn and CTvol software. The type of root canal isthmi was classified applying the Hsu & Kim and Fan criteria. The most frequent root canal configuration was Vertucci type IV (46.2%). Lateral canals were observed in all root canal thirds and the average number of apical foramina was 3.15 +/- 1.77. Regarding the presence of isthmus, Types I and II were the most prevalent, according to Hsu & Kim and Fan et al. criteria, respectively. Mesial root canals of mandibular molars showed high morphology variability. PMID- 29611891 TI - A Unified Approach for the Assembly of Atisine- and Hetidine-type Diterpenoid Alkaloids: Total Syntheses of Azitine and the Proposed Structure of Navirine C. AB - A tetracyclic dinitrile was synthesized in twelve steps from cyclohex-2-en-1-one by using a chelation-triggered conjugate addition to a gamma-hydroxy-substituted alpha,beta-unsaturated nitrile and an oxidative dearomatization/Diels-Alder cycloaddition cascade as the key steps. The first total synthesis of azitine (in 17 steps) was achieved through a simple reductive cyclization of this intermediate and subsequent transformations while the total synthesis of the proposed structure of navirine C (in 19 steps) was accomplished by a hydrogen atom-transfer reaction of the tetracyclic dinitrile, Pd/C-catalyzed reductive cyclization, and subsequent functional group manipulation. PMID- 29611890 TI - Biocompatibility of injectable resilin-based hydrogels. AB - Vocal folds are connective tissues housed in the larynx, which can be subjected to various injuries and traumatic stimuli that lead to aberrant tissue structural alterations and fibrotic-induced biomechanical stiffening observed in patients with voice disorders. Much effort has been devoted to generate soft biomaterials that are injectable directly to sites of injury. To date, materials applied toward these applications have been largely focused on natural extracellular matrix-derived materials such as collagen, fibrin or hyaluronic acid; these approaches have suffered from the fact that materials are not sufficiently robust mechanically nor offer sufficient flexibility to modulate material properties for targeted injection. We have recently developed multiple resilin-inspired elastomeric hydrogels that possess similar mechanical properties as those reported for vocal fold tissues, and that also show promising in vitro cytocompatibility and in vivo biocompatibility. Here we report studies that test the delivery of resilin-based hydrogels through injection to the subcutaneous tissue in a wild-type mice model; histological and genetic expression outcomes were monitored. The rapid kinetics of crosslinking enabled facile injection and ensured the rapid transition of the viscous resilin precursor solution to a solid like hydrogel in the subcutaneous space in vivo; the materials exhibited storage shear moduli in the range of 1000-2000 Pa when characterized through oscillatory rheology. Histological staining and gene expression profiles suggested minimal inflammatory profiles three weeks after injection, thereby demonstrating the potential suitability for site-specific in vivo injection of these elastomeric materials. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2229 2242, 2018. PMID- 29611892 TI - MLC901 (NeuroAiD IITM) for cognition after traumatic brain injury: a pilot randomized clinical trial. AB - BACKGROUND AND PURPOSE: Treatments to facilitate recovery after traumatic brain injury (TBI) are urgently needed. We conducted a 9-month pilot, randomized placebo-controlled clinical trial to examine the safety and potential effects of the herbal supplement MLC901 (NeuroAiD IITM) on cognitive functioning following TBI. METHODS: Adults aged 18-65 years at 1-12 months after mild or moderate TBI were randomized to receive MLC901 (0.8 g capsules 3 times daily) or placebo for 6 months. The primary outcome was cognitive functioning as assessed by the CNS Vital Signs online neuropsychological test. Secondary outcomes included the Cognitive Failures Questionnaire, the Rivermead Post-concussion Symptom Questionnaire (neurobehavioral sequelae), Quality of Life after Brain Injury, Hospital Anxiety and Depression Scale, Modified Fatigue Impact Scale and extended Glasgow Outcome Scale (physical disability). Assessments were completed at baseline and at 3-, 6- and 9-month follow-up. Linear mixed-effects models were conducted, with the primary outcome time-point of 6 months. RESULTS: A total of 78 participants [mean age 37.5 +/- 14.8 years, 39 (50%) female] were included in the analysis. Baseline variables were similar between groups (treatment group, n = 36; control group, n = 42). Linear mixed-effects models controlling for time, group allocation, repeated measurements, adherence and baseline assessment scores revealed significant improvements in complex attention (P = 0.04, d = 0.6) and executive functioning (P = 0.04, d = 0.4) at 6 months in the MLC901 group compared with controls. There were no significant differences between the groups for neurobehavioral sequelae, mood, fatigue, physical disability or overall quality of life at 6 months. No serious adverse events were reported. CONCLUSIONS: MLC901 was safe and well tolerated post-TBI. This study provided Class I/II evidence that, for patients with mild to moderate TBI, 6 months of MLC901 improved cognitive functioning. PMID- 29611894 TI - Unravelling a new catabolic pathway of C-19 steroids in Mycobacterium smegmatis. AB - In this work, we have characterized the C-19+ gene cluster (MSMEG_2851 to MSMEG_2901) of Mycobacterium smegmatis. By in silico analysis, we have identified the genes encoding enzymes involved in the modification of the A/B steroid rings during the catabolism of C-19 steroids in certain M. smegmatis mutants mapped in the PadR-like regulator (MSMEG_2868), that constitutively express the C-19+ gene cluster. By using gene complementation assays, resting-cell biotransformations and deletion mutants, we have characterized the most critical genes of the cluster, that is, kstD2, kstD3, kshA2, kshB2, hsaA2, hsaC2 and hsaD2. These results have allowed us to propose a new catabolic route named C-19+ pathway for the mineralization of C-19 steroids in M. smegmatis. Our data suggest that the deletion of the C-19+ gene cluster may be useful to engineer more robust and efficient M. smegmatis strains to produce C-19 steroids from sterols. Moreover, the new KshA2, KshB2, KstD2 and KstD3 isoenzymes may be useful to design new microbial cell factories for the 9alpha-hydroxylation and/or Delta1 dehydrogenation of 3-ketosteroids. PMID- 29611893 TI - Comparative proteome analysis of propionate degradation by Syntrophobacter fumaroxidans in pure culture and in coculture with methanogens. AB - Syntrophobacter fumaroxidans is a sulfate-reducing bacterium able to grow on propionate axenically or in syntrophic interaction with methanogens or other sulfate-reducing bacteria. We performed a proteome analysis of S. fumaroxidans growing with propionate axenically with sulfate or fumarate, and in syntrophy with Methanospirillum hungatei, Methanobacterium formicicum or Desulfovibrio desulfuricans. Special attention was put on the role of hydrogen and formate in interspecies electron transfer (IET) and energy conservation. Formate dehydrogenase Fdh1 and hydrogenase Hox were the main confurcating enzymes used for energy conservation. In the periplasm, Fdh2 and hydrogenase Hyn play an important role in reverse electron transport associated with succinate oxidation. Periplasmic Fdh3 and Fdh5 were involved in IET. The sulfate reduction pathway was poorly regulated and many enzymes associated with sulfate reduction (Sat, HppA, AprAB, DsrAB and DsrC) were abundant even at conditions where sulfate was not present. Proteins similar to heterodisulfide reductases (Hdr) were abundant. Hdr/Flox was detected in all conditions while HdrABC/HdrL was exclusively detected when sulfate was available; these complexes most likely confurcate electrons. Our results suggest that S. fumaroxidans mainly used formate for electron release and that different confurcating mechanisms were used in its sulfidogenic metabolism. PMID- 29611895 TI - Prereduction of Metal Oxides via Carbon Plasma Treatment for Efficient and Stable Electrocatalytic Hydrogen Evolution. AB - Prereduction of transition metal oxides is a feasible and efficient strategy to enhance their catalytic activity for hydrogen evolution. Unfortunately, the prereduction via the common H2 annealing method is unstable for nanomaterials during the hydrogen evolution process. Here, using NiMoO4 nanowire arrays as the example, it is demonstrated that carbon plasma (C-plasma) treatment can greatly enhance both the catalytic activity and the long-term stability of transition metal oxides for hydrogen evolution. The C-plasma treatment has two functions at the same time: it induces partial surface reduction of the NiMoO4 nanowire to form Ni4 Mo nanoclusters, and simultaneously deposits a thin graphitic carbon shell. As a result, the C-plasma treated NiMoO4 can maintain its array morphology, chemical composition, and catalytic activity during long-term intermittent hydrogen evolution process. This work may pave a new way for simultaneous activation and stabilization of transition metal oxide-based electrocatalysts. PMID- 29611896 TI - Outcomes of early versus delayed laparoscopic cholecystectomy for acute cholecystitis performed at a single institution. AB - INTRODUCTION: Debate continues regarding the clinical outcomes of early laparoscopic cholecystectomy (ELC) versus delayed laparoscopic cholecystectomy (DLC) for acute cholecystitis (AC). The aim of this retrospective study was to compare clinical outcomes of ELC and DLC. METHODS: This study consisted of 465 patients who had undergone laparoscopic cholecystectomy for AC between January 2000 and February 2017. Patients were divided between an ELC group (patients who underwent laparoscopic cholecystectomy within 6 days of symptom onset, n = 288) and a DLC group (patients who underwent laparoscopic cholecystectomy at least 7 days from symptom onset, n = 177), and clinical outcomes were compared. RESULTS: Operation time (105 vs 124 min), length of postoperative hospital stay (4 vs 4 days), conversion rate (1.3% vs 10.7%), bile leak (0.3% vs 3.3%), residual calculus (2.4% vs 6.7%), and readmission (1.0% vs 6.7%) were significantly better in the ELC group. A history of upper abdominal surgery, grade II or grade III AC, preoperative percutaneous transhepatic gallbladder drainage, and time between symptom onset and surgery of more than 7 days were independent risk factors for conversion. CONCLUSIONS: ELC for AC yields more favorable clinical outcomes than DLC. PMID- 29611897 TI - Fingerprints of partial oxidation of biogenic magnetite from cultivated and natural marine magnetotactic bacteria using synchrotron radiation. AB - Magnetotactic bacteria are a multi-phyletic group of bacteria that synthesize membrane-bound magnetic minerals. Understanding the preservation of these minerals in various environments (e.g., with varying oxygen concentrations and iron supply) is important for understanding their role as carriers of primary magnetizations in sediments and sedimentary rocks. Here we present X-ray near edge structure (XANES) spectra for Fe in magnetotactic bacteria samples from recent sediments to assess surface oxidation and crystal structure changes in bacterial magnetite during early burial. Our results are compared with a XANES spectrum of cultivated Magnetofaba australis samples, and with magnetic properties, and indicate that oxidation of magnetite to maghemite increases with depth in the sediment due to longer exposure to molecular oxygen. These results are relevant to understanding magnetic signatures carried by magnetofossils in oxic sediments and sedimentary rocks of different ages. PMID- 29611898 TI - Acanthamoeba S13WT relies on its bacterial endosymbiont to backpack human pathogenic bacteria and resist Legionella infection on solid media. AB - Soil-borne amoeba Acanthamoeba S13WT has an endosymbiotic relationship with an environmental Neochlamydia bacterial strain. However, regardless of extensive experiments in liquid media, the biological advantage of the symbiosis remained elusive. We therefore explored the role of the endosymbiont in predator-prey interactions on solid media. A mixed culture of the symbiotic or aposymbiotic amoebae and GFP-expressing Escherichia coli or Salmonella Enteritidis was spotted onto the centre of a LB or B-CYE agar plate preinoculated with a ring of mCherry expressing Legionella pneumophila (Legionella 'wall'). The spread of the amoebae on the plate was assessed using a fluorescence imaging system or scanning electron microscopy. As a result, in contrast to the aposymbiotic amoebae, the symbiotic amoebae backpacked these GFP-expressing bacteria and formed flower-like fluorescence patterns in an anticlockwise direction. Other bacteria (Pseudomonas aeruginosa and Stenotrophomonas maltophilia), but not Staphylococcus aureus, were also backpacked by the symbiotic amoebae on LB agar, although lacked the movement to anticlockwise direction. Furthermore, in contrast to the aposymbiotic amoebae, the symbiotic amoebae backpacking the E. coli broke through the Legionella 'wall' on B-CYE agar plates. Thus, we concluded that Acanthamoeba S13WT required the Neochlamydia endosymbiont to backpack human pathogenic bacteria and resist Legionella infection on solid agar. PMID- 29611899 TI - Determination of leaf respiration in the light: comparison between an isotopic disequilibrium method and the Laisk method. AB - Quantification of leaf respiration is important for understanding plant physiology and ecosystem biogeochemical processes. Leaf respiration continues in the light (RL ) but supposedly at a lower rate than in the dark (RDk ). However, there is no method for direct measurement of RL and the available methods require nonphysiological measurement conditions. A method based on isotopic disequilibrium quantified RL (RL13C ) and mesophyll conductance of young and old fully expanded leaves of six species. RL13C was compared to RL determined by the Laisk method (RL Laisk ) on the very same leaves with a minimum time lag. RL 13C and RL Laisk were generally lower than RDk , and were not significantly affected by leaf ageing. RL Laisk and RL 13C were positively correlated (r2 = 0.35), and both were positively correlated with RDk (r2 >= 0.6). RL Laisk was systematically lower than RL 13C by 0.4 MUmol m-2 s-1 . Using A/Cc instead of A/Ci curves, a higher photocompensation point Gamma* (by 5 MUmol mol-1 ) was found but no influence on RL Laisk estimates was observed. The results imply that the Laisk method underestimates actual RL significantly, probably related to the measurement condition of low CO2 and irradiance. The isotopic disequilibrium method is useful for assessing responses of RL to irradiance and CO2 , improving our mechanistic understanding of RL . PMID- 29611900 TI - In vitro effect of graphene structures as an osteoinductive factor in bone tissue engineering: A systematic review. AB - Graphene and its derivatives have been well-known as influential factors in differentiating stem/progenitor cells toward the osteoblastic lineage. However, there have been many controversies in the literature regarding the parameters effect on bone regeneration, including graphene concentration, size, type, dimension, hydrophilicity, functionalization, and composition. This study attempts to produce a comprehensive review regarding the given parameters and their effects on stimulating cell behaviors such as proliferation, viability, attachment and osteogenic differentiation. In this study, a systematic search of MEDLINE database was conducted for in vitro studies on the use of graphene and its derivatives for bone tissue engineering from January 2000 to February 2018, organized according to the PRISMA statement. According to reviewed articles, different graphene derivative, including graphene, graphene oxide (GO) and reduced graphene oxide (RGO) with mass ratio <=1.5 wt % for all and concentration up to 50 MUg/mL for graphene and GO, and 60 MUg/mL for RGO, are considered to be safe for most cell types. However, these concentrations highly depend on the types of cells. It was discovered that graphene with lateral size less than 5 um, along with GO and RGO with lateral dimension less than 1 um decrease cell viability. In addition, the three-dimensional structure of graphene can promote cell-cell interaction, migration and proliferation. When graphene and its derivatives are incorporated with metals, polymers, and minerals, they frequently show promoted mechanical properties and bioactivity. Last, graphene and its derivatives have been found to increase the surface roughness and porosity, which can highly enhance cell adhesion and differentiation. (c) 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 2284-2343, 2018. PMID- 29611901 TI - Personalize Your Workspace for Stress Reduction. PMID- 29611902 TI - Development of a Quality Dashboard Utilizing Cancer Registry Data. PMID- 29611903 TI - Developing a Model Cancer Registry: The Sarah Cannon Model. PMID- 29611904 TI - What Is Your Moonshot? PMID- 29611905 TI - [Pierre Pomet (1658-1699) and his Histoire des drogues (History of drugs) (1694 & 1735)]. AB - Pierre Pomet is a Parisian, but as all great botanists, he liked travelling and bringing back sample of drugs that he was ultimately showing during his course at the Jardin des Plantes (Royal Herbs garden in Paris). Member of druggists and groceries storekeepers' Community, he was not allowed to establish himself as an apothecary in Paris. It is as drug expert that he wrote and published in 1694 his "General History of Drugs, concerning herbs, animals and minerals, book enriched with more than 400 copper-plate engravings designed from nature : with explanations of their various names, their countries of origin, the way to differentiate them from falsified ones, and their properties, where one can see the errors coming from Ancients and modern writers ; the whole being very useful for the public". This book was translated into English in 1712 and German in 1717. It is part of the reference books of the 17th century for pharmacy. In his introduction, Pierre Pomet explains that his goal is to avoid for drugs errors and falsifications that very frequent at that time. The book is then dedicated not only to physicians, apothecaries or students, etc., but also to all that used drugs. PMID- 29611906 TI - [Pierre Pomet's opinion on Lemery revealed by the project of a second edition of his General History of Drugs, in 1699 ]. AB - General History of Drugs was first published in 1694 by Pierre Pomet, as a big in folio volume, illustrated by more than 400 engraved figures. It was a very expensive book. In 1698-1699, just after the publication of the Universal Treaty on Simple Drugs by Lemery, Pomet prepared a new edition in-8 degrees , less expensive. Unfortunately, it was not ready for publication when Pomet died in 1699. Only 208 pages were preprint, but together with manuscript mentions written on the exemplar gathered by BIU Sante, pole Pharmacie, they were sufficient to prove that Pomet deeply felt that Lemery had committed plagiarism, copying even some errors he had included in his first edition. PMID- 29611907 TI - [Responses and Questions]. PMID- 29611908 TI - [The role of French pharmacists in the chemical conflict of the First World War (1914-1918)]. PMID- 29611909 TI - [Greek science in the centre of the Dialogue between Orient and Occident ]. AB - Most pre-Socratic Greek philosophers originated from Ionia, in Minor Asia, where Achaeans had been installed since the 11th century B. C. During the Age of Pericles, Empedocles of Agrigento, in Sicily, Leucippus and Democritus from Abdera, Anaxagoras of Clazomenae, active in Athens, and Socrates in Athens also took over philosophy and science in Continental Greece. Plato, Socrates' disciple and founder of Academia, and his own disciple Aristotle, founder of the Lyceum, and his pupils, such as Theophrastus of Eresos, followed them. In the area of medicine and pharmacy, Hippocrates of Cos and his disciples and followers redacted between 450 and 300 B. C., what is known as Hippocratic corpus. Then came Galen from Pergamum who completed the theory of Humours, during the second century. Nestorian Christians, considered as heretical in the Byzantine Empire, were accepted in Sassanid Persia and carried Greek culture with them. After Arabic conquest and Baghdad City creation, in 762, they translated Hippocratic corpus in Arabic language so that Hippocratico-Galenic theory could pass in Arabic-Muslim world. It was then developed by Al-Kindi in Baghdad, Ibn Al-Jazzar in Kairouan, Razes or Avicenna, both Persians. The 11th and the 12th centuries were characterised by Latin translations, by Constantine the African in Monte Cassino, Gerard of Cremona or Mark of Toledo. The School of Salerno created then the conditions for the fusion of Greek, Arabic and Jewish medicines. The creation of modern science from Greek philosophy was a consequence of a permanent dialogue between Orient and Occident. PMID- 29611910 TI - [French influence in the US Dispensatory of 1843]. AB - The US Dispensatory first published in 1833 will see several editions and some of them are accessible on Internet. We have evaluated more specifically the 1843 edition, at a time where several similar reference books were published in France, and especially l'Officine of Dorvault, published for the first time in 1844. One can observe that the American book refers very often to French works coming from pharmacists, chemists and biologists who are, at the time, key references. They are particularly mentioned when talking about alkaloids, but also concerning herbs characterization and history of their discovery, as well as drugs or new active principles effects and toxicity. As opposed to Dorvault who try to help pharmacists by very practical information, the authors of the Dispensatory are doing a review of available scientific evidences, as an add on of the recently published American pharmacopeia in 1831. Among the main french authors that are mentioned, we can see Henry and Guibourt, Pelletier and Caventou, but also Soubeiran, Vauquelin, Robiquet, Orfila and many others. If the most consistent chapters are related to Quinquina, Opium and morphin, the American book, as l'Officine of Dorvault pay attention to have an almost exhaustive table of weight and measures that are still very different from one country to another. Globally speaking, the French authors are mentioned close to 700 times in the 1843 edition of the Dispensatory. PMID- 29611911 TI - [1916 and the two major pharmaceutical journals at that time : the " Journal de Pharmacie et de Chimie", the official journal of the Pharmacist' Society of Paris, and the " Bulletin des sciences pharmacologiques"]. AB - When looking at the content of both of them in the middle of the First World War, indeed one can see a number of articles related to the war, but also several other topics : it is the year of the new law on toxic drugs with the creation of A, B and C classification of drugs. The controversy about pharmaceutical specialties and the growing influence of the pharmaceutical industry still remain an important issue in 1916. It is also an eventful year for the history of pharmacy, three years after the creation of the French Society of History of Pharmacy. One can read also several biographies of pharmacists who died in 1916, not only in relation to war, and of famous pharmacists like Gerhardt (not only for the discovery of aspirin) who was born one century ago. macy, three years after the creation of the French Society of History of Pharmacy. One can read also several biographies of pharmacists who died in 1916, not only in relation to war, and of famous pharmacists like Gerhardt (not only for the discovery of aspirin) who was born one century ago. PMID- 29611912 TI - [Notes on a medieval apothecary : Ernulf, a spice merchant from Rennes during the XIIIth Century]. AB - The recent publication of the cartulary of Saint-Melaine abbey in Rennes allowed to deepen our knowledge of the city of Rennes and of the entire region of Upper Brittany. Amidst the hundreds of people's names that were conserved, appears that of Ernulf, piperarius, that we can translate by "pepper" and that we can connect by extension to the world of pharmacists. By chance, the preservation of Middle Ages sources enables us to find his trace in documents from Brittany but also from Anjou. Although it remains impossible to write his biography, the mention of Ernulf in several medieval texts enables us to assess our knowledge on health in Brittany during the Middle Ages. Most of all, these medieval acts quote the oldest " pharmacist" known in the Breton peninsula. PMID- 29611914 TI - [Towards Professionalization : the Editorial Discourse of Quebec Pharmacy magazine, 1960-2013 ]. AB - The second half of the twentieth century and the beginning of the 2000s marked deep changes in the practice of pharmacy in Quebec. The editorials of Quebec Pharmacie journal attest these changes on a 50-year period by relating power relationships, conflicts, problems and solutions that concerned pharmacists. This article proposes to analyze the editorial discourse of Quebec Pharmacie journal between 1960 and 2013, and to grasp the evolution of the speech. To do so, we analyze the major topics addressed by the editorialists. It appears that Quebec Pharmacie's editorialists aimed the professionalization of pharmacy. PMID- 29611915 TI - [The apothecaries of the Saint-Honore district of Paris in the 17th century. The apothecaries Antoine and Jacques Gregoire and Louis XIII's first painter, Simon Vouet]. AB - This article presents the biographies of the apothecaries who lived in the Rue Saint-Honore in Paris in the 17th century. Two major facts emerge from this study. The first concerns the formation of a family network involving the apothecaries and the royal artists. The apothecaries Antoine and Jacques Gregoire became allied with Simon Vouet, the first painter of Louis XIII . Links were also made between Antoine Gregoire and Jacques Sarazin, the King's sculptor, and then with Michel Corneille, painter to the King. The famous painting by Simon Vouet hanging in the assembly hall of the Faculty of Pharmacy in Paris is probably the fruit of his collaboration with Jacques Gregoire, his brother-in-law and an erudite botanist. The other notable fact concerns the relations between Anne de Furnes, widow of Antoine Brulon, the rich apothecary to the King Antoine Brulon, and Moliere, both in Paris and in the village of Auteuil. The other notable fact concerns the relations between Anne de Furnes, widow of Antoine Brulon, the rich apothecary to the King Antoine Brulon, and Moliere, both in Paris and in the village of Auteuil. PMID- 29611916 TI - [The Escouflaire Laboratories]. AB - Escouflaire antiasthmatic cigarettes and powders knew certain success during almost one century. The medical use of solanaceae with bronchodilator properties helped relieve numerous asthmatics. The Belgian pharmacist Charles Adolphe Escouflaire (1857-1909), pharmacist from the university of Leuven, Belgium, awarded his diploma in 1879. He created his antiasthmatic products in his pharmacy of Ath and established in 1885 a pharmaceutical laboratory. He registered trademarks under the brand name Zematone for its antiasthmatic cigarettes. His products will be rapidly known and sold all over the world. The discovery of a complete box of medical cigarettes in the Czech Republic allows us to evoke his products, the distributor F. S chnobling in this country, the modes of display and uses. This article redraws the history of the laboratory under the direction of three generations of the Escouflaire family. The laboratory will expand after WWII with production factories in Baisieux and Blandain before definitely close in 1974. PMID- 29611917 TI - [Guislain Decrombecque (1797-1870) and Alfred Wagon (1849-1928) originally of Auguste Behal career (1859-1941)?] AB - Auguste Behal (1859-1941), Maitre de Conferences (Assistant Professor) at the Sorbonne then Full Professor at the School of Pharmacy (Paris), leads many vocations among these students (Blaise, Delaby, Delepine, Detoeuf, Fourneau, Sommelet, Tiffeneau, Valeur, etc.). However, why is he embraced the vocation chemist organic chemist ? This choice is undoubtedly dictated by the meeting of Adolphe Wurtz (1817-1884) and Charles Friedel (1832-1899) who made mature in him a passion for chemical research during his formation. Nevertheless, the historical context of the city of Lens, a modest city of 2.500 inhabitants in the north of France, and the influence of two other characters : Guislain Decrombecque (1797-1870), agronomist, and Alfred Wagon (1849-1928), 2nd class pharmacist, are also noteworthy. We will outline how these two people have directly and indirectly contributed to the Behal career. PMID- 29611918 TI - [The History of Pharmacy via the Internet]. PMID- 29611919 TI - [The Ebreuil crocodile: a "remarkable monster"]. PMID- 29611920 TI - A Simple Method to Estimate the Impact of a Workplace Wellness Program on Absenteeism Cost. PMID- 29611922 TI - Exhibition of Specimens. PMID- 29611921 TI - Exhibition of Specimens. PMID- 29611923 TI - Exhibition of Specimens. PMID- 29611924 TI - Exhibition of Specimens. PMID- 29611925 TI - The Selection of Methods in Abdominal Hysterectomy (Synopsis). PMID- 29611926 TI - Notes on Two Cases of Cancer of the Cervix at the Fifth Month of Pregnancy Treated by Panhysterectomy: With Remarks on the Treatment of Cancer during Pregnancy. PMID- 29611928 TI - Some Experiences in the Gynaecological Surgery of the Abdomen. PMID- 29611927 TI - Cases in My Private Practice Which Illustrate Some of the Cases of Allowing Lactation and Pregnancy to Overlap. PMID- 29611929 TI - The Treatment of Eclampsia by Rapid Delivery by Means of Bossi's Dilator. PMID- 29611930 TI - The Anatomical Variations Presented by Two Cases of Twin Monsters, with an Account of Their Developmental Explanation. PMID- 29611932 TI - Papillary Cyst of the Labium Minus. PMID- 29611931 TI - Eclampsia with Rapid Delivery by Means of Bossi's Dilator. PMID- 29611933 TI - Two Cases of Albuminuria in Pregnancy; the Influence of Thyroid Extract. PMID- 29611935 TI - Exhibition of Specimens. PMID- 29611934 TI - Hydatid Mole and Its Relation to Deciduoma Malignum. PMID- 29611936 TI - Exhibition of Specimens. PMID- 29611938 TI - A Series of Cases of "Non-Septic" Puerperal Pyrexia. PMID- 29611937 TI - Case of Chorion-Epithelioma (Deciduoma Malignum). PMID- 29611939 TI - Presidential Address. PMID- 29611941 TI - Note on a Case of Fatal Tracheal Compression by Enlarged Thyroid in a New-Born Infant. PMID- 29611940 TI - The Treatment of the Auto-Intoxications of Pregnancy by Thyroid Extract; the Anticipation of Impending Eclampsia. PMID- 29611942 TI - Notes on Five Cases of Abdominal Section for Emergencies during Pregnancy. PMID- 29611943 TI - A New Method for Estimating the Relative Sizes of the Foetal Head and Maternal Pelvis. PMID- 29611944 TI - Three Cases of Unruptured Tubal Gestation Treated by Operation, with Notes of Cases Simulating This Condition. PMID- 29611945 TI - On the Treatment of Uterine Fibromyomata, with a Record of Twenty-Eight Consecutive Successful Abdominal Hysterectomies by the Supravaginal Method. PMID- 29611946 TI - Valedictory Address. PMID- 29611947 TI - Note on Bossi's Dilator. PMID- 29611949 TI - Exhibition of Specimens. PMID- 29611948 TI - Symphysotomy in Domestic and Hospital Practice. PMID- 29611950 TI - The Separation of the Placenta, with Special Reference to the Information Derived Regarding Its Mechanism from Cases of Conservative Caesarean Section. PMID- 29611951 TI - Expulsion of Dermoid Ovarian Cyst per Vaginam during Labour, with a Discussion on the Operative Treatment of Pelvic Ovarian Tumours Complicating Labour. PMID- 29611952 TI - Discussion on Haemorrhage during the Later Months of Pregnancy and Early Stages of Labour. PMID- 29611953 TI - A Case of Acute Pyelitis in Infancy. PMID- 29611954 TI - An Experimental Study of the Pelvic Changes Produced by Separation of the Pubic Bones in Symphysiotomy. PMID- 29611956 TI - Case of Full-Time Intact Extraperitoneal Gestation Successfully Removed after Five Years' Retention. PMID- 29611955 TI - On the Use and Abuse of Forceps in General Practice. PMID- 29611957 TI - The Nature of the Tuberose Fleshy Mole. PMID- 29611958 TI - Repeated Ovariotomy. PMID- 29611959 TI - Exhibition of Specimens. PMID- 29611960 TI - Exhibition of Specimens. PMID- 29611961 TI - A Case of Spontaneous Rupture of an Apparently Normal Uterus at the Commencement of Labour. PMID- 29611962 TI - Further Notes on the Use of Thyroid Extract in Puerperal Eclampsia and the Pre Eclampic State. PMID- 29611963 TI - Notes on the Symptoms and Treatment of Acute Pyelitis in Infants. PMID- 29611965 TI - Exhibition of Specimens. PMID- 29611964 TI - Exhibition of Specimens. PMID- 29611966 TI - The Problem of the Premature Infant. PMID- 29611967 TI - Some Remarks on Diagnostic Help in Gynaecology. PMID- 29611968 TI - Notes on a Case of Epithelioma of the Vulva; Operation; Recurrence. PMID- 29611970 TI - Exhibition of Specimens. PMID- 29611969 TI - The Anatomy and Histology of an Early Tubal Gestation: With Lantern Demonstration. PMID- 29611971 TI - Hyperemesis Gravidarum, with Notes on a Fatal Case. PMID- 29611972 TI - On the Transmission of Nitrogenous Compounds from Mother to Foetus. PMID- 29611973 TI - Birth-Stools in Egypt. PMID- 29611974 TI - Exhibition of Specimens. PMID- 29611975 TI - On the Frozen Sections by Bumm and Blumreich and by Zangemeister. Is There a Lower Uterine Segment? PMID- 29611976 TI - Rupture of the Uterus and Its Treatment Based on a Series of Fourteen Cases. PMID- 29611977 TI - On the Operative Treatment of Displacements of the Pelvic Viscera. PMID- 29611978 TI - Valedictory Address, Dealing Specially with the Hospital Treatment of Morbid Pregnancies: Part 2. PMID- 29611979 TI - Valedictory Address, Dealing Specially with the Hospital Treatment of Morbid Pregnancies: Part 1. PMID- 29611980 TI - Pregnancy Complicated by Fibro-Myomata of the Uterus-A Record of Ten Cases Treated by Laparotomy. PMID- 29611981 TI - Case of Angular Pregnancy Which Very Closely Resembled an Ectopic Gestation. PMID- 29611982 TI - On the Carbohydrate Metabolism of the Foetus. PMID- 29611984 TI - Exhibition of Specimens. PMID- 29611983 TI - Exhibition of Specimens. PMID- 29611985 TI - Exhibition of Specimens. PMID- 29611986 TI - Exhibition of Specimens. PMID- 29611987 TI - Note of a Case of Hysterectomy for Fibroid Tumour under Spinal Anaesthesia. PMID- 29611989 TI - The Practice of Artificial Infant Feeding. PMID- 29611988 TI - Exhibition of Specimens. PMID- 29611990 TI - Uterine Haemorrhage of Ovarian Origin, Including a Discussion of the Physiology and Pathology of the Corpus Luteum. PMID- 29611991 TI - On the Pressure Experienced by the Foetus in Utero during Pregnancy; with Special Reference to Achondroplasia (Chondrodystrophia Foetalis). PMID- 29611992 TI - The Retraction Ring as a Cause of Obstruction in Labour. PMID- 29611993 TI - Discussion on the Lower Uterine Segment in Labour. PMID- 29611994 TI - Three Cases of Symmetrical Necrosis of the Cortex of the Kidneys Associated with Puerperal Eclampsia and Suppression of Urine. PMID- 29611995 TI - Exhibition of Specimens. PMID- 29611996 TI - Presidential Address: Some Twentieth-Century Problems in Relation to Marriage and Childbirth. PMID- 29611997 TI - Exhibition of Specimens. PMID- 29611998 TI - Fatal Cases of Jaundice in the New-Born Child, with Notes of a Case in Successive Pregnancies. PMID- 29611999 TI - A Case of Ruptured Very Early Primary Ovarian Pregnancy. PMID- 29612000 TI - On the Duration of the Interval between Insemination and Parturition in Certain Mammals as Studied in Biometric Curves; with Special Reference to the Calculation of the Onset of Labour in Human Pregnancy. PMID- 29612002 TI - Exhibition of Specimens. PMID- 29612001 TI - Two Tumours Complicating Pregnancy. PMID- 29612003 TI - Exhibition of Specimens. PMID- 29612004 TI - Short Notes on Five Patients Who Suffered from Eclampsia. PMID- 29612005 TI - Pelvic Haematocele from Rupture of a Blood Cyst of Ovary. PMID- 29612006 TI - Notes on Some Cases of Eclampsia Treated by Veratrone. PMID- 29612007 TI - Exhibition of Specimens. PMID- 29612008 TI - Two Cases of Uterine Fibroid in Which Degeneration of the Tumour (Perithelioma and Necrobiosis) Caused Difficulty in Diagnosis. PMID- 29612009 TI - A Uterus from a Patient Who Died during Obstructed Labour; with Microscopic Sections through the Lower Uterine Segment. PMID- 29612010 TI - Unusual Case of Hydatidiform Mole Dealt with by Abdominal Hysterectomy. PMID- 29612011 TI - Exhibition of Specimens. PMID- 29612013 TI - Exhibition of Specimens. PMID- 29612012 TI - Some Rare Uterine New Growths-Simple Papilloma of Corpus Uteri; Primary Tubercle of Cervix; Diffuse Nodular Fibrosis. PMID- 29612014 TI - Fatal Case of Hydatidiform Mole. PMID- 29612015 TI - Pseudo-Eclampsia, with Two Illustrative Cases:-1. Cerebral Tumour; 2. Meningitis. PMID- 29612016 TI - Three Cases Illustrating Thyroid Relations in Gynaecology. PMID- 29612017 TI - A Case of Puerperal Eclampsia, Treated by Large Doses of Thyroid Extract. PMID- 29612018 TI - Exhibition of Specimens. PMID- 29612019 TI - Exhibition of Specimens. PMID- 29612020 TI - Caesarean Section in Eclampsia. PMID- 29612021 TI - Hypertrophy of the Foetal Thyroid with Maternal Eclampsia. PMID- 29612022 TI - The Use and Abuse of Midwifery Forceps. PMID- 29612023 TI - Eloge on the Late Dr. Milne Murray. PMID- 29612024 TI - Clinical Notes of a Series of Twenty-Two Cases of Obstructed Labours, Including Eight Cases of Induction of Labour, Four Cases of Symphysiotomy, and Ten Cases of Caesarean Section. PMID- 29612026 TI - Exhibition of Specimens. PMID- 29612025 TI - Note on Tubal Abortion. PMID- 29612027 TI - Some Renal Cases. PMID- 29612029 TI - Note on a Case of Hebotomy (Lateral Section of the Pubes). PMID- 29612028 TI - The Obstetric Satchel: A Problem in Asepsis. PMID- 29612030 TI - Vaginal Caesarean Section. PMID- 29612031 TI - Exhibition of Specimens. PMID- 29612032 TI - The Use of Bossi's Dilator in Eight Cases of Complicated Labour. PMID- 29612033 TI - Valedictory Address. PMID- 29612035 TI - Exhibition of Specimens. PMID- 29612034 TI - Malignant Uterine Complications of Fibromyomata of the Uterus. PMID- 29612036 TI - Leucocytosis in Pelvic Disease in the Female. PMID- 29612038 TI - Exhibition of Specimens. PMID- 29612037 TI - Demonstration of Naked Eye and Microscopic Specimens, Illustrating the Influence of a Pure Meat Diet on the Thyroid and Parathyroid Glands. PMID- 29612040 TI - Exhibition of Specimens. PMID- 29612039 TI - Exhibition of Specimens. PMID- 29612041 TI - Presidential Address. PMID- 29612043 TI - Exhibition of Specimens. PMID- 29612042 TI - A Clinical and Pathological Analysis of a Successive Series of 120 Abdominal Hysterectomies for Fibro-Myomata. PMID- 29612045 TI - Exhibition of Specimens. PMID- 29612044 TI - Malta Fever in Pregnancy. PMID- 29612046 TI - Exhibition of Specimens. PMID- 29612047 TI - A Series of Cases of Axial Rotation in Its Relation to the Pelvic Generative Organs. PMID- 29612048 TI - Exhibition of Specimens. PMID- 29612049 TI - On Endothelioma of the Ovary. PMID- 29612050 TI - Case of Fatal Complete Irreducible Prolapsus Uteri. PMID- 29612052 TI - Exhibition of Specimens. PMID- 29612051 TI - Note on a Case of Distended Gall-Bladder Simulating Ovarian Cyst. PMID- 29612053 TI - Interesting Case of Caesarean Section at Full Term: Patient Had Two Uteri and Two Vaginae. The Second Uterus Was Myomatous, and Was Impacted in the Pelvis: It Completely Obstructed Labour. PMID- 29612054 TI - Curiosities of Curetting. PMID- 29612055 TI - Case of Eclampsia in Which Lumbar Puncture Was Performed. PMID- 29612056 TI - Exhibition of Specimens. PMID- 29612057 TI - The Application of Bier's Treatment to Inflammatory Affections of the Female Genital Organs. PMID- 29612058 TI - On a Case of Sarcoma of the Cervix. PMID- 29612059 TI - Climacteric Haemorrhage Due to Sclerosis of the Uterine Vessels. PMID- 29612060 TI - The Germ-Content of the Uterus and Vagina during the Normal Puerperium. PMID- 29612062 TI - Heredity in Ovarian Cystoma: History of a Mother and Her Two Daughters Subjected to Ovariotomy. PMID- 29612061 TI - Hydrocephalic Infant Delivered by Spinal Tapping. PMID- 29612063 TI - In Defence of the Pessary. PMID- 29612064 TI - Pathological Condition of the Ovaries as a Possible Factor in the Etiology of Uterine Fibroids. PMID- 29612065 TI - Pudendal Myxoma. PMID- 29612066 TI - Irregular Manifestations of Puerperal Sepsis. PMID- 29612067 TI - Exhibition of Specimens. PMID- 29612068 TI - Exhibition of Specimens. PMID- 29612069 TI - What Position Should Gynaecology Hold in the Medical Curriculum? PMID- 29612070 TI - Note on a Case of Exomphalos with Accidental Haemorrhage and Delayed Second Stage. PMID- 29612071 TI - Delivery of the Hydrocephalic Foetus by Spinal Tapping: A Second Case. PMID- 29612073 TI - Exhibition of Specimens. PMID- 29612072 TI - Pyuria in the Female. PMID- 29612074 TI - Clinical Experience of Ectopic Gestation and Allied Conditions. PMID- 29612075 TI - A Case of Eclampsia Followed by Melancholia, Which Was Treated with Thyroid Gland Substance. PMID- 29612077 TI - Exhibition of Specimens. PMID- 29612076 TI - Withdrawal of the Liquor Amnii: A Cause of Foetal Death and Placental Changes; an Experimental Investigation in the Rabbit. PMID- 29612078 TI - Eclampsia during Pregnancy; Death from Suppression of Urine; Extensive Infarction of Both Kidneys. PMID- 29612079 TI - Note on a Case of Intraperitoneal Haemorrhage Occurring during Labour; Recovery. PMID- 29612080 TI - A Case of Heteroplastic Ovarian Grafting Followed by Pregnancy and a Living Child. Query-Who Is the Mother? PMID- 29612081 TI - Note on a Case of Pregnancy in a Bicornuate Uterus. PMID- 29612082 TI - Valedictory Address. PMID- 29612083 TI - Abdominal Hysterectomy for Acute Puerperal Metritis and Acute Salpingitis, with Record of a Successful Case. PMID- 29612084 TI - Exhibition of Specimens. PMID- 29612086 TI - Exhibition of Specimens. PMID- 29612085 TI - The "Byrth of Mankynde"; Its Author and Editions. PMID- 29612087 TI - A Plea for Operative Interference in Intracranial Haemorrhages in the New-Born. PMID- 29612088 TI - Exhibition of Specimens. PMID- 29612089 TI - Hernia of the Uterine Adnexa, with a Personal Experience of Seven Cases. PMID- 29612090 TI - Note on a Case of Broad Ligament Cyst, with Twisted Pedicle, and Blood Extravasation into the Cellular Tissue along Left Ovarian Vein. PMID- 29612091 TI - Malignant Endocarditis during Pregnancy, with an Illustrative Case. PMID- 29612093 TI - Eclampsia during and after Labour; Recovery after Upwards of Two Hundred Fits. PMID- 29612092 TI - Some of the Physiological Changes in the Maternal Organism during Pregnancy and Their Significance. PMID- 29612094 TI - Abdominal Hysterectomy for Inversion of the Uterus; Fatty Degeneration of the Inverted Portion. PMID- 29612095 TI - The Use of the Stereoscope in the Teaching of Obstetrics and Gynaecology. PMID- 29612097 TI - Exhibition of Specimens. PMID- 29612096 TI - Post-Partum Ovariotomy. PMID- 29612098 TI - A Case of Repeated Abortion Due to Syphilis; Treatment by Potassium Iodide. Birth of Child with Congenital Goitre. PMID- 29612099 TI - Inaugural Address on the Future of Obstetrics. PMID- 29612100 TI - The "Byrth of Mankynde": Its Contents. PMID- 29612101 TI - Exhibition of Specimens. PMID- 29612103 TI - A Clinical and Anatomical Study of Thirty Cervical Fibroids Removed by Abdominal Hysterectomy. PMID- 29612102 TI - Exhibition of Specimens. PMID- 29612104 TI - Bilateral Ovarian Dermoid Tumours, Complicating Pregnancy. PMID- 29612106 TI - Exhibition of Specimens. PMID- 29612105 TI - Epilepsy and the Status Epilepticus in Connection with Pregnancy and Labour, with Illustrative Cases. PMID- 29612107 TI - Case of Acute Albuminuria, Caused by the Pressure of a Tumour on Both Ureters Operation-Recovery. PMID- 29612108 TI - Exophthalmic Goitre in Its Relation to Obstetrics and Gynaecology. PMID- 29612109 TI - On the Prognosis of Pregnancy in Patients with One Kidney, with Notes of an Unusually Complicated Case of Labour after Nephrectomy. PMID- 29612110 TI - The Management of Some Difficult Occipito-Posterior Cases. PMID- 29612111 TI - Successful Treatment of Puerperal Fever by Antistreptococcic Serum. PMID- 29612113 TI - Exhibition of Specimens. PMID- 29612112 TI - Six Cases of Vaginal Caesarean Section. PMID- 29612114 TI - A Series of Five Cases of Caesarean Section for Contracted Pelvis. PMID- 29612115 TI - Exhibition of Specimens. PMID- 29612116 TI - Two Cases of Pregnancy Complicated by Fibroid Tumours, Treated by Hysterectomy. PMID- 29612117 TI - Intractable Uterine Haemorrhage, and Arterio-Sclerosis of the Uterine Vessels. PMID- 29612119 TI - Hysterectomy for Fibroid Tumours in Pregnancy. Two Cases. PMID- 29612118 TI - Exhibition of Specimens. PMID- 29612120 TI - The Organisation and Equipment of an Emergency Domiciliary Obstetrical Service. PMID- 29612121 TI - Further Observations on the Prevention of Puerperal Temperatures and Local Sepsis. PMID- 29612122 TI - Exhibition of a Specimen. PMID- 29612123 TI - The Therapeutic Uses of Progesterone. PMID- 29612124 TI - Anaemias of the Newborn and Early Infancy. PMID- 29612125 TI - The Principles of Radiation Treatment of Carcinoma Cervicis Uteri. PMID- 29612126 TI - Breech Delivery, with Special Reference to the Primigravida. PMID- 29612127 TI - Anatomical Variations in the Female Pelvis: Their Classification and Obstetrical Significance. PMID- 29612128 TI - Some Social Aspects of Abortion. PMID- 29612129 TI - Achondroplasia, Brachydactyly, and Cranio-Cleido-Dysostosis: Their Nature and Causation-A Preliminary Sketch. PMID- 29612130 TI - Exhibition of Specimens. PMID- 29612131 TI - Acute Dilatation of the Stomach as a Post-Operative Complication in Abdominal Cases. PMID- 29612132 TI - A Mongol of a Primiparous Mother; Parents Both Young and Healthy; Traumatic Shock to Mother Early in the Pregnancy. PMID- 29612134 TI - Exhibition of Specimens. PMID- 29612133 TI - Exhibition of Specimens. PMID- 29612135 TI - A Contribution to the Theory of Enzygotic (Monochorionic) Twins. PMID- 29612136 TI - Note on a Chylous Mesenteric Cyst, Simulating a Pelvic Tumour. PMID- 29612137 TI - On Caesarean Section and Repeated Caesarean Section for Contracted Pelvis, with Notes of a Case Performed for the Third Time on the Same Woman Successfully to Mother and Child. PMID- 29612138 TI - Note on a Case of Landry's Paralysis Occurring during Pregnancy and the Puerperium. PMID- 29612139 TI - Exhibition of Specimens. PMID- 29612140 TI - The Cystic Ovary. PMID- 29612141 TI - Two Rare Tumours: (1) Perithelioma of the Uterus; (2) Perithelioma of the Fallopian Tube. PMID- 29612142 TI - The Structure and Functions of the Uterine Mucosa: The Nature of the Chorionic Action and the Function of the Decidua. PMID- 29612143 TI - Exhibition of Specimens. PMID- 29612144 TI - Simple Papillomata Removed from the Vaginal Vault after Vaginal Hysterectomy for Cervical Cancer. PMID- 29612145 TI - Cervical Polypi Exhibiting Decidual Changes. PMID- 29612147 TI - Exhibition of Specimens. PMID- 29612146 TI - Some Considerations Regarding the Narrow Pelvis. PMID- 29612148 TI - On Adenoma Vaginae Diffusum (Adenomatosis Vaginae), with a Critical Discussion of Present Views of Vaginal and Hymeneal Development. PMID- 29612149 TI - Note on a Case of Adenoma of the Vagina under Observation for Fifteen Years. PMID- 29612150 TI - An Experimental Study of the Anaphylactic Theory of the Toxaemia of Pregnancy. PMID- 29612151 TI - Exhibition of Specimens. PMID- 29612152 TI - Presidential Address: A Retrospect and Comparision of the Progress of Midwifery and Gynaecology. PMID- 29612153 TI - Short Note of a Case of Superfoetation. PMID- 29612154 TI - Tuberculous Pyosalpinx. PMID- 29612155 TI - Exhibition of Specimens. PMID- 29612156 TI - Lateral Incision of the Perineum and Its Immediate Repair after Labour: With a Few Remarks on the Advisability of Immediate Suture of the Cervix after Labour. PMID- 29612157 TI - Eclampsia in the Edinburgh Maternity Hospital, with Special Reference to Its Seasonal Incidence. PMID- 29612158 TI - Two Examples of the Difficulty of Diagnosis of Ectopic Pregnancy. PMID- 29612159 TI - Note on an Unusual Cause of Pain in the Back. PMID- 29612160 TI - Numan, the Veterinarian and Comparative Anatomist of Utrecht: A Forgotten Observer on the Free-Martin. PMID- 29612161 TI - Exhibition of Specimens. PMID- 29612163 TI - The Technique of the More Extensive Abdominal Operations for Cancer of the Womb. PMID- 29612162 TI - Complete Absence of the Vagina: Regurgitation of Menstrual Blood through the Fallopian Tube into the Peritoneal Cavity; with Notes of an Unusual Case. PMID- 29612164 TI - Case of Fibroid of Uterus (Showing Unusual Form of Cystic Change), Removed by Supravaginal Hysterectomy, Where Severe Post-Operative Haemorrhage Occurred from a Corpus Luteum, Necessitating Reopening of the Abdomen and Removal of the Ovary. PMID- 29612165 TI - An Experience of Three Cases of Pubiotomy. PMID- 29612166 TI - Adeno-Carcinoma Complicating Myomata of the Uterus in Twin Sisters. PMID- 29612167 TI - Axial Rotation (Cervical Torsion) of the Myomatous Uterus. PMID- 29612168 TI - Exhibition of Specimens. PMID- 29612169 TI - Chorio-Angioma of the Placenta. PMID- 29612170 TI - Exhibition of Specimens. PMID- 29612172 TI - Exhibition of Specimens. PMID- 29612171 TI - Valedictory Address to the Edinburgh Obstetrical Society: Some Reminiscences of Sir James Y. Simpson's Association with the Edinburgh Obstetrical Society. PMID- 29612173 TI - Exhibition of Specimens. PMID- 29612174 TI - Exhibition of Specimens. PMID- 29612175 TI - Transplantation of the Ovary in the Human Being: Record of Three Cases. PMID- 29612176 TI - Exhibition of Specimens. PMID- 29612177 TI - Demonstration of a New Method of Measuring the Pelvic Brim by Radiography. PMID- 29612178 TI - Case of Pyosalpinx Successfully Removed by Abdominal Section during the Puerperium. PMID- 29612179 TI - Conjoint Meeting with the Glasgow Obstetrical and Gynaecological Society, to Consider the Probable Effects of the "Maternity Benefit" Clauses of the National Insurance Act upon Obstetrical Teaching and Practice in Scotland. PMID- 29612180 TI - Treatment of Contraction of Pelvic Outlet-Two Cases, One Treated by Pubiotomy, the Other by Induction. PMID- 29612182 TI - Exhibition of Specimens. PMID- 29612181 TI - Rheumatoid Arthritis: A Short Record of Two Cases, Presumably of Puerperal Causation. PMID- 29612183 TI - Some Practical Points in the Life-History of Uterine Fibromyomata. PMID- 29612184 TI - Valedictory Address. PMID- 29612185 TI - A Short Note on the Treatment of Vomiting Following Chloroform Anaesthesia, Including the Use of Adrenalin. PMID- 29612186 TI - Bacillus Coli Infection of Urinary Tract Complicating Pregnancy. PMID- 29612187 TI - Case of Antenatal Lobar Pneumonia. PMID- 29612188 TI - Ovarian Epilepsy and Its Treatment by Operation. PMID- 29612189 TI - Exhibition of Specimens. PMID- 29612190 TI - Note on Two Unusual Cases of Pelvic Abscess. PMID- 29612192 TI - Exhibition of Specimens. PMID- 29612191 TI - The Rational Puerperium. PMID- 29612193 TI - The Importance of Removing the Uterus in Certain Diseased Conditions of the Adnexa. PMID- 29612195 TI - Exhibition of Specimens. PMID- 29612194 TI - Vaginal Fixation for Uterine Displacements. PMID- 29612196 TI - Exhibition of Specimens. PMID- 29612197 TI - Exhibition of Specimens. PMID- 29612198 TI - A Simple Perineal Operation, as Used in Cases of Prolapsus Uteri and for Perineal Repair. PMID- 29612199 TI - Two Cases of Uterus Bicornis. PMID- 29612200 TI - The Histological Changes Associated with an Early Abortion, with Special Reference to the Vessels of the Decidua. PMID- 29612202 TI - Exhibition of Specimens. PMID- 29612201 TI - On a Supra-Pubic Transverse Fascial Incision in Gynaecological Coeliotomy. PMID- 29612203 TI - The Physiological Basis for Decapsulation of the Kidney in Eclamptic Anuria. PMID- 29612204 TI - Exhibition of Specimens. PMID- 29612205 TI - Renal Decapsulation in Puerperal Eclampsia. PMID- 29612206 TI - On the Value of Manipulative Action Combined with Axis Traction in the Use of the Forceps. PMID- 29612208 TI - Exhibition of Specimens. PMID- 29612207 TI - The Anatomy and Histology of the Pregnant Tube. PMID- 29612209 TI - Exhibition of Specimens. PMID- 29612211 TI - Thyroid Extract as a Preventive of Dystocia from Large Child. PMID- 29612210 TI - Clinical Notes of Seven Recent Cases of Extra-Uterine Gestation, with Remarks. PMID- 29612212 TI - The Complications and Difficulties in a Series of 250 Ovariotomies. PMID- 29612214 TI - A Short Experience of Scopolamine-Morphine Narcosis in Labour. PMID- 29612213 TI - A Plea for a Rational Puerperium, with a Record of 100 Cases. PMID- 29612215 TI - Exhibition of Specimens. PMID- 29612216 TI - Physiological Conditions Relative to the Conservative Surgery of the Uterus, Tubes, and Ovaries. PMID- 29612218 TI - Our Four Forefathers in Midwifery: A Historical Study. PMID- 29612217 TI - The Interpretation of the Porro Uterus in Relation to the Third Stage of Labour. PMID- 29612219 TI - Peritonitis as a Complication of Fibroids, Especially in Association with Torsion of the Pedicle, with an Illustrative Case. PMID- 29612220 TI - The Nature and Cause of the Physiological Descent of the Testes. PMID- 29612221 TI - Mendelian Action on Differentiated Sex. PMID- 29612222 TI - Pre-Maternity Hospital Practice: A Series of Thirty Cases of Morbid Pregnancy Treated in the Royal Maternity Hospital, Edinburgh, during the Autumn Quarter, 1908. PMID- 29612223 TI - Exhibition of Specimens. PMID- 29612224 TI - Exhibition of Specimens. PMID- 29612225 TI - The Physiological Descent of the Ovaries in the Human Foetus. PMID- 29612226 TI - Note on a Case of Pneumococcal Peritonitis at the Eighth Month of Pregnancy. PMID- 29612227 TI - Presidential Address on Preventive Midwifery and Gynaecology. PMID- 29612228 TI - Exhibition of Specimen. PMID- 29612229 TI - Exhibition of Specimens. PMID- 29612230 TI - A Note on a New Use of Oxygen Therapy. PMID- 29612231 TI - Exhibition of Specimens. PMID- 29612232 TI - The Failed Forceps Case and Its Treatment. PMID- 29612233 TI - Acute OEdema of the Anterior Lip of the Cervix. PMID- 29612234 TI - Exhibition of Specimens. PMID- 29612235 TI - The Routine Treatment of Eclampsia : Statement by the President. PMID- 29612236 TI - Treatment of Puerperal Infections. PMID- 29612237 TI - Note on a Case of Concealed Accidental Haemorrhage Treated by Hysterectomy. PMID- 29612238 TI - A Case of Fits during Fourth Month of Pregnancy without Other Signs of Toxaemia. PMID- 29612239 TI - Exhibition of Specimens. PMID- 29612241 TI - Exhibition of Specimens. PMID- 29612240 TI - Treatment of Concealed Accidental Haemorrhage by Conservative Caesarean Section. PMID- 29612242 TI - Some Observations on Gonococcal Infection of the Fallopian Tubes and Ovaries. PMID- 29612244 TI - Exhibition of Specimen. PMID- 29612243 TI - Note on the Relative Merits of Operations on the Round Ligaments for Retroversion of the Uterus, with a Suggestion for a Procedure for Increasing the Scope and Usefulness of the Alexander-Adams Operation. PMID- 29612245 TI - Record of Eclampsia in the Royal Maternity Hospital, Edinburgh, during Ten Years, 1912-1921. PMID- 29612246 TI - A Case of Caesarean Section in Multiple Pregnancy. PMID- 29612247 TI - Inversion of the Uterus, with a Record of Four Cases. PMID- 29612248 TI - Caesarean Section and Alternative Treatment. PMID- 29612249 TI - Icterus Neonatorum. PMID- 29612250 TI - The Diagnosis and Treatment of Acute Tubal Peritonitis. PMID- 29612252 TI - Exhibition of Specimens. PMID- 29612251 TI - Valedictory Address: The Society during Sessions 1919-1921. PMID- 29612253 TI - Omphalorrhagia, with a Record of Two Cases. PMID- 29612254 TI - Exhibition of Specimens. PMID- 29612255 TI - Further Study of an Organism Obtained from Cancerous Growths. PMID- 29612256 TI - The Induction of Premature Labour in Cases of Disproportion. PMID- 29612257 TI - Exhibition of Specimens. PMID- 29612258 TI - Pneumoperitoneum of the Pelvis as an Aid to Gynecological Diagnosis. PMID- 29612260 TI - Exhibition of Specimens. PMID- 29612259 TI - A Case of Ovarian Dermoid Rupturing into the Bowel during Labour. PMID- 29612261 TI - Presidential Address. PMID- 29612262 TI - Obstetric Experiences Amongst a Primitive Tribe. PMID- 29612264 TI - Concealed Accidental Haemorrhage Associated with Eclampsia. PMID- 29612263 TI - Case of Double Congenital Hydronephrosis. PMID- 29612265 TI - Pelvimetry as an Index of Treatment in Contracted Pelves. PMID- 29612266 TI - Still-Birth: Its Causes, Pathology, and Prevention. PMID- 29612267 TI - The Surgical Treatment of Uterine Prolapse. PMID- 29612269 TI - Exhibition of Specimens. PMID- 29612268 TI - Pregnancy and Labour in a Double Uterus. PMID- 29612270 TI - Description of an Organism Obtained from Carcinomatous Growths. PMID- 29612272 TI - A Case of Central Placenta Praevia Associated with Eclampsia. PMID- 29612271 TI - Exhibition of Specimens. PMID- 29612273 TI - A Further Experience of the Conduct of Labour under "Twilight Sleep": With Special Reference to Its Use in Private Practice. PMID- 29612275 TI - An Experimental Investigation into the Etiology of Accidental Haemorrhage and Placental Infarction. PMID- 29612274 TI - The Treatment of Concealed Accidental Haemorrhage. PMID- 29612276 TI - Some Practical Aspects of Ante-Natal Care. PMID- 29612277 TI - The Clinical Condition of the Uterine Wall in Concealed Accidental Haemorrhage. PMID- 29612278 TI - Exhibition of Specimens. PMID- 29612279 TI - Exhibition of Specimens. PMID- 29612280 TI - Notes on Three Cases of Caesarean Section. PMID- 29612281 TI - Exhibition of Specimens. PMID- 29612282 TI - A Simple and Improved Modification of the Midwifery Forceps. PMID- 29612283 TI - Note on a Case of Post-Mortem Caesarean Section in Twin Pregnancy, with Survival of One Child. PMID- 29612284 TI - A Case of Concealed Haemorrhage with Placenta Praevia. PMID- 29612285 TI - Exhibition of Specimens. PMID- 29612286 TI - Note on a Case of Post-Partum Convulsions Presenting Difficulties in Diagnosis. PMID- 29612287 TI - A Technique for the Operative Treatment of Rectocele. PMID- 29612288 TI - Exhibition of Specimens. PMID- 29612289 TI - Valedictory Address on the Treatment of Puerperal Sepsis. PMID- 29612290 TI - A Case of Ectopic Gestation with Unusual Clinical Features. PMID- 29612291 TI - Study of an Early Human Ovum and the Functional Similarity of the Ovarian and Placental Hormones. PMID- 29612292 TI - The Ethical and Scientific Aspects of the Prevention, Conservation, and Destruction of Intra-Uterine Life. PMID- 29612293 TI - Symptoms without Signs. PMID- 29612294 TI - Exhibition of Specimens. PMID- 29612296 TI - Chronic Pelvic Pain in Relation to Neurasthenia. PMID- 29612295 TI - Some Problems in the Bacteriology of Puerperal Sepsis. PMID- 29612297 TI - Exhibition of Specimens. PMID- 29612299 TI - Exhibition of Specimens. PMID- 29612298 TI - The Treatment of Placenta Praevia. PMID- 29612300 TI - An Account of an Epidemic of Puerperal Sepsis Due to Streptococcus Haemolyticus. PMID- 29612301 TI - Exhibition of Specimens. PMID- 29612303 TI - Exhibition of Specimens. PMID- 29612302 TI - Exhibition of Specimens. PMID- 29612304 TI - An Investigation of the Clinical Effects of Laevo-Rotary and Dextro-Rotary Hyoscine. PMID- 29612306 TI - Impressions of a Visit to Certain American and Canadian Obstetrical and Gynaecological Clinics. PMID- 29612305 TI - Abdominal Pregnancy Secondary to Tubal Gestation at Term, with Notes of a Case. PMID- 29612307 TI - Presidential Address on the Teaching of Obstetrics. PMID- 29612308 TI - The Mobility of the Uterus as a Factor in the Care of the Third Stage of Labour and in the Control of Post-Partum Haemorrhage? PMID- 29612310 TI - A Case of Unusually Slow Foetal Heart Beat during the First Stage of Labour. PMID- 29612309 TI - Is Plagiocephaly Ever a Birth Deformity? PMID- 29612312 TI - Report on Two Cases of Krukenberg Tumour of the Ovary. PMID- 29612311 TI - Exhibition of Specimens. PMID- 29612313 TI - Exhibition of Specimens. PMID- 29612315 TI - Exhibition of Specimens. PMID- 29612314 TI - Adenomyoma of the Uterus with Tuberculous Infection. PMID- 29612316 TI - Caesarean Section : Observations Based on an Operative Experience of over 100 Cases, with Special Reference to Clinical and Pathological Findings in Cases of Obstructed Labour, and Describing an Operative Technique in Infected Cases. PMID- 29612317 TI - The Association of Placenta Praevia and the Albuminuric Toxaemias. PMID- 29612318 TI - Further Observations on Still-Birth and Neonatal Death: Their Causes, Pathology, and Prevention. PMID- 29612319 TI - Exhibition of Specimens. PMID- 29612320 TI - Exhibition of Specimens. PMID- 29612321 TI - Induction of Labour by Quinine and Pituitrin. PMID- 29612322 TI - Exhibition of Specimens. PMID- 29612323 TI - Valedictory Address on Recent Advances in Obstetrics and Gynaecology. PMID- 29612324 TI - Note on a Case of Rupture of the Uterus Following the Administration of Pituitrin for the Induction of Labour. PMID- 29612325 TI - One Hundred Successive and Successful Caesarean Sections in Cases of Contracted Pelvis. PMID- 29612326 TI - Case of Early Chorion-Epithelioma. PMID- 29612327 TI - Some Observations on Seventy Years of Country Midwifery Practice. PMID- 29612328 TI - Administration of Thyroid Gland during Pregnancy. PMID- 29612329 TI - A Pendulous Tumour of the Labium Majus Exhibiting Unusual Features. PMID- 29612330 TI - A Case of Malignant Hydatidiform Mole with Pulmonary Metastases. PMID- 29612332 TI - Exhibition of Specimens. PMID- 29612331 TI - A Note on Pelvimetry. PMID- 29612333 TI - Hydroureter and Hydronephrosis Secondary to Prolapse and Cystocele. PMID- 29612334 TI - Veratrone-With Special Reference to a Case of Severe Reaction. PMID- 29612335 TI - Induction of Labour. PMID- 29612336 TI - Exhibition of Specimens. PMID- 29612338 TI - Public Business. PMID- 29612337 TI - Puerperal Gangrene : Report of Seven Cases in Four of Which Ergotamine Tartrate Was Suspected as Being Part Cause. PMID- 29612339 TI - Presidential Address: "Thoughts on the Life and Work of Sir James Young Simpson". PMID- 29612340 TI - The Treatment of Placenta Praevia. PMID- 29612341 TI - The Modification of Cow's Milk for Infant Feeding. PMID- 29612343 TI - Exhibition of Specimens. PMID- 29612342 TI - The Hormone of the Corpus Luteum. PMID- 29612344 TI - An Analysis of 306 Cases of Contracted Pelvis. PMID- 29612345 TI - Post-Partum Necrosis of the Anterior Pituitary. PMID- 29612346 TI - Endometriosis as a Pathological and Clinical Problem. PMID- 29612347 TI - Notes on Four Cases of Postpartum Collapse. PMID- 29612348 TI - Anaemia in Pregnancy and the Puerperium. PMID- 29612349 TI - The Treatment of Chronic Cervicitis. PMID- 29612350 TI - A Case of Unruptured Tubal Pregnancy Continuing to Full Term. PMID- 29612351 TI - President's Valedictory Address: "A Short Record of the Edinburgh Royal Maternity and Simpson Memorial Hospital". PMID- 29612353 TI - Exhibition of Specimens. PMID- 29612352 TI - On Spalding's Sign of Intra-Uterine Death of the Foetus : Report of a Case of a Live Child, the Death of Which Had Been Suggested by the Radiological Picture. PMID- 29612354 TI - Public Business. Exhibition of Specimens. PMID- 29612355 TI - Exhibition of Specimens. PMID- 29612356 TI - OEstradiol Benzoate Therapy in Senile Vaginitis. PMID- 29612357 TI - The Management of Labour in Cases of Contracted Pelvis. Discussion at a Joint Meeting of the Glasgow and Edinburgh Obstetrical Societies Opened by Hector R. MacLennan and Edwin M. Robertson. PMID- 29612359 TI - The Principles of Irradiation Treatment in Carcinoma of the Cervix. PMID- 29612358 TI - Struma Ovarii, with Report of a Case. PMID- 29612360 TI - Exhibition of Specimens. PMID- 29612361 TI - Report of Three Cases of Congenital Abnormality of the Genital Tract Complicating Labour. PMID- 29612362 TI - Exhibition of Specimens. PMID- 29612363 TI - Birth Injuries of the Child. PMID- 29612365 TI - Exhibition of Specimen. PMID- 29612364 TI - Discussion on the Scottish Departmental Report on Maternal Morbidity and Mortality. PMID- 29612366 TI - Valedictory Address: "The Personal Factor in Maternal Mortality". PMID- 29612367 TI - Radium and Cancer of the Neck of the Uterus. PMID- 29612368 TI - Exhibition of Specimens. PMID- 29612369 TI - The Etiology of Amenorrhoea with Special Reference to Treatment. PMID- 29612370 TI - Some Observations on the Management of the Third Stage of Labour. PMID- 29612371 TI - Exhibition of Specimens. PMID- 29612372 TI - Gonorrhoea in Children. PMID- 29612374 TI - Ten Cases of Caesarean Section for Varied Indications. PMID- 29612373 TI - The Advisability of Modification of the Existing Terms of Notification of Puerperal Fever and the Question of Including Other Causes of Pyrexia in the Puerperium. PMID- 29612376 TI - Measles, Diabetes, and Encephalitis Respectively Associated with Parturition. PMID- 29612375 TI - Loose Bodies in the Peritoneum: With Notes of a Case in Which a Loose Ovary (?) Was Found in the Pouch of Douglas. PMID- 29612377 TI - Exhibition of Specimens. PMID- 29612378 TI - Exhibition of Specimens. PMID- 29612379 TI - Ovulation in the Human Ovary. PMID- 29612380 TI - Valedictory Address: "The Preventive Frame of Mind in Obstetrics". PMID- 29612381 TI - A Clinical Record of Three Cases of Puerperal Haemorrhage. PMID- 29612382 TI - Maternal Mortality from Puerperal Sepsis: An Analysis of the Factors of Contagion, Trauma and Auto-Infection. PMID- 29612383 TI - The Value of Ovarian Extract after an Artificial Menopause. PMID- 29612384 TI - Results Obtained in the Treatment of Eclampsia by the Improved Prophylactic Method, and the Value of Telephonic Consultations. PMID- 29612385 TI - Exhibition of Specimens. PMID- 29612386 TI - Exhibition of Specimens. PMID- 29612387 TI - The Reduction of Forceps Delivery as a Basis for Prophylactic Gynaecology. PMID- 29612388 TI - Spontaneous Rupture of the Uterus, before or during Labour. PMID- 29612389 TI - Occipito-Posterior Position of the Vertex: A Survey of 750 Cases. PMID- 29612390 TI - Therapeutic Abortion with Special Reference to Methods of Induction. PMID- 29612391 TI - Hydatidiform Mole. PMID- 29612393 TI - Exhibition of Specimens. PMID- 29612392 TI - Presidential Address: "The Greater Gynaecology: Its Relations to Medicine and Surgery". PMID- 29612395 TI - Exhibition of Specimens. PMID- 29612394 TI - Do the Pharmacopoeal Preparations of Ergot Contain Any Active Principles? PMID- 29612396 TI - Exhibition of Specimens. PMID- 29612397 TI - Two Cases of Antepartum Rupture of the Uterus through a Caesarean Section Scar. PMID- 29612398 TI - Exhibition of Specimens. PMID- 29612399 TI - Some Problems of the Menstrual Function with Observations on the Relation of the Graafian Follicle and Corpus Luteum to Pathological Uterine Haemorrhage. PMID- 29612401 TI - Exhibition of Specimens. PMID- 29612400 TI - Diabetes and Pregnancy. PMID- 29612402 TI - The Human Sex-Ratio. PMID- 29612403 TI - Exhibition of Specimens. PMID- 29612404 TI - Rupture and Inversion of the Uterus. PMID- 29612405 TI - Recurrent Pregnancy Toxaemia and Its Relation to Placental Damage. PMID- 29612407 TI - Presidential Address: "James Matthews Duncan". PMID- 29612406 TI - Eclampsia - A Clinical Survey of 159 Cases Treated by Conservative Methods. PMID- 29612408 TI - Still-Birth and Neo-Natal Death : A Study of 300 Cases, with Special Reference to the Occurrence of Intracranial Haemorrhage and Asphyxia. PMID- 29612409 TI - Meeting - 12th December 1928. PMID- 29612410 TI - The Effect of Diet (Antenatal and Postnatal) on the Structure of the Teeth and the Incidence of Dental Caries. PMID- 29612411 TI - Private Business. PMID- 29612412 TI - Exhibition of Specimens. PMID- 29612413 TI - The Future of Obstetrics, with Special Reference to the Development of a Maternity Service. PMID- 29612414 TI - A Scheme of Maternity Service Co-Ordinating Antenatal, Domiciliary and Hospital Treatment. PMID- 29612415 TI - The Mechanics of Internal Rotation of the Foetus. PMID- 29612416 TI - A Study of the Bactericidal Power of the Blood during Pregnancy and the Puerperium, and Its Relationship to the Development and Course of Puerperal Infection. PMID- 29612417 TI - Ureteric Dilatation of Pregnancy, Its Complications and Sequelae. PMID- 29612418 TI - The Ganglion Cervicalia Uteri and the OEstrus Hormone. PMID- 29612419 TI - Exhibition of Specimens. PMID- 29612420 TI - Pseudopregnancy and Its Mechanism. PMID- 29612422 TI - The Colour Scheme in Pregnancy. PMID- 29612421 TI - Suppression of Urine in Pregnancy and the Puerperium, and Its Relation to Symmetrical Necrosis of the Renal Cortex. PMID- 29612423 TI - Suggestions as to the Causes of the Persistence of Puerperal Septicaemia Since the End of Pre-Antiseptic Times. PMID- 29612425 TI - Exhibition of Specimens. PMID- 29612424 TI - On Artificial Rotation of the Head in Persistent Occipito-Posterior Positions. PMID- 29612426 TI - Suggestions as to the Causes of the Persistence of Puerperal Septicaemia Since the End of Pre-Antiseptic Times. PMID- 29612427 TI - Valedictory Presidential Address. PMID- 29612428 TI - On Cranial Stress in the Foetus during Labour and on the Effects of Excessive Stress on the Intracranial Contents; with an Analysis of Eighty-One Cases of Torn Tentorium Cerebelli and Subdural Cerebral Haemorrhage. PMID- 29612429 TI - Vaccine Therapy in Gynecology and Obstetrics. PMID- 29612430 TI - On the Histology of Hydatidiform Mole in Its Relation to Prognosis. PMID- 29612431 TI - Exhibition of Specimens. PMID- 29612432 TI - Exhibition of Specimens. PMID- 29612433 TI - Still-Births' Registration. PMID- 29612434 TI - Biometric Analysis of Some Insemination-Labour and Menstrual-Labour Curves in Certain Mammalia. PMID- 29612436 TI - Exhibition of Specimens. PMID- 29612435 TI - Exhibition of Specimens. PMID- 29612437 TI - Notes on a Case of Pregnancy in a Malformed Uterus. PMID- 29612439 TI - Exhibition of Specimens. PMID- 29612438 TI - Still-Births' Registration. PMID- 29612440 TI - Exhibition of Specimens. PMID- 29612441 TI - Valedictory Presidential Address. PMID- 29612442 TI - Contribution to the Study of the Early Human Ovum, Based upon the Investigation of (1) a Very Early Ovum Embedded in the Uterus, and (2) a Very Early Ovum Embedded in the Infundibulum of the Tube. PMID- 29612443 TI - A New Route of Inquiry as to the Nature and Establishment of the Typical Sex Ensemble in the Mammalia. PMID- 29612444 TI - The Etiology of Eclampsia and Albuminuria and Their Relation to Accidental Haemorrhage. PMID- 29612445 TI - On the Need for Eugenic Reform. PMID- 29612446 TI - On the Atypical Male and Female Sex-Ensemble (So-Called Hermaphroditism and Pseudo-Hermaphroditism). PMID- 29612447 TI - The Place of Gynaecology in the Medical Curriculum and in General Practice. PMID- 29612448 TI - Advanced Extra-Uterine Gestation with Tuberculous Peritonitis. PMID- 29612449 TI - A Case of Cloacal Vesical Exstrophy in the Female. PMID- 29612450 TI - Note on a Case Involving Some Ethical Questions, Eugenic and Obstetric. PMID- 29612451 TI - The Maternal Mortality Problem in Some of Its Physiological and Medical Aspects. PMID- 29612452 TI - The Use of Ultra-Violet Light in the Treatment of Pre-Eclamptic Toxaemia. PMID- 29612453 TI - Some Major Disorders in Newly-Born Infants. PMID- 29612454 TI - An Effect on the Rat of Antenatal and Postnatal Administration of OEstrin. PMID- 29612455 TI - Some Observations on the Basophil Cells of the Human Hypophysis. PMID- 29612457 TI - Exhibition of Specimen. PMID- 29612456 TI - Some Comments on the Findings of the Maternal Mortality Report, with Special Reference to Failed Forceps Cases. PMID- 29612458 TI - Spondylolithesis, with Record of Spontaneous Delivery in a Severe Case. PMID- 29612459 TI - Exhibition of Specimen. PMID- 29612460 TI - Changes in Thought in a Half Century of Obstetrics. PMID- 29612461 TI - Exhibition of Specimens. PMID- 29612462 TI - The Maternity Hospital and Unitary Control. PMID- 29612463 TI - Exhibition of Specimens. PMID- 29612465 TI - Exhibition of Specimens. PMID- 29612464 TI - Note on Blood Pressure. PMID- 29612466 TI - The Presence and Effect of the Ovarian Hormones and Gonadotropic Substances. PMID- 29612468 TI - The AEtiology of Leucorrhoea in the Virgin. PMID- 29612467 TI - Recording the Contractions of the Human Pregnant and Non-Pregnant Uterus. PMID- 29612469 TI - The Position of General Practitioner Midwifery. PMID- 29612470 TI - Exhibition of Specimens. PMID- 29612471 TI - Exhibition of Specimens. PMID- 29612473 TI - Pyuria in the Puerperium. PMID- 29612472 TI - The Late Results of Caesarean Section: A Study of 463 Caesarean Section Cases, with Special Reference to the Late Results of 174 Operations. PMID- 29612474 TI - Exhibition of Specimens. PMID- 29612475 TI - Clinical Record of Two Cases Exemplifying Risks Attached to the Operation of Curettage of the Uterus. PMID- 29612476 TI - Broad Ligament Neuritis: Its Clinical Features and Treatment. PMID- 29612477 TI - The Treatment of Varicose Veins during Pregnancy. A Record of Fifty Cases Treated by the Injection of Sodium Morrhuate. PMID- 29612478 TI - Exhibition of Specimens. PMID- 29612479 TI - Bilateral Cortical Necrosis of the Kidneys : A Report of Three Cases Occurring during Pregnancy. PMID- 29612480 TI - Presidential Address: "The Medical Schools and the Nation's Health". PMID- 29612481 TI - The Diagnosis of Placenta Praevia with Special Reference to the Employment of X Rays for This Purpose. PMID- 29612482 TI - William Smellie and the Maternity Mortality Problem. PMID- 29612483 TI - Post-Menopausal Haemorrhage-Discussion. PMID- 29612484 TI - Clinical Use of a Preparation of OEstrin in the Treatment of Functional Secondary Amenorrhoea: A Record of Sixteen Cases. PMID- 29612485 TI - Case of Haemangio-Lymphangioma of the Neck of the Child Causing Delay in Labour. PMID- 29612486 TI - Clinical Record of Fifteen Cases of Pruritus Vulvae Treated by Injection of A. B. A. PMID- 29612488 TI - Exhibition of Specimens. PMID- 29612487 TI - Recent Views Regarding the Physiology of the Uterus with Special Reference to the Pregnant Uterus. PMID- 29612489 TI - Some Aspects of Radiotherapy in Relation to Gynaecology. PMID- 29612490 TI - An Aid in the Prevention of Puerperal Sepsis. PMID- 29612491 TI - Exhibition of Specimens. PMID- 29612492 TI - Exhibition of Specimens. PMID- 29612493 TI - Exhibition of Specimens. PMID- 29612494 TI - Menstruation in Mental Disease. PMID- 29612495 TI - Palliative Treatment of Salpingitis. PMID- 29612496 TI - AEtiology of the Toxaemias of Pregnancy in the Light of Recent Laboratory and Clinical Observations. PMID- 29612497 TI - Clinical Record of a Case of Exomphalos : Illustrating the Embryonic Type and Its Surgical Treatment. PMID- 29612498 TI - A Fatal Case of Eclampsia Associated with Intensive Cerebral Haemorrhage at the 36th Week of Pregnancy. PMID- 29612499 TI - Exhibition of Specimens. PMID- 29612501 TI - Some Points in the Investigation, Prognosis and Treatment of Tubal Conditions, with Special Reference to Insufflation and X-Ray Examination after Injection with Lipiodol. PMID- 29612500 TI - Primary Ovarian Pregnancy with a Report of Two Cases: Implantation on the Surface of the Ovary. Implantation in the Mature Follicle. PMID- 29612502 TI - The Influence of Age on the Process of Child-Birth: An Investigation into the Course of Labour in the Very Young and Elderly Primipara. PMID- 29612504 TI - Presidential Valedictory Address. PMID- 29612503 TI - Exhibition of Specimens. PMID- 29612505 TI - Puerperal Temperatures and Their Prevention. PMID- 29612506 TI - A Fatal Case of ? Acute Pregnancy Toxaemia at the 17th Week. PMID- 29612507 TI - Abortion: A Discussion on Its Social, Legal and Ethical Aspects. PMID- 29612509 TI - Exhibition of Specimens. PMID- 29612508 TI - Ureteric Lesions as a Cause of Abdominal Symptoms: A Consideration of "Ureteritis" or "Ureteral Stricture". PMID- 29612510 TI - Exhibition of Specimens. PMID- 29612511 TI - Exhibition of Specimens. PMID- 29612512 TI - Eclampsia and Puerperal Toxaemia: A Study of the Histological Changes Occurring in the Liver and Kidneys. PMID- 29612514 TI - Then and Now. PMID- 29612513 TI - Uterine Prolapse : An Investigation into 132 Cases. PMID- 29612515 TI - An Unusual Case of Traumatic Rupture of the Uterus Early in Pregnancy. PMID- 29612516 TI - Exhibition of Specimens. PMID- 29612517 TI - Heart Disease in Relation to Pregnancy. PMID- 29612518 TI - Some Minor Digestive Disorders in Breast-Fed Infants during the First Month. PMID- 29612519 TI - Vesical Exclusion in the Treatment of Carcinoma of the Cervix Uteri. PMID- 29612520 TI - A Discussion on Intracranial Injury in the New-Born and Its Relationship to Breech Delivery. PMID- 29612521 TI - A Case of Streptococcal Infection of the Uterus Complicating Pregnancy. PMID- 29612522 TI - Presidential Inaugural Address. PMID- 29612523 TI - Bilateral Cortical Necrosis of the Kidneys-A Clinical and Pathological Report of Four Cases. PMID- 29612524 TI - Abdominal Hysterotomy : A Review of 28 Cases. PMID- 29612526 TI - An Investigation of a Series of 100 Ovarian Tumours. PMID- 29612525 TI - A Study of the Vaginal Flora in Pregnancy. PMID- 29612527 TI - Some Observations on Puerperal Sepsis, with Special Reference to Its Occurrence in Maternity Hospitals. PMID- 29612529 TI - Exhibition of Specimen. PMID- 29612528 TI - Myomectomy : A Record of 154 Consecutive Cases. PMID- 29612530 TI - The Practicability of the Aschheim-Zondek Test for Pregnancy. PMID- 29612531 TI - Exhibition of Specimens. PMID- 29612532 TI - The Value of the Dick Test in Pregnancy. PMID- 29612533 TI - Exhibition of Specimens. PMID- 29612534 TI - Habitual Abortion or Miscarriage. PMID- 29612535 TI - Exhibition of Specimens. PMID- 29612537 TI - Chronic Infection of the Cervix : A Frequent Cause of Pelvic and General Illness. PMID- 29612536 TI - Exhibition of Specimens. PMID- 29612538 TI - A Clinical Record of Four Personal Cases Treated by Abdominal Hysterotomy. PMID- 29612539 TI - Valedictory Address. PMID- 29612540 TI - Notes on Three Cases of Interstitial Tubal Pregnancy. PMID- 29612541 TI - A Retrospect: Thirty Years' Midwifery in a Semi-Rural Area with Special Reference to Technique. PMID- 29612542 TI - Exhibition of Specimens. PMID- 29612543 TI - Note of a Case of Recurrent Peculiar Transverse Presentation, Apparently Due to the Malformation of the Uterus. PMID- 29612544 TI - A Case of Intrauterine Polypus. PMID- 29612545 TI - Report of, and Observations upon, a Case of Twins with Double Placenta Praevia (Partial), and Both Children Presenting Transversely-Abortion from Typhoid Fever in Previous Pregnancy. PMID- 29612546 TI - Antiseptic Treatment of Mammary Abscess. PMID- 29612547 TI - New Form of Galvanic Pessary. PMID- 29612548 TI - Strangulation in Utero. PMID- 29612549 TI - New Cause of Haemorrhage from the Placenta. PMID- 29612550 TI - Case of Acute Yellow Atrophy of the Liver. PMID- 29612551 TI - Pelvimetry; a Method of Estimating the Conjugata Vera. PMID- 29612552 TI - Abstract of Paper-An Obstetrical History-A Vesico-Vaginal Fistula, with Subsequent Conceptions. PMID- 29612553 TI - The Use of Barnes's Dilators in the Treatment of Complete Placenta Praevia. With Two Illustrative Cases. PMID- 29612554 TI - Malformation of the Umbilical Cord. PMID- 29612555 TI - A Third Case of Consecutive Spina Bifida. PMID- 29612556 TI - On the Construction and Salubrity of Maternity Hospitals. PMID- 29612557 TI - Specimen of Blighted Twin. PMID- 29612558 TI - Case of Cephalotripsy in a Labour Obstructed by Pelvic Deformity Originating in Necrosis of the Ischium. PMID- 29612559 TI - Case of Cholera in a Puerperal Woman-Recovery under the Use of Bromide of Potassium. PMID- 29612560 TI - Specimen of an Entire Ovum Expelled at Fifth Month. PMID- 29612561 TI - On the Scarification of the Gums of Infants in Dentition. PMID- 29612562 TI - Death of Foetus by Strangulation. PMID- 29612563 TI - Storer's Scarificator. PMID- 29612564 TI - Two Cases of Labour in Which the Tetrachloride of Carbon Was Used. PMID- 29612565 TI - New Sponge-Tents Dipped in Carbolic Acid, Tied, Dried, and Turned. PMID- 29612566 TI - Cephalotripsy after Turning, with Remarks. PMID- 29612567 TI - Notes on a Case of Hydatids. PMID- 29612568 TI - Case of Still-Born Child in Case of Albuminuria. PMID- 29612569 TI - On the Use of Chlorate of Potass in Certain Cases of Pregnancy. PMID- 29612570 TI - On the Application of Reflected Light in the Diagnosis and Operative Treatment of Uterine and Vaginal Diseases, with Cases. PMID- 29612571 TI - Microscopical Preparation of Unstriped Muscular Fibre. PMID- 29612573 TI - India-Rubber Sponge as Tents and Pessaries. PMID- 29612572 TI - Case of Placenta Praevia. PMID- 29612574 TI - Eastlake's and Storer's Instruments. PMID- 29612575 TI - Inflatable Pessary. PMID- 29612576 TI - Case of Profuse Post-Partum Haemorrhage, Due to Adherent Placenta. PMID- 29612577 TI - Specimen of Cephalotribe. PMID- 29612579 TI - On a Modification of the Fillet. PMID- 29612578 TI - On the Construction of the Cephalotribe. PMID- 29612580 TI - Notes of a Case of Puerperal Mania. PMID- 29612582 TI - Specimen of Large Placenta, with Exceedingly Entire Membranes. PMID- 29612581 TI - Case of Triplets. PMID- 29612583 TI - On the Combined External and Internal Method of Version, with Cases. PMID- 29612584 TI - Birth of an Extraordinary Large Child. PMID- 29612585 TI - On Complete Intra-Uterine Detachment of the Placenta before Labour. PMID- 29612586 TI - Case Illustrating the Use of Galvanism in Severe Post-Partum Haemorrhage. PMID- 29612588 TI - Case of Haemorrhage from the Bowel in a New-Born Infant. PMID- 29612587 TI - Case of Pelvic Haematocele. PMID- 29612589 TI - Two Cases of Convulsions during Dentition Arrested by Scarification of the Gums. PMID- 29612590 TI - Caoutchouc Dilator. PMID- 29612591 TI - Containing Titles and Dates, so Far as They Can Be Ascertained, of All Communications to the Society from Its Institution to 1868. PMID- 29612592 TI - Case of Sudden Death after Delivery. PMID- 29612593 TI - Cases Attended at the Maternity Hospital. PMID- 29612594 TI - A Case of Spontaneous Healing of Harelip in Utero. PMID- 29612595 TI - Case of Abnormal Soft-Palate in an Infant, Resulting Fatally. PMID- 29612596 TI - How Long May a Dead Foetus Remain in the Uterus? PMID- 29612597 TI - Notes of a Case of Ovarian Dropsy. PMID- 29612598 TI - Chloroform Inhaler. PMID- 29612599 TI - Specimen of Anencephalous Foetus with Club Feet. PMID- 29612600 TI - Case of Convulsions Occurring after Delivery. PMID- 29612601 TI - A Case of Puerperal Convulsions, with Amaurosis, Treated by Bleeding and Version. PMID- 29612602 TI - Case of Ruptured Ovary. PMID- 29612604 TI - The Connection between Laceration of the Perinaeum and Prolapsus Uteri. PMID- 29612603 TI - Obstetrical Instruments Used in France. PMID- 29612605 TI - On the Use of the Constant (Voltaic) Current in Pains of Pelvic Origin. PMID- 29612606 TI - Hydrate of Chloral in Puerperal Convulsions. PMID- 29612607 TI - Case of Fibroid Polypus of the Uterus, with Preparation. PMID- 29612608 TI - Case of Cephalotripsy. PMID- 29612609 TI - Notes of a Case of Anencephalous Foetus. PMID- 29612610 TI - Case of Puerperal Convulsions Treated by Chloral. PMID- 29612611 TI - On the Influence Exerted by Chloral on the Pain of Parturition. PMID- 29612612 TI - Fatty Placenta. PMID- 29612613 TI - Remarks on Pelvic Peritonitis and Pelvic Cellulitis, with Illustrative Cases. PMID- 29612615 TI - Polypus of the Rectum. PMID- 29612614 TI - Cyst of the Cervix Uteri. PMID- 29612617 TI - Development of Cysts in the Stroma of the Ovary. PMID- 29612616 TI - Notes of a Case of Extra-Uterine Gestation. PMID- 29612618 TI - Foetal Monstrosity (Phoco-Melos). PMID- 29612619 TI - Case of Vicarious Menstruation. PMID- 29612620 TI - On the Lacerations of the External Genital Organs, except the Hymen, during Labour in Primiparae. PMID- 29612621 TI - Notes of a Case of Anencephalous Foetus Born Co-Twin with a Healthy Child. PMID- 29612622 TI - Fibrous Polypus. PMID- 29612624 TI - Note on a Peculiar Form of Vaginal Hernia. PMID- 29612623 TI - Case of Hypogastric Fistula. PMID- 29612626 TI - Specula for Examining the Female Bladder. PMID- 29612625 TI - Fibrous Tumour of the Round Ligament. PMID- 29612627 TI - Case of Spina Bifida. PMID- 29612628 TI - Case of Central Rupture of the Perineum. PMID- 29612629 TI - Report of Delegates from the Society to the International Medical Congress in Philadelphia. PMID- 29612630 TI - Funis with a Double Knot on It. PMID- 29612631 TI - Hair in the Female Bladder. PMID- 29612632 TI - Case of So-Called Torsion of the Cord. PMID- 29612633 TI - Note on Uterine Mucous Membrane of a Woman Who Died Immediately after Menstruation. PMID- 29612635 TI - Cast of a Malformed Foetus. PMID- 29612634 TI - Cases of Fatal Haemorrhage after Childbirth. PMID- 29612636 TI - Remarks on a Case of Twin Conception. PMID- 29612638 TI - On the Complete Evacuation of the Uterus after Abortion. PMID- 29612637 TI - Exhibition of Urinary Calculi. PMID- 29612639 TI - New Instrument for Performing Vaccination. PMID- 29612640 TI - On the Condition of the Cervix Uteri in the Latter Months of Utero-Gestation. PMID- 29612641 TI - Abstract of a Paper on Obstetric Therapeutics. PMID- 29612642 TI - A Case of Intra-Uterine Fibrous Polypus. PMID- 29612643 TI - Case of Labour Complicated by Prolapse of the Leg. PMID- 29612644 TI - Some Remarks on Fibrous Tumours of the Uterus. PMID- 29612645 TI - The Structure of a True Mucous Polypus of the Cervix. PMID- 29612646 TI - Successful Case of Ovariotomy. PMID- 29612647 TI - Foetus with Intra-Uterine Peritonitis. PMID- 29612648 TI - On the Structure of Three Cervical Polypi. PMID- 29612649 TI - Remarks on the Inevitable and Other Lacerations of the Orifice of the Vagina, and near It, in Primiparae. PMID- 29612650 TI - Exhibition of a Partially Dimidiate Placenta. PMID- 29612651 TI - Foetus with Exomphalos and Sacral Hygroma. PMID- 29612652 TI - On a Diprosopus Triophthalmus Monster. PMID- 29612653 TI - Abstract of a Paper on the Bearings of Chronic Disease of the Heart upon Pregnancy and Parturition. PMID- 29612654 TI - Exhibition of a Plaster-Cast of a Group Illustrating the Process of Parturition Found in the Temple of Venus, at Golgos, in Cyprus. PMID- 29612655 TI - Specimens Illustrating Friability of the Cord, Torsion of the Cord, and Hydrorachis. PMID- 29612656 TI - Notes of a Case of Partial Placenta Praevia. PMID- 29612657 TI - On the Systematic Prevention of after Pains. PMID- 29612658 TI - On Some of the Relations of the Foetal Head to Rupture of the Perineum and Injuries of the External Genital Organs. PMID- 29612659 TI - Large Soft Fibroid Tumour of the Uterus. PMID- 29612660 TI - Rupture of the Perineum, and Especially on the Division of the Perineum and Recto Vaginal Septum by Post-Partum Sloughing. PMID- 29612661 TI - Extra-Uterine Foetation. PMID- 29612662 TI - Exhibition of Mucous Polypi. PMID- 29612664 TI - Note on the Use of the Stethoscope in Obstetrics. PMID- 29612663 TI - Case of Spontaneous Version after Rupture of the Membranes in a Primipara. PMID- 29612665 TI - Note of a Case in Which the Foetal Heart Was Heard at an Early Period of Pregnancy. PMID- 29612666 TI - Case of Cancer of the Liver in a Young Child. PMID- 29612667 TI - Exhibition of Iliac Veins of a Woman Who Died of Ovarian Disease. PMID- 29612668 TI - Exhibition of Nails of a Newly-Born Child, of Unusual Length. PMID- 29612669 TI - Exhibition of Acardiac Foetus. PMID- 29612670 TI - Anencephalous Foetus. PMID- 29612671 TI - Contributions to the Determination of the Diminution of the Uterus after Delivery. PMID- 29612672 TI - Entire Ovum from a Case of Miscarriage at the Sixth Month. PMID- 29612673 TI - Case of Triplets Complicated with Puerperal Convulsions after Delivery. PMID- 29612674 TI - Laceration of the Perineum. PMID- 29612675 TI - Exhibition of Mucous Polypi. PMID- 29612676 TI - Exhibition of a Foetus Papyraceus. PMID- 29612677 TI - Case of Emphysema during Labour. PMID- 29612679 TI - Notes of a Case of Fibro-Myomatous Polypus. PMID- 29612678 TI - Foreign Bodies in the Female Bladder. PMID- 29612680 TI - On the Nature and Mechanism of Spontaneous Rupture of the Uterus in Its Cervical Portion. PMID- 29612681 TI - Sketch of the Anatomy of the Placenta. PMID- 29612682 TI - Notes of a Fatal Case of Chorea Gravidarum. PMID- 29612683 TI - Exhibition of a Foetus, Born Dead and Doubled up with Spine Presenting. PMID- 29612685 TI - Exhibition of Two Polypi. PMID- 29612684 TI - Fatal Case of Post-Partum Haemorrhage. PMID- 29612686 TI - Exhibition of Cellular Polypus. PMID- 29612687 TI - On the Therapeutic Action of the Secale Cornutum. PMID- 29612688 TI - Case of Procidentia Uteri. PMID- 29612689 TI - Abstract of a Paper on the Uterine Souffle and the Foetal Heart. PMID- 29612690 TI - Placenta from a Case of Partial Placenta Praevia. PMID- 29612691 TI - Against the Pendulum Movement in Using the Midwifery Forceps. PMID- 29612692 TI - On the Means of Ascertaining the Length of Gestation by Measurements of the Foetus and Gravid Uterus during the Second Period of Pregnancy. PMID- 29612693 TI - Enlargement of the Thyroid Body in Pregnancy. PMID- 29612694 TI - Exhibition of Crosse's Work on Inversio Uteri. PMID- 29612696 TI - Emmenologia. PMID- 29612695 TI - Two Cases of Puerperal Pleuropneumonia. PMID- 29612697 TI - On the Influence of Digestion in the Mother on the Foetal Pulse. PMID- 29612698 TI - Note of a Case of Painless Second Stage of Labour in a Primipara. PMID- 29612699 TI - Notes on a Case of Hemiplegia in a Child Following the Application of the Forceps at Birth. PMID- 29612700 TI - Exhibition of the Placentae from a Case of Triplets. PMID- 29612701 TI - Albuminuria and Puerperal Eclampsia. PMID- 29612702 TI - Case of Coiling of the Umbilical Cord. PMID- 29612703 TI - Fibroid Polypus. PMID- 29612704 TI - Specimen of Insertio Velamentosa. PMID- 29612705 TI - Long Umbilical Cord. PMID- 29612706 TI - Case of Labour Impeded by Enlargement of the Kidneys. PMID- 29612708 TI - Case of Abortion. PMID- 29612707 TI - Exhibition of an Anencephalous Foetus, Born Co-Twin with a Healthy Child. PMID- 29612709 TI - On Prolapsus and Retroversion as Alternating Misplacements of the Gravid Uterus. PMID- 29612710 TI - Case of Fatty Degeneration of Placenta. PMID- 29612711 TI - Case of Intra-Uterine Peritonitis in the Foetus. PMID- 29612712 TI - Exhibition of a Compressed Foetus. PMID- 29612714 TI - Remarks on Vacher's Forceps. PMID- 29612713 TI - Case of Extra-Uterine Foetation Successfully Treated by Abdominal Section. PMID- 29612715 TI - Entire Ovum from Case of Partial Placenta Praevia. PMID- 29612716 TI - Exhibition of an Acardiac Foetus. PMID- 29612717 TI - Specimen of Siren Foetus. PMID- 29612718 TI - Exhibition of an Ovum of Very Early Period. PMID- 29612719 TI - Exhibition of a Rhinocephalous Cyclopean Foetal Lamb. PMID- 29612720 TI - On the Resuscitation of Still-Born Children. PMID- 29612721 TI - Notes of a Case of Labour Complicated with Emphysema. PMID- 29612722 TI - On Prickle Cells in the Capsule of a Fibrous Polypus of the Uterus. PMID- 29612723 TI - Sarcoma Uteri. PMID- 29612724 TI - Case of Puerperal Tetanus. PMID- 29612725 TI - Exhibition of Two Preparations Illustrating Extra-Uterine Pregnancy. PMID- 29612726 TI - Exhibition of Drawings Illustrating Haemorrhage during Pregnancy, Etc. PMID- 29612727 TI - Torsion of the Umbilical Cord. PMID- 29612728 TI - Remarks on Post-Partum Haemorrhage. PMID- 29612729 TI - Note on Intrauterine Craniometry. PMID- 29612730 TI - Exhibition of Umbilical Cord Tied with an Elastic Ligature. PMID- 29612731 TI - Specimen of Anencephalous Foetus. PMID- 29612732 TI - Specimen of Celosome Foetus. PMID- 29612734 TI - Placenta Praevia. PMID- 29612733 TI - Occlusion of Vagina. PMID- 29612736 TI - Exhibition of Specimens. PMID- 29612735 TI - Polycotyledonary Placenta. PMID- 29612737 TI - Cervix of Channelled Polypus. PMID- 29612739 TI - Exhibition of Specimens. PMID- 29612738 TI - Preparation of Case of Imperforate Anus. PMID- 29612740 TI - Fibroma of Vagina. PMID- 29612741 TI - Preparation of Abortion. PMID- 29612742 TI - Case of Placenta Praevia. PMID- 29612744 TI - Value of Rapid Dilatation of, as an Aid to Diagnosis Urethra. PMID- 29612743 TI - Accidental Haemorrhage. PMID- 29612745 TI - Knots of Umbilical Cord. PMID- 29612747 TI - Knots of Umbilical Cord. PMID- 29612746 TI - New Form Exhibited Forceps. PMID- 29612749 TI - Extra Uterine Foetation. PMID- 29612748 TI - Preparation of Pelvic Haematocele. PMID- 29612750 TI - Preparation of Pelvis and Contents. PMID- 29612751 TI - Retroversion of Gravid Uterus. PMID- 29612752 TI - Curettes and Curetting. PMID- 29612753 TI - Dull Wire Curette. PMID- 29612754 TI - Preparation of Fibrous Polypus. PMID- 29612755 TI - Abnormal Pregnancy. PMID- 29612756 TI - Fibroid Tumours of Uterus. PMID- 29612757 TI - Abnormal Placenta. PMID- 29612758 TI - Vesico-Vaginal Fistula. PMID- 29612759 TI - Torsion of the Cervix Uteri in a Cow. PMID- 29612760 TI - Two Contracted Forms of Weak Labour. PMID- 29612762 TI - Exhibition of Dull Wire Curette. PMID- 29612761 TI - Channelled Polypus. PMID- 29612763 TI - Exhibition of Placenta. PMID- 29612765 TI - Intrauterine Hydrocephalus. PMID- 29612764 TI - Preparation of Partial Atelectasis. PMID- 29612766 TI - Hymen in Cohabitation, Child-Bearing, Etc. PMID- 29612767 TI - Placenta Praevia. PMID- 29612768 TI - Hydatiginous Degeneration of Chorion. PMID- 29612769 TI - Retention of Urine. PMID- 29612770 TI - Post-Partum Preparation of Uterus. PMID- 29612771 TI - Preparation Constriction of Small Intestine. PMID- 29612773 TI - Plumstone in Rectum. PMID- 29612772 TI - Case of Cephalotripsy. PMID- 29612775 TI - Exhibition of Specimens. PMID- 29612774 TI - Preparation of Knotted Cord. PMID- 29612776 TI - Preparation of Early Ovum. PMID- 29612777 TI - Exhibition of Abdominal Bandage. PMID- 29612778 TI - Exhibition of Foetus and Placenta. PMID- 29612779 TI - Exhibition of Simpson's Forceps with Traction Rod. PMID- 29612780 TI - Case of Hystero-Epilepsy. PMID- 29612781 TI - Exhibition of Lawson Tait's Instruments for Dilating Cervix. PMID- 29612782 TI - Exhibition of Vascular Decidua. PMID- 29612783 TI - Head Flexion in Labour. PMID- 29612785 TI - Exhibition of Specimens. PMID- 29612784 TI - Exhibition of Uterus and Annexa. PMID- 29612786 TI - Prolapsus of the Uterus during Labour. PMID- 29612787 TI - Exhibition of Hydatigenous Placenta. PMID- 29612788 TI - The Use of Tarnier's Forceps. PMID- 29612789 TI - Exhibition of Specimens. PMID- 29612790 TI - Exhibition of Placenta. PMID- 29612791 TI - A Study of Two Mesial Vertical Sections of the Female Pelvis, Etc. PMID- 29612792 TI - Exhibition of Female Foetus with Dropsy. PMID- 29612793 TI - Exhibition of Uterine Hydatids. PMID- 29612794 TI - Exhibition of Foetus from Case of Embryotomy. PMID- 29612796 TI - Exhibition of Fibroid Polypi. PMID- 29612795 TI - Forceps in Tedious Labour. PMID- 29612797 TI - Locomotor Ataxia Complicating Labour. PMID- 29612798 TI - Senile Prolapsus. PMID- 29612799 TI - Case of Accidental Haemorrhage. PMID- 29612801 TI - Exibition of Specimens. PMID- 29612800 TI - Puerperal Eclampsia. PMID- 29612802 TI - Exhibition of Specimens. PMID- 29612803 TI - Treatment of Puerperal Septicaemia. PMID- 29612804 TI - Exihibition of Foetus, with Head Markings, and Another Similar Specimen. PMID- 29612806 TI - Exhibition of Hydrocephalic Foetus. PMID- 29612805 TI - Case of Calcified Fibroid Tumour. PMID- 29612808 TI - Adherent Prepuce in Children. PMID- 29612807 TI - Obstructed Labour from Dorsal Displacement of the Arm. PMID- 29612809 TI - Endometritis and Menorrhagia Treated by Intra-Uterine Medication. PMID- 29612810 TI - Exhibition of Ovum. PMID- 29612811 TI - Discussion on Education of Midwives. PMID- 29612812 TI - Exhibition of Tumour of Uvula of Child. PMID- 29612813 TI - Report of Cases Treated in the Royal Maternity and Simpson Memorial Hospital during the First Three Months after Its Opening. PMID- 29612814 TI - Exhibition of Uterus and Two Ovarian Tumours. PMID- 29612815 TI - Anencephalous Foetus, with Spina Bifida. PMID- 29612816 TI - Use of the Volsella in Gynecology. PMID- 29612817 TI - Exhibition of Ovarian Cyst. PMID- 29612819 TI - Carcinoma Cervicis Uteri et Orificii Urethrae. PMID- 29612818 TI - Exhibition of Cast of Foetal Head. PMID- 29612821 TI - Exhibition of a New Variety Forceps. PMID- 29612820 TI - Source of Error in the Clinical Estimation of the Elongation of the Cervix during Labour. PMID- 29612822 TI - Exhibition of Intra-Uterine Soft Rubber Spring Stem Pessary. PMID- 29612823 TI - Etiology of Puerperal Fever. PMID- 29612824 TI - Prevention of Mammary Abscess. PMID- 29612825 TI - Accidental Notes of a Case of Haemorrhage. PMID- 29612826 TI - Exhibition of Specimens. PMID- 29612827 TI - Exhibition of Placenta. PMID- 29612829 TI - Exhibition of Specimens. PMID- 29612828 TI - Exhibition of Fibroid Polypus. PMID- 29612830 TI - Carcinoma Vaginae in a Pregnant Female. PMID- 29612831 TI - Spasmodic Contraction of the Lower Uterine Segment during Labour. PMID- 29612832 TI - Bearings of the Shape of the Foetal Head on the Mechanism of Labour. PMID- 29612834 TI - Exhibition of Specimens. PMID- 29612833 TI - Exhibition of Right Ovary. PMID- 29612835 TI - Exhibition of Head of Tapeworm. PMID- 29612836 TI - Development and Structure of the Ovary. PMID- 29612837 TI - Exhibition of Entire Ovum. PMID- 29612839 TI - Notes of a Case of Fibroid Tumour Expelled under the Use of Subcutaneous Injections of Ergotin. PMID- 29612838 TI - Sterility and Placenta Praevia Primipara. PMID- 29612840 TI - Calculus in the Female Bladder. PMID- 29612841 TI - Exhibition of Specimens. PMID- 29612842 TI - Two Cases of Chronic Inversion of the Uterus. PMID- 29612844 TI - Case of Early Viability. PMID- 29612843 TI - An Improved Method of Treating Uterine Displacements. PMID- 29612845 TI - Exhibition of Specimens. PMID- 29612846 TI - Fourteen Cases of Completed Ovariotomy. PMID- 29612847 TI - Retro-Pharyngeal Abscess in an Infant. PMID- 29612848 TI - A Complication of Occipito-Posterior Position of the Vertex. PMID- 29612849 TI - On Placenta Praevia. PMID- 29612850 TI - Exhibition of Specimens. PMID- 29612851 TI - Exhibition of Specimens. PMID- 29612852 TI - On Extra-Uterine Conception. PMID- 29612853 TI - On a Method of Treatment of Certain Kinds of Incontinence of Urine. PMID- 29612854 TI - On the Systematic Use of Antiseptics in Midwifery Practice. PMID- 29612855 TI - On Some of the Phenomena of Parturition in Their Practical Aspects. PMID- 29612856 TI - Severe Case of Membranous Dysmenorrhoea. PMID- 29612857 TI - Case of Caesarean Hystero-Oophorectomy, or Porro's Operation. PMID- 29612858 TI - Congenital Closure of Posterior Nares. PMID- 29612859 TI - Case of Occlusion of the Small Intestine in a New-Born Child. PMID- 29612860 TI - Clinical Observations on Puerperal Temperatures. PMID- 29612862 TI - A Form of Post-Partum Incontinence of Urine, and Its Treatment by Faradism. PMID- 29612861 TI - On the Shape of the Empty Female Bladder. PMID- 29612863 TI - Exhibition of Specimens. PMID- 29612864 TI - Exhibition of Specimens. PMID- 29612865 TI - Fibroid Tumour of Uterus Complicating Labour. PMID- 29612866 TI - Exhibition of Specimens. PMID- 29612867 TI - Quarter Ending 31st January 1881. PMID- 29612868 TI - Exhibition of Specimens. PMID- 29612869 TI - Delivery by the Breech through a Greatly Narrowed, Flat, Rachitic Pelvis. PMID- 29612870 TI - Method of Case-Taking in Midwifery. PMID- 29612871 TI - Exhibition of Specimens. PMID- 29612872 TI - Exhibition of Specimens. PMID- 29612874 TI - Exhibition of Specimens. PMID- 29612873 TI - Exhibition of Specimens. PMID- 29612875 TI - Exhibition of Specimens. PMID- 29612876 TI - On the Use of the Catheter before Forceps-Delivery. PMID- 29612877 TI - Case of Abdominal Section in the Sixteenth Century. PMID- 29612878 TI - Two Cases of Puerperal Haematocele. PMID- 29612879 TI - Quarter Ending 31st October 1880. PMID- 29612880 TI - Quarter Ending 30th April 1881. PMID- 29612881 TI - Hare-Lip and Cleft Palate. PMID- 29612882 TI - Exhibition of Specimens. PMID- 29612883 TI - Quarter Ending 30th April 1882. PMID- 29612884 TI - Diagnosis of Advanced Extra-Uterine Gestation after the Death of the Foetus (with 1 Lithograph and 7 Woodcuts). PMID- 29612885 TI - Funic Haemorrhage during Labour (with 2 Lithographs). PMID- 29612886 TI - A Contribution to the Anatomy and Etiology of Rupture of the Peritoneal Portion of the Vagina during Labour. PMID- 29612887 TI - Extra-Uterine Gestation. PMID- 29612888 TI - Observations on the Bladder during the Early Puerperium. PMID- 29612889 TI - Note of a Case of Inversion of the Uterus Occurring Immediately Post-Partum, and Resulting in Spontaneous Amputation. PMID- 29612890 TI - A New Bivalve Speculum. PMID- 29612891 TI - Valedictory Address. PMID- 29612892 TI - Exhibition of Specimens. PMID- 29612894 TI - Exhibition of Specimens. PMID- 29612893 TI - Six Cases of Trachelorraphy. PMID- 29612896 TI - Exhibition of Instruments, Etc. PMID- 29612895 TI - Lupus of the Vulvo-Anal Region: With Cases. PMID- 29612897 TI - Fibrinous Polypoid Uterine Tumour; Secondary Haemorrhages; Removal of Tumour. PMID- 29612898 TI - Case of Caesarean Hystero-Oophorectomy, or Porro's Operation. PMID- 29612899 TI - Quarter Ending 31st October 1883. PMID- 29612900 TI - Erratum. AB - [This corrects the article on p. 188 in vol. 9.]. PMID- 29612901 TI - Extreme Cystic Dilatation of the Fallopian Tubes; Abdominal Section; Recovery. PMID- 29612902 TI - Quarter Ending 30th April 1884. PMID- 29612903 TI - Uterine Displacements, and Their Treatment by Means of Medicated Tampons. PMID- 29612904 TI - Exhibition of Specimens. PMID- 29612905 TI - Some Cases of Clinical and Pathological Interest in the Buchanan Ward, under Professor Simpson, 1883-4. PMID- 29612906 TI - Notes on Labour in Central Africa. PMID- 29612907 TI - Puerperal Albuminuria; Reflex Paralysis; Eclampsia. PMID- 29612909 TI - Exhibition of Specimens. PMID- 29612908 TI - Record of Two Cases of Extra-Uterine Pregnancy-One of Them Successfully Treated by Laparotomy and Intestinal Resection. PMID- 29612910 TI - Three Cases of Caesarean Section. PMID- 29612911 TI - Ante-Partum Haemorrhage, with Special Reference to a Recent Case. PMID- 29612912 TI - Discussion on Dr Leith Napier's Paper on Albuminuria and Reflex Paralysis. PMID- 29612914 TI - Fibrous Tumours in the Cervix Uteri Expelled in an Unusual Manner. PMID- 29612913 TI - Exhibition of Specimens. PMID- 29612915 TI - The Anatomy and Relations of the Uterus during the Third Stage of Labour and the First Days of the Puerperium. PMID- 29612916 TI - Exhibition of Specimens. PMID- 29612917 TI - Case of Placenta Praevia, with Fibroid of the Uterus: Turning: Probable Rupture of Uterus: Peritonitis and Death. PMID- 29612918 TI - Quarter Ending 31st January 1884. PMID- 29612919 TI - On Haemorrhagic Lupus of the Female Genital Organs. PMID- 29612921 TI - Exhibition of Specimens. PMID- 29612920 TI - Record of Cases Treated in Ward XXVIII., Royal Infirmary, Edinburgh, from 1st November 1883 to 30th April 1884. PMID- 29612922 TI - Some Cases of Intrauterine Hydrocephalus, with Remarks. PMID- 29612923 TI - Note on Saexinger's and Winter's Sections. PMID- 29612924 TI - The Relationship between Neuralgia and Abortion: A Clinico-Speculative Note. PMID- 29612925 TI - A Case of Rupture of the Uterus. PMID- 29612926 TI - A Case of Annular Hymen. PMID- 29612927 TI - Mitral Stenosis and Labour. PMID- 29612928 TI - The Nature and Aim of Investigations on the Structural Anatomy of the Female Pelvic Floor. PMID- 29612930 TI - Exhibition of Specimens. PMID- 29612929 TI - A Contribution to the Normal Anatomy of the Female Pelvic Floor. PMID- 29612931 TI - The Physiology of the Third Stage of Labour: A Clinical Contribution. PMID- 29612932 TI - Exhibition of Specimens. PMID- 29612933 TI - An Analysis of One Hundred and Thirty Cases of Abdominal Section. PMID- 29612934 TI - On the Relative Weights of the Placenta and Child. PMID- 29612935 TI - Exhibition of Specimens. PMID- 29612936 TI - Does the Increase of Civilisation Render the Occurrence of Sepsis More Common? PMID- 29612937 TI - On the Light Which Sectional Anatomy Will Throw upon the Mechanism of Labour. PMID- 29612938 TI - A Contribution to the Pathology, Symptoms, and Treatment of Adherent Placenta. PMID- 29612940 TI - Exhibition of Specimens. PMID- 29612939 TI - Introductory Address. PMID- 29612941 TI - Remarks on Injury to Foetal Neck through Pressure of Umbilical Cord. PMID- 29612942 TI - Exhibition of Specimens. PMID- 29612943 TI - Report of the Royal Maternity and Simpson Memorial Hospital-Dr Underhill's Quarter: February-April, 1889. PMID- 29612945 TI - Exhibition of Specimens. PMID- 29612944 TI - Exhibition of Specimens. PMID- 29612946 TI - On a Variety of Post-Partum Shock: Its Nature, Cause, and Prevention. PMID- 29612948 TI - Case of Heart Disease Complicating Labour Treated Successfully by Nitrite of Amyl. PMID- 29612947 TI - Note on Some Anomalous Cases of Separation and Expulsion of the Placenta before the Birth of the Child. PMID- 29612949 TI - Foetal Malaria, as Illustrated by Two Cases. PMID- 29612950 TI - Two Cases of Labour, Complicated by Shortness of the Cord. PMID- 29612952 TI - Report of the Royal Maternity and Simpson Memorial Hospital for the Quarter Ending 30th April 1888. PMID- 29612951 TI - Early Contributions of Anatomy to Obstetrics. PMID- 29612953 TI - On Alcoholism in Gynaecology and Obstetrics. PMID- 29612954 TI - Some Scarlatiniform Rashes Occurring during the Puerperium. PMID- 29612955 TI - Report of the Royal Maternity and Simpson Memorial Hospital for the Quarter Ending 31st October 1887. PMID- 29612956 TI - Fifty Consecutive Cases of Ovariotomy and Removal of Uterine Appendages. PMID- 29612957 TI - Exhibition of Specimens. PMID- 29612959 TI - Exhibition of Specimens. PMID- 29612958 TI - The Third Stage of Labour: A Criticism of Papers by Cohn, Champneys, and Berry Hart. PMID- 29612960 TI - Mitral Stenosis in Labour and the Puerperium, with Sphygmographic Tracings. PMID- 29612961 TI - The Labia Minora and Hymen. PMID- 29612963 TI - Exhibition of Specimens. PMID- 29612962 TI - Tubal Distension and Stricture: A Cause of Intra-Peritoneal Haemorrhage. PMID- 29612964 TI - Valedictory Address. PMID- 29612965 TI - Case of Extrauterine Gestation. PMID- 29612966 TI - Note of a Case of Labour in a Kyphotic Pelvis. PMID- 29612967 TI - Some Cases of Puerperal Septicaemia Due to Impure Atmosphere. PMID- 29612968 TI - The Cause of the Head Downward Presentation, and of the First Cranial Position. PMID- 29612970 TI - Case of Acute Phthisis with Large Cavities in an Infant Nursed by a Phthisical Mother. PMID- 29612969 TI - Exhibition of Specimens. PMID- 29612971 TI - Report of the Royal Maternity and Simpson Memorial Hospital for the Quarter Ending 31st January 1888. PMID- 29612972 TI - Errata. AB - [This corrects the article on p. 80 in vol. 13.]. PMID- 29612973 TI - Exhibition of Specimens. PMID- 29612974 TI - A Case of Parasitic Foetus. PMID- 29612975 TI - Mitral Stenosis and the Third Stage of Labour. PMID- 29612976 TI - Notes on the Obstetric Histories of Catharine of Arragon and Anne Boleyn. PMID- 29612977 TI - Twelve Cases of Laparotomy for Disease of the Uterine Appendages. PMID- 29612978 TI - Exhibition of Specimens. PMID- 29612979 TI - A Successful Case of Caesarean Section. PMID- 29612980 TI - On the Effects of Compression of the Foetal Skull, with Special Reference to Delivery in Minor Degrees of Flat Pelvis. PMID- 29612981 TI - Cystic Disease of the Ovaries. PMID- 29612983 TI - Exhibition of Specimens. PMID- 29612982 TI - Exhibition of Specimens. PMID- 29612984 TI - Report of the Royal Maternity and Simpson Memorial Hospital, for the Quarter Ending 31st January 1890. PMID- 29612985 TI - Report of the Royal Maternity and Simpson Memorial Hospital, for the Quarter Ending 31st July 1889. PMID- 29612986 TI - A Case of Myomectomy for a Large Fibro-Cystic Tumour of the Uterus. PMID- 29612987 TI - Exfoliation of the Bladder in the Female. PMID- 29612988 TI - Some Points in the Morbid Anatomy of the Fallopian Tubes. PMID- 29612989 TI - Exhibition of Specimens. PMID- 29612990 TI - Intra-Uterine Rickets. PMID- 29612991 TI - Exhibition of Specimens. PMID- 29612992 TI - The Head of the Infant at Birth: Part II. PMID- 29612993 TI - Note upon Conception with Unruptured Hymen. PMID- 29612995 TI - Exhibition of Specimens. PMID- 29612994 TI - A Case of Encephalocele. PMID- 29612996 TI - On the Treatment of Pelvic Disease by Electricity. PMID- 29612997 TI - Exhibition of Specimens. PMID- 29612998 TI - Notes on Heart Disease in Pregnancy and Labour. PMID- 29612999 TI - The Co-Existence of Heart Disease and Pelvic Lesions. PMID- 29613000 TI - The Relations of the Pelvic Viscera in the Infant. PMID- 29613002 TI - The Disposition of the Pubic Segment in Pregnancy and in Labour. PMID- 29613001 TI - Note on the Term "Position". PMID- 29613003 TI - Exhibition of Specimens. PMID- 29613004 TI - Notes on a Case of Hydrocephalus with Meningocele. PMID- 29613005 TI - Exhibition of Specimens. PMID- 29613006 TI - Gynaecological Cases Treated by Electricity in Professor Simpson's Clinique. PMID- 29613007 TI - Exhibition of Specimens. PMID- 29613008 TI - The Head of the Infant at Birth: Part I. PMID- 29613009 TI - Jubilee Address: Sketch of the History of the Obstetrical Society. PMID- 29613010 TI - Exhibiton of Specimens. PMID- 29613011 TI - On the Treatment of Rupture of the Uterus. PMID- 29613012 TI - Exhibition of Specimens. PMID- 29613013 TI - Physiological and Therapeutic Effects of Water at Different Temperatures. PMID- 29613014 TI - Note of a Case of Retention of Urine from an Unusual Cause. PMID- 29613016 TI - Report of the Royal Maternity and Simpson Memorial Hospital, for the Quarter Ending 30th April 1886. PMID- 29613015 TI - Discussion on Micro-Organisms in Relation to Puerperal Fever. PMID- 29613017 TI - Valedictory Address. PMID- 29613019 TI - Exhibition of Specimens. PMID- 29613018 TI - Exhibition of Specimens. PMID- 29613020 TI - Post-Partum Vaginal Haematoma. PMID- 29613021 TI - Nature and Cause of the Rotation of the Head during Labour. PMID- 29613022 TI - Report of the Royal Maternity and Simpson Memorial Hospital, for the Quarter Ending 31st October 1885. PMID- 29613023 TI - Exhibition of Specimens. PMID- 29613024 TI - Sphygmographic Tracings in Labour. PMID- 29613025 TI - Exhibition of Specimens. PMID- 29613026 TI - Report of the Royal Maternity and Simpson Memorial Hospital, for the Quarter Ending 31st January 1886. PMID- 29613027 TI - A Common Nomenclature in Obstetrics. PMID- 29613028 TI - Fibrous Polypi Complicating the Puerperium. PMID- 29613029 TI - Exhibition of Specimens. PMID- 29613030 TI - Exhibition of Specimens. PMID- 29613031 TI - A Contribution to the Determination of Sex. PMID- 29613033 TI - Exhibition of Specimens. PMID- 29613032 TI - Case of Alexander-Adams' Operation. PMID- 29613034 TI - Position of the Uterus in Child. PMID- 29613035 TI - Exhibition of Specimens. PMID- 29613036 TI - A Case of Suppurative Parotitis Following Ovariotomy. PMID- 29613037 TI - Exhibition of Specimens. PMID- 29613038 TI - Exhibition of Instrument, Etc. PMID- 29613039 TI - Notes of a Case of Face Presentation, with Peculiar Attitude of the Foetus. PMID- 29613040 TI - Exhibition of Specimens. PMID- 29613041 TI - On the Prevention of Lying-In Fever. PMID- 29613042 TI - Exhibition of Specimens. PMID- 29613043 TI - Exhibition of Specimens. PMID- 29613044 TI - Note of a Case of Decapitation. PMID- 29613045 TI - Report of the Royal Maternity and Simpson Memorial Hospital, for the Quarter Ending 30th April 1885. PMID- 29613046 TI - Further Report of Cases Treated in Ward XXVIII., Royal Infirmary, from May to November 1884. PMID- 29613047 TI - Case of Porro-Muller Operation in a Labour Obstructed by a Large Dermoid Tumour Adherent to the Posterior Aspect of the Brim of the Pelvis. PMID- 29613048 TI - Note on a Case of Triplets. PMID- 29613049 TI - Report of the Royal Maternity and Simpson Memorial Hospital, for the Quarter Ending 31st January 1885. PMID- 29613050 TI - Notes on a Case of Alexander-Adams' Operation. PMID- 29613051 TI - Introductory Address. PMID- 29613052 TI - Exhibition of Specimens. PMID- 29613054 TI - Exhibition of Specimens. PMID- 29613053 TI - Pathology of Post-Partum Uterus:-1. Puerperal Septicaemia; 2. Adherent Membranes. PMID- 29613055 TI - Pulmonary Thrombosis in a Puerpera. PMID- 29613056 TI - Rare Cases of Malignant Disease of the Female Sexual Organs. PMID- 29613057 TI - Exhibition of Specimens. PMID- 29613058 TI - Ten Cases of Laparotomy Performed in the Royal Infirmary, from May to November 1884; with Remarks. PMID- 29613060 TI - Exhibition of Specimens. PMID- 29613059 TI - A Synopsis of Some Cases of Craniotomy Treated in the Sir Jamsetjee Jejeebhoy Obstetric Institution, Bombay. PMID- 29613061 TI - How Sims' Speculum Ought to Be Held. PMID- 29613062 TI - Exhibition of Specimens. PMID- 29613063 TI - Sphygmographic Tracings in Puerperal Eclampsia. PMID- 29613064 TI - Exhibition of Specimens. PMID- 29613065 TI - A Case of Urethrocele. PMID- 29613066 TI - Some Practical Points with Regard to the Membranes in the Third Stage of Labour. PMID- 29613067 TI - Report of the Royal Maternity and Simpson Memorial Hospital, for the Quarter Ending 31st October 1884. PMID- 29613068 TI - Report of a Case of Pregnancy in the Left Horn of a Bifurcated Uterus Treated Successfully by Hysterectomy, with Observations upon the Nature and the Proper Treatment of So-Called "Missed Labour". PMID- 29613069 TI - Note on a Case of Diminution of Albuminuria in Pregnancy Coincident with the Death of the Foetus. PMID- 29613070 TI - A Critical Consideration of the Methods of Anatomical Research, with Special Reference to the Topographical Anatomy of the Female Pelvis. PMID- 29613071 TI - On Infant Feeding. PMID- 29613072 TI - Note of a Case of Measles Complicating Pregnancy and Parturition. PMID- 29613073 TI - Exhibition of Preparations. PMID- 29613074 TI - Case of Inversion of the Uterus after Labour. PMID- 29613075 TI - Sectional Anatomy of Labour: Puerperium. PMID- 29613076 TI - Report of the Royal Maternity and Simpson Memorial Hospital, for the Quarter Beginning 1st November 1886 and Ending 31st January 1887. PMID- 29613078 TI - Report of the Royal Maternity and Simpson Memorial Hospital, for the Quarter Ending 30th April 1887. PMID- 29613077 TI - Case of Myxomatous Degeneration of the Chorion; Profuse Haemorrhage; Transfusion; Recovery. PMID- 29613079 TI - A Report upon Some Cases of Haematocele and Congenital Deformity, Observed in the Buchanan Ward under the Care of Professor Simpson. PMID- 29613080 TI - How Can the Accoucheur Best Guard the Perineum While the Foetal Head Is Passing? PMID- 29613082 TI - An Unusual Case of Monstrosity. PMID- 29613081 TI - On Axis-Traction Forceps. PMID- 29613083 TI - Report of the Cases of the Royal Maternity and Simpson Memorial Hospital during Dr Halliday Croom's Quarter, Ending 31st October 1886. PMID- 29613084 TI - Introductory Address. PMID- 29613085 TI - Exhibition of Specimens. PMID- 29613087 TI - Exhibition of Instrument, Etc. PMID- 29613086 TI - Notes upon a Case of Chorea Gravidarum, from the Buchanan Ward, Royal Infirmary. PMID- 29613088 TI - Report of Some Cases in the Sir J. J. Obstetric Institution. PMID- 29613090 TI - Exhibition of Specimens. PMID- 29613089 TI - On a Case of Spontaneous Inversion of the Uterus. PMID- 29613091 TI - Upon the Formation of the "Bag of Waters" When Voluminous. PMID- 29613092 TI - A Contribution to the Sectional Anatomy of Advanced Extrauterine Gestation. PMID- 29613093 TI - Deformed Foetus at Seven Months. PMID- 29613095 TI - Exhibition of Drawings. PMID- 29613094 TI - Sectional Anatomy of Labour: Before Labour, and First Stage. PMID- 29613096 TI - Exhibition of Specimens. PMID- 29613098 TI - Note on the Mechanism of the Separation of the Placenta during the Third Stage of Labour. PMID- 29613097 TI - On the Indications for and Method of Washing out the Puerperal Uterus. PMID- 29613099 TI - Note on a Case of Dystocia from Dorsal Displacement of the Arm. PMID- 29613100 TI - On a Case of Vesicular Placenta from a Premature Birth at the Seventh Month, the Child Being Born Alive. PMID- 29613101 TI - Sectional Anatomy of Labour: Third Stage. PMID- 29613102 TI - Sectional Anatomy of Labour: Before Labour, and First Stage. PMID- 29613103 TI - Notes of Cases. PMID- 29613104 TI - Gastro-Intestinal Disorder in Sucklings. PMID- 29613105 TI - A Contribution to the Anatomy of the Post-Partum Uterus, with Special Reference to Placenta Praevia. PMID- 29613106 TI - The Clinical Teaching of Midwifery and the Diseases of Women. PMID- 29613108 TI - Exhibition of Specimens. PMID- 29613107 TI - Exhibition of Specimens. PMID- 29613109 TI - Exhibition of Specimens. PMID- 29613110 TI - Exhibition of Specimens. PMID- 29613111 TI - Notes on the Treatment of Uterine Prolapse, with an Account of a New Modified Method of Anterior Colporrhaphy. PMID- 29613112 TI - Notes of Six Months' Work in the Midwifery Wards of the Women's Hospital, Melbourne, from 1st January to 30th June 1886. PMID- 29613113 TI - A Series of Abdominal Sections. PMID- 29613114 TI - Removal of Large Encysted "Wedgewood" Ball Pessary from Vagina. PMID- 29613115 TI - Prefatory Note. PMID- 29613118 TI - On the Culture Diagnosis and Serum Treatment of Puerperal Infection, with Illustrative Cases. PMID- 29613117 TI - Index of Subjects. PMID- 29613119 TI - Notes on Several Preparations from the Obstetrico-Gynecological Clinic at Charkow, Russia. PMID- 29613120 TI - Electro-Negative Puncture in the Treatment of Uterine Fibromyomata: A Record of Three Cases. PMID- 29613122 TI - Exhibition of Specimens. PMID- 29613121 TI - A Case of Extra-Uterine Gestation. PMID- 29613124 TI - Exhibition of Specimens. PMID- 29613123 TI - Chloroform in Midwifery Practice. PMID- 29613125 TI - Hernia into the Umbilical Cord. PMID- 29613127 TI - Exhibition of Specimens. PMID- 29613126 TI - Laparotomy for Extra-Uterine Gestation Two and a Half Months after the Death of the Foetus at Five and a Half Months. PMID- 29613128 TI - On Some Peculiar Relations of Abdominal and Pelvic Tumours. PMID- 29613129 TI - Transverse Septal Atresia of the Lower Third of the Genital Tract. PMID- 29613130 TI - Is There a Positive Pressure in the Growing Pregnant Uterus? PMID- 29613131 TI - Retention of Menstrual Fluid in One Half of a Double Uterus. PMID- 29613132 TI - Exhibition of Specimens. PMID- 29613133 TI - Exhibition of Specimens. PMID- 29613134 TI - Exhibition of Specimens. PMID- 29613135 TI - Interstitial Pregnancy, with Notes of a Case. PMID- 29613136 TI - Notes on a Case of Triplets. PMID- 29613137 TI - Exhibition of Specimens. PMID- 29613138 TI - Note of a Case of Haemorrhage from Rupture through a Mucous Cyst at the Os Uteri (in a Case of Complete Senile Prolapse). PMID- 29613139 TI - On Vaginal Hysterectomy by Doyen's Method: With Six Successful Cases. PMID- 29613140 TI - The Causation of Twins, as Illustrated by Some Clinical Histories. PMID- 29613142 TI - On Deflection and Rotation of the Pregnant and Puerperal Uterus. PMID- 29613141 TI - Ascites in a Seven-Month's Foetus as a Hindrance in Labour. PMID- 29613143 TI - On Extra-Peritoneal Incision in Extra-Uterine Gestation Intact and at Mid-Term. PMID- 29613145 TI - On the Action of the Midwifery Forceps. PMID- 29613144 TI - The Further History of a Case of Fibroid Tumour Treated by Electricity. PMID- 29613146 TI - Exhibition of Specimens. PMID- 29613148 TI - Exhibition of Specimens. PMID- 29613147 TI - Exhibition of Specimens. PMID- 29613150 TI - Curettage of the Uterus: History, Indications, and Technique. PMID- 29613149 TI - Criminal Abortion in the Punjab. PMID- 29613151 TI - Case of Congenital Tumour on the Face of a Child. PMID- 29613152 TI - Peripheral Neuritis in Pregnancy. PMID- 29613153 TI - Forceps with Adjustable Axis-Traction, and Forceps for Occipito-Posterior Positions of the Vertex. PMID- 29613154 TI - Pan-Hysterectomy, or Total Extirpation of the Uterus. PMID- 29613156 TI - Exhibition of Specimens. PMID- 29613155 TI - Ovariotomy under Local Anaesthesia. PMID- 29613157 TI - Experimental Research into the Action of Viburnum Prunifolium (Black Haw). PMID- 29613158 TI - A Rare Form of Abortion-Expulsion of the Amniotic Sac Alone. PMID- 29613159 TI - Some Modifications of Midwifery Forceps. PMID- 29613160 TI - Indigestion of Breast Babies. PMID- 29613162 TI - Exhibition of Specimens. PMID- 29613161 TI - Puerperal Pulmonary Thrombosis, with an Illustrative Case. PMID- 29613163 TI - Preliminary Note on the Development of the Clitoris, Vagina, and Hymen. PMID- 29613165 TI - Exhibition of Specimens. PMID- 29613164 TI - Technique of the Dilatation of the Perineum in Labour. PMID- 29613166 TI - Braune's Os Internum and the Retraction Ring. PMID- 29613167 TI - Teratogenesis: An Inquiry into the Causes of Monstrosities. PMID- 29613168 TI - Congenital Teeth. PMID- 29613169 TI - Exhibition of Specimens. PMID- 29613170 TI - Osteomalacia: With a Discussion of Its AEtiology and Treatment. PMID- 29613171 TI - Use of Plaster Moulds as a Basis for Models in Gynaecology and Obstetrics. PMID- 29613172 TI - Two Teratological Cases. PMID- 29613173 TI - Case of Atresia Vaginae. PMID- 29613174 TI - Case of Ulcus Serpiginosum of the Vulva. PMID- 29613175 TI - Mittelschmerz. PMID- 29613176 TI - Valedictory Address. PMID- 29613177 TI - Exhibition of Specimens. PMID- 29613178 TI - Exhibition of Specimens. PMID- 29613179 TI - Case of Fatal Infantile Jaundice from Congenital Narrowing of the Common Bile Duct. PMID- 29613180 TI - Uterine Retraction, with Special Reference to the Mechanism and Management of the Third Stage of Labour. PMID- 29613181 TI - Spoon-Shaped Indentations in the Skulls of the New-Born, with Illustrative Cases, and a New Method of Treatment for the Immediate Relief of the Deformity. PMID- 29613183 TI - Exhibition of Specimens. PMID- 29613182 TI - Extroversio Vesicae. PMID- 29613184 TI - A Case of Pregnancy with Ovarian Cyst. PMID- 29613185 TI - Discussion on the Management of the Third Stage of Labour. PMID- 29613186 TI - Morphia and Cocaine in Emesis Gravidarum and Abortion. PMID- 29613187 TI - A Clinical Note on a Case of Eclampsia at the Sixth Month-Recovery-Successful Labour at Full Time. PMID- 29613189 TI - Exhibition of Specimens. PMID- 29613188 TI - Note of a Case of Spontaneous Rupture of a Varicose Vein of the Right Leg at the Seventh Month of Pregnancy. PMID- 29613190 TI - Case of Cerebral Haemorrhage Resulting from Deciduoma Malignum. PMID- 29613191 TI - Psychoses Following Pelvi-Abdominal Operations. PMID- 29613192 TI - A Case of Uterine Fibroid with Unusual Sequel. PMID- 29613193 TI - Extracts from the Talmud and from Celsus, Illustrative of the State of Medical Science at the Beginning of the Christian Era. (Gynaecological). PMID- 29613194 TI - A Contribution to the Morphology of the Human Urino-Genital Tract. PMID- 29613196 TI - Exhibition of Specimens. PMID- 29613195 TI - Eclampsia and the Thyroid Gland: A Preliminary Communication. PMID- 29613197 TI - On Intra-Peritoneal Rupture of Simple Ovarian Cysts, with Special Reference to Operative Treatment. PMID- 29613198 TI - The Art of Vaccination. PMID- 29613200 TI - Exhibition of Specimens. PMID- 29613199 TI - Presidential Address. PMID- 29613202 TI - Exhibition of Specimens. PMID- 29613201 TI - Primary Carcinoma of the Female Urethra. PMID- 29613204 TI - Exhibition of Specimens. PMID- 29613203 TI - Exhibition of Specimens. PMID- 29613205 TI - On Apparent Low Implantation of the Ureteric Opening. PMID- 29613207 TI - Exhibition of Specimens. PMID- 29613206 TI - Cleidotomy: An Operation Accessory to Craniotomy or Basilysis. PMID- 29613208 TI - On the Dilatation of the Anus and Urethra Resulting from Natural Labour. PMID- 29613210 TI - Exhibition of Specimens. PMID- 29613209 TI - On the Treatment of Fibroid Tumours of the Womb. PMID- 29613211 TI - Exhibition of Specimens. PMID- 29613212 TI - Report of the Royal Maternity and Simpson Memorial Hospital for the Quarter Ending 31st January 1891. PMID- 29613213 TI - Note of a Case of Porro-Caesarean Section. PMID- 29613214 TI - Note upon Nine Cases of Accidental Vaccination. PMID- 29613215 TI - Exhibition of Specimens. PMID- 29613216 TI - A First Series of Twenty Completed Abdominal Sections. PMID- 29613217 TI - The Diagnosis of Early Extra-Uterine Gestation, with Illustrative Cases. PMID- 29613218 TI - Three Cases of Rupture of the Uterus, One of Which Was Successfully Treated by Laparotomy. PMID- 29613220 TI - Exhibition of Specimens. PMID- 29613219 TI - On the Treatment of Eclampsia during Pregnancy. PMID- 29613238 TI - Note on a Case of Decapitation. PMID- 29613239 TI - Exhibition of Specimens. PMID- 29613240 TI - Haemorrhage during Labour, Due to Vascular Anomaly of the Membranes. PMID- 29613241 TI - The Nerve-Endings in the Labia Minora and Clitoris, with Special Reference to the Pathology of Pruritus Vulvae. PMID- 29613242 TI - Exhibition of Specimens. PMID- 29613243 TI - Exhibition of Specimens. PMID- 29613245 TI - Exhibition of Specimens. PMID- 29613244 TI - Note on Some Modifications of Barnes' Caoutchouc Dilators. PMID- 29613246 TI - Introductory Address. PMID- 29613247 TI - Note on a Portable Infant-Weigher. PMID- 29613248 TI - The Axis-Traction Forceps: Their Mechanical Principles, Construction, and Scope. PMID- 29613249 TI - On Displacement of the Placenta in Extra-Uterine Gestation, and Its Relation to Those Cases Ending in Pelvic Abscess. PMID- 29613250 TI - Exhibition of Specimens. PMID- 29613251 TI - A Criticism of Some of the Lesser Gynaecological Manipulations. PMID- 29613252 TI - Report of the Royal Maternity and Simpson Memorial Hospital for the Quarter Ending 31st July 1890. PMID- 29613254 TI - The Inconsistencies of the Present Obstetric Nomenclature for Positions. PMID- 29613253 TI - On the Operative Treatment of Cancer of the Cervix Uteri; with a Successful Case of Vaginal Hysterectomy. PMID- 29613255 TI - Maternal Impressions. PMID- 29613256 TI - Large Extra-Peritoneal Polycystic Ovarian Tumour Completely Removed by Abdominal Section without Opening into the Peritoneal Cavity. PMID- 29613258 TI - A Note on the Use of the Axis-Traction Forceps in the High and Low Operation. PMID- 29613257 TI - The Anatomy and Mechanism of Early Abortion. PMID- 29613259 TI - Cases Illustrative of Operative Interference with Fibroid Tumours during Pregnancy, Labour, and Puerperium. PMID- 29613260 TI - Studies in Foetal Pathology and Teratology: On a Case-Taking Scheme for Foetal Diseases and Deformities. PMID- 29613261 TI - Studies in Foetal Pathology and Teratology: Clinical Notes of Four Cases, and Description of Two Specimens of General Dropsy of the Foetus. PMID- 29613262 TI - On Congenital Obliteration of the Bile-Ducts. PMID- 29613263 TI - Pedunculated Uterine Growths: A Practical Resume of a Series of Cases. PMID- 29613264 TI - On the Structure of the Human Placenta, with Special Reference to the Origin of the Decidua Reflexa. PMID- 29613265 TI - Exhibition of Specimens. PMID- 29613266 TI - Report of the Royal Maternity and Simpson Memorial Hospital for the Quarter Ending 31st July 1891. PMID- 29613267 TI - Exhibition of Specimens. PMID- 29613268 TI - A Series of Thirteen Cases of Alleged Maternal Impression. PMID- 29613270 TI - Studies in Foetal Pathology and Teratology: General Dropsy of the Foetus. PMID- 29613269 TI - Studies in Foetal Pathology and Teratology: The Sectional Anatomy of an Anencephalic Foetus. PMID- 29613271 TI - On the Alleged Growth of the Placenta in Extra-Uterine Gestation after the Death of the Foetus. PMID- 29613273 TI - Exhibition of Specimens. PMID- 29613272 TI - Valedictory Address. PMID- 29613274 TI - Report of the Royal Maternity and Simpson Memorial Hospital for the Quarter Ending 30th April 1891. PMID- 29613276 TI - Exhibition of Specimens. PMID- 29613275 TI - The Female Pelvis in the Beginning of the Fifth Month of Pregnancy. PMID- 29613277 TI - The Influence of Influenza upon Women. PMID- 29613279 TI - Exhibition of Specimens. PMID- 29613278 TI - Notes of a Case Bearing on a Relation between Menstruation and Impregnation. PMID- 29613280 TI - Notes on a Case of Placenta Praevia. PMID- 29613281 TI - A Series of Abdominal Sections. PMID- 29613282 TI - Case of Congenital Obliteration of the Small Intestine. PMID- 29613283 TI - Studies in Foetal Pathology and Teratology: General Dropsy in the Twin Foetus. PMID- 29613285 TI - Exhibition of Specimens. PMID- 29613284 TI - On Asthma Gravidarum, with an Illustrative Case. PMID- 29613286 TI - Note on a Case of Vaginal Hysterectomy for Carcinoma Cervicis in Early Pregnancy. PMID- 29613287 TI - On Two Cases of Vaginal Hysterectomy for Sarcoma of the Uterus. PMID- 29613288 TI - Case of Partial Obliteration of the Gall-Bladder in a New-Born Infant, Associated with Numerous Other Congenital Malformations. PMID- 29613290 TI - On Thrombosis of the Pulmonary Arteries, with Reference to Treatment by Inhalation of Oxygen. PMID- 29613289 TI - Studies in Foetal Pathology and Teratology: The Investigation of Foetal Disease. PMID- 29613291 TI - Exhibition of Specimens. PMID- 29613292 TI - On the Cervix and the Attitude of the Foetus in Leopold's Sections-'Uterus and Child'. PMID- 29613293 TI - Exhibition of Specimens. PMID- 29613295 TI - Exhibition of Specimens. PMID- 29613294 TI - Notes on Four Cases of Caesarean Section. PMID- 29613297 TI - Exhibition of Specimens. PMID- 29613296 TI - Intra-Uterine Typhoid. PMID- 29613298 TI - Abstracts of Dr C. F. Ponder's Papers on the Midwifery Forceps. PMID- 29613299 TI - Induction of Premature Labour. PMID- 29613300 TI - Recent Modifications of Anterior Colporrhaphy-Case Operated on for Cystocele Remaining after Vaginal Hysterectomy. PMID- 29613301 TI - The Use of Quinine as a Substitute for Ergot in Midwifery. PMID- 29613303 TI - Note on Three Additional Cases of Congenital Teeth. PMID- 29613302 TI - Exhibition of Specimens. PMID- 29613304 TI - On the Position of the Promontory of the Sacrum as Shown by Frozen Sections. PMID- 29613305 TI - Modern Gynecological Surgery. PMID- 29613306 TI - Total Hysterectomy during Pregnancy for Rapidly Growing Fibromyomata. PMID- 29613307 TI - Toxaemia in Pregnancy, with Illustrative Cases. PMID- 29613308 TI - Short Note of a Curious Central Tear of the Perineum. PMID- 29613309 TI - Natural Parturition, with a Description of a New Instrument-The Vector. PMID- 29613310 TI - The Occurrence of a Non-Allantoic or Vitelline Placenta in the Human Subject. PMID- 29613311 TI - The Analogues of the Male and Female Genital Tract. PMID- 29613312 TI - Exhibition of Specimens. PMID- 29613313 TI - Valedictory Address: Responsibilities of the Medical Attendant in Obstetrical and Gynecological Cases. PMID- 29613315 TI - Exhibition of Specimens. PMID- 29613314 TI - Leopold's Description of the Placenta. PMID- 29613316 TI - Senile Uterine Catarrh. PMID- 29613317 TI - Appendix to Dr John Moir's Address on the Induction of Premature Labour. PMID- 29613318 TI - Vaginal Hysterectomy. PMID- 29613319 TI - Clinical Note of a Case of Eclampsia at the Sixth Month of Pregnancy, Treated by Saline Infusion and Veratrum Viride. PMID- 29613321 TI - Exhibition of Specimens. PMID- 29613320 TI - Pyosalpinx Removed by Laparotomy in the Early Puerperium. PMID- 29613322 TI - A Case of Puerperal Eclampsia, Having a Peculiar Puerperal History: And Observations on Coma and Its Treatment by Venesection. PMID- 29613323 TI - Clinical Noted on a Case of Vulvar Haematoma. PMID- 29613324 TI - Note of a Large Solid Intra-Ligamentary Tumour Removed by Abdominal Section. PMID- 29613325 TI - Vaporisation (Atmokausis) of the Endometrium. PMID- 29613326 TI - Exhibition of Specimens. PMID- 29613327 TI - Vaginal Coeliotomy. PMID- 29613328 TI - A Case of Caesarean Section Followed by Sub-Peritoneal Hysterectomy. PMID- 29613330 TI - Note on Levurine. PMID- 29613329 TI - Exhibition of Specimens. PMID- 29613331 TI - Delivery by Basilysis. PMID- 29613332 TI - Notes on a Case of Sudden Death Following Labour, Due to Cardiac Disease and Pneumonia. PMID- 29613333 TI - Complicated Case of Double Ovariotomy in a Girl Aged Eighteen. PMID- 29613334 TI - Kraurosis Vulvae. PMID- 29613335 TI - Notes of Five Cases of Eclampsia Treated by Saline Infusion. PMID- 29613337 TI - On the Cause of the Differentiation of Connective Tissue in the Human Foetus: With Special Reference to the Essential Nature of the Hydatid Mole. PMID- 29613336 TI - Errata. AB - [This corrects the article on p. 235 in vol. 25.]. PMID- 29613374 TI - Errata. AB - [This corrects the article on p. 2 in vol. 25.]. PMID- 29613376 TI - Exhibition of Specimens. PMID- 29613375 TI - The Chronology of Ante-Natal Life. PMID- 29613377 TI - Errata. AB - [This corrects the article on p. 206 in vol. 25.]. PMID- 29613378 TI - Valedictory Address. PMID- 29613379 TI - On the Nomenclature of Transverse Presentation and of Version, with Remarks on the Choice of the Leg Seized. PMID- 29613380 TI - On Cleansing the Peritoneum during Coeliotomy. PMID- 29613381 TI - Exhibition of Specimens. PMID- 29613382 TI - Albuminuria, Multiple Pregnancy, Papyraceous Foetus, and Placenta Praevia. PMID- 29613383 TI - On the Set of the Pelvis in the Body (Variations in the Inclination of the Brim Apart from Posture), and Its Obstetrical Significance. PMID- 29613384 TI - Discussion on the Treatment of Dysmenorrhoea. PMID- 29613385 TI - Chylous Ascites, with an Illustrative Case. PMID- 29613386 TI - Exhibition of Specimens. PMID- 29613387 TI - Suppression of Urine Following Cystitis. PMID- 29613388 TI - Pathological Amenorrhoea from Other Than Constitutional Causes, with Illustrative Cases. PMID- 29613389 TI - Presidential Address on Surgical Interference in Gynecology. PMID- 29613390 TI - Observations on Labour Complicated by a Minor Degree of Pelvic Contraction in Primiparae and Multiparae. PMID- 29613391 TI - Two Cases of Mistaken Sex in Adult Life. PMID- 29613392 TI - Exhibition of Specimens. PMID- 29613393 TI - Exhibition of Specimens. PMID- 29613394 TI - Repeated Ectopic Pregnancy in the Same Patient, with Account of a Case Where Two Gestation Sacs (One a Lithopaedion) Were Successfully Removed from Either Side at One Operation. PMID- 29613395 TI - Notes on Two Cases of Peritoneal Effusion, (a) Tubercular, (b) Malignant, with Microscopic Preparations. PMID- 29613397 TI - Exhibition of Specimens. PMID- 29613396 TI - Case of Fatal OEdema Glottidis Occurring during Pregnancy. PMID- 29613398 TI - Mother versus Child: Notes of a Case of Induction of Premature Labour in a Patient Who Had Rectal Carcinoma. PMID- 29613400 TI - Exhibition of Specimens. PMID- 29613399 TI - Case of Chronic Inversion of the Uterus Replaced by Manipulation after Posterior Colpotomy Had Been Performed. PMID- 29613401 TI - Vaginal Hysterectomy for Cancer. PMID- 29613402 TI - Acute Mania Following Simple Ovariotomy. PMID- 29613403 TI - Puerperal Hyperpyrexia, with an Illustrative Case. PMID- 29613404 TI - Exhibition of Specimens. PMID- 29613405 TI - Case of Fibrous Mole. PMID- 29613406 TI - Present Position of the Pessary in Gynecological Practice. PMID- 29613407 TI - Exhibition of Specimens. PMID- 29613408 TI - Retrospect of a First Series of One Hundred and Ten Abdominal Sections for Pelvi Abdominal Disease. PMID- 29613409 TI - Instrumental Assistance in Parturition, with Description of a New Instrument. PMID- 29613410 TI - A Case Bearing on the Latency of Gonorrhoeal Infection. PMID- 29613411 TI - Treatment of Eclampsia by Intercellular Injection of Saline Fluid. PMID- 29613413 TI - Foetus Which Had Been Expelled with the Membranes Entire. PMID- 29613412 TI - Case of Puerperal Tetanus, Coming on Nine Days after Parturition, and Terminating Fatally in Forty Hours. PMID- 29613414 TI - Case of Menstruation during Pregnancy. PMID- 29613416 TI - Pregnancy without Menstruation. PMID- 29613415 TI - A Few Notes on a Case of Phlegmonous Inflammation of the Left Labium, and Abscess. PMID- 29613417 TI - Epithelial Cancerous Growth. PMID- 29613419 TI - Melanotic Tumour. PMID- 29613418 TI - The Function of the Perinaeum in Procidentia Uteri. PMID- 29613420 TI - Case of Malformation of the Foetal Bowel. PMID- 29613421 TI - Foetus with the Membranes Entire. PMID- 29613422 TI - On the Immediate Treatment of Laceration of the Perinaeum. PMID- 29613424 TI - Observations on the Inflammations of the Mouth in Children, with an Illustrative Case of Cancrum Oris. PMID- 29613423 TI - Report by the Committee on Vaccination. PMID- 29613425 TI - Epitheliomatous Mass. PMID- 29613426 TI - Case of Puerperal Gastric Fever. PMID- 29613427 TI - Placenta Showing Clots and Indentations on Its Surface. PMID- 29613428 TI - Membranes, Etc., of a Foetus. PMID- 29613430 TI - Case in Which the Presenting Arm Was Wrenched off in an Unsuccessful Attempt to Deliver, with Remarks. PMID- 29613429 TI - Shell of the Upper Incisor Tooth, Obtained from an Infant between Four and Five Months Old. PMID- 29613431 TI - New Form of Galvanic Pessary. PMID- 29613432 TI - Case of Adherent Placenta. PMID- 29613433 TI - On the Synclitic Motion of the Foetal Head in the Mechanism of Parturition. PMID- 29613434 TI - On Some of the Dangers Attending the Use of Tangle Tents. PMID- 29613435 TI - Case of Retarded Labour. PMID- 29613436 TI - New Instrument for Rupturing the Membranes. PMID- 29613437 TI - The Mechanism of the Expulsion of the Placenta. PMID- 29613438 TI - Foetus Marked by a Malformation of the Thorax and Abdomen. PMID- 29613439 TI - Case of Early Pregnancy. PMID- 29613441 TI - Placenta from a Case of Placenta Praevia. PMID- 29613440 TI - Chloroform Inhaler. PMID- 29613442 TI - Foetus Which Had Been Expelled with Membranes Entire. PMID- 29613443 TI - Case of a Child Born without an Occipital Bone. PMID- 29613444 TI - Short Umbilical Cord. PMID- 29613445 TI - Placenta with Two Cords. PMID- 29613447 TI - Case of Short Umbilical Cord. PMID- 29613446 TI - Case of Rigid Os Treated by Hydrochlorate of Apomorphia. PMID- 29613448 TI - Case of Cephalotripsy. PMID- 29613449 TI - Removal of a Large Uterine Fibrous Polypus. PMID- 29613450 TI - On Incising the Cervix Uteri, and the Instruments Used and Required for the Operation. PMID- 29613451 TI - On the Production of Presentation of the Face. PMID- 29613453 TI - Exhibition of Dr Ziegler's New Models and Casts. PMID- 29613452 TI - An Aid to Parturition and to the Treatment of Displacement of the Uterus, by a New Mechanical Appliance. PMID- 29613454 TI - Long-Retained Gutta Percha Pessary. PMID- 29613455 TI - Case of Dorsal Displacement of the Arm, a New Variety, with Remarks on Dorsal Displacement in General. PMID- 29613456 TI - Case of Hydrops Ovarii, with Ascites and Hydrothorax. PMID- 29613457 TI - Case of Malposition of the Umbilical Cord. PMID- 29613458 TI - Series of Photographs of Deformities. PMID- 29613459 TI - Case of Poisoning of an Infant Six Weeks Old, by Six Drops of Laudanum-Recovery. PMID- 29613460 TI - Notice of an Anteversion Pessary. PMID- 29613461 TI - Statistics Regarding Vaccination, with Remarks. PMID- 29613462 TI - The Stethoscope as a Means of Diagnosing the Sex of the Child. PMID- 29613464 TI - Case of Decapitation and Evisceration, with Adherent Placenta. PMID- 29613463 TI - Specimen of Large Placenta. PMID- 29613465 TI - Post-Partum Dietetic Treatment. PMID- 29613466 TI - A Fibrous Tumour Removed from the Uterus. PMID- 29613467 TI - Additional Cases Treated at the Royal Maternity Hospital. PMID- 29613468 TI - Practice in the Prediction of the Day of Confinement. PMID- 29613469 TI - On a Case of Ovarian Dropsy. PMID- 29613470 TI - An Instrumental Labour, Complicated with Adherent Placenta and Haemorrhage. PMID- 29613471 TI - Two Cases of Placenta Praevia, the Former Treated by Complete Separation, the Latter by Version. PMID- 29613472 TI - Case of Puerperal Fever. PMID- 29613473 TI - On a Case of Puerpal Mania, Treated by Chloral. PMID- 29613474 TI - Case of Hypertrophy of the Cervix Uteri, with Amputation. PMID- 29613476 TI - Two Interesting Cases. PMID- 29613475 TI - Specimen of Hydatiginous Ovum. PMID- 29613477 TI - The Alloa Case of Death under Chloroform. PMID- 29613478 TI - On the Mode of Introducing the Midwifery Forceps, with Notes on Their Modification. PMID- 29613479 TI - A Sketch of the Mechanism of the Delivery of the Child, Compiled from Notes of Dr Matthews Duncan's Lectures. PMID- 29613480 TI - Foetus with the Membranes Entire. PMID- 29613482 TI - Memoranda on Carbonate of Lithia in Acute Rheumatism Associated with Scarlatina, and in Urticaria; Etc. PMID- 29613481 TI - On Vaccination, with Some Considerations Regarding Postponed Vaccination. PMID- 29613483 TI - Case of Retained Placenta. PMID- 29613484 TI - Notes of a Case of Puerperal Convulsions. PMID- 29613485 TI - Case of Puerperal Scarlet Fever. PMID- 29613486 TI - On the Influence of Childbearing on the Muscular Development of Women. PMID- 29613487 TI - Case of Death of Foetus from Coiling of the Funis. PMID- 29613488 TI - Case of Paralysis and Sudden Death in the Pregnant State. PMID- 29613489 TI - On the Effects of Chloral. PMID- 29613490 TI - Foetus Born Alive, with Cuticle Peeling off. PMID- 29613492 TI - Incision of the Cervix Uteri, with Description of a New Hysterotome. PMID- 29613491 TI - Cases of Phlebitis and Face Presentation, with Remarks on the Edinburgh Royal Maternity Hospital. PMID- 29613493 TI - Gall Bladder and Several Gall Stones. PMID- 29613495 TI - Tedious Labour from Enlarged Body of the Foetus. PMID- 29613494 TI - Case of Rupture of Fallopian Tube, and Death from Haemorrhage. PMID- 29613496 TI - A Case of Spontaneous Version. PMID- 29613498 TI - Case of Infantile Salivation by a Quack Medicine. PMID- 29613497 TI - Chloral in a Case of Puerperal Mania. PMID- 29613499 TI - Urethral Calculus. PMID- 29613500 TI - Case of Gonorrhoea of the Ducts of Cowper's Glands. PMID- 29613501 TI - Three Cases of Congenital Malformations. PMID- 29613502 TI - Case of Infantile Convulsions. PMID- 29613504 TI - Exhibition of a Foetus with Three Legs. PMID- 29613503 TI - Note on the Chief Directions and Extents of Uterine Shrinking; Specially at the Time of the Complete Expulsion of the Contents of the Gravid Uterus. PMID- 29613505 TI - A New Kind of Midwifery Forceps. PMID- 29613506 TI - Notes of a Case of Vaginal Rupture. PMID- 29613507 TI - On the Size of Aperture Necessary for the Passage of the Placenta, and for the Passage of the Accoucheur's Hand. PMID- 29613508 TI - On the Extension and Increase of the Scientific Spirit in Medicine. President's Inaugural Address, Session XXXIII. PMID- 29613510 TI - Case of Suppuration of a Dermoid Cyst after Delivery. PMID- 29613509 TI - Case of Pregnancy with Unruptured Hymen, and Extraordinary Ascent of the Uterus. PMID- 29613511 TI - On the Relation of the Vomiting of Pregnancy and the Quantity of the Liquor Amnii. PMID- 29613512 TI - Exhibition of a Monstrosity. PMID- 29613513 TI - Case of Syncope during Labour. PMID- 29613514 TI - Case of Pregnancy and Miscarriage Complicated by Diabetes Insipidus. PMID- 29613515 TI - Foetus Which Remained in Utero Three Months after Its Death. PMID- 29613516 TI - On the Use of the Bowl during Delivery. PMID- 29613517 TI - On the Occasional Arrestive and Discutient Influence of Pregnancy over Pelvi Abdominal Tumours. PMID- 29613518 TI - Craniotomy Contrasted with Cephalotripsy. PMID- 29613519 TI - On the Comparative Advantages of Forceps, of Turning, and of Premature Labour in Contracted Pelves: Illustrated by the Obstetrical Histories of Two Women. PMID- 29613520 TI - Abstract of Communication on the Use of Post Partum Binders. PMID- 29613521 TI - A Peculiar Case of Abortion. PMID- 29613522 TI - Comparative Anatomy of the Arterial Cerebral Circulation in Animals and the Human Subject, as Bearing on Parturient Apoplexy and Convulsions. PMID- 29613523 TI - Case of Pelvic Cellulitis Followed by Peritonitis. PMID- 29613524 TI - On a Case of Spurious Pregnancy with Labour. PMID- 29613525 TI - Case of Acute Inversion of the Uterus. PMID- 29613526 TI - Intervals between Births in Pluriparous Animals. PMID- 29613527 TI - Exhibition of Hecker's New Sling for Difficult Breech Cases. PMID- 29613528 TI - Note of a Proof of the Free Intercommunication near the Chorionic Surface, between Different Parts of the System of Maternal Cells or Blood-Caverns of the Placenta, in the Same, and in Different Cotyledons. PMID- 29613529 TI - On the Superior Value of Artificial Premature Labour and Turning, over the High Forceps Operation and Craniotomy, in Cases of Contracted Pelvis; with Cases. PMID- 29613530 TI - Interesting Case of Nephrocystosis, from an Obstetrical Point of View. PMID- 29613531 TI - On the Changes Undergone by the Cervix Uteri during Labour. PMID- 29613532 TI - Case of Cloaca in a Child. PMID- 29613533 TI - Abstract of Communication on Dystocia: The Exact Diagnosis of the Placental Position in Placenta Praevia by Vaginal Stethoscopy, and a Direct Mode of Haemostatic Treatment. PMID- 29613534 TI - Case of Fibroid of the Uterus, Complicating Pregnancy, and Proving Fatal by Torsion of the Pedicle. PMID- 29613535 TI - New Method of Tying the Umbilical Cord, with a View to Prevent Possible Haemorrhage, with Preparations. PMID- 29613537 TI - Case of Uraemic Convulsions, with Complications. PMID- 29613536 TI - On Certain Non-Instrumental Aids to Labour. PMID- 29613538 TI - Case of Unusual Illness in the Seventh Month of Pregnancy. PMID- 29613539 TI - Notes on Delivery in Cases of Breech Presentation, and on the Occurrence of the Vagitus Uterinus in Such Cases. PMID- 29613541 TI - Exhibition of Skoldberg's Zinc-Alum Sticks. PMID- 29613540 TI - Anencephalous Foetus. PMID- 29613543 TI - Abstract of Communication on Zymotic Diseases in Relation to Obstetrics. PMID- 29613542 TI - Case of Puerperal Convulsions. PMID- 29613544 TI - Abstract of Paper on the Use of the Electro-Magnetic Current in Labour. PMID- 29613545 TI - Latent Gonorrhoea in the Female Sex, with Special Relation to the Puerperal State. PMID- 29613546 TI - Notes of Some Cases of Atresia Vaginae. PMID- 29613547 TI - Case of Smallpox, from an Obstetrical and Medico-Legal Point of View. PMID- 29613548 TI - Some Points Ascertained in the Dissection of an Anencephalous Foetus, with Preparation. PMID- 29613550 TI - The Merits and Demerits of the Recent Trial for Malpractice at Stockton-On-Tees. PMID- 29613549 TI - Case of Repeated Cephalotripsy. PMID- 29613551 TI - Inaugural Address at the Commencement of Session XXXI. PMID- 29613552 TI - Mummified Premature Calf Expelled Long after Its Death in Utero-Missed Labour. PMID- 29613553 TI - Case of Shoulder Presentation, with Prolapse of the Cord and Rigid Os: Turning Impossible; Delivery by Spondylotomy. PMID- 29613554 TI - Case of Large Congenital Cranial Tumour. PMID- 29613555 TI - Exhibition of a Foetus Thrown off during an Attack of Smallpox. PMID- 29613556 TI - Deformed Foetus of a Cow (Ectopia). PMID- 29613557 TI - Case of Intrauterine Fracture of the Thigh. PMID- 29613559 TI - Exhibition of a Cast of a Congenital Malformation of the Palate. PMID- 29613558 TI - Abstract of Communication on Vomiting of Pregnancy; with a Case Requiring the Induction of Labour. PMID- 29613560 TI - A New Mode of Treating Puerperal Fever. PMID- 29613561 TI - On the Treatment of Cancer of the Uterus, by Means of Ergot and Escharotics. PMID- 29613562 TI - Notes of the Dissection of a Malformed Foetus. PMID- 29613563 TI - On a Congenital Cranial Tumour in a Calf. PMID- 29613564 TI - Abstract of Communication on the Curative Influence of Vaccination in the Treatment of Variola. PMID- 29613565 TI - Note of a Case of Secondary Syphilis Communicated by an Infant to Its Nurse. PMID- 29613566 TI - Abstract of Communication on the Use of the Electro-Magnetic Current in the Second Stage of Labour. PMID- 29613568 TI - On the Causation, Effects, and Treatment of Uterine Sub-Involution. PMID- 29613567 TI - Case of Cephalotripsy after Turning. PMID- 29613569 TI - Two Uterine Malformations. PMID- 29613570 TI - Case of Viable Child Born at Sixth Month. PMID- 29613571 TI - Abstract of Case of Eclampsia. PMID- 29613572 TI - Abstract of Notes on Placenta Praevia. PMID- 29613574 TI - Absence of Milk in Left Breast in Four Sisters. PMID- 29613573 TI - Exhibition of Placenta and Cord. PMID- 29613575 TI - Observations upon the Nature and Treatment of Difficult Occipito-Posterior Positions of the Head, Founded upon an Analysis of Twenty-Six Operative Cases. PMID- 29613577 TI - Exhibition of Specimens. PMID- 29613576 TI - On Endometritis Decidualis Chronica, as a Cause of Abortion in Some Cases of Displacement of the Pregnant Uterus. PMID- 29613579 TI - Exhibition of Specimens. PMID- 29613578 TI - Case of Sudden Prolapse of the Gravid Uterus. PMID- 29613580 TI - Two Cases of Labour in Rickety Pelves. PMID- 29613581 TI - On the Causation of the Movements of the Head at the Brim of the Rickety Pelvis (with Woodcuts). PMID- 29613582 TI - Quarter Ending 31st July 1881. PMID- 29613583 TI - Two Cases of Atresia Vaginae. PMID- 29613584 TI - Adjourned Discussion on Dr Milne Murray's Paper. PMID- 29613585 TI - Quarter Ending 31st October 1881. PMID- 29613586 TI - On the Uterine Sound. PMID- 29613587 TI - Large Congenital Cystic Tumor. PMID- 29613588 TI - Case Illustrating the Importance of Accurate Pelvimetry, with Description of a New Method. PMID- 29613589 TI - Hydramnios; and the Source of the Liquor Amnii. PMID- 29613590 TI - Exhibition of Specimens. PMID- 29613591 TI - Clinical and Experimental Observations on the Bladder during Parturition. PMID- 29613592 TI - Fibromyxoma Duplex Ovariorum. PMID- 29613593 TI - Exhibition of Specimens. PMID- 29613594 TI - Exhibition of Specimens. PMID- 29613595 TI - Exhibition of Specimens. PMID- 29613596 TI - Note on a Unique Cause of Delay in the Third Stage of Labour. PMID- 29613597 TI - Vaginal Enterocele. PMID- 29613598 TI - Quarter Ending 30th April 1882. PMID- 29613599 TI - Foetid Parametric and Perimetric Abscess. PMID- 29613600 TI - Quarter Ending 31st January 1882. PMID- 29613601 TI - On Some Points in the Physics of the Bladder and Rectum (with Woodcuts). PMID- 29613602 TI - Exhibition of Specimens. PMID- 29613603 TI - Case of Pregnancy at the Age of Sixty-Two. PMID- 29613605 TI - Note on the Naked Eye Anatomy of the Female External Genitals. PMID- 29613604 TI - Case of Induction of Premature Labour. PMID- 29613607 TI - Dystocia from Exomphalos of the Foetus. PMID- 29613606 TI - Case of Basilysis. PMID- 29613608 TI - Exhibition of Specimens. PMID- 29613609 TI - Graviditas Serotina et Praecox. PMID- 29613610 TI - Exhibition of Specimens. PMID- 29613611 TI - A Difficult Face Case. PMID- 29613612 TI - Case of Extirpation of the Cancerous Uterus through the Vagina. PMID- 29613613 TI - Case of Labour Complicated with Acute Nephritis and Eclampsia. PMID- 29613614 TI - Exhibition of Specimens. PMID- 29613615 TI - Exhibition of Specimens. PMID- 29613617 TI - Exhibition of Specimens. PMID- 29613616 TI - On the Development of Malignant from Non-Malignant Tumours of the Uterus. PMID- 29613619 TI - Exhibition of Specimens. PMID- 29613618 TI - Case of Extra-Uterine (Tubal) Gestation. PMID- 29613620 TI - Basilysis for Dystocia from Hypertrophic Elongation of the Cervix Uteri. PMID- 29613621 TI - Introductory Address. PMID- 29613622 TI - Again on Axis-Traction Forceps. PMID- 29613623 TI - Superinvolution of the Uterus. PMID- 29613624 TI - Obstinate Vomiting in Pregnancy. PMID- 29613625 TI - On Dangerous Haemorrhage from the External Genital Organs during and after Labour. PMID- 29613626 TI - Umbilical Cord Round the Child's Neck as a Cause of Delayed Labour, and Sometimes of Infantile Death. PMID- 29613627 TI - Quarter Ending 31st October 1882. PMID- 29613628 TI - Note of a Case of Hernia into the Umbilical Cord; Operation and Recovery. PMID- 29613629 TI - Quarter Ending 30th April 1883. PMID- 29613630 TI - Exhibition of Specimens. PMID- 29613631 TI - Exhibition of Specimens. PMID- 29613633 TI - Case of Twin with Exomphalos and Other Deformities. PMID- 29613632 TI - The Prophylaxis of Ophthalmia Neonatorum. PMID- 29613635 TI - The Formation of a Pathological Committee. PMID- 29613634 TI - Exhibition of Specimens. PMID- 29613636 TI - Statistics of Two Hundred and Fifty Consecutive Midwifery Cases in Private Practice. PMID- 29613637 TI - Case of Double Ovariotomy; Unusually Long and Twisted Pedicle; Note on the Question of Early Operations. PMID- 29613638 TI - Quarter Ending 31st January 1883. PMID- 29613639 TI - Exhibition of Specimens. PMID- 29613640 TI - On the Use of Chian Turpentine in Carcinoma. PMID- 29613641 TI - A Fourth Case of Resuscitation of the Still-Born Infant. PMID- 29613642 TI - Exhibition of Specimens. PMID- 29613643 TI - The Electrical Treatment of Uterine Fibroids and Subinvolution. PMID- 29613644 TI - Exhibition of Specimens. PMID- 29613645 TI - Valedictory Address. PMID- 29613646 TI - Note of a Case of Vesico-Rectal Fistula. PMID- 29613648 TI - A Case of Occlusion of the Vagina in a Primipara, Obstructing Labour. PMID- 29613647 TI - Discussion-Should Antiseptic Vaginal Douching Be Made a Routine Practice in the Puerperium. PMID- 29613649 TI - Note on a Case of Unusual Position of the Promontory Mark on the Foetal Head. PMID- 29613650 TI - Exhibition of Specimens. PMID- 29613651 TI - Extra-Uterine Gestation. PMID- 29613652 TI - The Third Stage of Labour. PMID- 29613654 TI - Three Cases Illustrative of Herman Freund's Law of Pedicle Torsion in Ovarian Tumours. PMID- 29613653 TI - A Case of Hysterectomy during Pregnancy. PMID- 29613655 TI - Administration of Organic Extracts. PMID- 29613656 TI - Exhibition of Specimens. PMID- 29613657 TI - Notes on a Case of Labour with Exomphalos of the Foetus. PMID- 29613658 TI - Exhibition of Specimens. PMID- 29613659 TI - Prolapse of the Bladder during Pregnancy and Parturition. PMID- 29613660 TI - Inspection of the Female Bladder and Urethra, with Special Reference to Dr Howard Kelly's Method. PMID- 29613661 TI - Dilatation of the Cervix by Champetier de Ribes's Bag. PMID- 29613663 TI - An Epidemic of Religious Mania, Originating from a Case of Spurious Pregnancy. PMID- 29613662 TI - A Case of Broad Ligament Cyst Removed by Enucleation. PMID- 29613664 TI - A Case of Severe Menstrual Headache Successfully Treated by Premenstrual Venesection. PMID- 29613665 TI - The Causation of the Sacculated Pregnant Uterus. PMID- 29613666 TI - The Pathological Classification of Diseases of Women, with a Plea for a Revision of Current Views. PMID- 29613667 TI - Extra-Uterine Gestation Simulating Retroversion of the Gravid Uterus. PMID- 29613668 TI - Ancient Greek Authors and Intra-Uterine Injections. PMID- 29613669 TI - Case of Fibroid Tumour Treated with Electricity. PMID- 29613670 TI - Notes of a Case in Which Premature Labour Was Induced for Contracted Pelvis. PMID- 29613671 TI - Exhibition of Specimens. PMID- 29613672 TI - Report of the Royal Maternity and Simpson Memorial Hospital for the Quarter Ending 31st July 1893. PMID- 29613673 TI - The Relation of Influenza to Gynecological, Obstetrical, and Pediatric Cases. PMID- 29613674 TI - The Operative Treatment of Cranial Depressions in the New-Born Infant. PMID- 29613675 TI - Studies in Foetal Pathology and Teratology: Allantoido - Angiopagous Twins - Description of an Anidean Foetus. PMID- 29613676 TI - Exhibition of Specimens, Etc. PMID- 29613677 TI - Exhibition of Specimens. PMID- 29613678 TI - Case of Retained Menses with Perforation of the Bladder. PMID- 29613679 TI - Note on the Presence of Different Albumoses in the Amniotic Fluid. PMID- 29613680 TI - Note of a Case of Double Rupture of the Membranes. PMID- 29613681 TI - The Nature of the Expulsive Phenomena of the Female Abdominal Cavity. PMID- 29613682 TI - Note on Three Living Cases of Achondroplasia (Chondrodystrophia Foetalis, or So Called Foetal Rickets). PMID- 29613683 TI - The Occurrence and Significance of Rotation of the Uterus. PMID- 29613684 TI - Note of a Case of Acephalic Acardiac Foetus. PMID- 29613685 TI - Exhibition of Specimen. PMID- 29613687 TI - Exhibition of Specimens. PMID- 29613686 TI - Uterine Rotation: Its Clinical Importance in Pregnancy and Labour. PMID- 29613688 TI - A Case of Puerperal Eclampsia. PMID- 29613689 TI - Premature Sexual Development in Relation Specially to Ovarian Tumours, with an Illustrative Case of Ovarian Sarcoma in a Child of Seven; Laparotomy; Recovery. PMID- 29613690 TI - Prolapse of the Female Urethra. PMID- 29613691 TI - On Parotitis Following Operations on the Abdomino-Pelvic Organs. PMID- 29613692 TI - The Etiology of Ectopic Gestation. PMID- 29613694 TI - Exhibition of Specimens. PMID- 29613693 TI - An Infant with a Bifid Hand. PMID- 29613695 TI - Report on Two Further Cases of General Dropsy of the Foetus. PMID- 29613697 TI - Placenta Praevia. PMID- 29613696 TI - Report of the Royal Maternity and Simpson Memorial Hospital for the Quarter Ending January 1893. PMID- 29613698 TI - Elephantiasis of the Vulva. PMID- 29613699 TI - Exhibitions of Specimens. PMID- 29613700 TI - Report of the Royal Maternity and Simpson Memorial Hospital for the Quarter Ending July 1892. PMID- 29613701 TI - On the Treatment of Diseases of Women at Pyrmont. PMID- 29613703 TI - Further Contributions to the Study of Version on One Leg. PMID- 29613702 TI - Exhibition of Specimens. PMID- 29613704 TI - Induction of Labour by Means of Intra-Uterine Injections of Glycerine in a Case of Eclampsia Gravidarum. PMID- 29613705 TI - The Anatomy of Advanced Pregnancy in Macacus Rhesus Studied by Frozen Sections, by Casts, and Microscopically. PMID- 29613706 TI - On the Extra-Peritoneal Form of Extra-Uterine Gestation. PMID- 29613707 TI - Exhibition of Specimens. PMID- 29613708 TI - A Case of Scarlet Fever in Pregnancy, with Infection of the Foetus. PMID- 29613709 TI - Exhibition of Specimens. PMID- 29613710 TI - Simple Growths of the Uterine Mucosa. PMID- 29613711 TI - Notes of a Case of Extra-Uterine Gestation. PMID- 29613712 TI - Tubo-Ovarian Disease: Two Illustrative Cases, Clinical and Pathological. PMID- 29613713 TI - Presidential Address. PMID- 29613714 TI - On Protracted Gestation. PMID- 29613716 TI - Exhibition of a Steam-Sterilizer, Photographs, Etc. PMID- 29613715 TI - Studies in Foetal Pathology and Teratology: Allantoido-Angiopagous Twins Description of a Foetus Paracephalus Dipus Acardiacus. PMID- 29613718 TI - Exhibition of Specimens. PMID- 29613717 TI - A Case of Bleeding by the Urachus. PMID- 29613719 TI - Pathological Amenorrhoea from Other Than Contributional Causes. PMID- 29613721 TI - Studies in Foetal Pathology and Teratology: Allantoido-Angiopagous Twins-The Foetus Amorphus Anideus. PMID- 29613720 TI - Studies in Foetal Pathology and Teratology: Allantoido-Angiopagous Twins-The Foetus Amorphus Mylacephalus. PMID- 29613722 TI - Studies in Foetal Pathology and Teratology: Allantoido-Angiopagous Twins Paracephalus Monopus, Apus, and Pseudo-Acormus. PMID- 29613723 TI - Studies in Foetal Pathology and Teratology: Allantoido-Angiopagous Twins Paracephalus Dipus Cardiacus. PMID- 29613724 TI - Studies in Foetal Pathology and Teratology: Allantoido-Angiopagous Twins Paracephalus Dipus Acardiacus. PMID- 29613725 TI - A Clinical Note on the Height of the Fundus Uteri during the First Stage of Labour and at the End of the Second Stage. PMID- 29613726 TI - Note on Methods of Artificial Respiration in the New-Born. PMID- 29613727 TI - Two Cases of Extra-Uterine Gestation Operated on after Rupture at the Fourth Month. PMID- 29613728 TI - The Clinical Aspects of Utero-Sacral Cellulitis. PMID- 29613729 TI - A Case of Rigor Mortis in the Foetus. PMID- 29613730 TI - A Case of Labour with Cardiac and Renal Complications. PMID- 29613732 TI - A Clinical Note on the Advantages of Walcher's Position in Delivery. PMID- 29613731 TI - Chorea Gravidarum: A Statistical Review of the Published Cases. PMID- 29613733 TI - Report of the Royal Maternity and Simpson Memorial Hospital for Professor Simpson's Quarter, Ending 31st January 1895. PMID- 29613734 TI - Note of a Gunshot Wound of the Abdomen. PMID- 29613735 TI - On a Case with Symptoms Simulating Hysteria in Pregnancy, Going on to Apparent Dementia; Death Shortly after Delivery; Brain-Lesion Found on Post-Mortem. Child Still-Born, with Contractures. PMID- 29613736 TI - Exhibition of Specimens, Etc. PMID- 29613737 TI - Exhibition of Specimens. PMID- 29613738 TI - A Case of Vesico-Vaginal Fistula from an Unusual Cause. PMID- 29613739 TI - On the Action of Quinine on the Kidneys and Genital Organs during Pregnancy. PMID- 29613740 TI - Exhibition of Specimens. PMID- 29613741 TI - Exhibition of Specimens. PMID- 29613742 TI - Some Observations on the Maternal and Foetal Blood at Birth. PMID- 29613743 TI - Simulation of Pregnancy and Abortion by Vesical Haemorrhage and Blood-Clot. PMID- 29613744 TI - Exhibition of Specimens, Etc. PMID- 29613745 TI - The Biddenden Maids. PMID- 29613746 TI - On a Delivery-Pan in Use at the Present Time in Spain. PMID- 29613747 TI - Exhibition of Specimens. PMID- 29613749 TI - Exhibition of Specimens, Etc. PMID- 29613748 TI - A Study of the More Recent Frozen Sections in Their Bearing on the Mechanism of Labour and the Third Stage. PMID- 29613751 TI - Ante-Natal Pathology and Heredity in the Hippocratic Writings. PMID- 29613750 TI - Discussion-Should Midwives Be Registered in Scotland? PMID- 29613753 TI - Exhibition of Specimens. PMID- 29613752 TI - Some Aspects of Heredity. PMID- 29613754 TI - On the Influence of the Removal of the Ovaries on Metabolism. PMID- 29613755 TI - A Copper Relay System Involving Two Periplasmic Chaperones Drives cbb3-Type Cytochrome c Oxidase Biogenesis in Rhodobacter capsulatus. AB - PccA and SenC are periplasmic copper chaperones required for the biogenesis of cbb3-type cytochrome c oxidase ( cbb3-Cox) in Rhodobacter capsulatus at physiological Cu concentrations. However, both proteins are dispensable for cbb3 Cox assembly when the external Cu concentration is high. PccA and SenC bind Cu using Met and His residues and Cys and His residues as ligands, respectively, and both proteins form a complex during cbb3-Cox biogenesis. SenC also interacts directly with cbb3-Cox, as shown by chemical cross-linking. Here we determined the periplasmic concentrations of both proteins in vivo and analyzed their Cu binding stoichiometries and their Cu(I) and Cu(II) binding affinity constants ( KD) in vitro. Our data show that both proteins bind a single Cu atom with high affinity. In vitro Cu transfer assays demonstrate Cu transfer both from PccA to SenC and from SenC to PccA at similar levels. We conclude that PccA and SenC constitute a Cu relay system that facilitates Cu delivery to cbb3-Cox. PMID- 29613756 TI - Unimolecular Decay of Criegee Intermediates to OH Radical Products: Prompt and Thermal Decay Processes. AB - Alkene ozonolysis is a primary oxidation pathway for anthropogenic and biogenic alkenes emitted into the troposphere. It is also an important source of atmospheric hydroxyl (OH) radicals, often called the atmosphere's detergent. Alkene ozonolysis takes place through a highly exothermic reaction pathway with multiple intermediates and barriers prior to releasing the OH radical products. This Account focuses on a key reaction intermediate with a carbonyl oxide functional group (-COO), known as the Criegee intermediate, which is formed along with a carbonyl coproduct in alkene ozonolysis reactions. Under atmospheric conditions, the initially energized Criegee intermediates may promptly decay to OH products or be collisionally stabilized prior to thermal decay to OH radicals and other products. Alternatively, the stabilized Criegee intermediates may undergo bimolecular reactions with atmospheric species, including water vapor and sulfur dioxide, which can lead to nucleation and growth of aerosols. The dimethyl substituted Criegee intermediate, (CH3)2COO, is utilized in this Account to showcase recent efforts to experimentally measure and theoretically predict the rates for prompt and thermal unimolecular decay processes of prototypical Criegee intermediates under laboratory and atmospheric conditions. The experimental laboratory studies utilize an alternative synthesis method to efficiently generate Criegee intermediates via the reaction of iodoalkyl radicals with O2. Infrared excitation is then used to prepare the (CH3)2COO Criegee intermediates at specific energies in the vicinity of the transition state barrier or significantly below the barrier for 1,4-hydrogen transfer that leads to OH products. The rate of unimolecular decay is revealed through direct time-domain measurements of the appearance of OH products utilizing ultraviolet laser-induced fluorescence detection under collision-free conditions. Complementary high-level theoretical calculations are carried out to evaluate the transition state barrier and the energy-dependent unimolecular decay rates for (CH3)2COO using Rice Ramsperger-Kassel-Marcus (RRKM) theory, which are in excellent accord with the experimental measurements. Quantum mechanical tunneling through the barrier, incorporated through Eckart and semiclassical transition state theory models, is shown to make a significant contribution to the unimolecular decay rates at energies in the vicinity of and much below the barrier. Master equation modeling is used to extend the energy-dependent unimolecular rates to thermal decay rates of (CH3)2COO under tropospheric conditions (high pressure limit), which agree well with recent laboratory measurements [ Smith et al. J. Phys. Chem. A 2016 , 120 , 4789 and Chhantyal-Pun et al. J. Phys. Chem. A 2017 , 121 , 4 - 15 ]. Again, tunneling is shown to enhance the thermal decay rate by orders of magnitude. The experimentally validated unimolecular rates are also utilized in modeling the prompt and thermal unimolecular decay of chemically activated (CH3)2COO formed upon ozonolysis of 2,3-dimethyl-2-butene under atmospheric conditions [ Drozd et al. J. Phys. Chem. A 2017 , 121 , 6036 - 6045 ]. Future challenges lie in extension of these spectroscopic and dynamical methods to Criegee intermediates derived from more complex ozonolysis reactions involving biogenic alkenes. PMID- 29613757 TI - Monodisperse Ultrasmall Manganese-Doped Multimetallic Oxysulfide Nanoparticles as Highly Efficient Oxygen Reduction Electrocatalyst. AB - The highly efficient and cheap non-Pt-based electrocatalysts such as transition based catalysts prepared via facile methods for oxygen reduction reaction (ORR) are desirable for large-scale practical industry applications in energy conversion and storage systems. Herein, we report a straightforward top-down synthesis of monodisperse ultrasmall manganese-doped multimetallic (ZnGe) oxysulfide nanoparticles (NPs) as an efficient ORR electrocatalyst by simple ultrasonic treatment of the Mn-doped Zn-Ge-S chalcogenidometalate crystal precursors in H2O/EtOH for only 1 h at room temperature. Thus obtained ultrasmall monodisperse Mn-doped oxysulfide NPs with ultralow Mn loading level (3.92 wt %) not only exhibit comparable onset and half-wave potential (0.92 and 0.86 V vs reversible hydrogen electrode, respectively) to the commercial 20 wt % Pt/C but also exceptionally high metal mass activity (189 mA/mg at 0.8 V) and good methanol tolerance. A combination of transmission electron microscopy, scanning electron microscopy, X-ray photoelectron spectroscopy, and electrochemical analysis demonstrated that the homogenous distribution of a large amount of Mn(III) on the surface of NPs mainly accounts for the high ORR activity. We believe that this simple synthesis of Mn-doped multimetallic (ZnGe) oxysulfide NPs derived from chalcogenidometalates will open a new route to explore the utilization of discrete-cluster-based chalcogenidometalates as novel non-Pt electrocatalysts for energy applications and provide a facile way to realize the effective reduction of the amount of catalyst while keeping desired catalytic performances. PMID- 29613758 TI - Homogeneously Dispersed Co9S8 Anchored on Nitrogen and Sulfur Co-Doped Carbon Derived from Soybean as Bifunctional Oxygen Electrocatalysts and Supercapacitors. AB - Developing low-cost and highly active multifunctional electrocatalysts to replace noble metal catalysts is crucial for the commercialization of future clean energy technology. Herein, homogeneous Co9S8 nanoparticles anchored on nitrogen and sulfur co-doped porous carbon nanomaterials (CoS@NSCs) are fabricated by pyrolysis of natural soybean treated with cobalt nitrate. The unique porous structures of the soybean are utilized to provide space for the oxidation and complexation reactions for cobalt compounds, thus leading to in situ generation of homogenously dispersed cobalt sulfide nanoparticles that anchored on the N,S co-doped carbon framework. Because of the coupling effect of cobalt sulfide and doping heteroatoms, CoS@NSC-800 not only displays excellent electrocatalytic performances with low overpotential and high current density toward both oxygen reduction reaction and oxygen evolution reaction comparable to the commercial Pt/C catalyst and IrO2 catalyst, but also might be a promising candidate for high performance supercapacitors. The method for the preparation of the multifunctional hybrids is simple but effective for the formation of uniformly distributed metal sulfide nanoparticles anchored on carbon materials, therefore providing a new perspective for the design and synthesis of multifunctional electrocatalysts for electrochemical energy conversion and storage at a large scale. PMID- 29613759 TI - Metal-Organic Frameworks for Cultural Heritage Preservation: The Case of Acetic Acid Removal. AB - The removal of low concentrations of acetic acid from indoor air at museums poses serious preservation problems that the current adsorbents cannot easily address owing to their poor affinity for acetic acid and/or their low adsorption selectivity versus water. In this context, a series of topical water-stable metal organic frameworks (MOFs) with different pore sizes, topologies, hydrophobic characters, and functional groups was explored through a joint experimental computational exploration. We demonstrate how a subtle combination of sufficient hydrophobicity and optimized host-guest interactions allows one to overcome the challenge of capturing traces of this very polar volatile organic compound in the presence of humidity. The optimal capture of acetic acid was accomplished with MOFs that do not show polar groups in the inorganic node or have lipophilic but polar (e.g., perfluoro) groups functionalized to the organic linkers, that is, the best candidates from the list of explored MOFs are MIL-140B and UiO-66-2CF3. These two MOFs present the appropriate pore size to favor a high degree of confinement, together with organic spacers that allow an enhancement of the van der Waals interactions with the acetic acid. We establish in this work that MOFs can be a viable solution to this highly challenging problem in cultural heritage protection, which is a new field of application for this type of hybrid materials. PMID- 29613760 TI - Novel Protic Ionic Liquid Composite Membranes with Fast and Selective Gas Transport Nanochannels for Ethylene/Ethane Separation. AB - Protic ionic liquids (PILs) were utilized for the fabrication of composite membranes containing silver salt as the C2H4 transport carrier to perform C2H4/C2H6 separation for the first time. The intrinsic nanostructures of PILs were adopted to construct fast and selective C2H4 transport nanochannels. The investigation of structure-performance relationships of composite membranes suggested that transport nanochannels (polar domains of PILs) could be tuned by the sizes of cations, which greatly manipulated activity of the carrier and determined the separation performances of membranes. The role of different carriers in the facilitated transport was studied, which revealed that the PILs were good solvents for dissolution and activation of the carrier due to their hydrogen bond networks and waterlike properties. The operating conditions of separation process were investigated systemically and optimized, confirming C2H4/C2H6 selectivity was enhanced with the increase of silver salt concentration, the flow rate of sweep gas, and the feed ratio of C2H4 to C2H6, as well as the decrease of the transmembrane pressure and operating temperature. Furthermore, the composite membranes exhibited long-term stability and obtained very competitive separation performances compared with other results. In summary, PIL composite membranes, which possess good long-term stability, high C2H4/C2H6 selectivity, and excellent C2H4 permeability, may have a good perspective in industrial C2H4/C2H6 separation. PMID- 29613761 TI - Digital Isotope Coding to Trace the Growth Process of Individual Single-Walled Carbon Nanotubes. AB - Single-walled carbon nanotubes (SWCNTs) are attracting increasing attention as an ideal material for high-performance electronics through the preparation of arrays of purely semiconducting SWCNTs. Despite significant progress in the controlled synthesis of SWCNTs, their growth mechanism remains unclear due to difficulties in analyzing the time-resolved growth of individual SWCNTs under practical growth conditions. Here we present a method for tracing the diverse growth profiles of individual SWCNTs by embedding digitally coded isotope labels. Raman mapping showed that, after various incubation times, SWCNTs elongated monotonically until their abrupt termination. Ex situ analysis offered an opportunity to capture rare chirality changes along the SWCNTs, which resulted in sudden acceleration/deceleration of the growth rate. Dependence on growth parameters, such as temperature and carbon concentration, was also traced along individual SWCNTs, which could provide clues to chirality control. Systematic growth studies with a variety of catalysts and conditions, which combine the presented method with other characterization techniques, will lead to further understanding and control of chirality, length, and density of SWCNTs. PMID- 29613762 TI - Synthetic Nanofiber-Reinforced Amniotic Membrane via Interfacial Bonding. AB - Severe damage to the ocular surface can result in limbal stem cell (LSC) deficiency, which contributes to loss of corneal clarity, potential vision loss, chronic pain, photophobia, and keratoplasty failure. Human amniotic membrane (AM) is the most effective substrate for LSC transplantation to treat patients with LSC deficiency. However, the widespread use of the AM in the clinic remains a challenge because of the high cost for preserving freshly prepared AM and the weak mechanical strength of lyophilized AM. Here, we developed a novel composite membrane consisting of an electrospun bioabsorbable polymer fiber mesh bonded to a decellularized AM (dAM) sheet through interfacial conjugation. This membrane engineering approach drastically improved the tensile property and toughness of dAM, preserved similar levels of bioactivities as the dAM itself in supporting LSC attachment, growth, and maintenance, and retained significant anti inflammatory capacity. These results demonstrate that the lyophilized nanofiber dAM composite membrane offers superior mechanical properties for easy handling and suturing to the dAM, while presenting biochemical cues and basement membrane structure to facilitate LSC transplantation. This composite membrane exhibits major advantages for clinical applications in treating soft tissue damage and LSC deficiency. PMID- 29613763 TI - Generalized 3D Printing of Graphene-Based Mixed-Dimensional Hybrid Aerogels. AB - Graphene-based mixed-dimensional materials hybridization is important for a myriad of applications. However, conventional manufacturing techniques face critical challenges in producing arbitrary geometries with programmable features, continuous interior networks, and multimaterials homogeneity. Here we propose a generalized three-dimensional (3D) printing methodology for graphene aerogels and graphene-based mixed-dimensional (2D + nD, where n is 0, 1, or 2) hybrid aerogels with complex architectures, by the development of hybrid inks and printing schemes to enable mix-dimensional hybrids printability, overcoming the limitations of multicomponents inhomogeneity and harsh post-treatments for additives removal. Importantly, nonplanar designed geometries are also demonstrated by shape-conformable printing on curved surfaces. We further demonstrate the 3D-printed hybrid aerogels as ultrathick electrodes in a symmetric compression tolerant microsupercapacitor, exhibiting quasi proportionally enhanced areal capacitances at high levels of mass loading. The excellent performance is attributed to the sufficient ion- and electron-transport paths provided by the 3D-printed highly interconnected networks. The encouraging finding indicates tremendous potentials for practical energy storage applications. As a proof of concept, this general strategy provides avenues for various next-generation complex-shaped hybrid architectures from microscale to macroscale, for example, seawater desalination devices, electromagnetic shielding systems, and so forth. PMID- 29613764 TI - Deep-Subwavelength Resolving and Manipulating of Hidden Chirality in Achiral Nanostructures. AB - The chiral state of light plays a vital role in light-matter interactions and the consequent revolution of nanophotonic devices and advanced modern chiroptics. As the light-matter interaction goes into the nano- and quantum world, numerous chiroptical technologies and quantum devices require precise knowledge of chiral electromagnetic modes and chiral radiative local density of states (LDOS) distributions in detail, which directly determine the chiral light-matter interaction for applications such as chiral light detection and emission. With classical optical techniques failing to directly measure the chiral radiative LDOS, deep-subwavelength imaging and control of circular polarization (CP) light associated phenomena are introduced into the agenda. Here, we simultaneously reveal the hidden chiral electromagnetic mode and acquire its chiral radiative LDOS distribution of a single symmetric nanostructure at the deep-subwavelength scale by using CP-resolved cathodoluminescence (CL) microscopy. The chirality of the symmetric nanostructure under normally incident light excitation, resulting from the interference between the symmetric and antisymmetric modes of the V shaped nanoantenna, is hidden in the near field with a giant chiral distribution (~99%) at the arm-ends, which enables the circularly polarized CL emission from the radiative LDOS hot-spot and the following active helicity control at the deep subwavelength scale. The proposed V-shaped nanostructure as a functional unit is further applied to the helicity-dependent binary encoding and the two-dimensional display applications. The proposed physical principle and experimental configuration can promote the future chiral characterization and manipulation at the deep-subwavelength scale and provide direct guidelines for the optimization of chiral light-matter interactions for future quantum studies. PMID- 29613765 TI - Multistep Lithiation of Tin Sulfide: An Investigation Using in Situ Electron Microscopy. AB - Two-dimensional (2D) metal sulfides have been widely explored as promising electrodes for lithium-ion batteries since their two-dimensional layered structure allows lithium ions to intercalate between layers. For tin disulfide, the lithiation process proceeds via a sequence of three different types of reactions: intercalation, conversion, and alloying, but the full scenario of reaction dynamics remains nebulous. Here, we investigate the dynamical process of the multistep reactions using in situ electron microscopy and discover the formation of an intermediate rock-salt phase with the disordering of Li and Sn cations after initial 2D intercalation. The disordered cations occupy all the octahedral sites and block the channels for intercalation, which alter the reaction pathways during further lithiation. Our first-principles calculations of the nonequilibrium lithiation of SnS2 corroborate the energetic preference of the disordered rock-salt structure over known layered polymorphs. The in situ observations and calculations suggest a two-phase reaction nature for intercalation, disordering, and following conversion reactions. In addition, in situ delithiation observation confirms that the alloying reaction is reversible, while the conversion reaction is not, which is consistent with the ex situ analysis. This work reveals the full lithiation characteristic of SnS2 and sheds light on the understanding of complex multistep reactions in 2D materials. PMID- 29613766 TI - Exciplex: An Intermolecular Charge-Transfer Approach for TADF. AB - Organic materials that display thermally activated delayed fluorescence (TADF) are a striking class of functional materials that have witnessed a booming progress in recent years. In addition to pure TADF emitters achieved by the subtle manipulations of intramolecular charge transfer processes with sophisticated molecular structures, a new class of efficient TADF-based OLEDs with emitting layer formed by blending electron donor and acceptor molecules that involve intermolecular charge transfer have also been fabricated. In contrast to pure TADF materials, the exciplex-based systems can realize small Delta EST (0 0.05 eV) much more easily since the electron and hole are positioned on two different molecules, thereby giving small exchange energy. Consequently, exciplex based OLEDs have the prospective to maximize the TADF contribution and achieve theoretical 100% internal quantum efficiency. Therefore, the challenging issue of achieving small Delta EST in organic systems could be solved. In this article, we summarize and discuss the latest and most significant developments regarding these rapidly evolving functional materials, wherein the majority of the reported exciplex forming systems are categorized into two subgroups, viz. (a) exciplex as TADF emitters and (b) those as hosts for fluorescent, phosphorescent and TADF dopants according to their structural features and applications. The working mechanisms of the direct electroluminescence from the donor/acceptor interface and the exciplex-forming systems as cohost for the realization of high efficiency OLEDs are reviewed and discussed. This article delivers a summary of the current progresses and achievements of exciplex-based researches and points out the future challenges to trigger more research endeavors to this growing field. PMID- 29613767 TI - Interface-Controlled Conductive Fibers for Wearable Strain Sensors and Stretchable Conducting Wires. AB - As an important subfield of flexible electronics, conductive fibers have been an active area of research. The interfacial interaction between nanostructured conductive materials with elastic substrates plays a vital role in the electromechanical performance of conductive fibers. However, the underlying mechanism has seldom been investigated. Here, we propose a fabricating strategy for a silver nanowire (Ag NW)/polyurethane composite fiber with a sheath-core architecture. The interfacial bonding layer is regulated, and its influence on the performance of conductive fibers is investigated, based on which an interfacial interaction model is proposed. The model underlines the significance of the embedding depth of the Ag NW network. Both supersensitive (gauge factor up to 9557) and ultrastable (negligible conductance degradation below the strain of 150%) conductive fibers are obtained via interface regulating, exhibiting great potential in the applications of wearable sensors and stretchable conducting connections. PMID- 29613768 TI - Decomposition of the Thermal Boundary Resistance across Carbon Nanotube-Graphene Junctions to Different Mechanisms. AB - Three different mechanisms are identified to contribute to thermal resistances across a carbon nanotube-graphene junction: material mismatch, nonplanar junction, and defects. To isolate the contributions of each mechanism, we have designed five types of junctions and performed nonequilibrium molecular dynamics simulations. The results show that the contributions from the three mechanisms are similar, each at around 2.5 * 10-11 m2 K/W. The relations between thermal boundary resistance and both defect number and turning angle at the interface are also studied. PMID- 29613770 TI - Nanoenzyme-Augmented Cancer Sonodynamic Therapy by Catalytic Tumor Oxygenation. AB - Ultrasound (US)-triggered sonodynamic therapy (SDT) can solve the critical issue of low tissue-penetrating depth of traditional phototriggered therapies, but the SDT efficacy is still not satisfactorily high in combating cancer at the current stage. Here we report on augmenting the SDT efficacy based on catalytic nanomedicine, which takes the efficient catalytic features of nanoenzymes to modulate the tumor microenvironment (TME). The multifunctional nanosonosensitizers have been successfully constructed by the integration of a MnO x component with biocompatible/biodegradable hollow mesoporous organosilica nanoparticles, followed by conjugation with protoporphyrin (as the sonosensitizer) and cyclic arginine-glycine-aspartic pentapeptide (as the targeting peptide). The MnO x component in the composite nanosonosensitizer acts as an inorganic nanoenzyme for converting the tumor-overexpressed hydrogen peroxide (H2O2) molecules into oxygen and enhancing the tumor oxygen level subsequently, which has been demonstrated to facilitate SDT-induced reactive oxygen species production and enhance SDT efficacy subsequently. The targeted accumulation of these composite nanosonosensitizers efficiently suppressed the growth of U87 tumor xenograft on nude mice after US-triggered SDT treatment. The high in vivo biocompatibility and easy excretion of these multifunctional nanosonosensitizers from the body have also been evaluated and demonstrated to guarantee their future clinical translation, and their TME-responsive T1-weighted magnetic resonance imaging capability provides the potential for therapeutic guidance and monitoring during SDT. PMID- 29613771 TI - Submultiple Data Collection to Explore Spectroscopic Instrument Instabilities Shows that Much of the "Noise" is not Stochastic. AB - As has long been understood, the noise on a spectrometric signal can be reduced by averaging over time, and the averaged noise is expected to decrease as t1/2, the square root of the data collection time. However, with contemporary capability for fast data collection and storage, we can retain and access a great deal more information about a signal train than just its average over time. During the same collection time, we can record the signal averaged over much shorter, equal, fixed periods. This is, then, the set of signals over submultiples of the total collection time. With a sufficiently large set of submultiples, the distribution of the signal's fluctuations over the submultiple periods of the data stream can be acquired at each wavelength (or frequency). From the autocorrelations of submultiple sets, we find only some fraction of these fluctuations consist of stochastic noise. Part of the fluctuations are what we call "fast drift", which is defined as drift over a time shorter than the complete measurement period of the average spectrum. In effect, what is usually assumed to be stochastic noise has a significant component of fast drift due to changes of conditions in the spectroscopic system. In addition, we show that the extreme values of the fluctuation of the signals are usually not balanced (equal magnitudes, equal probabilities) on either side of the mean or median without an inconveniently long measurement time; the data is almost inevitably biased. In other words, the unbalanced data is collected in an unbalanced manner around the mean, and so the median provides a better measure of the true spectrum. As is shown here, by using the medians of these distributions, the signal-to-noise of the spectrum can be increased and sampling bias reduced. The effect of this submultiple median data treatment is demonstrated for infrared, circular dichroism, and Raman spectrometry. PMID- 29613769 TI - Protein-Protein Interactions in the Molecular Chaperone Network. AB - Molecular chaperones play a central role in protein homeostasis (a.k.a. proteostasis) by balancing protein folding, quality control, and turnover. To perform these diverse tasks, chaperones need the malleability to bind nearly any "client" protein and the fidelity to detect when it is misfolded. Remarkably, these activities are carried out by only ~180 dedicated chaperones in humans. How do a relatively small number of chaperones maintain cellular and organismal proteostasis for an entire proteome? Furthermore, once a chaperone binds a client, how does it "decide" what to do with it? One clue comes from observations that individual chaperones engage in protein-protein interactions (PPIs)-both with each other and with their clients. These physical links coordinate multiple chaperones into organized, functional complexes and facilitate the "handoff" of clients between them. PPIs also link chaperones and their clients to other cellular pathways, such as those that mediate trafficking (e.g., cytoskeleton) and degradation (e.g., proteasome). The PPIs of the chaperone network have a wide range of affinity values (nanomolar to micromolar) and involve many distinct types of domain modules, such as J domains, zinc fingers, and tetratricopeptide repeats. Many of these motifs have the same binding surfaces on shared partners, such that members of one chaperone class often compete for the same interactions. Somehow, this collection of PPIs draws together chaperone families and creates multiprotein subnetworks that are able to make the "decisions" of protein quality control. The key to understanding chaperone-mediated proteostasis might be to understand how PPIs are regulated. This Account will discuss the efforts of our group and others to map, measure, and chemically perturb the PPIs within the molecular chaperone network. Structural biology methods, including X-ray crystallography, NMR spectroscopy, and electron microscopy, have all played important roles in visualizing the chaperone PPIs. Guided by these efforts and omics approaches to measure PPIs, new advances in high-throughput chemical screening that are specially designed to account for the challenges of this system have emerged. Indeed, chemical biology has played a particularly important role in this effort, as molecules that either promote or inhibit specific PPIs have proven to be invaluable research probes in cells and animals. In addition, these molecules have provided leads for the potential treatment of protein misfolding diseases. One of the major products of this research field has been the identification of putative PPI drug targets within the chaperone network, which might be used to change chaperone "decisions" and rebalance proteostasis. PMID- 29613772 TI - Decoding Surface Interaction of VIVO Metallodrug Candidates with Lysozyme. AB - The interaction of metallodrugs with proteins influences their transport, uptake, and mechanism of action. In this study, we present an integrative approach based on spectroscopic (EPR) and computational (docking) tools to elucidate the noncovalent binding modes of various VIVO compounds with lysozyme, a prototypical model of protein receptor. Five VIVO-flavonoid drug candidates formed by quercetin (que), morin (mor), 7,8-dihydroxyflavone (7,8-dhf), chrysin (chr), and 5-hydroxyflavone (5-hf)-effective against several osteosarcoma cell lines-and two benchmark VIVO species of acetylacetone (acac) and catechol (cat) are evaluated. The results show a gradual variation of the EPR spectra at room temperature, which is associated with the strength of the interaction between the square pyramidal complexes [VOL2] and the surface residues of lysozyme. The qualitative strength of the interaction from EPR is [VO(que)2]2- ~ [VO(mor)2] > [VO(7,8 dhf)2]2- > [VO(chr)2] ~ [VO(5-hf)2] > [VO(acac)2] ~ [VO(cat)2]2-. This observation is compared with protein- ligand docking calculations with GOLD software examining the GoldScore scoring function ( F), for which hydrogen bond and van der Waals contact terms have been optimized to account for the surface interaction. The best predicted binding modes display an energy trend in good agreement with the EPR spectroscopy. Computation indicates that the strength of the interaction can be predicted by the Fmax value and depends on the number of OH or CO groups of the ligands that can interact with different sites on the protein surface and, more particularly, with those in the vicinity of the active site of the enzyme. The interaction strength determines the type of signal revealed ( rigid limit, slow tumbling, or isotropic) in the EPR spectra. Spectroscopic and computational results also suggest that there are several sites with comparable binding energy, with the V complexes distributing among them in a bound state and in aqueous solution in an unbound state. This kind of study and analysis could be generalized to determine the noncovalent binding modes of a generic metal species with a generic protein. PMID- 29613773 TI - An Orthogonal and pH-Tunable Sensor-Selector for Muconic Acid Biosynthesis in Yeast. AB - Microbes offer enormous potential for production of industrially relevant chemicals and therapeutics, yet the rapid identification of high-producing microbes from large genetic libraries is a major bottleneck in modern cell factory development. Here, we develop and apply a synthetic selection system in Saccharomyces cerevisiae that couples the concentration of muconic acid, a plastic precursor, to cell fitness by using the prokaryotic transcriptional regulator BenM driving an antibiotic resistance gene. We show that the sensor selector does not affect production nor fitness, and find that tuning pH of the cultivation medium limits the rise of nonproducing cheaters. We apply the sensor selector to selectively enrich for best-producing variants out of a large library of muconic acid production strains, and identify an isolate that produces more than 2 g/L muconic acid in a bioreactor. We expect that this sensor-selector can aid the development of other synthetic selection systems based on allosteric transcription factors. PMID- 29613774 TI - Delicate Assembly of Ultrathin Hydroxyapatite Nanobelts with Nanoneedles Directed by Dissolved Cellulose. AB - Living organisms make use of a variety of inorganic and organic components to form biogenic minerals with hierarchical structures and fascinating properties, triggering the development of biomimetic mineralization. The introduction of organic additive is a versatile strategy, and a wide range of organics have already been adopted to mimic biosystems designing and synthesizing advanced functional minerals. Insoluble cellulose is the most abundant polysaccharide in nature, but the insolubility has limited its extensive applications. In this study, we first find that concentrated calcium chloride aqueous solution is an effective solvent for cellulose, and dissolved cellulose plays a pivotal role in directing the formation of ultrathin hydroxyapatite (HA) nanobelts of ca. 10 nm in thickness. To investigate the assembling process of the belt, samples collected at different reaction times were observed. The results indicate that nanoneedles form first, and then they assemble into the prototype of nanobelts by lateral/longitudinal aggregation and arrangement. Subsequently, the nanobelts gradually become dense, transparent, and smooth via crystallographic fusion of adjacent nanoneedles, indicating the highly elaborated evolution of morphology resulted from a time-dependent process. During the evolution of nanobelts, dissolved cellulose is supposed to participate in the mineralization of HA via the bonding of its hydrophilic groups with phosphate groups and calcium ions and the interaction of cellulose molecules with HA crystal planes. These findings provide unique insight into the application of dissolved cellulose in aqueous solution and an inspiration of a bottom-up strategy for designing delicate mineral assemblies directed by insoluble organics. PMID- 29613775 TI - Evaluation of Alkylamine Modified Pt Nanoparticles as Oxygen Reduction Reaction Electrocatalyst for Fuel Cells via Electrochemical Impedance Spectroscopy. AB - Organically (octyl amine, OA) surface modified electrocatalyst (OA-Pt/CB) was studied for its oxygen reduction reaction (ORR) activity via dc methods and its charge and mass transfer properties were studied via electrochemical impedance spectroscopy (EIS). Comparison with a commercial catalyst (TEC10V30E) with similar Pt content was also carried out. In EIS, both the catalysts showed a single time-constant with an emerging high-frequency semicircle of very small diameter which was fitted using suitable equivalent circuits. The organically modified catalyst showed lower charge-transfer resistance and hence, low polarization resistance in high potential region as compared to the commercial catalyst. The dominance of kinetic processes was observed at 0.925-1.000 V, whereas domination of diffusion based processes was observed at lower potential region for the organic catalyst. No effect due to the presence of carbon was observed in the EIS spectra. Using the hydrodynamic method, higher current penetration depth was obtained for the organically modified catalyst at 1600 rpm. Exchange current density and Tafel slopes for both the electrocatalysts were calculated from the polarization resistance obtained from EIS which was in correlation with the results obtained from dc methods. PMID- 29613776 TI - High Speed Intact Protein Characterization Using 4X Frequency Multiplication, Ion Trap Harmonization, and 21 Tesla FTICR-MS. AB - Mass spectrometric characterization of large biomolecules, such as intact proteins, requires the specificity afforded by ultrahigh resolution mass measurements performed at both the intact mass and product ion levels. Although the performance of time-of-flight mass analyzers is steadily increasing, the choice of mass analyzer for large biomolecules (e.g., proteins >50 kDa) is generally limited to the Fourier transform family of mass analyzers such as Orbitrap and ion cyclotron resonance (FTICR-MS), with the latter providing unmatched mass resolving power and measurement accuracy. Yet, protein analyses using FTMS are largely hindered by the low acquisition rates of spectra with ultrahigh resolving power. Frequency multiple detection schemes enable FTICR-MS to overcome this fundamental barrier and achieve resolving powers and acquisition speeds 4* greater than the limits imposed by magnetic field strength. Here we expand upon earlier work on the implementation of this technique for biomolecular characterization. We report the coupling of 21T FTICR-MS, 4X frequency multiplication, ion trapping field harmonization technology, and spectral data processing methods to achieve unprecedented acquisition rates and resolving power in mass spectrometry of large intact proteins. Isotopically resolved spectra of multiply charged ubiquitin ions were acquired using detection periods as short as 12 ms. Large proteins such as apo-transferrin (MW = 78 kDa) and monoclonal antibody (MW = 150 kDa) were isotopically resolved with detection periods of 384 and 768 ms, respectively. These results illustrate the future capability of accurate characterization of large proteins on time scales compatible with online separations. PMID- 29613777 TI - Interactions of Gaseous 2-Chlorophenol with Fe3+-Saturated Montmorillonite and Their Toxicity to Human Lung Cells. AB - The interactions of gaseous 2-chlorophenol with Fe3+-saturated montmorillonite particles in a gas-solid system were investigated to simulate the reactions of mineral dusts with volatile organic pollutants in the atmosphere. Results suggested that Fe3+-saturated montmorillonite mediated the dimerization of gaseous 2-chlorophenol to form hydroxylated polychlorinated biphenyl, hydroxylated polychlorinated diphenyl ether, and hydroxylated polychlorinated dibenzofuran. The toxicity of Fe3+-montmorillonite particles to A549 human lung epithelial cells before and after interaction with 2-chlorophenol was examined to explore their adverse impact on human health. Based on cell morphological analysis, cytotoxicity tests, and Fourier-transform infrared imaging spectra, surface-catalyzed reactions of Fe3+-montmorillonite with 2-chlorophenol increased the toxicity of montmorillonite particle on A549 cells. This was supported by increased cellular membrane permeability, the release of extracellular lactate dehydrogenase, and cell damages on cellular DNA, proteins, and lipids. Since mineral dusts are important components of particulate matter, our results help to understand the interactions of volatile organic pollutants with particulate matter in the atmosphere and their adverse impacts on human health. PMID- 29613778 TI - Manipulating the Relaxation of Quasi- D4 d Dysprosium Compounds through Alternation of the O-Donor Ligands. AB - Three mononuclear DyIII complexes with the same auxiliary ligand Lz (2,4-diamino 6-pyridyl-1,3,5-triazine), [Dy(TTA)3Lz] (1Dy) (TTA = 4,4,4-trifluoro-1-(2 thienyl)-1,3-butanedionate), [Dy(acac)3Lz].CH3OH.0.5H2O (2Dy) (acac = acetylacetonate), and [Dy(MQ)2Lz2]Br.CH3OH (3Dy) (HMQ = 2-methyl-8-quinolinol), have been synthesized through alteration of the ligands containing O donors. In all three complexes, the DyIII ions are eight-coordinate and submitted to pseudo- D4 d symmetry in the first coordination sphere. It is noteworthy that the TTA ligands in 1Dy are easily substituted by other bidentate capping ligands with O donors, leading to distinct magnetic properties, which were studied experimentally and via ab initio calculations. All three complexes were found to exhibit single-molecule magnet behavior with Ueff of 22 cm-1 (1Dy), 112 cm-1 (2Dy), and 56 cm-1 (3Dy) under zero applied dc field. Complex 1Dy demonstrates inferior SIM properties compared with 2Dy and 3Dy, which can be attributed to the strong electron-withdrawing effects of TTA ligands, as confirmed by theoretical calculations. However, butterfly-shaped magnetic hysteresis in 1Dy and 3Dy was observed at 1.9 K, while not in 2Dy. PMID- 29613779 TI - Local Tetragonal Structure of the Cubic Superionic Conductor Na3PS4. AB - The sodium superionic conductor Na3PS4 is known to crystallize in one of two different structural polymorphs at room temperature (i.e., cubic or tetragonal, depending on the synthetic conditions). Experimentally, the cubic structure is known to exhibit a higher ionic conductivity than the tetragonal structure, despite theoretical investigations suggesting that there should be no difference at all. Employing a combination of Rietveld and pair distribution function (PDF) analyses, as well as electrochemical impedance spectroscopy, we investigate the open question of how the crystal structure influences the ionic transport in Na3PS4. Despite the average structures of Na3PS4 prepared via ball-milling and high-temperature routes being cubic and tetragonal, respectively, the structural analysis by PDF indicates that both compounds are best described by the structural motifs of the tetragonal polymorph on the local scale. Ultimately, the high ionic conductivity of Na3PS4 prepared by the ball-milling approach is confirmed to be independent of the crystal structure. This work demonstrates that even in ionic conductors differences can be observed between the average and local crystal structures, and it reasserts that the high ionic conductivity in Na3PS4 is not related to the crystal structure but rather differences in the defect concentration. PMID- 29613780 TI - Ba4B8TeO19: A UV Nonlinear Optical Material. AB - We report a new noncentrosymmetric barium tellurium borate, Ba4B8TeO19 that has potential ultraviolet (UV) nonlinear optical (NLO) applications. Ba4B8TeO19 was synthesized by a flux method and crystallizes in the noncentrosymmetric space group Cc. The material exhibits a framework structure of [B8O17]infinity double layers connected to distorted TeO6 octahedra. Second harmonic generation (SHG) measurements at 1064 and 532 nm on polycrystalline Ba4B8TeO19 indicate that the title compound is phase-matchable (type I) with a moderate SHG response (1 * KH2PO4 at 1064 nm and 0.2 * beta-BaB2O4 at 532 nm). In addition, a short absorption edge (210 nm) was measured. Using density functional theory calculations, we show that the SHG response originates from contributions from O 2p and Te 5s states at the valence and conduction band edges. Finally, by computing the linear optical properties, we find that this compound displays a moderate birefringence of 0.055 at 1064 nm and 0.059 at 532 nm, necessary conditions for phase-matching in UV NLO materials. PMID- 29613781 TI - Correction to Efficient Synthesis of Tris-Heteroleptic Iridium(III) Complexes Based on the Zn2+-Promoted Degradation of Tris-Cyclometalated Iridium(III) Complexes and Their Photophysical Properties. PMID- 29613782 TI - Expanding the Library of Uranyl Amide Derivatives: New Complexes Featuring the tert-Butyldimethylsilylamide Ligand. AB - New uranyl derivatives featuring the amide ligand, -N(SiHMe2) tBu, were synthesized and characterized by X-ray crystallography, multinuclear NMR spectroscopy, and absorption spectroscopies. Steric properties of these complexes were also quantified using the computational program Solid-G. The increased basicity of the free ligand -N(SiHMe2) tBu was demonstrated by direct comparison to -N(SiMe3)2, a popular supporting ligand for uranyl. Substitutional lability on a uranyl center was also demonstrated by exchange with the -N(SiMe3)2 ligand. The increased basicity of this ligand and diverse characterization handles discussed here will make these compounds useful synthons for future reactivity. PMID- 29613783 TI - Endo and Exo Diels-Alder Adducts: Temperature-Tunable Building Blocks for Selective Chemical Functionalization. AB - The development and application of a novel endo furan-protected maleimide building block is reported. The endo isomer undergoes deprotection at temperatures ~50 degrees C below the exo derivative. This enables a simple and powerful approach to quantitatively and selectively introduce functional maleimide groups via temperature modulation. PMID- 29613785 TI - Statistical Analysis of Semiclassical Dispersion Corrections. AB - Semiclassical dispersion corrections developed by Grimme and co-workers have become indispensable in applications of Kohn-Sham density functional theory. A deeper understanding of the underlying parametrization might be crucial for well founded further improvements of this successful approach. To this end, we present an in-depth assessment of the fit parameters present in semiclassical (D3-type) dispersion corrections by means of a statistically rigorous analysis. We find that the choice of the cost function generally has a small effect on the empirical parameters of D3-type dispersion corrections with respect to the reference set under consideration. Only in a few cases, the choice of cost function has a surprisingly large effect on the total dispersion energies. In particular, the weighting scheme in the cost function can significantly affect the reliability of predictions. In order to obtain unbiased (data-independent) uncertainty estimates for both the empirical fit parameters and the corresponding predictions, we carried out a nonparametric bootstrap analysis. This analysis reveals that the standard deviation of the mean of the empirical D3 parameters is small. Moreover, the mean prediction uncertainty obtained by bootstrapping is not much larger than previously reported error measures. On the basis of a jackknife analysis, we find that the original reference set is slightly skewed, but our results also suggest that this feature hardly affects the prediction of dispersion energies. Furthermore, we find that the introduction of small uncertainties to the reference data does not change the conclusions drawn in this work. However, a rigorous analysis of error accumulation arising from different parametrizations reveals that error cancellation does not necessarily occur, leading to a monotonically increasing deviation in the dispersion energy with increasing molecule size. We discuss this issue in detail at the prominent example of the C60 "buckycatcher". We find deviations between individual parametrizations of several tens of kilocalories per mole in some cases. Hence, in combination with any calculation of dispersion energies, we recommend to always determine the associated uncertainties for which we will provide a software tool. PMID- 29613784 TI - Seed-Specific Expression of OsDWF4, a Rate-Limiting Gene Involved in Brassinosteroids Biosynthesis, Improves Both Grain Yield and Quality in Rice. AB - Brassinosteroids (BRs) are essential plant-specific steroidal hormones that regulate diverse growth and developmental processes in plants. We evaluated the effects of OsDWF4, a gene that encodes a rate-limiting enzyme in BR biosynthesis, on both rice yield and quality when driven by the Gt1 or Ubi promoter, which correspond to seed-specific or constitutive expression, respectively. Generally, transgenic plants expressing OsDWF4 showed increased grain yield with more tillers and longer and heavier seeds. Moreover, the starch physicochemical properties of the transgenic rice were also improved. Interestingly, OsDWF4 was found to exert different effects on either rice yield or quality when driven by the different promoters. The overall performance of the pGt1::OsDWF4 lines was better than that of the pUbi::OsDWF4 lines. Our data not only demonstrate the effects of OsDWF4 overexpression on both rice yield and quality but also suggest that a seed-specific promoter is a good choice in BR-mediated rice breeding programs. PMID- 29613786 TI - Synthesis and Physical Properties of the Oxofluoride Cu2(SeO3)F2. AB - Single crystals of the new compound Cu2(SeO3)F2 were successfully synthesized via a hydrothermal method, and the crystal structure was determined from single crystal X-ray diffraction data. The compound crystallizes in the orthorhombic space group Pnma with the unit cell parameters a = 7.066(4) A, b = 9.590(4) A, and c = 5.563(3) A. Cu2(SeO3)F2 is isostructural with the previously described compounds Co2TeO3F2 and CoSeO3F2. The crystal structure comprises a framework of corner- and edge-sharing distorted [CuO3F3] octahedra, within which [SeO3] trigonal pyramids are present in voids and are connected to [CuO3F3] octahedra by corner sharing. The presence of a single local environment in both the 19F and 77Se solid-state MAS NMR spectra supports the hypothesis that O and F do not mix at the same crystallographic positions. Also the specific phonon modes observed with Raman scattering support the coordination around the cations. At high temperatures the magnetic susceptibility follows the Curie-Weiss law with Curie temperature of Theta = -173(2) K and an effective magnetic moment of MUeff ~ 2.2 MUB. Antiferromagnetic ordering below ~44 K is indicated by a peak in the magnetic susceptibility. A second though smaller peak at ~16 K is tentatively ascribed to a magnetic reorientation transition. Both transitions are also confirmed by heat capacity measurements. Raman scattering experiments propose a structural phase instability in the temperature range 6-50 K based on phonon anomalies. Further changes in the Raman shift of modes at ~46 K and ~16 K arise from transitions of the magnetic lattice in accordance with the susceptibility and heat capacity measurements. PMID- 29613787 TI - Miuramides A and B, Trisoxazole Macrolides from a Mycale sp. Marine Sponge That Induce a Protrusion Phenotype in Cultured Mammalian Cells. AB - Morphology-guided cell-based screening of the extract of a Mycale sp. marine sponge led to the isolation of two trisoxazole macrolides, miuramides A (1) and B (2), which induced characteristic morphological changes in 3Y1 cells. The structure of 1 including absolute configuration was elucidated by a combination of the analysis of spectroscopic data, derivatization, and degradation. Both compounds exhibit potent cytotoxicity against 3Y1 cells. PMID- 29613789 TI - Design and Synthesis of Clinical Candidate PF-06751979: A Potent, Brain Penetrant, beta-Site Amyloid Precursor Protein Cleaving Enzyme 1 (BACE1) Inhibitor Lacking Hypopigmentation. AB - A major challenge in the development of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitors for the treatment of Alzheimer's disease is the alignment of potency, drug-like properties, and selectivity over related aspartyl proteases such as Cathepsin D (CatD) and BACE2. The potential liabilities of inhibiting BACE2 chronically have only recently begun to emerge as BACE2 impacts the processing of the premelanosome protein (PMEL17) and disrupts melanosome morphology resulting in a depigmentation phenotype. Herein, we describe the identification of clinical candidate PF-06751979 (64), which displays excellent brain penetration, potent in vivo efficacy, and broad selectivity over related aspartyl proteases including BACE2. Chronic dosing of 64 for up to 9 months in dog did not reveal any observation of hair coat color (pigmentation) changes and suggests a key differentiator over current BACE1 inhibitors that are nonselective against BACE2 in later stage clinical development. PMID- 29613790 TI - Total Synthesis of Gramistilbenoids A, B, and C. AB - Stilbenes are biologically active metabolites of plants that have the potential to attenuate a broad range of human diseases. Gramistilbenoids are a class of natural products with a stilbene skeleton, isolated from the bamboo orchid ( Arundina graminifolia), and with significant cytotoxicity against cancer cell lines (NB4, A549, SHSY5Y, PC3, and MCF7). These are the first identified naturally occurring diphenylethylenes to possess a hydroxyethyl unit. However, some of these compounds are not abundant in nature, and thus, their synthesis is advantageous. This paper reports the first synthesis of gramistilbenoids A (1), B (2), and C (3), with overall yields of 10, 2, and 8% respectively. These natural products were synthesized using key reactions, such as Horner-Wadsworth-Emmons olefination, Stille coupling, and hydroboration-oxidation. PMID- 29613791 TI - Surface Engineering of a Nickel Oxide-Nickel Hybrid Nanoarray as a Versatile Catalyst for Both Superior Water and Urea Oxidation. AB - Developing efficient and low-cost oxygen evolution reaction (OER) electrodes is a pressing but still challenging task for energy conversion technologies such as water electrolysis, regenerative fuel cells, and rechargeable metal-air batteries. Hence, this study reports that a nickel oxide-nickel hybrid nanoarray on nickel foam (NiO-Ni/NF) could act as a versatile anode for superior water and urea oxidation. Impressively, this anode could attain high current densities of 50 and 100 mA cm-2 at extremely low overpotentials of 292 and 323 mV for OER, respectively. Besides, this electrode also shows excellent activity for urea oxidation with the need for just 0.28 and 0.36 V (vs SCE) to attain 10 and 100 mA cm-2 in 1.0 M KOH with 0.33 M urea, respectively. The enhanced oxidation performance should be due to the synergistic effect of NiO and Ni, improved conductivity, and enlarged active surface area. PMID- 29613792 TI - Nutshell Extracts of Xanthoceras sorbifolia: A New Potential Source of Bioactive Phenolic Compounds as a Natural Antioxidant and Immunomodulator. AB - The nutshell of Xanthoceras sorbifolia, a waste product in the production of edible oil, is rich in health-promoting phenolic acids. However, the individual constituents, bioactivities, and mechanism of action are largely unknown. In this study, 20 phenolic compounds were characterized in nutshell extract (NE) of X. sorbifolia by gas chromatography-mass spectrometry. Four established in vitro studies showed that NE has significant antioxidant potential. Results in vivo indicated that oral administration of NE effectively ameliorated clinical disease severity of experimental autoimmune encephalomyelitis (EAE) and reduced the neuroinflammation and the central nervous system (CNS) demyelination. The underlying mechanism of NE-induced effects involved decreased penetration of pathogenic immunocyte into the CNS, a reduced production of proinflammatory cytokines and factors, and suppressed differentiation of type 1 T helper and type 17 T helper cells through the Janus kinase/signal transducer and activator of transcription pathway. Taken together, our studies showed that X. sorbifolia nutshell, considered a waste material in the food industry, is a novel source of a natural antioxidant and immunomodulator. PMID- 29613793 TI - In Situ Monitoring the Uptake of Moisture into Hybrid Perovskite Thin Films. AB - Solution-processed hybrid perovskites are of great interest for use in photovoltaics. However, polycrystalline perovskite thin films show strong degradation in humid atmospheres, which poses an important challenge for large scale market introduction. With in situ grazing incidence neutron scattering (GISANS) we analyzed water content, degradation products, and morphological changes during prolonged exposure to several humidity levels. In high humidity, the formation of metastable hydrate phases is accompanied by domain swelling, which transforms the faceted crystals to a round-washed, pebble-like form. The films incorporate much more water than is integrated into the hydrates, with smaller crystals being more affected, making the degradation strongly dependent on film morphology. Even at low humidity, water is adsorbed on the crystal surfaces without the formation of crystalline degradation products. Thus, although production in an ambient atmosphere is of interest for industrial production it might lead to long-term degradation without appropriate countermeasures like postproduction drying below 30% RH. PMID- 29613794 TI - Chirality-Controlled Syntheses of Double-Helical Au Nanowires. AB - The selective large-scale syntheses of noble metal nanocrystals with complex shapes using wet-chemical approaches remain exciting challenges. Here we report the chirality-controllable syntheses of double-helical Au nanowires (NWs) using chiral soft-templates composed of two organogelators with their own active functions; one organogelator serves to introduce helicity into the template and the other acts as a capping agent to control the Au shape. One-dimensional twisted-nanoribbon templates are prepared simply by mixing the two organogelators in water containing a small amount of toluene, followed by the addition of LiCl; template chirality is controlled through the selection of the handedness of the helicity-inducing organogelator. Double-helical Au NWs synthesized on these chiral templates have the same helical structure as the template because the Au NWs grow along both edges of the twisted nanoribbons with right- or left-handed helicities. Dispersions of the right- and left-handed double-helical Au NWs exhibit opposite CD signals. PMID- 29613795 TI - Palladium(II)-Catalyzed Oxidative Homo- and Cross-Coupling of Aryl ortho-sp2 C-H Bonds of Anilides at Room Temperature. AB - The preparation of secondary 2,2'-bisanilides has been successfully achieved through an oxidative coupling of aryl ortho-sp2 C-H bonds of anilides in the presence of catalytic Pd(OAc)2 and K2S2O8 as an oxidant in MsOH/CF3CO2H (TFA) at room temperature (25 degrees C). The aromatic rings of anilides substituted by various electron-donating or electron-withdrawing groups are tolerant in these coupling reactions. PMID- 29613796 TI - New Force Field Parameters for the Sodium Dodecyl Sulfate and Alpha Olefin Sulfonate Anionic Surfactants. AB - Molecular dynamics simulations were carried out to obtain new force field parameters of two most commonly used anionic surfactants: sodium dodecyl sulfate and alpha olefin sulfonate. The present united atom models, of those surfactants, fail to reproduce one of the most important thermodynamic properties, the surface tension. Therefore, by scaling the Lennard-Jones parameters, the potential well (epsilon) and the length (sigma), we were able to fit the experimental data. The correct micelle structure of the surfactants was also captured with the new set of parameters. The new proposed united atom models of both surfactants were tested with two different water models, TIP4P/epsilon and SPC/E, and good agreement with actual experiments was found. PMID- 29613797 TI - Simulation of the Two-Dimensional Electronic Spectroscopy and Energy Transfer Dynamics of Light-Harvesting Complex II at Ambient Temperature. AB - We simulate the two-dimensional electronic spectra (2DES) of the light-harvesting complex II (LHCII) at room temperature by combining the hierarchical equations of motion method and the equation-of-motion phase-matching approach. The laser excited population dynamics of LHCII is also calculated to help understanding the 2DES. Three different excitation schemes are studied, including (1) only the chlorophyll (Chl) b Q y states of LHCII are excited, (2) only the Chl a Q y states are excited, and (3) both the Chl b and Chl a states are excited. The energy transfer pathways and time scales revealed from the 2DES in schemes (1) and (2) agree with the recent experimental studies for the Chl b to Chl a energy transfer and the excitation energy relaxation process within the Chl a manifold. We also propose a different way to better present the signals of bottleneck states by investigating the diagonal peaks of the 2DES in scheme (3). PMID- 29613798 TI - Comprehensive Experimental and Computational Spectroscopic Study of Hexacyanoferrate Complexes in Water: From Infrared to X-ray Wavelengths. AB - We present a joint experimental and computational study of the hexacyanoferrate aqueous complexes at equilibrium in the 250 meV to 7.15 keV regime. The experiments and the computations include the vibrational spectroscopy of the cyanide ligands, the valence electronic absorption spectra, and Fe 1s core hole spectra using element-specific-resonant X-ray absorption and emission techniques. Density functional theory-based quantum mechanics/molecular mechanics molecular dynamics simulations are performed to generate explicit solute-solvent configurations, which serve as inputs for the spectroscopy calculations of the experiments spanning the IR to X-ray wavelengths. The spectroscopy simulations are performed at the same level of theory across this large energy window, which allows for a systematic comparison of the effects of explicit solute-solvent interactions in the vibrational, valence electronic, and core-level spectra of hexacyanoferrate complexes in water. Although the spectroscopy of hexacyanoferrate complexes in solution has been the subject of several studies, most of the previous works have focused on a narrow energy window and have not accounted for explicit solute-solvent interactions in their spectroscopy simulations. In this work, we focus our analysis on identifying how the local solvation environment around the hexacyanoferrate complexes influences the intensity and line shape of specific spectroscopic features in the UV/vis, X-ray absorption, and valence-to-core X-ray emission spectra. The identification of these features and their relationship to solute-solvent interactions is important because hexacyanoferrate complexes serve as model systems for understanding the photochemistry and photophysics of a large class of Fe(II) and Fe(III) complexes in solution. PMID- 29613799 TI - Synthesis of Sulfur-Containing Exo-Bicyclic Dienes and Their Diels-Alder Reactions To Access Thiacycle-Fused Polycyclic Systems. AB - The stereocontrolled synthesis of unprecedented sulfur-containing exo-bicyclic 1,3-dienes is reported through a palladium-catalyzed reductive cyclization of sulfur-linked 2-bromoenynes. The fused bicyclic structure provides a better stability to the thiacyclic diene compared to the simple 3,4 dimethylenetetrahydrothiophene. Their reactivity toward several dienophiles has been investigated, and various original thiacycle-fused polycyclic systems have been obtained with high or total diastereoselectivity. Moreover, they are the first exo-bicyclic dienes used in Diels-Alder reactions. The relative configurations of four cycloadducts have been unambiguously assigned by X-ray crystallographic analysis. Mechanistic details of the cycloadditions have been examined by computational means. PMID- 29613800 TI - The Role of FRET in Non-Fullerene Organic Solar Cells: Implications for Molecular Design. AB - Non-fullerene acceptors (NFAs) have been demonstrated to be promising candidates for highly efficient organic photovoltaic (OPV) devices. The tunability of absorption characteristics of NFAs can be used to make OPVs with complementary donor-acceptor absorption to cover a broad range of the solar spectrum. However, both charge transfer from donor to acceptor moieties and energy (energy) transfer from high-bandgap to low-bandgap materials are possible in such structures. Here, we show that when charge transfer and exciton transfer processes are both present, the coexistence of excitons in both domains can cause a loss mechanism. Charge separation of excitons in a low-bandgap material is hindered due to exciton population in the larger bandgap acceptor domains. Our results further show that excitons in low-bandgap material should have a relatively long lifetime compared to the transfer time of excitons from higher bandgap material in order to contribute to the charge separation. These observations provide significant guidance for design and development of new materials in OPV applications. PMID- 29613801 TI - Dative Bonding between Closed-Shell Atoms: The BeF- Anion. AB - Beryllium can exhibit unusually strong attractive interactions under conditions where it is nominally a closed-shell atom. Two prominent examples are the Be2 dimer and the He-BeO complex. In the present study, we examine the bonding of the closed-shell Be-F- anion. This molecule preserves the closed-shell character of the individual atoms as the electron affinity of F is high (328.16 kJ mol-1) while that of Be is negative. Photodetachment spectroscopy was used to determine the vibrational frequency for BeF- and the electron affinity of BeF (104.2 kJ mol 1). The latter has been used to determine a lower bound of 343 kJ mol-1 for the bond energy of BeF-. Electronic structure calculations yielded predictions that were in good agreement with the observed data. A natural bond orbital analysis shows that BeF- is primarily bound by a dative interaction. PMID- 29613802 TI - On the Physical Basis of Biological Signaling by Interface Pulses. AB - Currently, biological signaling is envisaged as a combination of activation and movement, triggered by local molecular interactions and molecular diffusion, respectively. However, here, we suggest that other fundamental physical mechanisms might play an at least equally important role. We have recently shown that lipid interfaces permit the excitation and propagation of sound pulses. Here, we demonstrate that these reversible perturbations can control the activity of membrane-embedded enzymes without a requirement for molecular transport. They can thus facilitate rapid communication between distant biological entities at the speed of sound, which is here on the order of 1 m/s within the membrane. The mechanism described provides a new physical framework for biological signaling that is fundamentally different from the molecular approach that currently dominates the textbooks. PMID- 29613803 TI - Treatment of Canine Oral Melanoma with Nanotechnology-Based Immunotherapy and Radiation. AB - The presence and benefit of a radiation therapy-associated immune reaction is of great interest as the overall interest in cancer immunotherapy expands. The pathological assessment of irradiated tumors rarely demonstrates consistent immune or inflammatory response. More recent information, primarily associated with the "abscopal effect", suggests a subtle radiation-based systemic immune response may be more common and have more therapeutic potential than previously believed. However, to be of consistent value, the immune stimulatory potential of radiation therapy (RT) will clearly need to be supported by combination with other immunotherapy efforts. In this study, using a spontaneous canine oral melanoma model, we have assessed the efficacy and tumor immunopathology of two nanotechnology-based immune adjuvants combined with RT. The immune adjuvants were administered intratumorally, in an approach termed "in situ vaccination", that puts immunostimulatory reagents into a recognized tumor and utilizes the endogenous antigens in the tumor as the antigens in the antigen/adjuvant combination that constitutes a vaccine. The radiation treatment consisted of a local 6 * 6 Gy tumor regimen given over a 12 day period. The immune adjuvants were a plant-based virus-like nanoparticle (VLP) and a 110 nm diameter magnetic iron oxide nanoparticle (mNPH) that was activated with an alternating magnetic field (AMF) to produce moderate heat (43 degrees C/60 min). The RT was used alone or combined with one or both adjuvants. The VLP (4 * 200 MUg) and mNPH (2 * 7.5 mg/gram tumor) were delivered intratumorally respectively during the RT regimen. All patients received a diagnostic biopsy and CT-based 3-D radiation treatment plan prior to initiating therapy. Patients were assessed clinically 14 21 days post-treatment, monthly for 3 months following treatment, and bimonthly, thereafter. Immunohistopathologic assessment of the tumors was performed before and 14-21 days following treatment. Results suggest that addition of VLPs and/or mNPH to a hypofractionated radiation regimen increases the immune cell infiltration in the tumor, extends the tumor control interval, and has important systemic therapeutic potential. PMID- 29613804 TI - Pd(II)-Catalyzed Asymmetric Oxidative 1,2-Diamination of Conjugated Dienes with Ureas. AB - A palladium(II)-catalyzed asymmetric 1,2-diamination of 1,3-dienes with readily available dialkylureas was established by using a chiral pyridine-oxazoline ligand. The diamination reaction exclusively occurs at the terminal C-C double bond of the 1,3-dienes to give 4-vinylimidazolidin-2-ones in high yields and with excellent levels of enantioselectivity (up to 99% yield, 97% ee). The reaction could feasibly be applied for gram-scale synthesis with a 1:1 ratio of the diene and the urea. PMID- 29613805 TI - Tin-Free Access to the ABC Core of the Calyciphylline A Alkaloids and Unexpected Formation of a D-Ring-Contracted Tetracyclic Core. AB - A tin-free strategy for the successful cyclization of a variety of internal alkyne-containing N-chloroamine precursors to the ABC core via cyclization of a neutral aminyl radical is established. Deuterium labeling experiments confirm that the solvent is the primary source of the final H atom in the cyclization cascade. These conditions enabled a streamlined route to a beta-ketoester intermediate poised for intramolecular Knoevenagel condensation to construct the seven-membered D-ring of calyciphylline A alkaloids. However, exposure to CsF in t-BuOH at elevated temperatures led to an unexpected decarboxylation to form a D ring-contracted tetracyclic core. PMID- 29613806 TI - Nanopatterned High-Frequency Supporting Structures Stably Eliminate Substrate Effects Imposed on Two-Dimensional Semiconductors. AB - Despite the outstanding physical and chemical properties of two-dimensional (2D) materials, due to their extremely thin nature, eliminating detrimental substrate effects such as serious degradation of charge-carrier mobility or light-emission yield remains a major challenge. However, previous approaches have suffered from limitations such as structural instability or the need of costly and high temperature deposition processes. Herein, we propose a new strategy based on the insertion of high-density topographic nanopatterns as a nanogap-containing supporter between 2D materials and substrate to minimize their contact and to block the substrate-induced undesirable effects. We show that well-controlled high-frequency SiO x nanopillar structures derived from the self-assembly of Si containing block copolymer securely prevent the collapse or deformation of transferred MoS2 and guarantee excellent mechanical stability. The nanogap supporters formed below monolayer MoS2 lead to dramatic enhancement of the photoluminescence emission intensity (8.7-fold), field-effect mobility (2.0-fold, with a maximum of 4.3-fold), and photoresponsivity (12.1-fold) compared to the sample on flat SiO2. Similar favorable effects observed for graphene strongly suggest that this simple but powerful nanogap-supporting method can be extensively applicable to a variety of low-dimensional materials and contribute to improved device performance. PMID- 29613807 TI - Photoredox-Induced Intramolecular 1,5-H Transfer Reaction of Aryl Iodides for the Synthesis of Spirocyclic gamma-Lactams. AB - This work develops a photocatalysis method for the synthesis of gamma spirolactams through a tandem intramolecular 1,5-HAT reaction-cyclization process. A variety of novel gamma-spirolactams are prepared in good to excellent yields with this method. This transformation features mild reaction conditions and exceptional functional group tolerance. Additionally, gamma-terpinene is applied to this transformation as a hydrogen atom donor for the first time. PMID- 29613808 TI - Magnetic Field Sensing by Exploiting Giant Nonstrain-Mediated Magnetodielectric Response in Epitaxial Composites. AB - Heteroepitaxial magnetoelectric (ME) composites are promising for the development of a new generation of multifunctional devices, such as sensors, tunable electronics, and energy harvesters. However, challenge remains in realizing practical epitaxial composite materials, mainly due to the interfacial lattice misfit strain between magnetostrictive and piezoelectric phases and strong substrate clamping that reduces the strain-mediated ME coupling. Here, we demonstrate a nonstrain-mediated ME coupling in PbZr0.52Ti0.48O3 (PZT)/La0.67Sr0.33MnO3 (LSMO) heteroepitaxial composites that resolves these challenges, thereby, providing a giant magnetodielectric (MD) response of ~27% at 310 K. The factors driving the magnitude of the MD response were found to be the magnetoresistance-coupled dielectric dispersion and piezoelectric strain-mediated modulation of magnetic moment. Building upon this giant MD response, we demonstrate a magnetic field sensor architecture exhibiting a high sensitivity of 54.7 pF/T and desirable linearity with respect to the applied external magnetic field. The demonstrated technique provides a new mechanism for detecting magnetic fields based upon the MD effect. PMID- 29613809 TI - One-Pot Regiospecific Synthesis of Indolizines: A Solvent-Free, Metal-Free, Three Component Reaction of 2-(Pyridin-2-yl)acetates, Ynals, and Alcohols or Thiols. AB - A novel approach for the synthesis of indolizines from 2-(pyridin-2-yl)acetates, ynals, and alcohols or thiols has been developed. This MCR (multicomponent reaction) that proceeds under the solvent- and metal-free conditions has provided a straightforward path to construct indolizines. Furthermore, this reaction demonstrates other attractive features such as widely available starting materials, mild conditions, good functional group tolerance, and high efficiency. PMID- 29613810 TI - On-Demand Final State Control of a Surface-Bound Bistable Single Molecule Switch. AB - Modern electronic devices perform their defined action because of the complete reliability of their individual active components (transistors, switches, diodes, and so forth). For instance, to encode basic computer units (bits) an electrical switch can be used. The reliability of the switch ensures that the desired outcome (the component's final state, 0 or 1) can be selected with certainty. No practical data storage device would otherwise exist. This reliability criterion will necessarily need to hold true for future molecular electronics to have the opportunity to emerge as a viable miniaturization alternative to our current silicon-based technology. Molecular electronics target the use of single molecules to perform the actions of individual electronic components. On-demand final state control over a bistable unimolecular component has therefore been one of the main challenges in the past decade (1-5) but has yet to be achieved. In this Letter, we demonstrate how control of the final state of a surface-supported bistable single molecule switch can be realized. On the basis of the observations and deductions presented here, we further suggest an alternative strategy to achieve final state control in unimolecular bistable switches. PMID- 29613811 TI - Discussion of "Effect of exercise-induced dehydration on circulatory markers of oxidative damage and antioxidant capacity". PMID- 29613812 TI - Concomitant changes in radiation resistance and trehalose levels during life stages of Drosophila melanogaster suggest radio-protective function of trehalose. AB - PURPOSE: During development, various life stages of Drosophila melanogaster (D. melanogaster) show different levels of resistance to gamma irradiation, with the early pupal stage being the most radiation sensitive. This provides us an opportunity to explore the biochemical basis of such variations. The present study was carried out to understand the mechanisms underlying radiation resistance during life stages of D. melanogaster. MATERIALS AND METHODS: Homogenates from all the life stages of D. melanogaster were prepared at stipulated age. These homogenates were used for the determination of (1) enzymatic antioxidants: superoxide dismutase (SOD), catalase, D. melanogaster glutathione peroxidase (DmGPx), and glutathione S-transferase (GST); (2) reducing non-enzymatic antioxidants: total antioxidant capacity (TAC), reduced glutathione (GSH) and non-reducing non-enzymatic antioxidant trehalose; and (3) levels of protein carbonyl (PC) content. Age-dependent changes in radiation resistance and associated biochemical changes were also studied in young (2 d) and old (20 and 30 d) flies. RESULTS: TAC and GSH were found high in the early pupal stage, whereas catalase and DmGPx were found to increase in the early pupal stage. The non-feeding third instar (NFTI) larvae were found to have high levels of SOD and GST, besides NFTI larvae showed high levels of trehalose. A remarkable decrease was observed in radiation resistance and trehalose levels during the early pupal stage. The PC level was the highest during early pupal stage and was the lowest in NFTI larvae. Older flies showed high level of PC compared with young flies. CONCLUSION: In vitro increments in trehalose concentration correspond to reduced formation of PCs, suggesting a protective role of trehalose against free radicals. A strong correlation between levels of trehalose and PC formation suggests amelioration of proteome damage due to ionizing radiation (IR). Stages with high trehalose levels showed protected proteome and high radiation resistance, suggesting a significant role for this disaccharide in radiation resistance. PMID- 29613813 TI - Post mortem Survival of Gallibacterium anatis in a Laying Hen Experimental Infection Model. AB - To assess the survival of Gallibacterium anatis in dead laying hens, 21-wk-old laying hens were injected intraperitoneally with 0.5 ml brain hearth infusion broth containing 108 colony-forming units (CFU) of G. anatis 12656-12 liver ( n = 16), Escherichia coli ST141 ( n = 16), or a mix of G. anatis 12656-12 liver and E. coli ST141 ( n = 16), respectively. Birds were euthanatized 24 hr post injection. From each group eight dead birds were kept at 4 C and eight at room temperature. Swab samples were taken at different time points post euthanatization and streaked on blood agar plates. From the birds kept at 4 C, G. anatis was reisolated from the G. anatis and the G. anatis- E. coli co-injected groups at least 12 days post euthanization. From birds kept at room temperature, G. anatis was reisolated up to 2 days post euthanatization. When using the gyrB based G. anatis-specific quantitative PCR (qPCR), G. anatis was detected within at least 5 days, and up to 5 days post euthanatization, from birds kept at room temperature and 4 C, respectively. Escherichia coli was reisolated from all the time points independent of how the birds were kept. No difference was observed between the reisolation rates for G. anatis or E. coli when comparing similar detection methods. For birds kept at 4 C, bacterial cultivation was a more sensitive method for detecting G. anatis ( P < 0.05), whereas for birds kept at room temperature, the G. anatis-specific qPCR outperformed bacterial culture ( P < 0.05). In conclusion, we demonstrated that G. anatis has a poorer survival rate than does E. coli in dead chickens kept at room temperature. That finding may affect the overall diagnostic sensitivity and lead to underdiagnosis of G. anatis in a normal production setting. PMID- 29613814 TI - Grape seed procyanidins extract attenuates Cisplatin-induced oxidative stress and testosterone synthase inhibition in rat testes. AB - : Cisplatin (CIS) is widely applied for its antihematological malignancies properties and as antisolid tumors drugs. However, it could cause testicular damage related with oxidative stress and testosterone synthesis disorder. Studies reported that grape seed procyanidins extract (GSPE) could improve CIS induced testes lesion via scavenging free radicals in animals, although its mechanisms were unclear. Therefore, the purpose of the present study was to explore the antagonistic mechanisms of GSPE on CIS-induced testes lesion. Rats were treated with 10 mg/kg by weight CIS by intraperitoneal injection singly on the 11th day, and different doses of GSPE were administrated via intragastric gavage for 15 days consecutively. The results showed that GSPE improved the pathological changes of testicular tissue, and the decreased concentrations of testosterone in serum induced by CIS. GSPE inhibited CIS-induced oxidative/nitrative stress, as well as increased the mRNA and protein levels of testosterone synthetase in rat testes. In conclusion, the main protection exerted by GSPE on CIS-induced testicular toxicity is related to its effects including suppressing oxidative/nitrative stress and up-regulating expression of testosterone synthetase. ABBREVIATIONS: CIS: Cisplatin; GSPE: grape seed procyanidins extract; LH: luteinizing hormone; FSH: follicle-stimulating hormone; STAR: steroidogenic acute regulatory protein; CYP11A1: P450 side chain cleavage enzyme; HSD3B1: 3beta hydroxysteroid dehydrogenase; CYP17A1: 17alpha-hydroxylase; HSD17B: 17beta hydroxysteroid dehydrogenase; ROS: reactive oxygen species; O2-: superoxide anion; H2O2: hydrogen peroxide; *OH: hydroxyl radicals; SOD: superoxide dismutase; CAT: catalase; GSH-Px: glutathione peroxidase; LPO: lipid peroxidation; 8-OHdG: 8-hydroxy-2-deoxyguanosine; HO-1: heme oxygenase-1; MT-1: metallothionein-1; NO: nitric oxide; ONOO-: peroxynitrite; NOS: nitric oxide synthases; nNOS: neuronal NOS; iNOS: inducible NOS; eNOS: endothelial NOS; MDA: malondialdehyde; GSH: glutathione; T-AOC: total antioxidant capacity; TNOS: total nitric oxide synthases; Lhcgr: luteinizing hormone receptor; Scarb1: lipoprotein receptor; Cyp19a1: 19alpha-hydroxylase; ELISA: enzyme linked immunosorbent assay; RT-qPCR: reverse transcription-quantitative polymerase chain reaction; PAS: periodic acid-Schiff; MTs: Metallothioneins; cAMP: cyclic adenosine monophosphate; cDNA: complementary DNA; RIPA: radioimmunoprecipitation buffer; PMSF: phenylmethanesulfonyl fluoride; PVDF: polyvinylidenedifluoride; beta-actin: beta-actin. PMID- 29613815 TI - Understanding Is Key: An Analysis of Factors Pertaining to Trust in a Real-World Automation System. AB - OBJECTIVE: This paper aims to explore the role of factors pertaining to trust in real-world automation systems through the application of observational methods in a case study from the railway sector. BACKGROUND: Trust in automation is widely acknowledged as an important mediator of automation use, but the majority of the research on automation trust is based on laboratory work. In contrast, this work explored trust in a real-world setting. METHOD: Experienced rail operators in four signaling centers were observed for 90 min, and their activities were coded into five mutually exclusive categories. Their observed activities were analyzed in relation to their reported trust levels, collected via a questionnaire. RESULTS: The results showed clear differences in activity, even when circumstances on the workstations were very similar, and significant differences in some trust dimensions were found between groups exhibiting different levels of intervention and time not involved with signaling. CONCLUSION: Although the empirical, lab-based studies in the literature have consistently found that reliability and competence of the automation are the most important aspects of trust development, understanding of the automation emerged as the strongest dimension in this study. The implications are that development and maintenance of trust in real-world, safety-critical automation systems may be distinct from artificial laboratory automation. APPLICATION: The findings have important implications for emerging automation concepts in diverse industries including highly automated vehicles and Internet of things. PMID- 29613816 TI - Anterior Cruciate Ligament Reconstruction Affects Tibiofemoral Joint Congruency During Dynamic Functional Movement. AB - BACKGROUND: Anterior cruciate ligament reconstruction (ACLR) has been shown to alter kinematics, which may influence dynamic tibiofemoral joint congruency (a measure of how well the bone surfaces fit together). This may lead to abnormal loading of cartilage and joint degeneration. However, joint congruency after ACLR has never been investigated. HYPOTHESES: The ACLR knee will be more congruent than the contralateral uninjured knee, and dynamic congruency will increase over time after ACLR. Side-to-side differences (SSD) in dynamic congruency will be related to cartilage contact location/area and subchondral bone curvatures. STUDY DESIGN: Descriptive laboratory study. METHODS: The authors examined 43 patients who underwent unilateral ACLR. At 6 months and 24 months after ACLR, patients performed downhill running on a treadmill while synchronized biplane radiographs were acquired at 150 images per second. Dynamic tibiofemoral kinematic values were determined by use of a validated volumetric model-based tracking process that matched patient-specific bone models, obtained from computed tomography, to biplane radiographs. Patient-specific cartilage models, obtained from magnetic resonance imaging, were registered to tracked bone models and used to calculate dynamic cartilage contact regions. Principle curvatures of the subchondral bone surfaces under each cartilage contact area were calculated to determine joint congruency. Repeated-measures analysis of variance was used to test the differences. Multiple linear regression was used to identify associations between SSD in congruency index, cartilage contact area, contact location, and global curvatures of femoral or tibial subchondral bone. RESULTS: Lateral compartment congruency in the ACLR knee was greater than in the contralateral knee ( P < .001 at 6 months and P = .010 at 24 months). From 6 to 24 months after surgery, dynamic congruency decreased in the medial compartment ( P = .002) and increased in the lateral compartment ( P = .007) in the ACLR knee. In the lateral compartment, SSD in joint congruency was related to contact location and femur global curvature, and in the medial compartment, SSD in joint congruency was related to contact area. CONCLUSION: ACLR appears to affect dynamic joint congruency. SSD in joint congruency was associated with changes in contact location, contact area, and femoral bony curvature. CLINICAL RELEVANCE: Alterations in tibiofemoral contact location, contact area, and bone shape affect dynamic joint congruency, potentially contributing to long-term degeneration after ACLR. PMID- 29613817 TI - Acute kidney injury after non-cardiovascular surgery: risk factors and impact on development of chronic kidney disease and long-term mortality. AB - OBJECTIVE: To identify factors associated with acute kidney injury (AKI) and its progression to chronic kidney disease (CKD) in a non-cardiac/non-vascular surgery setting. METHODS: This study examined the Veterans Affairs Surgical Quality database for surgical entries between 2000-2014. Demographics, comorbidities, laboratory findings and hospital outcomes were assessed. The primary end-point was the occurrence of AKI, defined as an increase of >=0.3 mg/dL, 48 h post operatively. Major adverse cardiac event (MACE) was defined as the composite first occurrence of myocardial infarction, cardiac arrest, and death in 30 days (secondary end-point) and was compared between two groups. Rates of progression to CKD in 1 year and long-term survival were examined. MAIN OUTCOME MEASURES: Occurrence of AKI 48 h post-operatively. RESULTS: AKI was documented in 8.5% of patients. Age, diabetes, and chronic obstructive pulmonary disease, chronic kidney disease, platelet count, serum albumin level, and duration of surgery were identified as independent predictors of AKI. In total, 6.4% patients developed MACE, which was more frequent in patients with AKI (p < .001). Age and pre operative hematocrit <30% were independent predictors of progression to CKD. Pre operative hematocrit with a cut-off value of 30% was the only modifiable factor to predict the long-term survival. CONCLUSION: Development of AKI is associated with increased odds of various post-operative complications and long-term renal insufficiency and mortality. PMID- 29613818 TI - Raymond E. Meyn. PMID- 29613819 TI - Information-Pooling Bias in Collaborative Security Incident Correlation Analysis. AB - OBJECTIVE: Incident correlation is a vital step in the cybersecurity threat detection process. This article presents research on the effect of group-level information-pooling bias on collaborative incident correlation analysis in a synthetic task environment. BACKGROUND: Past research has shown that uneven information distribution biases people to share information that is known to most team members and prevents them from sharing any unique information available with them. The effect of such biases on security team collaborations are largely unknown. METHOD: Thirty 3-person teams performed two threat detection missions involving information sharing and correlating security incidents. Incidents were predistributed to each person in the team based on the hidden profile paradigm. Participant teams, randomly assigned to three experimental groups, used different collaboration aids during Mission 2. RESULTS: Communication analysis revealed that participant teams were 3 times more likely to discuss security incidents commonly known to the majority. Unaided team collaboration was inefficient in finding associations between security incidents uniquely available to each member of the team. Visualizations that augment perceptual processing and recognition memory were found to mitigate the bias. CONCLUSION: The data suggest that (a) security analyst teams, when conducting collaborative correlation analysis, could be inefficient in pooling unique information from their peers; (b) employing off the-shelf collaboration tools in cybersecurity defense environments is inadequate; and (c) collaborative security visualization tools developed considering the human cognitive limitations of security analysts is necessary. APPLICATION: Potential applications of this research include development of team training procedures and collaboration tool development for security analysts. PMID- 29613820 TI - The Effects of Walking Workstations on Biomechanical Performance. AB - Prolonged sitting has been associated with negative health effects. Walking workstations have become increasingly popular in the workplace. There is a lack of research on the biomechanical effect of walking workstations. This study analyzed whether walking while working alters normal gait patterns. A total of 9 participants completed 4 walking trials at 2.4 and 4.0 km.h-1: baseline walking condition, walking while performing a math task, a reading task, and a typing task. Biomechanical data were collected using standard motion capture procedures. The first maximum vertical ground reaction force, stride width, stride length, minimum toe clearance, peak swing hip abduction and flexion angles, peak swing and stance ankle dorsiflexion, and knee flexion angles were analyzed. Differences between conditions were evaluated using analysis of variance tests with Bonferroni correction (P <= .05). Stride width decreased during the reading task at both speeds. Although other parameters exhibited significant differences when multitasking, these changes were within the normal range of gait variability. It appears that for short periods, walking workstations do not negatively impact gait in healthy young adults. PMID- 29613821 TI - Lower-Extremity Kinematics Differed Between a Controlled Drop-Jump and Volleyball Takeoffs. AB - Previous studies utilizing jump-landing biomechanics to predict anterior cruciate ligament injuries have shown inconsistent findings. The purpose of this study was to quantify the differences and correlations in jump-landing kinematics between a drop-jump, a controlled volleyball-takeoff, and a simulated-game volleyball takeoff. Seventeen female volleyball players performed these 3 tasks on a volleyball court, while 3-dimensional kinematic data were collected by 3 calibrated camcorders. Participants demonstrated significantly increased jump height, shorter stance time, increased time differences in initial contact between 2 feet, increased knee and hip flexion at initial contact and decreased peak knee and hip flexion for both left and right legs, and decreased knee-ankle distance ratio at the lowest height of midhip for the 2 volleyball-takeoffs compared with the drop-jump (P < .05, Cohen's dz >= 0.8). Significant correlations were observed for all variables between the 2 volleyball-takeoffs (P < .05, rho >= .6) but were not observed for most variables between the drop-jump and 2 volleyball-takeoffs. Controlled drop-jump kinematics may not represent jump landing kinematics exhibited during volleyball competition. Jump-landing mechanics during sports-specific tasks may better represent those exhibited during sports competition and their associated risk of anterior cruciate ligament injury compared with the drop-jump. PMID- 29613822 TI - A Practical Estimation Method for Center of Mass Velocity in Swimming Direction During Front Crawl Swimming. AB - Center of mass (CoM) velocity variation in swimming direction is related to swimming performance and efficiency. However, it is difficult to calculate the CoM velocity during swimming. Therefore, we aimed to establish a practical estimation method for the CoM velocity in swimming direction during front crawl swimming with underwater cameras. Ten swimmers were recorded during front crawl swimming (25 m, maximal effort) using a motion capture system with 18 underwater and 9 land cameras. Three CoM velocity estimation methods were constructed (single-hip velocity, both-hips velocity, and both-hips velocity with simulated arm velocity correction). Each model was validated against the actual CoM velocity. The difference between the single-hip velocity and the actual CoM velocity in swimming direction was significantly larger compared with that of the other 2 models. Furthermore, the accuracy of CoM velocity estimation was increased when both-hips velocity was corrected using the simulated arm velocity. The method allowed estimation of the CoM velocity with only 2 underwater cameras with a maximal difference of 0.06 m.s-1. This study established a novel and practical method for the estimation of the CoM velocity in swimming direction during front crawl swimming. PMID- 29613823 TI - Analysis of Gene Expression Changes in PHA-M Stimulated Lymphocytes - Unraveling PHA Activity as Prerequisite for Dicentric Chromosome Analysis. AB - Dicentric chromosome analysis (DCA) is the gold standard for individual radiation dose assessment. However, DCA is limited by the time-consuming phytohemagglutinin (PHA)-mediated lymphocyte activation. In this study using human peripheral blood lymphocytes, we investigated PHA-associated whole genome gene expression changes to elucidate this process and sought to identify suitable gene targets as a means of meeting our long-term objective of accelerating cell cycle kinetics to reduce DCA culture time. Human peripheral whole blood from three healthy donors was separately cultured in RPMI/FCS/antibiotics with BrdU and PHA-M. Diluted whole blood samples were transferred into PAXgene tubes at 0, 12, 24 and 36 h culture time. RNA was isolated and aliquots were used for whole genome gene expression screening. Microarray results were validated using qRT-PCR and differentially expressed genes [significantly (FDR corrected) twofold different from the 0 h value reference] were analyzed using several bioinformatic tools. The cell cycle positions and DNA-synthetic activities of lymphocytes were determined by analyzing the correlated total DNA content and incorporated BrdU level with flow cytometry after continued BrdU incubation. From 42,545 transcripts of the whole genome microarray 47.6%, on average, appeared expressed. The number of differentially expressed genes increased linearly from 855 to 2,858 and 4,607 at 12, 24 and 36 h after PHA addition, respectively. Approximately 2-3 times more up than downregulated genes were observed with several hundred genes differentially expressed at each time point. Earliest enrichment was observed for gene sets related to the nucleus (12 h) followed by genes assigned to intracellular structures such as organelles (24 h) and finally genes related to the membrane and the extracellular matrix were enriched (36 h). Early gene expression changes at 12 h, in particular, were associated with protein classes such as chemokines/cytokines (e.g., CXCL1, CXCL2) and chaperones. Genes coding for biological processes involved in cell cycle control (e.g., MYBL2, RBL1, CCNA, CCNE) and DNA replication (e.g., POLA, POLE, MCM) appeared enriched at 24 h and later, but many more biological processes (42 altogether) showed enrichment as well. Flow cytometry data fit together with gene expression and bioinformatic analyses as cell cycle transition into S phase was observed with interindividual differences from 12 h onward, whereas progression into G2 as well as into the second G1 occurred from 36 h onward after activation. Gene set enrichment analysis over time identifies, in particular, two molecular categories of PHA responsive gene targets (cytokine and cell cycle control genes). Based on that analysis target genes for cell cycle acceleration in lymphocytes have been identified ( CDKN1A/B/C, RBL-1/RBL-2, E2F2, Deaf-1), and it remains undetermined whether the time expenditure for DCA can be reduced by influencing gene expression involved in the regulatory circuits controlling PHA-associated cell cycle entry and/or progression at a specific early cell cycle phase. PMID- 29613824 TI - Laboratory Evaluation of Low-Cost Wearable Sensors for Measuring Head Impacts in Sports. AB - Advances in low-cost wearable head impact sensor technology provide potential benefits regarding sports safety for both consumers and researchers. However, previous laboratory evaluations are not directly comparable and do not incorporate test conditions representative of unhelmeted impacts. This study addresses those limitations. The xPatch by X2 Biosystems and the SIM-G by Triax Technologies were placed on a National Operating Committee on Standards for Athletic Equipment (NOCSAE) headform with a Hybrid III neck which underwent impact tests using a pendulum. Impact conditions included helmeted, padded impactor to bare head, and rigid impactor to bare head to represent long- and short-duration impacts seen in helmeted and unhelmeted sports. The wearable sensors were evaluated on their kinematic accuracy by comparing results to reference sensors located at the headform center of gravity. Statistical tests for equivalence were performed on the slope of the linear regression between wearable sensors and reference. The xPatch gave equivalent measurements to the reference in select longer-duration impacts, whereas the SIM-G had large variance leading to no equivalence. For the short-duration impacts, both wearable sensors underpredicted the reference. This error can be improved with increases in sampling rate from 1 to 1.5 kHz. Follow-up evaluations should be performed on the field to identify error in vivo. PMID- 29613825 TI - Limitations of Detecting Small Solid Lung Nodules by Using Digital Chest Tomosynthesis. PMID- 29613826 TI - Detection and Characterization of Solid Pulmonary Nodules at Digital Chest Tomosynthesis: Data from a Cohort of the Pilot Swedish Cardiopulmonary Bioimage Study. AB - Purpose To investigate the performance of digital tomosynthesis (DTS) for detection and characterization of incidental solid lung nodules. Materials and Methods This prospective study was based on a population study with 1111 randomly selected participants (age range, 50-64 years) who underwent a medical evaluation that included chest computed tomography (CT). Among these, 125 participants with incidental nodules 5 mm or larger were included in this study, which added DTS in conjunction with the follow-up CT and was performed between March 2012 and October 2014. DTS images were assessed by four thoracic radiologists blinded to the true number of nodules in two separate sessions according to the 5-mm (125 participants) and 6-mm (55 participants) cut-off for follow-up of incidental nodules. Pulmonary nodules were directly marked on the images by the readers and graded regarding confidence of presence and recommendation for follow-up. Statistical analyses included jackknife free-response receiver operating characteristic, receiver operating characteristic, and Cohen kappa coefficient. Results Overall detection rate ranges of CT-proven nodules 5 mm or larger and 6 mm or larger were, respectively, 49%-58% and 48%-62%. Jackknife free-response receiver operating characteristics figure of merit for detection of CT-proven nodules 5 mm or larger and 6 mm or larger was 0.47 and 0.51, respectively, and area under the receiver operating characteristic curve regarding recommendation for follow-up was 0.62 and 0.65, respectively. Conclusion Routine use of DTS would result in lower detection rates and reduced number of small nodules recommended for follow-up. (c) RSNA, 2018. PMID- 29613828 TI - Activation of Class I histone deacetylases contributes to mitochondrial dysfunction in cardiomyocytes with altered complex activities. AB - Histone deacetylases (HDACs) play vital roles in the pathophysiology of heart failure, which is associated with mitochondrial dysfunction. Tumor necrosis factor-alpha (TNF-alpha) contributes to the genesis of heart failure and impairs mitochondria. This study evaluated the role of HDACs in TNF-alpha-induced mitochondrial dysfunction and investigated their therapeutic potential and underlying mechanisms. We measured mitochondrial oxygen consumption rate (OCR) and ATP production using Seahorse XF24 extracellular flux analyzer and bioluminescent assay in control and TNF-alpha (10 ng/ml, 24 h)-treated HL-1 cells with or without HDAC inhibition. TNF-alpha increased Class I and II (but not Class IIa) HDAC activities (assessed by Luminescent) with enhanced expressions of Class I (HDAC1, HDAC2, HDAC3, and HDAC8) but not Class IIb HDAC (HDAC6 and HDAC10) proteins in HL-1 cells. TNF-alpha induced mitochondrial dysfunction with impaired basal, ATP-linked, and maximal respiration, decreased cellular ATP synthesis, and increased mitochondrial superoxide production (measured by MitoSOX red fluorescence), which were rescued by inhibiting HDACs with MPT0E014 (1 MUM, a Class I and IIb inhibitor), or MS-275 (1 MUM, a Class I inhibitor). MPT0E014 reduced TNF-alpha-decreased complex I and II enzyme (but not III or IV) activities (by enzyme activity microplate assays). Our results suggest that Class I HDAC actions contribute to TNF-alpha-induced mitochondrial dysfunction in cardiomyocytes with altered complex I and II enzyme regulation. HDAC inhibition improves dysfunctional mitochondrial bioenergetics with attenuation of TNF-alpha induced oxidative stress, suggesting the therapeutic potential of HDAC inhibition in cardiac dysfunction. PMID- 29613830 TI - Laryngeal Force Sensor: Quantifying Extralaryngeal Complications after Suspension Microlaryngoscopy. AB - Objectives To develop a novel sensor capable of dynamically analyzing the force exerted during suspension microlaryngoscopy and to examine the relationship between force and postoperative tongue complications. Study Design Prospective observational study. Setting Academic tertiary care center. Methods The laryngeal force sensor is a designed for use during microphonosurgery. Prospectively enrolled patients completed pre- and postoperative surveys to assess the development of tongue-related symptoms (dysgeusia, pain, paresthesia, and paresis) or dysphagia (10-item Eating Assessment Tool [EAT-10]). To prevent operator bias, surgeons were blinded to the force recordings during surgery. Results Fifty-six patients completed the study. Of these, 20 (36%) developed postoperative tongue symptoms, and 12 (21%) had abnormal EAT-10 scores. The mean maximum force across all procedures was 164.7 N (95% CI, 141.0-188.4; range, 48.5 402.6), while the mean suspension time was 34.3 minutes (95% CI, 27.4-41.2; range, 7.1-108.1). Multiple logistic regression showed maximum force (odds ratio, 1.15; 95% CI, 1.02-1.29; P = .019) and female sex (30.1%; 95% CI, 22.7%-37.5%; P < .001) as significant predictors for the development of tongue-related symptoms. The only significant predictor of an abnormal postoperative EAT-10 score was an increased maximum force (odds ratio, 1.03; 95% CI, 1.00-1.06; P = .045). Conclusions The laryngeal force sensor is capable of providing dynamic force measurements throughout suspension microlaryngoscopy. An increase in maximum force during surgery may be a significant predictor for the development of tongue related symptoms and an abnormal EAT-10 score. Female patients may also be at greater risk for developing postoperative tongue symptoms. PMID- 29613827 TI - Experience-dependent neuroplasticity of the developing hypothalamus: integrative epigenomic approaches. AB - Augmented maternal care during the first postnatal week promotes life-long stress resilience and improved memory compared with the outcome of routine rearing conditions. Recent evidence suggests that this programming commences with altered synaptic connectivity of stress sensitive hypothalamic neurons. However, the epigenomic basis of the long-lived consequences is not well understood. Here, we employed whole-genome bisulfite sequencing (WGBS), RNA-sequencing (RNA-seq), and a multiplex microRNA (miRNA) assay to examine the effects of augmented maternal care on DNA cytosine methylation, gene expression, and miRNA expression. A total of 9,439 differentially methylated regions (DMRs) associated with augmented maternal care were identified in male offspring hypothalamus, as well as a modest but significant decrease in global DNA methylation. Differentially methylated and expressed genes were enriched for functions in neurotransmission, neurodevelopment, protein synthesis, and oxidative phosphorylation, as well as known stress response genes. Twenty prioritized genes were identified as highly relevant to the stress resiliency phenotype. This combined unbiased approach enabled the discovery of novel genes and gene pathways that advance our understanding of the epigenomic mechanisms underlying the effects of maternal care on the developing brain. PMID- 29613831 TI - Maternal Thyroid Hormones: An Unexplored Mechanism Underlying Maternal Effects in an Ecological Framework. AB - Maternal effects are currently acknowledged as important causes of transgenerational phenotypic variation and a potential mechanism to adapt offspring to predicted environments, thus having a pivotal role in ecology and evolution. Research in hormonal mechanism underlying maternal effects has focused heavily on steroid hormones. Other hormones, such as thyroid hormones (THs; thyroxine and triiodothyronine), have been largely ignored in ecological research until recently. We summarize the recent findings, identify knowledge gaps, and provide future research directions investigating the role of TH-mediated maternal effects in ecological context across taxa. Surprisingly, data on the sources of naturally occurring variation in maternal THs and their fitness effects are lacking in most vertebrate taxa. There is considerable variation in maternal TH levels in eggs across taxa. Avian egg THs show heritable variation, and data from fish and amphibians suggest female consistency in egg TH levels. In birds, variation in maternal THs was associated with important ecological factors, such as food availability and temperature. THs also showed intraindividual variation varying systematically within clutches. Importantly, exposure to maternal THs within naturally occurring range affected offspring fitness-related traits (growth and survival) in birds and fish. These findings make THs an interesting mechanism underlying maternal effects, which likely shape offspring phenotypes. PMID- 29613832 TI - Concerns About Microsatellite Analysis and Biopsies in Wilms Tumor. PMID- 29613829 TI - Novel imprinted single CpG sites found by global DNA methylation analysis in human parthenogenetic induced pluripotent stem cells. AB - Genomic imprinting is the process of epigenetic modification whereby genes are expressed in a parent-of-origin dependent manner; it plays an important role in normal growth and development. Parthenogenetic embryos contain only the maternal genome. Parthenogenetic embryonic stem cells could be useful for studying imprinted genes. In humans, mature cystic ovarian teratomas originate from parthenogenetic activation of oocytes; they are composed of highly differentiated mature tissues containing all three germ layers. To establish human parthenogenetic induced pluripotent stem cell lines (PgHiPSCs), we generated parthenogenetic fibroblasts from ovarian teratoma tissues. We compared global DNA methylation status of PgHiPSCs with that of biparental human induced pluripotent stem cells by using Illumina Infinium HumanMethylation450 BeadChip array. This analysis identified novel single imprinted CpG sites. We further tested DNA methylation patterns of two of these sites using bisulfite sequencing and described novel candidate imprinted CpG sites. These results confirm that PgHiPSCs are a powerful tool for identifying imprinted genes and investigating their roles in human development and diseases. PMID- 29613833 TI - Reply to B. Zhang et al. PMID- 29613834 TI - Incidence of Osteochondritis Dissecans in Adults. AB - BACKGROUND: Osteochondritis dissecans (OCD) has frequently been described in children and adolescents, but cases of OCD in adults are certainly encountered. Little has been published on the epidemiology of OCD in adult patients. PURPOSE: To assess the frequency of OCD lesions in adults and assess the risk by age, sex, and ethnicity. STUDY DESIGN: Descriptive epidemiology study. METHODS: The authors assessed all patients aged 20 to 45 years from the entire database of patients enrolled as members of Kaiser Permanente Southern California from January 2011 until December 2013. Kaiser Southern California is an integrated health care system serving a racially, ethnically, and socioeconomically diverse population of >3.5 million patients. A retrospective chart review was done on OCD during this period. Inclusion criteria included OCD of any joint. Exclusion criteria included traumatic osteochondral fractures and coexistence of intra-articular lesions other than OCD. Joint involvement/location, laterality, and all patient demographics were recorded. RESULTS: Among 122 patients, a total of 124 OCD lesions were found. The majority of lesions were in the ankle (n = 76) and knee (n = 43), with 3 foot lesions and 2 elbow lesions identified. OCD lesions were identified in 75 men (62%) and 47 women (38%). Overall incidence rates per 100,000 person-years were 3.42 for all OCD, 2.08 for ankle OCD, and 1.21 for knee OCD. The relative risk of adult OCD for men was twice that of women. The relative risk of adult OCD for white patients was 2.3 that of Asians and 1.7 that of Hispanics. Risk of knee OCD was 3.6 times higher for men than women. As compared with women, men had a higher risk for lateral femoral condyle OCD lesions versus the medial femoral condyle ( P = .05; odds ratio [OR], 5.19). CONCLUSION: This large cohort study of Southern California adults with OCD demonstrated an increased OR for men (vs women) of OCD in all joints. The majority of symptomatic lesions were present in the ankle rather than the knee, as previously found in children. White and black patients had the highest OR of OCD; men had a significantly greater OR of lateral femoral condyle knee lesions as compared with women. PMID- 29613836 TI - IL-17 induces cellular stress microenvironment of melanocytes to promote autophagic cell apoptosis in vitiligo. AB - Vitiligo is a depigmentary disorder that develops as a result of the progressive disappearance of epidermal melanocytes. Stress can precipitate or exacerbate a skin disease through psychosomatic mechanisms. Stress exposure induces vitiligo like symptoms in mice, as cellular damage to melanocytes causes synthetic pigment loss. Stress also increases IL-17, IL-1beta, and antimelanocyte IgG in model mouse serum. Up-regulation of the IL-1beta transcript in patients suggests its possible role in autoimmune pathogenesis of vitiligo. We demonstrate that IL-17 promoted IL-1beta secretion from keratinocytes. Mitochondrial dysfunction, which can induce the excessive production of reactive oxygen species (ROS), is emerging as a mechanism that underlies various inflammatory and autoimmune diseases. In this study, we demonstrate that IL-17 inhibits melanogenesis of zebrafish, normal human epidermal melanocytes, and B16F10 cells. IL-17 increased mitochondrial dysfunction and ROS accumulation, which was related to autophagy induction. Autophagy is needed for autophagic apoptosis of B16F10 cells induced by IL-17. To inhibit ROS generation, B16F10 cells were pretreated with N-acetyl-l-cysteine (NAC), which inhibited autophagy. 3-Methyladenine (3-MA) also had an inhibiting effect on autophagy. NAC or 3-MA pretreatments inhibited IL-17-mediated cell apoptosis. In summary, IL-17 induces the cellular stress microenvironment in melanocytes to promote autophagic cell apoptosis in vitiligo.-Zhou, J., An, X., Dong, J., Wang, Y., Zhong, H., Duan, L., Ling, J., Ping, F., Shang, J. IL-17 induces cellular stress microenvironment of melanocytes to promote autophagic cell apoptosis in vitiligo. PMID- 29613835 TI - Therapeutic exploitation of IPSE, a urogenital parasite-derived host modulatory protein, for chemotherapy-induced hemorrhagic cystitis. AB - Chemotherapy-induced hemorrhagic cystitis (CHC) can be difficult to manage. Prior work suggests that IL-4 alleviates ifosfamide-induced hemorrhagic cystitis (IHC), but systemically administered IL-4 causes significant side effects. We hypothesized that the Schistosoma hematobium homolog of IL-4-inducing principle from Schistosoma mansoni eggs (H-IPSE), would reduce IHC and associated bladder pathology. IPSE binds IgE on basophils and mast cells, triggering IL-4 secretion by these cells. IPSE is also an "infiltrin," translocating into the host nucleus to modulate gene transcription. Mice were administered IL-4, H-IPSE protein or its nuclear localization sequence (NLS) mutant, with or without neutralizing anti IL-4 antibody, or 2-mercaptoethane sulfonate sodium (MESNA; a drug used to prevent IHC), followed by ifosfamide. Bladder tissue damage and hemoglobin content were measured. Spontaneous and evoked pain, urinary frequency, and bladdergene expression analysis were assessed. Pain behaviors were interpreted in a blinded fashion. One dose of H-IPSE was superior to MESNA and IL-4 in suppressing bladder hemorrhage in an IL-4-dependent fashion and comparable with MESNA in dampening ifosfamide-triggered pain behaviors in an NLS-dependent manner. H-IPSE also accelerated urothelial repair following IHC. Our work represents the first therapeutic exploitation of a uropathogen-derived host modulatory molecule in a clinically relevant bladder disease model and indicates that IPSE may be an alternative to MESNA for mitigating CHC.-Mbanefo, E. C., Le, L., Pennington, L. F., Odegaard, J. I., Jardetzky, T. S., Alouffi, A., Falcone, F. H., Hsieh, M. H. Therapeutic exploitation of IPSE, a urogenital parasite derived host modulatory protein, for chemotherapy-induced hemorrhagic cystitis. PMID- 29613837 TI - Lingual Frenulum Phenotypes in Brazilian Infants With Congenital Zika Syndrome. AB - OBJECTIVE: The present study aimed to evaluate lingual frenulum in children affected by congenital Zika syndrome (CZS) and to analyze the association of lingual frenulum phenotypes with other variables. DESIGN: This present work had a cross-sectional, descriptive study design. SETTING: This study was carried out in Fortaleza (Brazil). The health professionals provided tertiary level of care. Data collection occurred during a multidisciplinary task force for evaluating infants affected by CZS in December 2 to 3, 2016. PATIENTS: Fifty-four patients with CZS (1-12 months old; 32 girls and 22 boys) were recruited from a population of 70 infants. INTERVENTIONS: A multidisciplinary group comprised of speech language pathologist/audiologists and pediatric dentists evaluated all patients through an intraoral examination and a specific tongue maneuver protocol for infants. MAIN OUTCOME MEASURES: Lingual frenulum visibility was the primary outcome measure. Before initiating the study, we hypothesized that children with CZS had an absent lingual frenulum. RESULTS: Lingual frenula were visible in 34 (63%) infants, whereas in 20 (37%) infants lingual frenula visibility required a specific maneuver to retract the tongue. Six of 20 infants presented posteriorly positioned lingual frenula that were visible after maneuver. Lingual frenula were covered by mucous tissue in 14 infants. Presence of posterior frenulum was associated with dysphagia ( P = 0.038). However, the presence of dysphagia in a multivariate model did not associate with the presence of a posterior lingual frenulum ( P = .069) or neurologic symptoms ( P = .056). CONCLUSION: Children with CZS showed predominance of a posterior lingual frenula covered by an overlapping curtain-like mucous membrane. PMID- 29613838 TI - Salivary Cortisol Rhythms in Children With Cleft Lip and/or Palate: A Case Control Study. AB - OBJECTIVE: Knowledge about the stress response in children with cleft lip and/or palate (CL/P) is sparse and the association between the stress response and health-related quality of life (HRQoL) is unknown. Consequently, investigations on the influence of CL/P on the stress response alone and its association with HRQoL are of importance. The purpose was to determine whether salivary cortisol concentration in children with CL/P differs from that in children without clefts (controls) and whether there are any differences in salivary cortisol concentrations between ages, gender, and type of cleft. Furthermore, the final aim was to determine the correlation between salivary cortisol concentration and HRQoL. DESIGN: The study used a cross-sectional case-control design. PARTICIPANTS: Ninety-one 5- and 10-year-old children with CL/P and 180 age matched controls. MAIN OUTCOME MEASURES: Salivary samples were collected on 2 mornings and 1 evening for each child. Samples were analyzed using a commercial competitive radioimmunoassay and HRQoL was assessed using the KIDSCREEN-52. RESULTS: Salivary cortisol concentrations were similar in children with CL/P and controls. There was no difference in salivary cortisol concentrations between children with different types of cleft. There was no correlation between cortisol concentration and HRQoL. CONCLUSION: Five- and 10-year-old children with corrected CL/P seemed not to be more stressed than controls, and there were no correlation to HRQoL. The HRQoL levels - were comparable to that of a European norm population. PMID- 29613839 TI - Speech in 5-Year-Olds With Cleft Palate With or Without Cleft Lip Treated With Primary Palatal Surgery With Muscle Reconstruction According to Sommerlad. AB - OBJECTIVE: To evaluate speech in 5-year-olds with cleft palate with or without cleft lip (CP+/-L) treated with primary palatal surgery in 1 stage with muscle reconstruction according to Sommerlad at about 12 months of age. DESIGN: Retrospective study. SETTING: Primary care university hospital. PARTICIPANTS: Eight 5-year-olds with cleft soft palate (SP), 22 with cleft soft/hard palate (SHP), 33 with unilateral cleft lip and palate, and 17 with bilateral CLP (BCLP). MAIN OUTCOME MEASURES: Percent oral consonants correct (POCC), percent consonants correct adjusted for age (PCC-A), percent oral errors, percent nonoral errors, and variables related to velopharyngeal function were analyzed from assessments of audio recordings by 3 independent speech-language pathologists. RESULTS: The median POCC was 75.4% (range: 22.7%-98.9%), median PCC-A 96.9% (range: 36.9% 100%), median percent oral errors 3.4% (range: 0%-40.7%), and median percent nonoral errors 0% (range: 0%-20%), with significantly poorer results in children with more extensive clefts. The SP group had significantly less occurrence of audible nasal air leakage than the SHP and the BCLP groups. Before age 5 years, 1.3% of the children underwent fistula surgery and 6.3% secondary speech improving surgery. At age 5 years, 15% of the total group was perceived as having incompetent velopharyngeal function. CONCLUSIONS: Speech was poorer in many children with more extensive clefts. Children with CP+/-L had poorer speech compared to normative data of peers without CP+/-L, but the results indicated relatively good speech compared to speech of children with CP+/-L in previous studies. PMID- 29613840 TI - Effects of Palate Repair on Cranial Base and Maxillary Morphology in Patients With Unilateral Complete Cleft Lip and Palate. AB - OBJECTIVE: To identify the effects of palate repair on cranial base and maxillary morphology in patients with unilateral cleft lip and palate (UCLP) and to discover the relevance between cranial base and maxilla through cephalometric analysis. DESIGN: Retrospective. PATIENTS: Thirty-seven UCLP patients with operated lip (OL) and unoperated palate constituted OL group and were classified into 5 cervical vertebral maturation (CVM) stages. Thirty-seven UCLP patients with operated lip and palate (OLP) and 37 noncleft people with skeletal class I malocclusion were CVM- and sex-matched with the OL group as OLP group and control group, respectively. CVM stage I and II were combined into group 1, CVM stage III to V were combined into group 2. INTERVENTIONS: Lateral cephalograms of all participants were obtained. MAIN OUTCOME MEASURES: Cephalometric analysis was employed, and data were compared among groups. RESULTS: Length of posterior cranial base (Ba-S) of the OL group was shorter than controls in group 1; Ba-S and the ratio between length of posterior and anterior cranial base (Ba-S/S-N) of the OL and OLP groups were smaller than controls in group 2. No significant differences in cranial base were found between the OL and OLP groups. In group 1, patients of the OLP group showed smaller SNA, ANS-Ptm, and ANS-Ptm/S-N, and patients of the OL group showed smaller ANS-Ptm. In group 2, both OL and OLP groups had smaller sella-nasion-A point angle (SNA), projection distance between ANS and Ptm points on FH plane (ANS-Ptm), and the ratio between ANS-Ptm and anterior cranial base length (ANS-Ptm/S-N). CONCLUSIONS: Palate repair seems to have no obvious effects on cranial base morphology in patients with UCLP. Those patients with lip operated, whether cleft palate operated or not, tend to have a smaller length of maxilla sagittally and this deformity progresses with age. PMID- 29613841 TI - Increased Pancreatic Echogenicity with US: Relationship to Glycemic Progression and Incident Diabetes. AB - Purpose To evaluate the association between increased pancreatic echogenicity (IPE) and the risk of glycemic progression and incident diabetes. Materials and Methods This retrospective study was approved by the institutional review board, with waiver of informed consent. Consecutive individuals who had undergone abdominal ultrasonography as part of a health examination at a tertiary hospital between January 2005 and December 2011 were included. IPE was defined as increased echogenicity of the pancreas compared with that of the left lobe of liver. Glycemic progression was defined as the development of new prediabetes or diabetes in normoglycemic participants or as new diabetes in prediabetic participants during the follow-up period (median, 3.17 years; interquartile range, 2.01-4.67 years). The occurrence of incident diabetes, defined as a new diagnosis of diabetes during follow-up, was also analyzed. Results Mean age of the 32 346 participants was 50.4 years +/- 12.2, and 48% (15 489 of 32 346) were female. The prevalence of IPE and nonalcoholic fatty liver disease (NAFLD) was 8.4% (2720 of 32 346) and 41.4% (13 389 of 32 346), respectively. A total of 8856 participants were included in the follow-up analysis. During the 29 819.2 person years of follow-up, 1217 (13.7%) and 449 (5.1%) of the 8856 participants developed glycemic progression and new diabetes, respectively. IPE was associated with more glycemic progression (hazard ratio, 1.54; 95% confidence interval: 1.23, 1.92; P < .001) and incident diabetes (hazard ratio, 1.49; 95% confidence interval: 1.05, 2.11; P = .024) after adjustment for confounders, HbA1c concentration, and NAFLD. Conclusion Increased pancreatic echogenicity is associated with deteriorating glycemic parameters and higher risk of glycemic progression and incident diabetes, independent of HbA1c concentration and NAFLD. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 29613842 TI - Rapid Contour-based Segmentation for 18F-FDG PET Imaging of Lung Tumors by Using ITK-SNAP: Comparison to Expert-based Segmentation. AB - Purpose To assess the performance of the ITK-SNAP software for fluorodeoxyglucose (FDG) positron emission tomography (PET) segmentation of complex-shaped lung tumors compared with an optimized, expert-based manual reference standard. Materials and Methods Seventy-six FDG PET images of thoracic lesions were retrospectively segmented by using ITK-SNAP software. Each tumor was manually segmented by six raters to generate an optimized reference standard by using the simultaneous truth and performance level estimate algorithm. Four raters segmented 76 FDG PET images of lung tumors twice by using ITK-SNAP active contour algorithm. Accuracy of ITK-SNAP procedure was assessed by using Dice coefficient and Hausdorff metric. Interrater and intrarater reliability were estimated by using intraclass correlation coefficients of output volumes. Finally, the ITK SNAP procedure was compared with currently recommended PET tumor delineation methods on the basis of thresholding at 41% volume of interest (VOI; VOI41) and 50% VOI (VOI50) of the tumor's maximal metabolism intensity. Results Accuracy estimates for the ITK-SNAP procedure indicated a Dice coefficient of 0.83 (95% confidence interval: 0.77, 0.89) and a Hausdorff distance of 12.6 mm (95% confidence interval: 9.82, 15.32). Interrater reliability was an intraclass correlation coefficient of 0.94 (95% confidence interval: 0.91, 0.96). The intrarater reliabilities were intraclass correlation coefficients above 0.97. Finally, VOI41 and VOI50 accuracy metrics were as follows: Dice coefficient, 0.48 (95% confidence interval: 0.44, 0.51) and 0.34 (95% confidence interval: 0.30, 0.38), respectively, and Hausdorff distance, 25.6 mm (95% confidence interval: 21.7, 31.4) and 31.3 mm (95% confidence interval: 26.8, 38.4), respectively. Conclusion ITK-SNAP is accurate and reliable for active-contour-based segmentation of heterogeneous thoracic PET tumors. ITK-SNAP surpassed the recommended PET methods compared with ground truth manual segmentation. PMID- 29613843 TI - Intraprocedural Ablation Margin Assessment by Using Ammonia Perfusion PET during FDG PET/CT-guided Liver Tumor Ablation: A Pilot Study. AB - Purpose To prospectively determine whether nitrogen 13 (13N) ammonia perfusion positron emission tomography (PET) during fluorine 18 fluorodeoxyglucose (FDG) PET/computed tomography (CT)-guided liver tumor ablation can be used to intraprocedurally assess ablation margins. Materials and Methods Eight patients (five women and three men; age range, 36-74 years; mean age, 57 years) were enrolled in this pilot study and underwent FDG PET/CT-guided microwave ablation of 11 FDG-avid liver metastases (mean diameter, 22 mm; range, 11-34 mm). All procedures were performed between March 2014 and December 2016. Complete ablation margin visibility and minimum ablation margin thickness were assessed by using intraprocedural 13N-ammonia perfusion PET compared with 24-hour postprocedural MR imaging by two independent blinded radiologists. Local tumor progression for each ablated tumor was assessed at follow-up imaging for 3-38 months (median, 17.6 months). Descriptive analysis was performed. Results Eleven of 11 (100%) ablation margins were fully assessable by using intraprocedural perfusion PET by both readers; six of eleven (55%) margins were fully assessable by both readers at postprocedural 24-hour MR imaging. By using perfusion PET, one tumor that had been judged by both readers to have a minimum margin of 0 mm progressed locally. No tumors judged to have a minimum margin greater than 0 mm at perfusion PET progressed locally. Conclusion 13N-ammonia perfusion PET during FDG PET/CT-guided liver tumor ablations can potentially be used to intraprocedurally assess the entire ablation margin, including the minimum margin. (c) RSNA, 2018. PMID- 29613844 TI - Normal Cerebellar Growth by Using Three-dimensional US in the Preterm Infant from Birth to Term-corrected Age. AB - Purpose To establish cross-sectional and longitudinal reference values for cerebellar size in preterm infants with normal neuroimaging findings and normal 2 year neurodevelopmental outcome by using cranial ultrasonography (US). Materials and Methods This prospective study consecutively enrolled preterm infants admitted to a neonatal intensive care unit from June 2011 to June 2014 with a birth weight of less than or equal to 1500 g and/or gestational age (GA) of less than or equal to 32 weeks. They underwent weekly cranial US from birth to term equivalent age and magnetic resonance (MR) imaging at term-equivalent age. The infants underwent neurodevelopmental assessments at age 2 years with Bayley Scales of Infant and Toddler Development, 3rd edition (BSID-III). Patients with adverse outcomes (death or abnormal neuroimaging findings and/or BSID-III score of <85) were excluded. The following measurements were performed: vermis height, craniocaudal diameter, superior width, inferior width, vermis area, and transcerebellar diameter. Statistical analyses were conducted by using multilevel analyses. Results A total of 137 infants with a mean GA at birth of 29.4 weeks (range, 25-32 weeks) were included. Transcerebellar diameter increased by 1.04 mm per week on average; vermis height and craniocaudal diameter increased by 0.55 mm and 0.59 mm, respectively. Superior vermian width increased by an average of 0.45 mm, whereas inferior vermian width increased by an average of 0.51 mm per week. Vermis area was found to increase by 0.22 cm2 per week on average. The sex effect was significant (female lower than male) for vermis height (P < .05), craniocaudal diameter (P < .05), inferior vermian width (P <. 05), and vermis area (P <. 05). Conclusion Cross-sectional and longitudinal reference values were established for cerebellar growth in preterm infants, which may be included in routine cranial US. PMID- 29613846 TI - Association between Screening Mammography Recall Rate and Interval Cancers in the UK Breast Cancer Service Screening Program: A Cohort Study. AB - Purpose To determine whether low levels of recall lead to increased interval cancers and the magnitude of this effect. Materials and Methods The authors retrospectively analyzed prospectively collected data from the UK National Health Service Breast Screening Programme during a 36-month period (April 1, 2005 to March 31, 2008), with 3-year follow-up in women aged 50-70 years. Data on recall, cancers detected at screening, and interval cancers were available for each of the 84 breast screening units and for each year (n = 252). The association between interval cancers and recalls was modeled by using Poisson regression on aggregated data and according to age (5-year intervals) and screening type (prevalent vs incident). Results The authors analyzed 5 126 689 screening episodes, demonstrating an average recall to assessment rate (RAR) of 4.56% (range, 1.64%-8.42%; standard deviation, 1.15%), cancer detection rate of 8.1 per 1000 women screened, and interval cancer rate (ICR) of 3.1 per 1000 women screened. Overall, a significant negative association was found between RAR and ICR (Poisson regression coefficient: -0.039 [95% confidence interval: -0.062, 0.017]; P = .001), with approximately one fewer interval cancer for every additional 80-84 recalls. Subgroup analysis revealed similar negative correlations in women aged 50-54 years (P = .002), 60-64 years (P = .01), and 65 69 years (P = .008) as well as in incident screens (P = .001) and prevalent screens (P = .04). No significant relationship was found in women aged 55-59 years (P = .46). Conclusion There was a statistically significant negative correlation between RAR and ICR, which suggests the merit of a minimum threshold for RAR. (c) RSNA, 2018 Online supplemental material is available for this article. PMID- 29613847 TI - Myocardial Extracellular Volume Fraction and Change in Hematocrit Level: MR Evaluation by Using T1 Mapping in an Experimental Model of Anemia. AB - Purpose To evaluate the effect of changes in hematocrit level on myocardial extracellular volume (ECV) fraction, as quantified with cardiac magnetic resonance (MR) imaging in an animal model. Materials and Methods Thirteen adult male Sprague-Dawley rats underwent cardiac MR imaging before and after induction of anemia. MR imaging procedures, including unenhanced and contrast material enhanced T1 mapping, were performed by using a saturation recovery Look-Locker sequence with a 9.4-T unit. An optimized T1 mapping sequence was established in the phantom study. Systolic function of the left ventricle (LV) was calculated from the cine images. Native and postcontrast T1 values of the LV myocardium at the midcavity level and LV blood pool, partition coefficients, and ECV were calculated. Histopathologic examination of the heart was performed after sacrifice. Intergroup comparison of variables was performed with the paired t test. Results The postanemia models exhibited lower hematocrit levels, postcontrast T1 values of the LV pool, and partition coefficients (mean, 45.7% +/ 5.2 [standard deviation]; 563.8 msec +/- 155.7; and 29.2 +/- 3.5, respectively) than did the preanemia models (mean, 59.0% +/- 4.1; 690.2 msec +/- 109.7; and 38.2 +/- 4.4, respectively) (P < .05 for all comparisons). There were no differences between the pre- and postanemia groups in terms of LV ejection fraction (mean, 72.7% +/- 2.1 vs 73.2% +/- 4.7; P = .78) and ECV (mean, 15.5% +/- 2.0 vs 16.0% +/- 1.9; P = .24). Conclusion Myocardial ECV measured with contrast enhanced T1 mapping cardiac MR imaging did not significantly change despite changes in hematocrit level in anemic rat models. Extrapolation of this finding from animal models to human subjects suggests that ECV measured with MR imaging could be a robust parameter in anemic patients. PMID- 29613848 TI - Investigation of physico-mechanical properties of flexible poly (vinyl chloride) filled with antimony trioxide using ionizing radiation. AB - Composites of polyvinyl chloride (PVC) with 2% calcium carbonate, 2% diethyl phthalate, 2% paraffin wax and 2% lead sulphate and different contents of antimony trioxide (Sb2O3) prepared by melting and irradiated with gamma ray have been considered. Assessment of the mechanical and thermal properties of the unirradiated and irradiated flexible polyvinyl chloride (FPVC) were completed utilizing elasticity (TS), Elongation at break (Eb) and thermogravimetric analysis measurements. TS and thermal stability of FPVC displayed advanced improvement after addition of additives and this approach highlighted the efficiency of those ingredients on PVC. The compounding of FPVC with Sb2O3 in various extents was examined by FTIR, X-ray diffraction and scanning electron microscope methods. It is obvious that the presence of Sb2O3 begins impacting oxidative degradation, leading to a decrease in mechanical properties up to 10%. Moreover, a slight increase in the thermal stability of composites by exposure to ionizing radiation is apparently due to cross-linking of FPVC chains. PMID- 29613849 TI - Expanding reproductive justice through a supportability reparative justice framework: the case of abortion in South Africa. AB - Theoretical refinement of the concept of reproductive justice has been called for. In this paper, I propose the use of a supportability reparative justice approach. Drawing on intra-categorical intersectionality, the supportability aspect starts from the event of a pregnancy to unravel the interwoven embodied and social realities implicated in women experiencing pregnancy as personally supportable/unsupportable, and socially supported/unsupported. The reparative justice aspect highlights the need for social repair in the case of unsupportable pregnancies and relies on Ernesto Verdeja's critical theory of reparative justice in which he outlines four reparative dimensions. Using abortion within the South African context, I show how this framework may be put to use: (1) the facilitation of autonomous decision-making (individual material dimension) requires understanding women within context, and less emphasis on individual driven 'choice'; (2) the provision of legal, safe state-sponsored healthcare resources (collective material dimension) demands political will and abortion service provision to be regarded as a moral as well as a healthcare priority; (3) overcoming stigma and the spoiled identities (collective symbolic dimension) requires significant feminist action to deconstruct negative discourses and to foreground positive narratives; and (4) understanding individual lived experiences (individual symbolic dimension) means deep listening within the social dynamics of particular contexts. PMID- 29613851 TI - Solution to Detect, Classify, and Report Illicit Online Marketing and Sales of Controlled Substances via Twitter: Using Machine Learning and Web Forensics to Combat Digital Opioid Access. AB - BACKGROUND: On December 6 and 7, 2017, the US Department of Health and Human Services (HHS) hosted its first Code-a-Thon event aimed at leveraging technology and data-driven solutions to help combat the opioid epidemic. The authors-an interdisciplinary team from academia, the private sector, and the US Centers for Disease Control and Prevention-participated in the Code-a-Thon as part of the prevention track. OBJECTIVE: The aim of this study was to develop and deploy a methodology using machine learning to accurately detect the marketing and sale of opioids by illicit online sellers via Twitter as part of participation at the HHS Opioid Code-a-Thon event. METHODS: Tweets were collected from the Twitter public application programming interface stream filtered for common prescription opioid keywords in conjunction with participation in the Code-a-Thon from November 15, 2017 to December 5, 2017. An unsupervised machine learning-based approach was developed and used during the Code-a-Thon competition (24 hours) to obtain a summary of the content of the tweets to isolate those clusters associated with illegal online marketing and sale using a biterm topic model (BTM). After isolating relevant tweets, hyperlinks associated with these tweets were reviewed to assess the characteristics of illegal online sellers. RESULTS: We collected and analyzed 213,041 tweets over the course of the Code-a-Thon containing keywords codeine, percocet, vicodin, oxycontin, oxycodone, fentanyl, and hydrocodone. Using BTM, 0.32% (692/213,041) tweets were identified as being associated with illegal online marketing and sale of prescription opioids. After removing duplicates and dead links, we identified 34 unique "live" tweets, with 44% (15/34) directing consumers to illicit online pharmacies, 32% (11/34) linked to individual drug sellers, and 21% (7/34) used by marketing affiliates. In addition to offering the "no prescription" sale of opioids, many of these vendors also sold other controlled substances and illicit drugs. CONCLUSIONS: The results of this study are in line with prior studies that have identified social media platforms, including Twitter, as a potential conduit for supply and sale of illicit opioids. To translate these results into action, authors also developed a prototype wireframe for the purposes of detecting, classifying, and reporting illicit online pharmacy tweets selling controlled substances illegally to the US Food and Drug Administration and the US Drug Enforcement Agency. Further development of solutions based on these methods has the potential to proactively alert regulators and law enforcement agencies of illegal opioid sales, while also making the online environment safer for the public. PMID- 29613852 TI - Pulmonary infection of cystic fibrosis mice with Staphylococcus aureus requires expression of alpha-toxin. AB - Pulmonary infections of cystic fibrosis (CF) patients with Staphylococcus aureus (S. aureus) occur very early in the disease. The molecular details that cause infection-susceptibility of CF patients to and mediate infection with S. aureus are poorly characterized. Therefore, we aimed to identify the role of alpha toxin, a major S. aureus toxin, for pulmonary infection of CF mice. Infection with S. aureus JE2 resulted in severe pneumonia in CF mice, while wildtype mice were almost unaffected. Deficiency of alpha-toxin in JE2-Deltahla reduced the pathogenicity of S. aureus in CF mice. However, CF mice were still more susceptible to the mutant S. aureus strain than wildtype mice. The S. aureus JE2 induced a marked increase of ceramide and a downregulation of sphingosine and acid ceramidase expression in bronchi of CF mice. Deletion of alpha-toxin reduced these changes after infection of CF mice. Similar changes were observed in wildtype mice, but at much lower levels. Our data indicate that expression of alpha-toxin is a major factor causing S. aureus infections in CF mice. Wildtype S. aureus induces a marked increase of ceramide and a reduction of sphingosine and acid ceramidase expression in bronchial epithelial cells of wildtype and CF mice, changes that determine infection susceptibility. PMID- 29613853 TI - Non-invasive prenatal diagnosis of paternally inherited disorders from maternal plasma: detection of NF1 and CFTR mutations using droplet digital PCR. AB - BACKGROUND: To limit risks of miscarriages associated with invasive procedures of current prenatal diagnosis practice, we aim to develop a personalized medicine based protocol for non-invasive prenatal diagnosis (NIPD) of monogenic disorders relying on the detection of paternally inherited mutations in maternal blood using droplet digital PCR (ddPCR). METHODS: This study included four couples at risk of transmitting paternal neurofibromatosis type 1 (NF1) mutations and four couples at risk of transmitting compound heterozygous CFTR mutations. NIPD was performed between 8 and 15 weeks of gestation, in parallel to conventional invasive diagnosis. We designed specific hydrolysis probes to detect the paternal mutation and to assess the presence of cell-free fetal DNA by ddPCR. Analytical performances of each assay were determined from paternal sample, an then fetal genotype was inferred from maternal plasma sample. RESULTS: Presence or absence of the paternal mutant allele was correctly determined in all the studied plasma DNA samples. CONCLUSIONS: We report an NIPD protocol suitable for implementation in an experienced laboratory of molecular genetics. Our proof-of-principle results point out a high accuracy for early detection of paternal NF1 and CFTR mutations in cell-free DNA, and open new perspectives for extending the technology to NIPD of many other monogenic diseases. PMID- 29613854 TI - Nuclear receptor modulation by kinesin. PMID- 29613855 TI - Chiro-plasmonic refractory metamaterial with titanium nitride (TiN) core-shell nanohelices. AB - Chiral metamaterials are obtained by assembling plasmonic elements in geometries with broken mirror symmetry, which can have promising applications pertaining to generation, manipulation and detection of optical polarisation. The materials used to fabricate this promising nanosystem, especially in the visible-NIR regime, are limited to noble metals such as Au and Ag. However, they are not stable at elevated temperatures and in addition, incompatible with CMOS technologies. We demonstrate that it is possible to develop a chiro-plasmonic system based on a refractory material such as titanium nitride (TiN) which does not have these disadvantages. The building block of our metamaterial is a novel core-shell helix, obtained by coating TiN over silica nanohelices. These were arranged in a regular two-dimensional array over cm-scale areas, made possible by the use of scalable fabrication techniques such as laser interference lithography, glancing angle deposition and DC magnetron sputtering. The measured chiro-optical response was extremely broadband (<500 nm to >1400 nm), and had contributions from individual, as well as collective plasmon modes of the interacting nanohelices, whose spectral characteristics could be easily controlled by varying the direction of the incident radiation. PMID- 29613857 TI - A favorable neointimal proliferation healing process of large drug-eluting stent malapposition. PMID- 29613856 TI - TNF-driven adaptive response mediates resistance to EGFR inhibition in lung cancer. AB - Although aberrant EGFR signaling is widespread in cancer, EGFR inhibition is effective only in a subset of non-small cell lung cancer (NSCLC) with EGFR activating mutations. A majority of NSCLCs express EGFR wild type (EGFRwt) and do not respond to EGFR inhibition. TNF is a major mediator of inflammation-induced cancer. We find that a rapid increase in TNF level is a universal adaptive response to EGFR inhibition in NSCLC, regardless of EGFR status. EGFR signaling actively suppresses TNF mRNA levels by inducing expression of miR-21, resulting in decreased TNF mRNA stability. Conversely, EGFR inhibition results in loss of miR-21 and increased TNF mRNA stability. In addition, TNF-induced NF-kappaB activation leads to increased TNF transcription in a feed-forward loop. Inhibition of TNF signaling renders EGFRwt-expressing NSCLC cell lines and an EGFRwt patient-derived xenograft (PDX) model highly sensitive to EGFR inhibition. In EGFR-mutant oncogene-addicted cells, blocking TNF enhances the effectiveness of EGFR inhibition. EGFR plus TNF inhibition is also effective in NSCLC with acquired resistance to EGFR inhibition. We suggest concomitant EGFR and TNF inhibition as a potentially new treatment approach that could be beneficial for a majority of lung cancer patients. PMID- 29613859 TI - Magnetic work environments: Patient experience outcomes in Magnet versus non Magnet hospitals. AB - BACKGROUND: The term Magnet hospital is an official designation ascribed by the American Nurses Credentialing Center for hospitals that meet specific criteria indicating they have a "magnetic work environment" for nurses. The objective of the Magnet designation is to encourage hospitals to design work in such a way as to attract and retain high-quality nurses and thus improve the quality of patient care. Empirical research has demonstrated that hospitals who earn a Magnet designation appear to have nurses who are more satisfied and committed to their work environments. Although research on whether patients are more satisfied with their care in these hospitals is still in its infancy, preliminary studies suggest that patients receiving care at Magnet-designated hospitals report more positive care experiences. PURPOSE: This study used a large secondary survey data set to explore the extent to which inpatient perceptions differed between Magnet and non-Magnet hospitals. METHODOLOGY: Ordinal logistic and multinomial logistic regression analyses were used to examine whether Magnet hospital status and positive nurse communication are related to overall hospital rating and willingness of patients to recommend the hospital. RESULTS: Results indicated that patients treated at a Magnet hospital and patients who rated nurses' communication highly were significantly more satisfied and more likely to say they would recommend the hospital. CONCLUSIONS: Evidence from this study suggests that it would be worthwhile for hospital leaders to consider organizational policies and practices consistent with the criteria put forth for Magnet hospital designation. PMID- 29613858 TI - The Medical Necessity of Comprehensive Patch Testing. AB - Allergic contact dermatitis is associated with significant disease and economic burden in the United States. To properly manage allergic contact dermatitis, it is important to accurately identify the substance(s) implicated in the dermatitis to prevent disease recurrence. The commercially available T.R.U.E Test (36 allergens) screening panel has been reported to have a conservative hypothetical allergen detection rate of 66.0%, at most. Importantly, these calculations are based on the 78% of patients who had clinically relevant reactions to allergens present on the North American Contact Dermatitis Group screening series (70 allergens), without the use of supplemental allergens. Testing with supplemental allergens beyond a screening series can more fully evaluate an individual's environmental and occupational exposure, which may significantly increase diagnostic accuracy. Comprehensive patch testing with additional allergens in sunscreens, cosmetics, and fragrances, for example, may increase the diagnostic yield as well as the likelihood of achieving a cure if the dermatitis is chronic and recalcitrant. PMID- 29613860 TI - A systematic review of vertical integration and quality of care, efficiency, and patient-centered outcomes. AB - BACKGROUND: Small independent practices are increasingly giving way to more complex affiliations between provider organizations and hospital systems. There are several ways in which vertically integrated health systems could improve quality and lower the costs of care. But there are also concerns that integrated systems may increase the price and costs of care without commensurate improvements in quality and outcomes. PURPOSE: Despite a growing body of research on vertically integrated health systems, no systematic review that we know of compares vertically integrated health systems (defined as shared ownership or joint management of hospitals and physician practices) to nonintegrated hospitals or physician practices. METHODS: We conducted a systematic search of the literature published from January 1996 to November 2016. We considered articles for review if they compared the performance of a vertically integrated health system and examined an outcome related to quality of care, efficiency, or patient centered outcomes. RESULTS: Database searches generated 7,559 articles, with 29 articles included in this review. Vertical integration was associated with better quality, often measured as optimal care for specific conditions, but showed either no differences or lower efficiency as measured by utilization, spending, and prices. Few studies evaluated a patient-centered outcome; among those, most examined mortality and did not identify any effects. Across domains, most studies were observational and did not address the issue of selection bias. PRACTICE IMPLICATIONS: Recent evidence suggests the trend toward vertical integration will likely continue as providers respond to changing payment models and market factors. A growing body of research on comparative health system performance suggests that integration of physician practices with hospitals might not be enough to achieve higher-value care. More information is needed to identify the health system attributes that contribute to improved outcomes, as well as which policy levers can minimize anticompetitive effects and maximize the benefits of these affiliations. PMID- 29613861 TI - Trends in Use of Midodrine in the ICU: A Single-Center Retrospective Case Series. AB - OBJECTIVES: Midodrine is an oral alpha-agonist approved for orthostatic hypotension. The use of midodrine as a vasopressor sparing agent has steadily increased in the ICU despite limited evidence for its safety in that setting. We describe the trends in use and reported side effects and complications of midodrine in multidisciplinary ICUs of a tertiary care institution. DESIGN: Single-center retrospective case series. SETTING: Medical and surgical ICU patients from January 2011 to October 2016 at Mayo Clinic, Rochester. PATIENTS: Adult patients admitted to any ICU who received midodrine for hypotension were eligible. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We reviewed the mean arterial pressures and cumulative vasopressor dose before and after midodrine administration and assessed for reported complications. During the study period, a total of 1,119 patients were initiated on midodrine, 56% in surgical ICUs, 42% in medical ICUs, and 2% in a mixed medical and surgical neurology ICU. There was a significant decrease in the number of patients on vasopressors 24 hours after initiation of midodrine (663 to 344; p < 0.001); among the patients that remained on vasopressors, there was a significant decrease in the median cumulative vasopressor dose (p = 0.002). There was a significant increase in median mean arterial pressure 24 hours after initiation of midodrine among patients who were not on vasopressors (65-68; p < 0.01). Asymptomatic bradycardia (heart rate < 50 beats/min) was the most common side effect (n = 172 patients, median 39 beats/min). Two patients developed bowel ischemia after initiation of midodrine that prompted discontinuation of midodrine in one case. Evaluating trends of utilization, the off-label use of midodrine has increased steadily over the years across ICUs. CONCLUSIONS: Our results suggest that midodrine is being increasingly used as an adjunct to increase mean arterial pressure and facilitate weaning of vasopressors in the ICU. Prospective trials are required to further establish the appropriate timing, efficacy, safety, and cost-effectiveness of midodrine use in ICU patients. PMID- 29613862 TI - Comparative Histomorphometric Analysis of Maxillary Sinus Augmentation With Deproteinized Bovine Bone and Demineralized Particulate Human Tooth Graft: An Experimental Study in Rabbits. AB - PURPOSE: The aim of this animal study is to evaluate, by histomorphometric analysis, new bone formation in rabbit maxillary sinuses with Bio-Oss and demineralized particulate human tooth graft. MATERIALS AND METHODS: Bilateral sinus augmentation procedures were performed in 8 adult male rabbits. After preparation of replaceable bony windows on the lateral wall of the nasal cavity with a piezoelectric surgical device, deproteinized bovine graft (Bio-Oss) was grafted in the new compartment of the maxillary sinus after elevation of the sinus membrane in the control group. In the experimental group, the demineralized human particulate tooth bone was grafted in the sinus. The replaceable bony window was repositioned over the bone graft in both groups. Animals were killed at 2 and 8 weeks after the surgical procedure. The augmented sinuses were evaluated by histomorphometric analysis using hematoxylin-eosin and Masson trichrome stains. RESULTS: Histologically, new bone was revealed along the elevated sinus membrane and both bone grafts. In the control group, the new bone area at 8 weeks was not significantly different than that at 2 weeks. In the experimental group, the new bone area at 8 weeks was significantly greater than that at 2 weeks. CONCLUSION: Significant higher new bone formation was revealed in the experimental group than in the control group. PMID- 29613863 TI - Individuals have the right to avoid sex with partners unwilling to test for HIV but do not have a right to force them to test for HIV. PMID- 29613864 TI - Systemic Inflammation Complicates the Interpretation of Therapeutic Drug Monitoring of Risperidone. PMID- 29613865 TI - Rhabdomyolysis of Multifactorial Origin in Schizophrenia: Antipsychotics, Statins, Trauma. PMID- 29613866 TI - Outcomes Following Peripheral Nerve Transfers for Treatment of Non-Obstetric Brachial Plexus Upper-Extremity Neuropathy. PMID- 29613867 TI - Manipulation Under Anesthesia and Stiffness After Total Knee Arthroplasty. PMID- 29613868 TI - Biomechanical Consequences of Meniscal Tear, Partial Meniscectomy, and Meniscal Repair in the Knee. AB - UPDATE: This article was updated on April 26, 2018, because of a previous error. On pages 1 and 14, the author name that had read "Alan Z. Zhang, MD" now reads "Alan L. Zhang, MD." PMID- 29613872 TI - Repeal of Comprehensive Background Check Policies and Firearm Homicide and Suicide. AB - BACKGROUND: In 2016, firearms killed 38,658 people in the United States. Federal law requires licensed gun dealers, but not private parties, to conduct background checks on prospective firearm purchasers with the goal of preventing prohibited persons from obtaining firearms. Our objective was to estimate the effect of the repeal of comprehensive background check laws-requiring a background check for all handgun sales, not just sales by licensed dealers-on firearm homicide and suicide rates in Indiana and Tennessee. METHODS: We compared age-adjusted firearm homicide and suicide rates, measured annually from 1981 to 2008 and 1994 to 2008 in Indiana and Tennessee, respectively, to rates in control groups constructed using the synthetic control method. RESULTS: The average rates of firearm homicide and suicide in Indiana and Tennessee following repeal were within the range of what could be expected, given natural variation (differences = 0.7 firearm homicides and 0.5 firearm suicides per 100,000 residents in Indiana and 0.4 firearm homicides and 0.3 firearm suicides per 100,000 residents in Tennessee). Sensitivity analyses resulted in similar findings. CONCLUSION: We found no evidence of an association between the repeal of comprehensive background check policies and firearm homicide and suicide rates in Indiana and Tennessee. In order to understand whether comprehensive background check policies reduce firearm deaths in the United States generally, more evidence on the impact of such policies from other states is needed. See video abstract at, http://links.lww.com/EDE/B353. PMID- 29613871 TI - A New Tool for Case Studies in Epidemiology-the Synthetic Control Method. PMID- 29613873 TI - Quality of Primary Care Provided to Medicare Beneficiaries by Nurse Practitioners and Physicians. AB - OBJECTIVE: To examine differences in the quality of care provided by primary care nurse practitioners (PCNPs), primary care physicians (PCMDs), or both clinicians. DATA SOURCES: Medicare part A and part B claims during 2012-2013. STUDY DESIGN: Retrospective cohort design using standard risk-adjustment methodologies and propensity score weighting assessing 16 claims-based quality measures grouped into 4 domains of primary care: chronic disease management, preventable hospitalizations, adverse outcomes, and cancer screening. EXTRACTION METHODS: Continuously enrolled aged, disabled, and dual eligible beneficiaries who received at least 25% of their primary care services from a random sample of PCMDs, PCNPs, or both clinicians. PRINCIPAL FINDINGS: Beneficiaries attributed to PCNPs had lower hospital admissions, readmissions, inappropriate emergency department use, and low-value imaging for low back pain. Beneficiaries attributed to PCMDs were more likely than those attributed to PCNPs to receive chronic disease management and cancer screenings. Quality of care for beneficiaries jointly attributed to both clinicians generally scored in the middle of the PCNP and PCMD attributed beneficiaries with the exception of cancer screening. CONCLUSIONS: The quality of primary care varies by clinician type, with different strengths for PCNPs and PCMDs. These comparative advantages should be considered when determining how to organize primary care to Medicare beneficiaries. PMID- 29613875 TI - Perspectives From Family Caregivers of Persons With Spinal Cord Injury in Hospital Versus Rehabilitation: A Pilot Study. AB - PURPOSE: The study aims to assess differences in family preferences for involvement in the ongoing care of a hospitalized family member with spinal cord injury based on whether the patient was hospitalized for initial rehabilitation (Group R) or hospitalized to treat secondary complications (Group C). DESIGN: Explorative cross-sectional design. METHOD: Family members rated the importance and experience of involvement on five subscales of the Patient Participation in Rehabilitation Questionnaire. Differences among the importance and experience scores between the groups were tested using the Mann-Whitney U test. FINDINGS: Group C scored the importance to be involved significantly higher than Group R (M = 3.17 vs. M = 4.04, p =.01). No other significant differences between groups were detected. CONCLUSION: Family members of patients hospitalized for secondary complications want greater involvement in care compared to those hospitalized for rehabilitation. CLINICAL RELEVANCE: Results indicate the need for tailored interventions using a family-centered approach and ongoing needs assessment. PMID- 29613874 TI - Medical Care Costs Were Similar Across the Low-dose Computed Tomography and Chest X-Ray Arms of the National Lung Screening Trial Despite Different Rates of Significant Incidental Findings. AB - BACKGROUND: The National Lung Screening Trial (NLST) reported lung cancer and all cause mortality reductions for low-dose computed tomography (LDCT) versus chest x ray (CXR) screening. Although LDCT lung screening has received a grade B from the United States Preventive Services Task Force and is a covered service under most health plans, concerns remain on the costs engendered by screening, and the impact of the high rate of significant incidental finding (SIF) detection on those costs. METHODS: We linked American College of Radiology Imaging Network NLST and Medicare fee-for-service claims data for participants from 23 sites for 2002-2009. We performed participant-level analyses using generalized linear regression models to estimate the adjusted annual mean of the 3-year total medical costs per person in each study arm and within screen outcome categories (ever positive with abnormalities suspicious for lung cancer, always negative for abnormalities suspicious for lung cancer, but with SIFs, and always negative without SIFs). RESULTS: The adjusted annual mean total per person costs were not significantly different between screening arms [LDCT, $11,029 (95% confidence interval, $10,107-$11,951); CXR, $10,905 (95% confidence interval, $10,059 $11,751)], despite higher proportions of individuals with SIFs in the LDCT versus the CXR arm (18% vs. 4%; P<0.0001). CONCLUSIONS: We found little difference in total annual per person costs between LDCT-screened and CXR-screened Medicare participants, despite the higher number of SIFs in the LDCT arm of the study. PMID- 29613876 TI - Aquatic Exercise Program for Individuals With Osteoarthritis: Pain, Stiffness, Physical Function, Self-Efficacy. AB - PURPOSE: This research was conducted to determine the effects of an aquatic exercise program on pain, stiffness, physical function, and self-efficacy in individuals with osteoarthritis. DESIGN: A randomized controlled trial. METHODS: Participants in the experimental group participated in the aquatic exercise program three times a week for 8 weeks; participants in the control group did not. FINDINGS: The mean scores of the experimental group on the pain, stiffness, and difficulty in carrying out physical functions subscales of the Western Ontario and McMaster Universities Osteoarthritis Index decreased significantly, whereas those of the control group decreased very little. The mean scores of the experimental group on the Arthritis Self-Efficacy Scale and the isokinetic muscle strength measurements increased, but those of the control group did not change in the final measurements. The difference between the groups was statistically significant. CONCLUSIONS: Through the study, it was determined that the aquatic exercise program decreased pain, stiffness, and difficulty in carrying out physical functions and increased self-efficacy and muscle strength of individuals with osteoarthritis. CLINICAL RELEVANCE: The aquatic exercise program can be used by nurses as a reference in the management of osteoarthritic patients' health status. PMID- 29613877 TI - Killing Me Sovereignly: The Quiet Demise of the Americans With Disabilities Act. AB - PURPOSE: The aim of the study was to make rehabilitation nurses aware that the Supreme Court has limited some of the protections afforded by the Americans With Disabilities Act (1990) on the basis of "sovereign immunity." METHODS: The authors use the case review method to analyze Supreme Court cases and alternatives for people with disabilities discriminated against because of the state in which they live. FINDINGS: Sovereign immunity makes it more difficult for a disabled person to bring a lawsuit against a state government (as an employer or provider of a public service) under the Americans With Disabilities Act. CONCLUSION: The extent to which disabled Americans can fully participate in their communities should not depend on where in the country they live. CLINICAL RELEVANCE: As patient advocates, rehabilitation nurses are in an ideal position to educate patients and families and have a duty to make their voices heard to persuade lawmakers to strengthen legal protections for disabled Americans. PMID- 29613878 TI - Wandering Behaviors and Activities of Daily Living Among Older Adults With Cognitive Impairment. AB - PURPOSE: The aim of the study was to examine the characteristics of wandering associated with preserved versus worsened activities of daily living (ADL) function. DESIGN: Longitudinal prospective design. Twenty-two cognitively impaired residents of an assisted living facility with over 450 observations were followed up to 8 months. METHODS: Hierarchical linear modeling techniques examine how wandering activity (episodes, distance traveled, gait speed), measured by a real-time locating system, may affect ADL (the Barthel index, the Functional Independence Measure [FIM]). FINDINGS: Wandering episodes were associated with increased ADL (B = 0.11, p <= .05, FIM); wandering distance (B = -4.52, p <= .05, the Barthel index; B = -2.14, p <= .05, FIM) was associated with decreased ADL. CONCLUSION: Walking an average of 0.81 miles per week with 18 or fewer wandering episodes is associated with decreased ability to perform ADL. CLINICAL RELEVANCE: Tailored protocols that allow productive wandering with ongoing assessment for fatigue/other physiological needs to appropriately limit distance walked within wandering episodes are needed for this population. PMID- 29613879 TI - The Relationship Between Nursing Workload, Quality of Care, and Nursing Payment in Intensive Care Units. AB - BACKGROUND: Nursing workload is highly associated with patient safety. It has been argued that the imbalance between nursing payment and nursing workload in Taiwan National Health Insurance (NHI)-covered intensive care units (ICUs) has resulted in the inadequate allocation of nursing manpower. However, limited empirical data are currently available to support this argument. PURPOSE: The aim of this study was to investigate the correlation between nursing workload, quality of care, and NHI-covered nursing payments in ICU settings. METHODS: This macrodata analysis study retrieved data from the existing ICU patient classification system, nursing quality monitoring system, and infection control monitoring system of a medical center in central Taiwan. Data on the Therapeutic Intervention Scoring System-28 (TISS-28) and non-TISS-28 scores, nursing hours, and nursing labor utilization rate were retrieved for the 23-month period beginning in January 2013 and ending in November 2014. The indices of care quality used in this study included incidence of falls, pressure sore density, incidence of restraint use, incidence of tube self-extraction, and infection density. RESULTS: A total of 92,442 data sets were collected from eight ICUs, with 61% of the direct ICU nursing hours categorized as TISS-28 and 39% categorized as non-TISS-28. Mean nursing hours totaled 12.5 hours. The direct nursing hours, the total nursing hours, the bed occupancy rate, the nursing hours calculated by patient classification system, and the nursing hours calculated by nurse-patient ratio were statistically, significantly correlated respectively with all of the care quality indices except for incidence of falls. The number of items of patient care in the patient classification records was greater than that of NHI-covered nursing payments. The NHI-covered nursing payment for every patient accounted for only 4.77% of the total medical expenses in the ICU. CONCLUSIONS/IMPLICATIONS FOR PRACTICE: Data from the patient classification database, quality monitoring database, and medical cost database indicate excessive nursing workload and underpayment from the Taiwan NHI program. Current nursing workload was significantly associated with care quality. This study provides empirical data for administrators to consider when revising nursing staffing and NHI payment policies. PMID- 29613880 TI - Evaluation of Posterosuperior Labral Tear With Shoulder Sonography After Intra articular Injection. PMID- 29613881 TI - In Vivo Evaluation of Subacromial and Internal Impingement Risk in Asymptomatic Individuals. AB - OBJECTIVE: The study aim was to evaluate subacromial and internal impingement risk between shoulders (dominant/nondominant) during dynamic motion using subject specific anatomy and precise in vivo kinematics. DESIGN: In a prospective cross sectional study, nine subjects underwent bilateral magnetic resonance (N = 18 shoulders) and fluoroscopic imaging during elevation and external rotation at 90 degrees of abduction. Subject-specific bone models were created and distances from footprint to (a) acromion and (b) glenoid were measured to evaluate risk. RESULTS: Throughout elevation, subacromial impingement risk was greater in the dominant shoulder (P = 0.0178). Regardless of side, high subacromial impingement risk occurred at 30% (78 degrees), 50% (101 degrees), and 70% (57 degrees) of the elevation cycle (P < 0.0001). High subacromial impingement risk also occurred at 30% (94 degrees), 50% (120 degrees), and 70% (63 degrees) of the external rotation motion cycle (P < 0.0001). Throughout both motions, internal impingement risk was not observed; however, the footprint and glenoid were closest at 50% of the elevation (101 degrees) and external rotation (120 degrees) cycles (P < 0.0001). CONCLUSIONS: During elevation, subacromial impingement risk is greatest at lower arm positions (30% cycle, 78 degrees) and is greater in the dominant shoulder. High subacromial impingement risk also occurs with external rotation (63-120 degrees). Internal impingement risk does not occur with maximal elevation (101 degrees) or external rotation at 90-degree abduction but is more closely approached with elevation. PMID- 29613882 TI - Response to the Letter to the Editor on the Article "Evaluation of Posterosuperior Labral Tear With Shoulder Sonography After Intra-articular Injection". PMID- 29613883 TI - Long-Term Course of Shoulders After Ultrasound Therapy for Calcific Tendinitis: Results of the 10-Year Follow-Up of a Randomized Controlled Trial. AB - OBJECTIVE: The aim of the study was to follow both the structure- and function related long-term course of shoulders that had been treated with therapeutic ultrasound for symptomatic calcific tendinitis. DESIGN: This is a long-term follow-up of 45 shoulders (37 patients) that had been treated for symptomatic calcific tendinitis with either a series of ultrasound or sham ultrasound 10 yrs ago. The main outcome variables were presence of calcium deposits and subacromial impingement on standardized x-ray imaging, shoulder symptoms (Binder score), and function (Constant score). RESULTS: At 10 yrs, a similar proportion of calcium deposits had resolved in 78% of the originally ultrasound treated compared with 83% of sham-treated shoulders, whereas at 9 mos, significantly more calcium deposits had been resolved in the ultrasound group (P = 0.045). Relative to baseline, shoulder symptoms and function had significantly improved at both the 10-yr and 9-mo follow-up examinations with no significant differences between groups. Regular sports performance at baseline predicted a favorable long-term outcome. CONCLUSIONS: Symptomatic calcific tendinitis of the shoulder has a good likelihood to completely resolve in the long term. Treating the calcium deposit effectively, however, may not be causal to the recovery from symptoms and function in calcific tendinitis. PMID- 29613884 TI - Hamstring Co-Contraction in the Early Stage of Rehabilitation After Anterior Cruciate Ligament Reconstruction: A Longitudinal Study. AB - OBJECTIVE: Hamstring co-contraction may affect recovery from anterior cruciate ligament reconstruction. The aim of the study was to evaluate the changes in hamstring co-contraction during the early postoperative stages. DESIGN: Twenty five patients with anterior cruciate ligament reconstruction were followed up for 1-3 mos postoperatively, during which the Lysholm and International Knee Documentation Committee questionnaires were completed and surface electromyograms were assessed during terminal knee extension maximum voluntary contraction and step-up tests. The integrated electromyogram of the tested muscles and co contraction ratio were analyzed. RESULTS: Co-contraction ratio during terminal knee extension maximum voluntary contraction at 3 mos postoperatively was significantly less than that at 1 mo postoperatively (P < 0.0083), and it did not significantly differ from that of the uninvolved knee. In contrast, the co contraction ratio during step-up was significantly higher at 2 and 3 mos postoperatively than that before surgery (P < 0.0167) and for the uninvolved knee (P < 0.05). Moreover, the postoperative hamstring co-contraction ratio in patients with a chronic injury was significantly higher during the step-up test than in patients with an early injury (P = 0.017). CONCLUSIONS: Hamstring co contraction ratio during terminal knee extension maximum voluntary contraction recovers during the early postoperative stages. However, hamstring co-contraction ratio during step-up, which may be related to knee joint proprioception, remains high, particularly for patients with a chronic injury. CLINICAL TRIAL: ChiCTR-COC 17011167. PMID- 29613885 TI - Hormone therapy in menopausal women with fibroids: is it safe? AB - Menopause is an important transition in the life of women. It has been estimated that by the year 2030, worldwide 1.2 billion women will be menopausal. The most bothersome symptoms of menopause are believed to be due to declines in estrogen levels in postmenopausal women. Thus, hormone therapy is an effective treatment option for menopausal women, although prolonged use of hormone therapy is associated with a slightly increased risk of breast cancer, thromboembolism, and stroke. A literature search for studies evaluating the effects of hormone therapy in menopausal women with asymptomatic fibroids demonstrated variable effects of hormone therapy on the volume and size of the fibroids. Some studies have demonstrated an increase in size of pre-existing asymptomatic fibroids and formation of new fibroids with higher doses of progestogen in combination therapy. The finding of low resistance index in uterine arteries of women with asymptomatic fibroids is associated with an increased risk of fibroid growth, and thus making the measurement of pulsatility index of uterine arteries a possible screening tool before initiating hormone therapy in menopausal women with fibroids. Although the effect of hormone treatment is variable and statistically insignificant in many cases, the newer selective estrogen receptor modulators having tissue-specific estrogen agonistic and antagonistic actions such as raloxifene have a favorable clinical profile and may be better alternatives in women with asymptomatic fibroids. PMID- 29613886 TI - Male Surgical Neck Rejuvenation: Retraction. PMID- 29613887 TI - Clinical Outcomes and Reduced Pulmonary Artery Pressure With Intra-Aortic Balloon Pump During Central Extracorporeal Life Support. AB - Patients supported with extracorporeal life support (ECLS) can experience severe complications from increased left ventricular afterload. The intra-aortic balloon pump (IABP) is thought to unload the left ventricle (LV) and is routinely used with ECLS despite conflicting evidence of its clinical benefit. This retrospective, single-center study examined the effect of the simultaneous use of IABP and centrally cannulated ECLS on patient outcomes and provides new insights into IABP-mediated LV unloading. Thirty patients supported with central ECLS and IABP (ECLS-I) were compared with 30 patients with central ECLS alone (ECLS) for cardiogenic shock. Rates of survival to 30 days (p = 0.06) and intensive care unit (ICU) discharge (p = 0.17), and clinical outcomes were not significantly different between the two groups. In patients with pulmonary artery pressure monitoring, mean PA pressure was significantly reduced after 24 (p = 0.007) and 48 hours (p = 0.002) in the ECLS-I group. No significant difference in PA pressure was observed in the ECLS group after 24 or 48 hours. The IABP has the ability to reduce pulmonary artery pressure in patients supported by central ECLS. However, this did not translate into improved survival or clinical outcomes in our population. PMID- 29613888 TI - The Effect of Inflow Cannula Angle on the Intraventricular Flow Field of the Left Ventricular Assist Device-Assisted Heart: An In Vitro Flow Visualization Study. AB - Previous studies have identified left ventricular assist device (LVAD) inflow cannula (IC) malposition as a significant risk for pump thrombosis. Thrombus development is a consequence of altered flow dynamics, which can produce areas of flow stasis or high shear that promote coagulation. The goal of this study was to measure the effect of IC orientation on the left ventricle (LV) flow field using a mock circulatory loop, and identify flow-based indices that are sensitive measures of cannula malposition. Experimental studies were with a customized silicone model of the dilated LV and the EVAHEART LVAS. The velocity field of the LV midplane was measured for a transparent IC oriented parallel to and rotated 15 degrees toward the septum under matched hemodynamic conditions. Vortex structures were analyzed and localized stasis calculated within the IC and combined with a map of normalized pulsatile velocity. The velocity fields revealed increased apical stasis and lower pulsatility with a small angulation of the IC. A significant change in vortex dynamics with the angled IC was observed, doubling the size of the counterclockwise (CCW) vortex while reducing the kinetic energy provided by LVAD support. A significant decrease in average and systolic velocities within the IC was found with cannula angulation, suggesting an increased resistance that affects primarily systolic flow and is worsened with increased LVAD support. These common echocardiographic indices offer the opportunity for immediate clinical application during ramp study assessment. Optimized IC positioning may be determined preoperatively using imaging techniques to develop patient-specific surgical recommendations. PMID- 29613889 TI - Extracorporeal Membrane Oxygenation in a Pediatric Patient with Hepatopulmonary Syndrome and Interrupted Inferior Vena Cava After Living Related Liver Donation. AB - Extracorporeal membrane oxygenation (ECMO) is used for cardiopulmonary dysfunction. Hepatopulmonary syndrome (HPS) occurs in the setting of liver failure and may cause hypoxemia. Previous reports have described the use of ECMO for HPS after liver transplant. Our patient is a 19-month-old female with biliary atresia, an interrupted inferior vena cava, and HPS on 8 liters per minute of high-flow oxygen. Following liver transplantation, her postoperative course was complicated by severe hypoxemia requiring ECMO. Due to her interrupted inferior vena cava, our standard bi-caval cannula could not be used. Hence, a 16-French double lumen venovenous right internal jugular to right atrial cannula was used to provide extracorporeal life support. She was decannulated after 17 days, remained intubated for 2 days, and weaned to room air over the next 3 weeks. This is the third pediatric liver transplant patient supported with ECMO identified in the literature, and the youngest and smallest of those reported. This approach to cannulation is unique because of the use of a double lumen venovenous cannula for HPS in a child, selected due to complex anatomy. Posttransplant ECMO may provide pediatric patients with HPS and posttransplant hypoxemia a period of support for their pulmonary remodeling and recovery from HPS. PMID- 29613891 TI - An Issue to Decompress With. PMID- 29613892 TI - Approach to Myelopathy. AB - PURPOSE OF REVIEW: Myelopathy is commonly encountered in clinical practice and is associated with a large number of causes. This article reviews the anatomy of the spinal cord and discusses how the clinical findings, time course, and radiographic patterns can help to identify the causes of myelopathy. RECENT FINDINGS: Imaging observations such as MRI "pancake" gadolinium enhancement pattern with spondylotic myelopathy and subpial enhancement with neurosarcoidosis have improved diagnostic specificity. On the other hand, common diseases such as degenerative spine disease are now recognized as presenting much more variably. Improved imaging and the identification of genetic markers enhance the specificity of diagnosis. The improved identification of biomarkers has shown that the same cause, such as compressive myelopathy, can present more variably than previously appreciated. SUMMARY: Spinal cord dysfunction, or myelopathy, remains a clinical diagnosis, and determining the cause requires integration of clinical, laboratory, and imaging parameters, none of which have great specificity individually. Most cases of myelopathy will require further neuroimaging, and some require CSF analysis for diagnosis. This article presents an approach to the diagnosis of myelopathy based on excluding compressive myelopathy initially and then differentiating between acute and subacute processes and chronic causes. PMID- 29613893 TI - Vascular Disorders of the Spinal Cord. AB - PURPOSE OF REVIEW: Prompt recognition and timely management of vascular disorders of the spinal cord can improve patient outcomes. This article provides contemporary and practical knowledge about the most common vascular myelopathies. RECENT FINDINGS: New studies have provided additional information on the risk factors and impact of neurologic monitoring on perioperative spinal cord infarction. Additionally, recent publications have provided information on the impact of misdiagnosis, corticosteroid treatment, and postoperative prognosis in the treatment of spinal dural arteriovenous fistulas and have discussed the outcome of patients with spinal arteriovenous malformations treated with embolization, surgery, and stereotactic radiosurgery. Finally, recent studies have provided information on the natural history and postoperative prognosis of spinal cavernous malformations and on the risk factors and surgical outcome of patients with spinal epidural hematomas. SUMMARY: Diagnostic and therapeutic challenges are inherent in managing patients with vascular disorders of the spinal cord, and clinicians should have a thorough understanding of these disorders to facilitate optimal outcomes for patients with these potentially devastating illnesses. This article begins by reviewing functional vascular anatomy and subsequently describes the fundamental characteristics of both ischemic and hemorrhagic vascular myelopathies to equip clinicians with the knowledge to avoid common pitfalls. PMID- 29613894 TI - Metabolic and Toxic Myelopathies. AB - PURPOSE OF REVIEW: Myelopathy may occur as a consequence of various metabolic and toxic conditions. This article provides an update on the clinical presentations, diagnostic evaluations, and management of metabolic and toxic myelopathies. RECENT FINDINGS: Myelopathy and myeloneuropathy due to vitamin B12 deficiency is increasing in prevalence partly because of an aging population. Early recognition of the clinical symptoms and rapid initiation of treatment is essential. Copper deficiency is now also recognized as causing a similar clinical picture as vitamin B12 deficiency. Conditions leading to copper deficiency include bariatric surgery and excessive zinc intake. Unusual conditions such as lathyrism and konzo are relevant to all neurologists because of emigration from less well-developed countries. Myelopathy can also occur from substance abuse (eg, heroin and nitrous oxide), and early diagnosis could lead to improved patient outcomes. The spinal cord may also be injured in decompression illness that occurs in sport divers and individuals who work in pressurized atmospheres. SUMMARY: Knowledge and recognition of the various metabolic and toxic causes of myelopathy is important for the practicing neurologist, as timely diagnosis and rapid initiation of therapy is essential to improve the chances for recovery. PMID- 29613895 TI - Infectious Myelopathies. AB - PURPOSE OF REVIEW: This article reviews bacterial, viral, fungal, and parasitic pathogens associated with myelopathy. Infectious myelopathies may be due to direct infection or parainfectious autoimmune-mediated mechanisms; this article focuses primarily on the former. RECENT FINDINGS: Some microorganisms exhibit neurotropism for the spinal cord (eg, enteroviruses such as poliovirus and flaviviruses such as West Nile virus), while others are more protean in neurologic manifestations (eg, herpesviruses such as varicella-zoster virus), and others are only rarely reported to cause myelopathy (eg, certain fungal and parasitic infections). Individuals who are immunocompromised are at increased risk of disseminated infection to the central nervous system. Within the last few years, an enterovirus D68 outbreak has been associated with cases of acute flaccid paralysis in children, and emerging Zika virus infection has been concurrent with cases of acute flaccid paralysis due to Guillain-Barre syndrome, although cases of myelitis have also been reported. Associated pathogens differ by geographic distribution, with myelopathies related to Borrelia burgdorferi (Lyme disease) and West Nile virus more commonly seen in the United States and parasitic infections encountered more often in Latin America, Southeast Asia, and Africa. Characteristic CSF and MRI patterns have been identified with many of these infections. SUMMARY: A myriad of pathogens are associated with infectious myelopathies. Host factors, geographic distribution, clinical features, CSF profiles, and MRI findings can assist in formulating the differential diagnosis and ultimately guide management. PMID- 29613896 TI - Neoplastic Myelopathies. AB - PURPOSE OF REVIEW: This article discusses the diagnosis and management of neoplasms that affect the spinal cord as well as spinal cord disorders that can occur due to cancer treatments. RECENT FINDINGS: Neoplastic myelopathies are uncommon neurologic disorders but cause significant morbidity when they occur. Primary spinal cord tumors can be classified into intramedullary, intradural extramedullary, or extradural tumors. Diffuse gliomas and ependymal tumors are the most common intramedullary tumors. Diffuse gliomas include the World Health Organization (WHO) grade II and grade III astrocytomas, the grade II and grade III oligodendrogliomas, the grade IV glioblastomas, and newly recognized pediatric diffuse midline gliomas with H3 K27M mutation. The majority of diffuse and anaplastic astrocytomas are IDH-mutant tumors, whereas only 10% of glioblastomas are IDH-mutant. Oligodendrogliomas are typically IDH-mutant and are characterized by the molecular signature of 1p/19q codeletion. Nine distinct molecular subgroups of ependymomas have been identified based on their genetic features and location. NF2 mutations are frequently found in spinal cord ependymomas. Metastatic tumors are the most common tumors of the spine and can be extradural, leptomeningeal, or, rarely, intramedullary. Extradural metastatic spinal cord compression is a neurologic emergency and should be promptly diagnosed as pretreatment neurologic status dictates the posttreatment outcome. SUMMARY: Neoplastic myelopathies encompass many diagnoses ranging from benign and malignant spinal tumors to paraneoplastic syndromes heralding cancers. The knowledge of the clinical features and management of neoplastic myelopathies is essential to practicing neurologists as early diagnosis and treatment can prevent devastating neurologic sequelae. PMID- 29613897 TI - Immune-Mediated Myelopathies. AB - PURPOSE OF REVIEW: This article reviews the clinical presentation, diagnostic evaluation, and management of immune-mediated myelopathies. RECENT FINDINGS: The discovery of several neural autoantibodies and their antigenic targets has revolutionized the investigation and treatment of immune-mediated myelopathies. Detection of these serologic biomarkers can support or establish a diagnosis of an autoimmune myelopathy, and, in the case of paraneoplastic syndromes, indicate the likely presence of an underlying malignancy. Distinctive lesion patterns detected on spinal cord or brain MRI narrow the differential diagnosis in patients with acute or subacute inflammatory myelopathies, including those not associated with autoantibody markers. SUMMARY: Immune-mediated myelopathies usually present acutely or subacutely and have a broad differential diagnosis. A systematic diagnostic approach using data from the clinical setting and presentation, MRI lesion patterns, CSF data, and autoantibody markers can differentiate these disorders from noninflammatory myelopathies, often with precise disease classification. This, in turn, provides prognostic information, especially whether the disorder is likely to relapse, and facilitates therapeutic decision making. Diagnostic accuracy informs selection of acute immunotherapy aimed at arresting and reversing recent neurologic injury and, when necessary, selection of long-term treatment for prevention of disease progression or relapse. PMID- 29613898 TI - Hereditary Myelopathies. AB - PURPOSE OF REVIEW: Hereditary myelopathies are very diverse genetic disorders, and many of them represent a widespread neurodegenerative process rather than isolated spinal cord dysfunction. This article reviews various types of inherited myelopathies, with emphasis on hereditary spastic paraplegias and spastic ataxias. RECENT FINDINGS: The ever-growing number of myelopathy-causing genes and broadening of phenotype-genotype correlations makes the molecular diagnosis of inherited myelopathies a daunting task. This article emphasizes the main phenotypic clusters among inherited myelopathies that can facilitate the diagnostic process. This article focuses on newly identified genetic causes and the most important identifying clinical features that can aid the diagnosis, including the presence of a characteristic age of onset and additional neurologic signs such as leukodystrophy, thin corpus callosum, or amyotrophy. SUMMARY: The exclusion of potentially treatable causes of myelopathy remains the most important diagnostic step. Syndromic diagnosis can be supported by molecular diagnosis, but the genetic diagnosis at present does not change the management. Moreover, a negative genetic test does not exclude the diagnosis of a hereditary myelopathy because comprehensive molecular testing is not yet available, and many disease-causing genes remain unknown. PMID- 29613899 TI - Traumatic Spinal Cord Injury. AB - PURPOSE OF REVIEW: This article provides an update on the acute and subacute management and prognostication of patients with traumatic spinal cord injury. RECENT FINDINGS: Immobilization of the spine and spine clearance should be individualized depending on the ability to perform a reliable neurologic examination, the presence of neck pain, and the imaging findings. Early surgery (within 24 hours) to achieve definitive cord decompression and spine stabilization may be beneficial. Ensuring adequate oxygenation and perfusion and avoiding secondary systemic complications remain the goals of the critical care of these patients. No neuroprotective treatment has been shown to improve outcomes. In fact, the use of high-dose methylprednisolone is now generally discouraged because of its major systemic adverse effects. Survivors of severe cervical traumatic spinal cord injury typically sustain substantial long-term functional impairment. Advances in our understanding of neuroregenerative strategies, especially stem cell transplantation, can offer the future hope of functional improvement to the many patients currently living with the consequences of traumatic spinal cord injury. Yet, at present, these therapies remain strictly investigational. SUMMARY: The treatment of traumatic spinal cord injury remains supportive, and prognosis is still poor for patients who are severely affected. While much remains to be learned about how to optimize the acute management of these patients, future efforts would be most useful if focused on injury prevention and the development of effective neuroregenerative therapies. PMID- 29613900 TI - Myelopathies Due to Structural Cervical and Thoracic Disease. AB - PURPOSE OF REVIEW: The article discusses the current diagnostic and therapeutic approach to myelopathies occurring as a consequence of structural cervical and thoracic spine disease. RECENT FINDINGS: The exact pathophysiologic basis of cervical spondylotic myelopathy remains somewhat elusive. Diffusion-tensor imaging has emerged as a useful imaging modality that correlates more closely with clinical severity than standard MRI. Baseline disease severity, symptom duration, age, presence of impaired gait, and smoking status are significant factors related to surgical outcomes. SUMMARY: Advances in neuroimaging and the development of evidence-based algorithmic approaches to surgical intervention will likely further improve the outcomes of patients with spinal cord dysfunction from structural cervical and thoracic disease. PMID- 29613901 TI - Disorders of the Cauda Equina. AB - PURPOSE OF REVIEW: Conditions that affect the cauda equina are a diverse group of disorders that require timely recognition and management. This article reviews cauda equina anatomy, the diagnostic approach to disorders of the cauda equina, features of cauda equina syndrome, and diskogenic and nondiskogenic disorders of the cauda equina. RECENT FINDINGS: Establishing clinical criteria for cauda equina syndrome has been a focus of a number of reviews, although the clinician must maintain a low threshold for emergent imaging in cases of suspected cauda equina syndrome because of the suboptimal reliability of various signs and symptoms in identifying this condition clinically. The timing of surgical intervention for compressive causes of cauda equina dysfunction remains a point of contention, although urgent decompression remains standard practice. A recent review that focused on outcomes in patients with cauda equina compression who underwent surgical decompression identified significant residual deficits in patients despite appropriate and timely intervention. Autoimmune conditions targeting the cauda equina have been increasingly recognized, including chronic immune sensory polyradiculopathy and chronic immune sensorimotor polyradiculopathy. SUMMARY: Disorders that affect the cauda equina require thoughtful and timely clinical examination and diagnostic testing to establish a definitive cause and an appropriate treatment approach. PMID- 29613902 TI - Liability for Referrals to Other Physicians. AB - This article presents four hypothetical cases that demonstrate ways in which neurologists may be vulnerable to liability for how they manage patients they refer to other physicians for consultations. This article also discusses the importance of protecting neurologists from claims of negligence through documentation, which includes the rationale for ordering a consultation, deferring a consultation, or disagreeing with a consultant's recommendations. Lastly, the article discusses the importance of including patients in the decision-making process and detailing these conversations in the medical record. PMID- 29613906 TI - Learning Objectives and Core Competencies. PMID- 29613907 TI - Appendix. PMID- 29613909 TI - New alpha blockers to treat male lower urinary tract symptoms. AB - PURPOSE OF REVIEW: To date it is unclear whether the selectivity of new alpha blockers to alpha-adrenergic receptor subtypes translates into more clinical benefits and less adverse effects in clinical practice. We performed a systematic review of the two new Abs silodosin and naftopidil. With the availability of numerous alpha-blockers to treat lower urinary tract symptoms secondary to benign prostatic hyperplasia, the findings of this review will be highly relevant to the field of urology. RECENT FINDINGS: Silodosin was found to be more effective than placebo in improving International Prostate Symptom Score (IPSS) and quality of life scores and as effective as other alpha-blockers. Although the incidence of cardiovascular adverse events of silodosin was similar compared with placebo and other alpha-blockers (tamsulosin, naftopidil, alfuzosin), the sexual adverse events were more common with silodosin. No placebo-controlled randomized trial exists investigating the effects of naftopidil in men with lower urinary tract symptoms secondary to benign prostatic hyperplasia. Naftopidil had similar efficacy with regards to IPSS and quality of life compared with tamsulosin. The rate of adverse events was similar compared with tamsulosin. SUMMARY: The two new selective alpha-blockers, silodosin, and naftopidil showed similar efficacy in IPSS and quality of life compared with other alpha-blockers. However, silodosin has more sexual adverse events. PMID- 29613910 TI - Modality-specific effects of aversive expectancy in the anterior insula and medial prefrontal cortex. AB - Expectations modulate the subjective experience of pain by increasing sensitivity to nociceptive inputs, an effect mediated by brain regions such as the insula. However, it is still unknown whether the neural structures underlying pain expectancy hold sensory-specific information or, alternatively, code for modality independent features (eg, unpleasantness), potentially common with other negative experiences. We used functional magnetic resonance imaging to investigate neural activity underlying the expectation of different, but comparably unpleasant, pain and disgust. We presented participants with visual cues predicting either a painful heat or disgusting odor, and assessed how they affected the subsequent subjective experience of stimuli from the same (within-modality) or opposite (cross-modal) modality. We found a reliable influence of expectancy on the subjective experience of stimuli whose modality matched that of the previous cue. At the brain level, this effect was mediated by the intermediate dysgranular section of the insula, whereas it was suppressed by more anterior agranular portions of the same region. Instead, no expectancy modulation was observed when the modality of the cue differed from that of the subsequent stimulus. Our data suggest that the insular cortex encodes prospective aversive events in terms of their modality-specific features, and whether they match with subsequent stimulations. PMID- 29613912 TI - A small perceptive study on central poststroke pain. PMID- 29613914 TI - Advances in Hepatology: 2018. PMID- 29613915 TI - The black box of the GI tract? PMID- 29613911 TI - Cognitive impairment in a rat model of neuropathic pain: role of hippocampal microtubule stability. AB - Clinical evidence indicates that cognitive impairment is a common comorbid condition of chronic pain. However, the cellular basis for chronic pain-mediated cognitive impairment remains unclear. We report here that rats exhibited memory deficits after spared nerve injury (SNI). We found that levels of stable microtubule (MT) were increased in the hippocampus of the rats with memory deficits. This increase in stable MT is marked by alpha-tubulin hyperacetylation. Paclitaxel, a pharmacological MT stabilizer, increased the level of stable MT in the hippocampus and induced learning and memory deficits in normal rats. Furthermore, paclitaxel reduced long-term potentiation in hippocampal slices and increased stable MT (evidenced by alpha-tubulin hyperacetylation) levels in hippocampal neuronal cells. Intracerebroventricular infusion of nocodazole, an MT destabilizer, ameliorated memory deficits in rats with SNI-induced nociceptive behavior. Expression of HDAC6, an alpha-tubulin deacetylase, was reduced in the hippocampus in rats with cognitive impairment. These findings indicate that peripheral nerve injury (eg, SNI) affects the MT dynamic equilibrium, which is critical to neuronal structure and synaptic plasticity. PMID- 29613917 TI - Does Dolichoectasia of the Carotid Artery Cause Optic Neuropathy? PMID- 29613916 TI - Seronegative coeliac disease: clearing the diagnostic dilemma. AB - PURPOSE OF REVIEW: Seronegative coeliac disease is a poorly defined form of coeliac disease that poses an important challenge to clinicians particularly with regards to the differential diagnosis. This is probably because of lack of a consensus on its definition and incorrect use of specific coeliac serology. Seronegative coeliac disease (SCD) is uncommon and epidemiological data are scarce and contrasting. Therefore, the aim of this review is to provide a critical summary of the most recent work on this topic and a definition of SCD. RECENT FINDINGS: SCD is rare among coeliac patients but conversely SCD remains one of the most common causes of seronegative villous atrophy. The diagnostic workup of seronegative villous atrophy (SNVA) must ensure exclusion of other enteropathies before starting patients on a lifelong gluten-free diet. This is crucial in order to ensure that patients are not given the wrong diagnosis, which in turn can have implications for their inappropriate treatment and long-term morbidity. Finally, there is some data to suggest that seronegative enteropathies have a higher mortality than conventional coeliac disease. SUMMARY: Seronegative coeliac disease is a rare condition that accounts for a very small percentage of cases in the large population of coeliac patients. Strict criteria for the diagnosis of this condition need to be fulfilled and prompt identification of these patients is crucial in order to ensure the appropriate intervention on a case-by-case basis. PMID- 29613918 TI - The 100 Most Cited Articles on Healthcare Simulation: A Bibliometric Review. AB - STATEMENT: This article provides an overview and synthesis of the 100 most cited healthcare simulation publications to provide insight into the articles that have shaped current knowledge and practice. Searches of the Scopus and Web of Science databases were conducted in July 2017. Most articles were concerned with medical education and training (86%) and were most often published in surgical journals (33%). Manikins (20%), standardized patients (16%), inanimate part-task trainers (16%), fully simulated environments (17%), and virtual reality part-task trainers (14%) were the most commonly featured types of simulators. Healthcare simulation research has matured and grown during the preceding decades. There has been a move away from research questions focused on "does simulation work?" to an assessment of the conditions under which simulation is most effective. It is hoped that providing an overview of highly cited works will help identify topics for further research. PMID- 29613919 TI - Addressing Dual Patient and Staff Safety Through A Team-Based Standardized Patient Simulation for Agitation Management in the Emergency Department. AB - INTRODUCTION: Emergency departments (EDs) have seen harm rise for both patients and health workers from an increasing rate of agitation events. Team effectiveness during care of this population is particularly challenging because fear of physical harm leads to competing interests. Simulation is frequently employed to improve teamwork in medical resuscitations but has not yet been reported to address team-based behavioral emergency care. As part of a larger investigation of agitated patient care, we designed this secondary study to examine the impact of an interprofessional standardized patient simulation for ED agitation management. METHODS: We used a mixed-methods approach with emergency medicine resident and attending physicians, Physician Assistants (PAs) and Advanced Practice Registered Nurses (APRNs), ED nurses, technicians, and security officers at two hospital sites. After a simulated agitated patient encounter, we conducted uniprofessional and interprofessional focus groups. We undertook structured thematic analysis using a grounded theory approach. Quantitative data consisted of responses to the KidSIM Questionnaire addressing teamwork and simulation-based learning attitudes before and after each session. RESULTS: We reached data saturation with 57 participants. KidSIM scores revealed significant improvements in attitudes toward relevance of simulation, opportunities for interprofessional education, and situation awareness, as well as four of six questions for roles/responsibilities. Two broad themes emerged from the focus groups: (1) a team-based agitated patient simulation addressed dual safety of staff and patients simultaneously and (2) the experience fostered interprofessional discovery and cooperation in agitation management. CONCLUSIONS: A team-based simulated agitated patient encounter highlighted the need to consider the dual safety of staff and patients while facilitating interprofessional dialog and learning. Our findings suggest that simulation may be effective to enhance teamwork in behavioral emergency care. PMID- 29613920 TI - Correspondence. PMID- 29613921 TI - Markers of Environmental Enteric Dysfunction Are Associated With Neurodevelopmental Outcomes in Tanzanian Children. AB - BACKGROUND: Chronic exposure to enteropathogens may result in environmental enteric dysfunction (EED), a subclinical condition associated with poor child growth. Growth faltering is strongly associated with poor neurodevelopment, and occurs during sensitive periods of postnatal brain development. We investigated the role of novel EED biomarkers, systemic inflammation, and micronutrient status on neurodevelopment in Tanzanian children. METHODS: Non-stunted subjects with 6 week and 6-month blood samples and neurodevelopmental measures (n = 107) were included in this study. Samples were tested for biomarkers of gastrointestinal function (citrulline, antibodies to lipopolysaccharide, and flagellin), micronutrient status (iron, retinol binding protein [RBP], and vitamin D), systemic inflammation (C-reactive protein [CRP] and alpha-1-acid glycoprotein), and growth (insulin-like growth factor and insulin-like growth factor binding protein 3). RESULTS: Cognitive scores at 15 months were associated with higher concentrations of 6-month anti-lipopolysaccharide IgG (beta = 1.95, P = 0.02), anti-flagellin IgA (beta = 2.41, P = 0.04), and IgG (beta = 2.99, P = 0.009). Higher receptive language scores were positively associated with anti-flagellin IgG (beta = 0.95, P = 0.05), and receptive language and gross motor scores were positively associated with citrulline at 6 months (beta = 0.09, P = 0.02; beta = 0.10, P = 0.03, respectively). Gross motor scores were positively associated with RBP at 6 months (beta = 1.70, P = 0.03). Markers of systemic inflammation were not significantly associated with neurodevelopment. CONCLUSIONS: Plasma citrulline, a marker of gastrointestinal mucosal surface area, and vitamin A status were associated with higher gross motor development scores. Novel markers for EED, but not inflammation, were positively associated with cognitive scores, suggesting a possible mechanistic pathway involving immune response and neuroprotection. PMID- 29613923 TI - Nonoperative Management of Spinal Epidural Abscess: Development of a Predictive Algorithm for Failure. AB - BACKGROUND: Prompt diagnosis and treatment are critical in spinal epidural abscess, as delay can lead to paralysis or death. The initial management decision for spinal epidural abscess is not always clear, with the literature showing conflicting results. When considering nonoperative management, it is crucial to avoid failure of treatment, given the neurologic compromise incurred through failure. Unfortunately, data regarding risk factors associated with failure are scarce. METHODS: All patients admitted to our hospital system with a diagnosis of spinal epidural abscess from 1993 to 2016 were identified. Patients who were >=18 years of age and were initially managed nonoperatively were included. Explanatory variables and outcomes were collected retrospectively. Bivariate and multivariable analyses were performed on these variables to identify independent predictors of failure of nonoperative treatment. A nomogram was constructed to generate a risk of failure based on these predictors. RESULTS: We identified 367 patients who initially underwent nonoperative management. Of these, 99 patients underwent medical management that failed. Multivariable logistic regression yielded 6 independent predictors of failure: a presenting motor deficit, pathologic or compression fracture in affected levels, active malignancy, diabetes mellitus, sensory changes, and dorsal location of abscess. We constructed a nomogram that generates a probability of failure based on the presence of these factors. CONCLUSIONS: By quantifying the risk of failure on the basis of the presence of 6 independent predictors of treatment failure, our nomogram may provide a useful tool for the treatment team when weighing the risks and benefits of initial nonoperative treatment compared with operative management. LEVEL OF EVIDENCE: Prognostic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29613922 TI - Risk Reduction Compared with Access to Care: Quantifying the Trade-Off of Enforcing a Body Mass Index Eligibility Criterion for Joint Replacement. AB - BACKGROUND: Morbidly obese patients with severe osteoarthritis benefit from successful total joint arthroplasty. However, morbid obesity increases the risk of complications. Because of this, some surgeons enforce a body mass index (BMI) eligibility criterion above which total joint arthroplasty is denied. In this study, we investigate the trade-off between avoiding complications and restricting access to care when enforcing BMI-based eligibility criteria for total joint arthroplasty. METHODS: In this retrospective cohort study, the Veterans Health Administration (VHA) Corporate Data Warehouse (CDW) and Veterans Affairs Surgical Quality Improvement Program (VASQIP) databases were reviewed for patients undergoing total joint arthroplasty from October 2011 through September 2014. We determined, if various BMI eligibility criteria had been enforced over that period of time, how many short-term complications would have been avoided, how many complication-free surgical procedures would have been denied, and the positive predictive value of BMI eligibility criteria as tests for major complications. To provide a frame of reference, we also determined what would have happened if eligibility for total joint arthroplasty were arbitrarily determined by flipping a coin. RESULTS: In this study, 27,671 total joint arthroplasties were reviewed. With a BMI criterion of >=40 kg/m, 1,148 patients would have been denied a surgical procedure free of major complications, and 83 patients would have avoided a major complication. The positive predictive value of a complication using a BMI of >=40 kg/m as a test for major complications was 6.74% (95% confidence interval [CI], 5.44% to 8.33%). The positive predictive value of a complication using a BMI criterion of 30 kg/m was 5.33% (95% CI, 4.99% to 5.71%). Flipping a coin had a positive predictive value of 5.05%. CONCLUSIONS: A 30 kg/m criterion for total joint arthroplasty eligibility is marginally better than flipping a coin and should not determine surgical eligibility. With a BMI criterion of >=40 kg/m, the number of patients denied a complication-free surgical procedure is about 14 times larger than those spared a complication. Although the acceptable balance between avoiding complications and providing access to care can be debated, such a quantitative assessment helps to inform decisions regarding the advisability of enforcing a BMI criterion for total joint arthroplasty. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 29613924 TI - Assessing the Risk-Benefit Ratio of Scoliosis Surgery in Cerebral Palsy: Surgery Is Worth It. AB - BACKGROUND: The true benefits of scoliosis surgery in cerebral palsy (CP) remain uncertain. Our aims were to determine the benefits of spinal fusion according to health-related quality of life (HRQoL) improvement at long-term follow-up and to explore the effect of surgery-related complications on clinical outcomes. METHODS: The cases of consecutive patients who had Gross Motor Function Classification System (GMFCS) level-IV or V cerebral palsy with 5-year follow-up from a prospective, longitudinal, multicenter database were analyzed. Caregivers completed the Caregiver Priorities and Child Health Index of Life with Disabilities (CPCHILD) questionnaire and 4 Likert-type anchor questions preoperatively and at 1, 2, and 5 years of follow-up. Data on complications were collected prospectively. Preoperative CPCHILD scores were compared with postoperative scores at the 1, 2, and 5-year follow-up evaluations. Preoperative CPCHILD scores were compared with postoperative scores at the 1, 2, and 5-year follow-up evaluations using repeated-measures analysis of variance (ANOVA). Spearman correlation coefficient was used to explore the association between changes in the CPCHILD at 1, 2, and 5-year follow-up and the reported complications within the follow-up period. Similarly, a comparative analysis between the percentage distribution of the answers to the 4 anchor questions and the reported complications was also performed. RESULTS: Sixty-nine patients with a mean age (and standard deviation) of 13.4 +/- 2.6 years at enrollment were analyzed. The major Cobb angle was a mean of 81.9 degrees +/- 26.7 degrees preoperatively and improved to a mean of 28.7 degrees +/- 14.4 degrees at 2 years and 30.7 degrees +/- 15.3 degrees at 5 years postoperatively. Significant improvements in CPCHILD personal care, positioning, and comfort domains were noted at all time points. The mean increase in the total score was 7.19 (p < 0.001) at 1 year, and the score gain was maintained at 2 and 5 years postoperatively. The overall complication rate was 46.4% at 1 year, 1.4% between 1 and 2 years, and 4.3% at 2 to 5 years postoperatively, with surgical intervention required in 6 patients within 1 year and in 2 additional patients within 5 years following scoliosis surgery. There was no correlation between complications and CPCHILD scores postoperatively at all time points, with the only exception of a weak correlation (rho = -0.450, p = 0.002) with CPCHILD comfort score at 1 year after surgery. CONCLUSIONS: Scoliosis surgery in patients with CP leads to a significant improvement in HRQoL, which is maintained 5 years following surgery. The substantial complication rate does not correlate with HRQoL changes postoperatively, suggesting that the benefits of surgery outweigh the risks in this fragile population. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29613925 TI - Determination of Elbow Laxity in a Sequential Soft-Tissue Injury Model: A Cadaveric Study. AB - BACKGROUND: The objective of our study was to analyze, under fluoroscopy, joint angulation of uninjured elbows and elbows with distinct induced collateral ligament injury. METHODS: Twelve elbow specimens were tested for varus and valgus joint angulation using 4 different examination methods (application of both varus and valgus stress by each of 2 examiners [Examiner 1 and Examiner 2] and application of 1 and 2 Nm of torque using a calibrated electric force scale) in 4 elbow positions (in full extension with 90 degrees of supination and 90 degrees of pronation, and in 30 degrees of flexion with 90 degrees of supination and 90 degrees of pronation). Six elbow specimens were examined under varus stress at each of 5 sequential stages: (1) intact, (2) transection of the lateral ulnar collateral ligament (LUCL), (3) complete transection of the lateral collateral ligament complex (LCLC), (4) transection of the anterior aspect of the capsule (AC), and (5) transection of the medial collateral ligament (MCL). An additional 6 elbow specimens were examined under valgus stress at 5 sequential stages: (1) intact, (2) transection of the anteromedial collateral ligament (AML), (3) complete transection of the MCL, (4) transection of the AC, and (5) transection of the LCLC. Examinations under fluoroscopy were made to measure the joint angulation. Intraclass correlation coefficients (ICCs) were calculated. RESULTS: Testing of the intact elbow specimen by both examiners showed a joint angulation of <5 degrees . Transection of the LUCL led to a varus joint angulation of 4.3 degrees to 7.0 degrees , and transection of the AML resulted in a valgus joint angulation of 4.9 degrees to 8.8 degrees . Complete dissection of the respective collateral ligament complex resulted in a joint angulation of 7.9 degrees to 13.4 degrees (LCLC) and 9.1 degrees to 12.3 degrees (MCL), and additional transection of the AC led to a joint angulation of >20 degrees in some positions in both the medial and the lateral series. Under varus stress, elbow dislocations occurred only after dissection of the LCLC+AC (26% of the examinations) and additional dissection of the MCL (59%). Under valgus stress, elbow dislocations occurred only after dissection of the MCL+AC (30%) and additional dissection of the LCLC (47%). Very good to excellent ICCs were found among Examiners 1 and 2 and the tests done with the standardized torques at stages 1 through 4. CONCLUSIONS: Dynamic fluoroscopy makes it possible to distinguish among different stages of collateral ligament injury of the elbow and therefore might be helpful for guiding treatment of simple elbow dislocations. CLINICAL RELEVANCE: Assessment of collateral ligament injury with varus and valgus stress testing under fluoroscopy is an easily available method and is often used as the imaging modality of choice to determine the degree of elbow laxity. The technique and results described in this study should form the basis for additional clinical studies. PMID- 29613926 TI - Motor-Evoked Potential Analysis of Femoral Nerve Status During the Direct Anterior Approach for Total Hip Arthroplasty. AB - BACKGROUND: During the direct anterior approach for total hip arthroplasty, a retractor is placed on the anterior wall of the acetabulum to retract the iliopsoas muscle. This step with the retractor has been reported to put the patient at risk for femoral nerve damage. The present study aimed to clarify the effects of the anterior acetabular retractor on the status of the femoral nerve during the direct anterior approach on the basis of transcranial motor-evoked potential (MEP) analysis. METHODS: Between July 2016 and February 2017, 22 patients underwent primary total hip arthroplasty via the direct anterior approach with MEP analysis. The integrity of the femoral nerve was tested at 3 time points: preoperatively, as a control (first period); just after retractor placement on the anterior wall of the acetabulum (second period); and after the procedure (third period). The association between operative time and femoral nerve status was examined. Postoperative femoral nerve damage was determined by the presence of causalgia and the results of a manual muscle test (MMT) for strength of knee extension. RESULTS: The mean amplitude of the femoral nerve was significantly reduced, from 100% in the first period to 54% (range, 5% to 100%) in the second period (p < 0.01), but then significantly improved to 77% (range, 20% to 100%) in the third period (p < 0.01). In 17 (77%) of the 22 patients, the amplitude of the femoral nerve in the second period was reduced, while only 5 patients (23%) showed no reduction. The mean operative time was 83 minutes (range, 63 to 104 minutes), and no significant correlation was observed between operative time and improvement of femoral nerve status between the second and third periods (p = 0.83 and r = -0.05). All 22 patients had a postoperative MMT grade of 5 for knee extension without causalgia of the femoral nerve. CONCLUSIONS: On the basis of the MEP analysis, 17 (77%) of the 22 patients showed a significant reduction of the femoral nerve amplitude despite careful placement of the retractor on the anterior wall of the acetabulum. Although this reduction appears reversible, placement of an anterior retractor should be performed with careful attention to the femoral nerve. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29613927 TI - Mortality Following Periprosthetic Proximal Femoral Fractures Versus Native Hip Fractures. AB - BACKGROUND: The number of periprosthetic proximal femoral fractures is expected to increase with the increasing prevalence of hip arthroplasties. While native hip fractures have a well-known association with mortality, there are currently limited data on this outcome among the subset of patients with periprosthetic proximal femoral fractures. METHODS: Using the New York Statewide Planning and Research Cooperative System, we identified patients from 60 to 99 years old who were admitted to a hospital in the state with a periprosthetic proximal femoral fracture (n = 1,655) or a native hip (femoral neck or intertrochanteric) fracture (n = 97,231) between 2006 and 2014. Within the periprosthetic fracture cohort, the indication for the existing implant was not available in the data set. We used mixed-effects regression models to compare mortality at 1 and 6 months and 1 year for periprosthetic compared with native hip fractures. RESULTS: The risk of mortality for patients who sustained a periprosthetic proximal femoral fracture was no different from that for patients who sustained a native hip fracture at 1 month after injury (3.2% versus 4.6%; odds ratio [OR], 0.90; 95% confidence interval [CI], 0.68 to 1.19; p = 0.446), but was lower at 6 months (3.8% versus 6.5%; OR, 0.74; 95% CI, 0.57 to 0.95; p = 0.020) and 1 year (9.7% versus 15.9%; OR, 0.71; 95% CI, 0.60 to 0.85; p < 0.001). Among periprosthetic proximal femoral fractures, factors associated with a significantly increased risk of mortality at 1 year included advanced age, male sex, and higher Deyo comorbidity scores. CONCLUSIONS: In the acute phase, any type of hip fracture appears to confer a similar risk of death. Over the long term, however, periprosthetic proximal femoral fractures are associated with lower mortality rates than native hip fractures, even after accounting for age and comorbidities. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence. PMID- 29613928 TI - The Effect of an ACL Reconstruction in Controlling Rotational Knee Stability in Knees with Intact and Physiologic Laxity of Secondary Restraints as Defined by Tibiofemoral Compartment Translations and Graft Forces. AB - BACKGROUND: The effect of an anterior cruciate ligament (ACL) reconstruction on restoring normal knee kinematics in unstable knees with physiologic laxity of secondary ligamentous restraints remains unknown. The purpose of this study was to determine the stabilizing function of an ACL reconstruction and the resulting ACL graft forces in knees with severely abnormal anterior subluxation due to associated laxity of secondary restraints. METHODS: A 6-degree-of-freedom robotic simulator was used to test 21 cadaveric knees studied as a whole and in subgroups of lax secondary restraints (Lax-SR) and intact secondary restraints (Intact-SR), based on abnormal translations and tibial rotations. Native, ACL-sectioned, and ACL-reconstructed conditions were tested. An instrumented bone-patellar tendon bone (BPTB) graft measured ACL graft forces. The loading profile involved the Lachman test (25 degrees of flexion and 100-N anterior load), anterior tibial loading (100-N anterior load across 10 degrees to 90 degrees of flexion), internal rotation (25 degrees of flexion and 5-Nm torque), and 2 pivot-shift simulations (100-N anterior load, 7-Nm valgus, and either 5 Nm of internal rotation [Pivot Shift 1] or 1 Nm of internal rotation [Pivot Shift 2]). Equivalence between conditions was defined as being within 2 mm for compartment translation and within 2 degrees for internal tibial rotation, with p < 0.05. RESULTS: ACL sectioning increased center translation in the Lachman test by a mean of 10.9 mm (95% confidence interval [CI], 9.3 to 12.5 mm; p = 0.99), which was equivalent to native values after ACL reconstruction in all knees (mean difference, 0.0 mm [95% CI, -0.4 to 0.4 mm]; p = 0.0013), and in subgroups of Lax SR (mean difference, 0.2 mm [95% CI, -0.5 to 0.8 mm]; p = 0.03) and Intact-SR (mean difference, -0.2 mm [95% CI, -0.8 to 0.4 mm]; p = 0.002). ACL sectioning in the pivot-shift (5-Nm) test increased lateral compartment translation to non native-equivalent levels, which were restored to native-equivalent values after ACL reconstruction in all knees (mean difference, 0.9 mm [95% CI, 0.4 to 1.4 mm]; p = 0.055), in the Intact-SR subgroup (mean difference, 1.1 mm [95% CI, 0.5 to 1.8 mm]; p = 0.03), and to nearly native-equivalence in the Lax-SR subgroup (mean difference, 0.6 mm [95% CI, -0.3 to 1.6 mm; p = 0.06). The highest ACL graft force reached a mean of 190.9 N in the pivot-shift (5-Nm) test. CONCLUSIONS: The ACL reconstruction restored native kinematics and native rotational stability in all knees, including knees having laxity of secondary ligamentous restraints and clinically equivalent Grade-3 pivot-shift subluxation, and did so at ACL graft forces that were not excessive. CLINICAL RELEVANCE: An ACL reconstruction with a BPTB graft restored normal stability parameters regardless of the integrity of secondary ligamentous restraints. PMID- 29613929 TI - Long-Term Outcomes of Glenohumeral Arthrodesis. AB - BACKGROUND: Glenohumeral arthrodesis is associated with a high rate of complications. Although patients experience reasonable pain relief and shoulder stability, they experience marked limitations in their upper-extremity function. The purpose of this study was to examine the clinical outcomes of glenohumeral arthrodesis. METHODS: Twenty-nine patients with 29 affected shoulders underwent primary glenohumeral arthrodesis between 1992 and 2009. Surgical indications included rotator cuff arthropathy and pseudoparalysis (n = 7), neurologic injuries (n = 12), chronic infection (n = 3), recurrent dislocations (n = 3), and proximal humeral or shoulder girdle tumors (n = 4). Surgical fixation techniques included plates and screws in 18 patients and screws only in 11 patients. RESULTS: All patients were examined, with a mean follow-up of 12 years (range, 2 to 22 years). Twelve patients (41%) had postoperative complications, including 6 periprosthetic fractures, 7 nonunions, and 3 infections. Eleven patients (38%) required additional surgical procedures after arthrodesis, including revision internal fixation to achieve glenohumeral fusion after nonunions (n = 7), irrigation and debridement with antibiotic treatment for deep infections (n = 2), open reduction and internal fixation to treat fracture (n = 2), and implant removal to treat symptomatic patients (n = 3). Patients experienced reasonable overall pain relief. The mean postoperative scores were 35 points for the Subjective Shoulder Value, 58 points for the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire, and 54 points for the Short Form-36. Eighty-seven percent of patients reported postoperative limitations. Patients with neurologic injuries had worse functional outcomes, and an arthrodesis position of >=25 degrees yielded better functional outcomes. CONCLUSIONS: Glenohumeral arthrodesis is associated with a high rate of patients with complications (41%). Although patients experience reasonable pain relief and shoulder stability, they experience marked limitations in their upper-extremity function. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29613930 TI - Operative Experience During Orthopaedic Residency Compared with Early Practice in the U.S. AB - BACKGROUND: The goal of surgical education is to prepare the trainee for independent practice; however, the relevance of the current residency experience to practice remains uncertain. The purpose of this study was to identify the surgical procedures most frequently performed in orthopaedic residency and in early surgical practice and to identify surgical procedures performed more often or less often in orthopaedic residency compared with early surgical practice. METHODS: This retrospective cohort study included American Medical Association (AMA) Current Procedural Terminology (CPT) codes (n = 4,329,561 procedures) reported by all U.S. orthopaedic surgery residents completing residency between 2010 and 2012 (n = 1,978) and AMA CPT codes for all procedures (n = 413,370) reported by U.S. orthopaedic surgeons who took the American Board of Orthopaedic Surgery Part II certifying examination between 2013 and 2015 (n = 2,205). Relative rates were determined for AMA CPT codes and AMA CPT code categories for adult and pediatric surgeries that had frequencies of >=0.1% for both practitioners and residents. RESULTS: The top 25 adult AMA CPT code categories contributed 82.1% of the total case volume for residents and 82.4% for practitioners. Knee and shoulder arthroscopy were the most frequently performed procedures in adults in both residency and early practice. Humerus/elbow fracture and/or dislocation procedures and "other musculoskeletal-introduction or removal" procedures were the most frequently performed procedures in pediatric cases in both residency and early practice. Of the total 78 adult and 82 pediatric code categories included in our analysis that had a frequency of >1% in residency or early practice, there were 4 adult and 6 pediatric code categories demonstrating 44% to 1,164% greater frequency in residency than in early practice, and there were 8 adult and 7 pediatric code categories demonstrating 26% to 73% less frequency in residency than in early practice. CONCLUSIONS: Similarity between residency and early practice experience is generally strong. However, we identified several AMA CPT code categories and individual CPT codes for which the level of exposure during residency varied substantially from early practice experience. These findings can help residencies ensure adequate trainee exposure to procedures performed commonly in early practice. PMID- 29613931 TI - Comparison of Autograft and Allograft with Surface Modification for Flexor Tendon Reconstruction: A Canine in Vivo Model. AB - BACKGROUND: Flexor tendon injury is common, and tendon reconstruction is indicated clinically if the primary repair fails or cannot be performed immediately after tendon injury. The purpose of the current study was to compare clinically standard extrasynovial autologous graft (EAG) tendon and intrasynovial allogeneic graft (IAG) that had both undergone biolubricant surface modification in a canine in vivo model. METHODS: Twenty-four flexor digitorum profundus (FDP) tendons from the second and fifth digits of 12 dogs were used for this study. In the first phase, a model of failed FDP tendon repair was created. After 6 weeks, the ruptured FDP tendons with a scarred digit were reconstructed with the use of either EAG or IAG tendons treated with carbodiimide-derivatized hyaluronic acid and lubricin. At 12 weeks after tendon reconstruction, the digits were harvested for functional, biomechanical, and histologic evaluations. RESULTS: The tendon failure model was a clinically relevant and reproducible model for tendon reconstruction. The IAG group demonstrated improved digit function with decreased adhesion formation, lower digit work of flexion, and improved graft gliding ability compared with the EAG group. However, the IAG group had decreased healing at the distal tendon-bone junction. Our histologic findings verified the biomechanical evaluations and, further, showed that cellular repopulation of allograft at 12 weeks after reconstruction is still challenging. CONCLUSIONS: FDP tendon reconstruction using IAG with surface modification has some beneficial effects for reducing adhesions but demonstrated inferior healing at the distal tendon-bone junction compared with EAG. These mixed results indicate that vitalization and turnover acceleration are crucial to reducing failure of reconstruction with allograft. CLINICAL RELEVANCE: Flexor tendon reconstruction is a common surgical procedure. However, postoperative adhesion formation may lead to unsatisfactory clinical outcomes. In this study, we developed a potential flexor tendon allograft using chemical and tissue-engineering approaches. This technology could improve function following tendon reconstruction. PMID- 29613933 TI - What's Important: A Musculoskeletal Moonshot: Accelerating Orthopaedic Innovation. PMID- 29613932 TI - Controversies in the Management of Central Cord Syndrome: The State of the Art. PMID- 29613934 TI - The Socioeconomic Implications of Isolated Tibial and Femoral Fractures from Road Traffic Injuries in Uganda. AB - BACKGROUND: The purpose of this study was to determine the socioeconomic implications of isolated tibial and femoral fractures caused by road traffic injuries in Uganda. METHODS: This prospective longitudinal study included adult patients who were admitted to Uganda's national referral hospital with an isolated tibial or femoral fracture. The primary outcome was the time to recovery following injury. We assessed recovery using 4 domains: income, employment status, health-related quality of life (HRQoL) recovery, and school attendance of the patients' dependents. RESULTS: The majority of the study participants (83%) were employed, and they were the main income earner for their household (74.0%) at the time of injury, earning a mean annual income of 2,375 U.S. dollars (USD). All of the patients had been admitted with the intention of surgical treatment; however, because of resource constraints, only 56% received operative treatment. By 2 years postinjury, only 63% of the participants had returned to work, and 34% had returned to their previous income level. Overall, the mean monthly income was 62% less than preinjury earnings, and participants had accumulated 1,069 USD in debt since the injury; 41% of the participants had regained HRQoL scores near their baseline, and 62% of school-aged dependents, enrolled at the time of injury, were in school at 2 years postinjury. CONCLUSIONS: At 2 years postinjury, only 12% of our cohort of Ugandan patients who had sustained an isolated tibial or femoral fracture from a road traffic injury had recovered both economically and physically. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence. PMID- 29613935 TI - The Use of Emergency Physicians to Deliver Anesthesia for Orthopaedic Surgery in Austere Environments: The Expansion of the Emergency Physician's General Anesthesia Syllabus to Orthopaedic Surgery. AB - BACKGROUND: Five billion people, primarily in low-income and middle-income countries, cannot access safe, affordable surgical and anesthesia care, particularly for orthopaedic trauma. The rate-limiting step for many orthopaedic surgical procedures performed in the developing world is the absence of safe anesthesia. Even surgical mission teams providing surgical care are limited by the availability of anesthesiologists. Emergency physicians, who are already knowledgeable in airway management and procedural sedation, may be able to help to fulfill the need for anesthetists in disaster relief and surgical missions. METHODS: Following the 2010 earthquake in Haiti, an emergency physician was trained using the Emergency Physician's General Anesthesia Syllabus (EP GAS) to perform duties similar to those of certified registered nurse anesthetists. The emergency physician then provided anesthesia during surgical mission trips with an orthopaedic team from February 2011 to March 2017, in Milot, Haiti. This is a descriptive overview of this training program and prospectively collected data on the cohort of patients whom the surgical mission teams treated in Haiti during that time frame. RESULTS: A single emergency physician anesthetist provided anesthesia for 71 of the 172 orthopaedic surgical cases, nearly doubling the number of cases that could be performed. This also allowed the anesthesiologists to focus on pediatric and more difficult cases. Both immediately after the surgical procedure and at 1 year, there were no serious adverse events for cases in which the emergency physician provided anesthesia. CONCLUSIONS: Given emergency physicians' baseline training in airway management and sedation, well supervised and focused extra training under the vigilant supervision of a board certified anesthesiologist may allow emergency physicians to be able to safely administer anesthesia. Using emergency physicians as anesthetists in this closely supervised setting could increase the number of surgical cases that can be performed in a disaster setting. PMID- 29613936 TI - Surgical Decision-Making: The Province of the Patient or the Surgeon?: Commentary on an article by Nicholas J. Giori, MD, PhD, et al.: "Risk Reduction Compared with Access to Care: Quantifying the Trade-Off of Enforcing a Body Mass Index Eligibility Criterion for Joint Replacement". PMID- 29613937 TI - How Do Elbows Dislocate?: Commentary on an article by Marc Schnetzke, MD, et al.: "Determination of Elbow Laxity in a Sequential Soft-Tissue Injury Model. A Cadaveric Study". PMID- 29613938 TI - Anterolateral Structure Reconstruction Unnecessary with Anatomic ACL Reconstruction for Knee Stability: Commentary on an article by Frank R. Noyes, MD, et al.: "The Effect of an ACL Reconstruction in Controlling Rotational Knee Stability in Knees with Intact and Physiologic Laxity of Secondary Restraints as Defined by Tibiofemoral Compartment Translations and Graft Forces". PMID- 29613939 TI - Orthopaedic Trauma Outcomes in Developing Countries: Commentary on an article by Nathan N. O'Hara, MHA, et al.: "The Socioeconomic Implications of Isolated Tibial and Femoral Fractures from Road Traffic Injuries in Uganda". PMID- 29613940 TI - Enhancing Placebo Effects in Somatic Symptoms Through Oxytocin. AB - OBJECTIVE: Placebo effects relieve various somatic symptoms, but it is unclear how they can be enhanced to maximize positive treatment outcomes. Oxytocin administration may potentially enhance placebo effects, but few studies have been performed, and they have had conflicting findings. The study aim was to investigate the influence of positive verbal suggestions and oxytocin on treatment expectations and placebo effects for pain and itch. METHODS: One hundred eight female participants were allocated to one of the following four groups: (1) oxytocin with positive verbal suggestions, (2) placebo with positive verbal suggestions, (3) oxytocin without suggestions, and (4) placebo without suggestions. The administration of 24 IU oxytocin or a placebo spray was preceded by positive verbal suggestions regarding the pain- and itch-relieving properties of the spray or no suggestions, depending on group allocation. Pain was assessed with a cold pressor test, and itch was assessed with histamine iontophoresis. RESULTS: Positive verbal suggestions induced expectations of lower pain (F = 4.77, p = .031) and itch (F = 5.38, p = .022). Moreover, positive verbal suggestions elicited placebo analgesia (F = 5.48, p = .021) but did not decrease itch. No effect of oxytocin on the placebo effect or on expectations was found. CONCLUSIONS: Positive suggestions induced placebo analgesia but oxytocin did not enhance the placebo effect. Study limitations are that we only included a female sample and a failure to induce placebo effect for itch. Future studies should focus on how oxytocin might influence placebo effects, taken into account the role of sex, dose-dependent effects, and various expectation manipulations. TRIAL REGISTRATION: The study was registered as a clinical trial on www.trialregister.nl (number 6376). PMID- 29613942 TI - Duration of Pupillary Unresponsiveness to Light: A Physiological Adjunct to Electroencephalography and Motor Seizure Duration Monitoring During Electroconvulsive Therapy. AB - BACKGROUND: During electroconvulsive therapy (ECT) sessions, we observed that the time taken for the return of pupillary response to light (ROPL) outlasted both the electroencephalography (EEG) and the motor seizure duration after the delivery of the electrical stimulus to produce convulsions. OBJECTIVE: The objective of this study was to investigate whether ROPL can be used as a marker of cessation of seizure activity in the brain after ECT and also to study the effect of atropine premedication on seizure activity during ECT. METHODS: Forty one patients underwent 82 sessions of ECT in a cross-over design study. The duration of motor seizure, EEG seizure, and time for ROPL was observed and compared. RESULTS: The ROPL consistently outlasted EEG and motor seizures; the difference in their mean durations was statistically significant P < 0.05. There was good correlation among the 3 parameters. Atropine premedication did not alter the seizure activity and ROPL after ECT. CONCLUSIONS: The ROPL after ECT stimulus is a good bedside monitor for termination of seizure activity and can be a valuable adjunct to surface EEG in monitoring the duration of epileptic activity after delivery of ECT. PMID- 29613943 TI - Patient Experience of Electroconvulsive Therapy: A Retrospective Review of Clinical Outcomes and Satisfaction. AB - OBJECTIVE: The aim of the study was to explore patient perception and perceived benefit of electroconvulsive therapy (ECT) by assessing the real-world experience of adult patients who received ECT, focusing on clinical outcomes and patient satisfaction. METHODS: This retrospective study analyzed patient self-report of depressive symptoms (Patient Health Questionnaire), perception of physical and cognitive ECT adverse effects (ECT Outcomes Survey) and satisfaction with treatment (Patient Satisfaction Survey). Symptoms and adverse effects were measured at both intake and final ECT session for comparison over time. Data were collected from 1089 adult patients with depression, bipolar disorder, or schizoaffective disorder in 23 psychiatric facilities in the United States and its territories from 2014 to 2015. RESULTS: On average, patient scores reflect satisfaction with treatment and reduction in depressive symptoms and adverse effects across the course of ECT treatment. Patients reported a decrease in depression, with an average Patient Health Questionnaire change of 13.2 from intake to final ECT session (P < 0.001). Furthermore, 85.5% of patients indicated on the Patient Satisfaction Survey that they benefited or improved as a result of their ECT. Subsequent analyses revealed alleviation of depressive symptoms and ability to return to social, and work life tasks are significant contributors to satisfaction with treatment, whereas adverse effects including memory problems have less influence on satisfaction. CONCLUSIONS: Patients tend to perceive ECT as a safe and beneficial treatment option for severe mood disorders, even when considering adverse effects. This study reinforces the value of standardized data collection and outcomes measures to better monitor patient response to treatment, refine the clinical practice of ECT, and provide data to support patient education. PMID- 29613944 TI - Neurocognitive Effects of Repetitive Transcranial Magnetic Stimulation With a 2 Coil Device in Treatment-Resistant Major Depressive Disorder. AB - BACKGROUND: Neurocognitive dysfunction is an understudied and undertreated aspect of psychiatric research and treatment. There is emerging evidence to suggest that repetitive transcranial magnetic stimulation (rTMS) may possess neurocognition enhancing capabilities. METHODS: This study examined the neurocognitive data from a randomized, double-blind, sham-controlled trial of an investigational 2-coil rTMS device in antidepressant treatment or treatment-intolerant major depressive disorder patients. This device has the potential to stimulate deeper areas of the brain than the Food and Drug Administration-approved TMS devices, which primarily stimulate cortical brain areas and may therefore have different neurocognitive adverse effects. Patients received 20 daily rTMS treatments (10-Hz stimulation; either active or sham) with coil centers positioned over the left dorsolateral prefrontal cortex and dorsomedial prefrontal cortex. Neurocognitive safety was evaluated at baseline and within 72 hours of final treatment session with a computerized battery assessing aspects of attention and memory in 84 participants. RESULTS: There were no observed negative neurocognitive effects of the 2-coil rTMS device. A significant effect of active rTMS was observed on the quality of episodic memory. There were no observed effects for attention or working memory. Baseline quality of episodic memory predicted depression treatment response and remission, in that lower baseline episodic memory was associated with greater likelihood of depression response/remission. This was observed in logistic regression analyses controlling for treatment and baseline depressive symptoms. CONCLUSIONS: The 2-coil rTMS device is a cognitively safe treatment for treatment-resistant depression that may possess episodic memory enhancing capabilities. Furthermore, baseline episodic memory may reflect an important predictor of subsequent depression treatment response/remission to rTMS. PMID- 29613945 TI - Access to Outpatient Electroconvulsive Therapy at VA Medical Centers. PMID- 29613946 TI - Clinical Predictors of Response to Magnetic Seizure Therapy in Depression: A Preliminary Report. AB - OBJECTIVES: Magnetic seizure therapy (MST) is a novel convulsive brain stimulation method in clinical testing, which is used as an alternative for electroconvulsive therapy in patients with treatment-resistant depression (TRD). Preliminary studies have suggested that MST leads to fewer cognitive adverse effects than electroconvulsive therapy but has similar efficacy. However, the clinical predictors of response to MST have not been evaluated yet. This study aimed to investigate whether these predictors can be identified in patients with TRD. METHODS: Thirty-eight patients with TRD were included. As clinical predictors for treatment response, we used the diagnosis, sex, age, family history, and severity of depression, as well as the melancholic, psychotic, anxiety, and atypical depression symptoms. A response was defined as an improvement higher than 50% on the 28-item Hamilton Rating Scale for Depression. The binary logistic regression, stepwise linear regression, and effect sizes were calculated. RESULTS: We found that 68.4% of the patients responded to MST. The responders had significantly fewer previous depressive episodes, less severe depression, and fewer melancholic (anhedonia) and anxiety symptoms than the nonresponders. In addition, responders were more likely to have a positive family history of depression than nonresponders. In particular, the number of previous episodes and a family history of depression were significant predictors of the response to MST. CONCLUSIONS: We demonstrate that the chronicity, severity, and family history of depression, as well as the presence of melancholic and anxiety symptoms, can serve as clinical predictors of the response to MST. Further research with a larger sample size will be required to verify these preliminary findings. PMID- 29613947 TI - Nationwide trends in mortality following penetrating trauma: Are we up for the challenge? AB - BACKGROUND: Despite a focus on improved prehospital care, penetrating injuries contribute substantially to trauma mortality in the United States. We therefore analyzed contemporary trends in prehospital mortality from penetrating trauma in the past decade. METHODS: We identified patients in the The National Trauma Data Bank from 2007 to 2010 ("early period") and 2011 to 2014 ("late period") with gunshot wounds (GSW) and stab wounds (SW), who were treated at hospitals that recorded dead-on-arrival statistics. Multivariable logistic regressions assessed differences in body locations of trauma, prehospital mortality, and in-hospital mortality between the early and late periods. Models accounted for hospital clusters and adjusted for age, pulse, hypotension, New Injury Severity Score, Glasgow Coma Scale, and number of injured body parts. RESULTS: From 2007 to 2014, 437,398 patients experienced penetrating traumas, with equal distributions of GSW and SW. There were unadjusted differences in prehospital mortality (GSW: early, 2.0% vs. late, 4.9%; SW: early, 0.2% vs. late, 1.1%) and in-hospital mortality (GSW: early, 13.8% vs. late, 9.5%; SW: early, 1.8% vs. late, 1.0%) by both mechanisms. After adjustment, patients in the late period relative to those in the early period had significantly higher odds of prehospital death (GSWs: adjusted odds ratio [aOR], 4.54; 95% confidence interval [CI], 3.31-6.22; SWs: aOR, 8.98; 95% CI, 5.50-14.67) and lower odds of in-hospital death (GSWs: aOR, 0.85; 95% CI, 0.80-0.90; SWs: aOR, 0.81; 95% CI, 0.71-0.92). Sensitivity analyses assessing GSWs and SWs by locations of body injury found similar results. Additionally, patients in the late period were more likely to experience penetrating injuries to the face, spine, and lower extremities. CONCLUSION: In the United States, the prevalence of penetrating traumas remains a nationwide burden. The odds of prehospital mortality has increased over fourfold for GSWs and almost ninefold for SWs. Examining violence intensity, along with improvements in hospital care and data collection, may explain these findings. LEVEL OF EVIDENCE: Prognostic and epidemiological, level IV. PMID- 29613948 TI - On the complexity of shark bite wounds: From associated bacteria to trauma management and wound repair. AB - : The mouth of a shark is a breeding ground for a large variety of bacteria which can easily get transferred onto a human body in the event of a shark bite. Here, we review infections originating from shark oral bacterial flora, which originate from the microbiome of its prey, as well as from the surroundings where an incident takes place. We use the example of an incident which occurred in an aquarium involving a sandtiger shark, Carcharias taurus. In addition to a succinct analysis and interpretation of the wound and recovery process, an overview of currently known bacteria associated with shark bite wounds is given, as well as a summary of the effects of various previously tested antibiotics on bacteria derived from blacktip sharks, Carcharhinus limbatus, bull sharks, C. leucas, and tiger sharks, Galeocerdo cuvier. LEVEL OF EVIDENCE: Therapeutic study, level V. PMID- 29613949 TI - REDUCED DNASE ENZYME ACTIVITY IN RESPONSE TO HIGH POST-INJURY MITOCHONDRIAL DNA CONCENTRATION PROVIDES A THERAPEUTIC TARGET FOR SIRS. AB - BACKGROUND: Cell free mitochondrial DNA (mtDNA) is pro-inflammatory and has been detected in high concentrations in trauma patients' plasma. Deoxyribonuclease (DNase) is the free plasma enzyme responsible for the digestion of extracellular DNA. The relationship between mtDNA and DNase after major trauma is unknown. We hypothesized that DNase activity would be elevated after injury and trauma surgery, and would be associated with high concentrations of extracellular DNA. METHODS: 2-year prospective study was performed on 103 consecutive trauma patients (Male 81%, Age: 38 IQR 30-59 years; ISS: 18 IQR 12-26) who underwent standardised major orthopaedic trauma surgical interventions. Blood was collected at 5 peri-operative time points (pre-op, post-op, 7hrs, 24hrs and 3 days post operatively). Healthy control subjects (n=20) were also sampled. Cell free mtDNA and nuclear DNA(nDNA) was measured using quantitative polymerase chain reaction. DNase was also assayed in the same plasma samples. RESULTS: Increased levels of mtDNA (from Pre-op 163+/-86ng/ml to 3 days 282+/-201ng/ml p<0.0001) and nDNA (from pre-op 28+/-20ng/ml to 3 days 37+/-27ng/ml p<0.05) were present in trauma patients at all peri-operative time points compared to healthy controls (mtDNA: 4+/-2ng/ml; nDNA: 10+/-5ng/ml). DNase activity was lower in the trauma cohort (from Pre-op 0.06+/-0.04U/ml to 3 days 0.08+/-0.04U/ml p<0.0001) compared to healthy controls (DNase: 0.17+/-0.03U/ml). There was no correlation between DNase and peri-operative DNA concentrations. Elevated mtDNA (but not nDNA) correlated with the development of SIRS (p=0.026) but not MOF. CONCLUSIONS: The significant perioperative elevation in plasma free MtDNA concentration is associated with the development of SIRS. The fact that increased cell free DNA concentrations present with significantly lower than healthy control DNase activity suggests a potential therapeutic opportunity with DNase administration to modulate post-injury severe SIRS LEVEL OF EVIDENCE: Level II: Prospective comparative study. PMID- 29613950 TI - Immediate effects of blood donation on physical and cognitive performance-A randomized controlled double-blinded trial. AB - BACKGROUND: The success of implementing damage control resuscitation principles pre-hospital has been at the expense of several logistic burdens including the requirements for resupply, and the question of donor safety during the development of whole blood programs. Previous studies have reported effects on physical performance after blood donation; however, none have investigated the effects of blood donation on cognitive performance. METHOD: We describe a prospective double-blinded, randomized, controlled study comprised of a battery of tests: three cognitive tests, and VO2max testing on a cycle ergometer. Testing was performed 7 days before blinded donation (baseline day), immediately after donation (Day 0), and 7 days (Day 7) after donation. The inclusion criteria included being active blood donors at the Haukeland University Hospital blood bank, where eligibility requirements were met on the testing days, and providing informed consent. Participants were randomized to either the experimental (n = 26) or control group (n = 31). Control group participants underwent a 'mock donation" in which a phlebotomy needle was placed but blood was not withdrawn. RESULTS: In the experimental group, mean +/- SEM VO2max declined 6% from 41.35 +/ 1.7 mLO2/(min.kg) at baseline to 39.0 +/- 1.6 mLO2/(min.kg) on Day 0 and increased to 40.51 +/- 1.5 mLO2/(min.kg) on Day 7. Comparable values in the control group were 42.1 +/- 1.8 mLO2/(min.kg) at baseline, 41.6 +/- 1.8 mLO2/(min.kg)) on Day 1 (1% decline from baseline), and 41.8 +/- 1.8 mLO2/(min.kg) on Day 7.Comparing scores of all three cognitive tests on Day 0 and Day 7 showed no significant differences (p > 0.05). CONCLUSION: Our main findings are that executive cognitive and physical performances were well maintained after whole blood donation in healthy blood donors. The findings inform postdonation guidance on when donors may be required to return to duty. LEVEL OF EVIDENCE: Randomized, controlled, double-blinded prospective trial study, level 1. PMID- 29613951 TI - Firearm injury control: A call to arms for wide-ranging advocacy. PMID- 29613952 TI - 2018 Trauma Association of Canada Presidential Address: ABCs of trauma: Advocacy because we can. PMID- 29613953 TI - Management of cervical tracheoesophageal injuries: A 2018 EAST Master Class Video Presentation. AB - This video techniques article focuses on the choice of incision, and repair techniques, for cervical injuries to the trachea and esophagus. PMID- 29613954 TI - Left ventricular compressions improve return of spontaneous circulation and hemodynamics in a swine model of traumatic cardiopulmonary arrest. AB - BACKGROUND: Prehospital cardiopulmonary resuscitation, including closed chest compressions, has commonly been considered ineffective in traumatic cardiopulmonary arrest (TCPA) because traditional chest compressions do not produce substantial cardiac output. However, recent evidence suggests that chest compressions located over the left ventricle (LV) produce greater hemodynamics when compared to traditional compressions. We hypothesized that chest compressions located directly over the LV would improve return of spontaneous circulation (ROSC) and hemodynamics when compared with traditional chest compressions, in a swine model of TCPA. METHODS: Transthoracic echocardiography was used to mark the location of the aortic root (traditional compressions), and the center of the LV on animals (n = 26) which were randomized to receive chest compressions in one of the two locations. After hemorrhage, ventricular fibrillation was induced. After 10 minutes of ventricular fibrillation, basic life support (BLS) with mechanical cardiopulmonary resuscitation was initiated and performed for 10 minutes followed by advanced life support (ALS) for an additional 10 minutes. During BLS, the area of maximal compression was verified using transesophageal echocardiography. Hemodynamic variables were averaged over the final 2 minutes of the BLS and ALS periods. RESULTS: Five (38%) of the LV group achieved ROSC compared with zero of the aortic root group (p = 0.04). Additionally, there was an increase in aortic systolic blood pressure (SBP), aortic diastolic blood pressure (DBP) and coronary perfusion pressure (CPP) at the end of both the BLS (95% confidence interval, SBP, -49 to -21; DBP, -14 to 5.6; and CPP, -15 to -7.4) and ALS (95% confidence interval: SBP, -66 to -21; DBP, -49 to -6.8; and CPP, -51 to -7.5) resuscitation periods among the LV group. CONCLUSION: In our swine model of TCPA, chest compressions performed directly over the LV improved ROSC and hemodynamics when compared with traditional chest compressions. PMID- 29613955 TI - Influence of postoperative hepatic angiography on mortality after laparotomy in Grade IV/V hepatic injuries. AB - BACKGROUND: Mortality rate for severe liver injuries remains high. As an adjunct to surgery, postoperative hepatic angiography (PHA) may have a positive impact on outcomes. This study sought to compare outcomes following surgical management of severe liver injuries with and without PHA using propensity score matching analysis. METHODS: Data from the National Trauma Data Bank from 2007 to 2014 were analyzed. The study population consisted of patients older than 18 years, sustaining severe liver injuries (i.e., American Association for the Surgery of Trauma Organ Injury Scale (AAST-OIS) Grade IV or V) who underwent surgery. Patients were divided into two groups. The PHA group consisted of those undergoing surgery followed by PHA. In the surgery-only group, no angiography was performed. To determine the impact of PHA on outcomes, propensity score matching analysis (1:3) was used. RESULTS: A total of 3,871 patients met inclusion criteria. Of those, 205 (5.3%) patients underwent PHA. Prior to matching, patients in the PHA group had higher severity, but overall in-hospital mortality was found to be similar between the two groups. After 1:3 propensity-score matching, 196 patients in the PHA group were matched with 588 in the surgery-only group with well-balanced baseline characteristics. The in-hospital mortality was significantly lower in the PHA group compared with the surgery-only group (24.5% vs. 35.9%; odds ratio, 0.58; 95% confidence interval, 0.40-0.84). However, hospital length of stay was longer (16.0 [7.0-29.8] vs. 11 [1.0-25.0] days, p = 0.001), and the incidence of deep and organ/space surgical site infection (3.6% vs. 1.2%, 8.2% vs. 3.5%, respectively) was higher in the PHA group. CONCLUSION: The use of PHA was associated with decreased mortality rates. A multimodality approach using both surgical intervention followed by PHA appears to identify patients that may benefit from arterial embolization, leading to decreased mortality of severe liver injuries. LEVEL OF EVIDENCE: Therapeutic study, level IV. PMID- 29613956 TI - Optimal timing of initiation of thromboprophylaxis in spine trauma managed operatively: A nationwide propensity-matched analysis of trauma quality improvement program. AB - BACKGROUND: Patients with spinal trauma are at high risk for venous thromboembolic events (VTE). Guidelines recommend prophylactic anticoagulation but they are unclear on timing of initiation of thromboprophylaxis. The aim of our study was to assess the impact of early versus late initiation of venous thromboprophylaxis in patients with spinal trauma who underwent operative intervention. METHODS: We performed a 2-year (2013-2014) review of patients with isolated spine trauma (spine-Abbreviated Injury Scale score, >= 3 and no other injury in another body region with Abbreviated Injury Scale score, > 2) who underwent operative intervention and received thromboprophylaxis postoperatively. Patients were divided into two groups based on the timing of initiation of thromboprophylaxis: early(<48 hours) and late(>=48 hours), and were matched in a 1:1 ratio using propensity score matching for demographics, admission vitals, injury parameters, type of operative intervention, hospital course, and type of prophylaxis(low molecular weight heparin vs. unfractionated heparin). Outcomes were rates of deep vein thrombosis (DVT) and/or pulmonary embolism, red-cell transfusions, the rate of operative interventions for spinal cord decompression and mortality after initiation of thromboprophylaxis. RESULTS: Nine thousand five hundred eighty-five patients underwent operative intervention and received anticoagulants, of which 3554 patients (early, 1,772; late, 1,772) were matched. Matched groups were similar in demographics, injury parameters, emergency department vitals, hospital length of stay, rates of inferior vena cava (IVC) filter placement and time to operative procedure. Patients who received thromboprophylaxis within 48 hours of operative intervention, unlike those who did not, were less likely to develop DVT (2.1% vs. 10.8%, p < 0. 01). However, the rate of pulmonary embolism was similar in both groups (p = 0.75). Additionally, there was no difference in postprophylaxis red cell transfusion requirements (p = 0.61), rate of postprophylaxis decompressive procedure on the spinal cord (p = 0.27), and mortality (p = 0.53). CONCLUSION: Early VTE prophylaxis is associated with decreased rates of DVT in patients with operative spinal trauma without increasing the risk of bleeding and mortality. The VTE prophylaxis should be initiated within 48 hours of surgery to reduce the risk of DVT in this high-risk patient population. LEVEL OF EVIDENCE: Therapeutic studies, level IV. PMID- 29613958 TI - The impact of age on the innate immune response and outcomes after severe sepsis/septic shock in trauma and surgical intensive care unit patients. AB - BACKGROUND: Advancing age is a strong risk factor for adverse outcomes across multiple disease processes. However, septic surgical and trauma patients are unique in that they incur two or more inflammatory insults. The effects of advanced age on sepsis pathophysiology and outcomes remain unclear. METHODS: We performed a single-center, prospective observational cohort study of surgical intensive care unit patients with severe sepsis/septic shock. Peripheral blood was collected for genomic, cytokine, and biomarker analysis at 0.5 day, 1 day, 4 days, 7 days, 14 days, 21 days, and 28 days after sepsis onset. Based on sensitivity analysis, cohorts were defined as "young" (<55 years) and "aged" (>=55 years). We compared age-defined cohorts to determine differences in patient characteristics, biomarker profiles, and clinical outcomes. RESULTS: The cohort included 173 patients with severe sepsis (n = 93; 53.8%) or septic shock (n = 80; 46.2%), with a mean age of 60.9 (+/-14.5) years. Intra-abdominal sepsis was the leading source (n = 81; 46.8%), followed by necrotizing soft tissue infection (n = 33, 19.1%) and pneumonia (n = 30; 17.3%). Aged patients had a higher comorbidity burden, but were otherwise similar to the young cohort. The aged cohort had a higher severity of early physiologic derangement (median APACHE II, 23 vs. 18; p = 0.002), greater incidence of multiple organ failure (64.3% vs. 40.4%, p = 0.006), and hospital mortality (15.9% vs. 2.1%; p = 0.016). Six-month mortality was significantly higher in the aged cohort as compared with young cohort (31% vs. 9%; p = 0.003). Aged septic patients biomarker trajectories suggestive of persistent immunosuppression (absolute lymphocyte count, soluble programed death ligand-1) and catabolism (Urine 3MH-Cr ratio, insulin growth factor, IGF1BP3, albumin) out to 28 days after sepsis. CONCLUSION: Aged, critically ill surgical patients have greater organ dysfunction and incidence of adverse clinical outcomes after sepsis. Biomarker profiles suggest an immunophenotype of persistent immunosuppression and catabolism. Advanced age may necessitate novel therapeutic strategies to promote multisystem organ recovery and improve survival after sepsis. LEVEL OF EVIDENCE: Prognostic, level II. PMID- 29613959 TI - Evaluation and management of traumatic diaphragmatic injuries: A Practice Management Guideline from the Eastern Association for the Surgery of Trauma. AB - BACKGROUND: Traumatic diaphragm injuries (TDI) pose both diagnostic and therapeutic challenges in both the acute and chronic phases. There are no published practice management guidelines to date for TDI. We aim to formulate a practice management guideline for TDI using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology. METHODS: The working group formulated five Patient, Intervention, Comparator, Outcome questions regarding the following topics: (1) diagnostic approach (laparoscopy vs. computed tomography); (2) nonoperative management of penetrating right-sided injuries; (3) surgical approach (abdominal or thoracic) for acute TDI, including (4) the use of laparoscopy; and (5) surgical approach (abdominal or thoracic) for delayed TDI. A systematic review was undertaken and last updated December 2016. RevMan 5 (Cochran Collaboration) and GRADEpro (Grade Working Group) software were used. Recommendations were voted on by working group members. Consensus was obtained for each recommendation. RESULTS: A total of 56 articles were used to formulate the recommendations. Most studies were retrospective case series with variable reporting of outcomes measures and outcomes frequently not stratified to intervention or comparator. The overall quality of the evidence was very low for all Patient, Intervention, Comparator, Outcomes. Therefore, only conditional recommendations could be made. CONCLUSION: Recommendations were made in favor of laparoscopy over computed tomography for diagnosis, nonoperative versus operative approach for right-sided penetrating injuries, abdominal versus thoracic approach for acute TDI, and laparoscopy (with the appropriate skill set and resources) versus open approach for isolated TDI. No recommendation could be made for the preferred operative approach for delayed TDI. Very low-quality evidence precluded any strong recommendations. Further study of the diagnostic and therapeutic approaches to TDI is warranted. LEVEL OF EVIDENCE: Guideline; Systematic review, level IV. PMID- 29613960 TI - MR Imaging of Chest and Chest Wall Disease. PMID- 29613961 TI - MR Imaging of Thymic Epithelial Neoplasms. AB - Thymic epithelial neoplasms are malignant lesions that originate from the thymus and include thymoma, thymic carcinoma, and thymic neuroendocrine tumors. Although computed tomography (CT) is typically considered the imaging modality of choice for identifying thymic tumors, characterizing the primary neoplasm, and staging of disease, the role of magnetic resonance (MR) imaging continues to expand. MR imaging is effective in distinguishing thymic epithelial neoplasms and other malignant tumors from benign lesions in the prevascular mediastinum, can be used to characterize and stage thymic tumors in those patients with contraindications to contrast-enhanced CT, and can reveal morphologic features of thymic tumors. At least 15 different stage classifications have been proposed for thymic epithelial neoplasms and used to varying degrees in clinical practice. Recently, an official, consistent tumor node metastasis (TNM) staging system has been recognized by the American Joint Committee on Cancer (AJCC) and the Union for International Cancer Control (UICC), based on an analysis of a retrospective database performed by the International Association for the Study of Lung Cancer (IASLC) and the International Thymic Malignancy Interest Group (ITMIG). In this article, we discuss the appropriate utilization of MR imaging in the evaluation of patients with thymic epithelial neoplasms, key imaging features of the tumors, and the impact of imaging findings on overall staging. PMID- 29613962 TI - MR Imaging of Pleural Neoplasms. AB - The pleura may be affected by primary tumors or metastatic spread of intrathoracic or extrathoracic neoplasms. Primary pleural neoplasms represent ~10% of all pleural tumors, and malignant lesions are more common than benign lesions. The most common primary tumors include malignant pleural mesothelioma and solitary fibrous tumor. Although pleural neoplasms may initially be evaluated with computed tomography (CT) and/or fluorodeoxyglucose positron emission tomography (PET)/CT, magnetic resonance (MR) imaging is complementary to these other imaging modalities for disease staging and evaluation of patients. In this article, we discuss the etiology, clinical presentation, and imaging of pleural neoplasms, with specific attention given to the role of MR imaging. PMID- 29613963 TI - MR Imaging of Primary Chest Wall Neoplasms. AB - Primary chest wall neoplasms are uncommon and comprise a heterogeneous group of lesions that may be challenging to classify and diagnose. These tumors may be primary or secondary, malignant or benign, and arise from cartilaginous/osseous structures or soft tissues. The role of magnetic resonance (MR) imaging in the evaluation of chest wall tumors continues to expand given its superior soft tissue contrast relative to computed tomography. MR imaging can facilitate differentiation of neoplasms from normal chest wall structures and other disease processes due to infection and inflammation, and can fully characterize abnormalities by demonstrating the various internal components of complex lesions. It is important that radiologists be able to identify key features of primary chest wall neoplasms on MR imaging to provide focused differential diagnoses and guide patient management. PMID- 29613964 TI - MR Imaging of Thoracic Aortic Disease. AB - A number of congenital defects and acquired disease processes affect the thoracic aorta, and traditionally, computed tomography (CT) has been the mainstay of imaging, especially in evaluation of the acute aorta. However, recent advances in magnetic resonance (MR) imaging such as electrocardiographically (ECG) triggered breath-hold sequences and ultrafast 3-dimensional MR angiography (MRA) are bringing MR imaging to the forefront of imaging of the thoracic aorta. By providing high-resolution morphological imaging and sophisticated vascular flow analysis for functional data, this modality can provide a comprehensive, reproducible evaluation of the thoracic aorta. In this review, we discuss the role of MR imaging in the evaluation of thoracic aorta pathology along with pertinent examples of aortic abnormalities. PMID- 29613965 TI - MR Imaging of Cardiac Masses. AB - Cardiac masses present a diagnostic challenge given their relative rarity and the overall difficulty imaging the heart. With the increasing frequency and quality of imaging in general, however, the incidental discovery of cardiac masses is increasing. Cardiac masses seldom produce symptoms, and they are more commonly found during imaging for noncardiac indications. While echocardiography is useful in the initial evaluation of a suspected mass, cardiac magnetic resonance (MR) imaging is the best imaging modality to characterize cardiac tumors due to its superior tissue characterization and its higher contrast resolution. Due to the risk of embolization and arrhythmia, most benign cardiac tumors are removed, and imaging plays an important role in treatment planning. While primary resection remains the mainstay of treatment, new treatment strategies may prolong survival and slow the growth of metastases. A fundamental knowledge of common cardiac masses is vital to all radiologists, and here, we discuss the most pertinent imaging approach to cardiac masses emphasizing MR imaging. PMID- 29613967 TI - Comparison of Endoscopic Ultrasonography Guided Biliary Drainage and Percutaneous Transhepatic Biliary Drainage in the Management of Malignant Obstructive Jaundice After Failed ERCP: Erratum. PMID- 29613966 TI - Acute Paraesophageal Hernia: Laparoscopic Repair With Adjunct T-Fastener Gastropexy for the High Operative Risk Patient. AB - BACKGROUND: In the emergent setting, most paraesophageal hernia (PEH) repairs are done by laparotomy with adjunct gastropexy or gastrostomy tube (GT) placement. This adjunct to the repair can be performed expeditiously by a laparoscopic approach by utilizing T-fasteners. We present our case series of patients with PEHs and acute gastric volvulus that were managed with laparoscopy and how patient characteristics can influence the repair technique. METHODS: Patients with high operative risk who underwent laparoscopic hiatal hernia repair with adjunct T-fastener gastropexy in the emergent setting between July 2014 and July 2016 were included in this study. RESULTS: Thirteen patients underwent successful PEH repair and all were classified as urgent/emergent upon admission. In total, 30.7% were performed laparoscopically. The median patient age was 84 years. A laparoscopic GT or gastropexy was performed for fixation of the stomach. Crural closure by an anterior cruroplasty was performed in all patients. There were no mortalities. One patient required conversion of gastropexy into a GT given symptoms of dysphagia. Prolonged length of stay was related to postdischarge institutionalization. All patients remained free of obstructive symptoms. CONCLUSIONS: Laparoscopic PEH repair with adjunct gastropexy or GT placement should be considered in emergent cases for elderly patients with predominately obstructive symptoms. Laparoscopy for PEH repair is challenging and requires technical skills. T-fastener gastropexy or GT placement is safe, simple, and obviates the need for intracorporeal suturing. It also may be used to improve physician comfort with laparoscopy and to expedite the repair in this high-risk population. PMID- 29613969 TI - Recurrent Nontyphoidal Salmonella Bacteremia in a 3-Year Old Male. PMID- 29613968 TI - Dosimetry-based treatment for Graves' disease. AB - OBJECTIVE: The aim of this retrospective study was to assess the long-term outcome of a personalized dosimetry approach in Graves' disease aiming to render patients euthyroid from a planned thyroid absorbed dose of 60 Gy. PATIENTS AND METHODS: A total of 284 patients with Graves' disease were followed prospectively following administration of radioiodine calculated to deliver an absorbed dose of 60 Gy. Patients with cardiac disease were excluded. Outcomes were analysed at yearly intervals for up to 10 years with a median follow-up of 37.5 months. RESULTS: A single radioiodine administration was sufficient to render a patient either euthyroid or hypothyroid in 175 (62%) patients, the remainder requiring further radioiodine. The median radioactivity required to deliver 60 Gy was 77 MBq. Less than 2% patients required 400-600 MBq, the standard activity administered in many centres. In the cohort receiving a single administration, 38, 32 and 26% were euthyroid on no specific thyroid medication at 3, 5 and 10 years, respectively. Larger thyroid volumes were associated with the need for further therapy. The presence of nodules on ultrasonography did not adversely affect treatment outcome. CONCLUSION: A personalized dosimetric approach delayed the long-term onset of hypothyroidism in 26% of patients. This was achieved using much lower administered activities than currently recommended. Future studies will aim to identify those patients who would benefit most from this approach. PMID- 29613970 TI - Transient Tachypnea of the Newborn is Associated with an Increased Risk of Hospitalization Due to RSV Bronchiolitis. AB - BACKGROUND: Transient tachypnea of the newborn (TTN) is a self-limiting respiratory disorder, resulting from a failure to clear the lungs of perinatal fluid. As similar pathophysiological features are present in children with respiratory syncytial virus (RSV) bronchiolitis, we hypothesized that these two conditions may be connected. METHODS: This was a population-based cohort study that included all children born in term (>=37 weeks of gestation) without congenital malformations in Finland between 1996 and 2015. Children diagnosed with TTN (ICD-10 code P22.1) after birth and children hospitalized due to RSV bronchiolitis (ICD-10 code J21.0) during first year of life were identified from the Medical Birth Register and National Hospital Discharge Register, respectively, and the data were linked. Logistic regression was used to analyze the association between these two conditions. RESULTS: Of the 1 042 045 children included in the study cohort, 16 327 (1.57%) were diagnosed with TTN at birth and 12 345 (1.18%) were hospitalized due to RSV bronchiolitis during the first year of life. The rate of RSV hospitalization was higher in children with a history of TTN compared to children without TTN diagnosis (260/16 327 [1.59%] vs. 12 085/1 025 718 [1.18%], respectively; P value <0.0001). After adjusting for gestational age at birth, mode of delivery, gender, birth weight, multiple births, older siblings, and maternal smoking, TTN was associated with increased risk for RSV hospitalization (OR 1.31; 95% CI 1.16-1.48). CONCLUSIONS: TTN diagnosis after birth was associated with increased risk for RSV hospitalization during the first year of life. PMID- 29613971 TI - The Impact of Pediatric Outpatient Parenteral Antibiotic Therapy Implementation at a Tertiary Children's Hospital in the United Kingdom. AB - BACKGROUND: Recent advances in outpatient parenteral antibiotic therapy (OPAT) have largely focused on adult practice, and there are few published data on the safety and effectiveness of pediatric OPAT (p-OPAT). METHODS: During a 3-year period (2012 to 2015), data were prospectively collected on patients managed within the p-OPAT service at Southampton Children's Hospital, a tertiary pediatric hospital in the South of England. RESULTS: A total of 130 p-OPAT episodes were managed during this period. The most frequently managed pathologies were bone and joint infections (44.6%), followed by ear, nose and throat (10.7%), respiratory (10.0%) and central nervous system (10.0%) infections. The most frequently used antimicrobial agent was ceftriaxone (n = 103; 79.2%). For the majority of p-OPAT episodes, antimicrobials were delivered in prefilled syringes (n = 109; 83.8%); 24-hour infusions administered by elastomeric devices were used less commonly (n = 16; 12.3%). The median duration of p-OPAT treatment was 9.2 days (interquartile range: 7.6-19.0 days). With regard to patient outcomes, 113 (86.9%) p-OPAT episodes resulted in cure and 12 (9.2%) in improvement; treatment failure occurred in 5 (3.9%) episodes. Intravenous catheter-related complications were rare. A total of 1683 bed days were saved over the 3-year period. CONCLUSIONS: Our data suggest that p-OPAT is safe and effective, with the potential to offer considerable savings for the healthcare economy through reduced length of inpatient stay. PMID- 29613972 TI - Chronic Neutropenia in Children with Abscess Forming Cervical Lymphadenitis Caused by Staphylococcus aureus. AB - BACKGROUND: Suppurative cervical lymphadenitis is rare in children with limited information about the frequency of neutropenia in any series. METHODS: We conducted a retrospective review of pediatric patients in whom suppurative cervical lymphadenitis was diagnosed between April 2011 and March 2016 at a tertiary children's hospital in Tokyo, Japan. Microbiologically confirmed cases of cervical lymphadenitis with abscess formation were included in the analysis. RESULTS: Twenty-five patients (median age: 1 year old, 64% female) with abscess formation due to Staphylococcus aureus were identified. Among these 25 patients, five (20%) met the criteria for chronic neutropenia and four (80%) received the final diagnosis of autoimmune neutropenia based on the identification of the serum anti-CD16 antibodies. CONCLUSIONS: Chronic neutropenia and autoimmune neutropenia were relatively common among infants with suppurative cervical lymphadenitis caused by S. aureus. PMID- 29613973 TI - Genetic Relatedness of Staphylococcus haemolyticus in Gut and Skin of Preterm Neonates and Breast Milk of Their Mothers. AB - BACKGROUND: Staphylococcus haemolyticus is a common colonizer and cause of late onset sepsis (LOS) in preterm neonates. By describing genetic relatedness, we aimed to determine whether mother's breast milk (BM) is a source of S. haemolyticus colonizing neonatal gut and skin and/or causing LOS. METHODS: S. haemolyticus was isolated from stool and skin swabs of 49 BM-fed preterm neonates admitted to neonatal intensive care unit, 20 healthy BM-fed term neonates and BM of mothers once a week and typed by multilocus variable-number tandem-repeat analysis (MLVA) and multilocus sequence typing (MLST). Virulence-related genes were determined by PCR. RESULTS: Compared with term neonates S. haemolyticus colonized more commonly gut (35% vs 89.9%; p<0.001) and skin (50% vs 91.8%; p<0.001) of preterm neonates and mothers' BM (15% vs 38.8%). Isolates from preterm compared with term neonates and their mothers carried more commonly the mecA gene (83.5% vs 5.4%; p<0.001) and IS256 (52.4% vs 2.7%; p<0.001) and belonged to clonal complex 29 (89.1% vs 63%; p=0.014). Only 7 (14.3%) preterm and 3 (15%) term neonates were colonized in gut or on skin with MLVA-types indistinguishable from those in BM. Most frequent MLVA-types belonged to sequence type 3 or 42, comprised 71.1-78.4% of isolates from preterm neonates/mothers and caused all seven LOS episodes. LOS-causing strain colonized the gut of 4/7 and the skin of 5/7 neonates, but not BM, prior to onset of LOS. CONCLUSIONS: S. haemolyticus colonizing gut and skin or causing LOS in preterm neonates rarely originate from BM, but are mecA-positive strains adapted to hospital environment. PMID- 29613974 TI - Fatal P. jirovecii and Cytomegalovirus Infections in an Infant with Normal Trecs Count: Pitfalls of Newborn Screening for Severe Combined Immunodeficiency. AB - Newborn screening (NBS) for severe combined immunodeficiency (SCID) using T-cell receptor-excision circles (TRECs) allows prompt diagnosis and initiation of supportive and curative therapy thereby reducing morbidity and mortality. However, profound combined immunodeficiencies with normal numbers of non functional T cells will go undetected. We present a patient with ORAI1 deficiency and normal TREC numbers observed after diagnosis at the age of 14 months who suffered from disseminated fatal cytomegalovirus and Pneumocystis jirovecii infection, demonstrating a potential pitfall of the current NBS program. PMID- 29613975 TI - Antibiotic Overuse in Premature Low-Birth-Weight Infants in a Developing Country. AB - BACKGROUND: Neonatal sepsis is a leading cause of child morbidity and mortality, especially in premature and low-birth-weight (LBW) infants. Prompt antibiotic therapy is warranted, but its inappropriate use leads to bacterial resistance and adverse outcomes. Our objective is to describe the antibiotic use for late onset sepsis (LOS) in Peruvian premature infants. METHODS: Prospective study as a secondary analysis of a clinical trial in three Neonatal Care Units in Peru. We included infants in the first 72 hours of life, with birth weight (BW) <2000g. We described the antibiotic use as length of therapy (LOT) per 1000 patient days (PD) and antibiotic courses. RESULTS: We included 408 neonates, with 12204 PD of follow-up; 253 infants (62%) had a BW <=1500 g. Total antibiotic use for LOS was 2395 LOT (196 LOT/1000PD). 271 patients (66.4%) did not receive antibiotics for LOS during their hospitalization. In total, 204 antibiotic courses were administered; 92 infants (22.5%) received 1 course, and 45 (11.0%) received 2 to 5 antibiotic courses. Mean duration of antibiotic course was 10.8 days (SD: +/ 7.3). We found a significant association between a lower BW and increased antibiotic use per day (p<0.001). The most commonly used antibiotics were vancomycin (143 LOT/1000PD), carbapenems (115 LOT/1000PD), aminoglycosides (72 LOT/1000PD), and ampicillin (41 LOT/1000PD). CONCLUSIONS: Premature infants receive antibiotics for longer than recommended periods of time. Antibiotic overuse is greater in neonates with lower BW. Vancomycin is the most used antibiotic. There is an urgent need to develop antimicrobial stewardship programs in our setting. PMID- 29613976 TI - Similar Performance of Trabectome and Ahmed Glaucoma Devices in a Propensity Score-matched Comparison. AB - PURPOSE: To apply propensity score matching to Ahmed glaucoma drainage implants (AGI) to trabectome-mediated ab interno trabeculectomy (AIT). Recent data suggest that AIT can produce results similar to AGI traditionally reserved for more severe glaucoma. METHODS: AGI and AIT patients with at least 1 year of follow-up were included. The primary outcome measures were intraocular pressure (IOP), glaucoma medications, and a Glaucoma Index (GI) score. GI reflected glaucoma severity based on visual field, the number of preoperative medications, and preoperative IOP. Score matching used a genetic algorithm consisting of age, sex, type of glaucoma, concurrent phacoemulsification, baseline number of medications, and baseline IOP. Patients without a close match were excluded. RESULTS: Of 152 patients, 34 AIT patients were matched to 32 AGI patients. Baseline characteristics including ethnicity, IOP, the number of medications, glaucoma type, the degree of visual field loss and GI were not significantly different between AIT and AGI. AIT had a preoperative IOP of 23.6+/-8.1 mm Hg compared with 26.5+10.6 mm Hg for AGI. At 12 months, the mean IOP was 15.0+/-9 mm Hg for AIT versus 15.0+/-4 mm Hg for AGI (P=0.8), whereas the number of drops was 2.3+/-2.2 for AIT versus 3.6+/-1.3 for AGI (P=0.016). Only 6 AIT patients (17.6%) required further surgery within the first 12 months versus 9 (28%) for AGI. Success, defined as IOP<21 mm Hg, <20% reduction and no reoperation, was achieved in 76% of AIT versus 69% of AGI (P=0.48). Complications occurred in 13% of AGI and 0.8% of AIT. CONCLUSIONS: A propensity score-matched comparison of AIT and AGI showed an equivalent IOP reduction through 1 year. Surprisingly, the AGI group required more glaucoma medications than the AIT group at 6 and 12 months. PMID- 29613977 TI - Scanning Behavior and Daytime Driving Performance of Older Adults With Glaucoma. AB - PURPOSE: The purpose of this study was to assess the link between visual scanning behavior and closed-road driving performance in older drivers with glaucomatous visual impairment. MATERIALS AND METHODS: Participants included 13 older drivers with glaucoma [mean age=71.6+/-7.1 y; average better-eye mean deviation (MD)= 2.9+/-2.1 dB, average worse-eye MD=-12.5+/-7.1 dB] and 10 visually normal controls (mean age=70.6+/-7.4 y). Visual acuity, contrast sensitivity, visual fields, useful field of view, and motion sensitivity were assessed. Participants drove around a closed-road circuit while their eye movements were recorded with an ASL Mobile Eye-XG, and head movements recorded using the gyroscope sensors of a smart phone. Measures of driving performance included hazards hit, sign recognition, and lane-crossing time; an overall driving score was derived from these component measures. RESULTS: Participants with glaucoma had significantly poorer overall driving scores (P=0.026) and hit more hazards (P=0.043) than controls. The glaucoma group also exhibited larger saccades (P<0.001) and horizontal (P<0.001) and vertical search variances (P=0.002) than controls. Larger saccades were associated with better driving scores in the glaucoma group (P=0.001), but not the controls (P=0.75). Head movements did not differ between groups. For all participants, better-eye MD was the strongest visual predictor of overall driving score (P<0.001), followed by the other measures of visual fields, motion sensitivity, contrast sensitivity, and useful field of view (P<0.05). CONCLUSIONS: Older drivers with glaucoma had poorer driving performance than controls and demonstrated differences in eye movement patterns. The association between larger saccades and better driving scores in those with glaucoma suggests that altering scanning behavior may benefit driving performance and safety in this group. PMID- 29613979 TI - Anterior Chamber Sulfur Hexafluoride (SF6) Injection for the Management of Postsurgery Hypotony in Glaucoma Patients. AB - PURPOSE: The purpose of this article was to describe a new technique involving the injection of sulfur hexafluoride (SF6) gas in the anterior chamber (A/C) for the management of hypotony in patients with previous glaucoma surgery. MATERIALS AND METHODS: Seven patients were included in this prospective case series. All patients had advanced glaucoma that was managed surgically either by trabeculectomy (6 patients) or Ahmed valve (1 patient). All patients presented with intraocular pressure (IOP) <7 mm Etag, shallow A/C, and ultrasound images of choroidal detachment and ciliary body detachment. Patients' hypotony was treated by 0.4 to 0.6 mL of 100% pure SF6 injection in the A/C followed by supine posture. The purpose of this injection was dual: to displace the ciliary body to its normal position and restore aqueous humor normal production, and to block aqueous humor outflow through bubble formation, causing an increase in IOP. RESULTS: Surgical technique was successful in all 7 patients with IOP normalization (>10 mm Hg) and A/C depth increase within the first week after surgery. CONCLUSION: A new surgical technique of SF6 injection in the A/C for patients with choroidal detachment and hypotony shows promising results. PMID- 29613978 TI - Gonioscopy-assisted Transluminal Trabeculotomy: An Ab Interno Circumferential Trabeculotomy: 24 Months Follow-up. AB - PURPOSE: The purpose of this study was to provide 24-month follow-up on surgical success and safety of an ab interno circumferential 360-degree trabeculotomy. METHODS: Chart review of patients who underwent a gonioscopy-assisted transluminal trabeculotomy (GATT) procedure was performed by 4 of the authors (D.S.G., O.S., R.L.F., and D.G.G.). The surgery was performed in adults with various types of open-angle glaucoma with preoperative intraocular pressures (IOPs) of >=18 mm Hg. RESULTS: In total, 198 patients aged 24 to 89 years underwent the GATT procedure with at least 18 months follow-up. Patients with primary open-angle glaucoma had an average IOP decrease of 9.2 mm Hg at 24 months with an average decrease of 1.43 glaucoma medications. The mean percentage of IOP decrease in these primary open-angle glaucoma groups at 24 months was 37.3%. In secondary open-angle glaucoma, at 24 months there was an average decrease in IOP of 14.1 mm Hg on an average of 2.0 fewer medications. The mean percentage of IOP decrease in the secondary open-angle glaucoma groups at 24 months was 49.8%. The cumulative proportion of failure at 24 months ranged from 0.18 to 0.48, depending on the group. In all 6 study groups, at all 5 postoperative time points (3, 6, 12, 18, and 24 mo) the mean IOP and reduction in glaucoma medications was significantly reduced from baseline (P<0.001) with the exception of one time point. CONCLUSIONS: The 24-month results demonstrate that GATT is relatively safe and effective in treating various forms of open-angle glaucoma. The long-term results for GATT are relatively equivalent to those previously reported for GATT and ab externo trabeculotomy studies. PMID- 29613980 TI - Use of Intravitreal Bevacizumab for the Treatment of Secondary Glaucoma Caused by Metastatic Iris Tumor. AB - PURPOSE: The purpose of this article was to report the efficacy of intravitreal bevacizumab to resolve secondary angle-closure glaucoma caused by biliary tract carcinoma metastasis to the iris. MATERIALS AND METHODS: A 52-year-old white woman who was under systemic chemotherapy for biliary tract carcinoma presented with a metastatic tumor in the left iris. At presentation, her visual acuity was at the 20/50 level. The tumor was occupying the nasal half of the iris, and had already occupied 5.5 clock hours of the angle, resulting in intraocular pressure elevation to 34 mm Hg. Several small clumps of tumor seeds were also observed on the iris and along the angle. Her intraocular pressure remained high despite full medical therapy with dorzolamide, timolol, brimonidine, and oral acetozolamide. Because of the vascularized nature of the tumor, antivascular endothelial growth factor (anti-VEGF) treatment with 3 repeated injections of bevacizumab (1.25 mg/0.05 mL) was applied 1-month apart. Bevacizumab treatment resulted in an abrupt decrease in tumor mass and disappearance of tumoral seeds from the anterior chamber. The patient's vision improved to 20/20, and intraocular pressure decreased to normal levels. CONCLUSIONS: Anti-VEGF treatment with intravitreal bevacizumab can restore sight and achieve intraocular pressure control in metastatic iris tumors complicated with secondary glaucoma. Anti-VEGF drugs are viable alternatives for the treatment of secondary angle-closure glaucoma induced by metastatic iris tumors and can prevent enucleation of these eyes. PMID- 29613981 TI - Phacomorphic Angle-closure Following Silicone Oil Tamponade in a Pediatric Patient. AB - PURPOSE: The purpose of this study was to report a case of phacomorphic glaucoma following retinal detachment repair with silicone oil (SO) in a pediatric patient. STUDY DESIGN: Case report. METHODS: A chart review was conducted at St. Michael's Hospital and The Hospital for Sick Children (Toronto, Canada), where the patient received ophthalmic care from July 28, 2015 onwards. RESULTS: A 14 year-old boy with a history of traumatic retinal detachment and proliferative vitreoretinopathy in the left eye, requiring 2 pars plana vitrectomies, membrane peel, and SO tamponade, presented with 1-day history of decreased vision in the left eye, severe headache, nausea, and vomiting. Visual acuity was hand motions; intraocular pressure (IOP) was 54 mm Hg; the pupil was middilated and minimally reactive with a reverse relative afferent pupillary defect. Slit-lamp examination revealed an injected eye with diffuse microcystic corneal edema, a shallow anterior chamber (AC), and an intumescent cataract. Gonioscopy demonstrated closed angles in 3 quadrants. Compared with his last examination 6 weeks prior, where only a mild posterior subcapsular cataract was noted, the patient's presentation was suggestive of rapid lens intumescence causing acute angle closure glaucoma. He was given topical and systemic treatment, including intravenous mannitol, and his IOP reduced to 22 mm Hg after 7 hours. Urgent lensectomy was performed the following day. Preoperative ultrasound biomicroscopy revealed a greatly increased lens thickness of 5.12 mm and an AC depth of 1.12 mm. The integrity of both anterior and posterior lens capsules was confirmed intraoperatively, and SO remained confined to the posterior segment. Postoperatively, the iris returned to a normal configuration with open angles, and IOP was 16 mm Hg with no antiglaucoma medications at the last follow-up. CONCLUSIONS: Acute angle-closure in children is a rare event. To our knowledge, this is the first reported case of phacomorphic glaucoma secondary to vitreoretinal surgery in the pediatric population. Although uncommon, ophthalmologists should be aware of this potential complication with the intraocular use of SO and administer urgent treatment accordingly. PMID- 29613983 TI - In Vivo Abdominal Magnetic Resonance Elastography for the Assessment of Portal Hypertension Before and After Transjugular Intrahepatic Portosystemic Shunt Implantation: Erratum. PMID- 29613982 TI - Association Between the Deep-layer Microvasculature Dropout and the Visual Field Damage in Glaucoma. AB - PURPOSE: To compare the visual field (VF) sensitivity according to the presence of parapapillary deep-layer microvasculature dropout (MvD_P) and focal lamina cribrosa (LC) defect. MATERIALS AND METHODS: Among 158 open-angle glaucoma patients, 4 groups were formed according to the presence of MvD_P and focal LC defect determined by optical coherence tomography (OCT) angiography and by enhanced depth imaging spectral-domain OCT, respectively: (1) eyes without either focal LC defect or MvD_P (group 1); (2) eyes with focal LC defect but no MvD_P (group 2); (3) eyes without focal LC defect but with MvD_P (group 3); (4) eyes with both focal LC defect and MvD_P (group 4). VF sensitivity and retinal nerve fiber layer (RNFL) thickness were compared among the 4 groups for global area and 6 sectors. RESULTS: Both RNFL thickness and VF sensitivity differed among the 4 groups in all areas other than the nasal and superonasal sectors for RNFL thickness. On post hoc analysis, eyes with MvD_P (groups 3 and 4) had significantly worse VF sensitivity than group 2 [P<0.05, 1-way analysis of variance (ANOVA)] in all areas except the superotemporal and temporal sectors, whereas the RNFL thicknesses did not differ (P>0.05, 1-way ANOVA) in any areas except the superotemporal sector. CONCLUSIONS: Eyes with MvD_P had worse VF sensitivity than those without MvD_P, and VF difference was more distinguished than differences of axonal loss and focal LC change. Further studies on the temporal relationship between the MvD_P and glaucomatous VF progression are warranted. PMID- 29613984 TI - T2-Weighted Dixon Turbo Spin Echo for Accelerated Simultaneous Grading of Whole Body Skeletal Muscle Fat Infiltration and Edema in Patients With Neuromuscular Diseases. AB - OBJECTIVE: The assessment of fatty infiltration and edema in the musculature of patients with neuromuscular diseases (NMDs) typically requires the separate performance of T1-weighted and fat-suppressed T2-weighted sequences. T2-weighted Dixon turbo spin echo (TSE) enables the generation of T2-weighted fat- and water separated images, which can be used to assess both pathologies simultaneously. The present study examines the diagnostic performance of T2-weighted Dixon TSE compared with the standard sequences in 10 patients with NMDs and 10 healthy subjects. METHODS: Whole-body magnetic resonance imaging was performed including T1-weighted Dixon fast field echo, T2-weighted short-tau inversion recovery, and T2-weighted Dixon TSE. Fatty infiltration and intramuscular edema were rated by 2 radiologists using visual semiquantitative rating scales. To assess intermethod and interrater agreement, weighted Cohen's kappa coefficients were calculated. RESULTS: The ratings of fatty infiltration showed high intermethod and high interrater agreement (T1-weighted Dixon fast field echo vs T2-weighted Dixon TSE fat image). The evaluation of edematous changes showed high intermethod and good interrater agreement (T2-weighted short-tau inversion recovery vs T2-weighted Dixon TSE water image). CONCLUSIONS: T2-weighted Dixon TSE imaging is an alternative for accelerated simultaneous grading of whole-body skeletal muscle fat infiltration and edema in patients with NMDs. PMID- 29613985 TI - 11C-Methionine Positron Emission Tomography/Computed Tomography Versus 18F Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Evaluation of Residual or Recurrent World Health Organization Grades II and III Meningioma After Treatment. AB - OBJECTIVE: The aim of this study was to determine the assessment of positron emission tomography-computed tomography using C-methionine (MET PET/CT) for World Health Organization (WHO) grades II and III meningiomas; MET PET/CT was compared with PET/CT using F-fluorodeoxy glucose (FDG PET/CT). METHODS: This study was performed in 17 cases with residual and/or recurrent WHO grades II and III meningiomas. Two neuroradiologists reviewed both PET/CT scans. For agreement, the kappa coefficient was measured. Difference in tumor-to-normal brain uptake ratios (T/N ratios) between 2 PET/CT scans was analyzed. Correlation between the maximum tumor size and T/N ratio in PET/CT was studied. RESULTS: For agreement by both reviewers, the kappa coefficient was 0.51 (P < 0.05). The T/N ratio was significantly higher for MET PET/CT (3.24 +/- 1.36) than for FDG PET/CT (0.93 +/- 0.44) (P < 0.01). C-methionine ratio significantly correlated with tumor size (y = 8.1x + 16.3, n = 22, P < 0.05), but FDG ratio did not CONCLUSIONS: C-methionine PET/CT has superior potential for imaging of WHO grades II and III meningiomas with residual or recurrent tumors compared with FDG PET/CT. PMID- 29613986 TI - Malignant Pleural Mesothelioma: Are There Imaging Characteristics Associated With Different Histologic Subtypes on Computed Tomography? AB - OBJECTIVES: Determine imaging characteristics specific to epithelioid (eMPM), sarcomatoid (sMPM), and biphasic (bMPM) subtypes of malignant pleural mesothelioma (MPM) on computed tomography. METHODS: Preoperative computed tomography scans of patients with MPM were retrospectively assessed for numerous features including primary affected side, volume loss, pleural thickness, pleural calcifications, pleural effusion, and lymphadenopathy. RESULTS: One hundred twenty-five patients with MPM were included. Histologic subdivision was 97 eMPM (77%), 17 bMPM (14%), and 11 sMPM (9%). Nonepithelioid MPM (bMPM and sMPM) was more likely than eMPM to have calcified pleural plaques (P = 0.035). Analyzed separately, bMPM and sMPM each demonstrated calcified plaques more frequently than eMPM, and sMPM more often had internal mammary nodes; however, P values did not reach significance (P = 0.075 and 0.071, respectively). CONCLUSIONS: Calcified plaques are significantly more common in nonepithelioid subtypes compared with eMPM. Given the different prognoses and management of MPM subtypes, accurate noninvasive subtype classification is clinically vital. PMID- 29613987 TI - Focal Myocardial Damage in Cardiac Sarcoidosis Characterized by Strain Analysis on Magnetic Resonance Tagged Imaging in Comparison with Fluorodeoxyglucose Positron Emission Tomography Accumulation and Magnetic Resonance Late Gadolinium Enhancement. AB - OBJECTIVE: The aims of this study were to characterize focal myocardial damage of cardiac sarcoidosis by strain analysis and to compare it with late gadolinium enhancement (LGE) and fluorodeoxyglucose (FDG) positron emission tomography. METHODS: We reviewed 208 segments from 13 cardiac sarcoidosis patients and measured the circumferential strain (Ecc) and the strain change per second (Ecc rate). The mean Ecc and Ecc rate values were compared between the FDG(+) and FDG( ), and the LGE(+) and LGE(-) segments using Welch's t test. RESULTS: The peak and max Ecc rates were better in the LGE(-) segments than in the LGE(+) segments ( 11.8 vs -8.9%, 40.5 vs 29.7%/s, both P < 0.001). The max Ecc rate was higher in the FDG(-) segments than in the FDG(+) segments (39.2 vs 31.7%/s, P < 0.001), but the peak Ecc did not differ between the FDG(+) and FDG(-) segments (-11.2 vs 10.1%, P = 0.17). CONCLUSIONS: Strain analysis could reveal focal myocardial damage in the FDG(+) or the LGE(+) segments. PMID- 29613989 TI - How Well Does Dual-Energy Computed Tomography With Metal Artifact Reduction Software Improve Image Quality and Quantify Computed Tomography Number and Iodine Concentration? AB - OBJECTIVE: The objective of this study was to assess the accuracy of the quantitative measurements obtained using dual-energy computed tomography with metal artifact reduction software (MARS). METHODS: Dual-energy computed tomography scans (fast kV-switching) are performed on a phantom, by varying the number of metal rods (Ti and Pb) and reference iodine materials. Objective and subjective image analyses are performed on retroreconstructed virtual monochromatic images (VMIs) (VMI at 70 keV). RESULTS: The maximum artifact indices for VMI-Ti and VMI-Pb (5 metal rods) with MARS (without MARS) were 17.4 (166.7) and 34.6 (810.6), respectively; MARS significantly improved the mean subjective 5-point score (P < 0.05). The maximum differences between the measured Hounsfield unit and theoretical values for 5 mg/mL iodine and 2-mm core rods were -42.2% and -68.5%, for VMI-Ti and VMI-Pb (5 metal rods), respectively, and the corresponding differences in the iodine concentration were -64.7% and -73.0%, respectively. CONCLUSIONS: Metal artifact reduction software improved the objective and subjective image quality; however, the quantitative values were underestimated. PMID- 29613988 TI - Dual-Energy Computed Tomography-Based Iodine Quantitation for Response Evaluation of Lung Cancers to Chemoradiotherapy/Radiotherapy: A Comparison With Fluorine-18 Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography-Based Positron Emission Tomography/Computed Tomography Response Evaluation Criterion in Solid Tumors. AB - OBJECTIVE: The objective of this study was to investigate the correlation between dual-energy computed tomography (DECT)-based iodine quantitation and fluorine-18 fluorodeoxyglucose (F-FDG) positron emission tomography (PET)/computed tomography (CT) imaging for response evaluation of lung cancers to treatment. METHODS: In this prospective study, a total of 32 pairs of DECT and F-FDG PET/CT imaging acquired consecutively from 13 patients with primary or metastatic lung cancers receiving either radiotherapy alone or chemoradiotherapy were analyzed. Imaging examinations were performed before, immediately, and no later than 6 months after treatment for response evaluation. Iodine-related parameters including the total iodine uptake (TIU) and vital volume (VIV) from DECT and metabolic metrics such as the standardized uptake value normalized to lean body mass (SULpeak), metabolic tumor volume (MTV), and the total lesion glycolysis (TLG) from F-FDG PET/CT were generated and measured by semiautomatic approaches. Dual-energy CT and PET/CT metrics were calculated and followed up with comparison with response evaluation criteria in solid tumors (RECIST). RESULTS: Analysis of pretreatment imaging data revealed a strong correlation between DECT metrics (RECIST, TIU, and VIV) and F-FDG PET/CT metrics (MTV, TLG) with coefficients of R ranging from 0.86 to 0.90 (P < 0.01). With the delivery of treatment, all measured DECT and PET/CT metrics significantly decreased whereas the descending amplitude in RECIST was significantly smaller than that of the remaining parameters (P < 0.05). During follow-up examinations, both metrics followed a similar changing pattern. Overall, strong consistency was found between RECIST, TIU, VIV and SULpeak, MTV, TLG (R covers 0.78-0.96, P < 0.05). CONCLUSIONS: Semiautomatic iodine-related quantitation in DECT correlated well with metabolism-based measurements in F-FDG PET/CT, suggesting that DECT-based iodine quantitation might be a feasible substitute for assessment of lung cancer response to chemoradiotherapy/radiotherapy with comparison with F-FDG PET/CT. PMID- 29613990 TI - Motion Artifact Reduction From High-Pitch Dual-Source Computed Tomography Pulmonary Angiography. AB - PURPOSE: The purpose of this study was to compare quantitative and qualitative measures of aortic, cardiac, and respiratory motion artifact between high-pitch dual-source (DS) and single-source (SS) computed tomography pulmonary angiography (CTPA) protocols. METHODS: This institutional review board-approved, Health Insurance Portability and Accountability Act-compliant study retrospectively reviewed 80 non-electrocardiogram-gated CTPA examinations acquired with a second generation DS system at 100 kVp following 50 mL iodinated contrast injection - 40 consecutive SS and 40 consecutive DS studies. Quantitative measures of aortic, left ventricular, and diaphragmatic motion were recorded as the maximal excursion of a structure's "double image," and 3 independent readers performed qualitative motion assessments. Pulmonary arterial contrast enhancement, image noise, and radiation dose metrics were recorded. Statistical analyses were performed with 1 way analysis of variance and Fisher exact test. RESULTS: Dual source outperformed SS technique in both quantitative and qualitative measures of motion. Mean distances between motion-artifact double images were reduced with DS protocol at each location (all P <= 0.004), and DS examinations were more likely to receive an assessment of no motion in all locations (all P < 0.0001). The DS protocol demonstrated increases in contrast enhancement, although increased image noise resulted in lower enhancement to noise ratio. Mean radiation dose was 60% lower using the DS protocol. CONCLUSION: High-pitch DS CTPA significantly reduces artifacts resulting from ascending aortic, cardiac, and diaphragmatic motion. PMID- 29613991 TI - Imaging Findings in Papillary Breast Lesions: An Analysis of Ductal Findings on Magnetic Resonance Imaging and Ultrasound. AB - PURPOSE: This study aims to analyze the imaging features of dilated ducts or ductal extension/relation of masses detected by ultrasound (US) and magnetic resonance imaging (MRI) and to correlate the results obtained through these 2 different imaging methods. Furthermore, the ability of the ductal relation pattern in differentiating benign and malignant lesions was explored. METHODS AND MATERIALS: Magnetic resonance imaging and US findings of 56 patients who had a pathologic diagnosis of papillary lesion were examined. Ductal findings were classified into four types for both imaging methods: intraductal form, extraductal form, mixed form, and no ductal relation. The correlation between MRI and US was then analyzed with respect to ductal findings. Statistical analyses were performed to determine the value of ductal patterns determined by these 2 imaging methods in the differentiation of benign and malignant papillary lesions. RESULTS: A total of 56 cases with papillomatosis (n = 11), papillomas (n = 29), and papillary breast carcinomas (n = 16) were included. There was a statistically significant correlation between all ductal patterns on US and the corresponding ductal signs on MRI. Palpable masses were statistically more common in patients with papillary breast carcinoma compared with other groups (P < 0.01). Segmental contrast enhancement occurred at a significantly higher rate in papillary breast carcinoma and papillomatosis patients, as compared with papilloma patients (P < 0.05). CONCLUSIONS: Actual resolution of MRI is close to that of US in terms of the ability to demonstrate the ductal relation of masses. Segmental contrast enhancement on MRI and nonmass-like heterogeneous hypoechoic area or mass with multiple ductal extensions on US can be used in discriminating benign versus malignant papillary lesions. The absence of ductal sign in MRI indicates benignity. PMID- 29613992 TI - Whole-lesion Apparent Diffusion Coefficient First- and Second-Order Texture Features for the Characterization of Rectal Cancer Pathological Factors. AB - OBJECTIVE: The objective of this study was to explore the value of whole-volume apparent diffusion coefficient (ADC) features in characterizing pathologic features of rectal cancer. METHODS: A total of 50 patients who were diagnosed with rectal cancer via biopsy underwent 3-T pretreatment diffusion-weighted imaging. Apparent diffusion coefficient features, including mean, 10th-90th percentile, Entropy and Entropy(H), derived from whole-lesion volumes were compared between pathologic T1-2 and T3 stages, perineural invasion (PNI) present and absent, lymphangiovascular invasion present and absent, and pathological N0 and N+ stage groups. RESULTS: Entropy and Entropy(H) were significantly lower in rectal cancers at T1-2 stages than T3. The 90th percentile of rectal cancers with PNI was significantly lower than that of those without PNI. All P < 0.05. CONCLUSIONS: Whole-lesion ADC Entropy and Entropy(H) have potential in evaluating different T stages, and 90th percentile can be helpful for determining PNI presence of rectal cancers. PMID- 29613993 TI - Solid Papillary Carcinoma of the Breast: Magnetic Resonance Mammography, Digital Mammography, and Ultrasound Findings. AB - BACKGROUND: The aim of this study was to investigate the MR mammography (MRM), digital mammography (DM), and ultrasound (US) findings of solid papillary carcinoma (SPC) of breast and to raise awareness of this rare breast tumor. MATERIAL AND METHODS: Thirty patients diagnosed with breast SPC (age range, 21 72; mean age, 60.27 years) from January 2013 to August 2015 were enrolled. Their clinical presentation and MRM, DM, and US findings were retrospectively reviewed. All patients underwent both MRM and US, and 20 of them underwent DM. The research primarily investigated MRM features correlated with clinicopathological characteristics. RESULTS: Of all the patients, 13 were pure SPC in suit, whereas 17 were microinvasive SPC. The detection rates of US, DM, and magnetic resonance imaging for SPC were 30%, 50%, and 100%, respectively, and there were no specific imaging features on DM and US. The most common MRM appearances were located in the retroareolar area (16/30, 53.34%) with T2WI hyperintensity (24/30, 80%) and ductal ectasia (18/30, 60%). Non-mass enhancement of a linear or segmental distribution (17/18, 94.44%) together with clumped enhancement (12/18, 66.66%) and mass with a rim (6/12, 50%) or heterogeneous (6/12, 50%) enhancement were 2 of the typical enhancement features of SPC. Compared with pure SPC, SPC with microinvasive showed larger size of the lesion (t = 1.083, P = 0.026). CONCLUSION: Although SPC was difficult to detect in both DM and US, MRM gave better detection of this rare tumor. The MRM characteristics of SPC were distinct and highly similar to its clinicopathological features. PMID- 29613994 TI - Evaluation of Modified Look-Locker Inversion Recovery and Arrhythmia-Insensitive Rapid Cardiac T1 Mapping Pulse Sequences in Cardiomyopathy Patients. AB - OBJECTIVE: The aim of this study was to compare the performance of arrhythmia insensitive rapid (AIR) and modified Look-Locker inversion recovery (MOLLI) T1 mapping in patients with cardiomyopathies. METHODS: In 58 patients referred for clinical cardiac magnetic resonance imaging at 1.5 T, we compared MOLLI and AIR native and postcontrast T1 measurements. Two readers independently analyzed myocardial and blood T1 values. Agreement between techniques, interreader agreement per technique, and intrascan agreement per technique were evaluated. RESULTS: The MOLLI and AIR T1 values were strongly correlated (r = 0.98); however, statistically significantly different T1 values were derived (bias 80 milliseconds, pooled data, P < 0.01). Both techniques demonstrated high repeatability (MOLLI, r = 1.00 and coefficient of repeatability [CR] = 72 milliseconds; AIR, r = 0.99 and CR = 184.2 milliseconds) and produced high interreader agreement (MOLLI, r = 1.00 and CR = 51.7 milliseconds; AIR, r = 0.99 and CR = 183.5 milliseconds). CONCLUSIONS: Arrhythmia-insensitive rapid and MOLLI sequences produced significantly different T1 values in a diverse patient cohort. PMID- 29613995 TI - Perforation of a Peptic Ulcer in a Hiatal Hernia Into the Left Ventricle With Systemic Air and Food Embolism. AB - Perforation of a peptic ulcer into the ventricle is uncommon, and the definitive diagnosis is difficult in living patients. We herein report a case of perforation of a peptic ulcer in a hiatal hernia into the left ventricle with systemic air and food embolism. This is the first case report of the perforation diagnosed by computed tomography and confirmed by autopsy. Computed tomography was useful for the diagnosis of perforation into the ventricle. PMID- 29613996 TI - Timing and Predictors of Mild and Severe Heat Illness among New Military Enlistees. AB - PURPOSE: Heat illnesses are important and potentially fatal conditions among physically active individuals. We determined predictors of heat illness among enlistees in a large military population experiencing common physical activity patterns. METHODS: We estimated the adjusted odds of mild (MHI) and severe (SHI) heat illness associated with demographic, health-related, and geographic factors among active-duty, US Army soldiers enlisting between January 2011 and December 2014 (N = 238,168) using discrete-time multivariable logistic regression analyses. RESULTS: We observed 2612 incident cases of MHI and 732 incident cases of SHI during 427,922 person-years of follow-up, with a mean and median of 21.6 and 21 months per subject. During the first 6 duty months, 71.3% of the MHIs and 60.2% of the SHIs occurred, peaking at month 2. The odds of MHI quadrupled among those with prior SHI (odds ratio [OR], 4.02; 95% confidence interval [CI], 2.67 6.03). Body mass index (BMI) extremes increased the odds substantially (OR at BMI >=30 kg.m: for MHI, 1.41 (CI, 1.19-1.67); for SHI, 1.94 (CI, 1.47-2.56); OR at BMI <18.5 kg.m: for MHI, 1.50 (CI, 1.01-2.21); for SHI, 2.26 (CI, 1.16-4.39)). Tobacco use was associated with a 55% increase (CI, 1.37-1.77) in MHI odds. The odds of MHI increased if taking nonsteroidal anti-inflammatory drugs, opioids, or methylphenidate stimulants. Lower age and lower entry aptitude scores were associated with progressively increased MHI odds. CONCLUSIONS: Most heat illnesses occurred at the outset of service, indicating the need for focused prevention methods at the initiation of military duty. Prior heat illness, BMI extremes, medications, and tobacco use represent potentially actionable risk factors to address by education, policy, and/or clinician intervention. PMID- 29613997 TI - Neuromuscular Dysfunction and Cortical Impairment in Sleep Apnea Syndrome. AB - PURPOSE: Lower muscle strength and endurance have been reported in severe obstructive sleep apnea (OSA). Increased intracortical inhibition previously reported at rest in OSA suggests central neuromuscular impairments in these patients. We hypothesized that (i) OSA patients demonstrate reduced knee extensor strength and endurance due to central impairments and (ii) continuous positive airway pressure (CPAP) treatment improves neuromuscular function in these patients. METHODS: Twelve OSA patients and 11 healthy controls performed intermittent knee extensions until task failure before and after 8 wk of CPAP treatment or control period. Maximal voluntary contraction, voluntary activation and corticospinal excitability and inhibition assessed by single- and paired pulse transcranial magnetic stimulation were measured before and during the fatiguing task. RESULTS: Time to exhaustion was lower in OSA (before CPAP treatment: 1008 +/- 549 s; after CPAP treatment: 975 +/- 378 s) compared with controls (before control period: 1476 +/- 633 s; after control period: 1274 +/- 506 s; P = 0.017). Obstructive sleep apnea patients had reduced maximal voluntary contraction and VATMS compared with controls throughout the fatiguing task as well as increased intracortical inhibition (all P < 0.05). Continuous positive airway pressure treatment did not induce any changes in neuromuscular function (P > 0.05 for all parameters). CONCLUSIONS: This study demonstrates that severe OSA patients have cortical impairments which are likely contributing to their reduced knee extensors strength and endurance. Both cortical impairments and neuromuscular function are not improved after 8 wk of CPAP treatment. PMID- 29613998 TI - Continuous Glucose Monitoring at High Altitude-Effects on Glucose Homeostasis. AB - PURPOSE: Exposure to high altitude has been shown to enhance both glucose and lipid utilization depending on experimental protocol. In addition, high and low blood glucose levels have been reported at high altitude. We hypothesized that gradual ascent to high altitude results in changes in glucose levels in healthy young adults. METHODS: Twenty-five adult volunteers, split into two teams, took part in the British Services Dhaulagiri Medical Research Expedition completing 14 d of trekking around the Dhaulagiri circuit in Nepal reaching a peak altitude of 5300 m on day 11 of the trek. Participants wore blinded continuous glucose monitors (CGM) throughout. Blood samples for C-peptide, proinsulin, and triacylglycerides were taken at sea level (United Kingdom) and in acclimatization camps at 3600, 4650, and 5120 m. Energy intake was determined from food diaries. RESULTS: There was no difference in time spent in hypoglycemia stratified by altitude. Nocturnal CGM readings (2200-0600 h) were chosen to reduce the short term effect of physical activity and food intake and showed a significant (P < 0.0001) increase at 3600 m (5.53 +/- 0.22 mmol.L), 4650 m (4.77 +/- 0.30 mmol.L), and 5120 m (4.78 +/- 0.24 mmol.L) compared with baseline altitude 1100 m (vs 4.61 +/- 0.25 mmol.L). Energy intake did not differ by altitude. Insulin resistance and beta-cell function, calculated by homeostatic model assessment, were reduced at 3600 m compared with sea level. CONCLUSIONS: We observed a significant increase in nocturnal CGM glucose at 3600 m and greater despite gradual ascent from 1100 m. Taken with the changes in insulin resistance and beta-cell function, it is possible that the stress response to high altitude dominates exercise enhanced insulin sensitivity, resulting in relative hyperglycemia. PMID- 29613999 TI - Exercise Reduces Dopamine D1R and Increases D2R in Rats: Implications for Addiction. AB - INTRODUCTION: Exercise has been shown to be effective for preventing and treating substance abuse in both clinical and preclinical studies. Less is known, however, regarding the underlying neurobiological mechanisms driving these changes in drug seeking behavior. One possibility is that exercise may alter the mesolimbic dopamine pathway in such a way that makes drugs of abuse less salient and/or rewarding. METHODS: To examine possible exercise-induced changes in dopamine signaling, male and female Lewis rats were split into exercise and sedentary groups at 8 wk of age. Exercise rats were run on a treadmill at 10 m.min, 5 d.wk, for 6 wk, whereas sedentary rats remained in their home cage. Rats were killed after the 6 wk of treatment, and their brains were used for in vitro autoradiography using [H]SCH 23,390, [H]Spiperone, and [H]WIN55,428 ligands to quantify dopamine type 1-like receptor (D1R)-like, dopamine type 2-like receptor (D2R)-like, and dopamine transporter binding, respectively. RESULTS: Exercised rats had 18% and 21% lower D1R-like binding levels compared to sedentary rats within the olfactory tubercle and nucleus accumbens shell, respectively. In addition, male and female exercise rats showed greater D2R-like binding levels within the dorsomedial caudate putamen (30%), ventrolateral caudate putamen (24%), and ventromedial caudate putamen (27%), as well as the olfactory tubercle (19%). Greater D2R-like binding in the nucleus accumbens core (24%) and shell (25%) of exercised rats compared with sedentary rats approached significance. No effects were found for dopamine transporter binding. CONCLUSIONS: These findings support the hypothesis that aerobic exercise results in changes in the mesolimbic pathway that could mediate exercise-induced attenuation of drug-seeking behavior. PMID- 29614000 TI - Biomechanical Model for Stress Fracture-related Factors in Athletes and Soldiers. AB - : Stress fractures (SF) are one of the most common and potentially serious overuse injuries. PURPOSE: This study aimed to develop a computational biomechanical model of strain in human tibial bone that will facilitate better understanding of the pathophysiology of SF. METHODS: The MRI of a healthy, young male was used for full anatomical segmentation of the calf tissues, which considered hard-soft tissues biomechanical interactions. From the undeformed coronal MR images, the geometry of bones, muscles, connecting ligaments, and fat were reconstructed in three dimensions and meshed to a finite element model. A force that simulated walking was applied on the tibial plateaus. The model was then analyzed for strains in the tibia under various conditions: unloaded walking, walking with a load equivalent to 30% of bodyweight, and walking under conditions of muscular fatigue. In addition, the effect of tibia robustness on strain was analyzed. RESULTS: The model showed that the tibia is mostly loaded by compression, with maximal strains detected in the distal anterior surface: 1241 and 384 microstrain, compressive and tensile, respectively. Load carriage resulted in ~30% increase in maximal effective strains. Muscle fatigue has a complex effect; fatigued calf muscles (soleus) reduced the maximal effective strains up to 9%, but fatigued thigh muscles increased those strains by up to 3%. It had also been shown that a slender tibia is substantially prone to higher maximal effective strains compared with an average (22% higher) or robust tibia (39% higher). CONCLUSIONS: Thigh muscle fatigue, load carriage, and a slender tibia were detected as factors that may contribute to the development of SF. The methodology presented here is a novel tool for investigating the pathophysiology of SF. PMID- 29614001 TI - Relationships between Habitual Cadence, Footstrike, and Vertical Load Rates in Runners. AB - : Excessive vertical ground reaction force (VGRF) load rates have been linked with running injuries. Increasing cadence (CAD) has been shown to reduce load rates; however, relationships between habitual cadence and load rates across a population of runners have not been examined. PURPOSE: To examine the relationships between habitual running cadence and vertical load rates in healthy and injured runners using habitual footstrike patterns. As CAD increased, we expected vertical load rates would decrease. METHODS: Healthy runners (n = 32, 25 men) and injured runners (n = 93, 45 men) seeking treatment were analyzed. Footstrike classifications were heel at initial contact (rearfoot strike [RFS]) or forefoot at initial contact (forefoot strike [FFS]). Runners were divided into four injury status/footstrike pattern (FSP) subgroups: healthy RFS (n = 19), injured RFS (n = 70), healthy FFS (n = 13), and injured FFS (n = 23). The VGRF and CAD were recorded as participants ran on an instrumented treadmill at self selected speed (x- = 2.6 m.s +/-0.12). Healthy runners used laboratory footwear similar to their habitual footwear, and injured runners used habitual footwear. The vertical average load rates and vertical instantaneous load rates of the VGRF of each runner's right leg were calculated and correlated with CAD for four injury status-FSP subgroups and for all runners combined. RESULTS: There were no differences in CAD between all runners or any subgroup (P > 0.05). Vertical average load rates and vertical instantaneous load rates were significantly higher (P <= 0.01) in the injured RFS group compared with all other subgroups. Injured FFS and healthy FFS had similar load rates (P = 1.0). CONCLUSIONS: We found no relationships between habitual running cadence and vertical load rates. The highest load rates were in injured RFS runners, and the lowest load rates were in FFS runners, regardless of injury status. Future studies of gait retraining to increase CAD and reduce load rates should follow runners long term to examine this relationship once CAD has become habituated. PMID- 29614002 TI - Expression, Tissue Localization and Serodiagnostic Potential of Echinococcus granulosus Leucine Aminopeptidase. AB - Echinococcus granulosus is the causative agent of cystic echinococcosis (CE), a widespread parasitic zoonosis. Leucine aminopeptidases (LAPs) of the M17 peptidase family have important functions in regulating the balance of catabolism and anabolism, cell maintenance, growth and defense. In this study, we presented a bioinformatic characterization and experimentally determined the tissue distribution characteristics of E. granulosus LAP (Eg-LAP), and explored its potential value for diagnosis of CE in sheep based on indirect ELISA. Through fluorescence immunohistochemistry, we found that Eg-LAP was present in the tegument and hooks of PSCs, the whole germinal layer and adult worm parenchymatous tissue. Western blotting results revealed that the recombinant protein could be identified using E. granulosus-infected sheep serum. The diagnostic value of this recombinant protein was assessed by indirect ELISA, and compared with indirect ELISA based on hydatid fluid antigen. The sensitivity and specificity rEgLAP-ELISA were 95.8% (23/24) and 79.09% (87/110), respectively, while using hydatid fluid as antigen showed the values 41.7% (10/24) and 65.45% (72/110). This is the first report concerning leucine aminopeptidase from E. granulosus, and the results showed that Eg-LAP belong to M17 peptidase families, and that it is involved in important biological function of E. granulosus. Furthermore, rEg-LAP is appropriate for diagnosing and monitoring CE in sheep in field. Development of a rapid test using rEg-LAP to diagnose sheep CE deserves further study. PMID- 29614003 TI - Naked-Eye Detection of Glucose in Saliva with Bienzymatic Paper-Based Sensor. AB - The high incidence of Diabetes Mellitus in low-income regions has promoted the development of low-cost alternatives to replace blood-based procedures. In this work, we present a bienzymatic paper-based sensor suitable for the naked-eye detection of glucose in saliva samples. The sensor was obtained by a stamping procedure and modified with chitosan to improve the colorimetric readout. The bienzymatic reaction of GOx-HRP coupled with 2,4,6-tribromo-3-hydroxy benzoic acid was applied for the detection of glucose within a range from 0 to 180 mgdL-1 in buffer and artificial saliva solutions. The visual readout was perceived by the naked eye and registered with an office scanner to evaluate the analytical performance. The results showed a limit of detection of 0.37 mgdL-1 (S/N = 3) with an R.S.D. of 1.69% and a linear range from 1 to 22.5 mgdL-1 with an R2 of 0.99235. The analysis of human saliva samples was performed without pre processing, achieving recoveries from 92 to 114%. The naked-eye detection was evaluated under two different light settings, showing average recoveries of 108.58 and 90.65% for standard and low illumination. The proposed device showed potential for easy-to-use, sensitive, low-cost, fast, and device-free detection of salivary glucose suitable for untrained personnel operation and limited facilities. PMID- 29614004 TI - One-Step Green Hydrothermal Synthesis of Few-Layer Graphene Oxide from Humic Acid. AB - The conventional synthesis route of graphene oxide (GOG), based on Hummers method, suffers from explosion risk, environmental concerns and a tedious synthesis process, which increases production costs and hinders its practical applications. Herein, we report a novel strategy for preparing few-layer graphene oxide (GOH) from humic acid via simple hydrothermal treatment. The formation of GOH is mainly attributed to the hydrolysis, oxidation and aromatization of humic acid under hydrothermal conditions. The as-prepared few-layer GOH has typical morphology (thin and crumpled sheets with the thickness of ~3.2 nm), crystal structure (a Raman ID/IG ratio of 1.09) and chemical composition (an X-ray Photoelectron Spectroscopy (XPS) O/C atomic ratio of 0.36) of few-layer GOG. The thermally reduced GOH (r-GOH) delivers considerable area capacitance of 28 uF.cm 2, high rate capability and low electrochemical resistance as supercapacitor electrodes. The described hydrothermal process shows great promise for the cheap, green and efficient synthesis of few-layer graphene oxide for advanced applications. PMID- 29614006 TI - Rapid CRISPR/Cas9-Mediated Cloning of Full-Length Epstein-Barr Virus Genomes from Latently Infected Cells. AB - Herpesviruses have relatively large DNA genomes of more than 150 kb that are difficult to clone and sequence. Bacterial artificial chromosome (BAC) cloning of herpesvirus genomes is a powerful technique that greatly facilitates whole viral genome sequencing as well as functional characterization of reconstituted viruses. We describe recently invented technologies for rapid BAC cloning of herpesvirus genomes using CRISPR/Cas9-mediated homology-directed repair. We focus on recent BAC cloning techniques of Epstein-Barr virus (EBV) genomes and discuss the possible advantages of a CRISPR/Cas9-mediated strategy comparatively with precedent EBV-BAC cloning strategies. We also describe the design decisions of this technology as well as possible pitfalls and points to be improved in the future. The obtained EBV-BAC clones are subjected to long-read sequencing analysis to determine complete EBV genome sequence including repetitive regions. Rapid cloning and sequence determination of various EBV strains will greatly contribute to the understanding of their global geographical distribution. This technology can also be used to clone disease-associated EBV strains and test the hypothesis that they have special features that distinguish them from strains that infect asymptomatically. PMID- 29614005 TI - Role of Gene Therapy in Pancreatic Cancer-A Review. AB - Mortality from pancreatic ductal adenocarcinoma (PDAC) has remained essentially unchanged for decades and its relative contribution to overall cancer death is projected to only increase in the coming years. Current treatment for PDAC includes aggressive chemotherapy and surgical resection in a limited number of patients, with median survival of optimal treatment rather dismal. Recent advances in gene therapies offer novel opportunities for treatment, even in those with locally advanced disease. In this review, we summarize emerging techniques to the design and administration of virotherapy, synthetic vectors, and gene editing technology. Despite these promising advances, shortcomings continue to exist and here will also be highlighted those approaches to overcoming obstacles in current laboratory and clinical research. PMID- 29614007 TI - Pepsin Egg White Hydrolysate Improves Glucose Metabolism Complications Related to Metabolic Syndrome in Zucker Fatty Rats. AB - The purpose of this study was to evaluate the effect of the administration of two egg white hydrolysates on glucose metabolism complications related to Metabolic Syndrome (MS) in Zucker fatty rats (ZFR). ZFR were given 750 mg/kg/day of egg white hydrolyzed with pepsin (HEW1) or with aminopeptidase (HEW2) for 12 weeks in their drinking water or just water. Zucker lean rats (ZLR), which received water, were used as a control. The presence of tactile allodynia, which is a sign of peripheral neuropathy, was assessed. Blood samples and pancreas were collected to determine the effect of the hydrolysates on glucose metabolism. The intake of HEW1 significantly lowered plasma insulin levels and improved the quantitative indexes of insulin resistance, insulin sensitivity, and pancreatic beta-cell functionality (HOMA-IR, HOMA-beta, and QUICKI, respectively), but non-significant changes were observed in group treated with HEW2. Compared to ZLR, ZFR showed tactile allodynia, but the consumption of both hydrolysates significantly increased mechanical sensitivity in ZFR. In conclusion, HEW1 pepsin could improve the glucose metabolism abnormalities associated with MS in obese Zucker rats. PMID- 29614008 TI - Discovery of a Manduca sexta Allatotropin Antagonist from a Manduca sexta Allatotropin Receptor Homology Model. AB - Insect G protein coupled receptors (GPCRs) have important roles in modulating biology, physiology and behavior. They have been identified as candidate targets for next-generation insecticides, yet these targets have been relatively poorly exploited for insect control. In this study, we present a pipeline of novel Manduca sexta allatotropin (Manse-AT) antagonist discovery with homology modeling, docking, molecular dynamics simulation and structure-activity relationship. A series of truncated and alanine-replacement analogs of Manse-AT were assayed for the stimulation of juvenile hormone biosynthesis. The minimum sequence required to retain potent biological activity is the C-terminal amidated octapeptide Manse-AT (6-13). We identified three residues essential for bioactivity (Thr4, Arg6 and Phe8) by assaying alanine-replacement analogs of Manse-AT (6-13). Alanine replacement of other residues resulted in reduced potency but bioactivity was retained. The 3D structure of the receptor (Manse ATR) was built and the binding pocket was identified. The binding affinities of all the analogs were estimated by calculating the free energy of binding. The calculated binding affinities corresponded to the biological activities of the analogs, which supporting our localization of the binding pocket. Then, based on the docking and molecular dynamics studies of Manse-AT (10-13), we described it can act as a potent Manse-AT antagonist. The antagonistic effect on JH biosynthesis of Manse-AT (10-13) validated our hypothesis. The IC50 value of antagonist Manse-AT (10-13) is 0.9 nM. The structure-activity relationship of antagonist Manse-AT (10-13) was also studied for the further purpose of investigating theoretically the structure factors influencing activity. These data will be useful for the design of new Manse-AT agonist and antagonist as potential pest control agents. PMID- 29614010 TI - Extraction and Analysis of Gigantol from Dendrobium officinale with Response Surface Methodology. AB - In order to optimize the extraction of gigantol from Dendrobium officinale, the influence of methanol concentration, ultrasonic temperature, and liquid ratio on extraction efficiency was analysed by the response surface analysis method. The results show that the extraction rate reached a maximum when the methanol concentration was 92.98%, the solid-liquid ratio was 27.2 mL/g, and the extraction temperature was 41.41 degrees C. The content of gigantol of Dendrobium officinale in leaves was significantly higher than that in stems, reaching 4.7942 MUg/g. The content of gigantol in Dendrobium huoshanensis Fengdou was significantly higher than that of other species of Fengdou. This experiment has practical significance for improving the utilization rate of Dendrobium officinale, and provides a reference for the study of the pharmacological and biological activity of gigantol. PMID- 29614009 TI - Nutrition Labelling Use and Higher Adherence to Mediterranean Diet: Results from the DiSA-UMH Study. AB - The aim of this study was to identify determinants of the nutrition labelling (NL) use and explore its association with the adherence to Mediterranean Diet (MD) in Spanish health university students. We performed a cross-sectional analysis of the baseline data from 1026 university students aged 17-35 years enrolled in the DiSA-UMH (Dieta, Salud y Antropometria-Universidad Miguel Hernandez) cohort study. Students were asked about their NL use by the following question: "Do you usually read the nutrition labelling of packaged foods?" (No, Yes). Dietary intake was assessed using a validated food frequency questionnaire and the adherence to MD was measured by relative Mediterranean Diet score (rMED). Socio-demographic, lifestyle, and anthropometric variables were also collected. Multiple logistic regression models were applied for the analysis. Fifty-eight percent of the students were NL users and were most likely to be women (Odds Ratio (OR): 1.38; 95% Confidence Interval (CI): 1.01-1.89), be older (OR per year: 1.08; 95% CI: 1.03-1.13), be physically active/very active (OR: 1.68; 95% CI: 1.17-2.41), and spend less time watching television (OR per hour: 0.84; 95% CI: 0.74-0.95). After adjusting for potential confounding factors, our findings suggested that those university students who had higher adherence to MD used NL greatly (OR per 2 points increase: 1.30; 95% CI: 1.18-1.43) and had a larger consumption of fish (OR per 100 g/day: 1.94; 95 CI: 1.38-2.71), vegetables (OR per 100 g/day: 1.15; CI 95%: 1.08-1.12), and fruits (OR per 100 g/day: 1.22; 1.11 1.34) and a smaller intake of meats (OR per 100 g/day: 0.76; 95% CI: 0.58-0.99). Our approach contributes to exploring the role of NL use as a suitable tool to make healthier food choices from a different wider perspective based on dietary patterns such as MD, which can also indicate an overall healthy lifestyle. Given the lack of research in Mediterranean areas, further studies focused on exploring the potential role of NL in promoting healthy dietary habits are required. PMID- 29614011 TI - Uranyl Sulfate Nanotubules Templated by N-phenylglycine. AB - The synthesis, structure, and infrared spectroscopy properties of the new organically templated uranyl sulfate Na(phgH+)7[(UO2)6(SO4)10](H2O)3.5 (1), obtained at room temperature by evaporation from aqueous solution, are reported. Its structure contains unique uranyl sulfate [(UO2)6(SO4)10]8- nanotubules templated by protonated N-phenylglycine (C6H5NH2CH2COOH)+. Their internal diameter is 1.4 nm. Each of the nanotubules is built from uranyl sulfate rings sharing common SO4 tetrahedra. The template plays an important role in the formation of the complex structure of 1. The aromatic rings are stacked parallel to each other due to the effect of pi-pi interaction with their side chains extending into the gaps between the nanotubules. PMID- 29614012 TI - The Elderly Perceived Meanings and Values of Virtual Reality Leisure Activities: A Means-End Chain Approach. AB - This study uses means-end chain (MEC) techniques to examine the awareness, decision-making procedure, and personal values of the elderly with regard to virtual reality leisure activities. The results of the study show that elderly respondents value virtual reality leisure activities that are fun, safe, and easy. In terms of outcome benefits, elderly respondents value feeling physically and mentally healthy, firsthand experience, and satisfied curiosity. In value terms, elderly respondents hope that their chosen virtual reality leisure activities improve not only their relationships with others, but also their enjoyment, quality of life, and sense of belonging. The results show that, while consumers with different awarenesses of virtual reality leisure activities have different decision-making processes, they share creating "good memories" as the terminal value with the most significant effect. This presents a potential opportunity to promote virtual reality leisure activities. Relevant bodies or enterprises can seek to create good memories in consumers by developing activities that are safe and fun, promote good health, and provide good service, thereby attracting the interest of elderly consumers. PMID- 29614014 TI - Electrochemical Impedance and Polarization Corrosion Studies of Tantalum Surface Modified by DC Plasma Electrolytic Oxidation. AB - Tantalum has recently become an actively researched biomaterial for the bone reconstruction applications because of its excellent corrosion resistance and successful clinical records. However, a bare Ta surface is not capable of directly bonding to the bone upon implantation and requires some method of bioactivation. In this study, this was realized by direct current (DC) plasma electrolytic oxidation (PEO). Susceptibility to corrosion is a major factor determining the service-life of an implant. Therefore, herein, the corrosion resistance of the PEO coatings on Ta was investigated in Ringer's solution. The coatings were formed by galvanostatic anodization up to 200, 300 and 400 V, after which the treatment was conducted potentiostatically until the total process time amounted to 5 min. Three solutions containing Ca(H2PO2)2, Ca(HCOO)2 and Mg(CH3COO)2 were used in the treatment. For the corrosion characterization, electrochemical impedance spectroscopy and potentiodynamic polarization techniques were chosen. The coatings showed the best corrosion resistance at voltages low enough so that the intensive sparking was absent, which resulted in the formation of thin films. The impedance data were fitted to the equivalent electrical circuits with two time constants, namely R(Q[R(QR)]) and R(Q[R(Q[RW])]). The inclusion of W in the circuit helped to fit the low-frequency part of the samples PEO-ed at 400 V, hinting at the important role of diffusion in the corrosion resistance of the PEO coatings described in the research. PMID- 29614013 TI - Selection of Potential Therapeutic Bacteriophages that Lyse a CTX-M-15 Extended Spectrum beta-Lactamase Producing Salmonella enterica Serovar Typhi Strain from the Democratic Republic of the Congo. AB - Recently, a Salmonella Typhi isolate producing CTX-M-15 extended spectrum beta lactamase (ESBL) and with decreased ciprofloxacin susceptibility was isolated in the Democratic Republic of the Congo. We have selected bacteriophages that show strong lytic activity against this isolate and have potential for phage-based treatment of S. Typhi, and Salmonella in general. PMID- 29614015 TI - Effect of Silicon on the Tolerance of Wheat (Triticum aestivum L.) to Salt Stress at Different Growth Stages: Case Study for the Management of Irrigation Water. AB - This paper aims to determine the most tolerant growth stage(s) of wheat to salinity stress with the addition of silicon. The aim was to investigate whether saline water could be used instead of good quality water for irrigation without implicating a greater risk to crop production. Local wheat cv. Gimmiza 11 was germinated and grown in sand cultures. Four different NaCl salinity levels were used as treatments: 0, 60, 90 and 120 mM. This was in the presence of 0 and 0.78 mM Si which added as sodium meta- silicate (Na2SiO3.9H2O). Both the NaCl and Si treatments were carried out using a full strength nutrient solution that was adjusted at pH 6.0 and used for irrigation in four replications. The application of Si with the saline nutrient media significantly enhanced superoxide dismutase (SOD) and catalase (CAT) activities in plant leaves at the booting stage compared to the other stages. This was associated with a marked decline in the H2O2 content. At the booting stage, the Si treatment promoted CAT activity in 120 mM NaCl-stressed leaves compared to the leaves treated with only 120 mM NaCl solution. SOD showed greater prevalence at the booting stage when Si was added into the saline media, and it also revealed maximum activity at the milky stage with salinity stress. This was associated with a smaller reduction in shoot fresh and dry weights, greater reduction in the leaf Na+ content and an increase in the K+ content, which ultimately increased the cytosolic K+/Na+ ratio. Chlorophyll a and b and carotenoid (total photosynthetic pigments) were also higher at the booting stage of salt-stressed plants treated with Si compared to other stages. Accordingly, Si application enhanced the salt tolerance of wheat and reduced the inhibitory effect of Na+ and oxidative stress damage as growth proceeded towards maturity, particularly at the booting stage. This shows that saline water can be used for wheat irrigation at the booting stage (much water is consumed) when good quality water is not available for supplemental irrigation. A field study is needed to confirm the greenhouse results. PMID- 29614016 TI - Objecthood, Agency and Mutualism in Valenced Farm Animal Environments. AB - Genetic selection of farm animals for productivity, and intensification of farming practices have yielded substantial improvements in efficiency; however, the capacity of animals to cope with environmental challenges has diminished. Understanding how the animal and environment interact is central to efforts to improve the health, fitness, and welfare of animals through breeding and management strategies. The review examines aspects of the environment that are sensed by the animal. The predictive brain model of sensory perception and motor action (the Bayesian brain model) and its recent extension to account for anticipatory, predictive control of physiological activities is described. Afferent sensory input from the immune system, and induction of predictive immune functions by the efferent nervous system are also in accord with the Bayesian brain model. In this model, expected sensory input (from external, physiological and immunological environments) is reconciled with actual sensory input through behavioural, physiological and immune actions, and through updating future expectations. Sustained discrepancy between expected and actual sensory inputs occurs when environmental encounters cannot be predicted and controlled resulting in stress and negative affective states. Through these processes, from the animal's perspective, aspects of the environment acquire a negative or positive character: that is the environment becomes valenced. In a homeostatic manner, affective experience guides the animal towards synchronisation and a greater degree of mutualism with its environment. A better understanding of the dynamic among environmental valence, animal affect and mutualism may provide a better understanding of genetic and phenotypic links between temperament, immune function, metabolic performance, affective state, and resilience in farm animals, and provide further opportunities to improve their welfare. PMID- 29614017 TI - Flavonoid Functions in Plants and Their Interactions with Other Organisms. AB - Flavonoids are structurally diverse secondary metabolites in plants, with a multitude of functions. These span from functions in regulating plant development, pigmentation, and UV protection, to an array of roles in defence and signalling between plants and microorganisms. Because of their prevalence in the human diet, many flavonoids constitute important components of medicinal plants and are used in the control of inflammation and cancer prevention. Advances in the elucidation of flavonoid biosynthesis and its regulation have led to an increasing number of studies aimed at engineering the flavonoid pathway for enhancing nutritional value and plant defences against pathogens and herbivores, as well as modifying the feeding value of pastures. Many future opportunities await for the exploitation of this colourful pathway in crops, pastures, and medicinal plants. PMID- 29614019 TI - Hesitant Fuzzy Linguistic Preference Utility Set and Its Application in Selection of Fire Rescue Plans. AB - Hesitant fuzzy linguistic term set provides an effective tool to represent uncertain decision information. However, the semantics corresponding to the linguistic terms in it cannot accurately reflect the decision-makers' subjective cognition. In general, different decision-makers' sensitivities towards the semantics are different. Such sensitivities can be represented by the cumulative prospect theory value function. Inspired by this, we propose a linguistic scale function to transform the semantics corresponding to linguistic terms into the linguistic preference values. Furthermore, we propose the hesitant fuzzy linguistic preference utility set, based on which, the decision-makers can flexibly express their distinct semantics and obtain the decision results that are consistent with their cognition. For calculations and comparisons over the hesitant fuzzy linguistic preference utility sets, we introduce some distance measures and comparison laws. Afterwards, to apply the hesitant fuzzy linguistic preference utility sets in emergency management, we develop a method to obtain objective weights of attributes and then propose a hesitant fuzzy linguistic preference utility-TOPSIS method to select the best fire rescue plan. Finally, the validity of the proposed method is verified by some comparisons of the method with other two representative methods including the hesitant fuzzy linguistic TOPSIS method and the hesitant fuzzy linguistic-VIKOR method. PMID- 29614018 TI - In Vitro Influence of Extracts from Snail Helix aspersa Muller on the Colon Cancer Cell Line Caco-2. AB - Colorectal cancer is the third most widely diagnosed cancer. Extracts from snails may modulate growth and development of colorectal cancer cells. The objective of this study was to determine the chemical composition of tissues derived from Helix aspersa Muller and red-ox properties of tissue extracts. Then, the influence of extracts and their fractions of different molecular weights on viability of Caco-2 cells was examined. Tissue lyophilisates contained antioxidants that could be important in the prevention of colorectal cancer. Moreover, we confirmed the presence of a wide array of compounds that might be used in treatment of this disease. The decrease of cell viability after the application of extracts from lyophilized mucus and foot tissues was affirmed. The effect of extract from mucus could be related to the content of some proteins and peptides, proper essential amino acids (EAA)/non-essential amino acids (NEAA) ratio, Met restriction and the presence of Cu, Ca, Zn, Se. The influence of the extract from foot tissues could be assigned additionally to the presence of eicosapentaenoic, alpha-linolenic, linoleic and gamma-linolenic acids. The opposite effect was demonstrated by extract from lyophilized shells which increased cell viability. Further studies are needed to know whether dietary supplying of H. aspersa Muller tissues can be used as an approach in colorectal cancer management. PMID- 29614020 TI - Effects of Cable Sway, Electrode Surface Area, and Electrode Mass on Electroencephalography Signal Quality during Motion. AB - More neuroscience researchers are using scalp electroencephalography (EEG) to measure electrocortical dynamics during human locomotion and other types of movement. Motion artifacts corrupt the EEG and mask underlying neural signals of interest. The cause of motion artifacts in EEG is often attributed to electrode motion relative to the skin, but few studies have examined EEG signals under head motion. In the current study, we tested how motion artifacts are affected by the overall mass and surface area of commercially available electrodes, as well as how cable sway contributes to motion artifacts. To provide a ground-truth signal, we used a gelatin head phantom with embedded antennas broadcasting electrical signals, and recorded EEG with a commercially available electrode system. A robotic platform moved the phantom head through sinusoidal displacements at different frequencies (0-2 Hz). Results showed that a larger electrode surface area can have a small but significant effect on improving EEG signal quality during motion and that cable sway is a major contributor to motion artifacts. These results have implications in the development of future hardware for mobile brain imaging with EEG. PMID- 29614022 TI - Micro/Nano Structural Tantalum Coating for Enhanced Osteogenic Differentiation of Human Bone Marrow Stem Cells. AB - Recently, tantalum has been attracting much attention for its anticorrosion resistance and biocompatibility, and it has been widely used in surface modification for implant applications. To improve its osteogenic differentiation of human bone marrow stem cells (hBMSCs), a micro/nano structure has been fabricated on the tantalum coating surface through the combination of anodic oxidation and plasma spraying method. The morphology, composition, and microstructure of the modified coating were comprehensively studied by employing scanning electron microscopy (SEM), X-ray diffraction (XRD) as well as transmission electron microscopy (TEM). The effects of hierarchical structures as well as micro-porous structure of tantalum coating on the behavior for human bone marrow stem cells (hBMSCs) were evaluated and compared at both cellular and molecular levels in vitro. The experimental results show that a hierarchical micro/nano structure with Ta2O5 nanotubes spread onto a micro-scale tantalum coating has been fabricated successfully, which is confirmed to promote cell adhesion and spreading. Besides, the hierarchical micro/nano tantalum coating can provide 1.5~2.1 times improvement in gene expression, compared with the micro porous tantalum coating. It demonstrates that it can effectively enhance the proliferation and differentiation of hBMSCs in vitro. PMID- 29614021 TI - Non-Metastatic Cutaneous Melanoma Induces Chronodisruption in Central and Peripheral Circadian Clocks. AB - The biological clock has received increasing interest due to its key role in regulating body homeostasis in a time-dependent manner. Cancer development and progression has been linked to a disrupted molecular clock; however, in melanoma, the role of the biological clock is largely unknown. We investigated the effects of the tumor on its micro- (TME) and macro-environments (TMaE) in a non metastatic melanoma model. C57BL/6J mice were inoculated with murine B16-F10 melanoma cells and 2 weeks later the animals were euthanized every 6 h during 24 h. The presence of a localized tumor significantly impaired the biological clock of tumor-adjacent skin and affected the oscillatory expression of genes involved in light- and thermo-reception, proliferation, melanogenesis, and DNA repair. The expression of tumor molecular clock was significantly reduced compared to healthy skin but still displayed an oscillatory profile. We were able to cluster the affected genes using a human database and distinguish between primary melanoma and healthy skin. The molecular clocks of lungs and liver (common sites of metastasis), and the suprachiasmatic nucleus (SCN) were significantly affected by tumor presence, leading to chronodisruption in each organ. Taken altogether, the presence of non-metastatic melanoma significantly impairs the organism's biological clocks. We suggest that the clock alterations found in TME and TMaE could impact development, progression, and metastasis of melanoma; thus, making the molecular clock an interesting pharmacological target. PMID- 29614023 TI - Genomic Influence in the Prevention of Cardiovascular Diseases with a Sterol Based Treatment. AB - Raised serum cholesterol concentration is a well-established risk factor in cardiovascular disease. In addition, genetic load may have an indirect influence on cardiovascular risk. Plant-based sterol-supplemented foods are recommended to help reduce the serum low-density lipoprotein cholesterol level. The objective was to analyse the influence of different polymorphisms in hypercholesterolemia patients following a dietary treatment with plant sterols. A randomised double blind cross-over controlled clinical trial was carried out in 45 people (25 women). Commercial milk, containing 2.24 g of sterols, was ingested daily during a 3-week period, and then the same amount of skim milk, without sterols, was consumed daily during the 3-week placebo phase. Both phases were separated by a washout period of 2 weeks. At the beginning and end of each phase, blood draws were performed. Genes LIPC C-514T and APOA5 C56G are Ser19Trp carriers and greatly benefit from sterol intake in the diet. LIPC C-514T TT homozygous carriers had lower low-density lipoprotein cholesterol (LDL-c) levels than CC homozygote and CT heterozygote carriers after the ingestion of plant sterols (p = 0.001). These two genes also showed statistically significant changes in total cholesterol levels (p = 0.025; p = 0.005), and no significant changes in high density lipoprotein (HDL) cholesterol levels (p = 0.032; p = 0.003), respectively. No statistically significant differences were observed for other genes. Further studies are needed to establish which genotype combinations would be the most protective against hypercholesterolemia. PMID- 29614024 TI - Distributed Optical Fiber Sensors Based on Optical Frequency Domain Reflectometry: A review. AB - Distributed optical fiber sensors (DOFS) offer unprecedented features, the most unique one of which is the ability of monitoring variations of the physical and chemical parameters with spatial continuity along the fiber. Among all these distributed sensing techniques, optical frequency domain reflectometry (OFDR) has been given tremendous attention because of its high spatial resolution and large dynamic range. In addition, DOFS based on OFDR have been used to sense many parameters. In this review, we will survey the key technologies for improving sensing range, spatial resolution and sensing performance in DOFS based on OFDR. We also introduce the sensing mechanisms and the applications of DOFS based on OFDR including strain, stress, vibration, temperature, 3D shape, flow, refractive index, magnetic field, radiation, gas and so on. PMID- 29614025 TI - Vitamin E Supplementation Ameliorates Newcastle Disease Virus-Induced Oxidative Stress and Alleviates Tissue Damage in the Brains of Chickens. AB - Newcastle disease (ND), characterized by visceral, respiratory, and neurological pathologies, causes heavy economic loss in the poultry industry around the globe. While significant advances have been made in effective diagnosis and vaccine development, molecular mechanisms of ND virus (NDV)-induced neuropathologies remain elusive. In this study, we report the magnitude of oxidative stress and histopathological changes induced by the virulent NDV (ZJ1 strain) and assess the impact of vitamin E in alleviating these pathologies. Comparative profiling of plasma and brains from mock and NDV-infected chicken demonstrated alterations in several oxidative stress makers such as nitric oxide, glutathione, malondialdehyde, total antioxidant capacity, glutathione S-transferase, superoxide dismutase, and catalases. While decreased levels of glutathione and total antioxidant capacity and increased concentrations of malondialdehyde and nitric oxide were observed in NDV-challenged birds at all time points, these alterations were eminent at latter time points (5 days post infection). Additionally, significant decreases in the activities of glutathione S transferase, superoxide dismutase, and catalase were observed in the plasma and brains collected from NDV-infected chickens. Intriguingly, we observed that supplementation of vitamin E can significantly reduce the alteration of oxidative stress parameters. Under NDV infection, extensive histopathological alterations were observed in chicken brain including neural inflammation, capillary hyperemia, necrosis, and loss of prominent axons, which were reduced with the treatment of vitamin E. Taken together, our findings highlight that neurotropic NDV induces extensive tissue damage in the brain and alters plasma oxidative stress profiles. These findings also demonstrate that supplementing vitamin E ameliorates these pathologies in chickens and proposes its supplementation for NDV-induced stresses. PMID- 29614026 TI - Prenatal Metformin Therapy Attenuates Hypertension of Developmental Origin in Male Adult Offspring Exposed to Maternal High-Fructose and Post-Weaning High-Fat Diets. AB - Widespread consumption of a Western diet, comprised of highly refined carbohydrates and fat, may play a role in the epidemic of hypertension. Hypertension can take origin from early life. Metformin is the preferred treatment for type 2 diabetes. We examined whether prenatal metformin therapy can prevent maternal high-fructose plus post-weaning high-fat diets-induced hypertension of developmental origins via regulation of nutrient sensing signals, uric acid, oxidative stress, and the nitric oxide (NO) pathway. Gestating Sprague Dawley rats received regular chow (ND) or chow supplemented with 60% fructose diet (HFR) throughout pregnancy and lactation. Male offspring were onto either the ND or high-fat diet (HFA) from weaning to 12 weeks of age. A total of 40 male offspring were assigned to five groups (n = 8/group): ND/ND, HFR/ND, ND/HFA, HFR/HFA, and HFR/HFA+metformin. Metformin (500 mg/kg/day) was administered via gastric gavage for three weeks during the pregnancy period. Combined maternal HFR plus post-weaning HFA induced hypertension in male adult offspring, which prenatal metformin therapy prevented. The protective effects of prenatal metformin therapy on HFR/HFA-induced hypertension, including downregulation of the renin-angiotensin system, decrease in uric acid level, and reduction of oxidative stress. Our results highlighted that the programming effects of metformin administered prenatally might be different from those reported in adults, and that deserves further elucidation. PMID- 29614028 TI - Semantic Edge Based Disparity Estimation Using Adaptive Dynamic Programming for Binocular Sensors. AB - Disparity calculation is crucial for binocular sensor ranging. The disparity estimation based on edges is an important branch in the research of sparse stereo matching and plays an important role in visual navigation. In this paper, we propose a robust sparse stereo matching method based on the semantic edges. Some simple matching costs are used first, and then a novel adaptive dynamic programming algorithm is proposed to obtain optimal solutions. This algorithm makes use of the disparity or semantic consistency constraint between the stereo images to adaptively search parameters, which can improve the robustness of our method. The proposed method is compared quantitatively and qualitatively with the traditional dynamic programming method, some dense stereo matching methods, and the advanced edge-based method respectively. Experiments show that our method can provide superior performance on the above comparison. PMID- 29614027 TI - The Critical Role of Inflammation in the Pathogenesis and Progression of Myeloid Malignancies. AB - Hematopoietic stem cells (HSCs) maintain an organism's immune system for a lifetime, and derangements in HSC proliferation and differentiation result in hematologic malignancies. Chronic inflammation plays a contributory if not causal role in HSC dysfunction. Inflammation induces HSC exhaustion, which promotes the emergence of mutant clones that may be resistant to an inflammatory microenvironment; this likely promotes the onset of a myeloid hematologic malignancy. Inflammatory cytokines are characteristically high in patients with myeloid malignancies and are linked to disease initiation, symptom burden, disease progression, and worsened prognostic survival. This review will cover our current understanding of the role of inflammation in the initiation, progression, and complications of myeloid hematologic malignancies, drawing from clinical studies as well as murine models. We will also highlight inflammation as a therapeutic target in hematologic malignancies. PMID- 29614029 TI - The Mechanism of Low-Temperature Oxidation of Carbon Monoxide by Oxygen over the PdCl2-CuCl2/gamma-Al2O3 Nanocatalyst. AB - The state of palladium and copper on the surface of the PdCl2-CuCl2/gamma-Al2O3 nanocatalyst for the low-temperature oxidation of CO by molecular oxygen was studied by various spectroscopic techniques. Using X-ray absorption spectroscopy (XAS), powder X-ray diffraction (XRD), and diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS), freshly prepared samples of the catalyst were studied. The same samples were also evaluated after interaction with CO, O2, and H2O vapor in various combinations. It was shown that copper exists in the form of Cu2Cl(OH)3 (paratacamite) nanophase on the surface of the catalyst. No palladium containing crystalline phases were identified. Palladium coordination initially is comprised of four chlorine atoms. It was shown by XAS that this catalyst is not capable of oxidizing CO at room temperature in the absence of H2O and O2 over 12 h. Copper(II) and palladium(II) are reduced to Cu(I) and Pd(I,0) species, respectively, in the presence of CO and H2O vapor (without O2). It was found by DRIFTS that both linear (2114 cm-1, 1990 cm-1) and bridging (1928 cm-1) forms of coordinated CO were formed upon adsorption onto the catalyst surface. Moreover, the formation of CO2 was detected upon the interaction of the coordinated CO with oxygen. The kinetics of CO oxidation was studied at 18-38 degrees C at an atmospheric pressure for CO, O2, N2, and H2O (gas) mixtures in a flow reactor (steady state conditions). PMID- 29614030 TI - New Pyrazolium Salts as a Support for Ionic Liquid Crystals and Ionic Conductors. AB - Ionic liquid crystals (ILCs) are a class of materials that combine the properties of liquid crystals (LCs) and ionic liquids (ILs). This type of materials is directed towards properties such as conductivity in ordered systems at different temperatures. In this work, we synthesize five new families of ILCs containing symmetrical and unsymmetrical substituted pyrazolium cations, with different alkyl long-chains, and anions such as Cl-, BF4-, ReO4-, p-CH3-6H4SO3- (PTS) and CF3SO3- (OTf). We study their thermal behavior by polarized light optical microscopy (POM) and differential scanning calorimetry (DSC). All of them, except those with OTf as counteranion, show thermotropic mesomorphism. The observations by POM reveal textures of lamellar mesophases. Those agree with the arrangement observed in the X-ray crystal structure of [H2pzR(4),R(4)][ReO4]. The nature of the mesophases is also confirmed by variable temperature powder X-ray diffraction. On the other hand, the study of the dielectric properties at variable temperature in mesomorphic (Cl- and BF4-) and non-mesomorphic (OTf) salts indicates that the supramolecular arrangement of the mesophase favors a greater ionic mobility and therefore ionic conductivity. PMID- 29614031 TI - Role of Phenolic Acids from the Rhizosphere Soils of Panax notoginseng as a Double-Edge Sword in the Occurrence of Root-Rot Disease. AB - Chemical agents in the rhizosphere soils of plants might have an influence on root-rot disease, which therefore might reveal the mechanism of root rot in Panax notoginseng (P. notoginseng). With this hypothesis the alterations of phenolic acids (PAs) in the rhizosphere soils of P. notoginseng after pathogen infection were determined. The effects of PAs on the growth of Fusarium oxysporum (F. oxysporum), a fungal pathogenic factor for P. notoginseng, as well as production of fusaric acid, a wilting agent for the plants, were also examined. The results indicate the presence of five PAs (ferulic acid, syringic acid, p-hydroxybenzoic acid, p-coumaric acid, and vanillic acid) in the rhizosphere soils of P. notoginseng, whose contents in the rhizosphere soils of healthy plants are higher than those of the diseased ones. Further we found that individual PA could inhibit the mycelium growth and spore production of F. oxysporum, but stimulate fusaric acid production as well, disclosing the double-edge sword role of PAs in the occurrence of root rot of P. notoginseng and paving the way for the intervention of P. notoginseng root rot via balancing PAs. PMID- 29614033 TI - Radio Frequency Detection and Characterization of Water-Ethanol Solution through Spiral-Coupled Passive Micro-Resonator Sensor. AB - We present a microfabricated spiral-coupled passive resonator sensor realized through integrated passive device (IPD) technology for the sensitive detection and characterization of water-ethanol solutions. In order to validate the performance of the proposed device, we explicitly measured and analyzed the radio frequency (RF) characteristics of various water-ethanol solution compositions. The measured results showed a drift in the resonance frequency from 1.16 GHz for deionized (DI) water to 1.68 GHz for the solution containing 50% ethanol, whereas the rejection level given by the reflection coefficient decreased from -29.74 dB to -14.81 dB. The obtained limit of detection was 3.82% volume composition of ethanol in solution. The derived loaded capacitance was 21.76 pF for DI water, which gradually decreased to 8.70 pF for the 50% ethanol solution, and the corresponding relative permittivity of the solution decreased from 80.14 to 47.79. The dissipation factor increased with the concentration of ethanol in the solution. We demonstrated the reproducibility of the proposed sensor through iterative measures of the samples and the study of surface morphology. Successive measurement of different samples had no overlapping and had very minimum bias between RF characteristics for each measured sample. The surface profile for bare sensors was retained after the sample test, resulting a root mean square (RMS) value of 11.416 nm as compared to 10.902 nm for the bare test. The proposed sensor was shown to be a viable alternative to existing sensors for highly sensitive water-ethanol concentration detection. PMID- 29614032 TI - Effect of Red and Blue Light on Anthocyanin Accumulation and Differential Gene Expression in Strawberry (Fragaria * ananassa). AB - Light conditions can cause quantitative and qualitative changes in anthocyanin. However, little is known about the underlying mechanism of light quality regulated anthocyanin accumulation in fruits. In this study, light-emitting diodes (LEDs) were applied to explore the effect of red and blue light on strawberry coloration. The results showed contents of total anthocyanins (TA), pelargonidin 3-glucoside (Pg3G) and pelargonidin 3-malonylglucoside (Pg3MG) significantly increased after blue and red light treatment. Pg3G was the major anthocyanin component in strawberry fruits, accounting for more than 80% of TA, whereas Pg3MG accounted for a smaller proportion. Comparative transcriptome analysis was conducted using libraries from the treated strawberries. A total of 1402, 5034, and 3764 differentially-expressed genes (DEGs) were identified in three pairwise comparisons (red light versus white light, RL-VS-WL; blue light versus white light, BL-VS-WL; blue light versus red light, BL-VS-RL), respectively. Photoreceptors and light transduction components remained dynamic to up-regulate the expression of regulatory factors and structural genes related to anthocyanin biosynthesis under red and white light, whereas most genes had low expression levels that were not consistent with the highest total anthocyanin content under blue light. Therefore, the results indicated that light was an essential environmental factor for anthocyanin biosynthesis before the anthocyanin concentration reached saturation in strawberry fruits, and blue light could quickly stimulate the accumulation of anthocyanin in the fruit. In addition, red light might contribute to the synthesis of proanthocyanidins by inducing LAR and ANR. PMID- 29614034 TI - Novel (1E,3E,5E)-1,6-bis(Substituted phenyl)hexa-1,3,5-triene Analogs Inhibit Melanogenesis in B16F10 Cells and Zebrafish. AB - The present study aimed to evaluate the anti-melanogenic activity of 1,6-diphenyl 1,3,5-hexatriene and its derivatives in B16F10 murine melanoma cells and zebrafish embryos. Twenty five (1E,3E,5E)-1,6-bis(substituted phenyl)hexa-1,3,5 triene analogs were synthesized and their non-cytotoxic effects were predictively analyzed using three-dimensional quantitative structure-activity relationship approach. Inhibitory activities of these synthetic compounds against melanin synthesis were determined by evaluating melanin content and melanogenic regulatory enzyme expression in B16F10 cells. The anti-melanogenic activity was verified by observing body pigmentation in zebrafishes treated with these compounds. Compound #2, #4, and #6 effectively decreased melanogenesis induced by α-melanocyte-stimulating hormone. In particular, compound #2 remarkably lowered the mRNA and protein expression levels of microphthalmia-associated transcription factor (MITF), tyrosinase (TYR), tyrosinase-related protein 1 (TYRP1), and TYRP2 in B16F10 cells and substantially reduced skin pigmentation in the developed larvae of zebrafish. These findings suggest that compound #2 may be used as an anti-melanogenic agent for cosmetic purpose. PMID- 29614036 TI - Evanescent Properties of Optical Diffraction from 2-Dimensional Hexagonal Photonic Crystals and Their Sensor Applications. AB - The sensitivity of traditional diffraction grating sensors is limited by the spatial resolution of the measurement setup. Thus, a large space is required to improve sensor performance. Here, we demonstrate a compact hexagonal photonic crystal (PhC) optical sensor with high sensitivity. PhCs are able to diffract optical beams to various angles in azimuthal space. The critical wavelength that satisfies the phase matching or becomes evanescent was used to benchmark the refractive index of a target analyte applied on a PhC sensor. Using a glucose solution as an example, our sensor demonstrated very high sensitivity and a low limit of detection. This shows that the diffraction mechanism of hexagonal photonic crystals can be used for sensors when compact size is a concern. PMID- 29614035 TI - Investigating the Nutritional and Recovery Habits of Tennis Players. AB - In this study, the nutritional and recovery habits of tennis players pre-, during, and post-match-play were investigated. Seventy tennis players completed a bespoke nutrition and recovery habits questionnaire, with questions related to the following areas: match preparation, intra-match nutritional habits, situation dependent variables, and post-match nutrition and recovery. On match day-1, the consumption of balanced meals consisting of carbohydrate (CHO), fat and protein, with some micronutrient considerations were reported by 51% of players. On match days, CHOs were prioritised prior to match-play with CHO dominant meals consumed by the majority of players. During matches, all players adopted a nutritional strategy, with water (94%), banana(s) (86%) and sports drinks (50%) commonly used. Carbohydrate rich nutritional aids, including sports drinks (80%) and energy gels (26%) were utilised more readily during long matches (>2 h). The day after match-play, 39% of players reported the consumption of "nothing specific". Multiple post-match recovery strategies were adopted by 80% of players, with foam rolling (77%), ice baths (40%), protein shake intake (37%) and hot baths (26%) most used. Findings indicate highly variable eating and recovery habits in tennis players pre-, during and post-match-play, with scope for improved practices. PMID- 29614037 TI - New Parameters to Quantitatively Express the Invasiveness of Bacterial Strains from Implant-Related Orthopaedic Infections into Osteoblast Cells. AB - Complete eradication of bacterial infections is often a challenging task, especially in presence of prosthetic devices. Invasion of non-phagocytic host cells appears to be a critical mechanism of microbial persistence in host tissues. Hidden within host cells, bacteria elude host defences and antibiotic treatments that are intracellularly inactive. The intracellular invasiveness of bacteria is generally measured by conventional gentamicin protection assays. The efficiency of invasion, however, markedly differs across bacterial species and adjustments to the titre of the microbial inocula used in the assays are often needed to enumerate intracellular bacteria. Such changes affect the standardisation of the method and hamper a direct comparison of bacteria on a same scale. This study aims at investigating the precise relation between inoculum, in terms of multiplicity of infection (MOI), and internalised bacteria. The investigation included nine Staphylococcus aureus, seven Staphylococcus epidermidis, five Staphylococcus lugdunensis and two Enterococcus faecalis clinical strains, which are co-cultured with MG63 human osteoblasts. Unprecedented insights are offered on the relations existing between MOI, number of internalised bacteria and per cent of internalised bacteria. New parameters are identified that are of potential use for qualifying the efficiency of internalization and compare the behaviour of bacterial strains. PMID- 29614038 TI - Noise Source Visualization Using a Digital Voice Recorder and Low-Cost Sensors. AB - Accurate sound visualization of noise sources is required for optimal noise control. Typically, noise measurement systems require microphones, an analog digital converter, cables, a data acquisition system, etc., which may not be affordable for potential users. Also, many such systems are not highly portable and may not be convenient for travel. Handheld personal electronic devices such as smartphones and digital voice recorders with relatively lower costs and higher performance have become widely available recently. Even though such devices are highly portable, directly implementing them for noise measurement may lead to erroneous results since such equipment was originally designed for voice recording. In this study, external microphones were connected to a digital voice recorder to conduct measurements and the input received was processed for noise visualization. In this way, a low cost, compact sound visualization system was designed and introduced to visualize two actual noise sources for verification with different characteristics: an enclosed loud speaker and a small air compressor. Reasonable accuracy of noise visualization for these two sources was shown over a relatively wide frequency range. This very affordable and compact sound visualization system can be used for many actual noise visualization applications in addition to educational purposes. PMID- 29614039 TI - Three-Dimensional Modeling of Weed Plants Using Low-Cost Photogrammetry. AB - Sensing advances in plant phenotyping are of vital importance in basic and applied plant research. Plant phenotyping enables the modeling of complex shapes, which is useful, for example, in decision-making for agronomic management. In this sense, 3D processing algorithms for plant modeling is expanding rapidly with the emergence of new sensors and techniques designed to morphologically characterize. However, there are still some technical aspects to be improved, such as an accurate reconstruction of end-details. This study adapted low-cost techniques, Structure from Motion (SfM) and MultiView Stereo (MVS), to create 3D models for reconstructing plants of three weed species with contrasting shape and plant structures. Plant reconstruction was developed by applying SfM algorithms to an input set of digital images acquired sequentially following a track that was concentric and equidistant with respect to the plant axis and using three different angles, from a perpendicular to top view, which guaranteed the necessary overlap between images to obtain high precision 3D models. With this information, a dense point cloud was created using MVS, from which a 3D polygon mesh representing every plants' shape and geometry was generated. These 3D models were validated with ground truth values (e.g., plant height, leaf area (LA) and plant dry biomass) using regression methods. The results showed, in general, a good consistency in the correlation equations between the estimated values in the models and the actual values measured in the weed plants. Indeed, 3D modeling using SfM algorithms proved to be a valuable methodology for weed phenotyping, since it accurately estimated the actual values of plant height and LA. Additionally, image processing using the SfM method was relatively fast. Consequently, our results indicate the potential of this budget system for plant reconstruction at high detail, which may be usable in several scenarios, including outdoor conditions. Future research should address other issues, such as the time-cost relationship and the need for detail in the different approaches. PMID- 29614040 TI - Multi-GNSS PPP-RTK: From Large- to Small-Scale Networks. AB - Precise point positioning (PPP) and its integer ambiguity resolution-enabled variant, PPP-RTK (real-time kinematic), can benefit enormously from the integration of multiple global navigation satellite systems (GNSS). In such a multi-GNSS landscape, the positioning convergence time is expected to be reduced considerably as compared to the one obtained by a single-GNSS setup. It is therefore the goal of the present contribution to provide numerical insights into the role taken by the multi-GNSS integration in delivering fast and high precision positioning solutions (sub-decimeter and centimeter levels) using PPP RTK. To that end, we employ the Curtin PPP-RTK platform and process data-sets of GPS, BeiDou Navigation Satellite System (BDS) and Galileo in stand-alone and combined forms. The data-sets are collected by various receiver types, ranging from high-end multi-frequency geodetic receivers to low-cost single-frequency mass-market receivers. The corresponding stations form a large-scale (Australia wide) network as well as a small-scale network with inter-station distances less than 30 km. In case of the Australia-wide GPS-only ambiguity-float setup, 90% of the horizontal positioning errors (kinematic mode) are shown to become less than five centimeters after 103 min. The stated required time is reduced to 66 min for the corresponding GPS + BDS + Galieo setup. The time is further reduced to 15 min by applying single-receiver ambiguity resolution. The outcomes are supported by the positioning results of the small-scale network. PMID- 29614041 TI - Synthesis of Novel C-2- or C-15-Labeled BODIPY-Estrone Conjugates. AB - Novel BODIPY-estrone conjugates were synthesized via Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC). Estrone-alkynes or an estrone-azide as starting compounds were synthesized via Michael addition or Sonogashira reaction as key steps. Fluorescent dyes based on BODIPY-core were provided by azide or alkyne functional groups. Fluorescent labeling of estrone was efficiently achieved at the C-2 or C 15 position. The newly-elaborated coupling procedures might have a broad applicability in the synthesis of fluorescent-labeled estrone conjugates suitable for biological assays. PMID- 29614042 TI - Technological and Genomic Analysis of Roles of the Cell-Envelope Protease PrtS in Yoghurt Starter Development. AB - The cell-envelope protease PrtS was proved to be efficient in optimal bacterial growth and fast acidification in pure culture, while its positive effect on the performance of mixed-cultures in milk fermentation was not defined. The aim was to analyze effects of the PrtS on the symbiosis between strains during yoghurt production and cold storage. Two Streptococcus thermophilus strains, KLDS3.1012 and KLDS SM, and two different proteolytic strains of Lactobacillus delbrueckii subsp. Bulgaricus, L7 and L12, were used. Technological properties (viability, acid production, and proteolysis) were determined. Comparative genomics was used to analyze the proteolytic system (cell-envelope protease, transport system, intracellular peptidase) of Streptococcus thermophilus strains. S. thermophilus KLDS SM possesses an intact gene encoding PrtS (A9497_00420), which was not found in the genome of S. thermophilus KLDS3.1012. This gene is the main difference in the proteolytic system between the two genomes. PrtS endowed KLDS SM high levels of viability during fermentation and cold storage. When combined with a weaker lactobacillus strain during fermentation, the acceleration of acid production of mixed-culture by KLDS SM would start at an earlier time. KLDS SM increased the post-acidification of yoghurts during cold storage, but the pH was steadily maintained during 14-28 days. Results suggest that strains of Streptococcus thermophilus with strong proteolytic ability could be used in a wide range of dairy production. The present study provided data for yoghurt starter development from the point of view of proteolysis. PMID- 29614043 TI - Effect of the Microstructure and Distribution of the Second Phase on the Stress Corrosion Cracking of Biomedical Mg-Zn-Zr-xSr Alloys. AB - The stress corrosion cracking (SCC) properties of the bi-directional forged (BDF) Mg-4Zn-0.6Zr-xSr (ZK40-xSr, x = 0, 0.4, 0.8, 1.2, 1.6 wt %) alloys were studied by the slow strain rate tensile (SSRT) testing in modified simulated body fluid (m-SBF). The average grain size of the BDF alloys were approximately two orders of magnitude smaller than those of the as-cast alloys. However, grain refinement increased the hydrogen embrittlement effect, leading to a higher SCC susceptibility in the BDF ZK40-0/0.4Sr alloys. Apart from the grain refinements effect, the forging process also changed the distribution of second phase from the net-like shape along the grain boundary to a uniformly isolated island shape in the BDF alloys. The SCC susceptibility of the BDF ZK40-1.2/1.6Sr alloys were lower than those of the as-cast alloys. The change of distribution of the second phase suppressed the adverse effect of Sr on the SCC susceptibility in high Sr containing magnesium alloys. The results indicated the stress corrosion behavior of magnesium alloys was related to the average grain size of matrix and the distribution and shape of the second phase. PMID- 29614044 TI - Toxic Cyanobacteria in Svalbard: Chemical Diversity of Microcystins Detected Using a Liquid Chromatography Mass Spectrometry Precursor Ion Screening Method. AB - Cyanobacteria synthesize a large variety of secondary metabolites including toxins. Microcystins (MCs) with hepato- and neurotoxic potential are well studied in bloom-forming planktonic species of temperate and tropical regions. Cyanobacterial biofilms thriving in the polar regions have recently emerged as a rich source for cyanobacterial secondary metabolites including previously undescribed congeners of microcystin. However, detection and detailed identification of these compounds is difficult due to unusual sample matrices and structural congeners produced. We here report a time-efficient liquid chromatography-mass spectrometry (LC-MS) precursor ion screening method that facilitates microcystin detection and identification. We applied this method to detect six different MC congeners in 8 out of 26 microbial mat samples of the Svalbard Archipelago in the Arctic. The congeners, of which [Asp3, ADMAdda5, Dhb7] MC-LR was most abundant, were similar to those reported in other polar habitats. Microcystins were also determined using an Adda-specific enzyme-linked immunosorbent assay (Adda-ELISA). Nostoc sp. was identified as a putative toxin producer using molecular methods that targeted 16S rRNA genes and genes involved in microcystin production. The mcy genes detected showed highest similarities to other Arctic or Antarctic sequences. The LC-MS precursor ion screening method could be useful for microcystin detection in unusual matrices such as benthic biofilms or lichen. PMID- 29614045 TI - Progress of Nanocomposite Membranes for Water Treatment. AB - The use of membrane-based technologies has been applied for water treatment applications; however, the limitations of conventional polymeric membranes have led to the addition of inorganic fillers to enhance their performance. In recent years, nanocomposite membranes have greatly attracted the attention of scientists for water treatment applications such as wastewater treatment, water purification, removal of microorganisms, chemical compounds, heavy metals, etc. The incorporation of different nanofillers, such as carbon nanotubes, zinc oxide, graphene oxide, silver and copper nanoparticles, titanium dioxide, 2D materials, and some other novel nano-scale materials into polymeric membranes have provided great advances, e.g., enhancing on hydrophilicity, suppressing the accumulation of pollutants and foulants, enhancing rejection efficiencies and improving mechanical properties and thermal stabilities. Thereby, the aim of this work is to provide up-to-date information related to those novel nanocomposite membranes and their contribution for water treatment applications. PMID- 29614046 TI - The Influence of Milling and Spark Plasma Sintering on the Microstructure and Properties of the Al7075 Alloy. AB - The compact samples of an Al7075 alloy were prepared by a combination of gas atomization, high energy milling, and spark plasma sintering. The predominantly cellular morphology observed in gas atomized powder particles was completely changed by mechanical milling. The continuous-like intermetallic phases present along intercellular boundaries were destroyed; nevertheless, a small amount of Mg(Zn,Cu,Al)2 phase was observed also in the milled powder. Milling resulted in a severe plastic deformation of the material and led to a reduction of grain size from several um into the nanocrystalline region. The combination of these microstructural characteristics resulted in abnormally high microhardness values exceeding 300 HV. Consolidation through spark plasma sintering (SPS) resulted in bulk samples with negligible porosity. The heat exposition during SPS led to precipitation of intermetallic phases from the non-equilibrium microstructure of both gas atomized and milled powders. SPS of the milled powder resulted in a recrystallization of the severely deformed structure. An ultra-fine grained structure (grain size close to 500 nm) with grains divided primarily by high angle boundaries was formed. A simultaneous release of stored deformation energy and an increase in the grain size caused a drop of microhardness to values close to 150 HV. This value was retained even after annealing at 425 degrees C. PMID- 29614047 TI - Estimated Dietary Intake of Trace Metals from Swordfish Consumption: A Human Health Problem. AB - Trace element (Hg, Pb, Cd, Zn, Cu, Ni, and Cr) occurrence was determined in the muscle tissue of swordfish collected in the Mediterranean Sea to assess whether the intakes complied with the recommended levels for essential metals and permissible levels for toxic elements. Metals were analyzed by an atomic absorption spectrophotometer (Shimadzu AA 7000). The methodology of Target Hazard Quotient (THQ) was also evaluated. The ranking order of toxic metal concentration was Hg > Cd > Pb, while for essential elements the distribution pattern followed the sequence Zn > Cu > Ni > Cr. The Estimated Weekly Intakes (EWI) as well as THQ for Cd and Pb indicated that swordfish consumption did not pose a risk to human health, whereas the major concern was for Hg. Fish size-related changes in Hg concentrations resulted in high EWI and THQ values relative to larger fish consumption, implying a potential risk to human health. For consumer protection, catches of swordfish approximately above 44 kg should be avoided as these fish have a higher risk of containing toxic levels of Hg. PMID- 29614049 TI - Clustering and Flow Conservation Monitoring Tool for Software Defined Networks. AB - Prediction systems present some challenges on two fronts: the relation between video quality and observed session features and on the other hand, dynamics changes on the video quality. Software Defined Networks (SDN) is a new concept of network architecture that provides the separation of control plane (controller) and data plane (switches) in network devices. Due to the existence of the southbound interface, it is possible to deploy monitoring tools to obtain the network status and retrieve a statistics collection. Therefore, achieving the most accurate statistics depends on a strategy of monitoring and information requests of network devices. In this paper, we propose an enhanced algorithm for requesting statistics to measure the traffic flow in SDN networks. Such an algorithm is based on grouping network switches in clusters focusing on their number of ports to apply different monitoring techniques. Such grouping occurs by avoiding monitoring queries in network switches with common characteristics and then, by omitting redundant information. In this way, the present proposal decreases the number of monitoring queries to switches, improving the network traffic and preventing the switching overload. We have tested our optimization in a video streaming simulation using different types of videos. The experiments and comparison with traditional monitoring techniques demonstrate the feasibility of our proposal maintaining similar values decreasing the number of queries to the switches. PMID- 29614048 TI - Genomic Signatures of Reinforcement. AB - Reinforcement is the process by which selection against hybridization increases reproductive isolation between taxa. Much research has focused on demonstrating the existence of reinforcement, yet relatively little is known about the genetic basis of reinforcement or the evolutionary conditions under which reinforcement can occur. Inspired by reinforcement's characteristic phenotypic pattern of reproductive trait divergence in sympatry but not in allopatry, we discuss whether reinforcement also leaves a distinct genomic pattern. First, we describe three patterns of genetic variation we expect as a consequence of reinforcement. Then, we discuss a set of alternative processes and complicating factors that may make the identification of reinforcement at the genomic level difficult. Finally, we consider how genomic analyses can be leveraged to inform if and to what extent reinforcement evolved in the face of gene flow between sympatric lineages and between allopatric and sympatric populations of the same lineage. Our major goals are to understand if genome scans for particular patterns of genetic variation could identify reinforcement, isolate the genetic basis of reinforcement, or infer the conditions under which reinforcement evolved. PMID- 29614050 TI - Exposure to Formaldehyde Perturbs the Mouse Gut Microbiome. AB - Exposure to Formaldehyde (FA) results in many pathophysiological symptoms, however the underlying mechanisms are not well understood. Given the complicated modulatory role of intestinal microbiota on human health, we hypothesized that interactions between FA and the gut microbiome may account for FA's toxicity. Balb/c mice were allocated randomly to three groups: a control group, a methanol group (0.1 and 0.3 ng/mL MeOH subgroups), and an FA group (1 and 3 ng/mL FA subgroups). Groups of either three or six mice were used for the control or experiment. We applied high-throughput sequencing of 16S ribosomal RNA (rRNA) gene approaches and investigated possible alterations in the composition of mouse gut microbiota induced by FA. Changes in bacterial genera induced by FA exposure were identified. By analyzing KEGG metabolic pathways predicted by PICRUSt software, we also explored the potential metabolic changes, such as alpha Linolenic acid metabolism and pathways in cancer, associated with FA exposure in mice. To the best of our knowledge, this preliminary study is the first to identify changes in the mouse gut microbiome after FA exposure, and to analyze the relevant potential metabolisms. The limitation of this study: this study is relatively small and needs to be further confirmed through a larger study. PMID- 29614051 TI - The Effect of Seasonal Floods on Health: Analysis of Six Years of National Health Data and Flood Maps. AB - There is limited knowledge on the effect of seasonal flooding on health over time. We quantified the short- and long-term effects of floods on selected health indicators at public healthcare facilities in 11 districts in Cambodia, a flood prone setting. Counts of inpatient discharge diagnoses and outpatient consultations for diarrhea, acute respiratory infections, skin infections, injuries, noncommunicable diseases and vector-borne diseases were retrieved from public healthcare facilities for each month between January 2008 and December 2013. Flood water was mapped by month, in square kilometers, from satellite data. Poisson regression models with three lag months were constructed for the health problems in each district, controlled for seasonality and long-term trends. During times of flooding and three months after, there were small to moderate increases in visits to healthcare facilities for skin infections, acute respiratory infections, and diarrhea, while no association was seen at one to two months. The associations were small to moderate, and a few of our results were significant. We observed increases in care seeking for diarrhea, skin infections, and acute respiratory infections following floods, but the associations are uncertain. Additional research on previous exposure to flooding, using community- and facility-based data, would help identify expected health risks after floods in flood-prone settings. PMID- 29614052 TI - Genomic Characterization of Sixteen Yersinia enterocolitica-Infecting Podoviruses of Pig Origin. AB - Yersinia enterocolitica causes enteric infections in humans and animals. Human infections are often caused by contaminated pork meat. Y. enterocolitica colonizes pig tonsils and pigs secrete both the human pathogen and its specific bacteriophages into the stools. In this work, sixteen Y. enterocolitica-infecting lytic bacteriophages isolated from pig stools originating from several pig farms were characterized. All phages belong to the Podoviridae family and their genomes range between 38,391-40,451 bp in size. The overall genome organization of all the phages resembled that of T7-like phages, having 3-6 host RNA polymerase (RNAP)-specific promoters at the beginning of the genomes and 11-13 phage RNAP specific promoters as well as 3-5 rho-independent terminators, scattered throughout the genomes. Using a ligation-based approach, the physical termini of the genomes containing direct terminal repeats of 190-224 bp were established. No genes associated with lysogeny nor any toxin, virulence factor or antibiotic resistance genes were present in the genomes. Even though the phages had been isolated from different pig farms the nucleotide sequences of their genomes were 90-97% identical suggesting that the phages were undergoing microevolution within and between the farms. Lipopolysaccharide was found to be the surface receptor of all but one of the phages. The phages are classified as new species within the T7virus genus of Autographivirinae subfamily. PMID- 29614053 TI - Support Needs and Experiences of People Bereaved by Suicide: Qualitative Findings from a Cross-Sectional British Study of Bereaved Young Adults. AB - People bereaved by suicide are at increased risk of suicide, but evidence is lacking that available interventions reduce suicide risk. Few large-scale studies have described the views of suicide-bereaved people regarding their needs for support. Our objective was to explore the nature of young adults' experiences of support after bereavement by suicide and their views on valued and unhelpful aspects. We conducted a cross-sectional study of staff and students aged 18-40 at 37 United Kingdom (UK) higher educational institutions in 2010, eliciting qualitative responses to two questions probing experiences of support and unmet needs after the suicide of a close contact. We conducted thematic analysis of responses from 420 adults bereaved by suicide, of whom 75% had received support after the loss. We identified three broad descriptive areas corresponding to important aspects of support: value and experiences of the support received; views on specific support needs; and reasons for not seeking support. We found that needs for emotional support exist throughout the social networks of people who die by suicide but are often hidden. Our findings suggest a need for proactive offers of support from family, friends, and professionals after suicide, repeated regularly in case a bereaved person does not feel ready for support early on. PMID- 29614054 TI - A Novel Protocol to Assess Acclimation Rate in Bos taurus Heifers during Yard Weaning. AB - The speed with which animals acclimate to a new environment could be an important measure of ability to cope with management induced stress. This study developed a measure of acclimation rate in a group of 50 Bos taurus heifers during yard weaning over nine days. We recorded the time and order in which heifers moved through a novel funnel structure into a feeding yard daily. We hypothesised that addition of an obstacle at the entrance would increase the time it took heifers to move through the funnel, but that they would acclimate to the obstacle over a three-day period. The change in latency to move through could then be used as a measure of acclimation rate. We hypothesised that individuals which acclimated to obstacles at a faster rate might display favourable temperament as assessed by flight time. All heifers took longer to move through the funnel after a novel object was introduced, then latency decreased over the following two days while the object was present. This indicates the protocol could be useful for measuring acclimation rate at a group level. Individual acclimation rate variables, measured as change in times and orders of heifers between test days, did not appear to have any consistent relationships with flight time or weight change during or post-weaning (p > 0.05). We concluded that the protocol was inappropriate for assessing acclimation rate at an individual level, due to social effects while testing heifers as a group. Heifers which were consistently one of the first 20 to move through the funnel had a significantly greater average weight 5 and 10 months post-weaning (345 +/- 9 kg and 518 +/- 10 kg respectively) than heifers which were consistently one of the last 20 through the funnel (311 +/- 8 kg and 484 +/- 8 kg respectively; p < 0.001). This may indicate order of movement through the funnel was related to feeding motivation or another aspect of temperament not reflected by flight time. PMID- 29614056 TI - 'We All Work Together to Vaccinate the Child': A Formative Evaluation of a Community-Engagement Strategy Aimed at Closing the Immunization Gap in North-West Ethiopia. AB - The role of community engagement (CE) in improving demand for immunization merits investigation. The International Rescue Committee developed a CE strategy to implement a vaccine defaulter-tracing tool and a color-coded health calendar aimed at increasing uptake of immunization services in north-west Ethiopia ('The Fifth Child Project'). We report findings from a formative evaluation of this project. In May/June 2016 we conducted 18 participant observations of project activities, 46 semi-structured interviews and 6 focus groups with caregivers, health workers, community members/leaders. Audio-recordings and fieldnotes were transcribed, anonymized, translated and analyzed thematically using inductive and deductive coding. Additional data was collected in November 2016 to verify findings. The project was suitably integrated within the health extension program and established a practical system for defaulter-tracing. The calendar facilitated personalized interactions between health workers and caregivers and was a catalyst for health discussions within homes. At the community level, a regulation exercise of sanctions was observed, which served as a deterrent against vaccine default. Pre-existing community accountability mechanisms supported the CE, although varying levels of engagement between leaders and health workers were observed. The benefits of shared responsibility for immunization were evident; however, more transparency was required about community self-regulatory measures to ensure health-related discussions remain positive. PMID- 29614055 TI - Cell-Specific PEAR1 Methylation Studies Reveal a Locus that Coordinates Expression of Multiple Genes. AB - Chromosomal interactions connect distant enhancers and promoters on the same chromosome, activating or repressing gene expression. PEAR1 encodes the Platelet Endothelial Aggregation Receptor 1, a contact receptor involved in platelet function and megakaryocyte and endothelial cell proliferation. PEAR1 expression during megakaryocyte differentiation is controlled by DNA methylation at its first CpG island. We identified a PEAR1 cell-specific methylation sensitive region in endothelial cells and megakaryocytes that showed strong chromosomal interactions with ISGL20L2, RRNAD1, MRLP24, HDGF and PRCC, using available promoter capture Hi-C datasets. These genes are involved in ribosome processing, protein synthesis, cell cycle and cell proliferation. We next studied the methylation and expression profile of these five genes in Human Umbilical Vein Endothelial Cells (HUVECs) and megakaryocyte precursors. While cell-specific PEAR1 methylation corresponded to variability in expression for four out of five genes, no methylation change was observed in their promoter regions across cell types. Our data suggest that PEAR1 cell-type specific methylation changes may control long distance interactions with other genes. Further studies are needed to show whether such interaction data might be relevant for the genome-wide association data that showed a role for non-coding PEAR1 variants in the same region and platelet function, platelet count and cardiovascular risk. PMID- 29614058 TI - An Azimuth Antenna Pattern Estimation Method Based on Doppler Spectrum in SAR Ocean Images. AB - In synthetic aperture radar (SAR) ocean remote sensing, it is very difficult to estimate an accurate azimuth antenna pattern (AAP) from low-scattering SAR images without strong scattering targets. Therefore, an azimuth antenna pattern estimation method based on Doppler spectrum in SAR ocean images is proposed in this paper. In order to preserve the complete AAP information, an azimuth unweighted matched filter is used to re-image the SAR raw data in the proposed method. Then, the shape factor of AAP can be obtained by linear statistics of the relationship between Doppler center and edge frequency spectrum in Doppler spectrum of each distance gate. In addition, the impact of the uniformity and signal-to-noise ratio of SAR ocean images on the estimation results are also analyzed by simulation. Finally, the feasibility of proposed method is verified by data from ERS-2 (European remote sensing satellite (ERS) was the European Space Agency's first Earth-observing satellite). Experimental results show that the AAP estimated by proposed method has a good estimation result. PMID- 29614057 TI - Impact of Mutagens on DNA Replication in Barley Chromosomes. AB - Replication errors that are caused by mutagens are critical for living cells. The aim of the study was to analyze the distribution of a DNA replication pattern on chromosomes of the H. vulgare 'Start' variety using pulse 5-ethynyl-2' deoxyuridine (EdU) labeling, as well as its relationship to the DNA damage that is induced by mutagenic treatment with maleic hydrazide (MH) and gamma ray. To the best of our knowledge, this is the first example of a study of the effects of mutagens on the DNA replication pattern in chromosomes, as well as the first to use EdU labeling for these purposes. The duration of the cell cycle of the Hordeum vulgare 'Start' variety was estimated for the first time, as well as the influence of MH and gamma ray on it. The distribution of the signals of DNA replication along the chromosomes revealed relationships between DNA replication, the chromatin structure, and DNA damage. MH has a stronger impact on replication than gamma ray. Application of EdU seems to be promising for precise analyses of cell cycle disturbances in the future, especially in plant species with small genomes. PMID- 29614060 TI - TwitterSensing: An Event-Based Approach for Wireless Sensor Networks Optimization Exploiting Social Media in Smart City Applications. AB - Modern cities are subject to periodic or unexpected critical events, which may bring economic losses or even put people in danger. When some monitoring systems based on wireless sensor networks are deployed, sensing and transmission configurations of sensor nodes may be adjusted exploiting the relevance of the considered events, but efficient detection and classification of events of interest may be hard to achieve. In Smart City environments, several people spontaneously post information in social media about some event that is being observed and such information may be mined and processed for detection and classification of critical events. This article proposes an integrated approach to detect and classify events of interest posted in social media, notably in Twitter, and the assignment of sensing priorities to source nodes. By doing so, wireless sensor networks deployed in Smart City scenarios can be optimized for higher efficiency when monitoring areas under the influence of the detected events. PMID- 29614059 TI - Association between Internet Gaming Disorder or Pathological Video-Game Use and Comorbid Psychopathology: A Comprehensive Review. AB - The addictive use of video games is recognized as a problem with clinical relevance and is included in international diagnostic manuals and classifications of diseases. The association between "Internet addiction" and mental health has been well documented across a range of investigations. However, a major drawback of these studies is that no controls have been placed on the type of Internet use investigated. The aim of this study is to review systematically the current literature in order to explore the association between Internet Gaming Disorder (IGD) and psychopathology. An electronic literature search was conducted using PubMed, PsychINFO, ScienceDirect, Web of Science and Google Scholar (r.n. CRD42018082398). The effect sizes for the observed correlations were identified or computed. Twenty-four articles met the eligibility criteria. The studies included comprised 21 cross-sectional and three prospective designs. Most of the research was conducted in Europe. The significant correlations reported comprised: 92% between IGD and anxiety, 89% with depression, 85% with symptoms of attention deficit hyperactivity disorder (ADHD), and 75% with social phobia/anxiety and obsessive-compulsive symptoms. Most of the studies reported higher rates of IGD in males. The lack of longitudinal studies and the contradictory results obtained prevent detection of the directionality of the associations and, furthermore, show the complex relationship between both phenomena. PMID- 29614061 TI - Synthesis, Structural Studies and Biological Evaluation of Connections of Thiosemicarbazide, 1,2,4-Triazole and 1,3,4-Thiadiazole with Palmitic Acid. AB - Thirty new derivatives of palmitic acid were efficiently synthesized. All obtained compounds can be divided into three groups of derivatives: Thiosemicarbazides (compounds 1-10), 1,2,4-triazoles (compounds 1a-10a) and 1,3,4 thiadiazoles (compounds 1b-10b) moieties. 1H-NMR, 13C-NMR and MS methods were used to confirm the structure of derivatives. All obtained compounds were tested in vitro against a number of microorganisms, including Gram-positive cocci, Gram negative rods and Candida albicans. Compounds 4, 5, 6, 8 showed significant inhibition against C. albicans. The range of MIC values was 50-1.56 MUg/mL. The halogen atom, especially at the 3rd position of the phenyl group was significantly important for antifungal activity. The biological activity against Candida albicans and selected molecular descriptors were used as a basis for QSAR models, that have been determined by means of multiple linear regression. The models have been validated by means of the Leave-One-Out Cross Validation. The obtained QSAR models were characterized by high determination coefficients and good prediction power. PMID- 29614062 TI - Pseudotime Dynamics in Melanoma Single-Cell Transcriptomes Reveals Different Mechanisms of Tumor Progression. AB - Single-cell transcriptomics has been used for analysis of heterogeneous populations of cells during developmental processes and for analysis of tumor cell heterogeneity. More recently, analysis of pseudotime (PT) dynamics of heterogeneous cell populations has been established as a powerful concept to study developmental processes. Here we perform PT analysis of 3 melanoma short term cultures with different genetic backgrounds to study specific and concordant properties of PT dynamics of selected cellular programs with impact on melanoma progression. Overall, in our setting of melanoma cells PT dynamics towards higher tumor malignancy appears to be largely driven by cell cycle genes. Single cells of all three short-term cultures show a bipolar expression of microphthalmia associated transcription factor (MITF) and AXL receptor tyrosine kinase (AXL) signatures. Furthermore, opposing gene expression changes are observed for genes regulated by epigenetic mechanisms suggesting epigenetic reprogramming during melanoma progression. The three melanoma short-term cultures show common themes of PT dynamics such as a stromal signature at initiation, bipolar expression of the MITF/AXL signature and opposing regulation of poised and activated promoters. Differences are observed at the late stage of PT dynamics with high, low or intermediate MITF and anticorrelated AXL signatures. These findings may help to identify targets for interference at different stages of tumor progression. PMID- 29614063 TI - Comparisons of Efficacy, Safety, and Cost of Chemotherapy Regimens FOLFOX4 and FOLFIRINOX in Rectal Cancer: A Randomized, Multicenter Study. AB - BACKGROUND The currently available chemotherapeutic regimens do not use a specifically designed drug delivery system. The objective of this study was to compare outcome measures, adverse effects, and cost of FOLFOX4 and FOLFIRINOX treatments in rectal cancer patients. MATERIAL AND METHODS We enrolled patients who, after surgery, did not undergo chemotherapy or radiotherapy (Control group); were administered 200 mg/m2 folinic acid, 400 mg/m2 fluorouracil, and 85 mg/m2 oxaliplatin (FFO group); or were administered 400 mg/m2 folinic acid, 400 mg/m2 fluorouracil, 180 mg/m2 irinotecan, and 85 mg/m2 oxaliplatin (FFIO group). We recorded tumor and nodal staging, carbohydrate antigen 19-9, serum carcinoembryonic antigen, total cost of treatment, disease recurrence, overall survival, and adverse effects. We used the 2-tailed paired t test following Turkey post hoc test for adverse effects, recurrence analysis, and cost of treatment at 95% of confidence level. RESULTS Surgery (p=0.00089), FOLFOX4 (p=0.000167), and FOLFIRINOX (p=0.00013) improved disease-free conditions. Only surgery failed to maintain carbohydrate antigen and carcinoembryonic antigen 19-9 levels. The cost of chemotherapeutic treatments was in the order of FFIO group > FFO group > Control group. Non-fatal treatment-emergent adverse effects were due to chemotherapeutic drugs. However, fatal chemotherapeutic treatment-emergent adverse effects were observed only in the FFIO group. Overall survival, irrespective of cancerous condition, was higher in the FFO group. CONCLUSIONS FOLFIRINOX had less total cancer recurrence than FOLFOX4. However, FOLFIRINOX had more fatal treatment-emergent adverse effects and excessive cost of treatment than FOLFOX4 regimen. PMID- 29614064 TI - A deep (learning) dive into a cell. PMID- 29614065 TI - How to pull the blanket off dormant cancer cells. PMID- 29614066 TI - Spatial regularity control of phyllotaxis pattern generated by the mutual interaction between auxin and PIN1. AB - Phyllotaxis, the arrangement of leaves on a plant stem, is well known because of its beautiful geometric configuration, which is derived from the constant spacing between leaf primordia. This phyllotaxis is established by mutual interaction between a diffusible plant hormone auxin and its efflux carrier PIN1, which cooperatively generate a regular pattern of auxin maxima, small regions with high auxin concentrations, leading to leaf primordia. However, the molecular mechanism of the regular pattern of auxin maxima is still largely unknown. To better understand how the phyllotaxis pattern is controlled, we investigated mathematical models based on the auxin-PIN1 interaction through linear stability analysis and numerical simulations, focusing on the spatial regularity control of auxin maxima. As in previous reports, we first confirmed that this spatial regularity can be reproduced by a highly simplified and abstract model. However, this model lacks the extracellular region and is not appropriate for considering the molecular mechanism. Thus, we investigated how auxin maxima patterns are affected under more realistic conditions. We found that the spatial regularity is eliminated by introducing the extracellular region, even in the presence of direct diffusion between cells or between extracellular spaces, and this strongly suggests the existence of an unknown molecular mechanism. To unravel this mechanism, we assumed a diffusible molecule to verify various feedback interactions with auxin-PIN1 dynamics. We revealed that regular patterns can be restored by a diffusible molecule that mediates the signaling from auxin to PIN1 polarization. Furthermore, as in the one-dimensional case, similar results are observed in the two-dimensional space. These results provide a great insight into the theoretical and molecular basis for understanding the phyllotaxis pattern. Our theoretical analysis strongly predicts a diffusible molecule that is pivotal for the phyllotaxis pattern but is yet to be determined experimentally. PMID- 29614067 TI - Detection of sister-species in invasive populations of the fall armyworm Spodoptera frugiperda (Lepidoptera: Noctuidae) from Uganda. AB - The fall armyworm (FAW) Spodoptera frugiperda (J. E. Smith) is a species native to the Americas. This polyphagous lepidopteran pest was first reported in Nigeria and the Democratic Republic of Sao Tome and Principe in 2016, but its presence in eastern Africa has not been confirmed via molecular characterisation. In this study, FAW specimens from western and central Uganda were identified based on the partial mtDNA COI gene sequences, with mtDNA COI haplotypes matching those identified in Nigeria and Sao Tome. In this study, we sequence an additional partial mtDNA Cyt b gene and also the partial mtDNA COIII gene in Ugandan FAW samples. We detected identical mitochondrial DNA haplotypes for both the mtDNA Cyt b and COI partial genes, while combining the mtDNA COI/Cyt b haplotypes and mtDNA COIII haplotypes enabled a new maternal lineage in the Ugandan corn preferred FAW samples to be identified. Our results suggested that the African incursions of S. frugiperda involved at least three maternal lineages. Recent full genome, phylogenetic and microsatellite analyses provided evidence to support S. frugiperda as likely consisted of two sympatric sister species known as the corn-preferred and rice-preferred strains. In our Ugandan FAW populations, we identified the presence of mtDNA haplotypes representative of both sister species. It is not known if both FAW sister species were originally introduced together or separately, and whether they have since spread as a single population. Further analyses of additional specimens originally collected from Sao Tome, Nigeria and throughout Africa would be required to clarify this issue. Importantly, our finding showed that the genetic diversity of the African corn preferred FAW species is higher than previously reported. This potentially contributed to the success of FAW establishment in Africa. Furthermore, with the additional maternal lineages detected, there is likely an increase in paternal lineages, thereby increasing the diversity of the African FAW population. Knowledge of the FAW genetic diversity will be needed to assess the risks of introducing Bt-resistance traits and to understand the FAW incursion pathways into the Old World and its potential onward spread. The agricultural implications of the presence of two evolutionary divergent FAW lineages (the corn and the rice lineage) in the African continent are further considered and discussed. PMID- 29614068 TI - An exploratory, large-scale study of pain and quality of life outcomes in cancer patients with moderate or severe pain, and variables predicting improvement. AB - BACKGROUND: There have been few large-scale, real world studies in Spain to assess change in pain and quality of life (QOL) outcomes in cancer patients with moderate to severe pain. This study aimed to assess changes on both outcomes after 3 months of usual care and to investigate factors associated with change in QoL. PATIENTS AND METHODS: Large, multi-centre, observational study in patients with lung, head and neck, colorectal or breast cancer experiencing a first episode of moderate to severe pain while attending one of the participating centres. QoL was assessed using the EuroQol-5D questionnaire and pain using the Brief Pain Inventory (BPI). Instruments were administered at baseline and after 3 months of follow up. Multivariate analyses were used to assess the impact of treatment factors, demographic and clinical variables, pain and other symptoms on QoL scores. RESULTS: 1711 patients were included for analysis. After 3 months of usual care, a significant improvement was observed in pain and QoL in all four cancer groups (p<0.001). Effect sizes were medium to large on the BPI and EQ-5D Index and Visual Analogue Scale (VAS). Improvements were seen on the majority of EQ-5D dimensions in all patient groups, though breast cancer patients showed the largest gains. Poorer baseline performance status (ECOG) and the presence of anxiety/depression were associated with significantly poorer QOL outcomes. Improvements in BPI pain scores were associated with improved QoL. CONCLUSION: In the four cancer types studied, pain and QoL outcomes improved considerably after 3 months of usual care. Improvements in pain made a substantial contribution to QoL gains whilst the presence of anxiety and depression and poor baseline performance status significantly constrained improvement. PMID- 29614069 TI - Prediction of extended high viremia among newly HIV-1-infected persons in sub Saharan Africa. AB - OBJECTIVE: Prompt identification of newly HIV-infected persons, particularly those who are most at risk of extended high viremia (EHV), allows important clinical and transmission prevention benefits. We sought to determine whether EHV could be predicted during early HIV infection (EHI) from clinical, demographic, and laboratory indicators in a large HIV-1 incidence study in Africa. DESIGN: Adults acquiring HIV-1 infection were enrolled in an EHI study assessing acute retroviral syndrome (ARS) symptoms and viral dynamics. METHODS: Estimated date of infection (EDI) was based on a positive plasma viral load or p24 antigen test prior to seroconversion, or the mid-point between negative and positive serological tests. EHV was defined as mean untreated viral load >=5 log10 copies/ml 130-330 days post-EDI. We used logistic regression to develop risk score algorithms for predicting EHV based on sex, age, number of ARS symptoms, and CD4 and viral load at diagnosis. RESULTS: Models based on the full set of five predictors had excellent performance both in the full population (c statistic = 0.80) and when confined to persons with each of three HIV-1 subtypes (c-statistic = 0.80-0.83 within subtypes A, C, and D). Reduced models containing only 2-4 predictors performed similarly. In a risk score algorithm based on the final full-population model, predictor scores were one for male sex and enrollment CD4<350 cells/mm3, and two for having enrollment viral load >4.9 log10 copies/ml. With a risk score cut-point of two, this algorithm was 85% sensitive (95% CI: 76%-91%) and 61% specific (55%-68%) in predicting EHV. CONCLUSIONS: Simple risk score algorithms can reliably identify persons with EHI in sub Saharan Africa who are likely to sustain high viral loads if treatment is delayed. These algorithms may be useful for prioritizing intensified efforts around care linkage and retention, treatment initiation, adherence support, and partner services to optimize clinical and prevention outcomes. PMID- 29614070 TI - Combining independent decisions increases diagnostic accuracy of reading lumbosacral radiographs and magnetic resonance imaging. AB - Diagnosing the causes of low back pain is a challenging task, prone to errors. A novel approach to increase diagnostic accuracy in medical decision making is collective intelligence, which refers to the ability of groups to outperform individual decision makers in solving problems. We investigated whether combining the independent ratings of chiropractors, chiropractic radiologists and medical radiologists can improve diagnostic accuracy when interpreting diagnostic images of the lumbosacral spine. Evaluations were obtained from two previously published studies: study 1 consisted of 13 raters independently rating 300 lumbosacral radiographs; study 2 consisted of 14 raters independently rating 100 lumbosacral magnetic resonance images. In both studies, raters evaluated the presence of "abnormalities", which are indicators of a serious health risk and warrant immediate further examination. We combined independent decisions of raters using a majority rule which takes as final diagnosis the decision of the majority of the group. We compared the performance of the majority rule to the performance of single raters. Our results show that with increasing group size (i.e., increasing the number of independent decisions) both sensitivity and specificity increased in both data-sets, with groups consistently outperforming single raters. These results were found for radiographs and MR image reading alike. Our findings suggest that combining independent ratings can improve the accuracy of lumbosacral diagnostic image reading. PMID- 29614071 TI - Annual trends in arthroscopic meniscus surgery: Analysis of a national database in Japan. AB - BACKGROUND: The importance of meniscus preservation is widely recognized. There have been a few studies describing trends in meniscectomy and meniscus repair in the United States; however, they presented differing results. We reported annual trends in meniscus surgery, using a national database in Japan. METHODS: We interrogated the Diagnosis Procedure Combination database, which represents approximately half of all hospital admissions in Japan. We included the patients who underwent meniscectomy and meniscus repair between July 2007 and March 2015. The diagnosis, age and sex of each patient were recorded. RESULTS: We identified 83,105 patients: 69,310 underwent meniscectomy; 13,416 underwent meniscus repair and 379 underwent both in a single admission. The proportion of patients undergoing meniscus repair rose from 7.0% in 2007 to 25.9% in 2014 (p < 0.001), while the proportion undergoing meniscectomy fell from 92.8% in 2007 to 73.3% in 2014 (p < 0.001). Among patients under 30 years old, the proportions undergoing meniscus repair or meniscectomy in 2014 were 50.3% versus 48.3%, respectively. A bimodal age distribution was observed for meniscectomy, with peaks at 10-19 years of age and 60-69 years of age, whereas most patients undergoing meniscus repair were 10-19 years of age. CONCLUSIONS: We found characteristic trends where the popularity of meniscus repair increased rapidly at the expense of meniscectomy in Japan during the study period. In the last survey year, the proportion of meniscus repair exceeded that of meniscectomy in those younger than 30 years. Meniscectomy was undertaken most often in adolescents and early old age, while meniscus repair was undertaken most often in adolescents. PMID- 29614073 TI - Preprints: An underutilized mechanism to accelerate outbreak science. AB - In an Essay, Michael Johansson and colleagues advocate the posting of research studies addressing infectious disease outbreaks as preprints. PMID- 29614072 TI - Effect of Ca2+ on the promiscuous target-protein binding of calmodulin. AB - Calmodulin (CaM) is a calcium sensing protein that regulates the function of a large number of proteins, thus playing a crucial part in many cell signaling pathways. CaM has the ability to bind more than 300 different target peptides in a Ca2+-dependent manner, mainly through the exposure of hydrophobic residues. How CaM can bind a large number of targets while retaining some selectivity is a fascinating open question. Here, we explore the mechanism of CaM selective promiscuity for selected target proteins. Analyzing enhanced sampling molecular dynamics simulations of Ca2+-bound and Ca2+-free CaM via spectral clustering has allowed us to identify distinct conformational states, characterized by interhelical angles, secondary structure determinants and the solvent exposure of specific residues. We searched for indicators of conformational selection by mapping solvent exposure of residues in these conformational states to contacts in structures of CaM/target peptide complexes. We thereby identified CaM states involved in various binding classes arranged along a depth binding gradient. Binding Ca2+ modifies the accessible hydrophobic surface of the two lobes and allows for deeper binding. Apo CaM indeed shows shallow binding involving predominantly polar and charged residues. Furthermore, binding to the C-terminal lobe of CaM appears selective and involves specific conformational states that can facilitate deep binding to target proteins, while binding to the N-terminal lobe appears to happen through a more flexible mechanism. Thus the long-ranged electrostatic interactions of the charged residues of the N-terminal lobe of CaM may initiate binding, while the short-ranged interactions of hydrophobic residues in the C-terminal lobe of CaM may account for selectivity. This work furthers our understanding of the mechanism of CaM binding and selectivity to different target proteins and paves the way towards a comprehensive model of CaM selectivity. PMID- 29614074 TI - Serologic and behavioral risk survey of workers with wildlife contact in China. AB - We report on a study conducted in Guangdong Province, China, to characterize behaviors and perceptions associated with transmission of pathogens with pandemic potential in highly exposed human populations at the animal-human interface. A risk factor/exposure survey was administered to individuals with high levels of exposure to wildlife. Serological testing was performed to evaluate prior infection with several wildlife viral pathogens. Follow up serology was performed on a subset of the cohort as well as close contacts of individuals. 1,312 individuals were enrolled in the study. Contact with a wide range of wildlife species was reported in both occupational and occasional contexts. The overall proportion of individuals seropositive to any of the tested wildlife pathogens was approximately 4.0%. However, persons employed as butchers demonstrated a seropositivity of 9.0% to at least one pathogen of interest. By contrast, individuals working as hunters had lower rates of seropositivity. Among the study population, a number of other behaviors showed correlation with seropositivity, including contact with particular wildlife species such as field rats. These results demonstrate the need to further explore zoonotic risks of particular activities regarding wildlife contact, and to better understand risks of persons working as butchers with wildlife species. PMID- 29614075 TI - Association between the retinal vascular network with Singapore "I" Vessel Assessment (SIVA) software, cardiovascular history and risk factors in the elderly: The Montrachet study, population-based study. AB - PURPOSE: To identify patterns summarizing the retinal vascular network in the elderly and to investigate the relationship of these vascular patterns with cardiovascular history. METHODS: We conducted a population-based study, the Montrachet study (Maculopathy Optic Nerve nuTRition neurovAsCular and HEarT diseases), in participants older than 75 years. The history of cardiovascular disease and a score-based estimation of their 10-year risk of cardiovascular mortality (Heart SCORE) were collected. Retinal vascular network analysis was performed by means of Singapore "I" Vessel Assessment (SIVA) software. Principal component analysis was used to condense the information contained in the high number of variables provided and to identify independent retinal vascular patterns. RESULTS: Overall, 1069 photographs (1069 participants) were reviewed with SIVA software. The mean age was 80.0 +/- 3.8 years. We extracted three vascular patterns summarizing 41.3% of the vascular information. The most clinically relevant pattern, Sparse vascular network, accounted for 17.4% of the total variance. It corresponded to a lower density in the vascular network and higher variability in vessel width. Diabetic participants with hypoglycemic treatment had a sparser vascular network pattern than subjects without such treatment (odds ratio, [OR], 1.68; 95% CI, 1.04-2.72; P = 0.04). Participants with no history of cardiovascular disease who had a sparser vascular network were associated with a higher Heart SCORE (OR, 1.76; 95% CI, 1.08-2.25; P = 0.02). CONCLUSIONS: Three vascular patterns were identified. The Sparse vascular network pattern was associated with having a higher risk profile for cardiovascular mortality risk at 10 years. PMID- 29614076 TI - A deep-learning classifier identifies patients with clinical heart failure using whole-slide images of H&E tissue. AB - Over 26 million people worldwide suffer from heart failure annually. When the cause of heart failure cannot be identified, endomyocardial biopsy (EMB) represents the gold-standard for the evaluation of disease. However, manual EMB interpretation has high inter-rater variability. Deep convolutional neural networks (CNNs) have been successfully applied to detect cancer, diabetic retinopathy, and dermatologic lesions from images. In this study, we develop a CNN classifier to detect clinical heart failure from H&E stained whole-slide images from a total of 209 patients, 104 patients were used for training and the remaining 105 patients for independent testing. The CNN was able to identify patients with heart failure or severe pathology with a 99% sensitivity and 94% specificity on the test set, outperforming conventional feature-engineering approaches. Importantly, the CNN outperformed two expert pathologists by nearly 20%. Our results suggest that deep learning analytics of EMB can be used to predict cardiac outcome. PMID- 29614077 TI - A probabilistic, distributed, recursive mechanism for decision-making in the brain. AB - Decision formation recruits many brain regions, but the procedure they jointly execute is unknown. Here we characterize its essential composition, using as a framework a novel recursive Bayesian algorithm that makes decisions based on spike-trains with the statistics of those in sensory cortex (MT). Using it to simulate the random-dot-motion task, we demonstrate it quantitatively replicates the choice behaviour of monkeys, whilst predicting losses of otherwise usable information from MT. Its architecture maps to the recurrent cortico-basal-ganglia thalamo-cortical loops, whose components are all implicated in decision-making. We show that the dynamics of its mapped computations match those of neural activity in the sensorimotor cortex and striatum during decisions, and forecast those of basal ganglia output and thalamus. This also predicts which aspects of neural dynamics are and are not part of inference. Our single-equation algorithm is probabilistic, distributed, recursive, and parallel. Its success at capturing anatomy, behaviour, and electrophysiology suggests that the mechanism implemented by the brain has these same characteristics. PMID- 29614078 TI - A bi-stable feedback loop between GDNF, EGR1, and ERalpha contribute to endocrine resistant breast cancer. AB - Discovering regulatory interactions between genes that specify the behavioral properties of cells remains an important challenge. We used the dynamics of transcriptional changes resolved by PRO-seq to identify a regulatory network responsible for endocrine resistance in breast cancer. We show that GDNF leads to endocrine resistance by switching the active state in a bi-stable feedback loop between GDNF, EGR1, and the master transcription factor ERalpha. GDNF stimulates MAP kinase, activating the transcription factors SRF and AP-1. SRF initiates an immediate transcriptional response, activating EGR1 and suppressing ERalpha. Newly translated EGR1 protein activates endogenous GDNF, leading to constitutive GDNF and EGR1 up-regulation, and the sustained down-regulation of ERalpha. Endocrine resistant MCF-7 cells are constitutively in the GDNF-high/ ERalpha-low state, suggesting that the state in the bi-stable feedback loop may provide a 'memory' of endocrine resistance. Thus, we identified a regulatory network switch that contributes to drug resistance in breast cancer. PMID- 29614079 TI - Identification and characterization of wheat stem rust resistance gene Sr21 effective against the Ug99 race group at high temperature. AB - Wheat stem rust, caused by Puccinia graminis f. sp. tritici (Pgt), is a devastating foliar disease. The Ug99 race group has combined virulence to most stem rust (Sr) resistance genes deployed in wheat and is a threat to global wheat production. Here we identified a coiled-coil, nucleotide-binding leucine-rich repeat protein (NLR) completely linked to the Ug99 resistance gene Sr21 from Triticum monococcum. Loss-of-function mutations and transgenic complementation confirmed that this gene is Sr21. Sr21 transcripts were significantly higher at high temperatures, and this was associated with significant upregulation of pathogenesis related (PR) genes and increased levels of resistance at those temperatures. Introgression of Sr21 into hexaploid wheat resulted in lower levels of resistance than in diploid wheat, but transgenic hexaploid wheat lines with high levels of Sr21 expression showed high levels of resistance. Sr21 can be a valuable component of transgenic cassettes or gene pyramids combining multiple resistance genes against Ug99. PMID- 29614080 TI - New insights on repellent recognition by Anopheles gambiae odorant-binding protein 1. AB - It is generally recognized that insect odorant binding proteins (OBPs) mediate the solubilisation and transport of hydrophobic odorant molecules and contribute to the sensitivity of the insect olfactory system. However, the exact mechanism by which OBPs deliver odorants to olfactory receptors and their role, if any, as selectivity filters for specific odorants, are still a matter of debate. In the case of Anopheles gambiae, recent studies indicate that ligand discrimination is effected through the formation of heterodimers such as AgamOBP1 and AgamOBP4 (odorant binding proteins 1 and 4 from Anopheles gambiae). Furthermore, AgamOBPs have been reported to be promiscuous in binding more than one ligand simultaneously and repellents such as DEET (N,N-diethyl-3-toluamide) and 6-MH (6 methyl-5-hepten-2-one) interact directly with mosquito OBPs and/or compete for the binding of attractive odorants thus disrupting OBP heterodimerisation. In this paper, we propose mechanisms of action of DEET and 6-MH. We also predict that ligand binding can occur in several locations of AgamOBP1 with partial occupancies and propose structural features appropriate for repellent pharmacophores. PMID- 29614081 TI - Genetic scores to stratify risk of developing multiple islet autoantibodies and type 1 diabetes: A prospective study in children. AB - BACKGROUND: Around 0.3% of newborns will develop autoimmunity to pancreatic beta cells in childhood and subsequently develop type 1 diabetes before adulthood. Primary prevention of type 1 diabetes will require early intervention in genetically at-risk infants. The objective of this study was to determine to what extent genetic scores (two previous genetic scores and a merged genetic score) can improve the prediction of type 1 diabetes. METHODS AND FINDINGS: The Environmental Determinants of Diabetes in the Young (TEDDY) study followed genetically at-risk children at 3- to 6-monthly intervals from birth for the development of islet autoantibodies and type 1 diabetes. Infants were enrolled between 1 September 2004 and 28 February 2010 and monitored until 31 May 2016. The risk (positive predictive value) for developing multiple islet autoantibodies (pre-symptomatic type 1 diabetes) and type 1 diabetes was determined in 4,543 children who had no first-degree relatives with type 1 diabetes and either a heterozygous HLA DR3 and DR4-DQ8 risk genotype or a homozygous DR4-DQ8 genotype, and in 3,498 of these children in whom genetic scores were calculated from 41 single nucleotide polymorphisms. In the children with the HLA risk genotypes, risk for developing multiple islet autoantibodies was 5.8% (95% CI 5.0%-6.6%) by age 6 years, and risk for diabetes by age 10 years was 3.7% (95% CI 3.0%-4.4%). Risk for developing multiple islet autoantibodies was 11.0% (95% CI 8.7%-13.3%) in children with a merged genetic score of >14.4 (upper quartile; n = 907) compared to 4.1% (95% CI 3.3%-4.9%, P < 0.001) in children with a genetic score of <=14.4 (n = 2,591). Risk for developing diabetes by age 10 years was 7.6% (95% CI 5.3%-9.9%) in children with a merged score of >14.4 compared with 2.7% (95% CI 1.9%-3.6%) in children with a score of <=14.4 (P < 0.001). Of 173 children with multiple islet autoantibodies by age 6 years and 107 children with diabetes by age 10 years, 82 (sensitivity, 47.4%; 95% CI 40.1%-54.8%) and 52 (sensitivity, 48.6%, 95% CI 39.3%-60.0%), respectively, had a score >14.4. Scores were higher in European versus US children (P = 0.003). In children with a merged score of >14.4, risk for multiple islet autoantibodies was similar and consistently >10% in Europe and in the US; risk was greater in males than in females (P = 0.01). Limitations of the study include that the genetic scores were originally developed from case-control studies of clinical diabetes in individuals of mainly European decent. It is, therefore, possible that it may not be suitable to all populations. CONCLUSIONS: A type 1 diabetes genetic score identified infants without family history of type 1 diabetes who had a greater than 10% risk for pre symptomatic type 1 diabetes, and a nearly 2-fold higher risk than children identified by high-risk HLA genotypes alone. This finding extends the possibilities for enrolling children into type 1 diabetes primary prevention trials. PMID- 29614082 TI - Breast tuberculosis in men: A systematic review. AB - SETTING: Breast tuberculosis in male is a rarely reported and poorly described condition. OBJECTIVE: To quantify the number of breast tuberculosis in men, to describe clinical presentation and to present the diagnostic and therapeutic procedures applied. DESIGN: A systematic review of the literature including reports published in English, Spanish and French until December 2017. RESULTS: The search yielded 26 cases of male breast tuberculosis, median age 56.5 years. Most presented with an isolated breast lump (89%), associated with axillary lymphadenitis (27.8%) and skin inflammation (33.3%). The most common constitutional symptoms were pain (64.7%) and fever (35.3%). Fine-needle aspiration cytology and culture were the most common diagnostic modality (61.5%). Standard anti-tuberculosis regimen was the main treatment, alone or accompanied or preceded by incision and drainage. CONCLUSIONS: The risk of breast tuberculosis in men appears to be low, but the condition can be difficult to diagnose and the diagnostic delays can be long. Overall prognosis is good following standard anti-tuberculosis regimen with or without incision/drainage. PMID- 29614083 TI - Optimizing prevention of HIV mother to child transmission: Duration of antiretroviral therapy and viral suppression at delivery among pregnant Malawian women. AB - BACKGROUND: Effective antiretroviral therapy during pregnancy minimizes the risk of vertical HIV transmission. Some women present late in their pregnancy for first antenatal visit; whether these women achieve viral suppression by delivery and how suppression varies with time on ART is unclear. METHODS: We conducted a prospective cohort study of HIV-infected pregnant women initiating antiretroviral therapy for the first time at Bwaila Hospital in Lilongwe, Malawi from June 2015 to November 2016. Multivariable Poisson models with robust variance estimators were used to estimate risk ratios (RR) and 95% confidence intervals (CI) of the association between duration of ART and both viral load (VL) >=1000 copies/ml and VL >=40 copies/ml at delivery. RESULTS: Of the 252 women who had viral load testing at delivery, 40 (16%) and 78 (31%) had VL >=1000 copies/ml and VL >=40 copies/ml, respectively. The proportion of women with poor adherence to ART was higher among women who were on ART for <=12 weeks (9/50 = 18.0%) than among those who were on ART for 13-35 weeks (18/194 = 9.3%). Compared to women who were on ART for <=12 weeks, women who were on ART for 13-20 weeks (RR = 0.52; 95% CI: 0.36-0.74) or 21-35 weeks (RR = 0.26; 95% CI: 0.14-0.48) had a lower risk of VL >=40 copies/ml at delivery. Similar comparisons for VL >=1000 copies/ml at delivery showed decrease in risk although not significant for those on ART 13-20 weeks. CONCLUSION: Longer duration of ART during pregnancy was associated with suppressed viral load at delivery. Early ANC attendance in pregnancy to facilitate prompt ART initiation for HIV-positive women is essential in the effort to eliminate HIV vertical transmission. PMID- 29614084 TI - Identification of HLA-DRB1 association to adalimumab immunogenicity. AB - Anti-drug antibody formation occurs with most biological agents across disease states, but the mechanism by which they are formed is unknown. The formation of anti-drug antibodies to adalimumab (AAA) may decrease its therapeutic effects in some patients. HLA alleles have been reported to be associated with autoantibody formation against interferons and other TNF inhibitors, but not adalimumab. We analyzed samples from 634 subjects with either rheumatoid arthritis (RA) or hidradenitis suppurativa (HS): 37 subjects (17 RA and 20 HS) developed AAA (AAA+) during adalimumab treatment and 597 subjects (348 RA, 249 HS) did not develop AAA (AAA-) during the clinical trials. Using next-generation sequencing-based HLA typing, we identified three protective HLA alleles (HLA-DQB1*05, HLA-DRB1*01,and HLA-DRB1*07) that were less prevalent in AAA+ than AAA-subjects (ORs: 0.4, 0.25 and 0.28, respectively; and P values: 0.012, 0.012 and 0.018, respectively) and two risk HLA alleles (HLA-DRB1*03 and HLA-DRB1*011) that were more abundant in AAA+ than AAA-subjects (ORs: 2.52, and 2.64, respectively; and P values: 0.006 and 0.019). Similar to the finding of Billiet et al. who found that carriage of the HLA-DRB1*03 allele was more prevalent in those with anti-infliximab antibodies (OR = 3.6, p = 0.002, 95% CI: [1.5,8.6]).), we found HLA-DRB1*03 allele was also more prevalent in anti-adalimumab positive (OR = 2.52, p = 0.006, 95% CI: [1.37,4.63]). The results suggest that specific HLA alleles may play a key role in developing AAAs in RA and HS patients treated with adalimumab. PMID- 29614085 TI - Interactions between seed traits and digestive processes determine the germinability of bird-dispersed seeds. AB - Waterbirds disperse a wide range of plant seeds via their guts, promoting biotic connectivity between isolated habitat patches. However, the intensity of digestive forces encountered by seeds, and therefore their potential to survive digestive tract passage, varies within and between waterbird species. Here, we investigate under controlled conditions how the interaction between seed traits and digestive strategies affect the germinability of seeds following waterbird mediated dispersal. We exposed seeds of 30 wetland plant species to the main digestive processes in the dabbling duck digestive system: mechanical, chemical and intestinal digestion. These were simulated by 1) a pressure test and scarification treatment, 2) incubation in simulated gastric juice, and 3) incubation in intestinal contents of culled mallards (Anas platyrhynchos). We evaluated their separate and combined effects on seed germination, and identified the role of seed size and seed coat traits in resisting the digestive forces. Seeds were generally resistant to separate digestive processes, but highly sensitive to a combination. Resistance to mechanical break-down was reduced by up to 80% by chemical pre-treatment, especially for seeds with permeable coats. Scarified seeds were 12-17% more vulnerable to chemical and intestinal digestive processes than undamaged seeds. Large seeds and seeds with thin, permeable coats were particularly sensitive to chemical and intestinal digestion. These results indicate that efficient digestion of seeds requires multiple digestive processes. The gizzard, responsible for mechanical digestion, plays a key role in seed survival. Omnivorous birds, which have relatively light gizzards compared to pure herbivores or granivores, are thus most likely to disperse seeds successfully. Regardless of digestive strategy, small seeds with tough seed coats are most resistant to digestion and may be adapted to endozoochorous dispersal by waterbirds. PMID- 29614086 TI - All three quinone species play distinct roles in ensuring optimal growth under aerobic and fermentative conditions in E. coli K12. AB - The electron transport chain of E. coli contains three different quinone species, ubiquinone (UQ), menaquinone (MK) and demethylmenaquinone (DMK). The content and ratio of the different quinone species vary depending on the external conditions. To study the function of the different quinone species in more detail, strains with deletions preventing UQ synthesis, as well as MK and/or DMK synthesis were cultured under aerobic and anaerobic conditions. The strains were characterized with respect to growth and product synthesis. As quinones are also involved in the control of ArcB/A activity, we analyzed the phosphorylation state of the response regulator as well as the expression of selected genes.The data show reduced aerobic growth coupled to lactate production in the mutants defective in ubiquinone synthesis. This confirms the current assumption that ubiquinone is the main quinone under aerobic growth conditions. In the UQ mutant strains the amount of MK and DMK is significantly elevated. The strain synthesizing only DMK is less affected in growth than the strain synthesizing MK as well as DMK. An inhibitory effect of MK on aerobic growth due to increased oxidative stress is postulated.Under fermentative growth conditions the mutant synthesizing only UQ is severely impaired in growth. Obviously, UQ is not able to replace MK and DMK during anaerobic growth. Mutations affecting quinone synthesis have an impact on ArcA phosphorylation only under anaerobic conditions. ArcA phosphorylation is reduced in strains synthesizing only MK or MK plus DMK. PMID- 29614087 TI - Trajectories and predictors of women's health-related quality of life during pregnancy: A large longitudinal cohort study. AB - The objective of this study was to identify distinct trajectories and their predictors of health-related quality of life (HRQOL) of women during pregnancy in a prospective mother and child cohort. Analyses were based on 3936 Dutch pregnant women in Rotterdam area, the Netherlands. Information on potential predictors was collected in early pregnancy by questionnaire. Latent Class Mixture Modelling and Multinomial Logistic Regression were applied to assess the trajectory and predictors of HRQOL during pregnancy. HRQOL was measured by SF-12 in early, mid- and late pregnancy; physical and mental component summary (PCS-12/MCS-12) scores were calculated. Four physical HRQOL trajectories were identified: a healthy trajectory ('healthy') in 63.3%, consistently low ('vulnerable') in 10.8%; a small increase ('recovering') in 12.8% and a large decrease ('at risk') in 13.1%. Three mental HRQOL trajectories were identified: a healthy trajectory ('healthy') in 86.1%; a large increase ('recovering') in 7.5%; and a large decrease ('at risk') in 6.4%. Compared with healthy trajectories, the likelihood of following the 'vulnerable' physical HRQOL trajectory rather than a healthy trajectory was increased by daily fatigue(OR: 4.82[2.76, 8.40]), pelvic pain (OR:4.76[2.91, 7.78]) and back pain (OR:5.29[3.21, 8.70]); pregnancy-specific anxiety increased the likelihood of following the 'at risk' mental HRQOL trajectory (OR:7.95[4.84, 13.05]). Healthy physical and mental HRQOL trajectories during pregnancy were most common. Predictors indicative of poor HRQOL trajectories included pregnancy related symptoms and anxiety. PMID- 29614088 TI - Malaria burden and treatment targets in Kachin Special Region II, Myanmar from 2008 to 2016: A retrospective analysis. AB - Although drug-based treatment is the primary intervention for malaria control and elimination, optimal use of targeted treatments remains unclear. From 2008 to 2016, three targeted programs on treatment were undertaken in Kachin Special Region II (KR2), Myanmar. Program I (2008-2011) treated all confirmed, clinical and suspected cases; program II (2012-2013) treated confirmed and clinical cases; and program III (2014-2016) targeted confirmed cases only. This study aims to evaluate the impacts of the three programs on malaria burden individually based on the annual parasite incidence (API), slide positivity rate (SPR) and their relative values. The API is calculated from original collected data and the incidence rate ratio (IRR) for each year is calculated by using the first-year API as a reference in each program phase across the KR2. Same method is applied to calculate SPR and risk ratio (RR) at the sentinel hospital too. During program I (2008-2011), malaria burden was reduced by 61% (95%CI: 58%-74%) and the actual API decreased from 9.8 (95%CI: 9.6-10.1) per 100 person-years in 2008 to 3.8 (3.6 4.1) per 100 person-years in 2011. Amid program II (2012-2013), the malaria burden increased by 33% (95%CI: 22%-46%) and the actual API increased from 2.1(95%CI: 2.0-2.3) per 100 person-years in 2012 to 2.8 (95%CI: 2.7-2.9) per 100 person-years in 2013. During program III (2014-2016) the malaria burden increased furtherly by 60% (95%CI: 51% - 69%) and the actual API increased from 3.2(95%CI: 3.0-3.3) per 100 person-years in 2014 to 5.1 (95%CI: 4.9-5.2) per 100 person years in 2016. Results of the slide positivity of the sentinel hospital also confirm these results. Resurgence of malaria was mainly due to Plasmodium vivax during program II and III. This study indicates that strategy adopted in program I (2008-2011) should be more appropriate for the KR2. Quality-assured treatment of all confirmed, clinical and suspected malaria cases may be helpful for the reduction of malaria burden. PMID- 29614090 TI - Intra-abdominal pressure, vertebral column length, and spread of spinal anesthesia in parturients undergoing cesarean section: An observational study. AB - BACKGROUND: In parturients with increased physiologically intra-abdominal pressure (IAP) and a short stature, a greater cephalad spread of spinal anesthesia is often observed after a fixed amount of plain bupivacaine is administered. Therefore, we designed this prospective study to test whether IAP and vertebral column length (VCL) were predictors of spinal spread in parturients undergoing a cesarean section. METHODS: A total of 113 parturients, all undergoing elective cesarean sections with single-shot spinal anesthesia, were enrolled. The L3-L4 interspace was entered, and 2 mL of 0.5% plain bupivacaine was injected into the subarachnoid space. Upon loss of temperature sensation at the T4 level, IAP was measured through a bladder catheter while the patient was in the supine position with a 10 degrees left lateral tilt. Parturient demographic variables, including age, height, weight, IAP, and VCL were recorded. Linear regressions and multiple regressions were performed to analyze the relationships between parturient variables and the spread of spinal anesthesia. RESULTS: A total of 109 parturients were included in the analysis. Linear regression analysis showed a significant univariate correlation of height, weight, body mass index (BMI), IAP, and VCL with cephalad spread (all P< 0.004). Multiple linear regression analysis showed that IAP and VCL were the key determinants of spinal spread (both P < 0.0001), where as exclusion of age, weight, and height did not change the result (all P> 0.209). CONCLUSIONS: Our data indicated that IAP and VCL were significant predictors of intrathecal spread of plain bupivacaine, and there was a positive association between IAP and abdominal girth in term parturients. PMID- 29614089 TI - Hippocampal protein kinase D1 is necessary for DHPG-induced learning and memory impairments in rats. AB - BACKGROUND: Understanding molecular mechanisms underlying the induction of learning and memory impairments remains a challenge. Recent investigations have shown that the activation of group I mGluRs (mGluR1 and mGluR5) in cultured hippocampal neurons by application of (S)-3,5-Dihydroxyphenylglycine (DHPG) causes the regulated internalization of N-methyl-D-aspartate receptors (NMDARs), which subsequently activates protein kinase D1 (PKD1). Through phosphorylating the C-terminals of the NMDAR GluN2 subunits, PKD1 down-regulates the activity of remaining (non-internalized) surface NMDARs. The knockdown of PKD1 does not affect the DHPG-induced inhibition of AMPA receptor-mediated miniature excitatory post-synaptic currents (mEPSCs) but prevents the DHPG-induced inhibition of NMDAR mediated mEPSCs in vitro. Thus, we investigated the in vivo effects of bilateral infusions of DHPG into the hippocampal CA1 area of rats in the Morris water maze (MWM) and the novel object discrimination (NOD) tests. METHODS: A total of 300 adult male Sprague Dawley rats (250-280 g) were used for behavioral tests. One hundred ninety four were used in MWM test and the other 106 rats in the NOD test. Following one week of habituation to the vivarium, rats were bilaterally implanted under deep anesthesia with cannulas aimed at the CA1 area of the hippocampus (CA1 coordinates in mm from Bregma: AP -3.14; lateral +/-2; DV -3.0). Through implanted cannulas artificial cerebrospinal fluid (ACSF), the group1 mGluR antagonist 6-Methyl-2-(phenylethynyl)pyridine (MPEP), the dynamin-dependent internalization inhibitor Dynasore, or the PKD1 inhibitor CID755673 were infused into the bilateral hippocampal CA1 areas (2 MUL per side, over 5 min). The effects of these infusions and the effects of PKD1 knockdown were examined in MWM or NOD test. RESULTS: DHPG infusion increased the latency to reach the platform in the MWM test and reduced the preference for the novel object in the NOD task. We found that the DHPG effects were dose-dependent and could be maintained for up to 2 days. Notably, these effects could be prevented by pre-infusion of the group1 mGluR antagonist MPEP, the dynamin-dependent internalization inhibitor Dynasore, the PKD1 inhibitor CID755673, or by PKD1 knockdown in the hippocampal CA1 area. CONCLUSION: Altogether, these findings provide direct evidence that PKD1-mediated signaling may play a critical role in the induction of learning and memory impairments by DHPG infusion into the hippocampal CA1 area. PMID- 29614091 TI - Small group gender ratios impact biology class performance and peer evaluations. AB - Women are underrepresented in science, technology, engineering, and mathematics (STEM) disciplines. Evidence suggests the microclimate of the classroom is an important factor influencing female course grades and interest, which encourages retention of women in STEM fields. Here, we test whether the gender composition of small (8-9 person) learning groups impacts course performance, sense of social belonging, and intragroup peer evaluations of intellectual contributions. Across two undergraduate active learning courses in introductory biology, we manipulated the classroom microclimate by varying the gender ratios of learning groups, ranging from 0% female to 100% female. We found that as the percent of women in groups increased, so did overall course performance for all students, regardless of gender. Additionally, women assigned higher peer- evaluations in groups with more women than groups with less women. Our work demonstrates an added benefit of the retention of women in STEM: increased performance for all, and positive peer perceptions for women. PMID- 29614092 TI - Combined classification system based on ACR/EULAR and ultrasonographic scores for improving the diagnosis of Sjogren's syndrome. AB - We retrospectively evaluated the effectiveness of combined use of salivary gland ultrasonography (US) and the 2016 American College of Rheumatology/European League Against Rheumatic Disease (ACR/EULAR) classification criteria for improving the diagnostic efficiency in patients with Sjogren's syndrome (SS). A US-based salivary gland disease grading system was developed using a cohort comprising 213 SS or non-SS patients who fulfilled the minimum requirements for classifying SS based on the American-European Consensus Group (AECG) and ACR criteria. Using 62 SS or non-SS patients from the 213 patients and who had also undergone all the 5 examinations needed for the ACR/EULAR classification, we compared the diagnostic accuracy of various combinations of the ACR/EULAR and US classifications for diagnosing SS, using the clinical diagnosis of SS by rheumatologists as the gold standard. The ACR/EULAR criteria discriminated clinical SS patients with 77% and 79% accuracy for those with primary or secondary SS and for those with primary SS, respectively. However, the integrated score system of the ACR/EULAR and US classifications yielded 92% and 93% accuracy for these 2 SS patient groups, respectively, provided that US score of 3 was assigned to patients with US grade >=2, and then patients with integrated threshold score of >=5 were diagnosed as SS. Cross-validation also indicated improved accuracy of the integrated ACR/EULAR and US score system (91.9 and 93.0% for primary/secondary and primary SS patients, respectively) over that by the ACR/EULAR criteria alone. (74.2 and 86.0%, respectively). The integrated ACR/EULAR and US scoring system can improve the diagnosis of patients with clinical SS. PMID- 29614093 TI - Development of a landscape integrity model framework to support regional conservation planning. AB - Land managers increasingly rely upon landscape assessments to understand the status of natural resources and identify conservation priorities. Many of these landscape planning efforts rely on geospatial models that characterize the ecological integrity of the landscape. These general models utilize measures of habitat disturbance and human activity to map indices of ecological integrity. We built upon these modeling frameworks by developing a Landscape Integrity Index (LII) model using geospatial datasets of the human footprint, as well as incorporation of other indicators of ecological integrity such as biodiversity and vegetation departure. Our LII model serves as a general indicator of ecological integrity in a regional context of human activity, biodiversity, and change in habitat composition. We also discuss the application of the LII framework in two related coarse-filter landscape conservation approaches to expand the size and connectedness of protected areas as regional mitigation for anticipated land-use changes. PMID- 29614095 TI - Transfusional malaria in the neonatal period in Lagos, South-West Nigeria. AB - BACKGROUND AND OBJECTIVES: Sick neonates in malaria endemic areas are frequently transfused with donor blood unscreened for malaria parasite. Consequently, they are at risk of transfusional malaria which can lead to increased neonatal mortality. The study aimed to determine the burden of transfusional malaria in neonates to help in policy formulation on prevention of transfusional malaria. MATERIALS AND METHODS: One hundred and sixty four neonates admitted into the neonatal unit of a tertiary hospital over a 10 month period who were scheduled for blood transfusion were screened for malaria parasites pre-transfusion, at three and 14 days post transfusion using Giemsa stained thick and thin films. Donor blood was screened for malaria parasites at the point of transfusion. Neonates who developed malaria parasitaemia post transfusion were followed up for signs of malaria. RESULTS: All recruited neonates tested negative to malaria parasite pre- transfusion. One hundred and twenty (73.2%) were term neonates with 94(57.3%) aged 1-7days. Four (2.4%) neonates developed malaria parasitaemia three days post transfusion and all four developed fever that resolved on treatment for malaria. Three (1.8%) of 164 donor blood samples had malaria parasitaemia and all three (100%) neonates who were transfused with the infected donor blood developed malaria parasitaemia post transfusion. However, one neonate who developed malaria parasitaemia post transfusion was transfused with non-infected donor blood. CONCLUSIONS: The prevalence of transfusional malaria in this study is low (2.4%). However, 100% of neonates who received malaria infected donor blood developed transfusional malaria. We therefore recommend routine screening of donor pre transfusion, testing of neonates who develop fever post transfusion and treatment of those who test positive to malaria. PMID- 29614094 TI - Functional examination of novel kisspeptin phosphinic peptides. AB - Kisspeptins acting on their cognate G protein-coupled receptor, kisspeptin receptor, play important roles in the suppression of cancer cell metastasis and regulation of the reproductive system, and therefore are important for therapeutic intervention. All native functional human kisspeptins (kisspeptin-54, kisspsptin-14 and kisspeptin-13) share the 10 amino acids of kisspeptin-10 at their C-terminus (45-54). However, they are inactivated rapidly by matrix metalloproteinases (MMPs) through the cleavage of the peptide bond between glycine51 and leucine52, which limits their clinical applications. Development of MMP-resistant analogues of kisspeptins may provide better therapeutic outputs. In the present study, two kisspeptin phosphinic peptides were designed and synthesized, and their ability to induce phosphorylation of ERK1/2 through kisspeptin receptor and their inhibition on MMP-2 and MMP-9 whose activity correlates with cancer metastasis were assessed. The results showed that one analogue, phosphinic kisspeptin R isomer (PKPR), exhibited kisspeptin receptor agonistic activity and also inhibitory activity on MMP-2, indicating that PKPR may serve as a lead for the further development of kisspeptin analogues for therapeutic purpose. PMID- 29614096 TI - Abundance, diversity and domain architecture variability in prokaryotic DNA binding transcription factors. AB - Gene regulation at the transcriptional level is a central process in all organisms, and DNA-binding transcription factors, known as TFs, play a fundamental role. This class of proteins usually binds at specific DNA sequences, activating or repressing gene expression. In general, TFs are composed of two domains: the DNA-binding domain (DBD) and an extra domain, which in this work we have named "companion domain" (CD). This latter could be involved in one or more functions such as ligand binding, protein-protein interactions or even with enzymatic activity. In contrast to DBDs, which have been widely characterized both experimentally and bioinformatically, information on the abundance, distribution, variability and possible role of the CDs is scarce. Here, we investigated these issues associated with the domain architectures of TFs in prokaryotic genomes. To this end, 19 families of TFs in 761 non-redundant bacterial and archaeal genomes were evaluated. In this regard we found four main groups based on the abundance and distribution in the analyzed genomes: i) LysR and TetR/AcrR; ii) AraC/XylS, SinR, and others; iii) Lrp, Fis, ArsR, and others; and iv) a group that included only two families, ArgR and BirA. Based on a classification of the organisms according to the life-styles, a major abundance of regulatory families in free-living organisms, in contrast with pathogenic, extremophilic or intracellular organisms, was identified. Finally, the protein architecture diversity associated to the 19 families considering a weight score for domain promiscuity evidenced which regulatory families were characterized by either a large diversity of CDs, here named as "promiscuous" families given the elevated number of variable domains found in those TFs, or a low diversity of CDs. Altogether this information helped us to understand the diversity and distribution of the 19 Prokaryotes TF families. Moreover, initial steps were taken to comprehend the variability of the extra domain in those TFs, which eventually might assist in evolutionary and functional studies. PMID- 29614097 TI - Disrupted dispersal and its genetic consequences: Comparing protected and threatened baboon populations (Papio papio) in West Africa. AB - Dispersal is a demographic process that can potentially counterbalance the negative impacts of anthropogenic habitat fragmentation. However, mechanisms of dispersal may become modified in populations living in human-dominated habitats. Here, we investigated dispersal in Guinea baboons (Papio papio) in areas with contrasting levels of anthropogenic fragmentation, as a case study. Using molecular data, we compared the direction and extent of sex-biased gene flow in two baboon populations: from Guinea-Bissau (GB, fragmented distribution, human dominated habitat) and Senegal (SEN, continuous distribution, protected area). Individual-based Bayesian clustering, spatial autocorrelation, assignment tests and migrant identification suggested female-mediated gene flow at a large spatial scale for GB with evidence of contact between genetically differentiated males at one locality, which could be interpreted as male-mediated gene flow in southern GB. Gene flow was also found to be female-biased in SEN for a smaller scale. However, in the southwest coastal part of GB, at the same geographic scale as SEN, no sex-biased dispersal was detected and a modest or recent restriction in GB female dispersal seems to have occurred. This population-specific variation in dispersal is attributed to behavioural responses to human activity in GB. Our study highlights the importance of considering the genetic consequences of disrupted dispersal patterns as an additional impact of anthropogenic habitat fragmentation and is potentially relevant to the conservation of many species inhabiting human-dominated environments. PMID- 29614098 TI - A novel calcimimetic agent, evocalcet (MT-4580/KHK7580), suppresses the parathyroid cell function with little effect on the gastrointestinal tract or CYP isozymes in vivo and in vitro. AB - Cinacalcet hydrochloride (cinacalcet), an oral calcimimetic agent has been widely used for the management of secondary hyperparathyroidism (SHPT) in chronic kidney disease (CKD). In sharp contrast to vitamin D receptor activators, cinacalcet suppresses SHPT without inducing hypercalcemia or hyperphosphatemia. Nevertheless, some patients remain refractory to SHPT with this agent, as the dose cannot be sufficiently increased due to gastrointestinal symptoms. In order to resolve this issue, we have developed a newly synthesized calcimimetic agent, evocalcet (MT-4580/KHK7580). In a rat model of CKD induced by 5/6 nephrectomy, oral administration of evocalcet efficiently suppressed the secretion of parathyroid hormone (PTH). With regard to the gastro-intestinal effects, cinacalcet induced a significant delay in gastric emptying in rats, while evocalcet did no marked effects on it. Evocalcet also demonstrated the less induction of emesis compared to cinacalcet in common marmosets. The pharmacological effects of evocalcet were observed at lower doses because of its higher bioavailability than cinacalcet, which may have contributed to the reduced GI tract symptoms. In addition, evocalcet showed no substantial direct inhibition of any CYP isozymes in in vitro liver microsome assay, suggesting a better profile in drug interactions than cinacalcet that inhibits cytochrome P450 (CYP) 2D6. These findings suggest that evocalcet can be a better alternative to cinacalcet, an oral calcimimetic agent, with a wider safety margin. PMID- 29614099 TI - Time-series analysis for porcine reproductive and respiratory syndrome in the United States. AB - Industry-driven voluntary disease control programs for swine diseases emerged in North America in the early 2000's, and, since then, those programs have been used for monitoring diseases of economic importance to swine producers. One example of such initiatives is Dr. Morrison's Swine Health Monitoring Project, a nation-wide monitoring program for swine diseases including the porcine reproductive and respiratory syndrome (PRRS). PRRS has been extensively reported as a seasonal disease in the U.S., with predictable peaks that start in fall and are extended through the winter season. However, formal time series analysis stratified by geographic region has never been conducted for this important disease across the U.S. The main objective of this study was to use approximately seven years of PRRS incidence data in breeding swine herds to conduct time-series analysis in order to describe the temporal patterns of PRRS outbreaks at the farm level for five major swine-producing states across the U.S. including the states of Minnesota, Iowa, North Carolina, Nebraska and Illinois. Data was aggregated retrospectively at the week level for the number of herds containing animals actively shedding PRRS virus. Basic descriptive statistics were conducted followed by autoregressive integrated moving average (ARIMA) modelling, conducted separately for each of the above-mentioned states. Results showed that there was a difference in the nature of PRRS seasonality among states. Of note, when comparing states, the typical seasonal pattern previously described for PRRS could only be detected for farms located in the states of Minnesota, North Carolina and Nebraska. For the other two states, seasonal peaks every six months were detected within a year. In conclusion, we showed that epidemic patterns are not homogeneous across the U.S, with major peaks of disease occurring through the year. These findings highlight the importance of coordinating alternative control strategies in different regions considering the prevailing epidemiological patterns. PMID- 29614100 TI - Reducing inherent biases introduced during DNA viral metagenome analyses of municipal wastewater. AB - Metagenomics is a powerful tool for characterizing viral composition within environmental samples, but sample and molecular processing steps can bias the estimation of viral community structure. The objective of this study is to understand the inherent variability introduced when conducting viral metagenomic analyses of wastewater and provide a bioinformatic strategy to accurately analyze sequences for viral community analyses. A standard approach using a combination of ultrafiltration, membrane filtration, and DNase treatment, and multiple displacement amplification (MDA) produced DNA preparations without any bacterial derived genes. Results showed recoveries in wastewater matrix ranged between 60 100%. A bias towards small single stranded DNA (ssDNA; polyomavirus) virus types vs larger double stranded DNA (dsDNA; adenovirus) viruses was also observed with a total estimated recovery of small circular viruses to be as much as 173-fold higher. Notably, ssDNA abundance decreased with sample dilution while large dsDNA genomes (e.g., Caudovirales) initially increased in abundance with dilution before gradually decreasing with further dilution in wastewater samples. The present study revealed the inherent biases associated with different components of viral metagenomic methods applied to wastewater. Overall, these results provide a well-characterized approach for effectively conducting viral metagenomics analysis of wastewater and reveal that dilution can effectively mitigate MDA bias. PMID- 29614101 TI - Scientific productivity: An exploratory study of metrics and incentives. AB - Competitive pressure to maximize the current bibliometric measures of productivity is jeopardizing the integrity of the scientific literature. Efforts are underway to address the 'reproducibility crisis' by encouraging the use of more rigorous, confirmatory methods. However, as long as productivity continues to be defined by the number of discoveries scientists publish, the impact factor of the journals they publish in and the number of times their papers are cited, they will be reluctant to accept high quality methods and consistently conduct and publish confirmatory/replication studies. This exploratory study examined a sample of rigorous Phase II-IV clinical trials, including unpublished studies, to determine if more appropriate metrics and incentives can be developed. The results suggest that rigorous procedures will help reduce false positives, but to the extent that higher quality methods are accepted as the standard of practice, the current bibliometric incentives will discourage innovative studies and encourage scientists to shift their research to less informative studies of subjects that are already being more actively investigated. However, the results also suggest that it is possible to develop a more appropriate system of rewards. In contrast to the current bibliometric incentives, evaluations of the quality of the methods and reproducibility of the results, innovation and diversity of thought, and amount of information produced may serve as measures and incentives that maintain the integrity of the scientific literature and maximize scientific progress. PMID- 29614103 TI - Characteristics of clinical trials in rare vs. common diseases: A register-based Latvian study. AB - BACKGROUND: Conducting clinical studies in small populations may be very challenging; therefore quality of clinical evidence may differ between rare and non-rare disease therapies. OBJECTIVE: This register-based study aims to evaluate the characteristics of clinical trials in rare diseases conducted in Latvia and compare them with clinical trials in more common conditions. METHODS: The EU Clinical Trials Register (clinicaltrialsregister.eu) was used to identify interventional clinical trials related to rare diseases (n = 51) and to compose a control group of clinical trials in non-rare diseases (n = 102) for further comparison of the trial characteristics. RESULTS: We found no significant difference in the use of overall survival as a primary endpoint in clinical trials between rare and non-rare diseases (9.8% vs. 13.7%, respectively). However, clinical trials in rare diseases were less likely to be randomized controlled trials (62.7% vs. 83.3%). Rare and non-rare disease clinical trials varied in masking, with rare disease trials less likely to be double blind (45.1% vs. 63.7%). Active comparators were less frequently used in rare disease trials (36.4% vs. 58.8% of controlled trials). Clinical trials in rare diseases enrolled fewer participants than those in non-rare diseases: in Latvia (mean 18.3 vs. 40.2 subjects, respectively), in the European Economic Area (mean 181.0 vs. 626.9 subjects), and in the whole clinical trial (mean 335.8 vs. 1406.3 subjects). Although, we found no significant difference in trial duration between the groups (mean 38.3 vs. 36.4 months). CONCLUSIONS: The current study confirms that clinical trials in rare diseases vary from those in non-rare conditions, with notable differences in enrollment, randomization, masking, and the use of active comparators. However, we found no significant difference in trial duration and the use of overall survival as a primary endpoint. PMID- 29614102 TI - Does growth path influence beef lipid deposition and fatty acid composition? AB - Despite the recent advances in transcriptomics, gene expression studies addressing cattle's skeletal muscle adaptations in response to compensatory growth are warranted, particularly regarding lipid metabolism due to its impact in meat sensory and nutritional traits. In the present study, in comparison to ad libitum feeding, a period of feed restriction was used in order to understand the changes in bull's lipid metabolism and gene expression of the adipogenic and lipogenic pathways after re-alimentation. Thus, 40 young Alentejana bulls were either fed ad libitum (CG group) from 9 to 18 months of age or subjected to food restriction from 9 to 15 months of age, and fed ad libitum until 24 months of age (DG group). The intramuscular fat (IMF) and total fatty acids (FA) contents were similar between groups. The major FA (>2%) contents were similar (16:0, 16:1c9, 18:1c9 and 18:2n-6) between treatments with the exception of 18:0 content that was 15% lower in DG than in CG and 20:4n-6 that tended to be greater on DG bulls. Regarding minor FA (<2%), the DG group presented greater proportions (P<0.01) of 17:1c9, 18:1t9, 18:1t10 (, 18:1c11), 18:1c13, 18:3n-6, 22:0, 22:4n-6 and 22:6n-3 and lower (P<0.05) proportions of 20:0, 18:1t16+c14, and branched chain FA (iso 15:0, anteiso-15:0, iso-16:0 and anteiso-17:0) than the CG group. Delta-9 desaturase activity indices were consistently greater (P<0.05) in DG, when compared to the CG group. Regarding microarray analysis, differentially expressed genes between CG and DG bulls were grouped in 5 main biological functions: lipid and nucleic acid metabolisms, small molecule biochemistry, molecular transport and translational modification. Discontinuous growth down-regulated the expression of ACACB (FC (fold-change) = 1.32), FABP3 (FC = 1.45), HADHA (FC = 1.41) and SLC37A4 (FC = 1.40) genes, when compared to the CG system (FDR<0.05). In contrast, in the CG bulls, the expression of ELOVL5 (FC = 1.58) and FASN (FC = 1.71) was down-regulated when compared to DG bulls. These results were confirmed to be significant (P<0.05) in the case of ELOVL5, FASN and SLC37A4, and almost significant for FABP3 by qRT-PCR analysis. The SCD1 and SCD5 gene expressions were not found to be affected by growth path. These results contribute to the still scarce knowledge about the mechanisms involved in fatty acid metabolism during compensatory growth which have decisive role on meat quality produced in Mediterranean areas. PMID- 29614104 TI - Structural barriers to HIV prevention among men who have sex with men (MSM) in Vietnam: Diversity, stigma, and healthcare access. AB - Men who have sex with men (MSM) in Vietnam experience disproportionate rates of HIV infection. To advance understanding of how structural barriers may shape their engagement with HIV prevention services, we draw on 32 in-depth interviews and four focus groups (n = 31) conducted with MSM in Hanoi between October 2015- March 2016. Three primary factors emerged: (1) Diversity, both in relation to identity and income; Vietnamese MSM described themselves as segregated into Bong kin (hidden, often heterosexually-identified MSM) and Bong lo ('out,' transgender, or effeminate MSM). Lower-income, 'hidden' MSM from rural areas were reluctant to access MSM-targeted services; (2) Stigma: MSM reported being stigmatized by the healthcare system, family, and other MSM; and (3) Healthcare access: this was limited due to economic barriers and lack of MSM-friendly services. Our research suggests the need for multiple strategies to reach diverse types of MSM as well as to address barriers in access to health services such as stigma and costs. While a great deal has been written about the diversity of MSM in relation to gender performance and sexual identities, our research points to the substantial structural-level barriers that must be addressed in order to achieve meaningful and effective HIV prevention for MSM worldwide. PMID- 29614105 TI - Evaluating pre-pregnancy dietary diversity vs. dietary quality scores as predictors of gestational diabetes and hypertensive disorders of pregnancy. AB - BACKGROUND: Dietary diversity scores (DDS) are considered as metrics for monitoring the implementation of the UN's Sustainable Development Goals, but they need to be rigorously evaluated. OBJECTIVE: To examine two DDS, the Food Groups Index (FGI), and the Minimum Dietary Diversity-Women (MDD-W), alongside two dietary quality scores, the Alternate Healthy Eating Index (AHEI-2010) and the Prime Diet Quality Score (PDQS), with risks of gestational diabetes mellitus (GDM) and hypertensive disorders of pregnancy (HDPs). DESIGN: The analysis included 21,312 (GDM) and 19,917 (HDPs) singleton births reported in the Nurses' Health Study II cohort (1991-2001), among women without major chronic disease or GDM/HDPs. Scores were derived using prepregnancy diet collected by a comprehensive food frequency questionnaire. Multivariable models were utilized to calculate relative risks (RR) and confidence intervals (95%CIs). RESULTS: Incident GDM (n = 916) and HDPs (n = 1,421) were reported. The MDD-W and FGI were not associated with risk of GDM or HDPs, but the AHEI-2010 and PDQS were associated with a lower risk of GDM and marginally lower risk of HDP. The RR's of GDM comparing the highest vs. lowest quintiles were 1.00 (95%CI: 0.79, 1.27; p trend = 0.82) for MDD-W, 0.96 (95%CI: 0.76, 1.22; p-trend = 0.88) for FGI, 0.63 (95%CI: 0.50, 0.81; p-trend <0.0001) for the AHEI-2010 and 0.68 (95%CI: 0.54, 0.86; p-trend = 0.003) for the PDQS. Similarly, the RR's of HDPs were 0.92 (95%CI: 0.75, 1.12, p-trend = 0.94) for MDD-W, 0.97 (95%CI: 0.79, 1.17; p-trend = 0.83) for FGI, 0.84 (95%CI: 0.70, 1.02; p-trend = 0.07) for AHEI-2010 and 0.89 (95%CI: 0.74, 1.09; p-trend = 0.07) for PDQS. CONCLUSIONS: MDD-W and FGI did not predict the risk of GDM and HDPs. These DDS should not be widely used as metrics for achieving dietary goals in their present form. The Prime Diet Quality Score warrants further testing as a promising measure of a sustainable and healthy diet on a global scale. PMID- 29614106 TI - The effect of state self-control on the intertemporal decisions made by individuals with high and low trait self-control. AB - The present study aimed to explore how state self-control influences the intertemporal decisions made by individuals with high and low trait self-control. State self-control, represented by the degree of depletion, was manipulated by conducting Stroop tasks with different levels of difficulty, and the intertemporal decision task was used as a self-control task. Compared with participants with high trait self-control, the preferences of participants with low trait self-control for immediate rewards were more vulnerable to the difficulty of depletion tasks. Throughout the experimental stages, the heart rate variability (HRV) of participants with high trait self-control was significantly higher than that of participants with low trait self-control, indicating that individuals with high trait self-control may have stronger and more stable self control abilities. PMID- 29614108 TI - For better or worse: Factors predicting outcomes of family care of older people over a one-year period. A six-country European study. AB - OBJECTIVES: Demographic change has led to an increase of older people in need of long-term care in nearly all European countries. Informal carers primarily provide the care and support needed by dependent people. The supply and willingness of individuals to act as carers are critical to sustain informal care resources as part of the home health care provision. This paper describes a longitudinal study of informal care in six European countries and reports analyses that determine those factors predicting the outcomes of family care over a one-year period. METHODS: Analyses are based on data from the EUROFAMCARE project, a longitudinal survey study of family carers of older people with baseline data collection in 2004 and follow-up data collection a year later in six European countries (Germany, Greece, Italy, Poland, Sweden, and the United Kingdom), N = 3,348. Descriptive statistics of the sample characteristics are reported. Binary logistic random-intercept regressions were computed, predicting the outcome of change of the care dyad's status at follow-up. RESULTS: Where care is provided by a more distant family member or by a friend or neighbour, the care recipient is significantly more likely to be cared for by someone else (OR 1.62) or to be in residential care (OR 3.37) after one year. The same holds true if the care-recipient has memory problems with a dementia diagnosis (OR 1.79/OR 1.84). Higher dependency (OR 1.22) and behavioural problems (OR 1.76) in the care recipient also lead to a change of care dyad status. Country of residence explained a relatively small amount of variance (8%) in whether a care-recipient was cared for by someone else after one year, but explained a substantial amount of variance (52%) in whether a care-recipient was in residential care. Particularly in Sweden, care-recipients are much more likely to be cared for by another family or professional carer or to be in residential care, whereas in Greece the status of the care dyad is much less likely to change. DISCUSSION: The majority of family carers continued to provide care to their respective older relatives over a one-year period, despite often high levels of functional, cognitive and behavioural problems in the care-recipient. Those family carers could benefit most from appropriate support. The carer/care-recipient relationship plays an important role in whether or not a family care dyad remains intact over a one-year period. The support of health and social care services should be particularly targeted toward those care dyads where there is no partner or spouse acting as carer, or no extended family network that might absorb the caring role when required. Distant relatives, friends or acquaintances who are acting as carers might need substantial intervention if their caregiving role is to be maintained. PMID- 29614110 TI - The art and science of selecting graduate students in the biomedical sciences: Performance in doctoral study of the foundational sciences. AB - The goal of this study was to investigate associations between admissions criteria and performance in Ph.D. programs at Boston University School of Medicine. The initial phase of this project examined student performance in the classroom component of a newly established curriculum named "Foundations in Biomedical Sciences (FiBS)". Quantitative measures including undergraduate grade point average (GPA), graduate record examination (GRE; a standardized, computer based test) scores for the verbal (assessment of test takers' ability to analyze, evaluate, and synthesize information and concepts provided in writing) and quantitative (assessment of test takers' problem-solving ability) components of the examination, previous research experience, and competitiveness of previous research institution were used in the study. These criteria were compared with competencies in the program defined as students who pass the curriculum as well as students categorized as High Performers. These data indicated that there is a significant positive correlation between FiBS performance and undergraduate GPA, GRE scores, and competitiveness of undergraduate institution. No significant correlations were found between FiBS performance and research background. By taking a data-driven approach to examine admissions and performance, we hope to refine our admissions criteria to facilitate an unbiased approach to recruitment of students in the life sciences and to share our strategy to support similar goals at other institutions. PMID- 29614109 TI - Mutations in the pantothenate kinase of Plasmodium falciparum confer diverse sensitivity profiles to antiplasmodial pantothenate analogues. AB - The malaria-causing blood stage of Plasmodium falciparum requires extracellular pantothenate for proliferation. The parasite converts pantothenate into coenzyme A (CoA) via five enzymes, the first being a pantothenate kinase (PfPanK). Multiple antiplasmodial pantothenate analogues, including pantothenol and CJ 15,801, kill the parasite by targeting CoA biosynthesis/utilisation. Their mechanism of action, however, remains unknown. Here, we show that parasites pressured with pantothenol or CJ-15,801 become resistant to these analogues. Whole-genome sequencing revealed mutations in one of two putative PanK genes (Pfpank1) in each resistant line. These mutations significantly alter PfPanK activity, with two conferring a fitness cost, consistent with Pfpank1 coding for a functional PanK that is essential for normal growth. The mutants exhibit a different sensitivity profile to recently-described, potent, antiplasmodial pantothenate analogues, with one line being hypersensitive. We provide evidence consistent with different pantothenate analogue classes having different mechanisms of action: some inhibit CoA biosynthesis while others inhibit CoA utilising enzymes. PMID- 29614111 TI - Correction: Species-specific vulnerability of RanBP2 shaped the evolution of SIV as it transmitted in African apes. AB - [This corrects the article DOI: 10.1371/journal.ppat.1006906.]. PMID- 29614107 TI - Functional disruption of the Golgi apparatus protein ARF1 sensitizes MDA-MB-231 breast cancer cells to the antitumor drugs Actinomycin D and Vinblastine through ERK and AKT signaling. AB - Increasing evidence indicates that the Golgi apparatus plays active roles in cancer, but a comprehensive understanding of its functions in the oncogenic transformation has not yet emerged. At the same time, the Golgi is becoming well recognized as a hub that integrates its functions of protein and lipid biosynthesis to signal transduction for cell proliferation and migration in cancer cells. Nevertheless, the active function of the Golgi apparatus in cancer cells has not been fully evaluated as a target for combined treatment. Here, we analyzed the effect of perturbing the Golgi apparatus on the sensitivity of the MDA-MB-231 breast cancer cell line to the drugs Actinomycin D and Vinblastine. We disrupted the function of ARF1, a protein necessary for the homeostasis of the Golgi apparatus. We found that the expression of the ARF1-Q71L mutant increased the sensitivity of MDA-MB-231 cells to both Actinomycin D and Vinblastine, resulting in decreased cell proliferation and cell migration, as well as in increased apoptosis. Likewise, the combined treatment of cells with Actinomycin D or Vinblastine and Brefeldin A or Golgicide A, two disrupting agents of the ARF1 function, resulted in similar effects on cell proliferation, cell migration and apoptosis. Interestingly, each combined treatment had distinct effects on ERK1/2 and AKT signaling, as indicated by the decreased levels of either phospho-ERK1/2 or phospho-AKT. Our results suggest that disruption of Golgi function could be used as a strategy for the sensitization of cancer cells to chemotherapy. PMID- 29614112 TI - A fine-tuned vector-parasite dialogue in tsetse's cardia determines peritrophic matrix integrity and trypanosome transmission success. AB - Arthropod vectors have multiple physical and immunological barriers that impede the development and transmission of parasites to new vertebrate hosts. These barriers include the peritrophic matrix (PM), a chitinous barrier that separates the blood bolus from the midgut epithelia and modulates vector-pathogens interactions. In tsetse flies, a sleeve-like PM is continuously produced by the cardia organ located at the fore- and midgut junction. African trypanosomes, Trypanosoma brucei, must bypass the PM twice; first to colonize the midgut and secondly to reach the salivary glands (SG), to complete their transmission cycle in tsetse. However, not all flies with midgut infections develop mammalian transmissible SG infections-the reasons for which are unclear. Here, we used transcriptomics, microscopy and functional genomics analyses to understand the factors that regulate parasite migration from midgut to SG. In flies with midgut infections only, parasites fail to cross the PM as they are eliminated from the cardia by reactive oxygen intermediates (ROIs)-albeit at the expense of collateral cytotoxic damage to the cardia. In flies with midgut and SG infections, expression of genes encoding components of the PM is reduced in the cardia, and structural integrity of the PM barrier is compromised. Under these circumstances trypanosomes traverse through the newly secreted and compromised PM. The process of PM attrition that enables the parasites to re-enter into the midgut lumen is apparently mediated by components of the parasites residing in the cardia. Thus, a fine-tuned dialogue between tsetse and trypanosomes at the cardia determines the outcome of PM integrity and trypanosome transmission success. PMID- 29614113 TI - Searching for neurodegeneration in multiple sclerosis at clinical onset: Diagnostic value of biomarkers. AB - BACKGROUND: Neurodegeneration occurs during the early stages of multiple sclerosis. It is an essential, devastating part of the pathophysiology. Tools for measuring the degree of neurodegeneration could improve diagnostics and patient characterization. OBJECTIVE: This study aimed to determine the diagnostic value of biomarkers of degeneration in patients with recent clinical onset of suspected multiple sclerosis, and to evaluate these biomarkers for characterizing disease course. METHODS: This cross-sectional study included 271 patients with clinical features of suspected multiple sclerosis onset and was the baseline of a prospective study. After diagnostic investigations, the patients were classified into the following disease groups: patients with clinically isolated syndrome (n = 4) or early relapsing remitting multiple sclerosis (early RRMS; n = 93); patients with relapsing remitting multiple sclerosis with disease durations >=2 years (established RRMS; n = 39); patients without multiple sclerosis, but showing symptoms (symptomatic controls; n = 89); and patients diagnosed with other diseases (n = 46). In addition, we included healthy controls (n = 51) and patients with progressive multiple sclerosis (n = 23). We analyzed six biomarkers of neurodegeneration: cerebrospinal fluid neurofilament light chain levels; cerebral spinal fluid glial fibrillary acidic protein; cerebral spinal fluid tau; retinal nerve fiber layer thickness; macula volume; and the brain parenchymal fraction. RESULTS: Except for increased cerebral spinal fluid neurofilament light chain levels, median 670 ng/L (IQR 400-2110), we could not find signs of early degeneration in the early disease group with recent clinical onset. However, the intrathecal immunoglobin G production and cerebral spinal fluid neurofilament light chain levels showed diagnostic value. Moreover, elevated levels of cerebral spinal fluid glial fibrillary acidic protein, thin retinal nerve fiber layers, and low brain parenchymal fractions were associated with progressive disease, but not with the other phenotypes. Thin retinal nerve fiber layers and low brain parenchymal fractions, which indicated neurodegeneration, were associated with longer disease duration. CONCLUSIONS: In clinically suspected multiple sclerosis, intrathecal immunoglobin G production and neurofilament light chain levels had diagnostic value. Therefore, these biomarkers could be included in diagnostic work-ups for multiple sclerosis. We found that the thickness of the retinal nerve fiber layer and the brain parenchymal fraction were not different between individuals that were healthy, symptomatic, or newly diagnosed with multiple sclerosis. This finding suggested that neurodegeneration had not reached a significant magnitude in patients with a recent clinical onset of multiple sclerosis. PMID- 29614114 TI - Innovative technologies and social inequalities in health: A scoping review of the literature. AB - The aim of this study was to systematically review the range, nature, and extent of current research activity exploring the influence of innovative health-related technologies on social inequalities in health, with specific focus on a deeper understanding of the variables used to measure this connection and the pathways leading to the (re)production of inequalities. A review process was conducted, based on scoping review techniques, searching literature published from January 1, 1996 to November 25, 2016 using MEDLINE, Scopus, and ISI web of science. Search, sorting, and data extraction processes were conducted by a team of researchers and experts using a dynamic, reflexive examination process. Of 4139 studies collected from the search process, a total of 33 were included in the final analysis. Results of this study include the classification of technologies based on how these technologies are accessed and used by end users. In addition to the factors and mechanisms that influence unequal access to technologies, the results of this study highlight the importance of variations in use that importantly shape social inequalities in health. Additionally, focus on health care services technologies must be accompanied by investigating emerging technologies influencing healthy lifestyle, genomics, and personalized devices in health. Findings also suggest that choosing one measure of social position over another has important implications for the interpretation of research results. Furthermore, understanding the pathways through which various innovative health technologies reduce or (re)produce social inequalities in health is context dependent. In order to better understand social inequalities in health, these contextual variations draw attention to the need for critical distinctions between technologies based on how these various technologies are accessed and used. The results of this study provide a comprehensive starting point for future research to further investigate how innovative technologies may influence the unequal distribution of health as a human right. PMID- 29614115 TI - Context matters (but how and why?) A hypothesis-led literature review of performance based financing in fragile and conflict-affected health systems. AB - Performance-based financing (PBF) schemes have been expanding rapidly across low and middle income countries in the past decade, with considerable external financing from multilateral, bilateral and global health initiatives. Many of these countries have been fragile and conflict-affected (FCAS), but while the influence of context is acknowledged to be important to the operation of PBF, there has been little examination of how it affects adoption and implementation of PBF. This article lays out initial hypotheses about how FCAS contexts may influence the adoption, adaption, implementation and health system effects of PBF. These are then interrogated through a review of available grey and published literature (140 documents in total, covering 23 PBF schemes). We find that PBF has been more common in FCAS contexts, which were also more commonly early adopters. Very little explanation of the rationale for its adoption, in particular in relation with the contextual features, is given in programme documents. However, there are a number of factors which could explain this, including the greater role of external actors and donors, a greater openness to institutional reform, and lower levels of trust within the public system and between government and donors, all of which favour more contractual approaches. These suggest that rather than emerging despite fragility, conditions of fragility may favour the rapid emergence of PBF. We also document few emerging adaptations of PBF to humanitarian settings and limited evidence of health system effects which may be contextually driven, but these require more in-depth analysis. Another area meriting more study is the political economy of PBF and its diffusion across contexts. PMID- 29614117 TI - The performance of the IES-R for Latinos and non-Latinos: Assessing measurement invariance. AB - Violent acts on university campuses are becoming more frequent. Enrollment rates of Latinos at universities is increasing. Research has indicated that youths are more susceptible to trauma, particularly Latinos. Thus, it is imperative to evaluate the validity of commonly used posttraumatic stress measures among Latino college students. The Impact of Event Scale-Revised (IES-R) is one of the most commonly used metrics of posttraumatic stress disorder symptomatology. However, it is largely unknown if the IES-R is measuring the same construct across different sub-samples (e.g. Latino versus non-Latino). The current study aimed to assess measurement invariance for the IES-R between Latino and non-Latino participants. A total of 545 participants completed the IES-R. One- and three factor scoring solutions were compared using confirmatory factor analyses. Measurement invariance was then evaluated by estimating several multiple-group confirmatory factor analytic models. Four models with an increasing degree of invariance across groups were compared. A significant chi2 difference test was used to indicate a significant change in model fit between nested models within the measurement invariance testing process. The three-factor scoring solution could not be used for the measurement invariance process because the subscale correlations were too high for estimation (rs 0.92-1.00). Therefore, the one factor model was used for the invariance testing process. Invariance was met for each level of invariance: configural, metric, scalar, and strict. All measurement invariance testing results indicated that the one-factor solution for the IES-R was equivalent for the Latino and non-Latino participants. PMID- 29614116 TI - The explicit judgment of long durations of several minutes in everyday life: Conscious retrospective memory judgment and the role of affects? AB - In this study, individuals estimated interval times of several minutes (from 2 to 32 minutes) during their everyday lives using a cell phone they kept with them. Their emotional state, the difficulty of the activity performed during this interval, and the attention that it required were also assessed, together with their subjective experience of the passage of time. The results showed that the mean time estimates and their variability increased linearly with increasing interval duration, indicating that the fundamental scalar property of time found for short durations also applies to very long durations of several minutes. In addition, the emotional state and difficulty of the activity were significant predictors of the judgment of long durations. However, the awareness of the passage of time appeared to play a crucial role in the judgment of very long duration in humans. A theory on the emergence of the awareness of the passage of time and how it affects the judgment of interval durations lasting several minutes is therefore discussed. PMID- 29614118 TI - Effects of polyaluminum chloride and lanthanum-modified bentonite on the growth rates of three Cylindrospermopsis raciborskii strains. AB - In tropical and subtropical lakes, eutrophication often leads to nuisance blooms of Cylindrospermopsis raciborskii. In laboratory experiments, we tested the combined effects of flocculant polyaluminum chloride (PAC) and lanthanum-modified bentonite (LMB) on the sinking and growth rates of three C. raciborskii strains. We tested the hypothesis that the combination of PAC and LMB would (1) effectively sink C. raciborskii in a test tube experiment and (2) impair C. raciborskii growth, irrespective of the biomass of the inoculum (bloom) and the strain in the growth experiment. We tested the recommended (LMB1) and a three times higher dose of LMB (LMB3). The combined addition of PAC and LMB enhanced the sedimentation of all C. raciborskii strains. Moreover, both the PAC and LMB doses decreased the phosphate concentration. PAC and LMB1 decreased the growth rate of all strains, but the efficacy depended on the biomass and strain. The combined addition of PAC and LMB3 inhibited the growth of all strains independently of the biomass and strain. We conclude that a low dose of PAC in combination with the recommended dose of LMB decreases C. raciborskii blooms and that the efficiency of the technique depends on the biomass of the bloom. A higher dose of LMB is needed to obtain a more efficient control of C. raciborskii blooms. PMID- 29614120 TI - Stable hydrogen isotope variability within and among plumage tracts (delta2HF) of a migratory wood warbler. AB - Hydrogen isotope analysis of feather keratin (delta2HF) has become an essential tool for tracking movements between breeding and wintering populations of migratory birds. In particular, delta2HF has been used to create delta2HF isoscapes that can be used to assign the geographic origins of molt. The majority of past studies have sampled a portion of a single feather as an isotopic proxy for the entire plumage although surprisingly little is known about variation of stable isotopes within and between feather tracts of individuals in local populations. Here we examine delta2HF variation in 24 pterylographic variables (9 primaries, 6 secondaries, 6 rectrices, and 3 patches of ventral contour feathers) in individual specimens of black-throated blue warbler (Setophaga caerulescens) breeding in the Big Santeetlah Creek watershed (5350 ha), southern Appalachian Mountains. By restricting our study to territorial ASY males (after second year) inhabiting a small watershed, we could focus on delta2HF variation generated during the complete prebasic annual molt in a circumscribed population while factoring out age and sexual differences in foraging behavior, isotopic incorporation, and post-breeding dispersal. Summed within-individual variation (delta2HF) across 24 pterylographic variables ranged from 12 to 600/00 (= 21.8 +/ 9.40/00), with 81% of the individuals exhibiting variation >= 160/00 (reproducibility of analyses was <= 4 0/00). Adjacent feathers in feather tracts tend to have more similar delta2HF values than feathers grown weeks apart, consistent with the stepwise replacement of flight feathers. The pooled population sample exhibited significant delta2HF variation in primaries (-78 to 210/00), secondaries (-80 to -170/00), rectrices (-78 to -230/00), and ventral contour feathers (-92 to -320/00). Strong year effects in delta2HF variation were observed in each of the 24 pterylographic variables. Altitudinal effects were observed only in ventral contour feathers. The current findings demonstrate that within-individual variation (delta2HF) may be much greater than previously thought in migratory species that molt on or near breeding territories. Our study also highlights the need for greater pterylographic precision in research design of isotope-based studies of avian movement. Within-individual and within population delta2HF variation should be incorporated in geographic assignment models. In a broader context, the staggered Staffelmauser pattern of molt in wood warblers provides an exceptional view of the seasonal variation of hydrogen isotopes circulating in blood plasma during the six-week period of annual molt. PMID- 29614119 TI - Computational analysis of the oscillatory behavior at the translation level induced by mRNA levels oscillations due to finite intracellular resources. AB - Recent studies have demonstrated how the competition for the finite pool of available gene expression factors has important effect on fundamental gene expression aspects. In this study, based on a whole-cell model simulation of translation in S. cerevisiae, we evaluate for the first time the expected effect of mRNA levels fluctuations on translation due to the finite pool of ribosomes. We show that fluctuations of a single gene or a group of genes mRNA levels induce periodic behavior in all S. cerevisiae translation factors and aspects: the ribosomal densities and the translation rates of all S. cerevisiae mRNAs oscillate. We numerically measure the oscillation amplitudes demonstrating that fluctuations of endogenous and heterologous genes can cause a significant fluctuation of up to 50% in the steady-state translation rates of the rest of the genes. Furthermore, we demonstrate by synonymous mutations that oscillating the levels of mRNAs that experience high ribosomal occupancy (e.g. ribosomal "traffic jam") induces the largest impact on the translation of the S. cerevisiae genome. The results reported here should provide novel insights and principles related to the design of synthetic gene expression circuits and related to the evolutionary constraints shaping gene expression of endogenous genes. PMID- 29614121 TI - Dominant serotype distribution and antimicrobial resistance profile of Shigella spp. in Xinjiang, China. AB - Shigella represents one of the major diarrhea-inducing pathogens threatening public health, but its prevalence and antimicrobial resistance profile in Xinjiang Uygur Autonomous region, China, remains unclear. We conducted comprehensive investigation of Shigella serotype distribution and antimicrobial resistance pattern in Xinjiang, identifying 458 Shigella isolates between 2008 to 2014. Shigella flexneri was identified as predominant species, and several S. flexneri serotypes were isolated, including atypical serotypes 1c, 2c, and 4s. Dominant S. flexneri serotypes were 2a, 1b, 2b, and Xv, different from those generally dominant in China. A hybrid serotype pattern was observed, which included the major Chinese serotypes (2a, Xv) and those predominant in Pakistan (1b, 2b). Shigella sonnei was shown to have a lower frequency compared with that generally observed in China, but an increasing trend of infections associated with this pathogen was observed. Furthermore, a high frequency of drug resistance and different Shigella antimicrobial resistance patterns were demonstrated as well, including very severe resistance phenotypes, such as multidrug resistance and resistance to frontline antibiotics. Seventy-five cephalosporin-resistant Shigella isolates were frequently identified with the resistance determinants that can undergo horizontal transfer, such as blaOXA, blaTEM, blaCTX-M, and integrons, facilitating the development of cephalosporin resistance among Shigella subtypes. Additionally, genetic analyses demonstrated that all 86 quinolone-resistant S. flexneri isolates possess 3-4 mutation sites in quinolone resistance-determining regions, primarily contributing to their resistance to quinolone. However, S. sonnei isolates were not shown to be quinolone resistant. Co-resistance to cephalosporins and quinolones was detected in 17 S. flexneri isolates, and these isolates were additionally multidrug resistant and carried beta-lactamase genes and quinolone-resistance determinants. As is demonstrated in this study, dominant serotypes of Shigella were distributed in unique trend with dangerous drug resistance patterns. Novel strategies are urgently required to prevent the development of drug resistance among diarrhea-inducing pathogens. PMID- 29614122 TI - Complexes of myo-inositol-hexakisphosphate (InsP6) with zinc or lanthanum to enhance excretion of radioactive strontium from the body. AB - 90Sr, which was released into the atmosphere and the ocean following the Chernobyl and Fukushima Daiichi nuclear power plant disasters, is an important nuclear fission element. Compounds that inhibit the absorption of 90Sr into the bloodstream and enhance its elimination can be beneficial in decreasing the absorbed radiation dose in people exposed to 90Sr. Recently, we prepared complexes of myo-inositol-hexakisphosphate (InsP6) with zinc or lanthanum as decorporation agents. These complexes, called Zn-InsP6 and La-InsP6 respectively, are insoluble in water and can potentially chelate additional metal cations. Hypothesizing that these complexes can assist the excretion of 90Sr from the body, we evaluated them using 85Sr instead of 90Sr. In in vitro binding experiments, Zn-InsP6 showed higher strontium adsorption capacity than La-InsP6. We then performed in vivo biodistribution experiments of Zn-InsP6 in mice after oral administration of 85SrCl2. Mice treated with Zn-InsP6 showed significantly lower bone accumulation of radioactivity than mice in a non-treatment control group. Zn-InsP6 adsorbed radiostrontium in the gastrointestinal tract, inhibited this ion's absorption into the bloodstream, and enhanced its excretion in the feces. Therefore, Zn-InsP6 appears to be a promising 90Sr "decorporation" agent. PMID- 29614123 TI - China's science, technology, engineering, and mathematics (STEM) research environment: A snapshot. AB - In keeping with China's President Xi Jinping's "Chinese Dream," China has set a goal of becoming a world-class innovator by 2050. China's higher education Science, Technology, Engineering, and Math (STEM) research environment will play a pivotal role in influencing whether China is successful in transitioning from a manufacturing-based economy to an innovation-driven, knowledge-based economy. Past studies on China's research environment have been primarily qualitative in nature or based on anecdotal evidence. In this study, we surveyed STEM faculty from China's top 25 universities to get a clearer understanding of how faculty members view China's overall research environment. We received 731 completed survey responses, 17% of which were from individuals who received terminal degrees from abroad and 83% of which were from individuals who received terminal degrees from domestic institutions of higher education. We present results on why returnees decided to study abroad, returnees' decisions to return to China, and differences in perceptions between returnees and domestic degree holders on the advantages of having a foreign degree. The top five challenges to China's research environment identified by survey respondents were: a promotion of short term thinking and instant success (37% of all respondents); research funding (33%); too much bureaucratic or governmental intervention (31%); the evaluation system (27%); and a reliance on human relations (26%). Results indicated that while China has clearly made strides in its higher education system, there are numerous challenges that must be overcome before China can hope to effectively produce the kinds of innovative thinkers that are required if it is to achieve its ambitious goals. We also raise questions about the current direction of education and inquiry in China, particularly indications that government policy is turning inward, away from openness that is central to innovative thinking. PMID- 29614124 TI - Evaluation of glycemic variability in chronic liver disease patients with type 2 diabetes mellitus using continuous glucose monitoring. AB - BACKGROUND AND AIMS: The feature of blood glucose dynamics in patients with chronic liver disease (CLD) is marked blood glucose fluctuations. However, the detail of blood glucose dynamics is not well known. The aim of the present study was to evaluate glycemic fluctuations by continuous glucose monitoring (CGM). MATERIALS AND METHODS: A total of 105 CLD patients with type 2 diabetes mellitus (T2DM) were enrolled in this study. Various parameters of glycemic variability were evaluated. The association of these parameters with liver functional reserve was examined. The parameters were also evaluated according to glycated hemoglobin A1c (HbA1c) levels. RESULTS AND DISCUSSION: Data of all patients showed that mean blood glucose (MBG) levels and the difference between highest and lowest blood glucose (DeltaBG) increased significantly with worsening of liver functional reserve (P < 0.001 and P = 0.005, respectively). Although many of the cases were being treated for diabetes, postprandial hyperglycemia was seen in 92% of patients. Nocturnal hypoglycemia was seen in 22% of patients. In non-anemic patients with HbA1c levels of < 7.0%, the percentage of patients with mean amplitude of glycemic excursion (MAGE) of >= 77.4 mg/dL and that of MBG levels of > 145 mg/dL were higher in liver cirrhosis (LC) patients than in chronic hepatitis (CH) patients. In them, homeostasis model assessment for insulin resistance (HOMA-IR) of > 2.5 and LC were significantly associated with the increase in MAGE. LC was also significantly associated with increased MBG levels. CONCLUSION: The CGM systems were useful in finding hidden abnormalities of blood glucose fluctuations in CLD patients with T2DM, especially in non-anemic CLD patients with HbA1c levels of < 7.0%. PMID- 29614125 TI - The prevalence of brain abnormalities in boys with central precocious puberty may be overestimated. AB - Brain magnetic resonance imaging (MRI) is routinely performed to identify brain lesions in boys with central precocious puberty (CPP). We investigated the prevalence of CPP in Korean boys and the necessity for routine brain MRI examinations. This retrospective cross-sectional study was conducted from April 2003 to December 2016 at a Korean university hospital. Among 151 boys who were diagnosed with CPP, the data of 138 boys who underwent sellar MRI were evaluated. The mean age of the study subjects was 9.51 +/- 0.56 years (<8 years [n = 4] and >=8 years [n = 134]). We excluded patients who had been previously diagnosed with brain tumors and those who did not undergo a sellar MRI because of refusal or the decision of the pediatric endocrinologist. The main outcome measure was the prevalence of intracranial lesions among boys with CPP. Normal sellar MRI findings were observed in 128 of the 138 boys (93%). Mild brain abnormalities were found in 10 boys (7%), while none of the patients had pathological brain lesions. The prevalence (7%) of intracranial lesions among boys who were healthy, did not have neurological symptoms, and were diagnosed with CPP was different from that previously reported. None of the identified lesions necessitated treatment. Although this was a single country study, we found that the previously reported prevalence of brain lesions in boys with CPP is much higher than the prevalence observed in Korea. This study suggests the need to globally reevaluate the prevalence of pathological brain lesions among male pediatric patients with CPP. PMID- 29614126 TI - Study on the ownership balance and the efficiency of mixed ownership enterprises from the perspective of heterogeneous shareholders. AB - Based on the database data of Chinese industrial enterprises from 2000 to 2007 and the LP method, this paper measures the total factor productivity of enterprises and investigates the effect of different mixed ownership forms on enterprises' efficiency and the effect of heterogeneous ownership balance on the mixed ownership enterprises' efficiency. The state-owned enterprise and mixed ownership enterprise are identified by the enterprise's paid-up capital. The results show that, on the whole, for the mixed ownership enterprise, the higher the diversification degree of the shareholders is, the higher the efficiency becomes, and in different types of industries, the mixed forms of shareholders have different effects on the efficiency of enterprises. The heterogeneous ownership balance and the enterprise efficiency show nonlinear U-type relationships. Both the higher and lower heterogeneous ownership balance degrees will promote the enterprise's efficiency. However, when the ownership balance degree is in the range of [0.2 0.5], the increase in ownership balance will lead to the decline of enterprise efficiency. Therefore, when introducing non-state owned capital, state-owned enterprises should take full account of their own characteristics by rationally controlling the shareholding ratio of non-state owned capital and play the positive role of a mixed ownership structure in corporate governance with appropriate ownership balances. PMID- 29614127 TI - Regulatory T cells suppress virus-specific antibody responses to Friend retrovirus infection. AB - Recent vaccine studies with experimental antigens have shown that regulatory T cells (Tregs) constrain the magnitude of B cell responses. This homeostatic Treg mediated suppression is thought to reduce the potential of germinal center (GC) responses to generate autoreactive antibodies. However, essentially opposite results were observed in live influenza infections where Tregs promoted B cell and antibody responses. Thus, it remains unclear whether Tregs dampen or enhance B cell responses, especially during live viral infections. Here, we use mice infected with Friend retrovirus (FV), which induces a robust expansion of Tregs. Depletion of Tregs led to elevated activation, proliferation, and class switching of B cells. In addition, Treg depletion enhanced the production of virus-specific and virus-neutralizing antibodies and reduced FV viremia. Thus, in contrast to influenza infection, Tregs either directly or indirectly suppress B cells during mouse retroviral infection indicating that the ultimate effect of Tregs on B cell responses is specific to the particular infectious agent. PMID- 29614129 TI - A Bayesian hierarchical latent trait model for estimating rater bias and reliability in large-scale performance assessment. AB - We propose a novel approach to modelling rater effects in scoring-based assessment. The approach is based on a Bayesian hierarchical model and simulations from the posterior distribution. We apply it to large-scale essay assessment data over a period of 5 years. Empirical results suggest that the model provides a good fit for both the total scores and when applied to individual rubrics. We estimate the median impact of rater effects on the final grade to be +/- 2 points on a 50 point scale, while 10% of essays would receive a score at least +/- 5 different from their actual quality. Most of the impact is due to rater unreliability, not rater bias. PMID- 29614128 TI - Return-to-work for multiple jobholders with a work-related musculoskeletal disorder: A population-based, matched cohort in British Columbia. AB - INTRODUCTION: Multiple jobholders (MJHs) have a higher risk of injury compared to single jobholders (SJHs), but it is unknown if return-to-work (RTW) after a work injury is affected by multiple jobholding. This study examined the association between multiple versus single jobholding and time to RTW for workers with a work related musculoskeletal disorder (MSD). METHODS: We used administrative workers' compensation data to identify injured workers with an accepted MSD lost-time claim between 2010-2014 in British Columbia, Canada (n = 125,639 SJHs and 9,029 MJHs). The outcome was days until RTW during twelve months after the first day of time-loss. The MJH and SJH cohorts were balanced using coarsened exact matching that yielded a final matched cohort of 8,389 MJHs and 8,389 SJHs. The outcome was estimated with Cox regression, using piecewise models, and the hazard ratios were stratified by type of MSD, a serious injury indicator, gender, weekly workdays preceding MSD, and wage categories. RESULTS: MJHs were less likely to RTW compared to SJHs within the first six months after the first time-loss day, with greater and longer lasting effects for males, workers with a serious injury, and a higher wage. No difference between MJHs and SJHs was found for workers who had a six- or seven-day work week preceding MSD, for workers with dislocations, and for workers who were still off work after six months. CONCLUSIONS: Overall, MJHs with a workweek of maximum five days are disadvantaged compared to SJHs in terms of RTW following a work-related MSD within the first six months after the first time-loss day. This difference might be caused by more precarious job contracts for MJHs that challenges RTW because of lack of support for modified work, higher workload, and reduced likelihood that MJHs file a workers' compensation claim. Despite adjusting for type of MSD, severity of injury and occupation, the differences persisted for the vast majority of the study sample. PMID- 29614130 TI - A note on the analysis of two-stage task results: How changes in task structure affect what model-free and model-based strategies predict about the effects of reward and transition on the stay probability. AB - Many studies that aim to detect model-free and model-based influences on behavior employ two-stage behavioral tasks of the type pioneered by Daw and colleagues in 2011. Such studies commonly modify existing two-stage decision paradigms in order to better address a given hypothesis, which is an important means of scientific progress. It is, however, critical to fully appreciate the impact of any modified or novel experimental design features on the expected results. Here, we use two concrete examples to demonstrate that relatively small changes in the two-stage task design can substantially change the pattern of actions taken by model-free and model-based agents as a function of the reward outcomes and transitions on previous trials. In the first, we show that, under specific conditions, purely model-free agents will produce the reward by transition interactions typically thought to characterize model-based behavior on a two-stage task. The second example shows that model-based agents' behavior is driven by a main effect of transition-type in addition to the canonical reward by transition interaction whenever the reward probabilities of the final states do not sum to one. Together, these examples emphasize the task-dependence of model-free and model based behavior and highlight the benefits of using computer simulations to determine what pattern of results to expect from both model-free and model-based agents performing a given two-stage decision task in order to design choice paradigms and analysis strategies best suited to the current question. PMID- 29614131 TI - Association between quality domains and health care spending across physician networks. AB - One of the more fundamental health policy questions is the relationship between health care quality and spending. A better understanding of these relationships is needed to inform health systems interventions aimed at increasing quality and efficiency of care. We measured 65 validated quality indicators (QI) across Ontario physician networks. QIs were aggregated into domains representing six dimensions of care: screening and prevention, evidence-based medications, hospital-community transitions (7-day post-discharge visit with a primary care physician; 30-day post-discharge visit with a primary care physician and specialist), potentially avoidable hospitalizations and emergency department (ED) visits, potentially avoidable readmissions and unplanned returns to the ED, and poor cancer end of life care. Each domain rate was computed as a weighted average of QI rates, weighting by network population at risk. We also measured overall and sector-specific per capita healthcare network spending. We evaluated the associations between domain rates, and between domain rates and spending using weighted correlations, weighting by network population at risk, using an ecological design. All indicators were measured using Ontario health administrative databases. Large variations were seen in timely hospital-community transitions and potentially avoidable hospitalizations. Networks with timely hospital-community transitions had lower rates of avoidable admissions and readmissions (r = -0.89, -0.58, respectively). Higher physician spending, especially outpatient primary care spending, was associated with lower rates of avoidable hospitalizations (r = -0.83) and higher rates of timely hospital community transitions (r = 0.81) and moderately associated with lower readmission rates (r = -0.46). Investment in effective primary care services may help reduce burden on the acute care sector and associated expenditures. PMID- 29614132 TI - Only multi-taxon studies show the full range of arthropod responses to fire. AB - Fire is a major driver in many ecosystems. Yet, little is known about how different ground-living arthropods survive fire. Using three sampling methods, and time-since-fire (last fire event: 3 months, 1 year, and 7 years), we investigate how ground-living arthropod diversity responds to fire, and how species richness, diversity, abundance, and composition of the four dominant taxa: ants, beetles, cockroaches and mites, respond. We did this in the naturally fire-prone Mediterranean-type scrubland vegetation (fynbos) of the Cape Floristic Region. Surprisingly, overall species richness and diversity was the same for all time-since-fire categories. However, when each dominant taxon was analysed separately, effect of fire on species richness and abundance varied among taxa. This emphasizes that many taxa must be investigated to really understand fire driven events. We also highlight the importance of using different diversity measures, as fire did not influence species richness and abundance of particular taxa, while it affected others, overall greatly affecting assemblages of all taxa. Rockiness affected species richness, abundance and composition of a few taxa. We found that all time-since-fire categories supported distinctive assemblages. Some indicator species occurred across all time-since-fire categories, while others were restricted to a single time-since-fire category, showing that there is a wide range of responses to fire between taxa. Details of local landscape structure, abiotic and biotic, and frequency and intensity of fire add complexity to the fire-arthropod interaction. Overall, we show that the relationship between fire and arthropods is phylogenetically constrained, having been honed by many millennia of fire events, and highly complex. Present-day species manifest a variety of adaptations for surviving the great natural selective force of fire. PMID- 29614133 TI - Digestive enzymes and gut morphometric parameters of threespine stickleback (Gasterosteus aculeatus): Influence of body size and temperature. AB - Determining digestive enzyme activity is of potential interest to obtain and understand valuable information about fish digestive physiology, since digestion is an elementary process of fish metabolism. We described for the first time (i) three digestive enzymes: amylase, trypsin and intestinal alkaline phosphatase (IAP), and (ii) three gut morphometric parameters: relative gut length (RGL), relative gut mass (RGM) and Zihler's index (ZI) in threespine stickleback (Gasterosteus aculeatus), and we studied the effect of temperature and body size on these parameters. When mimicking seasonal variation in temperature, body size had no effect on digestive enzyme activity. The highest levels of amylase and trypsin activity were observed at 18 degrees C, while the highest IAP activity was recorded at 20 degrees C. When sticklebacks were exposed to three constant temperatures (16, 18 and 21 degrees C), a temporal effect correlated to fish growth was observed with inverse evolution patterns between amylase activity and the activities of trypsin and IAP. Temperature (in both experiments) had no effect on morphometric parameters. However, a temporal variation was recorded for both RGM (in the second experiment) and ZI (in both experiments), and the later was correlated to fish body mass. PMID- 29614135 TI - Introduction. PMID- 29614136 TI - The Evolving Landscape of Psoriasis Treatment. AB - The process of discovering new drugs for plaque psoriasis has revealed much about the multisystemic nature of the disease. Current and emerging biologic agents may reliably achieve a Psoriasis Area and Severity Index (PASI 75) up to 90. Initially, clinicians select therapies based on the severity of the psoriasis. Although mild disease can be treated with topical agents, for patients with moderate to severe disease, concurrent therapy with oral systemic agents, biologics, and/ or phototherapy needs to be considered. In some instances, clinicians may need to combine medications to provide patients with rapid relief of symptoms. Semin Cutan Med Surg 37(supp2):S39-S43. PMID- 29614137 TI - Treating to Target-A Realistic Goal in Psoriasis? AB - For many patients, the new biologic therapies for psoriasis can improve Psoriasis Area and Severity Index (PASI) scores in a relatively short time. But when results are less than optimal, patients often become frustrated. By providing effective medical treatment using a treat-to-target strategy, clinicians can relieve symptoms and halt disease progression. Although body surface area (BSA) and PASI scores are appropriate for analyzing results of clinical trials, clinicians need to use more patient-centered assessments of patients' progress such as the Dermatology Life Quality Index (DLQI) and Psoriasis Symptom Inventory (PSI), as well as other validated patientreported outcomes, which can enable them to set realistic and achievable goals for individual patients. Semin Cutan Med Surg 37(supp2):S44-S47. PMID- 29614134 TI - Titer estimation for quality control (TEQC) method: A practical approach for optimal production of protein complexes using the baculovirus expression vector system. AB - The baculovirus expression vector system (BEVS) is becoming the method of choice for expression of many eukaryotic proteins and protein complexes for biochemical, structural and pharmaceutical studies. Significant technological advancement has made generation of recombinant baculoviruses easy, efficient and user-friendly. However, there is a tremendous variability in the amount of proteins made using the BEVS, including different batches of virus made to express the same proteins. Yet, what influences the overall production of proteins or protein complexes remains largely unclear. Many downstream applications, particularly protein structure determination, require purification of large quantities of proteins in a repetitive manner, calling for a reliable experimental set-up to obtain proteins or protein complexes of interest consistently. During our investigation of optimizing the expression of the Mediator Head module, we discovered that the 'initial infectivity' was an excellent indicator of overall production of protein complexes. Further, we show that this initial infectivity can be mathematically described as a function of multiplicity of infection (MOI), correlating recombinant protein yield and virus titer. All these findings led us to develop the Titer Estimation for Quality Control (TEQC) method, which enables researchers to estimate initial infectivity, titer/MOI values in a simple and affordable way, and to use these values to quantitatively optimize protein expressions utilizing BEVS in a highly reproducible fashion. PMID- 29614138 TI - Common and Not-So-Common Comorbidities of Psoriasis. AB - Plaque psoriasis is increasingly recognized as a multisystemic disease whose most common comorbidities include psoriatic arthritis, cardiovascular disease, metabolic syndrome, overweight/obesity, inflammatory bowel disease, and depression. The presence of such comorbidities affects the therapeutic choices for clinicians. Patients often visit dermatologists more frequently than they do other clinicians, so it is incumbent upon dermatologists to recognize and address early signs of psoriatic comorbidities to prevent further deterioration and improve their patients' quality of life. Semin Cutan Med Surg 37(supp2):S48-S51. PMID- 29614139 TI - Practical Strategies for Optimizing Management of Psoriasis. AB - Approximately 30% of patients with moderate plaque psoriasis and 20% of those with severe psoriasis have inadequate disease control with their current therapeutic regimens. Among the factors that affect treatment efficacy are drug selection and lack of patient adherence to treatment, which is often due to patient frustration that psoriasis is a chronic, multisystemic, and incurable disease. By forming a strong therapeutic alliance with patients and by asking them about their expectations for treatment, clinicians have a better chance of providing patients with more effective and durable relief from their psoriasis symptoms. Semin Cutan Med Surg 37(supp2):S52-S55. PMID- 29614140 TI - We need to treat gun violence like an epidemic. PMID- 29614141 TI - Periprocedural management of oral anticoagulation: When and how to hit "pause". AB - Here's how best to assess patients' bleeding and thrombotic risks and 5 key questions to ask as you consider withholding oral anticoagulants. PMID- 29614142 TI - Getting the hypertension Dx right: Patient positioning matters. AB - Taking blood pressure with the patient seated on the edge of an exam table led to misclassification of prehypertension or hypertension in 13.2% of patients. PMID- 29614143 TI - Acupuncture for pain: 7 questions answered. AB - Is acupuncture an effective treatment for pain? Are there any adverse effects? Learn the answers to these and other questions in this review. PMID- 29614144 TI - Severe right upper chest pain . tender right sternoclavicular joint . Dx? AB - A 16-year-old hockey player presented to our emergency department with sharp pain in his right upper chest after "checking" another player during a game. The pain did not resolve with rest and was worse with movement and breathing. The patient did not have dysphagia, dyspnea, paresthesias, or hoarseness. The physical examination revealed tenderness over the right sternoclavicular joint (SCJ) without swelling or deformity. A distal neurovascular exam was intact, and a chest x-ray showed no evidence of dislocation or fracture. The patient's pain was refractory to multiple intravenous (IV) pain medications. PMID- 29614145 TI - PURL: Treating migraines: It's different for kids. AB - Certain medications used for migraine prevention in adults do not perform the same way in children and adolescents and can actually cause harm. PMID- 29614146 TI - Bilateral nonpitting edema and xerotic skin. AB - When treatment for cellulitis and a suspected exacerbation of congestive heart failure failed, we ordered a biopsy. The pathology report made the diagnosis clear. PMID- 29614147 TI - Clinical Inquiries: What are the benefits and risks of daily low-dose aspirin for primary prevention of CV events? AB - One nonfatal myocardial infarction (MI) will be avoided for every 126 to 138 adults who take daily aspirin for 10 years (strength of recommendation [SOR]: A, systematic reviews and meta-analyses of multiple randomized controlled trials [RCTs]). Taking low-dose aspirin for primary prevention shows no clear mortality benefit. A benefit for primary prevention of stroke is less certain. Although no evidence establishes increased risk of hemorrhagic stroke from daily low-dose aspirin, one gastrointestinal hemorrhage will occur for every 72 to 357 adults who take aspirin for longer than 10 years (SOR: A, systematic reviews and meta analyses of multiple RCTs and cohort studies). PMID- 29614148 TI - Clinical Inquiries: How well do POLST forms assure that patients get the end-of life care they requested? AB - Quite well, for cardiopulmonary resuscitation (CPR). Most patients (91%-100%) who select "do not resuscitate" (DNR) on their physician's orders for life-sustaining treatment (POLST) forms are allowed a natural death without attempted CPR across a variety of settings (community, skilled nursing facilities, emergency medical services, and hospice). Few patients (6%) who select "comfort measures only" die in the hospital, whereas more (22%) who choose "limited interventions," and still more (34%) without a POLST form, die in the hospital (strength of recommendation [SOR]: B, large, consistent cross-sectional and cohort studies). PMID- 29614149 TI - Bilateral thigh and knee pain . leg weakness . no history of trauma . Dx? PMID- 29614150 TI - A guide to providing wide-ranging care to newborns. AB - Here's how to refine your care, which includes an assessment of neonatal feedings, the evaluation of jaundice and fever, and the prevention of SIDS. PMID- 29614151 TI - Visual-vestibular estimation of the body's curvilinear motion through the world: A computational model. AB - Motion along curved paths (curvilinear self-motion) introduces a rotation component to the radial expanding patterns of visual motion generated in the eyes of moving animals with forward-facing eyes. The resultant image motion (vector flow field) is no longer purely radial, and it is difficult to infer the heading direction from such combined translation-plus-rotation flow fields. The eye need not rotate relative to the head or body during curvilinear self-motion, and so there is an absence of efference signals directing and indicating the rotation. Yet the eye's rotation relative to the world needs to be measured accurately and its effect removed from the combined translation-rotation image motion in order for successful navigation to occur. I demonstrate that to be able to account for human heading-estimation performance, the precision of the eye-in-world rotation velocity signal needs to be at least 0.2 degrees /s. I show that an accurate estimate of the eye's curvilinear motion path through the world can be achieved by combining relatively imprecise vestibular estimates of the rotation rate and direction with visual image-motion velocities distributed across the retina. Combined visual-vestibular signals produce greater accuracy than each on its own. The model can account for a wide range of existing human heading- and curvilinear estimation psychophysical data. PMID- 29614152 TI - Decision-variable correlation. AB - An extension of the signal-detection theory framework is described and demonstrated for two-alternative identification tasks. The extended framework assumes that the subject and an arbitrary model (or two subjects, or the same subject on two occasions) are performing the same task with the same stimuli, and that on each trial they both compute values of a decision variable. Thus, their joint performance is described by six fundamental quantities: two levels of intrinsic discriminability (d'), two values of decision criterion, and two decision-variable correlations (DVCs), one for each of the two categories of stimuli. The framework should be widely applicable for testing models and characterizing individual differences in behavioral and neurophysiological studies of perception and cognition. We demonstrate the framework for the well known task of detecting a Gaussian target in white noise. We find that (a) subjects' DVCs are approximately equal to the square root of their efficiency relative to ideal (in agreement with the prediction of a popular class of models), (b) between-subjects and within-subject (double-pass) DVCs increase with target contrast and are greater for target-present than target-absent trials (rejecting many models), PMID- 29614153 TI - Dissociation between perception and smooth pursuit eye movements in speed judgments of moving Gabor targets. AB - The relationship between eye movements and subjective perception is still relatively poorly understood. In this study, participants tracked the movement of a Gabor patch and made perceptual judgments of its speed using a two-interval forced choice task. The Gabor patch could either have a static carrier or a carrier moving in the same or opposite direction as the overall envelope motion. We found that smooth pursuit speed was strongly affected by the internal motion of the Gabor carrier, with faster smooth pursuit being made to targets with internal motion in the same direction as overall motion compared to targets with internal motion in the opposite direction. However, we found that there were only small and highly variable differences in the perceptual speed judgments made simultaneously, and that these perceptual and smooth pursuit measures did not significantly correlate with each other. This contrasts with the number of catch up saccades (saccades made in the direction of overall target motion), which was significantly correlated with the simultaneous perceptual judgments. There was also a significant correlation between perceptual judgments and the difference between the target and eye position immediately before a saccade. These results suggest that it is possible to see dissociations between vision and action in this task, and that the specific type of visual action studied may determine the relationship with perception. PMID- 29614154 TI - Criterion-free measurement of motion transparency perception at different speeds. AB - Transparency perception often occurs when objects within the visual scene partially occlude each other or move at the same time, at different velocities across the same spatial region. Although transparent motion perception has been extensively studied, we still do not understand how the distribution of velocities within a visual scene contribute to transparent perception. Here we use a novel psychophysical procedure to characterize the distribution of velocities in a scene that give rise to transparent motion perception. To prevent participants from adopting a subjective decision criterion when discriminating transparent motion, we used an "odd-one-out," three-alternative forced-choice procedure. Two intervals contained the standard-a random-dot-kinematogram with dot speeds or directions sampled from a uniform distribution. The other interval contained the comparison-speeds or directions sampled from a distribution with the same range as the standard, but with a notch of different widths removed. Our results suggest that transparent motion perception is driven primarily by relatively slow speeds, and does not emerge when only very fast speeds are present within a visual scene. Transparent perception of moving surfaces is modulated by stimulus-based characteristics, such as the separation between the means of the overlapping distributions or the range of speeds presented within an image. Our work illustrates the utility of using objective, forced-choice methods to reveal the mechanisms underlying motion transparency perception. PMID- 29614155 TI - Binocular benefits of optical treatment in anisometropic amblyopia. AB - In this study, we investigated the effect of optical treatment on sensory eye balance in anisometropic amblyopia. Fourteen individuals (age: 13.7 +/- 8.4 years old) with previously untreated anisometropic amblyopia were enrolled in the study. The average magnitude of their anisometropia (spherical equivalent) was 4.02 +/- 1.19 DS. Their best corrected monocular visual acuity and sensory eye balance were measured before and after a 2-month period of full refractive correction (i.e., our optical treatment). Spectacle-corrected distance visual acuity (at 5 m) was measured monocularly using the Tumbling E Chart. Sensory eye balance was quantitatively assessed using a binocular phase-combination paradigm to determine the interocular contrast ratio at which the two eyes were balanced in binocular sensory combination (i.e., the balance point). We found that both interocular contrast ratio at the balance point (p = 0.006) and visual acuity of the amblyopic eye (p < 0.001) were significantly improved after 2 months of optical treatment, often referred to as refractive adaptation. We conclude that sustained optical treatment improves interocular sensory balance in anisometropic amblyopia as well as monocular acuity. Optical treatment is a passive form of binocular therapy and a necessary first step in treating the binocular dysfunction that characterizes amblyopia. PMID- 29614156 TI - More is better: Relative prevalence of multiple targets affects search accuracy. AB - In real-world searches such as airport baggage screening and radiological examinations, miss errors can be life threatening. Misses increase for additional targets after detecting an initial target, termed "subsequent search misses" (SSMs), and also when targets are more often absent than present, termed the low prevalence effect. Real-world search tasks often contain more than one target, but the prevalence of these multitarget occasions varies. For example, a cancerous tumor sometimes coexists with a benign tumor and sometimes exists alone. This study aims to investigate how the relative prevalence of multiple targets affects search accuracy. Naive observers searched for all Ts (zero, one, or two) among Ls. In Experiment 1, SSMs occurred in small but not large set sizes, which may be explained by classic capacity limit effects such as the attentional blink and repetition blindness. Experiment 2 showed an interaction between SSMs and the relative prevalence of dual-target trials: Low prevalence of dual-target trials increased SSMs relative to high prevalence dual-target trials. The prevalence of dual-target trials did not affect accuracy on single-target trials. These results may provide a novel avenue for reducing misses by increasing the prevalence of instances with multiple targets. Future efforts should take into account the relative prevalence of multiple targets to effectively reduce life-threatening miss errors. PMID- 29614157 TI - Artistic Renaissance in Frontotemporal Dementia. PMID- 29614158 TI - Platelets' Role in Adaptive Immunity May Contribute to Sepsis and Shock. PMID- 29614160 TI - Units of Measure Error. PMID- 29614159 TI - Undisclosed Conflicts of Interest. PMID- 29614161 TI - Evaluation of the Direct Antiglobulin Test (DAT) in the Setting of Mycoplasma pneumoniae Infection. PMID- 29614162 TI - From Misfortune to Mortality: Sudden Loss of Wealth and Increased Risk of Death. PMID- 29614163 TI - To JAMA Authors, Reviewers, and Readers-Thank You. PMID- 29614164 TI - Reducing Lung Cancer Progression With Immunotherapy. PMID- 29614165 TI - New Stent for Small Vessels. PMID- 29614166 TI - Another Caution for Clarithromycin. PMID- 29614168 TI - Income, Poverty, and Health Inequality. PMID- 29614169 TI - The Ethics of Surgery. PMID- 29614170 TI - Mortality From Falls in Dutch Adults 80 Years and Older, 2000-2016. PMID- 29614171 TI - Continuous Glucose Monitors for Insulin Dosing. PMID- 29614172 TI - Interventions to Prevent Falls in Older Adults. PMID- 29614173 TI - Glyphosate Levels in Older Adults. PMID- 29614174 TI - Undisclosed Conflicts of Interest. PMID- 29614175 TI - Continuous Glucose Monitors for Insulin Dosing-Reply. PMID- 29614176 TI - Glyphosate Levels in Older Adults-Reply. PMID- 29614177 TI - Interventions to Prevent Falls in Older Adults-Reply. PMID- 29614178 TI - Association of a Negative Wealth Shock With All-Cause Mortality in Middle-aged and Older Adults in the United States. AB - Importance: A sudden loss of wealth-a negative wealth shock-may lead to a significant mental health toll and also leave fewer monetary resources for health related expenses. With limited years remaining to regain lost wealth in older age, the health consequences of these negative wealth shocks may be long-lasting. Objective: To determine whether a negative wealth shock was associated with all cause mortality during 20 years of follow-up. Design, Setting, and Participants: The Health and Retirement Study, a nationally representative prospective cohort study of US adults aged 51 through 61 years at study entry. The study population included 8714 adults, first assessed for a negative wealth shock in 1994 and followed biennially through 2014 (the most recent year of available data). Exposures: Experiencing a negative wealth shock, defined as a loss of 75% or more of total net worth over a 2-year period, or asset poverty, defined as 0 or negative total net worth at study entry. Main Outcomes and Measures: Mortality data were collected from the National Death Index and postmortem interviews with family members. Marginal structural survival methods were used to account for the potential bias due to changes in health status that may both trigger negative wealth shocks and act as the mechanism through which negative wealth shocks lead to increased mortality. Results: There were 8714 participants in the study sample (mean [SD] age at study entry, 55 [3.2] years; 53% women), 2430 experienced a negative wealth shock during follow-up, 749 had asset poverty at baseline, and 5535 had continuously positive wealth without shock. A total of 2823 deaths occurred during 80 683 person-years of follow-up. There were 30.6 vs 64.9 deaths per 1000 person-years for those with continuously positive wealth vs negative wealth shock (adjusted hazard ratio [HR], 1.50; 95% CI, 1.36-1.67). There were 73.4 deaths per 1000 person-years for those with asset poverty at baseline (adjusted HR, 1.67; 95% CI, 1.44-1.94; compared with continuously positive wealth). Conclusions and Relevance: Among US adults aged 51 years and older, loss of wealth over 2 years was associated with an increased risk of all-cause mortality. Further research is needed to better understand the possible mechanisms for this association and determine whether there is potential value for targeted interventions. PMID- 29614180 TI - Skin Abscess. PMID- 29614179 TI - Association of Solid Fuel Use With Risk of Cardiovascular and All-Cause Mortality in Rural China. AB - Importance: When combusted indoors, solid fuels generate a large amount of pollutants such as fine particulate matter. Objective: To assess the associations of solid fuel use for cooking and heating with cardiovascular and all-cause mortality. Design, Setting, and Participants: This nationwide prospective cohort study recruited participants from 5 rural areas across China between June 2004 and July 2008; mortality follow-up was until January 1, 2014. A total of 271 217 adults without a self-reported history of physician-diagnosed cardiovascular disease at baseline were included, with a random subset (n = 10 892) participating in a resurvey after a mean interval of 2.7 years. Exposures: Self reported primary cooking and heating fuels (solid: coal, wood, or charcoal; clean: gas, electricity, or central heating), switching of fuel type before baseline, and use of ventilated cookstoves. Main Outcomes and Measures: Death from cardiovascular and all causes, collected through established death registries. Results: Among the 271 217 participants, the mean (SD) age was 51.0 (10.2) years, and 59% (n = 158 914) were women. A total of 66% (n = 179 952) of the participants reported regular cooking (at least weekly) and 60% (n = 163 882) reported winter heating, of whom 84% (n = 150 992) and 90% (n = 147 272) used solid fuels, respectively. There were 15 468 deaths, including 5519 from cardiovascular causes, documented during a mean (SD) of 7.2 (1.4) years of follow up. Use of solid fuels for cooking was associated with greater risk of cardiovascular mortality (absolute rate difference [ARD] per 100 000 person years, 135 [95% CI, 77-193]; hazard ratio [HR], 1.20 [95% CI, 1.02-1.41]) and all cause mortality (ARD, 338 [95% CI, 249-427]; HR, 1.11 [95% CI, 1.03-1.20]). Use of solid fuels for heating was also associated with greater risk of cardiovascular mortality (ARD, 175 [95% CI, 118-231]; HR, 1.29 [95% CI, 1.06 1.55]) and all-cause mortality (ARD, 392 [95% CI, 297-487]; HR, 1.14 [95% CI, 1.03-1.26]). Compared with persistent solid fuel users, participants who reported having previously switched from solid to clean fuels for cooking had a lower risk of cardiovascular mortality (ARD, 138 [95% CI, 71-205]; HR, 0.83 [95% CI, 0.69 0.99]) and all-cause mortality (ARD, 407 [95% CI, 317-497]; HR, 0.87 [95% CI, 0.79-0.95]), while for heating, the ARDs were 193 (95% CI, 128-258) and 492 (95% CI, 383-601), and the HRs were 0.57 (95% CI, 0.42-0.77) and 0.67 (95% CI, 0.57 0.79), respectively. Among solid fuel users, use of ventilated cookstoves was also associated with lower risk of cardiovascular mortality (ARD, 33 [95% CI, -9 to 75]; HR, 0.89 [95% CI, 0.80-0.99]) and all-cause mortality (ARD, 87 [95% CI, 20-153]; HR, 0.91 [95% CI, 0.85-0.96]). Conclusions and Relevance: In rural China, solid fuel use for cooking and heating was associated with higher risks of cardiovascular and all-cause mortality. These risks may be lower among those who had previously switched to clean fuels and those who used ventilation. PMID- 29614182 TI - Sharing Connections. PMID- 29614186 TI - What Is Holistic Admissions Review, and Why Does It Matter? PMID- 29614184 TI - Neonatal Abstinence Syndrome: Advances in Diagnosis and Treatment. AB - Importance: Neonatal abstinence syndrome, which occurs as a result of in utero opioid exposure, affects between 6.0 and 20 newborns per 1000 live US births. There is substantial variability in how neonatal abstinence syndrome is diagnosed and managed. Objective: To summarize key studies examining the diagnosis and management (both pharmacologic and nonpharmacologic) of neonatal abstinence syndrome published during the past 10 years. Evidence Review: PubMed, Web of Science, and CINAHL were searched for articles published between July 1, 2007, and December 31, 2017. Abstracts were screened and included in the review if they pertained to neonatal abstinence syndrome diagnosis or management and were judged by the authors to be clinical trials, cohort studies, or case series. Findings: A total of 53 articles were included in the review, including 9 randomized clinical trials, 35 cohort studies, 1 cross-sectional study, and 8 case series representing a total of 11 905 unique opioid-exposed mother-infant dyads. Thirteen studies were identified that evaluated established or novel neonatal abstinence syndrome assessment methods, such as brief neonatal abstinence syndrome assessment scales or novel objective physiologic measures to predict withdrawal. None of the new techniques that measure infant physiologic parameters are routinely used in clinical practice. The most substantial number of studies of neonatal abstinence syndrome management pertain to nonpharmacologic care specifically, interventions that promote breastfeeding or encourage parents to room-in with their newborns. Although these nonpharmacologic interventions appear to decrease the need for pharmacologic treatment and result in shorter hospitalizations, the interventions are heterogeneous and there are no high quality clinical trials to support them. Regarding pharmacologic interventions, only 5 randomized clinical trials with prespecified sample size calculations (4 infant, 1 maternal treatment) have been published. Each of these trials was small (from 26 to 131 participants) and tested different therapies, limiting the extent to which results can be aggregated. There is insufficient evidence to support an association between any diagnostic or treatment approach and differential neurodevelopmental outcomes among infants with neonatal abstinence syndrome. Conclusions and Relevance: Evidence pertaining to the optimal diagnosis and treatment strategies for neonatal abstinence syndrome is based on small or low quality studies that focus on intermediate outcomes, such as need for pharmacologic treatment or length of hospital stay. Clinical trials are needed to evaluate health and neurodevelopmental outcomes associated with objective diagnostic approaches as well as pharmacologic and nonpharmacologic treatment modalities. PMID- 29614187 TI - Technology, Educator Intention, and Relationships in Virtual Learning Spaces: A Qualitative Metasynthesis. AB - BACKGROUND: A main concern that remains with the continued growth of online nursing education programs is the way educator and student relationships can be affected by new technologies. This interpretive study aims to gain an understanding of how technology influences the development of interpersonal relationships between the student and faculty in a virtual learning environment. METHOD: Using an established structured approach to qualitative metasynthesis, a search was conducted using PubMed, EBSCO, CINAHL, Medline, ProQuest, Ovid Nursing databases, and Google Scholar, focused on caring and relational aspects of online nursing education. RESULTS: Technology alters communication, thereby positioning the intentionality of the educator at the heart of interpersonal relationship development in virtual learning spaces. CONCLUSION: This interpretive synthesis of prior qualitative research supports the development of a framework for online nursing courses, the need for continuing education of nursing faculty, the value of caring intentions, and enhancement of the educator's technological proficiency. [J Nurs Educ. 2018;57(4):197-202.]. PMID- 29614188 TI - Diagnostic Reasoning and Cognitive Biases of Nurse Practitioners. AB - BACKGROUND: Diagnostic reasoning is often used colloquially to describe the process by which nurse practitioners and physicians come to the correct diagnosis, but a rich definition and description of this process has been lacking in the nursing literature. METHOD: A literature review was conducted with theoretical sampling seeking conceptual insight into diagnostic reasoning. RESULTS: Four common themes emerged: Cognitive Biases and Debiasing Strategies, the Dual Process Theory, Diagnostic Error, and Patient Harm. Relevant cognitive biases are discussed, followed by debiasing strategies and application of the dual process theory to reduce diagnostic error and harm. CONCLUSION: The accuracy of diagnostic reasoning of nurse practitioners may be improved by incorporating these items into nurse practitioner education and practice. [J Nurs Educ. 2018;57(4):203-208.]. PMID- 29614189 TI - Learning About Conflict and Conflict Management Through Drama in Nursing Education. AB - BACKGROUND: In the health care settings in which nurses work, involvement in some form of conflict is inevitable. The ability to manage conflicts is therefore necessary for nursing students to learn during their education. METHOD: A qualitative analysis of 43 written group assignments was undertaken using a content analysis approach. RESULTS: Three main categories emerged in the analysis to approach and integrate with the theoretical content, to step back and get an overview, and to concretize and practice-together with the overall theme, to learn by oscillating between closeness and distance. CONCLUSION: Learning about conflict and conflict management through drama enables nursing students to form new knowledge by oscillating between closeness and distance, to engage in both the fictional world and the real world at the same time. This helps students to form a personal understanding of theoretical concepts and a readiness about how to manage future conflicts. [J Nurs Educ. 2018;57(4):209-216.]. PMID- 29614190 TI - The Value of Peer Mentorship as an Educational Strategy in Nursing. AB - BACKGROUND: The emphasis of this article is to provide nursing instructors with a valuable educational strategy grounded in andragogical principles for reflection and implementation in their educational practice. METHOD: An expository review of the value of peer mentorship as an educational strategy that fits within the humanistic adult education philosophy and social constructivism theory was conducted. RESULTS: The value in peer mentorship is greatest for nursing students as mentors and mentees, predominantly in encouraging self-directed learning, building relationships, providing emotional and educational support, and developing collaboration and leadership skills. In addition, peer mentorship provides value to instructors and educational institutions by supporting a positive student-centered learning environment that enhances student success. CONCLUSION: Peer mentorship as a valuable educational strategy can be recognized for future use within all levels of nursing education and can be applied universally to teaching and learning within other health care educational settings. [J Nurs Educ. 2018;57(4):217-224.]. PMID- 29614191 TI - Difficult to Doable: Interprofessional Collaborative Practice in Distance Education. AB - BACKGROUND: This study investigated the effect of interprofessional educational (IPE) in a distance education setting on students' self-efficacy around the Interprofessional Collaborative Practice (IPEC) constructs. METHOD: Senior RN-to Bachelor of Science nursing students, students from health sciences, and dietetic intern students participated in the IPE learning experience. A pre- postsurvey design measured the change in student self-efficacy in relation to the IPEC constructs of values and ethics, roles and responsibilities, interprofessional communication, and teams and teamwork. RESULTS: In total, 92 students participated and 46 completed the pre-postsurvey. There were statistically significant changes in student self-efficacy across all constructs. Qualitative comments revealed themes of collaboration strengthening care, the value of exposure to different perspectives, and desire for commonly shared goals among the team. CONCLUSION: Research on IPE in distance education lags behind IPE in traditional settings. This study revealed that IPE is attainable in distance education, with significant changes in student's self-efficacy. Self-efficacy is a key indicator of future behavior. [J Nurs Educ. 2018;57(4):225-228.]. PMID- 29614192 TI - Epistemological Development in First-Year Nursing Students Undertaking Cultural Safety Education. AB - BACKGROUND: The process of teaching cultural safety is emancipatory, focused on wider social relations and the context in which they arise. As teachers of cultural safety, we are interested in the way that ideas are formed, held, and changed. The aim of this research was to examine whether epistemological shifts were demonstrated by nursing students over one semester of cultural safety teaching-learning. METHOD: NVivo software was used to analyze 34 nursing students' reflective journals, applying a cognitive-developmental framework. The framework comprised three epistemological positions-dualism, relativism, and propositional-and two in-between locations, referred to as stretching. RESULTS: The results showed student movement between early epistemological positions and students' efforts to stretch to new, yet untried, ways of thinking. CONCLUSION: In the classroom, these shifts may be subtle; thus, paying careful attention to evidence that students are trying out new ways of thinking is essential. Appreciating that these small but significant shifts are perhaps more important than 'aha' moments is crucial. [J Nurs Educ. 2018;57(4):229-232.]. PMID- 29614193 TI - Stepping Into Their Shoes: The Ostomy Experience. AB - BACKGROUND: Empathetic patient care and reflective practice are linked to improved patient outcomes. Nurse educators play a key role in facilitating the development of empathy in nursing students. Research reveals an interest in reflective learning using a variety of approaches. METHOD: Taking cues from the previous literature, "The Ostomy Experience" was developed, implemented, and evaluated qualitatively. The Ostomy Experience included paired learning, simulated ostomy stories, skills application in a laboratory setting, personal experience of an ostomate appliance, and structured reflective journaling throughout the process. Responses were evaluated for emerging themes. RESULTS: Data analysis revealed themes of Encountering Emotions, Becoming Aware, and Impacting Personal Practice. CONCLUSION: The structured reflective journaling yielded rich student learning data. Responses were evident of self-proclaimed change in attitudes, deeper understanding of the patient experience, and achievement of the learning objectives. [J Nurs Educ. 2018;57(4):233-236.]. PMID- 29614194 TI - Engaging Nursing Students in a Culture of Integrity. AB - BACKGROUND: In order to become safe, effective professionals, nursing students must have a working knowledge of academic and professional integrity principles. However, nursing students have knowledge gaps in these areas, which may lead to unethical practices postgraduation. Inconsistencies in faculty enforcement of integrity principles may lead to student confusion and further student risk. METHOD: An interactive online integrity course was designed to address knowledge gaps related to academic and professional integrity. Course engagement occurred through self-reflection, quizzes, and a commitment statement. The pilot course was deployed to all nursing faculty and staff for feedback and approval. RESULTS: Of the 38 faculty and staff invited, 20 participated in the course. Based on feedback, course adjustments were made to address navigation, quiz clarity, and content. The online integrity course received full faculty approval. CONCLUSION: An interactive online integrity course is one option to support student engagement in and assimilation to a culture of integrity. [J Nurs Educ. 2018;57(4):237-239.]. PMID- 29614195 TI - Enhancing Community Education Through Innovative Teaching Strategies in a Baccalaureate Nursing Program. AB - BACKGROUND: Nurse educators are relentlessly in search of innovative measures that enhance student learning and offer opportunities that prepare them for clinical practice. Collaborative opportunities between schools of nursing and community settings are beneficial for students and the community. METHOD: One strategy was developed by a southeastern baccalaureate nursing program through the assistance of the National Institutes of Health mini-grants program, related to their Safe Sleep campaign. Safe Sleep subject matter was integrated into the curriculum, where students learned content, developed teaching strategies, and taught community members components of Safe Sleep. RESULTS: The project provided faculty and baccalaureate nursing students with an opportunity to implement a community outreach education project addressing Safe Sleep. Students learned cultural assessment, teaching, and communication skills, and community members benefited from learned knowledge of health promotion programs. CONCLUSION: Future educational outreach projects are recommended to further examine program effectiveness and the value of teaching-learning strategies. [J Nurs Educ. 2018;57(4):240-244.]. PMID- 29614196 TI - Integrating Video Simulation Scenarios Into Online Nursing Instruction. AB - BACKGROUND: As nursing programs continue to expand online, innovative pedagogies that support online teaching and learning practices grounded in theoretical constructs are needed. METHOD: Video simulation scenarios and VoiceThread technology were used to create a model of online instruction that promotes active student participation and aligns with course objectives and content. Kolb's experiential learning theory serves as the framework for this project. RESULTS: The integration of multimedia in the course gave students a collaborative experience where they can apply their knowledge to the simulation scenarios. Inclusion of the vignettes was found to be effective in addressing specific areas of curriculum while stimulating student engagement. CONCLUSION: Increased use of online delivery for nursing education necessitates course designs that promote student interaction and foster community. Teaching and learning practices that include technologies and are supported by theoretical constructs promote best practices for online instruction. [J Nurs Educ. 2018;57(4):245-249.]. PMID- 29614197 TI - Standardized Patient Simulation to Facilitate Learning in Evidence-Based Oncology Symptom Management. AB - BACKGROUND: New graduate nurses lack the specialty knowledge and skills necessary to provide effective symptom management to oncology patients. The purpose of this article is to describe the development of a simulation-based learning experience using standardized patients to enhance undergraduate nursing students' ability to apply evidence-based principles learned in the classroom to oncology symptom management practice. METHOD: Faculty developed two standardized patient simulations for a 7-week senior seminar in evidence-based oncology symptom management. RESULTS: Faculty, students, and standardized patients provided positive feedback. Students appreciated the realism and innovation of using simulation in a seminar-style course. Faculty and students identified that more time was needed for the simulations, and revisions are planned for the next offering of the seminar to address this concern. CONCLUSION: The integration of standardized patients is a feasible learning strategy to facilitate learning of evidence-based oncology symptom management principles among undergraduate nursing students. [J Nurs Educ. 2018;57(4):250-253.]. PMID- 29614198 TI - Introduction of the Purcell Clinical Reasoning Tool in a Medical-Surgical Clinical Setting. PMID- 29614199 TI - Using Multimedia Resources to Enhance Active Learning During Office Hours. PMID- 29614200 TI - Reply to comment on: Sailer CO, et al. Primary polydipsia in the medical and psychiatric patient: characteristics, complications and therapy. PMID- 29614201 TI - Comment on: Sailer C, et al. Primary polydipsia in the medical and psychiatric patient: characteristics, complications and therapy. PMID- 29614202 TI - Health-related correlates of psychological well-being among girls and boys 6-8 years of age: The Physical Activity and Nutrition in Children study. AB - AIM: Due to limited knowledge on the differences in the correlates of psychological well-being (PSWB) between girls and boys, we compared the correlates of PSWB between primary school girls and boys. METHODS: A population sample of 412 children participated in the Physical Activity and Nutrition in Children study. Parents completed a questionnaire that included 19 questions on the components of PSWB, and a PSWB score was computed. We assessed correlates of PSWB, including physical activity, sedentary behaviour, cardiorespiratory fitness, diet quality, body fat content, sleep duration, sleep disordered breathing, prevalent diseases and parental characteristics. We used logistic regression to analyse the risk of being in the lowest third of the PSWB scores. RESULTS: Low parental education was associated with increased risk (odds ratio (OR) 2.34, P = 0.039) and high cardiorespiratory fitness with decreased risk (OR 0.26, P = 0.006) of poor PSWB in girls. At least 2 h of screen-based sedentary behaviour per day (OR 1.93, P = 0.037), daily parental smoking (OR 2.10, P = 0.034) and sleep disordered breathing (OR 4.24, P = 0.003) were related to increased risk of poor PSWB in boys. CONCLUSIONS: There are large differences in the correlates of PSWB between girls and boys. Most of these correlates are modifiable and related to the health behaviour of children and their parents. PMID- 29614203 TI - Changes in the expression of matrix extracellular genes and TGFB family members in rotator cuff tears. AB - Lack of synthesis of extracellular matrix compounds may contribute to degeneration of the tendons. Thus, we aimed to evaluate the expression of extracellular matrix and TGFB family members in ruptured and non-ruptured tendons of the rotator cuff, as well as the effect of clinical factors on gene expression in tendon samples, and the relationship between histological findings and altered gene expression. Injured and non-injured supraspinatus tendon samples and subscapular non-injured tendon samples were collected from 38 patients with rotator cuff tears. Non-injured supraspinatus tendons were obtained from eight controls. Specimens were used for histological evaluation, quantification of collagen fibers, and mRNA and protein expression analyses. Increased COL1A1, COL1A2, COL3A1, COL5A1, FN1, TNC, and TGFBR1 mRNA expression was observed in the tear samples (p < 0.05). Duration of symptoms was correlated with the levels of collagen type I/III fibers (p = 0.032; rho = 0.0447) and FN1 immunostaining (p = 0.031; rho = 0.417). Smoking was associated with increased frequency of microcysts, myxoid degeneration, and COL5A1, FN1, TNC, and TGFB1 mRNA expression (p < 0.05). FN1 immunostaining was correlated with the number of years of smoking (p = 0.048; rho = 0.384). Lower levels of collagen type I/III fibers were detected in samples with fissures (0 = 0.046). High frequency of microcysts was associated with increased COL5A1, FN1, and TNC expression (p < 0.05, for all comparisons). Neovascularization was associated with reduced FN1 (p = 0.035) and TGFBR1 expression (p = 0.034). Our findings show differential expression of matrix extracellular genes and TGFB family members in the degeneration process involved in rotator cuff tears. These molecular alterations are influenced by clinical factors. (c) 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2542-2553, 2018. PMID- 29614204 TI - 'An ant against an elephant': Retirement village residents' experiences of disputes and dispute resolution. AB - OBJECTIVE: To record Victorian retirement village residents' experiences of dispute management and satisfaction levels related to dispute resolution processes. METHODS: Survey distributed to 6500 retirement village residents. RESULTS: Surveys returned from 1876 residents (29% return rate). Most residents rated life in retirement villages as positive (mean 7.9/10), with an association between life satisfaction and management's ability to resolve disputes (rs = 0.44, P < 0.01). Almost 70% of respondents reported issues of concern to management were resolved satisfactorily; 38% were not resolved to residents' satisfaction. One-fifth reported contacting regional managers or higher personnel regarding issues affecting them, with two-thirds of these respondents reporting a negative outcome. Over 30% did not know if their village had dispute resolution processes in place. CONCLUSION: Despite finding retirement village life positive, residents of retirement villages found disputes and dispute resolution processes unsatisfactory and desired change to address these concerns. PMID- 29614206 TI - Medical cannabis for paediatric developmental-behavioural and psychiatric disorders. PMID- 29614205 TI - Associations between asthma status and radiologically confirmed fracture in children: A data-linkage study. AB - AIM: World-wide, approximately 14% of children have prevalent asthma. As most bone accrual occurs in childhood, and data suggest a detrimental role in bone from asthma and/or medications, we investigated whether asthma was associated with radiologically confirmed fractures in a large cohort of children. METHODS: Data from the Barwon Asthma Study (2005), a population-based, cross-sectional survey of all children attending 91 primary schools in the Barwon Statistical Division, were linked to the Geelong Osteoporosis Study Fracture Grid (2006 2007), a fracture register encompassing the Barwon Statistical Division (n = 16 438; 50.5% boys; aged 3.5-13.6 years). Asthma, ascertained from parent-reported symptoms using the International Study of Asthma and Allergies in Childhood questionnaire, was categorised as: (i) recent wheeze; and number of (ii) recent wheezy episodes; (iii) doctor visits for wheeze symptoms; and (iv) doctor visits for asthma check-ups. Using logistic regression analyses, stratified by sex and adjusted for age and medication use, we determined whether asthma was associated with radiologically confirmed fractures. RESULTS: In total, 961 fractures were observed among 823 Barwon Asthma Study participants (5.9% of total sample; 61.1% boys). Recent wheeze and 1-3 recent wheezy episodes were associated with increased odds of fracture in boys (odds ratio (OR) 1.26, 95% confidence interval (CI) 1.03-1.55; OR 1.40, 95% CI 1.12-1.77, respectively), but not girls (OR 1.03, 95% CI 0.78-1.37; OR 0.67, 95% CI 0.38-1.19). Results were independent of age, and sustained after adjustment for medication. CONCLUSIONS: Independent of age, asthma was associated with fracture for boys, but not girls. There is an imperative for strategies to promote bone health among children with asthma. PMID- 29614208 TI - Ecological medicine. PMID- 29614207 TI - Nurse-led multidisciplinary initiatives to improve outcomes and reduce hospital admissions for older adults: The Care coordination through Emergency Department, Residential Aged Care and Primary Health Collaboration project. AB - OBJECTIVES: This article describes the Care coordination through Emergency Department, Residential Aged Care and Primary Health Collaboration (CEDRiC) project. METHODS: CEDRiC is designed to improve the health outcomes for older people with an acute illness. It attempts this via enhanced primary care in residential aged care facilities, focused and streamlined care in the emergency department and enhanced intersectoral communication and referral. RESULTS: Implementing this approach has the potential to decrease inappropriate hospital admissions while improving care for older people in residential aged care and community settings. CONCLUSION: This article discusses an innovative way of caring for older adults in an ageing population utilising the existing evidence. A formal evaluation is currently underway. PMID- 29614209 TI - Plant potassium nutrition in ectomycorrhizal symbiosis: properties and roles of the three fungal TOK potassium channels in Hebeloma cylindrosporum. AB - Ectomycorrhizal fungi play an essential role in the ecology of boreal and temperate forests through the improvement of tree mineral nutrition. Potassium (K+ ) is an essential nutrient for plants and is needed in high amounts. We recently demonstrated that the ectomycorrhizal fungus Hebeloma cylindrosporum improves the K+ nutrition of Pinus pinaster under shortage conditions. Part of the transport systems involved in K+ uptake by the fungus has been deciphered, while the molecular players responsible for the transfer of this cation towards the plant remain totally unknown. Analysis of the genome of H. cylindrosporum revealed the presence of three putative tandem-pore outward-rectifying K+ (TOK) channels that could contribute to this transfer. Here, we report the functional characterization of these three channels through two-electrode voltage-clamp experiments in oocytes and yeast complementation assays. The expression pattern and physiological role of these channels were analysed in symbiotic interaction with P. pinaster. Pine seedlings colonized by fungal transformants overexpressing two of them displayed a larger accumulation of K+ in shoots. This study revealed that TOK channels have distinctive properties and functions in axenic and symbiotic conditions and suggested that HcTOK2.2 is implicated in the symbiotic transfer of K+ from the fungus towards the plant. PMID- 29614210 TI - Evidence for selective bacterial community structuring on microplastics. AB - In aquatic ecosystems, microplastics are a relatively new anthropogenic substrate that can readily be colonized by biofilm-forming organisms. To examine the effects of substrate type on microbial community assembly, we exposed ambient Baltic bacterioplankton to plastic substrates commonly found in marine environments (polyethylene, polypropylene and polystyrene) as well as native (cellulose) and inert (glass beads) particles for 2 weeks under controlled conditions. The source microbial communities and those of the biofilms were analyzed by Illumina sequencing of the 16S rRNA gene libraries. All biofilm communities displayed lower diversity and evenness compared with the source community, suggesting substrate-driven selection. Moreover, the plastics associated communities were distinctly different from those on the non-plastic substrates. Whereas plastics hosted greater than twofold higher abundance of Burkholderiales, the non-plastic substrates had a significantly higher proportion of Actinobacteria and Cytophagia. Variation in the community structure, but not the cell abundance, across the treatments was strongly linked to the substrate hydrophobicity. Thus, microplastics host distinct bacterial communities, at least during early successional stages. PMID- 29614211 TI - Histamine catabolism in Pseudomonas putida U: identification of the genes, catabolic enzymes and regulators. AB - In this study, the catabolic pathway required for the degradation of the biogenic amine histamine (Hin) was genetically and biochemically characterized in Pseudomonas putida U. The 11 proteins (HinABCDGHFLIJK) that participate in this pathway are encoded by genes belonging to three loci hin1, hin2 and hin3 and by the gene hinK. The enzymes HinABCD catalyze the transport and oxidative deamination of histamine to 4-imidazoleacetic acid (ImAA). This reaction is coupled to those of other well-known enzymatic systems (DadXAR and CoxBA-C) that ensure both the recovery of the pyruvate required for Hin deamination and the genesis of the energy needed for Hin uptake. The proteins HinGHFLKIJ catalyze the sequential transformation of ImAA to fumaric acid via N2 -formylisoasparagine, formylaspartic acid and aspartic acid. The identified Hin pathway encompasses all the genes and proteins (transporters, energizing systems, catabolic enzymes and regulators) needed for the biological degradation of Hin. Our work was facilitated by the design and isolation of genetically engineered strains that degrade Hin or ImAA and of mutants that accumulate Ala, Asp and Hin catabolites. The implications of this research with respect to potential biotechnological applications are discussed. PMID- 29614212 TI - The key gluconeogenic gene PCK1 is crucial for virulence of Botrytis cinerea via initiating its conidial germination and host penetration. AB - The process of initiation of host invasion and survival of some foliar phytopathogenic fungi in the absence of external nutrients on host leaf surfaces remains obscure. Here, we demonstrate that gluconeogenesis plays an important role in the process and nutrient-starvation adaptation before the pathogen host invasion. Deletion of phosphoenolpyruvate carboxykinase gene BcPCK1 in gluconeogenesis in Botrytis cinerea, the causative agent of grey mould, resulted in the failure of the DeltaBcpck1 mutant conidia to germinate on hard and hydrophobic surface and penetrate host cells in the absence of glucose, reduction in conidiation and slow conidium germination in a nutrient-rich medium. The wild type and DeltaBcpck1 conidia germinate similarly in the presence of glucose (higher concentration) as the sole carbon source. Conidial glucose-content should reach a threshold level to initiate germination and host penetration. Infection structure formation by the mutants displayed a glucose-dependent fashion, which corresponded to the mutant virulence reduction. Exogenous glucose or complementation of BcPCK1 completely rescued all the developmental and virulence defects of the mutants. Our findings demonstrate that BcPCK1 plays a crucial role in B. cinerea pathogenic growth and virulence, and provide new insights into gluconeogenesis mediating pathogenesis of plant fungal pathogens via initiation of conidial germination and host penetration. PMID- 29614213 TI - What will it take to understand the ecology of symbiotic microorganisms? PMID- 29614214 TI - A planktonic diatom displays genetic structure over small spatial scales. AB - Marine planktonic microalgae have potentially global dispersal, yet reduced gene flow has been confirmed repeatedly for several species. Over larger distances (>200 km) geographic isolation and restricted oceanographic connectivity have been recognized as instrumental in driving population divergence. Here we investigated whether similar patterns, that is, structured populations governed by geographic isolation and/or oceanographic connectivity, can be observed at smaller (6-152 km) geographic scales. To test this we established 425 clonal cultures of the planktonic diatom Skeletonema marinoi collected from 11 locations in the Archipelago Sea (northern Baltic Sea). The region is characterized by a complex topography, entailing several mixing regions of which four were included in the sampling area. Using eight microsatellite markers and conventional F statistics, significant genetic differentiation was observed between several sites. Moreover, Bayesian cluster analysis revealed the co-occurrence of two genetic groups spread throughout the area. However, geographic isolation and oceanographic connectivity could not explain the genetic patterns observed. Our data reveal hierarchical genetic structuring whereby despite high dispersal potential, significantly diverged populations have developed over small spatial scales. Our results suggest that biological characteristics and historical events may be more important in generating barriers to gene flow than physical barriers at small spatial scales. PMID- 29614215 TI - Flexible Polydimethylsiloxane Foams Decorated with Multiwalled Carbon Nanotubes Enable Unprecedented Detection of Ultralow Strain and Pressure Coupled with a Large Working Range. AB - Low-cost piezoresistive strain/pressure sensors with large working range, at the same time able to reliably detect ultralow strain (<=0.1%) and pressure (<=1 Pa), are one of the challenges that have still to be overcome for flexible piezoresistive materials toward personalized health-monitoring applications. In this work, we report on unprecedented, simultaneous detection of ultrasmall strain (0.1%, i.e., 10 MUm displacement over 10 mm) and subtle pressure (20 Pa, i.e., a force of only 2 mN over an area of 1 cm2) in compression mode, coupled with a large working range (i.e., up to 60% for strain-6 mm in displacement-and 50 kPa for pressure) using piezoresistive, flexible three-dimensional (3D) macroporous polydimethylsiloxane (pPDMS) foams decorated with pristine multiwalled carbon nanotubes (CNTs). pPDMS/CNT foams with pore size up to 500 MUm (i.e., twice the size of those of commonly used foams, at least) and porosity of 77%, decorated with a nanostructured surface network of CNTs at densities ranging from 7.5 to 37 mg/cm3 are prepared using a low-cost and scalable process, through replica molding of sacrificial sugar templates and subsequent drop-casting of CNT ink. A thorough characterization shows that piezoresistive properties of the foams can be finely tuned by controlling the CNT density and reach an optimum at a CNT density of 25 mg/cm3, for which a maximum change of the material resistivity (e.g., rho0/rho50 = 4 at 50% strain) is achieved under compression. Further static and dynamic characterization of the pPDMS/CNT foams with 25 mg/cm3 of CNTs highlights that detection limits for strain and pressure are 0.03% (3 MUm displacement over 10 mm) and 6 Pa (0.6 mN over an area of 1 cm2), respectively; moreover, good stability and limited hysteresis are apparent by cycling the foams with 255 compression-release cycles over the strain range of 0-60%, at different strain rates up to 10 mm/min. Our results on piezoresistive, flexible pPDMS/CNT foams pave the way toward breakthrough applications for personalized health care, though not limited to these, which have not been fully addressed to date with flexible strain/stress sensors. PMID- 29614216 TI - Water Oxidation Catalysis for NiOOH by a Metropolis Monte Carlo Algorithm. AB - Understanding catalytic mechanisms is important for discovering better catalysts, particularly for water splitting reactions that are of great interest to the renewable energy field. One of the best performing catalysts for water oxidation is nickel oxyhydroxide (NiOOH). However, only one mechanism has been adopted so far for modeling catalysis of the active plane: beta-NiOOH(015). In order to understand how a second reaction mechanism affects catalysis, we perform Density Functional Theory + U (DFT+U) calculations of a second mechanism for water oxidation reaction of NiOOH. Then, we use a Metropolis Monte Carlo algorithm to calculate how many catalytic cycles are completed when two reaction mechanisms are competing. We find that within the Metropolis algorithm, the second mechanism has a higher overpotential and is therefore not active even for large applied biases. PMID- 29614217 TI - Development of a Multicenter Density Functional Tight Binding Model for Plutonium Surface Hydriding. AB - We detail the creation of a multicenter density functional tight binding (DFTB) model for hydrogen on delta-plutonium, using a framework of new Slater-Koster interaction parameters and a repulsive energy based on the Chebyshev Interaction Model for Efficient Simulation (ChIMES), where two- and three-center atomic interactions are represented by linear combinations of Chebyshev polynomials. We find that our DFTB/ChIMES model yields a total electron density of states for bulk delta-Pu that compares well to that from Density Functional Theory, as well as to a grid of energy calculations representing approximate H2 dissociation paths on the delta-Pu (100) surface. We then perform molecular dynamics simulations and minimum energy pathway calculations to determine the energetics of surface dissociation and subsurface diffusion on the (100) and (111) surfaces. Our approach allows for the efficient creation of multicenter repulsive energies with a relatively small investment in initial DFT calculations. Our efforts are particularly pertinent to studies that rely on quantum calculations for interpretation and validation, such as experimental determination of chemical reactivity both on surfaces and in condensed phases. PMID- 29614218 TI - Toward Highly Accurate Spin State Energetics in First-Row Transition Metal Complexes: A Combined CASPT2/CC Approach. AB - In previous work on the performance of multiconfigurational second-order perturbation theory (CASPT2) in describing spin state energetics in first-row transition metal systems [ Pierloot et al. J. Chem. Theory Comput. 2017 , 13 , 537 - 553 ], we showed that standard CASPT2 works well for valence correlation but does not describe the metal semicore (3s3p) correlation effects accurately. This failure is partially responsible for the well-known bias toward high-spin states of CASPT2. In this paper, we expand our previous work and show that this bias could be partly removed with a combined CASPT2/CC approach: using high quality CASPT2 with extensive correlation-consistent basis sets for valence correlation and low-cost CCSD(T) calculations with minimal basis sets for the metal semicore (3s3p) correlation effects. We demonstrate that this approach is efficient by studying the spin state energetics of a series of iron complexes modeling important intermediates in oxidative catalytic processes in chemistry and biochemistry. On the basis of a comparison with bare CCSD(T) results from this and previous work, the average error of the CASPT2/CC approach is estimated at around 2 kcal mol-1 in favor of high spin states. PMID- 29614219 TI - Analysis of Multiplexed Nanosensor Arrays Based on Near-Infrared Fluorescent Single-Walled Carbon Nanotubes. AB - The high-throughput, label-free detection of biomolecules remains an important challenge in analytical chemistry with the potential of nanosensors to significantly increase the ability to multiplex such assays. In this work, we develop an optical sensor array, printable from a single-walled carbon nanotube/chitosan ink and functionalized to enable a divalent ion-based proximity quenching mechanism for transducing binding between a capture protein or an antibody with the target analyte. Arrays of 5 * 6, 200 MUm near-infrared (nIR) spots at a density of ~300 spots/cm2 are conjugated with immunoglobulin-binding proteins (proteins A, G, and L) for the detection of human IgG, mouse IgM, rat IgG2a, and human IgD. Binding kinetics are measured in a parallel, multiplexed fashion from each sensor spot using a custom laser scanning imaging configuration with an nIR photomultiplier tube detector. These arrays are used to examine cross reactivity, competitive and nonspecific binding of analyte mixtures. We find that protein G and protein L functionalized sensors report selective responses to mouse IgM on the latter, as anticipated. Optically addressable platforms such as the one examined in this work have potential to significantly advance the real time, multiplexed biomolecular detection of complex mixtures. PMID- 29614220 TI - Liquid-State NMR Analysis of Nanocelluloses. AB - Recent developments in ionic liquid electrolytes for cellulose or biomass dissolution has also allowed for high-resolution 1H and 13C NMR on very high molecular weight cellulose. This permits the development of advanced liquid-state quantitative NMR methods for characterization of unsubstituted and low degree of substitution celluloses, for example, surface-modified nanocelluloses, which are insoluble in all molecular solvents. As such, we present the use of the tetrabutylphosphonium acetate ([P4444][OAc]):DMSO- d6 electrolyte in the 1D and 2D NMR characterization of poly(methyl methacrylate) (PMMA)-grafted cellulose nanocrystals (CNCs). PMMA- g-CNCs was chosen as a difficult model to study, to illustrate the potential of the technique. The chemical shift range of [P4444][OAc] is completely upfield of the cellulose backbone signals, avoiding signal overlap. In addition, application of diffusion-editing for 1H and HSQC was shown to be effective in the discrimination between PMMA polymer graft resonances and those from low molecular weight components arising from the solvent system. The bulk ratio of methyl methacrylate monomer to anhydroglucose unit was determined using a combination of HSQC and quantitative 13C NMR. After detachment and recovery of the PMMA grafts, through methanolysis, DOSY NMR was used to determine the average self-diffusion coefficient and, hence, molecular weight of the grafts compared to self-diffusion coefficients for PMMA GPC standards. This finally led to a calculation of both graft length and graft density using liquid state NMR techniques. In addition, it was possible to discriminate between triads and tetrads, associated with PMMA tacticity, of the PMMA still attached to the CNCs (before methanolysis). CNC reducing end and sulfate half ester resonances, from sulfuric acid hydrolysis, were also assignable. Furthermore, other biopolymers, such as hemicelluloses and proteins (silk and wool), were found to be soluble in the electrolyte media, allowing for wider application of this method beyond just cellulose analytics. PMID- 29614221 TI - Dynamics, Conformational Entropy, and Frustration in Protein-Protein Interactions Involving an Intrinsically Disordered Protein Domain. AB - Intrinsically disordered proteins (IDPs) are abundant in the eukaryotic proteome. However, little is known about the role of subnanosecond dynamics and the conformational entropy that it represents in protein-protein interactions involving IDPs. Using nuclear magnetic resonance side chain and backbone relaxation, stopped-flow kinetics, isothermal titration calorimetry, and computational studies, we have characterized the interaction between the globular TAZ1 domain of the CREB binding protein and the intrinsically disordered transactivation domain of STAT2 (TAD-STAT2). We show that the TAZ1/TAD-STAT2 complex retains considerable subnanosecond motions, with TAD-STAT2 undergoing only a partial disorder-to-order transition. We report here the first experimental determination of the conformational entropy change for both binding partners in an IDP binding interaction and find that the total change even exceeds in magnitude the binding enthalpy and is comparable to the contribution from the hydrophobic effect, demonstrating its importance in the binding energetics. Furthermore, we show that the conformational entropy change for TAZ1 is also instrumental in maintaining a biologically meaningful binding affinity. Strikingly, a spatial clustering of very high amplitude motions and a cluster of more rigid sites in the complex exist, which through computational studies we found to overlap with regions that experience energetic frustration and are less frustrated, respectively. Thus, the residual dynamics in the bound state could be necessary for faster dissociation, which is important for proteins that interact with multiple binding partners. PMID- 29614222 TI - Infrared Chemiluminescence Study of the Reaction of Hydroxyl Radical with Formamide and the Secondary Unimolecular Reaction of Chemically Activated Carbamic Acid. AB - Reactions of OH and OD radicals with NH2CHO and ND2CHO were studied by Fourier transform infrared emission spectroscopy of the product molecules from a fast flow reactor at 298 K. Vibrational distributions of the HOD and H2O molecules from the primary reactions with the C-H bond were obtained by computer simulation of the emission spectra. The vibrational distributions resemble those for other direct H atom abstraction reactions, such as with acetaldehyde. The highest observed level gives an estimate of the C-H bond dissociation energy in formamide of 90.5 +/- 1.3 kcal mol-1. Observation of CO2, ammonia, and secondary water chemiluminescence gave evidence that recombination of OH and NH2CO forms carbamic acid (NH2COOH) with excitation energy of 103 kcal mol-1, which decomposes through two pathways forming either NH3 + CO2 or H2O + HNCO. The branching fraction for ammonia formation was estimated to be 2-3 times larger than formation of water. This observation was confirmed by RRKM calculation of the decomposition rate constants. A new simulation method was developed to analyze infrared emission from NH3, NH2D, ND2H, and ND3. Dynamical aspects of the primary and secondary reactions are discussed based on the vibrational distributions of CO2 and those of H/D isotopes of water and ammonia. PMID- 29614223 TI - High-Performance WSe2 Phototransistors with 2D/2D Ohmic Contacts. AB - We report high-performance WSe2 phototransistors with two-dimensional (2D) contacts formed between degenerately p-doped WSe2 and undoped WSe2 channel. A photoresponsivity of ~600 mA/W with a high external quantum efficiency up to 100% and a fast response time (both rise and decay times) shorter than 8 MUs have been achieved concurrently. More importantly, our WSe2 phototransistor exhibits a high specific detectivity (~1013 Jones) in vacuum, comparable or higher than commercial Si- and InGaAs-based photodetectors. Further studies have shown that the high photoresponsivity and short response time of our WSe2 phototransistor are mainly attributed to the lack of Schottky-barriers between degenerately p doped WSe2 source/drain contacts and undoped WSe2 channel, which can reduce the RC time constant and carrier transit time of a photodetector. Our experimental results provide an accessible strategy to achieve high-performance WSe2 phototransistor architectures by improving their electrical transport and photocurrent generation simultaneously, opening up new avenues for engineering future 2D optoelectronic devices. PMID- 29614224 TI - Orally Available Soluble Epoxide Hydrolase/Phosphodiesterase 4 Dual Inhibitor Treats Inflammatory Pain. AB - Inspired by previously discovered enhanced analgesic efficacy between soluble epoxide hydrolase (sEH) and phosphodiesterase 4 (PDE4) inhibitors, we designed, synthesized and characterized 21 novel sEH/PDE4 dual inhibitors. The best of these displayed good efficacy in in vitro assays. Further pharmacokinetic studies of a subset of four selected compounds led to the identification of a bioavailable dual inhibitor N-(4-methoxy-2-(trifluoromethyl)benzyl)-1 propionylpiperidine-4-carboxamide (MPPA). In a lipopolysaccharide induced inflammatory pain rat model, MPPA rapidly increased in the blood ( Tmax = 30 min; Cmax = 460 nM) after oral administration of 3 mg/kg and reduced inflammatory pain with rapid onset of action correlating with blood levels over a time course of 4 h. Additionally, MPPA does not alter self-motivated exploration of rats with inflammatory pain or the withdrawal latency in control rats. PMID- 29614225 TI - Interleukin-6 Neutralization by Antibodies Immobilized at the Surface of Polymeric Nanoparticles as a Therapeutic Strategy for Arthritic Diseases. AB - Arthritic diseases are disabling conditions affecting millions of patients worldwide. Pro-inflammatory cytokines, particularly interleukin-6 (IL-6), plays a crucial role in inflammation and cartilage destruction. Although the beneficial effects of antibody therapy, its efficacy is limited. Therefore, this work proposes the immobilization of antibodies at the surface of biodegradable polymeric nanoparticles (NPs) to capture and neutralize IL-6. Our system is intended to protect, extend and enhance the therapeutic efficacy after delivery. Chitosan-hyaluronic acid NPs are synthesized as a stable monodisperse population. After determining the maximum immobilization capacity (10 MUg/mL), the capture ability was confirmed. Biological assays demonstrate the NPs cytocompatibility with human articular chondrocytes (hACs) and human macrophages. hACs stimulated with macrophage conditioned medium shows the beneficial role of IL-6 capture and neutralization. Biofunctionalized NPs exhibit a prolonged action and stronger efficacy than the free antibody. In conclusion, this system can be an effective and long lasting treatment for arthritic diseases. PMID- 29614226 TI - Electronic Resonances of Nucleobases Using Stabilization Methods. AB - The interaction of low-energy electrons with nucleobases is important because of their potential to damage nucleic acids. In this work we investigate several low lying resonances of nucleobases using quantum chemical methods including static and dynamical correlation coupled with orbital stabilization methods. Specifically, the equation of motion for electron affinities via couple cluster singles and doubles and multireference perturbation theory methods were used, and their performance was explored. Low-lying pi* resonances were calculated and compared to previous theoretical and experimental results, showing good agreement for positions and widths. Feshbach/Core-excited resonances generated by attachment of an electron to a pipi* excited state of the bases were also calculated, providing for the first time accurate information for these resonances. Mixing between configurations corresponding to shape and Feshbach/core-excited resonances is present in all nucleobases, which complicates the theoretical treatment and necessitates multiconfigurational approaches for a proper description. PMID- 29614227 TI - Investigating the Secondary Structure of Membrane Peptides Utilizing Multiple 2H Labeled Hydrophobic Amino Acids via Electron Spin Echo Envelope Modulation (ESEEM) Spectroscopy. AB - An electron spin echo envelope modulation (ESEEM) approach was used to probe local secondary structures of membrane proteins and peptides. This ESEEM method detects dipolar couplings between 2H-labeled nuclei on the side chains of an amino acid (Leu or Val) and a strategically placed nitroxide spin-label in the proximity up to 8 A. ESEEM spectra patterns for different samples correlate directly to the periodic structural feature of different secondary structures. Since this pattern can be affected by the side chain length and flexibility of the 2H-labeled amino acid used in the experiment, it is important to examine several different hydrophobic amino acids (d3 Ala, d8 Val, d8 Phe) utilizing this ESEEM approach. In this work, a series of ESEEM data were collected on the AChR M2delta membrane peptide to build a reference for the future application of this approach for various biological systems. The results indicate that, despite the relative intensity and signal-to-noise level, all amino acids share a similar ESEEM modulation pattern for alpha-helical structures. Thus, all commercially available 2H-labeled hydrophobic amino acids can be utilized as probes for the further application of this ESEEM approach. Also, the ESEEM signal intensities increase as the side chain length gets longer or less rigid. In addition, longer side chain amino acids had a larger 2H ESEEM FT peak centered at the 2H Larmor frequency for the i +/- 4 sample when compared to the corresponding i +/- 3 sample. For shorter side chain amino acids, the 2H ESEEM FT peak intensity ratio between i +/- 4 and i +/- 3 was not well-defined. PMID- 29614228 TI - Temperature Dependence of the Air/Water Interface Revealed by Polarization Sensitive Sum-Frequency Generation Spectroscopy. AB - The temperature dependence of the vibrational sum-frequency generation (vSFG) spectra of the air/water interface is investigated using many-body molecular dynamics (MB-MD) simulations performed with the MB-pol potential energy function. The vSFG spectra calculated for different polarization combinations are then analyzed in terms of molecular autocorrelation and cross-correlation contributions. To provide molecular-level insights into interfacial hydrogen bonding topologies, which give rise to specific spectroscopic features, the vSFG spectra are further investigated by separating contributions associated with water molecules donating zero, one, or two hydrogen bonds to neighboring water molecules. This analysis suggests that the low frequency shoulder of the free OH peak which appears at ~3600 cm-1 is primarily due to intermolecular couplings between both singly and doubly hydrogen-bonded molecules. PMID- 29614229 TI - Comprehensive Database of Carotenoid Contents in Ibero-American Foods. A Valuable Tool in the Context of Functional Foods and the Establishment of Recommended Intakes of Bioactives. AB - Foods that are commonly consumed in the diet are considered to provide more than 40 different carotenoids. However, the content in carotenoids varies considerably in both qualitative and quantitative terms as a consequence of different genotypes, climatic conditions of the production area, and agronomic factors, among others. In this paper, analytical data, obtained by HPLC or UHPLC, of carotenoids in fruits and vegetables produced in Ibero-America have been compiled from peer-reviewed journals, organized in food categories, and documented in relation to the sampling and analytical quality system used. In addition to common products of the diet of the Ibero-American countries, other wild or little used fruit and vegetables have been included with the aim of contributing to promote and to value species and local varieties. The importance of the commodities containing carotenoids in food, health, agriculture, and biodiversity, and the need of their preservation, was evidenced in this work namely by the large differences in carotenoid content related to the locals of production and varieties, and the high levels of carotenoids in native fruits and vegetables. The contribution of these compounds to meet the needs of vitamin A as well as the necessity of establishing recommendation for the daily intakes of theses bioactive compounds were also discussed. PMID- 29614230 TI - How To Characterize Individual Nanosize Liposomes with Simple Self-Calibrating Fluorescence Microscopy. AB - Nanosize lipid vesicles are used extensively at the interface between nanotechnology and biology, e.g., as containers for chemical reactions at minute concentrations and vehicles for targeted delivery of pharmaceuticals. Typically, vesicle samples are heterogeneous as regards vesicle size and structural properties. Consequently, vesicles must be characterized individually to ensure correct interpretation of experimental results. Here we do that using dual-color fluorescence labeling of vesicles-of their lipid bilayers and lumens, separately. A vesicle then images as two spots, one in each color channel. A simple image analysis determines the total intensity and width of each spot. These four data all depend on the vesicle radius in a simple manner for vesicles that are spherical, unilamellar, and optimal encapsulators of molecular cargo. This permits identification of such ideal vesicles. They in turn enable calibration of the dual-color fluorescence microscopy images they appear in. Since this calibration is not a separate experiment but an analysis of images of vesicles to be characterized, it eliminates the potential source of error that a separate calibration experiment would have been. Nonideal vesicles in the same images were characterized by how their four data violate the calibrated relationship established for ideal vesicles. In this way, our method yields size, shape, lamellarity, and encapsulation efficiency of each imaged vesicle. Applying this procedure to extruded samples of vesicles, we found that, contrary to common assumptions, only a fraction of vesicles are ideal. PMID- 29614231 TI - Ligand Mediation of Vectorial Charge Transfer in Cu(I)diimine Chromophore Acceptor Dyads. AB - In this work, we present the photoinduced charge separation dynamics of four molecular dyads composed of heteroleptic Cu(I)bis(phenanthroline) chromophores linked directly to the common electron acceptor naphthalene diimide. The dyads were designed to allow us to (1) detect any kinetic preference for directionality during photoinduced electron transfer across the heteroleptic complex and (2) probe the influence of excited-state flattening on intramolecular charge separation. Singular value decomposition of ultrafast optical transient absorption spectra demonstrates that charge transfer occurs with strong directional preference, and charge separation occurs up to 35 times faster when the acceptor is linked to the sterically blocking ligand. Further, the charge separated state in these dyads is stabilized by polar solvents, resulting in dramatically longer lifetimes for dyads with minimal substitution about the Cu(I) center. This unexpected but exciting observation suggests a new approach to the design of Cu(I)bis(phenanthroline) chromophores that can support long-lived vectorial charge separation. PMID- 29614232 TI - On the Formation and Morphology of Lipid Nanoparticles Containing Ionizable Cationic Lipids and siRNA. AB - Lipid nanoparticles (LNPs) containing short interfering RNA (LNP-siRNA) and optimized ionizable cationic lipids are now clinically validated systems for silencing disease-causing genes in hepatocytes following intravenous administration. However, the mechanism of formation and certain structural features of LNP-siRNA remain obscure. These systems are formed from lipid mixtures (cationic lipid, distearoylphosphatidylcholine, cholesterol, and PEG lipid) dissolved in ethanol that is rapidly mixed with siRNA in aqueous buffer at a pH (pH 4) where the ionizable lipid is positively charged. The resulting dispersion is then dialyzed against a normal saline buffer to remove residual ethanol and raise the pH to 7.4 (above the p Ka of the cationic lipid) to produce the finished LNP-siRNA systems. Here we provide cryogenic transmission electron microscopy (cryo-TEM) and X-ray evidence that the complexes formed between siRNA and ionizable lipid at pH 4 correspond to tightly packed bilayer structures with siRNA sandwiched between closely apposed monolayers. Further, it is shown that ionizable lipid not complexed to siRNA promotes formation of very small vesicular structures at pH 4 that coalesce to form larger LNP structures with amorphous electron dense cores at pH 7.4. A mechanism of formation of LNP-siRNA systems is proposed whereby siRNA is first sandwiched between closely apposed lipid monolayers at pH 4 and subsequently trapped in these structures as the pH is raised to 7.4, whereas ionizable lipid not interacting with siRNA moves from bilayer structure to adopt an amorphous oil phase located in the center of the LNP as the pH is raised. This model is discussed in terms of previous hypotheses and potential relevance to the design of LNP-siRNA systems. PMID- 29614233 TI - The effect of speech-language pathology students on clinician time use and activity. AB - PURPOSE: This prospective study investigated the impact of supervising students on public health speech-language pathologists' (SLPs) time and patient activity levels in order to broaden evidence in the profession. METHOD: Thirty-four SLPs supervising students collected data profiling their time use and activity during the first, middle and penultimate placement week. They also collected data for a week when not supervising students. Pre- and post-placement surveys were used to supplement quantitative data with additional information such as clinician and student experience levels. RESULT: Overall clinical time (face-to-face and indirect) and the number of patients seen neither increased nor decreased during student placements. However, clinicians' use of time altered across placement periods. For example, SLP time delivering clinical services decreased but time observing students providing clinical services increased as the placement progressed. Some differences in time spent in non-clinical activities (e.g. student teaching and SLP administration) were found. Comparing data from placements with varying supervision models or student competence level showed few significant differences in time use, activity or productivity. CONCLUSION: There was no significant difference in overall clinical time used, nor patient activity or productivity whether clinicians were supervising students or not. Further research is required within SLP services. PMID- 29614234 TI - Naming Institutionalized Racism in the Public Health Literature: A Systematic Literature Review. AB - OBJECTIVES: Although a range of factors shapes health and well-being, institutionalized racism (societal allocation of privilege based on race) plays an important role in generating inequities by race. The goal of this analysis was to review the contemporary peer-reviewed public health literature from 2002-2015 to determine whether the concept of institutionalized racism was named (ie, explicitly mentioned) and whether it was a core concept in the article. METHODS: We used a systematic literature review methodology to find articles from the top 50 highest-impact journals in each of 6 categories (249 journals in total) that most closely represented the public health field, were published during 2002 2015, were US focused, were indexed in PubMed/MEDLINE and/or Ovid/MEDLINE, and mentioned terms relating to institutionalized racism in their titles or abstracts. We analyzed the content of these articles for the use of related terms and concepts. RESULTS: We found only 25 articles that named institutionalized racism in the title or abstract among all articles published in the public health literature during 2002-2015 in the 50 highest-impact journals and 6 categories representing the public health field in the United States. Institutionalized racism was a core concept in 16 of the 25 articles. CONCLUSIONS: Although institutionalized racism is recognized as a fundamental cause of health inequities, it was not often explicitly named in the titles or abstracts of articles published in the public health literature during 2002-2015. Our results highlight the need to explicitly name institutionalized racism in articles in the public health literature and to make it a central concept in inequities research. More public health research on institutionalized racism could help efforts to overcome its substantial, longstanding effects on health and well-being. PMID- 29614235 TI - The Evidence Base for the Maternal, Infant, and Early Childhood Home Visiting Program Constructs. AB - OBJECTIVES: The federal Maternal, Infant, and Early Childhood Home Visiting (MIECHV) program requires grantees to demonstrate program improvement as a condition of funding. The MIECHV program monitors grantee progress in federally mandated conceptual areas (ie, benchmarks) that are further subcategorized into related sub-areas or constructs (eg, breastfeeding). Each construct has an associated performance measure that helps MIECHV collect data on program implementation and performance. In 2016, MIECHV modified the constructs and associated performance measures required of grantees. Our objective was to identify whether the constructs were supported by the home visiting literature. METHODS: We conducted an evaluation of one of the MIECHV program's benchmarks (Benchmark 1: Maternal and Newborn Health) for alignment of the Benchmark 1 constructs (preterm birth, breastfeeding, depression screening, well-child visit, postpartum care, and tobacco cessation referrals) with home visiting evidence. In March 2016, we searched the Home Visiting Evidence of Effectiveness database for all publicly available articles on studies conducted in the United States to determine how well the study findings aligned with the MIECHV program constructs. RESULTS: Of 59 articles reviewed, only 3 of the 6 MIECHV constructs-preterm birth, breastfeeding, and well-child visits-were supported by home visiting evidence. CONCLUSIONS: This evaluation highlights a limited evidence base for the MIECHV Benchmark 1 constructs and a need to clarify other criteria, beyond evidence, used to choose constructs and associated performance measures. One implication of not having evidence-based performance measures is a lack of confidence that the program will drive positive outcomes. If performance measures are not evidence based, it is difficult to attribute positive outcomes to the home visiting services. PMID- 29614236 TI - Identifying Barriers to Collaboration Between Primary Care and Public Health: Experiences at the Local Level. AB - OBJECTIVES: Interest is increasing in collaborations between public health and primary care to address the health of a community. Although the understanding of how these collaborations work is growing, little is known about the barriers facing these partners at the local level. The objective of this study was to identify barriers to collaboration between primary care and public health at the local level in 4 states. METHODS: The study team, which comprised 12 representatives of Practice-Based Research Networks (networks of practitioners interested in conducting research in practice-based settings), identified 40 key informants from the public health and primary care fields in Colorado, Minnesota, Washington State, and Wisconsin. The key informants participated in standardized, semistructured telephone interviews with 8 study team members in 2014 and 2015. Interviews were audio recorded and transcribed verbatim. We analyzed key themes and subthemes by drawing on grounded theory. RESULTS: Primary care and public health participants identified similar barriers to collaboration. Barriers at the institutional level included the challenges of the primary care environment, in which providers feel overwhelmed and resources are tight; the need for systems change; a lack of partnership; and geographic challenges. Barriers to collaboration included mutual awareness, communication, data sharing, capacity, lack of resources, and prioritization of resources. CONCLUSIONS: Some barriers to collaboration (eg, changes to health care billing, demands on provider time) require systems change to overcome, whereas others (eg, a lack of shared priorities and mutual awareness) could be addressed through educational approaches, without adding resources or making a systemic change. Overcoming these common barriers may lead to more effective collaboration. PMID- 29614237 TI - Including a Novel Tobacco Product in Oregon's Indoor Clean Air Act: Lessons Learned for Clean Air Policy, 2015-2016. PMID- 29614238 TI - Changes in Lung Clearance Index in Preschool-aged Patients with Cystic Fibrosis Treated with Ivacaftor (GOAL): A Clinical Trial. PMID- 29614240 TI - Expression of ENPP3 in human cyclic endometrium: a novel molecule involved in embryo implantation. AB - Ectonucleotide pyrophosphatase-phosphodiesterase 3 (ENPP3), a protein detected in the human uterus, has been found to play an important role in the development and invasion of tumours. It was recently discovered that ENPP3 was upregulated during the window of implantation in the human endometrium but its functional relevance remains elusive. The objective was to determine ENPP3 expression in human endometrium and its roles in endometrial receptivity and embryo implantation. ENPP3 expression was analysed using immunohistochemistry and western blot assay. The effects of ENPP3 on embryo implantation were evaluated using a BeWo cell (a human choriocarcinoma cell line) spheroid attachment assay and BeWo cells were dual cultured with Ishikawa cells transfected with lentiviral vectors (LV5-NC or LV5-ENPP3) to mimic embryo implantation in a Transwell model. The effects of endometrial ENPP3 on factors related to endometrial receptivity were also determined. The results showed that ENPP3 was expressed in human endometrial epithelial cells and its expression levels changed during the menstrual cycle, peaking in the mid-secretory phase, corresponding to the time of embryo implantation. The overexpression of endometrial ENPP3 not only increased the embryo implantation rate but also had positive effects on the expression of factors related to endometrial receptivity in human endometrial cells. The results indicate that ENPP3 levels undergo cyclic changes in the endometrium and affect embryo adhesion and invasion via altering the expression of implantation factors in the human endometrium. Therefore, ENPP3 may play an important role in embryo implantation and may be a unique biomarker of endometrial receptivity. PMID- 29614239 TI - The Extracorporeal Life Support Organization Maastricht Treaty for Nomenclature in Extracorporeal Life Support. A Position Paper of the Extracorporeal Life Support Organization. AB - Extracorporeal life support (ECLS) was developed more than 50 years ago, initially with venoarterial and subsequently with venovenous configurations. As the technique of ECLS significantly improved and newer skills developed, complexity in terminology and advances in cannula design led to some misunderstanding of and inconsistency in definitions, both in clinical practice and in scientific research. This document is a consensus of multispecialty international representatives of the Extracorporeal Life Support Organization, including the North America, Latin America, EuroELSO, South West Asia and Africa, and Asia-Pacific chapters, imparting a global perspective on ECLS. The goal is to provide a consistent and unambiguous nomenclature for ECLS and to overcome the inconsistent use of abbreviations for ECLS cannulation. Secondary benefits are ease of multicenter collaboration in research, improved registry data quality, and clear communication among practitioners and researchers in the field. PMID- 29614241 TI - CASA-Mot technology: how results are affected by the frame rate and counting chamber. AB - For over 30 years, CASA-Mot technology has been used for kinematic analysis of sperm motility in different mammalian species, but insufficient attention has been paid to the technical limitations of commercial computer-aided sperm analysis (CASA) systems. Counting chamber type and frame rate are two of the most important aspects to be taken into account. Counting chambers can be disposable or reusable, with different depths. In human semen analysis, reusable chambers with a depth of 10um are the most frequently used, whereas for most farm animal species it is more common to use disposable chambers with a depth of 20um . The frame rate was previously limited by the hardware, although changes in the number of images collected could lead to significant variations in some kinematic parameters, mainly in curvilinear velocity (VCL). A frame rate of 60 frames s-1 is widely considered to be the minimum necessary for satisfactory results. However, the frame rate is species specific and must be defined in each experimental condition. In conclusion, we show that the optimal combination of frame rate and counting chamber type and depth should be defined for each species and experimental condition in order to obtain reliable results. PMID- 29614242 TI - Adverse reactions to tattoos in the general population of Denmark. PMID- 29614244 TI - Assessment of appropriate carbapenem prescribing in stewardship programmes. PMID- 29614243 TI - Safety and efficacy of a fixed combination of halobetasol and tazarotene in the treatment of moderate-to-severe plaque psoriasis: Results of 2 phase 3 randomized controlled trials. AB - BACKGROUND: Topical corticosteroids are the mainstay of psoriasis treatment, with long-term safety considerations limiting their use. Combining them with tazarotene may optimize their efficacy and minimize safety and tolerability concerns. OBJECTIVE: To investigate the safety and efficacy of halobetasol propionate 0.01% plus tazarotene 0.045% (HP/TAZ) lotion in moderate-to-severe plaque psoriasis. METHODS: Two multicenter, randomized, double-blind, vehicle controlled phase 3 studies (N = 418) were conducted. Subjects were randomized (2:1) to HP/TAZ lotion or vehicle once daily for 8 weeks with a 4-week follow-up. The primary efficacy assessment end point was treatment success (at least a 2 grade improvement from baseline in Investigator's Global Assessment score and a score of clear or almost clear). Safety and treatment-emergent adverse events were evaluated throughout. RESULTS: HP/TAZ lotion demonstrated statistically significant superiority over vehicle within as few as 2 weeks. By week 8, 35.8% (study 1) and 45.3% (study 2) of subjects were treatment successes compared with 7.0% and 12.5% of those treated with vehicle (P < .001). HP/TAZ lotion was also superior in reducing signs and symptoms of psoriasis and body surface area affected by psoriasis. The most frequently reported treatment-related adverse events were contact dermatitis (6.3%), application site pain (2.6%), and pruritus (2.2%). LIMITATIONS: Studies did not include subjects with more than 12% of their body surface area affected by psoriasis. CONCLUSIONS: HP/TAZ lotion was associated with significant reductions in the severity of the clinical signs of psoriasis, with no safety concerns. PMID- 29614245 TI - Respiratory syncytial virus burden among adults during flu season: an underestimated pathology. AB - BACKGROUND: Information on the role of respiratory syncytial virus (RSV) in adult patients with influenza-like syndrome is scarce. AIM: To assess the clinical characteristics of RSV in adult patients with respiratory manifestations during a regular influenza season. METHODS: Prospective study in a tertiary Spanish hospital from December 2015 to February 2016. The study population included only adult patients with either community-acquired or hospital/healthcare-associated influenza-like illness, according to the European Centre for Disease Prevention and Control criteria. Samples were analysed using a rapid molecular assay (Xpert(r) Flu/RSV). RSV-positive patients were compared with a randomly negative control group and with an influenza-positive control group. FINDINGS: Twelve hundred patients with influenza-like respiratory infection were included. Overall, 114 of the samples (9%) were positive for influenza and 95 (8%) were positive for RSV. When RSV-positive and influenza-positive patients were compared, RSV-positive patients were older (57.7 vs 48.9 years; P = 0.03), and their disease was more frequently healthcare-related (26/95, 27.3% vs 5/114, 1.7%; P < 0.001). They also had significantly more antibiotics prescribed (77/95, 81.0% vs 70/114, 61.4%; P < 0.001) and more frequently needed hospital admission (93/95, 97.8% vs 69/114, 60.5%; P < 0.001). Mortality was also significantly higher in RSV-positive patients (14/95, 14.7% vs 7/114, 6.1%; P = 0.04). CONCLUSION: RSV is a major cause of moderate-to-severe respiratory infection during the influenza season; acquisition is frequently nosocomial or healthcare related; and mortality is significantly higher than with influenza virus infection. The use of a rapid molecular test as a first-step diagnostic technique is necessary to ensure that isolation measures are implemented and that spread is prevented. PMID- 29614246 TI - Recurrent outbreaks caused by the same Salmonella enterica serovar Infantis clone in a German rehabilitation oncology clinic from 2002 to 2009. AB - BACKGROUND: Repeated outbreaks of salmonellosis caused by Salmonella enterica serovar Infantis at a rehabilitation clinic in Germany were investigated microbiologically from August 2002 to August 2009. AIM: To identify the sources of transmission and characterize the S. enterica serovar Infantis isolates. METHODS: Associated with these outbreaks, isolates from 98 patients, two kitchen staff, five food samples, four swabs of kitchen facilities, three samples of chicken faeces and one sample of sewage water were evaluated by phage typing. All S. enterica serovar Infantis isolates investigated (N=113) were related to phage type (PT) 29. Additionally, 44 of the 113 isolates were selected at random for typing by XbaI macrorestriction and pulsed-field gel electrophoresis (PFGE). FINDINGS: Typing of the 44 isolates showed that the recurrent infections were caused by the single clone PT 29/XB27+44 (42/44, 95.5%). The most likely route of transmission was only identified in the last outbreak in 2009 within the present study. It was found to be cross-contamination in the kitchen facilities (emanating from a contaminated wooden panel), in combination with carriers among the kitchen staff. CONCLUSIONS: This study demonstrated important details of hospital-specific epidemiological processes, and alludes to a long-term reservoir of an epidemic clone of S. enterica serovar Infantis either in a backyard flock of poultry or in an inanimate kitchen reservoir. PMID- 29614247 TI - Pseudomonas aeruginosa adapts to octenidine in the laboratory and a simulated clinical setting, leading to increased tolerance to chlorhexidine and other biocides. AB - BACKGROUND: Octenidine is frequently used for infection prevention in neonatal and burn intensive care units, where Pseudomonas aeruginosa has caused nosocomial outbreaks. AIM: To investigate the efficacy and impact of using octenidine against P. aeruginosa. METHODS: Seven clinical isolates of P. aeruginosa were exposed to increasing concentrations of octenidine over several days. Fitness, minimum bactericidal concentrations after 1 min, 5 min and 24 h, and minimum inhibitory concentrations (MICs) of a variety of antimicrobials were measured for the parental and octenidine-adapted P. aeruginosa strains. Octenidine and chlorhexidine MICs of a population of P. aeruginosa isolated from a hospital drain trap, exposed to a diluted octenidine formulation four times daily for three months, were also tested. FINDINGS: Some planktonic cultures of P. aeruginosa survived >50% of the working concentration of an in-use octenidine formulation at the recommended exposure time. Seven strains of P. aeruginosa stably adapted following continuous exposure to increasing concentrations of octenidine. Adaptation increased tolerance to octenidine formulations and chlorhexidine up to 32-fold. In one strain, it also led to increased MICs of antipseudomonal drugs. Subsequent to continuous octenidine exposure of a multi species community in a simulated clinical setting, up to eight-fold increased tolerance to octenidine and chlorhexidine of P. aeruginosa was also found, which was lost upon removal of octenidine. CONCLUSION: Incorrect use of octenidine formulations may lead to inadequate decontamination, and even increased tolerance of P. aeruginosa to octenidine, with resulting cross-resistance to other biocides. PMID- 29614248 TI - Comparative testing of HPV L1 protein monoclonal antibody panel for the detection of HPV in cervical exfoliated cells. AB - AIMS: To determine the value of a monoclonal antibody panel against a C-terminal conserved sequence polypeptide of human papillomavirus (HPV) L1 (a major capsid protein) for the detection of HPV in cervical exfoliated cells, as well as the potential of this antibody panel to be developed into an assay kit for the clinical screening of cervical cancer. METHODS: Cervical exfoliated cells were collected at a gynecology clinic. One part of each sample was sent to the Department of Pathology for HPV genotyping, and the other part was sent to the Department of Pathology for cytologic testing and then to the laboratory for immunological histological chemistry (IHC) assay in which an HPV L1 C-terminal conserved sequence polypeptide-induced mouse monoclonal antibody panel was used to detect HPV L1. RESULTS: Cervical cell samples were collected from 514 patients at the gynecology clinic; of these, 339 samples were sent for HPV genotyping, and 220 were HPV positive (64.90%, 220/339). Moreover, the duplicate samples from these 339 patients were sent for IHC assay, and 229 samples were positive (67.55%, 229/339). The IHC result was concordant with that obtained by HPV genotyping (Kappa = 0.743, p < 0.001). CONCLUSION: This study showed that use of the HPV L1 C-terminal conserved sequence polypeptide-induced mouse monoclonal antibody panel was of great value for the detection of HPV in cervical cells; the resulting detection rate was comparable to that obtained using the commercial HPV genotyping kit that is currently in use in clinical practice. PMID- 29614249 TI - Elavl3 regulates neuronal polarity through the alternative splicing of an embryo specific exon in AnkyrinG. AB - Alternative splicing of RNAs diversifies the functionalities of proteins, and it is optimized for each cell type and each developmental stage. nElavl (composed of Elavl2, Elavl3, and Elavl4) proteins are the RNA-binding proteins that is specifically expressed in neurons, regulate the alternative splicing of target RNAs, and promote neuronal differentiation and maturation. Recent studies revealed that Elavl3 knockout (Elavl3-/-) mice completely lost the expression of nElavl proteins in the Purkinje cells and exhibited cerebellar dysfunction. Here, we found that the alternative splicing of AnkyrinG exon 34 was misregulated in the cerebella of Elavl3-/- mice. AnkyrinG is an essential factor for the formation of neuronal polarity and is required for normal neuronal functions. We revealed that exon 34 of AnkyrinG was normally included in immature neurons and was mostly excluded in mature neurons; however, it was included in the cerebella of Elavl3-/- mice even in adulthood. In the Purkinje cells of adult Elavl3-/- mice, the length of the AnkyrinG-positive region shortened and somatic organelles leaked into the axons. These results suggested that exon 34 of AnkyrinG is an embryonic-stage-preferential exon that should be excluded from mature neurons and that Elavl3 regulates neuronal polarity through alternative splicing of this exon. PMID- 29614250 TI - Paternal physical exercise demethylates the hippocampal DNA of male pups without modifying the cognitive and physical development. AB - Maternal exercise is known to have beneficial effects in progeny development, but the influence of paternal exercise on the offspring still unclear. Since spermatogenesis is a continuous process, the father's life experiences can reprogram epigenetic content of the sperm and somehow interfere on offspring phenotype. This study was designed to evaluate the effects of paternal physical exercise on cognitive and physical development and on hippocampal DNA methylation levels of the offspring. Adult male Wistar rats were divided into two groups: sedentary and exercised. The exercise protocol occurred before mating and consisted of treadmill running, 5 consecutive days/week for 8 weeks (20 min/day). The mothers were not trained. The following developmental parameters were examined in male offspring: body growth, physical and cognitive performance, weights of adrenal glands, gonadal fat and hindlimb muscles, BDNF expression and global DNA methylation at the hippocampus. The progeny of trained and sedentary fathers did not differ in relation to physical parameters and performance, spatial memory and BDNF expression. However, paternal exercise promoted a decrease in offspring's relative gonadal fat weight and a lower percentage of global hippocampal DNA methylation compared to offspring of sedentary fathers. These results pointed to interference of male physical activity at the time of conception on adiposity and hippocampal epigenetic reprogramming of male offspring. The data reinforces that exercise does not harm the descendant's development and emphasize the benefits to include the practice of physical exercise in a healthier lifestyle of the parents. Nevertheless, future studies are necessary and should investigate further the long-effects of epigenetic mechanisms in order to elucidate the father's contribution in fetal programming. PMID- 29614251 TI - Complete genome sequence of Bacillus thuringiensis L-7601, a wild strain with high production of melanin. AB - Bacillus thuringiensis L-7601 (B. thuringiensis L-7601), belonging to Bacillus thuringiensis subsp. dendrolimus serotype H4a4b, is a wild-type strain which has the ability to produce melanin during the exponential phase of growth. The melanin produced is an excellent UV protective agent for the crystal insecticidal proteins. Here, we report the complete genome of B. thuringiensis L-7601 including one 5,790,408 bp chromosome and three plasmids. 6,519 CDSs and 150 RNA genes, including 106 tRNA genes, 39 rRNA genes and 5 ncRNA genes, were identified from the whole genome. In addition, our results indicated that homogentisic acid pathway is the melanogenic pathway in B. thuringiensis and accumulation of melanin is the consequence of hmgA frameshift mutant. PMID- 29614252 TI - Hemispheric processing in conventional metaphor comprehension: The role of general knowledge. AB - This study explored the relation between general knowledge and the hemispheric processing of metaphoric expressions in college age students. We hypothesized that prior knowledge influences how the hemispheres process metaphors in these individuals. In this study, 97 young (college-aged) adults completed a general knowledge and vocabulary test, and were then divided into high-knowledge/high vocabulary and low-knowledge/low-vocabulary groups. Next, participants viewed word pairs consisting of conventional metaphors, novel metaphors, word pairs with a literal meaning, and unrelated word pairs. The first word in each pair was presented centrally, and the second was presented to the right visual field-left hemisphere (rvf-LH) or the left visual field-right hemisphere (lvf-RH), and participants indicated whether each pair was a meaningful expression. Accuracy results showed an interaction between general knowledge and visual-field hemisphere. Low-knowledge participants were more accurate for metaphors presented to the rvf-LH than the lvf-RH, whereas high-knowledge participants showed no accuracy differences between the hemispheres. We also found an interaction between vocabulary and visual field-hemisphere for conventional metaphors. Specifically, low-vocabulary participants showed a left-hemisphere accuracy advantage, but high-vocabulary participants showed similar accuracy patterns in both hemispheres. These results suggest that young adult readers who have more general knowledge process conventional metaphors similarly in both hemispheres, whereas young adult readers who have less general knowledge may rely more heavily on left-hemisphere processes during conventional metaphor comprehension. PMID- 29614253 TI - Understanding the mechanisms of familiar voice-identity recognition in the human brain. AB - Humans have a remarkable skill for voice-identity recognition: most of us can remember many voices that surround us as 'unique'. In this review, we explore the computational and neural mechanisms which may support our ability to represent and recognise a unique voice-identity. We examine the functional architecture of voice-sensitive regions in the superior temporal gyrus/sulcus, and bring together findings on how these regions may interact with each other, and additional face sensitive regions, to support voice-identity processing. We also contrast findings from studies on neurotypicals and clinical populations which have examined the processing of familiar and unfamiliar voices. Taken together, the findings suggest that representations of familiar and unfamiliar voices might dissociate in the human brain. Such an observation does not fit well with current models for voice-identity processing, which by-and-large assume a common sequential analysis of the incoming voice signal, regardless of voice familiarity. We provide a revised audio-visual integrative model of voice identity processing which brings together traditional and prototype models of identity processing. This revised model includes a mechanism of how voice identity representations are established and provides a novel framework for understanding and examining the potential differences in familiar and unfamiliar voice processing in the human brain. PMID- 29614254 TI - Mechanistic studies of a cell-permeant peptide designed to enhance myosin light chain phosphorylation in polarized intestinal epithelia. AB - Tight junction (TJ) structures restrict the movement of solutes between adjacent epithelial cells to maintain homeostatic conditions. A peptide, termed PIP 640, with the capacity to regulate the transient opening of intestinal TJ structures through an endogenous mechanism involving the induction of myosin light chain (MLC) phosphorylation at serine 19 (MLC-pS19) has provided a promising new method to enhance the in vivo oral bioavailability of peptide therapeutics. PIP 640 is a decapeptide composed of all D-amino acids (rrdykvevrr-NH2) that contains a central sequence designed to emulates a specific domain of C-kinase potentiated protein phosphatase-1 inhibitor-17 kDa (CPI-17) surrounded by positively-charged amino acids that provide a cell penetrating peptide (CPP)-like character. Here, we examine compositional requirements of PIP 640 with regard to its actions on MLC phosphorylation, its intracellular localization to TJ structures, and its interactions with MLC phosphatase (MLCP) elements that correlate with enhanced solute uptake. These studies showed that a glutamic acid and tyrosine within this peptide are critical for PIP 640 to retain its ability to increase MLC-pS19 levels and enhance the permeability of macromolecular solutes of the size range of therapeutic peptides without detectable cytotoxicity. On the other hand, exchange of the aspartic acid for alanine and then arginine resulted in an increasingly greater bias toward protein phosphatase-1 (PP1) relative to MLCP inhibition, an outcome that resulted in increased paracellular permeability for solutes in the size range of therapeutic peptides, but with a significant increase in cytotoxicity. Together, these data further our understanding of the composition requirements of PIP 640 with respect to the desired goal of transiently altering the intestinal epithelial cell paracellular barrier properties through an endogenous mechanism, providing a novel approach to enhance the oral bioavailability of poorly absorbed therapeutic agents of < ~ 5 kDa. PMID- 29614255 TI - The other myeloperoxidase: Emerging functions. AB - Myeloperoxidase (MPO) is a member of the mammalian peroxidase family. It is mainly expressed in neutrophils, monocytes and macrophages. As a catalyzer of reactive oxidative species and radical species formation, it contributes to neutrophil bactericidal activity. Nevertheless MPO invalidation does not seem to have major health consequences in affected individuals. This suggests that MPO might have alternative functions supporting its conservation during evolution. We will review the available data supporting these non-canonical functions in terms of tissue specific expression, function and enzymatic activity. Thus, we discuss its cell type specific expression. We review in between others its roles in angiogenesis, endothelial (dys-) function, immune reaction, and inflammation. We summarize its pathological actions in clinical conditions such as cardiovascular disease and cancer. PMID- 29614256 TI - Interactions of staphyloxanthin and enterobactin with myeloperoxidase and reactive chlorine species. AB - When neutrophils engulf bacteria, myeloperoxidase converts hydrogen peroxide to hypochlorous acid, which is toxic to all micro-organisms. It has been suggested that some pathogens have virulence factors that target myeloperoxidase to dampen the oxidative reactions of neutrophils. These virulence factors include staphyloxanthin, the golden pigment of Staphylococcus aureus, and enterobactin - a siderophore released by gram-negative bacteria. We investigated the potential of staphyloxanthin and enterobactin to shield bacteria from hypochlorous acid and related chloramines. Clinical strains of S. aureus with high levels of staphyloxanthin and related carotenoids were in general more resistant to low doses of hypochlorous acid than non-pigmented bacteria. But some non-pigmented strains were also resistant to the oxidant. Doses of reactive chlorine species that killed bacteria also bleached their carotenoids. Hypochlorous acid, NH2Cl, and NHCl2 bleached purified staphyloxanthin. When S. aureus were phagocytosed by neutrophils there was no discernible loss of staphyloxanthin. These data suggest that staphyloxanthin is capable of protecting bacteria from low doses of reactive chlorine species formed inside phagosomes. Enterobactin was not an inhibitor of myeloperoxidase. We conclude that staphyloxanthin may protect some bacterial strains against oxidative killing by neutrophils, but enterobactin will not inhibit the production of hypochlorous acid. PMID- 29614257 TI - Which Valve? Sutureless, Stentless or TAVI? PMID- 29614258 TI - The Visionaries, the Virtuosos, and the History of Congenital Esophageal Atresia Surgery. AB - The year 2018 marks the 130th anniversary of the first known surgical attempt at correction of esophageal atresia, performed by Charles Steele. But before the first successful procedure happened, many other surgeons undertook heroic attempts to save newborns and infants with this defect. Two hundred seventy-one years passed from the first description of the defect to the first surgery survivor. This paper presents a fascinating history of these milestones in pediatric surgery and of its pioneers whose creativity, mastery, and fantasy created a basis of congenital esophageal atresia surgery. PMID- 29614259 TI - Isolated Mediastinal Lymphadenopathy Caused by Rhodococcus equi Infection. AB - Mediastinal lymphadenopathy is common finding in thoracic surgery, and it often requires morphologic confirmation to establish the definitive diagnosis. The most frequent diagnoses are metastatic lung cancer, sarcoidosis, lymphoma, tuberculosis, and other causes of granulomatous infections. Rhodococcus equi is a rare pathogen in humans that mostly affects immunocompromised patients. This report presents a case with isolated mediastinal lymphadenopathy caused by Rhodococcus equi infection in a 71-year-old immunocompetent patient. PMID- 29614260 TI - Primary Hydatid Cyst of the Thoracic Aorta Revealed by Peripheral Arterial Embolism. AB - Primitive aortic hydatidosis is exceptional. We report the case of a 55-year-old woman who had pain in her left lower limb for a week. A computed tomographic angiogram showed a multivesicular and fluid-density mass intimately contiguous to the descending thoracic aorta seen on an endoluminal subtraction image and hydatid cysts in the spleen. The surgical approach was through a thoracophrenolombotomy with right femorofemoral bypass. Complete resection of the destroyed aortic portion was performed, and continuity was restored by an aortoaortic bypass using a Dacron (INVISTA, Kennesaw, Georgia) prosthesis. Hydatid fragments were evacuated after thrombectomy of the left iliac artery. The surgical procedure was completed by a splenectomy. Postoperative follow-up was uneventful. After 6 months, computed tomographic angiography showed a patent bypass. PMID- 29614261 TI - The novel CaMKII inhibitor GS-680 reduces diastolic SR Ca leak and prevents CaMKII-dependent pro-arrhythmic activity. AB - RATIONALE: Ca/calmodulin-dependent protein kinase II (CaMKII) was shown to increase diastolic sarcoplasmic reticulum (SR) Ca leak, which can result in delayed afterdepolarizations and triggered arrhythmias. Since increased CaMKII expression and activity has been mechanistically linked to arrhythmias in human heart failure (HF) and atrial fibrillation (AF), specific strategies aimed at CaMKII inhibition may have therapeutic potential. OBJECTIVE: We tested the antiarrhythmic and inotropic effects of a novel selective and ATP-competitive CaMKII inhibitor (GS-680). METHODS AND RESULTS: Trabeculae were isolated from right atrial appendage biopsies of patients undergoing cardiac surgery. Premature atrial contractions (PACs) were induced by stimulation with isoproterenol (ISO, 100 nM) at increased [Ca]o (3.5 mM). Interestingly, compared to vehicle, PACs were significantly inhibited by exposure to GS-680 (at 100 and 300 nM). GS-680 also significantly decreased early and delayed afterdepolarizations in isolated human atrial myocytes. Moreover, GS-680 (at 100 or 300 nM) significantly inhibited diastolic SR Ca leak, measured as frequency of spontaneous SR Ca release events (Ca sparks) in isolated human atrial myocytes (Fluo-4 loaded) similar to the well-established peptide CaMKII inhibitor AIP. In accordance, GS 680 significantly reduced CaMKII autophosphorylation (Western blot) but enhanced developed tension after 10 or 30 s pause of electrical stimulation (post-rest behavior). Surprisingly, we found a strong negative inotropic effect of GS-680 in atrial trabeculae at 1 Hz stimulation rate, which was not observed at 4 Hz and abolished by beta-adrenergic stimulation. In contrast, GS-680 did not impair systolic force of isolated ventricular trabeculae from explanted hearts of heart transplant recipients at 1 Hz, blunted the negative force-frequency relationship (1-3 Hz) and significantly increased the Ca transient amplitude. CONCLUSION: The novel ATP-competitive and selective CaMKII inhibitor GS-680 inhibits pro arrhythmic activity in human atrium and improves contractility in failing human ventricle, which may have therapeutic implications. PMID- 29614262 TI - Cost-effectiveness analysis comparing lumen-apposing metal stents with plastic stents in the management of pancreatic walled-off necrosis. AB - BACKGROUND AND AIMS: EUS-guided transmural drainage is effective in the management of pancreatic walled-off necrosis (WON). A lumen-apposing metal stent (LAMS) has recently been developed specifically for the drainage of pancreatic fluid collections that shows promising results. However, no cost-effectiveness data have been published in comparison with endoscopic drainage with traditional plastic stents (PSs). Our aim here was to compare the cost-effectiveness of LAMSs to PSs in the management of WON. METHODS: A decision tree was developed to assess both LAMSs and PSs over a 6-month time horizon. For each strategy, after the insertion of the respective stents, patients were followed for subsequent need for direct endoscopic necrosectomy, adverse events requiring unplanned endoscopy, percutaneous drainage (PCD), or surgery using probabilities obtained from the literature. The unit of effectiveness was defined as successful endoscopic drainage without the need for PCD or surgery. Costs in 2016 U.S.$ were based on inpatient institutional costs. Sensitivity analyses were performed. An a priori willingness-to-pay threshold of U.S.$50,000 was established. RESULTS: LAMSs were found to be more efficacious than PSs, with 92% and 84%, respectively, of the patients achieving successful endoscopic drainage of WON. LAMSs, however, were more costly: the average cost per patient of U.S.$20,029 compared with U.S.$15,941 for PSs. The incremental cost-effectiveness ratio favored LAMSs at U.S.$49,214 per additional patient successfully treated. Sensitivity analyses confirmed the robustness of the results. CONCLUSION: LAMSs are more effective but also more costly than PSs in managing WON. Data from high-quality, adequately controlled, prospective, randomized trials are needed to confirm our findings. PMID- 29614263 TI - New technologies improve adenoma detection rate, adenoma miss rate, and polyp detection rate: a systematic review and meta-analysis. AB - BACKGROUND AND AIMS: The need to increase the adenoma detection rate (ADR) for colorectal cancer screening has ushered in devices that mechanically or optically improve conventional colonoscopy. Recently, new technology devices (NTDs) have become available. We aimed to compare the ADR, polyp detection rate (PDR), and adenoma miss rate (AMR) between NTDs and conventional colonoscopy and between mechanical and optical NTDs. METHODS: MEDLINE and Embase databases were searched from inception through September 2017 for articles or abstracts reporting ADR, PDR, and AMR with NTDs. Randomized controlled trials and case-control studies with >10 subjects were included. Primary outcomes included ADR, PDR, and AMR odds ratio (OR) between conventional colonoscopy and NTDs. Secondary outcomes included cecal intubation rates, adverse events, cecal intubation time, and total colonoscopy time. RESULTS: From 141 citations, 45 studies with 20,887 subjects were eligible for >=1 analyses. Overall, the ORs for ADR (1.35; 95% confidence interval [CI] 1.24-1.47; P < .01) and PDR (1.51; 95% CI, 1.37-1.67; P < .01) were higher with NTDs. Higher ADR (OR, 1.52 vs 1.25; P = .035) and PDR (OR, 1.63 vs 1.10; P <= .01) were observed with mechanical NTDs. The overall AMR with NTDs was lower compared with conventional colonoscopy (OR, .19; 95% CI, .14-.26; P < .01). Mechanical NTDs had lower AMRs compared with optical NTDs (OR, .10 vs .33; P < .01). No differences in cecal intubation rates, cecal intubation time, or total colonoscopy time were found. CONCLUSIONS: Newer endoscopic technologies are an effective option to improve ADR and PDR and decrease AMR, particularly with mechanical NTDs. No differences in operability and safety were found. PMID- 29614264 TI - Spatial correlation as an early warning signal of regime shifts in a multiplex disease-behaviour network. AB - Early warning signals of sudden regime shifts are a widely studied phenomenon for their ability to quantify a system's proximity to a tipping point to a new and contrasting dynamical regime. However, this effect has been little studied in the context of the complex interactions between disease dynamics and vaccinating behaviour. Our objective was to determine whether critical slowing down (CSD) occurs in a multiplex network that captures opinion propagation on one network layer and disease spread on a second network layer. We parameterized a network simulation model to represent a hypothetical self-limiting, acute, vaccine preventable infection with short-lived natural immunity. We tested five different network types: random, lattice, small-world, scale-free, and an empirically derived network. For the first four network types, the model exhibits a regime shift as perceived vaccine risk moves beyond a tipping point from full vaccine acceptance and disease elimination to full vaccine refusal and disease endemicity. This regime shift is preceded by an increase in the spatial correlation in non-vaccinator opinions beginning well before the bifurcation point, indicating CSD. The early warning signals occur across a wide range of parameter values. However, the more gradual transition exhibited in the empirically-derived network underscores the need for further research before it can be determined whether trends in spatial correlation in real-world social networks represent critical slowing down. The potential upside of having this monitoring ability suggests that this is a worthwhile area for further research. PMID- 29614265 TI - Pharmacokinetic/pharmacodynamic modeling of combination-chemotherapy for lung cancer. AB - Chemotherapy for non-small cell lung cancer (NSCLC) typically involves a doublet regimen for a number of cycles. For any particular patient, a course of treatment is usually chosen from a large number of combinational protocols with drugs in concomitant or sequential administration. In spite of newer drugs and protocols, half of patients with early disease will live less than five years and 95% of those with advanced disease survive for less than one year. Here, we apply mathematical modeling to simulate tumor response to multiple drug regimens, with the capability to assess maximum tolerated dose (MTD) as well as metronomic drug administration. We couple pharmacokinetic-pharmacodynamic intracellular multi compartment models with a model of vascularized tumor growth, setting input parameters from in vitro data, and using the models to project potential response in vivo. This represents an initial step towards the development of a comprehensive virtual system to evaluate tumor response to combinatorial drug regimens, with the goal to more efficiently identify optimal course of treatment with patient tumor-specific data. We evaluate cisplatin and gemcitabine with clinically-relevant dosages, and simulate four treatment NSCLC scenarios combining MTD and metronomic therapy. This work thus establishes a framework for systematic evaluation of tumor response to combination chemotherapy. The results with the chosen parameter set indicate that although a metronomic regimen may provide advantage over MTD, the combination of these regimens may not necessarily offer improved response. Future model evaluation of chemotherapy possibilities may help to assess their potential value to obtain sustained NSCLC regression for particular patients, with the ultimate goal of optimizing multiple-drug chemotherapy regimens in clinical practice. PMID- 29614266 TI - Genetic engineering in primary human B cells with CRISPR-Cas9 ribonucleoproteins. AB - Genome editing in human cells with targeted nucleases now enables diverse experimental and therapeutic genome engineering applications, but extension to primary human B cells remains limited. Here we report a method for targeted genetic engineering in primary human B cells, utilizing electroporation of CRISPR Cas9 ribonucleoproteins (RNPs) to introduce gene knockout mutations at protein coding loci with high efficiencies that in some cases exceeded 80%. Further, we demonstrate knock-in editing of targeted nucleotides with efficiency exceeding 10% through co-delivery of oligonucleotide templates for homology directed repair. We delivered Cas9 RNPs in two distinct in vitro culture systems to achieve editing in both undifferentiated B cells and activated B cells undergoing differentiation, reflecting utility in diverse experimental conditions. In summary, we demonstrate a powerful and scalable research tool for functional genetic studies of human B cell biology that may have further applications in engineered B cell therapeutics. PMID- 29614267 TI - Influence of delayed sample processing on blood immune cell phenotypes, immune cell responses and serum anti-influenza vaccine antibody titres. AB - Provision of blood from distant research partners to a central laboratory can result in delayed blood processing prior to assessment of immune parameters. It is important to evaluate the effect of such delays on immune parameters. This study investigated the effect of storage of blood at room temperature for up to 72 h prior to processing and analysis on a range of immune parameters. Blood was collected from 10 healthy participants and analysed immediately (day 0) or after storage at room temperature for 24, 48 or 72 h (days 1, 2 and 3). A full blood count, immune cell phenotypes (flow cytometry), plasma cytokines, chemokines and soluble receptors (multiplex immunoassay), neutrophil and monocyte phagocytosis (flow cytometry), whole blood cytokine responses to stimulation and antibody titres to the seasonal influenza vaccine were assessed. The full blood count, most immune cell phenotypes, monocyte phagocytosis and anti-influenza vaccine antibody titres were little affected by blood storage of <=72 h prior to processing. Plasma cytokine concentrations increased with blood storage time while whole blood responses to stimulation with lipopolysaccharide or phytohaemagglutinin decreased with blood storage time. In conclusion, while fresh blood is optimal for analysing human immune parameters, it is possible to store blood for up to 72 h at room temperature and obtain reliable measures of several immune markers. However, plasma cytokines and related mediators as well as whole blood cultures should be analysed using freshly isolated blood. Storage of blood for longer than one day may result in the unreliable assessment of these outcomes. PMID- 29614268 TI - Loss of RapC causes defects in cytokinesis, cell migration, and multicellular development of Dictyostelium. AB - The small GTPase Ras proteins are involved in diverse cellular processes. We investigated the functions of RapC, one of 15 Ras subfamily GTPases in Dictyostelium. Loss of RapC resulted in a spread shape of cells; severe defects in cytokinesis leading to multinucleation; decrease of migration speed in chemoattractant-mediated cell migration, likely through increased cell adhesion; and aberrations in multicellular development producing abnormal multiple tips from one mound and multi-branched developmental structures. Defects in cells lacking RapC were rescued by expressing GFP-RapC in rapC null cells. Our results demonstrate that RapC, despite its high sequence homology with Rap1, plays a negative role in cell spreading and cell adhesion, in contrast to Rap1, which is a key regulator of cell adhesion and cytoskeleton rearrangement. In addition, RapC appears to have a unique function in multicellular development and is involved in tip formation from mounds. This study contributes to the understanding of Ras-mediated cellular processes. PMID- 29614269 TI - Celastrol inhibits cancer metastasis by suppressing M2-like polarization of macrophages. AB - In recent years, a large amount of clinical and experimental data has shown that M2-like polarized tumor-associated macrophages (TAMs) play an important role in cancer metastasis. Therefore, TAMs, especially M2-like TAMs is a promising target for anti-tumor metastasis therapy. Here, we found that celastrol dose-dependently suppressed IL-13 induced CD206 expression both in RAW264.7 and in primary macrophages. Consistently, celastrol also inhibited the expression of M2-like specific genes, including MRC1, Arg1, Fizz1, Mgl2 and CD11c. Further, by the employment of 4T1 breast cancer model, we found that celastrol significantly prevented cancer metastasis in vivo. Mechanistically, celastrol completely ameliorated STAT6 phosphorylation, which is the key signal molecule responsible for M2 polarization. Our research puts forward a new application of celastrol in anti-cancer metastasis, by intervening M2-like polarization through inhibiting STAT6. PMID- 29614271 TI - The issue of the multipotency of the neural crest cells. AB - In the neural primordium of vertebrate embryos, the neural crest (NC) displays a unique character: the capacity of its component cells to leave the neural primordium, migrate along definite (and, for long, not identified) routes in the developing embryo and invade virtually all tissues and organs, while producing a large array of differentiated cell types. The most striking diversity of the NC derivatives is found in its cephalic domain that produces, not only melanocytes and peripheral nerves and ganglia, but also various mesenchymal derivatives (connective tissues, bones, cartilages...) which, in other parts of the body, are mesoderm-derived. The aim of this article was to review the large amount of work that has been devoted to solving the problem of the differentiation capacities of individual NC cells (NCC) arising from both the cephalic and trunk levels of the neural axis. A variety of experimental designs applied to NCC either in vivo or in vitro are evaluated, including the possibility to culture them in crestospheres, a technique previously designed for cells of the CNS, and which reinforces the notion, previously put forward, of the existence of NC stem cells. At the trunk level, the developmental potentialities of the NCC are more restricted than in their cephalic counterparts, but, in addition to the neural melanocytic fate that they exclusively express in vivo, it was clearly shown that they harbor mesenchymal capacities that can be revealed in vitro. Finally, a large amount of evidence has been obtained that, during the migration process, most of the NCC are multipotent with a variable array of potentialities among the cells considered. Investigations carried out in adults have shown that multipotent NC stem cells persist in the various sites of the body occupied by NCC. Enlightening new developments concerning the invasive capacity of NCC, the growing peripheral nerves were revealed as migration routes for NCC travelling to distant ventrolateral regions of the body. Designated "Schwann cell precursors" in the mouse embryo, these NCC can leave the nerves and are able to convert to a novel fate. The convertibility of the NC-derived cells, particularly evident in the Schwann cell-melanocyte lineage transition, has also been demonstrated for neuroendocrine cells of the adult carotid body and for the differentiation of parasympathetic neurons of ganglia distant from their origin, the NC. All these new developments attest the vitality of the research on the NC, a field that characterizes vertebrate development and for which the interest has constantly increased during the last decades. PMID- 29614270 TI - DNA damage response signaling does not trigger redistribution of SAMHD1 to nuclear foci. AB - SAMHD1 (Sterile alpha motif and histidine-aspartic acid (HD) domain containing protein 1) is a deoxyribonucleoside triphosphate (dNTP) triphosphohydrolase (dNTPase) that restricts viral replication in infected cells. This protein is also involved in DNA repair by assisting in DNA end resection by homologous recombination (HR) after DNA double-strand break (DSB) induction with camptothecin (CPT) or etoposide (ETO). We showed that a monoclonal anti-SAMHD1 antibody produced against the full-length protein detected an unspecific 50 kDa protein that colocalized with dot-like structures after CPT treatment in HeLa cells. In contrast, a polyclonal anti-SAMHD1 antibody raised against the N terminus of this protein specifically detected SAMHD1, as shown in Jurkat, HAP1KO and HEK293T SAMHD1-siRNA cell lysates compared with their respective controls. Our findings showed that SAMHD1 is not localized in dot-like structures under DSB induction in HeLa cells. PMID- 29614272 TI - Sun-Protection Behavior, Pubertal Development and Menarche: Factors Influencing the Melanocytic Nevi Development-The Results of an Observational Study of 1,512 Children. AB - Observational studies consistently show that melanocytic nevus prevalence increases with age and that phenotypic traits are significantly associated with nevus count in children. An observational study of 1,512 children and adolescents from 2010 to 2013 was conducted. Study dermatologists counted the full body, arm, and facial nevi of each participant. Children and their parents were asked to complete a survey to gather data on personal characteristics, pubertal development, and early-life sun exposure. The main aim of the study was to establish pediatric nevus prevalence and its relationship with age, phenotype, sex, menarche, early-life sun exposure, and sun-protection behaviors. Females had a significantly lower nevus count compared with males, but this sex-related difference was significantly modified by menarche. Sun exposure and sun protection habits were all significantly associated with nevus count; in particular, children who used sunscreen with a sun-protection factor > 30 had a lower nevus count compared with sun-protection factor <= 30 sunscreen users. This study shows that sex, menarche status, and sun-protection practices significantly influence nevus count in this pediatric population. PMID- 29614273 TI - Powder Compression Properties of Paracetamol, Paracetamol Hydrochloride, and Paracetamol Cocrystals and Coformers. AB - The objective was to study the relationship between crystal structure, particle deformation properties, and tablet-forming ability for the monoclinic form of paracetamol (PRA), 2 cocrystals and a salt crystal of PRA in addition to 2 coformers (oxalic acid and 4,4'-bipyridine). Thus, the structure-property performance relationship was investigated. Analytical powder compression was used for determination of effective plasticity, as inferred from the Heckel yield pressure and the Frenning parameter, and the elastic deformation was determined from in-die tablet elastic recovery. The plasticity could not be linked to the crystal lattice structure as crystals containing zig-zag layers displayed similar plasticity as crystals containing slip planes. In addition, crystals containing slip planes displayed both high and low plasticity. The mechanical properties could not be linked to the tablet-forming ability as the tablet tensile strength, unexpectedly, displayed a tendency to reduce with increased plasticity. Furthermore, the elastic deformation could not explain the tablet-forming ability. It was concluded that no relationship between structure-property performance for PRA and its cocrystals and salt could be established. Thus, it was indicated that to establish such a relationship, an improved knowledge of crystallographic structure and interparticle bonding during compaction is needed. PMID- 29614274 TI - A randomized double-blind placebo-controlled trial on the effect of local analgesia on postoperative gluteal pain in patients undergoing sacrospinous ligament colpopexy. AB - BACKGROUND: The incidence of temporary gluteal pain after sacrospinous ligament colpopexy ranges from 6.1% to 15.3%. Gluteal pain may occur as a result of injury to S3 to S5 nerve roots that course over the mid-portion of the coccygeus sacrospinous ligament complex at the time of suspension suture placement. There are no data on the use of injections to prevent postoperative pain from nerve entrapment at the time of suture placement. OBJECTIVE: The purpose of this study was to determine whether intraoperative local analgesia that is administered at the level of the sacrospinous ligament can lessen the gluteal pain felt by patients postoperatively after sacrospinous ligament colpopexy. STUDY DESIGN: In a randomized double-blind placebo-controlled trial, women with vaginal apex prolapse who were undergoing surgical treatment with sacrospinous ligament colpopexy underwent intraoperative injection with either 0.25% bupivacaine or normal saline solution. Subjects completed visual analog pain scales (0-10) and the Activities Assessment Scale and recorded the use of pain medications over a 6 week period. The primary outcome was postoperative gluteal pain. A sample size of 50 subjects (25 in each arm) was planned to test the hypothesis that local analgesia administration will lessen postoperative pain compared with placebo. RESULTS: Between April 2014 and March 2016, 51 women were enrolled in the study, and 46 women underwent sacrospinous ligament colpopexy. On postoperative day 1, 90.2% of all subjects (n=41) reported gluteal pain. At weeks 1 and 2, 63.8% (n=29) and 44.1% (n=20) women reported pain; at weeks 4 and 6, 33.3% (n=15) and 26.9% (n=12) women continued to have some pain. On day 1, the mean score for gluteal pain was 3.7+/-2.9. By week 1, the score was 1.8+/-2.6; by week 6, the mean score was 0.1+/-0.3. There were no differences in pain scores for patients who had undergone injection with 0.25% bupivacaine and those who were injected with normal saline solution. Patients in the placebo group used significantly more nonsteroidal antiinflammatory drugs than the treatment group: adjusted odds ratio, 1.25; 95% confidence interval, 1.04-1.35; P=.01). By 6 weeks, 87.5% of patients had returned to their baseline "light" activity level. There was no difference in time to return to baseline between the groups. CONCLUSION: Intraoperative administration of local analgesia does not reduce patients' perceptions of postoperative gluteal pain after sacrospinous ligament colpopexy; however, it may reduce the need for pain medication after surgery. PMID- 29614275 TI - Reply. PMID- 29614276 TI - Induction of labor using one dose vs multiple doses of misoprostol: a randomized controlled trial. AB - BACKGROUND: Misoprostol is a common agent that is used to ripen the cervix and induce labor, yet there is no clear evidence of the optimal number of doses needed to achieve a higher rate of vaginal delivery. OBJECTIVE: Our primary objective was to compare the rate of vaginal delivery within 24 hours between a 1 dose and a multiple-dose regimen of misoprostol for the induction of labor. STUDY DESIGN: A randomized controlled trial was conducted from March 2016 to March 2017 that compared a single dose to up to 4 doses of misoprostol. Randomization was stratified by parity. Women with a singleton pregnancy >=37 weeks gestation with intact membranes who had been admitted for labor induction with a Bishop score <=6 were included. Our primary outcome was the rate of vaginal delivery within 24 hours. Secondary outcomes included time to vaginal delivery, cesarean delivery rate, and maternal and neonatal morbidity. Based on a power of 80%, an alpha of .05, and the assumption that 50% of women in the multiple-misoprostol group would deliver vaginally in 24 hours, a sample size of 220 patients was needed to detect a 20% increase in vaginal delivery rate within 24 hours in the 1-misoprostol group. Continuous variables were compared with the use of the Mann-Whitney test. Categoric variables were compared with the use of the Fisher's exact test. Probability values <.05 were considered statistically significant. RESULTS: Two hundred fifty women were assigned randomly. Demographics and clinical characteristics were similar between groups. In the univariate analysis, there was no difference in the rate of vaginal delivery within 24 hours between the 1 misoprostol group and the multiple-dose group (41.7% vs 44.7%, respectively; P=.698) or time to vaginal delivery (1187 min vs 1321 min, respectively; P=.202). The 1-misoprostol group had a greater cesarean delivery rate (35.8% vs 22.8%; P=.034). In a Poisson regression that controlled for Bishop score before the initiation of oxytocin, parity, gestational age, body mass index, estimated fetal weight, artificial rupture of membrane at <6 cm, and Foley balloon placement, the treatment group was no longer associated with cesarean delivery rate. Instead, a Bishop score of <4 before the initiation of oxytocin and nulliparity were associated significantly with cesarean delivery rate. CONCLUSION: In this first randomized controlled trial in the literature to compare a single with a multiple dosing of misoprostol, we found that the 1-dose regimen is an acceptable alternative for the induction for labor, especially for multiparous women and for patients with a Bishop score >4 after the first dose. PMID- 29614277 TI - The past, present, and future of selective progesterone receptor modulators in the management of uterine fibroids: an alternative perspective. PMID- 29614278 TI - Progestogens in singleton gestations with preterm prelabor rupture of membranes: a systematic review and metaanalysis of randomized controlled trials. AB - OBJECTIVE DATA: Preterm prelabor rupture of membranes occurs in 3% of all pregnancies. Neonatal benefit is seen in uninfected women who do not deliver immediately after preterm prelabor rupture of membranes. The purpose of this study was to evaluate whether the administration of progestogens in singleton pregnancies prolongs pregnancy after preterm prelabor rupture of membranes. STUDY: Searches were performed in MEDLINE, OVID, Scopus, EMBASE, ClinicalTrials.gov, and the Cochrane Central Register of Controlled Trials with the use of a combination of keywords and text words related to "progesterone," "progestogen," "prematurity," and "preterm premature rupture of membranes" from the inception of the databases until January 2018. We included all randomized controlled trials of singleton gestations after preterm prelabor rupture of membranes that were randomized to either progestogens or control (either placebo or no treatment). Exclusion criteria were trials that included women who had contraindications to expectant management after preterm prelabor rupture of membranes (ie, chorioamnionitis, severe preeclampsia, and nonreassuring fetal status) and trials on multiple gestations. We planned to include all progestogens, including but not limited to 17-alpha hydroxyprogesterone caproate, and natural progesterone. STUDY APPRAISAL AND SYNTHESIS METHODS: The primary outcome was latency from randomization to delivery. Metaanalysis was performed with the use of the random effects model of DerSimonian and Laird to produce relative risk with 95% confidence interval. Analysis was performed for each mode of progestogen administration separately. RESULTS: Six randomized controlled trials (n=545 participants) were included. Four of the included trials assessed the efficacy of 17-alpha hydroxyprogesterone caproate; 1 trial assessed rectal progestogen, and 1 trial had 3 arms that compared 17-alpha hydroxyprogesterone caproate, rectal progestogen, and placebo. The mean gestational age at time randomization was 26.9 weeks in the 17-alpha hydroxyprogesterone caproate group and 27.3 weeks in the control group. 17-alpha Hydroxyprogesterone caproate administration was not found to prolong the latency period between randomization and delivery (mean difference, 0.11 days; 95% confidence interval, -3.30 to 3.53). There were no differences in mean gestational age at delivery, mode of delivery, or maternal or neonatal outcomes between the 2 groups. Similarly, there was no difference in latency for those women who received rectal progesterone (mean difference, 4.00 days; 95% confidence interval, -0.72 to 8.72). CONCLUSION: Progestogen administration does not prolong pregnancy in singleton gestations with preterm prelabor rupture of membranes. PMID- 29614279 TI - The Only Known Jawed Vertebrate with Four Eyes and the Bauplan of the Pineal Complex. AB - The pineal and parapineal organs are dorsal outpocketings of the vertebrate diencephalon that play key roles in orientation and in circadian and annual cycles. Lampreys are four eyed in that both the pineal and parapineal form eyelike photosensory structures, but the pineal is the dominant or sole median photosensory structure in most lower vertebrate clades. The pineal complex has been thought to evolve in a single direction by losing photosensory and augmenting secretory function in the transitions from three-eyed lower vertebrates to two-eyed mammals and archosaurs [1-3]. Yet the widely accepted elaboration of the parapineal instead of the pineal as the primary median photosensory organ [4] in Lepidosauria (lizards, snakes, and tuataras) hints at a more complex evolutionary history. Here we present evidence that a fourth eye re evolved from the pineal organ at least once within vertebrates, specifically in an extinct monitor lizard, Saniwa ensidens, in which pineal and parapineal eyes were present simultaneously. The tandem midline location of these structures confirms in a striking fashion the proposed homology of the parietal eye with the parapineal organ and refutes the classical model of pineal bilaterality. It furthermore raises questions about the evolution and functional interpretation of the median photosensory organ in other tetrapod clades. PMID- 29614280 TI - Early Life: Embracing the RNA World. PMID- 29614281 TI - Black Jacobin hummingbirds vocalize above the known hearing range of birds. PMID- 29614282 TI - Armillaria. AB - Lingering in forests around the world, some of the largest and oldest terrestrial organisms on earth hide in plain sight. In this Quick Guide, Sipos et al. shed light on the biology of the Armillaria fungi. PMID- 29614283 TI - African striped mice. AB - Mallarino et al. introduce the African striped mouse, which is being used in a number of fields of research, including animal behavior, evolutionary developmental biology, and chronobiology. PMID- 29614284 TI - Animal left-right asymmetry. AB - Symmetry is appealing, be it in architecture, art or facial expression, where symmetry is a key feature to finding someone attractive or not. Yet, asymmetries are widespread in nature, not as an erroneous deviation from the norm but as a way to adapt to the prevailing environmental conditions at a time. Asymmetries in many cases are actively selected for: they might well have increased the evolutionary fitness of a species. Even many single-celled organisms are built asymmetrically, such as the pear-shaped ciliate Paramecium, which may depend on its asymmetry to navigate towards the oxygen-richer surface of turbid waters, at least based on modeling. Everybody knows the lobster with its asymmetric pair of claws, the large crusher usually on the left and the smaller cutter on the right. Snail shells coil asymmetrically, as do the organs they house. Organ asymmetries are found throughout the animal kingdom, referring to asymmetric positioning, asymmetric morphology or both, with the vertebrate heart being an example for the latter. Functional asymmetries, such as that of the human brain with its localization of the language center in one hemisphere, add to the complexity of organ asymmetries and presumably played a decisive role for sociocultural evolution. The evolutionary origin of organ asymmetries may have been a longer than body length gut, which allows efficient retrieval of nutrients, and the need to stow a long gut in the body cavity in an orderly manner that ensures optimal functioning. Vertebrate organ asymmetries (situs solitus) are quite sophisticated: in humans, the apex of the asymmetrically built heart points to the left; the lung in turn, due to space restrictions, has fewer lobes on the left than on the right side (two versus three in humans), stomach and spleen are found on the left, the liver on the right, and small and large intestine coil in a chiral manner (Figure 1A). In very rare cases (1:10,000), the organ situs is inverted (situs inversus), while heterotaxia refers to another rare situation (about 1:1,000), in which subsets of organs show normal or aberrant positioning or morphology (Figure 1B). Individuals with situs solitus or situs inversus are healthy, whereas heterotaxia presents severe congenital malformations. Many human syndromes are known in which patients suffer from laterality defects, such as Katagener syndrome, in which the organ situs is inverted in one half of patients and males are sterile. Snail shells and vertebrate organs are examples of biased asymmetries with on average only one inversion in every 10,000 cases. Other asymmetries such as the coiling of the tails of piglets occur randomly with a 50:50 distribution. This primer exclusively deals with organ asymmetries in the animal kingdom, specifically with the mechanisms that ensure the development of biased asymmetries during embryogenesis. PMID- 29614285 TI - On Francis Crick, the genetic code, and a clever kid. AB - A few years ago, Francis Crick's son told me a story that I can't get out of my mind. I had contacted Michael Crick by email while digging through the background of the researchers who had cracked the genetic code in the 1960s. Francis had died in 2004, and I was contacting some of the people who knew him when he was struggling to decipher the code. Francis didn't appear to struggle often - he is known mostly for his successes - and, as it turns out, this one well-known struggle may have had a clue sitting just barely out of sight. PMID- 29614286 TI - Cell Division: Symbiotic Bacteria Turn It Upside Down. AB - Symbiotic bacteria of the genus Thiosymbion attach to the surface of their nematode hosts using their poles and divide by longitudinal binary fission. A new study now sheds light on the molecular mechanisms that underlie this peculiar mode of proliferation. PMID- 29614287 TI - Colour Vision: A Fresh View of Lateral Inhibition in Drosophila. AB - A recent study reports a novel form of lateral inhibition between photoreceptors supporting colour vision in the vinegar fly, Drosophila melanogaster. PMID- 29614288 TI - Paleoneurology: A Sight for Four Eyes. AB - The 'third eye' of the pineal complex is a curious component of the vertebrate brain associated with light sensation and melatonin production. A fossil lizard with a 'fourth eye' now calls for a reinterpretation of pineal evolution. PMID- 29614289 TI - Object Recognition: Complexity of Recognition Strategies. AB - Primate brains and state-of-the-art convolutional neural networks can recognize many faces, objects and scenes, though how they do so is often mysterious. New research unveils some of the mystery, revealing unexpected complexity in the recognition strategies of rodents. PMID- 29614290 TI - Vocal Communication: Decoding Sexy Songs. AB - Male birds communicate sexual motivation via song performance, and receiving females might eventually respond to such 'ornaments'. A new study now shows that female zebra finches have a specialized higher order sensory (forebrain) region that preferably responds to the males' mating songs. PMID- 29614291 TI - Sleep: Helicon Cells Charge the Circuit. AB - A new study in the fruit fly, Drosophila melanogaster, has identified a neural circuitry that connects regions that control sleep with those that encode sleep pressure. These novel cells, termed helicon cells for their unique morphology, are modulated by sleep control centers and integrate sensory information, providing a novel mechanism for gating of sleep. PMID- 29614292 TI - Evolution: Zeroing In on the Rate of Genome Doubling. AB - Changes in genome copy number have occurred numerous times throughout the history of life, with profound evolutionary consequences. New experiments with budding yeast shed light on how frequently spontaneous genome doubling occurs within populations and the environmental conditions that favour cells with doubled genomes. PMID- 29614293 TI - Social Immunity: The Disposable Individual. AB - Workers in an ant colony can kill fungus-infected brood, thereby protecting the rest of the colony from fungal infection. This form of social immunity is analogous to the immune system of multicellular organisms where immune cells kill infected cells. PMID- 29614294 TI - GPCR Signaling: The Interplay of Galphai and beta-arrestin. AB - Biased agonism at G-protein-coupled receptors is generally conceptualized as the ability of certain stimuli to trigger downstream signaling exclusively through one of two effectors. Recent studies reveal that signaling downstream of the beta1 adrenergic receptor and the angiotensin II type 1 receptor induced by biased stimuli actually involves both effectors. PMID- 29614296 TI - Automatic cardiac cycle determination directly from EEG-fMRI data by multi-scale peak detection method. AB - BACKGROUND: In simultaneous EEG-fMRI, identification of the period of cardioballistic artifact (BCG) in EEG is required for the artifact removal. Recording the electrocardiogram (ECG) waveform during fMRI is difficult, often causing inaccurate period detection. NEW METHOD: Since the waveform of the BCG extracted by independent component analysis (ICA) is relatively invariable compared to the ECG waveform, we propose a multiple-scale peak-detection algorithm to determine the BCG cycle directly from the EEG data. The algorithm first extracts the high contrast BCG component from the EEG data by ICA. The BCG cycle is then estimated by band-pass filtering the component around the fundamental frequency identified from its energy spectral density, and the peak of BCG artifact occurrence is selected from each of the estimated cycle. RESULTS: The algorithm is shown to achieve a high accuracy on a large EEG-fMRI dataset. It is also adaptive to various heart rates without the needs of adjusting the threshold parameters. The cycle detection remains accurate with the scan duration reduced to half a minute. Additionally, the algorithm gives a figure of merit to evaluate the reliability of the detection accuracy. COMPARISON WITH EXISTING METHOD: The algorithm is shown to give a higher detection accuracy than the commonly used cycle detection algorithm fmrib_qrsdetect implemented in EEGLAB. CONCLUSIONS: The achieved high cycle detection accuracy of our algorithm without using the ECG waveforms makes possible to create and automate pipelines for processing large EEG-fMRI datasets, and virtually eliminates the need for ECG recordings for BCG artifact removal. PMID- 29614297 TI - EEG-based neglect assessment: A feasibility study. AB - BACKGROUND: Spatial neglect (SN) is a neuropsychological syndrome that impairs automatic attention orienting to stimuli in the contralesional visual space of stroke patients. SN is commonly assessed using paper and pencil tests. Recently, computerized tests have been proposed to provide a dynamic assessment of SN. However, both paper- and computer-based methods have limitations. NEW METHOD: Electroencephalography (EEG) shows promise for overcoming the limitations of current assessment methods. The aim of this work is to introduce an objective passive BCI system that records EEG signals in response to visual stimuli appearing in random locations on a screen with a dynamically changing background. Our preliminary experimental studies focused on validating the system using healthy participants with intact brains rather than employing it initially in more complex environments with patients having cortical lesions. Therefore, we designed a version of the test in which we simulated SN by hiding target stimuli appearing on the left side of the screen so that the subject's attention is shifted to the right side. RESULTS: Results showed that there are statistically significant differences between EEG responses due to right and left side stimuli reflecting different processing and attention levels towards both sides of the screen. The system achieved average accuracy, sensitivity and specificity of 74.24%, 75.17% and 71.36% respectively. COMPARISON WITH EXISTING METHODS: The proposed test can examine both presence and severity of SN, unlike traditional paper and pencil tests and computer-based methods. CONCLUSIONS: The proposed test is a promising objective SN evaluation method. PMID- 29614295 TI - Methodology and effects of repeated intranasal delivery of DNSP-11 in awake Rhesus macaques. AB - BACKGROUND: To determine if the intranasal delivery of neuroactive compounds is a viable, long-term treatment strategy for progressive, chronic neurodegenerative disorders, such as Parkinson's disease (PD), intranasal methodologies in preclinical models comparable to humans are needed. NEW METHOD: We developed a methodology to evaluate the repeated intranasal delivery of neuroactive compounds on the non-human primate (NHP) brain, without the need for sedation. We evaluated the effects of the neuroactive peptide, DNSP-11 following repeated intranasal delivery and dose-escalation over the course of 10-weeks in Rhesus macaques. This approach allowed us to examine striatal target engagement, safety and tolerability, and brain distribution following a single 125I-labeled DNSP-11 dose. RESULTS: Our initial data support that repeated intranasal delivery and dose-escalation of DNSP-11 resulted in bilateral, striatal target engagement based on neurochemical changes in dopamine (DA) metabolites-without observable, adverse behavioral effects or weight loss in NHPs. Furthermore, a 125I-labeled DNSP-11 study illustrates diffuse rostral to caudal distribution in the brain including the striatum-our target region of interest. COMPARISON WITH EXISTING METHODS: The results of this study are compared to our experiments in normal and 6-OHDA lesioned rats, where DNSP-11 was repeatedly delivered intranasally using a micropipette with animals under light sedation. CONCLUSIONS: The results from this proof-of-concept study support the utility of our repeated intranasal dosing methodology in awake Rhesus macaques, to evaluate the effects of neuroactive compounds on the NHP brain. Additionally, results indicate that DNSP-11 can be safely and effectively delivered intranasally in MPTP-treated NHPs, while engaging the DA system. PMID- 29614298 TI - A Heart-Stopping Cause of Upper Gastrointestinal Bleeding. PMID- 29614299 TI - A Rare Cause of Gastrointestinal Bleeding and Rash in an Older Woman. PMID- 29614300 TI - New-Onset Undulatory Abdominal Pain: Revelations of Timely Endoscopic Intervention. PMID- 29614302 TI - An Endoscopic Double Take. PMID- 29614304 TI - Decreased Esophageal Distensibility in Children With Eosinophilic Esophagitis: Is Fibrosis Inevitable? PMID- 29614301 TI - Association Between Obesity and Weight Change and Risk of Diverticulitis in Women. AB - BACKGROUND & AIMS: There is little evidence that adiposity associates with diverticulitis, especially among women. We conducted a comprehensive evaluation of obesity, weight change, and incidence of diverticulitis in a large cohort of women. METHODS: We conducted a prospective cohort study of 46,079 women enrolled in the Nurses' Health Study who were 61-89 years old and free of diverticulitis, diverticular bleeding, cancers, or inflammatory bowel disease at baseline (in 2008). We used Cox proportional hazards models to examine the associations among risk of incident diverticulitis and body mass index (BMI), waist circumference, waist to hip ratio, and weight change from age 18 years to the present. The primary end point was first incident diverticulitis requiring antibiotic therapy or hospitalization. RESULTS: We documented 1084 incident cases of diverticulitis over 6 years of follow-up, encompassing 248,001 person-years. After adjustment for other risk factors, women with a BMI >=35.0 kg/m2 had a hazard ratio for diverticulitis of 1.42 (95% confidence interval [CI], 1.08-1.85) compared to women with a BMI <22.5 kg/m2. Compared to women in the lowest quintile, the multivariable hazard ratios among women in the highest quintile were 1.35 (95% CI, 1.02-1.78) for waist circumference and 1.40 (95% CI, 1.07-1.84) for waist to hip ratio; these associations were attenuated with further adjustment for BMI. Compared to women maintaining weight from age 18 years to the present, those who gained >=20 kg had a 73% increased risk of diverticulitis (95% CI, 27%-136%). CONCLUSIONS: During a 6-year follow-up period, we observed an association between obesity and risk of diverticulitis among women. Weight gain during adulthood was also associated with increased risk. PMID- 29614303 TI - A Unique Infusion Reaction to Vedolizumab in a Patient With Crohn's Disease. PMID- 29614305 TI - Could Fecal Transplantation Become Part of PD-1-Based Immunotherapy, Due to Effects of the Intestinal Microbiome? PMID- 29614306 TI - The prognostic role of programmed cell death-ligand 1 expression in non-small cell lung cancer patients: An updated meta-analysis. AB - BACKGROUND: Programmed cell death-ligand 1 (PD-L1) seemed to be associated with the outcomes of non-small cell lung cancer. However the prognostic role of PD-L1 expression among NSCLC remained unclear and inconsistent. The aim of the study set out to evaluate the correlation between PD-L1 expression and the prognosis of patients that developed NSCLC. METHODS: Identified literatures were extracted of various electronic databases and a meta-analysis was performed to evaluate the prognostic role of PD-L1 among NSCLC patients. RESULTS: Totally 25 studies from 11 countries containing 5861 patients were included in the meta-analysis. The pooled hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) were 1.176 (95% CI: 1.016-1.361, P = 0.029) and 1.170 (95% CI: 0.984-1.392, P = 0.076), respectively. High PD-L1 expression on NSCLC tissue was also related with worse OS among Asian patients (HR = 1.381, 95% CI: 1.127-1.629, P = 0.002), adenocarcinomas (HR = 1.899, 95% CI: 1.306-2.762, P = 0.001) and poor PFS in non-Asian patients (HR = 1.695, 95% CI: 1.158-2.480, P = 0.002). Sensitivity analysis indicated that removal of any particular included literature won't affect the pooled results. Publication bias among the studies was not significant neither. CONCLUSIONS: PD-L1 expression is a prognostic factor related with poor survival among patients that developed NSCLC. PMID- 29614307 TI - LC-MS/MS reveals the formation of reactive ortho-quinone and iminium intermediates in saracatinib metabolism: Phase I metabolic profiling. AB - Saracatinib (AZD-0530) is a drug under clinical trials that developed by AstraZeneca. It is considered a dual kinase inhibitor, with selective actions as a Src inhibitor and a Bcr-Abl tyrosine-kinase inhibitor. Saracatinib chemical structure contains N-methyl piperazine group and 1,3 benzodioxole group. N-methyl piperazine group that can be bioactivated to form iminium intermediates which can be captured by KCN. 1,3-Benzodioxole group can be bioactivated to form ortho quinone intermediate that can be conjugated with GSH. The formed conjugates are stable and can be identified using LC-MS/MS. In our current work, we are trying to give insight into the reasons that may be responsible for saracatinib side effects. Using LC-MS/MS, in vitro metabolic pathways were investigated for saracatinib in rat liver microsomes. Ten saracatinib phase I metabolites were characterized and the metabolic pathways were found to be hydroxylation, oxidation, reduction, dealkylation, N-oxidation and ether cleavage. Also, four potential reactive intermediates (three cyanide adducts and one GSH conjugate) were identified and the bioactivation mechanisms were explained. The existence of these four reactive metabolites may be the main reason for observed saracatinib side effects in clinical trials. Literature review showed no previous articles have been proposed the detailed structural identification of the formed reactive metabolites. PMID- 29614309 TI - Advances in biomarkers for dermatomyositis. AB - Dermatomyositis (DM) and polymyositis (PM) are heterogeneous complex autoimmune diseases involving muscle damage. Patients with DM and PM display a wide spectrum of clinical manifestations and serological biomarkers, which may mislead and delay the proper diagnosis. Therefore, specific biomarkers or indicators for diagnosing DM and PM and monitoring disease activity are essential. Significant progress has been made through identifying novel serological biomarkers for DM and PM in recent years. Our aim is to focus on novel biomarkers for diagnosing and monitoring disease activity in DM and PM to highlight their predictive value and applicability in clinical practice. PMID- 29614308 TI - Relationship between plasma angiogenic growth factors and diabetic foot ulcers. AB - BACKGROUND: Angiogenic growth factors play an important role in wound healing. However, their associations with diabetic foot ulcers (DFUs) in humans have rarely been investigated. We examined the relationships between circulating concentrations of vascular endothelial growth factor (VEGF)-A and placenta growth factor (PlGF), and DFU risk. METHODS: We recruited 447 participants, including 169 DFU patients, 182 diabetes patients without DFUs, and 96 diabetes-free individuals. Plasma VEGF-A and PlGF concentrations were measured using commercial enzyme immunoassay kits. RESULTS: Concentrations of VEGF-A and PlGF in DFU patients were higher than those in diabetes-free controls (P < 0.05), but lower than those in the diabetic controls (P < 0.05). Increased concentrations of VEGF A and PlGF were associated with a reduced risk of DFUs. The odds ratios (95% confidence intervals) were 0.93 (0.88, 0.97) for every 10 pg/ml increase in VEGF A concentrations, and 0.96 (0.94, 0.99) for every 5 pg/ml increase in PlGF concentrations. VEGF-A concentrations were positively related to BMI, glycated hemoglobin (HbA1c), hypertension, and neuropathy, and PlGF was positively correlated to age, HbA1c, and hypertension, among DFU patients. CONCLUSION: VEGF A and PlGF play important roles in the development of DFU but need to be confirmed in prospective studies. PMID- 29614310 TI - cxcl12 gene engineered endothelial progenitor cells further improve the functions of oligodendrocyte precursor cells. AB - Oligodendrocyte precursor cells (OPCs) are needed for white matter repair after various brain injury. Means that promote OPC functions could benefit white matter recovery after injury. Chemokine CXCL12 and endothelial progenitor cells (EPCs) both have been shown to promote remyelination. We hypothesize that the beneficial effects of EPCs and CXCL12 can be harnessed by genetically modifying EPCs with cxcl12 to synergistically improve the functions of OPCs. In this work, CXCL12-EPC was generated using virus-mediated gene transfer. OPCs were cultured with CXCL12 EPC conditioned media (CM) to analyze its impact on the proliferation, migration, differentiation and survival properties of OPCs. We blocked or knocked-down the receptors of CXCL12, namely CXCR4 and CXCR7, respectively to investigate their functions in regulating OPCs properties. Results revealed that CXCL12-EPC CM further promoted OPCs behavioral properties and upregulated the expression of PDGFR-alpha, bFGF, CXCR4 and CXCR7 in OPCs, albeit following different time course. Blocking CXCR4 diminished the beneficial effects of CXCL12 on OPCs proliferation and migration, while knocking down CXCR7 inhibited OPCs differentiation. Our results supported that cxcl12 gene modification of EPCs further promoted EPCs' ability in augmenting the remyelination properties of OPCs, suggesting that CXCL12-EPC hold great potential in white matter repair. PMID- 29614311 TI - MiR-138/SIRT1 axis is implicated in impaired learning and memory abilities of cerebral ischemia/reperfusion injured rats. AB - The present study aimed to explore whether deregulated miR-138 is implicated in cerebral I/R injury-impaired learning and memory abilities. Rats were subjected to bilateral common carotid occlusion followed by reperfusion to induce cerebral I/R injury. A model of oxygen-glucose deprivation and reperfusion (OGD/R) was conducted to mimic cerebral I/R conditions in vitro. MiR-138 expression levels were reduced in the hippocampus of cerebral I/R injured rats. Inhibition of miR 138 ameliorated the impaired learning and memory abilities of rats, and promoted autophagy and thus attenuated apoptosis in the OGD/R-treated hippocampal neurons. Moreover, miR-138 targets the 3'-UTR of SIRT1 and repressed its expression. These results showed that miR-138 could improve the learning and memory abilities via promoting autophagy under cerebral I/R injured conditions. PMID- 29614312 TI - Diacylglycerol lipase alpha promotes tumorigenesis in oral cancer by cell-cycle progression. AB - Diacylglycerol lipase alpha (DAGLA), which catalyzes the hydrolysis of diacylglycerol to 2-arachidonoylglycerol and free fatty acid, is required for axonal growth during the brain development and for retrograde synaptic signaling at mature synapses. So far, no information was found regarding the possible role of DAGLA in human tumorigenesis. Thus, the current study sought to clarify the contribution of DAGLA in oral squamous cell carcinomas (OSCCs) and assess the clinical possibilities for OSCC treatment. Using real-time quantitative reverse transcription-polymerase chain reaction, immunoblotting, and immunohistochemistry, we found a significant up-regulation of DAGLA in OSCCs compared with normal cells and tissues both at mRNA and protein expression levels. Knockdown models in OSCC-derived cell lines for DAGLA (siDAGLA) and treatment with a lipase inhibitor (orlistat) showed several depressed cellular functions, including cellular proliferation and migratory activities through cell cycle arrest at G1 phase. Furthermore, we found that DAGLA-positive OSCC samples were correlated highly with the primary tumoral size. We concluded that DAGLA may be a key determinant in tumoral progression and might be a therapeutic target for OSCCs. PMID- 29614313 TI - H2A.Z Represses Gene Expression by Modulating Promoter Nucleosome Structure and Enhancer Histone Modifications in Arabidopsis. PMID- 29614314 TI - GluN2B/CaMKII mediates CFA-induced hyperalgesia via HDAC4-modified spinal COX2 transcription. AB - Histone deacetylase 4 (HDAC4), which actively shuttles between the nucleus and cytoplasm, is an attractive candidate for a repressor mechanism in epigenetic modification. However, the potential role of HDAC4-dependent epigenetics in the neural plasticity underlying the development of inflammatory pain has not been well established. By injecting complete Freund's adjuvant (CFA) into the hind-paw of Sprague-Dawley rats (200-250 g), we found animals displayed behavioral hyperalgesia was accompanied with HDAC4 phosphorylation and cytoplasmic redistribution in the dorsal horn neurons. Cytoplasmic HDAC4 retention led to its uncoupling with the COX2 promoter, hence prompting spinal COX2 transcription and expression in the dorsal horn. Moreover, the GluN2B-bearing N-methyl-d-aspartate receptor (GluN2B-NMDAR)/calmodulin-dependent protein kinase II (CaMKII) acted as an upstream cascade to facilitate HDAC4 phosphorylation/redistribution-associated spinal COX2 expression after inflammatory insults. The results of this pilot study demonstrated that the development and/or maintenance of inflammatory pain involved the spinal HDAC4-dependent epigenetic mechanisms. Our findings open up a new avenue for the development of a novel medical strategy for the relief of inflammatory pain. PMID- 29614315 TI - A novel pharmacological activity of caffeine in the cholinergic system. AB - Cholinergic deficit is regarded as an important factor responsible for Alzheimer's disease (AD) symptoms. Acetylcholinesterase (AChE) and nicotinic receptor (AChR) are two molecular targets for the treatment of this disease. We found here that methanolic extracts of Camellia sinensis exhibited anticholinesterase activity and induced AChR conformational changes. From bioguided fractionation we confirmed that caffeine was the active compound exerting such effects. It is well-known that caffeine acts as an inhibitor of AChE and here we explored the effect of caffeine on the AChR by combining single channel recordings and fluorescent measurements. From single channel recordings we observed that caffeine activated both muscle and alpha7 AChRs at low concentrations, and behaved as an open channel blocker which was evident at high concentrations. Fluorescent measurements were performed with the conformational sensitive probe crystal violet (CrV) and AChR rich membranes from Torpedo californica. Caffeine induced changes in the KD value of CrV in a concentration dependent manner taking the AChR closer to a desentisized state. In the presence of alpha-bungarotoxin, an AChR competitive antagonist, high concentrations of caffeine increased the KD value of CrV, compatible with a competition with CrV molecules for the luminal channel. Our electrophysiological and fluorescent experiments show that caffeine has a dual effect on nicotinic receptors, behaving as an agonist and an ion channel blocker, probably through distinct AChR sites with quite different affinities. Thus, caffeine or its derivatives can be considered for the design of promising multitarget-directed drugs for AD treatment by modulation of different targets in the cholinergic pathway. PMID- 29614316 TI - Lacosamide protects striatal and hippocampal neurons from in vitro ischemia without altering physiological synaptic plasticity. AB - Lacosamide ([(R)-2-acetamido-N-benzyl-3-methoxypropanamide], LCM), is an antiepileptic that exerts anticonvulsant activity by selectively enhancing slow sodium channel inactivation. By inhibiting seizures and neuronal excitability it might therefore be a good candidate to stabilize neurons and protect them from energetic insults. Using electrophysiological analyses, we have investigated in mice the possible neuroprotective effect of LCM against in vitro ischemia obtained by oxygen and glucose deprivation (ODG), in striatal and hippocampal tissues, two brain structures particularly susceptible to ischemic injury and of pivotal importance for different form of learning and memory. We also explored in these regions the influence of LCM on firing discharge and on long-term synaptic plasticity. We found that in both areas LCM reduced the neuronal firing activity in a use-dependent manner without influencing the physiological synaptic transmission, confirming its anticonvulsant effects. Moreover, we found that this AED is able to protect, in a dose dependent manner, striatal and hippocampal neurons from energy metabolism failure produced by OGD. This neuroprotective effect does not imply impairment of long-term potentiation of striatal and hippocampal synapses and suggests that LCM might exert additional beneficial therapeutic effects beyond its use as antiepileptic. PMID- 29614317 TI - Effects of truncation of the peptide chain on the secondary structure and bioactivities of palmitoylated anoplin. AB - Anoplin (GLLKRIKTLL-NH2) is of current interest due to its short sequence and specificity towards bacteria. Recent studies on anoplin have shown that truncation and acylation compromises its antimicrobial activity and specificity, respectively. In this study, truncated analogues (pal-ano-9 to pal-ano-5) of palmitoylated anoplin (pal-anoplin) were synthesized to determine the effects of C-truncation on its bioactivities. Moreover, secondary structure of each analogue using circular dichroism (CD) spectroscopy was determined to correlate with bioactivities. Interestingly, pal-anoplin, pal-ano-9 and pal-ano-6 were helical in water, unlike anoplin. In contrast, pal-ano-8, pal-ano-7 and pal-ano-5, with polar amino acid residues at the C-terminus, were random coil in water. Nevertheless, all the peptides folded into helical structures in 30% trifluoroethanol/water (TFE/H2O) except for the shortest analogue pal-ano-5. Hydrophobicity played a significant role in the enhancement of activity against bacteria E. coli and S. aureus as all lipopeptides including the random coil pal ano-5 were more active than the parent anoplin. Meanwhile, the greatest improvement in activity against the fungus C. albicans was observed for pal anoplin analogues (pal-ano-9 and pal-ano-6) that were helical in water. Although, hydrophobicity is a major factor in the secondary structure and antimicrobial activity, it appears that the nature of amino acids at the C-terminus also influence folding of lipopeptides in water and its antifungal activity. Moreover, the hemolytic activity of the analogues was found to correlate with hydrophobicity, except for the least hemolytic, pal-ano-5. Since most of the analogues are more potent and shorter than anoplin, they are promising drug candidates for further development. PMID- 29614318 TI - Cadmium Phytoremediation: Call Rice CAL1. PMID- 29614319 TI - Genome-Wide Association Studies of Image Traits Reveal Genetic Architecture of Drought Resistance in Rice. AB - Understanding how plants respond to drought can benefit drought resistance (DR) breeding. Using a non-destructive phenotyping facility, 51 image-based traits (i traits) for 507 rice accessions were extracted. These i-traits can be used to monitor drought responses and evaluate DR. High heritability and large variation of these traits was observed under drought stress in the natural population. A genome-wide association study (GWAS) of i-traits and traditional DR traits identified 470 association loci, some containing known DR-related genes. Of these 470 loci, 443 loci (94%) were identified using i-traits, 437 loci (93%) co localized with previously reported DR-related quantitative trait loci, and 313 loci (66.6%) were reproducibly identified by GWAS in different years. Association networks, established based on GWAS results, revealed hub i-traits and hub loci. This demonstrates the feasibility and necessity of dissecting the complex DR trait into heritable and simple i-traits. As proof of principle, we illustrated the power of this integrated approach to identify previously unreported DR related genes. OsPP15 was associated with a hub i-trait, and its role in DR was confirmed by genetic transformation experiments. Furthermore, i-traits can be used for DR linkage analyses, and 69 i-trait locus associations were identified by both GWAS and linkage analysis of a recombinant inbred line population. Finally, we confirmed the relevance of i-traits to DR in the field. Our study provides a promising novel approach for the genetic dissection and discovery of causal genes for DR. PMID- 29614320 TI - Structure and Function of TPC1 Vacuole SV Channel Gains Shape. AB - Plants and animals in endosomes operate TPC1/SV-type cation channels. All plants harbor at least one TPC1 gene. Although the encoded SV channel was firstly discovered in the plant vacuole membrane two decades ago, its biological function has remained enigmatic. Recently, the structure of a plant TPC1/SV channel protein was determined. Insights into the 3D topology has now guided site directed mutation approaches, enabling structure-function analyses of TPC1/SV channels to shed new light on earlier findings. Fou2 plants carrying a hyperactive mutant form of TPC1 develop wounding stress phenotypes. Recent studies with fou2 and mutants that lack functional TPC1 have revealed atypical features in local and long-distance stress signaling, providing new access to the previously mysterious biology of this vacuolar cation channel type in planta. PMID- 29614321 TI - A Structural Equation Model on Korean Adolescents' Excessive Use of Smartphones. AB - PURPOSE: We develop a unified structural model that defines multi-relationships between systematic factors causing excessive use of smartphones and the corresponding results. METHODS: We conducted a survey with adolescents who live in Seoul, Pusan, Gangneung, Donghae, and Samcheok from Feb. to Mar. 2016. We utilized SPSS Ver. 22 and Amos Ver. 22 to analyze the survey result at a 0.05 significance level. To investigate demographic characteristics of the participants and their variations, we employed descriptive analysis. We adopted the maximum likelihood estimate method to verify the fitness of the hypothetical model and the hypotheses therein. We used chi2 statistics, GFI, AGFI, CFI, NFI, IFI, RMR, and RMSEA to verify the fitness of our structural model. RESULTS: (1) Our proposed structural model demonstrated a fine fitness level. (2) Our proposed structural model could describe the excessive use of a smartphone with 88.6% accuracy. (3) The absence of the family function and relationship between friends, impulsiveness, and low self-esteem were confirmed as key factors that cause excessive use of smartphones. (4) Further, impulsiveness and low self esteem are closely related to the absence of family functions and relations between friends by 68.3% and 54.4%, respectively. CONCLUSION: We suggest that nursing intervention programs from various angles are required to reduce adolescents' excessive use of smartphones. For example, family communication programs would be helpful for both parents and children. Consultant programs about friend relationship also meaningful for the program. PMID- 29614322 TI - Effects of the Educational Leadership of Nursing Unit Managers on Team Effectiveness: Mediating Effects of Organizational Communication. AB - : EDUCATIONAL LEADERSHIP OF NURSING UNIT MANAGERS ON TEAM EFFECTIVENESS: Mediating Effects of Organizational Communication Satisfaction. PURPOSE: This study identifies the effects of the educational leadership of nursing unit managers on team effectiveness and the mediating effects of organizational communication satisfaction; it highlights the importance of educational leadership and organizational communication and provides the data needed to enhance the education capacity of managers. METHODS: The participants were 216 nursing unit managers of staff nurses at a tertiary hospital located in C Region, South Korea, and nurses who had worked for more than six months at the same hospital. This study was conducted using questionnaires on educational leadership, team effectiveness, and organizational communication satisfaction. Data analysis was performed with a t-test, ANOVA, Scheffe, Pearson's correlation coefficient, and simple and multiple regression analyses using SPSS version 23.0. Mediation analysis was tested using Baron and Kenny's regression analysis and a Sobel test. RESULTS: The mean score for the educational leadership of nursing unit managers was 3.74(+/-0.68); for organizational communication satisfaction, 3.14(+/-0.51); and for team effectiveness, 3.52(+/-0.49). Educational leadership was significantly positively correlated with team effectiveness and organizational communication satisfaction. Organizational communication satisfaction demonstrated a complete mediating effect on the relationship between educational leadership and team effectiveness (beta=.61, p<.001) and was significant (Sobel test; Z=7.40, p<.001). CONCLUSION: The results indicate that the educational leadership of nursing unit managers increases communication satisfaction among nurses; this supports the idea that educational leadership can contribute to team effectiveness. This suggests that the educational leadership and communication capacity of nursing unit managers must be improved to enhance the performance of nursing organizations. PMID- 29614323 TI - Optimization of aqueous two-phase systems for the production of 6 aminopenicillanic acid in integrated microfluidic reactors-separators. AB - Aqueous two-phase systems (ATPSs) were screened for the production of 6 aminopenicillanic acid (6-APA) catalyzed by penicillin acylase, followed by the extractive separation of 6-APA from the reaction mixture. The key point of this study was to find an ATPS exhibiting a large difference in the partition coefficients of the biocatalyst and reaction products. Several ATPSs based on polyethylene glycol (PEG)/phosphate, PEG/citrate, and PEG/dextran were tested. We found that an ATPS consisting of 15 wt% of PEG 4000, 10 wt% of phosphates, 75 wt% of water (pH value 8.0 after dissolution) provided optimal separation of 6-APA from the enzyme. While the 6-APA was mainly found in the top PEG phase, the free enzyme favored the bottom salt-rich phase. This ATPS also fulfils other important requirements: (i) high buffering capacity, reducing an undesirable pH decrease due to the dissociation of phenylacetic acid (the side product of the reaction), (ii) a relatively low cost of the ATPS components, (iii) the possibility of electrophoretic transport of fine droplets as well as the reaction products for both the acceleration of phase separation and the enhancement of 6-APA concentration in the product stream. Extraction experiments in microcapillary and batch systems showed that the transport of 6-APA formed in the salt-rich phase to the corresponding PEG phase could occur within 30 s. The experimental results described form a base of knowledge for the development of continuously operating integrated microfluidic reactors-separators driven by an electric field for the efficient production of 6-APA. PMID- 29614324 TI - A subunit vaccine based on fiber-2 protein provides full protection against fowl adenovirus serotype 4 and induces quicker and stronger immune responses than an inactivated oil-emulsion vaccine. AB - As the number of hepatitis hydropericardium syndrome (HHS) cases has increased in recent years in China, development of a safe and effective vaccine is now urgent. To address this problem a subunit vaccine is a good option, we here systematically investigated the minimum immune dose of a subunit vaccine against HHS based on recombinant fowl adenovirus serotype 4 (FAdV-4) fiber-2 protein and compared the effects between this subunit vaccine and an inactivated oil-emulsion FAdV-4 vaccine in a vaccination trial. The results revealed that the lowest dose of recombinant fiber-2 protein that could provide 100% protection against challenge with virulent FAdV-4 strain HB1501 as well as elicit protective immunity was 2.5 MUg/bird. Neither clinical signs nor gross lesions were observed in chickens. In addition, immunization of specific-pathogen-free (SPF) chickens with recombinant fiber-2 protein (>=2.5 MUg/bird) could induce quicker and stronger immune responses than the inactivated oil-emulsion FAdV-4 vaccine. These findings provide important information about the development of subunit vaccines for the control of HHS. PMID- 29614325 TI - Equine-like G3 rotavirus strains as predominant strains among children in Indonesia in 2015-2016. AB - Rotavirus A (RVA) is a major cause of acute gastroenteritis in humans and animals worldwide. As a result of the segmented nature of the rotavirus genome, genetic reassortment commonly occurs. This study aims to clarify the genetic characteristics of RVAs circulating in Indonesia. From June 2015 through August 2016, stool samples were collected from 134 children aged <5 years (71 male and 63 female) with acute gastroenteritis who were inpatients at a private hospital in Surabaya, Indonesia. All stool samples were screened for RVA antigen using immunochromatography. Forty-two samples (31.3%, 42/134) were RVA antigen positive. All RVA positive samples tested showed the unusual combinations of G3P[8] (n = 36) and G3P[6] (n = 3) with a short RNA pattern by G/P typing and polyacrylamide gel electrophoresis (PAGE). Whole genome analysis by next generation sequencing (NGS) was performed for 11 strains to determine the RVA genotypes. Eleven rotavirus strains were found to carry a DS-like genetic backbone; nine strains showed a G3-P[8]-I2-R2-C2-M2-A2-N2-T2-E2-H2 genome constellation, which was recently reported in Australia, Hungary, Spain and Brazil; as well, two strains showed a G3-P[6]-I2-R2-C2-M2-A2-N2-T2-E2-H2 genome constellation. The phylogenetic tree based on the VP7 gene showed that all 11 strains were classified as equine-like G3, which is genetically distinct and different in origin from typical human G3 strains. The phylogenetic tree based on the NSP4 gene showed that six strains were classified as bovine-like strain and the remaining five were classified as human strain. In conclusion, we identified the strains which are intergenogroup reassortants containing an equine-like G3 VP7, a P[8])/P[6] VP4, with a DS-1-like genetic backbone. These findings suggest that equine-like G3P[8] and P[6] RVA strains have been circulating in the Indonesian population for at least 1 year and probably longer, indicating a diversity of RVAs in this area. PMID- 29614326 TI - Follicular Traction Urticaria. PMID- 29614327 TI - Neospora caninum in birds: A review. AB - Neospora caninum is an obligate intracellular protozoan parasite that infects domestic and wild animals. Canids are considered to be definitive hosts since they may shed oocysts into the environment through their feces. The disease is recognized as one of the major causes of bovine abortion worldwide, leading to important economic losses in the dairy and beef cattle industries. Previous studies have reported N. caninum infection in different species of birds; infection in birds has been associated with increased seroprevalence and reproductive problems in dairy cattle. Although the role of birds in the epidemiological cycle of neosporosis is unknown, birds are exposed to infection because they feed on the ground and could thus contribute to parasite dissemination. This review is focused on the current state of knowledge of neosporosis in birds. PMID- 29614328 TI - WITHDRAWN: Recommendations for evaluation and management of pain in patients with mucopolysaccharidosis in Latin America. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, https://doi.org/10.1016/j.jpainsymman.2018.03.023. The duplicate article has therefore been withdrawn. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our-business/policies/article-withdrawal. PMID- 29614329 TI - Presetting ECG electrodes for earlier heart rate detection in the delivery room. AB - AIM: To determine whether heart rate (HR) could be detected earlier than by pulse oximeter (POX), using a novel method of application of electrocardiogram (ECG) electrodes during neonatal resuscitation in the delivery room. METHODS: ECG electrodes were set before delivery to be applied to the back of infants' thorax. Time to detect HR was recorded as soon as a numerical HR along with a recognizable and persistent QRS complex was observed on ECG monitor (HRECG) and a plethysmographic waveform was seen on POX monitor (HRPOX). RESULTS: Out of 334 infants, 49 were <31 weeks of gestational age. Overall, the median (interquartile range, IQR) time to detect HRECG was significantly shorter [29 (5, 60) seconds] than time by POX [60 (45,120) seconds], (p < 0.001). Similarly, in <31-week infants, the median (IQR) time to detect HRECG was 10 (2, 40) seconds compared to 60 (30,120) seconds by POX, (p < 0.001). Failure to have HR detected by 1 minute occurred in 30%, 54% and 20% of infants by ECG, POX and either of the devices, respectively. CONCLUSION: In the delivery room, electrodes applied by the study method are more effective than pulse oximetry in providing the neonatal team with timely HR information that is necessary for proper resuscitative actions. PMID- 29614331 TI - Carnitine levels and mutations in the SLC22A5 gene in Faroes patients with Parkinson's disease. AB - INTRODUCTION: Mitochondrial dysfunction, oxidative stress and energy production have been implicated in the etiology of Parkinson's disease (PD). Several agents are under investigation for potential neuroprotective effects including acetyl-l carnitine (ALC). OBJECTIVE: To investigate whether low carnitine levels and mutations in the SLC22A5 gene encoding the carnitine transporter are associates with PD risk in the Faroe Islands where the prevalence of both PD and carnitine transporter deficiency (CTD) is high. METHODS: We conducted a case-control study with 121 cases and 235 randomly selected controls, matched by gender and age. Blood spots were analyzed for free and total carnitine levels by QUATTRO LC triple quadrupole mass spectrometry (MS/MS) and sequencing performed for five genetic mutations in the SLC22A5 gene with ABI PRISM 3130. RESULTS: PD cases had significantly lower levels of free and total carnitine levels compared with controls (P < .001). However, stratifying according to mutation status, the lower levels of carnitine was only evident among the non-mutation carriers. Specifically, no difference was found in c.95A > G mutation frequency in the SLC22A5 gene among cases and controls (p = .70). CONCLUSION: Low carnitine levels seem to be associated with PD, but only in individuals without the c.95A > G mutation rendering the carnitine transporter less efficient. Thus, the difference in carnitine levels is not caused by a higher frequency of c.95A > G mutation carriers in cases. The cause may be dietary or due to different gut microbiota among cases. PMID- 29614330 TI - Role of the equine CYP3A94, CYP3A95 and CYP3A97 in ketamine metabolism in presence of medetomidine, diazepam and methadone studied by enantioselective capillary electrophoresis. AB - The anesthetic ketamine is often combined with analgesics and benzodiazepines in equine medicine. Therefore, drug-drug interactions are possible. Enzyme kinetics for ketamine N-demethylation were determined using equine CYP3A94, CYP3A95 and CYP3A97, and the effect of medetomidine, diazepam and methadone on the ketamine metabolism was studied in vitro. Ketamine was incubated with the CYPs or equine liver microsomes (ELM) alone or in presence of medetomidine, diazepam and/or methadone for different times. Norketamine levels were determined using enantioselective capillary electrophoresis (CE) with highly sulfated gamma cyclodextrin as chiral selector. The three equine CYPs were demonstrated to be involved in ketamine N-demethylation and the kinetics can be described with the Michaelis-Menten model. Vmax values calculated for CYP3A94 and CYP3A97 were higher than for CYP3A95. The lowest Km value was found for CYP3A94. In contrast to diazepam and methadone, the alpha2-recepor agonist medetomidine diminished the norketamine formation significantly in CYP3A94 and CYP3A97. In ELM, increasing concentrations of diazepam inhibited the norketamine formation. Despite the differences in ketamine N-demethylation in combination with diazepam and methadone, the effect is unlikely to be of clinical relevance because ketamine and the other drugs do not have a small therapeutic margin. PMID- 29614333 TI - Pharmacological validation of individual animal locomotion, temperature and behavioural analysis in group-housed rats using a novel automated home cage analysis system: A comparison with the modified Irwin test. AB - BACKGROUND: The ActualHCATM system continuously monitors the activity, temperature and behavior of group-housed rats without invasive surgery. The system was validated to detect the contrasting effects of sedative and stimulant test agents (chlorpromazine, clonidine and amphetamine), and compared with the modified Irwin test (mIT) with rectal temperature measurements. METHODS: Six male Han Wistar rats per group were used to assess each test agent and vehicle controls in separate ActualHCATM recordings and mIT. The mIT was undertaken at 15, 30 mins, 1, 2, 4 and 24 h post-dose. ActualHCATM recorded continuously for 24 h post-dose under 3 experimental conditions: dosed during light phase, dark phase, and light phase with a scheduled cage change at the time of peak effects determined by mIT. RESULTS: ActualHCATM detected an increase stimulated activity from the cage change at 1-2 h post-dose which was obliterated by chlorpromazine and clonidine. Amphetamine increased activity up to 4 h post-dose in all conditions. Temperature from ActualHCATM was affected by all test agents in all conditions. The mIT showed effects on all 3 test agents up to 4 h post-dose, with maximal effects at 1-2 h post-dose. The maximal effects on temperature from ActualHCATM differed from mIT. Delayed effects on activity were detected by ActualHCATM, but not on mIT. CONCLUSIONS: Continuous monitoring has the advantage of capturing effects over time that may be missed with manual tests using pre determined time points. This automated behavioural system does not replace the need for conventional methods but could be implemented simultaneously to improve our understanding of behavioural pharmacology. PMID- 29614334 TI - Safety pharmacology in and for Africa: Establishment of the pre-clinical drug development platform. AB - Southern Africa (South Africa as well as neighboring countries) has not had an infrastructure for testing the safety of new drugs or other therapeutic entities, including plant-based or herbal treatments coming from the indigenous cultures, according to the current practice and regulatory requirements. Simultaneously, Southern Africa is challenged by very high rates of immune deficiency diseases which have further led to the resurgence of diseases such as tuberculosis, which is commonly thought to be eradicated, at least in Western cultures. Thus, there is high medical need for affordable, effective and safe treatments, but up to now there has been no local expertise and capabilities for state-of-the-art drug testing. Based on an initiative funded by the South African Department of Science and Technology, the Potchefstroom campus of North-West University was chosen for the establishment of a center of excellence for doing rodent-based drug testing research. The centerpiece of the Pre-Clinical Drug Development Platform (PCDDP) is a new rodent vivarium for breeding of SPF rats and mice and associated laboratories for conducting a wide range of physiological and pharmacological studies. Notably, the vivarium has become the first AAALAC-accredited animal facility in Sub-Sahara Africa and is qualified for conducting GLP studies. The establishment of safety pharmacology models is a first priority of the PCDDP, including expertise in studies to examine electrophysiological effects in vitro, and potential CNS, cardiovascular and respiratory effects. The intention is to offer the rodent-based safety pharmacology testing not only to local academic and company-related scientists, but also to those throughout South Africa and neighboring countries. PMID- 29614332 TI - New therapeutic approaches and novel alternatives for organophosphate toxicity. AB - Organophosphate compounds (OPCs) are commonly used as pesticides and were developed as nerve agents for chemical warfare. Exposure to OPCs results in toxicity due to their covalent binding and inhibition of acetylcholinesterase (AChE). Treatment for toxicity due to OPC exposure has been largely focused on the reactivation of AChE by oxime-based compounds via direct nucleophilic attack on the phosphorous center. However, due to the disadvantages to existing oxime based reactivators for treatment of OPC poisoning, we considered non-oxime mechanisms of reactivation. A high throughput screen of compound libraries was performed to discover previously unidentified reactivation compounds, followed by studies on their analogs. In the process, we discovered multiple non-oxime classes of compounds, the most robust of which we have already reported [1]. Herein, we report other classes of compounds we identified in our screen that are efficient at reactivation. During biochemical characterization, we also found some compounds with other activities that may inspire novel therapeutic approaches to OPC toxicity. Specifically, we found compounds that [1] increase the rate of substrate hydrolysis by AChE and, [2] protect the enzyme from inhibition by OPC. Further, we discovered that a subset of reactivator compounds recover activity from both AChE and the related enzyme butyrylcholinesterase (BuChE). We now report these compounds, their activities and discuss how each relates to therapeutic approaches that would provide alternatives to traditional oxime-based reactivation. PMID- 29614335 TI - Comparison of efficacy of TNF inhibitors and abatacept in patients with rheumatoid arthritis; Adjusted with propensity score matching. AB - The aim of this study was to compare the clinical outcome of patients with rheumatoid arthritis seen in routine clinical practice treated with either TNF inhibitors or abatacept. To overcome potential bias, both propensity score matching and Inverse Probability of Treatment Weighting were used for patient selection. The propensity score matching procedure selected 315 matched pairs of patients who were treated with TNF inhibitors or abatacept. At week 52, SDAI in TNF inhibitors was lower than abatacept. In contrast, analysis of biologics-naive patients using the propensity-score matching (n = 150; in each group) showed comparable clinical efficacy. Consistent results were obtained by the use of Inverse Probability of Treatment Weighting (581 patients treated with TNF inhibitors and 353 patients treated with abatacept). The predictors of response to each treatment were different; abatacept appeared to benefit patients with high baseline RF titers while TNF inhibitors appeared to benefit patients with low baseline HAQ-DI. PMID- 29614337 TI - Characterization of peripheral blood TCR repertoire in patients with ankylosing spondylitis by high-throughput sequencing. AB - Ankylosing spondylitis (AS) is a chronic and progressive autoimmune disease affecting the invasion of the spine, sacroiliac joints and peripheral joints. T cells play a vital role in the underlying pathogenesis of AS, which mediated autoimmune and inflammatory responses via specific recognition of autoantigen peptides presented by susceptibility HLA. Antigen-specific T cells triggered by HLA/antigen complexes will undergo a massive expansion that forming an uneven T cell repertoire. To enhance our understanding of T-cell-mediated autoimmune in AS, we applied TCR beta chains high-throughput sequencing to AS patients for in depth TCR repertoire analysis. A significantly lower TCR repertoire diversity was observed in peripheral blood of AS patients relative to controls. And severe patients in our AS cohort have a more restricted TCR repertoire than mild patients, suggesting that the TCR repertoire diversity might be associated with the clinical severity of disease. No V, J and VJ pairs with significant biased usage were identified, which indicated that the usage frequency deviation of certain V/J/V-J genes in AS patients is little. This is a pilot study with potentially interesting observation on reduced diversity of T cells repertoire in peripheral blood of AS patients and further studies are needed. PMID- 29614336 TI - Peripheral blood immune response-related gene analysis for evaluating the potential risk of chronic antibody-mediated rejection. AB - Noninvasive methods for the early diagnosis of chronic antibody-mediated rejection (cAMR) are desired for patients with de novo (dn) donor-specific HLA antibody (DSA). This study aimed to elucidate the clinical relevance of immune related gene expression in peripheral blood of kidney transplant recipients. The expression levels of fourteen key molecules (Foxp3, CTLA-4, CCR7, TGF-beta, IGLL 1, IL-10, ITCH, CBLB, Bcl-6, CXCR5, granzyme B, CIITA, Baff, TOAG-1/TCAIM) related to regulatory/cytotoxic function of immune cells were compared in 93 patients, which were divided into Groups A (clinical cAMR with dn DSA, n = 16), B (subclinical cAMR with dn DSA, n = 17), C (negative cAMR with dn DSA, n = 21) and D (stable function without dn DSA, n = 39). CIITA mRNA expression levels in groups B and C were significantly lower than those in group D (p < 0.01). Moreover, the CTLA-4 mRNA expression in group A was significantly higher than that in groups B and C (p < 0.01). ROC curve analysis suggested that CIITA (AUC = 0.902) and CTLA-4 (AUC = 0.785) may serve as valuable biomarkers of the stage of dn DSA production and clinical cAMR, respectively. In addition to dn DSA screening, monitoring of CIITA and CTLA-4 in peripheral blood could offer useful information on the time course of the development of cAMR. PMID- 29614338 TI - On the dilemma of fractal or fractional kinetics in drug release studies: A comparison between Weibull and Mittag-Leffler functions. AB - We compare two of the most successful models for the description and analysis of drug release data. The fractal kinetics approach leading to release profiles described by a Weibull function and the fractional kinetics approach leading to release profiles described by a Mittag-Leffler function. We used Monte Carlo simulations to generate artificial release data from euclidean and fractal substrates. We have also used real release data from the literature and found that both models are capable in describing release data up to roughly 85% of the release. For larger times both models systematically overestimate the number of particles remaining in the release device. PMID- 29614339 TI - Key gene co-expression modules and functional pathways involved in the pathogenesis of Graves' disease. AB - Graves' disease (GD) is a common autoimmune thyroid disease characterized by positive thyroid stimulating hormone receptor antibody. To better understand its molecular pathogenesis, we adopted the weighted gene co-expression network analysis to reveal co-expression modules of key genes involved in the pathogenesis of GD, protein-protein interaction network analysis to identify the hub genes related to GD development and functional analyses to explore their possible functions. Our results showed that 1) a total of 2667 differentially expressed genes in our microarray study and 16 different gene co-expression modules were associated with GD, and 2) the most significant module was associated with the percentage of macrophages, T follicular helper cells and CD4+ memory T cells and mainly enriched in immune regulation and immune response. Overall, our study reveals several key gene co-expression modules and functional pathways involved in GD, which provides some novel insights into the pathogenesis of GD. PMID- 29614340 TI - Maternal lipopolysaccharide exposure results in glucose metabolism disorders and sex hormone imbalance in male offspring. AB - An adverse intrauterine environment may be an important factor contributing to the development of type 2 diabetes in later life. The present study investigated the longitudinal effects of maternal lipopolysaccharide (LPS) exposure during the third trimester on glucose metabolism and sex hormone balance in the offspring. Pregnant mice were intraperitoneally injected with LPS (50 MUg/kg) daily from gestational day (GD) 15 to GD17. Glucose tolerance test (GTT) and insulin tolerance test (ITT) were assessed at postnatal day (PND) 60 and PND120. Sex hormones, their receptors, and metabolic enzymes (aromatase) were measured in male offspring at different phases of development (PND14: juvenile; PND35: adolescence; PND60: adulthood; and PND120: middle age). LPS-exposed male offspring exhibited glucose intolerance and insulin resistance by GTT and ITT at middle age, accompanied by an increase in fasting blood glucose and reductions in serum insulin levels and hepatic phosphorylated (p) -AKT/AKT ratio. However, glucose intolerance and insulin resistance were not observed in LPS-exposed female offspring. Maternal LPS exposure upregulated hepatic aromatase proteins and mRNA levels in male offspring at all time points. At adolescence, the testosterone/estradiol ratio (T/E2) was markedly reduced in LPS-exposed male offspring. Moreover, maternal LPS exposure significantly increased hepatic estrogen receptor (ER) alpha expressions and decreased hepatic androgen receptor (AR) expressions in male offspring. At adulthood, maternal LPS exposure increased serum estradiol levels, decreased serum testosterone levels and elevated hepatic ERbeta expressions in male offspring. In conclusion, maternal LPS exposure upregulated aromatase expressions, followed by a reduction in the T/E2 ratio and an alteration in sex hormone receptor activity, which might be involved in the development of glucose metabolism disorders in middle-aged male offspring. This study provides a novel clue and direction to clarify the pathogenesis of maternal infection-related diabetes in male offspring. PMID- 29614342 TI - Quantitative risk assessment of tobacco products: A potentially useful component of substantial equivalence evaluations. AB - Quantitative risk assessment (QRA), a scientific, evidence-based analytical process that combines chemical and biological data to quantify the probability and potential impact of some defined risk, is used by regulatory agencies for decision-making. Thus, in tobacco product regulation, specifically in substantial equivalence (SE) evaluations, QRA can provide a useful, practical, and efficient approach to address questions that might arise regarding human health risk and potential influence on public health. In SE reporting, when differences in product characteristics may necessitate the determination of whether a new product raises different questions of public health, the results from QRA are a valuable metric. An approach for QRA in this context is discussed, which is modeled after the methodology for assessment of constituent mixtures by the US Environmental Protection Agency for environmental Superfund site assessment. Given the intent in both cases is an assessment of the public health impact resulting from the totality of exposure to a mixture of constituents, the application is appropriate. Although some uncertainties in the information incorporated may exist, relying on the most appropriate of the available data increases the confidence and decreases the uncertainty in the risk characterization using this data-driven methodology. PMID- 29614341 TI - Lung pathologies analyzed with multi-frequency electrical impedance tomography: Pilot animal study. AB - In critically ill patients, correct diagnosis of lung disease is essential for successful therapy. Therefore, this study investigated whether new multi frequency electrical impedance tomography (mfEIT) can detect, monitor and differentiate between pathologies associated with the acute respiratory distress syndrome (ARDS). For this pilot study, 12 pigs were randomized into an ARDS (bronchoalveolar lavage) group (n = 7) and a healthy control group (n = 5). Animals were monitored by means of mfEIT. In addition to functional images, a new impaired-ventilation (rImpVent) index was developed and frequency-difference images were computed and analyzed. Amplitude functional images revealed only small differences between the groups. However, phase functional images were of greater importance in distinguishing between lung pathologies. Correlation images showed substantial differences between the two groups. The new rImpVent index achieved high sensitivity (91%) and specificity (92%) in detecting PaO2/FiO2 <= 200 mmHg. mfEIT was able to detect lung edema, differentiate this from atelectasis, and also monitor their progress over time in terms of global and regional differences. PMID- 29614343 TI - Criteria for grouping of manufactured nanomaterials to facilitate hazard and risk assessment, a systematic review of expert opinions. AB - With the emergence of nanotechnology the number of manufactured nanomaterials (MNM) in production and use is constantly increasing. Exposure of workers to MNM is of concern, because still much is unknown about health effects. MNM may have different properties, testing of each material is time consuming and costly. Experts have proposed various approaches to categorize MNM to facilitate risk assessment of human health effects based on shared properties of various materials. A systematic literature survey was undertaken to identify expert opinions on grouping of MNM published between the years 2000 and 2015. We summarized and synthesized the opinions according to a systematic review of text and opinion. We identified 22 articles that fulfilled our inclusion criteria reporting 17 proposals with three proposals for groups and 14 proposals for criteria for grouping. Five proposals suggested one or more of the following groups of concern: fibrous, biopersistent, high solubility with high toxicity, chemically active. Criteria proposed in multiple studies were: viable testing options, mode of action, physicochemical properties predicting toxicity. We conclude that a limited number of groups have been proposed to categorize MNM according to human health concern. Further research should be conducted to underpin the proposed groups with empirical evidence. PMID- 29614344 TI - Tubulointerstitial nephritis and uveitis (TINU) with granulomatosis: a novel report of simultaneous TINU and sarcoidosis in a pediatric patient. AB - We report the case of a 7-year-old girl who presented with bilateral anterior uveitis, acute interstitial nephritis, and asymptomatic pulmonary granulomas and provide novel clinical evidence of an association between tubulointerstitial nephritis and uveitis syndrome and sarcoidosis. PMID- 29614345 TI - Ancient hybridization and admixture in macaques (genus Macaca) inferred from whole genome sequences. AB - The evolutionary history of the stump-tailed macaque (Macaca arctoides) and its genetic relationship to other macaques is a subject of continuing controversy. Here, we have reported the first genome sequences of two stump-tailed macaques and one Assamese macaque (M. assamensis). Additionally, we have investigated the genetic diversity between macaque species and analyzed ancient hybridization events. Genome-wide analyses demonstrated that the stump-tailed macaque is more closely related to sinica species than to fascicularis/mulatta species. This topology contradicts the mitochondrial sequence-based phylogeny that places the stump-tailed macaque into the fascicularis/mulatta group. However, our results further show that stump-tailed macaques have genetic backgrounds distinct from sinica species, and present evidence of gene flows with rhesus macaques. We suggest that an ancient introgression occurred after stump-tailed macaques diverged from sinica species. The distinct gene flow between proto-arctoides and proto-mulatta resulted in the transfer of rhesus macaque-type mitochondria into proto-arctoides. The rhesus macaque-type mitochondria remained in populations because of genetic drift during the bottleneck. The PSMC results and morphological and geographic evidence are consistent with the mitochondria capture pattern in the stump-tailed macaque. The molecular clock estimates suggest that the mitochondrial transference into stump-tailed macaques occurred 0.4-1.4 million years ago. Furthermore, we detected extensive admixtures between different macaque species, indicating that gene flow has played an important role in the evolutionary history of the genus Macaca. PMID- 29614346 TI - Analysis of time-course microarray data: Comparison of common tools. AB - High-throughput time-series data have a special value for studying the dynamism of biological systems. However, the interpretation of such complex data can be challenging. The aim of this study was to compare common algorithms recently developed for the detection of differentially expressed genes in time-course microarray data. Using different measures such as sensitivity, specificity, predictive values, and related signaling pathways, we found that limma, timecourse, and gprege have reasonably good performance for the analysis of datasets in which only test group is followed over time. However, limma has the additional advantage of being able to report significance cut off, making it a more practical tool. In addition, limma and TTCA can be satisfactorily used for datasets with time-series data for all experimental groups. These findings may assist investigators to select appropriate tools for the detection of differentially expressed genes as an initial step in the interpretation of time course big data. PMID- 29614347 TI - Discovery of novel transcripts of the human tissue kallikrein (KLK1) and kallikrein-related peptidase 2 (KLK2) in human cancer cells, exploiting Next Generation Sequencing technology. AB - Tissue kallikrein, kallikrein-related peptidases (KLKs), and plasma kallikrein form the largest group of serine proteases in the human genome, sharing many structural and functional properties. Several KLK transcripts have been found aberrantly expressed in numerous human malignancies, confirming their prognostic or/and diagnostic values. However, the process of alternative splicing can now be studied in-depth due to the development of Next-Generation Sequencing (NGS). In the present study, we used NGS to discover novel transcripts of the KLK1 and KLK2 genes, after nested touchdown PCR. Bioinformatics analysis and PCR experiments revealed a total of eleven novel KLK transcripts (two KLK1 and nine KLK2 transcripts). In addition, the expression profiles of each novel transcript were investigated with nested PCR experiments using variant-specific primers. Since KLKs are implicated in human malignancies, qualifying as potential biomarkers, the quantification of the presented novel transcripts in human samples may have clinical applications in different types of cancer. PMID- 29614348 TI - Distinctive heritability patterns of subcortical-prefrontal cortex resting state connectivity in childhood: A twin study. AB - Connectivity between limbic/subcortical and prefrontal-cortical brain regions develops considerably across childhood, but less is known about the heritability of these networks at this age. We tested the heritability of limbic/subcortical cortical and limbic/subcortical-subcortical functional brain connectivity in 7- to 9-year-old twins (N = 220), focusing on two key limbic/subcortical structures: the ventral striatum and the amygdala, given their combined influence on changing incentivised behavior during childhood and adolescence. Whole brain analyses with ventral striatum (VS) and amygdala as seeds in genetically independent groups showed replicable functional connectivity patterns. The behavioral genetic analyses revealed that in general VS and amygdala connectivity showed distinct influences of genetics and environment. VS-prefrontal cortex connections were best described by genetic and unique environmental factors (the latter including measurement error), whereas amygdala-prefrontal cortex connectivity was mainly explained by environmental influences. Similarities were also found: connectivity between both the VS and amygdala and ventral anterior cingulate cortex (vACC) showed influences of shared environment, while connectivity with the orbitofrontal cortex (OFC) showed heritability. These findings may inform future interventions that target behavioral control and emotion regulation, by taking into account genetic dispositions as well as shared and unique environmental factors such as child rearing. PMID- 29614349 TI - Simulation for Training and Assessment in Hysteroscopy: A Systematic Review. AB - Hysteroscopy simulation complements conventional training on patients, yet evidence-based recommendations about its implementation and use are lacking. This systematic review analyzes and critically discusses hysteroscopy simulation literature published over the last 30 years. Systematic searches on PubMed, Embase, PsychINFO, ERIC, and the Cochrane Library produced 27 original articles published through 2017. Strategies based on different simulation models (e.g., animal organs, vegetables, synthetic uteri, virtual reality) were evaluated by users and appeared to facilitate learning. Observational studies have suggested a large impact on the knowledge and technical skills of novices for a wide range of hysteroscopic procedures, including for diagnosis, resection, and sterilization. Pretest/posttest studies show large improvements in performance time (6 studies; pooled effect size, 1.45; 95% confidence interval, 1.06-1.85) and overall performance scores (4 studies; pooled effect size, 3.19; 95% confidence interval, 1.45-4.94). Additionally, performance assessment on simulated models distinguishes novices from experts. Caution should be exercised because the available evidence largely originates from heterogeneous studies with weak designs, conducted in experimental settings with nonclinical participants (i.e., medical students). Moreover, neither clinical outcomes nor the clinical value of simulation-based assessment has been addressed. Hysteroscopy simulation may be supported ethically and pedagogically, but its role should be evaluated in pragmatic contexts, with robust interventional studies and broader competence defining outcomes that include nontechnical skills. PMID- 29614350 TI - The prosodic domain of phonological encoding: Evidence from speech errors. AB - Phonological encoding of segments is thought to occur within a prosodically defined frame, but it is not clear which of the constituent/s within the prosodic hierarchy (syllables, phonological words, intonational phrases and utterances) serve/s as the domain of phonological encoding. This experiment investigated whether segmental speech errors elicited in tongue-twisters were influenced by position within prosodic constituents above the level of the phonological word. Forty-four participants produced six repetitions each of 40 two-intonational phrase tongue-twisters with error-prone word-initial "target" segments in phrase initial and phrase-final words. If the domain of phonological encoding is the intonational phrase, we hypothesised that segments within a current intonational phrase would interact in more errors than would segments across intonational phrase boundaries. Participants made more anticipatory than perseveratory errors on target segments in phrase-initial words as predicted. They also made more perseveratory than anticipatory errors on targets in phrase-final words, but only in utterance-final phrases. These results suggest that the intonational phrase is one domain of phonological encoding, and that segments for upcoming phrases are activated while current phrases are being articulated. PMID- 29614351 TI - Revisiting norms of assertion. AB - A principal conclusion supported by convergent evidence from cognitive science, life science, and philosophy is that knowledge is a central norm of assertion that is, according to the rules of the practice, assertions should express knowledge. That view has recently been challenged with new experiments. This paper identifies a critical confound in the experiments. In the process, a new study is reported that provides additional support for the view that knowledge is a central norm of assertion. PMID- 29614352 TI - Place of Gamma Knife Stereotactic Radiosurgery in Grade 4 Vestibular Schwannoma Based on Case Series of 86 Patients with Long-Term Follow-Up. AB - INTRODUCTION: Grade IV vestibular schwannoma (Koos classification) is generally considered to be an indication for microsurgical resection or combined radiosurgery-microsurgery. However, the place of Gamma Knife stereotactic surgery (GK-SRS), either as first-line treatment or when progression of residual tumor compresses the brainstem, has not been clearly evaluated. This article reports the results of a large case series of patients with grade 4 vestibular schwannoma treated by GK-SRS. MATERIAL AND METHOD: All consecutive patients with grade IV vestibular schwannoma treated by GK-SRS in our department between 1996 and 2011 with a minimum follow-up of 3 years were included in this study. RESULTS: 86 patients were treated by GK-SRS with a minimum follow-up of 3 years. Mean follow up was 6.2 years (3-16 years). The mean age of the patients at the time of GK-SRS was 54.6 years (range: 23-84) and the sex ratio was 0.6. At the time of radiosurgery, no patient presented brainstem dysfunction prior to GK-SRS. 38 patients had functional hearing before treatment. One patient presented mild trigeminal neuralgia before GK-SRS. Tumor control with no clinical deterioration was obtained in 78 patients (90.7%). No radiation-induced brainstem or cranial nerve toxicity was observed in any of these patients. Functional hearing was maintained in 25 patients. 8 (9.3%) patients presented tumor growth and required microsurgical resection in 7 cases and ventricular shunt in 1 case. CONCLUSION: On the basis of this large series, GK-SRS appears to be a safe and effective treatment option for grade IV vestibular schwannoma for patients with no signs of brainstem dysfunction. PMID- 29614353 TI - Necrosulfonamide Attenuates Spinal Cord Injury via Necroptosis Inhibition. AB - OBJECTIVE: Spinal cord injury (SCI) is a serious trauma without efficient treatment currently. Necroptosis can be blocked post injury by special inhibitors. This study is to investigate the effects, mechanism, and potential benefit of necrosulfonamide (NSA) for SCI therapy. METHODS: Pathologic condition was detected using hematoxylin-eosin staining on injured spinal cord and other major organs. Necroptosis-related factors-RIP1, RIP3, and MLKL-were detected using Western blot. Detections on mitochondrial functions such as adenosine triphosphate generation and activities of superoxide dismutase and caspase-3 were also performed. Finally, ethologic performance was detected using a 21-point open field locomotion test. RESULTS: Reduced lesions and protected neurons were found in the injured spinal cord after treatment with NSA using hematoxylin-eosin staining for pathologic detection. No obvious toxicity on rat liver, kidney, heart, and spleen was detected. Rather than RIP1 and RIP3, MLKL was significantly inhibited by the NSA using Western blot detection. Adenosine triphosphate generation was obviously decreased post injury but slightly increased after the NSA treatment, especially 24 hours post injury. No significant changes were found on activities of superoxide dismutase and caspase-3 after the treatment of NSA. Ethologic performance was significantly improved using a 21-point, open-field locomotion test. CONCLUSIONS: Our research indicates NSA attenuates the spinal cord injury via necroptosis inhibition. It might be a potential and safe chemical benefit for SCI therapy. To our knowledge, this is the first study on the effects of NSA as treatment of traumatic SCI. PMID- 29614354 TI - Bony Dehiscence of the Horizontal Petrous Internal Carotid Artery Canal: An Anatomic Study with Surgical Implications. AB - OBJECTIVE: The cervical carotid segment is used routinely as donor site for high flow bypass procedures. The horizontal petrous segment would offer a shorter graft distance, complete graft protection intracranially, and avoid the need for surgical neck exposure. In a morphometric cadaveric study, we aimed to investigate variations of the petrous carotid anatomy, especially the incidence of bony dehiscence of the roof of the horizontal petrous carotid segment canal, which may facilitate exposure of the vessel and thereby potentially lower the morbidity of high-flow bypass procedures. METHODS: A subtemporal approach was used to expose the horizontal petrous internal carotid artery (ICA) on each side of 4 alcohol-embedded, silicone-injected human cadaver heads to perform a morphometric analysis of the vessel segment and surrounding bony anatomy. RESULTS: The following measurements were obtained of the horizontal petrous ICA (millimeters): long axis mean 9.6 (standard deviation [SD] 4.4, MIN 4.2, MAX 19.5), diameter mean 4.9 (SD 0.6, MIN 4, MAX 5.7), thickness of canal roof mean 2.1 (SD 1.7, MIN 0, MAX 5), and distance from temporal squama mean 22.5 (SD 6, MIN 17, MAX 35). Dehiscence of the bony roof of the horizontal petrous carotid canal was found in 25% of specimen investigated. CONCLUSIONS: A dehiscent bony roof of the horizontal petrous carotid canal potentially facilitates exposure of the vessel for high-flow bypass procedures and was observed in 25% of specimens. This feature could be identified on preoperative high-resolution imaging and thus aid in patient selection. PMID- 29614355 TI - A Rare Case of Brain Angiolipoma Imitating Arteriovenous Malformation: Differential Diagnosis, Surgical Treatment, and Literature Review. AB - BACKGROUND: Angiolipomas are mesenchymal tumors composed of mature adipocytes with abnormal vascular elements. They are most commonly found in subcutaneous tissues of the trunk and are rarely seen at craniospinal axes. CASE DESCRIPTION: We present an untypical case of frontal lobe angiolipoma manifested with seizures and initially described as an arteriovenous malformation. CONCLUSION: MRI with fat-suppression sequence plays key role in angiolipomas diagnostics. PMID- 29614356 TI - Application of Gelatin Sponge Impregnated with a Mixture of 3 Drugs to Intraoperative Nerve Root Block to Promote Early Postoperative Recovery of Lumbar Disc Herniation. AB - OBJECTIVE: To observe effect of application of gelatin sponge impregnated with a mixture of 3 drugs to intraoperative nerve root block to promote early postoperative recovery of lumbar disc herniation. METHODS: Retrospective analysis was performed of 265 patients with single-level lumbar disc herniation from January 2013 to October 2017. Patients were divided into intervention and control groups based on intraoperative application of gelatin sponge impregnated with a mixture of 3 drugs. All patients underwent unilateral minimally invasive surgical transforaminal lumbar interbody fusion. Clinical data, including bedridden period, postoperative hospital stay, visual analog scale scores for low back pain and leg pain, Japanese Orthopaedic Association score, postoperative satisfaction questionnaire results, and therapeutic effect, were collected. RESULTS: There were 136 cases in the intervention group and 129 cases in the control group. The intervention group had significantly shorter bedridden period and postoperative hospital stay than control group (P < 0.05). Visual analog scale scores for low back pain and leg pain at postoperative days 1-10 were significantly lower in the intervention group compared with control group (P < 0.05). The Japanese Orthopaedic Association score at postoperative day 6 and satisfaction at 72 hours postoperatively were significantly higher in the intervention group than in control group (P < 0.05). Clinical effect at postoperative day 6 was significantly better in the intervention group than control group (P < 0.05). CONCLUSIONS: Application of gelatin sponge impregnated with a mixture of 3 drugs to intraoperative nerve root block can significantly promote early postoperative recovery of lumbar disc herniation and has great short-term clinical efficacy. PMID- 29614357 TI - Primary Spinal Cord Melanoma: A Case Report and a Systemic Review of Overall Survival. AB - BACKGROUND: The incidence of primary spinal cord melanoma (PSCM) is rare. Several case series and case reports have been published in the literature. However, the predictive factors of PSCM survival and management options are not discussed in detail. METHODS: We present a case of PSCM; total resection was achieved and chemotherapy was given postoperatively. A comprehensive search was performed on PubMed's electronic database using the words "primary spinal cord melanoma." Survival rates with various gender, location, treatment, and metastasis condition were collected from the published articles and analyzed. RESULTS: Fifty nine cases were eligible for the survival analysis; 54% were male and 46% were female. Patient sex did not influence overall survival. The most common location was the thorax. Patient sex and tumor location did not influence overall survival. The major presenting symptoms were weakness and paresthesia of the extremities. Metastasis or dissemination was noted in 45.16% of 31 patients. In the Kaplan Meier survival analysis, patients who had metastasis had the worst prognosis. Extent of resection was not related to mortality. Patients who received surgery and surgery with adjuvant therapy had a better median survival than did those who had adjuvant therapy alone. Prognosis was worst in those patients who underwent only adjuvant therapy without surgery (5 months). CONCLUSIONS: Surgery is the first treatment of choice in treating PSCM. The goal of tumor resection is to reduce symptoms. Adjuvant therapy after surgery had a beneficial effect on limiting the metastasis. PMID- 29614358 TI - The Clinical Value of d-Dimer Level in Patients with Nonaneurysmal Subarachnoid Hemorrhage. AB - OBJECTIVE: More nonaneurysmal subarachnoid hemorrhage (NaSAH) are found in clinical practice. However, the precise mechanisms in which d-dimer level is associated with clinical condition in patients with NaSAH remain unclear. But even more, the data assessing the risk of clinical course in the patients with NaSAH are scarce. Our objective was to investigate whether d-dimer levels correlated with complication and outcome in patients with NaSAH. METHODS: Between February 2013 and May 2017, 92 patients suffering from NaSAH were treated in our hospital. Patient characteristics, radiologic features, laboratory findings, complications, and outcomes were analyzed retrospectively. Patients were stratified into the perimesencephalic (PM) subarachnoid hemorrhage (SAH) group and the nonperimesencephalic (NPM) SAH group according to the bleeding type, and the NPM-SAH group was further divided into 2 subgroups into the NPM-elevated group and the NPM-normal group based on the value of the d-dimer. After statistical analysis, the NPM-SAH and PM-SAH groups were compared; the same was true for the NPM-elevated group and the NPM-normal group. RESULTS: The rate of complications in the NPM-SAH group was higher than in the PM-SAH group, including early hydrocephalus, delayed cerebral ischemia, clinical vasospasm, pneumonia, and hyponatremia. Our results showed that d-dimer levels in patients with NPM-SAH were more elevated than in those with PM-SAH. Further analysis of subgroups demonstrated that patients with elevated d-dimer levels had a higher incidence of complications than those with normal d-dimer levels, especially the risks of shunt-dependent hydrocephalus and pneumonia. In addition, disability, and even death, could be seen in patients with higher levels of d-dimer, but the long-term outcomes were not particularly obvious between these groups. CONCLUSIONS: Elevated d-dimer levels on admission were significantly associated with complication in patients with NPM-SAH. In addition to conventional radiologic diagnosis, d-dimer levels can increase the ability of a rapid differential diagnosis between NPM-SAH and PM-SAH. PMID- 29614359 TI - Transient Splenial Lesion of the Corpus Callosum After Cabergoline Treatment. AB - BACKGROUND: Transient splenial lesion of the corpus callosum is an oval-shaped lesion in the center of the splenium of the corpus callosum. The disease characteristically occurs with restricted diffusion-weighted images. CASE DESCRIPTION: In the present study, we describe the magnetic resonance imaging findings of a patient with transient diffusion restriction in the splenium of the corpus callosum after cabergoline therapy. CONCLUSIONS: Cabergoline may be an unusual cause of transient splenial lesion of corpus callosum. PMID- 29614360 TI - Effectiveness of Stereotactic Radiotherapy and Bevacizumab for Recurrent High Grade Gliomas: A Potential Therapy for Isocitrate Dehydrogenase Wild-Type Recurrent High-Grade Gliomas. AB - OBJECTIVE: This study aimed to evaluate the efficacy of stereotactic radiotherapy combined with bevacizumab (SRT-Bv) compared with Bv treatment for recurrent high grade gliomas (HGGs). METHODS: Data for patients with recurrent HGGs who received SRT and Bv (n = 29) or Bv (n = 29) between June 2014 and September 2016 were retrospectively analyzed. All patients received conventional radiotherapy (total, 60 Gy) before this study. SRT was administered at a median dose of 42 Gy in 3-7 fractions. The recurrence pattern was classified into 3 groups: in-field, marginal, and out-field. RESULTS: The median overall survival in the SRT-Bv group was significantly longer than that in the Bv group (10.4 vs. 5.6 months; P = 0.02). In patients with isocitrate dehydrogenase wild-type tumors, the SRT-Bv treatment significantly prolonged survival more than the Bv treatment (10.9 vs. 8.2 months; P = 0.01). The World Health Organization grade and presence or absence of SRT were significant prognostic factors in the univariate analysis. Besides brain edema in 2 cases and asymptomatic subdural hematoma in 1 case, no other severe adverse effect due to SRT-Bv treatment was recorded. The pattern of recurrence was as follows: in-field, 2 cases (7%); marginal, 8 cases (28%); out field, 11 cases (38%); no recurrence on radiologic findings, 6 cases (21%); and uncertain, 2 cases (7%). CONCLUSIONS: SRT-Bv treatment significantly prolonged survival duration more than Bv treatment and provides good local control in patients with recurrent HGGs, especially those with isocitrate dehydrogenase wild type tumors. PMID- 29614361 TI - Effectiveness of Positron Emission Tomography/Computed Tomography as a Guide for Palliative Radiation Therapy for Spinal Metastases. AB - OBJECTIVE: As back pain is the presenting symptom in 95% of patients with epidural spinal metastases, appropriately identifying and treating the most symptomatic levels can provide significant palliation. The purpose of this study was to analyze the ability of combined positron emission tomography (PET)/computed tomography (CT) to identify spinal metastases with high metabolic activity and guide radiotherapy. We sought to correlate improvement in back pain with reduction in standard uptake value (SUV) after treatment. METHODS: Retrospective review was performed of 72 patients with spinal metastases treated with stereotactic ablative radiation therapy at a single center between 2002 and 2014. PET/CT was used to calculate SUVs for spinal metastases, and treatment planning was based on PET/CT results. Preoperative and postoperative pain levels were assessed in all patients. RESULTS: Reduction in pain scores was found in 78% of treated patients. A significant reduction in pain was identified in patients with >5 metastases compared with fewer lesions (P < 0.05). Degree of change in SUV did not correlate significantly with pain relief. However, comparing pretreatment and posttreatment PET/CT, patients with improved pain consistently displayed decreased SUV. CONCLUSIONS: PET/CT was shown to be a useful adjunct in radiation treatment planning with change in SUV correlating with symptomatic improvement. This study paves the way for future prospective studies to further assess utility and cost-effectiveness of this imaging modality in radiation treatment planning for spinal metastases. PMID- 29614362 TI - Spinal Cord Injury without Radiological Abnormality in Adults: Clinical and Radiological Discordance. AB - BACKGROUND: Patients with spinal cord injury without radiological abnormality (SCIWORA) show varying clinical prognostic courses independent of radiological findings. The fact that patients cannot be evaluated using a specific terminologic standard has led to the emergence of the real SCIWORA definition. In this study, clinical progressions of 11 patients diagnosed with SCIWORA were analyzed, and terminologic differences were discussed. METHODS: The clinical findings of 11 adults with a diagnosis of SCIWORA at the time of diagnosis and in the long term were analyzed according to the ASIA classification scheme. The presence of a correlation between radiological findings from the early and late periods and the clinical findings was investigated. High-dose methylprednisolone treatment was administered to all newly diagnosed patients in the early period, and the clinical response was observed. Clinical, prognostic, and radiological comparisons with SCIWORA cases reported in the literature were conducted. RESULTS: Seven patients received a diagnosis of cervical SCIWORA, and 4 patients had thoracal SCIWORA. Neurologic findings at the time of diagnosis and in the early and late periods vary independent of radiological findings. In the cases where significant neurologic recovery was not observed within the first 3 days, significant recovery also was not seen in the later period. In the cases where neurologic recovery was seen, improvements in sphincter function and sensory and motor deficits were observed. CONCLUSIONS: In patients diagnosed with SCIWORA, early neurologic response is the determining factor for prognosis. Clinical findings and prognosis demonstrate no correlation with radiological findings. PMID- 29614363 TI - Antiplatelet Premedication-Free Stent-Assisted Coil Embolization in Acutely Ruptured Aneurysms. AB - OBJECTIVE: Stent-assisted coil embolization (SAC) is one of the treatment options for patients with intracranial aneurysms. The purpose of this study was to assess clinical outcomes of patients who underwent coil embolization for acutely ruptured aneurysms without antiplatelet premedication. METHODS: A total of 449 patients with acutely ruptured aneurysms underwent endovascular treatment without antiplatelet premedication between April 2006 and October 2015. Among them, 55 patients underwent SAC (SAC group) and 394 underwent coiling without stent assistance (non-SAC group). Periprocedural complications and clinical outcomes at postictal 6 months were compared between the 2 groups. RESULTS: The rate of hemorrhagic complications showed no significant difference (SAC group vs. non-SAC group, 9.1% vs. 4.8%). Although procedural thromboembolism occurred more frequently in the SAC group (25.5% vs. 12.4%; P = 0.01), poor clinical outcomes (modified Rankin scale score >=3) were comparable (30.9% vs. 22.1%). In the multivariate analysis, Hunt-Hess grade (odds ratio [OR] = 4.22; P < 0.001), hemorrhagic complications (OR = 4.01; P = 0.018), and age (OR = 1.04, P = 0.001) were independent predictors of poor clinical outcomes, but stent-assisted coil embolization and procedural thromboembolism were not. CONCLUSIONS: Although procedure-related thromboembolism occurred more frequently, comparable treatment outcomes could be achieved with antiplatelet premedication-free SAC in patients with acutely ruptured aneurysms. The use of stents and thromboembolic complications were not significant risk factors for poor clinical outcome. PMID- 29614364 TI - Moderate Traumatic Brain Injury: Clinical Characteristics and a Prognostic Model of 12-Month Outcome. AB - BACKGROUND: Patients with moderate traumatic brain injury (TBI) often are studied together with patients with severe TBI, even though the expected outcome of the former is better. Therefore, we aimed to describe patient characteristics and 12 month outcomes, and to develop a prognostic model based on admission data, specifically for patients with moderate TBI. METHODS: Patients with Glasgow Coma Scale scores of 9-13 and age >=16 years were prospectively enrolled in 2 level I trauma centers in Europe. Glasgow Outcome Scale Extended (GOSE) score was assessed at 12 months. A prognostic model predicting moderate disability or worse (GOSE score <=6), as opposed to a good recovery, was fitted by penalized regression. Model performance was evaluated by area under the curve of the receiver operating characteristics curves. RESULTS: Of the 395 enrolled patients, 81% had intracranial lesions on head computed tomography, and 71% were admitted to an intensive care unit. At 12 months, 44% were moderately disabled or worse (GOSE score <=6), whereas 8% were severely disabled and 6% died (GOSE score <=4). Older age, lower Glasgow Coma Scale score, no day-of-injury alcohol intoxication, presence of a subdural hematoma, occurrence of hypoxia and/or hypotension, and preinjury disability were significant predictors of GOSE score <=6 (area under the curve = 0.80). CONCLUSIONS: Patients with moderate TBI exhibit characteristics of significant brain injury. Although few patients died or experienced severe disability, 44% did not experience good recovery, indicating that follow-up is needed. The model is a first step in development of prognostic models for moderate TBI that are valid across centers. PMID- 29614365 TI - The occurrence of immune priming can be species-specific in entomopathogens. AB - Immune priming in invertebrates refers to an improved immune response (and therefore a better chance of survival) upon a second encounter with a specific pathogen. Although the existence of immune priming has been evaluated in invertebrate hosts, the ability of a particular entomopathogen species or strain to influence the occurrence of immune priming has not been thoroughly evaluated. The aim of the current study was to compare the occurrence of immune priming in Tenebrio molitor larvae after homologous challenges (a dual exposure to similar entomopathogens) with Serratia marcescens, Bacillus thuringiensis and Metarhizium anisopliae. Larvae presented more effective immune priming (measured as survival rates) when exposed to M. anisopliae or B. thuringiensis than when exposed to S. marcescens. We hypothesize that the toll pathway may help T. molitor survive these enemies and that the IMD pathway may be expressed to a lesser degree in this species, which may explain why they succumb to Gram-negative bacteria. This and other recent evidence suggest that the occurrence of immune priming in these organisms must not be ruled out until this phenomenon is tested with different entomopathogens. PMID- 29614366 TI - Contributions of ferric uptake regulator Fur to the sensitivity and oxidative response of Acinetobacter baumannii to antibiotics. AB - Ferric uptake regulator (Fur) is important in the regulation of bacterial iron metabolism and uptake of Fe from the environment. We evaluated the contribution of fur to the sensitivity and oxidative response of A. baumannii to antibiotics. Deletion of fur increased the sensitivity of A. baumannii AB5075 to colistin, gentamicin, rifampicin and tigecycline. Furthermore, activities of superoxide dismutase and catalase in Deltafur mutant decreased significantly compared to the parental strain. Conversely, *O2- and H2O2 accumulate in colistin, gentamicin, rifampicin or tigecycline-treated Deltafur mutant compared to the parental strain. Ferrous ion (Fe2+) content of Deltafur mutant increased compared to the parental strain. Fe chelator 2,2'-bipyridyl lowered the sensitivity of A. baumannii to the antibiotics. The antibiotics, except tigecycline, raised the NAD+/NADH and ADP/ATP ratio of Deltafur mutant compared to the WT. Glutathione content of Deltafur mutant was significantly depleted compared to parental strain following exposure to the antibiotics. We conclude that decreased capability of Deltafur mutant to detoxify reactive oxygen species raised its susceptibility to antibiotics through Fenton chemistry. PMID- 29614367 TI - Expression and functional evaluation of CaZNF830 during pepper response to Ralstonia solanacearum or high temperature and humidity. AB - Extensive transcriptional reprogramming after pathogen attack determines immunity to these invaders and plant development. Zinc finger (ZNF) transcription factors regulate important processes in plants such as development, vegetative activities and plant immunity. Despite their immense significance, majority of ZNF transcription factors (TF) involved in pepper immunity and resistance to heat stress have not been focused much. Herein, we identified and functionally characterized CaZNF830 in pepper defense against Ralstonia solanacearum inoculation (RSI) and tolerance to high temperature and high humidity (HTHH). Transient expression analysis of CaZNF830-GFP fusion protein in tobacco leaves revealed its localization to the nucleus. Transcription of CaZNF830 is induced in pepper plants upon RSI or HTHH. Consistent with this, fluorometric GUS enzymatic assay driven by pCaZNF830 presented significantly enhanced activity under RSI and HTHH in comparison with the control plants. The silencing of CaZNF830 by virus induced gene silencing (VIGS) significantly compromised pepper immunity against RSI with enhanced growth of Ralstonia solanacearum in pepper plants. Silencing of CaZNF830 also impaired tolerance to HTHH coupled with decreased expression levels of immunity and thermo-tolerance associated marker genes including CaHIR1, CaNPR1, CaPR1, CaABR1 and CaHSP24. By contrast, the transient over-expression of CaZNF830 in pepper leaves by infiltration of GV3101 cells containing 35S::CaZNF830-HA induced HR mimic cell death, H2O2 accumulation and activated the transcriptions of the tested defense-relative or thermo-tolerance associated marker genes. RT-PCR and immune-blotting assay confirmed the stable expression of HA-tagged CaZNF830 mRNA and protein in pepper. All these results suggest that CaZNF830 acts as a positive regulator of plant immunity against RSI or tolerance to HTHH, it is induced by RSI or HTHH and consequently activate pepper immunity against RSI or tolerance to HTHH by directly or indirectly transcriptional modulation of many defense-linked genes. PMID- 29614368 TI - Serum galactomannan for diagnosing invasive aspergillosis in pediatric patients: A meta-analysis. AB - BACKGROUND: The serum galactomannan (GM) assay is used to diagnose invasive aspergillosis (IA). We conducted a systematic review and analysis to estimate the overall accuracy of the serum GM test for diagnosing pediatric IA. METHOD: A systematic literature review was conducted of all relevant studies published in PubMed and EMbase databases up to March 10, 2017. We selected and assessed articles that reported diagnostic data related to serum GM for diagnosis of pediatric IA. Pooled diagnostic odds ratios (DORs) and summary receiver operating characteristics (SROCs) were constructed with a cutoff value of 0.5. Additionally, pooled sensitivity (SEN), specificity (SPE), and positive and negative likelihood ratios (PLR and NLR, respectively) were estimated for summarizing overall test performance. RESULTS: Seventeen studies were included in this systematic review. The total number of patients (age range 0-21 years old) was 1768, with 178 that had proven or probable IA. The pooled serum GM assay results, with a cutoff value of 0.5 for proven or probable IA, were DOR: 41.16 (95% confidence interval (CI) 21.48-78.86), SEN: 0.85 (95% CI 0.72-0.93), SPE: 0.88 (95% CI 0.80-0.93), PLR: 6.92 (95% CI 4.40-10.88), and NLR: 0.17 (95% CI 0.09-0.32). The SROC was 0.93. CONCLUSION: Serum GM can be used to assist in diagnosis of proven or probable pediatric IA. However, serum GM test results should be interpreted in combination with clinical findings in pediatric IA cases, as the test results are not always sensitive or specific enough for pediatric IA. PMID- 29614369 TI - Candida parapsilosis isolates from burn wounds can penetrate an acellular dermal matrix. AB - We isolated and identified yeasts from burn wounds and evaluated the ability of Candida parapsilosis isolates from burn wounds to penetrate an acellular dermal matrix (ADM). A prospective study was conducted with patients from the burn treatment center of North Parana University Hospital in Londrina, Brazil from February 2015 to January 2016. Yeast cultures were obtained from the tissue of burn wounds that had been debrided and cleansed with 2% chlorhexidine. After identification and confirmation of the purity of the culture, the yeasts were placed on ADM fragments and incubated for three or seven days. During the study period, 273 patients were treated, and 36 of these patients fulfilled the inclusion criteria and provided samples for culture. Yeasts were isolated in 19.44% (n = 7) of the cultures, and the following species were identified: C. parapsilosis (57.1%), C. albicans (28.6%), and C. glabrata (14.3%). C. parapsilosis, the most frequent species, was chosen for the ADM tests. We demonstrated active penetration of the ADM by the yeast isolates from burn wounds. C. parapsilosis grew on ADM and penetrated the matrix, indicating that this yeast, which is common in skin and cutaneous wounds, has the potential to colonize and pass through ADM, a medical device that is frequently used to dress and regenerate burn wounds. PMID- 29614370 TI - Identification of oligopeptide-binding protein (OppA) and its role in the virulence of Streptococcus suis serotype 2. AB - The oligopeptide permease (Opp) cassette, an oligopeptide transport system belongs to the superfamily of ATP-binding cassette (ABC) transporter, is widely distributed in bacteria, including Streptococcus suis (S. suis). It is encoded by the opp operon containing oppA, oppB, oppC, oppD, and oppF. In addition to the uptake of peptide, the oppA gene also plays an important role in virulence of many pathogens. In this study, an oppA homologue from the highly virulent S. suis serotype 2 (S. suis 2) strain 05ZYH33 was identified. Flow cytometry and Western blot confirmed that OppA is a surface immunogenic protein and is expressed during S. suis 2 infection. To explore the role of oppA in S. suis 2 growth and pathogenicity, an isogenic 05ZYH33 mutant of oppA (?oppA) was obtained by homologous recombination. Although the complementary strain was not obtained due to the ?oppA strain is not transformable, the current data revealed that deletion of the oppA gene in S. suis 2 has greatly affected its growth and virulence. Our data revealed that the growth rate is significantly slow for the ?oppA. Adherence of the ?oppA strain to human epithelial cells is greatly reduced comparing to the wild strain. Mouse infection experiment showed that inactivation of oppA greatly attenuated the high pathogenicity of S. suis 2. The observed results suggest that OppA is a surface-exposed protein and plays important roles in the growth and pathogenicity of S. suis 2. PMID- 29614371 TI - First report of multidrug-resistant Escherichia coli isolates co-harbouring mcr-1 and blaOXA-48 from clinical patients in China. PMID- 29614372 TI - Incidence and risk of co-transmission of plasmid-mediated quinolone resistance and extended-spectrum beta-lactamase genes in fluoroquinolone-resistant uropathogenic Escherichia coli: a first study from Kolkata, India. AB - OBJECTIVES: Co-resistance to fluoroquinolones and beta-lactams results in treatment complications for uropathogenic Escherichia coli (UPEC) infections. This study aimed to detect the coexistence and co-transmission of plasmid mediated quinolone resistance (PMQR) and extended-spectrum beta-lactamase (ESBL) genes in UPEC from Kolkata, India. METHODS: Escherichia coli was detected biochemically from culture-positive urine samples. Antimicrobial resistance and ESBL production were confirmed by disk diffusion assay. Transfer of PMQR and ESBL genes was performed using azide-resistant E. coli J53 as recipient. PCR was conducted to identify PMQR and ESBL genes, plasmid incompatibility types, insertion sequences, integrons and ERIC-PCR patterns. RESULTS: PMQR determinants were detected in 50.0% (35/70) of ciprofloxacin-resistant isolates, with ESBL production in 42.9% (15/35) and a beta-lactamase inhibitor-resistant phenotype in 51.4% (18/35). The highest co-occurrence (37.1%; 13/35) and co-transmission of aac(6')-Ib-cr with blaTEM, blaCTX-M and blaOXA was observed. Among the conjugal plasmids, replicon types FrepB/FrepB+F1B were predominant, with rare incidences of A/C, N, X, I1, FIIS, L/M and H1. Distribution of integrons and ISEcp1 and IS26, either alone or in combination, irrespective of PMQR and ESBL gene types was observed. Discrete ERIC-PCR profiles indicated that acquisition of PMQR and ESBLs and their dissemination may be attributed to horizontal gene transfer. CONCLUSION: This study demonstrates for the first time the risk of co transmission of fluoroquinolone and beta-lactam resistance amongst UPEC from Kolkata, posing a major public-health threat and limiting treatment options. Monitoring at the molecular level is necessary to design appropriate prescription policies to combat the alarming rise in drug resistance amongst these uropathogens. PMID- 29614373 TI - PCR screening of antimicrobial resistance genes in faecal samples from Australian and Chinese children. AB - OBJECTIVES: Recent public awareness campaigns on the risk of antibiotic resistance in pathogenic microbes has placed pressure on governments to enforce stricter antimicrobial stewardship policies on hospitals and the agricultural industry. In this study, faecal samples from Australian and Chinese children were screened for the presence of antimicrobial resistance genes (ARGs) in order to identify demographics at risk of carriage of these genes and to examine antimicrobial stewardship policies from the two countries that may influence carriage. METHODS: Faecal samples from 46 Australian and 53 Chinese children were screened by PCR for the presence of six clinically relevant ARGs. Clinical and demographic data were also collected from each patient. RESULTS: More than 90% of faecal samples from Chinese children tested positive for beta-lactam, macrolide, tetracycline and aminoglycoside resistance genes, which was substantially higher than Australian samples. Besides country of origin, no clear trend could be seen to predict carriage of ARGs. The exception to this was Chinese-born children who immigrated to Australia having higher rates of carriage of blaTEM and tetM genes than children born and still living in Australia. CONCLUSIONS: These data indicate that Chinese children are more likely to carry certain ARGs than Australian children. The Chinese government has recently implemented strict policies to control the overuse of antibiotics in hospitals. However, many of these policies do not extend to the agricultural industry, which could explain the differences seen in this study. PMID- 29614374 TI - Running from fear: Exercise modulation of fear extinction. AB - Extinction-based exposure therapy is the most common behavioral therapy for anxiety and trauma-related disorders, but fear tends to resurface even after successful extinction. Identification of novel strategies to enhance fear extinction and reduce fear relapse is of paramount importance to mental health. Exercise can enhance cognitive function, but it is not yet well understood whether exercise can be an effective augmentation strategy for fear extinction. In the current review, we present the current state of knowledge on the effects of exercise on fear extinction. Effects of exercise duration, explanations for conflicting results, and potential mechanisms, focusing on a hypothesized role for dopamine, are all discussed. We also provide new data suggesting that the timing in which acute exercise occurs relative to fear extinction, is a crucial variable in determining whether exercise can enhance fear extinction. Clinical implications and ideas to guide future research endeavors in this area are provided. PMID- 29614375 TI - A1 adenosine receptors in the striatum play a role in the memory impairment caused by sleep deprivation through downregulation of the PKA pathway. AB - Sleep deprivation is known to affect memory formation, but how it interacts with different memory systems is not completely understood. Adenosine, a homeostatic regulator of sleep that has an increased extracellular concentration during sleep deprivation, is one of the neuromodulators that may be involved in this interaction. The A1 adenosine receptor is involved in both sleep regulation and memory formation. Among other pathways, the A1 receptor decreases cAMP levels in the cytosol and thus also regulates protein kinase A (PKA) and exchange protein activated by cAMP (EPAC) activity. To verify the role of the A1 receptor in the memory impairment caused by sleep deprivation, we tested the effect of 96 h of sleep deprivation (SD) and the administration of DPCPX, an A1 receptor antagonist on male Wistar rats prior to the training sessions for two memory tasks that relies on the hippocampal function: the multiple trial inhibitory avoidance (MTIA) task, which also requires the striatum, and the contextual fear conditioning (CFC) task, which does not. We also evaluated the effect of SD, DPCPX and the MTIA training session on the protein expression levels of the A1 receptor, PKA phosphorylation and EPAC activity in both the hippocampus and the striatum. Sleep deprivation impaired the performance in the test sessions of both tasks; DPCPX was able to prevent the impairment in the MTIA test but not in the CFC test. SD increased A1 receptor protein expression levels in the striatum but not in the hippocampus and also decreased PKA phosphorylation in both structures; DPCPX prevented this decrease in the striatum, but not in the hippocampus. Finally, SD had no effect on EPAC activity in either of the structures. These results indicate that the A1 adenosine receptors play a role in the memory impairment caused by sleep deprivation in tasks that involve the striatum through modulation of the cAMP/PKA pathway. PMID- 29614376 TI - Tell me what to do: Stress facilitates stimulus-response learning by instruction. AB - Learning by explicit instruction is a highly efficient way to instantaneously learn new behaviors and to overcome potentially harmful learning by trial-and error. Despite the importance of instructed learning for education, influences on the efficacy of an instruction are currently unknown. Decades of research, however, showed that stress is a powerful modulator of learning and memory, including the acquisition of stimulus-response (S-R) associations. Moreover, brain areas critical for instructed learning are a major target of hormones and neurotransmitters released during stress. Thus, we investigated here whether acute stress affects instructed S-R learning and whether this effect differs for trial-and-error learning. To this end, healthy participants underwent a stressor (Socially Evaluated Cold Pressor Test) or a control manipulation before learning arbitrary S-R associations. For half of the stimuli, participants were explicitly instructed about the correct association, whereas the remaining associations had to be learned by trial-and-error. As expected, the instruction resulted in better performance and enhanced explicit rule knowledge compared to trial-and-error learning. Stress further boosted the beneficial effect of an explicit instruction on learning performance, while leaving trial-and-error learning unchanged. These beneficial effects of stress were directly correlated with the activity of the autonomic nervous system and the concentration of cortisol. Moreover, acute stress could override the detrimental effect of high trait anxiety levels on instructed S-R learning performance. Our findings indicate that acute stress may facilitate learning from instruction, which may represent a highly efficient way to learn how to act, without the necessity of own experience, that helps to save cognitive resources during a stressful encounter. PMID- 29614377 TI - Neural representations of time-linked memory. AB - Many cognitive processes, such as episodic memory and decision making, rely on the ability to form associations between two events that occur separately in time. The formation of such temporal associations depends on neural representations of three types of information: what has been presented (trace holding), what will follow (temporal expectation), and when the following event will occur (explicit timing). The present review seeks to link these representations with firing patterns of single neurons recorded while rodents and non-human primates associate stimuli, outcomes, and motor responses over time intervals. Across these studies, two distinct firing patterns were observed in the hippocampus, neocortex, and striatum: some neurons change firing rates during or shortly after the stimulus presentation and sustain the firing rate stably or sidlingly during the subsequent intervals (tonic firings). Other neurons transiently change firing rates during a specific moment within the time intervals (phasic firings), and as a group, they form a sequential firing pattern that covers the entire interval. Clever task designs used in some of these studies collectively provide evidence that both tonic and phasic firing responses represent trace holding, temporal expectation, and explicit timing. Subsequently, we applied machine-learning based classification approaches to the two firing patterns within the same dataset collected from rat medial prefrontal cortex during trace eyeblink conditioning. This quantitative analysis revealed that phasic-firing patterns showed greater selectivity for stimulus identity and temporal position than tonic-firing patterns. Our summary illuminates distributed neural representations of temporal association in the forebrain and generates several ideas for future investigations. PMID- 29614378 TI - The role of avoidance behavior in the treatment of adolescents with irritable bowel syndrome: A mediation analysis. AB - Irritable bowel syndrome (IBS) is common in adolescents with a pronounced negative impact on quality of life. A pattern of avoidance behavior is commonly seen in the IBS population, which is associated with more gastrointestinal (GI) symptoms. Exposure-based cognitive behavior therapy (CBT) targets the avoidance behavior to reduce symptoms, but it is unknown whether reduced avoidance is a mediator of symptom improvement in adolescent IBS. Stress has been suggested to play a key role in worsening GI symptoms and is also a potential mediator of the treatment effect in IBS. This study was based on data from a randomized controlled trial (N = 101) that evaluated exposure-based internet-delivered CBT (Internet-CBT) compared with a wait-list for adolescents with IBS. We investigated whether avoidance behavior and perceived stress mediated the improvement in global GI symptoms due to treatment. We found that a change in avoidance behavior, but not perceived stress, mediated the effect of exposure based Internet-CBT on GI symptoms. The decrease in avoidance behavior explained a large portion (67%) of the total treatment effect. Moreover, a unidirectional relationship over time was observed between avoidance behavior and GI symptoms. Our conclusion is that exposure-based CBT in adolescent IBS reduces avoidance and, consequently, reduces GI symptoms. PMID- 29614380 TI - Serotonin as a link between the gut-brain-microbiome axis in autism spectrum disorders. AB - Autism-spectrum disorder (ASD) is a neurodevelopmental disorder characterized by persistent deficits in social communication and repetitive patterns of behavior. ASD is, however, often associated with medical comorbidities and gastrointestinal (GI) dysfunction is among the most common. Studies have demonstrated a correlation between GI dysfunction and the degree of social impairment in ASD. The etiology of GI abnormalities in ASD is unclear, though the association between GI dysfunction and ASD-associated behaviors suggest that overlapping developmental defects in the brain and the intestine and/or a defect in communication between the enteric and central nervous systems (ENS and CNS, respectively), known as the gut-brain axis, could be responsible for the observed phenotypes. Brain-gut abnormalities have been increasingly implicated in several disease processes, including ASD. As a critical modulator of ENS and CNS development and function, serotonin may be a nexus for the gut-brain axis in ASD. This paper reviews the role of serotonin in ASD from the perspective of the ENS. A murine model that has been demonstrated to possess brain, behavioral and GI abnormalities mimicking those seen in ASD harbors the most common serotonin transporter (SERT) based mutation (SERT Ala56) found in children with ASD. Discussion of the gut-brain manifestations in the SERT Ala56 mice, and their correction with developmental administration of a 5-HT4 agonist, are also addressed in conjunction with other future directions for diagnosis and treatment. PMID- 29614379 TI - Meal and snack-time eating disorder cognitions predict eating disorder behaviors and vice versa in a treatment seeking sample: A mobile technology based ecological momentary assessment study. AB - Individuals with eating disorders experience high anxiety when eating, which may contribute to the high relapse rates seen in the eating disorders. However, it is unknown if specific cognitions associated with such anxiety (e.g., fears of gaining weight) may lead to engagement in eating disorder behaviors (e.g., weighing oneself). Participants (N = 66) recently treated at a residential eating disorder facility and diagnosed with an eating disorder (primarily anorexia nervosa; n = 40; 60.6%) utilized a mobile application to answer questions about mealtime cognitions, anxiety, and eating disorder behaviors four times a day for one week. Hierarchical linear models using cross-lag analyses identified that there were quasi-causal (and sometimes reciprocal) within-person relationships between specific eating disorder cognitions and subsequent eating disorder behaviors. These cognitions predicted higher anxiety during the next meal and eating disorder pathology at one-month follow-up. Interventions personalized to target these specific cognitions in real time might reduce eating disorder relapse. PMID- 29614381 TI - Phytosome complex of curcumin as complementary therapy of advanced pancreatic cancer improves safety and efficacy of gemcitabine: Results of a prospective phase II trial. AB - A large body of biomedical evidence indicates that activation of Nrf2 by curcumin increases the nucleophilic tone and damps inflammation cumulatively supporting the malignant phenotype. Conversely, genetic analyses suggest a possible oncogenic nature of constitutive Nrf2 activation since an increased nucleophilic tone is alleged increasing chemoresistance of cancer cells. Aiming to contribute to solve this paradox, this study addressed the issue of safety and efficacy of curcumin as complementary therapy of gemcitabine on pancreatic cancer. This was a single centre, single arm prospective phase II trial. Patients received gemcitabine and Meriva(r), a patented preparation of curcumin complexed with phospholipids. Primary endpoint was response rate, secondary endpoints were progression free survival, overall survival, tolerability and quality of life. Analysis of inflammatory biomarkers was also carried out. Fifty-two consecutive patients were enrolled. Forty-four (13 locally advanced and 31 metastatic) were suitable for primary endpoint evaluation. Median age was 66 years (range 42-87); 42 patients had Eastern Cooperative Oncology Group performance status 0-1. The median number of treatment cycle was 4.5 (range 2-14). We observed 27.3% of response rate and 34.1% of cases with stable disease, totalizing a disease control rate of 61.4%. The median progression free survival and overall survival were 8.4 and 10.2 months, respectively. Higher IL-6 and sCD40L levels before treatment were associated to a worse overall survival (p < 0.01). Increases in sCD40L levels after 1 cycle of chemotherapy were associated with a reduced response to the therapy. Grade 3/4 toxicity was observed (neutropenia, 38.6%; anemia, 6.8%). There were no significant changes in quality of life during therapy. In conclusion, the complementary therapy to gemcitabine with phytosome complex of curcumin is not only safe but also efficiently translate in a good response rate in first line therapy of advanced pancreatic cancer. PMID- 29614382 TI - Extended exposure duration of cultured intestinal epithelial cell monolayers in characterizing hazardous and non-hazardous proteins. AB - Recent studies suggest that human derived intestinal epithelial cells (IECs) cultured as polarized monolayers on Transwell(r) filters may respond differently when exposed to hazardous and non-hazardous proteins. This experimental platform was based on apical exposure of IEC monolayers to test proteins for 24 h followed by assessment of barrier integrity and cell viability. In this study, Caco-2 and T84 IEC polarized monolayers were evaluated for barrier integrity and cytotoxicity following exposure to hazardous and non-hazardous proteins for 24, 48 and 72 h. Hazardous proteins included Clostridium difficile toxin A (ToxA), Streptolysin O (SLO), Wheat Germ Agglutinin (WGA), and Phaseolus vulgaris haemagglutinin-E (PHA-E). Non-hazardous proteins included bovine serum albumin (BSA), porcine serum albumin (PSA), and fibronectin (Fbn). In general, evidence of diminished barrier integrity or cell viability observed following exposure to hazardous proteins for 24 h was more pronounced after 48 and 72 h for both IEC monolayers. Non-hazardous proteins exhibiting no impact following 24 h of exposure elicited minimal effects over longer exposure durations. These results support the utility of using cultured human IEC polarized monolayers to differentiate between hazardous and non-hazardous proteins and suggest that longer durations of exposure may further improve the ability to distinguish between them. PMID- 29614383 TI - Evidence of insulin-dependent signalling mechanisms produced by Citrus sinensis (L.) Osbeck fruit peel in an insulin resistant diabetic animal model. AB - Citrus sinensis (L.) Osbeck is extensively cultivated worldwide and one of the most consumed fruits in the world. We evaluated the therapeutic properties of the methanol extract from Citrus sinensis fruit peel (CSMe) in high-fat diet-fed streptozotocin-induced insulin-resistant diabetic rats. Body weight, food intake, and water consumption were analysed. Biochemical and molecular biologic indices, and the expression of insulin receptor-induced signalling molecules were assessed to identify possible mechanisms. In addition, we conducted histology of pancreatic and adipose tissues. UHPLC-MS/MS analysis showed the presence of 17 dietary phenolics at substantial concentrations. High-fat diet-fed streptozotocin induced diabetic rats administered CSMe (50 and 100 mg/kg) had reduced fasting blood glucose (56.1% and 55.7%, respectively) and plasma insulin levels (22.9% and 32.7%, respectively) compared with untreated diabetic control rats. CSMe reversed the biochemical abnormalities in diabetic rats, showed cytoprotective activity, and increased the intensity of the positive immunoreactions for insulin in pancreatic islets. CSMe treatment increased the expression of PPARgamma in the adipose tissue and signalling molecules GLUT4 and insulin receptor. Our data suggest that CSMe could optimize glucose uptake of adipose tissues through the insulin-dependent signalling cascade mechanism and it should be investigated in the management of individuals with type 2 diabetes mellitus. PMID- 29614384 TI - Proteomic approaches to investigate age related vulnerability to lindane induced neurodegenerative effects in rats. AB - Proteomic studies were carried out in immature (3 week), adult (18 week) and aged (48 week) rats to understand the age dependent vulnerability to lindane induced neurodegeneration. 2-D and western blot analysis of protein extracts of hippocampus and substantia-nigra isolated from lindane treated rats (2.5 mg/kg; p.o. X 21 days) revealed marked dysregulation in the expression of proteins related to ubiquitin proteasome pathway, antioxidant activity, chaperones, energy metabolism, calcium homeostasis and proteins involved in neurodegeneration. These alterations were associated with marked increase in reactive oxygen species formation, lipid peroxidation, reduced glutathione content and antioxidant enzyme activities in lindane treated rats. Aged rats, in particular showed higher magnitude of alteration in these proteins when compared to immature or adult rats. Proteins involved in apoptosis and autophagy also showed marked alterations in their expression, particularly in the aged rats. Ultrastructural analysis revealed greater number of autophagic vesicle in hippocampus and substantia-nigra in treated aged rats. The data suggest that proteomic approaches could be used to investigate the vulnerability to lindane induced neurodegeneration in rats. PMID- 29614385 TI - Consequences of a recent past dengue infection for acute and long-term chikungunya outcome: A retrospective cohort study in Curacao. AB - BACKGROUND: Dengue and chikungunya co-infections are an emerging threat to public health in tropical and sub-tropical areas. This study investigates acute and long term clinical presentation patterns of chikungunya against a backdrop of preceding dengue infection and determines predicting factors for long-term chikungunya sequelae. METHODS: A retrospective cohort study was performed in 2015, including 299 previously confirmed chikungunya cases, of which 162 subjects were assessed for dengue serology at disease onset. RESULTS: Those with previous dengue infection (35.2% of the examined population) had a similar acute disease presentation, and suffered (not statistically significantly) more frequently from long-term musculoskeletal and neuropsychological symptoms compared to chikungunya only patients. Patients with a preceding dengue infection (vs. those without) (OR = 4.17; p = 0.004), female sex (OR = 3.17; p = 0.034) and pre-existing joint disease (OR = 2.95; p = 0.031) had a higher risk of developing aggravated long term chikungunya. Chronic disease (sequelae lasting >90 days) was predicted by an age between 41 and 60 (OR = 3.07; p = 0.009) and concomitant cardiovascular disease (OR = 4.08; p = 0.010), but not by a preceding dengue infection. CONCLUSIONS: This study suggests several predicting factors of, and a possible link between preceding dengue and chikungunya infection and aggravated long-term sequelae, which should be interpreted in the light of the limitations of this study. PMID- 29614386 TI - Residential agricultural pesticide exposures and risks of preeclampsia. AB - We investigated risks of preeclampsia phenotypes from potential residential pesticide exposures, including 543 individual chemicals and 69 physicochemical groupings that were applied in the San Joaquin Valley of California during the study period, 1998-2011. The study population was derived from birth certificate data linked with Office of Statewide Health Planning and Development maternal and infant hospital discharge data. The following numbers of women with preeclampsia phenotypes were identified: 1045 with superimposed (pre-existing hypertension with preeclampsia) preeclampsia (265 with gestational weeks 20-31 and 780 with gestational weeks 32-36); 3471 with severe preeclampsia (824 with gestational weeks 20-31 and 2647 with gestational weeks 32-36); and 2780 with mild preeclampsia (207 with gestational weeks 20-31 and 2573 with gestational weeks 32 36). The reference population for these groups was 197,461 women who did not have diabetes (gestational or pre-existing), did not have any hypertensive disorder, and who delivered at 37 weeks or later. The frequency of any exposure was lower or about the same in each preeclampsia case group (further delineated by gestational age), and month time period, relative to the frequency in reference population controls. Nearly all odds ratios were below 1.0 for these any vs no exposure comparisons. This study showed a general lack of increased risks between a range of agriculture pesticide exposures near women's residences and various preeclampsia phenotypes. PMID- 29614387 TI - Creation of virtual patients for midwifery education. AB - OBJECTIVE: The objective of the study was to create several new, original virtual patients (VPs) in the Slovak language, especially for educational purposes in midwifery. SETTING: Virtual patients have been created for the needs of university midwifery education in Slovakia. MODEL: The creation of the six virtual patients basically consisted of three fixed stages: preparation, design and development, implementation into the virtual environment. We used the Open Labyrinth (OL) virtual environment, an open-source system for creating VPs. The VPs include six various scenarios of the most common problems seen in midwifery practice: preterm birth, perinatal loss, gestational diabetes, ineffective breastfeeding, postpartum bleeding and sudden home birth. FINDINGS: Currently, six original virtual patients are used in university midwifery education in Slovakia. We use them for contact teaching as well as self-study of students. They present the first VPs in Slovakia and the Czech Republic created in academic settings in these countries. CONCLUSIONS: The future perspective of a virtual patient as an interactive process between the student and the medium is that it can deepen and improve learning outcomes, solve specific midwifery issues, and reduce mistakes in the clinical environment. PMID- 29614388 TI - Who are the European youths willing to engage in radicalisation? A multidisciplinary review of their psychological and social profiles. AB - BACKGROUND: A new model of radicalisation has appeared in Western countries since the 2010s. Radical groups are smaller, less hierarchical and are mainly composed of young, homegrown individuals. The aim of this review is to decipher the profiles of the European adolescents and young adults who have embraced the cause of radical Islamism and to define the role of psychiatry in dealing with this issue. METHODS: We performed a systematic search in several databases from January 2010 to July 2017 and reviewed the relevant studies that included European adolescents and/or young adults and presented empirical data. RESULTS: In total, 22 qualitative and quantitative studies were reviewed from various fields and using different methodologies. Psychotic disorders are rare among radicalised youths. However, they show numerous risk factors common with adolescent psychopathologies. We develop a comprehensive three-level model to explain the phenomenon of radicalisation among young Europeans: (1) individual risk factors include psychological vulnerabilities such as early experiences of abandonment, perceived injustice and personal uncertainty; (2) micro environmental risk factors include family dysfunction and friendships with radicalised individuals; (3) societal risk factors include geopolitical events and societal changes such as Durkheim's concept of anomie. Some systemic factors are also implicated as there is a specific encounter between recruiters and the individual. The former use sectarian techniques to isolate and dehumanise the latter and to offer him a new societal model. CONCLUSION: There are many similarities between psychopathological manifestations of adolescence and mechanisms at stake during the radicalisation process. As a consequence, and despite the rarity of psychotic disorders, mental health professionals have a role to play in the treatment and understanding of radical engagement among European youth. Studies with empirical data are limited, and more research should be promoted (in particular in females and in non-Muslim communities) to better understand the phenomenon and to propose recommendations for prevention and treatment. PMID- 29614389 TI - Duration of active psychosis and functional outcomes in first-episode non affective psychosis. AB - BACKGROUND: The duration of untreated psychosis (DUP) has been associated with negative outcomes in psychosis; however, few studies have focused on the duration of active psychotic symptoms after commencing treatment (DAT). In this study, we aimed to evaluate the effect of DUP and DAT on functional long-term outcomes (3 years) in patients with early psychosis. METHODS: We evaluated the Scale for the Assessment of Positive Symptoms (SAPS) at frequent intervals for 3 years after presentation to determine the DAT for 307 individuals with first-episode psychosis together with DUP and clinical variables. The functional outcomes were assessed using the Disability Assessment Scale (DAS) at three years, and functional recovery was defined as minimal impairment and return to activity. Associated variables, DAT and DUP were included in logistic regression models to predict functional outcomes. Receiver operating characteristic curves and Youden's index were applied to assess the best cut-off values. RESULTS: DAT, (Wald: 13.974; ExpB: 1.097; p < 0.001), premorbid adjustment, initial BPRS score, gender, age of onset and schizophrenia diagnosis were significant predictors of social functioning, whereas only premorbid adjustment (Wald: 11.383; ExpB:1.009), DAT (Wald: 4.850; ExpB: 1.058; p = 0.028) and education were significant predictors of recovery. The optimal cut-off of DAT for predicting social functioning was 3.17 months for DAT (sensitivity: 0.68; specificity: 0.64; Youden's index: 0.314). CONCLUSIONS: DAT is strongly related to functional outcomes independent of the DUP period or other variables. As a modifiable variable, the reduction of the DAT should be considered a main focus of intervention from the onset of the illness to improve long-term outcomes. PMID- 29614390 TI - Can neuropsychological testing facilitate differential diagnosis between at-risk mental state (ARMS) for psychosis and adult attention-deficit/hyperactivity disorder (ADHD)? AB - BACKGROUND: Patients with an at-risk mental state (ARMS) for psychosis and patients with attention-deficit/hyperactivity disorder (ADHD) have many overlapping signs and symptoms and hence can be difficult to differentiate clinically. The aim of this study was to investigate whether the differential diagnosis between ARMS and adult ADHD could be improved by neuropsychological testing. METHODS: 168 ARMS patients, 123 adult ADHD patients and 109 healthy controls (HC) were recruited via specialized clinics of the University of Basel Psychiatric Hospital. Sustained attention and impulsivity were tested with the Continuous Performance Test, verbal learning and memory with the California Verbal Learning Test, and problem solving abilities with the Tower of Hanoi Task. Group differences in neuropsychological performance were analyzed using generalized linear models. Furthermore, to investigate whether adult ADHD and ARMS can be correctly classified based on the pattern of cognitive deficits, machine learning (i.e. random forests) was applied. RESULTS: Compared to HC, both patient groups showed deficits in attention and impulsivity and verbal learning and memory. However, in adult ADHD patients the deficits were comparatively larger. Accordingly, a machine learning model predicted group membership based on the individual neurocognitive performance profile with good accuracy (AUC = 0.82). CONCLUSIONS: Our results are in line with current meta-analyses reporting that impairments in the domains of attention and verbal learning are of medium effect size in adult ADHD and of small effect size in ARMS patients and suggest that measures of these domains can be exploited to improve the differential diagnosis between adult ADHD and ARMS patients. PMID- 29614391 TI - Grey matter or social matters? Causal attributions in the era of biological psychiatry. PMID- 29614392 TI - Injecting drug use: Gendered risk. AB - BACKGROUND: Research demonstrates gender related differences in drug-use practices and risk behaviours. Females' structural vulnerability stemming from traditional gender roles and gender-power relations may enhance their propensity to experience injecting related risk. In this paper we explore gender differences in injection practices at the initiation event, during the first year of injecting and in the most recent 12-month period, to inform more effective harm reduction strategies. METHODS: Data used in this study were drawn from the Global Drug Survey 2015. The study employs chi-square and logistic regression to assess gender differences in injection behaviours in a sample of current injectors residing in six global regions: North-West Europe; Southern Eastern Europe; North America. South America and Oceania. RESULTS: Females were more likely than males to report being injected by an intimate partner at initiation (OR = 4.4, 95%CI: 2.2-8.8), during the first year of injecting (OR = 4.8, 95% CI: 2.4-9.3) and in the most recent 12-month period (OR = 2.5, 95%CI: 1.0-6.2). Females reported greater difficulties accessing sterile equipment (X2(2,N = 453) = 8.2, p = 0.02) and were more likely to share injecting equipment than males (X2(1,N = 463) = 3.9, p = 0.05). CONCLUSIONS: Our findings highlight females' continued dependence on their intimate partner to administer the injection into the first year of their injecting career. Females remained more likely than males to rely on intimate partners for injection during the most recent 12-month period. Females report greater difficulties in sourcing sterile equipment and are more likely to share injecting equipment. We suggest that these findings reflect the broader social structure in which females are disempowered through traditional gender roles and the lack of gender appropriate harm reduction services. PMID- 29614393 TI - Lenalidomide treatment in lower risk myelodysplastic syndromes-The experience of a Czech hematology center. (Positive effect of erythropoietin +/- prednisone addition to lenalidomide in refractory or relapsed patients). AB - Lenalidomide therapy represents meaningful progress in the treatment of anemic patients with myelodysplastic syndromes with del(5q). We present our initial lenalidomide experience and the positive effect of combining erythropoietin and steroids with lenalidomide in refractory and relapsed patients. We treated by lenalidomide 55 (42 female; 13 male; median age 69) chronically transfused lower risk MDS patients with del(5q) (45) and non-del(5q) (10). Response, meaning transfusion independence (TI) lasting >= eight weeks, was achieved in 38 (90%) of analyzed patients with del(5q), of whom three achieved TI only by adding erythropoietin +/- prednisone. Another five patients responded well to this combination when their anemia relapsed later during the treatment. In the non del(5q) group only one patient with RARS-T reached TI. Cytogenetic response was reached in 64% (32% complete, 32% partial response). The TP53 mutation was detected in 7 (18%) patients; four patients progressed to higher grade MDS or acute myeloid leukemia (AML). All seven RAEB-1 patients cleared bone marrow blasts during lenalidomide treatment and reached complete remission (CR); however, three later progressed to higher grade MDS or AML. Lenalidomide represents effective treatment for del(5q) group and combination with prednisone and erythropoietin may be used for non-responders or therapy failures. PMID- 29614394 TI - Spherical aberration correction in a scanning transmission electron microscope using a sculpted thin film. AB - Nearly eighty years ago, Scherzer showed that rotationally symmetric, charge free, static electron lenses are limited by an unavoidable, positive spherical aberration. Following a long struggle, a major breakthrough in the spatial resolution of electron microscopes was reached two decades ago by abandoning the first of these conditions, with the successful development of multipole aberration correctors. Here, we use a refractive silicon nitride thin film to tackle the second of Scherzer's constraints and demonstrate an alternative method for correcting spherical aberration in a scanning transmission electron microscope. We reveal features in Si and Cu samples that cannot be resolved in an uncorrected microscope. Our thin film corrector can be implemented as an immediate low cost upgrade to existing electron microscopes without re engineering of the electron column or complicated operation protocols and can be extended to the correction of additional aberrations. PMID- 29614395 TI - On the detection of multiple events in atom probe tomography. AB - In atom probe tomography (APT), multiple events can arise as a consequence of e.g. correlated field evaporation and molecular ion dissociation. They represent challenging cases for single-particle detectors and can cause compositional as well as spatial inaccuracies. Here, two state-of-the-art atom probe microscopes (Cameca LEAP 5000 XS and 5000 XR) were used to investigate cemented tungsten carbide, which exhibits high amounts of multiple events. By advanced data analysis methods, the natural character of the multiple events, as well as the performance of the APT detectors, are assessed. Accordingly, possible signal loss mechanisms are discussed. PMID- 29614396 TI - Cross-talk between ABA and sugar signaling is mediated by the ACGT core and CE1 element reciprocally in OsTIP3;1 promoter. AB - Recently, much effort has been made to determine the molecular links and cross talk between sugar and abscisic acid (ABA) signaling pathways. ABA-inducible expression of OsTIP3;1, encoding a rice tonoplast intrinsic protein, was enhanced by sugar depletion. Such a stimulatory increase in OsTIP3;1 expression under sugar-starvation is possibly not owing to changes in endogenous ABA content. The transient expression assay indicated that the 5' flanking region of OsTIP3;1 delivered similar collaborative responsiveness to starvation and ABA, suggesting that this gene promoter could be a good molecular probe to examine the interaction between sugar and ABA signaling pathways. Targeted mutagenesis demonstrated that disruption of ACGT cores decreased the induction of OsTIP3;1 promoter activity under either starvation or ABA, whereas mutation of coupling element 1 (CE1), which is an ABI4 binding site, reversely increased it, suggesting that those two distinct cis-regulatory elements reciprocally regulate the responsiveness of this promoter to both sugar and ABA. Consistent with this result, antisense inhibition of ABI4 increased the OsTIP3;1 promoter activity. ABI4 expression was also enhanced by sugars and repressed by ABA, suggesting that reduced ABI4 binding to CE1 in the absence of sugar and presence of ABA could increase ABA-induction of the OsTIP3;1 promoter activity. PMID- 29614397 TI - Heterologous expression and antimicrobial activity of OsGASR3 from rice (Oryza sativa L.). AB - According to an in silico analysis, OsGASR3 (LOC_Os03g55290) from rice (Oryza sativa L.) was predicted to be involved in plant defense mechanisms. A semi quantitative reverse transcription polymerase chain reaction assay revealed that OsGASR3 is highly expressed in the inflorescences of Thai jasmine rice (O. sativa L. subsp. indica 'KDML 105'). To characterize the biological activity of OsGASR3, we produced an OsGASR3-glutathione S-transferase fusion protein in Escherichia coli Rosetta-gami (DE3) cells for a final purified recombinant OsGASR3 yield of 0.65 mg/L. The purified OsGASR3 inhibited the hyphal growth of Fusarium oxysporum f.sp. cubense and Helminthosporium oryzae at a relatively low concentration (7.5 MUg/mL). Furthermore, OsGASR3 exhibited in planta inhibitory activity against Xanthomonas campestris, suggesting its involvement in defense mechanisms, in addition to its previously reported functions affecting growth and development. These observations indicate that recombinant OsGASR3 may be useful for protecting agriculturally important crops against pathogenic microbes. PMID- 29614398 TI - Evaluation of antimicrobial activity and retention behavior of newly synthesized vanilidene derivatives of Meldrum's acids using QSRR approach. AB - Increased antimicrobial resistance together with the lack of new antimicrobial drugs suggest on an urgent need for new therapeutics in this field. Vanilidene derivatives of Meldrum's acid present one of the possible approaches. In this work lipophilicity of 13 vanilidene derivatives of Meldrum's acid as well as their predicted antimicrobial activity towards several characteristic species has been evaluated. 10 vanilidene derivatives have been previously synthesized and 3 new compounds are synthetized afterwards following the same procedure. These selected 13 candidates were examined using thin layer chromatography in two different solvent systems. Gained retention parameters were a starting point for further Quantitative Structure Property Relationships (QSRR) studies in which minimum inhibitory concentration (MIC) for Candida albicans, Trichoderma viride, Penicillium italicum, Fuscarium oxysporum, Pseudomonas aeruginosa and Escherichia coli were determined. Statistically significant QSRR models were established and clustering of the compounds was performed with the help of principal component analysis (PCA) and hierarchical cluster analysis (HCA). Absorption, Distribution, Metabolism, and Excretion (ADME) properties of investigated molecules were subjected to sum of ranking differences (SRD) analysis in order to explore their pharmacokinetic properties. SRD analysis was also performed for the ranking of the established QSRR models. It was shown that compounds 6, 8 and 9 possess a significant antimicrobial activity, satisfied ADME properties and these candidates should be further optimized in order to utilize unexplored potential of Meldrum's acid in synthesis of novel antifungal compounds. PMID- 29614399 TI - A facile one-step fluorescence method for the quantitation of low-content single base deamination impurity in synthetic oligonucleotides. AB - Oligonucleotides are being researched and developed as potential drug candidates for the treatment of a broad spectrum of diseases. The characterization of antisense oligonucleotide (ASO) impurities caused by base mutations (e.g. deamination) which are closely related to the target ASO is a significant analytical challenge. Herein, we describe a novel one-step method, utilizing a strategy that combines fluorescence-ON detection with competitive hybridization, to achieve single base mutation quantitation in extensively modified synthetic ASOs. Given that this method is highly specific and sensitive (LoQ = 4 nM), we envision that it will find utility for screening other impurities as well as sequencing modified oligonucleotides. PMID- 29614400 TI - Effect of inhibin A on proliferation of porcine granulosa cells in vitro. AB - Inhibins regulate folliculogenesis, gametogenesis and hormone secretion via endocrine, paracrine and autocrine manners, and play roles in encouraging or suppressing proliferation of cells. In order to investigate the effects of inhibin A on proliferation and apoptosis of porcine granulosa cells (GCs), GCs were isolated from ovarian follicles (3-6 mm), treated with inhibin A at different concentrations. The cell viability, mitochondrial membrane potential (MMP), expression of proliferation-related genes and cell cycle were detected. Inhibin alpha subunit (INHA) gene was silenced to detect the effect of down regulation of inhibin on expression of proliferation-related genes in GCs. The results showed that cell viability was associated with inhibin A concentration and significantly enhanced by inhibin A at high doses (50 and 100 ng/mL, P < 0.05) compared to control group (0 ng/mL). Meanwhile, the MMP boosted after treated with 100 ng/mL inhibin A for 48 h. Expression of proliferating cell nuclear antigen (PCNA) (200 ng/mL) and CyclinB1 (100 and 200 ng/mL) was promoted while Caspase-3(100 and 200 ng/mL) and BAX (200 ng/mL) was inhibited in dose dependent manner after the cells were incubated with inhibin A for 24 h (P < 0.05) compared to control group, thereby the transition from G1 phase to S phase was promoted and the number of S phase cells was increased. After silencing the INHA gene expression, expression of Caspase-3 was enhanced and CyclinB1 was inhibited (P < 0.05) compared to Ri-negative group. All the results pointed to the conclusion that inhibin A promotes the proliferation of GCs while inhibits apoptosis. PMID- 29614401 TI - Improving number abilities in low achieving preschoolers: Symbolic versus non symbolic training programs. AB - BACKGROUND: Although previous correlational studies have shown that both symbolic and non-symbolic abilities relate to mathematical abilities, correlational studies cannot show the cause and effect of these abilities for mathematical success. AIMS: The current study examined the effect of a non-symbolic training program, called PLUS and a symbolic training program, called DIGIT, to provide further insight into the causal nature of domain specific factors that contribute to mathematical abilities. METHODS: and Procedures: Forty-nine preschool children who had low mathematical abilities were recruited and randomly allocated to the DIGIT and PLUS training programs. Performance on a number of mathematical tasks was compared to 20 preschoolers with no mathematical difficulties. OUTCOMES AND RESULTS: Performance in both training programs improved on the Test of Early Mathematical Abilities as well as on a non-symbolic Approximate Number Sense task, counting tasks, and digit recognition tasks, immediately after five weeks of training and this improvement remained six months later. CONCLUSIONS AND IMPLICATIONS: This study provides further evidence that symbolic and non-symbolic abilities bi-directionally impact on each other and that ordinality knowledge is an important factor of mathematical development. PMID- 29614402 TI - Fish can smell trace metals at environmentally relevant concentrations in freshwater. AB - The objective of the present study was to investigate the ability of the olfactory system of rainbow trout (Oncorhynchus mykiss) to detect three trace metals, cadmium (Cd), copper (Cu), and nickel (Ni), using electro-olfactography (EOG). The olfactory response to all three metals was measured at either 10-6 M or at a concentration established by Alberta Environment and Parks (AEP) as the criterion for the protection of aquatic life. Results of the present study demonstrated that the olfactory system of rainbow trout can detect all three metals (i.e. Cd, Cu, and Ni) in water at environmentally relevant concentrations. These results provide physiological evidence for a role of the olfactory system in fish behavioural responses (as shown in previous studies) when they encounter metal contaminated waters. PMID- 29614403 TI - Effect of pH on uranium(VI) biosorption and biomineralization by Saccharomyces cerevisiae. AB - Biosorption of radionuclides by microorganisms is a promising and effective method for the remediation of contaminated areas. pH is the most important factor during uranium biosorption by Saccharomyces cerevisiae because the pH value not only affects the biosorption rate but also affects the precipitation structure. This study investigated the effect of pH on uranium (VI) biosorption and biomineralization by S. cerevisiae. Cells have the ability to buffer the solution to neutral, allowing the biosorption system to reach an optimal level regardless of the initial pH value. This occurs because there is a release of phosphate and ammonium ions during the interaction between cells and uranium. The uranyl and phosphate ions formed nano-particles, which is chernikovite H2(UO2)2(PO4)2.8H2O (PDF #08-0296), on cell surface under the initial acidic conditions. However, under the initial alkaline conditions, the uranyl, phosphate and ammonium ions formed a large amount of scale-like precipitation, which is uramphite (NH4)(UO2)PO4.3H2O (PDF #42-0384), evenly over on cell surface. PMID- 29614404 TI - Role of oxalate in permanganate oxidation of 4-chlorophenol. AB - The role of oxalate in 4-chlorophenol (4-CP) oxidation by permanganate (Mn(VII)) was explored in this study. The performance of oxalate was heavily depended on pH and oxalate concentration. 4-CP degradation by Mn(VII) was significantly enhanced at pH 4.0-6.0 in the presence of oxalate, while negligible influence was observed at pH 7.0-9.0. The oxalate plays a dual role in Mn(VII) oxidation over the pH range of 4.0-6.0: one is the chelate, which coordinates with Mn(III) to form Mn(III)-oxalate complexes, and the other is the reductant, which reacts with Mn(III) to form Mn(II). The stable Mn(III)-oxalate complexes can work as an efficient oxidant for 4-CP. While their unstable counterparts, due to the lower concentration of oxalate or the higher pH, would auto-decomposed to MnO2 and Mn(II), and then the MnO2 works as both a catalyst and an oxidant for the decomposition of 4-CP. PMID- 29614405 TI - Recovery of organic matters in wastewater by self-forming dynamic membrane bioreactor: Performance and membrane fouling. AB - Formation process and fouling characteristics of the dynamic membrane were studied in a modified self-forming dynamic membrane bioreactor (SF-DMBR) for recovering the organic matters in wastewater, and the performance of this SF-DMBR was investigated. Results indicated that 80% of the organic matters in wastewater could be quickly recovered under continuous operation. Furthermore, the evolutions of the fouling components were determined during the formation and development processes of dynamic membrane. After the long-term operation, the decreases of protein concentration, accompanying with the increases of polysaccharides and microorganisms contents due to special operating conditions, were interestingly observed in the sludge of membrane surface. This could explain why membrane fouling was much weak. Therefore, though high membrane fluxes at 50 150 L/(m2.h) were adopted in this study, the reactor can still obtain a long-term stable operation and the operating cycle reached as long as 8 days. Finally, membrane fouling process was described by combined models. PMID- 29614407 TI - Application of molecular docking for the degradation of organic pollutants in the environmental remediation: A review. AB - The molecular docking has been employed successfully to study the mechanism of biodegradation in the environmental remediation in the past few years, although medical science and biology are the main application areas for it. Molecular docking is a very convenient and low cost method to understand the reaction mechanism of proteins or enzymes with ligands with a high accuracy. This paper mainly provides a review for the application of molecular docking between organic pollutants and enzymes. It summarizes the fundamental knowledge of molecular docking, such as its theory, available softwares and main databases. Moreover, five types of pollutants, including phenols, BTEX (benzene, toluene, ethylbenzene, and xylenes), nitrile, polycyclic aromatic hydrocarbons (PAHs), and high polymer (e.g., lignin and cellulose), are discussed from molecular level. Different removal mechanisms are also explained in detail via docking technology. Even though this method shows promising application in the research of biodegradation, further studies are still needed to relate with actual condition. PMID- 29614406 TI - Bivalve shell formation in a naturally CO2-enriched habitat: Unraveling the resilience mechanisms from elemental signatures. AB - Marine bivalves inhabiting naturally pCO2-enriched habitats can likely tolerate high levels of acidification. Consequently, elucidating the mechanisms behind such resilience can help to predict the fate of this economically and ecologically important group under near-future scenarios of CO2-driven ocean acidification. Here, we assess the effects of four environmentally realistic pCO2 levels (900, 1500, 2900 and 6600 MUatm) on the shell production rate of Mya arenaria juveniles originating from a periodically pCO2-enriched habitat (Kiel Fjord, Western Baltic Sea). We find a significant decline in the rate of shell growth as pCO2 increases, but also observe unchanged shell formation rates at moderate pCO2 levels of 1500 and 2900 MUatm, the latter illustrating the capacity of the juveniles to partially mitigate the impact of high pCO2. Using recently developed geochemical tracers we show that M. arenaria exposed to a natural pCO2 gradient from 900 to 2900 MUatm can likely concentrate HCO3- in the calcifying fluid through the exchange of HCO3-/Cl- and simultaneously maintain the pH homeostasis through active removal of protons, thereby being able to sustain the rate of shell formation to a certain extent. However, with increasing pCO2 beyond natural maximum the bivalves may have limited capacity to compensate for changes in the calcifying fluid chemistry, showing significant shell growth reduction. Findings of the present study may pave the way for elucidating the underlying mechanisms by which marine bivalves acclimate and adapt to high seawater pCO2. PMID- 29614408 TI - Mixture of commercial herbicides based on 2,4-D and glyphosate mixture can suppress the emergence of zooplankton from sediments. AB - It is generally assumed that zooplankton can recolonize lakes that have been exposed to pesticides, via their dormant egg banks. Hitherto, few studies have evaluated the relative importance of dormant egg bank recruitment in the re establishment of zooplankton communities in the presence of pesticide. This study investigated the effects of commercial products Bratt(r) (a.i. 2,4-D), Roundup(r) (a.i. glyphosate) and their mixture on the emergence (abundance and taxon richness) of dormant zooplankton egg banks from natural lake sediment. Sediment samples were collected from the surface sediment (<10 cm depth) in four lakes in Southeast Sao Paulo, Brazil. We performed a hatching experiment, in which natural lake sediments containing dormant eggs were exposed separately to Bratt(r) (applied concentrations ranging from 0.30 to 20 mg L-1), Roundup(r) (0.28-8.5 mg L-1), and combined mixtures of all concentrations, plus one control (non-exposure to formulated herbicides) for a period of 28 days. All tested concentrations of Bratt(r), Roundup(r) and their mixture reduced the abundance and taxon richness of emerging zooplankton (except 2 mg L-1 of Bratt(r)). This effect was more pronounced in rotifers. In comparison, there were no negative effects on the emergence of microcrustaceans. These findings suggest that commercial products Bratt(r), Roundup(r) and their mixture can suppress the emergence of rotifers, thereby influencing zooplankton recruitment potential in lakes impacted by the presence of these commercial herbicides. Our results stress the importance of the need for additional studies to assess the effects of pesticides on dormant egg banks. PMID- 29614409 TI - Biodegradation of phenanthrene by endophytic fungus Phomopsis liquidambari in vitro and in vivo. AB - Phenanthrene, as a widespread polycyclic aromatic hydrocarbons (PAHs) contaminant in vitro and in vivo of plant, has the characteristics of carcinogenicity, teratogenicity and mutagenicity. This work aimed to explore the phenanthrene metabolic mechanism by Phomopsis liquidambari in vitro, as well as the bioremediation ability through P. liquidambari-rice combination. This strain was able to use phenanthrene as source of carbon and energy to grow, more than 77% of added 50 mg L-1 phenanthrene was removed after 10 d in MSM. We identified the metabolic products via HPLC-MS and proposed two possible degradation pathways. Phenanthrene was firstly combined with oxygen to become phenanthrene 9,10-oxide, and then degraded to 9-phenanthrol, followed by oxidization to 9,10 dihydroxyphenanthrene. In addition, that epoxide (phenanthrene 9,10-oxide) was also hydrolyzed to phenanthrene trans-9,10-dihydrodiol, and then dehydrogenized to 9,10-dihydroxyphenanthrene, which was further degraded to 9,10 phenanthrenequinone; during this metabolic pathway, the changes of P450 monooxygenase, epoxide hydrolase, dehydrogenase and catechol 2,3-dioxygenase activities and their corresponding gene transcription levels were closely related. What's more, P. liquidambari could combine with rice to eliminate phenanthrene accumulated in vivo of rice seedlings, and the removal rate in inoculation treatment represented a significant difference (increased 25.68%) compared with uninoculation treatment after cultivation 30 d. Therefore, we concluded that P. liquidambari could not only respond to phenanthrene pollution stress in vitro but also exert a mitigation effect on plants accumulated phenanthrene. This work provides a foundation for applying endophytic fungi to PAHs bioremediation in vitro and in vivo. PMID- 29614410 TI - Aluminum trichloride-induced hippocampal inflammatory lesions are associated with IL-1beta-activated IL-1 signaling pathway in developing rats. AB - Aluminum (Al) is a recognized environmental pollutant that causes neuroinflammatory lesions, leading to neurodegenerative diseases. Interleukin-1 (IL-1) signaling pathway is responsible for regulating inflammatory lesions. However, it remains unclear whether IL-1 signaling pathway is involved in neuroinflammatory lesions induced by Al exposure. In the present study, one hundred and twenty Wistar rats were orally exposed to 0, 50, 150 and 450 mg/kg BW/d aluminum trichloride (AlCl3) for 90 days, respectively. We found that AlCl3 exposure increased hippocampal Al concentration, reduced hippocampus coefficient, impaired cognitive ability, deteriorated microstructure of hippocampal CA1 and CA3 regions, increased reactive oxygen species (ROS) level, activated astrocytes and microglia, increased pro-inflammatory cytokines contents and mRNA expressions, and decreased anti-inflammatory cytokines contents and mRNA expressions in the hippocampus. These results indicated that AlCl3 induced the hippocampal inflammatory lesion (HIL). Moreover, AlCl3 exposure increased the mRNA and protein expression of IL-1 signaling pathway core components in the hippocampus, demonstrating that AlCl3 activated IL-1 signaling pathway. Furthermore, the correlation between interleukin-1beta (IL-1beta) content and HIL and activation of the IL-1 signaling pathway was analyzed. Results showed that IL 1beta content was positively correlated with pro-inflammatory cytokines contents and mRNA expressions and activation of IL-1 signaling pathway, and was negatively correlated with hippocampus coefficient, anti-inflammatory cytokines contents and mRNA expressions, and the number of hippocampal neurons. The above results demonstrate that AlCl3-induced HIL is associated with IL-1 signaling pathway, in which IL-1beta is a link. PMID- 29614411 TI - Enhanced biochars can match activated carbon performance in sediments with high native bioavailability and low final porewater PCB concentrations. AB - A bench scale study was conducted to evaluate the effectiveness of in situ amendments to reduce the bioavailability of pollutants in sediments from a site impacted with polychlorinated biphenyls (PCBs), polycyclic aromatic hydrocarbons (PAHs) and cadmium. The amendments tested included fine and coarse coal-based activated carbons (AC), an enhanced pinewood derived biochar (EPB), organoclay, and coke dosed at 5% of sediment dry weight. Strong reductions in total PCB porewater concentrations were observed in sediments amended with the fine AC (94.9-99.5%) and EPB (99.6-99.8%). More modest reductions were observed for the coarse AC, organoclay, and coke. Strong reductions in porewater PCB concentrations were reflected in reductions in total PCB bioaccumulation in fresh water oligochaetes for both the fine AC (91.9-96.0%) and EPB (96.1-96.3%). Total PAH porewater concentrations were also greatly reduced by the fine AC (>96.1%) and EPB (>97.8%) treatments. EPB matched or slightly outperformed the fine AC throughout the study, despite sorption data indicating a much stronger affinity of PCBs for the fine AC. Modeling EPB and fine AC effectiveness on other sediments confirmed the high effectiveness of the EPB was due to the very low final porewater concentrations and differences in the native bioavailability between sediments. However, low bulk density and poor settling characteristics make biochars difficult to apply in an aquatic setting. Neither the EPB nor the fine AC amendments were able to significantly reduce Cd bioavailability. PMID- 29614412 TI - Hybrid functionalized chitosan-Al2O3@SiO2 composite for enhanced Cr(VI) adsorption. AB - In this study, we prepared a novel hybrid functionalized chitosan-Al2O3@SiO2 composite (FCAS) for removing hexavalent chromium [Cr(VI)] from aqueous system. Spectroscopic studies like Fourier transform infrared (FT-IR) spectroscopy, X-ray diffraction (XRD), field emission scanning electron microscope (FESEM) and energy dispersive spectroscope (EDS) were characterized. The effects such as dosage of adsorbent, pH, contact time and initial Cr(VI) concentration were evaluated. It has been illustrated that a wide acidic condition in the pH range of 2-6 was conducive to Cr(VI) adsorption and only 10 min was required to reach about 80% adsorption. Also, the adsorption properties of prepared adsorbent such as kinetics, thermodynamics and isotherms were comprehensively studied. Additionally, the adsorption capacity barely declined even after five cycles. Studies found that FCAS with characteristics of high performance of adsorption rate and capacity and better reusability would be a potential adsorbent for wastewater treatment. PMID- 29614413 TI - Differential behaviors of silver nanoparticles and silver ions towards cysteine: Bioremediation and toxicity to Phanerochaete chrysosporium. AB - Potential transformations of silver nanoparticles (AgNPs) upon interaction with naturally ubiquitous organic ligands in aquatic environments influence their transport, persistence, bioavailability, and subsequent toxicity to organisms. In this study, differential behaviors of AgNPs and silver ions (Ag+) towards cysteine (Cys), an amino acid representative of thiol ligands that easily coordinate to Ag+ and graft to nanoparticle surfaces, were investigated in the aspects of bioremediation and their toxicity to Phanerochaete chrysosporium. Total Ag removal, 2,4-dichlorophenol (2,4-DCP) degradation, extracellular protein secretion, and cellular viability were enhanced to some extent after supplement of various concentrations of cysteine under stress of AgNPs and Ag+. However, an obvious decrease in total Ag uptake was observed after 5-50 MUM cysteine addition in the groups treated with 10 MUM AgNPs and 1 MUM Ag+, especially at a Cys:Ag molar ratio of 5. More stabilization in uptake pattern at this ratio was detected under Ag+ exposure than that under AgNP exposure. Furthermore, in the absence of cysteine, all Ag+ treatments stimulated the generation of reactive oxygen species (ROS) more significantly than high-dose AgNPs did. However, cysteine supply under AgNP/Ag+ stress aggravated ROS levels, albeit alleviated at 100 MUM Ag+, indicating that the toxicity profiles of AgNPs and Ag+ to P. chrysosporium could be exacerbated or marginally mitigated by cysteine. The results obtained were possibly associated with the lability and bioavailability of AgNP/Ag+-cysteine complexes. PMID- 29614414 TI - Synthesis of magnetite from raw mill scale and its application for arsenate adsorption from contaminated water. AB - The magnetite particles were chemically synthesized from the waste of hot rolling steel industry. The characterization of the synthesized magnetite was done by using Fourier transform infrared spectroscopy (FTIR), Scanning electron microscopy (SEM), Energy Dispersive X-ray spectroscopy (EDS) and X-ray diffraction (XRD). The synthesized magnetite particles were used for the adsorptive removal of arsenate from the contaminated water. The maximum adsorption capacity of 7.69 mg was found on the surface of 1 g of the magnetite. The point of zero charge for magnetite is determined at the pH 6. The adsorption capacity of magnetite particles was successfully restored with alkali cleaning. Newly synthesized particles were found to be effective for arsenate removal up to 5 times with regeneration. The synthesis of magnetite from raw mill scale and its application for arsenate adsorption is a cost effective and ecofriendly process. PMID- 29614415 TI - Synergy of iron and copper oxides in the catalytic formation of PCDD/Fs from 2 monochlorophenol. AB - Transition metal oxides present in waste incineration systems have the ability to catalyze the formation of polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/Fs) through surface reactions involving organic dioxin precursors. However, studies have concentrated on the catalytic effects of individual transition metal oxides, while the complex elemental composition of fly ash introduces the possibility of synergistic or inhibiting effects between multiple, catalytically active components. In this study, we have tested fly ash surrogates containing different ratios (by weight) of iron (III) oxide and copper (II) oxide. Such Fe2O3/CuO mixed-oxide surrogates (in the Fe:Cu ratio of 3.5, 0.9 and 0.2 ) were used to study the cooperative effects between two transition metals that are present in high concentrations in most combustion systems and are known to individually catalyze the formation of PCDD/Fs. The presence of both iron and copper oxides increased the oxidative power of the fly ash surrogates in oxygen rich conditions and led to extremely high PCDD/F yields under pyrolytic conditions (up to >5% yield) from 2-monochlorophenol precursor. PCDD/F congener profiles from the mixed oxide samples are similar to results obtained from only CuO, however the total PCDD/F yield increases with increasing Fe2O3 content. Careful analysis of the reaction products and changes to the oxidation states of active metals indicate the CuO surface sites are centers for reaction while the Fe2O3 is affecting the bonds in CuO and increasing the ability of copper centers to form surface-bound radicals that are precursors to PCDD/Fs. PMID- 29614416 TI - Repositioning of the antipsychotic trifluoperazine: Synthesis, biological evaluation and in silico study of trifluoperazine analogs as anti-glioblastoma agents. AB - Repositioning of the antipsychotic drug trifluoperazine for treatment of glioblastoma, an aggressive brain tumor, has been previously suggested. However, trifluoperazine did not increase the survival time in mice models of glioblastoma. In attempt to identify an effective trifluoperazine analog, fourteen compounds have been synthesized and biologically in vitro and in vivo assessed. Using MTT assay, compounds 3dc and 3dd elicited 4-5 times more potent inhibitory activity than trifluoperazine with IC50 = 2.3 and 2.2 MUM against U87MG glioblastoma cells, as well as, IC50 = 2.2 and 2.1 MUM against GBL28 human glioblastoma patient derived primary cells, respectively. Furthermore, they have shown a reasonable selectivity for glioblastoma cells over NSC normal neural cell. In vivo evaluation of analog 3dc confirmed its advantageous effect on reduction of tumor size and increasing the survival time in brain xenograft mouse model of glioblastoma. Molecular modeling simulation provided a reasonable explanation for the observed variation in the capability of the synthesized analogs to increase the intracellular Ca2+ levels. In summary, this study presents compound 3dc as a proposed new tool for the adjuvant chemotherapy of glioblastoma. PMID- 29614417 TI - New potent and selective A1 adenosine receptor antagonists as potential tools for the treatment of gastrointestinal diseases. AB - The synthesis of 9-alkyl substituted adenine derivatives presenting aromatic groups and cycloalkyl rings in 8- and N6-position, respectively, is reported. The compounds were tested with radioligand binding studies showing, in some cases, a low nanomolar A1 adenosine receptor affinity and a very good selectivity versus the other adenosine receptor subtypes. Functional assays at human adenosine receptors and at a mouse ileum tissue preparation clearly demonstrate the antagonist profile of these molecules, with inhibitory potency at nanomolar level. A molecular modeling study, consisting in docking analysis at the recently reported A1 adenosine receptor crystal structure, was performed for the interpretation of the obtained pharmacological results. The N6-cyclopentyl-9 methyl-8-phenyladenine (17), resulting the most active derivative of the series (Ki = 2.8 nM and IC50 = 14 nM), was also very efficacious in counteracting the effect of the agonist CCPA on mouse ileum contractility. This new compound represents a tool for the development of new agents for the treatment of intestinal diseases as constipation and postoperative ileus. PMID- 29614418 TI - Synthesis and anticancer activity evaluation of novel azacalix[2]arene[2]pyrimidines. AB - A series of novel azacalix[2]arene[2]pyrimidines were synthesized, and evaluated for their antiproliferative activities against A549, MCF7, SH-SY5Y and CNE human cancer cell lines in vitro by using the CCK-8 assay. A number of compounds showed low micromolar antiproliferative activities against MCF7 cell line. Compound 4j, containing a pyrrolidine moiety, exhibited the strongest inhibitory activity with an IC50 value of 0.58 MUM. Furthermore, breast cancer cells were used to explore the inhibition mechanism of these azacalix[2]arene[2]pyrimidines. The results suggested these compounds were involved in inducing cell apoptosis via up regulation of caspase-3 and caspase-9 protein expression, and the cell cycle was arrested at the S phase. Our reports here represent the first studies on the biological activities of azacalix[2]arene[2]pyrimidines. PMID- 29614419 TI - Preparation of Rhodium(III) complexes with 2(1H)-quinolinone derivatives and evaluation of their in vitro and in vivo antitumor activity. AB - A series of 2(1H)-quinolinone derivatives and their rhodium (III) complexes were designed and synthesized. All the rhodium (III) complexes exhibited higher in vitro cytotoxicity for Hep G2, HeLa 229, MGC80-3, and NCI-H460 human tumor cell lines than their ligands and cisplatin, and among them complex 9 was found to be selectively cytotoxic to tumor cells. Further investigation revealed that complex 9 caused cell cycle arrest at the G2/M phase and induced apoptosis, and inhibited the proliferation of Hep G2 cells by impeding the phosphorylation of epidermal growth factor receptor (EGFR) and its downstream enzymes. Complex 9 also up regulated the proapoptotic proteins Bak, Bax, and Bim, which altogether activated caspase-3/9 to initiate cell apoptosis. Notably, complex 9 effectively inhibited tumor growth in the NCI-H460 xenograft mouse model with less adverse effect than cisplatin. PMID- 29614421 TI - Tuning the morphology and Fe/Ni ratio of a bimetallic Fe-Ni-S film supported on nickel foam for optimized electrolytic water splitting. AB - The surface composite and morphology of binary metal sulfides are the key for efficient overall water splitting. However, tuning the morphology and surface composition of binary metal sulfides in a facile way is still a challenge. Herein, binary Fe-Ni sulfides supported on nickel foam (FeNi-S/NF) with different morphology and composition ratio of Fe/Ni have been synthesized through a facile one-step electrodeposition assisted by liquidcrystaltemplate (LCT). The binary FeNi-S has improved activity and conductivity compared to single metal sulfides. LCT-assisted porous FeNi-S film composed of uniform nanospheres is obviously different from planar film electrodeposited in water solution. LCT-assisted FeNi S nanospheres are covered by many interwoven nanosheets, implying more exposed active sites for water splitting. Furthermore, the different Fe/Ni ratios of FeNi S/NF samples have been systematically studied to explore the influence of Fe incorporation on intrinsic activity of FeNi-S/NF. And the sample with Fe/Ni ratio (3/1) demonstrates the best activity and excellent stability for overall water electrolysis. Therefore, our work provides a facile and controllable access to binary metal sulfides with excellent performances for overall water splitting. PMID- 29614420 TI - Enhanced Cr(VI) removal by polyethylenimine- and phosphorus-codoped hierarchical porous carbons. AB - The amino- and phosphorus-codoped (N,P-codoped) porous carbons derived from oil tea shells were facilely fabricated through a combination of phosphoric acid (H3PO4) activation and amino (polyethylenimine, PEI) modification method. The as synthesized carbon adsorbents were systematically characterized and evaluated for Cr(VI) removal in aqueous solutions. The relationship between adsorbent properties and adsorption behaviors was illustrated. Moreover, the influences of contact time, initial Cr(VI) concentration, pH, coexisting anions and temperature were also investigated. The adsorption behavior of Cr(VI) could be perfectly described by the pseudo-second-order kinetic model and Sips adsorption model. The maximum adsorption capacity of Cr(VI) on the carbon adsorbents synthesized in this work was 355.0 mg/g, and this excellent Cr(VI) capacity could be sustained with other coexisting anions. In addition to high surface area and suitable pore size distribution, the high Cr(VI) removal capacity is induced by rich heteroatoms incorporation and the Cr(VI) removal mechanism was clearly illustrated. Furthermore, the continuous column breakthrough experiment on obtained N,P-codoped carbon was conducted and well fitted by the Thomas model. This work revealed that PEI modification and P-containing groups could significantly enhance Cr(VI) adsorption capacity and make these N,P-codoped biomass-derived carbons potent adsorbents in practical water treatment applications. PMID- 29614423 TI - Biomass based iron and nitrogen co-doped 3D porous carbon as an efficient oxygen reduction catalyst. AB - An iron and nitrogen co-doped 3D porous carbon catalyst with high performance for oxygen reduction reaction (ORR) is produced by pyrolysis. The precursor is a mixture of red date, ferrous (II) acetate, and graphitic carbon nitride (g-C3N4). g-C3N4 is the nitrogen source and also the sacrificial template, which plays a key role in the formation of a porous nitrogen rich carbon structure with high surface area. It is found that active sites and catalytic performance of synthetic materials are significantly influenced by the Fe content. In comparison with commercial Pt/C catalyst, the synthetic Fe-N-C with optimized composition exhibits comparable ORR activity and superior methanol tolerance. This work provides a feasible approach to develop cost-effective and highly efficient non precious metal electrochemical catalysts for oxygen reduction. PMID- 29614422 TI - Biomass derived nitrogen-doped hierarchical porous carbon sheets for supercapacitors with high performance. AB - A facile potassium chloride salt-locking technique combined with hydrothermal treatment on precursors was explored to prepare nitrogen-doped hierarchical porous carbon sheets in air from biomass. Benefiting from the effective synthesis strategy, the as-obtained carbon possesses a unique nitrogen-doped thin carbon sheet structure with abundant hierarchical pores and large specific surface areas of 1459 m2 g-1. The doped nitrogen in carbon framework has a positive effect on the electrochemical properties of the electrode material, the thin carbon sheet structure benefits for fast ion transfer, the abundant meso-pores provide convenient channels for rapid charge transportation, large specific surface area and lots of micro-pores guarantee sufficient ion-storage sites. Therefore, applied for supercapacitors, the carbon electrode material exhibits an outstanding specific capacitance of 451 F g-1 at 0.5 A g-1 in a three-electrode system. Moreover, the assembled symmetric supercapacitor based on two identical carbon electrodes also displays high specific capacitance of 309 F g-1 at 0.5 A g 1, excellent rate capacity and remarkable cycling stability with 99.3% of the initial capacitance retention after 10,000 cycles at 5 A-1. The synthesis strategy avoids expensive inert gas protection and the use of corrosive KOH and toxic ZnCl2 activated reagents, representing a promising green route to design advanced carbon electrode materials from biomass for high-capacity supercapacitors. PMID- 29614424 TI - A novel hollow-hierarchical structured Bi2WO6 with enhanced photocatalytic activity for CO2 photoreduction. AB - Converting CO2 into high-valued chemicals with sunlight is regarded as a promising way to solve the impending energy and environmental crisis. Development of efficient photocatalysts with suitable energy band gap, high stability and favorable structure is thus of very importance. Herein, a novel hierarchical Bi2WO6 photocatalyst assembled by Bi2WO6 nanosheets with a hollow and rod-shaped appearance has been developed via a facile hydrothermal process. Interestingly, we found that the hydrolysis of Bi(NO3)3 in water can produce solid Bi6O5(OH)3(NO3)5.3H2O microrods which can be transformed to hollow-hierarchical Bi2WO6 nanosheets by virtue of the Kirkendall effect. The developed Bi2WO6 nanosheets exhibit a 58 times higher specific surface area than that of bulk Bi2WO6 and a remarkable enhancement in electrochemical performance such as photocurrent and charge transfer. As a result, the hollow-hierarchical structured Bi2WO6 photocatalysts achieve a high CH4 yield of 2.6 MUmol g-1 h-1, 8 times higher than that of bulk Bi2WO6. Moreover, the developed photocatalysts exhibit a high stability during the recycling experiments. This work may present a new strategy to attain hierarchical structured photocatalysts with high activity and stability toward CO2 reduction. PMID- 29614425 TI - The Golgi complex in disease and therapy. AB - The Golgi complex occupies a strategic position in the endomembrane system and acts not only as a key trafficking and sorting station and a vital biosynthetic center for glycoproteins and lipids, but also as an active signaling hub. As such, the Golgi complex participates in the establishment and maintenance of cell compartmentalization and in general, cell processes such as cell growth and apoptosis. The different functions of the Golgi complex are executed by composite molecular machineries that have been exhaustively dissected over the last three decades. These machineries can become dysfunctional as a result of mutations in the respective encoding genes or may be hijacked by infectious agents or misregulated in the course of multifactorial diseases such as neurodegeneration and cancer. Small molecules targeting components of these machineries have been instrumental in dissecting their functions in in vitro studies and some of them have been developed or are currently under development for clinical use. PMID- 29614426 TI - Plasticity and biological diversity of myeloid derived suppressor cells. AB - Myeloid derived suppressor cells (MDSCs) are immature myeloid cells characterized by diverse phenotypes and functions. They impair effector functions of immune cells and promote tumor growth, angiogenesis, and tissue damage. In pathologies characterized by chronic inflammation, MDSCs are arrested in their immature state and migrate from the bone marrow to the periphery and to the site of inflammation, where they mediate immunosuppression. When reaching new environments, which exhibit a different array of cytokines, chemokines, and pro inflammatory mediators, MDSCs sense and adapt to the altered micro-environment by virtue of acquiring different suppressive features/functions that involve changing their cell fate, surface receptors, metabolism and intracellular as well as secreted molecules. This review summarizes some of the latest publications highlighting various layers of MDSC plasticity in relation to different pathologies. We discuss treatments capitalizing on MDSC plasticity aimed at combating MDSCs or manipulating their suppressive activity for improved therapy. PMID- 29614427 TI - Petrographic characterization to build an accurate rock model using micro-CT: Case study on low-permeable to tight turbidite sandstone from Eocene Shahejie Formation. AB - Pore scale flow simulations heavily depend on petrographic characterizing and modeling of reservoir rocks. Mineral phase segmentation and pore network modeling are crucial stages in micro-CT based rock modeling. The success of the pore network model (PNM) to predict petrophysical properties relies on image segmentation, image resolution and most importantly nature of rock (homogenous, complex or microporous). The pore network modeling has experienced extensive research and development during last decade, however the application of these models to a variety of naturally heterogenous reservoir rock is still a challenge. In this paper, four samples from a low permeable to tight sandstone reservoir were used to characterize their petrographic and petrophysical properties using high-resolution micro-CT imaging. The phase segmentation analysis from micro-CT images shows that 5-6% microporous regions are present in kaolinite rich sandstone (E3 and E4), while 1.7-1.8% are present in illite rich sandstone (E1 and E2). The pore system percolates without micropores in E1 and E2 while it does not percolate without micropores in E3 and E4. In E1 and E2, total MICP porosity is equal to the volume percent of macrospores determined from micro CT images, which indicate that the macropores are well connected and microspores do not play any role in non-wetting fluid (mercury) displacement process. Whereas in E3 and E4 sandstones, the volume percent of micropores is far less (almost 50%) than the total MICP porosity which means that almost half of the pore space was not detected by the micro-CT scan. PNM behaved well in E1 and E2 where better agreement exists in PNM and MICP measurements. While E3 and E4 exhibit multiscale pore space which cannot be addressed with single scale PNM method, a multiscale approach is needed to characterize such complex rocks. This study provides helpful insights towards the application of existing micro-CT based petrographic characterization methodology to naturally complex petroleum reservoir rocks. PMID- 29614428 TI - Involvement of autophagy and apoptosis and lipid accumulation in sclerotial morphogenesis of Morchella importuna. AB - Sclerotial formation is a key phase of the morel life cycle and lipids have been recorded as the main cytoplasmic reserves in sclerotia of Morchella fungi without any experimental verification. In this study, the ultrastructural features of the undifferentiated mycelia stage (MS) and three main sclerotial differentiation states (sclerotial initial [SI], sclerotial development [SD] and sclerotial maturation [SM]) were compared by transmission electron microscopy. The nature of the energy-rich substance in hypha and sclerotium of Morchella importuna was qualitatively investigated by confocal laser scanning microscopy and quantitatively studied by extraction of lipids. Sclerotia were observed to form from the repeated branching and enlargement of either terminal hyphae or subordinate hyphal branches, indicating a complex type of sclerotial development. Autophagy and apoptosis were involved in the sclerotial metamorphosis of the cultivated strain of M. importuna. During the SI phase, the characteristic features of autophagy (vacuolation, coalescence of small vacuoles, existence of autophagosomes and engulfment of autophagosomes by vacuoles) were observed. At the SD phase, apoptotic characteristics (condensation of the cytoplasm and nucleus, shrinkage of plasma membrane, extensive plasma membrane blebbing and existence of phagosomes) could be seen in some developing sclerotial cells. In the final stage of sclerotial morphogensis, the sclerotial cells showed a necrotic mode of cell death. In addition, confocal laser imaging studies of live cells indicated that the energy-rich substance in morel hyphae and sclerotia was lipid. The lipid content in sclerotia was significantly more than that in hyphal cells. To the best of our knowledge, this is the first detailed ultrastructural description highlighting the involvement of autophagy and apoptosis in sclerotial metamorphosis of Morchella species and lipid accumulation during morel sclerotial development was also first experimentally verified. This work will promote a better understanding of the mechanism of morel sclerotial metamorphosis. PMID- 29614430 TI - A novel wavelet sequence based on deep bidirectional LSTM network model for ECG signal classification. AB - Long-short term memory networks (LSTMs), which have recently emerged in sequential data analysis, are the most widely used type of recurrent neural networks (RNNs) architecture. Progress on the topic of deep learning includes successful adaptations of deep versions of these architectures. In this study, a new model for deep bidirectional LSTM network-based wavelet sequences called DBLSTM-WS was proposed for classifying electrocardiogram (ECG) signals. For this purpose, a new wavelet-based layer is implemented to generate ECG signal sequences. The ECG signals were decomposed into frequency sub-bands at different scales in this layer. These sub-bands are used as sequences for the input of LSTM networks. New network models that include unidirectional (ULSTM) and bidirectional (BLSTM) structures are designed for performance comparisons. Experimental studies have been performed for five different types of heartbeats obtained from the MIT-BIH arrhythmia database. These five types are Normal Sinus Rhythm (NSR), Ventricular Premature Contraction (VPC), Paced Beat (PB), Left Bundle Branch Block (LBBB), and Right Bundle Branch Block (RBBB). The results show that the DBLSTM-WS model gives a high recognition performance of 99.39%. It has been observed that the wavelet-based layer proposed in the study significantly improves the recognition performance of conventional networks. This proposed network structure is an important approach that can be applied to similar signal processing problems. PMID- 29614429 TI - Engineered viral vectors for functional interrogation, deconvolution, and manipulation of neural circuits. AB - Optimization of traditional replication-competent viral tracers has granted access to immediate synaptic partners of target neuronal populations, enabling the dissection of complex brain circuits into functional neural pathways. The excessive virulence of most conventional tracers, however, impedes their utility in revealing and genetically perturbing cellular function on long time scales. As a promising alternative, the natural capacity of adeno-associated viral (AAV) vectors to safely mediate persistent and robust gene expression has stimulated strong interest in adapting them for sparse neuronal labeling and physiological studies. Furthermore, increasingly refined engineering strategies have yielded novel AAV variants with enhanced target specificity, transduction, and retrograde trafficking in the CNS. These potent vectors offer new opportunities for characterizing the identity and connectivity of single neurons within immense networks and modulating their activity via robust delivery of functional genetic tools. PMID- 29614431 TI - 3D cell printing of in vitro stabilized skin model and in vivo pre-vascularized skin patch using tissue-specific extracellular matrix bioink: A step towards advanced skin tissue engineering. AB - 3D cell-printing technique has been under spotlight as an appealing biofabrication platform due to its ability to precisely pattern living cells in pre-defined spatial locations. In skin tissue engineering, a major remaining challenge is to seek for a suitable source of bioink capable of supporting and stimulating printed cells for tissue development. However, current bioinks for skin printing rely on homogeneous biomaterials, which has several shortcomings such as insufficient mechanical properties and recapitulation of microenvironment. In this study, we investigated the capability of skin-derived extracellular matrix (S-dECM) bioink for 3D cell printing-based skin tissue engineering. S-dECM was for the first time formulated as a printable material and retained the major ECM compositions of skin as well as favorable growth factors and cytokines. This bioink was used to print a full thickness 3D human skin model. The matured 3D cell-printed skin tissue using S-dECM bioink was stabilized with minimal shrinkage, whereas the collagen-based skin tissue was significantly contracted during in vitro tissue culture. This physical stabilization and the tissue-specific microenvironment from our bioink improved epidermal organization, dermal ECM secretion, and barrier function. We further used this bioink to print 3D pre-vascularized skin patch able to promote in vivo wound healing. In vivo results revealed that endothelial progenitor cells (EPCs)-laden 3D-printed skin patch together with adipose-derived stem cells (ASCs) accelerates wound closure, re-epithelization, and neovascularization as well as blood flow. We envision that the results of this paper can provide an insightful step towards the next generation source for bioink manufacturing. PMID- 29614432 TI - Pathological significance of lipoprotein(a) in aortic valve stenosis. AB - BACKGROUND AND AIMS: Aortic valve stenosis (AVS) affects a significant percentage of our elderly population and younger subjects with familial hypercholesterolemia. Lipoprotein(a) [Lp(a)] has been associated with AVS in recent genetic studies. The purpose of this study was to determine the effects of Lp(a) on human aortic valve interstitial cells (HAVICs), and to identify apolipoproteins and phospholipids in diseased human aortic valves. METHODS: We examined the effects of Lp(a) on HAVICs mineralization and oxidant formation. Proteomic analyses were used to determine the effects of Lp(a) on downstream intracellular markers. We also used mass spectroscopy to identify the different lipoproteins and oxidized phospholipids in calcified aortic valves. RESULTS: HAVICs incubated with either LDL or Lp(a) had significantly higher calcium deposition, compared to control (p<0.001), with Lp(a) having the most significant effect (p<0.01) compared to LDL. Proteomic analysis after 10 days of treatment with Lp(a) resulted in enrichment of proteins involved in calcium deposition and vesicle biogenesis. Treatment of HAVICs with Lp(a) significantly increased ROS formation (p<0.05). Patients with calcific aortic stenosis had higher plasma Lp(a) concentrations compared to non-CAD individuals (p<0.001). LC-MS/MS revealed the presence of apolipoproteins and phospholipids in calcified human aortic valves. CONCLUSIONS: The present study outlines an association between Lp(a) and AVS, and suggests that Lp(a) may serve as a potential target for therapeutic purposes to manage the progression of AVS. PMID- 29614434 TI - Evaluation of Morphological Characteristics to Delineate Taxa of the Genus Trigonopyxis (Amoebozoa, Arcellinida). AB - Morphological features are often the only characteristics suitable for identification of taxa in testate amoebae, especially in ecological and palaeoecological studies. However, whereas the morphology of some species is rather stable it may vary considerably in others. Within the order Arcellinida the genus Trigonopyxis with the type species Trigonopyxis arcula is morphologically highly variable. To identify reliable characteristics for morphology-based taxon delineation we investigated variations in shell size, pseudostome diameter and pseudostome form in T. arcula from three different sites of the Ecuadorian Andes, where these characteristics vary even more than previously described. Further, we investigated if morphological characteristics in Trigonopyxis varied with changes in environmental factors. We studied 951 shells of Trigonopyxis collected along an altitudinal gradient with varying abiotic factors. We established a method for characterization of the pseudostome form, which lead to five different morphotypes. Our results suggest that shell size alone is not an appropriate character for taxon delineation but can be used as an indicator for changes in environmental conditions. In contrast, the pseudostome form might be used for taxon delineation, but likely also varies considerably within taxa. Overall, the study provides an overview of the morphological variability of the genus Trigonopyxis. PMID- 29614433 TI - Acquired and congenital forms of heterotopic ossification: new pathogenic insights and therapeutic opportunities. AB - Heterotopic ossification (HO) involves the formation and accumulation of extraskeletal bone tissue at the expense of local tissues including muscles and connective tissues. There are common forms of HO that are triggered by extensive trauma, burns and other bodily insults, and there are also rare congenital severe forms of HO that occur in children with Fibrodysplasia Ossificans Progressiva or Progressive Osseous Heteroplasia. Given that HO is often preceded by inflammation, current treatments usually involve anti-inflammatory drugs alone or in combination with local irradiation, but are not very effective. Recent studies have provided novel insights into the pathogenesis of acquired and genetic forms of HO and have used the information to conceive and test new and more specific therapies in animal models. In this review, I provide salient examples of these exciting and promising advances that are undoubtedly paving the way toward resolution of this debilitating and at times fatal disease. PMID- 29614435 TI - Conventional and microwave prompted synthesis, antioxidant, anticholinesterase activity screening and molecular docking studies of new quinolone-triazole hybrids. AB - The synthesis of ethyl 4-oxo-1,4-dihydroquinoline-3-carboxylates (4, 5) was performed via the reaction of corresponding anilines with diethyl ethoxymethylenemalonate under conventional and also microwave promoted conditions. The treatment of 4 and 5 afforded the corresponding hydrazides (6 and 7). These hydrazides were converted to the corresponding carbo(thio)amides (9a-f and 10a-e) which were then subjected to an intramolecular cyclisation leading to the formation of quinolone-triazole hybrids (11a-f and 12a-e). The newly synthesized compounds were screened for their biological activities such as antioxidant capacity (AC) and acetylcholinesterase Activity. Inhibition of cholinesterases is an effective method to curb Alzheimer's disease, a progressive and fatal neurological disorder. A series of some novel quinolonederivatives were designed, synthesized, and their inhibitory effects on AChE were evaluated. We obtained our compounds and determined their anticholinesterase activities according to the Ellman's method. 9b and 10c showed the best AChE inhibition with 0.48 +/- 0.02 and 0.52 +/- 0.07, respectively. Docking studies were performed for the most active compounds (9b, 10c) and interaction modes with enzyme active sites were determined. As a result of these studies, a strong interaction between these compounds and the active sites of AChE enzyme was revealed. PMID- 29614436 TI - Competitive neutrophil elastase inhibitory isoflavones from the roots of Flemingia philippinensis. AB - Flemingia philippinensis has been used throughout history to cure rheumatism associated with neutrophil elastase (NE). In this study, we isolated sixteen NE inhibitory flavonoids (1-16), including the most potent and abundant prenyl isoflavones (1-9), from the F. philippinensis plant. These prenyl isoflavones (2, 3, 5, 7, and 9) competitively inhibited NE, with IC50 values of 1.3-12.0 MUM. In addition, they were reversible, simple, slow-binding inhibitors according to their respective parameters. Representative compound 3 had an IC50 = 1.3 MUM, k3 = 0.04172 MUM-1 min-1, k4 = 0.0064 min-1, and Kiapp = 0.1534 MUM. The Kik/Kiv ratios (18.5 ~ 24.6) for compound 3 were consistent with typical competitive inhibitors. The prenyl functionality of isoflavones significantly affected inhibitory potencies and mechanistic behavior by shifting the competitive mode to a noncompetitive one. The remaining flavonoids (10-16) were confirmed as mixed type I inhibitors that preferred to bind free enzyme rather than the enzyme substrate complex. Fluorescence quenching analyses indicated that the inhibitory potency (IC50) closely followed the binding affinity (KSV). PMID- 29614437 TI - Structure-based design, synthesis and evaluation of 2,4-diaminopyrimidine derivatives as novel caspase-1 inhibitors. AB - Interleukin-1beta converting enzyme contributes in various inflammatory and autoimmune diseases by maturing pro-inflammatory cytokines IL-1beta, IL-18 and IL 33. Therefore, inhibition caspase-1 may provide a potential therapeutic strategy for the treatment of chronic inflammatory diseases. Here we have reported structure-based design, synthesis and biological evaluation of 2,4 diaminopyrimidine derivatives (6a-6w) as potential caspase-1 inhibitors. Six compounds 6m, 6n, 6o, 6p, 6q and 6r showed significant enzymatic inhibition with IC50 ranging from 0.022 to 0.078 uM. These compounds also displayed excellent cellular potency at sub-micromolar concentration. Moreover, molecular docking studies provided the useful binding insights specific for caspase-1 inhibition. All these results indicated that compounds 6m, 6n and 6o could be potential leads for the development of newer caspase-1 inhibitors as anti-inflammatory agents. PMID- 29614438 TI - Synthesis, and In Vitro and In Silico alpha-Glucosidase Inhibitory Studies of 5 Chloro-2-Aryl Benzo[d]thiazoles. AB - Twenty-five derivatives of 5-chloro-2-aryl benzo[d]thiazole (1-25) were synthesized and evaluated for their alpha-glucosidase (S. cerevisiae EC 3.2.1.20) inhibitory activity in vitro. Among them eight compounds showed potent activity with IC50 values between 22.1 +/- 0.9 and 136.2 +/- 5.7 MUM, when compared with standard acarbose (IC50 = 840 +/- 1.73 MUM). The most potent compounds 4, 9, and 10 showed IC50 values in the range of 22.1 +/- 0.9 to 25.6 +/- 1.5 MUM. Compounds 2, 5, 11, and 19 showed IC50 values within the range of 40.2 +/- 0.5 to 60.9 +/- 2.0 MUM. Compounds 1 and 3 were also found to be good inhibitors with IC50 values 136.2 +/- 5.7 and 104.8 +/- 9.9 MUM, respectively. Their activities were compared with alpha-glucosidase inhibitor drug acarbose (standard) (IC50 = 840 +/- 1.73 MUM). The remaining compounds were inactive. Structure-activity relationships (SAR) have also been established. Kinetics studies indicated compounds 2, 3, 10, 19, and 25 to be non-competitive, while 1, 5, 9, and 11 as competitive inhibitors of alpha-glucosidase enzyme. All the active compounds (1-5, 9-11, and 19) were also found to be non-cytotoxic, in comparison to the standard drug i.e., doxorubicin (IC50 = 0.80 +/- 0.12 MUM) in MTT assay. Furthermore, molecular interactions of active compounds with the enzyme binding sites were predicted through molecular modeling studies. PMID- 29614439 TI - Recent advances in synthesis of three-dimensional porous graphene and its applications in construction of electrochemical (bio)sensors for small biomolecules detection. AB - Electrochemical (bio)sensors have attracted much attention due to their high sensitivity, fast response time, biocompatibility, low cost and easy miniaturization. Specially, ever-growing necessity and interest have given rise to the fast development of electrochemical (bio)sensors for the detection of small biomolecules. They play enormous roles in the life processes with various biological function, such as life signal transmission, genetic expression and metabolism. Moreover, their amount in body can be used as an indicator for diagnosis of many diseases. For example, an abnormal concentration of blood glucose can indicate hyperglycemia or hypoglycemia. Graphene (GR) shows great applications in electrochemical (bio)sensors. Compared with two-dimensional (2D) GR that is inclined to stack together due to the strong pi-pi interaction, monolithic 3D porous GR has larger specific area, superior mechanical strength, better stability, higher conductivity and electrocatalytic activity. So they attracted more and increasing attention as sensing materials for small biomolecules. This review focuses on the recent advances and strategies in the fabrication methods of 3D porous GR and the development of various electrochemical (bio)sensors based on porous GR and its nanocomposites for the detection of small biomolecules. The challenges and future efforts direction of high-performance electrochemical (bio)sensors based on 3D porous GR for more sensitive analysis of small biomolecules are discussed and proposed. It will give readers an overall understanding of their progress and provide some theoretical guidelines for their future efforts and development. PMID- 29614440 TI - Effect of phosphate nutrition on growth, physiology and phosphate transporter expression of cucumber seedlings. AB - Although abundantly present in soils, inorganic phosphate (Pi) acquisition by plants is highly dependent on the transmembrane phosphate transporter (PT) gene family. Cucumber (Cucumis sativus) requires a large amount of phosphorus (P). The purpose of this study was to isolate the CsPT2-1 from cucumber roots, and to determine the influence of Pi nutrition on cucumber growth, metabolism and transcript levels of CsPT2-1 in tissues. Full length CsPT2-1 was cloned and phylogenetically identified. In two greenhouse experiments, P-deficient seedlings provided with low or high P concentrations were sampled at 10 and 21 days post treatment, respectively. Addition of P dramatically reduced growth of roots but not shoots. Supplying plants with high P resulted in increased total protein in leaves. Acid phosphatase activity increased significantly in leaves at any rate higher than 4 mM P. Increasing P concentration had a notable decrease in glucose concentrations in leaves of plants supplied with >0.5 mM P. In roots, glucose and starch concentrations increased with increasing P supply. Steady-state transcript levels of CsPT2-1 were high in P-deprived roots, but declined when plants were provided >10 mM P. To our knowledge, this is the first report focusing on a PT and its expression levels in cucumber. PMID- 29614441 TI - Demonstration of monolignol beta-glucosidase activity of rice Os4BGlu14, Os4BGlu16 and Os4BGlu18 in Arabidopsis thaliana bglu45 mutant. AB - The glycoside hydrolase family 1 members Os4BGlu14, Os4BGlu16, and Os4BGlu18 were proposed to be rice monolignol beta-glucosidases. In vitro studies demonstrated that the Os4BGlu16 and Os4BGlu18 hydrolyze the monolignol glucosides coniferin and syringin with high efficiency compared to other substrates. The replacement of the conserved catalytic acid/base glutamate residue by a nonionizable glutamine residue in Os4BGlu14 suggested that it may be inactive as a beta glucosidase. Here, we investigated the activities of Os4BGlu14, Os4BGlu16, and Os4BGlu18 in planta by recombinant expression of their genes in the Arabidopsis bglu45-2 (monolignol beta-glucosidase) mutant and analysis of monolignol glucosides by ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MSMS). The bglu45-2 line exhibits elevated monolignol glucoside levels, but lower amounts of coniferin, syringin, and p-coumaryl alcohol glucoside were seen in Arabidopsis bglu45-2 rescued lines complemented by the Os4BGlu14, Os4BGlu16, and Os4BGlu18 genes. These data suggest that the bglu45-2 mutant has a broader effect on monolignols than previously reported and that the Os4BGlu14, Os4BGlu16 and Os4BGlu18 proteins act as monolignol beta-glucosidases to complement the defect. An OsBGlu16-GFP fusion protein localized to the cell wall. This apoplastic localization and the effect of these enzymes on monolignol glucoside levels suggest monolignol glucosides from the vacuole may meet the monolignol beta-glucosidases, despite their different localization. PMID- 29614442 TI - The role of genomic profiling in adolescents and young adults (AYAs) with advanced cancer participating in phase I clinical trials. AB - INTRODUCTION: Adolescents and young adults (AYAs) diagnosed with cancer between ages 15-39 years may harbour germline variants associated with cancer predisposition. Such variants represent putative therapeutic targets, as may somatic variants in the tumour. Germline and tumour molecular profiling is increasingly utilised to facilitate personalisation of cancer treatment in such individuals. AIM: Considering AYAs with advanced solid tumours managed in a specialist drug development unit (DDU), the aims of this study were to investigate the use and impact of: 1. Germline genetic assessment. 2. Tumour molecular profiling. METHODS: AYAs treated in the DDU at the Royal Marsden Hospital between 2002 and 2016 were identified from departmental databases. Data regarding clinicopathological features, clinical assessments and germline and tumour genetic testing were retrieved by chart review. RESULTS: The study cohort included 219 AYAs. Common cancer types included sarcoma (41, 19%); cervical (27, 12%); breast (25, 11%); ovarian (23, 11%) and colorectal (21, 10%) cancers. Germline testing was undertaken in 34 (16%) patients, 22 of whom carried a pathogenic variant. Using current testing criteria, an additional 32 (15%) would be eligible for germline testing based on their personal history of cancer alone. Tumour testing was undertaken in 46 (21%) individuals. Somatic mutations were commonly identified in TP53 13 (28%); PIK3CA (8, 18%); KRAS (4, 9%) and MET 5 (11%). DISCUSSION: A significant proportion of AYAs with advanced cancer have targetable somatic or germline mutations. Consideration of familial risk factors and inclusion of germline testing wherever appropriate can complement tumour testing to optimise patient management and inform management of at-risk relatives. PMID- 29614443 TI - Removal notice to "A "cough induced" pelvic fracture as the first sign of a malignant neoplasm" [IJSCR Volume 11 (2015) 75-77]. AB - This article has been removed: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/our-business/policies/article-withdrawal). This article has been removed at the request of the Authors. After publication the authors alerted the journal that the patient had not wanted the report published and that patient consent had not been granted. The article has therefore been removed. Elsevier apologises for any inconvenience caused. PMID- 29614444 TI - Scapular osteochondroma with winging: A case report. AB - INTRODUCTION: Osteochondroma, a type of cartilaginous tumour, is the most common benign tumour affecting the bone. These tumours usually arise around the knee, proximal humerus, and pelvis, but very rarely occur at the scapula. Osteochondromas are usually asymptomatic and uncomplicated, but must be treated by surgical resection. PRESENTATION OF CASE: In this report, we present a rare case of a symptomatic scapular osteochondroma associated with scapular winging in a 30-year-old man. This tumour exhibited positive radiological findings and was treated surgically, leading to a complete resolution of the patient's symptoms with no history of recurrence. DISCUSSION: This case was unique because although the patient presented in his fourth decade of life, he had not noticed any signs indicative of lesional growth during adolescence and the maturation process. Additionally, this case was symptomatic and involved an unusual site. CONCLUSION: By reporting this rare case of a ventral-side scapular osteochondroma that presented with scapular winging, we aim to increase the awareness of the unusual manifestations of osteochondroma, particularly atypical sites, signs, and symptoms. Furthermore, we have described the surgical treatment of this case in detail to assist other surgeons who face similar cases. PMID- 29614445 TI - Exploring full cervical dilatation caesarean sections-A retrospective cohort study. AB - BACKGROUND: The rate of caesarean sections at full cervical dilatation with their high risk of morbidity continues to rise mirroring the overall increase in caesarean section rates internationally. OBJECTIVES: The objectives of this study were to determine the rate of full dilatation caesarean section in a tertiary referral unit and evaluate key labour, maternal and fetal factors potentially linked to those deliveries. We also assessed maternal and fetal morbidity at full dilatation sections. Where possible, these were compared with successful operative vaginal deliveries carried out in theatre to determine key differences. STUDY DESIGN: Retrospective cohort study. We reviewed the rate of full dilatation caesarean section over a 10-year period. We analysed deliveries (caesarean sections or operative vaginal deliveries) in single cephalic pregnancies >=34 weeks with contemporaneously collected data from our unit's electronic database for 2015. RESULTS: The rate of full dilatation caesarean section increased by over a third in the ten-year period (56/6947 (0.80%) vs 92/7378 (1.24%), p = 0.01). Of 84 full dilatation caesarean sections who met the inclusion criteria, 63 (75%) were nulliparous and the mean maternal age was 33 (+/-5) years. Oxytocin was used in the second stage in less than half of second stage caesarean sections (22 out of a recorded 57, 38.6%). There were more fetal head malposition (occipito-posterior, or occipito-transverse) at full dilatation caesarean section compared to successful operative vaginal deliveries (41/46 (89.1%) vs 2/21 (9.5), p < 0.001). The rate of significant postpartum haemorrhage (defined as estimated blood loss >=1000 ml) was similar in both full dilatation caesarean section and operative vaginal deliveries. There was no difference in the mean birthweight at full dilatation caesarean sections compared to operative vaginal delivery (3.88 kg (2.80-5.33 kg) vs 3.48 kg (1.53-4.40 kg)). There was no difference in neonatal morbidity. CONCLUSION: Fetal head malposition is associated with a higher risk of full dilatation caesarean section. Interestingly, maternal and fetal morbidity were similar between full dilatation caesarean sections and anticipated difficult operative vaginal deliveries carried out in theatre. The management of labour in terms of the decision to use oxytocin judiciously in hope of correcting inefficient uterine contractions and continuous labour ward training, particularly the diagnosis of malposition and its correction may be beneficial in reducing the rate of full dilation caesarean sections. PMID- 29614446 TI - Intrapartum and perinatal results associated with different degrees of staining of meconium stained amniotic fluid. AB - OBJECTIVE: To determine the intrapartum and perinatal results associated with different degrees of staining of meconium stained amniotic fluid (MSAF). STUDY DESIGN: In a retrospective cohort study of all singleton deliveries over a period of one year (2015) in a tertiary hospital, we compared different degrees of MSAF (yellow, green and thick) to clear amniotic fluids, and analysed in each group maternal, intrapartum and neonatal variables as well as umbilical cord blood gas analysis. RESULTS: Of the 3590 deliveries included, 503 (14%) had MSAF. The incidence of MSAF rises with gestational age at delivery, reaching 20.7% in gestations above 41 weeks compared to 4.3% below 37 weeks. As the amniotic fluid staining progresses we found a higher proportion of intrapartum fevers (p < 0.001), pathological fetal heart rate patterns (p < 0.05), operative vaginal deliveries and cesarean sections (p < 0.001), as well as the need for advanced neonatal resuscitation (p < 0.001). There was also a correlation between MSAF and low Apgar scores at five minutes (p < 0.001) and fetal-neonatal mortality (p < 0.001) but there was not a higher proportion of neonatal intensive care admissions (p > 0.05). We have observed a similar distribution of umbilical artery pH ranges in all groups (p > 0.05). CONCLUSIONS: MSAF was associated with an increase in the rate of pathological fetal heart rate patterns, intrapartum fevers, operative vaginal and cesarean section deliveries, need for neonatal resuscitation, low Apgar scores and higher fetal-neonatal mortality. Moreover, we found that the risks increase as the staining and consistency of the amniotic fluid evolves so it should alert the obstetrician and paediatrician to the potential adverse outcomes. PMID- 29614447 TI - Nonmedical opioid use among electronic dance music party attendees in New York City. AB - BACKGROUND: Nonmedical opioid use remains an epidemic in the United States. Electronic dance music (EDM) party attendees have been found to be at high risk for the use of drugs such as ecstasy, but little is known about nonmedical opioid use in this population. METHODS: Using time-space sampling, we surveyed 954 individuals (ages 18-40) attending randomly selected EDM parties in New York City in 2017. Participants were asked about the use of 18 different opioids and about willingness to use if offered by a friend in the next 30 days. We estimated the prevalence of use in this population and examined correlates of past-year and past-month use. RESULTS: Almost a quarter (23.9%) of EDM party attendees are estimated to have used opioids non-medically in their lifetime, and one out of ten (9.8%) in the past year. 5% are estimated to be current users (reporting past month use), and 16.4% are willing to use opioids non-medically if offered by a friend in the next 30 days. Past-year nonmedical benzodiazepine users were at high odds for reporting current nonmedical opioid use (aOR = 10.11, p < 0.001) and, on average, report using more different opioid drugs in the past year than non-past-year-users (p = 0.012). Nearly three-quarters (73.6%) of those who have used in the past year indicated that they would use again if offered by a friend in the next 30 days. CONCLUSION: Nonmedical opioid use is prevalent in the EDM scene and many attendees are willing to use if offered. Prevention efforts are needed in this high-risk population. PMID- 29614448 TI - Global transcriptomic analysis of Rhodococcus erythropolis D310-1 in responding to chlorimuron-ethyl. AB - Chlorimuron-ethyl is a typical long-term residual sulfonylurea herbicide whose long period of residence poses a serious hazard to rotational crops. Microbial degradation is considered to be the most acceptable method for its removal, but the degradation mechanism is not clear. In this work, we investigated gene expression changes during the degradation of chlorimuron-ethyl by an effective chlorimuron-ethyl-degrading bacterium, Rhodococcus erythropolis D310-1. The genes that correspond to this degradation and their mode of action were identified using RNA-Seq and qRT-PCR. The RNA-Seq results revealed that 500 genes were up regulated during chlorimuron-ethyl degradation by strain D310-1. KEGG annotation showed that the dominant metabolic pathways were "Toluene degradation" and "Aminobenzoate degradation". Combining GO and KEGG classification with the relevant literature, we predicted that cytochrome P-450, carboxylesterase, and monooxygenase were involved in metabolic chlorimuron-ethyl biodegradation and that the enzyme active site and mode of action coincided with the degradation pathway proposed in our previous study. qRT-PCR experiments suggested that the R. erythropolis D310-1 carboxylesterase, cytochrome P-450 and glycosyltransferase genes were the key genes expressed during chlorimuron-ethyl biodegradation. To the best of our knowledge, this report is the first to describe the transcriptome analysis of a Rhodococcus species during the degradation of chlorimuron-ethyl. PMID- 29614449 TI - Cytogenetic damage in peripheral blood cultures of Chaetophractus villosus exposed in vivo to a glyphosate formulation (Roundup). AB - Different concentrations of a glyphosate formulation, Roundup(r) Full II (66.2% glyphosate) were tested in culture peripheral blood of armadillo Chaetophractus villosus with cytogenetic biomarkers like mitotic index (MI), chromosomal aberrations (CA), sister chromatid exchange (SCE) and cell proliferation kinetics (CPK) by means of replication index. Adults animals of both sexes were exposed to RU at four concentrations ranging from 0.026 mL RU solution to 0.379 mL RU daily in oral treatment with the same volume (0.2 mL) during 7 days. We analyzed the induced damage at different times considering T0 as control value, one (T1), seven (T7) and 30 days (T30). One day after, only the higher concentration shows MI significant differences (p < 0.05), at T7 the frequency increases and at T30 it decreases reaching T0 values. The analysis of CA frequencies shows that only 0.106 mL RU/day exhibit significant differences vs T0 values. A great variability is expressed in the values of standard deviation (SD) and in the wide confidence intervals of the media. One day after treatments (T1) all four concentrations shows significant differences in SCE vs T0 values. Replication Index (RI) does not show significant differences. The dose-response behavior was not observed in either CA or SCE. The consistency of the findings obtained with the same biomarkers in vitro support the idea of expanding studies in order to characterize the risk doses for these mammals. PMID- 29614450 TI - Evaluating the process performance and potential of a high-rate single airlift bioreactor for simultaneous carbon and nitrogen removal through coupling different pathways from a nitrogen-rich wastewater. AB - The feasibility of a continuous feed and intermittent discharge airlift bioreactor for simultaneous carbon and nitrogen removal from a low COD/N wastewater was evaluated. The effect of two independent variables, HRT (10-20 h) and NH4+/(NH4++NO3-) ratio (0.25-0.75), on the bioreactor performance was studied. The relatively high anaerobic to aerobic time ratio made an effective contribution to NH4+, NO3-, and TN removal. TN removal was enhanced with increase in HRT and decrease in NH4+/NH4++NO3- and at the optimum condition, 616 mg/L (88%) and 213 mg/L (76%) of sCOD and TN were removed, respectively. The results suggested that the nitrogen removal process was based on a combination of anaerobic ammonium oxidation (Anammox), simultaneous nitrification denitrification (SND), and presumable dissimilatory nitrate reduction to ammonium (DNRA) mechanisms. PMID- 29614451 TI - Exploration and optimization of mixed acid synergistic catalysis pretreatment for maximum C5 sugars. AB - The liquid hot water (LHW) pretreatment could be strengthened by acetic and lactic acids produced from the process. The synergistic effect of the mixed acid catalyst of lactic acid and acetic acid was investigated for the purpose of maximization of the overall C5 sugars yield. Individual acids (acetic and lactic acid) and mixed acid were used to strengthen the LHW pretreatment at different conditions. The results showed that the suitable conditions of mixed acid synergistic catalysis was at 180 degrees C for 60 min and 3 wt% mixed acid where the ratio of 40% (i.e. 0.40 in mass fraction of lactic acid in mixed acid). Response surface methodology (RSM) was applied to further optimize this process. The highest yield of C5 sugars of 93.83% according to theoretical predicted model, was close to the experiment value of 92.53% at 177 degrees C for 67 min and with the ratio of mixed acid of 40%. PMID- 29614452 TI - Recovery of high-concentration volatile fatty acids from wastewater using an acidogenesis-electrodialysis integrated system. AB - Recovery of volatile fatty acids (VFAs) from wastewater is an important route for wastewater valorization. Selective acidogenic fermentation enables an efficient production of VFAs from wastewater, whereas electrodialysis (ED) provides an effective approach to concentrate VFAs. However, these two processes have not been coupled in one single system previously. In this study, an acidogenesis-ED integrated system that coupled a continuous acidogenesis with a batch process of VFA concentration was developed for recovery of high-concentration VFAs from wastewater. Under 20.0 V voltage, the acetate was concentrated by 4-fold and the propionate and butyrate were concentrated by over 3-fold in the integrated system after 528-h operation. The declined VFAs recovery ratios at the later stage due to significant reverse diffusion indicate a need to prevent product over accumulation. This work demonstrated the feasibility of the acidogenesis-ED integrated reactor for wastewater valorization and discussed the remaining challenges and opportunities. PMID- 29614453 TI - Conversion of stranded waste-stream carbon and nutrients into value-added products via metabolically coupled binary heterotroph-photoautotroph system. AB - Growth of heterotrophic bacterium Bacillus subtilis was metabolically coupled with the photosynthetic activity of an astaxanthin-producing alga Haematococcus pluvialis for conversion of starch-containing waste stream into carotenoid enriched biomass. The H. pluvialis accounted for 63% of the produced co-culture biomass of 2.2 g/L. Importantly, the binary system requires neither exogenous supply of gaseous substrates nor application of energy-intensive mass transfer technologies due to in-situ exchange in CO2 and O2. The maximum reduction in COD, total nitrogen and phosphorus reached 65%, 55% and 30%, respectively. Conducted techno-economic assessment suggested that the astaxanthin-rich biomass may potentially offset the costs of waste treatment, and, with specific productivity enhancements (induction of astaxanthin to 2% and increase H. pluvialis fraction to 80%), provide and additional revenue stream. The outcome of this study demonstrates a successful proof-of-principle for conversion of waste carbon and nutrients into value-added products through metabolic coupling of heterotrophic and phototrophic metabolisms. PMID- 29614454 TI - One step synthesis of Co/Cr-codoped ZnO nanoparticle with superb adsorption properties for various anionic organic pollutants and its regeneration. AB - Adsorption is an effective means to remove organic pollutant. However, it is challenging to prepare the adsorbents with high adsorption capacities and their regeneration. Herein, Co/Cr-codoped ZnO nanoparticles (NPs) with superb adsorption for dyes and antibiotics have been successfully synthesized by a mild solvothermal method. At the optimal Co:Cr:Zn doping moral ratio of 4:6:100, the maximum adsorption capacities of methyl orange (MO) and tetracycline hydrochloride (TC-HCl) on Co/Cr-codoped ZnO NPs is 1057.90 mg g-1 and 874.46 mg g 1, respectively. The adsorption process of the sample over MO and TC-HCl both agreed well with the pseudo-second-order kinetic model and Langmuir isotherm model. Adsorption thermodynamics proved that the adsorption of MO and TC-HCl on Co/Cr-codoped ZnO NPs was a spontaneous and endothermic process. The mechanism shows that the surface of Co/Cr-codoped ZnO NPs have more positive charges, larger specific surface area and more crystal defects due to Co3+ and Cr3+ substitutes Zn2+ in ZnO lattice, improving their adsorption property. In addition, Co/Cr-codoped ZnO NPs have also excellent adsorption capacity for Direct Red, Congo Red, Evans Blue and Methyl Blue. More importantly, the regeneration of adsorbents was studied to achieve the reuse of materials, and avoid secondary pollution. Co/Cr-codoped ZnO NPs will be a promising choice for wastewater treatment owing to its excellent adsorption capacity and relatively low cost. PMID- 29614455 TI - Micropollutants removal and health risk reduction in a water reclamation and ecological reuse system. AB - As reclaimed water use is increasing, its safety attracts growing attention, particularly with respect to the health risks associated with the wide range of micropollutants found in the reclaimed water. In this study, sophisticated analysis was conducted for water samples from a water reclamation and ecological reuse system where domestic wastewater was treated using an anaerobic-anoxic-oxic unit followed by a membrane bioreactor (A2O-MBR), and the reclaimed water was used for replenishing a landscape lake. A total of 58 organic micropollutants were detected in the system, consisting of 13 polycyclic aromatic hydrocarbons (PAHs), 16 phenols, 3 pesticides, and 26 pharmaceuticals and personal care products (PPCPs). After treatment by the A2O-MBR process, effective removal of pesticides and phenols was achieved, while when the reclaimed water entered the landscape lake, PPCPs were further removed. From the physicochemical properties of micropollutants, it could be inferred that phenols and dichlorphos (the only pesticide with considerable concentration in the influent) would have been mainly removed by biodegradation and/or volatilization in the biological treatment process. Additionally, it is probable that sludge adsorption also contributed to the removal of dichlorphos. For the predominant PPCP removal in the landscape lake, various actions, such as adsorption, biodegradation, photolysis, and ecologically mediated processes (via aquatic plants and animals), would have played significant roles. However, according to their logKoc, logKow and logD (pH = 8) values, it could be concluded that adsorption by suspended solids might be an important action. Although carcinogenic and non-carcinogenic risks associated with all the detected micropollutants were at negligible levels, the hazard quotients (HQs) of PPCPs accounted for 92.03%-97.23% of the HQTotal. With the significant removal of PPCPs through the ecological processes in the landscape lake, the safety of reclaimed water use could be improved. Therefore, the introduction of ecological unit into the water reclamation and reuse system could be an effective measure for health risk reduction posed by micropollutants. PMID- 29614456 TI - Understanding human infectious Cryptosporidium risk in drinking water supply catchments. AB - Treating drinking water appropriately depends, in part, on the robustness of source water quality risk assessments, however quantifying the proportion of infectious, human pathogenic Cryptosporidium oocysts remains a significant challenge. We analysed 962 source water samples across nine locations to profile the occurrence, rate and timing of infectious, human pathogenic Cryptosporidium in surface waters entering drinking water reservoirs during rainfall-runoff conditions. At the catchment level, average infectivity over the four-year study period reached 18%; however, most locations averaged <5%. The maximum recorded infectivity fraction within a single rainfall runoff event was 65.4%, and was dominated by C. parvum. Twenty-two Cryptosporidium species and genotypes were identified using PCR-based molecular techniques; the most common being C. parvum, detected in 23% of water samples. Associations between landuse and livestock stocking characteristics with Cryptosporidium were determined using a linear mixed-effects model. The concentration of pathogens in water were significantly influenced by flow and dominance of land-use by commercial grazing properties (as opposed to lifestyle properties) in the catchment (p < 0.01). Inclusion of measured infectivity and human pathogenicity data into a quantitative microbial risk assessment (QMRA) could reduce the source water treatment requirements by up to 2.67 log removal values, depending on the catchment, and demonstrated the potential benefit of collating such data for QMRAs. PMID- 29614457 TI - Degradation kinetics and transformation products of chlorophene by aqueous permanganate. AB - This paper evaluates the oxidation of an antibacterial agent, chlorophene (4 chloro-2-(phenylmethyl)phenol, CP), by permanganate (Mn(VII)) in water. Second order rate constant (k) for the reaction between Mn(VII) and CP was measured as (2.05 +/- 0.05) * 101 M-1 s-1 at pH 7.0 for an initial CP concentration of 20.0 MUM and Mn(VII) concentration of 60.0 MUM. The value of k decreased with increasing pH in the pH range of 5.0-7.0, and then increased with an increase in solution pH from 7.0 to 10.0. The presence of MnO2 and Fe3+ in water generally enhanced the removal of CP, while the effect of humic acid was not obvious. Fourteen oxidation products of CP were identified by an electrospray time-of flight mass spectrometer, and direct oxidation, ring-opening, and decarboxylation were mainly observed in the reaction process. The initial reaction sites of CP by Mn(VII) oxidation were rationalized by density functional theory calculations. Toxicity changes of the reaction solutions were assessed by the luminescent bacteria P. phosphoreum, and the intermediate products posed a relatively low ecological risk during the degradation process. The efficient removal of CP in secondary clarifier effluent and river water demonstrated the potential application of this Mn(VII) oxidation method in water treatment. PMID- 29614458 TI - Kinetic modeling of the effect of solids retention time on methanethiol dynamics in anaerobic digestion. AB - The highly volatile methanethiol (MT) with an extremely low odor threshold and distinctive putrid smell is often identified as a major odorous compound generated under anaerobic conditions. As an intermediate compound in the course of anaerobic digestion, the extent of MT emission is closely related to the time of anaerobic reaction. In this study, lab-scale anaerobic digesters were operated at solids retention time (SRTs) of 15, 20, 25, 30, 40 and 50 days to investigate the effect of SRT on MT emission. The experimental results demonstrated a bell shaped curve of MT emission versus SRT with a peak around 20 days SRT. In order to understand this SRT effect, a kinetic model was developed to describe MT production and utilization dynamics in the course of anaerobic digestion and calibrated with the experimental results collected from this study. The model outcome revealed that the high protein content in the feed sludge together with the large maintenance coefficient of MT fermenters are responsible for the peak MT emission emergence in the range of typical SRT used for anaerobic digestion. A further analysis of the kinetic model shows that it can be extensively simplified with reasonable approximation to a form that anaerobic digestion practitioners could easily use to predict the MT and SRT relationship. PMID- 29614459 TI - Height in eighteenth-century Chilean men: Evidence from military records, 1730 1800s. AB - This article provides the first height estimates for the adult population for any period of Chilean history. Based on military records, it gives an analysis of the average heights of male soldiers in the last eight decades of the colonial period, c.1730-1800s. The average height of Chilean men was around 167 centimetres, making them on average taller than men from Mexico, Italy, Portugal, Spain and Venezuela, but of a similar height to men from Sweden. However, Chilean men were clearly shorter than men in neighbouring Argentina, the USA and the UK. Chilean height remained stable during the 1740-1770s, but it declined by some 2-3 centimetres between the 1780 s and the 1800s, in line with a fall in real wages due to increasing food prices and population growth. PMID- 29614460 TI - Inequality in old age cognition across the world. AB - Although cohort and country differences in average cognitive levels are well established, identifying the degree and determinants of inequalities in old age cognitive functioning could guide public health and policymaking efforts. We use all publicly available and representative old age surveys with comparable information to assess inequalities of cognitive functioning for six distinctive age groups in 29 countries. We document that cognitive inequalities in old age are largely determined by earlier educational inequalities as well as gender differential survival rates. For example, a one percentage point increase in the Gini index of past education is associated with an increase of 0.45 percentage points in the Gini index of delayed recall and 0.23 percentage points in the Gini of immediate recall. Results are robust to a variety of alternative explanations and persist even after controlling for gender-related biases in survival rates. Furthermore, we find evidence that unequal opportunities for education -captured by differences in parental background and gender- also have significant effects on inequality of old age cognition. PMID- 29614462 TI - Natural saliva as an adjuvant in a secondary caries model based on Streptococcus mutans. AB - OBJECTIVE: Two factors for secondary caries formation were evaluated using an artificial biofilm model, saliva as additive in culture medium and bonding procedures of composite materials for artificial gap creation. DESIGN: Standardized cavities were prepared in bovine tooth samples (n = 44), treated with two different bonding pretreatments, restored and after artificial ageing incubated with Streptococcus mutans in a Mueller-Hinton-Broth-Sugar medium with or without human saliva for seven days. Secondary caries formation was analyzed using confocal laser scanning microscopy and transversal microradiography. RESULTS: Lesions were significantly pronounced in groups using saliva, but were not influenced by the bonding pretreatments. CONCLUSIONS: The results indicate that the addition of saliva, but not the type of bonding procedure influences the outcome in the present biofilm-based secondary caries model. PMID- 29614461 TI - Prenatal exposure to disaster-related traumatic stress and developmental trajectories of temperament in early childhood: Superstorm Sandy pregnancy study. AB - BACKGROUND: Little is known about the impact of prenatal maternal stress (PNMS) on the developmental trajectory of temperament and few studies have been able to incorporate a natural disaster as a quasi-experimental stressor. The current study investigated PNMS related to Superstorm Sandy ('Sandy'), a hurricane that struck the New York metropolitan area in October 2012, in terms of objective exposure during pregnancy, subjective stress reaction as assessed by maternal symptoms of post-traumatic stress, and their impact on the developmental changes in temperament during early childhood. METHOD: A subsample of 318 mother-child dyads was drawn from the Stress in Pregnancy Study. Temperament was measured at 6, 12, 18, and 24 months of age. RESULTS: Objective exposure was associated with greater High-Intensity Pleasure, Approach, Perceptual Sensitivity and Fearfulness, but lower Cuddliness and Duration of Orientation at 6 months. Objective exposure and its interaction with subjective stress reaction predicted developmental changes in temperament. In particular, objective exposure was linked to greater increases in Activity Level but decreases in High-Intensity Pleasure, Approach, and Fearfulness. The combination of objective exposure and subjective stress reaction was also associated with greater increases in Activity Level. LIMITATIONS: Temperament was measured solely via maternal report. Trimester-specific effects of Sandy on temperament were not examined. CONCLUSION: This is the first study to examine the effects of prenatal maternal exposure to a natural disaster on trajectories of early childhood temperament. Findings suggest that both objective stress exposure and subjective stress reaction in-utero predict developmental trajectories of temperament in early childhood. PMID- 29614463 TI - Is symmetry of loading improved for injured runners during novice barefoot running? AB - BACKGROUND: As barefoot (BF) running provides important sensory information that influence landing patterns, it may also affect loading symmetry. RESEARCH QUESTION: The purpose of this investigation was to examine whether symmetry of loading in a group of injured runners would be improved in a novice, barefoot condition. METHODS: Cross-sectional design evaluating 67 injured RFS runners. Each subject ran on an instrumented treadmill, first with their habitual shod pattern and then in a BF condition with a FFS pattern, both at the same self selected speed. Data were averaged over 10 footstrikes. Variables of interest included vertical average load rate, vertical instantaneous load rate, and resultant instantaneous load rate. Symmetry indices (SI) for full population and within quartiles were compared for each loadrate variable (P <= 0.05) to evaluate changes between conditions. RESULTS: On average, symmetry of loading was similar in a novice BF condition of injured runners compared with their habitual RFS shod condition. However, a subanalysis of quartiles revealed that the injured runners with the highest asymmetry (greatest SI values) displayed significantly lower asymmetry when running BF for all three loadrate measures. SIGNIFICANCE: The addition of sensory input during barefoot running only improves symmetry of loading when habitual loading is highly asymmetric. PMID- 29614464 TI - Identifying balance impairments in people with Parkinson's disease using video and wearable sensors. AB - BACKGROUND: Falls and near falls are common among people with Parkinson's (PwP). To date, most wearable sensor research focussed on fall detection, few studies explored if wearable sensors can detect instability. RESEARCH QUESTION: Can instability (caution or near-falls) be detected using wearable sensors in comparison to video analysis? METHODS: Twenty-four people (aged 60-86) with and without Parkinson's were recruited from community groups. Movements (e.g. walking, turning, transfers and reaching) were observed in the gait laboratory and/or at home; recorded using clinical measures, video and five wearable sensors (attached on the waist, ankles and wrists). After defining 'caution' and 'instability', two researchers evaluated video data and a third the raw wearable sensor data; blinded to each other's evaluations. Agreement between video and sensor data was calculated on stability, timing, step count and strategy. RESULTS: Data was available for 117 performances: 82 (70%) appeared stable on video. Ratings agreed in 86/117 cases (74%). Highest agreement was noted for chair transfer, timed up and go test and 3 m walks. Video analysts noted caution (slow, contained movements, safety-enhancing postures and concentration) and/or instability (saving reactions, stopping after stumbling or veering) in 40/134 performances (30%): raw wearable sensor data identified 16/35 performances rated cautious or unstable (sensitivity 46%) and 70/82 rated stable (specificity 85%). There was a 54% chance that a performance identified from wearable sensors as cautious/unstable was so; rising to 80% for stable movements. SIGNIFICANCE: Agreement between wearable sensor and video data suggested that wearable sensors can detect subtle instability and near-falls. Caution and instability were observed in nearly a third of performances, suggesting that simple, mildly challenging actions, with clearly defined start- and end-points, may be most amenable to monitoring during free-living at home. Using the genuine near-falls recorded, work continues to automatically detect subtle instability using algorithms. PMID- 29614465 TI - Running at submaximal speeds, the role of the intact and prosthetic limbs for trans-tibial amputees. AB - BACKGROUND: Dynamic Elastic Response prostheses are designed to absorb and return strain energy in running. Past research has focused on running prostheses with a single toe spring designed for high speeds. RESEARCH QUESTION: To determine how runners with amputation modulate the ground reaction force of each limb to run at different speeds using a general-purpose dynamic prosthesis which has a heel spring. METHODS: Overground running data were collected in 16 recreational runners (8 transtibial amputee using their own BladeXT prosthesis and 8 controls) using Vicon Nexus V.2.5 with Kistler force plates. Participants ran at self selected running pace, 70% and 130% of that pace. Vertical, braking and propulsion peak ground reaction forces and impulses and vertical loading and decay rates were analysed between limbs at each speed (ANOVA) and their association with speed assessed (simple linear regression). RESULTS: The vertical, braking forces and impulses and propulsive force were significantly less (p < 0.05) on the prosthetic limb than controls at the faster speed, but there was no difference in the propulsive impulse. The intact limb did not evidence increased vertical force at any speed, but experienced increased braking (p < 0.05) compared to both prosthetic limb and controls at the slow speed. For all limbs, braking and propulsive peak forces, decay rate, step length and step frequency were strongly (r > 0.6) and significantly (p < 0.05) associated with speed. On the prosthetic limb vertical impulse was strongly and significantly negatively associated with speed and control's braking impulse was associated with speed. SIGNIFICANCE: A leg-specific response was found at different speeds. On the prosthetic limb the technique was to brake less not propel more at higher speeds with reduced vertical drive. Running at self-selected speed could be used for fitness without inducing detrimental ground reaction forces on the intact limb or evoking asymmetry in step length and frequency. PMID- 29614466 TI - Comparison of segmental analysis and sacral marker methods for determining the center of mass during level and slope walking. AB - BACKGROUND: A human's center of mass (COM) is a widely used parameter in both clinical and practical applications. The segmental analysis method for determining the COM is considered the gold standard but is difficult to apply in a real environment. RESEARCH QUESTION: The purpose of this study was to confirm the efficacy of an alternative COM determination method-the sacral marker method by comparing segmental analysis and sacral marker method results in three dimensions during level or slope walking. METHODS: Ten healthy young subjects (age = 24.0 +/- 4.5 yr, height = 174.5 +/- 5.9 cm, and weight = 66.9 +/- 9.4 kg) participated in the study. Each participant was monitored using a Helen Hayes full-body marker set and asked to walk on level and sloped (7 degrees ) terrain. The markers' trajectories were subsequently recorded. Each participant's COM was determined using segmental analysis and sacral marker methods via calculation and direct measurement, respectively. RESULTS: Comparative results indicated no significant differences (p > 0.05) between the segmental analysis and sacral marker method results for the COM displacement, velocity, or acceleration in the fore-aft and vertical directions. Conversely, significant differences (p < 0.05) between the two methods were observed for the COM displacement and acceleration in the medial-lateral direction, suggesting kinematic differences. SIGNIFICANCE: Based on this latter finding, caution should be exercised when determining COM kinematics using the sacral marker method. PMID- 29614468 TI - Energy expenditure in people with transtibial amputation walking with crossover and energy storing prosthetic feet: A randomized within-subject study. AB - BACKGROUND: Energy storing feet are unable to reduce the energy required for normal locomotion among people with transtibial amputation. Crossover feet, which incorporate aspects of energy storing and running specific feet, are designed to maximize energy return while providing stability for everyday activities. RESEARCH QUESTION: Do crossover prosthetic feet reduce the energy expenditure of walking across a range of speeds, when compared with energy storing feet among people with transtibial amputation due to non-dysvascular causes? METHODS: A randomized within-subject study was conducted with a volunteer sample of twenty seven adults with unilateral transtibial amputation due to non-dysvascular causes. Participants were fit with two prostheses. One had an energy storing foot (Ossur Variflex) and the other a crossover foot (Ossur Cheetah Xplore). Other components, including sockets, suspension, and interface were standardized. Energy expenditure was measured with a portable respirometer (Cosmed K4b2) while participants walked on a treadmill at self-selected slow, comfortable, and fast speeds with each prosthesis. Gross oxygen consumption rates (VO2 ml/min) were compared between foot conditions. Energy storing feet were used as the baseline condition because they are used by most people with a lower limb prosthesis. Analyses were performed to identify people who may benefit from transition to crossover feet. RESULTS: On average, participants had lower oxygen consumption in the crossover foot condition compared to the energy storing foot condition at each self-selected walking speed, but this difference was not statistically significant. Participants with farther six-minute walk test distances, higher daily step counts, and higher Medicare Functional Classification Levels at baseline were more likely to use less energy in the crossover foot. SIGNIFICANCE: Crossover feet may be most beneficial for people with higher activity levels and physical fitness. Further research is needed to examine the effect of crossover feet on energy expenditure during high-level activities. PMID- 29614467 TI - Trunk motion visual feedback during walking improves dynamic balance in older adults: Assessor blinded randomized controlled trial. AB - BACKGROUND: Virtual reality and augmented feedback have become more prevalent as training methods to improve balance. Few reports exist on the benefits of providing trunk motion visual feedback (VFB) during treadmill walking, and most of those reports only describe within session changes. RESEARCH QUESTION: To determine whether trunk motion VFB treadmill walking would improve over-ground balance for older adults with self-reported balance problems. METHODS: 40 adults (75.8 years (SD 6.5)) with self-reported balance difficulties or a history of falling were randomized to a control or experimental group. Everyone walked on a treadmill at a comfortable speed 3*/week for 4 weeks in 2 min bouts separated by a seated rest. The control group was instructed to look at a stationary bulls-eye target while the experimental group also saw a moving cursor superimposed on the stationary bulls-eye that represented VFB of their walking trunk motion. The experimental group was instructed to keep the cursor in the center of the bulls eye. Somatosensory (monofilaments and joint position testing) and vestibular function (canal specific clinical head impulses) was evaluated prior to intervention. Balance and mobility were tested before and after the intervention using Berg Balance Test, BESTest, mini-BESTest, and Six Minute Walk. RESULTS: There were no significant differences between groups before the intervention. The experimental group significantly improved on the BESTest (p = 0.031) and the mini BEST (p = 0.019). The control group did not improve significantly on any measure. Individuals with more profound sensory impairments had a larger improvement on dynamic balance subtests of the BESTest. SIGNIFICANCE: Older adults with self reported balance problems improve their dynamic balance after training using trunk motion VFB treadmill walking. Individuals with worse sensory function may benefit more from trunk motion VFB during walking than individuals with intact sensory function. PMID- 29614469 TI - Gait and functionality of individuals with visual impairment who participate in sports. AB - BACKGROUND: Individuals with visual impairment (VI) have often been observed to walk slower than individuals with unimpaired vision. These observations might be confounded by typical low levels of physical activity and greater sedentary behavior in individuals with VI than the overall population. RESEARCH QUESTION: Here, we compared gait and balance measures between individuals with VI who participate in disability sports, and activity level matched sighted individuals. METHODS: We assessed static balance, anthropometry, self-selected walking speed, locomotion rehabilitation index, and lower limb muscular endurance; and applied physical activity level and fear of falling questionnaires. RESULTS: Individuals with VI who participate in disability sports, self-selected a similar walking speed (1.29 +/- 0.26 m/s) as active sighted individuals (1.39 +/- 0.21 m/s). Locomotor rehabilitation index and muscular endurance of lower limbs were also similar between groups. Individuals with VI presented lower static balance (42.0 +/- 17.0s) than the sighted control group (45.0 +/- 0s) when the controls were tested with their eyes open. However, no difference was found when the controls were tested with their eyes closed (30.3 +/- 17.0s). Furthermore, individuals with VI showed a greater fear of falling. SIGNIFICANCE: In conclusion, individuals with VI who participate in disability sports, as goalball and football, walk with similar self-selected walking speeds as active sighted individuals, but have slightly worse static balance and fear of falling. PMID- 29614470 TI - Integrated use of histological and ultrastructural biomarkers for assessing mercury pollution in piranhas (Serrasalmus rhombeus) from the Amazon mining region. PMID- 29614471 TI - Maternal exposure to ambient air pollutant and risk of oral clefts in Wuhan, China. AB - Maternal exposure to ambient air pollution has been related to oral clefts in offspring; however, the epidemiologic evidence is equivocal. Especially, the association between high levels of exposure to ambient air pollution during pregnancy and oral clefts remains unclear. The objective of this study was to evaluate whether high levels of maternal exposure to PM2.5, PM10, O3, CO and SO2 are related to increased risk of oral clefts in Wuhan, China. A population-based study was conducted using cohort of 105,927 live-born infants, fetal deaths, and stillbirths during a two-year period from 2011 to 2013. For each participant, weekly and monthly averages of daily mean concentrations for each pollutant were estimated. Multiple logistic regression analyses were constructed to quantify the adjusted odds ratios (aORs) for the relationship between each air pollutant and oral clefts while controlling for key covariates. Using monthly averages, a cleft lip with or without cleft palate (CLP) was associated with PM2.5 (aORs 2nd month = 1.34, CI:1.19-1.49; aORs 3rd month=1.14, CI:1.02-1.28), PM10 (aORs 2nd month = 1.11, CI:1.00-1.23) and CO (aORs 2nd month = 1.31, CI:1.14-1.51; aORs 3rd month = 1.17, CI:1.03-1.33). A cleft palate only (CPO) was associated with PM2.5 (aORs 2nd month = 1.24, CI: 1.03-1.48), and O3 (aORs 2nd month = 1.21, CI: 1.03-1.42; aORs 3rd month = 1.18, CI: 1.02-1.37). Our findings reveal an association between air pollutants exposure and the risk of oral clefts. Future studies are needed to confirm these associations, and clarify the causality related to specific pollutants during the most relevant vulnerable exposure time windows for oral clefts during pregnancy. PMID- 29614472 TI - Titanium dioxide nanoparticles enhance inorganic arsenic bioavailability and methylation in two freshwater algae species. AB - The effect of titanium dioxide nanoparticles (nano-TiO2) on the bioaccumulation and biotransformation of arsenic (As) remains largely unknown. In this study, we exposed two freshwater algae (Microcystis aeruginosa and Scenedesmus obliquus) to inorganic As (arsenite and arsenate) with the aim of increasing our understanding on As bioaccumulation and methylation in the presence of nano-TiO2. Direct evidence from transmission electron microscope (TEM) images show that nano-TiO2 (anatase) entered exposed algae. Thus, nano-TiO2 as carriers boosted As accumulation and methylation in these two algae species, which varied between inorganic As speciation and algae species. Specifically, nano-TiO2 could markedly enhance arsenate (As(V)) accumulation in M. aeruginosa and arsenite (As(III)) accumulation in S. obliquus. Similarly, we found evidence of higher As methylation activity in the M. aeruginosa of As(III) 2 mg L-1 nano-TiO2 treatment. Although this was also true for the S. obliquus (As(V)) treatment, this species exhibited higher As methylation compared to M. aeruginosa, being more sensitive to As associated with nano-TiO2 compared to M. aeruginosa. Due to changes in pH levels inside these exposed algae, As dissociation from nano-TiO2 inside algal cells enhanced As methylation. Accordingly, the potential influence of nanoparticles on the bioaccumulation and biotransformation of their co contaminants deserves more attention. PMID- 29614473 TI - Generation of hydroxyl radicals and singlet oxygen by particulate matter and its inorganic components. AB - Particulate matter (PM) can strongly affect redox biochemistry and therefore induce the response of the immune system and aggravate the course of autoimmune diseases. Nanoparticles containing transition metal compounds possessing semiconductor properties (TiO2, ZnO) may act as photocatalysts and accelerate the generation of reactive oxygen species (ROS) and reactive nitrogen species (RNS). In this study, the NIST standard reference material, SRM 1648a, has been analyzed in terms of this consideration. Organic compounds present in SRM 1648a were removed by cold oxygen plasma treatment. Samples of SRM 1648a with removed organic content (<2% of organic carbon, <1% of nitrogen) were obtained within 2 h of this treatment. The treatment did not affect the morphology of the powder. The reference material and PM2.5 collected in Krakow are composed of smaller particles and nanoparticles forming aggregates. The efficiency of (photo)generation of hydroxyl radicals and singlet oxygen was compared for original and organics-free samples. The analyzed samples showed the highest activity towards ROS generation when exposed to UV-vis-NIR light, moderate under UV irradiation, and the lowest in dark. Data collected in the present study suggest that the organic fraction is mostly responsible for singlet oxygen generation, as almost twice higher efficiency of 1O2 generation was observed for the original NIST sample compared to the material without the organic fraction. However, particulate matter collected in Krakow was found to have a five times higher activity in singlet oxygen generation (compared for original NIST and Krakow dust samples). PMID- 29614474 TI - Arsenic mitigation in paddy soils by using microbial fuel cells. AB - Arsenic (As) behavior in paddy soils couples with the redox process of iron (Fe) minerals. When soil is flooded, Fe oxides are transformed to soluble ferrous ions by accepting the electrons from Fe reducers. This process can significantly affect the fate of As in paddy fields. In this study, we show a novel technique to manipulate the Fe redox processes in paddy soils by deploying soil microbial fuel cells (sMFC). The results showed that the sMFC bioanode can significantly decrease the release of Fe and As into soil porewater. Iron and As contents around sMFC anode were 65.0% and 47.0% of the control respectively at day 50. The observed phenomenon would be explained by a competition for organic substrate between sMFC bioanode and the iron- and arsenic-reducing bacteria in the soils. In the vicinity of bioanode, organic matter removal efficiencies were 10.3% and 14.0% higher than the control for lost on ignition carbon and total organic carbon respectively. Sequencing of the 16S rRNA genes suggested that the influence of bioanodes on bulk soil bacterial community structure was minimal. Moreover, during the experiment a maximum current and power density of 0.31 mA and 12.0 mWm-2 were obtained, respectively. This study shows a novel way to limit the release of Fe and As in soils porewater and simultaneously generate electricity. PMID- 29614475 TI - PCV2 infection aggravates ochratoxin A-induced nephrotoxicity via autophagy involving p38 signaling pathway in vivo and in vitro. AB - Ochratoxin A (OTA) is reported to induce nephrotoxicity in animals and humans. Porcine circovirus type 2 (PCV2) could induce porcine dermatitis and nephropathy syndrome. To date, little is known whether virus infection aggravates mycotoxin induced toxicity. This work aimed to study the effects of PCV2 infection on OTA induced nephrotoxicity and its mechanism in vivo and vitro. The results in vivo showed that PCV2 infection aggravated OTA-induced poor growth performance, nephrotoxicity, p38 phosphorylation and autophagy as demonstrated by Atg5, LC3 II and p62 protein expressions in kidney of pigs. The results in vitro indicated that PCV2 infection significantly aggravated OTA-induced nephrotoxicity as demonstrated by cell viabilities, annexin V/PI binding and caspase 3 activities, and induced p38 phosphorylation and autophagy in PK15 cells. p38 inhibitor decreased Atg5 and LC3 protein expression induced by PCV2 infection and OTA combined treatment. Adding autophagy inhibitor 3-MA or CQ alleviated the aggravating effects of PCV2 infection on OTA-induced nephrotoxicity. Atg5 specific siRNA eliminated the aggravating effects of PCV2 infection on OTA induced nephrotoxicity. Taken together, these data indicate that in vivo and in vitro PCV2 infection aggravated OTA-induced nephrotoxicity via p38-mediated autophagy. PMID- 29614477 TI - Characterisation and cleaning of biogas from sewage sludge for biomethane production. AB - This study investigates the conversion of sewage sludge from wastewater treatment plants (WWTP) into biomethane for automotive fuel or grid injection. A prototype plant was monitored in Northern Italy, based on vacuum swing adsorption (VSA) on synthetic zeolite 13*: this biogas upgrading method is similar to pressure swing adsorption (PSA) and commonly used for other kinds of biomass. Measurements of biogas inlet, biomethane outlet and off-gas were performed including CH4, CO2, CO, H2, O2, N2, HCl, HF, NH3, H2S and volatile organic compounds (VOCs). Critical levels were observed in the biogas for of H2S and HCl, whose concentrations were 1570 and 26.8 mg m-3, respectively. On the other hand, the concentration of halogenated VOCs (including tetrachloroethylene and traces of perfluoroalkilated substances, PFAS) and mercaptans were relatively low. A simultaneous and reversible adsorption on 13* zeolite was achieved for H2S and CO2, and carbon filters played a minor role in desulfurisation. The presence of HCl is due to clarifying agents, and its removal is necessary in order to meet the required biomethane characteristics: an additional carbon-supported basic adsorbent was successfully used to remove this contaminant. This study also highlights the interference of CO2 towards HCl if sampling is performed in compliance with the new EU standard for biomethane. High total volatile silicon (TVS) was confirmed in sewage sludge biogas, with a major contribution of siloxane D5: the suitability of this compound as an indicator of total siloxanes is discussed. Results demonstrate that volatile methyl siloxanes (VMS) do not represent a critical issue for the VSA upgrading methodology. PMID- 29614476 TI - Social relationships, inflammation markers, and breast cancer incidence in the Women's Health Initiative. AB - OBJECTIVES: Previous research has reported associations between social relationships and carcinogenesis. Inflammation is a potential mediator of these associations. To clarify these links for one tumor site, we examined associations between social relationships, circulating inflammation markers, and breast cancer incidence. MATERIALS AND METHODS: Among 132,262 participants from the prospective Women's Health Initiative, we used linear and logistic regression to evaluate associations between social relationship characteristics (social support, social strain, social network size) and inflammation markers of C-reactive protein (CRP) and white blood cell count (WBC). Cox regression was used to evaluate associations between inflammation markers and breast cancer incidence, as well as associations between social relationship characteristics and breast cancer incidence with and without adjustment for inflammation markers. RESULTS: Larger social networks were associated with lower continuous CRP (beta = -0.22, 95% CI 0.36, -0.08) and WBC (beta = -0.23, 95% CI -0.31, -0.16). Greater social strain was associated with higher continuous CRP (beta = 0.24, 95% CI 0.14, 0.33) and WBC (beta = 0.09, 95% CI 0.04, 0.14). When WBC was dichotomized at 10,000 cells/uL, high WBC was associated with greater hazards of in situ breast cancer (HR = 1.65, 95% CI 1.17, 2.33) but not invasive breast cancer. Social relationship characteristics were not associated with incidence of invasive or in situ breast cancer. CONCLUSION: Larger social networks were associated with lower inflammation and greater social strain was associated with higher inflammation. Higher inflammation might be associated with development of in situ breast cancer, but this appeared to be due to factors other than social relationships. PMID- 29614478 TI - Investigations of water-extractability of As in excavated urban soils using sequential leaching tests: Effect of testing parameters. AB - Excavated soils with low-level As contamination obtained from construction projects during city development have been of great concern in Japan. Water extractable As represents the most easily mobilized and ecotoxicologically relevant fraction in the soil environment. In the present study, the water extractability of As in excavated alkaline urban soils was assessed using sequential leaching tests (SLTs) with a focus on the effects of test parameters. In addition, the potentially water-leachable As over an extremely long period was assessed using the pollution potential leaching index (PPLI), from which one can estimate the number of extractions required to reduce the As in the cumulative leachates to below the Japanese environmental standard (10 MUg L-1). Total As concentrations varied from 6.75 to 79.4 mg kg-1, and As was continuously detectable among replicate SLT experiments. The water-extractable As obtained in the first step of the SLT accounted for 0.41%-7.60% of total As (average: 2.36%), while the cumulative released As in the SLTs corresponded to 1.30%-21.6% of the total (average: 10.6%). The variability of the water-soluble fractions was sensitive to the test conditions. The shaking time at each SLT step had the largest effect on the As water-extractability; followed by sample storage, shaking speed and shaking interruption. A longer shaking time in the standard leaching test of excavated soils is suggested for regulatory purposes in Japan. The use of the PPLI concept for quick estimation of the potential As leachability from excavated soils was supported by the good reproducibility of PPLI results obtained from SLTs under different test parameters. PMID- 29614479 TI - Preparation and characterization of a novel polyethyleneimine cation-modified persimmon tannin bioadsorbent for anionic dye adsorption. AB - A novel and recyclable bioadsorbent (PTP) has been prepared by the cationization of persimmon tannin (PT) using polyethyleneimine (PEI) for application in the removal of the anionic dye methyl orange (MO) from aqueous solution. The physicochemical properties of the prepared PTP were characterized by Fourier transform infrared spectroscopy, scanning electron microscopy, Zeta potential measurements, Brunauer-Emmett-Teller and thermogravimetric analysis. Systematic batch adsorption experiments were carried out with pH, bioadsorbent dosage, initial MO concentration and contact time. Kinetic regression analysis indicated that the adsorption processes followed the pseudo-second order model. The equilibrium isotherm was in good fit with the Freundlich model with a maximum adsorption capacity of 225.74 mg/g. Thermodynamics data revealed that the adsorption of MO onto PTP was feasible, spontaneous and endothermic. A possible biosorption mechanism was presented where electrostatic interactions, hydrogen bonding, and pi-pi interactions dominated the adsorption of MO onto PTP. Moreover, the regeneration of the PTP was easily achieved and MO removal efficiency remained high (81.47%) after six cycles. The actual sewage treatment simulation was evaluated and the PTP had a good preference to adsorption MO. All these results indicated that PTP could be considered a high performance and promising candidate for the effective removal of anionic dyes from aqueous solutions. PMID- 29614480 TI - Modeling potential tree belt functions in rural landscapes using a new GIS tool. AB - The increasing human pressure on the environment requires effective protection activities. One way to stop the degradation of natural resources is the presence of woody vegetation networks, mainly linear in character, called linear woody features, greenways or tree belts. These objects, thanks to the many natural and economic functions they serve, enable the realization of sustainable development policy. To properly design a greenway network, the natural conditions and degree of environmental degradation in a given area must first be evaluated. Based on these data, it is possible to determine appropriate afforestation needs. To evaluate the ability of a given area to meet the requirements of greenway functions, we propose a new computer modeling system - a tree belt modeling (TBM). TBM defines the availability of tree belt functions in the planned network and is one of preparation stages in the design of an optimal greenway structure. In this work, to analyze the studied area potential, application of a cadastral dataset was proposed. Thanks to this approach, the obtained results may be related to specific plot borders, which is optimal for greenway construction. To automatize the process of analysis, the TBM was implemented into an ArcGIS toolbox. The result of using this toolbox is a tree belt functions geodatabase. This database contains information about the available functions in the analyzed lines that are potential sites for afforestation. This solution, both at the methodological and technological levels, may significantly increase the effectiveness of greenway planning and thus contribute to more effective activities for sustainable development. PMID- 29614481 TI - Vertical stratification of volatile organic compounds and their photochemical product formation potential in an industrial urban area. AB - High emissions of volatile organic compounds (VOCs) from the petrochemical industry and vehicle exhaust may contribute to high ozone formation potential (OFP) and secondary organic aerosol formation potential (SOAFP). In this study, the vertical profiles of VOCs were created for the southern Taiwan industrial city of Kaohsiung. Vertical air samples were collected up to 1000 m using an unmanned aerial vehicle (UAV). In Renwu District, VOC distribution was affected by the inversion layer up to 200 m height. Total VOCs (36-327 ppbv), OFP (66-831 ppbv) and SOAFP (0.12-5.55 ppbv) stratified by height were the highest values at 300 m. The VOCs originated from both local and long-distance transport sources. These findings can be integrated into Kaohsiung's future air quality improvement plans and serve as a reference for other industrialized areas worldwide. PMID- 29614482 TI - Effects of oil spill response technologies on the physiological performance of the Arctic copepod Calanus glacialis. AB - A mesocosm study with oil in ice was performed in Van Mijenfjorden in Svalbard to compare effects of the oil spill responses (OSR) in situ burning, chemical dispersion and natural attenuation on the physiological performance of the Arctic copepod Calanus glacialis. Seawater collected from the mesocosms in winter and spring was used in laboratory incubation experiments, where effects on fecal pellet production, egg production and hatching success were investigated over a period of 14 days. Polycyclic aromatic hydrocarbon (PAH) seawater concentrations were lowest in winter. Brine channel formation in spring resulted in an 18 times increase in PAH concentration in the chemical dispersion treatment (1.67 MUg L 1), and a 3 fold increase in the natural attenuation (0.36 MUg L-1) and in situ burning (0.04 MUg L-1) treatments. The physiological performance of female C. glacialis was unaffected by the PAH seawater concentrations. However, a higher mortality and deformity of nauplii was observed in the chemical dispersion treatment, highlighting the importance of considering secondary effects on next generation in future environmental risk assessment of OSR. This study shows that during the ice-covered period, chemical dispersion of oil spills leads to higher PAH exposure than natural attenuation and in situ burning, with potential consequences for recruitment of Arctic copepods. PMID- 29614483 TI - Attachment and psychopathology: a dynamic model of the insecure cycle. PMID- 29614484 TI - Body packing and intra-vaginal body pushing of cocaine: A not-so-rare event. PMID- 29614485 TI - MiR-99a Enhances the Radiation Sensitivity of Non-Small Cell Lung Cancer by Targeting mTOR. AB - BACKGROUND/AIMS: Radiation therapy is an important and effective modality for the treatment of non-small cell lung cancer (NSCLC). MicroRNAs (miRNAs) are crucial post-transcriptional regulators that are involved in numerous important biologic processes. However, their potential involvement in radiation sensitivity remains unknown. MATERIALS: We performed integrated analysis of miRNA expression in NSCLC using The Cancer Genome Atlas datasets. miR-99a was found to be significantly upregulated in cancer tissue and regulated cell survival. Cell culture was used to assess the role of miR-99a in radiation sensitivity. We then used flow cytometry to examine the effects of miR-99a on the cell cycle and apoptosis in cells exposed to radiation. To identify gene targets of miR-99a, a bioinformatics approach was adopted, and the findings of this analysis were verified using luciferase reporter assays. Finally, an in vivo study was conducted to examine the effect of miR-99a on tumor volume in an NSCLC mouse model undergoing radiation therapy. RESULTS: miR-99a was significantly upregulated in radiation sensitive A549 cells compared with radiation-resistant A549 cells. miR-99a overexpression was shown to enhance radiosensitivity, while inhibition of miR-99a resulted in radioresistance of NSCLC cell lines in vitro and in vivo. In addition, by bioinformatics software analysis and luciferase assays, mammalian target of rapamycin (mTOR) was identified as a direct target of miR-99a. Furthermore, AZD2014, an inhibitor of mTOR, enhanced radiosensitivity and apoptosis in NSCLC cell lines, while mTOR overexpression resulted in radioresistance and cell survival from miR-99a-induced cell apoptosis. Moreover, miR-99a overexpression further increased the efficacy of radiation therapy in an NSCLC xenograft mouse model, and miR-99a and mTOR expression was significantly inversely correlated. CONCLUSIONS: Altogether, these data suggested miR-99a functions as a tumor suppressor that has a critical role in regulating radiosensitivity of NSCLC by targeting the mTOR signaling pathway. PMID- 29614486 TI - Prevention Effect of Antiplatelets on Aneurysm Rupture in a Mouse Intracranial Aneurysm Model. AB - BACKGROUND AND PURPOSE: Subarachnoid hemorrhage (SAH) from intracranial aneurysm rupture results in significant morbidity and mortality. In the present study, we examined the effect of most widely used antiplatelet drugs, aspirin and cilostazol, on aneurysm rupture prevention using a mouse intracranial aneurysm model. MATERIALS AND METHODS: Intracranial aneurysms were induced by a combination of deoxycorticosterone acetate-salt and a single injection of elastase into the cerebrospinal fluid in mice. Treatment with aspirin or cilostazol was started 1 day after aneurysm induction. Aneurysm rupture was detected by neurological symptoms and the presence of intracranial aneurysm with SAH was confirmed by post-mortem examination. RESULTS: Aspirin (10 mg/kg) significantly reduced aneurysm rupture (control:aspirin = 80%:31%, p < 0.05) without affecting the overall incidence of aneurysm formation (60%:62%). Cilostazol (3 mg/kg, 30 mg/kg) did not reduce both rupture rate (control:3 mg/kg:30 mg/kg = 81%:67%:77%) and the overall incidence of aneurysm formation (control:3 mg/kg:30 mg/kg = 72%:71%:76%). Tail vein bleeding time prolonged significantly in both aspirin and cilostazol groups (p < 0.01). CONCLUSION: Aspirin prevented aneurysm rupture in a mouse intracranial aneurysm model, while cilostazol did not. Aspirin, the most frequently used drug for patients with ischemic myocardial and cerebral diseases, is also effective in preventing cerebral aneurysmal rupture. PMID- 29614487 TI - Prevalence of Hypersensitivity Reactions in Children Associated with Acetaminophen: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Acetaminophen is the most commonly used antipyretic in children. However, there are limited data assessing hypersensitivity reactions related to acetaminophen usage. OBJECTIVES: To conduct a systematic review to characterize reported reactions to acetaminophen in adults and children, and perform a meta analysis to assess the prevalence of acetaminophen hypersensitivity in children with a suspected acetaminophen allergy. METHODS: We performed a systematic review of studies reporting hypersensitivity reactions to acetaminophen by searching 2 electronic databases. From the selected studies, we included those assessing the prevalence of acetaminophen hypersensitivity by performing oral challenge in our meta-analysis. RESULTS: Eighty-five studies were included in the systematic review, assessing a total of 1,030 participants. Immediate (within 1 h of exposure) hypersensitivity reactions were reported in > 25% of the articles, while cutaneous nonimmediate reactions were similarly reported in about 25% of the articles. The remaining articles reported Steven-Johnson syndrome/toxic epidermal necrolysis, fixed drug eruptions, and cross-intolerance reactions. Five pediatric studies were included in our meta-analysis. The prevalence of acetaminophen hypersensitivity reaction among children undergoing oral challenge was 10.1% (95% confidence interval 4.5-15.5). CONCLUSION: Future studies assessing the risk of immediate and nonimmediate hypersensitivity reactions to acetaminophen and elucidating the mechanism of acetaminophen hypersensitivity reactions are required. PMID- 29614488 TI - Efficacy and Safety of Pazopanib for Recurrent or Metastatic Solitary Fibrous Tumor. AB - OBJECTIVE: To investigate the efficacy and safety of pazopanib for recurrent or metastatic solitary fibrous tumor (SFT) in first- and second-line settings. METHODS: Patients histologically diagnosed with SFT at our hospital who received pazopanib monotherapy for inoperable disease between January 2013 and November 2016 were eligible. We retrospectively investigated treatment outcomes according to the treatment lines and assessed adverse events. RESULTS: Nine patients were eligible. The median age was 67 years (range 42-81), and 6 patients (66.7%) were male. Four patients (50%) received pazopanib as second-line treatment. According to the RECIST and Choi criteria, the respective response rates were 0 and 50%, while the respective disease control rates were 88.9 and 75%. The median progression-free survival (PFS) was 6.2 months (95% confidence interval 3.2-8.8). Treatment line and high frequency of mitosis were not predictive of PFS (p = 0.67, 0.92). Two patients (22.2%) experienced elevated liver enzymes of grade 3 or higher. CONCLUSION: Pazopanib is an effective treatment option for recurrent or metastatic SFT in first- and second-line settings. Liver injury is a major adverse event and adequate treatment withdrawal and dose reduction should be considered when necessary. PMID- 29614489 TI - Hyperbaric Oxygen Therapy as Adjuvant Treatment for Hardware-Related Infections in Neuromodulation. AB - BACKGROUND: In neuromodulation therapies, hardware-related infections are a major challenge often leading to hardware removal. OBJECTIVE: To investigate the role of adjuvant hyperbaric oxygen therapy (HBOT) in hardware-related infections. METHODS: Fourteen hardware-related infection events in 12 consecutive patients between 2002 and 2015 were treated with antibiotics and adjuvant HBOT at the Karolinska University Hospital (Stockholm, Sweden). Two time-independent infection events related to hardware replacements occurred in 2 patients. Infection resolution and the need for hardware removal were assessed. RESULTS: Twelve out of 14 events of hardware-related infection were successfully treated without hardware removal (86%). The 2 patients treated twice with HBOT on 2 time independent occasions could retain their hardware in both cases. Hardware was removed following HBOT failure in 2 infection events, with long-term infection control achieved in all patients. Further, an intrathecal pump malfunction caused by HBOT at 2.8 bars was observed, leading to a change in the manufacturer's guidelines. CONCLUSIONS: This study indicates a potential benefit of adjuvant HBOT in the treatment of hardware-related infections in neuromodulation, diminishing the need for hardware removal and treatment interruption. Prospective studies are warranted to establish the role of adjuvant HBOT in the treatment of hardware-related infections in neuromodulation. PMID- 29614490 TI - In Utero Exposure to Fine Particulate Matter Causes Hypertension Due to Impaired Renal Dopamine D1 Receptor in Offspring. AB - BACKGROUND/AIMS: Adverse environment in utero can modulate adult phenotypes including blood pressure. Fine particulate matter (PM2.5) exposure in utero causes hypertension in the offspring, but the exact mechanisms are not clear. Renal dopamine D1 receptor (D1R), regulated by G protein-coupled receptor kinase type 4 (GRK4), plays an important role in the regulation of renal sodium transport and blood pressure. In this present study, we determined if renal D1R dysfunction is involved in PM2.5-induced hypertension in the offspring. METHODS: Pregnant Sprague-Dawley rats were given an oropharyngeal drip of PM2.5 (1.0 mg/kg) at gestation day 8, 10, and 12. The blood pressure, 24-hour sodium excretion, and urine volume were measured in the offspring. The expression levels of GRK4 and D1R were determined by immunoblotting. The phosphorylation of D1R was investigated using immunoprecipitation. Plasma malondialdehyde and superoxide dismutase levels were also measured in the offspring. RESULTS: As compared with saline-treated dams, offspring of PM2.5-treated dams had increased blood pressure, impaired sodium excretion, and reduced D1R-mediated natriuresis and diuresis, accompanied by decreased renal D1R expression and GRK4 expression. The impaired renal D1R function and increased GRK4 expression could be caused by increased reactive oxidative stress (ROS) induced by PM2.5 exposure. Administration of tempol, a redox-cycling nitroxide, for 4 weeks in the offspring of PM2.5-treated dam normalized the decreased renal D1R expression and increased renal D1R phosphorylation and GRK4 expression. Furthermore, tempol normalized the increased renal expression of c-Myc, a transcription factor that regulates GRK4 expression. CONCLUSIONS: In utero exposure to PM2.5 increases ROS and GRK4 expression, impairs D1R-mediated sodium excretion, and increases blood pressure in the offspring. These studies suggest that normalization of D1R function may be a target for the prevention and treatment of the hypertension in offspring of mothers exposed to PM2.5 during pregnancy. PMID- 29614491 TI - The Biological Effect and Clinical Application of Long Noncoding RNAs in Colorectal Cancer. AB - Colorectal cancer (CRC) is one of the most common malignancies in the world. Easier recurrence and metastasis is the main cause of mortality in CRC patients, and the markers applied for diagnosis and treatment of CRC is still urgently needed to early diagnose and evaluate therapeutic effect. Long noncoding RNA (lncRNA) is a class of noncoding RNA that the length is more than 200 nucleotides. With the development of sequencing technique about transcriptome, increasing lncRNAs are focused on their function and mechanism related to the nosogenesis and pathology of CRC. Recent studies report that lncRNAs acted as crucial role in CRC and could be as biomarker for CRC diagnosis and treatment. In this review, we display the regulation of lncRNA by interacting with DNA, RNA and protein and highlight the double role of lncRNAs as oncogene or anti-tumor gene involved in Wnt signaling pathway, p53 signaling pathway or others to be an regulator in CRC development. Lastly, we discuss some new finding of lncRNAs, especially lncRNA in exosome, which could be as potential markers for diagnosis and treatment of CRC in future. PMID- 29614492 TI - Major Histocompatibility Complex Dmalpha/beta Genes and Their Expressional Diversity in Healthy and Diseased Water Buffalo Bubalus bubalis. AB - BACKGROUND/AIMS: The major histocompatibility complex (MHC) categorized into three (I, II and III) classes elicits the immunogenic response by presenting exogenous peptides to T cells. The MHC-II DM is composed of DMalpha and DMbeta, two polypeptide chains, both are encoded by separate MHC genes involved in antigen processing and presentation. Despite the acknowledged role of MHC complex in humans, the literature is silent on the organization and expression of these genes in water buffalo Bubalus bubalis, an agriculturally important animal species. METHODS: We deduced the full-length mRNA sequences of DMalpha and DMbeta genes, localized them onto the chromosome 2, assessed their copy number per haploid genome and studied tissue and disease specific expression. RESULTS: The Real Time PCR showed higher expression of both the genes and their seven interacting partners in spleen, gonads and spermatozoa. Significantly, upregulation of DMalpha and DMbeta genes and their interacting partners were detected in diseased group of buffaloes as compared to that in healthy ones. CONCLUSION: The upregulation of Bubalus bubalis (BuLA)-DMalpha and DMbeta genes and their interacting partners reflect their role in regulating immune responses towards the amelioration of diseases. Work on this line would enhance our understanding on the overall roles of MHC locus, allowing development of possible therapeutic treatment strategies. PMID- 29614493 TI - Propofol Disrupts Aerobic Glycolysis in Colorectal Cancer Cells via Inactivation of the NMDAR-CAMKII-ERK Pathway. AB - BACKGROUND/AIMS: To investigate the effect of propofol on glucose metabolism in colorectal cancer cells and in an in vivo xenograft model. METHODS: Glucose metabolism was assessed by measuring the extracellular acidification rate in HT29 and SW480 colorectal cancer cells. Quantitative real-time PCR and western blot analyses were used to detect mRNA and protein levels, respectively. Intracellular calcium was assessed by using a Fluo-3 AM fluorescence kit. Micro-positron emission tomography/computed tomography (microPET/CT) imaging was used to analyze glucose metabolism in the tumors of the xenograft model. RESULTS: Propofol exposure induced a dose-dependent decrease of aerobic glycolysis in HT29 and SW480 colorectal cancer cells. MicroPET/CT indicated that propofol also inhibited 18F-FDG uptake in the xenograft model. In addition, hypoxia-inducible factor 1alpha (HIF1alpha) was also reduced by propofol dose-dependently. Propofol repressed the NMDAR-CAMKII-ERK pathway to inactivate HIF1alpha and therefore reduced glycolysis. CONCLUSION: Propofol inhibited aerobic glycolysis in colorectal cancer cells through the inactivation of the NMDAR-CAMKII-ERK pathway, which may facilitate a better understanding of the use of propofol in the clinical setting. PMID- 29614494 TI - DEPTOR Deficiency-Mediated mTORc1 Hyperactivation in Vascular Endothelial Cells Promotes Angiogenesis. AB - BACKGROUND/AIMS: The mechanistic target of rapamycin (mTOR) signaling pathway is essential for angiogenesis and embryonic development. DEP domain-containing mTOR interacting protein (DEPTOR) is an mTOR binding protein that functions to inhibit the mTOR pathway In vitro experiments suggest that DEPTOR is crucial for vascular endothelial cell (EC) activation and angiogenic responses. However, knowledge of the effects of DEPTOR on angiogenesis in vivo is limited. This study aimed to determine the role of DEPTOR in tissue angiogenesis and to elucidate the molecular mechanisms. METHODS: Cre/loxP conditional gene knockout strategy was used to delete the Deptor gene in mouse vascular ECs. The expression or distribution of cluster of differentiation 31 (CD31), vascular endothelial growth factor (VEGF) and hypoxia inducible factor-1 alpha (HIF-1alpha) were detected by immunohistochemical staining or western blot. Tube formation assay was used to measure angiogenesis in vitro. RESULTS: Deptor knockdown led to increased expression of CD31, VEGF and HIF-1alpha in heart, liver, kidney and aorta. After treatment with rapamycin, their expression was significantly down regulated. In vitro, human umbilical vein endothelial cells (HUVECs) were transfected with DEPTOR-specific small interfering RNA (siRNA), which resulted in a significant increase in endothelial tube formation and migration rates. In contrast, DEPTOR overexpression markedly reduced the expression of CD31, VEGF and HIF-1alpha. CONCLUSIONS: Our findings demonstrated that deletion of the Deptor gene in vascular ECs resulted in upregulated expression of CD31 and HIF-1alpha, and further stimulated the expression of VEGF which promoted angiogenesis, indicating that disruption of normal angiogenic pathways may occur through hyperactivation of the mTORC1/HIF-1alpha/VEGF signaling pathway. PMID- 29614495 TI - Commentary on the "Evidence- and Consensus-Based (S3) Guidelines for the Treatment of Actinic Keratosis" Published by the International League of Dermatological Societies in Cooperation with the European Dermatology Forum. AB - In 2015, the International League of Dermatological Societies and the European Dermatology Forum published a guideline for the treatment of actinic keratosis, which is classified as an evidence- and consensus-based S3 guideline. From the point of view of the GD Task Force "Licht.Hautkrebs.Pravention," an interdisciplinary expert panel of the Society for Dermopharmacy for the prevention and treatment of skin cancer, this guideline reveals strengths and weaknesses but, in summary, does not meet the claim for an evidence- and consensus-based S3 guideline. PMID- 29614496 TI - Nail in the Coffin for Fibroblast Growth Factor 23 as a Predictor of Kidney Function Decline. PMID- 29614497 TI - Effect of Fluid Intake on Hydration Status and Skin Barrier Characteristics in Geriatric Patients: An Explorative Study. AB - BACKGROUND/AIM: Inadequate fluid intake is assumed to be a trigger of water-loss dehydration, which is a major health risk in aged and geriatric populations. Thus, there is a need to search for easy to use diagnostic tests to identify dehydration. Our overall aim was to investigate whether skin barrier parameters could be used for predicting fluid intake and/or hydration status in geriatric patients. METHODS: An explorative observational comparative study was conducted in a geriatric hospital including patients aged 65 years and older. We measured 3 day fluid intake, skin barrier parameters, Overall Dry Skin Score, serum osmolality, cognitive and functional health, and medications. RESULTS: Forty patients were included (mean age 78.45 years and 65% women) with a mean fluid intake of 1,747 mL/day. 20% of the patients were dehydrated and 22.5% had an impending dehydration according to serum osmolality. Multivariate analysis suggested that skin surface pH and epidermal hydration at the face were associated with fluid intake. Serum osmolality was associated with epidermal hydration at the leg and skin surface pH at the face. Fluid intake was not correlated with serum osmolality. Diuretics were associated with high serum osmolality. CONCLUSIONS: Approximately half of the patients were diagnosed as being dehydrated according to osmolality, which is the current reference standard. However, there was no association with fluid intake, questioning the clinical relevance of this measure. Results indicate that single skin barrier parameters are poor markers for fluid intake or osmolality. Epidermal hydration might play a role but most probably in combination with other tests. PMID- 29614498 TI - Development of an Algorithm for Stroke Prediction: A National Health Insurance Database Study in Korea. AB - BACKGROUND: Stroke is the second leading cause of death worldwide and remains an important health burden both for the individuals and for the national healthcare systems. Potentially modifiable risk factors for stroke include hypertension, cardiac disease, diabetes, and dysregulation of glucose metabolism, atrial fibrillation, and lifestyle factors. OBJECTS: We aimed to derive a model equation for developing a stroke pre-diagnosis algorithm with the potentially modifiable risk factors. METHODS: We used logistic regression for model derivation, together with data from the database of the Korea National Health Insurance Service (NHIS). We reviewed the NHIS records of 500,000 enrollees. For the regression analysis, data regarding 367 stroke patients were selected. The control group consisted of 500 patients followed up for 2 consecutive years and with no history of stroke. RESULTS: We developed a logistic regression model based on information regarding several well-known modifiable risk factors. The developed model could correctly discriminate between normal subjects and stroke patients in 65% of cases. CONCLUSION: The model developed in the present study can be applied in the clinical setting to estimate the probability of stroke in a year and thus improve the stroke prevention strategies in high-risk patients. The approach used to develop the stroke prevention algorithm can be applied for developing similar models for the pre-diagnosis of other diseases. PMID- 29614500 TI - Precursor T-Lymphoblastic Lymphoma Associated with t(8;9)(p11.2;q33): A Case Report and Review of the Literature. AB - The 8p11 myeloproliferative syndrome (EMS) is an aggressive neoplasm associated with chromosomal translocations involving the fibroblast growth factor receptor 1 (FGFR1) tyrosine kinase gene on chromosome 8p11-12. A new case of a 9-year-old boy with leukocytosis, eosinophilia, and general lymphadenopathy is reported in this study. Bone marrow examination showed eosinophilic hyperplasia, with blast cells amounting to 6-7%. Karyotyping revealed cytogenetic abnormalities, including t(8;9)(p11.2;q3?3). Fluorescence in situ hybridization for the FGFR1 gene rearrangement yielded positive results. Lymph node biopsy confirmed the diagnosis of precursor T-lymphoblastic lymphoma. The patient responded to chemotherapy, and unmatched related bone marrow transplantation was performed. A successful outcome was obtained with complete cytogenetic remission maintained for 14 months to date. In the future, FGFR1 inhibitors might be specific and effective therapeutic targets for EMS. Similar cases from the literature are reviewed. PMID- 29614499 TI - MicroRNA-330-3p Expression Indicates Good Prognosis and Suppresses Cell Proliferation by Targeting Bmi-1 in Osteosarcoma. AB - BACKGROUND/AIMS: Growing evidence has shown that miR-330-3p is closely related to the biological behavior of cancer, including proliferation, metastasis, and prognosis. However, there have been no reports on miR-330-3p expression and function in osteosarcoma. METHODS: Expression of miR-330-3p in osteosarcoma tissues and cell lines was examined by quantitative PCR. Effects of miR-330-3p on osteosarcoma cell proliferation were investigated in vitro with the Cell Counting Kit-8 colorimetric assay. Targets of miR-330-3p were identified by dual luciferase reporter assay. RESULTS: The results showed that expression of miR-330 decreased in osteosarcoma tissues and cell lines. Prognosis of patients with high miR-330-3p expression was much better than that of those with low expression (P=0.001), and multivariate analysis suggested that miR-330-3p is an independent prognostic factor for osteosarcoma. In addition, miR-330-3p overexpression significantly inhibited the growth of MG-63 and U2OS osteosarcoma cells. Dual luciferase reporter assay demonstrated that Bmi-1 was a direct target gene of miR 330-3p, and in a recovery experiment, miR-330-3p suppressed osteosarcoma cell proliferation by directly targeting Bmi-1. CONCLUSION: Our results suggest that miR-330-3p acts as a tumor suppressor by regulating Bmi-1 expression in osteosarcoma. Thus, miR-330-3p may represent a novel therapeutic target for the treatment of osteosarcoma. PMID- 29614501 TI - The Serotonin Transporter Gene Polymorphisms and Risk of Ischemic Stroke. AB - INTRODUCTION: Serotonin is known as a neurotransmitter; however, it also plays an important role in platelet aggregation as it is released upon platelet activation. The serotonin transporter (SERT) is responsible for the uptake of serotonin into platelets. Functional polymorphisms in the SERT gene may influence platelet activity, as they result in different levels of transporters and thereby different levels of serotonin in platelets. SERT gene polymorphisms have thus been associated with the risk of myocardial infarction. A similar association may exist between SERT gene polymorphisms and stroke. However, to our knowledge, this potential association has not previously been studied. We therefore aimed to investigate the association between polymorphisms in the SERT gene and the risk of ischemic stroke/transitory ischemic attack (TIA). MATERIALS AND METHODS: We conducted a case-control study including 834 consecutively admitted first-ever Caucasian ischemic stroke patients/TIA from Aarhus University Hospital, Denmark and 571 healthy controls. The control group comprised a sample from the Danish working population, who were all employees in the public sector in the Central Denmark Region. Two polymorphisms, the length variation (short = S/long = L) in the serotonin-transporter-linked polymorphic region and a single-nucleotide (A/G) polymorphism (rs25531) were studied. The genotypes were grouped according to the functional activity: SS, SLG and LGLG (low expression), SLA, LGLA (medium expression), and LALA (high expression). Data were analyzed using logistic regression and results presented as OR with 95% CI. RESULTS: The high-expression genotype was associated with a lower risk of ischemic stroke/TIA when compared to both the medium expression genotype (OR 0.72, 95% CI 0.56-0.93) and the low expression genotype (OR 0.75, 95% CI 0.55-1.01) as well as the combination of the low and medium expression genotypes (OR 0.73, 95% CI 0.58-0.93). The lower OR estimates associated with the high-expression genotype were consistent across all stroke subtypes, although not statistically significant. The results remained virtually unchanged, although not reaching statistical significance, when adjusting for age and gender. CONCLUSION: The presence of the high expression SERT genotype (LALA) may be associated with a lower risk of ischemic stroke/TIA. This is, to our knowledge, the first study examining the SERT gene polymorphisms and the risk of stroke. The present results raise interesting considerations for future personalized medicine potential, and we argue that further larger-scale studies with sufficient power to study subgroups according to stroke etiology and stroke-onset age are needed. PMID- 29614503 TI - Challenges of Retrograde Ureteroscopy in Patients with Urinary Diversion: Outcomes and Lessons Learnt from a Systematic Review of Literature. AB - INTRODUCTION: Retrograde ureteroscopy (URS) can be safely and successfully performed in patients who have had previous urinary diversion (UD). With broadening indications and advances in technology, URS can be used in complex cases. In this review article, we have summarized the relevant published literature regarding the outcomes and challenges encountered during retrograde URS in patients with UD. MATERIALS AND METHODS: We conducted a systematic review of literature according to Cochrane and preferred reporting items for systematic reviews and meta-analysis guidelines for all studies reporting on retrograde URS from inception to September 2017. A literature search was conducted through MEDLINE, EMBASE, CINAHL, and Cochrane library for all English language articles. RESULTS: Our literature search identified 6 retrospective studies. In total, 125 patients with a mean age of 67 years (range 28-90 years) underwent retrograde URS (190 procedures) after UD for diagnostic and therapeutic purposes. The main indications included upper urinary tract filling defects (due to either intrinsic pathology or extrinsic compression), strictures due to ureteral thickening, stone disease, and surveillance for suspected malignancy. The success rate and complications across the studies varied from 56 to 80% and 0 to 44% respectively, with most complications being Clavien I in nature. CONCLUSION: Retrograde URS can be technically challenging due to ureteric cannulation, strictures, and anatomical variations. However, there is very little evidence currently available on this topic with data based on retrospective case series. In experienced hands, it seems to be relatively successful with a low risk of major complications. PMID- 29614502 TI - Fluoride Levels in Unstimulated Whole Saliva following Clinical Application of Different 5% NaF Varnishes. AB - The aim of this study was to evaluate the fluoride release from differently formulated 5% NaF varnishes into unstimulated whole saliva in vivo. The fluoride concentration in unstimulated whole saliva was determined after the application of 3 different 5% NaF varnishes (5% NaF, 5% NaF + tricalcium phosphate [TCP], and 5% NaF + amorphous calcium phosphate [ACP]) or a placebo. Fifteen subjects were recruited and enrolled following Institutional Review Board approval based upon the inclusion/exclusion criteria of this study. A cross-over study design was used for the application of either one of the 5% NaF varnishes or a placebo. Unstimulated whole saliva was collected at baseline and at 1, 4, 6, 26, and 50 h following application and analyzed for supernatant ionic fluoride and whole fluoride by microdiffusion. Linear mixed-effects models (5% significance level) were used to determine the effects of varnish and time on the salivary fluoride concentration. The highest amount of fluoride in saliva was found 1 h after application of the fluoride varnishes, with no significant differences among the treatment varnishes with respect to whole fluoride but with lower levels for 5% NaF + ACP in the saliva supernatant. Salivary fluoride levels at 4, 6, and 26 h decreased at each time point and were generally significantly higher for 5% NaF and 5% NaF + TCP. After 50 h, fluoride levels in saliva for all groups were at or below baseline levels. In conclusion, the formulation of other ingredients in fluoride varnishes can affect the fluoride concentration in saliva. The reasons for this phenomenon warrant further investigation since it might affect efficacy of the treatment. This trial is registered at ClinicalTrials.gov (NCT01629290). PMID- 29614504 TI - Dialysis Modality towards Kidney Transplant Outcomes. PMID- 29614505 TI - HBV Facilitated Hepatocellular Carcinoma Cells Proliferation by Up-Regulating Angiogenin Expression Through IL-6. AB - BACKGROUND/AIMS: Patients with hepatitis B virus (HBV) infection are at a high risk of developing hepatocellular carcinoma (HCC). In this study, we aim to investigate the roles of HBV on angiogenin (ANG), as well as the effects on cell proliferation in presence of ANG down-regulation. METHODS: Serum ANG was determined by ELISA. The expression of ANG mRNA and protein in HCC cell lines with or without HBV/HBx were determined. Western blot and ELISA were conducted to determine the effects of HBV/HBx on IL-6 expression. The role of IL-6 on ANG was evaluated by IL-6 recombinant protein or IL-6 neutralizing antibody. Immunofluorescence staining was used to detect the nuclear translocation of ANG. MTT was performed to evaluate the relative inhibition ratio. RESULT: In vivo experiments showed elevation of serum ANG in patients infected with HBV. In vitro experiments showed HBV and HBx contributed to the transcription and translation of ANG. ANG expression showed increase after IL-6 stimulation, and ANG protein decreased in the presence of IL-6 blocking with its antibody. HBV promoted nuclear translocation of ANG. Inhibiting ANG expression or blocking of nuclear transfer of ANG attenuated the 45S rRNA synthesis and cell proliferation. CONCLUSION: HBV and HBx protein can increase the level of ANG through IL-6. HBV and HBx contributed to the nuclear translocation of ANG. Cell proliferation was inhibited after inhibiting the expression or nuclear transfer of ANG. PMID- 29614507 TI - Renoprotective Postoperative Monitoring: What Is the Best Method for Computing Renal Perfusion Pressure? An Observational, Prospective, Multicentre Study. AB - BACKGROUND: Low mean arterial pressure (MAP) is a well-known risk factor for postoperative acute kidney injury (AKI), but probably it is not the sole hemodynamic parameter that can influence the development of renal failure. There are data in cardiac patients supporting the role of renal venous congestion in the development of AKI. The aim of our study was to determine a combination of factors best predicting the development of AKI. METHODS: Data were collected prospectively for adult patients admitted after major abdominal surgery to 9 Hungarian intensive care units. Hemodynamic and laboratory parameters were compared in patients with AKI vs. no-AKI at the time of admission. Renal perfusion was computed by different methods from hemodynamic measurements involving MAP, central venous pressure (CVP), intraabdominal pressure (IAP), and mean airway pressures (Pmean). Twelve different, clinically interpretable equations were tested. Statistical evaluation was performed by the Mann-Whitney U test and ROC analysis. RESULTS: Eighty-four patients were enrolled in the study. Renal perfusion pressure was significantly lower in all equations. The equations MAP-IAP-Pmean (1-area under the curve [AUC]: 0.796; likelihood ratio [LR]+: 3.520; LR-: 0.337; p < 0.01), MAP-IAP-CVP-Pmean (1-AUC: 0.794; LR+: 2.743; LR-: 0.282; p < 0.01), and MAP-2 * IAP-CVP-Pmean (1-AUC: 0.791; LR+: 4.321; LR-: 0.262; p < 0.001) showed small to moderate effect on AKI but have better performance than severity score systems (SAPS II [AUC: 0.696; LR+: 3.143, LR-: 0.433; p < 0.01], SOFA [AUC: 0.717; LR+: 2.089; LR-: 0.528; p < 0.001]). CONCLUSION: We found that the best parameter predicting AKI is the MAP-2 * IAP CVP-Pmean. Further investigation is needed to analyze the role of CVP and Pmean, and to characterize renal venous congestion and tubular pressure more in detail. PMID- 29614506 TI - Inhibition of SIRT2 Alleviates Fibroblast Activation and Renal Tubulointerstitial Fibrosis via MDM2. AB - BACKGROUND/AIMS: Renal tubular epithelial cells and fibroblasts are the main sources of myofibroblasts, and these cells produce the extracellular matrix during tubulointerstitial fibrosis (TIF). Histone deacetylases (HDAC) inhibitors exert an antifibrogenic effect in the skin, liver and lung. Sirtuin 2 (SIRT2), which is a class III HDAC, is an important member of NAD+-dependent protein deacetylases. The current study evaluated the role of SIRT2 in renal TIF. METHODS: Immunohistochemical staining and Western blot were performed to evaluate SIRT2 expression in TIF patients and unilateral urethral obstruction (UUO) mice. Western blot was used to assess the protein levels of SIRT2, alpha-SMA, collagen III, fibronectin, and MDM2 in tubular epithelial cells and fibroblasts. The specific inhibitor AGK2 was used to inhibit SIRT2 activity, and targeted siRNA was used to suppress SIRT2 expression. RESULTS: SIRT2 expression increased in the tubulointerstitium of TIF patients and UUO mice. SIRT2 inhibition ameliorated TIF in UUO mice. SIRT2 expression in tubular cells was unchanged after exposure to TGF-beta1. The SIRT2-specifc inhibitor AGK2 did not attenuate TGF-beta1-induced tubular epithelial-mesenchymal transition. However, SIRT2 was upregulated in fibroblasts, and fibroblasts were activated after TGF-beta1 treatment. Genetic knockdown and chemical inhibition of SIRT2 attenuated TGF-beta1-induced fibroblast activation. We also explored the downstream signaling of SIRT2 during fibroblast activation. Genetic knockdown and chemical inhibition of SIRT2 suppressed TGF-beta1-induced increase in MDM2 expression, and inhibition of the MDM2-p53 interaction using Nutlin-3 did not suppress SIRT2 upregulation. CONCLUSION: Our results suggest that SIRT2 participates in the activation of fibroblasts and TIF, which is mediated via regulation of the MDM2 pathway, and the downregulation of SIRT2 may be a therapeutic strategy for renal fibrosis. PMID- 29614508 TI - Diagnosis and Management of Asthma - The Swiss Guidelines. AB - The Global Initiative for Asthma (GINA) is a network of individuals, organizations, and public health officials that was established to disseminate information about the care of patients with asthma and to improve asthma care. The GINA ("Global Strategy for Asthma Management and Prevention") report has been updated annually since 2002. Due to new knowledge and therapeutic development in the field, the Swiss Respiratory Society felt the need to provide a new document that is based on both the available literature and the recommendations of the 2016 GINA report. Key new features of the 2016 GINA report include a "new" definition of asthma, underscoring its heterogeneous nature, and the core elements of variable symptoms and variable expiratory airflow limitation; the importance of confirming the diagnosis of asthma in order to minimize both under- and overtreatment; practical tools for the assessment of symptom control and risk factors for adverse outcomes; a comprehensive approach to asthma management that acknowledges the foundational role of inhaled corticosteroid therapy, but also provides a framework for individualizing patient care; an emphasis on maximizing the benefit of available medications by addressing common problems such as incorrect inhaler technique and poor adherence; a continuum of care for worsening asthma, starting with early self-management and progressing to primary care or acute care management; and diagnosis of the asthma/chronic obstructive pulmonary disease overlap syndrome. This document is meant to advice the key stakeholders on the diagnosis and management of asthma and highlights the need to individualize the care of each and every asthmatic patient. PMID- 29614509 TI - Modest Impact of Serial Measurements of Acute Kidney Injury Biomarkers in an Adult Intensive Care Unit. AB - BACKGROUND/AIMS: Acute kidney injury (AKI) biomarkers have been developed with the aim of being able to detect kidney damage earlier than the detection process based on serum creatinine levels. However, single time-point measurements appear to furnish insufficient information for detecting and predicting AKI in intensive care unit patients who are frequently affected by multiple and transient/persistent renal insults. We evaluated whether serial measurements enable the prediction of AKI outcomes in such patients. METHODS: Serial measurements of AKI biomarkers, including plasma and urinary neutrophil gelatinase-associated lipocalin, urinary L-type fatty acid-binding protein, and urinary N-acethyl-beta-D-glucosaminidase, at intensive care unit (ICU) admission (d1) and 24 h later (d2) were performed for critically ill adult patients in a mixed ICU. We assessed whether each biomarker could predict newly developed AKI, recovery from AKI, worsening of AKI, and hospital mortality. RESULTS: Among the enrolled 272 patients, 33 were determined to show newly developed AKI after ICU admission, 58 showed worsening of AKI, 57 recovered from AKI, and 38 died in the hospital. ROC analysis showed that biomarkers at day 2 provided no significant additional benefit in predicting the above-mentioned AKI outcomes compared with those at day 1. However, net reclassification improvement analysis demonstrated that adding day 2 biomarkers to the clinical model comprising clinical variables along with day 1 biomarkers significantly improved the prediction of these AKI outcomes. CONCLUSION: Serial measurement of AKI biomarkers used in clinical models could contribute to the prediction of AKI outcomes in a heterogeneous cohort of adult mixed ICU patients, although its reliability seemed to be modest. PMID- 29614510 TI - Raymond John Lipicky, MD. PMID- 29614511 TI - Tumor-Derived Exosomal Long Noncoding RNAs as Promising Diagnostic Biomarkers for Prostate Cancer. AB - BACKGROUND/AIMS: Exosomal circulating long non-coding RNAs (lncRNAs) in blood are emerging as clinically useful and non-invasive biomarkers for tumor diagnosis. However, normal cells can also secrete exosomes, so it is a prerequisite to obtain tumor-derived exosomes for better understanding of their diagnostic impacts in cancer. In this study, a dual-antibody-functionalized immunoaffinity system was established to isolate exosomes and investigate their lncRNAs expression pattern and clinical significance in prostate cancer (PCa). METHODS: A commercially available kit was used to isolate total exosomes, which were then purified by a dual-antibody-functionalized immunoaffinity system. RT-qPCR was performed to detect the expression of exosomal lncRNAs. Receiver operating characteristic (ROC) curves were plotted to assess the diagnostic value. RESULTS: Expression levels of two lncRNAs in tumor-derived exosomes were significantly higher than those in total exosomes. The levels of SAP30L-AS1 were upregulated in benign prostatic hyperplasia (BPH), and SChLAP1 levels were significantly higher in PCa than in BPH and healthy individuals. The area under the ROC curve indicated that SAP30L-AS1 and SChLAP1 had adequate diagnostic value to distinguish PCa from controls. Two lncRNAs separately combined with prostate specific antigen (PSA) possessed a moderate ability for discrimination. SAP30L AS1 expression level was related to PSA values and tumor invasion. SChLAP1 expression was significantly higher in patients with higher Gleason scores, and was also effective in differentiating between BPH and PCa when the concentration of PSA was in the gray zone. CONCLUSION: The isolation of tumor-derived exosomes by dual-antibody-functionalized immunoaffinity systems and detection of their lncRNAs in plasma may lead to the identification of suitable biomarkers, with potential diagnostic utility. PMID- 29614514 TI - Successful Resuscitation Following Massive Obstetric Hemorrhage in a Patient of the Jehovah's Witness Faith: A Case Report: Erratum. PMID- 29614513 TI - Spinal Anesthesia for Emergent Abdominal Surgery in a Patient With a Tricuspid Valvectomy: A Case Report. AB - Tricuspid valvectomy without replacement is an accepted treatment for drug resistant endocarditis. The current intravenous drug abuse epidemic is leading to more occurrences of right-sided valvular endocarditis. This suggests that the incidence of tricuspid valvectomies may rise. Our academic hospital has seen 3 such patients in the past year alone. We review the implications of this pathophysiology and discuss the anesthetic management of a 33-year-old woman with previous tricuspid valvectomy presenting for emergent abdominal surgery. PMID- 29614512 TI - Dynamic Compression Promotes the Matrix Synthesis of Nucleus Pulposus Cells Through Up-Regulating N-CDH Expression in a Perfusion Bioreactor Culture. AB - BACKGROUND/AIMS: An adequate matrix production of nucleus pulposus (NP) cells is an important tissue engineering-based strategy to regenerate degenerative discs. Here, we mainly aimed to investigate the effects and mechanism of mechanical compression (i.e., static compression vs. dynamic compression) on the matrix synthesis of three-dimensional (3D) cultured NP cells in vitro. METHODS: Rat NP cells seeded on small intestinal submucosa (SIS) cryogel scaffolds were cultured in the chambers of a self-developed, mechanically active bioreactor for 10 days. Meanwhile, the NP cells were subjected to compression (static compression or dynamic compression at a 10% scaffold deformation) for 6 hours once per day. Unloaded NP cells were used as controls. The cellular phenotype and matrix biosynthesis of NP cells were investigated by real-time PCR and Western blotting assays. Lentivirus-mediated N-cadherin (N-CDH) knockdown and an inhibitor, LY294002, were used to further investigate the role of N-CDH and the PI3K/Akt pathway in this process. RESULTS: Dynamic compression better maintained the expression of cell-specific markers (keratin-19, FOXF1 and PAX1) and matrix macromolecules (aggrecan and collagen II), as well as N-CDH expression and the activity of the PI3K/Akt pathway, in the 3D-cultured NP cells compared with those expression levels and activity in the cells grown under static compression. Further analysis showed that the N-CDH knockdown significantly down-regulated the expression of NP cell-specific markers and matrix macromolecules and inhibited the activation of the PI3K/Akt pathway under dynamic compression. However, inhibition of the PI3K/Akt pathway had no effects on N-CDH expression but down regulated the expression of NP cell-specific markers and matrix macromolecules under dynamic compression. CONCLUSION: Dynamic compression increases the matrix synthesis of 3D-cultured NP cells compared with that of the cells under static compression, and the N-CDH-PI3K/Akt pathway is involved in this regulatory process. This study provides a promising strategy to promote the matrix deposition of tissue-engineered NP tissue in vitro prior to clinical transplantation. PMID- 29614515 TI - [25 Years of ESPED as a Surveillance Tool for Rare Diseases in Children in Germany: A Critical Analysis]. AB - BACKGROUND: The German Paediatric Surveillance Unit (ESPED) was founded in 1992 to generate incidence data and detailed clinical descriptions of rare, childhood onset diseases. METHODS: Retrospective analysis of the ESPED epidemiological data collection from 1992-2017, and analysis of all published national and international publications originating from ESPED surveys. Center of Disease Control and Prevention (CDC) criteria for evaluating surveillance systems (simplicity, flexibility, timeliness, usefulness, data quality, representativeness, stability and acceptability) were adopted and applied to available ESPED data. RESULTS: Between 1992 and 2017 ESPED completed 96 prospective studies on rare diseases in children. The 3 most frequent clinical entities were: Infectious/communicable disease (n=30), neurological diseases (n = 14) and hematologic diseases (n=10). Studies resulted in 337 publications in national and international journals. The median impact factor of the 192 journal publications with (impact factor) was 2,587 (range 0,032-28,409). The highest impact factors were seen in the fields of endocrinology/metabolism (n=130; median IF=3,534), infectious diseases (n=83; median IF=3,131) and hematology (n=37; median IF=2,497). Our analysis indicates that ESPED surveys meet CDC quality standards. CONCLUSION: ESPED surveys are an important contributor in the field of clinical epidemiology in children with rare diseases. The high quality of ESPED surveys is reflected by high-impact publications in both national and international journals. PMID- 29614516 TI - Identification of Non-Zinc Binding Inhibitors of MMP-2 Through Virtual Screening and Subsequent Rescoring. AB - MMP-2 belongs to a large family of proteases called matrix metalloproteinases (MMPs) that degrades type IV collagen, the main structural component of basement membranes and gelatin. The main pathologic role of MMP-2 overexpression is to contribute to the development of cancer through the progression of metastasis and angiogenesis. A structure-based virtual screening was employed to find new inhibitors with possible selectivity for MMP-2. The inhibitory activities of 3 inhibitors (one was not a suitable drug-like hit) among 19 purchased compounds were approved by enzyme inhibition assay. 5 hits were non-zinc-binding inhibitors of MMP-2. The results demonstrated that a computer-aided drug design could be successfully applied for discovering new MMP-2 inhibitors. We found inhibitors with new scaffolds for the inhibition of MMP-2 with some selectivity features that could be used for future lead optimization processes. According to the docked pose and MD simulation, compound 13 was expected to interact with the S1' specificity loop of MMP-2 and had 2 pi-pi interactions and a stable hydrogen bond with the MMP-2 active site. The key feature of compound 13 could be used to guide the design of new non-zinc-binding inhibitors of MMP-2. PMID- 29614518 TI - Hypobaric Hypoxia Causes Elevated Thrombin Generation Mediated by FVIII that is Balanced by Decreased Platelet Activation. AB - INTRODUCTION: Epidemiological studies suggest that hypobaric hypoxia at high altitude poses a risk for developing venous thromboembolism. The cause of this observed hypercoagulability remains unclear. Therefore, this study aimed to investigate the effect of hypobaric hypoxia at 3,883 m above sea level on thrombin generation and platelet activation. METHODS: After complying with medical ethical procedures, 18 participants were recruited, of whom 1 had to leave the study prematurely due to mild acute mountain sickness. Blood was drawn first at 50 m above sea level and second at 3,883 m altitude after gradual acclimatization for 6 days. Thrombin generation was measured in whole blood, platelet-rich plasma and platelet-poor plasma. Platelet activation was assessed using a whole blood flow-cytometric assay. Coagulation factor levels, D-dimer levels and markers of dehydration and inflammation were measured. RESULTS: Hypobaric hypoxia at 3,883 m altitude caused increased thrombin generation, measured as peak height and endogenous thrombin potential, in whole blood, platelet-rich and platelet-poor plasma without or at low tissue factor concentration. The elevated thrombin generation was mediated by increased factor VIII levels and not caused by dehydration or inflammation. In contrast, spontaneous and agonist-induced platelet activation was decreased at high altitude. CONCLUSION: Hypobaric hypoxia causes increased factor VIII-mediated thrombin generation. The hypercoagulability was balanced by decreased platelet activation. These findings may explain why venous, and not arterial thrombotic events occur more frequently at high altitude. PMID- 29614519 TI - Clinical Determinants of Thrombin Generation Measured in Presence and Absence of Platelets-Results from the Gutenberg Health Study. AB - The tendency of a plasma sample to generate thrombin, a central enzyme in blood coagulation, might be an important indicator of prothrombotic risk linked to cardiovascular disease (CVD), but the presence of platelets may be a critical determinant. Clinical data, laboratory markers and thrombin generation (TG), investigated in both platelet-rich plasma (PRP) and platelet-free plasma (PFP) at 1 pM TF, were available in 407 individuals from the Gutenberg Health Study. Given the well-known effect of anticoagulants on TG, subjects taking anticoagulants (n = 15) have been excluded resulting in 392 subjects for further analysis. Lag time, endogenous thrombin potential (ETP) and peak height were the investigated parameters of a TG curve. Multivariable linear regression analysis was used to identify TG determinants. Mean platelet volume (MPV) and platelet count were both negatively associated to lag time and positively to peak height (MPV, beta:6.35 [2.66; 10.0]; platelet count, beta:0.111 [0.054; 0.169]) in PRP only. C-reactive protein was positively associated with lag time and ETP in both PRP and PFP, with a stronger effect on ETP in PRP (PRP, beta:76.7 [47.5; 106]; PFP, beta:34.8 [10.3; 59.2]). After adjustment for fibrinogen, the relation between CRP and ETP was attenuated in PRP and PFP. Of the traditional cardiovascular risk factors (CVRFs), obesity was positively associated to TG in PRP only. Our findings support that TG, particularly in PRP, relates to traditional CVRFs in a representative sample from a population-based study. Assessment of procoagulant activity in a platelet-dependent manner by TG is a promising tool for assessing individual risk for CVD. PMID- 29614517 TI - Prediction of Post-Discharge Bleeding in Elderly Patients with Acute Coronary Syndromes: Insights from the BleeMACS Registry. AB - BACKGROUND: A poor ability of recommended risk scores for predicting in-hospital bleeding has been reported in elderly patients with acute coronary syndromes (ACS). No study assessed the prediction of post-discharge bleeding in the elderly. The new BleeMACS score (Bleeding complications in a Multicenter registry of patients discharged with diagnosis of Acute Coronary Syndrome), was designed to predict post-discharge bleeding in ACS patients. We aimed to assess the predictive ability of the BleeMACS score in elderly patients. METHODS: We assessed the incidence and characteristics of severe bleeding after discharge in ACS patients aged >= 75 years. Bleeding was defined as any intracranial bleeding or bleeding leading to hospitalization and/or red blood transfusion, occurring within the first year after discharge. We assessed the predictive ability of the BleeMACS score according to age by Fine-Gray proportional hazards regression analysis, calculating receiver-operating characteristic (ROC) curves and the area under the ROC curves (AUC). RESULTS: The BleeMACS registry included 15,401 patients of whom 3,376/15,401 (21.9%) were aged >= 75 years. Elderly patients were more commonly treated with clopidogrel and less often treated with ticagrelor or prasugrel. Of 3,376 elderly patients, 190 (5.6%) experienced post discharge bleeding. The incidence of bleeding was moderately higher in elderly patients (hazard ratio [HR], 2.31, 95% confidence interval [CI], 1.92-2.77). The predictive ability of the BleeMACS score was moderately lower in elderly patients (AUC, 0.652 vs. 0.691, p = 0.001). CONCLUSION: Elderly patients with ACS had a significantly higher incidence of post-discharge bleeding. Despite a lower predictive ability in older patients, the BleeMACS score exhibited an acceptable performance in these patients. PMID- 29614520 TI - Risk Factors for Higher-than-Expected Residual Rivaroxaban Plasma Concentrations in Real-Life Patients. AB - INTRODUCTION: Rivaroxaban (RXA) is a direct oral factor Xa (Xa) antagonist with a short half-life and a fast onset and offset of effect. Before elective surgery, discontinuation is recommended with an interval of at least > 24 hours. In clinical practice, this is, however, not always sufficient to achieve a residual RXA plasma concentration deemed appropriate for surgery, defined as <= 50 mcg/L. Our study aimed at identifying factors associated with a higher-than-expected residual RXA plasma concentration in a large group of real-life patients. MATERIALS AND METHODS: This retrospective single-centre study included all patients taking RXA between 2012 and 2016 where RXA plasma concentration was determined by pharmacodynamic anti-Xa assay (518 measurements in 368 patients). Medical records were reviewed. Residual RXA plasma concentrations were then compared with expected values according to a pharmacokinetic model. RESULTS: Residual RXA plasma concentration was significantly higher-than-expected in patients with atrial fibrillation, impaired kidney function (glomerular filtration rate [GFR] < 60 mL/min), CYP3A4-, CYP2J2- and PGP-inhibitory co medication including amiodarone. Impaired kidney function (odds ratio [OR], 2.22, 95% confidence interval [CI], 1.30-3.78, p = 0.003) and concomitant amiodarone intake (OR, 1.97, 95% CI, 1.04-3.72, p = 0.036) were significantly associated with RXA plasma concentrations > 50 mcg/L at 24 to 48 hours after the last RXA intake. CONCLUSION: In our group of real-life patients, impaired kidney function (GFR < 60 mL/min) and co-medication with amiodarone were independently associated with higher-than-expected residual RXA plasma concentrations. In these patients, standard intervals of RXA discontinuation may not always be sufficient before elective surgery and routine pre-operative determination of the residual RXA concentration could be advisable. PMID- 29614521 TI - Targeting Coagulase Activity in Staphylococcus aureus Bacteraemia: A Randomized Controlled Single-Centre Trial of Staphylothrombin Inhibition. AB - BACKGROUND: Staphylococcus aureus (S. aureus) bacteraemia is frequent and carries a high morbidity and mortality. Coagulases secreted by S. aureus initiate blood coagulation by directly activating prothrombin. This pathogen-activated coagulation is insensitive to most antithrombotic drugs, with the exception of small molecule direct thrombin inhibitors (DTIs). DTIs inhibit the coagulase prothrombin complex, or staphylothrombin, and improve outcome in preclinical models of S. aureus infection. OBJECTIVE: A single-centre, randomized, controlled feasibility and safety trial of staphylothrombin inhibition with DTIs in patients with S. aureus bacteraemia. PATIENTS AND METHODS: Consecutive eligible adult patients with S. aureus positive blood cultures in the University Hospitals Leuven (Belgium) were randomized 1:1 to DTI (oral dabigatran 110 mg twice daily or intravenous argatroban according to activated partial thromboplastin time [aPTT]) for 7 to 10 days, or subcutaneous enoxaparin 40 mg once daily. Primary outcomes were feasibility and safety of DTI in patients with S. aureus bacteraemia. Secondary outcomes include D-dimer evolution (day 0-4) as marker of coagulation activation; inflammatory and microbiological parameters; and clinical outcomes including metastatic infections. RESULTS: Thirty-one percent (94/303) of screened patients were enrolled. Dabigatran plasma levels inhibited staphylothrombin. Clinically relevant bleeding (5/47 vs. 5/47) and thrombotic (7/47 vs. 7/47) complications were similar in both groups. Coagulase inhibition with DTIs was associated with a trend towards faster D-dimer decrease at day 4 (-662 +/- 249 ng/mL vs. -40 +/- 213 ng/mL for DTI-treated patients vs. control; p = 0.06) and a numerically lower number of persistently positive blood cultures. No differences in inflammatory parameters or other clinical outcomes were observed. CONCLUSION: Targeting staphylothrombin with DTIs is feasible in a subset of S. aureus bacteraemic patients, with comparable safety to standard thromboprophylaxis. In future studies of staphylothrombin inhibition, feasibility can be further improved by rapid diagnostics and by strategies without concomitant anticoagulant effect. PMID- 29614522 TI - Contribution of Factor VIII A2 Domain Residues 400-409 to a Factor X-Interactive Site in the Factor Xase Complex. AB - The link between factor (F)VIII and FX is essential for optimum activity of the tenase complex. The interactive site(s) in FVIII for FX remains to be completely clarified, however. We investigated the FVIII A2 domain-FX association that was speculated from inhibitory mechanism(s) by an anti-A2 autoantibody. SDS-PAGE demonstrated that the purified inhibitor IgG recognizing residues 373-562 blocked FXa cleavage at Arg372 in FVIII, and surface-plasmon resonance (SPR)-based assays showed that intact A2 subunit directly bound to FX (Kd; 63 nM). The FVIII structure model indicated possible FX-binding site(s) in residues 400-429 in A2. One peptide corresponding to residues 400-409 competitively inhibited both the A2 FX binding and FVIIIa/FIXa-dependent FXa generation. Covalent cross-linking was observed between this peptide and FX following reaction with EDC (1-ethyl-3-(3 dimethylaminopropyl)-carbodiimide) using SDS-PAGE. K408 and S409 were not evident in N-terminal sequence analysis of the cross-linked product, suggesting that two residues participated in cross-link formation. SPR-based assays using recombinant FVIII mutants with one or both residues substituted to alanine demonstrated that K408A and K408A/S409A had approximately fourfold high Kd values of wild-type (WT )FVIII. FXa cleavages at Arg372 in both mutants were significantly delayed, suggesting a contribution of K408 for FXa cleavage at Arg372. Furthermore, FXa generation assays with these mutants demonstrated that the Km values were 1.4- to 1.7-fold greater, and overall catalytic efficiency (kcat/Km) was 0.49- to 0.89 fold lower than with WT-FVIII, suggesting a significant contribution of K408 for FVIII-FX interaction in tenase assembly. We concluded that the K408 in the A2 domain provided an interactive-site for FX. PMID- 29614523 TI - Evaluation of the Fully Automated HemosIL Acustar ADAMTS13 Activity Assay. PMID- 29614524 TI - International Normalized Ratio Targets for Left-Sided Mechanical Valve Replacement. AB - BACKGROUND: Guidelines recommend higher international normalized ratio (INR) targets for patients with mechanical valves believed to be at higher risk for thromboembolism. Higher INR targets are associated with increased bleeding risk. We performed a systematic review and meta-analysis assessing effects of lower and higher INR targets on thromboembolic and bleeding risk in patients with mechanical heart valves. METHODS: We searched Cochrane CENTRAL, MEDLINE and EMBASE for randomized controlled trials (RCTs) evaluating lower versus higher INR targets for adults with bileaflet mechanical valves. We performed title and abstract screening, full-text review, risk of bias evaluation and data collection independently and in duplicate. We pooled data using a random effects model and used the Grading of Recommendations Assessment, Development and Evaluation framework to evaluate overall quality of evidence. RESULTS: We identified six RCTs (n = 5,497). Lower INR targets were associated with significantly less bleeding-22% versus 40% (relative risk [RR]: 0.54, 95% confidence interval [CI]: 0.31, 0.93, p = 0.03, very low quality). There was no difference in thromboembolism-2% in both groups (RR: 1.28, 95% CI: 0.88, 1.85, p = 0.20, very low quality) or mortality-5.5% with lower INR targets versus 8.5% (RR: 1.00, 95% CI: 0.82, 1.21, p = 0.47, moderate quality). CONCLUSION: In patients with mechanical valves, higher INR targets are not supported by current evidence, which is of very low quality. In fact, our systematic review suggests that lower INR targets offer significantly lower bleeding risks with no significant difference in thromboembolic risk. PMID- 29614525 TI - Type of Combined Contraceptives, Factor V Leiden Mutation and Risk of Venous Thromboembolism. AB - OBJECTIVE: This article estimates the interaction between types of combined hormonal contraception (CHC) and factor V Leiden (FVL) mutation on the risk of venous thrombosis event (VTE). SUBJECTS AND METHODS: All premenopausal women with first incident VTE who were referred to our unit (Paris, France) between 2000 and 2009 were included in this case-only study. Differences in interactions by progestin type were assessed on a multiplicative scale, assuming the independence of genotype and prescription of type of CHC. RESULTS: Among 2,613 women with VTE, 15.9% had a FVL and 69% used CHC. The interaction between CHC use and presence of FVL on VTE risk was statistically significant (1.37, 1.06-1.77 95% confidence interval [CI]). This interaction appeared higher for drospirenone 1.99 (1.18-3.38 95% CI) (n = 98) or cyproterone acetate users 1.71 (1.20-2.45 95% CI) (n = 326), but not significant for 1st or 2nd or norgestimate CHC users. The results were similar when excluding women with a family history of VTE or with provoked VTE. In this sub-group of women, these interactions appeared higher for third generation, cyproterone acetate and drospirenone CHC users as compared with 1st or 2nd or norgestimate CHC users (odds ratio [OR], 1.68 [1.04-2.70; 95% CI], 2.91 [1.71-4.95 95% CI], 3.22 [1.54-6.73 95% CI], respectively). CONCLUSION: Our results show that the interaction between FVL and CHC use differ by progestin type, which is higher in CHC containing third-generation progestin, drospirenone or cyproterone acetate, compared with second generation. Further studies are needed to assess the cost-effectiveness of biological thrombophilia screening (FVL) when such prescription of CHC is planned. PMID- 29614526 TI - Changes in scoring of Direct Observation of Procedural Skills (DOPS) forms and the impact on competence assessment. AB - BACKGROUND: Direct Observation of Procedural Skills (DOPS) is an established competence assessment tool in endoscopy. In July 2016, the DOPS scoring format changed from a performance-based scale to a supervision-based scale. We aimed to evaluate the impact of changes to the DOPS scale format on the distribution of scores in novice trainees and on competence assessment. METHODS: We performed a prospective, multicenter (n = 276), observational study of formative DOPS assessments in endoscopy trainees with <= 100 lifetime procedures. DOPS were submitted in the 6-months before July 2016 (old scale) and after (new scale) for gastroscopy (n = 2998), sigmoidoscopy (n = 1310), colonoscopy (n = 3280), and polypectomy (n = 631). Scores for old and new DOPS were aligned to a 4-point scale and compared. RESULTS: 8219 DOPS (43 % new and 57 % old) submitted for 1300 trainees were analyzed. Compared with old DOPS, the use of the new DOPS was associated with greater utilization of the lowest score (2.4 % vs. 0.9 %; P < 0.001), broader range of scores, and a reduction in competent scores (60.8 % vs. 86.9 %; P < 0.001). The reduction in competent scores was evident on subgroup analysis across all procedure types (P < 0.001) and for each quartile of endoscopy experience. The new DOPS was superior in characterizing the endoscopy learning curve by demonstrating progression of competent scores across quartiles of procedural experience. CONCLUSIONS: Endoscopy assessors applied a greater range of scores using the new DOPS scale based on degree of supervision in two cohorts of trainees matched for experience. Our study provides construct validity evidence in support of the new scale format. PMID- 29614527 TI - [Documentation of the Treatment Indication Decisions in Depressive Disorders: Development and Feasibility Study of the STEP-D (Setting Guide for Patients with Depression)]. AB - OBJECTIVE: Depressive disorders require differential treatment. Therefore a new decision-tree (STEP-D, Setting Guide for Patients with Depression) was developed and evaluated to assist the documentation of the decision-process for a treatmentsetting for patients with depressive disorder. METHODS: The development of the decision tree followed several steps and was guided by the treatment guidelines. It was tested by 36 specialists on case reports. The case reports were rated with or without the decision tree. A questionnaire assessed transparency of the indication decision, simplification of documentation, time saving, improved communication in teams and confidence in the decision-making process. RESULTS: STEP-D was rated intelligible, feasible, and helpful to improve the communication in teams, transparency and documentation of indication decisions. CONCLUSION: Employing STEP-D can help documentation and facilitate communication with patients, benefactors and colleagues. PMID- 29614528 TI - [The Frequency of Depression Diagnoses in Different Groups of Insured Persons - A Routine Data Analysis of the Years 2006 to 2015]. AB - Depressive disorders are one of the most common type of mental disorders and are associated with a significant loss of social functioning and decrease in quality of life. While survey data from the Robert Koch-Institute show no increase in the prevalence of depression during recent years, data from social insurance agencies demonstrate an increasing social significance. Many people argue that changes in working conditions are a major reason for increasing depression diagnoses. Aim of the current study was to analyze the prevalence of depression diagnoses in health insurance data (administrative prevalence) for different types of insured persons and to examine the development over time with particular regard to working and non-working insured people. We conducted a cross-sectional analysis of administrative depression prevalence for the years 2006 to 2015 using F32 and F33 diagnoses. Analyses were stratified by sex and insured persons were grouped in (1.) employees, (2.) self-employed, (3.) spouses with insurance coverage as family member, (4.) pensioners, (5.) unemployed people receiving unemployment benefit I, (6.) people receiving unemployment benefit II and (7.) students and trainees. During the 10-year period, we found an increase in administrative prevalence from 12.0% in 2006 (women: 16.3%; men: 6.8%) to 16.3% in 2015 (women: 21.3%; men: 10.9%). In 2015, highest administrative prevalence rates were observed in people receiving unemployment benefit I or II and in pensioners. The lowest rates were found in students and trainees as well as self-employed. Employees had significantly lower administrative prevalence rates than people receiving unemployment benefit. We observed large increases in administrative prevalence over time in all groups of insured persons. The results highlight the increasing social significance of depressive disorders. A comparatively greater increase in the working population was not observed. A long-term health objective should be to further improve psychiatric care. PMID- 29614529 TI - [Speech Intelligibility and Marital Quality in Couples after Total Laryngectomy - Partners' View]. AB - BACKGROUND: Following the total removal of the larynx (TL) as a result of laryngeal cancer, both, patients and partners face significant challenges caused by altered speech intelligibility. We analysed effects of the altered speech intelligibility on dyadic communication and marital quality from the partners' point of view. METHODS: 70 partners of cancer patients with laryngectomy from 13 hospitals in Central Germany were interviewed 2 (t1) and 3 (t2) years after laryngectomy. Partners were administered a battery of questionnaires to assess speech intelligibility, coping with altered speech intelligibility and post laryngectomy dyadic communication pattern. Hahlwegs Partnership Questionnaire (PFB) was used to analyse martial quality. Patients with laryngectomy completed Post-Laryngektomie-Telefonverstandlichkeits-Test (PLTT) to measure speech intelligibility. RESULTS: Speech intelligibility was classified by partners as 'good' in 37% (t1) and 57% (t2). Female partners did not generally indicate an increased dispute behavior, compared with woman in general. However, dyadic communication and mutual activities were less satisfactory. Partners of aphonic patients argued more frequently, coped less adequately with the altered dyadic communication and perceived more frequently a decline in marital quality since the onset of the disease. CONCLUSION: Results indicate need and importance of logopaedic support also with respect to marital quality. Further, interventions which emphasize the improvement of dyadic communication and enhancement of mutual activities should be stimulated. PMID- 29614531 TI - [Deceleration: an Important First Step in Caring for Multimorbid Patients]. PMID- 29614530 TI - [Work and Training Conditions of Young German Physicians in Internal Medicine - Results of a Second Nationwide Survey by Young Internists from the German Society of Internal Medicine and the German Professional Association of Internists.] AB - BACKGROUND: Medical specialty training is the basis for career development of young internists and it is vital for the delivery of high-quality medical care. In 2014 the young internists of two professional bodies in Germany conducted a survey among their young members and described major factors influencing training and working conditions. We present the results of a follow-up survey to describe changes of these factors over time. An additional focus is set on the difficulties of balancing medical career and family. METHODS: In the end of 2016 we conducted an online-based survey of all members in training of the German Society of Internal Medicine (DGIM) and the Professional Association of German Internists (BDI). The questionnaire used in the 2014 survey was modified and items investigating the balance between career and family were added. RESULTS: A total of 1587 questionnaires were returned and analysed. Mayor findings did not change over time. Psychosocial strain remains very high among medical trainees in internal medicine. A structured training curriculum and meaningful feedback are associated with lower psychosocial strain and higher work satisfaction. Internists - and here especially women - with children experience the daily balance of medical career and family as extremely challenging. CONCLUSION: These results demonstrate that there is still a serious need for adjusting training and working conditions of young internists in Germany. Especially the role and increasing importance of female physicians has to be recognized by enabling a successful integration of medical career and family. PMID- 29614532 TI - [Current trends in diagnosis and treatment of giant cell arteritis]. AB - Giant cell arteritis (GCA) is the most common form of the primary large vessel vasculitides and typically occurs in individuals aged >= 50 years. This concise review article discusses current trends in the management of GCA, including important developments in sonographic assessment (B-mode sonography, contrast enhanced ultrasound) and medical treatment (biological treatment with the interleukin-6 receptor alpha inhibitor tocilizumab). PMID- 29614533 TI - [Differentiated thyroid cancer - is less (therapy) more?] PMID- 29614534 TI - [Current Concepts of Cardiologic Therapies in the Elderly]. AB - MYOCARDIAL INFARCTION IN THE OLD PATIENT: Even old patients may crucially benefit from reopening the occluded coronary artery by percutaneous coronary intervention with stent implantation. Bleeding complications can be reduced by choosing the radial instead of the femoral vascular approach for cardiac catheterization. STATINS FOR THE ELDERLY: WHEN TO START UND WHEN TO STOP?: Elderly benefit no less than the younger from statins. "Goal-oriented statin therapy" is preferable to the "statin strategy of fixed dose". In a patient with life expectancy of less than three years, statin therapy is dispensable. MALNUTRITION IN THE OLD AGE - SERIOUSLY UNDERVALUED AND UNDERTREATED: Cachexia, sarcopenia and deficiencies in micronutrients can effectively be met by an individualized nutrition therapy. TAVI APT FOR PATIENTS WITH INTERMEDIATE SURGICAL RISK, AS WELL: The SURTAVI trial showed TAVI to be a noninferior alternative to surgery in patients with severe aortic stenosis at intermediate surgical risk. POST-TAVI-ENDOCARDITIS: A NOVEL SYNDROME OF THE AGED PATIENT: Diabetes mellitus and preexisting aortic insufficiency increase the risk. Enterococci and S. aureus trigger every other post-TAVI-endocarditis. PMID- 29614535 TI - [Hodgkin Lymphoma - Update 2018]. AB - Hodgkin Lymphoma is one of the best curable tumor in adults. PET adapted therapy with BEACOPPescalated is standard for 1st line treatment of advanced stage disease and the majority of patient can be sufficiently treated with 4 cycles of BEACOPPescalated only. Maintenance therapy after autologous stem cell transplantation with Brentuximab Vedotin was recently introduced. PD-1 inhibitors such as Nivolumab and Pembrolizumab were approved for the treatment of relapsed Hodgkin Lymphoma after Brentuximab Vedotin. Ongoing trials focus on the introduction of this new drugs in earlier treatment lines to further reduce early and late side effects. PMID- 29614536 TI - [Prophylaxis and Therapy of Malaria: Current Recommendations]. AB - Malaria incidence is decreasing on a global scale, while the number of imported cases has remained at a high level in Germany. To decrease this number, counselling of travellers to malaria-endemic regions is important. Patients to high risk countries need regular chemoprophylaxis. The alternative of stand-by emergency treatment for travellers to regions with low or medium risk has been met with growing criticism. For the treatment of all malaria cases, artemisinins are a mainstay of treatment. Regular follow-up is warranted to prevent relapses. After treatment with intravenous artesunate for complicated malaria, delayed haemolysis must be kept in mind. A special situation has risen in Germany since 2014 with a growing number of Eritrean migrants presenting with Plasmodium vivax malaria. These patients need an additional course of primaquine to prevent relapses. PMID- 29614537 TI - [News in Cardiopulmonary Resuscitation]. AB - For the first time, the european guidelines for cardiopulmonary resuscitation (CPR) have been updated by the ILCOR in december 2017. If new data and findings are available, these guidelines can also be updated outside the 5-year cycle. Thus, it is now recommended that, depending on the level of training of the layer, a chest-compression-only CPR or in combination with ventilation should be done. The important function of the dispatchers in the context of telephone or dispatcher-assisted CPR is emphasized by the demand of a structured training. The use of mechanical chest compression devices remains reserved only for special situations. PMID- 29614538 TI - [Heart Transplant and Destination Therapy - Update 2018]. PMID- 29614539 TI - [Kidney Transplant and Dialysis - Update 2018]. PMID- 29614540 TI - [CT-Screening for Lung Cancer - what is the Evidence?] AB - In patients with lung cancer treatment opportunities and prognosis are correlated to the stage of disease with a chance for curative treatment in patients with early stage disease. Therefore, early detection of lung cancer is of paramount importance for improving the prognosis of lung cancer patients.The National Lung Screening Trial (NLST) has already shown that low-dose CT increases the number of identified early stage lung cancer patients and reduces lung cancer related mortality. Critically considered in terms of CT-screening are false-positive results, overdiagnosis and unessential invasive clarification. Preliminary results of relatively small European trials haven't yet confirmed the results of the NLST-study.Until now Lung Cancer Screening by low dose CT-scan or other methods is neither approved nor available in Germany.To improve the efficacy of CT-Screening and to introduce early detection of lung cancer in standard practice, additional, complementing methods should be further evaluated. One option might be the supplementary analysis of biomarkers in liquid biopsies or exhaled breath condensates. In addition, defining the high-risk population is of great relevance to identify candidates who might benefit of early detection programs. PMID- 29614541 TI - [ANCA-associated vasculitis: recent methodological advances for ANCA detection]. AB - Anti-neutrophil cytoplasmic antibodies (ANCA) play a central role in the diagnostic and pathogenesis of patients with small vessel vasculitis, so called ANCA-associated vasculitis (AAV). ANCA in these diseases are almost always directed against proteinase 3 (PR3-ANCA) and myeloperoxidase (MPO-ANCA). Most laboratories worldwide use as standard the indirect immunofluorescence technique (IFT), on human neutrophils, to screen for ANCA, and then confirm positive IFT results with antigen specific immunoassyas for PR3- and MPO-ANCA. New guidelines for ANCA testing have been developed based on a recent European multicentre study, and according to the revised 2017 international consensus recommendations, testing for ANCA in small vessel vasculitis can be done by PR3- and MPO-ANCA immunoassays, without the categorical need for IIF. The clinical utility of ANCA depends on type of assay performed and the appropiate ordering of testing the right clinical setting. Accurate identification of all patients with AAV and the avoidance of misdiagnosis can be achieved using a "gating policy" based on clinical information given to the laboratory at the time of request. PMID- 29614542 TI - [Gastrointestinal Bleeding: Update]. AB - PREENDOSCOPIC MANAGEMENT: In suspected gastrointestinal bleeding (GIB), standard operating procedures help in risk stratification, early patient management and endoscopy. If variceal bleeding is suspected, specific medication (vasoconstrictors, antimicrobial therapy) are additive to standard pharmacological management (PPI, erythromycin) prior to endoscopy. COAGULATION REQUIRMENTS: An emergency endoscopy can be performed independent of the patient's current coagulation status. DIAGNOSTIC: Endoscopic management remains the diagnostic and therapeutic standard in GIB. Propofol can be saafely used for emergency endoscopy. NON-VARICEAL BLEEDING: Injection therapy should be combined with mechanical or thermal therapy. Recent data suggests good efficacy of novel options (over-the-scope clips, hemostatic powder, stent compression) in defined clinical situations. Biopsies can usually be obtained during index endoscopy. In severe lower GIB, early colonoscopy after intensified bowel lavage is mandated to localize bleeding. VARICEAL BLEEDING: In high risk patients, insertion of a covered TIPS should be considered. In refractory or recurrent bleeding, stent insertion or balloon compression help to bridge the time for TIPS preparation. PMID- 29614543 TI - [58-Year Old Woman with Rare Manifestation of Diabetes Mellitus]. PMID- 29614544 TI - [Pulmonary Tumor Thrombotic Microangiopathy in a Patient with Metastatic Gastric Cancer]. AB - HISTORY AND CLINICAL FINDINGS: A 53-year-old woman with relapsed metastatic gastric cancer after multimodal therapy was hospitalized 6 months after the end of treatment due to acute dyspnea. INVESTIGATIONS AND DIAGNOSIS: The examination showed tachycardia and tachypnea. D-dimers and LDH were elevated, blood gases were still in the standard range. In the CT we could exclude a pulmonary embolism (LE) and pneumonia. The echocardiography (EC) showed no abnormalities. A new malignant pleural effusion on the left was detected. DIAGNOSIS: The diagnosis of pulmonary tumor thrombotic microangiopathy (PTTM) in the context of relapsed metastatic gastric cancer was confirmed. TREATMENT AND COURSE: The patient developed progressive respiratory failure and had to be moved to the intensive care unit. In the EC we discovered a progressive right ventricular heart failure. With the suspicion of a severe LE and vital indication we started a thrombolysis, but it remained unsuccessful. The CT showed changes consistent with a PTTM. The patient died a few days later. CONCLUSION: PTTM is a rare and often fatal tumor associated pulmonary complication. PMID- 29614545 TI - ? AB - At the end of the 1960 s, the German Society for Internal Medicine faced a period of intensifying factional struggles. Traditional conservative views increasingly met with critics demanding reform efforts. These debates covered, among other things, the self-definition of the society, doctor-patient relationship, medical studies, hospital regulations, and the relationship between doctors and nursing staff. In 1972/73, these opposing opinions within the society became particularly obvious, when the former NS-Gaustudentenfuhrer Gotthard Schettler, who felt strong resentments towards the members of the 1968 movement, was followed by the reform willing, politically left wing Herbert Begemann in the DGIM presidency. During his time in office, Begemann also focused on general political issues. PMID- 29614547 TI - [Hereditary auditory neuropathies: stepping into precision management from the discovery]. PMID- 29614546 TI - Cytologic Diagnosis of Noninvasive Follicular Thyroid Neoplasm with Papillary like Nuclear Features and Its Impact on the Risk of Malignancy in the Bethesda System for Reporting Thyroid Cytopathology: An Institutional Experience. AB - BACKGROUND: This study was performed to analyze cytologic diagnosis of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) and its impact on the risk of malignancy (ROM) in the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC). METHODS: Five thousand five hundred and forty-nine cases of thyroid fine-needle aspiration cytology (FNAC) diagnosed between 2012 and 2014 were included in this study. Diagnostic categories based on TBSRTC were compared with final surgical diagnoses, and the ROM in each category was calculated both when NIFTP was included in malignant lesions and when excluded from malignant lesions. RESULTS: Of the 5,549 thyroid FNAC cases, 1,891 cases underwent surgical resection. In final diagnosis, 1,700 cases were revealed as papillary thyroid carcinoma (PTC), and 25 cases were reclassified as NIFTP. The cytologic diagnoses of NIFTP were non-diagnostic in one, benign in five, atypia of undetermined significance (AUS) in 14, follicular neoplasm in two, and suspicious for malignancy in three cases. Collectively, NIFTP/encapsulated follicular variant of PTC (EFVPTC) were more frequently classified as benign, AUS, or follicular neoplasm and less frequently categorized as malignant compared to conventional PTCs. Exclusion of NIFTP from malignant diagnoses resulted in a slight decrease in malignancy rates in non-diagnostic, benign, AUS, follicular neoplasm, and suspicious for malignancy categories without any statistical significance. CONCLUSIONS: The decrease in the ROM was not significant when NIFTP was excluded from malignant lesions. In thyroid FNACs, NIFTP/EFVPTCs were mostly classified into indeterminate categories. Therefore, it might be feasible to separate NIFTP/EFVPTC from conventional PTC on FNAC to guide clinicians to conservative management for patients with NIFTP/EFVPTC. PMID- 29614548 TI - [Childhood delayed-onset hearing loss deserves close attention]. PMID- 29614549 TI - [The interpretation of Western Guidelines on central auditory processing disorder]. PMID- 29614550 TI - [Guideline for the early diagnostic evaluation and intervention of hearing loss in infants]. PMID- 29614551 TI - [A long term effect on speech recognition in the patients with simultaneous bilateral cochlear implants]. AB - Objective: To investigate an effect on speech recognition after bilateral cochlear implants(CI) simultaneously. Methods: Nine subjects who underwent bilateral CI operation simultaneously in Peking Union Hospital in 2007 were assigned as bilateral group, another 9 subjects with unilateral CI were chosen as unilateral group according to the age, gender, duration of deafness. Hearing threshold, speech recognition of phrases, disyllabic words, single word in quiet and noise environment were calculated, respectively. Three different sound source positions were set up to simulate the three effects of binaural hearing (head shadow, binaural redundancy and binaural squelch) in noise environment. The speech signal intensity was 70 dBSPL, the signal to noise ratio (SNR) was 0 dB, + 4 dB, + 8 dB, and the speech recognition of phrases were examined in bilateral CI group. All the data was analyzed by SPSS 19.0 software. Results: In quiet environment, the average aid-hearing threshold was significantly reduced as (7.2+/-3.0)dB in bilateral CI group compared to unilateral CI group(P<0.05). However, the speech recognition of phrases, disyllabic words, and single word in quiet and noise environment did not show significant differences between bilateral CI and unilateral CI groups (P>0.05). In the testing under noise environment, the speech recognition of bilateral CI group was significantly higher than that of unilateral CI group (P<0.05). In the estimation of noise environment (SNR=+ 8), the phrase test and speech recognition of head shadow model in bilateral groups were significantly better than that of unilateral group (P<0.01). Further, bilateral CI group showed statistical significances in binaural redundancy and binaural squelch models(P<0.01), there was statistically significant were also found difference between two groups (P<0.01); Bilateral CI group did not reveal significant difference compared with unbilateral CI group in binaural squelch model(P>0.05). Under different signal-to-noise ratio (SNR=+ 8, + 4) noise environment, all the three given models in bilateral CI group show higher signal-to-noise ratio, higher speech recognition rate (Independent-Samples t test, P<0.01). In addition, head shadow model presented negative influences on speech recognition rate compared with binaural redundancy and binaural squelch model by SNR(P<0.05). SNR influences on binaural redundancy and binaural squelch model were almost identical, F=0.371, P=0.549. Conclusion: The subjects who underwent simultaneous bilateral cochlear implantation could significantly reduce aid-hearing threshold, and greatly improve the speech recognition of phrases, disyllabic words, and single word under noise environment. PMID- 29614552 TI - [Retrospective analysis of auditory neuropathy patients after cochlear implantation]. AB - Objectives: To study an effects on hearing ability and speech performance of the patients with auditory neuropathy (AN) after cochlear implantation (CI). Methods: Thirty-five AN patients (26 males and 9 females) after CI in our center since 2007 were chosen, including 5 postlingual patients (implanted age from 14.3 to 38.6 years old) and 30 prelingual patients (implanted age from 1.1 to 13.7 years old). Hearing sensitivity and speech performance were estimated via following methods: (1) implanted hearing thresholds by sound field audiometry; (2) speech audiometry, including monosyllable, disyllable and sentences recognition test by computer-controlled software and sentence recognition test under noise condition (signal to noise ratio=+ 10dB); (3) Mandarin Early Speech Perception test (MESP), Mandarin Pediatric Speech Intelligibility test (MPSI), MAIS, or IT-MAIS for prelingual AN implantees. Results: The average implanted hearing threshold (250-4 000 Hz) was (41.1+/-11.7) dBHL in 22 AN implantees, while those prelingual implantees was (39.1+/-10.9) dBHL, and (44.9+/-12.3) dBHL in postlingual implantees. Speech audiometry were implemented in four of 5 postlingual AN implantees, the results showed increasing tendency in monosyllable recognition scores, dramatic individual variation in computer-controlled disyllable and sentences recognition test, and poor scores (<30%) in speech recognition test in noise condition. Four of 30 prelingual implantees reconstruct their speech recognition ability within 1-3 years after switch-on, characterized as recognition scores (>60%) in monosyllable, disyllable and sentences. The one of prelingual implantee gained recognition scores of speech in noise within 1 year after switch-on. MAIS or IT-MAIS were implemented in twenty-five prelingual implantees, the average score in these patients was 28.6+/-11.7. Conclusion: Cochlear implant can improve the hearing thresholds of AN patients, however, the improvement in speech performance presented significant variations among the implanted individuals. PMID- 29614553 TI - [Effects of bimodal intervention on the development of auditory and speech ability in infants with unilateral cochlear implantation]. AB - Objective: To explore the effects of bimodal intervention on the development of auditory and speech ability in the infants with unilateral cochlear implantation(CI). Methods: Total 35 bilateral profound sensorineural hearing loss infants with unilateral CI, aged 0.7 to 2.8 years old, were selected. The subjects were divided into two groups: the group with unilateral CI(cochlear implant alone, n= 15), and the bimodal group with CI and contralateral fitting hearing aid(n= 20). Their auditory and speech abilities were estimated at the different time points after switch-on(the 0th, 0.5th, 1st, 3rd, 6th, 12th, 18th, and 24th month, respectively) using Infant Toddler-Meaningful Auditory Integration Scale(IT-MAIS), Meaningful Use of Speech Scale(MUSS), Categories of Auditory Performance(CAP), and Speech Intelligibility Rating(SIR) scores. Results: The IT-MAIS scores of bimodal group after switch-on were higher than unilateral CI group(the 0.5th, 1st, 3rd, 6th, 12th, and 18th month), the statistical significances were identified at the 0.5th, 1st, 3rd, 6th, and 12th month, respectively(P<0.05). The CAP scores of bimodal group before CI operation and after switch-on(the 0.5th, 1st, 3rd, 6th, 12th, 18th and 24th month)were higher than unilateral CI group, the statistical significances were seen at the 3rd, 6th, 12th, 18th and 24th month after switch-on(P<0.05). The MUSS scores of bimodal group after switch-on were higher than unilateral CI group(the 1st, 3rd, 6th, 12th, 18th and 24th month), the statistical significances were found at the 12th, 18th and 24th month, respectively(P<0.05). The SIR scores of bimodal group after switch-on were higher than unilateral CI group(the 3rd, 6th, 12th, 18th and 24th month), and significant differences appeared at the 12th, 18th and 24th month after switch-on(P<0.05). Conclusion: Bimodal intervention could be helpful to the development of auditory and speech ability of infants. PMID- 29614554 TI - [Effect of foam sclerotherapy for the treatment of oropharyngeal venous malformation]. AB - Objective: To evaluate the safety and efficacy of foam sclerotherapy with polidocanol for the treatment of venous malformation in the oropharynx. Methods: The clinical data of 21 children with venous malformation in the oropharynx treated by foam sclerotherapy were retrospectively analyzed. There were 10 males and 11 females, ranging in age from 1 month to 13 years, with a median age of 2.3 years. MRI was performed in all children, and the diagnosis was further confirmed by radiography. After general anesthesia, the oropharynx was exposed by opening device. Scalp acupuncture was used to pucture lesions and polidocanol foam was injected after the nidus was confirmed by digital subtraction angiography(DSA). The follow-up time ranged from 2-29 months, with a mean time of 15 months. The clinical symptoms, imaging data, therapeutic effects and postoperative complications were evaluated. Results: Total numbers of treatment were 52 times, 1-6 times/case; 13 cases were cured, 7 cases was relieved and no response in one case. Postoperative swelling in 13 cases, fever in 3 cases, local mucosal ulcer in 2 cases, difficult extubation in 2 cases. No nerve injury, swallowing function damage and cardiopulmonary accidents were found in all patients. Conclusion: Foam sclerotherapy with polidocanol in the treatment of venous malformation in the oropharynx is a safe and effective method. PMID- 29614556 TI - [Clinical analysis of 24 cases of the vocal fungal infection]. PMID- 29614555 TI - [Assessment of the quality of life of tongue base cancer patients after reconstruction with anterolateral thigh perforator flap]. AB - Objective: To evaluate the quality of life (QOL) of patients who underwent resection of tongue base cancer and reconstruction by anterolateral thigh perforator free flap(ALTFF). Methods: A total of 77 patients with tongue cancer who underwent glossectomy and reconstruction by ALTFF were retrospectively analyzed in this work. At intervals of 3-month before operation, as well as both 3-month and 12-month post-operation, the QOL of these patients was assessed by using the 14-item Oral Health Impact Profile questionnaires(OHIP-14) and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Head and Neck Module(EORTC-QLQ-H&N35). Results: The OHIP-14 questionnaire showed the physiological pain can be significantly alleviated at 3 months postoperatively. The highest score were psychological discomfort and psychological disorders at 3 months postoperatively. Functional limitations cannot be restored to preoperative level at 12 months postoperatively, although lower than that in 3 months postoperatively(40.6+/-10.3 vs 39.2+/-10.6, t=-0.812, P=0.948). The EORTC-QLQ-H & N35 survey showed that swallowing, language and diet were higher at 3 months postoperatively, and improved significantly at 12 months postoperatively. Teeth and mouth opening was lower before and after surgery, and no significant difference was observed. Conclusion: The use of ALTFF to repair tongue base cancer, can restore the patient's appearance, language and chewing function of the basic needs and improve the quality of life of patients. PMID- 29614557 TI - [A case of lipoma in the parapharyngeal space]. PMID- 29614558 TI - [Characteristics of early hearing impairment in patients with diabetes mellitus]. AB - The early hearing loss in diabetic patients is not easy to be perceived, therefore, comprehensive and complete audiological examination is necessary. At present, hearing loss in diabetes patients characterized by high frequency decline, some of the examination for high frequency hearing loss such as speech audiometry and extended high frequency are applicated. In addition, electrophysiological techniques have also been rapidly developed in animal experiments. This review summarized the audiological characteristics in diabetes patients and progress in animal experiments, which provided the basis for early diagnosis and early treatment of hearing loss in diabetes mellitus. PMID- 29614559 TI - [Application of multiple acoustic immittance tests in evaluation of middle ear function in infants]. AB - Evaluation of middle ear function in infants is the key to distinguish sensorineural hearing loss and conductive hearing loss, and acoustic immittance test is the routine audiological evaluation of middle ear function.Because of the characteristics of middle ear in infants, middle ear examination parameters of adults are not suitable for infants. This article reviewd the current multiple acoustic immittance methods for detecting middle ear function in infants, and summarized the advantages and disadvantages of these methods. PMID- 29614560 TI - [Reorganization of central cross-model pattern after auditory deprivation and cortical reconstruction following cochlear implantation]. AB - The auditory nervous system has a rapid development period after birth, if there lack enough sensory(auditory) stimulation during this period, there should be a serious and negative impact on the growth and development of auditory center. In the auditory deprivation persist in the critical period, the auditory and visual cortex should be in cross-model reorganization and reorientation of cortical function. Cochlear implantation, especially intervention in the younger age, could excite the auditory cortex, and continuous stimulation to the cerebral cortex can promote the adaptation and reconstruction of auditory function. Speech and language skills can be developed by the synergistic effect of multiple sensory modalities. PMID- 29614562 TI - [Pay attention to congenital pulmonary diseases in children]. PMID- 29614561 TI - [Conference Summary of the First Meeting of the 11th Editorial Board]. PMID- 29614563 TI - [Intervention of neonatal genetic diseases in the era of precision medicine: challenges and opportunities]. PMID- 29614564 TI - [The classification of congenital respiratory diseases in children]. PMID- 29614565 TI - [Guideline for breastfeeding promotion strategies (2018)]. PMID- 29614566 TI - [Spectrum of mutations in benign familial neonatal-infantile epilepsy]. AB - Objective: To investigate the spectrum of mutations in families with benign familial neonatal-infantile epilepsy (BFNIE) . Methods: Clinical data and peripheral blood DNA samples of all BFNIE probands and their family members were collected from Peking University First Hospital between December 2012 and April 2016. Clinical phenotypes of affected members were analyzed. Genomic DNA was extracted from peripheral blood samples with standard protoco1. Mutations in PRRT2 were screened using Sanger sequencing. For families that PRRT2 mutations were not detected by Sanger sequencing, candidate gene mutations were further screened by next-generation sequencing for epilepsy. Results: A total of 7 families were collected. Of the 30 affected members, 15 were male and 15 were female. The age of epilepsy onset was from 2 days to 6 months. Genetic testing led to the identification of gene mutations in all families. One family had the PRRT2 hotspot mutation (c.649dupC). Three families had missense SCN2A mutations (c.2674G>A/p.V892I, c.2872A>G/p.M958V, and c.2627A>G/p.N876S) . Both c.2872A>G/p.M958V and c.2627A>G/p.N876S were novel SCN2A mutations. Three families had KCNQ2 mutations. Two of them had missense mutations (c.958G>A/p.V320I and c.998G>A/p.R333Q) . The KCNQ2 mutation c.958G>A/p.V320I was novel. One family had a gene deletion of KCNQ2, which also extended to the adjacent gene, CHRNA4; and the deletion involved all the exons of KCNQ2 and CHRNA4. Conclusions: Mutations in KCNQ2, SCN2A, and PRRT2 are genetic causes of BFNIE in Chinese families. The detection rate for gene mutations is high in BFNIE families. KCNQ2 and SCN2A mutations are common in BFNIE families. SCN2A mutations (c.2872A>G/p.M958V and c.2627A>G/p.N876S) and KCNQ2 mutation (c.958G>A/p.V320I) are novel mutations. PMID- 29614567 TI - [Predictive factors of mortality in extremely preterm infants]. AB - Objective: To investigate the predictive factors of mortality in extremely preterm infants. Methods: The retrospective case-control study was accomplished in the Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University. A total of 268 extremely preterm infants seen from January 1, 1999 to December 31, 2015 were divided into survival group (192 cases) and death group (76 cases). The potential predictive factors of mortality were identified by univariate analysis, and then analyzed by multivariate unconditional Logistic regression analysis. The mortality and predictive factors were also compared between two time periods, which were January 1, 1999 to December 31, 2007 (65 cases) and January 1, 2008 to December 31, 2015 (203 cases). Results: The median gestational age (GA) of extremely preterm infants was 27 weeks (23+3-27+6 weeks). The mortality was higher in infants with GA of 25-<26 weeks (OR=2.659, 95% CI: 1.211-5.840) and<25 weeks (OR=10.029, 95% CI: 3.266-30.792) compared to that in infants with GA> 26 weeks. From January 1, 2008 to December 31, 2015, the number of extremely preterm infants was increased significantly compared to the previous 9 years, while the mortality decreased significantly (OR=0.490, 95% CI: 0.272 0.884). Multivariate unconditional Logistic regression analysis showed that GA below 25 weeks (OR=6.033, 95% CI: 1.393-26.133), lower birth weight (OR=0.997, 95% CI: 0.995-1.000), stage III necrotizing enterocolitis (NEC) (OR=15.907, 95% CI: 3.613-70.033), grade I and II intraventricular hemorrhage (IVH) (OR=0.260, 95% CI: 0.117-0.575) and dependence on invasive mechanical ventilation (OR=3.630, 95% CI: 1.111-11.867) were predictive factors of mortality in extremely preterm infants. Conclusions: GA below 25 weeks, lower birth weight, stage III NEC and dependence on invasive mechanical ventilation are risk factors of mortality in extremely preterm infants. But grade IandII IVH is protective factor. PMID- 29614568 TI - [Serotype distribution and drug resistance of Streptococcus pneumoniae, Haemophilus influenzae and Moraxella catarrhalis isolated from nasopharynx of Uygur children]. AB - Objective: To investigate the serotype distribution and antimicrobial susceptibility pattern of Streptococcus pneumoniae (S. pneumoniae), Haemophilus influenzae (H. influenzae) and Moraxella catarrhalis (M. catarrhalis) isolates collected from nasopharyngeal swabs from Uygur children in Kashi. Methods: Nasopharyngeal swabs were collected from inpatient Uygur children aged from 1 month to 5 years with respiratory infections from the pediatric department, the First People's Hospital of Kashi, Xinjiang Uygur Autonomous Region. Antimicrobial susceptibilities of the isolates were determined with E-test and KB disk diffusion methods. The production of beta-lactamase was detected for H. influenzae and M. catarrhalisisolates using nitrocefin disc method. Quellung test and latex agglutination test were adopted to identify serotypes of S. pneumoniae and H. influenzae isolates. Results: Forty-seven S. pneumoniae, 13 H. influenzae and 16 M. catarrhalis isolates were detected. All of the 47 S. pneumoniae isolates were sensitive to parenteral penicillin, amoxicillin-clavulanic acid, vancomycin and levofloxacin; the susceptibility rates to cefotaxime, imipenem and chloramphenicol were 94% (44/47), 89% (42/47), and 98% (46/47). The resistance rate to erythromycin was 74% (35/47). The most common serotype of S. pneumoniae was serotype 19A (10 strains, 21%). The coverage rate of 13-valent conjugate vaccine (PCV13) was 70% (33/47). None of the 13 H. influenzae isolates could be typed. They were highly susceptible to tested beta-lactams antibiotics, except ampicillin. Only one H. influenzae isolate could produce beta-lactamase, and two isolates were identified as beta-lactamase-negative-ampicillin-resistant ones. The sixteen M. catarrhalis isolates were all positive in beta-lactamase detection, but sensitive to amoxicillin-clavulanic acid, cephalosporins and meropenem. Conclusions: In Kashi, Xinjiang Uygur Autonmous Region, S. pneumoniae isolates from Uygur children were highly sensitive to parenteral penicillin and other beta-lactams antibiotics. H. influenzae isolates from Uygur children were highly susceptible to amoxicillin-clavulanic acid, cephalosporins and ciprofloxacin. All M. catarrhalis isolates from Uygur children could produce beta lactamase, but were sensitive to the enzyme inhibitors and cephalosporins. PMID- 29614569 TI - [Relationship between continuous renal replacement therapy and hypophosphatemia in critically ill children]. AB - Objective: To investigate the incidence and prognosis of hypophosphatemia in critically ill children treated with continuous blood purification (CBP). Methods: The medical records of the critically ill patients, who were treated with CBP, admitted to pediatric intensive care unit (PICU) of Shanghai Children's Hospital from May 2014 to April 2017 were retrospectively analyzed. The serum phosphorus levels were tested before CBP, at 48-72 h during CBP, at the end of CBP and on the next day after CBP finished. Phosphorus supplement was given to the children with severe hypophosphatemia. Results: A total of 85 patients met the inclusion criteria. The serum phosphorus levels at the 4 indicated time points were (1.4+/-0.5), (0.7+/-0.3), (0.8+/-0.3), (0.9+/-0.4) mmol/L, respectively (F=45.21, P<0.05). Among the children, 66 cases (78%) had hypophosphatemia during CBP. The incidences of moderate and severe hypophosphatemia were 32 (48%) and 9 (14%), respectively. There were 41 patients with CBP replacement rates of (35-49) ml/(kg.h), while 44 patients with CBP replacement rates of 50-70 ml/(kg.h). There were significant differences at 48-72 h during CBP, the end of CBP and on the next day after CBP ((0.8+/-0.4) vs. (0.5+/-0.2), (1.0+/-0.3) vs. (0.6+/-0.2), and (1.1+/-0.4) vs. (0.8+/-0.2) mmol/L; t=7.672, 4.060, 14.440, P<0.05). Atotal of 9 cases were treated with sodium glycerophosphate. Among the 85 children, 24 (28%) patients died while 61 (72%) survived. There were no significant differences between the two groups in serum phosphorus levels at the indicated time points ((1.4+/-0.5) vs. (1.4+/-0.5), (0.7+/-0.3) vs. (0.7+/-0.3), (0.7+/-0.3) vs. (0.8+/-0.3), and (1.0+/-0.3) vs. (0.9+/-0.3) mmol/L, respectively, P>0.05). Conclusions: Hypophosphatemia is prone to occur during CBP, which probably related to the replacement rate. There was no significant relationship between hypophosphatemia and mortality in critically ill children after giving phosphorus supplementation. PMID- 29614570 TI - [Clinical features and genetic variants of Dent disease in 10 children]. AB - Objective: To summarize the clinical features and genetic analysis results of 10 children with Dent disease. Methods: The clinical data and gene test results of 10 boys aged from 8 months to 12 years with Dent disease diagnosed in Children's Hospital of Nanjing Medical University from January 2014 to July 2017 were analyzed retrospectively. Results: All patients had insidious onset, 5 cases were found to have proteinuria on routine urine examination after hospitalization duo to other diseases, 4 cases were admitted to hospital because increased foams in the urine, and 1 case was found to have proteinuria on health checkup. All cases presented with low molecular weight proteinuria, urine protein electrophoresis showed that the proportion of low molecular weight protein was greater than 50%, 7 cases had nephrotic-range proteinuria, but none had hypoproteinemia. Six cases had hypercalciuria, 3 cases had nephrocalcinosis, 1 case had nephrolithiasis, 2 cases had glomerular microscopic hematuria, in 1 case urine glucose wa weakly positive but blood glucose was normal. All patients had normal renal function, normal serum calcium, no hypophosphoremia and none had rickets. Genetic analysis results showed that 7 patients with variants in the CLCN5 gene, including 2 nonsense variants (p.R637X, p.Y143X), 3 missense variants (p.A540D, p.G135E, p.G703V), 1 deletion variant (exons 9, 10, 11, 12, 13, 1 missing), and 1 frameshift variant (p.T260Tfs*10). Three cases had missense variants of OCRL gene (p.I274T, p.I371T, p.F399S). Except for p.R637X and p.I274T, the other 8 cases had newly discovered variants. Five patients underwent a renal biopsy, the biopsy revealed focal global glomerulosclerosis in 3 patients, mild mesangial proliferative glomerulonephritis in 1 patient and renal minimal change in 1 patient. Mild focal tubular atrophy and interstitial fibrosis were noted in three cases. Mild segmental foot process effacement was noted under electron microscope in all five cases. Conclusions: All the children with Dent disease had insidious onset, low molecular weight proteinuria is the main clinical manifestation, most cases presented with nephrotic-range proteinuria, but there was no hypoalbuminemia, some cases were not associated with hypercalciuria. The pathogenic genes in most cases were CLCN5 and a few were OCRL. The types of genetic variation include missense variant, nonsense variant, deletion variant and frameshift variant. Although Dent disease is a renal tubular disease, renal biopsy suggests that most cases are associated with glomerular lesions. PMID- 29614571 TI - [Clinical analysis of three cases with beta-thalassemia]. AB - Objective: To study the diagnostic strategy of beta-thalassemia through retrospective analysis of 3 cases of beta-thalassemia. Methods: Three patients were admitted to the Department of Pediatrics, Sun Yat-sen Memorial Hospital of Sun Yat-sen University from January 2014 to June 2015. The clinical manifestations, hemoglobin electrophoresis and gene detection of these patients and their parents were analyzed, diagnostic ideas and key points were discussed when beta thalassemia gene detection did not explain clinical manifestations or hemoglobin electrophoresis. Results: Case 1, boy, 5 years old, was diagnosed as compound heterozygotes of beta41-42 and IVS-II-654 with hereditary persistence of fetal hemoglobin(HPFH) according to the clinical manifestations of mild anemia, normal size of liver and spleen, 92.8% fetal hemoglobin (HbF) and gene analysis. Case 2, girl, 3 years old, was confirmed the diagnosis of thalassemia intermedia with beta41-42 heterozygote compound and alphaalphaalphaanti3.7 heterozygote in accordance with the manifestations of severe anemia, hepatosplenomegaly, 8.6% HbF, 4.1% hemoglobin A2(HbA2) and gene analysis. Case 3, girl, 3 years old, with severe anemia, hepatosplenomegaly, 51.2% HbF and 3.7% HbA2, was diagnosed as thalassemia major with compound heterozygotes of PolyA (T->C) and beta17 by DNA sequencing. Conclusion: The diagnosis of beta-thalassemia should be confirmed by clinical manifestations of hemolytic anemia, hemoglobin electrophoresis, gene diagnosis and family survey. PMID- 29614572 TI - [Four cases of acute respiratory distress syndrome patients transported with veno venous extracorporeal membrane oxygenation]. AB - Objective: To retrospectively review 4 cases diagnosed with pediatric acute respiratory distress syndrome (ARDS) who were transported with veno-venous (V-V) extracorporeal membrane oxygenation (ECMO) from April 2016 to March 2017. Methods: Four patients were transported to Bayi Children's Hospital Afflicted to the PLA Army General Hospital, with V-V ECMO. Their vital signs, blood-gas analysis and chest X-ray before and after transportation were compared. The length of ECMO, pediatric intensive care unit (PICU) stay and hospitalization, and the prognosis were analyzed. Results: All the four cases were transported to our hospital successfully from distances between 1 000 km to 1 210 km. The 4 cases were 4 to 6 years old with the body weight of 19 to 35 kg, of whom 3 were boys and 1 was girl. The catheters were inserted in the right jugular vein and femoral vein. The vital signs and blood-gas analysis after transportation did not change significantly compared to baseline. The length of ECMO for the four patients were 48, 754, 157 and 438 hours. They stayed in the PICU for 10, 32, 14 and 19 days, respectively. At last, 2 of them were successfully discharged from hospital without any complications; however, the other 2 died of multiple organ failure. Conclusion: Transporting ARDS patients with a satisfactory cardiac function under VV-ECMO by an experienced ECMO team is safe. PMID- 29614573 TI - [Eperythrozoonosis complicated with hemophagocytic syndrome: report of four cases and review of literature]. AB - Objective: To analyze the clinical characteristics of eperythrozoonosis complicated with hemophagocytic syndrome (HPS) in 4 children. Methods: Four patients diagnosed with eperythrozoonosis complicated with HPS in the Children's Hospital Affiliated Capital Institute of Pediatrics during the period from June 2014 to July 2016 were enrolled. The clinical manifestations, laboratory examination data and therapeutic strategies were analyzed. A literature search (search terms included 'eperythrozoonosis' and 'hemophagocytic syndrome') was conducted using CNKI, Wanfang database, Chinese biomedical literature database and PubMed to include recently published studies (searched from the database establishment to January 2017). Results: Four patients were included in the study. One was boy and the other three were girls. The age range of the 4 patients was between 9 months and 17 years (9 months, 2 years and 17 years, 11 months respectively). All the patients presented with recurrent high fever. During the course of fever, 3 patients presented with rash, and 2 patients presented with joint pain and swelling, which mimicked systemic juvenile idiopathic arthritis. Only 1 patient had the contact history of infectious disease. All patients had normal or decreased white blood cell count ((0.80 13.12)*109/L), suffered from varied degrees of anemia and showed the increased C reactive protein (13.0-84.7 mg/L) anderythrocyte sedimentation rate (13-72 mm/1 h). Examination of peripheral blood smears confirmed eperythrozoonosis. After fever continued about 1 month, all the 4 patients rapidly progressed. Among the 4 patients, 1 patient died for giving up further therapy, and the other 3 patients completely recovered after treatment, including azithromycin for the treatment of eperythrozoonosis, and high-dose intravenous methylprednisolone pulse therapy and human immunoglobulin for the treatment of HPS. For the disease not satisfactory, the hemophagocytic lymphohistiocytosis-2004 (HLH-2004) protocol is given. After the hospitalization of 1 to 2 months, the conditions improved and the children were discharged from hospital. Three patients were followed up for 8 months to 2 years, and their conditions were stable. In the PubMed database, no report was found. Nine cases of children with eperythrozoonosis were found in CNKI, Wanfang database and Chinese biomedical literature database, and 1 case was complicated with HPS. These findings, taken together our report, provided the data of 5 children with eperythrozoonosis complicated with HPS (4 cases were younger than 2 years old). A patient had contact history of infectious disease. Five patientss showed fever of unknown origin. All the patients had severe eperythrozoonosis, and 2 cases at younger age died. Conclusions: Children with eperythrozoonosis often present with the protracted fever of unknown origin, and clinical manifestations mimic those of juvenile idiopathic arthritis (systemic type). The patients with eperythrozoonosis of mild-to-moderate disease severity may have a good prognosis. Children with severe eperythrozoonosis, especially those HPS cases with early onset before 2 years old, may have high risk of mortality. Once the patient's condition aggravates in the course of fever, HPS should be highly suspected. For the patients with eperythrozoonosis complicated with HPS, early diagnosis and the combination of anti-infection with the treatment of HPS are crucial for a good prognosis. For the treatment of HPS, HLH-2004 protocol is recommended. PMID- 29614575 TI - [An analysis of the hypothesis of newborn's intestinal microflora origin]. PMID- 29614574 TI - [Congenital unilateral pulmonary vein atresia in children: report of two cases]. PMID- 29614576 TI - [Research progress on pertussis resurgence]. PMID- 29614578 TI - [Glucose monitoring technology: its role in the management of diabetes, the critical issues and challenges]. PMID- 29614577 TI - [Advances research on progressive myoclonic epilepsy]. PMID- 29614579 TI - [Primary aldosteronism: pay attention to the important healthy issues]. PMID- 29614580 TI - [Enhance treat-to-target strategy by standardize the diagnosis and treatment of rheumatoid arthritis]. PMID- 29614581 TI - [2018 Chinese guideline for the diagnosis and treatment of rheumatoid arthritis]. AB - To develop a new evidence-based diagnosis, treatment guideline for rheumatoid arthritis (RA) in China.A multidisciplinary guideline development group was established. The grading of recommendations assessment, development and evaluation (GRADE) system was used to rate the quality of evidence and the strength of recommendations. Recommendations were derived from evidence body, the balance of benefits and harmsand patient's values and preferences.The guideline development group developed 10 recommendations for the diagnosis and treatment of RA. The guideline covered the classification criteria, disease activity monitoring and assessing, antirheumatic drugs (DMARDs) and glucocorticoids with treat-to-target approach of RA.This rheumatoid arthritis guideline was intended to serve as a tool for clinicians and patients for best decisions-making in China. PMID- 29614582 TI - [An efficacy and safety study of bifidobacterium tetragenous viable bacteria tablets in the treatment of constipation in patients with type 2 diabetes mellitus]. AB - Objective: The incidence of gastrointestinal symptoms in diabetes is higher than that of non-diabetes. Thus, the aim of the present study was to observe the efficacy and safety of bifidobacterium tetragenous viable bacteria tablets in the treatment of constipation in patients with type 2 diabetes mellitus. Methods: This is a multicenter, randomized, double-blind, placebo-controlled, parallel group-comparison clinical research. The subjects were randomly divided into study group and control group according to 1?1 ratio by computer generated random number method. The subjects were either treated with bifidobacterium tetragenous viable bacteria tablets (study group) or placebo (control group) for eight weeks, and they were followed up for four weeks without changing foundation therapy for diabetes. The primary outcome was the change of complete spontaneous bowel movements (CSBMs). Results: A total of 234 subjects (the study group:116 cases; the control group: 118 cases) from 7 centers were included in the present study. The baseline characteristics were comparable between the two groups. In the study group, the CSBMs at 0, 2, 4, 8 and 12 weeks were 0.0 (0.0, 1.0) , 1.0 (0.5, 2.0) , 2.0 (1.0, 3.0) , 3.0 (2.0, 3.5) , 2.0 (1.0, 3.0) times per week, respectively, while the CSBMs of the control group at each corresponding weeks were 0.0 (0.0, 1.0) , 1.0 (0.0, 1.5) , 1.0 (0.0, 1.5) , 1.0 (0.0, 2.0) , 1.0 (0.0, 1.5) times per week, respectively. There is significant difference in CSBMs between the two groups (P<0.05). Moreover, after 12 weeks treatment, the CSBMs over spontaneous bowel movements (SBMs) ratio in the study group was higher than that in the control group [0.53 (0.40, 0.67) vs 0.33 (0.00,0.50), P=0.048], indicating a more complete evacuation sensation in the study group. More subjects in the study group (66.38%) reached Bristol stool classification of normal criteria than those in the control group (48.31%, P=0.005). There were significantly improvement of bowel function index in the study group [study group 42.7 (33.3, 56.7), control group 60.6 (51.7, 75.7), P<0.000 1]. Furthermore, the symptoms of constipation was improved, and the satisfaction for the treatment was high in the study group. There were no significant differences of the safety indicators between the two groups. Conclusions: Bifidobacterium tetragenous viable bacteria tablets can be used in patients with type 2 diabetes mellitus and constipation. Compared with placebo, it improves constipation and has no obvious adverse effects. PMID- 29614583 TI - [Long-term prognostic value of lowering in free triiodothyronine in patients with hypertrophic cardiomyopathy]. AB - Objective: To determine whether thyroid hormone (TH) level could also be an independent and incremental predictor of adverse events in patients with hypertrophic cardiomyopathy (HCM). Methods: A total of 982 consecutive patients with HCM at the National Center for Cardiovascular Diseases (China) from October 2009 to December 2013 were included in the present study, and followed up till the end of December 2016. The patients were divided into three groups according to the levels of free triiodothyronine (FT3): the group 1 (FT3<=4.28 pmol/L, n=335), the group 2 (FT3>4.28-<4.79 pmol/L, n=310), and the group 3 (FT3 4.79 6.30 pmol/L, n=337). Results: After a follow-up period of (53.8+/-14.1) months, 39 patients (4.0%) either suffered death with all causes or received a cardiac transplantation (7.8%, 2.9% and 1.2% of the patients in the group 1, group 2 and group 3, respectively). A multivariable Cox regression analysis revealed that FT3<=4.28 pmol/L was associated with a significantly higher risk of all-cause mortality or cardiac transplantation (HR 8.83, 95% CI 1.115- 69.905,P=0.039) in HCM patients. Conclusions: Low levels of FT3 is a risk factor of adverse events for patients with HCM, indicting a role of FT3 as a marker for assessing the risk of long-term adverse events in these patients. PMID- 29614584 TI - [Glycogen storage disease type Ia: a rare cause of gout in adolescent and young adult patients]. AB - Objective: To analyze the clinical features of secondary gout in glycogen storage disease type Ia (GSD Ia), so as to improve the awareness of this disease. Methods: The clinical features, laboratory findings, treatments and prognosis of 5 GSD Ia patients with secondary gout who had been admitted to the Peking Union Medical College Hospital during 2006 to 2016 were collected and analyzed. GSD Ia was confirmed by liver biopsy and genotyping. Results: Among the 5 patients (median age: 27 years), 3 were males and 2 were females. The mean age of gout onset was 17 ranging from 10 to 22 years old. The common manifestations of GSD included hepatomegaly since childhood, hypoglycemia, growth retardation, anemia, hyperlactacidemia and hyperlipidemia. All the 5 patients were complicated with gouty tophi and kidney stone. Gouty tophi and kidney stone were identified 3.8 years and 10.2 years after the first occurrence of articular symptoms, respectively. Renal damage occurred in 3 cases. All the patients underwent several therapeutic modalities including lifestyle intervention, allopurinol, and raw corn starch treatment. Conclusions: Determination of the presence of primary disease should be performed actively for young-onset gout with early occurrence of gouty tophi. GSD should be suspected if there exist clinical manifestations like hepatomegaly, recurrent hypoglycemia, growth retardation. Early management of hyperuricemia and gout in GSD patients is important to prevent complications and improve prognosis. PMID- 29614586 TI - [The colonoscopic characteristics of colorectal endometriosis: a single-centered retrospective study]. AB - Objective: To reinforce the awareness of colorectal endometriosis (EM) in colonoscopy examination. Methods: Patients diagnosed as colorectal EM at Peking Union Medical College Hospital between February 2002 and February 2017 were enrolled in this study. The clinical characteristics and endoscopic features of EM lesions were summarized and compared between pathologically positive group and negative group. Results: A total of 34 cases were included with average age of (38.3+/-8.9) years old. All EM lesions located within rectum and sigmoid colon. The endoscopic lesions manifested as protrusion in 21 cases (61.8%) and protrusion-depression in 13 cases (38.2%), local stenosis in 8 cases (23.5%); erosive surface in 33 cases (97.1%) with local spontaneous hemorrhage in 4 cases (11.8%); nodal surface in 23 cases (67.6%), and lymphangiectasis base in 9 cases (26.4%). Endoscopic biopsy specimens were obtained in all cases with average 3 (2, 4) pieces. Positive results were found only in 4 patients (11.8%) with 3 endometriosis and one (endometrial) adenosarcoma. Compared with negative group, spontaneous hemorrhage was more frequent in positive group (2/4 vs. 2/30, P=0.013). Mean biopsy sample number was significantly larger in positive group (5 vs. 3, P=0.004). Conclusions: Colorectal endometriosis is mostly located within rectosigmoid region. Endoscopic features mainly include protrusion or protrusion depression lesions with erosive and nodular surface, or local stenosis. Spontaneous hemorrhage under colonoscopy yields higher positive rate for biopsy, thus increasing biopsy sample numbers may improve pathology results. PMID- 29614585 TI - [Coronary microvascular resistance and its relevant factors in patients with moderate coronary stenosis and chest pain]. AB - Objective: To evaluate the impact of cardiovascular risk factors on index of microvascular resistance (IMR) and coronary flow reserve (CFR) and to explore the characteristics of IMR and CFR and the relationship between IMR and angiographic features in patients with intermediate coronary stenosis and chest pain. Methods: Fractional flow reserve (FFR), CFR, and IMR were measured in patients who underwent invasive coronary angiography with 40%-70% stenosis by visual assessment. All patients with FFR>0.75 were enrolled and grouped with the cut-off points of IMR>=25 and CFR<=2.0. Patients with IMR>=25 were group H, including two sub-groups (high IMR-low CFR, group H1 and high IMR-high CFR, group H2), while those with IMR<25 were group N. The thrombolysis in myocardial infarction (TIMI) frame were counted. Results: A total of 34 patients with FFR>0.75 were enrolled with 61.8%(21 cases) of males and 38.2% (13 cases) of females. The mean age was (57.3+/-8.1) years old. High IMR accounted for 47.1% of all cases. There was significant difference between group H and N in TIMI frame (33.0 vs. 20.8, P=0.031). There were significant differences between group H1 and H2 in homocysteine (17.8 umol/L vs. 12.0 umol/L, P=0.005) and IMRcorr (58.0 vs. 36.1, P=0.002). IMRcorr was correlated to TIMI frame (r=0.40, P=0.012) for all cases. The sensitivity and specificity of inferring IMR>=35.3 by TIMI frame were 0.75 and 0.65 (P=0.049) with TIMI frame over 40.5. Conclusions: High IMR may be one of the reasons for chest pain in patients with intermediate coronary stenosis. There is no correlation between vascular risk factors and IMR or CFR, while there is positive correlation between TIMI frame and IMR. The specificity is 65% for inferring IMR rise with TIMI frame over 40.5. PMID- 29614587 TI - [Role of Rac1 signaling pathway of azathioprine and peptidoglycan in the regulation of monocyte-macrophage apoptosis in Crohn's disease]. AB - Objective: To evaluate the changes of macrophages and expression of Rac1 in the inflammatory site of Crohn's disease, and to investigate the effects of 6 thioguanine (6-TG) and peptidoglycan on apoptosis of human peripheral blood monocyte-macrophage by regulating Rac1 signaling pathway. Methods: Ten patients with Crohn's disease and eight healthy controls diagnosed were enrolled at Department of Gastroenterology and Hepatology, Tianjin Medical University General Hospital from January 2013 to January 2014. The number of macrophages, apoptosis and expression of Rac1 in the inflammation sites and non-inflammation sites of intestinal mucosa were detected in both patients and controls. Peripheral blood mononuclear cells (PBMCs) were sorted by CD14 immunomagnetic beads. The apoptosis of monocytes, expression of Rac1 and related apoptosis signaling molecules were detected in patients treated with peptidoglycan, 6-TG and Rac1 inhibitor NSC23766 and another 15 healthy donors. Results: The number of macrophages and apoptotic cells significantly increased in the inflammatory group of Crohn's disease patients compared with the non-inflammatory group. The expression of PAK1, downstream molecular of Rac1 signaling pathway of macrophages was also significantly higher in the inflammatory group of Crohn's disease patients than that in healthy controls and non-inflammatory group. Compared with control group, anti-apoptotic signals (NF-kappaB, Bcl-xL and STAT-3) in PBMCs increased in the peptidoglycan group, while slightly decreased in 6-TG group. 6-TG and NSC23766 significantly promoted peptidoglycan-related anti-apoptosis [peptidoglycan group (8.6+/-3.7)%, peptidoglycan+ 6-TG group (42.0+/-2.7)%, peptidoglycan+ NSC23766 group (58.5+/-6.9)%, P<0.05]. Conclusions: Peptidoglycan plays a role in the pathogenesis of Crohn's disease by recruiting macrophages. However, 6-TG inhibits peptidoglycan-induced activation of Rac1 signaling pathway leading to macrophage apoptosis. PMID- 29614588 TI - [The effect of continuous veno venous hemofiltration on neutrophil gelatinase associated lipocalin plasma levels in critically ill patients with acute kidney injury]. AB - Objective: To evaluate the effect of continuous veno venous hemofiltration (CVVH) on neutrophil gelatinase associated lipocalin (NGAL) in critically ill patients with acute kidney injury (AKI). Methods: Critically ill patients with AKI who needed CVVH and admitted to Department of Critical Care Medicine of Peking Union Medical College Hospital were enrolled prospectively from January 2015 to June 2015. AN69 membrane filters were used for CVVH. Prefilter, postfilter,and plasma NGAL measurements were taken at 10 mins, 4 hours and 8 hours (T 10 min, T 4 h, T 8 h) after CVVH. The influence of membrane filter and volume management on NGAL level was analyzed. Results: Forty patients were recruited.The acute physiology and chronic health evaluation II (APACHE II) score was 22.9+/-7.0. The sequential organ failure score (SOFA) was 12.1+/-2.9, and ICU mortality was 27.5%. During CVVH, there were no significant differences in NGAL levels between prefilter [T 10 min:39.3 (24.8, 62.4) MUg/min; T 4 h: (45.1+/-23.2)MUg/min; and T 8 h: (45.5+/ 22.4)MUg/min] and postfilter [T 10 min: 33.5 (25.1, 60.7) MUg/min; T 4 h: (44.2+/ 24.3)MUg/min, and T 8 h: (45.9+/-22.4)MUg/min] (P> 0.05 for all). Compared with the survival group[310.0(162.0, 588.0) MUg/L], plasma NGAL level in T 10 min [684.0(270.0, 944.0) MUg/L] was significantly higher in death group (P= 0.033). After fluid balance correction, T 4 h [603.4(484.8, 620.2) MUg/L] and T 8 h [590.2 (475.9, 749.4) MUg/L] plasma NGAL levels in death group were significantly higher than those in the survival group [T4 h: 419.5 (227.5, 552.4) MUg/L;T 8 h: 400.7(196.1, 517.4) MUg/L] with statistical significance (P<0.01 for both). Conclusions: During CVVH, AN69 membrane filter does not have significant effect on plasma NGAL level in critically ill patients with AKI. After volume balance correction, plasma NGAL level could be used as an effective indicator in these patients. PMID- 29614589 TI - [Two cases report of bone marrow hyperplastic tumor combined with portal spongy degeneration presenting with portal vein thrombosis and portal venous hypertension]. PMID- 29614590 TI - [A case report of periventricular meningioangiomatosis assosiated with meningioma]. PMID- 29614591 TI - [Clinical diagnosis and management of myocarditis in adults]. PMID- 29614593 TI - [Prevention of ulcerative colitis-related colorectal cancer]. PMID- 29614592 TI - [Etiologies and diagnosis of pituitary stalk thickening-related diseases]. PMID- 29614594 TI - [The research and advances in the effects of midkine on the development of inflammation]. PMID- 29614595 TI - [The 462nd case: chronic watery diarrhea and acute kidney injury]. AB - A 60-year-old man presented with severe watery diarrhea for 2 months complicated with weight loss and acute kidney injury. He did not respond well to antidiarrheal medicines, empirical antibiotics and dietary exclusion of gluten or even complete bowel rest. The final diagnosis of autoimmune enteropathy (AIE) was made based on histopathologic findings of endoscopic biopsy from duodenal mucosa after excluding neoplastic disease, inflammatory bowel disease, and infectious diarrhea, etc. Chronic diarrhea and oliguria alleviated after the administration of corticosteroids. PMID- 29614597 TI - [Antimicrobial resistance of animal-borne bacteria: progresses, challenges and strategies]. PMID- 29614596 TI - [The "One Health" approach must be followed in combating antimicrobial resistance]. PMID- 29614598 TI - [Climate change and population health]. PMID- 29614599 TI - [Climate change, health impacts in the vulnerable communities and adaptations]. PMID- 29614600 TI - [Prevalence and antimicrobial susceptibility of Salmonella isolated from broiler whole production process in four provinces of China]. AB - Objective: To determine the prevalence and antimicrobial susceptibility of Salmonella isolated from broiler production process in 4 provinces of China. Methods: Using convenience sampling method, 238 sample sites from broiler whole production process were chosen in Henan, Jiangsu, Heilongjiang and Shandong provinces in 2012. A total of 11 592 samples were collected and detected to analyze prevalence baseline, including 2 090 samples from breeding chicken farms and hatcheries, 1 421 samples from broiler farms, 5 610 samples from slaughterhouses and 2 471 samples from distribution and retail stores. All Salmonella strains were isolated through selective enrichment, and were serotyped according to Kauffmann-White scheme. The antimicrobial susceptibilities of selected Salmonella strains were determined by the broth microdilution method and fourteen antimicrobial agents were examined. Results: During incubation course, the average prevalence of Salmonella was 5.5% in feces of breeding hens, feces of chicks, and hatching eggs, 123 Salmonella strains were isolated. During cultivation course, the prevalence of Salmonella was 8.0% in feces from broiler farms, soil, feed, and workers, 114 Salmonella strains were isolated. During slaughter course, the prevalence of Salmonella was 24.9% in swabs pre-slaughter, dressed broiler carcasses, pre-cooled broiler carcasses, water from precooling pool, cutter and chipping boards, frozen chicken portions, and workers, 1 438 Salmonella strains were isolated. During distribution and sale course, the prevalence of Salmonella was 20.9% in transport carts, frozen chicken portions, retail chicken portions and workers, 551 Salmonella strains were isolated. The dominant Salmonella serotypes were Salmonella Enteritidis (n=1 229) and Salmonella Indiana (n=621). Among 1 231 examined strains, 97.2% Salmonella isolates were resistant to at least one antimicrobial, 69.9% Salmonella strains were multi-drug resistant isolates. Conclusion: Our findings indicated that Salmonella contamination was common and serious in commercial broiler whole production process in China, especially in the course of defeathering, precooling and selling. The environment of broiler farm is the important source of Salmonella contamination. Additionally, antibiotic resistance of Salmonella was serious for common antimicrobials and multi-drug resistant strains existed widespread, which can pose potential risk on public health and clinical therapy. PMID- 29614601 TI - [Antimicrobial susceptibility and drug-resistance genes of Yersinia spp. of retailed poultry in 4 provinces of China]. AB - Objective: To monitor the antimicrobial resistance and drug-resistance genes of Yersinia enterocolitis, Y. intermedia and Y. frederiksenii recovered from retailed fresh poultry of 4 provinces of China. Methods: The susceptibility of 25 isolated Yersinia spp. to 14 classes and 25 kinds of antibiotics was determined by broth microdilution method according to CLSI (Clinical and Laboratory Standards Institute). The antibiotic resistance genes were predicted with antibiotic resistance genes database (ARDB) using whole genome sequences of Yersinia spp. Results: In all 22 Y. enterocolitis tested, 63.7% (14 isolates), 22.8% (5 isolates), 4.6% and 4.6% of 1 isolates exhibited the resistance to cefoxitin, ampicillin-sulbactam, nitrofurantoin and trimethoprim sulfamethoxazole, respectively. All the 25 isolates were multi-drug resistant to more than 3 antibiotics, while 64.0% of isolates were resistant to more than 4 antibiotics. A few Y. enterocolitis isolates of this study were intermediate to ceftriaxone and ciprofloxacin. Most Yersinia spp. isolates contained antibiotic resistance genes mdtG, ksgA, bacA, blaA, rosAB and acrB, and 5 isolates recovered from fresh chicken also contained dfrA1, catB2 and ant3ia. Conclusion: The multi drug resistant Yersinia spp. isolated from retailed fresh poultry is very serious in the 4 provinces of China, and their contained many kinds of drug-resistance genes. PMID- 29614602 TI - [Molecular typing characterization of food-borne methicillin-resistant Staphylococcus aureus in China]. AB - Objective: To analyses the antimicrobial resistance and molecular characterization of 21 MRSA isolates cultured from retail foods from different provinces in China, and evaluate the molecular typing methods. Methods: Twenty one MRSA isolates were obtained from national foodborne pathogen surveillance network in 2012 (Chinese salad, n=3; milk, n=1; cake, n=2; rice, n=1; cold noodle, n=1; spiced beef, n=1; dumpling, n=1; packed meal, n=1; salad, n=1; raw pork, n=9). The antimicrobial resistance of 21 strains to 12 antimicrobial agents was tested by broth dilution method. Polymerase chain reaction (PCR) and DNA sequencing were performed to obtain the genetic types of MLST (ST) and spa typing. The clonal complex (CC) was assigned by eBURST soft and the MLVA type (MT) and MLVA complex (MC) were identified via the database of the MLVA website (http://www.mlva.net). SmaI pulsed-field gel electrophoresis (SmaI-PFGE) was also carried out to obtain the PFGE patterns of 21 strains. The genetic diversity and discriminatory power of typing were calculated by the Simpson's index of diversity (diversity index, DI) to find out the best genotyping method for MRSA. Results: All MRSA isolates showed multi-drug resistance(MDR), and were resistant to oxacillin, benzylpenicillin, clindamycin and erythromycin, and 71.4% (15/21), 47.6% (10/21), 42.9% (9/21) and 28.6% (6/21) of the MRSA isolates were resistant to tetracycline, ciprofloxacin, trimethoprim/sulfamethoxazole and gentamicin, respectively. Moreover, one strain was found to be resistant to all three antimicrobials of levofloxacin, moxifloxacin and rifampicin. Great diversity was found in these food-associated MRSA (6 STs, 7 spa types, and 9 MTs). PFGE patterns were more diverse than those of other three molecular typing methods (19 pulse types). The index of diversity (DI) of PFGE, MLVA, spa typing and MLST was 0.99, 0.80, 0.73, and 0.61, respectively. Among the MRSA isolates, CC9-ST9-t899 MT929-MC2236 (PFGE Cluster V) was the most prevalent clone, which were all cultured from raw pork (9 isolates). Besides, two MRSA were identified as CC59 ST338-t437-MT621-MC621 (PFGE Cluster IV). Different clone had their own resistance spectrum profiles. Conclusion: The food-borne MRSA isolates were all MDR in this study. Different clones had their own resistance spectrum profiles. MLVA represented a promising tool for molecular epidemiology tracing of MRSA in foodborne disease events. PMID- 29614603 TI - [Serotype distribution and antimicrobial resistance of Salmonella isolates from retail chicken carcasses in six provinces of China]. AB - Objective: To obtain the serotype diversity and antimicrobial resistance of Salmonella isolates recovered from retail chicken carcasses for sale in six regions of China. Methods: From August 2010 to March 2012, each month 20 retail chicken carcasses including freshly slaughtered, chilled and frozen samples were collected from supermarkets and farmer's markets in 7 monitoring sites in Beijing, Jilin province, Inner Mongolia Autonomous, Shanxi province, Jiangsu province and Guangdong province, respectively. Samples were routinely collected for 12 months for each site. 1 680 chicken carcasses were collected in total and 2 629 Salmonella strains were isolated by PCR and biochemical method. Luminex xMAP method and classical slide agglutination method were carried out to determine isolates' serotypes. Minimal inhibitory concentrations (MICs) of 10 classes of antimicrobials including 14 agents were determined using broth micro dilution method. Mocular methods were used to determine antimicrobial resistance genes of CIP-CTX-CT co-resistant isolates. Results: In all, 2 629 Salmonella isolates, there were 17 seorgroups and 58 serotypes, B and D1 were the dominant serogroups with rates of 34.7% (n=913) and 31.0% (n=815), Enteritidis (30.8%, n=810), Indiana (17.6%, n=463), Infantis (10.6%, n=278) were the top three serovars. We found 224 CIP-CTX co-resistant S. Indiana containing 3 colistin resistant strains, one of them carrying mcr-1 gene and being ESBLs positive, which demonstrated a nine multi drug resistance against 11 antimicrobials tested. Conclusion: These data began to describe the complicated serovar diversity and heavy antimicrobial resistance of Salmonella isolates recovered from retail chicken carcasses in six regions of China. The findings highlight the emergence of ciprofloxacin and cefotaxime co-resistant S. Indiana and also a mcr-1 positive S. Indiana with heavy multi drug resistance. PMID- 29614604 TI - [Effect of nutrition quality of breakfast on satiety among young white-collar workers]. AB - Objective: To analyze the effect of breakfast nutrition quality on the satiety among young white-collar workers. Methods: A total of 278 subjects were recruited from two cities, Shenyang and Chongqing, in June 2015. The inclusion criteria: white-collar workers aged 25-45 years involved mainly in office work, who did not experience major changes, and individuals who should follow the study protocol and sign the informed consent form. The study employed a three-phase crossover design trial. Each participant received nutritional-adequate breakfast, nutritional-inadequate breakfast, and no breakfast treatment on the basis of assignment to one of three sequences. The breakfast time was once a week and then changed, all participants underwent the tests for three successive weeks. At last, we compared the effect of participants to consume different nutritional quality on satiety sense and hunger sense. Results: A total of 232 participants completed three successive breakfast intervention studies, the age of participants was (35.2 +/- 7.9) years, comprised of 48.7% male (n=113). The numbers of participants of aged 25-35 year-old and aged 36-45 were 118 and 114, respectively. Satiety scores of nutrition-adequate breakfast group, nutrition inadequate breakfast group and no breakfast group were 63.5+/-14.7, 53.1+/-10.2 and 36.4+/-7.2, respectively (P<0.05). In nutrition-inadequate breakfast group and no breakfast group, male subjects scored significantly higher than female subjects (50.9+/-10.5 vs 46.6+/-9.4, 35.2+/-8.3 vs 31.8+/-5.4) (P<0.05). And, participants aged 25-35 year-old. got satiety score significantly higher than aged 36-45 (51.3+/-11.0 vs 45.6+/-12.1, 34.1+/-6.8 vs 32.5+/-7.9), the difference was statistically significant (P<0.05). The scores of hunger in the group of nutrition-adequate breakfast, nutrition-inadequate breakfast and no breakfast were 26.3 +/- 8.0, 35.1 +/- 11.2 and 57.3 +/- 17.0, respectively (P<0.05). Conclusion: The nutrition quality of breakfast affects the satiety of young white collar workers. The better the nutrition quality of breakfast is, the higher the satiety score and the lower the hunger score become. Compared with women and participants aged 36-45 year-old, men and those aged 25-35 year-old get satiety sense more easily. PMID- 29614605 TI - [The association of fruit and vegetable intake with the changes of serum lipid levels in middle-aged and older Chinese population]. AB - Objective: To investigate the association of fruit and vegetable intake with long term changes of serum lipid levels in middle-aged Chinese and older Chinese population. Methods: The study analyzed the data collected in the 2004 and 2007 2008 cohorts of China Multicenter Collaborative Study of Cardiovascular Epidemiology. Finally, 4 495 participants from 10 groups in various regions of China, who both were followed up in the two cohorts, were included for data analysis. They were aged 41-66 years in 2004. Fruit and vegetable consumption were collected with a simple food frequency questionnaire. The percent changes (Delta%) of serum TC, TG, HDL-C and LDL-C between the two surveys were calculated. Multivariate linear regression models were used to estimate the association of fruit and vegetable intake in 2004 with percentage changes of serum lipid levels during the two surveys. Results: The proportions of individuals who consumed fruits <250, 250-499 and >=500 g/week were 24.0%, 21.8% and 54.2%, respectively. The proportions of individuals who consumed vegetables <500 and >=500 g/day were 76.7% and 23.3%, respectively. Compared with fruit intake <250 g/week, the regression coefficients (95% CI) of DeltaTC% in 250-499 and >=500 g/week group were -1.54 (-2.71, -0.37) and -1.77 (-2.79, -0.76). And the regression coefficients (95% CI) of DeltaLDL-C% were -2.43 (-4.39, -0.48) and -2.89 (-4.59, -1.19). Compared with vegetable intake <500 g/d, the regression coefficients (95%CI) of DeltaTC% and DeltaLDL-C% in vegetable intake >=500 g/d group were -1.01 (-1.95, -0.06) and -1.83 (-3.41, -0.24). However, fruit and vegetable intake had no relationship with DeltaTG% and DeltaHDL-C%. Conclusion: The consumption of fruit and vegetable was inversely related to long-term changes of TC and LDL-C in middle-aged and older population, but no association was found for changes of TG and HDL-C. PMID- 29614606 TI - [The trend of intracerebral hemorrhage mortality of the residents with different characteristics in Tianjin, China, 1999-2015]. AB - Objective: To explore the trends and distribution of intracerebral hemorrhage (ICH) mortality of the residents with different characteristics from 1999 to 2015 in Tianjin. Methods: ICH mortality data in 1999-2015 were from Tianjin population based mortality surveillance system. The mortality rate of ICH, difference in the rate by gender, age, and geographic distribution, and trends over the years were analyzed. Standardized mortality rates of ICH were calculated using the year 2000 world standard population. Joinpoint regression and Cochran-Armitage trend were used to examine the trends in mortality. Results: A total of 102 279 ICH death cases were observed in Tianjin from year 1999 to 2015. The crude ICH mortality rate in Tianjin decreased from 76.35/100 000 in 1999 to 51.46/100 000 in 2015 (annual percent change (APC)=-1.96%, Z=-31.08, P<0.001) , and the standardized mortality rate decreased from 72.41/100 000 to 29.00/100 000 (APC=-5.20%, Z= 70.91, P<0.001). The crude mortality rate of ICH mortality in males decreased from 87.26/100 000 to 59.89/100 000 (APC=-1.79%, Z=-21.71, P<0.001) and the standardized mortality rate decreased from 85.65/100 000 to 35.75/100 000 (APC= 4.93%, Z=-52.32, P<0.001). The crude mortality rate of ICH mortality in females decreased from 65.21/100 000 to 42.98/100 000 (APC=-2.18%, Z=-22.28, P<0.001) and the standardized mortality rate decreased from 59.17/100 000 to 22.26/100 000 (APC=-5.63%, Z=-48.15, P<0.001). The ICH mortality rate under 35 years old increased from 0.78/100 000 to 0.92/100 000 (APC=4.41%, Z=5.07, P<0.001), especially in males increasing from 0.90/100 000 to 1.54/100 000 (APC=6.59%, Z=6.52, P<0.001). The crude mortality rate of ICH in urban areas decreased from 69.74/100 000 to 41.79/100 000 (APC=-3.18%, Z=-31.43, P<0.001) and the standardized mortality rate decreased from 57.56/100 000 to 20.42/100 000 (APC= 6.59%, Z=-53.43, P<0.001). The crude mortality rate of ICH in rural areas decreased from 82.99/100 000 to 61.49/100 000 (APC=-1.10%, Z=-14.06, P<0.001) and the standardized mortality rate decreased from 91.55/100 000 to 43.14/100 000 (APC=-3.78%, Z=-43.21, P<0.001). The ICH mortality rate in rural areas was higher than that in urban areas (P<0.05). Conclusion: ICH mortality rate in Tianjin decreased from 1999 to 2015. Further efforts to reduce ICH mortality in Tianjin is needed, in particular males, under 35 years old, and people in rural areas. PMID- 29614607 TI - [Effect of lifestyle intervention among high risk group of chronic diseases in Shenzhen Futian district]. AB - Objective: To evaluate the effect of lifestyle intervention among high risk group of chronic diseases in Shenzhen Futian district. Methods: 12 out of 115 communities were randomly selected in Futian district of Shenzhen city from October to November, 2013, and 1 923 cases were screened by multiple ways as high risk groups of chronic diseases. High risk groups of chronic diseases were divided into intervention group (1 338 cases, from five residential communities and three villages within city) and control group (585 cases, from four residential communities). The intervention group received group based health education activities as well as lifestyle intervention. The intervention group was provided with health management which was mainly lifestyle intervention. No intervention was implemented in the control group. All participants were followed up over two years. 1 563 participants (1 002 in intervention group and 561 in control group) were followed up from October to November, 2015. The changes of lifestyle related outcome indicators were analyzed to examine the effect of intervention. Results: In the intervention group, 21.8% (219 persons) in high risk groups of chronic diseases became healthy individuals and 15.2% (152 persons) became patients with chronic diseases. In the control group, 9.6% (54 persons) in high risk groups of chronic diseases became healthy individuals and 20.5% (115 persons) became patients with chronic diseases. The outcome of the intervention group was better than that of the control group and the difference was statistically significant (chi2=-5.67, P<0.001). The proportion of people who knew how to correctly use of oil control pot in the intervention group increased from 61.00% (61/100) to 80.00% (280/350). The proportion of people who took oil control measures in the intervention group increased from 36.43% (365/1 002) to 56.99%(571/1 002). The changes in the intervention group were statistically different (P<0.001), but there was no statistical difference in the control group over the years (P>0.05). The proportion of people who knew how to correctly use of the salt restriction spoon increased from 81.95% (109/133) to 97.99% (342/349). The proportion of people who took salt control measures increased from 45.61% (457/1 002) to 62.67% (628/1 002) in the intervention group. The changes in the intervention group were statistically different (P<0.001). There was no statistical difference in the control group over the years (P>0.05). Conclusion: The proportion of people who adopted healthy lifestyles has increased after 2 years intervention and the lifestyle intervention demonstrated good effect. PMID- 29614608 TI - [Primary prevention by hepatitis B vaccine on liver cancer in high incidence area of China]. AB - Objective: Incidence of primary liver cancer (PLC) in China is mostly related to chronic infection of hepatitis B virus (HBV). Qidong was one of the endemic areas with high incidence of PLC in China before 2000. We conducted a series of studies regarding on PLC etiological prevention during the past decades to develop better primary prevention strategies for PLC. Methods: Qidong Hepatitis B Intervention Study was conducted in 1983-1990. A total of 41 182 newborns were randomly assigned to vaccination group and 40 211 (97.64%) of them completed the three dose, 5 ug-plasma-derived hepatitis B (HB) vaccination series at age 0, 1, 6 month. Among them, 28 988 participants received one-dose 10 ug recombinant HB booster vaccination at age 10-14 years. A total of 41 730 newborns were randomly assigned to the control group. When they were at age 10-14 years, 23 368 participants received the catch-up vaccination with three-dose, 10 ug-recombinant HB vaccine. Two cross-sectional HBV serology surveys were conducted in 1996-2000 and 2008-2012. Information on PLC incidence and mortality of chronic liver diseases were collected through cancer registry and vital statistics until December 31, 2016. Cox proportional hazard models were employed to compute hazard ratio (HR) of PLC and other liver diseases for the participants with neonatal HB vaccination or catch-up vaccination, and the protective efficacy was also calculated. Results: During serologic survey in 1996-2000, a total of 22 689 participants in vaccination group and 12 395 participants in control group donated blood samples. The HBsAg seropositive rates in the vaccination group was 2.16% (491/22 689), which is significantly lower than that of control group (9.08%, 1 126/12 395) (chi2=896.61, P<0.001). During serologic survey in 2008 2012, a total of 17 386 participants in vaccination group and 18 060 participants in control group donated blood samples. The HBsAg seropositive rates in the vaccination group was 1.83% (319/17 386), which is still significantly lower than that of control group (6.77%,1 222/18 060) (chi2=518.05, P<0.001). By December 31, 2016, 4 cases of PLC in the vaccination group and 17 cases of PLC were identified in the vaccination and control group, respectively. The estimated efficacy of neonatal HB vaccination on HBsAg seroprevalence in childhood (at age 10-11 years), early adulthood (at age 19-28 years) and incidence rate of PLC at age below 33 years was 79% (95%CI: 76%-81%), 74% (95%CI: 71%-78%) and 79% (95%CI: 36%-93%), respectively. The estimated efficacy of three-dose, 10 ug-recombinant HB catch-up vaccination in early adulthood is 21% (95%CI: 11%-30%), which is significantly lower than that of neonatal HB vaccination. Conclusion: HB vaccination to neonates/infants is crucial against chronic HBV infection in childhood through young adulthood, and subsequently reduced the risk of PLC in young adults. PMID- 29614609 TI - [Characteristic analysis of molecular subtypes and recombinant structure of HIV-1 infection in Zhejiang Province, 2015]. AB - Objective: To understand the molecular subtypes and recombinant structure of HIV 1 infection in Zhejiang Province. Methods: According to the method of stratified random sampling method, a total of 302 newly HIV infected people (excluding AIDS patients) were selected as the subjects of the investigation from April to June, 2015, who were all newly HIV positive patients reported in Zhejiang Province and were diagnosed as HIV positive and had not received antiretroviral treatment. Questionnaires were used to collect information such as gender, residency, marital status, route of transmission and case reporting area. At least 8 ml of venous blood was collected from HIV infected people, reverse transcription polymerase chain reaction (RT-PCR) and nested PCR were used to amplify the pol gene sequence of HIV-1 strains and circulating recombination forms (CRF) and unique recombinant form (URF) strains were screened using phylogenetic tree, and molecular subtype analysis and recombinant analysis were performed. Results: Of the 302 HIV infected people, 18 cases were infected with new CRFs or URFs, among which 15 were male (83.3%), 3 were heterosexual transmission (17.7%); 8 cases (44.4%) were infected with new CRFs, which included CRF55_01B 5(27.8%), CRF67_01B 2 (11.1%), CRF69_01B 1 (5.6%); 10 cases (55.6%) were infected with URFs, in which 6 cases were infected with two groups of recombinant strains composed of CRF01_AE subtype and CRF07_BC subtypes in pol region, 3 cases were infected with three groups of recombinant strains of the two subtypes in pol region, and 1 case could not be accurately determined of the recombinant structure. The results of recombinant source analysis showed that the newly recombinant strains found from Zhejiang province were highly homologous to the strains from Guangdong, Anhui, Hebei, Yunnan, Liaoning province, and the sequence similarity was 94.4%-98.0%. Conclusion: The new recombinant strains of Zhejiang province included CRFs strains and URFs strains with CRF01_AE and CRF07_BC as the main recombinant structure mode, and all of them were introduced from other places and formed a trans-regional chain of HIV transmission. PMID- 29614610 TI - [Analysis of the influential factors of late diagnosis among newly identified HIV/AIDS cases in Anhui Province, 2011-2015]. AB - Objective: To analyze the base situation and influential factors of late diagnosis among newly identified HIV/AIDS cases in Anhui Province from 2011 to 2015. Methods: Database information of the newly identified HIV/AIDS cases in Anhui Province from 2011 to 2015 were downloaded from the National HIV/AIDS Comprehensive Information System of China's disease prevention and control information system. To analyze the data including basic information, sample source, route of HIV transmission, population mobility, venereal disease, death and first CD4 count; and the number of 7 073 cases were classified according to late diagnosis and non-late diagnosis criteria. The Chi-square test and logistic regression analysis were used to analyze the influential factors of HIV late diagnosis. Results: A total of 7 073 newly identified HIV/AIDS cases were analyzed, and the mean age was (38.5+/-15.0) years. The proportion of late diagnosis in all counted cases was 41.7% (2 949/7 073); from 2011 to 2015, the proportions of late diagnosis were 59.7% (485/812), 46.5% (531/1 141), 42.7% (587/1 376), 36.1% (609/1 686), and 35.8% (737/2 058), respectively. Compared with the 0 to 19 years group, the 40 to 59 years group and over 60 years old group have higher risk of late diagnosis (OR=2.68, 95%CI: 1.94-3.71; OR=2.18, 95%CI: 1.53-3.10, respectively). Compared with the high education group, the illiterate and primary school education group have higher risk of late diagnosis (OR=1.74, 95%CI: 1.36-2.22; OR=1.64, 95%CI: 1.34-2.01, respectively). Compared with other sample sources, medical institutions have higher risk of late diagnosis (OR=2.64, 95%CI: 2.28-3.05). Compared with migrant population, the resident population have higher risk of late diagnosis (OR=1.80, 95%CI: 1.53 2.11). Conclusion: The proportion of late diagnosis among newly identified HIV/AIDS cases in Anhui province was relatively high from 2011 to 2015. The main risk factors of late diagnosis included cases reported by medical institutions, resident population, over 40 years old age group and low education level. PMID- 29614611 TI - [Characterization analysis of gM, gL genes of varicella zoster virus in six provinces of China]. AB - Objective: To analyze the genetic characterization of glycoprotein M(gM.),glycoprotein L(gL) of varicella zoster virus. Methods: According to the program of "Ministry of Science and Technology of China" , Based on the 12 suspected VZV patients monitored in Beijing (1 case), Shanghai (5 cases), Jilin (2 cases), Qinghai (1 case), Guangdong (2 case) and Sichuan (case) in 2007-2015. A total of 12 Vesicle fluid and throat swab samples were collected. Positive samples were identified by Agarose gel electrophoresis and two glycoprotein genes were amplified by polymerase chain reaction (PCR). Nucleotide sequences were determined and analyzed by PCR amplification of VZV positive specimens V-OKA-BK of the domestic varicella attenuated live vaccine and the Varilrix-1 of the imported attenuated live vaccine. Nucleotide sequences of VZV positive specimens, vaccine strains (V-OKA-BK, varilrix-1) and GenBank foreign wild strains (41 strains), parent strains (P-oka), vaccine strains (V-oka, Varilrix, Varivax) were compared using BioEdit and MEGA 5.0. Results: 12 specimens were VZV positive. Compared with the vaccine strains and the parent strains, the GM gene of 1 positive specimen had radical mutation at 86686 sites, which resulted in amino acid mutation, 5 positive specimens had base mutation at 87844 sites, and 30 strains of foreign wild strains had the same variation at 87 844 sites. 1 positive specimens of gL gene in 101245 sites had base mutation, and led to amino acid mutation, 6 positive specimens at 101624, 101625, 101626 sites had base of loss and the foreign wild strains in these 3 sites had the same variation. Compared with the vaccine strains, the nucleotide and amino acid homology of gM of 12 VZV positive specimens were 99.2%-100% and 98.2%-100%, respectively, and gL of those were 99.3%-100% and 98.6%-100%, respectively. Compared with 41 strains of foreign wild strains, homology of gM's nucleotides and amino acid were 99.3% 100% and 98.5%-100%, respectively; 99.1%-100% and 98.6%-100% for gL. The results of phylogenetic analysis showed that 7 VZV positive samples were on the same branch with 4 vaccine strains and p-oka strain. Based on gL, 12 VZV positive samples were on the same branch as the vaccine strains and p-oka strain. Conclusion: This study demonstrates that the genes of gM, gL are highly conserved and remain stable immunogen, which may be involved in the attenuation of VZV and need to be further researched. PMID- 29614612 TI - [Intervention effect assessment of response to heatwave in communities of four cities, China]. AB - Objective: To evaluate the intervention effects of response to heatwave in communities of four cities, China. Methods: Baseline survey on heatwave and climate change related knowledge, attitude and practice (KAP) was conducted in the pilot communities in Harbin, Nanjing, Shenzhen and Chongqing, using face-to face questionnaire interview in November, 2011 to November, 2013. Finally, 1 604 residents were interviewed. Intervention measures were implemented in summers of 2013 and 2014, including delivering early warning information of heatwave health risk and launching health education and promotion. The second survey was conducted in same communities using the same questionnaire and sampling method as baseline survey in November, 2014, and 1 640 residents were interviewed. The Chi square test was used to compare the demographic characteristics and KAP of community residents between before and after intervention, and the factors that affected the intervention effect were selected by logistic multiple stepwise regression model. Results: The age of the residents interviewed before and after intervention was (46.4 +/- 15.5) years and (45.0 +/- 15.9) years, respectively. Overall, the residents' awareness rates of heatwave before and after intervention were 70.5% (1 131/1 604) and 82.9% (1 359/1 640) (chi2=69.40, P<0.001). The rate of residents who had wished to receive early warning information increased 6.3% (chi2=41.11, P<0.001), which reached 94.6% (1 551/1 604) after intervention from 88.3% (1 416/1 604) in baseline survey. Both heatwave health risk early warning and health education had big impacts to residents. There were 92.7% (1 105 residents) among the 1 192 residents who had received the early warning information arrange work and rest time according to the early warning information and 93.0% (1 231 residents) among the 1 323 residents who knew about health education activities being conducted in community thought that the community health education activities had made active role in protecting health from heatwaves. After a series of intervention, male had a effect on attitude about hot wave than female in Nanjing and Chongqing, OR (95%CI) were 1.48(1.02-2.16) and 1.45 (1.18-2.05) , respectively; compared with subjects below primary school education, people with college degree or above had higer KAP in all cities (ORs range from 1.18 to 2.05), P<0.05; regular physical exercise (ORs range from 1.39 to 2.70) also had profound impacts on KAP in all cities (P<0.05). Conclusion: s Early warning and health education were effective measures to enhance residents' response capacity to climate change. PMID- 29614613 TI - [Estimating and projecting the acute effect of cold spells on excess mortality under climate change in Guangzhou]. AB - Objective: To estimate future excess mortality attributable to cold spells in Guangzhou, China. Methods: We collected the mortality data and metrological data from 2009-2013 of Guangzhou to calculated the association between cold spell days and non-accidental mortality with GLM model. Then we projected future daily average temperatures (2020-2039 (2020s) , 2050-2069 (2050s) , 2080-2099 (2080s) ) with 5 GCMs models and 2 RCPs (RCP4.5 and RCP8.5) to identify cold spell days. The baseline period was the 1980s (1980-1999). Finally, calculated the yearly cold spells related excess death of 1980s, 2020s, 2050s, and 2080s with average daily death count of non-cold spell days, exposure-response relationship, and yearly number of cold spell days. Results: The average of daily non-accidental mortality in Guangzhou from 2009 to 2013 was 96, and the average of daily average was 22.0 C. Cold spell days were associated with 3.3% (95%CI: 0.4%-6.2%) increase in non-accidental mortality. In 1980s, yearly cold spells related deaths were 34 (95%CI: 4-64). In 2020s, the number will increase by 0-10; in 2050s, the number will increase by 1-9; and in 2080s, will increase by 1-9 under the RCP4.5 scenario. In 2020s, the number will increase by 0-9; in 2050s, the number will increase by 1-6; and in 2080s, will increase by 0-11 under the RCP8.5 scenario. Conclusion: The cold spells related non-accidental deaths in Guangzhou will increase in future under climate change. PMID- 29614614 TI - [Investigation and analysis of perioperative antimicrobials prophylaxis for type I incision surgery in a tertiary hospital from 2013 to 2016]. PMID- 29614615 TI - [Investigation and analysis on rural environmental sanitation in Xinjiang, 2016]. PMID- 29614616 TI - [State-of-the-art status on airborne antibiotic resistant bacteria and antibiotic resistance genes]. AB - The world is facing more deaths due to increasing antibiotic-resistant bacterial infections and the shortage of new highly effective antibiotics, however the air media as its important transmission route has not been adequately studied. Based on the latest literature acquired in this work, we have discussed the state-of the-art research progress of the concentration, distribution and spread of antibiotic resistant bacteria (ARB) and antibiotic resistance genes (ARGs) in different environmental air media, and also analyzed some future prevention and control measures. The large use of antibiotics in the medical settings and animal husbandry places has resulted in higher abundances of ARB and ARGs in the relevant and surrounding atmosphere than in urban and general indoor air environments. ARGs can be spread by adhering to airborne particles, and researchers have also found that air media contain more abundant ARGs than other environmental media such as soil, water and sediment. It was suggested in this review that strengthening the monitoring, study on spreading factors and biological toxicity, and also research and development on pathogen accurate diagnosis and new green antibiotic are expected to help effectively monitor, prevent and control of the impacts of airborne resistant bacteria and resistance genes on both human and ecologies. PMID- 29614617 TI - [Transformation of endogenous reactive oxygen species participates into bacterial antibiotic resistance]. AB - A growing body of diversified antibiotic resistances raises a significant challenge to anti-infection clinical therapeutics. The emergence of superbugs carrying MCR-1/2 or NDM-1 determinants underlines the importance and urgency in elucidation of molecular mechanisms shared by antibiotic resistances. It is aware that different classes of bactericidal antibiotics consistently stimulate the production of deleterious reactive oxygen species (ROS), which are accompanied with metabolic disturbance. The different destinations of ROS determine its consequence on bacterial fate. Here, we review antibiotic-induced production, progression and transformation of ROS, as well as its role in the development of antibiotic resistance. Additionally, we anticipate that mesosome-like structures aided exclusion of hydrogen peroxide might represent a previously-unknown mechanism for antibiotic resistance. This mini-review is aiming to present an update overview on antibiotic resistance and provide clues to the development of novel antibiotics. PMID- 29614619 TI - Corrigendum to "Review of recent advances in research on the toxicity, detection, occurrence and fate of cyclic volatile methyl siloxanes in the environment" [Chemosphere 93 (5) (2013) 711-725]. PMID- 29614618 TI - [Indispensability of cohort study in tumor prevention and prognosis assessment]. AB - Cancer is one of the major causes of human death. Early diagnosis and treatment are widely believed to be important in decreasing cancer mortality rate. However, biological factors (such as tumor heterogeneity) and social factors (such as profits driving), over-diagnosis and over-treatment exist in the practice of cancer diagnosis and treatment. The keys to avoid such issues are to identify what kinds of precancerous lesions are more likely to progress into malignant tumors, what kind of early cancer are prone to invading surrounding tissues, and what kinds of prophylactic and therapeutic options are of benefit to effective survival of patients. All above need to be accurately evaluated by cohort studies. Cohort study is the most reliable method to crystallize causal relationship of the exposures (interventions) with the development and recurrence of cancers and define the directions of cancer screening and therapy. Cohort studies shed light on the prediction, screening, and active prophylaxis for the occurrence and recurrence of cancers with specific types. Moreover, the prognostic effects of a given clinical treatment can be precisely evaluated in cohort study, rather than experience-directed clinical activity. Therefore, cohort study is indispensable for cancer research. PMID- 29614620 TI - Cross-sectional distributions of normal and abnormal red blood cells in capillary tubes determined by a new technique. AB - BACKGROUND: In the microcirculation, red blood cells (RBCs) were observed to be confined to an axial stream surrounded by a marginal RBC depleted layer. This axial accumulation of RBCs is considered to arise from the RBC deformability. OBJECTIVE: To quantitatively evaluate the effect of RBC deformability on their axial accumulation at a flow condition comparable to that in arterioles by developing a new observation system for accurate measurements of radial RBC positions in the cross section of capillary tubes. METHODS: The cross-sectional distributions of normal and hardened RBCs as well as softened RBCs suspended in capillary tube flows were measured with high spatial resolution. A new observation system was developed in which enface views of the cross-section of the tube were obtained at small distances upstream of the outlet at various longitudinal positions in the tube. RESULTS: The radial positions of individual RBCs were detected within 1 MUm accuracy. It was found that normal and softened RBCs rapidly migrated away from the wall towards the tube axis, whereas glutaraldehyde-hardened RBCs were dispersed widely over the tube cross-section, depending on the concentration of glutaraldehyde solution. CONCLUSIONS: The newly devised observation system revealed quantitatively the essential role of RBC deformability in their axial accumulation. PMID- 29614621 TI - Three dimensional finite element analysis of the influence of posterior tibial slope on the anterior cruciate ligament and knee joint forward stability. AB - OBJECTIVE: To explore the biomechanical influence of posterior tibial angle on the anterior cruciate ligament and knee joint forward stability. METHODS: The left knee joint of a healthy volunteer was scanned by CT and MRI. The data were imported into Mimics software to obtain 3D models of bone, cartilage, meniscus and ligament structures, and then Geomagic software was used to modify of the image. The relative displacement between tibia and femur and the stress of ACL were recorded. RESULTS: ACL tension was 12.195 N in model with 2? PTS, 12.639 N in model with 7? PTS, 18.658 N in model with 12? PTS. the relative displacement of the tibia and femur was 2.735 mm in model with 2? PTS, 3.086 mm in model with 7? PTS, 3.881 mm in model with 12? PTS. In the model with 30? flexion, the maximum tension of ACL was 24.585 N in model with 2? PTS, 25.612 N in model with 7? PTS, 31.481 N in model with 12? PTS. The relative displacement of the tibia and femur was 5.590 mm in model with 2? PTS, 6.721 mm in model with 7? PTS, 6.952 mm in model with 12? PTS. In the 90? flexion models, ACL tension was 5.119 N in model with 2? PTS, 8.674 N in model with 7? PTS, 9.314 N in model with 12? PTS. The relative displacement of the tibia and femur was 0.276 mm in model with 2? PTS, 0.577 mm in model with 7? PTS, 0.602 mm in model with 12? PTS. CONCLUSION: The steeper PTS may be a risk factor in ACL injury. PMID- 29614622 TI - Determination of physical parameters associated with self-efficacy in patients with chronic mechanic low back pain. AB - BACKGROUND: Self-efficacy that is associated with various pain-related disabilities such as chronic low back pain (LBP), should be questioned besides physical assessments. OBJECTIVES: To investigate the physical factors associated with self-efficacy in patients with chronic mechanic LBP. METHODS: One hundred nine patients diagnosed as chronic mechanic LBP (65 females, 44 males) between 20 50 years old were included to this study. The intensity of LBP was assessed by using a 10-cm Visual Analogue Scale. For musculoskeletal fitness measurement; muscle strength, muscle endurance, and flexibility tests were applied. Functional Reach Test for balance evaluation, Self-Efficacy Scale for self-efficacy measurement, Roland-Morris Disability Questionnaire for disability level evaluation were used. RESULTS: We found a moderate negative correlation between self-efficacy and pain intensity (r=-0.506); a negative and strong correlation between self-efficacy and disability level (r=-0.654) (p< 0.05). Self efficacy had a significant association with right (r= 0.265) and left (r= 0.290) lateral side bending flexibility (p< 0.05). According to multiple regression analysis results, it was found that disability level had a significant effect on self efficacy (beta=-2.014; p< 0.01). CONCLUSIONS: Poor musculoskeletal fitness and pain intensity may cause decreasing self-efficacy but the major determinant of decreased self-efficacy was low-back related disability scores. PMID- 29614623 TI - Ring finger sensorial conduction studies in grading carpal tunnel syndrome: Part II. AB - BACKGROUND: Comparison of sensory conduction of median nerve (MN) with the one of ulnar nerve (UN) over writs-to-ring finger (RF) segment is useful in electrodiagnosis of carpal tunnel syndrome (CTS). However, there is not any consensus regarding the usage of this technique in grading of CTS. OBJECTIVES: To determine whether the hands of CTS with elicitable MN sensory responses on index finger, but not on RF (non-respondings) compose a more severe electrophysiologic grade than the hands with elicitable responses on both fingers (respondings). MATERIAL AND METHODS: The patients with bilateral moderate grade of CTS in whom one hand was responding and the contralateral hand was non-responding were included. Conduction study results of MN and UN were compared between respondings and non-respondings. RESULTS: A total of 19 patients were included. Mean distal sensory onset latency (DSOL) of MN over index finger was longer (4.26 +/- 0.49 msec versus 3.44 +/- 0.39 msec; p< 0.001), sensory conduction velocity (SCV) was slower (33.7 +/- 4.3 m/sec versus 40.2 +/- 3.0 m/sec; p< 0.001), SNAP amplitude was smaller (10.3 +/- 3.3 MUV versus 19.1 +/- 7.7 MUV; p< 0.001), distal motor latency was longer (5.69 +/- 0.60 msec versus 4.63 +/- 0.32 msec; p< 0.001), and minimum F wave latency was longer (29.3 +/- 1.7 msec versus 26.8 +/- 1.4 msec; p< 0.001) in non-respondings than respondings. The nonresponding hand had a longer MN DSOL and slower SCV on index finger compared with contralateral responding hand in all of 19 patients. CONCLUSION: Non-responding hands have more progressed median neuropathies, and represent a more severe electrophysiologic grade than responding hands. Further studies are warranted to determine whether the absence of MN sensory responses on ring finger is related with forthcoming NCS worsening and a preferable hallmark for deciding surgical intervention or not. PMID- 29614624 TI - Baicalein suppresses non small cell lung cancer cell proliferation, invasion and Notch signaling pathway. AB - BACKGROUND: Baicalein is an important Chinese herbal medicine and has multiple pharmacological activities. However, the biological mechanisms of the anti-tumor effects of Baicalein on non small cell lung cancer (NSCLC) still need to be understood. METHODS: Human NSCLC A549 and H1299 cells were pretreated with Baicalein or DMSO. Cells viability and transwell cell invasion assays were performed to assess cell proliferation and invasion. QRT-PCR assay was used to analyze mRNA expression levels of Twist1, E-cadhertin, Vimentin, Notch1 and hes 1. Western blot analysis was also performed to determine protein expression. RESULTS: In the study, we found that Baicalein had a significantly inhibited effect on proliferation ability of A549 and H1299 cells. Cells treated with Baicalein showed a down-regulated expression of CyclinD1 and CDK1 in A549 and H1299 cells. Furthermore, we found that Baicalein significantly inhibited cell invasion and Epithelial-Mesenchymal Transition (EMT) by up-regulating the mRNA and protein expression of E-cadherin and down-regulated the Twist1 and Vimentin expression, Moreover, Treatment of Baicalein down-regulated Notch1 and hes-1 expression in A549 and H1299 cells, which indicated that Baicalein could suppress the Notch signaling pathway. CONCLUSION: Our studies suggest that Baicalein may be a potential phytochemical flavonoid for therapeutics of NSCLC and serve as a molecular target for NSCLC. PMID- 29614625 TI - Inhibition of E-cadherin expression by lnc-RNA H19 to facilitate bladder cancer metastasis. AB - Bladder cancer is derived from bladder mucosa and is the most common malignant tumor in urinary system. Long non-coding RNA (lnc-RNA) has high tissue specificity and can participate in cell proliferation and differentiation at various levels, and plays critical roles in occurrence of malignant tumors. This study aims to investigate the suppression of E-cadherin expression by lnc-RNA H19 to enhance bladder cancer metastasis.qRT-PCR was applied to analyze differential expression of lnc-RNA H19 in different bladder cancer tissues and tumor adjacent tissues. Patients clinical data were collected to analyze the correlation between H19 expression level and patient's clinical stage, tumor metastasis. RNA interference was employed to examine the effect of H19 on E-cadherin expression. The regulation of cancer metastasis was investigated on an animal model. H19 expression level was significantly higher in bladder cancer tissue compared to adjacent tissues (p< 0.05), and is correlated with advanced clinical stage (p< 0.05). In those metastatic patients, H19 expression level is significantly higher than those without metastasis (p< 0.05). RNA interference is applied to knockdown H19 expression in bladder cancer cell, and found potentiated E-cadherin expression (p< 0.05), accompanied with weakened metastatic potency (p< 0.05). H19 expression is up-regulated in bladder cancer, and is probably related with cancer clinical stage and metastasis. Cell transfection reveals up-regulation of E cadherin expression in bladder cancer cells when H19 expression is suppressed, accompanied with weakened metastasis potency. PMID- 29614626 TI - Special issue on sickle cell disease: Old and new concepts. PMID- 29614627 TI - Sickle cell disease: Classification of clinical complications and approaches to preventive and therapeutic management. AB - Sickle cell disease (SCD) is an inherited disorder of hemoglobin structure that has no established cure in adult patients. Cure has been achieved in selected children with sickle cell anemia (SCA) using allogeneic bone marrow transplantation or cord blood transplantation. SCD is essentially a triumvirate of (1) pain syndromes, (2) anemia and its sequelae and (3) organ failure, including infection. Pain, however, is the hallmark of SCD and dominates its clinical picture throughout the life of the patients. The prevalence of these complications varies with age from infancy through adult life. However, pain, infections and anemia requiring blood transfusion occur throughout the life span of affected patients. The overall medical care of patients with SCD in developed countries has improved such that their life expectancy has almost doubled since 1951. Currently, there are at least five major approaches for the general management of SCD and its complications. These include (i) symptomatic management, (ii) supportive management, (iii) preventive management, (iv) abortive management, and (v) curative therapy. PMID- 29614628 TI - Comorbidities in aging patients with sickle cell disease. AB - Sickle cell disease (SCD) in general and sickle cell anemia in particular is a highly complex disorder both at the molecular and clinical levels. Although the molecular lesion is a single-point mutation, the sickle gene is pleiotropic in nature causing multiple phenotypic expressions that constitute the various complications of the disease. Moreover, despite the fact that SCD is a chronic malady, its manifestations are both acute and chronic. The former include, among other things, the recurrent vaso-occlusive crises (its hallmark) and acute chest syndrome. The chronic complications include most commonly avascular necrosis and leg ulcers. Currently, survival of patients with SCD has improved dramatically thanks to newborn screening, antibiotic prophylaxis, better vaccine, safer blood transfusion and the use of hydroxyurea. It is the advent of these therapies that improved the survival. This improvement, however, introduced a third dimension of the disease: comorbidities that occur in aging people in the general population. There is concern that the gain in survival may be offset by the comorbidities. Thus it is the purpose of this review to identify the comorbidities in the elderly with SCD and differentiate them from the basis disease to implement proper therapies so that better survival could be maintained. PMID- 29614629 TI - Genetic modifiers of severity in sickle cell disease. AB - Sickle cell disease (SCD) is one of the most common single disease disorders world-wide. It is remarkable for its clinical heterogeneity, even among individuals with identical genotypes. Some individuals experience morbidity and mortality in early childhood, while others have a relatively mild course, and normal or near normal life expectancy. Many clinical complications are associated with SCD; most notably frequent pain episodes, stroke, acute chest syndrome, avascular necrosis, nephropathy, retinopathy and pulmonary hypertension. While the effects of higher fetal hemoglobin (HbF) levels, UGTA1A polymorphisms, alpha thalassemia and G6PD deficiency on SCD has been extensively studied, these variables do not explain all of the clinical heterogeneity of SCD. It is not known why some patients develop certain complications, and it is difficult to predict which complications a particular patient will experience. Much work has been done to identify genetic variants associated with these disease complications; many associations remain unvalidated. As the field continues to move beyond small sample collections and candidate gene approaches into whole genome sequencing and merging of samples from all over the world, we will identify more genetic variants associated with development of specific SCD related complications, and hopefully leverage this knowledge into targeted therapies. PMID- 29614630 TI - Blood rheological abnormalities in sickle cell anemia. AB - This review focuses on the contribution of abnormal blood rheology in the pathophysiology of sickle cell anemia (SCA). SCA is characterized by a reduction of red blood cell (RBC) deformability but this reduction is very heterogeneous among patients. Recent works have shown that patients with the lowest RBC deformability (measured by ektacytometry) have enhanced hemolysis and would be more prone to develop several complications such as priapism, leg ulcers and glomerulopathy. In contrast, patients with the highest deformability, and not under hydroxyurea therapy, seem to develop more frequently vaso-occlusive like events. Although less studied, RBC aggregation properties are very different between SCA and healthy individuals and it was demonstrated that increased RBC aggregates strength could be involved in some complications. Finally, several studies have established that the vascular system of SCA patients could not fully compensate any increase in blood viscosity because of the loss of vascular reactivity, which may result in vaso-occlusive crises. PMID- 29614632 TI - Sickle cell dehydration: Pathophysiology and therapeutic applications. AB - Cell dehydration is a distinguishing characteristic of sickle cell disease and an important contributor to disease pathophysiology. Due to the unique dependence of Hb S polymerization on cellular Hb S concentration, cell dehydration promotes polymerization and sickling. In double heterozygosis for Hb S and C (SC disease) dehydration is the determining factor in disease pathophysiology. Three major ion transport pathways are involved in sickle cell dehydration: the K-Cl cotransport (KCC), the Gardos channel (KCNN4) and Psickle, the polymerization induced membrane permeability, most likely mediated by the mechano-sensitive ion channel PIEZO1. Each of these pathways exhibit unique characteristics in regulation by oxygen tension, intracellular and extracellular environment, and functional expression in reticulocytes and mature red cells. The unique dependence of K-Cl cotransport on intracellular Mg and the abnormal reduction of erythrocyte Mg content in SS and SC cells had led to clinical studies assessing the effect of oral Mg supplementation. Inhibition of Gardos channel by clotrimazole and senicapoc has led to Phase 1,2,3 trials in patients with sickle cell disease. While none of these studies has resulted in the approval of a novel therapy for SS disease, they have highlighted the key role played by these pathways in disease pathophysiology. PMID- 29614633 TI - Vascular complications of sickle cell disease. AB - Sickle cell disease (SCD) is a monogenetic disorder caused by a mutation in the beta-globin gene HBB leading to polymerization of red blood cells causing damage to cell membranes, increasing its rigidity and intravascular hemolysis. Multiple lines of evidence suggest that SCD can be viewed as pan-vasculopathy associated with multiple mechanisms but driven by hemoglobin S polymerization. Here we review the pathophysiology, clinical manifestations and management strategies for cerebrovascular disease, pulmonary hypertension and renal disease associated with SCD. These "vascular phenotypes" reflect the systemic nature of the complications of SCD and are a major threat to the well-being of patients with the disorder. PMID- 29614631 TI - Simple chronic transfusion therapy, a crucial therapeutic option for sickle cell disease, improves but does not normalize blood rheology: What should be our goals for transfusion therapy? AB - Sickle cell anemia is characterized by a mutation resulting in the formation of an abnormal beta-hemoglobin called hemoglobin S. Hemoglobin S polymerizes upon deoxygenation, causing impaired red blood cell deformability and increased blood viscosity at equivalent hematocrits. Thus, sickle cell disease is a hemorheologic disease that results in various pathologic processes involving multiple organ systems including the lungs, heart, kidneys and brain. Red blood cell mechanics and the perturbations on blood flow-endothelial interaction underlie much of the pathology found in sickle cell disease. Transfusion therapy is one of the few therapeutic options available to patients, acting as both primary and secondary prevention of stroke. Transfusion therapy, both simple and exchange, is also used for unremitting and frequent pain crises and pulmonary hypertension. Therefore, understanding basic rheologic changes following transfusion inform other therapeutic options that aim to mitigate this diffuse pathologic process. This review will aim to highlight transfusion effects on blood rheology. PMID- 29614635 TI - Oxidative stress in sickle cell disease; more than a DAMP squib. AB - Sickle cell disease (SCD) is a monogenetic disorder marked by hemolytic anemia and vaso-occlusive complications. The hallmark of SCD is the intracellular polymerization of sickle hemoglobin (HbS) after deoxygenation, and the subsequent characteristic shape change (sickling) of red cells. Vaso-occlusion occurs after endothelial activation, expression of adhesion molecules and subsequent adhesion of leucocytes and sickle erythrocytes to the vascular wall. Here we review how oxidative stress from various sources influences this process. Emerging evidence points towards a dominant mechanism in which innate immune receptors, such as Toll like receptor 4, activate nicotinamide adenine dinucleotide phosphate (NADPH) oxidases to produce reactive oxygen species (ROS) which in turn enables downstream pro-inflammatory signaling and subsequent endothelial activation. By serving as an iron donor for the Fenton reaction, heme radically increases the amount of ROS further, thereby increasing the signal originating from the innate immune receptor and downstream effects of innate immune receptor activation. In SCD this results in the production of pro-inflammatory cytokines, endothelial activation and leucocyte adhesion, and eventually vaso-occlusion. Any intervention to stop this cascade, including Toll like receptor blockade, NADPH oxidase inhibition, ROS reduction, heme scavenging, iron chelation, or anti adhesion molecule antibodies has been successfully used in pre-clinical studies and holds promise for patients with SCD. PMID- 29614636 TI - Autonomic nervous system involvement in sickle cell disease. AB - Sickle cell disease (SCD) is a genetic disorder of hemoglobin producing hemoglobin-S (HbS) and resulting in recurrent severe episodes of pain, organ damage and premature death due to vaso- occlusion. Deoxy HbS polymerizes, causing red cells to become rigid and lodge in the microvasculature if they do not escape into larger vessels before this transformation occurs. The mechanism that triggers this transition from steady state to vaso-occlusive crisis (VOC) is not known. Patients state that cold, emotional stress, and pain itself can trigger these events. In spite of the connection between these symptoms and the autonomic nervous system (ANS), and the fact that the ANS regulates regional microvascular blood flow, the role of the ANS in sickle pathophysiology has not been significantly investigated. We will briefly review the mechanism of SCD vaso occlusion, the dysautonomia associated with SCD and sickle trait, and the role that the ANS may play in the genesis of sickle vaso-occlusive crisis. PMID- 29614637 TI - Inflammation in sickle cell disease. AB - The primary beta-globin gene mutation that causes sickle cell disease (SCD) has significant pathophysiological consequences that result in hemolytic events and the induction of the inflammatory processes that ultimately lead to vaso occlusion. In addition to their role in the initiation of the acute painful vaso occlusive episodes that are characteristic of SCD, inflammatory processes are also key components of many of the complications of the disease including autosplenectomy, acute chest syndrome, pulmonary hypertension, leg ulcers, nephropathy and stroke. We, herein, discuss the events that trigger inflammation in the disease, as well as the mechanisms, inflammatory molecules and cells that propagate these inflammatory processes. Given the central role that inflammation plays in SCD pathophysiology, many of the therapeutic approaches currently under pre-clinical and clinical development for the treatment of SCD endeavor to counter aspects or specific molecules of these inflammatory processes and it is possible that, in the future, we will see anti-inflammatory drugs being used either together with, or in place of, hydroxyurea in those SCD patients for whom hematopoietic stem cell transplants and evolving gene therapies are not a viable option. PMID- 29614634 TI - Nitric oxide pathology and therapeutics in sickle cell disease. AB - Sickle cell disease is caused by a mutant form of hemoglobin that polymerizes under hypoxic conditions which leads to red blood cell (RBC) distortion, calcium influx mediated RBC dehydration, increased RBC adhesivity, reduced RBC deformability, increased RBC fragility, and hemolysis. These impairments in RBC structure and function result in multifaceted downstream pathology including inflammation, endothelial cell activation, platelet and leukocyte activation and adhesion, and thrombosis, all of which contribute vascular occlusion and substantial morbidity and mortality. Hemoglobin released upon RBC hemolysis scavenges nitric oxide (NO) and generates reactive oxygen species (ROS) and thereby decreases bioavailability of this important signaling molecule. As the endothelium-derived relaxing factor, NO acts as a vasodilator and also decreases platelet, leukocyte, and endothelial cell activation. Thus, low NO bioavailability contributes to pathology in sickle cell disease and its restoration could serve as an effective treatment. Despite its promise, clinical trials based on restoring NO bioavailability have so far been mainly disappointing. However, particular "NO donating" agents such as nitrite, which unlike some other NO donors can improve sickle RBC properties, may yet prove effective. PMID- 29614638 TI - Hypercoagulable state in sickle cell disease. AB - Chronic activation of coagulation is one of the features of sickle cell disease (SCD). Increased tissue factor expression, phosphatidylserine exposure, thrombin generation and fibrinolysis, as well as decreased levels of natural anticoagulants have been reported in SCD patients and in the mouse models of SCD. Consistent with this, patients with SCD are prone to develop thrombotic complications. In addition, the altered morphology of sickle red blood cells (RBC) may also alter the properties and dynamics of clot formation in SCD patients. Clinical data and results from animal models have revealed complex interactions between coagulation, chronic hemolysis, and inflammation suggesting that activation of coagulation may contribute to the pathophysiology of SCD. PMID- 29614640 TI - Diagnostic Value of Diffusion Tensor Imaging and Positron Emission Tomography in Early Stages of Frontotemporal Dementia. AB - BACKGROUND: Due to suboptimal sensitivity and specificity of structural and molecular neuroimaging tools, the diagnosis of behavioral variant frontotemporal dementia (bvFTD) remains challenging. OBJECTIVE: Investigation of the sensitivity of diffusion tensor imaging (DTI) and fluorodeoxyglucose positron emission tomography (FDG-PET) to detect cerebral alterations in early stages of bvFTD despite inconspicuous conventional MRI. METHODS: Thirty patients with early stages of bvFTD underwent a detailed neuropsychological examination, cerebral 3T MRI with DTI analysis, and FDG-PET. After 12 months of follow-up, all patients finally fulfilled the diagnosis of bvFTD. Individual FDG-PET data analyses showed that 20 patients exhibited a "typical" pattern for bvFTD with bifrontal and/or temporal hypometabolism (bvFTD/PET+), and that 10 patients showed a "non typical"/normal pattern (bvFTD/PET-). DTI data were compared with 42 healthy controls in an individual and voxel-based group analysis. To examine the clinical relevance of the findings, associations between pathologically altered voxels of DTI or FDG-PET results and behavioral symptoms were estimated by linear regression analyses. RESULTS: DTI voxel-based group analyses revealed microstructural degeneration in bifrontal and bitemporal areas in bvFTD/PET+ and bvFTD/PET- groups. However, when comparing the sensitivity of individual DTI data analysis with FDG-PET, DTI appeared to be less sensitive. Neuropsychological symptoms were considerably related to neurodegeneration within frontotemporal areas identified by DTI and FDG-PET. CONCLUSION: DTI seems to be an interesting tool for detection of functionally relevant neurodegenerative alterations in early stages of bvFTD, even in bvFTD/PET- patients. However, at a single subject level, it seems to be less sensitive than FDG-PET. Thus, improvement of individual DTI analysis is necessary. PMID- 29614639 TI - Microparticles in sickle cell disease. AB - Several pathophysiological pathways in sickle cell disease (SCD), the most prevalent hemoglobinopathy worldwide, result in activation of circulating blood cells and the release of submicron vesicles, so-called microparticles (MPs). MPs are candidate biomarkers in vascular disease that exhibit functional biological properties. Compared to healthy individuals, higher level of plasma MPs, mostly derived from platelets and red blood cells (RBC), has been repeatedly observed in SCD patients in their steady-state condition. In contrast, conflicting results have been obtained on the impact of SCD complications and hydroxyurea treatment on circulating MP concentrations, largely due to non-standardized pre- and analytical procedures. Several factors responsible for the increased release of MPs by RBC have been identified in SCD such as sickling/unsickling, oxidative stress and abnormal activity of RBC acid sphingomyelinase. Besides their well known pro-coagulant effect, sickle RBC-derived MPs produced ex vivo can induce ROS production by endothelial cells and promote a pro-inflammatory and pro adhesive phenotype that may lead to renal occlusion in SCD mice. However, the functional properties of circulating MPs in human sickle cell disease remain to be studied and fully characterized. PMID- 29614641 TI - Neuropsychiatric Symptoms and the Diagnostic Stability of Mild Cognitive Impairment. AB - BACKGROUND: Mild cognitive impairment (MCI) is an intermediate diagnosis between normal cognition (NC) and dementia, including Alzheimer's disease (AD) dementia. However, MCI is heterogeneous; many individuals subsequently revert to NC while others remain stable at MCI for several years. Identifying factors associated with this diagnostic instability could assist in defining clinical populations and determining cognitive prognoses. OBJECTIVE: The current study examined whether neuropsychiatric symptoms could partially account for the temporal instability in cognitive diagnoses. METHOD: The sample included 6,763 participants from the National Alzheimer's Coordinating Center Uniform Data Set. All participants had NC at baseline, completed at least two follow-up visits (mean duration: 5.5 years), and had no recent neurological conditions. Generalized linear models estimated by generalized estimating equations examined associations between changes in cognitive diagnoses and symptoms on the Neuropsychiatric Inventory Questionnaire (NPI-Q) and Geriatric Depression Scale (GDS-15). RESULTS: 1,121 participants converted from NC to MCI; 324 reverted back to NC and 242 progressed to AD dementia. Higher symptoms on the GDS-15 and circumscribed symptom domains on the NPI-Q were associated with conversion from NC to MCI and a decreased likelihood of reversion from MCI to NC. Individuals with higher symptoms on NPI-Q Hyperactivity and Mood items were more likely to progress to AD dementia. DISCUSSION: The temporal instability of MCI can be partially explained by neuropsychiatric symptoms. Individuals with higher levels of specific symptoms are more likely to progress to AD dementia and less likely to revert to NC. Identification and treatment of these symptoms might support cognitive functioning in older adults. PMID- 29614642 TI - Negative 11C-PIB PET Predicts Lack of Alzheimer's Disease Pathology in Postmortem Examination. AB - Our aim was to assess whether in vivo11C-PIB negative memory-impaired subjects may nonetheless exhibit brain Alzheimer's disease (AD) pathology. We re-evaluated the PET images and systematically characterized the postmortem neuropathology of six individuals who had undergone clinically indicated amyloid PET. The single case with negligible amyloid-beta (Abeta) pathology had Lewy body disease, where concomitant AD changes are often seen. Further, the subject's plaques were predominantly diffuse. The predictive value of a negative 11C-PIB scan appears to be good, even in memory-impaired populations. Our results suggest that considerable neuritic Abeta plaque pathology in the absence of specific/cortical 11C-PIB binding upon PET is unlikely. PMID- 29614643 TI - Caregiving and Caregiver Burden in Dementia Home Care: Results from the Prospective Dementia Registry (PRODEM) of the Austrian Alzheimer Society. AB - BACKGROUND: Comprehensive studies on caregiver burden (CB) of persons caring for dementia patients differ methodologically and show variable results. OBJECTIVE: Analysis of known and hypothesized factors of CB in home care of dementia patients. METHODS: Multicenter longitudinal study comprising 585 persons caring mostly for Alzheimer's disease patients (age median 77.25 years, Mini-Mental State Examination raw score median 23) using the Zarit Caregiver Burden Interview (CBI). Known patient-related determinants of CB were studied, such as dementia severity (Clinical Dementia Rating, CDR), neuropsychological deficits (CERAD Plus), neuropsychiatric symptoms (Neuropsychiatric Inventory, NPI), disability (Disability Assessment for Dementia, DAD), dependency (Dependency Scale, DS), and moreover, unclarified potential factors (age, sex, education of patients; age, sex, occupational status of the caregivers; family relationship). Psychological and somatic effects of CB were analyzed (factor analysis). RESULTS: Caregiver age was median 61. Female caregivers prevailed (67.8%). Median CBI sum score (CBIss) was 16 at baseline. After two years, CBIss was 22 and 37% of the caregivers reported mild to moderate (CBIss 21-40), 16.8% moderate to severe or severe (>=41), and 46.2% absent to little CB (CBIss <= 20). CB correlated positively with NPI, CDR, DS scores, disability (DAD), years of education of the patients, and proximity of patient and caregiver sex (female), and negatively with caregiver age. Caregivers reported restrictions of time, health problems, and negative emotions. CONCLUSION: The findings are applicable to identify persons at risk for substantial CB and its consequences. There is demand for personal, psychological, and medical support of caregivers and increasing male participation. PMID- 29614644 TI - Visual Processing during Short-Term Memory Binding in Mild Alzheimer's Disease. AB - Patients with Alzheimer's disease (AD) typically present with attentional and oculomotor abnormalities that can have an impact on visual processing and associated cognitive functions. Over the last few years, we have witnessed a shift toward the analyses of eye movement behaviors as a means to further our understanding of the pathophysiology of common disorders such as AD. However, little work has been done to unveil the link between eye moment abnormalities and poor performance on cognitive tasks known to be markers for AD patients, such as the short-term memory-binding task. We analyzed eye movement fixation behaviors of thirteen healthy older adults (Controls) and thirteen patients with probable mild AD while they performed the visual short-term memory binding task. The short term memory binding task asks participants to detect changes across two consecutive arrays of two bicolored object whose features (i.e., colors) have to be remembered separately (i.e., Unbound Colors), or combined within integrated objects (i.e., Bound Colors). Patients with mild AD showed the well-known pattern of selective memory binding impairments. This was accompanied by significant impairments in their eye movements only when they processed Bound Colors. Patients with mild AD remarkably decreased their mean gaze duration during the encoding of color-color bindings. These findings open new windows of research into the pathophysiological mechanisms of memory deficits in AD patients and the link between its phenotypic expressions (i.e., oculomotor and cognitive disorders). We discuss these findings considering current trends regarding clinical assessment, neural correlates, and potential avenues for robust biomarkers. PMID- 29614645 TI - Structural Anatomical Investigation of Long-Term Memory Deficit in Behavioral Frontotemporal Dementia. AB - Although a growing body of work has shown that behavioral variant frontotemporal dementia (bvFTD) could present with severe amnesia in approximately half of cases, memory assessment is currently the clinical standard to distinguish bvFTD from Alzheimer's disease (AD). Thus, the concept of "relatively preserved episodic memory" in bvFTD remains the basis of its clinical distinction from AD and a criterion for bvFTD's diagnosis. This view is supported by the idea that bvFTD is not characterized by genuine amnesia and hippocampal degeneration, by contrast to AD. In this multicenter study, we aimed to investigate the neural correlates of memory performance in bvFTD as assessed by the Free and Cued Selective Reminding Test (FCSRT). Imaging explorations followed a two-step procedure, first relying on a visual rating of atrophy of 35 bvFTD and 34 AD patients' MRI, contrasted with 29 controls; and then using voxel-based morphometry (VBM) in a subset of bvFTD patients. Results showed that 43% of bvFTD patients presented with a genuine amnesia. Data-driven analysis on visual rating data showed that, in bvFTD, memory recall & storage performances were significantly predicted by atrophy in rostral prefrontal and hippocampal/perihippocampal regions, similar to mild AD. VBM results in bvFTD (pFWE<0.05) showed similar prefrontal and hippocampal regions in addition to striatal and lateral temporal involvement. Our findings showed the involvement of prefrontal as well as medial/lateral temporal atrophy in memory deficits of bvFTD patients. This contradicts the common view that only frontal deficits explain memory impairment in this disease and plead for an updated view on memory dysfunctions in bvFTD. PMID- 29614646 TI - Plasma Amyloid-beta (Abeta42) Correlates with Cerebrospinal Fluid Abeta42 in Alzheimer's Disease. AB - The 42 amino acid form of amyloid-beta (Abeta42) plays a key role in the pathogenesis of Alzheimer's disease (AD) and is a core biomarker for the diagnosis of AD. Numerous studies have shown that cerebrospinal fluid (CSF) Abeta42 concentrations are decreased in AD, when measured by enzyme-linked immunosorbent assay (ELISA) and other conventional immunoassays. While most studies report no change in plasma Abeta42, independent studies using the immunomagnetic reduction (IMR) technique report an increase in plasma Abeta42 levels in AD. To confirm the opposite changes of Abeta42 levels in CSF and plasma for AD, we assayed the levels of Abeta42 in plasma of subjects with known CSF Abeta42 levels. In total 43 controls and 63 AD patients were selected at two sites: the VU University Medical Center (n = 55) and Sahlgrenska University Hospital (n = 51). IMR and ELISA were applied to assay Abeta42 in plasma and CSF, respectively. We found a moderately negative correlation between plasma and CSF Abeta42 levels in AD patients (r = -0.352), and a weakly positive correlation in controls (r = 0.186). These findings further corroborate that there are opposite changes of Abeta42 levels in CSF and plasma in AD. The possible causes for the negative correlation are discussed by taken assay technologies, Abeta42 transport from brain to peripheral blood, and sample matrix into account. PMID- 29614647 TI - Reduced Cerebrovascular Reserve Capacity as a Biomarker of Microangiopathy in Alzheimer's Disease and Mild Cognitive Impairment. AB - BACKGROUND: Cerebral microangiopathy in Alzheimer's disease (AD) causes chronic hypoperfusion and probably accelerates neurodegenerative changes. OBJECTIVE: We hypothesize microvascular impairment could be present already in mild cognitive impairment (MCI) and can be revealed using transcranial color-coded sonography (TCCS) and the breath-holding maneuver. METHODS: Three groups of subjects (AD in the stage of dementia, MCI, and cognitively normal controls) with detailed neuropsychological testing and low cerebrovascular burden (no history of stroke, no intra- or extracranial artery stenoses, and no severe vascular lesions on brain MRI), underwent a TCCS assessment of peak systolic (PSV), mean flow (MFV), and end diastolic velocities (EDV) and resistance and pulsatility indices (RI, PI) in large intracranial vessels bilaterally. Cerebrovascular reserve capacity was assessed using the breath-holding index (BHI) in middle cerebral artery (MCA) bilaterally. The ultrasound parameters were compared between the groups, correlated with neuropsychological tests, and compared between amnestic and non amnestic MCI subtypes. RESULTS: Fourteen AD (3 males, 67.9+/-11.1 years, MMSE 18.0+/-4.6), 24 MCI (13 males, 71.9+/-7.3 years, MMSE 28.0+/-1.6), and 24 risk factor-matched controls (14 males, 67.8+/-6.4 years, MMSE 29.1+/-1.2) were enrolled. Significant differences were found between AD and controls in MFV, EDV, RI, PI in right MCA after breath holding, in PSV, MFV, EDV in left MCA after breath holding, and in BHI on the left side. The left BHI correlated positively with verbal memory test. CONCLUSION: Results show decreased cerebrovascular reserve capacity in AD as a sign of impaired cerebral hemodynamic status without severe underlying atherosclerosis. This can be identified using TCCS and BHI. PMID- 29614648 TI - Altered microRNA, mRNA, and Protein Expression of Neurodegeneration-Related Biomarkers and Their Transcriptional and Epigenetic Modifiers in a Human Tau Transgenic Mouse Model in Response to Developmental Lead Exposure. AB - Amyloid deposits originating from the amyloid-beta protein precursor (AbetaPP) and aggregates of the microtubule associated protein tau (MAPT) are the hallmarks of Alzheimer's disease (AD). Animal studies have demonstrated a link between early life exposure to lead (Pb) and latent overexpression of the AbetaPP and MAPT genes and their products via epigenetic reprogramming. The present study monitored APP gene and epigenetic mediators and transcription factors known to regulate it. Western blot analysis and quantitative polymerase chain reaction (qPCR) were used to study the mRNA, miRNA, and proteins levels of AbetaPP, specificity protein 1 (SP1; a transcriptional regulator of amyloid and tau pathway), and epigenetic intermediates namely: DNA methyltransferase (DNMT) 1, DNMT3a and Methyl- CpG protein binding 2 (MeCP2) in the cerebral cortex of transgenic mice (Knock-in for human MAPT). These transgenic mice were developmentally exposed to Pb and the impact on mRNA, miRNA, and protein levels was scrutinized on postnatal days (PND) 20 and 50. The data revealed a consistent inverse relationship between miRNA and protein levels for SP1 and AbetaPP both in the basal and exposed conditions, which may influence the levels of their corresponding proteins. On the other hand, the relationship between miRNA and protein levels was not correlative for DNMT1 and DNMT3a. MeCP2 miRNA protein levels corresponded only following environmental exposure. These results suggest that developmental exposure to Pb and subsequent AbetaPP protein levels may be controlled through transcriptional regulators and epigenetic mechanisms that mainly involve miRNA regulation. PMID- 29614649 TI - Chronic Lithium Treatment Increases Telomere Length in Parietal Cortex and Hippocampus of Triple-Transgenic Alzheimer's Disease Mice. AB - Telomere length (TL) is a biomarker of cell aging, and its shortening has been linked to several age-related diseases. In Alzheimer's disease (AD), telomere shortening has been associated with neuroinflammation and oxidative stress. The majority of studies on TL in AD were based on leucocyte DNA, with little information about its status in the central nervous system. In addition to other neuroprotective effects, lithium has been implicated in the maintenance of TL. The present study aims to determine the effect of chronic lithium treatment on TL in different regions of the mouse brain, using a triple-transgenic mouse model (3xTg-AD). Eighteen transgenic and 22 wild-type (Wt) male mice were treated for eight months with chow containing 1.0 g (Li1) or 2.0 g (Li2) of lithium carbonate/kg, or standard chow (Li0). DNA was extracted from parietal cortex, hippocampus and olfactory epithelium and TL was quantified by real-time PCR. Chronic lithium treatment was associated with longer telomeres in the hippocampus (Li2, p = 0.0159) and in the parietal cortex (Li1, p = 0.0375) of 3xTg-AD compared to Wt. Our findings suggest that chronic lithium treatment does affect telomere maintenance, but the magnitude and nature of this effect depend on the working concentrations of lithium and characteristics of the tissue. This effect was observed when comparing 3xTg-AD with Wt mice, suggesting that the presence of AD pathology was required for the lithium modulation of TL. PMID- 29614650 TI - The Progression of Dementia and Cognitive Decline in a Dutch 2-Year Cohort Study of People with Young-Onset Dementia. AB - BACKGROUND: The progression of dementia in people with young-onset dementia (YOD) is relatively unknown. OBJECTIVE: To investigate the progression of dementia and cognitive decline in the three most common subtypes in YOD and to explore which factors are associated with this course. METHODS: The course of dementia was examined in 198 people with YOD. The primary outcomes were cognitive function, as assessed by the Mini-Mental State Examination (MMSE) and dementia severity, as assessed by the Global Deterioration Scale (GDS). Mixed-model analyses were used to explore factors associated with the course of dementia of the diagnostic sub types. RESULTS: The mean overall two-year progression of dementia severity was 0.9 GDS points, this was a statistically significant change (p = 0.012) and was not significant different for the three dementia subtypes. The mean overall two year decline in cognitive function was 1.6 points on the MMSE. The differences in cognitive decline were statistically significant (p = 0.046) among the three diagnosis groups, AD participants showed the greatest decline, of 2.3 points. In addition to lower education (p = 0.010), higher scores on the Neuropsychiatric Inventory (NPI) sub-syndromes psychosis (p < 0.001) and hyperactivity (p = 0.002) were associated with higher rates of cognitive decline. In contrast, higher scores on the NPI affect cluster were associated with lower levels of cognitive decline (p < 0.001). CONCLUSION: Different YOD subtypes show different rates of decline in cognitive functioning, and this decline seems less progressive compared to those observed in studies in late-onset AD. Further research is needed to evaluate whether managing neuropsychiatric symptoms can positively influence the decline of cognitive function. PMID- 29614651 TI - Amyloid-beta Induces AMPA Receptor Ubiquitination and Degradation in Primary Neurons and Human Brains of Alzheimer's Disease. AB - As the primary mediator for synaptic transmission, AMPA receptors (AMPARs) are crucial for synaptic plasticity and higher brain functions. A downregulation of AMPAR expression has been indicated as one of the early pathological molecular alterations in Alzheimer's disease (AD), presumably via amyloid-beta (Abeta). However, the molecular mechanisms leading to the loss of AMPARs remain less clear. We report that in primary neurons, application of Abeta triggers AMPAR internalization accompanied with a decrease in cell-surface AMPAR expression. Importantly, in both Abeta-treated neurons and human brain tissue from AD patients, we observed a significant decrease in total AMPAR amount and an enhancement in AMPAR ubiquitination. Consistent with facilitated receptor degradation, AMPARs show higher turnover rates in the presence of Abeta. Furthermore, AD brain lysates and Abeta-incubated neurons show increased expression of the AMPAR E3 ligase Nedd4 and decreased expression of AMPAR deubiquitinase USP46. Changes in these enzymes are responsible for the Abeta dependent AMPAR reduction. These findings indicate that AMPAR ubiquitination acts as the key molecular event leading to the loss of AMPARs and thus suppressed synaptic transmission in AD. PMID- 29614652 TI - Single Subject Classification of Alzheimer's Disease and Behavioral Variant Frontotemporal Dementia Using Anatomical, Diffusion Tensor, and Resting-State Functional Magnetic Resonance Imaging. AB - BACKGROUND/OBJECTIVE: Overlapping clinical symptoms often complicate differential diagnosis between patients with Alzheimer's disease (AD) and behavioral variant frontotemporal dementia (bvFTD). Magnetic resonance imaging (MRI) reveals disease specific structural and functional differences that aid in differentiating AD from bvFTD patients. However, the benefit of combining structural and functional connectivity measures to-on a subject-basis-differentiate these dementia-types is not yet known. METHODS: Anatomical, diffusion tensor (DTI), and resting-state functional MRI (rs-fMRI) of 30 patients with early stage AD, 23 with bvFTD, and 35 control subjects were collected and used to calculate measures of structural and functional tissue status. All measures were used separately or selectively combined as predictors for training an elastic net regression classifier. Each classifier's ability to accurately distinguish dementia-types was quantified by calculating the area under the receiver operating characteristic curves (AUC). RESULTS: Highest AUC values for AD and bvFTD discrimination were obtained when mean diffusivity, full correlations between rs-fMRI-derived independent components, and fractional anisotropy (FA) were combined (0.811). Similarly, combining gray matter density (GMD), FA, and rs-fMRI correlations resulted in highest AUC of 0.922 for control and bvFTD classifications. This, however, was not observed for control and AD differentiations. Classifications with GMD (0.940) and a GMD and DTI combination (0.941) resulted in similar AUC values (p = 0.41). CONCLUSION: Combining functional and structural connectivity measures improve dementia-type differentiations and may contribute to more accurate and substantiated differential diagnosis of AD and bvFTD patients. Imaging protocols for differential diagnosis may benefit from also including DTI and rs-fMRI. PMID- 29614653 TI - Added Diagnostic Value of Cerebrospinal Fluid Biomarkers for Differential Dementia Diagnosis in an Autopsy-Confirmed Cohort. AB - BACKGROUND: Differential dementia diagnosis remains a challenge due to overlap of clinical profiles, which often results in diagnostic doubt. OBJECTIVE: Determine the added diagnostic value of cerebrospinal fluid (CSF) biomarkers for differential dementia diagnosis as compared to autopsy-confirmed diagnosis. METHODS: Seventy-one dementia patients with autopsy-confirmed diagnoses were included in this study. All neuropathological diagnoses were established according to standard neuropathological criteria and consisted of Alzheimer's disease (AD) or other dementias (NONAD). CSF levels of Abeta1 - 42, T-tau, and P tau181 were determined and interpreted based on the IWG-2 and NIA-AA criteria, separately. A panel of three neurologists experienced with dementia made clinical consensus dementia diagnoses. Clinical and CSF biomarker diagnoses were compared to the autopsy-confirmed diagnoses. RESULTS: Forty-two patients (59%) had autopsy confirmed AD, whereas 29 patients (41%) had autopsy-confirmed NONAD. Of the 24 patients with an ambiguous clinical dementia diagnosis, a correct diagnosis would have been established in 67% of the cases applying CSF biomarkers in the context of the IWG-2 or the NIA-AA criteria respectively. CONCLUSION: AD CSF biomarkers have an added diagnostic value in differential dementia diagnosis and can help establishing a correct dementia diagnosis in case of ambiguous clinical dementia diagnoses. PMID- 29614654 TI - Automated Multi-Atlas Segmentation of Hippocampal and Extrahippocampal Subregions in Alzheimer's Disease at 3T and 7T: What Atlas Composition Works Best? AB - BACKGROUND: Multi-atlas segmentation, a popular technique implemented in the Automated Segmentation of Hippocampal Subfields (ASHS) software, utilizes multiple expert-labelled images ("atlases") to delineate medial temporal lobe substructures. This multi-atlas method is increasingly being employed in early Alzheimer's disease (AD) research, it is therefore becoming important to know how the construction of the atlas set in terms of proportions of controls and patients with mild cognitive impairment (MCI) and/or AD affects segmentation accuracy. OBJECTIVE: To evaluate whether the proportion of controls in the training sets affects the segmentation accuracy of both controls and patients with MCI and/or early AD at 3T and 7T. METHODS: We performed cross-validation experiments varying the proportion of control subjects in the training set, ranging from a patient-only to a control-only set. Segmentation accuracy of the test set was evaluated by the Dice similarity coeffiecient (DSC). A two-stage statistical analysis was applied to determine whether atlas composition is linked to segmentation accuracy in control subjects and patients, for 3T and 7T. RESULTS: The different atlas compositions did not significantly affect segmentation accuracy at 3T and for patients at 7T. For controls at 7T, including more control subjects in the training set significantly improves the segmentation accuracy, but only marginally, with the maximum of 0.0003 DSC improvement per percent increment of control subject in the training set. CONCLUSION: ASHS is robust in this study, and the results indicate that future studies investigating hippocampal subfields in early AD populations can be flexible in the selection of their atlas compositions. PMID- 29614656 TI - Exposure to General Anesthesia and Risk of Dementia: A Nationwide Population Based Cohort Study. AB - BACKGROUND: There is a growing concern that general anesthesia could increase the risk of dementia. However, the relationship between anesthesia and subsequent dementia is still undetermined. OBJECTIVE: To determine whether the risk of dementia increases after exposure to general anesthesia. METHODS: A population based prospective cohort study analyzing the Korean National Health Insurance Service-National Sample Cohort database was conducted of all persons aged over 50 years (n = 219,423) from 1 January 2003 and 31 December 2013. RESULTS: 44,956 in the general anesthesia group and 174,469 in the control group were followed for 12 years. The risk of dementia associated with previous exposure to general anesthesia was increased after adjusting for all covariates such as gender, age, health care visit frequency, and co-morbidities (Hazard ratio = 1.285, 95% confidence interval = 1.262-1.384, time-varying Cox hazard model). In addition, the number of anesthetic agents administered, the number of exposures to general anesthesia, the cumulative exposure time, and the organ category involved in surgery were associated with risk of dementia. CONCLUSION: In light of the increasing societal burden of dementia, careful surveillance for dementia and prevention guidelines for patients after general anesthesia are needed. PMID- 29614655 TI - Low Cerebrospinal Fluid Abeta42 and Abeta40 are Related to White Matter Lesions in Cognitively Normal Elderly. AB - BACKGROUND: Low cerebrospinal fluid (CSF) levels of Abeta42 may be the earliest manifestation of Alzheimer's disease (AD). Knowledge on how CSF Abeta interacts with different brain pathologies early in the disease process is limited. We examined how CSF Abeta markers relate to brain atrophy and white matter lesions (WMLs) in octogenarians with and without dementia to explore the earliest pathogenetic pathways of AD in the oldest old. OBJECTIVE: To study CSF amyloid biomarkers in relation to brain atrophy and WMLs in 85-year-olds with and without dementia. METHODS: 53 octogenarians took part in neuropsychiatric examinations and underwent both a lumbar puncture and a brain CT scan. CSF levels of Abeta42 and Abeta40 were examined in relation to cerebral atrophy and WMLs. Dementia was diagnosed. RESULTS: In 85-year-olds without dementia, lower levels of both CSF Abeta42 and CSF Abeta40 were associated with WMLs. CSF Abeta42 also correlated with measures of central atrophy, but not with cortical atrophy. In participants with dementia, lower CSF levels of Abeta42 were related to frontal, temporal, and parietal cortical atrophy but not to WMLs. CONCLUSIONS: Our findings may suggest that there is an interrelationship between Abeta and subcortical WMLs in older persons without dementia. After onset of dementia, low CSF Abeta42, probably representing amyloid deposition in plaques, is associated with cortical atrophy. WMLs may be an earlier manifestation of Abeta deposition than cortical degeneration. PMID- 29614659 TI - Cardiorespiratory Fitness and Cognitive Function are Positively Related Among Participants with Mild and Subjective Cognitive Impairment. AB - BACKGROUND: By 2030, about 74 million people will be diagnosed with dementia, and many more will experience subjective (SCI) or mild cognitive impairment (MCI). As physical inactivity has been identified to be a strong modifiable risk factor for dementia, exercise and physical activity (PA) may be important parameters to predict the progression from MCI to dementia, but might also represent disease trajectory modifying strategies for SCI and MCI. OBJECTIVE: A better understanding of the relationship between activity, fitness, and cognitive function across the spectrum of MCI and SCI would provide an insight into the potential utility of PA and fitness as early markers, and treatment targets to prevent cognitive decline. METHODS: 121 participants were stratified into three groups, late MCI (LMCI), early MCI (EMCI), and SCI based on the Montreal Cognitive Assessment (MoCA). Cognitive function assessments also included the Trail Making Test A+B, and a verbal fluency test. PA levels were evaluated with an interviewer-administered questionnaire (LAPAQ) and an activity monitor. An incremental exercise test was performed to estimate cardiorespiratory fitness and to determine exercise capacity relative to population normative data. RESULTS: ANCOVA revealed that LMCI subjects had the lowest PA levels (LAPAQ, p = 0.018; activity monitor, p = 0.041), and the lowest exercise capacity in relation to normative values (p = 0.041). Moreover, a modest correlation between MoCA and cardiorespiratory fitness (r = 0.25; p < 0.05) was found. CONCLUSION: These findings suggest that during the earliest stages of cognitive impairment PA and exercise capacity might present a marker for the risk of further cognitive decline. This finding warrants further investigation using longitudinal cohort studies. PMID- 29614657 TI - Cerebral Amyloid Angiopathy: Similarity in African-Americans and Caucasians with Alzheimer's Disease. AB - Cerebral amyloid angiopathy (CAA) of the Abeta type is variably present in the brains of patients with Alzheimer's disease (AD). CAA contributes to cognitive decline and increases the risk of lobar hemorrhage; because both AD-typical dementia and lobar hemorrhage are more common in African-Americans than in Caucasians, we postulated that African-Americans with AD might be particularly susceptible to CAA. To test this hypothesis, we analyzed CAA histopathologically in the large vessels and capillaries of autopsy-derived frontal, temporal, parietal, and occipital cortical samples from African-Americans (n = 18) and Caucasians (n = 19) with end-stage AD. In the combined cohort of 37 subjects, 22% of the subjects had severe CAA in large vessels, and 11% had severe CAA in capillaries. However, the prevalence and histopathologic characteristics of CAA were similar in the African-Americans and Caucasians. This conclusion was substantiated in an independent sample from the National Alzheimer's Coordinating Center database, in which the degree of CAA was comparable in 1,554 Caucasians and 68 African-Americans with end-stage AD. These findings support a growing consensus that the fundamental histopathologic features of AD are largely impartial to the race of the afflicted. PMID- 29614658 TI - Separating Symptomatic Alzheimer's Disease from Depression based on Structural MRI. AB - Older patients with depression or Alzheimer's disease (AD) at the stage of early dementia or mild cognitive impairment may present with objective cognitive impairment, although the pathology and thus therapy and prognosis differ substantially. In this study, we assessed the potential of an automated algorithm to categorize a test set of 65 T1-weighted structural magnetic resonance images (MRI). A convenience sample of elderly individuals fulfilling clinical criteria of either AD (n = 28) or moderate and severe depression (n = 37) was recruited from different settings to assess the potential of the pattern recognition method to assist in the differential diagnosis of AD versus depression. We found that our algorithm learned discriminative patterns in the subject's grey matter distribution reflected by an area under the receiver operator characteristics curve of up to 0.83 (confidence interval ranged from 0.67 to 0.92) and a balanced accuracy of 0.79 for the separation of depression from AD, evaluated by leave-one out cross validation. The algorithm also identified consistent structural differences in a clinically more relevant scenario where the data used during training were independent from the data used for evaluation and, critically, which included five possible diagnoses (specifically AD, frontotemporal dementia, Lewy body dementia, depression, and healthy aging). While the output was insufficiently accurate to use it directly as a means for classification when multiple classes are possible, the continuous output computed by the machine learning algorithm differed between the two groups that were investigated. The automated analysis thus could complement, but not replace clinical assessments. PMID- 29614660 TI - Stimulation of SIRT1 Attenuates the Level of Oxidative Stress in the Brains of APP/PS1 Double Transgenic Mice and in Primary Neurons Exposed to Oligomers of the Amyloid-beta Peptide. AB - In the study, we examined whether the silent information regulator 1 (SIRT1) can attenuate oxidative stress in the brains of mice carrying the APP/PS1 double mutation and/or in primary neonatal rat neurons exposed to oligomers of amyloid beta peptide (AbetaOs). Starting at 4 or 8 months of age, the transgenic mice were treated with resveratrol (RSV, a stimulator of SIRT1) or suramin (an inhibitor) (each 20 mg/kg BW/day) for two months. The primary neurons were exposed to AbetaOs (0.5 MUM) for 48 h and thereafter RSV (20 MUM) or suramin (300 mg/ml) for 24 h. Cell viability was assessed by the CCK-8 assay; SIRT1 protein and mRNA determined by western blotting and real-time PCR, respectively; senile plaques examined immunohistochemically; ROS monitored by flow cytometry; and the contents of OH-, H2O2, O2.-, and MDA, and the activities of SOD and GSH-Px measured by standard biochemical procedures. In comparison to wild-type mice or untreated primary neurons, the expression of SIRT1 was significantly lower in the brains of APP/PS1 mice or neurons exposed to AbetaOs. In these same systems, increased numbers of senile plaques and a high level of oxidative stress were apparent. Interestingly, these two latter changes were attenuated by treatment with RSV, but enhanced by suramin. These findings indicate that SIRT1 may be neuroprotective. PMID- 29614662 TI - Some Methodological Characteristics of Alzheimer-Associated Urine Neuronal Thread Protein Detected by Enzyme-Linked Immunosorbent Assay. AB - BACKGROUND: Alzheimer-associated neuronal thread protein (AD7c-NTP) has been found to be a candidate biomarker of Alzheimer's disease (AD). OBJECTIVE: To investigate the effects of urine collected time, different preservatives addition, and storage condition on the measurement of urine AD7c-NTP by enzyme linked immunosorbent assay (ELISA). METHODS: Three hundred urine samples were collected from 20 participants at three time points on five consecutive days. These samples were immediately placed at 4 degrees C and detected within 2 h. The single spot samples of the first day morning were split into eleven duplicate aliquots (a-k) of 1 ml each, (a) without any preservative (untreated), (b) containing boric acid (2 g/L), (c) containing NaHCO3 (5 g/L), (a-c) were detected at six different time points. For the other eight preservative-free samples, (d g) were stored at -20 degrees C and (h-k) were stored at -70 degrees C, respectively, detected at different time points. All of the results were compared with the baseline urine. RESULTS: The urine AD7c-NTP levels at different time points behaved stably (p > 0.05). Urine samples without any preservative increased over time, and compared with the NaHCO3 addition group, boric acid addition group behaved stably. Samples stored at -20 degrees C and -70 degrees C led to an obviously false positive. CONCLUSIONS: AD7c-NTP can be tested using random urine instead of the first morning urine. If the specimen cannot be tested in time, boric acid appears to be an acceptable preservative with storage at 4 degrees C, freezing is not recommended. PMID- 29614661 TI - Hippocampal Sclerosis in the Oldest Old: A Finnish Population-Based Study. AB - BACKGROUND: There are only few population-based studies that have systemically investigated the prevalence of hippocampal sclerosis (HS) in the very old. The frequency of unilateral versus bilateral HS has been rarely studied. OBJECTIVE: We investigated the prevalence and laterality of HS and its association with other neurodegenerative and vascular pathologies in a population-based sample of very elderly. Furthermore, the concomitant presence of immunoreactivity for TDP 43, p62, and HPtau was studied. METHODS: The population-based Vantaa 85+ study includes all inhabitants of the city of Vantaa, who were >85 years in 1991 (n = 601). Neuropathological assessment was possible in 302 subjects. Severity of neuronal loss of CA sectors and subiculum was determined bilaterally by HE- staining. Immunohistochemistry performed using antibodies for TDP-43, p62, and HPtau. RESULTS: Neuronal loss and pathological changes in the hippocampus sector CA1 and subiculum were observed in 47 of the 302 individuals (16%), and 51% of these changes were bilateral. HS without comorbid neurodegenerative pathology was found in 1/47 subjects with HS (2%). Dementia (p < 0.001) and TDP-43 immunopositivity of the granular cell layer of the dentate fascia (p < 0.001) were strongly associated with HS. The CERAD score, immunopositivity for HPtau and p62 in the granular cell layer of the fascia dentate were also associated. CONCLUSION: HS is prevalent (16%) in the oldest old population, but HS without any comorbid neurodegenerative pathology is rare. The high frequency of unilateral HS (49%) implied that bilateral sampling of hippocampi should be routine practice in neuropathological examination. PMID- 29614663 TI - Sulforaphane Inhibits the Generation of Amyloid-beta Oligomer and Promotes Spatial Learning and Memory in Alzheimer's Disease (PS1V97L) Transgenic Mice. AB - Abnormal amyloid-beta (Abeta) aggregates are a striking feature of Alzheimer's disease (AD), and Abeta oligomers have been proven to be crucial in the pathology of AD. Any intervention targeting the generation or aggregation of Abeta can be expected to be useful in AD treatment. Oxidative stress and inflammation are common pathological changes in AD that are involved in the generation and aggregation of Abeta. In the present study, 6-month-old PS1V97L transgenic (Tg) mice were treated with sulforaphane, an antioxidant, for 4 months, and this treatment significantly inhibited the generation and aggregation of Abeta. Sulforaphane also alleviated several downstream pathological changes that including tau hyperphosphorylation, oxidative stress, and neuroinflammation. Most importantly, the cognition of the sulforaphane-treated PS1V97L Tg mice remained normal compared to that of wild-type mice at 10 months of age, when dementia typically emerges in PS1V97L Tg mice. Pretreating cultured cortical neurons with sulforaphane also protected against neuronal injury caused by Abeta oligomers in vitro. These findings suggest that sulforaphane may be a potential compound that can inhibit Abeta oligomer production in AD. PMID- 29614664 TI - Gait in Mild Alzheimer's Disease: Feasibility of Multi-Center Measurement in the Clinic and Home with Body-Worn Sensors: A Pilot Study. AB - Gait is emerging as a potential diagnostic tool for cognitive decline. The 'Deep and Frequent Phenotyping for Experimental Medicine in Dementia Study' (D&FP) is a multicenter feasibility study embedded in the United Kingdom Dementia Platform designed to determine participant acceptability and feasibility of extensive and repeated phenotyping to determine the optimal combination of biomarkers to detect disease progression and identify early risk of Alzheimer's disease (AD). Gait is included as a clinical biomarker. The tools to quantify gait in the clinic and home, and suitability for multi-center application have not been examined. Six centers from the National Institute for Health Research Translational Research Collaboration in Dementia initiative recruited 20 individuals with early onset AD. Participants wore a single wearable (tri-axial accelerometer) and completed both clinic-based and free-living gait assessment. A series of macro (behavioral) and micro (spatiotemporal) characteristics were derived from the resultant data using previously validated algorithms. Results indicate good participant acceptability, and potential for use of body-worn sensors in both the clinic and the home. Recommendations for future studies have been provided. Gait has been demonstrated to be a feasible and suitable measure, and future research should examine its suitability as a biomarker in AD. PMID- 29614665 TI - Blood Inflammatory Mediators and Cognitive Decline in Alzheimer's Disease: A Two Years Longitudinal Study. AB - Peripheral inflammatory processes are involved in Alzheimer's disease (AD). We aimed to determine whether plasma inflammatory mediator levels at diagnosis are associated with cognitive decline through a 2-year follow-up in AD patients. Patients (n = 109, mean age 79.44 (6.82) years) were included at diagnosis with MMSE scores between 16 and 25, with C-reactive protein <10 mg/L, and without any acute or chronic inflammation status. Plasma IL-1beta, IL-6, TNF-alpha, and CCL5 were measured using Luminex X-MAP technology at baseline, and after one year and two years of follow-up. The mean values of IL-1beta, IL-6, TNF-alpha, and CCL5 at diagnosis were 0.3, 1.94, 6.57, and 69,615.81 pg/mL, respectively. Mean cognitive decline in MMSE was 3.35 points. No correlation between plasmatic value of IL 1beta, IL-6, TNF-alpha, or CCL5 at diagnosis and cognitive decline during the two years of follow-up was found. Cognitive decline in AD does not appear to be predictable by the tested inflammatory mediators. PMID- 29614666 TI - Post Traumatic Stress Disorder Heralding the Onset of Semantic Frontotemporal Dementia. AB - BACKGROUND: Post traumatic stress disorder (PTSD) is associated with cognitive decline. The dementia type following PTSD is unclear. OBJECTIVE: To assess whether PTSD is associated with a specific dementia. METHODS: Prospective study: 46 PTSD patients (DSM-IV-TR) were followed for 6-10 years with clinical, neuropsychological, imaging evaluations for possible development of dementia.Retrospective study:849 dementia patients followed during 1999-2014 (509 Alzheimer's disease, AD; 207 dementia with Lewy bodies, DLB; 90 vascular dementia, VaD; 43 frontotemporal dementia, FTD) and 287 patients with any neurological condition (including patients with/without dementia) were evaluated for the presence of PTSD in their history. RESULTS: Prospective study: 8 patients developed dementia; 1 AD, 1 DLB, 6 semantic FTD (13.0% of the PTSD population). Retrospective study: 38 patients (4.5%) had a history of PTSD; 3.5% of AD, 4.3% of DLB, 14.0% of FTD, 5.6% of VaD. The percentage was higher in FTD than in AD or DLB (chi2 = 10, p = 0.001, and chi2 = 6, p = 0.02). At difference with AD, DLB, or VaD, FTD incidence among dementia patients with PTSD history (38 patients) was higher than in the dementia population overall (16% versus 5%, chi2 = 8, p = 0.005). The impact of possible demographical/clinical confounders (age, gender, MMSE) was excluded by Poisson regression. PTSD prevalence in the comparative group without dementia matched the prevalence in the Italian general population (1.1%). PTSD prevalence in the demented comparative group matched the prevalence in our dementia retrospective cohort, 3.7%). DISCUSSION: PTSD was associated with the development of semantic FTD. PMID- 29614668 TI - A Study of a Supplement Containing Huperzine A and Curcumin in Dementia Patients and Individuals with Mild Cognitive Impairment. AB - Extracts from Huperzia serrata (HS) function as a cholinesterase inhibitor and a glutamic acid receptor antagonist. We tested a supplement containing HS extracts, curcumin, and others in dementia patients and individuals with mild cognitive impairment (MCI) in an open label study. Most patients with Alzheimer's disease, dementia with Lewy bodies, and MCI individuals exhibited improvements in cognitive functions, as assessed by the Alzheimer's Disease Assessment Scale cognitive subscale Japanese version. The scores were significantly improved at 6 12 weeks compared with baseline scores (p = 0.007) and at 22-28 weeks (p = 0.004). Thus, this supplement may be administered to dementia patients as well as MCI individuals. PMID- 29614667 TI - Leisure-Time Physical Activity and the Risk of Incident Dementia: The Mayo Clinic Study of Aging. AB - We conducted a prospective cohort study derived from the population-based Mayo Clinic Study of Aging. We investigated if leisure-time physical activity among individuals with mild cognitive impairment (MCI) was associated with a decreased risk of developing dementia. 280 persons aged>=70 years (median 81 years, 165 males) with MCI and available data from neurologic evaluation, neuropsychological testing, and questionnaire-based physical activity assessment, were followed for a median of 3 years to the outcomes of incident dementia or censoring variables. We conducted Cox proportional hazards regression analyses with age as a time scale and adjusted for sex, education, medical comorbidity, depression, and APOE E4 status. Moderate intensity midlife physical activity among MCI participants was significantly associated with a decreased risk of incident dementia (HR = 0.64; 95% CI, 0.41-0.98). There was a non-significant trend for a decreased risk of dementia for light and vigorous intensity midlife physical activity, as well as light and moderate intensity late-life physical activity. In conclusion, we observed that physical activity may be associated with a reduced risk of dementia among individuals with MCI. Furthermore, intensity and timing of physical activity may be important factors when investigating this association. PMID- 29614669 TI - Harpagoside Rescues the Memory Impairments in Chronic Cerebral Hypoperfusion Rats by Inhibiting PTEN Activity. AB - Vascular dementia (VaD) is the second most common dementia worldwide. Unlike Alzheimer's disease, VaD does not yet have effective therapeutic drugs. Harpagoside is the most important component extracted from Harpagophytum procumbens, a traditional Chinese medicine that has been widely used. The neuroprotective effects of harpagoside have been studied in Abeta- and MPTP induced neurotoxicity. However, whether harpagoside is protective against VaD is not clear. In this study, with the use of chronic cerebral hypoperfusion rats, a well-known VaD model, we demonstrated that chronic administration (two months) of harpagoside was able to restore both the spatial learning/memory and fear memory impairments. Importantly, the protective effects of harpagoside were not due to alterations in the physiological conditions, metabolic parameters, or locomotor abilities of the rats. Meanwhile, we found that harpagoside suppressed the overactivation of PTEN induced by CCH by enhancing PTEN phosphorylation. Furthermore, harpagoside elevated the activity of Akt and inhibited the activity of GSK-3beta, downstream effectors of PTEN. Overall, our study suggested that harpagoside treatment might be a potential therapeutic drug targeting the cognitive impairments of VaD. PMID- 29614670 TI - Consent to Medical Procedures of Patients with Neurodegenerative Diseases: A Comparative Study of Legal Regulations in Selected European Countries and in the United States. AB - According to the projections of the statistical office of the European Union, Eurostat, nearly one third of EU citizens will be at least 65 in 2060. The U.S. population age 65 and older continues to increase and is projected to nearly double from 48 million to 88 million by 2050. Elderly people are especially exposed to neurodegenerative diseases (NDs). The most common ND is Alzheimer's disease (AD), a chronic and progressive disorder with a variety of pathological changes within neuronal tissue, which begin even 10-15 years before the onset of cognitive impairment symptoms. AD is perceived as a disease continuum and considered to include three basic phases: preclinical (asymptomatic) stage, mild cognitive impairment (MCI), and dementia due to AD. A very important issue, from medical and legal perspectives, is the NDs patient's consent to medical procedures, including diagnostic procedures, such as lumber puncture. NDs patients are not always able to express their consent and do not always understand the information provided by a physician. This applies to a group of patients in the final stages of NDs. This paper presents legal regulations of selected European countries and signalizes the U.S. legal solutions on the issue of NDs patients' informed consent to medical procedures. PMID- 29614672 TI - Our Tau Tales from Normal to Pathological Behavior. AB - The microtubule associated protein tau in a hyperphosphorylated form was identified as the building block of the filamentous aggregates found in the neurons of Alzheimer's disease (AD) patients. In the abnormal state, hyperphosphorylated tau from AD brains (AD P-tau) was unable to promote microtubule assembly and more importantly, it could inhibit the normal activity of tau and other MAPs. AD P-tau was able to disrupt preformed microtubules and, by binding to normal tau, turn the latter into an AD P-tau like molecule. AD P tau toxic behavior was prevalent in the soluble form and it was lost upon dephosphorylation. Mutations on tau associated with disease, e.g., R406W in frontotemporal dementia with Parkinsonism linked to chromosome 17, altered its conformation to make it a better substrate for kinases. Using phospho-mimetics, it was found that the minimum phospho-sites necessary to acquire such a toxic behavior of tau were at 199, 212, 231 and 262, and tau pseudophosphorylated at those sites in combination with R406W was named Pathological Human Tau (PH-Tau). PH-Tau expressed in cells had similar behavior to AD P-tau: disruption of the microtubule system, change in the normal subcellular localization, and gain of toxic function for cells. In animal models expressing PH-Tau, it was found that two putative mechanisms of neurodegeneration exist depending on the concentration of the toxic protein, both involving cognitive decline, due to synaptic dysfunction at lower concentration and neuronal death at higher. Studies investigating the mechanism of tau pathology and its transmission from neuron to neuron are currently ongoing. PMID- 29614671 TI - A Blood Test for Alzheimer's Disease: Progress, Challenges, and Recommendations. AB - Ever since the discovery of APOEE4 around 25 years ago, researchers have been excited about the potential of a blood test for Alzheimer's disease (AD). Since then researchers have looked for genetic, protein, metabolite, and/or gene expression markers of AD and related phenotypes. However, no blood test for AD is yet being used in the clinical setting. We first review the trends and challenges in AD blood biomarker research, before giving our personal recommendations to help researchers overcome these challenges. While some degree of consistency and replication has been seen across independent studies, several high-profile studies have seemingly failed to replicate. Partly due to academic incentives, there is a reluctance in the field to report predictive ability, to publish negative findings, and to independently replicate the work of others. If this can be addressed, then we will know sooner whether a blood test for AD or related phenotypes with clinical utility can be developed. PMID- 29614673 TI - Findings from the Swedish Study on Familial Alzheimer's Disease Including the APP Swedish Double Mutation. AB - This is a brief summary of the findings from the Swedish study on familial Alzheimer's disease (FAD). Similar to other FAD studies, it includes prospective assessments of cognitive function, tissue sampling, and technical analyses such as MRI and PET. This 24-year-old study involves 69 individuals with a 50% risk of inheriting a disease-causing mutation in presenilin 1 (PSEN1 H163Y or I143T), or amyloid precursor protein (the Swedish APP or the arctic APP mutation) who have made a total of 169 visits. Our results show the extraordinary power in this study design to unravel the earliest changes in preclinical AD. The Swedish FAD study will continue and future research will focus on disentangling the order of pathological change using longitudinal data as well as modeling the changes in patient derived cell systems. PMID- 29614674 TI - Optical Depolarization of DCX-Expressing Cells Promoted Cognitive Recovery and Maturation of Newborn Neurons via the Wnt/beta-Catenin Pathway. AB - Electrical excitability by membrane depolarization is crucial for survival and maturation of newborn cells in the dentate gyrus of the hippocampus. However, traditional technology for membrane depolarization lacks temporal and spatial precision. Optogenetics can be used to activate channelrhodopsin-2 (ChR2), allowing cationic current to depolarize genetically targeted cells. In this study, we used ChR2-EGFP driven by doublecortin (DCX) to promote survival and maturation of newborn cells in the dentate gyrus after traumatic brain injury (TBI). C57BL/6 mice underwent lateral fluid percussion TBI. TBI mice were transfected with a lentivirus carrying the DCX-ChR2-EGFP gene. We observed that not only immature neurons but also type-2b intermediate progenitor (IPs) and neuroblasts expressed DCX-EGFP, indicating that DCX-expressing newborn cells could provide a long time window for electrical activity regulation. Quantitative results showed that the number of EGFP-expressing cells began to rise at 3 days after TBI and peaked at 9 days after TBI. By optical depolarization of DCX-EGFP expressing cells between 3 and 12 days, we observed significantly improved cognitive deficits after TBI with enhanced survival and maturation of newborn cells in the dentate gyrus. We also investigated the role of optical depolarization in neural stem cells transfected with a lentivirus carrying the ChR2-DCX-EGFP gene in vitro. By administrating verapamil to block L-type calcium channels, we verified that the up-regulation of MAP2, NeuN, Neurog2, NeuroD1 and GluR2 in newborn cells was mediated by ChR2-elicted depolarization. By using beta catenin inhibitor Dkk1, we demonstrated that optical depolarization of DCX-EGFP expressing cells facilitated survival and maturation probably through the Wnt/beta-catenin signaling cascade. PMID- 29614675 TI - The Vascular Hypothesis of Alzheimer's Disease: A Key to Preclinical Prediction of Dementia Using Neuroimaging. AB - The vascular hypothesis of Alzheimer's disease (VHAD) was proposed 24 years ago from observations made in our laboratory using aging rats subjected to chronic brain hypoperfusion. In recent years, VHAD has become a mother-lode to numerous neuroimaging studies targeting cerebral hemodynamic changes, particularly brain hypoperfusion in elderly patients at risk of developing Alzheimer's disease (AD). There is a growing consensus among neuroradiologists that brain hypoperfusion is likely involved in the pathogenesis of AD and that disturbed cerebral blood flow (CBF) can serve as a key biomarker for predicting conversion of mild cognitive impairment to AD. The use of cerebral hypoperfusion as a preclinical predictor of AD is becoming decisive in stratifying low and high risk patients that may develop cognitive decline and for assessing the effectiveness of therapeutic interventions. There is currently an international research drive from neuroimaging groups to seek new perspectives that can broaden our understanding of AD and improve lifestyle. Diverse neuroimaging methods are currently being used to monitor normal and dyscognitive brain activity. Some techniques are very powerful and can detect, diagnose, quantify, prognose, and predict cognitive decline before AD onset, even from a healthy cognitive state. Multimodal imaging offers new insights in the treatment and prevention of cognitive decline during advanced aging and better understanding of the functional and structural organization of the human brain. This review discusses the impact the VHAD and CBF are having on the neuroimaging technology that can usher practical strategies to help prevent AD. PMID- 29614677 TI - 18F-Flortaucipir Binding in Choroid Plexus: Related to Race and Hippocampus Signal. AB - BACKGROUND: On target 18F-Flortaucipir (FTP) binding of Alzheimer's disease tau aggregates and off-target binding of melanocytes have been demonstrated with autoradiography. OBJECTIVE: We aimed to investigate the hypothesis that if binding in choroid plexus (CP) is due to melanocytes, the signal would be elevated in Black/African American (B/AA) compared to White (W) participants. In addition, we examined whether CP signal affects measurements in adjacent regions, and whether correcting for spill-in effects has an influence on associations between hippocampus (HC) FTP and amyloid or cognition. METHODS: FTP race differences in 147 Harvard Aging Brain Study participants (23 B/AA, 124W) were examined in CP, HC, HC covaried for CP, amygdala, inferior temporal gyrus, entorhinal cortex, and fusiform regions. Associations between CP FTP and other regions-of-interest (ROIs) were probed to assess spill-in effects. A statistical regression approach to attenuate CP spill-in was tested by relating adjusted HC SUVR residuals and unadjusted HC SUVR to race, cognition and amyloid. All analyses were covaried for age, sex, education and amyloid deposition, and Bonferroni-corrected for multiple comparisons. RESULTS: B/AA individuals had elevated CP and HC SUVR (p < 0.007), whereas other ROI SUVR and HC SUVR covaried for CP SUVR did not show race differences (p > 0.05). CP SUVR was associated with HC SUVR (p < 10-14), but with no other ROI SUVR (p > 0.05). When adjusting HC SUVR for CP SUVR, no race differences in residual HC SUVR were detected, and relationships with amyloid and memory became apparent. CONCLUSION: Melanocyte FTP binding may account partially for high CP signal. This off-target binding affects mainly HC FTP measurements, which should be interpreted with caution. PMID- 29614676 TI - Regional Distribution, Asymmetry, and Clinical Correlates of Tau Uptake on [18F]AV-1451 PET in Atypical Alzheimer's Disease. AB - BACKGROUND: Despite common pathology, Alzheimer's disease (AD) can have multiple clinical presentations which pathological studies suggest result from differences in the regional distribution of tau pathology. Positron emission tomography (PET) ligands are now available that can detect tau proteins in vivo and hence can be used to investigate the biological mechanisms underlying atypical AD. OBJECTIVE: To assess regional patterns of tau uptake on PET imaging in two atypical AD variants, posterior cortical atrophy (PCA) and logopenic progressive aphasia (lvPPA). METHODS: Eighteen PCA and 19 lvPPA subjects that showed amyloid-beta deposition on PET underwent tau-PET imaging with [18F]AV-1451. Group comparisons of tau uptake in PCA and lvPPA were performed using voxel-level and regional level analyses. We also assessed the degree of lobar tau asymmetry and correlated regional tau uptake to age and performance on clinical evaluations. RESULTS: Both syndromes showed diffuse tau uptake throughout all cortical regions, although PCA showed greater uptake in occipital regions compared to lvPPA, and lvPPA showed greater uptake in left frontal and temporal regions compared to PCA. While lvPPA showed predominant left-asymmetric tau deposition, PCA was more bilateral. Younger subjects showed greater tau uptake bilaterally in frontal and parietal lobes than older subjects, and sentence repetition, Boston naming test, simultanagnosia, and visuoperceptual function showed specific regional tau correlates. CONCLUSION: Tau deposition is closely related to clinical presentation in atypical AD with age playing a role in determining the degree of cortical tau deposition. PMID- 29614678 TI - Odor Identification Ability Predicts PET Amyloid Status and Memory Decline in Older Adults. AB - BACKGROUND: Odor identification deficits occur in Alzheimer's disease (AD), as measured by the 40-item University of Pennsylvania Smell Identification Test (UPSIT). OBJECTIVE: To determine if UPSIT scores predict amyloid-beta (Abeta) status, determined by 11C-Pittsburgh Compound B PET. We also compared UPSIT scores to Abeta status in predicting future memory decline. METHODS: Subjects were recruited into a longitudinal clinical prediction study. We analyzed data from those who had UPSIT, cognitive testing, PIB PET, and at least 12 months' clinical follow-up. Forty-six amnestic mild cognitive impairment patients and 25 cognitively normal controls were included. Amyloid-positivity was defined as composite PIB standardized uptake value ratio >1.5. Logistic regression and Receiver Operating Characteristic Curve analyses tested the predictive utility of impaired olfaction (defined as UPSIT score <35) and amyloid-positivity for memory decline. RESULTS: High UPSIT scores predicted absence of amyloidosis on PET, with negative predictive value of 100%. Positive predictive value of low UPSIT scores on positive Abeta status was only 41%. Both low UPSIT score (OR = 4.301, 95% CI = 1.248, 14.821, p = 0.021) and positive PET scan (OR = 20.898, 95% CI = 2.222, 196.581, p = 0.008) predicted memory decline. CONCLUSION: Individuals with high UPSIT scores are less likely to have cerebral amyloidosis or experience memory decline. Therefore, UPSIT has potential as a screening tool to determine utility of Abeta PET in clinical practice or enrollment in clinical trials. Low UPSIT score is a non-specific marker of neurodegeneration that could indicate further workup in patients with memory complaints. PMID- 29614679 TI - Effects of Composite Supplement Containing Astaxanthin and Sesamin on Cognitive Functions in People with Mild Cognitive Impairment: A Randomized, Double-Blind, Placebo-Controlled Trial. AB - BACKGROUND: Dementia and its first or transitional stage, mild cognitive impairment (MCI), is a major concern for the aging Japanese society. Thus, the use of dietary supplements to improve or maintain cognitive function has become a topic of public interest. OBJECTIVE: In this study, we evaluated the effects of a composite supplement containing food-derived antioxidants, specifically astaxanthin and sesamin (AS), on cognitive function in people with MCI. METHOD: Twenty-one healthy participants with MCI were recruited in our double-blind placebo-controlled pilot study. They were assigned to either an AS group, who received ingestible capsules containing AS, or a placebo group, who received identical placebo capsules. To assess cognitive functions, we performed the Japanese version of the Central Nervous System Vital Signs (CNSVS) test and the Alzheimer's Disease Assessment Scale-Cog test at baseline, after 6 weeks, and after 12 weeks of dietary supplementation. RESULTS: The CNSVS test revealed significant improvements in psychomotor speed and processing speed in the AS group compared with the placebo group, suggesting that the daily supplementation of AS improved cognitive functions related to the ability to comprehend, and perform complex tasks quickly and accurately. CONCLUSION: Our results provide support for the use of AS as a dietary supplementation for improving cognitive functions. PMID- 29614680 TI - Novel GRN Mutations in Alzheimer's Disease and Frontotemporal Lobar Degeneration. AB - BACKGROUND: During the twentieth century, frontotemporal dementia (FTD) was often misdiagnosed, confused with Alzheimer's disease or psychiatric disorders, jeopardizing care and research. OBJECTIVE: To analyze the FTD genes in the DNA samples of patients belonging to families clinically classified as probable Alzheimer's disease (FAD) in the early 1990s and not carrying mutation in the three main genes linked to FAD (Presenilin 1, Presenilin 2, and Amyloid precursor protein). METHODS: The genetic screening was performed on 63 probands diagnosed as FAD before the early 2000s. RESULTS: Four patients out of the 63 studied (4/63, 6.3%) resulted as carrying four different GRN genetic variations: p.T272SfsX10, p.R110X, p.C149LfsX10, and p.W304C. The first two mutations (p.T272SfsX10, p.R110X) are the most frequent ones in Italy in FTD patients; the latter two (p.C149LfsX10 and p.W304C) are not described in the scientific literature. CONCLUSION: Our data suggest that it can be important to re-examine FAD patients diagnosed when the FTD spectrum was not well recognized and the causative FTD genes had not yet been identified. Moreover, we propose initially analyzing genes associated with the first form of suspected dementia and, if the results are negative, studying genes implicated in the other form of dementia. PMID- 29614681 TI - Effect of Fluvoxamine on Amyloid-beta Peptide Generation and Memory. AB - Alzheimer's disease is characterized by abnormal amyloid-beta (Abeta) peptide accumulation beginning decades before symptom onset. An effective prophylactic treatment aimed at arresting the amyloidogenic pathway would therefore need to be initiated prior to the occurrence of Abeta pathology. The SIGMAR1 gene encodes a molecular chaperone that modulates processing of the amyloid-beta protein precursor (AbetaPP). Fluvoxamine is a selective serotonin reuptake inhibitor and a potent SIGMAR1 agonist. We therefore hypothesized that fluvoxamine treatment would reduce Abeta production and improve cognition. We firstly investigated the impact of SIGMAR1 on AbetaPP processing, and found that overexpression and knockdown of SIGMAR1 significantly affected gamma-secretase activity in SK-N-MC neuronal cells. We then tested the impact of fluvoxamine on Abeta production in an amyloidogenic cell model, and found that fluvoxamine significantly reduced Abeta production by inhibiting gamma-secretase activity. Finally, we assessed the efficacy of long-term treatment (i.e., ~8 months) of 10 mg/kg/day fluvoxamine in the J20 amyloidogenic mouse model; the treatment was initiated prior to the occurrence of predicted Abeta pathology. Physical examination of the animals revealed no overt pathology or change in weight. We conducted a series of behavioral tests to assess learning and memory, and found that the fluvoxamine treatment significantly improved memory function as measured by novel object recognition task. Two other tests revealed no significant change in memory function. In conclusion, fluvoxamine has a clear impact on gamma-secretase activity and AbetaPP processing to generate Abeta, and may have a protective effect on cognition in the J20 mice. PMID- 29614682 TI - Non-Genetic Risk Factors for Degenerative and Vascular Young Onset Dementia: Results from the INSPIRED and KGOW Studies. AB - BACKGROUND: Several brain reserve, vascular risk, and other modifiable factors have been associated with late-onset dementia, but their association with young onset dementia (YOD) has not been adequately explored. OBJECTIVE: To examine the association of cognitive reserve enhancing factors, cardiovascular risk factors (including smoking), depression, alcohol use, and traumatic brain injury (TBI) with non-autosomal dominant degenerative and/or vascular YOD. METHODS: Data for this matched case-control study were taken from two larger studies conducted in NSW, Australia. One comprised all people with YOD within a geographical region, while the other exclusively included Aboriginal and Torres Strait Islander participants. Dementia diagnosis was confirmed by clinical consensus, and risk exposure was retrospectively self- and/or informant-reported. RESULTS: Participants were 96 people with YOD (58.4% with probable Alzheimer's disease) and 175 age-group, sex, and sample matched control participants. Poor educational attainment, low participation in cognitive leisure activity, stroke, transient ischemic attack, and self-reported very heavy alcohol use were related to the risk of primary degenerative and/or vascular YOD. The effect of hypertension and depression varied depending on when they occurred relative to dementia onset. Current smoking was significantly associated with risk in univariate analyses but did not retain significance in multivariate modelling. There was no association with hypercholesterolemia, diabetes, or TBI of any kind. Some compensation for low educational attainment was possible via a complex occupation later in life. CONCLUSION: Non-genetic factors have a role in YOD, though the relative importance of each factor may be different to late onset dementia. The timing and severity of exposure, as well as the potential for compensation with later protective exposures, are important considerations for potential prevention strategies. PMID- 29614683 TI - Neuropsychological Predictors of Long-Term (10 Years) Mild Cognitive Impairment Stability. AB - BACKGROUND: Although the diagnosis of mild cognitive impairment (MCI) corresponds to a condition likely to progress to dementia, essentially Alzheimer's disease, longitudinal studies have shown that some patients may not convert to dementia and maintain the diagnosis of MCI even after many years. OBJECTIVES: To determine whether patients that maintain the diagnosis of MCI in the long term (10 years) are really stable or just declining slowly, and to identify clinical and neuropsychological characteristics associated with long-term stability. METHODS: The Cognitive Complaints Cohort (CCC) was searched for MCI cases who maintained that diagnosis for at least 10 years. For each long-term-stable MCI patient, two MCI patients that converted to dementia during follow-up, matched for age and education, were selected from the same database. The baseline and last neuropsychological evaluations for long-term-stable MCI and converter MCI were compared. Baseline neuropsychological predictors of long-term stability were searched for. RESULTS: Long-term-stable MCI (n = 22) and converter MCI (n = 44) patients did not differ in terms of gender distribution, education, age at first assessment and time between symptom onset and first evaluation. Time of follow-up was on average 11 years for long-term-stable MCI and 3 years for converter MCI. The baseline and follow-up neuropsychological tests were not significantly different in long-term-stable MCI patients, whereas a general decline was observed in converter MCI patients. Higher scores on one memory test, the Word Delayed Total Recall, and on the non-verbal abstraction test, Raven's Progressive Matrices, at the baseline predicted long-term (10 years) clinical stability. CONCLUSIONS: Some patients with MCI remain clinically and neuropsychologically stable for a decade. Better performances at baseline in memory and non-verbal abstraction tests predict long-term stability. PMID- 29614685 TI - Calpain I Activation Causes GLUT3 Proteolysis and Downregulation of O GlcNAcylation in Alzheimer's Disease Brain. AB - Impairment of cerebral glucose uptake/metabolism in individuals with Alzheimer's disease (AD) is believed to lead to downregulation of protein O-GlcNAcylation, which contributes to tau pathogenesis through tau hyperphosphorylation. Level of glucose transporter 3 (GLUT3), a neuronal specific glucose transporter, is decreased in AD brain, which may contribute to impaired brain glucose uptake/metabolism. However, what causes the reduction of GLUT3 in AD brain is not fully understood. Here, we report 1) that decrease of GLUT3 is associated with the reduction of protein O-GlcNAcylation in AD brain, 2) that GLUT3 level is negatively correlated with calpain I activation in human brain, 3) that calpain I proteolyzes GLUT3 at the N-terminus in vitro, and 4) that activation of calpain I is negatively correlated with protein O-GlcNAcylation in AD brain. Furthermore, we found that overexpression of GLUT3 enhances protein O-GlcNAcylation in N2a cells. Overexpression of calpain I suppresses protein O-GlcNAcylation in these cells. These findings suggest a novel mechanism by which calpain I overactivation leads to GLUT3 degradation and the consequent down-regulation of protein O GlcNAcylation in AD brain. PMID- 29614684 TI - Novel Lipidized Analog of Prolactin-Releasing Peptide Improves Memory Impairment and Attenuates Hyperphosphorylation of Tau Protein in a Mouse Model of Tauopathy. AB - Obesity and type 2 diabetes mellitus (T2DM) were characterized as risk factors for Alzheimer's disease (AD) development. Subsequently, T2DM drugs, such as liraglutide, were proven to be neuroprotective compounds attenuating levels of amyloid deposits, and tau hyperphosphorylation, both hallmarks of AD. The central anorexigenic effects of liraglutide inspired us to examine the potential neuroprotective effects of palm11-PrRP31, a strong anorexigenic analog with glucose-lowering properties, in THY-Tau22 mice overexpressing mutated human tau, a model of AD-like tau pathology. Seven-month-old THY-Tau22 mice were subcutaneously infused with palm11-PrRP31 for 2 months. Spatial memory was tested before and after the treatment, using a Y-maze. At the end of the treatment, mice were sacrificed by decapitation and hippocampi were dissected and analyzed by immunoblotting with specific antibodies. Treatment with palm11-PrRP31 resulted in significantly improved spatial memory. In the hippocampi of palm11-PrRP31-treated THY-Tau22 mice, tau protein phosphorylation was attenuated at Thr231, Ser396, and Ser404, the epitopes linked to AD progression. The mechanism of this attenuation remains unclear, since the activation of those kinases most implicated in tau hyperphosphorylation, such as GSK-3beta, JNK, or MAPK/ERK1/2, remained unchanged by palm11-PrRP31 treatment. Furthermore, we observed a significant increase in the amount of postsynaptic density protein PSD95, and a non-significant increase of synaptophysin, both markers of increased synaptic plasticity, which could also result in improved spatial memory of THY-Tau22 mice treated with palm11-PrRP31. Palm11-PrRP31 seems to be a potential tool for the attenuation of neurodegenerative disorders in the brain. However, the exact mechanism of its action must be elucidated. PMID- 29614686 TI - The Effect of Chronic Cerebral Hypoperfusion on Amyloid-beta Metabolism in a Transgenic Mouse Model of Alzheimer's Disease (PS1V97L). AB - Alzheimer's disease (AD) and cerebrovascular disease often coexist. However, it is difficult to determine how chronic cerebral hypoperfusion affects the metabolism of amyloid-beta peptides (Abeta) in a living patient with AD. Thus, we developed an animal model of this condition, using transgenic mice (PS1V97L) and right common carotid artery ligation to create chronic cerebral hypoperfusion. The metabolic processes associated with amyloid-beta peptide (Abeta) were observed and evaluated in this PS1V97L plus hypoperfusion model. Compared with control mice, the model revealed significantly upregulated expression of Abeta (including Abeta oligomers), with decreased alpha-secretase activity and expression and increased beta-secretase activity and expression. Furthermore, the model revealed increased mRNA and protein expression of the receptor for advanced glycation end products (RAGE) and decreased mRNA and protein expression of low density lipoprotein receptor-related protein 1 (LRP-1); both these are Abeta transporters. Moreover, the model revealed decreased activity and expression of neprilysin, which is a peripheral Abeta degrading enzyme. These findings suggest that hypoperfusion may magnify the effect of AD on Abeta metabolism by aggravating its abnormal production, transport, and clearance. PMID- 29614687 TI - Differences in Dementia Beliefs between Non-Demented Public Screeners and In-Home Screeners and Their Potential Impact on Future Dementia Screening Intention: The Nakajima Study. AB - In many cohort studies of dementia, while differences in sociodemographic characters between responders and non-responders of dementia screening have been reported, differences in dementia beliefs have been relatively less known. The aims of this study were to clarify dementia beliefs and to explore potential impacts on an intention to attend a future dementia screening in public screeners and in-home screeners, respectively. We performed a cross-sectional population based study using a question about an intention to attend a future dementia screening and a questionnaire on dementia beliefs. Subjects were all residents aged 65 years or older in the north area of Nakajima, Japan (n = 385). All subjects were asked to attend a public dementia screening first. An in-home dementia screening was subsequently conducted in subjects with non-responders to a public screening. The questionnaire consisted of four dementia beliefs: "perceived susceptibility," "perceived severity," "perceived barriers," and "perceived benefits." Public screeners significantly expressed an intention to attend a future dementia screening more than in-home screeners (p = 0.002). In in home screeners, low "perceived severity" were significantly associated with an intention to attend a future dementia screening [adjusted OR (95% CI) = 0.51 (0.32-0.80)]. In both public and in-home screeners, high "perceived benefits" were significantly associated with an intention to attend a future dementia screening [adjusted OR (95% CI) = 2.13 (1.46-3.10); adjusted OR (95% CI) = 2.56 (1.22-5.35), respectively]. It is necessary to reduce "perceived severity" among in-home screeners to increase dementia screening participants. PMID- 29614688 TI - Perseveration and Suicide in Huntington's Disease. AB - BACKGROUND: Huntington's disease (HD) patients are at significantly higher risk of suicidal behavior, and associated cognitive and behavioral factors play an important role. Impulsivity is commonly thought to be a risk factor, but does not completely account for all suicide attempts. OBJECTIVE: To provide clinical evidence that perseverative behavior may precipitate suicide attempts in HD. METHODS: Case review of four HD patients who attempted suicide. RESULTS: Each patient demonstrated a clinical history of perseverative behavior, and endorsed perseveration on upsetting thoughts leading up to their suicide attempts. The attempts were planned in response to these ruminations. CONCLUSIONS: The patients in this series experienced uncontrollable distressful thoughts prior to their thoughtfully planned suicide attempts. These patients did not appear to act impulsively in their decision to attempt suicide. PMID- 29614690 TI - Characteristics of Japanese Patients with Becker Muscular Dystrophy and Intermediate Muscular Dystrophy in a Japanese National Registry of Muscular Dystrophy (Remudy): Heterogeneity and Clinical Variation. AB - BACKGROUND: Obtaining an adequate number of patients to conduct a natural history study for rare diseases such as Becker muscular dystrophy (BMD) is difficult. OBJECTIVES: The present study used data from Remudy, a national registry for neuromuscular diseases in Japan, to conduct a phenotypic analysis of BMD. METHODS: We analyzed Remudy data of participants with dystrophinopathy. All participants who were aged 17 and older and were ambulant at age 13 were included in this study. Participants were divided into two groups: those with BMD who were ambulant at age 17, and those with intermediate muscular dystrophy (IMD) who lost ambulation by age 17. Frequent mutations were analyzed by age at ambulation, cardiopulmonary function, and genotype. For clinical comparisons, participants who were administered steroids were excluded. RESULTS: From July 2009 through September 2015, 192 participants had registered with Remudy. Mean participant age was 34.80+/-13.3 (range, 17-78) years, and 52.1% of participants were ambulant. Of the entire study population, 50.5% had cardiomyopathy and 35.9% had respiratory failure. Three participants required invasive ventilation and 30 required non-invasive ventilation. Nineteen of the 30 non-invasive ventilator users were part-time users. In total, 138 (71.9%) had BMD and 54 (28.1%) had IMD. The most frequent mutation was ex45_ex47del (36 participants). Among participants with frequent in-frame mutations, those with the ex45-49del mutation lost their ambulation earlier than those with the ex45_ex47del mutation. A total of 67 different exon deletions and duplications were identified in the study population. CONCLUSION: We clarified the clinical phenotypes of Japanese patients with BMD/IMD using data from Remudy. Our results suggest that not only IMD but also BMD are associated with risk of respiratory dysfunction. PMID- 29614692 TI - Determination of qPCR Reference Genes Suitable for Normalizing Gene Expression in a Canine Model of Duchenne Muscular Dystrophy. AB - BACKGROUND: Dogs with dystrophin-deficient muscular dystrophy are valuable models of the equivalent human disease, Duchenne Muscular Dystrophy (DMD): unlike the mdx mouse, these animals present a disease severity and progression that closely matches that found in human patients. Canine models are however less thoroughly characterised than the established mdx mouse in many aspects, including gene expression. Analysis of expression in muscle plays a key role in the study of DMD, allowing monitoring and assessment of disease progression, evaluation of novel biomarkers and gauging of therapeutic intervention efficacy. Appropriate normalization of expression data via carefully selected reference genes is consequently essential for accurate quantitative assessment. Unlike the expression profile of healthy skeletal muscle, the dystrophic muscle environment is highly dynamic: transcriptional profiles of dystrophic muscle might alter with age, disease progression, disease severity, genetic background and between muscle groups. OBJECTIVES: The aim of this work was to identify reference genes suitable for normalizing gene expression in healthy and dystrophic dogs under various comparative scenarios. METHODS: Using the delta-E50 MD canine model of DMD, we assessed a panel of candidate reference genes for stability of expression across healthy and dystrophic animals, at different ages and in different muscle groups. RESULTS: We show that the genes HPRT1, SDHA and RPL13a appear universally suitable for normalizing gene expression in healthy and dystrophic canine muscle, while other putative reference genes are exceptionally poor, and in the case of B2M, actively disease-correlated. CONCLUSIONS: Our findings suggest consistent cross-sample normalization is possible even throughout the dynamic progression of dystrophic pathology, and furthermore highlight the importance of empirical determination of suitable reference genes for neuromuscular diseases. PMID- 29614691 TI - Novel SPEG Mutations in Congenital Myopathy without Centralized Nuclei. AB - Congenital myopathies are clinically and genetically heterogeneous, and are classified based on typical structural abnormalities on muscle sections. Recessive mutations in the striated muscle preferentially expressed protein kinase (SPEG) were recently reported in patients with centronuclear myopathy (CNM) associated in most cases with dilated cardiomyopathy. Here we report the identification of novel biallelic truncating SPEG mutations in a patient with moderate congenital myopathy without clinical and histological hallmarks of CNM and without cardiomyopathy. This study expands the phenotypic spectrum of SPEG related myopathy and prompts to consider SPEG for congenital myopathies without specific histological features. PMID- 29614693 TI - Problems in Comparing Jitter Values Obtained with Voluntary Activation and Electrical Stimulation. AB - Comparing results from jitter studies performed with voluntary and electrical activation is difficult to perform quantitatively, particularly in complex signals as seen in reinnervation. High jitter values in individual spikes in these multispike signals can be missed with both activation methods, which introduces a bias towards more normal values.With voluntary activation, triggering on a spike from an abnormal end-plate in multispike potentials will overestimate individual jitter values and the number of abnormal jitter values.With electrical stimulation, artefactually-increased jitter may be caused by subliminal stimulation, which causes uncertainty at the stimulation point. Electrical stimulation also may activate many axons, causing signal summation, with erroneous or impossible jitter estimation.Awareness of such pitfalls can improve the correct performance and interpretation of jitter recordings. Quantitative comparisons of results can be made between studies in reinnervated muscle performed with the same activation method, but not between results obtained with different activation methods. PMID- 29614689 TI - A Critical Evaluation of Wet Biomarkers for Huntington's Disease: Current Status and Ways Forward. AB - There is an unmet clinical need for objective biomarkers to monitor disease progression and treatment response in Huntington's disease (HD). The aim of this review is, therefore, to provide practical advice for biomarker discovery and to summarise studies on biofluid markers for HD. A PubMed search was performed to review literature with regard to candidate saliva, urine, blood and cerebrospinal fluid biomarkers for HD. Information has been organised into tables to allow a pragmatic approach to the discussion of the evidence and generation of practical recommendations for future studies. Many of the markers published converge on metabolic and inflammatory pathways, although changes in other analytes representing antioxidant and growth factor pathways have also been found. The most promising markers reflect neuronal and glial degeneration, particularly neurofilament light chain. International collaboration to standardise assays and study protocols, as well as to recruit sufficiently large cohorts, will facilitate future biomarker discovery and development. PMID- 29614694 TI - An overview of the Cure SMA membership database: Highlights of key demographic and clinical characteristics of SMA members. AB - BACKGROUND: The Cure SMA database is one of the largest patient reported databases for people affected with SMA. OBJECTIVE: The purpose of this study was to examine a subset of affected SMA persons with types I, II, and III from a patient reported database. METHODS: Individuals with SMA were selected from the database using a date of first contact to Cure SMA between 2010 and 2016. Data analyzed included age at diagnosis, number of weeks from SMA diagnosis to contacting Cure SMA, and geographic distribution of individuals. RESULTS: A total of 1,966 individuals with SMA were included in the analysis. Of these individuals, 51.9% had type I, 32.3% had type II, and 15.8% had type III. The average age of diagnosis for type I patients was 5.2 months, 22.1 months for type II, and 97.8 months for type III. From published incidence, about 59.0% of affected individuals in the US are registered in the Cure SMA database. CONCLUSIONS: The Cure SMA database is a unique and robust source of patient reported data that informs on the burden of illness and supports the development of new therapeutic modalities. PMID- 29614695 TI - Treatment Algorithm for Infants Diagnosed with Spinal Muscular Atrophy through Newborn Screening. AB - BACKGROUND: Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by the degeneration of alpha motor neurons in the spinal cord, leading to muscular atrophy. SMA is caused by deletions or mutations in the survival motor neuron 1 gene (SMN1). In humans, a nearly identical copy gene, SMN2, is present. Because SMN2 has been shown to decrease disease severity in a dose-dependent manner, SMN2 copy number is predictive of disease severity. OBJECTIVE: To develop a treatment algorithm for SMA-positive infants identified through newborn screening based upon SMN2 copy number. METHODS: A working group comprised of 15 SMA experts participated in a modified Delphi process, moderated by a neutral third-party expert, to develop treatment guidelines. RESULTS: The overarching recommendation is that all infants with two or three copies of SMN2 should receive immediate treatment (n = 13). For those infants in which immediate treatment is not recommended, guidelines were developed that outline the timing and appropriate screens and tests to be used to determine the timing of treatment initiation. CONCLUSIONS: The identification SMA affected infants via newborn screening presents an unprecedented opportunity for achievement of maximal therapeutic benefit through the administration of treatment pre-symptomatically. The recommendations provided here are intended to help formulate treatment guidelines for infants who test positive during the newborn screening process. PMID- 29614696 TI - Impact of Subthalamic Deep Brain Stimulation Frequency on Upper Limb Motor Function in Parkinson's Disease. AB - BACKGROUND: Whilst changes in the frequency of subthalamic deep brain stimulation (STN-DBS) have been proposed to improve control of tremor or axial motor features in Parkinson's disease (PD), little is known about the effects of frequency changes on upper limb motor function, particularly bradykinesia. OBJECTIVE: To investigate the acute effects of various STN-DBS frequencies (40-160 Hz, 40 Hz intervals) on upper limb motor function. METHODS: We carried out a randomised, double-blind study on 20 PD patients with chronic STN-DBS using the Simple and Assembly components of the Purdue Pegboard (PP) test and a modified upper limb version of the UPDRS-III (UL-UPDRS-III). RESULTS: There was no significant effect of frequency on bradykinesia on the Simple PP task or the UL-UPDRS-III. There was an effect of frequency on the Assembly PP score when comparing all frequencies (p = 0.019) and between 80 Hz and 130 Hz (p = 0.007), with lower frequencies yielding a better performance. Rigidity and Tremor scores were significantly reduced with higher (>80 Hz) compared to lower (40 Hz) frequencies. CONCLUSIONS: Our findings suggest that a wide range of frequencies are efficacious in improving acute upper-limb motor function. Reducing the frequency of stimulation down to 80 Hz is safe and has a similar clinical effect to higher frequencies. Therefore, a wider range of frequencies are available when it comes adjusting patients' acute settings without the risk of worsening bradykinesia. PMID- 29614698 TI - Cognitive Rehabilitation in Parkinson's Disease: A Systematic Review. AB - BACKGROUND: Cognitive impairments are the most common non-motor symptoms in Parkinson's disease (PD). These symptoms have a negative impact on patients' quality of life and daily living activities. This review will focus on published articles that investigated the efficacy of cognitive rehabilitation in PD. OBJECTIVES: To review the existing literature on the efficacy of cognitive rehabilitation in PD and highlight the most effective form of intervention to prevent cognitive decline. This review will also point out any limitations and provide directions for future research. METHODS: Published articles available in the Web of Science and PubMed databases up to November 2017 were reviewed for possible inclusion. We identified 15 articles that examined the effects of cognitive rehabilitation in PD and met inclusion criteria. RESULTS: The main outcomes of this review indicated that, although previous studies used different cognitive rehabilitation methodologies, all studies reported cognitive improvements on at least one cognitive domain. Additionally, the most frequent cognitive domains showing improvements are executive functions and attention. CONCLUSION: This review reports the outcomes of studies that examined the effectiveness of cognitive rehabilitation in PD. It also points out the limitations of the studies indicating the limited availability of follow up data on the long-term effects of cognitive interventions. The review also highlights the fact that some of the studies did not include a PD group who did not undergo training. There remains, therefore, a need for longitudinal studies to investigate the potential long term benefits of cognitive training. In addition, future investigations should examine whether any disease characteristics such as disease stage, degree of cognitive impairment and/or the dominant side (right/left) or specific motor symptoms (rigidity/tremor) influence treatment efficacy. PMID- 29614697 TI - Are There Benefits in Adding Catechol-O Methyltransferase Inhibitors in the Pharmacotherapy of Parkinson's Disease Patients? A Systematic Review. AB - BACKGROUND: A qualified consensus suggests that a combination of levodopa with a peripherally acting dopa decarboxylase inhibitor continues to present the gold standard treatment of Parkinson's disease (PD). However, as the disease progresses the therapeutic window of levodopa becomes narrowed. Pharmacological strategies for motor fluctuations are focused on providing less pulsatile and more continuous dopaminergic stimulation. Peripheral catechol-O-methyltransferase (COMT) inhibition improves the bioavailability of levodopa and results in a prolonged response. OBJECTIVE: The primary aim of this study was to investigate the efficacy and safety of the two available COMT inhibitors; entacapone and tolcapone and the recently introduced opicapone. METHODS: Electronic databases were systematically searched for original studies published within the last 37 years. In addition, lists of identified studies, reviews and their references were examined. RESULTS: Twelve studies fulfilled the inclusion criteria. 3701 patients with PD were included in this systematic review. CONCLUSIONS: Adjuvant treatment of PD patients experiencing motor fluctuations with entacapone resulted in improvement of motor function and was well tolerated. Therefore, entacapone presented an acceptable benefit to risk ratio. Tolcapone appeared to result in a greater therapeutic effect. However, this was not consistent across all motor variables and studies, and thus would not support its use, given the current onerous monitoring that is required. Opicapone was not associated with adverse reactions in a phase III trial but did not present a greater efficacy than entacapone, and thus further studies are required in order to illustrate its cost effectiveness. PMID- 29614699 TI - Substantia Nigra Echogenicity Associated with Clinical Subtypes of Parkinson's Disease. AB - BACKGROUND: It is debatable whether transcranial sonography (TCS) could be a biomarker for monitoring disease progression. Various phenotypes of Parkinson's disease (PD) may be a major reason contributing to the inconsistency. OBJECTIVE: We classified PD patients into different subtypes and evaluated the correlation between SN echogenicity and disease progression. METHODS: A total of 411 PD patients were included in this study. TCS evaluations of the substantia nigra (SN) were performed, and motor and non-motor symptoms were assessed by a series of rating scales in all PD patients. RESULTS: Three hundred and thirteen patients had appropriate temporal acoustic bone windows, and they were divided into three subgroups according to disease onset age. SN hyperechogenicity (SN+) was found to be associated with age, gender, disease duration, H-Y stage and UPDRS-II scores in 220 middle-age onset patients. Regression analysis identified both disease duration and gender as independent predictors for SN+. When this distinct group was separated into male and female subgroups, the correlation between larger SN echogenicity (SNL) and disease duration was positive in males rather than females. When these middle-age onset male patients were classified as tremor dominant (TD) and non-TD subtypes, it turned out that correlation between disease duration and SNL only existed in male non-TD PD patients. CONCLUSIONS: Our study demonstrated correlation between the size of SN echogenicity and disease duration in Chinese patients with PD who were male non-TD subtypes with middle-age onset, suggesting the formation of SN echogenicity might be a dynamic process following disease progression in this distinct subtype. PMID- 29614700 TI - Personality Traits and Cortical Activity Affect Gambling Behavior in Parkinson's Disease. AB - BACKGROUND: Pathological gambling (PG) in Parkinson's disease (PD) manifests as a persistent and uncontrollable gambling behavior, characterized by dysfunctional decision-making and emotional impairment related to high-risk decisions. OBJECTIVE: The aim of this study was to explore the relationship between personality traits and prefrontal cortex activity in PD patients with or without PG. METHODS: Thus, hemodynamic cortical activity measured by functional near infrared spectroscopy (fNIRS) and Iowa Gambling Task (IGT) performance were recorded in forty-six PD patients, divided into three groups according to their gambling status: PD patients with active gambling behavior (PDG); PD patients who remitted from PG (PDNG); and a control group (CG) composed by patients with PD only. RESULTS: Results indicates that gambling behavior in PD patients is strongly predictive of dysfunctional cognitive strategy; affecting anomalous cortical response with a left hemispheric unbalance in dorsal areas; and it is related to more reward sensitivity than impulsivity personality components. CONCLUSIONS: PDG patients differed from PDNG and CG from both behavioral and brain response to decision-making. Overall, these effects confirm a pathological condition related to cognitive and emotional aspects which makes the patients with PGD victims of their dysfunctional behavior. PMID- 29614702 TI - High Prevalence of Undiagnosed Insulin Resistance in Non-Diabetic Subjects with Parkinson's Disease. AB - BACKGROUND: Reduced glucose tolerance has been long recognized as a potential risk factor for Parkinson's disease (PD), and increasing scrutiny is currently being placed on insulin resistance (IR) as a pathologic driver of neurodegeneration. However, the prevalence of IR in PD is unknown. OBJECTIVE: To determine IR prevalence in non-diabetic patients with PD and to correlate IR with other metabolic indicators, motor and non-motor symptoms (NMS) of PD, and quality of life (QoL). METHODS: Non-diabetic patients with a diagnosis of PD were identified and tested for fasting insulin, fasting glucose, and HbA1c. Patients were also offered to take a battery of clinical tests (MoCA, NMSQ, and PDQ-39) and had their PD medications, height, weight, and other demographic features recorded. IR was defined as HOMA-IR>=2.0 and/or HbA1c>=5.7. IR abnormalities were correlated with BMI and demographic features, in addition to motor and NMS. RESULTS: 154 subjects (109 M, 45F, mean age 67.7+/-10.5) were included in this study. Mean HOMA-IR was 2.3+/-1.8. Ninety out of 154 (58.4%) subjects had abnormal IR. IR was more frequent in overweight and obese subjects (61.1% and 82.8% respectively) than normal weight subjects (41.5%). Multivariate analysis showed that BMI was the only significant predictor of IR (p < 0.0001). There was no significant correlation between HOMA-IR and MoCA, PDQ-39, and NMSQ scores. CONCLUSIONS: IR is prevalent in PD and it correlates with BMI. A correlation between IR with cognitive and QoL measures cannot be determined on the basis of this sample. PMID- 29614703 TI - Potential risk of clonally expanded amnion mesenchymal stem cell transplants in contused spinal cords. AB - OBJECTIVE: Mesenchymal stem/stromal cells (MSC) promote recovery after spinal cord injury (SCI) using adult bone marrow MSC (BM-MSC). Newborn tissues are a convenient source of MSC that does not involve an invasive procedure for cell collection. In this study the authors tested the effects of rat amnion MSC clone (rAM-MSC) in SCI. METHODS: We tested intra-parenchymal injection of a GFP+ rat rAM-MSC clone derived from E18.5 rats in rat SCI and measured behavioral recovery (BBB scores), histology and X-ray opacity. Expression of aggrecan was measured in culture after treatment with TGFbeta. RESULTS: Injection of rAM-MSC after SCI did not improve BBB scores compared to control vehicle injections; rather they reduced scores significantly over 6 weeks. Spinal cords injected with rAM-MSC were hard in regions surrounding the SCI site, which was confirmed by X-ray opacity. Whole mount imaging of these cords showed minimal tissue loss in the SCI site that occurred in SCI controls, and persistence of GFP+ rAM-MSC. Mason's Trichrome staining of tissue sections showed more intense staining for extracellular matrix (ECM) surrounding and extending beyond the SCI site with injections of rAM-MSC but not in controls. In response to TGF-beta treatment in culture, chondrogenic aggrecan was expressed at higher levels in rAM-MSC than in rBM-MSC, suggesting that the upregulation of TGF-beta in SCI sites may promote chondrogenic differentiation. CONCLUSION: Acute injection after SCI of a clonally expanded rAM-MSC resulted in aberrant differentiation towards a chondrocytic phenotype that disrupts the spinal cord and inhibits behavioral recovery after SCI. It will be critical to ensure that injection of extensively expanded neonatal cells do not differentiate aberrantly in traumatic CNS tissue and disrupt recovery. PMID- 29614704 TI - Constitutively reduced sensory capacity promotes better recovery after spinal cord-injury (SCI) in blind rats of the dystrophic RCS strain. AB - BACKGROUND: We compared functional, electrophysiological and morphological parameters after SCI in two groups of rats Sprague Dawley (SD) rats with normal vision and blind rats from a SD-substrain "Royal College of Surgeons" (SD/RCS) who lose their photoreceptor cells after birth due to a genetic defect in the retinal pigment epithelium. For these animals skin-, intramuscular-, and tendon receptors are major available means to resolve spatial information. OBJECTIVE: The purpose of this study was to check whether increased sensitivity in SD/RCS rats would promote an improved recovery after SCI. METHODS: All rats were subjected to severe compression of the spinal cord at vertebra Th8, spinal cord segment Th10. Recovery of locomotion was analyzed at 1, 3, 6, 9, and 12 weeks after SCI using video recordings of beam walking and inclined ladder climbing. Five functional parameters were studied: foot-stepping angle (FSA), rump-height index (RHI) estimating paw placement and body weight support, respectively, number of correct ladder steps (CLS) assessing skilled hindlimb movements, the BBB-locomotor score and an established urinary bladder score (BS). Sensitivity tests were followed by electrophysiological measurement of M- and H-wave amplitudes from contractions of the plantar musculature after stimulation of the tibial nerve. The closing morphological measurements included lesion volume and expression of astro- and microglia below the lesion. RESULTS: Numerical assessments of BBB, FSA, BS, lesion volume and GFAP-expression revealed no significant differences between both strains. However, compared to SD-rats, the blind SD/RCS animals significantly improved RHI and CLS by 6 - 12 weeks after SCI. To our surprise the withdrawal latencies in the blind SD/RCS rats were longer and the amplitudes of M- and H-waves lower. The expression of IBA1 immunoreactivity in the lumbar enlargement was lower than in the SD-animals. CONCLUSION: The longer withdrawal latencies suggest a decreased sensitivity in the blind SD/RCS rats, which promotes better recovery after SCI. In this way our results provide indirect support to earlier work showing, that hypersensitivity and chronic pain after contusive SCI impair the recovery of locomotor function. PMID- 29614705 TI - Identification of a resilient mouse facial motoneuron population following target disconnection by injury or disease. AB - BACKGROUND: When nerve transection is performed on adult rodents, a substantial population of neurons survives short-term disconnection from target, and the immune system supports this neuronal survival, however long-term survival remains unknown. Understanding the effects of permanent axotomy on cell body survival is important as target disconnection is the first pathological occurrence in fatal motoneuron diseases such as amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). OBJECTIVE: The goal of this study was to determine if facial motoneurons (FMN) could survive permanent target disconnection up to 26 weeks post-operation (wpo) after facial nerve axotomy (FNA). In addition, the potentially additive effects of immunodeficiency and motoneuron disease on post axotomy FMN survival were examined. METHODS: This study included three wild type (WT) mouse strains (C57BL/6J, B6SJL, and FVB/NJ) and three experimental models (RAG-2-/-: immunodeficiency; mSOD1: ALS; Smn-/-/SMN2+/+: SMA). All animals received a unilateral FNA, and FMN survival was quantified at early and extended post-operative timepoints. RESULTS: In the C57BL/6J WT group, FMN survival significantly decreased at 10 wpo (55+/-6%), and then remained stable out to 26 wpo (47+/-6%). In the RAG-2-/- and mSOD1 groups, FMN death occurred much earlier at 4 wpo, and survival plateaued at approximately 50% at 10 wpo. The SMA model and other WT strains also exhibited approximately 50% FMN survival after FNA. CONCLUSION: These results indicate that immunodeficiency and motoneuron disease accelerate axotomy-induced neuron death, but do not increase total neuron death in the context of permanent target disconnection. This consistent finding of a target disconnection-resilient motoneuron population is prevalent in other peripheral nerve injury models and in neurodegenerative disease models as well. Characterization of the distinct populations of vulnerable and resilient motoneurons may reveal new therapeutic approaches for injury and disease. PMID- 29614701 TI - Targeting AMPK Signaling as a Neuroprotective Strategy in Parkinson's Disease. AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder. It is characterized by the accumulation of intracellular alpha-synuclein aggregates and the degeneration of nigrostriatal dopaminergic neurons. While no treatment strategy has been proven to slow or halt the progression of the disease, there is mounting evidence from preclinical PD models that activation of 5'-AMP-activated protein kinase (AMPK) may have broad neuroprotective effects. Numerous dietary supplements and pharmaceuticals (e.g., metformin) that increase AMPK activity are available for use in humans, but clinical studies of their effects in PD patients are limited. AMPK is an evolutionarily conserved serine/threonine kinase that is activated by falling energy levels and functions to restore cellular energy balance. However, in response to certain cellular stressors, AMPK activation may exacerbate neuronal atrophy and cell death. This review describes the regulation and functions of AMPK, evaluates the controversies in the field, and assesses the potential of targeting AMPK signaling as a neuroprotective treatment for PD. PMID- 29614706 TI - Yoga- and meditation-based lifestyle intervention increases neuroplasticity and reduces severity of major depressive disorder: A randomized controlled trial. AB - BACKGROUND: Current interventions for major depressive disorder (MDD) are suboptimal, and only one third respond to them on initial treatment. Neuroplasticity theories are the basis for several emerging treatments. Evidence on the impact of yoga, a well-known mind-body intervention, on neuroplasticity in MDD is limited. OBJECTIVES: To determine the effects of 12-week yoga- and meditation-based lifestyle intervention (YMLI) on depression severity and systemic biomarkers of neuroplasticity in adult MDD patients on routine drug treatment. METHODS: A total of 58 MDD patients were randomized into yoga or control group. The severity of depression was assessed with Beck Depression Inventory-II scale (BDI-II). Blood samples were collected before and after intervention for the measurement of the biomarkers that characterize neuroplasticity, including mind-body communicative and cellular health biomarkers. RESULTS: There was a significant decrease [difference between means, (95% CI)] in BDI-II score [-5.83 (-7.27, -4.39), p < 0.001] and significant increase in BDNF (ng/ml) [5.48 (3.50, 7.46), p < 0.001] after YMLI compared to control group. YMLI significantly increased DHEAS, sirtuin 1, and telomerase activity levels, and decreased cortisol, and IL-6 levels, in addition to decreasing DNA damage and balancing oxidative stress. Multiple regression analyses were used to associate neuroplasticity biomarkers with depression severity. A 'post-intervention change in BDNF' x 'group' interaction indicated that yoga group had more BDNF in association with less BDI-II scores relative to controls. Increased sirtuin 1 and telomerase activity and decreased cortisol significantly predicted this association (all p < 0.05). CONCLUSION: These results suggest that decrease in depression severity after YMLI in MDD is associated with improved systemic biomarkers of neuroplasticity. Thus YMLI can be considered as a therapeutic intervention in MDD management. PMID- 29614707 TI - Best core stabilization exercise to facilitate subcortical neuroplasticity: A functional MRI neuroimaging study. AB - OBJECTIVE: To investigate the effects of conscious (ADIM) and subconscious (DNS) core stabilization exercises on cortical changes in adults with core instability. PARTICIPANTS: Five non-symptomatic participants with core instability. METHODS: A novel core stabilization task switching paradigm was designed to separate cortical or subcortical neural substrates during a series of DNS or ADIM core stabilization tasks. RESULTS: fMRI blood BOLD analysis revealed a distinctive subcortical activation pattern during the performance of the DNS, whereas the cortical motor network was primarily activated during an ADIM. Peak voxel volume values showed significantly greater DNS (11.08 +/- 1.51) compared with the ADIM (8.81 +/- 0.21) (p= 0.043). CONCLUSION: The ADIM exercise activated the cortical PMC-SMC-SMA motor network, whereas the DNS exercise activated both these same cortical areas and the subcortical cerebellum-BG-thalamus-cingulate cortex network. PMID- 29614708 TI - Tobacco use status from clinical notes using Natural Language Processing and rule based algorithm. AB - BACKGROUND: This cross-sectional retrospective study utilized Natural Language Processing (NLP) to extract tobacco-use associated variables from clinical notes documented in the Electronic Health Record (EHR). OBJECITVE: To develop a rule based algorithm for determining the present status of the patient's tobacco-use. METHODS: Clinical notes (n= 5,371 documents) from 363 patients were mined and classified by NLP software into four classes namely: "Current Smoker", "Past Smoker", "Nonsmoker" and "Unknown". Two coders manually classified these documents into above mentioned classes (document-level gold standard classification (DLGSC)). A tobacco-use status was derived per patient (patient level gold standard classification (PLGSC)), based on individual documents' status by the same two coders. The DLGSC and PLGSC were compared to the results derived from NLP and rule-based algorithm, respectively. RESULTS: The initial Cohen's kappa (n= 1,000 documents) was 0.9448 (95% CI = 0.9281-0.9615), indicating a strong agreement between the two raters. Subsequently, for 371 documents the Cohen's kappa was 0.9889 (95% CI = 0.979-1.000). The F-measures for the document-level classification for the four classes were 0.700, 0.753, 0.839 and 0.988 while the patient-level classifications were 0.580, 0.771, 0.730 and 0.933 respectively. CONCLUSIONS: NLP and the rule-based algorithm exhibited utility for deriving the present tobacco-use status of patients. Current strategies are targeting further improvement in precision to enhance translational value of the tool. PMID- 29614709 TI - Effects of resistance exercise on antioxidant enzyme activities and apoptosis related protein expression of hippocampus in OLETF rats. AB - BACKGROUND: Studies on antioxidant enzyme activity and apoptosis related protein expression associated with diabetes are mainly limited to aerobic exercise. Since the effectiveness and efficiency of the resistance to diabetes has recently emerged, it is necessary to investigate the effects of regular resistance exercise on these factors. OBJECTIVE: The purpose of this study was to investigate the effects of resistance exercise on antioxidant enzymes activities and apoptosis related protein expression in hippocampus of diabetic rats. METHODS: Twenty-one male rats were divided into 3 groups: LETO (control group), OLETF (diabetes group) and OLETF + EX (OLETF with resistance exercise group). Resistance exercise consisted of ladder climbing every 5 days for 30 minutes for 8 weeks. The exercise group was trained to climb a 180-cm vertical ladder with weights secured to their tails. Antioxidant enzyme activities, apoptosis related protein expression, and HOMA-IR level were measured. RESULTS: The lipid peroxide and superoxide dismutase (SOD) activity were significantly increased in OLETF + EX compared to OLETF (p< 0.001). Glutathione peroxidase (GPx) activity was significantly lower in OLETF + EX than OLETF (p< 0.001). Caspase-3 expression of hippocampus was significantly decreased in OLETF + EX compared to OLETF (p< 0.05). Bax protein expression was significantly lower in OLETF + EX than OLETF (p< 0.05) whereas Bcl-2 expression was significantly higher in OLETF + EX than OLETF (p< 0.05). HOMA-IR level was significantly decreased in OLETF + EX compared to OLETF (p< 0.05). CONCLUSIONS: Regular resistance exercise intervention can decrease oxidative stress by enhancing antioxidant enzyme activity and this may lead to attenuate apoptosis related protein such as caspase-3, bax and bcl-2 expression in hippocampus of diabetic population. PMID- 29614710 TI - Patient-reported outcome measures (PROMs) in patients undergoing patellofemoral arthroplasty and total knee replacement: A comparative study. AB - BACKGROUND: Incongruity in the evaluation of outcomes between patients and surgeons has led to an increasing utilization of patient-reported outcome measures (PROMs) as an evaluation method of outcome. OBJECTIVE: The aim of this study was to compare Oxford Knee Score (OKS), KOOS-PS and Kujala Score results in patients who received either PFA or TKA with and without patella resurfacing in the tretament of knee osteoarthritis. METHODS: A total of 50 patients (PFA = 19 patients; TKA with patelloplasty = 15 patients; TKA with patellar resurfacing = 16 patients) undergone surgery between 2011 and 2014 and were included for final analysis. RESULTS: No statistical significance was found for OKS, KOOS-PS and Kujala scores between the three groups. However, although patients with PFA experienced higher levels of pain. CONCLUSIONS: According to our results, it is essential to discuss the treatment options and quality of life expectations with the patient prior joint replacement surgery in order to reduce patient dissatisfaction. LEVEL OF EVIDENCE: Level III, retrospective comparative study. PMID- 29614711 TI - Measuring upper limb movement to analyze intra-body communication channel attenuation characteristics. AB - BACKGROUND: This experiment was designed to study the respective effects of the closed-state human palm and dynamic arm bending on intra-body communication channel attenuation. METHODS: We selected the right upper arm of a healthy adult male as the experimental object to measure channel attenuation variation in a closed or open palm, and when the arm was bent, so as to analyze channel characteristics. CONCLUSIONS: The experiment showed that, in a quasi-static stable system, the effects of a closed palm on channel attenuation were negligibly minimal. In contrast, the physiological signal of the living body significantly interfered with the channel in the low-frequency mode. In the dynamic arm-bending experiment, we found that the attenuation variation range corresponds to the intersection angle (90??theta? 180?) of the upper arm and forearm; these results provide the basis for the establishment of a theoretical model. PMID- 29614712 TI - Influence of Inherent Surface and Internal Defects on Mechanical Properties of Additively Manufactured Ti6Al4V Alloy: Comparison between Selective Laser Melting and Electron Beam Melting. AB - Additive manufacture (AM) appears to be the most suitable technology to produce sophisticated, high quality, lightweight parts from Ti6Al4V alloy. However, the fatigue life of AM parts is of concern. In our study, we focused on a comparison of two techniques of additive manufacture-selective laser melting (SLM) and electron beam melting (EBM)-in terms of the mechanical properties during both static and dynamic loading. All of the samples were untreated to focus on the influence of surface condition inherent to SLM and EBM. The EBM samples were studied in the as-built state, while SLM was followed by heat treatment. The resulting similarity of microstructures led to comparable mechanical properties in tension, but, due to differences in surface roughness and specific internal defects, the fatigue strength of the EBM samples reached only half the value of the SLM samples. Higher surface roughness that is inherent to EBM contributed to multiple initiations of fatigue cracks, while only one crack initiated on the SLM surface. Also, facets that were formed by an intergranular cleavage fracture were observed in the EBM samples. PMID- 29614713 TI - Cooking Fuels in Lagos, Nigeria: Factors Associated with Household Choice of Kerosene or Liquefied Petroleum Gas (LPG). AB - Cooking with dirty-burning fuels is associated with health risk from household air pollution. We assessed the prevalence of and factors associated with the use of cooking fuels, and attitudes and barriers towards use of liquefied petroleum gas (LPG). This was a cross-sectional, population-based survey conducted in 519 households in Lagos, Nigeria. We used a structured questionnaire to obtain information regarding choice of household cooking fuel and the attitudes towards the use of LPG. Kerosene was the most frequently used cooking fuel (n = 475, 91.5%; primary use n = 364, 70.1%) followed by charcoal (n = 159, 30.6%; primary use n = 88, 17%) and LPG (n = 86, 16.6%; primary use n = 63, 12.1%). Higher level of education, higher income and younger age were associated with LPG vs. kerosene use. Fuel expenditure on LPG was significantly lower than for kerosene ( N (Naira) 2169.0 +/- 1507.0 vs. N 2581.6 +/- 1407.5). Over 90% of non-LPG users were willing to switch to LPG but cited safety issues and high cost as potential barriers to switching. Our findings suggest that misinformation and beliefs regarding benefits, safety and cost of LPG are important barriers to LPG use. An educational intervention program could be a cost-effective approach to improve LPG adoption and should be formally addressed through a well-designed community based intervention study. PMID- 29614714 TI - Cloning, Synthesis and Functional Characterization of a Novel alpha-Conotoxin Lt1.3. AB - alpha-Conotoxins (alpha-CTxs) are small peptides composed of 11 to 20 amino acid residues with two disulfide bridges. Most of them potently and selectively target nicotinic acetylcholine receptor (nAChR) subtypes, and a few were found to inhibit the GABAB receptor (GABABR)-coupled N-type calcium channels (Cav2.2). However, in all of alpha-CTxs targeting both receptors, the disulfide connectivity arrangement "C1-C3, C2-C4" is present. In this work, a novel alpha4/7-CTx named Lt1.3 (GCCSHPACSGNNPYFC-NH2) was cloned from the venom ducts of Conus litteratus (C. litteratus) in the South China Sea. Lt1.3 was then chemically synthesized and two isomers with disulfide bridges "C1-C3, C2-C4" and "C1-C4, C2-C3" were found and functionally characterized. Electrophysiological experiments showed that Lt1.3 containing the common disulfide bridges "C1-C3, C2 C4" potently and selectively inhibited alpha3beta2 nAChRs and not GABABR-coupled Cav2.2. Surprisingly, but the isomer with the disulfide bridges "C1-C4, C2-C3" showed exactly the opposite inhibitory activity, inhibiting only GABABR-coupled Cav2.2 and not alpha3beta2 nAChRs. These findings expand the knowledge of the targets and selectivity of alpha-CTxs and provide a new structural motif to inhibit the GABABR-coupled Cav2.2. PMID- 29614715 TI - Intraocular Penetration of a vNAR: In Vivo and In Vitro VEGF165 Neutralization. AB - Variable new antigen receptor domain (vNAR) antibodies are novel, naturally occurring antibodies that can be isolated from naive, immune or synthetic shark libraries. These molecules are very interesting to the biotechnology and pharmaceutical industries because of their unique characteristics related to size and tissue penetrability. There have been some approved anti-angiogenic therapies for ophthalmic conditions, not related to vNAR. This includes biologics and chimeric proteins that neutralize vascular endothelial growth factor (VEGF)165, which are injected intravitreal, causing discomfort and increasing the possibility of infection. In this paper, we present a vNAR antibody against human recombinant VEGF165 (rhVEGF165) that was isolated from an immunized Heterodontus francisci shark. A vNAR called V13, neutralizes VEGF165 cytokine starting at 75 MUg/mL in an in vitro assay based on co-culture of normal human dermal fibroblasts (NHDFs) and green fluorescence protein (GFP)-labeled human umbilical vein endothelial cells (HUVECs) cells. In the oxygen-induced retinopathy model in C57BL/6:Hsd mice, we demonstrate an endothelial cell count decrease. Further, we demonstrate the intraocular penetration after topical administration of 0.1 MUg/mL of vNAR V13 by its detection in aqueous humor in New Zealand rabbits with healthy eyes after 3 h of application. These findings demonstrate the potential of topical application of vNAR V13 as a possible new drug candidate for vascular eye diseases. PMID- 29614716 TI - Immunization of Domestic Ducks with Live Nonpathogenic H5N3 Influenza Virus Prevents Shedding and Transmission of Highly Pathogenic H5N1 Virus to Chickens. AB - Wild ducks are known to be able to carry avian influenza viruses over long distances and infect domestic ducks, which in their turn infect domestic chickens. Therefore, prevention of virus transmission between ducks and chickens is important to control the spread of avian influenza. Here we used a low pathogenic wild aquatic bird virus A/duck/Moscow/4182/2010 (H5N3) for prevention of highly pathogenic avian influenza virus (HPAIV) transmission between ducks and chickens. We first confirmed that the ducks orally infected with H5N1 HPAIV A/chicken/Kurgan/3/2005 excreted the virus in feces. All chickens that were in contact with the infected ducks became sick, excreted the virus, and died. However, the ducks orally inoculated with 104 50% tissue culture infective doses of A/duck/Moscow/4182/2010 and challenged 14 to 90 days later with H5N1 HPAIV did not excrete the challenge virus. All contact chickens survived and did not excrete the virus. Our results suggest that low pathogenic virus of wild aquatic birds can be used for prevention of transmission of H5N1 viruses between ducks and chickens. PMID- 29614717 TI - Non-Transfusional Hemocomponents: From Biology to the Clinic-A Literature Review. AB - Non-transfusional hemocomponents for surgical use are autogenous products prepared through the centrifugation of a blood sample from a patient. Their potential beneficial outcomes include hard and soft tissue regeneration, local hemostasis, and the acceleration of wound healing. Therefore, they are suitable for application in different medical fields as therapeutic options and in surgical practices that require tissue regeneration. PMID- 29614718 TI - Interaction of the Mouse Polyomavirus Capsid Proteins with Importins Is Required for Efficient Import of Viral DNA into the Cell Nucleus. AB - The mechanism used by mouse polyomavirus (MPyV) overcomes the crowded cytosol to reach the nucleus has not been fully elucidated. Here, we investigated the involvement of importin alpha/beta1 mediated transport in the delivery of MPyV genomes into the nucleus. Interactions of the virus with importin beta1 were studied by co-immunoprecipitation and proximity ligation assay. For infectivity and nucleus delivery assays, the virus and its capsid proteins mutated in the nuclear localization signals (NLSs) were prepared and produced. We found that at early times post infection, virions bound importin beta1 in a time dependent manner with a peak of interactions at 6 h post infection. Mutation analysis revealed that only when the NLSs of both VP1 and VP2/3 were disrupted, virus did not bind efficiently to importin beta1 and its infectivity remarkably decreased (by 80%). Nuclear targeting of capsid proteins was improved when VP1 and VP2 were co-expressed. VP1 and VP2 were effectively delivered into the nucleus, even when one of the NLS, either VP1 or VP2, was disrupted. Altogether, our results showed that MPyV virions can use VP1 and/or VP2/VP3 NLSs in concert or individually to bind importins to deliver their genomes into the cell nucleus. PMID- 29614720 TI - A Monolithic Electrochemical Micro Seismic Sensor Capable of Monitoring Three Dimensional Vibrations. AB - A monolithic electrochemical micro seismic sensor capable of monitoring three axial vibrations was proposed in this paper. The proposed micro sensor mainly consisted of four sensing units interconnected within flow channels and by interpreting the voltage outputs of the sensing units, vibrations with arbitrary directions can be quantified. The proposed seismic sensors are fabricated based on MEMS technologies and characterized, which produced sensitivities along x, y, and z axes as 2473.2 +/- 184.5 V/(m/s), 2261.7 +/- 119.6 V/(m/s), and 3480.7 +/- 417.2 V/(m/s) at 30 Hz. In addition, the vibrations in x-y, x-z, and y-z planes were applied to the developed seismic sensors, leading to comparable monitoring results after decoupling calculations with the input velocities. Furthermore, the results have shown its feasibilities for seismic data recording. PMID- 29614719 TI - A Specific Melon Concentrate Exhibits Photoprotective Effects from Antioxidant Activity in Healthy Adults. AB - Skin is the largest body organ and the first barrier to exogenous threats. This organ is constantly exposed to external factors such as ultraviolet radiation, which induces many adverse effects including sunburn, depigmentation, photo aging, photo immune suppression, and even skin cancer. Antioxidants seem to be good candidates in order to reduce ultraviolet-mediated damages and to prevent the health consequences of ultraviolet exposure. The present investigation aims to further characterize the potential skin photoprotective effects of a food supplementation and a topical administration of a melon concentrate alone or in combination. A clinical study assessing the Minimal Erythema Dose (MED) was first set up to evaluate photoprotection. Afterward, an independent in vitro study was performed on human skin explants from a donor to evaluate the effect of the melon concentrate at different levels including on the sunburn cells formation and on the endogenous antioxidant enzymes and its influence on melanin. Clinical study results demonstrate that melon concentrate application and/or supplementation increased MED. It also increased the endogenous antioxidant enzymes and reduced sunburn cells and melanin level on irradiated skin explants. Therefore, it is suggested that melon concentrate administration (oral and/or topical) could be a useful strategy for photoprotection due to its antioxidant properties. PMID- 29614721 TI - Antimicrobial Activity of Al2O3, CuO, Fe3O4, and ZnO Nanoparticles in Scope of Their Further Application in Cement-Based Building Materials. AB - Nanoparticles were proposed as antibacterial cement admixtures for the production of cement-based composites. Nevertheless, the standards for evaluation of such admixtures still do not indicate which model organisms to use, particularly in regard to the further application of material. Apart from the known toxicity of nanomaterials, in the case of cement-based composites there are limitations associated with the mixing and dispersion of nanomaterials. Therefore, four nanooxides (Al2O3, CuO, Fe3O4, and ZnO) and seven microorganisms were tested to initially evaluate the applicability of nanooxides in relation to their further use in cement-based composites. Studies of nanoparticles included chemical analysis, microbial growth kinetics, 4- and 24 h toxicity, and biofilm formation assay. Nanooxides showed toxicity against microorganisms in the used concentration, although the populations were able to re-grow. Furthermore, the effect of action was variable even between strains from the same genus. The effect of nanoparticles on biofilms depended on the used strain. Gathered results show several problems that can occur while studying nanoparticles for specific further application. Proper protocols for nanomaterial dispersion prior the preparation of cement-based composites, as well as a standardized approach for their testing, are the fundamental issues that have to be resolved to produce efficient composites. PMID- 29614723 TI - Carbon Fiber Reinforced Carbon-Al-Cu Composite for Friction Material. AB - A carbon/carbon-Al-Cu composite reinforced with carbon fiber 2.5D polyacrylonitrile-based preforms was fabricated using the pressureless infiltration technique. The Al-Cu alloy liquids were successfully infiltrated into the C/C composites at high temperature and under vacuum. The mechanical and metallographic properties, scanning electron microscopy (SEM), X-ray diffraction (XRD), and energy dispersive spectroscopy (EDS) of the C/C-Al-Cu composites were analyzed. The results showed that the bending property of the C/C-Al-Cu composites was 189 MPa, whereas that of the pure carbon slide material was only 85 MPa. The compressive strength of C/C-Al-Cu was 213 MPa, whereas that of the pure carbon slide material was only 102 MPa. The resistivity of C/C-Al-Cu was only 1.94 MUOmegam, which was lower than that of the pure carbon slide material (29.5 MUOmegam). This finding can be attributed to the "network conduction" structure. Excellent wettability was observed between Al and the carbon matrix at high temperature due to the existence of Al4C3. The friction coefficients of the C/C, C/C-Al-Cu, and pure carbon slide composites were 0.152, 0.175, and 0.121, respectively. The wear rate of the C/C-Al-Cu composites reached a minimum value of 2.56 * 10-7 mm3/Nm. The C/C-Al-Cu composite can be appropriately used as railway current collectors for locomotives. PMID- 29614724 TI - Two New Diketomorpholine Derivatives and a New Highly Conjugated Ergostane-Type Steroid from the Marine Algal-Derived Endophytic Fungus Aspergillus alabamensis EN-547. AB - Chemical investigation of the marine algal-derived endophytic fungus Aspergillus alabamensis EN-547 resulted in the isolation of 4-epi-seco-shornephine A methyl ester (1) and 4-epi-seco-shornephine A carboxylic acid (2), two new secondary metabolites having a rare diketomorpholine motif, and 28-acetoxy 12beta,15alpha,25-trihydroxyergosta-4,6,8(14),22-tetraen-3-one (3), a new highly conjugated ergostane-type steroid, together with four known metabolites (4-7). Their chemical structures were elucidated by detailed analysis of their NMR spectra, ECDs, HRESIMS, optical rotation, and X-ray crystallographic data, and by comparison with literature data as well. The antimicrobial activities of compounds 1-7 were evaluated. PMID- 29614725 TI - Assessment of Knowledge, Attitude and Barriers towards Pharmacovigilance among Physicians and Pharmacists of Abbottabad, Pakistan. AB - OBJECTIVES: Pharmacovigilance in Pakistan needs robust preference in terms of implementation and consistent movement of structured approaches. The objective of this study is to explore the knowledge, attitude and barriers towards adverse drug reaction (ADR) reporting among physicians and pharmacists and to explore the encouraging factors of ADR reporting. METHODS: The current research was a cross sectional study design in which a pre-validated questionnaire was administered to physicians and pharmacists in Abbottabad, Pakistan. The study was conducted for two months from January 2016 to February 2016. RESULTS: A total of 194 physicians and pharmacists responded with a response rate of 35.3%. All the respondents either strongly agreed or agreed that ADRs reporting is a part of their duty. Half of the respondents agreed that monitoring of drug safety is important. Around three quarters of respondents (74.2%) stated that they did not report ADRs due to unavailability of reporting forms while 70% cited lack of a proper pharmacovigilance center as one of the key barriers. Half of the respondents (52.2%) did not report due to their insufficient knowledge. A large majority (81.8%) said that they would report ADRs if there is pharmacovigilance center. On the point of incentives, opinion seems to be divided. Slightly less than half (47.8%) cited their wish to have few incentives while the remaining 52.2% either preferred to be neutral or disagreed. CONCLUSION: Based on the study findings, barriers were mostly related to general unfamiliarity with ADRs reporting guidelines and the non-existence of a pharmacovigilance center. It is highlighted that the regulatory body should carve a niche for a properly functional pharmacovigilance center and initiate educational programs for strengthening knowledge and attitudes towards ADR reporting. PMID- 29614727 TI - Mapping Soil Salinity/Sodicity by using Landsat OLI Imagery and PLSR Algorithm over Semiarid West Jilin Province, China. AB - Soil salinity and sodicity can significantly reduce the value and the productivity of affected lands, posing degradation, and threats to sustainable development of natural resources on earth. This research attempted to map soil salinity/sodicity via disentangling the relationships between Landsat 8 Operational Land Imager (OLI) imagery and in-situ measurements (EC, pH) over the west Jilin of China. We established the retrieval models for soil salinity and sodicity using Partial Least Square Regression (PLSR). Spatial distribution of the soils that were subjected to hybridized salinity and sodicity (HSS) was obtained by overlay analysis using maps of soil salinity and sodicity in geographical information system (GIS) environment. We analyzed the severity and occurring sizes of soil salinity, sodicity, and HSS with regard to specified soil types and land cover. Results indicated that the models' accuracy was improved by combining the reflectance bands and spectral indices that were mathematically transformed. Therefore, our results stipulated that the OLI imagery and PLSR method applied to mapping soil salinity and sodicity in the region. The mapping results revealed that the areas of soil salinity, sodicity, and HSS were 1.61 * 106 hm2, 1.46 * 106 hm2, and 1.36 * 106 hm2, respectively. Also, the occurring area of moderate and intensive sodicity was larger than that of salinity. This research may underpin efficiently mapping regional salinity/sodicity occurrences, understanding the linkages between spectral reflectance and ground measurements of soil salinity and sodicity, and provide tools for soil salinity monitoring and the sustainable utilization of land resources. PMID- 29614722 TI - Dietary Flavonoids in the Prevention of T2D: An Overview. AB - Type 2 diabetes (T2D) is a progressive metabolic disease that is increasing in prevalence globally. It is well established that insulin resistance (IR) and a progressive decline in functional beta-cell mass are hallmarks of developing T2D. Obesity is a leading pathogenic factor for developing IR. Constant IR will progress to T2D when beta-cells are unable to secret adequate amounts of insulin to compensate for decreased insulin sensitivity. Recently, a considerable amount of research has been devoted to identifying naturally occurring anti-diabetic compounds that are abundant in certain types of foods. Flavonoids are a group of polyphenols that have drawn great interest for their various health benefits. Results from many clinical and animal studies demonstrate that dietary intake of flavonoids might be helpful in preventing T2D, although cellular and molecular mechanisms underlying these effects are still not completely understood. This review discusses our current understanding of the pathophysiology of T2D and highlights the potential anti-diabetic effects of flavonoids and mechanisms of their actions. PMID- 29614726 TI - Mediterranean Diet and Health Outcomes in the SUN Cohort. AB - The Mediterranean Dietary (MedDiet) Pattern has been linked to many beneficial health effects. This review summarizes the main findings of a prospective cohort study, the Seguimiento Universidad de Navarra (SUN) cohort, specifically focused on MedDiet and the risk of major chronic disease. It is an open cohort in which 22,786 Spanish university graduates have participated since 1999 until February 2018. Data on diet, lifestyle and clinical diagnosis are collected at baseline and every two years. After reviewing 21 publications from the SUN cohort on the effects of the MedDiet, we conclude that this cohort has provided good evidence that a high MedDiet adherence is associated with a reduced incidence of all-cause mortality, fatal and non-fatal major cardiovascular disease (CVD), type 2 diabetes, weight gain, metabolic syndrome, depression, cognitive decline, and nephrolithiasis. An inverse dose-response relationship was found for many of these associations. The MedDiet was also associated with lower average heart rate, a mitigation of the harmful effects of overweight/obesity on the risk of CVD, and an attenuation of the effects of obesity on type 2 diabetes. A suggestion that the MedDiet may enhance fertility was also found. PMID- 29614728 TI - Diatomite Photonic Crystals for Facile On-Chip Chromatography and Sensing of Harmful Ingredients from Food. AB - Diatomaceous earth-otherwise called diatomite-is essentially composed of hydrated biosilica with periodic nanopores. Diatomite is derived from fossilized remains of diatom frustules and possesses photonic-crystal features. In this paper, diatomite simultaneously functions as the matrix of the chromatography plate and the substrate for surface-enhanced Raman scattering (SERS), by which the photonic crystal-features could enhance the optical field intensity. The on-chip separation performance of the device was confirmed by separating and detecting industrial dye (Sudan I) in an artificial aqueous mixture containing 4 mercaptobenzoic acid (MBA), where concentrated plasmonic Au colloid was casted onto the analyte spot for SERS measurement. The plasmonic-photonic hybrid mode between the Au nanoparticles (NP) and the diatomite layer could supply nearly 10 times the increment of SERS signal (MBA) intensity compared to the common silica gel chromatography plate. Furthermore, this lab-on-a-chip photonic crystal device was employed for food safety sensing in real samples and successfully monitored histamine in salmon and tuna. This on-chip food sensor can be used as a cheap, robust, and portable sensing platform for monitoring for histamine or other harmful ingredients at trace levels in food products. PMID- 29614730 TI - Extremely Low Frequency-Magnetic Field (ELF-MF) Exposure Characteristics among Semiconductor Workers. AB - We assessed the exposure of semiconductor workers to extremely low frequency magnetic fields (ELF-MF) and identified job characteristics affecting ELF-MF exposure. These were demonstrated by assessing the exposure of 117 workers involved in wafer fabrication (fab) and chip packaging wearing personal dosimeters for a full shift. A portable device was used to monitor ELF-MF in high temporal resolution. All measurements were categorized by operation, job and working activity during working time. ELF-MF exposure of workers were classified based on the quartiles of ELF-MF distribution. The average levels of ELF-MF exposure were 0.56 uT for fab workers, 0.59 uT for chip packaging workers and 0.89 uT for electrical engineers, respectively. Exposure to ELF-MF differed among types of factory, operation, job and activity. Workers engaged in the diffusion and chip testing activities showed the highest ELF-MF exposure. The ELF-MF exposures of process operators were found to be higher than those of maintenance engineers, although peak exposure and/or patterns varied. The groups with the highest quartile ELF-MF exposure level are operators in diffusion, ion implantation, module and testing operations, and maintenance engineers in diffusion, module and testing operations. In conclusion, ELF-MF exposure among workers can be substantially affected by the type of operation and job, and the activity or location. PMID- 29614731 TI - The Impact of Suicide Bereavement on Educational and Occupational Functioning: A Qualitative Study of 460 Bereaved Adults. AB - People bereaved by suicide are at an increased risk of suicide and of dropping out of education or work. Explanations for these associations are unclear, and more research is needed to understand how improving support in educational or work settings for people bereaved by suicide might contribute to reducing suicide risk. Our objective was to explore the impact of suicide on occupational functioning. We conducted a cross-sectional online study of bereaved adults aged 18-40, recruited from staff and students of British higher educational institutions in 2010. We used thematic analysis to analyse free text responses to two questions probing the impact of suicide bereavement on work and education. Our analysis of responses from 460 adults bereaved by suicide identified three main themes: (i) specific aspects of grief that impacted on work performance, cognitive and emotional domains, and social confidence; (ii) structural challenges in work or educational settings including a lack of institutional support, the impact of taking time off, and changes to caring roles; and (iii) new perspectives on the role of work, including determination to achieve. Institutional support should be tailored to take account of the difficulties and experiences described. PMID- 29614732 TI - Determinants of Child Health Behaviors in a Disadvantaged Area from a Community Perspective: A Participatory Needs Assessment. AB - Children from disadvantaged areas are hard to reach for interventions aimed at promoting healthy lifestyles. We conducted a participatory needs assessment, in which researchers collaborated with a community in a disadvantaged area in Amsterdam to gain an understanding of the health-related issues of children within this community. Qualitative data was collected through: three to four participatory group meetings with three groups of 9-12-year-old children (n = 5-9 per group); nine interviews with professionals working with youth; two interviews with parents and their children; and informal meetings including 31 parents. All transcriptions or summaries were coded and analyzed. Childhood overweight/obesity was indicated as the main health issue. A lack of physical activity and unhealthy dietary behavior were identified as the main risk factors, with underlying determinants such as culture, habits, finances, and social norms. Identified needs included more supervised, low-priced sports activities at a nearby location and more education on adopting a healthy diet. Our participatory health needs assessment resulted in a comprehensive overview of the most relevant risk factors and determinants of childhood overweight/obesity and needs from the community's perspective. This knowledge aids in the development of better tailored, and thereby potentially more effective, interventions. PMID- 29614733 TI - Factors that Predict Parental Willingness to Have Their Children Vaccinated against HPV in a Country with Low HPV Vaccination Coverage. AB - Background: Adolescent HPV (Human Papilloma Virus) vaccination is yet to be introduced as a mandatory program in Poland. Polish literature on factors associated with adolescent HPV vaccination is scant, despite the fact that uptake is one of the poorest in the European Union. Objectives: To assess HPV awareness and identify independent predictors for parental willingness to have their children vaccinated against HPV. Methods: All parents of first grade students from three selected high schools in Zgorzelec, Poland, who participated in parent teacher meetings at the time the study was conducted, had their children unvaccinated regarding HPV, and who gave informed consent to participate were included. There were 600 first grade students; 9 were vaccinated against HPV. This left 591 parents who met the eligibility criteria; the response rate was 76.1%. Results: Awareness of HPV was reported by 55.3% of 450 parents (mean age 42 years, 70.9% females); 85.1% expressed their willingness to vaccinate their children against HPV; 31.3% identified HPV as a sexually transmitted pathogen, and 36.2% identified it as a risk factor of cervical cancer. Multivariable logistic regression analyses indicated that being employed (OR 2.09; 95% CI: 1.10 3.86), having positive attitudes toward vaccines (OR 3.02; 95% CI: 1.34-6.49), previous information about HPV (OR 2.02; 95% CI: 1.17-3.51), and concerns about the side effects of the HPV vaccine (OR 0.60; 95% CI: 0.35-0.99) were independent predictors of parents' willingness to vaccinate. Conclusions: Attitudes regarding their child being vaccinated against HPV were positive among Polish parents, even though awareness and knowledge of HPV in this group were low. Most of the significant factors that influenced their willingness were modifiable, such as being informed about HPV and having positive attitudes toward vaccines. Future interventions should focus specifically on vulnerable subgroups, such as unemployed parents. PMID- 29614734 TI - Total Synthesis of Bioactive Marine Meroterpenoids: The Cases of Liphagal and Frondosin B. AB - Liphagal and frondosin B are two marine-derived secondary metabolites sharing a very similar polyfused-benzofuran skeleton. The two tetracyclic meroterpenoids were isolated from marine sponges, both featuring a 6-5-7-6 fused ring system. A preliminary bioactive study shows that (+)-liphagal is a selective kinase (PI3K alpha) inhibitor, while (+)-frondosin B is shown to inhibit the binding of the cytokine interleukin-8 (IL-8) to its receptor, CX-CLR1/2. The unique structures and interesting biological profiles of these two meroterpenoids have attracted considerable attention from synthetic chemists. Herein we summarize the synthetic efforts with respect to (+)-liphagal and (+)-frondosin B during the past two decades. PMID- 29614729 TI - Imaging, Tracking and Computational Analyses of Virus Entry and Egress with the Cytoskeleton. AB - Viruses have a dual nature: particles are “passive substances” lacking chemical energy transformation, whereas infected cells are “active substances” turning-over energy. How passive viral substances convert to active substances, comprising viral replication and assembly compartments has been of intense interest to virologists, cell and molecular biologists and immunologists. Infection starts with virus entry into a susceptible cell and delivers the viral genome to the replication site. This is a multi-step process, and involves the cytoskeleton and associated motor proteins. Likewise, the egress of progeny virus particles from the replication site to the extracellular space is enhanced by the cytoskeleton and associated motor proteins. This overcomes the limitation of thermal diffusion, and transports virions and virion components, often in association with cellular organelles. This review explores how the analysis of viral trajectories informs about mechanisms of infection. We discuss the methodology enabling researchers to visualize single virions in cells by fluorescence imaging and tracking. Virus visualization and tracking are increasingly enhanced by computational analyses of virus trajectories as well as in silico modeling. Combined approaches reveal previously unrecognized features of virus-infected cells. Using select examples of complementary methodology, we highlight the role of actin filaments and microtubules, and their associated motors in virus infections. In-depth studies of single virion dynamics at high temporal and spatial resolutions thereby provide deep insight into virus infection processes, and are a basis for uncovering underlying mechanisms of how cells function. PMID- 29614736 TI - Design of a Broadband Tunable Terahertz Metamaterial Absorber Based on Complementary Structural Graphene. AB - We present a simple design for a broadband tunable terahertz (THz) metamaterial absorber (MMA) consisting of a complementary cross-oval-shaped graphene (CCOSG) structure and dielectric substrate placed on a continuous metal film. Both numerical simulation and theoretical calculation results indicate that the absorbance is greater than 80% from 1.2 to 1.8 THz, and the corresponding relative bandwidth is up to 40%. Simulated electric field and power loss density distributions reveal that the broadband absorption mainly originates from the excitation of continuous surface plasmon resonance (SPR) on the CCOSG. In addition, the MMA is polarization-insensitive for both transverse-electric (TE) and transverse-magnetic (TM) modes due to the geometry rotational symmetry of the unit-cell structure. Furthermore, the broadband absorption properties of the designed MMA can be effectively tunable by varying the geometric parameters of the unit-cell and chemical potential of graphene. Our results may find promising applications in sensing, detecting, and optoelectronic-related devices. PMID- 29614735 TI - Children and Caregivers' Exposure to Adverse Childhood Experiences (ACES): Association with Children's and Caregivers' Psychological Outcomes in a Therapeutic Preschool Program. AB - Exposure to adverse childhood experiences (ACE) has been found to have a profound negative impact on multiple child outcomes, including academic achievement, social cognition patterns, and behavioral adjustment. However, these links have yet to be examined in preschool children that are already experiencing behavior or social-emotional problems. Thus, the present study examined the links between the caregiver's and the child's exposure to ACE and multiple child and caregiver's outcomes in a sample of 30 preschool children enrolled in a Therapeutic Nursery Program (TNP). Children are typically referred to this TNP due to significant delays in their social emotional development that often result in difficulty functioning in typical childcare, home, and community settings. Analyses revealed some contradictory patterns that may be specific to this clinical sample. Children with higher exposure to ACE showed more biased social information processing patterns and their caregivers reported lower child social skills than caregivers of children with less exposure, however their inhibitory control levels were higher (better control) and staff reported that these children exhibited better social skills as well as better approaches to learning than children with less exposure. No such contradictions were found in relation to the caregiver's exposure to ACE, as it was positively associated with a number of negative child and caregiver outcomes. PMID- 29614737 TI - Application of a Time-Stratified Case-Crossover Design to Explore the Effects of Air Pollution and Season on Childhood Asthma Hospitalization in Cities of Differing Urban Patterns: Big Data Analytics of Government Open Data. AB - Few studies have assessed the lagged effects of levels of different urban city air pollutants and seasons on asthma hospitalization in children. This study used big data analysis to explore the effects of daily changes in air pollution and season on childhood asthma hospitalization from 2001 to 2010 in Taipei and Kaohsiung City, Taiwan. A time-stratified case-crossover study and conditional logistic regression analysis were employed to identify associations between the risk of hospitalization due to asthma in children and the levels of air pollutants (PM2.5, PM10, O3, SO2, and NO2) in the days preceding hospitalization. During the study period, 2900 children in Taipei and 1337 in Kaohsiung aged <=15 years were hospitalized due to asthma for the first time. The results indicated that the levels of air pollutants were significantly associated with the risk of asthma hospitalization in children, and seasonal effects were observed. High levels of air pollution in Kaohsiung had greater effects than in Taipei after adjusting for seasonal variation. The most important factor was O3 in spring in Taipei. In children aged 0-6 years, asthma was associated with O3 in Taipei and SO2 in Kaohsiung, after controlling for the daily mean temperature and relative humidity. PMID- 29614739 TI - Positioning Locality Using Cognitive Directions Based on Indoor Landmark Reference System. AB - Locality descriptions are generally communicated using reference objects and spatial relations that reflect human spatial cognition. However, uncertainty is inevitable in locality descriptions. Positioning locality with locality description, with a mapping mechanism between the qualitative and quantitative data, is one of the important research issues in next-generation geographic information sciences. Spatial relations play an important role in the uncertainty of positioning locality. In indoor landmark reference systems, the nearest landmarks can be selected when describing localities by using direction relations indoors. By using probability operation, we combine a set of uncertainties, that is, near and direction relations to positioning locality. Some definitions are proposed from cognitive and computational perspectives. We evaluate the performance of our method through indoor cognitive experiments. Test results demonstrate that a positioning accuracy of 3.55 m can be achieved with the semantically derived direction relationships in indoor landmark reference systems. PMID- 29614740 TI - Assessing the Crop-Water Status in Almond (Prunus dulcis Mill.) Trees via Thermal Imaging Camera Connected to Smartphone. AB - Different tools are being implemented in order to improve the water management in agricultural irrigated areas of semiarid environments. Thermography has been progressively introduced as a promising technique for irrigation scheduling and the assessing of crop-water status, especially when deficit irrigation is being implemented. However, an important limitation is related to the cost of the actual cameras, this being a severe limitation to its practical usage by farmers and technicians. This work evaluates the potential and the robustness of a thermal imaging camera that is connected to smartphone (Flir One) recently developed by Flir Systems Inc. as a first step to assess the crop water status. The trial was developed in mature almond (Prunus dulcis Mill.) trees that are subjected to different irrigation treatments. Thermal information obtained by the Flir One camera was deal with the thermal information obtained with a conventional Thermal Camera (Flir SC660) with a high resolution, and subsequently, confronted with other related plant physiological parameters (leaf water potential, Psileaf, and stomatal conductance, gs). Thermal imaging camera connected to smartphone provided useful information in estimating the crop-water status in almond trees, being a potential promising tool to accelerate the monitoring process and thereby enhance water-stress management of almond orchards. PMID- 29614738 TI - Molecular Pathophysiology of Epithelial Barrier Dysfunction in Inflammatory Bowel Diseases. AB - Over the years, the scientific community has explored myriads of theories in search of the etiology and a cure for inflammatory bowel disease (IBD). The cumulative evidence has pointed to the key role of the intestinal barrier and the breakdown of these mechanisms in IBD. More and more scientists and clinicians are embracing the concept of the impaired intestinal epithelial barrier and its role in the pathogenesis and natural history of IBD. However, we are missing a key tool that bridges these scientific insights to clinical practice. Our goal is to overcome the limitations in understanding the molecular physiology of intestinal barrier function and develop a clinical tool to assess and quantify it. This review article explores the proteins in the intestinal tissue that are pivotal in regulating intestinal permeability. Understanding the molecular pathophysiology of impaired intestinal barrier function in IBD may lead to the development of a biochemical method of assessing intestinal tissue integrity which will have a significant impact on the development of novel therapies targeting the intestinal mucosa. PMID- 29614741 TI - Synthesis and Fluorescence Properties of a New Heterotrinuclear Co(II) Ce(III)Complex Constructed from a bis(salamo)-Type Tetraoxime Ligand. AB - [Co2(L)Ce(OAc)3(CH3CH2OH)].1.5CH3OH?0.5CH2Cl2, a heterotrinuclear Co(II)-Ce(III) bis(salamo)-type complex with a symmetric bi(salamo)-type ligand H4L and an acyclic naphthalenediol moiety, was designed, synthesized and characterized by elemental analyses, FT-IR, UV-Vis and fluorescence spectroscopy and X-ray crystallography. The X-ray crystallographic investigation revealed the heterotrinuclear complex consisted of two Co(II) atoms, one Ce(III) atom, one (L)4- unit, three MU2-acetate ions, one coordinated ethanol molecule, one and half crystallization methanol molecule and half crystallization dichloromethane molecule. Two Co(II) atoms located in the N2O2 coordination spheres, are both hexacoordinated, with slightly distorted octahedral geometries. The Ce(III) atom is nine-coordinated and located in the O6 cavity possesses a single square antiprismatic geometry. In addition, supramolecular interactions exist in the Co(II)-Ce(III) complex. Two infinite 2D supramolecular structures are built via intermolecular O-H...O, C-H...O and C-H...pi interactions, respectively. PMID- 29614742 TI - Preventing Opioid Use Disorders among Fishing Industry Workers. AB - Fishing industry workers are at high risk for work-related musculoskeletal disorders (MSDs) and injuries. Prescription opioids used to treat pain injuries may put these workers at increased risk for developing substance disorders. Using a Community-Based Participatory Research approach, formative research was conducted to inform the eventual development of relevant interventions to prevent and reduce opioid use disorders among fishing industry workers. Qualitative interviews (n = 21) were conducted to assess: knowledge and attitudes about opioid use disorders; features of fishing work that might affect use and/or access to treatment; and community and organizational capacity for prevention and treatment. Participants reported numerous pathways connecting commercial fishing with opioid use. The combination of high stress and physically tasking job duties requires comprehensive workplace interventions to prevent chronic pain and MSDs, in addition to tailored and culturally responsive treatment options to address opioid use disorders in this population. Public health programs must integrate workplace health and safety protection along with evidence-based primary, secondary, and tertiary interventions in order to address opioid use disorders, particularly among workers in strenuous jobs. PMID- 29614744 TI - Properties of Two-Variety Natural Luffa Sponge Columns as Potential Mattress Filling Materials. AB - Luffa sponge (LS) is a resourceful material with fibro-vascular reticulated structure and extremely high porosity, which make it a potential candidate for manufacturing light mattress. In this study, two types of LS columns, namely high density (HD) and low-density (LD) columns, were investigated as materials for filling the mattress. The results showed that the compressive strength of HD LS columns was significantly greater than that of LD LS columns. However, the densification strains of the two types of LS column were both in the range of 0.6 to 0.7. Besides, HD LS columns separately pressed to the smooth plateau region and the initial densification region exhibited a partial recovery of instant height when they were unloaded, and then both of them showed no more than 4.2% of height recovery after being allowed to rest at a constant temperature and humidity for 24 h. In contrast, when LD LS columns were compressed to the smooth plateau region, the height recovery was less than 1.62% compared to when they were pressed to the initial densification region, and that was more than 15.62%. Similar to other plant fibers used as mattress fillers, the two types of LS columns also showed good water absorption capacity-both of them could absorb water from as much as 2.07 to 3.45 times their own weight. At the same time, the two types of LS columns also showed good water desorption. The water desorption ratio of HD and LD LS columns separately reached 76.86 and 91.44%, respectively, after being let rest at a constant temperature and humidity for 13 h. PMID- 29614743 TI - Protective Effect of Polyphenol-Rich Extract from Bee Pollen in a High-Fat Diet. AB - We have studied a preventive effect of polyphenol-rich bee pollen ethanol extract (EEP) against histological changes in the liver and cardiac blood vessels, abnormalities of lipid profile, and the levels of oxidized low density lipoproteins (ox-LDL), asymmetric dimethylarginine (ADMA), angiotensin-converting enzyme (ACE), and angiotensin II (ANG II) caused by a high-fat diet in C57BL6 mice. Supplementing the diet with EEP in the doses of 0.1 g/kg body mass (BM) and 1 g/kg BM resulted in a decrease of total cholesterol by 31% and 35%, respectively. It also decreased the level of low density lipoproteins by 67% and 90%, respectively. No differences in the levels of high density lipoprotein and triacylglycerols were observed. EEP reduced the level of ox-LDL by 33% and 47%, ADMA by 13% and 51%, ACE by 17% and 30%, as well as ANG II by 11% and 15% in a dose-dependent manner, which proves a protective effect of EEP in a high-fat diet. EEP reduces and/or prevents hepatic steatosis and degenerative changes caused by a high-fat diet in C57BL6 mice, which indicates its hepatoprotective effect. EEP used with standard feed does not disturb a normal concentration of the assayed parameters. PMID- 29614745 TI - Assessment of Spatiotemporal Fusion Algorithms for Planet and Worldview Images. AB - Although Worldview-2 (WV) images (non-pansharpened) have 2-m resolution, the re visit times for the same areas may be seven days or more. In contrast, Planet images are collected using small satellites that can cover the whole Earth almost daily. However, the resolution of Planet images is 3.125 m. It would be ideal to fuse these two satellites images to generate high spatial resolution (2 m) and high temporal resolution (1 or 2 days) images for applications such as damage assessment, border monitoring, etc. that require quick decisions. In this paper, we evaluate three approaches to fusing Worldview (WV) and Planet images. These approaches are known as Spatial and Temporal Adaptive Reflectance Fusion Model (STARFM), Flexible Spatiotemporal Data Fusion (FSDAF), and Hybrid Color Mapping (HCM), which have been applied to the fusion of MODIS and Landsat images in recent years. Experimental results using actual Planet and Worldview images demonstrated that the three aforementioned approaches have comparable performance and can all generate high quality prediction images. PMID- 29614746 TI - New Digital Metal-Oxide (MOx) Sensor Platform. AB - The application of metal oxide gas sensors in Internet of Things (IoT) devices and mobile platforms like wearables and mobile phones offers new opportunities for sensing applications. Metal-oxide (MOx) sensors are promising candidates for such applications, thanks to the scientific progresses achieved in recent years. For the widespread application of MOx sensors, viable commercial offerings are required. In this publication, the authors show that with the new Sensirion Gas Platform (SGP) a milestone in the commercial application of MOx technology has been reached. The architecture of the new platform and its performance in selected applications are presented. PMID- 29614748 TI - Enhanced Supercapacitor Performance Using Electropolymerization of Self-Doped Polyaniline on Carbon Film. AB - In this work, we electrochemically deposited self-doped polyanilines (SPANI) on the surface of carbon-nanoparticle (CNP) film, enhancing the superficial faradic reactions in supercapacitors and thus improving their performance. SPANI was electrodeposited on the CNP-film employing electropolymerization of aniline (AN) and o-aminobenzene sulfonic acid (SAN) comonomers in solution. Here, SAN acts in dual roles of a self-doped monomer while it also provides an acidic environment which is suitable for electropolymerization. The performance of SPANI-CNP-based supercapacitors significantly depends upon the mole ratio of AN/SAN. Supercapacitor performance was investigated by using cyclic voltammetry (CV), galvanostatic charge and discharge (GCD), and electrochemical impedance spectroscopy (EIS). The optimal performance of SPANI-CNP-based supercapacitor exists at AN/SAN ratio of 1.0, having the specific capacitance of 273.3 Fg-1 at the charging current density of 0.5 Ag-1. PMID- 29614747 TI - Low Dose Carbon Black Nanoparticle Exposure Does Not Aggravate Allergic Airway Inflammation in Mice Irrespective of the Presence of Surface Polycyclic Aromatic Hydrocarbons. AB - Exposure to exogenous noxae, such as particulate matter, can trigger acute aggravations of allergic asthma-a chronic inflammatory airway disease. We tested whether Carbon Black nanoparticles (CBNP) with or without surface polycyclic aromatic hydrocarbons (PAH) aggravate an established allergic airway inflammation in mice. In an ovalbumin mouse model, Printex(r)90 (P90), P90 coated with benzo[a]pyrene (P90-BaP) or 9-nitroanthracene (P90-9NA), or acetylene soot exhibiting a mixture of surface PAH (AS-PAH) was administered twice (70 uL, 100 ug/mL) during an established allergic airway inflammation. We analyzed the immune cell numbers and chemokine/cytokine profiles in bronchoalveolar lavages, the mRNA expressions of markers for PAH metabolism (Cyp1a1, 1b1), oxidative stress (HO-1, Gr, Gpx-3), inflammation (KC, Mcp-1, IL-6, IL-13, IL-17a), mucin synthesis (Muc5ac, Muc5b), the histology of mucus-producing goblet cells, ciliary beat frequency (CBF), and the particle transport speed. CBNP had a comparable primary particle size, hydrodynamic diameter, and zeta-potential, but differed in the specific surface area (P90 > P90-BaP = P90-9NA = AS-PAH) and surface chemistry. None of the CBNP tested increased any parameter related to inflammation. The unmodified P90, however, decreased the tracheal CBF, decreased the Muc5b in intrapulmonary airways, but increased the tracheal Muc5ac. Our results demonstrated that irrespective of the surface PAH, a low dose of CBNP does not acutely aggravate an established allergic airway inflammation in mice. PMID- 29614749 TI - Robust Economic Control Decision Method of Uncertain System on Urban Domestic Water Supply. AB - As China quickly urbanizes, urban domestic water generally presents the circumstances of both rising tendency and seasonal cycle fluctuation. A robust economic control decision method for dynamic uncertain systems is proposed in this paper. It is developed based on the internal model principle and pole allocation method, and it is applied to an urban domestic water supply system with rising tendency and seasonal cycle fluctuation. To achieve this goal, first a multiplicative model is used to describe the urban domestic water demand. Then, a capital stock and a labor stock are selected as the state vector, and the investment and labor are designed as the control vector. Next, the compensator subsystem is devised in light of the internal model principle. Finally, by using the state feedback control strategy and pole allocation method, the multivariable robust economic control decision method is implemented. The implementation with this model can accomplish the urban domestic water supply control goal, with the robustness for the variation of parameters. The methodology presented in this study may be applied to the water management system in other parts of the world, provided all data used in this study are available. The robust control decision method in this paper is also applicable to deal with tracking control problems as well as stabilization control problems of other general dynamic uncertain systems. PMID- 29614750 TI - Feature Tracking for High Speed AFM Imaging of Biopolymers. AB - The scanning speed of atomic force microscopes continues to advance with some current commercial microscopes achieving on the order of one frame per second and at least one reaching 10 frames per second. Despite the success of these instruments, even higher frame rates are needed with scan ranges larger than are currently achievable. Moreover, there is a significant installed base of slower instruments that would benefit from algorithmic approaches to increasing their frame rate without requiring significant hardware modifications. In this paper, we present an experimental demonstration of high speed scanning on an existing, non-high speed instrument, through the use of a feedback-based, feature-tracking algorithm that reduces imaging time by focusing on features of interest to reduce the total imaging area. Experiments on both circular and square gratings, as well as silicon steps and DNA strands show a reduction in imaging time by a factor of 3-12 over raster scanning, depending on the parameters chosen. PMID- 29614752 TI - Molecular Structural Changes in Alfalfa Detected by ATR-FTIR Spectroscopy in Response to Silencing of TT8 and HB12 Genes. AB - This study investigated the spectral changes in alfalfa molecular structures induced by silencing of Transparent Testa 8 (TT8) and Homeobox 12 (HB12) genes with univariate and multivariate analyses. TT8-silenced (TT8i), HB12-silenced (HB12i) and wild type (WT) alfalfa were grown in a greenhouse under normal conditions and were harvested at early-to-mid vegetative stage. Samples were free dried and grounded through 0.02 mm sieve for spectra collections with attenuated total reflectance Fourier transform infrared (ATR-FTIR) spectroscopy. Afterwards, both univariate and multivariate analyses were conducted on amide, carbohydrate and lipid regions. Univariate results showed that silencing of TT8 and HB12 genes affected peak heights of most total carbohydrate (TC) and structural carbohydrate (STC), and structural carbohydrate area (STCA) in carbohydrate regions; and beta sheet height, amide areas, and ratios of amide I/II and alpha-helix/beta-sheet in amide region; and symmetric CH2 (SyCH2), asymmetric CH2 (AsCH2) and (a)symmetric CH2 and CH3 area (ASCCA) in the lipid region. Multivariate analysis showed that both hierarchy cluster analysis (HCA) and principal component analysis (PCA) clearly separated WT from transgenic plants in all carbohydrate regions and (a)symmetric CH2 and CH3 (ASCC) lipid region. In the amide region, PCA separated WT, TT8i and HB12i into different groups, while HCA clustered WT into a separate group. In conclusion, silencing of TT8 and HB12 affected intrinsic molecular structures of both amide and carbohydrate profiles in alfalfa, and multivariate analyses successfully distinguished gene-silenced alfalfa from its parental WT control. PMID- 29614753 TI - A Power-Frequency Electric Field Sensor for Portable Measurement. AB - In this paper, a new type of electric field sensor is proposed for the health and safety protection of inspection staff in high-voltage environments. Compared with the traditional power frequency electric field measurement instruments, the portable instrument has some special performance requirements and, thus, a new kind of double spherical shell sensor is presented. First, the mathematical relationships between the induced voltage of the sensor, the output voltage of the measurement circuit, and the original electric field in free space are deduced theoretically. These equations show the principle of the proposed sensor to measure the electric field and the effect factors of the measurement. Next, the characteristics of the sensor are analyzed through simulation. The simulation results are in good agreement with the theoretical analysis. The influencing rules of the size and material of the sensor on the measurement results are summarized. Then, the proposed sensor and the matching measurement system are used in a physical experiment. After calibration, the error of the measurement system is discussed. Lastly, the directional characteristic of the proposed sensor is experimentally tested. PMID- 29614751 TI - Annexin A1: Uncovering the Many Talents of an Old Protein. AB - Annexin A1 (ANXA1) has long been classed as an anti-inflammatory protein due to its control over leukocyte-mediated immune responses. However, it is now recognized that ANXA1 has widespread effects beyond the immune system with implications in maintaining the homeostatic environment within the entire body due to its ability to affect cellular signalling, hormonal secretion, foetal development, the aging process and development of disease. In this review, we aim to provide a global overview of the role of ANXA1 covering aspects of peripheral and central inflammation, immune repair and endocrine control with focus on the prognostic, diagnostic and therapeutic potential of the molecule in cancer, neurodegeneration and inflammatory-based disorders. PMID- 29614754 TI - Mixture Concentration-Response Modeling Reveals Antagonistic Effects of Estradiol and Genistein in Combination on Brain Aromatase Gene (cyp19a1b) in Zebrafish. AB - Comprehension of compound interactions in mixtures is of increasing interest to scientists, especially from a perspective of mixture risk assessment. However, most of conducted studies have been dedicated to the effects on gonads, while only few of them were. interested in the effects on the central nervous system which is a known target for estrogenic compounds. In the present study, the effects of estradiol (E2), a natural estrogen, and genistein (GEN), a phyto estrogen, on the brain ER-regulated cyp19a1b gene in radial glial cells were investigated alone and in mixtures. For that, zebrafish-specific in vitro and in vivo bioassays were used. In U251-MG transactivation assays, E2 and GEN produced antagonistic effects at low mixture concentrations. In the cyp19a1b-GFP transgenic zebrafish, this antagonism was observed at all ratios and all concentrations of mixtures, confirming the in vitro effects. In the present study, we confirm (i) that our in vitro and in vivo biological models are valuable complementary tools to assess the estrogenic potency of chemicals both alone and in mixtures; (ii) the usefulness of the ray design approach combined with the concentration-addition modeling to highlight interactions between mixture components. PMID- 29614756 TI - The Effectiveness of International Non-Governmental Organizations' Response Operations during Public Health Emergency: Lessons Learned from the 2014 Ebola Outbreak in Sierra Leone. AB - International Nongovernmental Organizations (INGOs) have played critical roles in improving the quality of primary health care in ordinary time and, indeed, responding to epidemic crises in developing countries. Due to a lack of empirical research for effectiveness of their responding activities, the legitimacy and accountability of nonprofits' engagement in the health crisis as a critical responder is doubted. This paper aims to examine the effectiveness of INGOs in a context of managing a fatal epidemic outbreak of Ebola in Sierra Leone during May November, 2014; building healthcare infrastructures, providing medical supplies, educating local residents, and training response staffs. The analysis results show that development of healthcare infrastructures and provision of medical supplies have been significantly effective in terms of decreasing the severity of the crisis in chiefdoms. The findings imply that policy tools, which allow INGOs to enter to the field in a timely manner, can improve the effectiveness of INGOs' responses in current and future epidemic outbreaks in developing countries where people suffer from a lack of health infrastructures. PMID- 29614757 TI - beta-Glucans: Multi-Functional Modulator of Wound Healing. AB - beta-glucans are derived from a variety of sources including yeast, grain and fungus and belong to the class of drugs known as biological response modifiers. They possess a broad spectrum of biological activities that enhance immunity in humans. One promising area for beta-glucans' application is dermatology, including wound care. Topical applications of beta-glucans are increasing, especially due to their pluripotent properties. Macrophages, keratinocytes and fibroblasts are considered the main target cells of beta-glucans during wound healing. beta-glucans enhance wound repair by increasing the infiltration of macrophages, which stimulates tissue granulation, collagen deposition and reepithelialization. beta-glucan wound dressings represent a suitable wound healing agent, with great stability and resistance to wound proteases. This review summarizes the current knowledge and progress made on characterizing beta glucans' wound healing properties in vitro and in vivo and their safety and efficacy in managing non-healing wounds or other chronic dermatological conditions and diseases. PMID- 29614758 TI - Pediatric Age Palm Oil Consumption. AB - Palm oil is widely used in the food industry for its chemical/physical properties, low cost and wide availability. Its widespread use has provoked an intense debate about whether it is a potential danger to human health. In a careful review of the scientific literature, we focused on nutritional characteristics and health effects of the use of palm oil with regards to children, seeking to determine whether there is evidence that justifies fears about the health effects of palm oil. Our review showed that palm oil represents a significant source of saturated fatty acids, to which scientific evidence attributes negative health effects when used in excess, especially with regards to cardiovascular diseases. However, to date, there is no evidence about the harmful effects of palm oil on the health of children. Nevertheless, palm oil has possible ill health effects linked to its composition of fatty acids: its consumption is not correlated to risk factors for cardiovascular diseases in young people with a normal weight and cholesterol level; the elderly and patients with dyslipidaemia or previous cardiovascular events or hypertension are at a greater risk. Therefore, the matter is not palm oil itself but the fatty-acid rich food group to which it belongs. The most important thing is to consume no more than 10% of saturated fatty acids, regardless of their origin and regardless of one's age. Correct information based on a careful analysis of the scientific evidence, rather than a focus on a singular presumed culprit substance, should encourage better lifestyles. PMID- 29614755 TI - Transplantable Melanomas in Hamsters and Gerbils as Models for Human Melanoma. Sensitization in Melanoma Radiotherapy-From Animal Models to Clinical Trials. AB - The focus of the present review is to investigate the role of melanin in the radioprotection of melanoma and attempts to sensitize tumors to radiation by inhibiting melanogenesis. Early studies showed radical scavenging, oxygen consumption and adsorption as mechanisms of melanin radioprotection. Experimental models of melanoma in hamsters and in gerbils are described as well as their use in biochemical and radiobiological studies, including a spontaneously metastasizing ocular model. Some results from in vitro studies on the inhibition of melanogenesis are presented as well as radio-chelation therapy in experimental and clinical settings. In contrast to cutaneous melanoma, uveal melanoma is very successfully treated with radiation, both using photon and proton beams. We point out that the presence or lack of melanin pigmentation should be considered, when choosing therapeutic options, and that both the experimental and clinical data suggest that melanin could be a target for radiosensitizing melanoma cells to increase efficacy of radiotherapy against melanoma. PMID- 29614760 TI - Bladder Cancer: New Insights into Its Molecular Pathology. AB - Bladder cancer is one of the most prevalent cancers worldwide. Unfortunately, there have been few advances in its clinical management due to a poor understanding of the correlations between its molecular and clinical features. Mounting evidence suggests that bladder cancer comprises a group of molecularly heterogeneous diseases that undergo a variety of clinical courses and possess diverse therapeutic responses. Owing to the close association between its molecular subtypes and clinicopathological features, specific therapeutic strategies have recently been suggested. This review summarizes the current understanding of the molecular pathology of bladder cancer, including its molecular biomarkers/pathways and molecular subtypes that have been newly identified using high-throughput technologies. It also discusses advances in our understanding of personalized treatments for specific molecular subtypes. PMID- 29614762 TI - Long-Term Satisfaction and Patient-Centered Outcomes of Deep Brain Stimulation in Parkinson's Disease. AB - Bilateral subthalamic nucleus (STN) deep brain stimulation (DBS) is an effective and proven treatment option for patients with advanced Parkinson's disease (PD). Long-term outcomes (>5 years) have demonstrated sustained improvement in objective motor symptoms; however, few studies have evaluated patient-centered outcomes other than quality of life (QOL). A locally developed DBS-patient centered outcomes questionnaire was administered to PD patients >5 years post DBS. All questions were scored on a ten-point scale, whereby 0 represented the most 'positive' answer and 10 the most 'negative' answer. Pre-operative scales were repeated at the time of survey. Fifty-two patients (mean 8.2 +/- 2.6 years post-DBS) were included. Satisfaction was high with median score (range) of 1/10 (0-8) at the time of survey. Patients endorsed having made the correct decision by undergoing DBS, with a score of 0 (0-10), would choose to have DBS again, with a score of 0 (0-10), and would recommend DBS to others, with a score of 0 (0-10). Pre-operative expectation target was set at a high level with a score of 2 (0 10). Parkinson's Disease QOL (PDQ-39) Questionnaire Summary Index (SI) scores were, mean (SD), 2.1 (18.2) above baseline (p = 0.44). Those with worsening in PDQ-39-SI scores had less satisfaction with DBS (rs = 0.57, p <= 0.0001). This is the first study to assess long-term patient satisfaction with STN DBS. We are currently collecting data prospectively to confirm the results of these preliminary findings. PMID- 29614759 TI - High Glucose-Induced Cardiomyocyte Death May Be Linked to Unbalanced Branched Chain Amino Acids and Energy Metabolism. AB - High glucose-induced cardiomyocyte death is a common symptom in advanced-stage diabetic patients, while its metabolic mechanism is still poorly understood. The aim of this study was to explore metabolic changes in high glucose-induced cardiomyocytes and the heart of streptozotocin-induced diabetic rats by 1H-NMR based metabolomics. We found that high glucose can promote cardiomyocyte death both in vitro and in vivo studies. Metabolomic results show that several metabolites exhibited inconsistent variations in vitro and in vivo. However, we also identified a series of common metabolic changes, including increases in branched-chain amino acids (BCAAs: leucine, isoleucine and valine) as well as decreases in aspartate and creatine under high glucose condition. Moreover, a reduced energy metabolism could also be a common metabolic characteristic, as indicated by decreases in ATP in vitro as well as AMP, fumarate and succinate in vivo. Therefore, this study reveals that a decrease in energy metabolism and an increase in BCAAs metabolism could be implicated in high glucose-induced cardiomyocyte death. PMID- 29614763 TI - A Distance Boundary with Virtual Nodes for the Weighted Centroid Localization Algorithm. AB - In wireless sensor networks, accurate location information is important for precise tracking of targets. In order to satisfy hardware installation cost and localization accuracy requirements, a weighted centroid localization (WCL) algorithm, which is considered a promising localization algorithm, was introduced. In our previous research, we proposed a test node-based WCL algorithm using a distance boundary to improve the localization accuracy in the corner and side areas. The proposed algorithm estimates the target location by averaging the test node locations that exactly match with the number of anchor nodes in the distribution map. However, since the received signal strength has large variability in real channel conditions, the number of anchor nodes is not exactly matched and the localization accuracy may deteriorate. Thus, we propose an intersection threshold to compensate for the localization accuracy in this paper. The simulation results show that the proposed test node-based WCL algorithm provides higher-precision location information than the conventional WCL algorithm in entire areas, with a reduced number of physical anchor nodes. Moreover, we show that the localization accuracy is improved by using the intersection threshold when considering small-scale fading channel conditions. PMID- 29614761 TI - Quality of Life and Stigma in Epilepsy, Perspectives from Selected Regions of Asia and Sub-Saharan Africa. AB - Epilepsy is an important and common worldwide public health problem that affects people of all ages. A significant number of individuals with epilepsy will be intractable to medication. These individuals experience an elevated mortality rate and negative psychosocial consequences of recurrent seizures. Surgery of epilepsy is highly effective to stop seizures in well-selected individuals, and seizure freedom is the most desirable result of epilepsy treatment due to the positive improvements in psychosocial function and the elimination of excess mortality associated with intractable epilepsy. Globally, there is inadequate data to fully assess epilepsy-related quality of life and stigma, although the preponderance of information we have points to a significant negative impact on people with epilepsy (PWE) and families of PWE. This review of the psychosocial impact of epilepsy focuses on regions of Asia and Sub-Saharan Africa that have been analyzed with population study approaches to determine the prevalence of epilepsy, treatment gaps, as well as factors impacting psychosocial function of PWE and their families. This review additionally identifies models of care for medically intractable epilepsy that have potential to significantly improve psychosocial function. PMID- 29614764 TI - How Safe Is Ginger Rhizome for Decreasing Nausea and Vomiting in Women during Early Pregnancy? AB - Ginger, Zingiber officinale Roscoe, is increasingly consumed as a food or in food supplements. It is also recognized as a popular nonpharmacological treatment for nausea and vomiting of pregnancy (NVP). However, its consumption is not recommended by all countries for pregnant women. Study results are heterogeneous and conclusions are not persuasive enough to permit heath care professionals to recommend ginger safely. Some drugs are also contraindicated, leaving pregnant women with NVP with few solutions. We conducted a review to assess effectiveness and safety of ginger consumption during early pregnancy. Systematic literature searches were conducted on Medline (via Pubmed) until the end of December 2017. For the evaluation of efficacy, only double-blind, randomized, controlled trials were included. For the evaluation of the safety, controlled, uncontrolled, and pre-clinical studies were included in the review. Concerning toxicity, none can be extrapolated to humans from in vitro results. In vivo studies do not identify any major toxicities. Concerning efficacy and safety, a total of 15 studies and 3 prospective clinical studies have been studied. For 1 g of fresh ginger root per day for four days, results show a significant decrease in nausea and vomiting and no risk for the mother or her future baby. The available evidence suggests that ginger is a safe and effective treatment for NVP. However, beyond the ginger quantity needed to be effective, ginger quality is important from the perspective of safety. PMID- 29614765 TI - Is a Water Content of 60% Maximum Water Holding Capacity Suitable for Folsomia candida Reproduction Tests? A Study with Silver Nanoparticles and AgNO3. AB - Silver nanoparticles (AgNP) are increasingly emitted to the environment due to a rise in application in various products; therefore, assessment of their potential risks for biota is important. In this study the effects of AgNP at environmentally relevant concentrations (0.6-375 ug kg-1 soil) on the soil invertebrate Folsomia candida in OECD (Organisation for Economic Co-operation and Development) soil was examined at different soil water contents. Animals were retrieved by heat extraction, which had an efficiency of about 90% compared with the floatation method. The tested water content range is set by OECD Guideline 232 (40-60% of the maximum water holding capacity, WHC), and we detected significant differences in toxicity due to these. With AgNO3, used as an ionic control, the number of juveniles significantly decreased only at 40% WHC, which might be due to dilution of the toxicant at higher soil water content. In turn, at 60% WHC, the reproduction of F. candida significantly increased in the presence of AgNP compared with in the control. However, at this water content, the required number of juveniles in the control treatment was not reached in three independent tests. The fact that the OECD validity criterion is not met indicates that the soil conditions are not suitable for reproduction at 60% WHC. PMID- 29614766 TI - Electrode Modified by Reduced Graphene Oxide for Monitoring of Total Thallium in Grain Products. AB - Grain products and the associated industry have a notable economic and social impact all over the world. The toxicological safety of grain products is a nutritional prerogative. This study focused on the determination of thallium content in grain product samples collected from a commercial brand commonly available in Poland. The samples were analyzed with the use of differential pulse anodic stripping voltammetry (DPASV) with graphene oxide based on glassy carbon. The stripping anodic peak current of thallium was linear over its concentration range from 9.78 * 10-9 to 97.8 * 10-9 M. The limit of detection (LOD) was calculated according to the formula LOD = (kappa * SDa)/b, where kappa is 3.3, SDa is the standard deviation of the intercept, and b is the slope. The determined value of LOD was 1.229 ug L-1 (6.01 * 10-9 M). The proposed method was successfully applied for the determination of thallium ions in samples of actual grain products. The obtained results confirmed that thallium was present in the studied cereal samples (average content at 0.0268 +/- 0.0798 mg/kg). Thallium has a half-life of 60 days; therefore, the consumption of foods with thallium content of approximately 0.08 mg/kg has the potential for harmful bioaccumulation in the body. Thallium contamination in cereal products should be a critical parameter for health environmental regulations. PMID- 29614767 TI - Divide and Conquer-Based 1D CNN Human Activity Recognition Using Test Data Sharpening. AB - Human Activity Recognition (HAR) aims to identify the actions performed by humans using signals collected from various sensors embedded in mobile devices. In recent years, deep learning techniques have further improved HAR performance on several benchmark datasets. In this paper, we propose one-dimensional Convolutional Neural Network (1D CNN) for HAR that employs a divide and conquer based classifier learning coupled with test data sharpening. Our approach leverages a two-stage learning of multiple 1D CNN models; we first build a binary classifier for recognizing abstract activities, and then build two multi-class 1D CNN models for recognizing individual activities. We then introduce test data sharpening during prediction phase to further improve the activity recognition accuracy. While there have been numerous researches exploring the benefits of activity signal denoising for HAR, few researches have examined the effect of test data sharpening for HAR. We evaluate the effectiveness of our approach on two popular HAR benchmark datasets, and show that our approach outperforms both the two-stage 1D CNN-only method and other state of the art approaches. PMID- 29614768 TI - The Effect of Leisure Activity Diversity and Exercise Time on the Prevention of Depression in the Middle-Aged and Elderly Residents of Taiwan. AB - Previous studies have confirmed that activity participation is beneficial to mental health, but few studies focus on older adults' depression. Based on the theory of social integration, this study examined the effects of leisure activity diversity and exercise time on depression in late adulthood. Subjects in the 2011 Survey of Health and Living Status of the Middle-Aged and Elderly in Taiwan were extracted. A series of logistic regressions were conducted to discern factors related to the odds of having depression. Among study subjects (N = 3727; age >= 58), 20.9% indicated an inclination of having depression (CESD-10 score >= 8). This study found that participating in diverse leisure activities and longer exercise time decreases older adults' risk of having depression. Additionally, the results confirmed that depression is positively correlated with chronic diseases. Consequently, efforts should be continually spent on encouraging older adults' participation in activities to reduce the prevalence of depression. PMID- 29614769 TI - Use of Selected Lactic Acid Bacteria and Quinoa Flour for Manufacturing Novel Yogurt-Like Beverages. AB - This study aimed at investigating the suitability of quinoa for making yogurt like beverages. After the selection of the adequate technological parameters, the fermentation was carried out by using different lactic acid bacteria strains: a probiotic (Lactobacillus rhamnosus SP1), an exopolysaccharides (EPS)-producing (Weissella confusa DSM 20194), and one isolated from quinoa (Lactobacillus plantarum T6B10). During the 20 h of fermentation, W. confusa caused the highest viscosity increase. All the strains had improved concentration of free amino acids and gamma-Aminobutyric acid (GABA), polyphenols availability, antioxidant activity (up to 54%), and protein digestibility. The nutritional index (NI) was the highest when L. rhamnosus SP1 was used. The starch hydrolysis index in vitro ranged from 52 to 60. During storage at 4 degrees C, viscosity and water holding capacity decreased with the exception of the beverage fermented with W. confusa, while all the nutritional characteristics remained stable or slightly increased. Sensory analyses showed that beverages had good textural and organoleptic profiles. Besides the well-known positive properties of the raw matrix, fermentation allowed the obtainment of beverages with different features. Due to the nutritional and functional characteristics conferred to the quinoa beverages, the use of the probiotic and EPS-producing strains showed adequate potential for the industrial application. PMID- 29614770 TI - Development and On-Field Testing of Low-Cost Portable System for Monitoring PM2.5 Concentrations. AB - Recent developments in the field of low-cost sensors enable the design and implementation of compact, inexpensive and portable sensing units for air pollution monitoring with fine-detailed spatial and temporal resolution, in order to support applications of wider interest in the area of intelligent transportation systems (ITS). In this context, the present work advances the concept of developing a low-cost portable air pollution monitoring system (APMS) for measuring the concentrations of particulate matter (PM), in particular fine particles with a diameter of 2.5 μm or less (PM2.5). Specifically, this paper presents the on-field testing of the proposed low-cost APMS implementation using roadside measurements from a mobile laboratory equipped with a calibrated instrument as the basis of comparison and showcases its accuracy on characterizing the PM2.5 concentrations on 1 min resolution in an on-road trial. Moreover, it demonstrates the intended application of collecting fine-grained spatio-temporal PM2.5 profiles by mounting the developed APMS on an electric bike as a case study in the city of Mons, Belgium. PMID- 29614771 TI - Sensitive and Selective NH3 Monitoring at Room Temperature Using ZnO Ceramic Nanofibers Decorated with Poly(styrene sulfonate). AB - Ammonia (NH3) gas is a prominent air pollutant that is frequently found in industrial and livestock production environments. Due to the importance in controlling pollution and protecting public health, the development of new platforms for sensing NH3 at room temperature has attracted great attention. In this study, a sensitive NH3 gas device with enhanced selectivity is developed based on zinc oxide nanofibers (ZnO NFs) decorated with poly(styrene sulfonate) (PSS) and operated at room temperature. ZnO NFs were prepared by electrospinning followed by calcination at 500 degrees C for 3 h. The electrospun ZnO NFs are characterized to evaluate the properties of the as-prepared sensing materials. The loading of PSS to prepare ZnO NFs/PSS composite is also optimized based on the best sensing performance. Under the optimal composition, ZnO NFs/PSS displays rapid, reversible, and sensitive response upon NH3 exposure at room temperature. The device shows a dynamic linear range up to 100 ppm and a limit of detection of 3.22 ppm and enhanced selectivity toward NH3 in synthetic air, against NO2 and CO, compared to pure ZnO NFs. Additionally, a sensing mechanism is proposed to illustrate the sensing performance using ZnO NFs/PSS composite. Therefore, this study provides a simple methodology to design a sensitive platform for NH3 monitoring at room temperature. PMID- 29614772 TI - A Teleo-Reactive Node for Implementing Internet of Things Systems. AB - The Internet of Things (IoT) is one of today's main disruptive technologies and, although massive research has been carried out in recent years, there are still some open issues such as the consideration of software engineering methods and tools. We propose the adoption of the Teleo-Reactive approach in order to facilitate the development of Internet of Things systems as a set of communicating Teleo-Reactive nodes. The software behavior of the nodes is specified in terms of goals, perceptions and actions over the environment, achieving higher abstraction than using general-purpose programming languages and therefore, enhancing the involvement of non-technical users in the specification process. Throughout this paper, we describe the elements of a Teleo-Reactive node and a systematic procedure for translating Teleo-Reactive specifications into executable code for Internet of Things devices. The case study of a robotic agent is used in order to validate the whole approach. PMID- 29614773 TI - A 2-Deoxyglucose-Resistant Mutant of Saccharomyces cerevisiae Shows Enhanced Maltose Fermentative Ability by the Activation of MAL Genes. AB - Saccharomyces cerevisiae MCD4 is a 2-deoxyglucose (2-DOG)-resistant mutant derived from the wild-type strain, AK46, wherein the 2-DOG resistance improves the maltose fermentative ability. In the MAL gene cluster, mutations were detected in MAL11 and MAL31, which encode maltose permeases, and in MAL13 and MAL33, which encode transcriptional activators. In maltose medium, the expression of MAL11 and MAL31 in MCD4 was 2.1 and 4.2 times significantly higher than that in AK46, respectively. Besides, the expression of MAL13 and MAL33 also tended to be higher than that of AK46. Although no mutations were found in MAL12 and MAL32 (which encode alpha-glucosidases), their expression was significantly higher (4.9 and 4.4 times, respectively) than that in AK46. Since the expression of major catabolite repression-related genes did not show significant differences between MCD4 and AK46, these results showed that the higher maltose fermentative ability of MCD4 is due to the activation of MAL genes encoding two maltose permeases and two alpha-glucosidases. PMID- 29614774 TI - The Brain-Intestinal Mucosa-Appendix- Microbiome-Brain Loop. AB - The brain and the gut are connected from early fetal life. The mother's exposure to microbial molecules is thought to exert in utero developmental effects on the fetus. These effects could importantly underpin the groundwork for subsequent pathophysiological mechanisms for achieving immunological tolerance and metabolic equilibrium post birth, events that continue through to 3-4 years of age. Furthermore, it is understood that the microbiome promotes cues that instruct the neonate's mucosal tissues and skin in the language of molecular and cellular biology. Post birth mucosal lymphoid tissue formation and maturation (most probably including the vermiform appendix) is microbiota-encouraged co establishing the intestinal microbiome with a developing immune system. Intestinal mucosal tissue maturation loops the brain-gut-brain and is postulated to influence mood dispositions via shifts in the intestinal microbiome phyla. A plausible appreciation is that dysregulated pro-inflammatory signals from intestinal resident macrophages could breach the loop by providing adverse mood signals via vagus nerve afferents to the brain. In this commentary, we further suggest that the intestinal resident macrophages act as an upstream traffic controller of translocated microbes and metabolites in order to maintain local neuro-endocrine-immunological equilibrium. When macrophages are overwhelmed through intestinal microbiome and intestinal epithelial cell dysbiosis, pro inflammatory signals are sustained, which may then lead to mood disorders. The administration of probiotics as an adjunctive medicine co-administered with antidepressant medications in improving depressed mood may have biological and clinical standing. PMID- 29614776 TI - Quantifying Rock Weakening Due to Decreasing Calcite Mineral Content by Numerical Simulations. AB - The quantification of changes in geomechanical properties due to chemical reactions is of paramount importance for geological subsurface utilisation, since mineral dissolution generally reduces rock stiffness. In the present study, the effective elastic moduli of two digital rock samples, the Fontainebleau and Bentheim sandstones, are numerically determined based on micro-CT images. Reduction in rock stiffness due to the dissolution of 10% calcite cement by volume out of the pore network is quantified for three synthetic spatial calcite distributions (coating, partial filling and random) using representative sub cubes derived from the digital rock samples. Due to the reduced calcite content, bulk and shear moduli decrease by 34% and 38% in maximum, respectively. Total porosity is clearly the dominant parameter, while spatial calcite distribution has a minor impact, except for a randomly chosen cement distribution within the pore network. Moreover, applying an initial stiffness reduced by 47% for the calcite cement results only in a slightly weaker mechanical behaviour. Using the quantitative approach introduced here substantially improves the accuracy of predictions in elastic rock properties compared to general analytical methods, and further enables quantification of uncertainties related to spatial variations in porosity and mineral distribution. PMID- 29614777 TI - Design of Dual-Mode Local Oscillators Using CMOS Technology for Motion Detection Sensors. AB - Recently, studies have been actively carried out to implement motion detecting sensors by applying radar techniques. Doppler radar or frequency-modulated continuous wave (FMCW) radar are mainly used, but each type has drawbacks. In Doppler radar, no signal is detected when the movement is stopped. Also, FMCW radar cannot function when the detection object is near the sensor. Therefore, by implementing a single continuous wave (CW) radar for operating in dual-mode, the disadvantages in each mode can be compensated for. In this paper, a dual mode local oscillator (LO) is proposed that makes a CW radar operate as a Doppler or FMCW radar. To make the dual-mode LO, a method that controls the division ratio of the phase locked loop (PLL) is used. To support both radar mode easily, the proposed LO is implemented by adding a frequency sweep generator (FSG) block to a fractional-N PLL. The operation mode of the LO is determined by according to whether this block is operating or not. Since most radar sensors are used in conjunction with microcontroller units (MCUs), the proposed architecture is capable of dual-mode operation by changing only the input control code. In addition, all components such as VCO, LDO, and loop filter are integrated into the chip, so complexity and interface issues can be solved when implementing radar sensors. Thus, the proposed dual-mode LO is suitable as a radar sensor. PMID- 29614778 TI - Sky Detection in Hazy Image. AB - Sky detection plays an essential role in various computer vision applications. Most existing sky detection approaches, being trained on ideal dataset, may lose efficacy when facing unfavorable conditions like the effects of weather and lighting conditions. In this paper, a novel algorithm for sky detection in hazy images is proposed from the perspective of probing the density of haze. We address the problem by an image segmentation and a region-level classification. To characterize the sky of hazy scenes, we unprecedentedly introduce several haze relevant features that reflect the perceptual hazy density and the scene depth. Based on these features, the sky is separated by two imbalance SVM classifiers and a similarity measurement. Moreover, a sky dataset (named HazySky) with 500 annotated hazy images is built for model training and performance evaluation. To evaluate the performance of our method, we conducted extensive experiments both on our HazySky dataset and the SkyFinder dataset. The results demonstrate that our method performs better on the detection accuracy than previous methods, not only under hazy scenes, but also under other weather conditions. PMID- 29614780 TI - Metabolomics and Transcriptomics Identify Multiple Downstream Targets of Paraburkholderia phymatum sigma54 During Symbiosis with Phaseolus vulgaris. AB - RpoN (or sigma54) is the key sigma factor for the regulation of transcription of nitrogen fixation genes in diazotrophic bacteria, which include alpha- and beta rhizobia. Our previous studies showed that an rpoN mutant of the beta-rhizobial strain Paraburkholderia phymatum STM815T formed root nodules on Phaseolus vulgaris cv. Negro jamapa, which were unable to reduce atmospheric nitrogen into ammonia. In an effort to further characterize the RpoN regulon of P. phymatum, transcriptomics was combined with a powerful metabolomics approach. The metabolome of P. vulgaris root nodules infected by a P. phymatumrpoN Fix- mutant revealed statistically significant metabolic changes compared to wild-type Fix+ nodules, including reduced amounts of chorismate and elevated levels of flavonoids. A transcriptome analysis on Fix- and Fix+ nodules-combined with a search for RpoN binding sequences in promoter regions of regulated genes confirmed the expected control of sigma54 on nitrogen fixation genes in nodules. The transcriptomic data also allowed us to identify additional target genes, whose differential expression was able to explain the observed metabolite changes in numerous cases. Moreover, the genes encoding the two-component regulatory system NtrBC were downregulated in root nodules induced by the rpoN mutant, and contained a putative RpoN binding motif in their promoter region, suggesting direct regulation. The construction and characterization of an ntrB mutant strain revealed impaired nitrogen assimilation in free-living conditions, as well as a noticeable symbiotic phenotype, as fewer but heavier nodules were formed on P. vulgaris roots. PMID- 29614775 TI - The Uptake and Metabolism of Amino Acids, and Their Unique Role in the Biology of Pathogenic Trypanosomatids. AB - Trypanosoma brucei, as well as Trypanosoma cruzi and more than 20 species of the genus Leishmania, form a group of flagellated protists that threaten human health. These organisms are transmitted by insects that, together with mammals, are their natural hosts. This implies that during their life cycles each of them faces environments with different physical, chemical, biochemical, and biological characteristics. In this work we review how amino acids are obtained from such environments, how they are metabolized, and how they and some of their intermediate metabolites are used as a survival toolbox to cope with the different conditions in which these parasites should establish the infections in the insects and mammalian hosts. PMID- 29614779 TI - Advances in HIV-1 Vaccine Development. AB - An efficacious HIV-1 vaccine is regarded as the best way to halt the ongoing HIV 1 epidemic. However, despite significant efforts to develop a safe and effective vaccine, the modestly protective RV144 trial remains the only efficacy trial to provide some level of protection against HIV-1 acquisition. This review will outline the history of HIV vaccine development, novel technologies being applied to HIV vaccinology and immunogen design, as well as the studies that are ongoing to advance our understanding of vaccine-induced immune correlates of protection. PMID- 29614782 TI - Influence of Codium tomentosum Extract in the Properties of Alginate and Chitosan Edible Films. AB - The growing search for natural alternatives to synthetic food packaging materials and additives has increased, and seaweed extracts' bioactivity has made them suitable candidates for incorporation in novel edible films. This study aims to investigate the effect of Codium tomentosum seaweed extract (SE) incorporation in alginate and chitosan edible films. Alginate- and chitosan-based films with and without the incorporation of 0.5% SE were characterized according to their physical, optical, mechanical, and thermal properties. Seaweed extract incorporation in chitosan films resulted in an increase of film solubility (50%), elasticity (18%), and decrease of puncture strength (27%) and energy at break (39%). In alginate films, the extract incorporation significantly decreased film solubility (6%), water vapour permeability (46%), and elasticity (24%), and had no effect on thermal properties. Depending on the type of application, the addition of SE in edible films can bring advantages for food conservation. PMID- 29614781 TI - Exploiting a Phage-Bacterium Interaction System as a Molecular Switch to Decipher Macromolecular Interactions in the Living Cell. AB - Pathogenicity islands of Staphylococcus aureus are under the strong control of helper phages, where regulation is communicated at the gene expression level via a family of specific repressor proteins. The repressor proteins are crucial to phage-host interactions and, based on their protein characteristics, may also be exploited as versatile molecular tools. The Stl repressor from this protein family has been recently investigated and although the binding site of Stl on DNA was recently discovered, there is a lack of knowledge on the specific protein segments involved in this interaction. Here, we develop a generally applicable system to reveal the mechanism of the interaction between Stl and its cognate DNA within the cellular environment. Our unbiased approach combines random mutagenesis with high-throughput analysis based on the lac operon to create a well-characterized gene expression system. Our results clearly indicate that, in addition to a previously implicated helix-turn-helix segment, other protein moieties also play decisive roles in the DNA binding capability of Stl. Structural model-based investigations provided a detailed understanding of Stl:DNA complex formation. The robustness and reliability of our novel test system were confirmed by several mutated Stl constructs, as well as by demonstrating the interaction between Stl and dUTPase from the Staphylococcal phi11 phage. Our system may be applied to high-throughput studies of protein:DNA and protein:protein interactions. PMID- 29614783 TI - A Comparative Study of Behavior Problems among Left-Behind Children, Migrant Children and Local Children. AB - This study aims to estimate the prevalence of behavioral problems among left behind children, migrant children and local children in China, and to compare the risks of behavioral problems among the three types of children. Data on 4479 children aged 6-16 used in this study were from a survey conducted in China in 2017. The school-age version of the Children Behavior Checklist was used to measure children's behavioral problems. Descriptive analysis, correlation analysis, and logistic regressions were conducted. The prevalence of behavioral problems was 18.80% and 13.59% for left-behind children and migrant children, respectively, both of which were higher than that of local children. Logistic regression analysis showed that after adjustments for individual and environmental variables, the likelihood of total, internalizing and externalizing behavior problems for left-behind children and migrant children were higher than those for local children; left-behind children had a higher likelihood of internalizing problems than externalizing problems, while migrant children had a higher prevalence of externalizing problems. Left-behind children had a higher prevalence of each specific syndrome than migrant and local children. Both individual and environmental factors were associated with child behavioral problems, and family migration may contribute to the increased risks. Left-behind and migrant children were more vulnerable than local children to behavioral problems. PMID- 29614785 TI - Swedish Consumers' Perception of Food Quality and Sustainability in Relation to Organic Food Production. AB - Consumers' demand for locally produced and organic foods has increased in Sweden. This paper presents the results obtained from the analysis of data acquired from 100 consumers in Sweden who participated in an online survey during March to June 2016. The objective was to identify consumers' demand in relation to organic food and sustainable food production, and to understand how the consumers evaluate food quality and make buying decisions. Qualitative descriptions, descriptive statistics and Pearson's Chi-square test (with alpha value of p < 0.05 as level of significance), and Pearson's correlation coefficient were used for analysis. About 72% of participants have the perception that organic food production method is more sustainable than conventional methods. Female consumers have more positive attitudes than men towards organic food. However, age difference, household size and income level do not significantly influence the consumers' perception of sustainable food production concepts. Regionality, sustainable methods of production and organic production are the most important parameters to characterize the food as high quality and make buying decisions. On the other hand, product uniformity, appearance, and price were found to be relatively less important parameters. Food buying decisions and food quality were found to be highly related with Pearson's correlation coefficient of r = 0.99. PMID- 29614784 TI - Sensors Based on Bio and Biomimetic Receptors in Medical Diagnostic, Environment, and Food Analysis. AB - Analytical chemistry is now developing mainly in two areas: automation and the creation of complexes that allow, on the one hand, for simultaneously analyzing a large number of samples without the participation of an operator, and on the other, the development of portable miniature devices for personalized medicine and the monitoring of a human habitat. The sensor devices, the great majority of which are biosensors and chemical sensors, perform the role of the latter. That last line is considered in the proposed review. Attention is paid to transducers, receptors, techniques of immobilization of the receptor layer on the transducer surface, processes of signal generation and detection, and methods for increasing sensitivity and accuracy. The features of sensors based on synthetic receptors and additional components (aptamers, molecular imprinted polymers, biomimetics) are discussed. Examples of bio- and chemical sensors' application are given. Miniaturization paths, new power supply means, and wearable and printed sensors are described. Progress in this area opens a revolutionary era in the development of methods of on-site and in-situ monitoring, that is, paving the way from the "test-tube to the smartphone". PMID- 29614787 TI - Comparative Plastid Genomes of Primula Species: Sequence Divergence and Phylogenetic Relationships. AB - Compared to traditional DNA markers, genome-scale datasets can provide mass information to effectively address historically difficult phylogenies. Primula is the largest genus in the family Primulaceae, with members distributed mainly throughout temperate and arctic areas of the Northern Hemisphere. The phylogenetic relationships among Primula taxa still maintain unresolved, mainly due to intra- and interspecific morphological variation, which was caused by frequent hybridization and introgression. In this study, we sequenced and assembled four complete plastid genomes (Primula handeliana, Primula woodwardii, Primula knuthiana, and Androsace laxa) by Illumina paired-end sequencing. A total of 10 Primula species (including 7 published plastid genomes) were analyzed to investigate the plastid genome sequence divergence and their inferences for the phylogeny of Primula. The 10 Primula plastid genomes were similar in terms of their gene content and order, GC content, and codon usage, but slightly different in the number of the repeat. Moderate sequence divergence was observed among Primula plastid genomes. Phylogenetic analysis strongly supported that Primula was monophyletic and more closely related to Androsace in the Primulaceae family. The phylogenetic relationships among the 10 Primula species showed that the placement of P. knuthiana-P. veris clade was uncertain in the phylogenetic tree. This study indicated that plastid genome data were highly effective to investigate the phylogeny. PMID- 29614786 TI - Epigenetic Modifications as Biomarkers of Tumor Development, Therapy Response, and Recurrence across the Cancer Care Continuum. AB - Aberrant epigenetic modifications are an early event in carcinogenesis, with the epigenetic landscape continuing to change during tumor progression and metastasis these observations suggest that specific epigenetic modifications could be used as diagnostic and prognostic biomarkers for many cancer types. DNA methylation, post-translational histone modifications, and non-coding RNAs are all dysregulated in cancer and are detectable to various degrees in liquid biopsies such as sputum, urine, stool, and blood. Here, we will focus on the application of liquid biopsies, as opposed to tissue biopsies, because of their potential as non-invasive diagnostic tools and possible use in monitoring therapy response and progression to metastatic disease. This includes a discussion of septin-9 (SEPT9) DNA hypermethylation for detecting colorectal cancer, which is by far the most developed epigenetic biomarker assay. Despite their potential as prognostic and diagnostic biomarkers, technical issues such as inconsistent methodology between studies, overall low yield of epigenetic material in samples, and the need for improved histone and non-coding RNA purification methods are limiting the use of epigenetic biomarkers. Once these technical limitations are overcome, epigenetic biomarkers could be used to monitor cancer development, disease progression, therapeutic response, and recurrence across the entire cancer care continuum. PMID- 29614788 TI - New Kids on the Block: RNA-Based Influenza Virus Vaccines. AB - RNA-based immunization strategies have emerged as promising alternatives to conventional vaccine approaches. A substantial body of published work demonstrates that RNA vaccines can elicit potent, protective immune responses against various pathogens. Consonant with its huge impact on public health, influenza virus is one of the best studied targets of RNA vaccine research. Currently licensed influenza vaccines show variable levels of protection against seasonal influenza virus strains but are inadequate against drifted and pandemic viruses. In recent years, several types of RNA vaccines demonstrated efficacy against influenza virus infections in preclinical models. Additionally, comparative studies demonstrated the superiority of some RNA vaccines over the currently used inactivated influenza virus vaccines in animal models. Based on these promising preclinical results, clinical trials have been initiated and should provide valuable information about the translatability of the impressive preclinical data to humans. This review briefly describes RNA-based vaccination strategies, summarizes published preclinical and clinical data, highlights the roadblocks that need to be overcome for clinical applications, discusses the landscape of industrial development, and shares the authors' personal perspectives about the future of RNA-based influenza virus vaccines. PMID- 29614789 TI - EBV+ and MSI Gastric Cancers Harbor High PD-L1/PD-1 Expression and High CD8+ Intratumoral Lymphocytes. AB - Both EBV+ and MSI gastric cancers (GCs) have high lymphoid infiltration which is rare in MSS/EBV- cancers. PD-L1/PD-1 interaction leads to a down-regulated immune response and it is one of the most promising targets for gastric cancer immunotherapy. PD-L1/PD-1 and CD8 expression were immunohistochemically investigated in a series of 169 FFPE GCs, including 33 EBV+, 59 MSI and 77 MSS/EBV- cases. PD-L1 membrane immunoreactivity in more than 5% of tumor cells was present in 31/169 GCs and was associated with high levels of CD8 intraepithelial lymphocytes (TILs; p < 0.001). PD-L1+ cases were mainly poorly differentiated (71%), intestinal type (85%) and high lymphoid response (HLR; 90%) tumors. PD-L1 expression was only present in EBV+ (46%), MSI (24%) and rare MSS/EBV- (3%) GCs with high CD8+ TILs (p < 0.001). Despite being associated with a better prognosis both in the whole series (p < 0.05) and in the MSI subset, PD L1 is not an independent prognostic factor. PD-L1 gene amplification was detected in 3/17 cases, including 2/7 EBV+ and 1/8 MSI GC. PD-1+ TILs were significantly higher in EBV+ than MSI and MSS/EBV- cases. PD-L1/PD-1 pathway is selectively activated in HLR GCs and could be considered an emerging therapeutic target, particularly for EBV and MSI GCs. PMID- 29614790 TI - MicroRNA Regulation of Telomerase Reverse Transcriptase (TERT): Micro Machines Pull Strings of Papier-Mache Puppets. AB - Substantial fraction of high-quality information is continuously being added into the existing pool of knowledge related to the biology of telomeres. Based on the insights gleaned from decades of research, it is clear that chromosomal stability needs a highly controlled and dynamic balance of DNA gain and loss in each terminal tract of telomeric repeats. Telomeres are formed by tandem repeats of TTAGGG sequences, which are gradually lost with each round of division of the cells. Targeted inhibition of telomerase to effectively induce apoptosis in cancer cells has attracted tremendous attention and overwhelmingly increasingly list of telomerase inhibitors truthfully advocates pharmacological significance of telomerase. Telomerase reverse transcriptase (TERT) is a multi-talented and catalytically active component of the telomerase-associated protein machinery. Different proteins of telomerase-associated machinery work in a synchronized and orchestrated manner to ensure proper maintenance of telomeric length of chromosomes. Rapidly emerging scientific findings about regulation of TERT by microRNAs has revolutionized our understanding related to the biology of telomeres and telomerase. In this review, we have comprehensively discussed how different miRNAs regulate TERT in different cancers. Use of miRNA-based therapeutics against TERT in different cancers needs detailed research in preclinical models for effective translation of laboratory findings to clinically effective therapeutics. PMID- 29614791 TI - Double-Windows-Based Motion Recognition in Multi-Floor Buildings Assisted by a Built-In Barometer. AB - Accelerometers, gyroscopes and magnetometers in smartphones are often used to recognize human motions. Since it is difficult to distinguish between vertical motions and horizontal motions in the data provided by these built-in sensors, the vertical motion recognition accuracy is relatively low. The emergence of a built-in barometer in smartphones improves the accuracy of motion recognition in the vertical direction. However, there is a lack of quantitative analysis and modelling of the barometer signals, which is the basis of barometer's application to motion recognition, and a problem of imbalanced data also exists. This work focuses on using the barometers inside smartphones for vertical motion recognition in multi-floor buildings through modelling and feature extraction of pressure signals. A novel double-windows pressure feature extraction method, which adopts two sliding time windows of different length, is proposed to balance recognition accuracy and response time. Then, a random forest classifier correlation rule is further designed to weaken the impact of imbalanced data on recognition accuracy. The results demonstrate that the recognition accuracy can reach 95.05% when pressure features and the improved random forest classifier are adopted. Specifically, the recognition accuracy of the stair and elevator motions is significantly improved with enhanced response time. The proposed approach proves effective and accurate, providing a robust strategy for increasing accuracy of vertical motions. PMID- 29614792 TI - Nitric Oxide Regulates Seedling Growth and Mitochondrial Responses in Aged Oat Seeds. AB - Mitochondria are the source of reactive oxygen species (ROS) in plant cells and play a central role in the mitochondrial electron transport chain (ETC) and tricarboxylic acid cycle (TCA) cycles; however, ROS production and regulation for seed germination, seedling growth, as well as mitochondrial responses to abiotic stress, are not clear. This study was conducted to obtain basic information on seed germination, embryo mitochondrial antioxidant responses, and protein profile changes in artificial aging in oat seeds (Avena sativa L.) exposed to exogenous nitric oxide (NO) treatment. The results showed that the accumulation of H2O2 in mitochondria increased significantly in aged seeds. Artificial aging can lead to a loss of seed vigor, which was shown by a decline in seed germination and the extension of mean germination time (MGT). Seedling growth was also inhibited. Some enzymes, including catalase (CAT), glutathione reductase (GR), dehydroascorbate reductase (DHAR), and monodehydroascorbate reductase (MDHAR), maintained a lower level in the ascorbate-glutathione (AsA-GSH) scavenging system. Proteomic analysis revealed that the expression of some proteins related to the TCA cycle were down-regulated and several enzymes related to mitochondrial ETC were up-regulated. With the application of 0.05 mM NO in aged oat seeds, a protective effect was observed, demonstrated by an improvement in seed vigor and increased H2O2 scavenging ability in mitochondria. There were also higher activities of CAT, GR, MDHAR, and DHAR in the AsA-GSH scavenging system, enhanced TCA cycle-related enzymes (malate dehydrogenase, succinate-CoA ligase, fumarate hydratase), and activated alternative pathways, as the cytochrome pathway was inhibited. Therefore, our results indicated that seedling growth and seed germinability could retain a certain level in aged oat seeds, predominantly depending on the lower NO regulation of the TCA cycle and AsA-GSH. Thus, it could be concluded that the application of 0.05 mM NO in aged oat seeds improved seed vigor by enhancing the mitochondrial TCA cycle and activating alternative pathways for improvement. PMID- 29614793 TI - Influence of Vehicle Speed on the Characteristics of Driver's Eye Movement at a Highway Tunnel Entrance during Day and Night Conditions: A Pilot Study. AB - The aim of this study was to investigate how vehicle speed influences the characteristics of driver's eye movement at highway tunnel entrances during day and night. In this study, six drivers' eye movement data (from 200 m before tunnel entrance to 200 m inside tunnel entrance) under five predetermined vehicle speeds (40, 50, 60, 70 and 80 km/h) in the daytime and three predetermined vehicle speeds (40, 60 and 80 km/h) in the nighttime were recorded using the non intrusive Dikablis Professional eye-tracking system. Pupil size, the average fixation duration time and the average number of fixation were analyzed and then the influence of the vehicle speed on these parameters was evaluated by means of IBM SPSS Statistics 20.0. The results for pupil size in daytime increased when approaching the tunnel entrance, while as for nighttime, pupil size decreased when approaching the tunnel entrance and then increased after entering the tunnel. The pupil size in daytime has a significant negative correlation with vehicle speed, while the pupil size in nighttime did not show a significant association with vehicle speed. Furthermore, the average fixation duration in daytime increased when entering the tunnel, and had a significant negative correlation with vehicle speed. Also, the average number of fixations in daytime decreased when entering the tunnel and has a significant negative correlation with vehicle speed. However, the average fixation duration and the average number of fixations in nighttime did not show any significant association with vehicle speed. Moreover, limitations and future directions of the study are discussed for the further investigation. PMID- 29614794 TI - Mobile Sinks Assisted Geographic and Opportunistic Routing Based Interference Avoidance for Underwater Wireless Sensor Network. AB - The distinctive features of acoustic communication channel-like high propagation delay, multi-path fading, quick attenuation of acoustic signal, etc. limit the utilization of underwater wireless sensor networks (UWSNs). The immutable selection of forwarder node leads to dramatic death of node resulting in imbalanced energy depletion and void hole creation. To reduce the probability of void occurrence and imbalance energy dissipation, in this paper, we propose mobility assisted geo-opportunistic routing paradigm based on interference avoidance for UWSNs. The network volume is divided into logical small cubes to reduce the interference and to make more informed routing decisions for efficient energy consumption. Additionally, an optimal number of forwarder nodes is elected from each cube based on its proximity with respect to the destination to avoid void occurrence. Moreover, the data packets are recovered from void regions with the help of mobile sinks which also reduce the data traffic on intermediate nodes. Extensive simulations are performed to verify that our proposed work maximizes the network lifetime and packet delivery ratio. PMID- 29614795 TI - Full Atrioventricular Block Secondary to Acute Poisoning Mercury: A Case Report. AB - Background: The biological behaviour and clinical significance of mercury toxicity vary according to its chemical structure. Mercury differs in its degree of toxicity and in its effects on the nervous, digestive and immune systems as well as on organs such as the lungs, kidneys, skin, eyes and heart. Human exposure occurs mainly through inhalation of elemental mercury vapours during industrial and artisanal processes such as artisanal and small-scale gold mining. Case presentation: A 52-years-old female, housewife, with a body mass index of 25.3 kg/cm2, without smoking or alcohol habits or any important clinical or chronic cardiovascular history, was admitted to the emergency room due to probable accidental poisoning by butane gas. Clinical manifestations with a headache, dizziness, cough, and dyspnoea of medium to small efforts. An initial physical exploration with Glasgow scored at 15, with arrhythmic heart sounds, pulmonary fields with bilateral subcrepitant rales and right basal predominance. Electrocardiographic findings were as follows: a cardiac frequency of 50 beats per minute and atrioventricular dissociation. Laboratory parameters were: white blood cells at 15.8 * 108/L; aspartate aminotransferase at 38 U/L; lactate dehydrogenase at 1288 U/L; creatine-kinase at 115 U/L; CK-MB fraction at 28 U/L; and other biochemical parameters were within the reference values. A radiographic evaluation showed flow cephalization, diffuse bilateral infiltrates with right basal predominance. In addition, the patient presented data of low secondary expenditure to third-degree atrioventricular (AV) block for which the placement of a transvenous pacemaker was decided, substantially improving the haemodynamic parameters. Subsequently, after a family interrogation, the diagnosis of mercury inhalation poisoning was established. An initial detection of mercury concentration (Hg(0)) was carried out, reporting 243.5 ug/L. In view of this new evidence, mercury chelation therapy with intravenous calcium disodium ethylenediamine tetraacetic acid (CaNa2.EDTA) was initiated. After 8-days of hospital stay, she presented a favourable evolution with both clinical and radiological improvements, so that the mechanical ventilation progressed to extubating. Subsequently, she was referred for cardiology because of her persistent 3rd-degree atrioventricular block, deciding to place a definitive bicameral pacemaker. The patient was discharged from the hospital 14 days after admission due to clinical improvements with mercury plasma levels at 5 umol/L and a heart rhythm from the pacemaker. Conclusions: We show evidence that acute exposure to elemental mercury can affect the heart rhythm, including a complete atrioventricular blockage. PMID- 29614796 TI - Voluntary Exercise Positively Affects the Recovery of Long-Nerve Gap Injury Following Tube-Bridging with Human Skeletal Muscle-Derived Stem Cell Transplantation. AB - The therapeutic effects of voluntary exercise on the recovery of long-gap nerve injury following the bridging of an acellular conduit filled with human skeletal muscle-derived stem cells (Sk-SCs) have been described. Human Sk-SCs were sorted as CD34+/45- (Sk-34) cells, then cultured/expanded under optimal conditions for 2 weeks. Surgery to generate a long-gap sciatic nerve injury was performed in athymic nude mice, after which the mice were divided into exercise (E) and non exercise (NE) groups. The mice were housed in standard individual cages, and voluntary exercise wheels were introduced to the cages of the E group one week after surgery. After 8 weeks, the human Sk-34 cells were actively engrafted, and showed differentiation into Schwann cells and perineurial cells, in both groups. The recovery in the number of axons and myelin in the conduit and downstream tibial nerve branches, and the lower hindlimb muscle mass and their tension output, was consistently higher by 15-25% in the E group. Moreover, a significantly higher innervation ratio of muscle spindles, reduced pathological muscle fiber area, and acceleration of blood vessel formation in the conduit were each observed in the E group. These results showed that the combined therapy of tube-bridging, Sk-34 cell transplantation, and voluntary exercise is a potentially practical approach for recovery following long-gap nerve injury. PMID- 29614797 TI - Impact of Subolesin and Cystatin Knockdown by RNA Interference in Adult Female Haemaphysalis longicornis (Acari: Ixodidae) on Blood Engorgement and Reproduction. AB - Currently, multi-antigenic vaccine use is the method of choice for the strategic control of ticks. Therefore, determining the efficacy of combined antigens is a promising avenue of research in the development of anti-tick vaccines. The antigen responsible for blood intake and reproduction has proven suitable as a vaccine antigen. It has been shown to silence Haemaphysalis longicornis salivary cystatin (HlSC-1) and subolesin by RNA interference. Adult unfed female ticks were injected with double-stranded RNA of (A) subolesin, (B) cystatin, (C) subolesin plus cystatin, and (D) injection buffer, then fed alongside normal unfed males up to spontaneous drop-down. The percentage of knockdowns was determined by real-time polymerase chain reaction. Sixty-three percent and 53% knockdown rates were observed in subolesin and cystatin double-stranded RNA injected ticks respectively, while 32 and 26% knockdown rates of subolesin and cystatin transcript were observed in subolesin plus cystatin double-stranded RNA injected ticks. Subolesin and/or cystatin knockdown causes a significant (p < 0.05) reduction in tick engorgement, egg mass weight, and egg conversion ratio. Most importantly, combined silencing did not act synergistically, but caused a similarly significant (p < 0.05) reduction in tick engorgement, egg mass weight, and egg conversion ratio. Therefore, the elucidation of multiple antigens may be helpful in the future of vaccines. PMID- 29614798 TI - Why Are New Tobacco Control Interventions Needed? AB - It has been known for years which policies and interventions work to decrease tobacco use in the population[...]. PMID- 29614799 TI - Folate and B12 Levels Correlate with Histological Severity in NASH Patients. AB - BACKGROUND: The correlation between abnormal vitamin serum levels and chronic liver disease has been previously described in literature. However, the association between the severity of folate serum levels (B9), vitamin B12 and nonalcoholic steatohepatitis (NASH) has not been widely evaluated. Therefore, the aim of this study was to investigate the existence of such a correlation in a cohort of NASH patients. METHODS: All patients aged 18 years and older who were diagnosed with biopsy-proven NASH at the EMMS hospital in Nazareth during the years 2015-2017 were enrolled in this study. Data regarding demographic, clinical and laboratory parameters was collected. Patients with other liver diseases were excluded. RESULTS: Eighty-three NASH patients were enrolled during the study period. The mean age was 41 +/- 11 years and the majority of patients were male. Mean values of folate and B12 were 9.85 +/- 10.90 ng/mL and 387.53 +/- 205.50 pg/mL, respectively. Half of the patients were presented with a grade 1 steatosis (43.4%), a grade 2 fibrosis (50.6%) and a grade 3 activity score (55.4%). The fibrosis grade was significantly correlated with low folate levels on multivariate analysis (p-value < 0.01). Similarly, low B12 levels were significantly associated with a higher fibrosis grade and NASH activity (p-value < 0.001 and p-value < 0.05 respectively). CONCLUSION: Our study demonstrated a statistically significant correlation between low levels of folate and vitamin B12 with the histological severity of NASH. These findings could have diagnostic and therapeutic implications for patient management and follow-up. PMID- 29614800 TI - Cross-Linked Poly(vinylidene fluoride-co-hexafluoropropene) (PVDF-co-HFP) Gel Polymer Electrolyte for Flexible Li-Ion Battery Integrated with Organic Light Emitting Diode (OLED). AB - Here, we fabricate poly(vinylidene fluoride-co-hexafluoropropene) (PVDF-co-HFP) by electrospinning for a gel polymer electrolyte (GPE) for use in flexible Li-ion batteries (LIBs). As a solvent, we use N-methyl-2-pyrrolidone (NMP), which helps produce the cross-linked morphology of PVDF-co-HFP separator, owing to its low volatility. The cross-linked PVDF-co-HFP separator shows an uptake rate higher than that of a commercialized polypropylene (PP) separator. Moreover, the PVDF-co HFP separator shows an ionic conductivity of 2.3 * 10-3 S/cm at room temperature, comparable with previously reported values. An LIB full-cell assembled with the PVDF-co-HFP-based GPE shows capacities higher than its counterpart with the commercialized PP separator, confirming that the cross-linked PVDF-co-HFP separator provides highly efficient ionic conducting pathways. In addition, we integrate a flexible LIB cell using the PVDF-co-HFP GPE with a flexible organic light emitting diode (OLED), demonstrating a fully flexible unit of LIB and OLED. PMID- 29614801 TI - Passion Fruit Chlorotic Mottle Virus: Molecular Characterization of a New Divergent Geminivirus in Brazil. AB - Brazil is one of the major passion fruit producers worldwide. Viral diseases are among the most important constraints for passion fruit production. Here we identify and characterize a new passion fruit infecting-virus belonging to the family Geminiviridae: passion fruit chlorotic mottle virus (PCMoV). PCMoV is a divergent geminivirus unlike previously characterized passion fruit-infecting geminiviruses that belonged to the genus Begomovirus. Among the presently known geminiviruses, it is most closely related to, and shares ~62% genome-wide identity with citrus chlorotic dwarf associated virus (CCDaV) and camelia chlorotic dwarf associated virus (CaCDaV). The 3743 nt PCMoV genome encodes a capsid protein (CP) and replication-associated protein (Rep) that respectively share 56 and 60% amino acid identity with those encoded by CaCDaV. The CPs of PCMoV, CCDaV, and CaCDaV cluster with those of begomovirus whereas their Reps with those of becurtoviruses. Hence, these viruses likely represent a lineage of recombinant begomo-like and becurto-like ancestral viruses. Furthermore, PCMoV, CCDaV, and CaCDaV genomes are ~12-30% larger than monopartite geminiviruses and this is primarily due to the encoded movement protein (MP; 891-921 nt) and this MP is most closely related to that encoded by the DNA-B component of bipartite begomoviruses. Hence, PCMoV, CCDaV, and CaCDaV lineage of viruses may represent molecules in an intermediary step in the evolution of bipartite begomoviruses (~5.3 kb) from monopartite geminiviruses (~2.7-3 kb). An infectious clone of PCMoV systemically infected Nicotiana benthamina, Arabidopsis thaliana, and Passiflora edulis. PMID- 29614803 TI - Improving Chronic Disease Self-Management by Older Home Health Patients through Community Health Coaching. AB - The purpose of the study was to pilot test a model to reduce hospital readmissions and emergency department use of rural, older adults with chronic diseases discharged from home health services (HHS) through the use of volunteers. The study's priority population consistently experiences poorer health outcomes than their urban counterparts due in part to lower socioeconomic status, reduced access to health services, and incidence of chronic diseases. When they are hospitalized for complications due to poorly managed chronic diseases, they are frequently readmitted for the same conditions. This pilot study examines the use of volunteer community members who were trained as Health Coaches to mentor discharged HHS patients in following the self-care plan developed by their HHS RN; improving chronic disease self-management behaviors; reducing risk of falls, pneumonia, and flu; and accessing community resources. Program participants increased their ability to monitor and track their chronic health conditions, make positive lifestyle changes, and reduce incidents of falls, pneumonia and flu. Although differences in the ED and hospital admission rates after discharge from HHS between the treatment and comparison group (matched for gender, age, and chronic condition) were not statistically significant, the treatment group's rate was less than the comparison group thus suggesting a promising impact of the HC program (90 day: 263 comparison vs. 129 treatment; p = 0.65; 180 day 666.67 vs. 290.32; p = 0.19). The community health coach model offers a potential approach for improving the ability of discharged older home health patients to manage chronic conditions and ultimately reduce emergent care. PMID- 29614802 TI - Associations between Job Strain and Arterial Stiffness: A Large Survey among Enterprise Employees from Thailand. AB - As an intermediate endpoint to cardiovascular disease, arterial stiffness has received much attention recently. So far, the research on work stress and arterial stiffness is still sparse and inconsistent, and no investigations on work stress and cardiovascular health among the Thai working population have been reported. Therefore, we conducted an epidemiological study among 2141 Thai enterprise employees (858 men and 1283 women) who were free from any diagnosed cardiovascular disease. Work stress was measured using Karasek's Job Demand Control model for job strain (a combination of high demand and low control). Arterial stiffness was evaluated by a non-invasive approach using pulse-wave analysis based on a finger photoplethysmogram. Multivariable linear regression was applied to examine associations between job strain and arterial stiffness. In men, job strain was significantly associated with arterial stiffness (beta = 0.078, 95% confidence interval = 0.026 to 0.130), after accounting for sociodemographic, behavioral, dietary and biomedical factors. However, the association in women was not significant. As the first study in Thailand on work stress and cardiovascular risk, we found that job strain might be an important risk factor for cardiovascular disease among Thai working men. Further studies with longitudinal design are warranted. PMID- 29614804 TI - Alginate in Wound Dressings. AB - Alginate is a biopolymer used in a variety of biomedical applications due to its favourable properties, such as biocompatibility and non-toxicity. It has been particularly attractive in wound healing applications to date. It can be tailored to materials with properties suitable for wound healing. Alginate has been used to prepare different forms of materials for wound dressings, such as hydrogels, films, wafers, foams, nanofibres, and in topical formulations. The wound dressings prepared from alginate are able to absorb excess wound fluid, maintain a physiologically moist environment, and minimize bacterial infections at the wound site. The therapeutic efficacy of these wound dressings is influenced by the ratio of other polymers used in combination with alginate, the nature of cross linkers used, the time of crosslinking, nature of excipients used, the incorporation of nanoparticles, and antibacterial agents. This review provides a comprehensive overview of the different forms of wound dressings containing alginate, in vitro, and in vivo results. PMID- 29614805 TI - 27Al NMR Study of the pH Dependent Hydrolysis Products of Al2(SO4)3 in Different Physiological Media. AB - Soluble inorganic aluminium compounds like aluminium sulfate or aluminium chloride have been challenged by the European Chemical Agency to induce germ cell mutagenicity. Before conducting mutagenicity tests, the hydrolysis products in water and in physiological solutions should be determined as a function of the concentration and pH. We used different 27Al NMR spectroscopic techniques (heteronuclear Overhauser effect spectroscopy (HOESY), exchange spectroscopy (EXSY), diffusion ordered (DOSY)) in this work to gain the information to study the aluminium species in solutions with Al2(SO4)3 concentrations of 50.0, 5.0, and 0.5 g/L and their pH and time dependent transformation. At low pH, three different species were present in all physiological solutions and water: [Al(OH)n(H2O)6 - n](3 - n)+ (n = 0-2), [Al(H2O)5SO4]+, and [Al2(OH)2(H2O)8]4+. Increasing pH reduced the amounts of the two monomer species, with a complete loss at pH 5 for solutions with a concentration of 50.0 g/L and at pH 4 for solutions with a concentration of 5.0 g/L. The dimer species [Al2(OH)2(H2O)8]4+ is present in a pH range between 3 and 6. Less symmetric oligomeric and probably asymmetric aluminium species are formed at pH of 5 and 6. The pH value is the driving force for the formation of aluminium species in all media, whereas the specific medium had only minor effect. No conclusive information could be obtained at pH 7 due to signal loss related to fast quadrupole relaxation of asymmetric aluminium species. A slight reduction of the content of the symmetric aluminium species due to the formation of oligomeric species was observed over a period of 6 weeks. Reference 27Al NMR experiments conducted on saturated water solutions of AlCl3 and those with a concentration of 50 g/L show that the type of salt/counter ion at the same concentration and pH influences the hydrolysis products formed. PMID- 29614806 TI - Prediction of Renal Acid Load in Adult Patients on Parenteral Nutrition. AB - Metabolic acidosis and metabolic bone disease are frequent complications in patients on parenteral nutrition (PN). A common contributor to these complications could be a daily high renal acid load. This study aims to find a method for predicting the potential total acid load (PTAL) and the pH of the compounded parenteral nutrition mixtures. The pH and titratable acidity (TA) of fifty compounded mixtures were measured. The potential metabolic acid load (PMAL) was calculated by considering the amount of nutrients that are acid producers and consumers. The PTAL of the TPN mixtures was calculated by adding TA to PMAL. Multiple linear regression analyses were used to develop a predictive model for the TA and pH of the compounded mixtures. The predicted TA and pH values of the analyzed mixtures agreed with those measured (Passing-Bablok analysis). The PTAL was >50 mmol/day for 82% of the mixtures, >75 mmol/day for 40% of the mixtures, and >100 mmol/day for 22% of the mixtures. The prediction of the renal acid load in patients on long-term PN could allow more appropriate acid-base balancing. Moreover, predicting the pH of such mixtures could be useful to pharmacists to assess the stability and compatibility of the components in the compounded mixtures. PMID- 29614807 TI - Delving Deep into Multiscale Pedestrian Detection via Single Scale Feature Maps. AB - The standard pipeline in pedestrian detection is sliding a pedestrian model on an image feature pyramid to detect pedestrians of different scales. In this pipeline, feature pyramid construction is time consuming and becomes the bottleneck for fast detection. Recently, a method called multiresolution filtered channels (MRFC) was proposed which only used single scale feature maps to achieve fast detection. However, there are two shortcomings in MRFC which limit its accuracy. One is that the receptive field correspondence in different scales is weak. Another is that the features used are not scale invariance. In this paper, two solutions are proposed to tackle with the two shortcomings respectively. Specifically, scale-aware pooling is proposed to make a better receptive field correspondence, and soft decision tree is proposed to relive scale variance problem. When coupled with efficient sliding window classification strategy, our detector achieves fast detecting speed at the same time with state-of-the-art accuracy. PMID- 29614808 TI - Effects of Ingestion of Different Amounts of Carbohydrate after Endurance Exercise on Circulating Cytokines and Markers of Neutrophil Activation. AB - We aimed to examine the effects of ingestion of different amounts of carbohydrate (CHO) after endurance exercise on neutrophil count, circulating cytokine levels, and the markers of neutrophil activation and muscle damage. Nine participants completed three separate experimental trials consisting of 1 h of cycling exercise at 70% V . O2 max, followed by ingestion of 1.2 g CHO.kg body mass-1.h-1 (HCHO trial), 0.2 g CHO.kg body mass-1.h-1 (LCHO trial), or placebo (PLA trial) during the 2 h recovery phase in random order. Circulating glucose, insulin, and cytokine levels, blood cell counts, and the markers of neutrophil activation and muscle damage were measured. The concentrations of plasma glucose and serum insulin at 1 h after exercise were higher in the HCHO trial than in the LCHO and PLA trials. Although there were significant main effects of time on several variables, including neutrophil count, cytokine levels, and the markers of neutrophil activation and muscle damage, significant time * trial interactions were not observed for any variables. These results suggest that CHO ingestion after endurance exercise does not enhance exercise-induced increase in circulating neutrophil and cytokine levels and markers of neutrophil activation and muscle damage, regardless of the amount of CHO ingested. PMID- 29614809 TI - Spatio-Temporal Epidemiology of Viral Hepatitis in China (2003-2015): Implications for Prevention and Control Policies. AB - Viral hepatitis, as one of the most serious notifiable infectious diseases in China, takes heavy tolls from the infected and causes a severe economic burden to society, yet few studies have systematically explored the spatio-temporal epidemiology of viral hepatitis in China. This study aims to explore, visualize and compare the epidemiologic trends and spatial changing patterns of different types of viral hepatitis (A, B, C, E and unspecified, based on the classification of CDC) at the provincial level in China. The growth rates of incidence are used and converted to box plots to visualize the epidemiologic trends, with the linear trend being tested by chi-square linear by linear association test. Two complementary spatial cluster methods are used to explore the overall agglomeration level and identify spatial clusters: spatial autocorrelation analysis (measured by global and local Moran's I) and space-time scan analysis. Based on the spatial autocorrelation analysis, the hotspots of hepatitis A remain relatively stable and gradually shrunk, with Yunnan and Sichuan successively moving out the high-high (HH) cluster area. The HH clustering feature of hepatitis B in China gradually disappeared with time. However, the HH cluster area of hepatitis C has gradually moved towards the west, while for hepatitis E, the provincial units around the Yangtze River Delta region have been revealing HH cluster features since 2005. The space-time scan analysis also indicates the distinct spatial changing patterns of different types of viral hepatitis in China. It is easy to conclude that there is no one-size-fits-all plan for the prevention and control of viral hepatitis in all the provincial units. An effective response requires a package of coordinated actions, which should vary across localities regarding the spatial-temporal epidemic dynamics of each type of virus and the specific conditions of each provincial unit. PMID- 29614810 TI - VpStyA1/VpStyA2B of Variovorax paradoxus EPS: An Aryl Alkyl Sulfoxidase Rather than a Styrene Epoxidizing Monooxygenase. AB - Herein we describe the first representative of an E2-type two-component styrene monooxygenase of proteobacteria. It comprises a single epoxidase protein (VpStyA1) and a two domain protein (VpStyA2B) harboring an epoxidase (A2) and a FAD-reductase (B) domain. It was annotated as VpStyA1/VpStyA2B of Variovorax paradoxus EPS. VpStyA2B serves mainly as NADH:FAD-oxidoreductase. A Km of 33.6 +/ 4.0 uM for FAD and a kcat of 22.3 +/- 1.1 s-1 were determined and resulted in a catalytic efficiency (kcatKm-1) of 0.64 s-1 MUM-1. To investigate its NADH:FAD oxidoreductase function the linker between A2- and B-domain (AREAV) was mutated. One mutant (AAAAA) showed 18.7-fold higher affinity for FAD (kcatKm-1 of 5.21 s-1 MUM-1) while keeping wildtype NADH-affinity and -oxidation activity. Both components, VpStyA2B and VpStyA1, showed monooxygenase activity on styrene of 0.14 U mg-1 and 0.46 U mg-1, as well as on benzyl methyl sulfide of 1.62 U mg-1 and 3.11 U mg-1, respectively. The high sulfoxidase activity was the reason to test several thioanisole-like substrates in biotransformations. VpStyA1 showed high substrate conversions (up to 95% in 2 h) and produced dominantly (S) enantiomeric sulfoxides of all tested substrates. The AAAAA-mutant showed a 1.6 fold increased monooxygenase activity. In comparison, the GQWCSQY-mutant did neither show monooxygenase nor efficient FAD-reductase activity. Hence, the linker between the two domains of VpStyA2B has effects on the reductase as well as on the monooxygenase performance. Overall, this monooxygenase represents a promising candidate for biocatalyst development and studying natural fusion proteins. PMID- 29614811 TI - Material Considerations for Fused-Filament Fabrication of Solid Dosage Forms. AB - Material choice is a fundamental consideration when it comes to designing a solid dosage form. The matrix material will ultimately determine the rate of drug release since the physical properties (solubility, viscosity, and more) of the material control both fluid ingress and disintegration of the dosage form. The bulk properties (powder flow, concentration, and more) of the material should also be considered since these properties will influence the ability of the material to be successfully manufactured. Furthermore, there is a limited number of approved materials for the production of solid dosage forms. The present study details the complications that can arise when adopting pharmaceutical grade polymers for fused-filament fabrication in the production of oral tablets. The paper also presents ways to overcome each issue. Fused-filament fabrication is a hot-melt extrusion-based 3D printing process. The paper describes the problems encountered in fused-filament fabrication with Kollidon(r) VA64, which is a material that has previously been utilized in direct compression and hot-melt extrusion processes. Formulation and melt-blending strategies were employed to increase the printability of the material. The paper defines for the first time the essential parameter profile required for successful 3D printing and lists several pre-screening tools that should be employed to guide future material formulation for the fused-filament fabrication of solid dosage forms. PMID- 29614812 TI - 20(S)-Protopanaxadiol-Induced Apoptosis in MCF-7 Breast Cancer Cell Line through the Inhibition of PI3K/AKT/mTOR Signaling Pathway. AB - 20(S)-Protopanaxadiol (PPD) is one of the major active metabolites of ginseng. It has been reported that 20(S)-PPD shows a broad spectrum of antitumor effects. Our research study aims were to investigate whether apoptosis of human breast cancer MCF-7 cells could be induced by 20(S)-PPD by targeting the Phosphatidylinositol 3 kinase/Protein kinase B/Mammalian target of rapamycin (PI3K/AKT/mTOR) signal pathway in vitro and in vivo. Cell cycle analysis was performed by Propidium Iodide (PI) staining. To overexpress and knock down the expression of mTOR, pcDNA3.1-mTOR and mTOR small interfering RNA (siRNA) transient transfection assays were used, respectively. Cell viability and apoptosis were evaluated by 3 (4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)-test and Annexin V /PI double-staining after transfection. The antitumor effect in vivo was determined by the nude mice xenograft assay. After 24 h of incubation, treatment with 20(S)-PPD could upregulate phosphorylated-Phosphatase and tensin homologue deleted on chromosome 10 (p-PTEN) expression and downregulate PI3K/AKT/mTOR pathway protein expression. Moreover, G0/G1 cell cycle arrest in MCF-7 cells could be induced by 20(S)-PPD treatment at high concentrations. Furthermore, overexpression or knockdown of mTOR could inhibit or promote the apoptotic effects of 20(S)-PPD. In addition, tumor volumes were partially reduced by 20(S) PPD at 100 mg/kg in a MCF-7 xenograft model. Immunohistochemical staining indicated a close relationship between the inhibition of tumor growth and the PI3K/AKT/mTOR signal pathway. PI3K/AKT/mTOR pathway-mediated apoptosis may be one of the potential mechanisms of 20(S)-PPD treatment. PMID- 29614813 TI - Automatic Fabric Defect Detection with a Multi-Scale Convolutional Denoising Autoencoder Network Model. AB - Fabric defect detection is a necessary and essential step of quality control in the textile manufacturing industry. Traditional fabric inspections are usually performed by manual visual methods, which are low in efficiency and poor in precision for long-term industrial applications. In this paper, we propose an unsupervised learning-based automated approach to detect and localize fabric defects without any manual intervention. This approach is used to reconstruct image patches with a convolutional denoising autoencoder network at multiple Gaussian pyramid levels and to synthesize detection results from the corresponding resolution channels. The reconstruction residual of each image patch is used as the indicator for direct pixel-wise prediction. By segmenting and synthesizing the reconstruction residual map at each resolution level, the final inspection result can be generated. This newly developed method has several prominent advantages for fabric defect detection. First, it can be trained with only a small amount of defect-free samples. This is especially important for situations in which collecting large amounts of defective samples is difficult and impracticable. Second, owing to the multi-modal integration strategy, it is relatively more robust and accurate compared to general inspection methods (the results at each resolution level can be viewed as a modality). Third, according to our results, it can address multiple types of textile fabrics, from simple to more complex. Experimental results demonstrate that the proposed model is robust and yields good overall performance with high precision and acceptable recall rates. PMID- 29614814 TI - The Role of Single-Molecule Force Spectroscopy in Unraveling Typical and Autoimmune Heparin-induced Thrombocytopenia. AB - For the last two decades, heparins have been widely used as anticoagulants. Besides numerous advantages, up to 5% patients with heparin administration suffer from a major adverse drug effect known as heparin-induced thrombocytopenia (HIT). This typical HIT can result in deep vein thrombosis, pulmonary embolism, occlusion of a limb artery, acute myocardial infarct, stroke, and a systemic reaction or skin necrosis. The basis of HIT may lead to clinical insights. Recent studies using single-molecule force spectroscopy (SMFS)-based atomic force microscopy revealed detailed binding mechanisms of the interactions between platelet factor 4 (PF4) and heparins of different lengths in typical HIT. Especially, SMFS results allowed identifying a new mechanism of the autoimmune HIT caused by a subset of human-derived antibodies in patients without heparin exposure. The findings proved that not only heparin but also a subset of antibodies induce thrombocytopenia. In this review, the role of SMFS in unraveling a major adverse drug effect and insights into molecular mechanisms inducing thrombocytopenia by both heparins and antibodies will be discussed. PMID- 29614815 TI - A New Design of a Single-Device 3D Hall Sensor: Cross-Shaped 3D Hall Sensor. AB - In this paper, a new single-device three-dimensional (3D) Hall sensor called a cross-shaped 3D Hall device is designed based on the five-contact vertical Hall device. Some of the device parameters are based on 0.18 MUm BCDliteTM technology provided by GLOBALFOUNDRIES. Two-dimensional (2D) and 3D finite element models implemented in COMSOL are applied to understand the device behavior under a constant magnetic field. Besides this, the influence of the sensing contacts, active region's depth, and P-type layers are taken into account by analyzing the distribution of the voltage along the top edge and the current density inside the devices. Due to the short-circuiting effect, the sensing contacts lead to degradation in sensitivities. The P-type layers and a deeper active region in turn are responsible for the improvement of sensitivities. To distinguish the P type layer from the active region which plays the dominant role in reducing the short-circuiting effect, the current-related sensitivity of the top edge (Stop) is defined. It is found that the short-circuiting effect fades as the depth of the active region grows. Despite the P-type layers, the behavior changes a little. When the depth of the active region is 7 MUm and the thickness of the P type layers is 3 MUm, the sensitivities in the x, y, and z directions can reach 91.70 V/AT, 92.36 V/AT, and 87.10 V/AT, respectively. PMID- 29614817 TI - Sparse Reconstruction Based Robust Near-Field Source Localization Algorithm. AB - Non-Gaussian impulsive noise widely exists in the real world, this paper takes the alpha-stable distribution as the mathematical model of non-Gaussian impulsive noise and works on the joint direction-of-arrival (DOA) and range estimation problem of near-field signals in impulsive noise environment. Since the conventional algorithms based on the classical second order correlation statistics degenerate severely in the impulsive noise environment, this paper adopts two robust correlations, the fractional lower order correlation (FLOC) and the nonlinear transform correlation (NTC), and presents two related near-field localization algorithms. In our proposed algorithms, by exploring the symmetrical characteristic of the array, we construct the robust far-field approximate correlation vector in relation with the DOA only, which allows for bearing estimation based on the sparse reconstruction. With the estimated bearing, the range can consequently be obtained by the sparse reconstruction of the output of a virtual array. The proposed algorithms have the merits of good noise suppression ability, and their effectiveness is demonstrated by the computer simulation results. PMID- 29614816 TI - Genetic and Epigenetic Control of CDKN1C Expression: Importance in Cell Commitment and Differentiation, Tissue Homeostasis and Human Diseases. AB - The CDKN1C gene encodes the p57Kip2 protein which has been identified as the third member of the CIP/Kip family, also including p27Kip1 and p21Cip1. In analogy with these proteins, p57Kip2 is able to bind tightly and inhibit cyclin/cyclin-dependent kinase complexes and, in turn, modulate cell division cycle progression. For a long time, the main function of p57Kip2 has been associated only to correct embryogenesis, since CDKN1C-ablated mice are not vital. Accordingly, it has been demonstrated that CDKN1C alterations cause three human hereditary syndromes, characterized by altered growth rate. Subsequently, the p57Kip2 role in several cell phenotypes has been clearly assessed as well as its down-regulation in human cancers. CDKN1C lies in a genetic locus, 11p15.5, characterized by a remarkable regional imprinting that results in the transcription of only the maternal allele. The control of CDKN1C transcription is also linked to additional mechanisms, including DNA methylation and specific histone methylation/acetylation. Finally, long non-coding RNAs and miRNAs appear to play important roles in controlling p57Kip2 levels. This review mostly represents an appraisal of the available data regarding the control of CDKN1C gene expression. In addition, the structure and function of p57Kip2 protein are briefly described and correlated to human physiology and diseases. PMID- 29614818 TI - Potential Interplay between Hyperosmolarity and Inflammation on Retinal Pigmented Epithelium in Pathogenesis of Diabetic Retinopathy. AB - Diabetic retinopathy is a frequent eyesight threatening complication of type 1 and type 2 diabetes. Under physiological conditions, the inner and the outer blood-retinal barriers protect the retina by regulating ion, protein, and water flux into and out of the retina. During diabetic retinopathy, many factors, including inflammation, contribute to the rupture of the inner and/or the outer blood-retinal barrier. This rupture leads the development of macular edema, a foremost cause of sight loss among diabetic patients. Under these conditions, it has been speculated that retinal pigmented epithelial cells, that constitute the outer blood-retinal barrier, may be subjected to hyperosmolar stress resulting from different mechanisms. Herein, we review the possible origins and consequences of hyperosmolar stress on retinal pigmented epithelial cells during diabetic retinopathy, with a special focus on the intimate interplay between inflammation and hyperosmolar stress, as well as the current and forthcoming new pharmacotherapies for the treatment of such condition. PMID- 29614821 TI - Artifact Noise Removal Techniques on Seismocardiogram Using Two Tri-Axial Accelerometers. AB - The aim of this study is on the investigation of motion noise removal techniques using two-accelerometer sensor system and various placements of the sensors on gentle movement and walking of the patients. A Wi-Fi based data acquisition system and a framework on Matlab are developed to collect and process data while the subjects are in motion. The tests include eight volunteers who have no record of heart disease. The walking and running data on the subjects are analyzed to find the minimal-noise bandwidth of the SCG signal. This bandwidth is used to design filters in the motion noise removal techniques and peak signal detection. There are two main techniques of combining signals from the two sensors to mitigate the motion artifact: analog processing and digital processing. The analog processing comprises analog circuits performing adding or subtracting functions and bandpass filter to remove artifact noises before entering the data acquisition system. The digital processing processes all the data using combinations of total acceleration and z-axis only acceleration. The two techniques are tested on three placements of accelerometer sensors including horizontal, vertical, and diagonal on gentle motion and walking. In general, the total acceleration and z-axis acceleration are the best techniques to deal with gentle motion on all sensor placements which improve average systolic signal noise-ratio (SNR) around 2 times and average diastolic SNR around 3 times comparing to traditional methods using only one accelerometer. With walking motion, ADDER and z-axis acceleration are the best techniques on all placements of the sensors on the body which enhance about 7 times of average systolic SNR and about 11 times of average diastolic SNR comparing to only one accelerometer method. Among the sensor placements, the performance of horizontal placement of the sensors is outstanding comparing with other positions on all motions. PMID- 29614820 TI - Targeted Metabolomic and Transcriptomic Analyses of "Red Russian" Kale (Brassicae napus var. pabularia) Following Methyl Jasmonate Treatment and Larval Infestation by the Cabbage Looper (Trichoplusia ni Hubner). AB - Methyl jasmonate (MeJA), synthesized in the jasmonic acid (JA) pathway, has been found to upregulate glucosinolate (GS) biosynthesis in plant species of the Brassicaceae family. Exogenous application of MeJA has shown to increase tissue GS concentrations and the formation of myrosinase-mediated GS hydrolysis products (GSHPs). In vitro and in vivo assays have demonstrated the potential health promoting effects of certain GSHPs. MeJA is also known to elicit and induce genes associated with defense mechanisms to insect herbivory in Brassica species. To investigate the relationship between MeJA-induced GS biosynthesis and insect defense, three treatments were applied to "Red Russian" kale (Brassicae napus var. pabularia) seedlings: (1) a 250 uM MeJA leaf spray treatment; (2) leaf infestation with larvae of the cabbage looper (Trichoplusia ni (Hubner)); (3) control treatment (neither larval infestation nor MeJA application). Samples of leaf tissue from the three treatments were then assayed for changes in GS and GSHP concentrations, GS gene biosynthesis expression, and myrosinase activity. Major differences were observed between the three treatments in the levels of GS accumulation and GS gene expression. The insect-damaged samples showed significantly lower aliphatic GS accumulation, while both MeJA and T. ni infestation treatments induced greater accumulation of indolyl GS. The gene expression levels of CYP81F4, MYB34, and MYB122 were significantly upregulated in samples treated with MeJA and insects compared to the control group, which explained the increased indolyl GS concentration. The results suggest that the metabolic changes promoted by MeJA application and the insect herbivory response share common mechanisms of induction. This work provides potentially useful information for kale pest control and nutritional quality. PMID- 29614819 TI - Emerging Roles of Vascular Cell Adhesion Molecule-1 (VCAM-1) in Immunological Disorders and Cancer. AB - Tumor necrosis factor alpha (TNFalpha) is a pro-inflammatory cytokine that triggers the expression of inflammatory molecules, including other cytokines and cell adhesion molecules. TNFalpha induces the expression of intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1 (VCAM-1). VCAM-1 was originally identified as a cell adhesion molecule that helps regulate inflammation-associated vascular adhesion and the transendothelial migration of leukocytes, such as macrophages and T cells. Recent evidence suggests that VCAM-1 is closely associated with the progression of various immunological disorders, including rheumatoid arthritis, asthma, transplant rejection, and cancer. This review covers the role and relevance of VCAM-1 in inflammation, and also highlights the emerging potential of VCAM-1 as a novel therapeutic target in immunological disorders and cancer. PMID- 29614822 TI - Coumarin Content, Morphological Variation, and Molecular Phylogenetics of Melilotus. AB - Melilotus albus and Melilotus officinalis are widely used in forage production and herbal medicine due to the biological activity of their coumarins, which have many biological and pharmacological activities, including anti-HIV and anti-tumor effects. To comprehensively evaluate M. albus and M. officinalis coumarin content (Cou), morphological variation, and molecular phylogeny, we examined the Cou, five morphological traits and the molecular characterization based on the trnL-F spacer and internal transcribed spacer (ITS) regions of 93 accessions. Significant (p < 0.05) variation was observed in the Cou and all five morphological traits in both species. Analysis of population differentiation (Pst) of the phenotypic traits showed that powdery mildew resistance (PMR) had the greatest Pst, meaning that this trait demonstrated the largest genetic differentiation among the accessions. The Pst values of dry matter yield (DMY) and Cou were relatively high. Biplot analysis identified accessions with higher DMY and higher and lower Cou. Analysis of molecular sequence variation identified seven haplotypes of the trnL-F spacer and 13 haplotypes of the ITS region. Based on haplotype and sequence analyses, the genetic variation of M. officinalis was higher than that of M. albus. Additionally, ITS sequence analysis showed that the variation among accessions was larger than that among species across three geographical areas: Asia, Europe, and North America. Similarly, variation among accessions for both the trnL-F and ITS sequences were larger than the differences between the geographical areas. Our results indicate that there has been considerable gene flow between the two Melilotus species. Our characterization of Cou and the morphological and genetic variations of these two Melilotus species may provide useful insights into germplasm improvement to enhance DMY and Cou. PMID- 29614823 TI - Combination of Superheated Steam with Laccase Pretreatment Together with Size Reduction to Enhance Enzymatic Hydrolysis of Oil Palm Biomass. AB - The combination of superheated steam (SHS) with ligninolytic enzyme laccase pretreatment together with size reduction was conducted in order to enhance the enzymatic hydrolysis of oil palm biomass into glucose. The oil palm empty fruit bunch (OPEFB) and oil palm mesocarp fiber (OPMF) were pretreated with SHS and ground using a hammer mill to sizes of 2, 1, 0.5 and 0.25 mm before pretreatment using laccase to remove lignin. This study showed that reduction of size from raw to 0.25 mm plays important role in lignin degradation by laccase that removed 38.7% and 39.6% of the lignin from OPEFB and OPMF, respectively. The subsequent saccharification process of these pretreated OPEFB and OPMF generates glucose yields of 71.5% and 63.0%, which represent a 4.6 and 4.8-fold increase, respectively, as compared to untreated samples. This study showed that the combination of SHS with laccase pretreatment together with size reduction could enhance the glucose yield. PMID- 29614824 TI - Oligo-Alginate with Low Molecular Mass Improves Growth and Physiological Activity of Eucomis autumnalis under Salinity Stress. AB - Biopolymers have become increasingly popular as biostimulators of plant growth. One of them, oligo-alginate, is a molecule that regulates plant biological processes and may be used in horticultural practice as a plant growth regulator. Biostimulators are mainly used to improve plant tolerance to abiotic stresses, including salinity. The aim of the study was to assess the effects of salinity and oligo-alginate of various molecular masses on the growth and physiological activity of Eucomis autumnalis. The species is an ornamental and medicinal plant that has been used for a long time in the traditional medicine of South Africa. The bulbs of E. autumnalis were coated using depolymerized sodium alginate of molecular mass 32,000; 42,000, and 64,000 g mol-1. All of these oligo-alginates fractions stimulated plant growth, and the effect was the strongest for the fraction of 32,000 g mol-1. This fraction was then selected for the second stage of the study, when plants were exposed to salt stress evoked by the presence of 100 mM NaCl. We found that the oligo-alginate coating mitigated the negative effects of salinity. Plants treated with the oligomer and watered with NaCl showed smaller reduction in the weight of the above-ground parts and bulbs, pigment content and antioxidant activity as compared with those not treated with the oligo-alginate. The study demonstrated for the first time that low molecular mass oligo-alginate may be used as plant biostimulator that limits negative effects of salinity in E. autumnalis. PMID- 29614826 TI - The Use of a Non-Penetrating Captive Bolt for the Euthanasia of Neonate Piglets. AB - The most common method for the on-farm euthanasia of neonate piglets is reported to be manual blunt force trauma. This paper presents the results of research to evaluate a mechanical non-penetrating captive bolt (the Accles and Shelvoke CASH small animal tool, Birmingham, UK) to produce an immediate stun/kill with neonate piglets. One hundred and forty-seven piglets (average dead weight = 1.20 kg +/- 0.58 (standard deviation, SD), mean age = 5.8 days (median = 3)) were euthanized with the device and demonstrated immediate loss of consciousness, subjectively assessed by behavioural signs and no recovery. The result that 147 out of 147 animals were effectively stun/killed gives a 95% confidence interval for the true percentage of animals that would be effectively stun/killed of 97.5-100% with the use of the CASH small animal tool under the conditions of the current study. This research concludes that the CASH small animal tool, using a 1 grain brown coded cartridge, is suitable for producing a stun/kill in neonate piglets when applied in a frontal/parietal position. PMID- 29614825 TI - Associations between Parents' Health Literacy and Sleeping Hours in Children: A Cross-Sectional Study. AB - BACKGROUND: Sleep in preschool children is an important factor for their health and active lives. The lack of adequate sleep in preschool children is a serious public problem in Japan. The relationship between health literacy (HL) and health status is well recognized. The purpose of this study was to investigate the association between the sleep duration of preschool children and the HL of their parents. METHODS: In the present study, participants were preschool children (3-6 years) and their parents. We assessed the HL of the parents with the 14-item Health Literacy Scale (HLS-14) questionnaire. Sleep duration of the children was reported by their parents. We divided parents into two groups according to HLS-14 score and analyzed children's sleeping time separately. RESULTS: Data from 279 parents and their children were ultimately analyzed. The high HL group comprised 210 families (75.3%) and the low HL group comprised 69 families (24.7%). Average children's sleep duration was significantly longer in the high HL group (9.5 +/- 0.9 h) than in the low HL group (9.1 +/- 1.1 h) (p = 0.013). A positive correlation was found in the low HL group between parents' HL and their children's sleeping times (p < 0.01, r = 0.32) but the difference was not significant in the high HL group (p = 0.98, r = -0.0009). CONCLUSION: The HL of parents appears to affect their children's sleep duration, suggesting that parental HL may be an appropriate target for interventions aiming to lengthen children's sleeping time. PMID- 29614827 TI - The Impact of Warming and Nutrients on Algae Production and Microcystins in Seston from the Iconic Lake Lesser Prespa, Greece. AB - Lake Lesser Prespa and its adjacent pond, Vromolimni in Greece, is a shallow freshwater system and a highly protected area hosting an exceptional biodiversity. The occurrence of microcystins (MCs) producing cyanobacterial blooms in these waters during recent years can be harmful to the wildlife. We tested the hypothesis that both cyanobacterial biomass and MCs are strongly influenced by nutrients (eutrophication) and warming (climate change). Lake and pond water was collected from two sites in each water body in 2013 and incubated at three temperatures (20 degrees C, 25 degrees C, 30 degrees C) with or without additional nutrients (nitrogen +N, phosphorus +P and both +N and +P). Based on both biovolume and chlorophyll-a concentrations, cyanobacteria in water from Lesser Prespa were promoted primarily by combined N and P additions and to a lesser extent by N alone. Warming seemed to yield more cyanobacteria biomass in these treatments. In water from Vromolimni, both N alone and N+P additions increased cyanobacteria and a warming effect was hardly discernible. MC concentrations were strongly increased by N and N+P additions in water from all four sites, which also promoted the more toxic variant MC-LR. Hence, both water bodies seem particularly vulnerable to further N-loading enhancing MC related risks. PMID- 29614828 TI - Synthesis, Structural Characterization and Antimicrobial Activity of Cu(II) and Fe(III) Complexes Incorporating Azo-Azomethine Ligand. AB - We are reporting a novel azo-azomethine ligand, HL and its complexes with Cu(II) and Fe(III) ions. The ligand and its complexes are characterized by various physico-chemical techniques using C,H,N analyses, FT-IR, 1H-NMR, ESI-MS and UV Vis studies. TGA analyses reveal complexes are sufficiently stable and undergo two-step degradation processes. The redox behavior of the complexes was evaluated by cyclic voltammetry. Furthermore, the ligand and its complexes were tested for antimicrobial activity against bacterial and fungal strains by determining inhibition zone, minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC). The complexes showed moderate antimicrobial activity when tested against Gram +ve and Gram -ve bacterial strains. To obtain insights into the structure of ligand, DFT studies are recorded. The results obtained are quite close to the experimental results. In addition, the energy gap, chemical hardness, softness, electronegativity, electrophilic index and chemical potential were calculated using HOMO, LUMO energy value of ligand. PMID- 29614829 TI - The Use of a Polyphenoloxidase Biosensor Obtained from the Fruit of Jurubeba (Solanum paniculatum L.) in the Determination of Paracetamol and Other Phenolic Drugs. AB - The vegetable kingdom is a wide source of a diverse variety of enzymes with broad biotechnological applications. Among the main classes of plant enzymes, the polyphenol oxidases, which convert phenolic compounds to the related quinones, have been successfully used for biosensor development. The oxidation products from such enzymes can be electrochemically reduced, and the sensing is easily achieved by amperometric transducers. In this work, the polyphenoloxidases were extracted from jurubeba (Solanum paniculatum L.) fruits, and the extract was used to construct a carbon paste-based biosensor for pharmaceutical analysis and applications. The assay optimization was performed using a 0.1 mM catechol probe, taking into account the amount of enzymatic extract (50 or 200 MUL) and the optimum pH (3.0 to 9.0) as well as some electrochemical differential pulse voltammetric (DPV) parameters (e.g., pulse amplitude, pulse range, pulse width, scan rate). Under optimized conditions, the biosensor was evaluated for the quantitative determination of acetaminophen, acetylsalicylic acid, methyldopa, and ascorbic acid. The best performance was obtained for acetaminophen, which responded linearly in the range between 5 and 245 MUM (R = 0.9994), presenting a limit of detection of 3 MUM and suitable repeatability ranging between 1.52% and 1.74% relative standard deviation (RSD). PMID- 29614831 TI - Medical Surveillance, Continuous Health Promotion and a Participatory Intervention in a Small Company. AB - The workplace is an ideal setting for health promotion. The regular medical examination of workers enables us to screen for numerous diseases, spread good practices and correct lifestyles, and obtain a favourable risk/benefit ratio. The continuous monitoring of the level of workers' wellbeing using a holistic approach during medical surveillance enables us to promptly identify problems in work organisation and the company climate. Problems of this kind can be adequately managed by using a participatory approach. The aim of this paper is twofold: to signal this way of proceeding with medical surveillance, and to describe an organisational development intervention. Participatory groups were used to improve occupational life in a small company. After intervention we observed a reduction in levels of perceived occupational stress measured with the Effort/Reward Imbalance questionnaire, and an improvement in psychological wellbeing assessed by means of the Goldberg Anxiety/Depression scale. Although the limited size of the sample and the lack of a control group call for a cautious evaluation of this study, the participatory strategy proved to be a useful tool due to its cost-effectiveness. PMID- 29614833 TI - Rhein Induces Cell Death in HepaRG Cells through Cell Cycle Arrest and Apoptotic Pathway. AB - Rhein, a naturally occurring active anthraquinone found abundantly in various medicinal and nutritional herbs, possesses a wide spectrum of pharmacological effects. Furthermore, previous studies have reported that rhein could induce hepatotoxicity in rats. However, its cytotoxicity and potential molecular mechanisms remain unclear. Therefore, the present study aimed to investigate the cytotoxicity of rhein on HepaRG cells and the underlying mechanisms of its cytotoxicity. Our results demonstrate, by 3-(4,5-dimethyl thiazol-2-yl-)-2,5 diphenyl tetrazolium bromide (MTT) and Annexin V-fluoresce isothiocyanate (FITC)/propidium iodide (PI) double-staining assays, that rhein significantly inhibited cell viability and induced apoptosis in HepaRG cells. Moreover, rhein treatment resulted in the generation of reactive oxygen species (ROS), loss of mitochondrial membrane potential (MMP), and S phase cell cycle arrest. The results of Western blotting showed that rhein treatment resulted in a significant increase in the protein levels of Fas, p53, p21, Bax, cleaved caspases-3, -8, -9, and poly(ADP-ribose)polymerase (PARP). The protein expression of Bcl-2, cyclin A, and cyclin-dependent kinase 2 (CDK 2) was decreased. In conclusion, these results suggest that rhein treatment could inhibit cell viability of HepaRG cells and induce cell death through cell cycle arrest in the S phase and activation of Fas- and mitochondrial-mediated pathways of apoptosis. These findings emphasize the need to assess the risk of exposure for humans to rhein. PMID- 29614832 TI - Ixeris dentata Extract Increases Salivary Secretion through the Regulation of Endoplasmic Reticulum Stress in a Diabetes-Induced Xerostomia Rat Model. AB - This study aimed to investigate the molecular mechanism of diabetes mellitus (DM) induced dry mouth and an application of natural products from Ixeris dentata (IXD), a recently suggested regulator of amylase secretion in salivary cells. Vehicle-treated or diabetic rats were orally treated with either water or an IXD extract for 10 days to observe the effect on salivary flow. We found that the IXD extract increased aquaporin 5 (AQP5) and alpha-amylase protein expression in the submandibular gland along with salivary flow rate. Similarly, the IXD extract and its purified compound increased amylase secretion in high glucose-exposed human salivary gland cells. Furthermore, increased endoplasmic reticulum stress response in the submandibular gland of diabetic rats was inhibited by treatment with the IXD extract, suggesting that IXD extract treatment improves the ER environment by increasing the protein folding capacity. Thus, pharmacological treatment with the IXD extract is suggested to relieve DM-induced dry mouth symptoms. PMID- 29614834 TI - The Use of a Mechanical Non-Penetrating Captive Bolt Device for the Euthanasia of Neonate Lambs. AB - A non-penetrating captive bolt device, powered by a 1-grain 0.22″ cartridge delivering a calculated kinetic energy of 47 Joules was tested as a euthanasia method on 200 neonate lambs (Ovis aries) of 4.464 kg (SD (Standard deviation) ± 1.056) mean dead weight, to assess effectiveness and shot position. Every lamb (n = 200) was effectively stunned when the weapon was applied powered by a brown, 1-grain cartridge but 10/200 (5%) of the lambs displayed rhythmic or agonal breathing and were subsequently euthanased using euthatal (Merial, UK, GTIN: 03661103015550). Evaluation of the method was conducted using behavioural indicators of brain dysfunction followed by post-mortem examination of the heads. A second trial was conducted using a higher velocity 1.25-grain cartridge and a specific shot position on 48 lambs (mean dead weight = 6.21 kg, SD ± 1.24) averaging 5 days old. One hundred percent of the lambs in the second trial were immediately stun-killed. Given this complete kill rate and the sample size of the study, the study provides a statistical 95% confidence interval of 92.6% to 100%. The use of the Accles & Shelvoke “CASH” Small Animal Tool (Birmingham, UK) can therefore be recommended for the euthanasia of neonate lambs with a 1.25-grain cartridge and a specific shooting position. PMID- 29614830 TI - Role of Stromal Paracrine Signals in Proliferative Diseases of the Aging Human Prostate. AB - Androgens are essential for the development, differentiation, growth, and function of the prostate through epithelial-stromal interactions. However, androgen concentrations in the hypertrophic human prostate decrease significantly with age, suggesting an inverse correlation between androgen levels and proliferative diseases of the aging prostate. In elderly males, age- and/or androgen-related stromal remodeling is spontaneously induced, i.e., increased fibroblast and myofibroblast numbers, but decreased smooth muscle cell numbers in the prostatic stroma. These fibroblasts produce not only growth factors, cytokines, and extracellular matrix proteins, but also microRNAs as stromal paracrine signals that stimulate prostate epithelial cell proliferation. Surgical or chemical castration is the standard systemic therapy for patients with advanced prostate cancer. Androgen deprivation therapy induces temporary remission, but the majority of patients eventually progress to castration resistant prostate cancer, which is associated with a high mortality rate. Androgen deprivation therapy-induced stromal remodeling may be involved in the development and progression of castration-resistant prostate cancer. In the tumor microenvironment, activated fibroblasts stimulating prostate cancer cell proliferation are called carcinoma-associated fibroblasts. In this review, we summarize the role of stromal paracrine signals in proliferative diseases of the aging human prostate and discuss the potential clinical applications of carcinoma associated fibroblast-derived exosomal microRNAs as promising biomarkers. PMID- 29614835 TI - Botulinum Toxin Type A-A Modulator of Spinal Neuron-Glia Interactions under Neuropathic Pain Conditions. AB - Neuropathic pain represents a significant clinical problem because it is a chronic condition often refractory to available therapy. Therefore, there is still a strong need for new analgesics. Botulinum neurotoxin A (BoNT/A) is used to treat a variety of clinical diseases associated with pain. Glia are in continuous bi-directional communication with neurons to direct the formation and refinement of synaptic connectivity. This review addresses the effects of BoNT/A on the relationship between glia and neurons under neuropathic pain. The inhibitory action of BoNT/A on synaptic vesicle fusion that blocks the release of miscellaneous pain-related neurotransmitters is known. However, increasing evidence suggests that the analgesic effect of BoNT/A is mediated through neurons and glial cells, especially microglia. In vitro studies provide evidence that BoNT/A exerts its anti-inflammatory effect by diminishing NF-kappaB, p38 and ERK1/2 phosphorylation in microglia and directly interacts with Toll-like receptor 2 (TLR2). Furthermore, BoNT/A appears to have no more than a slight effect on astroglia. The full activation of TLR2 in astroglia appears to require the presence of functional TLR4 in microglia, emphasizing the significant interaction between those cell types. In this review, we discuss whether and how BoNT/A affects the spinal neuron-glia interaction and reduces the development of neuropathy. PMID- 29614836 TI - Kv3.1 and Kv3.4, Are Involved in Cancer Cell Migration and Invasion. AB - Voltage-gated potassium (Kv) channels, including Kv3.1 and Kv3.4, are known as oxygen sensors, and their function in hypoxia has been well investigated. However, the relationship between Kv channels and tumor hypoxia has yet to be investigated. This study demonstrates that Kv3.1 and Kv3.4 are tumor hypoxia related Kv channels involved in cancer cell migration and invasion. Kv3.1 and Kv3.4 protein expression in A549 and MDA-MB-231 cells increased in a cell density dependent manner, and the pattern was similar to the expression patterns of hypoxia-inducible factor-1alpha (HIF-1alpha) and reactive oxygen species (ROS) according to cell density, whereas Kv3.3 protein expression did not change in A549 cells with an increase in cell density. The Kv3.1 and Kv3.4 blocker blood depressing substance (BDS) did not affect cell proliferation; instead, BDS inhibited cell migration and invasion. We found that BDS inhibited intracellular pH regulation and extracellular signal-regulated kinase (ERK) activation in A549 cells cultured at a high density, potentially resulting in BDS-induced inhibition of cell migration and invasion. Our data suggest that Kv3.1 and Kv3.4 might be new therapeutic targets for cancer metastasis. PMID- 29614839 TI - A High Throughput Integrated Hyperspectral Imaging and 3D Measurement System. AB - Hyperspectral and three-dimensional measurements can obtain the intrinsic physicochemical properties and external geometrical characteristics of objects, respectively. The combination of these two kinds of data can provide new insights into objects, which has gained attention in the fields of agricultural management, plant phenotyping, cultural heritage conservation, and food production. Currently, a variety of sensors are integrated into a system to collect spectral and morphological information in agriculture. However, previous experiments were usually performed with several commercial devices on a single platform. Inadequate registration and synchronization among instruments often resulted in mismatch between spectral and 3D information of the same target. In addition, using slit-based spectrometers and point-based 3D sensors extends the working hours in farms due to the narrow field of view (FOV). Therefore, we propose a high throughput prototype that combines stereo vision and grating dispersion to simultaneously acquire hyperspectral and 3D information. Furthermore, fiber-reformatting imaging spectrometry (FRIS) is adopted to acquire the hyperspectral images. Test experiments are conducted for the verification of the system accuracy, and vegetation measurements are carried out to demonstrate its feasibility. The proposed system is an improvement in multiple data acquisition and has the potential to improve plant phenotyping. PMID- 29614840 TI - Detection of Metallothionein in Javanese Medaka (Oryzias javanicus), Using a scFv Immobilized Protein Chip. AB - Environmental pollution by various industrial chemicals and biological agents poses serious risks to human health. Especially, marine contamination by potentially toxic elements (PTEs) has become a global concern in recent years. Many efforts have been undertaken to monitor the PTE contamination of the aquatic environment. However, there are few approaches available to assess the PTE exposure of aquatic organisms. In this research, we developed a strategy to evaluate the heavy metal exposure of marine organisms, by measuring the expression levels of metallothionein protein derived from Oryzias javanicus (OjaMT). OjaMT is a biomarker of heavy metal exposure because the expression level increases upon heavy metal exposure. The developed assay is based on a real time, label-free surface plasmon resonance (SPR) measurement. Anti-OjaMT antibody and anti-OjaMT single-chain fragment of variable region (scFv) were used as detection probes. Two types of SPR sensor chips were fabricated, by immobilizing antibody or Cys3-tagged scFv (scFv-Cys3) in a controlled orientation and were tested for in situ label-free OjaMT detection. Compared to the antibody presenting sensor chips, the scFv-presenting sensor chips showed improved performance, displaying enhanced sensitivity and enabling semi-quantitative detection. The portable SPR system combined with scFv-immobilized sensor chips is expected to provide an excellent point-of-care testing system that can monitor target biomarkers in real time. PMID- 29614841 TI - Quantitative Detection of Cracks in Steel Using Eddy Current Pulsed Thermography. AB - Small cracks are common defects in steel and often lead to catastrophic accidents in industrial applications. Various nondestructive testing methods have been investigated for crack detection; however, most current methods focus on qualitative crack identification and image processing. In this study, eddy current pulsed thermography (ECPT) was applied for quantitative crack detection based on derivative analysis of temperature variation. The effects of the incentive parameters on the temperature variation were analyzed in the simulation study. The crack profile and position are identified in the thermal image based on the Canny edge detection algorithm. Then, one or more trajectories are determined through the crack profile in order to determine the crack boundary through its temperature distribution. The slope curve along the trajectory is obtained. Finally, quantitative analysis of the crack sizes was performed by analyzing the features of the slope curves. The experimental verification showed that the crack sizes could be quantitatively detected with errors of less than 1%. Therefore, the proposed ECPT method was demonstrated to be a feasible and effective nondestructive approach for quantitative crack detection. PMID- 29614837 TI - CRISPR/Cas9-Mediated Mutagenesis of Carotenoid Cleavage Dioxygenase 8 (CCD8) in Tobacco Affects Shoot and Root Architecture. AB - Strigolactones (SLs) are a class of phytohormones that regulate plant architecture. Carotenoid cleavage dioxygenase (CCD) genes are involved in the biosynthesis of SLs and are identified and characterized in many plants. However, the function of CCD genes in tobacco remains poorly understood. In this study, two closely related genes NtCCD8A and NtCCD8B were cloned from tobacco (Nicotiana tabacum L.). The two NtCCD8 genes are orthologues of the tomato (Solanum lycopersicum) carotenoid cleavage dioxygenase 8 (SlCCD8) gene. NtCCD8A and NtCCD8B were primarily expressed in tobacco roots, but low expression levels of these genes were detected in all plant tissues, and their transcript levels significantly increased in response to phosphate limitation. NtCCD8A and NtCCD8B mutations were introduced into tobacco using the CRISPR/Cas9 system and transgenic tobacco lines for both ntccd8 mutant alleles were identified. The ntccd8a and ntccd8b mutant alleles were inactivated by a deletion of three nucleotides and insertion of one nucleotide, respectively, both of which led to the production of premature stop codons. The ntccd8 mutants had increased shoot branching, reduced plant height, increased number of leaves and nodes, and reduced total plant biomass compared to wild-type plants; however, the root-to shoot ratio was unchanged. In addition, mutant lines had shorter primary roots and more of lateral roots than wild type. These results suggest that NtCCD8 genes are important for changes in tobacco plant architecture. PMID- 29614838 TI - Molecular and Antigenic Characterization of Piscine orthoreovirus (PRV) from Rainbow Trout (Oncorhynchus mykiss). AB - Piscine orthoreovirus (PRV-1) causes heart and skeletal muscle inflammation (HSMI) in farmed Atlantic salmon (Salmo salar). Recently, a novel PRV (formerly PRV-Om, here called PRV-3), was found in rainbow trout (Oncorhynchus mykiss) with HSMI-like disease. PRV is considered to be an emerging pathogen in farmed salmonids. In this study, molecular and antigenic characterization of PRV-3 was performed. Erythrocytes are the main target cells for PRV, and blood samples that were collected from experimentally challenged fish were used as source of virus. Virus particles were purified by gradient ultracentrifugation and the complete coding sequences of PRV-3 were obtained by Illumina sequencing. When compared to PRV-1, the nucleotide identity of the coding regions was 80.1%, and the amino acid identities of the predicted PRV-3 proteins varied from 96.7% (lambda1) to 79.1% (sigma3). Phylogenetic analysis showed that PRV-3 belongs to a separate cluster. The region encoding sigma3 were sequenced from PRV-3 isolates collected from rainbow trout in Europe. These sequences clustered together, but were distant from PRV-3 that was isolated from rainbow trout in Norway. Bioinformatic analyses of PRV-3 proteins revealed that predicted secondary structures and functional domains were conserved between PRV-3 and PRV-1. Rabbit antisera raised against purified virus or various recombinant virus proteins from PRV-1 all cross reacted with PRV-3. Our findings indicate that despite different species preferences of the PRV subtypes, several genetic, antigenic, and structural properties are conserved between PRV-1 and-3. PMID- 29614842 TI - Microstructure and Mechanical Behaviors of Titanium Matrix Composites Containing In Situ Whiskers Synthesized via Plasma Activated Sintering. AB - In this paper, titanium matrix composites with in situ TiB whiskers were synthesized by the plasma activated sintering technique; crystalline boron and amorphous boron were used as reactants for in situ reactions, respectively. The influence of the sintering process and the crystallography type of boron on the microstructure and mechanical properties of composites were studied and compared. The densities were evaluated using Archimedes' principle. The microstructure and mechanical properties were characterized by SEM, XRD, EBSD, TEM, a universal testing machine, and a Vickers hardness tester. The prepared composite material showed a high density and excellent comprehensive performance under the PAS condition of 20 MPa at 1000 degrees C for 3 min. Amorphous boron had a higher reaction efficiency than crystalline boron, and it completely reacted with the titanium matrix to generate TiB whiskers, while there was still a certain amount of residual crystalline boron combining well with the titanium matrix at 1100 degrees C. The composite samples with a relative density of 98.33%, Vickers hardness of 389.75 HV, compression yield strength of up to 1190 MPa, and an ultimate compressive strength of up to 1710 MPa were obtained. Compared with the matrix material, the compressive strength of TC4 titanium alloy containing crystalline boron and amorphous boron was increased by 7.64% and 15.50%, respectively. PMID- 29614845 TI - Bee Venom Phospholipase A2 Alleviate House Dust Mite-Induced Atopic Dermatitis Like Skin Lesions by the CD206 Mannose Receptor. AB - Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by highly pruritic, erythematous, and eczematous skin plaques. We previously reported that phospholipase A2 (PLA2) derived from bee venom alleviates AD-like skin lesions induced by 2,4-dinitrochlorobenzene (DNCB) and house dust mite extract (Dermatophagoides farinae extract, DFE) in a murine model. However, the underlying mechanisms of PLA2 action in actopic dermatitis remain unclear. In this study, we showed that PLA2 treatment inhibited epidermal thickness, serum immunoglobulin E (IgE) and cytokine levels, macrophage and mast cell infiltration in the ear of an AD model induced by DFE and DNCB. In contrast, these effects were abrogated in CD206 mannose receptor-deficient mice exposed to DFE and DNCB in the ear. These data suggest that bvPLA2 alleviates atopic skin inflammation via interaction with CD206. PMID- 29614847 TI - Ventilator-induced lung injury in childhood. PMID- 29614846 TI - Antioxidant Activities of Phenolic Metabolites from Flemingia philippinensis Merr. et Rolfe and Their Application to DNA Damage Protection. AB - F. philippinensis Merr. et Rolfe has been cultivated on a large scale and is widely consumed by local inhabitants as an important nutraceutical, especially against rheumatism which has a deep connection with antioxidants. In this study, a total of 18 different phenolic metabolite compounds in F. philippinensis were isolated and identified, and evaluated for their antioxidant and DNA damage protection potential. The antioxidant activity of the 18 identified compounds was screened using DPPH, ORAC, hydroxyl and superoxide radical scavenging assays. The antioxidant potential of the compounds was found to differ by functionality and skeleton. However, most compounds showed a good antioxidant potential. In particular, seven of the identified compounds, namely, compounds 2, 3, 6, 10, 11, 15 and 16, showed significant protective effects on pBR322 plasmid DNA against the mutagenic and toxic effects of Fenton's reaction. The most active compound, compound 2, displayed a dose-dependent DNA damage protection potential in the range of 7.5~60.0 MUM. The DNA damage protective effect of the identified compounds was significantly correlated with the hydroxyl radical scavenging activity. Compounds that exhibited effective (IC50 = 5.4~12.5 MUg/mL) hydroxyl radical scavenging activity were found to be the ones with higher DNA damage protection potential. PMID- 29614843 TI - Role of Plant-Derived Flavonoids and Their Mechanism in Attenuation of Alzheimer's and Parkinson's Diseases: An Update of Recent Data. AB - Neurodegeneration is a progressive loss of neuronal cells in certain regions of the brain. Most of the neurodegenerative disorders (NDDs) share the communal characteristic such as damage or reduction of various cell types typically including astrocytes and microglial activity. Several compounds are being trialed to treat NDDs but they possess solitary symptomatic advantages along with copious side effects. The finding of more enthralling and captivating compounds to suspend and standstill the pathology of NDDs will be considered as a hallmark of present times. Phytochemicals possess the potential to alternate the synthetic line of therapy against NDDs. The present review explores the potential efficacy of plant-derived flavonoids against most common NDDs including Alzheimer's disease (AD) and Parkinson's disease (PD). Flavonoids are biologically active phytochemicals which possess potential pharmacological effects, including antiviral, anti-allergic, antiplatelet, anti-inflammatory, anti-tumor, anti apoptotic and anti-oxidant effects and are able to attenuate the pathology of various NDDs through down-regulating the nitric oxide (NO) production, by reducing the tumor necrosis factor-alpha (TNF-alpha), by reducing the excitotoxicity of superoxide as well as acting as tyrosine kinase (TK) and monoamine oxidase (MAO) inhibiting enzyme. PMID- 29614844 TI - Tryptophan-Rich and Proline-Rich Antimicrobial Peptides. AB - Due to the increasing emergence of drug-resistant pathogenic microorganisms, there is a world-wide quest to develop new-generation antibiotics. Antimicrobial peptides (AMPs) are small peptides with a broad spectrum of antibiotic activities against bacteria, fungi, protozoa, viruses and sometimes exhibit cytotoxic activity toward cancer cells. As a part of the native host defense system, most AMPs target the membrane integrity of the microorganism, leading to cell death by lysis. These membrane lytic effects are often toxic to mammalian cells and restrict their systemic application. However, AMPs containing predominantly either tryptophan or proline can kill microorganisms by targeting intracellular pathways and are therefore a promising source of next-generation antibiotics. A minimum length of six amino acids is required for high antimicrobial activity in tryptophan-rich AMPs and the position of these residues also affects their antimicrobial activity. The aromatic side chain of tryptophan is able to rapidly form hydrogen bonds with membrane bilayer components. Proline-rich AMPs interact with the 70S ribosome and disrupt protein synthesis. In addition, they can also target the heat shock protein in target pathogens, and consequently lead to protein misfolding. In this review, we will focus on describing the structures, sources, and mechanisms of action of the aforementioned AMPs. PMID- 29614848 TI - Outcomes of mitochondrial derived diseases: a single-center experience. AB - BACKGROUND: The purpose of this study is to help elucidate which part of the mitochondria is causing a problem through anamnesis, physical examination, and routine biochemical tests in the event of a suspected mitochondrial disease case. METHODS: The data were obtained retrospectively from the medical records of 75 cases; the mitochondrial-derived disease (MDD) cases were observed in our center from 2011 to 2017. RESULTS: The most commonly observed MDDs were oxidative phosphorylation disorders at 44%, followed by fatty acid oxidation disorder at 40%, pyruvate metabolism disorder at 12%, and ketone metabolism disorder at 4%, respectively. The most common clinical presentation at the time of referral to the hospital was metabolic acidosis (20%), and the most common symptom was respiratory distress (24%). There were abnormal findings in 84.3% of the cases subjected to cranial magnetic resonance imaging (MRI), with the most common being hyperintensity in the bilateral basal ganglia (49.0%). CONCLUSIONS: Anamnesis, physical examination, and simple laboratory data could provide some important clues in assessing MDD. Blood gas should definitely be measured in cases with respiratory symptoms, particularly if they have a history of consanguineous marriage or a sibling suffering from a similar disease. If metabolic acidosis exists in the blood gas, MDDs should absolutely be included in the differential diagnosis. Furthermore, ophthalmic and cardiac assessment and cranial MRI will also reveal significant data for diagnosing MDDs. PMID- 29614849 TI - Efficacy of the Life Goal-Focused Brief Intervention among Patients with Alcohol Use Disorder: A Preliminary Study. AB - OBJECTIVE: The aim of this study was to examine the efficacy of the life goal focused brief intervention, or the so-called the goal-focused self-regulation program (GFSRP), for patients with alcohol use disorder (AUD). METHODS: The GFSRP was developed as an 8-week group-program, which is based on a wide range of self regulation theories, such as goal setting and implementation intentions. Patients with AUD (n=50) took part in the GFSRP and were compared to the control group (n=48). This study examined the changes in outcome measures from baseline to follow-up (12-week) in a mixed design. RESULTS: The GFSRP group had higher scores for the abstinence self-efficacy in negative affect situations than the control group at the post-test. In addition, it showed greater scores of optimisms compared to the control group. Furthermore, in the GFSRP group, there was no difference in intrinsic life goals from baseline to the 12-week follow-up, whereas the control group showed a significant decrease. CONCLUSION: The GFSRP could increase the abstinence self-efficacy and optimism among patients with AUD. Moreover, it might prevent loss of life-goals as core factors in self-regulation among patients with AUD. PMID- 29614850 TI - Factor Analysis of Delirium in Elderly, Using the Korean Version of Delirium Rating Scale-Revised-98. AB - OBJECTIVE: This study aimed to identify the core symptoms of delirium, particularly in elderly people associated with major risk factors, using the Korean version of the Delirium Rating Scale-Revised-98. METHODS: The study sample consisted of 200 patients (mean age: 72.7+/-3.9 years, male: 68.5%) who had been diagnosed with delirium. Exploratory factor analysis was used to investigate the factor structure, and confirmatory factor analysis was used to evaluate the goodness of fit of the results. RESULTS: The results demonstrated three core domains of delirium in the elderly patients: 1) the cognitive domain (e.g., language, thought process, orientation, attention, long-term memory, and visuospatial ability); 2) the circadian domain (e.g., sleep-wake cycle and motor behavior); and 3) the short-term memory domain (short-term memory). These results were confirmed by confirmatory factor analysis. CONCLUSION: The findings of this study suggest a theoretical domain structure for delirium in elderly patients. PMID- 29614851 TI - The MAKE Biomarker Discovery for Enhancing anTidepressant Treatment Effect and Response Study: Design and Methodology. AB - OBJECTIVE: Depression is associated with a major disease burden, and many individuals suffer from depressive symptoms due to an insufficient response to ostensibly adequate antidepressant treatment. Therefore, it is important to identify reliable treatment response predictors for use in developing personalized treatment strategies. METHODS: The MAKE Biomarker discovery for Enhancing anTidepressant Treatment Effect and Response (MAKE BETTER) study was performed to identify predictors of antidepressant response using a 2-year naturalistic prospective design. Participants in the MAKE BETTER study were consecutively recruited from patients who visited the Psychiatry Department of Chonnam National University Hospital, Gwangju, South Korea for treatment of a depressive disorder. Data on demographic and clinical characteristics, genetic markers measured by whole-exome sequencing, and blood markers were obtained. The types and doses of antidepressants were determined based on the clinical judgment of the psychiatrist, and the treatment outcomes (e.g., depressive and other psychiatric symptoms and issues related to safety) were assessed. RESULTS: We will be able to use the data collected in this study to develop a treatment response prediction index composed of biomarkers. CONCLUSION: The MAKE BETTER study will provide an empirical basis for a personalized medicine approach to depression by enabling the prediction of antidepressant treatment response according the characteristics of each patient. It will thereby support evidence based decision-making that decreases the use of a trial-and-error approach to the treatment of depressive disorders. PMID- 29614852 TI - Advanced Daily Prediction Model for National Suicide Numbers with Social Media Data. AB - OBJECTIVE: Suicide is a significant public health concern worldwide. Social media data have a potential role in identifying high suicide risk individuals and also in predicting suicide rate at the population level. In this study, we report an advanced daily suicide prediction model using social media data combined with economic/meteorological variables along with observed suicide data lagged by 1 week. METHODS: The social media data were drawn from weblog posts. We examined a total of 10,035 social media keywords for suicide prediction. We made predictions of national suicide numbers 7 days in advance daily for 2 years, based on a daily moving 5-year prediction modeling period. RESULTS: Our model predicted the likely range of daily national suicide numbers with 82.9% accuracy. Among the social media variables, words denoting economic issues and mood status showed high predictive strength. Observed number of suicides one week previously, recent celebrity suicide, and day of week followed by stock index, consumer price index, and sunlight duration 7 days before the target date were notable predictors along with the social media variables. CONCLUSION: These results strengthen the case for social media data to supplement classical social/economic/climatic data in forecasting national suicide events. PMID- 29614854 TI - Resolving the Singlet Excited State Manifold of Benzophenone by First-Principles Simulations and Ultrafast Spectroscopy. AB - Accurate characterization of the high-lying excited state manifolds of organic molecules is of fundamental importance for the interpretation of the rich response detected in time-resolved nonlinear electronic spectroscopies. Here, we have characterized the singlet excited state manifold of benzophenone (BP), a versatile organic photoinitiator and a well-known DNA photosensitizer. Benchmarks of various multiconfigurational/multireference (RASSCF/PT2) and time-dependent density functional theory (TD-DFT) approaches allowed assignments of experimental linear absorption signals of BP in the ultraviolet (UV) region, with unprecedented characterization of ground state absorptions in the far UV. Experimental transient absorption spectra obtained by UV-vis pump-probe spectroscopy at very short time delays are shown to be directly comparable to theoretical estimates of excited state absorptions (from the low-lying nOpi* and pipi* singlet states) in the Franck-Condon region. Multireference computations provided reliable interpretation of the PP spectra, with TD-DFT results yielding a fair agreement as long as electronic transitions featuring double excitations contributions are not involved. These results lay the groundwork for further computational studies and interpretation of experimental nonlinear electronic spectra of benzophenone in more complex systems, such as BP/DNA adducts. PMID- 29614853 TI - A Functional Polymorphism in the DRD1 Gene, That Modulates Its Regulation by miR 504, Is Associated with Depressive Symptoms. AB - OBJECTIVE: The aim of this study was to examine a possible association between depressive symptoms and a functional polymorphism (rs686) that modulates the regulation of DRD1 gene by miR-504. METHODS: A total of 239 young Colombian subjects were evaluated with the Patient Health Questionnaire-9 (PHQ-9) scale and genotyped for the rs686 polymorphism. A linear regression model, corrected by age and gender, was used. RESULTS: A significant association between the rs686 polymorphism and PHQ-9 scores was found, under a dominant genetic model (p=0.0094). CONCLUSION: These results provide novel evidence about the growing role of inherited variants in binding sites for brain-expressed miRNAs on depressive symptomatology. PMID- 29614855 TI - On the Computational Characterization of Charge-Transfer Effects in Noncovalently Bound Molecular Complexes. AB - Charge-transfer (CT) is an important binding force in the formation of intermolecular complexes, and there have been a variety of theoretical models proposed to quantify this effect. These approaches, which typically rely on a definition of a "CT-free" state based on a partition of the system, sometimes yield significantly different results for a given intermolecular complex. Two widely used definitions of the "CT-free" state, the absolutely localized molecular orbitals (ALMO) method (where only on-fragment orbital mixings are permitted) and the constrained density functional theory (CDFT) approach (where fragment electron populations are fixed), are carefully examined in this work. Natural bond orbital (NBO) and the regularized symmetry-adapted perturbation theory (SAPT) are also briefly considered. Results for the ALMO and CDFT definitions of CT are compared on a broad range of model systems, including hydrogen-bonding systems, borane complexes, metal-carbonyl complexes, and complexes formed by water and metal cations. For most of these systems, CDFT yields a much smaller equilibrium CT energy compared to that given by the ALMO based definition. This is mainly because the CDFT population constraint does not fully inhibit CT, which means that the CDFT "CT-free" state is in fact CT contaminated. Examples of this contamination include (i) matching forward and backward donation (e.g., formic acid dimer) and (ii) unidirectional CT without changing fragment populations. The magnitude of the latter effect is quantified in systems such as the water dimer by employing a 3-space density constraint in addition to the orbital constraint. Furthermore, by means of the adiabatic EDA, it is shown that several observable effects of CT, such as the "pyramidalization" of the planar BH3 molecule upon the complexation with Lewis bases, already appear on the "CT-free" CDFT surface. These results reveal the essential distinctions between the ALMO and CDFT definitions of CT and suggest that the former is more consistent with accepted understanding of the role of CT in intermolecular binding. PMID- 29614856 TI - Benchmarks and Reliable DFT Results for Spin Gaps of Small Ligand Fe(II) Complexes. AB - All-electron fixed-node diffusion Monte Carlo provides benchmark spin gaps for four Fe(II) octahedral complexes. Standard quantum chemical methods (semilocal DFT and CCSD(T)) fail badly for the energy difference between their high- and low spin states. Density-corrected DFT is both significantly more accurate and reliable and yields a consistent prediction for the Fe-Porphyrin complex. PMID- 29614857 TI - Development of Comprehensive Online Two-Dimensional Liquid Chromatography/Mass Spectrometry Using Hydrophilic Interaction and Reversed-Phase Separations for Rapid and Deep Profiling of Therapeutic Antibodies. AB - Monoclonal antibodies (mAb) and related molecules are being developed at a remarkable pace as new therapeutics for the treatment of diseases ranging from cancer to inflammatory disorders. However, characterization of these molecules at all stages of development and manufacturing presents tremendous challenges to existing analytical technologies because of their large size (ca. 150 kDa) and inherent heterogeneity resulting from complex glycosylation patterns and other post-translational modifications. Multidimensional liquid chromatography is emerging as a powerful platform technology that can be used to both improve analysis speed for these molecules by combining existing one-dimensional separations into a single method (e.g., Protein A affinity separation and size exclusion chromatography) and increasing the resolving power of separations by moving from one dimension of separation to two. In the current study, we have demonstrated the ability to combine hydrophilic interaction (HILIC) and RP separations in an online comprehensive 2D separation coupled with high resolution MS detection (HILIC * RP-HRMS). We find that active solvent modulation (ASM) is critical for coupling these two separation modes, because it mitigates the otherwise serious negative impact of the acetonitrile-rich HILIC mobile phase on the second dimension RP separation. The chromatograms obtained from these HILIC * RP-HRMS separations of mAbs at the subunit level reveal the extent of glycosylation on the Fc/2 and Fd subunits in analysis times on the order of 2 h. In comparison to previous CEX * RP separations of the same molecules, we find that chromatograms from the HILIC * RP separations are richer and reveal separation of some glycoforms that coelute in the CEX * RP separations. PMID- 29614858 TI - Vapor-Phase Nanopatterning of Aminosilanes with Electron Beam Lithography: Understanding and Minimizing Background Functionalization. AB - Electron beam lithography (EBL) is a highly precise, serial method for patterning surfaces. Positive tone EBL resists enable patterned exposure of the underlying surface, which can be subsequently functionalized for the application of interest. In the case of widely used native oxide-capped silicon surfaces, coupling an activated silane with electron beam lithography would enable nanoscale chemical patterning of the exposed regions. Aminoalkoxysilanes are extremely useful due to their reactive amino functionality but have seen little attention for nanopatterning silicon surfaces with an EBL resist due to background contamination. In this work, we investigated three commercial positive tone EBL resists, PMMA (950k and 495k) and ZEP520A (57k), as templates for vapor phase patterning of two commonly used aminoalkoxysilanes, 3 aminopropyltrimethoxysilane (APTMS) and 3-aminopropyldiisopropylethoxysilane (APDIPES). The PMMA resists were susceptible to significant background reaction within unpatterned areas, a problem that was particularly acute with APTMS. On the other hand, with both APTMS and APDIPES exposure, unpatterned regions of silicon covered by the ZEP520A resist emerged pristine, as shown both with SEM images of the surfaces of the underlying silicon and through the lack of electrostatically driven binding of negatively charged gold nanoparticles. The ZEP520A resist allowed for the highly selective deposition of these alkoxyaminosilanes in the exposed areas, leaving the unpatterned areas clean, a claim also supported by contact angle measurements with four probe liquids and X ray photoelectron spectroscopy (XPS). We investigated the mechanistic reasons for the stark contrast between the PMMA resists and ZEP520A, and it was found that the efficacy of resist removal appeared to be the critical factor in reducing the background functionalization. Differences in the molecular weight of the PMMA resists and the resulting influence on APTMS diffusion through the resist films are unlikely to have a significant impact. Area-selective nanopatterning of 15 nm gold nanoparticles using the ZEP520A resist was demonstrated, with no observable background conjugation noted in the unexposed areas on the silicon surface by SEM. PMID- 29614859 TI - Click Conjugation of Cloaked Peptide Ligands to Microbubbles. AB - Interest in the use of targeted microbubbles for ultrasound molecular imaging (USMI) has been growing in recent years as a safe and efficacious means of diagnosing tumor angiogenesis and assessing response to therapy. Of particular interest are cloaked microbubbles, which improve specificity by concealing the ligand from blood components until they reach the target vasculature, where the ligand can be transiently revealed for firm receptor-binding by ultrasound acoustic radiation force pulses. Herein, a bio-orthogonal "click" conjugation chemistry is introduced to decorate the surface of cloaked 4-5-MUm-diameter microbubbles as part of a sterile and reproducible production process. Azido functionalized antagonists for the angiogenic biomarkers alphaVbeta3 integrin (cRGD) and VEGFR2 (A7R) proteins were conjugated to bimodal-brush microbubbles via strain-promoted [3 + 2] azide-alkyne cycloaddition (SPAAC) click chemistry. Ligand conjugation was validated by epifluorescent microscopy, flow cytometry, and Fourier-transform infrared spectroscopy. Sterility was validated by bacterial culture and endotoxin analysis. Additionally, clinically normal dogs receiving escalating microbubble doses were shown to experience no pathologic changes in physical examination, complete blood count, serum biochemistry profile, or coagulation panel. This bio-orthogonal microbubble conjugation process for cloaked peptide ligands may be leveraged for future USMI studies of tumor angiogenesis for translation to preclinical and clinical applications. PMID- 29614860 TI - A Rational Structured Epitope Defines a Distinct Subclass of Toxic Amyloid-beta Oligomers. AB - Oligomers of amyloid-beta (AbetaO) are deemed key in synaptotoxicity and amyloid seeding of Alzheimer's disease (AD). However, the heterogeneous and dynamic nature of AbetaO and inadequate markers for AbetaO subtypes have stymied effective AbetaO identification and therapeutic targeting in vivo. We identified an AbetaO-subclass epitope defined by differential solvent orientation of the lysine 28 side chain in a constrained loop of serine-asparagine-lysine (cSNK), rarely displayed in molecular dynamics simulations of monomer and fibril ensembles. A mouse monoclonal antibody targeting AbetaOcSNK recognizes ~50-60 kDa SDS-resistant soluble Abeta assemblages in AD brain and prolongs the lag phase of Abeta aggregation in vitro. Acute peripheral infusion of a murine IgG1 anti AbetaOcSNK in two AD mouse models reduced soluble brain Abeta aggregates by 20 30%. Chronic cSNK peptide immunization of APP/PS1 mice engendered an anti AbetaOcSNK IgG1 response without epitope spreading to Abeta monomers or fibrils and was accompanied by preservation of global PSD95 expression and improved cued fear memory. Our data indicate that the oligomer subtype AbetaOcSNK participates in synaptotoxicity and propagation of Abeta aggregation in vitro and in vivo. PMID- 29614862 TI - Nanomaterial interactions with biomembranes: Bridging the gap between soft matter models and biological context. AB - Synthetic polymers, nanoparticles, and carbon-based materials have great potential in applications including drug delivery, gene transfection, in vitro and in vivo imaging, and the alteration of biological function. Nature and humans use different design strategies to create nanomaterials: biological objects have emerged from billions of years of evolution and from adaptation to their environment resulting in high levels of structural complexity; in contrast, synthetic nanomaterials result from minimalistic but controlled design options limited by the authors' current understanding of the biological world. This conceptual mismatch makes it challenging to create synthetic nanomaterials that possess desired functions in biological media. In many biologically relevant applications, nanomaterials must enter the cell interior to perform their functions. An essential transport barrier is the cell-protecting plasma membrane and hence the understanding of its interaction with nanomaterials is a fundamental task in biotechnology. The authors present open questions in the field of nanomaterial interactions with biological membranes, including: how physical mechanisms and molecular forces acting at the nanoscale restrict or inspire design options; which levels of complexity to include next in computational and experimental models to describe how nanomaterials cross barriers via passive or active processes; and how the biological media and protein corona interfere with nanomaterial functionality. In this Perspective, the authors address these questions with the aim of offering guidelines for the development of next-generation nanomaterials that function in biological media. PMID- 29614863 TI - Implementation of an expanded-scope-of-practice physiotherapist role in a regional hospital emergency department. AB - INTRODUCTION: The aim of the present study was to describe the implementation of an expanded-scope physiotherapy service in a regional hospital emergency department (ED) in Australia and discuss the lessons learnt in terms of long-term sustainability of these roles in regional areas. METHODS: The existing ED advanced physiotherapist was trained in extended scope of practice skills. For sustainability, a senior physiotherapist was recruited to develop further ED practice skills through a locally developed professional development package and ultimately be eligible to complete extended-scope training. Mixed methods data collection included document review, patient and staff satisfaction surveys and data mining of routine clinical data sets. RESULTS: The extended-hours service operated for 12 months. The advanced physiotherapist completed postgraduate course requirements and was able to work to an expanded scope of practice including increased autonomy in management and discharge of patients treated in the ED and independent ordering and interpreting of plain film X-rays. The professional development package was not completed and the senior physiotherapist role was filled for only part of the study period. CONCLUSIONS: It is feasible to implement an expanded scope of physiotherapy service in a regional hospital ED. For sustainability in regional areas, a larger advanced-level physiotherapy workforce and easier access to expanded-scope training are required. PMID- 29614864 TI - Prognostication in Anoxic Brain Injury. AB - Cardiac arrest is a common cause of coma with frequent poor outcomes. Palliative medicine teams are often called upon to discuss the scope of treatment and future care in cases of anoxic brain injury. Understanding prognostic tools in this setting would help medical teams communicate more effectively with patients' families and caregivers and may promote improved quality of life overall. This article reviews multiple tools that are useful in determining outcomes in the setting of postarrest anoxic brain injury. PMID- 29614865 TI - A Randomized Multicenter Trial Comparing Low-Dose Prednisolone Versus Observation for Prevention of Recurrences in Adult Immune Thrombocytopenia. AB - Adult immune thrombocytopenia (ITP) commonly relapses after stopping treatments. This may be preventable by low-dose steroids. In this multicenter study, adult patients with ITP who had been responding to corticosteroids were randomized with the 2 strata of newly diagnosed and relapsed ITP to prednisolone 7.5 mg/d or observation for 6 months. Relapses were defined by a platelet count below 30 * 109/L and/or clinical bleeding. There were 75 patients evaluable for the efficacy and 77 for safety. The recurrent ITP comprised 57.3%. During the median follow-up of 42 weeks, there were 20.5% (8/39) and 25% (9/36) of recurrences in the prednisolone and control groups ( P = .643), with the hazard ratio (HR) of 0.75 ( P = .549). The significant factor that could predict recurrences was relapsed ITP with the HR of 2.79 (95% confidence interval, 1.02-7.64, P = .037). Prednisolone showed a trend toward a benefit in the relapsed subgroup ( P = .070). Adverse events were not different ( P = .540) and mostly mild. In conclusion, prednisolone maintenance could not prolong relapse-free survival. Relapsed patients deserve further investigations for preventive measures. PMID- 29614866 TI - Coercion in Outpatients under Community Treatment Orders: A Matched Comparison Study. AB - OBJECTIVE: Since the deinstitutionalization of psychiatric services around the world, the scope of outpatient psychiatric care has also increased to better support treatment access and adherence. For those with serious mental illness who may lack insight into their own illness, available interventions include coercive community practices such as mandated community treatment orders (CTOs). This paper examines the perceptions of coercion among service users treated with a CTO. METHOD: We used a cross-sectional comparative design where service users treated under a CTO were matched to a comparison group of voluntary psychiatric outpatients. Both groups were receiving intensive community mental health services ( n = 69 in each group). Participants were interviewed using a series of questionnaires aimed at evaluating their perceptions of coercion and other aspects of the psychiatric treatment. RESULTS: The level of coercion reported by service users treated under a CTO was significantly higher than that in the comparison group. However, in adjusted analyses, service users' perception of coercion, irrespective of their CTO status, was directly correlated with their previous experience with probation and inversely correlated with the sense of procedural justice in their treatment. CONCLUSIONS: Evaluation of psychiatric service users' experiences of coercion should consider their past and current involvement with other types of coercive measures, particularly history of probation. Clinicians may be able to minimize these experiences of coercion by incorporating procedural justice principles into their practice. PMID- 29614867 TI - New dammarane triterpenoid saponins from the leaves of Cyclocarya paliurus. AB - Three new dammarane triterpenoid saponins, cyclocariosides O-Q (1-3), were isolated from the ethanolic extracts of the leaves of Cyclocarya paliurus. The structures of these compounds were elucidated by spectroscopic methods. PMID- 29614868 TI - Effects of microwave heating on the gelation properties of heat-induced Alaska Pollock ( Theragra chalcogramma) surimi. AB - In the present study, we examined the properties of Alaska Pollock ( Theragra chalcogramma) surimi gels in response microwave heating at different powers (300, 400, or 500 W) and time (10, 20, or 30 min). The surimi gels heated by a microwave at 300 W for 10 min showed the highest gel strength and water-holding capacity. Increasing the power and time resulted in decreases in both the gel strength and water-holding capacity. The gel formation rate of microwave-heated gels was significantly higher than that produced by water bath heating. In addition, differential scanning calorimetry indicated that microwave heating caused less damage to the native structures of myosin and actin than water bath heating. Microstructure studies revealed that microwave heating contributed to the formation of a denser and stronger frame of the surimi gels. Raman spectroscopy indicated that the degree of the secondary structure denaturation caused by microwave heating was less than that induced by water bath heating. Thus, the results demonstrated that microwave heating is a promising method to enhance the gelation properties of surimi. PMID- 29614869 TI - Single screw extrusion of apple pomace-enriched blends: Extrudate characteristics and determination of optimum processing conditions. AB - Response surface methodology was used to investigate the single screw extrusion of apple pomace-defatted soy flour-corn grits blends and the product properties. Five different blends at a level of 0-20% w/w apple pomace were extrusion cooked with varied barrel and die temperature (100-140C), screw speed (100-200 rpm), and feed moisture content (14-20% wet basis). Increasing apple pomace content in the blends significantly ( P < 0.05) increased the bulk density, the total phenolic content, and the antioxidant activity of the extrudates. The expansion ratio increased with pomace inclusion level of 5% but decreased significantly ( P < 0.05) at higher levels of pomace inclusion (10-20%). Moisture content had quadratic influence on water absorption and solubility indices. Optimal extrusion cooking conditions most likely to produce apple pomace-enriched extruded snack products were at 140C barrel and die temperature, 20% feed moisture content, and 200 rpm screw speed. The results indicated active interaction between apple pomace and starch during expansion process. PMID- 29614870 TI - Identification and screening of active components from Ziziphora clinopodioides Lam. in regulating autophagy. AB - This study investigated the flavonoid constituents of a traditional Chinese medical plant Ziziphora clinopodioides Lam. by using ultra-performance liquid chromatography coupled with quadruple time-of-flight mass spectrometry and screened the active components in regulating autophagy.Normal rat kidney (NRK) cells transfected with green fluorescent protein- microtubule-associated protein 1 light Chain 3(GFP-LC3) were treated with Z. clinopodioides flavonoids and its chemical compositions. After 4 h of treatment, the auto-phagy spot aggregation in NRK cells was photographed and observed by laser scanning confocal microscopy. The following 10 flavonoid components of Z. clinopodioides were identified: baicalein(1), quercetin(2), hyperoside(3), quercetin3-O-beta-d glucopyranoside(4), apigenin(5), kaempferol(6), chrysin(7), diosimin(8), linarin(9) and rutin(10). Among these flavonoids, chrysin, apigenin and quercetin were identified as the active principles in activating autophagy. This research may provide a reference for further developing and utilizing Z. clinopodioides. PMID- 29614871 TI - Technical-scientific investigations to detect the temporal vicissitudes of the funeral monument of Innocent VIII (Giovanbattista Cibo, 1484-1492), compared with that of Sixtus IV (Francesco della Rovere 1471-1484), both made by Antonio del Pollaiolo. AB - The restoration of the funeral monument of Innocent VIII (Giovan-Battista Cibo, 1484-1492) was executed by Sante Guido with the support of the Knights of Columbus. The praiseworthy intervention aimed at restoring the monument from polluting aerodynamic agents has at the same time enabled a careful study of the work regarding, above all, the authenticity of the current coloring in relation to the original presentation intended by Antonio del Pollaiolo. In particular, an attempt has been made to uncover the historical vicissitudes of the work: from its realization to the present restoration. In this regard, I would like to recall that, as reported by Pasquale Rotondi, the restoration of a work is a very special moment in which it is possible to carry out all the studies aimed at understanding the causes which have determined its state of conservation, as well as, of course, its constituent elements and its implementing methods. PMID- 29614872 TI - Spasmolytic and antidiarrheal activities of Lippia thymoides (Verbenaceae) essential oil. AB - Lippia thymoides ('alecrim-do-mato' or 'alecrim-do-campo') is used in Brazilian folk medicine to treat various illnesses, including diarrhea. This work aimed to evaluate in vitro spasmolytic and in vivo antidiarrheal activities of the L. thymoides essential oil (OOS) and to correlate with the traditional use of this plant. In isolated guinea-pig ileum, OOS presented a concentration-dependent spasmolytic activity in preparations pre-contracted with KCl 40 mM [EC50 = 16.89 (11.56-24.66) MUg/mL], and antagonized phasic contractions induced by 1 MUM carbachol [IC50 = 42.71 (37.35-48.83) MUg/mL] or histamine [IC50 = 32.38 (27.44 38.20) MUg/mL]. In mice, OOS at 400 mg/kg reduced intestinal transit, at 200 and 400 mg/kg reduced total stool mass and at 400 mg/kg reduced intestinal fluid accumulation. It was shown that the antidiarrheal effect of OOS is related to the inhibition of smooth muscle contraction and may be due to the presence of major compound beta-caryophyllene in this essential oil. PMID- 29614873 TI - Vitamin D Status among Young Children Aged 6 to 23 Months from 4 Different Ethnic Groups in Yunnan, China. AB - OBJECTIVES: To determine the prevalence of vitamin D deficiency in 6- to 23-month old children from 4 different ethnic groups, Han, Lisu, Hani, and Bai, in Yunnan Province of China. METHODS: A large cohort of 938 young children aged 6 to 23 months who were living in Yunnan, China (23 degrees 28'-27 degrees 52' N), were selected and recruited in this study. Venous-blood sampling was conducted in all the participants, and serum 25-hydroxyvitamin D [25(OH)D] levels were measured. The children's physical status was measured. RESULTS: General mean serum 25(OH)D level was 21.46 +/- 7.95 ng/mL, which was obtained from a total of 938 cases. No significant difference was found in age, gender, height, and weight of participants from different ethnic groups. The mean 25(OH)D level was significantly lower in children of Lisu ethnic groups compared with that of Han and Hani participants, respectively ( P < .05). In addition, Bai children had lower 25(OH)D content than Hani children ( P < .001). Among the children with 25(OH)D sufficiency, the number of Lisu participants was significantly lower than Han children ( P < .001). CONCLUSION: The prevalence of vitamin D deficiency varied among the ethnically different children in Yunnan, China, and significantly fewer Lisu children maintained vitamin D sufficiency compared with other ethnic children. Recognizing these ethnic differences in treating children with vitamin D deficiency may improve the therapeutic outcome. PMID- 29614874 TI - Consumer Attitudes Toward Animal Welfare-Friendly Products and Willingness to Pay: Exploration of Mexican Market Segments. AB - The study aim was to identify consumer segmentation based on nonhuman animal welfare (AW) attitudes and their relationship with demographic features and willingness to pay (WTP) for welfare-friendly products (WFP) in Mexico. Personal interviews were conducted with 843 Mexican consumers who stated they purchased most of the animal products in their home. Respondents were selected using a quota sampling method with age, gender, education, and origin as quota control variables. The multivariate analysis suggested there were three clusters or consumer profiles labeled "skeptical," "concerned," and "ethical," which helped explain the association between AW attitudes, some demographic variables, and WTP for WFP. This study is one of the first to address consumer profiling in Latin America, and the findings could have implications for the commercialization of WFP. Hence, customers should receive information to consider welfare innovations when deciding to purchase animal products. The growth of the WFP food market establishes an element of a far more multifaceted phenomenon of sustainable consumption and support of a new paradigm called responsible marketing in emerging markets such as Mexico. PMID- 29614875 TI - Two new thiophene polyacetylene glycosides from Atractylodes lancea. AB - Phytochemical investigation on the rhizomes of Atractylodes lancea led to the isolation of two new thiophene polyacetylene glycosides (1 and 2) and six known compounds (3-8). Their structures were elucidated based on the extensive spectroscopic data (UV, IR, 1D and 2D NMR, and HRESIMS). The absolute configurations of new compounds were established by calculated and experimental circular dichroism. All the compounds were assessed on the lipopolysaccharide induced NO production in BV2 cells and compounds 3, 7, and 8 showed moderate inhibitory activities. PMID- 29614876 TI - Single long scleral tunnel technique for prevention of Ahmed valve tube exposure. AB - PURPOSE: To evaluate the outcome of single long scleral tunnel technique for the prevention of conjunctival erosions caused by the Ahmed glaucoma valve. METHODS: This study was a retrospective case series that included 30 eyes of 30 patients who underwent glaucoma valve implantation surgery by the single long scleral tunnel technique. RESULTS: The mean age of patients at the time of surgery was 52 +/- 21.6 years (range: 10-90 years). The mean visual acuity was 1.5 +/- 0.81 logMAR preoperatively. The intraocular pressure was 40.7 +/- 9.18 mm Hg (range: 25-58) before surgery that decreased significantly to 19.7 +/- 3.1 mm Hg (range: 14-25; p < 0.0001) after a mean follow-up of 37.2 +/- 5.9 months. During follow up, no case of tube exposure was detected in patients. CONCLUSION: Single long scleral technique was efficacious with no occurrence of tube exposure in relatively long period of follow-up. In this method, there is no need to harvest any additional material, and in situations with limited access to patch grafts, it is performable with the minimal facilities. PMID- 29614878 TI - Alzheimer's disease: clinical update on epidemiology, pathophysiology and diagnosis. AB - OBJECTIVES: To provide a clinical update for general psychiatrists on the assessment and diagnosis of Alzheimer's disease (AD), highlighting current issues regarding epidemiology, risk factors and pathophysiology from recent relevant research findings. CONCLUSIONS: Psychiatrists can apply their skills and training in the diagnosis of AD, which is based upon a comprehensive assessment comprising history, investigations, and cognitive and functional assessment, guided by accepted diagnostic criteria. PMID- 29614877 TI - A video-game group intervention: Experiences and perceptions of adults with chronic stroke and their therapists: Intervention de groupe a l'aide de jeux video : Experiences et perceptions d'adultes en phase chronique d'un accident vasculaire cerebral et de leurs ergotherapeutes. AB - BACKGROUND: Ongoing physical activity is important for maintaining the functional level of individuals with chronic stroke. Video games in a group setting might be a cost-effective way for providing mobility and preventing physical inactivity. PURPOSE: This study explores the experiences and perceptions of individuals with chronic stroke who participated in a novel community-based video-game group intervention and their therapists. METHOD: A qualitative study, nested in a randomized controlled trial, was conducted using semistructured interviews with eight individuals with chronic stroke (four men and four women) ages 29 to 69 and a focus group of their three occupational therapists, following a video-game intervention. Data were analyzed using content analysis. FINDINGS: Three main categories were identified by the study participants: (a) using video games, (b) the group/team experience, and (c) intervention outcomes/evolving understandings following the intervention. IMPLICATIONS: Playing video games was perceived not as treatment but as a motivating tool to facilitate whole-body movement. Therefore, this intervention might be suitable to be used in the community for ongoing intervention. PMID- 29614879 TI - The complexities of contagion: The experience of social isolation among children and youth living with cystic fibrosis in Canada. AB - While cross-respiratory infection guidelines reduce the risk of infection, this may have deleterious impacts on the socialization skills of young people living with cystic fibrosis (CF). The purpose of this study was to explore the experience of social isolation among young Canadians with CF, as well as how they navigate these complex contamination restrictions. The thematic analytic qualitative research tradition was adopted and social theories of risk provided theoretical grounding. The youth described a pressing sense of social isolation in their everyday lives. Although most of the youth 'obeyed' the cross contamination guidelines, some demonstrated a more carefree attitude. Social media was employed across the group as a tool to reduce isolation. In accordance with the sociology of risk, youth with CF demonstrate sophisticated decision making abilities, navigating exceedingly difficult choices to preserve an always precarious future. While necessary, cross-contamination guidelines might further marginalize an already isolated group of children and youth. PMID- 29614880 TI - Depression and appearance-related distress in functioning with lipedema. AB - Lipedema is a chronic, progressive adipose tissue disorder that may impact the quality of life of women who suffer from it. The main aim of this study was to asses the role of perceived symptom severity, physical and psychological functioning with the disease in predicting quality of life in patients with lipedema. We conducted an online study with 329 participants who responded to five questionnaires measuring quality of life (World Health Organization Quality of Life BREF), lipedema symptom severity, mobility (Lower Extremity Functional Scale), depression (Patients Health Questionnaire-9), and appearance-related distress (Derriford Appearance Scale 24). Multiple hierarchical regression analyses showed that appearance-related distress and depression explained significantly more variance in quality of life when added to the symptom severity and mobility. Lower quality of life was predicted by higher symptom severity, lower mobility, higher appearance-related distress and higher depression severity. Appearance-related distress and depression constitute important aspects of psychological functioning in women with lipedema. Considering their relationship with quality of life, their assessment should be included in lipedema treatment with appropriate interventions aimed at decreasing appearance related distress, as well as preventing and addressing depression. PMID- 29614881 TI - Perspectives of Fear as a Barrier to Self-Management in Non-Hispanic Black Men With Type 2 Diabetes. AB - BACKGROUND: Self-managing type 2 diabetes (T2D) is critical but often challenging for non-Hispanic Black (NHB) men. Fears may contribute to poor self-management; however, the evidence is sparse. The purpose of this study is to examine the relationship between fear and diabetes self-management in NHB men from the southern United States. METHODS: Nineteen NHB men with T2D were recruited from barbershops and churches. Interviews were conducted using a semistructured interview guide. Transcripts were analyzed using a phenomenological approach and focused on identifying common themes describing the perceptions of fear as a barrier to self-managing T2D in the study participants. RESULTS: More than 68% of the sample was >55 years of age, where 42% reported an annual income of >=$100,000, 74% were married, and 26% had a college degree. Fifty-three percent expressed fear with diabetes management, while 47% reported no fears with diabetes management. Direct fears associated with self-management included the use of needles and syringes for self-monitoring and medication adherence, respectively. Indirect fears were associated with the development of adverse complications resulting in poor mental and physical quality of life. No fears were reported secondary to diabetes knowledge, perceived control, and social support. CONCLUSIONS: In this sample of NHB men, fear was perceived by many as a direct barrier to self-management and an indirect barrier to optimal quality of life. These findings suggest the need to address the fears of NHB men when guiding treatment and developing research interventions to improve self management skills. PMID- 29614882 TI - The Polyphenolic Compound Curcumin Conjugation with an Alkyne Moiety in the Process of Autophagy. AB - Curcumin is a hydrophobic polyphenol derived from turmeric: the rhizome of the herb Curcumalonga. Autophagy is an evolutionarily conserved process, in which cellular proteins and organelles are engulfed in autophagosome and then fuses with lysosome for degradation. Our previous study showed that Curcumin activates lysosome and induce autophagy through inhibition of AKT (protein kinase K, PKB) mammalian target of rapamycin (mTOR) pathway. But whether Curucmin affects the fusion of autophagosome-lysosome is still not clear. Here, we used Curcumin-probe conjugation with an alkyne moiety to label mouse embryonic fibroblasts (MEFs) and found that Curcumin targets autophagy-related proteins, enhances autophagic flux and activates lysosome in cells. Moreover, Curcumin treatment promotes the fusion of autophasosome-lysosome in MEFs. Second, the enhanced fusion of autophagosome lysosome is attributed to mTOR suppression. Third, blockage of the autophagosome lysosome fusion leads to cell growth inhibition by Curcumin. Taken together, data from our study indicates the importance of the fusion of autophagosome-lysosome in Curcumin-induced autophagy, which may facilitate the development of Curcumin as a potential therapeutic agent for oxidative stress-related diseases. PMID- 29614883 TI - Bergamottin Inhibits Adipogenesis in 3T3-L1 Cells and Weight Regulation in Diet Induced Obese Mice. AB - Obesity is a serious and increasing health problem worldwide, and the inhibition of adipogenesis is considered to be a potential therapeutic target for it. Bergamottin (BGM), a component of grapefruit juice, has been reported to regulate lipolysis. However, the physiological role of BGM in obesity has not been evaluated so far. In the present study, we investigated the effects of BGM on obesity in 3T3-L1 cells and in mice fed a high-fat diet (HFD). BGM inhibited adipogenic differentiation of 3T3-L1 cells along with a significant decrease in the lipid content by downregulating the expression of two critical adipogenic factors, CCAAT enhancer-binding protein-alpha (C/EBP[Formula: see text]) and peroxisome proliferator activated receptor-gamma (PPAR[Formula: see text]). The expressions of target proteins such as adipocyte fatty acid-binding protein (aP2), adiponectin, and resistin were also decreased by BGM. It activated AMP activated protein kinase (AMPK) by increasing phosphorylation of AMPK and the downstream target acetyl-CoA carboxylase (ACC), indicating that BGM exerted its antiadipogenic effect through AMPK activation. In the HFD-induced obese mouse model, BGM administration significantly reduced the weight and sizes of white adipose tissue as well as the weight gain of mice fed HFD. Moreover, UCP1 and PGC1[Formula: see text] expressions, well-known as brown adipocyte marker genes, were higher in the BGM-treated HFD mice than that in the HFD-induced obese mice. This study suggests that BGM suppress adipogenesis by AMPK activation in vitro and reduces body weight in vivo. PMID- 29614884 TI - The Effectiveness of Acupuncture for Osteoporosis: A Systematic Review and Meta Analysis. AB - To summarize the existing evidence and evaluate the efficacy of acupuncture as a clinical treatment for osteoporosis. Six English and four Chinese databases were searched from their inception to April 2017. Randomized controlled trials were included, in which warm acupuncture, needling or electroacupuncture were compared with sole Western medicine with osteoporosis. All the data were assessed and extracted by two authors independently. The bias risk assessment recommended by the Cochrane Collaboration's tool was used to assess the quality of the selected studies. This meta-analysis was conducted by using RevMan 5.3. Pooled analyses were calculated by standardized mean difference (SMD) and 95% confidence interval (CI). Heterogeneity was assessed by I2 test. Thirty-five studies involving 3014 patients were located. Meta-analysis showed that warm acupuncture could increase the bone mineral density of lumar (SMD [Formula: see text] 0.93, 95% CI [Formula: see text] 0.65, 1.21, [Formula: see text][Formula: see text]0.00001) and femur (MD[Formula: see text][Formula: see text][Formula: see text]0.11, 95% CI[Formula: see text][Formula: see text][Formula: see text]0.05, 0.16, P[Formula: see text][Formula: see text][Formula: see text]0.0002), the level of serum calcium (MD[Formula: see text][Formula: see text][Formula: see text]0.18, 95% CI[Formula: see text][Formula: see text][Formula: see text]0.13, 0.24, [Formula: see text][Formula: see text]0.00001) and estradiol (SMD[Formula: see text][Formula: see text][Formula: see text]0.65, 95% CI[Formula: see text][Formula: see text][Formula: see text]0.32, 0.98, P[Formula: see text][Formula: see text][Formula: see text]0.0001), relieve pain (MD[Formula: see text][Formula: see text][Formula: see text]-1.64, 95% CI[Formula: see text][Formula: see text][Formula: see text]-2.69, -0.59, P[Formula: see text][Formula: see text][Formula: see text]0.002), decrease the level of serum alkaline phosphatase (MD[Formula: see text][Formula: see text][Formula: see text]-7.8, 95% CI[Formula: see text][Formula: see text][Formula: see text]-14.17, -0.84, P [Formula: see text] 0.03) compared with sole Western medicine. Electroacupuncture could relieve pain (MD[Formula: see text][Formula: see text] -1.32, 95% CI[Formula: see text][Formula: see text][Formula: see text]-2.15, -0.48, P[Formula: see text][Formula: see text][Formula: see text]0.002), increase the level of serum calcium (MD[Formula: see text][Formula: see text][Formula: see text]-0.12, 95% CI [Formula: see text] -0.16,-0.09, [Formula: see text][Formula: see text]0.00001) and decrease the level of serum alkaline phosphatase (MD [Formula: see text] 3.63, 95% CI [Formula: see text] -6.60, -0.66, P [Formula: see text] 0.02) compared with sole Western medicine. Needling could relieve pain (MD [Formula: see text] -2.27, 95% CI [Formula: see text] -3.11, -1.43, [Formula: see text][Formula: see text]0.00001) compared with sole Western medicine. This present systematic review indicated that acupuncture could be an effective therapy for treating osteoporosis. Warm acupuncture seemed to more effective than electroacupuncture and needling for osteoporosis in comparison to sole Western medicine. PMID- 29614886 TI - A Message from the Guest Editor. PMID- 29614887 TI - Vocal function exercises for normal voice: With and without semi-occlusion. AB - PURPOSE: This study examined the effect of varying degrees of vocal tract (VT) occlusion used during Vocal Function Exercises (VFEs) on attainment of maximum phonation time (MPT) goals in normal voice. Greater VT occlusion was expected to result in increased MPT. The overarching goal was to determine whether the semi occluded vocal tract (SOVT) posture used during VFEs could be modified while preserving efficacy. METHOD: Twenty-six females ages 18-30 participated in this pre-post longitudinal group study. Participants were randomly assigned to three experimental groups and completed a six-week VFE protocol. The first group performed exercises using the prescribed SOVT posture; the second group used the vowel /o/; group three used the vowel /a/. The primary outcome measure was MPT as performed on the exercise tasks using the assigned vocal tract posture. RESULT: MPT significantly improved in the prescribed SOVT group, but did not significantly improve in the modified /o/ and /a/ groups. CONCLUSION: The SOVT posture used during VFEs is modifiable to a small extent without significantly undermining efficacy. Changes in MPT are less robust with reduced VT occlusion. Research in a clinical population is warranted. PMID- 29614888 TI - Service quality and perceived customer value in community pharmacies. AB - A patient's perception of the service provided by a health care provider is essential for the successful delivery of health care. This study examines the value created by community pharmacies-defined as perceived customer value-in the prescription drug market through varying elements of service quality. We develop a path model that describes the relationship between service elements and perceived customer value. We then analyze the effect of perceived customer value on customer satisfaction and loyalty. We use data obtained from 289 standardized interviews on respondents' prescription fill in the last six months in Germany. The service elements personal interaction (path coefficient: 0.31), physical aspect (0.12), store policy (0.24), and availability (0.1) have a positive significant effect on perceived customer value. Consultation and reliability have no significant influence. We further find a strong positive interdependency between perceived customer value, customer satisfaction (0.75), and customer loyalty (0.71). Thus, pharmacies may enhance customer satisfaction and loyalty if they consider the customer perspective and focus on the relevant service elements. To enhance benefit, personal interaction appears to be most important to address appropriately. PMID- 29614889 TI - Benefit of Adjuvant Traditional Herbal Medicine With Chemotherapy for Resectable Gastric Cancer. AB - INTRODUCTION: Stomach cancer, historically, has a low survival rate advances in curative resection procedures. OBJECTIVES: To assess the potential benefits of traditional herbal medicines in conjunction with chemotherapy in postoperative gastric cancer patients in terms of overall survival and disease-free survival. DATA SOURCES: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, a Chinese database (CNKI), a Korean database, a Japanese database, AMED, and CINAHL up to September 2016. We summarized survival data from all RCTs. STUDY SELECTION: All RCTs of oral traditional medicines for resectable gastric cancer compared with chemotherapy alone were eligible. DATA EXTRACTION: Thirteen eligible trials with survival data (1075 patients) were deemed eligible for inclusion. RESULTS: There were 217 documented deaths of the 574 patients assigned to adjuvant traditional medicines groups and 319 documented deaths of the 501 patients assigned to the chemotherapy-only groups. Adjuvant traditional medicines were associated with a statistically significant benefit in terms of overall survival rate (hazard ratio = 0.56; 95% confidence interval = 0.47-0.66; P < .00001) and disease-free survival (hazard ratio = 0.54; 95% confidence interval = 0.43-0.66; P < .00001). CONCLUSION: Among the RCTs included, the inclusion of postoperative adjuvant traditional medicines was associated with reduced risk of death in gastric cancer patients, when survival rates were compared with the group of patients who received chemotherapy alone. However, most of the included studies utilized are thought to be of low quality, so it would certainly appear that more trials are both advisable and necessary to arrive at correct and convincing conclusions. PMID- 29614890 TI - Novel instantly-dispersible nanocarrier powder system (IDNPs) for intranasal delivery of dapoxetine hydrochloride: in-vitro optimization, ex-vivo permeation studies, and in-vivo evaluation. AB - Dapoxetine (D) suffers from poor oral bioavailability (42%) due to extensive metabolism in the liver. The aim of this study was to enhance the bioavailability of D via preparing instantly-dispersible nanocarrier powder system (IDNPs) for intranasal delivery of D. IDNPs were prepared using the thin film hydration technique, followed by freeze-drying to obtain easily reconstituted powder providing rapid and ready method of administration. The produced nanocarrier systems were evaluated for drug content, entrapment efficiency percentage, particle size, polydispersity index, zeta potential, and drug payload. The optimized nanocarrier system was morphologically evaluated via transmission electron microscopy and the optimized freeze-dried IDNPs were evaluated for ex vivo permeation and in-vivo pharmacokinetic studies in rabbits following intranasal and oral administration. The relative bioavailability of D after intranasal administration of freeze-dried IDNPs was about 235.41% compared to its corresponding oral nanocarrier formulation. The enhanced D permeation and improved bioavailability suggest that IDNPs could be a promising model for intranasal delivery of drugs suffering from hepatic first pass effect. PMID- 29614891 TI - Aphasia and reperfusion therapies in hyper-acute settings: A scoping review. AB - PURPOSE: Reperfusion therapies are medical treatments that restore blood flow either by surgical removal of a blood clot or with medications that dissolve clots. The introduction of reperfusion therapies has the potential to change the presentation of aphasia following acute ischaemic stroke (AIS). This scoping study will explore the relationship between aphasia and reperfusion therapies from a speech-language pathology perspective. METHOD: A systematic literature search was performed on studies published up until October 2016. Relevant studies that reported on aphasia and reperfusion therapy were assessed for quality and the relationship between the two. RESULTS: Overall, 27 studies were identified, these studies were heterogeneous in nature. Despite speech-language pathologists filling a central role in management of aphasia, only seven of these studies mentioned involvement of speech-language pathologists, with minimal information about the precise nature of the involvement of speech-language pathology services. CONCLUSION: Based on this scoping review, reperfusion therapy appears to be impacting on the presentation of aphasia. A prospective study into reperfusion therapy and aphasia is required to inform speech-language pathologists on this patient population. PMID- 29614892 TI - An evaluation of distal hair cortisol concentrations collected at delivery. AB - Distal hair segments collected at delivery may allow for the assessment of maternal cortisol secretion in early pregnancy, an important time window for fetal development. Therefore, an investigation of the validity of distal hair cortisol concentrations is warranted. We examined the concordance between proximal and distal hair cortisol concentrations (HCC), both representing the first trimester of pregnancy. The study population was comprised of a random sample of 97 women participating in the Pregnancy Outcomes Maternal and Infant Study, a prospective cohort study of pregnant women attending prenatal clinics in Lima, Peru. Each participant provided two hair samples: once at enrollment [mean gestational age (GA) = 13.1 weeks] and again at full-term delivery (mean GA = 39.0 weeks). Hair segments reflecting the first trimester were: 3 cm hair segments closest to the scalp on the first hair sample (proximal) and 6-9 cm from the scalp on the second hair sample (distal). HCC was determined using Luminescence Immunoassay. A subset (N = 28) had both hair segments additionally analyzed using liquid chromatography tandem mass spectrometry (LC-MS/MS). HCC values were log-transformed (logHCC), and proximal-distal differences tested using paired sample t-tests. Concordance was evaluated within and across assay types. LogHCC, measured using immunoassay, in distal hair segments was lower compared to proximal hair segments (1.35 versus 1.64 respectively; p = .02). No difference was observed using LC-MS/MS (1.99 versus 1.83, respectively; p=.33). Proximal-distal concordance was low within assay (immunoassay: Pearson = 0.27 and kappa = 0.10; LC-MS/MS: Pearson = 0.37 and kappa = 0.07). High correlation was observed across assays for both distal (Pearson = 0.78, p < .001; kappa = 0.64) and proximal segments (Pearson = 0.96, p < .001; kappa = 0.75). In conclusion, distal first-trimester hair segments collected at delivery have lower absolute HCC compared to HCC in proximal first trimester hair segments collected in early pregnancy, and are poorly concordant with HCC in proximal segments. Findings may inform the design of future studies. PMID- 29614894 TI - Management of fetal growth restriction using the contraction stress test: a case control study. AB - PURPOSE: Fetal growth restriction (FGR) is a concerning health issue. However, studies on FGR management are limited due to its rarity. We aimed to evaluate the efficacy of the contraction stress test (CST) for FGR management. MATERIALS AND METHODS: A case-control retrospective study design. Our institute innovated CST in FGR management in 2017. We included women in their 33rd-40th week of pregnancy with a diagnosis of FGR and retrospectively divided them into groups: the CST group (FGR management with CST) and no CST group (FGR management without CST) before and after CST development. Neonatal outcome, pH, and pO2 of umbilical artery (UA) were compared between the two groups. RESULTS: No significant differences in the rate of birth weight, Apgar score <7 (5 minutes), neonatal death, hospitalization to newborn childhood intensive care unit (NICU), and UA pH were found between groups. Average UA pH was 7.29 +/- 0.05 and 7.29 +/- 0.04 in the CST and no CST groups, respectively (p = .864). Average UA pO2 values were 21.1 +/- 8.6 and 15.7 +/- 5.0 mmHg in the CST and no CST groups, respectively (p = .016), showing significant differences. CONCLUSIONS: Neonatal outcomes and UA pH were slightly different between the groups managed with and without CST. However, UA pO2 values significantly differed between the groups. For FGR management, the use of a CST may allow for early intervention before fetal acidemia and acidosis. For establishing the effects of a CST for FGR management, analysis including several cases and investigation of long-term outcomes of newborn infants is necessary. PMID- 29614893 TI - Cerebral Artery Gas Embolism Following Navigational Bronchoscopy. AB - INTRODUCTION: Cerebral artery gas embolism (CAGE) is a rare but serious adverse event with potentially devastating neurologic sequelae. Bronchoscopy is a frequently performed procedure but with only a few reported cases of CAGE. METHODS: We report the first documented case of CAGE associated with electromagnetic navigational bronchoscopy. RESULTS: A 61-year-old man with a left lower lobe nodule underwent electromagnetic navigational bronchoscopy. The target lesion underwent transbronchial biopsy, brushing and an end-procedure lavage. Following the procedure, he developed seizures, evidence of hypoxic injury and cerebral edema, and air emboli were seen on computed tomography imaging. He then underwent treatment with hyperbaric oxygen with a full and complete neurologic recovery. Review of other cases reported in the literature suggests improved neurologic outcomes with hyperbaric oxygen treatment. CONCLUSIONS: Biopsy techniques performed during bronchoscopy and electromagnetic navigational bronchoscopy can result in CAGE. Comparison with other reported cases suggests improved neurologic outcomes in those treated with hyperbaric oxygen. Prompt recognition of this complication and timely treatment with hyperbaric oxygen are the cornerstones to recovery. PMID- 29614895 TI - Heart rate-reducing therapy with add-on ivabradine and bisoprolol before coronary computed tomographic angiography in a fast-track ambulatory setting. AB - Objective This study was performed to determine whether add-on oral ivabradine in patients treated with beta blockers 1 hour before coronary computed tomographic angiography (CCTA) is effective in lowering the heart rate and thus improving CCTA quality. Methods In this single-center cohort study, the data of 294 patients referred for ambulant CCTA were retrospectively screened. Patients with an initial heart rate of >=75 bpm (n = 112) were pretreated with either a combination of bisoprolol and ivabradine or with bisoprolol alone. Results During the scan, there was no difference in heart rate between the two groups Likewise, there was no significant difference in additionally administered intravenous bradycardic agents, the number of motion artifacts, or the radiation dose. Both drug regimens were tolerated well. Conclusion Additive oral ivabradine 1 hour before CCTA does not result in a further reduction of the heart rate. Consequently, neither movement artifacts nor radiation dose can be reduced. Therefore, pretreatment with ivabradine does not seem reasonably appropriate in an outpatient clinical setting with short patient contact. PMID- 29614896 TI - Modeling Strengthens Molecular Link between Circadian Polymorphisms and Major Mood Disorders. AB - Anxiety and other mood disorders, such as major depressive disorder (MDD) and seasonal affective disorder (SAD), affect nearly one-fifth of the global population and disproportionately affect young adults. Individuals affected by mood disorders are frequently plagued by sleep and circadian problems, and recent genetic studies provide ample support for the association of circadian and sleep syndromes with depression and anxiety. Mathematical modeling has been crucial in understanding some of the essential features of the mammalian circadian clock and is now a vital tool for dissecting how circadian genes regulate the molecular mechanisms that influence mood. Here, we model the effect of five clock gene polymorphisms, previously linked to mood disorders, on circadian gene expression and, ultimately, on the period length and amplitude of the clock, two parameters that dictate the phase, or alignment, of the clock relative to the environment. We then test whether these gene variants are associated with circadian phenotypes (Horne-Ostberg Morningness-Eveningness scores) and well-established measures of depression (Beck Depression Inventory) and anxiety (State-Trait Anxiety Inventory) in a population of undergraduates ( n = 546). In this population, we find significant allelic and/or genotypic associations between CRY2 and two PER3 variants and diurnal preference. The PER3 length polymorphism (rs57875989) was significantly associated with depression in this sample, and individuals homozygous for the PER3 single nucleotide polymorphism (SNP) (rs228697) reported significantly higher anxiety. Our simple model satisfies available experimental knockdown conditions as well as existing data on clock polymorphisms associated with mood. In addition, our model enables us to predict circadian phenotypes (e.g., altered period length, amplitude) associated with mood disorders in order to identify critical effects of clock gene mutations on CRY/BMAL binding and to predict that the intronic SNPs studied represent gain-of-function mutations, causing increased transcription rate. Given the user-friendly structure of our model, we anticipate that it will be useful for further study of the relationships among clock polymorphisms, circadian misalignment, and mood disorders. PMID- 29614897 TI - Effect of oral nutritional supplementation on growth and recurrent upper respiratory tract infections in picky eating children at nutritional risk: a randomized, controlled trial. AB - Objectives To evaluate the effect of oral nutritional supplementation (ONS) plus dietary counselling (DC) (intervention) versus DC alone (control) on growth and upper respiratory tract infection (URTI) in nutritionally at-risk, picky eating children in India. Methods We performed a 90-day, prospective, randomized, controlled trial. A total of 255 children aged 24-72 months with a weight-for-age z-score >=-2 and <-1, picky eating behaviour, and acute URTI were randomized to the control (n = 128) or intervention group (n = 127). The outcomes included the change in weight-for-age z-score from days 1 to 90 and the URTI incidence. Results The mean age was 44.0 +/- 14.3 months. The intervention group showed a significantly greater increase in mean weight-for-age and body mass index-for-age z-scores compared with the control group from day 10 onwards. Higher energy intake in the intervention group was observed at all follow-up visits, except for day 10. The incidence of URTI in the control group was 2.01 times higher than that in the intervention group, controlling for confounding factors. Conclusions ONS plus DC is effective for improving weight and reducing the incidence of URTI in nutritionally at-risk, picky eating children with an acute URTI episode. PMID- 29614898 TI - Osteomalacia, renal Fanconi syndrome, and bone tumor. AB - We herein report two cases of Fanconi syndrome with refractory hypophosphatemic osteomalacia that was difficult to correct by phosphorus replacement therapy. The pathological result was a bony giant cell tumor and osteosarcoma, respectively. Interestingly, after resection of the tumors, the patient with osteosarcoma recovered completely but the patient with the bony giant cell tumor had a relapse. Although she underwent nine operations, her symptoms and laboratory tests did not improve. These findings indicate that Fanconi syndrome can result from a bone tumor. PMID- 29614900 TI - Mineralocorticoid and glucocorticoid receptor-mediated control of genomic responses to stress in the brain. AB - Successful coping with stressful events involves adaptive and cognitive processes in the brain that make the individual more resilient to similar stressors in the future. Stressful events result in the secretion of glucocorticoids (GCs) from the adrenal glands into the blood stream. Early work proved instrumental for developing the concept that these hormones act in the brain to coordinate physiological and behavioral responses to stress through binding to two different GC-binding receptors. Once activated these receptors translocate to the nucleus where they act on target genes to facilitate (or sometimes inhibit) transcription. There are two types of receptors in the brain, the mineralocorticoid receptor (MR), and glucocorticoid receptor (GR). This review summarizes recent work which provides new insights regarding the genomic action of these receptors, both under baseline conditions and following exposure to acute stress. This work is discussed alongside the extensive studies undertaken in this field previously and new, and exciting "big data" studies which have generated a wealth of relevant data. The consequence of these new insights will challenge existing assumptions about the role of MRs and GRs and pave the way for the implementation of novel and improved methodologies to identify the role these corticosteroid receptors have in stress-related behavioral adaptation. PMID- 29614901 TI - Background distraction during vertical solid and character line bisections. AB - : Background-objectives: When vertical lines are positioned above or below the center of the page, line bisection deviates toward the center of the page, suggesting that the edges of the page distract the allocation of attention to the line. A letter-character line (LCL) bisection requires both global and focal attention, to identify the target letter closest to the line's center. If more focal and less global attention is allocated to a LCL, more global attentional resources may be available and inadvertently allocated to the page. Alternatively, if the allocation of focal attention to a LCL inhibits global attentional processing, there may be less distraction by the page. METHOD: Twenty four healthy adults (12 older) bisected vertical solid and character lines centered, or positioned closer to the top or bottom of the page. RESULTS: There was no difference between bisection of solid and character lines centered on the page. Page-related deviations were greater with character lines than solid line bisections, and greater for lines positioned toward the top than the bottom of the page. With lines positioned toward the top, the older participants' attempted bisections were higher than those of the younger participants. CONCLUSIONS: These results suggest that the allocation of focal attention increases global attentional distractibility and that global-background attentional distraction is greater when the vertical lines are placed in the upper part of the page. Older participants appeared to be less distracted when lines were placed toward the top of the page, but the reason for this age difference requires further research. PMID- 29614902 TI - Intravenous immunoglobulin (IVIG) efficiency in women with common variable immunodeficiency (CVID) decreases significantly during pregnancy. AB - Immunoglobulin replacement therapy, including intravenous immunoglobulin (IVIG), is essential for pregnant women with common variable immunodeficiency (CVID) since it prevents infection and improves the health of the newborn. There are no established IVIG treatment protocols for pregnant women with CVID, and the relationship between IVIG treatment and maternal serum IgG changes during pregnancy remains unclear. Therefore, we reviewed the medical charts of four CVID patients, including one receiving subcutaneous immunoglobulin (SCIG), for IVIG dose and frequency, maternal serum IgG changes, obstetrical findings, and perinatal outcomes. There were no serious infections but one abortion and all patients continued therapy without IVIG-related adverse events. All eight children born to the patients were healthy at one month. However, the IVIG efficiency in those with CVID significantly decreased with progression of the gestational period, suggesting that IVIG dose and frequency may be changed during pregnancy to maintain stable serum IgG trough levels in women with CVID. PMID- 29614903 TI - The Impacts of Social Protection Policies and Programs on Suicide: A Literature Review. AB - Despite vigorous interest in showing the association between economic determinants and suicide, not many studies have focused on the social protection that can moderate the detrimental impact of the economic environment on suicide. This article is the first to review the relationship between suicide and social protection. In this article, I summarize the empirical findings and theoretical approaches in published papers on the relationship between suicide and social protection, and I identify knowledge gaps for future studies. The review included all quantitative and qualitative articles published in peer-reviewed journals, regardless of study setting, language, and time period. Among 19 papers meeting the inclusion criteria, 16 studies reported at least one negative association, 2 studies failed to prove a statistical association, and 1 study showed ambiguous results. However, due to the heterogeneity of contexts, the diversity of indicators of social protection, and the paucity of theoretical mechanisms for interpreting the results, further research is required in this area. PMID- 29614905 TI - Anti-inflammatory effect of Mongolian drug Naru-3 on traumatic spinal cord injury and its mechanism of action. AB - Objective This study was performed to confirm the anti-inflammatory effect of the Mongolian drug Naru-3 on traumatic spinal cord injury (TSCI) and its possible mechanism of action. Methods We prepared a TSCI model using Sprague-Dawley rats. The rats were divided into a Naru-3 group and a methylprednisolone group. Real time polymerase chain reaction and western blotting were performed to measure the expression levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-1beta. Enzyme-linked immunosorbent assay kits were employed to detect serum inflammatory cytokine levels. The localization and expression of monocyte chemotactic protein-1 (MCP-1) in spinal cord tissue was determined by immunohistochemical analysis. Flow cytometry was performed to analyze the ratio of M1- and M2-phenotype macrophages. The locomotor function recovery was evaluated by the Basso, Beattie, and Bresnahan score. Results Naru-3 significantly inhibited the inflammatory response and reduced the expression of TNF-alpha, IL-6, and IL-1beta in both spinal cord and blood in a time- and concentration-dependent manner. Immunohistochemical analysis indicated that Naru 3 significantly reduced MCP-1 expression in spinal cord and promoted M2-phenotype macrophage differentiation. Conclusions Naru-3 is an effective treatment for impact-induced TSCI in rats. Naru-3 treatment affects inflammatory cytokine levels and macrophage differentiation, which play a role in TSCI remission. PMID- 29614899 TI - Biopolymer-based strategies in the design of smart medical devices and artificial organs. AB - Advances in regenerative medicine and in modern biomedical therapies are fast evolving and set goals causing an upheaval in the field of materials science. This review discusses recent developments involving the use of biopolymers as smart materials, in terms of material properties and stimulus-responsive behavior, in the presence of environmental physico-chemical changes. An overview on the transformations that can be triggered in natural-based polymeric systems (sol-gel transition, polymer relaxation, cross-linking, and swelling) is presented, with specific focus on the benefits these materials can provide in biomedical applications. PMID- 29614907 TI - Haemodialysis access thrombosis: Outcomes after surgical thrombectomy versus catheter-directed thrombolytic infusion. AB - INTRODUCTION:: Thrombosis is one of the most common complications of dialysis vascular access and is a significant source of morbidity and healthcare associated costs. In this retrospective study, outcomes for surgical thrombectomy and thrombolysis after access thrombosis in patients with arteriovenous fistulas or prosthetic grafts (arteriovenous grafts) were analysed. METHODS:: All patients with a primary episode of dialysis access thrombosis between 2005 and 2013 were included which yielded 131 patients with 149 episodes of access thrombosis (108 arteriovenous grafts; 41 arteriovenous fistulas). In all, 18 patients had two separate accesses during the study. Patient demographics, access anatomy, surgical and radiological procedural data were recorded. Kaplan-Meier estimates and Poisson regression were used for statistical analysis of access patency. RESULTS:: In total, 107 underwent surgical thrombectomy and 42 were treated with catheter-directed thrombolytic infusion. Technical success was 60% for surgical thrombectomy and 73% for thrombolysis (p = 0.18). There were no major complications and no deaths within 30 days of the procedure. More patients had adjunctive procedures in the thrombolysis group (65/107 vs 37/42; p = 0.002). There was an increasing risk of rethrombosis or a further access-related event for both arteriovenous fistulas and arteriovenous grafts after open thrombectomy compared with catheter-directed thrombolytic infusion, and arteriovenous fistulas exhibited a lower risk than arteriovenous grafts with an average increase in risk of 23.9% (95% confidence interval: 3.1-49) between each treatment group. CONCLUSION:: Thrombolysis for thrombosis of native and prosthetic dialysis accesses appears to yield better assisted primary patency compared to surgical thrombectomy. Our results suggest that thrombolysis may be considered the first choice method for treating the thrombosed dialysis access. PMID- 29614906 TI - Effect of rapid eye movement-related obstructive sleep apnea on adherence to continuous positive airway pressure. AB - Objective Rapid eye movement (REM)-related obstructive sleep apnea (OSA) is characterized by respiratory events such as apnea and hypopnea predominately or exclusively during REM sleep. Several studies have revealed clinical predictors of adherence to the use of continuous positive airway pressure (CPAP). However, the effect of REM-related OSA on adherence to CPAP use remains unclear. Therefore, we investigated the effects of REM-related OSA on adherence to CPAP use 6 months after treatment initiation. Methods We enrolled 161 patients in this study and divided them into 3 groups: the good adherence, poor adherence, and dropout groups. We compared polysomnographic data and clinical findings, including those regarding morbidity of REM-related OSA, among the three groups to identify predictors of adherence to CPAP use. Results None of the 43 patients in the good adherence group had REM-related OSA. Multivariate logistic regression analysis of the good adherence and dropout groups indicated that REM-related OSA was the only factor associated with adherence to CPAP use (odds ratio, 41.984; 95% confidence interval, 2.257-781.007). Conclusions REM-related OSA is a reliable risk factor for dropout from CPAP therapy. PMID- 29614908 TI - Two Cases of Aortic Root Replacement After Fontan Completion. AB - Aortic root dilatation is a well-known complication in patients with congenital aortic valve malformation, tetralogy of Fallot, or a double outlet right ventricle. We report two rare patients who underwent composite graft replacement of the aortic root with a mechanical valve, the so-called Bentall-type operation, after Fontan completion. The pathological examination on the resected aortic wall revealed mucoid degeneration in tunica media and elastic fiber fragmentation. Our report emphasizes the need for close observation of these patients over a long term period. PMID- 29614909 TI - Three's a Crowd-A Unique Combination of Coronary Artery Atresia, Fistula, and Stenosis: Multiple Congenital Coronary Artery Anomalies. AB - The incidence of congenital coronary artery anomalies in the general population is low. The combination of various significant coronary artery anomalies in a single patient is not very common. We describe a case of a 20-month-old child with a unique combination of congenital coronary anomalies (atresia, stenosis, fistula) which were accurately delineated by multimodal imaging and successfully managed surgically. PMID- 29614910 TI - One-Stage Repair of Tetralogy of Fallot and Pseudoaneurysm of the Ascending Aorta After Central Shunt. AB - Pseudoaneurysm of the ascending aorta following a central aortopulmonary shunt is a rare and potentially fatal complication. Loss of pulmonary artery continuity is another complication following an aortopulmonary shunt. We report an unusual combination of these two complications following an aortopulmonary shunt performed in a child with tetralogy of Fallot. This was managed successfully along with intracardiac repair of tetralogy of Fallot incorporating only the left pulmonary artery. PMID- 29614911 TI - Stenting Coarctation of the "Fifth Aortic Arch": A Safe and Attractive Therapeutic Alternative to Surgery. AB - "Persistence of the fifth aortic arch" is a rare congenital abnormal vessel arising from the distal ascending aorta connecting with the systemic or pulmonary circulation. We report a case of a type A interruption of the aortic arch and a coarctation of the fifth aortic arch, which connected the ascending with the descending aorta. No cardiac surgery was required because a covered stent was successfully implanted in the fifth aortic arch when the patient was 4 years old. A chromosome 9 q arm duplication of uncertain significance was also found, an anomaly never described before in this clinical context. PMID- 29614912 TI - Probing culture in the head: the neural correlates of relational models. AB - Relational Models Theory or RMT proposes that there are four universal ways in which socio-economic relations can be organized. According to the RMT, each of its four relational models (Communal Sharing, Authority Ranking, Equality Matching, and Market Pricing) is associated with a distinct cognitive representation, with a cumulative pattern in which each relational model is a superset of the next lower model. This report for the first time uses a combination of cognitive and the social neuroscience to put this model to the test. RMT proposes that members of every culture use all four relational models, just in different proportions. It should therefore be possible to study their neural correlates in a mono-cultural sample. In this study, thirty-nine European American students were imaged in a 3T Siemens Trio with a 24-channel head coil while rating the extent to which each relational model organized relationships with each of thirty-two acquaintances/friend/relatives in a boxcar design. FreeSurfer Functional Analysis Stream (FS-FAST) analyses revealed distinct patterns of activation for each of the relational models. The activations did not follow a cumulative hierarchical pattern, suggestive that this aspect of the RMT model should be revised. PMID- 29614913 TI - Conscientious objection and nurses: Results of an interpretive phenomenological study. AB - BACKGROUND: While conscientious objection is a well-known phenomenon in normative and bioethical literature, there is a lack of evidence to support an understanding of what it is like for nurses to make a conscientious objection in clinical practice including the meaning this holds for them and the nursing profession. RESEARCH QUESTION: The question guiding this research was: what is the lived experience of conscientious objection for Registered Nurses in Ontario? RESEARCH DESIGN: Interpretive phenomenological methodology was used to gain an in depth understanding of what it means to be a nurse making a conscientious objection. Purposive sampling with in-depth interview methods was used to collect and then analyze data through an iterative process. Participants and research context: Eight nurse participants were interviewed from across practice settings in Ontario, Canada. Each participant was interviewed twice over 9 months. Ethical considerations: This study was conducted in accordance with Health Science Research Ethics Board approval and all participants gave consent. FINDINGS: Six themes emerged from data analysis: encountering the problem, knowing oneself, taking a stand, alone and uncertain, caring for others, and perceptions of support. DISCUSSION: This study offers an initial understanding of what it is like to be a nurse making a conscientious objection in clinical practice. Implications for nursing practice, education, policy, and further research are discussed. CONCLUSION: Addressing ethical issues in nursing practice is complex. The need for education across nursing, healthcare disciplines and socio-political sectors is essential to respond to nurses' ethical concerns giving rise to objections. Conscience emerged as an informant to nurses' conscientious objections. The need for morally inclusive environments and addressing challenging ethical questions as well as the concept of conscience are relevant to advancing nursing ethics and ethical nursing practice. PMID- 29614914 TI - Visual perceptual deficits and their contribution to walking dysfunction in individuals with post-stroke visual neglect. AB - BACKGROUND: Unilateral spatial neglect (USN), a highly prevalent and disabling post-stroke deficit, severely affects functional mobility. Visual perceptual abilities (VPAs) are essential in activities involving mobility. However, whether and to what extent post-stroke USN affects VPAs and how they contribute to mobility impairments remains unclear. OBJECTIVES: To estimate the extent to which VPAs in left and right visual hemispaces are (1) affected in post-stroke USN; and (2) contribute to goal-directed locomotion. METHODS: Individuals with (USN+, n = 15) and without (USN-, n = 15) post-stroke USN and healthy controls (HC, n = 15) completed (1) psychophysical evaluation of contrast sensitivity, optic flow direction and coherence, and shape discrimination; and (2) goal-directed locomotion tasks. RESULTS: Higher discrimination thresholds were found for all VPAs in the USN+ group compared to USN- and HC groups (p < 0.05). Psychophysical tests showed high sensitivity in detecting deficits in individuals with a history of USN or with no USN on traditional assessments, and were found to be significantly correlated with goal-directed locomotor impairments. CONCLUSION: Deficits in VPAs may account for the functional difficulties experienced by individuals with post-stroke USN. Psychophysical tests used in the present study offer important advantages and can be implemented to enhance USN diagnostics and rehabilitation. PMID- 29614915 TI - Preliminary experience of tigecycline treatment in critically ill children with ventilator-associated pneumonia. AB - Objective Ventilator-associated pneumonia (VAP) is a life-threatening complication for children who are treated in a paediatric intensive care unit. Tigecycline treatment of children with VAP has not been well studied. This study aimed to describe tigecycline use in children with VAP in a tertiary care hospital. Methods We conducted a retrospective chart review in a tertiary hospital from May 1, 2012 to May 1, 2017. Results Twenty-four children (20 girls) with median age of 8 months (range, 27 days to 6 years and 9 months) were treated with tigecycline. In-hospital mortality was 41.7% (10/24). The primary diagnosis was congenital heart disease (15/24). A total of 70.8% (17/24) of patients received a loading dose (1.5 mg/kg), followed by 1 mg/kg every 12 hours. The median duration of tigecycline therapy was 10.75 days (range, 3-21.5 days). Sulperazone was the most frequently used concomitant antibiotic. Eighteen pathogens were isolated in 16 cases. Tigecycline therapy failed in 41.6% (10/24) of patients and 20.8% (5/24) died. The pathogen was eradicated in 37.5% (6/16) of patients. No serious adverse effects were detected. Conclusion Tigecycline combined with other agents as salvage therapy in children with VAP is well tolerated. Our preliminary results show a positive clinical response. PMID- 29614917 TI - Perfectionism and training distress in junior athletes: The mediating role of coping tendencies. AB - Training distress occurs when athletes fail to cope with physiological and psychological stress and can be an early sign of overtraining syndrome. Recent research has found that perfectionism predicts increases in training distress in junior athletes over time. The current study provides the first empirical test of the possibility that coping tendencies mediate the perfectionism-training distress relationship. Adopting a cross-sectional design, 171 junior athletes (mean age = 18.1 years) completed self-report measures of perfectionistic strivings, perfectionistic concerns, problem-focused coping, avoidant coping, and training distress. Structural equation modelling revealed that avoidant coping mediated the positive relationship between perfectionistic concerns and training distress, and mediated the negative relationship between perfectionistic strivings and training distress. Problem-focused coping did not mediate any relationships between dimensions of perfectionism and training distress. The findings suggest that the tendency to use coping strategies aimed at avoiding stress may partly explain the relationship between perfectionism and training distress but the tendency to use, or not use, problem-focussed coping does not. PMID- 29614918 TI - Does variability within natural turfgrass sports fields influence ground-derived injuries? AB - Natural turfgrass sports fields exhibit within-field variations due to climatic conditions, field construction, field management, and foot traffic patterns from field usage. Variations within a field could influence the playing surface predictability and require athletes to make abrupt or frequent adjustments that lead to increased ground-derived injury occurrence. This study introduces a new methodology aimed at evaluating the potential relationship between within-field variations of turfgrass sports field properties and ground-derived athlete injuries. Collegiate Club Sport athletes self-reported ground-derived injuries over two years. Soil moisture, turfgrass quality, surface hardness, and turfgrass shear strength were quantified from their two home fields. Hot spot analysis identified significantly high (hot spots) and low (cold spots) values within the fields. Injury locations were compared to hot spot maps each month. Binomial proportion tests determined if there were differences between observed injury proportions and expected proportions. Twenty-three ground-derived injuries were reported overall. The observed injury proportions occurring in turfgrass quality cold spots [0.52 (95% CI 0.29-0.76)] and soil moisture hot spots [0.43 (95% CI 0.22-0.66)] was significantly higher than expected [0.20 (p < .001) and 0.21 (p < .05), respectively]. Most injuries in significant areas of turfgrass quality, soil moisture, and surface hardness were along edges of hot and cold spots. These results suggest a potential relationship between within-field variations and ground-derived injuries, particularly in transition areas between non-significant and significant high and low values. Future larger-scale studies can incorporate the reported methodology to validate this relationship and implement strategies that reduce ground-derived injuries. PMID- 29614919 TI - Humoral immune response of childhood acute lymphoblastic leukemia survivors against the measles, mumps, and rubella vaccination. AB - BACKGROUND: There is a great risk of infection with viral-vaccine-preventable diseases like measles, mumps, and rubella (MMR) infections after the end of chemotherapy treatment of children with acute lymphoblastic leukemia (ALL), which could have been prevented with MMR vaccination. Previous studies reported widely variable rates of seropositivity (seroprotection) for MMR after ALL treatment ends. Also, few studies evaluated the response to MMR booster vaccinations after the end of ALL treatment and reported unclear and difficult to interpret results. MATERIAL AND METHODS: This retrospective cross-sectional study evaluated the prevalence of seropositive (protection) antibody titer levels for MMR among ALL childhood survivors who were followed-up at Jeddah Oncology Center, Saudi Arabia. The aim of the study was also to investigate and analyze the response of seronegative patients to a booster MMR vaccination. RESULTS: Fifty-seven ALL children were evaluated. Thirty-five patients (61.4%) were seropositive/seroprotected and the remaining 22 patients (38.6%) were seronegative for MMR. ALL Children under the age of 5 years had a higher prevalence of seronegative titers. Interestingly, the prevalence of seroprotection decreased as the time interval increased post-treatment, while seroconversion rates after administering a booster MMR vaccine were 57.1%, 87.5%, and 78.6%, respectively for MMR. CONCLUSION: We suggest the need for booster MMR vaccination, especially for ALL children under the age of 5 years and those who experienced a protracted time interval post-treatment. PMID- 29614920 TI - Objectively measured physical activity, body composition and physical fitness: Cross-sectional associations in 9- to 15-year-old children. AB - The aim of this study was to examine and quantify the cross-sectional associations of body composition (BC), physical activity (PA) and sedentary time (ST) with physical fitness (PF) in children and adolescents. A sample of 594 Finnish students (56% girls), aged 9-15 (12.4 +/- 1.3 years) were selected for a study performed in 2013. The measurements of the Move! monitoring system for physical functional capacity were used to measure cardiorespiratory and musculoskeletal fitness and fundamental movement skills. Moderate-to-vigorous PA (MVPA) and ST were measured objectively with an accelerometer and BC by a bioelectrical impedance analysis. Fat mass index (FMI) and fat-free mass index (FFMI) were calculated to represent height-adjusted BC. Associations were explored with a linear regression model. In general, FMI had statistically significant negative associations, while FFMI and MVPA had positive associations with PF. No statistically significant associations were observed between ST and PF. In general, FMI had the strongest association with PF, although some variation occurred with sex and PF component. However, associations were practically relevant only in 20-m shuttle run, push-up, curl-up and 5-leaps test. For example, approximately 5 kg increase in fat mass in 155 cm tall children was estimated to correspond to 8 laps in 20-m shuttle run. Similar increase in fat free mass corresponded to +4 and +6 laps, and 10 min increase in daily MVPA +3 and +2 laps in 20-m shuttle run, in boys and girls, respectively. Understanding these associations is necessary when interpreting children's PF and designing interventions. PMID- 29614921 TI - Increasing Opportunities for Health in a Southeast Michigan Community Through Local Policy Change. AB - Disparities in health outcomes are closely linked with social, economic, and environmental conditions. The burden of these disparities are most often experienced by racial and ethnic individuals of color, those with low income, and those who live in vulnerable communities. Local policy and systems change efforts provide a means to address health inequities and create sustainable change at the community level. The Inkster Partnership for a Healthier Community was formed in 2010 to create sustainable opportunities for health, with a special focus on diabetes prevention and management. Policy and infrastructure change efforts were documented and tracked over time and qualitative data were collected to create deeper understanding of the change efforts. Eleven policy outcomes have created sustainable change around access to health resources and services, access to healthy foods, opportunities for physical activity, diabetes prevention and management education, and increased capacity for ongoing community change. PMID- 29614922 TI - Experiences and Needs of Older Adults Following Hurricane Ike: A Pilot Study of Long-Term Consequences. AB - OBJECTIVE: This study explored the experiences and needs of older adults during and following Hurricane Ike. METHOD: Two focus group interviews were conducted among older adults who lived in or around Galveston Island before Hurricane Ike. Nine older adults (six women and three men) participated in two focus group sessions. These qualitative interviews were audio recorded, transcribed, and analyzed using thematic content analyses. RESULTS: The findings of this study reveal the need for continuity in health care services, medications, psychological support, social and family support, community-level services, and information among older adults. CONCLUSIONS: The contribution of factors such as health care continuity and psychological support reinforces the importance of specific postdisaster resources to meet the needs of older adults following hurricanes. These results suggest the importance of designing hurricane preparedness guidelines specifically for older adults. PMID- 29614923 TI - Using Job Analysis Techniques to Understand Training Needs for Promotores de Salud. AB - Despite the value of community health worker programs, such as Promotores de Salud, for addressing health disparities in the Latino community, little consensus has been reached to formally define the unique roles and duties associated with the job, thereby creating unique job training challenges. Understanding the job tasks and worker attributes central to this work is a critical first step for developing the training and evaluation systems of promotores programs. Here, we present the process and findings of a job analysis conducted for promotores working for Planned Parenthood. We employed a systematic approach, the combination job analysis method, to define the job in terms of its work and worker requirements, identifying key job tasks, as well as the worker attributes necessary to effectively perform them. Our results suggest that the promotores' job encompasses a broad range of activities and requires an equally broad range of personal characteristics to perform. These results played an important role in the development of our training and evaluation protocols. In this article, we introduce the technique of job analysis, provide an overview of the results from our own application of this technique, and discuss how these findings can be used to inform a training and performance evaluation system. This article provides a template for other organizations implementing similar community health worker programs and illustrates the value of conducting a job analysis for clarifying job roles, developing and evaluating job training materials, and selecting qualified job candidates. PMID- 29614924 TI - Parental Consent and Access to Oral Health Care for Adolescents. AB - While most states allow minors 12 years and older to consent to services for contraception, prenatal care, or sexually transmitted infections, the same adolescents are required to have parental consent for even preventive oral health care. Many adolescents are denied access to preventive oral health care because of the challenge of securing parental consent for care when parents are unwilling, unable, or unavailable to consent. Our purpose is to examine the barriers to preventive oral health care for U.S. adolescents related to parental consent laws, explore the issues surrounding these laws, and recommend policy changes. We explain the current range and status of consent laws across the country and arguments for parental consent law as it now stands. We discuss the difficulty of applying general medical consent law to preventive oral health care, neuroscience research on cognitive capacity among adolescents, and the distinction between parental consent and adolescent assent. We recommend replacing required "opt-in" consent with simpler "opt-out" consent; developing a tool for assessing adolescent decision-making capacity; advocating for consent laws that apply specifically to preventive oral health care; and empowering school nurses to lead local, state, and nationwide policy and legislation efforts. PMID- 29614925 TI - Selective map-following navigation deficit: A new case of developmental topographical disorientation. AB - INTRODUCTION: Developmental topographical disorientation (DTD) is a lifelong condition in which affected individuals are selectively impaired in navigating space. Although it seems that DTD is widespread in the population, only a few cases have been studied from both a behavioral and a neuroimaging point of view. Here, we report a new case of DTD, never described previously, of a young woman (C.F.) showing a specific deficit in translating allocentrically coded information into egocentrically guided navigation, in presence of spared ability of constructing such representations. METHOD: A series of behavioral experiments was performed together with a resting-state functional magnetic resonance imaging (fMRI). RESULTS: We demonstrated that C.F. was fully effective in learning and following routes and in building up cognitive maps as well as in recognizing landmarks. C.F.'s navigational skills, instead, dropped drastically in the map following task when she was required to use a map to navigate in a novel environment. The rs-fMRI experiment demonstrated aberrant functional connectivity between regions within the default-mode network (DMN), and in particular between medial prefrontal cortex and posterior cingulate, medial parietal, and temporal cortices. DISCUSSION: Our results would suggest that, at least in C.F., dysfunctional coactivation of core DMN regions would interfere with the ability to exploit cognitive maps for real-life navigation even when these maps can be correctly built. PMID- 29614926 TI - Towards the demise of the urban-rural contrast: a research design inadequate to understand urban influences on human biology. PMID- 29614928 TI - Traumatic cricket-related fatalities in Australia: a historical review of media reports. AB - OBJECTIVE: To undertake a historical review of direct trauma-related deaths in Australian cricket, both organised and informal. DESIGN, SETTING AND PARTICIPANTS: We conducted an extensive search of digitised print media (three databases) and traditional scientific literature (two databases) for on-field cricket incidents in Australia that resulted in deaths during the period 1858 2016. Main outcomes and measures: Numbers of cricket-related deaths by decade; type of cricket match (organised match or training, or informal play); site of fatal injury (eg, head, chest); activity at the time of the incident (eg, batting, fielding, watching). RESULTS: 174 relevant deaths were identified. The number peaked in the 1930s (33 fatalities), with five deaths in the past 30 years. There were 83 deaths in organised settings, and 91 deaths in informal play (at school, 31; backyard, street or beach cricket, 60). Of the 72 deaths in organised settings for which the activity of the deceased was reported, 45 were batsmen, 11 were fielders, six were wicketkeepers, one a bowler, and three were umpires. Of the 45 batsmen, 26 died of injuries resulting from a blow by a ball to the head, 13 of blows to the chest, three of peritonitis, at least two of vertebral artery dissection, and one of tetanus. None of the five cricket-related deaths over the past 30 years were caused by head injuries. CONCLUSIONS: There appears to have been a substantial decline in the number of cricket-related deaths in recent years, probably linked with the widespread use of helmets by batsmen and close-in fielders. PMID- 29614930 TI - MJA sports medicine issue. PMID- 29614931 TI - Exercise: an essential evidence-based medicine. PMID- 29614932 TI - How exercise medicine has evolved from sports medicine. PMID- 29614933 TI - An update to the AIS-AMA position statement on concussion in sport. PMID- 29614934 TI - Life after sport: swimming through transitions. PMID- 29614935 TI - A case of adult-onset Kawasaki disease. PMID- 29614936 TI - Assisting clinicians in managing musculoskeletal conditions. PMID- 29614937 TI - Providing a holistic background to the practicalities of retrieval medicine. PMID- 29614938 TI - Preventing recreational sports injuries: practicalities and governance. PMID- 29614939 TI - Sports injuries in Victoria, 2012-13 to 2014-15: evidence from emergency department records. AB - OBJECTIVES: To report the incidence of presentations to emergency departments (EDs) in Victoria for sport- and active recreation-related injuries; to establish which sports have the highest rates of injury per participant; to assess the effects of age and sport type on the rate of serious sport injury (resulting in admission to hospital). DESIGN, SETTING AND PARTICIPANTS: Retrospective analysis of 171 541 ED presentations to 38 Victorian hospitals, 2012-13 to 2014-15. Sports and active recreation-related injuries in people aged 5 years or more were identified from coded data and by text searches. MAIN OUTCOME MEASURES: Population rates of injuries by sport and ranking of sports by per participant injury rates (for people aged 15 years or more); proportions of presenting patients subsequently admitted to hospital (serious sport injuries) (for people aged 5 years or more). RESULTS: During 2012-13 to 2014-15, there were 171 541 presentations to EDs with sports-related injuries. Sports most commonly associated with presentation by people aged 15 years or more were Australian football, motor sports, and cycling/BMX; the highest per participant injury rates (people aged 15 or more) were for motor sports, rugby, and skateboarding/inline hockey/roller sports. 11% of ED patients aged 5 years or more were subsequently admitted to hospital; the odds of admission were highest for those with injuries from motor sports, horse riding, or cycling/BMX. CONCLUSIONS: Assessing sports injury rates corrected for participation rates and evaluating the relative severity of injuries is important for monitoring safety. Our findings can assist decisions about which sports should be the focus of injury prevention efforts. PMID- 29614940 TI - Changing trends in the incidence of invasive melanoma in Victoria, 1985-2015. AB - OBJECTIVES: To estimate the incidence of cutaneous malignant melanoma in Victoria; to examine trends in its incidence over the past 30 years. Secondary objectives were to examine the anatomic location and thickness of invasive melanoma tumours during the same period. DESIGN: Population-based, descriptive analysis of Victorian Cancer Registry data. PARTICIPANTS: Victorian residents diagnosed with melanoma, 1985-2015. MAIN OUTCOME MEASURES: Age-standardised incidence of invasive melanoma; estimated annual percentage changes in incidence. RESULTS: In 2015, the incidence of invasive melanoma in Victoria was 52.9 cases per 100 000 men and 39.2 cases per 100 000 women. Since the mid-1990s, the incidence for men increased annually by 0.9% (95% CI, 0.3-1.5%), but for women there was no significant change (estimated annual percentage change, -0.1%; 95% CI, -0.8% to 0.5%). The incidence of invasive melanoma has been declining in age groups under 55 years of age since 1996 (overall annual change, -1.7%; 95% CI, 2.5% to -0.9%), but is still increasing in those over 55 (overall annual change, 1.6%; 95% CI, 1.0-2.2%). The most frequent site of tumours in men was the trunk (40%), on women the upper (32%) and lower limbs (31%). CONCLUSIONS: Melanoma remains a significant health problem, warranting continued prevention efforts. Awareness of differences in presentation by men and women and in different age groups would facilitate improved screening and risk identification. PMID- 29614941 TI - Paediatric injuries during the Australian Junior Motocross Championship treated at a rural centre. PMID- 29614942 TI - Drowning deaths in Australia caused by hypoxic blackout, 2002-2015. PMID- 29614943 TI - Primary care management of non-specific low back pain: key messages from recent clinical guidelines. AB - INTRODUCTION: Research in the past decade supports some major changes to the primary care management of non-specific low back pain (LBP). The present article summarises recommendations from recently published United Kingdom, Danish, Belgian and United States guidelines to alert readers to the important changes in recommendations for management, and the recommendations from previous guidelines that remain unchanged. Main recommendations: Use a clinical assessment to triage patients with LBP. Further diagnostic workup is only required for the small number of patients with suspected serious pathology. For many patients with non specific LBP, simple first line care (advice, reassurance and self-management) and a review at 1-2 weeks is all that is required. If patients need second line care, non-pharmacological treatments (eg, physical and psychological therapies) should be tried before pharmacological therapies. If pharmacological therapies are used, they should be used at the lowest effective dose and for the shortest period of time possible. Exercise and/or cognitive behavioural therapy, with multidisciplinary treatment for more complex presentations, are recommended for patients with chronic LBP. Electrotherapy, traction, orthoses, bed rest, surgery, injections and denervation procedures are not recommended for patients with non specific LBP. Changes in management as a result of the guidelines: The major changes include: emphasising simple first line care with early follow-up; encouraging non-pharmacological treatments over pharmacological treatments; and recommending against the use of surgery, injections and denervation procedures. PMID- 29614944 TI - Untapped potential in Australian Hospitals for organ donation after circulatory death. PMID- 29614945 TI - Eradicating hepatitis C from the New South Wales prison system. PMID- 29614946 TI - Tackling antimicrobial resistance globally. PMID- 29614947 TI - Serendipity and the joy of surgery. PMID- 29614948 TI - Around the universities and medical institutes. PMID- 29614950 TI - Genetic insights into dispersal distance and disperser fitness of African lions (Panthera leo) from the latitudinal extremes of the Kruger National Park, South Africa. AB - BACKGROUND: Female lions generally do not disperse far beyond their natal range, while males can disperse distances of over 200 km. However, in bush-like ecosystems dispersal distances less than 25 km are reported. Here, we investigate dispersal in lions sampled from the northern and southern extremes of Kruger National Park, a bush-like ecosystem in South Africa where bovine tuberculosis prevalence ranges from low to high across a north-south gradient. RESULTS: A total of 109 individuals sampled from 1998 to 2004 were typed using 11 microsatellite markers, and mitochondrial RS-3 gene sequences were generated for 28 of these individuals. Considerable north-south genetic differentiation was observed in both datasets. Dispersal was male-biased and generally further than 25 km, with long-distance male gene flow (75-200 km, detected for two individuals) confirming that male lions can travel large distances, even in bush like ecosystems. In contrast, females generally did not disperse further than 20 km, with two distinctive RS-3 gene clusters for northern and southern females indicating no or rare long-distance female dispersal. However, dispersal rate for the predominantly non-territorial females from southern Kruger (fraction dispersers >=0.68) was higher than previously reported. Of relevance was the below-average body condition of dispersers and their low presence in prides, suggesting low fitness. CONCLUSIONS: Large genetic differences between the two sampling localities, and low relatedness among males and high dispersal rates among females in the south, suggestive of unstable territory structure and high pride turnover, have potential implications for spread of diseases and the management of the Kruger lion population. PMID- 29614951 TI - Synergistic effects of brain-derived neurotrophic factor (BDNF) and exercise intensity on memory in the adolescent brain: a commentary. AB - This commentary highlights the recently published study by Jeon and Ha (Environ Health Prev Med 22:27, 2017) examining the effects of exercise intensity and brain-derived neurotrophic factor (BDNF) on memory in adolescents. This 12-week training study elicited increases in BDNF and improvements in working memory during moderate- and high-intensity exercise, which may have been achieved through improved brain tissue oxygenation, nutrient delivery, and BDNF mRNA expression. These improvements highlight the positive neuroendocrinological effects of BDNF and its role as a potential candidate molecule, as a mediator of synaptic plasticity. In this commentary, we aim to highlight the strengths and potential areas of consideration of Jeon and Ha (Environ Health Prev Med 22:27, 2017). We also offer insight into the clinical implications of this study, such as advocating for exercise in healthy children and as adjunctive therapy in pathological states. This study is promising and further highlights the importance of cardiorespiratory exercise in improving physiological health and cognitive functioning in youth through the phenomenon of neuroplasticity. PMID- 29614952 TI - Mutations of DnaA-boxes in the oriR region increase replication frequency of the MiniR1-1 plasmid. AB - BACKGROUND: The MiniR1-1 plasmid is a derivative of the R1 plasmid, a low copy cloning vector. RESULTS: Nucleotide sequencing analysis shows that the MiniR1-1 plasmid is a 6316 bp circular double-stranded DNA molecule with an oriR1 (origin for replication). The plasmid carries the repA, tap, copA and bla genes, and genes for ORF1 and ORF2. MiniR1-1 contains eight DnaA-binding sites (DnaA-boxes). DnaA-box1 is in the oriR1 region and fully matched to the DnaA-box consensus sequence, and DnaA-box8, with one mismatch, is close to the copA gene. The presence of the MiniR1-1 plasmid leads to an accumulation of the D-period cells and an increase in cell size of slowly growing Escherichia coli cells, suggesting that the presence of MiniR1-1 delays cell division. Mutations in the MiniR1-1 DnaA-box1 and DnaA-box8 significantly increase the copy number of the plasmid and the mutations in DnaA-box1 also affect cell size. It is likely that titration of DnaA to DnaA-boxes negatively controls replication of the MiniR1-1 plasmid and delays cell division. Interestingly, DnaA weakly interacts with the initiator protein RepA in vivo. CONCLUSION: DnaA regulates the copy number of MiniR1-1 as a negative factor through interacting with the RepA protein. PMID- 29614954 TI - BS-Seeker3: ultrafast pipeline for bisulfite sequencing. AB - BACKGROUND: DNA methylation is an important epigenetic modification critical in regulation and transgenerational inheritance. The methylation level can be estimated at single-nucleotide resolution by whole-genome bisulfite sequencing (BS-seq; WGBS). Current bisulfite aligners provide pipelines for processing the reads by WGBS; however, few are able to analyze the BS-seqs in a reasonable timeframe that meets the needs of the rapid expansion of epigenome sequencing in biomedical research. RESULTS: We introduce BS-Seeker3, an extensively improved and optimized implementation of BS-Seeker2 that leverages the available computational power of a standard bioinformatics lab. BS-Seeker3 adopts all alignment features of BS-Seeker2. It performs ultrafast alignments and achieves both high accuracy and high mappability, more than twice that of the other aligners that we evaluated. Moreover, BS Seeker 3 is well linked with downstream analyzer MethGo for up to 9 types of genomic and epigenomic analyses. CONCLUSIONS: BS-Seeker3 is an accurate, versatile, ultra-fast pipeline for processing bisulfite-converted reads. It also helps the user better visualize the methylation data. PMID- 29614953 TI - Transcriptome and secretome analysis of Aspergillus fumigatus in the presence of sugarcane bagasse. AB - BACKGROUND: Sugarcane bagasse has been proposed as a lignocellulosic residue for second-generation ethanol (2G) produced by breaking down biomass into fermentable sugars. The enzymatic cocktails for biomass degradation are mostly produced by fungi, but low cost and high efficiency can consolidate 2G technologies. A. fumigatus plays an important role in plant biomass degradation capabilities and recycling. To gain more insight into the divergence in gene expression during steam-exploded bagasse (SEB) breakdown, this study profiled the transcriptome of A. fumigatus by RNA sequencing to compare transcriptional profiles of A. fumigatus grown on media containing SEB or fructose as the sole carbon source. Secretome analysis was also performed using SDS-PAGE and LC-MS/MS. RESULTS: The maximum activities of cellulases (0.032 U mL-1), endo-1,4-beta--xylanase (10.82 U mL-1) and endo-1,3-beta glucanases (0.77 U mL-1) showed that functional CAZymes (carbohydrate-active enzymes) were secreted in the SEB culture conditions. Correlations between transcriptome and secretome data identified several CAZymes in A. fumigatus. Particular attention was given to CAZymes related to lignocellulose degradation and sugar transporters. Genes encoding glycoside hydrolase classes commonly expressed during the breakdown of cellulose, such as GH-5, 6, 7, 43, 45, and hemicellulose, such as GH-2, 10, 11, 30, 43, were found to be highly expressed in SEB conditions. Lytic polysaccharide monooxygenases (LPMO) classified as auxiliary activity families AA9 (GH61), CE (1, 4, 8, 15, 16), PL (1, 3, 4, 20) and GT (1, 2, 4, 8, 20, 35, 48) were also differentially expressed in this condition. Similarly, the most important enzymes related to biomass degradation, including endoxylanases, xyloglucanases, beta-xylosidases, LPMOs, alpha-arabinofuranosidases, cellobiohydrolases, endoglucanases and beta glucosidases, were also identified in the secretome. CONCLUSIONS: This is the first report of a transcriptome and secretome experiment of Aspergillus fumigatus in the degradation of pretreated sugarcane bagasse. The results suggest that this strain employs important strategies for this complex degradation process. It was possible to identify a set of genes and proteins that might be applied in several biotechnology fields. This knowledge can be exploited for the improvement of 2G ethanol production by the rational design of enzymatic cocktails. PMID- 29614955 TI - A method for determining haploid and triploid genotypes and their association with vascular phenotypes in Williams syndrome and 7q11.23 duplication syndrome. AB - BACKGROUND: Williams syndrome ([WS], 7q11.23 hemideletion) and 7q11.23 duplication syndrome (Dup7) show contrasting syndromic symptoms. However, within each group there is considerable interindividual variability in the degree to which these phenotypes are expressed. Though software exists to identify areas of copy number variation (CNV) from commonly-available SNP-chip data, this software does not provide non-diploid genotypes in CNV regions. Here, we describe a method for identifying haploid and triploid genotypes in CNV regions, and then, as a proof-of-concept for applying this information to explain clinical variability, we test for genotype-phenotype associations. METHODS: Blood samples for 25 individuals with WS and 13 individuals with Dup7 were genotyped with Illumina HumanOmni5M SNP-chips. PennCNV and in-house code were used to make genotype calls for each SNP in the 7q11.23 locus. We tested for association between the presence of aortic arteriopathy and genotypes of the remaining (haploid in WS) or duplicated (triploid in Dup7) alleles. RESULTS: Haploid calls in the 7q11.23 region were made for 99.0% of SNPs in the WS group, and triploid calls for 98.8% of SNPs in those with Dup7. The G allele of SNP rs2528795 in the ELN gene was associated with aortic stenosis in WS participants (p < 0.0049) while the A allele of the same SNP was associated with aortic dilation in Dup7. CONCLUSIONS: Commonly available SNP-chip information can be used to make haploid and triploid calls in individuals with CNVs and then to relate variability in specific genes to variability in syndromic phenotypes, as demonstrated here using aortic arteriopathy. This work sets the stage for similar genotype-phenotype analyses in CNVs where phenotypes may be more complex and/or where there is less information about genetic mechanisms. PMID- 29614956 TI - Power and precision of QTL mapping in simulated multiple porcine F2 crosses using whole-genome sequence information. AB - BACKGROUND: During the last two decades, many QTL (quantitative trait locus) mapping experiments in pigs have been conducted using F2 crosses established from two outbred founder breeds. The founder breeds were frequently chosen from the Asian and European type breeds. A combination of next-generation sequencing, SNP (single nucleotide polymorphism) genotyping technology using SNP-chips, and genotype imputation techniques, can be used to infer the sequence information of all F2 individuals in a cost-effective way. The aim of the present simulation study was to analyze the power and precision of genome-wide association studies (GWASs) with whole-genome sequence data in several types of F2 crosses, including pooled crosses. METHODS: Based on a common historical population, three breeds representing two European type breeds (EU1 and EU2) and one Asian type breed (AS) were simulated. Two F2 designs of 500 individuals each were simulated. The cross EU1xEU2 (ASxEU2) was simulated using the phylogenetically closely related breeds EU1 and EU2 (or distantly related breeds AS and EU2) as the founder breeds. The simulated genomes comprised ten chromosomes, each with a length of 1 Morgan and whole-genome sequence information. A polygenic trait with a heritability of 0.5, which was affected by approximately 20 QTL per Morgan, was simulated. GWASs were conducted using single marker mixed linear models, either within the crosses or in their pooled datasets. Additionally, the studies were conducted in the breed EU2, which was a founder breed in both simulated crosses. RESULTS: The power to map QTL was high (low) in the ASxEU2 (EU1xEU2) cross and was highest when the data of both crosses were analyzed jointly. By contrast, the mapping precision was the highest in the EU1xEU2 cross. Pooling data led to a precision that was in between the precision of the EU1xEU2 cross and the ASxEU2 cross. A higher mapping precision was observed for QTL segregating within a founder breed. CONCLUSIONS: These results suggest that the existing F2 crosses are promising databases for QTL mapping when the founder breeds are closely related or several crosses can be pooled. This conclusion is particularly applicable for QTL that segregate in a founder breed. PMID- 29614957 TI - Naturally occurring variations in the nod-independent model legume Aeschynomene evenia and relatives: a resource for nodulation genetics. AB - BACKGROUND: Among semi-aquatic species of the legume genus Aeschynomene, some have the unique property of being root and stem-nodulated by photosynthetic Bradyrhizobium lacking the nodABC genes necessary for the production of Nod factors. These species provide an excellent biological system with which to explore the evolution of nodulation in legumes. Among them, Aeschynomene evenia has emerged as a model legume to undertake the genetic dissection of the so called Nod-independent symbiosis. In addition to the genetic analysis of nodulation on a reference line, natural variation in a germplasm collection could also be surveyed to uncover genetic determinants of nodulation. To this aim, we investigated the patterns of genetic diversity in a collection of 226 Nod independent Aeschynomene accessions. RESULTS: A combination of phylogenetic analyses, comprising ITS and low-copy nuclear genes, along with cytogenetic experiments and artificial hybridizations revealed the richness of the Nod independent Aeschynomene group with the identification of 13 diploid and 6 polyploid well-differentiated taxa. A set of 54 SSRs was used to further delineate taxon boundaries and to identify different genotypes. Patterns of microsatellite diversity also illuminated the genetic basis of the Aeschynomene taxa that were all found to be predominantly autogamous and with a predicted simple disomic inheritance, two attributes favorable for genetics. In addition, taxa displaying a pronounced genetic diversity, notably A. evenia, A. indica and A. sensitiva, were characterized by a clear geographically-based genetic structure and variations in root and stem nodulation. CONCLUSION: A well characterized germplasm collection now exists as a major genetic resource to thoroughly explore the natural variation of nodulation in response to different bradyrhizobial strains. Symbiotic polymorphisms are expected to be found notably in the induction of nodulation, in nitrogen fixation and also in stem nodulation. Subsequent genetic analysis and locus mapping will pave the way for the identification of the underlying genes through forward or reverse genetics. Such discoveries will significantly contribute to our understanding of the molecular mechanisms underpinning how some Aeschynomene species can be efficiently nodulated in a Nod-independent fashion. PMID- 29614958 TI - The skeletal ontogeny of Astatotilapia burtoni - a direct-developing model system for the evolution and development of the teleost body plan. AB - BACKGROUND: The experimental approach to the evolution and development of the vertebrate skeleton has to a large extent relied on "direct-developing" amniote model organisms, such as the mouse and the chicken. These organisms can however only be partially informative where it concerns secondarily lost features or anatomical novelties not present in their lineages. The widely used anamniotes Xenopus and zebrafish are "indirect-developing" organisms that proceed through an extended time as free-living larvae, before adopting many aspects of their adult morphology, complicating experiments at these stages, and increasing the risk for lethal pleiotropic effects using genetic strategies. RESULTS: Here, we provide a detailed description of the development of the osteology of the African mouthbrooding cichlid Astatotilapia burtoni, primarily focusing on the trunk (spinal column, ribs and epicentrals) and the appendicular skeleton (pectoral, pelvic, dorsal, anal, caudal fins and scales), and to a lesser extent on the cranium. We show that this species has an extremely "direct" mode of development, attains an adult body plan within 2 weeks after fertilization while living off its yolk supply only, and does not pass through a prolonged larval period. CONCLUSIONS: As husbandry of this species is easy, generation time is short, and the species is amenable to genetic targeting strategies through microinjection, we suggest that the use of this direct-developing cichlid will provide a valuable model system for the study of the vertebrate body plan, particularly where it concerns the evolution and development of fish or teleost specific traits. Based on our results we comment on the development of the homocercal caudal fin, on shared ontogenetic patterns between pectoral and pelvic girdles, and on the evolution of fin spines as novelty in acanthomorph fishes. We discuss the differences between "direct" and "indirect" developing actinopterygians using a comparison between zebrafish and A. burtoni development. PMID- 29614959 TI - The constitutive differential transcriptome of a brain circuit for vocal learning. AB - BACKGROUND: The ability to imitate the vocalizations of other organisms, a trait known as vocal learning, is shared by only a few organisms, including humans, where it subserves the acquisition of speech and language, and 3 groups of birds. In songbirds, vocal learning requires the coordinated activity of a set of specialized brain nuclei referred to as the song control system. Recent efforts have revealed some of the genes that are expressed in these vocal nuclei, however a thorough characterization of the transcriptional specializations of this system is still missing. We conducted a rigorous and comprehensive analysis of microarrays, and conducted a separate analysis of 380 genes by in situ hybridizations in order to identify molecular specializations of the major nuclei of the song system of zebra finches (Taeniopygia guttata), a songbird species. RESULTS: Our efforts identified more than 3300 genes that are differentially regulated in one or more vocal nuclei of adult male birds compared to the adjacent brain regions. Bioinformatics analyses provided insights into the possible involvement of these genes in molecular pathways such as cellular morphogenesis, intrinsic cellular excitability, neurotransmission and neuromodulation, axonal guidance and cela-to-cell interactions, and cell survival, which are known to strongly influence the functional properties of the song system. Moreover, an in-depth analysis of specific gene families with known involvement in regulating the development and physiological properties of neuronal circuits provides further insights into possible modulators of the song system. CONCLUSION: Our study represents one of the most comprehensive molecular characterizations of a brain circuit that evolved to facilitate a learned behavior in a vertebrate. The data provide novel insights into possible molecular determinants of the functional properties of the song control circuitry. It also provides lists of compelling targets for pharmacological and genetic manipulations to elucidate the molecular regulation of song behavior and vocal learning. PMID- 29614960 TI - Chair based exercise in community settings: a cluster randomised feasibility study. AB - BACKGROUND: Some older people who find standard exercise programmes too strenuous may be encouraged to exercise while remaining seated - chair based exercises (CBE). We previously developed a consensus CBE programme (CCBE) following a modified Delphi process. We firstly needed to test the feasibility and acceptability of this treatment approach and explore how best to evaluate it before undertaking a definitive trial. METHODS: A feasibility study with a cluster randomised controlled trial component was undertaken to 1. Examine the acceptability, feasibility and tolerability of the intervention and 2. Assess the feasibility of running a trial across 12 community settings (4 day centres, 4 care homes, 4 community groups). Centres were randomised to either CCBE, group reminiscence or usual care. Outcomes were collected to assess the feasibility of the trial parameters: level of recruitment interest and eligibility, randomisation, adverse events, retention, completion of health outcomes, missing data and delivery of the CCBE. Semi- structured interviews were conducted with participants and care staff following the intervention to explore acceptability. RESULTS: 48% (89 out of 184 contacted) of eligible centres were interested in participating with 12 recruited purposively. 73% (94) of the 128 older people screened consented to take part with 83 older people then randomised following mobility testing. Recruitment required greater staffing levels and resources due to 49% of participants requiring a consultee declaration. There was a high dropout rate (40%) primarily due to participants no longer attending the centres. The CCBE intervention was delivered once a week in day centres and community groups and twice a week in care homes. Older people and care staff found the CCBE intervention largely acceptable. CONCLUSION: There was a good level of interest from centres and older people and the CCBE intervention was largely welcomed. The trial design and governance procedures would need to be revised to maximise recruitment and retention. If the motivation for a future trial is physical health then this study has identified that further work to develop the CCBE delivery model is warranted to ensure it can be delivered at a frequency to elicit physiological change. If the motivation for a future trial is psychological outcomes then this study has identified that the current delivery model is feasible. TRIAL REGISTRATION: ISRCTN27271501 . Date registered: 30/01/2018. PMID- 29614962 TI - Daily routine versus on-demand chest radiograph policy and practice in adult ICU patients- clinicians' perspective. AB - BACKGROUND: Chest radiographs are taken daily as a part of routine investigations in Intensive care unit (ICU) patients. They are less effective and unlikely to alter the management of the majority of these patients compared to the radiographs obtained when indicated. According to the American College of Radiology (ACR) Appropriateness criteria, only selective ordering of chest radiographs is recommended, including elderly or high risk patients. The aim of this study was to identify and assess the clinician's perspective in abandoning the current practice of daily routine chest radiograph and replacing with the on demand radiograph in Saudi hospitals. METHODS: This was a cross-sectional study. A valid self-administered questionnaire was distributed to all clinical staff members working in ICUs in the major tertiary hospitals in Saudi Arabia. The study population was primarily the ICU intensivists (physicians), nurses and respiratory therapists (RT). The data collected were statistically processed using SPSS version 20.0; descriptive and inferential analyses were done. RESULTS: Out of 730 questionnaires sent, we received only 495 completed questionnaires with a response rate of 67.8%. Majority of them (n = 351) are working at academic hospitals. About half of the respondents (n = 247) are working in an open-format ICUs. Findings showed that the daily routine chest X-ray was performed in almost 96.8% of ICUs patients, which the majority of the clinical staff members (73%) thought that this current daily routine CXR protocol in the ICUs should be replaced with the on-demand CXR policy. Interestingly, the differences in demographic and work-related characteristics had no significant impact on the clinician's view and supported moving to on-demand CXR policy and practice. CONCLUSIONS: The daily routine CXR is still a common practice in most of the Saudi hospitals ICUs although enough empirical evidence shows that it can be avoided. We observed that intensivists support the change of the current practice and recommend an on-demand CXR policy likely to be followed in intensive care management. PMID- 29614961 TI - Phylogenomics and barcoding of Panax: toward the identification of ginseng species. AB - BACKGROUND: The economic value of ginseng in the global medicinal plant trade is estimated to be in excess of US$2.1 billion. At the same time, the evolutionary placement of ginseng (Panax ginseng) and the complex evolutionary history of the genus is poorly understood despite several molecular phylogenetic studies. In this study, we use a full plastome phylogenomic framework to resolve relationships in Panax and to identify molecular markers for species discrimination. RESULTS: We used high-throughput sequencing of MBD2-Fc fractionated Panax DNA to supplement publicly available plastid genomes to create a phylogeny based on fully assembled and annotated plastid genomes from 60 accessions of 8 species. The plastome phylogeny based on a 163 kbp matrix resolves the sister relationship of Panax ginseng with P. quinquefolius. The closely related species P. vietnamensis is supported as sister of P. japonicus. The plastome matrix also shows that the markers trnC-rps16, trnS-trnG, and trnE trnM could be used for unambiguous molecular identification of all the represented species in the genus. CONCLUSIONS: MBD2 depletion reduces the cost of plastome sequencing, which makes it a cost-effective alternative to Sanger sequencing based DNA barcoding for molecular identification. The plastome phylogeny provides a robust framework that can be used to study the evolution of morphological characters and biosynthesis pathways of ginsengosides for phylogenetic bioprospecting. Molecular identification of ginseng species is essential for authenticating ginseng in international trade and it provides an incentive for manufacturers to create authentic products with verified ingredients. PMID- 29614963 TI - Prevalence of carbapenem-resistant Acinetobacter baumannii from 2005 to 2016 in Switzerland. AB - BACKGROUND: We describe the prevalence of invasive carbapenem-resistant Acinetobacter spp. isolated from 2005 to 2016 in different regions of Switzerland. METHODS: Using the Swiss Antibiotic Resistance Centre (anresis) database that includes data from 70% of all hospitalized patients and one third of all ambulatory practitioners in Switzerland, we analysed the number of carbapenem-susceptible and resistant Acinetobacter spp. isolated from blood or cerebrospinal fluid, and further described their temporal and regional fluctuations. RESULTS: From 2005 to 2016, 58 cases of resistant or intermediate strains to carbapenem were observed among 632 cases of invasive Acinetobacter. Multivariable analyses indicated that the number of carbapenem-resistant isolates (mean 4.8 +/- sd 2.12) and carbapenem resistance rates per region per annum (8.4% +/- 13.9%) were low and stable over the studied period. Large fluctuations were observed at the regional level, with e.g. the North East region displaying resistance rates twice as high as that found in other regions. CONCLUSION: Despite a relatively stable number of carbapenem-resistant Acinetobacter isolates in Switzerland, our results suggest the existence of a diverse pool of A. baumannii species in hospital settings, and confirm the implication of carbapenem resistant Acinetobacter calcoaceticus-Acinetobacter baumannii (ACB) complex in the vast majority of clinical infections and nosocomial outbreaks with notable regional fluctuations. PMID- 29614965 TI - Genetic analysis and clinical assessment of four patients with Glycogen Storage Disease Type IIIa in China. AB - BACKGROUND: Glycogen Storage Disease Type III (GSD III) is a rare autosomal recessive metabolic disorder caused by AGL gene mutation. There is significant heterogeneity between the clinical manifestations and the gene mutation of AGL among different ethnic groups. However, GSD III is rarely reported in Chinese population. CASE PRESENTATION: In this study, we aimed to study the genetic and clinical characteristics of four patients with GSD IIIa from China, especially the neurological manifestations. Meanwhile, we conducted a literature review of GSD IIIa cases reported in Chinese population to investigate the relationship between genotype and phenotype. CONCLUSIONS: Three different AGL gene mutations were identified in our patients: c.206dupA, c.1735 + 1G > T and c.2590 C>T. Moreover, progressive myopathy accompanied by elevated creatine kinase level was the main manifestation of our patients in adolescents. Our results showed that AGL c.206dupA was a novel mutation and caused severe clinical manifestations. AGL c.1735 + 1G > T might be a recurrent mutation in the Chinese population. Genetic analysis of AGL gene mutation combined with muscle magnetic resonance imaging (MRI) might provide greater benefit to the patient in diagnosing GSD IIIa, rather than an invasive diagnostic procedure of biopsy. PMID- 29614964 TI - Spatio-temporal analysis of the relationship between meteorological factors and hand-foot-mouth disease in Beijing, China. AB - BACKGROUND: Hand-foot-mouth disease (HFMD) is a common infectious disease in China and occurs mostly in infants and children. Beijing is a densely populated megacity, in which HFMD has been increasing in the last decade. The aim of this study was to quantify spatio-temporal characteristics of HFMD and the relationship between meteorological factors and HFMD incidence in Beijing, China. METHODS: Daily counts of HFMD cases from January 2010 to December 2012 were obtained from the Beijing Center for Disease Prevention and Control (CDC). Seasonal trend decomposition with Loess smoothing was used to explore seasonal patterns and temporal trends of HFMD. Bayesian spatiotemporal Poisson regression models were used to quantify spatiotemporal patterns of HFMD incidence and associations with meteorological factors. RESULTS: There were 114,777 HFMD cases reported to Beijing CDC from 1 January 2010 to 31 December 2012 and the raw incidence was 568.6 per 100,000 people. May to July was the peak period of HFMD incidence each year. Low-incidence townships were clustered in central, northeast and southwest regions of Beijing. Mean temperature, relative humidity, wind velocity and sunshine hours were all positively associated with HFMD. The effect of wind velocity was significant with a RR of 3.30 (95%CI: 2.37, 4.60) per meter per second increase, as was sunshine hours with a RR of 1.20 (95%CI: 1.02, 1.40) per 1 hour increase. CONCLUSIONS: The distribution of HFMD in Beijing was spatiotemporally heterogeneous, and was associated with meteorological factors. Meteorological monitoring could be incorporated into prediction and surveillance of HFMD in Beijing. PMID- 29614966 TI - Molecular signatures of epithelial oviduct cells of a laying hen (Gallus gallus domesticus) and quail (Coturnix japonica). AB - BACKGROUND: In this work we have determined molecular signatures of oviduct epithelial and progenitor cells. We have proposed a panel of selected marker genes, which correspond with the phenotype of oviduct cells of a laying hen (Gallus gallus domesticus) and quail (Coturnix japonica). We demonstrated differences in characteristics of those cells, in tissue and in vitro, with respect to different anatomical and functional parts of the oviduct (infundibulum (INF), distal magnum (DM, and proximal magnum (PM)). The following gene expression signatures were studied: (1) oviduct markers (estrogen receptor 1, ovalbumin, and SPINK7 - ovomucoid), (2) epithelial markers (keratin 5, keratin 14, and occludin) and (3) stem-like/progenitor markers (CD44 glycoprotein, LGR5, Musashi-1, and sex determining region Y-box 9, Nanog homebox, OCT4/cPOUV gene encoding transcription factor POU5F3). RESULTS: In chicken, the expression of oviduct markers increased toward the proximal oviduct. Epithelial markers keratin14 and occludin were high in distal oviduct and decreased toward the proximal magnum. In quail oviduct tissue, the gene expression pattern of oviduct/epithelial markers was similar to chicken. The markers of progenitors/stemness in hen oviduct (Musashi-1 and CD44 glycoprotein) had the highest relative expression in the infundibulum and decreased toward the proximal magnum. In quail, we found significant expression of four progenitor markers (LGR5 gene, SRY sex determining region Y-box 9, OCT4/cPOUV gene, and CD44 glycoprotein) that were largely present in the distal oviduct. After in vitro culture of oviduct cells, the gene expression pattern has changed. High secretive potential of magnum-derived cells diminished by using decreased abundance of mRNA. On the other hand, chicken oviduct cells originating from the infundibulum gained ability to express OVM and OVAL. Epithelial character of the cells was maintained in vitro. Among progenitor markers, both hen and quail cells expressed high level of SOX9, LGR5 and Musashi-1. CONCLUSION: Analysis of tissue material revealed gradual increase/decrease pattern in majority of the oviduct markers in both species. This pattern changed after the oviductal cells have been cultured in vitro. The results can provide molecular tools to validate the phenotype of in vitro biological models from reproductive tissue. PMID- 29614967 TI - Cardiovascular outcomes of Nephrotic syndrome in childhood (CVONS) study: a protocol for prospective cohort study. AB - BACKGROUND: Nephrotic syndrome (NS) is characterized by dyslipidemia which is a well-known risk factor for atherogenesis. Atherosclerosis in childhood is mostly subclinical and endothelial dysfunction is known to precede this. Evidence for screening for endothelial dysfunction and cardiovascular risk factors and early identification of premature onset of atherosclerosis in childhood NS remains tenuous in the absence of well-designed prospective studies addressing cardiovascular comorbidity in NS. The objective of our study is to examine endothelial dysfunction and short-term cardiovascular outcomes in a carefully phenotyped cohort of patients with Nephrotic syndrome as compared to healthy controls. METHODS: In a multi-centric prospective cohort study, 70 Steroid Resistant NS (SRNS), 70 Steroid Sensitive (SSNS) patients along with 70 Healthy Controls are being recruited. After a baseline assessment of functional and structural status of heart (2D Echocardiography), arteries (Carotid Doppler and Intima Media Thickness measurements) and microcirculation [a combination of 2D Echocardiography, Laser Doppler Flowmetry (LDF) and Brachial Artery Flow mediated dilation (FMD) and Nail Fold Capillaroscopy (NFC)], the patients are being investigated for endothelial dysfunction. Venous blood sample (15 ml) is being collected for routine investigations and assay of biochemical endothelial markers through Flow Cytometry. The patients will be followed up at 12 months and 24 months after the recruitment to look for any change from baseline period. DISCUSSION: This study will able to provide a better understanding of the epidemiology of endothelial dysfunction and associated subclinical cardiovascular co-morbidity in childhood NS. Findings on characterization of prevalence of endothelial dysfunction and subclinical markers may be used to design future randomized controlled trials for evaluating the efficacy of preventive and therapeutic interventions in reducing the incidence of cardiovascular disease. PMID- 29614968 TI - Biological clocks and physical functioning in monozygotic female twins. AB - BACKGROUND: Biomarkers of biological aging - DNA methylation age (DNAm age) and leukocyte telomere length (LTL)- correlate strongly with chronological age across the life course. It is, however, unclear how these measures of cellular wear and tear are associated with muscle strength and functional capacity, which are known to decline with older age and are associated with mortality. We investigated if DNAm age and LTL were associated with body composition and physical functioning by examining 48 monozygotic twin sisters. METHODS: White blood cell DNAm age (predicted years) was calculated from Illumina 450 k BeadChip methylation data using an online calculator. DNAm age acceleration was defined from the residuals derived from a linear regression model of DNAm age on chronological age. LTL was measured by qPCR. Total body percentage of fat and lean mass were estimated using bioimpedance. Physical functioning was measured by grip strength, knee extension strength and by 10 m maximal walking speed test. RESULTS: In all participants, DNAm age (58.4 +/- 6.6) was lower than chronological age (61.3 +/- 5.9 years). Pairwise correlations of monozygotic co-twins were high for DNAm age (0.88, 95% CI 0.79, 0.97), age acceleration (0.68, 95% CI 0.30, 0.85) and LTL (0.77, 95% CI 0.60, 0.94). Increased age acceleration i.e. faster epigenetic aging compared to chronological age was associated with lower grip strength (beta = - 5.3 SE 1.9 p = 0.011), but not with other measures of physical functioning or body composition. LTL was not associated with body composition or physical functioning. CONCLUSIONS: To conclude, accelerated DNAm age is associated with lower grip strength, a biomarker known to be associated with physiological aging, and which predicts decline in physical functioning and mortality. Further studies may clarify whether epigenetic aging explains the decline in muscle strength with aging or whether DNAm age just illustrates the progress of aging. PMID- 29614969 TI - 27-Hydroxycholesterol increases alpha-synuclein protein levels through proteasomal inhibition in human dopaminergic neurons. AB - BACKGROUND: Accumulation of the alpha-synuclein (alpha-syn) protein is a hallmark of a group of brain disorders collectively known as synucleinopathies. The mechanisms responsible for alpha-syn accumulation are not well understood. Several studies suggest a link between synucleinopathies and the cholesterol metabolite 27-hydroxycholesterol (27-OHC). 27-OHC is the major cholesterol metabolite in the blood that crosses the blood brain barrier, and its levels can increase following hypercholesterolemia, aging, and oxidative stress, which are all factors for increased synucleinopathy risk. In this study, we determined the extent to which 27-OHC regulates alpha-syn levels in human dopaminergic neurons, the cell type in which alpha-syn accumulates in PD, a major synucleinopathy disorder. RESULTS: Our results show that 27-OHC significantly increases the protein levels, not the mRNA expression of alpha-syn. The effects of 27-OHC appear to be independent of an action through liver X receptors (LXR), its cognate receptors, as the LXR agonist, GW3965, or the LXR antagonist ECHS did not affect alpha-syn protein or mRNA levels. Furthermore, our data strongly suggest that the 27-OHC-induced increase in alpha-syn protein levels emanates from inhibition of the proteasomal degradation of this protein and a decrease in the heat shock protein 70 (HSP70). CONCLUSIONS: Identifying 27-OHC as a factor that can increase alpha-syn levels and the inhibition of the proteasomal function and reduction in HSP70 levels as potential cellular mechanisms involved in regulation of alpha-syn. This may help in targeting the correct degradation of alpha-syn as a potential avenue to preclude alpha-syn accumulation. PMID- 29614970 TI - A novel citrate-based protocol versus heparin anticoagulation for sustained low efficiency dialysis in the ICU: safety, efficacy, and cost. AB - BACKGROUND: The high cost, complexity of the available protocols, and metabolic complications are the major barriers that impede the clinical utilization of regional citrate anticoagulation (RCA) for sustained low efficiency dialysis (SLED) in critically ill patients. By comparing a novel protocol for SLED using 30% citrate solution with common protocol using unfractionated heparin, this study aimed to provide new insights for clinical applications of RCA. METHODS: In this retrospective study, a total of 282 critically ill patients who underwent SLED with citrate and/or heparin anticoagulation in six adult ICUs were enrolled. These patients were divided into three groups based on the anticoagulation regimens they had received during the treatment in ICU: Group 1 (Citrate) had only received treatment with citrate anticoagulation (n=75); Group 2 (Heparin) only with heparin anticoagulation (n=79); and Group 3 (Both) with both citrate and heparin anticoagulation (n=128). We compared the mortality, metabolic complications as well as cost among these groups using different anticoagulation regimens. RESULTS: The in-hospital mortality did not significantly differ among groups (p> 0.1). However, three patients in heparin group suffered from severe bleeding which led to death, while none in citrate group. Overall, 976 SLED sessions with heparin anticoagulation and 808 with citrate were analyzed. The incidence of extracorporeal circuit clotting was significantly less in citrate (5%), as compared to that in heparin (10%) (p< 0.001). Metabolic complications and hypotension which led to interruption of SLED occurred more frequently, though not significantly, in citrate (p= 0.06, p= 0.23). Furthermore, with 30% citrate solution, the cost of anticoagulant was reduced by 70% in comparison to previously reported protocol using Acid Citrate Dextrose solution A (ACD-A). CONCLUSIONS: Our results indicated that anticoagulation regimens for SLED did not significantly affect the mortality of patients. Citrate anticoagulation was superior to heparin in preventing severe bleeding and circuit clotting. The protocol adopted in this study using 30% citrate solution was safe as well as efficacious. In the meantime, it was much more cost-efficient than other citrate based protocol. PMID- 29614971 TI - Paradox lost on the U.S.-Mexico border: U.S. Latinas and cesarean rates. AB - BACKGROUND: We apply Intersectional Theory to examine how compounded disadvantage affects the odds of women having a cesarean in U.S.-Mexico border hospitals and in non-border hospitals. We define U.S. Latinas with compounded disadvantage as those who have neither a college education nor private health insurance. RESULTS: Analyzing quantitative and qualitative data from Childbirth Connection's Listening to Mothers III Survey, we find that, consistent with the notion of the Latinx Health Paradox, compounded disadvantage serves as a protective buffer and decreases the odds of cesarean among women in non-border hospitals. However, the Latinx Health Paradox is absent on the border. CONCLUSION: Our data show that women with compounded disadvantage who give birth on the border have significantly higher odds of a cesarean compared to women without such disadvantage. Further, women with compounded disadvantage who give birth in border hospitals report receiving insufficient prenatal, pregnancy, and postpartum information, providing a direction for future research to explain the border disparity in cesareans. PMID- 29614972 TI - Aortic stenosis is a risk factor for all-cause mortality in patients on dialysis: a multicenter prospective cohort analysis. AB - BACKGROUND: Aortic stenosis (AS) is common in patients on dialysis as well as in the general population. AS leads to difficulty with dialysis therapy because of unstable conditions such as intradialytic hypotension due to low cardiac output. However, the precise morbidity rates and risk factors of AS in patients on dialysis are unknown. Moreover, there are no large-scale observational studies regarding the association between AS in patients on dialysis and mortality. Therefore, we will investigate whether morbidity of AS in patients on dialysis is associated with mortality. METHODS: This is a multicenter prospective cohort analysis in the Tokai region of Japan. The 75 participating centers in this study will enroll approximately 2400 patients during 12 months, with or without AS. We started enrollment in July 2017 and will follow patents until June 2023. Transthoracic echocardiography will be performed to evaluate aortic valve. Parameters used for evaluation of aortic valve are mean pressure gradient between left ventricle and ascending aorta, aortic valve area, and maximum aortic jet velocity. We will diagnose AS using the criteria based on the 2014 American Heart Association/ American College of Cardiology Guideline. We will also perform transthoracic echocardiography at 12, 24, 36, 48, and 60 months. Survival prognosis and CV events will be determined at the end of June 2019, 2020, 2021, 2022, and 2023. Development of AS will be also evaluated as new onset or annual change in AS parameters. We will classify patients based on the presence or absence of AS and the stages of AS and will compare outcomes. Study outcomes will include the following: 1) all-cause mortality rates; 2) incidence of cardiovascular (CV) events; 3) CV-related mortality rates; 4) infection-related mortality rates; 5) new onset or development of AS. DISCUSSION: We will consider the following hypotheses in this study, among others: The prevalence of AS is higher in dialysis patients; new onset and development of AS are associated with factors that are specific for dialysis, such as hyperphosphatemia, hyperparathyroidism, and medication; and outcomes in AS patients are poorer than in patients without AS at baseline. TRIAL REGISTRATION: UMIN000026756 , Registered March 29 2017. PMID- 29614973 TI - In vitro antibacterial activity of bioactive glass S53P4 on multiresistant pathogens causing osteomyelitis and prosthetic joint infection. AB - BACKGROUND: Conventional local treatment for medullary osteomyelitis (OM) includes insertion of antibiotic-loaded polymethylmethacrylate (PMMA) cement. Nevertheless, PMMA may delivery irregular concentration of antibiotic to surrounding tissue. We aimed to compare the in vitro antibacterial activity of Bioactive Glass (BAG) S53P4, which is a compound showing local antibacterial activity, to that of antibiotic-loaded PMMA against multidrug resistant bacteria from OM isolates. METHODS: We studied convenience samples of multidrug resistant (MDR) microorganisms obtained from patients presenting OM and prosthetic joint infection (PJI). Mixtures containing tryptic soy broth (TSB) and inert glass beads (2 mm), BAG-S53P4 granules (0.5-0.8 mm and < 45 mm) and Gentamicin or Vancomycin-loaded PMMA beads were inoculated with methicillin-resistant Staphylococcus aureus (MRSA) and methicillin-resistant coagulase-negative Staphylococcus (MR-CoNS), Pseudomonas aeruginosa or Klebsiella pneumoniae isolates. Glass beads (2.0 mm) were used as a control. Antibacterial activity was evaluated by means of time-kill curve, through seeding the strains on blood agar plates, and subsequently performing colony counts after 24, 48, 72, 96, 120 and 168 h of incubation. Differences between groups were evaluated by means of two way analysis of variance (ANOVA) and Bonferroni's t test. RESULTS: Inhibition of bacterial growth started soon after 48 h of incubation, reached zero CFU/ml between 120 and 168 h of incubation for both antibiotic-loaded PMMA and BAG S53P4 groups, in comparison with inert glass (p < 0.05). No difference regarding time kill curves between antibiotic-loaded PMMA and BAG S53P4 was observed. CONCLUSIONS: BAG S53P4 presented antibacterial properties as much as antibiotic loaded PMMA for MDR bacteria producing OM and PJI. PMID- 29614975 TI - Evolutionary transitions in body plan and reproductive mode alter maintenance metabolism in squamates. AB - BACKGROUND: Energy (resources) acquired by animals should be allocated towards competing demands, maintenance, growth, reproduction and fat storage. Reproduction has the second lowest priority in energy allocation and only is allowed after meeting the energetic demands for maintenance and growth. This hierarchical allocation of energy suggests the hypothesis that species or taxa with high maintenance costs would be less likely to invest more energy in reproduction or to evolve an energetically more expensive mode of reproduction. Here, we used data on standard metabolic rate so far reported for 196 species of squamates to test this hypothesis. RESULTS: We found that maintenance costs were lower in snakes than in lizards, and that the costs were lower in viviparous species than in oviparous species. As snakes generally invest more energy per reproductive episode than lizards, and viviparity is an energetically more expensive mode of reproduction than oviparity, our results are consistent with the hypothesis tested. CONCLUSION: The transition from lizard-like to snake-like body form and the transition from oviparity to viviparity are major evolutionary transitions in vertebrates, which likely alter many aspects of biology of the organisms involved. Our study is the first to demonstrate that evolutionary transitions in body plan and reproductive mode alter maintenance metabolism in squamates. PMID- 29614974 TI - The Antarctic sea ice alga Chlamydomonas sp. ICE-L provides insights into adaptive patterns of chloroplast evolution. AB - BACKGROUND: The ice alga Chlamydomonas sp. ICE-L is the main contributor to primary productivity in Antarctic sea ice ecosystems and is well adapted to the extremely harsh environment. However, the adaptive mechanism of Chlamydomonas sp. ICE-L to sea-ice environment remains unclear. To study the adaptive strategies in Chlamydomonas sp. ICE-L, we investigated the molecular evolution of chloroplast photosynthetic genes that are essential for the accumulation of carbohydrate and energy living in Antarctic sea ice. RESULTS: The 60 chloroplast protein-coding genes of Chlamydomonas sp. ICE-L were obtained, and the branch-site test detected significant signatures of positive selection on atpB, psaB, and rbcL genes in Chlamydomonas sp. ICE-L associated with the photosynthetic machinery. These positively selected genes were further identified as being under convergent evolution between Chlamydomonas sp. ICE-L and the halotolerant alga Dunaliella salina. CONCLUSIONS: Our study provides evidence that the phototrophic component of Chlamydomonas sp. ICE-L exhibits adaptive evolution under extreme environment. The positive Darwinian selection operates on the chloroplast protein-coding genes of Antarctic ice algae adapted to extreme environment following functional specific and lineages-specific patterns. In addition, three positively selected genes with convergent substitutions in Chlamydomonas sp. ICE-L were identified, and the adaptive modifications in these genes were in functionally important regions of the proteins. Our study provides a foundation for future experiments on the biochemical and physiological impacts of photosynthetic genes in green algae. PMID- 29614976 TI - Primary results of abdominal aortic aneurysm screening in the at-risk residents in middle China. AB - BACKGROUND: There is a lack of information on the epidemiological data and risk factors associated with abdominal aortic aneurysm (AAA) in Chinese population. We reported the primary results from screening five-community population in Middle China for AAA. METHODS: From March 2014 to October 2015, an AAA screening program was performed in three urban and two rural communities. These communities were randomly selected. All at-risk residents (a total of 6925) aged 40 years or older were invited to attend an ultrasound scan for AAA. At-risk population was defined as having a family history of first-degree relative diagnosed with AAA; or smoking and aged 55 years or older; or having a history of CAD, cerebrovascular disease, hypercholesterolemia, obesity (BMI ? 26 kg/m2) or hypertension. RESULTS: The study investigated 5402 subjects and the mean age of them was 61.2 +/- 10.4 years old. It included 2847 women aged 62.5 +/- 10.4 years and 2555 men aged 59.7 +/- 10.2 years. The mean maximum infrarenal aortic diameter (Max-IAD) was 15.0 +/ 2.7 mm (from 4.1 to 51.5 mm). Eighteen people (aged 68.0 +/- 10.4 years) with AAAs were detected (prevalence rate was 0.33%), and the prevalence rate in males was higher than in females (0.55% vs 0.14%, respectively, P = 0.009). Additionally, the screened subjects aged 55 to 75 years had a higher prevalence rate of AAA than other age groups (0.51% vs 0.11%, respectively, P = 0.016). CONCLUSION: The mean Max-IAD of the screened population in Middle China was apparently small by comparison with other reports. The result of low prevalence rate of AAA didn't support routine screening in Chinese population. The at-risk males aged 55 to 75 years should be targeted for further screening. PMID- 29614977 TI - Diagnostic behaviour of general practitioners when suspecting Lyme disease: a database study from 2010-2015. AB - BACKGROUND: Due to the raised public awareness of Lyme Borreliosis (LB), its increased incidence and the increased availability of serological tests, the demand for diagnostic testing on LB has increased. This may affect the diagnostic behaviour of general practitioners (GPs). Aim of our study was to describe GPs' diagnostic behaviour when suspecting LB. METHODS: In this descriptive study from January 2010 to June 2015, we used the anonymized electronic medical records of 56,996 patients registered in 12 general practices in Amsterdam, The Netherlands. The target population was identified by means of an extensive search strategy, based on International Classification of Primary Care (ICPC-1) codes, free text and diagnostic test codes. All contacts related to LB were included in the analysis. RESULTS: 2311 patients were included, accounting for 3861 LB contacts and 2619 LB episodes. The distribution of LB contacts showed annual peaks during spring and summer. Serological testing was performed in 36.4% of LB episodes and was mostly requested in patients presenting with general symptoms (71.4%). Unnecessary testing often occurred and only 5.9% of the tests turned out to be positive by immunoblot. From January 2010 to June 2015, no significant differences were found in the number of requested serological tests. The level of serological testing during LB episodes differed significantly between the general practices (19.2% to 75.8%). CONCLUSIONS: Contrary to clinical guidelines, GPs regularly requested serology even when there was a low suspicion of LB. The development of an easy-to-use diagnostic algorithm may decrease overuse of diagnostic tests and thereby reduce overtreatment of LB. PMID- 29614978 TI - A 35-gene signature discriminates between rapidly- and slowly-progressing glioblastoma multiforme and predicts survival in known subtypes of the cancer. AB - BACKGROUND: Gene expression can be employed for the discovery of prognostic gene or multigene signatures cancer. In this study, we assessed the prognostic value of a 35-gene expression signature selected by pathway and machine learning based methods in adjuvant therapy-linked glioblastoma multiforme (GBM) patients from the Cancer Genome Atlas. METHODS: Genes with high expression variance was subjected to pathway enrichment analysis and those having roles in chemoradioresistance pathways were used in expression-based feature selection. A modified Support Vector Machine Recursive Feature Elimination algorithm was employed to select a subset of these genes that discriminated between rapidly progressing and slowly-progressing patients. RESULTS: Survival analysis on TCGA samples not used in feature selection and samples from four GBM subclasses, as well as from an entirely independent study, showed that the 35-gene signature discriminated between the survival groups in all cases (p<0.05) and could accurately predict survival irrespective of the subtype. In a multivariate analysis, the signature predicted progression-free and overall survival independently of other factors considered. CONCLUSION: We propose that the performance of the signature makes it an attractive candidate for further studies to assess its utility as a clinical prognostic and predictive biomarker in GBM patients. Additionally, the signature genes may also be useful therapeutic targets to improve both progression-free and overall survival in GBM patients. PMID- 29614979 TI - Gynecologic cancer survivor preferences for long-term surveillance. AB - BACKGROUND: With ongoing healthcare reform and shrinking numbers of oncologists, appropriate triaging of gynecologic cancer survivor care is crucial. Input from patients is a necessary part of this task. The objective of this study was to assess the preferences of gynecologic cancer survivors for surveillance after the completion of treatment. METHODS: A 38-item questionnaire was developed and launched in conjunction with the Foundation for Women's Cancer (FWC). All women who registered as gynecologic cancer survivors with the FWC were invited to participate. Patients were asked about physician preferences for multiple symptoms and diagnoses, and when they felt comfortable transferring care out of their oncologists' offices. Analyses were performed with chi-square and logistic regression. RESULTS: Six hundred twenty four patients completed the questionnaire. Sixty six percent had ovarian cancer, and 86% were primarily treated by a gynecologic oncologist. Fifty seven percent of the respondents reported being unwilling to see a physician other than their oncologist for survivorship care at any time. Women age > 60 years were less willing to leave their oncologists for survivorship care at any time compared to younger women (OR 1.53 [95% CI 1.03-2.27], p = 0.03). Ovarian cancer survivors were also more likely to report a desire to stay with their oncologists compared with uterine cancer survivors (p < 0.001). With few exceptions, respondents preferred management of non-oncologic medical problems by their oncologists. CONCLUSIONS: Gynecologic cancer survivors prefer that their oncologists remain heavily involved in survivorship care. Reconciling patient needs with physician and financial constraints will be a challenge as the survivor population continues to grow. PMID- 29614980 TI - Chemoradiotherapy versus chemotherapy as adjuvant treatment for localized gastric cancer: a propensity score-matched analysis. AB - BACKGROUND: Treatment of localized gastric cancer (LGC) consists of surgical resection followed by adjuvant treatment. Both chemoradiation (CRT) and chemotherapy (CT) regimens have shown benefit in survival outcomes versus observation. However, there are few data comparing these approaches. METHODS: This study included consecutive patients with LGC treated at Instituto do Cancer do Estado de Sao Paulo (ICESP) from 2012 to 2015. CRT was based on the INT-0116 regimen and CT consisted of a platinum and fluoropyrimidine doublet. Treatment choice was based on physician preference. Toxicity was evaluated for every cycle. Overall survival (OS) analysis was performed by Kaplan-Meier. A propensity score matched analysis was performed to minimize selection bias. RESULTS: A total of 309 patients were evaluated, 227 in CRT group and 82 in CT group. The most prevalent grade 3/4 toxicities in CRT and CT groups were: nausea/vomiting (9.25 vs 4.9%), fatigue (9.3% vs 2.4%), mucositis (4.4% vs 1.2%), neutropenia (37.8% vs 20.9%), febrile neutropenia (3.9% vs 0%), anemia (4.3% vs 6.1%), thrombocytopenia (2.6% vs 4.9%), neuropathy (0 vs 2.4%) and hand-foot syndrome (0.4% vs 2.4%). Two grade 5 toxicities (febrile neutropenia and anemia) occurred in CRT group. There was no difference in the pattern of recurrence. After a median follow-up of 23.5 months (CRT) and 20.6 months (CT), there was no difference in OS between groups. CONCLUSIONS: CT and CRT present similar efficacy and tolerability as adjuvant treatment for LGC. PMID- 29614981 TI - A comparison of the local immune status between the primary and metastatic tumor in colorectal cancer: a retrospective study. AB - BACKGROUND: The anticancer immune response has been reported to correlate with cancer progression. Tumor-infiltrating lymphocytes (TILs), which are one of the indicators of host immunity, affect the tumor growth, metastasis and chemoresistance. Both TILs in the primary tumor and those in the metastatic tumor have been reported to be a useful predictor of the survival and therapeutic outcome. However, the correlation between the density of TILs in the primary and metastatic tumor is unclear. The aim of this study was to elucidate the correlation between the density of TILs in the primary and metastatic tumor. METHODS: A total of 24 patients with stage IV colorectal cancer who underwent concurrent resection of the primary tumor and liver metastasis were enrolled in order to assess the correlation between the density of TILs in the primary tumor and that in the metastatic tumor. Hematoxylin and eosin (HE)-stained tumor sections were used for the evaluation of TILs. The density of TILs was assessed by the measurement of the area occupied by mononuclear inflammatory cells over the total stromal area at the invasive margin. In addition, to evaluate TIL subsets and the activation/suppression status of the lymphocytes, immunohistochemistry for CD4, CD8, Forkhead boxprotein P3 (FOXP3), programmed cell death 1 (PD-1), cytotoxic T-lymphocyte-associated protein 4 (CTLA4), inducible T-cell co-stimulator (ICOS), Glucocorticoid induced tumor necrosis factor receptor related protein (GITR), Human Leukocyte Antigen - antigen D Related (HLA-DR) and Granzyme B was performed, and the number of immunoreactive lymphocytes was counted. RESULTS: According to the evaluation using the HE stained sections, the density of tumor-infiltrating mononuclear inflammatory cells in the primary tumor was significantly associated with that in the metastatic tumor. In addition, according to the immunohistochemistry evaluation, the density of CD4+, CD8+ and FOXP3+ TILs in the primary tumor and that in the metastatic tumor were significantly correlated with that in the metastatic tumor. Furthermore, the activation/suppression marker values of the lymphocytes (i.e., such as PD-1, ICOS, Granzyme B and the PD-1/CD8 ratio) in the primary tumor were correlated with values in the metastatic tumor. CONCLUSIONS: The local immune status of the primary tumor was revealed to be similar to that of the metastatic tumor. This suggests that the evaluation of the local immunity of the primary tumor may be a substitute for the evaluation of the local immunity of the metastatic lesion. Therefore, information on the primary tumor may be useful when considering treatment strategies for metastatic lesions. PMID- 29614982 TI - How to customize a bona fide psychotherapy for generalized anxiety disorder? A two-arms, patient blinded, ABAB crossed-therapist randomized clinical implementation trial design [IMPLEMENT 2.0]. AB - BACKGROUND: Bona fide psychotherapy approaches are effective treatments for generalized anxiety disorder (GAD) compared to no-treatment conditions. Treatment manuals and protocols allow a relatively high degree of freedom for the way therapists implement these overall treatment packages and there is a systematic lack of knowledge on how therapists should customize these treatments. The present study experimentally examines two implementation strategies of customizing a bona fide psychotherapy approach based on a 16 session time-limited cognitive-behavioral therapy (CBT) protocol and their relation to the post session and ultimate treatment outcomes. METHODS: This trial contrasts two different implementation strategies of how to customize the in-session structure of a manual-based CBT-protocol for GAD. The patients will be randomly assigned to two implementation conditions: (1) a systematic focus on subtle changes lasting from 7 to 20 min at the check-in phase of every psychotherapy session and (2) a state-of-the-art (SOTA) check-in phase lasting several minutes mainly focused on the session goals. Potential therapist effects will be examined based on an ABAB crossed-therapist design. Treatment outcomes will be assessed at the following times: post-session outcomes, treatment outcome at post assessment and 6- as well as 12-month follow-up. DISCUSSION: The proposed randomized clinical implementation trial addresses the clinically relevant question of how to customize a bona fide psychotherapy protocol experimentally contrasting two implementation strategies. Through the development and testing of the proposed implementation design, this trial has the potential to inform therapists about efficacious implementation strategies of how to customize a manual-based treatment protocol in respect to the timing of the in-session structure. TRIAL REGISTRATION: This trial was registered at ClinicalTrials.gov ( NCT03079336 ) at March 14, 2017. PMID- 29614983 TI - Compared characteristics of current vs. past smokers at the time of diagnosis of a first-time lung or head and neck cancer: a cross-sectional study. AB - BACKGROUND: Active smoking at the time of diagnosis of a first head & neck (H&N) or lung cancer is associated with a worse cancer outcome and increased mortality. However, the compared characteristics of active vs. former smokers at cancer diagnosis are poorly known. METHODS: In 371 subjects with a first H&N or lung cancer, we assessed: 1) socio-demographic features; 2) lifelong types of smoking; 3) alcohol use disorder identification test (AUDIT); 4) cannabis abuse screening test (CAST); and 5) Mini International Neuropsychiatric Interview (MINI). Using a multivariable regression model, we compared the profile of current smokers and past smokers. RESULTS: Current smokers more frequently exhibited H&N cancer (OR 3.91; 95% CI [2.00-6.51]; p < 0.0001) and ever smoking of hand-rolled cigarettes (OR 2.2; 95% CI [1.25-3.88]; p = 0.007). Among subjects with lung cancer (n = 177), current smoking was primarily associated with ever smoking of hand-rolled cigarettes (OR 2.88; 95% CI [1.32-6.30]; p = 0.008) and negatively associated with age (OR 0.92; 95% CI [0.89-0.96]; p < 0.001). Among subjects with H&N cancer (n = 163), current smokers exhibited a significantly greater AUDIT score (OR = 1.08; 95% CI [1.01-1.16]; p = 0.03). CONCLUSION: At the time of diagnosis of the first lung or H&N cancer, current smoking is highly associated with previous type of smoking and alcohol drinking patterns. TRIAL REGISTRATION: NCT01647425 ; Registration date: July 23, 2012. PMID- 29614984 TI - Up-regulation of ceRNA TINCR by SP1 contributes to tumorigenesis in breast cancer. AB - BACKGROUND: Assembling evidences suggested that aberrant expression of tissue differentiation-inducing non-protein coding RNA (TINCR) intimately associated with variety of human cancer. However, the expression pattern and involvement of TINCR in breast cancer has not been fully investigated. Here we set out to analyze expression of TINCR in breast cancer and elucidate its mechanistic involvement in tumor incidence and progression. METHODS: The expression of TINCR was determined by q-PCR. SP1 binding sites were analyzed by ChIP-qPCR. The relative transcription activity was measured with luciferase reporter assay. Cell viability was measured with CCK-8 method. Clonogenic capacity was evaluated by soft agar assay. Cell apoptosis was analyzed by Annexin V/7-AAD staining. The migration and invasion were determined by trans-well assay and wound healing. The tumor growth in vivo was evaluated in xenograft mice model. Protein expression was quantified by immunoblotting. RESULTS: TINCR was aberrantly up-regulated by SP1, which in turn stimulated cell proliferation, anchorage-independent growth and suppressed cell apoptosis in breast cancer. TINCR silencing significantly suppressed migration and invasion in vitro and xenograft tumor growth in vivo. Mechanistically, TINCR modulated KLF4 expression via competing with miR-7, which consequently contributed to its oncogenic potential. MiR-7 inhibition severely compromised TINCR silencing-elicited tumor repressive effects. CONCLUSION: Our data uncovered a crucial role of TINCR-miR-7-KLF4 axis in human breast cancer. PMID- 29614985 TI - Modeling treatment-dependent glioma growth including a dormant tumor cell subpopulation. AB - BACKGROUND: Tumors comprise a variety of specialized cell phenotypes adapted to different ecological niches that massively influence the tumor growth and its response to treatment. METHODS: In the background of glioblastoma multiforme, a highly malignant brain tumor, we consider a rapid proliferating phenotype that appears susceptible to treatment, and a dormant phenotype which lacks this pronounced proliferative ability and is not affected by standard therapeutic strategies. To gain insight in the dynamically changing proportions of different tumor cell phenotypes under different treatment conditions, we develop a mathematical model and underline our assumptions with experimental data. RESULTS: We show that both cell phenotypes contribute to the distinct composition of the tumor, especially in cycling low and high dose treatment, and therefore may influence the tumor growth in a phenotype specific way. CONCLUSION: Our model of the dynamic proportions of dormant and rapidly growing glioblastoma cells in different therapy settings suggests that phenotypically different cells should be considered to plan dose and duration of treatment schedules. PMID- 29614986 TI - Rapunzel syndrome: an infrequent cause of severe iron deficiency anemia and abdominal pain presenting to the pediatric emergency department. AB - BACKGROUND: Iron deficiency anemia (IDA) and abdominal pain are commonly seen in a pediatric emergency department (8 and 18% incidence respectively in our center). They are manifestations of a wide variety of diseases ranging from benign to immediately life-threatening. Trichobezoar is an under-diagnosed entity that has to be considered in children and adolescents, expecially female, suffering from trichotillomania (compulsion to pull hair) and trichophagy (compulsion to swallow hair). When undiagnosed, gastric bezoars may cause gastric ulceration, perforation, haemorrhage and obstruction. CASE PRESENTATION: To underline the importance of including this pathology in the differential diagnosis of IDA and abdominal pain, we present the case of a 14 year-old girl with a huge trichobezoar which completely filled the stomach and extended into the small bowel. Since trichobezoar has an extension to the small bowel, it is classified as Rapunzel syndrome. As the bezoar couldn't be removed by endoscopy, the girl underwent surgical intervention. The patient passed through a gradual re feeding, with iron and vitamins supplementation, and through a psychiatric counselling. CONCLUSION: The Rapunzel syndrome is a rare entity that may be complicated by life-threatening events. A prompt diagnosis and an appropriate therapy can reduce comorbidities. Gradual re-feeding with supplementation of micronutrients allows adequate catch-up weight with normalization of haematochemical nutritional parameters. Since many of these patients suffer from psychiatric pathology such as PICA with emotional problems and mental retardation, psychological/psychiatric counselling plays an important role in order to prevent bezoar recurrence. PMID- 29614987 TI - The silent burden of stigmatisation: a qualitative study among Dutch people with a low socioeconomic position. AB - BACKGROUND: In-depth qualitative research into perceived socioeconomic position related stigmatisation among people living at the lower end of our socioeconomic hierarchy is necessary for getting more insight in the possible downside of living in an increasingly meritocratic and individualistic society. METHODS: Seventeen interviews were conducted among a group of Dutch people with a low socioeconomic position to examine their experiences with stigmatisation, how they coped with it and what they perceived as consequences. RESULTS: Social reactions perceived by participants related to being inferior, being physically recognisable as a poor person, and being responsible for their own financial problems. Participants with less experience of living in poverty, a heterogeneous social network and greater sense of financial responsibility seemed to be more aware of stigmas than people with long-term experience of poverty, a homogeneous social network and less sense of financial responsibility. Perceived stigmatisation mainly had emotional consequences. To maintain a certain level of self-respect, participants tried to escape from reality, showed their strengths or confronted other people who expressed negative attitudes towards them. CONCLUSION: Despite the good intentions of policies to enhance self-reliance, responsibility and active citizenship, these policies and related societal beliefs might affect people at the lower end of our socioeconomic hierarchies by making them feel inferior, ashamed and blamed, especially when they cannot meet societal expectations or when they feel treated disrespectfully, unjustly or unequally by social workers or volunteers of charity organisations. PMID- 29614988 TI - Altered monocyte differentiation and macrophage polarization patterns in patients with breast cancer. AB - BACKGROUND: Macrophage heterogeneity is the main feature of the tumour microenvironment. Breast cancer is one of the most life-threatening cancers. However, macrophage polarization patterns in different tumour stages and the importance of its relationship to human epidermal growth factor receptor 2 (HER2) in breast cancer remains highly unclear. The present study investigated the patterns of monocyte differentiation and macrophage polarization in breast cancer. METHODS: Patients with breast cancer (n = 48) and healthy controls (n = 39) were prospectively recruited. The percentages and subsets of circulating macrophage-like cells were analysed by flow cytometry, and the polarization patterns of these cells in the peripheral blood of patients with breast cancer were compared with those of healthy controls. In addition, macrophage polarization patterns in different stages and HER2 status in breast cancer were investigated. RESULTS: The percentages of circulating macrophages, which are defined as PM-2 K+ cells in the peripheral blood, were significantly higher in patients with breast cancer than in healthy controls. The percentages of M1-like macrophages were significantly lower, but those of M2-like macrophages were significantly higher in patients with breast cancer than in healthy controls. The percentage of M2c-like macrophages was significantly higher in advanced (stages II and III) breast cancer. However, the patterns of macrophage polarization were not associated with HER2 status in breast cancer. CONCLUSIONS: Aberrant macrophage polarization was observed in breast cancer and was correlated with breast cancer stage. These quantitative data may provide new molecular biomarkers and potential therapeutic targets in breast cancer. PMID- 29614989 TI - Using the ages and stages questionnaire in the general population as a measure for identifying children not at risk of a neurodevelopmental disorder. AB - BACKGROUND: Early detection of neurodevelopmental disorders (NDDs) enables access to early interventions for children. We assess the Ages and Stages Questionnaire (ASQ)'s ability to identify children with a NDD in population data. METHOD: Children 4 to 5 years old in the National Longitudinal Survey of Children and Youth (NLSCY) from cycles 5 to 8 were included. The sensitivity, specificity, positive and negative predictive values were calculated for the ASQ at 24, 27, 30, 33, 36 and 42 months. Fixed effects regression analyses assessed longitudinal associations between domain scores and child age. RESULTS: Specificity for the ASQ was high with 1SD or 2SD cutoffs, indicating good accuracy in detecting children who will not develop a NDD, however the sensitivity varied over time points and cut-offs. Sensitivity for the 1 SD cutoff at 24 months was above the recommended value of 70% for screening. Differences in ASQ domains scores between children with and without NDD increases with age. CONCLUSIONS: The high specificity and negative predictive values of the ASQ support its use in identifying children who are not at the risk of developing a NDD. The capacity of the ASQ to identify children with a NDD in the general population is limited except for the ASQ-24 months with 1SD and can be used to identify children at risk of NDD. PMID- 29614990 TI - Improved effects of honokiol on temozolomide-induced autophagy and apoptosis of drug-sensitive and -tolerant glioma cells. AB - BACKGROUND: Temozolomide (TMZ)-induced side effects and drug tolerance to human gliomas are still challenging issues now. Our previous studies showed that honokiol, a major bioactive constituent of Magnolia officinalis (Houpo), is safe for normal brain cells and can kill human glioma cells. This study was further aimed to evaluate the improved effects of honokiol and TMZ on drug-sensitive and resistant glioma cells and the possible mechanisms. METHODS: TMZ-sensitive human U87-MG and murine GL261 glioma cells and TMZ-resistant human U87-MR-R9 glioma cells were exposed to honokiol and TMZ, and cell viability and LC50 of honokiol were assayed. To determine the death mechanisms, caspase-3 activity, DNA fragmentation, apoptotic cells, necrotic cells, cell cycle, and autophagic cells. The glioma cells were pretreated with 3-methyladenine (3-MA) and chloroquine (CLQ), two inhibitors of autophagy, and then exposed to honokiol or TMZ. RESULTS: Exposure of human U87-MG glioma cells to honokiol caused cell death and significantly enhanced TMZ-induced insults. As to the mechanism, combined treatment of human U87-MG cells with honokiol and TMZ induced greater caspase-3 activation, DNA fragmentation, cell apoptosis, and cell-cycle arrest at the G1 phase but did not affect cell necrosis. The improved effects of honokiol on TMZ induced cell insults were further verified in mouse GL261 glioma cells. Moreover, exposure of drug-tolerant human U87-MG-R9 cells to honokiol induced autophagy and consequent apoptosis. Pretreatments with 3-MA and CLQ caused significant attenuations in honokiol- and TMZ-induced cell autophagy and apoptosis in human TMZ-sensitive and -tolerant glioma cells. CONCLUSIONS: Taken together, this study demonstrated the improved effects of honokiol with TMZ on autophagy and subsequent apoptosis of drug-sensitive and -tolerant glioma cells. Thus, honokiol has the potential to be a drug candidate for treating human gliomas. PMID- 29614991 TI - Influence of complete administration of adjuvant chemotherapy cycles on overall and disease-free survival in locally advanced rectal cancer: post hoc analysis of a randomized, multicenter, non-inferiority, phase 3 trial. AB - BACKGROUND: A randomized trial demonstrated that capecitabine is at least as effective as fluorouracil in the adjuvant treatment of patients with locally advanced rectal cancer. However, not all patients receive all planned cycles of chemotherapy. Therefore it is of interest how complete or partial administration of chemotherapy influences oncological outcome. METHODS: A post hoc analysis of a trial with 401 randomized patients, nine being excluded because of missing data, was performed. 392 patients (197 - capecitabine, 195 - fluorouracil) could be analyzed regarding the number of administered adjuvant chemotherapy cycles. In the subgroup of 361 patients with an overall survival of at least six months, five-year overall and disease-free survival were analyzed in respect to completion (complete vs. incomplete) of chemotherapy cycles. Survival rates and curves were calculated and compared using the log-rank test. The effect of completion of chemotherapy was adjusted for relevant confounding factors. RESULTS: Two hundred fifty-one (64.0%) of analyzed patients received all postoperative scheduled cycles. Five-year overall survival was significantly better in these patients compared to the incomplete group (76.0 vs. 60.6%, p < 0.0001). Of 361 patients with an overall survival of at least six months, 251(69.5%) patients received all cycles. Five-year overall survival was also significantly better than in the incomplete group (76.0 vs. 66.4%, p = 0.0073). Five-year disease free survival was numerically better (64.9 vs. 58.7%, p = 0.0646; HR [not all cycles vs. all cycles] = 1.42 95% CI: [0.98, 2.07]). Cox regression models show a non-significant better OS (p = 0.061) and DFS (p = 0.083), if chemotherapy cycles were administered completely. CONCLUSION: Complete administration of chemotherapy cycles was associated with improved five-year overall and disease-free survival in patients with locally advanced rectal cancer. PMID- 29614993 TI - Impact of resistance training on body composition and metabolic syndrome variables during androgen deprivation therapy for prostate cancer: a pilot randomized controlled trial. AB - BACKGROUND: Prostate cancer patients on androgen deprivation therapy (ADT) experience adverse effects such as lean mass loss, known as sarcopenia, fat gain, and changes in cardiometabolic factors that increase risk of metabolic syndrome (MetS). Resistance training can increase lean mass, reduce body fat, and improve physical function and quality of life, but no exercise interventions in prostate cancer patients on ADT have concomitantly improved body composition and MetS. This pilot trial investigated 12 weeks of resistance training on body composition and MetS changes in prostate cancer patients on ADT. An exploratory aim examined if a combined approach of training and protein supplementation would elicit greater changes in body composition. METHODS: Prostate cancer patients on ADT were randomized to resistance training and protein supplementation (TRAINPRO), resistance training (TRAIN), protein supplementation (PRO), or control stretching (STRETCH). Exercise groups (EXE = TRAINPRO, TRAIN) performed supervised exercise 3 days per week for 12 weeks, while non-exercise groups (NoEXE = PRO, STRETCH) performed a home-based stretching program. TRAINPRO and PRO received 50 g?day- 1 of whey protein. The primary outcome was change in lean mass assessed through dual energy x-ray absorptiometry. Secondary outcomes examined changes in sarcopenia, assessed through appendicular skeletal mass (ASM) index (kg/m2), body fat %, strength, physical function, quality of life, MetS score and the MetS components of waist circumference, blood pressure, glucose, high-density lipoprotein-cholesterol, and triglyceride levels. RESULTS: A total of 37 participants were randomized; 32 participated in the intervention (EXE n = 13; NoEXE n = 19). At baseline, 43.8% of participants were sarcopenic and 40.6% met the criteria for MetS. Post-intervention, EXE significantly improved lean mass (d = 0.9), sarcopenia prevalence (d = 0.8), body fat % (d = 1.1), strength (d = 0.8 3.0), and prostate cancer-specific quality of life (d = 0.9) compared to NoEXE (p < 0.05). No significant differences were observed between groups for physical function or MetS-related variables except waist circumference (d = 0.8). CONCLUSIONS: A 12-week resistance training intervention effectively improved sarcopenia, body fat %, strength and quality of life in hypogonadal prostate cancer patients, but did not change MetS or physical function. PRO did not offer additional benefit in improving body composition. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01909440 . Registered 24 July 2013. PMID- 29614994 TI - Theme trends and knowledge structure on choroidal neovascularization: a quantitative and co-word analysis. AB - BACKGROUND: The distribution pattern and knowledge structure of choroidal neovascularization (CNV) was surveyed based on literatures in PubMed. METHODS: Published scientific papers about CNV were retrieved from Jan 1st, 2012 to May 31st, 2017. Extracted MeSH terms were analyzed quantitatively by using Bibliographic Item Co-Occurrence Matrix Builder (BICOMB) and high-frequency MeSH terms were identified. Hierarchical cluster analysis was conducted by SPSS 19.0 according to the MeSH term-source article matrix. High-frequency MeSH terms co occurrence matrix was constructed to support strategic diagram and social network analysis (SNA). RESULTS: According to the searching strategy, all together 2366 papers were included, and the number of annual papers changed slightly from Jan 1st, 2012 to May 31st, 2017. Among all the extracted MeSH terms, 44 high frequency MeSH terms were identified and hotspots were clustered into 6 categories. In the strategic diagram, clinical drug therapy, pathology and diagnosis related researches of CNV were well developed. In contrast, the metabolism, etiology, complications, prevention and control of CNV in animal models, and genetics related researches of CNV were relatively immature, which offers potential research space for future study. As for the SNA result, the position status of each component was described by the centrality values. CONCLUSIONS: The studies on CNV are relatively divergent and the 6 research categories concluded from this study could reflect the publication trends on CNV to some extent. By providing a quantitative bibliometric research across a 5-year span, it could help to depict an overall command of the latest topics and provide some hints for researchers when launching new projects. PMID- 29614992 TI - A research study review of effectiveness of treatments for psychiatric conditions common to end-stage cancer patients: needs assessment for future research and an impassioned plea. AB - BACKGROUND: Rates of psychiatric conditions common to end-stage cancer patients (delirium, depression, anxiety disorders) remain unchanged. However, patient numbers have increased as the population has aged; indeed, cancer is a chief cause of mortality and morbidity in older populations. Effectiveness of psychiatric interventions and research to evaluate, inform, and improve interventions is critical to these patients' care. This article's intent is to report results from a recent review study on the effectiveness of interventions for psychiatric conditions common to end-stage cancer patients; the review study assessed the state of research regarding treatment effectiveness. Unlike previous review studies, this one included non-traditional/alternative therapies and spirituality interventions that have undergone scientific inquiry. METHODS: A five-phase systematic strategy and a theoretic grounded iterative methodology were used to identify studies for inclusion and to craft an integrated, synthesized, comprehensive, and reasonably current end-product. RESULTS: Psychiatric medication therapies undoubtedly are the most powerful treatments. Among them, the most effective (i.e., "best practices benchmarks") are: (1) for delirium, typical antipsychotics-though there is no difference between typical vs. atypical and other antipsychotics, except for different side-effect profiles, (2) for depression, if patient life expectancy is >=4-6 weeks, then a selective serotonin reuptake inhibitor (SSRI), and if < 3 weeks, then psychostimulants or ketamine, and these generally are useful anytime in the cancer disease course, and (3) for anxiety disorders, bio-diazepams (BDZs) are most used and most effective. A universal consensus suggests that psychosocial (i.e., talk) therapy and spirituality interventions fortify the therapeutic alliance and psychiatric medication protocols. However, trial studies have had mixed results regarding effectiveness in reducing psychiatric symptoms, even for touted psychotherapies. CONCLUSIONS: This study's findings prompted a testable linear conceptual model of co-factors and their importance for providing effective psychiatric care for end stage cancer patients. The complicated and tricky part is negotiating patients' diagnoses while articulating internal intricacies within and between each of the model's co-factors. There is a relative absence of scientifically derived information and need for more large-scale, diverse scientific inquiry. Thus, this article is an impassioned plea for accelerated study and better care for end stage cancer patients' psychiatric conditions. PMID- 29614995 TI - Racecadotril in the treatment of acute diarrhea in children: a systematic, comprehensive review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Racecadotril is a guideline-recommended option for the treatment of acute diarrhea in children but existing guidelines and previous reviews of the field are based on a small fraction of published evidence. Therefore, we have performed a systematic search for randomized controlled trials evaluating racecadotril as add-on or in comparison to other treatments. METHODS: A search was performed in PubMed, Scopus and Google Scholar without limits about country of origin or reporting language. A meta-analysis was conducted for the five most frequently used efficacy parameters. RESULTS: We have retrieved 58 trials, from nine countries including six in comparison to placebo, 15 in comparison to various active treatments and 41 as add-on to various standard treatments (some multi-armed studies allowing more than one comparison). Trials used 45 distinct efficacy parameters, most often time to cure, % of cured children after 3 days of treatment, global efficacy and number of stools on second day of treatment. Racecadotril was superior to comparator treatments in outpatients and hospitalized patients with a high degree of consistency as confirmed by meta analysis for the five most frequently used outcome parameters. For instance, it reduced time to cure from 106.2 h to 78.2 h (mean reduction 28.0 h; P < 0.0001 in 24 studies reporting on this parameter). Tolerability of racecadotril was comparable to that of placebo (10.4% vs. 10.6% adverse events incidence) or that of active comparator treatments other than loperamide (2.4% in both groups). CONCLUSIONS: Based on a comprehensive review of the existing evidence, we conclude that racecadotril is more efficacious than other treatments except for loperamide and has a tolerability similar to placebo and better than loperamide. These findings support the use of racecadotril in the treatment of acute diarrhea in children. PMID- 29614996 TI - More to gain: dietary energy density is related to smoking status in US adults. AB - BACKGROUND: Given the current prevalence of both cigarette use and obesity in the United States, identification of dietary patterns that reduce mortality risk are important public health priorities. The objective of the present study was to evaluate the correlation between cigarette use and dietary energy density, a marker for diet quality, in a population of current smokers, former smokers, and never smokers. METHODS: Data from a nationally representative sample of 5293 adults who participated in the 2013-2014 National Health and Nutrition Examination Surveys (NHANES) were analyzed. Specific survey procedures were used in the analysis to account for sample weights, unequal selection probability, and clustered design when evaluating the association between dietary energy density (ED, energy per weight of food, kcal/g) and current smoking status. Never smokers reported < 100 lifetime cigarettes. Smokers were identified as individuals reporting > 100 lifetime cigarettes and current smoking status was recorded as daily, some days (nondaily), or not at all (former). RESULTS: A strong linear relationship was observed between smoking pattern and dietary ED in current smokers. Compared to never smokers, daily smokers and nondaily smokers have significantly higher dietary ED (1.79 vs. 2.02 and 1.88, respectively; both p < 0.05); demonstrating that any amount of current cigarette consumption is associated with poor diet. Though former smokers had a higher dietary ED than never smokers, this difference still significantly lower than that of current smokers (p = 0.002). CONCLUSION: These findings suggest that smoking status is associated with poor diet quality. Former smokers had a slightly lower ED value (1.84) than current non-daily smokers (1.89) but a higher value than never smokers (1.79). PMID- 29614997 TI - Cancer patients' knowledge about their disease and treatment before, during and after treatment: a prospective, longitudinal study. AB - BACKGROUND: Knowledge about disease and treatment is necessary before patients can consent to treatment. One of the few established instruments for evaluating whether sufficient information has been provided, is the EORTC QLQ-INFO25 questionnaire which was developed to measure how patients perceive information. The aim of this study was to investigate whether cancer patients' level of knowledge about their disease and treatment was associated with their perception of and satisfaction with the information. METHODS: Breast cancer patients referred for adjuvant chemotherapy and prostate cancer patients referred for curative radiotherapy were included. Level of knowledge about their disease and treatment was measured using study-specific questionnaires. Patients' perception of and satisfaction with the received information was assessed using EORTC QLQ INFO25. Assessments were done before the first consultation with an oncologist (T1), after the consultation (T2) and 8 weeks after start of treatment (T3). RESULTS: Ninety eight patients were enrolled. Patients with higher education, daily Internet access and in paid employment had the highest baseline knowledge scores. The mean knowledge score increased significantly (T1: 16.4; T2: 20.8; T3: 21.3; p < 0.001.). During the same period, the patients reported on the INFO25 a significant, positive increase in how much information they had received, and that they were more satisfied with the information. CONCLUSIONS: Patients' knowledge increased significantly during the study period, and they reported that they felt better informed and were more satisfied with the information, suggesting that EORTC QLQ-INFO25 might be used to evaluate cancer patients' level of knowledge about their disease and treatment. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01699672 . Date of registration: September 21, 2012. PMID- 29614998 TI - Prevalence of anxiety and depression symptoms and their associated factors in mild COPD patients from community settings, Shanghai, China: a cross-sectional study. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a serious disease frequently accompanied by anxiety and depression. Few studies have focused on anxiety and depression for mild COPD patients in China. This study aimed to assess the prevalence and associated factors for anxiety and depression among patients with mild COPD in urban communities. METHODS: A cross-sectional survey of 275 mild COPD patients was conducted in 6 communities randomly sampled from Pudong New Area of Shanghai, China, in 2016. Data on socioeconomic factors and health conditions were acquired through a face-to-face interview as well as a physical examination. The Hospital Anxiety and Depression Scale (HAD) and EQ-5D visual analogue (EQ-5Dvas) were applied to evaluate their mental health and quality of life, respectively. Logistic regression model was used to estimate adjusted odds ratios (aORs) and their 95% confidential intervals (CI) for risk factors associated with anxiety or depression. RESULTS: Among 275 subjects, 8.1% had anxiety and 13.4% had depression. Logistic regression analysis indicated that female patients were more likely to suffer from anxiety than male patients (aOR = 6.41, 95% CI:1.73-23.80). Poor health status (EQ-5Dvas score < 70) was significantly associated with increased risks of anxiety (aOR = 5.99, 95% CI: 2.13-16.82) and depression (aOR = 2.67, 95% CI: 1.29-5.52). CONCLUSIONS: There were increased risks of anxiety and depression in mild COPD patients living in urban communities. Female sex and poor health status were significantly correlated to anxiety or depression. More interventions should be developed to reduce the risks of anxiety and depression at the early stage of COPD. PMID- 29615000 TI - Measuring sport experiences in children and youth to better understand the impact of sport on health and positive youth development: designing a brief measure for population health surveys. AB - BACKGROUND: Despite the proliferation of studies examining youth sport participation, there are significant gaps in knowledge regarding the impact of youth sport participation on health and development. These gaps are not new, but have persisted due to limitations with how sport participation is measured. Much of the research to date has measured sport participation as binary (yes/no) or count measures. This has been especially true in survey-based research. Yet, at the same time, research has investigated youths' experiences in sport such as the influence of coaches, teammates, and parents. The ability to measure these experiences is constrained by the need to use a number of measures along with gaps in the content covered in existing measures. We propose to develop and test the Sport Experiences Measure: Children and Youth (SEM:CY) as a population survey based measure that captures the salient aspects of youths' experience in sport. METHODS: The SEM:CY will be developed and tested across three phases. Phase I includes qualitative research with members of the sport community and engagement with an expert group to generate and obtain feedback on the initial item pool. In Phase II will recruit two consecutive samples of students from schools to complete the draft measure. Analysis will focus on assessing the items and factor structure of the measure. Factor structure will be assessed first with exploratory factor analysis and then confirmatory factor analysis. In phase III we will test the association between the SEM:CY with a measure of perceived competence, sport anxiety, and positive youth development to assess construct validity. We will also examine whether the structure of the measure varies by age or gender. DISCUSSION: The SEM:CY measure will provide a meaningful contribution to the measurement and understanding of youth sport participation. The SEM:CY can be used as a stand-alone measure to understand youth experiences in sport programs, or in combination with other health and development measures to better understand how youth sport can contribute to both positive and negative outcomes. PMID- 29614999 TI - Species-specific characteristics of the biofilm generated in silicone tube: an in vitro study. AB - BACKGROUND: To investigate characteristics of biofilm which is usually found in silicone tube for nasolacrimal duct surgery and can be the root of chronic bacterial infections eventually resulted in surgical failure. METHODS: To form a biofilm, sterile silicone tube was placed in culture media of Staphylococcus aureus, Corynebacterium matruchotii, Pseudomonas aeruginosa, or Streptococcus pneumonia. Biofilms formed on these silicone tubes were fixed with 95% ethanol and stained with 0.1% crystal violet. After staining, the optical densities of biofilms were measured using spectrophotometer on a weekly basis for 12 weeks. RESULTS: Staphylococcus aureus group and Pseudomonas aeruginosa group formed significantly more amounts of biofilms compared to the control group. The maximum optical densities of the two groups were found on week 3-4 followed by a tendency of decrease afterwards. However, the amounts of biofilms formed in other groups of silicone tubes were not statistically significant from that of the control group. CONCLUSIONS: Bacterial species that could form biofilm on silicone tube included Staphylococcus aureus (week 3) and Pseudomonas aeruginosa (Week 4). It is important to first consider that the cause of infection around 1 month after silicone tube intubation can be Staphylococcus aureus and Pseudomonas aeruginosa. PMID- 29615001 TI - Epstein-Barr virus positive peripheral T cell lymphoma with novel variants in STAT5B of a pediatric patient: a case report. AB - BACKGROUND: Epstein-Barr virus positive peripheral T cell lymphoma (EBV + PTCL) is a rare type of lymphoproliferative disorder which is always present in late adulthood. However, pediatric EBV + PTCL is extremely rare and always present with lymphadenopathy. Additionally, gene detection was not performed in all of these pediatric patients. CASE PRESENTATION: We report an EBV + PTCL in a 9-year old child with initial symptom of subcutaneous masses without lymph node involvement. Histologically, the neoplastic cells were centroblastoid with round or oval nuclei, slightly condensed chromatin and median eosinophilic inconspicuous nucleoli. Immunohistochemically, all neoplastic cells were positive for CD8, GranzymeB and TIA-1. Two novel variants (S420Y and E623K) were detected in STAT5B. CONCLUSION: To the best of our knowledge, this is the first case of EBV + PTCL with STAT5B variants of a pediatric patient presented as extranodal lesions. PMID- 29615002 TI - Triglycerides and total cholesterol concentrations in association with IFG/IGT in Chinese adults in Qingdao, China. AB - BACKGROUND: To investigative the association of triglycerides (TG) and total cholesterol (TC) concentrations with impaired fasting glucose/ impaired glucose tolerance (IFG/IGT) in Chinese adults. METHODS: The population-based cross sectional diabetes survey was conducted in 2006 and 2009 in Qingdao, separately. 4400 participants (1 793 men and 2607 women) were include in current analysis. IFG/IGT was defined according to fasting plasma glucose (FPG) and/or 2 h post load plasma glucose (2 h PG). Logistic regression models and areas under receiver operating characteristic curves (AUROC) were performed to estimate the associations between TG, TC levels and IFG/IGT. RESULTS: Spearman analysis showed that serum TG and TC was independently and positively associated with FPG and 2 h PG. As compared with normoglycaemia, the odds ratio[(95% confidence intervals), OR(95%CI)] for IFG/IGT corresponding to hypertriglyceridemia (HTG) were 1.61 (1. 17, 2. 22) in men and 1.57(1.15, 2.14) in women for TG and accompany with Hypercholesterolemia (HTC) 1.56 (1.15, 2.13) and 1. 20 (0.93, 1.54) for TC, when adjusting for confounding factor. The AUROCs of TG, TC for IFG/IGT were relatively smaller (0.50 < AUROC< 0. 7) in both gender. The optimal cut-offs for TG and TC was 1.61, 4.91 in men and 1. 24, 5. 32 in women, respectively. CONCLUSIONS: Evaluated TG in both gender and TC in men were independently associated with the present of the IFG/IGT, yet, could not be an authentic predictors of IFG/IGT in both men and women in current Chinese population. PMID- 29615004 TI - Laparoscopy-assisted colectomy as an Oncologically safe alternative for patients with stage T4 Colon Cancer: a propensity-matched cohort study. AB - BACKGROUND: It is still controversial whether laparoscopy-assisted colectomy (LAC) is suitable for patients with stage T4 colon cancer. This study aimed to compare the short- and long-term outcomes of LAC and open colectomy (OC) for patients with pathologic T4 colon cancer. METHODS: Data of eligible patients with colon cancer in our institution from March 2004 to September 2014 were retrospectively reviewed. The patients were followed up to September 2016. Propensity score matching was performed to control the bias. RESULTS: Two hundred and forty two patients were selected by propensity score matching, with 121 patients in the LAC group and 121 in the OC group. Mean operating time and rate of intraoperative blood transfusion were similar between two groups. In LAC group, shorter time to first flatus and first liquid intake were observed in patients with pT4b stage disease, but not for patients with pT4a stage disease. Less blood loss and shorter length of postoperative hospital stay were examined in LAC group, including pT4a and pT4b stages. Conversion was required in 9.1% (11 out of 121) cases. DFS and OS were similar between LAC and OC groups. The 5-year DFS rate was 64.2% for pT4a stage and 35.5% for pT4b stage in LAC group, and 62.9% and 33.7% in OC group for pT4a (p = 0.374) and pT4b (p = 0.385) stage respectively. For 5-year OS rates, two groups did not differ in pT4a stage (LAC 69.2% vs. OC 66.0%, p = 0.151) and pT4b stage (LAC 37.5% vs. OC 38.1%, p = 0.510). CONCLUSIONS: Laparoscopic colectomy appears to be safe for selected patients with pT4 colon cancer in centres with expertise in minimally invasive surgery. PMID- 29615003 TI - Role of cytarabine in paediatric acute promyelocytic leukemia treated with the combination of all-trans retinoic acid and arsenic trioxide: a randomized controlled trial. AB - BACKGROUND: The combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) has been suggested to be safe and effective for adult acute promyelocytic leukaemia (APL). As of 2010, the role of cytarabine (Ara-C) in APL was controversial. The aim of this study was to test the efficacy and safety of ATRA and ATO in paediatric APL patients. Also, we assessed whether Ara-C could be omitted in ATO and ATRA- based trials in children. METHODS: We performed a randomized controlled trial in paediatric APL patients (<=14 years of age) in our hospital from May 2010 to December 2016. All of the patients were assigned to receive ATRA plus ATO for induction followed by one course of idarubicin (IDA) and ATO (28 days). The patients were then randomly assigned to receive two courses of daunorubicin (DNR, no- Ara-C group) or DNR + Ara-C (Ara-C group). All of the patients were followed with maintenance therapy with oral ATRA, 6 mercaptopurine, and methotrexate for 1.5 years. RESULTS: Among the 66 patients, 43 were male and 23 were female. All of the patients achieved complete remission (CR) with the exception of one who gave up the treatment. During induction therapy, all toxicity events were reversed after appropriate management. Thirty patients in the Ara-C group underwent 57 courses of treatment, and 35 patients in the no-Ara-C group underwent 73 courses of treatment. No significant differences in age, genders, white blood cell counts, haemoglobin levels, and platelet counts were found between the Ara-C and no-Ara-c groups. Greater myelosuppression and sepsis were observed in the Ara-C group during the consolidation courses. No patient died at consolidation, and only one patient relapsed. No differences were found in event-free survival, disease-free survival and overall survival between the two groups. Additionally, our analysis of the arsenic levels in the plasma, urine, hair and nails of the patients indicated that no significant accumulation of arsenic occurred after ATO was discontinued for 12 months. CONCLUSIONS: Overall, ATO and ATRA are safe and effective for paediatric APL patients and Ara C could be omitted when ATO is used for two courses. TRIAL REGISTRATION: ClinicalTrials.gov ( NCT01191541 , retrospectively registered on 18 August 2010). PMID- 29615005 TI - Improving risk prediction accuracy for new soldiers in the U.S. Army by adding self-report survey data to administrative data. AB - BACKGROUND: High rates of mental disorders, suicidality, and interpersonal violence early in the military career have raised interest in implementing preventive interventions with high-risk new enlistees. The Army Study to Assess Risk and Resilience in Servicemembers (STARRS) developed risk-targeting systems for these outcomes based on machine learning methods using administrative data predictors. However, administrative data omit many risk factors, raising the question whether risk targeting could be improved by adding self-report survey data to prediction models. If so, the Army may gain from routinely administering surveys that assess additional risk factors. METHODS: The STARRS New Soldier Survey was administered to 21,790 Regular Army soldiers who agreed to have survey data linked to administrative records. As reported previously, machine learning models using administrative data as predictors found that small proportions of high-risk soldiers accounted for high proportions of negative outcomes. Other machine learning models using self-report survey data as predictors were developed previously for three of these outcomes: major physical violence and sexual violence perpetration among men and sexual violence victimization among women. Here we examined the extent to which this survey information increases prediction accuracy, over models based solely on administrative data, for those three outcomes. We used discrete-time survival analysis to estimate a series of models predicting first occurrence, assessing how model fit improved and concentration of risk increased when adding the predicted risk score based on survey data to the predicted risk score based on administrative data. RESULTS: The addition of survey data improved prediction significantly for all outcomes. In the most extreme case, the percentage of reported sexual violence victimization among the 5% of female soldiers with highest predicted risk increased from 17.5% using only administrative predictors to 29.4% adding survey predictors, a 67.9% proportional increase in prediction accuracy. Other proportional increases in concentration of risk ranged from 4.8% to 49.5% (median = 26.0%). CONCLUSIONS: Data from an ongoing New Soldier Survey could substantially improve accuracy of risk models compared to models based exclusively on administrative predictors. Depending upon the characteristics of interventions used, the increase in targeting accuracy from survey data might offset survey administration costs. PMID- 29615006 TI - Selected risk factors for atherosclerosis in children and their parents with positive family history of premature cardiovascular diseases: a prospective study. AB - BACKGROUND: The aim of the study was to evaluate serum parameters of lipid metabolism, homocysteine, soluble adhesion molecules and common carotid artery wall thickness in children from families with early symptoms of atherosclerosis. METHODS: The first stage included 137 pairs of mothers and newborns, and the second 18 children from the same group (age 18-30 months) and their parents (age 21-46 years) with a history of premature coronary artery disease (CAD), as well as 12 age- and sex-matched controls. RESULTS: During the first stage, inverse correlations were found between birthweight, cord blood concentrations of triglycerides (TG), VLDL cholesterol and apolipoprotein B (Apo B). Serum concentrations of total cholesterol (TC), apolipoprotein A1 (Apo A1), LDL and HDL cholesterol and were significantly higher in female than in male newborns. During the second stage, children from families with a history for premature CAD were shown to present with significantly higher serum concentrations of TG, VLDL cholesterol and lipoprotein A (Lp(a)) than the controls. Furthermore, their TC correlated positively with vascular cell adhesion molecule-1 (Rs=0.717, p<0.05) and intracellular adhesion molecule-1 (sICAM-1) levels (Rs=0.833, p<0.05). Moreover, positive correlations were found between maternal carotid intima media thickness (IMT) and TC (Rs=0.831, p<0.01), as well as between paternal IMT and Apo B (Rs=0.692, p<0.05), TG and sICAM-1 (Rs=0.912, p<0.01), TG and sE-selectin (Rs=0.678, p<0.05). CONCLUSIONS: Serum Lp(a) may serve as a maker of cardiovascular risk in children and adolescents. PMID- 29615007 TI - Plasma nesfatin-1 level is associated with severity of depression in Chinese depressive patients. AB - BACKGROUND: Nesfatin-1 plays a role in the regulation of emotional states like depression. The aim of this study was to investigate the plasma nesfatin-1levels in Chinese patients with depression and healthy subjects, and to determine the possible association between the plasma nesfatin-1 level and the severity of depression. METHODS: A total of 103 depressive patients and 32 healthy subjects were assessed. According to HAMD-17scores, 51, 18, and 34 patients were enrolled in the mild depression, moderate depression, and severe depression groups, respectively. Plasma nesfatin-1 levels were determined by the ELISA method. Differences between groups were compared and associations between plasma nesfatin 1 and other variables were analyzed. RESULTS: The plasma nesfatin-1 was significantly positively correlated with HAMD-17 score (r = 0.651). Compared with healthy controls (8.11 +/- 3.31 ng/mL), the plasma nesfatin-1 level significantly increased in patients with mild depression (11.17 +/- 3.58 ng/mL), with moderate depression (16.33 +/- 8.78 ng/mL), and with severe depression (27.65 +/- 8.26 ng/mL) respectively. Plasma nesfatin-1 level (Odds ratio [OR] = 1.269) was an independent indicator for severe depression by multivariate logistic regression analysis. CONCLUSION: The plasma nesfatin-1 level is positively correlated with the severity of depression. Plasma nesfatin-1 level may be a potential indicator for depression severity. PMID- 29615008 TI - Responses to textual and pictorial cigarette pack health warnings: findings from an exploratory cross-sectional survey study in Austria. AB - BACKGROUND: Packaging and labelling tobacco products has emerged as an effective policy to reduce the global health burden of tobacco use. The main purpose of this study was to explore Austrian smokers' and ex-smokers' responses to both the textual and pictorial cigarette pack health warnings (CPHWs) recently implemented. METHODS: We analysed self-reported data (N=500) from an Austrian cross-sectional survey that was conducted after the implementation of the new pictorial CPHWs in 2016. RESULTS: The results showed only weak effects of the CPHWs on the decision to quit or reduce smoking, and the level of impact of the CPHWs remained limited particularly because of smokers denying the ill-effects of tobacco use. CONCLUSIONS: Although the CPHWs seem to have the potential to promote a change in smoking behaviour, the warnings reached only a rather small group of smokers, while the majority of smokers appeared to remain unaffected by this intervention. Public health policies are challenged to increase the salience of CPHWs and to overcome smokers' denial of detrimental health effects. PMID- 29615009 TI - Striving for a balance between leading and following the patient and family - nurses' strategies to facilitate the transition from life-prolonging care to palliative care: an interview study. AB - BACKGROUND: The transition from life-prolonging to palliative care (PC) can be challenging often characterized by psychical, physiological, social and existential changes. Knowledge of how to support the patient and family in this specific care phase is lacking, and this area needs to be further explored. The aim of this study was to investigate strategies that registered nurses (RNs) use to ease the transition from life-prolonging care to PC for patients with incurable disease. METHODS: The study has a descriptive design. Fourteen RNs working in a specialized PC unit were interviewed. The data were analysed using content analysis. RESULTS: The RNs' strategies can be described under the categories "Getting to know the patient and creating a relationship", "Providing support", "Adapting to individuals' needs" and "Enabling conversations". CONCLUSION: The findings show that the RNs in this population used strategies that not only took time but also required knowledge about the transition process and required the ability to identify and meet patients' and families' unique needs. Patients' difficult and exposed situation needs to be addressed through a structured follow-up after informing about the change from life-prolonging care to PC. RNs have a unique role of supporting both the patient and the family in the transition from life-prolonging care to PC for patients with incurable disease. PMID- 29615010 TI - Malignant pleural mesothelioma: diagnostic value of medical thoracoscopy and long term prognostic analysis. AB - BACKGROUND: Malignant pleural mesothelioma (MPM) is marked by its difficult diagnosis and poor prognosis. Medical thoracoscopy (MT) is an effective and safe procedure for the diagnosis of exudative pleural effusions and many factors associated with poor prognosis of MPM. We conducted this study to investigate the value of MT for diagnosing of MPM and to identify prognostic factors for MPM patients. METHODS: From July 2005 through June 2014, a total of 833 patients with undiagnosed pleural effusions underwent MT and pleural biopsies were taken. Clinical data of all patients with MPM were retrospectively analyzed, and those with complete follow-up data were analyzed for prognostic factors. RESULTS: Eventually, MPM was the final diagnosis in 40 patients. Diagnostic efficiency of MT for MPM was 87.5%, since diagnosis of MPM failed to be established in 5 patients during the initial MT. Median survival was 17.1 mo (95% confidence interval: 13.6-20.7 mo). MT findings of pleural adhesion and plaques were adverse prognostic factors for MPM. In addition, old age, male gender, smoking history, histological type, poor staging, no treatment, low total protein level in pleural fluid, and computed tomographic findings such as pulmonary consolidation or infiltration, mediastinal lymphopathy, pulmonary mass or nodules, and pleural nodularity were also poor prognostic factors for MPM. CONCLUSIONS: MT is safe with a high positive rate in the diagnosis of MPM, and pleural adhesion and plaques seen under MT may be the adverse prognostic factors for MPM. Multiple clinical characteristics can affect the survival of MPM patients. PMID- 29615011 TI - Soluble expression of an amebic cysteine protease in the cytoplasm of Escherichia coli SHuffle Express cells and purification of active enzyme. AB - BACKGROUND: Recombinant production of amebic cysteine proteases using Escherichia coli cells as the bacterial system has become a challenging effort, with protein insolubility being the most common issue. Since many of these enzymes need a native conformation stabilized by disulfide bonds, an elaborate process of oxidative folding is usually demanded to get a functional protein. The cytoplasm of E. coli SHuffle Express cells owns an enhanced ability to properly fold proteins with disulfide bonds. Because of this cellular feature, it was possible to assume that this strain represents a reliable expression system and worthwhile been considered as an efficient bacterial host for the recombinant production of amebic cysteine proteases. RESULTS: Using E. coli SHuffle Express cells as the bacterial system, we efficiently produce soluble recombinant EhCP1protein. Enzymatic and inhibition analyses revealed that it exhibits proper catalytic abilities, proceeds effectively over the substrate (following an apparent Michaelis-Menten kinetics), and displays a typical inhibition profile. CONCLUSIONS: We report the first feasibility study of the recombinant production of amebic cysteine proteases using E. coli SHuffle Express as the bacterial host. We present a simple protocol for the recombinant expression and purification of fully soluble and active EhCP1 enzyme. We confirm the suitability of recombinant EhCP1 as a therapeutic target. We propose an approachable bacterial system for the recombinant production of amebic proteins, particularly for those with a need for proper oxidative folding. PMID- 29615012 TI - How does iliosacral bone tumor resection without reconstruction affect the ipsilateral hip joint? AB - BACKGROUND: Whether reconstruction is more beneficial after iliosacral bone tumor resection remains controversial. Because of high rates of complications and recurrence, few patients benefit from reconstruction. The aim of this study is to assess functional outcomes and to reveal changes in the ipsilateral hip joint after partial iliosacral resection. METHODS: From 1998 to 2016, 21 patients aged 20-66 years underwent iliosacral resection, 18 without reconstruction (group 1) and 3 with reconstruction (group 2). Function was evaluated using the Musculoskeletal Tumor Society 1993 rating scale (MSTS 1993), and disability was measured using the Toronto Extremity Salvage Score (TESS). I-A distance was defined as the distance from the iliosacral joint to the upper line of the acetabulum along the curved line. Group 1 were subdivided into two groups: group 1A included the patients with a defect less than one-third of the I-A distance and group 1B the remainder. Acetabulum-head index (AHI) and center-edge angle (CE angle) were measured. The relationship between defect length and femoral head coverage was analyzed. RESULTS: The mean follow-up was 67.3 months. Eighteen patients were included in group 1 and three in group 2. Preoperative data of the 3 groups were statistically equivalent. In addition, no difference of postoperative functional outcome has been highlighted. The final average MSTS 1993 score was 93.6% in group 1 and 93.3% in group 2. The mean TESS was 98 in group 1 and 98.5 in group 2. AHI and CE angle between groups 1 and 2 were not different. The AHI was 80 +/- 5.4% in group 1A and 67 +/- 9.0% in group 1B (t = - 3.740, P = 0.002), while the CE angle was 29 +/- 5.9 degrees in group 1A and 20 +/- 6.3 degrees in group 1B (t = - 3.172, P = 0.006) at the last follow-up. Regarding the limb-length discrepancy, group 1 and 2 were similar whereas group 1A and 1B were statistically different (group 1A: 0.7 +/- 0.7 cm; group 2: 2.6 +/ 1.0 cm; t = - 4.324, P = 0.001). CONCLUSIONS: Ilio-sacral resection without reconstruction removing more than one- third of the I-A distance leads to an impairement of the limb-length discrepancy and an increase of the defect of the acetabular coverage without altering the functional outcome. Nevertheless, iliosacral resection without reconstruction could serve as a viable treatment option for pelvic type I-IV tumors. PMID- 29615013 TI - Factors influencing government insurance scheme beneficiary acceptance of the gatekeeper policy: a cross-sectional study in Wuhan, China. AB - BACKGROUND: Gatekeeper policy, requiring a patient to visit a primary care provider first, and the patient needs to get his or her primary care provider's referral before seeing a specialist or going to a hospital, has been implemented in China for about ten years, and it is necessary to assess the patients' acceptance of gatekeeper policy and to explore the factors influencing patients' acceptance. METHODS: A cross-sectional study with 1162 respondents was conducted between July and September 2015 at four community health centers (CHCs) in Wuhan, China. Face-to-face interview was used to collect information on demographics, acceptance of the gate keeper policy and satisfaction with community health services. Patients' satisfaction with community health service was evaluated using the European Patients Evaluate General/Family Practice scale and binary logistic regression model was used to examine the factors influencing patients' acceptance of community health services as gate keepers. RESULTS: A total of 512 (43.06%) patients accepted gatekeeper policy. Mandatory reimbursement provision (OR: 1.63, 95% CI: 1.23-2.15), patient satisfaction with the aspects of medical care (OR: 1.92, 95% CI: 1.12-3.29) and organization of care (OR: 1.66, 95% CI: 1.05-2.62) were associated with acceptance of gatekeeper policy, after adjusting for potential confounders. Moreover, young people (OR: 0.35, 95%CI: 0.22-0.56) seemed to be more reluctant to accept the policy, when compared with the elder. CONCLUSIONS: Our study suggests that mandatory reimbursement provision greatly affects patients' acceptance of gatekeeper policy, therefore, the policy-maker should pay attention to the negative effect of its mandatory reimbursement provision on patients' acceptance of the policy. However, improving the aspects of medical care and organization of care will contribute to implementation of gatekeeper policy. PMID- 29615014 TI - Assessing the implementation processes of a large-scale, multi-year quality improvement initiative: survey of health care providers. AB - BACKGROUND: Beginning in 2012, Lean was introduced to improve health care quality and promote patient-centredness throughout the province of Saskatchewan, Canada with the aim of producing coordinated, system-wide change. Significant investments have been made in training and implementation, although limited evaluation of the outcomes have been reported. In order to better understand the complex influences that make innovations such as Lean "workable" in practice, Normalization Process Theory guided this study. The objectives of the study were to: a) evaluate the implementation processes associated with Lean implementation in the Saskatchewan health care system from the perspectives of health care professionals; and b) identify demographic, training and role variables associated with normalization of Lean. METHODS: Licensed health care professionals were invited through their professional associations to complete a cross-sectional, modified, online version of the NoMAD questionnaire in March, 2016. Analysis was based on 1032 completed surveys. Descriptive and univariate analyses were conducted. Multivariate multinomial regressions were used to quantify the associations between five NoMAD items representing the four Normalization Process Theory constructs (coherence, cognitive participation, collective action and reflexive monitoring). RESULTS: More than 75% of respondents indicated that neither sufficient training nor resources (collective action) had been made available to them for the implementation of Lean. Compared to other providers, nurses were more likely to report that Lean increased their workload. Significant differences in responses were evident between: leaders vs. direct care providers; nurses vs. other health professionals; and providers who reported increased workload as a result of Lean vs. those who did not. There were no associations between responses to normalization construct proxy items and: completion of introductory Lean training; participation in Lean activities; age group; years of professional experience; or employment status (full-time or part time). Lean leader training was positively associated with proxy items reflecting coherence, cognitive participation and reflexive monitoring. CONCLUSIONS: From the perspectives of the cross-section of health care professionals responding to this survey, major gaps remain in embedding Lean into healthcare. Strategies that address the challenges faced by nurses and direct care providers, in particular, are needed if intended goals are to be achieved. PMID- 29615015 TI - Prevalence of breast-related symptoms, health care seeking behaviour and diagnostic needs among women in Burkina Faso. AB - BACKGROUND: The prevalence of breast cancer has been increasing in sub-Saharan Africa over the last few years. Patients often present with late stage disease, resulting in a high mortality rate. This study aims to estimate the prevalence of breast -related symptoms in the female population of Burkina Faso. The findings can be used to advise on adequate diagnostic health services for breast symptoms to ensure early detection and down-staging of breast cancer. METHODS: A cross sectional, population based study of 996 women was conducted to investigate the proportion of women with breast-related symptoms. A semi-structured questionnaire was used to collect sociodemographic data, information about breast cancer knowledge and details about breast-related symptoms, health care seeking and medical care. Breast-related symptoms were categorised as currently present/not currently present to estimate the current prevalence of women requiring a diagnostic service. RESULTS: Among the 996 women, 120 reported having had a breast-related symptom in their life. Only 36 women sought medical advice and eight women had diagnostic confirmation by histological or imaging techniques. Current breast-related symptoms were reported by 33 women (3.3% of the sample). An extrapolation to Burkina Faso's female population suggests that 184,562 women are in current need of diagnostic services due to any breast-related symptoms. CONCLUSIONS: Imaging techniques at the community and referral level are needed in order to triage women with breast-related symptoms. Specialised services need to be strengthened to ensure appropriate diagnosis and treatment of breast diseases. Education campaigns among the general population and among health care professionals are required to increase awareness of breast cancer and improve prompt health care seeking and referral. PMID- 29615016 TI - Using differential item functioning to evaluate potential bias in a high stakes postgraduate knowledge based assessment. AB - BACKGROUND: Fairness is a critical component of defensible assessment. Candidates should perform according to ability without influence from background characteristics such as ethnicity or sex. However, performance differs by candidate background in many assessment environments. Many potential causes of such differences exist, and examinations must be routinely analysed to ensure they do not present inappropriate progression barriers for any candidate group. By analysing the individual questions of an examination through techniques such as Differential Item Functioning (DIF), we can test whether a subset of unfair questions explains group-level differences. Such items can then be revised or removed. METHODS: We used DIF to investigate fairness for 13,694 candidates sitting a major international summative postgraduate examination in internal medicine. We compared (a) ethnically white UK graduates against ethnically non white UK graduates and (b) male UK graduates against female UK graduates. DIF was used to test 2773 questions across 14 sittings. RESULTS: Across 2773 questions eight (0.29%) showed notable DIF after correcting for multiple comparisons: seven medium effects and one large effect. Blinded analysis of these questions by a panel of clinician assessors identified no plausible explanations for the differences. These questions were removed from the question bank and we present them here to share knowledge of questions with DIF. These questions did not significantly impact the overall performance of the cohort. Group-level differences in performance between the groups we studied in this examination cannot be explained by a subset of unfair questions. CONCLUSIONS: DIF helps explore fairness in assessment at the question level. This is especially important in high-stakes assessment where a small number of unfair questions may adversely impact the passing rates of some groups. However, very few questions exhibited notable DIF so differences in passing rates for the groups we studied cannot be explained by unfairness at the question level. PMID- 29615017 TI - Clinical and radiographic outcome of dynamic cervical implant (DCI) arthroplasty for degenerative cervical disc disease: a minimal five-year follow-up. AB - BACKGROUND: To evaluate the mid- to long-term clinical and radiographic outcomes of anterior cervical discectomy and dynamic cervical implant (DCI) arthroplasty for degenerative cervical disc disease. METHODS: From April 2010 to October 2010, 38 patients with single- or double-level cervical disc herniation underwent anterior cervical discectomy and DCI arthroplasty. The clinical results and radiographic outcomes of these 38 patients (42 levels) were retrospectively evaluated. The clinical results included the visual analogue scale, Japanese Orthopaedic Association score, Neck Disability Index score, 36-item short form health survey questionnaire, and incidences of complications and neurological deterioration. Radiographic results including cervical alignment, intervertebral height, cervical range of motion (ROM), ROM of the functional spinal unit, adjacent intervertebral ROM, migration, subsidence, and heterotopic ossification (HO) were assessed on plain radiography, three-dimensional computed tomography, and magnetic resonance imaging. RESULTS: The mean follow-up period was 72.3 months (range 68-78 months). During follow-up, all patients showed significant improvements in the visual analogue scale score, Japanese Orthopaedic Association score, Neck Disability Index score, 36-item short form health survey physical component summary score and mental component summary score. The ROM of the functional spinal unit was partly reduced. The DCI migrated forward in 10 of 42 (23.8%) cases, and HO was detected in 24 of the 42 (57.1%) DCI segments. Subsidence was observed in 14 of 42 (33.3%) DCI segments. Two patients experienced symptom recurrence, and were treated conservatively. CONCLUSIONS: The clinical efficacy of DCI arthroplasty was maintained during mid- to long-term follow-up. HO formation is a common phenomenon, leading to a substantial decrease in ROM at the index level and recurrence of neurological symptoms. The incidence of implant subsidence and migration is relatively high, leaving a potential risk of symptoms at the index level and adjacent segment degeneration. We consider that the first choice for patients with degenerative cervical disc disease should still be total disc replacement or anterior cervical discectomy and fusion, rather than DCI arthroplasty. PMID- 29615018 TI - Respiratory syncytial virus tracking using internet search engine data. AB - BACKGROUND: Respiratory Syncytial Virus (RSV) is the leading cause of hospitalization in children less than 1 year of age in the United States. Internet search engine queries may provide high resolution temporal and spatial data to estimate and predict disease activity. METHODS: After filtering an initial list of 613 symptoms using high-resolution Bing search logs, we used Google Trends data between 2004 and 2016 for a smaller list of 50 terms to build predictive models of RSV incidence for five states where long-term surveillance data was available. We then used domain adaptation to model RSV incidence for the 45 remaining US states. RESULTS: Surveillance data sources (hospitalization and laboratory reports) were highly correlated, as were laboratory reports with search engine data. The four terms which were most often statistically significantly correlated as time series with the surveillance data in the five state models were RSV, flu, pneumonia, and bronchiolitis. Using our models, we tracked the spread of RSV by observing the time of peak use of the search term in different states. In general, the RSV peak moved from south-east (Florida) to the north-west US. CONCLUSIONS: Our study represents the first time that RSV has been tracked using Internet data results and highlights successful use of search filters and domain adaptation techniques, using data at multiple resolutions. Our approach may assist in identifying spread of both local and more widespread RSV transmission and may be applicable to other seasonal conditions where comprehensive epidemiological data is difficult to collect or obtain. PMID- 29615019 TI - Wearable sensor shown to specifically quantify pruritic behaviors in dogs. AB - BACKGROUND: Wearable technology is an exciting new field in humans and animals. In dogs activity monitors have helped to provide objective measurement tools where pet owner observation had been the only source of information. Previous research has focused on measuring overall activity versus rest. This has been relatively useful in determining changes in activity in orthopedic disease or post-surgical cases [Malek et al., BMC Vet Res 8:185, 2012, Yashari et al., BMC Vet Res 11:146, 2015]. Assessment of pruritus via changes in activity, however, requires an assumption that increased activity is due to scratching or other pruritic behaviors. This is an inaccurate method with obvious flaws as other behaviors may also register as greater activity. The objective of this study was to validate the ability of a multidimensional high frequency sensor and advanced computer analysis system, (Vetrax(r), AgLogica Holdings, Inc., Norcross, GA, USA) to specifically identify pruritic behaviors (scratching and head shaking). To establish differences between behaviors, sensor and time stamped video data were collected from 361 normal and pruritic dogs. Video annotations were made by two observers independently, while blinded to sensor data, and then evaluated for agreement. Annotations that agreed between the two were used for further analysis. The annotations specified behaviors at specific times in order to compare with sensor data. A computer algorithm was developed to interpret and differentiate between these behaviors. Test subject data was then utilized to test and score the system's ability to accurately predict behaviors. RESULTS: Results for prediction of head shaking behavior included sensitivity and specificity of 72.16% and 99.78% respectively. Analysis of scratching produced sensitivity and specificity of 76.85% and 99.73% respectively. These results illustrate the ability of the system to accurately report both scratching and head shaking with an overall accuracy of 99.24% and 99.56% respectively. CONCLUSIONS: This study validates the use of this system to accurately and objectively report scratching and head shaking in dogs. While a small portion of scratching or head shaking behaviors may be missed, as indicated by the sensitivity, when detected, the confidence that these behaviors occurred is extremely high. These factors make this system a very useful tool for objective assessment of pruritus in clinical and research settings. PMID- 29615020 TI - Purification and MIC analysis of antimicrobial proteins from Cucumis sativus L. seeds. AB - BACKGROUND: Cucumis sativus L. (cucumber), from the family Cucurbitaceae, is a therapeutic plant with various pharmacological benefits, broadly utilized as a part of complementary medicine (e.g., Unani, Ayurveda, Siddha, and Traditional Chinese). In light of past research discoveries, this plant had been chosen to consider its potential antibacterial action. METHODS: Extracts were purified by dialysis and ion exchange chromatography strategy and then assayed for antibacterial activity against four standard pathogenic bacterial strains known to cause foodborne infections and spoilage of food and herbal drugs. Antimicrobial peptides were extracted from seeds using a sodium phosphate citrate (pH 7.2) - CTAB cradle (pH 6.0). RESULTS: The highest protein concentration was seen with elute fractions 1 and 3 (370 mg/mL) compared with elute fractions 2 and 4 (340 mg/mL). Among the bacteria utilized, E. coli was clearly the most sensitive out of selected four strains. CONCLUSION: Our results suggest that Cucumis sativus L seeds extracts have significant potentials as new antimicrobial agents. PMID- 29615021 TI - Reliability and validity of a novel quality of life questionnaire for female patients with adolescent idiopathic scoliosis: Scoliosis Japanese Questionnaire 27: a multicenter, cross-sectional study. AB - BACKGROUND: A progressive deformity associated with adolescent idiopathic scoliosis (AIS) negatively affects a patient's health-related quality of life (HRQOL). Although the Scoliosis Research Society-22 (SRS-22) is the standard measurement tool for assessing HRQOL in patients with AIS, it is partially suboptimal for evaluating HRQOL in Japanese patients with AIS because of cultural differences. The purpose of this study was to develop a novel patient-reported outcome measure for Japanese female patients with AIS and to evaluate the reliability and validity of this questionnaire in comparison with the SRS-22 tool. METHODS: We developed 27 questions based on the psychosocial problems in the daily life of young female patients with AIS in Japan, the Scoliosis Japanese Questionnaire-27 (SJ-27). To evaluate its reliability, the internal consistency was assessed using Cronbach's alpha coefficient. Concurrent validity was evaluated using Spearman's correlation coefficient between the SJ-27 and the SRS 22. To investigate the construct validity of the SJ-27, the correlation between the SJ-27 questions was assessed using Akaike's information criterion (AIC). RESULTS: We analyzed 384 female patients with AIS. Cronbach's alpha coefficients were 0.914 and 0.829 for the SJ-27 and the SRS-22, respectively. Spearman's correlation coefficient between the SJ-27 and the SRS-22 was 0.692 (p < 0.001). The AIC analysis indicated that the SJ-27 items are divided into five domains, indicating that the SJ-27 covered a wide range of health-related problems among female patients with AIS. CONCLUSIONS: The results suggest that the SJ-27 is a reliable and valid patient-reported outcome measure for evaluating HRQOL in female patients with AIS in Japan. PMID- 29615022 TI - Job satisfaction of nurses with master of nursing degrees in Poland: quantitative and qualitative analysis. AB - BACKGROUND: Understanding the issue of job satisfaction of nurses with master of nursing degrees may help develop organisational changes necessary for better functioning of health care institutions. This study aimed to evaluate the level of job satisfaction among holders of Masters of Nursing degrees employed at health care institutions and to ascertain its determinants. METHODS: The cross sectional study was carried out in randomly selected health care institutions in Poland using the Misener Nurse Practitioner Job Satisfaction Survey and an original survey questionnaire with two open-ended questions. Quantitative data were analysed using descriptive and summary statistics. RESULTS: The participants gave highest satisfaction ratings to their relationships with direct superiors and other nurses, as well as their social contacts at work. The lowest ratings were given to the pension scheme and factors connected with remuneration. A highly statistically significant relationship was found between the job classification and the level of professional satisfaction (p < 0.001). Qualitative analysis of responses to the two open-ended questions supported Herzberg's Two-Factor theory: internal factors promoted satisfaction, whilst external ones caused dissatisfaction. CONCLUSIONS: Managers of nurses should strengthen the areas that contribute to higher employee satisfaction, particularly interpersonal relationships, by commendation and recognition of work effects. PMID- 29615023 TI - Conserved community structure and simultaneous divergence events in the fig wasps associated with Ficus benjamina in Australia and China. AB - BACKGROUND: Localised patterns of species diversity can be influenced by many factors, including regional species pools, biogeographic features and interspecific interactions. Despite recognition of these issues, we still know surprisingly little about how invertebrate biodiversity is structured across geographic scales. In particular, there have been few studies of how insect communities vary geographically while using the same plant host. We compared the composition (species, genera) and functional structure (guilds) of the chalcid wasp communities associated with the widespread fig tree, Ficus benjamina, towards the northern (Hainan province, China) and southern (Queensland, Australia) edges of its natural range. Sequence data were generated for nuclear and mtDNA markers and used to delimit species, and Bayesian divergence analyses were used to test patterns of community cohesion through evolutionary time. RESULTS: Both communities host at least 14 fig wasp species, but no species are shared across continents. Community composition is similar at the genus level, with six genera shared although some differ in species diversity between China and Australia; a further three genera occur in only China or Australia. Community functional structure remains very similar in terms of numbers of species in each ecological guild despite community composition differing a little (genera) or a lot (species), depending on taxonomic level. Bayesian clustering analyses favour a single community divergence event across continents over multiple events for different ecological guilds. Molecular dating estimates of lineage splits between nearest inter-continental species pairs are broadly consistent with a scenario of synchronous community divergence from a shared "ancestral community". CONCLUSIONS: Fig wasp community structure and genus-level composition are largely conserved in a wide geographic comparison between China and Australia. Moreover, dating analyses suggest that the functional community structure has remained stable for long periods during historic range expansions. This suggests that ecological interactions between species may play a persistent role in shaping these communities, in contrast to findings in some comparable temperate systems. PMID- 29615024 TI - re-TAMD: exploring interactions between H3 peptide and YEATS domain using enhanced sampling. AB - BACKGROUND: Analysis of preferred binding regions of a ligand on a protein is important for detecting cryptic binding pockets and improving the ligand selectivity. RESULT: The enhanced sampling approach TAMD has been adapted to allow a ligand to unbind from its native binding site and explore the protein surface. This so-called re-TAMD procedure was then used to explore the interaction between the N terminal peptide of histone H3 and the YEATS domain. Depending on the length of the peptide, several regions of the protein surface were explored. The peptide conformations sampled during the re-TAMD correspond to peptide free diffusion around the protein surface. CONCLUSIONS: The re-TAMD approach permitted to get information on the relative influence of different regions of the N terminal peptide of H3 on the interaction between H3 and YEATS. PMID- 29615025 TI - First molecular detection and characterization of Marek's disease virus in red crowned cranes (Grus japonensis): a case report. AB - BACKGROUND: Marek's disease virus (MDV) resides in the genus Mardivirus in the family Herpesviridae. MDV is a highly contagious virus that can cause neurological lesions, lymphocytic proliferation, immune suppression, and death in avian species, including Galliformes (chickens, quails, partridges, and pheasants), Strigiformes (owls), Anseriformes (ducks, geese, and swans), and Falconiformes (kestrels). CASE PRESENTATION: In 2015, two red-crowned cranes died in Nanjing (Jiangsu, China). It was determined that the birds were infected with Marek's disease virus by histopathological examination, polymerase chain reaction (PCR), gene sequencing and sequence analysis of tissue samples from two cranes. Gross lesions included diffuse nodules in the skin, muscle, liver, spleen, kidney, gizzard and heart, along with liver enlargement and gizzard mucosa hemorrhage. Histopathological assay showed that infiltrative lymphocytes and mitotic figures existed in liver and heart. The presence of MDV was confirmed by PCR. The sequence analysis of the Meq gene showed 100% identity with Md5, while the VP22 gene showed the highest homology with CVI988. Furthermore, the phylogenetic analysis of the VP22 and Meq genes suggested that the MDV (from cranes) belongs to MDV serotype 1. CONCLUSION: We describe the first molecular detection of Marek's disease in red-crowned cranes based on the findings previously described. To our knowledge, this is also the first molecular identification of Marek's disease virus in the order Gruiformes and represents detection of a novel MDV strain. PMID- 29615026 TI - NHS health checks: a cross- sectional observational study on equity of uptake and outcomes. AB - BACKGROUND: The National Health Checks programme aims to reduce the incidence of cardiovascular diseases and health inequalities in England. We assessed equity of uptake and outcomes from NHS Health Checks in general practices in Bristol, UK. METHODS: A cross-sectional study using patient-level data, from 38 general practices. We descriptively analysed the socioeconomic status (SES) of patients invited and the SES and ethnicity of those attending. Logistic regression was used to test associations between invitation and attendance, with population characteristics. RESULTS: Between June 2010 to October 2014, 31,881 patients were invited, and 13,733 NHS Health Checks completed. 47% of patients invited from the three least and 39% from the two most-deprived index of multiple deprivation quintiles, completed a Check. Proportions of invited patients, by ethnicity were 64% non-black and Asian and 31% black and Asian. Men were less likely to attend than women (OR 0.73, 95% confidence interval 0.67 to 0.80), as were patients <= 49 compared to >= 70 years (OR 0.40, 95% confidence interval 0.65 to 0.83). After controlling for SES and population characteristics, compared to patients with low CVD risk, high risk patients were more likely to be prescribed cardiovascular drugs (OR 6.2, 95% confidence interval 4.51 to 8.40). Compared to men, women (OR 01.18, 95% confidence interval 1.03 to 1.35) were more likely to be prescribed cardiovascular drugs, as were those <= 49 years (50-59 years, OR 1.42, 95% confidence intervals 1.13-1.79, 60-69 years, OR 1.60, 95% confidence intervals, 1.22-2.10, >= 70 years, OR 1.64, 95% confidence intervals, 1.14 to 2.35). Controlling for population characteristics, the following groups were most likely to be referred to lifestyle services: younger women (OR 2.22, 95% CI 1.69 to 2.94), those in the most deprived IMD quintile (OR 3.22, 95% CI 1.63 to 6.36) and those at highest risk of CVD (OR, 2.77, 95% CI 1.91 to 4.02). CONCLUSIONS: We found no statistically significant evidence of inequity in attendance for an NHS Health Check by SES. Being older or a woman were associated with better attendance. Targeting men, younger patients and ethnic minority groups may improve equity in uptake for NHS Health Checks. PMID- 29615028 TI - Effect of a resistance and balance exercise programme for women with osteoporosis and vertebral fracture: study protocol for a randomized controlled trial. AB - BACKGROUND: Osteoporotic vertebral fractures are common, and are associated with reduced functioning and health related quality of life. The primary aims of this randomized controlled trial are to examine the immediate and long-term effects of a 12-weeks supervised group exercise programme on habitual walking speed in older women with osteoporosis and a history of vertebral fracture. The secondary aims are to examine the immediate and long-term effects of the exercise program on physical fitness, fear of falling and quality of life. METHODS: The study is a single-blinded randomized controlled trial. Women aged 65 years or older with osteoporosis and a history of vertebral fracture are included. The intervention group receives a 12-week multicomponent exercise programme, including resistance training combined with balance training. The control group receives usual care. Adherence to the programme will be of importance for the internal validity of the study. Participants in the exercise group who don't attend will be followed up with motivational phone calls. The primary outcome is habitual walking speed over 10 m. Secondary outcomes are health related quality of life (Qualeffo-41, SF-36), physical activity (I-PAQ), Patient Specific Functional Scale, Fear of falling (FES-1) and physical fitness (Senior Fitness test, Functional reach test, 4 square step test, grip strength). Sample size, based on the primary outcome, is 150 participants randomized into the two arms on a 1:1 allocation, including an estimated 20% drop out. Descriptive data will be reported as mean (standard deviation), median (range) or count (percent) as appropriate. The data will be analysed following the intention-to-treat principle. Between group differences in primary and secondary outcomes at 3 months follow-up will be assessed using linear regression models with respective outcome at baseline as covariate and the randomised group as factor. DISCUSSION: This trial will generate new knowledge on the effects of a multicomponent exercise programme among women over 65 years with osteoporosis and a history of vertebral fracture, knowledge that is of importance for clinicians, health managers and policy makers. TRIAL REGISTRATION: ClincialTrials.gov Identifier: NCT02781974 . Registered 18.05.16. Retrospectively registered. PMID- 29615027 TI - Comparative efficacy of Chinese herbal injections for treating acute cerebral infarction: a network meta-analysis of randomized controlled trials. AB - BACKGROUND: Chinese herbal injections (CHIs) are prepared by extracting and purifying effective substances from herbs (or decoction pieces) using modern scientific techniques and methods. CHIs combined with aspirin + anticoagulants + dehydrant + neuroprotectant (AADN) are believed to be effective for the treatment of acute cerebral infarction (ACI). However, no randomized controlled trial (RCT) has been performed to directly compare the efficacies of different regimens of CHIs. Therefore, we performed a systematic review and network meta-analysis (NMA) to compare the efficacies of different regimens of CHIs for ACI. METHODS: We conducted an overall and systematic retrieval from literature databases of RCTs focused on the use of CHIs to treat ACI up to June 2016. We used the Cochrane Handbook version 5.1.0 and CONSORT statement to assess the risk of bias. The data were analyzed using STATA 13.0 and WinBUGS 1.4.3 software. RESULTS: Overall, 64 studies with 6225 participants involving 15 CHIs were included in the NMA. In terms of the markedly effective rate, Danhong (DH) + AADN had the highest likelihood of being the best treatment. In terms of the improvement of neurological impairment, Shuxuening (SXN) + AADN had the highest likelihood of being the best treatment. Considering two outcomes, injections of SXN, Yinxingdamo (YXDM), DH, Shuxuetong (SXT), HongHuaHuangSeSu (HHHSS), DengZhanXiXin (DZXX) and Shenxiong glucose (SX) plus AADN were the optimum treatment regimens for ACI, especially SXN + AADN and YXDM + AADN. CONCLUSIONS: Based on the NMA, SXN, YXDM, DH, SXT, HHHSS, DZXX and SX plus AADN showed the highest probability of being the best treatment regimens. Due to the limitations of the present study, our findings should be verified by well-designed RCTs. PMID- 29615029 TI - A Chinese herbal decoction, Jian-Pi-Yi-Shen, regulates the expressions of erythropoietin and pro-inflammatory cytokines in cultured cells. AB - BACKGROUND: A Chinese herbal formula, namely Jian-Pi-Yi-Shen (JPYS), has been clinically prescribed for patients with chronic kidney disease associated-anemia, and which can improve the patient's immunological system. However, the mechanisms of JPYS involved in anemia and immune response have not been investigated. To study the role of JPYS in regulating hematopoietic and immunological functions, we investigated its activities on the expressions of erythropoietin and pro inflammatory cytokines in cultured cells. METHODS: The standardized herbal extracts of JPYS (0-30 MUg/ml) were applied onto cultured cells for 24-48 h. Total RNA was collected from the treated cells and subjected to real-time quantitative PCR analysis. Cultured HEK293T cells, transfected with a construct composed of hypoxia response element tagged with a luciferase gene, i.e. pHRE Luc, were treated with JPYS extracts (1-30 MUg/ml) for 24 h. The cell lysates were subjected to luciferase assay. RESULTS: The treatment with JPYS extract onto cultured HEK293T cells induced erythropoietin expression in a dose-dependent manner, having the highest response by ~ 50% of increase. In parallel, application of JPYS extract for 24 h stimulated expressions of interleukin (IL) 1beta, IL-6, and tumor necrosis factor (TNF)-alpha in cultured RAW 264.7 macrophages. In contrast, the pretreatment with JPYS extract suppressed expressions of IL-1beta, IL-6, and TNF-alpha in lipopolysaccharide-induced macrophages. CONCLUSIONS: These results confirmed the hematopoietic function of JPYS in regulating erythropoietin expression, as well as the bidirectional immune modulatory roles of JPYS by regulating the expression of pro-inflammatory cytokines in cultures. PMID- 29615031 TI - Intentional tanning behaviors among undergraduates on the United States' Gulf Coast. AB - BACKGROUND: Rates of melanoma have dramatically increased among adolescents and young adults in recent years, particularly among young women. Exposure to ultraviolet radiation from intentional tanning practices is likely a major contributor to this epidemic. Southern and coastal regions have higher melanoma mortality rates among non-Hispanic whites in other parts of the U.S., yet little is known about tanning practices of adolescents and young adults in these regions. This study determines the prevalence and methods of intentional tanning utilized by an undergraduate population located on the United States' Gulf Coast. METHODS: Undergraduate students enrolled at a university on the Gulf Coast completed an online survey from March-April 2016, self-reporting their engagement, knowledge, and attitudes regarding outdoor tanning (OT), indoor tanning (IT) and spray tanning (ST). Univariate and multivariate analyses were performed to identify factors associated with tanning behaviors. RESULTS: 2668 undergraduates completed the survey. Of these, 64.9% reported OT tanning, 50.7% reported ever IT, and 21.2% reported ever ST. CONCLUSIONS: In the largest study to date of intentional tanning behaviors of adolescents and young adults from coastal regions, we found high rates of intentional tanning behaviors. There was also significant engagement in spray tanning by this population, not previously reported for adolescents and young adults in a sample of this size. We also identified a high association between different tanning methods, indicating this population engages in multiple tanning behaviors, a phenomenon whose health consequences are not yet known. PMID- 29615030 TI - Systems biology analysis of mitogen activated protein kinase inhibitor resistance in malignant melanoma. AB - BACKGROUND: Kinase inhibition in the mitogen activated protein kinase (MAPK) pathway is a standard therapy for cancer patients with activating BRAF mutations. However, the anti-tumorigenic effect and clinical benefit are only transient, and tumors are prone to treatment resistance and relapse. To elucidate mechanistic insights into drug resistance, we have established an in vitro cellular model of MAPK inhibitor resistance in malignant melanoma. METHODS: The cellular model evolved in response to clinical dosage of the BRAF inhibitor, vemurafenib, PLX4032. We conducted transcriptomic expression profiling using RNA-Seq and RT qPCR arrays. Pathways of melanogenesis, MAPK signaling, cell cycle, and metabolism were significantly enriched among the set of differentially expressed genes of vemurafenib-resistant cells vs control. The underlying mechanism of treatment resistance and pathway rewiring was uncovered to be based on non genomic adaptation and validated in two distinct melanoma models, SK-MEL-28 and A375. Both cell lines have activating BRAF mutations and display metastatic potential. RESULTS: Downregulation of dual specific phosphatases, tumor suppressors, and negative MAPK regulators reengages mitogenic signaling. Upregulation of growth factors, cytokines, and cognate receptors triggers signaling pathways circumventing BRAF blockage. Further, changes in amino acid and one-carbon metabolism support cellular proliferation despite MAPK inhibitor treatment. In addition, treatment-resistant cells upregulate pigmentation and melanogenesis, pathways which partially overlap with MAPK signaling. Upstream regulator analysis discovered significant perturbation in oncogenic forkhead box and hypoxia inducible factor family transcription factors. CONCLUSIONS: The established cellular models offer mechanistic insight into cellular changes and therapeutic targets under inhibitor resistance in malignant melanoma. At a systems biology level, the MAPK pathway undergoes major rewiring while acquiring inhibitor resistance. The outcome of this transcriptional plasticity is selection for a set of transcriptional master regulators, which circumvent upstream targeted kinases and provide alternative routes of mitogenic activation. A fine woven network of redundant signals maintains similar effector genes allowing for tumor cell survival and malignant progression in therapy-resistant cancer. PMID- 29615032 TI - The impact of varus angulation on proximal fractures of the ulna. AB - BACKGROUND: We studied anteromedial varus angulation (VA) in the proximal third of the ulna. The importance of restoration of the anatomical orientation of the ulnar after a proximal fracture is unclear. The purpose of this study was to evaluate the impact of minimal proximal ulna malunion on elbow function after a proximal ulna fracture. METHODS: We reviewed the follow-up of 60 patients who had undergone open reduction with internal fixation (ORIF) of a proximal fracture of the ulna. Patients were divided into two groups, defined as either more or less than 5 degrees of the difference between the VA of the fractured and contralateral ulna. The range of motion(ROM)of elbow flexion, extension and forearm rotation on both sides, Mayo Elbow Performance Score (MEPS) and Visual Analogue Scale (VAS) were measured. RESULTS: The average postoperative time was 3.1 years (1-5 years). Mean VA of the fractured arm was different from the normal side (7.8 +/- 3.0 vs 12.7 +/- 3.0). Compared to the unfractured arm there was a loss in mean elbow flexion (14.2 +/- 4.9 vs 18.0 +/- 5.9), extension ROM (7.1 +/- 2.5 vs 9.3 +/- 1.9, p < 0.05) and forearm rotation ROM (15.6 +/- 8.6 vs 21.8 +/- 9.5) that were statistically significant (p < 0.05). There were no statistically significant differences in the MEPS and VAS score results between the two groups (p > 0.05). CONCLUSIONS: The function of the elbow and forearm was restricted after VA malunion in the proximal ulna, but the quality of life of these patients had not been significantly affected. We suggest that orthopedic surgeons should assess whether the specialized structures of the proximal ulna are damaged or not before surgery. If the anatomy of the fractured bone cannot be restored through manipulation of the connected end directly, it is better to image the anatomical structure of the healthy side from using an elbow X-ray before surgery, and then reset using a pre-shaped plate to prevent malunion. PMID- 29615033 TI - Health sector involvement in the management of female genital mutilation/cutting in 30 countries. AB - BACKGROUND: For the last decades, the international community has emphasised the importance of a multisectoral approach to tackle female genital mutilation (FGM/C). While considerable improvement concerning legislations and community involvement is reported, little is known about the involvement of the health sector. METHOD: A mixed methods approach was employed to map the involvement of the health sector in the management of FGM/C both in countries where FGM/C is a traditional practice (countries of origin), and countries where FGM/C is practiced mainly by migrant populations (countries of migration). Data was collected in 2016 using a pilot-tested questionnaire from 30 countries (11 countries of origin and 19 countries of migration). In 2017, interviews were conducted to check for data accuracy and to request relevant explanations. Qualitative data was used to elucidate the quantitative data. RESULTS: A total of 24 countries had a policy on FGM/C, of which 19 had assigned coordination bodies and 20 had partially or fully implemented the plans. Nevertheless, allocation of funding and incorporation of monitoring and evaluation systems was lacking in 11 and 13 of these countries respectively. The level of the health sectors' involvement varied considerably across and within countries. Systematic training of healthcare providers (HCP) was more prevalent in countries of origin, whereas involvement of HCP in the prevention of FGM/C was more prevalent in countries of migration. Most countries reported to forbid HCP from conducting FGM/C on both minors and adults, but not consistently forbidding re-infibulation. Availability of healthcare services for girls and women with FGM/C related complications also varied between countries dependent on the type of services. Deinfibulation was available in almost all countries, while clitoral reconstruction and psychological and sexual counselling were available predominantly in countries of migration and then in less than half the countries. Finally, systematic recording of FGM/C in medical records was completely lacking in countries of origin and very limited in countries of migration. CONCLUSION: Substantial progress has been made in the involvement of the health sector in both the treatment and prevention of FGM/C. Still, there are several areas in need for improvement, particularly monitoring and evaluation. PMID- 29615034 TI - Multipulse transcranial electrical stimulation (TES): normative data for motor evoked potentials in healthy horses. AB - BACKGROUND: There are indications that transcranial electrical stimulation (TES) assesses the motor function of the spinal cord in horses in a more sensitive and reproducible fashion than transcranial magnetic stimulation (TMS). However, no normative data of TES evoked motor potentials (MEP) is available. RESULTS: In this prospective study normative data of TES induced MEP wave characteristics (motor latency times (MLT); amplitude and waveform) was obtained from the extensor carpi radialis (ECR) and tibial cranialis (TC) muscles in a group of healthy horses to create a reference frame for functional diagnostic purposes. For the 12 horses involved in the study 95% confidence intervals for MLTs were 16.1-22.6 ms and 31.9-41.1 ms for ECR and TC muscles respectively. Intra individual coefficients of variation (CV) and mean of MLTs were: ECR: 2.2-8,2% and 4.5% and TC: 1.4-6.3% and 3.5% respectively. Inter-individual CVs for MLTs were higher, though below 10% on all occasions. The mean +/- sd of MEP amplitudes was respectively 3.61 +/- 2.55 mV (ECR muscle left) and 4.53 +/- 3.1 mV (right) and 2.66 +/- 2.22 mV (TC muscle left) and 2.55 +/- 1.85 mV (right). MLTs showed no significant left versus right differences. All MLTs showed significant (p < 0.05) voltage dependent decreases with slope coefficients of linear regression for ECR: - 0.049; - 0.061 ms/V and TC: - 0.082; - 0.089 ms/V (left; right). There was a positive correlation found between height at withers and MLTs in all 4 muscle groups. Finally, reliable assessment of MEP characteristics was for all muscle groups restricted to a transcranial time window of approximately 15-19 ms. CONCLUSIONS: TES is a novel and sensitive technique to assess spinal motor function in horses. It is easy applicable and highly reproducible. This study provides normative data in healthy horses on TES induced MEPs in the extensor carpi radialis and tibialis cranialis muscles bilaterally. No significant differences between MLTs of the left and right side could be demonstrated. A significant effect of stimulation voltage on MLTs was found. No significant effect of height at the withers could be found based upon the results of the current study. A study in which both TMS and TES are applied on the same group of horses is needed. PMID- 29615035 TI - Real-world evidence: How pragmatic are randomized controlled trials labeled as pragmatic? AB - INTRODUCTION: Pragmatic randomized controlled trials (RCTs) mimic usual clinical practice and they are critical to inform decision-making by patients, clinicians and policy-makers in real-world settings. Pragmatic RCTs assess effectiveness of available medicines, while explanatory RCTs assess efficacy of investigational medicines. Explanatory and pragmatic are the extremes of a continuum. This debate article seeks to evaluate and provide recommendation on how to characterize pragmatic RCTs in light of the current landscape of RCTs. It is supported by findings from a PubMed search conducted in August 2017, which retrieved 615 RCTs self-labeled in their titles as "pragmatic" or "naturalistic". We focused on 89 of these trials that assessed medicines (drugs or biologics). DISCUSSION: 36% of these 89 trials were placebo-controlled, performed before licensing of the medicine, or done in a single-center. In our opinion, such RCTs overtly deviate from usual care and pragmatism. It follows, that the use of the term 'pragmatic' to describe them, conveys a misleading message to patients and clinicians. Furthermore, many other trials among the 615 coined as 'pragmatic' and assessing other types of intervention are plausibly not very pragmatic; however, this is impossible for a reader to tell without access to the full protocol and insider knowledge of the trial conduct. The degree of pragmatism should be evaluated by the trial investigators themselves using the PRECIS-2 tool, a tool that comprises 9 domains, each scored from 1 (very explanatory) to 5 (very pragmatic). CONCLUSIONS: To allow for a more appropriate characterization of the degree of pragmatism in clinical research, submissions of RCTs to funders, research ethics committees and to peer-reviewed journals should include a PRECIS-2 tool assessment done by the trial investigators. Clarity and accuracy on the extent to which a RCT is pragmatic will help understand how much it is relevant to real world practice. PMID- 29615036 TI - A qualitative study into the perceived barriers of accessing healthcare among a vulnerable population involved with a community centre in Romania. AB - BACKGROUND: Minority vulnerable communities, such as the European Roma, often face numerous barriers to accessing healthcare services, resulting in negative health outcomes. Both these barriers and outcomes have been reported extensively in the literature. However, reports on barriers faced by European non-Roma native communities are limited. The "Health Care Access Barriers" (HCAB) model identifies pertinent financial, structural and cognitive barriers that can be measured and potentially modified. The present study thus aims to explore the barriers to accessing healthcare for a vulnerable population of mixed ethnicity from a charity community centre in Romania, as perceived by the centre's family users and staff members, and assess whether these reflect the barriers identified from the HCAB model. METHODS: Eleven community members whose children attend the centre and seven staff members working at the centre participated in face-to-face semi-structured interviews, exploring personal experiences and views on accessing healthcare. The interviews were transcribed and analysed using an initial deductive and secondary inductive approach to identify HCAB themes and other emerging themes and subthemes. RESULTS: Identified themes from both groups aligned with HCAB's themes of financial, structural and cognitive barriers and emergent subthemes important to the specific population were identified. Specifically, financial barriers related mostly to health insurance and bribery issues, structural barriers related mostly to service availability and accessibility, and cognitive barriers related mostly to healthcare professionals' attitudes and discrimination and the vulnerable population's lack of education and health literacy. A unique theme of psychological barriers emerged from both groups with associated subthemes of mistrust, hopelessness, fear and anxiety of this vulnerable population. CONCLUSION: The current study highlights healthcare access barriers to a vulnerable non-Roma native population involved with a charity community centre in Romania. The "Healthcare Access Barriers for Vulnerable Populations" (HABVP) model is proposed as an adaption to the existing HCAB model to account for the unique perceived barriers to healthcare for this population. Recommendations for future resolution of these identified barriers are proposed. PMID- 29615038 TI - How well are Swiss French physicians prepared for future practice in primary care? AB - BACKGROUND: Moving from postgraduate training into independent practice represents a major transition in physicians' professional life. Little is known about how Swiss primary care graduates experience such a transition. The aim of this study was to explore the extent to which primary care physicians who recently set up private practice felt prepared to work as independent practitioners. METHODS: We conducted 7 focus groups among recently established (<= 5 years) primary care physicians in Switzerland. Questions focused on positive and negative aspects of setting up a practice, and degree of preparedness. Transcripts were analysed according to organisational socialisation and work role transition frameworks. RESULTS: Participants felt relatively well prepared for most medical tasks except for some rheumatologic, minor traumatology, ENR, skin and psychiatric aspects. They felt unprepared for non clinical tasks such as office, insurance and medico-legal management issues and did not anticipate that the professional networking outside the hospital would be so important to their daily work. They faced dilemmas opposing professional values to the reality of practice which forced them to clarify their professional roles and expectations. Adjustment strategies were mainly informal. CONCLUSION: Although the postgraduate primary care curriculum is longer in Switzerland than in most European countries, it remains insufficiently connected with the reality of transitioning into independent practice, especially regarding role development and management tasks. A greater proportion of postgraduate training, with special emphasis on these issues, should take place directly in primary care. PMID- 29615037 TI - Identification of new progestogen-associated networks in mammalian ovulation using bioinformatics. AB - BACKGROUND: Progesterone plays an essential role in mammalian ovulation. Although much is known about this process, the gene networks involved in ovulation have yet to be established. When analyze the mechanisms of ovulation, we often need to determine key genes or pathways to investigate the reproduction features. However, traditional experimental methods have a number of limitations. RESULTS: Data, in this study, were acquired from GSE41836 and GSE54584 which provided different samples. They were analyzed with the GEO2R and 546 differentially expressed genes were obtained from two data sets using bioinformatics (absolute log2 FC > 1, P < 0.05). This study identified four genes (PGR, RELN, PDE10A and PLA2G4A) by protein-protein interaction networks and pathway analysis, and their functional enrichments were associated with ovulation. Then, the top 25 statistical pathway enrichments related to hCG treatment were analyzed. Furthermore, gene network analysis identified certain interconnected genes and pathways involved in progestogenic mechanisms, including progesterone-mediated oocyte maturation, the MAPK signaling pathway, the GnRH signaling pathway and focal adhesion, etc. Moreover, we explored the four target gene pathways. q-PCR analysis following hCG and RU486 treatments confirmed the certain novel progestogenic-associated genes (GNAI1, PRKCA, CAV1, EGFR, RHOA, ZYX, VCL, GRB2 and RAP1A). CONCLUSIONS: The results suggested four key genes, nine predicted genes and eight pathways to be involved in progestogenic networks. These networks provide important regulatory genes and signaling pathways which are involved in ovulation. This study provides a fundamental basis for subsequent functional studies to investigate the regulation of mammalian ovulation. PMID- 29615039 TI - Efficacy and safety of artemether-lumefantrine, artesunate-amodiaquine, and dihydroartemisinin-piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria in three provinces in Angola, 2017. AB - BACKGROUND: The Angolan government recommends three artemisinin-based combinations for the treatment of uncomplicated Plasmodium falciparum malaria: artemether-lumefantrine (AL), artesunate-amodiaquine (ASAQ), and dihydroartemisinin-piperaquine (DP). Due to the threat of emerging anti-malarial drug resistance, it is important to periodically monitor the efficacy of artemisinin-based combination therapy (ACT). This study evaluated these medications' therapeutic efficacy in Benguela, Lunda Sul, and Zaire Provinces. METHODS: Enrollment occurred between March and July 2017. Study participants were children with P. falciparum monoinfection from each provincial capital. Participants received a 3-day course of a quality-assured artemisinin-based combination and were monitored for 28 (AL and ASAQ arms) or 42 days (DP arm). Each ACT was assessed in two provinces. The primary study endpoints were: (1) follow-up without complications and (2) failure to respond to treatment or development of recurrent P. falciparum infection. Parasites from each patient experiencing recurrent infection were genotyped to differentiate new infection from recrudescence of persistent parasitaemia. These parasites were also analysed for molecular markers associated with ACT resistance. RESULTS: Of 608 children enrolled in the study, 540 (89%) reached a primary study endpoint. Parasitaemia was cleared within 3 days of medication administration in all participants, and no early treatment failures were observed. After exclusion of reinfections, the corrected efficacy of AL was 96% (91-100%, 95% confidence interval) in Zaire and 97% (93-100%) in Lunda Sul. The corrected efficacy of ASAQ was 100% (97-100%) in Benguela and 93% (88-99%) in Zaire. The corrected efficacy of DP was 100% (96 100%) in Benguela and 100% in Lunda Sul. No mutations associated with artemisinin resistance were identified in the pfk13 gene in the 38 cases of recurrent P. falciparum infection. All 33 treatment failures in the AL and ASAQ arms carried pfmdr1 or pfcrt mutations associated with lumefantrine and amodiaquine resistance, respectively, on day of failure. CONCLUSIONS: AL, ASAQ, and DP continue to be efficacious against P. falciparum malaria in these provinces of Angola. Rapid parasite clearance and the absence of genetic evidence of artemisinin resistance are consistent with full susceptibility to artemisinin derivatives. Periodic monitoring of in vivo drug efficacy remains a priority routine activity for Angola. PMID- 29615040 TI - Multicentre cross-sectional clinical evaluation study about quality of life in adults with disorders/differences of sex development (DSD) compared to country specific reference populations (dsd-LIFE). AB - BACKGROUND: Previous studies in quality of life (QOL) in individuals with disorders/differences of sex development (DSD) have been restricted to subpopulations of the condition. We describe QOL in adult persons with DSD compared to country specific references and assess the impact of diagnosis. METHODS: The multicentre cross-sectional clinical evaluation (dsd-LIFE) took place in 14 specialized clinics in six European countries. Adolescents (>=16 years) and adults having a DSD condition were included from 02/2014 to 09/2015. The main outcome QOL was measured by the WHOQOL-BREF (domains of physical health, psychological, social relationships, and environment). QOL was compared to country specific reference populations by using unpaired t-tests. Linear regression models explained the additional variance of the diagnosis on QOL. RESULTS: Three hundred one individuals with Turner Syndrome, 219 with Klinefelter Syndrome (including XYY), 226 with 46,XX CAH and 294 with rare DSD conditions (gonadal dysgenesis, androgen insensitivity syndrome, severe hypospadias, and androgen synthesis errors or other diagnosis) took part. Compared to healthy European populations, QOL was similar in psychological, slightly worse in physical health, and slightly better in environment. In social relationships, QOL was significantly poorer compared to healthy and non-healthy reference populations. In linear regression models health status was the most important predictor of QOL; additional variance was explained by feelings about household's income in all domains, and the relationship status in social relationships. Diagnosis explained nearly no additional variance. CONCLUSIONS: Except for social relationships, most people with DSD adapt well to their life circumstances and report a good QOL. Not diagnosis, but the individual's health status is much more important than previously thought. Therefore care for people with DSD should focus more on chronic physical or mental health problems both related and unrelated to the diagnosis itself. TRIAL REGISTRATION: German Clinical Trials Register DRKS00006072 . PMID- 29615041 TI - School-based malaria prevalence: informative systematic surveillance measure to assess epidemiological impact of malaria control interventions in the Democratic Republic of the Congo. AB - BACKGROUND: In southern Democratic Republic of the Congo, malaria transmission is stable with seasonal fluctuations. Different measurements can be used to monitor disease burden and estimate the performance of control programmes. Repeated school-based malaria prevalence surveys (SMPS) were conducted from 2007 to 2014 to generate up-to-date surveillance data and evaluate the impact of an integrated vector control programme. METHODS: Biannual SMPS used a stratified, randomized and proportional sampling method. Schools were randomly selected from the entire pool of facilities within each Health Area (HA). Subsequently, school-children from 6 to 12 years of age were randomly selected in a proportional manner. Initial point-of-care malaria diagnosis was made using a rapid detection test. A matching stained blood film was later examined by expert microscopy and used in the final analysis. Data was stratified and analysed based on age, survey time and location. RESULTS: The baseline SMPS (pre-control in 2007) prevalence was approximately 77%. From 2009 to 2014, 11,628 school-children were randomly screened. The mean age was 8.7 years with a near equal sex ratio. After exclusion, analysis of 10,493 students showed an overall malaria prevalence ratio of 1.92 in rural compared to urbanized areas. The distribution of Plasmodium falciparum malaria was significantly different between rural and urban HAs and between end of wet season and end of dry season surveys. The combined prevalence of single P. falciparum, Plasmodium malariae and Plasmodium ovale infections were 29.9, 1.8 and 0.3% of those examined, respectively. Only 1.8% were mixed Plasmodium species infections. From all microscopically detected infections (3545 of 10,493 samples examined), P. falciparum represented 88.5%, followed by P. malariae (5.4%) and P. ovale (0.8%). Cases with multiple species represented 5.3% of patent infections. Malaria prevalence was independent of age and gender. Control programme performance contributed to a significant decrease in mean P. falciparum infection density in urban compared to rural locations. Some rural areas remained highly refractory to control measures (insecticide-treated bed nets, periodic indoor residual spraying). CONCLUSION: The SMPS is a useful longitudinal measurement for estimating population malaria prevalence and demonstrating disease burden and impact of control interventions. SMPS can identify refractory areas of transmission and thus prioritize control strategies accordingly. PMID- 29615042 TI - Higher non-HDL-cholesterol to HDL-cholesterol ratio linked with increased nonalcoholic steatohepatitis. AB - BACKGROUND: Non-HDL-cholesterol to HDL-cholesterol (non-HDL-c/HDL-c) ratio is a feasible predictor for coronary heart disease, metabolic syndrome, and insulin resistance. Patients with nonalcoholic steatohepatitis (NASH) have an increased risk of developing cardiovascular problems and type 2 diabetes. However, the predictive role of non-HDL-c/HDL-c ratio in NASH hasn't been investigated yet. METHODS: We conducted a retrospective cohort study. A total of 3489 eligible subjects were selected in the present study. Prevalence and characteristics of NASH were demonstrated. Conditional logistic regression was used to analyze the association between non-HDL-c/HDL-c ratio and risks of NASH. Associations between non-HDL-c/HDL-c ratio and serum aminotransferase levels were also investigated. RESULTS: The overall prevalence of NASH was 6.13%, higher in male (6.89%) than that in female (5.04%). Interestingly, the prevalence of NASH showed a positive correlation with the elevation of non-HDL-c/HDL-c ratio (Pearson's Chi-squared test, linear trend 0.010, p < 0.05). The risk of NASH increased approximately 1.8-fold among subjects with higher non-HDL-c/HDL-c ratio. After adjustment for confounding factors, higher non-HDL-c/HDL-c ratio was still associated with a 54.4% increased risk of NASH. Male had higher risk of NASH than female when their non-HDL-c/HDL-c ratio increased. The risk of NASH in subjects with BMI more than 24 was 3 times higher than that in subjects with BMI less than 24. Every one unit increase in Non-HDL-c/HDL-c ratio was associated with 64.5% increase in ALT/AST level (p < 0.05) after adjustment for confounding factors. CONCLUSIONS: Our study provided strong evidence that subjects with higher non-HDL-c/HDL-c ratio had a higher risk of NASH, which suggested that non-HDL-c/HDL-c ratio might be a feasible predictor for NASH. PMID- 29615043 TI - A review of progress towards sub-national malaria elimination in Matabeleland South Province, Zimbabwe (2011-2015): a qualitative study. AB - BACKGROUND: Malaria remains a public health problem in Zimbabwe. However, malaria elimination has become a foreseeable prospect with Matabeleland South Province making significant gains towards halting local malaria transmission. This study reviews malaria elimination progress and challenges to date utilizing the World Health Organization's Malaria Programme Review framework. RESULTS: Between 2011 and 2015, malaria incidence was less than one case per 1000 population at risk in all districts save for Beitbridge and Gwanda. The majority of cases were from Beitbridge with local transmission in the same. Incidence declined in Bulilima (p = 0.01), Gwanda (p = 0.72) and Umzingwane (p = 0.44), increasing in Beitbridge (p = 0.35), Insiza (p = 0.79) and Mangwe (p = 0.60). Overall provincial incidence declined although this was not statistically significant. Malaria transmission was bimodal, with a major peak in April and a minor peak in October. A case based malaria surveillance system existed but was not real-time. Foci response guidelines were not domesticated. Artemisinin formed the backbone of case management regimens with primaquine for gametocyte clearance. Indoor residual spraying coverages were below the national target of 95% for rooms targeted for spraying. CONCLUSION: Matabeleland South province has set precedence for targeting sub-national malaria elimination in Zimbabwe. This experience may prove useful for national scale up. There is need to improve surveillance, foci response and intensification of activities to halt residual malaria transmission in Beitbridge District. PMID- 29615044 TI - Simulation models predict that school-age children are responsible for most human to-mosquito Plasmodium falciparum transmission in southern Malawi. AB - BACKGROUND: Malaria persists in some high-transmission areas despite extensive control efforts. Progress toward elimination may require effective targeting of specific human populations that act as key transmission reservoirs. METHODS: Parameterized using molecular-based Plasmodium falciparum infection data from cross-sectional community studies in southern Malawi, a simulation model was developed to predict the proportions of human-to-mosquito transmission arising from (a) children under 5 years old (U5s), (b) school-age children (SAC, 5-15 years), (c) young adults (16-30 years), and (d) adults > 30 years. The model incorporates mosquito biting heterogeneity and differential infectivity (i.e. probability that a blood-fed mosquito develops oocysts) by age and gametocyte density. RESULTS: The model predicted that SAC were responsible for more than 60% of new mosquito infections in both dry and rainy seasons, even though they comprise only 30% of this southern Malawi population. Young adults were the second largest contributors, while U5s and adults over 30 were each responsible for < 10% of transmission. While the specific predicted values are sensitive to the relative infectiousness of SAC, this group remained the most important contributor to mosquito infections under all realistic estimates. CONCLUSIONS: These results suggest that U5 children play a small role compared to SAC in maintaining P. falciparum transmission in southern Malawi. Models that assume biting homogeneity overestimate the importance of U5s. To reduce transmission, interventions will need to reach more SAC and young adults. This publicly available model can be used by others to estimate age-specific transmission contributions in epidemiologically similar sites with local parameter estimates of P. falciparum prevalence and bed net use. PMID- 29615045 TI - A common mechanism explains the induction of aerobic fermentation and adaptive antioxidant response in Phaffia rhodozyma. AB - BACKGROUND: Growth conditions that bring about stress on Phaffia rhodozyma cells encourage the synthesis of astaxanthin, an antioxidant carotenoid, which protects cells against oxidative damage. Using P. rhodozyma cultures performed with and without copper limitation, we examined the kinetics of astaxanthin synthesis along with the expression of asy, the key astaxanthin synthesis gene, as well as aox, which encodes an alternative oxidase protein. RESULTS: Copper deficiency had a detrimental effect on the rates of oxygen consumption and ethanol reassimilation at the diauxic shift. In contrast, copper deficiency prompted alcoholic fermentation under aerobic conditions and had a favorable effect on the astaxanthin content of cells, as well as on aox expression. Both cultures exhibited strong aox expression while consuming ethanol, but particularly when copper was absent. CONCLUSION: We show that the induction of either astaxanthin production, aox expression, or aerobic fermentation exemplifies the crucial role that redox imbalance plays in triggering any of these phenomena. Based on our own results and data from others, we propose a mechanism that rationalizes the central role played by changes of respiratory activity, which lead to redox imbalances, in triggering both the short-term antioxidant response as well as fermentation in yeasts and other cell types. PMID- 29615046 TI - Phytochemical composition, antilipidemic and antihypercholestrolemic perspectives of Bael leaf extracts. AB - BACKGROUND: In recent times, focus on plant research has improved all over the world and essential parts of plants provide bioactive compounds in human diet. The bael (Aegle marmelos) has enormous traditional uses in the treatment of chronic diarrhea, dysentery, peptic ulcers and as a laxative. The main focus of this study was characterization of bael leaf extract for its bioactive constituents, antihypercholestrolemic and antilipidemic perspectives. METHODS: After proximate composition of bael powder, the aqueous extract of bael leaf was used for phytochemical profiling (alkaloids, total phenolic content and total flavonoid content). Afterwards, normal rats group G0 was administrated basal diet while G1 and G2 normal rat groups were fed diets containing bael leaf extract 125 mg and 250 mg, respectively for consecutive 60 days. In a similar way, hyperlipidemic rats group Gh0 was administrated basal diet while Gh1 and Gh2 hyperlipidemic rat groups were fed diets containing bael leaf extract 125 mg and 250 mg, respectively for consecutive 60 days. The blood drawn on day 0, day 30 and day 60 was analyzed for serum parameters, such as total cholesterol, high density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides concentration and free and ester cholesterol. RESULTS: Bael leaf powder is a rich source of crude fiber (14.50 +/- 0.10 g/100 g). Aqueous extract of bael leaf contains alkaloids (15.58 +/- 0.05 mg/g), flavonoids (64.00 +/- 0.05 mg/g), phenolics (30.34 +/- 0.01 GAEmg/g). From the In vivo studies, the lowest weight gain was observed in group G2 and in Gh2 as compared to control of both groups. The decrease in serum TC for G1-15.06%, G2-17.27% while in Gh1-22.46% and Gh2-34.82% after day 60, respectively. The maximum decrease was observed in group G2 (- 14.33%) and in Gh2 (- 24.79%) for triglycerides after 60 days. For HDL cholesterol, significant increase (11.20%) in G2 and (49.83%) in Gh2 was observed of after 60 days. A trend in decrease of serum LDL-cholesterol in G2 (- 9.63%) and in Gh2 (- 44.65%) was also observed at day 60, and - 19.05% and - 30.06% decrease was noted in G2 and Gh2, respectively and decreasing trend was observed in free and total cholesterol - 22.30% and - 81.49% for groups G2 and Gh2 after day 60. CONCLUSIONS: The results of the present study demonstrated that the extract contents of bael leaf provide protective role against hypercholesterolemic and hyperlipidemic conditions. PMID- 29615047 TI - Potent antiplasmodial extracts and fractions from Terminalia mantaly and Terminalia superba. AB - BACKGROUND: The emergence and spread of malaria parasites resistant to artemisinin-based combination therapy stresses the need for novel drugs against malaria. Investigating plants used in traditional medicine to treat malaria remains a credible option for new anti-malarial drug development. This study was aimed at investigating the antiplasmodial activity and selectivity of extracts and fractions from Terminalia mantaly and Terminalia superba (Combretaceae) that are used in Cameroon to treat malaria. METHODS: Twelve methanolic (m) and water (w) extracts obtained by maceration of powdered dried leaves (l), stem bark (sb) and root (r) of Terminalia mantaly (Tm) and Terminalia superba (Ts) and 12 derived fractions of hexane, chloroform, ethyl acetate and 4 final residues of selected extracts were assessed for antiplasmodial potential in vitro against the chloroquine-resistant PfINDO and the chloroquine-sensitive Pf3D7 strains of Plasmodium falciparum using the SYBR green I-based fluorescence assay. The cytotoxicity of potent extracts and fractions was evaluated in vitro using the MTT assay on HEK239T cell line. RESULTS: The antiplasmodial IC50 of extracts from both plants ranged from 0.26 to > 25 ug/mL. Apart from the extracts Tmrm and Tsrw that exerted moderate antiplasmodial activities (IC50: 5-20 ug/mL) and Tmrw that was found to be non-active at the tested concentrations (IC50 > 25 ug/mL), all other tested crude extracts exhibited potent activities with IC50 < 5 ug/mL. The aqueous extracts from the stem bark of Terminalia mantaly (Tmsbw) and the leaf of Terminalia superba (Tslw) displayed the highest antiplasmodial activities (IC50: 0.26-1.26 ug/mL) and selectivity (SI > 158) on both resistant PfINDO and sensitive Pf3D7 strains. Four fractions upon further extraction with chloroform and ethyl acetate (TmlwChl, TmsbwChl, TmsbwEA, TsrmEA) afforded from three selected crude extracts (Tmlw, Tmsbw, Tsrm) exhibited highly potent activities against both P. falciparum strains (IC50 < 2 ug/mL) and high selectivity (SI > 109). CONCLUSIONS: The results achieved in this work validate the reported traditional use of Terminalia mantaly and Terminalia superba to treat malaria. Moreover, the highly potent and selective fractions warrant further investigation to characterize the active antiplasmodial principles and progress them to rodent malaria models studies if activity and selectivity are evidenced. PMID- 29615048 TI - Measurement properties of the Nepali version of the Connor Davidson resilience scales in individuals with chronic pain. AB - BACKGROUND: Resilience is an individual's ability to recover or "bounce back" from stressful events. It is commonly identified as a protective factor against psychological dysfunctions in wide range of clinical conditions including chronic pain. Resilience is commonly assessed using the Connor Davidson Resilience Scale (CD-RISC). Translation and cross-cultural adaptation of the CD-RISC into Nepali will allow for a deeper understanding of resilience as an important domain in health in Nepal, and will allow for cross-cultural comparison with other cultures. Therefore, the aims of the study were to translate and culturally adapt 10- and 2-item versions of the CD-RISC into Nepali and evaluate their psychometric properties. METHODS: After translating the measures, we performed exploratory and confirmatory factor analyses of the 10-item version in two independent samples (ns = 131 and 134) of individuals with chronic pain. We then evaluated the internal consistency, test-retest stability, and construct validity of the 10- and 2-item measures in these samples. We also evaluated the internal consistency, and the construct and concurrent validity of the 2-item version in an additional sample of 140 individuals. RESULTS: The results supported a single factor model for the 10-item measure; this measure also evidenced good to excellent internal consistency and excellent test-retest stability. Construct validity was supported via moderate associations with pain catastrophizing. The internal consistency of 2-item version was marginal, although construct validity was supported via weak to moderate associations with measures of pain catastrophizing, depression and anxiety, and concurrent validity was supported by strong association with the 10-item CD-RISC scale. CONCLUSION: The findings support the reliability and validity of the 10-item Nepali version of the CD RISC, and use of the 2-item version in survey studies in individuals with chronic pain. The availability of these translated measures will allow for cross-cultural comparisons of resilience in samples of individuals with chronic pain. PMID- 29615050 TI - Differential activity of methylene blue against erythrocytic and hepatic stages of Plasmodium. AB - BACKGROUND: In the context of malaria elimination/eradication, drugs that are effective against the different developmental stages of the parasite are highly desirable. The oldest synthetic anti-malarial drug, the thiazine dye methylene blue (MB), is known for its activity against Plasmodium blood stages, including gametocytes. The aim of the present study was to investigate a possible effect of MB against malaria parasite liver stages. METHODS: MB activity was investigated using both in vitro and in vivo models. In vitro assays consisted of testing MB activity on Plasmodium falciparum, Plasmodium cynomolgi and Plasmodium yoelii parasites in human, simian or murine primary hepatocytes, respectively. MB in vivo activity was evaluated using intravital imaging in BALB/c mice infected with a transgenic bioluminescent P. yoelii parasite line. The transmission-blocking activity of MB was also addressed using mosquitoes fed on MB-treated mice. RESULTS: MB shows no activity on Plasmodium liver stages, including hypnozoites, in vitro in primary hepatocytes. In BALB/c mice, MB has moderate effect on P. yoelii hepatic development but is highly effective against blood stage growth. MB is active against gametocytes and abrogates parasite transmission from mice to mosquitoes. CONCLUSION: While confirming activity of MB against both sexual and asexual blood stages, the results indicate that MB has only little activity on the development of the hepatic stages of malaria parasites. PMID- 29615049 TI - A GATA3-specific DNAzyme attenuates sputum eosinophilia in eosinophilic COPD patients: a feasibility randomized clinical trial. AB - BACKGROUND: A subset of COPD-patients presents with eosinophilic airway inflammation. While treatment of asthmatic patients with the GATA3-specific DNAzyme SB010 attenuated sputum eosinophilia after allergen challenge, this specific treatment has not been evaluated in patients with COPD. Our objective was to evaluate the feasibility and safety of inhaled SB010 in COPD patients with sputum eosinophilia. METHODS: We conducted a randomized, double-blind, placebo controlled, multicentre clinical trial in COPD-patients with sputum eosinophilia (>=2.5% non-squamous cells). Patients inhaled 10 mg SB010 bid or matching placebo via the controlled inhalation system AKITA2 APIXNEB for 28 days. Endpoints included the feasibility of the study (primary), patient's safety, sputum eosinophils, FENO, lung function, symptoms, and biomarkers. The study was registered in the German Clinical Trials Register: DRKS00006087. RESULTS: One hundred thirty patients were screened, 23 patients were randomized (FEV1 49.4 +/- 11.5%; sputum eosinophils 8.0 +/- 8.4%) and 19 patients completed the study (10 placebo, 9 SB010. After 28 days, SB010 decreased the relative sputum eosinophil count (p = 0.004) as compared to no changes in placebo-treated patients. FENO, lung function, and symptoms were not affected significantly. We found an increase in blood IFN-gamma (p = 0.02) and a trend to lower IL-5 levels in patients treated with SB010. SB010 was safe and well tolerated. Thirty five AEs (22 SB010, 13 placebo including 1 SAE) were observed with 3 AEs in each group judged to be possibly treatment-related. CONCLUSION: In patients with eosinophilic COPD, sputum eosinophils could be reduced by inhalation of SB010. Long-term studies are needed to demonstrate clinical efficacy. PMID- 29615051 TI - The nuclear transportation routes of membrane-bound transcription factors. AB - Membrane-bound transcription factors (MTFs) are transcription factors (TFs) that are anchored in membranes in a dormant state. Activated by external or internal stimuli, MTFs are released from parent membranes and are transported to the nucleus. Existing research indicates that some plasma membrane (PM)-bound proteins and some endoplasmic reticulum (ER) membrane-bound proteins have the ability to enter the nucleus. Upon specific signal recognition cues, some PM bound TFs undergo proteolytic cleavage to liberate the intracellular fragments that enter the nucleus to control gene transcription. However, lipid-anchored PM bound proteins enter the nucleus in their full length for depalmitoylation. In addition, some PM-bound TFs exist as full-length proteins in cell nucleus via trafficking to the Golgi and the ER, where membrane-releasing mechanisms rely on endocytosis. In contrast, the ER membrane-bound TFs relocate to the nucleus directly or by trafficking to the Golgi. In both of these pathways, only the fragments of the ER membrane-bound TFs transit to the nucleus. Several different nuclear trafficking modes of MTFs are summarized in this review, providing an effective supplement to the mechanisms of signal transduction and gene regulation. Moreover, targeting intracellular movement pathways of disease associated MTFs may significantly improve the survival of patients. PMID- 29615052 TI - The trend and features of physician workforce supply in China: after national medical licensing system reform. AB - BACKGROUND: The annual number of newly licensed physicians is an important indicator of medical workforce supply, which can accurately reflect an inflow into the health care market over a period. In order to both regulate medical professions and improve the quality of health care services, China established its medical licensing system from the point of the implementation of 'Law on Practising Doctors' in 1999. The objective of this study is to depict the trend and structure of newly licensed physicians thereafter. METHODS: This study analyses a unique census data set that provides the headcount of newly licensed physicians from 2005 to 2015 in China. We also review a short history of medical licensing system reform in China since the 1990s. RESULTS: The annual number of first-time licensed physicians in China increased from 159 489 in 2005 to 221 639 in 2015. Up to 2015, over half of newly licensed physicians had not received a medical education equivalent to a bachelor degree or higher. Around 51% of China's newly licensed physicians were female in 2005, while the same ratio for females in 2015 was 56%. CONCLUSION: This article first provides an exploratory analysis of physician inflow into health care market in China using physician licensing data. The medical licensing system in China allows entering physicians with a broad range of educational levels. Moreover, the feminisation of the physician supply in China has become increasingly apparent and its impacts on health care provision still require more rigorous examination. PMID- 29615053 TI - Correction to: Mechanisms of multiple neurotransmitters in the effects of Lycopene on brain injury induced by Hyperlipidemia. AB - Following publication of the original article [1] it came to the attention of the Research Integrity Group that the following corrections were required. PMID- 29615054 TI - Anti-plasmodial effect of plant extracts from Picrolemma huberi and Picramnia latifolia. AB - BACKGROUND: Malaria is an infectious disease caused by parasites of the genus Plasmodium, of which Plasmodium vivax and Plasmodium falciparum are the major species that cause the disease in humans. As there are relatively few alternatives for malaria treatment, it is necessary to search for new chemotherapeutic options. Colombia possesses a great diversity of plants, which are potential sources of new compounds of medical interest. Thus, in this study the antiplasmodial effect of extracts from two species of plants from the families Simaroubaceae and Picramniaceae (Picramnia latifolia and Picrolemma huberi) was evaluated in vitro and in vivo. These plants were chosen because they contain secondary metabolites with interesting medicinal effects. RESULTS: The ethanolic extracts of both species were highly active with IC50: 1.2 +/- 0.19 ug/mL for P. latifolia and IC50: 0.05 +/- 0.005 ug/mL for P. huberi. The P. latifolia extract had a stage specific effect on trophozoites and inhibited parasite growth in vivo by 52.1 +/- 3.4%, evaluated at 1000 mg/kg in Balb/c mice infected with Plasmodium berghei. On the other hand, evaluated at 150 mg/kg body weight in the same murine model, the ethanolic extract from P. huberi had an antiplasmodial effect in all the asexual intraerythrocytic stages of P. falciparum FCR3 and inhibited the parasitic growth in 93 +/- 32.9%. CONCLUSIONS: This is the first report of anti-malarial activity for these two species of plants. Thus, P. latifolia and P. huberi are potential candidates for the development of new drugs for treating malaria. PMID- 29615055 TI - Differential susceptibilities of Anopheles albimanus and Anopheles stephensi mosquitoes to ivermectin. AB - BACKGROUND: Vector control is a crucial element of anti-malaria campaigns and works best when there is a thorough knowledge of the biology and behaviour of the Anopheles vector species responsible for transmitting malaria within a given locale. With the push to eradicate malaria stronger than ever, there is a growing need to develop and deploy control strategies that exploit the behavioural attributes of local vector species. This is especially true in regions where the vectors are exophagic (i.e., prefer to bite outdoors), exophilic (i.e., prefer to remain outdoors), and zoophagic (i.e., as likely to feed on non-humans as humans). One promising strategy targeting vectors with these behavioural traits is the administration of avermectin-based endectocides, such as ivermectin, to humans and livestock. When ingested in a blood meal, ivermectin has been shown to reduce mosquito survivorship and fecundity in a number of Anopheles species. In this study, the relative toxicity of ivermectin was compared between two zoophagic, exophilic malaria vectors-Anopheles albimanus and Anopheles stephensi. RESULTS: Toxicity of ivermectin was assessed using membrane feedings, intrathoracic injections, and mosquito feedings on treated mice. When ingested in a blood meal, ivermectin was much less toxic to An. albimanus (4-day oral LC50 = 1468 ng/ml) than to An. stephensi (4-day oral LC50 = 7 ng/ml). However when injected into the haemocoel of An. albimanus, ivermectin was much more toxic (3 day parenteral LC50 = 188 ng/ml). Because the molecular targets of ivermectin (i.e., glutamate-gated chloride channels) reside outside the midgut in nerves and muscles, this suggests that ingested ivermectin was not readily absorbed across the midgut of An. albimanus. In contrast, ivermectin was considerably more toxic to An. stephensi when ingested (4-day oral LC50 = 7 ng/ml) than when injected (3 day parenteral LC50 = 49 ng/ml). This suggests that metabolic by-products from the digestion of ivermectin may play a role in the oral toxicity of ivermectin to An. stephensi. Blood meal digestion and subsequent oviposition rates were significantly hindered in both species by ingested ivermectin but only at concentrations at or above their respective oral LC50 concentrations. To test mosquitocidal activity of ivermectin in a live host system, two groups of three mice each received subcutaneous injections of either ivermectin (600 ug/kg BW) or saline (control). One day after injection, the ivermectin-treated mice (n = 3) exhibited significant mosquitocidal activity against both An. stephensi (85% mortality vs 0% in control-fed) and, to a lesser degree, An. albimanus (44% mortality vs 11% in control-fed). At 3 days, the mosquitocidal activity of ivermectin-treated mice waned and was effective only against An. stephensi (31% mortality vs 3% in control-fed). CONCLUSIONS: Ivermectin was not uniformly toxic to both Anopheles species. Previous studies indicate that ivermectin is a good choice of endectocide to use against malaria vectors in southeast Asia and Africa. However, these data suggest that ivermectin may not be the optimal endectocide to use in Central America or the Caribbean where An. albimanus is a major malaria vector species. If endectocides are to be used to help eradicate malaria, then additional efficacy data will be needed to define the activity of specific endectocides against the major malaria vector species of the world. PMID- 29615056 TI - Patient with multiple acyl-CoA dehydrogenase deficiency disease and ETFDH mutations benefits from riboflavin therapy: a case report. AB - BACKGROUND: Lipid storage myopathy (LSM) is a diverse group of lipid metabolic disorders with great variations in the clinical phenotype and age of onset. Classical multiple acyl-CoA dehydrogenase deficiency (MADD) is known to occur secondary to mutations in electron transfer flavoprotein dehydrogenase (ETFDH) gene. Whole exome sequencing (WES) with clinical correlations can be useful in identifying genomic alterations for targeted therapy. CASE PRESENTATION: We report a patient presented with severe muscle weakness and exercise intolerance, suggestive of LSM. Diagnostic testing demonstrated lipid accumulation in muscle fibres and elevated plasma acyl carnitine levels. Exome sequencing of the proband and two of his unaffected siblings revealed compound heterozygous mutations, c.250G > A (p.Ala84Thr) and c.770A > G (p.Tyr257Cys) in the ETFDH gene as the probable causative mutations. In addition, a previously unreported variant c.1042C > T (p.Arg348Trp) in ACOT11 gene was found. This missense variant was predicted to be deleterious but its association with lipid storage in muscle is unclear. The diagnosis of MADD was established and the patient was treated with riboflavin which resulted in rapid clinical and biochemical improvement. CONCLUSIONS: Our findings support the role of WES as an effective tool in the diagnosis of highly heterogeneous disease and this has important implications in the therapeutic strategy of LSM treatment. PMID- 29615057 TI - An in vitro investigation of telocytes-educated macrophages: morphology, heterocellular junctions, apoptosis and invasion analysis. AB - BACKGROUND: Telocytes (TCs), a recently discovered novel type of interstitial cells, were also found in a wide variety of human and mammalian reproductive organs/tissues, including uterus, oviduct and placenta. Previously, we demonstrated that TCs-conditioned media was capable of activating peritoneal macrophages (pMACs) through paracrine effects. This study investigates the hypothesis that direct interaction of TCs with pMACs will also play a significant role in immunoregulation of pMACs. METHODS: TCs and pMACs were derived from the uterus and intraperitoneal cavity of female BALB/c mice, respectively. TCs were identified by immunofluorescence and then co-cultured directly with pMACs for 24 h without added cytokines, to observe the in vitro biological behavior of pMACs. We used histochemical staining to study morphology and mitochondrial metabolism of pMACs, scanning electron microscopy to study heterocellular junctions, flow cytometry to investigate mitochondrial membrane potential (DeltaPsim) and apoptosis, and transwell chambers to study invasion ability. Student-t test was used accordingly. RESULTS: Presently, TCs with typical structure and immunophenotype of double CD-34-positive/vimentin-positive were successfully isolated. pMACs co-cultured with TCs showed obviously morphological activation, with enhanced energy metabolism (P < 0.05). Meanwhile, direct physical cell-to cell interaction promoted the development of heterocellular junctions between TCs and pMACs. Furthermore, TCs treatment markedly reduced the depletion of DeltaPsim in co-cultured pMACs (all P < 0.05), and inhibited their apoptosis (P < 0.05). Functionally, pMACs co-cultured with TCs showed enhanced invasion ability (P < 0.05). CONCLUSIONS: Direct physical cell-to-cell interaction promoted the development of heterocellular junctions between TCs and pMACs, presumably responsible for the observed novel efficient way of pMACs activation via mitochondrial signaling pathway. TCs-educated pMACs might be a promising way to restore the defective immunosurveillance in endometriosis (EMs), led to the enhanced treatment efficacy of EMs in a simple and clinically feasible fashion. PMID- 29615058 TI - Effects of recombinant human growth hormone administration on cardiovascular risk factors in obese children with relative growth hormone deficiency. AB - BACKGROUND: Based on the sample of obese children with relative growth hormone deficiency (GHD), the objective of our study was to determine the effects of rhGH treatment on cardiovascular risk factors, including body mass index (BMI), lipid levels and glucose metabolism index. METHODS: A total of 43 obese children with relative GHD were included in our final analysis. The obese subjects were divided into two groups: recombinant human growth hormone (rhGH) treatment group and untreated control group. RESULTS: After 6 months, subjects in the rhGH treatment group had significant reductions in BMI standard deviation scores (SDS) compared with controls (2.32 +/- 0.85 vs. 2.80 +/- 0.61; P = 0.041), and Insulin-like growth factor 1(IGF-1) level increased during rhGH treatment, in comparison with the control group (702.91 +/- 246.03 vs. 348.30 +/- 131.93 ng/mL, P < 0.001). GH treatment reduced low density lipoprotein cholesterol (LDL-C) (2.20 +/- 0.45 vs. 2.63 +/- 0.76 mmol/L, P = 0.027), aspartate aminotransferase (AST) (21.26 +/- 5.72 vs. 32.30 +/- 17.68 mmol/L, P = 0.006) as well as alanine aminotransferase (ALT) (16.70 +/- 6.72 vs. 45.20 +/- 46.62 mmol/L, P = 0.002), and increased high density lipoprotein cholesterol (HDL-C) (1.45 +/- 0.40 vs. 1.19 +/- 0.23 mmol/L, P = 0.016) levels compared with the control group. CONCLUSION: RhGH treatment for 6 months on obese children with relative GHD reduces BMI SDS, stabilize IGF-1 levels, and exerts beneficial effects on blood lipid profiles and live enzyme compared with untreated control group. Moreover, GH administration has no significant effects on increased insulin resistance and no adversely effect on glucose homeostasis. PMID- 29615059 TI - Local knowledge and practices towards malaria in an irrigated farming community in Ghana. AB - BACKGROUND: Although malaria is endemic across Ghana, the risk is generally elevated for residents living in and around stagnant water bodies such as dams and irrigated farming projects. What knowledge do these at-risk populations have about the aetiology and symptoms of malaria? What are their coping strategies? And what interventions are needed to help improve the health outcomes of people living in high-risk malaria communities? METHODS: This study addressed these research questions with primary data, comprising both qualitative interviews and quantitative surveys, collected in Asutsuare-a rural irrigated farming community located in the Greater Accra Region of Ghana. RESULTS: Results from the fieldwork showed that awareness of malaria as a major health concern in the community was universal. Respondents also displayed a high knowledge of some common clinical symptoms of malaria. Yet, only 3% out of the total survey respondents of 337 indicated they immediately visit a health facility for treatment whenever they suspected malaria. The overwhelming majority (about 97%) indicated they only visit a healthcare facility for treatment if they felt the suspected malaria illness was severe and/or other treatment options had failed. CONCLUSION: Malaria testing training for drug dispensing personnel as well as the provision of malaria testing kits in drug dispensing stores are necessary to facilitate early malaria screening and timely diagnosis particularly in rural endemic areas. PMID- 29615060 TI - Evaluating the reliability and validity of SF-8 with a large representative sample of urban Chinese. AB - BACKGROUND: The Short Form-8 (SF-8) is a widely used instrument for measuring health-related quality of life (HRQOL). The purpose of the current study is to evaluate the reliability and validity of the Chinese version SF-8 using a large, representative sample of city residents in mainland China. METHODS: We surveyed residents of 35 major cities in China using random digit dialing of both landlines and cell phones. We adopted a multi-stage stratified sampling scheme and selected a probability sample of 10,885 adults. Internal consistency reliability of the SF-8 was evaluated with item-total correlations and Cronbach's alphas. Construct validity was assessed with factor analysis. Known-groups validity was examined based on known HRQOL differences in age, gender, income, and overall quality of life. RESULTS: We showed that SF-8 has very good internal consistency reliability and known-groups validity. Our results also confirmed that the traditional 2-factor structure of SF-8 (physical and mental health) is reasonable among Chinese city residents. Further, we showed that a 3-factor model (physical, mental, and overall health) fit the data better than the traditional 2 factor model. CONCLUSIONS: This study is the first to confirm the traditional 2 factor structure of SF-8 using a large, representative sample from China. We have shown that the SF-8 Chinese version is feasible, reliable, and valid. Our findings support the use of the SF-8 summary scores for assessing general HRQOL among Chinese. Future studies may further explore the possibility of a 3-factor structure for the SF-8 among the Chinese population. PMID- 29615061 TI - Impact of scheduling multiple outdoor free-play periods in childcare on child moderate-to-vigorous physical activity: a cluster randomised trial. AB - BACKGROUND: Increasing the frequency of periods of outdoor free-play in childcare may represent an opportunity to increase child physical activity. This study aimed to assess the efficacy of scheduling multiple periods of outdoor free-play in increasing the time children spend in moderate-to-vigorous physical activity (MVPA) while attending childcare. METHODS: The study employed a cluster randomised controlled trial design involving children aged 3 to 6 years, attending ten childcare services in the Hunter New England region of New South Wales, Australia. Five services were randomised to receive the intervention and five to a control condition. The intervention involved services scheduling three separate periods of outdoor free-play from 9 am to 3 pm per day, each at least 15 min in duration, with the total equivalent to their usual daily duration of outdoor play period. Control services implemented the usual single continuous period of outdoor free-play over this time. The primary outcome, children's moderate-to-vigorous physical activity (MVPA) while in care per day, was measured over 5 days via accelerometers at baseline and at 3 months post baseline. Secondary outcomes included percentage of time spent in MVPA while in care per day, total physical activity while in care per day and documented child injury, a hypothesised potential unintended adverse event. Childcare services and data collectors were not blind to the experimental group allocation. RESULTS: Parents of 439 (71.6%) children attending participating childcare services consented for their child to participate in the trial. Of these, 316 (72.0%) children provided valid accelerometer data at both time points. Relative to children in control services, mean daily minutes of MVPA in care was significantly greater at follow up among children attending intervention services (adjusted difference between groups 5.21 min, 95% CI 0.59-9.83 p = 0.03). Percentage of time spent in MVPA in care per day was also greater at follow-up among children in intervention services relative to control services (adjusted difference between groups 1.57, 95% CI 0.64-2.49 p < 0.001). Total physical activity while in care per day, assessed via counts per minute approached but did not reach significance (adjusted difference between groups 14.25, 95% CI 2.26-30.76 p = 0.09). There were no differences between groups in child injury nor subgroup interactions for the primary trial outcome by child age, sex, or baseline MVPA levels. CONCLUSION: Scheduling multiple periods of outdoor free-play significantly increased the time children spent in MVPA while in attendance at childcare. This simple ecological intervention could be considered for broader dissemination as a strategy to increase child physical activity at a population level. TRIAL REGISTRATION: This trial was prospectively registered with the Australian New Zealand Clinical Trials Registry (ANZCTR) ( ACTRN1261000347460 ). Prospectively registered 17th March 2016. PMID- 29615062 TI - KARS-related diseases: progressive leukoencephalopathy with brainstem and spinal cord calcifications as new phenotype and a review of literature. AB - BACKGROUND: KARS encodes lysyl- transfer ribonucleic acid (tRNA) synthetase, which catalyzes the aminoacylation of tRNA-Lys in the cytoplasm and mitochondria. Eleven families/sporadic patients and 16 different mutations in KARS have been reported to date. The associated clinical phenotype is heterogeneous ranging from early onset encephalopathy to isolated peripheral neuropathy or nonsyndromic hearing impairment. Recently additional presentations including leukoencephalopathy as predominant cerebral involvement or cardiomyopathy, isolated or associated with muscular and cerebral involvement, have been reported. A progressive Leukoencephalopathy with brainstem and spinal cord calcifications was previously described in a singleton patient and in two siblings, without the identification of the genetic cause. We reported here about a new severe phenotype associated with biallelic KARS mutations and sharing some common points with the other already reported phenotypes, but with a distinct clinical and neuroimaging picture. Review of KARS mutant patients published to date will be also discussed. RESULTS: Herein, we report the clinical, biochemical and molecular findings of 2 unreported Italian patients affected by developmental delay, acquired microcephaly, spastic tetraparesis, epilepsy, sensory-neural hypoacusia, visual impairment, microcytic hypochromic anaemia and signs of hepatic dysfunction. MRI pattern in our patients was characterized by progressive diffuse leukoencephalopathy and calcifications extending in cerebral, brainstem and cerebellar white matter, with spinal cord involvement. Genetic analysis performed on these 2 patients and in one subject previously described with similar MRI pattern revealed the presence of biallelic mutations in KARS in all 3 subjects. CONCLUSIONS: With our report we define the molecular basis of the previously described Leukoencephalopathy with Brainstem and Spinal cord Calcification widening the spectrum of KARS related disorders, particularly in childhood onset disease suggestive for mitochondrial impairment. The review of previous cases does not suggest a strict and univocal genotype/phenotype correlation for this highly heterogeneous entity. Moreover, our cases confirm the usefulness of search for common brain and spine MR imaging pattern and of broad genetic screening, in syndromes clinically resembling mitochondrial disorders in spite of normal biochemical assay. PMID- 29615063 TI - Prediction of treatment responses to neoadjuvant chemotherapy in triple-negative breast cancer by analysis of immune checkpoint protein expression. AB - BACKGROUND: "Avoiding immune destruction" has recently been established as one of the hallmarks of cancer. The programmed cell death (PD)-1/programmed cell death ligand (PD-L) 1 pathway is an important immunosuppression mechanism that allows cancer cells to escape host immunity. The present study investigated how the expressions of these immune checkpoint proteins affected responses to neo adjuvant chemotherapy (NAC) in breast cancer. METHODS: A total of 177 patients with resectable early-stage breast cancer were treated with NAC. Estrogen receptor, progesteron receptor, human epidermal growth factor receptor 2, Ki67, PD-L1, PDL-2 and PD-1 status were assessed by immunohistochemistry. RESULTS: There were 37 (20.9%) patients with high PD-1 expression, 42 (23.7%) patients had high PD-L1 expression, and 52 (29.4%) patients had high PD-L2 expression. The patients with high PD-1 and PD-L1 expressions had a significantly higher rate of triple-negative breast cancer (TNBC) (p = 0.041) (p < 0.001). In TNBC, patients with high PD-1 and PD-L1 expressions had significantly higher rates of non-pCR (p = 0.003) (p < 0.001). Univariate analysis showed that PD-1 and PD-L1 expressions also significantly shortened disease free survival in TNBC (p = 0.048, HR = 3.318) (p = 0.007, HR = 8.375). However, multivariate analysis found that only PD L1 expression was an independent prognostic factor (p = 0.041, HR = 9.479). CONCLUSIONS: PD-1 and PD-L1 expressions may be useful as biomarkers to predict treatment responses to NAC in breast cancer. Above all, PD-L1 expression may also be useful as biomarkers for more effective chemotherapy in TNBC. PMID- 29615064 TI - Childhood and adolescent phenol and phthalate exposure and the age of menarche in Latina girls. AB - BACKGROUND: The age of menarche has been associated with metabolic and cardiovascular disease, as well as cancer risk. The decline in menarcheal age over the past century may be partially attributable to increased exposure to endocrine disrupting chemicals (EDCs). METHODS: We assessed the influence of 26 phenol and phthalate biomarkers on the timing of menarche in a longitudinal cohort of Chilean girls. These EDCs were quantified in urine collected prior to the onset of breast development (Tanner 1; B1), and during adolescence (Tanner 4; B4). Multivariable accelerated failure time (AFT) models were used to analyze associations between biomarker concentrations and the age of menarche adjusting for body mass index (BMI) Z-score and maternal education, accounting for within subject correlation. RESULTS: Several biomarkers were significantly associated with the age at menarche; however, these associations were dependent on the timing of biomarker assessment. A log(ng/ml) increase in B1 concentrations of di(2-ethylhexyl) phthalate biomarkers was associated with later menarche (hazard ratio (HR): 0.77; 95% CI: 0.60, 0.98), whereas higher B1 concentrations of 2,5 dichlorophenol and benzophenone-3 were associated with earlier menarche (HR: 1.13; 95% CI: 1.01, 1.27; HR: 1.17; 95% CI: 1.06, 1.29, respectively). Elevated B4 concentrations of monomethyl phthalate were similarly associated with earlier menarche (HR: 1.30; 95% CI: 1.10, 1.53). The impact of monoethyl phthalate and triclosan concentrations on pubertal timing were significantly modified by BMI Z score. Higher monoethyl phthalate and triclosan concentrations were associated with earlier menarche among overweight or obese girls, but not among those that were normal weight. CONCLUSIONS: This study identifies modulation of sexual maturation by specific EDC biomarkers in Latina girls. PMID- 29615065 TI - Efficacy, safety and recurrence of new progestins and selective progesterone receptor modulator for the treatment of endometriosis: a comparison study in mice. AB - BACKGROUND: Current medical treatments for endometriosis are very limited. Progestin and selective progesterone receptor modulators (SPRM) are developed but their efficacy, safety, mechanism and recurrence in endometriosis are not fully studied. METHODS: In order to compare therapeutic, side effects and therapeutic actions of Esmya, Duphaston and Dienogest in endometriosis. Experimental endometriosis was induced by either intraperitoneal or subcutaneous mouse endometrium transplantation. Lesion size, weight and histology at the end of intervention were compared. Expression of related markers in the endometriotic lesions were examined. Body, uterus and ovary weights, endometrial glands and thickness (ETI), and follicle count were measured. For recurrent study, lesion growth before and after intervention was monitored. RESULTS: After Esmya, Duphaston, Dienogest treatment, lesion size and weight were significantly decreased. Proliferation Pcna expression was significantly decreased in all groups, but proliferation cells were significantly decreased only in Duphaston group. Apoptosis Mapk1 expression and TUNEL-positive cells were significantly increased in Duphaston group. Adhesion Mmp2 and Itgavbeta3 expression were significantly increased in Esmya group. Plau, Hif1alpha and Vegfa expression, peritoneal fluid PGE2 levels, and ERalpha and ERbeta expression were not affected; while PR expression was significantly lower in all groups. Endometrial gland count in uterus was significantly increased in Dienogest group, ETI was significantly decreased in Duphaston group, and AFC were significantly increased in Esmya group. Upon treatment cessation, lesion growth rebound quickly in Dienogest and Duphaston groups, but slowly in Esmya group. CONCLUSION: Esmya, Duphaston and Dienogest are effective anti-endometriosis drugs targeting proliferation, apoptosis and adhesion. Esmya, Duphaston and Dienogest are all well tolerable, although endometrial glandular hyperplasia was found in Dienogest, endometrial atrophy in Duphaston, follicle accumulation in Esmya. PMID- 29615066 TI - A qualitative assessment of the challenges of WHO prequalification for anti malarial drugs in China. AB - BACKGROUND: While China is a major manufacturer of artemisinin and its derivatives, it lags as a global leader in terms of the total export value of anti-malarial drugs as finished pharmaceutical products ready for marketing and use by patients. This may be due to the limited number of World Health Organization (WHO) prequalified anti-malarial drugs from China. Understanding the reasons for the slow progress of WHO prequalification (PQ) in China can help improve the current situation and may lead to greater efforts in malaria eradication by Chinese manufacturers. METHODS: In-depth interviews were conducted in China between November 2014 and December 2016. A total of 26 key informants from central government agencies, pharmaceutical companies, universities, and research institutes were interviewed, all of which had current or previous experience overseeing or implementing anti-malarial research and development in China. RESULTS: Chinese anti-malarial drugs that lack WHO PQ are mainly exported for use in the African private market. High upfront costs with unpredictable benefits, as well as limited information and limited technical support on WHO PQ, were reported as the main barriers to obtain WHO PQ for anti-malarial drugs by respondents from Chinese pharmaceutical companies. Potential incentives identified by respondents included tax relief, human resource training and consultation, as well as other incentives related to drug approval, such as China's Fast Track Channel. CONCLUSIONS: Government support, as well as innovative incentives and collaboration mechanisms are needed for further adoption of WHO PQ for anti-malarial drugs in China. PMID- 29615067 TI - Does setup on rectal wall improve rectal cancer boost radiotherapy? AB - BACKGROUND: Rectal cancer patients that show a pathological complete response (pCR) after neo-adjuvant chemo-radiotherapy, have better prognosis. To increase pCR rates several studies escalate the tumor irradiation dose. However, due to lacking tumor contrast on online imaging techniques, no direct tumor setup can be performed and large boost margins are needed to ensure tumor coverage. The purpose of this study was to evaluate the feasibility of performing a setup on rectal wall for rectal cancer boost radiotherapy, thereby using rectal wall nearby the tumor as tumor position surrogate. METHODS: For sixteen patients, daily MRI's were performed during 1 week of radiotherapy. On each of these images, tumor and rectum were delineated. Residual displacements were determined per surface voxel after setup on bony anatomy or nearby rectal wall and setup errors for both setups were compared. Furthermore for every rectal wall voxel nearby the tumor, displacement was compared with the closest tumor point and correlation was determined. RESULTS: Mean (SD) setup error was 2.7 mm (3.3 mm) and 2.2 mm (3.2 mm) after setup on bony anatomy and rectal wall respectively. Nevertheless, similar PTV-margin estimates i.e. 95th percentile distances, were found; 8.0 mm. Also, a merely moderate correlation; rho = 0.66 was found between rectal wall and tumor displacement. Further investigation into tumor and rectal mobility differences showed that the rectal wall lacks appropriate anatomical landmarks to find true displacements, especially to capture motion along the rectal wall. CONCLUSIONS: Setup on rectal wall slightly reduces mean setup errors but requires a similar PTV-margin as compared to setup on bony anatomy. Rectal mobility might be similar to tumor mobility, but due the absence of anatomical landmarks in the rectum, displacements along the rectal wall are not detected on current online imaging. Therefore, to further reduce tumor position uncertainties, direct or indirect online tumor visualization is needed. PMID- 29615069 TI - Exploring perceptions of group antenatal Care in Urban India: results of a feasibility study. AB - BACKGROUND: Making high-quality health care available to all women during pregnancy is a critical strategy for improving perinatal outcomes for mothers and babies everywhere. Research from high-income countries suggests that antenatal care delivered in a group may be an effective way to improve the provision, experiences, and outcomes of care for pregnant women and newborns. A number of researchers and programmers are adapting group antenatal care (ANC) models for use in low- and middle-income countries (LMIC), but the evidence base from these settings is limited and no studies to date have assessed the feasibility and acceptability of group ANC in India. METHODS: We adapted a "generic" model of group antenatal care developed through a systematic scoping review of the existing evidence on group ANC in LMICs for use in an urban setting in India, after looking at local, national and global guidelines to tailor the model content. We demonstrated one session of the model to physicians, auxiliary nurse midwives, administrators, pregnant women, and support persons from three different types of health facilities in Vadodara, India and used qualitative methods to gather and analyze feedback from participants on the perceived feasibility and acceptability of the model. RESULTS: Providers and recipients of care expressed support and enthusiasm for the model and offered specific feedback on its components: physical assessment, active learning, and social support. In general, after witnessing a demonstration of the model, both groups of participants-providers and beneficiaries-saw group ANC as a vehicle for delivering more comprehensive ANC services, improving experiences of care, empowering women to become more active partners and participants in their care, and potentially addressing some current health system challenges. CONCLUSION: This study suggests that introducing group ANC would be feasible and acceptable to stakeholders from various care delivery settings, including an urban primary health clinic, a community-based mother and child health center, and a private hospital, in urban India. PMID- 29615068 TI - Modeling and rescue of defective blood-brain barrier function of induced brain microvascular endothelial cells from childhood cerebral adrenoleukodystrophy patients. AB - BACKGROUND: X-linked adrenoleukodystrophy (X-ALD) is caused by mutations in the ABCD1 gene. 40% of X-ALD patients will convert to the deadly childhood cerebral form (ccALD) characterized by increased permeability of the brain endothelium that constitutes the blood-brain barrier (BBB). Mutation information and molecular markers investigated to date are not predictive of conversion. Prior reports have focused on toxic metabolic byproducts and reactive oxygen species as instigators of cerebral inflammation and subsequent immune cell invasion leading to BBB breakdown. This study focuses on the BBB itself and evaluates differences in brain endothelium integrity using cells from ccALD patients and wild-type (WT) controls. METHODS: The blood-brain barrier of ccALD patients and WT controls was modeled using directed differentiation of induced pluripotent stem cells (iPSCs) into induced brain microvascular endothelial cells (iBMECs). Immunocytochemistry and PCR confirmed characteristic expression of brain microvascular endothelial cell (BMEC) markers. Barrier properties of iBMECs were measured via trans endothelial electrical resistance (TEER), sodium fluorescein permeability, and frayed junction analysis. Electron microscopy and RNA-seq were used to further characterize disease-specific differences. Oil-Red-O staining was used to quantify differences in lipid accumulation. To evaluate whether treatment with block copolymers of poly(ethylene oxide) and poly(propylene oxide) (PEO-PPO) could mitigate defective properties, ccALD-iBMECs were treated with PEO-PPO block copolymers and their barrier properties and lipid accumulation levels were quantified. RESULTS: iBMECs from patients with ccALD had significantly decreased TEER (2592 +/- 110 Omega cm2) compared to WT controls (5001 +/- 172 Omega cm2). They also accumulated lipid droplets to a greater extent than WT-iBMECs. Upon treatment with a PEO-PPO diblock copolymer during the differentiation process, an increase in TEER and a reduction in lipid accumulation were observed for the polymer treated ccALD-iBMECs compared to untreated controls. CONCLUSIONS: The finding that BBB integrity is decreased in ccALD and can be rescued with block copolymers opens the door for the discovery of BBB-specific molecular markers that can indicate the onset of ccALD and has therapeutic implications for preventing the conversion to ccALD. PMID- 29615070 TI - Exercise and postprandial lipemia: effects on vascular health in inactive adults. AB - BACKGROUND: There is evidence to suggest that postprandial lipemia are is linked to the impairment of endothelial function, which is characterized by an imbalance between the actions of vasodilators and vasoconstrictors. The aim of this study was to determine the effects of a 12-week high-intensity training (HIT) and moderate continuous training (MCT) protocol on postprandial lipemia, vascular function and arterial stiffness in inactive adults after high-fat meal (HFM) ingestion. METHODS: A randomized clinical trial was conducted in 20 healthy, inactive adults (31.6 +/- 7.1 years). Participants followed the two exercise protocols for 12 weeks. To induce a state of postprandial lipemia (PPL), all subjects received a HFM. Endothelial function was measured using flow-mediated vasodilation (FMD), normalized brachial artery FMD (nFMD), aortic pulse wave velocity (PWV) and augmentation index (AIx). Plasma total cholesterol, high density lipoprotein cholesterol (HDL-c), triglycerides and glucose were also measured. RESULTS: The effects of a HFM were evaluated in a fasted state and 60, 120, 180, and 240 min postprandially. A significant decrease in serum glucose between 0 min (fasted state) and 120 min postprandially was found in the HIT group (P = 0.035). Likewise, FMD (%) was significantly different between the fasted state and 60 min after a HFM in the HIT group (P = 0.042). The total cholesterol response expressed as area under curve (AUC)(0-240) was lower following HIT than following MCT, but no significant differences were observed (8%, P > 0.05). Similarly, triglycerides AUC(0-240) was also lower after HIT compared with MCT, which trended towards significance (24%, P = 0.076). The AUC(0 240) for the glucose response was significantly lower following HIT than MCT (10%, P = 0.008). FMD and nFMD AUC(0-240) were significantly higher following HIT than following MCT (46.9%, P = 0.021 and 67.3%, P = 0.009, respectively). PWV AUC(0-240) did not differ following between the two exercise groups (2.3%, P > 0.05). CONCLUSIONS: Supervised exercise training mitigates endothelial dysfunction and glucose response induced by PPL. Exercise intensity plays an important role in these protective effects, and medium-term HIT may be more effective than MCT in reducing postprandial glucose levels and attenuating vascular impairment. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT02738385 Date of registration: April 14, 2016. PMID- 29615071 TI - Mature and progenitor endothelial cells perform angiogenesis also under protease inhibition: the amoeboid angiogenesis. AB - BACKGROUND: Controlling vascular growth is a challenging aim for the inhibition of tumor growth and metastasis. The amoeboid and mesenchymal types of invasiveness are two modes of migration interchangeable in cancer cells: the Rac dependent mesenchymal migration requires the activity of proteases; the Rho-ROCK dependent amoeboid motility is protease-independent and has never been described in endothelial cells. METHODS: A cocktail of physiologic inhibitors (Ph-C) of serine-proteases, metallo-proteases and cysteine-proteases, mimicking the physiological environment that cells encounter during their migration within the angiogenesis sites was used to induce amoeboid style migration of Endothelial colony forming cells (ECFCs) and mature endothelial cells (ECs). To evaluate the mesenchymal-ameboid transition RhoA and Rac1 activation assays were performed along with immunofluorescence analysis of proteins involved in cytoskeleton organization. Cell invasion was studied in Boyden chambers and Matrigel plug assay for the in vivo angiogenesis. RESULTS: In the present study we showed in both ECFCs and ECs, a decrease of activated Rac1 and an increase of activated RhoA upon shifting of cells to the amoeboid conditions. In presence of Ph-C inhibitors both cell lines acquired a round morphology and Matrigel invasion was greatly enhanced with respect to that observed in the absence of protease inhibition. We also observed that the urokinase-plasminogen-activator (uPAR) receptor silencing and uPAR-integrin uncoupling with the M25 peptide abolished both mesenchymal and amoeboid angiogenesis of ECFCs and ECs in vitro and in vivo, indicating a role of the uPAR-integrin-actin axis in the regulation of amoeboid angiogenesis. Furthermore, under amoeboid conditions endothelial cells seem to be indifferent to VEGF stimulation, which induces an amoeboid signaling pattern also in mesenchymal conditions. CONCLUSION: Here we first provide a data set disclosing that endothelial cells can move and differentiate into vascular structures in vitro and in vivo also in the absence of proteases activity, performing a new type of neovascularization: the "amoeboid angiogenesis". uPAR is indispensable for ECs and ECFCs to perform an efficient amoeboid angiogenesis. Therefore, uPAR silencing or the block of its integrin-interaction, together with standard treatment against VEGF, could be a possible solution for angiogenesis inhibition. PMID- 29615072 TI - Digital breast tomosynthesis for breast cancer screening and diagnosis in women with dense breasts - a systematic review and meta-analysis. AB - BACKGROUND: This study aimed to systematically review and to meta-analyse the accuracy of digital breast tomosynthesis (DBT) versus digital mammography (DM) in women with mammographically dense breasts in screening and diagnosis. METHODS: Two independent reviewers identified screening or diagnostic studies reporting at least one of four outcomes (cancer detection rate-CDR, recall rate, sensitivity and specificity) for DBT and DM in women with mammographically dense breasts. Study quality was assessed using QUADAS-2. Meta-analysis of CDR and recall rate used a random effects model. Summary ROC curve summarized sensitivity and specificity. RESULTS: Sixteen studies were included (five diagnostic; eleven screening). In diagnosis, DBT increased sensitivity (84%-90%) versus DM alone (69%-86%) but not specificity. DBT improved CDR versus DM alone (RR: 1.16, 95% CI 1.02-1.31). In screening, DBT + DM increased CDR versus DM alone (RR: 1.33, 95% CI 1.20-1.47 for retrospective studies; RR: 1.52, 95% CI 1.08-2.11 for prospective studies). Recall rate was significantly reduced by DBT + DM in retrospective studies (RR: 0.72, 95% CI 0.64-0.80) but not in two prospective studies (RR: 1.12, 95% CI 0.76-1.63). CONCLUSION: In women with mammographically dense breasts, DBT+/-DM increased CDR significantly (versus DM) in screening and diagnosis. In diagnosis, DBT+/-DM increased sensitivity but not specificity. The effect of DBT + DM on recall rate in screening dense breasts varied between studies. PMID- 29615073 TI - Advanced airway management in hoist and longline operations in mountain HEMS - considerations in austere environments: a narrative review This review is endorsed by the International Commission for Mountain Emergency Medicine (ICAR MEDCOM). AB - BACKGROUND: Providing sufficient oxygenation and ventilation is of paramount importance for the survival of emergency patients. Therefore, advanced airway management is one of the core tasks for every rescue team. Endotracheal intubation is the gold standard to secure the airway in the prehospital setting. This review aims to highlight special considerations for advanced airway management preceding human external cargo (HEC) evacuations. METHODS: We systematically searched MEDLINE, EMBASE, and PubMed in August 2017 for articles on airway management and ventilation in patients before hoist or longline operation in HEMS. Relevant reference lists were hand-searched. RESULTS: Three articles with regard to advanced airway management and five articles concerning the epidemiology of advanced airway management in hoist or longline rescue missions were included. We found one case report regarding ventilation during hoist operations. The exact incidence of advanced airway management before evacuation of a patient by HEC is unknown but seems to be very low (< 5%). There are several hazards which can impede mechanical ventilation of patients during HEC extractions: loss of equipment, hyperventilation, inability to ventilate and consequent hypoxia, as well as inadequacy of monitoring. CONCLUSIONS: Advanced airway management prior to HEC operation is rarely performed. If intubation before helicopter hoist operations (HHO) and human cargo sling (HCS) extraction is considered by the rescue team, a risk/benefit analysis should be performed and a clear standard operating procedure (SOP) should be defined. Continuous and rigorous training including the whole crew is required. An international registry on airway management during HEC extraction would be desirable. PMID- 29615074 TI - A Klinefelter boy with congenital adrenal hyperplasia: too much or too little androgens? AB - BACKGROUND: The simultaneous occurrence of Klinefelter Syndrome (KS) and Congenital Adrenal Hyperplasia (CAH) is an exceptional event: there are just three case reports (two children and a 51 years old man) describing males affected by both KS and 21OHD (21-hydroxylase deficiency) CAH, the first causing androgen deficiency, the latter leading to androgen excess. CASE REPORT: We report the 4th case of association of KS and CAH in a young man with CAH with good androgen control and with normal secondary sex characteristics, whose Klinefelter syndrome was diagnosed because of reduced testicular volume. He was the first reported case of association of KS and CAH who started androgen replacement therapy in the pubertal age and whose pubertal development was described and followed up step by step. CONCLUSION: In a boy with CAH and small testicular volume, it's important to consider that hypogonadism may be masked by the adrenal androgens excess and a karyotype should be performed once testicular adrenal rests have been ruled out. PMID- 29615075 TI - Lipid accumulation in human breast cancer cells injured by iron depletors. AB - BACKGROUND: Current insights into the effects of iron deficiency in tumour cells are not commensurate with the importance of iron in cell metabolism. Studies have predominantly focused on the effects of oxygen or glucose scarcity in tumour cells, while attributing insufficient emphasis to the inadequate supply of iron in hypoxic regions. Cellular responses to iron deficiency and hypoxia are interlinked and may strongly affect tumour metabolism. METHODS: We examined the morphological, proteomic, and metabolic effects induced by two iron chelators deferoxamine (DFO) and di-2-pyridylketone 4,4-dimethyl-3-thiosemicarbazone (Dp44mT)-on MDA-MB-231 and MDA-MB-157 breast cancer cells. RESULTS: These chelators induced a cytoplasmic massive vacuolation and accumulation of lipid droplets (LDs), eventually followed by implosive, non-autophagic, and non apoptotic death similar to methuosis. Vacuoles and LDs are generated by expansion of the endoplasmic reticulum (ER) based on extracellular fluid import, which includes unsaturated fatty acids that accumulate in LDs. Typical physiological phenomena associated with hypoxia are observed, such as inhibition of translation, mitochondrial dysfunction, and metabolic remodelling. These survival oriented changes are associated with a greater expression of epithelial/mesenchymal transcription markers. CONCLUSIONS: Iron starvation induces a hypoxia-like program able to scavenge nutrients from the extracellular environment, and cells assume a hypertrophic phenotype. Such survival strategy is accompanied by the ER-dependent massive cytoplasmic vacuolization, mitochondrial dysfunctions, and LD accumulation and then evolves into cell death. LDs containing a greater proportion of unsaturated lipids are released as a consequence of cell death. The consequence of the disruption of iron metabolism in tumour tissue and the effects of LDs on intercellular communication, cancer inflammation axis, and immunity remain to be explored. Considering the potential benefits, these are crucial subjects for future mechanistic and clinical studies. PMID- 29615076 TI - Use of the tumor-infiltrating CD8 to FOXP3 lymphocyte ratio in predicting treatment responses to combination therapy with pertuzumab, trastuzumab, and docetaxel for advanced HER2-positive breast cancer. AB - BACKGROUND: The trastuzumab, pertuzumab, and docetaxel (TPD) regimen is strongly recommended as a treatment option for first-line therapy for advanced human epidermal growth factor receptor (HER) 2-positive breast cancer. Monitoring the host microenvironments in cancer plays a significant role in predicting prognoses and curative effects. It is important to clarify the role of immune related gene expression in tumor-infiltrating lymphocytes in the tumor microenvironment. In this study, we evaluated the impact of chemotherapy with a TPD regimen, on immune micro environments in HER2-positive breast cancer using immune related proteins as indicators. METHODS: The subjects consisted of 30 patients who received the TPD regimen. The expression levels of estrogen receptor, progesterone receptor, Ki67, CD8, forkhead box protein (FOXP) 3, programmed death (PD) 1, programmed death ligand (PD-L) 1, CD163, phosphatase and tensin homolog and lymphocyte activation gene 3 were evaluated in biopsy specimens, by immunostaining. RESULTS: CD8+, CD8/FOXP3 ratio (CFR)high and PD-L1- group had significantly longer PFS than the CD8-, CFRlow and PDL1+ group (p = 0.045, log-rank) (p = 0.007, log-rank) (p = 0.040, log-rank), respectively. The CFRhigh group had significantly better OS than the CFRlow group (p = 0.034, log-rank). In the univariate analysis, CD8+, CFRhigh groups extended PFS significantly (p = 0.027, hazard ratio [HR] = 0.162) (p = 0.008, HR = 0.195), respectively. The receiver operating characteristic (ROC) analyses showed that the results for CFR [area under the curve (AUC): 0.708] were better than those for other factors (AUC: CD8 = 0.681, FOXP3 = 0.639, PD1 = 0.528, PD-L1 = 0.681). CONCLUSIONS: This study shows with the TPD regimen, a high CFR leads to a high ORR and long PFS in HER2-positive breast cancer. CFR, therefore, may be one of the important prognostic factors for this disease. PMID- 29615077 TI - SPIRE - combining SGI-110 with cisplatin and gemcitabine chemotherapy for solid malignancies including bladder cancer: study protocol for a phase Ib/randomised IIa open label clinical trial. AB - BACKGROUND: Urothelial bladder cancer (UBC) accounts for 10,000 new diagnoses and 5000 deaths annually in the UK (Cancer Research UK, http://www.cancerresearchuk.org/health-professional/cancer-statistics/statistics by-cancer-type/bladder-cancer , Cancer Research UK, Accessed 26 Mar 2018). Cisplatin-based chemotherapy is standard of care therapy for UBC for both palliative first-line treatment of advanced/metastatic disease and radical neoadjuvant treatment of localised muscle invasive bladder cancer. However, cisplatin resistance remains a critical cause of treatment failure and a barrier to therapeutic advance in UBC. Based on supportive pre-clinical data, we hypothesised that DNA methyltransferase inhibition would circumvent cisplatin resistance in UBC and potentially other cancers. METHODS: The addition of SGI-110 (guadecitabine, a DNA methyltransferase inhibitor) to conventional doublet therapy of gemcitabine and cisplatin (GC) is being tested within the phase Ib/IIa SPIRE clinical trial. SPIRE incorporates an initial, modified rolling six-dose escalation phase Ib design of up to 36 patients with advanced solid tumours followed by a 20-patient open-label randomised controlled dose expansion phase IIa component as neoadjuvant treatment for UBC. Patients are being recruited from UK secondary care sites. The dose escalation phase will determine a recommended phase II dose (RP2D, primary endpoint) of SGI-110, by subcutaneous injection, on days 1-5 for combination with GC at conventional doses (cisplatin 70 mg/m2, IV infusion, day 8; gemcitabine 1000 mg/m2, IV infusion, days 8 and 15) in every 21 day cycle. In the dose expansion phase, patients will be randomised 1:1 to GC with or without SGI-110 at the proposed RP2D. Secondary endpoints will include toxicity profiles, SGI-110 pharmacokinetics and pharmacodynamic biomarkers, and pathological complete response rates in the dose expansion phase. Analyses will not be powered for formal statistical comparisons and descriptive statistics will be used to describe rates of toxicity, efficacy and translational endpoints by treatment arm. DISCUSSION: SPIRE will provide evidence for whether SGI-110 in combination with GC chemotherapy is safe and biologically effective prior to future phase II/III trials as a neoadjuvant therapy for UBC and potentially in other cancers treated with GC. TRIAL REGISTRATION: EudraCT Number: 2015-004062-29 (entered Dec 7, 2015) ISRCTN registry number: 16332228 (registered on Feb 3, 2016). PMID- 29615078 TI - A multicenter, randomized controlled trial comparing the identification rate of stigmata of recent hemorrhage and rebleeding rate between early and elective colonoscopy in outpatient-onset acute lower gastrointestinal bleeding: study protocol for a randomized controlled trial. AB - BACKGROUND: The clinical benefit of early colonoscopy within 24 h of arrival in patients with severe acute lower gastrointestinal bleeding (ALGIB) remains controversial. This trial will compare early colonoscopy (performed within 24 h) versus elective colonoscopy (performed between 24 and 96 h) to examine the identification rate of stigmata of recent hemorrhage (SRH) in ALGIB patients. We hypothesize that, compared with elective colonoscopy, early colonoscopy increases the identification of SRH and subsequently improves clinical outcomes. METHODS: This trial is an investigator-initiated, multicenter, randomized, open-label, parallel-group trial examining the superiority of early colonoscopy over elective colonoscopy (standard therapy) in ALGIB patients. The primary outcome measure is the identification of SRH. Secondary outcomes include 30-day rebleeding, success of endoscopic treatment, need for additional endoscopic examination, need for interventional radiology, need for surgery, need for transfusion during hospitalization, length of stay, 30-day thrombotic events, 30-day mortality, preparation-related adverse events, and colonoscopy-related adverse events. The sample size will enable detection of a 9% SRH rate in elective colonoscopy patients and a SRH rate of >= 26% in early colonoscopy patients with a risk of type I error of 5% and a power of 80%. DISCUSSION: This trial will provide high quality data on the benefits and risks of early colonoscopy in ALGIB patients. TRIAL REGISTRATION: UMIN-CTR Identifier, UMIN000021129 . Registered on 21 February 2016; ClinicalTrials.gov Identifier, NCT03098173 . Registered on 24 March 2017. PMID- 29615079 TI - Dosimetrical and radiobiological approach to manage the dosimetric shift in the transition of dose calculation algorithm in radiation oncology: how to improve high quality treatment and avoid unexpected outcomes? AB - BACKGROUND: For a given prescribed dose of radiotherapy, with the successive generations of dose calculation algorithms, more monitor units (MUs) are generally needed. This is due to the implementation of successive improvements in dose calculation: better heterogeneity correction and more accurate estimation of secondary electron transport contribution. More recently, there is the possibility to report the dose-to-medium, physically more accurate compared to the dose-to-water as the reference one. This last point is a recent concern and the main focus of this study. METHODS: In this paper, we propose steps for a general analysis procedure to estimate the dosimetric alterations, and the potential clinical changes, between a reference algorithm and a new one. This includes dosimetric parameters, gamma index, radiobiology indices based on equivalent uniform dose concept and statistics with bootstrap simulation. Finally, we provide a general recommendation on the clinical use of new algorithms regarding the dose prescription or dose limits to the organs at risks. RESULTS: The dosimetrical and radiobiological data showed a significant effect, which might exceed 5-10%, of the calculation method on the dose the distribution and clinical outcomes for lung cancer patients. Wilcoxon signed rank paired comparisons indicated that the delivered dose in MUs was significantly increased (> 2%) using more advanced dose calculation methods as compared to the reference one. CONCLUSION: This paper illustrates and explains the use of dosimetrical, radiobiologcal and statistical tests for dosimetric comparisons in radiotherapy. The change of dose calculation algorithm may induce a dosimetric shift, which has to be evaluated by the physicists and the oncologists. This includes the impact on tumor control and on the risk of toxicity based on normal tissue dose constraints. In fact, the alteration in dose distribution makes it hard to keep exactly the same tumor control probability along with the same normal tissue complication probability. PMID- 29615080 TI - Radiotherapy-induced cell death activates paracrine HMGB1-TLR2 signaling and accelerates pancreatic carcinoma metastasis. AB - BACKGROUND: Dying cells after irradiation could promote the repopulation of surviving cancer cells leading to tumor recurrence. We aim to define the role of dying cells in promoting pancreatic cancer cells metastasis following radiotherapy. METHODS: Using the transwell system as the in vitro co-culture model, a small number of untreated pancreatic cancer cells were seeded in the upper chamber, while a larger number of lethally treated pancreatic cancer cells were seeded in the lower chamber. A series of experiments were conducted to investigate the role of dying-cell-derived HMGB1 on the invasion of pancreatic cancer in vitro and cancer metastasis in vivo. We then designed shRNA knockdown and Western blot assays to detect signaling activity. RESULTS: We found that dying pancreatic cancer cells significantly promote the invasion of pancreatic cancer cells in vitro and cancer metastasis in vivo. HMGB1 gene knockdown attenuated the migration-stimulating effect of irradiated, dying cells on living pancreatic cancer cells. Finally, we showed that dying-cell-derived HMGB1 functions in a paracrine manner to affect cancer-cell migration dependent on acquiring an epithelial-mesenchymal transition (EMT) phenotype and PI3K/pAkt activation. This process is mediated by the receptor for TLR2. CONCLUSION: Our study indicates that, during radiotherapy, dying pancreatic cancer cells activate paracrine signaling events that promote the mobility of surviving tumor cells. We suggest a strategy to inhibit HMGB1 for preventing pancreatic carcinoma relapse and metastasis. PMID- 29615081 TI - Association between serum S100A9 levels and liver necroinflammation in chronic hepatitis B. AB - BACKGROUND: S100A9 protein, which is recently classified as a novel damage associated molecular pattern, is released from stressed cells undergoing necrosis or secreted by living cells undergoing a stress that act as endogenous danger signal associated with infection, tissue damage and cancer. Here, we evaluated the relationship of serum S100A9 with viral replication and liver necroinflammation in patients with chronic hepatitis B (CHB) infection. METHODS: A total of one hundred and eighty-three recruited patients with CHB infection underwent liver biopsy for grading of necroinflammation (G) and staging of fibrosis (S). Forty-nine healthy individuals were included as healthy controls (HCs). Serum S100A9 levels were determined by enzyme-linked immunosorbent assay. Correlations of serum S100A9 with viral replication and liver necroinflammation were analyzed. The receiver operating characteristic curve was used to assess the discriminating power of serum S100A9 to grade liver necroinflammation (G). Liver normal L02 cells were transfected with a HBV plasmid, and S100A9 levels were determined. RESULTS: Serum S100A9 levels were increased in CHB patients compared to HCs. Intrahepatic immunoreactivity for S100A9 was enhanced in liver sample from CHB patients. Infection of HBV also resulted in an elevated S100A9 expression in L02 cells. Serum S100A9 was correlated with the serum HBV DNA levels. CHB patients with moderate-to-severe liver necroinflammation (G >= 2) showed significantly higher serum S100A9 levels than those without or with mild necroinflammation (G < 2). In patients with normal ALT levels, the area under the curve (AUC) of S100A9 for discriminating patients with moderate-to-severe necroinflammation (G >= 2) was 0.791 [95% confidence interval (CI), 0.670-0.913] with 91.7% sensitivity, 65.0% specificity and 78.3% accuracy. In patients with an alanine aminotransferase (ALT) < 2 upper limit of normal, the AUC of S100A9 for discriminating patients with moderate-to-severe necroinflammation (G >= 2) was 0.826 (95% CI, 0.729-0.923) with 87.9% sensitivity, 72.5% specificity and 80.2% accuracy. CONCLUSIONS: HBV infection may enhance S100A9 expression. Serum S100A9 levels are correlated with viral load. Serum S100A9 has potential to discriminate the grades of liver necroinflammation, particularly in CHB patients with normal or mildly increased ALT levels. PMID- 29615082 TI - Response and progression-free survival according to planned treatment duration in patients with relapsed multiple myeloma treated with carfilzomib, lenalidomide, and dexamethasone (KRd) versus lenalidomide and dexamethasone (Rd) in the phase III ASPIRE study. AB - BACKGROUND: In ASPIRE, carfilzomib, lenalidomide, and dexamethasone (KRd) significantly improved progression-free survival (PFS) and response rates versus lenalidomide and dexamethasone (Rd) in patients with relapsed multiple myeloma. Per protocol, patients received KRd for a maximum of 18 cycles followed by Rd to progression, so the benefit/risk profile of KRd to progression was not established. METHODS: This post hoc analysis evaluated the efficacy and safety of KRd versus Rd at 18 months from randomization. Cumulative rates of complete response (CR) or better over time and PFS hazard ratio (HR) at 18 months were evaluated for KRd versus Rd. PFS HRs were also assessed according to cytogenetic risk, prior lines of therapy, and prior bortezomib treatment. Cox regression analysis was used to evaluate PFS HRs. RESULTS: The hazard ratio (HR) for PFS at 18 months was 0.58 versus 0.69 for the overall ASPIRE study. Patients with high risk cytogenetics, >= 1 prior lines of therapy, and prior bortezomib exposure benefited from KRd up to 18 months versus Rd. The HRs for PFS at 18 months in the pre-defined subgroups were lower than those in the overall study. The difference in the proportion of KRd and Rd patients achieving at least a complete response (CR) increased dramatically over the first 18 months and then remained relatively constant. The safety profile at 18 months was consistent with previous findings. CONCLUSIONS: The improved PFS HR at 18 months and the continued increase in CR rates for KRd through 18 cycles suggest that there may be a benefit of continued carfilzomib treatment. TRIAL REGISTRATION: Clinical trials.gov NCT01080391 . Registered 2 March 2010. PMID- 29615083 TI - Therapeutic potentials of Quercetin in management of polycystic ovarian syndrome using Letrozole induced rat model: a histological and a biochemical study. AB - BACKGROUND: PCOS is a leading endocrinopathy of young women instigating androgens elevation, insulin resistance, obesity, cardiometabolic and menstrual complications. The study investigated the effects of quercetin in a letrozole induced rat model of polycystic ovarian syndrome, which displayed both clinical and metabolic features as in PCOS women. METHODS: Female Sprague Dawley (SD) rats were divided into four groups; control group received aqueous solution of carboxymethyl (CMC 0.5%); PCOS group administered with letrozole (1 mg/kg) dissolved in solution (CMC 0.5%); Metformin group given with metformin (20 mg/kg) + letrozole (1 mg/kg); and Quercetin group provided with quercetin (30 mg/kg) + letrozole (1 mg/kg). All doses were given orally via gavage, for 21 consecutive days and colpocytological analysis was carried till end. After 21rst day, blood was taken out, centrifuged and plasma was kept for biochemical analysis (ELISA, anti-oxidant enzymes, lipid profile) and the reproductive organs were dissected out for histopathological evaluation. RESULTS: Quercetin as a chief member of flavonoid, showed beneficial effects by decreasing body weight, ovarian diameter, cysts and restoring healthy follicles, follicle's extra-glandular layers, and corpora lutea in contrast to the positive control. Additionally, lipid profile and anti-oxidant status were also maintained to baseline which was very high in diseased rats (p < 0.001).Quercetin depicted a mark regulation in steroidogenesis by decreasing the levels of testosterone (0.78 ng/ml +/- 0.14 in quercetin vs. PCOS positive control 1.69 ng/ml +/- 0.17, p < 0.001) and estradiol (8.85 pg/ml +/- 0.19 in quercetin vs. PCOS positive 1.61 pg/ml +/- 0.29) and increasing progesterone levels (34.47 ng/ml +/- 1.65 in quercetin vs. 11.08 ng/ml +/- 1.17 in PCOS positive). The effects of quercetin were moderately parallel to the standard drug available in market i.e. metformin. CONCLUSION: The present study has confirmed that quercetin has the potentials to alleviate the hormonal and metabolic disturbances occurring in PCOS. PMID- 29615084 TI - The association between self-rated health and social environments, health behaviors and health outcomes: a structural equation analysis. AB - BACKGROUND: The factors shaping the health of the current generation of adolescents are multi-dimensional and complex. The purpose of this study was to explore the determinants of self-rated health (SRH) of adolescents attending a faith-based school system in Australia. METHODS: A total of 788 students attending 21 Seventh-day Adventist schools in Australia responded to a health and lifestyle survey that assessed SRH as well as potential determinants of SRH including the health outcomes mental health, vitality, body mass index (BMI), select health behaviors, social factors and personal demographics. Structural equation modeling was used to analyze the data and examine the direct and indirect effects of these factors on SRH. RESULTS: The structural model developed was a good fit with the data. The health outcome mental health had the strongest association with SRH (beta = 0.17). Several upstream variables were also associated with higher SRH ratings. The health behavior sleep hours had the strongest association with SRH (betatotal = 0.178) followed by fruit/vegetable consumption (betatotal = 0.144), physical activity (betatotal = 0.135) and a vegetarian diet (betatotal = 0.103). Of the demographic and social variables measured, adverse childhood experiences (ACEs) had the strongest association with SRH (betatotal = - 0.125), negatively influencing SRH, and gender also associated with an increase in SRH (betatotal = 0.092), with the influence of these factors being mediated through other variables in the model. CONCLUSIONS: This study presents a conceptual model that illustrates the complex network of factors concomitantly associated with SRH in adolescents. The outcomes of the study provide insights into the determinants of adolescent SRH which may inform priority areas for improving this construct. PMID- 29615085 TI - Expression patterns of STAT3, ERK and estrogen-receptor alpha are associated with development and histologic severity of hepatic steatosis: a retrospective study. AB - BACKGROUND: Hepatic steatosis renders hepatocytes vulnerable to injury, resulting in the progression of preexisting liver disease. Previous animal and cell culture studies implicated mammalian target of rapamycin (mTOR), signal transducer and activator of transcription-3 (STAT3), extracellular signal-regulated kinase (ERK) and estrogen-receptor alpha in the pathogenesis of hepatic steatosis and disease progression. However, to date there have been few studies performed using human liver tissue to study hepatic steatosis. We examined the expression patterns of mTOR, STAT3, ERK and estrogen-receptor alpha in liver tissues from patients diagnosed with hepatic steatosis. METHODS: We reviewed the clinical and histomorphological features of 29 patients diagnosed with hepatic steatosis: 18 with non-alcoholic fatty liver disease (NAFLD), 11 with alcoholic fatty acid disease (AFLD), and a control group (16 biliary cysts and 22 hepatolithiasis). Immunohistochemistry was performed on liver tissue using an automated immunostainer. The histologic severity of hepatic steatosis was evaluated by assessing four key histomorphologic parameters common to NAFLD and AFLD: steatosis, lobular inflammation, ballooning degeneration and fibrosis. RESULTS: mTOR, phosphorylated STAT3, phosphorylated pERK, estrogen-receptor alpha were found to be more frequently expressed in the hepatic steatosis group than in the control group. Specifically, mTOR was expressed in 78% of hepatocytes, and ERK in 100% of hepatic stellate cells, respectively, in patients with NAFLD. Interestingly, estrogen-receptor alpha was diffusely expressed in hepatocytes in all NALFD cases. Phosphorylated (active) STAT3 was expressed in 73% of hepatocytes and 45% of hepatic stellate cells in patients with AFLD, and phosphorylated (active) ERK was expressed in hepatic stellate cells in all AFLD cases. Estrogen-receptor alpha was expressed in all AFLD cases (focally in 64% of AFLD cases, and diffusely in 36%). Phosphorylated STAT3 expression in hepatocytes and hepatic stellate cells correlated with severe lobular inflammation, severe ballooning degeneration and advanced fibrosis, whereas diffusely expressed estrogen-receptor alpha correlated with a mild stage of fibrosis. CONCLUSIONS: Our data indicate ERK activation and estrogen-receptor alpha may be relevant in the development of hepatic steatosis. However, diffuse expression of estrogen receptor alpha would appear to impede disease progression, including hepatic fibrosis. Finally, phosphorylated STAT3 may also contribute to disease progression. PMID- 29615086 TI - Comparison of lateral entry with crossed entry pinning for pediatric supracondylar humeral fractures: a meta-analysis. AB - BACKGROUND: The standard treatment for severe displaced pediatric supracondylar humeral fracture (SCHF) is closed reduction and percutaneous pin fixation. However, controversy persists concerning the optimal pin fixation technique. The purpose of this study was to compare the safety and efficacy on the configuration of lateral entry only with crossed entry pin fixation for SCHF, including Gartland type II and type III fractures in children. METHODS: Published literatures, including retrospective studies, prospective studies, and randomized controlled trials, presenting the probability of poor functional consequence of elbow and/or loss of reduction and/or iatrogenic ulnar nerve injury and/or superficial infection and/or cubitus varus were included. Statistical analysis was performed with the Review Manager 5.3 software. RESULTS: Twenty-four studies were included in the present meta-analysis involving 1163 patients with lateral entry pins and 1059 patients with crossed entry pins. An excellent score of Flynn criteria occurred more commonly in patients who treated with crossed pins than in patients with lateral pins only (RR = 0.93; 95% CI 0.87-0.99; P = 0.03). In accordance with previous systematic review, the incidence of iatrogenic ulnar nerve injury in crossed entry group was significantly more than in lateral entry group with statistical difference (RR = 0.26; 95% CI 0.14-0.47; P < 0.0001). And, results of subgroup analysis on iatrogenic ulnar nerve injury based on experimental design of retrospective study (RR = 0.23; 95% CI 0.10-0.52; P < 0.0004) and randomized control trial (RR = 0.29; 95% CI 0.10-0.79; P < 0.02) were similar. CONCLUSIONS: In consideration of the contradictoriness of lateral entry with two pins only (possible risk of poor functional consequence of elbow) and crossed entry pins (risk of iatrogenic ulnar nerve injury), the recommended strategy for the treatment of SCHF is the lateral entry technique with introducing divergent three pins which can provide a stable configuration and avoid the injury of the ulnar nerve. And additional protective measures for the ulnar nerve should be taken by surgeons that wish for the more stable structure with the crossed entry technique. PMID- 29615087 TI - Development of a sensitive Luminex xMAP-based microsphere immunoassay for specific detection of Iris yellow spot virus. AB - BACKGROUND: Iris yellow spot virus (IYSV) is an Orthotospovirus that infects most Allium species. Very few approaches for specific detection of IYSV from infected plants are available to date. We report the development of a high-sensitive Luminex xMAP-based microsphere immunoassay (MIA) for specific detection of IYSV. RESULTS: The nucleocapsid (N) gene of IYSV was cloned and expressed in Escherichia coli to produce the His-tagged recombinant N protein. A panel of monoclonal antibodies (MAbs) against IYSV was generated by immunizing the mice with recombinant N protein. Five specific MAbs (16D9, 11C6, 7F4, 12C10, and 14H12) were identified and used for developing the Luminex xMAP-based MIA systems along with a polyclonal antibody against IYSV. Comparative analyses of their sensitivity and specificity in detecting IYSV from infected tobacco leaves identified 7F4 as the best-performed MAb in MIA. We then optimized the working conditions of Luminex xMAP-based MIA in specific detection of IYSV from infected tobacco leaves by using appropriate blocking buffer and proper concentration of biotin-labeled antibodies as well as the suitable ratio between the antibodies and the streptavidin R-phycoerythrin (SA-RPE). Under the optimized conditions the Luminex xMAP-based MIA was able to specifically detect IYSV with much higher sensitivity than conventional enzyme-linked immunosorbent assay (ELISA). Importantly, the Luminex xMAP-based MIA is time-saving and the whole procedure could be completed within 2.5 h. CONCLUSIONS: We generated five specific MAbs against IYSV and developed the Luminex xMAP-based MIA method for specific detection of IYSV in plants. This assay provides a sensitive, high-specific, easy to perform and likely cost-effective approach for IYSV detection from infected plants, implicating potential broad usefulness of MIA in plant virus diagnosis. PMID- 29615088 TI - Ultrasound-guided needle release of the transverse carpal ligament with and without corticosteroid injection for the treatment of carpal tunnel syndrome. AB - BACKGROUND: To compare the clinical effectiveness of ultrasound-guided needle release of the transverse carpal ligament (TCL) with and without corticosteroid injection in carpal tunnel syndrome (CTS). METHODS: From June 2016 to June 2017, 49 CTS patients (50 wrists) were included in this study. Twenty-five wrists were treated with ultrasound-guided needle release of the TCL plus corticosteroid injection (group A), and 25 wrists were treated with single ultrasound-guided needle release of the TCL (group B). The following parameters were assessed and compared including postprocedure results according to relief of symptoms, ultrasound parameters (cross-sectional area of the median nerve at the levels of pisiform, flattening ratio of median nerve at the levels of the hamate bone, and the thicknesses of TCL on the cross-section at the level of the hamate bone), and electrophysiological parameters (distal motor latency and sensory conduction velocity). RESULTS: Group A had higher overall excellent and good rate 3 months after the procedure than group B (84 vs 52%, P < 0.05). There were significant differences regarding the above ultrasonic and electrophysiological parameters between the baseline and postprocedure values in both groups (all P < 0.05). There were significant differences regarding the postprocedure values of above ultrasonic and electrophysiological parameters between the two groups (all P < 0.05). No complications such as infection or tendon rupture were noted. No procedures were converted to the open release. CONCLUSIONS: Both techniques are effective in treating CTS. Ultrasound-guided needle release of the TCL with corticosteroid injection had better treatment benefits than single ultrasound guided needle release of the TCL in treating CTS. PMID- 29615089 TI - Decreased risk adjusted 30-day mortality for hospital admitted injuries: a multi centre longitudinal study. AB - BACKGROUND: The interpretation of changes in injury-related mortality over time requires an understanding of changes in the incidence of the various types of injury, and adjustment for their severity. Our aim was to investigate changes over time in incidence of hospital admission for injuries caused by falls, traffic incidents, or assaults, and to assess the risk-adjusted short-term mortality for these patients. METHODS: All patients admitted to hospital with injuries caused by falls, traffic incidents, or assaults during the years 2001-11 in Sweden were identified from the nationwide population-based Patient Registry. The trend in mortality over time for each cause of injury was adjusted for age, sex, comorbidity and severity of injury as classified from the International Classification of diseases, version 10 Injury Severity Score (ICISS). RESULTS: Both the incidence of fall (689 to 636/100000 inhabitants: p = 0.047, coefficient - 4.71) and traffic related injuries (169 to 123/100000 inhabitants: p < 0.0001, coefficient - 5.37) decreased over time while incidence of assault related injuries remained essentially unchanged during the study period. There was an overall decrease in risk-adjusted 30-day mortality in all three groups (OR 1.00; CI95% 0.99-1.00). Decreases in traffic (OR 0.95; 95% CI 0.93 to 0.97) and assault (OR 0.93; 95% CI 0.87 to 0.99) related injuries was significant whereas falls were not during this 11-year period. DISCUSSION: Risk-adjustment is a good way to use big materials to find epidemiological changes. However after adjusting for age, year, sex and risk we find that a possible factor is left in the pre- and/or in-hospital care. CONCLUSIONS: The decrease in risk-adjusted mortality may suggest changes over time in pre- and/or in-hospital care. A non significantdecrease in risk-adjusted mortality was registered for falls, which may indicate that low-energy trauma has not benefited for the increased survivability as much as high-energy trauma, ie traffic- and assault related injuries. PMID- 29615090 TI - Adolescent mental health education InSciEd Out: a case study of an alternative middle school population. AB - BACKGROUND: Mental illness contributes substantially to global disease burden, particularly when illness onset occurs during youth and help-seeking is delayed and/or limited. Yet, few mental health promotion interventions target youth, particularly those with or at high risk of developing mental illness ("at-risk" youth). Community-based translational research has the capacity to identify and intervene upon barriers to positive health outcomes. This is especially important for integrated care in at-risk youth populations. METHODS: Here the Integrated Science Education Outreach (InSciEd Out) program delivered a novel school-based anti-stigma intervention in mental health to a cohort of seventh and eighth grade at-risk students. These students were assessed for changes in mental health knowledge, stigmatization, and help-seeking intentions via a classroom activity, surveys, and teacher interviews. Descriptive statistics and Cohen's d effect sizes were employed to assess pre-post changes. Inferential statistical analyses were also conducted on pilot results to provide a benchmark to inform future studies. RESULTS: Elimination of mental health misconceptions (substance weakness p = 0.00; recovery p = 0.05; prevention p = 0.05; violent p = 0.05) was accompanied by slight gains in mental health literacy (d = 0.18) and small to medium improvements in help-seeking intentions (anxiety d = 0.24; depression d = 0.48; substance d = 0.43; psychosis d = 0.53). Within this particular cohort of students, stigma was exceptionally low at baseline and remained largely unchanged. Teacher narratives revealed positive teacher views of programming, increased student openness to talk about mental illness, and higher peer and self acceptance of mental health diagnoses and help-seeking. CONCLUSIONS: Curricular based efforts focused on mental illness in an alternative school setting are feasible and integrated well into general curricula under the InSciEd Out framework. Preliminary data suggest the existence of unique help-seeking barriers in at-risk youth. Increased focus upon community-based programming has potential to bridge gaps in translation, bringing this critical population to clinical care in pursuit of improved mental health for all. Trial registration ClinicalTrials.gov, ID:NCT02680899. Registered 12 February 2016, https://clinicaltrials.gov/ct2/show/NCT02680899. PMID- 29615091 TI - Rheumatic heart disease in the South West region of Cameroon: a hospital based echocardiographic study. AB - OBJECTIVE: Rheumatic heart disease (RHD) prevails as a major public health problem in sub-Saharan Africa. In Cameroon, reports on RHD have been so far limited to a few cities. We sought to describe the demographic, clinical and echocardiographic features of rheumatic heart disease in the Buea Regional Hospital, South West region of Cameroon. Echocardiography reports between June 2016 and June 2017 were reviewed. The diagnosis of RHD was based on the World Heart Federation Criteria for the diagnosis of RHD. RESULTS: A total of 669 echocardiograms were performed over the 1 year study period. Twenty-one (3.1%) had a definite echocardiographic diagnosis of RHD. There were 14 (66.7%) females. The age range was 13-94 years with a mean age of 47.8 +/- 20.3 years. The most common indications for echocardiography were heart failure (47.6%), and dyspnea (42.9%). The mitral valve was the most commonly affected valve in 80.9% of cases. The most common valve lesion was isolated mitral stenosis (42.9%), followed by isolated mitral regurgitation (28.6%). There were no lesions on the tricuspid and pulmonic valves. Severe lesions were found in 80.9% of the patients. The complications were pulmonary hypertension (66.7%) and atrial fibrillation (9.5%). PMID- 29615092 TI - Improving the effectiveness of psychological interventions for depression and anxiety in the cardiac rehabilitation pathway using group-based metacognitive therapy (PATHWAY Group MCT): study protocol for a randomised controlled trial. AB - BACKGROUND: Anxiety and depression are prevalent among cardiac rehabilitation patients but pharmacological and psychological treatments have limited effectiveness in this group. Furthermore, psychological interventions have not been systematically integrated into cardiac rehabilitation services despite being a strategic priority for the UK National Health Service. A promising new treatment, metacognitive therapy, may be well-suited to the needs of cardiac rehabilitation patients and has the potential to improve outcomes. It is based on the metacognitive model, which proposes that a thinking style dominated by rumination, worry and threat monitoring maintains emotional distress. Metacognitive therapy is highly effective at reducing this thinking style and alleviating anxiety and depression in mental health settings. This trial aims to evaluate the effectiveness and cost-effectiveness of group-based metacognitive therapy for cardiac rehabilitation patients with elevated anxiety and/or depressive symptoms. METHODS/DESIGN: The PATHWAY Group-MCT trial is a multicentre, two-arm, single-blind, randomised controlled trial comparing the clinical- and cost-effectiveness of group-based metacognitive therapy plus usual cardiac rehabilitation to usual cardiac rehabilitation alone. Cardiac rehabilitation patients (target sample n = 332) with elevated anxiety and/or depressive symptoms will be recruited across five UK National Health Service Trusts. Participants randomised to the intervention arm will receive six weekly sessions of group-based metacognitive therapy delivered by either cardiac rehabilitation professionals or research nurses. The intervention and control groups will both be offered the usual cardiac rehabilitation programme within their Trust. The primary outcome is severity of anxiety and depressive symptoms at 4-month follow-up measured by the Hospital Anxiety and Depression Scale total score. Secondary outcomes are severity of anxiety/depression at 12-month follow up, health-related quality of life, severity of post-traumatic stress symptoms and strength of metacognitive beliefs at 4- and 12-month follow-up. Qualitative interviews will help to develop an account of barriers and enablers to the effectiveness of the intervention. DISCUSSION: This trial will evaluate the effectiveness and cost-effectiveness of group-based metacognitive therapy in alleviating anxiety and depression in cardiac rehabilitation patients. The therapy, if effective, offers the potential to improve psychological wellbeing and quality of life in this large group of patients. TRIAL REGISTRATION: UK Clinical Trials Gateway, ISRCTN74643496 , Registered on 8 April 2015. PMID- 29615093 TI - Continuous versus intermittent endotracheal cuff pressure control for the prevention of ventilator-associated respiratory infections in Vietnam: study protocol for a randomised controlled trial. AB - BACKGROUND: Ventilator-associated respiratory infection (VARI) comprises ventilator-associated pneumonia (VAP) and ventilator-associated tracheobronchitis (VAT). Although their diagnostic criteria vary, together these are the most common hospital-acquired infections in intensive care units (ICUs) worldwide, responsible for a large proportion of antibiotic use within ICUs. Evidence-based strategies for the prevention of VARI in resource-limited settings are lacking. Preventing the leakage of oropharyngeal secretions into the lung using continuous endotracheal cuff pressure control is a promising strategy. The aim of this study is to investigate the efficacy of automated, continuous endotracheal cuff pressure control in preventing the development of VARI and reducing antibiotic use in ICUs in Vietnam. METHODS/DESIGN: This is an open-label randomised controlled multicentre trial. We will enrol 600 adult patients intubated for <= 24 h at the time of enrolment. Eligible patients will be stratified according to admission diagnosis (180 tetanus, 420 non-tetanus) and site and will be randomised in a 1:1 ratio to receive either (1) automated, continuous control of endotracheal cuff pressure or (2) intermittent measurement and control of endotracheal cuff pressure using a manual cuff pressure meter. The primary outcome is the occurrence of VARI, defined as either VAP or VAT during the ICU admission up to a maximum of 90 days after randomisation. Patients in both groups who are at risk for VARI will receive a standardised battery of investigations if their treating physician feels a new infection has occurred, the results of which will be used by an endpoint review committee, blinded to the allocated arm and independent of patient care, to determine the primary outcome. All enrolled patients will be followed for mortality and endotracheal tube cuff-related complications at 28 days and 90 days after randomisation. Other secondary outcomes include antibiotic use; days ventilated, in ICU and in hospital; inpatient mortality; costs of antibiotics in ICU; duration of ICU stay; and duration of hospital stay. DISCUSSION: This study will provide high-quality evidence concerning the use of continuous endotracheal cuff pressure control as a method to reduce VARI, antibiotic use and hospitalisation costs and to shorten stay. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02966392 . Registered on November 9, 2016. Protocol version: 2.0; issue date March 3, 2017. PMID- 29615094 TI - Heterogeneity in the in vitro susceptibility of Loa loa microfilariae to drugs commonly used in parasitological infections. AB - BACKGROUND: Co-infection with loiasis remains a potential problem in control programs targeting filarial infections. The effects of many anti-parasitic drugs often administered to Loa loa infected people are not well documented. This study compared the in vitro activity of several of these drugs on the viability of L. loa microfilariae (mf). METHODS: Human strain L. loa mf were isolated from baboon blood using iso-osmotic Percoll gradient, and cultured in RPMI 1640/10% FBS with antimalarial drugs (mefloquine, amodiaquine, artesunate, chloroquine and quinine), anthelmintics (ivermectin, praziquantel, flubendazole and its reduced and hydrolyzed metabolites), two potential trypanocidal agents (fexinidazole and Scynexis-7158) and the anticancer drug imatinib. The drug concentrations used varied between 0.156 MUg/ml and 10 MUg/ml. Mf motility (CR50 = 50% immotility) and a metabolic viability assay (MTT) were used to assess the effects of these drugs on the parasites. RESULTS: Mf in control cultures showed only a slight reduction in motility after 5 days of culture. Active inhibition of Loa loa motility was seen with mefloquine and amodiaquine (CR50 values of 3.87 and 4.05 MUg/ml, respectively), immobilizing > 90% mf within the first 24 hours: mefloquine killed the mf after 24 hours of culture at concentrations >= 5 MUg/ml. SCYX-7158 also induced a concentration-dependent reduction in mf motility, with > 50% reduction in mf motility seen after 5 days at 10 MUg/ml. The anticancer drug imatinib reduced mf motility at 10 MUg/ml from the first day of incubation to 55% by day 5, and the reduction in motility was concentration-dependent. Praziquantel and fexinidazole were inactive, and FLBZ and its metabolites, as well as ivermectin at concentrations > 5 MUg/ml, had very minimal effects on mf motility over the first 4 days of culture. CONCLUSIONS: The considerable action of the anti-malarial drugs mefloquine and amodiaquine on Loa mf in vitro highlights the possibility of repurposing the existing anti-infectious agents for the development of drugs against loiasis. The heterogeneity in the activity of anti parasitic agents on Loa loa mf supports the need for further investigation using animal models of loiasis. PMID- 29615095 TI - Loss of XBP1 accelerates age-related decline in retinal function and neurodegeneration. AB - BACKGROUND: Aging is the strongest risk factor for neurodegenerative diseases and extended age results in neuronal degeneration and functional decline in the visual system. Among many contributing factors to age-related deterioration of neurons is an insufficient activation of the Unfolded Protein Response (UPR) in the endoplasmic reticulum (ER) in response to cellular stress. X-box binding protein 1 (XBP1) is a major component of the UPR and is essential for maintaining protein homeostasis and reducing cellular stresses. Herein, we investigate the role of XBP1 in maintaining morphological and functional integrity in retinal neurons during adulthood and the early stages of aging. METHODS: The basal and induced levels of XBP1 activation in the retina were measured in young adult and aged mice. Conditional knockout (cKO) of XBP1 in retinal neurons was achieved by crossing XBP1 floxed mice with a retina specific Cre-recombinase line (Chx10 Cre). Retinal morphology, neuronal populations including photoreceptors, bipolar cells, and retinal ganglion cells (RGCs), synaptic structure, and microglial activation were examined with immunohistochemistry and staining of retinal sections. Retinal function was evaluated with light-adapted (photopic) and dark adapted (scotopic) electroretinograms. Retinal mitochondrial function and metabolism was assessed by Seahorse XFe24 Extracellular Flux Analyzer. RESULTS: The retinas of aged wild type (WT) mice display a significantly reduced basal level of Xbp1s and compromised activation of ER stress response. In XBP1 cKO mice, significant structural degeneration of the retina, evidenced by thinning of retinal layers and a loss of RGCs, and functional defects indicated by diminished photopic and scotopic ERG b-waves are observed at the age of 12-14 months. Furthermore, discontinuous and disorganized synaptic laminae, colocalized with activated microglia, in the inner plexiform layer is found in the XBP1 cKO retinas. In addition, cKO mice demonstrate a significant increase in ectopic synapses between bipolar cells and photoreceptors, which is strikingly similar to WT mice at 20-24 months of age. These changes are associated with defective retinal glycolysis while mitochondrial respiratory function appears normal in the cKO retina. CONCLUSIONS: XBP1 cKO mice at 12-14 months of age show significant structural, functional, and metabolic deficits that closely resemble WT mice twice that age. Our findings suggest that the absence of XBP1, a critical component of the UPR, accelerates age-related retinal neurodegeneration. PMID- 29615096 TI - CD6 expression has no effect on atherosclerosis in apolipoprotein E-deficient mice. AB - OBJECTIVE: To determine if deficiency of CD6, a cell surface protein on lymphocytes that alters natural antibody production, increases atherosclerosis in ApoE-deficient mice fed a chow or a western-type diet. RESULTS: We compared cholesterol levels, IgM, B1a cells, and aortic root lesion areas in ApoE deficient vs. CD6/ApoE double deficient mice. Feeding the high-fat western type diet increased all parameters, except for B1a cell numbers decreased. Sex also had an effect on many parameters with males having increased body weights, higher high density lipoprotein cholesterol, higher B1a cells, but smaller atherosclerotic lesions if chow fed mice; however, this sex effect on atherosclerosis was absent in mice fed the western-type diet. CD6 deficiency had no effect on atherosclerosis in both male and female mice on either diet. Thus, loss of CD6 on lymphocytes did not lead to expected reductions in B1a cells and protective IgM levels, and in turn did not alter atherosclerosis in mice. PMID- 29615097 TI - Multi-omics integration for neuroblastoma clinical endpoint prediction. AB - BACKGROUND: High-throughput methodologies such as microarrays and next-generation sequencing are routinely used in cancer research, generating complex data at different omics layers. The effective integration of omics data could provide a broader insight into the mechanisms of cancer biology, helping researchers and clinicians to develop personalized therapies. RESULTS: In the context of CAMDA 2017 Neuroblastoma Data Integration challenge, we explore the use of Integrative Network Fusion (INF), a bioinformatics framework combining a similarity network fusion with machine learning for the integration of multiple omics data. We apply the INF framework for the prediction of neuroblastoma patient outcome, integrating RNA-Seq, microarray and array comparative genomic hybridization data. We additionally explore the use of autoencoders as a method to integrate microarray expression and copy number data. CONCLUSIONS: The INF method is effective for the integration of multiple data sources providing compact feature signatures for patient classification with performances comparable to other methods. Latent space representation of the integrated data provided by the autoencoder approach gives promising results, both by improving classification on survival endpoints and by providing means to discover two groups of patients characterized by distinct overall survival (OS) curves. REVIEWERS: This article was reviewed by Djork-Arne Clevert and Tieliu Shi. PMID- 29615098 TI - MiR-10a-5p targets TFAP2C to promote gemcitabine resistance in pancreatic ductal adenocarcinoma. AB - BACKGROUND: By regulating target genes, microRNAs play essential roles in carcinogenesis and drug resistance in human pancreatic ductal adenocarcinoma (PDAC). Previous studies have shown that microRNA-10a-5p (miR-10a-5p) is overexpressed in PDAC and acts as an oncogene to promote the metastatic behavior of PDAC cells. However, the role of miR-10a-5p in PDAC chemoresistance remains unclear. METHODS: The effects of miR-10a-5p on biological behaviors were analyzed. MiR-10a-5p and TFAP2C levels in tissues were detected, and the clinical value was evaluated. RESULTS: We found that miR-10a-5p is up-regulated in gemcitabine-resistant PDAC cells and enhances PDAC cell gemcitabine resistance in vitro and vivo. Meanwhile, we also determined that miR-10a-5p promotes the migratory and invasive ability of PDAC cells. Next, we confirmed that transcription factor activating protein 2 gamma (TFAP2C) is a target of miR-10a 5p, and TFAP2C overexpression resensitizes PDAC cells to gemcitabine, which is initiated by miR-10a-5p. Further studies revealed that TFAP2C also decreased PDAC cell migration and invasion capability. Finally, survival analysis demonstrated that high miR-10a-5p expression levels and low TFAP2C expression levels were both independent adverse prognostic factors in patients with PDAC. CONCLUSION: Together, these results indicate that miR-10a-5p/TFAP2C may be new therapeutic target and prognostic marker in PDAC. PMID- 29615099 TI - Multimodal label-free imaging of living dermal equivalents including dermal papilla cells. AB - BACKGROUND: Despite the significant progress in the development of skin equivalents (SEs), the problem of noninvasively assessing the quality of the cell components and the collagen structure of living SEs both before and after transplantation remains. Undoubted preference is given to in vivo methods of noninvasive, label-free monitoring of the state of the SEs. Optical bioimaging methods, such as cross-polarization optical coherence tomography (CP OCT), multiphoton tomography (MPT), and fluorescence lifetime imaging microscopy (FLIM), present particular advantages for the visualization of such SEs. METHODS: In this study, we simultaneously applied several visualization techniques for skin model examination. We investigated the structure and quality of dermal equivalents containing dermal papilla (DP) cells and dermal fibroblasts (FBs) using CP OCT, MPT, and FLIM. Both the energy metabolism of the cell components and the structuring of the collagen fibrils were addressed. RESULTS: Based on the data from the fluorescence lifetimes and the contributions of protein-bound NAD(P)H, a bias toward oxidative metabolism was indicated, for the first time, in both the DP cells and FBs on day 14 of SE cultivation. The CP OCT and MPT data also indicated that both DP cells and FBs structured the collagen gel in a similar manner. CONCLUSION: In this study, multimodal label-free imaging of the structure and quality of living dermal equivalents was implemented for the first time with the use CP OCT, MPT, and FLIM of NAD(P)H. Our data suggest that the combination of different imaging techniques provides an integrated approach to data acquisition regarding the structure and quality of dermal equivalents, minimizes the potential disadvantages of using a single method, and provides an ideal information profile for clinical and research applications. PMID- 29615100 TI - Ultrasonography or direct radiography? A comparison of two techniques to detect dorsal screw penetration after volar plate fixation. AB - BACKGROUND: Complications related to extensor tendons have begun to increase with the use of volar plates in the treatment of distal radius fractures. In this study, we aimed to compare four-plane radiography and ultrasonography in the evaluation of dorsal cortex screw penetration following volar plate fixation. METHODS: We recruited 47 patients (33 males, 14 females, mean age 37.4 years; range 18-58 years). To evaluate dorsal screw penetration in all patients, we performed radiographs at 45 degrees pronation, 45 degrees supination and obtained dorsal tangential graphs at maximum palmar flexion, and a wrist lateral radiograph. Wrist ultrasonography was performed in all patients. RESULTS: Dorsal screw penetration was detected in 12 of the 47 patients undergoing VLP application. While there was > 2 mm screw penetration in seven patients, there was < 2 mm screw penetration in five patients. On four-plane radiographs, screw penetration > 2 mm was detected in seven patients and screw penetration < 2 mm was detected in two patients. On four-plane radiography, dorsal screw penetration was not detected in three out of five patients, who were shown to have < 2 mm screw penetration by ultrasonography. In addition to perioperative four-plane radiographs are also required to detect dorsal cortex penetration in patients undergoing VLP due to distal radius fracture. However, the detection of screw penetrations < 2 mm is more likely with ultrasonography compared to four-plane radiography. CONCLUSION: We recommend that dorsal cortex screw penetration should be evaluated with perioperative ultrasonography. TRIAL REGISTRATION: Research Registry, researchregistry3344 , Registered 10 January 2017. PMID- 29615101 TI - Aspergillus fumigatus during COPD exacerbation: a pair-matched retrospective study. AB - BACKGROUND: Recently awareness of the importance of Aspergillus colonization in the airway of patients with chronic obstructive pulmonary disease (COPD) was rising. The aim of this study was to investigate the clinical features and short term outcomes of COPD patients with Aspergillus colonization during acute exacerbation. METHODS: A pair-matched retrospective study on patients presenting with COPD exacerbation was conducted from January 2014 to March 2016 in Beijing Hospital, China. RESULTS: Twenty-three patients with Aspergillus colonization and 69 patients as controls, diagnosed of COPD exacerbation, were included in this study at a pair-matched ratio of 1:3. In stable stage, the percentage of patients with high-dose corticosteroids inhalation in the Aspergillus colonization group is higher than that of in control group (65.5% vs 33.3%, p = 0.048). Multivariate analysis showed that corticosteroids use was the risk factor for isolation of Aspergillus. In acute exacerbation stage, patients in Aspergillus colonization group received higher dose of inhaled corticosteroids and more types of antibiotics than control group. The short-time outcome hinted that the remission time and the duration of hospitalization were longer in the Aspergillus colonization group than in the control group (remission time: 11 +/- 4 days vs 7 +/- 4 days, p = 0.001; duration: 15 +/- 5 days vs 12 +/- 4 days, p = 0.011). CONCLUSIONS: Aspergillus colonization in the lower respiratory tract of COPD patients showed typical clinical manifestations, affected their short time outcome and provided a dilemma of clinical treatment strategy. PMID- 29615102 TI - A case report of nifedipine-induced hepatitis with jaundice. AB - BACKGROUND: Nifedipine is a generic, well-known and commonly-prescribed dihydropyridine calcium channel blocker used in the treatment of hypertension and Prinzmetal's angina. A known but very rare and serious adverse effect of nifedipine is clinically-apparent hepatitis which can take months to resolve. CASE PRESENTATION: Here we present a case of nifedipine-induced hepatitis in a 78 year-old Caucasian female with no prior history of liver or autoimmune disease. We discuss our investigative and management approach, and present a review of prior cases. We offer an approach for patients who present with signs of acute liver injury with jaundice and high elevations in serum transaminases. CONCLUSION: Not much is known about nifedipine-induced hepatitis due to its rare occurrence. Its prevalence is unknown. The disease appears to afflict older men and women. It can present acutely (within days) or subacutely (within 4-8 weeks after medication start) and in an idiosyncratic manner. Chronic or latent cases have also been described, some diagnosed as late as 3 years after medication start. Common symptoms include jaundice, nausea, chills, rigors, diaphoresis, fatigue, and abdominal pain. Laboratory investigations often reveal profound elevations in AST, ALT, GGT, and conjugated bilirubin. Peripheral blood smear may demonstrate eosinophilia. Histology from liver biopsy typically demonstrates infiltration of immune cells, cholestasis, and a picture of steatohepatitis. Treatment involves immediate discontinuation of the drug with supportive care. Thus far, all published instances of nifedipine-induced hepatitis were self limiting without mortality due to fulminant liver failure. However, this disease can take months to resolve. There is no randomized evidence for other treatments such as corticosteroids. PMID- 29615103 TI - The differentiation of mesenchymal stem cells to vascular cells regulated by the HMGB1/RAGE axis: its application in cell therapy for transplant arteriosclerosis. AB - BACKGROUND: Mesenchymal stem cell (MSC) transplantation shows promise for treating transplant arteriosclerosis, at least partly via promoting endothelial regeneration. However, the efficacy and safety are still under investigation especially regarding recent findings that neointimal smooth muscle cells are derived from MSC-like cells. The high mobility group box 1 (HMGB1)/receptor for advanced glycation end-product (RAGE) axis is involved in regulating proliferation, migration, and differentiation of MSCs, and therefore it can be presumably applied to improve the outcome of cell therapy. The aim of the current study was to investigate this hypothesis. METHODS: Rat MSCs were treated with HMGB1 or modified with HMGB1 vectors to activate the HMGB1/RAGE axis. RAGE was targeted and inhibited by specific short hairpin RNA vectors. We assessed the capacity for cell proliferation, migration, and differentiation after vector transfection in vitro and in a rat model of transplant arteriosclerosis. The expression of CD31 and alpha-smooth muscle actin (alphaSMA) was determined to evaluate the differentiation of MSCs to endothelial cells and smooth muscle cells. RESULTS: Exogenous HMGB1 treatment and transfection with HMGB1 vectors promoted MSC migration and vascular endothelial growth factor (VEGF)-induced differentiation to CD31+ cells while inhibiting their proliferation and platelet derived growth factor (PDGF)-induced differentiation to alphaSMA+ cells. Such an effect was blocked by RAGE knockdown. HMGB1-modified cells preferably migrated to graft neointima and differentiated to CD31+ cells along with significant relief of transplant arteriosclerosis and inhibition of HMGB1 and RAGE expression in graft vessels. RAGE knockdown inhibited cell migration to graft vessels. CONCLUSIONS: HMGB1 stimulated MSCs to migrate and differentiate to endothelial cells via RAGE signaling, which we translated to successful application in cell therapy for transplant arteriosclerosis. PMID- 29615104 TI - Genetic analysis for rs2280205 (A>G) and rs2276961 (T>C) in SLC2A9 polymorphism for the susceptibility of gout in Cameroonians: a pilot study. AB - OBJECTIVE: To determine the association of non-synonymous variants rs2280205 and rs2276961 of the SLC2A9 gene to gout in Cameroonians. RESULTS: In a case-control study including 30 patients with acute gout matched to 30 healthy volunteers. We searched for polymorphism of the targeted variants using Restriction Fragment Length Polymorphism following polymerize chain reaction. Fisher exact test and Student t-test were used to compare variables, with a threshold of significance set at 0.05. The mean age of participants was 58 +/- 8 years with 28 (93%) males. The family history of gout was found in one-third of the cases (p > 0.05). Uricemia was higher in cases than controls (p < 0.001) but 24 h urate excretion was similar in both groups (p > 0.05). Ancestral alleles (G and C) and their homozygous genotypes (GG and CC) of the targeted variants were predominant in both groups (p < 0.001). The polymorphisms of targeted variants were not associated with gout, and do not influence uric acid concentration in blood and urine. Non-synonymous variants rs2280205 and rs2276961 are not associated with gout in Cameroonians. However, the hereditary component of the disease suggests the influence of other genetic and/or environmental factors. PMID- 29615105 TI - TBX21 predicts prognosis of patients and drives cancer stem cell maintenance via the TBX21-IL-4 pathway in lung adenocarcinoma. AB - BACKGROUND: The Th1 cell-specific transcription factor TBX21 functions as a regulator of expression of a Th1 cytokine, interferon gamma (IFN-gamma). However, the specific function of TBX21 correlated with cancer stemness remains unclear. METHODS: Using univariate and multivariate survival analysis, TBX21was identified as an independent predictive factor and was associated with poor prognosis in 1389 patients with lung adenocarcinoma (LUAD). Its mechanism in the prognosis was explored by functional enrichment analysis and validated in bioexperiments. RESULTS: In the training and test sets, TBX21 could classify 1389 LUAD patients into high and low-risk groups with significantly different prognosis (P < 0.01). Its prognostic power was independent of other clinical factors including stage, age, gender and smoking status. Functional studies indicated that downregulating TBX21 in lung cancer cells decreased the fraction of cancer stem cells and their sphere and tumor initiation frequency. Furthermore, the study showed that TBX21 activation transduced a TBX21-IL-4 signaling cascade to promote tumor initiation, tumor growth and expression of stemness markers. CONCLUSIONS: These data demonstrated a key role of TBX21 in the maintenance of cancer stemness and that the TBX21-IL-4 pathway is a crucial factor contributing to lung carcinogenesis. TBX21 prognostic model correlated with cancer stemness via TBX21-IL-4 pathway in LUAD patients. PMID- 29615106 TI - Differentiation of human pluripotent stem cells into two distinct NKX6.1 populations of pancreatic progenitors. AB - BACKGROUND: The expression of a specific combination of transcription factors (TFs) in the multipotent progenitor cells (MPCs) is critical for determining pancreatic cell fate. NKX6.1 expression in PDX1+ MPCs is required for functional beta cell generation. We have recently demonstrated the generation of a novel population of human pluripotent stem cell (hPSC)-derived MPCs that exclusively express NKX6.1, independently of PDX1 (PDX1-/NKX6.1+). Therefore, the aim of this study was to characterize this novel population to elucidate its role in pancreatic development. METHODS: The hPSCs were exposed to two differentiation protocols to generate MPCs that were analyzed using different techniques. RESULTS: Based on the expression of PDX1 and NKX6.1, we generated three different populations of MPCs, two of them were NKX6.1+. One of these NKX6.1 populations coexpressed PDX1 (PDX1+/NKX6.1+) which is known to mature into functional beta cells, and an additional novel population did not express PDX1 (PDX1-/NKX6.1+) with an undefined role in pancreatic cell fate. This novel population was enriched using our recently established protocol, allowing their reorganization in three-dimensional (3D) structures. Since NKX6.1 induction in MPCs can direct them to endocrine and/or ductal cells in humans, we examined the coexpression of endocrine and ductal markers. We found that the expression of the pancreatic endocrine progenitor markers chromogranin A (CHGA) and neurogenin 3 (NGN3) was not detected in the NKX6.1+ 3D structures, while few structures were positive for NKX2.2, another endocrine progenitor marker, thereby shedding light on the origin of this novel population and its role in pancreatic endocrine development. Furthermore, SOX9 was highly expressed in the 3D structures, but cytokeratin 19, a main ductal marker, was not detected in these structures. CONCLUSIONS: These data support the existence of two independent NKX6.1+ MPC populations during human pancreatic development and the novel PDX1-/NKX6.1+ population may be involved in a unique trajectory to generate beta cells in humans. PMID- 29615107 TI - Development and validation of a tool to assess knowledge of healthy lifestyles in early grade school children. AB - OBJECTIVE: Healthy habits during childhood has been of prime importance. We aimed to gather baseline information about health habits from children in kindergarten and first grade (typically ages 5-7). Our objectives were to validate the questionnaire in assessing health habits, as well as the electronic audience response system, iClicker (MPS, Gordonsville, VA), in this age group. RESULTS: The questionnaire completed by 75 kindergarteners and 66 first graders. For the first graders, questions involving healthy choices were answered correctly 78% of the time (range 8-94%) and had 84% agreement on repeat testing (range 64-93%). Questions on diabetes were answered correctly 79% of the time (range 65-94%) and had 85% agreement on repeat testing. Crohnbach's alpha was calculated to determine the reliability of the questionnaire: on the revised kindergarten questionnaire, this ranged from 0.79 to 0.81 on Day 1 and 0.84-0.97 on Day 5; for the first graders, this ranged 0.79-0.81 on Day 1 and 0.84-0.97 on Day 5. Both kindergarteners and first graders answered the simplest of the basic knowledge questions correctly > 80% of the time, with acceptable test-retest agreement. Additionally, these children demonstrated acceptable understanding of the use of the iClicker classroom response system. PMID- 29615108 TI - Phages infecting Faecalibacterium prausnitzii belong to novel viral genera that help to decipher intestinal viromes. AB - BACKGROUND: Viral metagenomic studies have suggested a role for bacteriophages in intestinal dysbiosis associated with several human diseases. However, interpretation of viral metagenomic studies is limited by the lack of knowledge of phages infecting major human gut commensal bacteria, such as Faecalibacterium prausnitzii, a bacterial symbiont repeatedly found depleted in inflammatory bowel disease (IBD) patients. In particular, no complete genomes of phages infecting F. prausnitzii are present in viral databases. METHODS: We identified 18 prophages in 15 genomes of F. prausnitzii, used comparative genomics to define eight phage clades, and annotated the genome of the type phage of each clade. For two of the phages, we studied prophage induction in vitro and in vivo in mice. Finally, we aligned reads from already published viral metagenomic data onto the newly identified phages. RESULTS: We show that each phage clade represents a novel viral genus and that a surprisingly large fraction of them (10 of the 18 phages) codes for a diversity-generating retroelement, which could contribute to their adaptation to the digestive tract environment. We obtained either experimental or in silico evidence of activity for at least one member of each genus. In addition, four of these phages are either significantly more prevalent or more abundant in stools of IBD patients than in those of healthy controls. CONCLUSION: Since IBD patients generally have less F. prausnitzii in their microbiota than healthy controls, the higher prevalence or abundance of some of its phages may indicate that they are activated during disease. This in turn suggests that phages could trigger or aggravate F. prausnitzii depletion in patients. Our results show that prophage detection in sequenced strains of the microbiota can usefully complement viral metagenomic studies. PMID- 29615109 TI - Human chorionic plate-derived mesenchymal stem cells transplantation restores ovarian function in a chemotherapy-induced mouse model of premature ovarian failure. AB - BACKGROUND: Previous studies have reported that transplantation of mesenchymal stem cells (MSCs) from many human tissues could ameliorate ovarian dysfunction. However, no study has revealed the therapeutic efficiency of MSCs derived from the chorionic plate (CP-MSCs) for premature ovarian failure (POF). METHODS: We investigated the restorative effects of CP-MSCs on cyclophosphamide (CTX)-induced POF. The POF mouse models were established via intraperitoneal injection of 50 mg/kg CTX into female mice for 15 consecutive days. After that, CP-MSCs were intravenously transplanted into the mice once a week for 4 weeks. The serum estradiol (E2) and follicle-stimulating hormone (FSH) levels in the mouse models were detected using enzyme-linked immunosorbent assay (ELISA) before and after treatment. Ovarian function was evaluated through counting the follicles, estrous cycles, and oocytes. RESULTS: CP-MSC transplantation restored the serum hormone level and ovarian function of the mice in the mouse model of POF induced by CTX. The levels of serum E2 and FSH in the POF model group was 232.33 +/- 17.16 pg/mL and 4.48 +/- 0.29 mIU/mL, respectively, after 6 weeks of treatment, which were similar to the values in the wild-type (WT) group. The superovulation demonstrated that ovarian function was significantly improved compared with nontreated POF model mice. The CP-MSC transplantation could restore CTX-induced ovarian dysfunction. CONCLUSIONS: Our results offer a potential application for human CP-MSCs in POF treatment. PMID- 29615110 TI - Gut-dependent microbial translocation induces inflammation and cardiovascular events after ST-elevation myocardial infarction. AB - BACKGROUND: Post-infarction cardiovascular remodeling and heart failure are the leading cause of myocardial infarction (MI)-driven death during the past decades. Experimental observations have involved intestinal microbiota in the susceptibility to MI in mice; however, in humans, identifying whether translocation of gut bacteria to systemic circulation contributes to cardiovascular events post-MI remains a major challenge. RESULTS: Here, we carried out a metagenomic analysis to characterize the systemic bacteria in a cohort of 49 healthy control individuals, 50 stable coronary heart disease (CHD) subjects, and 100 ST-segment elevation myocardial infarction (STEMI) patients. We report for the first time higher microbial richness and diversity in the systemic microbiome of STEMI patients. More than 12% of post-STEMI blood bacteria were dominated by intestinal microbiota (Lactobacillus, Bacteroides, and Streptococcus). The significantly increased product of gut bacterial translocation (LPS and D-lactate) was correlated with systemic inflammation and predicted adverse cardiovascular events. Following experimental MI, compromised left ventricle (LV) function and intestinal hypoperfusion drove gut permeability elevation through tight junction protein suppression and intestinal mucosal injury. Upon abrogation of gut bacterial translocation by antibiotic treatment, both systemic inflammation and cardiomyocyte injury in MI mice were alleviated. CONCLUSIONS: Our results provide the first evidence that cardiovascular outcomes post-MI are driven by intestinal microbiota translocation into systemic circulation. New therapeutic strategies targeting to protect the gut barrier and eliminate gut bacteria translocation may reduce or even prevent cardiovascular events post-MI. PMID- 29615111 TI - Metabolic correlates of reserve and resilience in MCI due to Alzheimer's Disease (AD). AB - BACKGROUND: We explored the presence of both reserve and resilience in late converter mild cognitive impairment due to Alzheimer's disease (MCI-AD) and in patients with slowly progressing amyloid-positive MCI by assessing the topography and extent of neurodegeneration with respect to both "aggressive" and typically progressing phenotypes and in the whole group of patients with MCI, grounding the stratification on education level. METHODS: We analyzed 94 patients with MCI-AD followed until conversion to dementia and 39 patients with MCI who had brain amyloidosis (AMY+ MCI), all with available baseline 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) results. Using a data-driven approach based on conversion time, patients with MCI-AD were divided into typical AD and late-converter subgroups. Similarly, on the basis of annual rate of Mini Mental State Examination score reduction, AMY+ MCI group was divided, obtaining smoldering (first tertile) and aggressive (third tertile) subgroups. Finally, we divided the whole group (MCI-AD and AMY+ MCI) according to years of schooling, obtaining four subgroups: poorly educated (Low-EDUC; first quartile), patients with average education (Average-EDUC; second quartile), highly educated (High EDUC; third quartile), and exceptionally educated (Except-EDUC; fourth quartile). FDG-PET of typical AD, late converters, and aggressive and smoldering AMY+ MCI subgroups, as well as education level-based subgroups, were compared with healthy volunteer control subjects (CTR) and within each group using a two-samples t test design (SPM8; p < 0.05 family-wise error-corrected). RESULTS: Late converters were characterized by relatively preserved metabolism in the right middle temporal gyrus (Brodmann area [BA] 21) and in the left orbitofrontal cortex (BA 47) with respect to typical AD. When compared with CTR, the High-EDUC subgroup demonstrated a more extended bilateral hypometabolism in the posterior parietal cortex, posterior cingulate cortex, and precuneus than the Low- and Average-EDUC subgroups expressing the same level of cognitive impairment. The Except-EDUC subgroup showed a cluster of significant hypometabolism including only the left posterior parietal cortex (larger than the Low- and Average-EDUC subgroups but not further extended with respect to the High-EDUC subgroup). CONCLUSIONS: Middle and inferior temporal gyri may represent sites of resilience rather than a hallmark of a more aggressive pattern (when hypometabolic). These findings thus support the existence of a relatively homogeneous AD progression pattern of hypometabolism despite AD heterogeneity and interference of cognitive reserve. In fact, cortical regions whose "metabolic resistance" was associated with slower clinical progression had different localization with respect to the regions affected by education-related reserve. PMID- 29615112 TI - Where to from here? A quality improvement project investigating burns treatment and rehabilitation practices in India. AB - OBJECTIVE: To describe the capacity of the Indian healthcare system in providing appropriate and effective burns treatment and rehabilitation services. RESULTS: Health professionals involved in burns treatment or rehabilitation at seven hospitals from four states in India were invited to participate in consultative meetings. Existing treatment and rehabilitation strategies, barriers and enablers to patient flow across the continuum of care and details on inpatient and outpatient rehabilitation were discussed during the meetings. Seventeen health professionals from various clinical backgrounds were involved in the consultation process. Key themes highlighted (a) a lack of awareness on burn first aid at the community level, (b) a lack of human resource to treat burn injuries in hospital settings, (c) a gap in burn care training for medical staff, (d) poor hospital infrastructure and (e) a variation in treatment practices and rehabilitation services available between hospitals. A number of opportunities exist to improve burns treatment and rehabilitation in India. Improvements would most effectively be achieved through promoting multidisciplinary care across a number of facilities and service providers. Further research is required to develop context specific burn care models, determining how these can be integrated into the Indian healthcare system. PMID- 29615113 TI - Intraocular lens power calculation for the equine eye. AB - BACKGROUND: Phacoemulsification and intraocular lens (IOL) implantation during cataract surgery in horses occur with increasing frequency. To reduce the postoperative refractive error it is necessary to determine the proper IOL power. In the present study retinoscopy, keratometry and ultrasonographic biometry were performed on 98 healthy equine eyes from 49 horses. The refractive state, corneal curvature (keratometry) and the axial location of all optical interfaces (biometry) were measured. The influences of breed, height at the withers, gender and age on values obtained and the comparison between the left and right eye were evaluated statistically. Corresponding IOL power were calculated by use of Binkhorst and Retzlaff theoretical formulas. RESULTS: Mean +/- SD refractive state of the horses was + 0.32 +/- 0.66 D. Averaged corneal curvature for Haflinger, Friesian, Pony, Shetland pony and Warmblood were 21.30 +/- 0.56 D, 20.02 +/- 0.60 D, 22.61 +/- 1.76 D, 23.77 +/- 0.94 D and 20.76 +/- 0.88 D, respectively. The estimated postoperative anterior chamber depth (C) was calculated by the formula C = anterior chamber depth (ACD)/0.73. This formula was determined by a different research group. C and axial length of the globe averaged for Haflinger 9.30 +/- 0.54 mm and 39.43 +/- 1.26 mm, for Friesian 10.12 +/- 0.33 mm and 42.23 +/- 1.00 mm, for Pony 8.68 +/- 0.78 mm and 38.85 +/- 3.13 mm, for Shetland pony 8.71 +/- 0.81 mm and 37.21 +/- 1.50 mm and for Warmblood 9.39 +/- 0.51 mm and 40.65 +/- 1.30 mm. IOL power was calculated with the Binkhorst and Retzlaff theoretical formulas. Calculated IOL power for the several breeds ranged from 18.03 D to 19.55 D. The mean value across all horses was 18.73 D determined with Binkhorst formula and 18.54 D determined with Retzlaff formula. CONCLUSIONS: Mean result of this study is: an 18.5 D IOL seemed to be the most appropriate to achieve emmetropia after IOL implantation in horses. Cataract surgery without IOL implantation results in hyperopic and visual compromised horses. Retinoscopy, keratometry and ultrasonographic biometry should be performed on every affected horse and postoperative visual outcome should be determined. PMID- 29615114 TI - MeCP2-mediated epigenetic regulation in senescent endothelial progenitor cells. AB - BACKGROUND: Cellular aging may be associated with epigenetics. Methyl-CpG-binding protein 2 (MeCP2) and sirtuin 1 (SIRT1) are two important epigenetic factors. Our former work demonstrated that MeCP2 expression increased and SIRT1 expression decreased in senescent endothelial progenitor cells (EPCs). This article aims to reveal the epigenetic regulation caused by MeCP2 in EPCs and discuss its mechanism. METHODS: Tube formation assay and cell apoptosis detection were used to evaluate the function of senescent EPCs induced by MeCP2 overexpression. Western blot analysis was used to testify the relative protein expression changed by MeCP2. Bisulfite sequencing methylation assay and chromatin immunoprecipitation assay were used to assess the degree of methylation and the relation of MeCP2 and SIRT1. RESULTS: MeCP2 reduced angiogenesis of senescent EPCs, promoted apoptosis, and caused senescent EPC dysfunction through SIRT1 promoter hypermethylation and histone modification. CONCLUSIONS: MeCP2 mediated senescent EPC dysfunction through epigenetic regulation. PMID- 29615115 TI - Effectiveness of personal genomic testing for disease-prevention behavior when combined with careful consultation with a physician: a preliminary study. AB - OBJECTIVES: There are many direct-to-consumer (DTC)-type personal genomic testing (PGT) services commercially available to the public, providing the specific disease susceptibilities of individuals. While these services do not appear to stimulate disease-prevention behavior, few studies have addressed the methods to do so. We investigated the effectiveness of combining a consultation with a physician with the delivery of test results from a DTC-type PGT, as a preliminary study to identify the effective genomic testing for disease-prevention. A prepared physician disclosed the PGT results of twenty healthy subjects and provided a specific consultation on the high-risk diseases for each subject. The effects on the sense of health, understanding of possible future diseases, and preventive behaviors for each subject were examined pre-PGT, post-PGT, and 3, 6, and 12 months post-PGT. RESULTS: Significant increases between the pre- and post PGT scores were observed for the awareness of lifestyle effects on developing those diseases (P < 0.05) and the awareness of the ability to influence disease onset (P < 0.01). The follow-up questionnaire results showed that over 60% of the subjects changed their lifestyles in favor of disease prevention. These results suggest that combining the DTC-PGT with a careful physician consultation may be effective at motivating people toward preventive behavior. PMID- 29615116 TI - Expression and in vitro assessment of tumorigenicity for NOD1 and NOD2 receptors in breast cancer cell lines. AB - OBJECTIVE: Immune-related pathways have been frequently associated to tumorigenesis. NOD1 and NOD2 are innate immune receptors responsible for sensing a subset of bacterial-derived components, and to further translate these pathogenic signals through pro-inflammatory and survival pathways. NOD1 and NOD2 have been further associated with tumorigenesis, particularly in gastrointestinal cancers. NOD1 has also been suggested to be a tumor suppressor gene in a model of estrogen receptor-dependent breast cancer. Contrarily, NOD2 polymorphisms are associated with higher risk of breast cancer, with no tumor suppressor role being reported. To better delineate this issue, we investigated NOD1 and NOD2 expression in a panel of breast cancer cell lines, as well as their potential impact in breast tumorigenesis based on in vitro assays. RESULTS: The highly invasive Hs578T breast cell line presented the second highest NOD1 expression and the lowest NOD2 expression in our panel. Therefore, we investigated whether NOD1 and/or NOD2 might act as a tumor suppressor in this cell model. Our studies indicate that overexpression of either NOD1 or NOD2 reduces cell proliferation and increases clonogenic potential in vitro. Elucidation of NOD1 and NOD2 effects on tumor cell viability and proliferation may unveil potential targets for future therapeutic intervention. PMID- 29615117 TI - Arabidopsis mutants may represent recombinant introgression lines. AB - OBJECTIVES: It is a common practice in Arabidopsis to transfer a mutation generated in one genetic background to other genetic background via crossing. However, the drawback of this methodology is unavoidable presence of genomic fragments from the donor parent being often replacing desirable genomic fragments of the recurrent parent. Here, we highlighted problem of Arabidopsis mutants being recombinant introgression lines that can lead to unreliable and misinterpreted results. RESULTS: We studied the regulation of low copy number transposable elements Tag1 and Evelknievel (EK), located at the end of the bottom arm of chromosome 1 and both are present in the Arabidopsis Landsberg erecta (Ler) but not in Columbia (Col) ecotype. Using various epigenetic mutants (cmt3, ddm1, kyp2, ago4, rdr2 hen1 etc.), we found that certain mutants in the Ler background are deficient of Tag1 or EK or both and represent recombinant introgression lines whereby chromosomal regions from Col have been recombined into the Ler genome. Our data support a recent proposal calling for formulating standards for authentication of plant lines that are used in plant research. Most important is to verify that a given trait or genomic locus under study is correctly identified, particularly when using mutants generated by crossing. PMID- 29615118 TI - Global connectivity patterns of the notoriously invasive mussel, Mytilus galloprovincialis Lmk using archived CO1 sequence data. AB - OBJECTIVE: The invasive mussel, Mytilus galloprovincialis has established invasive populations across the globe and in some regions, have completely displaced native mussels through competitive exclusion. The objective of this study was to elucidate global connectivity patterns of M. galloprovincialis strictly using archived cytochrome c oxidase 1 sequence data obtained from public databases. Through exhaustive mining and the development of a systematic workflow, we compiled the most comprehensive global CO1 dataset for M. galloprovincialis thus far, consisting of 209 sequences representing 14 populations. Haplotype networks were constructed and genetic differentiation was assessed using pairwise analysis of molecular variance. RESULTS: There was significant genetic structuring across populations with significant geographic patterning of haplotypes. In particular, South Korea, South China, Turkey and Australasia appear to be the most genetically isolated populations. However, we were unable to recover a northern and southern hemisphere grouping for M. galloprovincialis as was found in previous studies. These results suggest a complex dispersal pattern for M. galloprovincialis driven by several contributors including both natural and anthropogenic dispersal mechanisms along with the possibility of potential hybridization and ancient vicariance events. PMID- 29615120 TI - Determinants of unjustified cesarean section in two hospitals southwestern Ethiopia: retrospective record review. AB - OBJECTIVE: The study aimed to identify determinants of unjustified cesarean section in two hospitals southwestern Ethiopia using retrospective record review from January 2015 to January 2016. RESULT: A total of 727 charts were included in the analysis. About 25% of the study participants had delivered by cesarean section in 1 year. Antenatal care visit (AOR = 0.003, 95% CI 0.00-0.07), labor abnormality (AOR = 10.1, 95% CI 4.61-22.1), and post term pregnancy (AOR = 10.6, 95% CI 4.85-23.1) were significantly associated with cesarean section when compared to their respective counterparts. PMID- 29615119 TI - Influence of cholesterol/caveolin-1/caveolae homeostasis on membrane properties and substrate adhesion characteristics of adult human mesenchymal stem cells. AB - BACKGROUND: Adult mesenchymal stem cells (MSCs) are an important resource for tissue growth, repair, and regeneration. To utilize MSCs more effectively, a clear understanding of how they react to environmental cues is essential. Currently, relatively little is known about how the composition of the plasma membranes affects stem cell phenotype and properties. The presence of lipid molecules, including cholesterol in particular, in the plasma membrane plays a crucial role in regulating a variety of physiological processes in cells. In this study, we examined the effects of perturbations in cholesterol/caveolin-1 (CAV 1)/caveolae homeostasis on the membrane properties and adhesive characteristics of MSCs. Findings from this study will contribute to the understanding of how cholesterol/CAV-1/caveolae regulates aspects of the cell membrane important to cell adhesion, substrate sensing, and microenvironment interaction. METHODS: We generated five experimental MSC groups: 1) untreated MSCs; 2) cholesterol depleted MSCs; 3) cholesterol-supplemented MSCs; 4) MSCs transfected with control, nonspecific small interfering (si)RNA; and 5) MSCs transfected with CAV 1 siRNA. Each cell group was analyzed for perturbation of cholesterol status and CAV-1 expression by performing Amplex Red cholesterol assay, filipin fluorescence staining, and real-time polymerase chain reaction (PCR). The membrane fluidity in the five experimental cell groups were measured using pyrene fluorescence probe staining followed by FACS analysis. Cell adhesion to collagen and fibronectin as well as cell surface integrin expression were examined. RESULTS: Cholesterol supplementation to MSCs increased membrane cholesterol, and resulted in decreased membrane fluidity and localization of elevated numbers of caveolae and CAV-1 to the cell membrane. These cells showed increased expression of alpha1, alpha4, and beta1 integrins, and exhibited higher adhesion rates to fibronectin and collagen. Conversely, knockdown of CAV-1 expression or cholesterol depletion on MSCs caused a parallel decrease in caveolae content and an increase in membrane fluidity due to decreased delivery of cholesterol to the cell membrane. Cells with depleted CAV-1 expression showed decreased cell surface integrin expression and slower adhesion to different substrates. CONCLUSIONS: Our results demonstrate that perturbations in cholesterol/CAV-1 levels significantly affect the membrane properties of MSCs. These findings suggest that modification of membrane cholesterol and/or CAV-1 and caveolae may be used to manipulate the biological activities of MSCs. PMID- 29615121 TI - The missing link in parasite manipulation of host behaviour. AB - The observation that certain species of parasite my adaptively manipulate its host behaviour is a fascinating phenomenon. As a result, the recently established field of 'host manipulation' has seen rapid expansion over the past few decades with public and scientific interest steadily increasing. However, progress appears to falter when researchers ask how parasites manipulate behaviour, rather than why. A vast majority of the published literature investigating the mechanistic basis underlying behavioural manipulation fails to connect the establishment of the parasite with the reported physiological changes in its host. This has left researchers unable to empirically distinguish/identify adaptive physiological changes enforced by the parasites from pathological side effects of infection, resulting in scientists relying on narratives to explain results, rather than empirical evidence. By contrasting correlative mechanistic evidence for host manipulation against rare cases of causative evidence and drawing from the advanced understanding of physiological systems from other disciplines it is clear we are often skipping over a crucial step in host manipulation: the production, potential storage, and release of molecules (manipulation factors) that must create the observed physiological changes in hosts if they are adaptive. Identifying these manipulation factors, via associating gene expression shifts in the parasite with behavioural changes in the host and following their effects will provide researchers with a bottom-up approach to unraveling the mechanisms of behavioural manipulation and by extension behaviour itself. PMID- 29615122 TI - Effect of CYP3 A4, CYP3 A5 and ABCB1 gene polymorphisms on the clinical efficacy of tacrolimus in the treatment of nephrotic syndrome. AB - BACKGROUND: The efficacy of tacrolimus (TAC) is variable in the treatment of nephrotic syndrome (NS), which might be related to genetic variation among patients. Therefore, we aim to investigate the effects of CYP3 A4, CYP3 A5 and ABCB1 gene polymorphisms on the clinical efficacy of TAC in the treatment of NS patients. Methods 100 NS patients were treated with TAC and prednisone and followed up for 3 months. Genotype differences (CYP3 A4*1G, CYP3 A5*3, ABCB1 1236C > T and ABCB1 2677G > T/A) were detected by Sanger sequencing. The clinical efficacy was evaluated by the 24 h urinary protein quantitation, albumin, renal function and the degree of edema. Multivariable logistic regression was used to analyze the effect of gene polymorphisms on the clinical efficacy of TAC. RESULTS: There were 35 patients (35%) with complete remission, 43 patients (43%) with partial remission, 22 patients (22%) without remission, and no patients with recurrence. For CYP3A4, there were 56, 42, and 2 patients with *1/*1, *1/*1G and *1G/*1G genotype, respectively. For CYP3A5, there were 8, 36 and 56 cases with*1/*1, *1/*3 and *3/*3 genotype, respectively. For ABCB1 C1236T, there were 10, 44, and 46 cases with 1236CC, 1236CT and 1236TT genotype, respectively. For ABCB1 G2677 T/A, there were 13, 57, and 30 patients with 2677GG genotype, 2677GT/GA genotype and 2677TT/AA/TA genotype, respectively. The mutant allele frequencies of CYP3A4*1G, CYP3A5*3, ABCB1 C1236T and ABCB1 G2677 T/A were 23%, 74%, 68% and 58.5%, respectively. Results reveal that the gene polymorphisms of CYP3A4 and CYP3A5 and CCB do not affect the clinical efficacy of TAC. For ABCB1 C1236T,TT genotype can increase the effectiveness 12.085 times compared with CC and CT genotype (P = 0.018, OR = 12.085, 95%CI 1.535-95.148). For ABCB1 G2677 T/A, the clinical efficacy of patients with mutant genotype is 8.683 times than that of wild-type and heterozygous patients (P = 0.042, OR = 8.683, 95%CI 1.080 69.819). Overweight patients can improve the clinical efficacy by 15.838 times (P = 0.020, OR = 15.838, 95%CI1.550-161.788). CONCLUSIONS: ABCB1 C1236T, ABCB1 G2677 T/A genotype and BMI are probably the factors influencing the clinical efficacy of TAC in treating patients with NS. PMID- 29615123 TI - Representativeness of European clinical trial populations in mild Alzheimer's disease dementia: a comparison of 18-month outcomes with real-world data from the GERAS observational study. AB - BACKGROUND: Comparison of disease progression between placebo-group patients from randomised controlled trials (RCTs) and real-world patients can aid in assessing the generalisability of RCT outcomes. This analysis compared outcomes between community-dwelling patients with mild Alzheimer's disease (AD) dementia from two RCTs (pooled European (EU) data from EXPEDITION and EXPEDITION 2) and similar patients from the EU GERAS observational study. METHODS: Data from placebo-group patients with mild AD dementia from the RCTs (EU countries only) were compared with data from GERAS patients with mild AD dementia. Between-group differences for changes over 18 months were analysed for cognition, functioning, neuropsychiatric symptoms, health-related quality of life (HRQoL) and caregiver time using propensity score-adjusted models. A sensitivity analysis compared EU/North American (EU/NA) EXPEDITION patients with GERAS patients. RESULTS: EU EXPEDITION patients (n = 168) were younger than GERAS patients (n = 566) (mean (standard deviation, SD) age 71.9 (7.4) versus 77.3 (6.9) years; p < 0.001) and were more likely to use AD treatment (95% versus 84%; p < 0.001). Cognitive performance was similar at baseline in both populations, although GERAS patients showed greater functional impairment (p = 0.005) and lower HRQoL (p < 0.05). At 18 months, no statistically significant differences between EXPEDITION (n = 133) and GERAS (n = 417) patients were observed for changes in cognitive, functional, neuropsychiatric and HRQoL outcomes. Least squares mean (95% confidence interval) change in caregiver time (hours/month) spent on instrumental activities of daily living (iADL; 29.22 (19.16, 39.27) versus 3.20 (-11.89, 18.28), p = 0.001) and supervision (66.59 (47.49, 85.69) versus 3.04 (-25.39, 31.48), p < 0.001) showed greater increases in GERAS than EXPEDITION. In the sensitivity analysis, changes in neuropsychiatric and HRQoL scores and caregiver time spent on basic ADL were also significantly greater in GERAS than in EU/NA EXPEDITION patients. CONCLUSIONS: Patients with mild AD dementia participating in the EU EXPEDITION RCTs and the GERAS observational study showed a similar decline in cognitive, functional and neuropsychiatric symptoms over 18 months, whereas changes in caregiver time measures were significantly greater in GERAS. Results indicate the importance of using similar regions when comparing real-world and RCT data. TRIAL REGISTRATION: ClinicalTrials.gov NCT00905372 EXPEDITION. Registered 18 May 2009. ClinicalTrials.gov NCT00904683 EXPEDITION 2. Registered 18 May 2009. PMID- 29615125 TI - In-office laryngeal procedures (IOLP) in Canada: current safety practices and procedural care. AB - BACKGROUND: The advent of chip tip technology combined with advanced endoscopy has revolutionized the field of laryngology in the past decade. Procedures such as transnasal esophagoscopy, site-specific steroid injections, injection laryngoplasty and laryngeal laser treatment can now be performed in the office setting under local anaesthesia. Although In-Office Laryngeal Procedures (IOLPs) have become standard-of-care in many American and several Canadian centers, there are no guidelines regulating the practice of these procedures. The goal of this report was to evaluate the current method of IOLP delivery in Canada. METHODS: An electronic survey was dispersed to 22 practicing Canadian laryngologists to assess safety and procedural care measures undertaken when performing IOLP. The survey consisted of 37 questions divided into 6 categories; 1) Demographic data 2) Facilities 3) Staff/personnel 4) Patient screening/monitoring 5) Procedure and emergency equipment 6) Reporting of adverse events. RESULTS: Data was collected for 16/22 laryngologists (72.7% response rate). Only 1 respondent did not perform IOLP. All performed injection augmentation laryngoplasty. Most performed laryngeal biopsies, intramuscular injection and/or electromyography guided injection for the treatment of spasmodic dysphonia and glottic/subglottic steroid injections. Only 4 respondents performed in-office KTP laser. Significant variation was found in procedural processes including intra procedural monitoring, anticoagulation screening, access to emergency equipment and documentation. CONCLUSION: Our survey demonstrates that the delivery of IOLP in Canada varies considerably. The construct of IOLP practice guidelines based on the evidence with consistent documentation would promote safe, efficient and quality care for patient with voice disorders. PMID- 29615124 TI - Differentiating snail intermediate hosts of Schistosoma spp. using molecular approaches: fundamental to successful integrated control mechanism in Africa. AB - BACKGROUND: Snail intermediate hosts play active roles in the transmission of snail-borne trematode infections in Africa. A good knowledge of snail-borne diseases epidemiology particularly snail intermediate host populations would provide the necessary impetus to complementing existing control strategy. MAIN BODY: This review highlights the importance of molecular approaches in differentiating snail hosts population structure and the need to provide adequate information on snail host populations by updating snail hosts genome database for Africa, in order to equip different stakeholders with adequate information on the ecology of snail intermediate hosts and their roles in the transmission of different diseases. Also, we identify the gaps and areas where there is need for urgent intervention to facilitate effective integrated control of schistosomiasis and other snail-borne trematode infections. CONCLUSIONS: Prioritizing snail studies, especially snail differentiation using molecular tools will boost disease surveillance and also enhance efficient schistosomaisis control programme in Africa. PMID- 29615127 TI - Inflammatory licensed equine MSCs are chondroprotective and exhibit enhanced immunomodulation in an inflammatory environment. AB - BACKGROUND: Inflammatory licensed mesenchymal stem cells (MSCs) have the ability to promote functional tissue repair. This study specifically sought to understand how the recipient tissue environment reciprocally affects MSC function. Inflammatory polarized macrophages, modeling an injured tissue environment, were exposed to licensed MSCs, and the resultant effects of MSC immunomodulation and functionality of the MSC secretome on chondrocyte homeostasis were studied. METHODS: Inflammatory licensed MSCs were generated through priming with either IFN-gamma or polyinosinic:polycytidylic acid (poly I:C). Macrophages were polarized to an inflammatory phenotype using IFN-gamma. Licensed MSCs were co cultured with inflammatory macrophages and immunomodulation of MSCs was assessed in a T-cell proliferation assay. MSC gene expression was analyzed for changes in immunogenicity (MHC-I, MHC-II), immunomodulation (IDO, PTGS2, NOS2, TGF-beta1), cytokine (IL-6, IL-8), and chemokine (CCL2, CXCL10) expression. Macrophages were assessed for changes in cytokine (IL-6, IL-10, TNF-alpha, IFN-gamma) and chemokine (CCL2, CXCL10) expression. Conditioned medium representing the secretome from IFN-gamma or poly I:C-primed MSCs was applied to IL-1beta stimulated chondrocytes, which were analyzed for catabolic (IL-6, TNF-alpha, CCL2, CXCL10, MMP-13, PTGS2) and matrix synthesis (ACAN, COL2A1) genes. RESULTS: IFN-gamma-primed MSCs had a superior ability to suppress T-cell proliferation compared to naive MSCs, and this ability was maintained following exposure to proinflammatory macrophages. In naive and licensed MSCs exposed to inflammatory macrophages, MHC-I and MHC-II gene expression was upregulated. The secretome from licensed MSCs was chondroprotective and downregulated inflammatory gene expression in IL-1beta-stimulated chondrocytes. CONCLUSIONS: In-vitro inflammatory licensing agents enhanced the immunomodulatory ability of MSCs exposed to inflammatory macrophages, and the resultant secretome was biologically active, protecting chondrocytes from catabolic stimulation. Use of licensing agents produced a more consistent immunomodulatory MSC population compared to exposure to inflammatory macrophages. The clinical implications of this study are that in-vitro licensing prior to therapeutic application could result in a more predictable immunomodulatory and reparative response to MSC therapy compared to in-vivo inflammatory licensing by the recipient environment. PMID- 29615126 TI - Mesenchymal stem cells and extracellular matrix scaffold promote muscle regeneration by synergistically regulating macrophage polarization toward the M2 phenotype. AB - BACKGROUND: Skeletal muscle plays an important role in the body's physiology but there are still no effective treatments for volumetric muscle loss (VML) resulting from severe traumatic injury or tumor excision. Recent studies show that a tissue engineering strategy using a compound containing mesenchymal stem cells (MSCs) and decellularized extracellular matrix (ECM) scaffold generates significant regenerative effects on VML injury, but the underlying mechanisms are not fully understood. METHODS: The characteristics of human umbilical cord MSCs, including multiplication capacity and multidifferentiation ability, were determined. We constructed a compound containing MSCs and decellularized ECM scaffold which was used for tissue regeneration in a VML model. RESULTS: We found that MSCs and decellularized ECM scaffold generated synergistic effects on promoting skeletal muscle tissue regeneration. Interestingly, both MSCs and decellularized ECM scaffold could promote macrophage polarization toward the M2 phenotype and suppress macrophage polarization toward the M1 phenotype, which is widely regarded as an important promoting factor in tissue regeneration. More importantly, MSCs and decellularized ECM scaffold generate synergistic promoting effects on macrophage polarization toward the M2 phenotype, not just an additive effect. CONCLUSIONS: Our findings uncover a previously unknown mechanism that MSCs and decellularized ECM scaffold promote tissue regeneration via collaboratively regulating macrophage polarization. PMID- 29615128 TI - Prion-like propagation of beta-amyloid aggregates in the absence of APP overexpression. AB - The amyloid cascade hypothesis posits that the initiating event in Alzheimer's disease (AD) is the aggregation and deposition of the beta-amyloid (Abeta) peptide, which is a proteolytic cleavage product of the amyloid precursor protein (APP). Mounting evidence suggests that the formation and spread of prion-like Abeta aggregates during AD may contribute to disease progression. Inoculation of transgenic mice that overexpress APP with pre-formed Abeta aggregates results in the prion-like induction of cerebral Abeta deposition. To determine whether Abeta deposition can also be induced when physiological APP levels are present in the brain, we inoculated AppNL-F mice, a knock-in model of AD that avoids potential artifacts associated with APP overexpression, with Abeta aggregates derived from the brains of AD patients or transgenic mice. In all cases, induced Abeta deposition was apparent in the corpus callosum, olfactory bulb, and meningeal blood vessels of inoculated mice at 130-150 days post-inoculation, whereas uninoculated and buffer-inoculated animals exhibited minimal or no Abeta deposits at these ages. Interestingly, despite being predominantly composed of protease resistant Abeta42 aggregates, the induced parenchymal Abeta deposits were largely diffuse and were unreactive to an amyloid-binding dye. These results demonstrate that APP overexpression is not a prerequisite for the prion-like induction of cerebral Abeta deposition. Accordingly, spreading of Abeta deposition may contribute to disease progression in AD patients. PMID- 29615129 TI - Antimicrobial susceptibility pattern of Staphylococcus aureus isolates from clinical specimens at Kenyatta National Hospital. AB - OBJECTIVE: To determine antibiotic susceptibility pattern of S. aureus isolates from clinical specimens collected from patients at Kenyatta National Hospital from March 2014-February 2016, and to determine the prevalence and quarterly trends of MRSA throughout the study period. RESULTS: A total of 944 S. aureus isolates were analyzed. High sensitivity of S. aureus was observed for quinupristin/dalfopristin (100%), tigecycline (98.2), imipenem (98%), nitrofurantoin (97.6%), linezolid (97.3%), teicoplanin (97.1%) and vancomycin (95.1%). High resistance was recorded against penicillin G (91.9%), trimethoprim/sulfamethoxazole (56.9%) and tetracycline (33.2%). MRSA prevalence among the patients at KNH was 27.8%. Highest proportion (80%) of MRSA was in burns unit. Both MRSA and MSSA were highly susceptible to quinupristin/dalfopristin, tigecycline, linezolid, nitrofurantoin, ampicillin/sulbactam and vancomycin and showed high resistance to commonly used antibiotics such as gentamycin, erythromycin, levofloxacin and tetracycline. A majority of isolates were from pus specimen (68%). PMID- 29615130 TI - New endoperoxides highly active in vivo and in vitro against artemisinin resistant Plasmodium falciparum. AB - BACKGROUND: The emergence and spread of Plasmodium falciparum resistance to artemisinin-based combination therapy in Southeast Asia prompted the need to develop new endoperoxide-type drugs. METHODS: A chemically diverse library of endoperoxides was designed and synthesized. The compounds were screened for in vitro and in vivo anti-malarial activity using, respectively, the SYBR Green I assay and a mouse model. Ring survival and mature stage survival assays were performed against artemisinin-resistant and artemisinin-sensitive P. falciparum strains. Cytotoxicity was evaluated against mammalian cell lines V79 and HepG2, using the MTT assay. RESULTS: The synthesis and anti-malarial activity of 21 new endoperoxide-derived compounds is reported, where the peroxide pharmacophore is part of a trioxolane (ozonide) or a tetraoxane moiety, flanked by adamantane and a substituted cyclohexyl ring. Eight compounds exhibited sub-micromolar anti malarial activity (IC50 0.3-71.1 nM), no cross-resistance with artemisinin or quinolone derivatives and negligible cytotoxicity towards mammalian cells. From these, six produced ring stage survival < 1% against the resistant strain IPC5202 and three of them totally suppressed Plasmodium berghei parasitaemia in mice after oral administration. CONCLUSION: The investigated, trioxolane-tetrazole conjugates LC131 and LC136 emerged as potential anti-malarial candidates; they show negligible toxicity towards mammalian cells, ability to kill intra erythrocytic asexual stages of artemisinin-resistant P. falciparum and capacity to totally suppress P. berghei parasitaemia in mice. PMID- 29615131 TI - Associations of neighbourhood walkability indices with weight gain. AB - BACKGROUND: Inconsistent associations of neighbourhood walkability with adults' body weight have been reported. Most studies examining the relationships of walkability and adiposity are cross-sectional in design. We examined the longitudinal relationships of two walkability indices - conventional walkability and space syntax walkability, and their individual components, with weight change among adults over four years. METHODS: Data were from the Physical Activity in Localities and Community study in Adelaide, Australia. In 2003-2004, 2650 adults living in 154 Census Collection Districts (CCDs) returned baseline questionnaires; in 2007-2008, the follow-up survey was completed by 1098. Participants reported their weight at baseline and at follow-up. Neighbourhood walkability indices were calculated using geographic information systems and space syntax software. Linear marginal models using generalized estimating equations with robust standard errors were fitted to examine associations of the two walkability indices and their individual components with the weight at follow up, adjusting for baseline weight, socio-demographic variables, and spatial clustering at the level of CCD. RESULTS: The overall mean weight gain over four years was 1.5 kg. The two walkability indices were closely correlated (r = 0.76, p < 0.01). No significant associations were found between the overall neighbourhood walkability indices and weight change. Among walkability components, there was a marginally significant negative association between space syntax measure of street integration and weight change: one standard deviation increment in street integration was associated with 0.31 kg less weight gain (p = 0.09). CONCLUSIONS: Using a prospective study design and a novel space-syntax based measure of walkability, we were not able to identify relationships between neighbourhood walkability with weight gain. This is consistent with other inconclusive findings on the built environment and obesity. Research on the built environment and adults' weight gain may need to consider not just local environments but also a larger scale environment within a city or workplace environment in order to capture multiple behaviours relevant to weight gain. PMID- 29615132 TI - Neuronal sphingosine kinase 2 subcellular localization is altered in Alzheimer's disease brain. AB - BACKGROUND: Alzheimer's disease (AD) is characterized by the accumulation of beta amyloid (Abeta) peptides and hyperphosphorylated tau protein accompanied by neuronal loss. Abeta accumulation has been associated with an impaired sphingosine 1-phosphate (S1P) metabolism. S1P is generated by sphingosine kinases (SphKs), of which there are two isoenzymes SphK1 and SphK2, and degraded by the sphingosine 1-phosphate lyase (SPL). We previously reported, that both a decrease in SphK1 expression and an increase in SPL expression, correlated with amyloid deposits in the entorhinal cortex of AD brains, suggesting a global loss of pro survival S1P in AD neurons. SphK2 contribution has also been examined in AD yielding to conflicting results that may reflect the complexity of SphK2 regulation. The subcellular localization of SphK2, hence the compartmentalization of generated S1P, is recognized to play a crucial role in dictating either its pro-survival or pro-apoptotic functions. We therefore aimed at studying the expression of SphK2 and notably its subcellular localization in brain tissues from patients with AD. RESULTS: We report that a decrease in SphK2 protein cytosolic expression correlated with the density of amyloid deposits in a cohort of 25 post-mortem brains. Interestingly, we observed that the equilibrium between cytoplasmic and nuclear SphK2 is disrupted and showed that SphK2 is preferentially localized in the nucleus in AD brain extracts as compared to control extracts, with a marked increase of cleaved SphK2. CONCLUSIONS: Our results suggest that a shift in the subcellular localization of the S1P generating SphK2 may compromise the well established pro-survival cytosolic S1P by favoring the production of nuclear S1P associated with adverse effects in AD pathogenesis. PMID- 29615133 TI - Total HIV DNA: a global marker of HIV persistence. AB - Among the different markers of HIV persistence in infected cells, total HIV DNA is to date the most widely used. It allows an overall quantification of all viral forms of HIV DNA in infected cells, each playing a different role in HIV replication and pathophysiology. The real-time PCR technology is to date, a precise, sensitive and reproducible technology that allows the description of the distribution of HIV infected cells in blood and tissues. The objective of this review is to present some examples which show the interest to quantify total HIV DNA levels. This marker brought an undeniable and considerable contribution to reservoir studies. Many results, both in clinical and basic research, allowed to get a large overview of the distribution of infected cells in the body, at all stages of HIV disease and during therapy. Future clinical studies aiming at reducing HIV reservoirs will benefit from HIV DNA quantification in blood and tissues, in association with other markers of HIV reservoir activity. PMID- 29615134 TI - Improving outcomes after pediatric cardiac arrest - the ICU-Resuscitation Project: study protocol for a randomized controlled trial. AB - BACKGROUND: Quality of cardiopulmonary resuscitation (CPR) is associated with survival, but recommended guidelines are often not met, and less than half the children with an in-hospital arrest will survive to discharge. A single-center before-and-after study demonstrated that outcomes may be improved with a novel training program in which all pediatric intensive care unit staff are encouraged to participate in frequent CPR refresher training and regular, structured resuscitation debriefings focused on patient-centric physiology. METHODS/DESIGN: This ongoing trial will assess whether a program of structured debriefings and point-of-care bedside practice that emphasizes physiologic resuscitation targets improves the rate of survival to hospital discharge with favorable neurologic outcome in children receiving CPR in the intensive care unit. This study is designed as a hybrid stepped-wedge trial in which two of ten participating hospitals are randomly assigned to enroll in the intervention group and two are assigned to enroll in the control group for the duration of the trial. The remaining six hospitals enroll initially in the control group but will transition to enrolling in the intervention group at randomly assigned staggered times during the enrollment period. DISCUSSION: To our knowledge, this is the first implementation of a hybrid stepped-wedge design. It was chosen over a traditional stepped-wedge design because the resulting improvement in statistical power reduces the required enrollment by 9 months (14%). However, this design comes with additional challenges, including logistics of implementing an intervention prior to the start of enrollment. Nevertheless, if results from the single-center pilot are confirmed in this trial, it will have a profound effect on CPR training and quality improvement initiatives. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02837497 . Registered on July 19, 2016. PMID- 29615135 TI - Analysis of factors associated with waiting times for GP appointments in Finnish health centres: a QUALICOPC study. AB - OBJECTIVE: Access to care is a multidimensional concept, considered as a structural aspect of health care quality; it reflects the functioning of a health care organization. The aim of this study was to investigate patients' experiences of access to care and to analyse factors associated with waiting times to GP appointments at Finnish health centres. A questionnaire survey was addressed to Finnish GPs within the Quality and Costs of Primary Care in Europe study framework. Two to nine patients per GP completed the questionnaire, altogether 1196. Main outcome measures were waiting times for appointments with GPs and factors associated with waiting times. In addition, patients' opinions of access to appointments were analysed. RESULTS: Of the 988 patients who had made their appointment in advance, 84.9% considered it easy to secure an appointment, with 51.9% obtaining an appointment within 1 week. Age and reason for contact were the most significant factors affecting the waiting time. Elderly patients tended to have longer waiting times than younger ones, even when reporting illness as their reason for contact. Thus, waiting times for appointments tend to be prolonged in particular for the elderly and there is room for improvement in the future. PMID- 29615137 TI - The relationship between obsessive compulsive personality and obsessive compulsive disorder treatment outcomes: Predictive utility and clinically significant change - CORRIGENDUM. PMID- 29615138 TI - Variability of renal colic management and outcomes in two Canadian cities. AB - CLINICIAN'S CAPSULE What is known about the topic? Most ureteral stones pass spontaneously, but intervention is an option. No trials have compared conservative vs. interventional treatment. What did this study ask? We compared 60-day outcomes for ED patients with ureteral colic in Calgary and Vancouver. What did this study find? Index intervention rate was seven-fold higher in Calgary. Calgary patients had more subsequent ED revisits and hospitalizations. Adverse outcomes were associated with intervention for small stones and with non intervention for large stones. Why does this study matter to clinicians? Conservative management of small stones and early intervention for large stones may improve system utilization and patient outcomes. PMID- 29615136 TI - Promoting psychosocial well-being following stroke: study protocol for a randomized, controlled trial. AB - BACKGROUND: Stroke is a major public health threat globally. Psychosocial well being may be affected following stroke. Depressive symptoms, anxiety, general psychological distress and social isolation are prevalent. Approximately one third report depressive symptoms and 20% report anxiety during the first months or years after the stroke. Psychosocial difficulties may impact significantly on long-term functioning and quality of life, reduce the effects of rehabilitation services and lead to higher mortality rates. The aim of the study is to evaluate the effect of a previously developed and feasibility tested dialogue-based psychosocial intervention aimed at promoting psychosocial well-being and coping following stroke among stroke survivors with and without aphasia. METHODS: The study will be conducted as a multicenter, randomized, single blind controlled trial with one intervention and one control arm. It will include a total of 330 stroke survivors randomly allocated into either an intervention group (dialogue based intervention to promote psychosocial well-being) or a control group (usual care). Participants in the intervention group will receive eight individual sessions of supported dialogues in their homes during the first six months following an acute stroke. The primary outcome measure will be psychosocial well being measured by the General Health Questionnaire (GHQ). Secondary outcome measures will be quality of life (SAQoL), sense of coherence (SOC), and depression (Yale). Process evaluation will be conducted in a longitudinal mixed methods study by individual qualitative interviews with 15-20 participants in the intervention and control groups, focus group interviews with the intervention personnel and data collectors, and a comprehensive analysis of implementation fidelity. DISCUSSION: The intervention described in this study protocol is based on thorough development and feasibility work, guided by the UK medical research council framework for developing and testing complex interventions. It combines classical effectiveness evaluation with a thorough process evaluation. The results from this study may inform the development of further trials aimed at promoting psychosocial well-being following stroke as well as inform the psychosocial follow up of stroke patients living at home. TRIAL REGISTRATION: NCT02338869 ; registered 10/04/2014 (On-going trial). PMID- 29615139 TI - Trends in the prevalence of elevated skinfold thickness among children and adolescents in Shandong Province, China, 1995-2014. AB - OBJECTIVE: There are abundant data on secular trends in BMI; however, information on the change in subcutaneous fat is limited. The present study examined the trends in the prevalence of elevated skinfold thickness among children and adolescents over the past 19 years (1995-2014) in Shandong Province, China. DESIGN: Data for the study were obtained from two cross-sectional surveys of schoolchildren carried out in 1995 and 2014. Triceps and subscapular skinfold thicknesses (SFT) of all participants were measured. The sum of triceps and subscapular SFT (SSFT) was applied. Children and adolescents with SSFT above or equal to the national age- and sex-specific 85th percentile were defined as 'high SFT'. SETTING: Shandong Province, China. SUBJECTS: A total of 16 917 students aged 7-18 years were included. RESULTS: For both boys and girls, an increasing trend in 'high SFT' was observed between 1995 and 2014. The overall prevalence of 'high SFT' increased from 10.31 % for boys and 13.40 % for girls in 1995 to 33.94 % for boys and 29.30 % for girls in 2014 (P<0.01). CONCLUSIONS: There are more children and adolescents with very high levels of SFT. These trends describe very unfavourable changes in the body composition and should give cause for concern. PMID- 29615141 TI - Children's Naive Concepts of OCD and How They Are Affected by Biomedical Versus Cognitive Behavioural Psychoeducation. AB - BACKGROUND: How we conceptualize mental health conditions is important as it impacts on a wide range of mediators of treatment outcome. We do not know how children intuitively conceptualize obsessive-compulsive disorder (OCD), nor do we know the relative impact of biomedical or cognitive behavioural conceptual explanations, yet both are being widely used in psychoeducation for children with OCD. AIMS: This study identified children's naive concepts of OCD, and the comparative impact of biomedical versus cognitive behavioural psychoeducation on perceived prognosis. METHOD: A within- and between-subjects experimental design was used. After watching a video of a young person describing their OCD, 202 children completed a questionnaire examining their concepts of the condition. They repeated the questionnaire following a second equivalent video, this time preceded by either biomedical or cognitive behavioural psychoeducation. RESULTS: Participants' naive concepts of OCD reflected predominant models of OCD in healthcare. Even at the minimal dose of psychoeducation, participants' conceptualizations of OCD changed. Prior exposure to OCD resulted in a stronger alignment with the biomedical model. Exposure to biomedical psychoeducation resulted in participants predicting a slower recovery with less chance of complete remission. CONCLUSION: Psychoeducation for childhood OCD is impactful. Despite its wide use by clinicians and mental health services, biomedical psychoeducation appears to have deleterious effects. Children's concepts of OCD merit attention but caution should be applied in how they are targeted. PMID- 29615140 TI - Adapted CBT to Stabilize Sleep on Psychiatric Wards: a Transdiagnostic Treatment Approach. AB - BACKGROUND: Almost all patients admitted at acute crisis to a psychiatric ward experience clinically significant symptoms of insomnia. Ward environments pose challenges to both sleep and the delivery of therapy. Despite this, there is no description of how to adapt cognitive behavioural therapy (CBT) for insomnia to overcome these challenges. AIMS: (i) To describe the key insomnia presentations observed in the Oxford Ward Sleep Solution (OWLS) trial and (ii) outline key adaptations aimed to increase accessibility and hence effectiveness of CBT for insomnia for a ward setting. METHODS: Trial therapists collaboratively agreed the key insomnia presentations and therapy adaptations based on their individual reflective logs used during the trial. RESULTS: Three key insomnia presentations are outlined. These are used to illustrate the application of 10 CBT for insomnia therapy adaptations. These include use of sleep monitoring watches to engage patients in treatment, stabilizing circadian rhythms, reducing the impact of night-time observations and managing discharge as a sleep challenge. CONCLUSIONS: Whilst inpatient wards bring challenges for sleep and therapy delivery, creative adaptations can increase the accessibility of evidence based CBT for insomnia techniques. This therapy has proven popular with patients. PMID- 29615142 TI - Impact of automatic milking systems on dairy cattle producers' reports of milking labour management, milk production and milk quality. AB - Automatic milking systems (AMS), or milking robots, are becoming widely accepted as a milking technology that reduces labour and increases milk yield. However, reported amount of labour saved, changes in milk yield, and milk quality when transitioning to AMS vary widely. The purpose of this study was to document the impact of adopting AMS on farms with regards to reported changes in milking labour management, milk production, milk quality, and participation in dairy herd improvement (DHI) programmes. A survey was conducted across Canada over the phone, online, and in-person. In total, 530 AMS farms were contacted between May 2014 and the end of June 2015. A total of 217 AMS producers participated in the General Survey (Part 1), resulting in a 41% response rate, and 69 of the respondents completed the more detailed follow-up questions (Part 2). On average, after adopting AMS, the number of employees (full- and part-time non-family labour combined) decreased from 2.5 to 2.0, whereas time devoted to milking related activities decreased by 62% (from 5.2 to 2.0 h/day). Median milking frequency was 3.0 milkings/day and robots were occupied on average 77% of the day. Producers went to fetch cows a median of 2 times/day, with a median of 3 fetch cows or 4% of the herd per robot/day. Farms had a median of 2.5 failed or incomplete milkings/robot per day. Producers reported an increase in milk yield, but little effect on milk quality. Mean milk yield on AMS farms was 32.6 kg/cow day. Median bulk tank somatic cell count was 180 000 cells/ml. Median milk fat on AMS farms was 4.0% and median milk protein was 3.3%. At the time of the survey, 67% of producers were current participants of a DHI programme. Half of the producers who were not DHI participants had stopped participation after adopting AMS. Overall, this study characterized impacts of adopting AMS and may be a useful guide for making this transition. PMID- 29615143 TI - Recovery and relapse from severe acute malnutrition after treatment: a prospective, observational cohort trial in Pakistan. AB - OBJECTIVE: Millions of children suffer from severe acute malnutrition (SAM) in low- and middle- income countries. Much is known about the effectiveness of community treatment programmes (CMAM) but little is known about post-discharge outcomes after successful treatment. The present study aimed to evaluate post discharge outcomes of children cured of SAM. DESIGN: Prospective, observational cohort study. Children with SAM who were discharged as cured were followed monthly for 6 months or until they experienced relapse to SAM. 'Cure' was defined as a child achieving a mid-upper arm circumference (MUAC) of >=115 mm with >=15 % weight gain after loss of oedema. Relapse was defined as a child with MUAC<115 mm and/or oedema at any monthly visit. SETTING: Save the Children CMAM programme in Swabi, Pakistan, from January 2012 to December 2014. SUBJECTS: Children aged 6-59 months (n 117) discharged as cured from the CMAM programme were eligible for the study and followed for 6 months. RESULTS: One hundred children (92.6 %) remained free of SAM, eight (7.4 %) relapsed to SAM, nine (8.3 %) were lost to follow-up and none died. Most relapses occurred within 3 months of discharge (mean time to relapse 73.4 (sd 36.2) d). At enrolment, 90 % had moderate acute malnutrition (MAM) and 10 % were not malnourished. By the end of 6 months, 35 % persisted with MAM and the remaining were not malnourished. CONCLUSIONS: In rural Pakistan, fewer than 10 % of children cured of SAM relapsed. The first 3 months is the most vulnerable time. PMID- 29615144 TI - A Pilot Investigation of Cognitive Behavioural Therapy for Clinical Perfectionism in Obsessive Compulsive Disorder-CORRIGENDUM. PMID- 29615145 TI - Challenge levels of everyday technologies as perceived over five years by older adults with mild cognitive impairment. AB - : ABSTRACTBackground:In clinical practice, efficient and valid functional markers are needed to detect subtle cognitive and functional decline in mild cognitive impairment (MCI). This prospective study explored whether changes in perceived challenge of certain everyday technologies (ETs) can be used to detect signs of functional change in MCI. METHODS: Baseline and five-year data from 37 older adults (mean age 67.5 years) with MCI regarding their perceived ability to use ET were used to generate Rasch-based ET item measures reflecting the relative challenge of 46 ETs. Actual differential item functioning in relation to time was analyzed based on these item measures. Data collection took place in 2008-2014. RESULTS: Seven (15%) of the ETs included were perceived to be significantly more challenging to use at year five compared to at baseline, while 39 ETs (85%) were perceived to be equally challenging to use, despite the fact that the participants' perceived ability to use ET had decreased. Common characteristics among the ETs that became more challenging to use could not be identified. The dropout rate was 43%, which limits the power of the study. CONCLUSIONS: Changes in the perceived challenge of ETs seem to capture functional change in persons with cognitive decline. Both easier and more challenging ETs typically used at home and in society need to be addressed to capture this functional change because significant changes occurred among ETs of all challenge levels and within all types of ETs. PMID- 29615146 TI - Curcumin suppress the growth of hepatocellular carcinoma via down-regulating SREBF1. AB - The aim of this study is to investigate the pharmacological effect of curcumin on hepatocellular carcinoma (HCC) Huh7 and PLC cells and to explore its mechanism in the pathological process by screening possible target genes. MTT assay was used to detect the effect of curcumin on the growth of Huh7 and PLC cells. The inhibitory effect was found to be in a time- and dose- dependent manner, and the cytoplasm was shrunk with round or elliptic morphology. Flow cytometry indicated that curcumin could significantly accelerate apoptosis of Huh7 and PLC cells, showing an obvious dosage effect. Retrieval in gene expression database and related gene-drug network analysis showed that the effect of curcumin on the apoptosis of HCC cells was related to SREBF1 (sterol regulatory element binding transcription factor 1) gene. In the in-vitro experiment, adding curcumin could significantly down-regulate SREBF1, and Western Blot suggested that down regulation of SREBF1 could suppress the tumor growth. In conclusion, Curcumin could significantly suppress the tumor growth by way of down-regulating SREBF1 expression. PMID- 29615147 TI - MiR-223-5p suppresses tumor growth and metastasis in non-small cell lung cancer by targeting E2F8. AB - MiR-223-5p has been demonstrated to regulate the development and progression of various cancers, such as hepatocellularcarcinoma, breast cancer and gastric carcinoma. However, the role of miR-223-5p in non-small cell lung cancer (NSCLC) requires further investigation. In this study, we found that the expression of miR-223-5p was significantly down-regulated in NSCLC tissues and cell lines. Moreover, the expression level of miR223-5p is negatively correlated with the malignance of NSCLC. Besides, we found that overexpression of miR-223-5p remarkably suppressed the proliferation of NSCLC cells in vitro and in vivo. MiR 223-5p overexpression also led to reduced migration and invasion in NSCLC cells. Mechanistically, we found that E2F8, a key transcription factor involved in many kinds of biological processes, was a direct target gene of miR-223-5p. Overexpression of miR-223-5p significantly decreased the mRNA and protein levels of E2F8 in NSCLC cells. What's more, we showed that restoration of E2F8 rescued the proliferation, migration and invasion of miR-223-5p-overexpressing NSCLC cells. Taken together, our findings demonstrated that miR-223-5p suppressed NSCLC progression through targeting E2F8. PMID- 29615148 TI - MicroRNA-495 inhibits proliferation, metastasis and promotes apoptosis by targeting Twist1 in gastric cancer cells. AB - Recently, microRNAs (miRNAs) have reported to participate in multiple biological processes. However, the effects of miR-495 on gastric cancer (GC) remain unclear. The purpose of this study is to explore the functions of miR-495 in GC cells proliferation, metastasis and apoptosis. SGC-7901 and BGC-823 were transfected with miR-495 mimic, miR-495 inhibitor and negative controls (mimic control and inhibitor control). The expressions of miR-495, cell viability, migration, apoptosis and apoptosis-related factors were examined by qRT-PCR, trypan blue staining, Transwell, flow cytometry and western blot, respectively. Simultaneously, the key factors expressions of EMT were detected by qRT-PCR again. The direct target gene of miR-495 was confirmed by dual luciferase assay. Additionally, sh-Twist1, pc-Twist1 and corresponding control were also transfected into SGC-7901 and BGC-823 cells, and then the protein levels of EMT associated factors were detected by western blot. MiR-495 was down-regulated in GC cells. MiR-495 expression level was effectively overexpressed or suppressed in SGC-7901 and BGC-823 cells. Overexpression of miR-495 significantly decreased cell viability, migration and increased apoptosis as well as inhibited EMT process. Suppression of miR-495 showed contrary results. Twist1 was clarified as a target gene of miR-495, and Twist1 silencing obviously reduced the promotion effect of miR-495 suppression on these biological processes. Besides, Twist1 silencing significantly blocked EMT signal pathway in both SGC-7901 and BGC-823 cells. MiR-495 inhibited proliferation, metastasis and promoted apoptosis by targeting Twist1 in GC cells. These data indicated that miR-495 might be a novel anti-tumor factor of GC and provide a new method for treatment of GC. PMID- 29615149 TI - MiR-455 functions as a tumor suppressor through targeting GATA6 in colorectal cancer. AB - Emerging evidence indicates microRNAs (miRNAs) are often aberrantly expressed in human cancers. Meanwhile, the importance of miRNAs in regulating multiplies cellular biological processes has been appreciated. The aim of this study was to investigate the significance of miR-455 and identify its possible mechanism in regulating colorectal cancer (CRC) progression. We found the expression of miR 455 was sharply reduced in CRC tissues and cell lines. Importantly, the low expression of miR-455 was associated with poor overall survival of CRC patients. Force the expression of miR-455 in CRC cell lines significantly inhibited cell proliferation and migration in vitro. Moreover, GATA binding protein 6 (GATA6), whose expression can be inversely regulated by miR-455 in CRC cell lines, was validated as a direct target of miR-455. Overall, our results revealed that miR 455 functions as a tumor suppressor and its downregulation may contribute to CRC progression. Our study may provide a novel therapeutic target for CRC in future. PMID- 29615150 TI - LncRNA BCAR4 increases viability, invasion and migration non-small cell lung cancer cells by targeting glioma-associated oncogene 2(GLI2). AB - OBJECTIVE: This study was aimed to explore the effects of lncRNA BCAR4 on the viability and aggressiveness of non-smallcell lung cancer (NSCLC) cells. METHODS: qRTPCR was used to determine the expression of lncRNA BCAR4 and GLI2 downstream genes in NSCLC tissues and cell lines. Chromatin isolation by RNA purification (CHIRP) and western blot were employed to measure the expression of GLI2 downstream proteins. Ki67 expression in nude mice tumors was tested by immunohistochemistry. MTT assay, wound healing assay, and transwell assay were used to assess NSCLC cell viability and aggressiveness, respectively. Tumor xenograft was conducted to determine the effects of lncRNA BCAR4 and GLI2 on NSCLC tumorigenesis in vivo. RESULTS: The expression of lncRNA BCAR4 in NSCLC tissues and cells was significantly higher than normal level. The overexpression of BCAR4 promoted NSCLC cell viability, migration, and invasion. The suppression of BCAR4 and GLI2 showed the opposite effects. The overexpression of BCAR4 led to the increase in the expression of GLI2 downstream proteins, while the suppression of BCAR4 and GLI2 reduced their expression. In tumor xenograft assay, tumors in mice of BCAR4 group showed the biggest volume, while those in mice of si-GLI2 group showed the smallest volume. Ki67 showed much higher level in BCAR4 overexpression group but much lower level in si-GLI2 group. PMID- 29615153 TI - Letters. PMID- 29615151 TI - Introduction to the Special Issue. PMID- 29615154 TI - Structured Educational Intervention Leads to Better Infant Positioning in the NICU. AB - PURPOSE: The purpose is to test the effectiveness of an educational intervention in improving infant positioning because positioning may interfere with neuromotor development. METHODS: A quality improvement (QI) project was initiated to increase knowledge and improve the compliance of nurses and physicians in infant positioning using the Infant Positioning Assessment Tool (IPAT). The project was part of Neonatal Individualized Developmental Care Assessment Program (NIDCAP) training. It included informal discussion and practice about infant positions. MAIN OUTCOME VARIABLES: Staff knowledge, IPAT score. RESULTS: Fifty-two pediatric residents and 39 NICU nurses participated in this project. The mean knowledge assessment test score improved significantly for both nurses (p < .0001) and residents (p < .0001) postintervention; IPAT scores increased significantly from 3.4 (+/-2. 5) to 8.1 (+/-2.7) (p < .001). CONCLUSION: Nurses' education with hands-on practice improved infant positioning in the NICU; this may lead to fewer positional deformities and possibly an improved developmental outcome. PMID- 29615155 TI - The History and State of Neonatal Nursing Quality Improvement Practice and Education. AB - Quality improvement has evolved rapidly in neonatal nursing. This review outlines the history and current state of quality improvement practice and education in neonatal nursing. The future of neonatal nursing includes a stronger emphasis on quality improvement in advanced practice education that promotes doctoral projects that result in clinical improvements. A collective focus will ensure that neonatal nurses not only deliver evidence-based care, but also continually improve the care they deliver. PMID- 29615156 TI - Promoting Newborn Safety Using the RAPPT Assessment and Considering Apgar Criteria: A Quality Improvement Project. AB - PURPOSE: The aim of this project was to evaluate the implementation of the Respiratory, Activity, Perfusion, Position, and Tone (RAPPT) instrument in assessing the infant's transition to extrauterine life while in skin-to-skin contact (SSC). Sample/Design: Nurses (n = 17) completed a pretest and posttest of RAPPT and Apgar scoring knowledge, attended an in-service about accurate scoring, and were observed during 17 deliveries when newborns were in SSC. OUTCOME VARIABLES: Primary variables were knowledge scores, use of RAPPT, and accurate RAPPT scoring. Apgar scoring was also measured. RESULTS: Knowledge scores increased significantly after education, RAPPT scores were correctly assessed, and 1 of 17 newborns had a sudden unexpected postnatal collapse. Apgar scoring accuracy did not change and nurses reported that their Apgar scores were based on their overall impressions of the infant instead of Apgar criteria. PMID- 29615157 TI - Implementing a Systematic Process for Consistent Nursing Care in a NICU: A Quality Improvement Project. AB - AIM: The global aim of this quality improvement project was to develop and implement a systematic process to assign and maintain consistent bedside nurses for infants and families. METHODS: A systematic process based on a primary care nursing model was implemented to assign consistent care for a 48-bed, single family room NICU. RESULTS: Four PDSA cycles were necessary to obtain agreement from the nursing staff as to the best process for assigning primary nurses. Post intervention data revealed a 9.5 percent decrease of consistent caregivers for infants in the NICU <= 28 days and a 2.3 percent increase of consistent caregivers for infants in the NICU >= 29 days. CONCLUSION: Although these findings did not meet the goal of the specific aim, a systematic process was created to assign bedside nurses to infants. Further PDSAs will be needed to refine the process to reach the aim. PMID- 29615158 TI - Reduction in Central Line-Associated Bloodstream Infections in a NICU: Practical Lessons for Its Achievement and Sustainability. AB - Central venous catheters are commonly used for the provision of parenteral nutrition and medications for critically ill neonates in the NICU. However, central line-associated bloodstream infections (CLABSIs) are a major complication associated with their use and remain an important cause of nosocomial sepsis in NICUs. Central line-associated bloodstream infection has shifted from being an expected routine complication of central line use to an adverse event now evaluated as a critical event with the goal of identifying root causes so future CLABSI events are prevented. Success has been achieved through multiple strategies including implementation and maintenance of care bundles, education strategies to promote consistent adherence to bundle components, and institutional and unit support. Although low CLABSI rates can be achieved, sustaining low CLABSI rates and achieving zero CLABSI remain an ongoing challenge. We describe our experience with lessons learned, with an emphasis on the areas of difficulty during implementation of the bundle elements and the strategies and tools we utilized to overcome them. PMID- 29615159 TI - Antimicrobial Stewardship in Neonates: Challenges and Opportunities. AB - Neonatal infections result in significant morbidity and mortality. Antibiotics are vital for the treatment of infections but disrupt the neonatal microbiome, put the infant at risk for an adverse drug reaction, and may lead to the development of antibiotic resistance. Immediately after birth, clinicians must determine which infants require empiric antibiotics. Online risk stratification tools may provide a superior approach to decision trees. In infants who require empiric therapy for early-onset sepsis, ampicillin and an aminoglycoside with dosing based on recent pharmacokinetic studies represents the most appropriate first-line agents; third-generation cephalosporins should be reserved for patients with a high likelihood of Gram-negative meningitis. An antistaphylococcal penicillin and gentamicin should be utilized for suspected late-onset sepsis. Vancomycin and other broad-spectrum agents are reserved for patients with a history of resistant organisms. Antibiotic duration should be guided by understanding the clinical indications and obtaining the necessary cultures appropriately (i.e., adequate volume blood cultures). In the absence of a positive culture, antibiotic duration should often be limited. Individual institutions should leverage a multidisciplinary, interprofessional team to identify opportunities for antimicrobial stewardship. A collaborative, transparent system is required to change unit culture and generate a sustained impact on antibiotic utilization with optimal patient outcomes. PMID- 29615160 TI - Continuing Education Course. PMID- 29615161 TI - News of the Academy of Neonatal Nursing. PMID- 29615162 TI - Myocardial Perfusion Imaging: The Gatekeeper and Advisor. PMID- 29615163 TI - Diagnostic Accuracy of Pelvic MRI for Determination of the Cervical Involvement in Endometrial Cancer. AB - OBJECTIVE: To determine the diagnostic accuracy of pelvic MRI for assessment of the cervical involvement in endometrial cancer. STUDY DESIGN: Cross-sectional analytical study. PLACE AND DURATION OF STUDY: Radiology Department of the Aga Khan University Hospital, Karachi from January 2014 to December 2015. METHODOLOGY: Patients with biopsy-proven endometrial cancer were included, who had both their MRI and histopathological diagnosis performed at our institution. Those patients treated with chemo/radiotherapy or had incomplete medical records, were excluded. The extent of cervical involvement by endometrial carcinoma was seen on T2WI images, and findings were correlated after surgery taking histopathology as the gold standard. The sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy were calculated. RESULTS: The mean age of the 56 patients was 60.87 +/-8.80 years (range 37-84 years). The most common clinical indication was post-menopausal bleeding (n=37, 66.1%). The most common histological subtype was endometrioid adenocarcinoma (n=50, 89.3%). The sensitivity, specificity, diagnostic accuracy, positive and negative predictive values of MRI in the detection of cervical invasion were 92.85%, 88.09%, 89.28%, 72.22% and 97.36%, respectively. CONCLUSION: MRI is a highly sensitive and specific imaging modality for detection of cervical invasion in endometrial carcinoma. PMID- 29615164 TI - Profile of Asphyxial Deaths in Faisalabad: A 10-Year Study. AB - OBJECTIVE: To determine the frequency of violent asphyxial deaths in Faisalabad over a span of a decade; and assessing the age and gender vulnerability. STUDY DESIGN: Descriptive cross-sectional study. PLACE AND DURATION OF STUDY: Department of Forensic Medicine and Toxicology, Punjab Medical College, Faisalabad, from January 2007 to December 2016. METHODOLOGY: Cases identified as violent asphyxial deaths according to police inquests and findings of the medico legal examiners were computed. Age, gender, and cause of asphyxia recorded in predesigned proformas and analysed by SPSS version 12.0. RESULTS: Asphyxial deaths accounted for 7.66% (259 / 3,381) of the medico-legal deaths during the 10 year span. Majority (28.57%) victims belonged to the 20-29 year age group, followed by the 10-19 year age group (20.07%). Male victims (56%) outnumbered the females (44%) by ratio of 1.3:1. Ligature strangulation was the cause of asphyxia in majority of the victims (40.93%), followed by hanging (28.96%). CONCLUSION: Young population between 20-29 years were the predominant victims of violent asphyxial deaths. Homicide due to ligature strangulation was the commonest form of violent asphyxial deaths. PMID- 29615165 TI - Relationship between Student Performances in Non-Cognitive Skills in Multiple Mini Interview and Integrated Practical Examination. AB - OBJECTIVE: To investigate the relationship between the performances of students in non-cognitive skills in Multiple Mini Interview (MMI) and Integrated Practical Examination (IPE) of the first year of medical school. STUDY DESIGN: Cross sectional observation study with statistical support. PLACE AND DURATION OF STUDY: Shifa College of Medicine/Shifa Tameer-e-Millat University, Islamabad between December 2015 and March 2016. METHODOLOGY: Student performance in communication skills, domain of the 8-station Multiple Mini Interview, was compared with their scores in communication skills in the first Integrated Practical Examination taken at the end of first block. Descriptive statistics were calculated for student demographics, scores in communication skills in MMI as well as IPE. Pearson's Correlation was calculated to investigate the relationship between the two scores. A p-value of <0.05 was taken as significant. RESULTS: The mean score in MMI was 130.38 +/-9.90 as compared to a score of 79.96 +/-19.74 in the IPE. This relationship has a statistically significant (p<0.001) positive correlation, with a Pearson's correlation of 0.52. CONCLUSION: Student performance shows a positive correlation in non-cognitive skills between Multiple Mini Interview and Integrated Practical Examination. PMID- 29615166 TI - Phenotypic Identification, Frequency Distribution and Antibiogram of Carbapenemase Producing Enterobacteriaceae in Clinical Isolates. AB - OBJECTIVE: To differentiate between Ambler class A, B and D of carbapenemase producing Enterobacteriaceae by using simple phenotypic methods that can be carried out in the laboratory without requiring any specialised techniques. STUDY DESIGN: Cross-sectional study. PLACE AND DURATION OF STUDY: Microbiology Department, Army Medical College, NUST, Islamabad, from November 2015 to November 2016. METHODOLOGY: Clinical specimens were subjected to identification of Enterobacteriaceae by colony morphology and API 20 E. Carbapenem resistance was detected by applying meropenem disc (10 ug) by disc diffusion method according to CLSI (Clinical Laboratory Standard Institute) criteria. Carbapenemase production among Enterobacteriaceae was detected by Modified Hodge test. Phenotypic methods, Phenylboronic acid (for Class A KPC producing Enterobacteriaceae) and EDTA inhibition tests (for Class B MBL producing Entrobacteriaceae) were applied. Presence of OXA 48 was detected by phenotypic method using imipenem 10 ug, EDTA and PBA discs. Antibiotic susceptibility was determined by Kirby-Bauer disc diffusion method. RESULTS: Forty-three out of 45 (95.45%) were carbapenemase producers. Thirty-eight out of 43 (88.3%) were KPC producers and 4 out of 43 (11.62%) were MBL producers. All KPC producers were Klebsiella pneumoniae. Among five MBL producers, one each (20%) was Enterobacter cloacae and Escherichia coli and 3 (60%) were Klebsiella pneumoniae. All MBL producers were resistant to aztreonam and amoxicillin/clavulanate. Two of the KPC producing Klebsiella pneumoniae were pan-drug resistant (resistant to colistin and tigecycline). Two were non-carbapenemase producers. CONCLUSION: Enterobacteriaceae strains producing KPC-type carbapenemase were the most prevalent (88.3%) in the studied healthcare setup. PMID- 29615168 TI - Reasons for Removal of Non-Tunneled Double Lumen Catheters in Incident Dialysis Patients. AB - OBJECTIVE: To evaluate the reasons of removal of non-tunneled double lumen catheters (NTDLC) in incident hemodialysis (HD) patients in a tertiary renal care hospital. STUDY DESIGN: Observational retrospective study. PLACE AND DURATION OF STUDY: Department of Nephrology, The Kidney Centre Postgraduate Training Institute (TKC PGTI), Karachi, from June 2015 to May 2016. METHODOLOGY: All patients were selected who had naive NTDLC placement at TKC PGTI either in Emergency Room (ER) or Intensive Care Unit (ICU) during the study period. The reason for removal were observed. Data was analysed by SPSS 21 and mean, percentages and frequencies were calculated. Cross tabulation between variables was done to find significance. RESULTS: A total of 429 NTDLCs were inserted in the study period, out of which 296 catheters were inserted for incident HD. One hundred and twenty-seven (42.9%) catheters were removed prematurely due to malfunction, and 50 (17%) due to catheter-related blood stream infection (CRBSI). Methicillin resistant Staphylococcus aureus was the commonest organism responsible for CRBSI. One hundred and five (35.47%) catheters were removed because the permanent vascular access (PVA) became usable. CONCLUSION: Catheter malfunctions and infections frequently occurred in NTDLC used for HD, which culminated early removal of catheter. Early creation of PVA should be encouraged to reduce the complications in already immunocompromised patients. PMID- 29615167 TI - Pseudomonas aeruginosa: Evaluation of Pathogen Burden and Drug-Resistance Trends in a Tertiary Care Hospital. AB - OBJECTIVE: To evaluate the pathogen burden and antibiotic-resistance trends of Pseudomonas aeruginosa among hospitalised patients at a tertiary care hospital. STUDY DESIGN: Retrospective, hospital record-based, cross-sectional study. PLACE AND DURATION OF STUDY: Microbiology Laboratory, Allama Iqbal Medical College/Jinnah Hospital, Lahore, from January 2014 to December 2016. METHODOLOGY: A total of 5,960 samples were collected from clinically suspected cases of bacterial infections, admitted to the hospital. Microbial identification and antibiotic susceptibility pattern were carried out and analysed. RESULTS: Out of a total of 5,960 samples, Pseudomonas aeruginosa was isolated from 1,268 (21.2%) specimens. Department-wise isolation rate was n=600 (42.9%), n=268 (15.4%), n=201 (12.6%), and n=199 (16.0%) from intensive care unit (ICU), surgical units, medical units, and Gynae wards, respectively (p<0.0001). Sample-wise isolation rate was, wound swabs n=448 (35%), urine n=356 (28%), sputum n=187 (14 %), tracheal aspirate n=127 (10%), blood n=99 (7%), and broncho-alveolar lavage n=51 (4%) (p<0.0001). Drug-resistance pattern showed low rates for carbapenems(meropenem n=440 (35%), Imipenem n=436 (34%) and beta-lactam + beta lactamase inhibitor combination (piperacillin+tazobactam n=437 (34%) while alarming rates were observed for cephalosporins (ceftazidime n=716 (56%), fluoroquinolones (ciprofloxacin n=690 (54%), cefoperazone+sulbactam n=685 (54%), aminoglycosides (gentamicin, n=669 (53%), amikacin n=608 (48%), and monobactams (aztreonam n=666 (52%). Decreasing trend was observed only for amikacin 63% to 37%, aztreonam showed similar pattern throughout, while there was an increasing trend of drug resistance in all groups of antibiotics. CONCLUSION: Emerging drug resistant strains of Pseudomonas aeruginosa are probably linked to the injudicious use of antibiotics, leading to ineffective empirical therapy. Therefore, we suggest that culture and antimicrobial susceptibility testing should be done for targeted antimicrobial therapy against Pseudomonas aeruginosa. PMID- 29615169 TI - Serum Cystatin C as an Early Diagnostic Biomarker of Diabetic Kidney Disease in Type 2 Diabetic Patients. AB - OBJECTIVE: To determine the diagnostic accuracy and cut-off values of serum cystatin C as early diagnostic biomarker of diabetic kidney disease. STUDY DESIGN: Cross-sectional analytical study. PLACE AND DURATION OF STUDY: Department of Pathology, Army Medical College, Rawalpindi in collaboration with Endocrinology Department, Military Hospital (MH), Rawalpindi from November 2015 to November 2016. METHODOLOGY: One hundred and nineteen diagnosed patients of type 2 diabetes mellitus were enrolled in the study from the outpatient Endocrinology Department of the MH Rawalpindi. Fifty disease-free controls were also included. Fasting blood samples of the patients and controls were analysed for creatinine by Jaffe's kinetic method and estimated GFR was calculated using MDRD-based equation for GFR. Serum cystatin C was estimated by quantitative turbidimetric method. RESULTS: Serum cystatin C was higher in the diabetic group (mean = 1.022 +/-0.33 mg/dl) as compared to the control group (mean = 0.63 +/ 0.14 mg/dl). ROC curve analysis, keeping less than 60 ml/min/1.73 m2 GFR (CKD MDRD based) as reference value of the stat variable/gold standard; revealed an area under the curve of 0.914 (95% CI 0.85-0.98) and at optimal sensitivity of 88.2% and specificity of 84.8% the established cut-off of serum cystatin C was 1.26 mg/L. CONCLUSION: Cystatin C is an accurate biomarker of diabetic kidney disease with good sensitivity and specificity. PMID- 29615170 TI - Disease Characteristics and Treatment Outcome of Testicular Germ Cell Tumors Treated with Platinum-Based Regimens. AB - OBJECTIVE: To determine the disease characteristics of testicular germ cell tumor, biochemical/radiological response to chemotherapy and common toxicity profile. STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: Institute of Nuclear Medicine and Oncology (INMOL), Lahore, from January 2010 to December 2013. METHODOLOGY: Fifty-one patients with histologically proven testicular germ cell tumor, who fulfilled the pre-defined eligibility criteria, were selected. Presenting symptoms and disease stage were studied. Patients were staged according to the AJCC 2010 staging criteria and prognosis was classified according to the IGCCCG Classification of Metastatic Germ Cell Cancer. Initial chemotherapy treatment was based upon the International Germ Cell Consensus Classification, 1997. Patients were also evaluated for chemotherapy-induced toxicity based on Common Toxicology Criteria version 4. SPSS version 16.0 was used for statistical analysis. RESULTS: Main presenting symptoms included testicular pain (37.3%), testicular swelling (25.5%), and abdominopelvic pain (11.8%). Most of the patients had mixed germ cell histology (p <0.001) and presented with advanced disease stage. Out of 51 patients, 41 (80.3%) achieved complete clinical remission after first line chemotherapy. All patients having complete response achieved 2-year survival and 37 (90.2%) had no evidence of recurrent disease. Four patients with recurrent disease achieved complete remission with second line chemotherapy. Five (9.8%) had partial response after first line chemotherapy while 2 (3.9%) progressed on treatment. All patients developed alopecia, 21 (41.1%) experienced other toxicities which were managed symptomatically and with minor dose modifications. CONCLUSION: Many patients with germ cell tumors presented with pain, and in an advanced stage, with mixed histology. Overall response rate was 90.2% with platinum-based chemotherapy. PMID- 29615171 TI - Optical Coherence Tomography Macular Findings after Successful Scleral Buckling in Eyes with Compromised Visual Status. AB - OBJECTIVE: To determine the optical coherence tomography (OCT) macular findings after successful scleral buckling in eyes with compromised visual status. STUDY DESIGN: Descriptive cross-sectional study. PLACE AND DURATION OF STUDY: Department of Clinical Ophthalmology, Khyber Institute of Ophthalmic Medical Sciences, Postgraduate Medical Institute, Hayatabad Medical Complex, Peshawar, Pakistan, from February 2015 to November 2016. METHODOLOGY: Patients with postoperative best corrected visual acuity (BCVA) less than 6/6, successful scleral buckling, and flat macula clinically, aged 18-70 years, were included. OCT scan (OCT-Spectralis, Heidelberg Engineering, GmbH 69121) of central 30 degrees around fovea was performed three months postoperatively. Foveal detachment, epimacular membrane (EMM) and cystoid macular edema (CME), were studied on OCT after successful buckling surgery in eyes with compromised visual status. RESULTS: A total of 164 eyes of 164 patients (92 males 72 females) were assessed with OCT. Foveal detachment (FD) was present in 54 cases (32.9%), cystoid macular edema (CME) in 30 (18.3%), and epimacular membrane (EMM) in 11 cases (6.7%); while no abnormality was detected in 69 (42.1%) cases on OCT. CONCLUSION: OCT is very helpful in identifying the cause of limited visual recovery after successful retinal detachment (RD) surgery. PMID- 29615172 TI - Comparison of Mean Corneal Endothelial Cell Loss after Trabeculectomy with and without Mitomycin C. AB - OBJECTIVE: To compare mean endothelial cell loss in patients of primary open angle glaucoma undergoing trabeculectomy with and without mitomycin C. STUDY DESIGN: Randomised control study. PLACE AND DURATION OF STUDY: Institute of Ophthalmology, Mayo Hospital, Lahore, from May 2016 to April 2017. METHODOLOGY: Patients with primary open angle glaucoma, not controlled with medication, were selected from the outpatient department. Patients with secondary glaucomas and concomitant ocular disease were excluded. Selected patients were divided into two groups of 30 each. Group A patients underwent trabeculectomy with adjunctive mitomycin C while group B patients underwent trabeculectomy alone. Pre- and post trabeculectomy endothelial cell counts were recorded with the help of specular microsope and entered on proforma. RESULTS: Median cell loss was 283 (66.50) when trabeculectomy was done with the use of adjunctive mitomycin C in group A while median endothelial cell loss was 72.50 (19.25) when the trabeculectomy was done without the use of adjunctive mitomycin C in group B. CONCLUSION: Use of mitomycin C causes more endothelial cell loss during trabeculectomy as compared to when done without it. PMID- 29615173 TI - Outcome of Chronic Kidney Disease Patients on the Basis of Referral to Nephrologist: A One-Year Follow-up Study. AB - OBJECTIVE: To determine the outcome of chronic kidney disease (CKD) patients presenting for dialysis on the basis of referral to nephrologist. STUDY DESIGN: Observational study. PLACE AND DURATION OF STUDY: Nephrology Department of King Edward Medical University/Mayo Hospital, Lahore, from January 2014 to January 2016. METHODOLOGY: All patients who were presented in nephrology outpatients department and with the indication of dialysis were included in study. Patients who refused dialysis, and with acute kidney failure were excluded from the study. Proforma was designed for demographics, vital signs, volume status, and laboratory data (hemoglobin, urea, creatinine, albumin, bicarbonate etc.) of all the patients. On the basis of referral, patients were divided into two groups, i.e. early referral and late referral. Early referrals were those patients who were referred to a nephrologist more than three months before dialysis initiation. Late referrals were those patients who were referred to a nephrologist less than three months before dialysis initiation. Patients were followed up at one, three, six, and 12 months for outcome, i.e. still on dialysis or died. RESULTS: One hundred and seventy-six patients were enrolled in the study, and 141 were followed up to one year. Seventy- two (51.1%) patients were male, 69 (48.9%) were female and most (n=69, 48.9%) were in the middle age group. Major causes of end-stage renal disease (ESRD) were hypertension 70 (49.6%) and diabetes mellitus 66 (46.8%). Seventy-six (53.9%) patients were in fluid overload and acidotic (n=123, 87.2%). Twenty-seven (19.1%) patients were referred early and 114 (80.9%) were referred late. Overall mortality was 78 (55.3%) at one year. Factors affecting mortality were financial status and metabolic acidosis, but not referral. Temporary access for hemodialysis has 1.38 times more risk for mortality than the patients with permanent access. CONCLUSION: There is no difference on the outcome of dialysis patients on the basis referral to nephrologist. Factors affecting overall mortality in both groups were financial status, metabolic acidosis, and temporary access for dialysis. Most of the patients were referred late to the nephrologists. PMID- 29615174 TI - Amending Umbilical Porting in Laparoscopic Totally Extra-peritoneal Hernioplasty: A Simplified Way. AB - An unambiguous identification of anterior rectus sheath (ARS) is a crucial initial step required for precise umbilical porting in order to achieve successful execution of laparoscopic totally extra-peritoneal (TEP) hernioplasty. However, it is scarcely discussed in the present-day literature. Backed with the experience of 1100 cases, we present an easy and rapid technique of exposing the anterior rectus sheath with the aim to save operative time without compromising the safety. Such a method is yet to be described in the literature. PMID- 29615175 TI - Differences in Empathy Levels of Medical Students Based on Gender, Year of Medical School and Career Choice. AB - OBJECTIVE: To measure mean empathy scores of Pakistani medical students and to explore any association of empathy scores with gender, medical school year and future career choice. STUDY DESIGN: Cross-sectional survey. PLACE AND DURATION OF STUDY: Shifa College of Medicine, Shifa Tameer-e-Millat University, during the academic year 2015-2016. METHODOLOGY: The student version of Jefferson Scale of Physician Empathy (JSPE) was distributed to the students electronically via the student portal. Response that were completed in full were included in the study. Descriptive statistics was used to analyse student demographic data. The student score on the JSPE was reported as the mean (out of 7) of each item. Independent samples t-test was employed to check the significant differences between genders. Empathy score with advancing year of study was investigated using ANOVA. ANOVA with post-hoc Tukey's test was used to study the relationship between career choice and empathy score. RESULTS: The response rate was 70.94%. The mean score was 4.51 +/-0.69. Females obtained greater, but statistically insignificant (p=0.08) empathy score (4.58) as compared to the male students (4.45). No statistically significant difference was seen between scores on the survey across the five academic years (F=0.88, p=0.47). Students who selected medicine and allied as career choice showed a significantly higher empathy score than those who opted for surgery. The internal consistency reliability (Cronbach's alpha) was 0.78. CONCLUSION: There were low levels of empathy in Pakistani medical students. Students with interest in medicine and allied showed higher empathy scores compared to surgical or technical specialties. No association of empathy scores with gender and medical school year was observed. PMID- 29615176 TI - 30-Day Readmission Rate and its Causes in General Surgical Patients. AB - OBJECTIVE: To find out the 30-day readmission rate for different surgical procedures and determine the causes for readmissions. STUDY DESIGN: An audit report. PLACE AND DURATION OF STUDY: Department of Surgery, The Aga Khan University Hospital, Karachi, in the calendar year 2014. METHODOLOGY: Records were retrospectively reviewed for 30-day readmission rate and their cause in general surgical patients who underwent a general surgical procedure at The Aga Khan University Hospital, Karachi, in the year 2014. RESULTS: Out of 217 (6.4%) readmissions in 3,387 patients, more than 50% unplanned readmissions were avoidable. The highest readmission rate was after placement of feeding tubes (28.5%). CONCLUSION: More than half of the readmissions could have been prevented by proper patient/attendant education, good communication and provision of nursing services to these patients beyond the hospital. PMID- 29615177 TI - Left-Sided Appendicitis in a 14-Year Girl with Midgut Malrotation. AB - We present a case of 14-year girl with left-sided acute appendicitis who presented with lower abdominal pain. Midgut malrotation occurs at a rate of 1 in 500 live births. The condition is incidentally diagnosed during various radiological investigations done for other purposes. However, such patients may present with conditions like acute appendicitis, which poses a diagnostic dilemma if a high index of suspicion is not kept. The purpose of this case report is to increase awareness in the emergency physicians and young surgeons of this rare presentation; and the importance of radiological investigations in the diagnosis of left-sided appendicitis, to decrease morbidity and mortality. PMID- 29615178 TI - Unusual Presentation of Fibrosarcoma in a Child. AB - Malignant soft tissue tumours are rare in infants. Specific radiologic features help differentiate benign from malignant musculoskeletal entities. We report a case of malignant soft tissue tumour with initial radiologic evaluation suggesting a benign entity, thus delaying diagnosis. The case was treated as a case of cystic hygroma, suggested by ultrasound and MRI with good initial response to bleomycin injection. Later, symptoms recurred with poor response to repeat therapy which led to review the diagnosis. Angiography, arterial embolisation, surgical excision, and finally histopathology showed that a cystic infantile fibrosarcoma was initially misinterpreted as cystic hygroma. A comprehensive literature review and discussion on infantile fibrosarcoma; and its mimics are provided. PMID- 29615179 TI - Pulmonary Nodular Amyloidosis Mimicking Metastatic Lung Lesion in a Patient with Colon Cancer. AB - Amyloidosis is defined as abnormal aggregation of amyloid proteins. Amyloidosis can be localised or systemic affecting the lung, heart, spleen, liver and kidneys. The most common form of pulmonary amyloidosis is the nodular type. The disease is idiopathic and linked to many systemic diseases. The clinical manifestations and prognosis of respiratory tract amyloidosis depends on its etiology and anatomical location. Radiologically, the nodular pulmonary amyloidosis may appear as single or multiple nodules in any lobe, and, therefore, may mimic as primary pulmonary or metastatic neoplasms. Here, we report a case of 70-year female who was diagnosed with colon cancer, which was treated by surgery. During metastatic follow-up, her CT chest showed right lung nodule highly suspicious for metastatic lesion from the colon. Thoracoscopic wedge resection of the lung nodule done after micro-coil localisation technique under CT guidance. The histopathology report showed pulmonary nodular amyloidosis. This case indicates that histological examination is necessary to differentiate a benign pulmonary nodule from a metastatic lung nodule, especially in a patient with underlying malignancy. PMID- 29615180 TI - A Case of Vogt-Koyanagi-Harada Syndrome Mimicking Optic Neuritis. AB - Vogt-Koyanagi-Harada syndrome is a rare disease that occurs commonly in pigmented individuals of Asian origin. A 25-year female presented in medical outpatient department (OPD) of Al-Khidmat Teaching Hospital, Mansoora, Lahore with headache and neck stiffness. She was referred to eye OPD for the complaint of decreased vision. On examination, there was 6/24 vision, sluggish pupillary reaction and disc hyperemia in both eyes. She was treated as a case of optic neuritis. Few days later, she developed bilateral panuveitis, shallow exudative detachments and alopecia. Clinical picture with normal magnetic resonance imaging (MRI) and laboratory tests helped us in reaching the diagnosis of Vogt-Koyanagi-Harada syndrome. PMID- 29615181 TI - Comparison of Geometric Design of a Brand of Stainless Steel K-Files: An In Vitro Study. AB - The purpose of this experimental study was to determine the diametric variations of a brand of handheld stainless-steel K-files, acquired from different countries, in accordance with the available standards. 20 Mani stainless-steel K files of identical size (ISO#25) were acquired from Pakistan and were designated as Group A while 20 Mani K-files were purchased from London, UK and designated as Group B. Files were assessed using profile projector Nikon B 24V. Data was statistically compared with ISO 3630:1 and ADA 101 by one sample T test. Significant difference was found between Groups A and B. Average discrepancy of Group A fell within the tolerance limit while that of Group B exceeded the limit. Findings in this study call attention towards adherence to the dimensional standards of stainless-steel endodontic files. PMID- 29615182 TI - A Rare Pathology of Difficult Laparoscopic Cholecystectomy: Xanthogranulomatous Cholecystitis. AB - Xanthogranulomatous cholecystitis (XGC) is a rare inflammatory condition of the gallbladder (GB). Preoperatively, it is a diagnostic challenge. One thousand and seventy nine laparoscopic cholecystectomy (LC) patients from September 2012 to June 2015 were retrospectively reviewed. Fourteen patients were identified with XGC. An analysis was carried out on this group of patients looking at postoperative pathology results, preoperative radiology, operative findings and outcome. The overall frequency of XGC was 1.3%. A thick walled GB was found in 11 patients on preoperative imaging. Retrospectively suggestive feature thick gallbladder walls with low attenuation mural nodules. No suspicion of cancer was demonstrated in the final histology or preoperatively. Five cases (36%) perforated intraoperatively. Although all were surgically challenging, no conversions to open were performed. The perforation risk could be higher. A difficult cholecystectomy should alert a surgeon to consider XGC as a diagnosis. Contrary to the popular belief, XGC was found to be difficult to differentiate from infection rather than malignancy. PMID- 29615183 TI - Basal Cell Ameloblastoma of Mandible: A Case with Proposed Diagnostic Criteria. PMID- 29615184 TI - A Case of Sitagliptin-Induced Mild Acute Pancreatitis. PMID- 29615185 TI - Predatory Journals: When Publications Fall Prey. PMID- 29615187 TI - Disparities in oral health by immigration status in the United States. AB - BACKGROUND: Few investigators have explored differences in oral health status between immigrants and natives. To address this gap, the authors used nationally representative data to characterize disparities in oral health among noncitizens, naturalized citizens, and native adults. METHODS: The 2013 to 2014 National Health and Nutrition Examination Survey, a nationally representative in-person survey, provides oral health data for US natives, naturalized citizens, and noncitizens. Univariate and multivariate regression analyses were conducted to compare evidence of caries and periodontal disease, as well as recommendations for oral health care, stratified by immigration status for adults. RESULTS: More than one-half of noncitizens (50.5%) received a diagnosis of periodontal disease, and 38.0% had caries; for natives, these rates were 34.4% and 27.0%, respectively. Differences between natives and naturalized citizens were not statistically significant. After adjusting for age, sex, race or ethnicity, education, poverty, tobacco smoking status, and number of permanent teeth, noncitizens still had 45% higher adjusted odds of periodontal disease and 60% higher odds of receiving recommendations for oral health care than natives. However, differences between noncitizens and natives were no longer important after adjusting for insurance. CONCLUSIONS: Noncitizen immigrants reported having substantially poorer oral health than natives in the United States. However, disparities between noncitizens and natives are no longer important when accounting for health insurance. PRACTICAL IMPLICATIONS: Although noncitizen adults have a higher likelihood of poor oral health than native adults, having insurance may close this gap. Health care reform initiatives should provide dental benefits for adults to help mitigate the current economic and legal barriers that many immigrants face when accessing oral health care. PMID- 29615186 TI - What externally presented information do VRUs require when interacting with fully Automated Road Transport Systems in shared space? AB - As the desire for deploying automated ("driverless") vehicles increases, there is a need to understand how they might communicate with other road users in a mixed traffic, urban, setting. In the absence of an active and responsible human controller in the driving seat, who might currently communicate with other road users in uncertain/conflicting situations, in the future, understanding a driverless car's behaviour and intentions will need to be relayed via easily comprehensible, intuitive and universally intelligible means, perhaps presented externally via new vehicle interfaces. This paper reports on the results of a questionnaire-based study, delivered to 664 participants, recruited during live demonstrations of an Automated Road Transport Systems (ARTS; SAE Level 4), in three European cities. The questionnaire sought the views of pedestrians and cyclists, focussing on whether respondents felt safe interacting with ARTS in shared space, and also what externally presented travel behaviour information from the ARTS was important to them. Results showed that most pedestrians felt safer when the ARTS were travelling in designated lanes, rather than in shared space, and the majority believed they had priority over the ARTS, in the absence of such infrastructure. Regardless of lane demarcations, all respondents highlighted the importance of receiving some communication information about the behaviour of the ARTS, with acknowledgement of their detection by the vehicle being the most important message. There were no clear patterns across the respondents, regarding preference of modality for these external messages, with cultural and infrastructural differences thought to govern responses. Generally, however, conventional signals (lights and beeps) were preferred to text-based messages and spoken words. The results suggest that until these driverless vehicles are able to provide universally comprehensible externally presented information or messages during interaction with other road users, they are likely to contribute to confusing and conflicting interactions between these actors, especially in a shared space setting, which may, therefore, reduce efficient traffic flow. PMID- 29615188 TI - Trends in annual dental visits among US dentate adults with and without self reported diabetes and prediabetes, 2004-2014. AB - BACKGROUND: The authors assessed the trends of annual dental visits in dentate adults with diabetes or prediabetes or no diabetes, and assessed whether the racial and ethnic disparities in dental visits changed from 2004 through 2014. METHODS: Data for this analysis came from the Behavioral Risk Factor Surveillance System, a US health survey that looks at behavioral risk factors that was developed by the Centers for Disease Control and Prevention in cooperation with state health departments. Respondents indicated whether they had a dental visit in the past 12 months. Weighted proportions were calculated for annual dental visits in adults by diabetes status, and trends were assessed by racial and ethnic groups. RESULTS: From 2004 through 2014, the proportion of annual dental visits declined from 66.1% to 61.4% (trend P = .02) in the diabetes group, 71.9% to 66.5% (trend P = .01) in the no diabetes group, and 66.0% to 64.9% (trend P = .33) in the prediabetes group. Age, income, and health insurance were moderators of the association between diabetes status and dental visits. Overall, the racial and ethnic disparity in dental visits did not change significantly during the period. CONCLUSIONS: Dental visits and services were less frequent in people with diabetes and prediabetes. Racial and ethnic disparities in use of dental services persisted during the observed period. PRACTICAL IMPLICATIONS: All patients, especially those with diabetes, are encouraged to visit a dentist at least annually. It is important for health care providers, such as primary care physicians and dental care and public health professionals, to make concerted efforts to promote oral health care in diabetes management. Improving access to dental services is vital to achieving this goal. PMID- 29615191 TI - Discussion of "Modified Appleby procedure for locally advanced pancreatic cancer". PMID- 29615189 TI - Translational Assessments of Reward and Anhedonia: A Tribute to Athina Markou. AB - Loss of pleasure (clinically referred to as anhedonia), impairments in other reward-related processes such as reward learning, motivation, and reward valuation, and blunted affect characterize several mood and other psychiatric disorders. Despite the availability of many therapeutic options for these disorders, reward-related impairments remain challenging to treat and often persist despite alleviation of other symptoms. Lack of animal models of reward related impairments and affect that have high construct and predictive validity is a key obstacle to developing novel treatments. This review highlights 1) guidelines to consider when developing translatable animal models; and 2) recent efforts to develop new reward-related assessments in humans and nonhuman animals that have been translated or back-translated from one species to another. The procedures described in this review are used to assess aspects of reward learning, motivated behavior, reward valuation, and affect. In several cases, researchers have attempted to implement task parameters that are as identical as possible to the parallel parameters used in existing cross-species tasks, with the goal of improving the translation of preclinical drug discovery findings to the clinic. In this regard, Dr. Athina Markou, who worked tirelessly throughout her career to understand and treat reward-related impairments across several psychiatric disorders, had great influence on conceptualizing the development and use of translational animal models of reward-related processes. PMID- 29615192 TI - Acute kidney injury predicts mortality in emergency general surgery patients. AB - BACKGROUND: Patients undergoing Emergency General Surgery (EGS) have increased risk of complications and death. The risk of AKI in patients undergoing EGS, along with associated outcomes, is unknown. METHODS: This two-institution observational study included adults admitted to intensive care units between 1997 and 2012. EGS was defined by 7 procedures occurring within 48 hours of ICU admission. The main outcome studied was AKI within 5 days, along with 90-day mortality. RESULTS: In our cohort of 59,604 patients, 1758 (2.9%) underwent EGS. Risk of AKI in EGD patients was significantly increased relative to non-EGS patients, with adjusted odds of 1.7 (95%CI 1.40-1.94; P < 0.001). Risk of renal replacement for EGS patients was also increased, with odds of 1.8 (95%CI 1.37 2.46; P < 0.001). EGS patients were at significantly higher risk of 90-day mortality, with adjusted odds of 3.1 (95%CI 2.16-4.33,p < 0.001) for AKI and 4.5 (95%CI 2.58-7.96,p < 0.001) for AKI requiring renal replacement, relative to the absence of AKI. CONCLUSIONS: EGS is a robust risk factor for AKI in critically ill patients, the development of which is strongly predictive of increased 90-day mortality. PMID- 29615190 TI - Ventral CA3 Activation Mediates Prophylactic Ketamine Efficacy Against Stress Induced Depressive-like Behavior. AB - BACKGROUND: We previously reported that a single injection of ketamine prior to stress protects against the onset of depressive-like behavior and attenuates learned fear. However, the molecular pathways and brain circuits underlying ketamine-induced stress resilience are still largely unknown. METHODS: Here, we tested whether prophylactic ketamine administration altered neural activity in the prefrontal cortex and/or hippocampus. Mice were injected with saline or ketamine (30 mg/kg) 1 week before social defeat. Following behavioral tests assessing depressive-like behavior, mice were sacrificed and brains were processed to quantify DeltaFosB expression. In a second set of experiments, mice were stereotaxically injected with viral vectors into ventral CA3 (vCA3) in order to silence or overexpress DeltaFosB prior to prophylactic ketamine administration. In a third set of experiments, ArcCreERT2 mice, a line that allows for the indelible labeling of neural ensembles activated by a single experience, were used to quantify memory traces representing a contextual fear conditioning experience following prophylactic ketamine administration. RESULTS: Prophylactic ketamine administration increased DeltaFosB expression in the ventral dentate gyrus and vCA3 of social defeat mice but not of control mice. Transcriptional silencing of DeltaFosB activity in vCA3 inhibited prophylactic ketamine efficacy, while overexpression of DeltaFosB mimicked and occluded ketamine's prophylactic effects. In ArcCreERT2 mice, ketamine administration altered memory traces representing the contextual fear conditioning experience in vCA3 but not in the ventral dentate gyrus. CONCLUSIONS: Our data indicate that prophylactic ketamine may be protective against a stressor by altering neural activity, specifically the neural ensembles representing an individual stressor in vCA3. PMID- 29615193 TI - Does the implementation of a pediatric appendicitis pathway promoting ultrasound work outside of a children's hospital? AB - BACKGROUND: Efficacy of care pathways for pediatric appendicitis is well established in children's hospitals, but not in community Emergency Departments (EDs). METHODS: A diagnostic pathway combining the Pediatric Appendicitis Score (PAS) with selective ultrasound was implemented. The charts of 2201 pediatric patients seen at four general EDs before and after implementation were retrospectively reviewed, identifying 611 children seriously considered for appendicitis. RESULTS: There were no cases of missed appendicitis within the pathway cohort (0/72). Low-PAS children on pathway had fewer computed tomography (CT) scans (0% vs. 21%; p < 0.02). Moderate-PAS patients also had a reduced CT first rate (2.4% vs. 23%; p < 0.01). However, pathway adoption in 2016 was only 24%. Correct pathway application would have avoided 58 ultrasounds and 17 CTs over three months (annual savings $281,276). CONCLUSION: A pediatric appendicitis pathway is safe, rules out low suspicion patients without imaging, and is cost effective in a general hospital setting. PMID- 29615194 TI - Discussion of "Tele-mentored emergency trauma surgery: A feasibility study using live-tissue models". PMID- 29615195 TI - Discussion of "Routine shave margins are not necessary in early stage breast cancer treated with breast conserving surgery". PMID- 29615196 TI - Editorial Decisions in Dermatology Journals: Is the Impact Factor a Double-Edged Sword? PMID- 29615197 TI - Reply to "Acquired Port-Wine Sain: Not a Simple Stain". PMID- 29615198 TI - Necrobiotic Xanthogranuloma: A Cutaneous Manifestation of Monoclonal Gammopathy. PMID- 29615199 TI - Can vagus nerve stimulation improve social cognition in autism? PMID- 29615200 TI - The natural environment and emergence of antibiotic resistance. PMID- 29615201 TI - Use of physiological evidence for heatwave public policy. PMID- 29615202 TI - Cognition, heuristics, and biases behind environment-related behaviours. PMID- 29615203 TI - Ambient carbon monoxide and cardiovascular mortality: a nationwide time-series analysis in 272 cities in China. AB - BACKGROUND: Evidence of the acute health effects of ambient carbon monoxide air pollution in developing countries is scarce and mixed. We aimed to evaluate short term associations between carbon monoxide and daily cardiovascular disease mortality in China. METHODS: We did a nationwide time-series analysis in 272 major cities in China from January, 2013, to December, 2015. We extracted daily cardiovascular disease mortality data from China's Disease Surveillance Points system. Data on daily carbon monoxide concentrations for each city were obtained from the National Urban Air Quality Real-time Publishing Platform. City-specific associations between carbon monoxide concentrations and daily mortality from cardiovascular disease, coronary heart disease, and stroke were estimated with over-dispersed generalised linear models. Bayesian hierarchical models were used to obtain national and regional average associations. Exposure-response association curves and potential effect modifiers were evaluated. Two-pollutant models were fit to evaluate the robustness of the effects of carbon monoxide on cardiovascular mortality. FINDINGS: The average annual mean carbon monoxide concentration in these cities from 2013 to 2015 was 1.20 mg/m3, ranging from 0.43 mg/m3 to 2.45 mg/m3. For a 1 mg/m3 increase in average carbon monoxide concentrations on the present day and previous day (lag 0-1), we observed significant increments in mortality of 1.12% (95% posterior interval [PI] 0.42 1.83) from cardiovascular disease, 1.75% (0.85-2.66) from coronary heart disease, and 0.88% (0.07-1.69) from stroke. These associations did not vary substantially by city, region, and demographic characteristics (age, sex, and level of education), and the associations for cardiovascular disease and coronary heart disease were robust to the adjustment of criteria co-pollutants. We did not find a threshold below which carbon monoxide exposure had no effect on cardiovascular disease mortality. INTERPRETATION: This analysis is, to our knowledge, the largest study done in a developing country, and provides robust evidence of the association between short-term exposure to ambient carbon monoxide and increased cardiovascular disease mortality, especially coronary heart disease mortality. FUNDING: Public Welfare Research Program. PMID- 29615204 TI - Effect of air quality alerts on human health: a regression discontinuity analysis in Toronto, Canada. AB - BACKGROUND: Ambient air pollution is a major health risk globally. To reduce adverse health effects on days when air pollution is high, government agencies worldwide have implemented air quality alert programmes. Despite their widespread use, little is known about whether these programmes produce any observable public health benefits. We assessed the effectiveness of such programmes using a quasi experimental approach. METHODS: We assembled a population-based cohort comprising all individuals who resided in the city of Toronto (Ontario, Canada) from 2003 to 2012 (about 2.6 million people). We ascertained seven health outcomes known to be affected by short-term elevation of air pollution, using provincial health administrative databases. These health outcomes were cardiovascular-related mortality, respiratory-related mortality, and hospital admissions or emergency department visits for acute myocardial infarction, heart failure, stroke, asthma, and chronic obstructive pulmonary disease (COPD). We applied a regression discontinuity design to assess the effectiveness of an intervention (ie, the air quality alert programme). To quantify the effect of the air quality alert programme, we estimated for each outcome both the absolute rate difference and the rate ratio attributable to programme eligibility (by intention-to-treat analysis) and the alerts themselves (by two-stage regression approach), respectively. FINDINGS: Between Jan 1, 2003, and Dec 31, 2012, on average between three and 27 daily cardiovascular or respiratory events were reported in Toronto (depending on the outcome). Alert announcements reduced asthma-related emergency department visits by 4.73 cases per 1 000 000 people per day (95% CI 0.55-9.38), or in relative terms by 25% (95% CI 1-47). Programme eligibility also led to 2.05 (95% CI 0.07-4.00) fewer daily emergency-department visits for asthma. We did not detect a significant reduction in any other health outcome as a result of alert announcements or programme eligibility. However, a non-significant trend was noted towards decreased asthma-related and COPD-related admissions. INTERPRETATION: In this population-based cohort, the air quality alert programme was related to some reductions in respiratory morbidity, but not any other health outcome examined. This finding suggests that issuing air quality alerts alone has a limited effect on public health and that implementing enforced public actions to reduce air pollution on high pollution days could be warranted. Together with accumulating evidence of substantial burden from long-term air pollution exposure, this study underscores the need for further strengthening of global efforts that can lead to long-term improvement of overall air quality. FUNDING: Public Health Ontario, Canadian Institutes for Health Research. PMID- 29615205 TI - Scientific opportunities for food and nutrition security. PMID- 29615206 TI - The carbon footprint of Australian health care. AB - BACKGROUND: Carbon footprints stemming from health care have been found to be variable, from 3% of the total national CO2 equivalent (CO2e) emissions in England to 10% of the national CO2e emissions in the USA. We aimed to measure the carbon footprint of Australia's health-care system. METHODS: We did an observational economic input-output lifecycle assessment of Australia's health care system. All expenditure data were obtained from the 15 sectors of the Australian Institute of Health and Welfare for the financial year 2014-15. The Australian Industrial Ecology Virtual Laboratory (IELab) data were used to obtain CO2e emissions per AUS$ spent on health care. FINDINGS: In 2014-15 Australia spent $161.6 billion on health care that led to CO2e emissions of about 35 772 (68% CI 25 398-46 146) kilotonnes. Australia's total CO2e emissions in 2014-15 were 494 930 kilotonnes, thus health care represented 35 772 (7%) of 494 930 kilotonnes total CO2e emissions in Australia. The five most important sectors within health care in decreasing order of total CO2e emissions were: public hospitals (12 295 [34%] of 35 772 kilotonnes CO2e), private hospitals (3635 kilotonnes [10%]), other medications (3347 kilotonnes [9%]), benefit-paid drugs (3257 kilotonnes [9%]), and capital expenditure for buildings (2776 kilotonnes [8%]). INTERPRETATION: The carbon footprint attributed to health care was 7% of Australia's total; with hospitals and pharmaceuticals the major contributors. We quantified Australian carbon footprint attributed to health care and identified health-care sectors that could be ameliorated. Our results suggest the need for carbon-efficient procedures, including greater public health measures, to lower the impact of health-care services on the environment. FUNDING: None. PMID- 29615207 TI - Research on climate change, health inequities, and migration in the Caribbean. PMID- 29615208 TI - Do air quality alerts benefit public health? New evidence from Canada. PMID- 29615210 TI - Can the Paris Agreement save us from a climate catastrophe? PMID- 29615209 TI - Carbon emissions and public health: an inverse association? PMID- 29615211 TI - Planetary Health Watch: integrated monitoring in the Anthropocene epoch. PMID- 29615212 TI - Missing in climate action: concrete health activities in nationally determined contributions. PMID- 29615213 TI - We must look further upstream to enable planetary health-literate urban development. PMID- 29615214 TI - The Paris Agreement could saves lives in China. PMID- 29615215 TI - Biological embedding, the air we breathe, and carcinogenesis. PMID- 29615216 TI - The Lancet Countdown on PM2.5 pollution-related health impacts of China's projected carbon dioxide mitigation in the electric power generation sector under the Paris Agreement: a modelling study. AB - BACKGROUND: Except for comparing the implementation costs of the Paris Agreement with potential health benefits at the national levels, previous studies have not explored the health impacts of the nationally determined contributions (NDCs) by countries and in regional details. In this Lancet Countdown study, we aimed to estimate and monetise the health benefits of China's NDCs in the electric power generation sector, and then compare them with the implementation costs, both at the national and regional levels. METHODS: In this modelling study, we linked the Multi-regional model for Energy Supply system and their Environmental ImpaCts, the Multi-resolution Emission Inventory for China model, the offline-coupled Weather Research and Forecasting model, the Community Multiscale Air Quality model, and the Integrated Health Impact Assessment model with a time scope from 2010 to 2050. We calculated the PM2.5 concentrations and compared the health impacts and implementation costs between two scenarios that reflect CO2 and air pollutant emissions-the reference (REF) scenario (no climate policy) and the NDC scenario (100% realisation of NDC targets: CO2 emission intensity needs to be about 40% below 2010 emissions by 2030 [roughly 35% below 2030 emissions in REF], and about 90% below 2010 emissions by 2050 [roughly 96% below 2050 emissions in REF]). FINDINGS: Under a comparatively optimistic health benefits valuation condition, at the national level, 18-62% of implementation costs could be covered by the health benefits in 2030. In 2050, the overall health benefits would substantially increase to 3-9 times of the implementation costs. However, northwest China would require the highest implementation costs and will also have more premature deaths because of a more carbon-intensive energy structure than business as usual. By 2030, people in northwest China (especially in Gansu, Shaanxi, and Xinjiang provinces) would need to bear worse air quality, and 10 083 (95% CI 3419-16 138) more premature deaths annually. This undesirable situation would diminish by about 2050. A solution that assumes no growth in air pollutant emissions in 2030 at the regional level is technically feasible, but would not be cost-effective. INTERPRETATION: Our results suggest that cost-benefit analysis of climate policy that omits regional air pollution could greatly underestimate benefits. A compensation mechanism for inter-regional interests (including financial, technological, and knowledge support) should be established for regions that give up their human health benefits for the sake of the whole nation to realise the climate change targets. FUNDING: National Natural Science Foundation of China and Cyrus Tang Foundation. PMID- 29615217 TI - Residential greenness and prevalence of major depressive disorders: a cross sectional, observational, associational study of 94 879 adult UK Biobank participants. AB - BACKGROUND: Increased urbanisation and the associated reduced contact of individuals with natural environments have led to a rise in mental disorders, including depression. Residential greenness, a fundamental component of urban design, has been shown to reduce the public health burden of mental disorders. The present study investigates the association between residential green exposure and prevalence of major depressive disorders using a large and diverse cross sectional dataset from the UK Biobank. METHODS: In this cross-sectional, observational, associational study, we used baseline data from the UK Biobank cohort of participants aged 37-73 years from across the UK. Environmental exposure data were derived from a modelled and linked built environment database. Residential greenness was assessed with a 0.5 m resolution Normalised Difference Vegetation Index, which is derived from spectral reflectance measurements in remotely sensed colour infrared data and measured within geocoded dwelling catchments. Other environment metrics included street-level movement density, terrain, and fine particulate exposures. A series of logistic models examined associations between residential greenness and odds of major depressive disorder after adjusting for activity-influencing environments and individual covariates. FINDINGS: Of 122 993 participants with data on major depressive disorder, the study analytical sample comprised 94 879 (77.1%) participants recruited across ten UK Biobank assessment centres between April 29, 2009, and Oct 1, 2010. A protective effect of greenness on depression was consistently observed, with 4.0% lower odds of major depressive disorder per interquartile increment in Normalised Difference Vegetation Index greenness (odds ratio 0.960, 95% CI 0.93-0.99; p=0.0044). Interaction analyses indicated that the beneficial effects of greenness were more pronounced among women, participants younger than 60 years, and participants residing in areas with low neighbourhood socioeconomic status or high urbanicity. INTERPRETATION: The results point to the benefits of well designed green environments on mental health. Further longitudinal studies are needed to decipher causal pathways. In the UK, policies aimed at optimising allocation and design of green spaces might help preserve psychological ecosystem services, thereby, improving the mental wellbeing of populations and enhancing the mental capital of cities. FUNDING: University of Hong Kong, UK Biobank, and the UK Economic & Social Research Council. PMID- 29615218 TI - Placental promoter methylation of DNA repair genes and prenatal exposure to particulate air pollution: an ENVIRONAGE cohort study. AB - BACKGROUND: Exposure to particulate air pollution has been linked with risk of carcinogenesis. Damage to repair pathways might have long-term adverse health effects. We aimed to investigate the association of prenatal exposure to air pollution with placental mutation rate and the DNA methylation of key placental DNA repair genes. METHODS: This cohort study used data from the ongoing ENVironmental Influence ON early AGEing (ENVIRONAGE) birth cohort, which enrols pairs of mothers and neonates (singleton births only) at the East-Limburg Hospital (Genk, Belgium). Placental DNA samples were collected after birth. We used bisulfite-PCR-pyrosequencing to investigate the mutation rate of Alu (a marker for overall DNA mutation) and DNA methylation in the promoter genes of key DNA repair and tumour suppressor genes (APEX1, OGG1, PARP1, ERCC1, ERCC4, p53, and DAPK1). We used a high-resolution air pollution model to estimate exposure to particulate matter with a diameter less than 2.5 MUm (PM2.5), black carbon, and NO2 over the entire pregnancy on the basis of maternal address. Alu mutation was analysed with a linear regression model, and methylation values of the selected genes were analysed in mixed-effects models. Effect estimates are presented as the relative percentage change in methylation for an ambient air pollution increment of one IQR (ie, the difference between the first and third quartiles of exposure in the entire cohort). FINDINGS: 500 biobanked placental DNA samples were randomly selected from 814 pairs of mothers and neonates who were recruited to the cohort between Feb 1, 2010, and Dec 31, 2014, of which 463 samples met the pyrosequencing quality control criteria. IQR exposure increments were 3.84 MUg/m3 for PM2.5, 0.36 MUg/m3 for black carbon, and 5.34 MUg/m3 for NO2. Among these samples, increased Alu mutation rate was associated with greater exposure to PM2.5 (r=0.26, p<0.0001) and black carbon (r=0.33, p<0.0001), but not NO2. Promoter methylation was positively associated with PM2.5 in APEX1 (7.34%, 95% CI 0.52 to 14.16, p=0.009), OGG1 (13.06, 3.88 to 22.24, p=0.005), ERCC4 (16.31%, 5.43 to 27.18, p=0.01), and p53 (10.60%, 4.46 to 16.74, p=0.01), whereas promoter methylation of DAPK1 (-12.92%, -22.35 to -3.49, p=0.007) was inversely associated with PM2.5 exposure. Black carbon exposure was associated with elevated promoter methylation in APEX1 (9.16%, 4.06 to 14.25, p=0.01) and ERCC4 (27.56%, 17.58 to 37.55, p<0.0001). Promoter methylation was not associated with pollutant exposure in PARP1 and ERCC1, and NO2 exposure was not associated with methylation in any of the genes studied. INTERPRETATION: Transplacental in-utero exposure to particulate matter is associated with an increased overall placental mutation rate (as measured with Alu), which occurred in concert with epigenetic alterations in key DNA repair and tumour suppressor genes. Our results suggest that exposure to air pollution can induce changes to fetal and neonatal DNA repair capacity. Future studies will be essential to elucidate whether these changes persist and have a role in carcinogenic insults later in life. FUNDING: European Research Council and the Flemish Scientific Fund. PMID- 29615219 TI - Framing planetary health: arguing for resource-centred science. PMID- 29615220 TI - Mitigating tropical cyclone risks and health consequences: urgencies and innovations. PMID- 29615221 TI - PM2.5: an important cause for chronic obstructive pulmonary disease? PMID- 29615222 TI - The health and economic benefits of climate mitigation and pollution control. PMID- 29615223 TI - Natural environments and suicide. PMID- 29615224 TI - Love and allergies in the city beautiful-Chandigarh, India. PMID- 29615225 TI - Love and allergies in the city beautiful-Chandigarh, India - Authors' reply. PMID- 29615226 TI - Effect of long-term exposure to fine particulate matter on lung function decline and risk of chronic obstructive pulmonary disease in Taiwan: a longitudinal, cohort study. AB - BACKGROUND: Information on the effects of long-term exposure to fine particulate matter with an aerodynamic diameter of 2.5 MUm or less (PM2.5) on lung health is scarce. We aimed to investigate the associations between long-term exposure to PM2.5, lung function, and chronic obstructive pulmonary disease (COPD) in a large scale longitudinal cohort. METHODS: We included 285 046 participants aged 20 years or older from the Taiwan MJ Health Management Institution cohort, who were recruited between 2001 and 2014 and had spirometric tests during the medical examination visit. We used a satellite-based spatiotemporal model to estimate the 2-year average ground concentration of PM2.5 (for the calendar year of each participant's medical examination and for the previous year) at each participant's address. We used the generalised linear mixed model to examine the associations between PM2.5 concentrations and lung function and the Cox proportional hazard regression model with time-dependent covariates to investigate the PM2.5 effects on COPD development. FINDINGS: Every 5 MUg/m3 increment in PM2.5 was associated with a decrease of 1.18% for forced vital capacity (FVC), 1.46% for forced expiratory volume in 1 s (FEV1), 1.65% for maximum mid-expiratory flow (MMEF), and 0.21% for FEV1:FVC ratio. The decrease accelerated over time. Additional annual declines were observed for FVC (0.14%), FEV1 (0.24%), MMEF (0.44%), and FEV1:FVC ratio (0.09%). Compared with the participants exposed to the first quartile of PM2.5, participants exposed to the fourth, third, and second quartiles of PM2.5 had a hazard ratio of 1.23 (95% CI 1.09-1.39), 1.30 (1.16-1.46), and 1.39 (1.24-1.56) for COPD development, respectively. INTERPRETATION: Long-term exposure to ambient PM2.5 is associated with reduced, and faster declines in, lung function. Long-term exposure to ambient PM2.5 is also associated with an increased risk of the incidence of COPD. This study reinforces the urgency of global strategies to mitigate air pollution for improvement of pulmonary health and prevention of COPD. FUNDING: Environmental Health Research Fund of the Chinese University of Hong Kong and PhD Studentship of the Chinese University of Hong Kong. PMID- 29615227 TI - Health co-benefits from air pollution and mitigation costs of the Paris Agreement: a modelling study. AB - BACKGROUND: Although the co-benefits from addressing problems related to both climate change and air pollution have been recognised, there is not much evidence comparing the mitigation costs and economic benefits of air pollution reduction for alternative approaches to meeting greenhouse gas targets. We analysed the extent to which health co-benefits would compensate the mitigation cost of achieving the targets of the Paris climate agreement (2 degrees C and 1.5 degrees C) under different scenarios in which the emissions abatement effort is shared between countries in accordance with three established equity criteria. METHODS: Our study had three stages. First, we used an integrated assessment model, the Global Change Assessment Model (GCAM), to investigate the emission (greenhouse gases and air pollutants) pathways and abatement costs of a set of scenarios with varying temperature objectives (nationally determined contributions, 2 degrees C, or 1.5 degrees C) and approaches to the distribution of climate change methods (capability, constant emission ratios, and equal per capita). The resulting emissions pathways were transferred to an air quality model (TM5-FASST) to estimate the concentrations of particulate matter and ozone in the atmosphere and the resulting associated premature deaths and morbidity. We then applied a monetary value to these health impacts by use of a term called the value of statistical life and compared these values with those of the mitigation costs calculated from GCAM, both globally and regionally. Our analysis looked forward to 2050 in accordance with the socioeconomic narrative Shared Socioeconomic Pathways 2. FINDINGS: The health co-benefits substantially outweighed the policy cost of achieving the target for all of the scenarios that we analysed. In some of the mitigation strategies, the median co-benefits were double the median costs at a global level. The ratio of health co-benefit to mitigation cost ranged from 1.4 to 2.45, depending on the scenario. At the regional level, the costs of reducing greenhouse gas emissions could be compensated with the health co benefits alone for China and India, whereas the proportion the co-benefits covered varied but could be substantial in the European Union (7-84%) and USA (10 41%), respectively. Finally, we found that the extra effort of trying to pursue the 1.5 degrees C target instead of the 2 degrees C target would generate a substantial net benefit in India (US$3.28-8.4 trillion) and China ($0.27-2.31 trillion), although this positive result was not seen in the other regions. INTERPRETATION: Substantial health gains can be achieved from taking action to prevent climate change, independent of any future reductions in damages due to climate change. Some countries, such as China and India, could justify stringent mitigation efforts just by including health co-benefits in the analysis. Our results also suggest that the statement in the Paris Agreement to pursue efforts to limit temperature increase to 1.5 degrees C could make economic sense in some scenarios and countries if health co-benefits are taken into account. FUNDING: European Union's Horizon 2020 research and innovation programme. PMID- 29615228 TI - Water crisis in Cape Town: a failure in governance. PMID- 29615229 TI - Pollution and non-communicable disease: time to end the neglect. PMID- 29615230 TI - Antimicrobial resistance: an urgent need for a planetary and ecosystem approach. PMID- 29615231 TI - The world's biggest threats are environmental risks. PMID- 29615232 TI - Ambient air pollution and diabetes in China. PMID- 29615233 TI - Operationalising planetary health as a game-changing paradigm: health impact assessments are key. PMID- 29615234 TI - Smarter solutions for hotter times: what the Philippines can do. PMID- 29615235 TI - Connecting planetary health, climate change, and migration. PMID- 29615236 TI - Decarbonisation, climate change, and human rights: a road map for the future of Puglia region. PMID- 29615237 TI - Implementation of policies to protect planetary health. PMID- 29615238 TI - Implementation of policies to protect planetary health - Authors' reply. PMID- 29615239 TI - Ambient air pollution in relation to diabetes and glucose-homoeostasis markers in China: a cross-sectional study with findings from the 33 Communities Chinese Health Study. AB - BACKGROUND: Health effects of air pollution on diabetes have been scarcely studied in developing countries. We aimed to explore the associations of long term exposure to ambient particulate matter (PM) and gaseous pollutants with diabetes prevalence and glucose-homoeostasis markers in China. METHODS: Between April 1 and Dec 31, 2009, we recruited a total of 15 477 participants aged 18-74 years using a random number generator and a four-staged, stratified and cluster sampling strategy from a large cross-sectional study (the 33 Communities Chinese Health Study) from three cities in Liaoning province, northeastern China. Fasting and 2 h insulin and glucose concentrations and the homoeostasis model assessment of insulin resistance index and beta-cell function were used as glucose homoeostasis markers. Diabetes was defined according to the American Diabetes Association's recommendations. We calculated exposure to air pollutants using data from monitoring stations (PM with an aerodynamic diameter of 10 MUm or less [PM10], sulphur dioxide, nitrogen dioxide, and ozone) and a spatial statistical model (PM with an aerodynamic diameter of 1 MUm or less [PM1] and 2.5 MUm or less [PM2.5]). We used two-level logistic regression and linear regression analyses to assess associations between exposure and outcomes, controlling for confounders. FINDINGS: All the studied pollutants were significantly associated with increased diabetes prevalence (eg, the adjusted odds ratios associated with an increase in IQR for PM1, PM2.5, and PM10 were 1.13, 95% CI 1.04-1.22; 1.14, 1.03-1.25; and 1.20, 1.12-1.28, respectively). These air pollutants were also associated with higher concentrations of fasting glucose (0.04-0.09 mmol/L), 2 h glucose (0.10 0.19 mmol/L), and 2 h insulin (0.70-2.74 MUU/L). No association was observed for the remaining biomarkers. Stratified analyses indicated greater effects on the individuals who were younger (<50 years) or overweight or obese. INTERPRETATION: Long-term exposure to air pollution was associated with increased risk of diabetes in a Chinese population, particularly in individuals who were younger or overweight or obese. FUNDING: The National Key Research and Development Program of China, the National Natural Science Foundation of China, the Fundamental Research Funds for the Central Universities, the Guangdong Province Natural Science Foundation, the Career Development Fellowship of Australian National Health and Medical Research Council, and the Early Career Fellowship of Australian National Health and Medical Research Council. PMID- 29615240 TI - Rapid improvements to rural Ugandan housing and their association with malaria from intense to reduced transmission: a cohort study. AB - BACKGROUND: Rapid population growth in Africa requires an urgent expansion and improvement of housing options. Improving housing presents a promising opportunity for malaria control by reducing indoor exposure to mosquitoes. We measured recent changes in house design in rural Uganda and evaluated their association with malaria in relation to a mass scale-up of control efforts. METHODS: This analysis was part of a cohort study designed to compare temporal changes in malaria incidence from a cohort of children and adults with temporal changes in malaria test positivity rate from health facility surveillance. All children aged 6 months to 10 years (n=384) living in 107 households in Nagongera sub-country, Tororo, Uganda, were given long-lasting insecticide-treated nets and followed between Aug 19, 2011, and June 30, 2017. Repeat rounds of indoor residual spraying of insecticide were initiated on Dec 5, 2014. Socioeconomic data were collected at two timepoints (Sept 25-Oct 9, 2013 and June 21-July 11, 2016) and houses were classified as modern (cement, wood, or metal walls, tiled or metal roof, and closed eaves) or traditional (all other homes). Associations between house design and three outcomes were evaluated before and after the introduction of indoor residual spraying: human biting rate estimated monthly in each household using US Centers for Disease Control and Prevention light traps; parasite prevalence measured routinely by microscopy every 3 months before indoor residual spraying and monthly after indoor residual spraying; and malaria incidence measured by passive surveillance. FINDINGS: The implementation of indoor residual spraying was associated with significant declines in human biting rate (33.5 vs 2.7 Anopheles per house per night after indoor residual spraying, p<0.0001), parasite prevalence (32.0% vs 14.0%, p<0.0001), and malaria incidence (3.0 vs 0.5 episodes per person-year at risk, p<0.0001). The prevalence of modern housing increased from 23.4% in 2013 to 45.4% in 2016 (p=0.001). Compared with traditional houses, modern houses were associated with a 48% reduction in human biting rate before indoor residual spraying (adjusted incidence rate ratio [aIRR] 0.52, 95% CI 0.36-0.73, p=0.0002), and a 73% reduction after indoor residual spraying (aIRR 0.27, 0.17-0.42, p<0.0001). Before indoor residual spraying, there was no association between house type and parasite prevalence, but after indoor residual spraying there was a 57% reduction in the odds of parasitaemia in modern houses compared with traditional houses, controlling for age, sex, and socioeconomic position (adjusted odds ratio 0.43, 95% CI 0.24-0.77, p=0.004). House type was not associated with malaria incidence before or after indoor residual spraying. INTERPRETATION: House design improved rapidly in rural Uganda and was associated with additional reductions in mosquito density and parasite prevalence following the introduction of indoor residual spraying. Changes to house design in endemic Africa, including closing eaves and the replacement of traditional building materials, might help further the gains achieved with more widely accepted malaria control interventions. FUNDING: US National Institutes of Health, Bill & Melinda Gates Foundation, and Medical Research Council UK. PMID- 29615241 TI - Proposal of serovars 17 and 18 of Actinobacillus pleuropneumoniae based on serological and genotypic analysis. AB - The aim of this study was to investigate isolates of Actinobacillus pleuropneumoniae previously designated serologically either as non-typable (NT) or as 'K2:07', which did not produce serovar-specific amplicons in PCR assays. We used whole genome sequencing to identify the capsule (CPS) loci of six previously designated biovar 1 NT and two biovar 1 'K2:O7' isolates of A. pleuropneumoniae from Denmark, as well as a recent biovar 2 NT isolate from Canada. All of the NT isolates have the same six-gene type I CPS locus, sharing common cpsABC genes with serovars 2, 3, 6, 7, 8, 9, 11 and 13. The two 'K2:O7' isolates contain a unique three-gene type II CPS locus, having a cpsA gene similar to that of serovars 1, 4, 12, 14 and 15. The previously NT isolates share the same O-antigen genes, found between erpA and rpsU, as serovars 3, 6, 8, and 15. Whereas the 'K2:O7' isolates, have the same O-antigen genes as serovar 7, which likely contributed to their previous mis-identification. All of the NT and 'K2:O7' isolates have only the genes required for production of ApxII (apxIICA structural genes, and apxIBD export genes). Rabbit polyclonal antisera raised against representative isolates with these new CPS loci demonstrated distinct reactivity compared to the 16 known serovars. The serological and genomic results indicate that the isolates constitute new serovars 17 (previously NT) and 18 (previously 'K2:O7'). Primers designed for amplification of specific serovar 17 and 18 sequences for molecular diagnostics will facilitate epidemiological tracking of these two new serovars of A. pleuropneumoniae. PMID- 29615243 TI - Consecutive antibiotic treatment with doxycycline and marbofloxacin clears bacteremia in Mycoplasma haemofelis-infected cats. AB - Mycoplasma haemofelis is the most pathogenic feline hemoplasma species and a causative agent of infectious hemolytic anemia in cats. Current treatment protocols are effective in reducing M. haemofelis blood loads and clinical signs but consistent bacteremia clearance is rarely achieved. The aim of this study was to develop an antibiotic treatment protocol capable of clearing M. haemofelis bacteremia. Doxycycline and marbofloxacin treatment protocols were evaluated in chronically M. haemofelis infected cats in two pre-experiments and a controlled treatment study (main experiment) using five treated and four untreated cats. The blood bacterial loads in the main experiment were monitored weekly by real-time PCR for 203 days. Cats were treated with doxycycline (5 mg/kg bid orally) for 28 days. Cats that remained M. haemofelis PCR-positive or became positive again (all 5 cats in the main experiment) were switched to marbofloxacin treatment (2 mg/kg sid orally) for 14 days; then, all cats were PCR-negative. Immunosuppression after the antibiotic treatment did not lead to reactivation of bacteremia. Fine needle aspirates of different organs and bone marrow collected before and after immunosuppression were PCR-negative. Overall, 5 cats cleared bacteremia with doxycycline alone (showing lower bacterial loads at the treatment start), while 10 cats needed to be switched to marbofloxacin. Based on our results, we recommend doxycycline treatment (10 mg/kg up to 28 days) for clearance of M. haemofelis infection and monitoring bacterial loads by real-time PCR. Only if bacteremia persists or reoccurs, antibiotic treatment should be switched to marbofloxacin (2 mg/kg sid for 14 days). PMID- 29615242 TI - Vaccination with outer membrane vesicles and the fimbrial protein FlfA offers improved protection against lesions following challenge with Gallibacterium anatis. AB - Gallibacterium anatis is an opportunistic poultry pathogen belonging to the Pasteurellaceae family. It has been shown to cause oophoritis, salpingitis and peritonitis in hens, as well as being associated with reduced semen quality in cockerels. Widespread multidrug resistance and substantial antigenic variation among strains of Gallibacterium anatis is a major constraint to treatment with antimicrobials and prevention of infection by vaccination. Novel vaccine strategies targeting G. anatis are therefore necessary. Outer membrane vesicles (OMVs) are nanosized vesicles formed from the outer membrane of Gram-negative bacteria. These vesicles have shown promising potential as both adjuvants and as vaccine candidates against numerous bacterial species. A high vesiculating mutant of G. anatis (G. anatis DeltatolR) has previously been made, enabling production of OMVs in large scale. In this study, we elucidated the potential of G. anatis DeltatolR OMVs as adjuvant for the conserved antigens GtxA-N (the N-terminal part of the RTX like toxin Gallibacterium toxin A) and FlfA (F17-like fimbria), as well as evaluated if combinations of OMVs together with antigens could facilitate cross-protective immunity against three different strains of G. anatis. We showed that DeltatolR OMVs function as an adjuvant for GtxA-N by inducing antigen specific antibody production. However, OMVs in combination with GtxA-N failed to induce protection against lesions after challenge infection. In contrast, vaccination with OMVs in combination with FlfA protected against lesions, especially in the salpinx, caused by two diverse strains of G. anatis, thereby indicating a cross-protective potential. No protection against the third G. anatis strain 7990 could be obtained in any of the experimental settings. In conclusion, DeltatolR OMVs and FlfA could serve as potential future vaccine components againt G. anatis. PMID- 29615244 TI - From the [Pasteurella] pneumotropica complex to Rodentibacter spp.: an update on [Pasteurella] pneumotropica. AB - The species [Pasteurella] pneumotropica has been reclassified into the new genus Rodentibacter, within the family Pasteurellaceae. Along with the type species (Rodentibacter pneumotropicus) of the new genus, seven new species have been named. These organisms were formerly mainly known as the [P.] pneumotropica complex and [P.] pneumotropica was considered as the most important Pasteurellaceae species colonizing laboratory rodents. The aim of this review is to update the veterinary relevant aspects of clinical manifestations, pathogenesis, virulence and diagnostics of members of Rodentibacter with a focus on the most important species from a veterinary perspective. The organisms are obligate commensals of the mucous membranes and members of Rodentibacter are not able to persist for long in the environment. Members of Rodentibacter spp. are responsible for the most prevalent bacterial infections in laboratory mice and rats, but are also common in rodents outside laboratory settings. Some Rodentibacter spp. produce mainly localised disease in connection with favouring factors and seldomly act as primary pathogens in healthy immunocompetent animals. The subclinical infection with Rodentibacter spp. can affect the results of certain types of research using contaminated animals thus placing them on a list of microbes which are often not tolerated in experimental rodent facilities. The presences of RTX toxins, YadA-like proteins and a capsule with possible role in the pathogenesis have been described. Some species of Rodentibacter are able to form robust biofilms which might be involved in colonisation and persistence within the host. Current possibilities for diagnostics and differentiation among Rodentibacter spp. are outlined and options for treatment and control are provided. PMID- 29615245 TI - Anaplasma ovis genetic diversity detected by major surface protein 1a and its prevalence in small ruminants. AB - Anaplasma ovis is a widely distributed tick-borne rickettsial pathogen of sheep, goats, and wild ruminants. The aims of this study were to assess the prevalence, associations of Anaplasma ovis in sheep and goats, as well as its genetic diversity based on analysis of the msp1alpha gene. A total of 416 DNA samples from sheep (n = 236) and goats (n = 180) from four provinces in southeastern Turkey were analyzed by PCR. The overall A. ovis prevalence was 18% (CI 14.4 22.1). The infection rates of A. ovis varied from 15.9% to 21.8% in sampled provinces, and they were not significantly different. There was no difference between Anaplasma ovis infection in sheep (20.3%, CI 15.4-26.0) and goats (15.0%, CI 10.1-21.1) or in infection rate of animals <1 year (21.8%, CI 14.9-30.1) compared to >1 year (16.4%, CI 12.4-21.2). A significant association between A. ovis infection and the presence of Rhipicephalus bursa and Rhipicephalus turanicus was observed (P < 0.05). Prevalence of A. ovis-positive animals was higher in animals showing co-infection with Babesia and Theileria compared to those not co-infected (P < 0.05). The Msp1a amino acid repeats were identified and used for the characterization of A. ovis strains. Forty partial msp1a gene sequences containing the repeated sequences of A. ovis were obtained, and 14 previously undescribed tandem repeats with 33 to 43 amino acids were found. Thirteen A. ovis genotypes were identified based on the structure of Msp1a tandem repeats. The majority of A. ovis isolates exhibited one Msp1a tandem repeat, with a maximum of three. This study revealed the Msp1a could be used as a marker for genotyping A. ovis, and high genetic diversity of A. ovis were found in small ruminants in Turkey. PMID- 29615246 TI - Antimicrobial susceptibility of Avibacterium paragallinarum isolates from outbreaks of infectious coryza in Dutch commercial poultry flocks, 2008-2017. AB - The objective of the present study was to determine the in vitro antimicrobial susceptibility of Avibacterium paragallinarum isolates from infectious coryza outbreaks in Dutch commercial poultry, from 2008 till mid-2017. By using a broth microdilution method, minimal inhibitory concentrations (MICs) of 15 antimicrobial agents were assessed, and MIC50 and MIC90 values were determined. Additionally, isolates were subjected to different PCRs for the presence of genes that may confer antimicrobial resistance. Besides field isolates, a set of reference strains, among which the nine Kume strains and one Page serovar strain, were included in the study. For broth microdilution testing a new growth medium, recently developed for susceptibility testing of Haemophilus parasuis, was used. The medium proved to be suitable for broth microdilution susceptibility testing of NAD dependent Av. paragallinarum as well; visible growth was obtained in growth control wells and accepting a deviation of one dilution step, MIC values were reproducible. Results of 44 field isolates originating from 25 outbreaks showed relatively good susceptibility to antimicrobial agents that are recommended for the treatment of infectious coryza in the Netherlands, except for tetracycline; circa 75% of the isolates were characterized by MIC values of tetracycline of >=16 MUg/ml. In almost a quarter of these isolates with high MICs of tetracycline, tet genes were detected. For the remaining isolates with elevated MIC values, the mechanism conferring resistance remains to be studied. Of most agents, low MIC values were determined for the nine Kume and one Page serovar reference strains, as well as negative PCR results for resistance genes, being concordant with agar diffusion results reported for these strains. PMID- 29615247 TI - Evaluation of bovine viral diarrhea virus transmission potential to naive calves by direct and indirect exposure routes. AB - Bovine viral diarrhea viruses (BVDV) can cause both acute and persistent infections in cattle. Exposure to BVDV persistently infected (PI) animals results in transmission of the virus to a naive animal which causes a transient acute infection. While it is known that direct exposure to PI animals is a highly efficient means of transmission, less information is available regarding the potential for transmission from acutely infected either by direct or indirect exposure to naive animals. Therefore, the objective of this study was to evaluate the potential for spread of the virus from calves acutely infected, with typical virulence field viruses know to have minimal shedding and viremia, to naive contact animals either by direct or indirect exposure. To accomplish this objective, two BVDV isolates belonging to two species of BVDV, type 1 and type 2, were used to inoculate calves. Subsequently on day 2 post-infection, naive calves were exposed to inoculated calves, either directly or indirectly, over a period of two weeks. All calves were evaluated for the presence of virus in blood samples and nasal swabs, pyrexia, lymphopenia and seroconversion. BVDV was isolated from inoculated calves but not from any of the direct and indirect contact animals or from control calves. Similarly, pyrexia and lymphopenia were observed in the inoculated calves, but not in contact and control calves. Only the inoculated calves seroconverted by day 38 of the study indicating that no transmission had occurred to the naive contact calves. This data would suggest that there may be an infectious dose needed for transmission of virus for typical virulent isolates. PMID- 29615248 TI - A two dose immunization with an inactivated reassortant H5N2 virus protects chickens against lethal challenge with homologous 2.3.2.1 clade and heterologous 2.2 clade highly pathogenic avian influenza H5N1 viruses. AB - The present study was aimed at generating a reassortant vaccine candidate virus with clade 2.3.2.1 Hemagglutinin (HA) and its evaluation in a challenge study for protection against homologous (2.3.2.1 clade) and heterologous (2.2 clade) highly pathogenic avian influenza (HPAI) H5N1 viruses. Plasmid-based reverse genetics technique was used to rescue a 5 + 3 reassortant H5N2 strain containing the modified HA of H5N1 (clade 2.3.2.1), the Neuraminidase (NA) of H9N2, the Matrix (M) of H5N1 and the internal genes of A/WSN/33 H1N1. In addition, another 6 + 2 reassortant virus containing modified HA from H5N1 (clade 2.3.2.1), the NA from H9N2 and the internal genes of A/WSN/33 H1N1 was also rescued. The 5 + 3 reassortant H5N2 virus could grow to a higher titer in both MDCK cells and chicken eggs compared to the 6 + 2 reassortant H5N2 virus. The vaccine containing the inactivated 5 + 3 reassortant H5N2 virus was used in a two-dose immunization regime which protected specific pathogen free (SPF) chickens against two repeated challenges with homologous 2.3.2.1 clade and heterologous 2.2 clade HPAI H5N1 viruses. The 5 + 3 reassortant H5N2 virus based on clade 2.3.2.1 generated in this study can be effective in protecting chickens in the case of an outbreak caused by antigenically different clade 2.2 HPAI H5N1 viruses and opens the way to explore its applicability as potential vaccine candidate especially in the Asian countries reporting these clades frequently. The study also indicates that sequential immunization can broaden protection level against antigenically diverse strains of H5N1 viruses. PMID- 29615249 TI - T160A mutation-induced deglycosylation at site 158 in hemagglutinin is a critical determinant of the dual receptor binding properties of clade 2.3.4.4 H5NX subtype avian influenza viruses. AB - Most clade 2.3.4.4 H5NX subtype avian influenza viruses possess a T160A amino acid substitution in the hemagglutinin (HA) protein that has been shown to affect the receptor binding properties of a clade 2.3.4 H5N1 virus. However, the effect of this single site mutation on the HA backbone of clade 2.3.4.4 H5NX viruses remains unclear. In this study, two H5N6 field isolates possessing HA-160A with dual alpha-2,3 and alpha-2,6 receptor binding properties (Y6 virus) and HA-160T with alpha-2,3 receptor binding affinity (HX virus), respectively, were selected to generate HA mutants containing all of the internal genes from A/PR8/H1N1 virus for comparative investigation. We found that the Y6-P-160A and RHX-P-160A viruses each with 160A in the HA resulting in loss of glycosylation at site 158 exhibited binding to the two receptor types, whereas the RY6-P-160T and HX-P-160T viruses each with 160T in the HA displayed selective binding to alpha-2,3 receptors only. In addition, differences were noted in the replication of these four H5N6 recombinants in avian and mammalian cells, as well as in their pathogenicity in mice. The contribution of deglycosylation at site 158 to the acquisition of human like receptors was further verified in H5N2, H5N5 and H5N8 reassortants. Therefore, we conclude that the lack of glycosylation at site 158 induced by the T160A mutation in HA is a critical determinant for the dual receptor binding properties of clade 2.3.4.4 H5NX viruses. This new insight may be helpful in assessing the pandemic potential of novel H5 isolates. PMID- 29615250 TI - Mycobacterium aviumsubsp. paratuberculosis isolated from wild red deer (Cervus elaphus) in Northern Italy. AB - Paratuberculosis (or Johne's disease) is an infectious disease which affects mainly ruminants and it is caused by Mycobacterium avium subsp. paratuberculosis (MAP). During a culling program (years 2011-2015) aimed at controlling the red deer (Cervus elaphus) population in Stelvio National Park (Italian Alps), where paratuberculosis was already described in this species, 382 tissue samples from the Lombardy Region and 102 fecal specimens from the Autonomous Province of Bolzano were analyzed by PCR. Of these, 77 samples (20.16%) from the Lombardy area and 19 specimens (18.63%) from the Bolzano area resulted PCR positive. The cultural test was carried out on PCR positive samples (n = 96), enabling the isolation of 19 MAP field strains which were genotyped using MIRU-VNTR typing and Short Sequence repeats (SSRs). Our results suggest that all isolates share an identical VNTR profile corresponding to the INMV1 genotype. The only variation was on the locus SSR2, but the utility of this last locus has already been questioned because of its instability. Overall, these data suggest a common clonal origin and host adaptation during the diffusion of paratuberculosis in this population. Finally, this profile is the same as that which has already been described in the cattle population in Northern Italy, suggesting a possible inter species disease transmission pattern from wildlife to domestic ruminants and vice versa. PMID- 29615251 TI - Effects of different types of flooring design on the development of antimicrobial resistance in commensal Escherichia coli in fattening turkeys. AB - The objective of this study was to evaluate the effects of different types of flooring designs on antimicrobial resistance in commensal Escherichia coli from turkeys treated with enrofloxacin. Two trials were performed with same feed, housing conditions and fattening duration, but with different flooring designs. Furthermore, the first trial was performed in an unchanged environment and the second trial in a changed environment. The flooring designs of the pens were assigned to four groups; G1 - entire floor pen covered with litter, G2 - floor pen with heating, G3 - partially slatted flooring including an area that was littered, G4 - fully slatted flooring with a sand bath. Enrofloxacin was given at days 10-14 via drinking water. The changed environment in the second trial was achieved by moving the animals to new pens with the respective same conditions as previously after antimicrobial administration at day 15. A total of 576 E. coli were isolated from cloacal swab and poultry manure samples. Sample collection was done before the treatment, after the treatment and at the end of the trials at day 35. The resistance of isolates to enrofloxacin and ampicillin was determined using broth microdilution A single treatment with enrofloxacin reduced the proportion of samples with susceptible E. coli isolates significantly in all flooring designs. Overall, frequencies of enrofloxacin resistance were significantly different between the unchanged and changed environment. At the same time, the proportion of ampicillin-resistant isolates increased in the first trial, although no ampicillin was applied in this study. PMID- 29615252 TI - Occurrence of quinolone resistant E. coli originating from different animal species in Norway. AB - The aim of this study was to describe and compare the occurrence of quinolone resistant Escherichia coli (QREC) in various animal species in relation to human population density. Data from the Norwegian monitoring programme for antimicrobial resistance in feed, food and animals from 2006 to 2016 was compiled and analysed. In total, 4568 E. coli isolates were included in this study. The isolates originated from broilers, layers, cattle, turkeys, dogs, wild birds, red foxes, reindeer, sheep, horses and pigs. Data regarding the geographical location of sampling was obtained for 4050 of these isolates and used to categorize the isolates depending on the human population density of the area. In total, 1.4% of the isolates were categorized as quinolone resistant. Compared to most European countries, there was an overall low occurrence of QREC in various animal species in Norway, though with an interspecies variation with the highest occurrence in broilers and wild birds (p < 0.05). Human population density was not associated with the occurrence of QREC. Since fluoroquinolones are not used prophylactically and in almost negligent amounts in various species in Norway, the interspecies variation in the occurrence of QREC suggests that other factors than fluoroquinolone use may be important in the development of QREC. PMID- 29615253 TI - Antimicrobial susceptibility of Haemophilus parasuis isolates from Germany by use of a proposed standard method for harmonized testing. AB - Haemophilus parasuis-related infections, especially among weaners are responsible for major economic losses on pig farms. A method for broth microdilution susceptibility testing of this fastidious organism has recently been developed, but the suitability of this method needs to be validated in a large collection of current field isolates. Using the proposed method, this study tested 123 H. parasuis isolates from different geographic regions in Germany (including five isolates from the Netherlands and Belgium) against a panel of 24 antimicrobial agents and antimicrobial combinations. The isolates were collected between 2013 and 2016. As there are no H. parasuis specific breakpoints available, the tested isolates could not be classified as susceptible, intermediate or resistant. Bi- or multi-modal distributions of minimum inhibitory concentration (MIC) values were observed for some antimicrobial agents (e.g. aminoglycosides, beta-lactams, fluoroquinolones and tetracyclines), indicative of non-wild type populations of H. parasuis. Susceptibility testing revealed broad distributions of MIC values for various antimicrobials (e.g. neomycin, streptomycin, tetracycline, tiamulin, tilmicosin, trimethoprim/sulfamethoxazole and tulathromycin). The lowest MIC90 (i.e. the concentration at which 90% of isolates were inhibited) was obtained for cefotaxime (<=0.015 MUg/ml), and the highest MIC90 (512 MUg/ml) was obtained for streptomycin. This study tested a large set of current field isolates and included the most common serovars (serovars 4 and 5). The results point to the suitability of the broth microdilution susceptibility testing method proposed previously for determining H. parasuis MIC values. In addition, the study provides a reliable overview of the susceptibility status of H. parasuis at present in Germany. PMID- 29615254 TI - Variability of SCCmec elements in livestock-associated CC398 MRSA. AB - The most common livestock-associated lineage of methicillin-resistant Staphylococcus aureus (MRSA) in Western Europe is currently clonal complex (CC) 398. CC398-MRSA spread extensively across livestock populations in several Western European countries, and livestock-derived CC398-MRSA strains can also be detected in humans. Based on their SCCmec elements, different CC398 strains can be distinguished. SCCmec elements of 100 veterinary and human CC398-MRSA isolates from Germany and Austria were examined using DNA microarray-based assays. In addition, 589 published SCC and/or genome sequences of CC398-MRSA (including both, fully finished and partially assembled sequences) were analysed by mapping them to the probe sequences of the microarrays. Several isolates and sequences showed an insertion of a large fragment of CC9 genomic DNA into the CC398 chromosome. Fifteen subtypes of SCCmec elements were detected among the 100 CC398 isolates and 41 subtypes could be discerned among the published CC398 sequences. Eleven of these were also experimentally detected within our strain collection, while four subtypes identified in the isolates where not found among the sequences. A high prevalence of heavy metal resistance genes, especially of czrC, was observed among CC398-MRSA. A possible co-selection of resistances to antibiotics and zinc/copper supplements in animal feed as well as a spill-over of SCCmec elements that have evolved in CC398-MRSA to other, possibly more virulent and/or medically relevant S. aureus lineages might pose public health problems in future. PMID- 29615255 TI - Diagnostics, epidemiological observations and genomic subtyping in an outbreak of pullorum disease in non-commercial chickens. AB - Salmonella Gallinarum biovar Pullorum (S. Pullorum) is a poultry pathogen associated with significant economic losses and animal suffering. Strict eradication programmes have eliminated S. Pullorum from the commercial poultry sector in most regions, but occasional outbreaks still occur in the non commercial population. In 2012, pullorum disease was diagnosed in a non commercial flock in Sweden. Epidemiological, post-mortem and bacteriological investigations identified three more infected flocks. To study the epidemiological relationships between the flocks and evaluate different subtyping methods for S. Pullorum, 13 isolates from the four infected flocks were investigated by pulsed-field gel electrophoresis (PFGE) and multi-locus variable number tandem repeat analysis (MLVA). Four isolates collected from two non commercial flocks in 2001 were also included. Six representative isolates from 2012 were further analysed by high-throughput sequencing. To differentiate between biovars Gallinarum and Pullorum, ten regions of difference (RODs) were investigated by in silico PCR. Three different PFGE-types were observed from the four epidemiologically linked farms in 2012 and MLVA further discriminated the isolates. SNP typing based on high-throughput sequencing clustered the four farms from the 2012 outbreak in two pairs. The PFGE, MLVA and high-throughput sequencing results suggested at least two different sources of infection or a common genetically mixed source in 2012. High-throughput sequencing is useful both for subtyping of S. Pullorum and may also be used for differentiating between the two biovars Pullorum and Gallinarum. PMID- 29615256 TI - F14:A-:B- and IncX4 Inc group cfr-positive plasmids circulating in Escherichia coli of animal origin in Northeast China. AB - The objective of this study was to investigate the prevalence of the cfr gene in Escherichia coli isolates from domestic animals in Northeast China and to characterize the cfr-containing plasmids. Between June 2015 and April 2016, 370 E. coli isolates were collected from pigs, chickens, and dairy cows in Northeast China. Among these, 111 were florfenicol resistant, including 109 isolates carrying the floR gene and 6 positives for cfr. The prevalence of cfr in E. coli isolates from the four northeast provinces in China was 1.6% (6/370), which was higher than that previously reported (0.08% and 0.5%). All six cfr-containing E. coli isolates were highly resistant to florfenicol (100%), cefotaxime (100%), and fosfomycin (100%). Complete sequence analysis of two cfr-carrying plasmids revealed high homology of the IncX4-type pEC14cfr plasmid with two other cfr harboring plasmids, pSD11 and pGXEC6, found in swine E. coli isolates from southern China. pEC14cfr-like plasmids have been isolated in five provinces in southern and northern China. The isolation sites were up to 2700 kilometers apart, implying that pEC14cfr-like plasmids are likely to be national epidemic cfr-carrying plasmids that mediate the dissemination of cfr in China. Moreover, the genetic structure (IS26-IS26-cfr-rec-pre/mob-ramA-IS26) of the second cfr carrying plasmid, IncF14:A-:B- pEC295cfr, represents a novel genetic environment for cfr identified for the first time in the present study. Sequence homology analysis indicated that the cfr-carrying element was most likely introduced into a cfr-negative pEC12 plasmid backbone, which evolved into the cfr-carrying vector, pEC295cfr. Moreover, isolation of the IncF14:A-:B- pEC295cfr plasmid harboring cfr suggests that IncFII plasmids maybe have become additional effective vehicles for cfr dissemination. These results highlight the importance of surveying the prevalence of IncX4 and IncFII plasmids in gram-negative bacteria, especially in swine E. coli isolates. PMID- 29615258 TI - GeneXpert-negative Group B streptococci detected by Accelerate PhenoTM System. PMID- 29615257 TI - Evaluating the most appropriate pooling ratio for EDTA blood samples to detect Bluetongue virus using real-time RT-PCR. AB - The control of Bluetongue virus (BTV) presents a significant challenge to European Union (EU) member states as trade restrictions are placed on animals imported from BTV-affected countries. BTV surveillance programs are costly to maintain, thus, pooling of EDTA blood samples is used to reduce costs and increase throughput. We investigated different pooling ratios (1:2, 1:5, 1:10 and 1:20) for EDTA blood samples to detect a single BTV positive animal. A published real-time RT-PCR assay (Hofmann et al., 2008) and a commercial assay (ThermoFisher VetMaxTM BTV NS3 kit) were used to analyse BTV RNA extracted from pooled EDTA blood samples. The detection rate was low for the onset of infection sample (0-2 days post infection (dpi); CT 36) irrespective of the pooling ratio. Both assays could reliably detect a single BTV-positive animal at early viraemia (3-6 dpi; CT 33) when pooled, however, detection rate diminished with increasing pooling ratio. A statistical model indicated that pooling samples up to 1:20, is suitable to detect a single BTV positive animal at peak viraemia (7-12 dpi) or late infection (13-30 dpi) with a probability of detection of >80% and >94% using the Hofmann et al. (2008) and VetMAX assays, respectively. Using the assays highlighted in our study, pooling at ratios of 1:20 would be technically suitable in BTV-endemic countries for surveillance purposes. As peak viraemia occurs between 7-12 days post infection, a 1:10 pooling ratio is appropriate for post import testing when animals are sampled within a similar time frame post-import. PMID- 29615259 TI - New trends in innovative vaccine development against Actinobacillus pleuropneumoniae. AB - Actinobacillus pleuropneumoniae is the etiological agent of porcine pleuropneumonia, a respiratory disease leading to severe economic losses in the swine industry. The most widely used commercial vaccines are bacterins comprising inactivated whole cells of A. pleuropneumoniae but these have only been partially effective in preventing disease. Innovative immuno-prophylactic preparations of A. pleuropneumoniae based on ApxI, ApxII, ApxIII, ApxIV toxins and outer membrane proteins, among others (i.e. RnhB, GalU, GalT, HflX, ComL, LolB, LppC), have high protective efficacy in mice and pigs. Some vaccine preparations have efficacy against homologous and heterologous A. pleuropneumoniae serovars, which constitute an important advance to control porcine pleuropneumonia. In this arena, subunit vaccines based on toxins are one of the most advanced and promising developments. Many research groups have focussed on the development of live attenuated vaccines comprising strains with inactivated Apx toxins and/or other virulence factors, their protective efficacy being determined in mouse and/or swine models. Other innovative approaches such as bacteria, yeast and plants as production and oral delivery platforms have been explored in animal models and the definitive host with encouraging results. In addition, further research into A. pleuropneumoniae-based DNA and nano-vaccines, as well as bioencapsulation of antigens in plants, is envisaged. Here, the recent findings and future trends in innovative vaccine development against A. pleuropneumoniae are reviewed and placed in perspective. PMID- 29615260 TI - Extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae in local and imported poultry meat in Ghana. AB - Antibiotic use in animal husbandry has raised concerns on the spread of resistant bacteria. Currently animal products are traded globally with unprecedented ease, which has been challenging the control of antimicrobial resistance. This study aims to detect and characterize extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli and Klebsiella pneumoniae from imported and locally produced poultry products sold in Ghana. Local and imported chicken meat was collected from 94 stores and markets throughout Kumasi (Ghana) and cultured on selective ESBL screening agar. Phenotypic ESBL-producing E. coli and K. pneumoniae isolates were confirmed by combined disc test and further characterized by antibiotic susceptibility testing, amplification of the blaCTX-M, blaTEM and blaSHV genes as well as multilocus sequence typing (MLST) and linked to the country of origin. Out of 200 meat samples, 71 (36%) samples revealed 81 ESBL-producing isolates (46 E. coli and 35 K. pneumoniae), with 44% (30/68) of local poultry and 31% (41/132) of imported products being contaminated. Most ESBL-producing isolates harboured the blaCTX-M-15 gene (61/81, 75%) and the dominant Sequence Types (ST) were ST2570 (7/35, 20%) among K. pneumoniae and ST10 (5/46, 11%) among E. coli. High numbers of ESBL-producing bacteria, particularly on local but also imported poultry meat, represent a potential source for human colonization and infection as well as spread within the community. Surveillance along the poultry production food-consumer chain would be a valuable tool to identify sources of emerging multidrug resistant pathogens in Ghana. PMID- 29615261 TI - Transmission and pathogenicity of Gallibacterium anatis and Escherichia coli in embryonated eggs. AB - In laying hens, Escherichia coli (E. coli) and Gallibacterium anatis (G. anatis) are considered the two major pathogens causing reproductive tract disorders, either as single infections or as co-infections. Vertical transmission has been confirmed for E. coli but remains to be clearly demonstrated for G. anatis. The aim of the present study was to investigate the ability of both G. anatis and E. coli at eggshell transmission using an embryonated egg dipping model, and to investigate the possible interaction between the two organisms in an embryonated egg injection model. Embryonated eggs were dipped into brain heart infusion broth containing 108 CFU/ml either of G. anatis 12656-12 liver, E. coli ST95 or E. coli ST141, respectively. E. coli ST95 and ST141 were re-isolated from the interior egg contents in 60% (12/20) and 85% (17/20) of the eggs, respectively, while G. anatis 12656-12 was only re-isolated from the interior egg contents in 6.7% (3/45) eggs. Eggs were injected with 10-1000 CFU of either G. anatis 12656-12, E. coli ST95 or ST141 into the allantoic cavity. As few as 10 CFU of G. anatis 12656 12 resulted in 100% mortality within 24 h post injection whereas the E. coli injected embryos all died at 48 h post injection. Significant difference in CFU counts were observed for G. anatis when compared G. anatis injection group with either of the two G. anatis - E. coli co-injection groups. Sixteen hours post injection, a significant difference in embryo mortality could be observed when comparing co-injected embryonated eggs (G. anatis and E. coli) and single injected (G. anatis or E. coli) embryonated eggs. In conclusion, bacterial transmission via the eggshell was demonstrated for both G. anatis and E. coli although at different magnitudes. The embryonated egg injection model revealed that G. anatis in particular was highly pathogenic when exposed directly to the developing embryo. PMID- 29615262 TI - New insights on pestivirus infections in transhumant sheep and sympatric Pyrenean chamois (Rupicapra p. pyrenaica). AB - Border Disease Virus (BDV) causes health and economic impact on livestock and is also of importance in wildlife conservation as it causes high mortality outbreaks in Pyrenean chamois (Rupicapra pyrenaica pyrenaica). Pastoral practices are known as a main interspecies pathogen transmission. Hence, the presence of pestivirus in transhumant sheep flocks and sympatric chamois was assessed in areas with different epidemiological scenarios of chamois BDV infections. Moreover, the present study had also the goal to identify if inter-specific infections occurred and when they happened. Five sheep flocks grazing in two alpine areas in the Pyrenees with two different BDV epidemiological scenarios in chamois populations were studied during two transhumant seasons. Sheep were sampled before and after transhumance. Pyrenean chamois sera and spleen samples from both areas where also studied during the same period. Antibodies against BDV were assessed by means of ELISA and VNT. A qRT-PCR was used in order to detect the virus. Seroprevalence in sheep ranged between 0 and 91.1% at the flock level. Chamois were found to have high seroprevalences (52.9-77.7%) in both areas, and four new BDV isolates were sequenced. One sheep farm presented persistent BDV circulation and three showed low BDV circulation. The after-transhumance period was identified as the moment when viral transmission occured in the first farm, associated to BDV strains of domestic origin, according to VNT results. However, the BDV isolate was genetical closely related to previous BDV strains from chamois origin. In another farm, antibodies in two of the three positive sera were associated to infection with a chamois-like BDV strain. Altogether indicates that occasional viral transmission from chamois to sheep may occur. PMID- 29615263 TI - Understanding the health and production impacts of endemic Chlamydia pecorum infections in lambs. AB - Lamydia pecorum is a globally recognised livestock pathogen that is capable of causing severe and economically significant diseases such as arthritis in sheep and cattle. Relatively little information is available on the clinical progression of disease and the long-term effects of asymptomatic and symptomatic chlamydiosis in sheep. Recent studies in calves indicate that endemic C. pecorum infections may reduce growth rates. To investigate the clinical health parameters and production impacts of endemic C. pecorum infection in an Australian commercial lamb flock, we performed bimonthly sampling and clinical health assessments on 105 Border Leicester lambs from two to ten months of age. Chlamydial status was investigated via serology and species-specific quantitative PCR. Throughout the study period, conjunctivitis remained a persistent clinical feature while signs of arthritis (e.g. palpable synovial joint effusions) resolved in a subset of lambs while persisting in others. Clinical disease and C. pecorum infection were highest at six months of age (weaning). As previously reported, peak seroconversion tends to occur two months after the onset of clinical symptoms (6 months of age), with lambs clearing chlamydial infection by 10 months of age, despite ongoing disease still being present at this time. Notably, the presence of chlamydial infection did not affect lamb mass or growth rates throughout the study. At necropsy, C. pecorum was not detected within the joints of lambs with chronic arthritis. Molecular analysis of the strains in this flock suggest that the infecting strains circulating in this flock are clonal C. pecorum pathotypes, denoted ST 23, commonly associated with conjunctivitis and polyarthritis in Australian sheep. This study provides a platform for further research in the epidemiology and disease transmission dynamics of C. pecorum infections in sheep. PMID- 29615265 TI - Update: Is Needle Aspiration Better Than Chest Tube Placement for the Management of Primary Spontaneous Pneumothorax? PMID- 29615264 TI - Extended-spectrum beta-lactamase (ESBL)- and carbapenemase-producing Enterobacteriaceae in water sources in Lebanon. AB - Extended-spectrum beta-lactamases (ESBLs) have been recurrently reported in both human and veterinary medicine, and carbapenemases have also emerged in these two sectors. Such resistance phenotypes were increasingly reported in the environment, which both receives and further disseminates multidrug-resistant (MDR) bacteria. Here, we report the high contamination of water samples (68.2%; 15/22) collected in estuaries in Lebanon. From these 15 contaminated sites, a total of 21 ESBL-producing (mostly harbouring the blaCTX-M-15 gene) and four carbapenemase-producing (two blaOXA-48 and two blaOXA-244) Enterobacteriaceae were recovered. ESBL contamination was also identified in water samples collected from rural wells and spring water, although at a lower frequency. Indeed, 1.9% (3/155) and 6.1% (7/115) of the wells and springs were contaminated, respectively, and all identified isolates were CTX-M-15-producing E. coli. Interestingly, sequence types (STs) previously associated both with animal and human reservoirs were detected (ST38, ST10 and ST131), suggesting a complex source of contamination. This situation is alarming since water drawn from wells or springs is directly intended for human consumption in Lebanon without any further treatment. Moreover, even though water from estuaries is not intended for human consumption, it is used to water animals and irrigate crops. Consequently, water contamination by ESBLs and carbapenemases in Lebanon is potentially a major risk to public health. Part of this work was presented at the 7th Symposium on Antimicrobial Resistance in Animals and the Environment (ARAE). PMID- 29615266 TI - Clinical depression and anxiety among ST-elevation myocardial infarction hospitalizations: Results from Nationwide Inpatient Sample 2004-2013. AB - Depression and anxiety are common among patients who have a major cardiovascular event. However, despite their frequency, there is a lack of evidence regarding the relationship between depression and/or anxiety and receiving revascularization in ST-elevation myocardial infarction (STEMI) hospitalizations. Using data from the Nationwide Inpatient Sample (NIS) from the years 2004 to 2013, we assessed whether a clinical co-diagnosis of depression and/or anxiety decreases the likelihood of revascularization among STEMI hospitalizations. Our central finding is that, paradoxically, the odds of in-hospital mortality were lower among STEMI hospitalizations with a clinical co-diagnosis of depression and/or anxiety as compared to those without. We further discovered that clinical diagnoses of depression and/or anxiety were less prevalent among revascularized as compared to non-revascularized STEMI hospitalizations. However, the percentage of clinical diagnoses of depression and/or anxiety among STEMI hospitalizations increased at a similar rate over a 10-year period irrespective of revascularization status. In conclusion, these results are suggestive of the potentially underdiagnosed mental health issues surrounding major cardiovascular events, and indeed, chronic disease as a whole. To our knowledge, this is the first study to document and examine the "depression paradox" among a population of cardiac patients. PMID- 29615267 TI - A 12-month study of the hikikomori syndrome of social withdrawal: Clinical characterization and different subtypes proposal. AB - Social withdrawal is a new mental health problem increasingly common, present in different cultures, whose psychopathology and treatment is not yet established. This study aims to determine the socio-demographic and clinical features and possible clinical subtypes that predict the 12-month outcomes of cases with hikikomori syndrome, a severe form of social withdrawal. Socio-demographic and clinical data at baseline were analysed as well as data obtained for 12 months after at-home treatment in 190 cases. The inclusion criteria were: spending all time at home, avoiding social situations and relationships, significant deterioration due to social isolation, with a minimum duration of 6 months. Six major diagnostic groups were identified: affective, anxiety, psychotic, drug use, personality and other Axis I disorders. The anxiety-affective subgroup demonstrated lower clinical severity, but worse evolution. Less than half of the cases were available for medical follow-up at 12-months. Subjects undergoing intensive treatment had a higher medical follow-up rate and better social networks at 12-months. Therefore, our findings provide data to reach consensus on the specific characteristics of social isolation hikikomori syndrome. The analysis demonstrated the fragility and tendency to relapse and have disengagement, particularly relevant in the anxiety-affective subgroup, suggesting that intensive treatments are more effective. PMID- 29615268 TI - Potential Impact of Medicare Payment Policy on Misclassification of Dialysis Requiring Acute Kidney Injury as ESRD: A National Temporal Trend Analysis. PMID- 29615269 TI - The public health value of vaccination for seniors in Europe. AB - Longer life expectancy and decreasing fertility rates mean that the proportion of older people is continually increasing worldwide, and particularly in Europe. Ageing is associated with an increase in the risk and severity of infectious diseases. These diseases are also more difficult to diagnose and manage in seniors who often have at least one comorbid condition (60% of seniors have two or more conditions). Infectious diseases increase the risk of hospitalization, loss of autonomy and death in seniors. Effective vaccines are available in Europe for infectious diseases such as influenza, pneumococcal diseases, herpes zoster, diphtheria, tetanus and pertussis. Their effectiveness has been demonstrated in terms of reducing the rates of hospitalization, disability, dependency and death. The prevention of diseases in seniors also results in savings in healthcare and societal costs each year in Europe. Despite the availability of vaccines, vaccine preventable diseases affect millions of European citizens annually, with the greatest burden of disease occurring in seniors, and the medical and economic benefits associated with are not being achieved. Vaccination coverage rates must be improved to achieve the full benefits of vaccination of seniors in Europe. PMID- 29615270 TI - Adaptive fixed-time trajectory tracking control of a stratospheric airship. AB - This paper addresses the fixed-time trajectory tracking control problem of a stratospheric airship. By extending the method of adding a power integrator to a novel adaptive fixed-time control method, the convergence of a stratospheric airship to its reference trajectory is guaranteed to be achieved within a fixed time. The control algorithm is firstly formulated without the consideration of external disturbances to establish the stability of the closed-loop system in fixed-time and demonstrate that the convergence time of the airship is essentially independent of its initial conditions. Subsequently, a smooth adaptive law is incorporated into the proposed fixed-time control framework to provide the system with robustness to external disturbances. Theoretical analyses demonstrate that under the adaptive fixed-time controller, the tracking errors will converge towards a residual set in fixed-time. The results of a comparative simulation study with other recent methods illustrate the remarkable performance and superiority of the proposed control method. PMID- 29615271 TI - [A bipallidal hyperintensity]. PMID- 29615272 TI - Mitochondrial mutations associated with hearing and balance disorders. AB - Hearing and balance disorders are related to the inner ear and are among the major cause of falls in older adults. Hearing loss that commonly occurs with aging (aka presbyacusis) can result from noise exposure, smoking, ototoxic drugs and genetic factors such as mutations in nuclear and mitochondrial genes. Mutations in mitochondrial DNA (mtDNA) have been reported to play an important role in cell function by providing energy, as well as, cell death (apoptosis). This study aims to systematically review mitochondrial mutations associated with presbyacusis and suggests preventive measurements to improve the quality of life in older adults. PMID- 29615273 TI - Intensive medicine services. How to add value to the surgical process? PMID- 29615274 TI - Conventional monitoring is not sufficient to assess respiratory effort during assisted ventilation. AB - OBJECTIVE: Study the relationship and concordance between calculated respiratory effort using the signals of the ventilator (Pmus) and that measured in esophageal pressure (Pes) on mechanical ventilation with different levels of respiratory assistance. DESIGN: Prospective cohort study. AMBIT: Intensive Care Unit of 2 universitary hospitals. Patients Patients on weaning time. PROCEDURE: Airway, esophageal and respiratory flow were recorded on CPAP, assist volume control (ACV) and pressure support (PS), with complete (ACV1,PS1) and partial assistance (ACV5,PS5). MEASUREMENT: respiratory variations of Pes and Pmus (Delta: cmH2O) and pressure time product (PTPm: cmH2O.s/m). RESULTS: Fourty one records were studied, the assistance was in CPAP of 5cmH2O, PS1 of 15+/-5 reduced to 9+/ 4cmH2O. In ACV1 the inspiratory flow was 1+/-0.2l/s, reduced to 0.49+/-0.1l/s for ACV5. The increase in respiratory assistance decreases respiratory effort, measured in Delta Pes (CPAP, ACV5, ACV1, PS5, PS1): 11+/-3, 6+/-3, 5+/-3, 9+/-6, 7+/-7 and in Pmus 16+/-5, 10+/-6, 5+/-3, 10+/-6, 5+/-4cmH2O (P<.001). The PTP per minute measured in Pes: 213+/-87, 96+/-91, 23+/-24, 206+/-121, 108+/-100 (P=.001) and in Pmus: 293+/-117, 156+/-84, 24+/-32, 233+/-121, 79+/-90 (P<.001). The measurements in Pes and Pmus showed the following correlation, in Delta: 0.72 and PTPm, 0.87. The Bland-Altman analysis indicates that the difference between Delta Pes-Pmus can be 16 and the PTPm of 264 and the systematic error in Delta: -0.98+/ 4.4 and PTPm -23.69+/-66.3cmH2O.s/m. CONCLUSIONS: Calculated and measured parameters of respiratory effort showed unacceptable differences in clinical practice. PMID- 29615275 TI - Biosurfactant-induced remediation of contaminated marine sediments: Current knowledge and future perspectives. AB - The contamination of marine sediments is widespread in coastal regions of the world and represents a major concern for the potential detrimental consequences on ecosystems' health and provision of goods and services for human wellbeing. Thus, there is an urgent need to find sustainable and eco-compatible solutions for the remediation of contaminated sediments. Bioremediation is a low cost and environmental-friendly strategy with a high potential for the remediation of contaminated marine sediments. Here we review the potential application of biosurfactants produced by microbial taxa for the remediation of contaminated marine sediments and we discuss future research needs to develop efficient and eco-sustainable biosurfactant-based strategies for the recovery of contaminated marine sediments, in view of large-scale applications. PMID- 29615276 TI - [CR-POSSUM and Surgical Apgar Score as predictive factors for patients' allocation after colorectal surgery]. AB - BACKGROUND AND OBJECTIVES: Surgical patients frequently require admission in high dependency units or intensive care units. Resources are scarce and there are no universally accepted admission criteria, so patients' allocation must be optimized. The purpose of this study was to investigate the relationship between postoperative destination of patients submitted to colorectal surgery and the scores ColoRectal Physiological and Operative Severity Score for the enUmeration of Mortality and Morbidity (CR-POSSUM) and Surgical Apgar Score (SAS) and, secondarily find cut-offs to aid this allocation. METHODS: A cross-sectional prospective observational study, including all adult patients undergoing colorectal surgery during a 2 years period. Data collected from the electronic clinical process and anesthesia records. RESULTS: A total of 358 patients were included. Median score for SAS was 8 and CR-POSSUM had a median mortality probability of 4.5%. Immediate admission on high-dependency units/intensive care units occurred in 51 patients and late admission in 18. Scores from ward and high dependency units/intensive care units patients were statistically different (SAS: 8 vs. 7, p<0.001; CR-POSSUM: 4.4% vs. 15.9%, p<0.001). Both scores were found to be predictors of immediate postoperative destination (p<0.001). Concerning immediate high-dependency units/intensive care units admission, CR-POSSUM showed a strong association (AUC 0.78, p=0.034) with a >=9.16 cut-off point (sensitivity: 62.5%; specificity: 75.2%), outperforming SAS (AUC 0.67, p=0.048), with a <=7 cut-off point (sensitivity: 67.3%; specificity: 56.1%). CONCLUSIONS: Both CR-POSSUM and SAS were associated with the clinical decision to admit a patient to the high-dependency units/intensive care units immediately after surgery. CR-POSSUM alone showed a better discriminative capacity. PMID- 29615277 TI - Evaluation of sarcopenia in children. PMID- 29615278 TI - Monitoring of the composting process of different agroindustrial waste: Influence of the operational variables on the odorous impact. AB - Composting is a conventional but economical and environmentally friendly way to transform organic waste into a valuable, organic soil amendment. However, the physico-chemical characterization required to monitor the process involves considerable investment in terms of cost and time. In this study, 52 samples of four compostable substrates were collected randomly during the composting process and analyzed physico-chemically. The physico-chemical characterization was evaluated and reduced by principal component analysis (PCA) (PC1 + PC2: 70% variance). Moreover, a study of the relationship between odor and the raw material and odor and the operational variables was carried out at pilot scale using PCA and multivariate regression. The substrates were grouped by PCA (PC1 + PC2: 87% variance). The odor emission rate (OER) and dynamic respirometric index (DRI) were found to be the most influential variables in the sample variance, being relevant to identify the different emission sources. Dynamic respirometry and multivariate regression could be suitable tools to predict these odor emissions for the majority of compostable substrates, identifying successfully the emission source. PMID- 29615279 TI - Challenging the concept of electrochemical discharge using salt solutions for lithium-ion batteries recycling. AB - The use of lithium-ion batteries (LIB) has grown significantly in recent years, making them a promising source of secondary raw materials due to their rich composition of valuable materials such as Co, Ni and Al. However, the high voltage and reactive components of LIBs pose safety hazards during crushing stages in recycling processes, and during storage and transportation. Electrochemical discharge by immersion of spent batteries in salt solutions has been generally accepted as a robust and straightforward discharging step to address these potential hazards. Nonetheless, there is no clear evidence in the literature to support the use of electrochemical discharge in real systems, neither are there clear indications of the real-world limitations of this practice. To that aim, this work presents a series of experiments systematically conducted to study the behavior of LIBs during electrochemical discharge in salt solutions. In the first part of this study, a LIB sample was discharged ex-situ using Pt wires connected to the battery poles and submerged into the electrolyte solution on the opposite end. The evolution of voltage in the battery was measured for solutions of NaCl, NaSO4, FeSO4, and ZnSO4. The results indicate that, among the electrolytes used in the present study, NaCl solution is the most effective for LIBs discharge. The discharge of LIB using sulfate salts is however only possible with the aid of stirring, as deposition of solid precipitated on the electrodes hinder the electrochemical discharge. Furthermore, it was found that the addition of particulates of Fe or Zn as sacrificial metal further enhances the discharging rate, likely due to an increased contact area with the electrolyte solution. While these findings support the idea of using electrochemical discharge as a pre-treatment of LIBs, severe corrosion of the battery poles was observed upon direct immersion of batteries into electrolyte solutions. Prevention of such corrosion requires further research efforts, perhaps focused on a new design-for-recycling approach of LIBs. PMID- 29615280 TI - Comparison of ocular wavefront aberrations in subluxated lenses before and after lens extraction with intraocular lens implantation. AB - PURPOSE: To compare the change in ocular higher-order wavefront aberrations (HOAs), visual acuity, and modulation transfer function (MTF) after lens extraction with intraocular lens (IOL) implantation in patients with subluxated lenses. SETTING: Iladevi Cataract & IOL Research Centre, Ahmedabad, India. DESIGN: Prospective case series. METHODS: Eyes with subluxated lenses having lens extraction with IOL implantation were included. Capsular bag fixation with in-the bag IOL implantation or sutured or sutureless scleral fixation of the IOL was performed. Aberrometry was performed preoperatively and 6 months postoperatively. The following were compared: root-mean-square (RMS) value for total ocular HOAs, coma aberration, spherical aberration, MTF, and corrected distance visual acuity (CDVA). RESULTS: Of the 39 eyes with subluxated lenses, 26 eyes had Cionni ring fixation, 9 had sutured scleral fixation, and 4 had intrascleral fixation of the IOL. The mean preoperative and postoperative values, respectively, were as follows: RMS HOAs, 10.5 MUm +/- 9.5 (SD) and 4.73 +/- 4.6 MUm (P < .001); coma aberration, 2.46 +/- 2.4 MUm and 0.11 +/- 0.1 MUm (P = .03); and spherical aberration, 0.37 +/- 0.9 MUm and 0.02 +/- 0.06 MUm (P = .02). The MTF improved significantly in all eyes (mean 0.05 +/- 0.02 preoperatively and 0.32 +/- 0.16 postoperatively) (P = .005). The CDVA was statistically significant improved 6 months postoperatively. CONCLUSION: Lens extraction with IOL fixation in eyes with subluxated lenses significantly reduced ocular HOAs and improved the MTF. PMID- 29615281 TI - Corneal biomechanics after laser refractive surgery: Unmasking differences between techniques. AB - The hypothesis that small-incision lenticule extraction provides better preservation of corneal biomechanics than previous laser refractive techniques has led to a growth in the interest in clinical and experimental research in this field. This hypothesis is based on the fact that corneal layers with greater stiffness are preserved with this new technique. However, this hypothesis is controversial because clinical research has shown a great disparity in the outcomes. In this review, we performed an in-depth analysis of the factors that might affect corneal biomechanics in laser refractive surgery procedures from a macrostructural to a microstructural viewpoint. New advances in algorithms with current devices or the introduction of new devices might help unmask the possible advantages of small-incision lenticule extraction in corneal biomechanics. PMID- 29615282 TI - Letter to the Editor: Central nervous system relapse rate and dose intensification in poor risk metastatic germ cell tumours-A comment on: 'Patterns of relapse in poor prognosis germ cell tumours in the GETUG-13 trial: Implications for the assessment of brain metastases.' by Loriot and colleagues. PMID- 29615283 TI - Medium throughput cage state stability screen of conditions for the generation of gold nanoparticles encapsulated within a mini-ferritin. AB - Methods for the generation of nanoparticles encapsulated within cage proteins, such as ferritins, provide particles with low polydispersities due to size constraint by the cage. The proteins can provide enhanced water solubility to enable biological applications and affinity and identification tags to facilitate delivery or the assembly of advanced materials. Many effective methods have been developed, however, they are often impeded by cage protein instability in the presence of reagents or conditions for formation of the nanoparticles. Although the stability of ferritin cage quaternary structure can be enhanced, application of ferritins to materials science remains limited by unpredictable behaviour. Recently, we reported a medium throughput technique to directly detect the ferritin cage state. Herein, we expand this strategy to screen conditions commonly used for the formation of gold nanoparticles. Not only do we report nanoparticle formation conditions that permit ferritin stability, we establish a general screening strategy based on protein cage stability that could be applied to other protein cages or for the generation of other types of particles. PMID- 29615284 TI - External Beam Radiotherapy in the Treatment of Gastroenteropancreatic Neuroendocrine Tumours: A Systematic Review. AB - AIMS: External beam radiotherapy (EBRT) is infrequently used to treat gastroenteropancreatic neuroendocrine tumours (GEPNETS), with little published data to date. We carried out a systematic review to assess the activity of EBRT for GEPNETS. MATERIALS AND METHODS: Major databases were searched for papers including at least five patients treated with contemporary EBRT techniques. Eligible studies underwent dual independent review. The primary end points were response rate for lesions treated with definitive intent and recurrence-free survival for primary lesions treated with neoadjuvant or adjuvant intent. RESULTS: Of 11 included studies (all retrospective), seven investigated pancreatic neuroendocrine tumours (PNETs, 100 patients, 14% grade 3) and four studies investigated extra-pancreatic neuroendocrine tumours (84 patients, 14% grade 3). Trials investigating PNETs administered a median of 50.4 Gy via three dimensional conformal radiotherapy and intensity-modulated radiotherapy. EBRT was given with neoadjuvant or adjuvant intent in 56 patients, with a recurrence rate of 15%. For the 44 patients not undergoing surgery, the radiological response rate was 46%. Grade 3 + toxicity rates were 11% (acute) and 4% (late). Twelve patients with anorectal neuroendocrine carcinoma received 58 Gy to the primary tumour. Seventy-two patients were treated to sites of metastatic disease (34 bone, 27 brain, 11 soft tissue). Local and distant control were poorly reported. Overall survival ranged from 9 to 19 months. No studies in this group reported toxicity outcomes. CONCLUSIONS: There are limited, retrospective data on the overall activity and safety of EBRT in GEPNETS. EBRT generally seems to be well tolerated in selected PNET patients with encouraging activity. Well-designed prospective studies in clearly defined populations are required to clarify the role of EBRT in neuroendocrine tumours. PMID- 29615285 TI - Gastric obstruction secondary to an intragastric balloon. PMID- 29615286 TI - Aortoenteric fistula: A worrisome endoscopic finding. PMID- 29615287 TI - Primary pancreatic lymphoma as a cause of obstructive jaundice. PMID- 29615288 TI - Cardiac effects of fish oil in a rat model of streptozotocin-induced diabetes. AB - BACKGROUND AND AIMS: Fish oil (FO) is rich in omega-3 polyunsaturated fatty acids, which have cardio-protective effects. This study aims to evaluate effects of FO in a rat model of streptozotocin (STZ) induced diabetes. METHODS AND RESULTS: Adults male Wistar rats were assigned to control (4 MUl corn oil/g corn oil given by oral gavage), FO (4 MUl Menhaden FO/g body weight given by oral gavage), diabetes (DM, 35 mg/kg STZ single intraperitoneal injection, corn oil), and DM + FO groups for 8 weeks. Plasma and cardiac biomarkers of oxidative stress, inflammation, and fibrosis were evaluated. STZ-induced diabetes as indicated by the significant increase in serum levels of glucose and percentage of glycated hemoglobins. FO reduced plasma arachidonic acid (AA) percentage and ratio of AA: docosahexaenoic acid (DHA). Plasma and cardiac levels of total nitrite, endothelin -1 (ET-1), and myeloperoxidase (MPO) increased in the DM group, whereas cardiac activities of catalase and superoxide dismutase (SOD) decreased. FO reduced cardiac nitrite and MPO, and plasma ET-1 levels. FO increased cardiac glutathione, catalase and SOD activities. Levels of thiobarbituric acid substances increased in the FO and DM groups with significant synergism in the DM + FO group. FO prevented cardiac fibrosis associated with DM and decreased cardiac transforming growth factor beta-1and p38 MAP kinases. Cardiac levels of matrix metalloproteinase -2 were significantly elevated in FO and DM + FO groups. CONCLUSIONS: FO decreased plasma and cardiac oxidative stress, inflammation and myocardial fibrosis. FO could be used in diabetes to reduce risk and burden of CVDs. PMID- 29615289 TI - Fasting and post-glucose load measures of insulin resistance and risk of incident atrial fibrillation: The Cardiovascular Health Study. AB - BACKGROUND AND AIMS: Existing literature in individuals without diabetes has not demonstrated a relationship between IR and incident AF; however, data are limited and only fasting glucose measures of IR were assessed. We evaluated the relationship of both fasting and post-glucose load IR measures with the development of atrial fibrillation in nondiabetic older adults. METHODS AND RESULTS: Among Cardiovascular Health Study participants, a population-based cohort of 5888 adults aged 65 years or older enrolled in two waves (1989-1990 and 1992-1993), those without prevalent AF or diabetes and with IR measures at baseline were followed for the development of AF, identified by follow-up visit electrocardiograms, hospital discharge diagnosis coding, or Medicare claims data, through 2014. Fasting IR was determined by the homeostatic model of insulin resistance (HOMA-IR) and post-glucose load IR was determined by the Gutt index. Cox proportional hazards models were used to determine the association of IR with risk of AF. Analyses included 3601 participants (41% men) with a mean age of 73 years. Over a median follow-up of 12.3 years, 1443 (40%) developed AF. After multivariate adjustment, neither HOMA-IR nor the Gutt index was associated with risk of developing AF [hazard ratios (95% confidence intervals): 0.96 (0.90, 1.03) for 1-SD increase in HOMA-IR and 1.03 (0.97, 1.10) for 1-SD decrease in the Gutt index]. CONCLUSIONS: We found no evidence of an association between either fasting or post-glucose load IR measures and incident AF. PMID- 29615290 TI - Gait training using a hybrid assistive limb (HAL) attenuates head drop: A case report. AB - Dropped head syndrome (DHS) is characterized by a chin-on-chest deformity, which can severely interfere with forward vision and impair activities of daily living. A standardized treatment strategy for DHS has not been established. To our knowledge, this is the first case report describing the efficacy of gait training using a hybrid assistive limb (HAL) for DHS. A 75-year-old man showed apparent head drop in a standing position, resulting in passively reducible chin-on-chest deformity. A radiograph image showed apparent cervical kyphosis. Center of gravity of the head (CGH)-C7 SVA was +115 mm, CL was -40 degrees , and T1S 39 degrees . The patient underwent a treatment program using HAL, in which gait training was mainly performed, 60 min a day, 5 days a week for 2 weeks (10 sessions). After 2-3 sessions, dropped head started to attenuate. At the end of 10 sessions, the patient was able to walk with normal posture and radiograph images showed cervical kyphosis dramatically decreased because of HAL training. CGH-C7 SVA was 42 mm, CL was -1.7 degrees , and T1S was 30 degrees . Three months' outpatient follow-up revealed a slight deterioration of cervical alignment. However, the patient was able to maintain a better cervical alignment than before HAL training and keep walking with forward vision. There were no complications in any HAL treatment session. In conclusion, gait training using HAL is an option for treatment of DHS in addition to previously reported neck extensor muscle training. PMID- 29615291 TI - Supplementation of ram semen extender to improve seminal quality and fertility rate. AB - In sheep, artificial insemination serves as an important technique for breed improvement. In this context, genetic material from a small number of superior sires can be used in a large number of females. During this process, the storage of ram sperm may influence the efficiency of artificial insemination. Two main methods are currently used for ram semen storage: liquid storage and cryopreservation. The oxidative stress during the storage process can injure ram sperm and in some cases this leads to irreversible damage at the cellular level. To reduce such negative effects, different preservation protocols, extenders and protective components have been tested to improve ram sperm quality and to achieve greater fertility rates. This review provides an overview of the recent progress in extender supplementation using antioxidants and other compounds to improve ram semen quality parameters and fertility rates. It will emphasize on enzymes, vitamins, amino acids, proteins, some plant extracts and other compounds such as sugars, seminal plasma and fatty acids that can be used to supplement the extenders to reduce the formation of oxidants in ram semen and maintain its quality and enhance its fertility. It will also stress on how these supplements act, what were the tested levels giving beneficial effects on motility, viability, plasma membrane integrity and DNA fragmentation in liquid, cooled and post-thawing semen? PMID- 29615292 TI - Dynamic Myocardial Response to Exercise in Childhood Cancer Survivors Treated with Anthracyclines. AB - BACKGROUND: Anthracycline cardiotoxicity can cause significant long-term morbidity in childhood cancer survivors (CCS), but many CCS do not manifest clinical symptoms until adulthood. The aims of this study were to characterize the dynamic myocardial response to exercise of CCS at long-term follow-up by combining semisupine bicycle exercise stress echocardiography with myocardial imaging techniques and to establish whether semisupine bicycle exercise stress echocardiography could identify CCS with abnormal exercise response. METHODS: This was a single-center prospective cross-sectional study. One hundred CCS and 51 control subjects underwent semisupine bicycle exercise stress echocardiography. Color Doppler tissue imaging peak systolic (s') and diastolic (e') velocities, myocardial acceleration during isovolumic contraction, and longitudinal strain were measured at rest and at incremental heart rates in the left ventricular (LV) lateral wall, basal septum, and right ventricle. The relationship with increasing heart rate was evaluated for each parameter by plotting the values against heart rate at each stage of exercise. Kernel density estimate was used to establish the normality of the individual CCS exercise responses. RESULTS: At rest, no significant differences were found for LV lateral wall, right ventricular (RV), and basal septal systolic and diastolic velocities between CCS and control subjects. Only septal e' was lower in CCS. LV longitudinal strain was similar between groups, while RV longitudinal strain was lower in CCS. At peak exercise, LV lateral wall, RV, and septal s' were not different between groups, while e' were significantly lower in CCS. LV lateral wall and septal isovolumic acceleration were also reduced in CCS. LV longitudinal strain was different between groups, while RV longitudinal strain was similar. The dynamic response of Doppler tissue imaging velocities, isovolumic acceleration, and strain was similar between CCS and control subjects. Kernel density estimate analysis confirmed that most CCS responses were within the normal range. CONCLUSIONS: At 10-year follow-up, anthracycline-treated CCS with normal baseline ejection fractions have LV and RV systolic and diastolic myocardial exercise response comparable with that of control subjects. Minor differences were observed between CCS and control subjects at rest and at peak exercise, but the dynamic response is within the normal range. PMID- 29615293 TI - Implant stability using piezoelectric bone surgery compared with conventional drilling: a systematic review and meta-analysis. AB - The aim of this systematic review was to assess the primary and secondary stability of dental implants placed at sites prepared with piezoelectric bone surgery (PBS) and conventional drilling (CD). The PubMed/MEDLINE and Cochrane Library databases were searched without date or language restriction up to June 2017. Controlled clinical trials in which each patient received implants placed at sites prepared with both PBS and CD were selected. Implant stability had to be measured on day 0 and during the osseointegration period. Methodological quality was assessed using the Cochrane Collaboration tool. A meta-analysis was performed to compare primary stability (on day 0) and secondary stability (after 2 and 3months) between the two groups. The studies included were determined to have a high risk of bias. There was no significant difference between the two groups for primary stability (on day 0) (P=0.51). After 2 and 3months, secondary stability was statistically higher in implants placed with PBS preparation (P=0.04 and P=0.01, respectively). The implant survival rate was 97.5% in the CD group and 100% in the PBS group. PBS preparation improves secondary stability after 2 and 3months in comparison to CD, with similar implant survival rates. Further studies are needed to determine whether implant osseointegration periods could be shortened with PBS preparation. PMID- 29615294 TI - Increased monocyte to high-density lipoprotein cholesterol ratio is associated with TIMI risk score in patients with ST-segment elevation myocardial infarction. AB - INTRODUCTION AND AIM: The monocyte to high-density lipoprotein cholesterol ratio (MHR) has recently been proposed as a new predictor and prognostic indicator in cardiovascular disease. The TIMI risk score predicts short-term mortality in ST elevation myocardial infarction (STEMI) patients. However, there have been no studies regarding the association between MHR and TIMI score in patients with STEMI. METHODS: A total of 161 patients admitted to our hospital were prospectively enrolled between January 2014 and June 2016. Of these, 111 consecutive patients with a diagnosis of STEMI who underwent primary percutaneous coronary intervention (PCI) were selected as the STEMI group, and the remaining 50 patients, who had angiographically normal coronary arteries, were selected as the control group. The 111 STEMI patients were then divided into two subgroups based on TIMI scores. RESULTS: MHR was significantly higher in the STEMI group than in the control group (1.71+/-0.47 vs. 2.21+/-0.98, p=0.001) and was significantly higher in the high TIMI score group than in the low TIMI score group (1.80+/-0.59 vs. 2.42+/-1.09, p=0.001). In multivariate logistic regression analysis, MHR was the only independent predictor of acute STEMI and high TIMI score. In correlation analysis, there was a significant positive correlation between MHR and TIMI score in STEMI patients (r=0.479, p<0.001). The cutoff value of MHR for high TIMI score in patients with STEMI was 2.409, with a sensitivity of 43.06% and a specificity of 87.18% (AUC 0.669; 95% CI 0.569-0.8769; p=0.003) on ROC curve analysis. CONCLUSION: This study indicates that MHR is independently and significantly associated with TIMI score in patients with STEMI. MHR is a novel inflammation-based marker and may be an independent predictor of future cardiovascular events in patients with STEMI. PMID- 29615296 TI - Reexamining post-transplant lymphoproliferative disorders: Newly recognized and enigmatic types. AB - Post-transplant lymphoproliferative disorders (PTLD) are a known risk for both solid organ transplant and stem cell transplant recipients. Overall transplant recipients have a six fold increase in risk for developing any kind of non Hodgkin lymphoma and PTLDs occur in up to 10% of SOT recipients. Several new entities have been accepted or renamed in the 2018 update of the WHO classification of tumors of hematopoietic and lymphoid neoplasms, including florid follicular hyperplasia and extranodal marginal zone lymphomas of mucosa associated lymphoid tissue (MALT-lymphoma) (excluding common locations such as stomach and salivary gland). Other more rare types of PTLD have been reclassified including EBV-positive mucocutaneous ulcer, which is now a recognized diagnosis in its own right and should not be considered polymorphous PTLD. In this paper newly recognized PTLD entities and more unusual PTLDs will be examined. PMID- 29615295 TI - Radiologic and pathologic response to neoadjuvant chemotherapy predicts survival in patients undergoing the liver-first approach for synchronous colorectal liver metastases. AB - PURPOSE: To investigate the short- and long-term outcomes of liver first approach (LFA) in patients with synchronous colorectal liver metastases (CRLM), evaluating the predictive factors of survival. METHODS: Sixty-two out of 301 patients presenting with synchronous CRLM underwent LFA between 2007 and 2016. All patients underwent neoadjuvant chemotherapy. After neoadjuvant treatment patients were re-evaluated according to the Response Evaluation Criteria in Solid Tumors (RECIST). Liver resection was scheduled after 4-6 weeks. Changes in non-tumoral parenchyma and the tumor response according to the Tumor Regression Grade score (TRG) were assessed on surgical specimens. Primary tumor resection was scheduled 4-8 weeks following hepatectomy. RESULTS: Five patients out of 62 (8.1%) showed "Progressive Disease" at re-evaluation after neoadjuvant chemotherapy, 22 (35.5%) showed "Stable Disease" and 35 (56.5%) "Partial Response"; of these latter, 29 (82%) showed histopathologic downstaging. The 5-year survival (OS) rate was 55%, while the 5-year disease-free survival (DFS) rate was 16%. RECIST criteria, T stage, N-stage and TRG were independently associated with OS. Bilobar presentation of disease, RECIST criteria, R1 margin and TRG were independently associated with DFS. Patients with response to neoadjuvant chemotherapy had better survival than those with stable or progressive disease (radiological response 5-y OS: 65% vs. 50%; 5-y DFS: 20% vs. 10%; pathological response 5-y OS: 75% vs. 56%; 5-y DFS: 45% vs. 11%). CONCLUSIONS: LFA is an oncologically safe strategy. Selection is a critical point, and the best results in terms of OS and DFS are observed in patients having radiological and pathological response to neoadjuvant chemotherapy. PMID- 29615298 TI - Urate and the risk of Parkinson's disease in men and women. AB - INTRODUCTION: High urate levels have consistently been associated with lower Parkinson's disease (PD) risk among men, but the association is less clear among women. In this study we prospectively investigated the association between high uric acid levels and PD, evaluating potential differences by sex and age. METHODS: This historical cohort study included the entire Norwegian population alive and at least 18 years old on 01/01/2004. We retrieved use of urate-lowering drugs, a marker of high urate levels/gout, from the Norwegian Prescription Database, and followed individuals from 01/01/2005 to PD onset, emigration, death, or end of follow-up on 31/12/2013. We identified 4523 incident PD cases during follow-up, and used Cox regression to estimate hazard ratios (HRadj) and 95% confidence intervals (CI), adjusting for sex, age, and level of education. We also tested for effect modification by sex and age. RESULTS: Exposure to urate lowering drugs was associated with a significantly lower PD risk (HRadj = 0.80, 95% CI: 0.68-0.95). The association was more marked in men (HRadj = 0.77, 95% CI: 0.63-0.94), compared to women (HRadj = 0.89, 95% CI: 0.65-1.22), but the difference was not significant (p for effect modification = 0.61). The association varied significantly by age among women (p = 0.01) with a protective effect suggested only at higher age (above 70 years) when urate levels are higher than premenopausally (HR = 0.65, 95% CI: 0.41-1.03), but not in men (p = 0.61). CONCLUSION: These findings suggest that urate may be protective against PD in both men and women. PMID- 29615299 TI - Procedures for central auditory processing screening in schoolchildren. AB - INTRODUCTION: Central auditory processing screening in schoolchildren has led to debates in literature, both regarding the protocol to be used and the importance of actions aimed at prevention and promotion of auditory health. Defining effective screening procedures for central auditory processing is a challenge in Audiology. OBJECTIVE: This study aimed to analyze the scientific research on central auditory processing screening and discuss the effectiveness of the procedures utilized. METHODS: A search was performed in the SciELO and PUBMed databases by two researchers. The descriptors used in Portuguese and English were: auditory processing, screening, hearing, auditory perception, children, auditory tests and their respective terms in Portuguese. INCLUSION CRITERIA: original articles involving schoolchildren, auditory screening of central auditory skills and articles in Portuguese or English. EXCLUSION CRITERIA: studies with adult and/or neonatal populations, peripheral auditory screening only, and duplicate articles. After applying the described criteria, 11 articles were included. RESULTS: At the international level, central auditory processing screening methods used were: screening test for auditory processing disorder and its revised version, screening test for auditory processing, scale of auditory behaviors, children's auditory performance scale and Feather Squadron. In the Brazilian scenario, the procedures used were the simplified auditory processing assessment and Zaidan's battery of tests. CONCLUSION: At the international level, the screening test for auditory processing and Feather Squadron batteries stand out as the most comprehensive evaluation of hearing skills. At the national level, there is a paucity of studies that use methods evaluating more than four skills, and are normalized by age group. The use of simplified auditory processing assessment and questionnaires can be complementary in the search for an easy access and low-cost alternative in the auditory screening of Brazilian schoolchildren. Interactive tools should be proposed, that allow the selection of as many hearing skills as possible, validated by comparison with the battery of tests used in the diagnosis. PMID- 29615297 TI - Is there synergy in syndemics? Psychosocial conditions and sexual risk among men who have sex with men in India. AB - Syndemic theory describes the clustering and synergistic interaction of disease driven by contextual and social factors, which worsen health outcomes for a population, and has been applied to men who have sex with men (MSM) and their risk for HIV and other sexually transmitted infections. Recent reviews, however, have critiqued prevailing approaches in syndemic studies that assess only additive associations without evaluation of synergy. Following these suggestions, we compared the traditional additive approach with a test for synergistic association of 5 syndemic conditions (alcohol dependence, illicit drug use, depression, intimate partner violence (IPV), and childhood sexual abuse (CSA)) with unprotected anal intercourse (UAI) and active syphilis infection among 11,771 MSM recruited through respondent driven sampling from 12 cities in India. UAI was assessed via self-report and active syphilis infection was diagnosed by RPR and THPA tests. An additive association was explored using a condition count (range 0-5), and synergy was tested using relative excess risk due to interactions (RERIs) calculated from all 2-way and common 3-way interactions between conditions in adjusted regression models. There was a significant dose response associated with the syndemic count and UAI, and a similar pattern for syphilis, though not statistically significant. RERIs showed synergy for only one pair of conditions for UAI and syphilis, respectively: IPV + depression and alcohol dependence + illicit drug use. In this study, we found an additive association between syndemic conditions and UAI with evidence of synergistic interaction between a pair of psychosocial conditions, and no significant additive association, but a synergistic interaction between another pair of psychosocial conditions for syphilis. Our results lend further support to a critical reassessment of syndemic analyses. Closer attention to the cumulative development, underlying causal pathways, and possible synergistic interaction of co-occurring epidemics through combined qualitative and quantitative methodologies may yield more effective interventions for vulnerable, marginalized populations. PMID- 29615300 TI - The Deep State of Self-Transformation. PMID- 29615301 TI - Early onset sporadic colorectal cancer: Worrisome trends and oncogenic features. AB - Early onset colorectal cancers, defined as arising before 50 years of age, are a growing health hazard in western and eastern countries alike. The incidence of colon and rectal cancers in young individuals is projected to increase by as much as 90% and 140%, respectively, by 2030. Although several known cancer risk factors (e.g. smoking, alcohol, dietary habits) have been investigated, there is no single compelling explanation for this epidemiological trend. While some early onset colorectal cancers have been associated with germline mutations in cancer predisposition genes, genetic syndromes are implicated in only a fraction of these cancers (20%) and do not explain the rising incidence. Colorectal neoplasms develop through microsatellite instability or chromosomal instability pathways, with most of the early onset colorectal cancers exhibiting microsatellite stable phenotypes. Genome-wide hypomethylation is a feature of a subgroup of early onset cancers, which appears to be correlated with chromosomal instability and poor prognosis. PMID- 29615302 TI - The Endothelial-Metabolic Axis: A Novel Cardiometabolic Disease Target. AB - Endothelial to mesenchymal transition (EndMT) involves cellular phenotypic switching from an endothelial to mesenchymal state. Interest in EndMT has been increasing with the appreciation that it has an important role in several cardiovascular diseases. New evidence indicates that fatty acid oxidation (FAO) and cell metabolism are major factors controlling this process. PMID- 29615303 TI - Early TCR Signaling Sweetens Effector Function through PDHK1. AB - T cells rapidly engage glycolysis upon activation. The signaling pathways through which T cell receptor (TCR) activation initiates glycolysis have been a mystery. A long-awaited answer has been provided by Menk et al., who show that pyruvate dehydrogenase kinase 1 (PDHK1) is in the center of signaling events linking TCR activation to glycolysis. PMID- 29615304 TI - Corneal Changes in Trastuzumab Emtansine Treatment. PMID- 29615305 TI - Early Stage HER2-Positive Breast Cancers Not Achieving a pCR From Neoadjuvant Trastuzumab- or Pertuzumab-Based Regimens Have an Immunosuppressive Phenotype. AB - BACKGROUND: Stromal tumor-infiltrating lymphocytes (TILs) might predict pathologic complete response (pCR) in patients with HER2-positive (HER2+) breast cancer treated with trastuzumab (H). Docetaxel (T), carboplatin (C), H, and pertuzumab (P) have immune-modulating effects. Pre- and post-treatment immune biomarkers in cancers treated with neoadjuvant TCH with or without P are lacking. In this study we quantified baseline and changes in TILs, cluster of differentiation (CD) 4+, CD8+, FoxP3+, and PD-L1+ cells using immunohistochemistry (IHC) and quantified productive T-cell receptor beta (TCRbeta) rearrangements and TCRbeta clonality using next-generation sequencing (NGS) in 30 HER2+ breast cancer tissues treated with neoadjuvant H with or without P regimens. MATERIALS AND METHODS: Thirty pre- and post-neoadjuvant TCH (n = 4) or TCHP (n = 26) breast cancer tissues were identified. TILs were quantified manually using hematoxylin and eosin. CD4, CD8, FoxP3, and PD-L1 were stained using IHC. TCRbeta was evaluated using NGS. Immune infiltrates were compared between pCR and non-pCR groups using the Wilcoxon rank sum test. RESULTS: A pCR occurred in 15 (n = 15; 50%) cancers (TCH n = 2; TCHP, n = 13). Pretreatment TILs, CD4+, CD8+, FoxP3+, and PD-L1+ cells were not associated with response (P = .42, P = .55, P = .19, P = .66, P = .87, respectively. Pretreatment productive TCRbeta and TCRbeta clonality did not predict response, P = .84 and P = .40, respectively). However, post-treatment CD4+ and FoxP3+ cells (T-regulatory cells) were elevated in the non-pCR cohort (P = .042 and P = .082, respectively). CONCLUSION: An increase in regulatory T cells in non-pCR tissues suggests the development of an immunosuppressive phenotype. Further investigation in a larger cohort of samples is warranted to validate these findings. PMID- 29615306 TI - Structural Equation Modeling to Explore Patient to Staff Ratios as an Explanatory Factor for Variation in Dialysis Facility Outcomes. AB - OBJECTIVE: Patient to staff ratios vary based on facility characteristics, and therefore have been proposed as an explanatory factor for the variation in dialysis facility outcomes. This analysis tested that hypothesis. DESIGN AND METHODS: Observational study using Dialysis Facility Report data. Reported staff numbers from the Annual Facility Survey were converted to full time equivalents (FTE). Subsequently, ratios were created for patients per FTE registered dietitian (RD), social worker, nurse, and patient care technician. Bivariate associations and structural equation modeling (SEM) were used to explore relationships between these ratios and patient outcomes: standardized mortality ratio and standardized hospitalization rate, when also considering the impact of non-modifiable facility characteristics (region, chain, profit status). Our focus was on RD staffing; therefore we also included serum phosphorus and normalized protein catabolic ratio in the model, and also conducted a sub-analysis of the 198 facilities that exceeded the KDOQI maximum of 150 patients:FTE RD. SUBJECTS: Dialysis centers in the US with at least 30 adult patients and no pediatric patients. 4035 facilities had complete data for the proposed variables. MAIN OUTCOME MEASURE: Standardized mortality ratio and standardized hospitalization rate were the primary outcomes. RESULTS: The mean and standard deviation for patients per FTE staff were 90.0 +/- 34.0, 88.7 +/- 32.8, 17.1 +/- 20.5 and 11.9 +/- 7.0 for RDs, social workers, nurses, and technicians, respectively. Facility characteristics impacted staffing in bivariate analyses and SEM. The only significant paths from staffing ratio to outcomes were for patient:FTE social worker to SMR (standardized beta = -0.09, 95% CI -0.13, -0.04) and Patients:FTE RD to SHR Days (standardized beta = 0.04, 95% CI 0.001, 0.09). In the sub analysis, there were no significant paths from staffing to outcomes. CONCLUSIONS: This study did not provide evidence that patient per staff ratios explain variation in dialysis facility outcomes. While there are some important bivariate relationships, these disappear in more complex models. Future research should investigate the impacts of staffing ratios on individual patients, to overcome the possible ecological fallacy. PMID- 29615307 TI - Reply to "Relationship between age and nerve dimensions in Charcot-Marie-Tooth disease. Do we know the reality?" PMID- 29615308 TI - High abnormal rate in the repetitive nerve stimulation test in acute onset myasthenia gravis. PMID- 29615309 TI - Metformin-associated lactic acidosis: Are we looking in the right direction? PMID- 29615310 TI - Meta-analysis of Modified FOLFIRINOX Regimens for Patients With Metastatic Pancreatic Cancer. AB - BACKGROUND: We performed a meta-analysis of previous reports evaluating the effect of mFIO (modified FOLFIRINOX; leucovorin, 5-fluorouracil, irinotecan, oxaliplatin) regimens in advanced pancreatic cancer. MATERIALS AND METHODS: We performed a meta-analysis of reported studies in PubMed, Scopus, and Web of Science (1950-2016) in December 2016. The inclusion criteria were randomized trials, prospective or retrospective cohorts, patients with metastatic pancreatic adenocarcinoma, the use of mFIO or FOLFIRINOX (FIO) chemotherapy, and available information for >= 1 efficacy endpoint (response rate, progression-free survival, and/or overall survival). The outcomes were compared according to the chemotherapy regimen using a random effects model. We also performed a meta regression analysis to evaluate the effect of dose reductions on outcomes. RESULTS: Of 2525 abstracts, 32 were considered eligible. Modifications in the FIO regimen included omission of the 5-fluorouracil bolus and/or dose reductions in infusional 5-fluorouracil, irinotecan, and/or oxaliplatin. mFIO was not associated with inferior response rates (32% vs. 33%; P = .879), lower rates of survival at 11 months (47% vs. 50%; P = .38), or lower 6-month progression-free survival rates (47% vs. 53%; P = .38). The meta-regression of the percentage of dose reduction failed to show any association. CONCLUSION: The results of the present meta-analysis with a combined sample size of 1461 patients suggest that it is reasonable to consider mFIO regimens for patients with metastatic pancreatic adenocarcinoma. PMID- 29615311 TI - MR imaging of hemorrhage associated with acute pancreatitis. AB - PURPOSE: To study MRI findings of hemorrhage in acute pancreatitis (AP) and correlate the presence and extent of hemorrhage with the MR severity index (MRSI), Acute Physiology And Chronic Health Evaluation (APACHE) II scores, and clinical outcome. MATERIALS AND METHODS: This retrospective study included 539 patients with AP. Hemorrhage was defined as areas of hyperintensity in or outside the pancreas on liver imaging with volume acceleration flexible (LAVA-Flex). The presence of hemorrhage was classified into three areas: within the pancreatic parenchyma, retroperitoneal space, and sub-or intraperitoneal space. Involvement of each area was awarded 1 point resulting in the hemorrhage severity index (HSI) score. The predicted severity of AP was graded by MRSI and APACHE II score. The association between HSI, MRSI, and APACHE II scores was analyzed. The length of hospital stay and organ dysfunction was used as clinical outcome parameters. RESULTS: Among 539 AP patients, 62 (11.5%) had hemorrhage. The prevalence of hemorrhage was 1.1% (2/186), 13.9% (43/310), and 39.5% (17/43) in predicted mild, moderate, and severe AP, respectively, based on MRSI (chi2 = 55.3, p = 0.00); and 7.7% (21/273) and 19.2% (18/94) in predicted mild and severe AP, respectively, based on APACHE II (chi2 = 21.2, p = 0.00). HSI score significantly correlated with MRSI (r = 0.36, p < 0.001) and APACHE II scores (r = 0.21, p = 0.00). The prevalence of organ dysfunction was higher and length of hospital stay was longer in patients with hemorrhage than in those without hemorrhage (p < 0.01). CONCLUSIONS: Hemorrhage in AP is common. The presence of hemorrhage, rather than its extent, correlates with poor clinical outcome. PMID- 29615312 TI - Integrated microRNA and mRNA expression profile analysis of tumor-associated macrophages after exposure to single-dose irradiation. AB - BACKGROUND: Radiotherapy (RT) is a common approach that accounts for nearly 50% of cancer patient treatment and has the potential for long-term tumor control. Recently, we published a research article on gene expression profiling of tumor associated macrophages (TAM) that were exposed to ionizing radiation (IR). Single dose irradiation of tumors could initiate differentially expressed genes in TAM as a time series from irradiated tumors that are associated with the immune response. It is also well known that human cancers are associated with microRNA (miRNA) alterations that are involved in cancer progression. However, the role of miRNA on TAM after exposure to irradiation remains unclear. RESULTS: In this study, miRNA expression profiles from microarrays were used to identify the key miRNAs and correlating pathways involved in the role of TAMs in tumor progression and recurrence after RT. Using a mouse tumor model, we identified miRNA pattern changes over time in response to irradiation. Based on our results, we hypothesize that miRNA expression in the irradiated tumor may be used as a distinguishing marker to indicate the best time for therapeutic intervention to prevent tumor recurrence after RT. CONCLUSIONS: We established a murine model irradiated with a single dose of 25 Gy that could initiate temporal changes in the expression of miRNAs associated with cell proliferation and the immune response, as evidenced by macrophages directly extracted from irradiated tumors after two weeks of IR. Statistical analyses were conducted by comparing the miRNA expression in macrophages from non-irradiated versus irradiated tumors. Thus, our study could lead to a better understanding of the function of miRNA expressions, which changed temporally in an irradiated tumor microenvironment. PMID- 29615313 TI - [Aberrant birth of a radial artery in the upper third of the forearm: A case report]. AB - We report the case of a 68-year-old patient, operated on in our department of a quadruple coronary bypass grafting. The grafting strategy consisted initially on harvesting the left internal thoracic artery and the left radial artery. The harvest of this latter failed because of a rare anatomical variation of the radial artery, which rose from the confluence of two branches: a superficial and a deep radial artery at the proximal third of the forearm approximately 10cm below the elbow. PMID- 29615314 TI - Exercise after Aortic Dissection: to Run or Not to Run. PMID- 29615315 TI - The use of buccal fat pad in surgical treatment of 'Krokodil' drug-related osteonecrosis of maxilla. AB - 'Krokodil' is the street name of a new synthetic drug mixture. It is a light brown liquid that is used intravenously without previous purification. Osteonecrosis of the jaw (ONJ) is a common complication among Krokodil users. Krokodil drug-related ONJ presents as alveolar process exposure in the oral cavity. Surgery is the main method for treatment of Krokodil drug-related ONJ patients. In a study by Poghosyan et al., no cases of recurrence were seen after surgery on the maxilla, but 38% of cases (8/21) developed an oroantral communication after surgical treatment for maxillary osteonecrosis (Poghosyan et al., 2014). The aim of this study is to report on the results of buccal fat pad use in closure of maxillary sinus floor defects after partial maxillary resection in Krokodil drug-related ONJ patients. Six male patients with Krokodil drug related distal maxillary osteonecrosis were included in this retrospective study. All patients underwent surgical treatment, which included surgical removal of necrotic bone, and closure of formed maxillary sinus floor defects with buccal fat pad and local mucoperiosteal flaps. In all patients the postoperative period was uneventful. After suture removal small areas of buccal fad pad exposure were found in all patients, which epithelialized successfully over the following month. During the postoperative follow-up period (8-12 months) no signs of recurrence were found. PMID- 29615316 TI - 18F-FDG PET and histopathologic findings in a patient with severe fever with thrombocytopenia syndrome. AB - We report on a patient with severe fever with thrombocytopenia syndrome who fully recovered. Imaging with 2-deoxy-2-fluoro-glucose positron emission tomography showed hypermetabolism in regional lymph nodes and the spleen. Histopathological findings of affected lymph nodes showed subacute necrotizing lymphadenitis and the presence of virus-infected cells. PMID- 29615317 TI - Interleukin-10 as a novel biomarker of metabolic risk factors. AB - BACKGROUND: Interleukin-10 (IL-10) is an adipocytokine that is abundantly expressed in visceral fat tissue. We investigated the association of interleukin 10 with the number of metabolic risk factors. FINDING: The study population comprised 220 children who underwent annual health checkups. Plasma Interleukin 10 levels were determined by enzyme-linked immunosorbent assay. We divided the subjects into 4 groups according to Interleukin-10 levels. A reduction of plasma interleukin-10 levels significantly correlated with an increase in the mean number of metabolic risk factors such as increased waist circumference, BMI, dyslipidaemia, high blood pressure and glucose intolerance. CONCLUSIONS: Circulating Interleukin-10 levels negatively correlated with the multiplicity of metabolic risk factors, suggesting that IL-10 acts as a biomarker of metabolic disorders. PMID- 29615318 TI - Effect of vitamin D supplementation on anthropometric indices among overweight and obese women: A double blind randomized controlled clinical trial. AB - AIMS: The aim of this study was to investigate effect of vitamin D supplementation on anthropometric indices among women with overweight and obesity. METHODS: This double blind randomize clinical trial was conducted on 66 overweight and obese women. Those in intervention group received oral supplement of vitamin D 50,000 IU (1250 mcg) per 25 day and in control group participants received placebo for 3 months. Anthropometric indices were measured before and after 3 months intervention. Before the intervention a 24-h dietary recall (3 days) were used to assess dietary intake of individuals. Independent t test and multivariate repeated measure were used to data analysis. RESULTS: The mean difference of anthropometric indices, serum calcium, 25 (OH) D3 and serum PTH between the intervention and control groups were significant (P < 0/05). However, no significant differences in serum phosphorus between the intervention and control groups were seen. CONCLUSION: Supplementation with vitamin D 50 MUg for each day for 3 months resulted in a significant reduction in anthropometric indices in women with obesity and overweight with normal primary 25(OH) D3 serum levels. PMID- 29615319 TI - Mechanochemical synthesis of covalent organic framework for the efficient extraction of benzoylurea insecticides. AB - A covalent organic framework named TpAzo was successfully fabricated by a simple and environmentally friendly mechanochemical grinding method based on the Schiff base aldehyde-amine condensation reaction between 1,3,5-triformylphloroglucinol (Tp) and 4,4'-azodianiline (Azo), with p-toluene sulphonic acid as a molecular organizer. The TpAzo was characterized by scanning electron microscopy, transmission electron microscopy, powder X-ray diffraction, nitrogen adsorption desorption isotherms, and thermogravimetric analysis. The TpAzo possessed a sheet like morphology, rich porosity and high thermal stability. The extraction performance of the TpAzo was investigated by using it as the solid phase extraction adsorbent for the extraction of benzoylurea insecticides (BUs) from juice, tomato and white radish samples prior to high performance liquid chromatographic analysis. Under the optimal conditions, a good linearity for the BUs existed in the range of 1.0-160.0 ng mL-1 for juice sample and 0.5-80.0 ng g 1 for tomato and white radish samples with the correlation coefficients of 0.9956 0.9999. The limits of detection for the analytes were 0.1-0.2 ng mL-1 for juice sample and 0.05-0.1 ng g-1 for tomato and white radish samples. The method recoveries for the analytes fell in the range of 84.1%-108.6%. The adsorption mechanism of the TpAzo was investigated by using it to extract different types of organic compounds, including phthalates, phenylurea herbicides and carbamate insecticides. The results showed that the pi-stacking and hydrophobic interactions between the TpAzo and the analytes played an important role for the adsorption. PMID- 29615320 TI - Co-Al bimetallic hydroxide nanocomposites coating for online in-tube solid-phase microextraction. AB - The Co-Al bimetallic hydroxide nanocomposites were synthesized and used as in tube solid-phase microextraction coating. The nanocomposites-coated fibers were packed in a PEEK tube and tested for the extraction of eight polycyclic aromatic hydrocarbons (PAHs) coupled with high performance liquid chromatography. Several parameters affecting the PAHs extraction including the sampling volume, sampling flow rate, methanol content and desorption time were investigated. Under the optimized conditions, the extraction tube with nanocomposites coating exhibited remarkable extraction performance towards PAH targets. An online analysis method was achieved with the limits of detection less than 0.02 MUg L-1 and the linearity in the range from 0.03 to 15 MUg L-1. The recoveries of the method for two water samples with spiking levels of 1 and 10 MUg L-1 ranged from 83 to 121%. Extraction repeatability and preparation repeatability were less than 4.0% and 10.9%, respectively. PMID- 29615321 TI - Graphene-coated polystyrene-divinylbenzene dispersive solid-phase extraction coupled with supercritical fluid chromatography for the rapid determination of 10 allergenic disperse dyes in industrial wastewater samples. AB - Allergenic disperse dyes are a group of environmental contaminants, which are toxic and mutagenic to human beings. In this work, a method of dispersive solid phase extraction (d-SPE) using graphene-coated polystyrene-divinylbenzene (G@PS DVB) microspheres coupled with supercritical fluid chromatography (SFC) was proposed for the rapid determination of 10 allergenic disperse dyes in industrial wastewater samples. G@PS-DVB microspheres were synthesized by coating graphene (G) sheets onto polystyrene-divinylbenzene (PS-DVB) polymers. Such novel sorbents were employed in d-SPE for the purification and concentration of allergenic disperse dyes in wastewater samples prior to the determination by SFC with UV detection. To achieve the maximum extraction efficiency for the target dyes, several parameters influencing d-SPE process such as sorbent dosage, extraction time, desorption conditions were investigated. SFC conditions including stationary phase, modifier composition and percentage, column temperature, backpressure and flow rate were optimized to well separate the allergenic disperse dyes. Under the optimum conditions, satisfactory linear relationship (R >= 0.9989) was observed with the concentration of dyes ranging from 0.02 to 10.0 MUg/mL. The limits of detection (LOD, S/N = 3) for the ten dyes were in the range of 1.1-15.6 ng/mL. Recoveries for the spiked samples were between 89.1% and 99.7% with relative standard deviations (RSD) lower than 10.5% in all cases. The proposed method is time-saving, green, precise and repeatable for the analysis of the target dyes. Furthermore, the application of G@PS-DVB based d-SPE process can be potentially expanded to isolate and concentrate other aromatic compounds in various matrices and supercritical fluid chromatography methodology featuring rapidity, accuracy and green will be an ideal candidate for the analysis of these compounds. PMID- 29615322 TI - Mixed hemimicelle solid-phase extraction based on magnetic halloysite nanotubes and ionic liquids for the determination and extraction of azo dyes in environmental water samples. AB - An effective and greener mixed hemimicelles magnetic solid phase extraction (MHMSPE) based on magnetic halloysite nanotubes (MHNTs) and ionic liquid (IL) is developed for the simultaneous enrichment and determination of anionic azo dyes in a spiked environmental water sample. In this MHMSPE, the formation of C16mimBr with mixed hemimicelles on the surface of MHNTs leads to the retention of analytes by strong hydrophobic, p-p and electrostatic interactions. This MHMSPE technique combines the advantages of MHNTs and mixed hemimicelles. Zeta potential data demonstrated that mixed hemimicelles were formed in [C16mimBr]/[MHNTs] ratios of the range from 0.15 to 1.33. Different important factors affecting the preconcentration of analytes were investigated and optimized by response surface methodology and one variable at a time. Under the optimum conditions, the limits of detection (LOD) for methyl red and methyl orange (MR and MO) were 0.042 and 0.050 MUg L-1 in samples, respectively. The accuracy of the method was assessed by recovery measurements on a spiked sample, and good recoveries 85-87% for MR and 89-93% for MO, with preconcentration factors of 481 and 524, respectively. The low relative standard deviations from 1.6-3.1% for tap water and 2.5-5.4% for lake water was achieved. So far as we know, this is the first development of a mixed hemimicelles SPE based on MHNTs and IL for the extraction of trace anionic azo dyes in environment water samples. PMID- 29615323 TI - A screening method for cardiovascular active compounds in marine algae. AB - The interaction of bioactive compounds from ethanolic extracts of selected marine algae samples, separated on chromatographic plates, with nitric/nitrous acid was investigated. The nature of bioactive compounds in the marine algae extracts was characterised using UV absorption spectra before and after reaction with diluted nitric acid, and from the characteristic colour reaction after derivatization with anisaldehyde. It was found that diterpenes from Dictyota dichotoma, an edible brown algae, and sterols from green algae Caulerpa brachypus, bind nitric oxide and may act as a nitric oxide carrier. Although the carotenoid fucoxanthin, found in all brown marine algae also binds nitric oxide, the bonds between nitrogen and the fucoxanthin molecule are much stronger. Further studies are required to evaluate the effects of diterpenes from Dictyota dichotoma and sterols from green algae Caulerpa brachypus to see if they have beneficial cardiovascular effects. The method reported here should prove useful in screening large numbers of algae species for compounds with cardiovascular activity. PMID- 29615324 TI - Comparing the accuracy (trueness and precision) of models of fixed dental prostheses fabricated by digital and conventional workflows. AB - PURPOSE: This study aimed to evaluate and compare the accuracy. METHODS: A reference model was prepared with three prepared teeth for three types of restorations: single crown, 3-unit bridge, and inlay. Stone models were fabricated from conventional impressions. Digital impressions of the reference model were created using an intraoral scanner (digital models). Physical models were fabricated using a three-dimensional (3D) printer. Reference, stone, and 3D printed models were subsequently scanned using an industrial optical scanner; files were exported in a stereolithography file format. All datasets were superimposed using 3D analysis software to evaluate the accuracy of the complete arch and trueness of the preparations. One-way and two-way analyses of variance (ANOVA) were performed to compare the accuracy among the three model groups and evaluate the trueness among the three types of preparation. RESULTS: For the complete arch, significant intergroup differences in precision were observed for the three groups (p<.001). However, no significant difference in trueness was found between the stone and digital models (p>.05). 3D printed models had the poorest accuracy. A two-way ANOVA revealed significant differences in trueness among the model groups (p<.001) and types of preparation (p<.001). CONCLUSIONS: Digital models had smaller root mean square values of trueness of the complete arch and preparations than stone models. However, the accuracy of the complete arch and trueness of the preparations of 3D printed models were inferior to those of the other groups. PMID- 29615325 TI - Consistency and Generalizability of Dietary Patterns in a Multiethnic Working Population. AB - BACKGROUND: Dietary pattern analysis is a complementary method to nutrient analysis in evaluating overall diet-disease hypotheses. Although studies have been conducted to derive dietary patterns among Malaysians, their consistency across subgroups has not been examined. OBJECTIVE: The study aimed to derive dietary patterns empirically and to examine the consistency and generalizability of patterns across sex, ethnicity, and urban status in a working population. DESIGN: This was a cross-sectional study using data from the Clustering of Lifestyle Risk Factors and Understanding its Association with Stress on Health and Well-Being among School Teachers in Malaysia study collected between August 2014 and November 2015. Dietary intake was assessed using a food frequency questionnaire, and dietary patterns were derived using factor analysis. PARTICIPANTS/SETTING: Participants were teachers from selected public schools from three states in Peninsular Malaysia (n=4,618). MAIN OUTCOME MEASURES: Dietary patterns derived using factor analysis. STATISTICAL ANALYSES PERFORMED: Separate factor analysis was conducted by sex, ethnicity, and urban status to identify dietary patterns. Eigenvalue >2, scree plot, Velicer's minimum average partial analysis, and Horn's parallel analysis were used to determine the number of factors to retain. The interpretability of each dietary pattern was evaluated. The consistency and generalizability of dietary patterns across subgroups were assessed using the Tucker congruence coefficient. RESULTS: There was no subgroup specific dietary pattern found. Thus, dietary patterns were derived using the pooled sample in the final model. Two dietary patterns (Western and Prudent) were derived. The Western dietary pattern explained 15.4% of total variance, characterized by high intakes of refined grains, animal-based foods, added fat, and sugar-sweetened beverages as well as fast food. The Prudent dietary pattern explained 11.1% of total variance and was loaded with pulses, legumes, vegetables, and fruits. CONCLUSIONS: The derived Western and Prudent dietary patterns were consistent and generalizable across subgroups of sex, ethnicity, and urban status. Further research is needed to explore associations between these dietary patterns and chronic diseases. PMID- 29615326 TI - Characterization of centriole duplication in human epidermis, Bowen's disease, and squamous cell carcinoma. AB - BACKGROUND: Centrosomes contain two centrioles: a pre-existing mature centriole and a newly formed immature centriole. Each centriole is duplicated once within a cell cycle, which is crucial for proper centrosome duplication and cell division. OBJECTIVE: To describe the centrosome duplication cycle in human epidermis, Bowen's disease (BD), and squamous cell carcinoma (SCC). METHODS: Immunofluorescent staining of centriolar proteins and Ki-67 was used to evaluate cell cycles and the number of centrioles. Centrobin and Outer dense fiber of sperm tails 2 (ODF2) were used as markers for immature and mature centrioles, respectively. RESULTS: Normal human primary epidermal keratinocytes in a monolayered culture have one centrobin+ centriole (CTRB1+ cells) supposed in G0/G1 phases or have two centrobin+ centrioles (CTRB2+ cells) supposed in S-G2 phase. In a three-dimensional culture and in vivo human epidermis, the majority of suprabasal cells were CTRB2+ cells, in spite of their non-proliferative Ki-67- nature. The tumor mass of BD and SCC contained CTRB1+ cells and Ki-67+ proliferating and Ki-67- non-proliferative CTRB2+ cells. Clumping cells in BD had increased numbers of centrioles, with an approximate 1:1 to 2:1 ratio of centrobin+ to ODF2+ centrioles. CONCLUSIONS: The cell cycle arrest of suprabasal cells is distinct from the G0 arrest of monolayered epithelial cells. Tumor mass of BD and SCC contained non-proliferative cells with the characteristics of the suprabasal cells of normal epidermis. A constant ratio of the number of centrobin+ to ODF2+ centrioles indicates that multiple centrioles were induced by cell division failure rather than centriole overduplication in clumping cells. PMID- 29615327 TI - Corrigendum to "Genetically defined variants of toll-like receptors 3, 7 and 9 as phenotype and risk modifier factors for psoriasis" [89 (March (3)) (2018) 301 304]. PMID- 29615328 TI - Adequate platelet counts in cirrhosis for laboratory-based optimum platelet functions. PMID- 29615330 TI - Alternative insertion site in the scapular region for etonogestrel contraceptive implant (Nexplanon(r)). PMID- 29615329 TI - Individuals affected by eosinophilic gastrointestinal disorders have complex unmet needs and frequently experience unique barriers to care. AB - INTRODUCTION: Eosinophilic gastrointestinal disorders (EGIDs) are a rare but emerging healthcare problem. Patient advocacy groups (PAGs) have an important role in representing the EGID community, and serve as valuable research partners. By leveraging the partnership between medical researchers and PAGs, we examined the unmet needs and barriers to care perceived by individuals affected by EGIDs. Next, we examined if these varied between adult EGID patients and adult caregivers of children with EGID. METHODS: Adult EGID patients and adult caregivers of children (<18 years) with EGIDs participated in this study. PAGs conducted focus groups comprised of individuals affected by EGIDs to identify domains and questions meaningful to the EGID community and this information was used to develop an online REDCap survey. The survey consisted of 58 questions across medical, healthcare, social, and emotional impact domains. It was distributed via the PAGs' web-based platforms. Demographic data, and responses to questions on a six-point Likert scale were collected and analyzed. RESULTS: Of the 361 responses analyzed, 90 (25%) were from adult EGID patients and 271 (75%) were from adult caregivers. Of the applicable responses, in the medical domain only 19% of participants indicated that repeated endoscopies to monitor response to treatment was convenient. In the healthcare domain, 67% indicated that lack of insurance coverage for elemental formula was a barrier. In the social domain, only 5% of respondents reported adequate awareness of EGIDs in schools. In the emotional domain, 64% had experienced significant stress due to EGID related out of-pocket costs. Multivariate logistic regression revealed that some of these responses varied between adult EGID patients and adult caregivers of children with EGID. The respondents indicated highest priority for improvement in the medical domain compared to other domains. CONCLUSIONS: Individuals affected by EGIDs have a constellation of complex unmet needs and perceived barriers across medical, healthcare, social and emotional domains. Addressing unmet needs in the medical domain is relatively more important for the EGID community. Understanding unmet needs and barriers will likely help design improved patient-centered EGID care paradigms. PMID- 29615331 TI - A novel wall water system for cardiopulmonary bypass may reduce the risk of aerosolized infection. AB - OBJECTIVE: Oxygenators for cardiopulmonary bypass require water flow for their integral heat exchanger. Heater-cooler units are nearly universally used for this requirement. Heater-cooler units pose the risk of aerosolized infection. The Centers for Disease Control and Prevention recommended discontinuing use of Stockert 3T heater-cooler units (LivaNova PLC, London, United Kingdom) in October 2016 because of this risk. We aimed to reduce the risk of aerosolized infection posed by heater-cooler units by eliminating those devices from our operating rooms. METHODS: The cardiac surgery division collaborated with in-house specialties to engineer a novel wall water system. The design called for service to 4 operating rooms with the actual water mixing valve in an operating room closet. Remote temperature control was mounted next to the heart-lung machine. Primary safety systems built into the water system include 5 MUm filtration, pressure regulating and relief valves, flow quantifiers, limits to the hot and chilled input temperatures, and a novel bridge near the heart-lung machine that allows the perfusionist to test the system before patient use and to quickly disconnect the patient in case of system malfunction. In addition, all water line connections can be made with the tubing drained and never under pressure. RESULTS: This novel wall water system has successfully provided heat exchanger water flow on 625 patients undergoing congenital heart surgery requiring cardiopulmonary bypass during its first 9 months of use. CONCLUSIONS: Wall water systems are an option for oxygenator heat exchangers that allow for improved heat exchange performance while reducing the risk of heater-cooler unit-associated infection during cardiac surgery. PMID- 29615332 TI - Effectiveness of radial artery-based multiarterial coronary artery bypass grafting: Role of body habitus. AB - BACKGROUND: The multiarterial grafting survival advantage noted in the overall population undergoing coronary artery bypass grafting is not well defined in the obese. We investigated the early to late survival effects of the radial artery in left internal thoracic artery-based multiarterial bypass grafting (radial artery multiarterial bypass grafting) versus single arterial bypass grafting (left internal thoracic artery-single arterial bypass grafting) in obese patients. METHODS: We analyzed 15-year Kaplan-Meier survival in 6102 patients receiving primary, left internal thoracic artery-based coronary artery bypass grafting with 2 or more grafts divided into body mass index groups: nonobese (<30 kg/m2) and all-obese, comprised of mildly obese (30-35 kg/m2) and morbidly obese (>35 kg/m2). Risk-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) of radial artery-multiarterial bypass grafting versus left internal thoracic artery single arterial bypass grafting were derived via Cox regression and applied separately for early (<0.5 years), intermediate (0.5-5 years), and late (5-15 years) follow-up in each body mass index cohort. Propensity score matching between radial artery-multiarterial bypass grafting and left internal thoracic artery-single arterial bypass grafting cohorts within the body mass index groups was performed as a corroborating analysis. RESULTS: Radial artery-multiarterial bypass grafting was more frequently used in obese patients who were younger (62 +/- 10 years; mild/morbid: 45.4%/54.4% radial artery-multiarterial bypass grafting) compared with nonobese patients (66 +/- 10 years; 37.4% radial artery multiarterial bypass grafting). Unadjusted 15-year survival was significantly better for radial artery-multiarterial bypass grafting in all body mass index groups. Multivariate analysis showed a survival benefit of radial artery multiarterial bypass grafting over the entire 0- to 15-year study period in the all-obese cohort (HR, 0.85; 95% CI, 0.74-0.98) and was more pronounced in the mildly obese (HR, 0.79; 95% CI, 0.66-0.96) versus morbidly obese (HR, 0.88; 95% CI, 0.69-1.13). The radial artery-multiarterial bypass grafting survival benefit was realized between 0.5 and 5 years postoperatively and was comparable for all obese (HR, 0.69; 95% CI, 0.51-0.94) and nonobese (HR, 0.68; 95% CI, 0.52-0.88) groups. Propensity score matching was confirmatory. CONCLUSIONS: Radial artery multiarterial bypass grafting confers a long-term survival advantage in both obese and nonobese patients. PMID- 29615333 TI - Immediate operation for acute type A aortic dissection complicated by visceral or peripheral malperfusion. AB - OBJECTIVE: To evaluate the effect of visceral, renal, or peripheral malperfusion on the outcome of acute type A aortic dissection. METHODS: We performed a retrospective review of the acute type A aortic dissection experience at Stanford Hospital between January 2005 and December 2015. Inverse probability weighting was used to account for differences between patients who experienced malperfusion syndromes and those who did not. Weighted logistic regression was used to evaluate in-hospital mortality, and midterm survival was assessed with the restricted mean survival time and weighted Cox regression. Reintervention was assessed with death as a competing risk. RESULTS: There were 305 patients with type A dissection extending beyond the ascending aorta, and 82 (26.9%) presented with a malperfusion syndrome. In-hospital mortality in the malperfusion subgroup was no different compared with patients without malperfusion in weighted logistic regression, odds ratio, 1.50 (95% confidence interval, 0.65-3.47; P = .3). There was no difference in midterm survival using restricted mean survival time, -50.2 days (95% CI, -366.8 to 266.4; P = .8) in patients with malperfusion compared with patients without malperfusion at 8 years. Patients with malperfusion had an increased risk of interventions (12.5%) on aortic branches compared with patients without (5.7%) in weighted analysis at 10-years, hazard ratio, 3.06 (95% CI, 1.24 7.56; P = .02). The median time to reintervention on aortic branches was 2 days for patients with malperfusion compared with 230 days without malperfusion, P = .01. CONCLUSIONS: Immediate operation for acute type A aortic dissection complicated by malperfusion is associated with good results. PMID- 29615334 TI - Emergency valve-sparing aortic root replacement and coronary artery bypass grafting for giant left sinus of Valsalva aneurysm presenting as acute coronary syndrome. PMID- 29615335 TI - Does left atrial appendage ligation during coronary bypass surgery decrease the incidence of postoperative stroke? AB - OBJECTIVE: The study objective was to evaluate the association between surgical left atrial appendage ligation and in-hospital stroke incidence after coronary artery bypass grafting among patients with atrial fibrillation. METHODS: A retrospective cohort study was performed by using the Nationwide Inpatient Sample between 2008 and 2014. All atrial fibrillation patients who underwent coronary artery bypass graft were included and categorized as left atrial appendage ligation or control group. Propensity score-weighted regression analyses were performed to assess the impact of left atrial appendage ligation on stroke incidence. RESULTS: A total of 234,642 patients were identified, among whom 20,664 (8.81%) received concomitant left atrial appendage ligation. The national postoperative stroke incidence was 0.92%. Results of the propensity-weighted regression analysis showed no significant association between LAA ligation and control with regard to postoperative stroke (odds ratio [OR], 0.83; confidence interval [CI], 0.57-1.22; P = .35), pericardial complications (OR, 1.15; CI, 0.88 1.49; P = .31), hemorrhage and/or hematoma (OR, 1.08; CI, 0.99-1.17; P = .07), mortality (OR, 1.29; CI, 0.99-1.68; P = .06), and length of stay (coefficient 0.21; CI, -0.44-0.02; P = .08). There was no specific CHA2DS2VASC score cutoff above which left atrial appendage ligation was demonstrated to have lower postoperative stroke incidence. CONCLUSIONS: The postoperative stroke risk after coronary artery bypass grafting was low at approximately 1% among patients with atrial fibrillation in the United States. Concomitant left atrial appendage ligation was not associated with lower postoperative stroke risk. PMID- 29615336 TI - Circulating tumor DNA: A promising biomarker to guide postoperative treatment and surveillance of non-small cell lung cancer. PMID- 29615337 TI - Immunohistochemical and molecular genetic study on epithelioid glioblastoma: Series of seven cases with review of literature. AB - Epithelioid glioblastoma (e-gbm) is a recently described variant of glioblastoma (GBM) which is associated with short survival and now added as a provisional entity to WHO 2016 classification of CNStumors. About half of these tumors show characteristic BRAF-V600E mutation. However, unlike conventional GBMs, e-gbm lack specific diagnostic and prognostic markers. Hence, we aimed to molecularly characterize these tumors. An extensive review of literature was performed.In a multi-institutional effort, all the cases of glioblastoma of year 2017 were reviewed. Cases with predominant epithelioid morphology were analysed. Seven cases of e-gbm (adults:4 and pediatric: 3) were identified. Duration of symptoms varied from 2 weeks to one month. Radiologically, all cases were supratentorial, contrast enhancing with solid and cystic appearance. Majority of the cases were immunopositive for GFAP (71%), EMA (71%), S100 (71%) and vimentin (85%). All the cases showed ATRX, INI-1 and H3K27me3 expression. BRAFV600Emutation was seen in 28% of cases. TERT mutation was seen in 40% cases, while one case showed EGFR amplification. H3F3A mutations and PTEN deletions were seen in none. Although e gbms are rare, epithelioid morphology of a CNS tumor in a young adult or children with areas of necrosis needs thorough histomorphological and genetic workup. PMID- 29615338 TI - Use of the Ion AmpliSeq Cancer Hotspot Panel in clinical molecular pathology laboratories for analysis of solid tumours: With emphasis on validation with relevant single molecular pathology tests and the Oncomine Focus Assay. AB - Targeted application of next-generation sequencing (NGS) technology allows detection of specific mutations that can provide treatment opportunities for cancer patients. We evaluated the applicability of the Ion AmpliSeq Cancer Hotspot Panel V2 (CHV2) using formalin-fixed, paraffin-embedded (FFPE) tissue of clinical specimens. Thirty-five FFPE tumour samples with known mutational status were collected from four different hospitals and sequenced with CHV2 using an Ion Chef System and Ion S5 XL system. Out of 35 cases, seven were sequenced with Oncomine focus Assay Panel for comparison. For the limit of detection test, we used an FFPE reference standard, a cell line that included an engineered 50% EGFR T790 M in an RKO cell line background. Coverage analysis results including number of mapped reads, on target percent, mean depth, and uniformity were not different according to hospitals. Sensitivity for mutation detection down to 3% was demonstrated. NGS results showed 100% concordance with the results from single molecular pathology tests Assay in 30 cases with 24 known positive mutations and 14 known negative mutations, and another NGS panel of the Oncomine focus in seven cases. The CHV2 NGS test for solid tumours using Ion chef system and S5 XL system in clinical molecular pathology laboratories for analysis of solid tumours could be routinely used and could replace some single molecular pathology tests after a stringent and thorough validation process. PMID- 29615339 TI - Benzoxazine derivatives of phytophenols show anti-plasmodial activity via sodium homeostasis disruption. AB - Development of new class of anti-malarial drugs is an essential requirement for the elimination of malaria. Bioactive components present in medicinal plants and their chemically modified derivatives could be a way forward towards the discovery of effective anti-malarial drugs. Herein, we describe a new class of compounds, 1,3-benzoxazine derivatives of pharmacologically active phytophenols eugenol (compound 3) and isoeugenol (compound 4) synthesised on the principles of green chemistry, as anti-malarials. Compound 4, showed highest anti-malarial activity with no cytotoxicity towards mammalian cells. Compound 4 induced alterations in the intracellular Na+ levels and mitochondrial depolarisation in intraerythrocytic Plasmodium falciparum leading to cell death. Knowing P-type cation ATPase PfATP4 is a regulator for sodium homeostasis, binding of compound 3, compound 4 and eugenol to PfATP4 was analysed by molecular docking studies. Compounds showed binding to the catalytic pocket of PfATP4, however compound 4 showed stronger binding due to the presence of propylene functionality, which corroborates its higher anti-malarial activity. Furthermore, anti-malarial half maximal effective concentration of compound 4 was reduced to 490 nM from 17.54 uM with nanomaterial graphene oxide. Altogether, this study presents anti-plasmodial potential of benzoxazine derivatives of phytophenols and establishes disruption of parasite sodium homeostasis as their mechanism of action. PMID- 29615340 TI - Next-generation small molecule therapies for heart failure: 2015 and beyond. AB - Poor prognosis coupled with significant economic burden makes heart failure (HF) one of the largest issues currently facing the world population. Although a significant number of new therapies have emerged over the past 20 years to treat the underlying physiological risk factors, only two new medications specifically for HF have been approved since 2007. This perspective provides an overview of recently approved treatment options for HF and as well as an update on additional small molecule therapies currently in clinical development. PMID- 29615342 TI - Synthesis of alkyne-tagged and biotin-tagged Sortin1 as novel photoaffinity probes. AB - Sortin1 is an inhibitor of vesicular biogenesis and transport, which is shared among eukaryotes and plants with an unknown mode of action. Toward exploration of its target proteins, we developed alkyne as well as biotin conjugated photoaffinity probes derived from Sortin1. Due to the presence of phenylketone moiety, Sortin1 was anticipated to serve as a photoreactive group in a similar manner to a commonly used photoreactive group, benzophenone. The core structure based on 5-oxo-1,4-dihydroindenopyridine was constructed in one step using three component Hantzsch dihydropyridine synthesis. We demonstrated that Sortin1 displayed photocrosslinking reactivity against a model binding protein, which would be useful for capturing and detecting binding proteins. PMID- 29615341 TI - A review of salvinorin analogs and their kappa-opioid receptor activity. AB - The plant metabolite salvinorin A potently and selectively agonizes the human kappa-opioid receptor, an emerging target for next-generation analgesics. Here we review analogs of the salvinorin chemotype and their effects on selectivity, affinity and potency. Extensive peripheral modifications using isolated salvinorin A have delivered a trove of SAR information. More deep-seated changes are now possible by advances in chemical synthesis. PMID- 29615343 TI - Synthesis, biological evaluation and SAR of naftopidil-based arylpiperazine derivatives. AB - For the development of potential anti-prostate cancer agents, 24 kinds of novel naftopidil-based arylpiperazine derivatives have been synthesized and characterized by spectroscopic methods. Their antitumor activities were evaluated against several classical prostate cancer cell lines including PC-3, LNCaP, and DU145. Among all the compounds, 9, 13, 17, 21 and 27 showed strong cytotoxic activities against DU145 cells (IC50 < 1 MUM). Further testing confirmed that compound 17 inhibited the growth of DU145 cells by inducing cell cycle arrest at G0/G1 phase. Besides, antagonistic activities of compounds (9, 13, 17, 21 and 27) towards a1-ARs (alpha1A, alpha1B, and alpha1D) were further evaluated using dual luciferase reporter assays, and the compounds 13 and 17 exhibited better a1-ARs subtype selectivity. The structure-activity relationship (SAR) of these developed arylpiperazine derivatives was rationally discussed. Taken together, these results suggested that further development of such compounds may be of great interest. PMID- 29615344 TI - Peptidomimetic nitrile inhibitors of malarial protease falcipain-2 with high selectivity against human cathepsins. AB - Falcipain-2 (FP2) is an essential enzyme in the lifecycle of malaria parasites such as Plasmodium falciparum, and its inhibition is viewed as an attractive mechanism of action for new anti-malarial agents. Selective inhibition of FP2 with respect to a family of human cysteine proteases (that include cathepsins B, K, L and S) is likely to be required for the development of agents targeting FP2. Here we describe a series of P2-modified aminonitrile based inhibitors of FP2 that provide a clear strategy toward addressing selectivity for the P. falciparum and show that it can provide potent FP2 inhibitors with strong selectivity against all four of these human cathepsin isoforms. PMID- 29615345 TI - Synthesis, biological evaluation, and molecular docking investigation of benzhydrol- and indole-based dual PPAR-gamma/FFAR1 agonists. AB - Type-2 diabetes mellitus is a progressive cluster of metabolic disorders, representing a global public health burden affecting more than 366 million people worldwide. We recently reported the discovery of three series of novel agents showing balanced activity on two metabolic receptors, peroxisome proliferator activated receptor-gamma (PPAR-gamma) and free fatty acid receptor 1 (FFAR1), also known as GPCR40. Our designing strategy relied on linking the thiazolidinedione head with known GPCR privilege structures. To further investigate this concept, two new scaffolds, the benzhydrol- and indole-based chemotypes, were introduced here in. Our optimization campaign resulted in three compounds; 15a, 15c, and 15d, with affinities in the low micromolar range on both targets. In vivo study of selected test compounds, revealed that 15c possesses a significant anti-hyperglycemic and anti-hyperlipidemic activities superior to rosiglitazone in fat-fed animal models. Molecular docking analysis was conducted to explain the binding modes of both series. These compounds could lead to the development of the unique antidiabetic agent acting as insulin sensitizer as well as insulin secretagogue. PMID- 29615346 TI - Corrigendum to "Mechanisms of resistance to delamanid, a drug for Mycobacterium tuberculosis" [Tuberculosis 108 (January 2018) 186-194]. PMID- 29615347 TI - Assessing the accuracy of cranial and pelvic ageing methods on human skeletal remains from a modern Greek assemblage. AB - The present study tests the accuracy of commonly adopted ageing methods based on the morphology of the pubic symphysis, auricular surface and cranial sutures. These methods are examined both in their traditional form as well as in the context of transition analysis using the ADBOU software in a modern Greek documented collection consisting of 140 individuals who lived mainly in the second half of the twentieth century and come from cemeteries in the area of Athens. The auricular surface overall produced the most accurate age estimates in our material, with different methods based on this anatomical area showing varying degrees of success for different age groups. The pubic symphysis produced accurate results primarily for young adults and the same applied to cranial sutures but the latter appeared completely inappropriate for older individuals. The use of transition analysis through the ADBOU software provided less accurate results than the corresponding traditional ageing methods in our sample. Our results are in agreement with those obtained from validation studies based on material from across the world, but certain differences identified with other studies on Greek material highlight the importance of taking into account intra- and inter-population variability in age estimation. PMID- 29615348 TI - Prevalence of and risk factors for nasal methicillin-resistant Staphylococcus aureus colonization among children in central Taiwan. AB - BACKGROUND/PURPOSE: Staphylococcus aureus (S. aureus) causes diseases ranging from mild skin infections to invasive diseases. Carriage of S. aureus, including methicillin-resistant S. aureus (MRSA), is a significant risk factor for subsequent staphylococcal infection. Several studies discussed MRSA colonization in Taiwan, but mostly in northern Taiwan. This is the first study that estimates the prevalence of MRSA nasal colonization in healthy children and identifies the potential risk factors in central Taiwan. METHODS: A total of 3144 healthy children aged 2-60 months who visited Taichung Veterans General Hospital (TCVGH) were screened for nasal S. aureus carriage from July 2005 to December 2010. Questionnaires included demographic information and potential risk factors for carriage of S. aureus were completed by parents/guardians. RESULTS: Prevalence of MSSA and MRSA were 12.09% and 5.25%, respectively. The youngest group aged 2-6 months had the highest S. aureus carriage rate, and the carriage rate revealed a peak in summer. The nasal colonization of Streptococcus pneumoniae (S. pneumoniae) was a protective factor against S. aureus colonization. 85% of the MRSA colonizing isolates belonged to clonal complex 59/staphylococcal cassette chromosome type IV or VT, the local community clone in Taiwan. CONCLUSION: An increasing trend of MRSA nasal carriage rate in Taiwan had been brought forward, however, it was not observed in central Taiwan during the period of 2005-2010. We found a summer peak on both MRSA and MSSA carriages. PMID- 29615349 TI - Assessment of extracellular matrix-related biomarkers in patients with lower extremity artery disease. AB - BACKGROUND: The prevalence of lower extremity artery disease (LEAD) is high (20% 25%) in the population older than 65 years, but patients are seldom identified until the disease is advanced. Circulating markers of disease activity might provide patients with a key opportunity for timely treatment. We tested the hypothesis that measuring blood-specific fragments generated during degradation of the extracellular matrix (ECM) could provide further insight into the pathophysiologic mechanism of arterial remodeling. METHODS: The protein profile of diseased arteries from patients undergoing infrainguinal limb revascularization was assessed by a liquid chromatography and tandem mass spectrometry, nontargeted proteomic approach. The information retrieved was the basis for measurement of neoepitope fragments of ECM proteins in the blood of 195 consecutive patients with LEAD by specific enzyme-linked immunosorbent assays. RESULTS: Histologic and proteomic analyses confirmed the structural disorganization of affected arteries. Fourteen of 81 proteins were identified as differentially expressed in diseased arteries with respect to healthy tissues. Most of them were related to ECM components, and the difference in expression was used in multivariate analyses to establish that severe arterial lesions in LEAD patients have a specific proteome. Analysis of neoepitope fragments in blood revealed that fragments of versican and collagen type IV, alone or in combination, segregated patients with mild to moderate symptoms (intermittent claudication, Fontaine I-II) from those with severe LEAD (critical limb ischemia, Fontaine III-IV). CONCLUSIONS: We propose noninvasive candidate biomarkers with the ability to be clinically useful across the LEAD spectrum. PMID- 29615350 TI - A technique for the salvage of megafistulas allowing immediate dialysis access. AB - OBJECTIVE: Almost two million individuals are undergoing renal replacement therapy worldwide, with hemodialysis being the common form. Many factors influence the primary patency of an arteriovenous fistula (AVF), including vessel size, fistula flow rates, cannulation practice, and thrombotic tendencies. Excess dilation of the AVF, resulting in the development of a megafistula, is a complication that can result in a need for AVF revision and subsequent failure. METHODS: The charts of patients who underwent autogenous AVF revision because of the development of a megafistula with aneurysmectomy and vein transposition by a single surgeon during a 7-year period from 2009 through 2016 were reviewed. A technique is described in which after aneurysmorrhaphy, the repaired venous component of the AVF is transposed through a new tunnel while the vein is rotated 90 degrees. This allows the AVF to be accessed immediately, making placement of a tunneled dialysis catheter unnecessary. RESULTS: There were 102 patients included in the study, with follow-up ranging from 7 to 95 months. In our cohort, 92 of the 102 revised AVFs (90.2%) maintained primary functional patency. Of the 102 patients who underwent this revision technique, there were 10 fistulas that subsequently failed after a mean of 29 months. There were only seven patients who experienced recurrent fistula dilation requiring repeated aneurysmectomy. CONCLUSIONS: We describe a technique for management of the development of a megafistula that uses only autogenous tissue and, perhaps most important, eliminates the need for temporary dialysis catheter placement. PMID- 29615351 TI - The incidence of delayed complications in acute type B aortic dissections is underestimated. AB - OBJECTIVE: Acute type B aortic dissections (TBADs) can have immediate or delayed complications within the first 2 weeks. Because the majority of clinical series retrospectively categorized TBAD, the incidence and outcome of delayed complications in initially uncomplicated TBAD within the first 14 days are not well described. METHODS: We retrospectively analyzed 86 patients (78% male; age, 62.5 +/- 13 years) with acute TBAD treated consecutively between January 2004 and May 2016 at a tertiary referral center. All TBADs were confirmed by computed tomography angiography (CTA) on admission, after 2 to 5 days, and after 10 to 14 days. Study end points were the incidence of immediate and delayed complications (aortic rupture, malperfusion, rapid aortic expansion >4 mm, pain or hypertension resistant to medical therapy) and in-hospital mortality. In addition, we looked at CTA-detected morphometric variables (maximum diameters of descending aorta, false lumen [FL], and primary entry tear; number of intimal tears; FL configuration; true lumen collapse; course of the dissection) and their association with delayed complications. Finally, we assessed treatment modalities and clinical outcomes. RESULTS: Of all TBADs, 22 (26%) presented with immediate complications (rupture, n = 11); 64 patients (74%) were initially assessed as having uncomplicated TBAD. Of these 64 patients, 24 (28% of all 86) suffered from delayed complications (malperfusion, n = 10; aortic rupture, n = 3; early expansion >4 mm, n = 8; refractory pain, n = 2; uncontrollable hypertension, n = 1) at a median interval of 7.1 (2-14) days after symptom onset. During the first 14 days, 40 patients (46%) remained uncomplicated. The CTA analysis revealed a significant association of initial thoracic aortic diameter (P = .009), size of the primary entry tear (P = .018), true lumen collapse (P = .019), and partially thrombosed FL (P = .019) with the occurrence of delayed complications within the first 14 days. Of the patients with delayed complications, 87.5% underwent surgery (90% thoracic endovascular aortic repair, 10% peripheral revascularization); 12.5% in this group died following aortic rupture before they received surgical repair. The mortality of patients with delayed complicated TBAD was significantly higher compared with those who remained uncomplicated within the 14-day period (12.5% vs 0%; P = .0221). CONCLUSIONS: Delayed complications in initially uncomplicated acute TBAD are not infrequent. Morphologic variables like maximum diameter of the descending aorta, primary entry tear, true lumen collapse, and partially thrombosed FL were associated with an increased risk of delayed complications in initially uncomplicated TBAD. Future clinical research must verify the predictive role of clinical and morphologic variables in the acute phase, particularly with regard to a possible early surgical treatment to prevent a fatal outcome. PMID- 29615352 TI - Long-term comparative effectiveness of carotid stenting versus carotid endarterectomy in a large tertiary care vascular surgery practice. AB - OBJECTIVE: Carotid interventional trials have strict inclusion and exclusion criteria that make translation of their results to the real-world population challenging. Furthermore, the specialty of the operating surgeon and the role of clinical decision-making are not well studied. This study compares the effectiveness of carotid endarterectomy (CEA) vs carotid artery stenting (CAS) in a real-world setting when the procedure is performed by fellowship-trained vascular surgeons. METHODS: A retrospective study was conducted of all consecutive patients undergoing CEA and CAS performed by vascular surgeons in a large rural tertiary health care system from 2004 to 2014. Postoperative outcomes of stroke, acute myocardial infarction (AMI), and death were analyzed at 30 days and during the long term (median follow-up of 5.5 years for CEA and 4.8 years for CAS). Standard statistical analysis was performed. Differences in long-term outcomes were expressed as cumulative incidence functions for nondeath outcomes (stroke and AMI), which account for the high death rate in this population of vascular patients, and as Kaplan-Meier curves for death itself. RESULTS: From January 1, 2004, through December 31, 2014, there were 2331 carotid interventions performed (CEA, 1853; CAS, 478), all by fellowship-trained vascular surgeons. The average age of the patients was 71 years, and 63% were male, with more men in the CAS group (61.5% vs 67.8%; P = .011). Preoperatively, 30% of patients were symptomatic, and 77% of patients had high-grade stenosis in the 70% to 99% range. CEA patients were more likely to have preoperative hypertension (89.7% vs 86.2%; P = .029) and were less likely to have a history of cardiovascular disease (53.4% vs 59.4%; P = .018). There were no significant differences in 30-day outcomes between CEA and CAS (stroke, 1.1% vs 1.3% [P = .743]; AMI, 2.2% vs 1.7% [P = .474]; death, 0.7% vs 0.6% [P = .859]) or long-term outcomes (stroke, 6.8% vs 7.7% [P = .321]; AMI, 22.7% vs 21.0% [P = .886]; death, 28.4% vs 28.2% [P = .122]). CONCLUSIONS: The short- and long-term outcomes after CEA vs CAS are similar when the procedure is performed in a real-world setting by fellowship trained vascular surgeons. PMID- 29615354 TI - Improved access to health care in Massachusetts after 2006 Massachusetts Healthcare Reform Law is associated with a significant decrease in mortality among vascular surgery patients. AB - BACKGROUND: Access to medical care, by adequate insurance coverage, has a direct impact on outcomes for patients undergoing vascular procedures. We evaluated in hospital mortality for patients undergoing index vascular procedures before and after the Massachusetts Healthcare Reform Law (MHRL) in 2006, which mandated insurance for all Massachusetts residents, both in Massachusetts and throughout the United States. METHODS: The National Inpatient Sample was queried to identify patients undergoing interventions for peripheral arterial disease, carotid artery stenosis, and abdominal aortic aneurysms based on International Classification of Diseases, Ninth Revision, Clinical Modification procedural and diagnostic codes. The cohort was then divided into patients treated within Massachusetts (MA) and non-Massachusetts (NMA) hospitals. Two time intervals were examined: before (2003 2006, P1) and after the MHRL (2007-2011, P2). The primary outcome of interest included in-hospital mortality. Patients in MA and NMA hospitals were described in terms of demographics and presentation by time interval (P2 vs P1) compared using chi2 and t-tests. Weighted logistic regression with term modeling change in the odds ratio (OR) for P2 was performed to test and to estimate trends in mortality. Time (year of procedure) and region interactions were investigated by inclusion of time-region interactions in our analyses. Subgroup analysis was performed for P2 vs P1 among nonwhite, nonelderly, and low-income patients. RESULTS: We identified 306,438 patients who underwent repair of abdominal aortic aneurysm, lower extremity bypass, or carotid endarterectomy in MA and NMA hospitals. MA hospital patients had an increase in both Medicaid and private insurance status after the MHRL (P1 = 2.6% and 21% vs P2 = 3.3% and 21.7%, respectively; P = .034). In-hospital mortality trended down for all groups across the entire study. In comparing P2 vs P1 trends, MA hospital odds of mortality per year was lowered by 26% (OR, 0.74; 95% confidence interval [CI], 0.56-0.99; P = .042) not seen in NMA hospitals (OR, 1.03; 95% CI, 0.97-1.09; P = .405). Time and region interaction terms indicated significant time trend difference in both unadjusted (P = .031) and adjusted (P = .033) analysis in MA hospitals not observed in NMA hospitals. This pattern continued when the samples were stratified by procedure. Patients undergoing vascular procedures in MA hospitals had a significantly lowered OR of mortality, with fewer patients presenting at late disease stages in P2 vs P1. Nonelderly patients in Massachusetts, who benefit from the Medicaid expansion provided by the MHRL, had a profound 92% drop in odds of mortality in P2 vs P1 (OR, 0.08; 95% CI, 0.010-0.641; P = .017) compared with the 14% drop in NMA (OR, 0.86; 95% CI, 0.709-1.032; P = .103). CONCLUSIONS: The 2006 MHRL is associated with a decrease in mortality for patients undergoing index vascular surgery procedures in MA compared with NMA hospitals. This study suggests that governmental policy may play a key role in positively affecting the outcomes for patients. PMID- 29615353 TI - Predictors of health-related quality of life in patients with symptomatic peripheral artery disease. AB - OBJECTIVE: The aim of this study was to identify predictors of baseline measures of health-related quality of life (HRQoL) in symptomatic patients with peripheral artery disease (PAD) from objective markers of severity of PAD, clinical and demographic characteristics, comorbid conditions, cardiovascular risk factors, objectively measured physical activity, and patient-based measures of physical function. METHODS: HRQoL measurements of 216 symptomatic men and women with PAD were assessed with the Medical Outcomes Study 36-Item Short Form Health Survey. Patients were further characterized on demographic variables, comorbid conditions, cardiovascular risk factors, ankle-brachial index, peak walking time during a maximal treadmill test, 6-minute walk distance, gait speed, ambulatory activity monitored during 1 week, activities of daily living (ADLs), Mini-Mental State Examination questionnaire, and Walking Impairment Questionnaire (WIQ). RESULTS: For the physical function HRQoL subscale, the significant predictors included WIQ speed score (P < .001), history of stumbling (P < .001), WIQ stair climbing score (P < .001), ADL associated with bathing (P = .001), 6-minute walk distance (P = .004), and daily walking cadence (P = .043). For the role emotional function HRQoL subscale, the significant predictors included a history of stumbling (P < .001), the ADL associated with transferring from a bed to a chair (P < .001), and the WIQ distance score (P = .022). CONCLUSIONS: Physical and mental subscales of HRQoL in symptomatic patients with PAD are primarily predicted by patient-based physical function rather than by more specific markers of PAD severity and comorbid conditions. The clinical significance is that interventions designed to improve HRQoL should focus on improving the quality of executing functional tasks, such as walking more steadily without stumbling; completing ADLs that are not specific to walking, such as bathing and transferring; and improving patient-based ability to walk various distances and speeds and to climb stairs. PMID- 29615355 TI - Feasibility of three-dimensional fusion imaging with multimodality roadmap system during endovascular aortic repair. AB - OBJECTIVE: Endovascular procedures for aortic aneurysm repair have become widely accepted as safe and effective surgical options. We investigated the efficacy of the multimodality roadmap (MMR) system with biplane fluoroscopy to attempt to reduce the use of contrast medium and exposure to radiation during surgery. METHODS: We retrospectively reviewed 263 consecutive cases with elective endovascular aneurysm repair (EVAR) and thoracic endovascular aortic repair (TEVAR). Patients were categorized into two groups, with and without introduction of the MMR system, which was applied in 164 patients (62.4%). The MMR- group included 62 EVAR and 37 TEVAR cases, and the MMR+ group consisted of 81 EVAR and 83 TEVAR cases. Radiation dose, contrast medium use, and complications were compared between the MMR- and MMR+ groups in the respective EVAR and TEVAR groups. RESULTS: There was a significantly lower amount of contrast medium use in the MMR+ group compared with the MMR- group in EVAR (32.9 +/- 10.6 g and 28.2 +/- 10.2 g; P = .009) and TEVAR (31.7 +/- 11.5 g and 26.9 +/- 7.8 g; P = .009). In addition, significantly lower radiation exposure was observed in the MMR+ group of TEVAR (872 +/- 623 mGy vs 638 +/- 463 mGy; P = .033). The operative time of the MMR+ group was significantly shorter for patients with TEVAR compared with the MMR- group (96.4 +/- 27.0 minutes vs 86.2 +/- 23.9 minutes; P = .023). The incidence of access injury and other complications was similar in both EVAR and TEVAR groups. CONCLUSIONS: The MMR system with three-dimensional fusion imaging can reduce the contrast medium dose in EVAR and the exposure to contrast medium and radiation in TEVAR. PMID- 29615356 TI - Antihypertensive medication adherence in chronic type B aortic dissection is an important consideration in the management debate. AB - OBJECTIVE: Early aortic stenting in chronic type B aortic dissection (TBAD) may lead to long-term benefit, although the optimal treatment strategy is hotly debated. A robust comparison to outcomes seen in medically managed patients is challenging as the rate of antihypertensive medication adherence is unknown. The aims of this study were therefore to identify the rate of antihypertensive medication adherence and predictors of adherence in TBAD. METHODS: This was a cross-sectional mixed methods study of patients with TBAD. Medication adherence was assessed by the eight-item Morisky Medication Adherence Scale together with an assessment of demographic, behavioral, and psychological variables and disease specific knowledge. RESULTS: There were 47 patients (mean age, 59 years; 81% male) who were recruited from a tertiary vascular unit. The mean total number of medications taken was 5.8 (2-14), and the mean number of antihypertensive medications was 1.9 (1-6). Of the 47 patients, 20 (43%) reported high levels of medication adherence, 17 (36%) reported moderate adherence, and 10 (21%) reported low adherence. Previous aortic surgery was associated with higher levels of adherence (beta = 0.332; P = .03), as was taking a greater number of medications (beta = 0.332; P = .026), perceived benefit from treatment (beta = 0.486; P < .001), good memory (beta = 0.579; P < .001), and low fears of side effects (beta = 0.272; P < .014). CONCLUSIONS: Medical management remains the mainstay of treatment in uncomplicated TBAD; however, the majority of patients are poorly adherent to their antihypertensive medications. The merits of thoracic endovascular aortic repair in TBAD are argued, and poor adherence is an important factor in the debate; one cannot robustly compare two strategies when half of a treatment group may not be receiving the stated intervention. To develop an evidence-based treatment strategy for TBAD, we must take into account the direct and indirect effects of medical therapy and thoracic endovascular aortic repair. Further work to improve medication adherence and to understand its impact on disease progression is vital to inform the debate and to deliver the best outcomes for patients. PMID- 29615357 TI - Use of extracorporeal bypass is associated with improved outcomes in open thoracic and thoracoabdominal aortic aneurysm repair. AB - OBJECTIVE: There is no consensus on the use or benefit of extracorporeal circulation (EC) during aneurysm repair of the descending thoracic aorta (DTA) or thoracoabdominal aorta (TAA). We evaluated the role of EC during DTA or TAA aneurysm repair using U.S. Medicare data. METHODS: Medicare (2004-2007) patients undergoing open repair of nonruptured DTA or TAA aneurysm were identified by International Classification of Diseases, Ninth Revision code. Specific exclusions included ascending aortic or arch repairs, concomitant cardiac procedures, and procedures employing deep hypothermic circulatory arrest. The impact of EC (code 3961) on early and late outcomes was analyzed using univariate analysis and multivariable regression. Survival was assessed using Kaplan-Meier analysis and Cox proportional hazards regression models. RESULTS: There were 4230 patients who had repair of intact DTA or TAA aneurysms, 2433 (57%) of which employed EC. Differences in baseline clinical features of EC and non-EC patients showed that patients undergoing aortic reconstruction with EC were older (73 +/- 1 years vs 72 +/- 1 years; P = .002), were more likely to be female (53% vs 47%; P < .001), and had more hypertension (56% vs 53%; P = .02); they had less chronic obstructive pulmonary disease (28% vs 34%; P < .0001), peripheral vascular disease (5.7% vs 11.3%; P < .001), and chronic kidney disease (7.7% vs 5.5%; P = .003). The 30-day mortality (9.7% for EC vs 12.2%; P = .02) and any major complication (49% for EC vs 58%; P < .001) were significantly reduced with EC use. EC use was associated with a shorter length of stay (13.5 +/- 13 days vs 17.2 +/- 18 days; P < .01) and lower total hospital charges ($151,000 +/- 140,000 vs $180,000 +/- 190,000; P < .01) compared with non-EC patients. EC patients were more likely to be discharged home instead of to an extended care facility (67% vs 56%; P < .01). Multivariable regression modeling to adjust for baseline clinical differences showed EC to independently reduce the risk of operative mortality (odds ratio [OR], 0.80; 95% confidence interval [CI], 0.65-0.97; P = .02), any complication (OR, 0.67; 95% CI, 0.59-0.76; P < .01), pulmonary complications (OR, 0.68; 95% CI, 0.59-0.79; P < .01), and acute renal failure (OR, 0.52; 95% CI, 0.44-0.61; P < .01). Long-term survival was higher (log-rank, P < .01) in EC patients at 1 year (81% +/- 0.8% vs 73% +/- 1%) and 5 years (67% +/- 1% vs 52% +/ 1%). Risk-adjusted Cox proportional hazards regression also showed that EC was independently associated with improved long-term survival (hazard ratio, 0.69; 95% CI, 0.63-0.74; P < .01). CONCLUSIONS: Although important clinical variables such as DTA or TAA aneurysm extent and spinal cord ischemic complications cannot be assessed with the Medicare database, EC use during open DTA and TAA aneurysm repair is associated with improved late survival and a significant reduction in operative mortality, morbidity, and procedural costs. These data indicate that EC should be a more widely applied adjunct in open DTA or TAA aneurysm repair. PMID- 29615358 TI - Outcomes of infrageniculate retrograde versus transfemoral access for endovascular intervention for chronic lower extremity ischemia. AB - OBJECTIVE: Retrograde infrageniculate access is an alternative treatment strategy for patients who have failed to respond to antegrade endovascular intervention. This study compares the outcomes of infrageniculate retrograde arterial access with the conventional transfemoral access for the endovascular management of chronic lower extremity ischemia. METHODS: This was a retrospective single-center review of retrograde endovascular intervention (REI) from 2012 to 2016. Indications for intervention, comorbidities, complications, procedural success, limb outcomes, and mortality were analyzed. Technical failure was defined as the inability to complete the procedure because of failed access or unsuccessful recanalization. Infrageniculate access and transfemoral access were obtained with ultrasound or angiographic roadmap guidance. Patency rates were calculated for technically successful interventions. RESULTS: There were 47 patients (85% presenting with critical limb ischemia) who underwent sheathless REI after failed antegrade recanalization of TransAtlantic Inter-Society Consensus class D infrainguinal lesions, whereas 93 patients (83% with critical limb ischemia) underwent standard transfemoral access. There were 16 (34%) femoropopliteal, 14 (30%) tibial, and 17 (36%) multilevel interventions in the retrograde group compared with 41 (41%) femoropopliteal, 20 (20%) tibial, and 39 (39%) multilevel interventions in the transfemoral group. Access sites for the retrograde group included the dorsalis pedis (26%), midcalf peroneal (24%), anterior tibial (22%), posterior tibial (26%), and popliteal (2%) arteries. Overall technical success was achieved in 57% of the retrograde group compared with 78% of the transfemoral group. Mean follow-up was 20 months (range, 1-45 months). There were no significant differences in the primary patency rates between the two groups at 1 year and 2 years. The primary assisted patency rates were significantly better in the transfemoral group at 1 year (66% vs 46%; P = .031) and 2 years (56% vs 29%; P = .031). The secondary patency rates were higher in the transfemoral group at 1 year (93% vs 83%; P = .079) and 2 years (91% vs 76%; P = .079), although this did not reach statistical significance. The rate of reintervention was 41% for the retrograde group vs 40% for the transfemoral group. Most of the reinterventions (70% in the retrograde group and 61% in the transfemoral group) were endovascular interventions for a restenosis or occlusion. CONCLUSIONS: Infrageniculate access for REI can result in primary patency rates similar to those of antegrade interventions and does not compromise the access site. Technical failure is high in this initial experience and is mostly due to failed recanalization. Limb salvage may be achieved after technical failure with either repeated antegrade intervention or surgical bypass. PMID- 29615359 TI - Re: "The Hatfields, the McCoys, and Anthem's New Policy for Advanced Diagnostic Imaging". PMID- 29615360 TI - ABR Psychometric Testing: Analysis of Validity and Effects. AB - Changes in the certification program of the ABR were first described in some detail in 2008 and have since undergone refinements. Controversies surrounding these changes have included the relevance of test questions, costs, effects of altering the examination scheduling, residency program curriculum changes, and issues related to preparing for the examinations. However, the role of psychometric testing in radiology itself, as the technical foundation for the new ABR Core and Certification Examinations, has undergone less scrutiny. This article examines the validity and consequences of the ABR psychometric testing process, and we conclude that its validity can be challenged and that negative consequences, including adverse effects on allocating human and financial resources and on what is taught and learned in residency programs, should be addressed. The ABR could collaborate with the ACGME, education experts, patients, and public representatives to reform their testing processes, especially by integrating modern evaluation techniques that more authentically simulate radiology practices to better align the examination with its intended purposes. PMID- 29615361 TI - Author's Reply. PMID- 29615362 TI - Grassroots Marketing in Radiology. PMID- 29615363 TI - Trends in Medicare Reimbursement and Work Relative Value Unit Production in Radiation Oncology. AB - PURPOSE: Medicare payments to individual physicians are released annually by the CMS. The purpose of this study is to analyze trends in Medicare reimbursement and work relative value unit (wRVU) production to radiation oncologists. MATERIALS AND METHODS: The Medicare Physician Supplier and Other Provider Public Use File and the CMS Physician Fee Schedule Relative Value Files (to calculate wRVUs) for the calendar years 2012 to 2015 were used in this analysis. Medicare reimbursement was aggregated for each calendar year. Using the CMS Physician Fee Schedule Relative Value Files, the number of Medicare wRVUs was calculated for each radiation oncologist. RESULTS: In 2015, 4,323 radiation oncologists produced 12,895,298 wRVUs compared with 11,352,286 wRVUs produced in 2012. These datasets include only Medicare reimbursements and do not include wRVUs from private insurance or other payers. In 2015, radiation oncologists produced a median of 2,486 wRVUs from Medicare (range 3 to 24,349). Billing to Healthcare Common Procedure Coding System Code 77427 (radiation treatment management, five treatments), a proxy for total radiation treatments, fell from 1,111,670 in 2012 to 1,039,403 in 2015, a decline of 7%. CONCLUSION: The total number of wRVUs produced by radiation oncologists has risen by 14% from 2012 to 2015. However, the number of external beam radiation fractions has declined by approximately 7% over this same period, likely due to a trend toward hypofractionated courses of treatment and use of special treatment modalities such as proton beam therapy or stereotactic body radiation therapy. PMID- 29615364 TI - Social Media for Global Education: Pearls and Pitfalls of Using Facebook, Twitter, and Instagram. PMID- 29615365 TI - Detection of insulin-like growth factor receptor-1 in the human cremaster muscle and its role in the etiology of the undescended testis. AB - PURPOSE: Previous studies of undescended testis (UT) has focused on insulin-like hormone 3 (INSL3), the genitofemoral nerve, and androgens in the testicular descent. Leydig cells, which are under the control of insulin-like growth factor 1 (IGF1), produce both androgens and INSL3. We aimed to investigate whether insulin-like growth factor receptor-1(IGFR1) exists in the cremaster muscle (CM) complex and is associated with normally descended testis as well as UT cases in humans. METHODS: We studied 30 CM from 15 patients who comprised the UT group (UTG), and 15 patients with unilateral testicular torsion (Control group; CG). Muscles, nerves, and vessels within the CM specimen were examined to determine the presence of IGFR1. RESULTS: The mean staining score (MSS) of IGFR1 in CM and its nerves were higher in the CG than in the UTG. These results were statistically significant (p = 0.01 and p = 0.02). Although the MSS of IGF1R was higher in the vessels of CM in the CG than the UTG, this was not statistically significant (p = 0.48). CONCLUSIONS: IGFR1 with heterotetrameric receptor via IGF1, IGF2, insulin, and probably androgen, contribute to the remodeling and development of CM as well as the testis descent. In the current study, the presence of the IGFR1 in the CM was shown. Additionally, the IGFR1 density of the CM was lower in the UT cases than in the CG cases. Further evaluation of IGFR1 and other etiological factors can elucidate how they interact. PMID- 29615366 TI - Ongoing brain rhythms shape I-wave properties in a computational model. AB - BACKGROUND: Responses to transcranial magnetic stimulation (TMS) are notoriously variable. Previous studies have observed a dependence of TMS-induced responses on ongoing brain activity, for instance sensorimotor rhythms. This suggests an opportunity for the development of more effective stimulation protocols through closed-loop TMS-EEG. However, it is not yet clear how features of ongoing activity affect the responses of cortical circuits to TMS. OBJECTIVE/HYPOTHESIS: Here we investigate the dependence of TMS-responses on power and phase of ongoing oscillatory activity in a computational model of TMS-induced I-waves. METHODS: The model comprises populations of cortical layer 2/3 (L2/3) neurons and a population of cortical layer 5 (L5) neurons and generates I-waves in response to TMS. Oscillatory input to the L2/3 neurons induces rhythmic fluctuations in activity of L5 neurons. TMS pulses are simulated at different phases and amplitudes of the ongoing rhythm. RESULTS: The model shows a robust dependence of I-wave properties on phase and power of ongoing rhythms, with the strongest response occurring for TMS at maximal L5 depolarization. The amount of phase modulation depends on stimulation intensity, with stronger modulation for lower intensity. CONCLUSION: The model predicts that responses to TMS are highly variable for low stimulation intensities if ongoing brain rhythms are not taken into account. Closed-loop TMS-EEG holds promise for obtaining more reliable TMS effects. PMID- 29615368 TI - Acute ischiofemoral impingement? AB - We report a case of rare clinical entity, which comes within the spectrum of hip impingements. The case deals with a 36 year old female, Olympic athlete, who developed ischiofemoral impingement 14 months after a surgical hamstring reattachment. She was treated conservatively and fully recovered. When looking into literature on this matter, we found that it is probably an under-diagnosed problem, particularly in patients with no history of prior surgery. To our knowledge, this is the first case reported after a hamstrings tendon reattachment. PMID- 29615367 TI - Boosting the LTP-like plasticity effect of intermittent theta-burst stimulation using gamma transcranial alternating current stimulation. AB - BACKGROUND: Transcranial Alternating Current Stimulation (tACS) consists in delivering electric current to the brain using an oscillatory pattern that may entrain the rhythmic activity of cortical neurons. When delivered at gamma frequency, tACS modulates motor performance and GABA-A-ergic interneuron activity. OBJECTIVE: Since interneuronal discharges play a crucial role in brain plasticity phenomena, here we co-stimulated the primary motor cortex (M1) in healthy subjects by means of tACS during intermittent theta-burst stimulation (iTBS), a transcranial magnetic stimulation paradigm known to induce long-term potentiation (LTP)-like plasticity. METHODS: We measured and compared motor evoked potentials before and after gamma, beta and sham tACS-iTBS. While we delivered gamma-tACS, we also measured short-interval intracortical inhibition (SICI) to detect any changes in GABA-A-ergic neurotransmission. RESULTS: Gamma, but not beta and sham tACS, significantly boosted and prolonged the iTBS-induced after-effects. Interestingly, the extent of the gamma tACS-iTBS after-effects correlated directly with SICI changes. CONCLUSIONS: Overall, our findings point to a link between gamma oscillations, interneuronal GABA-A-ergic activity and LTP like plasticity in the human M1. Gamma tACS-iTBS co-stimulation might represent a new strategy to enhance and prolong responses to plasticity-inducing protocols, thereby lending itself to future applications in the neurorehabilitation setting. PMID- 29615369 TI - Are Modic changes in patients with chronic low back pain indicative of a worse clinical course? 10 years of follow-up. AB - OBJECTIVE: Establish the long-term (10 years) predictive value of Modic changes in the course of lumbar pain and the need for surgical treatment. MATERIAL AND METHOD: Observational longitudinal prospective cohort study. Comparison of progression at 10 years of 2 groups of patients with chronic lumbar pain: group A with Modic changes in MRI and group B with no Modic changes. EXCLUSION CRITERIA: neoplasia, inflammatory or infectious diseases, or previous surgery. Assessment was done with the aid of the VAS for low lumbar and radicular pain and the Oswestry Disability Questionnaire. The need for surgical or medical treatment and occupational disability during the study period was analyzed. For the statistical analyses, the Mann-Whitney U test and logistic regression were applied. RESULTS: Seventy patients, 24 male and 46 female, with a mean age of 56.5 years (35 in each group) were included in the study. No statistically significant differences in the intensity of lumbar pain, degree of impairment, or need for medical or surgical treatment (P>.05) were found in patients with Modic changes types 1, 2, or 3 between the baseline assessment and 10 years after. No statistically significant differences between patients with/without changes in Modic at 10 years of follow-up (P>.05) were determined. CONCLUSIONS: There is no relationship between Modic changes in MRI and greater intensity of lumbar pain or need for medical or surgical treatment at 10 years of follow-up. Modic changes cannot be considered a sign of bad prognosis by themselves, or an indication for surgery. PMID- 29615370 TI - Hepatectomy with or without the thoraco-abdominal approach: impact on perioperative outcome. AB - BACKGROUND: Hepatectomy using the thoraco-abdominal approach (TAA) compared to the abdominal approach (AA) remains under debate. This study assessed the perioperative outcomes of patients operated with or without TAA. METHODS: 1:1 propensity score-matched analysis was applied in 744 patients operated between 2007 and 2013, identifying 246 patients who underwent hepatectomy with TAA compared to 246 patients with AA. These groups were matched for demographics, liver disease, comorbidity, tumor features, and extent of resection. Rates of morbidity and mortality were the study endpoints. RESULTS: The rates of morbidity or mortality were not different. With the TAA length of the operations (P = 0.002), length of the Pringle maneuver (P = 0.012), and rate of blood transfusions (P = 0.041) were significantly different. Hospital stay was similar. Independent significant prognostic factors for adverse perioperative outcome were: renal comorbidity (OR = 2.7; P = 0.001), extent of the resection (OR = 3.7; P = 0.001), and increased BILCHE score (OR = 2.4; P = 0.002). CONCLUSIONS: Hepatectomy using the TAA was not associated with adverse perioperative outcome. The associations with length of operation, Pringle maneuver and blood transfusions may have reflected the complexity of the tumor presentation rather than the technical approach. PMID- 29615371 TI - Intraluminal brachytherapy boost following external beam radiotherapy with concurrent chemotherapy of oesophagus carcinoma: Results of a prospective observational study. AB - PURPOSE: The main objective of our study is to evaluate response and toxicity profile in patients receiving external beam radiotherapy with concurrent chemotherapy followed by intraluminal brachytherapy boost for a carcinoma of the oesophagus. MATERIAL AND METHODS: Twenty patients with biopsy-proven carcinoma of the oesophagus received external beam radiotherapy (50Gy in 25 fractions) with concurrent chemotherapy (cisplatin: 40mg/m2). After a gap of two to three weeks, intraluminal brachytherapy (10Gy in two fractions each 1 week apart by a high dose rate 60Co source) was given. Response was evaluated at 1 month and at 1 year of completion of treatment. In addition, acute and chronic toxicity was evaluated at 1 month and 6 months of treatment. RESULTS: Complete response were seen in 80% of patients and partial response in 20% at 1 month. Moreover, there were 65% complete response, 10% local recurrences, 15% patients showed local control with distant metastasis and 10% patients died at 1 year. Grade 1, grade 2 and grade 3 oesophagitis were seen in 10%, 70% and 20% of patients respectively. Stricture was seen in 40% of patients and fistula in 10% of patients. There was no spinal cord, cardiac and nephrotoxicity found. CONCLUSIONS: With the concept that high tumoricidal dose for adequate tumor control achieved by intraluminal brachytherapy as a mean of dose escalation, while sparing surrounding normal tissue and potentially improving therapeutic ratio, external beam radiotherapy followed by intraluminal brachytherapy could be a better choice for oesophagus carcinoma. PMID- 29615372 TI - Catheter-directed interventions compared with systemic thrombolysis achieve improved ventricular function recovery at a potentially lower complication rate for acute pulmonary embolism. AB - OBJECTIVE: Catheter-directed interventions (CDIs) are increasingly performed for acute pulmonary embolism (PE) as they are presumed to provide similar therapeutic benefits to systemic thrombolysis (ST) while decreasing the associated complications. The purpose of this study was to compare outcomes between CDI and ST. METHODS: Consecutive patients who underwent CDIs or ST for massive or submassive PE between 2006 and 2016 were identified. Clinical and echocardiographic parameters at baseline and after treatment were recorded. Clinical success was defined as decompensation resolution (or prevention) without major bleeding, stroke, other major treatment-related event, or in-hospital death. The chi2 test and t-test were used for between-groups comparisons. RESULTS: There were 213 patients who received CDIs (standard catheter thrombolysis in 56, ultrasound-assisted thrombolysis in 146, suction thrombectomies in 10, and pharmacomechanical thrombolysis in 1) and 104 patients who received ST (94 high dose [100 mg], 10 low dose [50 mg]). At baseline, CDI and ST groups had comparable echocardiographic parameters, demographics, and comorbidities, except for PE type (massive PE, 8.5% for CDIs vs 69.2% for ST; P < .001), age (60.2 +/- 14.9 years for CDIs vs 55.9 +/- 17.3 years for ST; P = .023), and renal function (glomerular filtration rate, 78.1 +/- 33.7 mL/min/1.73 m2 for CDIs vs 64.1 +/- 35.2 mL/min/1.73 m2 for ST; P = .001). Without stratifying per PE type, CDIs had a higher clinical success rate (87.8% vs 66.3%; P < .001) and a lower rate of major bleed (8.0% vs 19.2%; P = .003), stroke (1.4% vs 4.8%; P = .120), and death (1.4% vs 13.5%; P < .001). On stratifying by PE type, there was no difference in clinical success between groups. The mean reduction in right ventricular/left ventricular diameter ratio between baseline and the first post-treatment echocardiographic examination (within 30 days) was significantly higher for CDI (0.27 +/- 0.20 vs 0.18 +/- 0.15; P = .037). Beyond 30 days, there was no echocardiographic difference between groups. There was no significant difference in clinical outcomes and echocardiographic parameters between standard and ultrasound-assisted CDIs. CONCLUSIONS: CDIs provide improved recovery of right ventricular function compared with ST. Major bleeding and stroke complications may be lower, but larger studies are needed to validate this. CDIs are complementary to ST, and their use should be individualized on the basis of the patients' clinical presentation, risk profile, and local resources. PMID- 29615373 TI - Interventional management of central vein occlusion in patients with peripherally inserted central catheter placement. AB - OBJECTIVE: This study evaluated the incidence of central vein occlusion (CVO) and analyzed the interventional management for CVO during peripherally inserted central catheter (PICC) placement to suggest an adequate management protocol to ensure the success and patency of PICCs. METHODS: We retrospectively reviewed the records of 2568 PICCs to identify CVO in two medical centers between January 2016 and June 2017. Procedural images were reviewed for the following items: date and indication for the PICC; type of catheter; accessed vein and arm; characteristics of CVO on ascending arm venography; PICC placement technique; indwelling period of the PICC; and follow-up records. A guidewire passage trial was performed to the CVO, as follows: a trial with a 0.018-inch single or double guidewire through the pretrimmed PICC lumen; and a trial with a combination of a 0.035-inch guidewire and a curved 5F diagnostic catheter through the PICC introducer sheath. RESULTS: The incidence of CVO was 3.2% (71/2232), and 59 patients were analyzed (23 men; mean age, 69 +/- 11 years; median age, 80 years; age range, 31-92 years). Forty-four patients had thrombotic CVO, and 12 patients had acute thrombotic CVO. Thirty-six patients had occlusion of the left innominate vein, and six patients had contiguous involvement of the adjacent central vein. Forty two patients had obtuse stump morphology of CVO, and 28 patients had grade >III collateral development. The PICC indwelling time was statistically different between the group with successful catheter advancement (n = 36, success group) and the group with failed catheter advancement (n = 18, failure group; P = .007) with ipsilateral trimmed PICCs. Eight patients had a symptomatic catheter associated with upper extremity deep venous thrombosis (UEDVT; <30 days), one in the success group and seven in the failure group. The incidence of catheter associated UEDVT after primary PICC placement on each arm was statistically different between the success and failure groups (P = .004). CONCLUSIONS: A PICC passage trial for ipsilateral CVO is challenging but frequently successful with a simple guidewire technique, which can preserve catheter patency, decrease contralateral arm access, and prevent the development of new catheter-associated UEDVT. PMID- 29615374 TI - [Post therapeutic cervical cancer surveillance in France: Priority for examination]. PMID- 29615375 TI - All Patients Should Be Screened for Diabetes Before Total Joint Arthroplasty. AB - BACKGROUND: Diabetes is highly prevalent in patients with osteoarthritis before total joint arthroplasty and presents a higher risk of adverse postoperative outcomes. However, the rate of diabetes in this population and optimal screening strategies remain unknown. METHODS: We prospectively screened patients undergoing elective total joint arthroplasty for diabetes using glycated hemoglobin (HbA1c) and fasting blood glucose (FBG) levels. Screening was conducted within 2 time periods between 2012 and 2017. The prevalence of diabetes was assessed using a previous diagnosis of diabetes or, in the absence of diagnosis, by measuring if HbA1c >= 6.5% or FBG >= 126 mg/dL. Prediabetes was defined as 5.7% <= HbA1c <= 6.4% or 100 mg/dL <= FBG <= 125 mg/dL. Occurrence of a 90-day periprosthetic joint infection and wound complications was noted. RESULTS: A total of 1461 patients were included in the study. The prevalence of diabetes was 20.6%; 178 patients (59.1%) had diagnosed diabetes, and 123 patients (40.9%) had undiagnosed diabetes. Prediabetes was identified in 559 patients (38.3%), resulting in a combined total of 860 (58.9%) patients with diabetes and prediabetes. Total diabetic rates were significantly higher in patients aged >65 years, of nonwhite ethnicity, and undergoing total knee arthroplasty. No significant differences in periprosthetic joint infection and wound complications were observed while comparing patients with diagnosed and undiagnosed diabetes. CONCLUSION: A significant proportion of patients with undiagnosed diabetes and prediabetes were identified. Preadmission testing provides an opportunity to identify and address this condition, potentially reducing short-term arthroplasty-related complications and avoiding long-term systemic diabetic complications. We strongly recommend universal glycemic screening to all elective arthroplasty patients. PMID- 29615376 TI - The 22-Modifier in Reimbursement for Orthopedic Procedures: Hip Arthroplasty and Obesity Are Worth the Effort. AB - BACKGROUND: Orthopedic surgeons utilize the 22-modifier when billing for complex procedures under the American Medical Association's Current Procedural Terminology (CPT) for reasons such as excessive blood loss, anatomic abnormality, and morbid obesity, cases that would ideally be reimbursed at a higher rate to compensate for additional physician work and time. We investigated how the 22 modifier affects physician reimbursement in knee and hip arthroplasty. METHODS: We queried hospital billing data from 2009 to 2016, identifying all cases performed at our urban tertiary care orthopedic center for knee arthroplasty (CPT codes 27438, 27447, 27487, and 27488) and hip arthroplasty (CPT codes 27130, 27132, 27134, 27236). We extracted patient insurance status and reimbursement data to compare the average reimbursement between cases with and without the 22 modifier. RESULTS: We analyzed data from 2605 procedures performed by 10 providers. There were 136 cases with 22-modifiers. For knee arthroplasty (n = 1323), the 22-modifier did not significantly increase reimbursement after adjusting for insurer, provider, and fiscal year (4.2% dollars higher on average, P = .159). For hip arthroplasty (n = 1282), cases with a 22-modifier had significantly higher reimbursement than those without the 22-modifier (6.2% dollars more, P = .049). For hip arthroplasty cases with a 22-modifier, those noting morbid obesity were reimbursed 29% higher than those cases with other etiology. CONCLUSIONS: The effect of the 22-modifier on reimbursement amount is differential between knee and hip arthroplasty. Hip arthroplasty procedures coded as 22-modifier are reimbursed more than those without the 22-modifier. Providers should consider these potential returns when considering submitting a 22 modifier. PMID- 29615377 TI - Correct Assessment of Acetabular Component Orientation in Total Hip Arthroplasty From Plane Radiographs. AB - BACKGROUND: Correct positioning of the cup is an important factor in total hip arthroplasty. Assessing its position from a plain anteroposterior pelvic radiograph is known to be hampered by systemic errors. This study focuses on developing a correction method to adjust for these potential sources of error and to eliminate them based on a 3D geometric analysis. METHODS: Computed tomography scans of 113 (66 male, 47 female) pelvices were reconstructed and virtually projected onto a plain radiograph with varying rotational and translational positions. Thus cup inclination and anteversion as measured on a 2D-radiograph and in the 3D environment were correlated. Projected offset of the symphysis from the mid-sacrum served as a mean to measure pelvic right/left-rotation. Pelvic tilt was determined from the projected height of the contour of the small pelvis. Correction formulas were verified by projecting a gimbal-mounted artificial pelvis with a cup implanted in a known position. RESULTS: We found gender specific formulas that correct for malrotated and off-centered radiographs. Applying these formulas cup inclination was assessed as close as 1.3 degrees (+/ 1.90 degrees ) to the true 3D value and cup anteversion as close as 1 degrees (+/-1.91 degrees ) although deviations between directly measured plain values and corrected values rose up to 18 degrees . CONCLUSION: Inherent effects of central projection and malrotations due to pelvic tilt, pelvic rotation, and noncentered radiographs are corrected. Evaluation of radiographic inclination and anteversion of acetabular cups from plain 2D-radiographs show improved precision. Real values are approached better than 1.3 degrees when applying our correction formulas. PMID- 29615378 TI - Intraoperative Psoas Compartment Block vs Preoperative Fascia Iliaca Block for Pain Control After Direct Anterior Total Hip Arthroplasty: A Randomized Controlled Trial. AB - BACKGROUND: Modern joint arthroplasty protocols place an emphasis on minimizing patient-reported postoperative pain while minimizing opioid consumption. The use of multimodal pain management protocols has been reported to improve patient outcomes and satisfaction after total hip arthroplasty. METHODS: In a prospective, single-surgeon trial, 50 patients undergoing primary direct anterior approach total hip arthroplasty were randomized to receive a preoperative fascia iliaca compartment block (FICB) or an intraoperative surgeon-delivered psoas compartment block (PCB). Patient-reported pain was recorded in the postanesthesia care unit, recovery floor and 3 weeks postoperatively. Opioid use was recorded during the hospital stay. RESULTS: Average visual analog scale pain scores in the postanesthesia care unit were 38.7 +/- 8.7 vs 35.6 +/- 8.3 (P = .502) for the preoperative FICB and intraoperative PCB groups, respectively. No significant difference was found between groups at the 3-week visit for postoperative pain (FICB: 2.9 +/- 1.4; PCB: 3.2 +/- 2.0; P = .970) and patient-reported pain satisfaction (FICB: 8.8 +/- 2.2; PCB: 9.7 +/- 0.6; P = .110). CONCLUSION: During the direct anterior approach for total hip arthroplasty, PCB is an effective and efficient regional anesthesia technique. It may be used to obtain satisfactory postoperative pain control and patient satisfaction while decreasing hospital resources. PMID- 29615379 TI - Doxycycline suppresses Chlamydia pneumoniae induced interferon-gamma responses in peripheral blood mononuclear cells in children with allergic asthma. AB - Persistent respiratory infections caused by Chlamydia pneumoniae have been implicated in the pathogenesis of chronic diseases (e.g. asthma). Antibiotics are used to treat C. pneumoniae respiratory infections; however, the use of antibiotics as anti-inflammatory agents in treatment of asthma remains controversial. The current study investigated whether ciprofloxacin, azithromycin, or doxycycline can suppress C. pneumoniae-induced production of immunoglobulin (Ig) E or cytokines in peripheral blood mononuclear cells (PBMC) obtained from asthmatic children. Apart from blood, nasopharyngeal swab specimens were also collected to test for the presence of C. pneumoniae and/or M. pneumoniae (qPCR). PBMC (1.5 x 106) from asthmatic pediatric patients (N = 18) were infected or mock infected for 1 h +/- C. pneumoniae AR-39 at a multiplicity of infection (MOI) = 0.1, and cultured +/- ciprofloxacin, azithromycin, or doxycycline (0.1 or 1.0 MUg/mLmL) for either 48 h (cytokines) or 10 days (IgE). Interleukin (IL)-4, interferon (IFN)-gamma and IgE levels in supernatants were measured (ELISA). When PBMC were infected with C. pneumoniae, IL-4 and IFNgamma production increased (p = 0.06 and 0.03, respectively); IgE levels were low. The now-elevated levels of IL-4 didn't decrease significantly after addition of ciprofloxacin, azithromycin, or doxycycline. However, infected PBMC IFNgamma formation decreased significantly when 0.1 MUg/mL doxycycline was employed (p = 0.04); no dose of ciprofloxacin or azithromycin had any impact. This inhibitory outcome with doxycycline lends support to the use of tetracyclines as immune modulators and anti-inflammatory medications in treatment of C. pneumoniae infected asthma patients. PMID- 29615380 TI - [AntibioticScout.ch: Decision support for the prudent use of antimicrobials: Application in cattle]. AB - INTRODUCTION: The administration of antibiotics in livestock has been criticized for many years, in particular because of an inappropriate use and the appearance of antibiotic residues in the environment, which can promote the emergence and spread of resistant bacteria. However, antibiotics are essential for the successful and sustainable control of bacterial pathogens. With the aim of optimizing the use of antibiotics in food animals and minimizing the prevalence of resistant bacteria, AntibioticScout. ch provides a decision aid for the prudent use of antimicrobial drugs. This approach emphasizes the importance of supportive therapy and the hallmarks of preventive concepts. Procedures to improve animal health and animal welfare in accordance with the principles of good veterinary practice are primary and effective tools to reduce the use of antimicrobial drugs. The necessary reduction in the use of antibiotics must, therefore, be accompanied by appropriate management strategies in animal husbandry. In particular, hygiene, animal welfare and biosecurity measures are crucial to ensure an optimal health status in farm animals. PMID- 29615381 TI - Hyperfibrinolysis diagnosed with rotational thromboelastometry and treated with tranexamic acid in a dog with acute traumatic coagulopathy. AB - INTRODUCTION: A 4-year old male Australian Cattle Dog involved in a road traffic accident was presented with severe polytrauma to the Small Animal Clinic, University of Zurich. He was presented in hemorrhagic shock, with an initial lactate of 10.3mmol/l and ongoing bleeding from multiple injury sites. Acute traumatic coagulopathy diagnosed with ROTEM within one hour after accident showed marked hypocoagulation and hyperfibrinolysis. Treatment with a total dose of 40mg/kg of tranexamic acid intravenously resulted in successful elimination of hyperfibrinolysis in the following, serially measured ROTEM tracings. PMID- 29615382 TI - Severe Heinz body anemia and methemoglobinemia in a kitten with chronic diarrhea. AB - INTRODUCTION: A 2-month-old kitten was referred for depression and partial anorexia since 3 days and chronic diarrhea lasting for over 3 weeks. General physical examination showed pale and cyanotic mucous membranes. Blood sample was of brownish appearance. Venous blood gas analysis and complete blood count showed 16% methemoglobin level and severe regenerative anemia with Heinz bodies in about 40% of the erythrocytes, respectively. The kitten was transfused with fresh whole blood and treated with supportive care, antimicrobial and antioxidant agents. The kitten totally recovered. To the authors' knowledge, this represents the first case report of severe Heinz body hemolytic anemia and methemoglobinemia with concurrent chronic diarrhea in a young kitten. Diarrhea resolution coincided with Heinz bodies and methemoglobin disappearance. The possibility that diarrhea might have stimulated an inflammatory state causing release of oxygen radicals and prolonged erythrocytes oxidative damage has been discussed. PMID- 29615383 TI - HIV Clustering in Mississippi: Spatial Epidemiological Study to Inform Implementation Science in the Deep South. AB - BACKGROUND: In recent years, more than half of new HIV infections in the United States occur among African Americans in the Southeastern United States. Spatial epidemiological analyses can inform public health responses in the Deep South by identifying HIV hotspots and community-level factors associated with clustering. OBJECTIVE: The goal of this study was to identify and characterize HIV clusters in Mississippi through analysis of state-level HIV surveillance data. METHODS: We used a combination of spatial epidemiology and statistical modeling to identify and characterize HIV hotspots in Mississippi census tracts (n=658) from 2008 to 2014. We conducted spatial analyses of all HIV infections, infections among men who have sex with men (MSM), and infections among African Americans. Multivariable logistic regression analyses identified community-level sociodemographic factors associated with HIV hotspots considering all cases. RESULTS: There were HIV hotspots for the entire population, MSM, and African American MSM identified in the Mississippi Delta region, Southern Mississippi, and in greater Jackson, including surrounding rural counties (P<.05). In multivariable models for all HIV cases, HIV hotspots were significantly more likely to include urban census tracts (adjusted odds ratio [AOR] 2.01, 95% CI 1.20-3.37) and census tracts that had a higher proportion of African Americans (AOR 3.85, 95% CI 2.23-6.65). The HIV hotspots were less likely to include census tracts with residents who had less than a high school education (AOR 0.95, 95% CI 0.92-0.98), census tracts with residents belonging to two or more racial/ethnic groups (AOR 0.46, 95% CI 0.30-0.70), and census tracts that had a higher percentage of the population living below the poverty level (AOR 0.51, 95% CI 0.28-0.92). CONCLUSIONS: We used spatial epidemiology and statistical modeling to identify and characterize HIV hotspots for the general population, MSM, and African Americans. HIV clusters concentrated in Jackson and the Mississippi Delta. African American race and urban location were positively associated with clusters, whereas having less than a high school education and having a higher percentage of the population living below the poverty level were negatively associated with clusters. Spatial epidemiological analyses can inform implementation science and public health response strategies, including improved HIV testing, targeted prevention and risk reduction education, and tailored preexposure prophylaxis to address HIV disparities in the South. PMID- 29615384 TI - Analysis of Content Shared in Online Cancer Communities: Systematic Review. AB - BACKGROUND: The content that cancer patients and their relatives (ie, posters) share in online cancer communities has been researched in various ways. In the past decade, researchers have used automated analysis methods in addition to manual coding methods. Patients, providers, researchers, and health care professionals can learn from experienced patients, provided that their experience is findable. OBJECTIVE: The aim of this study was to systematically review all relevant literature that analyzes user-generated content shared within online cancer communities. We reviewed the quality of available research and the kind of content that posters share with each other on the internet. METHODS: A computerized literature search was performed via PubMed (MEDLINE), PsycINFO (5 and 4 stars), Cochrane Central Register of Controlled Trials, and ScienceDirect. The last search was conducted in July 2017. Papers were selected if they included the following terms: (cancer patient) and (support group or health communities) and (online or internet). We selected 27 papers and then subjected them to a 14 item quality checklist independently scored by 2 investigators. RESULTS: The methodological quality of the selected studies varied: 16 were of high quality and 11 were of adequate quality. Of those 27 studies, 15 were manually coded, 7 automated, and 5 used a combination of methods. The best results can be seen in the papers that combined both analytical methods. The number of analyzed posts ranged from 200 to 1,500,000; the number of analyzed posters ranged from 75 to 90,000. The studies analyzing large numbers of posts mainly related to breast cancer, whereas those analyzing small numbers were related to other types of cancers. A total of 12 studies involved some or entirely automatic analysis of the user-generated content. All the authors referred to two main content categories: informational support and emotional support. In all, 15 studies reported only on the content, 6 studies explicitly reported on content and social aspects, and 6 studies focused on emotional changes. CONCLUSIONS: In the future, increasing amounts of user-generated content will become available on the internet. The results of content analysis, especially of the larger studies, give detailed insights into patients' concerns and worries, which can then be used to improve cancer care. To make the results of such analyses as usable as possible, automatic content analysis methods will need to be improved through interdisciplinary collaboration. PMID- 29615385 TI - Health-Related Internet Use by Children and Adolescents: Systematic Review. AB - BACKGROUND: The internet is widely used by children and adolescents, who generally have a high level of competency with technology. Thus, the internet has become a great resource for supporting youth self-care and health-related services. However, few studies have explored adolescents' internet use for health related matters. OBJECTIVE: The objective of this systematic literature review was to examine the phenomenon of children and adolescents' health-related internet use and to identify gaps in the research. METHODS: A total of 19 studies were selected from a search of major electronic databases: PubMed, Cumulative Index of Nursing and Allied Health Literature, and PsycINFO using the following search terms: "health-related internet use," "eHealth," "Internet use for health related purpose," "Web-based resource," "health information seeking," and "online resource," combined with "child," "adolescent," "student," "youth," and "teen." The children's and adolescents' ages were limited to 24 years and younger. The search was conducted from September 2015 to October 2017. The studies identified to contain youth (<24 years) health-related internet use were all published in peer-reviewed journals in the past 10 years; these studies examined general internet use seeking health care services, resources, information, or using the internet for health promotion and self-care. Studies were excluded if they explored the role of the internet as a modality for surveys, recruitment, or searching for relevant literature without specifically aiming to study participants' health-related internet use; focused solely on quality assurance for specific websites; or were designed to test a specific internet-based intervention. RESULTS: Interesting patterns in adolescents' health-related internet use, such as seeking preventative health care and specific information about medical issues, were identified. Quantitative studies reported rates of the internet use and access among youth, and the purpose and patterns of health related internet use among youth were identified. A major objective of health related internet use is to gain information, but there are inconsistencies in adolescents' perceptions of health-related internet use. CONCLUSIONS: This study's findings provide important information on how youth seek information and related support systems for their health care on the internet. The conceptual and methodological limitations of the identified studies, such as the lack of a theoretical background and unrepresentative samples, are discussed, and gaps within the studies are identified for future research. This review also suggests important features for potential Web-based health interventions for children and adolescents. PMID- 29615386 TI - Vaccine Images on Twitter: Analysis of What Images are Shared. AB - BACKGROUND: Visual imagery plays a key role in health communication; however, there is little understanding of what aspects of vaccine-related images make them effective communication aids. Twitter, a popular venue for discussions related to vaccination, provides numerous images that are shared with tweets. OBJECTIVE: The objectives of this study were to understand how images are used in vaccine related tweets and provide guidance with respect to the characteristics of vaccine-related images that correlate with the higher likelihood of being retweeted. METHODS: We collected more than one million vaccine image messages from Twitter and characterized various properties of these images using automated image analytics. We fit a logistic regression model to predict whether or not a vaccine image tweet was retweeted, thus identifying characteristics that correlate with a higher likelihood of being shared. For comparison, we built similar models for the sharing of vaccine news on Facebook and for general image tweets. RESULTS: Most vaccine-related images are duplicates (125,916/237,478; 53.02%) or taken from other sources, not necessarily created by the author of the tweet. Almost half of the images contain embedded text, and many include images of people and syringes. The visual content is highly correlated with a tweet's textual topics. Vaccine image tweets are twice as likely to be shared as nonimage tweets. The sentiment of an image and the objects shown in the image were the predictive factors in determining whether an image was retweeted. CONCLUSIONS: We are the first to study vaccine images on Twitter. Our findings suggest future directions for the study and use of vaccine imagery and may inform communication strategies around vaccination. Furthermore, our study demonstrates an effective study methodology for image analysis. PMID- 29615387 TI - Strengthening Routine Data Systems to Track the HIV Epidemic and Guide the Response in Sub-Saharan Africa. AB - The global HIV response has entered a new phase with the recommendation of treating all persons living with HIV with antiretroviral therapy, and with the goals of reducing new infections and AIDS-related deaths to fewer than 500,000 by 2020. This new phase has intensive data requirements that will need to utilize routine data collected through service delivery platforms to monitor progress toward these goals. With a focus on sub-Saharan African, we present the following priorities to improve the demand, supply, and use of routine HIV data: (1) strengthening patient-level HIV data systems that support continuity of clinical care and document sentinel events; (2) leveraging data from HIV testing programs; (3) using targeting data collection in communities and among clients; and (4) building capacity and promoting a culture of HIV data quality assessment and use. When fully leveraged, routine data can efficiently provide timely information at a local level to inform action, as well as provide information at scale with wide geographic coverage to strengthen estimation efforts. PMID- 29615388 TI - Quality of Web Information About Palliative Care on Websites from the United States and Japan: Comparative Evaluation Study. AB - BACKGROUND: Patients and their families are able to obtain information about palliative care from websites easily nowadays. However, there are concerns on the accuracy of information on the Web and how up to date it is. OBJECTIVE: The objective of this study was to elucidate problematic points of medical information about palliative care obtained from websites, and to compare the quality of the information between Japanese and US websites. METHODS: We searched Google Japan and Google USA for websites relating to palliative care. We then evaluated the top 50 websites from each search using the DISCERN and LIDA instruments. RESULTS: We found that Japanese websites were given a lower evaluation of reliability than US websites. In 3 LIDA instrument subcategories engagability (P<.001), currency (P=.001), and content production procedure (P<.001)-US websites scored significantly higher and had large effect sizes. CONCLUSIONS: Our results suggest that Japanese websites have problems with the frequency with which they are updated, their update procedures and policies, and the scrutiny process the evidence must undergo. Additionally, there was a weak association between search ranking and reliability, and simultaneously we found that reliability could not be assessed by search ranking alone. PMID- 29615390 TI - BMA registers interest in Bawa-Garba's appeal against erasure. PMID- 29615389 TI - Management of the General Process of Parenteral Nutrition Using mHealth Technologies: Evaluation and Validation Study. AB - BACKGROUND: Any system applied to the control of parenteral nutrition (PN) ought to prove that the process meets the established requirements and include a repository of records to allow evaluation of the information about PN processes at any time. OBJECTIVE: The goal of the research was to evaluate the mobile health (mHealth) app and validate its effectiveness in monitoring the management of the PN process. METHODS: We studied the evaluation and validation of the general process of PN using an mHealth app. The units of analysis were the PN bags prepared and administered at the Son Espases University Hospital, Palma, Spain, from June 1 to September 6, 2016. For the evaluation of the app, we used the Poststudy System Usability Questionnaire and subsequent analysis with the Cronbach alpha coefficient. Validation was performed by checking the compliance of control for all operations on each of the stages (validation and transcription of the prescription, preparation, conservation, and administration) and by monitoring the operative control points and critical control points. RESULTS: The results obtained from 387 bags were analyzed, with 30 interruptions of administration. The fulfillment of stages was 100%, including noncritical nonconformities in the storage control. The average deviation in the weight of the bags was less than 5%, and the infusion time did not present deviations greater than 1 hour. CONCLUSIONS: The developed app successfully passed the evaluation and validation tests and was implemented to perform the monitoring procedures for the overall PN process. A new mobile solution to manage the quality and traceability of sensitive medicines such as blood-derivative drugs and hazardous drugs derived from this project is currently being deployed. PMID- 29615391 TI - Differences in rates of switchbacks after switching from branded to authorized generic and branded to generic drug products: cohort study. AB - OBJECTIVES: To compare rates of switchbacks to branded drug products for patients switched from branded to authorized generic drug products, which have the same active ingredients, appearance, and excipients as the branded product, with patients switched from branded to generic drug products, which have the same active ingredients as the branded product but may differ in appearance and excipients. DESIGN: Observational cohort study. SETTING: Private (a large commercial health plan) and public (Medicaid) insurance programs in the US. PARTICIPANTS: Beneficiaries of a large US commercial health insurer between 2004 and 2013 (primary cohort) and Medicaid beneficiaries between 2000 and 2010 (replication cohort). MAIN OUTCOME MEASURES: Patients taking branded products for one of the study drugs (alendronate tablets, amlodipine tablets, amlodipine benazepril capsules, calcitonin salmon nasal spray, escitalopram tablets, glipizide extended release tablets, quinapril tablets, and sertraline tablets) were identified when they switched to an authorized generic or a generic drug product after the date of market entry of generic drug products. These patients were followed for switchbacks to the branded drug product in the year after their switch to an authorized generic or a generic drug product. Cox proportional hazard models were used to estimate hazard ratios and 95% confidence intervals after adjusting for demographics, including age, sex, and calendar year. Inverse variance meta-analysis was used to pool adjusted hazard ratios across all drug products. RESULTS: A total of 94 909 patients switched from branded to authorized generic drug products and 116 017 patients switched from branded to generic drug products and contributed to the switchback analysis. Unadjusted incidence rates of switchback varied across drug products, ranging from a low of 3.8 per 100 person years (for alendronate tablets) to a high of 17.8 per 100 person years (for amlodipine-benazepril capsules), with an overall rate of 8.2 per 100 person years across all drug products. Adjusted switchback rates were consistently lower for patients who switched from branded to authorized generic drug products compared with branded to generic drug products in the primary cohort (pooled hazard ratio 0.72, 95% confidence interval 0.64 to 0.81). Similar results (0.75, 0.62 to 0.91) were observed in the replication cohort. CONCLUSION: Switching from branded to authorized generic drug products was associated with lower switchback rates compared with switching from branded to generic drug products. PMID- 29615392 TI - Tobacco control policies in relation to child health and perinatal health outcomes. PMID- 29615393 TI - Ticking time bomb? High time for chronobiological research. PMID- 29615395 TI - Characteristics and Ongoing Autoimmunity of Patients With Long-standing Type 1 Diabetes Living in China. PMID- 29615394 TI - Nephrotoxicity and Chinese Herbal Medicine. AB - Chinese herbal medicine has been practiced for the prevention, treatment, and cure of diseases for thousands of years. Herbal medicine involves the use of natural compounds, which have relatively complex active ingredients with varying degrees of side effects. Some of these herbal medicines are known to cause nephrotoxicity, which can be overlooked by physicians and patients due to the belief that herbal medications are innocuous. Some of the nephrotoxic components from herbs are aristolochic acids and other plant alkaloids. In addition, anthraquinones, flavonoids, and glycosides from herbs also are known to cause kidney toxicity. The kidney manifestations of nephrotoxicity associated with herbal medicine include acute kidney injury, CKD, nephrolithiasis, rhabdomyolysis, Fanconi syndrome, and urothelial carcinoma. Several factors contribute to the nephrotoxicity of herbal medicines, including the intrinsic toxicity of herbs, incorrect processing or storage, adulteration, contamination by heavy metals, incorrect dosing, and interactions between herbal medicines and medications. The exact incidence of kidney injury due to nephrotoxic herbal medicine is not known. However, clinicians should consider herbal medicine use in patients with unexplained AKI or progressive CKD. In addition, exposure to herbal medicine containing aristolochic acid may increase risk for future uroepithelial cancers, and patients require appropriate postexposure screening. PMID- 29615397 TI - Deep anterior lamellar keratoplasty: dissection plane with viscoelastic and air can be different. AB - AIMS: To investigate and define the nature of big bubbles (BB) formed by injection of viscoelastic in deep anterior lamellar keratoplasty. METHODS: Intrastromal injections of 0.1 and 0.3 mL of sodium hyaluronate 1.2% and 0.6% were made into sclera-corneal discs (n = 32) at superficial (anterior-third), midstromal (middle-third) and deep (posterior-third) levels to simulate deep anterior lamellar keratoplasty. Postinjection optical coherence tomograms (OCT) were obtained with the needle in situ. The samples were sectioned and examined histologically. Twelve control samples were injected with air. RESULTS: With superficial injections (n=8) only intrastromal accumulation of viscoelastic was noted. With midstromal injections (n=10) intrastromal accumulation of viscoelastic (n=6) and intrastromal big bubbles (IBB) (n=4) with substantial and variable stromal tissue in the walls were noted. No type 1, type 2 or mixed BB were noted. With deep injections (n=14), type 1 BB (n=4), IBB (n=4) and mixed BB (n=6) were obtained.There was no difference in the results with the two different concentrations of viscoelastic used. With air injection (n=12), 10 type 1 and 1 type 2 BB and 1 mixed BB were obtained. No IBB was noted. CONCLUSIONS: BB obtained by injection of viscoelastic and air can be different. The former tends to occur at the site of injection, especially with midstromal injections, takes the form of tissue separation by stretch and tearing and does not cleave in a consistent plane like air. Surgeons should be aware of IBB created by viscodissection and not confuse it for a type1 BB. Intraoperative OCT should help identify IBB. PMID- 29615398 TI - IL21 Therapy Combined with PD-1 and Tim-3 Blockade Provides Enhanced NK Cell Antitumor Activity against MHC Class I-Deficient Tumors. AB - Increased expression of coinhibitory molecules such as PD-1 and Tim-3 on NK cells has been demonstrated in advanced cancer patients who harbor MHC class I deficient tumors. However, even in preclinical models, the antitumor effects of checkpoint blockade on NK cells have not been clearly elucidated. Here, we show that anti-PD-1/anti-Tim-3 treatment suppressed tumor progression in mice bearing MHC class I-deficient tumors, and the suppression was further enhanced by recombinant IL21 (rIL21) treatments through an NK-cell-dependent mechanism. We also show that the intratumoral delivery of rIL21 attracted NK cells to the tumor site in a CXCR3-dependent fashion. A combination of IL21 and checkpoint blockade facilitated the effector function of exhausted NK cells in cancer patients. Given the effects of the checkpoint blockade and rIL21 combination on NK cells infiltrating into MHC class I-deficient tumors, we suggest that the efficacy of checkpoint blockade can be enhanced through the administration of IL21 for advanced cancer patients with MHC class I-low/deficient tumors. Cancer Immunol Res; 6(6); 685-95. (c)2018 AACR. PMID- 29615396 TI - Different knowledge, different styles of reasoning: a challenge for guideline development. PMID- 29615399 TI - Human GUCY2C-Targeted Chimeric Antigen Receptor (CAR)-Expressing T Cells Eliminate Colorectal Cancer Metastases. AB - One major hurdle to the success of adoptive T-cell therapy is the identification of antigens that permit effective targeting of tumors in the absence of toxicities to essential organs. Previous work has demonstrated that T cells engineered to express chimeric antigen receptors (CAR-T cells) targeting the murine homolog of the colorectal cancer antigen GUCY2C treat established colorectal cancer metastases, without toxicity to the normal GUCY2C-expressing intestinal epithelium, reflecting structural compartmentalization of endogenous GUCY2C to apical membranes comprising the intestinal lumen. Here, we examined the utility of a human-specific, GUCY2C-directed single-chain variable fragment as the basis for a CAR construct targeting human GUCY2C-expressing metastases. Human GUCY2C-targeted murine CAR-T cells promoted antigen-dependent T-cell activation quantified by activation marker upregulation, cytokine production, and killing of GUCY2C-expressing, but not GUCY2C-deficient, cancer cells in vitro GUCY2C CAR-T cells provided long-term protection against lung metastases of murine colorectal cancer cells engineered to express human GUCY2C in a syngeneic mouse model. GUCY2C murine CAR-T cells recognized and killed human colorectal cancer cells endogenously expressing GUCY2C, providing durable survival in a human xenograft model in immunodeficient mice. Thus, we have identified a human GUCY2C-specific CAR-T cell therapy approach that may be developed for the treatment of GUCY2C expressing metastatic colorectal cancer. Cancer Immunol Res; 6(5); 509-16. (c)2018 AACR. PMID- 29615401 TI - CMS to Cover NGS Companion Diagnostics. AB - The Centers for Medicare & Medicaid Services recently announced that next generation sequencing-based companion diagnostics will be covered for beneficiaries with advanced cancer. This announcement takes coverage decisions out of the hands of local contractors, providing more uniform access to such tests. PMID- 29615400 TI - NetH2pan: A Computational Tool to Guide MHC Peptide Prediction on Murine Tumors. AB - With the advancement of personalized cancer immunotherapies, new tools are needed to identify tumor antigens and evaluate T-cell responses in model systems, specifically those that exhibit clinically relevant tumor progression. Key transgenic mouse models of breast cancer are generated and maintained on the FVB genetic background, and one such model is the mouse mammary tumor virus polyomavirus middle T antigen (MMTV-PyMT) mouse-an immunocompetent transgenic mouse that exhibits spontaneous mammary tumor development and metastasis with high penetrance. Backcrossing the MMTV-PyMT mouse from the FVB strain onto a C57BL/6 genetic background, in order to leverage well-developed C57BL/6 immunologic tools, results in delayed tumor development and variable metastatic phenotypes. Therefore, we initiated characterization of the FVB MHC class I H-2q haplotype to establish useful immunologic tools for evaluating antigen specificity in the murine FVB strain. Our study provides the first detailed molecular and immunoproteomic characterization of the FVB H-2q MHC class I alleles, including >8,500 unique peptide ligands, a multiallele murine MHC peptide prediction tool, and in vivo validation of these data using MMTV-PyMT primary tumors. This work allows researchers to rapidly predict H-2 peptide ligands for immune testing, including, but not limited to, the MMTV-PyMT model for metastatic breast cancer. Cancer Immunol Res; 6(6); 636-44. (c)2018 AACR. PMID- 29615402 TI - Screening Tool for Gynecologic Cancers Assessed. AB - Researchers have developed a test called PapSEEK that detects endometrial and ovarian cancers by analyzing DNA samples for mutations and aberrations in chromosome number. In a large, retrospective study, the test detected 81% of endometrial cancers and 33% of ovarian cancers with a low false-positive rate. PMID- 29615404 TI - The tumor suppressive TGF-beta/SMAD1/S1PR2 signaling axis is recurrently inactivated in diffuse large B-cell lymphoma. AB - The sphingosine-1-phosphate receptor S1PR2 and its downstream signaling pathway are commonly silenced in diffuse large B-cell lymphoma (DLBCL), either by mutational inactivation or through negative regulation by the oncogenic transcription factor FOXP1. In this study, we examined the upstream regulators of S1PR2 expression and have newly identified the transforming growth factor-beta (TGF-beta)/TGF-betaR2/SMAD1 axis as critically involved in S1PR2 transcriptional activation. Phosphorylated SMAD1 directly binds to regulatory elements in the S1PR2 locus as assessed by chromatin immunoprecipitation, and the CRISPR-mediated genomic editing of S1PR2, SMAD1, or TGFBR2 in DLBCL cell lines renders cells unresponsive to TGF-beta-induced apoptosis. DLBCL clones lacking any 1 of the 3 factors have a clear growth advantage in vitro, as well as in subcutaneous xenotransplantation models, and in a novel model of orthotopic growth of DLBCL cells in the spleens and bone marrow of MISTRG mice expressing various human cytokines. The loss of S1pr2 induces hyperproliferation of the germinal center (GC) B-cell compartment of immunized mice and accelerates MYC-driven lymphomagenesis in spontaneous and serial transplantation models. The specific loss of Tgfbr2 in murine GC B-cell phenocopies the effects of S1pr2 loss on GC B cell hyperproliferation. Finally, we show that SMAD1 expression is aberrantly downregulated in >85% of analyzed DLBCL patients. The combined results uncover an important novel tumor suppressive function of the TGF-beta/TGF-betaR2/SMAD1/S1PR2 axis in DLBCL, and show that DLBCL cells have evolved to inactivate the pathway at the level of SMAD1 expression. PMID- 29615403 TI - SOX11 augments BCR signaling to drive MCL-like tumor development. AB - Mantle cell lymphoma (MCL) is characterized by increased B-cell receptor (BCR) signaling, and BTK inhibition is an effective therapeutic intervention in MCL patients. The mechanisms leading to increased BCR signaling in MCL are poorly understood, as mutations in upstream regulators of BCR signaling such as CD79A, commonly observed in other lymphomas, are rare in MCL. The transcription factor SOX11 is overexpressed in the majority (78% to 93%) of MCL patients and is considered an MCL-specific oncogene. So far, attempts to understand SOX11 function in vivo have been hampered by the lack of appropriate animal models, because germline deletion of SOX11 is embryonically lethal. We have developed a transgenic mouse model (EMU-SOX11-EGFP) in the C57BL/6 background expressing murine SOX11 and EGFP under the control of a B-cell-specific IgH-EMU enhancer. The overexpression of SOX11 exclusively in B cells exhibits oligoclonal B-cell hyperplasia in the spleen, bone marrow, and peripheral blood, with an immunophenotype (CD5+CD19+CD23-) identical to human MCL. Furthermore, phosphocytometric time-of-flight analysis of the splenocytes from these mice shows hyperactivation of pBTK and other molecules in the BCR signaling pathway, and serial bone marrow transplant from transgenic donors produces lethality with decreasing latency. We report here that overexpression of SOX11 in B cells promotes BCR signaling and a disease phenotype that mimics human MCL. PMID- 29615405 TI - The enigma of monosomy 7. AB - Since a report of some 50 years ago describing refractory anemia associated with group C monosomy, monosomy 7 (-7) and interstitial deletions of chromosome 7 (del(7q)) have been established as one of the most frequent chromosomal aberrations found in essentially all types of myeloid tumors regardless of patient age and disease etiology. In the last century, researchers sought recessive myeloid tumor-suppressor genes by attempting to determine commonly deleted regions (CDRs) in del(7q) patients. However, these efforts were not successful. Today, tumor suppressors located in 7q are believed to act in a haploinsufficient fashion, and powerful new technologies such as microarray comparative genomic hybridization and high-throughput sequencing allow comprehensive searches throughout the genes encoded on 7q. Among those proposed as promising candidates, 4 have been validated by gene targeting in mouse models. SAMD9 (sterile alpha motif domain 9) and SAMD9L (SAMD9-like) encode related endosomal proteins, mutations of which cause hereditary diseases with strong propensity to infantile myelodysplastic syndrome (MDS) harboring monosomy 7. Because MDS develops in SAMD9L-deficient mice over their lifetime, SAMD9/SAMD9L are likely responsible for sporadic MDS with -7/del(7q) as the sole anomaly. EZH2 (enhancer of zeste homolog 2) and MLL3 (mixed lineage leukemia 3) encode histone modifying enzymes; loss-of-function mutations of these are detected in some myeloid tumors at high frequencies. In contrast to SAMD9/SAMD9L, loss of EZH2 or MLL3 likely contributes to myeloid tumorigenesis in cooperation with additional specific gene alterations such as of TET2 or genes involved in the p53/Ras pathway, respectively. Distinctive roles with different significance of the loss of multiple responsible genes render the complex nature of myeloid tumors carrying -7/del(7q). PMID- 29615406 TI - Selenoproteins regulate stress erythroid progenitors and spleen microenvironment during stress erythropoiesis. AB - Micronutrient selenium (Se) plays a key role in redox regulation through its incorporation into selenoproteins as the 21st amino acid selenocysteine (Sec). Because Se deficiency appears to be a cofactor in the anemia associated with chronic inflammatory diseases, we reasoned that selenoproteins may contribute to erythropoietic recovery from anemia, referred to as stress erythropoiesis. Here, we report that loss of selenoproteins through Se deficiency or by mutation of the Sec tRNA (tRNA[Sec]) gene (Trsp) severely impairs stress erythropoiesis at 2 stages. Early stress erythroid progenitors failed to expand and properly differentiate into burst-forming unit-erythroid cells , whereas late-stage erythroid progenitors exhibited a maturation defect that affected the transition of proerythroblasts to basophilic erythroblasts. These defects were, in part, a result of the loss of selenoprotein W (SelenoW), whose expression was reduced at both transcript and protein levels in Se-deficient erythroblasts. Mutation of SelenoW in the bone marrow cells significantly decreased the expansion of stress burst-forming unit-erythroid cell colonies, which recapitulated the phenotypes induced by Se deficiency or mutation of Trsp Similarly, mutation of SelenoW in murine erythroblast (G1E) cell line led to defects in terminal differentiation. In addition to the erythroid defects, the spleens of Se-deficient mice contained fewer red pulp macrophages and exhibited impaired development of erythroblastic island macrophages, which make up the niche supporting erythroblast development. Taken together, these data reveal a critical role of selenoproteins in the expansion and development of stress erythroid progenitors, as well as the erythroid niche during acute anemia recovery. PMID- 29615408 TI - GPs retain power to prescribe over-the-counter medicines. PMID- 29615409 TI - Response to: 'Comment on "Evaluation of the impact of concomitant fibromyalgia on TNF alpha blockers' effectiveness in axial spondyloarthritis: results of a prospective, multicentre study" by Molto et al: still a long way to go in the assessment of patients with spondyloarthritis and concomitant fibromyalgia?' by Altobelli et al. PMID- 29615407 TI - Effect of pasta in the context of low-glycaemic index dietary patterns on body weight and markers of adiposity: a systematic review and meta-analysis of randomised controlled trials in adults. AB - OBJECTIVE: Carbohydrate staples such as pasta have been implicated in the obesity epidemic. It is unclear whether pasta contributes to weight gain or like other low-glycaemic index (GI) foods contributes to weight loss. We synthesised the evidence of the effect of pasta on measures of adiposity. DESIGN: Systematic review and meta-analysis using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. DATA SOURCES: MEDLINE, Embase, CINAHL and the Cochrane Library were searched through 7 February 2017. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: We included randomised controlled trials >=3 weeks assessing the effect of pasta alone or in the context of low-GI dietary patterns on measures of global (body weight, body mass index (BMI), body fat) and regional (waist circumference (WC), waist-to-hip ratio (WHR), sagittal abdominal diameter (SAD)) adiposity in adults. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted data and assessed risk of bias. Data were pooled using the generic inverse-variance method and expressed as mean differences (MDs) with 95% CIs. Heterogeneity was assessed (Cochran Q statistic) and quantified (I2 statistic). GRADE assessed the certainty of the evidence. RESULTS: We identified no trial comparisons of the effect of pasta alone and 32 trial comparisons (n=2448 participants) of the effect of pasta in the context of low-GI dietary patterns. Pasta in the context of low-GI dietary patterns significantly reduced body weight (MD=-0.63 kg; 95% CI -0.84 to -0.42 kg) and BMI (MD=-0.26 kg/m2; 95% CI -0.36 to -0.16 kg/m2) compared with higher-GI dietary patterns. There was no effect on other measures of adiposity. The certainty of the evidence was graded as moderate for body weight, BMI, WHR and SAD and low for WC and body fat. CONCLUSIONS: Pasta in the context of low-GI dietary patterns does not adversely affect adiposity and even reduces body weight and BMI compared with higher-GI dietary patterns. Future trials should assess the effect of pasta in the context of other 'healthy' dietary patterns. TRIAL REGISTRATION NUMBER: NCT02961088; Results. PMID- 29615410 TI - Response to: 'Detection of myositis-specific antibodies: additional notes' by Infantino et al. PMID- 29615411 TI - ACPA IgG galactosylation associates with disease activity in pregnant patients with rheumatoid arthritis. AB - OBJECTIVES: Patients with autoantibody-positive rheumatoid arthritis (RA) are less likely to experience pregnancy-induced improvement of RA disease activity (DAS28-C reactive protein (CRP)) compared with patients with autoantibody negative RA. Anti-citrullinated protein antibodies (ACPAs) are the most specific autoantibodies for RA. We previously demonstrated that disease improvement is associated with changes in total IgG glycosylation, which regulate antibody effector function. Therefore, we sought to analyse the ACPA-IgG glycosylation profile during pregnancy with the aim to understand the lower change of pregnancy induced improvement of the disease in patients with autoantibody-positive RA. METHODS: ACPA-IgGs were purified from ACPA-positive patient sera (n=112) of the Pregnancy-induced Amelioration of Rheumatoid Arthritis cohort, a prospective study designed to investigate pregnancy-associated improvement of RA. The fragment crystallisable (Fc)glycosylation profile of ACPA-IgGs was characterised by mass spectrometry and compared with that of total IgG derived from the same patients or from ACPA-negative patients. RESULTS: All ACPA-IgG subclasses display significant changes in the level of galactosylation and sialylation during pregnancy, although less pronounced than in total IgG. The pregnancy-induced increase in ACPA-IgG galactosylation, but not sialylation, associates with lower DAS28-CRP. In ACPA-positive patients, no such association was found with changes in the galactosylation of total IgG, whereas in ACPA-negative patients changes in disease activity correlated well with changes in the galactosylation of total IgG. CONCLUSIONS: In ACPA-positive RA, the pregnancy-induced change in galactosylation of ACPA-IgG, and not that of total IgG, associates with changes in disease activity. These data may indicate that in ACPA-positive patients the galactosylation of ACPA-IgG is of more pathogenic relevance than that of total IgG. PMID- 29615412 TI - Tumour necrosis factor: out of my heart! PMID- 29615413 TI - Light chain type predicts organ involvement and survival in AL amyloidosis patients receiving stem cell transplantation. AB - We evaluated the impact of light chain type, lambda (lambda) or kappa (kappa), on disease features and outcomes in patients with immunoglobulin light chain (AL) amyloidosis receiving stem cell transplant at the Mayo Clinic between October 2002 and August 2016. Patients with lambda AL amyloidosis had higher rates of renal and neurological involvement (lambda 69% vs kappa 57%, P = .02 and lambda 16% vs kappa 9%, P = .03, respectively). Patients with kappa AL amyloidosis had more hepatic involvement (lambda 7% vs kappa 18%, P = .0003). Complete response rate was 43% for both groups and overall response rates were similar (lambda 85% vs kappa 91%, P = .12). Patients with kappa light chain amyloidosis had better progression-free and overall survival (PFS: lambda 74 months vs kappa 101 months, P = .0064 and OS: lambda 121 months vs kappa not reached, P = .003). Mayo stage 2004 was more predictive of survival in the lambda cohort (median OS of 143 months stage I vs 77 months stage II vs 33 months stage III, P < .0001) than in the kappa cohort (median OS not reached for stage I and II and 102 months for stage III, P = .044). Conditioning dose predicted survival in the lambda cohort only (median OS 149 months for melphalan 200 mg/m2 vs 50 months for melphalan <200 mg/m2, P < .0001; median OS kappa not reached for melphalan 200 mg/m2 or <200 mg/m2, P = .38). On multivariate analysis, light chain type remained an independent predictor of survival. Light chain type predicts organ involvement and survival in patients with AL amyloidosis receiving stem cell transplant. PMID- 29615414 TI - Suppression of miR-26a attenuates physiological disturbances arising from exposure of Nile tilapia (Oreochromis niloticus) to ammonia. AB - MicroRNAs may affect stress responses because they act as rapid responders at the post-translation level. In this study, we found that miR-26a is abundantly expressed in the brain and gill tissues of tilapia. Expression of miR-26a in the brain decreased significantly with increasing ammonia concentrations using stem loop qPCR. To analyze the function of miRNA in vivo, miR-26a was stably knocked down with an antagomir in tilapia. Following ammonia challenge, miR-26a antagomir treatment significantly suppressed blood ammonia/[Cl-]/[K+] concentration and the reactive oxygen species production, while it markedly enhanced glutamine accumulation and antioxidant enzyme activity in the brain of tilapia, indicating that miR-26a may be involved in the remission of physiological disturbances resulting from ammonia stress. We strongly conclude that there is a direct link between miR-26a and the responses to ammonia in tilapia. Furthermore, bioinformatics analysis and luciferase assays demonstrated that miR-26a regulates HSP70 (heat shock protein 70) and GS (glutamine synthetase) expression by targeting their 3'-UTR and that the suppression of miR-26a could increase the intracellular level of HSP70 and GS in vivo. PMID- 29615415 TI - Exposure of zebra mussels to extracorporeal shock waves demonstrates formation of new mineralized tissue inside and outside the focus zone. AB - The success rate of extracorporeal shock wave therapy (ESWT) for fracture nonunions in human medicine (i.e. radiographic union at 6 months after ESWT) is only approximately 75%. Detailed knowledge regarding the underlying mechanisms that induce bio-calcification after ESWT is limited. We analyzed the biological response within mineralized tissue of a new invertebrate model organism, the zebra mussel Dreissena polymorpha, after exposure with extracorporeal shock waves (ESWs). Mussels were exposed to ESWs with positive energy density of 0.4 mJ/mm2 (A) or were sham exposed (B). Detection of newly calcified tissue was performed by exposing the mussels to fluorescent markers. Two weeks later, the A-mussels showed a higher mean fluorescence signal intensity within the shell zone than the B-mussels (P<0.05). Acoustic measurements revealed that the increased mean fluorescence signal intensity within the shell of the A-mussels was independent of the size and position of the focal point of the ESWs. These data demonstrate that induction of bio-calcification after ESWT may not be restricted to the region of direct energy transfer of ESWs into calcified tissue. The results of the present study are of relevance for better understanding of the molecular and cellular mechanisms that induce formation of new mineralized tissue after ESWT. PMID- 29615419 TI - Awareness of the Link between Alcohol Consumption and Cancer across the World: A Review. AB - Since 1988, the International Agency for Research on Cancer has classified alcohol as a Group 1 carcinogen, the highest level of risk. Growing evidence suggests that alcohol increases the risk of several types of cancer including breast, bowel, prostate, and liver, and accounts for a significant proportion of preventable cancers. Despite ample evidence of this relationship, public awareness is less clear. Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we reviewed 32 studies examining lay awareness of alcohol as a risk factor for cancer in 16 countries. Our results show that awareness appears to be low and varies internationally; it is relatively higher in the United Kingdom, Morocco, and Australia. Methodologic differences in assessment obfuscate cross-country and cross-sample comparisons. In general, people are more likely to endorse alcohol as a risk factor when presented with a list of possible risk factors than when asked to list risk factors in an open-ended format. Attempts to increase awareness have been limited and constitute a significant public health need. We provide potential strategies to increase awareness, such as alcohol bottle labeling and fostering patient/physician discussions regarding the link. Cancer Epidemiol Biomarkers Prev; 27(4); 429-37. (c)2018 AACR. PMID- 29615418 TI - Editorial: The Fruits of the Genomic Revolution. PMID- 29615420 TI - Mobile cell phone technology puts the future of health care in our hands. PMID- 29615416 TI - The Drosophila TGF-beta/Activin-like ligands Dawdle and Myoglianin appear to modulate adult lifespan through regulation of 26S proteasome function in adult muscle. AB - The Drosophila Activin signaling pathway employs at least three separate ligands Activin-beta (Actbeta), Dawdle (Daw), and Myoglianin (Myo) - to regulate several general aspects of fruit fly larval development, including cell proliferation, neuronal remodeling, and metabolism. Here we provide experimental evidence indicating that both Daw and Myo are anti-ageing factors in adult fruit flies. Knockdown of Myo or Daw in adult fruit flies reduced mean lifespan, while overexpression of either ligand in adult muscle tissues but not in adipose tissues enhanced mean lifespan. An examination of ubiquitinated protein aggregates in adult muscles revealed a strong inverse correlation between Myo- or Daw-initiated Activin signaling and the amount of ubiquitinated protein aggregates. We show that this correlation has important functional implications by demonstrating that the lifespan extension effect caused by overexpression of wild-type Daw or Myo in adult muscle tissues can be completely abrogated by knockdown of a 26S proteasome regulatory subunit Rpn1 in adult fly muscle, and that the prolonged lifespan caused by overexpression of Daw or Myo in adult muscle could be due to enhanced protein levels of the key subunits of 26S proteasome. Overall, our data suggest that Activin signaling initiated by Myo and Daw in adult Drosophila muscles influences lifespan, in part, by modulation of protein homeostasis through either direct or indirect regulation of the 26S proteasome levels. Since Myo is closely related to the vertebrate muscle mass regulator Myostatin (GDF8) and the Myostatin paralog GDF11, our observations may offer a new experimental model for probing the roles of GDF11/8 in ageing regulation in vertebrates.This article has an associated First Person interview with the first author of the paper. PMID- 29615422 TI - Kidney age, not kidney disease. PMID- 29615421 TI - Photoplethysmography using a smartphone application for assessment of ulnar artery patency: a randomized clinical trial. AB - BACKGROUND: Radial artery access is commonly performed for coronary angiography and invasive hemodynamic monitoring. Despite limitations in diagnostic accuracy, the modified Allen test (manual occlusion of radial and ulnar arteries followed by release of the latter and assessment of palmar blush) is used routinely to evaluate the collateral circulation to the hand and, therefore, to determine patient eligibility for radial artery access. We sought to evaluate whether a smartphone application may provide a superior alternative to the modified Allen test. METHODS: We compared the modified Allen test with a smartphone heart rate monitoring application (photoplethysmography readings detected using a smartphone camera lens placed on the patient's index finger) in patients undergoing a planned cardiac catheterization. Test order was randomly assigned in a 1:1 fashion. All patients then underwent conventional plethysmography of the index finger, followed by Doppler ultrasonography of the radial and ulnar arteries (the diagnostic standard). The primary outcome was diagnostic accuracy of the heart rate-monitoring application. RESULTS: Among 438 patients who were included in the study, we found that the heart rate-monitoring application had a superior diagnostic accuracy compared with the modified Allen test (91.8% v. 81.7%, p = 0.002), attributable to its greater specificity (93.0% v. 82.8%, p = 0.001). We also found that this application had greater diagnostic accuracy for assessment of radial or ulnar artery patency in the ipsilateral and contralateral wrist (94.0% v. 84.0%, p < 0.001). INTERPRETATION: A smartphone application used at the bedside was diagnostically superior to traditional physical examination for confirming ulnar patency before radial artery access. This study highlights the potential for smartphone-based diagnostics to aid in clinical decision-making at the patient's bedside. Trial registration: Clinicaltrials.gov, no. NCT02519491. PMID- 29615424 TI - Cutaneous lymphoid hyperplasia (pseudolymphoma). PMID- 29615423 TI - Mycobacterium avium complex infection presenting as persistent ascites. PMID- 29615425 TI - The Canadian Medical Association and medical marijuana. PMID- 29615426 TI - Is aldosteronism really a relatively common cause of hypertension? PMID- 29615428 TI - Parliament debates junk food ads, vaping. PMID- 29615427 TI - Medicine changing as women make up more of physician workforce. PMID- 29615429 TI - Patient complaints about Canadian doctors on the rise. PMID- 29615430 TI - Diffuse skin thickening, myalgias and joint stiffness in a 41-year-old man. PMID- 29615431 TI - Clinical significance of RET and RAS mutations in sporadic medullary thyroid carcinoma: a meta-analysis. AB - There are ongoing debates with respect to the prognostic roles of molecular biomarkers in sporadic medullary thyroid carcinoma (MTC). In this study, we aimed at investigating the prognostic value of RET and RAS mutations - the two most common mutations in sporadic MTCs. A search was conducted in four electronic databases. Relevant data were extracted and pooled into odds ratios (OR), mean differences (MD) and corresponding 95% confidence intervals (CI) using the random effect model. We used Egger's regression test and visual of funnel plots to assess the publication bias. From 2581 studies, we included 23 studies with 964 MTCs for meta-analysis. Overall, the presence of RET mutation was associated with an elevated risk for lymph node metastasis (OR = 3.61; 95% CI = 2.33-5.60), distant metastasis (OR = 2.85; 95% CI = 1.64-4.94), advanced tumor stage (OR = 3.25; 95% CI = 2.02-5.25), tumor recurrence (OR = 3.01; 95% CI = 1.65-5.48) and patient mortality (OR = 2.43; 95% CI = 1.06-5.57). RAS mutation had no significant prognostic value in predicting tumor aggressiveness. To summarize, our results affirmed that RET mutation is a reliable molecular biomarker to identify a group of highly aggressive sporadic MTCs. It can help clinicians better assess patient prognosis and select appropriate treatment decisions. PMID- 29615432 TI - Adoptive Immunotherapy Using PRAME-Specific T Cells in Medulloblastoma. AB - Medulloblastoma is the most frequent malignant childhood brain tumor with a high morbidity. Identification of new therapeutic targets would be instrumental in improving patient outcomes. We evaluated the expression of the tumor-associated antigen PRAME in biopsies from 60 patients with medulloblastoma. PRAME expression was detectable in 82% of tissues independent of molecular and histopathologic subgroups. High PRAME expression also correlated with worse overall survival. We next investigated the relevance of PRAME as a target for immunotherapy. Medulloblastoma cells were targeted using genetically modified T cells with a PRAME-specific TCR (SLL TCR T cells). SLL TCR T cells efficiently killed medulloblastoma HLA-A*02+ DAOY cells as well as primary HLA-A*02+ medulloblastoma cells. Moreover, SLL TCR T cells controlled tumor growth in an orthotopic mouse model of medulloblastoma. To prevent unexpected T-cell-related toxicity, an inducible caspase-9 (iC9) gene was introduced in frame with the SLL TCR; this safety switch triggered prompt elimination of genetically modified T cells. Altogether, these data indicate that T cells genetically modified with a high affinity, PRAME-specific TCR and iC9 may represent a promising innovative approach for treating patients with HLA-A*02+ medulloblastoma.Significance: These findings identify PRAME as a medulloblastoma tumor-associated antigen that can be targeted using genetically modified T cells. Cancer Res; 78(12); 3337-49. (c)2018 AACR. PMID- 29615433 TI - Mutation Profiling of Key Cancer Genes in Primary Breast Cancers and Their Distant Metastases. AB - Although the repertoire of somatic genetic alterations of primary breast cancers has been extensively catalogued, the genetic differences between primary and metastatic tumors have been less studied. In this study, we compared somatic mutations and gene copy number alterations of primary breast cancers and their matched metastases from patients with estrogen receptor (ER)-negative disease. DNA samples obtained from formalin-fixed paraffin-embedded ER-negative/HER2 positive (n = 9) and ER-, progesterone receptor (PR-), HER2-negative (n = 8) primary breast cancers and from paired brain or skin metastases and normal tissue were subjected to a hybridization capture-based massively parallel sequencing assay, targeting 341 key cancer genes. A large subset of nonsynonymous somatic mutations (45%) and gene copy number alterations (55%) was shared between the primary tumors and paired metastases. However, mutations restricted to either a given primary tumor or its metastasis, the acquisition of loss of heterozygosity of the wild-type allele, and clonal shifts of genes affected by somatic mutations, such as TP53 and RB1, were observed in the progression from primary tumors to metastases. No metastasis location-specific alterations were identified, but synchronous metastases showed higher concordance with the paired primary tumor than metachronous metastases. Novel potentially targetable alterations were found in the metastases relative to their matched primary tumors. These data indicate that repertoires of somatic genetic alterations in ER negative metastatic breast cancers may differ from those of their primary tumors, even by the presence of driver and targetable somatic genetic alterations.Significance: Somatic genetic alterations in ER-negative breast cancer metastases may be distinct from those of their primary tumors, suggesting that for treatment-decision making, genetic analyses of DNA obtained from the metastatic lesion rather than from the primary tumor should be considered. Cancer Res; 78(12); 3112-21. (c)2018 AACR. PMID- 29615434 TI - Tyrosine kinase inhibitor induced rapidly progressive vasculopathy after intracranial stent placement. AB - Tyrosine kinase inhibitor (TKI) therapy for chronic myeloid leukemia (CML) has been associated with progressive peripheral arterial disease and, more recently, rare cases of intracranial vascular stenosis have been reported. We report the fourth case of TKI treatment associated intracranial vasculopathy and rapid progression of intracranial vascular stenosis following intracranial stent placement. This was a 49-year-old woman who developed right-sided weakness, paresthesias, numbness, and speech difficulties 7 years following TKI treatment for CML. Cerebral catheter angiography demonstrated 90% stenosis of the left supraclinoid internal carotid artery, for which the patient underwent intracranial stent placement with no residual stenosis and improved distal blood flow. Approximately 1 month following the procedure, the patient returned with similar symptoms. Catheter angiography demonstrated 70% and 50% stenosis just distal and proximal to the stent construct, respectively. Rapid disease progression and non-atherosclerotic vasculopathy may argue against endovascular therapy. PMID- 29615435 TI - Association of Biomarker Clusters With Cardiac Phenotypes and Mortality in Patients With HIV Infection. AB - BACKGROUND: Although individual cardiac biomarkers are associated with heart failure risk and all-cause mortality in HIV-infected individuals, their combined use for prediction has not been well studied. METHODS AND RESULTS: Unsupervised k means cluster analysis was performed blinded to the study outcomes in 332 HIV infected participants on 8 biomarkers: ST2, NT-proBNP (N-terminal pro-B-type natriuretic peptide), hsCRP (high-sensitivity C-reactive protein), GDF-15 (growth differentiation factor 15), cystatin C, IL-6 (interleukin-6), D-dimer, and troponin. We evaluated cross-sectional associations of each cluster with diastolic dysfunction, pulmonary hypertension (defined as echocardiographic pulmonary artery systolic pressure >=35 mm Hg), and longitudinal associations with all-cause mortality. The biomarker-derived clusters partitioned subjects into 3 groups. Cluster 3 (n=103) had higher levels of CRP, IL-6, and D-dimer (inflammatory phenotype). Cluster 2 (n=86) displayed elevated levels of ST2, NT proBNP, and GDF-15 (cardiac phenotype). Cluster 1 (n=143) had lower levels of both phenotype-associated biomarkers. After multivariable adjustment for traditional and HIV-related risk factors, cluster 3 was associated with a 51% increased risk of diastolic dysfunction (95% confidence interval, 1.12-2.02), and cluster 2 was associated with a 67% increased risk of pulmonary hypertension (95% confidence interval, 1.04-2.68), relative to cluster 1. Over a median 6.9-year follow-up, 48 deaths occurred. Cluster 3 was independently associated with a 3.3 fold higher risk of mortality relative to cluster 1 (95% confidence interval, 1.3 8.1), and cluster 2 had a 3.1-fold increased risk (95% confidence interval, 1.1 8.4), even after controlling for diastolic dysfunction, pulmonary hypertension, left ventricular mass, and ejection fraction. CONCLUSIONS: Serum biomarkers can be used to classify HIV-infected individuals into separate clusters for differentiating cardiopulmonary structural and functional abnormalities and can predict mortality independent of these structural and functional measures. PMID- 29615436 TI - TTR (Transthyretin) Stabilizers Are Associated With Improved Survival in Patients With TTR Cardiac Amyloidosis. AB - BACKGROUND: TTR (transthyretin) cardiac amyloidosis is caused by dissociation of TTR into monomers, which misassemble into amyloid fibrils. TTR stabilizers act at the dimer-dimer interface to prevent dissociation. We investigated differences in survival among patients with TTR cardiac amyloidosis on stabilizer medications compared with those not on stabilizers. METHODS AND RESULTS: A retrospective study of patients with TTR cardiac amyloidosis presenting to a single center was conducted. Baseline characteristics were compared between those treated with stabilizers and those not treated with stabilizers. Cox proportional hazards modeling assessed for univariate predictors of the composite outcome of death or orthotopic heart transplant (OHT). Multivariable Cox proportional hazards assessed whether stabilizer treatment was independently associated with improved death or OHT after controlling for significant univariate predictors. One hundred twenty patients (mean age, 75+/-8, 88% male) were included: 29 patients who received stabilizers and 91 patients who did not. Stabilizer use was associated with a lower risk of the combined end point of death or OHT (hazard ratio, 0.32; 95% confidence interval, 0.18-0.58; P<0.0001). Subjects treated with stabilizers were more likely to be of White race (93% versus 55%; P<0.001), classified as New York Heart Association classes I and II (79% versus 38%; P=0.002), less likely to have a mutation (10% versus 36%; P=0.010), have lower troponin I (median 0.06 versus 0.12 ng/mL; P=0.002), and higher left ventricular ejection fraction (49% versus 40%; P=0.011), suggesting earlier stage of disease. In multivariable Cox analysis, the association between stabilizer and death or OHT persisted when adjusted for all noncollinear univariate predictors with P<0.05 (hazard ratio, 0.37; 95% confidence interval, 0.19-0.75; P=0.003). CONCLUSIONS: TTR stabilizers are associated with decreased death and OHT in TTR cardiac amyloidosis. These results need to be confirmed by ongoing randomized clinical trials. PMID- 29615437 TI - Refinement of In Vitro Methods for Identification of Aldehyde Oxidase Substrates Reveals Metabolites of Kinase Inhibitors. AB - To identify aldehyde oxidase (AO) substrates, an assay procedure was developed that leverages the capabilities of high-resolution mass spectrometry to simultaneously monitor parent loss and formation of hydroxylated metabolite over time in incubations with liver cytosol. By incorporating metabolite monitoring, false positives resulting from metabolism by other cytosolic enzymes or processes were decreased. A diverse set of 34 kinase inhibitors containing AO-substrate motifs was screened, and 35% of the compounds were identified as human AO substrates. Confirmation was obtained through determination of the site of metabolism. Human AO substrates identified contained unsubstituted diazanaphthalene moieties (A77-01, INCB 28060, ML-347, LDN-193189, and SB 525334), 4-aminoquinazoline cores (lapatinib, lapatinib M1, and CL-387785), and terminal pyridine and pyrimidine groups (imatinib, bafetinib, and AMG 900). Rat and cynomolgus monkey AO displayed substrate specificities that overlapped moderately with human; rates of metabolism were often higher and lower for cynomolgus monkey and rat, respectively, compared with human. A subset of novel AO substrates identified in this study was also subjected to two other methods for AO substrate determination: comparison of human liver microsome and hepatocyte stability, and the effect of hydralazine, an AO-specific inhibitor, on hepatocyte stability. These methods appeared to correlate and be capable of identifying AO substrates when more than one-third of metabolism in hepatocytes was AO-mediated; however, significant limitations exist. Considering the sensitivity, efficiency, and definitiveness of the cytosol assay with metabolite monitoring, its use is recommended as a primary screen for AO substrates. PMID- 29615438 TI - Generation of Intestinal Organoids Suitable for Pharmacokinetic Studies from Human Induced Pluripotent Stem Cells. AB - Intestinal organoids morphologically resemble intestinal tissues and are expected to be used in both regenerative medicine and drug development studies, including pharmacokinetic studies. However, the pharmacokinetic properties of these organoids remain poorly characterized. In this study, we aimed to generate pharmacokinetically functional intestinal organoids from human induced pluripotent stem (iPS) cells. Human iPS cells were induced to differentiate into the midgut and then seeded on EZSPHERE plates (AGC Techno Glass Inc., Shizuoka, Japan) to generate uniform spheroids, and the floating spheroids were subsequently differentiated into intestinal organoids using small-molecule compounds. Exposure to the small-molecule compounds potently increased the expression of intestinal markers and pharmacokinetic-related genes in the organoids, and the organoids also included various intestinal cells such as enterocytes, intestinal stem cells, goblet cells, enteroendocrine cells, Paneth cells, smooth muscle cells, and fibroblasts. Moreover, microvilli and tight junctions were observed in the organoids. Furthermore, we detected not only the expression of drug transporters but also efflux transport activity through ABCB1/MDR1 and the induction of the drug-metabolizing enzyme CYP3A4 by ligands of nuclear receptors. Our results demonstrated the successful generation of pharmacokinetically functional intestinal organoids from human iPS cells. Thus, these intestinal organoids could be used as a pharmacokinetic evaluation system in drug development studies. PMID- 29615439 TI - Physician follow-up and long-term use of evidence-based medication for patients with hypertension who were discharged from an emergency department: a prospective cohort study. AB - BACKGROUND: More than 25% of the population has hypertension. The number of patients seeking care for hypertension in emergency departments has increased by more than 60% in the last decade, with less than 10% of these patients subsequently admitted to hospital. Managing physicians recommend early follow-up to patients who are discharged from the emergency department, but there is a paucity of literature assessing the impact or timing of follow-up on patient outcomes. METHODS: Using a population-based cohort design, we included patients more than 65 years of age who were discharged from an Ontario emergency department with a primary diagnosis of hypertension between 2007 and 2014. We identified 2 cohorts: an incident cohort, and a cohort in which patients were on no more than 1 class of evidence-based antihypertensive medication at the time of presentation. Using logistic regression, we assessed the association of early follow-up care (within 7 d) and basic care (8-30 d), compared with no care within 30 days, on patient use of a new evidence-based antihypertensive medication 1 year later. RESULTS: Our study included 2088 patients with a new diagnosis of hypertension (the first cohort), and 6420 patients in the second cohort. Of patients with new diagnoses, 48.2% and 30.2% obtained early and basic follow-up care, respectively, compared with 50.0% and 30.9% of patients in the second cohort. Compared with patients without follow-up care within 30 days, the adjusted odds of filling an evidence-based antihypertensive medication prescription 1 year later in the incident group were 2.36 (95% confidence interval [CI] 1.86-2.99) for those who received early care, and 2.00 (95% CI 1.55 2.58) for those who received basic care. The adjusted odds in the second cohort were 2.12 (95% CI 1.84-2.43) and 1.96 (95% CI 1.69-2.27), respectively. INTERPRETATION: Early follow-up care after leaving an emergency department with a diagnosis of hypertension was associated with improved long-term use of evidence based antihypertensive medication. As patients increasingly present to the emergency department for hypertension, a formal, timely follow-up care system could improve patient use of evidence-based antihypertensive medication. PMID- 29615440 TI - Inhibition of Soluble Epoxide Hydrolase 2 Ameliorates Diabetic Keratopathy and Impaired Wound Healing in Mouse Corneas. AB - EPHX2 (encoding soluble epoxide hydrolase [sEH]) converts biologically active epoxyeicosatrienoic acids (EETs), anti-inflammatory and profibrinolytic effectors, into the less biologically active metabolites, dihydroxyeicostrienoic acids. We sought to characterize the expression and the function of EPHX2 in diabetic corneas and during wound healing. The expression of EPHX2 at both mRNA and protein levels, as well as sEH enzymatic activity, was markedly upregulated in the tissues/cells, including corneal epithelial cells as well as the retina of human type 2 and mouse type 1 (streptozotocin [STZ] induced) and/or type 2 diabetes. Ephx2 depletion had no detectable effects on STZ-induced hyperglycemia but prevented the development of tear deficiency. Ephx2-/- mice showed an acceleration of hyperglycemia-delayed epithelium wound healing. Moreover, inhibition of sEH increased the rate of epithelium wound closure and restored hyperglycemia-suppressed STAT3 activation and heme oxygenase-1 (HO-1) expression in the diabetic corneas. Treatment of diabetic corneas with cobalt protoporphyrin, a well-known HO-1 inducer, restored wound-induced HO-1 upregulation and accelerated delayed wound healing. Finally, Ephx2 depletion enhanced sensory innervation and regeneration in diabetic corneas at 1 month after epithelial debridement. Our data suggest that increased sEH activity may be a contributing factor for diabetic corneal complications; targeting sEH pharmacologically or supplementing EETs may represent a new, adjunctive therapy for treating diabetic keratopathy. PMID- 29615441 TI - A discrete choice experiment to determine facility-based delivery services desired by women and men in rural Ethiopia. AB - OBJECTIVES: Despite global efforts to increase facility-based delivery (FBD), 90% of women in rural Ethiopia deliver at home without a skilled birth attendant. Men have an important role in increasing FBD due to their decision-making power, but this is largely unexplored. This study aimed to determine the FBD care attributes preferred by women and men, and whether poverty or household decision-making are associated with choice to deliver in a facility. SETTING AND PARTICIPANTS: We conducted a cross-sectional discrete choice experiment in 109 randomly selected households in rural Ethiopia in September-October 2015. We interviewed women who were pregnant or who had a child <2 years old and their male partners. RESULTS: Both women and men preferred health facilities where medications and supplies were available (OR=3.08; 95% CI 2.03 to 4.67 and OR=2.68; 95% CI 1.79 to 4.02, respectively), a support person was allowed in the delivery room (OR=1.69; 95% CI 1.37 to 2.07 and OR=1.74; 95% CI 1.42 to 2.14, respectively) and delivery cost was low (OR=1.15 95% CI 1.12 to 1.18 and OR=1.14; 95% CI 1.11 to 1.17, respectively). Women valued free ambulance service (OR=1.37; 95% CI 1.09 to 1.70), while men favoured nearby facilities (OR=1.09; 95% CI 1.06 to 1.13) with friendly providers (OR=1.30; 95% CI 1.03 to 1.64). Provider preferences were complex. Neither women nor men preferred female doctors to health extension workers (HEW) (OR=0.92; 95% CI 0.59 to 1.42 and OR=0.74; 95% CI 0.47 to 1.14, respectively), male doctors to HEW (OR=1.33; 95% CI 0.89 to 1.99 and OR=0.75; 95% CI 0.50 to 1.12, respectively) or female over male nurses (OR=0.68; 95% CI 0.94 to 1.71 and OR=1.03; 95% CI 0.77 to 2.94, respectively). While both women and men preferred male nurses to HEW (OR=1.86; 95% CI 1.23 to 2.80 and OR=1.95; 95% CI 1.30 to 2.95, respectively), men (OR=1.89; 95% CI 1.29 to 2.78), but not women (OR=1.47; 95% CI 1.00 to 2.13) preferred HEW to female nurses. Both women and men preferred female doctors to male nurses (OR=1.71; 95% CI 1.27 to 2.29 and OR=1.44; 95% CI 1.07 to 1.92, respectively), male doctors to female nurses (OR=1.95; 95% CI 1.44 to 2.62 and OR=1.41; 95% CI 1.05 to 1.90, respectively) and male doctors to male nurses (OR=2.47; 95% CI 1.84 to 3.32 and OR=1.46; 95% CI 1.09 to 1.95, respectively), while only women preferred male doctors to female doctors (OR=1.45; 95% CI 1.09 to 1.93 and OR=1.01; 95% CI 0.76 to 1.35, respectively) and only men preferred female nurses to female doctors (OR=1.34; 95% CI 0.98 to 1.84 and OR=1.39; 95% CI 1.02 to 1.89, respectively). Men were disproportionately involved in making household decisions (X2 (1, n=216)=72.18, p<0.001), including decisions to seek healthcare (X2 (1, n=216)=55.39, p<0.001), yet men were often unaware of their partners' prenatal care attendance (X2 (1, n=215)=82.59, p<0.001). CONCLUSION: Women's and men's preferences may influence delivery service choices. Considering these choices is one way the Ethiopian government and health facilities may encourage FBD in rural areas. PMID- 29615442 TI - Cost-effectiveness of interventions to control cardiovascular diseases and diabetes mellitus in South Asia: a systematic review. AB - OBJECTIVES: More than 80% of cardiovascular diseases (CVD) and diabetes mellitus (DM) burden now lies in low and middle-income countries. Hence, there is an urgent need to identify and implement the most cost-effective interventions, particularly in the resource-constraint South Asian settings. Thus, we aimed to systematically review the cost-effectiveness of individual-level, group-level and population-level interventions to control CVD and DM in South Asia. METHODS: We searched 14 electronic databases up to August 2016. The search strategy consisted of terms related to 'economic evaluation', 'CVD', 'DM' and 'South Asia'. Per protocol two reviewers assessed the eligibility and methodological quality of studies using standard checklists, and extracted incremental cost-effectiveness ratios of interventions. RESULTS: Of the 2949 identified studies, 42 met full inclusion criteria. Critical appraisal of studies revealed 15 excellent, 18 good and 9 poor quality studies. Most studies were from India (n=37), followed by Bangladesh (n=3), Pakistan (n=2) and Bhutan (n=1). The economic evaluations were based on observational studies (n=9), randomised trials (n=12) and decision models (n=21). Together, these studies evaluated 301 policy or clinical interventions or combination of both. We found a large number of interventions were cost-effective aimed at primordial prevention (tobacco taxation, salt reduction legislation, food labelling and food advertising regulation), and primary and secondary prevention (multidrug therapy for CVD in high-risk group, lifestyle modification and metformin treatment for diabetes prevention, and screening for diabetes complications every 2-5 years). Significant heterogeneity in analytical framework and outcome measures used in these studies restricted meta-analysis and direct ranking of the interventions by their degree of cost effectiveness. CONCLUSIONS: The cost-effectiveness evidence for CVD and DM interventions in South Asia is growing, but most evidence is from India and limited to decision modelled outcomes. There is an urgent need for formal health technology assessment and policy evaluations in South Asia using local research data. PROSPERO REGISTRATION NUMBER: CRD42013006479. PMID- 29615443 TI - Postpartum family planning integration with maternal, newborn and child health services: a cross-sectional analysis of client flow patterns in India and Kenya. AB - OBJECTIVES: Maternal, newborn and child health (MNCH) services represent opportunities to integrate postpartum family planning (PPFP). Objectives were to determine levels of MNCH-family planning (FP) integration and associations between integration, client characteristics and service delivery factors in facilities that received programmatic PPFP support. DESIGN AND SETTING: Cross sectional client flow assessment conducted during May-July 2014, over 5 days at 10 purposively selected public sector facilities in India (4 hospitals) and Kenya (2 hospitals and 4 health centres). PARTICIPANTS: 2158 client visits tracked (1294 India; 864 Kenya). Women aged 18 or older accessing services while pregnant and/or with a child under 2 years. INTERVENTIONS: PPFP/postpartum intrauterine device-Bihar, India (2012-2013); Jharkhand, India (2009-2014); Embu, Kenya (2006 2010). Maternal, infant and young child nutrition/FP integration-Bondo, Kenya (2011-2014). PRIMARY OUTCOME MEASURES: Proportion of visits where clients received integrated MNCH-FP services, client characteristics as predictors of MNCH-FP integration and MNCH-FP integration as predictor of length of time spent at facility. RESULTS: Levels of MNCH-FP integration varied widely across facilities (5.3% to 63.0%), as did proportion of clients receiving MNCH-FP integrated services by service area. Clients travelling 30-59 min were half as likely to receive integrated services versus those travelling under 30 min (OR 0.5, 95% CI 0.4 to 0.7, P<0.001). Clients receiving MNCH-FP services (vs MNCH services only) spent an average of 10.5 min longer at the facility (95% CI -0.1 to 21.9, not statistically significant). CONCLUSIONS: Findings suggest importance of focused programmatic support for integration by MNCH service area. FP integration was highest in areas receiving specific support. Integration does not seem to impose an undue burden on clients in terms of time spent at the facility. Clients living furthest from facilities are least likely to receive integrated services. PMID- 29615444 TI - Home interventions and light therapy for the treatment of vitiligo (HI-Light Vitiligo Trial): study protocol for a randomised controlled trial. AB - INTRODUCTION: Vitiligo is a condition resulting in white patches on the skin. People with vitiligo can suffer from low self-esteem, psychological disturbance and diminished quality of life. Vitiligo is often poorly managed, partly due to lack of high-quality evidence to inform clinical care. We describe here a large, independent, randomised controlled trial (RCT) assessing the comparative effectiveness of potent topical corticosteroid, home-based hand-held narrowband ultraviolet B-light (NB-UVB) or combination of the two, for the management of vitiligo. METHODS AND ANALYSIS: The HI-Light Vitiligo Trial is a multicentre, three-arm, parallel group, pragmatic, placebo-controlled RCT. 516 adults and children with actively spreading, but limited, vitiligo are randomised (1:1:1) to one of three groups: mometasone furoate 0.1% ointment plus dummy NB-UVB light, vehicle ointment plus NB-UVB light or mometasone furoate 0.1% ointment plus NB UVB light. Treatment of up to three patches of vitiligo is continued for up to 9 months with clinic visits at baseline, 3, 6 and 9 months and four post-treatment questionnaires.The HI-Light Vitiligo Trial assesses outcomes included in the vitiligo core outcome set and places emphasis on participants' views of treatment success. The primary outcome is proportion of participants achieving treatment success (patient-rated Vitiligo Noticeability Scale) for a target patch of vitiligo at 9 months with further independent blinded assessment using digital images of the target lesion before and after treatment. Secondary outcomes include time to onset of treatment response, treatment success by body region, percentage repigmentation, quality of life, time-burden of treatment, maintenance of response, safety and within-trial cost-effectiveness. ETHICS AND DISSEMINATION: Approvals were granted by East Midlands-Derby Research Ethics Committee (14/EM/1173) and the MHRA (EudraCT 2014-003473-42). The trial was registered 8 January 2015 ISRCTN (17160087). Results will be published in full as open access in the NIHR Journal library and elsewhere. TRIAL REGISTRATION NUMBER: ISRCTN17160087. PMID- 29615445 TI - Piloting the addition of contingency management to best practice counselling as an adjunct treatment for rural and remote disordered gamblers: study protocol. AB - INTRODUCTION: Problematic gambling is a significant Canadian public health concern that causes harm to the gambler, their families, and society. However, a significant minority of gambling treatment seekers drop out prior to the issue being resolved; those with higher impulsivity scores have the highest drop-out rates. Consequently, retention is a major concern for treatment providers. The aim of this study is to investigate the efficacy of internet-delivered cognitive behavioural therapy (CBT) and internet-delivered CBT and contingency management (CM+) as treatments for gambling disorder in rural Albertan populations. Contingency management (CM) is a successful treatment approach for substance dependence that uses small incentives to reinforce abstinence. This approach may be suitable for the treatment of gambling disorder. Furthermore, internet delivered CM may hold particular promise in rural contexts, as these communities typically struggle to access traditional clinic-based counselling opportunities. METHODS AND ANALYSIS: 54 adults with gambling disorder will be randomised into one of two conditions: CM and CBT (CM+) or CBT alone (CBT). Gambling will be assessed at intake, every treatment session, post-treatment, and follow-up. The primary outcome measures are treatment attendance, gambling abstinence, gambling, gambling symptomatology, and gambling urge. In addition, qualitative interviews assessing study experiences will be conducted with the supervising counsellor, graduate student counsellors, study affiliates, and a subset of treatment seekers. This is the first study to use CM as a treatment for gambling disorder in rural and remote populations. ETHICS AND DISSEMINATION: This study was approved by the University of Lethbridge's Human Subject Research Committee (#2016-080). The investigators plan to publish the results from this study in academic peer-reviewed journals. Summary information will be provided to the funder. TRIAL REGISTRATION NUMBER: NCT02953899; Pre-results. PMID- 29615446 TI - Longitudinal study of occupational noise exposure and joint effects with job strain and risk for coronary heart disease and stroke in Swedish men. AB - OBJECTIVES: The aims were to investigate whether occupational noise increased the risk for coronary heart disease (CHD) and stroke and to elucidate interactions with stressful working conditions in a cohort of Swedish men. DESIGN: This is a prospective cohort study on CHD and stroke in Swedish men followed until death, hospital discharge or until 75 years of age, using Swedish national registers on cause of death and hospital discharges. Baseline data on occupation from 1974 to 1977 were used for classification of levels of occupational noise and job demand control. Cox regression was used to analyse HRs for CHD and stroke. SETTING: Swedish men born in 1915-1925. PRIMARY AND SECONDARY OUTCOME MEASURES: CHD and stroke. PARTICIPANTS: The participants of the study were men from the Primary Prevention Study, a random sample of 10 000 men born in 1915-1925 in Gothenburg. Subjects with CHD or stroke at baseline or were not employed were excluded. The remaining subjects with complete baseline data on occupation, weight, height, hypertension, diabetes, serum cholesterol and smoking constituted the study sample (5753 men). RESULTS: There was an increased risk for CHD in relation to noise levels 75-85 dB(A) and >85 dB(A) compared with <75 dB(A) (HR 1.15, 95% CI 1.01 to 1.31, and HR 1.27, 95% CI 0.99 to 1.63, respectively). Exposure to noise peaks also increased the risk for CHD (HR 1.19, 95% CI 1.03 to 1.38). Among those with high strain (high demands and low control) combined with noise >75 dB(A), the risk for CHD further increased (HR 1.80, 95% CI 1.19 to 2.73). There was no significantly increased risk for stroke in any noise category. CONCLUSIONS: Exposure to occupational noise was associated with an increased risk for CHD and the risk further increased among those with concomitant exposure to high strain. None of the analysed variables were related to increased risk for stroke. PMID- 29615447 TI - Frequency-risk relationships between second-hand smoke exposure and respiratory symptoms among adolescents: a cross-sectional study in South China. AB - OBJECTIVES: Although previous studies have suggested an association between second-hand smoke (SHS) exposure and respiratory symptoms, current evidence is inconsistent. Additionally, it remains unclear whether there are frequency-risk relationships between SHS exposure and respiratory symptoms among adolescents. METHODS: A cross-sectional survey was conducted using a stratified cluster sampling method to obtain a representative sample of high school students in Guangzhou, China. The respiratory symptoms were defined as persistent cough or sputum for three consecutive months during the past 12 months. Self-reported SHS exposure was defined as non-smokers' inhalation of the smoke exhaled from smokers on >=1 day a week in the past 7 days. The univariable and multivariable logistic regression models were fitted to explore the potential frequency-risk relationships between SHS exposure and respiratory symptoms. RESULTS: Among 3575 students, the overall prevalence of SHS exposure was 69.2%, including 49.5% for SHS in public places, 34.5% in homes, 22.7% in indoor campuses and 29.2% in outdoor campuses. There were significantly increased risks of having respiratory symptoms corresponding to SHS exposure in public places (OR=1.60, 95% CI 1.30 to 1.95), in homes (OR=1.53, 95% CI 1.25 to 1.87), in indoor campuses (OR=1.43, 95% CI 1.14 to 1.79) and in outdoor campuses (OR=1.37, 95% CI 1.10 to 1.69) using no exposure as reference. Notably, we observed monotonic frequency-risk relationships between setting-specific(eg, homes, public places and campuses) SHS exposure and respiratory symptoms. CONCLUSION: Our findings suggest that setting specific SHS exposure is associated with a significant, dose-dependent increase in risk of respiratory symptoms. PMID- 29615448 TI - A protocol for a prospective observational study using chest and thumb ECG: transient ECG assessment in stroke evaluation (TEASE) in Sweden. AB - INTRODUCTION: Atrial fibrillation (AF) causes ischaemic stroke and based on risk factor evaluation warrants anticoagulation therapy. In stroke survivors, AF is typically detected with short-term ECG monitoring in the stroke unit. Prolonged continuous ECG monitoring requires substantial resources while insertable cardiac monitors are invasive and costly. Chest and thumb ECG could provide an alternative for AF detection poststroke.The primary objective of our study is to assess the incidence of newly diagnosed AF during 28 days of chest and thumb ECG monitoring in cryptogenic stroke. Secondary objectives are to assess health related quality of life (HRQoL) using short-form health survey (SF-36) and the feasibility of the Coala Heart Monitor in patients who had a stroke. METHODS: Stroke survivors in Region Gavleborg, Sweden, will be eligible for the study from October 2017. Patients with a history of ischaemic stroke without documented AF before or during ECG evaluation in the stroke unit will be evaluated by the chest and thumb ECG system Coala Heart Monitor. The monitoring system is connected to a smartphone application which allows for remote monitoring and prompt advice on clinical management. Over a period of 28 days, patients will be monitored two times a day and may activate the ECG recording at symptoms. On completion, the system is returned by mail. This system offers a possibility to evaluate the presence of AF poststroke, but the feasibility of this system in patients who recently suffered from a stroke is unknown. In addition, HRQoL using SF-36 in comparison to Swedish population norms will be assessed. The feasibility of the Coala Heart Monitor will be assessed by a self-developed questionnaire. ETHICS AND DISSEMINATION: The study was approved by The Regional Ethical Committee in Uppsala (2017/321). The database will be closed after the last follow-up, followed by statistical analyses, interpretation of results and dissemination to a scientific journal. TRIAL REGISTRATION NUMBER: NCT03301662; Pre-results. PMID- 29615449 TI - Prevalence and determinants of unplanned pregnancy in HIV-positive and HIV negative pregnant women in Cape Town, South Africa: a cross-sectional study. AB - OBJECTIVES: Prevention of unplanned pregnancy is a crucial aspect of preventing mother-to-child HIV transmission. There are few data investigating how HIV status and use of antiretroviral therapy (ART) may influence pregnancy planning in high HIV burden settings. Our objective was to examine the prevalence and determinants of unplanned pregnancy among HIV-positive and HIV-negative women in Cape Town, South Africa. DESIGN: Cross-sectional analysis. SETTINGS: Single primary-level antenatal care clinic in Cape Town, South Africa. PARTICIPANTS: HIV-positive and HIV-negative pregnant women, booking for antenatal care from March 2013 to August 2015, were included. MAIN OUTCOME MEASURES: Unplanned pregnancy was measured at the first antenatal care visit using the London Measure of Unplanned Pregnancy (LMUP). Analyses examined LMUP scores across four groups of participants defined by their HIV status, awareness of their HIV status prior to the current pregnancy and/or whether they were using antiretroviral therapy (ART) prior to the current pregnancy. RESULTS: Among 2105 pregnant women (1512 HIV positive; 593 HIV negative), median age was 28 years, 43% were married/cohabiting and 20% were nulliparous. Levels of unplanned pregnancy were significantly higher in HIV positive versus HIV-negative women (50% vs 33%, p<0.001); and highest in women who were known HIV positive but not on ART (53%). After adjusting for age, parity and marital status, unplanned pregnancy was most common among women newly diagnosed and women who were known HIV positive but not on ART (compared with HIV negative women, adjusted OR (aOR): 1.43; 95% CI 1.05 to 1.94 and aOR: 1.57; 95% CI 1.13 to 2.15, respectively). Increased parity and younger age (<24 years) were also associated with unplanned pregnancy (aOR: 1.42; 95% CI 1.25 to 1.60 and aOR: 1.83; 95% CI 1.23 to 2.74, respectively). CONCLUSIONS: We observed high levels of unplanned pregnancy among HIV-positive women, particularly among those not on ART, suggesting ongoing missed opportunities for improved family planning and counselling services for HIV-positive women. PMID- 29615451 TI - Publication catalysis-lowering activation energy. PMID- 29615450 TI - Prospective, single UK centre, comparative study of the predictive values of contrast-enhanced ultrasound compared to time-resolved CT angiography in the detection and characterisation of endoleaks in high-risk patients undergoing endovascular aneurysm repair surveillance: a protocol. AB - INTRODUCTION: Diagnosis of endoleaks is imperative to prevent failure of endovascular aneurysm repairs (EVARs). The gold standard for diagnosis of endoleaks is catheter-directed subtraction angiography, which is not a practicable choice for surveillance. CT angiography (CTA) is the historical surveillance modality of choice. Concerns over cost, potential nephrotoxicity of contrast agents and repeated radiation exposure led to colour duplex ultrasound scan (CDUS) becoming an established alternative. CDUS has a lower sensitivity and specificity for endoleaks detection compared to CTA. Contrast-enhanced ultrasound scan (CEUS) represents an improvement of ultrasound imaging but comparisons against CTA report widely varying results, likely due to technical factors of CEUS and limitations of single-phase CTA.The development of time-resolved CTA (tCTA) offers timing information that much more closely mirrors the dynamic information available from CEUS. Theoretically, these two imaging modalities have the best potential for diagnostic accuracy. The aim of this study will be to compare CEUS to tCTA and investigate the utility of other measurements available from tCTA. METHODS AND ANALYSIS: This is a prospective, single UK centre, comparative study of paired binary diagnostic imaging modalities. Patients identified in routine post-EVAR surveillance as at risk of having a graft-related endoleak will undergo a CEUS and tCTA on the same day. This will allow the first comparison of CEUS to a semidynamic form of CTA. CEUS sensitivity and specificity to endoleak detection will be calculated. ETHICS AND DISSEMINATION: The study has achieved ethical approval. We hope the results will define the diagnostic accuracy of CEUS in comparison to a semidynamic form of CTA, representing a methodological improvement from previous studies. Results will be submitted for presentation at national and international vascular surgeryandradiology meetings. The full results are planned to be published in a medical journal. TRIAL REGISTRATION NUMBER: NCT02688751. PMID- 29615452 TI - Glutamate transporter Slc1a3 mediates inter-niche stem cell activation during skin growth. AB - Tissues contain distinct stem cell niches, but whether cell turnover is coordinated between niches during growth is unknown. Here, we report that in mouse skin, hair growth is accompanied by sebaceous gland and interfollicular epidermis expansion. During hair growth, cells in the bulge and outer root sheath temporarily upregulate the glutamate transporter SLC1A3, and the number of SLC1A3+ basal cells in interfollicular epidermis and sebaceous gland increases. Fate mapping of SLC1A3+ cells in mice revealed transient expression in proliferating stem/progenitor cells in all three niches. Deletion of slc1a3 delays hair follicle anagen entry, uncouples interfollicular epidermis and sebaceous gland expansion from the hair cycle, and leads to reduced fur density in aged mice, indicating a role of SLC1A3 in stem/progenitor cell activation. Modulation of metabotropic glutamate receptor 5 activity mimics the effects of SLC1A3 deletion or inhibition. These data reveal that stem/progenitor cell activation is synchronized over distinct niches during growth and identify SLC1A3 as a general marker and effector of activated epithelial stem/progenitor cells throughout the skin. PMID- 29615453 TI - Synaptic activity-induced glycolysis facilitates membrane lipid provision and neurite outgrowth. AB - The formation of neurites is an important process affecting the cognitive abilities of an organism. Neurite growth requires the addition of new membranes, but the metabolic remodeling necessary to supply lipids for membrane expansion is poorly understood. Here, we show that synaptic activity, one of the most important inducers of neurite growth, transcriptionally regulates the expression of neuronal glucose transporter Glut3 and rate-limiting enzymes of glycolysis, resulting in enhanced glucose uptake and metabolism that is partly used for lipid synthesis. Mechanistically, CREB regulates the expression of Glut3 and Siah2, the latter and LDH activity promoting the normoxic stabilization of HIF-1alpha that regulates the expression of rate-limiting genes of glycolysis. The expression of dominant-negative HIF-1alpha or Glut3 knockdown blocks activity-dependent neurite growth in vitro while pharmacological inhibition of the glycolysis and specific ablation of HIF-1alpha in early postnatal mice impairs the neurite architecture. These results suggest that the manipulation of neuronal glucose metabolism could be used to treat some brain developmental disorders. PMID- 29615454 TI - Clinical Outcomes and Sustainability of Using CYP2C19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention. AB - BACKGROUND: CYP2C19 loss-of-function (LOF) alleles impair clopidogrel effectiveness after percutaneous coronary intervention. The feasibility, sustainability, and clinical impact of using CYP2C19 genotype-guided dual antiplatelet therapy (DAPT) selection in practice remains unclear. METHODS: A single-center observational study was conducted in 1193 patients who underwent percutaneous coronary intervention and received DAPT after implementation of an algorithm that recommends CYP2C19 testing in high-risk patients and alternative DAPT (prasugrel or ticagrelor) in LOF allele carriers. The frequency of genotype testing and alternative DAPT selection were the primary implementation end points. Risk of major adverse cardiovascular or cerebrovascular and clinically significant bleeding events over 12 months were compared across genotype and DAPT groups by proportional hazards regression. RESULTS: CYP2C19 genotype was obtained in 868 (72.8%) patients. Alternative DAPT was prescribed in 186 (70.7%) LOF allele carriers. CYP2C19 testing (P<0.001) and alternative DAPT use in LOF allele carriers (P=0.001) varied over time. Risk for major adverse cardiovascular or cerebrovascular was significantly higher in LOF carriers prescribed clopidogrel versus alternative DAPT (adjusted hazard ratio, 4.65; 95% confidence interval, 2.22-10.0; P<0.001), whereas no significant difference was observed in those without a LOF allele (adjusted hazard ratio, 1.37; 95% confidence interval, 0.72 2.85; P=0.347). Bleeding event rates were similar across groups (log-rank P=0.816). CONCLUSIONS: Implementing CYP2C19 genotype-guided DAPT is feasible and sustainable in a real-world setting but challenging to maintain at a consistently high level of fidelity. The higher risk of major adverse cardiovascular or cerebrovascular associated with clopidogrel use in CYP2C19 LOF allele carriers suggests that use of genotype-guided DAPT in practice may improve clinical outcomes. PMID- 29615455 TI - Implementation of Genotype-Guided Antiplatelet Therapy: Feasible but Not Without Obstacles. PMID- 29615456 TI - ZIP4 Promotes Pancreatic Cancer Progression by Repressing ZO-1 and Claudin-1 through a ZEB1-Dependent Transcriptional Mechanism. AB - Purpose: ZIP4 is overexpressed in human pancreatic cancer and promotes tumor growth. However, little is known about the role of ZIP4 in advanced stages of this dismal neoplasm. Our goal is to study the underlying mechanism and define a novel signaling pathway controlled by ZIP4-modulating pancreatic tumor metastasis.Experimental Design: The expression of ZIP4, ZO-1, claudin-1, and ZEB1 in human pancreatic cancer tissues, genetically engineered mouse model, xenograft tumor model, and pancreatic cancer cell lines were examined, and the correlations between ZIP4 and those markers were also analyzed. Functional analysis of ZO-1, claudin-1, and ZEB1 was investigated in pancreatic cancer cell lines and orthotopic xenografts.Results: Genetic inactivation of ZIP4 inhibited migration and invasion in pancreatic cancer and increased the expression of ZO-1 and claudin-1. Conversely, overexpression of ZIP4 promoted migration and invasion and increased the expression of ZEB1 and downregulation of the aforementioned epithelial genes. ZIP4 downregulation of ZO-1 and claudin-1 requires the transcriptional repressor ZEB1. Further analysis demonstrated that ZIP4-mediated repression of ZO-1 and claudin-1 leads to upregulation of their targets FAK and Paxillin. Silencing of ZIP4 caused reduced phosphorylation of FAK and Paxillin, which was rescued by simultaneous blocking of ZO-1 or claudin-1. Clinically, we demonstrated that ZIP4 positively correlates with the levels of ZEB1 and inversely associates with the expression of ZO-1 and claudin-1.Conclusions: These findings suggest a novel pathway activated by ZIP4-controlling pancreatic cancer invasiveness and metastasis, which could serve as a new therapeutic target for this devastating disease. Clin Cancer Res; 24(13); 3186-96. (c)2018 AACR. PMID- 29615457 TI - Mechanistic Insights of an Immunological Adverse Event Induced by an Anti-KIT Antibody Drug Conjugate and Mitigation Strategies. AB - Purpose: Hypersensitivity reactions (HSRs) were observed in three patients dosed in a phase I clinical trial treated with LOP628, a KIT targeted antibody drug conjugate. Mast cell degranulation was implicated as the root cause for the HSR. Underlying mechanism of this reported HSR was investigated with an aim to identifying potential mitigation strategies.Experimental Design: Biomarkers for mast cell degranulation were evaluated in patient samples and in human peripheral blood cell-derived mast cell (PBC-MC) cultures treated with LOP628. Mitigation strategies interrogated include pretreatment of mast cells with small molecule inhibitors that target KIT or signaling pathways downstream of FcepsilonR1, FcgammaR, and treatment with Fc silencing antibody formats.Results: Transient elevation of serum tryptase was observed in patients 1-hour posttreatment of LOP628. In agreement with the clinical observation, LOP628 and its parental antibody LMJ729 induced degranulation of human PBC-MCs. Unexpectedly, KIT small molecule inhibitors did not abrogate mast cell degranulation. By contrast, small molecule inhibitors that targeted pathways downstream of Fc receptors blunted degranulation. Furthermore, interference of the KIT antibody to engage Fc receptors by pre-incubation with IgG or using engineered Fc silencing mutations reduced or prevented degranulation. Characterization of Fcgamma receptors revealed human PBC-MCs expressed both FcgammaRII and low levels of FcgammaRI. Interestingly, increasing the level of FcgammaRI upon addition of IFNgamma, significantly enhanced LOP628-mediated mast cell degranulation.Conclusions: Our data suggest LOP628-mediated mast cell degranulation is the likely cause of HSR observed in the clinic due to co-engagement of the FcgammaR and KIT, resulting in mast cell activation. Clin Cancer Res; 24(14); 3465-74. (c)2018 AACR. PMID- 29615458 TI - An Effective Epigenetic-PARP Inhibitor Combination Therapy for Breast and Ovarian Cancers Independent of BRCA Mutations. AB - Purpose: PARP inhibitors (PARPi) are primarily effective against BRCA1/2-mutated breast and ovarian cancers, but resistance due to reversion of mutated BRCA1/2 and other mechanisms is common. Based on previous reports demonstrating a functional role for DNMT1 in DNA repair and our previous studies demonstrating an ability of DNA methyltransferase inhibitor (DNMTi) to resensitize tumors to primary therapies, we hypothesized that combining a DNMTi with PARPi would sensitize PARPi-resistant breast and ovarian cancers to PARPi therapy, independent of BRCA status.Experimental Design: Breast and ovarian cancer cell lines (BRCA-wild-type/mutant) were treated with PARPi talazoparib and DNMTi guadecitabine. Effects on cell survival, ROS accumulation, and cAMP levels were examined. In vivo, mice bearing either BRCA-proficient breast or ovarian cancer cells were treated with talazoparib and guadecitabine, alone or in combination. Tumor progression, gene expression, and overall survival were analyzed.Results: Combination of guadecitabine and talazoparib synergized to enhance PARPi efficacy, irrespective of BRCA mutation status. Coadministration of guadecitabine with talazoparib increased accumulation of ROS, promoted PARP activation, and further sensitized, in a cAMP/PKA-dependent manner, breast and ovarian cancer cells to PARPi. In addition, DNMTi enhanced PARP "trapping" by talazoparib. Guadecitabine plus talazoparib decreased xenograft tumor growth and increased overall survival in BRCA-proficient high-grade serous ovarian and triple-negative breast cancer models.Conclusions: The novel combination of the next-generation DNMTi guadecitabine and the first-in-class PARPi talazoparib inhibited breast and ovarian cancers harboring either wild-type- or mutant-BRCA, supporting further clinical exploration of this drug combination in PARPi-resistant cancers. Clin Cancer Res; 24(13); 3163-75. (c)2018 AACR. PMID- 29615459 TI - Genetic Analysis of 779 Advanced Differentiated and Anaplastic Thyroid Cancers. AB - Purpose: To define the genetic landscape of advanced differentiated and anaplastic thyroid cancer (ATC) and identify genetic alterations of potential diagnostic, prognostic, and therapeutic significance.Experimental Design: The genetic profiles of 583 advanced differentiated and 196 ATCs generated with targeted next-generation sequencing cancer-associated gene panels MSK-IMPACT and FoundationOne were analyzed.Results: ATC had more genetic alterations per tumor, and pediatric papillary thyroid cancer had fewer genetic alterations per tumor when compared with other thyroid cancer types. DNA mismatch repair deficit and activity of APOBEC cytidine deaminases were identified as mechanisms associated with high mutational burden in a subset of differentiated thyroid cancers and ATCs. Copy number losses and mutations of CDKN2A and CDKN2B, amplification of CCNE1, amplification of receptor tyrosine kinase genes KDR, KIT, and PDGFRA, amplification of immune evasion genes CD274, PDCD1LG2, and JAK2, and activating point mutations in small GTPase RAC1 were associated with ATC. An association of KDR, KIT, and PDGFRA amplification with the sensitivity of thyroid cancer cells to lenvatinib was shown in vitro Three genetically distinct types of ATCs are proposed.Conclusions: This large-scale analysis describes genetic alterations in a cohort of thyroid cancers enriched in advanced cases. Many novel genetic events previously not seen in thyroid cancer were found. Genetic alterations associated with anaplastic transformation were identified. An updated schematic of thyroid cancer genetic evolution is proposed. Clin Cancer Res; 24(13); 3059-68. (c)2018 AACR. PMID- 29615460 TI - Clinical and Pathological Characteristics of KEAP1- and NFE2L2-Mutated Non-Small Cell Lung Carcinoma (NSCLC). AB - Purpose:KEAP1 and NFE2L2 mutations are associated with impaired prognosis in a variety of cancers and with squamous cell carcinoma formation in non-small cell lung cancer (NSCLC). However, little is known about frequency, histology dependence, molecular and clinical presentation as well as response to systemic treatment in NSCLC.Experimental Design: Tumor tissue of 1,391 patients with NSCLC was analyzed using next-generation sequencing (NGS). Clinical and pathologic characteristics, survival, and treatment outcome of patients with KEAP1 or NFE2L2 mutations were assessed.Results:KEAP1 mutations occurred with a frequency of 11.3% (n = 157) and NFE2L2 mutations with a frequency of 3.5% (n = 49) in NSCLC patients. In the vast majority of patients, both mutations did not occur simultaneously. KEAP1 mutations were found mainly in adenocarcinoma (AD; 72%), while NFE2L2 mutations were more common in squamous cell carcinoma (LSCC; 59%). KEAP1 mutations were spread over the whole protein, whereas NFE2L2 mutations were clustered in specific hotspot regions. In over 80% of the patients both mutations co-occurred with other cancer-related mutations, among them also targetable aberrations like activating EGFR mutations or MET amplification. Both patient groups showed different patterns of metastases, stage distribution and performance state. No patient with KEAP1 mutation had a response on systemic treatment in first-, second-, or third-line setting. Of NFE2L2-mutated patients, none responded to second- or third-line therapy.Conclusions:KEAP1- and NFE2L2 mutated NSCLC patients represent a highly heterogeneous patient cohort. Both are associated with different histologies and usually are found together with other cancer-related, partly targetable, genetic aberrations. In addition, both markers seem to be predictive for chemotherapy resistance. Clin Cancer Res; 24(13); 3087 96. (c)2018 AACR. PMID- 29615461 TI - Molecular Diagnosis of Diffuse Gliomas through Sequencing of Cell-Free Circulating Tumor DNA from Cerebrospinal Fluid. AB - Purpose: Diffuse gliomas are the most common primary tumor of the brain and include different subtypes with diverse prognosis. The genomic characterization of diffuse gliomas facilitates their molecular diagnosis. The anatomical localization of diffuse gliomas complicates access to tumor specimens for diagnosis, in some cases incurring high-risk surgical procedures and stereotactic biopsies. Recently, cell-free circulating tumor DNA (ctDNA) has been identified in the cerebrospinal fluid (CSF) of patients with brain malignancies.Experimental Design: We performed an analysis of IDH1, IDH2, TP53, TERT, ATRX, H3F3A, and HIST1H3B gene mutations in two tumor cohorts from The Cancer Genome Atlas (TCGA) including 648 diffuse gliomas. We also performed targeted exome sequencing and droplet digital PCR (ddPCR) analysis of these seven genes in 20 clinical tumor specimens and CSF from glioma patients and performed a histopathologic characterization of the tumors.Results: Analysis of the mutational status of the IDH1, IDH2, TP53, TERT, ATRX, H3F3A, and HIST1H3B genes allowed the classification of 79% of the 648 diffuse gliomas analyzed, into IDH-wild-type glioblastoma, IDH-mutant glioblastoma/diffuse astrocytoma and oligodendroglioma, each subtype exhibiting diverse median overall survival (1.1, 6.7, and 11.2 years, respectively). We developed a sequencing platform to simultaneously and rapidly genotype these seven genes in CSF ctDNA allowing the subclassification of diffuse gliomas.Conclusions: The genomic analysis of IDH1, IDH2, TP53, ATRX, TERT, H3F3A, and HIST1H3B gene mutations in CSF ctDNA facilitates the diagnosis of diffuse gliomas in a timely manner to support the surgical and clinical management of these patients. Clin Cancer Res; 24(12); 2812-9. (c)2018 AACR. PMID- 29615462 TI - Cell-Free DNA Modification Dynamics in Abiraterone Acetate-Treated Prostate Cancer Patients. AB - Purpose: Primary resistance to abiraterone acetate (AA), a key medication for the treatment of metastatic castration-resistant prostate cancer, occurs in 20% to 40% of patients. We aim to identify predictive biomarkers for AA-treatment response and understand the mechanisms related to treatment resistance.Experimental Design: We used the Infinium Human Methylation 450K BeadChip to monitor modification profiles of cell-free circulating DNA (cfDNA) in 108 plasma samples collected from 33 AA-treated patients.Results: Thirty cytosines showed significant modification differences (FDR Q < 0.05) between AA sensitive and AA-resistant patients during the treatment, of which 21 cytosines were differentially modified prior to treatment. In addition, AA-sensitive patients, but not AA-resistant patients, lost interindividual variation of cfDNA modification shortly after starting AA treatment, but such variation returned to initial levels in the later phases of treatment.Conclusions: Our findings provide a list of potential biomarkers for predicting AA-treatment response, highlight the prognostic value of using cytosine modification variance as biomarkers, and shed new insights into the mechanisms of prostate cancer relapse in AA-sensitive patients. Clin Cancer Res; 24(14); 3317-24. (c)2018 AACR. PMID- 29615465 TI - Heterogeneous fates and dynamic rearrangement of regenerative epidermis-derived cells during zebrafish fin regeneration. AB - The regenerative epidermis (RE) is a specialized tissue that plays an essential role in tissue regeneration. However, the fate of the RE during and after regeneration is unknown. In this study, we performed Cre-loxP-mediated cell fate tracking and revealed the fates of a major population of the RE cells that express fibronectin 1b (fn1b) during zebrafish fin regeneration. Our study showed that these RE cells are mainly recruited from the inter-ray epidermis, and that they follow heterogeneous cell fates. Early recruited cells contribute to initial wound healing and soon disappear by apoptosis, while the later recruited cells contribute to the regenerated epidermis. Intriguingly, many of these cells are also expelled from the regenerated tissue by a dynamic caudal movement of the epidermis over time, and in turn the loss of epidermal cells is replenished by a global self-replication of basal and suprabasal cells in fin. De-differentiation of non-basal epidermal cells into the basal epidermal cells did not occur during regeneration. Overall, our study reveals the heterogeneous fates of RE cells and a dynamic rearrangement of the epidermis during and after regeneration. PMID- 29615464 TI - Coordinated directional outgrowth and pattern formation by integration of Wnt5a and Fgf signaling in planar cell polarity. AB - Embryonic morphogenesis of a complex organism requires proper regulation of patterning and directional growth. Planar cell polarity (PCP) signaling is emerging as a crucial evolutionarily conserved mechanism whereby directional information is conveyed. PCP is thought to be established by global cues, and recent studies have revealed an instructive role of a Wnt signaling gradient in epithelial tissues of both invertebrates and vertebrates. However, it remains unclear whether Wnt/PCP signaling is regulated in a coordinated manner with embryonic patterning during morphogenesis. Here, in mouse developing limbs, we find that apical ectoderm ridge-derived Fgfs required for limb patterning regulate PCP along the proximal-distal axis in a Wnt5a-dependent manner. We demonstrate with genetic evidence that the Wnt5a gradient acts as a global cue that is instructive in establishing PCP in the limb mesenchyme, and that Wnt5a also plays a permissive role to allow Fgf signaling to orient PCP. Our results indicate that limb morphogenesis is regulated by coordination of directional growth and patterning through integration of Wnt5a and Fgf signaling. PMID- 29615466 TI - Lmx1a is required for the development of the ovarian stem cell niche in Drosophila. AB - The Drosophila ovary serves as a model for pioneering studies of stem cell niches, with defined cell types and signaling pathways supporting both germline and somatic stem cells. The establishment of the niche units begins during larval stages with the formation of terminal filament-cap structures; however, the genetics underlying their development remains largely unknown. Here, we show that the transcription factor Lmx1a is required for ovary morphogenesis. We found that Lmx1a is expressed in early ovarian somatic lineages and becomes progressively restricted to terminal filaments and cap cells. We show that Lmx1a is required for the formation of terminal filaments, during the larval-pupal transition. Finally, our data demonstrate that Lmx1a functions genetically downstream of Bric a-Brac, and is crucial for the expression of key components of several conserved pathways essential to ovarian stem cell niche development. Importantly, expression of chicken Lmx1b is sufficient to rescue the null Lmx1a phenotype, indicating functional conservation across the animal kingdom. These results significantly expand our understanding of the mechanisms controlling stem cell niche development in the fly ovary. PMID- 29615468 TI - Intrahepatic bile ducts guide establishment of the intrahepatic nerve network in developing and regenerating mouse liver. AB - Epithelial organs consist of multiple tissue structures, such as epithelial sheets, blood vessels and nerves, which are spatially organized to achieve optimal physiological functions. The hepatic nervous system has been implicated in physiological functions and regeneration of the liver. However, the processes of development and reconstruction of the intrahepatic nerve network and its underlying mechanisms remain unknown. Here, we demonstrate that neural class III beta-tubulin (TUBB3)+ nerve fibers are not distributed in intrahepatic tissue at embryonic day 17.5; instead, they gradually extend along the periportal tissue, including intrahepatic bile ducts (IHBDs), after birth. Nerve growth factor (Ngf) expression increased in biliary epithelial cells (BECs) and mesenchymal cells next to BECs before nerve fiber extension, and Ngf was upregulated by hairy enhancer of slit 1 (Hes family bHLH transcription factor 1; Hes1). Ectopic NGF expression in mature hepatocytes induced nerve fiber extension into the parenchymal region, from where these fibers are normally excluded. Furthermore, after BECs were damaged by the administration of 4,4-diaminodiphenylmethane, the nerve network appeared shrunken; however, it was reconstructed after IHBD regeneration, which depended on the NGF signal. These results suggest that IHBDs guide the extension of nerve fibers by secreting NGF during nerve fiber development and regeneration. PMID- 29615467 TI - Late neuroprogenitors contribute to normal retinal vascular development in a Hif2a-dependent manner. AB - In the adult central nervous system, endothelial and neuronal cells engage in tight cross-talk as key components of the so-called neurovascular unit. Impairment of this important relationship adversely affects tissue homeostasis, as observed in neurodegenerative conditions including Alzheimer's and Parkinson's disease. In development, the influence of neuroprogenitor cells on angiogenesis is poorly understood. Here, we show in mouse that these cells interact intimately with the growing retinal vascular network, and we identify a novel regulatory mechanism of vasculature development mediated by hypoxia-inducible factor 2a (Hif2a). By Cre-lox gene excision, we show that Hif2a in retinal neuroprogenitor cells upregulates the expression of the pro-angiogenic mediators vascular endothelial growth factor and erythropoietin, whereas it locally downregulates the angiogenesis inhibitor endostatin. Importantly, absence of Hif2a in retinal neuroprogenitor cells causes a marked reduction of proliferating endothelial cells at the angiogenic front. This results in delayed retinal vascular development, fewer major retinal vessels and reduced density of the peripheral deep retinal vascular plexus. Our findings demonstrate that retinal neuroprogenitor cells are a crucial component of the developing neurovascular unit. PMID- 29615469 TI - Thrombopoietin protects hematopoietic stem cells from retrotransposon-mediated damage by promoting an antiviral response. AB - Maintenance of genomic integrity is crucial for the preservation of hematopoietic stem cell (HSC) potential. Retrotransposons, spreading in the genome through an RNA intermediate, have been associated with loss of self-renewal, aging, and DNA damage. However, their role in HSCs has not been addressed. Here, we show that mouse HSCs express various retroelements (REs), including long interspersed element-1 (L1) recent family members that further increase upon irradiation. Using mice expressing an engineered human L1 retrotransposition reporter cassette and reverse transcription inhibitors, we demonstrate that L1 retransposition occurs in vivo and is involved in irradiation-induced persistent gammaH2AX foci and HSC loss of function. Thus, RE represents an important intrinsic HSC threat. Furthermore, we show that RE activity is restrained by thrombopoietin, a critical HSC maintenance factor, through its ability to promote a potent interferon-like, antiviral gene response in HSCs. This uncovers a novel mechanism allowing HSCs to minimize irradiation-induced injury and reinforces the links between DNA damage, REs, and antiviral immunity. PMID- 29615471 TI - Pharmacological Characterization of H05, a Novel Serotonin and Noradrenaline Reuptake Inhibitor with Moderate 5-HT2A Antagonist Activity for the Treatment of Depression. AB - Multitarget antidepressants selectively inhibiting monoaminergic transporters and 5-hydroxytryptamine (5-HT) 2A receptor have demonstrated higher efficacy and fewer side effects than selective serotonin reuptake inhibitors. In the present study, we synthesized a series of novel 3-(benzo[d][1,3]dioxol-4-yloxy)-3 arylpropyl amine derivatives, among which compound H05 was identified as a lead, exhibiting potent inhibitory effects on both serotonin (Ki = 4.81 nM) and norepinephrine (NE) (Ki = 6.72 nM) transporters and moderate 5-HT2A antagonist activity (IC50 = 60.37 nM). H05 was able to dose-dependently reduce the immobility duration in mouse forced swimming test and tail suspension test, with the minimal effective doses lower than those of duloxetine, and showed no stimulatory effect on locomotor activity. The administration of H05 (5, 10, and 20 mg/kg, by mouth) significantly shortened the immobility time of adrenocorticotropin-treated rats that serve as a model of treatment-resistant depression, whereas imipramine (30 mg/kg, by mouth) and duloxetine (30 mg/kg, by mouth) showed no obvious effects. Chronic treatment with H05 reversed the depressive-like behaviors in a rat model of chronic unpredictable mild stress and a mouse model of corticosterone-induced depression. Microdialysis analysis revealed that the administration of H05 at either 10 or 20 mg/kg increased the release of 5-HT and NE from the frontal cortex. The pharmacokinetic (PK) and brain penetration analyses suggest that H05 has favorable PK properties with good blood-brain penetration ability. Therefore, it can be concluded that H05, a novel serotonin and NE reuptake inhibitor with 5-HT2A antagonist activity, possesses efficacious activity in the preclinical models of depression and treatment resistant depression, and it may warrant further evaluation for clinical development. PMID- 29615470 TI - Modulation of Gq-Rho Signaling by the ERK MAPK Pathway Controls Locomotion in Caenorhabditis elegans. AB - The heterotrimeric G protein Gq regulates neuronal activity through distinct downstream effector pathways. In addition to the canonical Gq effector phospholipase Cbeta, the small GTPase Rho was recently identified as a conserved effector of Gq. To identify additional molecules important for Gq signaling in neurons, we performed a forward genetic screen in the nematode Caenorhabditis elegans for suppressors of the hyperactivity and exaggerated waveform of an activated Gq mutant. We isolated two mutations affecting the MAP kinase scaffold protein KSR-1 and found that KSR-1 modulates locomotion downstream of, or in parallel to, the Gq-Rho pathway. Through epistasis experiments, we found that the core ERK MAPK cascade is required for Gq-Rho regulation of locomotion, but that the canonical ERK activator LET-60/Ras may not be required. Through neuron specific rescue experiments, we found that the ERK pathway functions in head acetylcholine neurons to control Gq-dependent locomotion. Additionally, expression of activated LIN-45/Raf in head acetylcholine neurons is sufficient to cause an exaggerated waveform phenotype and hypersensitivity to the acetylcholinesterase inhibitor aldicarb, similar to an activated Gq mutant. Taken together, our results suggest that the ERK MAPK pathway modulates the output of Gq-Rho signaling to control locomotion behavior in C. elegans. PMID- 29615472 TI - Epigenetic regulation in the tumorigenesis of MEN1-associated endocrine cell types. AB - Epigenetic regulation is emerging as a key feature in the molecular characteristics of various human diseases. Epigenetic aberrations can occur from mutations in genes associated with epigenetic regulation, improper deposition, removal or reading of histone modifications, DNA methylation/demethylation and impaired non-coding RNA interactions in chromatin. Menin, the protein product of the gene causative for the multiple endocrine neoplasia type 1 (MEN1) syndrome, interacts with chromatin-associated protein complexes and also regulates some non coding RNAs, thus participating in epigenetic control mechanisms. Germline inactivating mutations in the MEN1 gene that encodes menin predispose patients to develop endocrine tumors of the parathyroids, anterior pituitary and the duodenopancreatic neuroendocrine tissues. Therefore, functional loss of menin in the various MEN1-associated endocrine cell types can result in epigenetic changes that promote tumorigenesis. Because epigenetic changes are reversible, they can be targeted to develop therapeutics for restoring the tumor epigenome to the normal state. Irrespective of whether epigenetic alterations are the cause or consequence of the tumorigenesis process, targeting the endocrine tumor associated epigenome offers opportunities for exploring therapeutic options. This review presents epigenetic control mechanisms relevant to the interactions and targets of menin, and the contribution of epigenetics in the tumorigenesis of endocrine cell types from menin loss. PMID- 29615473 TI - PKA-RII subunit phosphorylation precedes activation by cAMP and regulates activity termination. AB - Type II isoforms of cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA-II) contain a phosphorylatable epitope within the inhibitory domain of RII subunits (pRII) with still unclear function. In vitro, RII phosphorylation occurs in the absence of cAMP, whereas staining of cells with pRII-specific antibodies revealed a cAMP-dependent pattern. In sensory neurons, we found that increased pRII immunoreactivity reflects increased accessibility of the already phosphorylated RII epitope during cAMP-induced opening of the tetrameric RII2:C2 holoenzyme. Accordingly, induction of pRII by cAMP was sensitive to novel inhibitors of dissociation, whereas blocking catalytic activity was ineffective. Also in vitro, cAMP increased the binding of pRII antibodies to RII2:C2 holoenzymes. Identification of an antibody specific for the glycine-rich loop of catalytic subunits facing the pRII-epitope confirmed activity-dependent binding with similar kinetics, proving that the reassociation is rapid and precisely controlled. Mechanistic modeling further supported that RII phosphorylation precedes cAMP binding and controls the inactivation by modulating the reassociation involving the coordinated action of phosphodiesterases and phosphatases. PMID- 29615474 TI - How adolescent health influences education and employment: investigating longitudinal associations and mechanisms. AB - BACKGROUND: Education is recognised as a strong determinant of health. Yet there is increasing concern that health in adolescence may also influence educational attainments and future life chances. We examined associations between health in early adolescence and subsequent academic and employment outcomes, exploring potential mediators of these relationships to inform intervention strategies. METHODS: We used data from the Longitudinal Study of Young People in England. Adolescent health was measured at waves 1 and 2. Outcomes included educational attainment at age 16 years and being NEET (not in education, employment or training) at age 19 years. Associations were adjusted for ethnicity, area-level deprivation and early adolescent academic attainment. Where significant associations were identified, we examined the role of hypothesised mediators including attendance and truancy, classroom behaviour, substance use and psychological distress. RESULTS: Health conditions in early adolescence predicted poor subsequent education and employment outcomes (ORs ranged from 1.25 to 1.72) with the exception of long-term chronic conditions and NEET status, which were unassociated. The most consistent mediating variable was social exclusion. School behaviour, truancy and substance use were significant mediators for mental health. Long-term absences mediated associations between mental health and physical health and later outcomes. CONCLUSIONS: Health is a key component of academic and vocational achievement. Investment in health is a way of improving life chances. The identification of key mediators such as social exclusion and truancy indicate areas where screening for health conditions and provision of targeted support could improve educational, employment and health outcomes. PMID- 29615475 TI - MicroRNAs: crucial regulators of placental development. AB - MicroRNAs (miRNAs) are small non-coding single-stranded RNAs that are integral to a wide range of cellular processes mainly through the regulation of translation and mRNA stability of their target genes. The placenta is a transient organ that exists throughout gestation in mammals, facilitating nutrient and gas exchange and waste removal between the mother and the fetus. miRNAs are expressed in the placenta, and many studies have shown that miRNAs play an important role in regulating trophoblast differentiation, migration, invasion, proliferation, apoptosis, vasculogenesis/angiogenesis and cellular metabolism. In this review, we provide a brief overview of canonical and non-canonical pathways of miRNA biogenesis and mechanisms of miRNA actions. We highlight the current knowledge of the role of miRNAs in placental development. Finally, we point out several limitations of the current research and suggest future directions. PMID- 29615476 TI - Neuronostatin exerts actions on pituitary that are unique from its sibling peptide somatostatin. AB - Neuronostatin, a somatostatin gene-encoded peptide, exerts important physiological and metabolic actions in diverse tissues. However, the direct biological effects of neuronostatin on pituitary function of humans and primates are still unknown. This study used baboon (Papio anubis) primary pituitary cell cultures, a species that closely models human physiology, to demonstrate that neuronostatin inhibits basal, but not ghrelin-/GnRH-stimulated, growth hormone (GH) and luteinizing hormone (LH) secretion in a dose- and time-dependent fashion, without affecting the secretion of other pituitary hormones (prolactin, ACTH, FSH, thyroid-stimulating hormone (TSH)) or changing mRNA levels. Actions of neuronostatin differs from somatostatin which in this study reduced GH/PRL/ACTH/LH/TSH secretion and GH/PRL/POMC/LH gene expression. Remarkably, we found that inhibitory actions of neuronostatin are likely mediated through: (1) the orphan receptor GPCR107 (found to be highly expressed in pituitary compared to somatostatin-receptors), (2) common (i.e. adenylyl cyclase/protein kinase A/MAPK/extra-/intracellular Ca2+ mobilization, but not phospholipase C/protein kinase C/mTOR) and distinct (i.e. PI3K) signaling pathways than somatostatin and; (3) dissimilar molecular mechanisms than somatostatin (i.e. upregulation of GPCR107 and downregulation of GHS-R/Kiss1-R expression by neuronostatin and, upregulation of sst1-5 expression by somatostatin). Altogether, the results of this study provide the first evidence that there is a functional neuronostatin signaling circuit, unique from somatostatin, which may work in concert with somatostatin to fine-tune hormone release from somatostropes and gonadotropes. PMID- 29615478 TI - Partnering with Life Science Alliance. PMID- 29615477 TI - Leptin stimulates aromatase in the growth plate: limiting catch-up growth efficiency. AB - Catch-up growth (CUG) in childhood is defined as periods of growth acceleration, after the resolution of growth attenuation causes, bringing the children back to their original growth trajectory. Sometimes, however, CUG is incomplete, leading to permanent growth deficit and short stature. The aim of this study was to investigate the mechanisms that limit nutritional-CUG. Specifically, we focused on the crosstalk between leptin, increased by re-feeding, and sex hormones, which increase with age. In vivo studies were performed in young male Sprague Dawley rats fed ad libitum or subjected to 10/36 days of 40% food restriction followed by 90-120 days of re-feeding. In vitro studies were performed on ATDC5 cells. Analyses of mRNA and protein levels were done using qPCR and Western blot, respectively. CUG was complete in body weight and humerus length in animals that were food-restricted for 10 days but not for those food-restricted for 36 days. In vitro studies showed that leptin significantly increased aromatase gene expression and protein level as well as the expression of estrogen and leptin receptors in a dose- and time-dependent manner. The effect of leptin on aromatase was direct and was mediated through the MAPK/Erk, STAT3 and PI3K pathways. The crosstalk between leptin and aromatase in the growth plate suggests that re feeding during puberty may lead to increased estrogen level and activity, and consequently, irreversible premature epiphyseal growth plate closure. These results may have important implications for the development of novel treatment strategies for short stature in children. PMID- 29615479 TI - The Role of Pediatric Trainees in Addressing Oral Health Disparities in Children. PMID- 29615480 TI - Improving Anaphylaxis Care: The Impact of a Clinical Pathway. AB - BACKGROUND: Recommended durations of observation after anaphylaxis have been widely variable, with many ranging from 4 to 24 hours. Prolonged durations often prompt admission for ongoing observation. METHODS: In a multidisciplinary quality improvement initiative, we revised our emergency department (ED) anaphylaxis clinical pathway. Our primary aim was to safely decrease the recommended length of observation from 8 to 4 hours and thereby decrease unnecessary hospitalizations. Secondary aims included provider education on anaphylaxis diagnostic criteria, emphasizing epinephrine as first-line therapy, and implementing a practice of discharging ED patients with an epinephrine autoinjector in hand. The study period consisted of the 18 months before pathway revision (baseline) and the 18 months after revision. RESULTS: The overall admission rate decreased from 58.2% (106 of 182) in the baseline period to 25.3% (65 of 257) after pathway revision (P < .0001). There was no significant difference in the percentage of patients returning to the ED within 72 hours, and there were no adverse outcomes or deaths throughout the study period. After pathway revision, the median time to first epinephrine administration for the most critical patients was 10 minutes, and 85.4% (164 of 192) of patients were discharged with an epinephrine autoinjector in hand. CONCLUSIONS: By revising an anaphylaxis clinical pathway, we were able to streamline the care of patients with anaphylaxis presenting to a busy pediatric ED, without any compromise in safety. Most notably, decreasing the recommended length of observation from 8 to 4 hours resulted in a near 60% reduction in the average rate of admission. PMID- 29615481 TI - SRSF3 recruits DROSHA to the basal junction of primary microRNAs. AB - The Microprocessor complex, consisting of an RNase III DROSHA and the DGCR8 dimer, cleaves primary microRNA transcripts (pri-miRNAs) to initiate microRNA (miRNA) maturation. Pri-miRNAs are stem-loop RNAs, and ~79% of them contain at least one of the three major and conserved RNA motifs, UG, UGU, and CNNC. We recently demonstrated that the basal UG and apical UGU motifs of pri-miRNAs interact with DROSHA and DGCR8, respectively. They help orient Microprocessor on pri-miRNA in a proper direction in which DROSHA and DGCR8 localize to the basal and apical pri-miRNA junctions, respectively. In addition, CNNC, located at ~17 nucleotides (nt) from the Microprocessor cleavage site, interacts with SRSF3 (SRp20) to stimulate Microprocessor to process pri-miRNAs. The mechanism underlying this stimulation, however, is unknown. In this study, we discovered that SRSF3 recruits DROSHA to the basal junction in a CNNC-dependent manner, thereby enhancing Microprocessor activity. Furthermore, by generating various pri miRNA substrates containing CNNC at different locations, we demonstrated that such stimulation only occurs when CNNC is located at ~17 nt from the Microprocessor cleavage site. Our findings reveal the molecular mechanism of SRSF3 in pri-miRNA processing and support the previously proposed explanation for the highly conserved position of CNNC in SRSF3-enhanced pri-miRNA processing. PMID- 29615482 TI - Defining essential elements and genetic interactions of the yeast Lsm2-8 ring and demonstration that essentiality of Lsm2-8 is bypassed via overexpression of U6 snRNA or the U6 snRNP subunit Prp24. AB - A seven-subunit Lsm2-8 protein ring assembles on the U-rich 3' end of the U6 snRNA. A structure-guided mutational analysis of the Saccharomyces cerevisiae Lsm2-8 ring affords new insights to structure-function relations and genetic interactions of the Lsm subunits. Alanine scanning of 39 amino acids comprising the RNA-binding sites or intersubunit interfaces of Lsm2, Lsm3, Lsm4, Lsm5, and Lsm8 identified only one instance of lethality (Lsm3-R69A) and one severe growth defect (Lsm2-R63A), both involving amino acids that bind the 3'-terminal UUU trinucleotide. All other Ala mutations were benign with respect to vegetative growth. Tests of 235 pairwise combinations of benign Lsm mutants identified six instances of inter-Lsm synthetic lethality and 45 cases of nonlethal synthetic growth defects. Thus, Lsm2-8 ring function is buffered by a network of internal genetic redundancies. A salient finding was that otherwise lethal single-gene deletions lsm2Delta, lsm3Delta, lsm4Delta, lsm5, and lsm8Delta were rescued by overexpression of U6 snRNA from a high-copy plasmid. Moreover, U6 overexpression rescued myriad lsmDelta lsmDelta double-deletions and lsmDelta lsmDelta lsmDelta triple-deletions. We find that U6 overexpression also rescues a lethal deletion of the U6 snRNP protein subunit Prp24 and that Prp24 overexpression bypasses the essentiality of the U6-associated Lsm subunits. Our results indicate that abetting U6 snRNA is the only essential function of the yeast Lsm2-8 proteins. PMID- 29615483 TI - Incidence of Hypocapnia, Hypercapnia, and Acidosis and the Associated Risk of Adverse Events in Preterm Neonates. AB - BACKGROUND: Permissive hypercapnia is a lung-protection strategy. We sought to review our current clinical practice for the range of permissive hypercapnia and identify the relationship between PaCO2 and pH and adverse outcomes. METHODS: A secondary analysis of a delayed cord-clamping clinical trial was performed on all arterial blood gas tests in the first 72 h in infants < 32 weeks gestational age. All arterial blood gas values were categorized into a clinical range to determine the percent likelihood of occurring in the total sample. The univariate and multivariate relationships of severe adverse events and the time-weighted PaCO2 , fluctuation of PaCO2 , maximal and minimal PaCO2 , base excess, and pH were assessed. RESULTS: 147 infants with birthweight of 1,206 +/- 395 g and gestational age of 28 +/- 2 weeks were included. Of the 1,316 total samples, < 2% had hypocapnia (PaCO2 <30 mm Hg), 47% were normocapnic (PaCO2 35-45 mm Hg), 26.5% had mild hypercapnia (PaCO2 45-55 mm Hg), 13% had moderate hypercapnia (PaCO2 55 65 mm Hg), and 6.5% had severe hypercapnia (PaCO2 >= 65 mm Hg). There were no adverse events associated with hypocapnia. Subjects with death/severe intraventricular hemorrhage had a higher mean PaCO2 of 52.3 versus 44.7 (odds ratio [OR] 1.16, 95% CI 1.04-1.29, P = .006), higher variability of PaCO2 with a standard deviation of 12.6 versus 7.8 (OR 1.15, 95% CI 1.03-1.27, P = .01), and a lower minimum pH of 7.03 versus 7.23 (OR 0, 95% CI 0-0.06, P = .003). There was no significant difference in any variables in subjects who developed other adverse events. CONCLUSION: The routine targeting of higher than normal PaCO2 goals may lead to a low incidence of hypocapnia and associated adverse events. Hypercapnia is common, and moderate hypercapnia may increase the risk of neurologic injury and provide little pulmonary benefit. PMID- 29615484 TI - The Synaptic Properties of Cells Define the Hallmarks of Interval Timing in a Recurrent Neural Network. AB - Extensive research has described two key features of interval timing. The bias property is associated with accuracy and implies that time is overestimated for short intervals and underestimated for long intervals. The scalar property is linked to precision and states that the variability of interval estimates increases as a function of interval duration. The neural mechanisms behind these properties are not well understood. Here we implemented a recurrent neural network that mimics a cortical ensemble and includes cells that show paired-pulse facilitation and slow inhibitory synaptic currents. The network produces interval selective responses and reproduces both bias and scalar properties when a Bayesian decoder reads its activity. Notably, the interval-selectivity, timing accuracy, and precision of the network showed complex changes as a function of the decay time constants of the modeled synaptic properties and the level of background activity of the cells. These findings suggest that physiological values of the time constants for paired-pulse facilitation and GABAb, as well as the internal state of the network, determine the bias and scalar properties of interval timing.SIGNIFICANCE STATEMENT Timing is a fundamental element of complex behavior, including music and language. Temporal processing in a wide variety of contexts shows two primary features: time estimates exhibit a shift toward the mean (the bias property) and are more variable for longer intervals (the scalar property). We implemented a recurrent neural network that includes long-lasting synaptic currents, which cannot only produce interval-selective responses but also follow the bias and scalar properties. Interestingly, only physiological values of the time constants for paired-pulse facilitation and GABAb, as well as intermediate background activity within the network can reproduce the two key features of interval timing. PMID- 29615485 TI - Alpha Oscillations Are Causally Linked to Inhibitory Abilities in Ageing. AB - Aging adults typically show reduced ability to ignore task-irrelevant information, an essential skill for optimal performance in many cognitive operations, including those requiring working memory (WM) resources. In a first experiment, young and elderly human participants of both genders performed an established WM paradigm probing inhibitory abilities by means of valid, invalid, and neutral retro-cues. Elderly participants showed an overall cost, especially in performing invalid trials, whereas younger participants' general performance was comparatively higher, as expected.Inhibitory abilities have been linked to alpha brain oscillations but it is yet unknown whether in aging these oscillations (also typically impoverished) and inhibitory abilities are causally linked. To probe this possible causal link in aging, we compared in a second experiment parietal alpha-transcranial alternating current stimulation (tACS) with either no stimulation (Sham) or with two control stimulation frequencies (theta- and gamma-tACS) in the elderly group while performing the same WM paradigm. Alpha- (but not theta- or gamma-) tACS selectively and significantly improved performance (now comparable to younger adults' performance in the first experiment), particularly for invalid cues where initially elderly showed the highest costs. Alpha oscillations are therefore causally linked to inhibitory abilities and frequency-tuned alpha-tACS interventions can selectively change these abilities in the elderly.SIGNIFICANCE STATEMENT Ignoring task-irrelevant information, an ability associated to rhythmic brain activity in the alpha frequency band, is fundamental for optimal performance. Indeed, impoverished inhibitory abilities contribute to age-related decline in cognitive functions like working memory (WM), the capacity to briefly hold information in mind. Whether in aging adults alpha oscillations and inhibitory abilities are causally linked is yet unknown. We experimentally manipulated frequency-tuned brain activity using transcranial alternating current stimulation (tACS), combined with a retro-cue paradigm assessing WM and inhibition. We found that alpha-tACS induced a significant improvement in target responses and misbinding errors, two indexes of inhibition. We concluded that in aging alpha oscillations are causally linked to inhibitory abilities, and that despite being impoverished, these abilities are still malleable. PMID- 29615486 TI - Human Episodic Memory Retrieval Is Accompanied by a Neural Contiguity Effect. AB - Cognitive psychologists have long hypothesized that experiences are encoded in a temporal context that changes gradually over time. When an episodic memory is retrieved, the state of context is recovered-a jump back in time. We recorded from single units in the medial temporal lobe of epilepsy patients performing an item recognition task. The population vector changed gradually over minutes during presentation of the list. When a probe from the list was remembered with high confidence, the population vector reinstated the temporal context of the original presentation of that probe during study, a neural contiguity effect that provides a possible mechanism for behavioral contiguity effects. This pattern was only observed for well remembered probes; old probes that were not well remembered showed an anti-contiguity effect. These results constitute the first direct evidence that recovery of an episodic memory in humans is associated with retrieval of a gradually changing state of temporal context, a neural "jump back in time" that parallels the act of remembering.SIGNIFICANCE STATEMENT Episodic memory is the ability to relive a specific experience from one's life. For decades, researchers have hypothesized that, unlike other forms of memory that can be described as simple associations between stimuli, episodic memory depends on the recovery of a neural representation of spatiotemporal context. During study of a sequence of stimuli, the brain state of epilepsy patients changed slowly over at least a minute. When the participant remembered a particular event from the list, this gradually changing state was recovered. This provides direct confirmation of the prediction from computational models of episodic memory. The resolution of this point means that the study of episodic memory can focus on the mechanisms by which this representation of spatiotemporal context is maintained and sometimes recovered. PMID- 29615487 TI - Comparison of prognostic models to predict the occurrence of colorectal cancer in asymptomatic individuals: a systematic literature review and external validation in the EPIC and UK Biobank prospective cohort studies. AB - OBJECTIVE: To systematically identify and validate published colorectal cancer risk prediction models that do not require invasive testing in two large population-based prospective cohorts. DESIGN: Models were identified through an update of a published systematic review and validated in the European Prospective Investigation into Cancer and Nutrition (EPIC) and the UK Biobank. The performance of the models to predict the occurrence of colorectal cancer within 5 or 10 years after study enrolment was assessed by discrimination (C-statistic) and calibration (plots of observed vs predicted probability). RESULTS: The systematic review and its update identified 16 models from 8 publications (8 colorectal, 5 colon and 3 rectal). The number of participants included in each model validation ranged from 41 587 to 396 515, and the number of cases ranged from 115 to 1781. Eligible and ineligible participants across the models were largely comparable. Calibration of the models, where assessable, was very good and further improved by recalibration. The C-statistics of the models were largely similar between validation cohorts with the highest values achieved being 0.70 (95% CI 0.68 to 0.72) in the UK Biobank and 0.71 (95% CI 0.67 to 0.74) in EPIC. CONCLUSION: Several of these non-invasive models exhibited good calibration and discrimination within both external validation populations and are therefore potentially suitable candidates for the facilitation of risk stratification in population-based colorectal screening programmes. Future work should both evaluate this potential, through modelling and impact studies, and ascertain if further enhancement in their performance can be obtained. PMID- 29615489 TI - Long-term proton pump inhibitors use and risk of gastric cancer: a meta-analysis of 926 386 participants. PMID- 29615490 TI - Multiple balloon-like lesions in the small intestine of an adult with chronic diarrhoea. PMID- 29615488 TI - Development and clinical validation of the Genedrive point-of-care test for qualitative detection of hepatitis C virus. AB - OBJECTIVE: Recently approved direct acting antivirals provide transformative therapies for chronic hepatitis C virus (HCV) infection. The major clinical challenge remains to identify the undiagnosed patients worldwide, many of whom live in low-income and middle-income countries, where access to nucleic acid testing remains limited. The aim of this study was to develop and validate a point-of-care (PoC) assay for the qualitative detection of HCV RNA. DESIGN: We developed a PoC assay for the qualitative detection of HCV RNA on the PCR Genedrive instrument. We validated the Genedrive HCV assay through a case-control study comparing results with those obtained with the Abbott RealTime HCV test. RESULTS: The PoC assay identified all major HCV genotypes, with a limit of detection of 2362 IU/mL (95% CI 1966 to 2788). Using 422 patients chronically infected with HCV and 503 controls negative for anti-HCV and HCV RNA, the Genedrive HCV assay showed 98.6% sensitivity (95% CI 96.9% to 99.5%) and 100% specificity (95% CI 99.3% to 100%) to detect HCV. In addition, melting peak ratiometric analysis demonstrated proof-of-principle for semiquantification of HCV. The test was further validated in a real clinical setting in a resource limited country. CONCLUSION: We report a rapid, simple, portable and accurate PoC molecular test for HCV, with sensitivity and specificity that fulfils the recent FIND/WHO Target Product Profile for HCV decentralised testing in low-income and middle-income countries. This Genedrive HCV assay may positively impact the continuum of HCV care from screening to cure by supporting real-time treatment decisions. TRIAL REGISTRATION NUMBER: NCT02992184 . PMID- 29615491 TI - Neuronal adaptor FE65 stimulates Rac1-mediated neurite outgrowth by recruiting and activating ELMO1. AB - Neurite outgrowth is a crucial process in developing neurons for neural network formation. Understanding the regulatory mechanisms of neurite outgrowth is essential for developing strategies to stimulate neurite regeneration after nerve injury and in neurodegenerative disorders. FE65 is a brain-enriched adaptor that stimulates Rac1-mediated neurite elongation. However, the precise mechanism by which FE65 promotes the process remains elusive. Here, we show that ELMO1, a subunit of ELMO1-DOCK180 bipartite Rac1 guanine nucleotide exchange factor (GEF), interacts with the FE65 N-terminal region. Overexpression of FE65 and/or ELMO1 enhances, whereas knockdown of FE65 or ELMO1 inhibits, neurite outgrowth and Rac1 activation. The effect of FE65 alone or together with ELMO1 is attenuated by an FE65 double mutation that disrupts FE65-ELMO1 interaction. Notably, FE65 is found to activate ELMO1 by diminishing ELMO1 intramolecular autoinhibitory interaction and to promote the targeting of ELMO1 to the plasma membrane, where Rac1 is activated. We also show that FE65, ELMO1, and DOCK180 form a tripartite complex. Knockdown of DOCK180 reduces the stimulatory effect of FE65-ELMO1 on Rac1 activation and neurite outgrowth. Thus, we identify a novel mechanism by which FE65 stimulates Rac1-mediated neurite outgrowth by recruiting and activating ELMO1. PMID- 29615492 TI - Surface-exposed loops and an acidic patch in the Scl1 protein of group A Streptococcus enable Scl1 binding to wound-associated fibronectin. AB - Keratinized epidermis constitutes a powerful barrier of the mucosa and skin, effectively preventing bacterial invasion, unless it is wounded and no longer protective. Wound healing involves deposition of distinct extracellular matrix (ECM) proteins enriched in cellular fibronectin (cFn) isoforms containing extra domain A (EDA). The streptococcal collagen-like protein 1 (Scl1) is a surface adhesin of group A Streptococcus (GAS), which contains an N-terminal variable (V) domain and a C-terminally located collagen-like domain. During wound infection, Scl1 selectively binds EDA/cFn isoforms and laminin, as well as low-density lipoprotein (LDL), through its V domain. The trimeric V domain has a six-helical bundle fold composed of three pairs of anti-parallel alpha-helices interconnected by hypervariable loops, but the roles of these structures in EDA/cFn binding are unclear. Here, using recombinant Scl (rScl) constructs to investigate structure function determinants of the Scl1-EDA/cFn interaction, we found that full-length rScl1, containing both the globular V and the collagen domains, is necessary for EDA/cFn binding. We established that the surface-exposed loops, interconnecting conserved alpha-helices, guide recognition and binding of Scl1-V to EDA and binding to laminin and LDL. Moreover, electrostatic surface potential models of the Scl1-V domains pointed to a conserved, negatively charged pocket, surrounded by positively charged and neutral regions, as a determining factor for the binding. In light of these findings, we propose an updated model of EDA/cFn recognition by the Scl1 adhesin from GAS, representing a significant step in understanding the Scl1-ECM interactions within the wound microenvironment that underlie GAS pathogenesis. PMID- 29615493 TI - Proline hydroxylation in collagen supports integrin binding by two distinct mechanisms. AB - Collagens are the most abundant extracellular matrix proteins in vertebrates and have a characteristic triple-helix structure. Hydroxylation of proline residues is critical for helix stability, and diminished prolyl hydroxylase activity causes wide-spread defects in connective tissues. Still, the role of proline hydroxylation in the binding of collagen receptors such as integrins is unclear. Here, we isolated skin collagen from genetically modified mice having reduced prolyl 4-hydroxylase activity. At room temperature, the reduced proline hydroxylation did not affect interactions with the recombinant integrin alpha2I domain, but at 37 degrees C, collagen hydroxylation correlated with the avidity of alpha2I domain binding. Of note, LC-MS/MS analysis of isolated skin collagens revealed no major changes in the hydroxyproline content of the main integrin binding sites. Thus, the disrupted alpha2I domain binding at physiological temperatures was most likely due to structural destabilization of the collagenous helix. Integrin alpha2I binding to the triple-helical GFPGER motif was slightly weaker than to GFOGER (O = hydroxyproline). This phenomenon was more prominent when alpha1 integrin was tested. Integrin alpha1beta1 expressed on CHO cells and recombinant alpha1I domain showed remarkably slower binding velocity and weaker avidity to GFPGER when compared with GFOGER. Structural modeling revealed the critical interaction between Arg-218 in alpha1I and the hydroxyproline residue in the integrin-binding motif. The role of Arg-218 was further validated by testing a variant R218D alpha1I domain in solid-phase binding assays. Thus, our results show that the lack of proline hydroxylation in collagen can affect integrin binding by a direct mechanism and via structural destabilization of the triple helix. PMID- 29615494 TI - Small molecules that inhibit the late stage of Munc13-4-dependent secretory granule exocytosis in mast cells. AB - Ca2+-dependent secretory granule fusion with the plasma membrane is the final step for the exocytic release of inflammatory mediators, neuropeptides, and peptide hormones. Secretory cells use a similar protein machinery at late steps in the regulated secretory pathway, employing protein isoforms from the Rab, Sec1/Munc18, Munc13/CAPS, SNARE, and synaptotagmin protein families. However, no small-molecule inhibitors of secretory granule exocytosis that target these proteins are currently available but could have clinical utility. Here we utilized a high-throughput screen of a 25,000-compound library that identified 129 small-molecule inhibitors of Ca2+-triggered secretory granule exocytosis in RBL-2H3 mast cells. These inhibitors broadly fell into six different chemical classes, and follow-up permeable cell and liposome fusion assays identified the target for one class of these inhibitors. A family of 2-aminobenzothiazoles (termed benzothiazole exocytosis inhibitors or bexins) was found to inhibit mast cell secretory granule fusion by acting on a Ca2+-dependent, C2 domain-containing priming factor, Munc13-4. Our findings further indicated that bexins interfere with Munc13-4-membrane interactions and thereby inhibit Munc13-4-dependent membrane fusion. We conclude that bexins represent a class of specific secretory pathway inhibitors with potential as therapeutic agents. PMID- 29615495 TI - Software for Peak Finding and Elemental Composition Assignment for Glycosaminoglycan Tandem Mass Spectra. AB - Glycosaminoglycans (GAGs) covalently linked to proteoglycans (PGs) are characterized by repeating disaccharide units and variable sulfation patterns along the chain. GAG length and sulfation patterns impact disease etiology, cellular signaling, and structural support for cells. We and others have demonstrated the usefulness of tandem mass spectrometry (MS2) for assigning the structures of GAG saccharides; however, manual interpretation of tandem mass spectra is time-consuming, so computational methods must be employed. In the proteomics domain, the identification of monoisotopic peaks and charge states relies on algorithms that use averagine, or the average building block of the compound class being analyzed. Although these methods perform well for protein and peptide spectra, they perform poorly on GAG tandem mass spectra, because a single average building block does not characterize the variable sulfation of GAG disaccharide units. In addition, it is necessary to assign product ion isotope patterns to interpret the tandem mass spectra of GAG saccharides. To address these problems, we developed GAGfinder, the first tandem mass spectrum peak finding algorithm developed specifically for GAGs. We define peak finding as assigning experimental isotopic peaks directly to a given product ion composition, as opposed to deconvolution or peak picking, which are terms more accurately describing the existing methods previously mentioned. GAGfinder is a targeted, brute force approach to spectrum analysis that uses precursor composition information to generate all theoretical fragments. GAGfinder also performs peak isotope composition annotation, which is typically a subsequent step for averagine-based methods. Data are available via ProteomeXchange with identifier PXD009101. PMID- 29615496 TI - CRISPR/Cas9-mediated Genomic Editing of Cluap1/IFT38 Reveals a New Role in Actin Arrangement. AB - CRISPR/Cas9-mediated gene editing allows manipulation of a gene of interest in its own chromosomal context. When applied to the analysis of protein interactions and in contrast to exogenous expression of a protein, this can be studied maintaining physiological stoichiometry, topology, and context. We have used CRISPR/Cas9-mediated genomic editing to investigate Cluap1/IFT38, a component of the intraflagellar transport complex B (IFT-B). Cluap1 has been implicated in human development as well as in cancer progression. Cluap1 loss of function results in early developmental defects with neural tube closure, sonic hedgehog signaling and left-right defects. Herein, we generated an endogenously tagged Cluap1 for protein complex analysis, which was then correlated to the corresponding interactome determined by ectopic expression. Besides IFT-B complex components, new interacting proteins like Ephrin-B1 and TRIP6, which are known to be involved in cytoskeletal arrangement and protein transport, were identified. With the identification of platelet-derived growth factor A (PDGFA) and coiled coil domain-containing protein 6 (CCDC6) two new interactions were discovered, which link Cluap1 to ciliogenesis and cancer development. The CRISPR/Cas9 mediated knockout of Cluap1 revealed a new phenotype affecting the actin cytoskeleton. Together, these data provide first evidence for a role of Cluap1 not only for cilia assembly and maintenance but also for cytoskeletal rearrangement and intracellular transport processes. PMID- 29615497 TI - Novel, Broadly Reactive Anticapsular Antibodies against Carbapenem-Resistant Klebsiella pneumoniae Protect from Infection. AB - Carbapenem-resistant (CR) sequence type 258 (ST258) Klebsiella pneumoniae has become an urgent health care threat, causing an increasing number of high mortality infections. Its resistance to numerous antibiotics and threat to immunocompromised patients necessitate finding new therapies to combat these infections. Previous successes in the laboratory, as well as the conservation of capsular polysaccharide (CPS) among the members of the ST258 clone, suggest that monoclonal antibody (MAb) therapy targeting the outer polysaccharide capsule of K. pneumoniae could serve as a valuable treatment alternative for afflicted patients. Here, we isolated several IgG antibodies from mice inoculated with a mixture of CR K. pneumoniae CPS conjugated to anthrax protective antigen. Two of these MAbs, 17H12 and 8F12, bind whole and oligosaccharide epitopes of the CPS of clade 2 ST258 CR K. pneumoniae, which is responsible for the most virulent CR K. pneumoniae infections in the United States. These antibodies were shown to agglutinate all clade 2 strains and were also shown to promote extracellular processes killing these bacteria, including biofilm inhibition, complement deposition, and deployment of neutrophil extracellular traps. Additionally, they promoted opsonophagocytosis and intracellular killing of CR K. pneumoniae by human-derived neutrophils and cultured murine macrophages. Finally, when mice were intratracheally infected with preopsonized clade 2 CR K. pneumoniae, these MAbs reduced bacterial dissemination to organs. Our data suggest that broadly reactive anticapsular antibodies and vaccines against clade 2 ST258 CR K. pneumoniae are possible. Such MAbs and vaccines would benefit those susceptible populations at risk of infection with this group of multidrug-resistant bacteria.IMPORTANCE Carbapenem-resistant Klebsiella pneumoniae is an enteric bacterium that has been responsible for an increasing number of deadly outbreaks and hospital-acquired infections. The pathogen's resistance to numerous antibiotics, including new drugs, leaves few therapeutic options available for infected patients, who often are too sick to fight the infection themselves. Immunotherapy utilizing monoclonal antibodies has been successful in other medical fields, and antibodies targeting the outer polysaccharide capsule of these bacteria could be a valuable treatment alternative. This study presents two anticapsular antibodies, 17H12 and 8F12, that were found to be protective against the most virulent carbapenem-resistant K. pneumoniae clinical strains. These antibodies are shown to promote the killing of these strains through several extracellular and intracellular processes and prevent the spread of infection in mice from the lungs to distal organs. Thus, they could ultimately treat or protect patients infected or at risk of infection by this multidrug-resistant bacterium. PMID- 29615498 TI - Chlamydia trachomatis dapF Encodes a Bifunctional Enzyme Capable of Both d Glutamate Racemase and Diaminopimelate Epimerase Activities. AB - Peptidoglycan is a sugar/amino acid polymer unique to bacteria and essential for division and cell shape maintenance. The d-amino acids that make up its cross linked stem peptides are not abundant in nature and must be synthesized by bacteria de novo d-Glutamate is present at the second position of the pentapeptide stem and is strictly conserved in all bacterial species. In Gram negative bacteria, d-glutamate is generated via the racemization of l-glutamate by glutamate racemase (MurI). Chlamydia trachomatis is the leading cause of infectious blindness and sexually transmitted bacterial infections worldwide. While its genome encodes a majority of the enzymes involved in peptidoglycan synthesis, no murI homologue has ever been annotated. Recent studies have revealed the presence of peptidoglycan in C. trachomatis and confirmed that its pentapeptide includes d-glutamate. In this study, we show that C. trachomatis synthesizes d-glutamate by utilizing a novel, bifunctional homologue of diaminopimelate epimerase (DapF). DapF catalyzes the final step in the synthesis of meso-diaminopimelate, another amino acid unique to peptidoglycan. Genetic complementation of an Escherichia coli murI mutant demonstrated that Chlamydia DapF can generate d-glutamate. Biochemical analysis showed robust activity, but unlike canonical glutamate racemases, activity was dependent on the cofactor pyridoxal phosphate. Genetic complementation, enzymatic characterization, and bioinformatic analyses indicate that chlamydial DapF shares characteristics with other promiscuous/primordial enzymes, presenting a potential mechanism for d glutamate synthesis not only in Chlamydia but also numerous other genera within the Planctomycetes-Verrucomicrobiae-Chlamydiae superphylum that lack recognized glutamate racemases.IMPORTANCE Here we describe one of the last remaining "missing" steps in peptidoglycan synthesis in pathogenic Chlamydia species, the synthesis of d-glutamate. We have determined that the diaminopimelate epimerase (DapF) encoded by Chlamydia trachomatis is capable of carrying out both the epimerization of DAP and the pyridoxal phosphate-dependent racemization of glutamate. Enzyme promiscuity is thought to be the hallmark of early microbial life on this planet, and there is currently an active debate as to whether "moonlighting enzymes" represent primordial evolutionary relics or are a product of more recent reductionist evolutionary pressures. Given the large number of Chlamydia species (as well as members of the Planctomycetes-Verrucomicrobiae Chlamydiae superphylum) that possess DapF but lack homologues of MurI, it is likely that DapF is a primordial isomerase that functions as both racemase and epimerase in these organisms, suggesting that specialized d-glutamate racemase enzymes never evolved in these microbes. PMID- 29615499 TI - EF-P Posttranslational Modification Has Variable Impact on Polyproline Translation in Bacillus subtilis. AB - Elongation factor P (EF-P) is a ubiquitous translation factor that facilitates translation of polyproline motifs. In order to perform this function, EF-P generally requires posttranslational modification (PTM) on a conserved residue. Although the position of the modification is highly conserved, the structure can vary widely between organisms. In Bacillus subtilis, EF-P is modified at Lys32 with a 5-aminopentanol moiety. Here, we use a forward genetic screen to identify genes involved in 5-aminopentanolylation. Tandem mass spectrometry analysis of the PTM mutant strains indicated that ynbB, gsaB, and ymfI are required for modification and that yaaO, yfkA, and ywlG influence the level of modification. Structural analyses also showed that EF-P can retain unique intermediate modifications, suggesting that 5-aminopentanol is likely directly assembled on EF P through a novel modification pathway. Phenotypic characterization of these PTM mutants showed that each mutant does not strictly phenocopy the efp mutant, as has previously been observed in other organisms. Rather, each mutant displays phenotypic characteristics consistent with those of either the efp mutant or wild type B. subtilis depending on the growth condition. In vivo polyproline reporter data indicate that the observed phenotypic differences result from variation in both the severity of polyproline translation defects and altered EF-P context dependence in each mutant. Together, these findings establish a new EF-P PTM pathway and also highlight a unique relationship between EF-P modification and polyproline context dependence.IMPORTANCE Despite the high level of conservation of EF-P, the posttranslational modification pathway that activates EF-P is highly divergent between species. Here, we have identified and characterized in B. subtilis a novel posttranslational modification pathway. This pathway not only broadens the scope of potential EF-P modification strategies, but it also indicates that EF-P modifications can be assembled directly on EF-P. Furthermore, characterization of these PTM mutants has established that an altered modification state can impact both the severity of polyproline translational defects and context dependence. PMID- 29615500 TI - Structural and Regulatory Changes in PBP4 Trigger Decreased beta-Lactam Susceptibility in Enterococcus faecalis. AB - Enterococcus faecalis strains resistant to penicillin and ampicillin are rare and have been associated with increases in quantities of low-affinity penicillin binding protein 4 (PBP4) or with amino acid substitutions in PBP4. We report an E. faecalis strain (LS4828) isolated from a prosthetic knee joint that was subjected to long-term exposure to aminopenicillins. Subsequent cultures yielded E. faecalis with MICs of penicillins and carbapenems higher than those for wild type strain E. faecalis JH2-2. Sequence analysis of the pbp4 gene of LS4828 compared to that of JH2-2 revealed two point mutations with amino acid substitutions (V223I, A617T) and deletion of an adenine from the region upstream of the predicted pbp4 -35 promoter sequence (UP region). Purified PBP4 from LS4828 exhibited less affinity for Bocillin FL than did PBP4 from JH2-2, which was recapitulated by purified PBP4 containing only the A617T mutation. Differential scanning fluorimetry studies showed that the LS4828 and A617T variants are destabilized compared to wild-type PBP4. Further, reverse transcription-PCR indicated increased transcription of pbp4 in LS4828 and Western blot analysis with polyclonal PBP4 antibody revealed greater quantities of PBP4 in LS4828 than in JH2-2 lysates and membrane preparations. Placing the promoter regions from LS4828 or JH2-2 upstream of a green fluorescent protein reporter gene confirmed that the adenine deletion was associated with increased transcription. Together, these data suggest that the reduced susceptibility to beta-lactam antibiotics observed in E. faecalis LS4828 results from a combination of both increased expression and remodeling of the active site, resulting in reduced affinity for penicillins and carbapenems.IMPORTANCEEnterococcus faecalis is an important cause of community-acquired and nosocomial infections and creates therapeutic dilemmas because of its frequent resistance to several classes of antibiotics. We report an E. faecalis strain with decreased ampicillin and imipenem susceptibility isolated after prolonged courses of aminopenicillin therapy for a prosthetic joint infection. Its reduced susceptibility is attributable to a combination of increased quantities of low-affinity PBP4 and an amino acid substitution in proximity to the active site that destabilizes the protein. Our findings provide a cautionary tale for clinicians who elect to "suppress" infections in prosthetic joints and offer novel insights into the interaction of beta-lactam antibiotics with low-affinity PBP4. These insights will help inform future efforts to develop therapeutics capable of inhibiting clinical enterococcal strains. PMID- 29615501 TI - CRISPR/Cas9-Mediated Gene Disruption Reveals the Importance of Zinc Metabolism for Fitness of the Dimorphic Fungal Pathogen Blastomyces dermatitidis. AB - Blastomyces dermatitidis is a human fungal pathogen of the lung that can lead to disseminated disease in healthy and immunocompromised individuals. Genetic analysis of this fungus is hampered by the relative inefficiency of traditional recombination-based gene-targeting approaches. Here, we demonstrate the feasibility of applying CRISPR/Cas9-mediated gene editing to Blastomyces, including to simultaneously target multiple genes. We created targeting plasmid vectors expressing Cas9 and either one or two single guide RNAs and introduced these plasmids into Blastomyces via Agrobacterium gene transfer. We succeeded in disrupting several fungal genes, including PRA1 and ZRT1, which are involved in scavenging and uptake of zinc from the extracellular environment. Single-gene targeting efficiencies varied by locus (median, 60% across four loci) but were approximately 100-fold greater than traditional methods of Blastomyces gene disruption. Simultaneous dual-gene targeting proceeded with efficiencies similar to those of single-gene-targeting frequencies for the respective targets. CRISPR/Cas9 disruption of PRA1 or ZRT1 had a variable impact on growth under zinc limiting conditions, showing reduced growth at early time points in low-passage number cultures and growth similar to wild-type levels by later passage. Individual impairment of PRA1 or ZRT1 resulted in a reduction of the fungal burden in a mouse model of Blastomyces infection by a factor of ~1 log (range, up to 3 logs), and combined disruption of both genes had no additional impact on the fungal burden. These results underscore the utility of CRISPR/Cas9 for efficient gene disruption in dimorphic fungi and reveal a role for zinc metabolism in Blastomyces fitness in vivoIMPORTANCEBlastomyces is a human fungal pathogen that can cause serious, even fatal, lung infections. Genetic analysis of this fungus is possible but inefficient. We applied a recently developed gene editing technology, CRISPR/Cas9, to dramatically improve the efficiency with which gene disruptions are introduced into Blastomyces We used this system to disrupt genes involved in zinc uptake and found that this reduced the fitness of the fungus upon infection. PMID- 29615502 TI - Postgenomics Characterization of an Essential Genetic Determinant of Mammary Pathogenic Escherichia coli. AB - Escherichia coli are major bacterial pathogens causing bovine mastitis, a disease of great economic impact on dairy production worldwide. This work aimed to study the virulence determinants of mammary pathogenic E. coli (MPEC). By whole-genome sequencing analysis of 40 MPEC and 22 environmental ("dairy-farm" E. coli [DFEC]) strains, we found that only the fec locus (fecIRABCDE) for ferric dicitrate uptake was present in the core genome of MPEC and that it was absent in DFEC genomes (P < 0.05). Expression of the FecA receptor in the outer membrane was shown to be citrate dependent by mass spectrometry. FecA was overexpressed when bacteria were grown in milk. Transcription of the fecA gene and of the inner membrane transport component fecB gene was upregulated in bacteria recovered from experimental intramammary infection. The presence of the fec system was shown to affect the ability of E. coli to grow in milk. While the rate of growth in milk of fec-positive (fec+) DFEC was similar to that of MPEC, it was significantly lower in DFEC lacking fec Furthermore, deletion of fec reduced the rate of growth in milk of MPEC strain P4, whereas fec-transformed non-mammary gland-pathogenic DFEC strain K71 gained the phenotype of the level of growth in milk observed in MPEC. The role of fec in E. coli intramammary pathogenicity was investigated in vivo in cows, with results showing that an MPEC P4 mutant lacking fec lost its ability to induce mastitis, whereas the fec+ DFEC K71 mutant was able to trigger intramammary inflammation. For the first time, a single molecular locus was shown to be crucial in MPEC pathogenicity.IMPORTANCE Bovine mastitis is the major infectious disease in dairy cows and the leading cause of economic loss to the global dairy industry, directly contributing to the price of dairy products on supermarket shelves and the financial hardships suffered by dairy farmers. Mastitis is also the leading reason for the use of antibiotics in dairy farms. Good farm management practices in many countries have dramatically reduced the incidence of contagious mastitis; however, the problems associated with the incidence of environmental mastitis caused by bacteria such as Escherichia coli have proven intractable. E. coli bacteria cause acute mastitis, which affects the health and welfare of cows and in extreme cases may be fatal. Here we show for the first time that the pathogenicity of E. coli causing mastitis in cows is highly dependent on the fecIRABCDE ferric citrate uptake system that allows the bacterium to capture iron from citrate. The Fec system is highly expressed during infection in the bovine udder and is ubiquitous in and necessary for the E. coli bacteria that cause mammary infections in cattle. These results have far-reaching implications, raising the possibility that mastitis may be controllable by targeting this system. PMID- 29615503 TI - Genomic Analysis of a Pan-Resistant Isolate of Klebsiella pneumoniae, United States 2016. AB - : Antimicrobial resistance is a threat to public health globally and leads to an estimated 23,000 deaths annually in the United States alone. Here, we report the genomic characterization of an unusual Klebsiella pneumoniae, nonsusceptible to all 26 antibiotics tested, that was isolated from a U.S. PATIENT: The isolate harbored four known beta-lactamase genes, including plasmid-mediated blaNDM-1 and blaCMY-6, as well as chromosomal blaCTX-M-15 and blaSHV-28, which accounted for resistance to all beta-lactams tested. In addition, sequence analysis identified mechanisms that could explain all other reported nonsusceptibility results, including nonsusceptibility to colistin, tigecycline, and chloramphenicol. Two plasmids, IncA/C2 and IncFIB, were closely related to mobile elements described previously and isolated from Gram-negative bacteria from China, Nepal, India, the United States, and Kenya, suggesting possible origins of the isolate and plasmids. This is one of the first K. pneumoniae isolates in the United States to have been reported to the Centers for Disease Control and Prevention (CDC) as nonsusceptible to all drugs tested, including all beta-lactams, colistin, and tigecycline.IMPORTANCE Antimicrobial resistance is a major public health threat worldwide. Bacteria that are nonsusceptible or resistant to all antimicrobials available are of major concern to patients and the public because of lack of treatment options and potential for spread. A Klebsiella pneumoniae strain that was nonsusceptible to all tested antibiotics was isolated from a U.S. PATIENT: Mechanisms that could explain all observed phenotypic antimicrobial resistance phenotypes, including resistance to colistin and beta-lactams, were identified through whole-genome sequencing. The large variety of resistance determinants identified demonstrates the usefulness of whole-genome sequencing for detecting these genes in an outbreak response. Sequencing of isolates with rare and unusual phenotypes can provide information on how these extremely resistant isolates develop, including whether resistance is acquired on mobile elements or accumulated through chromosomal mutations. Moreover, this provides further insight into not only detecting these highly resistant organisms but also preventing their spread. PMID- 29615505 TI - Using Preprints for Journal Clubs. AB - Journal clubs are important mechanisms for teaching how to approach the scientific literature critically and for disseminating findings. Papers from high impact journals often dominate journal club selections, a practice that reinforces the unscientific emphasis of placing high value on publishing venue rather than scientific content and critical analysis of the publications. We suggest improving journal clubs by including preprints rather than focusing completely on published papers. This change in practice might benefit the scientific enterprise in numerous ways, including by providing direct criticisms to preprint authors before publication, deemphasizing publishing venue, teaching students the art of reviewing papers, and making journal clubs more current by discussing unpublished data. PMID- 29615504 TI - Conservation and Divergence in the Candida Species Biofilm Matrix Mannan-Glucan Complex Structure, Function, and Genetic Control. AB - Candida biofilms resist the effects of available antifungal therapies. Prior studies with Candida albicans biofilms show that an extracellular matrix mannan glucan complex (MGCx) contributes to antifungal sequestration, leading to drug resistance. Here we implement biochemical, pharmacological, and genetic approaches to explore a similar mechanism of resistance for the three most common clinically encountered non-albicansCandida species (NAC). Our findings reveal that each Candida species biofilm synthesizes a mannan-glucan complex and that the antifungal-protective function of this complex is conserved. Structural similarities extended primarily to the polysaccharide backbone (alpha-1,6-mannan and beta-1,6-glucan). Surprisingly, biochemical analysis uncovered stark differences in the branching side chains of the MGCx among the species. Consistent with the structural analysis, similarities in the genetic control of MGCx production for each Candida species also appeared limited to the synthesis of the polysaccharide backbone. Each species appears to employ a unique subset of modification enzymes for MGCx synthesis, likely accounting for the observed side chain diversity. Our results argue for the conservation of matrix function among Candida spp. While biogenesis is preserved at the level of the mannan-glucan complex backbone, divergence emerges for construction of branching side chains. Thus, the MGCx backbone represents an ideal drug target for effective pan-Candida species biofilm therapy.IMPORTANCECandida species, the most common fungal pathogens, frequently grow as a biofilm. These adherent communities tolerate extremely high concentrations of antifungal agents, due in large part, to a protective extracellular matrix. The present studies define the structural, functional, and genetic similarities and differences in the biofilm matrix from the four most common Candida species. Each species synthesizes an extracellular mannan-glucan complex (MGCx) which contributes to sequestration of antifungal drug, shielding the fungus from this external assault. Synthesis of a common polysaccharide backbone appears conserved. However, subtle structural differences in the branching side chains likely rely upon unique modification enzymes, which are species specific. Our findings identify MGCx backbone synthesis as a potential pan-Candida biofilm therapeutic target. PMID- 29615506 TI - Coexistence of Multiple Endemic and Pandemic Lineages of the Rice Blast Pathogen. AB - The rice blast fungus Magnaporthe oryzae (syn., Pyricularia oryzae) is both a threat to global food security and a model for plant pathology. Molecular pathologists need an accurate understanding of the origins and line of descent of M. oryzae populations in order to identify the genetic and functional bases of pathogen adaptation and to guide the development of more effective control strategies. We used a whole-genome sequence analysis of samples from different times and places to infer details about the genetic makeup of M. oryzae from a global collection of isolates. Analyses of population structure identified six lineages within M. oryzae, including two pandemic on japonica and indica rice, respectively, and four lineages with more restricted distributions. Tip-dating calibration indicated that M. oryzae lineages separated about a millennium ago, long after the initial domestication of rice. The major lineage endemic to continental Southeast Asia displayed signatures of sexual recombination and evidence of DNA acquisition from multiple lineages. Tests for weak natural selection revealed that the pandemic spread of clonal lineages entailed an evolutionary "cost," in terms of the accumulation of deleterious mutations. Our findings reveal the coexistence of multiple endemic and pandemic lineages with contrasting population and genetic characteristics within a widely distributed pathogen.IMPORTANCE The rice blast fungus Magnaporthe oryzae (syn., Pyricularia oryzae) is a textbook example of a rapidly adapting pathogen, and it is responsible for one of the most damaging diseases of rice. Improvements in our understanding of Magnaporthe oryzae's diversity and evolution are required to guide the development of more effective control strategies. We used genome sequencing data for samples from around the world to infer the evolutionary history of M. oryzae We found that M. oryzae diversified about 1,000 years ago, separating into six main lineages: two pandemic on japonica and indica rice, respectively, and four with more restricted distributions. We also found that a lineage endemic to continental Southeast Asia displayed signatures of sexual recombination and the acquisition of genetic material from multiple lineages. This work provides a population-level genomic framework for defining molecular markers for the control of rice blast and investigations of the molecular basis of differences in pathogenicity between M. oryzae lineages. PMID- 29615507 TI - In Vivo-Selected Compensatory Mutations Restore the Fitness Cost of Mosaic penA Alleles That Confer Ceftriaxone Resistance in Neisseria gonorrhoeae. AB - Resistance to ceftriaxone in Neisseria gonorrhoeae is mainly conferred by mosaic penA alleles that encode penicillin-binding protein 2 (PBP2) variants with markedly lower rates of acylation by ceftriaxone. To assess the impact of these mosaic penA alleles on gonococcal fitness, we introduced the mosaic penA alleles from two ceftriaxone-resistant (Cror) clinical isolates (H041 and F89) into a Cros strain (FA19) by allelic exchange and showed that the resultant Cror mutants were significantly outcompeted by the Cros parent strain in vitro and in a murine infection model. Four Cror compensatory mutants of FA19 penA41 were isolated independently from mice that outcompeted the parent strain both in vitro and in vivo One of these compensatory mutants (LV41C) displayed a unique growth profile, with rapid log growth followed by a sharp plateau/gradual decline at stationary phase. Genome sequencing of LV41C revealed a mutation (G348D) in the acnB gene encoding the bifunctional aconitate hydratase 2/2 methylisocitrate dehydratase. Introduction of the acnBG348D allele into FA19 penA41 conferred both a growth profile that phenocopied that of LV41C and a fitness advantage, although not as strongly as that exhibited by the original compensatory mutant, suggesting the existence of additional compensatory mutations. The mutant aconitase appears to be a functional knockout with lower activity and expression than wild-type aconitase. Transcriptome sequencing (RNA-seq) analysis of FA19 penA41 acnBG348D revealed a large set of upregulated genes involved in carbon and energy metabolism. We conclude that compensatory mutations can be selected in Cror gonococcal strains that increase metabolism to ameliorate their fitness deficit.IMPORTANCE The emergence of ceftriaxone-resistant (Cror) Neisseria gonorrhoeae has led to the looming threat of untreatable gonorrhea. Whether Cro resistance is likely to spread can be predicted from studies that compare the relative fitnesses of susceptible and resistant strains that differ only in the penA gene that confers Cro resistance. We showed that mosaic penA alleles found in Cror clinical isolates are outcompeted by the Cros parent strain in vitro and in vivo but that compensatory mutations that allow ceftriaxone resistance to be maintained by increasing bacterial fitness are selected during mouse infection. One compensatory mutant that was studied in more detail had a mutation in acnB, which encodes the aconitase that functions in the tricarboxylic acid (TCA) cycle. This study illustrates that compensatory mutations can be selected during infection, which we hypothesize may allow the spread of Cro resistance in nature. This study also provides novel insights into gonococcal metabolism and physiology. PMID- 29615509 TI - MYR1-Dependent Effectors Are the Major Drivers of a Host Cell's Early Response to Toxoplasma, Including Counteracting MYR1-Independent Effects. AB - The obligate intracellular parasite Toxoplasma gondii controls its host cell from within the parasitophorous vacuole (PV) by using a number of diverse effector proteins, a subset of which require the aspartyl protease 5 enzyme (ASP5) and/or the recently discovered MYR1 protein to cross the PV membrane. To examine the impact these effectors have in the context of the entirety of the host response to Toxoplasma, we used RNA-Seq to analyze the transcriptome expression profiles of human foreskin fibroblasts infected with wild-type RH (RH-WT), RHDeltamyr1, and RHDeltaasp5 tachyzoites. Interestingly, the majority of the differentially regulated genes responding to Toxoplasma infection are MYR1 dependent. A subset of MYR1 responses were ASP5 independent, and MYR1 function did not require ASP5 cleavage, suggesting the export of some effectors requires only MYR1. Gene set enrichment analysis of MYR1-dependent host responses suggests an upregulation of E2F transcription factors and the cell cycle and a downregulation related to interferon signaling, among numerous others. Most surprisingly, "hidden" responses arising in RHDeltamyr1- but not RH-WT-infected host cells indicate counterbalancing actions of MYR1-dependent and -independent activities. The host genes and gene sets revealed here to be MYR1 dependent provide new insight into the parasite's ability to co-opt host cell functions.IMPORTANCEToxoplasma gondii is unique in its ability to successfully invade and replicate in a broad range of host species and cells within those hosts. The complex interplay of effector proteins exported by Toxoplasma is key to its success in co-opting the host cell to create a favorable replicative niche. Here we show that a majority of the transcriptomic effects in tachyzoite-infected cells depend on the activity of a novel translocation system involving MYR1 and that the effectors delivered by this system are part of an intricate interplay of activators and suppressors. Removal of all MYR1-dependent effectors reveals previously unknown activities that are masked or hidden by the action of these proteins. PMID- 29615508 TI - NAction! How Can Neuraminidase-Based Immunity Contribute to Better Influenza Virus Vaccines? AB - Neuraminidase is one of the two surface glycoproteins of influenza A and B viruses. It has enzymatic activity that cleaves terminal sialic acid from glycans, and that activity is essential at several points in the virus life cycle. While neuraminidase is a major target for influenza antivirals, it is largely ignored in vaccine development. Current inactivated influenza virus vaccines might contain neuraminidase, but the antigen quantity and quality are varied and not standardized. While there are data that show a protective role of anti-neuraminidase immunity, many questions remain unanswered. These questions, among others, concern the targeted epitopes or antigenic sites, the potential for antigenic drift, and, connected to that, the breadth of protection, differences in induction of immune responses by vaccination versus infection, mechanisms of protection, the role of mucosal antineuraminidase antibodies, stability, and the immunogenicity of neuraminidase in vaccine formulations. Reagents for analysis of neuraminidase-based immunity are scarce, and assays are not widely used for clinical studies evaluating vaccines. However, efforts to better understand neuraminidase-based immunity have been made recently. A neuraminidase focus group, NAction!, was formed at a Centers of Excellence for Influenza Research and Surveillance meeting at the National Institutes of Health in Bethesda, MD, to promote research that helps to understand neuraminidase-based immunity and how it can contribute to the design of better and broadly protective influenza virus vaccines. Here, we review open questions and knowledge gaps that have been identified by this group and discuss how the gaps can be addressed, with the ultimate goal of designing better influenza virus vaccines. PMID- 29615510 TI - Reply to Chien: Clarification of the effect of ligand on gammadelta-TCR repertoire selection. PMID- 29615511 TI - Does selecting ligand shape gammadelta-TCR repertoire? PMID- 29615512 TI - Phytophthora palmivora establishes tissue-specific intracellular infection structures in the earliest divergent land plant lineage. AB - The expansion of plants onto land was a formative event that brought forth profound changes to the earth's geochemistry and biota. Filamentous eukaryotic microbes developed the ability to colonize plant tissues early during the evolution of land plants, as demonstrated by intimate, symbiosis-like associations in >400 million-year-old fossils. However, the degree to which filamentous microbes establish pathogenic interactions with early divergent land plants is unclear. Here, we demonstrate that the broad host-range oomycete pathogen Phytophthora palmivora colonizes liverworts, the earliest divergent land plant lineage. We show that P. palmivora establishes a complex tissue-specific interaction with Marchantia polymorpha, where it completes a full infection cycle within air chambers of the dorsal photosynthetic layer. Remarkably, P. palmivora invaginates M. polymorpha cells with haustoria-like structures that accumulate host cellular trafficking machinery and the membrane syntaxin MpSYP13B, but not the related MpSYP13A. Our results indicate that the intracellular accommodation of filamentous microbes is an ancient plant trait that is successfully exploited by pathogens like P. palmivora. PMID- 29615513 TI - Word embeddings quantify 100 years of gender and ethnic stereotypes. AB - Word embeddings are a powerful machine-learning framework that represents each English word by a vector. The geometric relationship between these vectors captures meaningful semantic relationships between the corresponding words. In this paper, we develop a framework to demonstrate how the temporal dynamics of the embedding helps to quantify changes in stereotypes and attitudes toward women and ethnic minorities in the 20th and 21st centuries in the United States. We integrate word embeddings trained on 100 y of text data with the US Census to show that changes in the embedding track closely with demographic and occupation shifts over time. The embedding captures societal shifts-e.g., the women's movement in the 1960s and Asian immigration into the United States-and also illuminates how specific adjectives and occupations became more closely associated with certain populations over time. Our framework for temporal analysis of word embedding opens up a fruitful intersection between machine learning and quantitative social science. PMID- 29615515 TI - A hierarchy of affinities between cytokine receptors and the common gamma chain leads to pathway cross-talk. AB - Cytokines belonging to the common gamma chain (gammac) family depend on the shared gammac receptor subunit for signaling. We report the existence of a fast, cytokine-induced pathway cross-talk acting at the receptor level, resulting from a limiting amount of gammac on the surface of T cells. We found that this limited abundance of gammac reduced interleukin-4 (IL-4) and IL-21 responses after IL-7 preexposure but not vice versa. Computational modeling combined with quantitative experimental assays indicated that the asymmetric cross-talk resulted from the ability of the "private" IL-7 receptor subunits (IL-7Ralpha) to bind to many of the gammac molecules even before stimulation with cytokine. Upon exposure of T cells to IL-7, the high affinity of the IL-7Ralpha:IL-7 complex for gammac further reduced the amount of free gammac in a manner dependent on the concentration of IL-7. Measurements of bioluminescence resonance energy transfer (BRET) between IL-4Ralpha and gammac were reduced when IL-7Ralpha was overexpressed. Furthermore, in a system expressing IL-7Ralpha, IL-4Ralpha, and gammac, BRET between IL-4Ralpha and gammac increased after IL-4 binding and decreased when cells were preexposed to IL-7, supporting the assumption that IL 7Ralpha and the IL-7Ralpha:IL-7 complex limit the accessibility of gammac for other cytokine receptor complexes. We propose that in complex inflammatory environments, such asymmetric cross-talk establishes a hierarchy of cytokine responsiveness. PMID- 29615516 TI - Mutant and wild-type p53 form complexes with p73 upon phosphorylation by the kinase JNK. AB - The transcription factors p53 and p73 are critical to the induction of apoptotic cell death, particularly in response to cell stress that activates c-Jun N terminal kinase (JNK). Mutations in the DNA-binding domain of p53, which are commonly seen in cancers, result in conformational changes that enable p53 to interact with and inhibit p73, thereby suppressing apoptosis. In contrast, wild type p53 reportedly does not interact with p73. We found that JNK-mediated phosphorylation of Thr81 in the proline-rich domain (PRD) of p53 enabled wild type p53, as well as mutant p53, to form a complex with p73. Structural algorithms predicted that phosphorylation of Thr81 exposes the DNA-binding domain in p53 to enable its binding to p73. The dimerization of wild-type p53 with p73 facilitated the expression of apoptotic target genes [such as those encoding p53 up-regulated modulator of apoptosis (PUMA) and Bcl-2-associated X protein (BAX)] and, subsequently, the induction of apoptosis in response to JNK activation by cell stress in various cells. Thus, JNK phosphorylation of mutant and wild-type p53 promotes the formation of a p53/p73 complex that determines cell fate: apoptosis in the context of wild-type p53 or cell survival in the context of the mutant. These findings refine our current understanding of both the mechanistic links between p53 and p73 and the functional role for Thr81 phosphorylation. PMID- 29615514 TI - Targeting galectin-1 inhibits pancreatic cancer progression by modulating tumor stroma crosstalk. AB - Pancreatic ductal adenocarcinoma (PDA) remains one of the most lethal tumor types, with extremely low survival rates due to late diagnosis and resistance to standard therapies. A more comprehensive understanding of the complexity of PDA pathobiology, and especially of the role of the tumor microenvironment in disease progression, should pave the way for therapies to improve patient response rates. In this study, we identify galectin-1 (Gal1), a glycan-binding protein that is highly overexpressed in PDA stroma, as a major driver of pancreatic cancer progression. Genetic deletion of Gal1 in a Kras-driven mouse model of PDA (Ela KrasG12Vp53-/- ) results in a significant increase in survival through mechanisms involving decreased stroma activation, attenuated vascularization, and enhanced T cell infiltration leading to diminished metastasis rates. In a human setting, human pancreatic stellate cells (HPSCs) promote cancer proliferation, migration, and invasion via Gal1-driven pathways. Moreover, in vivo orthotopic coinjection of pancreatic tumor cells with Gal1-depleted HPSCs leads to impaired tumor formation and metastasis in mice. Gene-expression analyses of pancreatic tumor cells exposed to Gal1 reveal modulation of multiple regulatory pathways involved in tumor progression. Thus, Gal1 hierarchically regulates different events implicated in PDA biology including tumor cell proliferation, invasion, angiogenesis, inflammation, and metastasis, highlighting the broad therapeutic potential of Gal1-specific inhibitors, either alone or in combination with other therapeutic modalities. PMID- 29615517 TI - The nociceptin receptor inhibits axonal regeneration and recovery from spinal cord injury. AB - Axonal growth after traumatic spinal cord injury is limited by endogenous inhibitors, selective blockade of which promotes partial neurological recovery. The partial repair phenotypes suggest that compensatory pathways limit improvement. Gene expression profiles of mice deficient in Ngr1, which encodes a receptor for myelin-associated inhibitors of axonal regeneration such as Nogo, revealed that trauma increased the mRNA expression of ORL1, which encodes the receptor for the opioid-related peptide nociceptin. Endogenous and overexpressed ORL1 coimmunoprecipitated with immature NgR1 protein, and ORL1 enhanced the O linked glycosylation and surface expression of NgR1 in HEK293T and Neuro2A cells and primary neurons. ORL1 overexpression inhibited cortical neuron axon regeneration independently of NgR1. Furthermore, regeneration was inhibited by an ORL1 agonist and enhanced by the ORL1 antagonist J113397 through a ROCK-dependent mechanism. Mice treated with J113397 after dorsal hemisection of the mid-thoracic spinal cord recovered greater locomotor function and exhibited lumbar raphespinal axon sprouting. These effects were further enhanced by combined Ngr1 deletion and ORL1 inhibition. Thus, ORL1 limits neural repair directly and indirectly by enhancing NgR1 maturation, and ORL1 antagonists enhance recovery from traumatic CNS injuries in wild-type and Ngr1 null mice. PMID- 29615518 TI - Structural basis for the preference of the Arabidopsis thaliana phosphatase RLPH2 for tyrosine-phosphorylated substrates. AB - Despite belonging to the phosphoserine- and phosphothreonine-specific phosphoprotein phosphatase (PPP) family, Arabidopsis thaliana Rhizobiales-like phosphatase 2 (RLPH2) strongly prefers substrates bearing phosphorylated tyrosine residues. We solved the structures of RLPH2 crystallized in the presence or absence of sodium tungstate. These structures revealed the presence of a central domain that forms a binding site for two divalent metal ions that closely resembles that of other PPP-family enzymes. Unique structural elements from two flanking domains suggest a mechanism for the selective dephosphorylation of phosphotyrosine residues. Cocrystallization with the phosphate mimetic tungstate also suggests how positively charged residues that are highly conserved in the RLPH2 class form an additional pocket that is specific for a phosphothreonine residue located near the phosphotyrosine residue that is bound to the active site. Site-directed mutagenesis confirmed that this auxiliary recognition element facilitates the recruitment of dual-phosphorylated substrates containing a pTxpY motif. PMID- 29615519 TI - FGF21 acts as a negative regulator of bile acid synthesis. AB - Fibroblast growth factor 21 (FGF21) is a potent regulator of glucose and lipid homeostasis in vivo; its most closely related subfamily member, FGF19, is known to be a critical negative regulator of bile acid synthesis. To delineate whether FGF21 also plays a functional role in bile acid metabolism, we evaluated the effects of short- and long-term exposure to native FGF21 and long-acting FGF21 analogs on hepatic signal transduction, gene expression and enterohepatic bile acid levels in primary hepatocytes and in rodent and monkey models. FGF21 acutely induced ERK phosphorylation and inhibited Cyp7A1 mRNA expression in primary hepatocytes and in different rodent models, although less potently than recombinant human FGF19. Long-term administration of FGF21 in mice fed a standard chow diet resulted in a 50-60% decrease in bile acid levels in the liver and small intestines and consequently a 60% reduction of bile acid pool size. In parallel, colonic and fecal bile acid was decreased, whereas fecal cholesterol and fatty acid excretions were elevated. The long-acting FGF21 analog showed superiority to recombinant human FGF21 and FGF19 in decreasing bile acid levels with long duration of effect action in mice. Long-term administration of the long acting FGF21 analogs in obese cynomolgus monkeys suppressed plasma total bile acid and 7alpha-hydroxy-4-cholesten-3-one levels, a biomarker for bile acid synthesis. Collectively, these data reveal a previously unidentified role of FGF21 in bile acid metabolism as a negative regulator of bile acid synthesis. PMID- 29615520 TI - Turbulent flow reduces oxygen consumption in the labriform swimming shiner perch, Cymatogaster aggregata. AB - Fish swimming energetics are often measured in laboratory environments which attempt to minimize turbulence, though turbulent flows are common in the natural environment. To test whether the swimming energetics and kinematics of shiner perch, Cymatogaster aggregata (a labriform swimmer), were affected by turbulence, two flow conditions were constructed in a swim-tunnel respirometer. A low turbulence flow was created using a common swim-tunnel respirometry setup with a flow straightener and fine-mesh grid to minimize velocity fluctuations. A high turbulence flow condition was created by allowing large velocity fluctuations to persist without a flow straightener or fine grid. The two conditions were tested with particle image velocimetry to confirm significantly different turbulence properties throughout a range of mean flow speeds. Oxygen consumption rate of the swimming fish increased with swimming speed and pectoral fin beat frequency in both flow conditions. Higher turbulence also caused a greater positional variability in swimming individuals (versus low-turbulence flow) at medium and high speeds. Surprisingly, fish used less oxygen in high-turbulence compared with low-turbulence flow at medium and high swimming speeds. Simultaneous measurements of swimming kinematics indicated that these reductions in oxygen consumption could not be explained by specific known flow-adaptive behaviours such as Karman gaiting or entraining. Therefore, fish in high-turbulence flow may take advantage of the high variability in turbulent energy through time. These results suggest that swimming behaviour and energetics measured in the lab in straightened flow, typical of standard swimming respirometers, might differ from that of more turbulent, semi-natural flow conditions. PMID- 29615521 TI - Contribution of active atrial contraction to cardiac output in anesthetized American alligators (Alligator mississippiensis). AB - Ventricular filling may occur directly from the venous circulation during early diastole or via atrial contraction in late diastole. The contribution of atrial contraction to ventricular filling is typically small in mammals (10-40%), but has been suggested to predominate in reptiles. We investigated the importance of atrial contraction in filling of the ventricle in American alligators (Alligator mississippiensis) by bypassing both atria (with the use of ligatures to prevent atrial filling) and measuring the resultant effects on cardiac output in anesthetized animals. Atrial ligation had no significant effects on total systemic blood flow before or after adrenaline injection. Unexpectedly, pulmonary flow was increased following atrial ligation prior to adrenaline treatment, but was unaffected after it. These findings suggest that the atria are non-essential (i.e. redundant) for ventricular filling in alligators, at least under anesthesia, but may serve as important volume reservoirs. PMID- 29615522 TI - Effect of water temperature on diel feeding, locomotion behaviour and digestive physiology in the sea cucumber Apostichopus japonicus. AB - This study used controlled laboratory conditions to directly assess the role of water temperature in controlling diel feeding and locomotion behaviours, and digestive physiology, in the sea cucumber Apostichopus japonicus The results revealed that both the proportion of feeding individuals and ingestion rate were highest at 16 degrees C. Regardless of water temperature, sea cucumbers appeared to be nocturnal and their peak feeding activity occurred at 00:00 h to 04:00 h. Tentacle insertion rate was not significantly correlated with water temperature (<24 degrees C). In all temperature treatments except 24 degrees C, the proportion of moving sea cucumbers was also observed to be higher at night than during the day. The water temperature above thermal threshold (24 degrees C) for aestivation may alter the diel locomotion rhythm. The highest lipase and amylase activities were both observed at 20 degrees C. The highest activities of lipase and amylase at all temperature treatments were observed at 22:00 h to 02:00 h, which was slightly earlier than the feeding peak. In conclusion, even in total darkness, A. japonicus showed more active feeding and moving activities, and higher digestive enzyme activities, at night than during the day. These results demonstrated that diel feeding and locomotion behaviours, at least in the short term, were not controlled by light or low water temperature (<24 degrees C) but by an endogenous rhythm, and A. japonicus had the ability to optimize the digestive function for the coming feeding peak. These findings should provide valuable information for the development of the aquaculture of this species. PMID- 29615523 TI - Reflectance variation in the blue tit crown in relation to feather structure. AB - Structural plumage colour is one of the most enigmatic sexually selected traits. The information content of structural colour variation is debated, and the heterogeneity of the findings is hard to explain because the proximate background of within-species colour differences is very scarcely studied. We combined measurements of feather macrostructure and nanostructure to explain within population variability in blue tit crown reflectance. We found that sexual dichromatism in aspects of crown reflectance was explained only by feather macrostructure, whereas nanostructural predictors accounted for some of the age related differences in reflectance. Moreover, we found that both mean reflectance and spectral shape traits reflected a combination of quantity and regularity aspects in macrostructure and nanostructure. This rich proximate background provides ample scope for reflectance to convey various types of information on individual quality. PMID- 29615524 TI - Biochemical bases of growth variation during development: a study of protein turnover in pedigreed families of bivalve larvae (Crassostrea gigas). AB - Animal size is a highly variable trait regulated by complex interactions between biological and environmental processes. Despite the importance of understanding the mechanistic bases of growth, predicting size variation in early stages of development remains challenging. Pedigreed lines of the Pacific oyster (Crassostrea gigas) were crossed to produce contrasting growth phenotypes to analyze the metabolic bases of growth variation in larval stages. Under controlled environmental conditions, substantial growth variation of up to 430% in shell length occurred among 12 larval families. Protein was the major biochemical constituent in larvae, with an average protein-to-lipid content ratio of 2.8. On average, 86% of protein synthesized was turned over (i.e. only 14% retained as protein accreted), with a regulatory shift in depositional efficiency resulting in increased protein accretion during later larval growth. Variation in protein depositional efficiency among families did not explain the range in larval growth rates. Instead, changes in protein synthesis rates predicted 72% of growth variation. High rates of protein synthesis to support faster growth, in turn, necessitated greater allocation of the total ATP pool to protein synthesis. An ATP allocation model is presented for larvae of C. gigas that includes the major components (82%) of energy demand: protein synthesis (45%), ion pump activity (20%), shell formation (14%) and protein degradation (3%). The metabolic trade-offs between faster growth and the need for higher ATP allocation to protein synthesis could be a major determinant of fitness for larvae of different genotypes responding to the stress of environmental change. PMID- 29615525 TI - Paralytic hypo-energetic state facilitates anoxia tolerance despite ionic imbalance in adult Drosophila melanogaster. AB - Oxygen limitation plays a key role in many pathologies; yet, we still lack a fundamental understanding of the mechanisms responsible for variation in anoxia tolerance. Most vertebrate studies suggest that anoxia tolerance involves the ability to maintain cellular ATP despite the loss of aerobic metabolism. However, insects such as adult Drosophila melanogaster are able to survive long periods of anoxia (LT50: ~8 h) in a hypo-energetic state characterized by low [ATP]. In this study, we tested for possible mechanisms that allow D. melanogaster adults to survive long periods of anoxia. Adults are paralyzed within 30 s, and after 2 h of anoxia, ATP was 3% of normal, extracellular potassium concentration ([K+]o) increased threefold, pH dropped 1 unit, yet survival was 100%. With 0.5-6 h of anoxia, adults maintained low but constant ATP levels while [K+]o and pHo continued to change. When returned to normoxia, adults restored [K+]o and activity. With longer durations of anoxia, ATP levels decreased and [K+]o rose further, and both correlated tightly with decreased survival. This response contrasts with the anoxia-sensitive larval stage (LT50: ~1 h). During anoxia, larvae attempted escape for up to 30 min and after 2 h of anoxia, ATP was <1% of resting, [K+]o increased by 50%, hemolymph pH fell by 1 unit, and survival was zero. The superior anoxia tolerance of adult D. melanogaster appears to be due to the capacity to maintain a paralytic hypometabolic state with low but non-zero ATP levels, and to be able to tolerate extreme extracellular ionic variability. PMID- 29615526 TI - The effect of rearing environment on memory formation. AB - Lymnaea stagnalis is a well-studied model system for determining how changes in the environment influence associative learning and memory formation. For example, some wild strains of L. stagnalis, collected from separate geographic locations, show superior memory-forming abilities compared with others. Here, we studied memory formation in two laboratory-bred L. stagnalis strains, derived from the same original population in The Netherlands. The two strains were reared in two different laboratories at the University of Calgary (C-strain) and at Brock University (B-strain) for many years and we found that they differed in their memory-forming ability. Specifically, the C-strain required only two training sessions to form long-term memory (LTM) whereas the B-strain required four sessions to form LTM. Additionally, the LTM formed by the B-strain persisted for a shorter amount of time than the memory formed by the C-strain. Thus, despite being derived from the same original population, the C- and B-strains have developed different memory-forming abilities. Next, we raised the two strains from embryos away from home (i.e. in the other laboratory) over two generations and assessed their memory-forming abilities. The B-strain reared and maintained at the University of Calgary demonstrated improved memory-forming ability within a single generation, while the C-strain reared at Brock University retained their normal LTM-forming ability across two subsequent generations. This suggests that local environmental factors may contribute to the behavioural divergence observed between these two laboratory-bred strains. PMID- 29615527 TI - Coping with the climate: cuticular hydrocarbon acclimation of ants under constant and fluctuating conditions. AB - Terrestrial arthropods achieve waterproofing by a layer of cuticular hydrocarbons (CHCs). At the same time, CHCs also serve as communication signals. To maintain waterproofing under different climate conditions, insects adjust the chemical composition of their CHC layer, but this may affect the communication via CHCs. The detailed acclimatory changes of CHCs and how these influence their physical properties are still unknown. Here, we studied acclimation in two closely related ant species with distinct CHC profiles, Myrmica rubra and Myrmica ruginodis, in response to constant or fluctuating temperature and humidity regimes. We measured how acclimation affected CHC composition and viscosity, and the ants' drought survival. In both species, CHC composition showed strong, predictable responses to temperature regimes. Warm-acclimated individuals had higher proportions of linear alkanes, and less methyl-branched or unsaturated CHCs. These changes coincided with higher solid content and viscosity of CHCs in warm-acclimated ants. Temperature fluctuation caused effects similar to those observed under constant-cool conditions in Mrubra, but led to entirely different profiles in Mruginodis, suggesting that fluctuating and constant conditions pose very different challenges. Acclimation to dry conditions led to higher absolute amounts of CHCs, which increased the ants' drought survival, whereas temperature acclimation did not. Hence, the temperature-induced CHC changes cannot be explained by the need for waterproofing alone. Although these changes could be non-adaptive, we propose that they serve to maintain a constant CHC viscosity, which may be essential for communication and other functions. PMID- 29615528 TI - Independent and combined effects of egg pro- and anti-oxidants on gull chick phenotype. AB - Oviparous mothers transfer to their eggs components that have both independent and combined effects on offspring phenotype. The functional interaction between egg components, such as antioxidants and hormones, suggests that a change in the concentration of one component will have effects on offspring traits that depend on the concentration of other interacting components. However, the combined effects of variation in different egg components are virtually unknown. Bird eggs contain vitamin E, a major antioxidant, and also maternal corticosterone. The independent consequences of variation in the egg concentrations of these compounds for offspring phenotype are largely unknown and no study has investigated their combined effects. We manipulated the concentration of vitamin E and corticosterone in the eggs of the yellow-legged gull (Larus michahellis) by administering a physiological (2 s.d.) dose both independently and in combination. We tested for an effect on chick post-natal growth, plasma antioxidant capacity (TAC) and oxidative compounds (TOS). Separate administration of vitamin E or corticosterone caused a reduction in body mass relative to controls, whereas the combined administration of the two compounds reversed their negative effects. These results suggest that maternal egg components, such as antioxidants and steroid hormones, interact and mothers must balance their concentrations in order to achieve optimal offspring phenotype. The functional relationship between vitamin E and corticosterone is corroborated by the observation of positive covariation between these compounds. PMID- 29615529 TI - Japanese macaque phonatory physiology. AB - Although the call repertoire and its communicative function are relatively well explored in Japanese macaques (Macaca fuscata), little empirical data are available on the physics and the physiology of this species' vocal production mechanism. Here, a 6 year old female Japanese macaque was trained to phonate under an operant conditioning paradigm. The resulting 'coo' calls and spontaneously uttered 'growl' and 'chirp' calls were recorded with sound pressure level (SPL) calibrated microphones and electroglottography (EGG), a non-invasive method for assessing the dynamics of phonation. A total of 448 calls were recorded, complemented by ex vivo recordings on an excised Japanese macaque larynx. In this novel multidimensional investigative paradigm, in vivo and ex vivo data were matched via comparable EGG waveforms. Subsequent analysis suggests that the vocal range (range of fundamental frequency and SPL) of the macaque was comparable to that of a 7-10 year old human, with the exception of low intensity chirps, the production of which may be facilitated by the species' vocal membranes. In coo calls, redundant control of fundamental frequency in relation to SPL was also comparable to that in humans. EGG data revealed that growls, coos and chirps were produced by distinct laryngeal vibratory mechanisms. EGG further suggested changes in the degree of vocal fold adduction in vivo, resulting in spectral variation within the emitted coo calls, ranging from 'breathy' (including aerodynamic noise components) to 'non-breathy'. This is again analogous to humans, corroborating the notion that phonation in humans and non human primates is based on universal physical and physiological principles. PMID- 29615530 TI - An eDNA-qPCR assay to detect the presence of the parasite Schistocephalus solidus inside its threespine stickleback host. AB - Detecting the presence of a parasite within its host is crucial to the study of host-parasite interactions. The Schistocephalus solidus-threespine stickleback pair has been studied extensively to investigate host phenotypic alterations associated with a parasite with a complex life cycle. This cestode is localized inside the stickleback's abdominal cavity and can be visually detected only once it passes a mass threshold. We present a non-lethal quantitative PCR (qPCR) approach based on detection of environmental DNA from the worm (eDNA), sampled in the fish abdominal cavity. Using this approach on two fish populations (n=151), 98% of fish were correctly assigned to their S. solidus infection status. There was a significant correlation between eDNA concentration and total parasitic mass. We also assessed ventilation rate as a complementary mean to detect infection. Our eDNA detection method gives a reliable presence/absence response and its future use for quantitative assessment of infection is promising. PMID- 29615531 TI - Rapid adaptive response to a Mediterranean environment reduces phenotypic mismatch in a recent amphibian invader. AB - Invasive species frequently cope with ecological conditions that are different from those to which they adapted, presenting an opportunity to investigate how phenotypes change across short time scales. In 2000, the guttural toad Sclerophrys gutturalis was first detected in a peri-urban area of Cape Town, where it is now invasive. The ability of the species to invade Cape Town is surprising as the area is characterized by a Mediterranean climate significantly drier and colder than that of the native source area. We measured field hydration state of guttural toads from the invasive Cape Town population and a native source population from Durban. We also obtained from laboratory trials: rates of evaporative water loss and water uptake, sensitivity of locomotor endurance to hydration state, critical thermal minimum (CTmin) and sensitivity of CTmin to hydration state. Field hydration state of invasive toads was significantly lower than that of native toads. Although the two populations had similar rates of water loss and uptake, invasive toads were more efficient in minimizing water loss through postural adjustments. In locomotor trials, invasive individuals noticeably outperformed native individuals when dehydrated but not when fully hydrated. CTmin was lower in invasive individuals than in native individuals, independent of hydration state. Our results indicate that an invasive population that is only 20 years old shows adaptive responses that reduce phenotypic mismatch with the novel environment. The invasion potential of the species in Cape Town is higher than we could infer from its characteristics in the native source population. PMID- 29615532 TI - Science and Culture: Wearable tech meets tattoo art in a bid to revolutionize both. PMID- 29615533 TI - Core Concept: Organoids have opened avenues into investigating numerous diseases. But how well do they mimic the real thing? PMID- 29615535 TI - The memory remains. PMID- 29615536 TI - Protective effects of melatonin against nicotine-induced disorder of mouse early folliculogenesis. AB - In this paper, we show that neonatal mice injected for five consecutive days with nicotine display impaired germ cell cyst breakdown and primordial follicle assembly resulting in decreased ovarian reserve lasting until sex maturation age. The effects of nicotine on the pups ovaries were associated with decreased expression of oocyte specific genes such as Nobox, Lhx8, Figlalpha and Sohlh2. Moreover, the ovaries of pups injected with nicotine showed increased level of cell oxidative stress and autophagic markers (upregulation of AMPKalpha-1, increased ratio LC3-II/LC3-I, downregulation of AKT and mTOR). Noteworthy, all these effects were counteracted by the administration of the hormone melatonin in 1 MUM. In vitro culture of 0 dpp ovaries for 5 days in the presence of 10 MUM nicotine reproduced its effect on germ cell cyst breakdown and primordial follicle assembly, furthermore it also revealing about 20% reduction of somatic cells proliferation, and these effects was prevented when melatonin was added to the medium. Taken together these results show that nicotine exposure can adversely affect the establishment of the ovarian reserve in the mouse likely by locally inducing cellular stress altering the primordial follicle assembly and that melatonin, however, is able to counteract such effects. PMID- 29615538 TI - Mitochondrial avatars for quantitative aging research. PMID- 29615537 TI - Strong impact of natural-selection-free heterogeneity in genetics of age-related phenotypes. AB - A conceptual difficulty in genetics of age-related phenotypes that make individuals vulnerable to disease in post-reproductive life is genetic heterogeneity attributed to an undefined role of evolution in establishing their molecular mechanisms. Here, we performed univariate and pleiotropic genome-wide meta-analyses of 20 age-related phenotypes leveraging longitudinal information in a sample of 33,431 individuals and dealing with the natural-selection-free genetic heterogeneity. We identified 142 non-proxy single nucleotide polymorphisms (SNPs) with phenotype-specific (18 SNPs) and pleiotropic (124 SNPs) associations at genome-wide level. Univariate meta-analysis identified two novel (11.1%) and replicated 16 SNPs whereas pleiotropic meta-analysis identified 115 novel (92.7%) and nine replicated SNPs. Pleiotropic associations for most novel (93.9%) and all replicated SNPs were strongly impacted by the natural-selection free genetic heterogeneity in its unconventional form of antagonistic heterogeneity, implying antagonistic directions of genetic effects for directly correlated phenotypes. Our results show that the common genome-wide approach is well adapted to handle homogeneous univariate associations within Mendelian framework whereas most associations with age-related phenotypes are more complex and well beyond that framework. Dissecting the natural-selection-free genetic heterogeneity is critical for gaining insights into genetics of age-related phenotypes and has substantial and unexplored yet potential for improving efficiency of genome-wide analysis. PMID- 29615540 TI - Can Serum Cystatin C predict long-term survival in cardiac surgery patients? AB - Renal dysfunction is a risk factor for morbidity and mortality in cardiac surgery patients. Serum Cystatin C (sCysC) is a well-recognized marker of early renal dysfunction but few reports evaluate its prognostic cardio-vascular role. The aim of the study is to consider the prognostic value of sCysC for cardiovascular mortality. Four hundred twenty-four cardiac-surgery patients (264 men and 160 women) were enrolled. At admission, all patients were tested for renal function and inflammatory status. Patients were subdivided in subgroups according to the values of the following variables: sCysC, serum Creatinine (sCrea), age, high sensitivity-C Reactive Protein, fibrinogen, surgical procedures and Kaplan-Meier cumulative survival curves were plotted. The primary end-point was cardiovascular mortality. In order to evaluate the simultaneous independent impact of all measured variables on survival we fitted a multivariate Cox-Proportional Hazard Model (CPHM). In Kaplan-Meier analysis 124 patients (29.4%) reached the end point. In multivariate CPHM, the only significant predictors of mortality were sCysC (p<0.00001, risk ratio: 1.529, CI: 1.29-1.80) and age (p=0.039, risk ratio: 1.019, CI: 1.001-1.037). When replacing sCysC with sCrea, the only significant predictor of mortality was sCrea (p=0.0026; risk ratio 1.20; CI: 1.06-1.36). Increased levels of sCysC can be considered a useful biomarker of cardiovascular mortality in cardiac-surgery patients. PMID- 29615539 TI - Induction, regulation and roles of neural adhesion molecule L1CAM in cellular senescence. AB - Aging involves tissue accumulation of senescent cells (SC) whose elimination through senolytic approaches may evoke organismal rejuvenation. SC also contribute to aging-associated pathologies including cancer, hence it is imperative to better identify and target SC. Here, we aimed to identify new cell surface proteins differentially expressed on human SC. Besides previously reported proteins enriched on SC, we identified 78 proteins enriched and 73 proteins underrepresented in replicatively senescent BJ fibroblasts, including L1CAM, whose expression is normally restricted to the neural system and kidneys. L1CAM was: 1) induced in premature forms of cellular senescence triggered chemically and by gamma-radiation, but not in Ras-induced senescence; 2) induced upon inhibition of cyclin-dependent kinases by p16INK4a; 3) induced by TGFbeta and suppressed by RAS/MAPK(Erk) signaling (the latter explaining the lack of L1CAM induction in RAS-induced senescence); and 4) induced upon downregulation of growth-associated gene ANT2, growth in low-glucose medium or inhibition of the mevalonate pathway. These data indicate that L1CAM is controlled by a number of cell growth- and metabolism-related pathways during SC development. Functionally, SC with enhanced surface L1CAM showed increased adhesion to extracellular matrix and migrated faster. Our results provide mechanistic insights into senescence of human cells, with implications for future senolytic strategies. PMID- 29615541 TI - Correction: Identification of new genetic variants of HLA-DQB1 associated with human longevity and lipid homeostasis-a cross-sectional study in a Chinese population. PMID- 29615542 TI - Associations between lncRNA MEG3 polymorphisms and neuroblastoma risk in Chinese children. AB - Neuroblastoma is the third most common childhood cancer after leukemias and cancer of the central nervous system. Long noncoding RNA MEG3 polymorphisms have been shown to confer cancer susceptibility; however, their roles in the genetic predisposition to neuroblastoma remain unclarified. To answer this question, we genotyped two MEG3 polymorphisms, rs7158663 G>A and rs4081134 G>A, in 392 neuroblastoma children and 783 controls by TaqMan method. The results showed that neither single locus nor the combination analysis supported an association between MEG3 polymorphism and neuroblastoma risk. Interestingly, we found that subjects carrying rs4081134 AG/AA genotypes significantly tended to develop neuroblastoma among subgroups with age >18 month (adjusted OR=1.36, 95% CI=1.01 1.84) and clinical stage III+IV disease (adjusted OR=1.47, 95% CI=1.08-1.99), when compared with reference group. In the combined analysis of MEG3 polymorphisms, we found that carriers of 2 risk genotypes were more likely to have higher risk of developing neuroblastoma than those with 0-1 risk genotype among children more than 18 months of age (adjusted OR=1.36, 95% CI=1.01-1.84, P=0.042), and with clinical stages III+IV disease (adjusted OR=1.47, 95% CI=1.08 2.00, P=0.014). Our data suggest MEG3 as a weak-effect neuroblastoma susceptibility gene. Well-designed studies with large sample studies are needed to further validate this finding. PMID- 29615543 TI - Intermittent hypoxia induces beneficial cardiovascular remodeling in left ventricular function of type 1 diabetic rat. AB - OBJECTIVE: Depressed mechanical activity is a marked complication in diabetics. Hypoxia has properties for novel diagnostic and therapeutic strategies, while intermittent hypoxia (IH) provides early functional and histologic remodeling, including some cardio benefits in early hemodynamic alterations with histologic remodeling and delayed changes in peripheral vasoreactivity. Therefore, we aimed to examine whether IH application presents a cardioprotective effect, via stabilization of hypoxia-inducible factor (HIF) in streptozotocin (STZ)-induced diabetic rat heart. METHODS: Male 10-week-old Wistar rats were randomly assigned as control group (C), IH group, (STZ)-induced diabetic group (DM) and IH applied DM group (DM+IH). Diabetes duration was kept 6 weeks and IH groups were exposed to hypobaric hypoxia at about 70 kPa (including ~14% PO2; 6 h/day for 6-weeks). RESULTS: Depressed left ventricular developed pressure (LVDP) and prolonged contraction and relaxation of Langendorff-perfused hearts, as well as increased total oxidative status from streptozotocin (STZ)-induced diabetic rats were markedly prevented with IH application. IH application induced significant increase in protein expression levels of both HIF-1alpha and vascular endothelial growth factor (VEGF), in both control and diabetic rat hearts, whereas there were significant decreases in the protein levels of prolyl-4 hydroxylase domain enzymes, PHD2, and PHD3 in diabetic hearts. Furthermore, IH application induced marked increases in protein levels of matrix metalloproteinases, MMP-2 and MMP-9 and capillary density in left ventricle of diabetic rats. CONCLUSION: Overall, we presented how IH application has a beneficial cardiovascular remodeling effect in left ventricular function of diabetic rats, at most, via affecting increased oxidative stress and HIF-VEGF related angiogenesis, providing information on hyperglycemia associated new targets and therapeutic strategies. PMID- 29615544 TI - Is there a relationship between resistin levels and left ventricular end diastolic pressure? AB - OBJECTIVE: Resistin, a cysteine-rich peptide, is associated with atherosclerosis and diabetes. Resistin levels increase corresponding to coronary artery disease (CAD) and heart failure severity. Since resistin level tends to elevate with symptomatic heart failure, it is expected to be associated with left ventricular end-diastolic pressure (LVEDP). However, there is no relevant literature on the relationship between resistin levels and LVEDP. We aimed to evaluate the association between resistin levels and LVEDP, severity of CAD, carotid intima media thickness (CIMT), and echocardiographic diastolic dysfunction parameters. METHODS: For this study, 128 euvolemic patients with creatinine clearance >50 mg/dL and without acute coronary syndrome, who had typical chest pain or were stress test positive, were enrolled. Resistin level was measured by Enzyme-linked immunosorbent assays (ELISA) method. Severe CAD is defined as >=50% stenosis in one of the major coronary arteries. LVEDP was measured during left heart catheterization. RESULTS: After coronary angiography, 60 patients (46.9%) had severe CAD. The mean LVEDPs were similar for patients with and without severe CAD (p=0.480). The resistin levels did not differ between the groups (p=0.154). The resistin levels did not correlate with LVEDP (r=-0.045, p=0.627), ejection fraction (EF; r=0.110, p=0.228), the Gensini score (r=-0.091, p=0.328), and CIMT (r=0.082, p=0.457). No significant correlation was found between the echocardiographic diastolic dysfunction parameters and resistin levels. CONCLUSION: There was no significant correlation between resistin level and LVEDP, CAD severity, echocardiographic diastolic dysfunction parameters, and CIMT. Further studies are warranted to determine the efficacy of resistin in clinical use. PMID- 29615545 TI - Pulmonary endarterectomy for patients with chronic thromboembolic disease. AB - OBJECTIVE: Chronic thromboembolic disease (CTED) is characterized by persistent pulmonary thromboembolic occlusions without pulmonary hypertension. Early surgical treatment by performing pulmonary endarterectomy (PEA) may improve symptoms. The goal of the study was to review our experience and early outcome of PEA in patients with CTED. METHODS: Data were prospectively collected on all patients who underwent PEA between 2011 and 2015. Patients with CTED and a mean pulmonary artery pressure (mPAP) of <25 mm Hg were identified. All patients were in New York Heart Association (NYHA) functional class II or III. Measured outcomes were in-hospital complications, improvement in cardiac function and exercise capacity, and survival after PEA. Patients were reassessed at 6 months following surgery. RESULTS: A total of 23 patients underwent surgery. There was no in-hospital mortality, but complications occurred in six patients (26%). At 6 months following surgery, 93% of the patients remained alive. Following PEA, the mPAP fell significantly from 21.0+/-2.7 mm Hg to 18.2+/-5.5 mm Hg (p<.001). Pulmonary vascular resistance also significantly decreased from 2.2+/-0.7 wood to 1.5+/-0.5 wood (p<.001). The 6-min walking distance significantly increased from 322.6+/-80.4 m to 379.9+/-68.2 m (p<.001). There was a significant symptomatic improvement in all survivors in NYHA functional classes I or II at 6 months following surgery (p=.001). CONCLUSION: PEA in selected patients with CTED resulted in significant improvement in symptoms. The selection of patients for undergoing PEA in the absence of pulmonary hypertension must be made based on patients' expectations and their acceptance of the perioperative risk. PMID- 29615546 TI - Author's Reply. PMID- 29615547 TI - High anthracycline cumulative dose without cardiac toxicity: A possible protective role of morphine. PMID- 29615548 TI - New editor and short introductory notes. PMID- 29615549 TI - Correlation of rs1122608 SNP with acute myocardial infarction susceptibility and clinical characteristics in a Chinese Han population: A case-control study. AB - OBJECTIVE: The correlation of the BRG1 rs1122608 single nucleotide polymorphism (SNP) with acute myocardial infarction (AMI) has been reported in American and European populations. However, whether rs1122608 acts as a protective factor or a risk factor for AMI is controversial. In this study, we aimed to detect the associations between rs1122608 and the clinical characteristics of AMI as well as susceptibility, gene-environment interactions, and risk factors for AMI in a Chinese Han population. METHODS: In this study, 300 AMI patients and 300 healthy controls of Chinese Han ancestry were enrolled. PCR-RFLP was used to genotype rs1122608 SNPs. Genotypic and allelic frequencies of rs1122608 were compared between the AMI and control groups and among four AMI subgroups, which were subdivided by typical symptom, diagnosis time (DT), infarction location andserious complication. RESULTS: Significant differences were detected between the AMI patients and the controls in both the genotypic and allelic frequencies of rs1122608 (p<0.001 for each). There were also interactions between the subjects with a minor T allele and smoking or alcohol consumption (p<0.001 for each). CONCLUSION: In the Chinese Han study population, the mutant GT and TT genotypes and minor T allele of rs1122608 were positively correlated with the risk of AMI. For the first time, we discovered that the GT genotype of the rs1122608 SNP is significantly correlated with diagnosis time of AMI. In addition, the interactions between the minor T allele of rs1122608 and smoking or alcohol use and between the rs1122608 CC genotype and alcohol use appear to increase the risk of AMI. PMID- 29615550 TI - Modeling Alzheimer's and Other Age Related Human Diseases in Embryonic Systems. AB - Modeling human disease in animals is an important strategy to discover potential methods of intervention. We suggest that there is much to be gained by employing a multi-model approach that takes advantage of different animal systems used in the laboratory simultaneously. We use the example of modeling Alzheimer's disease in Drosophila melanogaster, Caenorhabditis elegans, and Danio rerio to illustrate how such an approach can be employed to investigate the pathophysiology of the disease. PMID- 29615551 TI - The Biology of SUMO-Targeted Ubiquitin Ligases in Drosophila Development, Immunity, and Cancer. AB - The ubiquitin and SUMO (small ubiquitin-like modifier) pathways modify proteins that in turn regulate diverse cellular processes, embryonic development, and adult tissue physiology. These pathways were originally discovered biochemically in vitro, leading to a long-standing challenge of elucidating both the molecular cross-talk between these pathways and their biological importance. Recent discoveries in Drosophila established that ubiquitin and SUMO pathways are interconnected via evolutionally conserved SUMO-targeted ubiquitin ligase (STUbL) proteins. STUbL are RING ubiquitin ligases that recognize SUMOylated substrates and catalyze their ubiquitination, and include Degringolade (Dgrn) in Drosophila and RNF4 and RNF111 in humans. STUbL are essential for early development of both the fly and mouse embryos. In the fly embryo, Dgrn regulates early cell cycle progression, sex determination, zygotic gene transcription, segmentation, and neurogenesis, among other processes. In the fly adult, Dgrn is required for systemic immune response to pathogens and intestinal stem cell regeneration upon infection. These functions of Dgrn are highly conserved in humans, where RNF4 dependent ubiquitination potentiates key oncoproteins, thereby accelerating tumorigenesis. Here, we review the lessons learned to date in Drosophila and highlight their relevance to cancer biology. PMID- 29615552 TI - Taking the Occam's Razor Approach to Hedgehog Lipidation and Its Role in Development. AB - All Hedgehog (Hh) proteins signal from producing cells to distant receiving cells despite being synthesized as N-and C-terminally lipidated, membrane-tethered molecules. To explain this paradoxical situation, over the past 15 years, several hypotheses have been postulated that tie directly into this property, such as Hh transport on cellular extensions called cytonemes or on secreted vesicles called lipophorins and exosomes. The alternative situation that tight membrane association merely serves to prevent unregulated Hh solubilization has been addressed by biochemical and structural studies suggesting Hh extraction from the membrane or proteolytic Hh release. While some of these models may act in different organisms, tissues or developmental programs, others may act together to specify Hh short- and long-range signaling in the same tissues. To test and rank these possibilities, we here review major models of Hh release and transport and hypothesize that the (bio)chemical and physical properties of firmly established, homologous, and functionally essential biochemical Hh modifications are adapted to specify and determine interdependent steps of Hh release, transport and signaling, while ruling out other steps. This is also described by the term "congruence", meaning that the logical combination of biochemical Hh modifications can reveal their true functional implications. This combined approach reveals potential links between models of Hh release and transport that were previously regarded as unrelated, thereby expanding our view of how Hhs can steer development in a simple, yet extremely versatile, manner. PMID- 29615553 TI - Dynamic Tissue Rearrangements during Vertebrate Eye Morphogenesis: Insights from Fish Models. AB - Over the last thirty years, fish models, such as the zebrafish and medaka, have become essential to pursue developmental studies and model human disease. Community efforts have led to the generation of wide collections of mutants, a complete sequence of their genomes, and the development of sophisticated genetic tools, enabling the manipulation of gene activity and labelling and tracking of specific groups of cells during embryonic development. When combined with the accessibility and optical clarity of fish embryos, these approaches have made of them an unbeatable model to monitor developmental processes in vivo and in real time. Over the last few years, live-imaging studies in fish have provided fascinating insights into tissue morphogenesis and organogenesis. This review will illustrate the advantages of fish models to pursue morphogenetic studies by highlighting the findings that, in the last decade, have transformed our understanding of eye morphogenesis. PMID- 29615554 TI - Flying the RNA Nest: Drosophila Reveals Novel Insights into the Transcriptome Dynamics of Early Development. AB - Early development is punctuated by a series of pervasive and fast paced transitions. These events reshape a differentiated oocyte into a totipotent embryo and allow it to gradually mount a genetic program of its own, thereby framing a new organism. Specifically, developmental transitions that ensure the maternal to embryonic control of developmental events entail a deep remodeling of transcriptional and transcriptomic landscapes. Drosophila provides an elegant and genetically tractable system to investigate these conserved changes at a dazzling developmental pace. Here, we review recent studies applying emerging technologies such as ribosome profiling, in situ Hi-C chromatin probing and live embryo RNA imaging to investigate the transcriptional dynamics at play during Drosophila embryogenesis. In light of this new literature, we revisit the main models of zygotic genome activation (ZGA). We also review the contributions played by zygotic transcription in shaping embryogenesis and explore emerging concepts of processes such as transcriptional bursting and transcriptional memory. PMID- 29615555 TI - Imaging Neuronal Activity in the Optic Tectum of Late Stage Larval Zebrafish. AB - The zebrafish is an established model to study the development and function of visual neuronal circuits in vivo, largely due to their optical accessibility at embryonic and larval stages. In the past decade multiple experimental paradigms have been developed to study visually-driven behaviours, particularly those regulated by the optic tectum, the main visual centre in lower vertebrates. With few exceptions these techniques are limited to young larvae (7-9 days post fertilisation, dpf). However, many forms of visually-driven behaviour, such as shoaling, emerge at later developmental stages. Consequently, there is a need for an experimental paradigm to image the visual system in zebrafish larvae beyond 9 dpf. Here, we show that using NBT:GCaMP3 line allows for imaging neuronal activity in the optic tectum in late stage larvae until at least 21 dpf. Utilising this line, we have characterised the receptive field properties of tectal neurons of the 2-3 weeks old fish in the cell bodies and the neuropil. The NBT:GCaMP3 line provides a complementary approach and additional opportunities to study neuronal activity in late stage zebrafish larvae. PMID- 29615556 TI - Ethanol Exposure Causes Muscle Degeneration in Zebrafish. AB - Alcoholic myopathies are characterized by neuromusculoskeletal symptoms such as compromised movement and weakness. Although these symptoms have been attributed to neurological damage, EtOH may also target skeletal muscle. EtOH exposure during zebrafish primary muscle development or adulthood results in smaller muscle fibers. However, the effects of EtOH exposure on skeletal muscle during the growth period that follows primary muscle development are not well understood. We determined the effects of EtOH exposure on muscle during this phase of development. Strikingly, muscle fibers at this stage are acutely sensitive to EtOH treatment: EtOH induces muscle degeneration. The severity of EtOH-induced muscle damage varies but muscle becomes more refractory to EtOH as muscle develops. NF-kB induction in muscle indicates that EtOH triggers a pro inflammatory response. EtOH-induced muscle damage is p53-independent. Uptake of Evans blue dye shows that EtOH treatment causes sarcolemmal instability before muscle fiber detachment. Dystrophin-null sapje mutant zebrafish also exhibit sarcolemmal instability. We tested whether Trichostatin A (TSA), which reduces muscle degeneration in sapje mutants, would affect EtOH-treated zebrafish. We found that TSA and EtOH are a lethal combination. EtOH does, however, exacerbate muscle degeneration in sapje mutants. EtOH also disrupts adhesion of muscle fibers to their extracellular matrix at the myotendinous junction: some detached muscle fibers retain beta-Dystroglycan indicating failure of muscle end attachments. Overexpression of Paxillin, which reduces muscle degeneration in zebrafish deficient for beta-Dystroglycan, is not sufficient to rescue degeneration. Taken together, our results suggest that EtOH exposure has pleiotropic deleterious effects on skeletal muscle. PMID- 29615558 TI - Requirement of the Dynein-Adaptor Spindly for Mitotic and Post-Mitotic Functions in Drosophila. AB - Spindly was originally identified as a specific regulator of Dynein activity at the kinetochore. In early prometaphase, Spindly recruits the Dynein/Dynactin complex, promoting the establishment of stable kinetochore-microtubule interactions and progression into anaphase. While details of Spindly function in mitosis have been worked out in cultured human cells and in the C. elegans zygote, the function of Spindly within the context of an organism has not yet been addressed. Here, we present loss- and gain-of-function studies of Spindly using transgenic RNAi in Drosophila. Knock-down of Spindly in the female germ line results in mitotic arrest during embryonic cleavage divisions. We investigated the requirements of Spindly protein domains for its localisation and function, and found that the carboxy-terminal region controls Spindly localisation in a cell-type specific manner. Overexpression of Spindly in the female germ line is embryonic lethal and results in altered egg morphology. To determine whether Spindly plays a role in post-mitotic cells, we altered Spindly protein levels in migrating cells and found that ovarian border cell migration is sensitive to the levels of Spindly protein. Our study uncovers novel functions of Spindly and a differential, functional requirement for its carboxy-terminal region in Drosophila. PMID- 29615557 TI - Wingless/Wnt Signaling in Intestinal Development, Homeostasis, Regeneration and Tumorigenesis: A Drosophila Perspective. AB - In mammals, the Wnt/beta-catenin signal transduction pathway regulates intestinal stem cell maintenance and proliferation, whereas Wnt pathway hyperactivation, resulting primarily from the inactivation of the tumor suppressor Adenomatous polyposis coli (APC), triggers the development of the vast majority of colorectal cancers. The Drosophila adult gut has recently emerged as a powerful model to elucidate the mechanisms by which Wingless/Wnt signaling regulates intestinal development, homeostasis, regeneration, and tumorigenesis. Herein, we review recent insights on the roles of Wnt signaling in Drosophila intestinal physiology and pathology. PMID- 29615560 TI - Sonic -'Jack-of-All-Trades' in Neural Circuit Formation. AB - As reflected by the term morphogen, molecules such as Shh and Wnts were identified based on their role in early development when they instruct precursor cells to adopt a specific cell fate. Only much later were they implicated in neural circuit formation. Both in vitro and in vivo studies indicated that morphogens direct axons during their navigation through the developing nervous system. Today, the best understood role of Shh and Wnt in axon guidance is their effect on commissural axons in the spinal cord. Shh was shown to affect commissural axons both directly and indirectly via its effect on Wnt signaling. In fact, throughout neural circuit formation there is cross-talk and collaboration of Shh and Wnt signaling. Thus, although the focus of this review is on the role of Shh in neural circuit formation, a separation from Wnt signaling is not possible. PMID- 29615561 TI - Canonical Sonic Hedgehog Signaling in Early Lung Development. AB - The canonical hedgehog (HH) signaling pathway is of major importance during embryonic development. HH is a key regulatory morphogen of numerous cellular processes, namely, cell growth and survival, differentiation, migration, and tissue polarity. Overall, it is able to trigger tissue-specific responses that, ultimately, contribute to the formation of a fully functional organism. Of all three HH proteins, Sonic Hedgehog (SHH) plays an essential role during lung development. In fact, abnormal levels of this secreted protein lead to severe foregut defects and lung hypoplasia. Canonical SHH signal transduction relies on the presence of transmembrane receptors, such as Patched1 and Smoothened, accessory proteins, as Hedgehog-interacting protein 1, and intracellular effector proteins, like GLI transcription factors. Altogether, this complex signaling machinery contributes to conveying SHH response. Pulmonary morphogenesis is deeply dependent on SHH and on its molecular interactions with other signaling pathways. In this review, the role of SHH in early stages of lung development, specifically in lung specification, primary bud formation, and branching morphogenesis is thoroughly reviewed. PMID- 29615563 TI - Special Issue on HOX Genes in Development. AB - This Special Issue of Journal of Developmental Biology (JDB) covers an indeed very "special" (at least to me) family of highly evolutionarily conserved genes, the Hox genes.[...]. PMID- 29615562 TI - Moving the Shh Source over Time: What Impact on Neural Cell Diversification in the Developing Spinal Cord? AB - A substantial amount of data has highlighted the crucial influence of Shh signalling on the generation of diverse classes of neurons and glial cells throughout the developing central nervous system. A critical step leading to this diversity is the establishment of distinct neural progenitor cell domains during the process of pattern formation. The forming spinal cord, in particular, has served as an excellent model to unravel how progenitor cells respond to Shh to produce the appropriate pattern. In recent years, considerable advances have been made in our understanding of important parameters that control the temporal and spatial interpretation of the morphogen signal at the level of Shh-receiving progenitor cells. Although less studied, the identity and position of Shh source cells also undergo significant changes over time, raising the question of how moving the Shh source contributes to cell diversification in response to the morphogen. Here, we focus on the dynamics of Shh-producing cells and discuss specific roles for these time-variant Shh sources with regard to the temporal events occurring in the receiving field. PMID- 29615565 TI - A Kinase Duet Performance in the Asymmetric Division of Drosophila Neuroblasts. AB - The ability of progenitor stem cells to divide asymmetrically allows for the production of diverse daughter cell fates.[...]. PMID- 29615564 TI - Sonic Hedgehog Signaling and Development of the Dentition. AB - Sonic hedgehog (Shh) is an essential signaling peptide required for normal embryonic development. It represents a highly-conserved marker of odontogenesis amongst the toothed vertebrates. Signal transduction is involved in early specification of the tooth-forming epithelium in the oral cavity, and, ultimately, in defining tooth number within the established dentition. Shh also promotes the morphogenetic movement of epithelial cells in the early tooth bud, and influences cell cycle regulation, morphogenesis, and differentiation in the tooth germ. More recently, Shh has been identified as a stem cell regulator in the continuously erupting incisors of mice. Here, we review contemporary data relating to the role of Shh in odontogenesis, focusing on tooth development in mammals and cartilaginous fishes. We also describe the multiple actions of this signaling protein at the cellular level. PMID- 29615566 TI - Introduction: Drosophila-A Model System for Developmental Biology. AB - Drosophila melanogaster, known colloquially as the fruit fly, remains one of the most commonly used model organisms for biomedical science.[...]. PMID- 29615567 TI - The Roles of the Wnt-Antagonists Axin and Lrp4 during Embryogenesis of the Red Flour Beetle Tribolium castaneum. AB - In both vertebrates and invertebrates, the Wnt-signaling pathway is essential for numerous processes in embryogenesis and during adult life. Wnt activity is fine tuned at various levels by the interplay of a number of Wnt-agonists (Wnt ligands, Frizzled-receptors, Lrp5/6 coreceptors) and Wnt-antagonists (among them Axin, Secreted frizzled and Lrp4) to define anterior-posterior polarity of the early embryo and specify cell fate in organogenesis. So far, the functional analysis of Wnt-pathway components in insects has concentrated on the roles of Wnt-agonists and on the Wnt-antagonist Axin. We depict here additional features of the Wnt-antagonist Axin in the flour beetle Tribolium castaneum. We show that Tc-axin is dynamically expressed throughout embryogenesis and confirm its essential role in head development. In addition, we describe an as yet undetected, more extreme Tc-axin RNAi-phenotype, the ectopic formation of posterior abdominal segments in reverse polarity and a second hindgut at the anterior. For the first time, we describe here that an lrp4 ortholog is involved in axis formation in an insect. The Tribolium Lrp4 ortholog is ubiquitously expressed throughout embryogenesis. Its downregulation via maternal RNAi results in the reduction of head structures but not in axis polarity reversal. Furthermore, segmentation is impaired and larvae develop with a severe gap phenotype. We conclude that, as in vertebrates, Tc-lrp4 functions as a Wnt inhibitor in Tribolium during various stages of embryogenesis. We discuss the role of both components as negative modulators of Wnt signaling in respect to axis formation and segmentation in Tribolium. PMID- 29615568 TI - Roles of the Hedgehog Signaling Pathway in Epidermal and Hair Follicle Development, Homeostasis, and Cancer. AB - The epidermis is the outermost layer of the skin and provides a protective barrier against environmental insults. It is a rapidly-renewing tissue undergoing constant regeneration, maintained by several types of stem cells. The Hedgehog (HH) signaling pathway is one of the fundamental signaling pathways that contributes to epidermal development, homeostasis, and repair, as well as to hair follicle development and follicle bulge stem cell maintenance. The HH pathway interacts with other signal transduction pathways, including those activated by Wnt, bone morphogenetic protein, platelet-derived growth factor, Notch, and ectodysplasin. Furthermore, aberrant activation of HH signaling is associated with various tumors, including basal cell carcinoma. Therefore, an understanding of the regulatory mechanisms of the HH signaling pathway is important for elucidating fundamental mechanisms underlying both organogenesis and carcinogenesis. In this review, we discuss the role of the HH signaling pathway in the development and homeostasis epidermis and hair follicles, and in basal cell carcinoma formation, providing an update of current knowledge in this field. PMID- 29615569 TI - Emerging Roles of DYRK Kinases in Embryogenesis and Hedgehog Pathway Control. AB - Hedgehog (Hh)/GLI signaling is an important instructive cue in various processes during embryonic development, such as tissue patterning, stem cell maintenance, and cell differentiation. It also plays crucial roles in the development of many pediatric and adult malignancies. Understanding the molecular mechanisms of pathway regulation is therefore of high interest. Dual-specificity tyrosine phosphorylation-regulated kinases (DYRKs) comprise a group of protein kinases which are emerging modulators of signal transduction, cell proliferation, survival, and cell differentiation. Work from the last years has identified a close regulatory connection between DYRKs and the Hh signaling system. In this manuscript, we outline the mechanistic influence of DYRK kinases on Hh signaling with a focus on the mammalian situation. We furthermore aim to bring together what is known about the functional consequences of a DYRK-Hh cross-talk and how this might affect cellular processes in development, physiology, and pathology. PMID- 29615570 TI - Drosophila as a Model to Study the Link between Metabolism and Cancer. AB - Cellular metabolism has recently been recognized as a hallmark of cancer. Investigating the origin and effects of the reprogrammed metabolism of tumor cells, and identifying its genetic mediators, will improve our understanding of how these changes contribute to disease progression and may suggest new approaches to therapy. Drosophila melanogaster is emerging as a valuable model to study multiple aspects of tumor formation and malignant transformation. In this review, we discuss the use of Drosophila as model to study how changes in cellular metabolism, as well as metabolic disease, contribute to cancer. PMID- 29615571 TI - Engineering the Drosophila Genome for Developmental Biology. AB - The recent development of transposon and CRISPR-Cas9-based tools for manipulating the fly genome in vivo promises tremendous progress in our ability to study developmental processes. Tools for introducing tags into genes at their endogenous genomic loci facilitate imaging or biochemistry approaches at the cellular or subcellular levels. Similarly, the ability to make specific alterations to the genome sequence allows much more precise genetic control to address questions of gene function. PMID- 29615573 TI - Ttc21b Is Required in Bergmann Glia for Proper Granule Cell Radial Migration. AB - Proper cerebellar development is dependent on tightly regulated proliferation, migration, and differentiation events. Disruptions in any of these leads to a range of cerebellar phenotypes from ataxia to childhood tumors. Animal models have shown that proper regulation of sonic hedgehog (Shh) signaling is crucial for normal cerebellar architecture, and increased signaling leads to cerebellar tumor formation. Primary cilia are known to be required for the proper regulation of multiple developmental signaling pathways, including Shh. Tetratricopeptide Repeat Domain 21B (Ttc21b) is required for proper primary cilia form and function, and is primarily thought to restrict Shh signaling. Here we investigated a role for Ttc21b in cerebellar development. Surprisingly, Ttc21b ablation in Bergmann glia resulted in the accumulation of ectopic granule cells in the lower/posterior lobes of the cerebellum and a reduction in Shh signaling. Ttc21b ablation in just Purkinje cells resulted in a similar phenotype seen in fewer cells, but across the entire extent of the cerebellum. These results suggest that Ttc21b expression is required for Bergmann glia structure and signaling in the developing cerebellum, and in some contexts, augments rather than attenuates Shh signaling. PMID- 29615572 TI - The Role of Hedgehog Signalling in the Formation of the Ventricular Septum. AB - An incomplete septation of the ventricles in the vertebrate heart that disturbes the strict separation between the contents of the two ventricles is termed a ventricular septal defect (VSD). Together with bicuspid aortic valves, it is the most frequent congenital heart disease in humans. Until now, life-threatening VSDs are usually treated surgically. To avoid surgery and to develop an alternative therapy (e.g., a small molecule therapy), it is necessary to understand the molecular mechanisms underlying ventricular septum (VS) development. Consequently, various studies focus on the investigation of signalling pathways, which play essential roles in the formation of the VS. In the past decade, several reports found evidence for an involvement of Hedgehog (HH) signalling in VS development. In this review article, we will summarise the current knowledge about the association between HH signalling and VS formation and discuss the use of such knowledge to design treatment strategies against the development of VSDs. PMID- 29615574 TI - Beyond the Mammalian Heart: Fish and Amphibians as a Model for Cardiac Repair and Regeneration. AB - The epidemic of heart disease, the leading cause of death worldwide, is made worse by the fact that the adult mammalian heart is especially poor at repair. Damage to the mammal heart-such as that caused by myocardial infarction-leads to scarring, resulting in cardiac dysfunction and heart failure. In contrast, the hearts of fish and urodele amphibians are capable of complete regeneration of cardiac tissue from multiple types of damage, with full restoration of functionality. In the last decades, research has revealed a wealth of information on how these animals are able to perform this remarkable feat, and non-mammalian models of heart repair have become a burgeoning new source of data on the morphological, cellular, and molecular processes necessary to heal cardiac damage. In this review we present the major findings from recent research on the underlying mechanisms of fish and amphibian heart regeneration. We also discuss the tools and techniques that have been developed to answer these important questions. PMID- 29615575 TI - Alterations in Synthesis and Repair of DNA during the Development of Loach Misgurnus fossilis. AB - Using a modified radiolabeled primer extension method (we named this modification misGvA-"misincorporation of G versus A") we have investigated the DNA synthesis and repair at early and late stages of development of loach Misgurnus fossilis. The misincorporation activity of DNA polymerase iota (Pol iota) in wild-type loach could not be detected by this method at any stage of loach development. In transgenic loach overexpressing human Pol iota we have shown that the bypassing of DNA synthesis arrest after incorporation of mismatched nucleotide by Pol iota (the T-stop) was not associated with this enzyme. Non-transgenic loach larvae are virtually lacking the capacity for error correction of DNA duplex containing a mismatched nucleotide. Such repair activity develops only in the adult fish. It appears that the initial stages of development are characterized by more intensive DNA synthesis, while in terminal stages the repair activities become more prominent. The misGvA approach clearly indicates substantial changes in the DNA synthesis intensity, although the role of particular replicative and repair DNA polymerases in this process requires further study. PMID- 29615576 TI - Solving Classification Problems for Large Sets of Protein Sequences with the Example of Hox and ParaHox Proteins. AB - Phylogenetic methods are key to providing models for how a given protein family evolved. However, these methods run into difficulties when sequence divergence is either too low or too high. Here, we provide a case study of Hox and ParaHox proteins so that additional insights can be gained using a new computational approach to help solve old classification problems. For two (Gsx and Cdx) out of three ParaHox proteins the assignments differ between the currently most established view and four alternative scenarios. We use a non-phylogenetic, pairwise-sequence-similarity-based method to assess which of the previous predictions, if any, are best supported by the sequence-similarity relationships between Hox and ParaHox proteins. The overall sequence-similarities show Gsx to be most similar to Hox2-3, and Cdx to be most similar to Hox4-8. The results indicate that a purely pairwise-sequence-similarity-based approach can provide additional information not only when phylogenetic inference methods have insufficient information to provide reliable classifications (as was shown previously for central Hox proteins), but also when the sequence variation is so high that the resulting phylogenetic reconstructions are likely plagued by long branch-attraction artifacts. PMID- 29615577 TI - The Roles of Aquaporins in Plant Stress Responses. AB - Aquaporins are membrane channel proteins ubiquitously present in all kingdoms of life. Although aquaporins were originally discovered as water channels, their roles in the transport of small neutral solutes, gasses, and metal ions are now well established. Plants contain the largest number and greatest diversity of aquaporin homologs with diverse subcellular localization patterns, gating properties, and solute specificity. The roles of aquaporins in physiological functions throughout plant growth and development are well known. As an integral regulator of plant-water relations, they are presumed to play an important role in plant defense responses against biotic and abiotic stressors. This review highlights involvement of various aquaporin homologs in plant stress responses against a variety of environmental stresses that disturb plant cell osmotic balance and nutrient homeostasis. PMID- 29615578 TI - HoxA Genes and the Fin-to-Limb Transition in Vertebrates. AB - HoxA genes encode for important DNA-binding transcription factors that act during limb development, regulating primarily gene expression and, consequently, morphogenesis and skeletal differentiation. Within these genes, HoxA11 and HoxA13 were proposed to have played an essential role in the enigmatic evolutionary transition from fish fins to tetrapod limbs. Indeed, comparative gene expression analyses led to the suggestion that changes in their regulation might have been essential for the diversification of vertebrates' appendages. In this review, we highlight three potential modifications in the regulation and function of these genes that may have boosted appendage evolution: (1) the expansion of polyalanine repeats in the HoxA11 and HoxA13 proteins; (2) the origin of +a novel long-non coding RNA with a possible inhibitory function on HoxA11; and (3) the acquisition of cis-regulatory elements modulating 5' HoxA transcription. We discuss the relevance of these mechanisms for appendage diversification reviewing the current state of the art and performing additional comparative analyses to characterize, in a phylogenetic framework, HoxA11 and HoxA13 expression, alanine composition within the encoded proteins, long-non-coding RNAs and cis-regulatory elements. PMID- 29615579 TI - Histologic Assessment of Drug-Eluting Grafts Related to Implantation Site. AB - Drug-eluting vascular prostheses represent a new direction in vascular surgery to reduce early thrombosis and late intimal hyperplasia for small calibre grafts. Subcutaneous implantation in rats is a rapid and cost-effective screening model to assess the drug-elution effect and could, to some extent, be useful to forecast results for vascular prostheses. We compared biological and histological responses to scaffolds in different implantation sites. Polycaprolactone (PCL), paclitaxel-loaded PCL (PCL-PTX) and dexamethasone-loaded PCL (PCL-DXM) electrospun scaffolds were implanted subcutaneously and in an infrarenal abdominal aortic model in rats for up to 12 weeks. At the conclusion of the study, a histological analysis was performed. Cellular graft invasion revealed differences in the progression of cellular infiltration between PCL-PTX and PCL/PCL-DXM groups in both models. Cell infiltration increased over time in the aortic model compared to the subcutaneous model for all groups. Cell counting revealed major differences in fibroblast, macrophage and giant cell graft colonisation in all groups and models over time. Macrophages and giant cells increased in the PCL aortic model; whereas in the subcutaneous model these cell types increased only after three weeks or even decreased in the drug-eluting PCL groups. Other major findings were observed only in the aortic replacement such as extracellular matrix deposition and neo-angiogenesis. The subcutaneous implant model can be used for screening, especially when drug-eluting effects are studied. However, major histological differences were observed in cell type reaction and depth of cell penetration compared to the aortic model. Our results demonstrate that the implantation site is a critical determinant of the biological response. PMID- 29615580 TI - An Overview of Hox Genes in Lophotrochozoa: Evolution and Functionality. AB - Hox genes are regulators of animal embryonic development. Changes in the number and sequence of Hox genes as well as in their expression patterns have been related to the evolution of the body plan. Lophotrochozoa is a clade of Protostomia characterized by several phyla which show a wide morphological diversity. Despite that the works summarized in this review emphasize the fragmentary nature of the data available regarding the presence and expression of Hox genes, they also offer interesting insight into the evolution of the Hox cluster and the role played by Hox genes in several phyla. However, the number of genes involved in the cluster of the lophotrochozoan ancestor is still a question of debate. The data presented here suggest that at least nine genes were present while two other genes, Lox4 and Post-2, may either have been present in the ancestor or may have arisen as a result of duplication in the Brachiopoda Mollusca-Annelida lineage. Spatial and temporal collinearity is a feature of Hox gene expression which was probably present in the ancestor of deuterostomes and protostomes. However, in Lophotrochozoa, it has been detected in only a few species belonging to Annelida and Mollusca. PMID- 29615581 TI - Hox Genes in Cardiovascular Development and Diseases. AB - Congenital heart defects (CHD) are the leading cause of death in the first year of life. Over the past 20 years, much effort has been focused on unraveling the genetic bases of CHD. In particular, studies in human genetics coupled with those of model organisms have provided valuable insights into the gene regulatory networks underlying CHD pathogenesis. Hox genes encode transcription factors that are required for the patterning of the anterior-posterior axis in the embryo. In this review, we focus on the emerging role of anteriorly expressed Hox genes (Hoxa1, Hoxb1, and Hoxa3) in cardiac development, specifically their contribution to patterning of cardiac progenitor cells and formation of the great arteries. Recent evidence regarding the cooperative regulation of heart development by Hox proteins with members of the TALE-class of homeodomain proteins such as Pbx and Meis transcription factors is also discussed. These findings are highly relevant to human pathologies as they pinpoint new genes that increase susceptibility to cardiac anomalies and provide novel mechanistic insights into CHD. PMID- 29615582 TI - Hoxa5: A Key Player in Development and Disease. AB - A critical position in the developmental hierarchy is occupied by the Hox genes, which encode transcription factors. Hox genes are crucial in specifying regional identity along the embryonic axes and in regulating morphogenesis. In mouse, targeted mutations of Hox genes cause skeletal transformations and organ defects that can impair viability. Here, we present the current knowledge about the Hoxa5 gene, a paradigm for the function and the regulation of Hox genes. The phenotypic survey of Hoxa5-/- mice has unveiled its critical role in the regional specification of the skeleton and in organogenesis. Most Hoxa5-/- mice die at birth from respiratory distress due to tracheal and lung dysmorphogenesis and impaired diaphragm innervation. The severity of the phenotype establishes that Hoxa5 plays a predominant role in lung organogenesis versus other Hox genes. Hoxa5 also governs digestive tract morphogenesis, thyroid and mammary glands development, and ovary homeostasis. Deregulated Hoxa5 expression is reported in cancers, indicating Hoxa5 involvement in tumor predisposition and progression. The dynamic Hoxa5 expression profile is under the transcriptional control of multiple cis-acting sequences and trans-acting regulators. It is also modulated by epigenetic mechanisms, implicating chromatin modifications and microRNAs. Finally, lncRNAs originating from alternative splicing and distal promoters encompass the Hoxa5 locus. PMID- 29615583 TI - Functional and Comparative Genomics of Hoxa2 Gene cis-Regulatory Elements: Evidence for Evolutionary Modification of Ancestral Core Element Activity. AB - Hoxa2 is an evolutionarily conserved developmental regulatory gene that functions to specify rhombomere (r) and pharyngeal arch (PA) identities throughout the Osteichthyes. Japanese medaka (Oryzias latipes) hoxa2a, like orthologous Hoxa2 genes from other osteichthyans, is expressed during embryogenesis in r2-7 and PA2 7, whereas the paralogous medaka pseudogene, psihoxa2b, is expressed in noncanonical Hoxa2 domains, including the pectoral fin buds. To understand the evolution of cis-regulatory element (CRE) control of gene expression, we conducted eGFP reporter gene expression studies with extensive functional mapping of several conserved CREs upstream of medaka hoxa2a and psihoxa2b in transient and stable-line transgenic medaka embryos. The CREs tested were previously shown to contribute to directing mouse Hoxa2 gene expression in r3, r5, and PA2-4. Our results reveal the presence of sequence elements embedded in the medaka hoxa2a and psihoxa2b upstream enhancer regions (UERs) that mediate expression in r4 and the PAs (hoxa2a r4/CNCC element) or in r3-7 and the PAs psihoxa2b r3-7/CNCC element), respectively. Further, these elements were shown to be highly conserved among osteichthyans, which suggests that the r4 specifying element embedded in the UER of Hoxa2 is a deeply rooted rhombomere specifying element and the activity of this element has been modified by the evolution of flanking sequences that redirect its activity to alternative developmental compartments. PMID- 29615584 TI - Developmental Mechanism of Limb Field Specification along the Anterior-Posterior Axis during Vertebrate Evolution. AB - In gnathostomes, limb buds arise from the lateral plate mesoderm at discrete positions along the body axis. Specification of these limb-forming fields can be subdivided into several steps. The lateral plate mesoderm is regionalized into the anterior lateral plate mesoderm (ALPM; cardiac mesoderm) and the posterior lateral plate mesoderm (PLPM). Subsequently, Hox genes appear in a nested fashion in the PLPM and provide positional information along the body axis. The lateral plate mesoderm then splits into the somatic and splanchnic layers. In the somatic layer of the PLPM, the expression of limb initiation genes appears in the limb forming region, leading to limb bud initiation. Furthermore, past and current work in limbless amphioxus and lampreys suggests that evolutionary changes in developmental programs occurred during the acquisition of paired fins during vertebrate evolution. This review presents these recent advances and discusses the mechanisms of limb field specification during development and evolution, with a focus on the role of Hox genes in this process. PMID- 29615586 TI - Hedgehog Signaling in Endochondral Ossification. AB - Hedgehog (Hh) signaling plays crucial roles in the patterning and morphogenesis of various organs within the bodies of vertebrates and insects. Endochondral ossification is one of the notable developmental events in which Hh signaling acts as a master regulator. Among three Hh proteins in mammals, Indian hedgehog (Ihh) is known to work as a major Hh input that induces biological impact of Hh signaling on the endochondral ossification. Ihh is expressed in prehypertrophic and hypertrophic chondrocytes of developing endochondral bones. Genetic studies so far have demonstrated that the Ihh-mediated activation of Hh signaling synchronizes chondrogenesis and osteogenesis during endochondral ossification by regulating the following processes: (1) chondrocyte differentiation; (2) chondrocyte proliferation; and (3) specification of bone-forming osteoblasts. Ihh not only forms a negative feedback loop with parathyroid hormone-related protein (PTHrP) to maintain the growth plate length, but also directly promotes chondrocyte propagation. Ihh input is required for the specification of progenitors into osteoblast precursors. The combinatorial approaches of genome wide analyses and mouse genetics will facilitate understanding of the regulatory mechanisms underlying the roles of Hh signaling in endochondral ossification, providing genome-level evidence of the potential of Hh signaling for the treatment of skeletal disorders. PMID- 29615585 TI - Regulation of Silk Genes by Hox and Homeodomain Proteins in the Terminal Differentiated Silk Gland of the Silkworm Bombyx mori. AB - The silk gland of the silkworm Bombyx mori is a long tubular organ that is divided into several subparts along its anteroposterior (AP) axis. As a trait of terminal differentiation of the silk gland, several silk protein genes are expressed with unique regional specificities. Most of the Hox and some of the homeobox genes are also expressed in the differentiated silk gland with regional specificities. The expression patterns of Hox genes in the silk gland roughly correspond to those in embryogenesis showing "colinearity". The central Hox class protein Antennapedia (Antp) directly regulates the expression of several middle silk gland-specific silk genes, whereas the Lin-1/Isl-1/Mec3 (LIM)-homeodomain transcriptional factor Arrowhead (Awh) regulates the expression of posterior silk gland-specific genes for silk fiber proteins. We summarize our results and discuss the usefulness of the silk gland of Bombyx mori for analyzing the function of Hox genes. Further analyses of the regulatory mechanisms underlying the region-specific expression of silk genes will provide novel insights into the molecular bases for target-gene selection and regulation by Hox and homeodomain proteins. PMID- 29615588 TI - The Role of Sonic Hedgehog in Craniofacial Patterning, Morphogenesis and Cranial Neural Crest Survival. AB - Craniofacial defects (CFD) are a significant healthcare problem worldwide. Understanding both the morphogenetic movements which underpin normal facial development, as well as the molecular factors which regulate these processes, forms the cornerstone of future diagnostic, and ultimately, preventative therapies. The soluble morphogen Sonic hedgehog (Shh), a vertebrate orthologue of Drosophila hedgehog, is a key signalling factor in the regulation of craniofacial skeleton development in vertebrates, operating within numerous tissue types in the craniofacial primordia to spatiotemporally regulate the formation of the face and jaws. This review will provide an overview of normal craniofacial skeleton development, and focus specifically on the known roles of Shh in regulating the development and progression of the first pharyngeal arch, which in turn gives rise to both the upper jaw (maxilla) and lower jaw (mandible). PMID- 29615587 TI - Signalling by Transforming Growth Factor Beta Isoforms in Wound Healing and Tissue Regeneration. AB - Transforming growth factor beta (TGFbeta) signalling is essential for wound healing, including both non-specific scar formation and tissue-specific regeneration. Specific TGFbeta isoforms and downstream mediators of canonical and non-canonical signalling play different roles in each of these processes. Here we review the role of TGFbeta signalling during tissue repair, with a particular focus on the prototypic isoforms TGFbeta1, TGFbeta2, and TGFbeta3. We begin by introducing TGFbeta signalling and then discuss the role of these growth factors and their key downstream signalling mediators in determining the balance between scar formation and tissue regeneration. Next we discuss examples of the pleiotropic roles of TGFbeta ligands during cutaneous wound healing and blastema mediated regeneration, and how inhibition of the canonical signalling pathway (using small molecule inhibitors) blocks regeneration. Finally, we review various TGFbeta-targeting therapeutic strategies that hold promise for enhancing tissue repair. PMID- 29615589 TI - A Joint Less Ordinary: Intriguing Roles for Hedgehog Signalling in the Development of the Temporomandibular Synovial Joint. AB - This review highlights the essential role of Hedgehog (Hh) signalling in the developmental steps of temporomandibular joint (TMJ) formation. We review evidence for intra- and potentially inter-tissue Hh signaling as well as Glioma Associated Oncogene Homolog (GLI) dependent and independent functions. Morphogenesis and maturation of the TMJ's individual components and the general landscape of Hh signalling is also covered. Comparison of the appendicular knee and axial TMJ also reveals interesting differences and similarities in their mechanisms of development, chondrogenesis and reliance on Hh signalling. PMID- 29615590 TI - Hedgehog Promotes Production of Inhibitory Interneurons in Vivo and in Vitro from Pluripotent Stem Cells. AB - Loss or damage of cortical inhibitory interneurons characterizes a number of neurological disorders. There is therefore a great deal of interest in learning how to generate these neurons from a pluripotent stem cell source so they can be used for cell replacement therapies or for in vitro drug testing. To design a directed differentiation protocol, a number of groups have used the information gained in the last 15 years detailing the conditions that promote interneuron progenitor differentiation in the ventral telencephalon during embryogenesis. The use of Hedgehog peptides and agonists is featured prominently in these approaches. We review here the data documenting a role for Hedgehog in specifying interneurons in both the embryonic brain during development and in vitro during the directed differentiation of pluripotent stem cells. PMID- 29615592 TI - Hedgehog: A Key Signaling in the Development of the Oligodendrocyte Lineage. AB - The Hedgehog morphogen aroused an enormous interest since it was characterized as an essential signal for ventral patterning of the spinal cord two decades ago. The pathway is notably implicated in the initial appearance of the progenitors of oligodendrocytes (OPCs), the glial cells of the central nervous system which after maturation are responsible for axon myelination. In accordance with the requirement for Hedgehog signaling in ventral patterning, the earliest identifiable cells in the oligodendrocyte lineage are derived from the ventral ventricular zone of the developing spinal cord and brain. Here, we present the current knowledge about the involvement of Hedgehog signaling in the strict spatial and temporal regulation which characterizes the initiation and progression of the oligodendrocyte lineage. We notably describe the ability of the Hedgehog signaling to tightly orchestrate the appearance of specific combinations of genes in concert with other pathways. We document the molecular mechanisms controlling Hedgehog temporal activity during OPC specification. The contribution of the pathway to aspects of OPC development different from their specification is also highlighted especially in the optic nerve. Finally, we report the data demonstrating that Hedgehog signaling-dependency is not a universal situation for oligodendrocyte generation as evidenced in the dorsal spinal cord in contrast to the dorsal forebrain. PMID- 29615593 TI - Hedgehog Signaling in Prostate Development, Regeneration and Cancer. AB - The prostate is a developmental model system study of prostate growth regulation. Historically the research focus was on androgen regulation of development and growth and instructive interactions between the mesenchyme and epithelium. The study of Hh signaling in prostate development revealed important roles in ductal morphogenesis and in epithelial growth regulation that appear to be recapitulated in prostate cancer. This overview of Hh signaling in the prostate will address the well-described role of paracrine signaling prostate development as well as new evidence suggesting a role for autocrine signaling, the role of Hh signaling in prostate regeneration and reiterative activities in prostate cancer. PMID- 29615591 TI - Control of Hedgehog Signalling by the Cilia-Regulated Proteasome. AB - The Hedgehog signalling pathway is evolutionarily highly conserved and essential for embryonic development of invertebrates and vertebrates. Consequently, impaired Hedgehog signalling results in very severe human diseases, ranging from holoprosencephaly to Pallister-Hall syndrome. Due to this great importance for human health, the focus of numerous research groups is placed on the investigation of the detailed mechanisms underlying Hedgehog signalling. Today, it is known that tiny cell protrusions, known as primary cilia, are necessary to mediate Hedgehog signalling in vertebrates. Although the Hedgehog pathway is one of the best studied signalling pathways, many questions remain. One of these questions is: How do primary cilia control Hedgehog signalling in vertebrates? Recently, it was shown that primary cilia regulate a special kind of proteasome which is essential for proper Hedgehog signalling. This review article will cover this novel cilia-proteasome association in embryonic Hedgehog signalling and discuss the possibilities provided by future investigations on this topic. PMID- 29615595 TI - Asxl2-/- Mice Exhibit De Novo Cardiomyocyte Production during Adulthood. AB - Heart attacks affect more than seven million people worldwide each year. A heart attack, or myocardial infarction, may result in the death of a billion cardiomyocytes within hours. The adult mammalian heart does not have an effective mechanism to replace lost cardiomyocytes. Instead, lost muscle is replaced with scar tissue, which decreases blood pumping ability and leads to heart failure over time. Here, we report that the loss of the chromatin factor ASXL2 results in spontaneous proliferation and cardiogenic differentiation of a subset of interstitial non-cardiomyocytes. The adult Asxl2-/- heart displays spontaneous overgrowth without cardiomyocyte hypertrophy. Thymidine analog labeling and Ki67 staining of 12-week-old hearts revealed 3- and 5-fold increases of proliferation rate for vimentin+ non-cardiomyocytes in Asxl2-/- over age- and sex-matched wildtype controls, respectively. Approximately 10% of proliferating non cardiomyocytes in the Asxl2-/- heart express the cardiogenic marker NKX2-5, a frequency that is ~7-fold higher than that observed in the wildtype. EdU lineage tracing experiments showed that ~6% of pulsed-labeled non-cardiomyocytes in Asxl2 /- hearts differentiate into mature cardiomyocytes after a four-week chase, a phenomenon not observed for similarly pulse-chased wildtype controls. Taken together, these data indicate de novo cardiomyocyte production in the Asxl2-/- heart due to activation of a population of proliferative cardiogenic non cardiomyocytes. Our study suggests the existence of an epigenetic barrier to cardiogenicity in the adult heart and raises the intriguing possibility of unlocking regenerative potential via transient modulation of epigenetic activity. PMID- 29615594 TI - An Evolutionarily Conserved Network Mediates Development of the zona limitans intrathalamica, a Sonic Hedgehog-Secreting Caudal Forebrain Signaling Center. AB - Recent studies revealed new insights into the development of a unique caudal forebrain-signaling center: the zona limitans intrathalamica (zli). The zli is the last brain signaling center to form and the first forebrain compartment to be established. It is the only part of the dorsal neural tube expressing the morphogen Sonic Hedgehog (Shh) whose activity participates in the survival, growth and patterning of neuronal progenitor subpopulations within the thalamic complex. Here, we review the gene regulatory network of transcription factors and cis-regulatory elements that underlies formation of a shh-expressing delimitated domain in the anterior brain. We discuss evidence that this network predates the origin of chordates. We highlight the contribution of Shh, Wnt and Notch signaling to zli development and discuss implications for the fact that the morphogen Shh relies on primary cilia for signal transduction. The network that underlies zli development also contributes to thalamus induction, and to its patterning once the zli has been set up. We present an overview of the brain malformations possibly associated with developmental defects in this gene regulatory network (GRN). PMID- 29615596 TI - Yeast Gup1(2) Proteins Are Homologues of the Hedgehog Morphogens Acyltransferases HHAT(L): Facts and Implications. AB - In multiple tissues, the Hedgehog secreted morphogen activates in the receiving cells a pathway involved in cell fate, proliferation and differentiation in the receiving cells. This pathway is particularly important during embryogenesis. The protein HHAT (Hedgehog O-acyltransferase) modifies Hh morphogens prior to their secretion, while HHATL (Hh O-acyltransferase-like) negatively regulates the pathway. HHAT and HHATL are homologous to Saccharomyces cerevisiae Gup2 and Gup1, respectively. In yeast, Gup1 is associated with a high number and diversity of biological functions, namely polarity establishment, secretory/endocytic pathway functionality, vacuole morphology and wall and membrane composition, structure and maintenance. Phenotypes underlying death, morphogenesis and differentiation are also included. Paracrine signalling, like the one promoted by the Hh pathway, has not been shown to occur in microbial communities, despite the fact that large aggregates of cells like biofilms or colonies behave as proto-tissues. Instead, these have been suggested to sense the population density through the secretion of quorum-sensing chemicals. This review focuses on Gup1/HHATL and Gup2/HHAT proteins. We review the functions and physiology associated with these proteins in yeasts and higher eukaryotes. We suggest standardisation of the presently chaotic Gup-related nomenclature, which includes KIAA117, c3orf3, RASP, Skinny, Sightless and Central Missing, in order to avoid the disclosure of otherwise unnoticed information. PMID- 29615597 TI - Perspectives on Intra- and Intercellular Trafficking of Hedgehog for Tissue Patterning. AB - Intercellular communication is a fundamental process for correct tissue development. The mechanism of this process involves, among other things, the production and secretion of signaling molecules by specialized cell types and the capability of these signals to reach the target cells in order to trigger specific responses. Hedgehog (Hh) is one of the best-studied signaling pathways because of its importance during morphogenesis in many organisms. The Hh protein acts as a morphogen, activating its targets at a distance in a concentration dependent manner. Post-translational modifications of Hh lead to a molecule covalently bond to two lipid moieties. These lipid modifications confer Hh high affinity to lipidic membranes, and intense studies have been carried out to explain its release into the extracellular matrix. This work reviews Hh molecule maturation, the intracellular recycling needed for its secretion and the proposed carriers to explain Hh transportation to the receiving cells. Special focus is placed on the role of specialized filopodia, also named cytonemes, in morphogen transport and gradient formation. PMID- 29615600 TI - Persistent Hiccups After Cervical Epidural Steroid Injection. AB - BACKGROUND Hiccup is a rare complication after a cervical epidural steroid injection used in the treatment of chronic pain. A few studies have reported on the physiological and pharmacological aspects of hiccups after epidural steroid injection and there have been some case reports published. Our presented case report provides insight into the side effect of hiccups that can occur in association with cervical epidural analgesia, and will help inform anesthesiologist about this unpleasant complication. CASE REPORT We present a rare case of persistent hiccups after a cervical epidural steroid injection in a 60-year-old male patient with chronic pain due to disc protrusion in C3-C7. CONCLUSIONS Persistent hiccups after epidural injection is a serious complication. As the exact mechanism of hiccups is not yet known, regardless the level of epidural or the mixture of drugs used, and the incident of hiccups after epidural injection is not well-reported, we think that the etiology and the incident rate must be further evaluated. PMID- 29615598 TI - The Many Hats of Sonic Hedgehog Signaling in Nervous System Development and Disease. AB - Sonic hedgehog (Shh) signaling occurs concurrently with the many processes that constitute nervous system development. Although Shh is mostly known for its proliferative and morphogenic action through its effects on neural stem cells and progenitors, it also contributes to neuronal differentiation, axonal pathfinding and synapse formation and function. To participate in these diverse events, Shh signaling manifests differently depending on the maturational state of the responsive cell, on the other signaling pathways regulating neural cell function and the environmental cues that surround target cells. Shh signaling is particularly dynamic in the nervous system, ranging from canonical transcription dependent, to non-canonical and localized to axonal growth cones. Here, we review the variety of Shh functions in the developing nervous system and their consequences for neurodevelopmental diseases and neural regeneration, with particular emphasis on the signaling mechanisms underlying Shh action. PMID- 29615601 TI - Anticancer Effects of Gingerol in Retinoblastoma Cancer Cells (RB355 Cell Line) Are Mediated via Apoptosis Induction, Cell Cycle Arrest and Upregulation of PI3K/Akt Signaling Pathway. AB - BACKGROUND The main aim of the current investigation was to study the antiproliferative activity of gingerol in RB355 human retinoblastoma cancer cells. The effects of gingerol on apoptosis induction, cell cycle arrest, and PI3K/Akt signaling pathway were also evaluated. MATERIAL AND METHODS MTT cell viability assay was used to assess the cytotoxic effects of gingerol in these cells while. To study apoptotic effects in these cells, we used inverted microscopy along with fluorescence microscopy using acridine orange/propidium iodide and Hoechst 33258 as staining dyes. Flow cytometry was used to study cell cycle phase distribution and Western blot assay indicated effects on PI3K/Akt protein expression levels. RESULTS Results showed that gingerol exerted dose dependent and time-dependent growth inhibitory effects in these retinoblastoma cells. However, the growth inhibitory effects of gingerol were less pronounced against normal fr2 cells. As compared to the untreated control cells, gingerol treated cells at concentrations of 25, 75, and 150 MUM had drastic changes in cell morphology, including rounding and withering of cells, with disorganized cell layers. Gingerol-treated cells exhibited bright fluorescence, indicating rupture of the cell membrane. These results were further confirmed by acridine orange/propidium iodide staining, in which untreated cells showed normal green fluorescence and gingerol-treated cells showed yellow/red fluorescence. Gingerol also led to dose-dependent G2/M phase cell cycle arrest in RB355 retinoblastoma cells, as well as concentration-dependent activation of PI3K-related protein expressions. CONCLUSIONS Gingerol exhibits potent anticancer effects in RB355 human retinoblastoma cancer cells and these effects were mediated via apoptosis induction, cell cycle arrest, and modulation of the PI3K/Akt signaling pathway. PMID- 29615599 TI - Differential Cellular Responses to Hedgehog Signalling in Vertebrates-What is the Role of Competence? AB - A surprisingly small number of signalling pathways generate a plethora of cellular responses ranging from the acquisition of multiple cell fates to proliferation, differentiation, morphogenesis and cell death. These diverse responses may be due to the dose-dependent activities of signalling factors, or to intrinsic differences in the response of cells to a given signal-a phenomenon called differential cellular competence. In this review, we focus on temporal and spatial differences in competence for Hedgehog (HH) signalling, a signalling pathway that is reiteratively employed in embryos and adult organisms. We discuss the upstream signals and mechanisms that may establish differential competence for HHs in a range of different tissues. We argue that the changing competence for HH signalling provides a four-dimensional framework for the interpretation of the signal that is essential for the emergence of functional anatomy. A number of diseases-including several types of cancer-are caused by malfunctions of the HH pathway. A better understanding of what provides differential competence for this signal may reveal HH-related disease mechanisms and equip us with more specific tools to manipulate HH signalling in the clinic. PMID- 29615602 TI - Potential transferability of mcr-3 via IS26-mediated homologous recombination in Escherichia coli. PMID- 29615603 TI - SIVcpz closely related to the ancestral HIV-1 is less or non-pathogenic to humans in a hu-BLT mouse model. AB - The HIV-1 pandemic is a consequence of the cross-species transmission of simian immunodeficiency virus in wild chimpanzees (SIVcpz) to humans. Our previous study demonstrated SIVcpz strains that are closely related to the ancestral viruses of HIV-1 groups M (SIVcpzMB897) and N (SIVcpzEK505) and two SIVcpz lineages that are not associated with any known HIV-1 infections in humans (SIVcpzMT145 and SIVcpzBF1167), all can readily infect and robustly replicate in the humanized-BLT mouse model of humans. However, the comparative pathogenicity of different SIVcpz strains remains unknown. Herein, we compared the pathogenicity of the above four SIVcpz strains with HIV-1 using humanized-BLT mice. Unexpectedly, we found that all four SIVcpz strains were significantly less pathogenic or non-pathogenic compared to HIV-1, manifesting lower degrees of CD4+ T-cell depletion and immune activation. Transcriptome analyses of CD4+ T cells from hu-BLT mice infected with SIVcpz versus HIV-1 revealed enhanced expression of genes related to cell survival and reduced inflammation/immune activation in SIVcpz-infected mice. Together, our study results demonstrate for the first time that SIVcpz is significantly less or non-pathogenic to human immune cells compared to HIV-1. Our findings lay the groundwork for a possible new understanding of the evolutionary origins of HIV-1, where the initial SIVcpz cross-species transmission virus may be initially less pathogenic to humans. PMID- 29615604 TI - Experimentally quantifying anion polarizability at the air/water interface. AB - The adsorption of large, polarizable anions from aqueous solution on the air/water interface controls important atmospheric chemistry and is thought to resemble anion adsorption at hydrophobic interfaces generally. While the favourability of adsorption of such ions is clear, quantifying adsorption thermodynamics has proven challenging because it requires accurate description of the structure of the anion and its solvation shell at the interface. In principle anion polarizability offers a structural window, but to the best of our knowledge there has so far been no experimental technique that allowed its characterization with interfacial specificity. Here, we meet this challenge using interface specific vibrational spectroscopy of Cl-O vibrations of the [Formula: see text] anion at the air/water interface and report that the interface breaks the symmetry of the anion, the anisotropy of [Formula: see text]'s polarizability tensor is more than two times larger than in bulk water and concentration dependent, and concentration-dependent polarizability changes are consistent with correlated changes in surface tension. PMID- 29615605 TI - Metal-organic frameworks for precise inclusion of single-stranded DNA and transfection in immune cells. AB - Effective transfection of genetic molecules such as DNA usually relies on vectors that can reversibly uptake and release these molecules, and protect them from digestion by nuclease. Non-viral vectors meeting these requirements are rare due to the lack of specific interactions with DNA. Here, we design a series of four isoreticular metal-organic frameworks (Ni-IRMOF-74-II to -V) with progressively tuned pore size from 2.2 to 4.2 nm to precisely include single-stranded DNA (ssDNA, 11-53 nt), and to achieve reversible interaction between MOFs and ssDNA. The entire nucleic acid chain is completely confined inside the pores providing excellent protection, and the geometric distribution of the confined ssDNA is visualized by X-ray diffraction. Two MOFs in this series exhibit excellent transfection efficiency in mammalian immune cells, 92% in the primary mouse immune cells (CD4+ T cell) and 30% in human immune cells (THP-1 cell), unrivaled by the commercialized agents (Lipo and Neofect). PMID- 29615606 TI - Chiral induction in covalent organic frameworks. AB - Synthetic control over chirality and function is the crowning achievement for metal-organic frameworks, but the same level of control has not been achieved for covalent organic frameworks (COFs). Here we demonstrate chiral COFs (CCOFs) can be crystallized from achiral organic precursors by chiral catalytic induction. A total of nine two-dimensional CCOFs are solvothermally prepared by imine condensations of the C3-symmetric 1,3,5-triformylphloroglucinol (Tp) with diamine or triamine linkers in the presence of catalytic amount of (R)- or (S)-1 phenylethylamine. Homochirality of these CCOFs results from chiral catalyst induced immobilization of threefold-symmetric tris(N-salicylideneamine) cores with a propeller-like conformation of one single handedness during crystallization. The CCOF-TpTab showed high enantioselectivity toward chiral carbohydrates in fluorescence quenching and, after postsynthetic modification of enaminone groups located in chiral channels with Cu(II) ions, it can also be utilized as a heterogeneous catalyst for the asymmetric Henry reaction of nitroalkane with aldehydes. PMID- 29615607 TI - Enzootic situation and molecular epidemiology of Brucella in livestock from 2011 to 2015 in Qingyang, China. AB - A large-scale survey was conducted in domestic animal populations from 2011 to 2015 in Qingyang, China. A total of 448,398 animals from different districts of Qingyang were tested for the presence of Brucella-specific antibodies using the Rose Bengal Plate Test (RBPT) and the Standard Agglutination Test (SAT). From 2011 to 2015, the yearly average positive rates were between 0.04 and 4.75% in the eight counties tested. In addition, the prevalence rates were between 0 and 9.96% in these eight counties. Sheep was the dominant host of Brucella in Qingyang, and the prevalence rate in sheep (2.74%) was higher than those in the other animals tested. Identification of 10 Brucella isolates from sheep confirmed that the epidemic strains were B. melitensis biovar 3 (n = 9) and B. melitensis biovar 1 (n = 1). MLVA-11 (multiple-locus variable-number tandem repeat analysis) analysis of the 10 isolates showed three genotypes: genotype 116 (n = 8), genotype 115 (n = 1) and genotype 136 (n = 1). Furthermore, analysis of the whole genome sequences of the representative B. melitensis strain QY1 indicated that this isolate was closely related to isolates from China and India. The results of serum epidemiology confirmed that the region of northern Qingyang was a critical Brucella epidemic area and that the disease showed a rising trend, especially from 2013 to 2015. An analysis of the isolate genotypes suggested that sheep brucellosis mainly resulted from conventional B. melitensis (East Mediterranean group), although the external strain (American group) also occurred in Qingyang. PMID- 29615608 TI - Novel bovine hepacivirus in dairy cattle, China. PMID- 29615609 TI - Conformational switching within dynamic oligomers underpins toxic gain-of function by diabetes-associated amyloid. AB - Peptide mediated gain-of-toxic function is central to pathology in Alzheimer's, Parkinson's and diabetes. In each system, self-assembly into oligomers is observed and can also result in poration of artificial membranes. Structural requirements for poration and the relationship of structure to cytotoxicity is unaddressed. Here we focus on islet amyloid polypeptide (IAPP) mediated loss-of insulin secreting cells in patients with diabetes. Newly developed methods enable structure-function enquiry to focus on intracellular oligomers composed of hundreds of IAPP. The key insights are that porating oligomers are internally dynamic, grow in discrete steps and are not canonical amyloid. Moreover, two classes of poration occur; an IAPP-specific ligand establishes that only one is cytotoxic. Toxic rescue occurs by stabilising non-toxic poration without displacing IAPP from mitochondria. These insights illuminate cytotoxic mechanism in diabetes and also provide a generalisable approach for enquiry applicable to other partially ordered protein assemblies. PMID- 29615610 TI - Alcohol exposure disrupts mu opioid receptor-mediated long-term depression at insular cortex inputs to dorsolateral striatum. AB - Drugs of abuse, including alcohol, ablate the expression of specific forms of long-term synaptic depression (LTD) at glutamatergic synapses in dorsal striatum (DS), a brain region involved in goal-directed and habitual behaviors. This loss of LTD is associated with altered DS-dependent behavior. Given the role of the u opioid receptor (MOR) in behavioral responding for alcohol, we explored the impact of alcohol on various forms of MOR-mediated synaptic depression that we find are differentially expressed at specific DS synapses. Corticostriatal MOR mediated LTD (mOP-LTD) in the dorsolateral striatum occurs exclusively at inputs from anterior insular cortex and is selectively disrupted by in vivo alcohol exposure. Alcohol has no effect on corticostriatal mOP-LTD in dorsomedial striatum, thalamostriatal MOR-mediated short-term depression, or mOP-LTD of cholinergic interneuron-driven glutamate release. Disrupted mOP-LTD at anterior insular cortex-dorsolateral striatum synapses may therefore be a key mechanism of alcohol-induced neuroadaptations involved in the development of alcohol use disorders. PMID- 29615611 TI - Spatial fidelity of workers predicts collective response to disturbance in a social insect. AB - Individuals in social insect colonies cooperate to perform collective work. While colonies often respond to changing environmental conditions by flexibly reallocating workers to different tasks, the factors determining which workers switch and why are not well understood. Here, we use an automated tracking system to continuously monitor nest behavior and foraging activity of uniquely identified workers from entire bumble bee (Bombus impatiens) colonies foraging in a natural outdoor environment. We show that most foraging is performed by a small number of workers and that the intensity and distribution of foraging is actively regulated at the colony level in response to forager removal. By analyzing worker nest behavior before and after forager removal, we show that spatial fidelity of workers within the nest generates uneven interaction with relevant localized information sources, and predicts which workers initiate foraging after disturbance. Our results highlight the importance of spatial fidelity for structuring information flow and regulating collective behavior in social insect colonies. PMID- 29615612 TI - Giant optical nonlinearities from Rydberg excitons in semiconductor microcavities. AB - The realization of exciton polaritons-hybrid excitations of semiconductor quantum well excitons and cavity photons-has been of great technological and scientific significance. In particular, the short-range collisional interaction between excitons has enabled explorations into a wealth of nonequilibrium and hydrodynamical effects that arise in weakly nonlinear polariton condensates. Yet, the ability to enhance optical nonlinearities would enable quantum photonics applications and open up a new realm of photonic many-body physics in a scalable and engineerable solid-state environment. Here we outline a route to such capabilities in cavity-coupled semiconductors by exploiting the giant interactions between excitons in Rydberg states. We demonstrate that optical nonlinearities in such systems can be vastly enhanced by several orders of magnitude and induce nonlinear processes at the level of single photons. PMID- 29615613 TI - Multi-omics analysis reveals neoantigen-independent immune cell infiltration in copy-number driven cancers. AB - To realize the full potential of immunotherapy, it is critical to understand the drivers of tumor infiltration by immune cells. Previous studies have linked immune infiltration with tumor neoantigen levels, but the broad applicability of this concept remains unknown. Here, we find that while this observation is true across cancers characterized by recurrent mutations, it does not hold for cancers driven by recurrent copy number alterations, such as breast and pancreatic tumors. To understand immune invasion in these cancers, we developed an integrative multi-omics framework, identifying the DNA damage response protein ATM as a driver of cytokine production leading to increased immune infiltration. This prediction was validated in numerous orthogonal datasets, as well as experimentally in vitro and in vivo by cytokine release and immune cell migration. These findings demonstrate diverse drivers of immune cell infiltration across cancer lineages and may facilitate the clinical adaption of immunotherapies across diverse malignancies. PMID- 29615614 TI - Gon4l regulates notochord boundary formation and cell polarity underlying axis extension by repressing adhesion genes. AB - Anteroposterior (AP) axis extension during gastrulation requires embryonic patterning and morphogenesis to be spatiotemporally coordinated, but the underlying genetic mechanisms remain poorly understood. Here we define a role for the conserved chromatin factor Gon4l, encoded by ugly duckling (udu), in coordinating tissue patterning and axis extension during zebrafish gastrulation through direct positive and negative regulation of gene expression. Although identified as a recessive enhancer of impaired axis extension in planar cell polarity (PCP) mutants, udu functions in a genetically independent, partially overlapping fashion with PCP signaling to regulate mediolateral cell polarity underlying axis extension in part by promoting notochord boundary formation. Gon4l limits expression of the cell-cell and cell-matrix adhesion molecules EpCAM and Integrinalpha3b, excesses of which perturb the notochord boundary via tension dependent and -independent mechanisms, respectively. By promoting formation of this AP-aligned boundary and associated cell polarity, Gon4l cooperates with PCP signaling to coordinate morphogenesis along the AP embryonic axis. PMID- 29615615 TI - Towards an arthritis flare-responsive drug delivery system. AB - Local delivery of therapeutics for the treatment of inflammatory arthritis (IA) is limited by short intra-articular half-lives. Since IA severity often fluctuates over time, a local drug delivery method that titrates drug release to arthritis activity would represent an attractive paradigm in IA therapy. Here we report the development of a hydrogel platform that exhibits disassembly and drug release controlled by the concentration of enzymes expressed during arthritis flares. In vitro, hydrogel loaded with triamcinolone acetonide (TA) releases drug on-demand upon exposure to enzymes or synovial fluid from patients with rheumatoid arthritis. In arthritic mice, hydrogel loaded with a fluorescent dye demonstrates flare-dependent disassembly measured as loss of fluorescence. Moreover, a single dose of TA-loaded hydrogel but not the equivalent dose of locally injected free TA reduces arthritis activity in the injected paw. Together, our data suggest flare-responsive hydrogel as a promising next generation drug delivery approach for the treatment of IA. PMID- 29615617 TI - Prokaryotic nanocompartments form synthetic organelles in a eukaryote. AB - Compartmentalization of proteins into organelles is a promising strategy for enhancing the productivity of engineered eukaryotic organisms. However, approaches that co-opt endogenous organelles may be limited by the potential for unwanted crosstalk and disruption of native metabolic functions. Here, we present the construction of synthetic non-endogenous organelles in the eukaryotic yeast Saccharomyces cerevisiae, based on the prokaryotic family of self-assembling proteins known as encapsulins. We establish that encapsulins self-assemble to form nanoscale compartments in yeast, and that heterologous proteins can be selectively targeted for compartmentalization. Housing destabilized proteins within encapsulin compartments afford protection against proteolytic degradation in vivo, while the interaction between split protein components is enhanced upon co-localization within the compartment interior. Furthermore, encapsulin compartments can support enzymatic catalysis, with substrate turnover observed for an encapsulated yeast enzyme. Encapsulin compartments therefore represent a modular platform, orthogonal to existing organelles, for programming synthetic compartmentalization in eukaryotes. PMID- 29615616 TI - Heterogeneity in VEGFR3 levels drives lymphatic vessel hyperplasia through cell autonomous and non-cell-autonomous mechanisms. AB - Incomplete delivery to the target cells is an obstacle for successful gene therapy approaches. Here we show unexpected effects of incomplete targeting, by demonstrating how heterogeneous inhibition of a growth promoting signaling pathway promotes tissue hyperplasia. We studied the function of the lymphangiogenic VEGFR3 receptor during embryonic and post-natal development. Inducible genetic deletion of Vegfr3 in lymphatic endothelial cells (LECs) leads to selection of non-targeted VEGFR3+ cells at vessel tips, indicating an indispensable cell-autonomous function in migrating tip cells. Although Vegfr3 deletion results in lymphatic hypoplasia in mouse embryos, incomplete deletion during post-natal development instead causes excessive lymphangiogenesis. Analysis of mosaically targeted endothelium shows that VEGFR3- LECs non-cell autonomously drive abnormal vessel anastomosis and hyperplasia by inducing proliferation of non-targeted VEGFR3+ LECs through cell-contact-dependent reduction of Notch signaling. Heterogeneity in VEGFR3 levels thus drives vessel hyperplasia, which has implications for the understanding of mechanisms of developmental and pathological tissue growth. PMID- 29615618 TI - Instability of expanding bacterial droplets. AB - Suspensions of motile bacteria or synthetic microswimmers, termed active matter, manifest a remarkable propensity for self-organization, and formation of large scale coherent structures. Most active matter research deals with almost homogeneous in space systems and little is known about the dynamics of strongly heterogeneous active matter. Here we report on experimental and theoretical studies on the expansion of highly concentrated bacterial droplets into an ambient bacteria-free fluid. The droplet is formed beneath a rapidly rotating solid macroscopic particle inserted in the suspension. We observe vigorous instability of the droplet reminiscent of a violent explosion. The phenomenon is explained in terms of continuum first-principle theory based on the swim pressure concept. Our findings provide insights into the dynamics of active matter with strong density gradients and significantly expand the scope of experimental and analytic tools for control and manipulation of active systems. PMID- 29615619 TI - Pharmacologically induced amnesia for learned fear is time and sleep dependent. AB - The discovery in animal research that fear memories may change upon retrieval has sparked a wave of interest into whether this phenomenon of reconsolidation also occurs in humans. The critical conditions under which memory reconsolidation can be observed and targeted in humans, however, remain elusive. Here we report that blocking beta-adrenergic receptors in the brain, either before or after reactivation, effectively neutralizes the expression of fear memory. We show a specific time-window during which beta-adrenergic receptors are involved in the reconsolidation of fear memory. Finally, we observe intact fear memory expression 12 h after reactivation and amnesic drug intake when the retention test takes place during the same day as the intervention, but post-reactivation amnesia after a night of sleep (12 h or 24 h later). We conclude that memory reconsolidation is not simply time-dependent, but that sleep is a final and necessary link to fundamentally change the fear memory engram. PMID- 29615621 TI - Ultrathin bismuth nanosheets from in situ topotactic transformation for selective electrocatalytic CO2 reduction to formate. AB - Electrocatalytic carbon dioxide reduction to formate is desirable but challenging. Current attention is mostly focused on tin-based materials, which, unfortunately, often suffer from limited Faradaic efficiency. The potential of bismuth in carbon dioxide reduction has been suggested but remained understudied. Here, we report that ultrathin bismuth nanosheets are prepared from the in situ topotactic transformation of bismuth oxyiodide nanosheets. They process single crystallinity and enlarged surface areas. Such an advantageous nanostructure affords the material with excellent electrocatalytic performance for carbon dioxide reduction to formate. High selectivity (~100%) and large current density are measured over a broad potential, as well as excellent durability for >10 h. Its selectivity for formate is also understood by density functional theory calculations. In addition, bismuth nanosheets were coupled with an iridium-based oxygen evolution electrocatalyst to achieve efficient full-cell electrolysis. When powered by two AA-size alkaline batteries, the full cell exhibits impressive Faradaic efficiency and electricity-to-formate conversion efficiency. PMID- 29615620 TI - Tuning defects in oxides at room temperature by lithium reduction. AB - Defects can greatly influence the properties of oxide materials; however, facile defect engineering of oxides at room temperature remains challenging. The generation of defects in oxides is difficult to control by conventional chemical reduction methods that usually require high temperatures and are time consuming. Here, we develop a facile room-temperature lithium reduction strategy to implant defects into a series of oxide nanoparticles including titanium dioxide (TiO2), zinc oxide (ZnO), tin dioxide (SnO2), and cerium dioxide (CeO2). Our lithium reduction strategy shows advantages including all-room-temperature processing, controllability, time efficiency, versatility and scalability. As a potential application, the photocatalytic hydrogen evolution performance of defective TiO2 is examined. The hydrogen evolution rate increases up to 41.8 mmol g-1 h-1 under one solar light irradiation, which is ~3 times higher than that of the pristine nanoparticles. The strategy of tuning defect oxides used in this work may be beneficial for many other related applications. PMID- 29615622 TI - Water-promoted C-S bond formation reactions. AB - Allylic sulfones, owning to their widespread distributions in biologically active molecules, received increasing attention in the past few years. However, the synthetic method under mild conditions is still a challenging task. In this paper, we report a sulfinic acids ligation with allylic alcohols via metal-free dehydrative cross-coupling. Both aliphatic and aromatic sulfinic acids react with various allylic alcohols to deliver the desired allylic sulfones in high yields with excellent selectivity. This carbon-sulfur bond formation reaction is highly efficient and practical since it works under metal-free, neutral, aqueous media and at room temperature in which the products even can be obtained by simple filtration without the need for organic extraction or column chromatography. Water is found to be essential for the success of this carbon-sulfur bond formation reaction. DFT calculations imply that water acts as promoter in this transformation via intermolecular hydrogen bonds. PMID- 29615623 TI - Biogeography of Leptospira in wild animal communities inhabiting the insular ecosystem of the western Indian Ocean islands and neighboring Africa. AB - Understanding the processes driving parasite assemblages is particularly important in the context of zoonotic infectious diseases. Leptospirosis is a widespread zoonotic bacterial infection caused by pathogenic species of the genus Leptospira. Despite a wide range of animal hosts, information is still lacking on the factors shaping Leptospira diversity in wild animal communities, especially in regions, such as tropical insular ecosystems, with high host species richness and complex biogeographical patterns. Using a large dataset (34 mammal species) and a multilocus approach at a regional scale, we analyzed the role of both host species diversity and geography in Leptospira genetic diversity in terrestrial small mammals (rodents, tenrecs, and shrews) and bats from 10 different islands/countries in the western Indian Ocean (WIO) and neighboring Africa. At least four Leptospira spp. (L. interrogans, L. borgpetersenii, L. kirschneri, and L. mayottensis) and several yet-unidentified genetic clades contributed to a remarkable regional Leptospira diversity, which was generally related to the local occurrence of the host species rather than the geography. In addition, the genetic structure patterns varied between Leptospira spp., suggesting different evolutionary histories in the region, which might reflect both in situ diversification of native mammals (for L. borgpetersenii) and the more recent introduction of non-native host species (for L. interrogans). Our data also suggested that host shifts occurred between bats and rodents, but further investigations are needed to determine how host ecology may influence these events. PMID- 29615624 TI - Rescue of conformational dynamics in enzyme catalysis by directed evolution. AB - Rational design and directed evolution have proved to be successful approaches to increase catalytic efficiencies of both natural and artificial enzymes. Protein dynamics is recognized as important, but due to the inherent flexibility of biological macromolecules it is often difficult to distinguish which conformational changes are directly related to function. Here, we use directed evolution on an impaired mutant of the proline isomerase CypA and identify two second-shell mutations that partially restore its catalytic activity. We show both kinetically, using NMR spectroscopy, and structurally, by room-temperature X ray crystallography, how local perturbations propagate through a large allosteric network to facilitate conformational dynamics. The increased catalysis selected for in the evolutionary screen is correlated with an accelerated interconversion between the two catalytically essential conformational sub-states, which are both captured in the high-resolution X-ray ensembles. Our data provide a glimpse of an evolutionary trajectory and show how subtle changes can fine-tune enzyme function. PMID- 29615626 TI - Land-use change interacts with climate to determine elevational species redistribution. AB - Climate change is driving global species redistribution with profound social and economic impacts. However, species movement is largely constrained by habitat availability and connectivity, of which the interaction effects with climate change remain largely unknown. Here we examine published data on 2798 elevational range shifts from 43 study sites to assess the confounding effect of land-use change on climate-driven species redistribution. We show that baseline forest cover and recent forest cover change are critical predictors in determining the magnitude of elevational range shifts. Forest loss positively interacts with baseline temperature conditions, such that forest loss in warmer regions tends to accelerate species' upslope movement. Consequently, not only climate but also habitat loss stressors and, importantly, their synergistic effects matter in forecasting species elevational redistribution, especially in the tropics where both stressors will increase the risk of net lowland biotic attrition. PMID- 29615625 TI - Ranavirus genotypes in the Netherlands and their potential association with virulence in water frogs (Pelophylax spp.). AB - Ranaviruses are pathogenic viruses for poikilothermic vertebrates worldwide. The identification of a common midwife toad virus (CMTV) associated with massive die offs in water frogs (Pelophylax spp.) in the Netherlands has increased awareness for emerging viruses in amphibians in the country. Complete genome sequencing of 13 ranavirus isolates collected from ten different sites in the period 2011-2016 revealed three CMTV groups present in distinct geographical areas in the Netherlands. Phylogenetic analysis showed that emerging viruses from the northern part of the Netherlands belonged to CMTV-NL group I. Group II and III viruses were derived from the animals located in the center-east and south of the country, and shared a more recent common ancestor to CMTV-amphibian associated ranaviruses reported in China, Italy, Denmark, and Switzerland. Field monitoring revealed differences in water frog host abundance at sites where distinct ranavirus groups occur; with ranavirus-associated deaths, host counts decreasing progressively, and few juveniles found in the north where CMTV-NL group I occurs but not in the south with CMTV-NL group III. Investigation of tandem repeats of coding genes gave no conclusive information about phylo-geographical clustering, while genetic analysis of the genomes revealed truncations in 17 genes across CMTV-NL groups II and III compared to group I. Further studies are needed to elucidate the contribution of these genes as well as environmental variables to explain the observed differences in host abundance. PMID- 29615627 TI - Rolling up transition metal dichalcogenide nanoscrolls via one drop of ethanol. AB - Two-dimensional transition metal dichalcogenides (TMDs) have attracted lots of interest because of their potential for electronic and optoelectronic applications. Atomically thin TMD flakes were believed capable to scroll into nanoscrolls (NSs) with distinct properties. However, limited by mechanical strength and chemical stability, production of high-quality TMD NSs remains challenging. Here, we scroll chemical vapor deposition-grown monolayer TMD flakes into high-quality NSs in situ in 5 s with a nearly 100% yield by only one droplet of ethanol solution. An obvious photoluminescence is demonstrated in NSs and the self-encapsulated structure makes NSs more insensitive to external factors in optical and electrical properties. Furthermore, based on the internal open topology, NSs hybridized with a variety of functional materials have been fabricated, which is expected to confer TMD NSs with additional properties and functions attractive for potential application. PMID- 29615628 TI - 'Exacerbation-free time' to assess the impact of exacerbations in patients with chronic obstructive pulmonary disease (COPD): a prospective observational study. AB - COPD exacerbations are commonly quantified as rate per year. However, the total amount of time a patient suffers from exacerbations may be stronger related to his or her disease burden than just counting exacerbation episodes. In this study, we examined the relationship between exacerbation frequency and exacerbation-free time, and their associations with baseline characteristics and health-related quality of life. A total of 166 COPD patients reported symptom changes during 12 months. Symptom-defined exacerbation episodes were correlated to the number of exacerbation-free weeks per year. Analysis of covariance was used to examine the effects of baseline characteristics on annual exacerbation frequency and exacerbation-free weeks, Spearman's rank correlations to examine associations between the two methods to express exacerbations and the Chronic Respiratory Questionnaire (CRQ). The correlation between exacerbation frequency and exacerbation-free weeks was -0.71 (p < 0.001). However, among frequent exacerbators (i.e., >=3 exacerbations/year, n = 113) the correlation was weak (r = -0.25; p < 0.01). Smokers had less exacerbation-free weeks than non-smokers (beta = -5.709, p < 0.05). More exacerbation-free weeks were related to better CRQ Total (r = 0.22, p < 0.05), Mastery (r = 0.22, p < 0.05), and Fatigue (r = 0.23, p < 0.05) scores, whereas no significant associations were found between exacerbation frequency and CRQ scores. In COPD patients with frequent exacerbations, there is substantial variation in exacerbation-free time. Exacerbation-free time may better reflect the burden of exacerbations in patients with COPD than exacerbation frequency does. PMID- 29615629 TI - Asbestosis is prevalent in a variety of construction industry trades. AB - A diagnosis of asbestosis, which is a long-latency, fibrotic lung disease, has implications for the patient in terms of prognosis, treatment and compensation. Identifying and quantifying asbestos exposure is difficult without a detailed occupational history, and the threshold dose of asbestos required to cause asbestosis is not well understood. We reviewed all cases of asbestosis diagnosed between 2001 and 2016 at the Birmingham Regional NHS Occupational Lung Disease Service to determine the industries and occupations most frequently implicated in causation, in order to help clinicians identify where asbestosis might enter the differential diagnosis for a patient with chronic respiratory symptoms. A variety of construction trades were frequently reported including carpenters and joiners, pipe fitters, laggers, labourers, painters and shop fitters. Traditionally heavily exposed occupations such as shipbuilding were not commonly seen. PMID- 29615630 TI - Photonic zero mode in a non-Hermitian photonic lattice. AB - Zero-energy particles (such as Majorana fermions) are newly predicted quasiparticles and are expected to play an important role in fault-tolerant quantum computation. In conventional Hermitian quantum systems, however, such zero states are vulnerable and even become vanishing if couplings with surroundings are of the same topological nature. Here we demonstrate a robust photonic zero mode sustained by a spatial non-Hermitian phase transition in a parity-time (PT) symmetric lattice, despite the same topological order across the entire system. The non-Hermitian-enhanced topological protection ensures the reemergence of the zero mode at the phase transition interface when the two semi lattices under different PT phases are decoupled effectively in their real spectra. Residing at the midgap level of the PT symmetric spectrum, the zero mode is topologically protected against topological disorder. We experimentally validated the robustness of the zero-energy mode by ultrafast heterodyne measurements of light transport dynamics in a silicon waveguide lattice. PMID- 29615631 TI - Silicon-Organic Hybrid (SOH) Mach-Zehnder Modulators for 100 Gbit/s on-off Keying. AB - Electro-optic modulators for high-speed on-off keying (OOK) are key components of short- and medium-reach interconnects in data-center networks. Small footprint, cost-efficient large-scale production, small drive voltages and ultra-low power consumption are of paramount importance for such devices. Here we demonstrate that the concept of silicon-organic hybrid (SOH) integration perfectly meets these challenges. The approach combines the unique processing advantages of large scale silicon photonics with unrivalled electro-optic (EO) coefficients obtained by molecular engineering of organic materials. Our proof-of-concept experiments demonstrate generation and transmission of OOK signals at line rates of up to 100 Gbit/s using a 1.1 mm-long SOH Mach-Zehnder modulator (MZM) featuring a pi voltage of only 0.9 V. The experiment represents the first demonstration of 100 Gbit/s OOK on the silicon photonic platform, featuring the lowest drive voltage and energy consumption ever demonstrated for a semiconductor-based device at this data rate. We support our results by a theoretical analysis showing that the nonlinear transfer characteristic of the MZM can help to overcome bandwidth limitations of the modulator and the electric driver circuitry. We expect that high-speed, power-efficient SOH modulators may have transformative impact on short-reach networks, enabling compact transceivers with unprecedented efficiency, thus building the base of future interfaces with Tbit/s data rates. PMID- 29615633 TI - Glucose-regulated protein 78 substrate-binding domain alters its conformation upon EGCG inhibitor binding to nucleotide-binding domain: Molecular dynamics studies. AB - Glucose-regulated protein 78 (GRP78), is overexpressed in glioblastoma, other tumors and during viral and bacterial infections, and so, it is postulated to be a key drug target. EGCG, an ATP-competitive natural inhibitor, inhibits GRP78 effect in glioblastoma. Structural basis of its action on GRP78 nucleotide binding domain and selectivity has been investigated. We were interested in exploring the large-scale conformational movements travelling to substrate binding domain via linker region. Conformational effects of EGCG inhibitor as well as ATP on full length GRP78 protein were studied using powerful MD simulations. Binding of EGCG decreases mobility of residues in SBDalpha lid region as compared to ATP-bound state and similar to apo state. The decreased mobility may prevent its opening and closing over SBDbeta. This hindrance to SBDalpha subdomain movement, in turn, may reduce the binding of substrate peptide to SBDbeta. EGCG binding folds the protein stably as opposed to ATP binding. Several results from EGCG binding simulations are similar to that of the apo state. Key insights from these results reveal that after EGCG binding upon competitive inhibition with ATP, GRP78 conformation may revert to that of inactive, apo state. Further, SBD may adopt a semi-open conformation unable to facilitate association of substrates. PMID- 29615632 TI - Influence of intrauterine administration of Lactobacillus buchneri on reproductive performance and pro-inflammatory endometrial mRNA expression of cows with subclinical endometritis. AB - Potential beneficial effects of lactic acid bacteria on the genital health of cows become of particular interest when considering the importance of an optimal uterine health status for the success of breeding in dairy farming. Therefore, the aim of the present study was to analyse the influence of an intrauterine administration of the Lactobacillus buchneri DSM 32407 on reproductive performance, uterine health status, endometrial mRNA expression of pro inflammatory factors of cows with signs of subclinical endometritis (SCE). L. buchneri DSM 32407 (n = 56; [LAC]) or a placebo (n = 60; [PLA]) was administered on day 24-30 postpartum. Endometrial cytobrush samples of cows with SCE were taken before the administration and at three following weeks (n = 16 cows each for LAC/SCE and PLA/SCE). A higher proportion of cows of the LAC and LAC/SCE group was pregnant after the first service and median days to conception for cows pregnant on day 200 pp were shorter. Three weeks after the administration, the endometrial mRNA expression of CXCL1/2, CXCL3, CXCR2, IL1B, IL8 and PTPRC was lower in the LAC/SCE group compared with the PLA/SCE group. These findings suggest that the presence of L. buchneri DSM 32407 contributes to a uterine environment that results in a better reproductive performance. PMID- 29615634 TI - Use of SU8 as a stable and biocompatible adhesion layer for gold bioelectrodes. AB - Gold is the most widely used electrode material for bioelectronic applications due to its high electrical conductivity, good chemical stability and proven biocompatibility. However, it adheres only weakly to widely used substrate materials such as glass and silicon oxide, typically requiring the use of a thin layer of chromium between the substrate and the metal to achieve adequate adhesion. Unfortunately, this approach can reduce biocompatibility relative to pure gold films due to the risk of the underlying layer of chromium becoming exposed. Here we report on an alternative adhesion layer for gold and other metals formed from a thin layer of the negative-tone photoresist SU-8, which we find to be significantly less cytotoxic than chromium, being broadly comparable to bare glass in terms of its biocompatibility. Various treatment protocols for SU-8 were investigated, with a view to attaining high transparency and good mechanical and biochemical stability. Thermal annealing to induce partial cross linking of the SU-8 film prior to gold deposition, with further annealing after deposition to complete cross-linking, was found to yield the best electrode properties. The optimized glass/SU8-Au electrodes were highly transparent, resilient to delamination, stable in biological culture medium, and exhibited similar biocompatibility to glass. PMID- 29615635 TI - Characterization of Sex-Based Dna Methylation Signatures in the Airways During Early Life. AB - Human respiratory conditions are largely influenced by the individual's sex resulting in overall higher risk for males. Sex-based respiratory differences are present at birth suggesting a strong genetic component. Our objective was to characterize early life sex-based genomic signatures determined by variable X chromosome methylation in the airways. We compared male versus female genome-wide DNA methylation in nasal airway samples from newborns and infants aged 1-6 months (N = 12). We analyzed methylation signals across CpG sites mapped to each X linked gene using an unsupervised classifier (principal components) followed by an internal evaluation and an exhaustive cross-validation. Results were validated in an independent population of children (N = 72) following the same algorithm. X linked genes with significant sex-based differential methylation in the nasal airway of infants represented only about 50% of the unique protein coding transcripts. X-linked genes without significant sex-based differential methylation included genes with evidence of escaping X-inactivation and female biased airway expression. These genes showed similar methylation patterns in males and females suggesting unbalanced X-chromosome dosage. In conclusion, we identified that the human airways have already sex-based DNA methylation signatures at birth. These early airway epigenomic marks may determine sex-based respiratory phenotypes and overall predisposition to develop respiratory disorders later in life. PMID- 29615636 TI - Millet manuring as a driving force for the Late Neolithic agricultural expansion of north China. AB - Research in to the nature of Neolithic agriculture in China is often focused on topics such as the domestication and spread of cereal crops and the reconstruction of human and animal diets in the past. Field management practices, such as organic manuring, have not been systematically investigated in Chinese archaeology. Here we present an isotopic dataset for archaeological foxtail millet (Setaria italica) and common millet (Panicum miliaceum) grains as well as associated faunal remains (both domesticated and wild) from seven sites in the Baishui Valley of north China, in order to find direct evidence of organic manuring during the Late Neolithic period. The elevated nitrogen isotope values of the millet grains (5500-3500 cal BP) in comparison with the estimated local vegetation indicates that millets were organically manured by animal dung, mostly likely originating from domestic pigs. Considering the low nitrogen contents of loess soils and their unsuitability for intensive cultivation, this organic manuring by animal dung would have played a key role in maintaining soil productivity and crop yield, which was necessary to support the demands of agriculture and cultural expansion during the Late Neolithic on the Loess Plateau of China. PMID- 29615637 TI - alpha2A-adrenergic blockade attenuates septic cardiomyopathy by increasing cardiac norepinephrine concentration and inhibiting cardiac endothelial activation. AB - Cardiomyopathy is a common complication associated with increased mortality in sepsis, but lacks specific therapy. Here, using genetic and pharmacological approaches, we explored the therapeutic effect of alpha2A-adrenergic receptor (AR) blockade on septic cardiomyopathy. CLP-induced septic rats were treated with BRL44408 (alpha2A-AR antagonist), prazosin (alpha1-AR antagonist) and/or reserpine. CLP-induced cardiomyopathy, indicated by reduced dP/dt and increased cardiac troponin I phosphorylation, was attenuated by BRL44408, this was associated with reduced cardiac TNF-alpha and endothelial VCAM-1 expression, cardiomyocyte apoptosis and related signal molecule phosphorylation. BRL44408 increased cardiac norepinephrine (NE) concentration in CLP rats. Pretreatment with reserpine that exhausts cardiac NE without affecting the circulating NE concentration or with prazosin partially abolished the cardioprotection of BRL44408 and reversed its inhibitory effects on myocardial TNF-alpha, apoptosis and related signal molecule phosphorylation, but not on VCAM-1 expression in septic rats. These effects of BRL44408 were confirmed by alpha2A-AR gene deletion in septic mice. Furthermore, alpha2-AR agonist not only enhanced LPS-induced TNF alpha and VCAM-1 expression in cardiac endothelial cells that express alpha2A-AR, but also enhanced LPS-induced cardiac dysfunction in isolated rat hearts. Our data indicate that alpha2A-AR blockade attenuates septic cardiomyopathy by promoting cardiac NE release that activates myocardial alpha1-AR and suppressing cardiac endothelial activation. PMID- 29615638 TI - Experimental determination of the energy difference between competing isomers of deposited, size-selected gold nanoclusters. AB - The equilibrium structures and dynamics of a nanoscale system are regulated by a complex potential energy surface (PES). This is a key target of theoretical calculations but experimentally elusive. We report the measurement of a key PES parameter for a model nanosystem: size-selected Au nanoclusters, soft-landed on amorphous silicon nitride supports. We obtain the energy difference between the most abundant structural isomers of magic number Au561 clusters, the decahedron and face-centred-cubic (fcc) structures, from the equilibrium proportions of the isomers. These are measured by atomic-resolution scanning transmission electron microscopy, with an ultra-stable heating stage, as a function of temperature (125 500 degrees C). At lower temperatures (20-125 degrees C) the behaviour is kinetic, exhibiting down conversion of metastable decahedra into fcc structures; the higher state is repopulated at higher temperatures in equilibrium. We find the decahedron is 0.040 +/- 0.020 eV higher in energy than the fcc isomer, providing a benchmark for the theoretical treatment of nanoparticles. PMID- 29615639 TI - TRPM7 in CHBP-induced renoprotection upon ischemia reperfusion-related injury. AB - Transient receptor potential melastatin 7 (TRPM7) is a membrane ion channel and kinase. TRPM7 was abundantly expressed in the kidney, and up-regulated by ischemia reperfusion (IR) injury. Our previous studies showed that cyclic helix B peptide (CHBP) improved renal IR-related injury, but its underlying mechanism is not well defined. IR-related injury was established in renal tubular epithelial cells (TCMK-1 and HK-2) via 12 to 24-h hypoxia (H) followed by 2-24 h reoxygenation (R), and in mouse kidneys subjected to 30-min ischemia and 12-h to 7-day reperfusion. TRPM7-like current in TCMK-1 cells, TRPM7 mRNA and protein in the in vitro and in vivo models were increased, but reversed by CHBP. TRPM7 was also positively associated with LDH, HMGB1, caspase-3, Bax/Bcl-2, inflammation, apoptosis, tubulointerstitial damage and renal function respectively. Furthermore, silencing TRPM7 improved injury parameters, renal histology and function in the both models. Specific TRPM7 agonist, bradykinin, exaggerated HR induced injury in TCMK-1 cells, and partially blocked the renoprotection of CHBP as well. In conclusion, TRPM7 is involved not only in IR-related injury, but also CHBP-induced renoprotection, which are through its ion channel and subsequent affects inflammation and apoptosis. Therefore, TRPM7 could be a potential biomarker for IR-induced acute kidney injury. PMID- 29615640 TI - Renal Prognosis and Related Risk Factors for Henoch-Schonlein Purpura Nephritis: A Chinese Adult Patient Cohort. AB - This study investigated the clinicopathological characteristics of Henoch Schonlein purpura nephritis (HSPN) in Chinese adult patients and analyzed the renal outcomes and prognostic risk factors for progression to end-stage renal disease (ESRD). Adult patients who had biopsy-proven HSPN were studied. Their clinicopathological data, renal prognoses and related risk factors were assessed. A total of 698 patients were studied, including 363 men (52.0%) and 335 women (48.0%). Most of the patients had hematuria (85.8%) and/or proteinuria (82.1%). During a median follow-up of 54.0 months, 32 patients (4.6%) progressed to ESRD. The 5- and 10-year cumulative renal survival rates from ESRD were 96.4% and 88.6%, respectively. Baseline urinary protein, renal insufficiency, glomerular sclerosis and tubular atrophy/interstitial fibrosis were independent predictors of renal outcomes. Both the time-average mean arterial pressure and proteinuria during follow-up also influenced the renal prognosis. The patients with a time average proteinuria <0.4 g/day had the lowest rates of ESRD or a 50% decline in renal function. In conclusion, identifying of clinical and histological prognostic factors may permit the prediction of renal outcomes. The optimal goal of therapy for HSPN patients may be to lower proteinuria to <0.4 g/day and control hypertension to achieve an ideal renal outcome. PMID- 29615641 TI - Maresin-1 suppresses imiquimod-induced skin inflammation by regulating IL-23 receptor expression. AB - The anti-inflammatory effect of omega 3 polyunsaturated fatty acids has been confirmed in various inflammatory disease models. Maresin-1 (MaR1) is a lipid mediator derived from the omega-3 fatty acid docosahexaenoic acid (DHA) that has displayed strong anti-inflammatory effects in various inflammatory disease models. However, the effect of topical MaR1 on cutaneous inflammation remains unclear. Therefore, we initially examined the anti-inflammatory effects of topical Maresin-1 using an imiquimod (IMQ)-induced psoriasis-like mouse model of inflammation. Topical MaR1 reduced the ear swelling response as seen in histological findings. RT-PCR and flow cytometry analyses revealed MaR1 had no inhibitory effect on IL-23, but MaR1 suppressed IL-17A production by gammadeltaTCRmid+ and CD4+ cells in the skin. These inhibitory effects were also observed in a subcutaneous IL-23-injected psoriasis model. MaR1 downmodulated IL 23 receptor (IL-23R) expression by suppressing retinoic acid-related orphan receptor gammat (RORgammat) expression and internalization in a clathrin dependent manner in gammadeltaTCRmid+ and CD4+ cells. These results lead to assumptions that topical MaR1 may be a new therapeutic agent for psoriasis and other IL-17-mediated cutaneous inflammatory diseases. PMID- 29615642 TI - Analysis of protein structure changes and quality regulation of surimi during gelation based on infrared spectroscopy and microscopic imaging. AB - A developed Fourier transform infrared spectroscopy (FT-IR) was employed to investigate changes of protein conformation, which played significant roles in maintaining stable protein networks of white croaker surimi gel, exploring the relationship between protein conformation and surimi gel networks. Spectra of surimi and gels with different grades (A, AA, FA and SA) were analyzed by tri step FT-IR method and peak-fitting of deconvolved and baseline corrected amide I bands (1600~1700 cm-1). The result showed that alpha-helix was the main conformation of surimi proteins. During surimi gelation, alpha-helix of myosin partially transformed into beta-sheet, beta-turn and random coil structures. beta sheet and random coil structures were the main protein conformations maintaining the structure of surimi gel, of which beta-sheet made the main contribution to gel strength. Scanning electron microscopy (SEM) result revealed that surimi gels had a fibrous and homogeneous network structure. Moreover, ordered interconnections between three-dimensional proteins networks of gels were inclined to emerge in higher grade surimi, in agreement with the gel strength results. It was demonstrated that the tri-step FT-IR spectroscopy combined with peak-fitting could be applicable for exploration of surimi protein conformation changes during gelation to deepen understanding of its effect on gel quality. PMID- 29615644 TI - Dominating role of crystal structure over defect chemistry in black and white zirconia on visible light photocatalytic activity. AB - Nanometric powder particles of white zirconia were synthesized through precursor route by the pyrolysis of zirconium (IV) butoxide at varied temperatures in air ranging from 900-1400 degrees C and were predominantly monoclinic in nature. To control the defect chemistry, the precursor was also pyrolyzed in a reduced atmosphere at 900 degrees C, eventually resulting in black zirconia. The stabilization of tetragonal phase and observed color change from white to black in samples pyrolyzed under reduced atmosphere was attributed to the creation of oxygen vacancies and disorder. The black and white zirconia produced delineated the influence of crystal structure and oxygen vacancies on the photocatalytic performance. Furthermore, zirconia synthesized at lower temperatures (600 and 800 degrees C) in air confirmed the detrimental role of tetragonal phase on the degradation behavior of methylene blue dye. High photocatalytic degradation rate for white zirconia was attributed to the presence of increased density of nano sized pores and low recombination rate of electron-hole pairs as confirmed by PL measurements. Interestingly, black zirconia exemplified relatively limited activity albeit presence of oxygen vacancies. This negative effect was attributed to the presence of tetragonal phase and possibly, the insufficient creation of new energy states near valence and conduction band towards Fermi energy level. PMID- 29615643 TI - Computational repositioning and preclinical validation of mifepristone for human vestibular schwannoma. AB - The computational repositioning of existing drugs represents an appealing avenue for identifying effective compounds to treat diseases with no FDA-approved pharmacotherapies. Here we present the largest meta-analysis to date of differential gene expression in human vestibular schwannoma (VS), a debilitating intracranial tumor, and use these data to inform the first application of algorithm-based drug repositioning for this tumor class. We apply an open-source computational drug repositioning platform to gene expression data from 80 patient tumors and identify eight promising FDA-approved drugs with potential for repurposing in VS. Of these eight, mifepristone, a progesterone and glucocorticoid receptor antagonist, consistently and adversely affects the morphology, metabolic activity, and proliferation of primary human VS cells and HEI-193 human schwannoma cells. Mifepristone treatment reduces VS cell viability more significantly than cells derived from patient meningiomas, while healthy human Schwann cells remain unaffected. Our data recommend a Phase II clinical trial of mifepristone in VS. PMID- 29615645 TI - Antidepressant drug-specific prediction of depression treatment outcomes from genetic and clinical variables. AB - Individuals with depression differ substantially in their response to treatment with antidepressants. Specific predictors explain only a small proportion of these differences. To meaningfully predict who will respond to which antidepressant, it may be necessary to combine multiple biomarkers and clinical variables. Using statistical learning on common genetic variants and clinical information in a training sample of 280 individuals randomly allocated to 12-week treatment with antidepressants escitalopram or nortriptyline, we derived models to predict remission with each antidepressant drug. We tested the reproducibility of each prediction in a validation set of 150 participants not used in model derivation. An elastic net logistic model based on eleven genetic and six clinical variables predicted remission with escitalopram in the validation dataset with area under the curve 0.77 (95%CI; 0.66-0.88; p = 0.004), explaining approximately 30% of variance in who achieves remission. A model derived from 20 genetic variables predicted remission with nortriptyline in the validation dataset with an area under the curve 0.77 (95%CI; 0.65-0.90; p < 0.001), explaining approximately 36% of variance in who achieves remission. The predictive models were antidepressant drug-specific. Validated drug-specific predictions suggest that a relatively small number of genetic and clinical variables can help select treatment between escitalopram and nortriptyline. PMID- 29615646 TI - Bile Acids Increase Doxorubicin Sensitivity in ABCC1-expressing Tumour Cells. AB - Tumour cells possess or acquire various mechanisms to circumvent the cytotoxic effects of chemotherapy drugs. One such mechanism involves the overexpression of ABC transporters that facilitate the extrusion of a variety of structurally distinct chemotherapy drugs from the cytoplasm into the extracellular space. While specific ABC transporter inhibitors have been developed, many affect other ABC transporters, particularly at elevated concentrations. It is also unclear whether they show clear efficacy for combatting drug resistance in cancer patients with minimal host toxicity. In this study, we demonstrate the ability of two bile acids [beta-cholanic acid (urso-cholanic acid) and deoxycholic acid] to specifically inhibit ABCC1-mediated drug transport, augmenting doxorubicin accumulation in breast and lung tumour cells selected for doxorubicin resistance through overexpression of the ABCC1 (but not ABCB1) drug transporter. The bile acids could also restore uptake and sensitivity to doxorubicin in human endothelial kidney cells genetically engineered to overexpress the ABCC1 drug transporter. These observations suggest a previously unreported role for bile acids as ABCC1 inhibitors or regulators. Given its additional properties of minimal clinical toxicity in humans and its ability to inhibit aldo-keto reductases involved in anthracycline resistance and anthracycline-induced cardiotoxicity, beta-cholanic acid merits further in vivo and clinical investigation. PMID- 29615647 TI - Early clinical experience with Guidezilla for transradial interventions in China. AB - Anatomic variations, calcified, tortuous, angulated lesions, and lack of support to increase the complexity of transradial intervention (TRI). Guidezilla is a mother-and-child catheter enabling increased support during complex interventions. As there are few published reports of its use, we describe our experience using this device to assist TRI in Chinese patients. The aim of this study was to investigate the efficacy and safety of the Guidezilla guide extension catheter in complex coronary interventions. Thirty-two patients' clinical characteristics, angiographic details, and in-hospital outcome retrospectively collected between June 2015 and August 2017. Patients were 59.44 +/- 10.48 years of age and 26 (81%) were men. The most frequent target vessels were the RCA (34%) and LAD (31%), patients had complex type C (53%) or B (47%) lesions, severely tortuous (41%) and angulated (22%).With the use of Guidezilla, technique success was 100%, and procedural success was 94%. The mean diameter of the deployed stents was 2.97 +/- 0.37 mm, and the length was 27.19 +/- 8.14 mm. The estimated mean distance of Guidezilla intubation into the target vessel was 7.66 +/- 2.29 cm.The Guidezilla catheter extension safely facilitated successful completion of TRI in complex coronary artery lesions. This device can help interventionalists successfully perform difficult procedures. PMID- 29615648 TI - Enrichment of ODMR-active nitrogen-vacancy centres in five-nanometre-sized detonation-synthesized nanodiamonds: Nanoprobes for temperature, angle and position. AB - The development of sensors to estimate physical properties, and their temporal and spatial variation, has been a central driving force in scientific breakthroughs. In recent years, nanosensors based on quantum measurements, such as nitrogen-vacancy centres (NVCs) in nanodiamonds, have been attracting much attention as ultrastable, sensitive, accurate and versatile physical sensors for quantitative cellular measurements. However, the nanodiamonds currently available for use as sensors have diameters of several tens of nanometres, much larger than the usual size of a protein. Therefore, their actual applications remain limited. Here we show that NVCs in an aggregation of 5-nm-sized detonation-synthesized nanodiamond treated by Kruger's surface reduction (termed DND-OH) retains the same characteristics as observed in larger diamonds. We show that the negative charge at the NVC are stabilized, have a relatively long T2 spin relaxation time of up to 4 MUs, and are applicable to thermosensing, one-degree orientation determination and nanometric super-resolution imaging. Our results clearly demonstrate the significant potential of DND-OH as a physical sensor. Thus, DND OH will raise new possibilities for spatiotemporal monitoring of live cells and dynamic biomolecules in individual cells at single-molecule resolution. PMID- 29615649 TI - Elevated tropospheric CO2 and O3 concentrations impair organic pollutant removal from grassland soil. AB - The concentrations of tropospheric CO2 and O3 have been rising due to human activities. These rising concentrations may have strong impacts on soil functions as changes in plant physiology may lead to altered plant-soil interactions. Here, the effects of eCO2 and eO3 on the removal of polycyclic aromatic hydrocarbon (PAH) pollutants in grassland soil were studied. Both elevated CO2 and O3 concentrations decreased PAH removal with lowest removal rates at elevated CO2 and elevated O3 concentrations. This effect was linked to a shift in soil microbial community structure by structural equation modeling. Elevated CO2 and O3 concentrations reduced the abundance of gram-positive bacteria, which were tightly linked to soil enzyme production and PAH degradation. Although plant diversity did not buffer CO2 and O3 effects, certain soil microbial communities and functions were affected by plant communities, indicating the potential for longer-term phytoremediation approaches. Results of this study show that elevated CO2 and O3 concentrations may compromise the ability of soils to degrade organic pollutants. On the other hand, the present study also indicates that the targeted assembly of plant communities may be a promising tool to shape soil microbial communities for the degradation of organic pollutants in a changing world. PMID- 29615650 TI - Rapid, topology-based particle tracking for high-resolution measurements of large complex 3D motion fields. AB - Spatiotemporal tracking of tracer particles or objects of interest can reveal localized behaviors in biological and physical systems. However, existing tracking algorithms are most effective for relatively low numbers of particles that undergo displacements smaller than their typical interparticle separation distance. Here, we demonstrate a single particle tracking algorithm to reconstruct large complex motion fields with large particle numbers, orders of magnitude larger than previously tractably resolvable, thus opening the door for attaining very high Nyquist spatial frequency motion recovery in the images. Our key innovations are feature vectors that encode nearest neighbor positions, a rigorous outlier removal scheme, and an iterative deformation warping scheme. We test this technique for its accuracy and computational efficacy using synthetically and experimentally generated 3D particle images, including non affine deformation fields in soft materials, complex fluid flows, and cell generated deformations. We augment this algorithm with additional particle information (e.g., color, size, or shape) to further enhance tracking accuracy for high gradient and large displacement fields. These applications demonstrate that this versatile technique can rapidly track unprecedented numbers of particles to resolve large and complex motion fields in 2D and 3D images, particularly when spatial correlations exist. PMID- 29615651 TI - Low testosterone in ApoE/LDL receptor double-knockout mice is associated with rarefied testicular capillaries together with fewer and smaller Leydig cells. AB - The testis as a site for atherosclerotic changes has so far attracted little attention. We used the apolipoprotein E (ApoE)/low density lipoprotein (LDL) receptor deficient mouse model (KO) for atherosclerosis (20, 40, 60 and 87-week old) to investigate whether Leydig cells or the capillary network are responsible for reduced serum testosterone levels previously observed in extreme ages of this model. In KO mice, overall testosterone levels were reduced whereas the adrenal gland-specific corticosterone was increased excluding a general defect of steroid hormone production. In addition to micro-CT investigations for bigger vessels, stereology revealed a reduction of capillary length, volume and surface area suggesting capillary rarefaction as a factor for diminished testosterone. Stereological analyses of interstitial cells demonstrated significantly reduced Leydig cell numbers and size. These structural changes in the testis occurred on an inflammatory background revealed by qPCR. Reduced litter size of the KO mice suggests hypo- or infertility as a consequence of the testicular defects. Our data suggest reduced testosterone levels in this atherosclerosis model might be explained by both, rarefication of the capillary network and reduced Leydig cell number and size. Thus, this study calls for specific treatment of male infertility induced by microvascular damage through hypercholesterolemia and atherosclerosis. PMID- 29615652 TI - Interleukin-23 as a therapeutic target for inflammatory myopathy. AB - Current treatments of polymyositis and dermatomyositis (PM/DM) depend on non specific immunosuppressants. This study was performed to elucidate the role of interleukin (IL)-23, as their possible therapeutic target. As was reported earlier in PM/DM patients, serum IL-23 levels were elevated in mice with C protein induced-myositis (CIM), a murine model of PM. IL-23 was expressed by macrophages in the PM/DM and CIM muscles and by dendritic cells and macrophages in the lymph nodes from the CIM mice. It was also expressed by macrophages in the chemically injured muscles, but not those recruited into the muscles by footpad injection of Freund's complete adjuvant, demonstrating that IL-23 production should be associated with muscle damage. Genetic deletion of IL-23 as well as preventive and therapeutic administration of blocking antibodies against IL-23p19 subunit suppressed CIM. When lymph node cells from the CIM mice were transferred adoptively into naive wild type or IL-23p19 deficient recipient mice, both recipients developed myositis equally. Thus, elevated IL-23 should promote dendritic cells and macrophages to activate the autoaggressive T cells. Our findings suggest that IL-23 should mediate positive feedback loop from the muscle damage to the T cell activation and be a promising therapeutic target for autoimmune myositis. PMID- 29615653 TI - Importance of Serum Amino Acid Profile for Induction of Hepatic Steatosis under Protein Malnutrition. AB - We previously reported that a low-protein diet caused animals to develop fatty liver containing a high level of triglycerides (TG), similar to the human nutritional disorder "kwashiorkor". To investigate the underlying mechanisms, we cultured hepatocytes in amino acid-sufficient or deficient medium. Surprisingly, the intracellular TG level was increased by amino acid deficiency without addition of any lipids or hormones, accompanied by enhanced lipid synthesis, indicating that hepatocytes themselves monitored the extracellular amino acid concentrations to induce lipid accumulation in a cell-autonomous manner. We then confirmed that a low-amino acid diet also resulted in the development of fatty liver, and supplementation of the low-amino acid diet with glutamic acid to compensate the loss of nitrogen source did not completely suppress the hepatic TG accumulation. Only a dietary arginine or threonine deficiency was sufficient to induce hepatic TG accumulation. However, supplementation of a low-amino acid diet with arginine or threonine failed to reverse it. In silico analysis succeeded in predicting liver TG level from the serum amino acid profile. Based on these results, we conclude that dietary amino acid composition dynamically affects the serum amino acid profile, which is sensed by hepatocytes and lipid synthesis was activated cell-autonomously, leading to hepatic steatosis. PMID- 29615654 TI - Functional metagenomic approach to identify overlooked antibiotic resistance mutations in bacterial rRNA. AB - Our knowledge as to how bacteria acquire antibiotic resistance is still fragmented, especially for the ribosome-targeting drugs. In this study, with the aim of finding novel mechanisms that render bacteria resistant to the ribosome targeting antibiotics, we developed a general method to systematically screen for antibiotic resistant 16 S ribosomal RNAs (rRNAs), which are the major target for multiple antibiotics (e.g. spectinomycin, tetracycline, and aminoglycosides), and identify point mutations therein. We used Escherichia coli ?7, a null mutant of the rrn (ribosomal RNA) operons, as a surrogate host organism to construct a metagenomic library of 16 S rRNA genes from the natural (non-clinical) environment. The library was screened for spectinomycin resistance to obtain four resistant 16 S rRNA genes from non-E. coli bacterial species. Bioinformatic analysis and site-directed mutagenesis identified three novel mutations - U1183C (the first mutation discovered in a region other than helix 34), and C1063U and U1189C in helix 34 - as well as three well-described mutations (C1066U, C1192G, and G1193A). These results strongly suggest that uncharacterized antibiotic resistance mutations still exist, even for traditional antibiotics. PMID- 29615655 TI - Supplementation of Pelleted Hazel (Corylus avellana) Leaves Decreases Methane and Urinary Nitrogen Emissions by Sheep at Unchanged Forage Intake. AB - This study is the first to quantify the effects of hazel (Corylus avellana) leaves on methane and urinary nitrogen emissions, digestibility, nitrogen and the energy balance of ruminants. Four experimental pellets were produced with 0, 30% and 60% hazel leaves, the latter also with 4% polyethylene glycol. Hazel leaves gradually replaced lucerne. The diet was composed of the pellets and grass hay (80%: 20%). Six adult sheep were allocated to all four treatments in a 6 * 4 crossover design. Including hazel leaves did not affect the feed intake, but it decreased the apparent digestibility of organic matter and fibre, especially at the high level. Methane emission was reduced by up to 25 to 33% per day, per unit of intake and per unit of organic matter digested. Urinary nitrogen excretion decreased by 33 to 72% with increasing levels of hazel leaves. The treatment with polyethylene glycol demonstrated that tannins in hazel leaves caused significant shares of the effects. In conclusion, the current results indicated a significant potential of hazel leaves as forage for ruminants to mitigate methane and urinary nitrogen emissions. Even high dietary hazel leaf proportions were palatable. The lower digestibility needs to be compensated with easily digestible diet ingredients. PMID- 29615656 TI - How Semantic Radicals in Chinese characters Facilitate Hierarchical Category Based Induction. AB - Prior studies indicate that the semantic radical in Chinese characters contains category information that can support the independent retrieval of category information through the lexical network to the conceptual network. Inductive reasoning relies on category information; thus, semantic radicals may influence inductive reasoning. As most natural concepts are hierarchically structured in the human brain, this study examined how semantic radicals impact inductive reasoning for hierarchical concepts. The study used animal and plant nouns, organized in basic, superordinate, and subordinate levels; half had a semantic radical and half did not. Eighteen participants completed an inductive reasoning task. Behavioural and event-related potential (ERP) data were collected. The behavioural results showed that participants reacted faster and more accurately in the with-semantic-radical condition than in the without-semantic-radical condition. For the ERPs, differences between the conditions were found, and these differences lasted from the very early cognitive processing stage (i.e., the N1 time window) to the relatively late processing stages (i.e., the N400 and LPC time windows). Semantic radicals can help to distinguish the hierarchies earlier (in the N400 period) than characters without a semantic radical (in the LPC period). These results provide electrophysiological evidence that semantic radicals may improve sensitivity to distinguish between hierarchical concepts. PMID- 29615657 TI - Integrated transcriptomes throughout swine oestrous cycle reveal dynamic changes in reproductive tissues interacting networks. AB - Female fertility is a highly regulated process involving the synchronized activities of multiple tissues. The underlying genomic regulation of the tissue synchronization is poorly understood. To understand this better we investigated the transcriptomes of the porcine ovary, endometrium, and oviduct at days 0, 3, 6, 9, 12, 15, or 18 of the oestrous cycle. We analysed the transcriptome profiles of the individual tissues and focus on the bridging genes shared by two or more tissues. The three tissue-networks were connected forming a triangular shape. We identified 65 bridging genes with a high level of connectivity to all other genes in the network. The expression levels showed negative correlations between the ovary and the other two tissues, and low correlations between endometrium and oviduct. The main functional annotations involved biosynthesis of steroid hormones, cell-to-cell adhesion, and cell apoptosis, suggesting that regulation of steroid hormone synthesis and tissue viability are major regulatory mechanisms. PMID- 29615658 TI - Systemic IGF-1 gene delivery by rAAV9 improves spontaneous autoimmune peripheral polyneuropathy (SAPP). AB - Spontaneous autoimmune peripheral polyneuropathy (SAPP) is a mouse model of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) in non-obese diabetic (NOD) mice null for costimulatory molecule, B7-2 gene (B7-2-/-). SAPP is a chronic progressive and multifocal inflammatory and demyelinating polyneuropathy of spontaneous onset with secondary axonal degeneration. Insulin like growth factor 1(IGF-1) is a pleiotropic factor with neuroprotective, regenerative, and anti-inflammatory effects with extensive experience in its preclinical and clinical use. Systemic delivery of recombinant adeno-associated virus serotype 9 (rAAV9) provides robust and widespread gene transfer to central and peripheral nervous systems making it suitable for gene delivery in neurological diseases. A significant proportion of patients with inflammatory neuropathies like CIDP do not respond to current clinical therapies and there is a need for new treatments. In this study, we examined the efficacy IGF-1 gene therapy by systemic delivery with rAAV9 in SAPP model. The rAAV9 construct also contained a reporter gene to monitor the surrogate expression of IGF-1. We found significant improvement in neuropathic disease after systemic delivery of rAAV9/IGF-1 gene at presymptomatic and symptomatic stages of SAPP model. These findings support that IGF-1 treatment (including gene therapy) is a viable therapeutic option in immune neuropathies such as CIDP. PMID- 29615659 TI - Sex-based differences in phagocyte metabolic profile in rats with monosodium glutamate-induced obesity. AB - The important component of obesity pathogenesis is inflammatory activation of innate immune cells within adipose tissue and in other body locations. Both the course of obesity and innate immune reactivity are characterized by sex associated differences. The aim of the work was a comparative investigation of metabolic profiles of phagocytes from different locations in male and female rats with MSG-induced obesity. The administration of monosodium glutamate (MSG) caused obesity, with sex-associated differences, that was more severe in male rats. Obesity was associated with pro-inflammatory activation of CD14+ phagocytes from adipose tissue in female, but not in male rats, which was demonstrated by decreased phagocytosis activity along with increased ROS generation. Phagocytes from the peritoneal cavity and peripheral blood of obese female rats exhibited neutral metabolic profile, whereas those cells from obese male rats displayed a pro-inflammatory metabolic profile. Thus, the manifestation of obesity-induced inflammation was characterized by different patterns of metabolic profile of phagocytes in male and female rats. Identified immune cell characteristics expand our knowledge of obesity immunobiology and may help to develop more effective preventive and therapeutic interventions for obese patients of different sexes. PMID- 29615660 TI - Mesenchymal Stromal Cells-Derived beta2-Microglobulin Promotes Epithelial Mesenchymal Transition of Esophageal Squamous Cell Carcinoma Cells. AB - Mesenchymal stromal cells (MSCs) have been considered as one of the pivotal type of cells composing the tumor microenvironment. Although contact-dependent mechanisms and paracrine factors are thought to collaborate in governing the MSCs based effects on tumors progression, the underlying mechanisms remain largely unknown. In particular, the involvement of MSCs-derived cytokines in the epithelial-mesenchymal transition (EMT) of esophageal squamous cell carcinoma (ESCC) has not been clarified. In this study, we observed that beta2 Microglobulin (B2M) is highly expressed in MSCs but scarcely in ESCC cells. Based on the previously described EMT promoting effect of B2M, we investigated the in vitro effect of MSCs-derived B2M on the EMT of ESCC cells, and discovered its subsequent enhancing effects on cell mobility and tumor-initiation. Further xenograft transplantation experiments confirmed the in vivo induction of tumor initiation by MSCs-derived B2M. Noteworthy, we showed that the B2M expression positively correlated with poor prognosis. The fact that B2M is primarily expressed by the stroma of the ESCC tissue strengthens our hypothesis that in ESCC, MSCs-derived B2M promotes tumor-initiation and invasion via enhancing EMT, resulting in an adverse prognosis for the patients. Our results will be valuable for the prediction of the development and treatment of ESCC. PMID- 29615661 TI - Microbiota Composition May Predict Anti-Tnf Alpha Response in Spondyloarthritis Patients: an Exploratory Study. AB - Spondyloarthritis (SpA) pathophysiology remains largely unknown. While the association with genetic factors has been established for decades, the influence of gut microbiota is only an emerging direction of research. Despite the remarkable efficacy of anti-TNF-alpha treatments, non-responders are frequent and no predictive factors of patient outcome have been identified. Our objective was to investigate the modifications of intestinal microbiota composition in patients suffering from SpA three months after an anti-TNF-alpha treatment. We performed 16S rDNA sequencing of 38 stool samples from 19 spondyloarthritis patients before and three months after anti-TNF-alpha treatment onset. SpA activity was assessed at each time using ASDAS and BASDAI scores. Some modifications of the microbiota composition were observed after three months of anti-TNF-alpha treatment, but no specific taxon was modified, whatever the clinical response. We identified a particular taxonomic node before anti-TNF-alpha treatment that can predict the clinical response as a biomarker, with a higher proportion of Burkholderiales order in future responder patients. This study suggests a cross-influence between anti-TNF-alpha treatment and intestinal microbiota. If its results are confirmed on larger groups of patients, it may pave the way to the development of predictive tests suitable for clinical practices. PMID- 29615662 TI - Environmental DNA (eDNA) detects the pool frog (Pelophylax lessonae) at times when traditional monitoring methods are insensitive. AB - Detection of endangered species is invaluable for conservation efforts, yet many traditional sampling techniques are ineffective at low population abundances or during certain periods of the year. Here, we compared results from a newly developed eDNA approach and the traditional observational method for the endangered pool frog (Pelophylax lessonae). Analysis using an occupancy-modeling framework indicated that the probability of pools being occupied using eDNA (0.93) was higher than for the traditional method of counting calling males and silent observed individuals (0.72). Detailed analysis revealed complementarity among the methods. That is, the traditional method gave a high rate of observation in June, whereas eDNA gave at least as many or more observations during other parts of the year. Discrepancies among the methods depended on the dominant lifecycle stage, and eDNA concentrations were higher when juveniles were present than at times when spawning occurred. eDNA concentrations were also positively related to P. lessonae observations. Our study demonstrates that an eDNA protocol for monitoring of endangered amphibian species can be particularly valuable during periods when individuals are hard to detect by observational methods, and provides guidance to sampling efforts for research and monitoring programs in other regions and systems. PMID- 29615663 TI - Low affinity uniporter carrier proteins can increase net substrate uptake rate by reducing efflux. AB - Many organisms have several similar transporters with different affinities for the same substrate. Typically, high-affinity transporters are expressed when substrate is scarce and low-affinity ones when it is abundant. The benefit of using low instead of high-affinity transporters remains unclear, especially when additional nutrient sensors are present. Here, we investigate two hypotheses. It was previously hypothesized that there is a trade-off between the affinity and the catalytic efficiency of transporters, and we find some but no definitive support for it. Additionally, we propose that for uptake by facilitated diffusion, at saturating substrate concentrations, lowering the affinity enhances the net uptake rate by reducing substrate efflux. As a consequence, there exists an optimal, external-substrate-concentration dependent transporter affinity. A computational model of Saccharomyces cerevisiae glycolysis shows that using the low affinity HXT3 transporter instead of the high affinity HXT6 enhances the steady-state flux by 36%. We tried to test this hypothesis with yeast strains expressing a single glucose transporter modified to have either a high or a low affinity. However, due to the intimate link between glucose perception and metabolism, direct experimental proof for this hypothesis remained inconclusive. Still, our theoretical results provide a novel reason for the presence of low affinity transport systems. PMID- 29615664 TI - Metabolomics coupled with pathway analysis characterizes metabolic changes in response to BDE-3 induced reproductive toxicity in mice. AB - Polybrominated diphenyl ethers (PBDEs) may affect male reproductive function. 4 bromodiphenyl ether (BDE-3), the photodegradation products of higher brominated PBDEs, is the most fundamental mono-BDE in environment but is less studied. The purpose of this study was to investigate the reproductive toxicity induced by BDE 3 and explore the mechanism by metabolomics approach. In this study, mice were treated intragastrically with BDE-3 for consecutive six weeks at the dosages of 0.0015, 1.5, 10 and 30 mg/kg. The reproductive toxicity was evaluated by sperm analysis and histopathology examinations. UPLC-Q-TOF/MS was applied to profile the metabolites of testis tissue, urine and serum samples in the control and BDE 3 treated mice. Results showed the sperm count was dose-dependently decreased and percentage of abnormal sperms increased by the treatment of BDE-3. Histopathology examination also revealed changes in seminiferous tubules and epididymides in BDE 3 treated mice. Metabolomics analysis revealed that different BDE-3 groups showed metabolic disturbances to varying degrees. We identified 76, 38 and 31 differential metabolites in testis tissue, urine and serum respectively. Pathway analysis revealed several pathways including Tyrosine metabolism, Purine metabolism and Riboflavin metabolism, which may give a possible explanation for the toxic mechanism of BDE-3. This study indicates that UHPLC-Q-TOFMS-based metabolomics approach provided a better understanding of PBDEs-induced toxicity dynamically. PMID- 29615666 TI - Insensitivity to atorvastatin is associated with increased accumulation of intracellular lipid droplets and fatty acid metabolism in breast cancer cells. AB - Apart from the relevant lipid-lowering effects, statins have demonstrated significant, although heterogeneous, anti-tumor activities in preventing breast cancer (BC) progression. To characterize the critical pathways behind the diverse responses to therapy, we investigated statin-induced changes in regulation of lipid metabolism and abundance of neutral lipid-containing cytoplasmic lipid droplets (LDs) in BC cells displaying different sensitivity to atorvastatin. Following atorvastatin treatment, accumulated LD levels inversely mirrored the marginal anti-proliferative effects in a dose and time-dependent manner in the less-sensitive BC cells. Transcriptional profiling excluded dysregulation of lipid uptake and efflux as specific mechanisms associated with differences in LD accumulation and anti-proliferative effects of atorvastatin. Notably, significant upregulation of genes involved in unsaturated fatty acid metabolism [stearoyl-CoA desaturase (SCD)] and cholesterol biosynthesis [3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR)], were associated with atorvastatin insensitivity. Taken together, the increased ability to store neutral lipids in LDs as consequence of atorvastatin treatment likely confers a proliferative advantage to BC cells and may serve as potential biomarker of statin resistance in BC. Contributions of cholesterol biosynthesis and unsaturated fatty acid metabolism to LD formation should be thoroughly explored for better understanding of the molecular mechanisms underlying statin-induced effects against BC progression. PMID- 29615665 TI - Unbiased Strain-Typing of Arbovirus Directly from Mosquitoes Using Nanopore Sequencing: A Field-forward Biosurveillance Protocol. AB - The future of infectious disease surveillance and outbreak response is trending towards smaller hand-held solutions for point-of-need pathogen detection. Here, samples of Culex cedecei mosquitoes collected in Southern Florida, USA were tested for Venezuelan Equine Encephalitis Virus (VEEV), a previously-weaponized arthropod-borne RNA-virus capable of causing acute and fatal encephalitis in animal and human hosts. A single 20-mosquito pool tested positive for VEEV by quantitative reverse transcription polymerase chain reaction (RT-qPCR) on the Biomeme two3. The virus-positive sample was subjected to unbiased metatranscriptome sequencing on the Oxford Nanopore MinION and shown to contain Everglades Virus (EVEV), an alphavirus in the VEEV serocomplex. Our results demonstrate, for the first time, the use of unbiased sequence-based detection and subtyping of a high-consequence biothreat pathogen directly from an environmental sample using field-forward protocols. The development and validation of methods designed for field-based diagnostic metagenomics and pathogen discovery, such as those suitable for use in mobile "pocket laboratories", will address a growing demand for public health teams to carry out their mission where it is most urgent: at the point-of-need. PMID- 29615667 TI - Lipoprotein lipase regulates hematopoietic stem progenitor cell maintenance through DHA supply. AB - Lipoprotein lipase (LPL) mediates hydrolysis of triglycerides (TGs) to supply free fatty acids (FFAs) to tissues. Here, we show that LPL activity is also required for hematopoietic stem progenitor cell (HSPC) maintenance. Knockout of Lpl or its obligatory cofactor Apoc2 results in significantly reduced HSPC expansion during definitive hematopoiesis in zebrafish. A human APOC2 mimetic peptide or the human very low-density lipoprotein, which carries APOC2, rescues the phenotype in apoc2 but not in lpl mutant zebrafish. Creating parabiotic apoc2 and lpl mutant zebrafish rescues the hematopoietic defect in both. Docosahexaenoic acid (DHA) is identified as an important factor in HSPC expansion. FFA-DHA, but not TG-DHA, rescues the HSPC defects in apoc2 and lpl mutant zebrafish. Reduced blood cell counts are also observed in Apoc2 mutant mice at the time of weaning. These results indicate that LPL-mediated release of the essential fatty acid DHA regulates HSPC expansion and definitive hematopoiesis. PMID- 29615668 TI - Endophytes of Withania somnifera modulate in planta content and the site of withanolide biosynthesis. AB - Tissue specific biosynthesis of secondary metabolites is a distinguished feature of medicinal plants. Withania somnifera, source of pharmaceutically important withanolides biosynthesizes withaferin-A in leaves and withanolide-A in roots. To increase the in planta withanolides production, a sustainable approach needs to be explored. Here, we isolated endophytes from different parts of W. somnifera plants and their promising role in in planta withanolide biosynthesis was established in both in-vivo grown as well in in-vitro raised composite W. somnifera plants. Overall, the fungal endophytes improved photosynthesis, plant growth and biomass, and the root-associated bacterial endophytes enhanced the withanolide content in both in-vivo and in-vitro grown plants by modulating the expression of withanolide biosynthesis genes in leaves and roots. Surprisingly, a few indole-3-acetic acid (IAA)-producing and nitrogen-fixing root-associated endophytes could induce the biosynthesis of withaferin-A in roots by inducing in planta IAA-production and upregulating the expression of withanolide biosynthesis genes especially MEP-pathway genes (DXS and DXR) in roots as well. Results indicate the role of endophytes in modulating the synthesis and site of withanolides production and the selected endophytes can be used for enhancing the in planta withanolide production and enriching roots with pharmaceutically important withaferin-A which is generally absent in roots. PMID- 29615670 TI - Landau-Zener-Stuckelberg interference in coherent charge oscillations of a one electron double quantum dot. AB - Landau-Zener (LZ) transition has received renewed interest as an alternative approach to control single-qubit states. An LZ transition occurs when a system passes through an avoided crossing that arises from quantum mechanical coupling of two levels, taking the system to a coherent superposition of the two states. Then, multiple LZ transitions induce interference known as Landau-Zener Stuckelberg (LZS) interference whose amplitude strongly depends on the velocity or adiabaticity of the passage. Here, we study the roles of LZ transitions and LZS interference in coherent charge oscillations of a one-electron semiconductor double quantum dot by time-domain experiments using standard rectangular voltage pulses. By employing density matrix simulations, we show that, in the standard setup using rectangular pulses, even a small distortion of the pulse can give rise to LZ transitions and hence LZS interference, which significantly enhances the measured oscillation amplitude. We further show experimentally that the nature of the coherent charge oscillations changes from Rabi-type to LZS oscillations with increasing pulse distortion. Our results thus demonstrate that it is essential to take into account LZS interference for both precise control of charge qubits and correct interpretation of measurement results. PMID- 29615669 TI - A powerful on line ABTS+-CE-DAD method to screen and quantify major antioxidants for quality control of Shuxuening Injection. AB - A novel method of on-line 2,2'-Azinobis-(3-ethylbenzthiazoline-6-sulphonate) Capillary Electrophoresis-Diode Array Detector (on-line ABTS+-CE-DAD) was developed to screen the major antioxidants from complex herbal medicines. ABTS+, one of well-known oxygen free radicals was firstly integrated into the capillary. For simultaneously detecting and separating ABTS+ and chemical components of herb medicines, some conditions were optimized. The on-line ABTS+-CE-DAD method has successfully been used to screen the main antioxidants from Shuxuening injection (SI), an herbal medicines injection. Under the optimum conditions, nine ingredients of SI including clitorin, rutin, isoquercitrin, Quercetin-3-O-D glucosyl]-(1-2)-L-rhamnoside, kaempferol-3-O-rutinoside, kaempferol-7-O-beta-D glucopyranoside, apigenin-7-O-Glucoside, quercetin-3-O-[2-O-(6-O-p-hydroxyl-E coumaroyl)-D-glucosyl]-(1-2)-L-rhamnoside, 3-O-{2-O-[6-O-(p-hydroxyl-E-coumaroyl) glucosyl]}-(1-2) rhamnosyl kaempfero were separated and identified as the major antioxidants. There is a linear relationship between the total amount of major antioxidants and total antioxidative activity of SI with a linear correlation coefficient of 0.9456. All the Relative standard deviations of recovery, precision and stability were below 7.5%. Based on these results, these nine ingredients could be selected as combinatorial markers to evaluate quality control of SI. It was concluded that on-line ABTS+-CE-DAD method was a simple, reliable and powerful tool to screen and quantify active ingredients for evaluating quality of herbal medicines. PMID- 29615671 TI - Local oceanographic variability influences the performance of juvenile abalone under climate change. AB - Climate change is causing warming, deoxygenation, and acidification of the global ocean. However, manifestation of climate change may vary at local scales due to oceanographic conditions. Variation in stressors, such as high temperature and low oxygen, at local scales may lead to variable biological responses and spatial refuges from climate impacts. We conducted outplant experiments at two locations separated by ~2.5 km and two sites at each location separated by ~200 m in the nearshore of Isla Natividad, Mexico to assess how local ocean conditions (warming and hypoxia) may affect juvenile abalone performance. Here, we show that abalone growth and mortality mapped to variability in stress exposure across sites and locations. These insights indicate that management decisions aimed at maintaining and recovering valuable marine species in the face of climate change need to be informed by local variability in environmental conditions. PMID- 29615672 TI - Morphometric analysis of spread platelets identifies integrin alphaIIbbeta3 specific contractile phenotype. AB - Haemostatic platelet function is intimately linked to cellular mechanics and cytoskeletal morphology. How cytoskeletal reorganizations give rise to a highly contractile phenotype that is necessary for clot contraction remains poorly understood. To elucidate this process in vitro, we developed a morphometric screen to quantify the spatial organization of actin fibres and vinculin adhesion sites in single spread platelets. Platelets from healthy donors predominantly adopted a bipolar morphology on fibrinogen and fibronectin, whereas distinguishable, more isotropic phenotypes on collagen type I or laminin. Specific integrin alphaIIbbeta3 inhibitors induced an isotropic cytoskeletal organization in a dose-dependent manner. The same trend was observed with decreasing matrix stiffness. Circular F-actin arrangements in platelets from a patient with type II Glanzmann thrombasthenia (GT) were consistent with the residual activity of a small number of alphaIIbbeta3 integrins. Cytoskeletal morphologies in vitro thus inform about platelet adhesion receptor identity and functionality, and integrin alphaIIbbeta3 mechanotransduction fundamentally determines the adoption of a bipolar phenotype associated with contraction. Super resolution microscopy and electron microscopies further confirmed the stress fibre-like contractile actin architecture. For the first time, our assay allows the unbiased and quantitative assessment of platelet morphologies and could help to identify defective platelet behaviour contributing to elusive bleeding phenotypes. PMID- 29615673 TI - Quantifying extracellular matrix turnover in human lung scaffold cultures. AB - Remodelling of the extracellular matrix is accomplished by altering the balance between matrix macromolecule production and degradation. However, it is not well understood how cells balance production of new matrix molecules and degradation of existing ones during tissue remodelling and regeneration. In this study, we used decellularized lung scaffolds repopulated with allogenic lung fibroblasts cultured with stable isotope labelled amino acids to quantify the balance between matrix production and degradation at a proteome-wide scale. Specific temporal dynamics of different matrisome proteins were found to correspond to the proliferative activity of the repopulating cells and the degree of extracellular deposition. The remodeling of the scaffold was characterized by an initial phase with cell proliferation and high production of cell adhesion proteins such as emilin-1 and fibronectin. Extended culture time resulted in increased levels of core matrisome proteins. In a comparison with monolayer cultures on plastic, culture in lung scaffolds lead to a pronounced accumulation of proteoglycans, such as versican and decorin, resulting in regeneration of an extracellular matrix with greater resemblance to native lung tissue compared to standard monolayer cultures. Collectively, the study presents a promising technique for increasing the understanding of cell- extracellular matrix interactions under healthy and diseased conditions. PMID- 29615674 TI - Acute metabolic actions of the major polyphenols in chamomile: an in vitro mechanistic study on their potential to attenuate postprandial hyperglycaemia. AB - Transient hyperglycaemia is a risk factor for type 2 diabetes and endothelial dysfunction, especially in subjects with impaired glucose tolerance. Nutritional interventions and strategies for controlling postprandial overshoot of blood sugars are considered key in preventing progress to the disease state. We have identified apigenin-7-O-glucoside, apigenin, and (Z) and (E)-2-hydroxy-4 methoxycinnamic acid glucosides as the active (poly)phenols in Chamomile (Matricaria recutita) able to modulate carbohydrate digestion and absorption in vitro as assessed by inhibition of alpha-amylase and maltase activities. The latter two compounds previously mistakenly identified as ferulic acid hexosides were purified and characterised and studied for their contribution to the overall bioactivity of chamomile. Molecular docking studies revealed that apigenin and cinnamic acids present totally different poses in the active site of human alpha amylase. In differentiated Caco-2/TC7 cell monolayers, apigenin-7-O-glucoside and apigenin strongly inhibited D-[U-14C]-glucose and D-[U-14C]-sucrose transport, and less effectively D-[U-14C]-fructose transport. Inhibition of D-[U-14C] glucose transport by apigenin was stronger under Na+-depleted conditions, suggesting interaction with the GLUT2 transporter. Competitive binding studies with molecular probes indicate apigenin interacts primarily at the exofacial binding site of GLUT2. Taken together, the individual components of Chamomile are promising agents for regulating carbohydrate digestion and sugar absorption at the site of the gastrointestinal tract. PMID- 29615675 TI - Predicting individual responses to the electroconvulsive therapy with hippocampal subfield volumes in major depression disorder. AB - Electroconvulsive therapy (ECT) is one of the most effective treatments for major depression disorder (MDD). ECT can induce neurogenesis and synaptogenesis in hippocampus, which contains distinct subfields, e.g., the cornu ammonis (CA) subfields, a granule cell layer (GCL), a molecular layer (ML), and the subiculum. It is unclear which subfields are affected by ECT and whether we predict the future treatment response to ECT by using volumetric information of hippocampal subfields at baseline? In this study, 24 patients with severe MDD received the ECT and their structural brain images were acquired with magnetic resonance imaging before and after ECT. A state-of-the-art hippocampal segmentation algorithm from Freesurfer 6.0 was used. We found that ECT induced volume increases in CA subfields, GCL, ML and subiculum. We applied a machine learning algorithm to the hippocampal subfield volumes at baseline and were able to predict the change in depressive symptoms (r = 0.81; within remitters, r = 0.93). Receiver operating characteristic analysis also showed robust prediction of remission with an area under the curve of 0.90. Our findings provide evidence for particular hippocampal subfields having specific roles in the response to ECT. We also provide an analytic approach for generating predictions about clinical outcomes for ECT in MDD. PMID- 29615676 TI - Silent infection of human dendritic cells by African and Asian strains of Zika virus. AB - While Zika virus (ZIKV) circulated for decades (African lineage strains) without report of outbreaks and severe complications, its emergence in French Polynesia and subsequently in the Americas (Asian lineage strains) was associated with description of severe neurological defects in newborns/neonates and adults. With the aim to identify virus lineage-dependent factors, we compared cell susceptibility, virus replication, cell death and innate immune responses following infection with two African and three contemporary Asian lineage strains of ZIKV. To this end, we used green monkey Vero and Aedes albopictus C6/36 cells and human monocyte-derived dendritic cells (DCs). The latter are involved in the pathogenesis of several mosquito-borne Flavivirus infections. In Vero and C6/36 cells, we observed strain- but not lineage-dependent differences in infection profiles. Nevertheless, in human DCs, no significant differences in susceptibility and virus replication were found between lineages and strains. ZIKV induced antiviral interferon type I/III in a limited fashion, with the exception of one African strain. None of the strains induced cell death or DC maturation in terms of MHC II, CD40, CD80/86 or CCR7 expression. Taken together, our data suggest that a large collection of virus isolates needs to be investigated before conclusions on lineage differences can be made. PMID- 29615677 TI - Longitudinal outcomes of amyloid positive versus negative amnestic mild cognitive impairments: a three-year longitudinal study. AB - We aimed to compare the longitudinal outcome of amnestic mild cognitive impairment (aMCI) patients with significant Pittsburgh Compound B uptake [PiB(+) aMCI] and those without [PiB(-) aMCI]. Cerebral beta-amyloid was measured in 47 patients with aMCI using PiB-positron emission tomography (PET) (31 PiB(+) aMCI and 16 PiB(-) aMCI). Clinical (N = 47) and neuropsychological follow-up (N = 37), and follow-up with brain magnetic resonance imaging (N = 38) and PiB-PET (N = 30) were performed for three years. PiB(+) aMCI had a higher risk of progression to dementia (hazard ratio = 3.74, 95% CI = 1.21-11.58) and faster rate of cortical thinning in the bilateral precuneus and right medial and lateral temporal cortices compared to PiB(-) aMCI. Among six PiB(-) aMCI patients who had regional PiB uptake ratio >1.5 in the posterior cingulate cortex (PCC), three (50.0%) progressed to dementia, and two of them had global PiB uptake ratio >1.5 at the follow-up PiB-PET. Our findings suggest that amyloid imaging is important for predicting the prognosis of aMCI patients, and that it is necessary to pay more attention to PiB(-) aMCI with increased regional PiB uptake in the PCC. PMID- 29615678 TI - Protein-bound NAD(P)H Lifetime is Sensitive to Multiple Fates of Glucose Carbon. AB - While NAD(P)H fluorescence lifetime imaging (FLIM) can detect changes in flux through the TCA cycle and electron transport chain (ETC), it remains unclear whether NAD(P)H FLIM is sensitive to other potential fates of glucose. Glucose carbon can be diverted from mitochondria by the pentose phosphate pathway (via glucose 6-phosphate dehydrogenase, G6PDH), lactate production (via lactate dehydrogenase, LDH), and rejection of carbon from the TCA cycle (via pyruvate dehydrogenase kinase, PDK), all of which can be upregulated in cancer cells. Here, we demonstrate that multiphoton NAD(P)H FLIM can be used to quantify the relative concentrations of recombinant LDH and malate dehydrogenase (MDH) in solution. In multiple epithelial cell lines, NAD(P)H FLIM was also sensitive to inhibition of LDH and PDK, as well as the directionality of LDH in cells forced to use pyruvate versus lactate as fuel sources. Among the parameters measurable by FLIM, only the lifetime of protein-bound NAD(P)H (tau2) was sensitive to these changes, in contrast to the optical redox ratio, mean NAD(P)H lifetime, free NAD(P)H lifetime, or the relative amount of free and protein-bound NAD(P)H. NAD(P)H tau2 offers the ability to non-invasively quantify diversions of carbon away from the TCA cycle/ETC, which may support mechanisms of drug resistance. PMID- 29615679 TI - An accessible visible-light actinometer for the determination of photon flux and optical pathlength in flow photo microreactors. AB - Coupling photochemistry with flow microreactors enables novel synthesis strategies with higher efficiencies compared to batch systems. Improving the reproducibility and understanding of the photochemical reaction mechanisms requires quantitative tools such as chemical actinometry. However, the choice of actinometric systems which can be applied in microreactors is limited, due to their short optical pathlength in combination with a large received photon flux. Furthermore, actinometers for the characterization of reactions driven by visible light between 500 and 600 nm (e.g. photosensitized oxidations) are largely missing. In this paper, we propose a new visible-light actinometer which can be applied in flow microreactors between 480 and 620 nm. This actinometric system is based on the photoisomerization reaction of a diarylethene derivative from its closed to the open form. The experimental protocol for actinometric measurements is facile and characterized by excellent reproducibility and we also present an analytical estimation to calculate the photon flux. Furthermore, we propose an experimental methodology to determine the average pathlength in microreactors using actinometric measurements. In the context of a growing research interest on using flow microreactors for photochemical reactions, the proposed visible-light actinometer facilitates the determination of the received photon flux and average pathlength in confined geometries. PMID- 29615680 TI - Water-Soluble Metalated Covalent Organic Nanobelts with Improved Bioavailability for Protein Transportation. AB - An available pathway to prepare the ionized covalent organic nanosheets (iCONs) has been proposed by a metal-assisted aqueous-phase exfoliation route from covalent organic frameworks. The soluble and belt-shaped iCONs could immobilize a large quantity of proteins (2.73 mg/mg, BSA/iCONs) and hence serve as transporters to enhance the protein uptake by cancer cells. Meanwhile, their energy-dependent endocytosis pathway via clathrin-coated pits has been proved as well. PMID- 29615681 TI - Emotion Regulation Compensation Following Situation Selection Failure. AB - We conducted two within-subjects experiments to determine whether people use alternative emotion regulation (ER) strategies to compensate for failure of situation selection, a form of ER in which one chooses situations based on the emotions those situations afford. Participants viewed negative and neutral (Study 1, N = 58) or negative, neutral, and positive pictures (Study 2, N = 90). They indicated for each picture whether they wanted to terminate presentation (Study 1) or view it again (Study 2). We manipulated the outcome of this decision to be congruent with participants' wishes (success) or not (failure), and measured self reported ER strategies and emotional responses. Although participants terminated negative situations more often than neutral situations (Study 1), or chose to view positive pictures more frequently than neutral, and neutral more frequently than negative (Study 2), there was little evidence of compensation in the wake of situation selection failure. Overall, we conclude that although people choose situations based on affect (i.e., attempt to end or avoid high-arousal negative situations and pursue high-arousal pleasant ones), they do not generally use the alternative ER strategies that we assessed (rumination, reappraisal, distraction) to compensate when the situations they select fail to materialize in this experimental context. PMID- 29615683 TI - Non-neutralizing Antibody Responses against VP1 in Enterovirus A, B, C and Rhinovirus A species among Infants and Children in Shanghai. AB - The overall non-neutralizing antibody responses against EV infections among infants and children remain unknown. The non-neutralizing antibody responses against VP1 of EV-A species (Enterovirus 71 (EV71), Coxsackievirus A16 (CA16)), EV-B species (Coxsackievirus B3 (CB3)), EV-C species (Poliovirus 1 (PV1)) and RV A species (Rhinovirus A N13 (RV13)) were detected and analyzed using a novel evolved immunoglobulin-binding molecule (NEIBM)-based ELISA among infants and children aged 1 day to 6 years in Shanghai. The anti-VP1 reactivity against these EVs changed similarly in an age-related dynamic: being high level in the 1-28-day age group, declining to the lowest level in the 1-12-month age group, gradually increasing to the peak level in the 13-60-month age group, and remarkably declining in the 61-72-month age group, which reflects the conversion from maternally-derived to primary antibody responses. The anti-RV13 VP1 antibodies were demonstrated at the highest level, with anti-CB3 and PV1 VP1 antibodies at the second highest level and anti-CA16 and EV71 VP1 antibodies at the lowest level. These findings are the first to describe the overall non-neutralizing antibody responses against VP1 of the EV-A, B, C and RV-A viruses among the infants and children and could be helpful for further understanding the ubiquitous EV infections among children. PMID- 29615682 TI - The p53-S100A2 Positive Feedback Loop Negatively Regulates Epithelialization in Cutaneous Wound Healing. AB - The S100A2 protein is an important regulator of keratinocyte differentiation, but its role in wound healing remains unknown. We establish epithelial-specific S100A2 transgenic (TG) mice and study its role in wound repair using punch biopsy wounding assays. In line with the observed increase in proliferation and migration of S100A2-depleted human keratinocytes, mice expressing human S100A2 exhibit delayed cutaneous wound repair. This was accompanied by the reduction of re-epithelialization as well as a slow, attenuated response of Mcp1, Il6, Il1beta, Cox2, and Tnf mRNA expression in the early phase. We also observed delayed Vegfa mRNA induction, a delayed enhancement of the Tgfbeta1-mediated alpha smooth muscle actin (alpha-Sma) axis and a differential expression of collagen type 1 and 3. The stress-activated p53 tumor suppressor protein plays an important role in cutaneous wound healing and is an S100A2 inducer. Notably, S100A2 complexes with p53, potentiates p53-mediated transcription and increases p53 expression both transcriptionally and posttranscriptionally. Consistent with a role of p53 in repressing NF-kappaB-mediated transcriptional activation, S100A2 enhanced p53-mediated promoter suppression of Cox2, an early inducible NF-kappaB target gene upon wound injury. Our study thus supports a model in which the p53 S100A2 positive feedback loop regulates wound repair process. PMID- 29615684 TI - A dynamic approach merging network theory and credit risk techniques to assess systemic risk in financial networks. AB - The interconnectedness of financial institutions affects instability and credit crises. To quantify systemic risk we introduce here the PD model, a dynamic model that combines credit risk techniques with a contagion mechanism on the network of exposures among banks. A potential loss distribution is obtained through a multi period Monte Carlo simulation that considers the probability of default (PD) of the banks and their tendency of defaulting in the same time interval. A contagion process increases the PD of banks exposed toward distressed counterparties. The systemic risk is measured by statistics of the loss distribution, while the contribution of each node is quantified by the new measures PDRank and PDImpact. We illustrate how the model works on the network of the European Global Systemically Important Banks. For a certain range of the banks' capital and of their assets volatility, our results reveal the emergence of a strong contagion regime where lower default correlation between banks corresponds to higher losses. This is the opposite of the diversification benefits postulated by standard credit risk models used by banks and regulators who could therefore underestimate the capital needed to overcome a period of crisis, thereby contributing to the financial system instability. PMID- 29615687 TI - Efficient decomposition methods for controlled-R n using a single ancillary qubit. AB - We consider decomposition for a controlled-R n gate with a standard set of universal gates. For this problem, a method exists that uses a single ancillary qubit to reduce the number of gates. In this work, we extend this method to three ends. First, we find a method that can decompose into fewer gates than the best known results in decomposition of controlled-R n . We also confirm that the proposed method reduces the total number of gates of the quantum Fourier transform. Second, we propose another efficient decomposition that can be mapped to a nearest-neighbor architecture with only local CNOT gates. Finally, we find a method that can minimize the depth to 5 gate steps in a nearest-neighbor architecture with only local CNOT gates. PMID- 29615686 TI - Lentiviral vector delivery of short hairpin RNA to NgR1 promotes nerve regeneration and locomotor recovery in injured rat spinal cord. AB - Nogo receptor 1 (NgR1) is a high-affinity receptor of myelin-associated inhibitors (MAIs), and suppresses neurogenesis. Lentiviral vector are commonly used to alter the expression of targeted genes. However, little is known about the potential function of lentiviral vector harboring NgR1 shRNA (LV-NgR1 shRNA) on neurogenesis in spinal cord injury (SCI). In this study, the rats were randomly divided into three groups: including the LN (LV-NgR1 shRNA injection), LC (LV-control shRNA injection) and Sham (laminectomy only). Eight weeks post injection of LV, spinal cords were examined by histology for changes in cavity size and by immunohistochemistry for changes in expression of NgR1, cell apoptosis, astrocytes, neurons and myelination. Motor function was assessed using the Basso, Beattie and Bresnahan (BBB) locomotor scale. Animals that received LV NgR1 shRNA remarkably improved the motor function. These animals also showed an increase in levels of nerve fibers, synapses and myelination, a decrease in levels of lesion cavity and cell apoptosis at 8 weeks post-treatment. These findings give evidence that NgR1 may be a promising target for SCI treatment. PMID- 29615685 TI - Genome-wide analysis of dirigent gene family in pepper (Capsicum annuum L.) and characterization of CaDIR7 in biotic and abiotic stresses. AB - The dirigent (DIR and DIR-like) proteins involved in lignification, play a pivotal role against biotic and abiotic stresses in plants. However, no information is available about DIR gene family in pepper (Capsicum annuum L.). In this study, 24 putative dirigent genes (CaDIRs) were identified, their gene structure, genome location, gene duplication and phylogenetic relationship were elucidated. Tissue-specific expression analysis displayed the highest transcription levels in flower, stem and leaf. Some CaDIRs were up-regulated by virulent (CaDIR2, 3, 6, 7, 11, 14, 16, 22 and 23) and avirulent (CaDIR3, 5, 7, 16, 20, 22, 23 and 24) Phytophthora capsici strains, as well as by Methyl jasmonate, salicylic acid, NaCl and mannitol stresses. Acid-soluble lignin content increased (103.21%) after P. capsici inoculation (48-hour). Silencing of CaDIR7 weakened plant defense by reducing (~50%) root activity and made plants more susceptible (35.7%) to P. capsici and NaCl (300 mM). Leaf discs of the CaDIR7:silenced plants exposed to NaCl and mannitol (300 mM each), exhibited a significant decrease (56.25% and 48% respectively) in the chlorophyll content. These results suggested that CaDIR7 is involved in pepper defense response against pathogen and abiotic stresses and the study will provide basic insights for future research regarding CaDIRs. PMID- 29615688 TI - On the spot: utilization of directional cues in vibrational communication of a stink bug. AB - Although vibrational signalling is among the most ancient and common forms of communication, many fundamental aspects of this communication channel are still poorly understood. Here, we studied mechanisms underlying orientation towards the source of vibrational signals in the stink bug Nezara viridula (Hemiptera, Pentatomidae), where female vibrational song enables male to locate her on the bean plant. At the junction between the main stem and the leaf stalks, male placed his legs on different sides of the branching and orientation at the branching point was not random. Analyses of signal transmission revealed that only a time delay between the arrival of vibrational wave to receptors located in the legs stretched across the branching was a reliable directional cue underlying orientation, since, unexpectedly, the signal amplitude at the branching point was often higher on the stalk away from the female. The plant and the position of the vibrational source on the plant were the most important factors influencing the unpredictability of the amplitude cue. Determined time delays as short as 0.5 ms resulted in marked changes in interneuron activity and the decision model suggests that the behavioural threshold is in the range between 0.3 and 0.5 ms. PMID- 29615689 TI - Involvement of RSK1 activation in malformin-enhanced cellular fibrinolytic activity. AB - Pharmacological interventions to enhance fibrinolysis are effective for treating thrombotic disorders. Utilizing the in vitro U937 cell line-based fibrin degradation assay, we had previously found a cyclic pentapeptide malformin A1 (MA1) as a novel activating compound for cellular fibrinolytic activity. The mechanism by which MA1 enhances cellular fibrinolytic activity remains unknown. In the present study, we show that RSK1 is a crucial mediator of MA1-induced cellular fibrinolysis. Treatment with rhodamine-conjugated MA1 showed that MA1 localizes mainly in the cytoplasm of U937 cells. Screening with an antibody macroarray revealed that MA1 induces the phosphorylation of RSK1 at Ser380 in U937 cells. SL0101, an inhibitor of RSK, inhibited MA1-induced fibrinolytic activity, and CRISPR/Cas9-mediated knockout of RSK1 but not RSK2 suppressed MA1 enhanced fibrinolysis in U937 cells. Synthetic active MA1 derivatives also induced the phosphorylation of RSK1. Furthermore, MA1 treatment stimulated phosphorylation of ERK1/2 and MEK1/2. PD98059, an inhibitor of MEK1/2, inhibited MA1-induced phosphorylation of RSK1 and ERK1/2, indicating that MA1 induces the activation of the MEK-ERK-RSK pathway. Moreover, MA1 upregulated the expression of urokinase-type plasminogen activator (uPA) and increased uPA secretion. These inductions were abrogated in RSK1 knockout cells. These results indicate that RSK1 is a key regulator of MA1-induced extracellular fibrinolytic activity. PMID- 29615690 TI - Porphyrins inactivate Nosema spp. microsporidia. AB - The study of organic/inorganic molecules with activity against intracellular fungi of the phylum Microsporidia is of critical importance. Here, for the first time, the inactivation of these parasitic fungi by porphyrins is reported. The biological effects of porphyrins (10 uM and 100 uM) on the microsporidian Nosema ceranae was investigated in honeybee hosts using cage experiments. A significant reduction in the number of spores (from 2.6 to 5 fold) was observed in Nosema infected honeybees with a sucrose-protoporphyrin amide [PP(Asp)2] syrup diet compared to the control honeybees. PP(Asp)2 and the other porphyrin examined in vitro, TMePyP, had a direct impact on the microsporidia. Notably, neither porphyrin requires light excitation to be active against microsporidia. Moreover, microsporidia preincubated with these porphyrins exhibited decreased ability to infect honeybees. In particular, PP(Asp)2, possessing amphiphilic characteristics, exhibited significant inactivation of microsporidia, preventing the development of the microsporidia and diminishing the mortality of infected honeybees. In addition, the porphyrin-treated spores examined by scanning electron microscopy (SEM) showed morphological changes in their exosporium layers, which were distinctly deformed. Thus, we postulate that the mechanism of action of porphyrins on microsporidia is not based on photodynamic inactivation but on the destruction of the cell walls of the spores. PMID- 29615692 TI - An Inverse Optimal Control Approach to Explain Human Arm Reaching Control Based on Multiple Internal Models. AB - Human motor control is highly efficient in generating accurate and appropriate motor behavior for a multitude of tasks. This paper examines how kinematic and dynamic properties of the musculoskeletal system are controlled to achieve such efficiency. Even though recent studies have shown that the human motor control relies on multiple models, how the central nervous system (CNS) controls this combination is not fully addressed. In this study, we utilize an Inverse Optimal Control (IOC) framework in order to find the combination of those internal models and how this combination changes for different reaching tasks. We conducted an experiment where participants executed a comprehensive set of free-space reaching motions. The results show that there is a trade-off between kinematics and dynamics based controllers depending on the reaching task. In addition, this trade-off depends on the initial and final arm configurations, which in turn affect the musculoskeletal load to be controlled. Given this insight, we further provide a discomfort metric to demonstrate its influence on the contribution of different inverse internal models. This formulation together with our analysis not only support the multiple internal models (MIMs) hypothesis but also suggest a hierarchical framework for the control of human reaching motions by the CNS. PMID- 29615691 TI - Effects of Intestinal Microbiota on Brain Development in Humanized Gnotobiotic Mice. AB - Poor growth in the Neonatal Intensive Care Unit is associated with an increased risk for poor neurodevelopmental outcomes for preterm infants, however the mechanism is unclear. The microbiome has increasingly been recognized as a modifiable environmental factor to influence host development. Here we explore the hypothesis that the microbiome influences both growth phenotype and brain development. A germ free mouse transfaunation model was used to examine the effects of preterm infant microbiotas known to induce either high growth or low growth phenotypes on postnatal brain development. The microbiome which induced the low growth phenotype was associated with decreases in the neuronal markers NeuN and neurofilament-L as well as the myelination marker MBP when compared to the microbiome associated with the high growth phenotype. Additionally, poor growth phenotype-associated microbiota was associated with increased neuroinflammation marked by increased Nos1, as well as alteration in IGF-1 pathway including decreased circulating and brain IGF-1, decreased circulating IGFBP3, and increased Igfbp3 brain mRNA expression. This study suggests that growth-associated microbiota can influence early neuron and oligodendrocyte development and that this effect may be mediated by effects on neuroinflammation and circulating IGF-1. PMID- 29615693 TI - Micro-epidemiology of mixed-species malaria infections in a rural population living in the Colombian Amazon region. AB - Malaria outbreaks have been reported in recent years in the Colombian Amazon region, malaria has been re-emerging in areas where it was previously controlled. Information from malaria transmission networks and knowledge about the population characteristics influencing the dispersal of parasite species is limited. This study aimed to determine the distribution patterns of Plasmodium vivax, P. malariae and P. falciparum single and mixed infections, as well as the significant socio-spatial groupings relating to the appearance of such infections. An active search in 57 localities resulted in 2,106 symptomatic patients being enrolled. Parasitaemia levels were assessed by optical microscopy, and parasites were detected by PCR. The association between mixed infections (in 43.2% of the population) and socio-spatial factors was modelled using logistic regression and multiple correspondence analyses. P. vivax occurred most frequently (71.0%), followed by P. malariae (43.2%), in all localities. The results suggest that a parasite density-dependent regulation model (with fever playing a central role) was appropriate for modelling the frequency of mixed species infections in this population. This study highlights the under-reporting of Plasmodium spp. mixed infections in the malaria-endemic area of the Colombian Amazon region and the association between causative and environmental factors in such areas. PMID- 29615694 TI - Filamentous Virus-based Assembly: Their Oriented Structures and Thermal Diffusivity. AB - Organic polymers are generally regarded as thermal insulators because amorphous arrangement of molecular chains reduces the mean free path of heat-conducting phonons. However, recent studies indicated that single chains of polymers with highly oriented structures could have high thermal conductivity than bulk polymers because stretched polymer chains effectively conduct phonons through polymeric covalent bonds. Here, we demonstrated the possibility of non-covalent virus assembly prepared by simple flow-induced methods toward high thermal conductive polymeric materials. Films with high thermal diffusivity composed of non-covalent bond-based assemblies of liquid crystalline filamentous viruses were prepared using a simple flow-induced orientation method. Structural and thermal characterization demonstrated that highly oriented structures of the viruses in the film were attributed to the high thermal diffusivity. Our results will open attractive opportunities for biomolecular-based thermally conductive soft materials even though the assemblies are based on non-covalent bonds. PMID- 29615695 TI - GLYI and D-LDH play key role in methylglyoxal detoxification and abiotic stress tolerance. AB - Methylglyoxal(MG) is a potent cytotoxin that is produced as a byproduct of various metabolic reactions in the cell. The major enzymes for MG detoxification are Glyoxalase I(GLYI), Glyoxalase II(GLYII) and D-lactate dehydrogenase(D-LDH). These three enzymes work together and convert MG into D-pyruvate, which directly goes to TCA cycle. Here, a comparative study of the ability of MG detoxification of these three enzymes has been done in both E. coli and yeast. Ectopic expression of these three genes from Arabidopsis in E. coli in presence of different abiotic stress revealed the contribution of each of these genes in detoxifying MG. Yeast mutants of MG detoxification enzymes were also grown in different stress conditions to record the effect of each gene. These mutants were also used for complementation assays using the respective MG detoxifying genes from Arabidopsis in presence of various stress conditions. The MG content and the corresponding growth of cells was measured in all the bacterial as well as yeast strains. This study reveals differential contribution of MG detoxification enzymes in mitigating MG levels and alleviating stress in both prokaryotes as well as eukaryotes. GLYI and D-LDH were found to be key enzymes in MG detoxification under various abiotic stresses. PMID- 29615696 TI - Synthesis of inverse ringwoodite sheds light on the subduction history of Tibetan ophiolites. AB - Tibetan ophiolites are shallow mantle material and crustal slabs that were subducted as deep as the mantle transition zone, a conclusion supported by the discovery of high-pressure phases like inverse ringwoodite in these sequences. Ringwoodite, Mg2SiO4, exhibits the normal spinel structure, with Mg in the octahedral A site and Si in the tetrahedral B site. Through A and B site disorder, the inverse spinel has four-coordinated A cations and the six coordinated site hosts a mixture of A and B cations. This process affects the density and impedance contrasts across the boundaries in the transition zone and seismic-wave velocities in this portion of the Earth. We report the first synthesis at high pressure (20 GPa) and high temperature (1600 degrees C) of a Cr-bearing ringwoodite with a completely inverse-spinel structure. Chemical, structural, and computational analysis confirm the stability of inverse ringwoodite and add further constraints to the subduction history of the Luobusa peridotite of the Tibetan ophiolites. PMID- 29615697 TI - Fathers' eye colour sways daughters' choice of both long- and short-term partners. AB - In several species, mate choice is influenced by parental features through sexual imprinting, but in humans evidence is scarce and open to alternative explanations. We examined whether daughters' preference for mates with light vs dark eyes is affected by the eye colour of parents. In an online study, over one thousand women rated the attractiveness of men as potential partners for either a long- or a short-term relationship. Each male face was shown twice, with light (blue or green) and with dark (brown or dark brown) eyes. Having a light-eyed father increased the preference for light-eyed men in both relationship contexts. Having light eyes increased this preference too, but only when men were regarded as potential long-term companions. Asymmetrically, in real life, father's eye colour was the only predictor of partner's eye colour; own colour was irrelevant. Mother's eye colour never mattered, affecting neither preferences nor real-life choices. The effect of paternal eye colour was modulated by the quality of the relationship between father and daughter, suggesting (flexible) sexual imprinting rather than a simple inheritance of maternal preferences. Our data provide evidence that in humans, as in birds and sheep, visual experience of parental features shapes later sexual preferences. PMID- 29615699 TI - Using bivalve chronologies for quantifying environmental drivers in a semi enclosed temperate sea. AB - Annual growth increments formed in bivalve shells are increasingly used as proxies of environmental variability and change in marine ecosystems, especially at higher latitudes. Here, we document that well-replicated and exactly dated chronologies can also be developed to capture oceanographic processes in temperate and semi-enclosed seas, such as the Mediterranean. A chronology is constructed for Glycymeris pilosa from a shallow embayment of the northern Adriatic and extends from 1979 to 2016. The chronology significantly (p < 0.05) and positively correlates to winter sea surface temperatures, but negatively correlates to summer temperatures, which suggests that extreme winter lows and extreme summer highs may be limiting to growth. However, the strongest and most consistent relationships are negative correlations with an index of the Adriatic Ionian Bimodal Oscillating System (BiOS) for which positive values indicate the inflow of the ultraoligotrophic Eastern Mediterranean waters to the Adriatic. In contrast, the substantial freshwater flows that discharge into the Adriatic do not correlate to the bivalve chronology, emphasizing the importance of remote oceanographic processes to growth at this highly coastal site. Overall, this study underscores the potential of bivalve chronologies to capture biologically relevant, local- to regional-scale patterns of ocean circulation in mid-latitude, temperate systems. PMID- 29615698 TI - Characterization of two novel mycoviruses from Penicillium digitatum and the related fungicide resistance analysis. AB - Pathogenic fungi including Penicillium digitatum and Penicillium italicum are the main destructive pathogens in the citrus industry, causing great losses during postharvest process. To our knowledge, only one mycovirus from P. digitatum has been reported, and the prevalence of such mycoviruses against citrus postharvest pathogenic fungi and their genotyping were still under investigation. In the present study, we showed that 39 of 152 Penicillium isolates from main citrus growing areas in China were infected with various mycoviruses belonging to polymycoviruses, Narna-like viruses, and families Totiviridae, Partitivirdae and Chrysoviridae. The next generation sequencing (NGS) towards virus genome library and the following molecular analysis revealed two novel mycoviruses Penicillium digitatum polymycovirus 1 (PdPmV1) and Penicillium digitatum Narna-like virus 1 (PdNLV1), coexisting in P. digitatum strain HS-RH2. The fungicide-resistant P. digitatum strains HS-F6 and HS-E9 coinfected by PdPmV1 and PdNLV1 exhibited obvious reduction in triazole drug prochloraz resistance by mycelial growth analysis on both PDA plates and citrus fruit epidermis with given prochloraz concentration. This report at the first time characterized two novel mycoviruses from P. digitatum and revealed the mycovirus-induced reduction of fungicide resistance. PMID- 29615700 TI - Affinity maturation of humanized anti-epidermal growth factor receptor antibody using a modified phage-based open sandwich selection method. AB - Affinity maturation is one of the cardinal strategies for improving antibody function using in vitro evolutionary methods; one such well-established method is phage display. To minimise gene deletion, we previously developed an open sandwich (OS) method wherein selection was performed using only phage-displaying VH fragments after mixing with soluble VL fragments. The decrease in anti-EGFR antibody 528 affinity through humanization was successfully recovered by selecting VH mutants using this OS method. However, the affinity was not similar to that of parental 528. For further affinity maturation, we aimed to isolate VL mutants that act in synergy with VH mutants. However, the OS method could not be applied for selecting VL fragments because the preparation of soluble VH fragments was hampered by their instability and insolubility. Therefore, we initially designed a modified OS method based on domain-swapping of VH fragments, from added soluble Fv fragments to phage-displaying VL fragments. Using this novel Fv-added OS selection method, we successfully isolated VL mutants, and one of the Fv comprising VH and VL mutants showed affinity almost equivalent to that of parental 528. This method is applicable for engineering other VL fragments for affinity maturation. PMID- 29615701 TI - Diffusion-localization transition caused by nonlinear transport on complex networks. AB - We analyzed nonlinear transport as defined for directed complex networks, where the flux from one node to a neighboring node is given preferentially according to the scalar quantities at the neighbor nodes. This is known as the generalized gravity interaction. In our research, we discovered a novel phase transition type. In the diffusion phase, the scalar quantity is scattered over the whole system, whereas in the localization phase, the flow tends to form localized confluence patterns owing to nonlinearity, resulting in the appearance of special nodes that irreversibly attract huge amounts of flow. We analytically considered the transition for selected network configurations, demonstrating that the transition point depends on the network topology. We also demonstrated that the diffusion phase of this transport model fits well with data from business firms, implying that the whole network structure can be used to model money flow in the real world. PMID- 29615702 TI - Global Proteomics Deciphered Novel-Function of Osthole Against Pulmonary Arterial Hypertension. AB - Pulmonary arterial hypertension (PAH) is a progressive cardiovascular-disease with high mortality lacking high-efficiency drug. Our efforts attempted to delineate therapeutic action of osthole produced by Angelica Pubescens Maxim, which has the capacity to treat PAH by exploiting an iTRAQ-based proteomic method. Excitingly, osthole was observed to significantly restore 98 of 315 differential proteins significantly modified by PAH progression. They were primarily annotated into 24 signaling pathways. Four mostly affected proteins (RPL15, Cathepsin S, Histone H3.3 and HMGB1) were experimentially validated which belonged to ribosome pathway, oxidative phosphorylation pathway, systemic lupus erythematosus pathway, complement and coagulation cascades pathway, whose modifications and modulations mostly accounted for therapeutic capacity of this compound against PAH. Altogether, our findings demonstrated that global proteomics is a promising systems-biology approach for deciphering therapeutic actions and associated mechanisms of natural products derived from traditional Chinese medicine. Importantly, osthole is supposed to be a candidate compound for new drug development to treat PAH. PMID- 29615703 TI - Foxn1 expression in keratinocytes is stimulated by hypoxia: further evidence of its role in skin wound healing. AB - Recent studies have shown that the transcription factor Foxn1, which is expressed in keratinocytes, is involved in the skin wound healing process, yet how Foxn1 functions remains largely unknown. Our latest data indicate that Foxn1 drives skin healing via engagement in re-epithelization and the epithelial-mesenchymal transition (EMT) process. In the present study, 2D-DIGE proteomic profiling analysis of in vitro cultured keratinocytes transfected with adenoviral vector carrying Foxn1-GFP or GFP alone (control) revealed forty proteins with differential abundance between the compared groups. Among the proteins with Foxn1 dependent expression, several enable adaptation to hypoxia. Subsequent experiments revealed that hypoxic conditions (1% O2) stimulate endogenous and exogenous (transfected Ad-Foxn1) Foxn1 expression in cultured keratinocytes. A proteomics analysis also identified proteins that can act as a factors controlling the balance between cell proliferation, differentiation and apoptosis in response to Foxn1. We also showed that in C57BL/6 keratinocytes, the stimulation of Foxn1 by hypoxia is accompanied by increases in Mmp-9 expression. These data corroborate the detected co-localization of Foxn1 and Mmp-9 expression in vivo in post-wounding skin samples of Foxn1::Egfp transgenic mice. Together, our data indicate that Foxn1 orchestrates cellular changes in keratinocytes in both physiological (self-renewal) and pathological (skin wound healing) contexts. PMID- 29615704 TI - Virtual screening, Docking, ADMET and System Pharmacology studies on Garcinia caged Xanthone derivatives for Anticancer activity. AB - Caged xanthones are bioactive compounds mainly derived from the Garcinia genus. In this study, a structure-activity relationship (SAR) of caged xanthones and their derivatives for anticancer activity against different cancer cell lines such as A549, HepG2 and U251 were developed through quantitative (Q)-SAR modeling approach. The regression coefficient (r2), internal cross-validation regression coefficient (q2) and external cross-validation regression coefficient (pred_r2) of derived QSAR models were 0.87, 0.81 and 0.82, for A549, whereas, 0.87, 0.84 and 0.90, for HepG2, and 0.86, 0.83 and 0.83, for U251 respectively. These models were used to design and screened the potential caged xanthone derivatives. Further, the compounds were filtered through the rule of five, ADMET-risk and synthetic accessibility. Filtered compounds were then docked to identify the possible target binding pocket, to obtain a set of aligned ligand poses and to prioritize the predicted active compounds. The scrutinized compounds, as well as their metabolites, were evaluated for different pharmacokinetics parameters such as absorption, distribution, metabolism, excretion, and toxicity. Finally, the top hit compound 1G was analyzed by system pharmacology approaches such as gene ontology, metabolic networks, process networks, drug target network, signaling pathway maps as well as identification of off-target proteins that may cause adverse reactions. PMID- 29615705 TI - GDNF-expressing macrophages mitigate loss of dopamine neurons and improve Parkinsonian symptoms in MitoPark mice. AB - Glial cell line-derived neurotrophic factor (GDNF) is the most potent neuroprotective agent tested in cellular and animal models of Parkinson's disease (PD). However, CNS delivery of GDNF is restricted by the blood-brain barrier (BBB). Using total body irradiation as transplant preconditioning, we previously reported that hematopoietic stem cell (HSC) transplantation (HSCT)-based macrophage-mediated gene therapy could deliver GDNF to the brain to prevent degeneration of nigrostriatal dopamine (DA) neurons in an acute murine neurotoxicity model. Here, we validate this therapeutic approach in a chronic progressive PD model - the MitoPark mouse, with head shielding to avoid inducing neuroinflammation and compromising BBB integrity. Bone marrow HSCs were transduced ex vivo with a lentiviral vector expressing macrophage promoter-driven GDNF and transplanted into MitoPark mice exhibiting well developed PD-like impairments. Transgene-expressing macrophages infiltrated the midbrains of MitoPark mice, but not normal littermates, and delivered GDNF locally. Macrophage GDNF delivery markedly improved both motor and non-motor symptoms, and dramatically mitigated the loss of both DA neurons in the substantia nigra and tyrosine hydroxylase-positive axonal terminals in the striatum. Our data support further development of this HSCT-based macrophage-mediated GDNF delivery approach in order to address the unmet need for a disease-modifying therapy for PD. PMID- 29615706 TI - Analysis of the CaMKIIalpha and beta splice-variant distribution among brain regions reveals isoform-specific differences in holoenzyme formation. AB - Four CaMKII isoforms are encoded by distinct genes, and alternative splicing within the variable linker-region generates additional diversity. The alpha and beta isoforms are largely brain-specific, where they mediate synaptic functions underlying learning, memory and cognition. Here, we determined the alpha and beta splice-variant distribution among different mouse brain regions. Surprisingly, the nuclear variant alphaB was detected in all regions, and even dominated in hypothalamus and brain stem. For CaMKIIbeta, the full-length variant dominated in most regions (with higher amounts of minor variants again seen in hypothalamus and brain stem). The mammalian but not fish CaMKIIbeta gene lacks exon v3N that encodes the nuclear localization signal in alphaB, but contains three exons not found in the CaMKIIalpha gene (exons v1, v4, v5). While skipping of exons v1 and/or v5 generated the minor splice-variants beta', betae and betae', essentially all transcripts contained exon v4. However, we instead detected another minor splice-variant (now termed betaH), which lacks part of the hub domain that mediates formation of CaMKII holoenzymes. Surprisingly, in an optogenetic cellular assay of protein interactions, CaMKIIbetaH was impaired for binding to the beta hub domain, but still bound CaMKIIalpha. This provides the first indication for isoform-specific differences in holoenzyme formation. PMID- 29615707 TI - A quantum mechanical computational method for modeling electrostatic and solvation effects of protein. AB - An efficient computational approach for modeling protein electrostatic is developed according to static point-charge model distributions based on the linear-scaling EE-GMFCC (electrostatically embedded generalized molecular fractionation with conjugate caps) quantum mechanical (QM) method. In this approach, the Electrostatic-Potential atomic charges are obtained from ab initio calculation of protein, both polarization and charge transfer effect are taken into consideration. This approach shows a significant improvement in the description of electrostatic potential and solvation energy of proteins comparing with current popular molecular mechanics (MM) force fields. Therefore, it has gorgeous prospect in many applications, including accurate calculations of electric field or vibrational Stark spectroscopy in proteins and predicting protein-ligand binding affinity. It can also be applied in QM/MM calculations or electronic embedding method of ONIOM to provide a better electrostatic environment. PMID- 29615708 TI - Genomic diversity in ochratoxigenic and non ochratoxigenic strains of Aspergillus carbonarius. AB - Ochratoxin A (OTA) is a mycotoxin with nephrotoxic effects on animals and humans. Aspergillus carbonarius is the main responsible for OTA contamination of grapes and derived products. We present the genome resequencing of four A. carbonarius strains, one OTA producer and three atypical and unique non-OTA producing strains. These strains were sequenced using Illumina technology and compared with a reference genome of this species. We performed some specific bioinformatics analyses in genes involved in OTA biosynthesis. Data obtained in this study revealed the high genomic diversity within A. carbonarius strains. Although some gaps of more than 1,000 bp were identified in non-ochratoxigenic strains, no large deletions in functional genes related with OTA production were found. Moreover, the expression of five genes of the putative OTA biosynthetic cluster was down regulated under OTA-inducing conditions in the non-ochratoxigenic strains. Knowledge of the regulatory mechanisms involved in OTA biosynthesis will provide a deeper understanding of these non-ochratoxigenic strains. PMID- 29615709 TI - In-situ Observation of Hierarchical Self-Assembly Driven by Bicontinuous Gelation in Mixed Nanodisc Dispersions. AB - The search for new functional soft materials with precise and reconfigurable structures at the nano and meso-scale is a major challenge as well as objective of the current science. Patchy colloids of different shapes and functionalities are considered important new building blocks of a bottom-up approach towards rational design of new soft materials largely governed by anisotropic interactions. Herein, we investigate the self-assembly, growth of hierarchical microstructures and aging dynamics of 2D nano-platelets of two different aspect ratios (Laponite ~25 and Montmorillonite ~250) which form gels with different porosity that is achieved by tuning their mixing ratios. Qualitative in situ real space studies are carried out, including fluorescent confocal microscopy imaging of the bicontinuous gelation process or final states, which provides dynamic visualization of the self-organization. The bicontinuous gels exhibit a foam-like morphology having pores of a few micrometers in size that can be tuned by varying the mixing ratio of nanoplatelets. It is shown that this new class of clay gels has unique and tunable physical properties that will find potential applications in the development of low cost lithium ion batteries, nanocomposites and nuclear waste management. PMID- 29615710 TI - Entropic effect of macromolecular crowding enhances binding between nucleosome clutches in heterochromatin, but not in euchromatin. AB - Sharp increase in macromolecular crowding induces abnormal chromatin compaction in the cell nucleus, suggesting its non-negligible impact on chromatin structure and function. However, the details of the crowding-induced chromatin compaction remain poorly understood. In this work, we present a computer simulation study on the entropic effect of macromolecular crowding on the interaction between chromatin structural units called nucleosome clutches. Nucleosome clutches were modeled by a chain of nucleosomes collapsed by harmonic restraints implicitly mimicking the nucleosome association mediated by histone tails and linker histones. The nucleosome density of the clutches was set close to either that of high-density heterochromatin or that of low-density euchromatin. The effective interactions between these nucleosome clutches were calculated in various crowding conditions, and it was found that the increase in the degree of macromolecular crowding induced attractive interaction between two clutches with high nucleosome density. Interestingly, the increased degree of macromolecular crowding did not induce any attraction between two clutches with low nucleosome density. Our results suggest that the entropic effect of macromolecular crowding can enhance binding between nucleosome clutches in heterochromatin, but not in euchromatin, as a result of the difference in nucleosome packing degrees. PMID- 29615711 TI - Relation between colour- and phase changes of a leuco dye-based thermochromic composite. AB - Reversible colour change of leuco dye-based composites is in general closely related to their phase change, thus the two phenomena should occur at around the same temperature and should be influenced similarly. However, spatial confinement of the analysed sample affects the change in colour differently compared to its phase transition and the most pronounced effects can be observed during cooling. The bulk composite is coloured while still liquid and the colour hysteresis does not exhibit a loop. In an open-porous medium the colouration coincides well with the crystallization and the colour hysteresis widens to about 4 degrees C. Microencapsulated composite exhibits two crystallization processes, one of them taking place at the bulk crystallization temperature and the other one at about 20 degrees C lower. Under such conditions the composite is coloured just before the onset of the second crystallization, i.e. about 15 degrees C below crystallization in the bulk, and the corresponding colour hysteresis widens to 18 degrees C. The two crystallization forms are thermally independent and have the same crystalline structure. These effects should be taken into account when designing future applications where the phase-changing materials are implemented. PMID- 29615712 TI - Biomimetic Moth-eye Nanofabrication: Enhanced Antireflection with Superior Self cleaning Characteristic. AB - Sub-wavelength antireflection moth-eye structures were fabricated with Nickel mold using Roll-to-Plate (R2P) ultraviolet nanoimprint lithography (UV-NIL) on transparent polycarbonate (PC) substrates. Samples with well replicated patterns established an average reflection of 1.21% in the visible light range, 380 to 760 nm, at normal incidence. An excellent antireflection property of a wide range of incidence angles was shown with the average reflection below 4% at 50 degrees . Compared with the unpatterned ultraviolet-curable resin coating, the resulting sub-wavelength moth-eye structure also exhibited increased hydrophobicity in addition to antireflection. This R2P method is especially suitable for large-area product preparation and the biomimetic moth-eye structure with multiple performances can be applied to optical devices such as display screens, solar cells, or light emitting diodes. PMID- 29615714 TI - A behavioral approach to shared mapping of peripersonal space between oneself and others. AB - Recent physiological studies have showed that some visuotactile brain areas respond to other's peripersonal spaces (PPS) as they would their own. This study investigates this PPS remapping phenomenon in terms of human behavior. Participants placed their left hands on a tabletop screen where visual stimuli were projected. A vibrotactile stimulator was attached to the tip of their index finger. While a white disk approached or receded from the hand in the participant's near or far space, the participant was instructed to quickly detect a target (vibrotactile stimulation, change in the moving disk's color or both). When performing this task alone, the participants exhibited shorter detection times when the disk approached the hand in their near space. In contrast, when performing the task with a partner across the table, the participants exhibited shorter detection times both when the disk approached their own hand in their near space and when it approached the partner's hand in the partner's near space but the participants' far space. This phenomenon was also observed when the body parts from which the visual stimuli approached/receded differed between the participant and partner. These results suggest that humans can share PPS representations and/or body-derived attention/arousal mechanisms with others. PMID- 29615713 TI - Targeted expression of step-function opsins in transgenic rats for optogenetic studies. AB - Rats are excellent animal models for experimental neuroscience. However, the application of optogenetics in rats has been hindered because of the limited number of established transgenic rat strains. To accomplish cell-type specific targeting of an optimized optogenetic molecular tool, we generated ROSA26/CAG floxed STOP-ChRFR(C167A)-Venus BAC rats that conditionally express the step function mutant channelrhodopsin ChRFR(C167A) under the control of extrinsic Cre recombinase. In primary cultured cortical neurons derived from this reporter rat, only Cre-positive cells expressing ChRFR(C167A) became bi-stable, that is, their excitability was enhanced by blue light and returned to the baseline by yellow~red light. In bigenic pups carrying the Phox2B-Cre driver, ChRFR(C167A) was specifically expressed in the rostral parafacial respiratory group (pFRG) in the medulla, where endogenous Phox2b immunoreactivity was detected. These neurons were sensitive to blue light with an increase in the firing frequency. Thus, this transgenic rat actuator/reporter system should facilitate optogenetic studies involving the effective in vivo manipulation of the activities of specific cell fractions using light of minimal intensity. PMID- 29615715 TI - Blocking interleukin-4 enhances efficacy of vaccines for treatment of opioid abuse and prevention of opioid overdose. AB - Vaccines offer an option to treat heroin and prescription opioid abuse and prevent fatal overdoses. Opioid vaccines elicit antibodies that block opioid distribution to the brain and reduce opioid-induced behavioral effects and toxicity. The major limitation to the translation of addiction vaccines is that efficacy is observed only in subjects achieving optimal drug-specific serum antibody levels. This study tested whether efficacy of a vaccine against oxycodone is increased by immunomodulators targeting key cytokine signaling pathways involved in B and T cell lymphocyte activation. Blockage of IL-4 signaling increased vaccine efficacy in blocking oxycodone distribution to the brain and protection against opioid-induced behavior and toxicity in mice. This strategy generalized to a peptide-protein conjugate immunogen, and a tetanus diphtheria-pertussis vaccine. These data demonstrate that cytokine-based immunomodulators increase efficacy of vaccines against small molecules, peptides and proteins, and identify IL-4 as a pharmacological target for improving efficacy of next-generation vaccines. PMID- 29615716 TI - A multi-step transcriptional cascade underlies vascular regeneration in vivo. AB - The molecular mechanisms underlying vascular regeneration and repair are largely unknown. To gain insight into this process, we developed a method of intima denudation, characterized the progression of endothelial healing, and performed transcriptome analysis over time. Next-generation RNA sequencing (RNAseq) provided a quantitative and unbiased gene expression profile during in vivo regeneration following denudation injury. Our data indicate that shortly after injury, cells immediately adjacent to the wound mount a robust and rapid response with upregulation of genes like Jun, Fos, Myc, as well as cell adhesion genes. This was quickly followed by a wave of proliferative genes. After completion of endothelial healing a vigorous array of extracellular matrix transcripts were upregulated. Gene ontology enrichment and protein network analysis were used to identify transcriptional profiles over time. Further data mining revealed four distinct stages of regeneration: shock, proliferation, acclimation, and maturation. The transcriptional signature of those stages provides insight into the regenerative machinery responsible for arterial repair under normal physiologic conditions. PMID- 29615717 TI - Age is reflected in the Fractal Dimensionality of MRI Diffusion Based Tractography. AB - Fractal analysis is a widely used tool to analyze the geometrical complexity of biological structures. The geometry of natural objects such as plants, clouds, cellular structures, blood vessel, and many others cannot be described sufficiently with Euclidian geometric properties, but can be represented by a parameter called the fractal dimension. Here we show that a specific estimate of fractal dimension, the correlation dimension, is able to describe changes in the structural complexity of the human brain, based on data from magnetic resonance diffusion imaging. White matter nerve fiber bundles, represented by tractograms, were analyzed with regards to geometrical complexity, using fractal geometry. The well-known age-related change of white matter tissue was used to verify changes by means of fractal dimension. Structural changes in the brain were successfully be observed and quantified by fractal dimension and compared with changes in fractional anisotropy. PMID- 29615718 TI - Genetic abrogation of immune checkpoints in antigen-specific cytotoxic T lymphocyte as a potential alternative to blockade immunotherapy. AB - T cell function can be compromised during chronic infections or through continuous exposure to tumor antigens by the action of immune checkpoint receptors, such as programmed cell death protein 1 (PD-1). Systemic administration of blocking antibodies against the PD-1 pathway can restore T cell function, and has been approved for the treatment of several malignancies, although there is a risk of adverse immune-related side-effects. We have developed a method for generating gene knockouts in human antigen (Ag)-specific cytotoxic T-Lymphocyte (CTLs) using clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) genome editing. Using this method, we generated several transduced CD4+ or CD8+ antigen-specific polyclonal CTL lines and clones, and validated gene modifications of the PD-1 gene. We compared these T-cell lines and clones with control groups in the presence of programmed death-ligand 1 (PD-L1) and observed improved effector functions in the PD1-disrupted cell group. Overall, we have developed a versatile tool for functional genomics in human antigen-specific CTL studies. Furthermore, we provide an alternative strategy for current cell-based immunotherapy that will minimize the side effects caused by antibody blockade therapy. PMID- 29615719 TI - State-dependent representation of stimulus-evoked activity in high-density recordings of neural cultures. AB - Neuronal responses to external stimuli vary from trial to trial partly because they depend on continuous spontaneous variations of the state of neural circuits, reflected in variations of ongoing activity prior to stimulus presentation. Understanding how post-stimulus responses relate to the pre-stimulus spontaneous activity is thus important to understand how state dependence affects information processing and neural coding, and how state variations can be discounted to better decode single-trial neural responses. Here we exploited high-resolution CMOS electrode arrays to record simultaneously from thousands of electrodes in in vitro cultures stimulated at specific sites. We used information-theoretic analyses to study how ongoing activity affects the information that neuronal responses carry about the location of the stimuli. We found that responses exhibited state dependence on the time between the last spontaneous burst and the stimulus presentation and that the dependence could be described with a linear model. Importantly, we found that a small number of selected neurons carry most of the stimulus information and contribute to the state-dependent information gain. This suggests that a major value of large-scale recording is that it individuates the small subset of neurons that carry most information and that benefit the most from knowledge of its state dependence. PMID- 29615720 TI - Involvement of AMP-activated protein kinase and Death Receptor 5 in TRAIL Berberine-induced apoptosis of cancer cells. AB - Our previous studies indicated that combination of Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and PPARgamma ligand Troglitazone (TZD), can induce significant apoptosis in various TRAIL-resistant prostate and hepatocellular carcinoma (HCC) cells. These also suggested serine/threonine kinase AMP-activated protein kinase (AMPK) to be a mediator of TRAIL-TZD-induced apoptosis. To further validate AMPK's role in TRAIL sensitization, we determined the apoptotic potential of TRAIL in combination with the natural compound Berberine (BBR), the latter being a potent activator of AMPK. These demonstrated a significant reduction of cell viability and induction of apoptosis (increased cleavage of caspase 3, 8, 9) when treated with TRAIL-BBR combination. This apoptosis is attenuated in cells overexpressing AMPKalpha-dominant negative (DN) or following AMPKalpha knockdown, confirming involvement of AMPK. To identify potential downstream mediators involved, an apoptosis RT2 PCR array analysis was performed. These showed induction of several genes including TNFRSF10B (expresses DR5) and Harakiri following BBR treatment, which were further validated by qPCR analysis. Furthermore, knocking down DR5 expression significantly attenuated TRAIL-BBR-induced apoptosis, suggesting DR5 to be a mediator of this apoptosis. Our studies indicate that combination of TRAIL and AMPK activator BBR might be an effective means of ameliorating TRAIL-resistance involving DR5 in advanced cancer. PMID- 29615721 TI - Structural basis of interaction between dimeric cyclophilin 1 and Myb1 transcription factor in Trichomonas vaginalis. AB - Cyclophilin 1 (TvCyP1), a cyclophilin type peptidyl-prolyl isomerase present in the human parasite Trichomonas vaginalis, interacts with Myb1 and assists in its nuclear translocation. Myb1 regulates the expression of ap65-1 gene that encodes for a disease causing cytoadherence enzyme. Here, we determined the crystal structures of TvCyP1 and its complex with the minimum TvCyP1-binding sequence of Myb1 (Myb1104-111), where TvCyP1 formed a homodimer, unlike other single domain cyclophilins. In the complex structure, one Myb1104-111 peptide was bound to each TvCyP1 protomer, with G106-P107 and Y105 fitting well into the active site and auxiliary S2 pocket, respectively. NMR data further showed that TvCyP1 can catalyze the cis/trans isomerization of P107 in Myb1104-111. Interestingly, in the well-folded Myb1 protein (Myb135-141), the minimum binding sequence adopted a different conformation from that of unstructured Myb1104-111 peptide, that could make P107 binding to the active site of TvCyP1 difficult. However, NMR studies showed that similar to Myb1104-111 peptide, Myb135-141 also interacted with the active site of TvCyP1 and the dynamics of the Myb135-141 residues near P107 was reduced upon interaction. Together, the structure of TvCyP1 and detailed structural insights on TvCyP1-Myb1 interaction provided here could pave the way for newer drugs to treat drug-resistant strains. PMID- 29615723 TI - Identification of Migratory Insects from their Physical Features using a Decision Tree Support Vector Machine and its Application to Radar Entomology. AB - Migration is a key process in the population dynamics of numerous insect species, including many that are pests or vectors of disease. Identification of insect migrants is critically important to studies of insect migration. Radar is an effective means of monitoring nocturnal insect migrants. However, species identification of migrating insects is often unachievable with current radar technology. Special-purpose entomological radar can measure radar cross-sections (RCSs) from which the insect mass, wingbeat frequency and body length-to-width ratio (a measure of morphological form) can be estimated. These features may be valuable for species identification. This paper explores the identification of insect migrants based on the mass, wingbeat frequency and length-to-width ratio, and body length is also introduced to assess the benefit of adding another variable. A total of 23 species of migratory insects captured by a searchlight trap are used to develop a classification model based on decision-tree support vector machine method. The results reveal that the identification accuracy exceeds 80% for all species if the mass, wingbeat frequency and length-to-width ratio are utilized, and the addition of body length is shown to further increase accuracy. It is also shown that improving the precision of the measurements leads to increased identification accuracy. PMID- 29615722 TI - Discrimination between the human prostate normal and cancer cell exometabolome by GC-MS. AB - Serum prostate-specific antigen (PSA) is currently the most used biomarker in clinical practice for prostate cancer (PCa) detection. However, this biomarker has several drawbacks. In this work, an untargeted gas chromatography-mass spectrometry (GC-MS)-based metabolomic profiling of PCa cells was performed to prove the concept that metabolic alterations might differentiate PCa cell lines from normal prostate cell line. For that, we assessed the differences in volatile organic compounds (VOCs) profile in the extracellular medium (exometabolome) of four PCa cell lines and one normal prostate cell line at two pH values (pH 2 and 7) by GC-MS. Multivariate analysis revealed a panel of volatile metabolites that discriminated cancerous from normal prostate cells. The most altered metabolites included ketones, aldehydes and organic acids. Among these, we highlight pentadecane-2-one and decanoic acid, which were significantly increased in PCa compared to normal cells, and cyclohexanone, 4-methylheptan-2-one, 2 methylpentane-1,3-diol, 4-methylbenzaldehyde, 1-(3,5-dimethylfuran-2-yl)ethanone, methyl benzoate and nonanoic acid, which were significantly decreased in PCa cells. The PCa volatilome was markedly influenced by the VOCs extraction pH, though the discriminant capability was similar. Overall, our data suggest that VOCs monitoring has the potential to be used as a PCa screening methodology. PMID- 29615724 TI - Dual mTOR/PI3K inhibition limits PI3K-dependent pathways activated upon mTOR inhibition in autosomal dominant polycystic kidney disease. AB - Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development of kidney cysts leading to kidney failure in adulthood. Inhibition of mammalian target of rapamycin (mTOR) slows polycystic kidney disease (PKD) progression in animal models, but randomized controlled trials failed to prove efficacy of mTOR inhibitor treatment. Here, we demonstrate that treatment with mTOR inhibitors result in the removal of negative feedback loops and up-regulates pro-proliferative phosphatidylinositol 3-kinase (PI3K)-Akt and PI3K-extracellular signal-regulated kinase (ERK) signaling in rat and mouse PKD models. Dual mTOR/PI3K inhibition with NVP-BEZ235 abrogated these pro-proliferative signals and normalized kidney morphology and function by blocking proliferation and fibrosis. Our findings suggest that multi-target PI3K/mTOR inhibition may represent a potential treatment for ADPKD. PMID- 29615725 TI - Epigenetic alterations are associated with monocyte immune dysfunctions in HIV-1 infection. AB - Monocytes are key cells in the immune dysregulation observed during human immunodeficiency virus (HIV) infection. The events that take place specifically in monocytes may contribute to the systemic immune dysfunction characterized by excessive immune activation in infected individuals, which directly correlates with pathogenesis and progression of the disease. Here, we investigated the immune dysfunction in monocytes from untreated and treated HIV + patients and associated these findings with epigenetic changes. Monocytes from HIV patients showed dysfunctional ability of phagocytosis and killing, and exhibited dysregulated cytokines and reactive oxygen species production after M. tuberculosis challenge in vitro. In addition, we showed that the expression of enzymes responsible for epigenetic changes was altered during HIV infection and was more prominent in patients that had high levels of soluble CD163 (sCD163), a newly identified plasmatic HIV progression biomarker. Among the enzymes, histone acetyltransferase 1 (HAT1) was the best epigenetic biomarker correlated with HIV sCD163 high patients. In conclusion, we confirmed that HIV impairs effector functions of monocytes and these alterations are associated with epigenetic changes that once identified could be used as targets in therapies aiming the reduction of the systemic activation state found in HIV patients. PMID- 29615726 TI - Enhanced labeling density and whole-cell 3D dSTORM imaging by repetitive labeling of target proteins. AB - With continuing advances in the resolving power of super-resolution microscopy, the inefficient labeling of proteins with suitable fluorophores becomes a limiting factor. For example, the low labeling density achieved with antibodies or small molecule tags limits attempts to reveal local protein nano-architecture of cellular compartments. On the other hand, high laser intensities cause photobleaching within and nearby an imaged region, thereby further reducing labeling density and impairing multi-plane whole-cell 3D super-resolution imaging. Here, we show that both labeling density and photobleaching can be addressed by repetitive application of trisNTA-fluorophore conjugates reversibly binding to a histidine-tagged protein by a novel approach called single-epitope repetitive imaging (SERI). For single-plane super-resolution microscopy, we demonstrate that, after multiple rounds of labeling and imaging, the signal density is increased. Using the same approach of repetitive imaging, washing and re-labeling, we demonstrate whole-cell 3D super-resolution imaging compensated for photobleaching above or below the imaging plane. This proof-of-principle study demonstrates that repetitive labeling of histidine-tagged proteins provides a versatile solution to break the 'labeling barrier' and to bypass photobleaching in multi-plane, whole-cell 3D experiments. PMID- 29615727 TI - Ribosome-dependent conformational flexibility changes and RNA dynamics of IRES domains revealed by differential SHAPE. AB - Internal ribosome entry site (IRES) elements are RNA regions that recruit the translation machinery internally. Here we investigated the conformational changes and RNA dynamics of a picornavirus IRES upon incubation with distinct ribosomal fractions. Differential SHAPE analysis of the free RNA showed that nucleotides reaching the final conformation on long timescales were placed at domains 4 and 5, while candidates for long-range interactions were located in domain 3. Salt washed ribosomes induced a fast RNA local flexibility modification of domains 2 and 3, while ribosome-associated factors changed domains 4 and 5. Consistent with this, modeling of the three-dimensional RNA structure indicated that incubation of the IRES with native ribosomes induced a local rearrangement of the apical region of domain 3, and a reorientation of domains 4 and 5. Furthermore, specific motifs within domains 2 and 3 showed a decreased flexibility upon incubation with ribosomal subunits in vitro, and presence of the IRES enhanced mRNA association to the ribosomal subunits in whole cell lysates. The finding that RNA modules can provide direct IRES-ribosome interaction suggests that linking these motifs to additional sequences able to recruit trans-acting factors could be useful to design synthetic IRESs with novel activities. PMID- 29615728 TI - Causal Inference in the Perception of Verticality. AB - The perceptual upright is thought to be constructed by the central nervous system (CNS) as a vector sum; by combining estimates on the upright provided by the visual system and the body's inertial sensors with prior knowledge that upright is usually above the head. Recent findings furthermore show that the weighting of the respective sensory signals is proportional to their reliability, consistent with a Bayesian interpretation of a vector sum (Forced Fusion, FF). However, violations of FF have also been reported, suggesting that the CNS may rely on a single sensory system (Cue Capture, CC), or choose to process sensory signals based on inferred signal causality (Causal Inference, CI). We developed a novel alternative-reality system to manipulate visual and physical tilt independently. We tasked participants (n = 36) to indicate the perceived upright for various (in )congruent combinations of visual-inertial stimuli, and compared models based on their agreement with the data. The results favor the CI model over FF, although this effect became unambiguous only for large discrepancies (+/-60 degrees ). We conclude that the notion of a vector sum does not provide a comprehensive explanation of the perception of the upright, and that CI offers a better alternative. PMID- 29615729 TI - Stochastic Modeling of Radiation-induced Dendritic Damage on in silico Mouse Hippocampal Neurons. AB - Cognitive dysfunction associated with radiotherapy for cancer treatment has been correlated to several factors, one of which is changes to the dendritic morphology of neuronal cells. Alterations in dendritic geometry and branching patterns are often accompanied by deficits that impact learning and memory. The purpose of this study is to develop a novel predictive model of neuronal dendritic damages caused by exposure to low linear energy transfer (LET) radiation, such as X-rays, gamma-rays and high-energy protons. We established in silico representations of mouse hippocampal dentate granule cell layer (GCL) and CA1 pyramidal neurons, which are frequently examined in radiation-induced cognitive decrements. The in silico representations are used in a stochastic model that describes time dependent dendritic damage induced by exposure to low LET radiation. Changes in morphometric parameters, such as total dendritic length, number of branch points and branch number, including the Sholl analysis for single neurons are described by the model. Our model based predictions for different patterns of morphological changes based on energy deposition in dendritic segments (EDDS) will serve as a useful basis to compare specific patterns of morphological alterations caused by EDDS mechanisms. PMID- 29615730 TI - Retrospective Study of Hemodynamic Changes Before and After Carotid Stenosis Formation by Vessel Surface Repairing. AB - Prospective observation of hemodynamic changes before and after the formation of atherosclerotic stenosis in the carotid artery is difficult. Thus, a vessel surface repairing method was used for retrospective hemodynamic study before and after atherosclerotic stenosis formation in carotid artery. The three-dimensional geometry of sixteen sinus atherosclerotic stenosis carotid arteries were repaired and restored as normal arteries. Computational fluid dynamics analysis was performed to estimate wall shear stress (WSS), velocity and vortex in atherosclerosis-free areas and sinus in stenosis-repaired carotid artery. The analysis was also performed in the stenotic segment and upstream and downstream of stenosis in stenotic carotid artery. Compared to the atherosclerosis-free areas in stenosis-repaired carotid artery, sinus presented significantly lower WSS (P < 0.05), lower velocity (P < 0.05) and apparent vortex. Compared to the sinus, the WSS in the upstream of stenosis was lower (P < 0.05), while in the downstream area was similar (P = 0.87), both upstream and downstream of stenosis demonstrated similar velocity to sinus (P = 0.76 and P = 0.36, respectively) and apparent vortex. Atherosclerosis-prone areas including normal carotid sinus and upstream and downstream of stenosis in stenotic carotid artery were subjected to lower WSS and velocity as well as apparent vortex, thereby might be associated with the formation and progress of atherosclerosis. PMID- 29615731 TI - Genome-wide comparative and evolutionary analysis of Calmodulin-binding Transcription Activator (CAMTA) family in Gossypium species. AB - The CAMTA gene family is crucial in managing both biotic and abiotic stresses in plants. Our comprehensive analysis of this gene family in cotton resulted in the identification of 6, 7 and 9 CAMTAs in three sequenced cotton species, i.e., Gossypium arboreum, Gossypium raimondii, and Gossypium hirsutum, respectively. All cotton CAMTAs were localized in the nucleus and possessed calmodulin-binding domain (CaMBD) as identified computationally. Phylogenetically four significant groups of cotton CAMTAs were identified out of which, Group II CAMTAs experienced higher evolutionary pressure, leading to a faster evolution in diploid cotton. The expansion of cotton CAMTAs in the genome was mainly due to segmental duplication. Purifying selection played a significant role in the evolution of cotton CAMTAs. Expression profiles of GhCAMTAs revealed that GhCAMTA2A.2 and GhCAMTA7A express profoundly in different stages of cotton fiber development. Positive correlation between expression of these two CAMTAs and fiber strength confirmed their functional relevance in fiber development. The promoter region of co-expressing genes network of GhCAMTA2A.2 and GhCAMTA7A showed a higher frequency of occurrence of CAMTA binding motifs. Our present study thus contributes to broad probing into the structure and probable function of CAMTA genes in Gossypium species. PMID- 29615732 TI - Drug resistance of oral bacteria to new antibacterial dental monomer dimethylaminohexadecyl methacrylate. AB - Only two reports exist on drug-resistance of quaternary ammonium monomers against oral bacteria; both studies tested planktonic bacteria for 10 passages, and neither study tested biofilms or resins. The objectives of this study were to investigate the drug-resistance of Streptococcus mutans, Streptococcus sanguinis and Streptococcus gordonii against dimethylaminohexadecyl methacrylate (DMAHDM), and to evaluate biofilms on resins with repeated exposures for 20 passages for the first time. DMAHDM, dimethylaminododecyl methacrylate (DMADDM) and chlorhexidine (CHX) were tested with planktonic bacteria. Biofilms were grown on a resin containing 3% DMAHDM. Minimum-inhibitory concentrations were measured. To detect drug-resistance, the survived bacteria from the previous passage were used as inoculum for the next passage for repeated exposures. S. gordonii developed drug-resistance against DMADDM and CHX, but not against DMAHDM. Biofilm colony forming units (CFU) on DMAHDM-resin was reduced by 3-4 log; there was no difference from passages 1 to 20 (p > 0.1). No drug-resistance to DMAHDM was detected for all three bacterial species. In conclusion, this study showed that DMAHDM induced no drug-resistance, and DMAHDM-resin reduced biofilm CFU by 3-4 log, with no significant change from 1 to 20 passages. DMAHDM with potent antibacterial activities and no drug-resistance is promising for dental applications. PMID- 29615733 TI - Locus coeruleus complex of the family Delphinidae. AB - The locus coeruleus (LC) is the largest catecholaminergic nucleus and extensively projects to widespread areas of the brain and spinal cord. The LC is the largest source of noradrenaline in the brain. To date, the only examined Delphinidae species for the LC has been a bottlenose dolphin (Tursiops truncatus). In our experimental series including different Delphinidae species, the LC was composed of five subdivisions: A6d, A6v, A7, A5, and A4. The examined animals had the A4 subdivision, which had not been previously described in the only Delphinidae in which this nucleus was investigated. Moreover, the neurons had a large amount of neuromelanin in the interior of their perikarya, making this nucleus highly similar to that of humans and non-human primates. This report also presents the first description of neuromelanin in the cetaceans' LC complex, as well as in the cetaceans' brain. PMID- 29615734 TI - Constitutive modeling of high temperature flow behavior in a Ti-45Al-8Nb-2Cr-2Mn 0.2Y alloy. AB - A constitutive equation based on the hyperbolic sinusoidal Arrhenius-type model has been developed to describe the hot deformation behavior of a beta-gamma Ti-Al alloy containing 8 at.% of Nb. Experimental true stress-true strain data were acquired from isothermal hot compression tests conducted across a wide range of temperatures (1273 K~1473 K) and strain rates (0.001 s-1~1 s-1), and the changes in the experimental conditions were reflected in the values of the Zener-Hollomon parameter. The impact of true strain was expressed through material constants (A, alpha, n and Q), and it was found that a 7th order polynomial is appropriate to express the relations between the true strain and these material constants. The average absolute relative error (AARE) and correlation coefficient (R) were used to evaluate the accuracy of the constitutive equation, and the values obtained were 6.009% and 0.9961, respectively. These results indicate that the type of constitutive equation developed here can predict the flow stress for this alloy with good accuracy over a wide range of experimental conditions. Thus, equations of this form could be applied more widely to analyses of hot deformation mechanism and microstructure evolution. PMID- 29615735 TI - Attraction and Compaction of Migratory Breast Cancer Cells by Bone Matrix Proteins through Tumor-Osteocyte Interactions. AB - Bone is a frequent site of metastasis from breast cancer. To understand the potential role of osteocytes in bone metastasis, we investigated tumor-osteocyte interactions using two cell lines derived from the MDA-MB-231 breast cancer cells, primary breast cancer cells, and MLO-A5/MLO-Y4 osteocyte cells. When three dimensional (3D) tumor spheroids were grown with osteocyte spheroids, tumor spheroids fused with osteocyte spheroids and shrank. This size reduction was also observed when tumor spheroids were exposed to conditioned medium isolated from osteocyte cells. Mass spectrometry-based analysis predicted that several bone matrix proteins (e.g., collagen, biglycan) in conditioned medium could be responsible for tumor shrinkage. The osteocyte-driven shrinkage was mimicked by type I collagen, the most abundant organic component in bone, but not by hydroxyapatite, a major inorganic component in bone. RNA and protein expression analysis revealed that tumor-osteocyte interactions downregulated Snail, a transcription factor involved in epithelial-to-mesenchymal transition (EMT). An agarose bead assay showed that bone matrix proteins act as a tumor attractant. Collectively, the study herein demonstrates that osteocytes attract and compact migratory breast cancer cells through bone matrix proteins, suppress tumor migration, by Snail downregulation, and promote subsequent metastatic colonization. PMID- 29615736 TI - Centrifugation-free extraction of circulating nucleic acids using immiscible liquid under vacuum pressure. AB - Extraction of cell-free DNA (cfDNA), which exists at an extremely low concentration in plasma, is a critical process for either targeted-sensing or massive sequencing of DNAs. However, such small amount of DNA cannot be fully obtained without high-speed centrifugation (<20,000 g). Here, we developed a centrifugation-free cfDNA extraction method and system that utilizes an immiscible solvent under single low vacuum pressure throughout the entire process. It has been named Pressure and Immiscibility-Based EXtraction (PIBEX). The amounts of extracted cfDNA by PIBEX were compared with those extracted by the conventional gold standards such as QIAGEN using quantitative PCR (qPCR). The PIBEX system showed equal performance regarding extraction amount and efficiency compared to the existing method. Because the PIBEX eliminates the troublous and repetitive centrifugation processes in DNA extraction, it can be further utilized in microfluidic-sample preparation systems for circulating nucleic acids, which would lead to an integrated sample-to-answer system in liquid biopsies. PMID- 29615737 TI - Longterm Reversal of Severe Visual Loss by Mitochondrial Gene Transfer in a Mouse Model of Leber Hereditary Optic Neuropathy. AB - In many human disorders mitochondrial dysfunction is central to degeneration of retinal ganglion cells. As these cells do not regenerate, vision is irreversibly lost. Here we show reversal of visual dysfunction by a mitochondrially targeted adeno associated virus in transgenic mice harboring a G11778A mutation in the ND4 subunit of complex I persists longterm and it is associated with reduced loss of RGCs and their axons, improved oxidative phosphorylation, persistence of transferred ND4 DNA and transcription of ND4 mRNA. PMID- 29615738 TI - Abundant fish protein inhibits alpha-synuclein amyloid formation. AB - The most common allergen in fish, the highly-abundant protein beta-parvalbumin, forms amyloid structures as a way to avoid gastrointestinal degradation and transit to the blood. In humans, the same amyloid structures are mostly associated with neurodegenerative disorders such as Alzheimer's and Parkinson's. We here assessed a putative connection between these amyloids using recombinant Atlantic cod beta-parvalbumin and the key amyloidogenic protein in Parkinson's disease, alpha-synuclein. Using a set of in vitro biophysical methods, we discovered that beta-parvalbumin readily inhibits amyloid formation of alpha synuclein. The underlying mechanism was found to involve alpha-synuclein binding to the surface of beta-parvalbumin amyloid fibers. In addition to being a new amyloid inhibition mechanism, the data suggest that health benefits of fish may be explained in part by cross-reaction of beta-parvalbumin with human amyloidogenic proteins. PMID- 29615739 TI - Potential impact of ocean circulation on the declining Japanese eel catches. AB - Recruitment of Japanese eels, Anguilla japonica, has declined in recent decades possibly due to both anthropogenic and ocean-atmosphere factors. The potential impact of ocean circulation on the decreasing Japanese eel catches in the western North Pacific was examined based on a three-dimensional particle-tracking method, in which virtual larvae (v-larvae) were programmed to swim horizontally and vertically, in addition to being transported by ocean currents after being released in their North Equatorial Current (NEC) spawning area. Transport patterns varied among years between 1993 and 2013, and dispersion of v-larvae towards East Asia decreased in the last two decades, especially for the western Taiwan and Japan regions. In recent years, instead of entering the Kuroshio and moving towards East Asia as in the 1990s', more v-larvae tended to enter the southern areas due to the weakening of the NEC and strengthening of subsurface southward flow near the spawning area. Changes in ocean circulation in the western Pacific appear to be caused by the weakening of subtropical and tropical wind stress curl in the past two decades. This suggests that decadal changes in ocean circulation have occurred that affect the larval migration success of the Japanese eel to their recruitment areas. PMID- 29615740 TI - Addressing the impact of urban exposure on the incidence of type 2 diabetes mellitus: The PERU MIGRANT Study. AB - The aim of this study was to estimate the incidence of T2DM in three population groups: rural, rural-to-urban migrants and urban dwellers. Data from the PERU MIGRANT Study was analysed. The baseline assessment was conducted in 2007-2008 using a single-stage random sample and further follow-up was undertaken in 2015 16. T2DM was defined based on fasting glucose and self-reported diagnosis. Poisson regression models and robust variance to account for cluster effects were used for reporting risk ratios (RR) and 95%CI. At baseline, T2DM prevalence was 8% in urban, 3.6% in rural-to-urban migrants and 1.5% in rural dwellers. After 7.7 (SD: 1.1) years, 6,076 person-years of follow-up, 61 new cases were identified. The incidence rates in the urban, migrant and rural groups were 1.6, 0.9 and 0.5 per 100 person-years, respectively. Relative to rural dwellers, a 4.3 fold higher risk (95%CI: 1.6-11.9) for developing T2DM was found in urban dwellers and 2.7-fold higher (95%CI: 1.1-6.8) in migrants with >=30 years of urban exposure. Migration and urban exposure were found as significant risk factors for developing T2DM. Within-country migration is a sociodemographic phenomenon occurring worldwide; thus, it is necessary to disentangle the effect of urban exposure on non-healthy habits and T2DM development. PMID- 29615741 TI - A porcine ex vivo model of pigmentary glaucoma. AB - Pigment dispersion can lead to pigmentary glaucoma, a poorly understood condition of younger myopic eyes with fluctuating high intraocular pressure. It has been difficult to investigate its pathogenesis without a model similar to human eyes in size and behavior. Here we present a porcine ex vivo model that recreates several features of pigmentary glaucoma, including intraocular hypertension, accumulation of pigment in the trabecular meshwork, and declining phagocytosis. We found that trabecular meshwork cells regulate outflow, form actin stress fibers, and have a decreased phagocytic activity. Gene expression microarrays and a pathway analysis of TM monolayers as well as ex vivo anterior segment perfusion cultures indicated that RhoA plays a central role in regulating the cytoskeleton, motility, and phagocytosis in the trabecular meshwork, providing new insights and targets to investigate in pigmentary glaucoma. PMID- 29615742 TI - Systemic and specific effects of antihypertensive and lipid-lowering medication on plasma protein biomarkers for cardiovascular diseases. AB - A large fraction of the adult population is on lifelong medication for cardiovascular disorders, but the metabolic consequences are largely unknown. This study determines the effects of common anti-hypertensive and lipid lowering drugs on circulating plasma protein biomarkers. We studied 425 proteins in plasma together with anthropometric and lifestyle variables, and the genetic profile in a cross-sectional cohort. We found 8406 covariate-protein associations, and a two stage GWAS identified 17253 SNPs to be associated with 109 proteins. By computationally removing variation due to lifestyle and genetic factors, we could determine that medication, per se, affected the abundance levels of 35.7% of the plasma proteins. Medication either affected a single, a few, or a large number of protein, and were found to have a negative or positive influence on known disease pathways and biomarkers. Anti-hypertensive or lipid lowering drugs affected 33.1% of the proteins. Angiotensin-converting enzyme inhibitors showed the strongest lowering effect by decreasing plasma levels of myostatin. Cell-culture experiments showed that angiotensin-converting enzyme inhibitors reducted myostatin RNA levels. Thus, understanding the effects of lifelong medication on the plasma proteome is important both for sharpening the diagnostic precision of protein biomarkers and in disease management. PMID- 29615743 TI - Attentional advantages in video-game experts are not related to perceptual tendencies. AB - Previous studies have suggested that extensive action video gaming may enhance perceptual and attentional capacities. Here, we probed whether attentional differences between video-game experts and non-experts hold when attention is selectively directed at global or local structures. We measured performance on a modified attentional-blink task using hierarchically structured stimuli that consisted of global and local elements. Stimuli carried congruent or incongruent information. In two experiments, we asked observers to direct their attention globally (Experiment 1) or locally (Experiment 2). In each RSVP trial, observers were asked to identify the identity of an initial target (T1), and detect the presence or absence of a second target (T2). Experts showed a markedly attenuated attentional blink, as quantified by higher T2 detection sensitivity, relative to non-experts, in both global and local tasks. Notably, experts and non-experts were comparably affected by stimulus congruency. We speculate that the observed visuo-attentional advantage is unlikely to be related to mere differences perceptual tendencies (i.e., greater global precedence), which has been previously associated with diminished attentional blink. PMID- 29615744 TI - Activation of the complement system in an osteosarcoma cell line promotes angiogenesis through enhanced production of growth factors. AB - There is increasing evidence that the complement system is activated in various cancer tissues. Besides being involved in innate immunity against pathogens, the complement system also participates in inflammation and the modulation of tumor microenvironment. Recent studies suggest that complement activation promotes tumor progression in various ways. Among some cancer cell lines, we found that human bone osteosarcoma epithelial cells (U2-OS) can activate the alternative pathway of the complement system by pooled normal human serum. Interestingly, U2 OS cells showed less expression of complement regulatory proteins, compared to other cancer cell lines. Furthermore, the activated complement system enhanced the production of growth factors, which promoted angiogenesis of human endothelial cells. Our results demonstrated a direct linkage between the complement system and angiogenesis using the in vitro model, which suggest the complement system and related mechanisms might be potential targets for cancer treatment. PMID- 29615745 TI - Simple Method for De Novo Structural Determination of Underivatised Glucose Oligosaccharides. AB - Carbohydrates have various functions in biological systems. However, the structural analysis of carbohydrates remains challenging. Most of the commonly used methods involve derivatization of carbohydrates or can only identify part of the structure. Here, we report a de novo method for completely structural identification of underivatised oligosaccharides. This method, which can provide assignments of linkages, anomeric configurations, and branch locations, entails low-energy collision-induced dissociation (CID) of sodium ion adducts that enable the cleavage of selective chemical bonds, a logical procedure to identify structurally decisive fragment ions for subsequent CID, and the specially prepared disaccharide CID spectrum databases. This method was first applied to determine the structures of four underivatised glucose oligosaccharides. Then, high-performance liquid chromatography and a mass spectrometer with a built-in logical procedure were established to demonstrate the capability of the in situ CID spectrum measurement and structural determination of the oligosaccharides in chromatogram. This consolidation provides a simple, rapid, sensitive method for the structural determination of glucose oligosaccharides, and applications to oligosaccharides containing hexoses other than glucose can be made provided the corresponding disaccharide databases are available. PMID- 29615746 TI - Mechanical Enhancement of Core-Shell Microlattices through High-Entropy Alloy Coating. AB - Mechanical metamaterials such as microlattices are an emerging kind of new materials that utilize the combination of structural enhancement effect by geometrical modification and the intrinsic properties of its material constituents. Prior studies have reported the mechanical properties of ceramic or metal-coated composite lattices. However, the scalable synthesis and characterization of high-entropy alloy (HEA) as thin film coating for such cellular materials have not been studied previously. In this work, stereolithography was combined with Radio Frequency (RF) magnetron sputtering to conformally deposit a thin layer (~800 nm) of CrMnFeCoNi HEA film onto a polymer template to produce HEA-coated three-dimensional (3D) core-shell microlattice structures for the first time. The presented polymer/HEA hybrid microlattice exhibits high specific compressive strength (~0.018 MPa kg-1 m3) at a density well below 1000 kg m-3, significantly enhanced stiffness (>5 times), and superior elastic recoverability compared to its polymer counterpart due to its composite nature. The findings imply that this highly scalable and effective route to synthesizing HEA-coated microlattices have the potential to produce novel metamaterials with desirable properties to cater specialized engineering applications. PMID- 29615748 TI - Enamel apatite crystallinity significantly contributes to mammalian dental adaptations. AB - The monophyodont molar teeth, prismatic enamel and the complexity of enamel microarchitecture are regarded as essential dental apomorphies of mammals. As prominent background factors of feeding efficiency and individual longevity these characters are crucial components of mammalian adaptive dynamics. Little is known, however, to which degree these adaptations are influenced by the crystallographic properties of elementary hydroxyapatite crystallites, the only inorganic component of enamel. In a miniature pig where individual molars differ significantly in duration of their development and in enamel resistance to attrition stress, we found highly significant differences between the molars in the size of crystallites, amount of microstrain, crystallinity and in enamel stiffness and elasticity, all clearly scaled with the duration of tooth calcification. The same pattern was found also in red deer bearing different molar type. The results suggest that the prolongation of tooth development is associated with an increase of crystallinity, i.e. the atomic order of enamel hydroxyapatite, an obvious component of micromechanical property of mature enamel. This relation could contribute to prolongation of dental development, characteristic of mammals in general. The aspects of enamel crystallinity, omitted in previous studies on mammalian and vertebrate dental evolution, are to be taken in account in these topics. PMID- 29615747 TI - A Critical Domain of Ebolavirus Envelope Glycoprotein Determines Glycoform and Infectivity. AB - Ebolaviruses comprises 5 species that exert varying degrees of mortality/infectivity in humans with Reston ebolaviruses (REBOV) showing the lowest and Zaire ebolaviruses (ZEBOV) showing the highest. However, the molecular basis of this differential mortality/infectivity remains unclear. Here, we report that the structural features of ebolavirus envelope glycoproteins (GPs) and one of their counter receptors, macrophage galactose-type calcium-type lectin (MGL/CD301), play crucial roles in determining viral infectivity. The low infectivity of REBOV mediated by the interaction between GPs and MGL/CD301 dramatically increased when the N-terminal 18 amino acids (33rd through 50th) of GPs were replaced with that of ZEBOV. Furthermore, structural analysis of glycans of GPs revealed that N-glycans were more extended in REBOV than in ZEBOV. N glycan extension was reversed by the replacement of aforementioned N-terminal 18 amino acid residues. Therefore, these data strongly suggest that extended N glycans on GPs reduce MGL/CD301-mediated viral infectivity by hindering the interaction between GPs and MGL/CD301 preferentially binds O-glycans. PMID- 29615751 TI - Spatiotemporal deformation patterns of the Lake Urmia Causeway as characterized by multisensor InSAR analysis. AB - We present deformation patterns in the Lake Urmia Causeway (LUC) in NW Iran based on data collected from four SAR sensors in the form of interferometric synthetic aperture radar (InSAR) time series. Sixty-eight images from Envisat (2004-2008), ALOS-1 (2006-2010), TerraSAR-X (2012-2013) and Sentinel-1 (2015-2017) were acquired, and 227 filtered interferograms were generated using the small baseline subset (SBAS) technique. The rate of line-of-sight (LOS) subsidence of the LUC peaked at 90 mm/year between 2012 and 2013, mainly due to the loss of most of the water in Lake Urmia. Principal component analysis (PCA) was conducted on 200 randomly selected time series of the LUC, and the results are presented in the form of the three major components. The InSAR scores obtained from the PCA were used in a hydro-thermal model to investigate the dynamics of consolidation settlement along the LUC based on detrended water level and temperature data. The results can be used to establish a geodetic network around the LUC to identify more detailed deformation patterns and to help plan future efforts to reduce the possible costs of damage. PMID- 29615749 TI - Blocking distinct interactions between Glioblastoma cells and their tissue microenvironment: A novel multi-targeted therapeutic approach. AB - Due to the highly invasive nature of Glioblastoma (GB), complete surgical resection is not feasible, while motile tumour cells are often associated with several specific brain structures that enhance treatment-resistance. Here, we investigate the therapeutic potential of Disulfiram and Carbenoxolone, that inhibit two distinct interactions between GB and the brain tissue microenvironment: stress-induced cell-matrix adhesion and gap junction mediated cell-cell communication, respectively. Increase in cell numbers of tumour initiating cells, which are cultured in suspension as cell clusters, and adherent differentiated cells can be blocked to a similar extent by Carbenoxolone, as both cell populations form gap junctions, but the adherent differentiated cells are much more sensitive to Disulfiram treatment, which - via modulation of NF-kappaB signalling - interferes with cell-substrate adhesion. Interestingly, inducing adhesion in tumour-initiating cells without differentiating them does not sensitize for Disulfiram. Importantly, combining Disulfiram, Carbenoxolone and the standard chemotherapeutic drug Temozolomide reduces tumour size in an orthotopic mouse model. Isolating GB cells from their direct environment within the brain represents an important addition to current therapeutic approaches. The blockage of cellular interactions via the clinically relevant substances Disulfiram and Carbenoxolone, has distinct effects on different cell populations within a tumour, potentially reducing motility and/or resistance to apoptosis. PMID- 29615750 TI - Impact of Systemic Volume Status on Cardiac Magnetic Resonance T1 Mapping. AB - Diffuse myocardial fibrosis is a key pathophysiologic feature in heart failure and can be quantified by cardiac magnetic resonance (CMR) T1 mapping. However, increases in myocardial free water also prolong native T1 times and may impact fibrosis quantification. Thus far, the impact of systemic patient volume status remains unclear. In this study, native T1 time by CMR was investigated in hemodialysis (HD) patients (n = 37) and compared with healthy controls (n = 35). Volume status was quantified by bioimpedance spectroscopy and correlated with CMR T1 time. While no differences between HD patients and controls were present with regard to age (p = 0.180), height (p = 0.535), weight (p = 0.559) and left ventricular (LV) ejection fraction (p = 0.273), cardiac size was significantly larger in HD patients (LV end-diastolic volume 164 +/- 53 vs. 132 +/- 26 ml, p = 0.002). Fluid overloaded HD patients had significantly longer native T1 times than normovolemic HD patients and healthy controls (1,042 +/- 46 vs. 1,005 +/- 49 vs. 998 +/- 47 ms, p = 0.030). By regression analysis, T1 time was significantly associated with fluid status (r = 0.530, p = 0.009, post-HD fluid status). Our data strongly indicate that native CMR T1 time is significantly influenced by systemic volume status. As fluid overload is common in patients with cardiovascular diseases, this finding is important and requires further study. PMID- 29615752 TI - Endothelial indoleamine 2,3-dioxygenase-1 regulates the placental vascular tone and is deficient in intrauterine growth restriction and pre-eclampsia. AB - Indoleamine 2,3-dioxygenase-1 (IDO1) mediates the degradation of L-tryptophan (L Trp) and is constitutively expressed in the chorionic vascular endothelium of the human placenta with highest levels in the microvasculature. Given that endothelial expression of IDO1 has been shown to regulate vascular tone and blood pressure in mice under the condition of systemic inflammation, we asked whether IDO1 is also involved in the regulation of placental blood flow and if yes, whether this function is potentially impaired in intrauterine growth restriction (IUGR) and pre-eclampsia (PE). In the large arteries of the chorionic plate L-Trp induced relaxation only after upregulation of IDO1 using interferon gamma and tumor necrosis factor alpha. However, ex vivo placental perfusion of pre constricted cotyledonic vasculature with L-Trp decreases the vessel back pressure without prior IDO1 induction. Further to this finding, IDO1 protein expression and activity is reduced in IUGR and PE when compared to gestational age-matched control tissue. These data suggest that L-Trp catabolism plays a role in the regulation of placental vascular tone, a finding which is potentially linked to placental and fetal growth. In this context our data suggest that IDO1 deficiency is related to the pathogenesis of IUGR and PE. PMID- 29615753 TI - Health status in subjects with suspected obstructive sleep apnea and comparison with a general population. AB - The purpose of this study was to assess health status (HS) in patients with clinical suspicion of obstructive sleep apnea (OSA) in order to estimate the dose response relationship between HS and OSA severity, and to compare HS in this clinical cohort with a general population sample (N = 5000). Patients referred to an overnight sleep study due to suspected OSA, whom also responded to the SF-36 questionnaire, were included (N = 418). Of these, 194 showed normal findings, while 111, 60 and 53 demonstrated mild, moderate and severe OSA, respectively. Mean age was 47.5 (SD 11.9) and 69% were males. Only the mental health scale (p = 0.015) and mental component summary score (p = 0.023) were associated with OSA severity. This association, however, disappeared in multivariable analysis. All SF-36 scores in the sleep study group were lower than that of the general population sample, in both unadjusted and multivariable linear regression analysis. In this study, there was a lack of association between OSA severity and general HS. However, as a whole, patients in this clinical population referred to an overnight sleep study due to suspected OSA had impaired HS on all scales compared to a general population, with greatest differences in the vitality domain. PMID- 29615754 TI - Phylogenomic and comparative analysis of the distribution and regulatory patterns of TPP riboswitches in fungi. AB - Riboswitches are metabolite or ion sensing cis-regulatory elements that regulate the expression of the associated genes involved in biosynthesis or transport of the corresponding metabolite. Among the nearly 40 different classes of riboswitches discovered in bacteria so far, only the TPP riboswitch has also been found in algae, plants, and in fungi where their presence has been experimentally validated in a few instances. We analyzed all the available complete fungal and related genomes and identified TPP riboswitch-based regulation systems in 138 fungi and 15 oomycetes. We find that TPP riboswitches are most abundant in Ascomycota and Basidiomycota where they regulate TPP biosynthesis and/or transporter genes. Many of these transporter genes were found to contain conserved domains consistent with nucleoside, urea and amino acid transporter gene families. The genomic location of TPP riboswitches when correlated with the intron structure of the regulated genes enabled prediction of the precise regulation mechanism employed by each riboswitch. Our comprehensive analysis of TPP riboswitches in fungi provides insights about the phylogenomic distribution, regulatory patterns and functioning mechanisms of TPP riboswitches across diverse fungal species and provides a useful resource that will enhance the understanding of RNA-based gene regulation in eukaryotes. PMID- 29615756 TI - The seasonal occupancy and diel behaviour of Antarctic sperm whales revealed by acoustic monitoring. AB - The seasonal occupancy and diel behaviour of sperm whales (Physeter macrocephalus) was investigated using data from long-term acoustic recorders deployed off east Antarctica. An automated method for investigating acoustic presence of sperm whales was developed, characterised, and applied to multi-year acoustic datasets at three locations. Instead of focusing on the acoustic properties of detected clicks, the method relied solely on the inter-click interval (ICI) for determining presence within an hour-long recording. Parameters for our classifier were informed by knowledge of typical vocal behaviour of sperm whales. Sperm whales were detected predominantly from Dec-Feb, occasionally in Nov, Mar, Apr, and May, but never in the Austral winter or early spring months. Ice cover was found to have a statistically significant negative effect on sperm whale presence. In ice-free months sperm whales were detected more often during daylight hours and were seldom detected at night, and this effect was also statistically significant. Seasonal presence at the three east Antarctic recording sites were in accord with what has been inferred from 20th century whale catches off western Antarctica and from stomach contents of whales caught off South Africa. PMID- 29615755 TI - Effects of methamphetamine abuse on spatial cognitive function. AB - Methamphetamine (MA) abuse has been rising rapidly over the past decade, however, its impact in spatial cognitive function remains unknown. To understand its effect on visuospatial ability and spatial orientation ability, 40 MA users and 40 non-MA users conducted the Simple Reaction Task (Task 1), the Spatial Orientation Task (Task 2), and the Mental Rotation Task (Task 3), respectively. There was no significant difference in either accuracy or reaction time (RT) between 2 groups in Task 1. During Task 2, in comparison with non-MA users, MA users performed poorer on RT, but not in accuracy for foot and hand stimuli. In addition, both non-MA and MA users responded much more quickly to upward stimuli than downward stimuli on vertical surface, however, only non-MA users exhibited leftward visual field advantage in horizontal orientation processing. As for Task 3, MA users exhibited poorer performance and more errors than their healthy counterparts. For each group, linear relationship was revealed between RT and orientation angle, whereas MA abuse led to longer intercept for all stimuli involved. Our findings suggested that MA abuse may lead to a general deficit in the visuospatial ability and the spatial orientation ability with more serious impact in the former. PMID- 29615757 TI - Facile fabrication of wire-type indium gallium zinc oxide thin-film transistors applicable to ultrasensitive flexible sensors. AB - We fabricated wire-type indium gallium zinc oxide (IGZO) thin-film transistors (TFTs) using a self-formed cracked template based on a lift-off process. The electrical characteristics of wire-type IGZO TFTs could be controlled by changing the width and density of IGZO wires through varying the coating conditions of template solution or multi-stacking additional layers. The fabricated wire-type devices were applied to sensors after functionalizing the surface. The wire-type pH sensor showed a sensitivity of 45.4 mV/pH, and this value was an improved sensitivity compared with that of the film-type device (27.6 mV/pH). Similarly, when the wire-type device was used as a glucose sensor, it showed more variation in electrical characteristics than the film-type device. The improved sensing properties resulted from the large surface area of the wire-type device compared with that of the film-type device. In addition, we fabricated wire-type IGZO TFTs on flexible substrates and confirmed that such structures were very resistant to mechanical stresses at a bending radius of 10 mm. PMID- 29615758 TI - Von Willebrand factor and ADAMTS13 activity in relation to risk of dementia: a population-based study. AB - Low ADAMTS13 activity is associated with an increased risk of cardiovascular disease, which is generally attributed to its proteolytic effects on Von Willebrand factor (VWF). Cardiovascular health is an important determinant of cognitive decline, but the association of either VWF or ADAMTS13 with risk of dementia is unknown. Between 1997-2002, we measured VWF antigen and ADAMTS13 activity in 6055 participants of the population-based Rotterdam Study (mean age 69.3 years, 57.2% women). At baseline, 85 participants had dementia, and during 15 years of follow-up 821 developed dementia. Higher VWF was associated with prevalence and risk of dementia, unaffected by concurrent ADAMTS13 activity, but estimates strongly attenuated over time and were no longer statistically significant at 4 years of follow-up (relative risks [95% CI] per standard deviation increase- cross-sectional: 1.37 [1.06-1.77], and longitudinal: 1.05 [0.97-1.14]). In contrast, low ADAMTS13 was associated with increased risk of dementia throughout follow-up (hazard ratio per SD decrease- 1.16 [1.06-1.28]), which alike for ischaemic stroke, was modified by the presence of diabetes (P interaction = 0.003). In conclusion, higher VWF and low ADAMTS13 activity are associated with increased risk of dementia, but differences in time-course and lack of synergistic effects may indicate in part independent underlying mechanisms. PMID- 29615759 TI - Directed -in vitro- evolution of Precambrian and extant Rubiscos. AB - Rubisco is an ancient, catalytically conserved yet slow enzyme, which plays a central role in the biosphere's carbon cycle. The design of Rubiscos to increase agricultural productivity has hitherto relied on the use of in vivo selection systems, precluding the exploration of biochemical traits that are not wired to cell survival. We present a directed -in vitro- evolution platform that extracts the enzyme from its biological context to provide a new avenue for Rubisco engineering. Precambrian and extant form II Rubiscos were subjected to an ensemble of directed evolution strategies aimed at improving thermostability. The most recent ancestor of proteobacteria -dating back 2.4 billion years- was uniquely tolerant to mutagenic loading. Adaptive evolution, focused evolution and genetic drift revealed a panel of thermostable mutants, some deviating from the characteristic trade-offs in CO2-fixing speed and specificity. Our findings provide a novel approach for identifying Rubisco variants with improved catalytic evolution potential. PMID- 29615760 TI - Human Sertoli cells support high levels of Zika virus replication and persistence. AB - Zika virus is a teratogenic mosquito-transmitted flavivirus that is associated with birth defects in newborns and Guillain-Barre syndrome in adults. The virus can also be sexually transmitted, but currently, very little is known about the cell types supporting virus replication and persistence in human testes. Using primary cell cultures, we observed that Sertoli but not Leydig cells are highly susceptible to Zika virus infection, a process that is dependent on the TAM family receptor Axl. In cell culture, Sertoli cells could be productively infected with Zika virus for at least 6-weeks. Infection of Sertoli cells resulted in dramatic changes to the transcriptional profile of these cells. The most upregulated mRNA in infected cells was basic fibroblast growth factor (FGF2), a cytokine that was found to enhance Zika virus replication and support viral persistence. Together these findings provide key insights into understanding how Zika virus persists in the male reproductive tract and in turn may aid in developing antiviral therapies or strategies to minimize sexual transmission of this pathogen. PMID- 29615761 TI - Proteolysis inhibition by hibernating bear serum leads to increased protein content in human muscle cells. AB - Muscle atrophy is one of the main characteristics of human ageing and physical inactivity, with resulting adverse health outcomes. To date, there are still no efficient therapeutic strategies for its prevention and/or treatment. However, during hibernation, bears exhibit a unique ability for preserving muscle in conditions where muscle atrophy would be expected in humans. Therefore, our objective was to determine whether there are components of bear serum which can control protein balance in human muscles. In this study, we exposed cultured human differentiated muscle cells to bear serum collected during winter and summer periods, and measured the impact on cell protein content and turnover. In addition, we explored the signalling pathways that control rates of protein synthesis and degradation. We show that the protein turnover of human myotubes is reduced when incubated with winter bear serum, with a dramatic inhibition of proteolysis involving both proteasomal and lysosomal systems, and resulting in an increase in muscle cell protein content. By modulating intracellular signalling pathways and inducing a protein sparing phenotype in human muscle cells, winter bear serum therefore holds potential for developing new tools to fight human muscle atrophy and related metabolic disorders. PMID- 29615762 TI - Small Molecules Attenuate the Interplay between Conformational Fluctuations, Early Oligomerization and Amyloidosis of Alpha Synuclein. AB - Aggregation of alpha synuclein has strong implications in Parkinson's disease. The heterogeneity of folding/aggregation landscape and transient nature of the early intermediates result in difficulty in developing a successful therapeutic intervention. Here we used fluorescence measurements at ensemble and single molecule resolution to study how the late and early events of alpha synuclein aggregation modulate each other. In-vitro aggregation data was complemented using measurements inside live neuroblastoma cells by employing a small molecule labeling technique. An inhibitor molecule (arginine), which delayed the late event of amyloidosis, was found to bind to the protein, shifting the early conformational fluctuations towards a compact state. In contrast, a facilitator of late aggregation (glutamate), was found to be excluded from the protein surface. The presence of glutamate was found to speed up the oligomer formation at the early stage. We found that the effects of the inhibitor and facilitator were additive and as a result they maintained a ratio at which they cancelled each other's influence on different stages of alpha synuclein aggregation. PMID- 29615763 TI - Implementation, coverage and equity of large-scale door-to-door delivery of Seasonal Malaria Chemoprevention (SMC) to children under 10 in Senegal. AB - SMC has been introduced widely in the Sahel since its recommendation by WHO in 2012. This study, which provided evidence of feasibility that supported the recommendation, included school-age and pre-school children. School-age children were not included in the 2012 recommendation but bear an increasing proportion of cases. In 2006, consultations with health-staff were held to choose delivery methods. The preferred approach, door-to-door with the first daily-dose supervised by a community-health-worker (CHW), was piloted and subsequently evaluated on a large-scale in under-5's in 2008 and then in under-10's 2009-2010. Coverage was higher among school-age children (96%(95%CI 94%,98%) received three treatments in 2010) than among under 5's (90%(86%,94%)). SMC was more equitable than LLINs (odds-ratio for increase in coverage for a one-level rise in socioeconomic-ranking (a 5-point scale), was 1.1 (0.95,1.2) in 2009, compared with OR 1.3 (1.2,1.5) for sleeping under an LLIN. Effective communication was important in achieving high levels of uptake. Continued training and supervision were needed to ensure CHWs adhered to treatment guidelines. SMC door-to-door can, if carefully supervised, achieve high equitable coverage and high-quality delivery. SMC programmes can be adapted to include school-age children, a neglected group that bears a substantial burden of malaria. PMID- 29615764 TI - Genome-wide screen for universal individual identification SNPs based on the HapMap and 1000 Genomes databases. AB - Differences among SNP panels for individual identification in SNP-selecting and populations led to few common SNPs, compromising their universal applicability. To screen all universal SNPs, we performed a genome-wide SNP mining in multiple populations based on HapMap and 1000Genomes databases. SNPs with high minor allele frequencies (MAF) in 37 populations were selected. With MAF from >=0.35 to >=0.43, the number of selected SNPs decreased from 2769 to 0. A total of 117 SNPs with MAF >=0.39 have no linkage disequilibrium with each other in every population. For 116 of the 117 SNPs, cumulative match probability (CMP) ranged from 2.01 * 10-48 to 1.93 * 10-50 and cumulative exclusion probability (CEP) ranged from 0.9999999996653 to 0.9999999999945. In 134 tested Han samples, 110 of the 117 SNPs remained within high MAF and conformed to Hardy-Weinberg equilibrium, with CMP = 4.70 * 10-47 and CEP = 0.999999999862. By analyzing the same number of autosomal SNPs as in the HID-Ion AmpliSeq Identity Panel, i.e. 90 randomized out of the 110 SNPs, our panel yielded preferable CMP and CEP. Taken together, the 110-SNPs panel is advantageous for forensic test, and this study provided plenty of highly informative SNPs for compiling final universal panels. PMID- 29615765 TI - Anisotropy and Strain Localization in Dynamic Impact Experiments of Tantalum Single Crystals. AB - Deformation mechanisms in bcc metals, especially in dynamic regimes, show unusual complexity, which complicates their use in high-reliability applications. Here, we employ novel, high-velocity cylinder impact experiments to explore plastic anisotropy in single crystal specimens under high-rate loading. The bcc tantalum single crystals exhibit unusually high deformation localization and strong plastic anisotropy when compared to polycrystalline samples. Several impact orientations - [100], [110], [111] and [[Formula: see text]] - are characterized over a range of impact velocities to examine orientation-dependent mechanical behavior versus strain rate. Moreover, the anisotropy and localized plastic strain seen in the recovered cylinders exhibit strong axial symmetries which differed according to lattice orientation. Two-, three-, and four-fold symmetries are observed. We propose a simple crystallographic argument, based on the Schmid law, to understand the observed symmetries. These tests are the first to explore the role of single-crystal orientation in Taylor impact tests and they clearly demonstrate the importance of crystallography in high strain rate and temperature deformation regimes. These results provide critical data to allow dramatically improved high-rate crystal plasticity models and will spur renewed interest in the role of crystallography to deformation in dynamics regimes. PMID- 29615766 TI - Aspermerodione, a novel fungal metabolite with an unusual 2,6 dioxabicyclo[2.2.1]heptane skeleton, as an inhibitor of penicillin-binding protein 2a. AB - Rising drug resistance limits the treatment options infected by methicillin resistant Staphylococcus aureus (MRSA). A promising solution for overcoming the resistance of MRSA is to inhibit the penicillin-binding protein 2a (PBP2a). A novel terpene-polyketide hybrid meroterpenoid, aspermerodione (1), characterized by an unusual 2,6-dioxabicyclo[2.2.1]heptane core skeleton, and a new heptacyclic analogue, andiconin C (2), were isolated and identified from the liquid cultures of endophytic fungus Aspergillus sp. TJ23. The structures and their absolute configurations of all chiral centers were elucidated via extensive spectroscopic analyses and electronic circular dichroism (ECD) calculations and determined via single-crystal X-ray diffraction analysis. Aspemerodione (1) was found to be a potential inhibitor of PBP2a, and work synergistically with the beta-lactam antibiotics oxacillin and piperacillin against MRSA. PMID- 29615767 TI - A water-based green approach to large-scale production of aqueous compatible graphene nanoplatelets. AB - The unique properties of graphene are highly desired for printing electronics, coatings, energy storage, separation membranes, biomedicine, and composites. However, the high efficiency exfoliation of graphene into single- or few-layered nanoplates remains a grand challenge and becomes the bottleneck in essential studies and applications of graphene. Here, we report a scalable and green method to exfoliate graphene nanoplatelets (GNPs) from nature graphite in pure water without using any chemicals or surfactants. The essence of this strategy lies in the facile liquid exfoliation route with the assistance of vapor pretreatment for the preparation of edge hydroxylated graphene. The produced graphene consisted primarily of fewer than ten atomic layers. Such the water soluble graphene can be stored in the form of dispersion (~0.55 g L-1) or filter cake for more than 6 months without the risk of re-stacking. This method paves the way for the environmentally friendly and cost-effective production of graphene-based materials. PMID- 29615768 TI - Anomalous transparency in photonic crystals and its application to point-by-point grating inscription in photonic crystal fibers. AB - It is common belief that photonic crystals behave similarly to isotropic and transparent media only when their feature sizes are much smaller than the wavelength of light. Here, we counter that belief and we report on photonic crystals that are transparent for anomalously high normalized frequencies up to 0.9, where the crystal's feature sizes are comparable with the free space wavelength. Using traditional photonic band theory, we demonstrate that the isofrequency curves can be circular in the region above the first stop band for triangular lattice photonic crystals. In addition, by simulating how efficiently a tightly focused Gaussian beam propagates through the photonic crystal slab, we judge on the photonic crystal's transparency rather than on isotropy only. Using this approach, we identified a wide range of photonic crystal parameters that provide anomalous transparency. Our findings indicate the possibility to scale up the features of photonic crystals and to extend their operational wavelength range for applications including optical cloaking and graded index guiding. We applied our result in the domain of femtosecond laser micromachining, by demonstrating what we believe to be the first point-by-point grating inscribed in a multi-ring photonic crystal fiber. PMID- 29615769 TI - Simultaneous Monitoring of Cell-surface Receptor and Tumor-targeted Photodynamic Therapy via TdT-initiated Poly-G-Quadruplexes. AB - Cancer cells contain a unique set of cell surface receptors that provide potential targets for tumor theranostics. Here, we propose an efficient approach to construct G-quadruplex-based aptamers that specifically recognize cell-surface receptors and monitor them in an amplified manner. This designed aptamer combined particular sequence for the c-Met on the cell surface and poly-G-quadruplexes structures that allow a rapid and amplified fluorescent readout upon the binding of thioflavin T (ThT). The poly-G-quadruplexes also function as a carrier for photosensitizers such as TMPyP4 in that, the aptamer further trigger the production of reactive oxygen species (ROS) to commit cells to death. This unique c-Met targeting aptamer enabled simultaneous monitoring of c-Met on the cell surface with ThT and photodynamic killing of these lung cancer cells with TMPyP4. This strategy is expected to enhance the development of tumor-targeted diagnosis and drug delivery. PMID- 29615770 TI - Mixture toxicity assisting the design of eco-friendlier plant protection products: a case-study using a commercial herbicide combining nicosulfuron and terbuthylazine. AB - The development of environmentally friendly plant protection products (PPPs), including pesticides, is a challenge nowadays. A commercial herbicide combining terbuthylazine and nicosulfuron as active substances (a.s.) was selected as a model PPP. The suitability of manipulating the ratio between a.s. towards alternative formulations with reduced impacts in a non-target indicator (Lemna minor) was assessed. The efficacy of such eco-friendlier a.s. ratios was then assessed using a target weed, Portulaca oleracea. Single and mixture toxicity testing with L. minor revealed an antagonistic joint action of the a.s., suggesting an environmentally protective effect of the combination compared to single dosing of a.s. The efficacy testing against the target weed of single and combined treatments of the a.s. showed that (i) the a.s. behave antagonistically throughout the whole P. oleracea response surface; (ii) there were no environmentally safe a.s. combinations ensuring target-efficacy; (iii) terbuthylazine alone was effective in controlling P. oleracea with no environmental hazardous potential, dosed at concentrations 10-fold lower than those involved in commercially recommended application doses. Overall, this case study suggests that modelling tools widely used in the field of environmental risk assessment of PPPs may also have application in PPP design stages for a more efficient meeting of efficacy and environmental friendliness requirements. PMID- 29615771 TI - Uptake of plant-derived specific alkaloids allows males of a butterfly to copulate. AB - Certain butterflies utilize plant-acquired alkaloids for their own chemical defense and/or for producing male sex pheromone; a trait known as pharmacophagy. Males of the danaine butterfly, Parantica sita, have been reported to ingest pyrrolizidine alkaloids (PAs) as adults to produce two PA-derived sex pheromone components, viz. danaidone (major) and 7R-hydroxydanaidal. We found, however, that not all PAs that can be precursors for the pheromone serve for mating success of males. Here we show that although the sex pheromone is regarded as a requisite for successful mating, uptake of specific PA(s) (lycopsamine-type PAs) is also imperative for the males to achieve copulation. The increase in the levels of two biogenic amines, octopamine and/or serotonin, in the brain and thoracic ganglia of males fed with specific PA(s) suggested that these alkaloids most likely enhance male mating activity. The results can present new evidence for the evolutionary provenance of pharmacophagous acquisition of PAs in PA adapted insects. PMID- 29615772 TI - High-Density Genetic Map Construction and Identification of QTLs Controlling Oleic and Linoleic Acid in Peanut using SLAF-seq and SSRs. AB - The cultivated peanut, A. hypogaea L., is an important oil and food crop globally.High-density genetic linkage mapping is a valuable and effective method for exploring complex quantitative traits. In this context, a recombinant inbred line (RIL) of 146 lines was developed by crossing Huayu28 and P76. We developed 433,679 high-quality SLAFs, of which 29,075 were polymorphic. 4,817 SLAFs were encoded and grouped into different segregation patterns. A high-resolution genetic map containing 2,334 markers (68 SSRs and 2,266 SNPs) on 20 linkage groups (LGs) spanning 2586.37 cM was constructed for peanut. The average distance between adjacent markers was 2.25 cM. Based on phenotyping in seven environments, QTLs for oleic acid (C18:1), linoleic acid (C18:2) and the ratio of oleic acid to linoleic acid (O/L) were identified and positioned on linkage groups A03, A04, A09, B09 and B10. Marker2575339 and Marker2379598 in B09 were associated with C18:1, C18:2 and O/L in seven environments, Marker4391589 and Marker4463600 in A09 were associated with C18:1, C18:2 and O/L in six environments. This map exhibits high resolution and accuracy, which will facilitate QTL discovery for essential agronomic traits in peanut. PMID- 29615774 TI - Engineered optical and electrical performance of rf-sputtered undoped nickel oxide thin films for inverted perovskite solar cells. AB - Inverted perovskite solar cells incorporating RF sputtered NiO thin films as a hole transport layer and window layer are demonstrated. The electrical and optical properties of the NiO thin films are engineered using varied sputtering conditions. The localized states within bandgap owing to its crystal disorder and nonstoichiometric features affect the transmittance and the optical bandgap of the NiO thin films which in turn influences the Jsc of the perovskite solar cells. In addition, the electrical properties of the NiO thin films can be also varied during sputtering condition affecting the concentration of nickel vacancies and the resulting hole concentration. The conductivity largely originates from the hole concentration relating to the density of states in the NiO thin films which influence the fill factor (FF) of the solar cells. The solar cells fabricated with the NiO thin films made at 4 Pa of deposition pressure show highest performance owing to excellent transmittance and wider bandgap along with moderate conductivity. With further optimization, the perovskite solar cells exhibit ~20 mA/cm2 of Jsc and a 12.4% PCE (11.3% of averaged PCE). PMID- 29615773 TI - MTGO: PPI Network Analysis Via Topological and Functional Module Identification. AB - Protein-protein interaction (PPI) networks are viable tools to understand cell functions, disease machinery, and drug design/repositioning. Interpreting a PPI, however, it is a particularly challenging task because of network complexity. Several algorithms have been proposed for an automatic PPI interpretation, at first by solely considering the network topology, and later by integrating Gene Ontology (GO) terms as node similarity attributes. Here we present MTGO - Module detection via Topological information and GO knowledge, a novel functional module identification approach. MTGO let emerge the bimolecular machinery underpinning PPI networks by leveraging on both biological knowledge and topological properties. In particular, it directly exploits GO terms during the module assembling process, and labels each module with its best fit GO term, easing its functional interpretation. MTGO shows largely better results than other state of the art algorithms (including recent GO-based ones) when searching for small or sparse functional modules, while providing comparable or better results all other cases. MTGO correctly identifies molecular complexes and literature-consistent processes in an experimentally derived PPI network of Myocardial infarction. A software version of MTGO is available freely for non-commercial purposes at https://gitlab.com/d1vella/MTGO . PMID- 29615775 TI - NMR Structure, Dynamics and Interactions of the Integrin beta2 Cytoplasmic Tail with Filamin Domain IgFLNa21. AB - Integrins are transmembrane proteins that mediate cell adhesion and migration. Each integrin is a heterodimer formed by an alpha and a beta subunit. A large number of cytoplasmic proteins interact with the cytoplasmic tails (CTs) of integrins. The actin-binding cytoskeletal protein filamin A is a negative regulator of integrin activation. The IgFLNa21 domain of filamin A binds to the C terminus of beta2 CT that contains a TTT-motif. Based on x-ray crystallography, it has been reported that the integrin beta2 CT forms a beta strand that docks into the beta strands C and D of IgFLNa21. In this study, we performed solution NMR analyses of IgFLNa21 in the presence of integrin beta2 CT peptides, and hybrid IgFLNa21, a construct of covalently linked IgFLNa21 and beta2 CT. The atomic resolution structure of the hybrid IgFLNa21 demonstrated conserved binding mode with beta2 CT. Although, 15N relaxation, model free analyses and H-D exchange studies have uncovered important insights into the conformational dynamics and stability of beta2 CT in complex with IgFLNa21. Such dynamical characteristics are likely to be necessary for the TTT-motif to serve as a phosphorylation switch that regulates filamin A binding to integrin beta2 CT. PMID- 29615776 TI - Dysbiosis of the salivary microbiota in pediatric-onset primary sclerosing cholangitis and its potential as a biomarker. AB - Primary sclerosing cholangitis (PSC) is a liver disease known for its frequent concurrence with inflammatory bowel disease. Dysbiosis of the gut microbiota in PSC was reported in several studies, but the microbiological features of the salivary microbiota in PSC have not been established. Here we compared the salivary microbial communities of 24 pediatric-onset PSC patients, 16 age-matched ulcerative colitis (UC) patients, and 24 healthy controls (HCs) by analyzing the bacterial 16S rRNA gene sequence data. The species-richness (alpha-diversity) showed no significant between-group differences, whereas the overall salivary microbiota structure (beta-diversity) showed significant differences among the three groups. Taxonomic assignment revealed that the PSC salivary microbiota were characterized by significant decreases in the abundance of Rothia and Haemophilus compared to the HC group, and significantly decreased Haemophilus and increased Oribacterium compared to the UC group. By combining the genera selected by the random forest algorithm in machine learning, followed by confirmation with 10 fold cross-validation, we were able to distinguish the PSC group from the HC group with the area under the curve (AUC) of 0.7423, and from the UC group with the AUC of 0.8756. Our results indicate the potential of salivary microbiota as biomarkers for a noninvasive diagnosis of PSC. PMID- 29615777 TI - A comparative analysis of rod bipolar cell transcriptomes identifies novel genes implicated in night vision. AB - In the mammalian retina, rods and a specialised rod-driven signalling pathway mediate visual responses under scotopic (dim light) conditions. As rods primarily signal to rod bipolar cells (RBCs) under scoptic conditions, disorders that affect rod or RBC function are often associated with impaired night vision. To identify novel genes expressed by RBCs and, therefore, likely to be involved in night vision, we took advantage of the adult Bhlhe23-/- mouse retina (that lacks RBCs) to derive the RBC transcriptome. We found that genes expressed by adult RBCs are mainly involved in synaptic structure and signalling, whereas genes that influence RBC development are also involved in the cell cycle and transcription/translation. By comparing our data with other published retinal and bipolar cell transcriptomes (where we identify RBCs by the presence of Prkca and/or Pcp2 transcripts), we have derived a consensus for the adult RBC transcriptome. These findings ought to facilitate further research into physiological mechanisms underlying mammalian night vision as well as proposing candidate genes for patients with inherited causes of night blindness. PMID- 29615778 TI - Hybridization and differential introgression associated with environmental shifts in a mistletoe species complex. AB - Host specialization after host shifting is traditionally viewed as the pathway to speciation in parasitic plants. However, geographical and environmental changes can also influence parasite speciation, through hybridization processes. Here we investigated the impact of past climatic fluctuations, environment, and host shifts on the genetic structure and patterns of hybridization and gene flow between Psittacanthus calyculatus and P. schiedeanus, a Mesoamerican species complex. Using microsatellites (408 individuals), we document moderate genetic diversity but high genetic differentiation between widespread parental clusters, calyculatus in dry pine-oak forests and schiedeanus in cloud forests. Bayesian analyses identified a third cluster, with admixture between parental clusters in areas of xeric and tropical dry forests and high levels of migration rates following secondary contact. Coincidently host associations in these areas differ from those in areas of parental species, suggesting that past hybridization played a role in environmental and host shifts. Overall, the observed genetic and geographic patterns suggest that these Psittacanthus populations could have entered a distinct evolutionary pathway. The results provide evidence for highlights on the importance of the Pleistocene climate changes, habitat differences, and potential host shifts in the evolutionary history of Neotropical mistletoes. PMID- 29615779 TI - Collective electrical oscillations of a diatom population induced by dark stress. AB - Diatoms are photosynthetic microalgae, a group with a major environmental role on the planet due to the biogeochemical cycling of silica and global fixation of carbon. However, they can evolve into harmful blooms through a resourceful communication mechanism, not yet fully understood. Here, we demonstrate that a population of diatoms under darkness show quasi-periodic electrical oscillations, or intercellular waves. The origin is paracrine signaling, which is a feedback, or survival, mechanism that counteracts changes in the physicochemical environment. The intracellular messenger is related to Ca2+ ions since spatiotemporal changes in their concentration match the characteristics of the intercellular waves. Our conclusion is supported by using a Ca2+ channel inhibitor. The transport of Ca2+ ions through the membrane to the extracellular medium is blocked and the intercellular waves disappear. The translation of microalgae cooperative signaling paves the way for early detection and prevention of harmful blooms and an extensive range of stress-induced alterations in the aquatic ecosystem. PMID- 29615781 TI - How accurate is the clinical and radiological evaluation of orbital lesions in comparison to surgical orbital biopsy? AB - AIMS: The purpose of the present study is to determine the overall and disease related accuracy of clinical and radiological diagnosis when compared to the histology result of the surgical orbital biopsy. METHODS: A retrospective case notes analysis of patients who underwent surgical orbital biopsy during a 12-year period involving more than 100 orbital lesions. The accuracy of clinical and radiological diagnosis was compared with histological diagnosis. RESULTS: A total of 112 orbital biopsies were carried out in 104 eyes of 101 patients between 2003 and 2015. Correct diagnosis was reached in <50% of cases by both ophthalmologists and radiologists alike. Vascular lesions exhibit characteristic clinical and imaging features that allow for accurate diagnosis and can often be managed conservatively. The greatest challenge, both clinically and on imaging was in differentiating between inflammatory and haematological orbital lesions which represented half of our cases. There was no operative mortality and there were no post-operative complications recorded. CONCLUSION: Surgical orbital biopsy is a safe and accurate diagnostic tool for orbital lesions of unknown aetiology and, in our opinion, remains the gold standard. PMID- 29615782 TI - Preventive Effect of Low Intensity Pulsed Ultrasound against Experimental Cerebral Ischemia/Reperfusion Injury via Apoptosis Reduction and Brain-derived Neurotrophic Factor Induction. AB - Stroke is known as the top 10 causes of death worldwide. Development of effectively neuroprotective or preventive strategies for ischemia stroke is imperative. For the purpose of stroke prevention, we tested the neuroprotective effects of low-intensity pulsed ultrasound (LIPUS) on ischemic stroke. Adult C57BL/6 mice were used to daily treatment with LIPUS for 5 days on left hemisphere before middle cerebral artery occlusion (MCAO)-induced cerebral ischemia/reperfusion injury. Western blotting and immunohistochemistry were performed to assess the protein expressions of signaling molecules. Pretreatment with LIPUS significantly ameliorated the brain ischemic damage, including the reduction of neurological deficit score, infarct area, histopathological score, and showed a better performance in neurological and behavior functions. LIPUS pretreatment could also significantly decrease the neuronal cell apoptosis and upregulation of apoptosis-related signaling molecules and downregulation of brain derived neurotrophic factor (BDNF) in brain tissues of MCAO-treated mice. Furthermore, LIPUS significantly prevented the decreased cell viability, the increased caspase-3 cleavage, and the decreased BDNF expression in ischemia/reperfusion-treated microglial cells. These results demonstrate that LIPUS effectively prevented the cerebral ischemia/reperfusion injury through apoptosis reduction and BDNF induction in a MCAO mouse model. The neuroprotective potential of LIPUS may provide a novel preventive strategy for ischemic stroke in high-risk patients. PMID- 29615780 TI - De novo draft assembly of the Botrylloides leachii genome provides further insight into tunicate evolution. AB - Tunicates are marine invertebrates that compose the closest phylogenetic group to the vertebrates. These chordates present a particularly diverse range of regenerative abilities and life-history strategies. Consequently, tunicates provide an extraordinary perspective into the emergence and diversity of these traits. Here we describe the genome sequencing, annotation and analysis of the Stolidobranchian Botrylloides leachii. We have produced a high-quality 159 Mb assembly, 82% of the predicted 194 Mb genome. Analysing genome size, gene number, repetitive elements, orthologs clustering and gene ontology terms show that B. leachii has a genomic architecture similar to that of most solitary tunicates, while other recently sequenced colonial ascidians have undergone genome expansion. In addition, ortholog clustering has identified groups of candidate genes for the study of colonialism and whole-body regeneration. By analysing the structure and composition of conserved gene linkages, we observed examples of cluster breaks and gene dispersions, suggesting that several lineage-specific genome rearrangements occurred during tunicate evolution. We also found lineage specific gene gain and loss within conserved cell-signalling pathways. Such examples of genetic changes within conserved cell-signalling pathways commonly associated with regeneration and development that may underlie some of the diverse regenerative abilities observed in tunicates. Overall, these results provide a novel resource for the study of tunicates and of colonial ascidians. PMID- 29615784 TI - Choose your yeast strain carefully: the RAD5 gene matters. PMID- 29615783 TI - Isolation and characterisation of CD9-positive pituitary adult stem/progenitor cells in rats. AB - S100beta protein and SOX2-double positive (S100beta/SOX2-positive) cells have been suggested to be adult pituitary stem/progenitor cells exhibiting plasticity and multipotency. The aim of the present study was to isolate S100beta/SOX2 positive cells from the adult anterior lobes of rats using a specific antibody against a novel membrane marker and to study their characteristics in vitro. We found that cluster of differentiation (CD) 9 is expressed in the majority of adult rat S100beta/SOX2-positive cells, and we succeeded in isolating CD9 positive cells using an anti-CD9 antibody with a pluriBead-cascade cell isolation system. Cultivation of these cells showed their capacity to differentiate into endothelial cells via bone morphogenetic protein signalling. By using the anterior lobes of prolactinoma model rats, the localisation of CD9-positive cells was confirmed in the tumour-induced neovascularisation region. Thus, the present study provides novel insights into adult pituitary stem/progenitor cells involved in the vascularisation of the anterior lobe. PMID- 29615785 TI - Shared neural correlates for building phrases in signed and spoken language. AB - Research on the mental representation of human language has convincingly shown that sign languages are structured similarly to spoken languages. However, whether the same neurobiology underlies the online construction of complex linguistic structures in sign and speech remains unknown. To investigate this question with maximally controlled stimuli, we studied the production of minimal two-word phrases in sign and speech. Signers and speakers viewed the same pictures during magnetoencephalography recording and named them with semantically identical expressions. For both signers and speakers, phrase building engaged left anterior temporal and ventromedial cortices with similar timing, despite different linguistic articulators. Thus the neurobiological similarity of sign and speech goes beyond gross measures such as lateralization: the same fronto temporal network achieves the planning of structured linguistic expressions. PMID- 29615786 TI - Rapid selection of sulphadoxine-resistant Plasmodium falciparum and its effect on within-population genetic diversity in Papua New Guinea. AB - The ability of the human malarial parasite Plasmodium falciparum to adapt to environmental changes depends considerably on its ability to maintain within population genetic variation. Strong selection, consequent to widespread antimalarial drug usage, occasionally elicits a rapid expansion of drug-resistant isolates, which can act as founders. To investigate whether this phenomenon induces a loss of within-population genetic variation, we performed a population genetic analysis on 302 P. falciparum cases detected during two cross-sectional surveys in 2002/2003, just after the official introduction of sulphadoxine/pyrimethamine as a first-line treatment, and again in 2010/2011, in highly endemic areas in Papua New Guinea. We found that a single-origin sulphadoxine-resistant parasite isolate rapidly increased from 0% in 2002/2003 to 54% in 2010 and 84% in 2011. However, a considerable number of pairs exhibited random associations among 10 neutral microsatellite markers located in various chromosomes, suggesting that outcrossing effectively reduced non-random associations, albeit at a low average multiplicity of infection (1.35-1.52). Within-population genetic diversity was maintained throughout the study period. This indicates that the parasites maintained within-population variation, even after a clonal expansion of drug-resistant parasites. Outcrossing played a role in the preservation of within-population genetic diversity despite low levels of multiplicity of infection. PMID- 29615787 TI - Serum brain-derived neurotrophic factor predicting reduction in pulse pressure after a one-hour rest in nurses working night shifts. AB - Night shift work is associated with cardiovascular disease and central nervous system disorders in female nurses. Brain-derived neurotrophic factor (BDNF) exerts protective effects on neural and endothelial functions. This study examined the association between serum BDNF levels and pulse pressure after rest in female nurses working night shifts. In this study, blood samples were collected for BDNF measurement after a night shift when nurses had been working night shifts for three continuous weeks. Blood pressure was assessed before and after a one-hour morning rest within a week of resuming the night shift after one month without any night shift work. The pulse pressure of nurses (n = 48, age 29 +/- 5 years) was significantly reduced (from 43 +/- 7 to 41 +/- 6 mmHg, P = 0.003) after rest, and serum BDNF were significantly and inversely correlated with pulse pressure changes (r = -0.435, P = 0.002). Higher serum BDNF was an independent factor for greater reduction in pulse pressure (95%CI = -0.609 - 0.174, P = 0.001). Using a receiver operating characteristic curve analysis, serum BDNF >20.6 ng/mL predicted a pulse pressure reduction after a one-hour rest (sensitivity 66.7%, specificity 77.8%). In conclusion, higher serum BDNF predicted greater recovery of pulse pressure after a one-hour rest in female nurses after night shift work. PMID- 29615788 TI - Disturbed retrieval network and prospective memory decline in postpartum women. AB - Prospective memory (PM) refers to the ability to remember to execute an intended action in the future. For successful PM performance, both top-down strategic monitoring and bottom-up spontaneous retrieval processes need to be appropriately recruited. We assessed PM performance and used fMRI to discover relevant neural correlates and possible predictors for PM performance in 25 postpartum and 26 nulliparous age- and education-matched women. Postpartum women showed decreased PM performance, a higher number of nocturnal awakenings, and lower estradiol level. The postpartum women had decreased functional connectivity (FC) in the right hippocampus and ventral frontoparietal networks (FPN) during retrieval dominant PM trials relative to maintenance-dominant ongoing trials in the PM block. On multivariate analyses, decreased FC between the right hippocampus and ventral FPN and a higher number of nocturnal awakenings were independent predictors for poor PM performance after adjusting for age, education, estradiol level, and depressive symptoms. On mediation analyses, the estradiol level was found to have an indirect effect on PM accuracy via altered FC as a mediator. This suggests that decreased FC within the spontaneous retrieval-related regions including the right hippocampus and ventral FPN, disrupted sleep rhythms, and decreased estradiol level may contribute to poor PM performance in postpartum women. PMID- 29615789 TI - Metabolic enzyme PFKFB4 activates transcriptional coactivator SRC-3 to drive breast cancer. AB - Alterations in both cell metabolism and transcriptional programs are hallmarks of cancer that sustain rapid proliferation and metastasis 1 . However, the mechanisms that control the interaction between metabolic reprogramming and transcriptional regulation remain unclear. Here we show that the metabolic enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 4 (PFKFB4) regulates transcriptional reprogramming by activating the oncogenic steroid receptor coactivator-3 (SRC-3). We used a kinome-wide RNA interference-based screening method to identify potential kinases that modulate the intrinsic SRC-3 transcriptional response. PFKFB4, a regulatory enzyme that synthesizes a potent stimulator of glycolysis 2 , is found to be a robust stimulator of SRC-3 that coregulates oestrogen receptor. PFKFB4 phosphorylates SRC-3 at serine 857 and enhances its transcriptional activity, whereas either suppression of PFKFB4 or ectopic expression of a phosphorylation-deficient Ser857Ala mutant SRC-3 abolishes the SRC-3-mediated transcriptional output. Functionally, PFKFB4-driven SRC-3 activation drives glucose flux towards the pentose phosphate pathway and enables purine synthesis by transcriptionally upregulating the expression of the enzyme transketolase. In addition, the two enzymes adenosine monophosphate deaminase-1 (AMPD1) and xanthine dehydrogenase (XDH), which are involved in purine metabolism, were identified as SRC-3 targets that may or may not be directly involved in purine synthesis. Mechanistically, phosphorylation of SRC-3 at Ser857 increases its interaction with the transcription factor ATF4 by stabilizing the recruitment of SRC-3 and ATF4 to target gene promoters. Ablation of SRC-3 or PFKFB4 suppresses breast tumour growth in mice and prevents metastasis to the lung from an orthotopic setting, as does Ser857Ala-mutant SRC 3. PFKFB4 and phosphorylated SRC-3 levels are increased and correlate in oestrogen receptor-positive tumours, whereas, in patients with the basal subtype, PFKFB4 and SRC-3 drive a common protein signature that correlates with the poor survival of patients with breast cancer. These findings suggest that the Warburg pathway enzyme PFKFB4 acts as a molecular fulcrum that couples sugar metabolism to transcriptional activation by stimulating SRC-3 to promote aggressive metastatic tumours. PMID- 29615790 TI - Multivariate Granger causality unveils directed parietal to prefrontal cortex connectivity during task-free MRI. AB - While a large body of research has focused on the study of functional brain "connectivity", few investigators have focused on directionality of brain-brain interactions which, in spite of the mostly bidirectional anatomical substrates, cannot be assumed to be symmetrical. We employ a multivariate Granger Causality based approach to estimating directed in-network interactions and quantify its advantages using extensive realistic synthetic BOLD data simulations to match Human Connectome Project (HCP) data specification. We then apply our framework to resting state functional MRI (rs-fMRI) data provided by the HCP to estimate the directed connectome of the human brain. We show that the functional interactions between parietal and prefrontal cortices commonly observed in rs-fMRI studies are not symmetrical, but consists of directional connectivity from parietal areas to prefrontal cortices rather than vice versa. These effects are localized within the same hemisphere and do not generalize to cross-hemispheric functional interactions. Our data are consistent with neurophysiological evidence that posterior parietal cortices involved in processing and integration of multi sensory information modulate the function of more anterior prefrontal regions implicated in action control and goal-directed behaviour. The directionality of functional connectivity can provide an additional layer of information in interpreting rs-fMRI studies both in health and disease. PMID- 29615791 TI - Autoantibody Profiling in Lupus Patients using Synthetic Nucleic Acids. AB - Autoantibodies to nuclear components of cells (antinuclear antibodies, ANA), including DNA (a-DNA), are widely used in the diagnosis and subtyping of certain autoimmune diseases, including systemic lupus erythematosus (SLE). Despite clinical use over decades, precise, reproducible measurement of a-DNA titers remains difficult, likely due to the substantial sequence and length heterogeneity of DNA purified from natural sources. We designed and tested a panel of synthetic nucleic acid molecules composed of native deoxyribonucleotide units to measure a-DNA. ELISA assays using these antigens show specificity and reproducibility. Applying the ELISA tests to serological studies of pediatric and adult SLE, we identified novel clinical correlations. We also observed preferential recognition of a specific synthetic antigen by antibodies in SLE sera. We determined the probable basis for this finding using computational analyses, providing valuable structural information for future development of DNA antigens. Synthetic nucleic acid molecules offer the opportunity to standardize assays and to dissect antibody-antigen interactions. PMID- 29615792 TI - Exercise in patients with hypertension and chronic kidney disease: a randomized controlled trial. AB - Hypertension and chronic kidney disease (CKD) are global public health problems, both associated with higher risk of cardiovascular (CV) and renal events. This trial randomized non-diabetic adult patients with hypertension and CKD stages 2-4 to 16 weeks of aerobic and resistance training or usual care. The primary outcome was the change in estimated glomerular filtration rate (eGFR). Secondary outcomes included changes in systolic and diastolic blood pressure (BP), body weight, fasting blood glucose, lipid profile, high-sensitivity C-reactive protein (hs CRP), and functional capacity. The analysis was performed by intention-to-treat, using linear mixed-effects models for repeated measures over time. A hundred fifty patients were included in the intervention (76) or control (74) groups. No difference was found in eGFR, BP, body weight, or lipid profile changes between the groups. However, there were significant decreases in hs-CRP [-6.7(-11.7 to 1.8) mg/L] and fasting blood glucose [-11.3(-20.0 to -1.8) mg/dL], and an increase in functional capacity [2' Step Test 33.9 (17.7-50.0); 30" Stand Test 2.3 (0.9-3.7)] in exercise group compared with control group. The results of this RCT show that combined aerobic and resistance training could reduce inflammation and insulin resistance in hypertensive patients with earlier stages of CKD, without a significant effect on kidney disease progression. Clinical trials.gov NCT01155128. PMID- 29615794 TI - Effect of magnetic fullerene on magnetization reversal created at the Fe/C60 interface. AB - Probing the hybridized magnetic interface between organic semiconductor (OSC) and ferromagnetic (FM) layers has drawn significant attention in recent years because of their potential in spintronic applications. Recent studies demonstrate various aspects of organic spintronics such as magnetoresistance, induced interface moment etc. However, not much work has been performed to investigate the implications of such OSC/FM interfaces on the magnetization reversal and domain structure which are the utmost requirements for any applications. Here, we show that non-magnetic Fullerene can obtain non-negligible magnetic moment at the interface of Fe(15 nm)/C60(40 nm) bilayer. This leads to substantial effect on both the magnetic domain structure as well as the magnetization reversal when compared to a single layer of Fe(15 nm). This is corroborated by the polarized neutron reflectivity (PNR) data which indicates presence of hybridization at the interface by the reduction of magnetic moment in Fe. Afterwards, upto 1.9 nm of C60 near the interface exhibits magnetic moment. From the PNR measurements it was found that the magnetic C60 layer prefers to be aligned anti-parallel with the Fe layer at the remanant state. The later observation has been confirmed by domain imaging via magneto-optic Kerr microscopy. PMID- 29615793 TI - Association between hypertension and circulating vascular-related microRNAs. AB - microRNAs (miRNAs) have a key role in regulating inflammation, vascular health and in turn, cardiovascular disease. Specifically, altered circulating expression of miR-17, miR-21, miR-34a, miR-92a, miR-126, miR-145, miR-146a, and miR-150 has been linked with the pathogenesis and progression of cardiovascular disease. The aim of this study was to determine whether the circulating profile of these vascular-related miRNAs is disrupted with hypertension. Thirty sedentary, middle aged adults were studied: 15 normotensive (10M/5F; age: 56 +/- 1 year; BP: 113/71 +/- 2/1 mmHg) and 15 hypertensive (10M/5F; 56 +/- 2 year; 140/87 +/- 2/2 mmHg). All subjects were non-obese and free of other cardiometabolic disorders. Circulating miRNAs were determined in plasma using standard RT-PCR techniques with miRNA primers of interest. Expression was normalized to exogenous C. elegans miR-39 and reported as relative expression in arbitrary units (AU). Circulating expression of miR-34a (9.18 +/- 0.94 vs 5.33 +/- 0.91 AU) was higher (~170%; P < 0.01) whereas the expression of miR-21 (1.32 +/- 0.25 vs 2.50 +/- 0.29 AU), miR 126 (0.85 +/- 0.10 vs 1.74 +/- 0.27 AU) and miR-146a (1.50 +/- 0.20 vs 3.10 +/- 0.50 AU) were markedly lower (~50%, ~55%, and ~55% respectively; P < 0.05) in the hypertensive vs normotensive groups. Moreover, circulating levels of miR-34a, miR 21, and miR-126 were significantly related to systolic blood pressure (r = 0.48, r = -0.38; r = -0.48); whereas, miR-146a was significantly related to both systolic (r = -0.58) and diastolic (r = -0.55) blood pressure. There were no significant group differences in circulating miR-17, miR-92a, miR-145, and miR 150. In summary, these results suggest that hypertension, independent of other cardiometabolic risk factors, adversely affects the circulating profile of a subset of vascular-related miRNAs that have been link to CVD risk and development. PMID- 29615795 TI - Characterization of Population Genetic Structure of red swamp crayfish, Procambarus clarkii, in China. AB - The red swamp crayfish (Procambarus clarkii) is one of the most economically important farmed aquatic species in China. However, it is also a famous invasive species in the world. This invasive species was dispersed most via human activities including intentional or unintentional carry in China. Thus, P. clarkii naturally distributed in China provides us a desirable mode to investigate the genetic structure of an invasive species dispersed mainly by human-mediated factors. To reveal the impact of human-mediated dispersal on genetic structure of P. clarkii in China, a total of 22,043 genome-wide SNPs were obtained from approximately 7.4 billion raw reads using 2b-RAD technique in this study. An evident pattern of population genetic structure and the asymmetrical migrational rates between different regions were observed with 22 populations based on these SNPs. This study provide a better understanding of the population genetic structure and demographic history of P. clarkii populations in China, inferring that anthropogenic factors (aquaculture or by accident) and ecological factors (e.g., complicated topography and climatic environment), as well as its special biological traits could account for the current population structure pattern and dispersal history of P. clarkii. PMID- 29615796 TI - A high nutrient dense diet alters hypothalamic gene expressions to influence energy intake in pigs born with low birth weight. AB - The low birth weight (LBW) individual had greater risk of developing metabolic dysfunction in adulthood. The aim of this study was to test whether the LBW individual is more prone to glucose intolerance on a high nutrient dense (HND) diet, and to investigate the associated hypothalamic gene expressions using pigs as model. The intake of digestible energy intake, if calculated on a body weight basis, was greater in LBW pigs than that of normal birth weight (NBW) pigs. The LBW pigs fed the HND diet had greater digestible energy intake than those fed the NND diet at adulthood, which did not occur for NBW pigs. Notably, up-regulated hypothalamic toll-like receptor 4, interleukin 6 and phospho-NFkappaB p65 expressions, and the altered expressions of hypothalamic leptin receptor, suppressor of cytokine signaling 3, agouti-related protein and proopiomelanocortin predicted the overconsumption of energy intake and development of glucose intolerance in LBW pigs fed the HND diet. Collectively, pigs born with LBW had a distinct hypothalamic leptin signaling to a high nutrient dense diet, which contributed to greater energy intake and glucose intolerance. PMID- 29615797 TI - A statistical method for analyzing and comparing spatiotemporal cortical activation patterns. AB - Information in the cortex is encoded in spatiotemporal patterns of neuronal activity, but the exact nature of that code still remains elusive. While onset responses to simple stimuli are associated with specific loci in cortical sensory maps, it is completely unclear how the information about a sustained stimulus is encoded that is perceived for minutes or even longer, when discharge rates have decayed back to spontaneous levels. Using a newly developed statistical approach (multidimensional cluster statistics (MCS)) that allows for a comparison of clusters of data points in n-dimensional space, we here demonstrate that the information about long-lasting stimuli is encoded in the ongoing spatiotemporal activity patterns in sensory cortex. We successfully apply MCS to multichannel local field potential recordings in different rodent models and sensory modalities, as well as to human MEG and EEG data, demonstrating its universal applicability. MCS thus indicates novel ways for the development of powerful read out algorithms of spatiotemporal brain activity that may be implemented in innovative brain-computer interfaces (BCI). PMID- 29615798 TI - Aligned laminin core-polydioxanone/collagen shell fiber matrices effective for neuritogenesis. AB - Neural tissue regeneration is a significant challenge, because severe nerve injury is quite difficult to regenerate spontaneously. Although, many studies have been devoted to promote nerve regeneration, there are still many technical challenges to achieve satisfactory results. In this study, we designed biomimetic matrices composed of aligned laminin core-polydioxanone/collagen shell (Lam PDO/Col) fibers, which can provide both topographical and biochemical cues for promoting neuritogenesis. The aligned Lam-PDO/Col core-shell fiber matrices were fabricated by magnetic field-assisted electrospinning with the coaxial system, and their potential as biofunctional scaffolds for promoting neuritogenesis was explored. It was demonstrated that the aligned Lam-PDO/Col core-shell fibers were successfully fabricated, and the laminin in the core of fibers was steadily and continuously released from fibers. In addition, the cellular behaviors of hippocampal neuronal cells on the matrices were significantly enhanced. Moreover, the aligned Lam-PDO/Col fiber matrices effectively improved and guided neurite outgrowth as well as the neurogenic differentiation by providing both topographical and biochemical cues through aligned fiber structure and sustained release of laminin. Collectively, it is suggested that the aligned Lam-PDO/Col core-shell fiber matrices are one of the most promising approaches for promoting neuritogenesis and neural tissue regeneration. PMID- 29615799 TI - Idelalisib impairs TREM-1 mediated neutrophil inflammatory responses. AB - Triggering receptor expressed on myeloid cells (TREM)-1 on polymorphonuclear neutrophils (PMN) regulates innate immune activation in infectious and non infectious conditions. TREM-1 ligation activates phosphatidyl-inositol 3 kinase (PI3K) triggering all neutrophil effector functions. As idelalisib is a PI3K inhibitor in clinical use for the treatment of non-Hodgkin lymphomas, we asked whether this inhibitor affects PMN functionalities. We analyzed PMNs from healthy donors or lymphoma patients for oxidative burst, phagocytosis, activation markers and IL-8 release upon TREM-1 or TLR ligation ex vivo. In addition, we performed western blot analyses to characterize the signaling events inhibited by idelalisib and other PI3K inhibitors. Upon TREM-1 ligation, the oxidative burst, degranulation, L-selectin shedding and cytokine release were all strongly reduced in the presence of idelalisib along impaired phosphorylation of P38, AKT and ERK by western blot analyses. In line with this, PMNs from patients receiving idelalisib also displayed an impaired TREM-1 mediated PMN activation ex vivo. In conclusion, PI3K inhibitors might cause a neutropenia-like susceptibility to infections in patients by leading to impaired PMN functionality. This should be considered when evaluating patients for infections treated with such inhibitors in daily clinical routine. PMID- 29615800 TI - Clear variation of spin splitting by changing electron distribution at non magnetic metal/Bi2O3 interfaces. AB - Large spin splitting at Rashba interface, giving rise to strong spin-momentum locking, is essential for efficient spin-to-charge conversion. Recently, a Cu/Bismuth oxide (Bi2O3) interface has been found to exhibit an efficient spin-to charge conversion similar to a Ag/Bi interface with large Rashba spin splitting. However, the guiding principle of designing the metal/oxide interface for the efficient conversion has not been clarified yet. Here we report strong non magnetic (NM) material dependence of spin splitting at NM/Bi2O3 interfaces. We employed spin pumping technique to inject spin current into the interface and evaluated the magnitude of interfacial spin-to-charge conversion. We observed large modulation and sign change in conversion coefficient which corresponds to the variation of spin splitting. Our experimental results together with first principles calculations indicate that such large variation is caused by material dependent electron distribution near the interface. The results suggest that control of interfacial electron distribution by tuning the difference in work function across the interface may be an effective way to tune the magnitude and sign of spin-to-charge conversion and Rashba parameter at interface. PMID- 29615801 TI - Real-time Detection and Monitoring of Loop Mediated Amplification (LAMP) Reaction Using Self-quenching and De-quenching Fluorogenic Probes. AB - Loop-mediated isothermal amplification (LAMP) is an isothermal nucleic acid amplification (iNAAT) technique known for its simplicity, sensitivity and speed. Its low-cost feature has resulted in its wide scale application, especially in low resource settings. The major disadvantage of LAMP is its heavy reliance on indirect detection methods like turbidity and non-specific dyes, which often leads to the detection of false positive results. In the present work, we have developed a direct detection approach, whereby a labelled loop probe quenched in its unbound state, fluoresces only when bound to its target (amplicon). Henceforth, referred to as Fluorescence of Loop Primer Upon Self Dequenching-LAMP (FLOS-LAMP), it allows for the sequence-specific detection of LAMP amplicons. The FLOS-LAMP concept was validated for rapid detection of the human pathogen, Varicella-zoster virus, from clinical samples. The FLOS-LAMP had a limit of detection of 500 copies of the target with a clinical sensitivity and specificity of 96.8% and 100%, respectively. The high level of specificity is a major advance and solves one of the main shortcomings of the LAMP technology, i.e. false positives. Self-quenching/de-quenching probes were further used with other LAMP primer sets and different fluorophores, thereby demonstrating its versatility and adaptability. PMID- 29615802 TI - Low heart deceleration capacity imply higher atrial fibrillation-free rate after ablation. AB - How deceleration capacity (DC) and acceleration capacity (AC) of heart rate associated with atrial fibrillation (AF) and ablation is still not clear. The dynamic changes of AC, DC and conventional heart rate variability (HRV) parameters were characterized in 154 subjects before circumferential pulmonary veins isolation (CPVI) and three days, 3 months and 6 months after CPVI. The DCs of the recurrent group decreased significantly at each time point after CPVI; the DCs of the recurrence-free group before CPVI and three days, 3 months and 6 months after CPVI were 7.06 +/- 1.77, 3.79 +/- 1.18, 4.22 +/- 1.96 and 3.97 +/- 0.98 ms respectively, which also decreased significantly at each time point and were significantly lower than these of recurrent group. Conversely, the AC of recurrent and recurrence-free groups increased significantly at each time point after CPVI; the ACs of recurrence-fee group were significantly higher than these of recurrent group at each time point. No stable difference trend of HRV parameters was found between two groups. Further Kaplan-Meier analysis showed that DC < 4.8 ms or AC >= -5.1 ms displayed significant higher recurrence-free rates. In conclusion, high AC and low DC imply higher AF-free rate after ablation. PMID- 29615803 TI - Physiological and transcriptome changes induced by Pseudomonas putida acquisition of an integrative and conjugative element. AB - Integrative and conjugative elements (ICEs) comprise ubiquitous large mobile regions in prokaryotic chromosomes that transmit vertically to daughter cells and transfer horizontally to distantly related lineages. Their evolutionary success originates in maximized combined ICE-host fitness trade-offs, but how the ICE impacts on the host metabolism and physiology is poorly understood. Here we investigate global changes in the host genetic network and physiology of Pseudomonas putida with or without an integrated ICEclc, a model ICE widely distributed in proteobacterial genomes. Genome-wide gene expression differences were analyzed by RNA-seq using exponentially growing or stationary phase restimulated cultures on 3-chlorobenzoate, an aromatic compound metabolizable thanks to specific ICEclc-located genes. We found that the presence of ICEclc imposes a variety of changes in global pathways such as cell cycle and amino acid metabolism, which were more numerous in stationary-restimulated than exponential phase cells. Unexpectedly, ICEclc stimulates cellular motility and leads to more rapid growth on 3-chlorobenzoate than cells carrying only the integrated clc genes. ICEclc also concomitantly activates the P. putida Pspu28-prophage, but this in itself did not provoke measurable fitness effects. ICEclc thus interferes in a number of cellular pathways, inducing both direct benefits as well as indirect costs in P. putida. PMID- 29615805 TI - Anthropogenic disturbance keeps the coastal seafloor biogeochemistry in a transient state. AB - Coastal sediments and continental shelves play a crucial role in global biogeochemistry, as they form the prime site of organic carbon burial. Bottom trawling and dredging are known to increasingly impact the coastal seafloor through relocation and homogenisation of sediments, yet little is known about the effects of such anthropogenic sediment reworking on the overall cycling of carbon and other elements within the coastal seafloor. Here, we document the transient recovery of the seafloor biogeochemistry after an in situ disturbance. Evidence from pore-water data and model simulations reveal a short-term increase in the overall carbon mineralisation rate, as well as a longer-term shift in the redox pathways of organic matter mineralisation, favouring organoclastic sulphate reduction over methane formation. This data suggests that anthropogenic sediment reworking could have a sizeable impact on the carbon cycle in cohesive sediments on continental shelves. This imprint will increase in the near future, along with the growing economic exploitation of the coastal ocean. PMID- 29615804 TI - Combining streptozotocin and unilateral nephrectomy is an effective method for inducing experimental diabetic nephropathy in the 'resistant' C57Bl/6J mouse strain. AB - Diabetic nephropathy (DN) is the leading cause of chronic kidney disease. Animal models are essential tools for designing new strategies to prevent DN. C57Bl/6 (B6) mice are widely used for transgenic mouse models, but are relatively resistant to DN. This study aims to identify the most effective method to induce DN in a type 1 (T1D) and a type 2 diabetes (T2D) model in B6 mice. For T1D induced DN, mice were fed a control diet, and randomised to streptozotocin (STZ) alone, STZ+unilateral nephrectomy (UNx), or vehicle/sham. For T2D-induced DN, mice were fed a western (high fat) diet, and randomised to either STZ alone, STZ+UNx, UNx alone, or vehicle/sham. Mice subjected to a control diet with STZ +UNx developed albuminuria, glomerular lesions, thickening of the glomerular basement membrane, and tubular injury. Mice on control diet and STZ developed only mild renal lesions. Furthermore, kidneys from mice on a western diet were hardly affected by diabetes, UNx or the combination. We conclude that STZ combined with UNx is the most effective model to induce T1D-induced DN in B6 mice. In our hands, combining western diet and STZ treatment with or without UNx did not result in a T2D-induced DN model in B6 mice. PMID- 29615806 TI - Controlled biocide release from hierarchically-structured biogenic silica: surface chemistry to tune release rate and responsiveness. AB - Biocides are essential for crop protection, packaging and several other biosystem applications. Therein, properties such as tailored and controlled release are paramount in the development of sustainable biocide delivery systems. We explore the self-similar nano-organized architecture of biogenic silica particles to achieve high biocide payload. The high surface area accessibility of the carrier allowed us to develop an efficient, low energy loading strategy, reaching significant dynamic loadings of up to 100 mg.g-1. The release rate and responsiveness were tuned by manipulating the interfaces, using either the native hydroxyl surfaces of the carrier or systems modified with amines or carboxylic acids in high density. We thoroughly evaluated the impact of the carrier-biocide interactions on the release rate as a function of pH, ionic strength and temperature. The amine and carboxyl functionalization strategy led to three-fold decrease in the release rate, while higher responsiveness against important agro industrial variables. Key to our discoveries, nanostructuring thymol in the biogenic silica endowed systems with controlled, responsive release promoting remarkable, high and localized biocidal activity. The interfacial factors affecting related delivery were elucidated for an increased and localized biocidal activity, bringing a new light for the development of controlled release systems from porous materials. PMID- 29615807 TI - An intronic mutation in Chd7 creates a cryptic splice site, causing aberrant splicing in a mouse model of CHARGE syndrome. AB - Alternate splicing is a critical regulator of gene expression in eukaryotes, however genetic mutations can cause erroneous splicing and disease. Most recorded splicing disorders are caused by mutations of splice donor/acceptor sites, however intronic mutations can affect splicing. Clinical exome analyses largely ignore intronic sequence, limiting the detection of mutations to within coding regions. We describe 'Trooper', a novel mouse model of CHARGE syndrome harbouring a pathogenic point mutation in Chd7. The mutation is 18 nucleotides upstream of exon 10 and creates a cryptic acceptor site, causing exon skipping and partial intron retention. This mutation, though detectable in exome sequence, was initially dismissed by computational filtering due to its intronic location. The Trooper strain exhibited many of the previously described CHARGE-like anomalies of CHD7 deficient mouse lines; including hearing impairment, vestibular hypoplasia and growth retardation. However, more common features such as facial asymmetry and circling were rarely observed. Recognition of these characteristic features prompted manual reexamination of Chd7 sequence and subsequent validation of the intronic mutation, highlighting the importance of phenotyping alongside exome analyses. The Trooper mouse serves as a valuable model of atypical CHARGE syndrome and reveals a molecular mechanism that may underpin milder clinical presentation of the syndrome. PMID- 29615808 TI - Long-term Western diet fed apolipoprotein E-deficient rats exhibit only modest early atherosclerotic characteristics. AB - In the apolipoprotein E-deficient mouse, the gut microbiota has an impact on the development of atherosclerosis, but whether such correlations are also present in rats requires investigation. Therefore, we studied female SD-Apoe tm1sage (Apoe-/ ) rats fed either a Western diet or a low-fat control diet with or without gluten, which is known to promote gut microbiota changes, until 20 weeks of age. We hypothesized that the manifestation of atherosclerosis would be more severe in Apoe-/- rats fed the Western high-fat diet, as compared with rats fed the low-fat diet, and that atherosclerosis would be accelerated by gluten. Both Western diet feeding and gluten resulted in significant changes in gut microbiota, but the microbiota impact of gluten was transient. Compared with Apoe-/- rats fed a low fat diet, Western diet-fed Apoe-/- rats were heavier and became glucose intolerant with increased levels of oxidative stress. They developed early fatty streak lesions in their aortic sinus, while there was no evidence of atherosclerosis in the thoracic aorta. No conclusions could be made on the impact of gluten on atherosclerosis. Although Western diet-fed Apoe-/- rats exhibited a more human-like LDL dominated blood lipid profile, signs of obesity, type 2 diabetes and cardiovascular disease were modest. PMID- 29615809 TI - TAGLN2 polymerizes G-actin in a low ionic state but blocks Arp2/3-nucleated actin branching in physiological conditions. AB - TAGLN is an actin-binding protein family that comprises three isoforms with theorized roles in smooth muscle differentiation, tumour development, lymphocyte activation, and brain chemistry. However, their fundamental characteristics in regulation of the actin-based cytoskeleton are not fully understood. Here we show that TAGLN2 (including TAGLN1 and TAGLN3) extensively nucleates G-actin polymerization under low-salt conditions, where polymerization would be completely suppressed. The calponin homology domain and actin-binding loop are essential to mechanically connect two adjacent G-actins, thereby mediating multimeric interactions. However, TAGLN2 blocked the Arp2/3 complex binding to actin filaments under physiological salt conditions, thereby inhibiting branched actin nucleation. In HeLa and T cells, TAGLN2 enhanced filopodium-like membrane protrusion. Collectively, the dual functional nature of TAGLN2-G-actin polymerization and Arp2/3 complex inhibition-may account for the mechanisms of filopodia development at the edge of Arp2/3-rich lamellipodia in various cell types. PMID- 29615811 TI - Rapid evaluation of seed vigor by the absolute content of protein in seed within the same crop. AB - Seed vigor, an important index of seed quality, determines the potential for rapid and uniform emergence of plants. The objective of this study was to explore a rapid method for evaluating seed vigor. To analyze the correlation of seed traits and seedling traits related to seed vigor, we designed five experiments including nitrogen fertilizer, irrigation and seed sorting treatments in wheat. The results showed that only the absolute content of protein (ACP) in wheat seed was significantly correlated with plant dry weight in five experiments. Subsequently, another experiment including 30 wheat seed lots was used to validate the above results. Although 100-grain weight was also correlated with plant dry weight (R = 0.799, p < 0.01), the correlation coefficient was lower than that between ACP in seed and plant dry weight (R = 0.897, p < 0.01). Moreover, the results of three experiments using maize seeds was similar with above. The relative content of protein in seed detected by near-infrared spectrum combining with seed weight could realize rapid and nondestructive testing ACP in seed. Collectively, ACP in crop seed could be applied in rapid evaluation of seed vigor and could potentially be used for processing and screening high vigor seeds. PMID- 29615810 TI - Population genetic analysis of the recently rediscovered Hula painted frog (Latonia nigriventer) reveals high genetic diversity and low inbreeding. AB - After its recent rediscovery, the Hula painted frog (Latonia nigriventer) has remained one of the world's rarest and least understood amphibian species. Together with its apparently low dispersal capability and highly disturbed niche, the low abundance of this living fossil calls for urgent conservation measures. We used 18 newly developed microsatellite loci and four different models to calculate the effective population size (Ne) of a total of 125 Hula painted frog individuals sampled at a single location. We compare the Ne estimates to the estimates of potentially reproducing adults in this population (Nad) determined through a capture-recapture study on 118 adult Hula painted frogs captured at the same site. Surprisingly, our data suggests that, despite Nad estimates of only ~234-244 and Ne estimates of ~16.6-35.8, the species appears to maintain a very high genetic diversity (HO = 0.771) and low inbreeding coefficient (FIS = 0.018). This puzzling outcome could perhaps be explained by the hypotheses of either genetic rescue from one or more unknown Hula painted frog populations nearby or by recent admixture of genetically divergent subpopulations. Independent of which scenario is correct, the original locations of these populations still remain to be determined. PMID- 29615812 TI - Structure-function analysis and therapeutic efficacy of antibodies to fungal melanin for melanoma radioimmunotherapy. AB - Metastatic melanoma remains difficult to treat despite recent approvals of several new drugs. Recently we reported encouraging results of Phase I clinical trial of radiolabeled with 188Re murine monoclonal IgM 6D2 to melanin in patients with Stage III/IV melanoma. Subsequently we generated a novel murine IgG 8C3 to melanin. IgGs are more amenable to humanization and cGMP (current Good Manufacturing Practice) manufacturing than IgMs. We performed comparative structural analysis of melanin-binding IgM 6D2 and IgG 8C3. The therapeutic efficacy of 213Bi- and 188Re-labeled 8C3 and its comparison with anti-CTLA4 immunotherapy was performed in B16-F10 murine melanoma model. The primary structures of these antibodies revealed significant homology, with the CDRs containing a high percentage of positively charged amino acids. The 8C3 model has a negatively charged binding surface and significant number of aromatic residues in its H3 domain, suggesting that hydrophobic interactions contribute to the antibody-melanin interaction. Radiolabeled IgG 8C3 showed significant therapeutic efficacy in murine melanoma, safety towards healthy melanin-containing tissues and favorable comparison with the anti-CTLA4 antibody. We have demonstrated that antibody binding to melanin relies on both charge and hydrophobic interactions while the in vivo data supports further development of 8C3 IgG as radioimmunotherapy reagent for metastatic melanoma. PMID- 29615813 TI - High hemoglobin levels are associated with decreased risk of diabetic retinopathy in Korean type 2 diabetes. AB - Anemia is an independent risk factor for the development of diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (DM). Hemoglobin levels may also be associated with DR. We investigated the association between hemoglobin levels and DR risk. This cross-sectional, population-based study utilized data from 2,123 type 2 DM patients aged >=30 years who participated in the Korea National Health and Nutrition Examination Survey from 2008 to 2012. Participants underwent an ophthalmic examination, including fundus photographs. A multiple logistic regression analysis was performed to evaluate the relationship between hemoglobin levels and DR risk. The mean hemoglobin levels in patients with and without DR were 13.76 +/- 0.12 and 14.33 +/- 0.05 g/dL, respectively, with anemia observed in 16.2 (2.4)% and 7.8 (0.8)%, respectively. A 19% decrease in DR risk was found with a 1.0-g/dL increase in hemoglobin level. DR risk exhibited a decreasing trend with increasing hemoglobin levels (P for trend <0.0001). The adjusted odds ratio of DR was significantly lower in the highest hemoglobin quartile. Our findings indicate that high hemoglobin levels are significantly related to a decreased DR risk in Korean type 2 diabetes. PMID- 29615814 TI - The impact of circulating preeclampsia-associated extracellular vesicles on the migratory activity and phenotype of THP-1 monocytic cells. AB - Intercellular communication via extracellular vesicles (EVs) and their target cells, especially immune cells, results in functional and phenotype changes that consequently may play a significant role in various physiological states and the pathogenesis of immune-mediated disorders. Monocytes are the most prominent environment-sensing immune cells in circulation, skilled to shape their microenvironments via cytokine secretion and further differentiation. Both the circulating monocyte subset distribution and the blood plasma EV pattern are characteristic for preeclampsia, a pregnancy induced immune-mediated hypertensive disorder. We hypothesized that preeclampsia-associated EVs (PE-EVs) induced functional and phenotypic alterations of monocytes. First, we proved EV binding and uptake by THP-1 cells. Cellular origin and protein cargo of circulating PE EVs were characterized by flow cytometry and mass spectrometry. An altered phagocytosis-associated molecular pattern was found on 12.5 K fraction of PE-EVs: an elevated CD47 "don't eat me" signal (p < 0.01) and decreased exofacial phosphatidylserine "eat-me" signal (p < 0.001) were found along with decreased uptake of these PE-EVs (p < 0.05). The 12.5 K fraction of PE-EVs induced significantly lower chemotaxis (p < 0.01) and cell motility but accelerated cell adhesion of THP-1 cells (p < 0.05). The 12.5 K fraction of PE-EVs induced altered monocyte functions suggest that circulating EVs may have a role in the pathogenesis of preeclampsia. PMID- 29615815 TI - Cardiac (myo)fibroblasts modulate the migration of monocyte subsets. AB - Cardiac fibroblasts play an important role in the regulation of the extracellular matrix and are newly recognized as inflammatory supporter cells. Interferon (IFN) gamma is known to counteract transforming growth factor (TGF)-beta1-induced myofibroblast differentiation. This study aims at investigating in vitro how IFN gamma affects TGF-beta1-induced monocyte attraction. Therefore, C4 fibroblasts and fibroblasts obtained by outgrowth culture from the left ventricle (LV) of male C57BL6/j mice were stimulated with TGF-beta1, IFN-gamma and TGF-beta1 + IFN gamma. Confirming previous studies, IFN-gamma decreased the TGF-beta1-induced myofibroblast differentiation, as obviated by lower collagen I, III, alpha-smooth muscle actin (alpha-SMA), lysyl oxidase (Lox)-1 and lysyl oxidase-like (LoxL)-2 levels in TGF-beta1 + IFN-gamma- versus TGF-beta1-stimulated cardiac fibroblasts. TGF-beta1 + IFN-gamma-stimulated C4 and cardiac fibroblasts displayed a higher CC chemokine ligand (CCL) 2, CCL7 and chemokine C-X3-C motif ligand (Cx3CL1) release versus sole TGF-beta1-stimulated fibroblasts. Analysis of migrated monocyte subsets towards the different conditioned media further revealed that sole TGF beta1- and IFN-gamma-conditioned media particularly attracted Ly6Clow and Ly6Chigh monocytes, respectively, as compared to control media. In line with theses findings, TGF-beta1 + IFN-gamma-conditioned media led to a lower Ly6Clow/Ly6Chigh monocyte migration ratio compared to sole TGF-beta1 treatment. These differences in monocyte migration reflect the complex interplay of pro inflammatory cytokines and pro-fibrotic factors in cardiac remodelling and inflammation. PMID- 29615816 TI - Distinct Metabolic features differentiating FLT3-ITD AML from FLT3-WT childhood Acute Myeloid Leukemia. AB - Acute myeloid leukemia (AML) is a heterogeneous disease with dismal response warranting the need for enhancing our understanding of AML biology. One prognostic feature associated with inferior response is the presence of activating mutations in FMS-like tyrosine kinase 3 (FLT3) especially occurrence of internal tandem duplication (FLT3-ITD). Although poorly understood, differential metabolic and signaling pathways associated with FLT3-ITD might contribute towards the observed poor prognosis. We performed a non-targeted global metabolic profiling of matched cell and plasma samples obtained at diagnosis to establish metabolic differences within FLT3-ITD and FLT3-WT pediatric AML. Metabolomic profiling by Ultra-High Performance-Liquid Chromatography-Mass Spectrometry identified differential abundance of 21 known metabolites in plasma and 33 known metabolites in leukemic cells by FLT3 status. These metabolic features mapped to pathways of significant biological importance. Of interest were metabolites with roles in cancer, cell progression and involvement in purine metabolism and biosynthesis, cysteine/methionine metabolism, tryptophan metabolism, carnitine mediated fatty acid oxidation, and lysophospholipid metabolism. Although validation in a larger cohort is required, our results for the first time investigated global metabolic profile in FLT3-ITD AML. PMID- 29615817 TI - In Vivo 3D Histomorphometry Quantifies Bone Apposition and Skeletal Progenitor Cell Differentiation. AB - Histomorphometry and Micro-CT are commonly used to assess bone remodeling and bone microarchitecture. These approaches typically require separate cohorts of animals to analyze 3D morphological changes and involve time-consuming immunohistochemistry preparation. Intravital Microscopy (IVM) in combination with mouse genetics may represent an attractive option to obtain bone architectural measurements while performing longitudinal monitoring of dynamic cellular processes in vivo. In this study we utilized two-photon, multicolor fluorescence IVM together with a lineage tracing reporter mouse model to image skeletal stem cells (SSCs) in their calvarial suture niche and analyze their differentiation fate after stimulation with an agonist of the canonical Wnt pathway (recombinant Wnt3a). Our in vivo histomorphometry analyses of bone formation, suture volume, and cellular dynamics showed that recombinant Wnt3a induces new bone formation, differentiation and incorporation of SSCs progeny into newly forming bone. IVM technology can therefore provide additional dynamic 3D information to the traditional static 2D histomorphometry. PMID- 29615818 TI - Effect of Phosphatidylserine and Cholesterol on Membrane-mediated Fibril Formation by the N-terminal Amyloidogenic Fragment of Apolipoprotein A-I. AB - Here, we examined the effects of phosphatidylserine (PS) and cholesterol on the fibril-forming properties of the N-terminal 1-83 fragment of an amyloidogenic G26R variant of apoA-I bound to small unilamellar vesicles. A thioflavin T fluorescence assay together with microscopic observations showed that PS significantly retards the nucleation step in fibril formation by apoA-I 1 83/G26R, whereas cholesterol slightly enhances fibril formation. Circular dichroism analyses demonstrated that PS facilitates a structural transition from random coil to alpha-helix in apoA-I 1-83/G26R with great stabilization of the alpha-helical structure upon lipid binding. Isothermal titration calorimetry measurements revealed that PS induces a marked increase in capacity for binding of apoA-I 1-83/G26R to the membrane surface, perhaps due to electrostatic interactions of positively charged amino acids in apoA-I with PS. Such effects of PS to enhance lipid interactions and inhibit fibril formation of apoA-I were also observed for the amyloidogenic region-containing apoA-I 8-33/G26R peptide. Fluorescence measurements using environment-sensitive probes indicated that PS induces a more solvent-exposed, membrane-bound conformation in the amyloidogenic region of apoA-I without affecting membrane fluidity. Since cell membranes have highly heterogeneous lipid compositions, our findings may provide a molecular basis for the preferential deposition of apoA-I amyloid fibrils in tissues and organs. PMID- 29615819 TI - Unfolded protein response is activated in Krabbe disease in a manner dependent on the mutation type. AB - Krabbe disease, one of the autosomal-recessive lysosomal storage disorders (LSDs), is caused by a deficiency of galactocerebrosidase (GALC) activity, resulting in the intracellular accumulation of psychosine, which is cytotoxic for neuronal cells. Genetically pathogenic mutations result in conformational changes in GALC and disrupt the lysosmal trafficking of cargos, which subsequently accumulate in the endoplasmic reticulum (ER). Recently, ER stress together with the activation of the unfolded protein response (UPR) has been suggested to play a key role in the pathogenesis of LSDs. In this study, we hence investigated whether the UPR is activated in Krabbe disease using COS-7 cells expressing pathogenic GALC mutants and skin fibroblasts (SFs) from Krabbe disease patients with various phenotypes, using a combination of semiquantitative and quantitative real-time polymerase chain reactions. We found that UPR activation in Krabbe disease depends on the mutations and cell types, and there is the possibility that multiple pathways, involving ER chaperones, inositol-requiring kinase 1, and protein kinase regulated by RNA-like ER kinase are activated by mutations associated with the infantile form. These results indicate that in Krabbe disease, each misfolded/unfolded protein evokes different UPR activation depending on the mutation, and that the activated pathways affect the phenotypes. PMID- 29615820 TI - Human evolution: Archaic admixture with Denisovans. PMID- 29615821 TI - Environmental microbiology: Marine biogeochemical cycles in a changing world. PMID- 29615823 TI - Interrupted breeding in a songbird migrant triggers development of nocturnal locomotor activity. AB - Long-distance avian migrants, e.g. Eurasian reed warblers (Acrocephalus scirpaceus), can precisely schedule events of their annual cycle. However, the proximate mechanisms controlling annual cycle and their interplay with environmental factors are poorly understood. We artificially interrupted breeding in reed warblers by bringing them into captivity and recording birds' locomotor activity for 5-7 days. Over this time, most of the captive birds gradually developed nocturnal locomotor activity not observed in breeding birds. When the birds were later released and radio-tracked, the individuals with highly developed caged activity performed nocturnal flights. We also found that reed warblers kept indoors without access to local cues developed a higher level of nocturnal activity compared to the birds kept outdoors with an access to the familiar environment. Also, birds translocated from a distant site (21 km) had a higher motivation to fly at night-time after release compared to the birds captured within 1 km of a study site. Our study suggests that an interrupted breeding triggers development of nocturnal locomotor activity in cages, and the level of activity is correlated with motivation to perform nocturnal flights in the wild, which can be restrained by familiar environment. PMID- 29615824 TI - Numerical simulations of the effects of regional topography on haze pollution in Beijing. AB - In addition to weather conditions and pollutant emissions, the degree to which topography influences the occurrence and development of haze pollution in downtown Beijing and the mechanisms that may be involved remain open questions. A series of atmospheric chemistry simulations are executed by using the online coupled Weather Research and Forecasting with Chemistry (WRF-Chem) model for November-December 2015 with different hypothetical topographic height scenarios. The simulation results show that topography exerts an important influence on haze pollution in downtown Beijing, particularly the typical development of haze pollution. A possible mechanism that underlies the response of haze pollution to topography is that the mountains that surround Beijing tend to produce anomalous southerly winds, high relative humidity, low boundary layer heights, and sinking motion over most of Beijing. These conditions favor the formation and development of haze pollution in downtown Beijing. Furthermore, the reduction percentage in PM2.5 concentrations due to reduced terrain height in the southerly wind (S) mode is almost three times larger than that in the northerly wind (N) mode. In the context of the regional topography, the simple S and N modes represent useful indicators for haze prediction in Beijing to some extent, especially over medium to long time scales. PMID- 29615825 TI - Epigenetic alterations to Polycomb targets precede malignant transition in a mouse model of breast cancer. AB - Malignant breast cancer remains a major health threat to women of all ages worldwide and epigenetic variations on DNA methylation have been widely reported in cancers of different types. We profiled DNA methylation with ERRBS (Enhanced Reduced Representation Bisulfite Sequencing) across four main stages of tumor progression in the MMTV-PyMT mouse model (hyperplasia, adenoma/mammary intraepithelial neoplasia, early carcinoma and late carcinoma), during which malignant transition occurs. We identified a large number of differentially methylated cytosines (DMCs) in tumors relative to age-matched normal mammary glands from FVB mice. Despite similarities, the methylation differences of the premalignant stages were distinct from the malignant ones. Many differentially methylated loci were preserved from the first to the last stage throughout tumor progression. Genes affected by methylation gains were enriched in Polycomb repressive complex 2 (PRC2) targets, which may present biomarkers for early diagnosis and targets for treatment. PMID- 29615826 TI - [Optimization of the method for the determination of diethyl sulfate at workplaces]. AB - BACKGROUND: Diethyl sulfate (DES) is a substance classified to the group of carcinogens. The value of maximum admissible concentration for this substance in workplace air is not specified in Poland. Due to the use of DES in domestic companies there is a need to develop a sensitive method for the determination of diethyl sulfate in the work environment. MATERIAL AND METHODS: Studies were performed using gas chromatography (GC) technique. An Agilent Technologies chromatograph, series 7890A, with a mass selective detector (5975C, Agilent Technologies, USA) was used in the experiment. Separation was performed on a capillary column with Rtx-5MS (30 m * 0.25 mm * 0.25 MUm) (Restek, USA). The possibility of using sorbent tubes filled with activated carbon (100 mg/50 mg), silica gel (100 mg/50 mg) and Porapak Q (150 mg/75 mg) for absorption of diethyl sulphate was investigated. RESULTS: The method of sampling air containing diethyl sulfate was developed. Among the sorbents to absorb DES Porapak Q was chosen. Determination of the adsorbed vapor includes desorption of DES, using dichloromethane/methanol mixture (95:5, v/v) and chromatographic analysis of so obtained solution. Method is linear (r = 0.999) within the investigated working range of 0.27- -5.42 MUg/ml, which is an equivalent to air concentrations 0.0075 0.15 mg/m3 for a 36 l air sample. CONCLUSIONS: The analytical method described in this paper allows for selective determination of diethyl sulfate in the workplace air in the presence of dimethyl sulfate, ethanol, dichloromethane, triethylamine, 2-(diethylamino)ethanol, and triethylenetetramine. The method meets the criteria for performing procedures aimed at measuring chemical agents, listed in EN 482. Med Pr 2018;69(3):291-300. PMID- 29615827 TI - Antecedents of job search self-efficacy of Syrian refugees in Greece and the Netherlands. AB - The goal of the current study was to investigate the relationships among psychological resources, career barriers, and job search self-efficacy in a sample of post-2014 Syrian refugees. Participants included 330 refugees in Greece and the Netherlands. Data were obtained using paper-based surveys, with all measures translated into Arabic. Drawing from career construction theory (Savickas, 2005), we hypothesized that adaptive readiness, operationalized in terms of psychological capital, would be positively related to job search self efficacy through career adaptability. In addition, social and administrative career barriers were hypothesized to moderate the first stage of the indirect effect between psychological capital and job search self-efficacy, such that this relationship is weaker when refugees experience higher career barriers. Results indicated that individuals with higher psychological capital more confidently engaged in job search behavior in the destination country, mostly due to their enhanced career adaptability. However, this relationship weakened when participants experienced higher social barriers and strengthened when they experienced higher administrative barriers. The findings provide further support for the career construction model of adaptation (Savickas & Porfeli, 2012) and pinpoint career adapt-ability resources as critical self-regulatory strengths that help individuals in this particularly vulnerable group adapt to occupational transitions. Moreover, the results highlight the potentially detrimental role of social barriers in this process. Based on the results, we offer implications for formulating training and career construction theory-based career counseling focused on enhancing career adaptability and psychological capital. PMID- 29615828 TI - Modelling field scale spatial variation in water run-off, soil moisture, N2O emissions and herbage biomass of a grazed pasture using the SPACSYS model. AB - In this study, we evaluated the ability of the SPACSYS model to simulate water run-off, soil moisture, N2O fluxes and grass growth using data generated from a field of the North Wyke Farm Platform. The field-scale model is adapted via a linked and grid-based approach (grid-to-grid) to account for not only temporal dynamics but also the within-field spatial variation in these key ecosystem indicators. Spatial variability in nutrient and water presence at the field-scale is a key source of uncertainty when quantifying nutrient cycling and water movement in an agricultural system. Results demonstrated that the new spatially distributed version of SPACSYS provided a worthy improvement in accuracy over the standard (single-point) version for biomass productivity. No difference in model prediction performance was observed for water run-off, reflecting the closed system nature of this variable. Similarly, no difference in model prediction performance was found for N2O fluxes, but here the N2O predictions were noticeably poor in both cases. Further developmental work, informed by this study's findings, is proposed to improve model predictions for N2O. Soil moisture results with the spatially distributed version appeared promising but this promise could not be objectively verified. PMID- 29615829 TI - Towards a durability test for washing-machines. AB - Durability plays a key role in enhancing resource conservation and contributing to waste minimization. The washing-machine product group represents a relevant case study for the development of a durability test and as a potential trigger to systematically address durability in the design of products. We developed a procedure to test the durability performance of washing-machines as a main objective of this research. The research method consisted of an analysis of available durability standards and procedures to test products and components, followed by an analysis of relevant references related to frequent failures. Finally, we defined the criteria and the conditions for a repeatable, relatively fast and relevant endurance test. The durability test considered the whole product tested under conditions of stress. A series of spinning cycles with fixed imbalanced loads was run on two washing-machines to observe failures and performance changes during the test. Even though no hard failures occurred, results clearly showed that not all washing-machines can sustain such a test without abrasion or performance deterioration. However, the attempt to reproduce the stress induced on a washing-machine by carrying out a high number of pure spinning cycles with fixed loads did not allow equal testing conditions: the actions of the control procedure regarding imbalanced loads differ from machine to machine. The outcomes of this research can be used as grounds to develop standardised durability tests and to, hence, contribute to the development of future product policy measures. PMID- 29615830 TI - Towards automatic SAR-optical stereogrammetry over urban areas using very high resolution imagery. AB - In this paper we discuss the potential and challenges regarding SAR-optical stereogrammetry for urban areas, using very-high-resolution (VHR) remote sensing imagery. Since we do this mainly from a geometrical point of view, we first analyze the height reconstruction accuracy to be expected for different stereogrammetric configurations. Then, we propose a strategy for simultaneous tie point matching and 3D reconstruction, which exploits an epipolar-like search window constraint. To drive the matching and ensure some robustness, we combine different established hand-crafted similarity measures. For the experiments, we use real test data acquired by the Worldview-2, TerraSAR-X and MEMPHIS sensors. Our results show that SAR-optical stereogrammetry using VHR imagery is generally feasible with 3D positioning accuracies in the meter-domain, although the matching of these strongly hetereogeneous multi-sensor data remains very challenging. PMID- 29615831 TI - Classroom assignments as measures of teaching quality. AB - We investigate classroom assignments and resulting student work to identify important characteristics of assignments in terms of instructional quality and their validity as measures of teaching quality. We examine assignment quality within a large-scale project exploring multiple measures including classroom observations, teacher knowledge measures, and value-added estimates based on student achievement scores. Analyses included descriptive statistics, multivariate analyses to understand factors contributing to score variance, and correlational analyses exploring the relationship of assignment scores to other measures. Results indicate relatively low demand levels in all teacher assignments, a marked difference in score distributions for mathematics (math) and English language arts (ELA), and a substantial relationship between what was asked of and produced by students. Relationships between assignments scores, classroom characteristics, and other measures of teaching quality are examined for both domains. These findings help us understand the nature of and factors associated with assignment quality in terms of intellectual demand. PMID- 29615832 TI - Prevalence and risk factors of diabetic retinopathy among an elderly population with diabetes in Nepal: the Bhaktapur Retina Study. AB - Aim: Diabetic retinopathy (DR) is an emerging cause of blindness in developing countries. This study aimed to explore the prevalence and risk factors of DR in an elderly population in Nepal. Subjects and methods: This is a population-based, cross-sectional study. A total of 1860 subjects at the age 60 years and above participated (response rate 88.6%). A detailed history was obtained, presenting and best-corrected visual acuity were measured, and anterior segment and posterior segment examinations were carried out. Blood pressure and random blood sugar were recorded; body mass index was calculated, and abdominal girth was measured. DR was graded by clinical examination using Early Treatment Diabetic Retinopathy Study criteria. Results: Diabetes was found in 168 (9%) subjects (mean age 69.6 years), 31 (18.5%) of whom were newly diagnosed. The prevalence of DR was 23.8% (95% confidence interval [CI]: 17.7%-31%) among the persons with diabetes. The prevalence of DR among newly diagnosed subjects with diabetes was 6.5% (95% CI: 0.8%-21.4%). The prevalence of vision-threatening DR was 9.5% (95% CI: 5.5%-15%) and was higher in males. The prevalence of DR was 83.3% (95% CI: 35.9%-99.6%) among those with diabetes for over 20 years. In multivariable logistic regression analysis, duration of diabetes, hypertension, and alcohol consumption were significantly associated with DR. Conclusion: DR is a common problem among the elderly population with diabetes in Nepal. The duration of diabetes, hypertension, and alcohol consumption are the risk factors for the development of DR. Strategies have to be developed for timely diagnosis of diabetes and screening for DR. PMID- 29615833 TI - Patient and physician perspectives on the use of cyclosporine ophthalmic emulsion 0.05% for the management of chronic dry eye. AB - Dry eye disease (DED) is a multifactorial disease of the ocular surface and is one of the most common reasons for patients to visit an eye care provider. Cyclosporine A (CsA) is an immune modulating drug that was approved in the US for topical use in the treatment of DED in 2003, which led to a paradigm change in our understanding and treatment of DED, turning attention to control of inflammation for treatment. This review summarizes the literature to date regarding the impact of CsA on the treatment of DED. A special focus is given to the patient and physician perspectives of CsA, including dry eye symptom improvement, medication side effects, and overall patient satisfaction. Studies evaluating CsA in DED have considerable heterogeneity making generalized conclusions about the effect of CsA difficult. However, most studies have demonstrated improvement in at least some symptoms of dry eye in CsA-treated patients. Side effects, most commonly ocular burning on administration of CsA, are common. The literature is sparse regarding long-term follow-up of patients treated with CsA, optimal duration of treatment, and identifying which patients may receive the most benefit from CsA. PMID- 29615834 TI - Corneal clarity measurements in patients with keratoconus undergoing either penetrating or deep anterior lamellar keratoplasty. AB - Purpose: To compare the corneal clarity measurement between penetrating keratoplasty (PK) and deep anterior lamellar keratoplasty (DALK) in patients with keratoconus, using densitometry software for the Oculus Pentacam. Methods: A retrospective comparative study was carried out at Manchester Royal Eye Hospital. Data were collected 12-18 months after corneal transplantation for keratoconus, including postoperative corneal densitometry, best corrected visual acuity (BCVA), central corneal thickness (CCT), and other relevant clinical details. Results: Analysis of 37 keratoconus eyes from 36 patients found there was a significantly higher corneal densitometry measurement after DALK than PK. This was predominantly in the posterior layer of the concentric zone 0-2 mm of the cornea (P=0.0004). A significant correlation was found between postoperative BCVA and corneal densitometry in DALK groups at full thickness (P=0.03). This correlation was seen in the central 0-2 mm (P=0.03) and posterior 0-2 mm (P=0.04) zones. In addition, within the DALK group, a correlation was found between central corneal thickness and densitometry at full thickness 2-6 mm (P=0.007), central 0-2 (P=0.04), central 2-6 mm (P=0.01), and at posterior 2-6 mm (P=0.01) zones. Conclusion: This study showed that corneal densitometry measurement differs depending on the type of corneal transplantation used to treat keratoconus patients. Densitometry may have an important role to play in the final BCVA achieved by patients undergoing corneal transplantation for keratoconus. Analysis of Oculus Pentacam images provides an objective evaluation to monitor the cornea status after the surgery. PMID- 29615835 TI - The effect of electronic cigarette and tobacco smoke exposure on COPD bronchial epithelial cell inflammatory responses. AB - Background: Electronic cigarettes (e-cigs) are used to help smoking cessation. However, these devices contain harmful chemicals, and there are safety concerns. We have investigated the effects of e-cigs on the inflammatory response and viability of COPD bronchial epithelial cells (BECs). Methods: BECs from COPD patients and controls were exposed to e-cig vapor extract (ECVE) and the levels of interleukin (IL)-6, C-X-C motif ligand 8 (CXCL8), and lactate dehydrogenase release were measured. We also examined the effect of ECVE pretreatment on polyinosinic:polycytidylic acid (poly I:C)-stimulated cytokine release from BECs. Parallel experiments using Calu-3 cells were performed. Comparisons were made with cigarette smoke extract (CSE). Results: ECVE and CSE caused an increase in the release of IL-6 and CXCL8 from Calu-3 cells. ECVE only caused toxicity in BECs and Calu-3 cells. Furthermore, ECVE and CSE dampened poly I:C-stimulated C-X C motif ligand 10 release from both cell culture models, reaching statistical significance for CSE at an optical density of 0.3. Conclusion: ECVE caused toxicity and reduced the antiviral response to poly I:C. This raises concerns over the safety of e-cig use. PMID- 29615836 TI - Long-term evolution of lung function in individuals with alpha-1 antitrypsin deficiency from the Spanish registry (REDAAT). AB - Background: The clinical course of alpha-1 antitrypsin deficiency (AATD) is very heterogeneous. It is estimated that 60% of individuals with severe AATD (Pi*ZZ) develop emphysema. The main objective of this study was to describe the outcomes of long-term lung function in individuals with AATD-associated emphysema after at least 8 years of follow-up. Materials and methods: We performed a retrospective analysis of longitudinal follow-up data of AATD PiZZ patients from the Spanish registry (AATD Spanish Registry [REDAAT]). The main follow-up outcome was the annual rate of decline in forced expiratory volume in 1 second (FEV1) calculated using the FEV1 values at baseline and in the last post-bronchodilator spirometry available. Results: One hundred and twenty-two AATD PiZZ patients were analyzed. The median follow-up was 11 years (interquartile range =9-14). The mean FEV1 decline was 28 mL/year (SD=54), with a median of 33 mL/year. Tobacco consumption (beta=19.8, p<0.001), previous pneumonia (beta=27.8, p=0.026) and higher baseline FEV1% (beta=0.798, p=0.016) were independently related to a faster FEV1 decline. Conclusion: In this large cohort with a long follow-up, we observed a very variable decline of FEV1. However, the mean FEV1 decline was similar to that observed in large cohorts of smoking-related COPD. Tobacco consumption, previous pneumonia and better lung function at baseline were related to a faster decline in FEV1. These results highlight the importance of early diagnosis and effective treatment. PMID- 29615837 TI - Synovitis in mice with inflammatory arthritis monitored with quantitative analysis of dynamic contrast-enhanced NIR fluorescence imaging using iRGD targeted liposomes as fluorescence probes. AB - Background: Rheumatoid arthritis (RA) is a common inflammatory disorder characterized primarily by synovitis and pannus formation in multiple joints, causing joints destruction and irreversible disability in most cases. Early diagnosis and effective therapy monitoring of RA are of importance for achieving the favorable prognosis. Methods: We first prepared the targeted fluorescence probes, and then explored the feasibility of near-infrared (NIR) fluorescence molecular imaging to detect and evaluate the RA via the targeted fluorescence probes by quantitative analysis in this study. Results: The targeted fluorescence probes (indocyanine green-liposomes decorated with iRGD peptide [iLPs]) was successfully prepared. The quantitative analysis found that strong fluorescence signal was detected in inflamed paws and the fluorescence signal in iLPs group was 3.03-fold higher than that in non-targeted (indocyanine green-liposomes decorated without iRGD peptide [LPs]) group (P<0.01) at 15 min after injection, whereas the fluorescence signal from iLPs signal can almost not be observed in the non-inflamed paws, showing the high sensitivity and accuracy for arthritis by the NIR fluorescence imaging based on iLPs. Conclusion: The NIR fluorescence imaging by iLPs may facilitate improved arthritis diagnosis and early assessment of the disease progression by providing an in vivo characterization of angiogenesis in inflammatory joint diseases. PMID- 29615838 TI - Spontaneous perirenal urinoma induced by NSAID-associated acute interstitial nephritis. AB - Urinoma, defined as the urine leakage beyond the urinary tract, is commonly induced by blunt trauma or urinary tract obstruction by stone, intra-abdominal malignancy, or retroperitoneal fibrosis. Spontaneous urinoma is rare and parenchymal pathologic change is rarely mentioned when urinoma is found. We present a case of a 28-year-old woman with bilateral flank pain induced by spontaneous urinoma. The lady received chronic analgesics because of migraine. After intravenous ketorolac injection, bilateral perirenal urinoma developed. Renal biopsy showed acute interstitial nephritis associated with nonsteroid anti inflammatory drug (NSAID). After discontinuing the medication, urinoma subsided, and the patient was discharged with normal serum creatinine. This was the first case of urinoma induced by NSAID-related interstitial nephritis, and pathophysiology and management of spontaneous urinoma are discussed. PMID- 29615839 TI - miR-342-3p suppresses hepatocellular carcinoma proliferation through inhibition of IGF-1R-mediated Warburg effect. AB - Background: Insulin-like growth factor-1 receptor (IGF-1R) is a well-studied oncogenic factor that promotes cell proliferation and energy metabolism and is overexpressed in numerous cancers including hepatocellular carcinoma (HCC). Aerobic glycolysis is a hallmark of cancer, and drugs targeting its regulators, including IGF-1R, are being developed. However, the mechanisms of IGF-1R inhibition and the physiological significance of the IGF-1R inhibitors in cancer cells are unclear. Materials and methods: Cell proliferation was evaluated by cell counting Kit-8 and colony formation assay. Western blot and real-time PCR were accordingly used to detect the relevant proteins, miRNA and gene expression. Luciferase reporter assays were used to illustrate the interaction between miR 342-3p and IGF-1R. The effect of miR-342-3p on glycolysis was determined by glucose uptake, ATP concentration, lactate generation, extracellular acidification rate and oxygen consumption rate assays. In vivo, subcutaneous tumor formation assay and PET were performed in nude mice. Results: In this study, we demonstrate that by directly targeting the 3'-UTR (3'-untranslated regions) of IGF-1R, microRNA-342-3p (miR-342-3p) suppresses IGF-1R-mediated PI3K/AKT/GLUT1 signaling pathway both in vitro and in vivo. Through suppression of IGF-1R, miR-342-3p dampens glycolysis by decreasing glucose uptake, lactate generation, ATP production, and extracellular acidification rate (ECAR), and increasing oxygen consumption rate (OCR) in hepatoma cells. Importantly, glycolysis regulated by miR-342-3p is critical for its regulating HCC growth both in vitro and in vivo. Conclusion: Our findings provide clues regarding the role of miR-342-3p as a tumor suppressor in liver cancer mainly through the inhibition of IGF-1R. Targeting IGF-1R by miR-342-3p could be a potential therapeutic strategy in liver cancer. PMID- 29615840 TI - Biomarker expression in rectal cancer tissue before and after neoadjuvant therapy. AB - Purpose: Intraoperative identification of rectal cancer (RC) can be challenging, especially because of fibrosis after treatment with preoperative chemo- and radiotherapy (CRT). Tumor-targeted fluorescence imaging can enhance the contrast between tumor and normal tissue during surgery. Promising targets for RC imaging are carcinoembryonic antigen (CEA), epithelial cell adhesion molecule (EpCAM) and the tyrosine-kinase receptor Met (c-Met). The effect of CRT on their expression determines their applicability for imaging. Therefore, we investigated whether CRT modifies expression patterns in tumors, lymph node (LN) metastases and adjacent normal rectal tissues. Patients and methods: Preoperative biopsies, primary tumor specimens and metastatic LNs were collected from 38 RC patients who did not receive CRT (cohort 1) and 34 patients who did (cohort 2). CEA, EpCAM and c-Met expression was determined using immunohistochemical staining and was semiquantified by a total immunostaining score (TIS), consisting of the percentage and intensity of stained tumor cells (0-12). Results: In both cohorts CEA, EpCAM and c-Met were significantly highly expressed in >60% of tumor tissues compared with adjacent normal epithelium (T/N ratio, P<0.01). EpCAM showed the most homogenous expression in tumors, whereas CEA showed the highest T/N ratio. Most importantly, CEA and EpCAM expression did not significantly change in normal or neoplastic RC tissue after CRT, whereas levels of c-Met changed (P=0.02). Tissues of eight patients with a pathological complete response after CRT showed expression of all biomarkers with TIS close to normal epithelium. Conclusion: Histological evaluation shows that CEA, EpCAM and c-Met are suitable targets for RC imaging, because all three are significantly enhanced in cancer tissue from primary tumors or LN metastases compared with normal adjacent tissue. Furthermore, the expression of CEA and EpCAM is not significantly changed after CRT. These data underscore the applicability of c-Met and especially, CEA and EpCAM as targets for image-guided RC surgery, both before and after CRT. PMID- 29615841 TI - The incidence of postoperative radiotherapy-induced acute dermatitis in breast cancer and its influencing factors for Chinese women. AB - Purpose: To investigate the incidence of skin acute reaction and its influencing factors in postoperative breast cancer radiotherapy patients. Methods: One hundred and seventy three cases of breast cancer patients treated with postoperative radiotherapy were consecutively enrolled from June 1, 2016 to July 31, 2017 in our breast cancer center. Irradiation technology includes conformal intensity-modulated radiotherapy and a conventional two-dimensional one with conventional fraction. Any acute radiation dermatitis was recorded and the influencing factors were analyzed at the end of the radiation treatment. Results: Radiotherapy-induced acute dermatitis in patients with breast-conserving surgery was relatively mild. Among the 173 patients, 33 cases had no obvious changes in the skin (grade 0); 121 cases had grade 1 skin reactions, manifested as local dark erythema and dry peeling; 29 cases had grade 2 skin reactions, characterized by edema, hyperemia, or erosion part; no grade 3 cases of skin reactions were observed. The incidence of grade 0, grade 1, and grade 2 reactions in all patients was 19.1%, 69.9%, and 11.0%, respectively. The severity of skin acute reaction is independent of the tumor sites, molecular subtypes, patients' age, and irradiation modalities, but it depends on the surgical types, fields treated, and planned total radiation. There is a trend favoring no chemotherapy over chemotherapy, though p-value is 0.074. Conclusion: Skin acute reaction in postoperative radiotherapy breast cancer patients is generally common but mild, and there are quite a few patients who need interruption or cessation of the radiotherapy process. The patients need to be well informed and made aware that any skin reaction will likely be mild, especially for the breast-conserving patients. PMID- 29615842 TI - MiR-216b suppresses colorectal cancer proliferation, migration, and invasion by targeting SRPK1. AB - Background: MiR-216b has been reported to be involved in the development of some cancers, however, the role of miR-216b in colorectal cancer (CRC) remains unclear. Purpose: This study aimed to investigate the mechanism underlying miR 216b-induced CRC development. Methods: We detected the expression of miR-216b in 80 cases of CRC tissues and cell lines, and further analyzed the association between miR-216b and clinical pathological indicators as well as prognosis. In vitro, the miR-216b overexpression cell model was established for further functional assay. Results: We demonstrated that miR-216b in CRC tissues and cell lines was markedly decreased compared with corresponding adjacent normal tissues and colonic mucosal epithelial cell line, and was obviously associated with the TNM stage, lymph node metastases, and poor overall survival as well as recurrence free survival. Furthermore, we found that miR-216b inhibited cell proliferation, cell cycle, migration, and invasion by targeting 3'-UTR of SRPK1. Besides, SRPK1 over-expression reversed miR-216b-inhibited cell proliferation, migration and invasion, while SRPK1 inhibition aggravated these effects. Conclusions: We identified that miR-216b suppresses colorectal cancer proliferation, migration and invasion by targeting SRPK1, which shed light on how miR-216b functions in CRC pathogenesis. PMID- 29615843 TI - Bioinformatic analysis of prognostic value of ZW10 interacting protein in lung cancer. AB - Background: ZWINT is a crucial component of the mitotic checkpoint. However, its possible role in lung cancer is unclear. In this study, we determined its correlation with lung cancer. Methods: Real-time PCR and immunohistochemistry (IHC) were used to determine 40 collected clinical lung cancer samples. Chi square test was used to examine possible correlations between ZWINT expression and clinicopathological factors. The prognostic significance of mRNA expression of ZWINT in lung cancer was evaluated using the Kaplan-Meier plotter. Univariate and multivariate Cox proportional hazards regression analysis were performed to determine whether ZWINT is an independent risk factor for overall survival (OS) and disease-free survival (DFS) of lung cancer patients. Additionally, STRING database was used to analyze protein-protein interactions. Results: In this study, we screened 13 GSE datasets and detected that ZWINT is highly expressed in multiple carcinomas including lung, melanoma, prostate, nasopharyngeal, gastric, pancreatic, colon, esophageal, ovarian, renal, breast and liver cancer. Real-time PCR and IHC results of collected clinical lung cancer samples confirmed that ZWINT is highly expressed in tumor tissues compared with adjacent non-tumor tissues. Additionally, high expression of ZWINT might predict poor OS and DFS in lung cancer patients. Moreover, disease stage and expression level of ZWINT were correlated with recurrence-free survival and OS in lung cancer. Analysis of protein-protein interaction based on STRING database gained 8 top genes which could interact with ZWINT, including PMF1, MIS12, DSN1, ZW10, BUB1, BUB1B, CASC5, NDC80, NSL1 and NUF2. Conclusion: ZWINT is aberrantly highly expressed in lung tumor tissues and might be involved in the pathogenesis of lung cancer. PMID- 29615844 TI - Bepotastine besilate ophthalmic solution 1.5% for alleviating nasal symptoms in patients with allergic conjunctivitis. AB - Background: Bepotastine besilate ophthalmic solution (BBOS) 1.5% is a topical antihistamine for the treatment of ocular itching associated with allergic conjunctivitis (AC). Allergic rhinitis and AC are common comorbid conditions. We explored the efficacy of BBOS 1.5% in alleviating nasal symptoms in an integrated analysis of two Phase III conjunctival allergen challenge (CAC) studies and a Phase IV environmental allergen study. Methods: In the Phase III trials, a CAC was performed 15 minutes, 8 hours, and 16 hours following ocular instillation of BBOS 1.5% (n=78) or placebo (n=79), and subjects evaluated nasal symptoms. In the environmental study, subjects instilled BBOS 1.5% (n=123) or placebo (n=122) twice daily and nasal symptoms were evaluated over 2 weeks. Results: In the Phase III trials, BBOS 1.5% had reduced CAC-induced nasal congestion and pruritus at 15 minutes and 8 hours postdosing and rhinorrhea and a non-ocular composite-symptom score (sum of nasal scores plus ear or palate pruritus) at all time points postdosing (all P<=0.01 vs placebo). In the Phase IV environmental study, BBOS 1.5% reduced sneezing and nasal pruritus over 2 weeks and median number of days to improvement of nasal pruritus and total nasal symptom score (sum for rhinorrhea, sneezing, nasal pruritus, and nasal congestion; P<=0.04 vs placebo). Additionally, investigator-reported improvement in overall ocular (pruritus, hyperemia, tearing) and nasal symptoms was greater with BBOS 1.5% vs placebo (P<=0.03). Conclusion: Results of these exploratory analyses indicate that topical ocular BBOS 1.5% reduced nasal symptoms, supporting its use for alleviating rhinitis symptoms associated with AC. PMID- 29615845 TI - Novel mutation in ABBC9 gene associated with congenital hypertrichosis and acromegaloid facial features, without cardiac or skeletal anomalies: a new phenotype. AB - Introduction: Mutations in ABCC9 are associated with Cantu syndrome (CS), a very rare genetic disorder characterized by congenital hypertrichosis, acromegaloid facial appearance (AFA), cardiomegaly, and skeletal anomalies. Case report: We report an 8-year-old female patient with congenital generalized hypertrichosis and coarse facial appearance but without cardiovascular or skeletal compromise. Whole exome sequencing revealed a novel de novo heterozygous mutation in ABCC9. In addition, the genotype and phenotype of the patient were compared with those of the patients reported in the literature and with other related conditions that include AFA, hypertrichosis and AFA, and CS. Conclusion: This is the first report of a South-American patient with mutation in ABCC9. We propose that her phenotype is a part of a spectrum of features associated with congenital hypertrichosis and mutations in ABCC9, which differs from CS and related disorders. Whole exome sequencing enabled the identification of the causality of this disease characterized by high clinical and genetic heterogeneity. PMID- 29615846 TI - Eotaxin levels in patients with primary dysmenorrhea. AB - Purpose: Primary dysmenorrhea (PD) is a common cause of pelvic pain that can cause limitations in daily activities. Treatment options sometimes result in failure, suggesting that different mechanisms may be effective in etiopathogenesis. Eosinophils are cells that are present in endometrium only in the perimenstrual period. The aim of this study was to evaluate the levels of eotaxin, a potent eosinophilic chemoattractant, in patients with PD. Patients and methods: Thirty patients with PD and thirty healthy women were included in the study. Venous blood sample of 10 mL was collected from each participant. Blood samples were taken in the first 2 days of the menstrual cycle at any period of the day. Serum eotaxin levels were determined by enzyme-linked immunofluorescence assay. Results: There were no statistically significant differences between the demographic properties of groups in terms of age and body mass index. Eotaxin levels were significantly different in patients with PD than the control subjects (p=0.012). Conclusion: Detection of different levels of eotaxin in patients with PD may be a new and important step in determining the factors contributing to the pathogenesis of dysmenorrhea. PMID- 29615847 TI - Uncommon EGFR mutations in cytological specimens of 1,874 newly diagnosed Indonesian lung cancer patients. AB - Purpose: We aimed to evaluate the distribution of individual epidermal growth factor receptor (EGFR) mutation subtypes found in routine cytological specimens. Patients and methods: A retrospective audit was performed on EGFR testing results of 1,874 consecutive cytological samples of newly diagnosed or treatment-naive Indonesian lung cancer patients (years 2015-2016). Testing was performed by ISO15189 accredited central laboratory. Results: Overall test failure rate was 5.1%, with the highest failure (7.1%) observed in pleural effusion and lowest (1.6%) in needle aspiration samples. EGFR mutation frequency was 44.4%. Tyrosine kinase inhibitor (TKI)-sensitive common EGFR mutations (ins/dels exon 19, L858R) and uncommon mutations (G719X, T790M, L861Q) contributed 57.1% and 29%, respectively. Approximately 13.9% of mutation-positive patients carried a mixture of common and uncommon mutations. Women had higher EGFR mutation rate (52.9%) vs men (39.1%; p<0.05). In contrast, uncommon mutations conferring either TKI responsive (G719X, L861Q) or TKI resistance (T790M, exon 20 insertions) were consistently more frequent in men than in women (67.3% vs 32.7% or 69.4% vs 30.6%; p<0.05). Up to 10% EGFR mutation-positive patients had baseline single mutation T790M, exon 20 insertion, or in coexistence with TKI-sensitive mutations. Up to 9% patients had complex or multiple EGFR mutations, whereby 48.7% patients harbored TKI-resistant mutations. One patient presented third generation TKI-resistant mutation L792F simultaneously with T790M. Conclusion: Routine diagnostic cytological techniques yielded similar success rate to detect EGFR mutations. Uncommon EGFR mutations were frequent events in Indonesian lung cancer patients. PMID- 29615848 TI - Decoding Imagined 3D Hand Movement Trajectories From EEG: Evidence to Support the Use of Mu, Beta, and Low Gamma Oscillations. AB - Objective: To date, motion trajectory prediction (MTP) of a limb from non invasive electroencephalography (EEG) has relied, primarily, on band-pass filtered samples of EEG potentials i.e., the potential time-series model. Most MTP studies involve decoding 2D and 3D arm movements i.e., executed arm movements. Decoding of observed or imagined 3D movements has been demonstrated with limited success and only reported in a few studies. MTP studies normally use EEG potentials filtered in the low delta (~1 Hz) band for reconstructing the trajectory of an executed or an imagined/observed movement. In contrast to MTP, multiclass classification based sensorimotor rhythm brain-computer interfaces aim to classify movements using the power spectral density of mu (8-12 Hz) and beta (12-28 Hz) bands. Approach: We investigated if replacing the standard potentials time-series input with a power spectral density based bandpower time-series improves trajectory decoding accuracy of kinesthetically imagined 3D hand movement tasks (i.e., imagined 3D trajectory of the hand joint) and whether imagined 3D hand movements kinematics are encoded also in mu and beta bands. Twelve naive subjects were asked to generate or imagine generating pointing movements with their right dominant arm to four targets distributed in 3D space in synchrony with an auditory cue (beep). Main results: Using the bandpower time series based model, the highest decoding accuracy for motor execution was observed in mu and beta bands whilst for imagined movements the low gamma (28-40 Hz) band was also observed to improve decoding accuracy for some subjects. Moreover, for both (executed and imagined) movements, the bandpower time-series model with mu, beta, and low gamma bands produced significantly higher reconstruction accuracy than the commonly used potential time-series model and delta oscillations. Significance: Contrary to many studies that investigated only executed hand movements and recommend using delta oscillations for decoding directional information of a single limb joint, our findings suggest that motor kinematics for imagined movements are reflected mostly in power spectral density of mu, beta and low gamma bands, and that these bands may be most informative for decoding 3D trajectories of imagined limb movements. PMID- 29615849 TI - Targeting mGlu5 Metabotropic Glutamate Receptors in the Treatment of Cognitive Dysfunction in a Mouse Model of Phenylketonuria. AB - We studied group-I metabotropic glutamate (mGlu) receptors in Pahenu2 (ENU2) mice, which mimic the genetics and neurobiology of human phenylketonuria (PKU), a metabolic disorder characterized, if untreated, by autism, and intellectual disability (ID). Male ENU2 mice showed increased mGlu5 receptor protein levels in the hippocampus and corpus striatum (but not in the prefrontal cortex) whereas the transcript of the mGlu5 receptor was unchanged. No changes in mGlu1 receptor mRNA and protein levels were found in any of the three brain regions of ENU2 mice. We extended the analysis to Homer proteins, which act as scaffolds by linking mGlu1 and mGlu5 receptors to effector proteins. Expression of the long isoforms of Homer was significantly reduced in the hippocampus of ENU2 mice, whereas levels of the short Homer isoform (Homer 1a) were unchanged. mGlu5 receptors were less associated to immunoprecipitated Homer in the hippocampus of ENU2 mice. The lack of mGlu5 receptor-mediated long-term depression (LTD) in wild type mice (of BTBR strain) precluded the analysis of hippocampal synaptic plasticity in ENU2 mice. We therefore performed a behavioral analysis to examine whether pharmacological blockade of mGlu5 receptors could correct behavioral abnormalities in ENU2 mice. Using the same apparatus we sequentially assessed locomotor activity, object exploration, and spatial object recognition (spatial novelty test) after displacing some of the objects from their original position in the arena. Systemic treatment with the mGlu5 receptor antagonist, MPEP (20 mg/kg, i.p.), had a striking effect in the spatial novelty test by substantially increasing the time spent in exploring the displaced objects in ENU2 mice (but not in wild-type mice). These suggest a role for mGlu5 receptors in the pathophysiology of ID in PKU and suggest that, also in adult untreated animals, cognitive dysfunction may be improved by targeting these receptors with an appropriate therapy. PMID- 29615851 TI - The Effects of Money on Fake Rating Behavior in E-Commerce: Electrophysiological Time Course Evidence From Consumers. AB - Online ratings impose significant effects on the behaviors of potential customers. Thus, online merchants try to adopt strategies that affect this rating behavior, and most of these strategies are connected to money, such as the strategies of returning cash coupons if a consumer gives a five-star rating (RI strategy, an acronym for "returning" and "if") or returning cash coupons directly with no additional requirements (RN strategy, an acronym for "returning" and "no"). The current study explored whether a certain strategy (RN or RI) was more likely to give rise to false rating behaviors, as assessed by event-related potentials. A two-stimulus paradigm was used in this experiment. The first stimulus (S1) was the picture of a product with four Chinese characters that reflected the product quality (slightly defective vs. seriously defective vs. not defective), and the second stimulus (S2) displayed the coupon strategy (RN or RI). The participants were asked to decide whether or not to give a five-star rating. The behavioral results showed that the RI strategy led to a higher rate of five-star ratings than the RN strategy. For the electrophysiological time courses, the N1, N2, and LPP components were evaluated. The slightly defective products elicited a larger amplitude of the N1 component than the seriously defective and not-defective products, reflecting that perceptual difficulty was associated with the processing of the slightly defective products. The RI strategy evoked a less negative N2 and a more positive LPP than the RN strategy, indicating that the subjects perceived less conflict and experienced stronger incentives when processing the RI strategy. These findings will benefit future studies of fake online comments and provide evidence supporting the policy of forbidding the use of the RI strategy in e-commerce. PMID- 29615852 TI - Comparison of Visually Guided Flight in Insects and Birds. AB - Over the last half century, work with flies, bees, and moths have revealed a number of visual guidance strategies for controlling different aspects of flight. Some algorithms, such as the use of pattern velocity in forward flight, are employed by all insects studied so far, and are used to control multiple flight tasks such as regulation of speed, measurement of distance, and positioning through narrow passages. Although much attention has been devoted to long-range navigation and homing in birds, until recently, very little was known about how birds control flight in a moment-to-moment fashion. A bird that flies rapidly through dense foliage to land on a branch-as birds often do-engages in a veritable three-dimensional slalom, in which it has to continually dodge branches and leaves, and find, and possibly even plan a collision-free path to the goal in real time. Each mode of flight from take-off to goal could potentially involve a different visual guidance algorithm. Here, we briefly review strategies for visual guidance of flight in insects, synthesize recent work from short-range visual guidance in birds, and offer a general comparison between the two groups of organisms. PMID- 29615850 TI - Interplay Between the Gut-Brain Axis, Obesity and Cognitive Function. AB - Obesity continues to be one of the major public health problems due to its high prevalence and co-morbidities. Common co-morbidities not only include cardiometabolic disorders but also mood and cognitive disorders. Obese subjects often show deficits in memory, learning and executive functions compared to normal weight subjects. Epidemiological studies also indicate that obesity is associated with a higher risk of developing depression and anxiety, and vice versa. These associations between pathologies that presumably have different etiologies suggest shared pathological mechanisms. Gut microbiota is a mediating factor between the environmental pressures (e.g., diet, lifestyle) and host physiology, and its alteration could partly explain the cross-link between those pathologies. Westernized dietary patterns are known to be a major cause of the obesity epidemic, which also promotes a dysbiotic drift in the gut microbiota; this, in turn, seems to contribute to obesity-related complications. Experimental studies in animal models and, to a lesser extent, in humans suggest that the obesity-associated microbiota may contribute to the endocrine, neurochemical and inflammatory alterations underlying obesity and its comorbidities. These include dysregulation of the HPA-axis with overproduction of glucocorticoids, alterations in levels of neuroactive metabolites (e.g., neurotransmitters, short-chain fatty acids) and activation of a pro-inflammatory milieu that can cause neuro inflammation. This review updates current knowledge about the role and mode of action of the gut microbiota in the cross-link between energy metabolism, mood and cognitive function. PMID- 29615853 TI - Exploring EEG Features in Cross-Subject Emotion Recognition. AB - Recognizing cross-subject emotions based on brain imaging data, e.g., EEG, has always been difficult due to the poor generalizability of features across subjects. Thus, systematically exploring the ability of different EEG features to identify emotional information across subjects is crucial. Prior related work has explored this question based only on one or two kinds of features, and different findings and conclusions have been presented. In this work, we aim at a more comprehensive investigation on this question with a wider range of feature types, including 18 kinds of linear and non-linear EEG features. The effectiveness of these features was examined on two publicly accessible datasets, namely, the dataset for emotion analysis using physiological signals (DEAP) and the SJTU emotion EEG dataset (SEED). We adopted the support vector machine (SVM) approach and the "leave-one-subject-out" verification strategy to evaluate recognition performance. Using automatic feature selection methods, the highest mean recognition accuracy of 59.06% (AUC = 0.605) on the DEAP dataset and of 83.33% (AUC = 0.904) on the SEED dataset were reached. Furthermore, using manually operated feature selection on the SEED dataset, we explored the importance of different EEG features in cross-subject emotion recognition from multiple perspectives, including different channels, brain regions, rhythms, and feature types. For example, we found that the Hjorth parameter of mobility in the beta rhythm achieved the best mean recognition accuracy compared to the other features. Through a pilot correlation analysis, we further examined the highly correlated features, for a better understanding of the implications hidden in those features that allow for differentiating cross-subject emotions. Various remarkable observations have been made. The results of this paper validate the possibility of exploring robust EEG features in cross-subject emotion recognition. PMID- 29615854 TI - Contributions of Lateral and Orbital Frontal Regions to Abstract Rule Acquisition and Reversal in Monkeys. AB - The ability to learn and follow abstract rules relies on intact prefrontal regions including the lateral prefrontal cortex (LPFC) and the orbitofrontal cortex (OFC). Here, we investigate the specific roles of these brain regions in learning rules that depend critically on the formation of abstract concepts as opposed to simpler input-output associations. To this aim, we tested monkeys with bilateral removals of either LPFC or OFC on a rapidly learned task requiring the formation of the abstract concept of same vs. different. While monkeys with OFC removals were significantly slower than controls at both acquiring and reversing the concept-based rule, monkeys with LPFC removals were not impaired in acquiring the task, but were significantly slower at rule reversal. Neither group was impaired in the acquisition or reversal of a delayed visual cue-outcome association task without a concept-based rule. These results suggest that OFC is essential for the implementation of a concept-based rule, whereas LPFC seems essential for its modification once established. PMID- 29615856 TI - Weighted Synapses Without Carry Operations for RRAM-Based Neuromorphic Systems. AB - The parallel updating scheme of RRAM-based analog neuromorphic systems based on sign stochastic gradient descent (SGD) can dramatically accelerate the training of neural networks. However, sign SGD can decrease accuracy. Also, some non-ideal factors of RRAM devices, such as intrinsic variations and the quantity of intermediate states, may significantly damage their convergence. In this paper, we analyzed the effects of these issues on the parallel updating scheme and found that it performed poorly on the task of MNIST recognition when the number of intermediate states was limited or the variation was too large. Thus, we propose a weighted synapse method to optimize the parallel updating scheme. Weighted synapses consist of major and minor synapses with different gain factors. Such a method can be widely used in RRAM-based analog neuromorphic systems to increase the number of equivalent intermediate states exponentially. The proposed method also generates a more suitable Delta W , diminishing the distortion caused by sign SGD. Unlike when several RRAM cells are combined to achieve higher resolution, there are no carry operations for weighted synapses, even if a saturation on the minor synapses occurs. The proposed method also simplifies the circuit overhead, rendering it highly suitable to the parallel updating scheme. With the aid of weighted synapses, convergence is highly optimized, and the error rate decreases significantly. Weighted synapses are also robust against the intrinsic variations of RRAM devices. PMID- 29615855 TI - Null Effects on Working Memory and Verbal Fluency Tasks When Applying Anodal tDCS to the Inferior Frontal Gyrus of Healthy Participants. AB - Transcranial direct current stimulation (tDCS) is a technique used to modify cognition by modulating underlying cortical excitability via weak electric current applied through the scalp. Although many studies have reported positive effects with tDCS, a number of recent studies highlight that tDCS effects can be small and difficult to reproduce. This is especially the case when attempting to modulate performance using single applications of tDCS in healthy participants. Possible reasons may be that optimal stimulation parameters have yet to be identified, and that individual variation in cortical activity and/or level of ability confound outcomes. To address these points, we carried out a series of experiments in which we attempted to modulate performance in fluency and working memory probe tasks using stimulation parameters which have been associated with positive outcomes: we targeted the left inferior frontal gyrus (LIFG) and compared performance when applying a 1.5 mA anodal current for 25 min and with sham stimulation. There is evidence that LIFG plays a role in these tasks and previous studies have found positive effects of stimulation. We also compared our experimental group (N = 19-20) with a control group receiving no stimulation (n = 24). More importantly, we also considered effects on subgroups subdivided according to memory span as well as to more direct measures of executive function abilities and motivational levels. We found no systematic effect of stimulation. Our findings are in line with a growing body of evidence that tDCS produces unreliable effects. We acknowledge that our findings speak to the conditions we investigated, and that alternative protocols (e.g., multiple sessions, clinical samples, and different stimulation polarities) may be more effective. We encourage further research to explore optimal conditions for tDCS efficacy, given the potential benefits that this technique poses for understanding and enhancing cognition. PMID- 29615857 TI - Closed-Loop Efficient Searching of Optimal Electrical Stimulation Parameters for Preferential Excitation of Retinal Ganglion Cells. AB - The ability for visual prostheses to preferentially activate functionally distinct retinal ganglion cells (RGCs) is important for improving visual perception. This study investigates the use of high frequency stimulation (HFS) to elicit RGC activation, using a closed-loop algorithm to search for optimal stimulation parameters for preferential ON and OFF RGC activation, resembling natural physiological neural encoding in response to visual stimuli. We evaluated the performance of a wide range of electrical stimulation amplitudes and frequencies on RGC responses in vitro using murine retinal preparations. It was possible to preferentially excite either ON or OFF RGCs by adjusting amplitudes and frequencies in HFS. ON RGCs can be preferentially activated at relatively higher stimulation amplitudes (>150 MUA) and frequencies (2-6.25 kHz) while OFF RGCs are activated by lower stimulation amplitudes (40-90 MUA) across all tested frequencies (1-6.25 kHz). These stimuli also showed great promise in eliciting RGC responses that parallel natural RGC encoding: ON RGCs exhibited an increase in spiking activity during electrical stimulation while OFF RGCs exhibited decreased spiking activity, given the same stimulation amplitude. In conjunction with the in vitro studies, in silico simulations indicated that optimal HFS parameters could be rapidly identified in practice, whilst sampling spiking activity of relevant neuronal subtypes. This closed-loop approach represents a step forward in modulating stimulation parameters to achieve appropriate neural encoding in retinal prostheses, advancing control over RGC subtypes activated by electrical stimulation. PMID- 29615858 TI - Electrophysiological Responses to Expectancy Violations in Semantic and Gambling Tasks: A Comparison of Different EEG Reference Approaches. AB - Dynamically evaluating the outcomes of our actions and thoughts is a fundamental cognitive ability. Given its excellent temporal resolution, the event-related potential (ERP) technology has been used to address this issue. The feedback related negativity (FRN) component of ERPs has been studied intensively with the averaged linked mastoid reference method (LM). However, it is unknown whether FRN can be induced by an expectancy violation in an antonym relations context and whether LM is the most suitable reference approach. To address these issues, the current research directly compared the ERP components induced by expectancy violations in antonym expectation and gambling tasks with a within-subjects design and investigated the effect of the reference approach on the experimental effects. Specifically, we systematically compared the influence of the LM, reference electrode standardization technique (REST) and average reference (AVE) approaches on the amplitude, scalp distribution and magnitude of ERP effects as a function of expectancy violation type. The expectancy deviation in the antonym expectation task elicited an N400 effect that differed from the FRN effect induced in the gambling task; this difference was confirmed by all the three reference methods. Both the amplitudes of the ERP effects (N400 and FRN) and the magnitude as the expectancy violation increased were greater under the LM approach than those under the REST approach, followed by those under the AVE approach. Based on the statistical results, the electrode sites that showed the N400 and FRN effects critically depended on the reference method, and the results of the REST analysis were consistent with previous ERP studies. Combined with evidence from simulation studies, we suggest that REST is an optional reference method to be used in future ERP data analysis. PMID- 29615860 TI - Endocannabinoid System and Migraine Pain: An Update. AB - The trigeminovascular system (TS) activation and the vasoactive release from trigeminal endings, in proximity of the meningeal vessels, are considered two of the main effector mechanisms of migraine attacks. Several other structures and mediators are involved, however, both upstream and alongside the TS. Among these, the endocannabinoid system (ES) has recently attracted considerable attention. Experimental and clinical data suggest indeed a link between dysregulation of this signaling complex and migraine headache. Clinical observations, in particular, show that the levels of anandamide (AEA)-one of the two primary endocannabinoid lipids-are reduced in cerebrospinal fluid and plasma of patients with chronic migraine (CM), and that this reduction is associated with pain facilitation in the spinal cord. AEA is produced on demand during inflammatory conditions and exerts most of its effects by acting on cannabinoid (CB) receptors. AEA is rapidly degraded by fatty acid amide hydrolase (FAAH) enzyme and its levels can be modulated in the peripheral and central nervous system (CNS) by FAAH inhibitors. Inhibition of AEA degradation via FAAH is a promising therapeutic target for migraine pain, since it is presumably associated to an increased availability of the endocannabinoid, specifically at the site where its formation is stimulated (e.g., trigeminal ganglion and/or meninges), thus prolonging its action. PMID- 29615859 TI - Human Postural Control. AB - From ancient Greece to nowadays, research on posture control was guided and shaped by many concepts. Equilibrium control is often considered part of postural control. However, two different levels have become increasingly apparent in the postural control system, one level sets a distribution of tonic muscle activity ("posture") and the other is assigned to compensate for internal or external perturbations ("equilibrium"). While the two levels are inherently interrelated, both neurophysiological and functional considerations point toward distinct neuromuscular underpinnings. Disturbances of muscle tone may in turn affect movement performance. The unique structure, specialization and properties of skeletal muscles should also be taken into account for understanding important peripheral contributors to postural regulation. Here, we will consider the neuromechanical basis of habitual posture and various concepts that were rather influential in many experimental studies and mathematical models of human posture control. PMID- 29615861 TI - Lead-Induced Atypical Parkinsonism in Rats: Behavioral, Electrophysiological, and Neurochemical Evidence for a Role of Noradrenaline Depletion. AB - Background: Lead neurotoxicity is a major health problem known as a risk factor for neurodegenerative diseases, including the manifestation of parkinsonism-like disorder. While lead is known to preferentially accumulate in basal ganglia, the mechanisms underlying behavioral disorders remain unknown. Here, we investigated the neurophysiological and biochemical correlates of motor deficits induced by sub-chronic injections of lead. Methods: Sprague Dawely rats were exposed to sub chronic injections of lead (10 mg/kg, i.p.) or to a single i.p. injection of 50 mg/kg N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine hydrochloride (DSP-4), a drug known to induce selective depletion of noradrenaline. Rats were submitted to a battery of behavioral tests, including the open field for locomotor activity and rotarod for motor coordination. Electrophysiological recordings were carried out in three major basal ganglia nuclei, the subthalamic nucleus (STN), globus pallidus (GP), and substantia nigra pars reticulata (SNr). At the end of experiments, post-mortem tissue level of the three monoamines (dopamine, noradrenaline, and serotonin) and their metabolites has been determined using HPLC. Results: Lead intoxication significantly impaired exploratory and locomotor activity as well as motor coordination. It resulted in a significant reduction in the level of noradrenaline in the cortex and dopamine and its metabolites, DOPAC, and HVA, in the striatum. The tissue level of serotonin and its metabolite 5-HIAA was not affected in the two structures. Similarly, DSP-4, which induced a selective depletion of noradrenaline, significantly decreased exploratory, and locomotor activity as well as motor coordination. L-DOPA treatment did not improve motor deficits induced by lead and DSP-4 in the two animal groups. Electrophysiological recordings showed that both lead and DSP-4 did not change the firing rate but resulted in a switch from the regular normal firing to irregular and bursty discharge patterns of STN neurons. Neither lead nor DSP-4 treatments changed the firing rate and the pattern of GP and SNr neurons. Conclusions: Our findings provide evidence that lead represents a risk factor for inducing parkinsonism-like deficits. As the motor deficits induced by lead were not improved by L-DOPA, we suggest that the deficits may be due to the depletion of noradrenaline and the parallel disorganization of STN neuronal activity. PMID- 29615862 TI - Serotonergic Dysfunction in Amyotrophic Lateral Sclerosis and Parkinson's Disease: Similar Mechanisms, Dissimilar Outcomes. AB - Amyotrophic lateral sclerosis (ALS) and Parkinson's disease (PD) share similar pathophysiological mechanisms. From a neurochemical point of view, the serotonin (5-hydroxytryptamine; 5-HT) dysfunction in both movement disorders-related to probable lesioning of the raphe nuclei-is profound, and, therefore, may be partially responsible for motor as well as non-motor disturbances. More specifically, in ALS, it has been hypothesized that serotonergic denervation leads to loss of its inhibitory control on glutamate release, resulting into glutamate-induced neurotoxicity in lower and/or upper motor neurons, combined with a detrimental decrease of its facilitatory effects on glutamatergic motor neuron excitation. Both events then may eventually give rise to the well-known clinical motor phenotype. Similarly, disruption of the organized serotonergic control on complex mesencephalic dopaminergic connections between basal ganglia (BG) nuclei and across the BG-cortico-thalamic circuits, has shown to be closely involved in the onset of parkinsonian symptoms. Levodopa (L-DOPA) therapy in PD largely seems to confirm the influential role of 5-HT, since serotonergic rather than dopaminergic projections release L-DOPA-derived dopamine, particularly in extrastriatal regions, emphasizing the strongly interwoven interactions between both monoamine systems. Apart from its orchestrating function, the 5-HT system also exerts neuroprotective and anti-inflammatory effects. In line with this observation, emerging therapies have recently focused on boosting the serotonergic system in ALS and PD, which may provide novel rationale for treating these devastating conditions both on the disease-modifying, as well as symptomatic level. PMID- 29615863 TI - The D2 Dopamine Receptor Interferes With the Protective Effect of the A2A Adenosine Receptor on TDP-43 Mislocalization in Experimental Models of Motor Neuron Degeneration. AB - The A2A adenosine receptor (A2AR) and D2 dopamine receptor (D2R) are two G protein-coupled receptors that can form dimers and negatively regulate their partners. TAR DNA-binding protein (TDP-43) is a nuclear protein that has been implicated in amyotrophic lateral sclerosis (ALS). Mislocalization of TDP-43 from the nucleus to the cytoplasm is an early step of TDP-43 proteinopathy. Our previous studies indicated that A2AR is a potential drug target for ALS because treatment with an A2AR agonist (JMF1907; a T1-11 analog) prevents reactive oxygen species (ROS)-induced TDP-43 mislocalization in a motor neuron cell line (NSC34) and delays motor impairment in a TDP-43 transgenic ALS mouse model. Here, we set out to assess whether activation of D2R interferes with the beneficial effects of an A2AR agonist on motor neurons. We first demonstrated that A2AR and D2R are both located in motor neurons of mouse and human spinal cords and human iPSC derived motor neurons. Expression of A2AR and D2R in NSC34 cells led to dimer formation without affecting the binding affinity of A2AR toward T1-11. Importantly, activation of D2R reduced T1-11-mediated activation of cAMP/PKA signaling and subsequent inhibition of TDP-43 mislocalization in NSC34 cells. Treatment with quinpirole (a D2 agonist) blunted the rescuing effect of T1-11 on TDP-43 mislocalization and impaired grip strength in a mouse model of ALS. Our findings suggest that D2R activation may limit the beneficial responses of an A2AR agonist in motor neurons and may have an important role in ALS pathogenesis. PMID- 29615866 TI - Expression Pattern of the Aspartyl-tRNA Synthetase DARS in the Human Brain. AB - Translation of mRNA into protein is an evolutionarily conserved, fundamental process of life. A prerequisite for translation is the accurate charging of tRNAs with their cognate amino acids, a reaction catalyzed by specific aminoacyl-tRNA synthetases. One of these enzymes is the aspartyl-tRNA synthetase DARS, which pairs aspartate with its corresponding tRNA. Missense mutations of the gene encoding DARS result in the leukodystrophy hypomyelination with brainstem and spinal cord involvement and leg spasticity (HBSL) with a distinct pattern of hypomyelination, motor abnormalities, and cognitive impairment. A thorough understanding of the DARS expression domains in the central nervous system is essential for the development of targeted therapies to treat HBSL. Here, we analyzed endogenous DARS expression on the mRNA and protein level in different brain regions and cell types of human post mortem brain tissue as well as in human stem cell derived neurons, oligodendrocytes, and astrocytes. DARS expression is significantly enriched in the cerebellum, a region affected in HBSL patients and important for motor control. Although obligatorily expressed in all cells, DARS shows a distinct expression pattern with enrichment in neurons but only low abundance in oligodendrocytes, astrocytes, and microglia. Our results reveal little homogeneity across the different cell types, largely matching previously published data in the murine brain. This human gene expression study will significantly contribute to the understanding of DARS gene function and HBSL pathology and will be instrumental for future development of animal models and targeted therapies. In particular, we anticipate high benefit from a gene replacement approach in neurons of HBSL mouse models, given the abundant endogenous DARS expression in this lineage cell. PMID- 29615864 TI - Molecular Neuropathology of Astrocytes and Oligodendrocytes in Alcohol Use Disorders. AB - Postmortem studies reveal structural and molecular alterations of astrocytes and oligodendrocytes in both the gray and white matter (GM and WM) of the prefrontal cortex (PFC) in human subjects with chronic alcohol abuse or dependence. These glial cellular changes appear to parallel and may largely explain structural and functional alterations detected using neuroimaging techniques in subjects with alcohol use disorders (AUDs). Moreover, due to the crucial roles of astrocytes and oligodendrocytes in neurotransmission and signal conduction, these cells are very likely major players in the molecular mechanisms underpinning alcoholism related connectivity disturbances between the PFC and relevant interconnecting brain regions. The glia-mediated etiology of alcohol-related brain damage is likely multifactorial since metabolic, hormonal, hepatic and hemodynamic factors as well as direct actions of ethanol or its metabolites have the potential to disrupt distinct aspects of glial neurobiology. Studies in animal models of alcoholism and postmortem human brains have identified astrocyte markers altered in response to significant exposures to ethanol or during alcohol withdrawal, such as gap-junction proteins, glutamate transporters or enzymes related to glutamate and gamma-aminobutyric acid (GABA) metabolism. Changes in these proteins and their regulatory pathways would not only cause GM neuronal dysfunction, but also disturbances in the ability of WM axons to convey impulses. In addition, alcoholism alters the expression of astrocyte and myelin proteins and of oligodendrocyte transcription factors important for the maintenance and plasticity of myelin sheaths in WM and GM. These changes are concomitant with epigenetic DNA and histone modifications as well as alterations in regulatory microRNAs (miRNAs) that likely cause profound disturbances of gene expression and protein translation. Knowledge is also available about interactions between astrocytes and oligodendrocytes not only at the Nodes of Ranvier (NR), but also in gap junction-based astrocyte-oligodendrocyte contacts and other forms of cell to-cell communication now understood to be critical for the maintenance and formation of myelin. Close interactions between astrocytes and oligodendrocytes also suggest that therapies for alcoholism based on a specific glial cell type pathology will require a better understanding of molecular interactions between different cell types, as well as considering the possibility of using combined molecular approaches for more effective therapies. PMID- 29615865 TI - The Regulatory Mechanisms and Therapeutic Potential of MicroRNAs: From Chronic Pain to Morphine Tolerance. AB - Chronic pain, including cancer-related pain, is a pain condition often caused by inflammation or dysfunctional nerves. Chronic pain treatment poses a significant health care challenge, where opioids especially morphine are widely used and patients often develop tolerance over time with aggravated pain. microRNA (miRNA) is known to play important roles in regulating gene expressions in the nervous system to affect neuronal network plasticity related to algogenesis and the developing of morphine tolerance. In this article, we reviewed studies conducted in rodent animal models investigating the mechanisms of miRNAs regulation in chronic pain with different phenotypes and morphine tolerance. In addition, the potential of targeting miRNAs for chronic pain and morphine tolerance treatment is also reviewed. Finally, we point out the directions of the future research in chronic pain and morphine tolerance. PMID- 29615867 TI - Stable Density and Dynamics of Dendritic Spines of Cortical Neurons Across the Estrous Cycle While Expressing Differential Levels of Sensory-Evoked Plasticity. AB - Periodic oscillations of gonadal hormone levels during the estrous cycle exert effects on the female brain, impacting cognition and behavior. While previous research suggests that changes in hormone levels across the cycle affect dendritic spine dynamics in the hippocampus, little is known about the effects on cortical dendritic spines and previous studies showed contradictory results. In this in vivo imaging study, we investigated the impact of the estrous cycle on the density and dynamics of dendritic spines of pyramidal neurons in the primary somatosensory cortex of mice. We also examined if the induction of synaptic plasticity during proestrus, estrus, and metestrus/diestrus had differential effects on the degree of remodeling of synapses in this brain area. We used chronic two-photon excitation (2PE) microscopy during steady-state conditions and after evoking synaptic plasticity by whisker stimulation at the different stages of the cycle. We imaged apical dendritic tufts of layer 5 pyramidal neurons of naturally cycling virgin young female mice. Spine density, turnover rate (TOR), survival fraction, morphology, and volume of mushroom spines remained unaltered across the estrous cycle, and the values of these parameters were comparable with those of young male mice. However, while whisker stimulation of female mice during proestrus and estrus resulted in increases in the TOR of spines (74.2 +/- 14.9% and 75.1 +/- 12.7% vs. baseline, respectively), sensory-evoked plasticity was significantly lower during metestrus/diestrus (32.3 +/- 12.8%). In males, whisker stimulation produced 46.5 +/- 20% increase in TOR compared with baseline not significantly different from female mice at any stage of the cycle. These results indicate that, while steady-state density and dynamics of dendritic spines of layer 5 pyramidal neurons in the primary somatosensory cortex of female mice are constant during the estrous cycle, the susceptibility of these neurons to sensory-evoked structural plasticity may be dependent on the stage of the cycle. Since dendritic spines are more plastic during proestrus and estrus than during metestrus/diestrus, certain stages of the cycle could be more suitable for forms of memory requiring de novo formation and elimination of spines and other stages for forms of memory where retention and/or repurposing of already existing synaptic connections is more pertinent. PMID- 29615868 TI - Insect Responses to Linearly Polarized Reflections: Orphan Behaviors Without Neural Circuits. AB - The e-vector orientation of linearly polarized light represents an important visual stimulus for many insects. Especially the detection of polarized skylight by many navigating insect species is known to improve their orientation skills. While great progress has been made towards describing both the anatomy and function of neural circuit elements mediating behaviors related to navigation, relatively little is known about how insects perceive non-celestial polarized light stimuli, like reflections off water, leaves, or shiny body surfaces. Work on different species suggests that these behaviors are not mediated by the "Dorsal Rim Area" (DRA), a specialized region in the dorsal periphery of the adult compound eye, where ommatidia contain highly polarization-sensitive photoreceptor cells whose receptive fields point towards the sky. So far, only few cases of polarization-sensitive photoreceptors have been described in the ventral periphery of the insect retina. Furthermore, both the structure and function of those neural circuits connecting to these photoreceptor inputs remain largely uncharacterized. Here we review the known data on non-celestial polarization vision from different insect species (dragonflies, butterflies, beetles, bugs and flies) and present three well-characterized examples for functionally specialized non-DRA detectors from different insects that seem perfectly suited for mediating such behaviors. Finally, using recent advances from circuit dissection in Drosophila melanogaster, we discuss what types of potential candidate neurons could be involved in forming the underlying neural circuitry mediating non-celestial polarization vision. PMID- 29615869 TI - Heterogeneous Cytoskeletal Force Distribution Delineates the Onset Ca2+ Influx Under Fluid Shear Stress in Astrocytes. AB - Mechanical perturbations increase intracellular Ca2+ in cells, but the coupling of mechanical forces to the Ca2+ influx is not well understood. We used a microfluidic chamber driven with a high-speed pressure servo to generate defined fluid shear stress to cultured astrocytes, and simultaneously measured cytoskeletal forces using a force sensitive actinin optical sensor and intracellular Ca2+. Fluid shear generated non-uniform forces in actinin that critically depended on the stimulus rise time emphasizing the presence of viscoelasticity in the activating sequence. A short (ms) shear pulse with fast rise time (2 ms) produced an immediate increase in actinin tension at the upstream end of the cell with minimal changes at the downstream end. The onset of Ca2+ rise began at highly strained areas. In contrast to stimulus steps, slow ramp stimuli produced uniform forces throughout the cells and only a small Ca2+ response. The heterogeneity of force distribution is exaggerated in cells having fewer stress fibers and lower pre-tension in actinin. Disruption of cytoskeleton with cytochalasin-D (Cyt-D) eliminated force gradients, and in those cells Ca2+ elevation started from the soma. Thus, Ca2+ influx with a mechanical stimulus depends on local stress within the cell and that is time dependent due to viscoelastic mechanics. PMID- 29615870 TI - ATP and Odor Mixture Activate TRPM5-Expressing Microvillous Cells and Potentially Induce Acetylcholine Release to Enhance Supporting Cell Endocytosis in Mouse Main Olfactory Epithelium. AB - The main olfactory epithelium (MOE) functions to detect odor molecules, provide an epithelial surface barrier, and remove xenobiotics from inhaled air. Mechanisms coordinating the activities of different cell types within the MOE to maintain these functions are poorly understood. Previously, we showed that superficially located microvillous cells (MCs) in the MOE expressing transient receptor potential channel M5 (TRPM5) are cholinergic and chemoresponsive and that they play an important role in maintaining odor responses and olfactory guided behavior under challenging chemical environment. Here we investigated TRPM5-MC activation and subsequent paracrine regulation. Ca2+ imaging showed that TRPM5-MCs dose-dependently increase their intracellular Ca2+ levels in response to ATP, an important signaling molecule for airway mucociliary movement, and to an odor mixture. Pharmacological examination showed that the ATP responses are primarily mediated by P2X purinergic receptors. Interestingly, using the endocytosis dye pHrodo Red dextran, we found that chemical-activated TRPM5-MCs significantly increase the number of pHrodo-labeled puncta compared to controls without stimulation and compared to cells that do not respond to ATP or to the odor mixture. These results indicate potential vesicle recycling after release of the signaling molecule acetylcholine (ACh). Interestingly, TRPM5 knockout (KO) results in a decrease in ATP-induced pHrodo internalization. We further investigated cholinergic regulation of neighboring supporting cells (SCs). We found that ACh strongly elevates intracellular Ca2+ and potentiates pHrodo endocytosis in SCs. The ACh effects are diminished in the presence of atropine or M3 muscarinic receptor antagonist and in SCs lacking M3 receptors. Collectively, these data suggest that TRPM5-MCs may regulate the MOE's multicellular network activity via cholinergic paracrine signaling for functional maintenance and adaptive plasticity. PMID- 29615871 TI - A Novel KCNJ2 Mutation Identified in an Autistic Proband Affects the Single Channel Properties of Kir2.1. AB - Inwardly rectifying potassium channels (Kir) have been historically associated to several cardiovascular disorders. In particular, loss-of-function mutations in the Kir2.1 channel have been reported in cases affected by Andersen-Tawil syndrome while gain-of-function mutations in the same channel cause the short QT3 syndrome. Recently, a missense mutation in Kir2.1, as well as mutations in the Kir4.1, were reported to be involved in autism spectrum disorders (ASDs) suggesting a role of potassium channels in these diseases and introducing the idea of the existence of K+ channel ASDs. Here, we report the identification in an Italian affected family of a novel missense mutation (p.Phe58Ser) in the KCNJ2 gene detected in heterozygosity in a proband affected by autism and borderline for short QT syndrome type 3. The mutation is located in the N-terminal region of the gene coding for the Kir2.1 channel and in particular in a very conserved domain. In vitro assays demonstrated that this mutation results in an increase of the channel conductance and in its open probability. This gain-of-function of the protein is consistent with the autistic phenotype, which is normally associated to an altered neuronal excitability. PMID- 29615872 TI - Projections of the Diencephalospinal Dopaminergic System to Peripheral Sense Organs in Larval Zebrafish (Danio rerio). AB - Dopaminergic neurons of the descending diencephalospinal system are located in the posterior tuberculum (PT) in zebrafish (Danio rerio), and correspond in mammals to the A11 group in hypothalamus and thalamus. In the larval zebrafish, they are likely the only source of central dopaminergic projections to the periphery. Here, we characterized posterior tubercular dopaminergic fibers projecting to peripheral sense organs, with a focus on the lateral line neuromasts. We labeled and identified catecholaminergic neurons and their projections by combining two immunofluorescence techniques, (i) using an antibody against Tyrosine hydroxylase, and (ii) using an antibody against GFP in transgenic zebrafish expressing in catecholaminergic neurons either membrane anchored GFP to track fibers, or a Synaptophysin-GFP fusion to visualize putative synapses. We applied the CLARITY method to 6 days old whole zebrafish larvae to stain and analyze dopaminergic projections by confocal microscopy. We found that all lateral line neuromasts receive direct innervation by posterior tubercular dopaminergic neurons, and tracked these projections in detail. In addition, we found dopaminergic fibers projecting to the anterior and posterior lateral line ganglia, and extensive central dopaminergic arborizations around the terminal projection field of the lateral line afferent neurons in the hindbrain medial octavolateralis nucleus (MON). Therefore, dopaminergic innervation may affect lateral line sense information at different processing stages. Additional dopaminergic fibers innervate the trigeminal ganglion, and we observed fine catecholaminergic fibers in the skin with arborization patterns similar to free sensory nerve endings. We also detected potentially dopaminergic fibers innervating inner ear sensory epithelia. Therefore, the diencephalospinal A11 type dopaminergic system may broadly modulate peripheral senses. We also briefly report peripheral sympathetic catecholaminergic projections labeled in our experiments, and their innervation of the developing intestine, swim bladder and abdominal organs. PMID- 29615873 TI - Alterations of White Matter Integrity and Hippocampal Functional Connectivity in Type 2 Diabetes Without Mild Cognitive Impairment. AB - Aims: To investigate the white matter (WM) integrity and hippocampal functional connectivity (FC) in type 2 diabetes mellitus (T2DM) patients without mild cognitive impairment (MCI) by using diffusion tensor imaging (DTI) and resting state functional magnetic resonance imaging (rs-fMRI), respectively. Methods: Twelve T2DM patients without MCI and 24 age, sex and education matched healthy controls (HC) were recruited. DTI and rs-fMRI data were subsequently acquired on a 3.0T MR scanner. Tract-based spatial statistics (TBSS) combining region of interests (ROIs) analysis was used to investigate the alterations of DTI metrics (fractional anisotropy (FA), mean diffusivity (MD), lambda1 and lambda23) and FC measurement was performed to calculate hippocampal FC with other brain regions. Cognitive function was evaluated by using Mini-Mental State Examination (MMSE) and Montreal Cognitive Assessment (MoCA). Brain volumes were also evaluated among these participants. Results: There were no difference of MMSE and MoCA scores between two groups. Neither whole brain nor regional brain volume decrease was revealed in T2DM patients without MCI. DTI analysis revealed extensive WM disruptions, especially in the body of corpus callosum (CC). Significant decreases of hippocampal FC with certain brain structures were revealed, especially with the bilateral frontal cortex. Furthermore, the decreased FA in left posterior thalamic radiation (PTR) and increased MD in the splenium of CC were closely related with the decreased hippocampal FC to caudate nucleus and frontal cortex. Conclusions: T2DM patients without MCI showed extensive WM disruptions and abnormal hippocampal FC. Moreover, the WM disruptions and abnormal hippocampal FC were closely associated. Highlights -T2DM patients without MCI demonstrated no obvious brain volume decrease.-Extensive white matter disruptions, especially within the body of corpus callosum, were revealed with DTI analysis among the T2DM patients.-Despite no MCI in T2DM patients, decreased functional connectivity between hippocampal region and some critical brain regions were detected.-The alterations in hippocampal functional connectivity were closely associated with those of the white matter structures in T2DM patients. This trial was registered to ClinicalTrials.gov (NCT02420470, https://www.clinicaltrials.gov/). PMID- 29615874 TI - Structural and Molecular Properties of Insect Type II Motor Axon Terminals. AB - A comparison between the axon terminals of octopaminergic efferent dorsal or ventral unpaired median neurons in either desert locusts (Schistocerca gregaria) or fruit flies (Drosophila melanogaster) across skeletal muscles reveals many similarities. In both species the octopaminergic axon forms beaded fibers where the boutons or varicosities form type II terminals in contrast to the neuromuscular junction (NMJ) or type I terminals. These type II terminals are immunopositive for both tyramine and octopamine and, in contrast to the type I terminals, which possess clear synaptic vesicles, only contain dense core vesicles. These dense core vesicles contain octopamine as shown by immunogold methods. With respect to the cytomatrix and active zone peptides the type II terminals exhibit active zone-like accumulations of the scaffold protein Bruchpilot (BRP) only sparsely in contrast to the many accumulations of BRP identifying active zones of NMJ type I terminals. In the fruit fly larva marked dynamic changes of octopaminergic fibers have been reported after short starvation which not only affects the formation of new branches ("synaptopods") but also affects the type I terminals or NMJs via octopamine-signaling (Koon et al., 2011). Our starvation experiments of Drosophila-larvae revealed a time dependency of the formation of additional branches. Whereas after 2 h of starvation we find a decrease in "synaptopods", the increase is significant after 6 h of starvation. In addition, we provide evidence that the release of octopamine from dendritic and/or axonal type II terminals uses a similar synaptic machinery to glutamate release from type I terminals of excitatory motor neurons. Indeed, blocking this canonical synaptic release machinery via RNAi induced downregulation of BRP in neurons with type II terminals leads to flight performance deficits similar to those observed for octopamine mutants or flies lacking this class of neurons (Brembs et al., 2007). PMID- 29615875 TI - Speed Biases With Real-Life Video Clips. AB - We live almost literally immersed in an artificial visual world, especially motion pictures. In this exploratory study, we asked whether the best speed for reproducing a video is its original, shooting speed. By using adjustment and double staircase methods, we examined speed biases in viewing real-life video clips in three experiments, and assessed their robustness by manipulating visual and auditory factors. With the tested stimuli (short clips of human motion, mixed human-physical motion, physical motion and ego-motion), speed underestimation was the rule rather than the exception, although it depended largely on clip content, ranging on average from 2% (ego-motion) to 32% (physical motion). Manipulating display size or adding arbitrary soundtracks did not modify these speed biases. Estimated speed was not correlated with estimated duration of these same video clips. These results indicate that the sense of speed for real-life video clips can be systematically biased, independently of the impression of elapsed time. Measuring subjective visual tempo may integrate traditional methods that assess time perception: speed biases may be exploited to develop a simple, objective test of reality flow, to be used for example in clinical and developmental contexts. From the perspective of video media, measuring speed biases may help to optimize video reproduction speed and validate "natural" video compression techniques based on sub-threshold temporal squeezing. PMID- 29615876 TI - A Method to Train Marmosets in Visual Working Memory Task and Their Performance. AB - Learning and memory processes are similarly organized in humans and monkeys; therefore, monkeys can be ideal models for analyzing human aging processes and neurodegenerative diseases such as Alzheimer's disease. With the development of novel gene modification methods, common marmosets (Callithrix jacchus) have been suggested as an animal model for neurodegenerative diseases. Furthermore, the common marmoset's lifespan is relatively short, which makes it a practical animal model for aging. Working memory deficits are a prominent symptom of both dementia and aging, but no data are currently available for visual working memory in common marmosets. The delayed matching-to-sample task is a powerful tool for evaluating visual working memory in humans and monkeys; therefore, we developed a novel procedure for training common marmosets in such a task. Using visual discrimination and reversal tasks to direct the marmosets' attention to the physical properties of visual stimuli, we successfully trained 11 out of 13 marmosets in the initial stage of the delayed matching-to-sample task and provided the first available data on visual working memory in common marmosets. We found that the marmosets required many trials to initially learn the task (median: 1316 trials), but once the task was learned, the animals needed fewer trials to learn the task with novel stimuli (476 trials or fewer, with the exception of one marmoset). The marmosets could retain visual information for up to 16 s. Our novel training procedure could enable us to use the common marmoset as a useful non-human primate model for studying visual working memory deficits in neurodegenerative diseases and aging. PMID- 29615877 TI - Repeated Administration of Cigarette Smoke Condensate Increases Glutamate Levels and Behavioral Sensitization. AB - Nicotine, a nicotinic acetylcholine receptor agonist, produces the reinforcing effects of tobacco dependence by potentiating dopaminergic and glutamatergic neurotransmission. Non-nicotine alkaloids in tobacco also contribute to dependence by activating the cholinergic system. However, glutamatergic neurotransmission in the dorsal striatum associated with behavioral changes in response to cigarette smoking has not been investigated. In this study, the authors investigated alterations in glutamate levels in the rat dorsal striatum related to behavioral alterations after repeated administration of cigarette smoke condensate (CSC) using the real-time glutamate biosensing and an open-field behavioral assessment. Repeated administration of CSC including 0.4 mg nicotine (1.0 mL/kg/day, subcutaneous) for 14 days significantly increased extracellular glutamate concentrations more than repeated nicotine administration. In parallel with the hyperactivation of glutamate levels, repeated administration of CSC evoked prolonged hypersensitization of psychomotor activity, including locomotor and rearing activities. These findings suggest that the CSC-induced psychomotor activities are closely associated with the elevation of glutamate concentrations in the rat dorsal striatum. PMID- 29615879 TI - Specificity in Sociality: Mice and Prairie Voles Exhibit Different Patterns of Peer Affiliation. AB - Social behavior is often described as a unified concept, but highly social (group living) species exhibit distinct social structures and may make different social decisions. Prairie voles (Microtus ochrogaster) are socially monogamous rodents that often reside in extended family groups, and exhibit robust preferences for familiar social partners (same- and opposite-sex) during extended choice tests, although short-term preferences are not known. Mice (Mus musculus) are gregarious and colonial, but in brief laboratory tests of social preference they typically prefer social novelty. This preference for novel vs. familiar peers may represent a species-specific difference in social decision-making between mice and prairie voles. However, the tests used to measure preferences in each species differ markedly in duration and degree of contact, such that the behaviors cannot be directly compared. We assessed whether social preferences for novelty or familiarity differed between mice and prairie voles of both sexes when assessed with matching protocols: the sociability/social preference test (SPT) typically used in mice (short, no direct contact), and the partner preference test (PPT) used in voles (long, direct contact). A subset of voles also underwent a PPT using barriers (long, no direct contact). In the short SPT, behavior did not differ between species. In the longer test, pronounced partner preferences emerged in prairie voles, but mice exhibited no social preferences and rarely huddled. No sex differences were evident in either test. Direct physical contact was required for partner preferences in huddling time in voles, but preference for the partner chamber was evident with or without contact. Both prairie voles and mice are social, but they exhibit important differences in the specificity and extent of their social behavior. While mice are often used to study social approach and other behaviors, voles are a more suitable species for the study of selective social relationships. Consideration of these differences will be important for studies examining the neural mechanisms supporting different kinds of peer social behavior. PMID- 29615878 TI - Elevated Anxiety and Impaired Attention in Super-Smeller, Kv1.3 Knockout Mice. AB - It has long been recognized that olfaction and emotion are linked. While chemosensory research using both human and rodent models have indicated a change in emotion can contribute to olfactory dysfunction, there are few studies addressing the contribution of olfaction to a modulation in emotion. In mice, olfactory deficits have been linked with heightened anxiety levels, suggesting that there could be an inverse relationship between olfaction and anxiety. Furthermore, increased anxiety is often co-morbid with psychiatric conditions such as attention disorders. Our study aimed to investigate the roles of olfaction in modulating anxiety. Voltage-gated potassium ion channel Kv1.3 knockout mice (Kv1.3-/-), which have heightened olfaction, and wild-type (WT) mice were examined for anxiety-like behaviors using marble burying (MB), light dark box (LDB) and elevated-plus maze (EPM) tests. Because Kv1.3-/- mice have increased locomotor activity, inattentive and hyperactive behaviors were quantified for both genotypes. Kv1.3-/- mice showed increased anxiety levels compared to their WT counterparts and administration of methylphenidate (MPH) via oral gavage alleviated their increased anxiety. Object-based attention testing indicated young and older Kv1.3-/- mice had attention deficits and treatment with MPH also ameliorated this condition. Locomotor testing through use of a metabolic chamber indicated that Kv1.3-/- mice were not significantly hyperactive and MPH treatment failed to modify this activity. Our data suggest that heightened olfaction does not necessarily lead to decreased anxiety levels, and that Kv1.3-/ mice may have behaviors associated with inattentiveness. PMID- 29615880 TI - Behavioral Characterization of beta-Arrestin 1 Knockout Mice in Anxiety-Like and Alcohol Behaviors. AB - beta-Arrestin 1 and 2 are highly expressed proteins involved in the desensitization of G protein-coupled receptor signaling which also regulate a variety of intracellular signaling pathways. Gene knockout (KO) studies suggest that the two isoforms are not homologous in their effects on baseline and drug induced behavior; yet, the role of beta-arrestin 1 in the central nervous system has been less investigated compared to beta-arrestin 2. Here, we investigate how global beta-arrestin 1 KO affects anxiety-like and alcohol-related behaviors in male and female C57BL/6 mice. We observed increased baseline locomotor activity in beta-arrestin 1 KO animals compared with wild-type (WT) or heterozygous (HET) mice with a sex effect. KO male mice were less anxious in a light/dark transition test, although this effect may have been confounded by increased locomotor activity. No differences in sucrose intake were observed between genotypes or sexes. Female beta-arrestin 1 KO mice consumed more 10% alcohol than HET females in a limited 4-h access, two-bottle choice, drinking-in-the-dark model. In a 20% alcohol binge-like access model, female KO animals consumed significantly more alcohol than HET and WT females. A significant sex effect was observed in both alcohol consumption models, with female mice consuming greater amounts of alcohol than males relative to body weight. Increased sensitivity to latency to loss of righting reflex (LORR) was observed in beta-arrestin 1 KO mice although no differences were observed in duration of LORR. Overall, our efforts suggest that beta-arrestin 1 may be protective against increased alcohol consumption in females and hyperactivity in both sexes. PMID- 29615881 TI - Age Dependent Hypothalamic and Pituitary Responses to Novel Environment Stress or Lipopolysaccharide in Rats. AB - Previously, we have shown that the transcription factor nuclear factor interleukin (NF-IL)6 can be used as an activation marker for inflammatory lipopolysaccharide (LPS)-induced and psychological novel environment stress (NES) in the rat brain. Here, we aimed to investigate age dependent changes of hypothalamic and pituitary responses to NES (cage switch) or LPS (100 MUg/kg) in 2 and 24 months old rats. Animals were sacrificed at specific time points, blood and brains withdrawn and analyzed using immunohistochemistry, RT-PCR and bioassays. In the old rats, telemetric recording revealed that NES-induced hyperthermia was enhanced and prolonged compared to the young group. Plasma IL-6 levels remained unchanged and hypothalamic IL-6 mRNA expression was increased in the old rats. Interestingly, this response was accompanied by a significant upregulation of corticotropin-releasing hormone mRNA expression only in young rats after NES and overall higher plasma corticosterone levels in all aged animals. Immunohistochemical analysis revealed a significant upregulation of NF IL6-positive cells in the pituitary after NES or LPS-injection. In another important brain structure implicated in immune-to-brain communication, namely, in the median eminence (ME), NF-IL6-immunoreactivity was increased in aged animals, while the young group showed just minor activation after LPS-stimulation. Interestingly, we found a higher amount of NF-IL6-CD68-positive cells in the posterior pituitary of old rats compared to the young counterparts. Moreover, aging affected the regulation of cytokine interaction in the anterior pituitary lobe. LPS-treatment significantly enhanced the secretion of the cytokines IL-6 and TNFalpha into supernatants of primary cell cultures of the anterior pituitary. Furthermore, in the young rats, incubation with IL-6 and IL-10 antibodies before LPS-stimulation led to a robust decrease of IL-6 production and an increase of TNFalpha production by the pituitary cells. In the old rats, this specific cytokine interaction could not be detected. Overall, the present results revealed strong differences in the activation patterns and pathways between old and young rats after both stressors. The prolonged hyperthermic and inflammatory response seen in aged animals seems to be linked to dysregulated pituitary cytokine interactions and brain cell activation (NF-IL6) in the hypothalamus pituitary-adrenal axis. PMID- 29615882 TI - Multivariate Pattern Classification of Facial Expressions Based on Large-Scale Functional Connectivity. AB - It is an important question how human beings achieve efficient recognition of others' facial expressions in cognitive neuroscience, and it has been identified that specific cortical regions show preferential activation to facial expressions in previous studies. However, the potential contributions of the connectivity patterns in the processing of facial expressions remained unclear. The present functional magnetic resonance imaging (fMRI) study explored whether facial expressions could be decoded from the functional connectivity (FC) patterns using multivariate pattern analysis combined with machine learning algorithms (fcMVPA). We employed a block design experiment and collected neural activities while participants viewed facial expressions of six basic emotions (anger, disgust, fear, joy, sadness, and surprise). Both static and dynamic expression stimuli were included in our study. A behavioral experiment after scanning confirmed the validity of the facial stimuli presented during the fMRI experiment with classification accuracies and emotional intensities. We obtained whole-brain FC patterns for each facial expression and found that both static and dynamic facial expressions could be successfully decoded from the FC patterns. Moreover, we identified the expression-discriminative networks for the static and dynamic facial expressions, which span beyond the conventional face-selective areas. Overall, these results reveal that large-scale FC patterns may also contain rich expression information to accurately decode facial expressions, suggesting a novel mechanism, which includes general interactions between distributed brain regions, and that contributes to the human facial expression recognition. PMID- 29615883 TI - Effective Connectivity in Response to Posture Changes in Elderly Subjects as Assessed Using Functional Near-Infrared Spectroscopy. AB - This study aims to assess the posture-related changes in frequency-specific effective connectivity (EC) in elderly subjects by coupling function measured using functional near-infrared spectroscopy (fNIRS). The fNIRS signals were continuously recorded from the bilateral prefrontal cortex (PFC), motor cortex (MC), and occipital lobe (OL) in 17 healthy elderly and 19 healthy young subjects during sitting and standing states. EC was calculated based on Dynamic Bayesian inference in one low frequency interval I: 0.052-0.145 Hz and one very low frequency interval II: 0.021-0.052 Hz. Results show that in response to posture change, the coupling strength significantly increased in interval I of the young group from right PFC to MC (p < 0.05). Meanwhile, the coupling strength of the elderly group was significantly increased in interval II from the left PFC to right PFC (p = 0.008) and to left MC (p = 0.031) in the standing state as compared with that in the sitting state. Compared with that of the young group, the coupling strength of the elderly group was significantly decreased (p < 0.05) between the right PFC and left PFC in interval I and from PFC and OL to MC in interval II during the sitting state. The decreased EC in interval I was also positively correlated with cognitive scores in the elderly group. In addition, the coupling strength from MC to PFC in interval II during standing state was significantly increased in elderly subjects as compared with that in the young group. These results revealed the age-related changes in reorganization of interregional interactions for different postures. These findings may provide evidence of impaired cognitive function in the elderly and can deepen the understanding on age-related changes in neurovascular coupling. PMID- 29615884 TI - Central Disorders of Hypersomnolence, Restless Legs Syndrome, and Surgery With General Anesthesia: Patient Perceptions. AB - Introduction: The importance of obstructive sleep apnea in patients undergoing surgery with general anesthesia is well-defined, but the surgical and anesthetic implications of other sleep disorders are less clear. We sought to evaluate response to surgery with general anesthesia in patients with central disorders of hypersomnolence or restless legs syndrome. Methods: We surveyed patients on their most recent surgical procedure with general anesthesia, querying about procedure, recovery, and any changes in sleep disorder symptomatology following the procedure. Results: Forty-five patients with restless legs syndrome and 57 patients with central disorders of hypersomnolence (15 narcolepsy type 2, 1 narcolepsy type 1, 30 idiopathic hypersomnia, 1 Kleine-Levin syndrome, and 10 subjective sleepiness) completed the survey, with response rates of 45.5 and 53.8%, respectively. While patients in both groups were equally likely to report surgical complications and difficulty awakening from anesthesia, hypersomnolent patients were more likely to report worsened sleepiness (40% of the hypersomnolent group vs. 11% of the RLS group, p = 0.001) and worsening of their sleep disorder symptoms (40% of the hypersomnolent group vs. 9% of the RLS group, p = 0.0001). Conclusion: Patients with sleep disorders other than sleep apnea frequently report surgical or anesthetic complications. Patients with hypersomnolence disorders commonly perceive that their sleep disorder worsened following a procedure; whether this might be related to long term effects of general anesthesia in a particularly vulnerable clinical population requires further study. PMID- 29615885 TI - Powerful Statistical Inference for Nested Data Using Sufficient Summary Statistics. AB - Hierarchically-organized data arise naturally in many psychology and neuroscience studies. As the standard assumption of independent and identically distributed samples does not hold for such data, two important problems are to accurately estimate group-level effect sizes, and to obtain powerful statistical tests against group-level null hypotheses. A common approach is to summarize subject level data by a single quantity per subject, which is often the mean or the difference between class means, and treat these as samples in a group-level t test. This "naive" approach is, however, suboptimal in terms of statistical power, as it ignores information about the intra-subject variance. To address this issue, we review several approaches to deal with nested data, with a focus on methods that are easy to implement. With what we call the sufficient-summary statistic approach, we highlight a computationally efficient technique that can improve statistical power by taking into account within-subject variances, and we provide step-by-step instructions on how to apply this approach to a number of frequently-used measures of effect size. The properties of the reviewed approaches and the potential benefits over a group-level t-test are quantitatively assessed on simulated data and demonstrated on EEG data from a simulated-driving experiment. PMID- 29615886 TI - Evidence in Support of the Independent Channel Model Describing the Sensorimotor Control of Human Stance Using a Humanoid Robot. AB - The Independent Channel (IC) model is a commonly used linear balance control model in the frequency domain to analyze human balance control using system identification and parameter estimation. The IC model is a rudimentary and noise free description of balance behavior in the frequency domain, where a stable model representation is not guaranteed. In this study, we conducted firstly time domain simulations with added noise, and secondly robot experiments by implementing the IC model in a real-world robot (PostuRob II) to test the validity and stability of the model in the time domain and for real world situations. Balance behavior of seven healthy participants was measured during upright stance by applying pseudorandom continuous support surface rotations. System identification and parameter estimation were used to describe the balance behavior with the IC model in the frequency domain. The IC model with the estimated parameters from human experiments was implemented in Simulink for computer simulations including noise in the time domain and robot experiments using the humanoid robot PostuRob II. Again, system identification and parameter estimation were used to describe the simulated balance behavior. Time series, Frequency Response Functions, and estimated parameters from human experiments, computer simulations, and robot experiments were compared with each other. The computer simulations showed similar balance behavior and estimated control parameters compared to the human experiments, in the time and frequency domain. Also, the IC model was able to control the humanoid robot by keeping it upright, but showed small differences compared to the human experiments in the time and frequency domain, especially at high frequencies. We conclude that the IC model, a descriptive model in the frequency domain, can imitate human balance behavior also in the time domain, both in computer simulations with added noise and real world situations with a humanoid robot. This provides further evidence that the IC model is a valid description of human balance control. PMID- 29615887 TI - A Density-Driven Method for the Placement of Biological Cells Over Two Dimensional Manifolds. AB - We introduce a graphical method originating from the computer graphics domain that is used for the arbitrary placement of cells over a two-dimensional manifold. Using a bitmap image whose luminance provides cell density, this method guarantees a discrete distribution of the positions of the cells respecting the local density. This method scales to any number of cells, allows one to specify arbitrary enclosing shapes and provides a scalable and versatile alternative to the more classical assumption of a uniform spatial distribution. The method is illustrated on a discrete homogeneous neural field, on the distribution of cones and rods in the retina and on the neural density of a flattened piece of cortex. PMID- 29615888 TI - Learning Semantics of Gestural Instructions for Human-Robot Collaboration. AB - Designed to work safely alongside humans, collaborative robots need to be capable partners in human-robot teams. Besides having key capabilities like detecting gestures, recognizing objects, grasping them, and handing them over, these robots need to seamlessly adapt their behavior for efficient human-robot collaboration. In this context we present the fast, supervised Proactive Incremental Learning (PIL) framework for learning associations between human hand gestures and the intended robotic manipulation actions. With the proactive aspect, the robot is competent to predict the human's intent and perform an action without waiting for an instruction. The incremental aspect enables the robot to learn associations on the fly while performing a task. It is a probabilistic, statistically-driven approach. As a proof of concept, we focus on a table assembly task where the robot assists its human partner. We investigate how the accuracy of gesture detection affects the number of interactions required to complete the task. We also conducted a human-robot interaction study with non-roboticist users comparing a proactive with a reactive robot that waits for instructions. PMID- 29615889 TI - Elastic Elements in a Wrist Prosthesis for Drumming Reduce Muscular Effort, but Increase Imprecision and Perceived Stress. AB - Recently, progress has been made in the development of mechanical joints with variable intrinsic stiffness, opening up the search for application areas of such variable-stiffness joints. By varying the stiffness of its joints, the resonant frequency of a system can be tuned to perform cyclical tasks most energy efficiently, making the variable-stiffness joint a candidate element for an advanced prosthetic device specifically designed for the cyclical task of drumming. A prerequisite for a successful variable-stiffness drumming prosthesis is the ability of human drummers to profitably employ different stiffness levels for playing different beats. In this pilot study, 29 able-bodied subjects (20 drumming novices and 9 experts) wear a cuff on the forearm, to which a drumstick is connected using changeable adapters, consisting of several leaf springs with different stiffness and one maximally stiff connection element. The subjects are asked to play simple regular drum beats at different frequencies, one of which is the resonant frequency of the adapter-drumstick system. The subject's performance of each drumming task is rated in terms of accuracy and precision, and the effort is measured using questionnaires for the perceived stress as well as electromyography (EMG) for the muscular activity. The experiments show that using springs instead of the stiff connection leads to lower muscular activity, indicating that humans are able to use the energy-storing capabilities of the springs, or that muscular activity is reduced due to the lower mass of the springs. However, the perceived stress is increased and the novices' performance lowered, possibly due to a higher cerebral load for controlling the elastic system. The hypothesis that "matching the resonant frequency of the spring drumstick system to the desired frequency leads to better performance and lower effort" is not confirmed. Possible explanations are discussed. In conclusion, a series-elastic element appears to lower the muscular effort of drumming, while a stiff connection appears to minimize the mental load and has a positive effect on the performance of drumming novices. PMID- 29615890 TI - Automatic Setting Procedure for Exoskeleton-Assisted Overground Gait: Proof of Concept on Stroke Population. AB - Stroke-related locomotor impairments are often associated with abnormal timing and intensity of recruitment of the affected and non-affected lower limb muscles. Restoring the proper lower limbs muscles activation is a key factor to facilitate recovery of gait capacity and performance, and to reduce maladaptive plasticity. Ekso is a wearable powered exoskeleton robot able to support over-ground gait training. The user controls the exoskeleton by triggering each single step during the gait cycle. The fine-tuning of the exoskeleton control system is crucial-it is set according to the residual functional abilities of the patient, and it needs to ensure lower limbs powered gait to be the most physiological as possible. This work focuses on the definition of an automatic calibration procedure able to detect the best Ekso setting for each patient. EMG activity has been recorded from Tibialis Anterior, Soleus, Rectus Femoris, and Semitendinosus muscles in a group of 7 healthy controls and 13 neurological patients. EMG signals have been processed so to obtain muscles activation patterns. The mean muscular activation pattern derived from the controls cohort has been set as reference. The developed automatic calibration procedure requires the patient to perform overground walking trials supported by the exoskeleton while changing parameters setting. The Gait Metric index is calculated for each trial, where the closer the performance is to the normative muscular activation pattern, in terms of both relative amplitude and timing, the higher the Gait Metric index is. The trial with the best Gait Metric index corresponds to the best parameters set. It has to be noted that the automatic computational calibration procedure is based on the same number of overground walking trials, and the same experimental set-up as in the current manual calibration procedure. The proposed approach allows supporting the rehabilitation team in the setting procedure. It has been demonstrated to be robust, and to be in agreement with the current gold standard (i.e., manual calibration performed by an expert engineer). The use of a graphical user interface is a promising tool for the effective use of an automatic procedure in a clinical context. PMID- 29615891 TI - Catalpol Inhibits Amyloid-beta Generation Through Promoting alpha-Cleavage of APP in Swedish Mutant APP Overexpressed N2a Cells. AB - Amyloid-beta (Abeta) peptides play a crucial role in the pathogenesis of Alzheimer's disease (AD), due to its neurotoxicity. Thus, blocking Abeta generation and aggregation in the brain has been realized as an efficient way for the prevention of AD. The natural product catalpol, isolated from Rehmannia glutinosa, has shown neuroprotective activities through inhibiting soluble Abeta production, degrading Abeta peptide, and attenuating Abeta toxicity and neuroinflammatory responses. In the present study, we aimed to evaluate whether catalpol reduce Abeta generation associated with regulating amyloid precursor protein (APP) proteolytic processing. By using Swedish mutant APP overexpressed N2a (SweAPP N2a) cells treated with catalpol, we found that catalpol was not able to reduce the expression levels of beta-secretase (BACE-1) and gamma-secretase (PS1, APH-1, PEN-2 and Nicastrin). By contrast, catalpol had a significant promotion effect on the expression of alpha-secretase (ADAM10) and its proteolytic products, sAPPalpha and C83, suggesting that catalpol reduced the production of Abeta might be involved in non-amyloidogenic APP pathway. In addition, we confirmed that the extracellular signal-related kinase/cAMP-response element binding protein (ERK/CREB) signaling pathways were responsible for the up regulation of ADAM10 in catalpol-treated SweAPP N2a cells. The present data, for the first time, have demonstrated that the effect of catalpol on the inhibiting Abeta generation might be closely related to alpha-cleavage of APP processing. PMID- 29615892 TI - Narrative Discourse in Young and Older Adults: Behavioral and NIRS Analyses. AB - Discourse comprehension is at the core of communication capabilities, making it an important component of elderly populations' quality of life. The aim of this study is to evaluate changes in discourse comprehension and the underlying brain activity. Thirty-six participants read short stories and answered related probes in three conditions: micropropositions, macropropositions and situation models. Using near-infrared spectroscopy (NIRS), the variation in oxyhemoglobin (HbO2) and deoxyhemoglobin (HbR) concentrations was assessed throughout the task. The results revealed that the older adults performed with equivalent accuracy to the young ones at the macroproposition level of discourse comprehension, but were less accurate at the microproposition and situation model levels. Similar to what is described in the compensation-related utilization of neural circuits hypothesis (CRUNCH) model, older participants tended to have greater activation in the left dorsolateral prefrontal cortex while reading in all conditions. Although it did not enable them to perform similarly to younger participants in all conditions, this over-activation could be interpreted as a compensation mechanism. PMID- 29615893 TI - A New Measure for Neural Compensation Is Positively Correlated With Working Memory and Gait Speed. AB - Neuroimaging studies suggest that older adults may compensate for declines in brain function and cognition through reorganization of neural resources. A limitation of prior research is reliance on between-group comparisons of neural activation (e.g., younger vs. older), which cannot be used to assess compensatory ability quantitatively. It is also unclear about the relationship between compensatory ability with cognitive function or how other factors such as physical exercise modulates compensatory ability. Here, we proposed a data-driven method to semi-quantitatively measure neural compensation under a challenging cognitive task, and we then explored connections between neural compensation to cognitive engagement and cognitive reserve (CR). Functional and structural magnetic resonance imaging scans were acquired for 26 healthy older adults during a face-name memory task. Spatial independent component analysis (ICA) identified visual, attentional and left executive as core networks. Results show that the smaller the volumes of the gray matter (GM) structures within core networks, the more networks were needed to conduct the task (r = -0.408, p = 0.035). Therefore, the number of task-activated networks controlling for the GM volume within core networks was defined as a measure of neural compensatory ability. We found that compensatory ability correlated with working memory performance (r = 0.528, p = 0.035). Among subjects with good memory task performance, those with higher CR used fewer networks than subjects with lower CR. Among poor-performance subjects, those using more networks had higher CR. Our results indicated that using a high cognitive-demanding task to measure the number of activated neural networks could be a useful and sensitive measure of neural compensation in older adults. PMID- 29615894 TI - TRPC1 Deletion Causes Striatal Neuronal Cell Apoptosis and Proteomic Alterations in Mice. AB - Transient receptor potential channel 1 (TRPC1) is widely expressed throughout the nervous system, while its biological role remains unclear. In this study, we showed that TRPC1 deletion caused striatal neuronal loss and significantly increased TUNEL-positive and 8-hydroxy-2'-deoxyguanosine (8-OHdG) staining in the striatum. Proteomic analysis by two-dimensional fluorescence difference gel electrophoresis (2D-DIGE) coupled with mass spectrometry (MS) revealed a total of 51 differentially expressed proteins (26 increased and 25 decreased) in the stratum of TRPC1 knockout (TRPC1-/-) mice compared to that of wild type (WT) mice. Bioinformatics analysis showed these dysregulated proteins included: oxidative stress-related proteins, synaptic proteins, endoplasmic reticulum (ER) stress-related proteins and apoptosis-related proteins. STRING analysis showed these differential proteins have a well-established interaction network. Based on the proteomic data, we revealed by Western-blot analysis that TRPC1 deletion caused ER stress as evidenced by the dysregulation of GRP78 and PERK activation related signaling pathway, and elevated oxidative stress as suggested by increased 8-OHdG staining, increased NADH dehydrogenase (ubiquinone) flavoprotein 2 (NDUV2) and decreased protein deglycase (DJ-1), two oxidative stress-related proteins. In addition, we also demonstrated that TRPC1 deletion led to significantly increased apoptosis in striatum with concurrent decrease in both 14 3-3Z and dynamin-1 (D2 dopamine (DA) receptor binding), two apoptosis-related proteins. Taken together, we concluded that TRPC1 deletion might cause striatal neuronal apoptosis by disturbing multiple biological processes (i.e., ER stress, oxidative stress and apoptosis-related signaling). These data suggest that TRPC1 may be a key player in the regulation of striatal cellular survival and death. PMID- 29615895 TI - Hypertension Accelerates Alzheimer's Disease-Related Pathologies in Pigs and 3xTg Mice. AB - Epidemiological studies suggest there is an association between midlife hypertension and increased risk of late-life Alzheimer's disease (AD). However, whether hypertension accelerates the onset of AD or is a distinct disease that becomes more prevalent with age (comorbidity) remains unclear. This study aimed to test the possible relationship between hypertension and AD pathogenesis. Two animal models were used in this study. For the first model, 7-month-old Lanyu miniature-pigs were given the abdominal aortic constriction operation to induce hypertension and their AD-related pathologies were assessed at 1, 2, and 3 months after the operation. The results showed that hypertension was detected since 1 month after the operation in the pigs. Levels of Abeta, amyloid precursor protein, RAGE, phosphorylated tau and activated GSK3beta in the hippocampi increased at 3 months after the operation. For the second model, 3xTg mice at the ages of 2, 5, and 7 months were subjected to the "two-kidney-one-clip" operation to induce hypertension. One month after the operation, blood pressure was significantly increased in the 3xTg mice in any age. Abeta, amyloid plaque load, and phosphorylated tau levels increased in the operated mice. Furthermore, the operation also induced shrinkage in the dendritic arbor of hippocampal dentate gyrus granule neurons, leakage in the blood-brain barrier, activation in microglia, and impairment in the hippocampus-dependent learning and memory in the 3xTg mice. In conclusion, hypertension accelerates the onset of AD. Blood pressure control during midlife may delay the onset of AD. PMID- 29615896 TI - Brain Aging and APOE epsilon4 Interact to Reveal Potential Neuronal Compensation in Healthy Older Adults. AB - Compensation implies the recruitment of additional neuronal resources to prevent the detrimental effect of age-related neuronal decline on cognition. Recently suggested statistical models comprise behavioral performance, brain activation, and measures related to aging- or disease-specific pathological burden to characterize compensation. Higher chronological age as well as the APOE epsilon4 allele are risk factors for Alzheimer's disease. A more biological approach to characterize aging compared with chronological age is the brain age gap estimation (BrainAGE), taking into account structural brain characteristics. We utilized this estimate in an fMRI experiment together with APOE variant as measures related to pathological burden and aimed at identifying compensatory regions during working memory (WM) processing in a group of 34 healthy older adults. According to published compensation criteria, better performance along with increased brain activation would indicate successful compensation. We examined the moderating effects of BrainAGE on the relationship between task performance and brain activation in prefrontal cortex, as previous studies suggest predominantly frontal compensatory activation. Then we statistically compared them to the effects of chronological age (CA) tested in a previous study. Moreover, we examined the effects of adding APOE variant as a further moderator. Herewith, we strived to uncover neuronal compensation in healthy older adults at risk for neurodegenerative disease. Higher BrainAGE alone was not associated with an increased recruitment in prefrontal cortex. When adding APOE variant as a second moderator, we found an interaction of BrainAGE and APOE variant, such that epsilon4 carriers recruited right inferior frontal gyrus with higher BrainAGE to maintain WM performance, thus showing a pattern compatible with successful neuronal compensation. Exploratory analyses yielded similar patterns in left inferior and bilateral middle frontal gyrus. These results contrast those from a previous study, where we found no indication of compensation in prefrontal cortex in epsilon4 carriers with increasing CA. We conclude that BrainAGE together with APOE variant can help to reveal potential neuronal compensation in healthy older adults. Previous results on neuronal compensation in frontal areas corroborate our findings. Compensatory brain regions could be targeted in affected individuals by training or stimulation protocols to maintain cognitive functioning as long as possible. PMID- 29615897 TI - Adenosine A2A Receptors Control Glutamatergic Synaptic Plasticity in Fast Spiking Interneurons of the Prefrontal Cortex. AB - Adenosine A2A receptors (A2AR) are activated upon increased synaptic activity to assist in the implementation of long-term plastic changes at synapses. While it is reported that A2AR are involved in the control of prefrontal cortex (PFC) dependent behavior such as working memory, reversal learning and effort-based decision making, it is not known whether A2AR control glutamatergic synapse plasticity within the medial PFC (mPFC). To elucidate that, we tested whether A2AR blockade affects long-term plasticity (LTP) of excitatory post-synaptic potentials in pyramidal neurons and fast spiking (FS) interneurons in layer 5 of the mPFC and of population spikes. Our results show that A2AR are enriched at mPFC synapses, where their blockade reversed the direction of plasticity at excitatory synapses onto layer 5 FS interneurons from LTP to long-term depression, while their blockade had no effect on the induction of LTP at excitatory synapses onto layer 5 pyramidal neurons. At the network level, extracellularly induced LTP of population spikes was reduced by A2AR blockade. The interneuron-specificity of A2AR in controlling glutamatergic synapse LTP may ensure that during periods of high synaptic activity, a proper excitation/inhibition balance is maintained within the mPFC. PMID- 29615898 TI - Antihyperalgesic Properties of Honokiol in Inflammatory Pain Models by Targeting of NF-kappaB and Nrf2 Signaling. AB - The present study investigates the possible anti-nociceptive effect of intraperitoneal (i.p.) honokiol: a phenolic compound originally isolated from Magnolia officinalis, in acute and chronic inflammatory pain models. Doses of 0.1, 5, and 10 mg/kg honokiol were administered in carrageenan induced pain and the dose (honokiol 10 mg/kg i.p.) with most significant response among behavioral tests was selected for further experiments. The i.p. administration of honokiol inhibits mechanical hyperalgesia, mechanical allodynia, and thermal hyperalgesia, without causing any apparent toxicity. To elucidate the effect of honokiol on various cytokines and antioxidant enzymes, quantitative real-time-PCR was performed to determine the expression levels of pro-inflammatory cytokines and antioxidant enzymes. It is demonstrated that honokiol significantly reduced the expression levels of tumor necrosis factor (TNF-alpha), interleukin-1beta (IL 1beta), interleukin-6 (IL-6), and vascular endothelial growth factor (VEGF). Similarly, honokiol was also found to potentiate the expression of nuclear factor erythroid 2-related factor 2 (Nrf2), superoxide dismutase 2 (SOD2), and heme oxygenase-1 (HO-1) levels. Additionally, honokiol significantly reduced plasma nitrite levels as compared to complete Freund's adjuvant (CFA) induced group. X ray analysis and hematoxylin and eosin (H&E) staining of inflamed and treated paws showed that honokiol reduced the inflammation with significantly less leukocyte infiltration and soft tissue inflammation. In order to explore the possible mechanism of action of honokiol, agonists [piroxicam (5 mg/kg), tramadol (50 mg/kg), and gabapentin (5 mg/kg) i.p.] as well as antagonists [naloxone (4 mg/kg), olanzapine (10 mg/kg), and flumazenil (0.2 mg/kg) i.p.] were used to study involvement of various receptors on the anti-nociceptive effect of honokiol. The potential side effects of honokiol on muscle activity were assessed. An adverse effect testing of honokiol by liver and renal functions were also carried out. The effect of oral honokiol was also assessed on gastrointestinal (GIT) mucosa. Our results demonstrate that honokiol has a significant anti-nociceptive activity through inhibition of anti-inflammatory mediators. PMID- 29615899 TI - Extracellular Guanosine 5'-Triphosphate Induces Human Muscle Satellite Cells to Release Exosomes Stuffed With Guanosine. AB - The extracellular guanosine 5'-triphosphate, GTP, has been demonstrated to be an enhancer of myogenic cell differentiation in a murine cell line, not yet in human muscle cells. Our hypothesis was that GTP could influence also human skeletal muscle regeneration, specifically in the first phases. We tested GTP stimulus on human muscle precursor cells established in culture by human satellite cells derived from Vastus Lateralis of three young male. Our data show that extracellular GTP (a) up-regulated miRNA (specifically miR133a and miR133b) and myogenic regulator factor and (b) induces human myogenic precursor cells to release exosomes stuffed with guanosine based molecules (mainly guanosine) in the extracellular milieu. We think that probably these exosomes could be addressed to influence by means of their content (mainly guanosine) in paracrine or autocrine manner the surrounding cells and/or at distance other muscles or tissues. PMID- 29615900 TI - Peripheral CB1 Receptor Neutral Antagonist, AM6545, Ameliorates Hypometabolic Obesity and Improves Adipokine Secretion in Monosodium Glutamate Induced Obese Mice. AB - Effect of peripheral cannabinoid receptor 1 (CB1R) blockade by AM6545 in the monosodium glutamate (MSG)-induced hypometabolic and hypothalamic obesity was observed, and the impact on intraperitoneal adipose tissue and adipokines was investigated. The MSG mice is characterized by excessive abdominal obesity, and combined with dyslipidemia and insulin resistance. 3-Week AM6545 treatment dose dependently decreased the body weight, intraperitoneal fat mass, and rectified the accompanied dyslipidemia include elevated serum triglyceride, total cholesterol, free fatty acids, and lowered LDLc level. Glucose intolerance and hyperinsulinemia were also alleviated. But AM6545 didn't affect the food-intake consistently through the experiment. In line with the reduction on fat mass, the size of adipocyte was reduced markedly. Most interestingly, AM6545 showed significant improvement on levels of circulating adipokines including lowering leptin, asprosin and TNFalpha, and increasing HMW adiponectin. Correspondingly, dysregulated gene expression of lipogenesis, lipolysis, and adipokines in the adipose tissue were nearly recovered to normal level after AM6545 treatment. Additionally, western blot analysis revealed that AM6545 corrected the elevated CB1R and PPARgamma protein expression, while increased the key energy uncoupling protein UCP1 expression in adipose tissue. Taken together, the current study indicates that AM6545 induced a comprehensive metabolic improvement in the MSG mice including counteracting the hypometabolic and hypothalamic obesity, and improving the accompanied dyslipidemia and insulin resistance. One key underlying mechanism is related to ameliorate on the metabolic deregulation of adipose tissue, the synthesis and secretion of adipokines were thus rectified, and finally the catabolism was increased and the anabolism was reduced in intraperitoneal adipose tissue. Findings from this study will provide the valuable information about peripheral CB1R antagonist in managing hypometabolic obesity. PMID- 29615901 TI - Isoquercetin as an Adjunct Therapy in Patients With Kidney Cancer Receiving First Line Sunitinib (QUASAR): Results of a Phase I Trial. AB - Sunitinib is the most commonly prescribed drug for advanced renal cell carcinoma in the first-line setting and has been associated with multiple adverse events related to its on-and off-target effects, including hand and foot syndrome and fatigue. It was hypothesized that sunitinib-induced fatigue may be related to off target inhibition of the AMPK enzyme, which results in impairment of energy producing processes at a systemic level. Quercetin is a naturally occurring flavonol with established AMPK-stimulating activity. While clinical use of quercetin is limited by its poor bio-availability, quercetin-3-O-beta-d glucopyranoside, that is isoquercetin, has an improved pharmacokinetic profile. On the grounds of the in vitro stimulatory activity with respect to AMPk, we hypothesized that oral isoquercetin could improve fatigue in kidney cancer patients receiving sunitinib. Given the lack of data on the safety of isoquercetin given concomitantly with sunitinib, we conducted a phase I trial to assess the safety of GMP manufactured isoquercetin given at two dose levels (450 and 900 mg a day). In the 12-patient study cohort included in this study, isoquercetin was administered concomitantly with 50 mg sunitinib for a median 81 days (IQR, 75.5, 86.5). None of the 12 patients required isoquercetin suspension or isoquercetin dose reduction because of adverse events. No abnormalities in ECG, heart or lower limbs doppler ultrasound were detected. A statistically significant improvement was reported for the FACIT fatigue score (6.8 points; 95% CI: 2.8-10.8; p = 0.002) and for the FACIT Adverse Events score (18.9 points; 95% CI: 9.1-28.8; p < 0.001) after isoquercetin consumption vs. baseline. In this phase I trial, isoquercetin was remarkably safe, with a preliminary signal of activity in terms of improvement of sunitinib adverse events. PMID- 29615903 TI - Adenosine A2A Receptor Blockade Modulates Glucocorticoid-Induced Morphological Alterations in Axons, But Not in Dendrites, of Hippocampal Neurons. AB - The exposure to supra-physiological levels of glucocorticoids in prenatal life can lead to a long-term impact in brain cytoarchitecture, increasing the susceptibility to neuropsychiatric disorders. Dexamethasone, an exogenous glucocorticoid widely used in pregnant women in risk of preterm delivery, is associated with higher rates of neuropsychiatric conditions throughout life of the descendants. In animal models, prenatal dexamethasone exposure leads to anxious-like behavior and increased susceptibility to depressive-like behavior in adulthood, concomitant with alterations in neuronal morphology in brain regions implicated in the control of emotions and mood. The pharmacologic blockade of the purinergic adenosine A2A receptor, which was previously described as anxiolytic, is also able to modulate neuronal morphology, namely in the hippocampus. Additionally, recent observations point to an interaction between glucocorticoid receptors (GRs) and adenosine A2A receptors. In this work, we explored the impact of dexamethasone on neuronal morphology, and the putative implication of adenosine A2A receptor in the mediation of dexamethasone effects. We report that in vitro hippocampal neurons exposed to dexamethasone (250 nM), in the early phases of development, exhibit a polarized morphology alteration: dendritic atrophy and axonal hypertrophy. While the effect of dexamethasone in the axon is dependent on the activation of adenosine A2A receptor, the effect in the dendrites relies on the activation of GRs, regardless of the activation of adenosine A2A receptor. These results support the hypothesis of the interaction between GRs and adenosine A2A receptors and the potential therapeutic value of modulating adenosine A2A receptors activation in order to prevent glucocorticoid induced alterations in developing neurons. PMID- 29615902 TI - Drug Repositioning in Glioblastoma: A Pathway Perspective. AB - Glioblastoma multiforme (GBM) is the most malignant primary adult brain tumor. The current standard of care is surgical resection, radiation, and chemotherapy treatment, which extends life in most cases. Unfortunately, tumor recurrence is nearly universal and patients with recurrent glioblastoma typically survive <1 year. Therefore, new therapies and therapeutic combinations need to be developed that can be quickly approved for use in patients. However, in order to gain approval, therapies need to be safe as well as effective. One possible means of attaining rapid approval is repurposing FDA approved compounds for GBM therapy. However, candidate compounds must be able to penetrate the blood-brain barrier (BBB) and therefore a selection process has to be implemented to identify such compounds that can eliminate GBM tumor expansion. We review here psychiatric and non-psychiatric compounds that may be effective in GBM, as well as potential drugs targeting cell death pathways. We also discuss the potential of data-driven computational approaches to identify compounds that induce cell death in GBM cells, enabled by large reference databases such as the Library of Integrated Network Cell Signatures (LINCS). Finally, we argue that identifying pathways dysregulated in GBM in a patient specific manner is essential for effective repurposing in GBM and other gliomas. PMID- 29615904 TI - Canonical TSH Regulation of Cathepsin-Mediated Thyroglobulin Processing in the Thyroid Gland of Male Mice Requires Taar1 Expression. AB - Trace amine-associated receptor 1 (Taar1) has been suggested as putative receptor of thyronamines. These are aminergic messengers with potential metabolic and neurological effects countering their contingent precursors, the thyroid hormones (THs). Recently, we found Taar1 to be localized at the primary cilia of rodent thyroid epithelial cells in vitro and in situ. Thus, Taar1 is present in a location of thyroid follicles where it might be involved in regulation of cathepsin-mediated proteolytic processing of thyroglobulin, and consequently TH synthesis. In this study, taar1 knock-out male mice (taar1-/-) were used to determine whether Taar1 function would entail differential alterations in thyroid states of young and adult animals. Analyses of blood serum revealed unaltered T4 and T3 concentrations and unaltered T3-over-T4 ratios upon Taar1 deficiency accompanied, however, by elevated TSH concentrations. Interestingly, TSH receptors, typically localized at the basolateral plasma membrane domain of wild type controls, were located at vesicular membranes in thyrocytes of taar1-/- mice. In addition, determination of epithelial extensions in taar1-/- thyroids showed prismatic cells, which might indicate activation states higher than in the wild type. While gross degradation of thyroglobulin was comparable to controls, deregulated thyroglobulin turnover in taar1-/- mice was indicated by luminal accumulation of covalently cross-linked thyroglobulin storage forms. These findings were in line with decreased proteolytic activities of thyroglobulin solubilizing and -processing proteases, due to upregulated cystatins acting as their endogenous inhibitors in situ. In conclusion, Taar1-deficient mice are hyperthyrotropinemic in the absence of respective signs of primary hypothyroidism such as changes in body weight or TH concentrations in blood serum. Thyrocytes of taar1-/- mice are characterized by non-canonical TSH receptor localization in intracellular compartments, which is accompanied by altered thyroglobulin turnover due to a disbalanced proteolytic network. These finding are of significance considering the rising popularity of using TAAR1 agonists or antagonists as neuromodulating pharmacological drugs. Our study highlights the importance of further evaluating potential off-target effects regarding TSH receptor mislocalization and the thyroglobulin processing machinery, which may not only affect the TH-generating thyroid gland, but may emanate to other TH target organs like the CNS dependent on their proper supply. PMID- 29615905 TI - Four Weekly Ayahuasca Sessions Lead to Increases in "Acceptance" Capacities: A Comparison Study With a Standard 8-Week Mindfulness Training Program. AB - Background: The therapeutic effects of the Amazonian plant tea ayahuasca may relate to its ability to enhance mindfulness capacities. Ayahuasca induces a modified state of awareness through the combined action of its active principles: the psychedelic N,N-dimethyltryptamine (DMT) and a series of centrally acting beta-carbolines, mainly harmine and tetrahydroharmine. To better understand the therapeutic potential of ayahuasca, here we compared the impact on mindfulness capacities induced by two independent interventions: (a) participation in four ayahuasca sessions without any specific purpose related to improving mindfulness capacities; and (b) participation in a standard mindfulness training course: 8 weeks mindfulness-based stress reduction (MBSR), with the specific goal of improving these skills. Methods: Participants of two independent groups completed two self-report instruments: The Five Facet Mindfulness Questionnaire (FFMQ) and the Experiences Questionnaire (EQ). The MINDSENS Composite Index was also calculated, including those EQ and FFMQ items that have proven to be the most sensitive to meditation practice. Group A (n = 10) was assessed before and after the last of four closely spaced consecutive ayahuasca sessions. Group B (n = 10) was assessed before and after completion of a standard 8-week MBSR course. Results: MBSR training led to greater increases in overall mindfulness scores after the 8-week period. MBSR but not ayahuasca led to increases in the MINDSENS Composite Index. However, the ayahuasca sessions induced comparable increases in the Non-Judging subscale of the FFMQ, specifically measuring "acceptance." Improving this capacity allows for a more detached and less judgmental stance toward potentially distressing thoughts and emotions. Results: The present findings suggest that a small number of ayahuasca sessions can be as effective at improving acceptance as more lengthy and costly interventions. Future studies should address the benefits of combining ayahuasca administration with mindfulness-based interventions. This will allow us to investigate if ayahuasca will improve the outcome of psychotherapeutic interventions. PMID- 29615906 TI - Mechanisms of Triptolide-Induced Hepatotoxicity and Protective Effect of Combined Use of Isoliquiritigenin: Possible Roles of Nrf2 and Hepatic Transporters. AB - Triptolide (TP), the main bioactive component of Tripterygium wilfordii Hook F, can cause severe hepatotoxicity. Isoliquiritigenin (ISL) has been reported to be able to protect against TP-induced liver injury, but the mechanisms are not fully elucidated. This study aims to explore the role of nuclear transcription factor E2-related factor 2 (Nrf2) and hepatic transporters in TP-induced hepatotoxicity and the reversal protective effect of ISL. TP treatment caused both cytotoxicity in L02 hepatocytes and acute liver injury in mice. Particularly, TP led to the disorder of bile acid (BA) profiles in mice livers. Combined treatment of TP with ISL effectively alleviated TP-induced hepatotoxicity. Furthermore, ISL pretreatment enhanced Nrf2 expressions and nuclear accumulations and its downstream NAD(P)H: quinine oxidoreductase 1 (NQO1) expression. Expressions of hepatic P-gp, MRP2, MRP4, bile salt export pump, and OATP2 were also induced. In addition, in vitro transport assays identified that neither was TP exported by MRP2, OATP1B1, or OATP1B3, nor did TP influence the transport activities of P-gp or MRP2. All these results indicate that ISL may reduce the hepatic oxidative stress and hepatic accumulations of both endogenous BAs and exogenous TP as well as its metabolites by enhancing the expressions of Nrf2, NQO1, and hepatic influx and efflux transporters. Effects of TP on hepatic transporters are mainly at the transcriptional levels, and changes of hepatic BA profiles are very important in the mechanisms of TP-induced hepatotoxicity. PMID- 29615907 TI - Suppression of Cisplatin-Induced Vomiting by Cannabis sativa in Pigeons: Neurochemical Evidences. AB - Cannabis sativa (CS, family Cannabinaceae) has been reported for its anti-emetic activity against cancer chemotherapy-induced emesis in animal models and in clinics. The current study was designed to investigate CS for potential effectiveness to attenuate cisplatin-induced vomiting in healthy pigeons and to study the impact on neurotransmitters involved centrally and peripherally in the act of vomiting. High-performance liquid chromatography system coupled with electrochemical detector was used for the quantification of neurotransmitters 5 hydroxytryptamine (5HT), dopamine (DA) and their metabolites; Di-hydroxy Phenyl Acetic acid (Dopac), Homovanillic acid (HVA), and 5-hydroxy indole acetic acid (5HIAA) centrally in specific brain areas (area postrema and brain stem) while, peripherally in small intestine. Cisplatin (7 mg/kg i.v.) induce emesis without lethality across the 24 h observation period. CS hexane fraction (CS-HexFr; 10 mg/kg) attenuated cisplatin-induced emesis ~ 65.85% (P < 0.05); the reference anti-emetic drug, metoclopramide (MCP; 30 mg/kg), produced ~43.90% reduction (P < 0.05). At acute time point (3rd h), CS-HexFr decreased (P < 0.001) the concentration of 5HT and 5HIAA in the area postrema, brain stem and intestine, while at 18th h (delayed time point) CS-HexFr attenuated (P < 0.001) the upsurge of 5HT caused by cisplatin in the brain stem and intestine and dopamine in the area postrema. CS-HexFr treatment alone did not alter the basal neurotransmitters and their metabolites in the brain areas and intestine except 5HIAA and HVA, which were decreased significantly. In conclusion the anti-emetic effect of CS HexFr is mediated by anti-serotonergic and anti-dopaminergic components in a blended manner at the two different time points, i.e., 3rd and 18th h in pigeons. PMID- 29615908 TI - Time and Concentration Dependent Effects of Short Chain Fatty Acids on Lipopolysaccharide- or Tumor Necrosis Factor alpha-Induced Endothelial Activation. AB - Background and Aim: Endothelial activation is characterized by excessive production of cytokines and chemokines as well as adhesion molecules expression which is involved in the development of atherosclerosis. The aim of our study is to investigate the effects of short chain fatty acids (SCFA) on lipopolysaccharide (LPS) or tumor necrosis factor alpha (TNFalpha)-induced endothelial activation. Methods and Results: Human umbilical vein endothelial cells (HUVEC) were pre-treated with acetate (10 mM), butyrate (0.1 mM) or propionate (0.3 mM) for 1, 16, or 24 h and then stimulated with LPS (1 or 10 MUg/ml) or TNFalpha (100 pg/ml or 1 ng/ml) for 6, 12, or 24 h. Cytokines in the supernatant were measured by ELISA. HUVEC were pre-treated with acetate (10 mM), butyrate (5 mM) or propionate (10 mM) for 24 h and then stimulated with LPS (1 MUg/ml) or TNFalpha (1 ng/ml) for 8 h. The expression of the adhesion molecules intracellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) was detected by flow cytometry. The human blood mononuclear cell adhesive level to HUVEC monolayer was measured. LPS and TNFalpha induced a significant increase in the release of interleukin-6 (IL-6) and IL-8. Acetate, butyrate and propionate reduced IL-6 and IL-8 levels and the magnitude was dependent on the incubation times. LPS or TNFalpha increased ICAM-1 and VCAM-1 expression. Pre-incubation with acetate had no effect. In contrast, butyrate and propionate decreased VCAM-1 expression in TNFalpha stimulated cells but showed no effects on ICAM-1 expression. Butyrate significantly inhibited the adhesion of mononuclear cells to an endothelial monolayer and propionate was less effective. Conclusion: SCFA, including acetate, butyrate and propionate, influenced LPS- or TNFalpha-induced endothelial activation by inhibiting the production of IL-6 and IL-8, and reducing the expression of VCAM-1 and subsequent cell adhesion. Results were dependent on the concentrations and pre-incubation time of each SCFA and stimulation time of LPS or TNFalpha. PMID- 29615909 TI - Systems Pharmacology Based Strategy for Q-Markers Discovery of HuangQin Decoction to Attenuate Intestinal Damage. AB - The quality control research of traditional Chinese medicine (TCM) is lagged far behind the space of progress in modernization and globalization. Thus the concept of quality marker (Q-marker) was proposed recently to guide the quality investigations of TCM. However, how to discover and validate the Q-marker is still a challenge. In this paper, a system pharmacology based strategy was proposed to discover Q-marker of HuangQin decoction (HQD) to attenuate Intestinal Damage. Using this strategy, nine measurable compounds including paeoniflorin, baicalin, scutellarein, liquiritigenin, norwogonin, baicalein, glycyrrhizic acid, wogonin, and oroxylin A were screened out as potential markers. Standard references of these nine compounds were pooled together as components combination according to their corresponding concentration in HQD. The bioactive equivalence between components combination and HQD was validated using wound healing test and inflammatory factor determination experiment. The comprehensive results indicated that components combination is almost bioactive equivalent to HQD and could serve as the Q-markers. In conclusion, our study put forward a promising strategy for Q markers discovery. PMID- 29615910 TI - Kinsenoside Ameliorates Oxidative Stress-Induced RPE Cell Apoptosis and Inhibits Angiogenesis via Erk/p38/NF-kappaB/VEGF Signaling. AB - The pathological superoxidative condition that retinal pigment epithelium (RPE) cells experience contributed to the advancement of age-related macular degeneration (AMD), which was accompanied by significant neovascularization. Therefore, the discovery of novel pharmacological candidates to ameliorate oxidative damage (H2O2) against RPE cells and inhibit the following angiogenesis simultaneously is urgently needed. Herein, we found that kinsenoside (Kin), an active component derived from Anoectochilus roxburghii, was able to protect RPE cells effectively and attenuate subsequent angiogenesis. In this study, H2O2 induced oxidative injury reduced RPE cell viability and increased cell apoptosis, which was significantly rescued by the treatment with Kin. Compared with H2O2 alone, Kin decreased the levels of Bax and increased the production of Bcl-2 in RPE cells. H2O2-stimulated VEGF up-regulation was inhibited by Kin treatment. Human umbilical vein endothelial cell (HUVEC) neovascularization induced by conditioned medium (CM) from H2O2-stimulated RPE cells was attenuated by treatment with Kin, VEGF antagonist, NF-kappaB, Erk-MAPK, and p38-MAPK inhibitors. Additionally, H2O2-activated phosphorylated expression of IkappaBalpha, p65, Erk, and p38 in RPE cells was inhibited by treatment with Kin. Taken together, Kin protected RPE from apoptosis against oxidative stress while simultaneously decreasing apoptosis-related neovascularization. This could be ascribed to the inhibition of Erk/p38/NF-kappaB signaling by Kin that contributed to the resulting decreased VEGF expression in H2O2-treated RPE cells. PMID- 29615913 TI - Fatty Acids Rich Extract From Clerodendrum volubile Suppresses Cell Migration; Abates Oxidative Stress; and Regulates Cell Cycle Progression in Glioblastoma Multiforme (U87 MG) Cells. AB - Glioblastoma multiforme (GBM) is a malignant primary type of brain cancer with high proliferation and metastasis rates due to involvement of the microglial cell. It is resistant against available chemotherapy. Many strategic protocols have been developed but prognosis and patient life has not improved substantially. In this study, the anti-metastatic and antioxidant effect of fatty acids from Clerodendrum volubile leaves were investigated in U87-MG (Human Glioblastoma Multiforme) cell lines. The extracted fatty acids were incubated with U87-MG cells for 48 h. The anti-proliferative effect was determined by MTT assay, while apoptosis and cell cycle were analyzed with BD FACSCalibur. The transwell assay protocol was utilized in the analysis of cell migration and invasion. The treated cell lines were also assessed for reduced glutathione (GSH) level, catalase, superoxide dismutase (SOD) and lipid peroxidation. The fatty acid extract showed significant inhibitory activity on cell proliferation and cell cycle progression, mitigated oxidative stress, and suppressed migration and invasion in U-87 MG cell lines. These results give credence to the therapeutic potential of this plant against cancer, especially GBM. PMID- 29615911 TI - Epigenetic Regulation and Its Therapeutic Potential in Pulmonary Hypertension. AB - Recent advances in epigenetics have made a tremendous impact on our knowledge of biological phenomena and the environmental stressors on complex diseases. Understanding the mechanism of epigenetic reprogramming during the occurrence of pulmonary hypertension (PH) is important for advanced studies and clinical therapy. In this article, we review the discovery of novel epigenetic mechanisms associated with PH including DNA methylation, histone modification, and noncoding RNA interference. In addition, we highlight the role of epigenetic mechanisms in adult PAH resulting from undesirable perinatal environments-Extrauterine growth restriction (EUGR) and Intrauterine growth retardation (IUGR). Lastly, we give a comprehensive summary for the remaining challenges and discuss future methods of epigenetic targeted therapy for pulmonary hypertension. PMID- 29615912 TI - Oral Ultramicronized Palmitoylethanolamide: Plasma and Tissue Levels and Spinal Anti-hyperalgesic Effect. AB - Palmitoylethanolamide (PEA) is a pleiotropic lipid mediator with established anti inflammatory and anti-hyperalgesic activity. Ultramicronized PEA (PEA-um) has superior oral efficacy compared to naive (non-micronized) PEA. The aim of the present study was two-fold: (1) to evaluate whether oral PEA-um has greater absorbability compared to naive PEA, and its ability to reach peripheral and central tissues under healthy and local inflammatory conditions (carrageenan paw edema); (2) to better characterize the molecular pathways involved in PEA-um action, particularly at the spinal level. Rats were dosed with 30 mg/kg of [13C]4 PEA-um or naive [13C]4-PEA by oral gavage, and [13C]4-PEA levels quantified, as a function of time, by liquid chromatography/atmospheric pressure chemical ionization/mass spectrometry. Overall plasma levels were higher in both healthy and carrageenan-injected rats administered [13C]4-PEA-um as compared to those receiving naive [13C]4-PEA, indicating the greater absorbability of PEA-um. Furthermore, carrageenan injection markedly favored an increase in levels of [13C]4-PEA in plasma, paw and spinal cord. Oral treatment of carrageenan-injected rats with PEA-um (10 mg/kg) confirmed beneficial peripheral effects on paw inflammation, thermal hyperalgesia and tissue damage. Notably, PEA-um down regulated distinct spinal inflammatory and oxidative pathways. These last findings instruct on spinal mechanisms involved in the anti-hyperalgesic effect of PEA-um in inflammatory pain. PMID- 29615914 TI - Exposure to Alumina Nanoparticles in Female Mice During Pregnancy Induces Neurodevelopmental Toxicity in the Offspring. AB - Alumina nanoparticles (AlNP) have been shown to accumulate in organs and penetrate biological barriers which lead to toxic effects in many organ systems. However, it is not known whether AlNP exposure to female mice during pregnancy can affect the development of the central nervous system or induce neurodevelopmental toxicity in the offspring. The present study aims to examine the effect of AlNP on neurodevelopment and associated underlying mechanism. ICR strain adult female mice were randomly divided into four groups, which were treated with normal saline (control), 10 MUm particle size of alumina (bulk-Al), and 50 and 13 nm AlNP during entire pregnancy period. Aluminum contents in the hippocampus of newborns were measured and neurodevelopmental behaviors were tracked in the offspring from birth to 1 month of age. Furthermore, oxidative stress and neurotransmitter levels were measured in the cerebral cortex of the adolescents. Our results showed that aluminum contents in the hippocampus of newborns in AlNP-treated groups were significantly higher than those in bulk-Al and controls. Moreover, the offspring delivered by AlNP-treated female mice displayed stunted neurodevelopmental behaviors. Finally, the offspring of AlNP treated mice demonstrated significantly increased anxiety-like behavior with impaired learning and memory performance at 1 month of age. The underlying mechanism could be related to increased oxidative stress and decreased neurotransmitter levels in the cerebral cortex. We therefore conclude that AlNP exposure of female mice during pregnancy can induce neurodevelopmental toxicity in offspring. PMID- 29615916 TI - Implications Enzymatic Degradation of the Endothelial Glycocalyx on the Microvascular Hemodynamics and the Arteriolar Red Cell Free Layer of the Rat Cremaster Muscle. AB - The endothelial glycocalyx is a complex network of glycoproteins, proteoglycans, and glycosaminoglycans; it lines the vascular endothelial cells facing the lumen of blood vessels forming the endothelial glycocalyx layer (EGL). This study aims to investigate the microvascular hemodynamics implications of the EGL by quantifying changes in blood flow hydrodynamics post-enzymatic degradation of the glycocalyx layer. High-speed intravital microscopy videos of small arteries (around 35 MUm) of the rat cremaster muscle were recorded at various time points after enzymatic degradation of the EGL. The thickness of the cell free layer (CFL), blood flow velocity profiles, and volumetric flow rates were quantified. Hydrodynamic effects of the presence of the EGL were observed in the differences between the thickness of CFL in microvessels with an intact EGL and glass tubes of similar diameters. Maximal changes in the thickness of CFL were observed 40 min post-enzymatic degradation of the EGL. Analysis of the frequency distribution of the thickness of CFL allows for estimation of the thickness of the endothelial surface layer (ESL), the plasma layer, and the glycocalyx. Peak flow, maximum velocity, and mean velocity were found to statistically increase by 24, 27, and 25%, respectively, after enzymatic degradation of the glycocalyx. The change in peak-to-peak maximum velocity and mean velocity were found to statistically increase by 39 and 32%, respectively, after 40 min post-enzymatic degradation of the EGL. The bluntness of blood flow velocity profiles was found to be reduced post-degradation of the EGL, as the exclusion volume occupied by the EGL increased the effective volume impermeable to RBCs in microvessels. This study presents the effects of the EGL on microvascular hemodynamics. Enzymatic degradation of the EGL resulted in a decrease in the thickness of CFL, an increase in blood velocity, blood flow, and decrease of the bluntness of the blood flow velocity profile in small arterioles. In summary, the EGL functions as a molecular sieve to solute transport and as a lubrication layer to protect the endothelium from red blood cell (RBC) motion near the vessel wall, determining wall shear stress. PMID- 29615915 TI - Application of Mesenchymal Stem Cells for Therapeutic Agent Delivery in Anti tumor Treatment. AB - Mesenchymal stem cells (MSCs) are non-hematopoietic progenitor cells, which can be isolated from different types of tissues including bone marrow, adipose tissue, tooth pulp, and placenta/umbilical cord blood. There isolation from adult tissues circumvents the ethical concerns of working with embryonic or fetal stem cells, whilst still providing cells capable of differentiating into various cell lineages, such as adipocytes, osteocytes and chondrocytes. An important feature of MSCs is the low immunogenicity due to the lack of co-stimulatory molecules expression, meaning there is no need for immunosuppression during allogenic transplantation. The tropism of MSCs to damaged tissues and tumor sites makes them a promising vector for therapeutic agent delivery to tumors and metastatic niches. MSCs can be genetically modified by virus vectors to encode tumor suppressor genes, immunomodulating cytokines and their combinations, other therapeutic approaches include MSCs priming/loading with chemotherapeutic drugs or nanoparticles. MSCs derived membrane microvesicles (MVs), which play an important role in intercellular communication, are also considered as a new therapeutic agent and drug delivery vector. Recruited by the tumor, MSCs can exhibit both pro- and anti-oncogenic properties. In this regard, for the development of new methods for cancer therapy using MSCs, a deeper understanding of the molecular and cellular interactions between MSCs and the tumor microenvironment is necessary. In this review, we discuss MSC and tumor interaction mechanisms and review the new therapeutic strategies using MSCs and MSCs derived MVs for cancer treatment. PMID- 29615917 TI - Advances in Glioblastoma Multiforme Treatment: New Models for Nanoparticle Therapy. AB - The most lethal form of brain cancer, glioblastoma multiforme, is characterized by rapid growth and invasion facilitated by cell migration and degradation of the extracellular matrix. Despite technological advances in surgery and radio chemotherapy, glioblastoma remains largely resistant to treatment. New approaches to study glioblastoma and to design optimized therapies are greatly needed. One such approach harnesses computational modeling to support the design and delivery of glioblastoma treatment. In this paper, we critically summarize current glioblastoma therapy, with a focus on emerging nanomedicine and therapies that capitalize on cell-specific signaling in glioblastoma. We follow this summary by discussing computational modeling approaches focused on optimizing these emerging nanotherapeutics for brain cancer. We conclude by illustrating how mathematical analysis can be used to compare the delivery of a high potential anticancer molecule, delphinidin, in both free and nanoparticle loaded forms across the blood-brain barrier for glioblastoma. PMID- 29615918 TI - Skeletal Muscle Pyruvate Dehydrogenase Phosphorylation and Lactate Accumulation During Sprint Exercise in Normoxia and Severe Acute Hypoxia: Effects of Antioxidants. AB - Compared to normoxia, during sprint exercise in severe acute hypoxia the glycolytic rate is increased leading to greater lactate accumulation, acidification, and oxidative stress. To determine the role played by pyruvate dehydrogenase (PDH) activation and reactive nitrogen and oxygen species (RNOS) in muscle lactate accumulation, nine volunteers performed a single 30-s sprint (Wingate test) on four occasions: two after the ingestion of placebo and another two following the intake of antioxidants, while breathing either hypoxic gas (PIO2 = 75 mmHg) or room air (PIO2 = 143 mmHg). Vastus lateralis muscle biopsies were obtained before, immediately after, 30 and 120 min post-sprint. Antioxidants reduced the glycolytic rate without altering performance or VO2. Immediately after the sprints, Ser293- and Ser300-PDH-E1alpha phosphorylations were reduced to similar levels in all conditions (~66 and 91%, respectively). However, 30 min into recovery Ser293-PDH-E1alpha phosphorylation reached pre-exercise values while Ser300-PDH-E1alpha was still reduced by 44%. Thirty minutes after the sprint Ser293-PDH-E1alpha phosphorylation was greater with antioxidants, resulting in 74% higher muscle lactate concentration. Changes in Ser293 and Ser300-PDH-E1alpha phosphorylation from pre to immediately after the sprints were linearly related after placebo (r = 0.74, P < 0.001; n = 18), but not after antioxidants ingestion (r = 0.35, P = 0.15). In summary, lactate accumulation during sprint exercise in severe acute hypoxia is not caused by a reduced activation of the PDH. The ingestion of antioxidants is associated with increased PDH re-phosphorylation and slower elimination of muscle lactate during the recovery period. Ser293 re-phosphorylates at a faster rate than Ser300-PDH E1alpha during the recovery period, suggesting slightly different regulatory mechanisms. PMID- 29615919 TI - Using Aiptasia as a Model to Study Metabolic Interactions in Cnidarian Symbiodinium Symbioses. AB - The symbiosis between cnidarian hosts and microalgae of the genus Symbiodinium provides the foundation of coral reefs in oligotrophic waters. Understanding the nutrient-exchange between these partners is key to identifying the fundamental mechanisms behind this symbiosis, yet has proven difficult given the endosymbiotic nature of this relationship. In this study, we investigated the respective contribution of host and symbiont to carbon and nitrogen assimilation in the coral model anemone Aiptaisa. For this, we combined traditional measurements with nanoscale secondary ion mass spectrometry (NanoSIMS) and stable isotope labeling to investigate patterns of nutrient uptake and translocation both at the organismal scale and at the cellular scale. Our results show that the rate of carbon and nitrogen assimilation in Aiptasia depends on the identity of the host and the symbiont. NanoSIMS analysis confirmed that both host and symbiont incorporated carbon and nitrogen into their cells, implying a rapid uptake and cycling of nutrients in this symbiotic relationship. Gross carbon fixation was highest in Aiptasia associated with their native Symbiodinium communities. However, differences in fixation rates were only reflected in the delta13C enrichment of the cnidarian host, whereas the algal symbiont showed stable enrichment levels regardless of host identity. Thereby, our results point toward a "selfish" character of the cnidarian-Symbiodinium association in which both partners directly compete for available resources. Consequently, this symbiosis may be inherently instable and highly susceptible to environmental change. While questions remain regarding the underlying cellular controls of nutrient exchange and the nature of metabolites involved, the approach outlined in this study constitutes a powerful toolset to address these questions. PMID- 29615921 TI - A Rhodopsin-Like Gene May Be Associated With the Light-Sensitivity of Adult Pacific Oyster Crassostrea gigas. AB - Light-sensitivity is important for mollusc survival, as it plays a vital role in reproduction and predator avoidance. Light-sensitivity has been demonstrated in the adult Pacific oyster Crassostrea gigas, but the genes associated with light sensitivity remain unclear. In the present study, we designed experiments to identify the genes associated with light-sensitivity in adult oysters. First, we assessed the Pacific oyster genome and identified 368 genes annotated with the terms associated with light-sensitivity. Second, the function of the four rhodopsin-like superfamily member genes was tested by using RNAi. The results showed that the highest level of mRNA expression of the vision-related genes was in the mantle; however, this finding is not true for all oyster genes. Interestingly, we also found four rhodopsin-like superfamily member genes expressed at an very high level in the mantle tissue. In the RNAi experiment, when one of rhodopsin-like superfamily member genes (CGI_1001253) was inhibited, the light-sensitivity capacity of the injected oysters was significantly reduced, suggesting that CGI_10012534 may be associated with light-sensitivity in the adult Pacific oyster. PMID- 29615920 TI - Redox Aspects of Chaperones in Cardiac Function. AB - Molecular chaperones are stress proteins that allow the correct folding or unfolding as well as the assembly or disassembly of macromolecular cellular components. Changes in expression and post-translational modifications of chaperones have been linked to a number of age- and stress-related diseases including cancer, neurodegeneration, and cardiovascular diseases. Redox sensible post-translational modifications, such as S-nitrosylation, glutathionylation and phosphorylation of chaperone proteins have been reported. Redox-dependent regulation of chaperones is likely to be a phenomenon involved in metabolic processes and may represent an adaptive response to several stress conditions, especially within mitochondria, where it impacts cellular bioenergetics. These post-translational modifications might underlie the mechanisms leading to cardioprotection by conditioning maneuvers as well as to ischemia/reperfusion injury. In this review, we discuss this topic and focus on two important aspects of redox-regulated chaperones, namely redox regulation of mitochondrial chaperone function and cardiac protection against ischemia/reperfusion injury. PMID- 29615922 TI - Sensory Processing and Integration at the Carotid Body Tripartite Synapse: Neurotransmitter Functions and Effects of Chronic Hypoxia. AB - Maintenance of homeostasis in the respiratory and cardiovascular systems depends on reflexes that are initiated at specialized peripheral chemoreceptors that sense changes in the chemical composition of arterial blood. In mammals, the bilaterally-paired carotid bodies (CBs) are the main peripheral chemoreceptor organs that are richly vascularized and are strategically located at the carotid bifurcation. The CBs contribute to the maintenance of O2, CO2/H+, and glucose homeostasis and have attracted much clinical interest because hyperactivity in these organs is associated with several pathophysiological conditions including sleep apnea, obstructive lung disease, heart failure, hypertension, and diabetes. In response to a decrease in O2 availability (hypoxia) and elevated CO2/H+ (acid hypercapnia), CB receptor type I (glomus) cells depolarize and release neurotransmitters that stimulate apposed chemoafferent nerve fibers. The central projections of those fibers in turn activate cardiorespiratory centers in the brainstem, leading to an increase in ventilation and sympathetic drive that helps restore blood PO2 and protect vital organs, e.g., the brain. Significant progress has been made in understanding how neurochemicals released from type I cells such as ATP, adenosine, dopamine, 5-HT, ACh, and angiotensin II help shape the CB afferent discharge during both normal and pathophysiological conditions. However, type I cells typically occur in clusters and in addition to their sensory innervation are ensheathed by the processes of neighboring glial-like, sustentacular type II cells. This morphological arrangement is reminiscent of a "tripartite synapse" and emerging evidence suggests that paracrine stimulation of type II cells by a variety of CB neurochemicals may trigger the release of "gliotransmitters" such as ATP via pannexin-1 channels. Further, recent data suggest novel mechanisms by which dopamine, acting via D2 receptors (D2R), may inhibit action potential firing at petrosal nerve endings. This review will update current ideas concerning the presynaptic and postsynaptic mechanisms that underlie chemosensory processing in the CB. Paracrine signaling pathways will be highlighted, and particularly those that allow the glial-like type II cells to participate in the integrated sensory response during exposures to chemostimuli, including acute and chronic hypoxia. PMID- 29615923 TI - Mental Fatigue Alters Cortical Activation and Psychological Responses, Impairing Performance in a Distance-Based Cycling Trial. AB - Purpose: We sought to verify if alterations in prefrontal cortex (PFC) activation and psychological responses would play along with impairments in pacing and performance of mentally fatigued cyclists. Materials and Methods: Eight recreational cyclists performed two preliminary sessions to familiarize them with the rapid visual information processing (RVP) test, psychological scales and 20 km cycling time trial (TT20km) (session 1), as well as to perform a VO2MAX test (session 2). Thereafter, they performed a TT20km either after a RVP test (30 min) or a time-matched rest control session (session 3 and 4 in counterbalanced order). Performance and psychological responses were obtained throughout the TT20km while PFC electroencephalography (EEG) was obtained at 10 and 20 km of the TT20km and throughout the RVP test. Increases in EEG theta band power indicated a mental fatigue condition. Repeated-measures mixed models design and post-hoc effect size (ES) were used in comparisons. Results: Cyclists completed the trial ~2.7% slower in mental fatigue (34.3 +/- 1.3 min) than in control (33.4 +/- 1.1 min, p = 0.02, very large ES), with a lower WMEAN (224.5 +/- 17.9 W vs. 240.2 +/- 20.9 W, respectively; p = 0.03; extremely large ES). There was a higher EEG theta band power during RVP test (p = 0.03; extremely large ES), which remained during the TT20km (p = 0.01; extremely large ES). RPE increased steeper in mental fatigue than in control, together with isolated reductions in motivation at 2th km (p = 0.04; extremely large ES), felt arousal at the 2nd and 4th km (p = 0.01; extremely large ES), and associative thoughts to exercise at the 6th and 16th km (p = 0.02; extremely large ES) of the TT20km.Conclusions: Mentally fatigued recreational cyclists showed impaired performance, altered PFC activation and faster increase in RPE during a TT20km. PMID- 29615924 TI - Protective Role of Perivascular Adipose Tissue in Endothelial Dysfunction and Insulin-Induced Vasodilatation of Hypercholesterolemic LDL Receptor-Deficient Mice. AB - Background: Endothelial dysfunction plays a pivotal role in the initiation of atherosclerosis. Vascular insulin resistance might contribute to a reduction in endothelial nitric oxide (NO) production, leading to impaired endothelium dependent relaxation in cardiometabolic diseases. Because perivascular adipose tissue (PVAT) controls endothelial function and NO bioavailability, we hypothesized a role for this fat deposit in the vascular complications associated with the initial stages of atherosclerosis. Therefore, we investigated the potential involvement of PVAT in the early endothelial dysfunction in hypercholesterolemic LDL receptor knockout mice (LDLr-KO). Methods: Thoracic aortas with and without PVAT were isolated from 4-month-old C57BL/6J (WT) and LDLr-KO mice. The contribution of PVAT to relaxation responses to acetylcholine, insulin, and sodium nitroprusside was investigated. Western blotting was used to examine endothelial NO synthase (eNOS) and adiponectin expression, as well the insulin signaling pathway in aortic PVAT. Results: PVAT-free aortas of LDLr-KO mice exhibited impaired acetylcholine- and insulin-induced relaxation compared with those of WT mice. Both vasodilatory responses were restored by the presence of PVAT in LDLr-KO mice, associated with enhanced acetylcholine-induced NO levels. PVAT did not change vasodilatory responses to acetylcholine and insulin in WT mice, while vascular relaxation evoked by the NO donor sodium nitroprusside was not modified by either genotype or PVAT. The expression of insulin receptor substrate-1 (IRS-1), phosphatidylinositol 3-kinase (PI3K), AKT, ERK1/2, phosphorylation of AKT (Ser473) and ERK1/2 (Thr202/Tyr204), and adiponectin was similar in the PVAT of WT and LDLr-KO mice, suggesting no changes in PVAT insulin signaling. However, eNOS expression was enhanced in the PVAT of LDLr-KO mice, while eNOS expression was less abundant in PVAT-free aortas. Conclusion: These results suggest that elevated eNOS-derived NO production in aortic PVAT might be a compensatory mechanism for the endothelial dysfunction and impaired vasodilator action of insulin in hypercholesterolemic LDLr-deficient mice. This protective effect may limit the progression of atherosclerosis in genetic hypercholesterolemia in the absence of an atherogenic diet. PMID- 29615925 TI - On Variations in the Level of PER in Glial Clocks of Drosophila Optic Lobe and Its Negative Regulation by PDF Signaling. AB - We show that the level of the core protein of the circadian clock Period (PER) expressed by glial peripheral oscillators depends on their location in the Drosophila optic lobe. It appears to be controlled by the ventral lateral neurons (LNvs) that release the circadian neurotransmitter Pigment Dispersing Factor (PDF). We demonstrate that glial cells of the distal medulla neuropil (dMnGl) that lie in the vicinity of the PDF-releasing terminals of the LNvs possess receptors for PDF (PDFRs) and express PER at significantly higher level than other types of glia. Surprisingly, the amplitude of PER molecular oscillations in dMnGl is increased twofold in PDF-free environment, that is in Pdf0 mutants. The Pdf0 mutants also reveal an increased level of glia-specific protein REPO in dMnGl. The photoreceptors of the compound eye (R-cells) of the PDF-null flies, on the other hand, exhibit de-synchrony of PER molecular oscillations, which manifests itself as increased variability of PER-specific immunofluorescence among the R-cells. Moreover, the daily pattern of expression of the presynaptic protein Bruchpilot (BRP) in the lamina terminals of the R-cells is changed in Pdf0 mutant. Considering that PDFRs are also expressed by the marginal glia of the lamina that surround the R-cell terminals, the LNv pacemakers appear to be the likely modulators of molecular cycling in the peripheral clocks of both the glial cells and the photoreceptors of the compound eye. Consequently, some form of PDF-based coupling of the glial clocks and the photoreceptors of the eye with the central LNv pacemakers must be operational. PMID- 29615926 TI - Circadian Differences in the Contribution of the Brain Renin-Angiotensin System in Genetically Hypertensive Mice. AB - Objective: Genetically hypertensive BPH/2J mice are recognized as a neurogenic model of hypertension, primarily based on sympathetic overactivity and greater neuronal activity in cardiovascular regulatory brain regions. Greater activity of the central renin angiotensin system (RAS) and reactive oxygen species (ROS) reportedly contribute to other models of hypertension. Importantly the peripheral RAS contributes to the hypertension in BPH/2J mice, predominantly during the dark period of the 24 h light cycle. The aim of the present study was to determine whether central AT1 receptor stimulation and the associated ROS signaling contribute to hypertension in BPH/2J mice in a circadian dependent manner. Methods: Blood pressure (BP) was measured in BPH/2J and normotensive BPN/3J mice (n = 7-8) via pre-implanted telemetry devices. Acute intracerebroventricular (ICV) microinjections of AT1 receptor antagonist, candesartan, and the superoxide dismutase (SOD) mimetic, tempol, were administered during the dark and light period of the 24 h light cycle via a pre-implanted ICV guide cannula. In separate mice, the BP effect of ICV infusion of the AT1 receptor antagonist losartan for 7 days was compared with subcutaneous infusion to determine the contribution of the central RAS to hypertension in BPH/2J mice. Results: Candesartan administered ICV during the dark period induced depressor responses which were 40% smaller in BPH/2J than BPN/3J mice (Pstrain < 0.05), suggesting AT1 receptor stimulation may contribute less to BP maintenance in BPH/2J mice. During the light period candesartan had minimal effect on BP in either strain. ICV tempol had comparable effects on BP between strains during the light and dark period (Pstrain > 0.08), suggesting ROS signaling is also not contributing to the hypertension in BPH/2J mice. Chronic ICV administration of losartan (22 nmol/h) had minimal effect on BPN/3J mice. By contrast in BPH/2J mice, both ICV and subcutaneously administered losartan induced similar hypotensive responses (-12.1 +/- 1.8 vs. -14.7 +/- 1.8 mmHg, Proute = 0.31). Conclusion: While central effects of peripheral losartan cannot be excluded, we suggest the hypotensive effect of chronic ICV losartan was likely peripherally mediated. Thus, based on both acute and chronic AT1 receptor inhibition and acute ROS inhibition, our findings suggest that greater activation of central AT1 receptors or ROS are unlikely to be mediating the hypertension in BPH/2J mice. PMID- 29615927 TI - Hemodynamic and Metabolic Assessment of Neonates With Punctate White Matter Lesions Using Phase-Contrast MRI and T2-Relaxation-Under-Spin-Tagging (TRUST) MRI. AB - The brain's hemodynamic and metabolism of punctate white matter lesions (PWML) is poorly understood due to a scarcity of non-invasive imaging techniques. The aim of this study was to apply new MRI techniques to quantify cerebral metabolic rate of oxygen (CMRO2), global cerebral blood flow (CBF), oxygen saturation fractions in venous blood (Yv) and oxygen extraction fraction (OEF) in neonates with PWML, for better understanding of the pathophysiology of PWML. Fifty-one newborns were recruited continuously, including 23 neonatal patients with PWML and 28 normal control neonates. Phase-contrast (PC) MRI and T2-Relaxation-Under-Spin-Tagging (TRUST) MRI were performed for the measurement of CBF and Yv. OEF and CMRO2 were calculated from the CBF and Yv values. The total maturation score (TMS) was assessed for each neonate on standard T1, 2-weighted images to evaluate cerebral maturation. The CMRO2, CBF, Yv, and OEF values were compared between groups, and their associations with age and TMS were evaluated. Significant differences between PWML group and control group were found in CMRO2 (P = 0.020), CBF (P = 0.027), Yv (P = 0.012), OEF (P = 0.018). After age/maturation is accounted for, Yv and OEF showed significant dependence on the groups (P < 0.05). Newborns with PWML had lower OEF and higher Yv. CMRO2, CBF and brain volume were correlated with age (P < 0.001) and TMS (P < 0.05). It is feasible to use non-invasive MRI methods to measure cerebral oxygen supply and consumption in neonates with PWML. Newborns with PWML have lower oxygen consumption. Yv and OEF may be helpful for the diagnosis of PWML. The positive correlation between CBF and TMS, and between CMRO2 and TMS suggested that as myelination progresses, the blood supply and oxygen metabolism in the brain increase to meet the escalating energy demand. PMID- 29615928 TI - Curcumol Exerts Anticancer Effect in Cholangiocarcinoma Cells via Down-Regulating CDKL3. AB - Curcumol is the major component extracted from root of Rhizoma Curcumae. Recent studies have shown that curcumol exerts therapeutic effects against multiple conditions, particularly cancers. However, the therapeutic role and mechanism of curcumol against cholangiocarcinoma cells are still unclear. In our current research, we tested the effect of curcumol in cholangiocarcinoma cells, and using two-dimensional electrophoresis, proteomics and bioinformatics, we identified cyclin-dependent kinase like 3 (CDKL3) as a potential target for curcumol. We have demonstrated that curcumol can evidently suppress growth and migration of cholangiocarcinoma cells. Furthermore, curcumol could significantly block the cell cycle progression of the cholangiocarcinoma cells. These effects could be largely attributed to the inhibition of CDKL3 by curcumol. Further studies have recapitulated the oncogenic role of CDKL3 in that knockdown of CDKL3 by lentiviral mediated transfection of shRNA against CDKL3 also led to a significant inhibition on cell proliferation, migration, invasion, and cell cycle progression. Given the high level of CDKL3 expression in human cholangiocarcinoma tissues and cell lines, we speculated that CDKL3 may constitute a potential biological target for curcumol in cholangiocarcinoma. PMID- 29615930 TI - Arachidonic Acid Metabolism Pathway Is Not Only Dominant in Metabolic Modulation but Associated With Phenotypic Variation After Acute Hypoxia Exposure. AB - Background: The modulation of arachidonic acid (AA) metabolism pathway is identified in metabolic alterations after hypoxia exposure, but its biological function is controversial. We aimed at integrating plasma metabolomic and transcriptomic approaches to systematically explore the roles of the AA metabolism pathway in response to acute hypoxia using an acute mountain sickness (AMS) model. Methods: Blood samples were obtained from 53 enrolled subjects before and after exposure to high altitude. Ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry and RNA sequencing were separately performed for metabolomic and transcriptomic profiling, respectively. Influential modules comprising essential metabolites and genes were identified by weighted gene co-expression network analysis (WGCNA) after integrating metabolic information with phenotypic and transcriptomic datasets, respectively. Results: Enrolled subjects exhibited diverse response manners to hypoxia. Combined with obviously altered heart rate, oxygen saturation, hemoglobin, and Lake Louise Score (LLS), metabolomic profiling detected that 36 metabolites were highly related to clinical features in hypoxia responses, out of which 27 were upregulated and nine were downregulated, and could be mapped to AA metabolism pathway significantly. Integrated analysis of metabolomic and transcriptomic data revealed that these dominant molecules showed remarkable association with genes in gas transport incapacitation and disorders of hemoglobin metabolism pathways, such as ALAS2, HEMGN. After detailed description of AA metabolism pathway, we found that the molecules of 15-d-PGJ2, PGA2, PGE2, 12-O-3-OH-LTB4, LTD4, LTE4 were significantly up-regulated after hypoxia stimuli, and increased in those with poor response manner to hypoxia particularly. Further analysis in another cohort showed that genes in AA metabolism pathway such as PTGES, PTGS1, GGT1, TBAS1 et al. were excessively elevated in subjects in maladaptation to hypoxia. Conclusion: This is the first study to construct the map of AA metabolism pathway in response to hypoxia and reveal the crosstalk between phenotypic variation under hypoxia and the AA metabolism pathway. These findings may improve our understanding of the advanced pathophysiological mechanisms in acute hypoxic diseases and provide new insights into critical roles of the AA metabolism pathway in the development and prevention of these diseases. PMID- 29615931 TI - Current Challenges in Elucidating Respiratory Supercomplexes in Mitochondria: Methodological Obstacles. PMID- 29615929 TI - Muscle Atrophy Induced by Mechanical Unloading: Mechanisms and Potential Countermeasures. AB - Prolonged periods of skeletal muscle inactivity or mechanical unloading (bed rest, hindlimb unloading, immobilization, spaceflight and reduced step) can result in a significant loss of musculoskeletal mass, size and strength which ultimately lead to muscle atrophy. With advancement in understanding of the molecular and cellular mechanisms involved in disuse skeletal muscle atrophy, several different signaling pathways have been studied to understand their regulatory role in this process. However, substantial gaps exist in our understanding of the regulatory mechanisms involved, as well as their functional significance. This review aims to update the current state of knowledge and the underlying cellular mechanisms related to skeletal muscle loss during a variety of unloading conditions, both in humans and animals. Recent advancements in understanding of cellular and molecular mechanisms, including IGF1-Akt-mTOR, MuRF1/MAFbx, FOXO, and potential triggers of disuse atrophy, such as calcium overload and ROS overproduction, as well as their role in skeletal muscle protein adaptation to disuse is emphasized. We have also elaborated potential therapeutic countermeasures that have shown promising results in preventing and restoring disuse-induced muscle loss. Finally, identified are the key challenges in this field as well as some future prospectives. PMID- 29615933 TI - Dexamethasone Protects Against Tourniquet-Induced Acute Ischemia-Reperfusion Injury in Mouse Hindlimb. AB - Extremity injuries with hemorrhage have been a significant cause of death in civilian medicine and on the battlefield. The use of a tourniquet as an intervention is necessary for treatment to an injured limb; however, the tourniquet and subsequent release results in serious acute ischemia-reperfusion (IR) injury in the skeletal muscle and neuromuscular junction (NMJ). Much evidence demonstrates that inflammation is an important factor to cause acute IR injury. To find effective therapeutic interventions for tourniquet-induced acute IR injuries, our current study investigated effect of dexamethasone, an anti inflammatory drug, on tourniquet-induced acute IR injury in mouse hindlimb. In C57/BL6 mice, a tourniquet was placed on unilateral hindlimb (left hindlimb) at the hip joint for 3 h, and then released for 24 h to induce IR. Three hours of tourniquet and 24 h of release (24-h IR) caused gastrocnemius muscle injuries including rupture of the muscle sarcolemma and necrosis (42.8 +/- 2.3% for infarct size of the gastrocnemius muscle). In the NMJ, motor nerve terminals disappeared, and endplate potentials were undetectable in 24-h IR mice. There was no gastrocnemius muscle contraction in 24-h IR mice. Western blot data showed that inflammatory cytokines (TNFalpha and IL-1beta) were increased in the gastrocnemius muscle after 24-h IR. Treatment with dexamethasone at the beginning of reperfusion (1 mg/kg, i.p.) significantly inhibited expression of TNFalpha and IL-1beta, reduced rupture of the muscle sarcolemma and infarct size (24.8 +/- 2.0%), and improved direct muscle stimulation-induced gastrocnemius muscle contraction in 24-h IR mice. However, this anti-inflammatory drug did not improve NMJ morphology and function, and sciatic nerve-stimulated skeletal muscle contraction in 24-h IR mice. The data suggest that one-time treatment with dexamethasone at the beginning of reperfusion only reduced structural and functional impairments of the skeletal muscle but not the NMJ through inhibiting inflammatory cytokines. PMID- 29615932 TI - Synaptic Plasticity in Cardiac Innervation and Its Potential Role in Atrial Fibrillation. AB - Synaptic plasticity is defined as the ability of synapses to change their strength of transmission. Plasticity of synaptic connections in the brain is a major focus of neuroscience research, as it is the primary mechanism underpinning learning and memory. Beyond the brain however, plasticity in peripheral neurons is less well understood, particularly in the neurons innervating the heart. The atria receive rich innervation from the autonomic branch of the peripheral nervous system. Sympathetic neurons are clustered in stellate and cervical ganglia alongside the spinal cord and extend fibers to the heart directly innervating the myocardium. These neurons are major drivers of hyperactive sympathetic activity observed in heart disease, ventricular arrhythmias, and sudden cardiac death. Both pre- and postsynaptic changes have been observed to occur at synapses formed by sympathetic ganglion neurons, suggesting that plasticity at sympathetic neuro-cardiac synapses is a major contributor to arrhythmias. Less is known about the plasticity in parasympathetic neurons located in clusters on the heart surface. These neuronal clusters, termed ganglionated plexi, or "little brains," can independently modulate neural control of the heart and stimulation that enhances their excitability can induce arrhythmia such as atrial fibrillation. The ability of these neurons to alter parasympathetic activity suggests that plasticity may indeed occur at the synapses formed on and by ganglionated plexi neurons. Such changes may not only fine-tune autonomic innervation of the heart, but could also be a source of maladaptive plasticity during atrial fibrillation. PMID- 29615934 TI - Chamazulene Attenuates ROS Levels in Bovine Aortic Endothelial Cells Exposed to High Glucose Concentrations and Hydrogen Peroxide. AB - Endothelial cells surround the lumen of blood vessels and modulate many physiological processes, including vascular tone, blood fluidity, inflammation, immunity and neovascularization. Many pathological conditions, including hyperglycemia, may alter endothelial function through oxidative stress, leading to impaired nitric oxide bioavailability and to the onset of an inflammatory state. As widely shown in the last decade, dietary intervention could represent a good strategy to control endothelial dysfunction and atherosclerosis. In particular, extensive research in the field of antioxidant natural derivatives has been conducted. In this study, we evaluated the capability of Chamazulene (Cham), an azulene compound from chamomile essential oil, to attenuate ROS levels in bovine aortic endothelial cells (BAECs) stressed with either high glucose or H2O2. Cell viability at different concentrations of Cham was evaluated through the WST-1 assay, while ROS production acutely induced by High Glucose (HG, 4.5 g/L) treatment or H2O2 (0.5 mM) for 3 h, was quantified with 2'-7' Dichlorofluorescein diacetate (DCFH-DA) probe using confocal microscopy and flow cytometry. Our results showed a reduction in ROS produced after simultaneous treatment with High Glucose or H2O2 and Cham, thus suggesting an in vitro antioxidant activity of the compound. On the whole, this study shows for the first time the potential role of Cham as a scavenging molecule, suggesting its possible use to prevent the rise of endothelial ROS levels and the consequent vascular damage. PMID- 29615935 TI - Transcranial Magnetic Stimulation of Medial Prefrontal and Cingulate Cortices Reduces Cocaine Self-Administration: A Pilot Study. AB - Background: Previous studies have shown that repetitive transcranial magnetic stimulation (rTMS) to the dorsolateral prefrontal cortex may serve as a potential treatment for cocaine use disorder (CUD), which remains a public health problem that is refractory to treatment. The goal of this pilot study was to investigate the effect of rTMS on cocaine self-administration in the laboratory. In the self administration sessions, CUD participants chose between cocaine and an alternative reinforcer (money) in order to directly measure cocaine-seeking behavior. The rTMS was delivered with the H7 coil, which provides stimulation to the medial prefrontal cortex (mPFC) and anterior cingulate cortex (ACC). These brain regions were targeted based on previous imaging studies demonstrating alterations in their activation and connectivity in CUD. Methods: Volunteers with CUD were admitted to an inpatient unit for the entire study and assigned to one of three rTMS groups: high frequency (10 Hz), low frequency (1 Hz), and sham. Six participants were included in each group and the rTMS was delivered on weekdays for 3 weeks. The cocaine self-administration sessions were performed at three time points: at baseline (pre-TMS, session 1), after 4 days of rTMS (session 2), and after 13 days of rTMS (session 3). During each self-administration session, the outcome measure was the number of choices for cocaine. Results: The results showed a significant group by time effect (p = 0.02), where the choices for cocaine decreased between sessions 2 and 3 in the high frequency group. There was no effect of rTMS on cocaine self-administration in the low frequency or sham groups. Conclusion: Taken in the context of the existing literature, these results contribute to the data showing that high frequency rTMS to the prefrontal cortex may serve as a potential treatment for CUD. PMID- 29615936 TI - Event-Related Potential Measures of Attention Capture in Adolescent Inpatients With Acute Suicidal Behavior. AB - Impaired executive functions, modulated by the frontal lobes, have been suggested to be associated with suicidal behavior. The present study examines one of these executive functions, attentional control, maintaining attention to the task-at hand. A group of inpatient adolescents with acute suicidal behavior and healthy controls were studied using a passively presented auditory optimal paradigm. This "optimal" paradigm consisted of a series of frequently presented homogenous pure tone "standards" and different "deviants," constructed by changing one or more features of the standard. The optimal paradigm has been shown to be a more time efficient replacement to the traditional oddball paradigm, which makes it suitable for use in clinical populations. The extent of processing of these "to be-ignored" auditory stimuli was measured by recording event-related potentials (ERPs). The P3a ERP component is thought to reflect processes associated with the capturing of attention. Rare and novel stimuli may result in an executive decision to switch attention away from the current cognitive task and toward a probe of the potentially more relevant "interrupting" auditory input. On the other hand, stimuli that are quite similar to the standard should not elicit P3a. The P3a has been shown to be larger in immature brains in early compared to later adolescence. An overall enhanced P3a was observed in the suicidal group. The P3a was larger in this group for both the environmental sound and white noise deviants, although only the environmental sound P3a attained significance. Other deviants representing only a small change from the standard did not elicit a P3a in healthy controls. They did elicit a small P3a in the suicidal group. These findings suggest a lowered threshold for the triggering of the involuntary switch of attention in these patients, which may play a role in their reported distractibility. The enhanced P3a is also suggestive of an immature frontal central executive and may provide a promising marker for early identification of some of the risk factors for some of the cognitive difficulties linked to suicidality. PMID- 29615937 TI - Reflecting on the Germanwings Disaster: A Systematic Review of Depression and Suicide in Commercial Airline Pilots. AB - Background: The 2015 Germanwings Flight 9525 disaster, in which 150 people were killed after the co-pilot may have intentionally crashed the plane in a suicide attempt, highlights the importance of better understanding the mental health of commercial airline pilots. However, there have been few systematic reviews investigating the topic of mental health in commercial aviation. This systematic review aims to identify the types and prevalence of mental health disorders that commercial airline pilots experience with a focus on mood disorders and suicide risk. Methods: A systematic literature search was performed using PubMed, EMBASE, and PsycINFO databases. Eligible studies were assessed and data was extracted and analyzed. Results: 20 studies were identified. The prevalence of depression experienced by commercial airline pilots in this review ranged from 1.9% to 12.6%. Factors that negatively impacted the mental health of pilots included substance abuse, experiencing verbal or sexual abuse, disruption in sleep circadian rhythms and fatigue. Discussion: This systematic review identifies that commercial airline pilots may experience depression at least as frequently as the general population. Commercial airline pilots experience occupational stressors, such as disrupted circadian rhythms and fatigue which may increase risks of developing mood disorders. Most studies identified in this review were cross sectional in nature with substantial limitations. There is a clear need for further higher quality longitudinal studies to better understand the mental health of commercial airline pilots. PMID- 29615939 TI - Association Between Cerebral Microbleeds and Depression in the General Elderly Population: A Meta-Analysis. AB - Background: It remains unclear whether cerebral microbleeds (CMBs) are associated with depression in the general elderly population. We thus performed a meta analysis to evaluate the relationship between depression and CMBs. Methods: A systematic literature search was conducted in EBSCO, PubMed, and Web of Science for relevant studies that assessed the relationship between depression and the prevalence of CMBs. Results: Five eligible studies including 7,328 patients were pooled in meta-analysis. The prevalence of CMBs was 18.0%. The prevalence of depression was 11.1%. The pooled analysis demonstrated odds ratio for CMBs and depression to be 1.187 (95% confidence interval 1.005-1.403; p = 0.043) with no evidence of statistical heterogeneity (I2 = 0.0%, p = 0.621). Conclusion: Our meta-analysis of available published data indicated an increased prevalence of depression in the subjects with pre-existing CMBs. This finding supports the vascular depression hypothesis. Further studies are needed to investigate the role of CMBs in the pathogenesis and progression of depression, which might provide a potential target for the prevention and treatment. PMID- 29615938 TI - Increased Salience Network Activity in Patients With Insomnia Complaints in Major Depressive Disorder. AB - Background: Insomnia is one of the main symptom correlates of major depressive disorder (MDD), but the neural mechanisms underlying the multifaceted interplay between insomnia and depression are not fully understood. Materials and methods: Patients with MDD and high insomnia (MDD-HI, n = 24), patients with MDD and low insomnia (MDD-LI, n = 37), and healthy controls (HCs, n = 51) were recruited to participate in the present study. The amplitude of low-frequency fluctuations (ALFF) during the resting state were compared among the three groups. Results: We observed ALFF differences between the three groups in the right inferior frontal gyrus/anterior insula (IFG/AI), right middle temporal gyrus, left calcarine, and bilateral dorsolateral prefrontal cortex (dlPFC). Further region of interest (ROI) comparisons showed that the increases in the right IFG/AI reflected an abnormality specific to insomnia in MDD, while increases in the bilateral dlPFC reflected an abnormality specific to MDD generally. Increased ALFF in the right IFG/AI was also found to be correlated with sleep disturbance scores when regressing out the influence of the severity of anxiety and depression. Conclusion: Our findings suggest that increased resting state ALLF in IFG/AI may be specifically related to hyperarousal state of insomnia in patients with MDD, independently of the effects of anxiety and depression. PMID- 29615940 TI - Impact of Cognitive Remediation Therapy on Neurocognitive Processing in Anorexia Nervosa. AB - Background: Anorexia nervosa (AN) is characterized by severe malnutrition as well as inefficiencies in neurocognitive functioning, which are believed to contribute to the maintenance of disordered eating. The aim of this study was to examine the impact of individual cognitive remediation therapy (CRT) on neurocognition in AN. Methods: A total of 145 adult women from an eating disorders inpatient program took part in the present study. All participants were given individual CRT in addition to treatment as usual. Neurocognitive processes were assessed at baseline and at the end of treatment using task-based and self-report measures. The task-based measures included the Rey-Osterrieth Complex Figure test and the Brixton test, which were used to assess central coherence and set-shifting. The Detail and Flexibility Questionnaire was used to examine patients self-reported detail focus and cognitive flexibility. Results: Participants showed significant improvement in task-based measures of neurocognition following CRT. There were no significant changes in self-report measures. Conclusion: These findings suggest that CRT may be an effective intervention targeting inefficiencies in neurocognition in AN. Future studies may benefit from assessing neural changes associated with these improvements and conducting randomized controlled trials to replicate these findings. PMID- 29615941 TI - One Way or Another: Evidence for Perceptual Asymmetry in Pre-attentive Learning of Non-native Contrasts. AB - Research investigating listeners' neural sensitivity to speech sounds has largely focused on segmental features. We examined Australian English listeners' perception and learning of a supra-segmental feature, pitch direction in a non native tonal contrast, using a passive oddball paradigm and electroencephalography. The stimuli were two contours generated from naturally produced high-level and high-falling tones in Mandarin Chinese, differing only in pitch direction (Liu and Kager, 2014). While both contours had similar pitch onsets, the pitch offset of the falling contour was lower than that of the level one. The contrast was presented in two orientations (standard and deviant reversed) and tested in two blocks with the order of block presentation counterbalanced. Mismatch negativity (MMN) responses showed that listeners discriminated the non-native tonal contrast only in the second block, reflecting indications of learning through exposure during the first block. In addition, listeners showed a later MMN peak for their second block of test relative to listeners who did the same block first, suggesting linguistic (as opposed to acoustic) processing or a misapplication of perceptual strategies from the first to the second block. The results also showed a perceptual asymmetry for change in pitch direction: listeners who encountered a falling tone deviant in the first block had larger frontal MMN amplitudes than listeners who encountered a level tone deviant in the first block. The implications of our findings for second language speech and the developmental trajectory for tone perception are discussed. PMID- 29615942 TI - Association Between Fear and Beauty Evaluation of Snakes: Cross-Cultural Findings. AB - According to the fear module theory, humans are evolutionarily predisposed to perceive snakes as prioritized stimuli and exhibit a fast emotional and behavioral response toward them. In Europe, highly dangerous snake species are distributed almost exclusively in the Mediterranean and Caspian areas. While the risk of a snakebite is relatively low in Central Europe, Azerbaijan, on the other hand, has a high occurrence of the deadly venomous Levant viper (Macrovipera lebetina). We hypothesize that co-habitation with this dangerous snake has shaped the way in which humans evaluate snake species resembling it. For that purpose, we asked respondents from the Czech Republic and Azerbaijan to rank photographs depicting 36 snake species according to perceived fear and beauty. The results revealed a high cross-cultural agreement in both evaluations (fear r2 = 0.683, p < 0.0001; beauty: r2 = 0.816, p < 0.0001). Snakes species eliciting higher fear tend to be also perceived as more beautiful, yet people are able to clearly distinguish between these two dimensions. Deadly venomous snakes representing a serious risk are perceived as highly fearful. This is especially true for the vipers and allies (pit vipers) possessing a characteristic body shape with a distinct triangular head and thick body, which was found as the most fear evoking by respondents from both countries. Although the attitude toward snakes is more negative among the respondents from Azerbaijan, their fear evaluation is similar to the Czechs. For instance, despite co-habitation with the Levant viper, it was not rated by the Azerbaijanis as more fearful than other dangerous snakes. In conclusion, agreement in the evaluation of snake fear and beauty is cross culturally high and relative fear attributed to selected snake species is not directly explainable by the current environmental and cultural differences. This may provide some support for the evolutionary hypothesis of preparedness to fear snakes. PMID- 29615943 TI - Observation of Communication by Physical Education Teachers: Detecting Patterns in Verbal Behavior. AB - The aim of this study was to analyze the verbal behavior of primary school physical education teachers in a natural classroom setting in order to investigate patterns in social constructivist communication strategies before and after participation in a training program designed to familiarize teachers with these strategies. The participants were three experienced physical education teachers interacting separately with 65 students over a series of classes. Written informed consent was obtained from all the students' parents or legal guardians. An indirect observation tool (ADDEF) was designed specifically for the study within the theoretical framework, and consisted of a combined field format, with three dimensions, and category systems. Each dimension formed the basis for building a subsequent system of exhaustive and mutually exclusive categories. Twenty-nine sessions, grouped into two separate modules, were coded using the Atlas.ti 7 program, and a total of 1991 units (messages containing constructivist discursive strategies) were recorded. Analysis of intraobserver reliability showed almost perfect agreement. Lag sequential analysis, which is a powerful statistical technique based on the calculation of conditional and unconditional probabilities in prospective and retrospective lags, was performed in GSEQ5 software to search for verbal behavior patterns before and after the training program. At both time points, we detected a pattern formed by requests for information combined with the incorporation of students' contributions into the teachers' discourse and re-elaborations of answers. In the post-training phase, we detected new and stronger patterns in certain sessions, indicating that programs combining theoretical and practical knowledge can effectively increase teachers' repertoire of discursive strategies and ultimately promote active engagement in learning. This has important implications for the evaluation and development of teacher effectiveness in practice and formal education programs. PMID- 29615945 TI - The Italian Version of the Inventory of Interpersonal Problems (IIP-32): Psychometric Properties and Factor Structure in Clinical and Non-clinical Groups. AB - All versions of the Inventory of Interpersonal Problems (IIP) are broadly used to measure people's interpersonal functioning. The aims of the current study are: (a) to examine the psychometric properties and factor structure of the Italian version of the Inventory of Interpersonal Problems-short version (IIP-32); and (b) to evaluate its associations with core symptoms of different eating disorders. One thousand two hundred and twenty three participants (n = 623 non clinical and n = 600 clinical participants with eating disorders and obesity) filled out the Inventory of Interpersonal Problems-short version (IIP-32) along with measures of self-esteem (Rosenberg Self-Esteem Scale, RSES), psychological functioning (Outcome Questionnaire, OQ-45), and eating disorders (Eating Disorder Inventory, EDI-3). The present study examined the eight-factor structure of the IIP-32 with Confirmatory Factor Analysis (CFA) and Exploratory Structural Equation Modeling (ESEM). ESEM was also used to test the measurement invariance of the IIP-32 across clinical and non-clinical groups. It was found that CFA had unsatisfactory model fit, whereas the corresponding ESEM solution provided a better fit to the observed data. However, six target factor loadings tend to be modest, and ten items showed cross-loadings higher than 0.30. The configural and metric invariance as well as the scalar and partial strict invariance of the IIP 32 were supported across clinical and non-clinical groups. The internal consistency of the IIP-32 was acceptable and the construct validity was confirmed by significant correlations between IIP-32, RSES, and OQ-45. Furthermore, overall interpersonal difficulties were consistently associated with core eating disorder symptoms, whereas interpersonal styles that reflect the inability to form close relationships, social awkwardness, the inability to be assertive, and a tendency to self-sacrificing were positively associated with general psychological maladjustment. Although further validation of the Italian version of the IIP-32 is needed to support these findings, the results on its cross-cultural validity are promising. PMID- 29615944 TI - Prosody in the Auditory and Visual Domains: A Developmental Perspective. AB - The development of body movements such as hand or head gestures, or facial expressions, seems to go hand-in-hand with the development of speech abilities. We know that very young infants rely on the movements of their caregivers' mouth to segment the speech stream, that infants' canonical babbling is temporally related to rhythmic hand movements, that narrative abilities emerge at a similar time in speech and gestures, and that children make use of both modalities to access complex pragmatic intentions. Prosody has emerged as a key linguistic component in this speech-gesture relationship, yet its exact role in the development of multimodal communication is still not well understood. For example, it is not clear what the relative weights of speech prosody and body gestures are in language acquisition, or whether both modalities develop at the same time or whether one modality needs to be in place for the other to emerge. The present paper reviews existing literature on the interactions between speech prosody and body movements from a developmental perspective in order to shed some light on these issues. PMID- 29615946 TI - Development and Validation of a Specific Self-Efficacy Scale in Adherence to a Gluten-Free Diet. AB - The aim of this study was to develop a scale to assess the levels of specific self-efficacy in order to enhance adherence to a gluten-free diet and the life quality of celiac patients. Celiac disease is a chronic small intestinal immune mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed people. The only treatment is a strict lifelong gluten-free diet. Within the framework of Social Cognitive Theory, expectation of self-efficacy is understood as the degree in which a person believes himself to be capable of performing a certain task (e.g., adhering to a gluten-free diet), a construct which has been widely studied in its relation with adopting healthy behaviors, but scarcely in relation to celiac disease. A validation study was carried out in various stages: preparation of the protocol; construction of the questionnaire and a pilot run with 20 patients; validation of the scale with 563 patients and statistical analysis. A 25-item scale was developed. Feasibility was excellent (99.82% of participants completed all the questions). Factorial analysis pointed to the existence of five factors that explained 70.98% of the variance with a Cronbach alpha of 0.81 for the scale overall and between 0.64 and 0.90 for each factor. The scale showed a Spearman's Rho coefficient of 0.279 with the General self-efficacy Scale. This easily administered scale provides good psychometric properties for evaluating specific self-efficacy of celiac patients in adhering to treatment. It seeks to be the first scale that provides not only a measurement of specific self-efficacy in celiac disease, but also to determine its levels for each of the areas as a first step toward designing interventions of self management and empowerment programs to cope with the disease. PMID- 29615947 TI - Disentangling the Dyadic Dance: Theoretical, Methodological and Outcomes Systematic Review of Mother-Infant Dyadic Processes. AB - Background: During the last decades, the research on mother-infant dyad has produced a great amount of data, methods and theories, which largely contributed to set a revolution in the way we look at developmental changes during infancy and childhood. Very different constructs depict the different aspects of the "dyadic dance" occurring between a mother and her infant; nonetheless, a comprehensive and consistent systematization of these concepts in a coherent theoretical landscape is still lacking. Aim: In the present work, we aim at disentangling the different theoretical and methodological definitions of 9 dyadic constructs and we highlight their effects on infants' and children developmental outcomes. Methods: A literature search has been conducted on three databases-PubMed, Scopus, Web of Science. Three different reviews are reported here: (1) a review on the theoretical definitions of dyadic constructs; (2) a review of operational definitions, settings and methods of dyadic processes; (3) a systematic review of dyadic processes' outcomes for infants' and children developmental trajectories. Results: Two constructs emerged as wide meta theoretical concepts (reciprocity and mutuality) and seven described specific processes (attunement, contingency, coordination, matching, mirroring, reparation, synchrony). A global model resuming the relationships among different processes is reported, which highlights the emergence of two specific cycles of dyadic functioning (i.e., matching-mismatching-reparation-synchrony; contingency, coordination, attunement, mirroring). A comprehensive review of the adopted measures is also provided. Finally, all the processes provided significant contributions to infants' behavioral, cognitive, and socio-emotional development during the first 3 years of age, but limited research has been conducted on specific processes (e.g. reparation and mirroring). Conclusion: The present study provides an original research-grounded framework to consider the different nature of mother-infant dyadic processes within a unified dyadic eco-system. Different levels of evidence emerged for the role of diverse mother-infant dyadic processes on infants' and children development. Open questions and future research directions are highlighted. PMID- 29615949 TI - Recognizing the Effects of Language Mode on the Cognitive Advantages of Bilingualism. AB - For bilinguals, it is argued that a cognitive advantage can be linked to the constant management and need for conflict resolution that occurs when the two languages are co-activated (Bialystok, 2015). Language mode (Grosjean, 1998, 2001) is a significant variable that defines and shapes the language experiences of bilinguals and consequently, the cognitive advantages of bilingualism. Previous work, however, has not sufficiently tested the effects of language mode on the bilingual experience. In this brief conceptual analysis, we discuss the significance of language mode in bilingual work on speech perception, production, and reading. We offer possible explanations for conflicting findings and ways in which future work should control for its modulating effects. PMID- 29615948 TI - Higher Status Honesty Is Worth More: The Effect of Social Status on Honesty Evaluation. AB - Promises are crucial for maintaining trust in social hierarchies. It is well known that not all promises are kept; yet the effect of social status on responses to promises being kept or broken is far from understood, as are the neural processes underlying this effect. Here we manipulated participants' social status before measuring their investment behavior as Investor in iterated Trust Game (TG). Participants decided how much to invest in their partners, who acted as Trustees in TG, after being informed that their partners of higher or lower social status either promised to return half of the multiplied sum (4 * invested amount), did not promise, or had no opportunity to promise. Event-related potentials (ERPs) were recorded when the participants saw the Trustees' decisions in which the partners always returned half of the time, regardless of the experimental conditions. Trustee decisions to return or not after promising to do so were defined as honesty and dishonesty, respectively. Behaviorally, participants invested more when Trustees promised than when Trustees had no opportunity to promise, and this effect was greater for higher status than lower status Trustees. Neurally, when viewing Trustees' return decisions, participants' medial frontal negativity (MFN) responses (250-310 ms post onset) were more negative when Trustees did not return than when they did return, suggesting that not returning was an expectancy violation. P300 responses were only sensitive to higher status return feedback, and were more positive-going for higher status partner returns than for lower status partner returns, suggesting that higher status returns may have been more rewarding/motivationally significant. Importantly, only participants in low subjective socioeconomic status (SES) evidenced an increased P300 effect for higher status than lower status honesty (honesty - dishonesty), suggesting that higher status honesty was especially rewarding/motivationally significant for participants with low SES. Taken together, our results suggest that in an earlier time window, MFN encodes return valence, regardless of honesty or social status, which are addressed in a later cognitive appraisal process (P300). Our findings suggest that social status influences honesty perception at both a behavioral and neural level, and that subjective SES may modulate this effect. PMID- 29615951 TI - Do We Need the Environment to Explain Operant Behavior? AB - By way of operant conditioning, human behavior is continuously shaped and maintained by its consequences - and understanding this process is important to most fields of psychology and neuroscience. The role of the learning organism's environment has long been contentious, however. Much relevant research is being done by people identifying with the Skinnerian tradition, who tend to agree that the causes of behavior can be found exclusively in the environment. The meaning of this proposition is not clear, however. Some authors say the environment is outside the body, others claim it is also inside it. Among those who say the environment is outside the body, many are of the opinion that events inside the body and hence (in their view) not in the environment can also cause behavior, though they claim that events inside the body cannot be causes in the same sense as events taking place outside it. This is confusing, and the present paper argues that the "environment" may neither be a useful nor a necessary concept in the analysis of behavior. Moreover, abolishing the concept could clear the way for a reintegration of Skinnerian psychology into the mainstream. PMID- 29615950 TI - Personality Influences the Relationship Between Primary Emotions and Religious/Spiritual Well-Being. AB - The study of human emotions and personality provides valuable insights into the parameters of mental health and well-being. Affective neuroscience proposes that several levels of emotions - ranging from primary ones such as LUST or FEAR up to higher emotions such as spirituality - interact on a neural level. The present study aimed to further explore this theory. Furthermore, we hypothesized that personality - formed by bottom-up primary emotions and cortical top-down regulation - might act as a link between primary emotions and religious/spiritual well-being. A total sample of 167 (78% female) student participants completed the Affective Neuroscience Personality Scale (primary emotions), the Big Five Personality Inventory and the Multidimensional Inventory of Religious/Spiritual Well-Being (higher emotions). Correlation analyses confirmed the link between primary and higher emotions as well as their relation to personality. Further regression analyses indicated that personality dimensions mediate the relationship between primary and higher emotions. A substantial interaction between primary emotions, personality dimensions, and religious/spiritual well being could be confirmed. From a developmental perspective, cortical top-down regulation might influence religious/spiritual well-being by forming relevant personality dimensions. Hence, CARE as well as Agreeableness seem of special importance. Future studies might focus on implications for clinical groups. PMID- 29615952 TI - Editorial: Vestibular Contributions to Health and Disease. PMID- 29615953 TI - Inflammasome Proteins As Biomarkers of Multiple Sclerosis. AB - Multiple sclerosis (MS) is an autoimmune disease that affects the brain and spinal cord. The inflammasome is a multiprotein complex that contributes to the innate immune response in animal models of MS as well as in patients with the disease. Important to the care of patients with MS is the need for biomarkers that can predict disease onset, disease exacerbation, as well as response to treatment. In this study, we analyzed serum samples from 32 patients with MS and 120 age-matched controls, and provide receiver operator characteristic (ROC) curves with associated confidence intervals following analyses of serum samples from patients with MS, most of which had the relapsing-remitting form of the disease, and from healthy unaffected donors, and determine the sensitivity and specificity of inflammasome proteins as biomarkers of MS. We report that caspase 1 (1.662 +/- 0.6024 difference between means), apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) (407.5 +/- 35.79), and interleukin (IL)-18 (78.53 + 17.86) were elevated in the serum of MS patients when compared to controls. Interestingly, the levels of IL-1beta (-0.5961 +/- 0.265) were lower in the MS cohort. Importantly, the area under the curve (AUC) for ASC and caspase-1 were 0.9448 and 0.848, respectively. Taken together, these data suggest that ASC and caspase-1 could be potential candidate biomarkers for MS onset. PMID- 29615955 TI - Commentary: Early Screening Parameters for Dysphagia in Acute Ischemic Stroke. PMID- 29615954 TI - Microbiome-Mediated Upregulation of MicroRNA-146a in Sporadic Alzheimer's Disease. AB - The first indication of a potential mechanistic link between the pathobiology of the human gastrointestinal (GI)-tract microbiome and its contribution to the pathogenetic mechanisms of sporadic Alzheimer's disease (AD) came a scant 4 years ago (1). Ongoing research continues to strengthen the hypothesis that neurotoxic microbial-derived components of the GI tract microbiome can cross aging GI tract and blood-brain barriers and contribute to progressive proinflammatory neurodegeneration, as exemplified by the AD-process. Of central interest in these recent investigations are the pathological roles played by human GI tract resident Gram-negative anaerobic bacteria and neurotropic viruses-two prominent divisions of GI tract microbiome-derived microbiota-which harbor considerable pathogenic potential. It is noteworthy that the first two well-studied microbiota the GI tract abundant Gram-negative bacteria Bacteroides fragilis and the neurotropic herpes simplex virus-1 both share a final common pathway of NF-kappaB (p50/p65) activation and microRNA-146a induction with ensuing pathogenic stimulation of innate-immune and neuroinflammatory pathways. These appear to strongly contribute to the inflammation-mediated amyloidogenic neuropathology of AD. This communication: (i) will review recent research contributions that have expanded our understanding of the nature of the translocation of microbiome derived neurotoxins-across biophysiological barriers; (ii) will assess multiple recent investigations of the induction of the proinflammatory pathogenic microRNA 146a by these two prominent classes of human microbiota; and (iii) will discuss the role of molecular neurobiology and mechanistic contribution of polymicrobial infections to AD-type neuropathological change. PMID- 29615956 TI - Initial Clinical Evaluation of the Modular Prosthetic Limb. AB - The Modular Prosthetic Limb (MPL) was examined for its feasibility and usability as an advanced, dexterous upper extremity prosthesis with surface electromyography (sEMG) control in with two individuals with below-elbow amputations. Compared to currently marketed prostheses, the MPL has a greater number of sequential and simultaneous degrees of motion, as well as wrist modularity, haptic feedback, and individual digit control. The MPL was successfully fit to a 33-year-old with a trans-radial amputation (TR01) and a 30 year-old with a wrist disarticulation amputation (TR02). To preserve anatomical limb length, we adjusted the powered degrees of freedom of wrist motion between users. Motor training began with practicing sEMG and pattern recognition control within the virtual integration environment (VIE). Prosthetic training sessions then allowed participants to complete a variety of activities of daily living with the MPL. Training and Motion Control Accuracy scores quantified their ability to consistently train and execute unique muscle-to-motion contraction patterns. Each user also completed one prosthetic functional metric-the Southampton Hand Assessment Procedure (SHAP) for TR01 and the Jebsen-Taylor Hand Function Test (JHFT) for TR02. Haptic feedback capabilities were integrated for TR01. TR01 achieved 95% accuracy at 84% of his VIE sessions. He demonstrated improved scores over a year of prosthetic training sessions, ultimately achieving simultaneous control of 13 of the 17 (76%) attempted motions. His performance on the SHAP improved from baseline to final assessment with an increase in number of tasks achieved. TR01 also used vibrotactile sensors to successfully discriminate between hard and soft objects being grasped by the MPL hand. TR02 demonstrated 95% accuracy at 79% of his VIE sessions. He demonstrated improved scores over months of prosthetic training sessions, however there was a significant drop in scores initially following a mid-study pause in testing. He ultimately achieved simultaneous control of all 13 attempted powered motions, and both attempted passive motions. He completed 5 of the 7 (71%) JHFT tasks within the testing time limit. These case studies confirm that it is possible to use non-invasive motor control to increase functional outcomes with individuals with below-elbow amputation and will help to guide future myoelectric prosthetic studies. PMID- 29615957 TI - Local Delivery Is Critical for Monocyte Chemotactic Protein-1 Mediated Site Specific Murine Aneurysm Healing. AB - Background: Local delivery of monocyte chemotactic protein-1 (MCP-1/CCL2) via our drug-eluting coil has been shown to promote intrasaccular aneurysm healing via an inflammatory pathway. Objective: In this study, we validate the importance of local MCP-1 in murine aneurysm healing. Whether systemic, rather than local, delivery of MCP-1 can direct site-specific aneurysm healing has significant translational implications. If systemic MCP-1 is effective, then MCP-1 could be administered as a pill rather than by endovascular procedure. Furthermore, we confirm that MCP-1 is the primary effector in our MCP-1 eluting coil-mediated murine aneurysm healing model. Methods: We compare aneurysm healing with repeated intraperitoneal MCP-1 versus vehicle injection, in animals with control poly(lactic-co-glycolic) acid (PLGA)-coated coils. We demonstrate elimination of the MCP-1-associated tissue-healing response by knockout of MCP-1 or CCR2 (MCP-1 receptor) and by selectively inhibiting MCP-1 or CCR2. Using immunofluorescent probing, we explore the cell populations found in healed aneurysm tissue following each intervention. Results: Systemically administered MCP-1 with PLGA coil control does not produce comparable aneurysm healing, as seen with MCP-1 eluting coils. MCP-1-directed aneurysm healing is eliminated by selective inhibition of MCP-1 or CCR2 and in MCP-1-deficient or CCR2-deficient mice. No difference was detected in M2 macrophage and myofibroblast/smooth muscle cell staining with systemic MCP-1 versus vehicle in aneurysm wall, but a significant increase in these cell types was observed with MCP-1 eluting coil implant and attenuated by MCP-1/CCR2 blockade or deficiency. Conclusion: We show that systemic MCP-1 concurrent with PLGA-coated platinum coil implant is not sufficient to produce site-specific aneurysm healing. MCP-1 is a critical, not merely complementary, actor in the aneurysm healing pathway. PMID- 29615958 TI - Lymphocytes Contribute to the Pathophysiology of Neonatal Brain Injury. AB - Background: Periventricular leukomalacia (PVL) is the most common form of preterm brain injury affecting the cerebral white matter. This type of injury involves a multiphase process and is induced by many factors, including hypoxia-ischemia (HI) and infection. Previous studies have suggested that lymphocytes play a significant role in the pathogenesis of brain injury, and the aim of this study was to determine the contribution of lymphocyte subsets to preterm brain injury. Methods: Immunohistochemistry on brain sections from neonatal mice was performed to evaluate the extent of brain injury in wild-type and T cell and B cell deficient neonatal mice (Rag1-/- mice) using a mouse model of HI-induced preterm brain injury. Flow cytometry was performed to determine the presence of different types of immune cells in mouse brains following HI. In addition, immunostaining for CD3 T cells and CD20 B cells was performed on postmortem preterm human infant brains with PVL. Results: Mature lymphocyte-deficient Rag1-/- mice showed protection from white matter loss compared to wild type mice as indicated by myelin basic protein immunostaining of mouse brains. CD3+ T cells and CD20+ B cells were observed in the postmortem preterm infant brains with PVL. Flow cytometry analysis of mouse brains after HI-induced injury showed increased frequency of CD3+ T, alphabetaT and B cells at 7 days after HI in the ipsilateral (injured) hemisphere compared to the contralateral (control, uninjured) hemisphere. Conclusion: Lymphocytes were found in the injured brain after injury in both mice and humans, and lack of mature lymphocytes protected neonatal mice from HI-induced brain white matter injury. This finding provides insight into the pathology of perinatal brain injury and suggests new avenues for the development of therapeutic strategies. PMID- 29615959 TI - Rorschach Evaluation of Personality and Emotional Characteristics in Adolescents With Migraine Versus Epilepsy and Controls. AB - The literature examining primary headache, including migraine, in adolescents, has pointed out the key role played by a wide range of psychiatric disorders in reducing the patients' quality of life. Moreover, pioneering studies showed that preexisting personality characteristics, specific emotion regulation styles and psychological-psychiatric difficulties are likely to increase the risk of the onset, maintenance, and outcome of headache. Still personality issues in migraine have been poorly studied, in particular in children and adolescents. This study aims, therefore, to investigate the specific characteristics of personality, and in particular emotion regulation and coping strategies, in adolescent with migraine, comparing them with age-matched patients with idiopathic epilepsy and healthy adolescents. 52 adolescents (age: 11-17) were assessed using a multi method test battery, which included a self-report questionnaire (the youth self report), a proxy-report (child behavior checklist) along with a projective personality test, the Rorschach Test, administered and scored according to the Exner comprehensive system. The results showed specific personality characteristics in adolescents with migraine, revealing a marked difficulty in modulating and regulating affections through thoughts and reflections, resorting instead to impulsive acts and maladaptive coping strategies, thus revealing a vague and immature perception of reality. Differently from adolescents belonging to the general population, but similarly to patients with epilepsy, adolescents with migraine perceive a high situational stress, probably related to the condition of suffering from chronic disease. They have, therefore, a lower self consideration and self-esteem along with a poorer insight regarding themselves as well as the relations with others. In line with previous findings, these preliminary results suggest the need for further research on ample samples, using also standardized projective test in order to better understand the pathogenesis of psychological difficulties in patients with migraine. As a clinical implication, the results seem to indicate that providing a psychological integrated approach can play a pivotal role in the assessment and treatment of adolescent with migraine, in order to improve the outcome and the quality of life of the young patients. PMID- 29615960 TI - Reported Changes in Dietary Behavior Following a First Clinical Diagnosis of Central Nervous System Demyelination. AB - Background/objectives: Although the current evidence is insufficient to recommend a special diet for people with multiple sclerosis (MS), dietary advice for people with MS is prolific online and in the media. This study aimed to describe dietary changes made in the year following a first clinical diagnosis of central nervous system demyelination (FCD), a common precursor to MS. Subjects/methods: We used follow-up data from the Ausimmune Study, a multicentre matched case-control study examining the environmental risk factors for a FCD. A total of 244 cases (60 male, 184 female) completed a 1-year follow-up interview, which included a question about dietary changes. We described the number and proportion (%) of participants who reported making dietary changes and the type of change made. We investigated independent predictors of making a dietary change using a multivariable logistic regression model. Results: A total of 38% (n = 92) of participants at the 1-year follow-up reported making at least one dietary change over the last year. There were no statistically significant independent associations between any participant characteristic and odds of making a dietary change. Of those who made at least one dietary change, the most common changes were increasing fruit and/or vegetable intake (27%, n = 25) and following a low fat diet (25%, n = 23). Conclusion: A considerable proportion of the study population reported making at least one dietary change in the year following a FCD, with the majority of changes being toward a healthier diet. Further research is warranted to investigate the reasons behind any dietary changes adopted by people with a FCD or with MS, and whether making a dietary change has benefits for the progression of demyelinating diseases, e.g., to a diagnosis of MS, as well as for general health and well-being. PMID- 29615962 TI - Acute Hemichorea Can Be the Only Clinical Manifestation of Post-Varicella Vasculopathy: Two Pediatric Clinical Cases. AB - Acute hemichorea can occur in the context of infectious, autoimmune, metabolic, toxic, and vascular neuropathologies. Primary infection by varicella zoster virus (VZV) can result in vasculopathy with neurological manifestations, such as hemiparesis, at times accompanied by hemichorea. Isolated hemichorea, however, had not been reported. We here describe two cases of VZV-induced vasculopathy whose sole clinical manifestation was acute hemichorea. Both cases involved young boys of 3 years of age, who presented with acute hemichorea 4-6 months after initial VZV infection. All hematological, immunological, and toxicological tests were normal, except for the presence of VZV IgG. Brain structural magnetic resonance imaging (MRI) and magnetic resonance angiography revealed specific signs of vasculitis and ischemic lesions in the basal ganglia region (lentiform nucleus, thalamus, and internal capsule). Following corticosteroid and acetylsalicylic acid treatment, full symptomatic recovery was achieved within 3 weeks. Repeated MRI documented full neurostructural recovery, which was confirmed at extended follow-up for more than 1 year. These cases indicate that VZV-induced vasculopathy should be considered in the case of pediatric isolated acute hemichorea. PMID- 29615961 TI - Hypertension and Diagnosis of Parkinson's Disease: A Meta-Analysis of Cohort Studies. AB - Background: Hypertension has been associated with cognitive dysfunction in the general population and patients with Alzheimer's disease (AD). However, there are contradictory data regarding the potential association between hypertension and diagnosis of Parkinson's disease (PD), the second most common neurodegenerative disorder after AD. The purpose of this meta-analysis is to synthesize data from cohort studies to explore the potential association between preexisting hypertension and subsequent PD diagnosis. Methods: The PubMed and Embase databases were searched to identify all relevant studies. Two independent investigators performed the data extraction. Eligible cohort studies providing risk and precision estimates related to hypertension and PD were selected. Pooled risk ratios (RRs) with 95% confidence interval (CI) were calculated by using a random-effects model or a fixed-effects model. Sensitivity analyses after excluding one study at a time were performed to assess the stability of the results. Publication bias was assessed with Begg's test and Egger's test. Results: Seven cohort studies were identified, including 3,170 persons who were confirmed to have developed PD and 339,517 participants who did not have PD during follow-up. The onset of hypertension before PD diagnosis was significantly associated with an increased risk of motor stage PD (RR = 1.799, 95% CI [1.066 3.037]). This relationship was further confirmed by secondary analyses based on estimates adjusted for potential vascular confounders (RR = 1.319, 95% CI [1.073 1.622]). After excluding one study at a time, the sensitivity analyses still showed that hypertension history was significantly associated with an increased risk of motor stage PD (RR with 95% CI ranging from 1.11 [1.075-1.35] to 1.42 [1.65-1.83]). No publication bias was observed in this meta-analysis. Conclusion: The findings of this meta-analysis suggest that hypertension may be a risk factor for motor stage PD, which may provide novel insights into the etiology and pathogenesis of this neurodegenerative disorder. However, large-scale well designed studies that consider various confounders are still needed to further verify and clarify the association between hypertension and PD diagnosis. PMID- 29615963 TI - Intensity- and Duration-Adaptive Functional Electrical Stimulation Using Fuzzy Logic Control and a Linear Model for Dropfoot Correction. AB - Functional electrical stimulation (FES) is important in gait rehabilitation for patients with dropfoot. Since there are time-varying velocities during FES assisted walking, it is difficult to achieve a good movement performance during walking. To account for the time-varying walking velocities, seven poststroke subjects were recruited and fuzzy logic control and a linear model were applied in FES-assisted walking to enable intensity- and duration-adaptive stimulation (IDAS) for poststroke subjects with dropfoot. In this study, the performance of IDAS was evaluated using kinematic data, and was compared with the performance under no stimulation (NS), FES-assisted walking triggered by heel-off stimulation (HOS), and speed-adaptive stimulation. A larger maximum ankle dorsiflexion angle in the IDAS condition than those in other conditions was observed. The ankle plantar flexion angle in the IDAS condition was similar to that of normal walking. Improvement in the maximum ankle dorsiflexion and plantar flexion angles in the IDAS condition could be attributed to having the appropriate stimulation intensity and duration. In summary, the intensity- and duration-adaptive controller can attain better movement performance and may have great potential in future clinical applications. PMID- 29615964 TI - Regulatory T Cells As Supporters of Psychoimmune Resilience: Toward Immunotherapy of Major Depressive Disorder. AB - There is growing evidence that inflammation plays a role in major depressive disorder (MDD). As the main role of regulatory T cells (Tregs) is to control inflammation, this might denote a Treg insufficiency in MDD. However, neither a qualitative nor a quantitative defect of Tregs has been ascertained and no causality direction between inflammation and depression has been established. Here, after reviewing the evidence supporting a relation between Treg insufficiency and MDD, we conclude that a novel therapeutic approach based on Treg stimulation could be valuable in at least the subset of patients with inflammatory MDD. Low-dose interleukin-2 appears to be a good candidate as it is not only a safe stimulator of Tregs in humans but also an inhibitor of pro inflammatory Th17 lymphocytes. Here, we discuss that a thorough immune investigation as well as immunotherapy will be heuristic for deciphering the pathophysiology of MDD. PMID- 29615965 TI - Neurofascin and Compact Myelin Antigen-Specific T Cell Response Pattern in Chronic Inflammatory Demyelinating Polyneuropathy Subtypes. AB - Objective: The objective of this study is to investigate whether chronic inflammatory demyelinating polyneuropathy (CIDP) and its subtypes differ in their type 1 T-helper (TH1) cell response against nodal/paranodal neurofascin (NF186, NF155) as well as myelin protein zero (P0 180-199) and myelin basic protein (MBP 82-100). Methods: Interferon-gamma (IFN-gamma) enzyme-linked immunospot assay was used to detect antigen-specific T cell responses in 48 patients suffering typical CIDP (n = 18), distal acquired demyelinating polyneuropathy (n = 8), multifocal acquired demyelinating sensory and motor polyneuropathy (MADSAM; n = 9), and sensory CIDP (n = 13) compared to other non-immune polyneuropathy (ON; n = 19) and healthy controls (n = 9). Results: Compared to controls, MADSAM and sensory CIDP patients showed broadest IFN-gamma T cell responses to all four antigens. Positive IFN-gamma responses against two or more antigens were highly predictive for CIDP (positive predictive value = 0.95) and were found in 77% of CIDP patients. Patients with limited antigen-specific response were females, more severely affected with neuropathic pain and proximal paresis. The area under the receiver operating characteristics curve (AUC) of NF186 in MADSAM was 0.94 [95% confidential interval (CI) 0.82-1.00] compared to ON. For sensory CIDP, AUC of P0 180-199 was 0.94 (95% CI 0.86-1.00) and for MBP 82-100 0.95 (95% CI 0.88-1.00) compared to ON. Conclusion: Cell-mediated immune responses to (para)nodal and myelin-derived antigens are common in CIDP. TH1 response against NF186 may be used as a biomarker for MADSAM and TH1 responses against P0 180-199 and MBP 82 100 as biomarkers for sensory CIDP. Larger multicenter studies study are warranted in order to establish these immunological markers as a diagnostic tools. PMID- 29615967 TI - Therapeutic Inertia in the New Landscape of Multiple Sclerosis Care. AB - The landscape of multiple sclerosis (MS) treatment is constantly changing. Significant heterogeneity exists in the efficacy and risks associated with these therapies. Therefore, clinicians have the challenge to tailor treatment based on several factors (disease activity level, risk of progression, individual patient preferences and characteristics, personal expertise, etc.), to identify the optimal balance between safety and efficacy. However, most clinicians have limited education in decision-making and formal training in risk management. Together, these factors may lead to therapeutic inertia (TI); defined as the absence of treatment initiation or intensification when therapeutic goals are unmet. TI may lead to suboptimal treatments choices, worse clinical outcomes, and more disability. This article provides a succinct overview on factors influencing TI in MS care. PMID- 29615968 TI - Epilepsy an Update on Disease Mechanisms: The Potential Role of MicroRNAs. AB - So far, research on epilepsy mechanisms has been designed mainly using animal models and tracking down molecular mechanisms underlying seizures in that model. While this approach is clearly valuable, it can be questioned if it is the best possible. One attractive alternative approach may stem from the consideration of epilepsy as a complex disease of a very complex organ, the brain. This short review summarizes data from analyses of the alterations in expression of microRNAs and their target messenger RNAs in a specific brain subregion, the dentate gyrus of the hippocampus, in three experimental models of lesional epilepsy. The findings are discussed within the conceptual framework of complex systems. PMID- 29615966 TI - Dysfunction of Protein Quality Control in Parkinsonism-Dementia Complex of Guam. AB - Guam parkinsonism-dementia complex (G-PDC) is an enigmatic neurodegenerative disease that is endemic to the Pacific island of Guam. G-PDC patients are clinically characterized by progressive cognitive impairment and parkinsonism. Neuropathologically, G-PDC is characterized by abundant neurofibrillary tangles, which are composed of hyperphosphorylated tau, marked deposition of 43-kDa TAR DNA-binding protein, and neuronal loss. Although both genetic and environmental factors have been implicated, the etiology and pathogenesis of G-PDC remain unknown. Recent neuropathological studies have provided new clues about the pathomechanisms involved in G-PDC. For example, deposition of abnormal components of the protein quality control system in brains of G-PDC patients indicates a role for proteostasis imbalance in the disease. This opens up promising avenues for new research on G-PDC and could have important implications for the study of other neurodegenerative disorders. PMID- 29615969 TI - Postoperative Delirium, Learning, and Anesthetic Neurotoxicity: Some Perspectives and Directions. AB - Evidence of anesthetic neurotoxicity is unequivocal when studied in animal models. These findings have translated poorly to the clinical domain when equated to postoperative delirium (POD) in adults and postoperative cognitive dysfunction (POCD) in either children or the elderly. In this perspective, we examine various reasons for the differences between animal modeling of neurotoxicity and the clinical situation of POD and POCD and make suggestions as to potential directions for ongoing research. We hypothesize that the animal anesthetic neurotoxicity models are limited, in part, due to failed scaling correction of physiological time. We posit that important insights into POCD in children and adults may be gleaned from studies in adults examining alterations in perioperative management designed to limit POD. In this way, POD may be more useful as the proxy for POCD rather than neuronal dropout or behavioral abnormalities that have been used in animal models but which may not be proxies for the human condition. We argue that it is time to move beyond animal models of neurotoxicity to directly examine these problems in well-conducted clinical trials with comprehensive preoperative neuropsychometric and psychiatric testing, high fidelity intraoperative monitoring of physiological parameters during the anesthetic course and postoperative assessment of subthreshold and full classification of POD. In this manner, we can "model ourselves" to better understand these important and poorly understood conditions. PMID- 29615971 TI - Impact of Glucose Loading on Variations in CD4+ and CD8+ T Cells in Japanese Participants with or without Type 2 Diabetes. AB - Objective: The aim of this study was to examine the fluctuations in CD4+ T cells, CD8+ T cells, and natural CD4+CD25+FoxP3+T-regulatory (Treg) cells following an oral glucose tolerance test (OGTT) in participants with and those without type 2 diabetes (T2DM). Methods: 19 Japanese participants with T2DM (DM group) and 21 participants without diabetes (non-DM group) were recruited and underwent a 75-g OGTT. The cell numbers of leukocytes, lymphocytes, and the T cell compartment, such as CD4+, CD8+, and Treg, were calculated for blood samples obtained after an overnight 12 h fast and during a 75-g OGTT at 60 and 120 min. Results: Before glucose loading, no differences in the cell numbers of leukocytes, lymphocytes, CD4+, CD8+, and Treg were observed between the DM group and the non-DM group. The proportion of CD8+ was significantly reduced, whereas the proportion of CD4+ was significantly increased, after 120 min of glucose loading in both groups. The proportion of Treg was not affected. Furthermore, a significant positive correlation was observed between the AUC0-120 min of CD8+ and the change in the free fatty acid level following the OGTT (rho = 0.39, P < 0.05), but not that of glucose or insulin. Conclusion: The proportion of CD4+ T cells was increased and that of CD8+ T cells was reduced after glucose loading in both subjects with and without diabetes. These findings suggest that glucose loading dynamically affects the balance of the circulating T lymphocyte subset, regardless of glucose tolerance. PMID- 29615972 TI - Prediction of Glucose Tolerance without an Oral Glucose Tolerance Test. AB - Introduction: Impaired glucose tolerance (IGT) is diagnosed by a standardized oral glucose tolerance test (OGTT). However, the OGTT is laborious, and when not performed, glucose tolerance cannot be determined from fasting samples retrospectively. We tested if glucose tolerance status is reasonably predictable from a combination of demographic, anthropometric, and laboratory data assessed at one time point in a fasting state. Methods: Given a set of 22 variables selected upon clinical feasibility such as sex, age, height, weight, waist circumference, blood pressure, fasting glucose, HbA1c, hemoglobin, mean corpuscular volume, serum potassium, fasting levels of insulin, C-peptide, triglyceride, non-esterified fatty acids (NEFA), proinsulin, prolactin, cholesterol, low-density lipoprotein, HDL, uric acid, liver transaminases, and ferritin, we used supervised machine learning to estimate glucose tolerance status in 2,337 participants of the TUEF study who were recruited before 2012. We tested the performance of 10 different machine learning classifiers on data from 929 participants in the test set who were recruited after 2012. In addition, reproducibility of IGT was analyzed in 78 participants who had 2 repeated OGTTs within 1 year. Results: The most accurate prediction of IGT was reached with the recursive partitioning method (accuracy = 0.78). For all classifiers, mean accuracy was 0.73 +/- 0.04. The most important model variable was fasting glucose in all models. Using mean variable importance across all models, fasting glucose was followed by NEFA, triglycerides, HbA1c, and C-peptide. The accuracy of predicting IGT from a previous OGTT was 0.77. Conclusion: Machine learning methods yield moderate accuracy in predicting glucose tolerance from a wide set of clinical and laboratory variables. A substitution of OGTT does not currently seem to be feasible. An important constraint could be the limited reproducibility of glucose tolerance status during a subsequent OGTT. PMID- 29615970 TI - The Potential Role of Platelet-Related microRNAs in the Development of Cardiovascular Events in High-Risk Populations, Including Diabetic Patients: A Review. AB - Platelet activation plays a pivotal role in the development and progression of atherosclerosis, which often leads to potentially fatal ischemic events at later stages of the disease. Platelets and platelet microvesicles (PMVs) contain large amounts of microRNA (miRNA), which contributes largely to the pool of circulating miRNAs. Hence, they represent a promising option for the development of innovative diagnostic biomarkers, that can be specific for the underlying etiology. Circulating miRNAs can be responsible for intracellular communication and may have a biological effect on target cells. As miRNAs associated to both cardiovascular diseases (CVD) and diabetes mellitus can be measured by means of a wide array of techniques, they can be exploited as an innovative class of smart disease biomarkers. In this manuscript, we provide an outline of miRNAs associated with platelet function and reactivity (miR-223, miR-126, miR-197, miR 191, miR-21, miR-150, miR-155, miR-140, miR-96, miR-98) that should be evaluated as novel biomarkers to improve diagnostics and treatment of CVD. PMID- 29615973 TI - Evidence for Ongoing Modeling-Based Bone Formation in Human Femoral Head Trabeculae via Forming Minimodeling Structures: A Study in Patients with Fractures and Arthritis. AB - Bone modeling is a biological process of bone formation that adapts bone size and shape to mechanical loads, especially during childhood and adolescence. Bone modeling in cortical bone can be easily detected using sequential radiographic images, while its assessment in trabecular bone is challenging. Here, we performed histomorphometric analysis in 21 bone specimens from biopsies collected during hip arthroplasty, and we proposed the criteria for histologically identifying an active modeling-based bone formation, which we call a "forming minimodeling structure" (FMiS). Evidence of FMiSs was found in 9 of 20 specimens (45%). In histomorphometric analysis, bone volume was significant higher in specimens displaying FMiSs compared with the specimens without these structures (BV/TV, 31.7 +/- 10.2 vs. 23.1 +/- 3.9%; p < 0.05). Osteoid parameters were raised in FMiS-containing bone specimens (OV/BV, 2.1 +/- 1.6 vs. 0.6 +/- 0.3%; p < 0.001, OS/BS, 23.6 +/- 15.5 vs. 7.6 +/- 4.2%; p < 0.001, and O.Th, 7.4 um +/- 2.0 vs. 5.2 +/- 1.0; p < 0.05). Our results showed that the modeling-based bone formation on trabecular bone surfaces occurs even during adulthood. As FMiSs can represent histological evidence of modeling-based bone formation, understanding of this physiology in relation to bone homeostasis is crucial. PMID- 29615975 TI - Daytime Variation in Serum Progesterone During the Mid-Luteal Phase in Women Undergoing In Vitro Fertilization Treatment. AB - Objective: To investigate whether mid-luteal serum progesterone (P4) exhibits significant fluctuations during a 12-h daytime period in women undergoing in vitro fertilization (IVF) and to explore whether the extent of these fluctuations could impact the interpretation of luteal progesterone levels in a clinical setting. Design: Explorative pilot study. Setting: Public hospital-based fertility unit. Patients: Ten women undergoing IVF treatment. Intervention: Seven days after oocyte pick-up, patients underwent frequent repeated blood sampling (every 60 min for 12 h and during two of these hours, every 15 min). Serum samples were analyzed for progesterone, estradiol, and luteinizing hormone (LH). Main outcome measures: Daytime fluctuations in s-progesterone and s-estradiol. Results: There was a significant positive correlation between median P4 levels and the magnitude of P4 variations-women with median P4 < 60 nmol/l had clinically stable P4 levels throughout the day, while patients with median P4 > 250 nmol/l exhibited periodic P4 peaks of several hundred nanomoles per liter. These endogenous P4 fluctuations were observed irrespective of the type of stimulation protocol or mode of triggering of final oocyte maturation and despite the fact that LH was under the detection limit at the time of measurement. Simultaneously, large fluctuations were seen in s-estradiol. Conclusion: Monitoring of early to mid-luteal P4 levels in IVF cycles may be valuable in the planning of individualized luteal phase support in the attempt to increase reproductive outcomes. The prerequisite for luteal phase monitoring is, however, that the validity of a single measured P4 value is reliable. We show for the first time, that a single P4 measurement in the low progesterone patient quite accurately reflects the corpus luteum function and that the measurement can be used to detect IVF patients with a need of additional exogenous luteal P4 administration. PMID- 29615974 TI - Presence and Effects of Pituitary Adenylate Cyclase Activating Polypeptide Under Physiological and Pathological Conditions in the Stomach. AB - Pituitary adenylate cyclase activating polypeptide (PACAP) is a multifunctional neuropeptide with widespread occurrence throughout the body including the gastrointestinal system. In the small and large intestine, effects of PACAP on cell proliferation, secretion, motility, gut immunology and blood flow, as well as its importance in bowel inflammatory reactions and cancer development have been shown and reviewed earlier. However, no current review is available on the actions of PACAP in the stomach in spite of numerous data published on the gastric presence and actions of the peptide. Therefore, the aim of the present review is to summarize currently available data on the distribution and effects of PACAP in the stomach. We review data on the localization of PACAP and its receptors in the stomach wall of various mammalian and non-mammalian species, we then give an overview on PACAP's effects on secretion of gastric acid and various hormones. Effects on cell proliferation, differentiation, blood flow and gastric motility are also reviewed. Finally, we outline PACAP's involvement and changes in various human pathological conditions. PMID- 29615976 TI - Higher Prevalence of "Low T3 Syndrome" in Patients With Chronic Fatigue Syndrome: A Case-Control Study. AB - Chronic fatigue syndrome (CFS) is a heterogeneous disease with unknown cause(s). CFS symptoms resemble a hypothyroid state, possibly secondary to chronic (low grade) (metabolic) inflammation. We studied 98 CFS patients (21-69 years, 21 males) and 99 age- and sex-matched controls (19-65 years, 23 males). We measured parameters of thyroid function, (metabolic) inflammation, gut wall integrity and nutrients influencing thyroid function and/or inflammation. Most remarkably, CFS patients exhibited similar thyrotropin, but lower free triiodothyronine (FT3) (difference of medians 0.1%), total thyroxine (TT4) (11.9%), total triiodothyronine (TT3) (12.5%), %TT3 (4.7%), sum activity of deiodinases (14.4%), secretory capacity of the thyroid gland (14.9%), 24-h urinary iodine (27.6%), and higher % reverse T3 (rT3) (13.3%). FT3 below the reference range, consistent with the "low T3 syndrome," was found in 16/98 CFS patients vs. 7/99 controls (OR 2.56; 95% confidence interval = 1.00-6.54). Most observations persisted in two sensitivity analyses with more stringent cutoff values for body mass index, high sensitive C-reactive protein (hsCRP), and WBC. We found possible evidence of (chronic) low-grade metabolic inflammation (ferritin and HDL-C). FT3, TT3, TT4, and rT3 correlated positively with hsCRP in CFS patients and all subjects. TT3 and TT4 were positively related to hsCRP in controls. Low circulating T3 and the apparent shift from T3 to rT3 may reflect more severely depressed tissue T3 levels. The present findings might be in line with recent metabolomic studies pointing at a hypometabolic state. They resemble a mild form of "non-thyroidal illness syndrome" and "low T3 syndrome" experienced by a subgroup of hypothyroid patients receiving T4 monotherapy. Our study needs confirmation and extension by others. If confirmed, trials with, e.g., T3 and iodide supplements might be indicated. PMID- 29615977 TI - Overview of the Pathophysiological Implications of Organotins on the Endocrine System. AB - Organotins (OTs) are pollutants that are used widely by industry as disinfectants, pesticides, and most frequently as biocides in antifouling paints. This mini-review presents the main evidences from the literature about morphophysiological changes induced by OTs in the mammal endocrine system, focusing on the metabolism and reproductive control. Similar to other toxic compounds, the main effects with potential health risks to humans and experimental animals are not only related to dose and time of exposure but also to age, gender, and tissue/cell exposed. Regarding the underlying mechanisms, current literature indicates that OTs can directly damage endocrine glands, as well as interfere with neurohormonal control of endocrine function (i.e., in the hypothalamic-pituitary axis), altering hormone synthesis and/or bioavailability or activity of hormone receptors in the target cells. Importantly, OTs induces biochemical and morphological changes in gonads, abnormal steroidogenesis, both associated with reproductive dysfunctions such as irregular estrous cyclicity in female or spermatogenic disorders in male animals. Additionally, due to their role on endocrine systems predisposing to obesity, OTs are also included in the metabolism disrupting chemical hypothesis, either by central (e.g., accurate nucleus and lateral hypothalamus) or peripheral (e.g., adipose tissue) mechanisms. Thus, OTs should be indeed considered a major endocrine disruptor, being indispensable to understand the main toxic effects on the different tissues and its causative role for endocrine, metabolic, and reproductive dysfunctions observed. PMID- 29615978 TI - Genome-Wide Analyses Identify Filamin-A As a Novel Downstream Target for Insulin and IGF1 Action. AB - Insulin analogs were developed to improve diabetes therapy. However, certain modifications introduced into the insulin molecule were shown to enhance their affinity to the insulin-like growth factor-1 receptor (IGF1R). Most tumors, including endometrial cancers, express high levels of IGF1R. The present study was aimed at identifying the entire set of genes that are differentially activated by insulin glargine or detemir, in comparison to insulin and IGF1, in Type 1 and Type 2 endometrial cancer cell lines (ECC-1 and USPC-1, respectively). Global gene expression analyses demonstrated a ligand-dependent upregulated expression of filamin-A (FLNA), a gene that encodes an actin filament cross linking protein, in both endometrial cancer cell types. Silencing experiments linked to migration assays confirmed the role of FLNA in cell growth and motility. Our data suggest that the activation of distinct sets of genes by glargine may lead to stimulation of specific pathways or, alternatively, may provide additive effects, different from those classically induced by insulin. Given that metastases are probably the main factor contributing to tumor invasiveness, the identification of FLNA as a downstream target for insulin-like hormones may be of translational relevance in oncology. Clinical studies in endometrial cancer may add further relevant information regarding the possible differential actions of insulin analogs with respect to native insulin. PMID- 29615979 TI - Landscape of Molecular Events in Pituitary Apoplexy. AB - Apoplectic pituitary adenomas cause significant morbidity and even mortality. The pituitary apoplexy denotes a pituitary adenoma presenting with hemorrhage and/or infarction, implementation in remedial effects of various of drugs in pituitary apoplexy is a promising pharmacogenomic field in the near future adenoma treatment. Indisputably, this is an important horizon for complicated pituitary adenomas. In a pituitary adenoma, the interplay between genetic, cytokine, and growth factors promotes the pathogenic transformation into an apoplectic formation. However, till date, little is known about how all these factors together lead to the pathogenesis of apoplectic pituitary. The vascular endothelial growth factor, tumor necrosis factor-alpha (TNF-alpha), pituitary tumor-transforming gene (PTTG), matrix metalloproteinase-2/9 (MMP-2/9), proliferating marker (Ki-67), as well as hypoxia-inducing factor are the major contributing factors involved in pituitary apoplexy. The molecular mechanism involved in pituitary apoplexy has never been described so far. In this review, we discuss the various proteins/cytokines/growth factors and signaling molecules which are involved in the pathogenesis of pituitary apoplexy and their potential role as biomarkers or as therapeutic targets. PMID- 29615980 TI - Histamine Regulates Molecular Clock Oscillations in Human Retinal Pigment Epithelial Cells via H1 Receptors. AB - Vertebrate eyes are known to contain circadian clocks, but their regulatory mechanisms remain largely unknown. To address this, we used a cell line from human retinal pigment epithelium (hRPE-YC) with stable coexpression of reporters for molecular clock oscillations (Bmal1-luciferase) and intracellular Ca2+ concentrations (YC3.6). We observed concentration-dependent increases in cytosolic Ca2+ concentrations after treatment with histamine (1-100 uM) and complete suppression of histamine-induced Ca2+ mobilizations by H1 histamine receptor (H1R) antagonist d-chlorpheniramine (d-CPA) in hRPE-YC cells. Consistently, real-time RT-PCR assays revealed that H1R showed the highest expression among the four subtypes (H1-H4) of histamine receptors in hRPE-YC cells. Stimulation of hRPE-YC cells with histamine transiently increased nuclear localization of phosphorylated Ca2+/cAMP-response element-binding protein that regulates clock gene transcriptions. Administration of histamine also shifted the Bmal1-luciferase rhythms with a type-1 phase-response curve, similar to previous results with carbachol stimulations. Treatment of hRPE-YC cells with d-CPA or with more specific H1R antagonist, ketotifen, blocked the histamine-induced phase shifts. Furthermore, an H2 histamine receptor agonist, amthamine, had little effect on the Bmal1-luciferase rhythms. Although the function of the in vivo histaminergic system within the eye remains obscure, the present results suggest histaminergic control of the molecular clock via H1R in retinal pigment epithelial cells. Also, since d-CPA and ketotifen have been widely used (e.g., to treat allergy and inflammation) in our daily life and thus raise a possible cause for circadian rhythm disorders by improper use of antihistamines. PMID- 29615981 TI - Editorial: Non-Coding RNAs: Entwining Metabolism and Aging. PMID- 29615982 TI - Effects of Oleacein on High-Fat Diet-Dependent Steatosis, Weight Gain, and Insulin Resistance in Mice. AB - Many reports indicate that the protective action of nutraceuticals in the Mediterranean diet, against metabolic and cardiovascular diseases, can be attributed to the action of polyphenolic components of extra-virgin olive oil (EVOO). Here, we evaluated the protective effects of oleacein, one of the most abundant secoiridoids in EVOO, on the damages/metabolic alterations caused by high-fat diet (HFD) in male C57BL/6JolaHsd mice. After 5 weeks of treatment with 20 mg/kg of oleacein, body weight, glycemia, insulinemia, serum lipids, and histologic examination of liver tissue indicated a protective action of oleacein against abdominal fat accumulation, weight gain, and liver steatosis, with improvement of insulin-dependent glucose and lipid metabolism. Both serum parameters and hepatic histologic examination were altered in mice fed with HFD. By contrast, in the animals that received oleacein, plasma glucose, cholesterol and triglyceride serum levels, and liver histology were similar to controls fed with normocaloric diet. In addition, protein levels of FAS, SREBP-1, and phospho ERK in liver were positively modulated by oleacein, indicating an improvement in liver insulin sensitivity. In a group of obese mice, treatment with oleacein determined a light, but still significant reduction of the increase in body weight, mainly due to lesser liver steatosis enlargement, associated with reduced levels of SREBP-1 and phospho-ERK and lower levels of total serum cholesterol; in these animals, altered plasma glucose and triglyceride serum levels were not reverted by oleacein. These results indicate that HFD-related hepatic insulin resistance may be partially prevented by oral administration of oleacein, suggesting a protective role of this nutraceutical against diet-dependent metabolic alterations. Additional studies are necessary to check whether oleacein can be used as an adjuvant to improve insulin sensitivity in humans. PMID- 29615983 TI - Spaceflight Modifies Escherichia coli Gene Expression in Response to Antibiotic Exposure and Reveals Role of Oxidative Stress Response. AB - Bacteria grown in space experiments under microgravity conditions have been found to undergo unique physiological responses, ranging from modified cell morphology and growth dynamics to a putative increased tolerance to antibiotics. A common theory for this behavior is the loss of gravity-driven convection processes in the orbital environment, resulting in both reduction of extracellular nutrient availability and the accumulation of bacterial byproducts near the cell. To further characterize the responses, this study investigated the transcriptomic response of Escherichia coli to both microgravity and antibiotic concentration. E. coli was grown aboard International Space Station in the presence of increasing concentrations of the antibiotic gentamicin with identical ground controls conducted on Earth. Here we show that within 49 h of being cultured, E. coli adapted to grow at higher antibiotic concentrations in space compared to Earth, and demonstrated consistent changes in expression of 63 genes in response to an increase in drug concentration in both environments, including specific responses related to oxidative stress and starvation response. Additionally, we find 50 stress-response genes upregulated in response to the microgravity when compared directly to the equivalent concentration in the ground control. We conclude that the increased antibiotic tolerance in microgravity may be attributed not only to diminished transport processes, but also to a resultant antibiotic cross-resistance response conferred by an overlapping effect of stress response genes. Our data suggest that direct stresses of nutrient starvation and acid-shock conveyed by the microgravity environment can incidentally upregulate stress response pathways related to antibiotic stress and in doing so contribute to the increased antibiotic stress tolerance observed for bacteria in space experiments. These results provide insights into the ability of bacteria to adapt under extreme stress conditions and potential strategies to prevent antimicrobial resistance in space and on Earth. PMID- 29615984 TI - Mycobiome of Cysts of the Soybean Cyst Nematode Under Long Term Crop Rotation. AB - The soybean cyst nematode (SCN), Heterodera glycines Ichinohe (Phylum Nematoda), is a major pathogen of soybean. It causes substantial yield losses worldwide and is difficult to control because the cyst protects the eggs which can remain viable for nearly a decade. Crop rotation with non-host crops and use of biocontrol organisms such as fungi and bacteria offer promising approaches, but remain hampered by lack of knowledge of the biology of nematode parasitic organisms. We used a high-throughput metabarcoding approach to characterize fungal communities associated with the SCN cyst, a microenvironment in soil that may harbor both nematode parasites and plant pathogens. SCN cysts were collected from a long-term crop rotation experiment in Southeastern Minnesota at three time points over two growing seasons to characterize diversity of fungi inhabiting cysts and to examine how crop rotation and seasonal variation affects fungal communities. A majority of fungi in cysts belonged to Ascomycota and Basidiomycota, but the presence of several early diverging fungal subphyla thought to be primarily plant and litter associated, including Mortierellomycotina and Glomeromycotina (e.g., arbuscular mycorrhizal fungi), suggests a possible role as nematode egg parasites. Species richness varied by both crop rotation and season and was higher in early years of crop rotation and in fall at the end of the growing season. Crop rotation and season also impacted fungal community composition and identified several classes of fungi, including Eurotiomycetes, Sordariomycetes, and Orbiliomycetes (e.g., nematode trapping fungi), with higher relative abundance in early soybean rotations. The relative abundance of several genera was correlated with increasing years of soybean. Fungal communities also varied by season and were most divergent at midseason. The percentage of OTUs assigned to Mortierellomycotina_cls_Incertae_sedis and Sordariomycetes increased at midseason, while Orbiliomycetes decreased at midseason, and Glomeromycetes increased in fall. Ecological guilds of fungi containing an animal-pathogen lifestyle, as well as potential egg-parasitic taxa previously isolated from parasitized SCN eggs, increased at midseason. The animal pathogen guilds included known (e.g., Pochonia chlamydosporia) and new candidate biocontrol organisms. This research advances knowledge of the ecology of nematophagous fungi in agroecosystems and their use as biocontrol agents of the SCN. PMID- 29615985 TI - Analysis of Mouse Brain Transcriptome After Experimental Duvenhage Virus Infection Shows Activation of Innate Immune Response and Pyroptotic Cell Death Pathway. AB - Rabies is an important neglected disease, characterized by invariably fatal encephalitis. Several studies focus on understanding the pathogenic mechanisms of the prototype lyssavirus rabies virus (RABV) infection, and little is known about the pathogenesis of rabies caused by other lyssaviruses. We sought to characterize the host response to Duvenhage virus infection and compare it with responses observed during RABV infection by gene expression profiling of brains of mice with the respective infections. We found in both infections differentially expressed genes leading to increased expression of type I interferons (IFNs), chemokines, and proinflammatory cytokines. In addition several genes of the IFN signaling pathway are up-regulated, indicating a strong antiviral response and activation of the negative feedback mechanism to limit type I IFN responses. Furthermore we provide evidence that in the absence of significant neuronal apoptotic death, cell death of neurons is mediated via the pyroptotic pathway in both infections. Taken together, we have identified several genes and/or pathways for both infections that could be used to explore novel approaches for intervention strategies against rabies. PMID- 29615986 TI - Whole Genome Sequencing and Multiplex qPCR Methods to Identify Campylobacter jejuni Encoding cst-II or cst-III Sialyltransferase. AB - Campylobacter jejuni causes more than 2 million cases of gastroenteritis annually in the United States, and is also linked to the autoimmune sequelae Guillan-Barre syndrome (GBS). GBS often results in flaccid paralysis, as the myelin sheaths of nerve cells are degraded by the adaptive immune response. Certain strains of C. jejuni modify their lipooligosaccharide (LOS) with the addition of neuraminic acid, resulting in LOS moieties that are structurally similar to gangliosides present on nerve cells. This can trigger GBS in a susceptible host, as antibodies generated against C. jejuni can cross-react with gangliosides, leading to demyelination of nerves and a loss of signal transduction. The goal of this study was to develop a quantitative PCR (qPCR) method and use whole genome sequencing data to detect the Campylobacter sialyltransferase (cst) genes responsible for the addition of neuraminic acid to LOS. The qPCR method was used to screen a library of 89 C. jejuni field samples collected by the Food and Drug Administration Pacific Northwest Lab (PNL) as well as clinical isolates transferred to PNL. In silico analysis was used to screen 827 C. jejuni genomes in the FDA GenomeTrakr SRA database. The results indicate that a majority of C. jejuni strains could produce LOS with ganglioside mimicry, as 43.8% of PNL isolates and 46.9% of the GenomeTrakr isolates lacked the cst genes. The methods described in this study can be used by public health laboratories to rapidly determine whether a C. jejuni isolate has the potential to induce GBS. Based on these results, a majority of C. jejuni in the PNL collection and submitted to GenomeTrakr have the potential to produce LOS that mimics human gangliosides. PMID- 29615987 TI - Mutacin 1140 Lantibiotic Variants Are Efficacious Against Clostridium difficile Infection. AB - Lantibiotics offer an untapped pipeline for the development of novel antibiotics to treat serious Gram-positive (+) infections including Clostridium difficile. Mutacin 1140 (MU1140) is a lantibiotic produced by Streptococcus mutans and acts via a novel mechanism of action, which may limit the development of resistance. This study sought to identify a lead compound for the treatment of C. difficile associated diarrhea (CDAD). Compounds were selected from a saturation mutagenesis library of 418 single amino acid variants of MU1140. Compounds were produced by small scale fermentation, purified, characterized and then subjected to a panel of assays aimed at identifying the best performers. The screening assays included: in vitro susceptibility testing [MIC against Micrococcus luteus, Clostridium difficile, vancomycin-resistant enterococci (VRE), Staphylococcus aureus, Streptococcus pneumonia, Mycobacterium phlei, and Pseudomonas aeruginosa; cytotoxicity screening on HepG2 hepatocytes; in vitro pharmacological profiling with the Safety Screen 44TM, metabolic and chemical stability in biologically relevant fluids (FaSSGF, FaSSIF and serum); and efficacy in vivo]. Several lantibiotic compounds had better MIC against C. difficile, compared to vancomycin, but not against other bacterial species tested. The Safety Screen 44TMin vitro pharmacological profiling assay suggested that this class of compounds has relatively low overall toxicity and that compound OG253 (MU1140, Phe1Ile) is not likely to present inadvertent off-target effects, as evidenced by a low promiscuity score. The in vitro cytotoxicity assay also indicated that this class of compounds was characterized by low toxicity; the EC50 of OG253 was 636 mg/mL on HepG2 cells. The half-life in simulated gastric fluid was >240 min. for all compound tested. The stability in simulated intestinal fluid ranged between a half-life of 5 min to >240 min, and paralleled the half-life in serum. OG253 ultimately emerged as the lead compound based on superior in vivo efficacy along with an apparent lack of relapse in a hamster model of infection. The lessons learned from this report are applicable to therapeutic lanthipeptides in general and may assist in the design of novel molecules with improved pharmacological, therapeutic and physicochemical profiles. The data presented also support the continued clinical development of OG253 as a novel antibiotic against CDAD that could prevent recurrence of the infection. PMID- 29615988 TI - Parallel Evolution of High-Level Aminoglycoside Resistance in Escherichia coli Under Low and High Mutation Supply Rates. AB - Antibiotic resistance is a major concern in public health worldwide, thus there is much interest in characterizing the mutational pathways through which susceptible bacteria evolve resistance. Here we use experimental evolution to explore the mutational pathways toward aminoglycoside resistance, using gentamicin as a model, under low and high mutation supply rates. Our results show that both normo and hypermutable strains of Escherichia coli are able to develop resistance to drug dosages > 1,000-fold higher than the minimal inhibitory concentration for their ancestors. Interestingly, such level of resistance was often associated with changes in susceptibility to other antibiotics, most prominently with increased resistance to fosfomycin. Whole-genome sequencing revealed that all resistant derivatives presented diverse mutations in five common genetic elements: fhuA, fusA and the atpIBEFHAGDC, cyoABCDE, and potABCD operons. Despite the large number of mutations acquired, hypermutable strains did not pay, apparently, fitness cost. In contrast to recent studies, we found that the mutation supply rate mainly affected the speed (tempo) but not the pattern (mode) of evolution: both backgrounds acquired the mutations in the same order, although the hypermutator strain did it faster. This observation is compatible with the adaptive landscape for high-level gentamicin resistance being relatively smooth, with few local maxima; which might be a common feature among antibiotics for which resistance involves multiple loci. PMID- 29615990 TI - The Role of Strigolactone in the Cross-Talk Between Arabidopsis thaliana and the Endophytic Fungus Mucor sp. AB - Over the last years the role of fungal endophytes in plant biology has been extensively studied. A number of species were shown to positively affect plant growth and fitness, thus attempts have been made to utilize these microorganisms in agriculture and phytoremediation. Plant-fungi symbiosis requires multiple metabolic adjustments of both of the interacting organisms. The mechanisms of these adaptations are mostly unknown, however, plant hormones seem to play a central role in this process. The plant hormone strigolactone (SL) was previously shown to activate hyphae branching of mycorrhizal fungi and to negatively affect pathogenic fungi growth. Its role in the plant-endophytic fungi interaction is unknown. The effect of the synthetic SL analog GR24 on the endophytic fungi Mucor sp. growth, respiration, H2O2 production and the activity of antioxidant enzymes was evaluated. We found fungi colony growth rate was decreased in a GR24 concentration dependent manner. Additionally, the fungi accumulated more H2O2 what was accompanied by an altered activity of antioxidant enzymes. Symbiosis with Mucor sp. positively affected Arabidopsis thaliana growth, but SL was necessary for the establishment of the beneficial interaction. A. thaliana biosynthesis mutants max1 and max4, but not the SL signaling mutant max2 did not develop the beneficial phenotype. The negative growth response was correlated with alterations in SA homeostasis and a significant upregulation of genes encoding selected plant defensins. The fungi were also shown to be able to decompose SL in planta and to downregulate the expression of SL biosynthesis genes. Additionally, we have shown that GR24 treatment with a dose of 1 MUM activates the production of SA in A. thaliana. The results presented here provide evidence for a role of SL in the plant-endophyte cross-talk during the mutualistic interaction between Arabidopsis thaliana and Mucor sp. PMID- 29615989 TI - Intestinal Pathogenic Escherichia coli: Insights for Vaccine Development. AB - Diarrheal diseases are one of the major causes of mortality among children under five years old and intestinal pathogenic Escherichia coli (InPEC) plays a role as one of the large causative groups of these infections worldwide. InPECs contribute significantly to the burden of intestinal diseases, which are a critical issue in low- and middle-income countries (Asia, Africa and Latin America). Intestinal pathotypes such as enteropathogenic E. coli (EPEC) and enterotoxigenic E. coli (ETEC) are mainly endemic in developing countries, while ETEC strains are the major cause of diarrhea in travelers to these countries. On the other hand, enterohemorrhagic E. coli (EHEC) are the cause of large outbreaks around the world, mainly affecting developed countries and responsible for not only diarrheal disease but also severe clinical complications like hemorrhagic colitis and hemolytic uremic syndrome (HUS). Overall, the emergence of antibiotic resistant strains, the annual cost increase in the health care system, the high incidence of traveler diarrhea and the increased number of HUS episodes have raised the need for effective preventive treatments. Although the use of antibiotics is still important in treating such infections, non-antibiotic strategies are either a crucial option to limit the increase in antibiotic resistant strains or absolutely necessary for diseases such as those caused by EHEC infections, for which antibiotic therapies are not recommended. Among non antibiotic therapies, vaccine development is a strategy of choice but, to date, there is no effective licensed vaccine against InPEC infections. For several years, there has been a sustained effort to identify efficacious vaccine candidates able to reduce the burden of diarrheal disease. The aim of this review is to summarize recent milestones and insights in vaccine development against InPECs. PMID- 29615991 TI - HTLV-1: Regulating the Balance Between Proviral Latency and Reactivation. AB - HTLV-1 plus-strand transcription begins with the production of doubly-spliced tax/rex transcripts, the levels of which are usually undetectable in freshly isolated peripheral blood mononuclear cells (PBMCs) from HTLV-1-infected individuals. However, the presence of a sustained chronically active cytotoxic T cell response to HTLV-1 antigens in virtually all HTLV-1-infected individuals, regardless of their proviral load, argues against complete latency of the virus in vivo. There is an immediate burst of plus-strand transcription when blood from infected individuals is cultured ex vivo. How is the HTLV-1 plus strand silenced in PBMCs? Is it silenced in other anatomical compartments within the host? What reactivates the latent provirus in fresh PBMCs? While plus-strand transcription of the provirus appears to be intermittent, the minus-strand hbz transcripts are present in a majority of cells, albeit at low levels. What regulates the difference between the 5'- and 3'-LTR promoter activities and thereby the tax-hbz interplay? Finally, T lymphocytes are a migratory population of cells that encounter variable environments in different compartments of the body. Could these micro-environment changes influence the reactivation kinetics of the provirus? In this review we discuss the questions raised above, focusing on the early events leading to HTLV-1 reactivation from latency, and suggest future research directions. PMID- 29615992 TI - Epstein-Barr Virus Acquires Its Final Envelope on Intracellular Compartments With Golgi Markers. AB - Herpesvirus subfamilies typically acquire their final envelope in various cytoplasmic compartments such as the trans-Golgi network (TGN), and endosomes prior to their secretion into the extracellular space. However, the sites for the final envelopment of Epstein-Barr virus (EBV), a ubiquitous human gamma herpesvirus, are poorly understood. Here, we characterized the sites for the final envelopment of EBV in Burkitt's lymphoma cell lines induced into the lytic cycle by crosslinking cell surface IgG. Electron microscopy revealed the various stages of maturation and egress of progeny virions including mature EBV in irregular cytoplasmic vesicles. Immunofluorescence staining showed that gp350/220, the major EBV glycoprotein, and the viral capsid antigen, p18, efficiently colocalized with a cis-Golgi marker, GM130. gp350/220 partly colocalized with the TGN, which was distributed in a fragmented and dispersed pattern in the cells induced into the lytic cycle. In contrast, limited colocalization was observed between gp350/220 and endosomal markers, such as a multi-vesicular bodies marker, CD63, a recycling endosome marker, Rab11, and a regulatory secretion vesicles marker, Rab27a. Finally, we observed that treatment of cells with brefeldin A, an inhibitor of vesicle trafficking between the endoplasmic reticulum and Golgi apparatus, resulted in the perinuclear accumulation of gp350/220 and inhibition of its distribution to the plasma membrane. Brefeldin A also inhibited the release of infectious EBV. Taken together, our findings support a model in which EBV acquires its final envelope in intracellular compartments containing markers of Golgi apparatus, providing new insights into how EBV matures. PMID- 29615993 TI - Antibacterial Activity of Glutathione-Stabilized Silver Nanoparticles Against Campylobacter Multidrug-Resistant Strains. AB - Campylobacter is the leading cause of bacterial diarrheal disease worldwide. Although most episodes of campylobacteriosis are self-limiting, antibiotic treatment is usually needed in patients with serious enteritis, and especially in childrens or the elderly. In the last years, antibiotic resistance in Campylobacter has become a major public health concern and a great interest exists in developing new antimicrobial strategies for reducing the impact of this food-borne pathogen on human health. Among them, the use of silver nanoparticles as antibacterial agents has taken on increased importance in the field of medicine. The aim of the present study was to evaluate the antimicrobial effectiveness of glutathione-stabilized silver nanoparticles (GSH-Ag NPs) against multidrug resistant (MDR) Campylobacter strains isolated from the chicken food chain (FC) and clinical patients (C). The results obtained showed that GSH-Ag NPs were highly effective against all MDR Campylobacter strains tested. The minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) were in a range from 4.92 to 39.4 MUg/mL and 9.85 to 39.4 MUg/mL, respectively. Cytotoxicity assays were also assessed using human intestinal HT-29, Caco-2, and CCD-18 epithelial cells. Exposure of GSH-Ag NPs to intestinal cells showed a dose dependent cytotoxic effect in all cell lines between 9.85 and 39.4 MUg/mL. More than 60% of the tested Campylobacter strains were susceptible to GSH-Ag NPs concentrations <= 9.85 MUg/mL, suggesting that practical inhibitory levels could be reached at low GSH-Ag NPs concentrations. Further works are needed with the purpose to evaluate the practical implications of the toxicity studies and to know more about other attributes linked to the biological compatibility. This behavior makes GSH-Ag NPs as a promising tool for the design of novel antibacterial agents for controlling Campylobacter. PMID- 29615994 TI - Hepatitis E Virus Induces Hepatocyte Apoptosis via Mitochondrial Pathway in Mongolian Gerbils. AB - Previous studies demonstrated that Mongolian gerbils can be infected by hepatitis E virus (HEV), which induces the hepatic injury. Here, the mitochondria in hepatocytes from HEV-infected gerbils were considerably swollen, thin cristae. After HEV infection, the activity of superoxide dismutase significantly decreased (p < 0.01), while malondialdehyde concentrations significantly increased, compared with those in the control group (p < 0.01). Adenosine triphosphatase levels decreased significantly in the hepatocyte of the inoculated groups, compared with those in control group (p < 0.05) at days 21, 28, 42 post inoculation (dpi) as well. Furthermore, the levels of ATP synthetase ATP5A1 significantly decreased during HEV infection, compared with those in the control group (p < 0.05). According to the TdT mediated dUTP nick end labeling (TUNEL) detection, TUNEL positive hepatocytes increased in the inoculated group, compared with that in the control group (p < 0.05). Up-regulation of the mitochondrion mediated apoptosis regulating proteins, Bax and Bcl-2, in the HEV-infected gerbils (p < 0.05) was observed. However, cytochrome c levels in mitochondria decreased, while this molecule was detected in the cytoplasm of the infected animals, in contrast to that in the control group. Apaf-1, and active caspase-9 and -3 levels were shown to be significantly higher in the inoculated group compared with those in the control group (p < 0.05). Taken together, our results demonstrated that HEV infection induces hepatocyte injuries and activity of the mitochondrial apoptotic pathway, which trigger the hepatocyte apoptosis in Mongolian gerbils. PMID- 29615995 TI - HTLV-1 Alters T Cells for Viral Persistence and Transmission. AB - Human T-cell leukemia virus type 1 (HTLV-1) was the first retrovirus to be discovered as a causative agent of adult T-cell leukemia-lymphoma (ATL) and chronic inflammatory diseases. Two viral factors, Tax and HTLV-1 bZIP factor (HBZ), are thought to be involved in the leukemogenesis of ATL. Tax expression is frequently lost due to DNA methylation in the promoter region, genetic changes to the tax gene, and deletion of the 5' long terminal repeat (LTR) in approximately half of all ATL cases. On the other hand, HBZ is expressed in all ATL cases. HBZ is known to function in both protein form and mRNA form, and both forms play an important role in the oncogenic process of HTLV-1. HBZ protein has a variety of functions, including the suppression of apoptosis, the promotion of proliferation, and the impairment of anti-viral activity, through the interaction with several host cellular proteins including p300/CBP, Foxp3, and Foxo3a. These functions dramatically modify the transcriptional profiling of host T cells. HBZ mRNA also promotes T cell proliferation and viability. HBZ changes infected T cells to CCR4+TIGIT+CD4+ effector/memory T cells. This unique immunophenotype enables T cells to migrate into various organs and tissues and to survive in vivo. In this review, we summarize how HBZ hijacks the transcriptional networks and immune systems of host T cells to contribute to HTLV-1 pathogenesis on the basis of recent new findings about HBZ and tax. PMID- 29615996 TI - Effect of Oxygen on Verbenone Conversion From cis-Verbenol by Gut Facultative Anaerobes of Dendroctonus valens. AB - Since its introduction from North America, Dendroctonus valens LeConte has become a destructive forest pest in China. Although gut aerobic bacteria have been investigated and some are implicated in beetle pheromone production, little is known about the abundance and significance of facultative anaerobic bacteria in beetle gut, especially with regards to effects of oxygen on their role in pheromone production. In this study, we isolated and identified gut bacteria of D. valens adults in an anaerobic environment, and further compared their ability to convert cis-verbenol into verbenone (a multi-functional pheromone of D. valens) under different O2 concentrations. Pantoea conspicua, Enterobacter xiangfangensis, Staphylococcus warneri were the most frequently isolated species among the total of 10 species identified from beetle gut in anaerobic conditions. Among all isolated species, nine were capable of cis-verbenol to verbenone conversion, and the conversion efficiency increased with increased oxygen concentration. This O2-mediated conversion of cis-verbenol to verbenone suggests that gut facultative anaerobes of D. valens might play an important role in the frass, where there is higher exposure to oxygen, hence the higher verbenone production. This claim is further supported by distinctly differential oxygen concentrations between gut and frass of D. valens females. PMID- 29615997 TI - The Skin Microbiome of the Neotropical Frog Craugastor fitzingeri: Inferring Potential Bacterial-Host-Pathogen Interactions From Metagenomic Data. AB - Skin symbiotic bacteria on amphibians can play a role in protecting their host against pathogens. Chytridiomycosis, the disease caused by Batrachochytrium dendrobatidis, Bd, has caused dramatic population declines and extinctions of amphibians worldwide. Anti-Bd bacteria from amphibian skin have been cultured, and skin bacterial communities have been described through 16S rRNA gene amplicon sequencing. Here, we present a shotgun metagenomic analysis of skin bacterial communities from a Neotropical frog, Craugastor fitzingeri. We sequenced the metagenome of six frogs from two different sites in Panama: three frogs from Soberania (Sob), a Bd-endemic site, and three frogs from Serrania del Sapo (Sapo), a Bd-naive site. We described the taxonomic composition of skin microbiomes and found that Pseudomonas was a major component of these communities. We also identified that Sob communities were enriched in Actinobacteria while Sapo communities were enriched in Gammaproteobacteria. We described gene abundances within the main functional classes and found genes enriched either in Sapo or Sob. We then focused our study on five functional classes of genes: biosynthesis of secondary metabolites, metabolism of terpenoids and polyketides, membrane transport, cellular communication and antimicrobial drug resistance. These gene classes are potentially involved in bacterial communication, bacterial-host and bacterial-pathogen interactions among other functions. We found that C. fitzingeri metagenomes have a wide array of genes that code for secondary metabolites, including antibiotics and bacterial toxins, which may be involved in bacterial communication, but could also have a defensive role against pathogens. Several genes involved in bacterial communication and bacterial-host interactions, such as biofilm formation and bacterial secretion systems were found. We identified specific genes and pathways enriched at the different sites and determined that gene co-occurrence networks differed between sites. Our results suggest that skin microbiomes are composed of distinct bacterial taxa with a wide range of metabolic capabilities involved in bacterial defense and communication. Differences in taxonomic composition and pathway enrichments suggest that skin microbiomes from different sites have unique functional properties. This study strongly supports the need for shotgun metagenomic analyses to describe the functional capacities of skin microbiomes and to tease apart their role in host defense against pathogens. PMID- 29615998 TI - PCR-Based Analysis of ColE1 Plasmids in Clinical Isolates and Metagenomic Samples Reveals Their Importance as Gene Capture Platforms. AB - ColE1 plasmids are important vehicles for the spread of antibiotic resistance in the Enterobacteriaceae and Pasteurellaceae families of bacteria. Their monitoring is essential, as they harbor important resistant determinants in humans, animals and the environment. In this work, we have analyzed ColE1 replicons using bioinformatic and experimental approaches. First, we carried out a computational study examining the structure of different ColE1 plasmids deposited in databases. Bioinformatic analysis of these ColE1 replicons revealed a mosaic genetic structure consisting of a host-adapted conserved region responsible for the housekeeping functions of the plasmid, and a variable region encoding a wide variety of genes, including multiple antibiotic resistance determinants. From this exhaustive computational analysis we developed a new PCR-based technique, targeting a specific sequence in the conserved region, for the screening, capture and sequencing of these small plasmids, either specific for Enterobacteriaceae or specific for Pasteurellaceae. To validate this PCR-based system, we tested various collections of isolates from both bacterial families, finding that ColE1 replicons were not only highly prevalent in antibiotic-resistant isolates, but also present in susceptible bacteria. In Pasteurellaceae, ColE1 plasmids carried almost exclusively antibiotic resistance genes. In Enterobacteriaceae, these plasmids encoded a large range of traits, including not only antibiotic resistance determinants, but also a wide variety of genes, showing the huge genetic plasticity of these small replicons. Finally, we also used a metagenomic approach in order to validate this technique, performing this PCR system using total DNA extractions from fecal samples from poultry, turkeys, pigs and humans. Using Illumina sequencing of the PCR products we identified a great diversity of genes encoded by ColE1 replicons, including different antibiotic resistance determinants, supporting the previous results achieved with the collections of bacterial isolates. In addition, we detected cryptic ColE1 plasmids in both families with no known genes in their variable region, which we have named sentinel plasmids. In conclusion, in this work we present a useful genetic tool for the detection and analysis of ColE1 plasmids, and confirm their important role in the dissemination of antibiotic resistance, especially in the Pasteurellaceae family of bacteria. PMID- 29615999 TI - Prevalence of Thermophilic Campylobacter in Cattle Production at Slaughterhouse Level in France and Link Between C. jejuni Bovine Strains and Campylobacteriosis. AB - Campylobacter is the leading cause of bacterial gastroenteritis in industrialized countries, with poultry reservoir as the main source of infection. Nevertheless, a recent study on source attribution showed that cattle could be a source of human contamination in France (Thepault et al., 2017). However, few data are available on thermophilic Campylobacter epidemiology in cattle in France. The aim of this study is to collect new data of thermophilic Campylobacter prevalence in these animals and to subtype C. jejuni isolates to assess the potential implication of cattle in campylobacteriosis. A 6-month survey was carried out in one of the largest European slaughterhouse of cattle. Based on a statistical representative sampling plan, 959 intestinal content samples (483 adult cattle and 476 calves) were collected. An adapted version of the ISO 10272 standard and Maldi-Tof were used for detection and speciation of thermophilic Campylobacter isolates. Within more than 2000 thermophilic Campylobacter isolates collected, a selection of 649 C. jejuni isolates was typed with Comparative Genomic Fingerprinting (CGF40) and a subset of 77 isolates was typed using Multilocus Sequence Typing (MLST). Simultaneously, clinical isolates occurred in France were genotyped. Prevalence of thermophilic Campylobacter in the global cattle population was 69.1% (CI95% = 66.1, 72.1) at slaughterhouse level. In adult cattle, the prevalence was 39.3%, while 99.4% of calves were contaminated, and C. jejuni was the most prevalent species with prevalence of 37.3 and 98.5%, respectively and a higher genetic diversity in adult cattle. The prevalence of C. coli was lower with 3% in adult cattle and 12.5% in calves. MLST and CGF40 genotyping did not showed a high number of clusters within cattle isolates but the predominance of few clusters accounted for a large part of the population (CC 21, CC-61, CC-48, and CC-257). By comparison with clinical genotypes, genetic diversity was significantly lower in cattle. Moreover, significant overlap was observed between genotypes from both origins, with 3 of the 4 main cattle clusters present in human isolates. This study provides new insights on the epidemiology of thermophilic Campylobacter and C. jejuni in cattle production in France and their potential implication in human infection. PMID- 29616000 TI - PVP-SVM: Sequence-Based Prediction of Phage Virion Proteins Using a Support Vector Machine. AB - Accurately identifying bacteriophage virion proteins from uncharacterized sequences is important to understand interactions between the phage and its host bacteria in order to develop new antibacterial drugs. However, identification of such proteins using experimental techniques is expensive and often time consuming; hence, development of an efficient computational algorithm for the prediction of phage virion proteins (PVPs) prior to in vitro experimentation is needed. Here, we describe a support vector machine (SVM)-based PVP predictor, called PVP-SVM, which was trained with 136 optimal features. A feature selection protocol was employed to identify the optimal features from a large set that included amino acid composition, dipeptide composition, atomic composition, physicochemical properties, and chain-transition-distribution. PVP-SVM achieved an accuracy of 0.870 during leave-one-out cross-validation, which was 6% higher than control SVM predictors trained with all features, indicating the efficiency of the feature selection method. Furthermore, PVP-SVM displayed superior performance compared to the currently available method, PVPred, and two other machine-learning methods developed in this study when objectively evaluated with an independent dataset. For the convenience of the scientific community, a user friendly and publicly accessible web server has been established at www.thegleelab.org/PVP-SVM/PVP-SVM.html. PMID- 29616001 TI - Dissemination of KPC-2-Encoding IncX6 Plasmids Among Multiple Enterobacteriaceae Species in a Single Chinese Hospital. AB - Forty-five KPC-producing Enterobacteriaceae strains were isolated from multiple departments in a Chinese public hospital from 2014 to 2015. Genome sequencing of four representative strains, namely Proteus mirabilis GN2, Serratia marcescens GN26, Morganella morganii GN28, and Klebsiella aerogenes E20, indicated the presence of blaKPC-2-carrying IncX6 plasmids pGN2-KPC, pGN26-KPC, pGN28-KPC, and pE20-KPC in the four strains, respectively. These plasmids were genetically closely related to one another and to the only previously sequenced IncX6 plasmid, pKPC3_SZ. Each of the plasmids carried a single accessory module containing the blaKPC-2/3-carrying DeltaTn6296 derivatives. The DeltaTn6292 element from pGN26-KPC also contained qnrS, which was absent from all other plasmids. Overall, pKPC3_SZ-like blaKPC-carrying IncX6 plasmids were detected by PCR in 44.4% of the KPC-producing isolates, which included K. aerogenes, P. mirabilis, S. marcescens, M. morganii, Escherichia coli, and Klebsiella pneumoniae, and were obtained from six different departments of the hospital. Data presented herein provided insights into the genomic diversity and evolution of IncX6 plasmids, as well as the dissemination and epidemiology of blaKPC carrying IncX6 plasmids among Enterobacteriaceae in a hospital setting. PMID- 29616002 TI - Effect of Salt on the Metabolism of 'Candidatus Accumulibacter' Clade I and II. AB - Saline wastewater is known to affect the performance of phosphate-accumulating organisms (PAOs) in enhanced biological phosphorus removal (EBPR) process. However, studies comparing the effect of salinity on different PAO clades are lacking. In this study, 'Candidatus Accumulibacter phosphatis' Clade I and II (hereafter referred to as PAOI and PAOII) were highly enriched (~90% in relative abundance as determined by quantitative FISH) in the form of granules in two sequencing batch reactors. Anaerobic and aerobic batch experiments were conducted to evaluate the effect of salinity on the kinetics and stoichiometry of PAOI and PAOII. PAOI and PAOII communities showed different priority in using polyphosphate (poly-P) and glycogen to generate ATP in the anaerobic phase when exposed to salt, with PAOI depending more on intracellular poly-P degradation (e.g., the proportion of calculated ATP derived from poly-P increased by 5-6% at 0.256 mol/L NaCl or KCl) while PAOII on glycolysis of intracellularly stored glycogen (e.g., the proportion of calculated ATP derived from glycogen increased by 29-30% at 0.256 mol/L NaCl or KCl). In the aerobic phase, the loss of phosphate uptake capability was more pronounced in PAOII due to the higher energy cost to synthesize their larger glycogen pool compared to PAOI. For both PAOI and PAOII, aerobic conversion rates were more sensitive to salt than anaerobic conversion rates. Potassium (K+) and sodium (Na+) ions exhibited different effect regardless of the enriched PAO culture, suggesting that the composition of salt is an important factor to consider when studying the effect of salt on EBPR performance. PMID- 29616003 TI - Simple Sample Preparation Method for Direct Microbial Identification and Susceptibility Testing From Positive Blood Cultures. AB - Rapid identification and determination of the antibiotic susceptibility profiles of the infectious agents in patients with bloodstream infections are critical steps in choosing an effective targeted antibiotic for treatment. However, there has been minimal effort focused on developing combined methods for the simultaneous direct identification and antibiotic susceptibility determination of bacteria in positive blood cultures. In this study, we constructed a lysis centrifugation-wash procedure to prepare a bacterial pellet from positive blood cultures, which can be used directly for identification by matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry (MALDI-TOF MS) and antibiotic susceptibility testing by the Vitek 2 system. The method was evaluated using a total of 129 clinical bacteria-positive blood cultures. The whole sample preparation process could be completed in <15 min. The correct rate of direct MALDI-TOF MS identification was 96.49% for gram-negative bacteria and 97.22% for gram-positive bacteria. Vitek 2 antimicrobial susceptibility testing of gram negative bacteria showed an agreement rate of antimicrobial categories of 96.89% with a minor error, major error, and very major error rate of 2.63, 0.24, and 0.24%, respectively. Category agreement of antimicrobials against gram-positive bacteria was 92.81%, with a minor error, major error, and very major error rate of 4.51, 1.22, and 1.46%, respectively. These results indicated that our direct antibiotic susceptibility analysis method worked well compared to the conventional culture-dependent laboratory method. Overall, this fast, easy, and accurate method can facilitate the direct identification and antibiotic susceptibility testing of bacteria in positive blood cultures. PMID- 29616004 TI - The Roles of Picornavirus Untranslated Regions in Infection and Innate Immunity. AB - Viral genomes have evolved to maximize their potential of overcoming host defense mechanisms and to induce a variety of disease syndromes. Structurally, a genome of a virus consists of coding and noncoding regions, and both have been shown to contribute to initiation and progression of disease. Accumulated work in picornaviruses has stressed out the importance of the noncoding RNAs, or untranslated 5'- and 3'-regions (UTRs), in both replication and translation of viral genomes. Unsurprisingly, defects in these processes have been reported to cause viral attenuation and affect viral pathogenicity. However, substantial evidence suggests that these untranslated RNAs may influence the outcome of the host innate immune response. This review discusses the involvement of 5'- and 3' terminus UTRs in induction and regulation of host immunity and its consequences for viral life cycle and virulence. PMID- 29616006 TI - Genetic Engineering of Crypthecodinium cohnii to Increase Growth and Lipid Accumulation. AB - In this study, we evaluated suitable selected markers and optimized transformation protocols to develop a new genetic transformation methodology for DHA-producing Crypthecodinium cohnii. Additionally, ribulose 1,5-bisphosphate carboxylase/oxygenase (RuBisCO), potentially involved in CO2 fixation under autotrophic conditions, was selected as the target for construction of a gene knockdown mutant. Our results show that the constructs were successfully inserted into the C. cohnii chromosome by homologous recombination. Comparative analysis showed that deletion of the RuBisCO gene promoted cell growth and increased the lipid content of C. cohnii under heterotrophic conditions compared with those of the wild-type. The liquid chromatography-mass spectrometry (LC-MS) based metabolomic analysis showed that the metabolites involved in energy metabolism were upregulated, suggesting that the deletion of the RuBisCO gene may contribute to the re-direction of more carbon or energy toward growth and lipid accumulation under heterotrophic conditions. PMID- 29616005 TI - A Comparative Analysis of Vibrio cholerae Contamination in Point-of-Drinking and Source Water in a Low-Income Urban Community, Bangladesh. AB - Bangladesh is a cholera endemic country with a population at high risk of cholera. Toxigenic and non-toxigenic Vibrio cholerae (V. cholerae) can cause cholera and cholera-like diarrheal illness and outbreaks. Drinking water is one of the primary routes of cholera transmission in Bangladesh. The aim of this study was to conduct a comparative assessment of the presence of V. cholerae between point-of-drinking water and source water, and to investigate the variability of virulence profile using molecular methods of a densely populated low-income settlement of Dhaka, Bangladesh. Water samples were collected and tested for V. cholerae from "point-of-drinking" and "source" in 477 study households in routine visits at 6 week intervals over a period of 14 months. We studied the virulence profiles of V. cholerae positive water samples using 22 different virulence gene markers present in toxigenic O1/O139 and non-O1/O139 V. cholerae using polymerase chain reaction (PCR). A total of 1,463 water samples were collected, with 1,082 samples from point-of-drinking water in 388 households and 381 samples from 66 water sources. V. cholerae was detected in 10% of point of-drinking water samples and in 9% of source water samples. Twenty-three percent of households and 38% of the sources were positive for V. cholerae in at least one visit. Samples collected from point-of-drinking and linked sources in a 7 day interval showed significantly higher odds (P < 0.05) of V. cholerae presence in point-of-drinking compared to source [OR = 17.24 (95% CI = 7.14-42.89)] water. Based on the 7 day interval data, 53% (17/32) of source water samples were negative for V. cholerae while linked point-of-drinking water samples were positive. There were significantly higher odds (p < 0.05) of the presence of V. cholerae O1 [OR = 9.13 (95% CI = 2.85-29.26)] and V. cholerae O139 [OR = 4.73 (95% CI = 1.19-18.79)] in source water samples than in point-of-drinking water samples. Contamination of water at the point-of-drinking is less likely to depend on the contamination at the water source. Hygiene education interventions and programs should focus and emphasize on water at the point-of-drinking, including repeated cleaning of drinking vessels, which is of paramount importance in preventing cholera. PMID- 29616007 TI - Altered Mycobacterium tuberculosis Cell Wall Metabolism and Physiology Associated With RpoB Mutation H526D. AB - Background:Mycobacterium tuberculosis (Mtb) rpoB mutations are associated with global metabolic remodeling. However, the net effects of rpoB mutations on Mtb physiology, metabolism and function are not completely understood. Based on previous work, we hypothesized that changes in the expression of cell wall molecules in Mtb mutant RpoB 526D lead to changes in cell wall permeability and to altered resistance to environmental stresses and drugs. Methods: The phenotypes of a fully drug-susceptible clinical strain of Mtb and its paired rifampin-monoresistant, RpoB H526D mutant progeny strain were compared. Results: The rpoB mutant showed altered colony morphology, bacillary length and cell wall thickness, which were associated with increased cell wall permeability and susceptibility to the cell wall detergent sodium dodecyl sulfate (SDS) after exposure to nutrient starvation. Relative to the isogenic rifampin-susceptible strain, the RpoB H526D mutant showed altered bacterial cellular metabolic activity and an eightfold increase in susceptibility to the cell-wall acting drug vancomycin. Conclusion: Our data suggest that RpoB mutation H526D is associated with altered cell wall physiology and resistance to cell wall-related stress. These findings are expected to contribute to an improved understanding of the pathogenesis of drug-resistant M. tuberculosis infections. PMID- 29616008 TI - Host Age Affects the Development of Southern Catfish Gut Bacterial Community Divergent From That in the Food and Rearing Water. AB - Host development influences gut microbial assemblies that may be confounded partly by dietary shifts and the changing environmental microbiota during ontogenesis. However, little is known about microbial colonization by excluding dietary effects and compositional differences in microbiota between the gut and environment at different ontogenetic stages. Herein, a developmental gut microbial experiment under controlled laboratory conditions was conducted with carnivorous southern catfish Silurus meridionalis fed on an identical prey with commensal and abundant microbiota. In this study, we provided a long-term analysis of gut microbiota associated with host age at 8, 18, 35, 65, and 125 day post-fertilization (dpf) and explored microbial relationships among host, food and water environment at 8, 35, and 125 dpf. The results showed that gut microbial diversity in southern catfish tended to increase linearly as host aged. Gut microbiota underwent significant temporal shifts despite similar microbial communities in food and rearing water during the host development and dramatically differed from the environmental microbiota. At the compositional abundance, Tenericutes and Fusobacteria were enriched in the gut and markedly varied with host age, whereas Spirochaetes and Bacteroidetes detected were persistently the most abundant phyla in food and water, respectively. In addition to alterations in individual microbial taxa, the individual differences in gut microbiota were at a lower level at the early stages than at the late stages and in which gut microbiota reached a stable status, suggesting the course of microbial successions. These results indicate that host development fundamentally shapes a key transition in microbial community structure, which is independent of dietary effects. In addition, the dominant taxa residing in the gut do not share their niche habitats with the abundant microbiota in the surrounding environment. It's inferred that complex gut microbiota could not be simple reflections of environmental microbiota. The knowledge enhances the understanding of gut microbial establishment in the developing fish and provides a useful resource for such studies of fish- or egg-associated microbiota in aquaculture. PMID- 29616009 TI - Application of Microfluidics in Experimental Ecology: The Importance of Being Spatial. AB - Microfluidics is an emerging technology that is used more and more in biology experiments. Its capabilities of creating precisely controlled conditions in cellular dimensions make it ideal to explore cell-cell and cell-environment interactions. Thus, a wide spectrum of problems in microbial ecology can be studied using engineered microbial habitats. Moreover, artificial microfluidic ecosystems can serve as model systems to test ecology theories and principles that apply on a higher level in the hierarchy of biological organization. In this mini review we aim to demonstrate the versatility of microfluidics and the diversity of its applications that help the advance of microbiology, and in more general, experimental ecology. PMID- 29616010 TI - Outer Membrane Vesicles From Probiotic and Commensal Escherichia coli Activate NOD1-Mediated Immune Responses in Intestinal Epithelial Cells. AB - Gut microbiota plays a critical role in maintaining human intestinal homeostasis and host health. Bacterial extracellular vesicles are key players in bacteria host communication, as they allow delivery of effector molecules into the host cells. Outer membrane vesicles (OMVs) released by Gram-negative bacteria carry many ligands of pattern recognition receptors that are key components of innate immunity. NOD1 and NOD2 cytosolic receptors specifically recognize peptidoglycans present within the bacterial cell wall. These intracellular immune receptors are essential in host defense against bacterial infections and in the regulation of inflammatory responses. Recent contributions show that NODs are also fundamental to maintain intestinal homeostasis and microbiota balance. Peptidoglycan from non invasive pathogens is delivered to cytosolic NODs through OMVs, which are internalized via endocytosis. Whether this pathway could be used by microbiota to activate NOD receptors remains unexplored. Here, we report that OMVs isolated from the probiotic Escherichia coli Nissle 1917 and the commensal ECOR12 activate NOD1 signaling pathways in intestinal epithelial cells. NOD1 silencing and RIP2 inhibition significantly abolished OMV-mediated activation of NF-kappaB and subsequent IL-6 and IL-8 expression. Confocal fluorescence microscopy analysis confirmed that endocytosed OMVs colocalize with NOD1, trigger the formation of NOD1 aggregates, and promote NOD1 association with early endosomes. This study shows for the first time the activation of NOD1-signaling pathways by extracellular vesicles released by gut microbiota. PMID- 29616011 TI - Lipid Bodies as Sites of Prostaglandin E2 Synthesis During Chagas Disease: Impact in the Parasite Escape Mechanism. AB - During Chagas disease, the Trypanosoma cruzi can induce some changes in the host cells in order to escape or manipulate the host immune response. The modulation of the lipid metabolism in the host phagocytes or in the parasite itself is one feature that has been observed. The goal of this mini review is to discuss the mechanisms that regulate intracellular lipid body (LB) biogenesis in the course of this parasite infection and their meaning to the pathophysiology of the disease. The interaction host-parasite induces LB (or lipid droplet) formation in a Toll-like receptor 2-dependent mechanism in macrophages and is enhanced by apoptotic cell uptake. Simultaneously, there is a lipid accumulation in the parasite due to the incorporation of host fatty acids. The increase in the LB accumulation during infection is correlated with an increase in the synthesis of PGE2 within the host cells and the parasite LBs. Moreover, the treatment with fatty acid synthase inhibitor C75 or non-steroidal anti-inflammatory drugs such as NS-398 and aspirin inhibited the LB biogenesis and also induced the down modulation of the eicosanoid production and the parasite replication. These findings show that LBs are organelles up modulated during the course of infection. Furthermore, the biogenesis of the LB is involved in the lipid mediator generation by both the macrophages and the parasite triggering escape mechanisms. PMID- 29616012 TI - Establishment of a Molecular Serotyping Scheme and a Multiplexed Luminex-Based Array for Enterobacter aerogenes. AB - Serotyping based on surface polysaccharide antigens is important for the clinical detection and epidemiological surveillance of pathogens. Polysaccharide gene clusters (PSgcs) are typically responsible for the diversity of bacterial surface polysaccharides. Through whole-genome sequencing and analysis, eight putative PSgc types were identified in 23 Enterobacter aerogenes strains from several geographic areas, allowing us to present the first molecular serotyping system for E. aerogenes. A conventional antigenic scheme was also established and correlated well with the molecular serotyping system that was based on PSgc genetic variation, indicating that PSgc-based molecular typing and immunological serology provide equally valid results. Further, a multiplex Luminex-based array was developed, and a double-blind test was conducted with 97 clinical specimens from Shanghai, China, to validate our array. The results of these analyses indicated that strains containing PSgc4 and PSgc7 comprised the predominant groups. We then examined 86 publicly available E. aerogenes strain genomes and identified an additional seven novel PSgc types, with PSgc10 being the most abundant type. In total, our study identified 15 PSgc types in E. aerogenes, providing the basis for a molecular serotyping scheme. From these results, differing epidemic patterns were identified between strains that were predominant in different regions. Our study highlights the feasibility and reliability of a serotyping system based on PSgc diversity, and for the first time, presents a molecular serotyping system, as well as an antigenic scheme for E. aerogenes, providing the basis for molecular diagnostics and epidemiological surveillance of this important emerging pathogen. PMID- 29616013 TI - Csn5 Is Required for the Conidiogenesis and Pathogenesis of the Alternaria alternata Tangerine Pathotype. AB - The COP9 signalosome (CSN) is a highly conserved protein complex involved in the ubiquitin-proteasome system. Its metalloisopeptidase activity resides in subunit 5 (CSN5). Functions of csn5 in phytopathogenic fungi are poorly understood. Here, we knocked out the csn5 ortholog (Aacsn5) in the tangerine pathotype of Alternaria alternata. The DeltaAacsn5 mutant showed a moderately reduced growth rate compared to the wildtype strain and was unable to produce conidia. The growth of DeltaAacsn5 mutant was not affected in response to oxidative and osmotic stresses. Virulence assays revealed that DeltaAacsn5 induced no or significantly reduced necrotic lesions on detached citrus leaves. The defects in hyphal growth, conidial sporulation, and pathogenicity of DeltaAacsn5 were restored by genetic complementation of the mutant with wildtype Aacsn5. To explore the molecular mechanisms of conidiation and pathogenesis underlying Aacsn5 regulation, we systematically examined the transcriptomes of both DeltaAacsn5 and the wildtype. Generally, 881 genes were overexpressed and 777 were underexpressed in the DeltaAacsn5 mutant during conidiation while 694 overexpressed and 993 underexpressed during infection. During asexual development, genes related to the transport processes and nitrogen metabolism were significantly downregulated; the expression of csn1-4 and csn7 in DeltaAacsn5 was significantly elevated; secondary metabolism gene clusters were broadly affected; especially, the transcript level of the whole of cluster 28 and 30 was strongly induced. During infection, the expression of the host-specific ACT toxin gene cluster which controls the biosynthesis of the citrus specific toxin was significantly repressed; many other SM clusters with unknown products were also regulated; 86 out of 373 carbohydrate-active enzymes responsible for breaking down the plant dead tissues showed uniquely decreased expression. Taken together, our results expand our understanding of the roles of csn5 on conidiation and pathogenicity in plant pathogenic fungi and provide a foundation for future investigations. PMID- 29616014 TI - Routine Whole-Genome Sequencing for Outbreak Investigations of Staphylococcus aureus in a National Reference Center. AB - The French National Reference Center for Staphylococci currently uses DNA arrays and spa typing for the initial epidemiological characterization of Staphylococcus aureus strains. We here describe the use of whole-genome sequencing (WGS) to investigate retrospectively four distinct and virulent S. aureus lineages [clonal complexes (CCs): CC1, CC5, CC8, CC30] involved in hospital and community outbreaks or sporadic infections in France. We used a WGS bioinformatics pipeline based on de novo assembly (reference-free approach), single nucleotide polymorphism analysis, and on the inclusion of epidemiological markers. We examined the phylogeographic diversity of the French dominant hospital-acquired CC8-MRSA (methicillin-resistant S. aureus) Lyon clone through WGS analysis which did not demonstrate evidence of large-scale geographic clustering. We analyzed sporadic cases along with two outbreaks of a CC1-MSSA (methicillin-susceptible S. aureus) clone containing the Panton-Valentine leukocidin (PVL) and results showed that two sporadic cases were closely related. We investigated an outbreak of PVL positive CC30-MSSA in a school environment and were able to reconstruct the transmission history between eight families. We explored different outbreaks among newborns due to the CC5-MRSA Geraldine clone and we found evidence of an unsuspected link between two otherwise distinct outbreaks. Here, WGS provides the resolving power to disprove transmission events indicated by conventional methods (same sequence type, spa type, toxin profile, and antibiotic resistance profile) and, most importantly, WGS can reveal unsuspected transmission events. Therefore, WGS allows to better describe and understand outbreaks and (inter-)national dissemination of S. aureus lineages. Our findings underscore the importance of adding WGS for (inter-)national surveillance of infections caused by virulent clones of S. aureus but also substantiate the fact that technological optimization at the bioinformatics level is still urgently needed for routine use. However, the greatest limitation of WGS analysis is the completeness and the correctness of the reference database being used and the conversion of floods of data into actionable results. The WGS bioinformatics pipeline (EpiSeqTM) we used here can easily generate a uniform database and associated metadata for epidemiological applications. PMID- 29616015 TI - Nitrate-Dependent Iron Oxidation: A Potential Mars Metabolism. AB - This work considers the hypothetical viability of microbial nitrate-dependent Fe2+ oxidation (NDFO) for supporting simple life in the context of the early Mars environment. This draws on knowledge built up over several decades of remote and in situ observation, as well as recent discoveries that have shaped current understanding of early Mars. Our current understanding is that certain early martian environments fulfill several of the key requirements for microbes with NDFO metabolism. First, abundant Fe2+ has been identified on Mars and provides evidence of an accessible electron donor; evidence of anoxia suggests that abiotic Fe2+ oxidation by molecular oxygen would not have interfered and competed with microbial iron metabolism in these environments. Second, nitrate, which can be used by some iron oxidizing microorganisms as an electron acceptor, has also been confirmed in modern aeolian and ancient sediment deposits on Mars. In addition to redox substrates, reservoirs of both organic and inorganic carbon are available for biosynthesis, and geochemical evidence suggests that lacustrine systems during the hydrologically active Noachian period (4.1-3.7 Ga) match the circumneutral pH requirements of nitrate-dependent iron-oxidizing microorganisms. As well as potentially acting as a primary producer in early martian lakes and fluvial systems, the light-independent nature of NDFO suggests that such microbes could have persisted in sub-surface aquifers long after the desiccation of the surface, provided that adequate carbon and nitrates sources were prevalent. Traces of NDFO microorganisms may be preserved in the rock record by biomineralization and cellular encrustation in zones of high Fe2+ concentrations. These processes could produce morphological biosignatures, preserve distinctive Fe-isotope variation patterns, and enhance preservation of biological organic compounds. Such biosignatures could be detectable by future missions to Mars with appropriate instrumentation. PMID- 29616016 TI - Heparan Sulfate Induces Necroptosis in Murine Cardiomyocytes: A Medical-In silico Approach Combining In vitro Experiments and Machine Learning. AB - Life-threatening cardiomyopathy is a severe, but common, complication associated with severe trauma or sepsis. Several signaling pathways involved in apoptosis and necroptosis are linked to trauma- or sepsis-associated cardiomyopathy. However, the underling causative factors are still debatable. Heparan sulfate (HS) fragments belong to the class of danger/damage-associated molecular patterns liberated from endothelial-bound proteoglycans by heparanase during tissue injury associated with trauma or sepsis. We hypothesized that HS induces apoptosis or necroptosis in murine cardiomyocytes. By using a novel Medical-In silico approach that combines conventional cell culture experiments with machine learning algorithms, we aimed to reduce a significant part of the expensive and time consuming cell culture experiments and data generation by using computational intelligence (refinement and replacement). Cardiomyocytes exposed to HS showed an activation of the intrinsic apoptosis signal pathway via cytochrome C and the activation of caspase 3 (both p < 0.001). Notably, the exposure of HS resulted in the induction of necroptosis by tumor necrosis factor alpha and receptor interaction protein 3 (p < 0.05; p < 0.01) and, hence, an increased level of necrotic cardiomyocytes. In conclusion, using this novel Medical-In silico approach, our data suggest (i) that HS induces necroptosis in cardiomyocytes by phosphorylation (activation) of receptor-interacting protein 3, (ii) that HS is a therapeutic target in trauma- or sepsis-associated cardiomyopathy, and (iii) indicate that this proof-of-concept is a first step toward simulating the extent of activated components in the pro-apoptotic pathway induced by HS with only a small data set gained from the in vitro experiments by using machine learning algorithms. PMID- 29616017 TI - Phenotypic and Functional Changes of Peripheral Ly6C+ T Regulatory Cells Driven by Conventional Effector T Cells. AB - A relatively high affinity/avidity of T cell receptor (TCR) recognition for self peptide bound to major histocompatibility complex II (self-pMHC) ligands is a distinctive feature of CD4 T regulatory (Treg) cells, including their development in the thymus and maintenance of their suppressive functions in the periphery. Despite such high self-reactivity, however, all thymic-derived peripheral Treg populations are neither homogenous in their phenotype nor uniformly immune suppressive in their function under steady state condition. We show here that based on the previously defined heterogeneity in the phenotype of peripheral Treg populations, Ly6C expression on Treg marks a lower degree of activation, proliferation, and differentiation status as well as functional incompetence. We also demonstrate that Ly6C expression on Treg in a steady state is either up- or downregulated depending on relative amounts of tonic TCR signals derived from its contacts with self-ligands. Interestingly, peripheral appearance and maintenance of these Ly6C-expressing Treg cells largely differed in an age-dependent manner, with their proportion being continuously increased from perinatal to young adult period but then being gradually declined with age. The reduction of Ly6C+ Treg in the aged mice was not due to their augmented cell death but rather resulted from downregulation of Ly6C expression. The Ly6C downregulation was accompanied by proliferation of Ly6C+ Treg cells and subsequent change into Ly6C- effector Treg with concomitant restoration of immune-suppressive activity. Importantly, we found that this phenotypic and functional change of Ly6C+ Treg is largely driven by conventional effector T cell population. Collectively, these findings suggest a potential cross-talk between peripheral Treg subsets and effector T cells and provides better understanding for Treg homeostasis and function on maintaining self-tolerance. PMID- 29616019 TI - The Syk-Coupled C-Type Lectin Receptors Dectin-2 and Dectin-3 Are Involved in Paracoccidioides brasiliensis Recognition by Human Plasmacytoid Dendritic Cells. AB - Plasmacytoid dendritic cells (pDCs), which have been extensively studied in the context of the immune response to viruses, have recently been implicated in host defense mechanisms against fungal infections. Nevertheless, the involvement of human pDCs during paracoccidioidomycosis (PCM), a fungal infection endemic to Latin America, has been scarcely studied. However, pDCs were found in the cutaneous lesions of PCM patients, and in pulmonary model of murine PCM these cells were shown to control disease severity. These findings led us to investigate the role of human pDCs in the innate phase of PCM. Moreover, considering our previous data on the engagement of diverse Toll-like receptors and C-type lectin receptors receptors in Paracoccidioides brasiliensis recognition, we decided to characterize the innate immune receptors involved in the interaction between human pDCs and yeast cells. Purified pDCs were obtained from peripheral blood mononuclear cells from healthy donors and they were stimulated with P. brasiliensis with or without blocking antibodies to innate immune receptors. Here we demonstrated that P. brasiliensis stimulation activates human pDCs that inhibit fungal growth and secrete pro-inflammatory cytokines and type I IFNs. Surprisingly, P. brasiliensis-stimulated pDCs produce mature IL 1beta and activate caspase 1, possibly via inflammasome activation, which is a phenomenon not yet described during pDC engagement by microorganisms. Importantly, we also demonstrate that dectin-2 and dectin-3 are expressed on pDCs and appear to be involved (via Syk signaling) in the pDC-P. brasiliensis interaction. Moreover, P. brasiliensis-stimulated pDCs exhibited an efficient antigen presentation and were able to effectively activate CD4+ and CD8+ T cells. In conclusion, our study demonstrated for the first time that human pDCs are involved in P. brasiliensis recognition and may play an important role in the innate and adaptive immunity against this fungal pathogen. PMID- 29616018 TI - Induction of Interleukin-10 Producing Dendritic Cells As a Tool to Suppress Allergen-Specific T Helper 2 Responses. AB - Dendritic cells (DCs) are gatekeepers of the immune system that control induction and polarization of primary, antigen-specific immune responses. Depending on their maturation/activation status, the molecules expressed on their surface, and the cytokines produced DCs have been shown to either elicit immune responses through activation of effector T cells or induce tolerance through induction of either T cell anergy, regulatory T cells, or production of regulatory cytokines. Among the cytokines produced by tolerogenic DCs, interleukin 10 (IL-10) is a key regulatory cytokine limiting und ultimately terminating excessive T-cell responses to microbial pathogens to prevent chronic inflammation and tissue damage. Because of their important role in preventing autoimmune diseases, transplant rejection, allergic reactions, or in controlling chronic inflammation DCs have become an interesting tool to modulate antigen-specific immune responses. For the treatment of allergic inflammation, the aim is to downregulate allergen-specific T helper 2 (Th2) responses and the associated clinical symptoms [allergen-driven Th2 activation, Th2-driven immunoglobulin E (IgE) production, IgE-mediated mast cell and basophil activation, allergic inflammation]. Here, combining the presentation of allergens by DCs with a pro-tolerogenic, IL-10 producing phenotype is of special interest to modulate allergen-specific immune responses in the treatment of allergic diseases. This review discusses the reported strategies to induce DC-derived IL-10 secretion for the suppression of allergen-specific Th2-responses with a focus on IL-10 treatment, IL-10 transduction, and the usage of both whole bacteria and bacteria-derived components. Interestingly, while IL-10-producing DCs induced either by IL-10 treatment or IL-10 transduction are arrested in an immature/semi-mature state, treatment of DCs with live or killed bacteria as well as isolated bacterial components results in the induction of both anti-inflammatory IL-10 and pro inflammatory, Th1-promoting IL-12 secretion often paralleled by an enhanced expression of co-stimulatory molecules on the stimulated DCs. By the secretion of DC-derived exosomes or CC-chemokine ligand 18, as well as the expression of inhibitory molecules like cytotoxic T lymphocyte-associated antigen 4, TNF receptor superfamily member 4, Ig-like transcript-22/cluster of differentiation 85, or programmed death-1, IL-10-producing DCs have been repeatedly shown to suppress antigen-specific Th2-responses. Therefore, DC-based vaccination approaches hold great potential to improve the treatment of allergic diseases. PMID- 29616021 TI - Adaptive Reconfiguration of Natural Killer Cells in HIV-1 Infection. AB - Human cytomegalovirus (HCMV) co-infection is highly prevalent within HIV-1 cohorts and is an important cofactor in driving ongoing immune activation, even during effective antiretroviral treatment. HCMV infection has recently been associated with expansion of adaptive-like natural killer (NK) cells, which harbor epigenetic alterations that impact on their cellular function and phenotype. The influence of HCMV co-infection on the considerable heterogeneity among NK cells and their functional responses to different stimuli was assessed in a cohort of HIV-1-infected individuals sampled during different stages of infection, compared with healthy subjects stratified according to HCMV serostatus. Our data demonstrate a reshaping of the NK cell pool in HIV-1 infection of HCMV-seropositive individuals, with an accentuated peripheral transition of CD56dim NK cells toward a mature CD57+ CD85j+ NKG2C+ NKG2A- phenotype. Lack of PLZF further distinguishes adaptive NK cells from other NK cells expressing CD57 or NKG2C. PLZF- NK cells from HIV-infected individuals had high expression of CD2, were Siglec-7 negative and exhibited downregulation of key signaling molecules, SYK and FcepsilonRI-gamma, overwhelmingly displaying features of adaptive NK cells that correlated with HCMV serum Ab levels. Notably this adaptive-like signature was detected during early HIV-1 infection and persisted during treatment. Adaptive-like NK cell subsets in HIV-1-infected individuals displayed enhanced IFN-gamma production following Fc receptor triggering compared with their conventional NK cell counterparts, and their ability to produce TNF-alpha and degranulate was preserved. Together, these data suggest that HMCV infection/reactivation, a hallmark of HIV-1 infection, plays a role in driving a relative expansion of NK cells with adaptive features during HIV-1 infection. The identification of selective NK subsets with retained effector activity in HIV-1-infected subjects raises the possibility of developing therapeutic strategies that exploit specific NK subpopulations to achieve better HIV-1 control. PMID- 29616020 TI - Hyper-Expression of PD-1 Is Associated with the Levels of Exhausted and Dysfunctional Phenotypes of Circulating CD161++TCR iValpha7.2+ Mucosal-Associated Invariant T Cells in Chronic Hepatitis B Virus Infection. AB - Mucosal-associated invariant T (MAIT) cells, defined as CD161++TCR iValpha7.2+ T cells, play an important role in the innate defense against bacterial infections, and their functionality is impaired in chronic viral infections. Here, we investigated the frequency and functional role of MAIT cells in chronic hepatitis B virus (HBV) infection. The peripheral CD3+CD161++TCR iValpha7.2+ MAIT cells in chronic HBV-infected patients and healthy controls were phenotypically characterized based on CD57, PD-1, TIM-3, and CTLA-4, as well as HLA-DR and CD38 expression. The frequency of MAIT cells was significantly decreased among chronic HBV-infected individuals as compared to controls. Expression of CD57, PD-1, CTLA 4, as well as HLA-DR and CD38 on MAIT cells was significantly elevated in chronic HBV-infected individuals relative to controls. The percentage of T cell receptor (TCR) iValpha7.2+ CD161+ MAIT cells did not correlate with HBV viral load but inversely with HLA-DR on CD4+ T cells and MAIT cells and with CD57 on CD8+ T cells suggesting that decrease of MAIT cells may not be attributed to direct infection by HBV but driven by HBV-induced chronic immune activation. The percentage and expression levels of PD-1 as well as CTLA-4 on MAIT cells inversely correlated with plasma HBV-DNA levels, which may suggest either a role for MAIT cells in the control of HBV infection or the effect of HBV replication in the liver on MAIT cell phenotype. We report that decrease of TCR iValpha7.2+ MAIT cells in the peripheral blood and their functions were seemingly impaired in chronic HBV-infected patients likely because of the increased expression of PD-1. PMID- 29616022 TI - Temporal Regulation of Natural Killer T Cell Interferon Gamma Responses by beta Catenin-Dependent and -Independent Wnt Signaling. AB - Natural killer T (NKT) cells are prominent innate-like lymphocytes in the liver with critical roles in immune responses during infection, cancer, and autoimmunity. Interferon gamma (IFN-gamma) and IL-4 are key cytokines rapidly produced by NKT cells upon recognition of glycolipid antigens presented by antigen-presenting cells (APCs). It has previously been reported that the transcriptional coactivator beta-catenin regulates NKT cell differentiation and functionally biases NKT cell responses toward IL-4, at the expense of IFN-gamma production. beta-Catenin is not only a central effector of Wnt signaling but also contributes to other signaling networks. It is currently unknown whether Wnt ligands regulate NKT cell functions. We thus investigated how Wnt ligands and beta-catenin activity shape liver NKT cell functions in vivo in response to the glycolipid antigen, alpha-galactosylceramide (alpha-GalCer) using a mouse model. Pharmacologic targeting of beta-catenin activity with ICG001, as well as myeloid specific genetic ablation of Wntless (Wls), to specifically target Wnt protein release by APCs, enhanced early IFN-gamma responses. By contrast, within several hours of alpha-GalCer challenge, myeloid-specific Wls deficiency, as well as pharmacologic targeting of Wnt release using the small molecule inhibitor IWP-2 impaired alpha-GalCer-induced IFN-gamma responses, independent of beta-catenin activity. These data suggest that myeloid cell-derived Wnt ligands drive early Wnt/beta-catenin signaling that curbs IFN-gamma responses, but that, subsequently, Wnt ligands sustain IFN-gamma expression independent of beta catenin activity. Our analyses in ICG001-treated mice confirmed a role for beta catenin activity in driving early IL-4 responses by liver NKT cells. However, neither pharmacologic nor genetic perturbation of Wnt production affected the IL 4 response, suggesting that IL-4 production by NKT cells in response to alpha GalCer is not driven by released Wnt ligands. Collectively, these data reveal complex temporal roles of Wnt ligands and beta-catenin signaling in the regulation of liver NKT cell activation, and highlight Wnt-dependent and independent contributions of beta-catenin to NKT cell functions. PMID- 29616023 TI - Immune Control of Burkholderia pseudomallei--Common, High-Frequency T-Cell Responses to a Broad Repertoire of Immunoprevalent Epitopes. AB - Burkholderia pseudomallei (Bp) is an environmental bacterial pathogen that causes potentially lethal sepsis in susceptible individuals and is considered a Category B, Tier-1 biothreat agent. As such, it is crucial to gain an improved understanding of protective immunity and potential vaccine candidates. The nature of immune correlates dictating why most exposed individuals in endemic regions undergo asymptomatic seroconversion while others succumb to life-threatening sepsis is largely uncharted. Bp seroreactive, immunogenic proteins have previously been identified by antigen microarray. We here set out to conduct an analysis of T-cell recognition of the Bp immunome using serodominant antigens represented in the original antigen microarray, examining immune correlates of disease in healthy seropositive individuals and those with acute disease or in convalescence. By screening a library of 739 overlapping peptides representing the sequences of 20 different Bp antigens, we aimed to define immune correlates of protection at the level of immunoprevalent T-cell epitopes. Responses to a large number of epitopes were common in healthy seropositive individuals: we found remarkably broad responsiveness to Bp epitopes, with 235 of 739 peptides recognized by >=80% of all tested donors. The cumulative response to Bp epitopes in healthy, seropositive, donors from this endemic region were of the order of thousands of spot forming cells per million cells, making Bp recognition a significant component of the T-cell repertoire. Noteworthy among our findings, analysis revealed 10 highly immunoprevalent T-cell epitopes, able to induce Bp specific IFNgamma responses that were high in responding T-cell frequency within the repertoire, and also common across individuals with different human leukocyte antigen types. Acute melioidosis patients showed poor T-cell responses to the immunoprevalent epitopes, but acquired responsiveness following recovery from infection. Our findings suggest that a large repertoire of CD4 T cells, high in frequency and with broad coverage of antigens and epitopes, is important in controlling Bp infection. This offers an attractive potential strategy for subunit or epitope-based vaccines. PMID- 29616025 TI - Differences Between Pediatric and Adult T Cell Responses to In Vitro Staphylococcal Enterotoxin B Stimulation. AB - Toxic shock syndrome (TSS) is capable of inducing life-threatening fever, rash, and systemic organ failure, though the specific mechanisms behind these symptoms remain poorly understood. Staphylococcal enterotoxin B (SEB) and other superantigens have shown to be important factors in TSS, capable of promoting cross-linking between T cell receptors and major histocompatibility complexes which results in overwhelming T cell activation, proliferation, and cytokine production. The resulting proinflammatory cytokine cascade, often referred to as the "cytokine storm," seems to be critical to the development of disease. Interestingly, clinical studies have shown that children exhibit less severe TSS associated morbidity than adults, though the mechanism behind this phenomenon has not been addressed. Indeed, despite the fact that most novel antigen exposure occurs early in life, be it from environmentally acquired pathogens or routine vaccination, normal pediatric T cell immune functions remain critically underexplored. This is largely due to difficulty in obtaining enough samples to explore more than a narrow sliver of the cell-mediated immune compartment. To address this limitation, we optimized a T effector (Teff)/circulating T follicular helper (cTFH) cell mass cytometry panel which allowed us to analyze a wide array of T cell populations and effector functions following in vitro SEB stimulation. We show that T cell activation-as measured by CD69 expression following SEB stimulation is lower in pediatric participants, increasing throughout childhood, and reaching adult levels by around 15 years old. Further, while individual CD4+ effector memory T cell (TEM) effector molecules show limited age-associated differences following SEB stimulation, multifunctional CD4+ TEM are shown to positively correlate with increasing age through adolescence. Individual CD8+ TEM effectors and multifunctional phenotypes also show very strong age-associated increases following SEB stimulation. SEB stimulation has little impact on cTFH activation or functional cellular markers, regardless of age. These results, coupled with the fact that a robust proinflammatory cytokine response seems critical to developing severe TSS, suggest a possible connection between the significantly reduced T cell activation and multifunctional populations following in vitro SEB stimulation in our pediatric participants and clinical observations relating to reduced TSS mortality in children. PMID- 29616024 TI - Simian Immunodeficiency Virus (SIV)-Specific Chimeric Antigen Receptor-T Cells Engineered to Target B Cell Follicles and Suppress SIV Replication. AB - There is a need to develop improved methods to treat and potentially cure HIV infection. During chronic HIV infection, replication is concentrated within T follicular helper cells (Tfh) located within B cell follicles, where low levels of virus-specific CTL permit ongoing viral replication. We previously showed that elevated levels of simian immunodeficiency virus (SIV)-specific CTL in B cell follicles are linked to both decreased levels of viral replication in follicles and decreased plasma viral loads. These findings provide the rationale to develop a strategy for targeting follicular viral-producing (Tfh) cells using antiviral chimeric antigen receptor (CAR) T cells co-expressing the follicular homing chemokine receptor CXCR5. We hypothesize that antiviral CAR/CXCR5-expressing T cells, when infused into an SIV-infected animal or an HIV-infected individual, will home to B cell follicles, suppress viral replication, and lead to long-term durable remission of SIV and HIV. To begin to test this hypothesis, we engineered gammaretroviral transduction vectors for co-expression of a bispecific anti-SIV CAR and rhesus macaque CXCR5. Viral suppression by CAR/CXCR5-transduced T cells was measured in vitro, and CXCR5-mediated migration was evaluated using both an in vitro transwell migration assay, as well as a novel ex vivo tissue migration assay. The functionality of the CAR/CXCR5 T cells was demonstrated through their potent suppression of SIVmac239 and SIVE660 replication in in vitro and migration to the ligand CXCL13 in vitro, and concentration in B cell follicles in tissues ex vivo. These novel antiviral immunotherapy products have the potential to provide long-term durable remission (functional cure) of HIV and SIV infections. PMID- 29616026 TI - Downregulation of SLC7A7 Triggers an Inflammatory Phenotype in Human Macrophages and Airway Epithelial Cells. AB - Lysinuric protein intolerance (LPI) is a recessively inherited aminoaciduria caused by mutations of SLC7A7, the gene encoding y+LAT1 light chain of system y+L for cationic amino acid transport. The pathogenesis of LPI is still unknown. In this study, we have utilized a gene silencing approach in macrophages and airway epithelial cells to investigate whether complications affecting lung and immune system are directly ascribable to the lack of SLC7A7 or, rather, mediated by an abnormal accumulation of arginine in mutated cells. When SLC7A7/y+LAT1 was silenced in human THP-1 macrophages and A549 airway epithelial cells by means of short interference RNA (siRNA), a significant induction of the expression and release of the inflammatory mediators IL1beta and TNFalpha was observed, no matter the intracellular arginine availability. This effect was mainly regulated at transcriptional level through the activation of NFkappaB signaling pathway. Moreover, since respiratory epithelial cells are the important sources of chemokines in response to pro-inflammatory stimuli, the effect of IL1beta has been addressed on SLC7A7 silenced A549 cells. Results obtained indicated that the downregulation of SLC7A7/y+LAT1 markedly strengthened the stimulatory effect of the cytokine on CCL5/RANTES expression and release without affecting the levels of CXCL8/IL8. Consistently, also the conditioned medium of silenced THP-1 macrophages activated airway epithelial cells in terms of CCL5/RANTES expression due to the presence of elevated amount of proinflammatory cytokines. In conclusion, our results point to a novel thus far unknown function of SLC7A7/y+LAT1, that, under physiological conditions, besides transporting arginine, may act as a brake to restrain inflammation. PMID- 29616027 TI - Detailed Characterization of T Cell Receptor Repertoires in Multiple Sclerosis Brain Lesions. AB - The antigen-specific activation of pathogenic T cells is considered essential in the initiation and maintenance of multiple sclerosis (MS). The site of activation, the differential involvement of CD4+, and CD8+ T cells, their functional phenotype, and specificity, are important aspects to understand MS pathogenesis. The analysis of clonal expansions of brain-infiltrating T cells may reveal local antigen-driven activation or specific brain homing and allow the identification of putatively pathogenic T cells. We used high-throughput T cell receptor beta-chain variable gene (TRBV) sequencing (-seq) of genomic (g)DNA, which reflects the quantity and diversity of the TRBV repertoire, to characterize three white matter demyelinating lesions with different location and inflammatory activity, and paired peripheral blood memory CD4+ and CD8+ T cell pools from a secondary progressive (SP)MS patient. Our results revealed an important sharing of clonally expanded T cells with identical TRBV sequence (clonotypes) across MS lesions independently of their proximity or inflammatory activity. Comparison with circulating T cells showed that the most frequent brain-infiltrating CD8+, but not CD4+ clonotypes were also those with highest frequency in the peripheral blood, indicating clonal expansion inside the brain or specific brain homing of CD4+ but not CD8+ T cells. Parallel TRBV-seq of complementary (c)DNA that reflects the activation status of the cells, revealed differences between lesions regarding inflammatory activity and appears to facilitate the identification of putatively pathogenic T cells in active lesions. Approaches to identify pathogenic T cells in brain lesions using TRBV-seq may benefit from focusing on lesions with high inflammatory activity and from combining gDNA and cDNA sequencing. PMID- 29616028 TI - Human gammadelta T Cell Receptor Repertoires in Peripheral Blood Remain Stable Despite Clearance of Persistent Hepatitis C Virus Infection by Direct-Acting Antiviral Drug Therapy. AB - Human gammadelta T cells can contribute to clearance of hepatitis C virus (HCV) infection but also mediate liver inflammation. This study aimed to understand the clonal distribution of gammadelta T cells in peripheral blood of chronic HCV patients and following HCV clearance by interferon-free direct-acting antiviral drug therapies. To this end, gammadelta T cell receptor (TCR) repertoires were monitored by mRNA-based next-generation sequencing. While the percentage of Vgamma9+ T cells was higher in patients with elevated liver enzymes and a few expanded Vdelta3 clones could be identified in peripheral blood of 23 HCV infected non-cirrhotic patients, overall clonality and complexity of gammadelta TCR repertoires were largely comparable to those of matched healthy donors. Monitoring eight chronic HCV patients before, during and up to 1 year after therapy revealed that direct-acting antiviral (DAA) drug therapies induced only minor alterations of TRG and TRD repertoires of Vgamma9+ and Vgamma9- cells. Together, we show that peripheral gammadelta TCR repertoires display a high stability (1) by chronic HCV infection in the absence of liver cirrhosis and (2) by HCV clearance in the course of DAA drug therapy. PMID- 29616029 TI - Neuroprotective Role of the Ron Receptor Tyrosine Kinase Underlying Central Nervous System Inflammation in Health and Disease. AB - Neurodegeneration is a critical problem in aging populations and is characterized by severe central nervous system (CNS) inflammation. Macrophages closely regulate inflammation in the CNS and periphery by taking on different activation states. The source of inflammation in many neurodegenerative diseases has been preliminarily linked to a decrease in the CNS M2 macrophage population and a subsequent increase in M1-mediated neuroinflammation. The Recepteur D'Origine Nantais (Ron) is a receptor tyrosine kinase expressed on tissue-resident macrophages including microglia. Activation of Ron by its ligand, macrophage stimulating protein, attenuates obesity-mediated inflammation in the periphery. An in vivo deletion of the ligand binding domain of Ron (Ron-/-) promotes inflammatory (M1) and limits a reparative (M2) macrophage activation. However, whether or not this response influences CNS inflammation has not been determined. In this study, we demonstrate that in homeostasis Ron-/- mice developed an inflammatory CNS niche with increased tissue expression of M1-associated markers when compared to age-matched wild-type (WT) mice. Baseline metabolic analysis of CNS tissue indicates exacerbated levels of metabolic stress in Ron-/- CNS. In a disease model of multiple sclerosis, experimental autoimmune encephalomyelitis, Ron-/- mice exhibit higher disease severity when compared to WT mice associated with increased CNS tissue inflammation. In a model of diet-induced obesity (DIO), Ron-/- mice exhibit exacerbated CNS inflammation with decreased expression of the M2 marker Arginase-1 (Arg-1) and a robust increase in M1 markers compared to WT mice following 27 weeks of DIO. Collectively, these results illustrate that activation of Ron in the CNS could be a potential therapeutic approach to treating various grades of CNS inflammation underlying neurodegeneration. PMID- 29616030 TI - Recognition of Double-Stranded RNA and Regulation of Interferon Pathway by Toll Like Receptor 10. AB - Toll-like receptor (TLR)-10 remains an orphan receptor without well-characterized ligands or functions. Here, we reveal that TLR10 is predominantly localized to endosomes and binds dsRNA in vitro at endosomal pH, suggesting that dsRNA is a ligand of TLR10. Recognition of dsRNA by TLR10 activates recruitment of myeloid differentiation primary response gene 88 for signal transduction and suppression of interferon regulatory factor-7 dependent type I IFN production. We also demonstrate crosstalk between TLR10 and TLR3, as they compete with each other for dsRNA binding. Our results suggest for the first time that dsRNA is a ligand for TLR10 and propose novel dual functions of TLR10 in regulating IFN signaling: first, recognition of dsRNA as a nucleotide-sensing receptor and second, sequestration of dsRNA from TLR3 to inhibit TLR3 signaling in response to dsRNA stimulation. PMID- 29616032 TI - Astrocytic Interleukin-15 Reduces Pathology of Neuromyelitis Optica in Mice. AB - Astrocyte loss induced by neuromyelitis optica (NMO)-IgG and complement-dependent cytotoxicity (CDC) is the hallmark of NMO pathology. The survival of astrocytes is thought to reflect astrocyte exposure to environmental factors in the CNS and the response of astrocytes to these factors. However, still unclear are how astrocytes respond to NMO-IgG and CDC, and what CNS environmental factors may impact the survival of astrocytes. In a murine model of NMO induced by intracerebral injection of NMO-IgG and human complement, we found dramatic upregulation of IL-15 in astrocytes. To study the role of astrocytic IL-15 in NMO, we generated a transgenic mouse line with targeted expression of IL-15 in astrocytes (IL-15tg), in which the expression of IL-15 is controlled by a glial fibrillary acidic protein promoter. We showed that astrocyte-targeted expression of IL-15 attenuates astrocyte injury and the loss of aquaporin-4 in the brain. Reduced blood-brain barrier leakage and immune cell infiltration are also found in the lesion of IL-15tg mice subjected to NMO induction. IL-15tg astrocytes are less susceptible to NMO-IgG-mediated CDC than their wild-type counterparts. The enhanced resistance of IL-15tg astrocytes to cytotoxicity and cell death involves NF-kappaB signaling pathway. Our findings suggest that IL-15 reduces astrocyte loss and NMO pathology. PMID- 29616033 TI - Keratins Regulate p38MAPK-Dependent Desmoglein Binding Properties in Pemphigus. AB - Keratins are crucial for the anchorage of desmosomes. Severe alterations of keratin organization and detachment of filaments from the desmosomal plaque occur in the autoimmune dermatoses pemphigus vulgaris and pemphigus foliaceus (PF), which are mainly caused by autoantibodies against desmoglein (Dsg) 1 and 3. Keratin alterations are a structural hallmark in pemphigus pathogenesis and correlate with loss of intercellular adhesion. However, the significance for autoantibody-induced loss of intercellular adhesion is largely unknown. In wild type (wt) murine keratinocytes, pemphigus autoantibodies induced keratin filament retraction. Under the same conditions, we used murine keratinocytes lacking all keratin filaments (KtyII k.o.) as a model system to dissect the role of keratins in pemphigus. KtyII k.o. cells show compromised intercellular adhesion without antibody (Ab) treatment, which was not impaired further by pathogenic pemphigus autoantibodies. Nevertheless, direct activation of p38MAPK via anisomycin further decreased intercellular adhesion indicating that cell cohesion was not completely abrogated in the absence of keratins. Direct inhibition of Dsg3, but not of Dsg1, interaction via pathogenic autoantibodies as revealed by atomic force microscopy was detectable in both cell lines demonstrating that keratins are not required for this phenomenon. However, PF-IgG shifted Dsg1-binding events from cell borders toward the free cell surface in wt cells. This led to a distribution pattern of Dsg1-binding events similar to KtyII k.o. cells under resting conditions. In keratin-deficient keratinocytes, PF-IgG impaired Dsg1-binding strength, which was not different from wt cells under resting conditions. In addition, pathogenic autoantibodies were capable of activating p38MAPK in both KtyII wt and k.o. cells, the latter of which already displayed robust p38MAPK activation under resting conditions. Since inhibition of p38MAPK blocked autoantibody-induced loss of intercellular adhesion in wt cells and restored baseline cell cohesion in keratin-deficient cells, we conclude that p38MAPK signaling is (i) critical for regulation of cell adhesion, (ii) regulated by keratins, and (iii) targets both keratin-dependent and -independent mechanisms. PMID- 29616031 TI - The Impact of the Epithelial-Mesenchymal Transition Regulator Hepatocyte Growth Factor Receptor/Met on Skin Immunity by Modulating Langerhans Cell Migration. AB - Langerhans cells (LCs), the epidermal dendritic cell (DC) subset, express the transmembrane tyrosine kinase receptor Met also known as hepatocyte growth factor (HGF) receptor. HGF is the exclusive ligand of Met and upon binding executes mitogenic, morphogenic, and motogenic activities to various cells. HGF exerts anti-inflammatory activities via Met signaling and was found to regulate various functions of immune cells, including differentiation and maturation, cytokine production, cellular migration and adhesion, and T cell effector function. It has only recently become evident that a number of HGF-regulated functions in inflammatory processes and immune responses are imparted via DCs. However, the mechanisms by which Met signaling in DCs conveys its immunoregulatory effects have not yet been fully understood. In this review, we focus on the current knowledge of Met signaling in DCs with particular attention on the morphogenic and motogenic activities. Met signaling was shown to promote DC mobility by regulating matrix metalloproteinase activities and adhesion. This is a striking resemblance to the role of Met in regulating a cell fate program during embryonic development, wound healing, and in tumor invasion known as epithelial-mesenchymal transition (EMT). Hence, we propose the concept that an EMT program is executed by Met signaling in LCs. PMID- 29616034 TI - Specific Inhibition of Complement Activation Significantly Ameliorates Autoimmune Blistering Disease in Mice. AB - Epidermolysis bullosa acquisita (EBA) is an antibody-mediated blistering skin disease associated with tissue-bound and circulating autoantibodies to type VII collagen (COL7). Transfer of antibodies against COL7 into mice results in a subepidermal blistering phenotype, strictly depending on the complement component C5. Further, activation predominantly by the alternative pathway is required to induce experimental EBA, as blistering was delayed and significantly ameliorated only in factor B-/- mice. However, C5 deficiency not only blocked the activation of terminal complement components and assembly of the membrane attack complex (MAC) but also eliminated the formation of C5a. Therefore, in the present study, we first aimed to elucidate which molecules downstream of C5 are relevant for blister formation in this EBA model and could be subsequently pharmaceutically targeted. For this purpose, we injected mice deficient in C5a receptor 1 (C5aR1) or C6 with antibodies to murine COL7. Importantly, C5ar1-/- mice were significantly protected from experimental EBA, demonstrating that C5a-C5aR1 interactions are critical intermediates linking pathogenic antibodies to tissue damage in this experimental model of EBA. By contrast, C6-/- mice developed widespread blistering disease, suggesting that MAC is dispensable for blister formation in this model. In further experiments, we tested the therapeutic potential of inhibitors of complement components which were identified to play a key role in this experimental model. Complement components C5, factor B (fB), and C5aR1 were specifically targeted using complement inhibitors both prophylactically and in mice that had already developed disease. All complement inhibitors led to a significant improvement of the blistering phenotype when injected shortly before anti-COL7 antibodies. To simulate a therapeutic intervention, anti-fB treatment was first administered in full-blown EBA (day 5) and induced significant amelioration only in the final phase of disease evolution, suggesting that early intervention in disease development may be necessary to achieve higher efficacy. Anti-C5 treatment in incipient EBA (day 2) significantly ameliorated disease during the whole experiment. This finding is therapeutically relevant, since the humanized anti-C5 antibody eculizumab is already successfully used in patients. In conclusion, in this study, we have identified promising candidate molecules for complement-directed therapeutic intervention in EBA and similar autoantibody-mediated diseases. PMID- 29616035 TI - A Framework for Understanding the Evasion of Host Immunity by Candida Biofilms. AB - Candida biofilms are a major cause of nosocomial morbidity and mortality. The mechanism by which Candida biofilms evade the immune system remains unknown. In this perspective, we develop a theoretical framework of the three, not mutually exclusive, models, which could explain biofilm evasion of host immunity. First, biofilms may exhibit properties of immunological silence, preventing immune activation. Second, biofilms may produce immune-deviating factors, converting effective immunity into ineffective immunity. Third, biofilms may resist host immunity, which would otherwise be effective. Using a murine subcutaneous biofilm model, we found that mice infected with biofilms developed sterilizing immunity effective when challenged with yeast form Candida. Despite the induction of effective anti-Candida immunity, no spontaneous clearance of the biofilm was observed. These results support the immune resistance model of biofilm immune evasion and demonstrate an asymmetric relationship between the host and biofilms, with biofilms eliciting effective immune responses yet being resistant to immunological clearance. PMID- 29616038 TI - Spontaneous T Cell Proliferation: A Physiologic Process to Create and Maintain Homeostatic Balance and Diversity of the Immune System. AB - Naive T lymphocytes undergo heterogeneous proliferative responses when introduced into lymphopenic hosts, referred to as "homeostatic proliferation" and "spontaneous proliferation." Spontaneous proliferation is a unique process through which the immune system generates memory phenotype cells with increasing T cell receptors repertoire complexity. Here, the mechanisms that initiate and control spontaneous proliferation are discussed. PMID- 29616037 TI - MicroRNA Roles in the Nuclear Factor Kappa B Signaling Pathway in Cancer. AB - Nuclear factor kappa B (NF-kappaB) is a pluripotent and crucial dimer transcription factor that orchestrates various physiological and pathological processes, especially cell proliferation, inflammation, and cancer development and progression. NF-kappaB expression is transient and tightly regulated in normal cells, but it is activated in cancer cells. Recently, numerous studies have demonstrated microRNAs (miRNAs) play a vital role in the NF-kappaB signaling pathway and NF-kappaB-associated immune responses, radioresistance and drug resistance of cancer, some acting as inhibitors and the others as activators. Although it is still in infancy, targeting NF-kappaB or the NF-kappaB signaling pathway by miRNAs is becoming a promising strategy of cancer treatment. PMID- 29616036 TI - CD1-Restricted T Cells During Persistent Virus Infections: "Sympathy for the Devil". AB - Some of the clinically most important viruses persist in the human host after acute infection. In this situation, the host immune system and the viral pathogen attempt to establish an equilibrium. At best, overt disease is avoided. This attempt may fail, however, resulting in eventual loss of viral control or inadequate immune regulation. Consequently, direct virus-induced tissue damage or immunopathology may occur. The cluster of differentiation 1 (CD1) family of non classical major histocompatibility complex class I molecules are known to present hydrophobic, primarily lipid antigens. There is ample evidence that both CD1 dependent and CD1-independent mechanisms activate CD1-restricted T cells during persistent virus infections. Sophisticated viral mechanisms subvert these immune responses and help the pathogens to avoid clearance from the host organism. CD1 restricted T cells are not only crucial for the antiviral host defense but may also contribute to tissue damage. This review highlights the two edged role of CD1-restricted T cells in persistent virus infections and summarizes the viral immune evasion mechanisms that target these fascinating immune cells. PMID- 29616039 TI - Mast Cells Are Activated by Streptococcus pneumoniae In Vitro but Dispensable for the Host Defense Against Pneumococcal Central Nervous System Infection In Vivo. AB - Mast cells reside on and near the cerebral vasculature, the predominant site of pneumococcal entry into the central nervous system (CNS). Although mast cells have been reported to be crucial in protecting from systemic bacterial infections, their role in bacterial infections of the CNS remained elusive. Here, we assessed the role of mast cells in pneumococcal infection in vitro and in vivo. In introductory experiments using mouse bone marrow-derived mast cells (BMMC), we found that (i) BMMC degranulate and release selected cytokines upon exposure to Streptococcus pneumoniae, (ii) the response of BMMC varies between different pneumococcal serotypes and (iii) is dependent on pneumolysin. Intriguingly though, apart from a slight enhancement of cerebrospinal fluid (CSF) pleocytosis, neither two different mast cell-deficient Kit mutant mouse strains (WBB6F1-KitW/Wv and C57BL/6 KitW-sh/W-sh mice) nor pharmacologic mast cell stabilization with cromoglycate had any significant impact on the disease phenotype of experimental pneumococcal meningitis. The incomplete reversal of the enhanced CSF pleocytosis by local mast cell engraftment suggests that this phenomenon is caused by other c-Kit mutation-related mechanisms than mast cell deficiency. In conclusion, our study suggests that mast cells can be activated by S. pneumoniae in vitro. However, mast cells do not play a significant role as sentinels of pneumococcal CSF invasion and initiators of innate immunity in vivo. PMID- 29616040 TI - Cholinergic Activation Enhances Resistance to Oral Salmonella Infection by Modulating Innate Immune Defense Mechanisms at the Intestinal Barrier. AB - Inflammation is a crucial defense mechanism that protects the body from the devastating effects of invading pathogens. However, an unrestrained inflammatory reaction may result in systemic manifestations with dire consequences to the host. The extent of activation of the inflammatory response is tightly regulated through immunological and neural pathways. Previously, we demonstrated that cholinergic stimulation confers enhanced protection in experimental animals orally infected with virulent Salmonella enterica serovar Typhimurium. In this study, we investigated the mechanism by which this enhanced protection takes place. Cholinergic stimulation was induced by a 3-week pretreatment with paraoxon, a highly specific acetylcholinesterase (AChE) inhibitor. This treatment enhanced host survival following oral-route infection and this correlated with significantly reduced bacterial load in systemic target organs. Enhanced protection was not due to increased gut motility or rapid bacterial clearance from the gastrointestinal tract. Moreover, protection against bacterial infection was not evident when the animals were infected systemically, suggesting that acetylcholine-mediated protective effect was mostly confined to the gut mucosal tissue. In vivo imaging demonstrated a more localized infection and delay in bacterial dissemination into systemic organs in mice pretreated with paraoxon. Morphological analysis of the small intestine (ileum) showed that AChE inhibition induced the degranulation of goblet cells and Paneth cells, two specialized secretory cells involved in innate immunity. Our findings demonstrate a crucial pathway between neural and immune systems that acts at the mucosal interface to protect the host against oral pathogens. PMID- 29616041 TI - Novel Concepts of Altered Immunoglobulin G Galactosylation in Autoimmune Diseases. AB - The composition of the conserved N297 glycan in immunoglobulin G (IgG) has been shown to affect antibody effector functions via C1q of the complement system and Fc gamma receptors (FcgammaR) on immune cells. Changes in the general levels of IgG-glycoforms, such as lowered total IgG galactosylation observed in many autoimmune diseases have been associated with elevated disease severity. Agalactosyslated IgG has therefore been regarded and classified by many as pro inflammatory. However, and somewhat counterintuitively, agalactosylation has been shown by several groups to decrease affinity for FcgammaRIII and decrease C1q binding and downstream activation, which seems at odds with this proposed pro inflammatory nature. In this review, we discuss these circumstances where altered IgG galactosylation/glycosylation is found. We propose a novel model based on these observations and current biochemical evidence, where the levels of IgG galactosylation found in the total bulk IgG affect the threshold required to achieve immune activation by autoantibodies through either C1q or FcgammaR. Although this model needs experimental verification, it is supported by several clinical observations and reconciles apparent discrepancies in the literature, and suggests a general mechanism in IgG-mediated autoimmune diseases. PMID- 29616043 TI - Lineage-Specific Analysis of Syk Function in Autoantibody-Induced Arthritis. AB - Autoantibody production and autoantibody-mediated inflammation are hallmarks of a number of autoimmune diseases. The K/BxN serum-transfer arthritis is one of the most widely used models of the effector phase of autoantibody-induced pathology. Several hematopoietic lineages including neutrophils, platelets, and mast cells have been proposed to contribute to inflammation and tissue damage in this model. We have previously shown that the Syk tyrosine kinase is critically involved in the development in K/BxN serum-transfer arthritis and bone marrow chimeric experiments indicated that Syk is likely involved in one or more hematopoietic lineages during the disease course. The aim of the present study was to further define the lineage(s) in which Syk expression is required for autoantibody induced arthritis. To this end, K/BxN serum-transfer arthritis was tested in conditional mutant mice in which Syk was deleted in a lineage-specific manner from neutrophils, platelets, or mast cells. Combination of the MRP8-Cre, PF4-Cre, or Mcpt5-Cre transgene with floxed Syk alleles allowed efficient and selective deletion of Syk from neutrophils, platelets, or mast cells, respectively. This has also been confirmed by defective Syk-dependent in vitro functional responses of the respective cell types. In vivo studies revealed nearly complete defect of the development of K/BxN serum-transfer arthritis upon neutrophil-specific deletion of Syk. By contrast, Syk deletion from platelets or mast cells did not affect the development of K/BxN serum-transfer arthritis. Our results indicate that autoantibody-induced arthritis requires Syk expression in neutrophils, whereas, contrary to prior assumptions, Syk expression in platelets or mast cells is dispensable for disease development in this model. PMID- 29616044 TI - Adoptive T Cell Therapy for Epstein-Barr Virus Complications in Patients With Primary Immunodeficiency Disorders. AB - Patients with primary immunodeficiency disorders (PID) have an increased risk from acute and chronic Epstein-Barr Virus (EBV) viral infections and EBV associated malignancies. Hematopoietic stem cell transplantation (HSCT) is a curative strategy for many patients with PID, but EBV-related complications are common in the immediate post-transplant period due to delayed reconstitution of T cell immunity. Adoptive T cell therapy with EBV-specific T cells is a promising therapeutic strategy for patients with PID both before and after HSCT. Here we review the methods used to manufacture EBV-specific T cells, the clinical outcomes, and the ongoing challenges for future development of the strategy. PMID- 29616042 TI - Gene Therapy With Regulatory T Cells: A Beneficial Alliance. AB - Gene therapy aims to replace a defective or a deficient protein at therapeutic or curative levels. Improved vector designs have enhanced safety, efficacy, and delivery, with potential for lasting treatment. However, innate and adaptive immune responses to the viral vector and transgene product remain obstacles to the establishment of therapeutic efficacy. It is widely accepted that endogenous regulatory T cells (Tregs) are critical for tolerance induction to the transgene product and in some cases the viral vector. There are two basic strategies to harness the suppressive ability of Tregs: in vivo induction of adaptive Tregs specific to the introduced gene product and concurrent administration of autologous, ex vivo expanded Tregs. The latter may be polyclonal or engineered to direct specificity to the therapeutic antigen. Recent clinical trials have advanced adoptive immunotherapy with Tregs for the treatment of autoimmune disease and in patients receiving cell transplants. Here, we highlight the potential benefit of combining gene therapy with Treg adoptive transfer to achieve a sustained transgene expression. Furthermore, techniques to engineer antigen-specific Treg cell populations, either through reprogramming conventional CD4+ T cells or transferring T cell receptors with known specificity into polyclonal Tregs, are promising in preclinical studies. Thus, based upon these observations and the successful use of chimeric (IgG-based) antigen receptors (CARs) in antigen-specific effector T cells, different types of CAR-Tregs could be added to the repertoire of inhibitory modalities to suppress immune responses to therapeutic cargos of gene therapy vectors. The diverse approaches to harness the ability of Tregs to suppress unwanted immune responses to gene therapy and their perspectives are reviewed in this article. PMID- 29616045 TI - Complement Factor H Inhibits Anti-Neutrophil Cytoplasmic Autoantibody-Induced Neutrophil Activation by Interacting With Neutrophils. AB - Our previous study demonstrated that plasma levels of complement factor H (FH) were inversely associated with the disease activity of patients with anti neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). In addition to serving as an inhibitor of the alternative complement pathway, there is increasing evidence demonstrating direct regulatory roles of FH on several cell types. Here, we investigated the role of FH in the process of ANCA-mediated activation of neutrophils and neutrophil-endothelium interaction. We demonstrated that FH bound to neutrophils by immunostaining and flow cytometry. Interestingly, ANCA-induced activation of neutrophils, including respiratory burst and degranulation, was inhibited by FH. Although FH enhanced neutrophils adhesion and migration toward human glomerular endothelial cells (hGEnCs), it inhibited ANCA induced activation of neutrophils in the coculture system of hGEnCs and neutrophils. Moreover, the activation and injury of hGEnCs, reflected by the level of endothelin-1 in the supernatant of cocultures, was markedly reduced by FH. However, we found that FH from patients with active AAV exhibited a deficient ability in binding neutrophils and inhibiting ANCA-induced neutrophil activation in fluid phase and on endothelial cells, as compared with that from healthy controls. Therefore, our findings indicate a novel role of FH in inhibiting ANCA induced neutrophil activation and protecting against glomerular endothelial injury. However, FH from patients with active AAV are deficient in their ability to bind neutrophils and inhibit neutrophil activation by ANCA. It further extends the current understanding of the pathogenesis of AAV, thus providing potential clues for intervention strategies. PMID- 29616046 TI - Trimethyl Chitosan Nanoparticles Encapsulated Protective Antigen Protects the Mice Against Anthrax. AB - Anthrax is an era old deadly disease against which there are only two currently available licensed vaccines named anthrax vaccine adsorbed and precipitated (AVP). Though they can provide a protective immunity, their multiple side-effects owing to their ill-defined composition and presence of toxic proteins (LF and EF) of Bacillus anthracis, the causative organism of anthrax, in the vaccine formulation makes their widespread use objectionable. Hence, an anthrax vaccine that contains well-defined and controlled components would be highly desirable. In this context, we have evaluated the potential of various vaccine formulations comprising of protective antigen (PA) encapsulated trimethyl-chitosan nanoparticles (TMC-PA) in conjunction with either CpG-C ODN 2395 (CpG) or Poly I:C. Each formulation was administered via three different routes, viz., subcutaneous (SC), intramuscular (IM), and intraperitoneal in female BALB/c mice. Irrespective of the route of immunization, CpG or Poly I:C adjuvanted TMC-PA nanoparticles induced a significantly higher humoral response (total serum IgG and its isotypes viz., IgG1, IgG2a, and IgG2b), compared to their CpG or Poly I:C PA counterparts. This clearly demonstrates the synergistic behavior of CpG and Poly I:C with TMC nanoparticles. The adjuvant potential of TMC nanoparticles could be observed in all the three routes as the TMC-PA nanoparticles by themselves induced IgG titers (1-1.5 * 105) significantly higher than both CpG PA and Poly I:C PA groups (2-8 * 104). The effect of formulations on T-helper (Th) cell development was assessed by quantifying the Th1-dependant (TNF-alpha, IFN gamma, and IL-2), Th2-dependant (IL-4, IL-6, and IL-10), and Th17-type (IL-17A) cytokines. Adjuvanation with CpG and Poly I:C, the TMC-PA nanoparticles triggered a Th1 skewed immune response, as suggested by an increase in the levels of total IgG2a along with IFN-gamma cytokine production. Interestingly, the TMC-PA group showed a Th2-biased immune response. Upon challenge with the B. anthracis Ames strain, CpG and Poly I:C adjuvanted TMC-PA nanoparticles immunized via the SC and IM routes showed the highest protective efficacy of ~83%. Altogether, the results suggest that CpG or Poly I:C adjuvanted, PA-loaded TMC nanoparticles could be used as an effective, non-toxic, second generation subunit-vaccine candidate against anthrax. PMID- 29616048 TI - TNFSF14 (LIGHT) Exhibits Inflammatory Activities in Lung Fibroblasts Complementary to IL-13 and TGF-beta. AB - The cytokine TNFSF14 [homologous to Lymphotoxin, exhibits Inducible expression and competes with HSV Glycoprotein D for binding to HVEM, a receptor expressed on T lymphocytes (LIGHT)] has been shown in mouse models to be important for development of lung tissue remodeling that is characteristic of asthma, idiopathic pulmonary fibrosis (IPF), and systemic sclerosis (SSc). However, its cellular targets are not fully delineated. In the present report, we show that LTbetaR and HVEM, the receptors for LIGHT, are constitutively expressed in primary human lung fibroblasts (HLFs). We asked whether LIGHT could promote inflammatory and remodeling-relevant activity in HLFs and how this was similar to, or distinct from, IL-13 or TGF-beta, two cytokines strongly implicated in the pathogenesis of asthma, IPF, and SSc. Accumulation of myofibroblasts expressing alpha smooth muscle actin is a feature of lung inflammatory diseases. LIGHT promoted cell cycle progression and proliferation of HLFs, but not alpha smooth muscle actin expression. In contrast, TGF-beta upregulated alpha smooth muscle actin but did not drive their proliferation. LIGHT also increased the gene or protein expression of a number of proinflammatory mediators, including ICAM-1 and VCAM-1, IL-6 and GM-CSF, the chemokines CCL5 and 20, and CXCL5, 11, and 12, and lung remodeling-associated proteinases MMP-9 and ADAM8. These were dependent on LTbetaR but not HVEM. LIGHT displayed overlapping and synergistic activities with IL-13 for a number of the activities, but LIGHT additionally enhanced the gene expression of several molecules, including the innate cytokines IL-33 and TSLP, which were not upregulated by IL-13. Our results highlight the varied and pleiotropic effects of LIGHT in HLFs. LIGHT might then be a therapeutic target for modulation of inflammation and remodeling associated with asthma and other similar diseases of the lung that involve fibroblasts. PMID- 29616047 TI - Molecular Mechanisms of Human Disease Mediated by Oncogenic and Primary Immunodeficiency Mutations in Class IA Phosphoinositide 3-Kinases. AB - The signaling lipid phosphatidylinositol 3,4,5, trisphosphate (PIP3) is an essential mediator of many vital cellular processes, including growth, survival, and metabolism. PIP3 is generated through the action of the class I phosphoinositide 3-kinases (PI3K), and their activity is tightly controlled through interactions with regulatory proteins and activating stimuli. The class IA PI3Ks are composed of three distinct p110 catalytic subunits (p110alpha, p110beta, and p110delta), and they play different roles in specific tissues due to disparities in both expression and engagement downstream of cell-surface receptors. Disruption of PI3K regulation is a frequent driver of numerous human diseases. Activating mutations in the PIK3CA gene encoding the p110alpha catalytic subunit of class IA PI3K are frequently mutated in several cancer types, and mutations in the PIK3CD gene encoding the p110delta catalytic subunit have been identified in primary immunodeficiency patients. All class IA p110 subunits interact with p85 regulatory subunits, and mutations/deletions in different p85 regulatory subunits have been identified in both cancer and primary immunodeficiencies. In this review, we will summarize our current understanding for the molecular basis of how class IA PI3K catalytic activity is regulated by p85 regulatory subunits, and how activating mutations in the PI3K catalytic subunits PIK3CA and PIK3CD (p110alpha, p110delta) and regulatory subunits PIK3R1 (p85alpha) mediate PI3K activation and human disease. PMID- 29616049 TI - Regulation of the Development and Function of B Cells by ZBTB Transcription Factors. AB - The large ZBTB family comprises a diverse group of transcriptional factors. Several ZBTB proteins have emerged as critical factors that regulate the lineage commitment, differentiation, and function of lymphoid cells as well as many other developmental events. For instance, dysfunctions of ZBTB20 or ZBTB24 have been linked to multisystem failures in humans. Within the B-cell lineage, BCL6, ZBTB7A, ZBTB17, and ZBTB1 regulate the development/differentiation of B cells in both bone marrow and peripheral lymphoid organs, while ZBTB20 and ZBTB32 seem to mainly impact the maintenance of terminal plasma cells. Given the importance of B cells in the prevention and treatment of infectious or autoimmune disorders, we herein summarize the roles of seven ZBTB family members (BCL6, ZBTB7A, ZBTB17, ZBTB20, ZBTB32, ZBTB1, and ZBTB24) in the development, differentiation, and function of B cells as well as the underlying molecular mechanisms. PMID- 29616050 TI - IPD3 and IPD3L Function Redundantly in Rhizobial and Mycorrhizal Symbioses. AB - Legume plants form symbiotic associations with either nitrogen-fixing bacteria or arbuscular mycorrhizal (AM) fungi, which are regulated by a set of common symbiotic signaling pathway genes. Central to the signaling pathway is the activation of the DMI3/IPD3 protein complex by Ca2+ oscillations, and the initiation of nodule organogenesis and mycorrhizal symbiosis. DMI3 is essential for rhizobial infection and nodule organogenesis; however, ipd3 mutants have been shown to be impaired only in infection thread formation but not in root nodule organogenesis in Medicago truncatula. We identified an IPD3-like (IPD3L) gene in the M. truncatula genome. A single ipd3l mutant exhibits a normal root nodule phenotype. The ipd3l/ipd3-2 double mutant is completely unable to initiate infection threads and nodule primordia. IPD3L can functionally replace IPD3 when expressed under the control of the IPD3 promoter, indicating functional redundancy between these two transcriptional regulators. We constructed a version of IPD3 that was phosphomimetic with respect to two conserved serine residues (IPD3-2D). This was sufficient to trigger root nodule organogenesis, but the increased multisite phosphorylation of IPD3 (IPD3-8D) led to low transcriptional activity, suggesting that the phosphorylation levels of IPD3 fine-tune its transcriptional activity in the root nodule symbiosis. Intriguingly, the phosphomimetic version of IPD3 triggers spontaneous root-like nodules on the roots of dmi3-1 and dmi2-1 (DMI2 is an LRR-containing receptor-like kinase gene which is required for Ca2+ spiking), but not on the roots of wild-type or ipd3l ipd3-2 plants. In addition, fully developed arbuscules were formed in the ipd3l ipd3-2 mutants but not the ccamk/dmi3-1 mutants. Collectively, our data indicate that, in addition to IPD3 and IPD3L, another new genetic component or other new phosphorylation sites of IPD3 function downstream of DMI3 in rhizobial and mycorrhizal symbioses. PMID- 29616051 TI - Effect of Solid Biological Waste Compost on the Metabolite Profile of Brassica rapa ssp. chinensis. AB - Large quantities of biological waste are generated at various steps within the food production chain and a great utilization potential for this solid biological waste exists apart from the current main usage for the feedstuff sector. It remains unclear how the usage of biological waste as compost modulates plant metabolites. We investigated the effect of biological waste of the processing of coffee, aronia, and hop added to soil on the plant metabolite profile by means of liquid chromatography in pak choi sprouts. Here we demonstrate that the solid biological waste composts induced specific changes in the metabolite profiles and the changes are depending on the type of the organic residues and its concentration in soil. The targeted analysis of selected plant metabolites, associated with health beneficial properties of the Brassicaceae family, revealed increased concentrations of carotenoids (up to 3.2-fold) and decreased amounts of glucosinolates (up to 4.7-fold) as well as phenolic compounds (up to 1.5-fold). PMID- 29616052 TI - The Role of Programmed Cell Death Regulator LSD1 in Nematode-Induced Syncytium Formation. AB - Cyst-forming plant-parasitic nematodes are common pests of many crops. They inject secretions into host cells to induce the developmental and metabolic reprogramming that leads to the formation of a syncytium, which is the sole food source for growing nematodes. As in other host-parasite models, avirulence leads to rapid and local programmed cell death (PCD) known as the hypersensitive response (HR), whereas in the case of virulence, PCD is still observed but is limited to only some cells. Several regulators of PCD were analyzed to understand the role of PCD in compatible plant-nematode interactions. Thus, Arabidopsis plants carrying recessive mutations in LESION SIMULATING DISEASE1 (LSD1) family genes were subjected to nematode infection assays with juveniles of Heterodera schachtii. LSD1 is a negative and conditional regulator of PCD, and fewer and smaller syncytia were induced in the roots of lsd1 mutants than in wild-type Col 0 plants. Mutation in LSD ONE LIKE2 (LOL2) revealed a pattern of susceptibility to H. schachtii antagonistic to lsd1. Syncytia induced on lsd1 roots compared to Col0 showed significantly retarded growth, modified cell wall structure, increased vesiculation, and some myelin-like bodies present at 7 and 12 days post infection. To place these data in a wider context, RNA-sequencing analysis of infected and uninfected roots was conducted. During nematode infection, the number of transcripts with changed expression in lsd1 was approximately three times smaller than in wild-type plants (1440 vs. 4206 differentially expressed genes, respectively). LSD1-dependent PCD in roots is thus a highly regulated process in compatible plant-nematode interactions. Two genes identified in this analysis, coding for AUTOPHAGY-RELATED PROTEIN 8F and 8H were down-regulated in syncytia in the presence of LSD1 and showed an increased susceptibility to nematode infection contrasting with lsd1 phenotype. Our data indicate that molecular regulators belonging to the LSD1 family play an important role in precise balancing of diverse PCD players during syncytium development required for successful nematode parasitism. PMID- 29616053 TI - The Aspergillus flavus Spermidine Synthase (spds) Gene, Is Required for Normal Development, Aflatoxin Production, and Pathogenesis During Infection of Maize Kernels. AB - Aspergillus flavus is a soil-borne saprophyte and an opportunistic pathogen of both humans and plants. This fungus not only causes disease in important food and feed crops such as maize, peanut, cottonseed, and tree nuts but also produces the toxic and carcinogenic secondary metabolites (SMs) known as aflatoxins. Polyamines (PAs) are ubiquitous polycations that influence normal growth, development, and stress responses in living organisms and have been shown to play a significant role in fungal pathogenesis. Biosynthesis of spermidine (Spd) is critical for cell growth as it is required for hypusination-mediated activation of eukaryotic translation initiation factor 5A (eIF5A), and other biochemical functions. The tri-amine Spd is synthesized from the diamine putrescine (Put) by the enzyme spermidine synthase (Spds). Inactivation of spds resulted in a total loss of growth and sporulation in vitro which could be partially restored by addition of exogenous Spd. Complementation of the Deltaspds mutant with a wild type (WT) A. flavus spds gene restored the WT phenotype. In WT A. flavus, exogenous supply of Spd (in vitro) significantly increased the production of sclerotia and SMs. Infection of maize kernels with the Deltaspds mutant resulted in a significant reduction in fungal growth, sporulation, and aflatoxin production compared to controls. Quantitative PCR of Deltaspds mutant infected seeds showed down-regulation of aflatoxin biosynthetic genes in the mutant compared to WT A. flavus infected seeds. Expression analyses of PA metabolism/transport genes during A. flavus-maize interaction showed significant increase in the expression of arginine decarboxylase (Adc) and S adenosylmethionine decarboxylase (Samdc) genes in the maize host and PA uptake transporters in the fungus. The results presented here demonstrate that Spd biosynthesis is critical for normal development and pathogenesis of A. flavus and pre-treatment of a Deltaspds mutant with Spd or Spd uptake from the host plant, are insufficient to restore WT levels of pathogenesis and aflatoxin production during seed infection. The data presented here suggest that future studies targeting spermidine biosynthesis in A. flavus, using RNA interference-based host induced gene silencing approaches, may be an effective strategy to reduce aflatoxin contamination in maize and possibly in other susceptible crops. PMID- 29616054 TI - WRKY2/34-VQ20 Modules in Arabidopsis thaliana Negatively Regulate Expression of a Trio of Related MYB Transcription Factors During Pollen Development. AB - Male gametogenesis in plants is tightly controlled and involves the complex and precise regulation of transcriptional reprogramming. Interactions between WRKY proteins and VQ motif-containing proteins are required to control these complicated transcriptional networks. However, our understanding of the mechanisms by which these complexes affect downstream gene expression is quite limited. In this study, we found that WRKY2 and WKRY34 repress MYB97, MYB101, and MYB120 expression during male gametogenesis. MYB expression was up-regulated in the wrky2-1 wrky34-1 vq20-1 triple mutant during male gametogenesis. The expression levels of six potential targets of the three MYBs increased the most in the wrky2-1 wrky34-1 vq20-1 triple mutant, followed by the wrky2-1 wrky34-1 double mutant, compared with in wild-type. Yeast one-hybrid and dual luciferase reporter assays indicated that WRKY2 and WRKY34 recognized the MYB97 promoter by binding to its W-boxes. MYB97 overexpression caused defects in pollen germination and pollen tube length, which impacted male fertility. Thus, WRKY2/34-VQ20 complexes appear to negatively regulate the expression of certain MYBs during plant male gametogenesis. PMID- 29616055 TI - Genetic Architecture and Candidate Genes for Deep-Sowing Tolerance in Rice Revealed by Non-syn GWAS. AB - Dry direct-seeding of rice is rapidly increasing in China, but variable planting depth associated with machine sowing can lead to low seedling emergence rates. Phenotype analysis of 621 rice accessions showed that mesocotyl length (ML) was induced by deep soil covering and was important in deep-sowing tolerance in the field. Here, we performed and compared GWAS using three types of SNPs (non synonymous SNP, non-synonymous SNPs and SNPs within promoters and 3 million randomly selected SNPs from the entire set of SNPs) and found that Non-Syn GWAS (GWAS using non-synonyomous SNP) decreased computation time and eliminated confounding by other loci relative to GWAS using randomly selected SNPs. Thirteen QTLs were finally detected, and two new major-effect genes, named OsML1 and OsML2, were identified by an integrated analysis. There were 2 and 7 non synonymous SNPs in OsML1 and OsML2, respectively, from which 3 and 4 haplotypes were detected in cultivated rice. Combinations of superior haplotypes of OsML1 and OsML2 increased ML by up to 4 cm, representing high emergence rate (85%) in the field with 10 cm of soil cover. The studies provide key loci and naturally occurring alleles of ML that can be used in improving tolerance to dry direct seeding. PMID- 29616056 TI - Perfluorodecalins and Hexenol as Inducers of Secondary Metabolism in Taxus media and Vitis vinifera Cell Cultures. AB - Plant cell cultures constitute a potentially efficient and sustainable tool for the production of high added-value bioactive compounds. However, due to the inherent restrictions in the expression of secondary metabolism, to date the yields obtained have generally been low. Plant cell culture elicitation can boost production, sometimes leading to dramatic improvements in yield, as well as providing insight into the target biosynthetic pathways and the regulation of the genes involved. Among the secondary compounds successfully being produced in biotechnological platforms are taxanes and trans-resveratrol (t-R). In the current study, perfluorodecalins (PFDs) and hexenol (Hex) were tested for the first time with Taxus media and Vitis vinifera cell cultures to explore their effect on plant cell growth and secondary metabolite production, either alone or combined with other elicitors already established as highly effective, such as methyl jasmonate (MeJa), coronatine (Coro) or randomly methylated beta cyclodextrins (beta-CDs). The total taxane content at the peak of production in T. media cell cultures treated with PFDs together with Coro plus beta-CDs was 3.3 fold higher than in the control, whereas the t-R production in MeJa and beta-CD treated V. vinifera cell cultures increased 552.6-fold compared to the extremely low-yielding control. Hex was ineffective as an elicitor in V. vinifera cell cultures, and in T. media cell suspensions it blocked the taxol production but induced a clear enhancement of baccatin III. Regarding biosynthetic gene expression, a strong positive relationship was observed between the transcript level of targeted genes and taxol production in the T. media cell cultures, but not with t-R production in the elicited V. vinifera cell cultures. PMID- 29616057 TI - The Polycistronic miR166k-166h Positively Regulates Rice Immunity via Post transcriptional Control of EIN2. AB - MicroRNAs (miRNAs) are small RNAs acting as regulators of gene expression at the post-transcriptional level. In plants, most miRNAs are generated from independent transcriptional units, and only a few polycistronic miRNAs have been described. miR166 is a conserved miRNA in plants targeting the HD-ZIP III transcription factor genes. Here, we show that a polycistronic miRNA comprising two miR166 family members, miR166k and miR166h, functions as a positive regulator of rice immunity. Rice plants with activated MIR166k-166h expression showed enhanced resistance to infection by the fungal pathogens Magnaporthe oryzae and Fusarium fujikuroi, the causal agents of the rice blast and bakanae disease, respectively. Disease resistance in rice plants with activated MIR166k-166h expression was associated with a stronger expression of defense responses during pathogen infection. Stronger induction of MIR166k-166h expression occurred in resistant but not susceptible rice cultivars. Notably, the ethylene-insensitive 2 (EIN2) gene was identified as a novel target gene for miR166k. The regulatory role of the miR166h-166k polycistron on the newly identified target gene results from the activity of the miR166k-5p specie generated from the miR166k-166h precursor. Collectively, our findings support a role for miR166k-5p in rice immunity by controlling EIN2 expression. Because rice blast is one of the most destructive diseases of cultivated rice worldwide, unraveling miR166k-166h-mediated mechanisms underlying blast resistance could ultimately help in designing appropriate strategies for rice protection. PMID- 29616058 TI - Plant Fructokinases: Evolutionary, Developmental, and Metabolic Aspects in Sink Tissues. AB - Sucrose, a glucose-fructose disaccharide, is the main sugar transported in the phloem of most plants and is the origin of most of the organic matter. Upon arrival in sink tissues, the sucrose must be cleaved by invertase or sucrose synthase. Both sucrose-cleaving enzymes yield free fructose, which must be phosphorylated by either fructokinase (FRK) or hexokinase (HXK). The affinity of FRK to fructose is much higher than that of HXK, making FRKs central for fructose metabolism. An FRK gene family seems to exist in most, if not all plants and usually consists of several cytosolic FRKs and a single plastidic FRK. These genes are expressed mainly in sink tissues such as roots, stems, flowers, fruits, and seeds, with lower levels of expression often seen in leaves. Plant FRK enzymes vary in their biochemical properties such as affinity for fructose, inhibition by their substrate (i.e., fructose), and expression level in different tissues. This review describes recently revealed roles of plant FRKs in plant development, including the combined roles of the plastidic and cytosolic FRKs in vascular tissues and seed development. PMID- 29616059 TI - A Novel WRKY Transcription Factor, MuWRKY3 (Macrotyloma uniflorum Lam. Verdc.) Enhances Drought Stress Tolerance in Transgenic Groundnut (Arachis hypogaea L.) Plants. AB - Drought stress has adverse effects on growth, water relations, photosynthesis and yield of groundnut. WRKY transcription factors (TFs) are the plant-specific TFs which regulate several down-stream stress-responsive genes and play an essential role in plant biotic and abiotic stress responses. We found that WRKY3 gene is highly up-regulated under drought stress conditions and therefore isolated a new WRKY3TF gene from a drought-adapted horsegram (Macrotyloma uniflorum Lam. Verdc.). Conserved domain studies revealed that protein encoded by this gene contains highly conserved regions of two WRKY domains and two C2H2 zinc-finger motifs. The fusion protein localization studies of transient MuWRKY3-YFP revealed its nuclear localization. Overexpression of MuWRKY3 TF gene in groundnut (Arachis hypogaea L.) showed increased tolerance to drought stress compared to wild-type (WT) plants. MuWRKY3 groundnut transgenics displayed lesser and delayed wilting symptoms than WT plants after 10-days of drought stress imposition. The transgenic groundnut plants expressing MuWRKY3 showed less accumulation of malondialdehyde, hydrogen peroxide (H2O2), and superoxide anion (O2?-), accompanied by more free proline, total soluble sugar content, and activities of antioxidant enzymes than WT plants under drought stress. Moreover, a series of stress-related LEA, HSP, MIPS, APX, SOD, and CAT genes found up-regulated in the transgenic groundnut plants. The study demonstrates that nuclear-localized MuWRKY3 TF regulates the expression of stress-responsive genes and the activity of ROS scavenging enzymes which results in improved drought tolerance in groundnut. We conclude that MuWRKY3 may serve as a new putative candidate gene for the improvement of stress resistance in plants. PMID- 29616060 TI - Arabidopsis GAAP1 and GAAP3 Modulate the Unfolded Protein Response and the Onset of Cell Death in Response to ER Stress. AB - The function of human Golgi antiapoptotic proteins (GAAPs) resembles that of BAX inhibitor-1, with apoptosis inhibition triggered by intrinsic and extrinsic stimuli. However, little is known about the function of GAAP-related proteins in plants. Here, we studied Arabidopsis GAAP1 and GAAP3 and found that they were localized on the cellular membrane, including the endoplasmic reticulum (ER) membrane. The function of GAAP1/GAAP3 in ER-stress response was tested, and results showed that single or double mutation in GAAP1 and GAAP3 reduced plant survival and enhanced cell death under ER stress. The expression of both genes was induced by various abiotic stress signals. Quantitative real-time polymerase chain reaction analysis showed that GAAP1/GAAP3 level affected the expression pattern of the unfolded-protein response (UPR) signaling pathway genes upon prolonged ER stress. The mutation in both GAAP1 and GAAP3 genes promoted and enhanced UPR signaling when confronted with mild ER stress. Moreover, GAAP1/GAAP3 inhibited cell death caused by ER stress and promoted plant-growth recovery by turning down inositol-requiring enzyme 1 (IRE1) signaling after ER stress had been relieved. Co-immunoprecipitation (Co-Ip) and BiFC assays showed that GAAP1/GAAP3 interacted with IRE1. These data suggested that GAAP1/GAAP3 played dual roles in the negative regulation of IRE1 activity and anti-programmed cell death. PMID- 29616061 TI - Identifying Quantitative Trait Loci (QTLs) and Developing Diagnostic Markers Linked to Orange Rust Resistance in Sugarcane (Saccharum spp.). AB - Sugarcane (Saccharum spp.) is an important economic crop, contributing up to 80% of table sugar used in the world and has become a promising feedstock for biofuel production. Sugarcane production has been threatened by many diseases, and fungicide applications for disease control have been opted out for sustainable agriculture. Orange rust is one of the major diseases impacting sugarcane production worldwide. Identifying quantitative trait loci (QTLs) and developing diagnostic markers are valuable for breeding programs to expedite release of superior sugarcane cultivars for disease control. In this study, an F1 segregating population derived from a cross between two hybrid sugarcane clones, CP95-1039 and CP88-1762, was evaluated for orange rust resistance in replicated trails. Three QTLs controlling orange rust resistance in sugarcane (qORR109, qORR4 and qORR102) were identified for the first time ever, which can explain 58, 12 and 8% of the phenotypic variation, separately. We also characterized 1,574 sugarcane putative resistance (R) genes. These sugarcane putative R genes and simple sequence repeats in the QTL intervals were further used to develop diagnostic markers for marker-assisted selection of orange rust resistance. A PCR based Resistance gene-derived maker, G1 was developed, which showed significant association with orange rust resistance. The putative QTLs and marker developed in this study can be effectively utilized in sugarcane breeding programs to facilitate the selection process, thus contributing to the sustainable agriculture for orange rust disease control. PMID- 29616062 TI - Complementary Evaluation of Iron Deficiency Root Responses to Assess the Effectiveness of Different Iron Foliar Applications for Chlorosis Remediation. AB - Iron deficiency in plants is caused by a low availability of iron in the soil, and its main visual symptom is leaf yellowing due to a decrease in chlorophyll content, along with a reduction in plant growth and fruit quality. Foliar sprays with Fe compounds are an economic alternative to the treatment with expensive synthetic Fe-chelates applied to the soil, although the efficacy of foliar treatments is rather limited. Generally, plant response to Fe-foliar treatments is monitored by measuring chlorophyll content (or related parameters as SPAD index). However, different studies have shown that foliar Fe sprays cause a local regreening and that translocation of the applied Fe within the plant is quite low. In this context, the aim of this study was to assess the effects of foliar applications of different Fe compounds [FeSO4, Fe(III)-EDTA, and Fe(III) heptagluconate] on Fe-deficient cucumber plants, by studying the main physiological plant root responses to Fe deficiency [root Fe(III) chelate reductase (FCR) activity; acidification of the nutrient solution; and expression of the Fe deficiency responsive genes encoding FCR, CsFRO1, Fe(II) root transporter CsIRT1, and two plasma membrane H+-ATPases, CsHA1 and CsHA2], along with SPAD index, plant growth and Fe content. The results showed that the overall assessment of Fe-deficiency root responses improved the evaluation of the efficacy of the Fe-foliar treatments compared to just monitoring SPAD indexes. Thus, FCR activity and expression of Fe-deficiency response genes, especially CsFRO1 and CsHA1, preceded the trend of SPAD index and acted as indicators of whether the plant was sensing or not metabolically active Fe due to the treatments. Principal component analysis of the data also provided a graphical tool to evaluate the evolution of plant responses to foliar Fe treatments with time. PMID- 29616064 TI - A Novel Complementation Assay for Quick and Specific Screen of Genes Encoding Glycerol-3-Phosphate Acyltransferases. AB - The initial step in glycerolipid biosynthesis, especially in diverse allopolyploid crop species, is poorly understood, mainly due to the lack of an effective and convenient method for functional characterization of genes encoding glycerol-3-phosphate acyltransferases (GPATs) catalyzing this reaction. Here we present a novel complementation assay for quick and specific characterization of GPAT-encoding genes. Its key design involves rational construction of yeast conditional lethal gat1Deltagat2Delta double mutant bearing the heterologous Arabidopsis AtGPAT1 gene whose leaky expression under repressed conditions does not support any non-specific growth, thereby circumventing the false positive problem encountered with the system based on the gat1Deltagat2Delta mutant harboring the native episomal GAT1 gene whose leaky expression appears to be sufficient for generating enough GPAT activities for the non-specific restoration of the mutant growth. A complementation assay developed based on this novel mutant enables quick phenotypic screen of GPAT sequences. A high degree of specificity of our assay was exemplified by its ability to differentiate effectively GPAT-encoding genes from those of other fatty acyltransferases and lipid-related sequences. Using this assay, we show that Arabidopsis AtGPAT1, AtGPAT5, and AtGPAT7 can complement the phosphatidate biosynthetic defect in the double mutants. Collectively, our assay provides a powerful tool for rapid screening, validation and optimization of GPAT sequences, aiding future engineering of the initial step of the triacylglycerol biosynthesis in oilseeds. PMID- 29616063 TI - MorphDB: Prioritizing Genes for Specialized Metabolism Pathways and Gene Ontology Categories in Plants. AB - Recent times have seen an enormous growth of "omics" data, of which high throughput gene expression data are arguably the most important from a functional perspective. Despite huge improvements in computational techniques for the functional classification of gene sequences, common similarity-based methods often fall short of providing full and reliable functional information. Recently, the combination of comparative genomics with approaches in functional genomics has received considerable interest for gene function analysis, leveraging both gene expression based guilt-by-association methods and annotation efforts in closely related model organisms. Besides the identification of missing genes in pathways, these methods also typically enable the discovery of biological regulators (i.e., transcription factors or signaling genes). A previously built guilt-by-association method is MORPH, which was proven to be an efficient algorithm that performs particularly well in identifying and prioritizing missing genes in plant metabolic pathways. Here, we present MorphDB, a resource where MORPH-based candidate genes for large-scale functional annotations (Gene Ontology, MapMan bins) are integrated across multiple plant species. Besides a gene centric query utility, we present a comparative network approach that enables researchers to efficiently browse MORPH predictions across functional gene sets and species, facilitating efficient gene discovery and candidate gene prioritization. MorphDB is available at http://bioinformatics.psb.ugent.be/webtools/morphdb/morphDB/index/. We also provide a toolkit, named "MORPH bulk" (https://github.com/arzwa/morph-bulk), for running MORPH in bulk mode on novel data sets, enabling researchers to apply MORPH to their own species of interest. PMID- 29616065 TI - The Variable Effect of Polyploidization on the Phenotype in Escallonia. AB - To induce new variation within the Escallonia genus, chromosome doubling was performed in E. rubra, E. rosea, and E. illinita, three important species within this genus of mainly evergreen woody ornamental species. Obtained tetraploids and diploid controls were analyzed for rooting capacity, leaf and flower characteristics, and plant architecture using image analysis and cold tolerance. In the present study, a breeders' collection of 23 accessions was characterized cytogenetically and described morphologically. All analyzed species and cultivars were diploid (2n = 2x = 24), with exception of E. pendula, a tetraploid. Today, breeding in Escallonia is limited to lucky finds in seedling populations and few efforts in interspecific hybridization. Three selected Escallonia species underwent an in vitro chromosome doubling with both oryzalin and trifluralin applied as either a continuous or shock treatment. The treatments successfully induced polyploids in all three species. Image analysis revealed that tetraploid E. rosea had decreased shoot length (from 3.8 to 1.3 cm), higher circularity and more dense growth habit compared to diploids. No significant changes in cold tolerance were seen. Tetraploid E. illinita did not differ in shoot length, but an increased outgrowth of axillary buds on the main axis led to denser plants. For tetraploid E. rubra, an increase in plant height (from 4.9 to 5.5 cm) was observed together with a large decrease in circularity and density due to a more polar outgrowth of branches on the main axis. E. rubra tetraploids bore larger flowers than diploids and had an increased cold tolerance (from -7.7 to -11.8 degrees C). Leaf width and area of tetraploids increased for both E. illinita and E. rubra, while a decrease was seen in E. rosea genotypes. For all three species, the rooting capacity of the tetraploids did not differ from the diploids. We conclude that the effect of polyploidization on Escallonia was highly variable and species dependent. PMID- 29616067 TI - Flow Management to Control Excessive Growth of Macrophytes - An Assessment Based on Habitat Suitability Modeling. AB - Mediterranean rivers in intensive agricultural watersheds usually display outgrowths of macrophytes - notably alien species - due to a combination of high concentrations of nutrients in the water runoff and low flows resulting from water abstraction for irrigation. Standard mechanical and chemical control is used to mitigate the problems associated with excessive growth of plant biomass: mainly less drainage capacity and higher flood risk. However, such control measures are cost and labor-intensive and do not present long-term efficiency. Although the high sensitivity of aquatic vegetation to instream hydraulic conditions is well known, management approaches based on flow management remain relatively unexplored. The aim of our study was therefore to apply physical habitat simulation techniques promoted by the Instream Flow Incremental Method (IFIM) to aquatic macrophytes - the first time it has been applied in this context - in order to model shifts in habitat suitability under different flow scenarios in the Sorraia river in central Portugal. We used this approach to test whether the risk of invasion and channel encroachment by nuisance species can be controlled by setting minimum annual flows. We used 960 randomly distributed survey points to analyze the habitat suitability for the most important aquatic species (including the invasive Brazilian milfoil Myriophyllum aquaticum, Sparganium erectum, and Potamogeton crispus) in regard to the physical parameters 'flow velocity,' 'water depth,' and 'substrate size'. We chose the lowest discharge period of the year in order to assess the hydraulic conditions while disturbances were at a low-point, thus allowing aquatic vegetation establishment and subsistence. We then used the two-dimensional hydraulic River2D software to model the potential habitat availability for different flow conditions based on the site-specific habitat suitability index for each physical parameter and species. Our results show that the growth and distribution of macrophytes in the hydrologically stable vegetation period is primarily a function of the local physical instream condition. Using site-specific preference curves and a two dimensional hydraulic model, it was possible to determine minimum annual flows that might prevent the excessive growth and channel encroachment caused by Myriophyllum aquaticum. PMID- 29616066 TI - Modify the Histone to Win the Battle: Chromatin Dynamics in Plant-Pathogen Interactions. AB - Relying on an immune system comes with a high energetic cost for plants. Defense responses in these organisms are therefore highly regulated and fine-tuned, permitting them to respond pertinently to the attack of a microbial pathogen. In recent years, the importance of the physical modification of chromatin, a highly organized structure composed of genomic DNA and its interacting proteins, has become evident in the research field of plant-pathogen interactions. Several processes, including DNA methylation, changes in histone density and variants, and various histone modifications, have been described as regulators of various developmental and defense responses. Herein, we review the state of the art in the epigenomic aspects of plant immunity, focusing on chromatin modifications, chromatin modifiers, and their physiological consequences. In addition, we explore the exciting field of understanding how plant pathogens have adapted to manipulate the plant epigenomic regulation in order to weaken their immune system and thrive in their host, as well as how histone modifications in eukaryotic pathogens are involved in the regulation of their virulence. PMID- 29616068 TI - Structure and Function of the Photosystem Supercomplexes. AB - Photosynthesis converts solar energy into chemical energy to sustain all life on earth by providing oxygen and food, and controlling the atmospheric carbon dioxide. During this process, the water-splitting and oxygen-evolving reaction is catalyzed by photosystem II (PSII), while photosystem I (PSI) generates the reducing power for the reduction of NADP+ to NADPH. Together with their peripheral light-harvesting complexes (LHCs), photosystems function as multisubunit supercomplexes located in the thylakoid membranes of cyanobacteria, algae, and plants. Recent advances in single-particle cryo-electron microscopy (cryoEM), X-ray free electron laser (XFEL) and other techniques have revealed unprecedented structural and catalytic details concerning the two supercomplexes. Several high-resolution structures of the complexes from plants were solved, and serial time-resolved crystallography and "radiation-damage-free" femtosecond XFEL also provided important insights into the mechanism of water oxidation. Here, we review these exciting advances in the studies of the photosystem supercomplexes with an emphasis on PSII-LHCII, propose presently unresolved problems in this field, and suggest potential tendencies for future studies. PMID- 29616069 TI - Association Study Reveals Novel Genes Related to Yield and Quality of Fruit in Cape Gooseberry (Physalis peruviana L.). AB - Association mapping has been proposed as an efficient approach to assist plant breeding programs to investigate the genetic basis of agronomic traits. In this study, we evaluated 18 traits related to yield, (FWP, NF, FWI, and FWII), fruit size-shape (FP, FA, MW, WMH, MH, HMW, DI, FSI, FSII, OVO, OBO), and fruit quality (FIR, CF, and SST), in a diverse collection of 100 accessions of Physalis peruviana including wild, landraces, and anther culture derived lines. We identified seven accessions with suitable traits: fruit weight per plant (FWP) > 7,000 g/plant and cracked fruits (CF) < 4%, to be used as parents in cape gooseberry breeding program. In addition, the accessions were also characterized using Genotyping By Sequencing (GBS). We discovered 27,982 and 36,142 informative SNP markers based on the alignment against the two cape gooseberry references transcriptomes. Besides, 30,344 SNPs were identified based on alignment to the tomato reference genome. Genetic structure analysis showed that the population could be divided into two or three sub-groups, corresponding to landraces-anther culture and wild accessions for K = 2 and wild, landraces, and anther culture plants for K = 3. Association analysis was carried out using a Mixed Linear Model (MLM) and 34 SNP markers were significantly associated. These results reveal the basis of the genetic control of important agronomic traits and may facilitate marker-based breeding in P. peruviana. PMID- 29616070 TI - The Rice Rolled Fine Striped (RFS) CHD3/Mi-2 Chromatin Remodeling Factor Epigenetically Regulates Genes Involved in Oxidative Stress Responses During Leaf Development. AB - In rice (Oryza sativa), moderate leaf rolling increases photosynthetic competence and raises grain yield; therefore, this important agronomic trait has attracted much attention from plant biologists and breeders. However, the relevant molecular mechanism remains unclear. Here, we isolated and characterized Rolled Fine Striped (RFS), a key gene affecting rice leaf rolling, chloroplast development, and reactive oxygen species (ROS) scavenging. The rfs-1 gamma-ray allele and the rfs-2 T-DNA insertion allele of RFS failed to complement each other and their mutants had similar phenotypes, producing extremely incurved leaves due to defective development of vascular cells on the adaxial side. Map based cloning showed that the rfs-1 mutant harbors a 9-bp deletion in a gene encoding a predicted CHD3/Mi-2 chromatin remodeling factor belonging to the SNF2 ATP-dependent chromatin remodeling family. RFS was expressed in various tissues and accumulated mainly in the vascular cells throughout leaf development. Furthermore, RFS deficiency resulted in a cell death phenotype that was caused by ROS accumulation in developing leaves. We found that expression of five ROS scavenging genes [encoding catalase C, ascorbate peroxidase 8, a putative copper/zinc superoxide dismutase (SOD), a putative SOD, and peroxiredoxin IIE2] decreased in rfs-2 mutants. Western-blot and chromatin immunoprecipitation (ChIP) assays demonstrated that rfs-2 mutants have reduced H3K4me3 levels in ROS-related genes. Loss-of-function in RFS also led to multiple developmental defects, affecting pollen development, grain filling, and root development. Our results suggest that RFS is required for many aspects of plant development and its function is closely associated with epigenetic regulation of genes that modulate ROS homeostasis. PMID- 29616071 TI - Molecular Cytogenetic Characterization of New Wheat-Dasypyrum breviaristatum Introgression Lines for Improving Grain Quality of Wheat. AB - As an important relative of wheat (Triticum aestivum L), Dasypyrum breviaristatum contains novel high molecular weight glutenin subunits (HMW-GSs) encoded by Glu 1Vb genes. We identified new wheat-D. breviaristatum chromosome introgression lines including chromosomes 1Vb and 1VbL.5VbL by fluorescence in situ hybridization (FISH) combined with molecular markers. We found that chromosome changes occurred in the wheat-D. breviaristatum introgression lines and particularly induced the deletion of 5BS terminal repeats and formation of a new type of 5B-7B reciprocal translocation. The results imply that the D. breviaristatum chromosome 1Vb may contain genes which induce chromosomal recombination in wheat background. Ten putative high molecular weight glutenin subunit (HMW-GS) genes from D. breviaristatum and wheat-D. breviaristatum introgression lines were isolated. The lengths of the HMW-GS genes in Dasypyrum were significantly shorter than typical HMW-GS of common wheat. A new y-type HMW GS gene, named Glu-Vb1y, was characterized in wheat-D. breviaristatum 1Vb introgression lines. The new wheat-D. breviaristatum germplasm displayed reduced plant height, increased tillers and superior grain protein and gluten contents, improved gluten performance index. The results showed considerable potential for utilization of D. breviaristatum chromosome 1Vb segments in future wheat improvement. PMID- 29616072 TI - Genomic Selection Outperforms Marker Assisted Selection for Grain Yield and Physiological Traits in a Maize Doubled Haploid Population Across Water Treatments. AB - To increase genetic gain for tolerance to drought, we aimed to identify environmentally stable QTL in per se and testcross combination under well-watered (WW) and drought stressed (DS) conditions and evaluate the possible deployment of QTL using marker assisted and/or genomic selection (QTL/GS-MAS). A total of 169 doubled haploid lines derived from the cross between CML495 and LPSC7F64 and 190 testcrosses (tester CML494) were evaluated in a total of 11 treatment-by population combinations under WW and DS conditions. In response to DS, grain yield (GY) and plant height (PHT) were reduced while time to anthesis and the anthesis silking interval (ASI) increased for both lines and hybrids. Forty-eight QTL were detected for a total of nine traits. The allele derived from CML495 generally increased trait values for anthesis, ASI, PHT, the normalized difference vegetative index (NDVI) and the green leaf area duration (GLAD; a composite trait of NDVI, PHT and senescence) while it reduced trait values for leaf rolling and senescence. The LOD scores for all detected QTL ranged from 2.0 to 7.2 explaining 4.4 to 19.4% of the observed phenotypic variance with R2 ranging from 0 (GY, DS, lines) to 37.3% (PHT, WW, lines). Prediction accuracy of the model used for genomic selection was generally higher than phenotypic variance explained by the sum of QTL for individual traits indicative of the polygenic control of traits evaluated here. We therefore propose to use QTL-MAS in forward breeding to enrich the allelic frequency for a few desired traits with strong additive QTL in early selection cycles while GS-MAS could be used in more mature breeding programs to additionally capture alleles with smaller additive effects. PMID- 29616073 TI - Defective APETALA2 Genes Lead to Sepal Modification in Brassica Crops. AB - Many vegetable and oilseed crops belong to Brassica species. The seed production of these crops is hampered often by abnormal floral organs, especially under the conditions of abiotic conditions. However, the molecular reasons for these abnormal floral organs remains poorly understood. Here, we report a novel pistil like flower mutant of B. rapa. In the flower of this mutant, the four sepals are modified to one merged carpel that look like a ring in the sepal positions, enveloping some abnormal stamens and a pistil, and resulting in poor seed production. This novel mutant is named sepal-carpel modification (scm). DNA sequencing showed that the BrAP2a gene, the ortholog of Arabidopsis APETALA2 (AP2) that specifies sepal identity, losses the function of in scm mutant due to a 119-bp repeated sequence insertion that resulted in an early transcription termination. BrAP2b, the paralog of BrAP2a featured two single-nucleotide substitutions that cause a single amino acid substitution in the highly conserved acidic serine-rich transcriptional activation domain. Each of the two BrAP2 genes rescues the sepal defective phenotype of the ap2-5 mutant of Arabidopsis. Furthermore, the knockout mutation of the corresponding BnAP2 genes of oilseed rape (B. napus) by CRISPR/Cas9-mediated genome editing system resulted in scm like phenotype. These results suggest that BrAP2 gene plays a key role in sepal modification. Our finding provides an insight into molecular mechanism underlying morphological modification of floral organs and is useful for genetic manipulation of flower modification and improvement of seed production of Brassica crops. PMID- 29616074 TI - The Impact of Phosphorus Supply on Selenium Uptake During Hydroponics Experiment of Winter Wheat (Triticum aestivum) in China. AB - Selenium (Se) is a necessary trace element for humans and animals, and Se fertilization is an efficient way to increase Se concentration in the edible parts of crops, thus enhance the beneficiary effects of Se in human and animal health. Due to the similarity of physical and chemical properties between phosphate () and selenite (), phosphorus (P) supply often significantly impacts the absorption of Se in plants, but little is known about how P supply influences the subcellular distribution and chemical forms of Se. In this study, the effects of P supply on subcellular distribution and chemical forms of Se in winter wheat were investigated in a hydroponic trial with medium Se level (0.1 mg Se L-1). P was applied with three concentrations (0.31, 3.1, and 31 mg P L-1) in the experiment. The results showed that increasing P supply significantly decreased the concentration and accumulation of Se in the roots, stems, and leaves of winter wheat. An increase in P supply significantly inhibited Se accumulation in the root cell wall, but enhanced Se distribution in the organelles and soluble fraction of root cells. These findings suggest that increased P supply inhibited the root-to-shoot transport of Se. An increase in P supply enhanced Se accumulation in the cell wall of plant stems (both apical and axillary stem) and cell organelles of plants leaves, but inhibited Se distribution in the soluble fraction of stems and leaves. This suggests that P supply enhances Se transportation across the cell membrane in shoots of winter wheat. In addition, increased P supply also altered the chemical forms of Se in tissues of winter wheat. These findings will help in understanding of the regulation grain Se accumulation and provide a practical way to enhance Se intake for humans inform Se-enriched grains. PMID- 29616075 TI - Genome-Wide Gene Expression Disturbance by Single A1/C1 Chromosome Substitution in Brassica rapa Restituted From Natural B. napus. AB - Alien chromosome substitution (CS) lines are treated as vital germplasms for breeding and genetic mapping. Previously, a whole set of nine Brassica rapa oleracea monosonic alien addition lines (MAALs, C1-C9) was established in the background of natural B. napus genotype "Oro," after the restituted B. rapa (RBR) for Oro was realized. Herein, a monosomic substitution line with one alien C1 chromosome (Cs1) in the RBR complement was selected in the progenies of MAAL C1 and RBR, by the PCR amplification of specific gene markers and fluorescence in situ hybridization. Cs1 exhibited the whole plant morphology similar to RBR except for the defective stamens without fertile pollen grains, but it produced some seeds and progeny plants carrying the C1 chromosome at high rate besides those without the alien chromosome after pollinated by RBR. The viability of the substitution and its progeny for the RBR diploid further elucidated the functional compensation between the chromosome pairs with high homoeology. To reveal the impact of such aneuploidy on genome-wide gene expression, the transcriptomes of MAAL C1, Cs1 and euploid RBR were analyzed. Compared to RBR, Cs1 had sharply reduced gene expression level across chromosome A1, demonstrating the loss of one copy of A1 chromosome. Both additional chromosome C1 in MAAL and substitutional chromosome C1 in Cs1 caused not only cis-effect but also prevalent trans-effect differentially expressed genes. A dominant gene dosage effects prevailed among low expressed genes across chromosome A1 in Cs1, and moreover, dosage effects for some genes potentially contributed to the phenotype deviations. Our results provided novel insights into the transcriptomic perturbation and gene dosage effects on phenotype in CS related to one naturally evolved allopolyploid. PMID- 29616076 TI - Transcriptional Responses Reveal Similarities Between Preclinical Rat Liver Testing Systems. AB - Toxicogenomics (TGx) is an important tool to gain an enhanced understanding of toxicity at the molecular level. Previously, we developed a pair ranking (PRank) method to assess in vitro to in vivo extrapolation (IVIVE) using toxicogenomic datasets from the Open Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System (TG-GATEs) database. With this method, we investiagted three important questions that were not addressed in our previous study: (1) is a 1-day in vivo short-term assay able to replace the 28-day standard and expensive toxicological assay? (2) are some biological processes more conservative across different preclinical testing systems than others? and (3) do these preclinical testing systems have the similar resolution in differentiating drugs by their therapeutic uses? For question 1, a high similarity was noted (PRank score = 0.90), indicating the potential utility of shorter term in vivo studies to predict outcome in longer term and more expensive in vivo model systems. There was a moderate similarity between rat primary hepatocytes and in vivo repeat-dose studies (PRank score = 0.71) but a low similarity (PRank score = 0.56) between rat primary hepatocytes and in vivo single dose studies. To address question 2, we limited the analysis to gene sets relevant to specific toxicogenomic pathways and we found that pathways such as lipid metabolism were consistently over represented in all three assay systems. For question 3, all three preclinical assay systems could distinguish compounds from different therapeutic categories. This suggests that any noted differences in assay systems was biological process dependent and furthermore that all three systems have utility in assessing drug responses within a certain drug class. In conclusion, this comparison of three commonly used rat TGx systems provides useful information in utility and application of TGx assays. PMID- 29616077 TI - Karyotypic Diversity and Evolution in a Sympatric Assemblage of Neotropical Electric Knifefish. AB - Chromosome changes can perform an important role in speciation by acting as post zygotic reproductive barriers. The Neotropical electric fish genus Brachyhypopomus (Gymnotiformes, Hypopomidae) has 28 described species, but cytogenetic data are hitherto available only for four of them. To understand karyotype evolution and investigate the possible role of chromosome changes in the diversification of this genus, we describe here the karyotype of eight species of Brachyhypopomus from a sympatric assemblage in the central Amazon basin. We analyzed cytogenetic data in the context of a phylogenetic reconstruction of the genus and known patterns of geographical distribution. We found a strong phylogenetic signal for chromosome number and noted that sympatric species have exclusive karyotypes. Additional insights into the role of chromosome changes in the diversification of Brachyhypopomus are discussed. PMID- 29616078 TI - Adjusting for Batch Effects in DNA Methylation Microarray Data, a Lesson Learned. AB - It is well-known, but frequently overlooked, that low- and high-throughput molecular data may contain batch effects, i.e., systematic technical variation. Confounding of experimental batches with the variable(s) of interest is especially concerning, as a batch effect may then be interpreted as a biologically significant finding. An integral step toward reducing false discovery in molecular data analysis includes inspection for batch effects and accounting for this signal if present. In a 30-sample pilot Illumina Infinium HumanMethylation450 (450k array) experiment, we identified two sources of batch effects: row and chip. Here, we demonstrate two approaches taken to process the 450k data in which an R function, ComBat, was applied to adjust for the non biological signal. In the "initial analysis," the application of ComBat to an unbalanced study design resulted in 9,612 and 19,214 significant (FDR < 0.05) DNA methylation differences, despite none present prior to correction. Suspicious of this dramatic change, a "revised processing" included changes to our analysis as well as a greater number of samples, and successfully reduced batch effects without introducing false signal. Our work supports conclusions made by an article previously published in this journal: though the ultimate antidote to batch effects is thoughtful study design, every DNA methylation microarray analysis should inspect, assess and, if necessary, account for batch effects. The analysis experience presented here can serve as a reminder to the broader community to establish research questions a priori, ensure that they match with study design and encourage communication between technicians and analysts. PMID- 29616081 TI - Insertion/Deletion Within the KDM6A Gene Is Significantly Associated With Litter Size in Goat. AB - A previous whole-genome association analysis identified lysine demethylase 6A (KDM6A), which encodes a type of histone demethylase, as a candidate gene associated to goat fecundity. KDM6A gene knockout mouse disrupts gametophyte development, suggesting that it has a critical role in reproduction. In this study, goat KDM6A mRNA expression profiles were determined, insertion/deletion (indel) variants in the gene identified, indel variants effect on KDM6A gene expression assessed, and their association with first-born litter size analyzed in 2326 healthy female Shaanbei white cashmere goats. KDM6A mRNA was expressed in all tissues tested (heart, liver, spleen, lung, kidney, muscle, brain, skin and testis); the expression levels in testes at different developmental stages [1 week-old (wk), 2, 3 wk, 1-month-old (mo), 1.5 and 2 mo] indicated a potential association with the mitosis-to-meiosis transition, implying that KDM6A may have an essential role in goat fertility. Meanwhile, two novel intronic indels of 16 bp and 5 bp were identified. Statistical analysis revealed that only the 16 bp indel was associated with first-born litter size (P < 0.01), and the average first-born litter size of individuals with an insertion/insertion genotype higher than that of those with the deletion/deletion genotype (P < 0.05). There was also a significant difference in genotype distributions of the 16 bp indel between mothers of single-lamb and multi-lamb litters in the studied goat population (P = 0.001). Consistently, the 16 bp indel also had a significant effect on KDM6A gene expression. Additionally, there was no significant linkage disequilibrium (LD) between these two indel loci, consistent with the association analysis results. Together, these findings suggest that the 16 bp indel in KDM6A may be useful for marker-assisted selection (MAS) of goats. PMID- 29616079 TI - STAT6, PBX2, and PBRM1 Emerge as Predicted Regulators of 452 Differentially Expressed Genes Associated With Puberty in Brahman Heifers. AB - The liver plays a central role in metabolism and produces important hormones. Hepatic estrogen receptors and the release of insulin-like growth factor 1 (IGF1) are critical links between liver function and the reproductive system. However, the role of liver in pubertal development is not fully understood. To explore this question, we applied transcriptomic analyses to liver samples of pre- and post-pubertal Brahman heifers and identified differentially expressed (DE) genes and genes encoding transcription factors (TFs). Differential expression of genes suggests potential biological mechanisms and pathways linking liver function to puberty. The analyses identified 452 DE genes and 82 TF with significant contribution to differential gene expression by using a regulatory impact factor metric. Brain-derived neurotrophic factor was observed as the most down-regulated gene (P = 0.003) in post-pubertal heifers and we propose this gene influences pubertal development in Brahman heifers. Additionally, co-expression network analysis provided evidence for three TF as key regulators of liver function during pubertal development: the signal transducer and activator of transcription 6, PBX homeobox 2, and polybromo 1. Pathway enrichment analysis identified transforming growth factor-beta and Wnt signaling pathways as significant annotation terms for the list of DE genes and TF in the co-expression network. Molecular information regarding genes and pathways described in this work are important to further our understanding of puberty onset in Brahman heifers. PMID- 29616080 TI - Fishing Into the MicroRNA Transcriptome. AB - In the last decade, several studies have been focused on revealing the microRNA (miRNA) repertoire and determining their functions in farm animals such as poultry, pigs, cattle, and fish. These small non-protein coding RNA molecules (18 25 nucleotides) are capable of controlling gene expression by binding to messenger RNA (mRNA) targets, thus interfering in the final protein output. MiRNAs have been recognized as the main regulators of biological features of economic interest, including body growth, muscle development, fat deposition, and immunology, among other highly valuable traits, in aquatic livestock. Currently, the miRNA repertoire of some farmed fish species has been identified and characterized, bringing insights about miRNA functions, and novel perspectives for improving health and productivity. In this review, we summarize the current advances in miRNA research by examining available data on Neotropical and other key species exploited by fisheries and in aquaculture worldwide and discuss how future studies on Neotropical fish could benefit from this knowledge. We also make a horizontal comparison of major results and discuss forefront strategies for miRNA manipulation in aquaculture focusing on forward-looking ideas for forthcoming research. PMID- 29616082 TI - Disruption of Claudin-1 Expression by miRNA-182 Alters the Susceptibility to Viral Infectivity in HCV Cell Models. AB - HCV entry involves a complex interplay between viral and host molecules. During post-binding interactions, the viral E2 complexes with CD81 receptor for delivery to the tight junction proteins CLDN1 and OCLN, which aid in viral internalization. Targeting HCV entry receptors represents an appealing approach to inhibit viral infectivity. This study aimed at investigating the impact of targeting CLDN1 by microRNAs on HCV infectivity. miR-155 was previously shown to target the 3'UTR of CLDN1 mRNA. Therefore, miR-155 was used as a control in this study. In-silico analysis and luciferase reporter assay were utilized to identify potential targeting miRNAs. The impact of the identified miRNAs on CLDN1 mRNA and protein expression was examined by qRT-PCR, indirect immunofluorescence and western blotting, respectively. The role of the selected miRNAs on HCV infectivity was assessed by measuring the viral load following the ectopic expression of the selected miRNAs. miR-182 was identified in-silico and by experimental validation to target CLDN1. Both miR-155 and miR-182 inhibited CLDN1 mRNA and protein expression in infected Huh7 cells. Ectopic expression of miR-155 increased, while miR-182 reduced the viral load. In conclusion, despite repressing CLDN1, the impact of miR-155 and miR-182 on HCV infectivity is contradictory. Ectopic miR-182 expression is suggested as an upstream regulator of the entry factor CLDN1, harnessing HCV infection. PMID- 29616084 TI - ? AB - [This retracts the article on p. 672 in vol. 31, PMID: 26150866.]. PMID- 29616083 TI - Defining the Damaged DNA Mobility Paradox as Revealed by the Study of Telomeres, DSBs, Microtubules and Motors. AB - Eukaryotic genomes are non-randomly arranged inside the nucleus. Despite this ordered spatial genome organization, damaged DNA exhibits increased random mobility within nuclear space. This increased random movement is thought to promote DNA repair by facilitating homology search, allowing targeting to repair conducive nuclear domains, or releasing damage from repair-repressive locations. Recent studies focusing on the relationship between telomeres, DNA repair processes, and nuclear organization have revealed that the disruption of motor proteins or microtubules, which typically mediate the directed motion of cargo, disrupts the random mobility of damaged DNA. These findings define a new biological paradox. Here, I define this as the damaged DNA mobility paradox, describe how it uncovers key gaps in knowledge, and highlight key questions to help guide us toward paradox resolution. PMID- 29616085 TI - Assessment of telomerase activity in leukocytes of type 2 diabetes mellitus patients having or not foot ulcer: Possible correlation with other clinical parameters. AB - Telomerase is the enzyme that maintains telomere length by adding telomeric repeats after each cell division. Numerous metabolic factors such as obesity, insulin resistance or physical inactivity have been associated with shortened telomeres. In the present study, we assessed telomerase activity in diabetic patients having or not foot ulcer. A total of 90 adult patients with type 2 diabetes mellitus (T2DM) were studied. Patients were allocated into two groups according to the absence or presence of active foot ulcers as follows: Nuon-ulcer group (N=58) and ulcer group (N=32). Our data revealed that the patients with diabetic ulcers had significantly greater waist circumference and neuropathy disability score, while exhibiting lower telomerase activity, indicating the possible existence of a common clinical profile among ulcer-bearing diabetic patients. Validation of our findings by extending the study in larger patient groups may contribute to the understanding of T2DM pathophysiology and its main clinical implications. PMID- 29616086 TI - Kissing aneurysms of the distal anterior cerebral artery: A case report and literature review. AB - Intracranial 'kissing' aneurysms are rare types of multiple aneurysms referring to two adjacent aneurysms arising from identical or different arteries with separate origins and partially adherent walls. The present study reported a 54 year-old female patient, who was identified with a 'kissing' aneurysm in the A3 segment of the bilateral anterior cerebral arteries, as demonstrated by head computed tomography and emergency cerebral digital subtraction angiography analysis. In total, 12 days following the clipping of the aneurysms, the patient was discharged with a Modified Rankin Scale=0 and recovered well with no neurological deficits. Based on previous literature, it was indicated that the majority of patients with 'kissing' aneurysm have a good prognosis and the cure rate is as high as 96.8%. However, the recovery rate may not be that high as the sample size is not large enough to thoroughly demonstrate the complete prognosis of 'kissing' aneurysms. PMID- 29616087 TI - Identification of potential key genes and high-frequency mutant genes in prostate cancer by using RNA-Seq data. AB - The aim of the present study was to identify potential key genes and single nucleotide variations (SNVs) in prostate cancer. RNA sequencing (RNA-seq) data, GSE22260, were downloaded from the Gene Expression Omnibus database, including 4 prostate cancer samples and 4 normal tissues samples. RNA-Seq reads were processed using Tophat and differentially-expressed genes (DEGs) were identified using the Cufflinks package. Gene Ontology enrichment analysis of DEGs was performed. Subsequently, Seqpos was used to identify the potential upstream regulatory elements of DEGs. SNV was analyzed using Genome Analysis Toolkit. In addition, the frequency and risk-level of mutant genes were calculated using VarioWatch. A total of 150 upregulated and 211 downregulated DEGs were selected and 25 upregulated and 17 downregulated potential upstream regulatory elements were identified, respectively. The SNV annotations of somatic mutations revealed that 65% were base transition and 35% were base transversion. At frequencies >=2, a total of 17 mutation sites were identified. The mutation site with the highest frequency was located in the folate hydrolase 1B (FOLH1B) gene. Furthermore, 20 high-risk mutant genes with high frequency were identified using VarioWatch, including ribosomal protein S4 Y-linked 2 (RPS4Y2), polycystin 1 transient receptor potential channel interacting (PKD1) and FOLH1B. In addition, kallikrein 1 (KLK1) and PKD1 are known tumor suppressor genes. The potential regulatory elements and high-frequency mutant genes (RPS4Y2, KLK1, PKD1 and FOLH1B) may have key functions in prostate cancer. The results of the present study may provide novel information for the understanding of prostate cancer development. PMID- 29616088 TI - Retrospective screening of microarray data to identify candidate IFN-inducible genes in a HTLV-1 transformed model. AB - HuT-102 cells are considered one of the most representable human T-lymphotropic virus 1 (HTLV-1)-infected cell lines for studying adult T-cell lymphoma (ATL). In our previous studies, genome-wide screening was performed using the GeneChip system with Human Genome Array U133 Plus 2.0 for transforming growth factor-beta activated kinase 1 (TAK1)-, interferon regulatory factor 3 (IRF3)- and IRF4 regulated genes to demonstrate the effects of interferon-inducible genes in HuT 102 cells. Our previous findings demonstrated that TAK1 induced interferon inducible genes via an IRF3-dependent pathway and that IRF4 has a counteracting effect. As our previous data was performed by manual selection of common interferon-related genes mentioned in the literature, there has been some obscure genes that have not been considered. In an attempt to maximize the outcome of those microarrays, the present study reanalyzed the data collected in previous studies through a set of computational rules implemented using 'R' software, to identify important candidate genes that have been missed in the previous two studies. The final list obtained consisted of ten genes that are highly recommend as potential candidate for therapies targeting the HTLV-1 infected cancer cells. Those genes are ATM, CFTR, MUC4, PARP14, QK1, UBR2, CLEC7A (Dectin-1), L3MBTL, SEC24D and TMEM140. Notably, PARP14 has gained increased attention as a promising target in cancer cells. PMID- 29616089 TI - Pedigree analysis, diagnosis and treatment in Von Hippel-Lindau syndrome: A report of three cases. AB - The objective of the present study was to systematically investigate the clinical features, diagnosis and therapeutic treatment of Von Hippel-Lindau (VHL) syndrome in order to improve understanding of this disease. A total of 3 cases of VHL syndrome treated at the Affiliated Hospital of Zunyi Medical College (Zunyi, China) between September 2014 and October 2015 were retrospectively analyzed. The associated literature was reviewed, and the diagnostic and therapeutic features were discussed. Case 1 was diagnosed as VHL syndrome accompanied by a renal tumor on the right side, and radical tumor resection in the right kidney was performed. Postoperative pathological examination indicated clear cell carcinoma. Case 2 was diagnosed as VHL syndrome accompanied by bilateral adrenal pheochromocytoma. The left-side adrenal tumor was removed, and postoperative pathological analysis was suggestive of adrenal pheochromocytoma. Case 3 visited the hospital due to the presence of masses on the left and right sides of the kidney, but did not undergo surgery for personal reasons. Follow-ups were scheduled subsequent to surgery at another hospital. The diagnosis in all 3 cases was confirmed by genetic testing, where VHL mutations were detected in all patients. Following surgery, pedigree and genetic analysis was performed in all 3 pedigrees and VHL mutations were identified in 7 family members. The diagnosis of VHL syndrome should be based on the clinical manifestation of the patients and the results of genetic tests. DNA analysis of mutations is the main method for diagnosis. An appropriate surgical plan should be formulated based on the site, size and number of tumors, and the condition of the patient. Since VHL syndrome is an inheritable genetic disorder and relapse following surgery is common, pedigree analysis of the patient and lifelong follow-ups are essential. Additionally, physicians should pay attention to VHL syndrome in order to avoid missing diagnosis or misdiagnosis. PMID- 29616090 TI - Clinical value and potential pathways of miR-183-5p in bladder cancer: A study based on miRNA-seq data and bioinformatics analysis. AB - The clinicopathological value and exploration of the potential molecular mechanism of microRNA-183-5p (miR-183-5p) have been investigated in various cancers; however, to the best of the author's knowledge, no similar research has been reported for bladder cancer. In the present study, it was revealed that the expression level of miR-183-5p was notably increased in bladder cancer tissues compared with adjacent non-cancerous tissues (P=0.001) and was markedly increased in the tissue samples of papillary, pathological T stage (T0-T2) and pathological stage (I-II) compared with tissue samples of their counterparts (P=0.05), according to data from The Cancer Genome Atlas. Receiver operating characteristic analysis revealed the robust diagnostic value of miR-183-5p for distinguishing bladder cancer from non-cancerous bladder tissues (area under curve=0.948; 95% confidence interval: 0.919-0.977). Amplification and deep deletion of miR-183-5p were indicated by cBioPortal, accounting for 1% (4/412) of bladder cancer cases. Data from YM500v3 demonstrated that compared with other cancers, bladder cancer exhibited high expression levels of miR-183-5p, and miR-183-5p expression in primary solid tumors was much higher compared with solid normal tissues. A meta analysis indicated that miR-183-5p was more highly expressed in bladder cancer samples compared with normal counterparts. A total of 88 potential target genes of miR-183-5p were identified, 13 of which were discerned as hub genes by protein protein interaction. The epithelial-to-mesenchymal transition pathway was the most significantly enriched pathway by FunRich (P=0.0001). In summary, miR-183-5p may participate in the tumorigenesis and development of bladder cancer via certain signaling pathways, particularly the epithelial-to-mesenchymal transition pathway. However, the exact molecular mechanism of miR-183-5p in bladder cancer must be validated by in vitro and in vivo experiments. PMID- 29616093 TI - Expression of the microRNA-143/145 cluster is decreased in hepatitis B virus associated hepatocellular carcinoma and may serve as a biomarker for tumorigenesis in patients with chronic hepatitis B. AB - The aims of the present study were to identify the expression profile of microRNA (miR)-143/145 in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC), explore its association with prognosis and investigate whether the serum miR-143/145 expression levels may serve as a diagnostic indicator of HBV associated HCC. The microRNA (miRNA) chromatin immunoprecipitation dataset was obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus databases, and analyzed using the Wilcoxon signed-rank test. It was observed that the expression of miR-143 and miR-145 was decreased 1.5-fold in HBV-associated HCC samples compared with non-tumor tissue in the TCGA and the GSE22058 datasets (P<0.01). Using the reverse transcription-quantitative polymerase chain reaction, it was further confirmed that miR-143/145 and their host gene MIR143HG were downregulated in HBV-associated HCC tissues compared with corresponding distal non-tumor tissues. The lower level of miR-143 and miR-145 expression was associated with tumor differentiation, and may thus be responsible for a poor prognosis of patients with HBV-associated HCC. The receiver-operating characteristic (ROC) curves were used to explore the potential value of miR-143 and miR-145 as biomarkers for predicting HBV-associated HCC tumorigenesis. In serum, miR-143/145 were identified to be significantly decreased in patients with HBV-associated HCC compared with negative control patients, and their associated areas under the ROC curves were calculated at 0.813 and 0.852 (P<0.05), with each having a sensitivity and a specificity close to 0.80. These results indicated that the decreased expression of the miR-143/145 cluster and their host gene MIR143HG in HBV-associated HCC tissue was associated with prognosis, and each of these miRNAs may serve as a valuable diagnostic biomarker for predicting HBV associated HCC tumorigenesis. PMID- 29616092 TI - Endoplasmic reticulum chaperone glucose-regulated protein 78 in gastric cancer: An emerging biomarker. AB - The endoplasmic reticulum (ER) is the principal organelle responsible for the synthesis, initial post-translational modification, folding, export and secretion of proteins. It is also responsible for the maintenance of cellular homeostasis. In response to cellular stress conditions including glucose deprivation, hypoxia and changes in calcium homeostasis, ER stress machinery is activated and triggers the unfolded protein response, resulting in the restoration of homeostasis or activation of cell death. Glucose-regulated protein 78 (GRP78), a molecular chaperone, may be induced by ER stress at the transcriptional and translational level. A number of studies have demonstrated that GRP78 serves an important role in tumor cell proliferation, metastasis, angiogenesis and drug-resistance. The present review systematically describes the association between GRP78 expression and gastric cancer pathogenesis, and emphasizes that GRP78 is a novel diagnostic and therapeutic biomarker of gastric cancer. PMID- 29616091 TI - Molecular and cellular mechanisms of castration resistant prostate cancer. AB - With increases in the mortality rate and number of patients with prostate cancer (PCa), PCa, particularly the advanced and metastatic disease, has been the focus of a number of studies globally. Over the past seven decades, androgen deprivation therapy has been the primary therapeutic option for patients with advanced PCa; however, the majority of patients developed a poor prognosis stage of castration resistant prostate cancer (CRPC), which eventually led to mortality. Due to CRPC being incurable, laboratory investigations and clinical studies focusing on CRPC have been conducted worldwide. Clarification of the molecular pathways that may lead to CRPC is important for discovering novel therapeutic strategies to delay or reverse the progression of disease. A sustained androgen receptor (AR) signal is still regarded as the main cause of CRPC. Increasing number of studies have proposed different potential mechanisms that cause CRPC, and this has led to the development of novel agents targeting the AR-dependent pathway or AR-independent signaling. In the present review, the major underlying mechanisms causing CRPC, including several major categories of AR-dependent mechanisms, AR bypass signaling, AR-independent mechanisms and other important hypotheses (including the functions of autophagy, PCa stem cell and microRNAs in CRPC progression), are summarized with retrospective pre-clinical or clinical trials to guide future research and therapy. PMID- 29616094 TI - Suv4-20h1 promotes G1 to S phase transition by downregulating p21WAF1/CIP1 expression in chronic myeloid leukemia K562 cells. AB - Methylation of histone H4 lysine 20 (H4K20) has been associated with cancer. However, the functions of the histone methyltransferases that trigger histone H4K20 methylation in cancers, including suppressor of variegation 4-20 homolog 1 (Suv4-20h1), remain elusive. In the present study, it was demonstrated that the knockdown of the histone H4K20 methyltransferase Suv4-20h1 resulted in growth inhibition in chronic myeloid leukemia K562 cells. Disruption of Suv4-20h1 expression induced G1 arrest in the cell cycle and increased expression levels of cyclin dependent kinase inhibitor 1A (p21WAF1/CIP1), an essential cell cycle protein involved in checkpoint regulation. Chromatin immunoprecipitation analysis demonstrated that Suv4-20h1 directly binds to the promoter of the p21 gene and that methylation of histone H4K20 correlates with repression of p21 expression. Thus, these data suggest that Suv4-20h1 is important for the regulation of the cell cycle in K562 cells and may be a potential therapeutic target for leukemia. PMID- 29616095 TI - miR-148a-3p suppresses epithelial ovarian cancer progression primarily by targeting c-Met. AB - MicroRNAs (miRNAs) are a group of small non-coding RNAs that modulate post transcriptional gene expression. It has been demonstrated that various miRNAs may be expressed at different levels in different types of tumors. The present study assessed the role of microRNA-148a-3p (miR-148a-3p) in epithelial ovarian cancer (EOC). The results demonstrated that miR-148a-3p was decreased in EOC tissues and that a lower miRa-148-3p concentration was associated with a higher overall survival rate. Transfection of miR-148a-3p suppressed the invasive and proliferative capacity of SKOV3 cells. The induced overexpression of miR-148a-3p significantly inhibited the relative luciferase activity of the pmirGLO-c-Met 3'untranslated region compared with an empty vector. In addition, c-Met silencing led to a decrease in the invasive and proliferative capacity of EOC cells. The inhibition of miR-148a-3p did not increase the invasiveness of SKOV3 cells, even when c-Met was silenced. To the best of our knowledge, the present study is the first to demonstrate that miR-148a-3p expression is decreased in EOC cancer tissues and cell lines. The present study therefore demonstrated that miR-148a-3p may serve as a tumor suppressor in EOC by targeting c-Met. PMID- 29616096 TI - A comprehensive analysis of the predicted targets of miR-642b-3p associated with the long non-coding RNA HOXA11-AS in NSCLC cells. AB - Long non-coding RNA HOXA11 antisense RNA (HOXA11-AS) has been previously reported to be involved in the tumorigenesis and progression of ovarian cancer and glioma. However, the function of HOXA11-AS in lung cancer remains unclear. Following the knockdown of HOXA11-AS in A549 cells, a microarray analysis was performed in order to detect the differences in microRNA (miRNA/miR) profiles. Subsequently, miR-642b-3p was selected for further analysis. Four miRNA target prediction algorithms were used to identify potential target genes of miR-642b-3p. Bioinformatics analyses, including Gene Ontology (GO), Kyoto Encyclopaedia of Genes and Genomes, protein-protein interactions (PPIs) and network analysis, were performed to investigate the potential functions, pathways and networks of the target genes. Furthermore, the differential expression of miR-642b-3p and its target genes between normal lung and non-small cell lung cancer (NSCLC) tissues was verified using The Cancer Genome Atlas (TCGA) database. Six target genes [zinc finger protein 350, heterogeneous nuclear ribonucleoprotein U, high mobility group box 1, phosphodiesterase 4D (PDE4D), synaptotagmin binding cytoplasmic RNA interacting protein and basic helix-loop-helix family member B9] of miR-642b-3p were predicted using all 4 algorithms. It was revealed that miR 642b-3p was overexpressed in adenocarcinoma and squamous cell carcinoma tissues compared with non-cancerous lung tissues based on the TCGA database. From the 6 target genes, PDE4D was downregulated in lung adenocarcinoma and squamous cell carcinoma tissues, and a weak negative correlation between HOXA11-AS and PDE4D was identified. The area under the curve of PDE4D was 0.905 [95% confidence interval (CI), 0.879-0.931] for patients with lung adenocarcinoma and 0.665 (95% CI, 0.606-0.725) for patients with squamous cell carcinoma. Additionally, GO analysis of the target genes revealed that miR-642b-3p was specifically involved in complex cellular pathways. The target gene RAN binding protein 2 possessed the highest degree of interactions in the PPI network (degree=40). It was hypothesized that HOXA11-AS may have a function in NSCLC by regulating the expression of miR-642b-3p and PDE4D, which laid the foundation for the further elucidation of the potential molecular mechanisms of NSCLC. PMID- 29616097 TI - Prognostic significance of CD117 expression and TP53 missense mutations in triple negative breast cancer. AB - Triple-negative breast cancer (TNBC) is extremely aggressive and associated with poor prognosis. There are no known predictive or prognostic markers for TNBC. Inhibition of tumor protein P53 (TP53) has been demonstrated to increase the levels of cluster of differentiation 117 (CD117) in human colorectal cancer cells. However, the function of TP53 in the regulation of CD117 in TNBC has, to the best of our knowledge, not been reported. In the present study, the association between the expression of CD117 protein and TP53 mutations was investigated, and their prognostic value in patients with TNBC was assessed. A total of 58 TNBC and 48 non-TNBC breast cancer tissue samples were assessed for the expression of CD117, p53 and TP53 mutations. The marker of proliferation Ki 67 (MKI67) proliferation index and vascular invasion index (obtained by measuring D2-40 and CD34) was investigated via immunohistochemistry, and mutations in exons 4-8 of TP53 were measured using direct sequencing. Associations between CD117 and p53 levels or TP53 mutations and clinical parameters were statistically evaluated. The rates of CD117 or MKI67 positivity, CD117+/TP53 missense mutation+, TP53 missense mutations or recurrence were significantly higher in patients with TNBC than in patients with non-TNBC. In TNBC tissues, the presence of CD117 was associated with TP53 missense mutations (P=0.031), vascular invasion, recurrence and MKI67. CD117+/TP53 missense mutation+ also associated with vascular invasion, recurrence and MKI67. Under univariate analysis, MKI67, vascular invasion, CD117, CD117+/TP53 missense mutation+ and TP53 missense mutations were associated with the overall survival of patients with TNBC. Multivariate analysis revealed that vascular invasion and CD117+/TP53 missense mutation+ in primary tumors were independent prognostic factors in patients with TNBC. In conclusion, CD117+/TP53 missense mutation+ was associated with MKI67, vascular invasion and tumor recurrence in TNBC. The presence of CD117 and TP53 missense mutations together in the primary tumors was an independent prognostic factor for survival of patients with TNBC. PMID- 29616098 TI - The function of Notch1 intracellular domain in the differentiation of gastric cancer. AB - Due to the complex function of the Notch signal pathway in gastric cancer (GC), the association between Notch homolog 1 (Notch1) intracellular domain (NICD) and differentiation of GC remains unknown. The present study aimed to investigate the potential association between NICD and GC differentiation, and demonstrated that poorly differentiated GC expressed increased NICD levels compared with well differentiated GC. A gamma-secretase inhibitor inhibited the growth of AGS cells through downregulating NICD level. Additional data suggested that a COX-2 inhibitor caused a marked reduction of NICD level in comparison with a control group treated with dimethyl sulfoxide. Combined administration of gamma-secretase and COX-2 inhibitor produced a marked inhibition of growth in AGS cells, which suggests that patients with poorly differentiated GC may benefit from the blockage of NICD, which potentially serves a role in GC differentiation. PMID- 29616099 TI - Analysis of H3K27me3 expression and DNA methylation at CCGG sites in smoking and non-smoking patients with non-small cell lung cancer and their clinical significance. AB - Smoking frequently leads to epigenetic alterations, including DNA methylation and histone modifications. The effect that smoking has on the DNA methylation levels at CCGG sites, the expression of trimethylation of histone H3 at lysine 27 (H3K27me3) and enhancer of zeste homolog 2 (EZH2), and their interactions in patients with non-small cell lung cancer (NSCLC) were analyzed. There were a total of 42 patients with NSCLC, 22 with adenocarcinomas and 20 with squamous cell carcinomas enrolled in the present study. Expression of H3K27me3, EZH2 and proliferating cellular nuclear antigen (PCNA) were immunohistochemically detected. DNA methylation at CCGG sites was evaluated via histoendonuclease linked detection of DNA methylation sites. The apoptotic index of cancerous tissues obtained from patients of different smoking statuses was evaluated via the terminal deoxynucleotidyl-transferase-mediated dUTP-biotin nick end labeling method. The association with clinicopathological data was calculated relative to different smoking statuses. Compared with the non-smokers, smokers with NSCLC exhibited a significantly lower apoptotic index (P<0.05), and frequently had a lower level of DNA methylation at CCGG sites, lower H3K27me3 expression and a higher EZH2 expression (P<0.05). DNA methylation levels at CCGG sites were negatively correlated to the Brinkman index (P=0.017). Furthermore, there was a parallel association between the H3K27me3 and EZH2 expression levels in the majority of smokers, whereas in the majority of non-smokers, there was a diverging association (P=0.015). There was a diverging association between the PCNA and EZH2 expression levels in the majority of smokers; however, in the majority of non-smokers, there was a parallel association (P=0.048). In addition, the association between the CCGG methylation ratio and immunohistochemical expression of H3K27me3 was a parallel association in the majority of smokers, while in the majority of non-smokers there was a diverging association (P=0.049). Conclusively, patients with NSCLC and different smoking statuses exhibit different epigenetic characteristics. Additionally, DNA methylation levels at the CCGG sites may have the ability to determine associations between the expression levels of H3K27me3, EZH2 and PCNA. PMID- 29616100 TI - Diagnosis and treatment of submucous myoma of the uterus with interventional ultrasound. AB - The value of interventional ultrasound in the diagnosis and treatment of submucous myoma of the uterus was assessed to study the ultrasonographic features of modified sonohysterography for submucous polyp of uterus. A total of 25 patients diagnosed preliminarily as submucous myoma of the uterus via conventional ultrasound examination from June 2014 to December 2016 were enrolled in the study. The diagnosis was made via the comprehensive analysis of ultrasound guided modified SHG, followed by ultrasound-guided needle biopsy and sclerotherapy of tumor. After modified SHG and ultrasound-guided needle biopsy, 96% (24/25) cases were confirmed pathologically as submucous myoma of the uterus. After treatment, the maximum diameter of myoma in patients with submucous myoma of uterus was significantly different, and the volume of myoma was significantly reduced. After treatment, the clinical symptoms of patients with submucous myoma of the uterus were obviously improved compared to before treatment (P<0.05). It was found in the follow-up after treatment that a small number of patients suffered from mild abdominal pain, increased secretion, slight vaginal bleeding, cold sweat, pale complexion, dizziness and other symptoms, which, however, disappeared after treatment for about 1 week. The score of 36 item Short-Form Health Survey Questionnaire of patients with submucous myoma of the uterus was significantly different before and after treatment (P<0.05). Interventional ultrasonography can effectively diagnose the submucous myoma of uterus. The treatment of submucous myoma of uterus with ultrasound-guided intratumor injection of lauromacrogol is characterized by simple operation, which can effectively reduce the tumor diameter and volume, improve the blood flow in patients, reduce the postoperative adverse reactions and alleviate the patient's pain, so it is a new type of minimally invasive treatment method of submucous myoma of the uterus, and it is worthy of clinical promotion and application. PMID- 29616101 TI - Expression of cancer-associated fibroblast markers in advanced colorectal cancer. AB - Colorectal cancer is one of the most common causes of mortality from cancer worldwide. Previous studies have demonstrated that cancer-associated fibroblasts (CAFs) promote neoangiogenesis and tumor growth for various tumors. The present study analyzed CAF markers, including alpha-smooth muscle actin (alpha-SMA), collagen I, platelet-derived growth factor receptor-beta (PDGFR-beta), and D2-40 (antibody recognizing podoplanin), and vessel markers, including cluster of differentiation (CD)31 and CD34, for 121 advanced colorectal cancer cases using a digital image analyzing technique. The association between CAF markers and vessel markers with clinicopathological factors was investigated. Furthermore, the association between CAF markers with each other, and their association with vessel markers was analyzed. Mean/median expression area of stromal and vessel markers in tumors were collagen I, 26.787%; D2-40, 1.372%; PDGFR-beta, 11.646%; alpha-SMA-positive and desmin-negative myofibroblasts (alpha-SMA subtraction), 15.372%; CD31, 3.635%; and CD34, 2.226%. The expression area of alpha-SMA subtraction was significantly correlated with collagen I (P<0.001, correlation rho=0.509). High levels of alpha-SMA subtraction (P=0.002), collagen I (P=0.040), and PDGFR-beta (P=0.040) expressions tended to be associated with high venous invasion. D2-40 did not correlate with other CAF and vessel markers. These results indicated that individual CAFs may have different expression patterns, and different strength effects for venous invasion in advanced colorectal cancer stroma. PMID- 29616102 TI - Hepa1-6-FLuc cell line with the stable expression of firefly luciferase retains its primary properties with promising bioluminescence imaging ability. AB - Reliable animal models are required for the in vivo study of the molecular mechanisms and effects of chemotherapeutic drugs in hepatocarcinoma. In vivo tracing techniques based on firefly luciferase (FLuc) may optimize the non invasive monitoring of experimental animals. The present study established a murine Hepa1-6-FLuc cell line that stably expressed a retrovirus-delivered FLuc protein gene. The cell morphology, proliferation, migration and invasion ability of Hepa1-6-FLuc cells were the same as that of the Hepa1-6 cells, and thus is suitable to replace Hepa1-6 cells in the construction of hepatocarcinoma animal models. No differences in subcutaneous tumor mass and its pathomorphology from implanted Hepa1-6-FLuc cells were observed compared with Hepa1-6 control tumors. Bioluminescence imaging indicated that the Luc signal of the Hepa1-6-FLuc cells was consistently strengthened with increases in tumor mass; however, the Luc signal of Hepa1-6-AdFLuc became weaker and eventually disappeared during tumor development. Therefore, compared with the transient expression by adenovirus, stable expression of the FLuc gene in Hepa1-6 cells may better reflect cell proliferation and survival in vivo, and provide a reliable source for the establishment of hepatocarcinoma models. PMID- 29616103 TI - Paclitaxel increases the sensitivity of lung cancer cells to lobaplatin via PI3K/Akt pathway. AB - The effect of paclitaxel combined with lobaplatin on the sensitivity of lung cancer cell line NCI-H446 through influencing the phosphatidylinositol 3-kinase (PI3K)/Akt pathway was investigated. The sensitivity of lobaplatin to NCI-H446 and the effect of paclitaxel and PI3K inhibitor LY294002 combined with lobaplatin on the sensitivity to NCI-H446 were detected via methyl thiazolyltetrazolium (MTT) assay. The effect of paclitaxel combined with lobaplatin on cell apoptosis was detected using flow cytometry, the effect of paclitaxel combined with lobaplatin on the cell migration was detected via cell wound scratch assay, and the effect of paclitaxel combined with lobaplatin on the cell invasion was detected via Transwell assay. Finally, the effect of paclitaxel on PI3K/Akt pathway was detected via western blotting. MTT assay showed that 30 ug/ml lobaplatin could significantly inhibit the growth of NCI-H446 (p<0.01). Lobaplatin group (group L), 2 ug/ml paclitaxel combined with lobaplatin group (group LP) and lobaplatin combined with 10 umol/ml LY294002 group (group LL) were set up. The cell survival rates in group LP and group LL were significantly lower than that in group L (p<0.01), and the cell survival rate in group LP was similar to that in group LL (p>0.05). Flow cytometry revealed that the cell apoptotic levels in group LP and group LL were obviously higher than that in group L (p<0.01), and there was no statistically significant difference in the cell apoptotic level between group LP and group LL (p>0.05). Cell wound scratch assay showed that the cell migration capacity in group LP was significantly lower than those in group L and group LL (p<0.01, p<0.05), and the cell migration capacity in group LL was lower than that in group L (p<0.05). Besides, Transwell assay revealed that the cell invasion capacity in group LP was obviously lower than those in group L and group LL (p<0.01, p<0.05), and the cell invasion capacity in group LL was lower than that in group L (p<0.01). Finally, western blotting showed that the levels of PI3K, phosphorylated-Akt (p-Akt) and phosphorylated glycogen synthase kinase 3beta (p-GSK3beta) in group LP and group LL were significantly lower than those in group L, and the differences were statistically significant (p<0.01). Paclitaxel can significantly increase the sensitivity of lobaplatin to lung cancer cell line NCI-H446. Moreover, paclitaxel can enhance the effect of lobaplatin on lung cancer cells and reduce the drug resistance through inhibiting PI3K/Akt pathway. PMID- 29616104 TI - High density of CD68+ tumor-associated macrophages predicts a poor prognosis in gastric cancer mediated by IL-6 expression. AB - The aim of the present study was to explore the potential role of cluster of differentiation CD68+ tumor-associated macrophages (TAMs) induced by interleukin (IL)-6 in the progression of gastric cancer (GC) and patient prognosis. The expression levels of IL-6 and CD68 were detected by immunohistochemical staining in 60 samples of tumor and non-tumor gastric tissues. CD14+ monocytes were isolated from peripheral blood mononuclear cells and stimulated with macrophage colony stimulation factor (M-CSF) and IL-6, and the expression levels of IL-10, IL-12, vascular endothelial growth factor (VEGF)-C and transforming growth factor (TGF)-beta were measured by reverse transcription polymerase chain reaction and ELISA. The GC MGC-803 cell line was co-cultured with monocytes stimulated by M CSF and IL-6 and the invasion ability of the MGC-803 was evaluated by Transwell analysis. The levels of STAT3, P-STAT3 and interferon-regulatory factor 4 (IRF4) in the monocytes stimulated by M-CSF and IL-6 were detected by western blotting. The results demonstrated that the frequencies of IL-6+ macrophages (Mphis) and CD68+ Mphis were significantly higher in tumor regions compared with the corresponding non-tumor regions of GC tissues. Kaplan-Meier analysis revealed that the densities of tumor-infiltrating CD68+ or IL-6+ Mphis were inversely associated with the overall survival rates of the patients. In vitro, the expression levels of IL-10, VEGF-C and TGF-beta significantly increased in CD14+ monocytes subsequent to M-CSF and IL-6 stimulation. The invasion abilities of MGC 803 were increased by the monocytes stimulated with M-CSF and IL-6. The levels of STAT3, P-STAT3 and IRF4 proteins increased in the monocytes stimulated by M-CSF and IL-6. In conclusion, the results from the present study suggest that a high density of CD68+ TAMs predicts a poor prognosis in GC. IL-6 may polarize the Mphis and promote tumor invasion through the IL-6/STAT3/IRF4 signaling pathway. PMID- 29616105 TI - Establishment of a murine breast tumor model by subcutaneous or orthotopic implantation. AB - A number of murine models are used to mimic the pathology of breast cancer. Tissue inoculation and cell inoculation using orthotopic implantation (OS) and subcutaneous implantation (SQ) are commonly used to generate murine models to investigate cancer. However, limited information is available in regard to the variations of these methods. The present study compared growth, metastasis, survival and histopathology of tumors produced using OS and SQ to characterize features of the tumors produced by the two distinct methods. Additionally, the present study aimed at providing increased options for investigators when designing experiments. 4T1-luc2 cell suspension or 4T1-luc2 tissue suspension was inoculated using either OS or SQ into BALB/c mice. Tumor growth and metastasis were detected using an in vivo imaging system and calipers. Excised tumors and lung were assessed by tissue staining with hematoxylin and eosin, and the vessel marker cluster of differentiation 31. The results of the present study revealed that the cell suspension generated breast tumors of increased size, which was visualized and determined, following inoculation, using calipers at an earlier time point compared with tumors produced by tissue suspension. The increasing bioluminescent trend of OS tumors was more marked compared with that of SQ tumors. The volume of OS tumor was increased with decreased variation, compared with that of SQ tumors. In addition, the OS tumor exhibited increased microvessel density. Bioluminescent signals and histological results in regard to metastasis were consistent: OS implantation produced increased lung metastasis compared with that of SQ implantation, although they exhibited similar survival times. The results of the present study indicated that the inocula from distinct sources (tissue or cell) affected tumor growth. Furthermore, breast tumor progression and histopathological characteristics were distinct between OS and SQ, whereas OS exhibited increased malignant behavior. Understanding the characteristics of murine breast cancer models established by diverse methods may aid investigators to select appropriate animal models, according to the requirements of the study. PMID- 29616106 TI - Data mining of pediatric medulloblastoma microarray expression reveals a novel potential subdivision of the Group 4 molecular subgroup. AB - Medulloblastoma is the most common type of solid brain tumor in children. This type of embryonic tumor is highly heterogeneous and has been classified into 4 molecular subgroups based on their gene expression profiles: WNT, SHH, Group 3 (G3) and Group 4 (G4). WNT and SHH tumors exhibit the specific dysregulation of genes and pathways, whereas G3 and G4 tumors, two of the more frequent subtypes, are the least characterized. Thus, novel markers to aid in the diagnosis, prognosis and management of medulloblastoma are required. In the present study, microarray gene expression data was downloaded from the Gene Expression Omnibus database, including data from the 4 subgroups of medulloblastoma and healthy cerebellum tissue (CT). The data was utilized in an in silico analysis to characterize each subgroup at a transcriptomic level. Using Partek Genomics Suite software, the data were visualized via hierarchical clustering and principal component analysis. The differentially expressed genes were uploaded to the MetaCore portal to perform enrichment analysis using CT gene expression as baseline, with fold change thresholds of <-5 and >5 for differential expression. The data mining analysis of microarray gene expression data enabled the identification of a range of dysregulated molecules associated with each subgroup of medulloblastoma. G4 is the most heterogeneous subgroup, as no definitive pathway defines its pathogenesis; analysis of the gene expression profiles were associated with the G4alpha and G4beta subcategories. TOX high mobility group box family member 3, synuclein alpha interacting protein and, potassium voltage-gated channel interacting protein 4 were identified as three novel potential markers for distinguishing the alpha and beta subcategories of G4. These genes may be associated with medulloblastoma pathogenesis, and thus may provide a basis for researching novel targeted treatment strategies for G4 medulloblastoma. PMID- 29616107 TI - Awareness of hepatic arterial variants is required in surgical oncology decision making strategy: Case report and review of literature. AB - Surgery for the treatment of pancreatic cancer remains the gold standard, however, the identification of the vascular supply of the pancreas and the nearby organs remains a crucial difficulties in a curative resection. During pancreatic head resection for carcinoma dissection of regional arterial vasculature is mandatory. Normal coeliac and hepatic arterial anatomy occurs in ~50-70% of patients and multiple variations have been described. Knowledge of multiple arterial anomalies is essential in hepato-pancreatico-billary surgery to avoid unnecessary complications. The present study presents coeliac trunk and common hepatic artery (CHA) anomalies along with their clinical importance, as reviewed according to the available literature. Patients diagnosed with cancer of the pancreatic head were hospitalized for staging and planning of radical surgical therapy. Computed tomography (CT) revealed a large tumour mass in the head of the pancreas and CHA, which branched directly from the superior mesenteric artery. A three-dimensional CT reconstruction revealed a demonstrative vascular anomaly, which was confirmed during an operation. Despite the anomalous origin of the CHA, pylorus preserving pancreatoduodenectomy and regional lymph node dissection without intraoperative complications was performed in each case. The patient's postoperative clinical course was uneventful and adjuvant chemotherapy could be administered without delay. In the multidisciplinary treatment of pancreatic carcinoma the surgeon and radiologist must be aware of the aberrant anatomy in order to avoid potential complications. As CT scans used for the preoperative staging are of diagnostic value for vascular anomaly, it is required for appropriate surgical decision making. PMID- 29616108 TI - Liver regeneration during the associating liver partition and portal vein ligation for staged hepatectomy procedure in Sus scrofa is positively modulated by stem cells. AB - This present study investigated the impact of the application of stem cells to liver regeneration following the first stage of associating liver partition and portal vein ligation for staged hepatectomy (ALPPS). The experiment was conducted on a pig model (n=6, 3 that did not receive application of stem cells, 3 that received application stem cells). Collected samples of liver (day 0 and 9 following surgery) were subjected to complete transcriptome sequencing. In total, 39 differentially expressed genes were found in the group without the application of the stem cells (genes of unwanted processes such as fibrosis and inflammation). In the group that did receive application of stem cells, no significantly differentially expressed genes were found, indicating a properly regenerated liver remnant. The present study therefore demonstrated, to the best of our knowledge for the first time, the positive effect of stem cells application in the liver regeneration process during ALPPS procedure in the pig model. PMID- 29616109 TI - Hydroxycamptothecin mediates antiproliferative effects through apoptosis and autophagy in A549 cells. AB - Hydroxycamptothecin (HCPT) represents a new generation of anticancer drugs, with almost no side effects when used for the treatment of a number of types of cancer. Autophagy is becoming recognized as an important biological mechanism in human cancer, including lung cancer. However, the involvement of autophagy in the antiproliferative effects of HCPT on lung cancer remains unclear. In the present study, A549 cells, an accepted model of non-small cell lung cancer (NSCLC) cells, were employed. It was demonstrated that HCPT was able to suppress proliferation and induce apoptosis and autophagy in A549 cells. The molecular mechanism underlying HCPT-induced cell death was attributed to apoptosis and autophagy. Furthermore, it was demonstrated that an autophagy inhibitor, 3-methyladenine, accelerated HCPT-induced cell death in A549 cells. The results of the present study may lead to a deeper understanding of the molecular mechanism by which HCPT regulates NSCLC A549 cells. These results highlight the potential use of autophagy inhibitors in combination with traditional chemotherapy drugs for the treatment of lung cancer. PMID- 29616110 TI - Overexpression of xeroderma pigmentosum group C decreases the chemotherapeutic sensitivity of colorectal carcinoma cells to cisplatin. AB - Xeroderma pigmentosum group C (XPC) is a DNA-damage-recognition gene active at the early stage of DNA repair. XPC also participates in regulation of cell-cycle checkpoint and DNA-damage-induced apoptosis. In the present study, the expression levels of genes involved in nucleotide excision repair (NER) were assessed in human colorectal cancer (CRC) tissue. This analysis revealed that expression of XPC mRNA significantly increased in colorectal carcinoma tissues compared with matched normal controls. Expression of XPC gradually increased along with the degree of progression of CRC. In vitro, an XTT assay demonstrated that small interfering RNA (siRNA) targeting XPC significantly increased the sensitivity of CRC SW480 cells to cisplatin, whereas cells transfected with a XPC-overexpression plasmid became more resistant to cisplatin. Furthermore, flow cytometry revealed that the proportion of apoptotic cells significantly increased in XPC-knockdown cells upon cisplatin treatment. However, the overexpression XPC significantly increased the resistance of cells to cisplatin. In vivo, tumor growth was significantly reduced in tumor-bearing mice when the XPC gene was knocked down. Upregulation of the expression of pro-apoptotic Bcl-associated X and downregulation of the anti-apoptotic B-cell lymphoma 2 proteins was observed in the implanted tumor tissue. In conclusion, XPC serves a key role in chemotherapeutic sensitivity of CRC to cisplatin, meaning that it may be a potential target for chemotherapy of CRC. PMID- 29616111 TI - MicroRNA-425 is downregulated in nasopharyngeal carcinoma and regulates tumor cell viability and invasion by targeting hepatoma-derived growth factor. AB - Nasopharyngeal carcinoma (NPC), which arises from the nasopharynx epithelium, is most common in Southeast Asia, particularly in Southern China. To date, a variety of microRNAs have been demonstrated to serve key functions in the progression and development of NPC. microRNA-425 (miR-425) has previously been reported to be frequently abnormally expressed in a number of different types of human cancer, including lung, gastric, cervical, breast and prostate cancer. However, to the best of our knowledge, the expression patterns, functions and underlying mechanisms of miR-425 in NPC remain largely unexplored. In the present study, the expression of miR-425 was revealed to be low in NPC tissues and cell line. Resumption of miR-425 expression suppressed cell viability and invasion in NPC. Hepatoma-derived growth factor (HDGF) was identified as a direct target gene of miR-425 in NPC. HDGF was highly expressed at mRNA and protein levels in NPC tissues. Additionally, HDGF mRNA was negatively correlated with miR-425 expression in NPC tissues. Furthermore, overexpression of HDGF almost completely rescued the tumor-suppressing effects of miR-425 on NPC cell viability and invasion. Taken together, these results demonstrated that miR-425 acted as a tumor suppressor in NPC by targeting HDGF, suggesting that it may be a novel therapeutic target for the treatments of patients with NPC. PMID- 29616112 TI - Potential tumor suppressing role of microRNA-545 in epithelial ovarian cancer. AB - Epithelial ovarian cancer (EOC) is the most common type of ovarian cancer, which exhibits invasive traits. MicroRNAs (miRNAs/miRs) have been demonstrated to serve important functions in the pathogenesis of EOC. However, the function of miR-545 in EOC remains unknown. In the present study, the function of miR-545 in EOC was analyzed and it was identified that miR-545 is downregulated in EOC tissues and cell lines. Additionally, a low level of miR-545 expression was associated with a low survival rate of patients with EOC. Furthermore, overexpression of miR-545 inhibited cell growth and promoted apoptosis. Suppression of miR-545 promoted cell growth and inhibited apoptosis. Additionally, the RAC-gamma serine/threonine protein kinase gene was targeted by miR-545. Thus, it may be concluded that miR 545 exhibited antitumor traits in EOC. PMID- 29616113 TI - Clinical significance of high expression of miR-452-5p in lung squamous cell carcinoma. AB - The role of microRNA (miRNA)-452-5p in lung squamous cell carcinoma (LUSC) remains unclear. Therefore, the present systematic study was performed to investigate the clinical significance and the rudimentary mechanism of the function of miR-452-5p in LUSC. The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were utilized to confirm the expression level and clinical value of miR-452-5p in LUSC. Using online databases and bioinformatic software, gene ontology (GO), pathway and protein-protein interaction (PPI) analyses of miR-452-5p target genes were performed to examine the molecular mechanism of miR-452-5p. The association between the expression of miR-452-5p and that of its hub genes was verified using TCGA. Based on TCGA data on 387 clinical specimens, the expression of miR-452-5p in LUSC was significantly increased compared with adjacent lung tissues (7.1525+/-1.39063 vs. 6.0885+/ 0.35298; P<0.001). The expression levels of miR-452-5p were significantly correlated with age (P=0.001) and tumor-node metastasis stage (P=0.028). Furthermore, the increased expression of miR-452-5p in LUSC compared with non cancerous tissue [standard mean deviation (SMD), 0.372; 95% confidence interval (CI), 0.020-0.724; z=2.07; P=0.038] was validated by a meta-analysis of 720 clinical samples. The GO and pathway analyses revealed that miR-452-5p target genes were mainly enriched in the 'regulation of transcription', 'nucleoplasm', 'protein binding' and 'cell cycle' pathways. A total of 10 hub genes were identified by PPI analysis, and 5 hub genes (SMAD4, SMAD2, CDKN1B, YWHAE and YWHAB) were significantly enriched in the 'cell cycle' pathway. The expression of CDKN1B was negatively correlated with miR-452-5p (P=0.003). It was concluded that miR-452-5p may serve an essential role in the occurrence and progression of LUSC by targeting CDKN1B, which is involved in the cell cycle. PMID- 29616114 TI - Bufalin induces DNA damage response under hypoxic condition in myeloma cells. AB - Hypoxia serves a crucial role in the development of drug resistance in various cancer cells. Therefore, many attempts targeting hypoxia are underway to overcome the drug resistance mediated by hypoxia. This strategy is useful for multiple myeloma (MM) cells, as MM cells reside within the bone marrow, where oxygen concentrations are relatively low. A natural compound library was screened to identify compounds exerting cytotoxicity in MM cells under hypoxic conditions. Bufalin exhibited marked cytotoxicity to MM cells under normoxic and hypoxic conditions. No significant toxicity was observed in lymphocytes obtained from healthy donors. Under normoxic conditions, bufalin induced a DNA double strand break (DSB) response, ROS induction and apoptosis within 24 with a rapid response compared with melphalan. Interestingly, the bufalin-induced DSB response was not impaired by low oxygen concentrations while the DSB response by melphalan was reduced. Furthermore, treatment with bufalin abolished HIF-1alpha expression under hypoxia, suggesting that bufalin exerts cytotoxicity under hypoxia by regulating HIF-1alpha. These results indicate that bufalin induces apoptosis in MM cells through DSB under hypoxic conditions by inhibiting HIF-1alpha, suggesting that bufalin could be useful for eradication of drug-resistant MM cells in the hypoxic microenvironment. PMID- 29616115 TI - Expression of multiple immune checkpoint molecules on T cells in malignant ascites from epithelial ovarian carcinoma. AB - Expression of immune checkpoint molecules, including programmed cell death protein-1 (PD-1), has been reported on T cells in various types of cancer. However, the expression status of these molecules in the tumor microenvironment of epithelial ovarian cancer (EOC) has not yet been studied. A total of 54 cases of malignant ascites from patients with EOC were analyzed in the present study. The expression of PD-1, lymphocyte-activation gene-3 (LAG-3), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) and B and T lymphocyte attenuator (BTLA) on cluster of differentiation (CD)4+ and CD8+ T cells in malignant EOC ascites were investigated using multicolor flow cytometric analysis. The expression of PD-L1 in tumor cells, PD-L2 in HLA-DR-positive cells and galectin-9 in ascitic fluid was also analyzed. In addition, cytokine profiling of ascitic fluid was performed to understand the immune microenvironment of EOC. PD-1, LAG-3 TIM-3, and BTLA were expressed on 65.8, 10.6, 4.3 and 37.6% of CD4+ T cells, and on 57.7, 5.0, 4.9 and 15.7% of CD8+ T cells, respectively. Programmed cell death protein-1 (PD-1), LAG-3 and BTLA were more frequently expressed on CD4+ compared with CD8+ T cells. The co-expression of immune checkpoints was further investigated and results indicated that 39 (72.2%) and 37 patients (68.5%) expressed multiple immune checkpoints on CD4+ T cells and CD8+ T cells, respectively. In addition, lower levels of TNF-alpha and interleukin-6 in ascitic fluid were significantly associated with multiple immune checkpoint expression on CD8+ T cells. The present findings indicated that multiple immune checkpoint molecules were expressed on T cells in the EOC tumor microenvironment and the results may suggest the significance of simultaneous blockade of immune checkpoints to control EOC. PMID- 29616116 TI - Lenalidomide improvement of cisplatin antitumor efficacy on triple-negative breast cancer cells in vitro. AB - Lenalidomide is an immunomodulatory drug and possesses anti-angiogenic and immunomodulatory activities against multiple myeloma. The present study assessed the in vitro effect of lenalidomide combined with cisplatin on MDA-MB-231, a triple-negative breast cancer (TNBC) cell line and explored the underlying molecular mechanism of this combination. Cell viability, apoptosis and the protein expression of phosphorylated (p) and total extracellular signal-regulated kinase (ERK), B-cell lymphoma-2 (Bcl-2), caspase-3, cleaved poly-adenosine diphosphate-ribose polymerase (cPARP), vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were measured in MDA-MB-231 cells treated with different concentrations of lenalidomide, cisplatin and their combination using different biochemical assays. Lenalidomide demonstrated no significant effect on the cell viability of MDA-MB-231 cells, even at high concentrations, whereas lenalidomide in combination with cisplatin, significantly reduced cisplatin IC50 from 7.8 to 3.0 uM in MDA-MB-231 cells. In addition, lenalidomide and cisplatin in combination significantly induced cell apoptosis by 1.6- and 1.38-fold, respectively compared with lenalidomide and cisplatin alone (P<0.05). The expression levels of VEGF, bFGF and Bcl-2 proteins were significantly reduced (P<0.01), whereas caspase-3 and cleaved PARP expression were significantly increased in MDA-MB-231 cells treated with the combination compared to those treated with single agents (P<0.01). Lenalidomide treatment alone significantly reduced the p-ERK level compared with the control (P<0.05) and cisplatin treatment alone significantly increased it (P<0.01), however treatment with them in combination significantly reduced the p-ERK level in MDA MB-231 cells compared with cisplatin treatment alone (P<0.05). In conclusion, the present study provides the basis for using lenalidomide in combination with cisplatin in TNBC therapy. PMID- 29616117 TI - Correlation of hypoxia status with radiosensitizing effects of sodium glycididazole: A preclinical study. AB - The correlation of pretreatment hypoxia status with the radiosensitization effect of sodium glycididazole (CMNa) was not previously defined. The purpose of the present study was to evaluate the tumor hypoxia status in various cancer xenografts and to investigate the correlation between tumor hypoxia status and radiosensitizing effects of CMNa based on the pharmacokinetic and pharmacodynamic parameters. Human esophageal cancer (EC109), head and neck cancer (FaDu) and lung cancer (A549) nude mice xenografts were used. The concentrations of CMNa and its metabolites in the tumors and normal tissues were determined by high-performance liquid chromatography following intravenous injection of 171.9, 57.3 or 19.1 mg/kg CMNa. The tumors were irradiated with 30 Gy in 6 fractions with CMNa administration prior to each irradiation. The tumor growth delay values were calculated for each treatment group and compared with groups treated with radiation alone. Tumor hypoxia status was verified by immunohistostaining of tissues for hypoxia inducible factor 1alpha (HIF-1alpha) staining, and the concentration of plasma osteopontin (OPN) was determined using ELISA. The correlation between OPN concentration and tumor growth delay was subsequently analyzed. It was observed that the drug concentration in the tumor was 1.6-2.8 times higher compared with adjacent muscle, particularly at high and medium doses. CMNa was able to sensitize tumors to irradiation, particularly for EC109 and FaDu xenografts at high dose (P<0.05). Furthermore, there was markedly increased expression of HIF-1alpha and plasma OPN levels in FaDu and EC109 xenografts compared with A549. Additionally, it was indicated that pretreatment hypoxia status might be correlated with the radiosensitizing effects of CMNa. The present data demonstrated that tumor hypoxia status might be correlated with the radiosensitizing effects of CMNa in different tumor models. PMID- 29616119 TI - Small nucleolar host gene 6 promotes esophageal squamous cell carcinoma cell proliferation and inhibits cell apoptosis. AB - Esophageal cancer (ESCC) is one of the most common causes of cancer-associated mortality in China. The present investigation reveals that non-coding RNAs (ncRNAs), including long ncRNAs (lncRNAs), exert a significant effect on the initiation, development and metastasis of malignant tumors, including ESCC. However, to the best of our knowledge, the function of non-protein-coding genes that host small nucleolar RNAs has not been investigated in cancer, particularly in ESCC. The expression of small nucleolar host gene 6 (SNHG6) in 70 ESCC tissues and paired adjacent tissues was measured by reverse transcription quantitative polymerase chain reaction. Analysis demonstrated that SNHG6 expression was significantly increased in ESCC tissues, and associated with tumor size (P=0.040) and Tumor-Node-Metastasis stage (P<0.01). Knockdown of SNHG6 may inhibit proliferative and colony-forming abilities, and induce apoptosis, in ESCC cells. To the best of our knowledge, the data from the present study indicated for the first time that SNHG6 was upregulated in ESCC tissues and cell lines. This novel lncRNA may exert a marked effect on the generation and progression of ESCC, potentially providing a novel perspective on ESCC diagnosis and management. PMID- 29616118 TI - Adenosine induces intrinsic apoptosis via the PI3K/Akt/mTOR signaling pathway in human pharyngeal squamous carcinoma FaDu cells. AB - Adenosine has been identified to occur abundantly intra-and extracellularly, and to exert diverse biological functions, including the suppression of cell proliferation and the induction of apoptosis. Adenosine has been reported to induce apoptosis in several cancer cell lines; however, to the best of our knowledge, the effect of adenosine on head and neck cancer cells has not been investigated. Therefore, the purpose of the present study was to evaluate whether adenosine exerts any anticancer effect via induction of apoptosis in human pharyngeal squamous carcinoma FaDu cells. An MTT assay demonstrated that adenosine-treated FaDu cells inhibited a dose-dependent rate of cell growth, whereas human oral keratinocytes cells were unaffected by adenosine treatment. In addition, A1 and A2a adenosine receptor mRNA was detected in FaDu cells by reverse transcription-polymerase chain reaction, and adenosine-induced FaDu cell death was significantly suppressed by treatment with ATL-444, an antagonist of these receptors. Furthermore, adenosine-induced cell growth inhibition was exerted via apoptosis, as confirmed by the analysis of DNA fragmentation, Hoechst nuclear staining and flow cytometry with Annexin V-fluorescein isothiocyanate and propidium iodide staining. Adenosine was also demonstrated to induce an increase in Bcl-associated X expression, a decrease in B-cell lymphoma 2 expression, the release of cytochrome c from mitochondria, and the activation of caspase-3, -9 and poly(ADP-ribose) polymerase in FaDu cells. Finally, phosphoinositide 3-kinase (PI3K), RAC serine/threonine-protein kinase (Akt) and mechanistic target of rapamycin (mTOR) phosphorylation was found to be significantly inhibited in adenosine-treated FaDu cells, as was phosphorylation of the mTOR downregulators, S6 kinase beta1, eukaryotic translation initiation factor 4E-binding protein 1, and eukaryotic translation initiation factor 4 gamma1. Taken together, these results indicate that adenosine induces apoptosis via the mitochondrial intrinsic pathway, and activates caspase-3 and -9 activity via the PI3K/Akt/mTOR signaling pathway. PMID- 29616120 TI - Salidroside induces apoptosis in human ovarian cancer SKOV3 and A2780 cells through the p53 signaling pathway. AB - Salidroside is one of the most potent compounds extracted from the plant Rhodiola rosea, and its cardiovascular protective effects have been studied extensively. However, the role of salidroside in human ovarian carcinoma remains unknown. The aim of the current study was to investigate the effects of salidroside on the proliferation and apoptosis of SKOV3 and A2780 cells using MTT assay and acridine orange/ethidium bromide staining. Salidroside activated caspase-3 and upregulated the levels of apoptosis-inducing factor, Bcl-2-associated X and Bcl-2-associated death promoter (Bad) proteins. Furthermore, salidroside downregulated the levels of Bcl-2, p-Bad and X-linked inhibitor of apoptosis proteins. Salidroside activated the caspase-dependent pathway in SKOV3 and A2780 cells, upregulating p53, p21Cip1/Waf1 and p16INK4a. These results suggest that the p53/p21Cip1/Waf1/p16INK4a pathway may serve a key function in salidroside mediated effects on SKOV3 and A2780 cells. The current findings indicate that salidroside may be a promising novel drug candidate for ovarian cancer therapy. PMID- 29616121 TI - Three-dimensional proton magnetic resonance spectroscopy and diffusion-weighted imaging in the differentiation of incidental prostate carcinoma from benign prostate hyperplasia. AB - The present study evaluated three-dimensional proton magnetic resonance spectroscopy (MRS) and diffusion-weighted imaging (DWI) features in differentiating incidental prostate carcinoma (IPCa) and benign prostate hyperplasia (BPH) in the central gland of the prostate. The clinical and imaging data of 9 patients with IPCa, 118 patients with BPH [including those with glandular hyperplasia (GH), stromal hyperplasia (SH) and mixed hyperplasia (MH)], were retrospectively analyzed. The mean (choline + creatine)/citrate (CC/C) value of 3D MRS, the apparent diffusion coefficient (ADC) value and the minimal ADC value of DWI were compared between carcinoma and non-carcinoma tissues. The mean CC/C values were 1.04+/-0.28, and 1.09+/-0.58 in IPCa and BPH, respectively (t= 0.205, P=0.838). No significant difference in CC/C values (chi2=2.595, P=0.458) could be detected between IPCa, GH, SH and MH groups. The ADC values of the central gland only differed between IPCa (1.48+/-0.18) *10-3 and GH (1.60+/-0.16) *10-3 mm2/sec (P=0.037). The minimal ADC values were similar between IPCa (1.15+/ 0.10) *10-3 and BPH (1.14+/-0.11) *10-3 mm2/sec, no significant differences could be detected between IPCa and GH (P=0.930), IPCa and SH (P=0.192), and IPCa and MH (P=0.544). Although the ADC values of the central gland of the prostate differed between IPCa and GH, the findings of the present study therefore indicate that combining 3D MRS with DWI cannot potentially improve the detection of IPCa. PMID- 29616123 TI - Overexpression and clinical significance of IBP in epithelial ovarian carcinoma. AB - Interferon regulatory factor-4 binding protein (IBP) is as a type of rho GTPase suggested to serve an important role in tumor occurrence and development through the effects of cytoskeletal remodeling, and cell conduction mechanism. IBP is widely expressed in the immune system and expressed in several types of tumors. However, its expression and prognostic value in epithelial ovarian carcinoma (EOC) remain unclear. The present study aimed to investigate the expression of IBP in EOC, and its effect on clinicopathological variables and prognosis. A total of 107 and 30 cases of epithelial ovarian carcinoma and benign ovarian disease tissue sections, respectively, were examined using immunohistochemistry. The results indicated that the IBP expression status was negative or markedly weak in normal tissues, but highly expressed in EOC tissues. A significant association was observed between IBP overexpression and various clinicopathological factors, including advanced International Federation of Gynecology and Obstetrics stage (P<0.001), poor histologic grade (P=0.002), peritoneal carcinomatosis (P<0.001), lymph-node metastasis (P=0.023) and recurrence (P<0.001). Multivariate Cox regression analysis additionally suggested that IBP overexpression was an independent factor affecting recurrence-free survival [hazard ratio (HR)=4.099; 95% confidence interval (CI), 2.209-7.606; P<0.001) and overall survival (HR=2.317; 95% CI, 1.484-3.617; P<0.001) in patients with EOC. The results of the present study demonstrated that IBP overexpression may be associated with tumor development and progression in EOC, and therefore may serve as a novel target for treating this disease. PMID- 29616122 TI - Plasmodium circumsporozoite protein suppresses the growth of A549 cells via inhibiting nuclear transcription factor kappaB. AB - Blocking the activation of nuclear factor kappaB (NF-kappaB) is a promising strategy for the treatment of non-small cell lung cancer. The circumsporozoite protein (CSP), a key component of the sporozoite stage of the malaria parasite, was previously reported to block NF-kappaB activation in hepatocytes. Therefore, in the present study, the effect of CSP on the growth of the human lung cancer cell line, A549, was investigated. It was demonstrated that transfection with a recombinant plasmid expressing CSP was able to inhibit the proliferation of A549 cells in a dose-dependent manner and induce the apoptosis of A549 cells. A NF kappaB gene reporter assay indicated that CSP and its nuclear localization signal (NLS) motif were able to equally suppress the activation of NF-kappaB following stimulation with human recombinant tumor necrosis factor (TNF)-alpha in A549 cells. Furthermore, western blot analysis indicated that NLS did not affect the phosphorylation and degradation of IkappaB, but was able to markedly inhibit the nuclear translocation of NF-kappaB in TNF-alpha stimulated A549 cells. Therefore, the data suggest that CSP may be investigated as a potential novel NF-kappaB inhibitor for the treatment of lung cancer. PMID- 29616124 TI - Sodium citrate inhibits the proliferation of human gastric adenocarcinoma epithelia cells. AB - The objective of the present study was to investigate the cytotoxic effects of sodium citrate on human gastric adenocarcinoma epithelia AGS cells. Numerous cytotoxicity-associated sodium citrate-induced effects were assessed, including cell viability and proliferation, cytokine expression and caspase activity. In vitro studies demonstrated that incubation with sodium citrate (>3.125 mM) inhibited AGS cell viability and proliferation in a dose-dependent manner. Incubation with sodium citrate for 24 h revealed that the levels of interleukin 1beta (IL-1beta), IL-8 and tumor necrosis factor increased with an increasing of dose of sodium citrate, whereas the IL-6 levels exhibited only a slight alteration. In addition, increases in caspase-3 and -9 activities were associated with increased duration of treatment and dosage of sodium citrate. Collectively, the results of the present study demonstrated that treatment with sodium citrate at higher concentrations or for longer durations exerts a cytotoxic effect on AGS cells via the induction of the intrinsic apoptosis pathway and the alteration in the levels of certain cytokines. PMID- 29616125 TI - HER4 isoform CYT2 and its ligand NRG1III are expressed at high levels in human colorectal cancer. AB - The present study aimed to evaluate the expression of human epidermal growth factor receptor (HER4) isoforms and their ligand neuregulin 1 (NRG1) isoforms in human primary colorectal cancer (CRC). The mRNA expression of HER4 isoforms JM-a, JM-b, CYT1 and CYT2, and their ligand isoforms NRG1 I, II and III in CRC tissues and adjacent normal tissues were quantified by reverse transcription-quantitative polymerase chain reaction analysis. Univariate analysis and logistic regression analysis were performed to analyze the association between HER4 and NRG1 expression and lymph node metastasis in CRC. The expression levels of CYT1 (P=0.002), CYT2 (P=0.002) and NRG1 type III (P<0.001) were significantly higher in the CRC tissues than in the adjacent normal tissues. The expression of CYT2 was correlated with tumor stage (P=0.018), lymph node status (P=0.015) and tumor node-metastasis (P=0.038) in CRC. The expression of NRG1III was correlated with lymph node metastasis, and the expression of CYT2 was associated with the expression of NRG1III (r=0.691, P<0.01). The logistic regression analysis indicated that expression of CYT2 >50 was a risk factor for lymph node metastasis in CRC. In conclusion the expression levels of CYT1, CYT2 and NRG1III were upregulated in CRC. An expression of CYT-2 >50 was identified as a risk factor for lymph node metastasis in CRC. Therefore, CY-2 and NRG1III may be involved in the progression of CRC. PMID- 29616126 TI - Dendritic cells loaded with HeLa-derived exosomes simulate an antitumor immune response. AB - The aim of the present study was to investigate the effect of loading dendritic cells (DCs) with HeLa-derived exosomes on cytotoxic T-lymphocyte (CTL) responses, and the cytotoxic effects of CTL responses on the HeLa cell line. Ultrafiltration centrifugation combined with sucrose density gradient ultracentrifugation was applied to isolate exosomes (HeLa-exo) from the supernatant of HeLa cells. Morphological features of HeLa-exo were identified by transmission electron microscopy (TEM), and the expression of cluster of differentiation (CD)63 was detected by western blotting. Next, monocytes were isolated from peripheral blood and cultured with the removal of adherent cells to induce DC proliferation. DCs were then phenotypically characterized by flow cytometry. Finally, MTT assays were performed to analyze the effects of DCs loaded with HeLa-exo on T cell proliferation and cytotoxicity assays to evaluate the effect of CTL responses on HeLa cells. TEM revealed that HeLa-exo exhibit typical cup-shaped morphology with a diameter range of 30-100 nm. It was also identified that the CD63 surface antigen is expressed on HeLa-exo. Furthermore, monocyte-derived DCs were able to express CD1a, suggesting that DC induction was a success. DCs exhibited hair-like protrusions and other typical dendritic cell morphology. Furthermore, DCs loaded with HeLa-exo could enhance CTL proliferation and the cytotoxic activity of CTLs compared with DCs without HeLa-exo (P<0.05). In conclusion, DCs loaded with HeLa exo may promote T cell proliferation and induce CTL responses to inhibit the growth of cervical cancer cells in vitro. PMID- 29616127 TI - Therapeutic approach in glioblastoma multiforme with primitive neuroectodermal tumor components: Case report and review of the literature. AB - Glioblastoma multiforme (GBM) is the most common and aggressive malignant glioma that is treated with first-line therapy, using surgical resection followed by local radiotherapy and concomitant/adjuvant temozolomide (TMZ) treatment. GBM is characterised by a high local recurrence rate and a low response to therapy. Primitive neuroectodermal tumour (PNET) of the brain revealed a low local recurrence rate; however, it also exhibited a high risk of cerebrospinal fluid (CSF) dissemination. PNET is treated with surgery followed by craniospinal irradiation (CSI) and platinum-based chemotherapy in order to prevent CSF dissemination. GBM with PNET-like components (GBM/PNET) is an emerging variant of GBM, characterised by a PNET-like clinical behaviour with an increased risk of CSF dissemination; it also may benefit from platinum-based chemotherapy upfront or following failure of GBM therapy. The results presented regarding the management of GBM/PNET are based on case reports or case series, so a standard therapeutic approach for GBM/PNET is not defined, constituing a challenging diagnostic and therapeutic dilemma. In this report, a case of a recurrent GBM/PNET treated with surgical resection and radiochemotherapy as Stupp protocol, and successive platinum-based chemotherapy due to the development of leptomeningeal dissemintation and an extracranial metastasis, is discussed. A review of the main papers regarding this rare GBM variant and its therapeutic approach are also reported. In conclusion, GBM/PNET should be treated with a multimodal approach including surgery, chemoradiotherapy, and/or the early introduction of CSI and platinum-based chemotherapy upfront or at recurrence. PMID- 29616128 TI - EGFR-TKI resistance and MAP17 are associated with cancer stem cell like properties. AB - Patients with non-small-cell lung cancer (NSCLC) with sensitive epidermal growth factor receptor (EGFR) mutations generally react well to tyrosine kinase inhibitors (TKIs). However acquired resistance eventually occurs. Several mechanisms contribute to the resistance including T790M mutation, c-Met amplification and PIK3CA mutation. In recent years, cancer stem cells (CSCs) have been suggested to be involved in TKI resistance. MAP17 is aberrantly overexpressed in a number of malignancies. However, the expression pattern and function of MAP17 in CSCs are still unclear. The aim the present study was to illustrate the effect of CSC-like cells on the resistance to TKIs in EGFR mutant NSCLC cells and explore the possible role of MAP17 in CSCs. The EGFR mutant cell line PC9 was cultured under serum-deprived undifferentiated conditions. The CSC properties including expression of stem cell markers CD133, CD44, Oct-4 and ABCG2, ability of self-renewal, invasion, proliferation and tumorigenesis were examined. The expression of MAP17 was compared in sphere and parent cells. Sphere cells displayed stem cells phenotypes and were resistant to erlotinib. Sphere cells expressed higher levels of MAP17, and MAP17 was associated with self renewal and TKI resistance. The function of MAP17 demonstrated to be partially dependent on Na-dependent glucose transporter 1. Collectively these findings suggest that MAP17 serves a role in TKI resistance through regulation of CSCs in lung cancer. PMID- 29616129 TI - LINE-1 hypomethylation is inversely correlated with UHRF1 overexpression in gastric cancer. AB - DNA methylation is an important epigenetic modification that alters gene expression; DNA hypomethylation contributes to tumorigenesis through multiple processes. In the present study, the methylation of long interspersed element-1 (LINE-1) in 95 gastric cancer (GC) tissues and matched adjacent normal tissues was investigated by pyrosequencing. LINE-1 methylation was compared with the expression of ubiquitin-like with PHD and ring-finger protein 1 (UHRF1), an essential regulator of DNA methylation, using reverse transcription-quantitative polymerase chain reaction. Significant hypomethylation of LINE-1 and overexpression of UHRF1 were observed in GC tissues compared with the matched controls (P<0.001 and P=0.001, respectively). LINE-1 hypomethylation was inversely correlated with UHRF1 overexpression in GC tissues (r=-0.026, P=0.028). In addition, LINE-1 hypomethylation in GC was significantly associated with Lauren's histological classification, tumor differentiation and background intestinal metaplasia (P=0.014, P=0.042 and P=0.034, respectively). These results suggest that LINE-1 hypomethylation may be a potential biomarker for GC and it is indirectly regulated by UHRF1 overexpression. PMID- 29616130 TI - Co-expression of ATP binding cassette transporters is associated with poor prognosis in acute myeloid leukemia. AB - Chemotherapy failure remains a challenge when treating patients with acute myeloid leukemia (AML), who often suffer from persistent or relapsed disease. The multidrug resistance (MDR) mediated by efflux transporters of the ATP binding cassette (ABC) superfamily is a major obstacle for successful chemotherapy. The present study aimed to elucidate whether the expression of ABC transporters was associated with prognostic factors and responses to chemotherapy in patients with AML, with particular focus on whether co-expression of multiple ABC transporters resulted in a worse prognosis. In the present study, the mRNA expression levels of ABC transporters ABCB1, ABCB4, ABCC1, ABCC4 and ABCG2 in bone marrow (BM) mononuclear cell (MNC) samples from 96 de novo patients with AML and in the peripheral blood (PB) MNC samples from 22 normal individuals were investigated using reverse transcription-quantitative polymerase chain reaction analysis. It was revealed that ABCB1, ABCC1, ABCC4 and ABCG2 were expressed at higher levels in patients with AML compared with normal individuals, whereas ABCB4 had a lower expression level. The expression of ABCB4 in patients with AML was significantly lower than in normal individuals (P<0.001). Patients risk status was associated with ABCB1 (P=0.037), ABCC1 (P=0.047), ABCC4 (P=0.015) and ABCG2 (P=0.027). The 4 genes were expressed a significantly higher levels in the poor response group compared with the good response group (ABCB1, P=0.014; ABCC1, P=0.021; ABCC4, P=0.005; ABCG2, P=0.009). The overexpression of the 4 ABC transporters and the complete remission rate were inversely correlated (P<0.001). These results suggest that the co-expression of multiple ABC transporters may contribute to a worse prognosis in AML. PMID- 29616131 TI - Chemoprevention with phosphatidylcholine non-steroidal anti-inflammatory drugs in vivo and in vitro. AB - The chemopreventive activity of non-steroidal anti-inflammatory drugs (NSAIDs), particularly aspirin, has been well demonstrated in preclinical and clinical studies. However, the primary side effect from this class of drug is gastrointestinal (GI) bleeding, which has limited the widespread use of NSAIDs for the prevention of cancer. The development of GI-safer NSAIDs, which are associated with phosphatidylcholine (PC) may provide a solution to this therapeutic problem. In the present study, the efficacy of two NSAIDs, aspirin and indomethacin, were compared using murine colon cancer cell line MC-26. Each NSAID was assessed alone and in combination with PC, using in vitro and in vivo systems. The results reveal that the PC-associated NSAIDs had a significantly higher degree of protection against cancer cell growth compared with the unmodified NSAIDs. It was also observed that Aspirin-PC and Indomethacin-PC prevented the metastatic spread of cancer cells in a syngeneic mouse model. These results support the potential use of PC-NSAIDs for the chemoprevention of colorectal cancer. PMID- 29616132 TI - A radioresistant fraction of acute promyelocytic leukemia cells exhibit CD38 cell surface antigen and mRNA expression. AB - In the present study, the cell viability and cluster of differentiation (CD)38 mRNA expression were evaluated in radioresistant (Res)-HL60 acute promyelocytic leukemia (APL) cells. Cell viability in Res-HL60 cells was higher compared with wild-type HL60 cells, but did not differ between high and mid/low CD38 antigen expression groups in Res-HL60 cells. A higher expression of CD38 mRNA in Res-HL60 cells was observed, particularly in the CD38high cell subpopulation. Furthermore, the expression of CD38 mRNA was upregulated following exposure to X-irradiation. In contrast, the characteristic expression of CD45 and CCAAT/enhancer-binding protein alpha mRNA were not altered. These results suggest that the accumulation of CD38 protein in radioresistant APL cells, resulting from the constant expression of CD38 mRNA induced by X-irradiation, is a characteristic response of the radioresistant-surviving fraction; however, the accumulation of CD38 did not influence the extent of radioresistant behavior. PMID- 29616134 TI - MicroRNA-216b reduces growth, migration and invasion of pancreatic ductal adenocarcinoma cells by directly targeting rho-associated coiled-coil containing protein kinase 1. AB - Developments in cancer therapy have greatly improved the survival time for patients with pancreatic ductal adenocarcinoma (PDAC); however, the prognosis of patients with PDAC remains poor. Understanding the expression patterns and functions of microRNAs may provide strategies for the diagnosis and treatment of patients with PDAC. The present study aimed to explore the expression and functions of microRNA-216b (miR-216b) in PDAC. The expression of miR-216b in PDAC tissues and cell lines was quantified with reverse transcription-quantitative polymerase chain reaction. An miR-216b mimic was introduced into PDAC cells to induce the effects of miR-21b overexpression. The effects of miR-216b overexpression on growth, migration and invasion of PDAC cells were evaluated by cell proliferation assay, migration and invasion assays, respectively. The molecular mechanism underlying the suppressive effects of miR-216b on PDAC was also examined; a direct target gene of miR-216b, rho-associated coiled-coil containing protein kinase 1 (ROCK1), was downregulated by ROCK1 short interfering RNA to investigate the effects on growth, migration and invasion of PDAC cells. The present study revealed that miR-216b was significantly downregulated in PDAC tissues and cell lines. Overexpression of miR-216b inhibited growth, migration and invasion of PDAC cells in vitro. ROCK1 was identified as a direct target gene of miR-216b in pancreatic cancer and the downregulation of ROCK1 resembled the effects of miR-216b overexpression in PDAC cells. Taken together, miR-216b acted as a tumor suppressor in PDAC and may represent a novel therapeutic target in PDAC. PMID- 29616133 TI - Mismatch repair single nucleotide polymorphisms and thyroid cancer susceptibility. AB - Thyroid cancer (TC) is the most common endocrine malignancy and its incidence continues to rise worldwide. Ionizing radiation exposure is the best established etiological factor. Heritability is high; however, despite valuable contribution from recent genome-wide association studies, the current understanding of genetic susceptibility to TC remains limited. Several studies suggest that altered function or expression of the DNA mismatch repair (MMR) system may contribute to TC pathogenesis. Therefore, the present study aimed to evaluate the potential role of a panel of MMR single nucleotide polymorphisms (SNPs) on the individual susceptibility to well-differentiated TC (DTC). A case-control study was performed involving 106 DTC patients and 212 age- and gender-matched controls, who were all Caucasian Portuguese. Six SNPs present in distinct MMR genes (MLH1 rs1799977, MSH3 rs26279, MSH4 rs5745325, PMS1 rs5742933, MLH3 rs175080 and MSH6 rs1042821) were genotyped through TaqMan(r) assays and genotype-associated risk estimates were calculated. An increased risk was observed in MSH6 rs1042821 variant homozygotes [adjusted odds ratio (OR)=3.42, 95% CI: 1.04-11.24, P=0.04, under the co-dominant model; adjusted OR=3.84, 95% CI: 1.18-12.44, P=0.03, under the recessive model]. The association was especially evident for the follicular histotype and female sex. The association was also apparent when MSH6 was analysed in combination with other MMR SNPs such as MSH3 rs26279. Interestingly, two other SNP combinations, both containing the MSH6 heterozygous genotype, were associated with a risk reduction, suggesting a protective effect for these genotype combinations. These data support the idea that MMR SNPs such as MSH6 rs1042821, alone or in combination, may contribute to DTC susceptibility. This is coherent with the limited evidence available. Nevertheless, further studies are needed to validate these findings and to establish the usefulness of these SNPs as genetic susceptibility biomarkers for DTC so that, in the near future, cancer prevention policies may be optimized under a personalized medicine perspective. PMID- 29616135 TI - EGFR inhibition enhances the antitumor efficacy of a selective BRAF V600E inhibitor in thyroid cancer cell lines. AB - BRAF V600E is the most common genetic alteration in thyroid cancer and is indicative of a relatively poor prognosis. A selective inhibitor of BRAF V600E has been proposed as a novel treatment for patients with thyroid cancer exhibiting BRAF V600E mutations. However, this inhibitor has demonstrated a limited therapeutic effect. In the present study, possible adaptive mechanisms of resistance of thyroid cancer cells to the specific BRAF V600E inhibitor, PLX4032, were investigated. MTT assays were performed to determine the anti-proliferative efficiencies and half maximal inhibitory concentration (IC50) of inhibitory treatments. The level of phosphorylated ERK was used to evaluate the activity of the mitogen assisted protein kinase (MAPK) pathway. Flow cytometry was performed to evaluate the rate of apoptosis. The IC50 measurements of PLX4032 in K1 and BCPAP cells were 0.550 and 1.772 uM, respectively. Co-treatment with an endothelial growth factor receptor (EGFR) inhibitor decreased the IC50 of PLX4032 to 0.206 uM, and prolonged the inhibitory effect of PLX4032 in K1 cells. In cells treated with PLX4032 alone, the MAPK pathway was reactivated after 24 h. However, the addition of an EGFR inhibitor suppressed this reactivation and increased the rate of apoptosis. In summary, the present study demonstrated that thyroid cancer harboring the BRAF V600E mutation was resistant to a selective BRAF inhibitor due to reactivation of the MAPK pathway. Co-treatment with an EGFR inhibitor increased antitumor efficacy and suppressed resistance to the BRAF V600E inhibitor. PMID- 29616136 TI - Curcumin differentially affects cell cycle and cell death in acute and chronic myeloid leukemia cells. AB - Curcumin is a phytochemical with potent anti-neoplastic properties. The antitumoral effects of curcumin in cells derived from chronic or acute myeloid leukemia have been already described. However, a comparative study of the cytostatic and cytotoxic effects of curcumin on chronic and acute myeloid leukemia cells has not yet been performed. In the present study, the cellular effects of curcumin on cell lines derived from chronic or acute myeloid leukemia were examined. Dose and time-response assays were performed with curcumin on HL 60 and K562 cells. Cell viability was evaluated with trypan blue exclusion test and cell death by flow cytometry using a fluorescent molecular probe. A cell cycle profile was analyzed, and protein markers of cell cycle progression and cell death were investigated. In the present study, the K562 cells showed a higher sensitivity to the cytostatic and cytotoxic effects of curcumin compared with HL-60. In addition, curcumin induced G1 phase arrest in HL-60 cells and G2/M phase arrest in K562 cells. Furthermore, curcumin-related cell death in HL-60 was associated with the processed forms of caspases-9 and -3 proteins, whereas in K562 cells, both the processed and the unprocessed forms were present. Accordingly, activity of these caspases was significantly higher in HL-60 cells compared with that in K562. In conclusion, curcumin elicits different cellular mechanisms in chronic or acute myeloid leukemia cells and the powerful antitumoral effect was more potent in K562 compared with HL-60 cells. PMID- 29616138 TI - Reviewer Acknowledgement. PMID- 29616137 TI - Video Monitoring a Simulation-Based Quality Improvement Program in Bihar, India. AB - Background: Simulation-based training has become an accepted clinical training andragogy in high-resource settings with its use increasing in low-resource settings. Video recordings of simulated scenarios are commonly used by facilitators. Beyond using the videos during debrief sessions, researchers can also analyze the simulation videos to quantify technical and nontechnical skills during simulated scenarios over time. Little is known about the feasibility and use of large-scale systems to video record and analyze simulation and debriefing data for monitoring and evaluation in low-resource settings. Methods: This manuscript describes the process of designing and implementing a large-scale video monitoring system. Mentees and Mentors were consented and all simulations and debriefs conducted at 320 Primary Health Centers (PHCs) were video recorded. The system design, number of video recordings, and inter-rater reliability of the coded videos were assessed. Results: The final dataset included a total of 11,278 videos. Overall, a total of 2,124 simulation videos were coded and 183 (12%) were blindly double-coded. For the double-coded sample, the average inter-rater reliability (IRR) scores were 80% for nontechnical skills, and 94% for clinical technical skills. Among 4,450 long debrief videos received, 216 were selected for coding and all were double-coded. Data quality of simulation videos was found to be very good in terms of recorded instances of "unable to see" and "unable to hear" in Phases 1 and 2. Conclusion: This study demonstrates that video monitoring systems can be effectively implemented at scale in resource limited settings. Further, video monitoring systems can play several vital roles within program implementation, including monitoring and evaluation, provision of actionable feedback to program implementers, and assurance of program fidelity. PMID- 29616139 TI - Association of P53 gene polymorphism with gastric cancer in Northern Iran as a high-risk region. AB - Gastric cancer has the fourth highest morbidity rate of all cancers worldwide. Genetic factors including alterations in oncogenes and tumor suppressor genes serve an important role in gastric cancer development and progression. The P53 gene acts as a tumor suppressor gene by regulating the cell cycle, DNA transcription and repair, apoptosis, senescence and genome stability. In addition to somatic P53 mutations in cancer development, germline polymorphisms are also involved in different malignancies. The polymorphism of P53 at codon 72 (Arg72Pro) is established as a common variant that increases susceptibility to various cancers. The present case-control study was conducted to evaluate the possible association between this P53 polymorphism and gastric cancer in the Iranian population. A total of 59 patients with gastric cancer and 59 healthy controls were enrolled in the present study. Genomic DNA was extracted from peripheral blood mononuclear cells and genotype analysis was performed using a polymerase chain reaction-based restriction fragment length polymorphism assay. Genotype frequencies did not differ significantly between the patients and controls (P=0.4); the frequencies of the three genotypes Arg/Arg, Arg/Pro and Pro/Pro in gastric cancer patients were 28.8, 49.2 and 22.0%, and in controls were 37.3, 49.2 and 13.6%. Additionally, there were no differences in genotype frequencies based on tumor location, histological differentiation or tumor stage. Based on these findings, it may be concluded that the P53 codon 72 polymorphism does not contribute to gastric cancer susceptibility in Northern Iran. PMID- 29616140 TI - Effect of idiopathic thoracic scoliosis on the tracheobronchial tree. AB - Introduction: High prevalence of obstructive lung disease has been reported in patients undergoing surgical correction of thoracic scoliosis. Airway narrowing due to spine morphology is analysed as a contributing factor. Methods: Preoperative surgical planning CTs of 34 patients with right-sided thoracic scoliosis (age: 17.6+/-9.0) were retrospectively analysed and compared with 15 non-scoliotic controls (age: 16.3+/-5.1). Three-dimensional models of spine and airway lumen were reconstructed. Based on thoracic sagittal profile, patients were divided into hypokyphosis (HypoS: <10 degrees ), normal kyphosis (NormS: >=10 degrees and <40 degrees ) and hyperkyphosis (HyperS: >=40 degrees ) groups. Lumen area of bronchi, bifurcation angles and minimum spine-airway distance were measured. Pulmonary function tests were correlated to scoliosis, kyphosis and lumen area. Results: Loss of kyphosis led to proximity between bronchus intermedius (BI) and spine. HypoS (NormS) had lumen area reductions in the right main bronchus of 29% (19%), BI of 45% (23%), right middle lobar bronchus of 46% (32%) and right lower lobe bronchus (RLL7) of 66% (37%), respectively (P<0.05). The lower right superior segmental bronchus was reduced across all scoliotic groups (P<0.05). Airways were displaced caudal by 0.65+/-0.45 vertebra in patients with scoliosis. Loss of kyphosis correlated negatively with forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC), FVC/(FVC predicted) and FEV1/(FEV1 predicted) (P<0.01). Lumen area of trachea, right upper lobar bronchus, BI and RLL7 correlated negatively with FEV1/FVC. BI and RLL7 narrowing were strong predictors of FVC and FEV1 loss (P<0.001). Conclusions: Right-sided main stem airways are narrowed in HypoS and NormS. Loss of kyphosis leads to narrowing of BI and its trifurcation. FEV1/FVC correlated negatively with airway narrowing, implying an obstructive element to lung function impairment in patients with scoliosis and hypokyphosis. PMID- 29616141 TI - Randomised controlled trial to compare the diagnostic yield of positron emission tomography CT (PET-CT) TARGETed pleural biopsy versus CT-guided pleural biopsy in suspected pleural malignancy (TARGET trial). AB - Introduction: Pleural malignancy, particularly malignant pleural mesothelioma (MPM) is increasing in incidence due to the long latency period from exposure to asbestos to development of the disease. MPM can be challenging to diagnose. For patients presenting without a pleural effusion, CT-guided biopsy remains the primary choice of biopsy, but the diagnostic sensitivity of this investigation is 70%-75%. Therefore, a proportion of patients will go on to require further biopsies. If the first biopsy is non-diagnostic, the chances of further non diagnostic biopsies are high in MPM. Methods: Target is a multicentre randomised controlled trial, aiming to recruit 78 patients over a 30-month period, from 10 centres in the UK. Patients will be randomised to either the standard arm which is a second CT-guided biopsy, or the interventional arm, a positron emission tomography-CT scan followed by a targeted CT-guided biopsy. Patients will be followed up for 12 months (patients recruited in the last 6 months of recruitment will have 6 months of follow-up). MPM biomarker mesothelin will be checked at baseline, 6 month and 12 month follow-up appointments where patients are able to attend these appointments. Ethics and dissemination: Ethical approval for this trial was granted by the South West-Exeter research and ethics committee (reference number 15/SW/0156). Results of the trial will be published in a peer reviewed journal and presented at an international conference. Trial registration number: ISRCTN 14024829; Pre-results. PMID- 29616142 TI - High-intensity interval training improves obstructive sleep apnoea. AB - Background: Three hours per week of vigorous physical activity is found to be associated with reduced odds of sleep-disordered breathing. Aim: To investigate whether 12 weeks of high-intensity interval training (HIIT) reduced the apnoea hypopnea index (AHI) in obese subjects with moderate-to-severe obstructive sleep apnoea. Methods: In a prospective randomised controlled exercise study, 30 (body mass index 37+/-6 kg/m2, age 51+/-9 years) patients with sleep apnoea (AHI 41.5+/ 25.3 events/hour) were randomised 1:1 to control or 12 weeks of supervised HIIT (4*4 min of treadmill running or walking at 90%-95% of maximal heart rate two times per week). Results: In the HIIT group, the AHI was reduced by 7.5+/-11.6 events/hour (within-group p<0.05), self-reported sleepiness (Epworth scale) improved from 10.0+/-3.6 to 7.3+/-3.7 (between-group p<0.05) and maximal oxygen uptake improved from 28.2+/-7.4 to 30.2+/-7.7 mL/kg/min (between-group p<0.05) from baseline to 12 weeks. The AHI, self-reported sleepiness and VO2maxwere unchanged from baseline to 12 weeks in controls (baseline AHI 50.3+/-25.5 events/hour, Epworth score 5.9+/-4.3, maximal oxygen uptake 27.0+/-6.8 mL/kg/min). Body weight remained unchanged in both groups. Conclusion: Twelve weeks of HIIT improved the AHI and self-reported daytime sleepiness in subjects with obese sleep apnoea without any change in the desaturation index and body weight. PMID- 29616143 TI - Modelling the Functional Comorbidity Index as a predictor of health-related quality of life in patients with glenoid labrum disorders. AB - Background/aim: Health-related quality of life (HRQoL) is increasingly assessed within orthopaedic research. For those patients presenting with glenoid labral pathologies, there is little information on how baseline comorbidities affect long-term outcomes and HRQoL. This study aimed to investigate a model, including baseline comorbidities and demographics, to predict change in 2-year HRQoL scores in adult patients with glenoid labral tears or degenerations. Methods: Participants provided Functional Comorbidity Index (FCI) scores and self completed the Western Ontario Rotator Cuff (WORC) index at 6, 12 and 24 months. Univariable and multivariable linear regressions were performed to assess predictive quality of baseline comorbidities and demographics on the primary outcome measure of interest (change in WORC score). Results: Multivariate regression with a continuous scaled FCI (beta=617.8, p=0.042), age (by decade) (beta=297, p<0.01), surgical group (beta=-476.69, p<0.01) and an interaction term between FCI and age (beta=-103.65, p=0.03) were significant predictors of change in WORC scores at 2-year follow-up (r2=0.293858). Multivariate regression with FCI scaled categorically reported only patients with three comorbidities (beta= 454.06, p=0.057) and age (by decade) (beta=156.87, p=0.04) as the only significant predictors of change in WORC scores at 2-year follow-up (r2=0.1279). Conclusion: The continuous FCI model is better suited to predict future WORC and HRQoL scores among this patient population. Patients reporting with higher numbers of baseline comorbidities improved significantly more than patients with fewer comorbidities. This information on expected change in HRQoL scores among patients with a wide range of FCI scores at baseline may help guide treatment decisions based on these criteria. PMID- 29616144 TI - Optimising secondary prevention in the acute period following a TIA of ischaemic origin. AB - Background: Transient ischaemic attacks (TIAs) are highly prevalent conditions, with at least 46 000 people per year in the UK having a TIA for the first time. TIAs are a warning that the patient is at risk of further vascular events and the 90-day risk of vascular events following a TIA, excluding events within the first week after diagnosis when the risk is highest, can be as high as 18%. Immediate assessment of patients with TIA, either at accident and emergency, general practice and/or TIA clinics, is therefore required to address secondary prevention and prevent further vascular events. Discussion: This article addresses the need for optimising secondary prevention in the acute period following a TIA of ischaemic origin to reduce the risk of further vascular events as per recent Cochrane review advice and presents a novel project, Stroke Prevention Rehabilitation Intervention Trial of Exercise (SPRITE), to do this. Summary: One novel way to tackle vascular risk factors and promote secondary prevention in patients with TIA could be to adapt a cardiac rehabilitation programme for these patients. SPRITE, a feasibility and pilot study (ClinicalTrials.gov Identifier: NCT02712385) funded by the National Institute for Health Research, is attempting to adapt a home-based cardiac rehabilitation programme, 'The Healthy Brain Rehabilitation Manual', for use in the acute period following a TIA. The use of cardiac rehabilitation programmes post-TIA requires further research, particularly within the primary care setting. PMID- 29616145 TI - The validity of the Youth Physical Activity Questionnaire in 12-13-year-old Scottish adolescents. AB - Background: The development of accurate methods to measure health-behaviours forms an integral component in behavioural epidemiology. Population surveillance of physical activity often relies on self/proxy reported questionnaires due to cost and relative ease of administration. The aim of this study was to examine the criterion validity and measurement agreement between the Youth Physical Activity Questionnaire (YPAQ) and accelerometry before being included in a Scotland-wide study. Methods: Forty four participants (12-13 years old; 61% girls) completed the YPAQ following 7 days wearing the Actigraph GT3X+. Mean moderate-to-vigorous physical activity (MVPA) per day was derived from YPAQ and accelerometer and validity was assessed using Spearman's correlation; Bland Altman plots examined absolute agreement between methods. Results: Pearson's and Spearman's correlations between YPAQ and accelerometer were r = 0.47 and rs = 0.39 (p<0.01) respectively. The YPAQ over reported mean MVPA by 25.6 +/- 50.2 minutes (95% CI 10.4-40.9 minutes; p <0.001), with 95% limits of agreement of 72.69 minutes and + 123.99 minutes. Evidence of underreporting at lower levels of activity and over reporting at higher levels of activity was evident (Pearson's r=0.81), in addition to heteroscedasticity, where variances increased as MVPA increased. Conclusions: Although a moderate correlation between the two methods was apparent, the YPAQ should not be used interchangeably with accelerometry. The YPAQ does demonstrate a reasonable ability to rank MVPA, although it tends to under-report lower levels and over-report higher levels. This, and other administering factors, should be taken into consideration if being used for group or individual level analyses. PMID- 29616146 TI - Expectations for nursing care in newborn units in Kenya: moving from implicit to explicit standards. AB - Neonatal mortality currently accounts for 45% of all child mortality in Kenya, standing at 22 per 1000 live births. Access to basic but high quality inpatient neonatal services for small and sick newborns will be key in reducing neonatal mortality. Neonatal inpatient care is reliant on nursing care, yet explicit nursing standards for such care do not currently exist in Kenya. We reviewed the Nursing Council of Kenya 'Manual of Clinical Procedures' to identify tasks relevant for the care of inpatient neonates. An expert advisory group comprising major stakeholders, policy-makers, trainers, and frontline health-workers was invited to a workshop with the purpose of defining tasks for which nurses are responsible and the minimum standard with which these tasks should be delivered to inpatient neonates in Kenyan hospitals. Despite differences in opinions at the beginning of the process, consensus was reached on the minimum standards of neonatal nursing. The key outcome was a comprehensive list and grouping of neonatal nursing task and the minimum frequency with which these tasks should be performed. Second, a simple categorisation of neonatal patients based on care needs was agreed. In addition, acceptable forms of task sharing with other cadres and the patient's family for the neonatal nursing tasks were agreed and described. The process was found to be acceptable to policy-makers and practitioners, who recognised the value of standards in neonatal nursing to improve the quality of neonatal inpatient care. Such standards could form the basis for audit and quality evaluation. PMID- 29616148 TI - Weeded Out? Gendered Responses to Failing Calculus. AB - Although women graduate from college at higher rates than men, they remain underrepresented in science, technology, engineering, and mathematics (STEM) fields. This study examines whether women react to failing a STEM weed-out course by switching to a non-STEM major and graduating with a bachelor's degree in a non STEM field. While competitive courses designed to weed out potential STEM majors are often invoked in discussions around why students exit the STEM pipeline, relatively little is known about how women and men react to failing these courses. We use detailed individual-level data from the National Educational Longitudinal Study (NELS) Postsecondary Transcript Study (PETS): 1988-2000 to show that women who failed an introductory calculus course are substantially less likely to earn a bachelor's degree in STEM. In doing so, we provide evidence that weed-out course failure might help us to better understand why women are less likely to earn degrees. PMID- 29616147 TI - Dynamics of paediatric urogenital schistosome infection, morbidity and treatment: a longitudinal study among preschool children in Zimbabwe. AB - Background: Recent research has shown that in schistosome-endemic areas preschool aged children (PSAC), that is, <=5 years, are at risk of infection. However, there exists a knowledge gap on the dynamics of infection and morbidity in this age group. In this study, we determined the incidence and dynamics of the first urogenital schistosome infections, morbidity and treatment in PSAC. Methods: Children (6 months to 5 years) were recruited and followed up for 12 months. Baseline demographics, anthropometric and parasitology data were collected from 1502 children. Urinary morbidity was assessed by haematuria and growth-related morbidity was assessed using standard WHO anthropometric indices. Children negative for Schistosoma haematobium infection were followed up quarterly to determine infection and morbidity incidence. Results: At baseline, the prevalence of S haematobium infection and microhaematuria was 8.5% and 8.6%, respectively. Based on different anthropometric indices, 2.2%-8.2% of children were malnourished, 10.1% underweight and 18.0% stunted. The fraction of morbidity attributable to schistosome infection was 92% for microhaematuria, 38% for stunting and malnutrition at 9%-34%, depending on indices used. S haematobium positive children were at greater odds of presenting with microhaematuria (adjusted OR (AOR)=25.6; 95% CI 14.5 to 45.1) and stunting (AOR=1.7; 95% CI 1.1 to 2.7). Annual incidence of S haematobium infection and microhaematuria was 17.4% and 20.4%, respectively. Microhaematuria occurred within 3 months of first infection and resolved in a significant number of children, 12 weeks post praziquantel treatment, from 42.3% to 10.3%; P<0.001. Conclusion: We demonstrated for the first time the incidence of schistosome infection in PSAC, along with microhaematuria, which appears within 3 months of first infection and resolves after praziquantel treatment. A proportion of stunting and malnutrition is attributable to S haematobium infection. The study adds scientific evidence to the calls for inclusion of PSAC in schistosome control programmes. PMID- 29616149 TI - Immersive Virtual Reality Therapy with Myoelectric Control for Treatment resistant Phantom Limb Pain: Case Report. AB - Objective: Phantom limb pain is a condition frequently experienced after amputation. One treatment for phantom limb pain is traditional mirror therapy, yet some patients do not respond to this intervention, and immersive virtual reality mirror therapy offers some potential advantages. We report the case of a patient with severe phantom limb pain following an upper limb amputation and successful treatment with therapy in a custom virtual reality environment. Methods: An interactive 3-D kitchen environment was developed based on the principles of mirror therapy to allow for control of virtual hands while wearing a motion-tracked, head-mounted virtual reality display. The patient used myoelectric control of a virtual hand as well as motion-tracking control in this setting for five therapy sessions. Pain scale measurements and subjective feedback was elicited at each session. Results: Analysis of the measured pain scales showed statistically significant decreases per session [Visual Analog Scale, Short Form McGill Pain Questionnaire, and Wong-Baker FACES pain scores decreased by 55 percent (p=0.0143), 60 percent (p=0.023), and 90 percent (p=0.0024), respectively]. Significant subjective pain relief persisting between sessions was also reported, as well as marked immersion within the virtual environments. On followup at six weeks, the patient noted continued decrease in phantom limb pain symptoms. Conclusions: Currently available immersive virtual reality technology with myolectric and motion tracking control may represent a possible therapy option for treatment-resistant phantom limb pain. PMID- 29616150 TI - Methadone Treatment of Opiate Addiction: A Systematic Review of Comparative Studies. AB - Opiate misuse is a chronic relapsing disease that has become an epidemic in the United States. Methadone is the mainstay of treatment for opiate addiction and has been researched widely. Recently, new avenues of treatment have been researched and developed. The objective of this review is to study methadone in comparison to other pharmacological options available or being considered for opiate addiction treatment through a methodical search and review of evidence provided by recent clinical trials conducted in this regard. There is a paucity of high quality randomized controlled trials focusing on the comparison between buprenorphine and methadone for treatment of opiate use disorder. Buprenorphine should be researched more for patient retention and satisfaction, as well as for its prospect for better outcomes in neonatal abstinence syndrome to generate more decisive recommendations. Current data suggest monitoring of liver enzymes with the use of buprenorphine/naloxone for better liver outcomes. In light of the analyzed data, the authors conclude that methadone should still be considered the preferred treatment mode in comparison to slow-release oral morphine and heroin. PMID- 29616151 TI - Narcolepsy in Adolescence-A Missed Diagnosis: A Case Report. AB - Narcolepsy is an uncommon sleep cycle disorder with a usual onset in adolescence, but it is often misdiagnosed and underdiagnosed. Rarely is the tetrad of excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis seen in patients. The clinical characteristics of narcolepsy are often confused with many psychiatric and neurologic disorders. Lack of clinical awareness about narcolepsy leads to frequent prescriptions of antiepileptics and psychotropics, which can adversely affect the quality of life of children and adolescents. We report a case of an adolescent male who presented with all four cardinal symptoms of narcolepsy and had been misdiagnosed with epilepsy, psychosis, and depression. We discuss various issues regarding narcolepsy in children and adolescents. PMID- 29616152 TI - Sustained Dorzolamide Release Prevents Axonal and Retinal Ganglion Cell Loss in a Rat Model of IOP-Glaucoma. AB - Purpose: To determine if one injection of a sustained release formulation of dorzolamide in biodegradable microparticles (DPP) reduces retinal ganglion cell (RGC) loss in a rat model of glaucoma. Methods: We injected either DPP or control microparticles intravitreally in rats. Two days later, unilateral ocular hypertension was induced by translimbal, diode laser treatment by a surgeon masked to treatment group. IOP and clinical exams were performed until sacrifice 6 weeks after laser treatment. RGC loss was measured by masked observers in both optic nerve cross-sections and RGC layer counts from retinal whole mounts. Results: Cumulative IOP exposure was significantly reduced by DPP injection (49 +/- 48 mm Hg * days in treated versus 227 +/- 191 mm Hg * days in control microparticle eyes; P = 0.012, t-test). While control-injected eyes increased in axial length by 2.4 +/- 1.7%, DPP eyes did not significantly enlarge (0.3 +/- 2.2%, difference from control, P = 0.03, t-test). RGC loss was significantly less in DPP eyes compared with control microparticle injection alone (RGC axon count reduction: 21% vs. 52%; RGC body reduction: 25% vs. 50% [beta tubulin labeling]; P = 0.02, t-test). Conclusions: A single injection of sustained release DPP protected against RGC loss and axial elongation in a rat model of IOP glaucoma. Translational Relevance: Sustained release IOP-lowering medications have the potential to stop glaucoma progression. PMID- 29616153 TI - Evaluation of a Region-of-Interest Approach for Detecting Progressive Glaucomatous Macular Damage on Optical Coherence Tomography. AB - Purpose: To evaluate a manual region-of-interest (ROI) approach for detecting progressive macular ganglion cell complex (GCC) changes on optical coherence tomography (OCT) imaging. Methods: One hundred forty-six eyes with a clinical diagnosis of glaucoma or suspected glaucoma with macular OCT scans obtained at least 1 year apart were evaluated. Changes in the GCC thickness were identified using a manual ROI approach (ROIM), whereby region(s) of observed or suspected glaucomatous damage were manually identified when using key features from the macular OCT scan on the second visit. Progression was also evaluated using the global GCC thickness and an automatic ROI approach (ROIA), where contiguous region(s) that fell below the 1% lower normative limit and exceeded 288 MUm2 in size were evaluated. Longitudinal signal-to-noise ratios (SNRs) were calculated for progressive changes detected by each of these methods using individualized estimates of test-retest variability and age-related changes, obtained from 303 glaucoma and 394 healthy eyes, respectively. Results: On average, the longitudinal SNR for the global thickness, ROIA and ROIM methods were -0.90 y-1, 0.91 y-1, and -1.03 y-1, respectively, and was significantly more negative for the ROIM compared with the global thickness (P = 0.003) and ROIA methods (P = 0.021). Conclusions: Progressive glaucomatous macular GCC changes were optimally detected with a manual ROI approach. Translational Relevance: These findings suggests that an approach based on a qualitative evaluation of OCT imaging information and consideration of known patterns of damage can improve the detection of progressive glaucomatous macular damage. PMID- 29616154 TI - Higher-Order-Aberrations Following Hyperopia Treatment: Small Incision Lenticule Extraction, Laser-Assisted In Situ Keratomileusis and Lenticule Implantation. AB - Purpose: To compare the postoperative higher-order-aberrations (HOAs) after hyperopic small incision lenticule extraction (SMILE), hyperopic laser-assisted in situ keratomileusis (LASIK), and lenticule implantation for correction of hyperopia. Methods: Eighteen monkeys were divided to six groups: +2.00 D and +4.00 D hyperopic SMILE, +2.00 D and +4.00 D hyperopic LASIK (n = 6 eyes for each), and lenticule implantation with a -2.00 D and -4.00 D lenticule (n = 3 eyes for each). The corneal HOAs were evaluated preoperatively and 3-month postoperatively. Results: At 3-month postoperatively, the spherical aberrations significantly increased toward negative direction in all +4.00 D groups (all P < 0.05). There was a significant change toward more negative values in the third order vertical coma in the SMILE +4.00 D and LASIK +4.00 D groups (P = 0.026 and P = 0.036, respectively). There were also significant changes in the third-order horizontal trefoil (P = 0.034) and oblique secondary astigmatism (P = 0.012) in the LASIK +4.00 D group. In the eyes that underwent +4.00 D lenticule implantation, the fourth-order horizontal quatrefoil significantly increased (P = 0.029). In low hyperopia correction (+2.00 D), treatment with lenticule implantation tended to have less changes in HOAs, compared to the other two groups. Conclusions: In hyperopic SMILE, hyperopic LASIK or lenticule implantation surgery, significant induction of third- and fourth-order HOAs were seen in moderate hyperopia correction but not in low hyperopia correction. In low hyperopia treatment, lenticule implantation might offer a favorable trend in the aspect of HOAs. Translational Relevance: The results provided the knowledge of surgically induced HOAs and understanding of the effects of surgery in different types of hyperopic correction. PMID- 29616155 TI - Cesarean Scar Pregnancy: An Experience of Three Cases with Review of Literature. AB - Cesarean scar pregnancy (CSP), often considered the rarest form of ectopic pregnancy, is a result of implantation of the gestational sac into the fibrous tissue scar of a previous cesarean section. With an increase in the rate of cesarean sections, along with better awareness and improvement in sonographic diagnosis, the number and detection of scar pregnancies are on the rise. Because of its early invasion of the myometrium, usually in the first trimester, CSP is considered to be potentially lethal, leading to high risks of uterine rupture. We report a series of three cases of scar pregnancy that presented at different gestational ages and were managed by different methods. The aim of this case series is to share our experience with CSP, review previous literature, and emphasize on the radiological criteria to making a confident diagnosis. Diagnosis and management of CSP needs considerable expertise and a multidisciplinary approach to prevent complications. PMID- 29616156 TI - A Case of Postpartum Ovarian Vein Thrombosis. AB - Ovarian vein thrombosis (OVT) is an rare condition, which can present in the postpartum period. We present a case of a 35-year-old female who presented with right lower quadrant pain and fever. Her computed tomography (CT) abdomen revealed a dilated right ovarian vein with soft tissue attenuation material in its lumen that extended into the inferior vena cava, along with fat stranding of the surrounding soft tissues signifying thrombophlebitis. She was treated with enoxaparin and piperacillin-tazobactam, which lead to a resolution of the thrombus. Our case highlights the importance of prompt diagnosis and treatment of OVT in order to prevent morbidity and mortality. PMID- 29616157 TI - Erosive Benign Fibro-osseous Lesion of the External Auditory Canal. AB - The term fibro-osseous lesion encompasses a spectrum of disorders ranging from inflammatory to neoplastic that microscopically exhibit a connective tissue matrix containing formless trabeculae of compact bone. Characteristically, they are located over healthy bone, from which they are abruptly differentiated. The majority of the lesions arise from the maxillofacial region; the occurrence of a lesion in the external auditory canal (EAC) being extremely rare as is in our case. The lesions present with a range of symptoms ranging from conductive hearing loss, Eustachian tube obstruction to bone erosion that develop due to the mass effect. We report a case of a 35-year-old male patient who presented with insidious onset left aural fullness, decreased hearing followed by intermittent mucopurulent discharge from the ear, who was eventually diagnosed with a benign fibro-osseous lesion of the external auditory canal. PMID- 29616158 TI - Extra Oxygen Leads to Bubble Trouble: Portal Vein Gas Embolism from 3% Hydrogen Peroxide Ingestion. AB - Hydrogen peroxide ingestion can cause gastric irritation and gas embolism; however, most reported cases are from the highly concentrated (>=35%) solution used in the industry and data on household-used 3% solution ingestion is scarce. We report a case of a portal vein gas embolism after ingestion of 3% hydrogen peroxide. The patient was managed conservatively with antacids and improved in 48 hours. Endoscopy and hyperbaric treatment were considered but not pursued. This is the fifth reported case of gas embolism after 3% hydrogen peroxide ingestion and stands in line with other reports where the patients improved with conservative management. PMID- 29616159 TI - Clinical Application of Botulinum Toxin A for Calf Hypertrophy Followed by 3 Dimensional Computed Tomography. PMID- 29616160 TI - Reconstruction of Anterior Neck Scar Contracture Using A Perforator-Supercharged Transposition Flap. AB - Reconstruction of the anterior neck requires attention to both aesthetic and functional outcomes. In general, skin grafts are not suitable for anterior neck reconstruction in Asian patients, even when artificial dermis is used before skin grafting. Therefore, we have employed various types of thin flaps for anterior neck reconstruction, including the cervico-pectoral flap. However, we have realized that, to fully release neck contractures and therefore achieve the full range of neck extension, the skin pedicle must be sufficiently wide. Therefore, we have started reconstructing anterior neck scar contractures using wide, thin, and long flaps that are harvested from the anterior chest wall. In this article, we describe the case of a 71-year-old man who presented with a neck contracture and tracheal fistula after receiving extensive burns. A transposition flap bearing the internal mammary artery perforator was harvested from the anterior chest wall to repair the neck wounds that were left after removing the scar. At the same time, the tracheal fistula was covered by the flap. The aesthetic and functional results were acceptable. The effectiveness of supercharged transposition flaps from the anterior chest wall for reconstructing anterior neck scar contraction is discussed. PMID- 29616162 TI - Successfully Managing Impending Skin Necrosis following Hyaluronic Acid Filler Injection, using High-Dose Pulsed Hyaluronidase. AB - Facial fillers are becoming increasingly popular as aesthetic procedures to temporarily reduce the depth of wrinkles or to contour faces. However, even in the hands of very experienced injectors, there is always a small possibility of vascular complications like intra-arterial injection of filler substance. We present a case report of a patient who developed features of vascular obstruction in right infraorbital artery and tell-tale signs of impending skin necrosis, after hyaluronic acid filler injection by an experienced injector. The diagnosis of a vascular complication was made quickly with the help of clinical features like blanching, livedo reticularis, and poor capillary refill. Patient was treated promptly with "high-dose pulsed hyaluronidase protocol" comprising three 1,000-unit pulses of hyaluronidase, administered hourly. There was no further increase in size of the involved area after the first dose of hyaluronidase. All of the involved area, along with 1 cm overlapping in uninvolved skin area, was injected during each injection pulse, using a combination of cannula and needle. Complete reperfusion and good capillary filling were achieved after completion of 3 pulses, and these were taken as the end-point of high-dose pulsed hyaluronidase treatment. Immediate skin changes after filler injections, as well as after hyaluronidase injections and during the 3-week recovery period, were documented with photographs and clinical notes. Involved skin was found to have been fully recovered from this vascular episode, thus indicating that complete recovery of the ischemic skin changes secondary to possible intra-arterial injection could be achieved using high-dose pulsed hyaluronidase protocol. PMID- 29616161 TI - Associated Malformations in Children with Orofacial Clefts in Portugal: A 31-Year Study. AB - Background: Orofacial clefts are among the most common congenital craniofacial malformations and may be associated with other birth defects. However, the proportion and type of additional anomalies vary greatly between studies. This study assessed the prevalence and type of associated congenital malformations in children with orofacial clefts, who attended the largest cleft lip and palate tertiary referral center in Portugal. Methods: Consecutive children with orofacial clefts who attended at least 1 consultation in our Clefts Unit between 1981 and 2012 were studied. Demographic and clinical data regarding the number and type of associated malformations were retrospectively collected and analyzed. Results: Of the 701 patients studied, 219 (31.2%) had associated congenital malformations. These malformations were more frequent in children with cleft palate (43.4%) than in children with cleft lip and palate (27.5%) or with cleft lip only (19.4%). Within the group with associated anomalies, 73 cases (33.3%) had conditions related with known chromosomal defects, monogenic syndromes or sequences, and 146 cases (66.7%) had multiple congenital anomalies of unknown origin. From those, head and neck malformations were the most common (60.3%), followed by malformations in the cardiovascular (28.3%) and musculoskeletal systems (26%). Conclusions: The overall prevalence of associated malformations of nearly 1 in 3 children with orofacial clefts stressed the need for a comprehensive evaluation of these patients by a multidisciplinary cleft team. Moreover, one-third of the children had multiple congenital anomalies of known origins. Thus, early routine screening for other malformations and genetic counseling might be valuable for orofacial clefts management. PMID- 29616163 TI - Lubricating the Insertion Funnel with Autologous Fat Tissue for Inserting Breast Implants. PMID- 29616166 TI - Predator-in-Chief: Wolves in Editors' Clothing. PMID- 29616165 TI - A Systematic Review and Meta-analysis of Free-style Flaps: Risk Analysis of Complications. AB - Background: Free-style flaps allow surgeons to overcome anatomical variations and raise perforator flaps wherever a pulsatile signal can be detected. We performed a systematic review and meta-analysis to identify the risk factors for complications and indications for free-style flaps in soft-tissue defect reconstructions. Methods: This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. The databases of MEDLINE, PubMed, ScienceDirect, and Cochrane Library were searched from January 1991 to January 2017 for original articles describing free-style flaps in soft-tissue defect reconstruction. Results: A total of 17 articles met the inclusion criteria, representing 453 free-style flaps. The percentage of free style flaps conducted after primary oncologic resection was 54.4% (246/453). Free style flaps were mostly used in the head and neck region (35.5%), and most of them were designed as pedicled perforator flaps (96.7%). Complete flap survival was accomplished in 91.8% of the free-style flaps. Complications were found in 13.5% of cases, and 2 risk factors were identified: extremity defects (risk ratio, 2.39; P = 0.006) and single perforator flaps (risk ratio, 4.93; P = 0.002). No significant differences were found among the criteria including patients aged greater than 60 years, female gender, chronic etiology, flap size over 100 cm2, flap rotation, or perforator skeletonization. Conclusions: Free style flaps are both reliable and advanced forms of perforator flaps for use in soft-tissue defect reconstructions. Defects located on the extremities and flaps with single perforators are risk factors for flap failure and complications. PMID- 29616164 TI - The Impact of Recipient Site External Expansion in Fat Grafting Surgical Outcomes. AB - Background: The fat grafting process includes the 4 phases of tissue harvesting, processing, recipient-site preparation, and reinjection. Among them, the preparation of the recipient site has never been exhaustively reviewed. We aim to provide a comprehensive overview of the methods to prepare the recipient site through external expansion with the resulting outcomes. Methods: PubMed/Medline database was searched for studies on fat grafting recipient site preparation by applying the following algorithm: ((fat grafting) OR (lipofilling) OR (lipograft) AND (recipient site)). A priori criteria were used to review the resulting articles and identify those dealing with external expansion. Results: Fourteen studies published from 2008 through 2016 met inclusion criteria (4 case reports, 6 retrospective, and 4 prospective studies), representing 1,274 treated patients. Two devices for preexpansion were used with different protocols: BRAVA system and Kiwi VAC-6000M with a PalmPump. The 13 studies that applied the BRAVA system reported large fat volume transplantation to the breast (average > 200 cc). The most common complications were localized edema (14.2%), temporary bruising, and superficial skin blisters (11.3%), while the most serious was pneumothorax (0.5%). The majority of the studies reported enhancement of fat graft survival, which ranged between 53% and 82% at 6 months to 1 year follow-up, and high satisfaction of patients and surgeon. Conclusions: External expansion and fat grafting is a promising technique for breast reconstruction and augmentation. However, due to the overall low level of evidence of the available studies, further research is needed to validate the procedure. PMID- 29616167 TI - Patient-reported Outcomes after ADM-assisted Implant-based Breast Reconstruction: A Cross-sectional Study. AB - Background: Although the use of acellular dermal matrices (ADMs) in implant-based reconstruction increases, there is a lack of studies evaluating patient-reported outcome measures after this reconstruction method. We aim to evaluate the patient satisfaction after ADM-assisted implant-based breast reconstruction (IBBR) in 1 of the largest series of patients undergoing ADM-assisted IBBR. Methods: Patients with ADM-assisted IBBR were invited to fill out the BREAST-Q, a validated and standardized questionnaire to measure patient satisfaction after a breast reconstruction. A retrospective chart review was performed to identify patient and surgical characteristics. Results: In total, 208 patients (38.4%) responded and reported a mean satisfaction of 70.6 +/- 20.2 with their breasts and 78.0 +/- 20.5 with the outcome. An overall complication rate of 7.7% was noted, with 1.5% severe complications leading to hospital readmission (0.5%) and implant removal (0.5%). Patients with complications and unilateral reconstruction for oncological reasons reported overall less satisfaction rates compared with patients with bilateral, preventive surgery, and an uncomplicated postoperative course. Strongly related domains indicate the importance of patient satisfaction with their breasts and outcome on psychosocial and sexual functioning and satisfaction with information on satisfaction with breasts, outcome, and surgeon. Conclusion: There is an increased demand for patient-reported outcome measures in a changing practice to which the opinion of the patient assumes a larger role. With high satisfaction rates, ADM-assisted IBBR is a valuable reconstruction method, provided that complication rates remain low. Hence, it should only be performed in a selected group of women. PMID- 29616168 TI - Personalized 3D Printed Surgical Tool for Guiding the Chisel during Hump Reduction in Rhinoplasty. AB - The authors aimed to present an introduction of patient-specific model in rhinoplasty by introducing a 3D printed surgical guide designed and adapted in an individualized manner for guiding dorsal hump reduction. To introduce the tool, we have designed a six step workflow. First, we obtain a digital 3D model of patient anatomy using computed tomography (CT) images. Second, we conduct a surgical preoperative planning of the rhinoplasty on the mentioned model. Third step consists of designing the guide, while taking into account nasal anthropometries and resection objectives. Fourth step is printing the guide and sterilizing it. Fifth step is performing the surgery. The last step is analyzing the main outcomes of the surgery. Our surgical guide allowed us to perform only 1 step osteotomy instead of the usual multistep osteotomy and remove exactly the amount of dorsum that we decided to remove during the preoperative planning. The duration of intervention was considerably shorter than conventional osteotomy. Using the guide was technically easier than the conventional method and reduced the learning curve from years to minutes (once the guide is printed). Moreover, the patient understanding of the procedure was significantly better after showing the 3D model of the surgery. The surgical guide allows a surgeon to transfer with extreme simplicity the presurgical planning to the surgical field. We have to point out that the design of the study does not allow us to quantify predictability, so future studies are needed to demonstrate an accuracy benefit over the former techniques. PMID- 29616169 TI - Clinical Application of Foci Contralateral Facial Artery Myomucosal Flap for Tongue Defect Repair. AB - This study aims to investigate the clinical efficacy of foci contralateral facial artery myomucosal flap (FAMF) in repairing the defect of tongue after tumor resection. There were 10 cases who received the operation to repair tongue tissue defects caused by tumor resection from January 2010 to January 2016. FAMF flap size ranged from 2.5 * 3 cm to 5 * 5 cm. All flaps survived after surgery, and no local necrosis occurred. For the donor and receptor sites of 10 cases, 8 cases got wounds healed at stage I, wound dehiscence of donor site occurred in 2 cases, and the dehisced wounds were healed after local cleaning. All 10 patients were followed up for 13 months to 5 years, with an average of 2 years and 4 months. No obvious deformity appeared on face after surgery, and there was no mouth floor leakage. After surgery, 3 cases had clinical manifestations of facial nerve marginal mandibular branch injury and returned to normal in 3 months. All patients had a limitation for mouth opening after surgery, 9 cases returned to normal after 1 year, and 1 case still had a mild limitation for mouth opening. There was no impact on patients' eating, swallowing, language, or other functions. The foci contralateral FAMF surgery is simple and brings ideal plastic effect, high survival rate of flap, less donor site lesion, simple postoperative care, no breaking after surgery, and no impact on radical cure of tumor, which is suitable for repairing defect of tongue. PMID- 29616170 TI - Spindle Cell Lipoma of the Thumb. AB - We report the case of a 34-year-old man who presented with a 4-year history of a soft tissue on the palmar aspect of the thumb. Magnetic resonance imaging demonstrated the presence of a mass with heterogeneous high intensities on T1 weighted images and high intensities on T2-weighted images. We performed excisional biopsy. Histologically, the tumor was composed of mature adipocytes and spindle cells in a collagen background. Immunohistochemically, the tumor cells showed strong expression of CD34. Therefore, we diagnosed it as spindle cell lipoma. To the best of our knowledge, only 2 cases of spindle cell lipoma of the thumb have previously been reported. PMID- 29616171 TI - Combining Breast Reduction Techniques to Treat Gigantomastia in Ghana. AB - In this presentation of 2 consecutive cases of symptomatic juvenile breast hypertrophy in Ghana, we review the patient presentation, workup, and discuss outcomes following a combined technique of inferior pedicle stump with free nipple graft reduction mammoplasty. Surgical goals for treatment of gigantomastia were 2-fold: to resect adequate tissue to obtain symptomatic relief with improved quality of life, while avoiding a flat, boxy-appearing breast shape. PMID- 29616172 TI - Pork Belly: A Simulation Training Model for Intramuscular Perforator Dissection. AB - Background: Free tissue transfer has evolved from muscle flaps to fasciocutaneous flaps. Dissection of the intramuscular course of feeding vessels is technically challenging. Simulation-based microsurgery skills acquisition is moving toward nonliving training models. Living porcine model or human cadavers are currently cost-ineffective methods for the early learning curve in teaching intramuscular dissection. The aim of this study was to validate an inexpensive ex vivo porcine model simulating harvest of the deep inferior epigastric artery perforator (DIEAP) flap, specifically including perforator intramuscular dissection. Methods: An initial needs analysis and anatomical dissections (characteristics of vascular anatomy) established the necessity and surgical design (step-by-step) of the ex vivo DIEAP flap harvesting model. A pilot study utilizing objective assessment methodology (time to complete flap raising and hand motion analysis) demonstrated the surgeons' performance. A detailed feedback questionnaire was used to assess the participants' perception of this model. Results: Fifty-seven participants completed the initial needs analysis. Fifteen pork bellies were dissected and the vascular anatomical characteristics of the inferior epigastric vessels are presented. Eight surgeons performed the step-by-step flap design demonstrating construct validity in flap raising and intramuscular dissection. All surgeons completed the ex vivo DIEAP harvesting and they recommend this model as the first step in training for intramuscular dissection. Conclusions: The pork belly simulation is a cheap, easy, ethically considerate, and high-fidelity simulation model for intramuscular dissection for the DIEAP free flap. This study guides future validation trials to explore if the absence of physiological blood flow affects skills acquisition in the intramuscular dissection learning curve. The pork belly could be the first step in perforators dissection before progressing to the in vivo porcine model. PMID- 29616173 TI - Beyond Serendipity to an Algorithmic Approach. PMID- 29616174 TI - Management of Severely Atrophic Maxilla in Ectrodactyly Ectodermal Dysplasia cleft Syndrome. AB - Background: Ectrodactyly ectodermal dysplasia-cleft syndrome is a rare genetic syndrome with an incidence of 1/90,000 live births, characterized by cleft lip and palate, severely hypoplastic maxilla, and hypodontia. Patients diagnosed with ectrodactyly ectodermal dysplasia-cleft syndrome suffer from a severely hypoplastic maxilla that is highly difficult to treat using traditional orthognathic methods. In this study, we propose using distraction osteogenesis to achieve a major advancement while maintaining good stability and minimal relapse. To our knowledge, this is the first description of patients with this syndrome treated using distraction osteogenesis. Methods: Five patients diagnosed with ectrodactyly ectodermal dysplasia-cleft syndrome were included in the study. All patients had been operated on according to the well-established protocol of cleft lip and palate reconstruction before maxillary distraction osteogenesis. Hard and soft-tissue changes were evaluated by cone beam computed tomography and lateral cephalograms before distraction osteogenesis (T1), at the postdistraction point (T2) and after 1 year of follow-up (T3). Results: Examination revealed marked maxillary advancement in all our patients with a significant mean difference in hard tissue parameters (condylion to A point = 18 mm; nasion-sella line to A point = 15.2 degrees) and a notable improvement in facial convexity (20.9 degrees). One year follow-up measurements demonstrated mild relapse rates of 6% in the horizontal plane. Conclusions: We conclude that despite the challenging anatomic and physiological features of ectrodactyly ectodermal dysplasia-cleft patients, by enhancing current surgical techniques, there is promising potential for improved patient outcomes, achieving normognathic facial appearance with implant supported rehabilitation. PMID- 29616176 TI - Surgical Treatment for Kirner's Deformity-Single Osteotomy through a Palmar Approach. AB - Background: Patients with Kirner's deformity often seek medical attention for aesthetic improvement when they reach the age of approximately 10 years, when the deformity becomes evident. The operative technique described in textbooks is the palmar opening-wedge with multiple osteotomies through a mid-lateral incision, which is technically demanding. The purpose of this article was to introduce our surgical technique of a single transverse osteotomy through a palmar approach and to present the short-term outcomes of this technique. Methods: The surgical outcomes of 7 digits in 4 children were retrospectively reviewed. The deformed distal phalanx was approached with an oblique incision of the pulp, and the palmar cortex was incised at the apex of the curvature. The dorsal cortex was only partially incised and broken manually when correcting the deformity by a palmar opening-wedge. The dorsal aspect of the phalanx was not exposed, and the nail plate was left intact. The fragments were fixed with Kirschner wires. Results: There was no postoperative complication, and the osteotomy sites all healed uneventfully. None of the patients complained about scar pain or hypersensitivity of the finger pulp. The patients and their parents were satisfied with the aesthetic results. Conclusions: A single palmar opening-wedge osteotomy at the apex sufficiently corrected the main curvature, and the subtle curvature remaining at the tip of the phalanx did not affect the appearance. This technique is simple and easy; therefore, it is recommended as a reliable procedure for patients with Kirner's deformity who are approaching puberty. PMID- 29616175 TI - Single Lymphaticovenular Anastomosis for Early-Stage Lower Extremity Lymphedema Treated by the Superior-Edge-of-the-Knee Incision Method. AB - Background: Surgical treatment of lower extremity lymphedema (LEL) remains challenging. Application of the superior-edge-of-the-knee incision method for lymphaticovenular anastomosis (LVA) is reported to have a strong therapeutic effect in patients with LEL because lymph-to-venous flow at the anastomosis is enhanced by knee joint movement during normal walking. We investigated whether a single LVA created by this method is adequate for early LEL. Methods: The study involved 10 patients with LEL characterized by stage 2 or 3 leg dermal backflow and treated by a single LVA at the thigh via the superior-edge-of-the-knee incision method. The lymphatic vessel and direction of flow were assessed intraoperatively, and reduction in lymphedema volume was assessed postoperatively. Results: Use of our incision method yielded a single anastomosis in all patients with stage 2 leg dermal backflow and in all patients with stage 3 leg dermal backflow. The lymphatic vessel was 0.65 +/- 0.08 mm in diameter (0.65 +/- 0.09 and 0.65 +/- 0.09 mm, respectively; P = 1.000). No venous reflux occurred in any patient. Mean follow-up was 7.70 +/- 3.30 months (9.60 +/- 3.29 and 5.80 +/- 2.17 months, respectively; P = 0.068). Mean reduction in the LEL index was 20.160 +/- 9.892 (22.651 +/- 12.272 and 17.668 +/- 7.353, respectively; P = 0.462). Conclusion: A single LVA created by the superior-edge-of-the-knee incision method can be expected to have a strong therapeutic effect in patients with stage 2 or 3 leg dermal backflow. PMID- 29616177 TI - Flat Incision Technique for Reconstructive Brow Surgery: A Wound Healing Model and Clinical Evaluation. AB - Background: Skin incision is considered to be placed at 90 degrees in reference to the skin to get perfect wound edge adaptation. The incision on hair-bearing tissues, as the scalp, is considered to be bevelled at 45 degrees to promote hair growth through the scar. There is no consensus about the preferred incision angle on the brow. The aim of this article was to demonstrate the feasibility of the "flat incision technique" for brow repositioning, where brow deformation results after forehead reconstruction. A wound-healing model for the bevelled incision is presented. Methods: Brow incisions are bevelled with an angle of 20 degrees . The lower incision is placed inside the brow so that the upper 2 rows of hair are included; the dermis is completely transected and dissection is continued into the subdermal plane. The procedure is presented in a patient who underwent resection of the forehead due to melanoma. Results: The bevelled incision increases the surface area of dermal layer by a factor of 2 compared with the standard vertical skin incision at 90 degrees . Loss of the dermal tissue integrity and continuity due to trauma hinders the recovery of cell migration and function, resulting in a more prominent scar formation. It appears reasonable that with the increased surface area of the dermal layers in the wound edges, the scar quality improves. The case study demonstrates the feasibility of the procedure. Conclusion: The bevelled 20 degrees incision for brow repositioning and reshaping showed to be a viable and predictable procedure. PMID- 29616178 TI - Scarless Breast Reconstruction: Indications and Techniques for Optimizing Aesthetic Outcomes in Autologous Breast Reconstruction. AB - Breast reconstruction that leaves no visible scars on the breast is possible for a subset of patients. This article reviews a cohort of 10 patients who underwent 14 autologous breast reconstructions. To achieve a reconstruction without visible breast scars, the mastectomy and autologous reconstruction are carried out through a periareolar incision. At the completion of the reconstruction, a small skin paddle is externalized through the mastectomy incision and in a subsequent stage entirely incorporated into a nipple areola reconstruction. Following completion of the breast and nipple areola reconstruction, a tattoo is performed that extends beyond the perimeter of the reconstructed areola and conceals all scars on the breast mound. The ideal candidate for this technique has a small or medium size breast, which is non- or minimally ptotic, and a donor site that can yield a flap larger than the volume of the native breast. In properly selected patients, this technique consistently yields high-quality results, which match or even surpass the aesthetics of the original breast. PMID- 29616180 TI - First Case of Lymphaticovenular Anastomosis for Treatment of Secondary Lymphedema in Costa Rica: Japanese Contribution to Microsurgery Development. AB - Although a large number of treatments have been developed for lymphedema, definitive management still remains a challenge for plastic surgery, because not all surgical techniques have a positive effect on every patient, and good results are difficult to reproduce. However, it is important to recognize the efforts that Professor Isao Koshima and his colleagues together with the Government of Japan are carrying out to spread information to the different countries on the newest surgical techniques available in current plastic surgery and to motivate young doctors in developing countries to create a microsurgery unit in their home country, providing them with the necessary knowledge and skills to deliver real solutions to complex problems that were previously unanswered. As a result of this program, the authors present the first case of secondary lymphedema successfully treated with lymphaticovenular anastomosis in Costa Rica, Central America. PMID- 29616179 TI - Expression and Localization of Cathepsins B, D, and G in Dupuytren's Disease. AB - Background: The pathogenesis of Dupuytren's disease (DD) remains unclear. An embryonic stem cell (ESC)-like population in the endothelium of the microvessels around tissues that expresses components of the renin-angiotensin system (RAS) has been reported. This study investigated if this primitive population expresses cathepsins B, D, and G, that contribute to RAS bypass loops. Methods: 3,3 Diaminobenzidine immunohistochemical (IHC) staining for cathepsins B, D, and G was performed on sections of formalin-fixed paraffin-embedded DD cords (n = 10) and nodules (n = 10). Immunofluorescence IHC staining was utilized to demonstrate co-expression of these cathepsins with ESC markers. Protein and gene expression of these cathepsins was investigated in snap-frozen DD cords (n = 3) and nodules (n = 3) by Western blotting and NanoString analysis, respectively. Enzymatic activity of these cathepsins was investigated by enzymatic activity assays. Results: 3,3-Diaminobenzidine IHC staining demonstrated expression of cathepsins B, D, and G in DD cords and nodules. Gene expression of cathepsins B, D, and G was confirmed by NanoString analysis. Western blotting confirmed expression of cathepsins B and D, but not cathepsin G. Immunofluorescent IHC staining demonstrated high abundance of cathepsins B and D on the OCT4+/angiotensin converting enzyme+ endothelium and the smooth muscle layer of the microvessels. Cathepsin G was localized to trypase+ cells within the stroma in DD cords and nodules with limited expression on the microvessels. Enzyme activity assays demonstrated functional activity of cathepsins B and D. Conclusions: Cathepsins B, D, and G were expressed in the DD tissues, with cathepsins B and D localized to the primitive population in the endothelium of the microvessels, whereas cathepsin G was localized to phenotypic mast cells, suggesting the presence of bypass loops for the RAS. PMID- 29616181 TI - Heparin-enhanced Harvest and Decanting for Autologous Fat Transfer. PMID- 29616182 TI - Molecular cloning, characterization and expression analysis of MADS-box genes associated with reproductive development in Momordica dioica Roxb. AB - The repertoire and functions of MADS-box family transcription factors (TFs) largely remains unexplored with respect to floral organogenesis of Momordica dioica Roxb. Degenerative PCR followed by rapid amplification of cDNA ends was employed in the present study to clone and characterize 17 MADS-box genes (designated as MdMADS01 to MdMADS17) from the floral buds of M. dioica. The cloned genes were clustered into three subgroups (11 MIKCC, 4 MIKC* and 2 Malpha) based on phylogenetic relationships with the MADS-box genes from Cucumis sativus, Cucumis melo and Arabidopsis thaliana. Southern hybridization showed that all the isolated genes were represented by single copy locus in the M. dioica genome. Gene structure analysis revealed 1-8 exons in MdMADS-box genes with the number of exons in MIKC greatly exceeding from that in M-type genes. Motif elicitation of the MdMADS-box genes indicated the presence of additional domains with MIKC type, suggesting that they had more complex structures. Expression analysis of MdMADS genes in six M. dioica transcriptome suggested that, 11 MIKCC-type genes are associated with floral homeotic functions, 4 MIKC*-type genes (MdMADS12 to MdMADS15) controlled the growth of male gametophyte, while the two M-type genes (MdMADS16 and MdMADS17) played significant role in female gametogenesis and seed development. Overall, these are the first set of MADS-box genes from M. dioica exhibiting a differential expression pattern during floral development. The results from this study will provide valuable information for further functional studies of candidate MADS-box genes in the sexual dimorphism of this economically important dioecious cucurbit. PMID- 29616183 TI - Sustainability assessment of biogas production from buffalo grass and dung: biogas purification and bio-fertilizer. AB - Biomass from wetland aquatic grass and buffalo grass can be exploited for biogas production, because this substrate is plenteous and does not compete with food production. In this study, the grass substrate was physically pretreated by boiling with different retention time to increase its biodegradability and was examined in batch mode. Boiling pretreatment suggested that 100 degrees C with 2 h retention time was the best condition. The results showed that the optimum grass concentration in the 1:1 ratio of co-digestion mixture with manure produced the highest methane yield. The results suggested that co-digestion of buffalo grass and buffalo dung was a promising approach for improving biogas production. This study was achieved the upgraded biogas through biological purification contained 90.42% CH4 8.04% CO2 1.43% O2 and 0.11% other trace gases-a remarkable performance based on an efficiency criteria. Furthermore, the digestate has high nutrient concentrations that can potentially use as fertilizer. PMID- 29616184 TI - Bioremediation of phenol from synthetic and real wastewater using Leptolyngbya sp.: a comparison and assessment of lipid production. AB - Bioremediation of wastewater is gaining popularity over chemical treatment due to the greener aspect. The volume of literature containing algal biodegradation is small. Especially, removal of toxic materials like phenol from coke-oven wastewater using fast-growing cyanobacteria was not tried. The current study, therefore, targeted at bioremediation of phenol from wastewater using Leptolyngbya sp., a cyanobacterial strain, as a finishing step. Furthermore, the growth of the strain was studied under different conditions, varying phenol concentration 50-150 mg/L, pH 5-11, inoculum size 2-10% to assess its ability to produce lipid. The strain was initially grown in BG-11 as a reference medium and later in phenolic solution. The strain was found to sustain 150 mg/L concentration of phenol. SEM study had shown the clear difference in the structure of cyanobacterial strain when grown in pure BG-11 medium and phenolic solution. Maximum removal of phenol (98.5 +/- 0.14%) was achieved with an initial concentration 100 mg/L, 5% inoculum size at pH 11, while the maximum amount of dry biomass (0.38 +/- 0.02 g/L) was obtained at pH 7, initial phenol concentration of 50 mg/L, and 5% inoculum size. Highest lipid yield was achieved at pH 11, initial phenol concentration of 100 mg/L, and 5% inoculum size. Coke oven wastewater collected from secondary clarifier of effluent treatment plant was also treated with the said strain and the removal of different pollutants was observed. The study suggests the utilization of such potential cyanobacterial strain in treating industrial effluent containing phenol. PMID- 29616185 TI - Racial/ethnic representation in lifestyle weight loss intervention studies in the United States: A systematic review. AB - Obesity remains a persistent public health and health disparity concern in the United States. Eliminating health disparities, particularly among racial/ethnic minority groups, is a major health priority in the US. The primary aim of this review was to evaluate representation of racial/ethnic sub-group members in behavioral weight loss interventions conducted among adults in the United States. The secondary aims were to assess recruitment and study design approaches to include racial/ethnic groups and the extent of racial/ethnic sub-group analyses conducted in these studies. PubMed, PsycInfo, Medline, and CINAHL were searched for behavioral weight loss intervention trials conducted in 2009-2015 using keywords: weight, loss, overweight, obese, intervention and trial. Most of the 94 studies included a majority of White participants compared to any other racial/ethnic group. Across the included studies, 58.9% of participants were White, 18.2% were African American, 8.7% were Hispanic/Latino, 5.0% were Asian and 1.0% were Native Americans. An additional 8.2% were categorized as "Other". Nine of the 94 studies exclusively included minority samples. Lack of adequate representation of racial and ethnic minority populations in behavioral trials limits the generalizability and potential public health impact of these interventions to groups that might most benefit from weight loss. Given racial/ethnic disparities in obesity rates and the burden of obesity and obesity related diseases among minority groups in the United States, greater inclusion in weight loss intervention studies is warranted. PMID- 29616186 TI - Novel 1,3,4-Oxadiazole Induces Anticancer Activity by Targeting NF-kappaB in Hepatocellular Carcinoma Cells. AB - Aberrant activation of NF-kappaB is linked with the progression of human malignancies including hepatocellular carcinoma (HCC), and blockade of NF-kappaB signaling could be a potential target in the treatment of several cancers. Therefore, designing of novel small molecule inhibitors that target NF-kappaB activation is of prime importance in the treatment of several cancers. In the present work, we report the synthesis of series of 1,3,4-oxadiazoles, investigated their anticancer potential against HCC cells, and identified 2-(3 chlorobenzo[b]thiophen-2-yl)-5-(3-methoxyphenyl)-1,3,4-oxadiazole (CMO) as the lead compound. Further, we examined the effect of CMO on cell cycle distribution (flow cytometry), apoptosis (annexin V-propidium iodide-FITC staining), and phosphorylation of NF-kappaB signaling pathway proteins (IkappaB and p65) in HCC cells. We found that CMO induced antiproliferative effect in dose- and time dependent manner. Also, CMO significantly increased the percentage of sub-G1 cell population and induced apoptosis. Furthermore, CMO found to decrease the phosphorylation of IkappaB (Ser 32) in the cytoplasmic extract and p65 (Ser 536) in the nuclear extract of HCC cells. It also abrogated the DNA binding ability and transcriptional activity of NF-kappaB. CMO induced the cleavage of PARP and caspase-3 in a time-dependent manner. In addition, transfection with p65 small interfering RNA blocks CMO-induced caspase-3/7 activation. Molecular docking analysis revealed that CMO interacts with the hydrophobic region of p65 protein. Thus, we are reporting CMO as an inhibitor of NF-kappaB signaling pathway. PMID- 29616187 TI - An Ensemble Approach to Knowledge-Based Intensity-Modulated Radiation Therapy Planning. AB - Knowledge-based planning (KBP) utilizes experienced planners' knowledge embedded in prior plans to estimate optimal achievable dose volume histogram (DVH) of new cases. In the regression-based KBP framework, previously planned patients' anatomical features and DVHs are extracted, and prior knowledge is summarized as the regression coefficients that transform features to organ-at-risk DVH predictions. In our study, we find that in different settings, different regression methods work better. To improve the robustness of KBP models, we propose an ensemble method that combines the strengths of various linear regression models, including stepwise, lasso, elastic net, and ridge regression. In the ensemble approach, we first obtain individual model prediction metadata using in-training-set leave-one-out cross validation. A constrained optimization is subsequently performed to decide individual model weights. The metadata is also used to filter out impactful training set outliers. We evaluate our method on a fresh set of retrospectively retrieved anonymized prostate intensity modulated radiation therapy (IMRT) cases and head and neck IMRT cases. The proposed approach is more robust against small training set size, wrongly labeled cases, and dosimetric inferior plans, compared with other individual models. In summary, we believe the improved robustness makes the proposed method more suitable for clinical settings than individual models. PMID- 29616188 TI - The Origin and Functions of Exosomes in Cancer. AB - Exosomes are nanovesicles having a maximum size of 150 nm and is a newly emerging focus in various fields of research. Its role in cargo trafficking along with its differential expression is associated with the disrupted homeostasis and provides an opportunity to defend against different diseases like cancer. Furthermore, exosomes are rich in cargos, which contain proteins and nucleic acids that directly reflect the metabolic state of the cells from which it originates. This review summarizes recent studies on tumor-derived exosomes with an overview about biogenesis, their functions and potential of using as diagnostic and prognostic markers. We also discussed the current challenges and microfluidic-based detection approaches that might improve the detection of exosomes in different settings. More intricate studies of the molecular mechanisms in angiogenesis, pre metastatic niche formation, and metastasis can give more promising insights and novel strategies in oncotherapeutics. PMID- 29616189 TI - Impact of l-Arginine Metabolism on Immune Response and Anticancer Immunotherapy. AB - The progression from neoplastic initiation to malignancy happens in part because of the failure of immune surveillance. Cancer cells successfully escape immune recognition and elimination and create an immune-suppressive microenvironment. A suppressive metabolic microenvironment may also contribute to ineffective T-cell function. Tumor progression is characterized by a complex network of interactions among different cell types that cooperatively exploit metabolic reprogramming. As we start to recognize that cancer cells use different metabolism processes than normal cells do, a better understanding of the functional mechanisms of the regulation and reprogramming of the metabolic landscape in cancer cells is crucial to successful immunotherapy strategies. However, the exact role of metabolism in T cells and in the tumor microenvironment is not known. One pathway that plays an important role in the regulation of immune cell reactivity is arginine metabolism, which has complex cellular functions. l-arginine and its downstream metabolites (e.g., ornithine and citrulline) could be essential to T cell activation and thus modulate innate and adaptive immunity to further promote tumor survival and growth. Identifying metabolic targets that mediate immunosuppression and are fundamental to sustaining tumor growth is key to increasing the efficacy of immunotherapies. PMID- 29616191 TI - Ataxia-Telangiectasia Mutated Kinase in the Control of Oxidative Stress, Mitochondria, and Autophagy in Cancer: A Maestro With a Large Orchestra. AB - Ataxia-telangiectasia mutated kinase (ATM) plays a central role in the DNA damage response (DDR) and mutations in its gene lead to the development of a rare autosomic genetic disorder, ataxia telangiectasia (A-T) characterized by neurodegeneration, premature aging, defects in the immune response, and higher incidence of lymphoma development. The ability of ATM to control genome stability several pointed to ATM as tumor suppressor gene. Growing evidence clearly support a significant role of ATM, in addition to its master ability to control the DDR, as principle modulator of oxidative stress response and mitochondrial homeostasis, as well as in the regulation of autophagy, hypoxia, and cancer stem cell survival. Consistently, A-T is strongly characterized by aberrant oxidative stress, significant inability to remove damaged organelles such as mitochondria. These findings raise the question whether ATM may contribute to a more general hijack of signaling networks in cancer, therefore, playing a dual role in this context. Indeed, an unexpected tumorigenic role for ATM, in particular, tumor contexts has been demonstrated. Genetic inactivation of Beclin-1, an autophagy regulator, significantly reverses mitochondrial abnormalities and tumor development in ATM-null mice, independently of DDR. Furthermore, ATM sustains cancer stem cells survival by promoting the autophagic flux and ATM kinase activity is enhanced in HER2-dependent tumors. This mini-review aims to shed new light on the complexity of these new molecular circuits through which ATM may modulate cancer progression and to highlight a novel role of ATM in the control of proteostasis. PMID- 29616190 TI - The Biology and Therapeutic Implications of Tumor Dormancy and Reactivation. AB - Advancements in the early detection of cancer coupled with improved surgery, radiotherapy, and adjuvant therapy led to substantial increase in patient survival. Nevertheless, cancer metastasis is the leading cause of death in several cancer patients. The majority of these deaths are associated with metastatic relapse kinetics after a variable period of clinical remission. Most of the cancer recurrences are thought to be associated with the reactivation of dormant disseminated tumor cells (DTCs). In this review, we have summarized the cellular and molecular mechanisms related to DTCs and the role of microenvironmental niche. These mechanisms regulate the dormant state and help in the reactivation, which leads to metastatic outgrowth. Identification of novel therapeutic targets to eliminate these dormant tumor cells will be highly useful in controlling the metastatic relapse-related death with several cancers. PMID- 29616192 TI - Editorial: Biomarkers of Radio-Sensitivity and Radio-Resistance. PMID- 29616193 TI - A Comprehensive in Silico Analysis of Regulatory SNPs of Human CLEC7A Gene and Its Validation as Genotypic and Phenotypic Disease Marker in Recurrent Vulvovaginal Infections. AB - Recurrent Vulvovaginal infections (RVVI) are the commonly reported microbiological syndrome affecting millions of women globally. Various molecules of innate immune system are instrumental in clearance of these microbial pathogens, thus suggested as one of the most important contributing factor in determining the disease outcome. Dendritic cell-associated C-type lectin-1 (Dectin-1) is an important molecule of innate immunity that is primarily known for its role in antifungal defenses. However, role of dectin-1 in recognition of other pathogens is also documented. The intracellular expression of dectin-1 was shown to be up-regulated by Mannose Binding Lectin (MBL)-mediated opsonophagocytosis of pathogens. Dectin-1 is encoded by CLEC7A, postulated to be a candidate gene in modulating risk of developing RVVI. In this study, we identified CLEC7A causal variants using in silico analysis. To assess their impact on susceptibility to RVVI, these causal variants along with serum dectin-1 levels (sDectin-1) were investigated using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and Enzyme Linked Immnosorbent Assay (ELISA) respectively, under a case-control design. Furthermore, effect of these polymorphisms was also assessed on sMBL levels. In silico analysis revealed 9 putative functional conserved SNPs of CLEC7A. Association analysis revealed a significantly lower risk of developing RVVI and its types in carriers of CLEC7A rs3901533 G allele and its homozygous genotypes (p < 0.05). The heterozygous genotype was associated with significant protection against RVVI (p = 0.004). Haplotypes GGG and GTA showed significant protection against RVVI (p < 0.0001; p = 0.0003), Bacterial Vaginosis (p = 0.03; p = 0.002), Vulvovaginal Candidiasis (p = 0.03; p = 0.01) and Mixed Infections (p = 0.007; p = 0.04). Mean sDectin-1 levels were significantly high in RVVI and its types compared to controls (p < 0.05). Further, genotype-phenotype stratification showed significant differences within/between cases groups and controls. The CLEC7A rs3901533 polymorphism was also found to be associated with sMBL levels. The present study contributed novel insights into the role of dectin-1 in RVVI. CLEC7A rs3901533 polymorphism and high sDectin-1 levels along with low sMBL levels were found to be associated with RVVI susceptibility. Thus, screening of women with RVVI for these novel associations may lead to better diagnosis and treatment. Also genotyping method used in this study constitutes a simple and reliable assay, which can be confidently, used as a cheaper alternative for genotyping these variants in clinical settings. Finally, new restorative markers for other infectious diseases might be found by exploring nine functionally identified CLEC7A SNPs. PMID- 29616194 TI - Heterologous Complementation Studies With the YscX and YscY Protein Families Reveals a Specificity for Yersinia pseudotuberculosis Type III Secretion. AB - Type III secretion systems harbored by several Gram-negative bacteria are often used to deliver host-modulating effectors into infected eukaryotic cells. About 20 core proteins are needed for assembly of a secretion apparatus. Several of these proteins are genetically and functionally conserved in type III secretion systems of bacteria associated with invertebrate or vertebrate hosts. In the Ysc family of type III secretion systems are two poorly characterized protein families, the YscX family and the YscY family. In the plasmid-encoded Ysc-Yop type III secretion system of human pathogenic Yersinia species, YscX is a secreted substrate while YscY is its non-secreted cognate chaperone. Critically, neither an yscX nor yscY null mutant of Yersinia is capable of type III secretion. In this study, we show that the genetic equivalents of these proteins produced as components of other type III secretion systems of Pseudomonas aeruginosa (PscX and PscY), Aeromonas species (AscX and AscY), Vibrio species (VscX and VscY), and Photorhabdus luminescens (SctX and SctY) all possess an ability to interact with its native cognate partner and also establish cross reciprocal binding to non-cognate partners as judged by a yeast two-hybrid assay. Moreover, a yeast three-hybrid assay also revealed that these heterodimeric complexes could maintain an interaction with YscV family members, a core membrane component of all type III secretion systems. Despite maintaining these molecular interactions, only expression of the native yscX in the near full-length yscX deletion and native yscY in the near full-length yscY deletion were able to complement for their general substrate secretion defects. Hence, YscX and YscY must have co-evolved to confer an important function specifically critical for Yersinia type III secretion. PMID- 29616195 TI - The ATP-P2X7 Signaling Axis Is an Essential Sentinel for Intracellular Clostridium difficile Pathogen-Induced Inflammasome Activation. AB - Clostridium difficile infection (CDI) is the leading cause of nosocomial infection in hospitalized patients receiving long-term antibiotic treatment. An excessive host inflammatory response is believed to be the major mechanism underlying the pathogenesis of C. difficile infection, and various proinflammatory cytokines such as IL-1beta are detected in patients with C. difficile infection. IL-1beta is known to be processed by caspase-1, a cysteine protease that is regulated by a protein complex called the inflammasome, which leads to a specialized form of cell death called pyroptosis. The function of inflammasome activation-induced pyroptosis is to clear or limit the spread of invading pathogens via infiltrated neutrophils. Here, we focused on inflammasome activation induced by intact C. difficile to re-evaluate the nature of inflammasome activation in CDI pathogenesis, which could provide information that leads to an alternative therapeutic strategy for the treatment of this condition in humans. First, we found that caspase-1-dependent IL-1beta production was induced by C. difficile pathogens in macrophages and increased in a time dependent manner. Moreover, intracellular toxigenic C. difficile was essential for ATP-P2X7 pathway of inflammasome activation and subsequent caspase-1 dependent pyroptotic cell death, leading to the loss of membrane integrity and release of intracellular contents such as LDH. Notably, we also observed that bacterial components such as surface layer proteins (SLPs) were released from pyroptotic cells. In addition, pro-IL-1beta production was completely MyD88 and partially TLR2 dependent. Finally, to investigate the role of the caspase-1 dependent inflammasome in host defense, we found that colonic inflammasome activation was also induced by CDI and that caspase-1 inhibition by Ac-YVAD-CMK led to increased disease progression and C. difficile load. Taken together, the present results suggest that MyD88 and TLR2 are critical component in pro-IL 1beta production and intracellular C. difficile following the ATP-P2X7 pathway of inflammasome activation and pyroptosis, which play important roles in host defense through the utilization of inflammation-mediated bacterial clearance mechanisms during C. difficile infection. PMID- 29616197 TI - The Use of CRISPR/Cas9 Gene Editing to Confirm Congenic Contaminations in Host Pathogen Interaction Studies. AB - Murine models of Salmonella enterica serovar Typhimurium infection are one of the commonest tools to study host-pathogen interactions during bacterial infections. Critically, the outcome of S. Typhimurium infection is impacted by the genetic background of the mouse strain used, with macrophages from C57BL/6 and BALB/c mice lacking the capacity to control intracellular bacterial replication. For this reason, the use of congenic strains, which mix the genetic backgrounds of naturally protected mouse strains with those of susceptible strains, has the capacity to significantly alter results and interpretation of S. Typhimurium infection studies. Here, we describe how macrophage knockout cell lines generated by CRISPR/Cas9 gene editing can help determine the contribution of background contaminations in the phenotypes of primary macrophages from congenic mice, on the outcome of S. Typhimurium infection studies. Our own experience illustrates how the CRISPR/Cas9 technology can be used to complement pre-existing knockout models, and shows that there is great merit in performing concurrent studies with both genetic models, to exclude unanticipated side-effects on host-pathogen interactions. PMID- 29616196 TI - Streptococcus suis DivIVA Protein Is a Substrate of Ser/Thr Kinase STK and Involved in Cell Division Regulation. AB - Streptococcus suis serotype 2 is an important swine pathogen and an emerging zoonotic agent that causes severe infections. Recent studies have reported a eukaryotic-like Ser/Thr protein kinase (STK) gene and characterized its role in the growth and virulence of different S. suis 2 strains. In the present study, phosphoproteomic analysis was adopted to identify substrates of the STK protein. Seven proteins that were annotated to participate in different cell processes were identified as potential substrates, which suggests the pleiotropic effects of stk on S. suis 2 by targeting multiple pathways. Among them, a protein characterized as cell division initiation protein (DivIVA) was further investigated. In vitro analysis demonstrated that the recombinant STK protein directly phosphorylates threonine at amino acid position 199 (Thr-199) of DivIVA. This effect could be completely abolished by the T199A mutation. To determine the specific role of DivIVA in growth and division, a divIVA mutant was constructed. The DeltadivIVA strain exhibited impaired growth and division, including lower viability, enlarged cell mass, asymmetrical division caused by aberrant septum, and extremely weak pathogenicity in a mouse infection model. Collectively, our results reveal that STK regulates the cell growth and virulence of S. suis 2 by targeting substrates that are involved in different biological pathways. The inactivation of DivIVA leads to severe defects in cell division and strongly attenuates pathogenicity, thereby indicating its potential as a molecular drug target against S. suis. PMID- 29616198 TI - Regulation of Nicotine Tolerance by Quorum Sensing and High Efficiency of Quorum Quenching Under Nicotine Stress in Pseudomonas aeruginosa PAO1. AB - Quorum sensing (QS) regulates the behavior of bacterial populations and promotes their adaptation and survival under stress. As QS is responsible for the virulence of vast majority of bacteria, quorum quenching (QQ), the interruption of QS, has become an attractive therapeutic strategy. However, the role of QS in stress tolerance and the efficiency of QQ under stress in bacteria are seldom explored. In this study, we demonstrated that QS-regulated catalase (CAT) expression and biofilm formation help Pseudomonas aeruginosa PAO1 resist nicotine stress. CAT activity and biofilm formation in wild type (WT) and DeltarhlR strains are significantly higher than those in the DeltalasR strain. Supplementation of DeltalasI strain with 3OC12-HSL showed similar CAT activity and biofilm formation as those of the WT strain. LasIR circuit rather than RhlIR circuit is vital to nicotine tolerance. Acylase I significantly decreased the production of virulence factors, namely elastase, pyocyanin, and pyoverdine under nicotine stress compared to the levels observed in the absence of nicotine stress. Thus, QQ is more efficient under stress. To our knowledge, this is the first study to report that QS contributes to nicotine tolerance in P. aeruginosa. This work facilitates a better application of QQ for the treatment of bacterial infections, especially under stress. PMID- 29616199 TI - Monte Carlo Simulation of Siemens Primus plus Linac for 6 and 18 MV Photon Beams. AB - Objective: The aim of the present study is to simulate 6 MV and 18 MV photon beam energies of a Siemens Primus Plus medical linear accelerator (Linac) and to verify the simulation by comparing the results with the measured data. Methods: The main components of the head of Siemens Primus Plus linac were simulated using MCNPX Monte Carlo (MC) code. To verify the results, experimental data of percentage depth dose (PDD) and beam dose profile for 5 * 5 cm2, 10 * 10 cm2 and 20 * 20 cm2 field sizes were measured and compared with simulation results. Moreover, gamma function was used to compare the measurement and simulation data. Results: The results show a good agreement, within 1%, was observed between the data calculated by the simulations and those obtained by measurement for 6 MV photon beam, while it was within 2% for 18 MV photon beam, except in the build-up region for both beams. Gamma index values were less than unity in most data points for all the mentioned energies and fields. To calculate the dose in the phantom, cells were selected in different modes, one of the modes due to the lack of dose gradient and overlapping, produced better results than others produce. Conclusion: There was good settlement between measured and MC simulation values in this research. The simulation programs can be used for photon modes of Siemens Primus Plus linac in conditions in which it is not possible to perform experimental measurements. PMID- 29616201 TI - Cannulation for Neonatal and Pediatric Extracorporeal Membrane Oxygenation for Cardiac Support. AB - The use of extracorporeal membrane oxygenation (ECMO) has increased over recent years providing respiratory and cardiac support. Optimal cannula placement is essential for successful patient outcomes. Multiple cannulation strategies may be employed depending on the age/weight of the patient and their underlying condition. This article discusses cannulation technique focusing on the cannulation of pediatric and neonatal patients for cardiac support on ECMO. PMID- 29616202 TI - Pediatric Critical Care in Resource-Limited Settings-Overview and Lessons Learned. AB - Pediatric critical care is an important component of reducing morbidity and mortality globally. Currently, pediatric critical care in low middle-income countries (LMICs) remains in its infancy in most hospitals. The majority of hospitals lack designated intensive care units, healthcare staff trained to care for critically ill children, adequate numbers of staff, and rapid access to necessary medications, supplies and equipment. In addition, most LMICs lack pediatric critical care training programs for healthcare providers or certification procedures to accredit healthcare providers working in their pediatric intensive care units (PICU) and high dependency areas. PICU can improve the quality of pediatric care in general and, if properly organized, can effectively treat the severe complications of high burden diseases, such as diarrhea, severe malaria, and respiratory distress using low-cost interventions. Setting up a PICU in a LMIC setting requires planning, specific resources, and most importantly investment in the nursing and permanent medical staff. A thoughtful approach to developing pediatric critical care services in LMICs starts with fundamental building blocks: training healthcare professionals in skills and knowledge, selecting resource appropriate effective equipment, and having supportive leadership to provide an enabling environment for appropriate care. If these fundamentals can be built on in a sustainable manner, an appropriate critical care service will be established with the potential to significantly decrease pediatric morbidity and mortality in the context of public health goals as we reach toward the sustainable development goals. PMID- 29616200 TI - Oncolytic virotherapy in upper gastrointestinal tract cancers. AB - Upper gastrointestinal tract malignancies are among the most challenging cancers with regard to response to treatment and prognosis. Cancers of the esophagus, stomach, pancreas, liver, and biliary tree have dismal 5-year survival, and very modest improvements in this rate have been made in recent times. Oncolytic viruses are being developed to address these malignancies, with a focus on high safety profiles and low off-target toxicities. Each viral platform has evolved to enhance oncolytic potency and the clinical response to either single-agent viral therapy or combined viral treatment with radiotherapy and chemotherapy. A panel of genomic alterations, chimeric proteins, and pseudotyped capsids are the breakthroughs for vector success. This article revisits developments for each viral platform to each tumor type, in an attempt to achieve maximum tumor selectivity. From the bench to clinical trials, the scope of this review is to highlight the beginnings of translational oncolytic virotherapy research in upper gastrointestinal tract malignancies and provide a bioengineering perspective of the most promising platforms. PMID- 29616204 TI - Parent Communication Prompt to Increase Shared Decision-Making: A New Intervention Approach. AB - Objective: Shared decision-making (SDM) is the process by which patients, clinicians, and in pediatrics, parents/caregivers, discuss treatment options, communicate available evidence for or against the different options, share preferences and values, and eventually arrive at a joint decision. This study evaluates the use of a novel, universally applicable, SDM intervention, provided to parents, intended to promote engagement and participation with their child's clinician. Methods: Two-arm randomized controlled trial comparing the impact of a SDM-focused intervention prompt to a neutral comparison prompt on perception of SDM participation. Participants included English-speaking parents of children (0 17 years) attending one Developmental-Behavioral Pediatric (DBP) clinic and their child's clinician. Prior to visit start, parents received either the intervention prompt encouraging engagement with the clinician in decision-making, or the comparison prompt reminding them to request a school/work excuse note if needed. After the visit, SDM was assessed by both parents and DBP clinicians. SDM was scored as present if the respondent answered "strongly agree" to all SDM-related items. Logistic regression tested effects of visit, child, parent, clinician characteristics, and intervention group status on parent-reported SDM. Cohen's kappa assessed alignment between parent and clinician perceptions of SDM. Results: Of 88 parents screened, 50 (61%) met eligibility criteria and agreed to participate (intervention n = 26; comparison n = 24). Eligible participants (parents and clinicians) for analysis completed the surveys with no missing data. Overall, SDM was present in 76% of parents and 34% of clinicians. With high rates of parent-reported SDM in both intervention and comparison groups, no main intervention effect was detected. Compared to the comparison group, there was greater alignment between parent and clinician perception of SDM in the intervention group. Conclusions: Parent and clinician enrollment and data collection with minimal loss suggest that this novel approach is easy to use and could be employed in future outpatient studies exploring SDM. In this clinical setting, both intervention and comparison group parents reported high levels of SDM participation and no main group effect was detected. Further study of this novel parent-directed SDM intervention approach is needed in a larger sample with greater variability in parent-reported SDM to determine its efficacy. PMID- 29616205 TI - Megaprepuce Reconstruction: A Single Center Experience. AB - Introduction: Surgical treatment of congenital megaprepuce is challenging and controversial. We report our 10-year experience treating patients with this deformity using a standardized procedure that has similarities to a technique reported by Smeulders et al. (1). Our postoperative complications and mid-term follow-up cosmetic appearance of the genitalia after reconstruction are reviewed. Material and methods: Fifteen patients operated on between 2005 and 2015 were evaluated. Age at surgical repair ranged from 3 to 20 months (mean 9). Treatment included unfolding the preputial sac via a ventral approach, excision of redundant inner preputial skin, and ventral skin coverage with the outer preputial layer. Twelve patients presented associated partial scrotal engulfment, which was simultaneously treated. Mean follow-up was 4.6 years (range 2-7 years). Results: Short-term complications occurred in three patients: scrotal hematoma in one patient and small skin dehiscence at the penoscrotal junction in two patients. Skin disruption healed by secondary epithelial ingrowth. All cases resulted in a satisfactory genital cosmetic outcome. There were no late complications. All patients preserved normal external genitalia appearance. Conclusion: Our experience is in agreement with reports of other authors; suggesting that excision of the inner preputial layer and using the external one for penile coverage provide good and durable mid-term esthetic results in megaprepuce reconstruction. PMID- 29616203 TI - Non-Invasive Brain Stimulation in Children With Unilateral Cerebral Palsy: A Protocol and Risk Mitigation Guide. AB - Non-invasive brain stimulation has been increasingly investigated, mainly in adults, with the aims of influencing motor recovery after stroke. However, a consensus on safety and optimal study design has not been established in pediatrics. The low incidence of reported major adverse events in adults with and without clinical conditions has expedited the exploration of NIBS in children with paralleled purposes to influence motor skill development after neurological injury. Considering developmental variability in children, with or without a neurologic diagnosis, adult dosing and protocols may not be appropriate. The purpose of this paper is to present recommendations and tools for the prevention and mitigation of adverse events (AEs) during NIBS in children with unilateral cerebral palsy (UCP). Our recommendations provide a framework for pediatric NIBS study design. The key components of this report on NIBS AEs are (a) a summary of related literature to provide the background evidence and (b) tools for anticipating and managing AEs from four international pediatric laboratories. These recommendations provide a preliminary guide for the assessment of safety and risk mitigation of NIBS in children with UCP. Consistent reporting of safety, feasibility, and tolerability will refine NIBS practice guidelines contributing to future clinical translations of NIBS. PMID- 29616206 TI - Parental Factors Influencing the Development of Early Childhood Caries in Developing Nations: A Systematic Review. AB - Background: Early childhood caries (ECC) is one of the most prevalent and chronic conditions of childhood. Various factors including biological and dietary factors along with an overlay of parental social factors have been found to be associated with the progression of ECC. The objective of this systematic review is to synthesize available literature and to identify parent-level proximal and distal risk factors associated with the development of ECC in developing nations. Methods: Studies conducted in developing nations, published between 2005 and 2017 in English, that included children younger than 6 years and examined ECC were included. The outcome of interest were parental risk factors, which included parental knowledge, behavior, attitudes, sense of coherence (SOC), stress, socioeconomic status (SES), education, and breastfeeding duration. The studies were retrieved from MEDLINE, Ovid Medline, and PubMed. Results: The search yielded 325 studies, of which 18 were considered eligible for inclusion in this review. Ten studies found maternal education, and seven studies found parental education to be significantly associated with ECC. SES was significantly associated with ECC in 13 studies in the form of annual household income and occupation level. Four studies observed the significant association between oral health knowledge and attitudes with ECC, whereas only two studies found maternal attitude to be associated with ECC. Breastfeeding duration was a significant risk factor in four studies. One study each found significant associations of SOC, parental distress, and secondary smoke with ECC. Conclusion: To date, most of the researches done in developing countries have reported distal parental factors such as income and education being significant risk factors in caries development compared to proximal risk factors in low-income groups. Only a few studies analyzed the psychosocial and behavioral factors. Interventions could be designed to improve parental oral health knowledge and behaviors in these nations. PMID- 29616207 TI - Evidence of Increase in Mortality After the Introduction of Diphtheria-Tetanus Pertussis Vaccine to Children Aged 6-35 Months in Guinea-Bissau: A Time for Reflection? AB - Background: Whole-cell diphtheria-tetanus-pertussis (DTP) and oral polio vaccine (OPV) were introduced to children in Guinea-Bissau in 1981. We previously reported that DTP in the target age group from 3 to 5 months of age was associated with higher overall mortality. DTP and OPV were also given to older children and in this study we tested the effect on mortality in children aged 6 35 months. Methods: In the 1980s, the suburb Bandim in the capital of Guinea Bissau was followed with demographic surveillance and tri-monthly weighing sessions for children under 3 years of age. From June 1981, routine vaccinations were offered at the weighing sessions. We calculated mortality hazard ratio (HR) for DTP-vaccinated and DTP-unvaccinated children aged 6-35 months using Cox proportional hazard models. Including this study, the introduction of DTP vaccine and child mortality has been studied in three studies; we made a meta-estimate of these studies. Results: At the first weighing session after the introduction of vaccines, 6-35-month-old children who received DTP vaccination had better weight for-age z-scores (WAZ) than children who did not receive DTP; one unit increase in WAZ was associated with an odds ratio of 1.32 (95% CI = 1.13-1.55) for receiving DTP vaccination. Though lower mortality compared with not being DTP vaccinated was, therefore, expected, DTP vaccination was associated with a non significant trend in the opposite direction, the HR being 2.22 (0.82-6.04) adjusted for WAZ. In a sensitivity analysis, including all children weighed at least once before the vaccination program started, DTP (+/-OPV) as the most recent vaccination compared with live vaccines or no vaccine was associated with a HR of 1.89 (1.00-3.55). In the three studies of the introduction of DTP in rural and urban Guinea-Bissau, DTP-vaccinated children had an HR of 2.14 (1.42 3.23) compared to DTP-unvaccinated children; this effect was separately significant for girls [HR = 2.60 (1.57-4.32)], but not for boys [HR = 1.71 (0.99 2.93)] (test for interaction p = 0.27). Conclusion: Although having better nutritional status and being protected against three infections, 6-35 months old DTP-vaccinated children tended to have higher mortality than DTP-unvaccinated children. All studies of the introduction of DTP have found increased overall mortality. PMID- 29616209 TI - Promoting Sustained Breastfeeding of Infants at Risk for Asthma: Explaining the "Active Ingredients" of an Effective Program Using Intervention Mapping. AB - Infants whose parents and/or siblings have a history of asthma or allergy may profit from receiving exclusive breastfeeding during the first 6 months of life. This is expected to diminish the chance of developing childhood asthma and/or atopic disease. Ongoing breastfeeding for 6 months seems challenging for many women. An educational program was developed using Intervention Mapping as a logic model to guide development and was found successful in improving breastfeeding rates at 6 months postpartum, improving knowledge and beliefs about breastfeeding for 6 months, after exposure to the program compared to controls. Intervention elements included an evidence- and theory-based booklet addressed during pre- and postnatal home visits by trained assistants. This paper elucidates the inner workings of the program by systematically describing and illustrating the steps for intervention development. PMID- 29616208 TI - Genomic and Bioinformatics Approaches for Analysis of Genes Associated With Cancer Risks Following Exposure to Tobacco Smoking. AB - Cancer is a significant health problem in the Middle East and global population. It is well established that there is a direct link between tobacco smoking and cancer, which will continue to pose a significant threat to human health. The impact of long-term exposure to tobacco smoke on the risk of cancer encouraged the study of biomarkers for vulnerable individuals to tobacco smoking, especially children, who are more susceptible than adults to the action of environmental carcinogens. The carcinogens in tobacco smoke condensate induce DNA damage and play a significant role in determining the health and well-being of smokers, non smoker, and primarily children. Cancer is a result of genomic and epigenomic malfunctions that lead to an initial premalignant condition. Although premalignancy genetic cascade is a much-delayed process, it will end with adverse health consequences. In addition to the DNA damage and mutations, tobacco smoke can cause changes in the DNA methylation and gene expression associated with cancer. The genetic events hint on the possible use of genomic-epigenomic changes in genes related to cancer, in predicting cancer risks associated with exposure to tobacco smoking. Bioinformatics provides indispensable tools to identify the cascade of expressed genes in active smokers and non-smokers and could assist the development of a framework to manage this cascade of events linked with the evolvement of disease including cancer. The aim of this mini review is to cognize the essential genomic processes and health risks associated with tobacco smoking and the implications of bioinformatics in cancer prediction, prevention, and intervention. PMID- 29616211 TI - Granulated Bog Iron Ores as Sorbents in Passive (Bio)Remediation Systems for Arsenic Removal. AB - The main element of PbRS (passive (bio)remediation systems) are sorbents, which act as natural filters retaining heavy metals and carriers of microorganisms involved in water treatment. Thus, the effectiveness of PbRS is determined by the quality of the (ad)sorbents, which should be stable under various environmental conditions, have a wide range of applications and be non-toxic to (micro)organisms used in these systems. Our previous studies showed that bog iron ores (BIOs) meet these requirements. However, further investigation of the physical and chemical parameters of BIOs under environmental conditions is required before their large-scale application in PbRS. The aim of this study was (i) to investigate the ability of granulated BIOs (gBIOs) to remove arsenic from various types of contaminated waters, and (ii) to estimate the application potential of gBIOs in technologies dedicated to water treatment. These studies were conducted on synthetic solutions of arsenic and environmental samples of arsenic contaminated water using a set of adsorption columns filled with gBIOs. The experiments performed in a static system revealed that gBIOs are appropriate arsenic and zinc adsorbent. Dynamic adsorption studies confirmed these results and showed, that the actual sorption efficiency of gBIOs depends on the adsorbate concentration and is directly proportional to them. Desorption analysis showed that As-loaded gBIOs are characterized by high chemical stability and they may be reused for the (ad)sorption of other elements, i.e., zinc. It was also shown that gBIOs may be used for remediation of both highly oxygenated waters and groundwater or settling ponds, where the oxygen level is low, as both forms of inorganic arsenic (arsenate and arsenite) were effectively removed. Arsenic concentration after treatment was <100 MUg/L, which is below the limit for industrial water. PMID- 29616212 TI - A New Porous Hybrid Material Derived From Silica Fume and Alginate for Sustainable Pollutants Reduction. AB - In this work a new mesoporous adsorbent material obtained from a natural, high abundant raw material and a high volume industrial by-product is presented. The material is consolidated by the gelling properties of alginate and by decomposition of sodium-bicarbonate controlled porosity at low temperatures (70 80 degrees C) at different scale lengths. The structural, thermal, and morphological characterization shows that the material is a mesoporous organic inorganic hybrid. The material is tested as adsorbent, showing high performances. Methylene blue, used as model pollutant, can be adsorbed and removed from aqueous solutions even at a high concentration with efficiency up to 94%. By coating the material with a 100 nm thin film of titania, good photodegradation performance (more than 20%) can be imparted. Based on embodied energy and carbon footprint of its primary production, the sustainability of the new obtained material is evaluated and quantified in respect to activated carbon as well. It is shown that the new proposed material has an embodied energy lower than one order of magnitude in respect to the one of activated carbon, which represents the gold standards. The versatility of the new material is also demonstrated in terms of its design and manufacturing possibilities In addition, this material can be printed in 3D. Finally, preliminary results about its ability to capture diesel exhaust particulate matter are reported. The sample exposed to diesel contains a large amount of carbon in its surface. At the best of our knowledge, this is the first time that hybrid porous materials are proposed as a new class of sustainable materials, produced to reduce pollutants in the wastewaters and in the atmosphere. PMID- 29616213 TI - Synthesis, Characterization, and Handling of EuII-Containing Complexes for Molecular Imaging Applications. AB - Considerable research effort has focused on the in vivo use of responsive imaging probes that change imaging properties upon reacting with oxygen because hypoxia is relevant to diagnosing, treating, and monitoring diseases. One promising class of compounds for oxygen-responsive imaging is EuII-containing complexes because the EuII/III redox couple enables imaging with multiple modalities including magnetic resonance and photoacoustic imaging. The use of EuII requires care in handling to avoid unintended oxidation during synthesis and characterization. This review describes recent advances in the field of imaging agents based on discrete EuII-containing complexes with specific focus on the synthesis, characterization, and handling of aqueous EuII-containing complexes. PMID- 29616214 TI - Norisoprenoids, Sesquiterpenes and Terpenoids Content of Valpolicella Wines During Aging: Investigating Aroma Potential in Relationship to Evolution of Tobacco and Balsamic Aroma in Aged Wine. AB - During wine aging, tobacco and balsamic aroma notes appear. In this paper, volatile compounds directly or potentially related to those aromas have been investigated in Corvina and Corvinone wines during aging. Corvina and Corvinone are two northern-Italy autochthonous red grape varieties, used to produce Valpolicella Classico and Amarone wines, both characterized by tobacco and balsamic aroma notes. Wines were analyzed shortly after bottling or following model aging at 60 degrees C for 48, 72, and 168 h. Volatile compounds were analyzed by HS-SPME-GC-MS. Results showed that compounds related to tobacco aroma [beta-damascenone, 3-oxo-alpha-ionol, (E)-1-(2,3,6-Trimethylphenyl)-buta-1,3 diene (TPB), and megastigmatrienones] increased in relationship to storage time with different patterns. beta-Damascenone and 3-oxo-alpha-ionol rapidly increased to reach a plateau in the first 48-72 h of model aging. Instead, TPB and megastigmatrienones concentration showed a linear correlation with aging time. During model aging, several cyclic terpenes tended to increase. Among them 1,8 cineole and 1,4-cineole, previously reported to contribute to red wine eucalyptus notes increased proportionally to storage time, and this behavior was clearly associated with reactions involving alpha-terpineol, limonene, and terpinolene, as confirmed by studies with model wine solutions. Among other relevant volatile compounds, sesquiterpenes appear to contribute potentially balsamic and spicy aroma notes. In this study, linear sesquiterpenes (nerolidol, farnesol) underwent acid hydrolysis during long wine aging, while cyclic sesquiterpenes seemed to increase with time. The chemical pathways associated with evolution of some of the compounds investigated have been studied in model wine. PMID- 29616210 TI - Natural Products Research in China From 2015 to 2016. AB - This review covers the literature published by chemists from China during the 2015-2016 on natural products (NPs), with 1,985 citations referring to 6,944 new compounds isolated from marine or terrestrial microorganisms, plants, and animals. The emphasis is on 730 new compounds with a novel skeleton or/and significant bioactivity, together with their source organism and country of origin. PMID- 29616215 TI - Self-Propagating Combustion Synthesis, Luminescent Properties and Photocatalytic Activities of Pure Ca12Al14O33: Tb3+(Sm3+). AB - The dual-functional Ca12Al14O33: Tb3+ and Ca12Al14O33: Sm3+ materials were prepared by the Self-Propagating Combustion Synthesis (SPCS) technology. The structure, morphology and light absorption property were investigated by XRD, FT IR, UV-Vis DRS and SEM etc. The doping of Tb3+ and Sm3+ ions had not changed cubic structure of Ca12Al14O33 but leaded to the slight lattice dilatation and the red-shifts of absorption peaks/edges. The excitation and emission spectra indicated that Ca12Al14O33: Tb3+ and Ca12Al14O33: Sm3+ are superior green and red luminescent materials, respectively, and it displayed the distinctly refined structure characteristics which had importantly reference value for the energy level investigation of Tb3+ and Sm3+ ions. Meanwhile, Ca12Al14O33: Tb3+ and Ca12Al14O33: Sm3+ also exhibited the improved photocatalytic degradation for removing dye MB compared with bare Ca12Al14O33. PMID- 29616216 TI - Microstructure Evolution in Mg-Zn-Zr-Gd Biodegradable Alloy: The Decisive Bridge Between Extrusion Temperature and Performance. AB - Being a biocompatible metal with similar mechanical properties as bones, magnesium bears both biodegradability suitable for bone substitution and chemical reactivity detrimental in bio-ambiences. To benefit its biomaterial applications, we developed Mg-2.0Zn-0.5Zr-3.0Gd (wt%) alloy through hot extrusion and tailored its biodegradability by just varying the extrusion temperatures during alloy preparations. The as-cast alloy is composed of the alpha-Mg matrix, a network of the fish-bone shaped and ellipsoidal (Mg, Zn)3Gd phase, and a lamellar long period stacking ordered phase. Surface content of dynamically recrystallized (DRXed) and large deformed grains increases within 330-350 degrees C of the extrusion temperature, and decreases within 350-370 degrees C. Sample second phase contains the (Mg, Zn)3Gd nano-rods parallel to the extrusion direction, and Mg2Zn11 nanoprecipitation when temperature tuned above 350 degrees C. Refining microstructures leads to different anticorrosive ability of the alloys as given by immersion and electrochemical corrosion tests in the simulated body fluids. The sample extruded at 350 degrees C owns the best anticorrosive ability thanks to structural impacts where large DRXed portions and uniform nanosized grains reduce chemical potentials among composites, and passivate the extruded surfaces. Besides materials applications, the in vitro mechanism revealed here is hoped to inspire similar researches in biometal developments. PMID- 29616217 TI - Thermal Expansion and Magnetostriction Measurements at Cryogenic Temperature Using the Strain Gauge Method. AB - Thermal expansion and magnetostriction, the strain responses of a material to temperature and a magnetic field, especially properties at low temperature, are extremely useful to study electronic and phononic properties, phase transitions, quantum criticality, and other interesting phenomena in cryogenic engineering and materials science. However, traditional dilatometers cannot provide magnetic field and ultra-low temperature (<77 K) environment easily. This paper describes the design and test results of thermal expansion and magnetostriction at cryogenic temperature using the strain gauge method based on a Physical Properties Measurements System (PPMS). The interfacing software and automation were developed using LabVIEW. The sample temperature range can be tuned continuously between 1.8 and 400 K. With this PPMS-aided measuring system, we can observe temperature and magnetic field dependence of the linear thermal expansion of different solid materials easily and accurately. PMID- 29616218 TI - Recent Insights into the Contribution of the Changing Hypertrophic Chondrocyte Phenotype in the Development and Progression of Osteoarthritis. AB - Osteoarthritis (OA) is an extremely prevalent age-related condition. The economic and societal burden due to the cost of symptomatic treatment, inability to work, joint replacement, and rehabilitation is huge and increasing. Currently, there are no effective medical therapies that delay or reverse the pathological manifestations of OA. Current treatment options are, without exception, focused on slowing down progression of the disease to postpone total joint replacement surgery for as long as possible and keeping the associated pain and joint immobility manageable. Alterations in the articular cartilage chondrocyte phenotype might be fundamental in the pathological mechanisms of OA development. In many ways, the changing chondrocyte phenotype in osteoarthritic cartilage resembles the process of endochondral ossification as seen, for instance, in developing growth plates. However, the relative contribution of endochondral ossification to the changing chondrocyte phenotype in the development and progression of OA remains poorly described. In this review, we will discuss the current knowledge regarding the cartilage endochondral phenotypic changes occurring during OA development and progression, as well as the molecular and environmental effectors driving these changes. Understanding how these molecular mechanisms determine the chondrocyte cell fate in OA will be essential in enabling cartilage regenerative approaches in future treatments of OA. PMID- 29616221 TI - Incidence Trends of Cervical Cancer and Its Precancerous Lesions in Women of Central Switzerland from 2000 until 2014. AB - Objective: Cervical cancer (CC) screening by Pap smears has led to a decrease in the incidence of CC worldwide. Indeed, the incidence of CC in Switzerland is very low; however, there is a lack of data to evaluate the efficiency of the Pap smear as a screening tool. Until now, only Pap smears have been used and other methods such as the presence of an infection with HPV have not been integrated into the routine screening. The aim of this study is to evaluate trends in the incidence of CC and its precancerous lesions in Central Switzerland, which represents a rural region, with those in urban regions and the entire country of Switzerland. Methods: All conizations and CC registered between 2000 and 2014 at the Institute of Pathology at the Cantonal Hospital of Lucerne have been included in our study. The incidence of CC and its precancerous lesions have been categorized according to age, stage, morphology, and study period. Age-standardized incidence in the Canton of Zurich and the entire country served as reference for the assessment of trends in CC incidence in the study region. Results: In Central Switzerland, the number of conizations performed annually has more than doubled over the observed 15 years. There has been a significant increase in precancerous lesions, which were found in approximately 50% of conizations. The total number of CC diagnosed by conization increased by 37.5% and the total of CIN3 increased by 130%. Age standardized incidence of CC and CIN3 increased from 2.4 to 3.3/100,000 and from 11.6 to 26.9/100,000, respectively. The incidence of CC was lower in Central Switzerland compared to incidence in the Canton of Zurich and in Switzerland generally. Conclusion: Approximately 50% of all conizations were performed on women without serious precancerous lesions. For this reason, we recommend the adaptation of screening modalities and the use of risk stratification to avoid overtreatment. In light of the forthcoming implementation of an HPV vaccination program, our data provides important baseline information. PMID- 29616220 TI - The Role of Immune and Inflammatory Cells in Idiopathic Pulmonary Fibrosis. AB - The contribution of the immune system to idiopathic pulmonary fibrosis (IPF) remains poorly understood. While most sources agree that IPF does not result from a primary immunopathogenic mechanism, evidence gleaned from animal modeling and human studies suggests that innate and adaptive immune processes can orchestrate existing fibrotic responses. This review will synthesize the available data regarding the complex role of professional immune cells in IPF. The role of innate immune populations such as monocytes, macrophages, myeloid suppressor cells, and innate lymphoid cells will be discussed, as will the activation of these cells via pathogen-associated molecular patterns derived from invading or commensural microbes, and danger-associated molecular patterns derived from injured cells and tissues. The contribution of adaptive immune responses driven by T-helper cells and B cells will be reviewed as well. Each form of immune activation will be discussed in the context of its relationship to environmental and genetic factors, disease outcomes, and potential therapies. We conclude with discussion of unanswered questions and opportunities for future study in this area. PMID- 29616219 TI - Developmental Functions of the Dynamic DNA Methylome and Hydroxymethylome in the Mouse and Zebrafish: Similarities and Differences. AB - 5-methylcytosine (5mC) is the best understood DNA modification and is generally believed to be associated with repression of gene expression. Over the last decade, sequentially oxidized forms of 5mC (oxi-mCs) have been discovered within the genomes of vertebrates. Their discovery was accompanied by that of the ten eleven translocation (TET) methylcytosine dioxygenases, the enzymes that catalyze the formation of the oxi-mCs. Although a number of studies performed on different vertebrate models and embryonic stem cells demonstrated that both TET enzymes and oxi-mCs are likely to be important for several developmental processes it is currently unclear whether their developmental roles are conserved among vertebrates. Here, we summarize recent developments in this field suggesting that biological roles of TETs/oxi-mCs may significantly differ between mice and zebrafish. Thus, although the role of TET proteins in late organogenesis has been documented for both these systems; unlike in mice the enzymatic oxidation of 5mC does not seem to be involved in zygotic reprogramming or gastrulation in zebrafish. Our analysis may provide an insight into the general principles of epigenetic regulation of animal development and cellular differentiation. PMID- 29616223 TI - Geraniin Protects High-Fat Diet-Induced Oxidative Stress in Sprague Dawley Rats. AB - Geraniin, a hydrolysable polyphenol derived from Nephelium lappaceum L. fruit rind, has been shown to possess significant antioxidant activity in vitro and recently been recognized for its therapeutic potential in metabolic syndrome. This study investigated its antioxidative strength and protective effects on organs in high-fat diet (HFD)-induced rodents. Rats were fed HFD for 6 weeks to induce obesity, followed by 10 and 50 mg/kg of geraniin supplementation for 4 weeks to assess its protective potential. The control groups were maintained on standard rat chows and HFD for the same period. At the 10th week, oxidative status was assessed and the pancreas, liver, heart and aorta, kidney, and brain of the Sprague Dawley rats were harvested and subjected to pathological studies. HFD rats demonstrated changes in redox balance; increased protein carbonyl content, decreased levels of superoxide dismutase, glutathione peroxidase, and glutathione reductase with a reduction in the non-enzymatic antioxidant mechanisms and total antioxidant capacity, indicating a higher oxidative stress (OS) index. In addition, HFD rats demonstrated significant diet-induced changes particularly in the pancreas. Four-week oral geraniin supplementation, restored the OS observed in the HFD rats. It was able to restore OS biomarkers, serum antioxidants, and the glutathione redox balance (reduced glutathione/oxidized glutathione ratio) to levels comparable with that of the control group, particularly at dosage of 50 mg geraniin. Geraniin was not toxic to the HFD rats but exhibited protection against glucotoxicity and lipotoxicity particularly in the pancreas of the obese rodents. It is suggested that geraniin has the pharmaceutical potential to be developed as a supplement to primary drugs in the treatment of obesity and its pathophysiological sequels. PMID- 29616222 TI - Does a Better Perfusion of Deconditioned Muscle Tissue Release Chronic Low Back Pain? AB - Non-specific chronic low back pain (nsCLBP) is a multifactorial condition of unknown etiology and pathogenesis. Physical and genetic factors may influence the predisposition of individuals to CLBP, which in many instances share a musculoskeletal origin. A reduced pain level in low back pain patients that participate in exercise therapy highlights that disuse-related muscle deconditioning may predispose individuals to nsCLBP. In this context, musculoskeletal pain may be the consequence of capillary rarefaction in inactive muscle as this would lower local tissue drainage and washing out of toxic waste. Muscle activity is translated into an angio-adaptative process, which implicates angiogenic-gene expression and individual response differences due to heritable modifications of such genes (gene polymorphisms). The pathophysiologic mechanism underlying nsCLBP is still largely unaddressed. We hypothesize that capillary rarefaction due to a deconditioning of dorsal muscle groups exacerbates nsCLBP by increasing noxious sensation, reducing muscle strength and fatigue resistance by initiating a downward spiral of local deconditioning of back muscles which diminishes their load-bearing capacity. We address the idea that specific factors such as angiotensin-converting enzyme and Tenascin-C might play an important role in altering susceptibility to nsCLBP via their effects on microvascular perfusion and vascular remodeling of skeletal muscle, inflammation, and pain sensation. The genetic profile may help to explain the individual predisposition to nsCLBP, thus identifying subgroups of patients, which could benefit from ad hoc treatment types. Future therapeutic approaches aimed at relieving the pain associated with nsCLBP should be based on the verification of mechanistic processes of activity induced angio-adaptation and muscle-perfusion. PMID- 29616224 TI - The Relevance of Sexual Dysfunction Related to Groin Pain After Inguinal Hernia Repair - The SexIHQ Short Form Questionnaire Assessment. AB - Background: Chronic postoperative pain after inguinal hernia surgery can affect sexual function. A new short form questionnaire for inguinal hernia pain related sexual dysfunction (SexIHQ) was introduced and applied to a register based cohort of total extra-peritoneal hernioplasty (TEP) operated patients. Methods: Sexually active men, 30-60 years old, recorded in the Swedish Hernia Register for a primary inguinal hernia TEP operation were included. Two initial questions of the SexIHQ identify patients with pain at sexual activity. Only these patients proceeded to answer the specific questions on pain-induced impairment of sexual activity, pain frequency and intensity, physical functions (erection and ejaculation), and symptoms of depression. SexIHQ, the Short Form-36 (SF-36), the Inguinal Pain Questionnaire (IPQ) were mailed to participants for long term follow up. Results: In 538 included patients, 44 (8.2%) reported pain during sexual activity at mean 33 months after surgery. Sexual dysfunction was seen in 33 of these patients. A postoperative complication was a risk factor for pain during sexual activity; OR 4.89 (95% CI 1.92-12.43; p < 0.001). Quality-of-life was reduced in almost all SF-36 domains in patients with pain during sexual activity. Conclusions: A short form questionnaire, suitable for large cohorts, was developed to assess sexual dysfunction due to groin pain after inguinal hernia repair in male patients. Sexual dysfunction due to groin pain after hernia surgery by TEP is surprisingly common. Patients should preoperatively be informed of the risk of having pain during sexual activity following groin hernia surgery. PMID- 29616225 TI - Toxicological Effects of Berberine and Sanguinarine. AB - Berberine and Sanguinarine alkaloids belong to a group of naturally occurring chemical compounds that mostly contain basic nitrogen atoms. This group also includes some related compounds with neutral or weakly acidic properties. Alkaloids are produced by a large number of organisms including bacteria, fungi, plants, and animals. Berberine and Sanguinarine both are isoquinoline derivatives and belong to protoberberine and benzophenanthridines, respectively. Tyrosine or phenylalanine is common precursor for the biosynthesis of both. Sanguinarine [13 methyl (1,3) benzodioxolo(5,6-c)-1,3-dioxolo (4,5) phenanthridinium] is a toxin that kills animal cells through its action on the Na+-K+-ATPase transmembrane protein. Berberine, on the other hand, has been reported to cause cytotoxicity and adversely influence the synthesis of DNA. Several workers have reported varied pharmacological properties of these alkaloids as they exhibit antibacterial, antiasthma, anticancer, anti-inflammatory, and antidiabetic activities. This review article illustrates the toxicological effects of berberine and sanguinarine as well as mechanistic part of berberine and sanguinarine mediated toxicity in different living systems. This manuscript has included the lethal doses (LD50) of berberine and sanguinarine in different animals via different routs of exposure. Also, the effects of these alkaloids on the activities of some key enzymes, cell lines and organ development etc. have been summarized. PMID- 29616227 TI - A One Health Evaluation of the Southern African Centre for Infectious Disease Surveillance. AB - Rooted in the recognition that emerging infectious diseases occur at the interface of human, animal, and ecosystem health, the Southern African Centre for Infectious Disease Surveillance (SACIDS) initiative aims to promote a trans sectoral approach to address better infectious disease risk management in five countries of the Southern African Development Community. Nine years after SACIDS' inception, this study aimed to evaluate the program by applying a One Health (OH) evaluation framework developed by the Network for Evaluation of One Health (NEOH). The evaluation included a description of the context and the initiative, illustration of the theory of change, identification of outputs and outcomes, and assessment of the One Healthness. The latter is the sum of characteristics that defines an integrated approach and includes OH thinking, OH planning, OH working, sharing infrastructure, learning infrastructure, and systemic organization. The protocols made available by NEOH were used to develop data collection protocols and identify the study design. The framework relies on a mixed methods approach by combining a descriptive and qualitative assessment with a semi-quantitative evaluation (scoring). Data for the analysis were gathered during a document review, in group and individual interviews and in an online survey. Operational aspects (i.e., OH thinking, planning, and working) were found to be balanced overall with the highest score in the planning dimension, whereas the infrastructure (learning infrastructure, systemic organization, and sharing infrastructure) was high for the first two dimensions, but low for sharing. The OH index calculated was 0.359, and the OH ratio calculated was 1.495. The program was praised for its great innovative energy in a difficult landscape dominated by poor infrastructure and its ability to create awareness for OH and enthuse people for the concept; training of people and networking. Shortcomings were identified regarding the balance of contributions, funds and activities across member countries in the South, lack of data sharing, unequal allocation of resources, top-down management structures, and limited horizontal collaboration. Despite these challenges, SACIDS is perceived to be an effective agent in tackling infectious diseases in an integrated manner. PMID- 29616226 TI - XPD-The Lynchpin of NER: Molecule, Gene, Polymorphisms, and Role in Colorectal Carcinogenesis. AB - In mammals the bulky DNA adduct lesions known to result in deleterious phenotypes are acted upon and removed from the genomic DNA by nucleotide excision repair (NER) pathway. TFIIH multi-protein complex with its important helicase-Xeroderma Pigmentosum Protein (XPD) serves as the pivotal factor for opening up of the damaged lesion DNA site and carry out the repair process. The initial damage verification step of the TFIIH is in part dependent upon the helicase activity of XPD. Besides, XPD is also actively involved in the initiation steps of transcription and in the regulation of the cell cycle and apoptosis. In this review, we will be exploring the new insights in scientific research on the functioning of the NER pathway, the role of TFIIH as the central complex of NER, the pivotal helicase XPD as the lynchpin of NER and the effects of various single nucleotide polymorphisms (SNPs) of XPD on its functioning and their consequent role in colorectal carcinogenesis. PMID- 29616228 TI - Modeling the Effects of Duration and Size of the Control Zones on the Consequences of a Hypothetical African Swine Fever Epidemic in Denmark. AB - African swine fever (ASF) is a notifiable infectious disease. The disease is endemic in certain regions in Eastern Europe constituting a risk of ASF spread toward Western Europe. Therefore, as part of contingency planning, it is important to continuously explore strategies that can effectively control an epidemic of ASF. A previously published and well documented simulation model for ASF virus spread between herds was used to examine the epidemiologic and economic impacts of the duration and size of the control zones around affected herds. In the current study, scenarios were run, where the duration of the protection and surveillance zones were reduced from 50 and 45 days to 35 and 25 days or to 35 and 25 days, respectively. These scenarios were run with or without enlargement of the surveillance zone around detected herds from 10 to 15 km. The scenarios were also run with only clinical or clinical and serological surveillance of herds within the zones. Sensitivity analysis was conducted on influential input parameters in the model. The model predicts that reducing the duration of the protection and surveillance zones has no impact on the epidemiological consequences of the epidemics, while it may result in a substantial reduction in the total economic losses. In addition, the model predicts that increasing the size of the surveillance zone from 10 to 15 km may reduce both the epidemic duration and the total economic losses, in case of large epidemics. The ranking of the control strategies by the total costs of the epidemics was not influenced by changes of input parameters in the sensitivity analyses. PMID- 29616229 TI - Investigation of the Behavioral Characteristics of Dogs Purpose-Bred and Prepared to Perform Vapor Wake(r) Detection of Person-Borne Explosives. AB - Specialized detector dogs are increasingly being utilized for the detection of modern threats. The Vapor Wake(r) (VW) dog was developed to create a dog phenotype ideally suited for detecting hand-carried and body-worn explosives. VW dogs (VWDs) are trained to sample and alert to target odors in the aerodynamic wakes of moving persons, which entrains vapor and small particles from the person. The behavioral characteristics necessary for dogs to be successfully trained and employed for the application of VW are a distinct subset of the desired general characteristics of dogs used for detection tasks due to the dynamic nature of moving targets. The purpose of this study was to examine the behavioral characteristics of candidate detector dogs to determine the particular qualities that set apart VW-capable dogs from others. We assessed 146 candidate detector dogs from a VW breeding and training program. Dogs received identical puppy development and foundational odor training and underwent performance evaluations at 3, 6, 10, and 12 months old, after which they were sold for service. Dogs were categorized based on their final outcome of the training program, independently determined by private vendors, corresponding to three groups: dogs successfully sold for VW, dogs sold for standard explosives detection, and dogs that failed to be placed in any type of detector dog service (Washouts). Comparisons of behavioral evaluations between the groups were made across domains pertaining to search-related behaviors (Performance), reactions to novel stimuli (Environmental), and overall ease of learning new tasks (Trainability). Comparisons were also made at each evaluation to determine any early emergence of differences. VWDs scored significantly higher on Performance characteristics compared to standard explosives detection dogs (EDDs) and Washouts. However, Environmental characteristics did not differentiate VWDs from EDDs, though scores on these measures were significantly lower in the Washouts. Furthermore, differences between groups emerged as early as 3 and 6 months for select measures. We describe the behavioral characteristics targeted for selection in developing the VW phenotype and discuss the relative merit and degree of expression of those characteristics in the success of dogs bred and trained for the VW application. PMID- 29616231 TI - Composite Resection of Tumors of the Rostral Maxilla and Dorsolateral Muzzle Utilizing an Upper Lip-Sparing, Combined Approach in Dogs. AB - Tumors of the rostral maxilla that involve both the oral mucosa and the dermis or subdermis of the dorsolateral muzzle provide unique challenges for the oromaxillofacial surgeon. Traditionally described approaches to such lesions may involve an intraoral incision that extends and involves the upper lip to envelope the involved dermis of the dorsolateral muzzle. However, such an approach unnecessarily resects upper lip tissue resulting in a large defect that likely requires advanced skin flaps or grafts for reconstruction. Such flaps are technically challenging and introduce potential for significance postoperative complications. In this article, we provide a detailed description a combined intra- and extraoral approach that allows for composite resection of tumors of the rostral maxilla that also involve the dorsolateral muzzle. The described technique allows for excellent intraoperative visualization and provides a superior cosmetic outcome that minimizes postoperative complications. In addition, we describe our experience utilizing the technique in three clinical cases. PMID- 29616232 TI - Pruritus in anti-DPPX encephalitis. PMID- 29616234 TI - Diagnosing MRI-negative autoimmune diseases. PMID- 29616233 TI - Normal brain imaging accompanies neuroimmunologically justified, autoimmune encephalomyelitis. AB - Objective: To examine cases with a clinical course, signs, and symptoms mimicking MS, but without abnormalities on conventional MRI. Methods: Among 550 people with a tentative diagnosis of MS or neuromyelitis optica spectrum disorder (NMOSD), we selected patients, who met the 2010 McDonald diagnosis criteria for MS, but did not show abnormal findings on conventional brain and spinal cord MRI. After evaluating their clinical data, we analyzed fractional anisotropy (FA) values in the brain white matter on diffusion tensor MRIs and the frequencies of B-cell subsets in the peripheral blood in the corresponding cases as compared to healthy controls. Results: Eleven patients (age: 41.1 +/- 8.0 years, 9 women and 2 men) met the selection criteria. They were functionally disabled, with a median expanded disability status scale score of 6.0 (2.0-8.0). CSF oligoclonal bands were negative in all cases. IV methylprednisolone and plasmapheresis (PP) were found to be efficacious. Diffusion tensor MRI analysis revealed extensive white matter abnormalities characterized by significantly decreased FA values. The frequency of plasmablasts in the peripheral blood was significantly increased in these patients similar to NMOSD. Conclusions: The neurologic disabilities in these patients could be ascribed to brain white matter damage, as revealed by MRI analysis, whereas the efficacy of PP and B-cell abnormalities in the patients suggested an autoimmune-mediated pathogenesis. In the differential diagnosis of MS, we propose that this condition be referred to as, "Normal-appearing Imaging associated, Neuroimmunologically Justified, Autoimmune encephalomyelitis." PMID- 29616230 TI - Anesthesia-Associated Relative Hypovolemia: Mechanisms, Monitoring, and Treatment Considerations. AB - Although the utility and benefits of anesthesia and analgesia are irrefutable, their practice is not void of risks. Almost all drugs that produce anesthesia endanger cardiovascular stability by producing dose-dependent impairment of cardiac function, vascular reactivity, and compensatory autoregulatory responses. Whereas anesthesia-related depression of cardiac performance and arterial vasodilation are well recognized adverse effects contributing to anesthetic risk, far less emphasis has been placed on effects impacting venous physiology and venous return. The venous circulation, containing about 65-70% of the total blood volume, is a pivotal contributor to stroke volume and cardiac output. Vasodilation, particularly venodilation, is the primary cause of relative hypovolemia produced by anesthetic drugs and is often associated with increased venous compliance, decreased venous return, and reduced response to vasoactive substances. Depending on factors such as patient status and monitoring, a state of relative hypovolemia may remain clinically undetected, with impending consequences owing to impaired oxygen delivery and tissue perfusion. Concurrent processes related to comorbidities, hypothermia, inflammation, trauma, sepsis, or other causes of hemodynamic or metabolic compromise, may further exacerbate the condition. Despite scientific and technological advances, clinical monitoring and treatment of relative hypovolemia still pose relevant challenges to the anesthesiologist. This short perspective seeks to define relative hypovolemia, describe the venous system's role in supporting normal cardiovascular function, characterize effects of anesthetic drugs on venous physiology, and address current considerations and challenges for monitoring and treatment of relative hypovolemia, with focus on insights for future therapies. PMID- 29616235 TI - Effect of water quality, sanitation, hand washing, and nutritional interventions on child development in rural Bangladesh (WASH Benefits Bangladesh): a cluster randomised controlled trial. AB - Background: Poor nutrition and hygiene make children vulnerable to delays in growth and development. We aimed to assess the effects of water quality, sanitation, handwashing, and nutritional interventions individually or in combination on the cognitive, motor, and language development of children in rural Bangladesh. Methods: In this cluster-randomised controlled trial, we enrolled pregnant women in their first or second trimester from rural villages of Gazipur, Kishoreganj, Mymensingh, and Tangail districts of central Bangladesh, with an average of eight women per cluster. Groups of eight geographically adjacent clusters were block-randomised, using a random number generator, into six intervention groups (all of which received weekly visits from a community health promoter for the first 6 months and every 2 weeks for the next 18 months) and a double-sized control group (no intervention or health promoter visit). The six intervention groups were: chlorinated drinking water; improved sanitation; handwashing with soap; combined water, sanitation, and handwashing; improved nutrition through counselling and provision of lipid-based nutrient supplements; and combined water, sanitation, handwashing, and nutrition. Here, we report on the prespecified secondary child development outcomes: gross motor milestone achievement assessed with the WHO module at age 1 year, and communication, gross motor, personal social, and combined scores measured by the Extended Ages and Stages Questionnaire (EASQ) at age 2 years. Masking of participants was not possible. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01590095. Findings: Between May 31, 2012, and July 7, 2013, 5551 pregnant women residing in 720 clusters were enrolled. Index children of 928 (17%) enrolled women were lost to follow-up in year 1 and an additional 201 (3%) in year 2. 4757 children were assessed at 1 year and 4403 at 2 years. At year 1, compared with the control group, the combined water, sanitation, handwashing, and nutrition group had a higher rate of attaining the standing alone milestone (hazard ratio 1.19, 95% CI 1.01-1 .40), and the nutrition group had a higher rate of attaining the walking alone milestone (1.32, 95% CI 1.07-1.62). The combined water, sanitation, handwashing, and nutrition group had a higher rate of attaining the walking alone milestone than those in the water, sanitation, and handwashing group (1.29, 1.01-1.65). At 2 years, we noted beneficial effects in the combined EASQ score in all intervention groups, with effect sizes smallest in the water treatment group (difference 0.15, 95% CI 0.04 to 0.26 vs control) and largest in the combined water, sanitation, handwashing, and nutrition treatment group (0.37, 0.27-0.46). Interpretation: Improvements in water quality, handwashing, sanitation, or nutrition supported by intensive interpersonal communication, when delivered either individually or in combination, contributed to improvements in child development. A crucial next step is to establish whether similar effects can be achieved with reduced intensity of promoter contacts that could be supported in large-scale interventions. Funding: Bill & Melinda Gates Foundation. PMID- 29616236 TI - Effects of water quality, sanitation, handwashing, and nutritional interventions on child development in rural Kenya (WASH Benefits Kenya): a cluster-randomised controlled trial. AB - Background: Poor nutrition and infectious diseases can prevent children from reaching their developmental potential. We aimed to assess the effects of improvements in water, sanitation, handwashing, and nutrition on early child development in rural Kenya. Methods: In this cluster-randomised controlled trial, we enrolled pregnant women in their second or third trimester from three counties (Kakamega, Bungoma, and Vihiga) in Kenya's western region, with an average of 12 households per cluster. Groups of nine geographically adjacent clusters were block-randomised, using a random number generator, into the six intervention groups (including monthly visits to promote target behaviours), a passive control group (no visits), or a double-sized active control group (monthly household visits to measure child mid-upper arm circumference). The six intervention groups were: chlorinated drinking water; improved sanitation; handwashing with soap; combined water, sanitation, and handwashing; improved nutrition through counselling and provision of lipid-based nutrient supplements; and combined water, sanitation, handwashing, and nutrition. Here we report on the prespecified secondary child development outcomes: gross motor milestone achievement assessed with the WHO module at year 1, and communication, gross motor, personal social, and combined scores measured by the Extended Ages and Stages Questionnaire (EASQ) at year 2. Masking of participants was not possible, but data assessors were masked. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01704105. Findings: Between Nov 27, 2012, and May 21, 2014, 8246 women residing in 702 clusters were enrolled. No clusters were lost to follow-up, but 2212 households with 2279 children were lost to follow-up by year 2. 5791 (69%) children were measured at year 1 and 6107 (73%) at year 2. At year 1, compared with the active control group, the combined water, sanitation, handwashing, and nutrition group had greater rates of attaining the standing with assistance milestone (hazard ratio 1.23, 95% CI 1.09-1.40) and the walking with assistance milestone (1.32, 1.17-1.50), and the handwashing group had a greater rate of attaining the standing alone milestone (1.15, 1.01-1.31). There were no differences when comparing the other intervention groups with the active control group on any of the motor milestone measures at year 1. At year 2, there were no differences among groups for the communication, gross motor, personal social, or combined EASQ scores. Interpretation: The handwashing and combined water, sanitation, handwashing, and nutrition interventions might have improved child motor development after 1 year, although after 2 years there were no other differences between groups. Future research should examine ways to make community health and nutrition programmes more effective at supporting child development. Funding: Bill & Melinda Gates Foundation. PMID- 29616237 TI - The impact of Endocuff-assisted colonoscopy on adenoma detection in an organized screening program. AB - Background and study aims: Colorectal cancer (CRC) screening with biennial fecal occult blood test has been shown to reduce CRC mortality. For the effectiveness of the CRC screening program is crucial that a high-quality colonoscopy with a high adenoma detection rate (ADR) be performed. To improve ADR, various endoscopic devices have been developed. Endocuff, an endoscopic cap with finger like projections, has been shown to improve ADR. The aim of this study was to compare in an organized CRC screening program ADR, advanced adenoma detection rate (AADR) and mean number of adenomas per patient (MAP) using standard colonoscopy (SC) and Endocuff-assisted colonoscopy (EAC). Patients and methods: We compared performance of SC (in 2014) and EAC (in 2015) in consecutive participants in an organized CRC screening program. Results: SC and EAC were performed in 546 (284 males) and 519 (293 males) subjects, respectively (mean age 60 years). Cecal intubation rate was 97.4 % for SC and 97.1 % for EAC and not significantly different ( P = 0.7). ADR was 47 % for SC and 52 % for EAC, P = 0.1. MAP in SC and EAC were 0.87 (range: 0 - 7) and 1.11 (range: 0 - 13) respectively, P = 0.02. AADR rate was 25 % and 23 % for SC and EAC, respectively, P = 0.5. Conclusion: Endocuff-assisted colonoscopy does not improve the number of patients with at least one adenoma but it may increase the number of detected adenomas per procedure. PMID- 29616238 TI - Development and validation of an automated algorithm to evaluate the abundance of bubbles in small bowel capsule endoscopy. AB - Background and study aims : Bubbles can impair visualization of the small bowel (SB) mucosa during capsule endoscopy (CE). We aimed to develop and validate a computed algorithm that would allow evaluation of the abundance of bubbles in SB CE still frames. Patients and methods : Two sets of 200 SB-CE normal still frames were created. Two experienced SB-CE readers analyzed both sets of images twice, in a random order. Each still frame was categorized as presenting with < 10 % or >= 10 % of bubbles. Reproducibility (kappa), sensitivity (Se), specificity (Sp), receiver operating characteristic curve, and calculation time were measured for different algorithms (Grey-level of co-occurrence matrix [GLCM], fractal dimension, Hough transform, and speeded-up robust features [SURF]) using the experts' analysis as reference. Algorithms with highest reproducibility, Se and Sp were then selected for a validation step on the second set of frames. Criteria for validation were kappa = 1, Se >= 90 %, Sp >= 85 %, and a calculation time < 1 second. Results : Both SURF and GLCM algorithms had high operating points (Se and Sp over 90 %) and a perfect reproducibility (kappa = 1). The validation step showed the GLCM detector strategy had the best diagnostic performances, with a Se of 95.79 %, a Sp of 95.19 %, and a calculation time of 0.037 seconds per frame. Conclusion : A computed algorithm based on a GLCM detector strategy had high diagnostic performance allowing assessment of the abundance of bubbles in SB-CE still frames. This algorithm could be of interest for clinical use (quality reporting) and for research purposes (objective comparison tool of different preparations). PMID- 29616240 TI - A fluorene-core-based electron acceptor for fullerene-free BHJ organic solar cells-towards power conversion efficiencies over 10. AB - A small molecule non-fullerene electron acceptor (SMNFEA), bearing a furan pi spacer and dicyano-n-hexyl rhodanine as flanking groups, was designed and synthesized for organic solar cell applications. Organic photovoltaic devices based on FRdCN2 and PTB7-Th polymer donors exhibited a highly improved efficient power conversion efficiency of 10.7%, which is the highest so far for OSCs fabricated from fluorene-core-based SMNFEAs. PMID- 29616239 TI - Cricopharyngeal myotomy with thulium laser through flexible endoscopy: proof-of concept study. AB - Background and study aims : Endoscopic treatment of Zenker's diverticulum has proven feasible, but electrocautery and CO 2 laser technology carry the risk of collateral thermal injury. Thulium laser septum incision may overcome this limitation. We describe for the first time the use of thulium laser through flexible endoscopy in a small cohort of patients with Zenker diverticulum. Patients and methods : Thulium laser septum division was performed via flexible endoscopy under general anesthesia in consecutive symptomatic patients with primary or recurrent Zenker diverticulum. Primary study outcomes were feasibility and safety of the procedure. A 1.9-MUm laser fiber was used with an emission power of 10 - 16 W. Results : Five patients were treated between May and June 2017. Two patients presented with recurrent symptomatic diverticulum after previous transoral septum stapling. Complete division of the septum was achieved in all patients. There was no bleeding nor need of adjunctive electrocautery devices to complete the procedure. The postoperative course was uneventful in all patients; the chest film and gastrographin swallow study on postoperative Day 1 were negative for pneumomediastinum, leaks or residual pouch. All patients were discharged within 48 hours on a soft diet. At the 1- and 3-month follow-up visits, all patients were satisfied with the procedure and reported improved swallowing and absence of regurgitation and cough. Conclusions : Division of Zenker's septum with thulium laser is feasible and safe through flexible endoscopy. Longer-term follow-up is required to establish efficacy and effectiveness of this novel procedure. PMID- 29616241 TI - Surfactants as mesogenic agents in layer-by-layer assembled polyelectrolyte/surfactant multilayers: nanoarchitectured "soft" thin films displaying a tailored mesostructure. AB - Interfacial supramolecular architectures displaying mesoscale organized components are of fundamental importance for developing materials with novel or optimized properties. Nevertheless, engineering the multilayer assembly of different building blocks onto a surface and exerting control over the internal mesostructure of the resulting film is still a challenging task in materials science. In the present work we demonstrate that the integration of surfactants (as mesogenic agents) into layer-by-layer (LbL) assembled polyelectrolyte multilayers offers a straightforward approach to control the internal film organization at the mesoscale level. The mesostructure of films constituted of hexadecyltrimethylammonium bromide, CTAB, and polyacrylic acid, PAA (of different molecular weights), was characterized as a function of the number of assembled layers. Structural characterization of the multilayered films by grazing incidence small-angle X-ray scattering (GISAXS), showed the formation of mesostructured composite polyelectrolyte assemblies. Interestingly, the (PAA/CTA)n assemblies prepared with low PAA molecular weight presented different mesostructural regimes which were dependent on the number of assembled layers: a lamellar mesophase for the first bilayers, and a hexagonal circular mesophase for n >= 7. This interesting observation was explained in terms of the strong interaction between the substrate and the first layers leading to a particular mesophase. As the film increases its thickness, the prevalence of this strong interaction decreases and the supramolecular architecture exhibits a "bulk" mesophase. Finally, we demonstrated that the molecular weight of the polyelectrolyte has a considerable impact on the meso-organization for the (PAA/CTA)n assemblies. We consider that these studies open a path to new rational methodologies to construct "nanoarchitectured" polyelectrolyte multilayers. PMID- 29616242 TI - Dietary impact on esophageal cancer in humans: a review. AB - Cancer is the abnormal growth of cells that tend to proliferate in an uncontrolled way. About 32.6 million people in the world are affected by different types of cancer; 456 000 have esophageal cancer, which is the eighth most common cancer and the sixth most common cause of cancer-related deaths with a toll of 400 000 in 2012. About 80% of cases were reported from the less developed regions of the world. An incidence ratio of 2.4 : 1 for men and women reveals the gender disparity. Esophageal cancer is mainly of two types, namely, squamous cell carcinoma and adenocarcinoma. Most of the studies show a positive correlation of esophageal cancer with alcohol and tobacco consumption, but a negative correlation with fruit and vegetable intake. The type and amount of cereal, fat, meat and beverages consumed are also under study. Significant statistical synergistic interaction has been registered in studies considering the joint effect of the amount of beverage swallowed and its temperature, especially among heavy consumers. The role of non-nutritional components is gaining increasing attention because of their antioxidant, anti-inflammatory, anti-mutagenic and anti-carcinogenic properties. Socioeconomic status is another factor that cannot be ignored. Nevertheless, the predominant cause appears to be different in different regions, and in spite of the great advancements in the medical field, this still remains an enigma for researchers. PMID- 29616243 TI - Disease-related metabolites affect protein-nanoparticle interactions. AB - Once in biological fluids, the surface of nanoparticles (NPs) is rapidly covered with a layer of biomolecules (i.e., the "protein corona") whose composition strongly determines their biological identity, regulates interactions with biological entities including cells and the immune system, and consequently directs the biological fate and pharmacokinetics of nanoparticles. We recently introduced the concept of a "personalized protein corona" which refers to the formation of different biological identities of the exact same type of NP after being exposed to extract plasmas from individuals who have various types of diseases. As different diseases have distinct metabolomic profiles and metabolites can interact with proteins, it is legitimate to hypothesize that metabolomic profiles in plasma may have the capacity to, at least partially, drive the formation of a personalized protein corona. To test this hypothesis, we employed a multi-scale approach composed of coarse-grained (CG) and all atom (AA) molecular dynamics (MD) simulations to probe the role of glucose and cholesterol (model metabolites in diabetes and hypercholesterolemia patients) in the interaction of fibrinogen protein and polystyrene NPs. Our results revealed that glucose and cholesterol had the capacity to induce substantial changes in the binding site of fibrinogen to the surface of NPs. More specifically, the simulation results demonstrated that increasing the metabolite amount could change the profiles of fibrinogen adsorption and replacement, what is known as the Vroman effect, on the NP surface. In addition, we also found out that metabolites can substantially determine the immune triggering potency of the fibrinogen-NP complex. Our proof-of-concept outcomes further emphasize the need for the development of patient-specific NPs in a disease type-specific manner for high yielding and safe clinical applications. PMID- 29616244 TI - The microscale Weissenberg effect for high-viscosity solution pumping at the picoliter level. AB - Transportation of highly viscous solutions at the picoliter level with a rapid dynamic response is paramount for micro/nano-fabrication. With the advantages of a higher length-wall (thickness) ratio and a more stable free surface compared to those of the traditional Weissenberg effect (TWE), the microscale Weissenberg effect (MWE) can continuously and controllably pump high-viscosity solutions at the picoliter scale. Some typical characteristics and behaviors of MWE are investigated as the rotation rod diameter decreases to the microscale of ~100 MUm. The pumped minimum solution volume can reach 167.5 pL per second, and the minimum response time of solution pumping is 0.3 s, which is much shorter than that of pressure driven pumping. Then, a new direct writing with an adjustable jet diameter based on the MWE is proposed to write microstructures on a substrate from a solution with a viscosity of approximately 130.1 Pa s. The stability of the as-spun jet and the deposited structures is improved when a high voltage is applied. To fully demonstrate the advantages of MWE, MWE-based direct writing is performed to successfully fabricate microfluidic channels with variable diameters. Thus, the system can overcome the problems of high transport resistance to the pumping of a high-viscosity solution. PMID- 29616246 TI - Engineering of charge carriers via a two-dimensional heterostructure to enhance the thermoelectric figure of merit. AB - High band degeneracy and glassy phonon transport are two remarkable features of highly efficient thermoelectric (TE) materials. The former promotes the power factor, while the latter aims to break the lower limit of lattice thermal conductivity through phonon scattering. Herein, we use the unique possibility offered by a two-dimensional superlattice-monolayer structure (SLM) to engineer the band degeneracy, charge density and phonon spectrum to maximize the thermoelectric figure of merit (ZT). First-principles calculations with Boltzmann transport equations reveal that the conduction bands of ZrSe2/HfSe2 SLM possess a highly degenerate level which gives a high n-type power factor; at the same time, the stair-like density of states yields a high Seebeck coefficient. These characteristics are absent in the individual monolayers. In addition, the SLM shows a suppressed lattice thermal conductivity along the superlattice period as phonons are effectively scattered by the interfaces. An intrinsic ZT of 5.3 (300 K) is achieved in n-type SLM, and it is 3.2 in the p-type counterpart. Compared with the theoretical predictions calculated with the same level of accuracy, these values are at least four-fold higher than those in the two parent materials, monolayer ZrSe2 and HfSe2. Our results provide a new strategy for the maximum thermoelectric performance, and clearly demonstrate the advantage of two dimensional material heterostructures in the application of renewable energy. PMID- 29616245 TI - Octahydrocurcumin, a final hydrogenated metabolite of curcumin, possesses superior anti-tumor activity through induction of cellular apoptosis. AB - The biological activity of curcumin (CUR), a promising naturally occurring dietary compound for the treatment of hepatocellular carcinoma (HCC), was closely associated with its metabolite. Octahydrocurcumin (OHC) is the final hydrogenated metabolite of CUR and has been reported to have potential biological activities. However, difficulties in access have hampered its biological studies. In the current investigation, we designed an efficient synthesis method to produce OHC, and comparatively explored the anti-cancer effect and potential mechanism of OHC and CUR in an H22 ascites tumor-bearing mice model. The results indicated that OHC had a relatively wide margin of safety, and exhibited superior effects to CUR in suppressing the tumor growth, including ascending weight, abdominal circumference, ascites volume and cancer cell viability. OHC significantly induced H22 cell apoptosis by upregulating the p53 expression and downregulating the MDM2 expression. OHC also remarkably decreased the Bcl-2 and Bcl-xl protein expressions, and increased the Bax and Bad expressions in ascitic cells. Furthermore, THC substantially induced the release of cytochrome C, caspase-3, caspase-9 and the cleavage of PARP to induce H22 cell apoptosis. Taken together, OHC was more effective than CUR in suppressing H22-induced HCC through the activation of the mitochondrial apoptosis pathway. OHC may thus be a promising anti-HCC agent. PMID- 29616247 TI - Evaporation, diffusion and self-assembly at drying interfaces. AB - Water evaporation from complex aqueous solutions leads to the build-up of structure and composition gradients at their interface with air. We recently introduced an experimental setup for quantitatively studying such gradients and discussed how structure formation can lead to a self-regulation mechanism for controlling water evaporation through self-assembly. Here, we provide a detailed theoretical analysis using an advection/diffusion transport equation that takes into account thermodynamically non-ideal conditions and we directly relate the theoretical description to quantitative experimental data. We derive that the concentration profile develops according to a general square root of time scaling law, which fully agrees with experimental observations. The evaporation rate notably decreases with time as t-1/2, which shows that diffusion in the liquid phase is the rate limiting step for this system, in contrast to pure water evaporation. For the particular binary system that was investigated experimentally, which is composed of water and a sugar-based surfactant (alpha dodecylmaltoside), the interfacial layer consists in a sequence of liquid crystalline phases of different mesostructures. We extract values for mutual diffusion coefficients of lamellar, hexagonal and micellar cubic phases, which are consistent with previously reported values and simple models. We thus provide a method to estimate the transport properties of oriented mesophases. The macroscopic humidity-independence of the evaporation rate up to 85% relative humidities is shown to result from both an extremely low mutual diffusion coefficient and the large range of water activities corresponding to relative humidities below 85%, at which the lamellar phase exists. Such a humidity self regulation mechanism is expected for a large variety of complex system. PMID- 29616248 TI - Tuning plasmons layer-by-layer for quantitative colloidal sensing with surface enhanced Raman spectroscopy. AB - Surface-enhanced Raman spectroscopy (SERS) is well known for its high sensitivity that emerges due to the plasmonic enhancement of electric fields typically on gold and silver nanostructures. However, difficulties associated with the preparation of nanostructured substrates with uniform and reproducible features limit reliability and quantitation using SERS measurements. In this work we use layer-by-layer (LbL) self-assembly to incorporate multiple functional building blocks of collaborative assemblies of nanoparticles on colloidal spheres to fabricate SERS sensors. Gold nanoparticles (AuNPs) are packaged in discrete layers, effectively 'freezing nano-gaps', on spherical colloidal cores to achieve multifunctionality and reproducible sensing. Coupling between layers tunes the plasmon resonance for optimum SERS signal generation to achieve a 10 nM limit of detection. Significantly, using the layer-by-layer construction, SERS-active AuNP layers are spaced out and thus optically isolated. This uniquely allows the creation of an internal standard within each colloidal sensor to enable highly reproducible self-calibrated sensing. By using 4-mercaptobenzoic acid (4-MBA) as the internal standard adenine concentrations are quantified to an accuracy of 92.6-99.5%. Our versatile approach paves the way for rationally designed yet quantitative colloidal SERS sensors and their use in a variety of sensing applications. PMID- 29616249 TI - Anti-aging potential of tree nuts with a focus on the phytochemical composition, molecular mechanisms and thermal stability of major bioactive compounds. AB - Tree nuts, complete functional foods, contain macro- and micronutrients of high biological value. These bioactive compounds have a synergistic effect in preventing and delaying many age-related pathologies (e.g. cardiovascular diseases, stroke, type 2 diabetes mellitus, certain types of cancer, and several neurodegenerative diseases). Tree nuts are low in carbohydrates, but they abound in healthy fatty acids, in optimal proportion for a good plasma lipid profile, and are a good source of proteins, rich in proteinogenic amino acids. They contain significant amounts of vitamin E, minerals, polyphenols, and phytosterols. Polyphenols, which are powerful phytochemicals, act as direct and indirect antioxidants, reduce the inflammatory response, improve proteostasis and mitochondrial biogenesis, modulate many cell signaling pathways, have a major role in cytoprotection, are Nrf2/ARE activators, down-regulate the NFkappaB system, promote anticancer potential, and prevent cell senescence. Some of them have senolytic effects, interfere in specific cell signaling pathways modulated by caloric restriction, and protect against UV radiation and photoaging. Moreover, tree nuts are good prebiotics and improve gut microbiota. The stability of polyphenolic compounds and their antioxidant activity can be influenced by cooking techniques, temperature of storage, and post-harvest processing methods. The consumption of tree nuts has been scientifically proven to improve lifespan and healthspan and should be a part of a healthy diet in the elderly. PMID- 29616250 TI - Synergistic effects of hyaluronate - epidermal growth factor conjugate patch on chronic wound healing. AB - The proteolytic microenvironment in the wound area reduces the stability and the half-life of growth factors in vivo, making difficult the topical delivery of growth factors. Here, epidermal growth factor (EGF) was conjugated to hyaluronate (HA) to improve the long-term stability against enzymatic degradation and the therapeutic effect by enhancing the biological interaction with HA receptors on skin cells. After the synthesis of HA-EGF conjugates, they were incorporated into a patch-type formulation for the facile topical application and sustained release of EGF. According to ELISA, the HA-EGF conjugates showed a long-term stability compared with native EGF. Furthermore, HA-EGF conjugates appeared to interact with skin cells through two types of HA and EGF receptors, resulting in a synergistically improved healing effect. Taken together, we could confirm the feasibility of HA-EGF conjugates for the transdermal treatment of chronic wounds. PMID- 29616252 TI - Synthesis, structural characterization and transformation of an eight-electron superatomic alloy, [Au@Ag19{S2P(OPr)2}12]. AB - Controlling the metal nanoclusters with atomic precision is highly difficult and further studies on their transformation reactions are even more challenging. Herein we report the controlled formation of a silver alloy nanocluster [AuAg19{S2P(OnPr)2}12] (1) from an Ag20 template via a galvanic exchange route. X ray structural analysis reveals that the alloy structure comprises of a gold centered Ag12 icosahedron, Au@Ag12, capped by seven silver atoms. Interestingly upon reacting with one equiv. of silver(i) salt, (1) can transform into a higher nuclearity nanocluster, [Au@Ag20{S2P(OnPr)2}12]+ (2). The conversion process is studied via ESI mass spectrometry and 31P NMR spectroscopy. This kind of size structural transformation at the single atom level is quite remarkable. Furthermore, the compositions of all the doped nanoclusters (1, 2) were fully characterized with ESI-MS and EDS. The blue shift depicted in the UV-visible and emission spectra of the doped nanoclusters (1, 2) compared with the precursor, Ag20, demonstrates that the doping atoms have significant effects on the electronic structures. PMID- 29616253 TI - Correction: Unravelling the impact of hydrocarbon structure on the fumarate addition mechanism - a gas-phase ab initio study. AB - Correction for 'Unravelling the impact of hydrocarbon structure on the fumarate addition mechanism - a gas-phase ab initio study' by Vivek S. Bharadwaj et al., Phys. Chem. Chem. Phys., 2015, 17, 4054-4066. PMID- 29616254 TI - Graphene growth by molecular beam epitaxy: an interplay between desorption, diffusion and intercalation of elemental C species on islands. AB - The growth of graphene by molecular beam epitaxy from an elemental carbon precursor is a very promising technique to overcome some of the main limitations of the chemical vapour deposition approach, such as the possibility to synthesize graphene directly on a wide variety of surfaces including semiconductors and insulators. However, while the individual steps of the chemical vapour deposition growth process have been extensively studied for several surfaces, such knowledge is still missing for the case of molecular beam epitaxy, even though it is a key ingredient to optimise its performance and effectiveness. In this work, we have performed a combined experimental and theoretical study comparing the growth rate of the molecular beam epitaxy and chemical vapour deposition processes on the prototypical Ir (111) surface. In particular, by employing high-resolution fast X ray photoelectron spectroscopy, we were able to follow the growth of both single- and multi-layer graphene in real time, and to identify the spectroscopic fingerprints of the different C layers. Our experiments, supported by density functional theory calculations, highlight the role of the interaction between different C precursor species and the growing graphene flakes on the growth rate of graphene. These results provide an overview of the main differences between chemical vapour deposition and molecular beam epitaxy growth and thus on the main parameters which can be tuned to optimise growth conditions. PMID- 29616255 TI - A common anchor facilitated GO-DNA nano-system for multiplex microRNA analysis in live cells. AB - The design of a nano-system for the detection of intracellular microRNAs is challenging as it must fulfill complex requirements, i.e., it must have a high sensitivity to determine the dynamic expression level, a good reliability for multiplex and simultaneous detection, and a satisfactory biostability to work in biological environments. Instead of employing a commonly used physisorption or a full-conjugation strategy, here, a GO-DNA nano-system was developed under graft/base-pairing construction. The common anchor sequence was chemically grafted to GO to base-pair with various microRNA probes; and the hybridization with miRNAs drives the dyes on the probes to leave away from GO, resulting in "turned-on" fluorescence. This strategy not only simplifies the synthesis but also efficiently balances the loading yields of different probes. Moreover, the conjugation yield of GO with a base-paired hybrid has been improved by more than two-fold compared to that of the conjugation with a single strand. We demonstrated that base-paired DNA probes could be efficiently delivered into cells along with GO and are properly stabilized by the conjugated anchor sequence. The resultant GO-DNA nano-system exhibited high stability in a complex biological environment and good resistance to nucleases, and was able to accurately discriminate various miRNAs without cross-reaction. With all of these positive features, the GO-DNA nano-system can simultaneously detect three miRNAs and monitor their dynamic expression levels. PMID- 29616259 TI - Non-destructive characterization of extended crystalline defects in confined semiconductor device structures. AB - Semiconductor heterostructures are at the heart of most nanoelectronic and photonic devices such as advanced transistors, lasers, light emitting diodes, optical modulators and photo-detectors. However, the performance and reliability of the respective devices are often limited by the presence of crystalline defects which arise from plastic relaxation of misfit strain present in these heterogeneous systems. To date, characterizing the nature and distribution of such defects in 3D nanoscale devices precisely and non-destructively remains a critical metrology challenge. In this paper we demonstrate that electron channeling contrast imaging (ECCI) is capable of analyzing individual dislocations and stacking faults in confined 3D nanostructures, thereby fulfilling the aforementioned requirements. For this purpose we imaged the intensity of electrons backscattered from the sample under test under controlled diffraction conditions using a scanning electron microscope (SEM). In contrast to transmission electron microscopy (TEM) analysis, no electron transparent specimens need to be prepared. This enables a significant reduction of the detection limit (i.e. lowest defect density that can be assessed) as our approach facilitates the analysis of large sampling volumes, thereby providing excellent statistics. We applied the methodology to SiGe nanostructures grown by selective area epitaxy to study in detail how the nature and distribution of crystalline defects are affected by the dimensions of the structure. By comparing our observations with the results obtained using X-ray diffraction, TEM and chemical defect etching, we could verify the validity of the method. Our findings firmly establish that ECCI must be considered the method of choice for analyzing the crystalline quality of 3D semiconductor heterostructures with excellent precision even at low defect densities. As such, the technique aids in better understanding of strain relaxation and defect formation mechanisms at the nanoscale and, moreover, facilitates the development and fabrication of next generation nanoelectronic and photonic devices. PMID- 29616261 TI - Fast and efficient direct formation of size-controlled nanostructures of coordination polymers based on copper(i)-iodine bearing functional pyridine terminal ligands. AB - We report on the direct formation of 1D nanostructures of two coordination polymers based on copper(i)-iodine double chains decorated with ethyl isonicotinate or 2-amino-5-nitropyridine as terminal ligands. The use of different reaction conditions, e.g. energy of the formation process, solvents, and/or concentration of reactants, has allowed the control of the size of the fibres and ribbons directly formed in this process going from micron- to submicron- up to nano-size. We show experiments that direct the formation of materials kinetically versus thermodynamically controlled, adjusting simple experimental parameters. Finally, a morphological study on the Cu(i)-iodine bearing 2-amino-5-nitropyridine nanofibres has confirmed their reversible molecular recognition ability towards acetic acid vapours. PMID- 29616262 TI - How do plants see the world? - UV imaging with a TiO2 nanowire array by artificial photosynthesis. AB - The concept of plant vision refers to the fact that plants are receptive to their visual environment, although the mechanism involved is quite distinct from the human visual system. The mechanism in plants is not well understood and has yet to be fully investigated. In this work, we have exploited the properties of TiO2 nanowires as a UV sensor to simulate the phenomenon of photosynthesis in order to come one step closer to understanding how plants see the world. To the best of our knowledge, this study is the first approach to emulate and depict plant vision. We have emulated the visual map perceived by plants with a single-pixel imaging system combined with a mechanical scanner. The image acquisition has been demonstrated for several electrolyte environments, in both transmissive and reflective configurations, in order to explore the different conditions in which plants perceive light. PMID- 29616263 TI - Lightweight, compressible and electrically conductive polyurethane sponges coated with synergistic multiwalled carbon nanotubes and graphene for piezoresistive sensors. AB - Lightweight, compressible and highly sensitive pressure/strain sensing materials are highly desirable for the development of health monitoring, wearable devices and artificial intelligence. Herein, a very simple, low-cost and solution-based approach is presented to fabricate versatile piezoresistive sensors based on conductive polyurethane (PU) sponges coated with synergistic multiwalled carbon nanotubes (MWCNTs) and graphene. These sensor materials are fabricated by convenient dip-coating layer-by-layer (LBL) electrostatic assembly followed by in situ reduction without using any complicated microfabrication processes. The resultant conductive MWCNT/RGO@PU sponges exhibit very low densities (0.027-0.064 g cm-3), outstanding compressibility (up to 75%) and high electrical conductivity benefiting from the porous PU sponges and synergistic conductive MWCNT/RGO structures. In addition, the MWCNT/RGO@PU sponges present larger relative resistance changes and superior sensing performances under external applied pressures (0-5.6 kPa) and a wide range of strains (0-75%) compared with the RGO@PU and MWCNT@PU sponges, due to the synergistic effect of multiple mechanisms: "disconnect-connect" transition of nanogaps, microcracks and fractured skeletons at low compression strain and compressive contact of the conductive skeletons at high compression strain. The electrical and piezoresistive properties of MWCNT/RGO@PU sponges are strongly associated with the dip-coating cycle, suspension concentration, and the applied pressure and strain. Fully functional applications of MWCNT/RGO@PU sponge-based piezoresistive sensors in lighting LED lamps and detecting human body movements are demonstrated, indicating their excellent potential for emerging applications such as health monitoring, wearable devices and artificial intelligence. PMID- 29616264 TI - A novel red phosphor of seven-coordinated Mn4+ ion-doped tridecafluorodizirconate Na5Zr2F13 for warm WLEDs. AB - Herein, a novel red phosphor based on seven-coordinated Mn4+ ion-doped tridecafluorodizirconate, Na5Zr2F13 (NZF), has been synthesized by stirring a mixture of K2MnF6, NaF, and H2ZrF6 at room temperature. The crystal structure and morphology of the as-obtained phosphor NZF:Mn have been determined by X-ray diffraction (XRD) and scanning electron microscopy (SEM), respectively. The composition and distribution of Mn4+ ions in NZF have been confirmed by energy dispersive spectroscopy (EDS) and element mapping via transmission electron microscopy (TEM). The phosphor NZF:Mn exhibits a strong zero phonon line (ZPL) at 616 nm under excitation of blue light from a GaN light-emitting diode (LED) chip; this is attributed to the low symmetry of Mn4+ ions occupied in a seven coordinated environment. The luminescence intensity of NZF:Mn has been optimized by controlling the synthesis procedure and synthetic parameters. The luminescence mechanism of the red phosphor NZF:Mn has been investigated according to the detailed experimental results. A warm white light has been produced by a WLED fabricated with the red phosphor NZF:Mn and the commercial yellow phosphor Y3Al5O12:Ce3+ (YAG:Ce) on a GaN LED chip. PMID- 29616265 TI - The adsorption of silicon on an iridium surface ruling out silicene growth. AB - The adsorption of Si atoms on a metal surface might proceed through complex surface processes, whose rate is determined differently by factors such as temperature, Si coverage, and metal cohesive energy. Among other transition metals, iridium is a special case since the Ir(111) surface was reported first, in addition to Ag(111), as being suitable for the epitaxy of silicene monolayers. In this study we followed the adsorption of Si on the Ir(111) surface via high resolution core level photoelectron spectroscopy, starting from the clean metal surface up to a coverage exceeding one monolayer, in a temperature range between 300 and 670 K. Density functional theory calculations were carried out in order to evaluate the stability of the different Si adsorption configurations as a function of the coverage. Results indicate that, at low coverage, the Si adatoms tend to occupy the hollow Ir sites, although a small fraction of them penetrates the first Ir layer. Si penetration of the Ir surface can take place if the energy gained upon Si adsorption is used to displace the Ir surface atoms, rather then being dissipated differently. At a Si coverage of ~1 monolayer, the Ir 4f spectrum indicates that not only the metal surface but also the layers underneath are perturbed. Our results point out that the Si/Ir(111) interface is unstable towards Si-Ir intermixing, in agreement with the silicide phase formation reported in the literature for the reverted interface. PMID- 29616266 TI - Laser inscription of pseudorandom structures for microphotonic diffuser applications. AB - Optical diffusers provide a solution for a variety of applications requiring a Gaussian intensity distribution including imaging systems, biomedical optics, and aerospace. Advances in laser ablation processes have allowed the rapid production of efficient optical diffusers. Here, we demonstrate a novel technique to fabricate high-quality glass optical diffusers with cost-efficiency using a continuous CO2 laser. Surface relief pseudorandom microstructures were patterned on both sides of the glass substrates. A numerical simulation of the temperature distribution showed that the CO2 laser drills a 137 MUm hole in the glass for every 2 ms of processing time. FFT simulation was utilized to design predictable optical diffusers. The pseudorandom microstructures were characterized by optical microscopy, Raman spectroscopy, and angle-resolved spectroscopy to assess their chemical properties, optical scattering, transmittance, and polarization response. Increasing laser exposure and the number of diffusing surfaces enhanced the diffusion and homogenized the incident light. The recorded speckle pattern showed high contrast with sharp bright spot free diffusion in the far field view range (250 mm). A model of glass surface peeling was also developed to prevent its occurrence during the fabrication process. The demonstrated method provides an economical approach in fabricating optical glass diffusers in a controlled and predictable manner. The produced optical diffusers have application in fibre optics, LED systems, and spotlights. PMID- 29616268 TI - Synthesis of single crystalline two-dimensional transition-metal phosphides via a salt-templating method. AB - Transition-metal phosphides (TMPs) are considered as promising non-noble electrochemical catalysts for hydrogen evolution reaction (HER). Their highly active sites are located on certain facets, and single crystalline two dimensional (2D) structures enable them to expose the most active facets for HER. However, the synthesis of single crystalline 2D TMPs is still a challenge owing to their intrinsically non-layered structures. Herein, we demonstrate the synthesis of various single crystalline 2D TMPs (Co2P, MoP2, Ni12P5 and WP2) by a salt-templating method. The as-synthesized 2D Co2P exhibited efficient electrocatalytic ability for HER with an overpotential of 41 mV at 10 mA cm-2 and a Tafel slope of 35 mV dec-1 in 0.5 M H2SO4 solution. We expect that the synthesis of 2D TMPs reported here will open the way to expand the family of 2D materials for electrocatalysis and beyond. PMID- 29616267 TI - Boosting photocatalytic overall water splitting by Co doping into Mn3O4 nanoparticles as oxygen evolution cocatalysts. AB - The effect of cobalt doping into a manganese oxide (tetragonal spinel Mn3O4) nanoparticle cocatalyst up to Co/(Co + Mn) = 0.4 (mol/mol) on the activity of photocatalytic water oxidation was studied. Monodisperse ~10 nm CoyMn1-yO (0 <=y<= 0.4) nanoparticles were uniformly loaded onto photocatalysts and converted to CoxMn3-xO4 nanoparticles through calcination. 40 mol% cobalt-doped Mn3O4 nanoparticle-loaded Rh@Cr2O3/SrTiO3 photocatalyst exhibited 1.8 times-higher overall water splitting activity than that with pure Mn3O4 nanoparticles. Investigation on the band structure and electrocatalytic water oxidation activity of CoxMn3-xO4 nanoparticles revealed that the Co doping mainly contributes to the improvement of water oxidation kinetics on the surface of the cocatalyst nanoparticles. PMID- 29616269 TI - A bio-inspired dumbbell-shaped nanochannel with a controllable structure and ionic rectification. AB - Inspired by the potassium ion channel, here, we firstly report a structure tailorable dumbbell-shaped nanochannel with controllable ionic rectification. This system creates an ideal experimental and theoretical platform for the precision transportation of ions, which have potential applications in analytical sciences. PMID- 29616270 TI - Heterostructures of MXenes and N-doped graphene as highly active bifunctional electrocatalysts. AB - MXenes with versatile chemistry and superior electrical conductivity are prevalent candidate materials for energy storage and catalysts. Inspired by recent experiments of hybridizing MXenes with carbon materials, here we theoretically design a series of heterostructures of N-doped graphene supported by MXene monolayers as bifunctional electrocatalysts for the oxygen reduction reaction (ORR) and hydrogen evolution reaction (HER). Our first-principles calculations show that the graphitic sheet on V2C and Mo2C MXenes are highly active with an ORR overpotential down to 0.36 V and reaction free energies for the HER approaching zero, both with low kinetic barriers. Such outstanding catalytic activities originate from the electronic coupling between the graphitic sheet and the MXene, and can be correlated with the pz band center of surface carbon atoms and the work function of the heterostructures. Our findings screen a novel form of highly active electrocatalysts by taking advantage of the fast charge transfer kinetics and strong interfacial coupling of MXenes, and illuminate a universal mechanism for modulating the catalytic properties of two dimensional hybrid materials. PMID- 29616272 TI - A lead-free two-dimensional perovskite for a high-performance flexible photoconductor and a light-stimulated synaptic device. AB - Organo-lead halide perovskites have emerged as promising materials for high performance photodetectors. However, the toxicity of lead cations in these materials limits their further applications. Here, a flexible photoconductor is developed based on lead-free two-dimensional (2D) perovskite (PEA)2SnI4via a one step solution processing method. The flexible transparent electrodes are patterned from rGO/(PEDOT:PSS) hybrid films. The stability and reproducibility of the devices are significantly improved on adding 30 mol% SnF2 to the perovskite. The flexible photoconductors show a photoresponsivity of 16 A W-1 and a detectivity of 1.92 * 1011 Jones under 470 nm illumination, which are higher than those of most of the similar devices. Besides, the devices possess much better mechanical flexibility and durability than the flexible devices with an Au electrode. Finally, this flexible photoconductor is applied as a light-stimulated synaptic device and can mimic the short-term plasticity of biological synapses. This is the first study to report that lead-free 2D perovskite can be used in flexible photoconductors and synaptic devices. PMID- 29616271 TI - Boron-passivated surface Fe(iv) defects in hematite for highly efficient water oxidation. AB - Hematite is a good photocatalyst for solar water oxidation but its performance is highly limited by the strong electron-hole recombination. Surface defects as recombination centers were considered as one of the most important factors in determining the efficiency of hematite. However, the defects have never been clearly identified, which strongly limits the targeted modification. Here we report the identification of surface Fe(iv) defects in hematite by using synchrotron radiation based X-ray absorption spectroscopy. Moreover, the Fe(iv) defects can be effectively passivated by facile surface engineering with boron termination, which can suppress the surface recombination and then significantly improve the performance. The B-passivated hematite thus shows a large cathodic shift (up to 100 mV) of the onset potential when compared to the pristine sample, and can be effectively coupled with Ti-treatment and Co-Pi co-catalyst to finally achieve a high photocurrent of 2.61 mA cm-2 at 1.23 V vs. RHE. The results may open up a new way by targeted surface engineering to effectively passivate the defects in hematite. PMID- 29616273 TI - Lifetime and linewidth of individual quantum dots interfaced with graphene. AB - We report on luminescence lifetimes and linewidths from an array of individual quantum dots (QDs) that were either interfaced with graphene surface guides or dispersed on aluminum electrodes. The observed fluorescence quenching is consistent with screening by charge carriers. Fluorescence quenching is typically mentioned as a sign that chromophores are interfacing with a conductive surface (metal or graphene); we find that the QDs interfaced with the metal film exhibit shortened lifetime and line-broadening but not necessarily fluorescence quenching as the latter may be impacted by molecular concentration, reflectivity and conductor imperfections. We also comment on angle-dependent lifetime measurements, which we postulate depend on the specifics of the local density-of states involved. PMID- 29616274 TI - Physical stimuli-responsive liposomes and polymersomes as drug delivery vehicles based on phase transitions in the membrane. AB - This paper reviews liposomes with crystalline phase and polymersomes exhibiting crystalline and thermotropic liquid crystalline phases in the membrane. Intriguing morphologies of vesicles are described, including spherical, ellipsoidal and faceted vesicles, produced by a large variety of amphiphilic molecules and polymers with nematic phase, smectic phase or crystalline phase. It is highlighted how the phase transitions and the phase grain boundaries could be used ingeniously to destabilize the vesicular structure and to achieve cargo release under the action of external stimulation. These liposomes and polymersomes are responsive to physical stimuli, such as temperature variation, shear stress, light illumination, and magnetic and electric fields. These stimuli responsive properties make them promising candidates as new smart drug delivery systems. PMID- 29616275 TI - Enantioselective addition of selenosulfonates to alpha,beta-unsaturated ketones. AB - An organo-catalyzed enantioselective addition of selenosulfonates to alpha,beta unsaturated ketones was developed for the first time. With a chiral squaramide as an efficient catalyst, the desired alpha-selenylated ketones were obtained in a good yields with high enantioselectivity up to 89% ee, and good results could be obtained on a gram scale. The products could also be efficiently transformed into useful building blocks with a propenylic stereocenter; the strategy presented in this study may find further applications in organic synthesis. PMID- 29616276 TI - Phosphine-catalyzed [4 + 2] annulation of gamma-benzyl allenoates: facile synthesis of benzothieno[3,2-b]pyran derivatives. AB - An efficient tris(4-methoxyphenyl)phosphine-catalyzed domino reaction between gamma-benzyl allenoates and ethyl (Z)-2-(3-oxobenzo[b]thiophen-2(3H) ylidene)acetate has been developed, which produces a series of 2H benzo[4,5]thieno[3,2-b]pyran derivatives in high yields. The substrate scope includes both electron-withdrawing (e.g., halogen) and electron-donating (e.g., methoxy) groups on both the benzothiophene and allenoate moieties. The reaction can also be performed on the gram scale with good yield (e.g., 77%). In this reaction, gamma-substituted allenoate acts as a two-carbon synthon, in a manner rarely reported in the literature to date. PMID- 29616277 TI - Arsenic for high-capacity lithium- and sodium-ion batteries. AB - We report arsenic (As) as a promising alternative to graphite anode materials in lithium- and sodium-ion batteries (LIBs and SIBs). The electrochemical properties of the As/carbon nanocomposite for both LIBs and SIBs were investigated using experimental and theoretical approaches. The LIBs showed excellent cycling performance, with a reversible capacity of 1306 mA h g-1 (after 100 cycles), which is much higher than that of Li3As (1072 mA h g-1). In the corresponding SIBs, the measured reversible capacity was 750 mA h g-1 (after 200 cycles), which is lower than that of Na3As. Extensive first-principles calculations were performed employing a structure prediction method for crystalline LixAs and NaxAs (x = 1-6) phases, as well as ab initio molecular dynamics simulations for their amorphous phases. In good agreement with the experimental LIB data, our calculations successfully predict the discharge capacity versus voltage curves, showing that the capacity of the amorphous phase reaches up to that of Li4As. In contrast, the SIB exhibited difficulty in reaching the predicted capacity (x = 3.5), probably due to significant volume expansion. Comparison of the theoretical discharge curves with the experimental data provides valuable information for the development of high-performance LIBs and SIBs. PMID- 29616278 TI - Rehabilitation service models for people with physical and/or mental disability living in low- and middle-income countries: A systematic review. AB - OBJECTIVE: To compare models of rehabilitation services for people with mental and/or physical disability in order to determine optimal models for therapy and interventions in low- to middle-income countries. DATA SOURCES: CINAHL, EMBASE, MEDLINE, CENTRAL, PsycINFO, Business Source Premier, HINARI, CEBHA and PubMed. STUDY SELECTION: Systematic reviews, randomized control trials and observational studies comparing >2 models of rehabilitation care in any language. Date extraction: Standardized forms were used. Methodological quality was assessed using AMSTAR and quality of evidence was assessed using GRADE. DATA SYNTHESIS: Twenty-four systematic reviews which included 578 studies and 202,307 participants were selected. In addition, four primary studies were included to complement the gaps in the systematic reviews. The studies were all done at various countries. Moderate- to high-quality evidence supports the following models of rehabilitation services: psychological intervention in primary care settings for people with major depression, admission into an inpatient, multidisciplinary, specialized rehabilitation unit for those with recent onset of a severe disabling condition; outpatient rehabilitation with multidisciplinary care in the community, hospital or home is recommended for less severe conditions; However, a model of rehabilitation service that includes early discharge is not recommended for elderly patients with severe stroke, chronic obstructive pulmonary disease, hip fracture and total joints. CONCLUSION: Models of rehabilitation care in inpatient, multidisciplinary and specialized rehabilitation units are recommended for the treatment of severe conditions with recent onset, as they reduce mortality and the need for institutionalized care, especially among elderly patients, stroke patients, or those with chronic back pain. Results are expected to be generalizable for brain/spinal cord injury and complex fractures. PMID- 29616279 TI - Narrowing beam-walking is a clinically feasible approach for assessing balance ability in lower-limb prosthesis users. AB - OBJECTIVE: Challenging clinical balance tests are needed to expose balance deficits in lower-limb prost-hesis users. This study examined whether narrowing beam-walking could overcome conceptual and practical limitations identified in fixed-width beam-walking. DESIGN: Cross-sectional. PARTICIPANTS: Unilateral lower limb prosthesis users. METHODS: Participants walked 10 times along a low, narrowing beam. Performance was quantified using the normalized distance walked. Heuristic rules were applied to determine whether the narrowing beam task was "too easy," "too hard," or "appropriately challenging" for each participant. Linear regression and Bland-Altman plots were used to determine whether combinations of the first 5 trials could predict participants' stable beam walking performance. RESULTS: Forty unilateral lower-limb prosthesis users participated. Narrowing beam-walking was appropriately challenging for 98% of participants. Performance stabilized for 93% of participants within 5 trials, while 62% were stable across all trials. The mean of trials 3-5 accurately predicted stable performance. CONCLUSION: A clinical narrowing beam-walking test is likely to challenge a range of lower-limb prosthesis users, have minimal administrative burden, and exhibit no floor or ceiling effects. Narrowing beam walking is therefore a clinically viable method to evaluate lower-limb prosthesis users' balance ability, but requires psychometric testing before it is used to assess fall risk. PMID- 29616280 TI - [Surgical treatment of peritoneal metastases of gastric cancer]. AB - BACKGROUND: Up to 17% of all patients with gastric cancer are diagnosed with the presence of peritoneal metastases, which is associated with a poor prognosis. The most promising results were shown with multimodal treatment regimens including systemic chemotherapy and cytoreductive surgery (CRS). A subsequent hyperthermic intraperitoneal chemotherapy (HIPEC).possibly has a positive effect and is currently being tested. OBJECTIVES: This manuscript highlights the key role of CRS and HIPEC in patients with peritoneal metastases of gastric cancer and illustrates which patients benefit from this intensive therapy. METHODS: We performed a comprehensive review of the literature to demonstrate relevant aspects in the treatment of peritoneal metastases in gastric cancer. RESULTS: The use of CRS and HIPEC improves the overall survival to 11 months compared to best supportive care in selected patients. Patients who present with low volume peritoneal disease (peritoneal cancer index <=6) have the best prognosis. This intensive treatment is associated with a relatively high morbidity (15-50%) and mortality (1-10%). Complete cytoreduction, i.e. a complete macroscopic absence of tumor tissue after resection is the most important prognostic factor. CONCLUSION: The CRS and HIPEC procedures have a proven survival benefit in selected patients. Due to the relatively high morbidity and mortality, the evaluation should be performed by an experienced team including a surgical oncologist, medical oncologist and intensive care physician, to achieve the highest rate of complete cytoreduction in combination with low morbidity; however, the effect of HIPEC has to be proven and the results of the randomized GASTRIPEC trial are awaited. PMID- 29616281 TI - Effects of Lactogen 13, a New Probiotic Preparation, on Gut Microbiota and Endocrine Signals Controlling Growth and Appetite of Oreochromis niloticus Juveniles. AB - In the present study, Nile tilapia Oreochromis niloticus was used as experimental model to study the molecular effects of a new probiotic preparation, Lactogen 13 (Lactobacillus rhamnosus IMC 501(r) encapsulated with vegetable fat matrices by spray chilling and further indicated as probiotic microgranules), on growth and appetite during larval development. Probiotic microgranules were administered for 30 days to tilapia larvae starting from first feeding. Molecular analysis using high-throughput sequencing revealed that the probiotic could populate the gastrointestinal tract and modulate the microbial communities by significantly increasing the proportion of Lactobacillus as well as reducing the proportion of potential pathogens such as members of the Family Microbacteriaceae, Legionellaceae, and Weeksellaceae. Morphometric analysis evidenced that body weight and total length significantly increased after probiotic treatment. This increase coincided with the modulation of genes belonging to the insulin-like growth factors (igfs) system and genes involved on myogenesis, such as myogenin, and myogenic differentiation (myod). Alongside the improvement of growth, an increase of feed intake was evidenced at 40 days post-fertilization (dpf) in treated larvae. Gene codifying for signals belonging to the most prominent systems involved in appetite regulation, such as neuropeptide y (npy), agouti related protein (agrp), leptin, and ghrelin were significantly modulated. These results support the hypothesis that gastrointestinal (GI) microbiota changes due to probiotic administration modulate growth and appetite control, activating the endocrine system of tilapia larvae. PMID- 29616284 TI - [Urology and alternative medicine (1900-1970)]. AB - Disorders of the lower abdomen were often associated with sexually transmitted diseases (STDs) or related conditions. The urological diagnostic workup and treatment was based on the idea that technical devices and objective scientific examination methods would lead to targeted success. The fact that illnesses such as urinary retention, urinary incontinence, urge incontinence, orchitis or urethritis often implicated psychosomatic complications and had a possibly far more important impact on sexual life did not play a role in the early years of urology. In contrast, the concepts of naturopaths and homoeopaths were based on the humoral pathology view that was rejected by conventional medicine after 1850. They advocated abstinence and the use of hydrotherapeutic measures instead of urological surgery or potassium bromide treatment commonly prescribed by psychiatrists. The success of the naturopaths and homeopaths was based on several factors: they relied on taking into account a comprehensive patient history including psychosomatic factors and a combined dietary and pharmacological treatment. Naturopathic or homeopathic treatment was cheaper and more acceptable to the patient than conventional medical treatment or use of catheters and dilators. In addition, lay practitioners often came from the same milieu as their patients, so that the physician-patient communication, which is extremely important for psychosomatic disorders, was much easier. PMID- 29616282 TI - A large lung gene expression study identifying IL1B as a novel player in airway inflammation in COPD airway epithelial cells. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic and progressive lung disease characterized by a mixture of small airway disease and lung tissue parenchymal destruction. Abnormal inflammatory responses to cigarette smoking and other noxious particles are generally thought to be responsible for causing of COPD. Since airway inflammation is a key factor in COPD progress, it is crucial to unravel its underlying molecular mechanisms. Unbiased analysis of genome-wide gene expression profiles in lung small airway epithelial cells provides a powerful tool to investigate this. METHODS: Gene expression data of GSE611906, GSE20257, GSE8545 were downloaded from GEO database. All 288 lung small airway samples in these cohorts, including donors with (n = 61) and without (n = 227) COPD, were chosen for differential gene expression analysis. The gene ontology (GO) function, Kyoto Encyclopedia of Genes and Genomes pathway (KEGG) enrichment analyses, gene co-expression network analysis (WGCNA) and protein protein interaction (PPI) network analysis were performed. Subsequently, the analyses of IL1B expression level, the Pearson correlation between IL1B and several COPD biomarkers were performed using other cohorts to validate our main findings. RESULTS: With a change >= twofold and P value < 0.05 cutoff, we found 38 genes were up-regulated and 114 genes were down-regulated in patients with COPD compared with health controls, while using cutoff fold change 1.5 and P value < 0.05, there were 318 genes up-regulated and 333 genes down-regulated. Among the most up-regulated genes were IL1B, CCL2, CCL23, and CXCL14, all implicated in inflammation triggering. GO, KEGG and WGCNA analysis all disclosed IL1B was highly correlated to COPD disease trait. The expression profile of IL1B was further validated using independent cohorts from COPD airway epithelium, lung tissue, sputum, and blood. We demonstrated higher IL1B gene expression in COPD small airway epithelial cells, but not in COPD lung tissue, sputum, and blood. Strong co-expression of IL1B with COPD biomarkers, such as DUOX2, MMP12, CCL2, and CXCL14, were validated in silico analysis. Finally, PPI network analysis using enriched data showed IL1B, CCL2, CCL7 and BMP7 were in the same hub node with high degrees. CONCLUSIONS: We identified IL1B was significantly up-regulated in COPD small airway epithelial cells and propose IL1B as a novel player in airway inflammation in COPD. PMID- 29616283 TI - [Unjustified recommendations regarding the ketogenic diet]. PMID- 29616286 TI - The lateral crescent sign. PMID- 29616285 TI - Similar outcome during short-term follow-up after coated and uncoated total knee arthroplasty: a randomized controlled study. AB - PURPOSE: Patients with known hypersensitivity to metals often require hypoallergenic TKA implants. Coating of a standard implant is a common solution, and although in vitro tests have demonstrated reduction of polyethylene wear for these coatings, it is still unknown whether these implants have any clinical benefit. This study was initiated to investigate metal ion concentrations, knee function and patient-reported outcome (PRO) after coated and uncoated TKA. METHODS: One hundred and twenty-two (122) patients were randomized to receive a coated or a standard TKA and, after exclusions, 59 patients were included in each group. Knee function and PRO were assessed with validated scores up to 3 years after surgery. Metal ion concentrations in blood samples were determined for chromium, cobalt, molybdenum and nickel, preoperatively and 1 year after surgery. RESULTS: Chromium concentrations in patient plasma increased from a median of 0.25 to 1.30 ug/l in the standard TKA group, and from 0.25 to 0.75 ug/l in the coated TKA group (p = 0.012). Thirteen patients (3 coated, 10 standard TKA) had chromium concentrations above 2 ug/l. The concentrations of cobalt, molybdenum and nickel did not change. Patient-reported outcome measures (PROM) demonstrated a substantial improvement after TKA, without any differences between the groups. CONCLUSION: The increase in chromium concentration in the standard group needs further investigation. If surgeons use coated implants, they can be confident that these implants perform as well as standard implants. LEVEL OF EVIDENCE: I. PMID- 29616287 TI - Correlation between CT morphologic appearance and histologic findings in colorectal liver metastasis after preoperative chemotherapy. AB - PURPOSE: Radiological evaluation of the efficacy of preoperative chemotherapy for colorectal liver metastasis (CRLM) is the most important tool for determining treatment strategies. The aim of this study was to identify a correlation between morphologic appearance on computed tomography (CT) and histologic findings of CRLM after preoperative chemotherapy. METHODS: We examined 47 patients who had undergone a first hepatic resection for CRLM after preoperative chemotherapy and had received contrast-enhanced CT scans. We assessed the morphologic appearance of the overall attenuation based on metastases changing from heterogeneous to mixed and homogenous lesions, the tumor-liver interface, and the peripheral rim enhancement on CT. Histologic parameters included usual necrosis (UN), infarct like necrosis (ILN), three-zonal change, dangerous halo, mucous lake, shape of ILN, dominant type of necrosis, and presence of viable tumor cells. The relationship between morphologic appearance and histologic findings was evaluated. RESULTS: CT overall attenuation revealed that UN predominance was more common in the heterogeneous group than in the mixed and homogeneous groups (P = 0.011). The frequency of ILN increased sequentially from ill-defined to variable and sharp at the tumor-liver interface (P = 0.038), and the frequency of UN decreased sequentially from present to partially resolved and completely resolved in the peripheral rim enhancement (P = 0.023). The histologic presence of viable tumor cells was closely associated with the tumor-liver interface (P = 0.0003) and the peripheral rim enhancement (P = 0.004). CONCLUSIONS: CT morphologic appearance of CRLM after preoperative chemotherapy is correlated with histologic findings regarding necrosis. PMID- 29616289 TI - [Transmission pathways for resistant bacteria between animals and humans: antibiotics resistance in the One Health context]. AB - People and animals share the same environment and antibiotics are used in both. Thus, antibiotics resistance is a major common issue for human and veterinary medicine. The potential impact of antibiotics use in animals on resistance in humans is frequently the focus of debate. In this paper the transmission pathways of resistant bacteria between animals and humans are described and the question is addressed whether a reduction in antibiotics use in animals contributes to the improvement of the resistance situation in humans. Direct contact between humans and animals, transmission of bacteria via food, and indirect transmission via emissions in the environment and the subsequent exposure of humans via the environment are the major transmission routes to be considered. It can thus be established that the relevance of these various transmission routes varies significantly among bacterial species. Furthermore, despite numerous investigations, the exact significance of transmission pathways and the bacteria transferred for the resistance situation in humans cannot yet be precisely quantified. There is evidence that antibiotics use in animals fosters the spread of resistant organisms in animals. Recent studies also suggest that there might be a relationship between antibiotics use in animals and the occurrence of resistance in humans. However, this relationship is complex, and for a better understanding of it and the role of the various transmission pathways, further collaborative studies between veterinary and medical science are needed. PMID- 29616288 TI - Organ support therapy in the intensive care unit and return to work: a nationwide, register-based cohort study. AB - PURPOSE: The association between severity of illness and ability to return to work is unclear. Therefore, we investigated return to work and associations with measures of illness severity in ICU survivors. METHODS: We conducted this cohort study using Danish registry data for the period 2005-2014 on ICU patients who were discharged alive from hospital, had an ICU length of stay (LOS) of at least 72 h, were not treated with dialysis before hospital admission and were working prior to admission. We assessed (1) the cumulative incidence (chance) of return to work (2005-2017) and receipt of social benefits after discharge from a hospital stay with ICU admission and (2) the association between organ support therapies (renal replacement therapy, cardiovascular support and mechanical ventilation), and during 2011-2014 SAPS II and ICU LOS, and return to work, using multivariable Cox regression. RESULTS: Among 5762 ICU survivors, 68% returned to work within 2 years after hospital discharge. Disability and sickness benefits constituted 89% of social benefits among patients not returning to work and 59% among patients withdrawing from work following an initial return to work. Mechanical ventilation (HR 0.70, 95% CI [0.65-0.77]), but not RRT (HR 0.85, 95% CI [0.71-1.02]), cardiovascular support (HR 0.93, 95% CI [0.82-1.07]) and increasing SAPS II, was associated with decreased chance of return to work. Increasing ICU LOS was also associated with a decreased chance of return to work. CONCLUSIONS: The majority of a nationwide cohort of ICU survivors returned to work. Sick leave and receipt of disability pension were common following ICU admission. Mechanical ventilation and longer ICU LOS were associated with reduced chances of return to work. PMID- 29616290 TI - Effect of ganaxolone in patients with posttraumatic stress disorder. PMID- 29616291 TI - The role of hepatic cytochrome P450s in the cytotoxicity of dronedarone. AB - Dronedarone is used to treat patients with cardiac arrhythmias and has been reported to be associated with liver injury. Our previous mechanistic work demonstrated that DNA damage-induced apoptosis contributes to the cytotoxicity of dronedarone. In this study, we examined further the underlying mechanisms and found that after a 24-h treatment of HepG2 cells, dronedarone caused cytotoxicity, G1-phase cell cycle arrest, suppression of topoisomerase II, and DNA damage in a concentration-dependent manner. We also investigated the role of cytochrome P450s (CYPs)-mediated metabolism in the dronedarone-induced toxicity using our previously established HepG2 cell lines expressing individually 14 human CYPs (1A1, 1A2, 1B1, 2A6, 2B6, 2C8, 2C9, 2C18, 2C19, 2D6, 2E1, 3A4, 3A5, and 3A7). We demonstrated that CYP3A4, 3A5, and 2D6 were the major enzymes that metabolize dronedarone, and that CYP3A7, 2E1, 2C19, 2C18, 1A1, and 2B6 also metabolize dronedarone, but to a lesser extent. Our data showed that the cytotoxicity of dronedarone was decreased in CYP3A4-, 3A5-, or 2D6-overexpressing cells compared to the control HepG2 cells, indicating that the parent dronedarone has higher potency than the metabolites to induce cytotoxicity in these cells. In contrast, cytotoxicity was increased in CYP1A1-overexpressing cells, demonstrating that CYP1A1 exerts an opposite effect in dronedarone's toxicity, comparing to CYP3A4, 3A5, or 2D6. We also studied the involvement of topoisomerase II in dronedarone-induced toxicity, and demonstrated that the overexpression of topoisomerase II caused an increase in cell viability and a decrease in gamma-H2A.X induction, suggesting that suppression of topoisomerase II may be one of the mechanisms involved in dronedarone-induced liver toxicity. PMID- 29616292 TI - Racial Variation in Echocardiographic Reference Ranges for Left Chamber Dimensions in Children and Adolescents: A Systematic Review. AB - Echocardiography plays a critical role in the assessment of cardiac disease. Important differences in echocardiographically derived cardiac chamber dimensions have been previously highlighted in different population groups in adult studies, but this has not been systematically studied in children, whose body size changes throughout childhood. The aim of this study was to review the distribution of available reference ranges for the left cardiac chamber dimensions in older children and adolescents. The following electronic data bases were searched: Medline, Embase and Web of Science were searched to identify studies which have established echocardiographic reference ranges of left heart parameters in children and adolescents from 1975 to December 2017. There was no geographical limitation. All results were imported into Endnote. Retrieved articles were screened and data extracted by two independent reviewers. A total of 4398 studies were retrieved, with 36 studies finally included in this review. 29 (81%) references were from North America and European (Caucasians) populations, with only one study each from Africa and South America. Two-dimensional and M-mode techniques were the most commonly used echocardiography techniques. There were methodological variations in techniques and normalisation of references. Comparison of selected cardiac measures showed significant differences for interventricular septal thickness among Black African, Indian, German and US American children. Available echocardiographic references cannot be generalised to all settings and therefore, there is need for locally relevant reference ranges. Africa and South America are particularly under-represented. Future studies should focus on developing comprehensive echocardiographic reference ranges for children from different racial backgrounds and should use standardised techniques. PMID- 29616293 TI - Physicochemical study of natural fractionated biocolloid by asymmetric flow field flow fractionation in tandem with various complementary techniques using biologically synthesized silver nanocomposites. AB - Asymmetric flow field-flow fractionation coupled with use of ultraviolet-visible, multiangle light scattering (MALLS), and dynamic light scattering (DLS) detectors was used for separation and characterization of biologically synthesized silver composites in two liquid compositions. Moreover, to supplement the DLS/MALLS information, various complementary techniques such as transmission electron spectroscopy, Fourier transform infrared spectroscopy, and matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF MS) were used. The hydrodynamic diameter and the radius of gyration of silver composites were slightly larger than the sizes obtained by transmission electron microscopy (TEM). Moreover, the TEM results revealed the presence of silver clusters and even several morphologies, including multitwinned. Additionally, MALDI-TOF MS examination showed that the particles have an uncommon cluster structure. It can be described as being composed of two or more silver clusters. The organic surface of the nanoparticles can modify their dispersion. We demonstrated that the variation of the silver surface coating directly influenced the migration rate of biologically synthesized silver composites. Moreover, this study proves that the fractionation mechanism of silver biocolloids relies not only on the particle size but also on the type and mass of the surface coatings. Because silver nanoparticles typically have size-dependent cytotoxicity, this behavior is particularly relevant for biomedical applications. Graphical abstract Workflow for asymmetric flow field-flow fractionation of natural biologically synthesized silver nanocomposites. PMID- 29616294 TI - Online low-field NMR spectroscopy for process control of an industrial lithiation reaction-automated data analysis. AB - Monitoring specific chemical properties is the key to chemical process control. Today, mainly optical online methods are applied, which require time- and cost intensive calibration effort. NMR spectroscopy, with its advantage being a direct comparison method without need for calibration, has a high potential for enabling closed-loop process control while exhibiting short set-up times. Compact NMR instruments make NMR spectroscopy accessible in industrial and rough environments for process monitoring and advanced process control strategies. We present a fully automated data analysis approach which is completely based on physically motivated spectral models as first principles information (indirect hard modeling IHM) and applied it to a given pharmaceutical lithiation reaction in the framework of the European Union's Horizon 2020 project CONSENS. Online low-field NMR (LF NMR) data was analyzed by IHM with low calibration effort, compared to a multivariate PLS-R (partial least squares regression) approach, and both validated using online high-field NMR (HF NMR) spectroscopy. Graphical abstract NMR sensor module for monitoring of the aromatic coupling of 1-fluoro-2 nitrobenzene (FNB) with aniline to 2-nitrodiphenylamine (NDPA) using lithium bis(trimethylsilyl) amide (Li-HMDS) in continuous operation. Online 43.5 MHz low field NMR (LF) was compared to 500 MHz high-field NMR spectroscopy (HF) as reference method. PMID- 29616295 TI - Reply to Comment on Saku et al.: Reasons and risk factors for ninety day re admission following primary total knee arthroplasty in a high-volume centre. PMID- 29616296 TI - PSMA-PET guided hook-wire localization of nodal metastases in prostate cancer: a targeted approach. AB - Prostate Specific Membrane Antigen Positron Emission Tomography/Computed Tomography (PSMA-PET/CT) has increased the sensitivity and specificity of imaging to identify metastatic prostate cancer in the group of patients with early biochemical recurrence when compared to conventional imaging. In patients who develop biochemical recurrence of prostate cancer following surgical resection, salvage lymph node dissection may reduce prostate specific antigen (PSA) levels and delay the time for commencement of systemic therapies. However, PLND may be an anatomically and technically difficult procedure, particularly with small metastatic diseases which can be problematic for intra-operative identification. We describe the technique using PSMA-PET imaging to pre-operatively localise areas of low-volume nodal metastatic disease with hookwire to allow targeted lymph node dissection with direct visualisation and palpation to ensure adequate clearance of involved nodes. PMID- 29616297 TI - A contemporary lower pole approach for complete staghorn calculi: outcomes and efficacy. AB - PURPOSE: Percutaneous nephrolithotomy (PCNL) is the preferred surgical treatment for staghorn stones. Two approaches are commonly employed to gain access into the collecting system which consists of either an upper pole (UP) approach or lower pole (LP) approach. However, opinions vary on which approach offers the best access and outcome. In this study, we aim to challenge the traditional paradigm that staghorn stones are most effectively treated through a prone UP approach. We herein report our institutional experience using a prone LP access in PCNL for patients with complete staghorn stones. METHODS: Data were prospectively collected over 3 years on 473 PCNL procedures, of which 76 patients had complete staghorn calculi (five or more calyces). Operative and peri-operative outcomes were analyzed to compare a modified LP approach with the more widely accepted UP approach. RESULTS: A total of 59/76 (77.6%) patients had LP access. There was no difference in the ability of completing the surgery utilizing a single tract as opposed to multiple tracts (74.6% of LP patients vs. 76.5% of UP patients). Stone free rates for LP and UP access were similar (74.5 versus 70.5%, respectively; p = 0.760. Complication rates were lower for LP access vs. UP access (3.4 vs. 23.5%, p = 0.02) with two pulmonary complications in the UP group. Overall median operative time was not significantly different between LP and UP access (112.0 vs. 126.0 min, p = 0.486). CONCLUSIONS: Prone LP access demonstrated similar efficacy with decreased morbidity in patients with complete staghorn calculi compared to prone UP access. PMID- 29616298 TI - Intracranial malignant peripheral nerve sheath tumor variant: an unusual neurovascular phenotype sarcoma case invading through the petrous bone. AB - INTRODUCTION: Intracranial malignant peripheral nerve sheath tumor (MPNST) is exceedingly rare. Previously reported cases of intracranial MPNST have been associated with development within a prominent cranial nerve. METHODS: This is the first report of an MPNST with both nerve sheath and vascular phenotype that follows the neurovascular bundle, without arising in a major cranial nerve or in the setting of neurofibromatosis type 1 (NF1). RESULTS: The patient is a 14-year old boy with a history of worsening headaches for the past several months, left sided hearing loss, nausea, vomiting, and vertigo. MRI was performed that demonstrated a large extra-axial tumor compressing the left infratemporal posterior temporal region. The tumor was associated with significant destruction of the superior portion of the petrous bone and extension through the petrous into the upper posterior fossa, immediately below the tentorium. The patient underwent surgical debulking and adjuvant chemotherapy with doxorubicin and ifosfamide. Pathology demonstrated a variant malignant peripheral nerve sheath tumor with both nerve sheath and vascular phenotype by immunostains. The patient's symptoms improved following treatment. CONCLUSION: We present the first reported case of an intracranial MPNST variant that developed along the neurovascular bundle as a sarcoma with both nerve sheath and vascular phenotype through the petrous bone and not associated with a major cranial nerve or with stigmata of neurofibromatosis type 1 (NF1). Although this is an extremely unusual presentation due to location and lack of prominent cranial nerves in that location, it is not unusual for benign nerve sheath tumors to follow the neurovascular bundle through foramen of cortical long bone or pelvis. This case suggests that physicians should incorporate intracranial MPNST variant into their differential diagnosis in the cranium, even when tumor is not located near a prominent cranial nerve. Surgical debulking and adjuvant chemotherapy with doxorubicin and ifosfamide has led to improvement in patient symptoms. PMID- 29616299 TI - Intraoperative X-rays during coccygectomy. PMID- 29616304 TI - Tumor metabolism assessed by FDG-PET/CT and tumor proliferation assessed by genomic grade index to predict response to neoadjuvant chemotherapy in triple negative breast cancer. AB - PURPOSE: Survival is increased when pathological complete response (pCR) is reached after neoadjuvant chemotherapy (NAC), especially in triple-negative breast cancer (TNBC) patients. Positron emission tomography/computed tomography (PET/CT) with 18F-fluorodeoxyglucose (FDG) and the genomic grade index (GGI), each separately, showed good potential to predict pCR. Our study was designed to evaluate the predictive value for the therapeutic response of a combination of parameters based on FDG-PET, histoclinical features and molecular markers of proliferation. METHODS: Molecular parameters were measured on pre-treatment biopsy. Tumor metabolic activity was measured using two PET/CT scans, one before and one after 2 cycles of NAC. The pCR was determined on specimen after NAC. Event-free survival (EFS) was estimated using the Kaplan Meier method. RESULTS: Of 55 TNBC patients, 19 (35%) reached pCR after NAC. Tumor grade and Ki67 were not associated with pCR whereas GGI (P = 0.04) and its component KPNA2 (P = 0.04) showed a predictive value. The change of FDG uptake between PET1 and PET2 (DeltaSUVmax) was highly associated with pCR (P = 0.0001) but the absolute value of baseline SUVmax was not (P = 0.11). However, the AUC of pCR prediction increased from 0.63 to 0.76 when baseline SUVmax was combined with the GGI (P = 0.016). The only two parameters associated with EFS were DeltaSUVmax (P = 0.048) and pathological response (P = 0.014). CONCLUSIONS: The early tumor metabolic change during NAC is a powerful parameter to predict pCR and outcome in TNBC patients. The GGI, determined on pretreatment biopsy, is also predictive of pCR and the combination GGI and baseline SUVmax improves the prediction. PMID- 29616303 TI - Serum drug levels of biologic agents in the management of rheumatoid arthritis and spondyloarthritis: a systematic review. AB - The utility of monitoring drug levels in rheumatoid arthritis and spondyloarthritis patients on biological therapy is called into question. The objective was to study relevant clinical questions on the topic, i.e., (1) whether drug levels predict relapse in patients whose biologic was optimized because of remission or low disease activity; (2) whether information about drug levels influences the prognosis of patients with primary or secondary failure to a biological therapy; and (3) whether methotrexate (MTX) influences the association between drug levels and response. Medline, Embase, Cochrane databases were screened, from inception to December 2016 in search for all studies related to the three research questions about. Overall characteristics and outcomes of the studies were collected in a table of evidence and the quality of the studies was assessed with the Newcastle-Ottawa scale or the GRADEpro. Two studies responded the first question, 5 the second, and 7 the third. Studies were small and with limitations, but suggest that measurement drug levels may be useful in patients in remission; that higher drug levels predict a longer relapse-free optimization, and in patients with failure to a biological agent, treatment may need individual adjustment according to the presence of drug levels or antidrug antibodies. In addition, MTX influences the association between response and drug levels. Monitoring drug levels would allow optimal use of current biological therapies, but more studies and of better quality are needed to draw definitive conclusions. PMID- 29616302 TI - Alterations in white matter network topology contribute to freezing of gait in Parkinson's disease. AB - Freezing of gait (FOG) is a common symptom in advanced Parkinson's disease (PD). Despite current advances, the neural mechanisms underpinning this disturbance remain poorly understood. To this end, we investigated the structural organisation of the white matter connectome in PD freezers and PD non-freezers. We hypothesized that freezers would show an altered network architecture, which could hinder the effective information processing that characterizes the disorder. Twenty-six freezers and twenty-four well-matched non-freezers were included in this study. Using diffusion tensor imaging, we investigated the modularity and integration of the regional connectome by calculating the module degree z score and the participation coefficient, respectively. Compared to non freezers, freezers demonstrated lower participation coefficients in the right caudate, thalamus, and hippocampus, as well as within superior frontal and parietal cortical regions. Importantly, several of these nodes were found within the brain's 'rich club'. Furthermore, group differences in module degree z scores within cortical frontal and sensory processing areas were found. Together, our results suggest that changes in the structural network topology contribute to the manifestation of FOG in PD, specifically due to a lack of structural integration between key information processing hubs of the brain. PMID- 29616305 TI - Polyunsaturated fatty acids from Phyllocaulis boraceiensis mucus block the replication of influenza virus. AB - Influenza viruses cause worldwide outbreaks and pandemics in humans and animals every year with considerable morbidity and mortality. The molecular diversity of secondary metabolites extracted from mollusks is a good alternative for the discovery of novel bioactive compounds with unique structures and diverse biological activities. Phyllocaulis boraceiensis is a hermaphroditic slug that exudes mucus, in which was detected hydroxy polyunsaturated fatty acids that exhibited potent antiviral activity against measles virus. The objective of this study was to evaluate this property against Influenza viruses. Cell viability and toxicity of the mucus were evaluated on Madin-Darby canine kidney (MDCK) cells by MTT assay. Antiviral activity from mucus against influenza viruses was carried out by determination of the virus infection dose and by immunofluorescence assays. The crude mucus and its fractions exhibited low cytotoxicity on MDCK cells. A significant inhibition of viral replication, reduced by the order of eight times, was observed in influenza-induced cytopathic effect. In immunofluorescence assay was observed a decrease of more than 80% of the viral load on infected MDCK cell treated with mucus and its fractions. The viral glycoproteins hemagglutinin and neuraminidase located on the surface of the virus are crucial for the replications and infectivity of the influenza virus. Some authors demonstrated that lipids, such as, polyunsaturated fatty acids exhibited multiple roles in antiviral innate and adaptive responses, control of inflammation, and in the development of antiviral therapeutics. As corroborated by other studies, hydroxy polyunsaturated fatty acids interfered with the binding of influenza virus on host cell receptor and reduced viral titers. The results obtained indicated that polyunsaturated fatty acids from P. boraceiensis crude mucus and fractions 39 exerted antiviral activity against influenza virus. PMID- 29616306 TI - Prodigiosin pigment of Serratia marcescens is associated with increased biomass production. AB - Serratia marcescens is a gram-negative, facultatively-anaerobic bacterium and opportunistic pathogen which produces the red pigment prodigiosin. We employed both batch culture and chemostat growth methods to investigate prodigiosin function in the producing organism. Pigmentation correlated with an increased rate of ATP production during population lag phase. Results with a lacZ transcriptional fusion to the prodigiosin (pig) biosynthetic operon revealed that operon transcription is activated by low cellular levels of ATP at high cell density. Furthermore, these data enabled estimation of the ATP per cell minimum value at which the operon is induced. Pigmented cells were found to accumulate ATP more rapidly and to multiply more quickly than non-pigmented cells during the high density growth phase. Finally, results with both batch and chemostat culture revealed that pigmented cells grow to approximately twice the biomass yield as non-pigmented S. marcescens bacteria. Prodigiosin production may, therefore, provide a growth advantage at ambient temperatures. PMID- 29616301 TI - Reconstructing the molecular life history of gliomas. AB - At the time of their clinical manifestation, the heterogeneous group of adult and pediatric gliomas carries a wide range of diverse somatic genomic alterations, ranging from somatic single-nucleotide variants to structural chromosomal rearrangements. Somatic abnormalities may have functional consequences, such as a decrease, increase or change in mRNA transcripts, and cells pay a penalty for maintaining them. These abnormalities, therefore, must provide cells with a competitive advantage to become engrained into the glioma genome. Here, we propose a model of gliomagenesis consisting of the following five consecutive phases that glioma cells have traversed prior to clinical manifestation: (I) initial growth; (II) oncogene-induced senescence; (III) stressed growth; (IV) replicative senescence/crisis; (V) immortal growth. We have integrated the findings from a large number of studies in biology and (neuro)oncology and relate somatic alterations and other results discussed in these papers to each of these five phases. Understanding the story that each glioma tells at presentation may ultimately facilitate the design of novel, more effective therapeutic approaches. PMID- 29616307 TI - Extracellular vesicles and their immunomodulatory functions in pregnancy. AB - Extracellular vesicles (EVs) are membrane-bound vesicles released into the extracellular space by almost all types of cells. EVs can cross the physiological barriers, and a variety of biological fluids are enriched in them. EVs are a heterogeneous population of vesicles, including exosomes, microvesicles, and apoptotic bodies. The different subpopulations of vesicles can be differentiated by size and origin, in which exosomes (~100 nm and from endocytic origin) are the most studied so far. EVs have essential roles in cell-to-cell communication and are critical modulators of immune response under normal and pathological conditions. Pregnancy is a unique situation of immune-modulation in which the maternal immune system protects the fetus from allogenic rejection and maintains the immunosurveillance. The placenta is a vital organ that performs a multitude of functions to support the pregnancy. The EVs derived from the human placenta have crucial roles in regulating the maternal immune response for successful pregnancy outcome. Placenta-derived vesicles perform a myriad of functions like suppression of immune reaction to the developing fetus and establishment and maintenance of a systemic inflammatory response to combat infectious intruders. A fine-tuning of these mechanisms is quintessential for successful completion of pregnancy and healthy outcome for mother and fetus. Dysregulation in the mechanisms mentioned above can lead to several pregnancy disorders. In this review, we summarize the current literature regarding the critical roles played by the EVs in immunomodulation during pregnancy with particular attention to the placenta-derived exosomes. PMID- 29616310 TI - What are the prevalence, characteristics and significance of fetal lateral neck cysts detected in an early anatomical scan? AB - PURPOSE: This study evaluated the association of fetal lateral neck cysts (FLNC) with adverse pregnancy outcomes, in relation to specific sonographic characteristics and co-existing findings. METHODS: Pregnancies in which FLNC were detected by a single examiner in early anatomical scans (14-16 weeks) were included. Data regarding the pregnancy and its outcome were retrieved from telephone-based questionnaires, patient charts and from the examiner's reports. RESULTS: 654 cases of FLNC were detected among 9446 early anatomical scans (6.9%). Complete data regarding 219 pregnancies were available. FLNC were significantly more prevalent in males (65.2%). The prevalence of heart malformations was 3.2% [all were non-isolated cases or with abnormal nuchal translucency (NT) and/or nuchal fold (NF)]. Amniocentesis performed in 165 pregnancies was abnormal in 1.2%. Among 206 children born from this cohort, adverse medical outcomes were reported in 5.3%. The likelihood of adverse pregnancy outcomes was significantly higher in non-isolated cases and in cases with abnormal NT or NF. Sonographic characteristics such as cyst size and bilateral findings were not linked to adverse pregnancy outcomes. CONCLUSION: Isolated FLNC are benign findings which do not require additional work up. FLNC with additional sonographic abnormalities are associated with a significantly increased risk for adverse pregnancy outcomes. PMID- 29616308 TI - The role of extracellular vesicles when innate meets adaptive. AB - Innate immune cells are recognized for their rapid and critical contribution to the body's first line of defense against invading pathogens and harmful agents. These actions can be further amplified by specific adaptive immune responses adapted to the activating stimulus. Recently, the awareness has grown that virtually all innate immune cells, i.e., mast cells, neutrophils, macrophages, eosinophils, basophils, and NK cells, are able to communicate with dendritic cells (DCs) and/or T and B cells, and thereby significantly contribute to the orchestration of adaptive immune responses. The means of communication that are thus far primarily associated with this function are cell-cell contacts and the release of a broad range of soluble mediators. Moreover, the possible contribution of innate immune cell-derived extracellular vesicles (EVs) to the modulation of adaptive immunity will be outlined in this review. EVs are submicron particles composed of a lipid bilayer, proteins, and nucleic acids released by cells in a regulated fashion. EVs are involved in intercellular communication between multiple cell types, including those of the immune system. A good understanding of the mechanisms by which innate immune cell-derived EVs influence adaptive immune responses, or vice versa, may reveal novel insights in the regulation of the immune system and can open up new possibilities for EVs (or their components) in controlling immune responses, either as a therapy, target, or as an adjuvant in future immune modulating treatments. PMID- 29616311 TI - Serum levels of Pentraxin 3 differ significantly at the time of blastocyst transfer depending on implantation success: a pilot study. AB - OBJECTIVE: Many approaches try to identify the underlying molecular mechanisms to detect new potential biomarkers for successful artificial reproductive therapies. One factor has been described as a possible regulator of inflammation during implantation: Pentraxin 3 (PTX3), which seems to be essential for female fertility on one hand, but whose overexpression has been described in many obstetric complications based on abnormal placentation on the other hand. Therefore, we investigated if serum levels of PTX3 at the time of embryo transfer differ between women with an ongoing pregnancy compared to those without implantation. METHODS/DESIGN: During in vitro fertilization cycles of 51 patients, PTX3 levels at the time of embryo transfer were compared between patients without implantation (n = 26) and those with ongoing pregnancy (n = 25) using an enzyme-linked immunosorbent assay. Statistical analysis was performed using the Kolmogorov-Smirnov test, Fisher's exact test and Student's t test RESULTS: No significant differences were found concerning possible confounders (patients age, smoking pattern, embryo quality, number of embryos transferred and prior IVF attempts). Patients without implantation presented with significantly higher serum levels of PTX3 at the time of embryo transfer compared to women who became pregnant (0.781 +/- 0.074 ng/ml vs. 0.578 +/- 0.055 ng/ml, p < 0.05). CONCLUSIONS: PTX3 could present as a possible biomarker for ART success. The main limitation of this pilot study is its small sample size that needs validation with a larger study population. PMID- 29616309 TI - A historical perspective on the role of sensory nerves in neurogenic inflammation. AB - The term 'neurogenic inflammation' is commonly used, especially with respect to the role of sensory nerves within inflammatory disease. However, despite over a century of research, we remain unclear about the role of these nerves in the vascular biology of inflammation, as compared with their interacting role in pain processing and of their potential for therapeutic manipulation. This chapter attempts to discuss the progress in understanding, from the initial discovery of sensory nerves until the present day. This covers pioneering findings that these nerves exist, are involved in vascular events and act as important sensors of environmental changes, including injury and infection. This is followed by discovery of the contents they release such as the established vasoactive neuropeptides substance P and CGRP as well as anti-inflammatory peptides such as the opioids and somatostatin. The more recent emergence of the importance of the transient receptor potential (TRP) channels has revealed some of the mechanisms by which these nerves sense environmental stimuli. This knowledge enables a platform from which to learn of the potential role of neurogenic inflammation in disease and in turn of novel therapeutic targets. PMID- 29616312 TI - Extracellular polymer substance synthesized by a halophilic bacterium Chromohalobacter canadensis 28. AB - Halophilic microorganisms are producers of a lot of new compounds whose properties suggest promising perspectives for their biotechnological exploration. Moderate halophilic bacterium Chromohalobacter canadensis 28 was isolated from Pomorie salterns as an extracellular polymer substance (EP) producer. The best carbon source for extracellular polymer production was found to be lactose, a sugar received as a by-product from the dairy industry. After optimization of the culture medium and physicochemical conditions for cultivation, polymer biosynthesis increased more than 2-fold. The highest level of extracellular polymer synthesis by C. canadensis 28 was observed in an unusually high NaCl concentration (15% w/v). Chemical analysis of the purified polymer revealed the presence of an exopolysaccharide (EPS) fraction (14.3% w/w) and protein fraction (72% w/w). HPLC analysis of the protein fraction showed the main presence of polyglutamic acid (PGA) (75.7% w/w). EPS fraction analysis revealed the following sugar composition (% w/w): glucosamine 36.7, glucose 32.3, rhamnose 25.4, xylose 1.7, and not identified sugar 3.9. The hydrogel formed by PGA and EPS fractions showed high swelling behavior, very good emulsifying and stabilizing properties, and good foaming ability. This is the first report for halophilic bacterium able to synthesize a polymer containing PGA fraction. The synthesized biopolymer shows an extremely high hydrophilicity, due to the simultaneous presence of PGA and EPS. The analysis of its functional properties and the presence of glucosamine in the highest proportion in EPS fraction clearly determine the potential of EP synthesized by C. canadensis 28 for application in the cosmetics industry. PMID- 29616313 TI - Role of a membrane-bound aldehyde dehydrogenase complex AldFGH in acetic acid fermentation with Acetobacter pasteurianus SKU1108. AB - Acetic acid fermentation is widely considered a consequence of ethanol oxidation by two membrane-bound enzymes-alcohol dehydrogenase and aldehyde dehydrogenase (ALDH)-of acetic acid bacteria. Here, we used a markerless gene disruption method to construct a mutant of the Acetobacter pasteurianus strain SKU1108 with a deletion in the aldH gene, which encodes the large catalytic subunit of a heterotrimeric ALDH complex (AldFGH), to examine the role of AldFGH in acetic acid fermentation. The DeltaaldH strain grew less on ethanol-containing medium, i.e., acetic acid fermentation conditions, than the wild-type strain and significantly accumulated acetaldehyde in the culture medium. Unexpectedly, acetaldehyde oxidase activity levels of the intact DeltaaldH cells and the DeltaaldH cell membranes were similar to those of the wild-type strain, which might be attributed to an additional ALDH isozyme (AldSLC). The apparent KM values of the wild-type and DeltaaldH membranes for acetaldehyde were similar to each other, when the cells were cultured in nonfermentation conditions, where DeltaaldH cells grow as well as the wild-type cells. However, the membranes of the wild-type cells grown under fermentation conditions showed a 10-fold lower apparent KM value than those of the cells grown under nonfermentation conditions. Under fermentation conditions, transcriptional levels of a gene for AldSLC were 10-fold lower than those under nonfermentation conditions, whereas aldH transcript levels were not dramatically changed under the two conditions. We suggest that A. pasteurianus SKU1108 has two ALDHs, and the AldFGH complex is indispensable for acetic acid fermentation and is the major enzyme under fermentation conditions. PMID- 29616314 TI - Involvement of organic acids and amino acids in ameliorating Ni(II) toxicity induced cell cycle dysregulation in Caulobacter crescentus: a metabolomics analysis. AB - Nickel (Ni(II)) toxicity is addressed by many different bacteria, but bacterial responses to nickel stress are still unclear. Therefore, we studied the effect of Ni(II) toxicity on cell proliferation of alpha-proteobacterium Caulobacter crescentus. Next, we showed the mechanism that allows C. crescentus to survive in Ni(II) stress condition. Our results revealed that the growth of C. crescentus is severely affected when the bacterium was exposed to different Ni(II) concentrations, 0.003 mM slightly affected the growth, 0.008 mM reduced the growth by 50%, and growth was completely inhibited at 0.015 mM. It was further shown that Ni(II) toxicity induced mislocalization of major regulatory proteins such as MipZ, FtsZ, ParB, and MreB, resulting in dysregulation of the cell cycle. GC-MS metabolomics analysis of Ni(II) stressed C. crescentus showed an increased level of nine important metabolites including TCA cycle intermediates and amino acids. This indicates that changes in central carbon metabolism and nitrogen metabolism are linked with the disruption of cell division process. Addition of malic acid, citric acid, alanine, proline, and glutamine to 0.015 mM Ni(II) treated C. crescentus restored its growth. Thus, the present work shows a protective effect of these organic acids and amino acids on Ni(II) toxicity. Metabolic stimulation through the PutA/GlnA pathway, accelerated degradation of CtrA, and Ni-chelation by organic acids or amino acids are some of the possible mechanisms suggested to be involved in enhancing C. crescentus's tolerance. Our results shed light on the mechanism of increased Ni(II) tolerance in C. crescentus which may be useful in bioremediation strategies and synthetic biology applications such as the development of whole cell biosensor. PMID- 29616315 TI - Two Rab GTPases play different roles in conidiation, trap formation, stress resistance, and virulence in the nematode-trapping fungus Arthrobotrys oligospora. AB - Rab GTPases are the largest group of the small GTPases family, which play a pivotal role in the secretion of proteins. Arthrobotrys oligospora is a representative nematode-trapping fungus that can produce adhesive networks to capture nematodes. In this study, the roles of two Rab GTPases AoRab-7A and AoRab 2 were characterized by gene knockout in the fungus A. oligospora. The disruption of AoRab-7A hindered the mycelial growth in different media, the conidiation of DeltaAoRab-7A transformants was almost abolished, and the transcription of four sporulation-related genes (AbaA, FluG, Hyp1, and VosA) was downregulated compared to the wild-type strain (WT). Furthermore, the tolerance of the DeltaAoRab-7A mutants to sodium dodecyl sulfate (SDS) and H2O2 was also significantly reduced compared to the WT, and the transcription of several genes related to environmental resistance, such as genes for catalase and trehalose synthase, was downregulated. Similarly, the extracellular proteolytic activity was decreased. Importantly, the DeltaAoRab-7A mutants were unable to produce traps and capture nematodes. However, the disruption of gene AoRab-2 only affected the conidiation slightly but non-significantly, while other phenotypic traits were unaffected. Moreover, the gene AoRab-7A was also involved in the autophagy induced by nitrogen deprivation in A. oligospora. Our results revealed for the first time that the Rab GTPases are involved in the regulation of mycelial growth, conidiation, trap formation, stress resistance, and pathogenicity in the nematode trapping fungus A. oligospora. PMID- 29616316 TI - Temporal trajectory of quality of life and its predictors in recipients of hematopoietic stem cell transplantation. AB - This prospective longitudinal study evaluated the temporal trajectory of health related quality of life (HRQOL) and its associated factors in patients who received hematopoietic stem cell transplantation (SCT) 6 months after transplantation. Eighty-nine adult patients who were admitted to Seoul National University Hospital for SCT were consecutively included in the study. The participants completed three standardized questionnaires: Insomnia Severity Index, Hospital Anxiety and Depression Scale, and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire. The participants completed the study questionnaires at three time points: before SCT (T1), immediately after SCT (T1), and 6 months after SCT (T3). Immediately after SCT, HRQOL decreased significantly (p < 0.001), followed by recovery over 6 months. The conditioning regimen for SCT showed no correlation with HRQOL at T2 (p = 0.283) or T3 (p = 0.799), with no significant difference in HRQOL between allogeneic and autologous SCT recipients at T2 (p = 0.829) or T3 (p = 0.824). Depression (p = 0.042), pain (p = 0.023), and appetite loss (p = 0.004) negatively influenced HRQOL at T1, whereas only pain (p = 0.048) remained an important factor at T2. Six months after SCT, the two most frequent symptoms, fatigue and financial problems, became major factors (p = 0.004 and p = 0.005, respectively). Depression began to play an important role in HRQOL again at T3 (p = 0.040). These findings demonstrate that SCT recipients need both psychological and medical support to achieve a better HRQOL after SCT. PMID- 29616317 TI - Outcomes of patients with myelofibrosis treated with compassionate use pacritinib: a sponsor-independent international study. AB - Myelofibrosis (MF) is a chronic yet progressive myeloid neoplasm in which only a minority of patients undergo curative therapy, hematopoietic stem cell transplantation. Ruxolitinib, a JAK1/2 inhibitor, is the lone therapy approved for MF, offering a clear symptom and spleen benefit at the expense of treatment related cytopenias. Pacritinib (PAC), a multi-kinase inhibitor with specificity for JAK2, FLT3, and IRAK1 but sparing JAK1, has demonstrated clinical activity in MF with minimal myelosuppression. Due to an FDA-mandated full clinical hold, the randomized phase 3 PERSIST trials were abruptly stopped and PAC was immediately discontinued for all patients. Thirty-three patients benefitting from PAC on clinical trial prior to the hold were allowed to resume therapy on an individual, compassionate-use basis. This study reports the detailed outcomes of 19 of these PAC retreatment patients with a median follow-up of 8 months. Despite a median platelet count of 49 * 109/L at restart of PAC, no significant change in hematologic profile was observed. Grade 3/4 adverse events of epistaxis (n = 1), asymptomatic QT prolongation (n = 1), and bradycardia (n = 1) occurred in three patients within the first 3 months of retreatment. One death due to catheter associated sepsis occurred. The median time to discontinuation of PAC therapy on compassionate use for all 33 patients was 12.2 (95% CI 8.3-NR) months. PAC retreatment was associated with modest improvement in splenomegaly without progressive myelosuppression and supports the continued development of this agent for the treatment of MF second line to ruxolitinib or in the setting of treatment limiting thrombocytopenia. PMID- 29616318 TI - Re-transplantation for Hepatic Artery Thrombosis: A National Perspective. AB - BACKGROUND: Hepatic artery thrombosis (HAT) is a major complication after liver transplantation that commonly requires re-transplantation. METHODS: We queried the UNOS dataset for all patients transplanted between 1995 and 2015 for HAT. RESULTS: We identified 623 patients who underwent re-transplantation for HAT with a mean age of 51.25 + 10.4 years. The mean BMI was 26.72 kg/m2, and mean MELD score was 19.62 + 9.09. There was a higher proportion of male patients, with higher prevalence of pre-transplant portal vein thrombosis (7.4 vs. 5.4%, p = 0.04), lower incidence of hepatitis C virus infection (29.5 vs. 35.8%, p = 0.002), and shorter waiting time (61 vs. 111 days, p = 0.001) in the HAT group compared to those re-transplanted for other indications. The perioperative 90-day mortality was lower in patients re-transplanted for HAT (16 vs. 20%, p = 0.02). Patients undergoing re-transplantation for HAT had 13% decreased graft survival and 13% increased long-term survival. After case-control matched analysis, graft survival and patient survival were significantly better in the HAT group. Late re transplantation (>30 days) for HAT was linked to decreased graft and patient survival when compared to those undergoing early re-transplantation (within 30 days). CONCLUSIONS: Improved outcomes were seen in patients undergoing re transplantation for HAT compared to patients who underwent re-transplantation for other indications. Those re-transplanted late after HAT (>30 days) were associated with worse outcomes when compared to early re-transplantation. PMID- 29616320 TI - Trauma Patients with an Open Abdomen Following Damage Control Laparotomy can be Extubated Prior to Abdominal Closure. AB - BACKGROUND: The open abdomen (OA) is commonly utilized as a technique during damage control laparotomy (DCL). We propose that a selected group of these OA patients can be extubated prior to abdominal closure to decrease ventilator days and risk of pneumonia. METHODS: A retrospective chart review was performed at a Level I trauma center on all adult trauma patients with an OA following DCL. Patients were stratified into two groups: extubated prior to (PRE) and extubated after (POST) abdominal closure. Successful extubation in the PRE group was measured by the absence of re-intubation. The two groups were compared using the Mann-Whitney U and Fisher's exact tests. Multivariate logistic regression identified independent predictors for successful extubation prior to abdominal closure. RESULTS: Thirty-one patients were in the PRE group, and 59 patients in the POST group. There were no differences between the groups with regard to age, gender, or hours from admission to completion of DCL. The PRE group had a significantly higher incidence of penetrating trauma (77 vs. 53%; p = 0.02), a significantly lower number of days from OA to extubation [0.6 (0.2-1.1) vs. 3.4 (2--8) days; p < 0.001], and a significant decrease in pneumonia (10 vs. 31%; p = 0.04). Two patients in each group required re-intubation [PRE (6%) vs. POST (3%); p = 0.61]. In a multivariate binominal logistic regression, penetrating trauma (p = 0.024), GCS on admission (p < 0.0001), and Injury Severity Score (p = 0.024) were identified as independent predictors for successful extubation. CONCLUSION: Presence of an OA following DCL does not require mechanical ventilation. Extubation of appropriate trauma patients prior to abdominal closure decreases pneumonia and hospital length of stay. PMID- 29616319 TI - Acute Pancreatitis After Laparoscopic Transcystic Common Bile Duct Exploration: An Analysis of Predisposing Factors in 447 Patients. AB - INTRODUCTION: In laparoscopic transcystic common bile duct exploration (LTCBDE), the risk of acute pancreatitis (AP) is well recognized. The present study assesses the incidence, risk factors, and clinical impact of AP in patients with choledocholithiasis treated with LTCBDE. METHODS: A retrospective database was completed including patients who underwent LTCBDE between 2007 and 2017. Univariate and multivariate analyses were performed by logistic regression. RESULTS: After exclusion criteria, 447 patients were identified. There were 70 patients (15.7%) who showed post-procedure hyperamylasemia, including 20 patients (4.5%) who developed post-LTCBDE AP. Of these, 19 were edematous and one was a necrotizing pancreatitis. Patients with post-LTCBDE AP were statistically more likely to have leukocytosis (p < 0.004) and jaundice (p = 0.019) before surgery and longer operative times (OT, p < 0.001); they were less likely to have incidental intraoperative diagnosis (p = 0.031) or to have biliary colic as the reason for surgery (p = 0.031). In the final multivariate model, leukocytosis (p = 0.013) and OT (p < 0.001) remained significant predictors for AP. Mean postoperative hospital stay (HS) was significantly longer in AP group (p < 0.001). CONCLUSION: The risk of AP is moderate and should be considered in patients with preoperative leukocytosis and jaundice and exposed to longer OT. AP has a strong impact on postoperative HS. PMID- 29616321 TI - Saturated, mono- and polyunsaturated fatty acid intake and cancer risk: results from the French prospective cohort NutriNet-Sante. AB - PURPOSE: Lipid intakes such as saturated (SFA), monounsaturated (MUFA) and polyunsaturated (PUFA) fatty acids have been widely studied regarding cardiovascular health, but their relevance to cancer is unclear. Inconsistent epidemiological results may be explained by varied mechanisms involving PUFAs and redox balance, inflammatory status and cell signalling, along with interactions with other dietary components such as antioxidants, dietary fibre and more generally fruits and vegetable intakes. Therefore, this study aimed to investigate the associations between lipid intakes and cancer risk, and their potential modulation by vitamin C, vitamin E, dietary fibre and fruit and vegetable intakes. METHODS: This prospective study included 44,039 participants aged >= 45 years from the NutriNet-Sante cohort (2009-2017). Dietary data were collected using repeated 24 h-dietary records. Multivariable Cox models were performed to characterize associations. RESULTS: SFA intake was associated with increased overall [n = 1722 cases, HRQ5vsQ1 = 1.44 (1.10-1.87), p-trend = 0.008] and breast [n = 545 cases, HRQ5vsQ1 = 1.98 (1.24-3.17), p-trend = 0.01] cancer risks. n-6 PUFA [HRQ5vsQ1 = 0.56 (0.32-0.97), p-trend = 0.01] and MUFA (HRQ5vsQ1 = 0.41 [0.18-0.0.95), p-trend = 0.009] intakes were associated with a decreased risk of digestive cancers (n = 190 cases). Associations between n-6 PUFA, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) intakes and digestive cancer risk were modulated by dietary fibre, vitamin C and fruit and vegetable intakes. CONCLUSION: These findings suggested that SFA intake could increase overall and breast cancer risks while some unsaturated fatty acids could decrease digestive cancer risk. However, in line with mechanistic hypotheses, our results suggest that intakes of fruits and vegetables and their constituents (antioxidants, fibre) may interact with PUFAs to modulate these associations. PMID- 29616322 TI - Inter-individual variability in the production of flavan-3-ol colonic metabolites: preliminary elucidation of urinary metabotypes. AB - PURPOSE: There is much information on the bioavailability of (poly)phenolic compounds following acute intake of various foods. However, there are only limited data on the effects of repeated and combined exposure to specific (poly)phenol food sources and the inter-individual variability in their bioavailability. This study evaluated the combined urinary excretion of (poly)phenols from green tea and coffee following daily consumption by healthy subjects in free-living conditions. The inter-individual variability in the production of phenolic metabolites was also investigated. METHODS: Eleven participants consumed both tablets of green tea and green coffee bean extracts daily for 8 weeks and 24-h urine was collected on five different occasions. The urinary profile of phenolic metabolites and a set of multivariate statistical tests were used to investigate the putative existence of characteristic metabotypes in the production of flavan-3-ol microbial metabolites. RESULTS: (Poly)phenolic compounds in the green tea and green coffee bean extracts were absorbed and excreted after simultaneous consumption, with green tea resulting in more inter-individual variability in urinary excretion of phenolic metabolites. Three metabotypes in the production of flavan-3-ol microbial metabolites were tentatively defined, characterized by the excretion of different amounts of trihydroxyphenyl-gamma-valerolactones, dihydroxyphenyl-gamma-valerolactones, and hydroxyphenylpropionic acids. CONCLUSIONS: The selective production of microbiota derived metabolites from flavan-3-ols and the putative existence of characteristic metabotypes in their production represent an important development in the study of the bioavailability of plant bioactives. These observations will contribute to better understand the health effects and individual differences associated with consumption of flavan-3-ols, arguably the main class of flavonoids in the human diet. PMID- 29616323 TI - Effects of dietary nucleotide supplementation on growth in infants: a meta analysis of randomized controlled trials. AB - PURPOSE: Dietary nucleotides are thought to be conditionally essential nutrients in infancy. However, studies have reported inconsistent findings regarding the association between nucleotide supplementation and infant physical growth. We conducted this meta-analysis to examine the efficacy of nucleotide supplementation of infant formula in promoting early infant growth. METHODS: Randomized controlled trials that evaluated the association between nucleotide supplementation and infant growth through June 2017 were included. Study quality was assessed using the Cochrane Collaboration's Risk of Bias tool. Standardized mean differences (SMD) with 95% confidence intervals (CIs) were calculated. Heterogeneity was assessed using Q and I2 tests. RESULTS: Nucleotide supplementation significantly increased the rate of weight gain (SMD 0.26; 95% CI 0.06-0.47), but had no effect on weight (SMD - 0.16; 95% CI - 0.55-0.23), weight Z score (SMD, - 0.42; 95% CI - 1.64-0.81), length (SMD 0.01; 95% CI - 0.18-0.21) and length Z score (SMD 0.15; 95% CI - 0.10-0.40). Occipitofrontal head circumference (OFC) at 7-8 weeks (SMD 0.30; 95% CI 0.10-0.50) and the rate of OFC gain (SMD 0.34; 95% CI 0.09-0.58) were significantly improved with nucleotide supplementation, whereas, 16- and 20-week OFC values did not differ. CONCLUSIONS: Our meta-analysis indicated that nucleotide supplementation can increase the rate of weight gain, OFC and rate of OFC gain; however, we cannot conclude that it affects weight, weight Z score, length or length Z score. Large-scale randomized controlled trials of long-term nucleotide supplementation are needed to reach definitive conclusions. PMID- 29616325 TI - Correction to: Real-World Switching to Riociguat: Management and Practicalities in Patients with PAH and CTEPH. AB - The original version of this article unfortunately contained a mistake. In the "Results" section, the percentage of patients with inoperable or persistent/recurrent CTEPH included in the study was reported as 85%. This has been corrected to 68% with this erratum. PMID- 29616324 TI - Variability in circulating gas emboli after a same scuba diving exposure. AB - PURPOSE: A reduction in ambient pressure or decompression from scuba diving can result in ultrasound-detectable venous gas emboli (VGE). These environmental exposures carry a risk of decompression sickness (DCS) which is mitigated by adherence to decompression schedules; however, bubbles are routinely observed for dives well within these limits and significant inter-personal variability in DCS risk exists. Here, we assess the variability and evolution of VGE for 2 h post dive using echocardiography, following a standardized pool dive in calm warm conditions. METHODS: 14 divers performed either one or two (with a 24 h interval) standardized scuba dives to 33 mfw (400 kPa) for 20 min of immersion time at NEMO 33 in Brussels, Belgium. Measurements were performed at 21, 56, 91 and 126 min post-dive: bubbles were counted for all 68 echocardiography recordings and the average over ten consecutive cardiac cycles taken as the bubble score. RESULTS: Significant inter-personal variability was demonstrated despite all divers following the same protocol in controlled pool conditions: in the detection or not of VGE, in the peak VGE score, as well as time to VGE peak. In addition, intra-personal differences in 2/3 of the consecutive day dives were seen (lower VGE counts or faster clearance). CONCLUSIONS: Since VGE evolution post-dive varies between people, more work is clearly needed to isolate contributing factors. In this respect, going toward a more continuous evaluation, or developing new means to detect decompression stress markers, may offer the ability to better assess dynamic correlations to other physiological parameters. PMID- 29616326 TI - Role of natural killer cells in lung cancer. AB - PURPOSE: One of the key immune cells involved in the pathogenesis of lung cancer is natural killer (NK) cells and these cells are novel targets for therapeutic applications in lung cancer. The purpose of this review is to summarize the current literature on lung cancer pathogenesis with a focus on the interaction between NK cells and smoking, how these factors are related to the pathogenesis of lung cancer and how NK cell-based immunotherapy effect lung cancer survival. METHODS: The relevant literature from PubMed and Medline databases is reviewed in this article. RESULTS: The cytolytic potential of NK cells are reduced in lung cancer and increasing evidence suggests that improving NK cell functioning may induce tumor regression. Recent clinical trials on NK cell-based novel therapies such as cytokines including interleukin (IL)-15, IL-12 and IL-2, NK-92 cell lines and allogenic NK cell immunotherapy showed promising results with less adverse effects on the lung cancer survival. CONCLUSIONS: The NK cell targeting strategy has not yet been approved for lung cancer treatment. More clinical studies focusing on the role of NK cells in lung cancer pathogenesis are warranted to develop novel NK cell-based therapeutic approaches for the treatment of lung cancer. PMID- 29616327 TI - Whole-exome sequencing identifies key mutated genes in T790M wildtype/cMET unamplified lung adenocarcinoma with acquired resistance to first-generation EGFR tyrosine kinase inhibitors. AB - PURPOSE: Lung cancer is the leading cause of cancer-related death worldwide. Lung adenocarcinoma harboring EGFR-activating mutations will inevitably acquire resistance to first-generation EGFR tyrosine kinase inhibitors (TKIs). EGFR T790M mutation and cMET amplification are common mechanisms. Further study is needed to explore unknown genomic alterations contributing to drug resistance. METHODS: Tumor and blood samples from 69 stage IIIB-IV NSCLC patients defined as acquired resistance to first-generation EGFR TKIs (gefitinib, erlotinib or ecotinib) were collected. The cobas(r) and Droplet digital PCR (ddPCR) were used to detect T790M mutations in tumor samples and plasma ctDNA. cMET amplification was evaluated by fluorescence in situ hybridization (FISH). Exome sequencing was performed in four T790M wildtype/cMET-unamplified samples. RESULTS: The overall T790M-positive rate was 52.2% considering all testing methods. Out of 21 samples in which tumor re biopsy was performed, 14 were T790M positive (66.7%). cMET amplification was identified in three out of seven T790M-negative samples. Exome sequencing in four T790M wildtype/cMET-unamplified samples and paired white blood cells identified a cohort of candidate key mutated genes including BRAF, FGFR1, PAK1, PCNT, PEBP4 and SOX3. CONCLUSIONS: EGFR T790M mutation and cMET amplification are main mechanisms leading to EGFR TKI resistance in lung adenocarcinoma. These key mutated genes identified in the present study would need further validation in large number of patients. PMID- 29616328 TI - Thoracoscopic anterior stabilization for thoracolumbar fractures in patients without spinal cord injury: quality of life and long-term results. AB - PURPOSE: To determine the health-related quality of life (QOL), safety and radiologic parameters after thoracoscopic treatment of traumatic thoracolumbar fractures using a distractible cage in patients without spinal cord injury (SCI). METHODS: Retrospective cohort study of patients treated between 2004 and 2012 in a university level-one trauma center. Patient and treatment characteristics were collected from the hospital information system. All available radiographic material was assessed for fracture characteristics and Cobb angle at consecutive times. Patients completed the SF-36 and EQ-5D QOL questionnaires at follow-up. RESULTS: 105 patients were treated with a distractible cage, which was performed thoracoscopically in 86 cases, including 16 patients with SCI. Of 70 eligible patients, 46 were available for follow-up and completed the questionnaires at median 49 months after surgery. QOL was lower on most domains compared to the general population. Compared to patients who underwent solely posterior fixation for less severe fractures, QOL did not differ significantly. The complication rate was low (10%) with one re-operation. Mean loss of correction was 6.8 degrees and bony fusion on CT scan was present in 98% of patients. Maintenance of kyphosis correction was significantly better for two segments anterior fixation compared to one segment. CONCLUSIONS: Thoracoscopic anterior stabilization leads to a high percentage of bony fusion in highly unstable thoracic and thoracolumbar fractures with limited post-operative loss of correction and no hardware failure. QOL of these patients does not return to normal population values but is comparable to that of patients with less severe fractures treated with solely posterior instrumentation. These slides can be retrieved under Electronic Supplementary Material. PMID- 29616329 TI - Proliferative glomerulonephritis with monoclonal IgG deposits in children and young adults. AB - BACKGROUND: Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) has been recognized as a distinct entity in recent years. To the best of our knowledge, all patients with PGNMID reported thus far were older than 20 years of age. We now report five cases of PGNMID in patients under 20 years of age. METHODS: The clinical database was searched for patients with native kidney biopsies from 9/2011 to 8/2017, and cases with a diagnosis of PGNMID were retrieved. Light microscopy specimens and immunofluorescence and electron microscopy images were revisited. Clinical data and kidney biopsy findings for patients under the age of 20 were recorded. RESULTS: Five (0.78%) of a total of 637 patients younger than 20 with native renal biopsies had a diagnosis of PGNMID, including three males and two females with an average age of 14 years old (range 10-19). All five patients presented with microscopic hematuria and proteinuria. Three patients were nephrotic and their C3 levels were low. All five cases showed a membranoproliferative pattern with abundant mesangial and subendothelial monoclonal IgG3 deposits (3 kappa and 2 lambda light chain, respectively). The patients were followed up to 56 months. Two patients had re biopsies 28 and 18 months after initial diagnosis and both showed similar morphologic changes. Various treatments were attempted including prednisone, mycophenolate mofetil, tacrolimus, rituximab, and eculizmab, with mixed responses. CONCLUSIONS: PGNMID does occur in children and young adults. Membranoproliferative glomerulonephritis pattern with monoclonal IgG3 deposits is a common feature. Despite various immunosuppressive treatments, the disease appears slowly progressive. PMID- 29616330 TI - Colorectal Cancer in the Young. AB - PURPOSE OF REVIEW: Colorectal cancer incidence has been rapidly rising in those under the age of 50 over the last 20 years. This paper will review the epidemiology, clinicopathologic, molecular features, proposed risk factors, and prevention/treatment approach for early onset CRC (EOCRC) patients. RECENT FINDINGS: EOCRC appears to have a different spectrum of clinical, pathologic, and molecular presentation compared to CRC diagnosed in older individuals. EOCRCs are disproportionately located in the distal colon; these patients tend to present with symptoms, and there is a longer interval between symptoms and diagnosis. There may be a distinct molecular signature, including progression through the microsatellite and chromosomal stable (MACS) pathway and LINE-1 hypomethylation for a subset of EOCRCs. The majority of EOCRCs are sporadic without clear risk factors that would have made the patient eligible for earlier screening. There is an acute need for educational efforts aimed at both providers and patients to raise awareness about CRC in the young. Improving adherence to screening in young patients eligible for screening and emphasizing early evaluation of symptoms are important steps to decreasing the burden of CRC in younger patients. Modeling and empiric data are needed to determine whether our current screening approach should be modified and whether causation and treatment options may be different in a molecular subset EOCRCs. PMID- 29616331 TI - A proposed treatment algorithm for mild to moderate ulcerative colitis-with an emphasis on budesonide foam and mucosal healing. PMID- 29616332 TI - Author's reply: can budesonide form be alterative treatment for ulcerative proctosigmoiditis? PMID- 29616333 TI - Production of ethanol and xylitol by Trametes membranacea. AB - The potential to produce ethanol and xylitol from xylose by the macro basidiomycete Trametes membranacea was evaluated. All strains studied showed ethanol and xylitol production. The highest ethanol production of xylose was obtained by T. membranacea strain TM158/10 with 5.65 +/- 0.21 g/L at pH 4 and 28 degrees C with 288 h of fermentation and 5.59 +/- 0.05 g/L ethanol concentration at pH 5 and 24 degrees C with 360 h of fermentation. When the conversion was carried out using sugars generated from enzymatic hydrolysis of sugarcane bagasse, there were higher yields from 74 to 15% for ethanol and xylitol, respectively. Although the ethanol and xylitol production need to be optimized, this study showed for the first time the possibility of using T. membranacea for the simultaneous xylitol and ethanol production from pentose sugars, allowing for the possibility of using all released sugars during the hydrolysis of lignocelluloses. PMID- 29616334 TI - Effectiveness of self-help psychological interventions for treating and preventing postpartum depression: a meta-analysis. AB - Previous studies have reported different effect sizes for self-help interventions designed to reduce postpartum depression symptoms; therefore, a comprehensive quantitative review of the research was required. A meta-analysis was conducted to examine the effectiveness of self-help interventions designed to treat and prevent postpartum depression, and identified nine relevant randomized controlled trials. Differences in depressive symptoms between self-help interventions and control conditions, changes in depressive symptoms following self-help interventions, and differences in postintervention recovery and improvement rates between self-help interventions and control conditions were assessed in separate analyses. In treatment trials, depression scores continued to decrease from baseline to posttreatment and follow-up assessment in treatment subgroups. Changes in treatment subgroups' depression scores from baseline to postintervention assessment were greater relative to those observed in prevention subgroups. Self-help interventions produced larger overall effects on postpartum depression, relative to those observed in control conditions, in posttreatment (Hedges' g = 0.51) and follow-up (Hedges' g = 0.32) assessments; and self-help interventions were significantly more effective, relative to control conditions, in promoting recovery from postpartum depression. Effectiveness in preventing depression did not differ significantly between self-help interventions and control conditions.The findings suggested that self-help interventions designed to treat postpartum depression reduced levels of depressive symptoms effectively and decreased the risk of postpartum depression. PMID- 29616335 TI - Behavioral mechanisms underlying the maternal disruptive effect of serotonin 5 HT2A receptor activation in Sprague-Dawley rats. AB - Recent evidence indicates that acute activation of 5-HT2A receptors causes a disruption of maternal behavior in rats. However, the behavioral mechanisms underlying such a disruption are not known. We addressed this issue using two behavioral approaches targeting the maternal motivational and emotional processing systems. First, we used the pup-separation technique to increase maternal motivation to see whether pup separation is capable of reducing the maternal disruptive effect of TCB-2 (a high-affinity 5-HT2A agonist) treatment. On postpartum days 4 and 6, different groups of Sprague-Dawley dams were treated with the TCB-2 (5.0 mg/kg, sc) or vehicle and their maternal behaviors were tested after either a 4-h pup-separation or no-pup-separation condition. Although acute TCB-2 injection disrupted maternal behavior, this disruption was not attenuated by pup separation, even after we optimized the timing of separation to maximize its increase on maternal motivation. Acute TCB-2 also impaired the retrieval of food pellets, suggesting a general effect on motivated behaviors. Next, we used a pup preference test and found that dams treated with TCB-2 exhibited an even stronger preference to pups over a male conspecific than vehicle-treated dams, indicating an enhanced motivational and emotional processing of the rewarding property of pups. These findings suggest that TCB-2 has a disruptive effect on rat maternal behavior, and this disruption is not likely due to the drug's effect on mothers' motivational and emotional processing of the incentive salience of pups, although this motivational suppression account cannot be completely ruled out. Future work could explore other possible behavioral mechanisms, such as the drug's effect on executive function. PMID- 29616336 TI - Chubby hands or little fingers: sex differences in hand representation. AB - Disturbed body representation is a condition defined by the perception that one's body size is different from their anatomical size. While equal amounts of males and females suffer from disturbed body representation, there appear to be differences in the direction of this distortion. Females will typically overestimate, whereas males will typically underestimate body size. One part of the body that has been consistently misperceived is the hands. This misrepresentation consists of two distinct characteristics: an overestimation of hand width, and an underestimation of finger length. Many of these studies, however, have used predominately female participants, allowing for the possibility that women are driving this distortion. The aim of the present study was to examine possible sex differences in hand perception. To this end, participants estimated the location of ten landmarks on their hands when their hands were hidden from view. Our results indicate that females follow the characteristic distortion, whereas males only underestimate finger length (albeit more than females). These findings are surprising, because the hands are not an area of concern for weight gain/loss. We discuss these findings in relation to body dysmorphia literature. PMID- 29616337 TI - The effects of attentional focus in the preparation and execution of a standing long jump. AB - Attentional focus research suggests an external focus leads to improved motor performance compared to an internal focus (Wulf in Int Rev Sport Exerc Psychol 6:77-104, 2013), but skilled athletes often report using an internal focus (Fairbrother et al., Front Psychol 7:1028, 2016) and sometimes shifting between different foci in the preparation and execution phases of performance (Bernier et al. in J Appl Sport Psychol 23:326-341, 2011; Bernier et al. in Sport Psychol 30:256-266, 2016). To date, focus shifts have been unexplored in experimental research, thus the purpose of this study was to determine the effect of shifting focus between the preparation and execution phases of a standing long jump. Participants (N = 29) completed two jumps in a control condition (CON), followed by two jumps in four experimental conditions presented in a counterbalanced order. Conditions included using an external focus (EF) and internal focus (IF) in both preparation and execution of the skill, as well as shifting from an internal focus in preparation to an external focus in execution (ITE), and an external focus in preparation to an internal focus in execution (ETI). Jump distance was analyzed with a repeated measures ANOVA. The main effect of condition was significant, p < .001, with EF producing longer jumps than all other conditions (p's < 0.05). ITE also generated farther jumps than IF and CON (p's < 0.05). The superiority of the EF and ITE conditions suggests that the focus employed in execution has the strongest impact on performance. Additionally, if an internal focus must be used in preparation, the performance decrement can be ameliorated by shifting to an external focus during execution. PMID- 29616338 TI - The problem of water body status misclassification-a Hierarchical Approach. AB - This article addresses the issue of estimating probability of misclassification (PoM), when assessing the status of a water body (w.b.). The standard deviation of a monitoring data is considered a good measure of the uncertainty of the assessed w.b. status. However, when PoM is to be estimated from the biological data, a problem caused by too few monitoring data emerges. The problem is overcome by developing Monte-Carlo models to simulate sufficient synthetic measurements of these elements, thereby accounting for random "disturbances" in the measurements. At each level of a procedure, called the Hierarchical Approach, values of PoM were derived from the Monte-Carlo-simulated data as for the assessment of w.b. status. It is assumed in the Hierarchical Approach that PoMs on each upper level can be estimated by processing PoMs inherited from the lower levels. Data from the river monitoring systems in three Polish regions were used in the study. Values of PoM calculated for biological elements show that 70-80% of cases belong to < 0.0, 0.1 > interval, whereas PoMs for physico-chemical elements in only 20% belong in this interval whereas for 25-40% of cases, PoMs are greater than 0.5. Moreover, when analyzing PoMs for cases when the w.b. status was classified as good, 22-52% of them are characterized by 0.5 or higher probability to be assessed wrongly. These pessimistic results suggest the need for formulation of new directions for future research in determining the PoM (in general, the uncertainty) of the w.b. status estimated from monitoring data. PMID- 29616339 TI - Major hepatectomy for primary hepatolithiasis: a comparative study of laparoscopic versus open treatment. AB - BACKGROUND: Due to higher technical requirements, laparoscopic major hepatectomy (LMH) for primary hepatolithiasis have been limited to a few institutions. This retrospective study was performed to evaluate the therapeutic safety, and perioperative and long-term outcomes of LMH versus open major hepatectomy (OMH) for hepatolithiasis. METHODS: From January 2012 to December 2016, 61 patients with hepatolithiasis who underwent major hepatectomy were enrolled, including 29 LMH and 32 OMH. The perioperative outcomes and postoperative complications, as well as long-term outcomes, including the stone clearance and recurrence rate, were evaluated. RESULTS: There was no difference of surgical procedures between the two groups. The mean operation time was (262 +/- 83) min in the LMH group and (214 +/- 66) min in the OMH group (p = 0.05). There is no difference of intra operative bleeding (310 +/- 233) ml versus (421 +/- 359) ml (p = 0.05). In the LMH group, there were shorter time to postoperative oral intake ((1.1 +/- 0.6) days versus (3.1 +/- 1.8) days, p = 0.01) and shorter hospital stay [(7.2 +/- 2.3) days versus (11.8 +/- 5.5) days, p = 0.03] than the open group. The LMH group had comparable stone clearance rate with the OMH group during the initial surgery (82.8% vs. 84.4%, p = 0.86). CONCLUSIONS: LMH could be an effective and safe treatment for selected patients with hepatolithiasis, with an advantage over OMH in the field of less intra-operative blood loss, less intra-operative transfusion, less overall complications, and faster postoperative recovery. PMID- 29616340 TI - Dopamine and Wakefulness: Pharmacology, Genetics, and Circuitry. AB - Over the period of decades in the mid to late twentieth century, arousal promoting functions were attributed to neuromodulators including serotonin, hypocretin, histamine, and noradrenaline. For some time, a relatively minor role in regulating sleep and wake states was ascribed to dopamine and the dopamine producing cells of the ventral tegmental area, despite the fact that dopaminergic signaling is a major target, if not the primary target, for wake-promoting agents. In recent years, due to observations from human genetic studies, pharmacogenetic studies in animal models, and the increasingly sophisticated methods used to manipulate the nervous systems of experimental animals, it has become clear that dopaminergic signaling is central to the regulation of arousal. This chapter reviews this central role of dopaminergic signaling, and in particular its antagonistic interaction with adenosinergic signaling, in maintaining vigilance and in the response to wake-promoting therapeutics. PMID- 29616341 TI - Privacy-Preserving Hypothesis Testing for Reduced Cancer Risk on Daily Physical Activity. AB - Privacy preserving data mining for medical information is an important issue to guarantee confidentiality of integrated multiple data sets. In this paper, we propose a secured scheme to estimate related risk of cancers accurately and effectively in a privacy-preserving way. We study models to configure the appropriate set of attributes to reduce risk of identity of an individual from being determined. We examine the proposed privacy preserving protocol for encrypted hypothesis test, using actual cohort data supplied by National Cancer Center. PMID- 29616342 TI - Evaluation of metal removal efficiency and its influence in the physicochemical parameters at two sewage treatment plants. AB - In sewage treatment plants, physicochemical parameters are highly controlled since treated sewage can be returned to water bodies or reused. In addition, pollutants such as heavy metals also deserve attention due to their potential toxicity. In general, these characteristics of sewage and treated water are evaluated independently, with the support of Brazilian legislation that does not require a routine for the analysis of metals as frequent as for the physicochemical parameters. In this work, 66 samples of raw sewage, treated sewage, and effluents from two treatment plants in the city of Bauru, Sao Paulo, Brazil, were evaluated to assess the efficiency of the treatment plants in the removal of metals. In addition, the influence of these pollutants on the quantification of physicochemical parameters was evaluated. The quantification of metals was performed using inductively coupled plasma optical spectroscopy (ICP OES), and Spearman's test was applied to evaluate correlation between physicochemical parameters and metal content. The main metals found in the samples were Ba, Mn, Zn, Cu, Se, Fe, and Al. The results indicate that concentrations of metals in the aquatic environment can significantly affect the physicochemical parameters, since high concentrations of metals can interfere mainly in the pH, chemical oxygen demand, and dissolved oxygen. PMID- 29616343 TI - New Imaging Markers for Movement Disorders. AB - PURPOSE OF REVIEW: For decades, identifying in vivo imaging biomarkers to accurately differentiate between various movement disorders as well as to understand their underlying pathophysiological abnormalities has been the aim of scientific work. Recent advances in multimodal imaging enable the visualization of structural and functional brain changes in these pathological conditions, thus raising the value of imaging techniques as powerful tools to improve sensitivity and specificity of clinical diagnoses. This article reviews well-established and recent developments in imaging markers for movement disorders. RECENT FINDINGS: Whereas several imaging approaches seem to be promising, many modalities are still under development and may not provide decisive answers. Thus, the use of combined imaging modalities as well as the acquisition of methodological consensus in the scientific community may provide more conclusive findings in the future of biomarkers. Although a single biomarker has yet not been identified, multiple markers derived from different imaging modalities may represent the right approach. PMID- 29616346 TI - In reply: Why remifentanil? PMID- 29616345 TI - Accuracy and trending ability of the fourth-generation FloTrac/Vigileo SystemTM in patients undergoing abdominal aortic aneurysm surgery. AB - PURPOSE: The fourth-generation FloTrac/VigileoTM improved its algorithm to follow changes in systemic vascular resistance index (SVRI). This revision may improve the accuracy and trending ability of CI even in patients who undergo abdominal aortic aneurysm (AAA) surgery which cause drastic change of SVRI by aortic clamping. The purpose of this study is to elucidate the accuracy and trending ability of the fourth-generation FloTrac/VigileoTM in patients with AAA surgery by comparing the FloTrac/VigileoTM-derived CI (CIFT) with that measured by three dimensional echocardiography (CI3D). METHODS: Twenty-six patients undergoing elective AAA surgery were included in this study. CIFT and CI3D were determined simultaneously in eight points including before and after aortic clamp. We used CI3D as the reference method. RESULTS: In the Bland-Altman analysis, CIFT had a wide limit of agreement with CI3D showing a percentage error of 46.7%. Subgroup analysis showed that the percentage error between CO3D and COFT was 56.3% in patients with cardiac index < 2.5 L/min/m2 and 28.4% in patients with cardiac index >= 2.5 L/min/m2. SVRI was significantly higher in patients with cardiac index < 2.5 L/min/m2 (1703 +/- 330 vs. 2757 +/- 798; p < 0.001). The tracking ability of fourth generation of FloTrac/VigileoTM after aortic clamp was not clinically acceptable (26.9%). CONCLUSIONS: The degree of accuracy of the fourth generation FloTrac/VigileoTM in patients with AAA surgery was not acceptable. The tracking ability of the fourth-generation FloTrac/VigileoTM after aortic clamp was below the acceptable limit. PMID- 29616344 TI - Novel Pharmacological Nonopioid Therapies in Chronic Pain. AB - PURPOSE OF REVIEW: Opioid use and abuse has led to a worldwide opioid epidemic. And while opioids are clinically useful when appropriately indicated, they are associated with a wide range of dangerous side effects and whether they are effective at treating or eliminating chronic pain is controversial. There has long been a need for the development of nonopioid alternative treatments for patients that live in pain, and until recently, only a few effective treatments were available. Today, there are a wide range of nonopioid treatments available including NSAIDs, acetaminophen, corticosteroids, nerve blocks, SSRIs, neurostimulators, and anticonvulsants. However, these treatments are still not entirely effective at treating pain, which has sparked a new exploration of novel nonopioid pharmacotherapies. RECENT FINDINGS: This manuscript will outline the most recent trends in novel nonopioid pharmacotherapy development including tramadol/dexketoprofen, TrkA inhibitors, tapentadol, opioid agonists, Nektar 181, TRV 130, betaarrestin2, bisphosphonates, antibodies, sodium channel blockers, NMDA antagonists, TRP receptors, transdermal vitamin D, AAK1 kinase inhibition, calcitonin gene-related peptide (CGRP), TRPV4 antagonists, cholecystokinin, delta opioid receptor, neurokinin, and gene therapy. The pharmacotherapies discussed in this manuscript outline promising opioid alternatives which can change the future of chronic pain treatment. PMID- 29616347 TI - Early nodule senescence is activated in symbiotic mutants of pea (Pisum sativum L.) forming ineffective nodules blocked at different nodule developmental stages. AB - Plant symbiotic mutants are useful tool to uncover the molecular-genetic mechanisms of nodule senescence. The pea (Pisum sativum L.) mutants SGEFix--1 (sym40), SGEFix--3 (sym26), and SGEFix--7 (sym27) display an early nodule senescence phenotype, whereas the mutant SGEFix--2 (sym33) does not show premature degradation of symbiotic structures, but its nodules show an enhanced immune response. The nodules of these mutants were compared with each other and with those of the wild-type SGE line using seven marker genes that are known to be activated during nodule senescence. In wild-type SGE nodules, transcript levels of all of the senescence-associated genes were highest at 6 weeks after inoculation (WAI). The senescence-associated genes showed higher transcript abundance in mutant nodules than in wild-type nodules at 2 WAI and attained maximum levels in the mutant nodules at 4 WAI. Immunolocalization analyses showed that the ethylene precursor 1-aminocyclopropane-1-carboxylate accumulated earlier in the mutant nodules than in wild-type nodules. Together, these results showed that nodule senescence was activated in ineffective nodules blocked at different developmental stages in pea lines that harbor mutations in four symbiotic genes. PMID- 29616348 TI - Amperometric determination of L-cysteine using a glassy carbon electrode modified with palladium nanoparticles grown on reduced graphene oxide in a Nafion matrix. AB - An amperometric sensor for L-Cys is described which consists of a glassy carbon electrode (GCE) that was modified with reduced graphene oxide placed in a Nafion film and decorated with palladium nanoparticles (PdNPs). The film was synthesized by a hydrothermal method. The PdNPs have an average diameter of about 10 nm and a spherical shape. The modified GCE gives a linear electro-oxidative response to L Cys (typically at +0.6 V vs. SCE) within the 0.5 to 10 MUM concentration range. Other figures of merit include a response time of less than 2 s, a 0.15 MUM lower detection limit (at signal to noise ratio of 3), and an analytical sensitivity of 1.30 MUA.MUM-1.cm-2. The sensor displays selectivity over ascorbic acid, uric acid, dopamine, hydrogen peroxide, urea, and glucose. The modified GCE was applied to the determination of L-Cys in human urine samples and gave excellent recoveries. Graphical abstract Spherical palladium nanoparticles (PdNPs) on reduced graphene oxide-Nafion (rGO-Nf) films were synthesized using a hydrothermal method. This nanohybrid was used for modifying a glassy carbon electrode to develop a sensor electrode for detecting L-cysteine that has fast response (less than 2 s), low detection limit (0.15 MUM), and good sensitivity (0.092 MUA MUM-1 cm-2). PMID- 29616349 TI - In vitro and in vivo effects of chitosan-praziquantel and chitosan-albendazole nanoparticles on Echinococcus granulosus Metacestodes. AB - Cystic echinococcosis (CE), which is caused by the metacestode of Echinococcus granulosus, is one of the most important zoonoses affecting humans. Benzimidazoles (in particular albendazole) and praziquantel (PZQ) are effective against CE, but poor water solubility of these agents often leads to inadequate results. Here, we evaluate the effects of chitosan-albendazole (ChABZ) and chitosan-praziquantel (ChPZQ) nanoparticles as a new formulation on hydatid cysts both in vitro and in vivo. Developed microcysts in culture were treated with different concentrations of ChABZ and ChPZQ nanoparticles (either alone or in combination), and ABZ + PZQ suspension. The viability rate of microcysts was used to evaluate the drug efficacies. In addition, the prophylactic and therapeutic effects of the drugs were studied on infected DBA/2 mice. Transmission electron microscopy was used to observe the ultra-structural changes. The viability rate of microcysts and differences in cyst weights were compared by ANOVA, and the cyst numbers were compared using the Kruskal-Wallis test. The combination of ChABZ + ChPZQ nanoparticles was more effective than the ABZ + PZQ suspension in vitro (p < 0.05). In prophylaxy, a significant reduction was observed both in size and in number of the cysts in ChABZ + ChPZQ nanoparticle groups compared with the control group (p < 0.05). In the therapeutic stage, however, this treatment only reduced the cyst numbers. Degeneration of the microcysts treated with the drugs was evident in the ultra-structural imaging. Overall, the nanoparticulate drugs were more effective than their suspension counterparts, but further studies are recommended to evaluate the full potential of these nanoparticles in the treatment of human CE. PMID- 29616352 TI - eFAST for the diagnosis of a perioperative complication during percutaneous nephrolithotomy. AB - A 29-year-old patient with normal preanesthetic evaluation was planned for percutaneous nephrolithotomy (PCNL) for right nephrolithiasis with right pyelolithiasis. Surgery was performed under general anesthesia with endotracheal intubation with muscle relaxation. At the conclusion of surgery, when the patient was turned over to supine position, tense abdomen was noted. Immediately extended focused assessment with sonography in trauma (eFAST) was done in which both right and left quadrants of abdomen including pericardial and suprapubic region, right and left thoracic, and both lung basis were examined. Fluid collection was seen in Morison's pouch which was drained by the urologist under real-time ultrasonography guidance by anesthesiologist. Distension of abdomen subsequently subsided and patient had normal vitals. Trachea was extubated and patient shifted to post-operative ward. eFAST and FAST scans are routine procedures in the rapid assessment of trauma victims in emergency settings. The fluid extravasation during a routine PCNL procedure may lead to abdominal compartment syndrome. This case demonstrated that use of eFAST rapidly detected abdominal collection and ruled out life-threatening conditions such as hemothorax and pneumothorax and prevented abdominal compartment syndrome. Our case is only an example that potentially lethal conditions like these may be encountered in the perioperative setting and the knowledge of eFAST scan may be of great help. PMID- 29616351 TI - Superciliums in white-eared hummingbirds as badges of status signaling dominance. AB - The role of badges as indicators of contest ability has been previously described. In hummingbirds, the exhibition of a badge is expected to save energy expenditure in agonistic interactions and to favor energy intake. Here, we investigate whether variable supercilium size in the white-eared hummingbird has a role in dominance status signaling. Firstly, 45 hummingbird males were captured and their superciliums were photographed to investigate variation in size and any possible allometric relationships. Secondly, 42 male birds were used to analyze whether the supercilium has a role in dominance status signaling in a dyadic contest. We found that supercilium size varied continuously but that despite variability between individuals, there was no relationship between supercilium size and body size. However, our dyad experiment indicated that birds with larger badges were able to make more visits to the feeders than individuals with smaller badges. We suggest a status signaling function of the supercilium. PMID- 29616350 TI - Mitochondrial Dysfunction in Parkinson's Disease: New Mechanistic Insights and Therapeutic Perspectives. AB - PURPOSE OF REVIEW: Parkinson's disease (PD) is a complex neurodegenerative disorder, the aetiology of which is still largely unknown. Overwhelming evidence indicates that mitochondrial dysfunction is a central factor in PD pathophysiology. Here we review recent developments around mitochondrial dysfunction in familial and sporadic PD, with a brief overview of emerging therapies targeting mitochondrial dysfunction. RECENT FINDINGS: Increasing evidence supports the critical role for mitochondrial dysfunction in the development of sporadic PD, while the involvement of familial PD-related genes in the regulation of mitochondrial biology has been expanded by the discovery of new mitochondria-associated disease loci and the identification of their novel functions. Recent research has expanded knowledge on the mechanistic details underlying mitochondrial dysfunction in PD, with the discovery of new therapeutic targets providing invaluable insights into the essential role of mitochondria in PD pathogenesis and unique opportunities for drug development. PMID- 29616353 TI - High-Performance Self-Powered UV Detector Based on SnO2-TiO2 Nanomace Arrays. AB - Photoelectrochemical cell-typed self-powered UV detectors have attracted intensive research interest due to their low cost, simple fabrication process, and fast response. In this paper, SnO2-TiO2 nanomace arrays composed of SnO2 nanotube trunk and TiO2 nanobranches were prepared using soft chemical methods, and an environment-friendly self-powered UV photodetector using this nanostructure as the photoanode was assembled. Due to the synergistic effect of greatly accelerated electron-hole separation, enhanced surface area, and reduced charge recombination provided by SnO2-TiO2 nanomace array, the nanostructured detector displays an excellent performance over that based on bare SnO2 arrays. The impact of the growing time of TiO2 branches on the performance of UV photodetector was systematically studied. The device based on optimized SnO2-TiO2 nanomace arrays exhibits a high responsivity of 0.145 A/W at 365 nm, a fast rising time of 0.037 s, and a decay time of 0.015 s, as well as excellent spectral selectivity. This self-powered photodetector is a promising candidate for high-sensitivity, high-speed UV-detecting application. PMID- 29616354 TI - A Facile Method for Loading CeO2 Nanoparticles on Anodic TiO2 Nanotube Arrays. AB - In this paper, a facile method was proposed to load CeO2 nanoparticles (NPs) on anodic TiO2 nanotube (NT) arrays, which leads to a formation of CeO2/TiO2 heterojunctions. Highly ordered anatase phase TiO2 NT arrays were fabricated by using anodic oxidation method, then these individual TiO2 NTs were used as tiny "nano-containers" to load a small amount of Ce(NO3)3 solutions. The loaded anodic TiO2 NTs were baked and heated to a high temperature of 450 degrees C, under which the Ce(NO3)3 would be thermally decomposed inside those nano-containers. After the thermal decomposition of Ce(NO3)3, cubic crystal CeO2 NPs were obtained and successfully loaded into the anodic TiO2 NT arrays. The prepared CeO2/TiO2 heterojunction structures were characterized by a variety of analytical technologies, including XRD, SEM, and Raman spectra. This study provides a facile approach to prepare CeO2/TiO2 films, which could be very useful for environmental and energy-related areas. PMID- 29616355 TI - Vertical structure of the velocity field induced by mode-I and mode-II solitary waves in a stratified fluid. AB - The structure of the velocity field induced by internal solitary waves of the first and second modes is determined. The contribution from second-order terms in asymptotic expansion into the horizontal velocity is estimated for the models of almost two- and three-layer fluid for solitons of positive and negative polarity. The influence of the nonlinear correction manifests itself firstly in the shape of the lines of zero horizontal velocity: they are curved and the shape depends on the soliton amplitude and polarity, while for the leading-order wave field they are horizontal. Also the wave field accounting for the nonlinear correction for mode I has smaller maximal absolute values of negative velocities (near surface for the soliton of elevation, and near-bottom for the soliton of depression) and larger maximums of positive velocities. For solitary waves of negative polarity, which are the most typical for hydrological conditions in the ocean for low and middle latitudes, the situation is the opposite. The velocity field of the mode-II soliton in a smoothed two-layer fluid reaches its maximal absolute values in a middle layer instead of near-bottom and near-surface maximums for mode-I solitons. PMID- 29616356 TI - Evaluation of risk factors and assessment models for predicting venous thromboembolism in lung cancer patients. AB - The aim of the study was to investigate the prognostic significance of selected risk assessment models (RAMs) for predicting venous thromboembolism (VTE) events in patients undergoing outpatient chemotherapy for lung cancer. We evaluated the following VTE-risk assessment tools: Khorana risk score (KRS), PROTECHT score, CONKO score and COMPASS-cancer-associated thrombosis score (COMPASS-CAT). Retrospective analyses were performed on 118 patients with lung cancer, 20 of whom developed VTE with a median of 2.5 months from diagnosis. Patients receiving gemcitabine-based regimen (25%), patients with a history of atrial fibrillation (AF) and patients with chronic kidney disease developed VTE more often than other patients. In the multivariate analysis, high COMPASS-CAT score (OR 8.73; 95% CI 1.01-75.22, P = 0.049), gemcitabine chemotherapy (OR 3.37; 95% CI 1.09-10.39, P = 0.035) and AF (OR 7.19; 95% CI 1.89-27.33, P = 0.004) were all significantly associated with VTE development. VTE occurred in; 13% (n = 2) of the KRS high risk group, 17.7% (n = 11) of the PROTECHT high-risk group, 15% (n = 4) of the CONKO high-risk group and 23.8% (n = 20) of the COMPASS-CAT high-risk group (n = 84). Only the COMPASS-CAT score was able to identify 100% of patients who developed VTE, and best discriminated between patients with high and low risk of VTE development (C statistic 0.89). The ROC analysis indicated a cutoff value of 11 points (95% CI 0.821-0.962) for COMPASS-CAT for VTE development in patients with lung cancer. In conclusion, in our study of all the VTE-RAMs analyzed, the COMPASS-CAT model was the most accurate predictor of VTE development in patients with lung cancer. PMID- 29616357 TI - Preliminary experience on the safety and tolerability of mechanical "insufflation exsufflation" in subjects with artificial airway. AB - BACKGROUND: Catheter suctioning of respiratory secretions in intubated subjects is limited to the proximal airway and associated with traumatic lesions to the mucosa and poor tolerance. "Mechanical insufflation-exsufflation" exerts positive pressure, followed by an abrupt drop to negative pressure. Potential advantages of this technique are aspiration of distal airway secretions, avoiding trauma, and improving tolerance. METHODS: We applied insufflation of 50 cmH2O for 3 s and exsufflation of - 45 cmH2O for 4 s in patients with an endotracheal tube or tracheostomy cannula requiring secretion suctioning. Cycles of 10 to 12 insufflations-exsufflations were performed and repeated if secretions were aspirated and visible in the proximal artificial airway. Clinical and laboratory parameters were collected before and 5 and 60 min after the procedure. Subjects were followed during their ICU stay until discharge or death. RESULTS: Mechanical insufflation-exsufflation was applied 26 times to 7 male and 6 female subjects requiring suctioning. Mean age was 62.6 +/- 20 years and mean Apache II score 23.3 +/- 7.4 points. At each session, a median of 2 (IQR 1; 2) cycles on median day of intubation 11.5 (IQR 6.25; 25.75) were performed. Mean insufflation tidal volume was 1043.6 +/- 649.9 ml. No statistically significant differences were identified between baseline and post-procedure time points. Barotrauma, desaturation, atelectasis, hemoptysis, or other airway complication and hemodynamic complications were not detected. All, except one, of the mechanical insufflation-exsufflation sessions were productive, showing secretions in the proximal artificial airway, and were well tolerated. CONCLUSIONS: Our preliminary data suggest that mechanical insufflation-exsufflation may be safe and effective in patients with artificial airway. Safety and efficacy need to be confirmed in larger studies with different patient populations. TRIAL REGISTRATION: EudraCT 2017-005201-13 (EU Clinical Trials Register). PMID- 29616358 TI - Morphology, taxonomy and mating-type loci in natural populations of Volvox carteri in Taiwan. AB - BACKGROUND: Volvox carteri f. nagariensis is a model taxon that has been studied extensively at the cellular and molecular level. The most distinctive morphological attribute of V. carteri f. nagariensis within V. carteri is the production of sexual male spheroids with only a 1:1 ratio of somatic cells to sperm packets or androgonidia (sperm packet initials). However, the morphology of male spheroids of V. carteri f. nagariensis has been examined only in Japanese strains. In addition, V. carteri f. nagariensis has heterothallic sexuality; male and female sexes are determined by the sex-determining chromosomal region or mating-type locus composed of a > 1 Mbp linear chromosome. Fifteen sex-specific genes and many sex-based divergent shared genes (gametologs) are present within this region. Thus far, such genes have not been identified in natural populations of this species. RESULTS: During a recent fieldwork in Taiwan, we encountered natural populations of V. carteri that had not previously been recorded from Taiwan. In total, 33 strains of this species were established from water samples collected in Northern Taiwan. Based on sequences of the internal transcribed spacer 2 region of nuclear ribosomal DNA and the presence of asexual spheroids with up to 16 gonidia, the species was clearly identified as V. carteri f. nagariensis. However, the sexual male spheroids of the Taiwanese strains generally exhibited a 1:1 to > 50:1 ratio of somatic cells to androgonidia. We also investigated the presence or absence of several sex-specific genes and the sex-based divergent genes MAT3m, MAT3f and LEU1Sm. We did not identify recombination or deletion of such genes between the male and female mating-type locus haplotypes in 32 of the 33 strains. In one putative female strain, the female-specific gene HMG1f was not amplified by genomic polymerase chain reaction. When sexually induced, apparently normal female sexual spheroids developed in this strain. CONCLUSIONS: Male spheroids are actually variable within V. carteri f. nagariensis. Therefore, the minimum ratio of somatic cells to androgonidia in male spheroids and the maximum number of gonidia in asexual spheroids may be diagnostic for V. carteri f. nagariensis. HMG1f may not be directly related to the formation of female spheroids in this taxon. PMID- 29616359 TI - Liver abscess due to Fusobacterium species detected on ultrasonography: a case report. AB - An oral infection harboring Fusobacterium species can gain entrance to the liver via hematogenous spread in the form of septic embolus, and can thereby cause abscesses. Such spread, described as Lemierre syndrome, is life threatening. We present such a case history of a man in his mid-40s, who presented with infection and Fusobacterium liver abscess with an acute fulminant disease course. The initial diagnosis was arrived at by ultrasound imaging and blood investigations. He was treated with antibiotics, ultrasound-guided liver abscess drainage, and extraction of the infected molar tooth. He was discharged 6 weeks after admission. To date, there have been no reports describing the ultrasound images of a Fusobacterium liver abscess in detail. Hence, we herein present the ultrasound images of a Fusobacterium liver abscess. PMID- 29616360 TI - Novel Anodic Catalyst Support for Direct Methanol Fuel Cell: Characterizations and Single-Cell Performances. AB - This study introduces a novel titanium dioxide carbon nanofiber (TiO2-CNF) support for anodic catalyst in direct methanol fuel cell. The catalytic synthesis process involves several methods, namely the sol-gel, electrospinning, and deposition methods. The synthesized electrocatalyst is compared with other three electrocatalysts with different types of support. All of these electrocatalysts differ based on a number of physical and electrochemical characteristics. Experimental results show that the TiO2-CNF support gave the highest current density at 345.64 mA mgcatalyst-1, which is equivalent to 5.54-fold that of carbon support while the power density is almost double that of the commercial electrocatalyst. PMID- 29616361 TI - Fabrication of 20.19% Efficient Single-Crystalline Silicon Solar Cell with Inverted Pyramid Microstructure. AB - This paper reports inverted pyramid microstructure-based single-crystalline silicon (sc-Si) solar cell with a conversion efficiency up to 20.19% in standard size of 156.75 * 156.75 mm2. The inverted pyramid microstructures were fabricated jointly by metal-assisted chemical etching process (MACE) with ultra-low concentration of silver ions and optimized alkaline anisotropic texturing process. And the inverted pyramid sizes were controlled by changing the parameters in both MACE and alkaline anisotropic texturing. Regarding passivation efficiency, the textured sc-Si with normal reflectivity of 9.2% and inverted pyramid size of 1 MUm was used to fabricate solar cells. The best batch of solar cells showed a 0.19% higher of conversion efficiency and a 0.22 mA cm-2 improvement in short-circuit current density, and the excellent photoelectric property surpasses that of the same structure solar cell reported before. This technology shows great potential to be an alternative for large-scale production of high efficient sc-Si solar cells in the future. PMID- 29616362 TI - Association between ALDH2 and ADH1B polymorphisms, alcohol drinking and gastric cancer: a replication and mediation analysis. AB - BACKGROUND: Aldehyde dehydrogenase 2 (ALDH2; rs671, Glu504Lys) and alcohol dehydrogenase 1B (ADH1B; rs1229984, His47Arg) polymorphisms have a strong impact on carcinogenic acetaldehyde accumulation after alcohol drinking. To date, however, evidence for a significant ALDH2-alcohol drinking interaction and a mediation effect of ALDH2/ADH1B through alcohol drinking on gastric cancer have remained unclear. We conducted two case-control studies to validate the interaction and to estimate the mediation effect on gastric cancer. METHODS: We calculated odds ratios (OR) and 95% confidence intervals (CI) for ALDH2/ADH1B genotypes and alcohol drinking using conditional logistic regression models after adjustment for potential confounding in the HERPACC-2 (697 cases and 1372 controls) and HERPACC-3 studies (678 cases and 678 controls). We also conducted a mediation analysis of the combination of the two studies to assess whether the effects of these polymorphisms operated through alcohol drinking or through other pathways. RESULTS: ALDH2 Lys alleles had a higher risk with increased alcohol consumption compared with ALDH2 Glu/Glu (OR for heavy drinking, 3.57; 95% CI 2.04 6.27; P for trend = 0.007), indicating a significant ALDH2-alcohol drinking interaction (Pinteraction = 0.024). The mediation analysis indicated a significant positive direct effect (OR 1.67; 95% CI 1.38-2.03) and a protective indirect effect (OR 0.84; 95% CI 0.76-0.92) of the ALDH2 Lys alleles with the ALDH2-alcohol drinking interaction. No significant association of ADH1B with gastric cancer was observed. CONCLUSION: The observed ALDH2-alcohol drinking interaction and the direct effect of ALDH2 Lys alleles may suggest the involvement of acetaldehyde in the development of gastric cancer. PMID- 29616363 TI - A Comparative In Vivo Scrutiny of Biosynthesized Copper and Zinc Oxide Nanoparticles by Intraperitoneal and Intravenous Administration Routes in Rats. AB - During the present time, anti-microbial features of copper (Cu) and zinc oxide (ZnO) nanoparticles (NPs) are extensively used to combat the growth of pathogenic microbes. CuNPs and ZnONPs are recurrently used in cosmetics, medicine and food additives, and their potential for toxic impacts on human and ecosystem is of high concern. In this study, the fate and toxicity of 16- to 96-nm-ranged biosynthesized copper (Bio-CuNPs) and zinc oxide (Bio-ZnONPs) was assessed in male Wistar rats. In vivo exposures of the two nanoparticles are achieved through two different administration routes namely, intraperitoneal (i/p) and intravenous (i/v) injections. The three different concentrations, no observable adverse effect concentration (NOAEC), inhibitory concentration (IC50) and total lethal concentration (TLC), were appraised at the dose range of 6.1 to 19.82 MUg/kg and 11.14 to 30.3 MUg/kg for Bio-CuNPs and Bio-ZnONPs respectively, for both i/p and i/v routes on 14th and 28th day of observation. These dose ranges are considered based on the previous study of antibacterial dose on multidrug-resistant pathogenic bacteria. In this study, we investigated the toxic effect of Bio-CuNPs and Bio-ZnONPs on animal behaviour, animal mass, haematologic indices, organ indices and histopathology of liver, spleen, kidney and brain organs. We found that i/v and i/p administration of Bio-ZnONPs in three different doses did not cause mortality and body weight was slightly reduced up to second week of administration compared with the vehicle control group. At the dose ranges of 11 16 MUg/kg (i/v) and 24-30 MUg/kg (i/p), no significant changes were observed in the serum creatinine level as well as serum ALT, serum AST level and ALP level which were 40.7 mg/dl, 37.9 IU/L and 82.4 IU/L normal as compared to vehicle control on 14th and 28th day of observation. These findings are confirmed in liver, kidney and spleen indices and histopathology studies. Furthermore, liver and kidney injury occurred when the concentrations of Bio-CuNPs were at 9.5 MUg/kg (IC50) and 11.7 MUg/kg (TLC) for i/v route of administration. Similarly, increase in serum ALT (67.7 mg/dl), AST level (70 IU/L) and ALP (128 IU/L) was also observed. And the body weight was significantly lower than in the control group after 14th day, and there were statistically significant differences observed by this route; interestingly, the toxicity of Bio-CuNPs in serum is prolonged (up to 28th day). Effect of Bio-CuNPs through i/p route was considerably low as compare to the control. Results of the present study revealed that Bio-ZnONPs have no effect on kidney and liver function biomarkers (both i/v and i/p) as compared to Bio-CuNPs. Graphical abstract As shown in graphical abstract (Fig. 1), our aim is to assess the toxicity of Bio-CuNPs and Bio-ZnONPs through in vivo protocol. According to Kahru and Dubourguier reviews, AgNPs, CuNPs and ZnONPs have been historically used as biocides, for preventing the growth of microorganisms and algae (Kahru and Dubourguier 2010). Therefore, as like pesticides, nanomaterials should be monitored for their toxic response toward non-target species, including humans and animals. To gain a better understanding whether the accidental release of metal-containing NPs may pose a threat to non-target species, assessing of toxic effect is indispensable.The 'non target organism' is an organism which will be exposed to NPs after their incidental release into the environment. PMID- 29616364 TI - The dye-sensitized solar cell database. AB - BACKGROUND: Dye-sensitized solar cells (DSSCs) have garnered a lot of attention in recent years. The solar energy to power conversion efficiency of a DSSC is influenced by various components of the cell such as the dye, electrolyte, electrodes and additives among others leading to varying experimental configurations. A large number of metal-based and metal-free dye sensitizers have now been reported and tools using such data to indicate new directions for design and development are on the rise. DESCRIPTION: DSSCDB, the first of its kind dye sensitized solar cell database, aims to provide users with up-to-date information from publications on the molecular structures of the dyes, experimental details and reported measurements (efficiencies and spectral properties) and thereby facilitate a comprehensive and critical evaluation of the data. Currently, the DSSCDB contains over 4000 experimental observations spanning multiple dye classes such as triphenylamines, carbazoles, coumarins, phenothiazines, ruthenium and porphyrins. CONCLUSION: The DSSCDB offers a web-based, comprehensive source of property data for dye sensitized solar cells. Access to the database is available through the following URL: www.dyedb.com . PMID- 29616365 TI - Multi institutional quantitative phantom study of yttrium-90 PET in PET/MRI: the MR-QUEST study. AB - BACKGROUND: Yttrium-90 (90Y) radioembolization involves the intra-arterial delivery of radioactive microspheres to treat hepatic malignancies. Though this therapy involves careful pre-treatment planning and imaging, little is known about the precise location of the microspheres once they are administered. Recently, there has been growing interest post-radioembolization imaging using positron-emission tomography (PET) for quantitative dosimetry and identifying lesions that may benefit from additional salvage therapy. In this study, we aim to measure the inter-center variability of 90Y PET measurements as measured on PET/MRI in preparation for a multi-institutional prospective phase I/II clinical trial. Eight institutions participated in this study and followed a standardized phantom filling and imaging protocol. The NEMA NU2-2012 body phantom was filled with 3 GBq of 90Y chloride solution. The phantom was imaged for 30 min in listmode on a Siemens Biograph mMR non-TOF PET/MRI scanner at five time points across 10 days (0.3-3.0 GBq). Raw PET data were sent to a central site for image reconstruction and data analysis. Images were reconstructed with optimal parameters determined from a previous study. Volumes of interest (VOIs) matching the known sphere diameters were drawn on the vendor-provided attenuation map and propagated to the PET images. Recovery coefficients (RCs) and coefficient of variation of the RCs (COV) were calculated from these VOIs for each sphere size and activity level. RESULTS: Mean RCs ranged from 14.5 to 75.4%, with the lowest mean RC coming from the smallest sphere (10 mm) on the last day of imaging (0.16 MBq/ml) and the highest mean RC coming from the largest sphere (37 mm) on the first day of imaging (2.16 MBq/ml). The smaller spheres tended to exhibit higher COVs. In contrast, the larger spheres tended to exhibit lower COVs. COVs from the 37 mm sphere were < 25.3% in all scans. For scans with >= 0.60 MBq/ml, COVs were <= 25% in spheres >= 22 mm. However, for all other spheres sizes and activity levels, COVs were usually > 25%. CONCLUSIONS: Post-radioembolization dosimetry of lesions or other VOIs >= 22 mm in diameter can be consistently obtained (< 25% variability) at a multi-institutional level using PET/MRI for any clinically significant activity for 90Y radioembolization. PMID- 29616367 TI - Anatomical study of the Cleveland Clinic continuous-flow total artificial heart in adult and pediatric configurations. AB - The purpose of this study was to assess the smallest possible body sizes of patients in whom the Cleveland Clinic continuous-flow total artificial heart for adult (CFTAH) and pediatric configurations (P-CFTAH) can fit. One of the most critical dimensions is the vertebra-to-sternum distance at the junction of the right atrium to the inferior vena cava (V-S distance). Our previous CFTAH anatomical fitting study suggested that the CFTAH would fit patients of V-S distance >= 7.5 cm and the P-CFTAH of V-S distance >= 5.25 cm (70% of 7.5 cm). To confirm this, we assessed the relationship between body surface area (BSA) and V S distance in 15 adult patients (BSA 1.86-2.62 m2) and 31 pediatric patients (BSA 0.17-1.80 m2) whose computed tomography scans were available. We found a highly significant correlation between BSA and V-S distance (p < 1.0 * 10-25). It appears that the CFTAH will fit in most patients with BSA >= 1.0 m2 (corresponding height of >= 130 cm and age of 9 years) and the P-CFTAH in patients with BSA >= 0.3 m2 (corresponding height of >= 55 cm and age of 1 month). Further anatomical fitting studies are needed to evaluate the two pump models inside human chests to determine the smallest patient size/critical dimensions and device port configurations. PMID- 29616366 TI - De-escalation of breast radiotherapy after conserving surgery in low-risk early breast cancer patients. AB - The reduction in the burden related to treatment is becoming more and more important in modern oncology. Radiation therapy is a mainstay option in the postoperative setting for early breast cancer patients after breast-conserving surgery. Nowadays, different options are available to de-escalate radiotherapy in this scenario such as the use of hypofractionated whole-breast radiation, the selective delivery of the boost dose to the lumpectomy cavity, the introduction of accelerated partial breast irradiation and the omission of treatment in appropriately selected patients with low-risk features. We herein provide a review article on this topic. PMID- 29616368 TI - Beneficial effect of hot spring bathing on stress levels in Japanese macaques. AB - The ability of animals to survive dramatic climates depends on their physiology, morphology and behaviour, but is often influenced by the configuration of their habitat. Along with autonomic responses, thermoregulatory behaviours, including postural adjustments, social aggregation, and use of trees for shelter, help individuals maintain homeostasis across climate variations. Japanese macaques (Macaca fuscata) are the world's most northerly species of nonhuman primates and have adapted to extremely cold environments. Given that thermoregulatory stress can increase glucocorticoid concentrations in primates, we hypothesized that by using an available hot spring, Japanese macaques could gain protection against weather-induced cold stress during winter. We studied 12 adult female Japanese macaques living in Jigokudani Monkey Park, Japan, during the spring birth season (April to June) and winter mating season (October to December). We collected faecal samples for determination of faecal glucocorticoid (fGC) metabolite concentrations by enzyme immunoassay, as well as behavioural data to determine time spent in the hot springs, dominance rank, aggression rates, and affiliative behaviours. We used nonparametric statistics to examine seasonal changes in hot spring bathing, and the relationship between rank and air temperature on hot spring bathing. We used general linear mixed-effect models to examine factors impacting hormone concentrations. We found that Japanese macaques use hot spring bathing for thermoregulation during the winter. In the studied troop, the single hot spring is a restricted resource favoured by dominant females. High social rank had both costs and benefits: dominant females sustained high fGC levels, which were associated with high aggression rates in winter, but benefited by priority of access to the hot spring, which was associated with low fGC concentrations and therefore might help reduce energy expenditure and subsequent body heat loss. This unique habit of hot spring bathing by Japanese macaques illustrates how behavioural flexibility can help counter cold climate stress, with likely implications for reproduction and survival. PMID- 29616370 TI - First evaluation of alkylpyrazine application as a novel method to decrease microbial contaminations in processed meat products. AB - Every year about 20% of the globally produced meat gets lost due to microbial spoilage. Nevertheless, the demand for processed meat is constantly rising and producers are searching for novel strategies to reduce microbial contaminations in their products. In the present study, we evaluated the applicability of alkylpyrazines as antimicrobial agents. These fragrant molecules naturally occur in different vegetables, fruits, roasted nut and meat. Several pyrazine derivatives are readily added to processed products for flavoring purposes in the food industry. To evaluate their potential for application, two derivatives were tested for their antimicrobial activity against meat-associated bacterial contaminants and chicken meat as a whole. Isolates assigned to Carnobacteriaceae, Enterobacteriaceae, Listeriaceae, and Moraxellaceae were substantially inhibited in the pilot tests. Moreover, treatments of pyrazine-susceptible isolates resulted in 4-log reductions in bacterial cell counts. The effect was more pronounced when the model contaminants were exposed to higher concentrations of 5 isobutyl-2,3-dimethylpyrazine. In a first small-scale application with processed chicken meat, it was demonstrated that the antimicrobial effects of 2-isobutyl-3 methylpyrazine can be improved by additionally lowering the water activity on the meat surface when maltodextrin is used as a carrier substance. At low pyrazine dosages, the number of viable bacteria was decreased up to 95% in comparison to the corresponding controls. A complementary imaging method that was developed to assess the efficacy on the product, reinforced the applicability of this two component system. PMID- 29616369 TI - Treatment response assessment with (R)-[11CPAQ PET in the MMTV-PyMT mouse model of breast cancer. AB - BACKGROUND: The goal of the study was to assess the potential of the vascular endothelial growth factor receptor (VEGFR)-2-targeting carbon-11 labeled (R)-N-(4 bromo-2-fluorophenyl)-6-methoxy-7-((1-methyl-3-piperidinyl)methoxy)-4 quinazolineamine ((R)-[11C]PAQ) as a positron emission tomography (PET) imaging biomarker for evaluation of the efficacy of anticancer drugs in preclinical models. METHODS: MMTV-PyMT mice were treated with vehicle alone (VEH), murine anti-VEGFA antibody (B20-4.1.1), and paclitaxel (PTX) in combination or as single agents. The treatment response was measured with (R)-[11C]PAQ PET as standardized uptake value (SUV)mean, SUVmax relative changes at the baseline (day 0) and follow-up (day 4) time points, and magnetic resonance imaging (MRI)-derived PyMT mammary tumor volume (TV) changes. Expression of Ki67, VEGFR-2, and CD31 in tumor tissue was determined by immunohistochemistry (IHC). Non-parametric statistical tests were used to evaluate the relation between (R)-[11C]PAQ radiotracer uptake and therapy response biomarkers. RESULTS: The (R)-[11C]PAQ SUVmax in tumors was significantly reduced after 4 days in the B20-4.1.1/PTX combinational and B20 4.1.1 monotherapy groups (p < 0.0005 and p < 0.003, respectively). No significant change was observed in the PTX monotherapy group. There was a significant difference in the SUVmax change between the VEH group and B20-4.1.1/PTX combinational group, as well as between the VEH group and the B20-4.1.1 monotherapy group (p < 0.05). MRI revealed significant decreases in TV in the B20 4.1.1/PTX treatment group (p < 0.005) but not the other therapy groups. A positive trend was observed between the (R)-[11C]PAQ SUVmax change and TV reduction in the B20-4.1.1/PTX group. Statistical testing showed a significant difference in the blood vessel density between the B20-4.1.1/PTX combinational group and the VEH group (p < 0.05) but no significant difference in the Ki67 positive signal between treatment groups. CONCLUSIONS: The results of this study are promising. However, additional studies are necessary before (R)-[11C]PAQ can be approved as a predictive radiotracer for cancer therapy response. PMID- 29616371 TI - A case of local recurrence following transanal total mesorectal excision: a new form of port-site metastasis? PMID- 29616372 TI - A novel technique for minimally invasive removal of a foreign body in the rectal wall. PMID- 29616373 TI - Ethylene signaling modulates contents of catechin and ability of antioxidant in Camellia sinensis. AB - BACKGROUND: Tea is one of the most popular beverages in the world. There are many secondary metabolites can be found in tea such as anthocyanins, proanthocyanidins, flavonols and catechins. These secondary metabolites in plants are proved to act protective components for human health effect. Plant hormone ethylene is considered to have an important role in regulation of plant development and signal transduction. This study evaluated the effect of ethylene signaling regulation in phenolic compounds in tea plants. The ethylene precursor 1-aminocyclopropane-1-carboxylic acid (ACC) enhanced contents of total catechin in treated oolong tea seedlings. RESULTS: The degree of epigallocatechin and epicatechin galloylation was increased after ACC treatment in oolong tea seedlings by high performance liquid chromatography determination. The contents of anthocyanins, flavonoids, and total polyphenol were higher after ACC treatment in comparison with control. Antioxidant enzyme such as catalase, superoxide dismutase, and total peroxidase decreased their antioxidant activities after ACC treatment, yet the activity of ascorbate peroxidase is increased. The ability of oxygen radical absorption and 2,2-diphenyl-1-picrylhydrazyl was used to evaluate the antioxidant activity, which was enhanced by ACC treatment. CONCLUSIONS: Taken together the results of this study demonstrate that the ethylene signaling is involved in modulation of secondary metabolites accumulation and antioxidant ability that to enhance the benefit of human health in tea products. PMID- 29616374 TI - Heart Failure with Recovered EF and Heart Failure with Mid-Range EF: Current Recommendations and Controversies. AB - PURPOSE OF REVIEW: This review explores key features and potential management controversies in two emerging populations in heart failure: heart failure with recovered ejection fraction (HF-recovered EF) and heart failure with mid-range ejection fraction (HFmrEF). RECENT FINDINGS: While HF-recovered EF patients have better outcomes than heart failure with reduced ejection fraction (HFrEF), they continue to have symptoms, persistent biomarker elevations, and abnormal outcomes suggesting a continued disease process. HFmrEF patients appear to have features of HFrEF and heart failure with preserved ejection fraction (HFpEF), but have a high prevalence of ischemic heart disease and may represent a transitory phase between the HFrEF and HFpEF. Management strategies have insufficient data to warrant standardization at this time. HF-recovered EF and HFmrEF represent new populations with unmet needs and expose the pitfalls of an EF basis for heart failure classification. PMID- 29616375 TI - Increased cardiac sympathetic activity: Cause or compensation in vasovagal syncope? PMID- 29616376 TI - Chemical Fertility Signaling in Termites: Idiosyncrasies and Commonalities in Comparison with Ants. AB - Termites evolved eusociality independently from social Hymenoptera. As a common trait, reproductive monopoly is maintained through chemical communication. The queen (and in termites also a king) prevents workers from reproduction by conveying their reproductive status. In termites all soldiers are sterile, but workers' potential to reproduce differs between species. It ranges from totipotency in wood-dwelling lower termites where workers are a transient stage from which all other castes develop, to sterile workers in some higher termites. Intermediate are species in which workers can develop into replacement sexuals within the nest but not into winged sexuals. I summarize the patchy picture about fertility signaling that we currently have for termites, pointing also to potential conflicts over reproduction that differ from those in social Hymenoptera. Recent findings imply that, similar to many social Hymenoptera, wood dwelling termites that live in confined nests use long-chain cuticular hydrocarbons (CHCs) as fertility signals. Yet other compounds are important as well, comprising proteinaceous secretions and especially volatiles. For a subterranean termite, two volatiles have been identified as primer pheromones that prevent reproductive differentiation of workers. It requires more data to test whether wood-dwelling termites use CHCs, while species with larger colonies and less confined nests use volatiles, or whether all species rely on multicomponent signals. Ultimately, we need more effort to model and test potential conflicts over reproduction between queens, kings and workers. Here results from social Hymenoptera cannot be transferred to termites as the latter are diploid and commonly inbred. This review illustrates promising future research avenues. PMID- 29616377 TI - Male secretory breast cancer: case in a 6-year-old boy with a peculiar gene duplication and review of the literature. AB - PURPOSE: Secretory breast cancer (SBC) is one of the rarest breast cancer (BC), representing the majority of BC in childhood. Nevertheless, it elicits a lot of interest both for the peculiar morphology and the characteristic genetic features. Currently, there is no consensus on optimal treatment strategy. Therefore, it is useful to report every case in order to establish treatment algorithms. METHODS: We describe the case of a 6-year-old boy diagnosed with a SBC, with peculiar genomic and immunohistochemical features. Moreover, we carried out a review of the literature in order to analyze the present state of knowledge about this rare entity. RESULTS: To the best of our knowledge, there are only 120 cases published in literature, only 32 in males and only 2 younger than 6 years. Furthermore, this one had peculiar genomic and immunohistochemical features. Indeed, even if SBC expresses basal-cell markers, our patient had a triple negative tumor expressing both basal and luminal cell markers. Furthermore, the boy's genomic profile revealed not only positivity for the typical SBC's translocation t(12;15), but also for a 3q28 duplication, found in his father (healthy) and paternal grandfather (with a previous BC). None were positive for BRCA mutation. This locus includes only one gene encoding for a growth factor recently linked to Early Infantile Epileptic Encephalopathy-47 and Idiopathic ventricular tachycardia. Even if the literature does not provide evidence of a pathogenic role it is not possible to exclude a cancer-predisposing activity. CONCLUSIONS: SBC is a rare type of BC, characterized by triple-negative features with an unexpectedly good prognosis. More data are needed to fully understand the behavior of this cancer and genomic profiling could be helpful in improving its diagnosis and management. PMID- 29616379 TI - Assessing the toxicity of thiamethoxam, in natural LUFA 2.2 soil, through three generations of Folsomia candida. AB - In the field, long-term exposure is a rule rather than an exception. As a consequence, the relatively short-term standard toxicity tests may not be adequate for assessing long-term effects of pesticide exposure. This study determined the toxicity of the neonicotinoid thiamethoxam, both pure and in the formulation Actara(r) (25% active substance), to the springtail Folsomia candida, over three generations (P, F1 and F2). For the parental generation (P), the toxicity of pure thiamethoxam and Actara(r) did not differ significantly, with LC50s and EC50s of 0.32-0.35 and 0.23-0.25 mg a.s./kg dry soil, respectively. For the F1 and F2 generations, LC50s were >0.37 mg a.s./kg dry soil for both compounds. Actara was more toxic towards reproduction in the F1 generation (EC50 0.16 mg a.s./kg dry soil) than pure thiamethoxam (EC50 0.23 mg a.s./kg dry soil). For generation F2, there was no significant difference in the toxicity of the compounds towards reproduction, with EC50s of >0.37 and 0.30 mg a.s./kg dry soil for Actara(r) and pure thiamethoxam respectively. These results suggest a slight decrease in the toxicity of the compounds throughout the generations tested. The similarity in the toxicity of pure and formulated thiamethoxam indicates that the ingredients in the formulation Actara(r) do not enhance toxicity. PMID- 29616380 TI - Culture and the Trajectories of Developmental Pathology: Insights from Control and Information Theories. AB - Cognition in living entities-and their social groupings or institutional artifacts-is necessarily as complicated as their embedding environments, which, for humans, includes a particularly rich cultural milieu. The asymptotic limit theorems of information and control theories permit construction of a new class of empirical 'regression-like' statistical models for cognitive developmental processes, their dynamics, and modes of dysfunction. Such models may, as have their simpler analogs, prove useful in the study and re-mediation of cognitive failure at and across the scales and levels of organization that constitute and drive the phenomena of life. These new models particularly focus on the roles of sociocultural environment and stress, in a large sense, as both trigger for the failure of the regulation of bio-cognition and as 'riverbanks' determining the channels of pathology, with implications across life-course developmental trajectories. We examine the effects of an embedding cultural milieu and its socioeconomic implementations using the 'lenses' of metabolic optimization, control system theory, and an extension of symmetry-breaking appropriate to information systems. A central implication is that most, if not all, human developmental disorders are fundamentally culture-bound syndromes. This has deep implications for both individual treatment and public health policy. PMID- 29616378 TI - Diagnosis of Celiac Disease: Taking a Bite Out of the Controversy. AB - Celiac disease is a common autoimmune disorder of the small intestine, triggered by an immunological response to the gluten present in wheat, barley, and rye in individuals who are genetically at risk. A key to reducing the complications of this disease is early diagnosis, preferably in childhood, and consuming a lifelong gluten-free diet once diagnosis is confirmed. Yet, the diagnosis of celiac disease is often considerably delayed, exposing patients to needless suffering and morbidity. It is also difficult to confirm histologically if dietary gluten has been restricted prior to obtaining a diagnostic biopsy, a significant problem given the current growing popularity of gluten-free diets. Furthermore, failure to understand or follow current guidelines means physicians may recommend patients commence the gluten-free diet before initiating referral to a gastroenterologist. Finally, adding further confusion, pediatric guidelines in Europe support a diagnosis based on serology rather than on histology, whereas those based in North America do not. The purpose of this review is to discuss these issues and other controversies in the diagnosis of celiac disease and to consider ways to optimize diagnosis across the lifespan. PMID- 29616381 TI - Monitoring Subcellular Stress Response via a Cell-permeant Rotor Dye. AB - Monitoring the response of cells to environmental challenges, e.g. after exposure to oxidative stress or pharmaceutical substances, not only provides clues for fundamental biological processes but can also serve as a valuable tool in drug development. Obtaining such insights on the subcellular level in a rapid and simple manner is therefore of major importance. Ideally, such an approach not only reports on compartment-specific responses but also allows for an inherent subcellular segmentation using the same data set. Here, we propose such a method based on fluorescence lifetimes of a single cell-permeant rotor dye with a broad emission spectrum. Using a k-means clustering approach, a straightforward, unsupervised, and rapid segmentation protocol allows for subcellular segmentation in addition to monitoring the differential response of these compartments to environmental stress, e.g. induced by hydrogen peroxide or the widely used chemotherapeutic cisplatin. Based on our data we suggest that our automatable approach can be a valuable and robust tool for pharmaceutical screening applications. PMID- 29616382 TI - Phase model-based neuron stabilization into arbitrary clusters. AB - Deep brain stimulation (DBS) is a common method of combating pathological conditions associated with Parkinson's disease, Tourette syndrome, essential tremor, and other disorders, but whose mechanisms are not fully understood. One hypothesis, supported experimentally, is that some symptoms of these disorders are associated with pathological synchronization of neurons in the basal ganglia and thalamus. For this reason, there has been interest in recent years in finding efficient ways to desynchronize neurons that are both fast-acting and low-power. Recent results on coordinated reset and periodically forced oscillators suggest that forming distinct clusters of neurons may prove to be more effective than achieving complete desynchronization, in particular by promoting plasticity effects that might persist after stimulation is turned off. Current proposed methods for achieving clustering frequently require either multiple input sources or precomputing the control signal. We propose here a control strategy for clustering, based on an analysis of the reduced phase model for a set of identical neurons, that allows for real-time, single-input control of a population of neurons with low-amplitude, low total energy signals. After demonstrating its effectiveness on phase models, we apply it to full state models to demonstrate its validity. We also discuss the effects of coupling on the efficacy of the strategy proposed and demonstrate that the clustering can still be accomplished in the presence of weak to moderate electrotonic coupling. PMID- 29616383 TI - Progression of conventional hepatic cell culture models to bioengineered HepG2 cells for evaluation of herbal bioactivities. AB - Cancer cell lines of human tissue origin have been extensively used to investigate antiproliferative activity and toxicity of herbal extracts, isolated compounds, and anticancer drugs. These cell lines are genetically and/or epigenetically well characterized to determine the altered expression of proteins within given cellular pathways and critical genes in cancer. Human derived hepatoma (HepG2) cell line has been extensively exploited to examine cytoprotective, antioxidative, hepatoprotective, anti-hepatoma, hypocholesterolemic, anti-steatosis, bioenergetic homeostatic and anti-insulin resistant properties. Moreover, mechanism of action of various botanicals and bioactive constituents has been reported using these cells. HepG2 cells have significant differences as compared to primary hepatocytes with respect to expression of cytochrome P450 enzymes and xenobiotic receptors in conventional in vitro culture conditions. Therefore, strategies have been employed to overcome limitations of two dimensional (2D) in vitro HepG2 cell culture in order to recognize functional biomarkers more accurately and to boost its predictive value in clinical research. In consequence, three dimensional (3D) human hepatoma cell culture models are being developed as a resource to achieve these goals of simulating the in vivo tumor microenvironment. It is assumed that bioengineered 3D hepatoma cell culture models can provide significant assistance in scrutinizing the molecular response of herbal natural products to recognize novel prognostic targets and crucial biomarkers in treatment strategies for cancer patients in near future. PMID- 29616385 TI - Ethnic Cultural Features in Organized Activities: Relations to Latino Adolescents' Activity Experiences and Parental Involvement. AB - Cultural responsiveness is a key aspect of the quality of organized activities, yet has rarely been examined. Based on developmental theories and a theoretical framework for culturally responsive activities, the current study investigated the prevalence and correlates of two ethnic cultural features (i.e., ethnic cultural content & ethnic cultural respect) in organized activities. Using data from 154 Latino adolescents (Mage = 12.36, SD = .53; 59% Female) and parents, we examined associations between adolescent perceptions of both ethnic cultural features and their activity experiences; and associations between parent perceptions of both ethnic cultural features and parental involvement in the activity. Latino adolescents and parents in general perceived lower than average ethnic cultural content and moderate to high ethnic cultural respect in the reported activity. Both adolescents and parents were more likely to perceive ethnic cultural content and respect in activities where Latino youth were the numerical ethnic majority than in activities where Latino youth were the numerical ethnic minority. Latino adolescents' perceptions of ethnic cultural respect were associated with more positive activity experiences, whereas their perceptions of ethnic cultural content were associated with more negative feelings. Latino parents' perceptions of ethnic cultural content predicted higher involvement. To design culturally responsive activities, ethnic cultural features should be incorporated in a thoughtful, meaningful way that reflects both adolescents' and parents' perspectives. PMID- 29616384 TI - An Examination of Reciprocal Associations Between Social Preference, Popularity, and Friendship during Early Adolescence. AB - Getting along with peers becomes increasingly important to health and well-being during early adolescence (10-14 years). Young adolescents may succeed with peers when they are well-liked by and popular among the larger peer group (or at the group-level of social complexity). They might also fare well with peers when they are able to form numerous mutual and high quality friendships (at the dyadic level of social complexity). Theory emphasizes the interrelatedness of different types of peer experiences, but few longitudinal studies have examined the interplay among and between group- and dyadic-level peer experiences in the same study. As a result, it is not known whether group-level peer experiences are predictors of dyadic-level peer experiences, and/or vice versa. To address this limitation, this study examined the prospective and reciprocal relations between four indices of peer experiences, preference (or being highly liked and not disliked by peers), popularity (or having a reputation as popular), friendship quantity (or having many mutual friends), and friendship or relationship quality, during early adolescence. Participants were 271 adolescents (49% girls; Mage = 11.52 years) who completed peer nominations of preference and popularity, a self report measure of friendship quality, and nominated friends at two waves (Wave 1: November, Grade 6; Wave 2: October, Grade 7). Structural equation modeling indicated that friendship quantity predicted increases in preference and popularity and that friendship quality predicted increases in friendship quantity. Initial popularity was associated with decreases in preference. The importance of these findings for future research is discussed along with study limitations. PMID- 29616386 TI - Performance Assessment of a Radiofrequency Powered Guidewire for Crossing Peripheral Arterial Occlusions Based on Lesion Morphology. AB - Endovascular wires and devices for peripheral arterial disease therapy have evolved greatly, yet failure rates of these procedures remain high. Information on lesion composition may inform device selection to improve the success rates of these procedures. This paper, presents an approach for informed guidewire selection. The objective of this study is to quantitatively assess the performance of a radiofrequency powered guidewire in the crossing of various morphology types of peripheral chronic total occlusions. Samples taken from amputated patient limbs are characterized by magnetic resonance imaging. Using a customized catheter test station, the performance of a radiofrequency powered guidewire in puncturing these lesions is compared to a conventional guidewire, and to itself when not powered. The analysis includes quantitative and statistical comparisons of the puncture forces experienced by the different guidewires in "hard" vs. "soft" lesions as well as qualitative assessment of deflections, buckling and puncture success of the wires. Results indicate that the use of radiofrequency ablation significantly reduces the required puncture force, reduced events of buckling and deflection, and resulted in a significantly higher puncture success rate. PMID- 29616387 TI - Correction to: A Systematic Review of Community Health Workers' Role in Occupational Safety and Health Research. AB - The original version of this article unfortunately contained a mistake in the affiliation of co-author Ashley M. Bush. PMID- 29616389 TI - Radiation dose from cardiac catheterization procedures in young patients may not contribute to increased cancer risk. PMID- 29616388 TI - Cardiac resynchronization therapy response in heart failure patients with different subtypes of true left bundle branch block. AB - PURPOSE: Left bundle branch block (LBBB) configuration has been described as a predictor of response to cardiac resynchronization therapy (CRT). We investigated whether different subtypes of true LBBB configuration could help select patients with better response and clinical outcome. METHODS: This retrospective study included 198 consecutive LBBB patients implanted with a CRT. True LBBB was defined using the Strauss and the Predict study criteria. Echocardiographic response was evaluated by the reduction in left ventricular end-systolic volume (LVESV) and the increase in left ventricular ejection fraction (LVEF). Clinical response was defined as an improvement in one category of the NYHA functional class. RESULTS: Patients with true LBBB had a greater improvement in both LVESV reduction (median = - 27.6%, interquartile range = [- 4.9, - 50.1]) and LVEF increase (median 10.8 +/- 10) than those with non-true LBBB (- 19.7%, [16.7, - 48.0]) p = 0.04 and 5.1 +/- 10, p = 0.03, respectively. No differences were exhibited between true LBBB Strauss group (- 26.7%, [- 11.0, - 46.9]) and true LBBB Predict group (- 26.6%, [- 15.9, - 39.4]). There were no statistically significant differences in the percentage of patients with clinical response, assessed by NYHA improvement, among all groups. In the Cox model for death, age, ischemic etiology, and DeltaLVESV were independent predictors of mortality. True LBBB (Strauss + Predict) patients had a trend towards lower mortality than non true LBBB [HR = 0.55, 95% CI = (0.22-1.15)], p = 0.08. In the Cox model for HF hospitalization, age, sex male, prior LVEF, and DeltaLVESV were independent predictors. True LBBB (Strauss + Predict) patients had a significantly lower risk of developing HF hospitalization than those with non-true LBBB [0.45 (0.21 0.90)], p = 0.029. CONCLUSIONS: Patients with true LBBB, either Strauss or Predict criteria, had greater echocardiographic response and lower incidence of HF hospitalization than non-true LBBB when implanted with CRT. PMID- 29616390 TI - The impact of aging on CD4+ T cell responses to influenza infection. AB - CD4+ T cells are important for generating high quality and robust immune responses to influenza infection. Immunosenescence that occurs with aging, however, compromises the ability of CD4+ T cells to differentiate into functional subsets resulting in a multitude of dysregulated responses namely, delayed viral clearance and prolonged inflammation leading to increased pathology. Current research employing animal models and human subjects has provided new insights into the description and mechanisms of age-related CD4+ T cell changes. In this review, we will discuss the consequences of aging on CD4+ T cell differentiation and function and how this influences the initial CD4+ T cell effector responses to influenza infection. Understanding these age-related alterations will aid in the pharmacological development of therapeutic treatments and improved vaccination strategies for the vulnerable elderly population. PMID- 29616391 TI - Nardosinone-Type Sesquiterpenes from the Hexane Fraction of Nardostachys jatamansi Attenuate NF-kappaB and MAPK Signaling Pathways in Lipopolysaccharide Stimulated BV2 Microglial Cells. AB - Four nardosinone-type sesquiterpenes, nardosinone, isonardosinone, kanshone E, and kanshone B, were isolated from the hexane fraction of Nardostachys jatamansi (Valerianaceae) methanol extract. The structures of these compounds were mainly established by analyzing the data obtained from nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS). In this study, we investigated their anti-neuroinflammatory effects in lipopolysaccharide (LPS)-induced BV2 microglial cells. The results showed that nardosinone-type sesquiterpenes inhibited the production of pro-inflammatory mediators, such as nitric oxide (NO) and prostaglandin E2 (PGE2) in LPS-induced BV2 microglial cells. These inhibitory effects were correlated with the downregulation of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Moreover, these sesquiterpenes also attenuated the mRNA expression of pro-inflammatory cytokines including interleukin-1beta (IL-1beta), IL-6, and tumor necrosis factor-alpha (TNF-alpha) in LPS-induced BV2 microglial cells. During the evaluation of the signaling pathways involved in these anti-neuroinflammatory effects, western blot analysis and DNA-binding activity assay revealed that the suppression of inflammatory reaction by these sesquiterpenes was mediated by the inactivation of nuclear factor-kappa B (NF-kappaB) pathway. These sesquiterpenes also suppressed the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (MAPK) signaling pathways in LPS-stimulated BV2 microglial cells. Taken together, these four nardosinone type sesquiterpenes inhibited NF-kappaB- and MAPK-mediated inflammatory pathways, demonstrating their potential role in the treatment of neuroinflammation conditions. PMID- 29616392 TI - Pain-Relieving Effectiveness of Co-Treatment with Local Tramadol and Systemic Minocycline in Carrageenan-Induced Inflammatory Pain Model. AB - In this study, we tested our working hypothesis that inhibiting the activation of microglia by systemic minocycline treatments can decrease the dosage of local tramadol injection in inflammatory pain. This study was therefore aimed to evaluate the actions of intraplantarly injected tramadol, intraperitoneally injected minocycline, or their combined treatments on the inflammation-induced hypernociception (thermal hyperalgesia, mechanical allodynia), edema, and pro- and anti-inflammatory cytokine levels of paw and spinal cord tissues in a rat model of carrageenan-induced hindpaw inflammation. While local tramadol or systemic minocycline caused a significant anti-hypernociceptive effect their combined treatments significantly enhanced anti-hypernociceptive action compared to each agent applied alone. Also anti-edematous actions of combined treatment were higher than that of their individual administrations. In addition, combined treatment significantly decreased the level of the pro-inflammatory cytokines and caused significant increases in anti-inflammatory cytokine level of paw and spinal cord tissues. The present finding can suggest that combined treatments of local tramadol and systemic minocycline may decrease the dose requirements for anti-hypernociceptive actions of local tramadol and this combination therapy might be a beneficial option for the inflammatory pain relief. PMID- 29616393 TI - Overview of pharmacovigilance practices at the largest academic healthcare system in the State of Qatar. AB - Adverse Drug Reactions (ADRs) are major global concern, adversely impacting patient safety and health outcomes. ADRs cause significant morbidity and mortality among hospitalised patients, causing greater length of hospital stay, increased healthcare costs and patient dissatisfaction to the treatments. Pharmacovigilance (PV), a process of detecting, monitoring and preventing drug related harm, plays a vital role to ensure patient safety. ADR reporting is the cornerstone of PV. PV practices in Qatar are relatively new and are evolving rapidly. The purpose of this article is to explore the medication safety practices (notably ADR reporting) at the largest academic healthcare center in Qatar. The article further provides evidence on how information related to ADRs are generated and interpreted. Furthermore, it describes how a designated center for monitoring medication safety activities was established at the largest healthcare provider in Qatar. PMID- 29616394 TI - Contrasting insect attraction and herbivore-induced plant volatile production in maize. AB - MAIN CONCLUSION: The maize inbred line W22 has lower herbivore-induced volatile production than B73 but both fall armyworm larvae and the wasps that parasitize them prefer W22 over B73. Maize inbred line W22 is an important resource for genetic studies due to the availability of the UniformMu mutant population and a complete genome sequence. In this study, we assessed the suitability of W22 as a model for tritrophic interactions between maize, Spodoptera frugiperda (fall armyworm) and the parasitoid wasp Cotesia marginiventris. W22 was found to be a good model for studying the interaction as S. frugiperda prefers W22 over B73 and a higher parasitism rate by C. marginiventris was observed on W22 compared to the inbred line B73. W22 also produced lower amounts of many herbivore-induced volatile terpenes and indole emission upon treatment with S. frugiperda oral secretions. We propose that some of the major herbivore-induced terpene volatiles are perhaps impeding S. frugiperda and C. marginiventris preference and that as yet unidentified compounds are produced at low abundance may be positively impacting these interactions. PMID- 29616395 TI - Expression of TaGF14b, a 14-3-3 adaptor protein gene from wheat, enhances drought and salt tolerance in transgenic tobacco. AB - MAIN CONCLUSION: TaGF14b enhances tolerance to multiple stresses through ABA signaling pathway by altering physiological and biochemical processes, including ROS-scavenging system, stomatal closure, compatible osmolytes, and stress-related gene expressions in tobaccos. The 14-3-3 proteins are involved in plant growth, development, and in responding to abiotic stresses. However, the precise functions of 14-3-3s in responding to drought and salt stresses remained unclear, especially in wheat. In this study, a 14-3-3 gene from wheat, designated TaGF14b, was cloned and characterized. TaGF14b was upregulated by polyethylene glycol 6000, sodium chloride, hydrogen peroxide, and abscisic acid (ABA) treatments. Ectopic expression of TaGF14b in tobacco conferred enhanced tolerance to drought and salt stresses. Transgenic tobaccos had longer root, better growth status, and higher relative water content, survival rate, photosynthetic rate, and water use efficiency than control plants under drought and salt stresses. The contribution of TaGF14b to drought and salt tolerance relies on the regulations of ABA biosynthesis and ABA signaling, as well as stomatal closure and stress-related gene expressions. Moreover, TaGF14b expression could significantly enhance the reactive oxygen species (ROS) scavenging system to ameliorate oxidative damage to cells. In addition, TaGF14b increased tolerance to osmotic stress evoked by drought and salinity through modifying water conservation and compatible osmolytes in plants. In conclusion, TaGF14b enhances tolerance to multiple abiotic stresses through the ABA signaling pathway in transgenic tobaccos by altering physiological and biochemical processes. PMID- 29616396 TI - Genomic analysis of dengue virus serotype 1 (DENV-1) genotypes from Surabaya, Indonesia. AB - Dengue has caused a significant public health impact globally. With the diverse genetic of the causative viruses, analysis of dengue virus (DENV) genomes is important to supplement epidemiological data with information that can be used to reconstruct the history of epidemics in time and space. We have reported the clinical and virological characteristics of dengue in Surabaya, Indonesia and revealed the presence of all four DENV serotypes and the predominance of DENV-1. The further classification of Surabaya DENV-1 into two different genotypes warrants in-depth genomic analysis to study the dynamics of both genotypes and their contribution to virus evolution, virus transmission, and disease. We performed full-length genome sequencing to nine isolates' representatives from DENV-1 Genotype I and Genotype IV. Phylogenetic and evolutionary analyses suggested the more recent introduction of Genotype I viruses compared to the more endemic Genotype IV. Comparative analysis of Surabaya DENV-1 genomes and other sequences available publicly revealed that the majority of the DENV-1 codons were under strong purifying selection, while seven codon sites identified to be under positive selection. We highlight a unique codon site under the positive pressure in the NS1 gene of DENV-1. Our results provide additional genomic data of DENV from Indonesia that may contribute to the better understanding of dengue disease dynamics. PMID- 29616397 TI - Adenosine Augmentation Evoked by an ENT1 Inhibitor Improves Memory Impairment and Neuronal Plasticity in the APP/PS1 Mouse Model of Alzheimer's Disease. AB - Alzheimer's disease (AD) is a neurodegenerative disorder characterized by cognitive impairment and synaptic dysfunction. Adenosine is an important homeostatic modulator that controls the bioenergetic network in the brain through regulating receptor-evoked signaling pathways, bioenergetic machineries, and epigenetic-mediated gene regulation. Equilibrative nucleoside transporter 1 (ENT1) is a major adenosine transporter that recycles adenosine from the extracellular space. In the present study, we report that a small adenosine analogue (designated J4) that inhibited ENT1 prevented the decline in spatial memory in an AD mouse model (APP/PS1). Electrophysiological and biochemical analyses further demonstrated that chronic treatment with J4 normalized the impaired basal synaptic transmission and long-term potentiation (LTP) at Schaffer collateral synapses as well as the aberrant expression of synaptic proteins (e.g., NR2A and NR2B), abnormal neuronal plasticity-related signaling pathways (e.g., PKA and GSK3beta), and detrimental elevation in astrocytic A2AR expression in the hippocampus and cortex of APP/PS1 mice. In conclusion, our findings suggest that modulation of adenosine homeostasis by J4 is beneficial in a mouse model of AD. Our study provides a potential therapeutic strategy to delay the progression of AD. PMID- 29616399 TI - Techniques of adrenal venous sampling in patients with inferior vena cava or renal vein anomalies. AB - PURPOSE: To review the techniques and technical success rate of adrenal venous sampling (AVS) in patients with inferior vena cava (IVC) or renal vein anomalies. MATERIALS AND METHODS: The techniques and success rate of AVS in 15 patients with anomalies [8 with double IVC (dIVC), 3 with left IVC (ltIVC), 2 with retroaortic left renal vein (LRV), and 2 with circumaortic LRV] underwent AVS was retrospectively reviewed. RESULTS: Among 11 patients with IVC anomalies, the success rates for sampling the right and left adrenal veins (RAV and LAV) were 81.8 and 90.9%, respectively. In dIVC, the LAV was selected using the following four methods: approaching through the right IVC from the right femoral vein, flipping the LAV catheter tip in the LRV (n = 4) or the interiliac-communicating vein (n = 1), or through the ltIVC from the right (n = 1) or left (n = 2) femoral vein. Among the four patients with LRV anomalies, the success rate was 100% for each adrenal vein. CONCLUSION: AVS can be successfully performed in patients with anomalies. The key to technical success is understanding the venous anatomy based on pre-procedural CT images and choosing appropriate methods. PMID- 29616398 TI - Automatic spectral imaging protocol selection combined with iterative reconstruction can enhance image quality and decrease radiation and contrast dosage in abdominal CT angiography. AB - PURPOSE: To investigate the effect of automatic spectral imaging protocol selection (ASIS) and adaptive statistical iterative reconstruction (ASIR) technology in reducing radiation and contrast dosage. METHODS: Sixty-four patients were randomly divided into two groups for abdominal computed tomography (CT): the experiment group with ASIS plus 50% ASIR and the control with 120 kVp voltage. RESULTS: The CT dose-index volume decreased by 23.68 and 23.57% and the dose-length product dropped by 25.59 and 18.45% in the arterial and portal venous phases, respectively, in the experiment than control group. The contrast dose was reduced by 16.86% in the experiment group. In the 55 keV + 50% ASIR group, the arterial contrast-to-noise ratio and scores were significantly (P < 0.05) higher than in the control group in the arterial phase while the portal contrast-to noise ratio and scores were not significantly different between the two groups (P > 0.05). CONCLUSION: The ASIS technique plus 50% ASIR can enhance image quality of the abdominal structures while decreasing the radiation and contrast dosage compared with the conventional scan mode. PMID- 29616400 TI - Stable Expression of Adalimumab in Nicotiana tabacum. AB - Production of monoclonal antibodies and pharmaceutical proteins in transgenic plants has been the focus of many research efforts for close to 30 years. Use of plants as bioreactors reduces large-scale production costs and minimizes risk for human pathogens contamination. Stable nuclear transformation of the plant genome offers a clear advantage in agricultural protein production platforms, limited only by the number of hectares that can be cultivated. We report here, for the first time, successful and stable expression of adalimumab in transgenic Nicotiana tabacum plants. The plant-derived adalimumab proved fully active and was shown to rescue L929 cells from the in vitro lethal effect of rhTNFalpha just as effectively as commercially available CHO-derived adalimumab (Humira). These results indicate that agricultural biopharming is an efficient alternative to mammalian cell-based expression platforms for the large-scale production of recombinant antibodies. PMID- 29616401 TI - DNA metabarcoding of nestling feces reveals provisioning of aquatic prey and resource partitioning among Neotropical migratory songbirds in a riparian habitat. AB - Riparian habitats are characterized by substantial flows of emergent aquatic insects that cross the stream-forest interface and provide an important source of prey for insectivorous birds. The increased availability of prey arising from aquatic subsidies attracts high densities of Neotropical migratory songbirds that are thought to exploit emergent aquatic insects as a nestling food resource; however, the prey preferences and diets of birds in these communities are only broadly understood. In this study, we utilized DNA metabarcoding to investigate the extent to which three syntopic species of migratory songbirds-Acadian Flycatcher, Louisiana Waterthrush, and Wood Thrush-breeding in Appalachian riparian habitats (Pennsylvania, USA) exploit and partition aquatic prey subsidies as a nestling food resource. Despite substantial differences in adult foraging strategies, nearly every nestling in this study consumed aquatic taxa, suggesting that aquatic subsidies are an important prey resource for Neotropical migrants nesting in riparian habitats. While our results revealed significant interspecific dietary niche divergence, the diets of Acadian Flycatcher and Wood Thrush nestlings were strikingly similar and exhibited significantly more overlap than expected. These results suggest that the dietary niches of Neotropical migrants with divergent foraging strategies may converge due to the opportunistic provisioning of non-limiting prey resources in riparian habitats. In addition to providing the first application of DNA metabarcoding to investigate diet in a community of Neotropical migrants, this study emphasizes the importance of aquatic subsidies in supporting breeding songbirds and improves our understanding of how anthropogenic disturbances to riparian habitats may negatively impact long term avian conservation. PMID- 29616402 TI - Space use of suburban pileated woodpeckers (Dryocopus pileatus): insights on the relationship between home range, core areas, and territory. AB - Home range, territory, and core areas are concepts that have been used to describe a species' space use. However, little research has been done to understand potential spatial relationships between them. While the relative importance of different areas of the home range has been addressed with utilization distributions, there is a lack of such analysis for territories. We mapped the locations of territorial advertisements (calls and drumming) of the pileated woodpecker in suburban areas to determine a more objective, behavior based approach to define areas of importance within territories, which we called 'highly-defended areas'. We then analyzed the relationship between such highly defended areas and a bird's home range and territory. On average, territories represented 69.6 +/- 0.06% (mean +/- SE) of a woodpecker's home range, and highly defended areas were 34.3 +/- 0.03% of their home range. Highly-defended areas objectively determined the portion of the territory that was important for fitness. For example, they contained a significant proportion of the nests and roost sites of pileated woodpeckers, which are important for reproduction and survivorship. This approach could be useful to further incorporate behavior in the study of the spatial ecology of species. PMID- 29616403 TI - Colour polymorphism in owls is linked to light variability. AB - Owls show an astonishing variation in their degree of colour polymorphism, although the exact mechanisms driving such variation remain controversial. Here we address this fundamental question by considering information on all extant owls and recent advances in comparative methods in the frame of three mutually non-exclusive evolutionary scenarios. In addition, we study for the first time whether the evolution of influential ecological characters facilitated the evolution of colour polymorphism (or vice versa). In agreement with the niche divergence hypothesis, we found that species living under more variable luminal conditions, i.e., species with diurnal and crepuscular habits and those inhabiting in a mixture of open and closed habitats, were more likely to show colour polymorphism. Correlated evolution analyses revealed that a change in the luminal niche might be a fundamental requisite for the evolution of colour polymorphism. Moreover, polymorphism was more frequent among owl species occupying lower trophic levels, which could be explained by a particularly high selection for crypsis on small predator owls. Our results, thus, provide support for the idea that colour polymorphism in owls is an adaptive character likely maintained by the selective advantage of morphs under different environmental conditions via disruptive selection mechanisms. PMID- 29616405 TI - Ventilator Associated Pneumonia in Pediatric Intensive Care Unit: Incidence, Risk Factors and Etiological Agents. AB - OBJECTIVES: To study the incidence, etiology and risk factors associated with ventilator associated pneumonia (VAP) in children. METHODS: This prospective cohort study was conducted on patients admitted to the Pediatric Intensive Care Unit (PICU) of a tertiary care institute of North India, from June 2012 through March 2014, who received mechanical ventilation for more than 24 h. All enrolled children were assessed daily for development of ventilator associated pneumonia (VAP) using the case definition given by Centers for Disease Control and Prevention (CDC). Chest radiograph and microbiologic samplings were performed in children suspected to have VAP. Risk factors associated with VAP were calculated by doing bivariate and multivariate analysis. RESULTS: A total of 128 patients were screened and 86 were enrolled (median age 30 mo 95% CI 4.0-84.0; 72% boys). The most common admitting diagnosis was sepsis (16%) followed by acyanotic congenital heart disease with pneumonia (14%) and the most common indication for ventilation was respiratory failure (45.3%). The incidence of VAP according to CDC criteria was 38.4%, while the incidence of microbiologically confirmed VAP was 24.4%. The incidence of ventilator associated tracheobronchitis (VAT) was found to be 11.6%. Acinetobacter was the most frequently isolated organism (47%) followed by Pseudomonas (28%), Klebsiella (15%), E. coli (5%) and Enterobacter (5%). Risk factors for VAP on bivariate analysis were use of proton pump inhibitor (PPI) (p = 0.027, OR 5.2, 95% CI 1.1-24.3), enteral feeding (p < 0.001, OR 6.5, 95% CI 2.1-19.4) and re-intubation (p = 0.024, OR 3.3 and 95% CI 1.1 9.6). On multivariate analysis, use of PPI (p = 0.03, OR 8.47, 95% CI 1.19-60.33) and enteral feeding (p < 0.001, OR 12.2, 95% CI 2.58-57.78) were identified as independent risk factors for VAP. CONCLUSIONS: Ventilator associated pneumonia is an important complication in children receiving mechanical ventilation in PICU and Gram negative bacilli (Acinetobacter and Pseudomonas) being the important causative agents. Ventilator associated tracheobronchitis is an emerging entity; recognition and treatment of same might prevent the development of VAP. PMID- 29616404 TI - Intensive Care Management of Patients with Cirrhosis. AB - PURPOSE OF REVIEW: Cirrhosis is a major worldwide health problem which results in a high level of morbidity and mortality. Patients with cirrhosis who require intensive care support have high mortality rates of near 50%. The goal of this review is to address the management of common complications of cirrhosis in the ICU. RECENT FINDINGS: Recent epidemiological studies have shown an increase in hospitalizations due to advanced liver disease with an associated increase in intensive care utilization. Given an increasing burden on the healthcare system, it is imperative that we strive to improve our management cirrhotic patients in the intensive care unit. Large studies evaluating the management of patients in the intensive care setting are lacking. To date, most recommendations are based on extrapolation of data from studies in cirrhosis outside of the ICU or by applying general critical care principles which may or may not be appropriate for the critically ill cirrhotic patient. Future research is required to answer important management questions. PMID- 29616406 TI - Georgy Gause's shift from ecology and evolutionary biology to antibiotics research: reasons, objectives, circumstances. AB - Georgy Gause (1910-1986) is best known for his contribution to ecology and evolutionary theory. His book "The Struggle for Existence" (1934) inspired generations of ecologists. Yet his scientific interests were diverse, embracing many aspects of the life sciences and medicine. The most notable shift in his research took place in the early 1940s when he began to study antibiotics and discovered Gramicidin S. Superficially, this shift looked like an attempt to switch from purely theoretical to applied research during the years of World War II, but Gause's decision may also have been seriously affected by the "Great Purge" and the growth of Lysenkoism. Personal factors played a significant role in his career too. In this article, we propose four factors which drove Gause to switch his focus from ecology to antibiotics: the inner logic of his scientific research, Stalin's science policy and the growth of Lysenkoism, the sociopolitical influence of World War II, and personal relationships. We will also show how all these factors are interdependent to some extent. PMID- 29616408 TI - Difference in intraocular pressure measurements between non-contact tonometry and Goldmann applanation tonometry and the role of central corneal thickness in affecting glaucoma referrals. AB - BACKGROUND: Patients at glaucoma risk are commonly identified by optometrists and subsequently referred to glaucoma specialists. Optometrists mainly use non contact tonometry (NCT) for intraocular pressure (IOP) measurement. AIMS: To investigate the role of differences in IOP measurement between NCT and Goldmann applanation tonometry (GAT) and the effect of central corneal thickness (CCT) on these differences in optometrist referrals METHODS: Details of the initial clinical visit of patients referred with IOP > 21 mmHg in either eye as measured by NCT to a consultant glaucoma specialist were retrospectively reviewed. Demographic and referral data, IOP, CCT, and glaucoma diagnosis were obtained. The main outcome measure was the IOP measurement differences between NCT and GAT. RESULTS: Of the 98 patients referred, only 23% had IOP > 21 mmHg when measured by GAT. NCT (Nidek NT400, Reichert Puff, Pulsair Easy Eye) measured the IOP greater than GAT by a mean of 5.8 mmHg (NCT 24.1 +/- 3.5, GAT 18.3 +/- 3.0). The effect of CCT on IOP measurement was less for GAT (R2 0.034, p = 0.067) than for NCT (R2 0.088, p = 0.003). The NCT/GAT IOP differences increased with increasing CCT (R2 0.166, p < 0.0001). The NCT/GAT differences decreased with patient age (R2 0.048, p = 0.03). Patients were classified as normal 67% (66/98), ocular hypertension 11% (11/98), glaucoma suspect 14% (14/98), and glaucoma 7% (7/98). CONCLUSIONS: The difference in IOP measurement between NCT and GAT leads to a possible increase in glaucoma referrals, particularly in patients with thicker corneas. Repeat IOP using GAT and CCT measurement would help in triaging referrals. PMID- 29616407 TI - A meta-summary of case reports of non-vitamin K antagonist oral anticoagulant use in patients with left ventricular thrombus. AB - Left ventricular (LV) thrombus is commonly seen in patients with extensive anterior ST-elevation myocardial infarction. The standard of care for LV thrombus is anticoagulation with warfarin. However, there has been an increasing trend of case reports using non-vitamin K antagonist oral anticoagulants (NOAC) for the treatment of LV thrombus. This study aimed to perform a meta-summary of the literature to characterise and evaluate the safety and feasibility of using NOAC in patients with LV thrombus. We searched for articles published in four electronic databases: PubMed, EMBASE, Scopus and Google Scholar using an appropriate keyword/MeSH term search strategy. Twenty-four studies comprising 36 patients were included in the analysis. Rivaroxaban was used in majority of patients (47.2%), whilst Apixaban and Dabigatran were prescribed in 25.0% and 27.8% of patients respectively. The most commonly associated risk factor found was post-acute myocardial infarction in 15 patients (41.7%). LV thrombus resolution was met by most patients (87.9%), and the median duration of treatment to resolution was 30.0 days (IQR = 22.5-47.0). One non-fatal bleeding event (3.0%) and no embolic events were reported. The use of NOAC may have a role in the treatment of LV thrombus in selected patients. Further randomized controlled trials are needed to evaluate this treatment strategy. PMID- 29616409 TI - Cardiotoxicity in Hematological Diseases: Are the Tyrosine Kinase Inhibitors Imatinib and Nilotinib Safe? AB - Chemotherapy-induced cardiotoxicity is a growing concern. The cardiotoxic impact of new drugs such as tyrosine kinase inhibitors is unknown, especially the ones used for chronic myeloid leukemia. We aim to evaluate nilotinib- and imatinib induced cardiotoxicity. Single-center prospective study of consecutive patients with chronic myeloid leukemia treated with tyrosine kinase inhibitors was conducted during 2015. Patients underwent an initial clinical, laboratorial and echocardiographic evaluation, repeated after 1 year. Eleven patients were included [60.0 (11) years, 63.6% of males; seven patients treated with imatinib and four with nilotinib]. After 1 year of follow-up, all patients remained in functional NYHA class I, with a similar Minnesota quality of life score. Also there was no difference in the biomarkers evaluated (cystatin-C and NT-proBNP). Likewise, no modification in systolic or diastolic function evaluated by echocardiography was observed. All patients presented normal values of longitudinal, circumferential and radial strain in the baseline study, without changes during follow-up. In addition, there were no differences between the two tyrosine kinase inhibitors used, considering all the aforementioned variables. No clinical, laboratory or echocardiographic evidence of nilotinib- and imatinib induced cardiotoxicity was observed. However, these results should be confirmed in multicenter studies given the low incidence of chronic myeloid leukemia. PMID- 29616410 TI - Identification of microRNA-like RNAs in Ophiocordyceps sinensis. AB - Ophiocordyceps sinensis is well known as a traditional Chinese medicine and has widely been used for over 2,000 years to stimulate immune system, decrease blood pressure and to inhibit tumor growth. While miRNAs are increasingly recognized for their roles in post-transcriptional regulation of gene expression in animals and plants, miRNAs in fungi were less studied until the discovery of microRNA like RNA (milRNA). High-throughput sequencing and bioinformatics approaches were used to identify conserved and novel milRNAs in O. sinensis. 40 conserved milRNAs were identified, while 23 pre-miRNA candidates encoding 31 novel milRNAs were predicted. Furthermore, the potential target genes of milRNAs in human were predicted and gene ontology analysis was applied to these genes. Enrichment analysis of GO-represented biological process showed that target genes of both conserved and novel milRNAs are involved in development, metabolic and immune processes, indicating the potential roles of milRNAs of O. sinensis in pharmacological effects as health food and traditional Chinese medicine. This study is the first report on genome-wide analysis of milRNAs in O. sinensis and it provides a useful resource to further study the potential roles of milRNAs as active components of O. sinensis in health food or traditional Chinese medicine. PMID- 29616411 TI - Benefits of Retroperitoneoscopic Surgery in Pediatric Urology. AB - PURPOSE OF REVIEW: The aim of this review is to find out the benefits of retroperitoneoscopy for the most common urological diseases in children. RECENT FINDINGS: The emergence of minimally invasive surgery about 20 years ago revolutionized pediatric urology. In this context, laparoscopy and later retroperitoneoscopy were developed and applied to a wide spectrum of urological diseases. Both approaches have since presented benefits and disadvantages that have been documented in various series. The main indications of retroperitoneoscopy are presented, from the classical ablative surgery, like total or partial nephrectomy, to more advanced reconstructive surgery. The success rate is similar to open surgery. However, few comparative studies have been conducted. According to the most recent findings, retroperitoneoscopic surgery in children is feasible and safe if performed by well-trained surgeons. A pediatric urologist would favor the retroperitoneoscopic access to reach the upper urinary tract and the kidney because this is the "natural" way to treat the most common urological pediatric diseases. PMID- 29616412 TI - A Duplex Real-Time PCR Assay for the Simultaneous Detection of Porcine Circovirus 2 and Circovirus 3. AB - Porcine circoviruses (PCV) include PCV1, PCV2, and the new-emerging PCV3. PCV2 is pathogenic to pigs, but the pathogenicity of PCV3 in pigs is debatable. Recently, there have been frequent reports of PCV2 and PCV3 co-infections in clinical samples. Thus, it would be practical to develop a duplex PCR method to detect PCV2 and PCV3 simultaneously. In this study, specific primers and probes were designed to target PCV2 cap and PCV3 rep genes. A duplex real-time PCR method was then developed to detect the two viruses. The assay was found to be highly specific, sensitive, and reproducible for PCV2/3 without cross-reactions with other swine pathogens. The sensitivity of this assay was 2.9 copies for the PCV2 plasmid and 22.5 copies for the PCV3 plasmid. The established assay was then used to detect PCV2/3 infection in 340 clinical samples collected in the first half of 2017. The results showed that the co-infection rate of PCV2/3 in the samples was 27.6%. Our study provides an important tool that can be used to perform urgently needed surveys for the two porcine circoviruses to evaluate their impact on the swine industry. PMID- 29616413 TI - Prothrombin gene mutation in Budd-Chiari syndrome-The first case report from India. PMID- 29616414 TI - Complete nucleotide sequences of the large RNA genome segments of Main Drain and Northway viruses (family Peribunyaviridae). AB - The large RNA genome segments of Main Drain virus (MDV) and Northway virus (NORV) were fully sequenced and shown to consist of 6860 and 6875 nucleotides, respectively. Sequence alignments revealed that the large RNA segment of MDV is most closely related to the corresponding region of NORV, with 76.8% nucleotide sequence identity, and the large RNA segment of NORV is most closely related to the corresponding region of Maguari virus, with 79.1% identity. PMID- 29616415 TI - Host serum microRNA profiling during the early stage of foot-and-mouth disease virus infection. AB - Foot-and-mouth disease virus (FMDV) causes a highly contagious infection in cloven-hoofed animals, with many outbreaks in the developing world. MicroRNAs (miRNAs) are non-coding RNAs that regulate antiviral defence by post transcriptional regulation of gene expression. In this study, the host miRNA response following FMDV infection was investigated in cattle, a natural host for FMDV. A significant alteration in serum miRNA expression was detected at early stages of infection. Compared to prior to infection, on day 2 postinfection (PI), 119 miRNAs were upregulated, of which 39 were significantly upregulated (P < 0.05). Gene target prediction and pathway enrichment analysis suggested that upregulated miRNAs target innate immune signalling pathways, suggesting a homeostasis effect, possibly to limit inappropriate immune responses. Further, for the significantly upregulated miRNAs, nine miRNA recognition elements were identified in the genome sequence of FMDV serotype O, which was used for infection. The antiviral effect of four of these miRNAs was confirmed in a cell culture system. These data demonstrate that changes in miRNA expression occur during early pathogenesis, and the identification of possible miRNA targets genes could help in elucidating molecular events involved in virus-host interaction and thus could be useful in developing therapeutic strategies. PMID- 29616416 TI - Jurin's law revisited: Exact meniscus shape and column height. AB - Capillary rise of a liquid column is a historical problem, which has normally been formulated by Jurin's law. In the present study, we investigate the exact solutions of the column height, considering the real shape of the meniscus according to the Young-Laplace equation. The analytical solution in the planar model and the numerical solution in the axisymmetric model on the meniscus shape are both given, which are compared with the results from Jurin's law, modified Jurin's law and Surface Evolver simulation. The results quantitatively show that when the distance between the two plates or the diameter of the tube becomes bigger, Jurin's law and modified Jurin's law would cause serious errors, and the profile morphology of the meniscus must be calculated according to the Young Laplace equation. These findings are beneficial for us to better understand the mechanism of capillarity and wetting, which are promising for such areas as oil displacement, ore floatation, building materials, fabrics, etc. PMID- 29616418 TI - A right coronary artery aneurysm presenting as a mass in echocardiography. PMID- 29616417 TI - Anti-inflammatory monocytes-interplay of innate and adaptive immunity. AB - Monocytes are central to our health as they contribute to both hemispheres of our immune system, the innate and the adaptive arm. Sensing signals from the outside world, monocytes govern the innate immunity by initiating inflammation, e.g., through production of IL-1beta. Uncontrolled and sustained inflammation, however, leads to auto-inflammatory syndromes and sometimes to autoimmune diseases. Monocytes can be a driving force for the establishment of such diseases when their ability to also contribute to the resolution of inflammation is impaired. It is therefore of vast importance to gain knowledge about the anti-inflammatory mechanisms monocytes can use to participate in downregulation and resolution of inflammation. Here, we summarize some of the known anti-inflammatory mechanisms and features of regulatory monocytes and shed light on their importance in governing innate and adaptive immune responses. Considering anti-inflammatory mechanisms of monocytes will also help to develop new strategies to use monocytes as therapeutic targets in the future. PMID- 29616420 TI - Poor Prognostic Factors in Patients with Malignant Pleural Mesothelioma Classified as Pathological Stage IB According to the Eighth Edition TNM Classification. AB - INTRODUCTION: The change in TNM classification of malignant pleural mesothelioma (MPM) between the seventh and eighth edition classifications has resulted in the downstaging of many advanced-stage patients into pathological stage IB. Many mesotheliomas without lymph node metastasis have been classified as stage IB in the eighth edition classification. Stage IB mesotheliomas comprised a heterogeneous group with different prognosis. It is necessary to clarify the prognostic factors in this group. METHODS: Between September 2009 and August 2016, a total of 89 patients with MPM underwent curative intent surgery [pleurectomy decortication n = 57 (64.1%), extrapleural pneumonectomy n = 32 (35.9%)] at our institution. Of these, 40 were reclassified as stage IB according to the eighth edition TNM classification. Independent unfavorable prognostic factors were identified by univariate analyses using the log-rank test and Cox proportional hazards regression models. RESULTS: Three independent significant factors were identified that indicated an unfavorable prognosis: a nonepithelioid subtype, lymphovascular invasion, and preoperative forced expiratory volume in 1 s (FEV1) < 2000 ml. Patients with no, one, and two of these risk factors showed 3 year overall survival probabilities of 94.7, 62.5, and 0%, respectively. The 3 year survival of patients with one factor did not differ significantly from that of patients with stage III MPM, whereas that of patients with two factors was significantly shorter (p = 0.015). CONCLUSIONS: Independent poor prognostic factors for patients with stage IB MPM patients, allowing subgroups with poorer and more favorable prognoses to be identified. This should help personalize decisions on adjuvant chemotherapy. PMID- 29616419 TI - Clinical presentation and management of patients with primary hyperparathyroidism in Italy. AB - PURPOSE: Evaluation of the phenotype of primary hyperparathyroidism (PHPT), adherence to International Guidelines for parathyroidectomy (PTx), and rate of surgical cure. METHOD: From January 2014-January 2016, we performed a prospective, multicenter study in patients with newly diagnosed PHPT. Biochemical and instrumental data were collected at baseline and during 1-year follow-up. RESULTS: Over the first year we enrolled 604 patients (age 61 +/- 14 years), mostly women (83%), referred for further evaluation and treatment advice. Five hundred sixty-six patients had sporadic PHPT (93.7%, age 63 +/- 13 years), the remaining 38 (6.3%, age 41 +/- 17 years) had familial PHPT. The majority of patients (59%) were asymptomatic. Surgery was advised in 281 (46.5%). Follow-up data were available in 345 patients. Eighty-seven of 158 (55.1%) symptomatic patients underwent PTx. Sixty-five (53.7%) of 121 asymptomatic patients with at least one criterion for surgery underwent PTx and 56 (46.3%) were followed without surgery. Negative parathyroid imaging studies predicted a conservative approach [symptomatic PHPT: OR 18.0 (95% CI 4.2-81.0) P < 0.001; asymptomatic PHPT: OR 10.8, (95% CI 3.1-37.15) P < 0.001). PTx was also performed in 16 of 66 (25.7%) asymptomatic patients without surgical criteria. Young age, serum calcium concentration, 24 h urinary calcium, positive parathyroid imaging (either ultrasound or MIBI scan positive in 75% vs. 16.7%, P = 0.001) were predictors of parathyroid surgery. Almost all (94%) of patients were cured by PTx. CONCLUSIONS: Italian endocrinologists do not follow guidelines for the management of PHPT. Negative parathyroid imaging studies are strong predictors of a non-surgical approach. PTx is successful in almost all patients. PMID- 29616421 TI - Analysis of the Vascular Interrelationships Among the First Jejunal Vein, the Superior Mesenteric Artery, and the Middle Colic Artery. AB - BACKGROUND: The technical difficulty of laparoscopic surgery for transverse colon cancer is partly due to the vascular variability around the middle colic vessels. Although individual variations in the arteries or veins in this area were previously investigated, the vascular interrelationships between these vessels remain unknown. This study was designed to investigate the vascular interrelationships between the arteries and veins around the middle colic vessels and to provide practically useful classifications. METHODS: This study included 105 consecutive patients who underwent colorectal surgery for colorectal tumors in our institution in 2016. Patients with a history of colectomy were excluded. Vascular anatomical classifications were analyzed by evaluating thin-slice images of preoperative contrast-enhanced computed tomography. RESULTS: Vascular anatomical patterns were classified according to whether the first jejunal vein ran behind (type A) or in front (type B) of the superior mesenteric artery. Type B was subclassified into two subtypes, depending on whether the middle colic artery originated cephalad (type B1) or caudad (type B2) to the first jejunal vein. We identified 83 (79.0%) cases of type A, 11 (10.5%) of type B1, and 11 (10.5%) of type B2. In 17 cases, the middle colic vein drained into the inferior mesenteric vein, and all of these were type A (P = 0.0202). Furthermore, in eight cases, the middle colic vein drained into the first jejunal vein, and all of these were type B (P < 0.0001). CONCLUSIONS: This study elucidated the vascular interrelationships around the middle colic vessels. Our findings provided important knowledge for laparoscopic surgery in treating transverse colon cancer. PMID- 29616422 TI - AJCC 8th Edition: Colorectal Cancer. PMID- 29616423 TI - Pharmacokinetics of the P-gp Inhibitor Tariquidar in Rats After Intravenous, Oral, and Intraperitoneal Administration. AB - BACKGROUND AND OBJECTIVE: P-glycoprotein (P-gp), a transmembrane transporter expressed at the blood-brain barrier, restricts the distribution of diverse central nervous system-targeted drugs from blood into brain, reducing their therapeutic efficacy. The third-generation P-gp inhibitor tariquidar (XR9576) was shown to enhance brain distribution of P-gp substrate drugs in humans. Oral bioavailability of tariquidar was found to be low in humans requiring the compound to be administered intravenously, which hinders a broader clinical use. The objective of the present study was to investigate the plasma pharmacokinetics of tariquidar in rats after single intravenous, oral, and intraperitoneal administration. METHODS: Two different tariquidar formulations (A and B) were used, both at a dosage of 15 mg/kg, respectively. Formulation A was a solution and formulation B was a microemulsion which was previously shown to improve the oral bioavailability of the structurally related P-gp inhibitor elacridar in mice. RESULTS: In contrast to human data, the present study found a high bioavailability of tariquidar in rats after oral dosing. Oral bioavailability was significantly higher (p = 0.032) for formulation B (86.3%) than for formulation A (71.6%). After intraperitoneal dosing bioavailability was 91.4% for formulation A and 99.6% for formulation B. CONCLUSION: The present findings extend the available information on tariquidar and provide a basis for future studies involving oral administration of this compound. PMID- 29616424 TI - Approaches to Regulating Adolescent Sexual Behavior in Ghana: Qualitative Evidence from Somanya and Adidome. AB - This article examines perceptions of why HIV infection is severe among adolescents in Somanya and less so in Adidome-two seemingly similar communities in Ghana-through analysis of the social control measures employed by these communities to regulate adolescent sexual initiation. Using focus group discussions with parents and caregivers of adolescent children, the study found that parents in Somanya and Adidome used different regulatory mechanisms to influence adolescent sexual initiation. While parents in Somanya relied largely on parental monitoring, parents in Adidome depended more on a combination of neighborhood monitoring and community barriers (informal rules) to control adolescent sexual onset. The study findings showed that contextual factors (socioeconomic and cultural) shaped the social realities of people in these two communities accounting for the differences in HIV prevalence. PMID- 29616425 TI - A confidence predictor for logD using conformal regression and a support-vector machine. AB - Lipophilicity is a major determinant of ADMET properties and overall suitability of drug candidates. We have developed large-scale models to predict water-octanol distribution coefficient (logD) for chemical compounds, aiding drug discovery projects. Using ACD/logD data for 1.6 million compounds from the ChEMBL database, models are created and evaluated by a support-vector machine with a linear kernel using conformal prediction methodology, outputting prediction intervals at a specified confidence level. The resulting model shows a predictive ability of [Formula: see text] and with the best performing nonconformity measure having median prediction interval of [Formula: see text] log units at 80% confidence and [Formula: see text] log units at 90% confidence. The model is available as an online service via an OpenAPI interface, a web page with a molecular editor, and we also publish predictive values at 90% confidence level for 91 M PubChem structures in RDF format for download and as an URI resolver service. PMID- 29616426 TI - Protecting fertility clinics against sperm-related fraud: a call to action. PMID- 29616427 TI - People in states worse than dead according to the EQ-5D UK value set: would they rather be dead? AB - PURPOSE: Quality-adjusted life years (QALYs) measure health by combining length and quality of life. QALYs constitute the effect side of incremental cost effectiveness ratios, describing the results of health economic evaluations. The objectives of this study were to (1) investigate the prevalence of states worse than dead (SWD) when using the EuroQol-5D UK value set, and (2) to study to what extent SWDs are reasonable with a starting point in experience-based valuations of health states. METHODS: Data from a Swedish cross-sectional population survey were used. The survey was directed to 10,000 persons 65 years and older and its primary aim was to investigate the prevalence and consequences of chronic pain. The survey included questions reflecting life situation and well-being. Some of these were used in order to characterise people in SWD. RESULTS: SWD were found in 1.8% of the 6611 respondents. The prevalence of SWD increased with advancing age and was more common among women than men. The control questions used indicated that most of the persons being in SWD according to the EQ-5D UK value set most probably would not judge themselves to be in a SWD. CONCLUSIONS: Though negative QALY-weights are not very common, they constitute a non-negligible part of health states in a Swedish population 65 years and older. Prevalence of SWD is higher among women than men and increases with age. From responses to other questions on well-being and life situation, there is reason to doubt the reasonableness of experience-based negative QALY-weights in many cases. PMID- 29616428 TI - Differences in health-related quality of life by academic performance in children of the city of Cordoba-Argentina. AB - PURPOSE: The purpose of the study was to assess the differences in health-related quality of life (HRQoL) according to academic performance (AP) in children who attend public schools in the city of Cordoba, Argentina. METHODS: Cross-sectional study carried out in a sample of 494 children aged 9-12 years (mean = 9.5; standard deviation [SD] = 0.65; IQR 1) who attended 4th grade of public schools in the city of Cordoba, Argentina in 2014. HRQoL was assessed by self administration of the KIDSCREEN-52 child version in classroom. AP was established with the final grades in language and mathematics obtained from the school records. Marginal means and SD's of the HRQoL scores were compared between AP groups by calculating the effect size (ES), and linear mixed effect models were used to evaluate the (independent) association of AP with HRQoL. RESULTS: Statistically significant differences were found in the psychosocial dimensions of the HRQoL between the AP groups. The main differences in HRQoL between children with very good-excellent grades and those with unsatisfactory AP were found in school environment (ES = 0.69), parent relation and home life (ES = 0.61), autonomy (ES = 0.61), self-perception (ES = 0.49), and social acceptance (ES = 0.48). Children with very good-excellent grades scored better in all of these dimensions. CONCLUSIONS: Children with very good-excellent grades in language and mathematics scored better in the psychosocial domains of HRQoL. AP is an important factor in the analysis of the social and psychological aspects of children's health. Further research is required to explore more deeply the direction and characteristics of this association. PMID- 29616429 TI - The different faces of mass action in virus assembly. AB - The spontaneous encapsulation of genomic and non-genomic polyanions by coat proteins of simple icosahedral viruses is driven, in the first instance, by electrostatic interactions with polycationic RNA binding domains on these proteins. The efficiency with which the polyanions can be encapsulated in vitro, and presumably also in vivo, must in addition be governed by the loss of translational and mixing entropy associated with co-assembly, at least if this co assembly constitutes a reversible process. These forms of entropy counteract the impact of attractive interactions between the constituents and hence they counteract complexation. By invoking mass action-type arguments and a simple model describing electrostatic interactions, we show how these forms of entropy might settle the competition between negatively charged polymers of different molecular weights for co-assembly with the coat proteins. In direct competition, mass action turns out to strongly work against the encapsulation of RNAs that are significantly shorter, which is typically the case for non-viral (host) RNAs. We also find that coat proteins favor forming virus particles over nonspecific binding to other proteins in the cytosol even if these are present in vast excess. Our results rationalize a number of recent in vitro co-assembly experiments showing that short polyanions are less effective at attracting virus coat proteins to form virus-like particles than long ones do, even if both are present at equal weight concentrations in the assembly mixture. PMID- 29616430 TI - Gonadal Transcriptome Analysis of Pacific Abalone Haliotis discus discus: Identification of Genes Involved in Germ Cell Development. AB - Little is known about the molecular mechanisms governing gonadal developmental processes in abalones. Here, we conducted transcriptome analysis of Pacific abalone Haliotis discus discus for gene discovery in the brain, ovary, testis, and unfertilized eggs. Among the annotated unigenes, 48.6% of unigenes were identified by Venn diagram analysis as having universal or tissue-specific expression. Twenty-three genes with gonad-biased gene ontology (GO) terms were first obtained. Secondly, 36 genes were found by screening known gene names related to germ cell development. Finally, 17 genes were obtained by querying the annotated unigene database for zygotically expressed gonadal genes (ovary and testis) and maternally expressed gonadal genes (ovary, testis, and unfertilized eggs) using keywords related to reproduction. To further verify tissue distribution pattern and subcellular localization of these genes, RT-PCR and in situ hybridization were performed using a unigene encoding a germ cell marker, vasa, as control. The results showed that vasa was expressed mainly in the early developmental stages of germ cells in both sexes. One of the candidate genes, vitelline envelope zona pellucida domain protein 12 (ZP12), was expressed in the primordial germ cells of immature gonad and early developmental stages of germ cells of the adult female. The results obtained from the present study suggest that vasa and ZP12 are involved in germ cell development of Pacific abalone and that ZP12 is an especially useful germ cell-specific marker in immature adults. The current gonadal transcriptome profile is an extensive resource for future reproductive molecular biology studies of this species. PMID- 29616432 TI - Pseudodelphis eleginopsis n. sp. (Nematoda: Guyanemidae), a new tissue-dwelling parasite of the Patagonian blennie Eleginops maclovinus (Cuvier) (Perciformes: Eleginopsidae) in Argentina, with notes on related forms. AB - Based on light and scanning electron microscopical studies, a new nematode parasite, Pseudodelphis eleginopsis n. sp. (Dracunculoidea: Guyanemidae), is described from tissues behind the gills of the Patagonian blennie Eleginops maclovinus (Cuvier) (Perciformes: Eleginopsidae) off the Atlantic coast (San Matias and San Jose Gulfs) of Patagonia, Argentina. The new species is mainly characterised by the length of the body (males 10-13 mm, larvigerous females 31 59 mm), the number (14) and arrangement of cephalic papillae, the absence of a buccal capsule, the muscular to glandular oesophagus length ratio (1:3-4) of larvigerous females, the length of the spicules (48-63 um) and the number (7 pairs) and arrangement of the caudal papillae in the male. Pseudodelphis eleginopsis n. sp. is the first species of this genus described from a marine fish in the Atlantic Ocean and the first known dracunculoid parasitising the fish host belonging to the family Eleginopsidae. As revealed by the examination of very young females of the new species, the female genital tract of Pseudodelphis spp. is monodelphic. The genus Syngnathinema Moravec, Spangenberg & Frasca, 2001 is considered a junior synonym of Pseudodelphis Adamson & Roth, 1990 and, consequently, S. californiense and S. chitwoodi are transferred to Pseudodelphis as P. californiensis (Moravec, Spangenberg & Frasca, 2001) n. comb. and P. chitwoodi (Moravec & Kuchta, 2013) n. comb., respectively. Two dracunculoid species, Pseudodelphis limnicola Brugni & Viozzi, 2006 and the previously established Philonema percichthydis Moravec, Urawa & Coria, 1997, both described from the same freshwater host species, Percichthys trucha (Valenciennes), in the same region (Patagonia), are considered to be identical; therefore, the valid name of this species is Pseudodelphis percichthydis n. comb. and P. limnicola becomes its junior synonym. A key to the species of Pseudodelphis is provided. PMID- 29616431 TI - Cuttlebone as a Marine-Derived Material for Preparing Bone Grafts. AB - The use of synthetic materials for biomedical applications still presents issues owing to the potential for unfavourable safety characteristics. Currently, there is increasing interest in using natural, marine-derived raw materials for bone tissue engineering. In our study, the endoskeleton of the mollusc Sepia, i.e. cuttlebone (CB), was used with regenerated cellulose (RC) to prepare three dimensional composite bone grafts. CB microparticles were mechanically immobilised within a cellulose gel, resulting in a macroporous structure upon lyophilisation. The interconnected porous structure of the regenerated cellulose/cuttlebone (RC/CB) composite was evaluated by micro-computed tomography. The porosity of the composite was 80%, and the pore size predominantly ranged from 200 to 500 MUm. The addition of CB microparticles increased the specific scaffold surface by almost threefold and was found to be approximately 40 mm-1. The modulus of elasticity and compressive strength of the RC/CB composite were 4.0 +/- 0.6 and 22.0 +/- 0.9 MPa, respectively. The biocompatibility of the prepared RC/CB composite with rat hepatocytes and extensor digitorum longus muscle tissue was evaluated. The obtained data demonstrated that both the composite and cellulose matrix samples were non cytotoxic and had no damaging effects. These results indicate that this RC/CB composite is a novel material suitable for bone tissue-engineering applications. PMID- 29616433 TI - Mortality and detailed characteristics of pre-ICU qSOFA-negative patients with suspected sepsis: an observational study. AB - BACKGROUND: Recent studies have suggested that quick Sequential Organ Failure Assessment (qSOFA) scores have limited utility in early prognostication in high mortality populations. The purpose of this study was to investigate the association between pre-ICU qSOFA scores and in-hospital mortality among patients admitted to the ICU with suspected sepsis. This study also aimed to describe detailed clinical characteristics of qSOFA-negative (< 2) patients. METHODS: This single center, observational study, conducted in a Japanese tertiary care teaching hospital between May 2012 and June 2016, enrolled all consecutive adult patients admitted to the ICU with suspected sepsis. We assessed pre-ICU qSOFA scores with the most abnormal vital signs during the 24-h period before ICU admission. The primary outcome was in-hospital mortality censored at 90 days. We analyzed the association between pre-ICU qSOFA scores and in-hospital mortality. RESULTS: Among 185 ICU patients with suspected sepsis, 14.1% (26/185) of patients remained qSOFA-negative at the time of ICU admission and 29.2% (54/185) of patients died while in hospital. In-hospital mortality was similar between the groups (qSOFA-positive [>= 2]: 30.2% [48/159] vs qSOFA-negative: 23.1% [6/26], p = 0.642). The Cox proportional hazard regression model revealed that being qSOFA positive was not significantly associated with in-hospital mortality (adjusted hazard ratio 1.35, 95% confidence interval 0.56-3.22, p = 0.506). Bloodstream infection, immunosuppression, and hematologic malignancy were observed more frequently in qSOFA-negative patients. CONCLUSIONS: Among ICU patients with suspected sepsis, we could not find a strong association between pre-ICU qSOFA scores and in-hospital mortality. Our study suggested high mortality and bacterial diversity in pre-ICU qSOFA-negative patients. PMID- 29616435 TI - Getting granted. PMID- 29616434 TI - Control charts for monitoring mood stability as a predictor of severe episodes in patients with bipolar disorder. AB - BACKGROUND: Recurrent mood episodes and subsyndromal mood instability cause substantial disability in patients with bipolar disorder. Early identification of mood episodes enabling timely mood stabilization is an important clinical goal. This study investigates the ability of control chart methodology to predict manic and/or depressive episodes by applying Shewhart's control rules to weekly self reported scores from mania and depression questionnaires. METHODS: Shewhart's control rules were applied to weekly self-reported scores from the Altman Self Rating Mania Scale (ASRM) and the Quick Inventory of Depressive Symptomatology Self-Report (QIDS) collected from 2001 to 2012 as part of the OXTEXT programme. Manic and depressive episodes were defined as an ASRM score >= 10 or a QIDS score >= 15, respectively. An episode-free run-in period of eight consecutive weeks without an episode of either type was used to calibrate control charts. Shewhart's rules were then applied to follow-up data. Their sensitivity and positive predictive value for predicting manic or depressive episodes within the next 4 weeks were calculated focusing on the first episode. Secondary analyses varying control chart type, length of episode-free run-in period, time frames to evaluate diagnostic accuracy, thresholds defining either manic or depressive episodes, and missing data methods were performed. RESULTS: Data from 146 participants (37% men) were included. The mean age was 43.4 (SD = 13.3) years. The median follow-up was 10 (IQR 5-40) weeks for mania and 10 (IQR 5-23) weeks for depression. A total of 53 (36%) participants had a manic episode and 67 (46%) had a depressive episode. For manic episodes, the sensitivity and positive predictive value of Shewhart's control rules were 30% (95% CI 19-45%) and 7% (95% CI 5-9%), and for depressive episodes, 33% (95% CI 22-46%) and 9% (95% CI 6-12%), respectively. Results from secondary analyses were similar to these. CONCLUSIONS: Tele-monitoring with control rules has the potential to predict about one-third of manic or depressive episodes before they occur, at the cost of a high false positive rate. Given the severe consequences of manic and depressive episodes, this trade-off may be desirable. PMID- 29616436 TI - Functionally redundant LNG3 and LNG4 genes regulate turgor-driven polar cell elongation through activation of XTH17 and XTH24. AB - KEY MESSAGE: In this work, we genetically characterized the function of Arabidopsis thaliana, LONGIFOLIA (LNG1), LNG2, LNG3, LNG4, their contribution to regulate vegetative architecture in plant. We used molecular and biophysical approaches to elucidate a gene function that regulates vegetative architecture, as revealed by the leaf phenotype and later effects on flowering patterns in Arabidopsis loss-of-function mutants. As a result, LNG genes play an important role in polar cell elongation by turgor pressure controlling the activation of XTH17 and XTH24. Plant vegetative architecture is related to important traits that later influence the floral architecture involved in seed production. Leaf morphology is the primary key trait to compose plant vegetative architecture. However, molecular mechanism on leaf shape determination is not fully understood even in the model plant A. thaliana. We previously showed that LONGIFOLIA (LNG1) and LONGIFOLIA2 (LNG2) genes regulate leaf morphology by promoting longitudinal cell elongation in Arabidopsis. In this study, we further characterized two homologs of LNG1, LNG3, and LNG4, using genetic, biophysical, and molecular approaches. Single loss-of-function mutants, lng3 and lng4, do not show any phenotypic difference, but mutants of lng quadruple (lngq), and lng1/2/3 and lng1/2/4 triples, display reduced leaf length, compared to wild type. Using the paradermal analysis, we conclude that the reduced leaf size of lngq is due to decreased cell elongation in the direction of longitudinal leaf growth, and not decreased cell proliferation. This data indicate that LNG1/2/3/4 are functionally redundant, and are involved in polar cell elongation in Arabidopsis leaf. Using a biophysical approach, we show that the LNGs contribute to maintain high turgor pressure, thus regulating turgor pressure-dependent polar cell elongation. In addition, gene expression analysis showed that LNGs positively regulate the expression of the cell wall modifying enzyme encoded by a multi-gene family, xyloglucan endotransglucosylase/hydrolase (XTH). Taking all of these together, we propose that LNG related genes play an important role in polar cell elongation by changing turgor pressure and controlling the activation of XTH17 and XTH24. PMID- 29616438 TI - A novel compound-primed multiplex ARMS-PCR (CPMAP) for simultaneous detection of common PAH gene mutations. AB - In this study, we introduce a novel compound-primed multiplex ARMS PCR (CPMAP) for simultaneous detection of common PAH gene mutations. This approach was used successfully for simultaneous identification of six most common PAH gene mutations in 137 phenylketonuria patients in the Iranian population. A total of six normal and six mutant allele-specific primers and 4 common primers containing a tag sequence of 12 base pair at the 5'-end were designed and used in two separate optimized multiplex ARMS reactions followed by hot-start PCR. The products were separated and visualized on 3% agarose gel. The CPMAP genotyping data were completely in accordance with the direct sequencing results. The CPMAP suggests a reliable, economical and rapid method for simultaneous detection of PAH point mutations using conventional PCR, which could be applied for diagnosis of other gene mutations. PMID- 29616437 TI - Tea plant SWEET transporters: expression profiling, sugar transport, and the involvement of CsSWEET16 in modifying cold tolerance in Arabidopsis. AB - KEY MESSAGE: Thirteen SWEET transporters were identified in Camellia sinensis and the cold-suppression gene CsSWEET16 contributed to sugar compartmentation across the vacuole and function in modifying cold tolerance in Arabidopsis. The sugars will eventually be exported transporters (SWEET) family of sugar transporters in plants is a recently identified protein family of sugar uniporters that contain seven transmembrane helices harbouring two MtN3 motifs. SWEETs play important roles in various biological processes, including plant responses to environmental stimuli. In this study, 13 SWEET transporters were identified in Camellia sinensis and were divided into four clades. Transcript abundances of CsSWEET genes were detected in various tissues. CsSWEET1a/1b/2a/2b/2c/3/9b/16/17 were expressed in all of the selected tissues, whereas the expression of CsSWEET5/7/9a/15 was not detected in some tissues, including those of mature leaves. Expression analysis of nine CsSWEET genes in leaves in response to abiotic stresses, natural cold acclimation and Colletotrichum camelliae infection revealed that eight CsSWEET genes responded to abiotic stress, while CsSWEET3 responded to C. camelliae infection. Functional analysis of 13 CsSWEET activities in yeast revealed that CsSWEET1a/1b/7/17 exhibit transport activity for glucose analogues and other types of hexose molecules. Further characterization of the cold-suppression gene CsSWEET16 revealed that this gene is localized in the vacuolar membrane. CsSWEET16 contributed to sugar compartmentation across the vacuole and function in modifying cold tolerance in Arabidopsis. Together, these findings demonstrate that CsSWEET genes play important roles in the response to abiotic and biotic stresses in tea plants and provide insights into the characteristics of SWEET genes in tea plants, which could serve as the basis for further functional identification of such genes. PMID- 29616439 TI - Nab-paclitaxel plus gemcitabine versus FOLFIRINOX as the first-line chemotherapy for patients with metastatic pancreatic cancer: retrospective analysis. AB - Purpose nab-paclitaxel plus gemcitabine (AG) and FOLFIRINOX have been established as standard first-line treatment in metastatic pancreatic cancer (mPC). We performed retrospective analysis comparing the efficacies of AG and FOLFIRINOX in daily practice setting. Materials and Methods We analyzed 308 patients who presented initially as mPC and received AG (n = 149) or FOLFIRINOX (n = 159) as first-line treatment between 2013 and 2016. Primary endpoints were progression free survival (PFS) and overall survival (OS). Result There were no significant differences between the two groups in terms of baseline characteristics, except older age and higher Charlson Comorbidity Index (CCI) score in AG group. The response rates (34% vs 34%) and median PFS (6.8 vs 5.1 months) were comparable between two groups (p = 0.88 and p = 0.19, respectively), while median OS was significantly better with AG than FOLFIRINOX (11.4 vs 9.6 months; p = 0.002). Elevated baseline CA19-9 level and liver metastasis were independent adverse prognostic factors for PFS and OS. In subgroup analyses, PFS with AG was better in patients with age >= 65 years, peritoneal metastasis, and higher CCI than that with FOLFIRINOX. Conclusion Both AG and FOLFIRINOX showed comparable efficacy outcomes in daily practice setting. AG might be preferentially considered in patients with peritoneal metastasis, comorbid medical conditions or old age. PMID- 29616440 TI - Distortion of the temporary cavity and its influence on staining in firearm barrels. AB - After contact shots to the head, biological traces can be found inside the barrel of the firearm. Experimental protocols to generate this sort of staining, using 12 cm gelatin cubes containing thin foil bags filled with acrylic paint, human blood, and radiocontrast agent, have been developed. Previous research on shots fired at a distance has shown the underlay sustaining these gelatin cubes has an influence on experimental results. This study was conducted to investigate the role of the sustaining base of the gelatin blocks during contact shots, and its influence on the staining result inside firearm barrels. Eighteen contact shots were performed using 22 LR, 32 ACP (7.65 Browning) and 9 mm Luger semi-automatic pistols. With each pistol, shots were fired onto six gelatin cubes; three placed upon a rigid platform and three upon an elastic underlay. The shots were recorded by a high-speed video camera as they penetrated the gelatin cube. Any staining present inside the firearm barrels after the shots were fired was documented by endoscopy. Cross sections of the gelatin blocks were then compared to the high speed video. It was found that the nature of the staining inside the barrel was not influenced by the underlay sustaining the target model. In the experiment using a 9 mm Luger, the rigid counterfort provoked a visible distortion of the temporary cavity, but, cross sectional analysis of the gelatin cubes did not reveal a relevant influence of the sustaining underlay on the crack length in the gelatin. This could be explained by a secondary expansion of the temporary cavity left by the projectile as a consequence of subsequent inflow of muzzle gases. PMID- 29616441 TI - Newborn Screening Collection and Delivery Processes in Michigan Birthing Hospitals: Strategies to Improve Timeliness. AB - Objectives This study aimed to determine which steps in the newborn screening collection and delivery processes contribute to delays and identify strategies to improve timeliness. Methods Data was analyzed from infants (N = 94,770) who underwent newborn screening at 83 hospitals in Michigan between April 2014 and March 2015. Linear mixed effects models estimated effects of hospital and newborn characteristics on times between steps in the process, whereas simulation explored how to improve timeliness through adjustments to schedules for the state laboratory and for specimen pickup from hospitals. Results Time from collection to receipt of arrival to the state laboratory varied greatly with collection timing (P < 0.001), with specimens collected on Friday or Saturday delayed an average of 9-12 h compared to other specimens. Simulation estimates shifting specimen pickup from 6 p.m. Sunday-Friday to 9 p.m. Sunday-Friday could lead to an additional 12.6% of specimens received by the Michigan laboratory within 60 h of birth. Conclusions for Practice The time between when a specimen is collected and received by the laboratory can be a significant bottleneck in the newborn screening process. Modifying hospital pickup schedules appears to be a simple way to improve timeliness. PMID- 29616442 TI - Distribution and Morphological Features of Microglia in the Developing Cerebral Cortex of Gyrencephalic Mammals. AB - Microglia have been attracting much attention because of their fundamental importance in both the mature brain and the developing brain. Though important roles of microglia in the developing cerebral cortex of mice have been uncovered, their distribution and roles in the developing cerebral cortex in gyrencephalic higher mammals have remained elusive. Here we examined the distribution and morphology of microglia in the developing cerebral cortex of gyrencephalic carnivore ferrets. We found that a number of microglia were accumulated in the germinal zones (GZs), especially in the outer subventricular zone (OSVZ), which is a GZ found in higher mammals. Furthermore, we uncovered that microglia extended their processes tangentially along inner fiber layer (IFL)-like fibers in the developing ferret cortex. The OSVZ and the IFL are the prominent features of the cerebral cortex of higher mammals. Our findings indicate that microglia may play important roles in the OSVZ and the IFL in the developing cerebral cortex of higher mammals. PMID- 29616444 TI - Magnetic Resonance Spectroscopy in Schizophrenia: Evidence for Glutamatergic Dysfunction and Impaired Energy Metabolism. AB - In the past couple of decades, major efforts were made to increase reliability of metabolic assessments by magnetic resonance methods. Magnetic resonance spectroscopy (MRS) has been valuable for providing in vivo evidence and investigating biomarkers in neuropsychiatric disorders, namely schizophrenia. Alterations of glutamate and glutamine levels in brains of schizophrenia patients relative to healthy subjects are generally interpreted as markers of glutamatergic dysfunction. However, only a small fraction of MRS-detectable glutamate is involved in neurotransmission. Here we review and discuss brain metabolic processes that involve glutamate and that are likely to be implicated in neuropsychiatric disorders. PMID- 29616443 TI - Changes in the Serum Urate Level Can Predict the Development of Parkinsonism in the 6-Hydroxydopamine Animal Model. AB - Epidemiological studies indicate that a higher plasma level of uric acid (UA) associates with the reduced risk of Parkinson's disease (PD). To confirm the role of UA as a biomarker for PD, we evaluated changes in the serum UA level in the 6 hydroxydopamine (6-OHDA)-induced hemiparkinsonism in rat. For this purpose, 6 OHDA was administered in the medial forebrain bundle by stereotaxic surgery. According to the apomorphine-induced rotational test, the increased intensity of behavioral symptoms as a function of time was associated with the further reduction of UA level. On the other hand, the level of UA increased in the midbrain of the injured hemisphere. The level of reduction in the serum UA level of rats with severe and moderate symptoms was significantly higher than that of rats with mild symptoms. The immunohistofluorescence and biochemical analyses showed that the serum UA level was also correlated with the death of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra pars compacta (SNc), reduced level of striatal dopamine, and severity of oxidative stress in the midbrain. The rats with mild symptoms also showed a significant decrease in TH positive neurons and striatal dopamine level. These findings suggest a positive correlation between the level of reduction in the serum urate level and severity of 6-OHDA-induced Parkinsonism. In addition, our findings indicated that UA had no marked neuroprotective effects, at least at concentrations obtained in this study. On the other hand, UA was introduced as a biomarker for PD, as a significant decline was observed in the serum UA level of rats with mild behavioral symptoms but with significant dopaminergic cell death in the SNc. PMID- 29616447 TI - Reviewer Names for 2017. PMID- 29616446 TI - Biomechanics-based graph matching for augmented CT-CBCT. AB - PURPOSE: Augmenting intraoperative cone beam computed tomography (CBCT) images with preoperative computed tomography data in the context of image-guided liver therapy is proposed. The expected benefit is an improved visualization of tumor(s), vascular system and other internal structures of interest. METHOD: An automatic elastic registration based on matching of vascular trees extracted from both the preoperative and intraoperative images is presented. Although methods dedicated to nonrigid graph matching exist, they are not efficient when large intraoperative deformations of tissues occur, as is the case during the liver surgery. The contribution is an extension of the graph matching algorithm using Gaussian process regression (GPR) (Serradell et al. in IEEE Trans Pattern Anal Mach Intell 37(3):625-638, 2015): First, an improved GPR matching is introduced by imposing additional constraints during the matching when the number of hypothesis is large; like the original algorithm, this extended version does not require a manual initialization of matching. Second, a fast biomechanical model is employed to make the method capable of handling large deformations. RESULTS: The proposed automatic intraoperative augmentation is evaluated on both synthetic and real data. It is demonstrated that the algorithm is capable of handling large deformations, thus being more robust and reliable than previous approaches. Moreover, the time required to perform the elastic registration is compatible with the intraoperative navigation scenario. CONCLUSION: A biomechanics-based graph matching method, which can handle large deformations and augment intraoperative CBCT, is presented and evaluated. PMID- 29616445 TI - Voluntary Exercise During Adolescence Mitigated Negative the Effects of Maternal Separation Stress on the Depressive-Like Behaviors of Adult Male Rats: Role of NMDA Receptors. AB - Evidence indicates that experiencing early-life stress (ELS) is a risk factor for the development of mental disorders such as depression. Maternal separation stress (MS) is a valid animal model of ELS that caused to induce long-lasting effects on the brain and behaviors of animals. It hypothesized that adolescence is a critical stage in which the brain is still developing, and applying (non)pharmacological therapies in this period may attenuate the effects of ELS on the brain and behavior. Male rats were subjected to MS from postnatal day (PND) 2 14, and the stressed animals were then treated with (1) chronic fluoxetine (FLX) (5 mg/kg) and (2) voluntary running wheel exercise (RW) from PND 30, for 30 days. Then, we subjected the animals to behavioral and molecular assessments at PND 60. Our data showed that MS provoked depressive-like behaviors in rats, tested by the forced swimming test, splash test, and sucrose preference test. Additionally, we found that MS increased the gene expression of the NR2A (and not NR2B) subunit of N-methyl-D-aspartate (NMDA) receptors in the hippocampus of adult rats. Both FLX and RW treatments during adolescence were able to mitigate the negative effects of ELS on stressed animals. These results highlighted the importance of adolescence in treating stressed animals with FLX/voluntary RW exercise to alleviate the depressive effects of ELS. In addition, we found that ELS altered the transcriptional level of Grin2a (and not Grin2b) in the hippocampus. Finally, our results showed that FLX/voluntary RW exercise during adolescence could normalize altered expression of Grin2a in the hippocampus of adult rats. PMID- 29616448 TI - Reliability and One-Year Stability of the PIN3 Neighborhood Environmental Audit in Urban and Rural Neighborhoods. AB - Reliable and stable environmental audit instruments are needed to successfully identify the physical and social attributes that may influence physical activity. This study described the reliability and stability of the PIN3 environmental audit instrument in both urban and rural neighborhoods. Four randomly sampled road segments in and around a one-quarter mile buffer of participants' residences from the Pregnancy, Infection, and Nutrition (PIN3) study were rated twice, approximately 2 weeks apart. One year later, 253 of the year 1 sampled roads were re-audited. The instrument included 43 measures that resulted in 73 item scores for calculation of percent overall agreement, kappa statistics, and log-linear models. For same-day reliability, 81% of items had moderate to outstanding kappa statistics (kappas >= 0.4). Two-week reliability was slightly lower, with 77% of items having moderate to outstanding agreement using kappa statistics. One-year stability had 68% of items showing moderate to outstanding agreement using kappa statistics. The reliability of the audit measures was largely consistent when comparing urban to rural locations, with only 8% of items exhibiting significant differences (alpha < 0.05) by urbanicity. The PIN3 instrument is a reliable and stable audit tool for studies assessing neighborhood attributes in urban and rural environments. PMID- 29616449 TI - Correlates of Sexual Coercion among People Who Inject Drugs (PWID) in Los Angeles and San Francisco, CA. AB - Experiences of coerced or forced sex have been associated with risk for HIV infection for all adults and may be more common for gays, lesbians, bisexuals (GLB) and people who inject drugs (PWID). In this study, we explored factors associated with prior 12-month experiences of forced or coerced sex among a sample of PWID, with a focus on sexual orientation and gender. PWID (N = 772) from Los Angeles and San Francisco were recruited using targeted sampling methods in 2011-2013 and surveyed on a range of items related to demographics, drug use, HIV risk, and violence, including experiences of forced or coerced sex in the prior 12 months. In this racially/ethnically diverse, mostly homeless, and low income sample of PWID, 25% of participants were female and 15% identified as GLB. Sexual coercion was reported by 9% of gay and bisexual men, 8% of heterosexual females, 5% of lesbians and bisexual women, and less than 1% of heterosexual men. In multivariate analyses, compared to heterosexual males, gay or bisexual males (adjusted odds ratio [AOR] = 10.68; 95% confidence interval [CI] = 2.03, 56.23), and heterosexual females (AOR = 9.69; 95% CI = 2.04, 45.94) had increased odds of coerced sex in the prior 12 months. Having a paying sex partner (AOR = 3.49; 95% CI = 1.42, 8.54) or having had forced sex prior to the age of 16 by someone at least five years older (AOR = 4.74; 95% CI = 1.88, 11.93) also elevated the odds of coercive sex. Sexual coercion is common among PWID, but especially for gay and bisexual men and heterosexual females. Efforts to reduce sexual violence among PWID are urgently needed. PMID- 29616450 TI - Implementation of Urban Health Equity Assessment and Response Tool: a Case of Matsapha, Swaziland. AB - Equity in health implies that ideally everyone could attain their full health potential and that no one should be disadvantaged from achieving this potential because of their social position or other socially determined circumstances. Making cities and human settlements inclusive, safe, resilient and sustainable contributes towards ensuring healthy lives and promoting well-being for all at all ages in dignity, equality and in a healthy environment. This paper illustrates a case of applying the Urban Health Equity Assessment and Response Tool (Urban HEART) in a small town in Africa. It describes the process followed, facilitating factors and challenges faced. A descriptive single-case study design using qualitative research methods was adopted to collect data from purposively selected respondents. The study revealed that residents of the Matsapha peri urban informal settlements faced challenges with conditions of daily living which impacted negatively on their health. There were health equity gaps. The application of the tools was facilitated by the formation of an all-inclusive team, intersectoral collaboration and incorporating strategies for improving urban health equity into existing programmes and projects. Urban HEART is a simple and easy to use valuable tool for pursuing the goal of health equity towards attaining sustainable development through evidence-based approaches for intersectoral action and community involvement. PMID- 29616451 TI - Assessing the Impact of Language Access Regulations on the Provision of Pharmacy Services. AB - Approximately 25 million people in the United States are limited English proficient (LEP). Appropriate language services can improve care for LEP individuals, and health care facilities receiving federal funds are required to provide such services. Recognizing the risk of inadequate comprehension of prescription medication instructions, between 2008 and 2012, New York City and State passed a series of regulations that require chain pharmacies to provide translated prescription labels and other language services to LEP patients. We surveyed pharmacists before (2006) and after (2015) implementation of the regulations to assess their impact in chain pharmacies. Our findings demonstrate a significant improvement in capacity of chains to assist LEP patients. A higher proportion of chain pharmacies surveyed in 2015 reported printing translated labels, access and use of telephone interpreter services, multilingual signage, and documentation of language needs in patient records. These findings illustrate the potential impact of policy changes on institutional practices that impact large and vulnerable portions of the population. PMID- 29616452 TI - Flavonoid quercetin-methotrexate combination inhibits inflammatory mediators and matrix metalloproteinase expression, providing protection to joints in collagen induced arthritis. AB - Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation of synovial tissues in joints, leading to progressive destruction of cartilage and joints. The disease-modifying anti-rheumatic drugs currently in use have side-effects. Thus, there is an urgent need for safe anti-inflammatory therapies for RA. This study aimed to evaluate the therapeutic effect of the flavonoid quercetin on arthritis in mice immunized with type II collagen (CII). An arthritis model was established in C57/BL6 mice by intradermal administration of chicken CII mixed with Freund's complete adjuvant. Quercetin (30 mg/kg orally) and methotrexate (0.75 mg intraperitoneally twice a week) were administered to investigate their protective effects against collagen-induced arthritis (CIA). Levels of tumour necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL 1beta), IL-6, and the matrix metalloproteinases (MMP), 3, and 9 were detected to assess the anti-inflammatory effect of quercetin. The mRNA expression of MMP3, MMP9, CCL2, and TNF-alpha was also measured by quantitative real-time PCR. Quercetin significantly alleviated joint inflammation by reducing the levels of circulating cytokines and MMPs. There was a significant decrease in the expression of TNFalpha and MMP genes in the ankle joints of arthritic mice. A significant reduction in the levels of knee-joint inflammatory mediators were observed with combined quercetin and methotrexate treatment. Thus, quercetin has the potential to prevent joint inflammation and could be used as an adjunct therapy for RA patients who have an inadequate response to anti-rheumatic monotherapy. PMID- 29616453 TI - Gastrodin microinjection suppresses 6-OHDA-induced motor impairments in parkinsonian rats: insights into oxidative balance and microglial activation in SNc. AB - PURPOSE OF THE RESEARCH: In this study, we appraised the effect of pre-treatment with intra-cerebro ventricular (i.c.v) microinjection of gastrodin (Gst) on catalepsy, motor imbalance, substantia nigra pars compacta (SNc) myeloperoxidase (MPO) activity, lipid peroxidation levels, nitric oxide (NO) production and total antioxidant capacity (TAC) in 6-hydroxydopamine (6-OHDA) rats model of PD. MATERIALS AND METHODS: Male Wistar rats were pre-treated with i.c.v microinjections of Gst (20, 40 and 80 MUg/3 MUl/rat) for five consecutive days. Then, catalepsy and motor balance were induced by unilateral infusion of 6-OHDA (8 MUg/2 MUl/rat) into the SNc. The anti-cataleptic and motor balance improving effect of Gst was assessed by the Bar test and Rotarod 3 weeks after neurotoxin injection, respectively. SNc MPO activity and lipid peroxidation levels, NO production and TAC were assessed at the end of behavioral experiments. RESULTS: Our data demonstrated that Gst pre-treatment significantly (p < 0.001) was prevented motor in-coordination and catalepsy in neurotoxin lesioned rats. The most motor improving effect was seen at 80 MUg Gst (p < 0.001). Pre-treatment of parkinsonian rats with Gst meaningfully (p < 0.001) was suppressed MPO activity, lipid peroxidation and NO production. Furthermore, the TAC level in the SNc was increased (p < 0.001) in Gst-microinjected rats about to the normal non parkinsonian animals. MAJOR CONCLUSIONS: In summary, pre-treatment with Gst abolished 6-OHDA-induced catalepsy and improved motor incoordination by decreasing: SNc MPO activity, lipid peroxidation levels and NO production, and restoring SNc levels of TAC to the levels of healthy rats. PMID- 29616454 TI - Effects of Social Exclusion on Cardiovascular and Affective Reactivity to a Socially Evaluative Stressor. AB - PURPOSE: Socially disconnected individuals have worse health than those who feel socially connected. The mechanisms through which social disconnection influences physiological and psychological outcomes warrant study. The current study tested whether experimental manipulations of social exclusion, relative to inclusion, influenced subsequent cardiovascular (CV) and affective reactivity to socially evaluative stress. METHODS: Young adults (N = 81) were assigned through block randomization to experience either social exclusion or inclusion, using a standardized computer-based task (Cyberball). Immediately after exposure to Cyberball, participants either underwent a socially evaluative stressor or an active control task, based on block randomization. Physiological activity (systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR)) and state anxiety were assessed throughout the experiment. RESULTS: Excluded participants evidenced a significant increase in cardiovascular and affective responses to a socially evaluative stressor. Included participants who underwent the stressor evidenced similar increases in anxiety, but systolic blood pressure, diastolic blood pressure, and heart rate did not change significantly in response to the stressor. CONCLUSIONS: Results contribute to the understanding of physiological consequences of social exclusion. Further investigation is needed to test whether social inclusion can buffer CV stress reactivity, which would carry implications for how positive social factors may protect against the harmful effects of stress. PMID- 29616455 TI - Topical heat shock protein 70 prevents imiquimod-induced psoriasis-like inflammation in mice. AB - Psoriasis is a chronic inflammatory skin disease with systemic manifestations and potential genetic etiology. The newest treatments utilize antibodies against one of several cytokines known to underlie the inflammatory signaling molecules that produce the skin and systemic symptoms. However, these agents must be regularly injected, and they may compromise the normal responses of the immune system. Furthermore, they do not address the causes of the abnormal immunoregulatory responses of the disease because the etiology is not yet completely understood. In this short-term treatment study, the potential anti-inflammatory activity of an alfalfa-derived Hsp70-containing skin cream (aHsp70) was tested on imiquimod (IMQ)-induced psoriasis-like lesions in wild-type mice. Treatment of the mice with the aHsp70 skin cream simultaneously with the imiquimod application mitigated the induction of psoriatic-like lesions and correlated with altered expression of various skin cytokines. PMID- 29616456 TI - A new parameter tuning approach for enhanced motor imagery EEG signal classification. AB - A brain-computer interface (BCI) system allows direct communication between the brain and the external world. Common spatial pattern (CSP) has been used effectively for feature extraction of data used in BCI systems. However, many studies show that the performance of a BCI system using CSP largely depends on the filter parameters. The filter parameters that yield most discriminating information vary from subject to subject and manually tuning of the filter parameters is a difficult and time-consuming exercise. In this paper, we propose a new automated filter tuning approach for motor imagery electroencephalography (EEG) signal classification, which automatically and flexibly finds the filter parameters for optimal performance. We have evaluated the performance of our proposed method on two public benchmark datasets. Compared to the existing conventional CSP approach, our method reduces the average classification error rate by 2.89% and 3.61% for BCI Competition III dataset IVa and BCI Competition IV dataset I, respectively. Moreover, our proposed approach also achieved lowest average classification error rate compared to state-of-the-art methods studied in this paper. Thus, our proposed method can be potentially used for developing improved BCI systems, which can assist people with disabilities to recover their environmental control. It can also be used for enhanced disease recognition such as epileptic seizure detection using EEG signals. Graphical abstract ?. PMID- 29616457 TI - Presepsin as a diagnostic marker of bacterial infections in febrile neutropenic pediatric patients with hematological malignancies. AB - Febrile neutropenia (FN) is often observed in hematological malignancies (HEM). Presepsin is also known as soluble CD14 subtype; it is a glycoprotein fragment derived from monocytes and macrophages. We aimed to evaluate the significance of presepsin and other biomarkers for diagnosis of bacteremia in children with HEM. Sixty pediatric patients with different HEM (acute lymphoblastic leukemia 36, acute myeloid leukemia 12, non-Hodgkin lymphoma 10, and Hodgkin disease 2). Thirty age and sex-matched healthy children serving as control were enrolled in this study. Estimation of presepsin, procalcitonin (PCT), and C-reactive protein (CRP) during episode of FN in addition to absolute neutrophils count (ANC) and blood culture was performed for all the participants. Presepsin levels were higher in the patients than in control with a higher increments in the positive blood cultures than the sterile cases. Presepsin concentration was significantly higher in bacteremia than clinically proved infection and fever of unknown origin. A statistically significant positive correlation between presepsin and CRP plus PCT levels but negative correlation with ANC were observed in the patients subgroups. Presepsin is a useful marker for detection of bacteremia with sensitivity and specificity (100 and 85.7%). This finding supported that presepsin was superior to PCT and CRP in identifying bacterial infection in FN. PMID- 29616458 TI - Notifiable infectious diseases in refugees and asylum seekers: experience from a major reception center in Munich, Germany. AB - PURPOSE: In 2016, the number of refugees worldwide reached 65.6 million. So far, only limited data are available on the health status of refugees and asylum seekers (RAs). Especially, notifiable infectious diseases (NIDs) carry the risk of outbreaks in communal accommodations hosting RAs. METHODS: We conducted a monocentric retrolective cross-sectional study including 15,137 RAs treated in a special health care unit for RAs located in the major reception center in Munich from November 2014 to October 2016. Altogether 811 RAs with NIDs according to sections 6 and 7 of the German Infection Protection Act or with other infections relevant in the setting of a communal accommodation (RIDs) could be identified. RESULTS: The gender and age distribution was generally comparable to that of refugees in Germany. However, patients from East Africa and Nigeria were significantly overrepresented. NIDs/RIDs were dominated by cases of tuberculosis, hepatitis B, and vaccine-preventable and parasitic diseases. Significant risk factors included country of origin (COI) and age for hepatitis B, age for hepatitis C, gender and age for HIV, and COI, gender and age for tuberculosis and ectoparasitosis. Calculated prevalences of hepatitis B, hepatitis C, and HIV were mostly below those of the COI. Incidences of tuberculosis were mostly strongly elevated. CONCLUSIONS: COI, gender, and age have an impact on the occurrence of NIDs/RIDs. Early vaccinations and improved hygiene could be effective in preventing NIDs/RIDs in communal accommodations. Screening, prompt therapy, and infection protection measures are necessary to prevent the transmission of diseases. PMID- 29616459 TI - Implicit sequence learning is preserved in dyslexic children. AB - This study investigates the implicit sequence learning abilities of dyslexic children using an artificial grammar learning task with an extended exposure period. Twenty children with developmental dyslexia participated in the study and were matched with two control groups-one matched for age and other for reading skills. During 3 days, all participants performed an acquisition task, where they were exposed to colored geometrical forms sequences with an underlying grammatical structure. On the last day, after the acquisition task, participants were tested in a grammaticality classification task. Implicit sequence learning was present in dyslexic children, as well as in both control groups, and no differences between groups were observed. These results suggest that implicit learning deficits per se cannot explain the characteristic reading difficulties of the dyslexics. PMID- 29616460 TI - The Memokath-051 Stent for the Treatment of Ureteric Obstruction: A NICE Medical Technology Guidance. AB - Memokath-051 is a thermo-expandable, nickel-titanium alloy spiral stent used to treat ureteric obstruction resulting from malignant or benign strictures. The National Institute for Health and Care Excellence (NICE) selected Memokath-051 for evaluation. The company, PNN Medical, claimed Memokath-051 has clinical superiority and cost savings compared with double-J stents. It identified five studies reporting clinical evidence on Memokath-051 and constructed a de novo cost model comparing Memokath-051 to double-J stents. Results indicated that Memokath-051 generated cost savings of L4156 per patient over 2.5 years. The External Assessment Centre (EAC) critiqued the company's submission and completed substantial additional work. Sixteen studies were identified assessing Memokath 051 and all listed comparators in the scope (double-J stents, reconstructive surgery and metallic and alloy stents) except nephrostomy. Similar success rates were reported for Memokath-051 compared with double-J and Resonance stents and worse outcomes compared with other options with evidence available. The EAC updated the company's cost model structure and modified several inputs. The EAC's model estimated that Memokath-051 generated savings of at least L1619 per patient over 5 years compared with double-J stents, was cost neutral compared with other metallic stents and was cost saving compared with surgery up to month 55. Overall, Memokath-051 is likely to be cost saving in patients not indicated for reconstructive surgery and those expected to require a ureteral stent for at least 30 months. The Medical Technologies Advisory Committee (MTAC) reviewed the evidence and supported the case for adoption, issuing partially supportive recommendations published after public consultation as Medical Technologies Guidance 35. PMID- 29616461 TI - Management of systolic anterior motion of the mitral valve: a mechanism-based approach. AB - Although the mechanism of systolic anterior motion (SAM) of the mitral valve is unknown, it is known to have a multifactorial pathophysiology. Echocardiographic analysis of the mitral leaflet revealed the step-wise progression of SAM, and intraventricular flow analysis revealed the contribution of drag force generated by the misled flow below the posterior leaflet. Although several diverse clinical features of SAM are already known, some key features need to be abstracted from among them to understand the regulation of SAM establishment. This paper reviews past articles that have investigated the mechanism of SAM and proposes a mechanism-based concept to provide insights for better comprehension of SAM recognition. PMID- 29616462 TI - Devising a technique for distal anastomosis during total arch replacement using the frozen elephant trunk technique: reverse stepwise anastomosis. AB - Frozen elephant technique is an effective procedure used to repair complex thoracic aortic disease involving the aortic arch and the descending aorta, or to treat aortic dissection. However, the technique often requires some creativity to properly place the stent graft and anastomose the graft to the aorta. We recently used the J Graft FROZENIX(r) (Japan Lifeline Co., Ltd., Tokyo, Japan) in total arch replacement, and devise a technique for distal anastomosis (called "reverse stepwise anastomosis") that was simple and easy and caused minimal bleeding. PMID- 29616463 TI - The influence of comorbidity on the postoperative survival in elderly (>= 75 years old) with lung cancer. AB - OBJECTIVES: We conducted a multi-institutional prospective observational study of elderly patients (>= 75 years-old) with resected non-small cell lung cancer. In this report, we have followed the cohorts for 2 years after surgery and examined both the influence of preoperative comorbidity [Adult Comorbidity Evaluation-27 (ACE-27) index] on the postoperative survival and the change in the Karnofsky Performance Status (KPS). METHODS: From March 2014 to April 2015, 264 patients were prospectively registered from 22 hospitals affiliated with the National Hospital Organization. The mean age at the time of surgery was 79.3 years (range 75-90 years), and 41% of the patients were >= 80 years of age. A total of 26% underwent sublobar resection. The study endpoints were the postoperative overall survival (OS), its prognostic factors, and the changes in the postoperative KPS. RESULTS: The 2-year OS was 85.3% (95% confidence interval 80.4-89.1%). Male gender, age >= 80, a smoking history, grade 2 of ACE-27, and an advanced disease stage were significantly poor prognostic factors for the OS in the univariate risk analysis. The multivariate analysis showed that male gender, age >= 80, an advanced disease stage and sublobar resection were significantly poor prognostic factors for the OS. In comparison with the preoperative KPS, no marked decline was observed in the postoperative chorological change of KPS. CONCLUSIONS: In the surgical treatment of elderly patients, the comorbidity as assessed by the ACE-27 index might affect the postoperative survival, and therefore should be taken into accounts in the preoperative evaluation of the surgical indications. PMID- 29616464 TI - Practices Concerning Revisional Bariatric Surgery: a Survey of 460 Surgeons. AB - BACKGROUND: There is currently little evidence available on various aspects of Revisional Bariatric Surgery (RBS) and no published consensus amongst experts. The purpose of this study was to understand variation in practices concerning RBS. METHODS: Bariatric surgeons from around the world who perform RBS were invited to participate in a questionnaire-based survey on SurveyMonkey(r). RESULTS: A total of 460 respondents from 62 countries took the survey. For revision after gastric banding, Roux-en-Y gastric bypass (RYGB) (75.5%, n = 345) emerged as the commonest choice followed by sleeve gastrectomy (SG) (56.9%, n = 260) and one anastomosis gastric bypass (OAGB) (37.2%, n = 170). For revision after SG, RYGB (77.7%, n = 355) was the commonest option followed by OAGB (42.45%, n = 194) and re-sleeve (22.32%, n = 102). For revision after RYGB, surgical pouch reduction (49.1%, n = 223), prolongation of bilio-pancreatic limb (30.0%, n = 136), and surgical stoma size reduction (26.43%, n = 120) were the most preferred options. Approximately 90.0% of respondents (n = 406/454) routinely perform an upper gastrointestinal endoscopy before an RBS, and 85.6% (n = 388/453) routinely perform a contrast study. Ninety percent (n = 403/445) reported that the demand for RBS was usually patient-driven, and there was wide variation in criteria used to define successful response, non-responders, and significant weight regain. CONCLUSIONS: This survey is the first attempt to understand various aspects of RBS. The findings will help in identifying areas for research and allow consensus building amongst experts. PMID- 29616465 TI - Incidence, Indications, and Predictive Factors for ICU Admission in Elderly, High Risk Patients Undergoing Laparoscopic Sleeve Gastrectomy. AB - BACKGROUND: Obesity affects the elderly, leading to increased prevalence of age- and obesity-associated comorbidities. There are no guidelines for indications and risk assessment for the elderly undergoing bariatric surgery. OBJECTIVES: To determine the incidence, indications, and outcomes of planned ICU admission in elderly, high-risk patients after laparoscopic sleeve gastrectomy (LSG) and to assess if preoperative risk factors for planned postoperative ICU admission in elderly patients undergoing LSG could be predicted preoperatively. METHODS: Retrospective review of prospectively collected data for all patients aged >= 60 years who underwent LSG (2011-2016) at Hamad General Hospital in Qatar. RESULTS: We followed up 58 patients aged 60-75 years for 28 +/- 17 months. About 77.6% of patients were in the intermediate-risk group of the Obesity Surgery Mortality Risk Score (OS-MRS). Fourteen patients (24%) required ICU admission for 2 +/- 1.2 days; all patients belonged to the American Society of Anesthesiologists (ASA) III class and intermediate to high risk on OS-MRS. There were no reported mortalities. The mean body mass index (BMI) decreased from 49 +/- 10.6 to 37.6 +/ 10.1 kg/m2. The number of patient comorbidities (OR, 1.43; 95% CI, 1.03-1.99) and the diagnosis of obstructive sleep apnea (OSA; OR, 7.8; 95% CI, 1.92-31.68) were associated with planned ICU admission. CONCLUSION: Elderly patients undergoing LSG usually have excellent postoperative course despite the associated high risk and the required ICU admission. The number of comorbidities, diagnosis of OSA, and ASA score are possible clinically significant predictive factors for the need of post-LSG ICU admission. PMID- 29616466 TI - Weight Loss and Comorbidity Resolution 3 Years After Bariatric Surgery-an Indian Perspective. AB - INTRODUCTION: Bariatric surgery has seen a sharp rise in India in the last decade. India is one of the 10 most obese nations of the world, ranking second in number of type 2 diabetics. AIMS: To evaluate clinical outcomes of bariatric surgery after 3 years of follow-up in terms of weight loss, co-morbidity resolution, complaints of gastroesophageal reflux disease and weight regain. METHODOLOGY: All patients who underwent bariatric surgery from January to December 2013 with a minimum follow-up of 3 years were included in the study. Their demographic, preoperative, and postoperative data were prospectively maintained on Microsoft Office Excel and analyzed statistically. RESULTS: One hundred seventy-eight patients (157 lap. sleeve gastrectomy and 21 patients lap. RYGB) completed 3 years of follow-up. In the LSG group, patients had a pre operative BMI 44.8 +/- 8.33 kg/sq. m (mean +/- S.D.) and excess body weight 52.3 +/- 23.0 kg. In the RYGB group, pre-operative BMI was 42.7 +/- 8.82 kg/sq. m and excess body weight 45 +/- 18.7 kg. In the LSG group, % excess weight loss (EWL) at 1 year was 87.6 +/- 24.4% and 3 years was 71.8 +/- 26.7%. In the RYGB group, % EWL at 1 year was 97.2 +/- 27.3% and at 3 years was 85.8 +/- 25.3%. Diabetes resolution was seen in 32 (80%) in LSG group and 11 (91.7%) in RYGB group (Figs. 1, 2, 3, and 4). CONCLUSION: Our study reflects that there is no statistically significant difference between outcomes of sleeve gastrectomy and Roux-en-Y gastric bypass surgery in terms of weight loss and diabetes resolution at 3 years. PMID- 29616467 TI - Left Gastric Artery Embolisation for the Treatment of Obesity: a Systematic Review. AB - BACKGROUND: Endovascular left gastric artery (LGA) embolisation has gained significant attention in the treatment of obesity/morbid obesity and reduction of ghrelin. The objective of this systematic review is to evaluate the recent literature, strengths, limitations and practical aspects of this new procedure in combination with its physiological and anatomical paradigm. METHODS: A systematic electronic search of literature from 1966 to June 2017 in Medline, CINHAL, Embase, Scopus and Cochrane library in English language and adult subjects was conducted. This search was conducted in accordance with Preferred Reporting in Systematic Review and Meta-Analysis (PRISMA) guidelines. Quality assessment of the articles was performed, using Oxford critical appraisal skills programme (CASP), and their recommendation for practice was examined through National Institute for health Care Excellence (NICE). Inter-related reliability (Cronbach's Alpha) was assessed between the two independent reviewers. RESULTS: A total of n = 62 individuals were subjected to LGA embolisation. At 1-3 months, 7 11% and, at 12 months, 2% weight reduction was associated with ghrelin concentration reduction of 36% at 6 months. There was Haemoglobin A1c reduction (7.4 to 6.3%) and improved quality of life (SF-36 questionnaire) at 6 months (9.5 points) (range, 3.2-17.2). Despite immediate epigastric pain and mucosal ulceration, no long-term adverse outcome was identified. The overall length of stay was 2-3 days. CONCLUSIONS: The outcome of this review (level of evidence 3) suggests LGA embolisation is feasible and effective and perhaps a safe procedure in the treatment of obesity and reduction of ghrelin. However, further trials are highly advocated. PMID- 29616468 TI - Prevalence and Prediction of Obstructive Sleep Apnea Prior to Bariatric Surgery Gender-Specific Performance of Four Sleep Questionnaires. AB - PURPOSE: Bariatric surgery (BS) is a treatment option for morbid obesity leading to substantial and sustained weight loss in adults. As obstructive sleep apnea (OSA) is highly prevalent in obese subjects and may increase the perioperative risk, screening for OSA is recommended prior to BS. In clinical routine, BS is performed more frequently in women. Therefore, we sought to assess the gender specific performance of four sleep questionnaires (Epworth Sleepiness Scale (ESS), Fatigue Severity Scale (FSS), STOPBang, and NoSAS) to predict moderate to severe OSA in the morbidly obese population. MATERIAL AND METHODS: We applied all four questionnaires to patients scheduled for BS with polygraphic OSA screening at our institution between 2012 and 2015 and performed gender-specific sensitivity analyses. RESULTS: We included 251 bariatric patients (76% female, median age 39 years, median BMI 42.0 kg/m2). OSA (AHI > 5/h; AHI > 15/h) was present in 43% (females 35%, males 68%; p < 0.001) and 21% (females 13%, males 45%; p < 0.001). STOPBang and NoSAS performed markedly better than ESS and FSS. With the exception of the ESS, all sleep questionnaires allowed better OSA prediction in women than in men. CONCLUSION: In obese patients scheduled for BS, a gender-specific difference was observed in the performance of the evaluated OSA screening questionnaires. This needs to be considered when these questionnaires are used. Our results underline the need for better gender-specific OSA screening algorithms in morbidly obese patients. PMID- 29616470 TI - Peritoneal dialysis as initial dialysis modality: a viable option for late presenting end-stage renal disease. AB - Late-presenting end-stage renal disease is a significant problem worldwide. Up to 70% of patients start dialysis in an unplanned manner without a definitive dialysis access in place. Haemodialysis via a central venous catheter is the default modality for the majority of such patients, and peritoneal dialysis is usually not considered as a feasible option. However, in the recent years, some reports on urgent-start peritoneal dialysis in the late-presenting end-stage renal disease have been published. The collective experience shows that PD can be a safe, efficient and cost-effective alternative to haemodialysis in late presenting end-stage renal disease with comparable outcomes to the conventional peritoneal dialysis and urgent-start haemodialysis. More importantly, as compared to urgent-start haemodialysis via a central venous catheter, urgent-start peritoneal dialysis has significantly fewer incidences of catheter-related bloodstream infections, dialysis-related complications and need for dialysis catheter re-insertions during the initial phase of the therapy. This article examines the rationale and feasibility for starting peritoneal dialysis urgently in late-presenting end-stage renal disease patients and reviews the literature to compare the urgent-start peritoneal dialysis with conventional peritoneal dialysis and urgent-start haemodialysis. PMID- 29616469 TI - Racial Disparities in Obesity Treatment. AB - PURPOSE OF REVIEW: Obesity rates in the USA have reached pandemic levels with one third of the population with obesity in 2015-2016 (39.8% of adults and 18.5% of youth). It is a major public health concern, and it is prudent to understand the factors which contribute. Racial and ethnic disparities are pronounced in both the prevalence and treatment of obesity and must be addressed in the efforts to combat obesity. RECENT FINDINGS: Disparities in prevalence of obesity in racial/ethnic minorities are apparent as early as the preschool years and factors including genetics, diet, physical activity, psychological factors, stress, income, and discrimination, among others, must be taken into consideration. A multidisciplinary team optimizes lifestyle and behavioral interventions, pharmacologic therapy, and access to bariatric surgery to develop the most beneficial and equitable treatment plans. The reviewed studies outline disparities that exist and the impact that race/ethnicity have on disease prevalence and treatment response. Higher prevalence and reduced treatment response to lifestyle, behavior, pharmacotherapy, and surgery, are observed in racial and ethnic minorities. Increased research, diagnosis, and access to treatment in the pediatric and adult populations of racial and ethnic minorities are proposed to combat the burgeoning obesity epidemic and to prevent increasing disparity. PMID- 29616473 TI - Does 1.5 T mpMRI play a definite role in detection of clinically significant prostate cancer? Findings from a prospective study comparing blind 24-core saturation and targeted biopsies with a novel data remodeling model. AB - BACKGROUND: Multiparametric-magnetic resonance imaging (mpMRI) can accurately detect high-grade and larger prostate cancers (PC). AIMS: To evaluate the ability of 1.5 T magnetic field mpMRI-targeted Prostate Biopsies (PBx) in predicting PC in comparison with blind 24-core saturation PBx (sPBx). METHODS: We prospectively collected data from patients undergoing transrectal sPBx and, if needed, targeted PBx of suspected lesions based on the 16-'region-of-interest' (ROI) PI-RADS graph. Data remodeling: for each 'target' (each suspected lesion at mpMRI), we identified all the 16 'ROIs' into which the lesion extended: these single 'ROIs' were identified as 'macro-targets'. For each 'ROI' and 'macro-target', we compared the mpMRI result with that of a saturation and targeted biopsy (if performed). RESULTS: 1.5T mpMRI showed a PI-RADS value >= 3 in 101 patients (82.1%). We found a PC in 50 (40.6%). Negative-positive predictive values for mpMRI were 82-45%, respectively. Of the 22 patients with normal mpMRI, four had a PC, but none had a clinically significant cancer. After the data remodeling, we demonstrated the presence of PC in 228 'ROIs': (a) only in targeted biopsies in 15 'ROIs'/'macro-targets' (6.6%); (b) only in sPBx in 177 'ROIs' (77.6%); (c) in both targeted and sPBx in 36 'ROIs' (15.8%). DISCUSSION: 81.8% of patients with normal 1.5T mpMRI were negative at PBx. Performing only targeted PBx may lead to lack of PC diagnosis in about 50% of patients. CONCLUSIONS: In patients with suspected PC and a previous negative PBx, a normal mpMRI may exclude a clinically significant PC, avoiding sPBx. PMID- 29616472 TI - Risk seeking for losses modulates the functional connectivity of the default mode and left frontoparietal networks in young males. AB - Value-based decision making (VBDM) is a principle that states that humans and other species adapt their behavior according to the dynamic subjective values of the chosen or unchosen options. The neural bases of this process have been extensively investigated using task-based fMRI and lesion studies. However, the growing field of resting-state functional connectivity (RSFC) may shed light on the organization and function of brain connections across different decision making domains. With this aim, we used independent component analysis to study the brain network dynamics in a large cohort of young males (N = 145) and the relationship of these dynamics with VBDM. Participants completed a battery of behavioral tests that evaluated delay aversion, risk seeking for losses, risk aversion for gains, and loss aversion, followed by an RSFC scan session. We identified a set of large-scale brain networks and conducted our analysis only on the default mode network (DMN) and networks comprising cognitive control, appetitive-driven, and reward-processing regions. Higher risk seeking for losses was associated with increased connectivity between medial temporal regions, frontal regions, and the DMN. Higher risk seeking for losses was also associated with increased coupling between the left frontoparietal network and occipital cortices. These associations illustrate the participation of brain regions involved in prospective thinking, affective decision making, and visual processing in participants who are greater risk-seekers, and they demonstrate the sensitivity of RSFC to detect brain connectivity differences associated with distinct VBDM parameters. PMID- 29616474 TI - Long-term trends in Swiss rivers sampled continuously over 39 years reflect changes in geochemical processes and pollution. AB - Long-term changes of 14 water constituents measured in continuously and water discharge proportionally collected samples of four Swiss rivers over a period of 39 years are analyzed using several statistical techniques. Possible drivers and causes for the identified trends and shifts are explained by consideration of catchment characteristics and anthropogenic activities. Water temperatures increased by 0.8-1.3 degrees C, whereas water discharges remained largely unchanged. Concentrations of alkalinity, total hardness, Ca, and Mg regulated by dominant carbonate lithologies in catchments increased by up to 10%. We attribute this change to an increase in the partial pressure of CO2 in the subsurface, provoked by increasing temperatures. Re-oligotrophication processes in lakes also influence the behavior of alkalinity and silicic acid. In contrast to concentrations, most loads did not change significantly, due to their large variances. Therefore, no changes in overall weathering rates of carbonate rocks can be detected. The outgassing of CO2 in rivers from the place of carbonate dissolution to measurement stations amounts up to 6% (mean) of CO2 sequestered (mean 1.1 mol m-2 a-1) by the weathering of rock minerals. Changes in alkalinity/Ca/Mg ratios indicate an increase in calcite precipitation over time. Total nitrogen concentrations and loads peaked at the end of the 1980s and then decreased up to 50%, while NO3 concentrations showed almost no changes. This dynamic matches the changes in the agricultural N balance. Concentrations and loads of Na and Cl increased up to 60% due to an increase in the various uses of rock salt. PMID- 29616471 TI - A Review of the New Antiepileptic Drugs for Focal-Onset Seizures in Pediatrics: Role of Extrapolation. AB - Most antiepileptic drugs (AEDs) receive regulatory approval for children years after the drug is available in adults, encouraging off-label use of the drug in children and hindering attempts to obtain quality pediatric data in controlled trials. Extrapolating adult efficacy data to pediatrics can reduce the time between approval in adults and that in children. To extrapolate efficacy from adults to children, several assumptions must be supported, such as (1) a similar disease progression and response to interventions in adults and children, and (2) similar exposure response in adults and children. The Pediatric Epilepsy Academic Consortium for Extrapolation (PEACE) addressed these assumptions in focal-onset seizures (FOS), the most common seizure type in both adults and children. PEACE reviewed the biological and clinical evidence that supported the assumptions that children with FOS have a similar disease progression and response to intervention as adults with FOS. After age 2 years, the pathophysiological underpinnings of FOS and the biological milieu in which seizures are initiated and propagated in children, seizure semiology, electroencephalographic features, etiology and AED response to FOS in children are similar to those in adults with FOS. PEACE concluded that extrapolation of efficacy data in adults to pediatrics in FOS is supported by strong scientific and clinical evidence. However, safety and pharmacokinetic (PK) data cannot be extrapolated from adults to children. Based on extrapolation, eslicarbazepine is now approved for children with FOS, down to age 4 years. Perampanel, lacosamide and brivaracetam are now undergoing PK and safety studies for the purposes of extrapolation down to age 2 or 4 years. When done in conjunction with PK and safety investigations in children, extrapolation of adult data from adults to children can reduce the time delay between approval of effective and safe AEDs in adults and approval in children. PMID- 29616475 TI - Variation laws and release characteristics of phosphorus on surface sediment of Dongting Lake. AB - The variation trend and growth rate of P were analyzed by the concentration of the phosphorus fraction on surface sediment of Dongting Lake from 2012 to 2016, to reveal the cumulative effect of P in the actual environment. Meanwhile, the adsorption kinetics and adsorption isotherm were employed to examine the P release possibility of sediment, which predicts the yearly released sediment phosphorus in Dongting Lake. The actual growth rate of TP (Total Phosphorus) is 53 mg.(kg.year)-1 in East Dongting Lake, 39 mg.(kg.year)-1 in South Dongting Lake, and 29 mg.(kg.year)-1 in West Dongting Lake, while the sum of the phosphorus fraction growth rates has little difference from the rate of TP in sediments of the three areas of Dongting Lake. Furthermore, the Elovich model and the Langmuir crossover-type equations are established to present the adsorption characteristic of sediment in Dongting Lake; the result shows that the sediments play a source role for phosphorus in East and South Dongting Lake from zero equilibrium phosphorus concentration (EPC0) in the present situation, but an adsorption effect on TP is shown in West Dongting Lake. When the conditions of environment change are ignored, the maximum P-sorption level in sediments of East Dongting Lake will reach in 2040 according to the actual growth rate of sediments, while that in West Dongting Lake and South Dongting Lake will be in 2046 and 2061, respectively. PMID- 29616476 TI - Contribution to the understanding of biologic concentrations of arsenic in children living in an urban area from Rio de Janeiro, Brazil. AB - There are few studies about children's environmental exposure to arsenic (As) in Brazil, most of them being in mining regions. The objective of this study was to contribute to the understanding of biologic concentrations of arsenic in children living in an urban area, in Brazil. A study of arsenic concentrations in capillary blood (n = 270), nail (n = 261), and urine (n = 99) samples, in male and female children, 8 to 10 years old, from two public schools in Rio de Janeiro, was conducted. Socio-economic and health data were obtained through questionnaires. The nail and capillary blood analysis were performed by inductively coupled plasma mass spectrometry (ICP-MS), while urine samples were analyzed using hydride generation atomic absorption spectrometry (HG-AAS). The median, geometric mean, and 95th percentiles of total arsenic concentrations were, respectively, 2.53, 2.40, and 3.58 MUg/L in capillary blood; 0.09, 0.10, and 0.24 MUg/g in nails; and 12.50, 10.97, and 39.45 MUg/L in urine. The geometric mean of urinary arsenic level was above the values reported by international surveys for non-exposed populations. The arsenic concentrations in nails were compatible with the values found in national studies. These outcomes can contribute to the increase of knowledge on biologic concentrations of arsenic in children living in urban areas, in Brazil. PMID- 29616477 TI - Characterization of toluene metabolism by methanotroph and its effect on methane oxidation. AB - Methanotrophs not only oxidize CH4, but also can oxidize a relatively broad range of other substrates, including trichloroethylene, alkanes, alkenes, and aromatic compounds. In this study, Methylosinus sporium was used as a model organism to characterize toluene metabolism by methanotrophs. Reverse transcription quantitative PCR analysis showed that toluene enhanced the mmoX expression of M. sporium. When the toluene concentration was below 2000 mg m-3, the kinetics of toluene metabolism by M. sporium conformed to the Michaelis-Menten equation (Vmax = 0.238 g gdry weight-1 h-1, K m = 545.2 mg m-3). The use of a solid-phase extraction technique followed by a gas chromatography-mass spectrometry analysis and molecular docking calculation showed that toluene was likely to primarily bind the di-iron center structural region of soluble methane monooxygenase (sMMO) hydroxylase and then be oxidized to o-cresol. Although M. sporium oxidized toluene, it did not incorporate toluene into its biomass. The coexistence of toluene and CH4 could influence CH4 oxidation, the growth of methanotrophs, and the distribution of CH4-derived carbon, which were related to the ratio of the toluene concentration to biomass. These results would be helpful to understand the metabolism of CH4 and non-methane volatile organic compounds in the environment. PMID- 29616478 TI - Official control of plant protection products in Poland: detection of illegal products. AB - Market presence of illegal and counterfeit pesticides is now a global problem. According to data published in 2012 by the European Crop Protection Association (ECPA), illegal products represent over 10% of the global market of plant protection products. Financial benefits are the main reason for the prevalence of this practice. Counterfeit and illegal pesticides may contain substances that may pose a threat to the environment, crops, animals, and humans, inconsistent with the label and registration dossier. In Poland, action against illegal and counterfeit plant protection products is undertaken by the Main Inspectorate of Plant Health and Seed Inspection (PIORiN), the police, the prosecution, and the pesticide producers. Results of chemical analyses carried out by the Institute of Plant Protection - National Research Institute Sosnicowice Branch, Pesticide Quality Testing Laboratory (PQTL IPP-NRI Sosnicowice Branch) indicate that a majority of illegal pesticides in Poland are detected in the group of herbicides. Products from parallel trade tend to have the most irregularities. This article describes the official quality control system of plant protection products in Poland and presents the analytical methods for testing pesticides suspected of adulteration and recent test results. PMID- 29616479 TI - The role of the water footprint in the context of green marketing. AB - The environmental degradation, because of various factors, such as climate change, human activities, increase of population globally, etc. have brought on pressures on the fresh water supplies that vary on time and space. Consequently, economic, environmental, and social tools have emerged known as footprints, in an effort to examine and measure the needs and consequences of humanity on the Earth's life support systems and take measures towards sustainable development. Furthermore, the constantly worsening environmental conditions have resulted in the cultivation of a green culture among society stakeholders that brought on terms such as green marketing and green products. This paper deals with the water footprint (WF) concept and an effort is performed, to explore through a literature review, in which ways it can contribute to the sustainable development of water use, in the context of green marketing (GM) strategies. The approach of the analysis is based on the discrimination to the following aspects: international scale, national and subnational scale, farmers, business, and consumers, in order to track the affection of each part in water issues. The main findings of the literature review showed that the aforementioned factors are playing a key role in protecting water recourses, by the way they formulate their water use and they are interrelated and interdependent. WFs can be useful in the context of GM, by providing helpful information about direct and indirect water consumption, to every contributor factor in supply chains, to consumers, governments, and water managers. PMID- 29616480 TI - Review on applications of artificial intelligence methods for dam and reservoir hydro-environment models. AB - Efficacious operation for dam and reservoir system could guarantee not only a defenselessness policy against natural hazard but also identify rule to meet the water demand. Successful operation of dam and reservoir systems to ensure optimal use of water resources could be unattainable without accurate and reliable simulation models. According to the highly stochastic nature of hydrologic parameters, developing accurate predictive model that efficiently mimic such a complex pattern is an increasing domain of research. During the last two decades, artificial intelligence (AI) techniques have been significantly utilized for attaining a robust modeling to handle different stochastic hydrological parameters. AI techniques have also shown considerable progress in finding optimal rules for reservoir operation. This review research explores the history of developing AI in reservoir inflow forecasting and prediction of evaporation from a reservoir as the major components of the reservoir simulation. In addition, critical assessment of the advantages and disadvantages of integrated AI simulation methods with optimization methods has been reported. Future research on the potential of utilizing new innovative methods based AI techniques for reservoir simulation and optimization models have also been discussed. Finally, proposal for the new mathematical procedure to accomplish the realistic evaluation of the whole optimization model performance (reliability, resilience, and vulnerability indices) has been recommended. PMID- 29616481 TI - Preoperative Rehabilitation in Lung Cancer Patients: Yoga Approach. AB - Lung cancer is one of the leading causes of cancer death worldwide. Surgical removal remains the best option for most tumors of this type. Reduction of cigarette consumption in patients with lung cancer candidates for the surgery could limit the impact of tobacco on postsurgical outcomes. Breathing exercises appear to help combat cigarette cravings. Yoga exercise benefits have been studied in lung cancer survivors, rather than in the preoperative setting. In this study, we have recruited 32 active smokers affected by lung cancer and being candidates for pulmonary surgery. The patients were randomly assigned to two groups: one treated by standard breathing and the other treated by yoga breathing (YB). The groups were evaluated at times T0 (baseline) and T1 (after 7 days of treatment) to compare the effects of the two breathing treatments on pulmonary performance in a presurgery setting. Pulmonary and cardiocirculatory functions have been tested using a self-calibrating computerized spirometer and a portable pulse oximetry device. The findings demonstrate appreciable short-term improvement in lung function assessed by spirometry. We conclude that yoga breathing can be a beneficial preoperative support for thoracic surgery. PMID- 29616482 TI - Impact of a Health Management Program on Healthcare Outcomes among Patients on Augmentation Therapy for Alpha 1-Antitrypsin Deficiency: An Insurance Claims Analysis. AB - INTRODUCTION: Alpha 1-antitrypsin deficiency (AATD) is a genetic disorder which reduces serum alpha 1-antitrypsin (AAT or alpha1-proteinase inhibitor, A1PI) and increases the risk of chronic obstructive pulmonary disease (COPD). Management strategies include intravenous A1PI augmentation, and, in some cases, a health management program (Prolastin Direct(r); PD). OBJECTIVES: This study compared clinical and economic outcomes between patients with and without PD program participation. METHODS: This retrospective study included commercial and Medicare Advantage health insurance plan members with >= 1 claim with diagnosis codes for COPD and >= 1 medical or pharmacy claim including A1PI (on index date). Outcomes were compared between patients receiving only Prolastin(r) or Prolastin(r)-C (PD cohort) and patients who received a different brand without PD (Comparator cohort). Demographic and clinical characteristics were captured during 6 months pre-index. Post-index exacerbation episodes and healthcare utilization and costs were compared between cohorts. RESULTS: The study sample comprised 445 patients (n = 213 in PD cohort; n = 232 in Comparator cohort), with a mean age 55.5 years, 50.8% male, and 78.9% commercially insured. The average follow-up was 822 days (2.25 years), and the average time on A1PI was 747 days (2.04 years). Few differences were observed in demographic or clinical characteristics. Adjusting for differences in patient characteristics, the rate of severe exacerbation episodes was reduced by 36.1% in the PD cohort. Adjusted total annual all-cause costs were 11.4% lower, and adjusted mean respiratory-related costs were 10.6% lower in the PD cohort than the Comparator cohort. Annual savings in all-cause total costs in the PD cohort relative to the Comparator cohort was US$25,529 per patient, largely due to significantly fewer and shorter hospitalizations. CONCLUSIONS: These results suggest that comprehensive health management services may improve both clinical and economic outcomes among patients with COPD and AATD who receive augmentation therapy. FUNDING: Grifols Shared Services of North America, Inc. PMID- 29616483 TI - Brief Report: Postural Balance and Daily Living Skills in Children and Adolescents with Autism. AB - The current study investigated the relation between postural balance and performance of daily living skills (DLS) in youth with autism spectrum disorder (ASD). Fifty-two youth with ASD (6-17 years; IQ >= 67) completed standardized balance testing and parent-reported DLS measures. Results showed a positive association between balance and DLS that was specific to youth with below-average IQ. While balance challenges were evident across the IQ spectrum, youth with above-average IQ did not exhibit an association between balance and DLS, perhaps suggestive of compensatory strategies implemented to offset balance challenges during daily-living tasks. These results underscore the need to better understand the contributions of motor challenges to DLS in youth with ASD within the context of broader cognitive and environmental factors. PMID- 29616484 TI - Broad Autism Phenotypic Traits and the Relationship to Sexual Orientation and Sexual Behavior. AB - Individuals with higher levels of the broad autism phenotype (BAP) have some symptoms of autism spectrum disorder (ASD). Like individuals with ASD, people with higher-BAP may have fewer sexual experiences and may experience more same sex attraction. This study measured BAP traits, sexual experiences, and sexual orientation in typically developing (TD) individuals to see if patterns of sexual behavior and sexual orientation in higher-BAP resemble those in ASD. Although BAP characteristics did not predict sexual experiences, one BAP measure significantly predicted sexual orientation, beta = 0.22, t = 2.72, p = .007, controlling for demographic variables (R2 change = .04, F = 7.41, p = .007), showing individuals with higher-BAP also reported increased same-sex attraction. This finding supports the hypothesis that individuals with higher-BAP resemble ASD individuals in being more likely than TD individuals to experience same-sex attraction. PMID- 29616487 TI - Effect of pH, temperature and freezing-thawing on quantity changes and cellular uptake of exosomes. PMID- 29616485 TI - Do Children with Autism Spectrum Disorder Benefit from Structural Alignment When Constructing Categories? AB - Individuals with ASD seem to construct categories via processes different to typically developing individuals. We examined whether individuals with ASD engage in structural alignment of exemplars when constructing categories. We taught children with ASD and typically developing children novel nouns for either single or multiple exemplars, and then examined their extensions of the learned nouns to objects that were either a perceptual or conceptual match to the original exemplar(s). Results indicated that, unlike typically developing participants, those with ASD gained no benefit from seeing multiple exemplars of the category and, thus, did not appear to engage in structural alignment in their formation of categories. However, they demonstrated superior performance compared to typically developing children when presented with a single exemplar. PMID- 29616486 TI - Adaptive Behaviour and Cognitive Skills: Stability and Change from 7 Months to 7 Years in Siblings at High Familial Risk of Autism Spectrum Disorder. AB - Cognitive and adaptive behaviour abilities early in life provide important clinical prognostic information. We examined stability of such skills in children at high familial risk for ASD who either met diagnostic criteria for ASD at age 7 years (HR-ASD, n = 15) or did not (HR-non-ASD, n = 24) and low-risk control children (LR, n = 37), prospectively studied from infancy. For both HR groups, cognitive skills were consistently lower across time than those of LR children. HR-ASD children showed increasing difficulties in adaptive behaviour over time compared to LR children, while the HR-non-ASD children showed no such difficulties. This pattern of change may inform our understanding of developmental profiles of HR siblings beyond core ASD symptoms. PMID- 29616488 TI - Daptomycin Proliposomes for Oral Delivery: Formulation, Characterization, and In Vivo Pharmacokinetics. AB - The aim of this study was to develop a proliposomal formulation of lipopeptide antibiotic drug daptomycin (DAP) for oral delivery. Thin film hydration was the selected method for preparation of proliposomes. Different phospholipids including soy-phosphatidylcholine (SPC), hydrogenated egg-phosphatidylcholine (HEPC), and distearoyl-phosphatidylcholine (DSPC) were evaluated in combination with cholesterol. The inclusion of surface charge modifiers in the formulation such as dicetyl phosphate (DCP) and stearylamine (SA) to enhance drug encapsulation was also evaluated. Particle size, surface charge, and encapsulation efficiency were performed on daptomycin-hydrated proliposomes as part of physical characterization. USP type II dissolution apparatus with phosphate buffer (pH 6.8) was used for in vitro drug release studies. Optimized formulation was evaluated for in vivo pharmacokinetics after oral administration to Sprague-Dawley rats. Proliposomes composed of SPC exhibited higher entrapment efficiency than those containing HEPC or DSPC. The highest entrapment efficiency was achieved by positively charged SPC-SA proliposomes, showing an encapsulation efficiency of 92% and a zeta potential of + 28 mV. In vitro drug release of optimized formulation demonstrated efficient drug retention totaling for less than 20% drug release within the first 60 min and only 42% drug release after 2 h. Pharmacokinetic parameters after single oral administration of optimized proliposomal formulation indicated a significant increase in oral bioavailability of DAP administered as SPC-SA proliposomes when compared to drug solution. Based on these results, incorporation of charge modifiers into proliposomes may increase drug loading and proliposomes an attractive carrier for oral delivery of daptomycin. PMID- 29616489 TI - Zein Microneedles for Localized Delivery of Chemotherapeutic Agents to Treat Breast Cancer: Drug Loading, Release Behavior, and Skin Permeation Studies. AB - Localized delivery of chemotherapeutic agents to treat breast cancer could limit their adverse drug reactions. The aim of this study was to investigate the influence of physico-chemical properties of chemotherapeutic agents in their loading, release behavior, and skin permeation using microneedles. Zein microneedles were fabricated using the micromolding technique containing 36 microneedles in a 1-cm2 area. These microneedles were loaded with two anti-breast cancer drugs, tamoxifen and gemcitabine, having different water solubilities. Entrapment or surface coating of chemotherapeutic agents in zein microneedles was optimized to achieve greater loading efficiency. The greatest loading achieved was 607 +/- 21 and 1459 +/- 74 MUg for tamoxifen and gemcitabine using the entrapment approach, respectively. Skin permeation studies in excised porcine skin showed that the coating on microneedles approach results in greater skin deposition for tamoxifen; while the poke-and-patch approach would provide greater skin permeation for gemcitabine. Taken together, it can be concluded that different loading strategies and skin penetration approaches have to be studied for delivery of small molecules using polymeric microneedles. PMID- 29616490 TI - Experimental Aspects of Measuring the Vial Heat Transfer Coefficient in Pharmaceutical Freeze-Drying. AB - One of the current methods for cycle optimization in primary drying to is develop a graphical design space based on quality by design (QbD). In order to construct the design space, the vial heat transfer coefficient (Kv) is needed. This paper investigated experimental factors that can affect the Kv result, examined the relationship between the batch average Kv and Kv values for individual vials, and recommended best practices for measuring Kv. Factors investigated included the technique for measuring ice temperature, shelf temperature, the use of a radiation shield on the door of the freeze-dry chamber, and shelf spacing. All experiments reported here used a chamber pressure of 100 mTorr. The most important factor was the technique for ice temperature measurement, where it is important to assure that any restrictions to vapor flow at the top of the vial are the same between monitored and non-monitored vials. Another factor that was found to play a role was the shelf temperature whereby the lower the shelf temperature, the larger the "edge effect," and the larger the average Kv. Factors that were found to not have a significant effect were the use of a radiation shield inside the chamber door and the shelf spacing. Being aware of these factors and knowing best practices when determining the vial heat coefficient will lead to more accurate design spaces and better cycle optimization. PMID- 29616491 TI - Management of Sleep Disordered Breathing in Patients with Heart Failure. AB - PURPOSE OF REVIEW: This paper reviews treatment options for sleep disordered breathing (SDB) in patients with heart failure. We sought to identify therapies for SDB with the best evidence for long-term use in patients with heart failure and to minimize uncertainties in clinical practice by examining frequently discussed questions: what is the role of continuous positive airway pressure (CPAP) in patients with heart failure? Is adaptive servo-ventilation (ASV) safe in patients with heart failure? To what extent is SDB a modifiable risk factor? RECENT FINDINGS: Consistent evidence has demonstrated that the development of SDB in patients with heart failure is a poor prognostic indicator and a risk factor for cardiovascular mortality. However, despite numerous available interventions for obstructive sleep apnea and central sleep apnea, it remains unclear what effect these therapies have on patients with heart failure. To date, all major randomized clinical trials have failed to demonstrate a survival benefit with SDB therapy and one major study investigating the use of adaptive servo-ventilation demonstrated harm. Significant questions persist regarding the management of SDB in patients with heart failure. Until appropriately powered trials identify a treatment modality that increases cardiovascular survival in patients with SDB and heart failure, a patient's heart failure management should remain the priority of medical care. PMID- 29616492 TI - Contraceptive Strategies in Women With Heart Failure or With Cardiac Transplantation. AB - PURPOSE OF REVIEW: We describe contraception for two groups of women: (1) women with heart failure and (2) women with cardiac transplantation. RECENT FINDINGS: Medical Eligibility Criteria for contraceptive agents address women with peripartum cardiomyopathy and women with valvular heart disease (Curtis et al. MMWR Recomm Rep 65:1-103, 2016). Recommendations for women with other forms of heart failure are extrapolated from these populations. Recommendations for women with cardiac transplantation have shifted since the 1980s: use of long-acting reversible contraception has increased, and there is a better understanding of the interactions between contraceptive and immunosuppressive regimens. Women with heart failure may utilize long-acting reversible contraception and permanent sterilization. Modifications should be made according to the specific etiology of the heart failure. In women with cardiac transplantation, pregnancy is high risk and should be avoided altogether for 1-2 years after transplantation. In uncomplicated transplantation, almost all forms of contraception are allowable. In complicated transplantation, combined hormonal contraceptives are contraindicated, and de novo IUD insertion is not recommended. PMID- 29616493 TI - Non-Pharmacological Approaches for Migraine. AB - Migraine is one of the most common and debilitating neurological disorders. However, the efficacy of pharmacological therapies may have unsatisfactory efficacy and can be poorly tolerated. There is a strong need in clinical practice for alternative approaches for both acute and preventive treatment. Occasionally, this need might arise in the context of low-frequency migraneurs who are not keen to use medication or fear the potential side effects. At the opposite end of the spectrum, clinicians might be faced with patients who have proven refractory to numerous medications. These patients may benefit from invasive treatment strategies. In recent years, promising strategies for migraine therapy have emerged alongside a progressively better understanding of the complex pathophysiology underlying this disease. This review discusses the most recent and evidence-based advances in non-pharmacological therapeutic approaches for migraine, offering alternatives to drug treatment for both the commonly encountered episodic cases as well as the more complex migraine phenotypes, which are capable of challenging even the headache specialist. PMID- 29616494 TI - The Biology of Monoclonal Antibodies: Focus on Calcitonin Gene-Related Peptide for Prophylactic Migraine Therapy. AB - Calcitonin gene-related peptide (CGRP) is 37-amino-acid neuropeptide, crucially involved in migraine pathophysiology. Four monoclonal antibodies (mAbs) targeting the CGRP pathway are currently under evaluation for the prevention of episodic and chronic migraine: eptinezumab (ALD403), fremanezumab (TEV-48125), galcanezumab (LY2951742), and erenumab (AMG334). As reviewed in this article, all 4 antibodies have been proven effective, tolerable, and safe as migraine prophylactic treatments in phase II clinical trials. The mean decrease in migraine days per month was between 3.4 and 6.3 days/month after 8 to 12 weeks of treatment, and the placebo subtracted benefit ranged from 1 to 2.18 days. Notably, up to 32% of subjects experienced total migraine freedom after drug administration. Substance class-specific adverse events and treatment-related serious adverse event did not occur. Further long-term and large-scale trials are currently under way to verify the safety and efficacy profile of mAbs. In particular, the potential risk of vascular adverse events and the role of anti drug antibodies deserve special attention. Anti-CGRP peptide and anti-CGRP receptor antibodies are the first effective treatments, which were specifically developed for the prevention of migraine. Their site of action in migraine prevention is most likely peripheral due to large molecule size, which prevents the penetration through the blood-brain barrier and thereby shows that peripheral components play a pivotal role in the pathophysiology of a CNS disease. PMID- 29616496 TI - How to use the Kaiser score as a clinical decision rule for diagnosis in multiparametric breast MRI: a pictorial essay. AB - : Due to its superior sensitivity, breast MRI (bMRI) has been established as an important additional diagnostic tool in the breast clinic and is used for screening in patients with an elevated risk for breast cancer. Breast MRI, however, is a complex tool, providing multiple images containing several contrasts. Thus, reading bMRI requires a structured approach. A lack of structure will increase the rate of false-positive findings and sacrifice most of the advantages of bMRI as additional work-up will be required. While the BI-RADS (Breast Imaging Reporting And Data System) lexicon is a major step toward standardised and structured reporting, it does not provide a clinical decision rule with which to guide diagnostic decisions. Such a clinical decision rule, however, is provided by the Kaiser score, which combines five independent diagnostic BI-RADS lexicon criteria (margins, SI-time curve type, internal enhancement and presence of oedema) in an intuitive flowchart. The resulting score provides probabilities of malignancy that can be used for evidence-based decision-making in the breast clinic. Notably, considerable benefits have been demonstrated for radiologists with initial and intermediate experience in bMRI. This pictorial essay is a practical guide to the application of the Kaiser score in the interpretation of breast MRI examinations. TEACHING POINTS: * bMRI requires standardisation of patient-management, protocols, and reading set-up. * Reading bMRI includes the assessment of breast parenchyma, associated findings, and lesions. * Diagnostic decisions should be made according to evidence-based clinical decision rules. * The evidence-based Kaiser score is applicable independent of bMRI protocol and scanner. * The Kaiser score provides high diagnostic accuracy with low inter-observer variability. PMID- 29616495 TI - Role of Methotrexate in the Management of Psoriatic Arthritis. AB - Methotrexate is known to be safe and efficacious in the management of rheumatoid arthritis and psoriasis and thus has been used for the management of psoriatic arthritis despite a lack of evidence to support efficacy in psoriatic arthritis from randomized controlled trials. Although the largest randomized trial to date did not support its use as a disease-modifying therapy, observational studies have supported its role, and current treatment recommendations approve of its use as a first-line agent for the management of psoriatic arthritis with predominant peripheral arthritis. The first treat-to-target study in psoriatic arthritis, comparing tight control with standard care, has shown the efficacy of methotrexate as monotherapy in the first 12 weeks. This trial demonstrated the effectiveness of methotrexate with improvement in peripheral arthritis, skin and nail disease, enthesitis, and dactylitis over the course of 12 weeks. There is conflicting evidence about the role of combination (concomitant methotrexate and anti-tumor necrosis factor) therapy. However, drug survival and immunogenicity of certain anti-tumor necrosis factors seem to be better when used in combination with methotrexate. This report reviews the available evidence on the efficacy and effectiveness of methotrexate in psoriatic arthritis and its role in treating psoriatic arthritis to target, as well as in combination with biologic agents. Ideally, randomized placebo-controlled clinical trials evaluating methotrexate (using subcutaneous route of delivery) would provide much-needed clarity on the role of methotrexate in the management of psoriatic arthritis; however, issues around using a placebo in patients with active psoriatic arthritis may render such a trial unfeasible. PMID- 29616497 TI - Malformed vertebrae: a clinical and imaging review. AB - A variety of structural developmental anomalies affect the vertebral column. Malformed vertebrae can arise secondary to errors of vertebral formation, fusion and/or segmentation and developmental variation. Malformations can be simple with little or no clinical consequence, or complex with serious structural and neurologic implications. These anomalies can occasionally mimic acute trauma (bipartite atlas versus Jefferson fracture, butterfly vertebra versus burst fracture), or predispose the affected individual to myelopathy. Accurate imaging interpretation of vertebral malformations requires knowledge of ageappropriate normal, variant and abnormal vertebral morphology and the clinical implications of each entity. This knowledge will improve diagnostic confidence in acute situations and confounding clinical scenarios.This review article seeks to familiarize the reader with the embryology, normal and variant anatomy of the vertebral column and the imaging appearance and clinical impact of the spectrum of vertebral malformations arising as a consequence of disordered embryological development.Teaching points * Some vertebral malformations predispose the affected individual to trauma or myelopathy. * On imaging, malformed vertebrae can be indistinguishable from acute trauma. * Abnormalities in spinal cord development may be associated and must be searched for. * Accurate interpretation requires knowledge of normal, variant and abnormal vertebral morphology. PMID- 29616499 TI - Incidence of Complications Following Thermocautery-assisted Circumcisions. AB - PURPOSE: This study aimed to examine the short- and long-term complications of thermocautery-assisted circumcisions. MATERIALS AND METHODS: A total of 1780 children who consecutively underwent thermocautery-assisted circumcisions from May 2014 to May 2016 in Yuksekova State Hospital in Turkey were included in this study. Thesechildren were classified into perioperative, early postoperative, and long-term complication groups. In addition, the age groups were compared in terms of complications. RESULTS: The patient age and surgical duration means were 4.16 +/- 3.805 years old and 6.14 +/- 1.703 minutes, respectively. Complications were observed in twelve patients, or 0.6% of the whole observation set. One patient exhibited bleeding and was included in the perioperative complications group. Four patients were included in the early postoperative complications group; three of them had bleeding and one had an infection. Finally, three patients had trapped penises, two patients had meatitis, one patient had a delayed wound healing issue, and one hada glans-skin bridge. These seven patients fell into the long-term complications group. The patients younger than 3 years old had significantly higher complication rates when compared to the older patients, and this comparison was statistically significant (P = 0.001). CONCLUSION: The results showed that thermocautery-assisted circumcision is a safe and efficient surgical technique for use in children. PMID- 29616498 TI - Quality of Care in Rheumatoid Disease from the Clinician Perspective: A Modified Delphi Panel Approach. AB - INTRODUCTION: To establish clinical consensus on important and relevant quality of-care (QoC) attributes in rheumatic disease (RD) treatment that may improve treatment outcomes and guide best practices. METHODS: Twenty-three QoC attributes were identified in a literature review. Fifteen European-based clinicians were selected based on their contributions to RD guidelines, publications, and patient care. A three-round (an interview round and two web-based rounds) modified Delphi panel was conducted to reach consensus and finalize a QoC attribute list. RESULTS: In round 1 (clinician interviews), clinicians reported 52 unique QoC attributes across 14 themes, with the greatest number of attributes reported in the "treatment goals" (n = 7) and "remote monitoring" (n = 7) themes. During rounds 2 and 3, the critically important QoC attributes most frequently reported were access to care/treatment (n = 14, 93.3%), safety of treatment (round 2 n = 14, 93.3%, round 3 n = 13, 86.7%), and access to clinicians and specialists (round 2: n = 13, 86.7%, round 3: n = 14, 93.3%). The final list contained 53 QoC attributes. CONCLUSION: The study demonstrates consensus across several themes of QoC. Quality of care is a complex, multidimensional, and fluid concept that can be improved by ensuring patients have access to care, open communication between patients and clinicians, and the use of novel strategies, such as remote monitoring. Utilization of the attribute list can potentially improve the lives of patients, provide clinicians with tools to provide greater QoC, and improve the healthcare system as a whole. FUNDING: Merck & Co., Inc. PMID- 29616500 TI - Effect of Obesity on Postacute Outcomes of Skilled Nursing Facility Residents with Hip Fracture. AB - OBJECTIVES: To examine the effect of obesity (body mass index (BMI)>=30.0 kg/m2 ) on outcomes of older adults admitted to skilled nursing facilities (SNFs) for hip fracture postacute care (PAC). DESIGN: Retrospective cohort study. SETTING: U.S. Medicare- and Medicaid-certified SNFs from 2008 to 2015. PARTICIPANTS: Medicare fee-for-service beneficiaries discharged to a SNF after hospitalization for hip fracture (N=586,683; n=82,768 (14.1%) meeting obesity criteria). Exclusion criteria were aged younger than 65, being underweight (BMI<18.5 kg/m2 ), and SNF use in the year prior to index hospitalization. MEASUREMENTS: Residents were divided into 4 BMI categories according to cutoffs that the World Health Organization has established: not obese (BMI 18.5-29.9 kg/m2 ), mild obesity (BMI 30.0-34.9 kg/m2 ), moderate obesity (BMI 35.0-39.9 kg/m2 ), and severe obesity (BMI>=40.0 kg/m2 ). Robust Poisson regression was used to compare differences in average nursing facility length of stay (LOS) and rates of 30-day hospital readmission, successful discharge to community, and becoming a long-stay resident (LOS>100) according to obesity level. Models were adjusted for individual-level covariates and facility fixed effects. RESULTS: Residents with mild (adjusted relative risk (aRR)=1.16, 95% CI=1.12-1.19), moderate (aRR=1.27, 95% CI=1.20 1.35), and severe (aRR=1.67, 95% CI=1.54-1.82) obesity were more likely to be readmitted within 30 days than those who were not obese. The average difference in LOS between residents without obesity and those with mild obesity was 2.6 days (95% CI=2.2-2.9 days); moderate obesity, 4.2 days (95% CI=3.7-5.1 days); and severe obesity, 7.0 days (95% CI=5.9-8.2 days). Residents with obesity were less likely to be successfully discharged and more likely to become long-stay nursing home residents. CONCLUSION: Obesity was associated with worse outcomes in postacute SNF residents with hip fracture. Efforts to provide targeted care to residents with obesity may be essential to improve outcomes. Obesity may be an overlooked risk adjuster in quality-of-care measures and in payment reforms related to PAC for individuals with hip fracture. PMID- 29616501 TI - Effectiveness of omega-3 polyunsaturated fatty acids against microbial pathogens. AB - Microorganisms provide both beneficial and harmful effects to human beings. Beneficial effects come from the symbiotic relationship that exists between humans and microbiota, but then several human illnesses have turned some friendly microbes into opportunistic pathogens, causing several microbial-related diseases. Various efforts have been made to create and utilize antimicrobial agents in the treatment and prevention of these infections, but such efforts have been hampered by the emergence of antimicrobial resistance. Despite extensive studies on drug discovery to alleviate this problem, issues with the toxicity and tolerance of certain compounds and continuous microbial evolution have forced researchers to focus on screening various phytochemical dietary compounds for antimicrobial activity. Linolenic acid and its derivatives (eicosapentaenoic acid and docosahexaenoic acid) are omega-3 fatty acids that have been studied due to their role in human health, being important for the brain, the eye, the cardiovascular system, and general human growth. However, their utilization as antimicrobial agents has not been widely appreciated, perhaps due to a lack of understanding of antimicrobial mechanisms, toxicity, and route of administration. Therefore, this review focuses on the efficacy, mechanism, and toxicity of omega 3 fatty acids as alternative therapeutic agents for treating and preventing diseases associated with pathogenic microorganisms. PMID- 29616502 TI - PGL3 is required for chlorophyll synthesis and impacts leaf senescence in rice. AB - Rice leaf color mutants play a great role in research about the formation and development of chloroplasts and the genetic mechanism of the chlorophyll (Chl) metabolism pathway. pgl3 is a rice leaf color mutant derived from Xiushui11 (Oryza sativa L. spp. japonica), treated with ethyl methane sulfonate (EMS). The mutant exhibited a pale-green leaf (pgl) phenotype throughout the whole development as well as reduced grain quality. Map-based cloning of PGL3 revealed that it encodes the chloroplast signal recognition particle 43 kDa protein (cpSRP43). PGL3 affected the Chl synthesis by regulating the expression levels of the Chl synthesis-associated genes. Considerable reactive oxygen species were accumulated in the leaves of pgl3, and the transcription levels of its scavenging genes were down-regulated, indicating that pgl3 can accelerate senescence. In addition, high temperatures could inhibit the plant's growth and facilitate the process of senescence in pgl3. PMID- 29616503 TI - A novel endogenous badnavirus exists in Alhagi sparsifolia. AB - We report the recovery of a 7068-nt viral sequence from the "viral fossils" embedded in the genome of Alhagi sparsifolia, a typical desert plant. Although the full viral genome remains to be completed, the putative genome structure, the deduced amino acids and phylogenetic analysis unambiguously demonstrate that this viral sequence represents a novel species of the genus Badnavirus. The putative virus is tentatively termed Alhagi bacilliform virus (ABV). Southern blotting and inverse polymerase chain reaction (PCR) data indicate that the ABV-related sequence is integrated into the A. sparsifolia genome, and probably does not give rise to functional episomal virus. Molecular evidence that the ABV sequence exists widely in A. sparsifolia is also presented. To our knowledge, this is the first endogenous badnavirus identified from plants in the Gobi desert, and may provide new clues on the evolution, geographical distribution as well as the host range of the badnaviruses. PMID- 29616504 TI - Biosynthesis of (R)-2-hydroxy-3-phenylpropionic acid using whole recombinant Escherichia coli cells in an aqueous/n-octane biphasic system. AB - (R)-2-hydroxy-3-phenylpropionic acid (PLA) is an ideal antimicrobial compound with broad-spectrum activity against a wide range of Gram-positive bacteria, some Gram-negative bacteria, and fungi. We studied the bioconversion of phenylpyruvate (PPA) to PLA using whole recombinant Escherichia coli cells in a series of buffer/organic solvent systems. Octane was found to be the best organic solvent. The optimum volume ratio of the water phase to the n-octane phase, conversion temperature, substrate concentration, and cell concentration were 6:4, 40 degrees C, 12.5 g/L, and 30 g/L wet cells, respectively. Under the optimized conditions, the average PLA productivity in the aqueous/ n-octane system was 30.69% higher than that in the aqueous system, and 32.31 g/L PLA was obtained with the use of a stirred reactor (2-L scale). Taken together, our findings indicated that PLA biosynthesis was more efficient in an aqueous/n-octane biphasic system than in a monophasic aqueous system. The proposed biphasic system is an effective strategy for enhancing PLA yield and the biosynthesis of its analogues. PMID- 29616505 TI - Network analysis of microRNAs, transcription factors, and target genes involved in axon regeneration. AB - Axon regeneration is crucial for recovery from neurological diseases. Numerous studies have identified several genes, microRNAs (miRNAs), and transcription factors (TFs) that influence axon regeneration. However, the regulatory networks involved have not been fully elucidated. In the present study, we analyzed a regulatory network of 51 miRNAs, 27 TFs, and 59 target genes, which is involved in axon regeneration. We identified 359 pairs of feed-forward loops (FFLs), seven important genes (Nap1l1, Arhgef12, Sema6d, Akt3, Trim2, Rab11fip2, and Rps6ka3), six important miRNAs (hsa-miR-204-5p, hsa-miR-124-3p, hsa-miR-26a-5p, hsa-miR-16 5p, hsa-miR-17-5p, and hsa-miR-15b-5p), and eight important TFs (Smada2, Fli1, Wt1, Sp6, Sp3, Smad4, Smad5, and Creb1), which appear to play an important role in axon regeneration. Functional enrichment analysis revealed that axon associated genes are involved mainly in the regulation of cellular component organization, axonogenesis, and cell morphogenesis during neuronal differentiation. However, these findings need to be validated by further studies. PMID- 29616506 TI - Effects of different external carbon sources and electron acceptors on interactions between denitrification and phosphorus removal in biological nutrient removal processes. AB - The effects of two different external carbon sources (acetate and ethanol) and electron acceptors (dissolved oxygen, nitrate, and nitrite) were investigated under aerobic and anoxic conditions with non-acclimated process biomass from a full-scale biological nutrient removal-activated sludge system. When acetate was added as an external carbon source, phosphate release was observed even in the presence of electron acceptors. The release rates were 1.7, 7.8, and 3.5 mg P/(g MLVSS.h) (MLVSS: mixed liquor volatile suspended solids), respectively, for dissolved oxygen, nitrate, and nitrite. In the case of ethanol, no phosphate release was observed in the presence of electron acceptors. Results of the experiments with nitrite showed that approximately 25 mg NO2-N/L of nitrite inhibited anoxic phosphorus uptake regardless of the concentration of the tested external carbon sources. Furthermore, higher denitrification rates were obtained with acetate (1.4 and 0.8 mg N/(g MLVSS.h)) compared to ethanol (1.1 and 0.7 mg N/ (g MLVSS.h)) for both anoxic electron acceptors (nitrate and nitrite). PMID- 29616509 TI - [Comment on: Post-exposure prophylaxis against HIV, the view from the emergency department]. PMID- 29616507 TI - Physical and chemical characteristics of PM2.5 and its toxicity to human bronchial cells BEAS-2B in the winter and summer. AB - With the increasing occurrence of haze during the summer, the physicochemical characteristics and toxicity differences in PM2.5 in different seasons are of great concern. Hangzhou is located in an area that has a subtropical monsoon climate where the humidity is very high during both the summer and winter. However, there are limited studies on the seasonal differences in PM2.5 in these weather conditions. In this test, PM2.5 samples were collected in the winter and summer, the morphology and chemical composition of PM2.5 were analyzed, the toxicity of PM2.5 to human bronchial cells BEAS-2B was compared, and the correlation between PM2.5 toxicity and the chemical composition was discussed. The results showed that during both the winter and summer, the main compounds in the PM2.5 samples were water-soluble ions, particularly SO42-, NO3-, and NH4+, followed by organic components, while heavy metals were present at lower levels. The higher the mass concentration of PM2.5, the greater its impact on cell viability and ROS levels. However, when the mass concentration of PM2.5 was similar, the water extraction from the summer samples showed a greater impact on BEAS-2B than that from the winter samples. The cytotoxicity of PM2.5 was closely associated with heavy metals and organic pollutants but less related to water soluble ions. PMID- 29616508 TI - An efficacy analysis of anti-vascular endothelial growth factor therapy for choroidal neovascularization secondary to multifocal choroiditis and comparison with wet age-related macular degeneration. AB - OBJECTIVE: To evaluate the effect of anti-vascular endothelial growth factor (VEGF) on juxtafoveal choroidal neovascularization (CNV) secondary to multifocal choroiditis (MFC) and wet age-related macular degeneration (AMD). METHODS: In this retrospective, comparative study, 20 unique eyes with CNV were divided into two groups: 10 patients affected by MFC and 10 patients diagnosed with wet AMD. They all received local intravitreal (IVT) injections of ranibizumab, with 6 months of follow-up. Retreatment injections were performed based on findings suggestive of active neovascularization. RESULTS: Significant improvements were observed in the juxtafoveal CNV lesions, and average central macular thickness decreased in both groups following the anti-VEGF therapy (P<0.05). The average number of injections used in MFC patients was 1.6, while three injections on average were used in wet AMD patients (Z=-2.844, P=0.009). Best-corrected visual acuity was significantly improved in MFC patients after anti-VEGF therapy (P<0.05), and there was no significant difference in wet AMD patients between before anti-VEGF therapy and 6 months later (P>0.05). CONCLUSIONS: IVT ranibizumab resulted in good clinical outcomes for juxtafoveal CNV secondary to MFC and wet AMD, but the average number of injections used in MFC was fewer than that used in wet AMD over a 6-month observation period. Compared with the wet AMD group, visual acuity was obviously improved in the MFC group at 6 months. PMID- 29616510 TI - First clinical isolation report of Shewanella algae from the stools of a patient with acute enteritis in Spain. AB - We report a case of acute enteritis caused by Shewanella algae in a cirrhotic patient. Biochemical identification systems revealed to be insufficient to identify the Shewanella isolate at the species level, thus requiring 16S rRNA and gyrB partial gene sequencing. Even if co-infection by Clostridium difficile could not be ruled out, this is, to our knowledge, the first report of acute enteritis caused by Shewanella algae in Europe. PMID- 29616511 TI - Distribution of the genotype of the Hepatitis C Virus in Cordoba-Spain. PMID- 29616512 TI - [First male's Mycobaterium iranicum clinical isolation in Spain]. PMID- 29616513 TI - A rare case of pleural infection due to Propionibacterium acnes (Cutibacterium acnes). PMID- 29616514 TI - Peritonitis caused by Blastomonas natatoria in a patient submitted to peritoneal dyalisis. PMID- 29616515 TI - [Moraxella osloensis emerging infection. Visiting to genital infection]. PMID- 29616516 TI - [Chronic suppurative otitis media by Mycobacterium tuberculosis. A diagnostic challenge]. PMID- 29616517 TI - [Influenza vaccination coverage in Health Spanish Military Personnel]. PMID- 29616518 TI - Coronary artery bypass surgery in patients with chronic brain hypoperfusion. AB - BACKGROUND: Cerebrovascular disease (CVD) is a risk factor of stroke and cerebral hypoperfusion is one of the underlying mechanisms. We hypothesized that coronary artery bypass grafting (CABG) can be performed at an acceptable risk for such patients without concomitant surgery for CVD. METHODS: Carotid echo was carried out for 538 consecutive patients undergoing isolated CABG between 2005 and 2016. Magnetic resonance image/angiography (MRI/A) for neck and brain was performed for 288 patients (stenoses >=50% in echo were basically included). Patients with multiple severe stenoses (>=70%) and/or occlusion in carotid and/or vertebral systems associated with contra-lateral carotid and/or Willis circle lesions (reduced collateral flow) on MRI/A (N.=43) were investigated. Whenever possible, single photon emission computed tomography (SPECT, N.=20) with or without acetazolamide challenge was performed. Off-pump CABG was used in all patients. Systolic arterial pressure was maintained >=100 mmHg or >=90 mmHg with intra aortic counter-pulsation. Patients were followed up for one year and MRI was performed. RESULTS: Hypoperfusion and reduced cerebrovascular reserve were observed in 90.0% and 88.9% respectively in patients underwent SPECT. There was one postoperative stroke and no mortality. MRI (N.=32) revealed no new stroke, however, five other patients experienced strokes during follow-up period. In patients without the CVD, there was one stroke in the study period, which was seen postoperatively. CONCLUSIONS: CABG can be performed at an acceptable risk in patients with brain hypoperfusion. However, these patients suffered high stroke incidence during the follow-up. It is therefore, important to identify those patients preoperatively to plan and implement an appropriate treatment regime. PMID- 29616519 TI - Outcomes of Solo Smart valve in a single-center experience of 270 patients. AB - BACKGROUND: The Solo Smart pericardial aortic valve has been widely used in Europe as an option for aortic valve replacement (AVR). We are reporting early and midterm clinical outcomes of AVR with the Solo Smart valve in a single North America center. METHODS: This is a retrospective study of 270 consecutive patients who had AVR at Mazankowski Alberta Heart Institute from February 2011 to March 2015. Follow-up and echocardiographic data were collected retrospectively from electronic and paper charts. Univariate and multivariate analysis were performed to evaluate the results. RESULTS: The mean age was 71.2+/-10.0 years, 67.4% were male, and 79.3% had combined procedures. Mean STS Score was 4.18+/ 3.91. Early mortality was 3.7% for the entire group and 0% for isolated AVR group. Mean cross-clamp time for isolated AVR and AVR with concomitant procedure was 70.8+/-12.7 min and 117.0+/-45.0 min, respectively. Permanent pacemaker implantation was necessary in 2.2% of patients. Echocardiography demonstrated a reduction in mean gradients from 40.8+/-17.4 mmHg to 7.6+/-3.7 mmHg and peak gradient from 72.5+/-48.8 mmHg to 15.5+/-7.5 mmHg. The 1-, 3-, and 5-year overall survival was 93.0%, 86.5% and 75.9%, respectively. At 5 years, freedom from valve related death was 92.4%, freedom from structural valve deterioration and freedom from aortic valve reoperation were 96.4% and 98%, respectively. CONCLUSIONS: The Solo Smart valve is safe and has excellent hemodynamic performance. Aortic valve reoperation and rates of valve-related adverse events during midterm follow-up were low. PMID- 29616520 TI - Comparison of endovascular aneurysm sealing and repair with respect to contrast use and radiation in comparable patient cohorts. AB - BACKGROUND: Due to recent advances in endograft design and percutaneous access, technical success could be increased during endovascular aneurysm repair (EVAR). Beside EVAR, endovascular aneurysm sealing (EVAS) provides an alternative procedure to treat aneurysms. To compare the two methods, additional benchmark criteria should be evaluated: Screening time, dose area product (DAP), procedure time and contrast use. In this study these technical variables are analysed for EVAS vs. EVAR in comparable patient cohorts. METHODS: It is a retrospective, single-centre study. Only elective cases of infrarenal aortic aneurysms were included, all treated by the same surgeon (D.B.). Procedures were performed within the instructions for use without additional procedures. All operations were undertaken in a hybrid operating theatre. For EVAR, only the Medtronic Endurant(r) and the Gore C3 Excluder(r) were included. For EVAS the Nellix(r) from Endologix was used. RESULTS: Between 2012 and 2016, 67 patients were treated with EVAS and 40 with EVAR; of these 20 and 16 could be introduced into the study respectively. Median age was 73 and 72 years respectively (only men). The two groups were comparable in terms of BMI, GFR and ASA-status. Screening time was reduced for EVAS (10,6 vs. 14,5 min., p<0,01), while the DAP was not significantly different. Procedural time and contrast use were increased for EVAS (120 vs. 96 min., 120 vs. 79 ml, p<0,01). CONCLUSIONS: Especially the younger EVAS-procedure requires ongoing review in order to further reduce contrast agent. Reduced screening time for EVAS does not have a significant impact on radiation dose. PMID- 29616521 TI - The relationship between cerebral oxygen saturation and quantitative metrics of neurological function after coronary bypass surgery: a feasibility study. AB - BACKGROUND: It is well-known that patients undergoing coronary artery bypass grafting (CABG) surgery may experience neurological dysfunction following their operation. However, the nature of this dysfunction has not been properly quantified. Furthermore, the relationship between postoperative impairment and cerebral oxygen saturation during surgery has remained unclear. This study aims to define the feasibility of using robotic technology to quantify post-CABG neurocognitive function, and to correlate these objective metrics with intraoperative cerebral oxygenation. METHODS: Neurological function was tested using robotic technology and a standardized questionnaire before and 3 months after surgery. In addition, frontal lobe cerebral oxygenation was recorded using the FORESIGHT near-infrared spectrometer for the duration of the operation. Pre- and postoperative neurological assessment was performed for 24 participants. Of those 24, 20 participants had cerebral oxygenation recorded during their surgery. RESULTS: The cerebral oximeter captured 97.2% of the data. Majority of patients experienced no significant decline in overall neurocognitive function. Abnormal postoperative scores were most frequent in a sensorimotor task that involved additional cognitive load. In this reverse visually guided reaching task, postoperative scores significantly correlated with mean and minimum intraoperative cerebral oxygenation values, with lower values being associated with worse performance. CONCLUSIONS: It is feasible to use robotic technology as a quantitative and objective neurocognitive assessment method for patients undergoing CABG. The relationship between quantitative metrics of neurocognitive function and intraoperative cerebral oxygenation warrants further investigation. PMID- 29616522 TI - Further options and survival results after failure following ECLS implantation. AB - BACKGROUND: A retrospective study was designed to analyze the outcome of patients with extracorporeal life support (ECLS) who needed a consecutive cardiac or pulmonary support system. METHODS: From 2006 to 2016, 93 out of 587 patients with their age ranging from 2.4 to 77.3 years required an exchange of an ECLS by another mechanical support system. Sixty- one patients were inhospital cases, 39 patients were referred with ECLS from other institutions by ambulance car (n=15) or helicopter (n=24). Sixty-five patients came from internal medicine wards, of which 38 patients had CPR, whereas 24 patients suffered post- cardiotomy failure with CPR in 11 cases. Ten patients were referred from other hospitals for failure to wean from ECLS. RESULTS: Leading symptoms were continuing cardiac failure in 43 patients (46%) and ongoing respiratory failure after cardiac recovery in 50 patients (54%). Patients with cardiac failure underwent implantation of a ventricular assist device (n=36) or remained on long-term ECLS (n=7) until a donor organ for heart transplantation was available (mean waiting time 43 days). Respiratory failure was treated by veno-venous ECMO (n=34) or vav-ECMO (n=16). Overall inhouse survival was 50.5 % (n=47). Only 22.6 % of patients (n=21) died during ongoing support. In contrast, 26.9 % of patients (n=25) deceased 35+/-51 days after weaning from vv- or vav-ECMO. Major reasons of death were multi-organ failure in 16 patients, cerebral hypoxia in 12 patients, sepsis in 10 patients, and intractable ow output in 5 patients. CONCLUSIONS: Despite a switch from ECLS to another mechanical support system, survival remains limited as irreversible multi-organ failure and sepsis still jeopardize the patients' life. PMID- 29616523 TI - Short-term outcome of cardiac surgery under cardiopulmonary bypass in patients who refuse transfusion: a controlled study. AB - BACKGROUND: Although bloodless cardiac surgery has been successfully performed for many years, studies with controls permitting transfusion are few and their results inconclusive. This study compares the outcome of cardiac surgery on Jehovah's Witnesses (JW) refusing transfusion, with that of controls permitting transfusion if required. METHODS: Data from 172 operations in 162 JW were compared with 172 matched controls. Risk factors, preoperative, operative, 48 hour postoperative variables, outcome data and transfusions were recorded. RESULTS: Preoperative and operative variables were similar in both groups except for more previous cardiac operations, and more frequent use of cell saver and aprotinin in JW, who bled less and had higher hemoglobin concentrations at all periods. Thirty-day mortality was higher in JW (9.9% vs. 3.5%; P=0.03) (Risk difference 6.4%; CI95%: 2.7-10.1). Nevertheless operative mortality was similar in both groups (9.9% vs. 7.6%; P=0.44). Mortality in low-risk subjects was higher in JW (8.9% vs. 1.0%; P=0.02) (Risk difference 7.9%; CI95%: 2.7-13.2). Moreover, death associated with hemorrhage and anemia tended to be more frequent in JW. Mortality of transfused controls (14.1%) and their matched JW (13.0%) was similar. In contrast, mortality of non-transfused controls was zero versus 6.3% in their matched JW (P=0.059). CONCLUSIONS: Low-risk JW had significantly higher mortality than controls. Bleeding related deaths tended to be more frequent in JW. Blood-sparing maneuvers should be intensively implemented in both JW and patients permitting transfusion in order to reduce bleeding and the need for transfusion with its harmful effects. PMID- 29616524 TI - Systematic review of type IIIb endoleak after elective endovascular aneurysm repair. AB - INTRODUCTION: To investigate the presentation, aetiology, management and outcomes of type IIIb endoleak after endovascular aneurysm repair (EVAR). EVIDENCE ACQUISITION: Electronic bibliographic databases were searched to identify published reports of type IIIb endoleak after EVAR, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards. EVIDENCE SYNTHESIS: In total 33 articles were identified reporting on a total of 50 patients spanning 19 years of EVAR (1998-2017). Some 11 device-types were used. The median time from implantation to intervention was 27 months (0-168). There was a significant aneurysm sac expansion in 69% of reported cases. Thirteen patients (26%) presented with aneurysm rupture. A definitive diagnosis of type IIIb endoleak made on computed tomographic angiography (CTA) in only 20% of cases. Proposed failure modes included suture breakage, graft erosion by stents, iatrogenic, graft infection and presumed manufacturing faults. Endoleak location was in the main body in 81% of reported cases. Almost one third (31%) of patients were treated with open repair. The remaining patients were treated with endovascular techniques or hybrid procedures. Some novel off-label endovascular solutions were proposed to maintain a bifurcated configuration. Thirty-day mortality in patients treated for aneurysm rupture was 50%. The 30-day mortality rate in non- rupture cases was 2% (endovascular 0% treatment, open 2%). CONCLUSIONS: Type IIIb endoleak is a serious condition associated with a significant risk of rupture. Definitive diagnosis is challenging and has been described in almost all conventional devices. Most patients can be treated successfully by endovascular means, though maintaining a bifurcated configuration may require non-standard techniques or off-label use. PMID- 29616525 TI - Cardiac rehabilitation for patients having cardiac surgery: a systematic review. AB - INTRODUCTION: Cardiac rehabilitation (CR) is recommended for all cardiac patients including patients after cardiac surgery. Since the effect of CR after cardiac surgery has not been well established yet, we conducted a systematic review on the effects of CR for patients after cardiac surgery compared to treatment as usual. EVIDENCE ACQUISITION: A systematic review of randomized clinical trials (RCTs), quasi-randomized and prospective observational studies in The Cochrane Library, PubMed/MEDLINE and EMBASE was undertaken until October 18th, 2017. Adults after any kind of cardiac surgery were included. Primary outcome was all cause mortality, other outcomes were serious adverse events, health-related quality of life, work participation, functioning and costs/cost-effectiveness. Risk of bias was evaluated, and the quality of evidence was assessed by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) criteria. EVIDENCE SYNTHESIS: Eighteen RCTs and 15 observational studies were included. Low risk of bias was only observed in one observational study. Meta analysis of RCTs suggested no significant difference of CR compared to control on mortality (random-effects relative risk (RR) 0.93 (95% CI: 0.40-1.81), while observational studies suggested statistically significant beneficial effect associated with CR (random-effects RR=0.49, 95% CI: 0.35 - 0.68). CR did not significantly affect any of the other outcomes. Due to the limited data TSA could not be performed. CONCLUSIONS: The body of evidence does not allow us to reach any reliable conclusions about the effectiveness of CR following cardiac surgery. Future trials need to be conducted with low risks of bias and clearly defined outcomes. PMID- 29616526 TI - Effects of chronic statin use on 30-day major adverse cardiac and cerebrovascular events after thoracic endovascular aortic repair. AB - BACKGROUND: Cardiac and cerebrovascular complications are major causes of adverse outcomes following thoracic endovascular aortic repair (TEVAR). The benefits of statins have been established, but little is known about their impact on patients undergoing TEVAR. We investigated whether chronic statin use protected against early postoperative major adverse cardiac and cerebrovascular events (MACCEs) after TEVAR. METHODS: We retrospectively reviewed 211 patients who underwent TEVAR between February 2013 and March 2017 classified into two groups, those with acute aortic syndrome (AAS, N.=79) and those without (non-AAS, N.=132). Patients were subdivided according to preoperative statin therapy for >=3 months or not. The primary endpoint was 30-day MACCE, defined as myocardial infarction, stroke, arrhythmia, cardiovascular death, or cerebrovascular death. Acute kidney injury (AKI) occurrence within 48 hours was also evaluated. Multivariate logistic regression analysis was performed to identify independent risk factors for MACCEs and AKI. RESULTS: Incidence of MACCEs (1% vs. 11%, P=0.019) was significantly lower in the statin group than in the no-statin group in non-AAS patients. Multivariate logistic regression analysis revealed statin use (odds ratio 0.85, 95% confidence interval 0.01-0.95, P=0.046) as an independent predictor for MACCE in non-AAS patients. The AKI incidence was significantly higher in the statin group than in the no-statin group in AAS patients (44% vs. 15%, P=0.018). CONCLUSIONS: In patients undergoing TEVAR, chronic statin use was associated with reduced 30-day MACCEs in non-AAS patients, but not in AAS patients. It might rather be associated with increased risk of AKI in AAS patients. PMID- 29616527 TI - Retrospective study reveals the circulation of norovirus genotype GII.P21-GII.2 in Romania AB - Noroviruses are the leading cause of acutegastroenteritis, causing significant economic burdenglobally. Infection is self-limiting, occurring as sporadiccases or producing outbreaks associated withconsumption of contaminated water or food. All agegroups are affected and person to person transmission isfrequent. Except a recent outbreak in Romania caused bythe emergent genotype GII.P17-GII.17, few dataregarding the circulation of noroviruses in our country areavailable. We retrospectively analyzed stool samples fromacute gastroenteritis patients hospitalized in Romaniabetween 2005 and 2008. Noroviruses were detected byRT-PCR and phylogenetic analysis was inferred frompartial sequences spanning ORF1 and ORF2.Recombinant GII.P21-GII.2 isolates were found in twoadult patients from a cluster of acute gastroenteritis in2006. Molecular analysis based on partial genomicsequences indicated high degree of similarity between thetwo isolates and grouped them with cosmopolitan strainscirculating in the same period of time. Along with the highrate of mutation, recombination is an important drivingforce in norovirus evolution. GII.P21 isolates, formerlyknown as GII.b recombinants, have been detected inEurope since 2000 and associated with sporadic cases andoutbreaks of gastroenteritis worldwide. This is the firstwork describing norovirus GII.P21-GII.2 identified inRomania. PMID- 29616528 TI - The impact of the molecular diagnosis in the surveillance of the Clostridium difficile infection. AB - Clostridium difficile is the agent of many cases ofantibiotic associated diarrhea. The prevalence of thetoxigenic Clostridium difficile strains was assessed byreal-time PCR between May 2014- January 2015, at theEmergency University Hospital, Bucharest, Romania. Theincidence of the Clostridium difficile infection was 0.47%.Among the 1119 stool specimens tested, 165 (13.8%)were positive for C. difficile toxins A and B byimmunochromatography test. All 165 positive sampleswere investigated by real time PCR and 134 (81%)samples were positive for toxin B and for the binary toxin,while the rest were positive for toxin B. A high numberof samples positive for binary toxin was recorded in theGeneral surgery department (29.85%), Neurology(13.43%), and Internal medicine (12.68%). Many of theinfected patients presented as underlying pathology,cancer, diabetes mellitus and stroke. A rapid decisionconcerning the antibiotic therapy was made, to decreasethe risk of nosocomial spread. PMID- 29616529 TI - Expression signature of some immunity genes triggered in Apis mellifera carpatica model by Pseudomonas entomophila experimental infection. AB - Herein we report the expression profiles ofcertain immunity genes from Apis melliferacarpatica worker individuals experimentallyinfected with Pseudomonas entomophila L48strain. Changes of the relative expression ofabaecin, Relish, dorsal, Toll-1, domeless, andDuox genes were monitored by qRT-PCR. Ourresults were compared with similar ones fromDrosophila melanogaster model and suggest thatthese genes are involved in the anti-infectivedefense mechanisms. Our study opensinvestigation avenues for modern prophylacticand therapeutic approaches of infections affectingthe honeybees, but also for identifying neworthologous genes involved in the human innateimmune response. PMID- 29616530 TI - Resistance pattern of multi-drug resistant strains of Mycobacterium tuberculosis and characteristics of patients with multi-drug resistant tuberculosis. AB - Introduction: Multi-drug resistant tuberculosis(MDR-TB) is a major concern in the medical community.Knowledge about the drug resistance pattern ofMycobacterium tuberculosis strains plays an essential rolein the management of the disease. Material and methods: We conducted a retrospective,3-year study (2009-2011), in an urban area. We collecteddata on the drug resistance for 497 M. tuberculosis strains,isolated from patients with pulmonary TB. Among the 497strains, we identified 158 MDR strains. Eighty medicalrecorders of patients infected with MDR strains were availableand we included those patients in the study group. Results: Of the 497 analysed strains, 8% wereresistant to a single anti-TB drug. We identified 5.2% polyresistantdrug strains, the most frequent combination beingINH+EMB (1.4%). Of the 158 MDR strains identified(31.8%), over 60% were resistant to all first line anti-TBdrugs tested. Most of them presented resistance to STM(86.1%) and EMB (67.7%). With respect to second lineanti-TB drugs resistance to KM (23.4%) was the mostcommon, followed by OFX (8.2%). With respect to thepatients with MDR-TB, a percentage of 61.2% of them hada history of anti-TB treatment. Regarding lifestyle habits,61.2% of the patients were smokers and 18.8% wereabusing alcohol. Out of 51 patients, for whom informationwas available regarding their occupation, only 33.3 % wereemployees. Conclusion: MDR strains of Mycobacteriumtuberculosis display an increased resistance to first lineanti-TB drugs. Extension of resistance to second lineanti-TB drugs narrows the therapeutic options. Knowledgeof MDR-TB risk factors is imperative for the correct andrapid initiation of the treatment. PMID- 29616531 TI - Effects of Pseudomonas aeruginosa infection on the expression profile of transient receptor potential-like (TRPL) gene from Drosophila melanogaster. AB - In an endeavor to monitor the effects ofexperimental infections with Pseudomonasaeruginosa on gene expression profiles of theeukaryotic model host, we focused on transientreceptor potential-like (trpl) pleiotropic gene ofDrosophila melanogaster (the fruit fly). Herein wereport qRT-PCR data derived from experimentalinfections of male fruit flies with different geneticbackgrounds by pricking and ingesta procedures, ascompared to previous results obtained by microarraytechnology consecutive to ingesta experiments.Whenever statistically significant, the qRT-PCRresults obtained for the whole body and intestine ofOregon wild-type flies infected with P. aeruginosaare in agreement with the microarray ones. Bothexpression profiling technologies revealed similarvalues of downregulation, supporting the robustnessof trpl as a novel gene model for inquiring hostpathogeninteractions. On the other hand, thedownregulation of trpl in gammaCop mutant malesis not confirmed by qRT-PCR data, suggesting thatthis mutant background is more sensitive toenvironmental and experimental conditions. PMID- 29616532 TI - Characterization of MRSA strains by phenotypic and OCR-based methods. AB - With the emergence and spread of newmethicilin resistant Staphylococcus aureus(MRSA) strains, control of dissemination, both inhospitals and in the community, requires the molecularcharacterization of the circulating strainsin order to establish their dynamics and identifythe sources of infection. During this study we analyzedthe MRSA isolates by means of PCR-basedmethods in order to improve epidemiologicalsurveillance and early application of preventionmeasures. The presence of mecA, nuc, lukF-PVand lukS-PV genes, as well as SCCmec types wasassessed in relation to clinical characteristics andmultidrug resistance (MDR) for 86 MRSA isolatesand showed that 51% of MDR strains were carriersof mobile genetic elements SCCmec IV and themajority of non-MDR SCCmec type IV strainswere PVL-positive (81.8%). Comparison of diagnosticmethods showed that PBP2 detection representsan extremely useful alternative to PCR forthe rapid screening of MRSA isolates, in laboratoriesthat lack facilities necessary for moleculardiagnosis, such as PFGE (Pulse Field Gel Electrophoresis),spa-typing and/or MLST (MultilocusSequence Typing). PMID- 29616533 TI - Polyploidization on SK-N-MC human neuroblastoma cells infected with herpes simplex virus 1. AB - Polyploidization is one of the most dramaticchanges occurring within cell genome owing tovarious reasons including under many viral infections.We examined the impact of herpes simplexvirus-1 (HSV-1) on SK-N-MC human neuroblastomacell line.The infected cells were followed from 6 hours upto 96 hours post infection (hpi). A large number ofpolyploid cells with giant nuclei was observed underthe influence of HSV-1 at 24 hpi with the DNAcontent of 32c to 64c or more, in comparison withcontrol SK-N-MC cells that were characterized byrelatively moderate values of ploidy, i.e. 8s to 16s(where 1c is the haploid amount of nuclear DNAfound in normal diploid populations in G0/G1). After48-96 hpi, the population of polyploid cells with giantnuclei decreased to the benchmark level. The SK-NMCcells infected with HSV-1 for 24 hours werestained with gallocyanine and monitored forcytological features.The infected cells underwent virus induced cellcelland nuclei fusion with the formation of densenuclei syncytium. The metabolic activity of HSV-1infected cells was higher in both nuclei and nucleoliwhen compared to control cells. PMID- 29616534 TI - Short communication: Could the genexpert system be a new tool for poliovirus detection in the sewage water? AB - Environmental enterovirus surveillance plays a keyrole in the detection and identification of importation ofcirculating vaccine-derived polioviruses into polio-freeareas. In 2015, 2 cases of paralytic poliomyelitis causedby circulating vaccine-derived poliovirus type 1(cVDPV1), from south-western Ukraine, borderingRomania, were confirmed. Romania was considered acountry at risk and the environmental enterovirussurveillance was enhanced. In this context we tried tofind a diagnosis algorithm for the rapid detection ofpoliovirus (PV) in the sewage water, using acombination between a rapid molecular method forhuman enterovirus (HEV) detection using theGeneXpert system and the virus isolation on cell culturelines. By using this algorithm, we would be able to givea rapid response in an emergency situation, such as therisk of polio importation. PMID- 29616535 TI - Late onset rheumatoid arthritis an observational study. AB - Rheumatoid arthritis (RA) may have an onset at older age. The onset of the disease at the age of 60 andover is called late-onset rheumatoid arthritis (LORA). The aim of this study was to analyze the clinical, laboratory,radiological, and treatment characteristics of patients with LORA compared to those with early-onset RA (EaORA),provided that all the patients had an approximately equal duration of the disease. This is an observational single centerstudy, which involved 120 patients with an established diagnosis of RA, of which 60 patients had LORA, and 60 patientsEaORA. The disease activity, measured by the Disease Activity Score 28 (DAS28-ESR), was significantly higher in theLORA group compared to the EaORA group (p<0.05). Significantly more patients with LORA had involvement of theshoulders (LORA vs. EaORA, 30% vs. 15%; p <0.05) and knees (LORA vs. EaORA, 46.7% vs. 16.7%; p <0.05). Radiologicalerosive changes were significantly more frequent in the LORA group in comparison with EaORA (p <0.05).There was no difference between the groups regarding rheumatoid factor (RF) positivity (p>0.05), while the numberof patients positive for anti citrullinated protein antibody (ACPA) was signifi cantly greater in the EaORA group(p<0.05). The values of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were significantly higherin the LORA than in the EaORA group. Hemoglobin levels were lower in the LORA group (11.96+/-1.64 g/dL) than inthe EaORA group (12.18+/-1.56 g/dL). The most used disease-modifying antirheumatic drugs (DMARDs) were methotrexateand sulfasalazine, while biological drugs were not used.In conclusion, based on the results of our study, LORA has some features that distinguish it from EaORA, such ashigher disease activity, more frequent involvement of large joints, and more pronounced structural damage. Thisshould be taken in account in clinical practice, especially regarding treatment choices. PMID- 29616536 TI - [Pregnant patient with rheumatoid arthritis treated with methotrexate and infliximab]. AB - Tumor necrosis factor-alpha inhibitors have become an established therapeutic regimen for patientswith rheumatoid arthritis. Regarding their harmful potential they are classified as category B medications. Animalreproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well controlledstudies in pregnant women. Disease-modifying antirheumatic drugs (DMARDs) are often used in combination withbiological therapy and treatment with methotrexate has shown good results. This antimetabolite is classified as acategory X drug and its teratogenic effect is well known. The incidence of inflammatory rheumatic diseases is significantly higher in women. There are many reports on pregnant patients treated with biological therapy, oft en in combinationwith DMARDs. The effects of such a therapy on reproductive health is a theme of debate, with controversialviews on the matter. We present a patient with rheumatoid arthritis whose pregnancy was discovered at 31 weeks ofgestation. During that period she had been treated with methotrexate and infliximab, with no adverse effects. PMID- 29616537 TI - [Polymyositis and systemic sclerosis overlap - A case report and a review of the literature]. AB - Polymyositis (PM) is an autoimmune disease which affects skeletal muscles. In young age, it usuallyoccurs as an idiopathic disorder associated with specific autoantibodies (anti-Jo), while in older age it is often associatedwith neoplasms. It can present with symptoms of other autoimmune diseases, such as systemic sclerosis (SSc), arare progressive disease characterized by collagen deposits in various tissues and organs.A 65-year-old patient, long-time smoker, came to the ER because of painful edema in the distal parts of his limbsand proximal muscle weakness of his arms and legs. Although his muscle enzymes were not increased, PM was confirmedby the characteristic pathohistological finding. The patient had sclerodermal skin lesions on his back, but he didnot have other typical SSc symptoms, and the specific autoantibodies were negative. He received glucocorticoid therapy(GC) after we had finished screening for malignant tumors. He felt better, his muscle strength returned, and thelimb edema disappeared. Four weeks later, he developed symptoms which are more typical of SSc, such as dysphagia,Raynaud's phenomenon, and skin thickening of the limbs that had been swollen.PM is often associated with SSc. It is not clear if the exacerbation of latent SSc was stimulated by GC, or if it wasjust a simple overlap of the two diseases with different onsets. There are no therapy guidelines for the treatment of thiscombination of diseases. Careful use of GC is necessary even if SSc symptoms are discreet, because of the well-knowneffects of GC in SSc. PMID- 29616538 TI - [Long-term glucocorticoid therapy and the rapid development of squamous cell carcinoma in systemic sclerosis: Is there a connection?]. AB - Systemic sclerosis (SSC) is an autoimmune disease associated with the risk of malignancies, especiallylung cancer, among which adenocarcinoma and squamous cell carcinoma are the most frequent.A 63-year-old female patient with SSC was hospitalized due to blackouts, poor general condition, and changes inher fingers. Because of subsequent epileptic seizures resulting in weakness of the left side of her body, computerizedtomography (CT) of the neurocranium was performed which showed metastatic lesions. A CT scan of the thoracicorgans displayed pulmonary neoplasia in the right hilum, which were histologically evaluated as grade 2 squamous cellcarcinoma. After one month of hospitalization with supportive therapy, the patient's clinical condition improved, andshe was discharged into home care with recommendations for further oncological treatment. However, the patient diedseveral days later.In comparison to adenocarcinomas, squamous cell carcinomas of the lungs usually develop through a significantlylonger period. We consider that the unusually rapid development of the carcinoma in this patient was stimulated by theimmunosuppressive effect of high doses of glucocorticoids that she had been taking for several years on her own initiative. PMID- 29616539 TI - [Controlled-release oxycodone in the treatment of chronic musculoskeletal pain: A preliminary experience of rheumatology center]. AB - In the etiology of non-malignant pain, a significant proportion is constituted by patients with painoriginating in the musculoskeletal system. The use of strong opioids in the treatment of non-malignant pain is stillcontroversial. Therefore, the aim of this study was to establish the efficacy and safety of oxycodone with a controlledrelease of the active substance (CR) in the treatment of patients with chronic, not well-controlled musculoskeletal pain.Here we present our preliminary results.In this prospective, open, single-center study conducted at a rheumatology center we enrolled consecutive patientswith musculoskeletal pain due to a variety of musculoskeletal diseases (osteoarthritis, pain in the lower back, spondyloarthritis),who suffered from moderate to severe pain despite previous analgesic therapy (with NSAIDs, weak opioids,or a fixed combination of paracetamol and weak opioids). Patients were switched to therapy with oxycodone CR andfollowed for 14 days. The starting dose of oxycodone CR was 10 mg, and later the dose was adapted as necessary. Theprimary endpoint was to assess the effectiveness of oxycodone CR on pain intensity, and the secondary goal wasto assess the efficiency on the general health of the patient (both on a horizontal visual analogue scale, VAS 0 = best,10 = worst). Fifteen patients (12 women, 3 men), with a mean age of 61 +/- 12 years and a diagnosis of osteoarthritis,pain in the lower back, or inflammatory arthritis, were included in the study. The duration of pain was 41 +/- 12 months.The average intensity of pain before oxycodone CR treatment was 7.87 +/- 2.28 (range 7-10), and at the end of the studyit was 5.92 +/- 2.43 (range 4-9) (p=0.069). General health was rated 7.27 +/ 2.14 (range 3-10) before the start and 6.00 +/-1.53 (range 3-9) at the end of the study (p=0.028). In one patient the treatment was discontinued due to dizziness andnausea, and one patient voluntarily left the study because of fear and the subjective impression of no adequate paincontrol after 2 days of treatment. The oxycodone side-effect profile was as expected.Results of our preliminary study show that in patients with chronic non-malignant pain which is not well controlledby simple analgesics, NSAIDs, and weak opioids, treatment with oxycodone CR contributed to a significantreduction in the level of pain and improved the general health of the subjects. PMID- 29616540 TI - What's new in... Capnography Monitoring for Dental Conscious Sedation: A Clinical Review. AB - Capnography monitoring during conscious sedation is notcurrently required for dentistry in Britain and Ireland. Othercountries have introduced guidelines and standards requiringcapnography monitoring for procedural sedation. This reviewhighlights the variability of procedural sedation including thesetting, the position on the sedation continuum, and the routineuse of supplemental oxygen. Specific research is required forconscious sedation in a dental setting to support standards andguidelines with regard to capnography monitoring.The Academy of Medical Royal Colleges and their Facultiesemphasise that each specialty must produce its own guidance forthe use of sedative techniques.1 Clinical practice guidelines for themonitoring and safe practice of sedation vary by specialty andinstitution. Standards are generally set from the best availableevidence based research. There is a growing body of literature thatrecognises the potential additional value of capnography (ETCO2)monitoring during procedural sedation in different settings and fordifferent sedation techniques.2-5 In these studies, capnographyreduced the incidence of hypoxaemia during procedural sedation.A meta analysis published by Waugh et al. (2010) concluded thatend-tidal carbon dioxide monitoring is an important addition indetecting respiratory depression during procedural sedation.6 Amore recent systematic review by Conway et al. (2016) concludedthat patients monitored with capnography in addition to standardmonitoring had a reduced risk of hypoxaemia compared to thosewith only standard monitoring.7 However, it has to be noted thatboth the Waugh and Conway reviews contained substantialstatistical heterogenicity which is likely to affect the quality of theevidence.As research evidence for capnography monitoring from themedical settings studied became available, new standards forcapnography monitoring were introduced in several countries(Table 1). PMID- 29616541 TI - Bispectral Index Guided Target Controlled Midazolam Sedation: a new advanced technique for dental procedures. AB - Objectives: To assess the efficacy and safety of Bispectral Index(BIS) guided Target Controlled Infusion (TCI) of midazolam foranxiolysis or minimal sedation during extensive periodontal orimplant surgery in a single operator/sedationist model. Methods: Retrospective analysis of thirty adult ASA 1 or ASA 2patients undergoing periodontal surgery or dental implant surgeryunder local anaesthesia were included.The calculated effect site concentration (Ce) of midazolam appliedby TCI, BIS, heart rate (HR), and peripheral oxygen saturation (SpO2)were monitored continuously. Non-invasive blood pressure (NIBP)and mean arterial pressure (MAP) were measured every 10minutes. All peri-operative parameters were recorded every10 minutes. All patients were interviewed 1 week after theprocedure to explore their experience of sedation and theperiodontal or implant surgery procedure. Results: Extensive periodontal or implant surgery treatment in all30 patients was completed in a mean time of 120 min (range50-180 min). The calculated mean effect site concentration formidazolam was 50 ng/ml (range 24 80). The mean BIS was 85(74-100) during induction and was maintained between 80 and 90during the oral surgical procedure by adjusting TCI Ce. There wereno clinically significant cardiopulmonary changes duringmidazolam infusion with regard to SpO2, NIBP, MAP and heart rate.Patients experienced profound anterograde amnesia and werevery satisfied with the sedation and the surgical procedure. Conclusions: BIS guided TCI sedation with midazolam facilitatespredictable minimal sedation enabling long periodontal or implantsurgery procedures by a single operator/sedationist within safephysiological limits. PMID- 29616542 TI - A Review of the use of Flumazenil for the Reversal of Midazolam Conscious Sedation in Dentistry. AB - The practice of midazolam conscious sedation is well establishedin dentistry. The drug flumazenil is a specific benzodiazepineantagonist and is an essential requirement in settings wheremidazolam is used.A literature review has been carried out, examining the availableinformation regarding flumazenil's safety, administration, potentialcomplications and the regulatory documentation which governsits use.Flumazenil is a safe drug to use for the reversal of midazolaminduced conscious sedation although the evidence surrounding itsuse is limited. PMID- 29616543 TI - The Decisional Needs of Young Patients Faced with the Decision to Undergo Dental Treatment with Sedation or GA. AB - Aim: To explore the decisional needs of young patients faced withthe choice of dental treatment with either sedation or generalanaesthetic (GA). Design: Twelve qualitative interviews were conducted withpatients, aged 10-16 yr (n=12), who had prior experience of dentaltreatment with sedation or GA, together with their parents/guardians (n=13). Results: A number of themes were identified as being important inthe decision-making process including: the method ofadministration; waiting and treatment times; perceived side effectsand risks; treatment type; control and communication, and the longterm impact of sedation or GA. Conclusion: The decision to undergo dental treatment withsedation or GA is a complex healthcare decision and warrantsadditional decisional support for both patients and their parents/guardians. PMID- 29616544 TI - Application of the Mental Capacity Act (2005) and Consenting for Treatment under Concious Sedation. AB - The Mental Capacity Act 2005 (MCA) is one piece of legislationwith which all clinicians should be familiar. As treating clinicians, acapacity assessment is carried out each time a patient is seen, inorder to obtain informed consent. When clinicians question thecapacity of their patients, they should ensure steps are taken toprovide relevant adjuncts to aid understanding, from visual aids toalternative time and environment. If a patient is deemed to lackcapacity, it should be determined if this is temporary, fluctuating orpermanent, as well as the severity. For those who lack capacity abest interest assessment should be undertaken with all relevantparties involved, with the overall decision being made in thepatient's best interest and in the least restrictive manner.Considerations of sedation technique, clinical holding, or any otherprocedures should be included in the consent form, with periodicreview of the best interest decision as a patient's circumstancesmay change over time. PMID- 29616545 TI - Combining Sedation and Cognitive Behavioural Therapy (CBT) to Overcome Dental Phobia: a Case Report. AB - This case report presents a Cognitive Behavioural Therapy (CBT)intervention provided for a 63-year-old male, who had experienceddental phobia for over 50 years. This gentleman initially receivedintravenous sedation (IVS) for 5-years within a Specialist Sedationand Special Care dental department, before being referred for thelong-term management of his dental phobia, within theembedded specialist Dental Health Psychology Service in aLondon Dental Hospital. This brief report will consider aspects ofthe CBT intervention delivered in relation to assessment, caseconceptualisation, course of treatment and outcomes; reflecting onthe complementary aspects of sedation and CBT. Learning pointswill be identified for the role of CBT or CBT-based techniqueswithin dental anxiety management settings. PMID- 29616546 TI - Quantitative SERS Detection of Dopamine in Cerebrospinal Fluid by Dual Recognition-Induced Hot Spot Generation. AB - Reliable profiling of the extracellular dopamine (DA) concentration in the central nervous system is essential for a deep understanding of its biological and pathological functions. However, quantitative determination of this neurotransmitter remains a challenge because of the extremely low concentration of DA in the cerebrospinal fluid (CSF) of patients. Herein, on the basis of the specific recognition of boronate toward diol and N-hydroxysuccinimide ester toward the amine group, a simple and highly sensitive strategy was presented for DA detection by using surface-enhanced Raman scattering (SERS) spectroscopy as a signal readout. This was realized by first immobilizing 3,3'-dithiodipropionic acid di( N-hydroxysuccinimide ester) on gold thin film surfaces to capture DA, followed by introducing 3-mercaptophenylboronic acid (3-MPBA)-functionalized silver nanoparticles to generate numerous plasmonic "hot spots" with the nanoparticle-on-mirror geometry. Such a dual-recognition mechanism not only avoids complicated bioelement-based manipulations but also efficiently decreases the background signal. With the direct use of the recognition probe 3-MPBA as a Raman reporter, the "signal-on" SERS method was employed to quantify the concentration of DA from 1 pM to 1 MUM with a detection limit of 0.3 pM. Moreover, our dual-recognition-directed SERS assay exhibited a high resistance to cerebral interference and was successfully applied to monitoring of DA in CSF samples of patients. PMID- 29616547 TI - Synergistically Enhanced Interfacial Interaction to Polysulfide via N,O Dual Doped Highly Porous Carbon Microrods for Advanced Lithium-Sulfur Batteries. AB - Lithium-sulfur (Li-S) batteries have received tremendous attention because of their extremely high theoretical capacity (1672 mA h g-1) and energy density (2600 W h kg-1). Nevertheless, the commercialization of Li-S batteries has been blocked by the shuttle effect of lithium polysulfide intermediates, the insulating nature of sulfur, and the volume expansion during cycling. Here, hierarchical porous N,O dual-doped carbon microrods (NOCMs) were developed as sulfur host materials with a large pore volume (1.5 cm3 g-1) and a high surface area (1147 m2 g-1). The highly porous structure of the NOCMs can act as a physical barrier to lithium polysulfides, while N and O functional groups enhance the interfacial interaction to trap lithium polysulfides, permitting a high loading amount of sulfur (79-90 wt % in the composite). Benefiting from the physical and chemical anchoring effect to prevent shuttling of polysulfides, S@NOCMs composites successfully solve the problems of low sulfur utilization and fast capacity fade and exhibit a stable reversible capacity of 1071 mA h g-1 after 160 cycles with nearly 100% Coulombic efficiency at 0.2 C. The N,O dual doping treatment to porous carbon microrods paves a way toward rational design of high-performance Li-S cathodes with high energy density. PMID- 29616548 TI - Urban Mining of E-Waste is Becoming More Cost-Effective Than Virgin Mining. AB - Stocks of virgin-mined materials utilized in linear economic flows continue to present enormous challenges. E-waste is one of the fastest growing waste streams, and threatens to grow into a global problem of unmanageable proportions. An effective form of management of resource recycling and environmental improvement is available, in the form of extraction and purification of precious metals taken from waste streams, in a process known as urban mining. In this work, we demonstrate utilizing real cost data from e-waste processors in China that ingots of pure copper and gold could be recovered from e-waste streams at costs that are comparable to those encountered in virgin mining of ores. Our results are confined to the cases of copper and gold extracted and processed from e-waste streams made up of recycled TV sets, but these results indicate a trend and potential if applied across a broader range of e-waste sources and metals extracted. If these results can be extended to other metals and countries, they promise to have positive impact on waste disposal and mining activities globally, as the circular economy comes to displace linear economic pathways. PMID- 29616549 TI - Self-Assembly and Functions of Star-Shaped Oligomeric Surfactants. AB - Oligomeric surfactants consist of three or more amphiphilic moieties which are connected by spacer groups covalently at the level of headgroups. It provides a possible route to bridge the gap from conventional single-chain surfactants to polymeric surfactants and leads to many profound improvements in the properties of surfactants in aqueous solution and at the air/water and water/solid interfaces. Generally, oligomeric surfactants are categorized into linear, ring like, and star-shaped on the basis of the topological structures of their spacer groups, and their aggregation behavior strongly depends on the resultant topological structures. In recent years, we studied trimeric, tetrameric, and hexameric surfactants with a star-shaped spacer which spreads from a central site of elemental nitrogen or carbon, and their charged headgroups connect with each other through the spacers. It has been found that both the nature of spacer groups and the degree of oligomerization show important influences on the self assembly of oligomeric surfactants and provide great possibilities in fabricating various surfactant aggregate morphologies by adjusting the molecule conformations. The unique self-assembly behavior endows them with superior physicochemical properties and potential applications. This feature article summarizes the development of star-shaped oligomeric surfactants, including self assembly at the air/water and water/solid interfaces, self-assembly in aqueous solution, and their functions. We expect that this review could provide a comprehensive understanding of the structure-property relationship and various potential applications of star-shaped oligomeric surfactants and offer additional motivation for their future research. PMID- 29616550 TI - Energetic and Structural Properties of Two Phenolic Antioxidants: Tyrosol and Hydroxytyrosol. AB - Theoretical and experimental studies on the energetic, structural and some other relevant physicochemical properties of the antioxidant tyrosol (1), hydroxytyrosol (1OH) molecules and the corresponding radicals 1rad* and 1Orad* are reported in this work. The experimental values of the gas-phase enthalpy of formation, Deltaf Hm0(g), in kJ.mol-1, of 1 (-302.4 +/- 3.4) and 1OH (-486.3 +/- 4.1) have been determined. Quantum chemical calculations, at DFT (M05-2X) and composite ab initio G3 and G4 levels of theory, provided results that served to (i) confirm the excellent consistency of the experimental measurements performed, (ii) establish that the stabilizing effect of H-bond of hydroxyethyl chain and aromatic ring (OH...pi interaction) is smaller in radicals than in parent molecules, (iii) deduce-combining experimental data in isodesmic reactions-Deltaf Hm0(g) of radicals 1rad* (-152.3 +/- 4.4 kJ.mol-1) and 1Orad* (-370.6 +/- 3.8 kJ.mol-1), (iv) estimate a reliable O-H bond dissociation enthalpy, BDE of 1 (368.1 +/- 5.6 kJ.mol-1) and of 1OH (333.7 +/- 5.6 kJ.mol-1), and (v) corroborate using "BDE criteria"-than 1OH is a more effective antioxidant than 1. PMID- 29616551 TI - Stereoselective Synthesis of Functionalized Benzooxazepino[5,4- a]isoindolone Derivatives via Cesium Carbonate Catalyzed Formal [5 + 2] Annulation of 2-(2 Hydroxyphenyl)isoindoline-1,3-dione with Allenoates. AB - In this work, we present a strategy for the stereoselective synthesis of functionalized benzooxazepino[5,4- a]isoindolone derivatives via a Cs2CO3 catalyzed domino beta-addition and gamma-aldol reaction of 2-(2 hydroxyphenyl)isoindoline-1,3-dione derivatives with allenoates, which offers an avenue for a combination of the structural unity between benzooxazepine and isoindolone motifs in synthetically useful yields with high stereoselectivities under mild conditions. Remarkably, it is the first example of highly stereoselective Cs2CO3-catalyzed formal [5 + 2] annulation of 2-(2 hydroxyphenyl)isoindoline-1,3-dione with allenoates. PMID- 29616552 TI - Nano-Protrusive Gold Nanoparticle-Hybridized Polymer Thin Film as a Sensitive, Multipatternable, and Antifouling Biosensor Platform. AB - Hybrid films consisting of anisotropic octahedral gold nanoparticles (AuNPs) and polymers had their surfaces functionalized and were immobilized on surface plasmon resonance (SPR) sensors for biomolecule detection. Specifically, carboxylated octahedral AuNPs (C-Oh-AuNPs) and poly(allylamine hydrochloride) (PAH) were assembled as ultrathin films by using a layer-by-layer process. The ionic strength generated from the functional groups of C-Oh-AuNP and PAH influenced the composition, its surface morphology, and the reactivity of the film toward further chemical reactions such as the synthesis of spherical AuNPs (S-AuNPs). We were thus able to control the size and the structure of the C-Oh AuNP and S-AuNPs converted to nano-raspberry-shaped particles. This hierarchical AuNP hybrid film exhibits much more sensitive and stable detection of biomolecules than regular flat chip systems, and this result may be due to the SPR of the AuNP at its surface being able to markedly enhance the local optical field of the chip. The micropatterning of the hybrid coating was also studied by using a soft lithographic patterning method. We, in particular, worked on creating multiplex patterns having different combinations of shapes and fluorescent colors. We expect our hybrid coating system with multicode biomolecular arrays to be used as a powerful platform for biosensor applications. PMID- 29616553 TI - Orthogonal Tip-to-Tip Nanocapillary Alignment Allows for Easy Detection of Fluorescent Emitters in Femtomolar Concentrations. AB - Here we present the realization of a novel fluorescence detection method based on the electromigration of fluorescent molecules within a nanocapillary combined with the laser excitation through a platinum (Pt)-coated nanocapillary. By using the Pt nanocapillary assisted focusing of a laser beam, we completely remove the background scattering on the tip of the electrophoretic nanocapillary. In this excitation geometry, we demonstrate a 1000-fold sensitivity enhancement (1.0 nM to 1.0 pM) compared to the detection in microcapillaries with epifluorescence illumination and fluorescence spectrophotometry. Due to a significant electroosmotic flow, we observe a decelerating migration of DNA molecules close to the tip of the electrophoretic nanocapillary. The reduced DNA translocation velocity causes a two-step stacking process of molecules in the tip of the nanocapillary and can be used as a way to locally concentrate molecules. The sensitivity of our method is further improved by a continuous electrokinetic injection of DNA molecules followed by sample zone stacking on the tip of the nanocapillary. Concentrations ranging from 0.1 pM to 1.0 fM can be directly observed on the orifice of the electrophoretic nanocapillary. This is a 1000-fold improvement compared to traditional capillary electrophoresis with laser-induced fluorescence. PMID- 29616554 TI - Novel Sulfur Host Composed of Cobalt and Porous Graphitic Carbon Derived from MOFs for the High-Performance Li-S Battery. AB - A composite consisting of cobalt and graphitic porous carbon (Co@GC-PC) is synthesized from bimetallic metal-organic frameworks and employed as the sulfur host for high-performance Li-S batteries. Because of the presence of a large surface area (724 m2 g-1) and an abundance of macro-/mesopores, the Co@GC-PC electrode is able to alleviate the debilitating effect originating from the volume expansion/contraction of sulfur species during the cycling process. Our in situ UV/vis analysis indicates that the existence of Co@GC-PC promotes the adsorption of polysulfides during the discharge process. Density functional theory calculations show a strong interaction between Co and Li2S and a low decomposition barrier of Li2S on Co(111), which is beneficial to the following Li2S oxidation in the charge process. As a result, at 0.2C, the discharge capacity of the S/Co@GC-PC cathode is stabilized at 790 mAh g-1 after 220 cycles, much higher than that of a carbon-based cathode, which delivers a discharge capacity of 188 mAh g-1. PMID- 29616555 TI - Improvement in Therapeutic Efficacy and Reduction in Cellular Toxicity: Introduction of a Novel Anti-PSMA-Conjugated Hybrid Antiandrogen Nanoparticle. AB - Second generation antiandrogens have improved overall survival for men with metastatic castrate resistant prostate cancer; however, the antiandrogens result in suppression of androgen receptor (AR) activity in all tissues resulting in dose limiting toxicity. We sought to overcome this limitation through encapsulation in a prostate specific membrane antigen (PSMA)-conjugated nanoparticle. We designed and characterized a novel nanoparticle containing an antiandrogen, enzalutamide. Selectivity and enhanced efficacy was achieved through coating the particle with PSMA. The PSMA-conjugated nanoparticle was internalized selectively in AR expressing prostate cancer cells. It did not elicit an inflammatory effect. The efficacy of enzalutamide was not compromised through insertion into the nanoparticle; in fact, lower systemic drug concentrations of enzalutamide resulted in comparable clinical activity. Normal muscle cells were not impacted by the PSMA-conjugated containing antiandrogen. This approach represents a novel strategy to increase the specificity and effectiveness of antiandrogen treatment for men with castrate resistant prostate cancer. The ability to deliver higher drug concentrations in prostate cancer cells may translate into improved clinical end points including overall survival. PMID- 29616556 TI - Triaxial Nanocables of Conducting Polypyrrole@SnS2@Carbon Nanofiber Enabling Significantly Enhanced Li-Ion Storage. AB - Two-dimensional (2D) SnS2 materials represent a class of high-capacity candidates as anodes of Li-ion batteries (LIBs); however, they are limited by inferior rate and cycling performance. Herein, we demonstrate unique triaxial nanocables of conducting polypyrrole@SnS2@carbon nanofiber (PPy@SnS2@CNF) prepared via a facile combination of hydrothermal method and vapor-phase polymerization. The PPy@SnS2@CNF manifests a strong synergistic effect from its hierarchical nanoarchitecture, which provides enlarged electrode/electrolyte contact interfaces, highly electrical conductive pathways, sufficient electrolyte ingress/transport channels, and an intimate mechanical/electrochemical safeguard for fast electrode kinetics and good structural stability. When evaluated as binder-free anodes of LIBs, the ternary nanocomposite delivers an ultrahigh reversible capacity of 1165 mAh g-1 after 100 cycles and outstanding rate/cycling performance (880 mAh g-1 at 2000 mA g-1), which are among the best results of the previously reported SnS2 electrodes. This work may pave a rational avenue of developing 2D materials with hierarchical structures for highly efficient energy storage systems. PMID- 29616557 TI - Bright Single InAsP Quantum Dots at Telecom Wavelengths in Position-Controlled InP Nanowires: The Role of the Photonic Waveguide. AB - We report on the site-selected growth of bright single InAsP quantum dots embedded within InP photonic nanowire waveguides emitting at telecom wavelengths. We demonstrate a dramatic dependence of the emission rate on both the emission wavelength and the nanowire diameter. With an appropriately designed waveguide, tailored to the emission wavelength of the dot, an increase in the count rate by nearly 2 orders of magnitude (0.4 to 35 kcps) is obtained for quantum dots emitting in the telecom O-band, showing high single-photon purity with multiphoton emission probabilities down to 2%. Using emission-wavelength optimized waveguides, we demonstrate bright, narrow-line-width emission from single InAsP quantum dots with an unprecedented tuning range of 880 to 1550 nm. These results pave the way toward efficient single-photon sources at telecom wavelengths using deterministically grown InAsP/InP nanowire quantum dots. PMID- 29616559 TI - Urinary Bladder Stone Passing Using a Persian Herbal Recipe. AB - OBJECTIVE: The intrauterine device (IUD) is a popular contraceptive instrument with reported complications. IUD migration to the urinary bladder, a rare genitourinary tricky situation, may cause stone formation and result in urinary system sequels such as a stone formation and a recurrent infection. CASE REPORT: This is a case report of IUD migration to the urinary bladder, mineralization, and subsequent complications. We report the case of a 35-year-old woman with a copper IUD nidus stone in her urinary bladder. She received a Persian medicine formulation including goat's head, cornflower, silk corn, field horsetail, cumin, black Spanish radish, and common dandelion. She passed an oxalate stone 3 days later. CONCLUSION: Inexpensive common traditional recommendations might be helpful in current obstetrics and gynecology practice in our region. PMID- 29616558 TI - Synthetic Analogues of the Snail Toxin 6-Bromo-2-mercaptotryptamine Dimer (BrMT) Reveal That Lipid Bilayer Perturbation Does Not Underlie Its Modulation of Voltage-Gated Potassium Channels. AB - Drugs do not act solely by canonical ligand-receptor binding interactions. Amphiphilic drugs partition into membranes, thereby perturbing bulk lipid bilayer properties and possibly altering the function of membrane proteins. Distinguishing membrane perturbation from more direct protein-ligand interactions is an ongoing challenge in chemical biology. Herein, we present one strategy for doing so, using dimeric 6-bromo-2-mercaptotryptamine (BrMT) and synthetic analogues. BrMT is a chemically unstable marine snail toxin that has unique effects on voltage-gated K+ channel proteins, making it an attractive medicinal chemistry lead. BrMT is amphiphilic and perturbs lipid bilayers, raising the question of whether its action against K+ channels is merely a manifestation of membrane perturbation. To determine whether medicinal chemistry approaches to improve BrMT might be viable, we synthesized BrMT and 11 analogues and determined their activities in parallel assays measuring K+ channel activity and lipid bilayer properties. Structure-activity relationships were determined for modulation of the Kv1.4 channel, bilayer partitioning, and bilayer perturbation. Neither membrane partitioning nor bilayer perturbation correlates with K+ channel modulation. We conclude that BrMT's membrane interactions are not critical for its inhibition of Kv1.4 activation. Further, we found that alkyl or ether linkages can replace the chemically labile disulfide bond in the BrMT pharmacophore, and we identified additional regions of the scaffold that are amenable to chemical modification. Our work demonstrates a strategy for determining if drugs act by specific interactions or bilayer-dependent mechanisms, and chemically stable modulators of Kv1 channels are reported. PMID- 29616560 TI - Complementary and Alternative Medicine: A Cross-Sectional Observational Study in Pediatric Inpatients. AB - The aim was to study the prevalence of complementary and alternative medicine use in acutely sick hospitalized children and factors associated with it. This is a cross-sectional, hospital-based study in a tertiary care center of Delhi, India. Children admitted to a pediatric unit during the study period were assessed using a specially designed questionnaire. Out of the total 887 admitted children, 161 (18.1%) were using complementary and alternate medicine in one form or another. Of these, 113 (70.2%) were using complementary and alternate medicine for the current illness directly leading to admission and the remaining 48 (29.8%) had used complementary and alternate medicine in past. The common complementary and alternate medicine use observed in our study was combined ayurveda and spiritual approach (25.5%), ayurveda (24.8%), spiritual (21.7%), homeopathic (13%), and 47.2% of children were using spiritual approach in form of Jhada (tying piece of cloth on arm or leg or keeping a knife by the side of child). The significant factors associated with complementary and alternate medicine use were younger age, female gender, and father being employed. Complementary and alternate medicine is commonly used even in acutely sick children. PMID- 29616561 TI - Denosumab: A Unique Perspective on Adherence and Cost-effectiveness Compared With Oral Bisphosphonates in Osteoporosis Patients. AB - OBJECTIVE: To assess the cost-effectiveness as well as adherence and patient preference for denosumab compared with oral bisphosphonates for the treatment of osteoporosis. DATA SOURCES: Two comprehensive PubMed literature searches (from data inception to December 2017) were performed. The first search included the terms osteoporosis, denosumab, bisphosphonate, and adherence or persistence or compliance or preference. The search terms osteoporosis, denosumab, cost, and effectiveness were used in the second literature search. Additional references were included from reviewing literature citations. STUDY SELECTION AND DATA EXTRACTION: All English-language clinical trials on adherence (as compliance and persistence) or patient preference for denosumab compared with oral bisphosphonates were evaluated. In addition, articles analyzing the cost effectiveness of denosumab compared with generic alendronate were evaluated. DATA SYNTHESIS: Four studies that assessed patient preference showed positive outcomes for preference and satisfaction for subcutaneous use of denosumab every 6 months versus oral alendronate weekly, oral ibandronate monthly, or oral risedronate monthly. Three studies evaluated persistence and compliance and/or adherence and showed improved persistence and compliance rates with denosumab compared with bisphosphonate therapy. Twelve articles and 3 abstracts assessed cost effectiveness of denosumab compared with generic alendronate. The majority of articles showed that denosumab was cost-effective, and even cost-saving in patients older than 75 years of age and those who have a history of previous fractures, lower bone mineral density T-scores, and more risk factors. CONCLUSIONS: Denosumab compared with oral bisphosphonates may improve patient preference and adherence as well as provide a cost-effective treatment strategy, especially among higher-risk and older adults with osteoporosis. PMID- 29616562 TI - Avelumab: A Review of Its Application in Metastatic Merkel Cell Carcinoma. AB - OBJECTIVE: To summarize the clinical development of avelumab and its clinical relevance in metastatic Merkel cell carcinoma (MCC). DATA SOURCES: An English language literature search using PubMed was performed using the terms avelumab, anti-PD-1, anti-PD-L1, and MCC from January of 1950 to March 2018. Data were also obtained from package inserts, meeting abstracts, and clinical registries. STUDY SELECTION/DATA EXTRACTION: All relevant published articles of avelumab were reviewed. Clinical trial registries and meeting abstracts were used for information about ongoing trials. DATA SYNTHESIS: Avelumab is a fully human monoclonal antibody that inhibits programmed death ligand-1, which reverses T cell exhaustion and induces antitumor responses. Avelumab is safe and effective in previously treated metastatic MCC based on a phase II trial of previously treated patients with objective response rates in 28 of 88 patients, including 10 complete responses and 19 partial responses. Median overall survival (OS) was 12.9 months, and 1-year progression-free survival and OS were 30% and 52%, respectively. Grade 3 treatment-related side effects included lymphopenia (2 patients), serum creatine phosphokinase increase (1 patient), aminotransferase elevation (1 patient), and serum cholesterol increase (1 patient). Relevance to Patient Care and Clinical Practice: This review outlines the pharmacology and clinical trial data for avelumab in metastatic MCC and guides clinicians on avelumab's place in therapy. CONCLUSIONS: Avelumab is the first Food and Drug Administration-approved medication for metastatic MCC and provides an advantage of durable responses and possibly improved tolerability compared with traditional platinum-based chemotherapy. Clinical trials are under way to expand its utility into the adjuvant and frontline settings. PMID- 29616563 TI - Using student-generated case studies to teach respiratory physiology. PMID- 29616564 TI - This will never do. PMID- 29616565 TI - Pumping the pulse: a bicycle pump to simulate the arterial pulse waveform. PMID- 29616566 TI - Report on first certificate course on applied physiology of pain, analgesia, anesthesia, and euthanasia for laboratory animals held in Sri Lanka. AB - Similar to human beings, pain is an unpleasant sensation experienced by animals as well. There is no exception when the animals are subjected to experimental procedures. Our duty as researchers/scientists is to prevent or minimize the pain in animals so as to lessen their suffering and distress during experimental procedures. The basics of the physiology of pain and pain perception, analgesia, anesthesia, and euthanasia of laboratory animals were included to complete the program, before the practical part was attempted and before advanced topics, such as comparison of anesthetic combinations, were discussed. Therefore, this course was organized in Sri Lanka for the first time in collaboration with the Comparative Biology Centre of Newcastle University, UK. During this course, we were able to demonstrate how an anesthesia machine could be used in laboratory animal anesthesia for the first time in the country. None of the animal houses in the country were equipped with an anesthesia machine at the time of conducting the course. PMID- 29616567 TI - Value of artisanal simulators to teach ultrasound-guided percutaneous biopsy using a tru-cut needle for veterinary and medical students. AB - The present study aimed to evaluate the applicability of artisanal simulators to teach veterinary and medical students the ultrasound-guided percutaneous biopsy using a tru-cut needle. The artisanal simulators consisted of bovine liver between two layers of commercially available grape gelatin. Students were paired, with one doing the biopsy and the other the ultrasound guidance. After performing the biopsies, each student answered a questionnaire with close-ended questions using a visual analog scale. The evaluated items were realism of the model, liver scanning, procedure instructions, biopsy feasibility, tru-cut needle handling, technique learning, and confidence to perform in vivo procedures. Items that received a score of 7 or higher were considered strong items; items with a score between 5 and 6.9 were classified as average items; and items with a score of 5 or lower were considered weak items. The answers to all questions had an average score of 7 or higher, suggesting that the simulator was classified as strong for all of the evaluated items. Answers to question 7 suggested that some of the students did not develop confidence to perform a tru-cut biopsy on a patient. Students evaluated the artisanal simulator as a strong method to be used in ultrasound-guided percutaneous biopsy with a tru-cut needle. Additionally, the model presented a low cost of production and was proven accurate to teach biopsy skills in health professional schools dealing with veterinary or human medicine. PMID- 29616568 TI - A large drawing of a nephron for teaching medical students renal physiology, histology, and pharmacology. AB - The purpose of this study is to see whether a large drawing of a nephron helped medical students in self-directed learning groups learn renal physiology, histology, and pharmacology before discussing clinical cases. The end points were the grades on the renal examination and a student survey. The classes in the fall of 2014 and 2015 used the drawing, but not those of 2012 and 2013. The Charles E. Schmidt College of Medicine at Florida Atlantic University is a newly formed Florida medical school, which enrolled its first class in the fall of 2011. The school relies on self-directed problem-based learning in year 1 and changes over to a case inquiry method in the latter part of year 1 and throughout year 2. At the start of the renal course, each student group received a poster of a nephron with the objective of learning the cell functions of the different nephron parts. During the first year of using the drawing, there was no improvement in grades. After a student suggested adjustment to the drawing, there was a statistically significant difference in the total test score in the second year ( P < 0.001). An unexpected finding was lower grades in all 4 yr in the area of acid-base balance and electrolytes compared with the other four areas tested. In the survey, the students found the drawing useful. PMID- 29616569 TI - Who perceives they are smarter? Exploring the influence of student characteristics on student academic self-concept in physiology. AB - Academic self-concept is one's perception of his or her ability in an academic domain and is formed by comparing oneself to other students. As college biology classrooms transition from lecturing to active learning, students interact more with each other and are likely comparing themselves more to other students in the class. Student characteristics can impact students' academic self-concept; however, this has been unexplored in the context of undergraduate biology. In this study, we explored whether student characteristics can affect academic self concept in the context of an active learning college physiology course. Using a survey, students self-reported how smart they perceived themselves to be in the context of physiology relative to the whole class and relative to their groupmate, the student with whom they worked most closely in class. Using linear regression, we found that men and native English speakers had significantly higher academic self-concept relative to the whole class compared with women and nonnative English speakers. Using logistic regression, we found that men had significantly higher academic self-concept relative to their groupmate compared with women. Using constant comparison methods, we identified nine factors that students reported influenced how they determined whether they were more or less smart than their groupmate. Finally, we found that students were more likely to report participating more than their groupmate if they had a higher academic self concept. These findings suggest that student characteristics can influence students' academic self-concept, which in turn may influence their participation in small-group discussion and their academic achievement in active learning classes. PMID- 29616570 TI - "Show me the beat!": a kinesthetic activity for teaching undergraduates the relationships between cardiac electrical rhythm and contractile patterns. PMID- 29616571 TI - Flowcharts to aid student comprehension of Nernst equation calculations. PMID- 29616572 TI - Science reflects history as society influences science: brief history of "race," "race correction," and the spirometer. AB - Spirometers are used globally to diagnose respiratory diseases, and most commercially available spirometers "correct" for race. "Race correction" is built into the software of spirometers. To evaluate pulmonary function and to make recordings, the operator must enter the subject's race. In fact, the Joint Working Party of the American Thoracic Society/European Respiratory Society recommends the use of race- and ethnic-specific reference values. In the United States, spirometers apply correction factors of 10-15% for individuals labeled "Black" and 4-6% for people labeled "Asian." Thus race is purported to be a biologically important and scientifically valid category. However, history suggests that race corrections may represent an implicit bias, discrimination, and racism. Furthermore, this practice masks economic and environmental factors. The flawed logic of innate, racial difference is also considered with disability estimates, preemployment physicals, and clinical diagnoses that rely on the spirometer. Thomas Jefferson's Notes on the State of Virginia (1832) may have initiated this mistaken belief by noting deficiencies of the "pulmonary apparatus" of blacks. Plantation physicians used Jefferson's statement to support slavery, believing that forced labor was a way to "vitalize the blood" of deficient black slaves. Samuel Cartwright, a Southern physician and slave holder, was the first to use spirometry to record deficiencies in pulmonary function of blacks. A massive study by Benjamin Apthorp Gould (1869) during the Civil War validated his results. The history of slavery created an environment where racial difference in lung capacity become so widely accepted that race correction became a scientifically valid procedure. PMID- 29616573 TI - Physiology learning for veterinary students: impact of guided practices on students' opinion and physiological parameters. AB - Over recent decades, education has increasingly focused on student-centered learning. Guided practices represent a new way of learning for undergraduate students of physiology, whereby the students turn into teacher-students and become more deeply involved in the subject by preparing and teaching a practical (laboratory) class to their peers. The goal was to assess the students' opinions about guided practices and how physiological parameters change during the activity. For this objective, two experiments were performed. First, a voluntary questionnaire on guided practices was completed by the students during 2 academic years. Students could also write a free text commentary. The positive answers obtained in the questionnaire and the free commentary responses point to the effectiveness of this methodology in students' minds. Negative aspects included the time spent preparing the activity, and the stress that students experienced in the teaching role. Second, information about how the teacher-students felt before teaching the practical class was self-reported, and physiological parameters related to stress (heart rate, pulse rate, blood pressure, arterial oxygen saturation, respiratory rate, and electrocardiogram recorded to evaluate R R interval and heart rate variability) were measured immediately before and while the practical class was taught. This evaluation reported an increase in stress during the execution of the practice. In conclusion, despite a new and stressful situation, guided practices are of interest for the students as a learning tool and for the acquisition of skills that may be of use in their later professional lives. PMID- 29616574 TI - The art of talking about science: beginning to teach physiology students how to communicate with nonscientists. AB - The ability to clearly disseminate scientific knowledge is a skill that is necessary for any undergraduate student within the sciences. Traditionally, this is accomplished through the instruction of scientific presentation or writing with a focus on peer-to-peer communication at the expense of teaching communication aimed at a nonscientific audience. One of the ramifications of focusing on peer-to-peer communication has presented itself as an apprehension toward scientific knowledge within the general populace. This apprehension can be seen in a variety of venues, including the traditional media, popular culture, and education, which generally paint scientists as aloof and with an inability to discuss scientific issues to anyone other than other scientists. This paper describes a curriculum designed to teach Introduction to Anatomy and Physiology students the tools necessary for communicating complex concepts that were covered during the semester using approachable language. Students were assessed on their word usage in associated writing activities, the student's ability to reduce complexity of their statements, and performance in an informal scientific presentation to a lay audience. Results showed that this pedagogical approach has increased students' ability to reduce the complexity of their language in both a written and oral format. This, in turn, led to evaluators reporting greater levels of understanding of the topic presented following the presentation. PMID- 29616575 TI - Organizing a large-scale Physiology Understanding (PhUn) Week event at a science center. AB - For the past 6 yr, the Department of Physiology at Michigan State University (MSU) has partnered with Impression 5 Science Center in Lansing, MI. Together, we host a day-long community engagement event on a Saturday each year in early November coinciding with the American Physiological Society's Physiology Understanding Week. The purpose was to provide a fun and memorable hands-on experience for children and families. This paper describes the detailed planning and logistics. The event takes place in the main exhibit space at the science center, generally has 15-17 physiology activities stations set up as booths run by volunteers, and the event runs as an open-house format. Three to five trained volunteers were needed per station for the full day. Since this was primarily based on undergraduate student volunteer involvement (a population already limited for time), morning, afternoon, and/or full-day shifts were offered to accommodate a variety of schedules. Additional set-up, clean-up, and general help was also recruited. Overall, ~100-150 MSU students, faculty, and staff members served as volunteers, alongside Impression 5 staff. Hosting the event at the science center generated a larger audience, aided in advertisement, and allowed for access to a large facility capable of handling the 600-1,000 attendees. The partnership facilitated the sharing of equipment and supplies for physiology demonstrations, allowed for activities on site in the chemistry laboratory space, and facilitated the growth of new community partnerships with local schools and groups who attended the event. PMID- 29616576 TI - Social media interruption affects the acquisition of visually, not aurally, acquired information during a pathophysiology lecture. AB - Poor academic performance from extensive social media usage appears to be due to students' inability to multitask between distractions and academic work. However, the degree to which visually distracted students can acquire lecture information presented aurally is unknown. This study examined the ability of students visually distracted by social media to acquire information presented during a voice-over PowerPoint lecture, and to compare performance on examination questions derived from information presented aurally vs. that presented visually. Students ( n = 20) listened to a 42-min cardiovascular pathophysiology lecture containing embedded cartoons while taking notes. The experimental group ( n = 10) was visually, but not aurally, distracted by social media during times when cartoon information was presented, ~40% of total lecture time. Overall performance among distracted students on a follow-up, open-note quiz was 30% poorer than that for controls ( P < 0.001). When the modality of presentation (visual vs. aural) was compared, performance decreased on examination questions from information presented visually. However, performance on questions from information presented aurally was similar to that of controls. Our findings suggest the ability to acquire information during lecture may vary, depending on the degree of competition between the modalities of the distraction and the lecture presentation. Within the context of current literature, our findings also suggest that timing of the distraction relative to delivery of material examined affects performance more than total distraction time. Therefore, when delivering lectures, instructors should incorporate organizational cues and active learning strategies that assist students in maintaining focus and acquiring relevant information. PMID- 29616577 TI - Collaborative-group testing improves learning and knowledge retention of human physiology topics in second-year medical students. AB - The present study examined the relationship between second-year medical students' group performance and individual performance in a collaborative-learning environment. In recent decades, university professors in the scientific and humanistic disciplines have successfully put into practice different modalities of collaborative approaches to teaching. Essentially, collaborative approach refers to a variety of techniques that involves the joint intellectual effort of a small group of students, which encourages interaction and discussion among students and professors. The present results show the efficacy of collaborative learning, which, furthermore, allowed students to participate actively in the physiology class. Average student's grades were significantly higher when they engaged in single-best-response, multiple-choice tests as a student team, compared with taking the same examinations individually. The method improved notably knowledge retention, as learning is more effective when performed in the context of collaborative partnership. A selected subset of questions answered wrongly in an initial test, both individually and collectively, was used on a second test to examine student retention of studied material. Grade averages were significantly improved, both individually and groupwise, when students responded to the subset of questions a second time, 1, 2, or 3 wk after the first attempt. These results suggest that the collaborative approach to teaching allowed a more effective understanding of course content, which meant an improved capacity for retention of human physiology knowledge. PMID- 29616578 TI - Building community by serving the community. PMID- 29616579 TI - All play and no work: skits and models in teaching skeletal muscle physiology. PMID- 29616580 TI - Use of case-based or hands-on laboratory exercises with physiology lectures improves knowledge retention, but veterinary medicine students prefer case-based activities. AB - Didactic lectures are prevalent in physiology courses within veterinary medicine programs, but more active learning methods have also been utilized. Our goal was to identify the most appropriate learning method to augment the lecture component of our physiology course. We hypothesized that case-based learning would be well received by students and would be more effective at helping them learn physiological concepts compared with more traditional laboratory exercises. In this study, approximately one-half of the laboratory sessions for the two semester course were dedicated to traditional hands-on laboratory exercises, whereas the remaining one-half of the sessions were dedicated to case-based exercises. The lecture portion of the course was not altered. Student attitudes were evaluated after each session and at the end of each semester via quantitative and qualitative survey questions. Student performance was evaluated using section exams and end-of-semester posttests. The vast majority of survey responses received were positive for both cased-based activities and traditional hands-on laboratories. In addition, participation in both types of active learning activities, but not lecture, was associated with retention of conceptual knowledge based on student performance between the section exams and posttests ( P < 0.002). These results indicate that both case-based learning and laboratory exercises are beneficial learning activities to incorporate into a lecture-based physiology course. However, positive survey responses were significantly greater following case-based activities vs. traditional hands-on laboratories, and only participation in case-based activities resulted in greater student performance on the posttest ( P < 0.04). Therefore, case-based activities may be the preferred supplemental learning activity for veterinary medical physiology. PMID- 29616582 TI - Kinetics of carnitine concentration after switching from oral administration to intravenous injection in hemodialysis patients. AB - Carnitine has high dialyzability and is often deficient in dialysis patients. This deficiency is treated by either intravenous (IV) or oral supplementation of carnitine. In this study, the mode of carnitine administration was changed from oral to IV in 17 hemodialysis (HD) patients, and the treatment was discontinued after 1 year. We found that the levels of total carnitine (TC), free-carnitine (FC), and acyl-carnitine (AC) significantly increased after 3 months of switching to IV administration (p < .05). After discontinuation of carnitine administration, the TC, FC, and AC levels decreased before dialysis. The average FC value was maintained at the normal levels until 9 months, but fell below the normal values when measured at the 12th month of discontinuation. In conclusion, carnitine was maintained at significantly high levels despite the smaller dose by IV infusion as compared with that by oral administration. We therefore suggest that our results be considered while determining both the carnitine administration route and the administration period in dialysis patients under clinical settings. PMID- 29616583 TI - Match analyses of table tennis in China: a systematic review. AB - This study is a systematic review of match analyses of table tennis that can be used for reference in China. Using the China National Knowledge Infrastructure (CNKI) as the search tool and "table tennis" as the keyword, we searched for all papers on table tennis published in Chinese core sports journals between 1980 and 2016. Then, we read through 1209 papers and divided them into different categories according to their publication types and main topics. Among them, 128 papers on match analyses met three inclusion criteria, and hence they were chosen as the reviewed studies. The results show that match analyses of table tennis in China have a sound research foundation, with the "three-phase evaluation method" and research on different topics playing an active role in helping coaches and players understand table tennis matches. Computer-aided match analysis not only enhanced the capacity and speed of data processing, but it also facilitated coaches' and players' understanding of tactical features by video feedback and multimedia presentation. Although match analyses of table tennis based on different theories or models are still in a preliminary stage, these studies are indeed pushing the development of this field. PMID- 29616584 TI - Trends and costs of pertussis hospitalizations in Portugal, 2000 to 2015: from 0 to 95 years old. AB - BACKGROUND: Pertussis has caused several outbreaks and concern worldwide. Despite high vaccination coverage, people of all ages are still affected with significant morbidity and mortality. We aimed to analyse all pertussis hospitalizations in Portugal to help to delineate preventive policies. METHODS: Data were collected from a Portuguese administrative database, which contains all registered hospitalizations in mainland Portugal. Cases were identified using the ICD-9-CM code 033.x (whooping cough) as principal or secondary diagnosis, with hospital discharges between 2000 and 2015. Data were analysed by age groups. RESULTS: Of 2281 hospitalizations, 94% occurred in infants (<1 year). The mean and median ages were 20 and 2 months, respectively. A seasonal pattern was observed, with higher number of hospitalizations during the winter for infants, and during the summer for other age groups. Higher hospitalization rates were registered in the Southern regions. The mean and median lengths of hospital stay were 8 and 6 days, respectively. The main complications were acute respiratory failure and pneumonia. Invasive or non-invasive ventilation, or both, was required in 2.4, 1.8 and 0.6% of hospitalized cases, respectively. The overall inpatient case fatality rate was 0.7%; 0.8, 11.5 and 17.4% for the age groups 0-1 months, 18-64 years and >=65 years, respectively. Total hospitalization costs were estimated to be 2,698,995?. CONCLUSION: Our study emphasizes the need to adopt new preventive strategies mainly focused on infants, to reduce morbidity and costs of hospitalizations related to pertussis. PMID- 29616587 TI - Biomechanical Strength of Retrograde Fixation in Proximal Third Scaphoid Fractures. AB - BACKGROUND: Current techniques for fixation of proximal pole scaphoid fractures utilize antegrade fixation via a dorsal approach endangering the delicate vascular supply of the dorsal scaphoid. Volar and dorsal approaches demonstrate equivalent clinical outcomes in scaphoid wrist fractures, but no study has evaluated the biomechanical strength for fractures of the proximal pole. This study compares biomechanical strength of antegrade and retrograde fixation for fractures of the proximal pole of the scaphoid. METHODS: A simulated proximal pole scaphoid fracture was produced in 22 matched cadaveric scaphoids, which were then assigned randomly to either antegrade or retrograde fixation with a cannulated headless compression screw. Cyclic loading and load to failure testing were performed and screw length, number of cycles, and maximum load sustained were recorded. RESULTS: There were no significant differences in average screw length (25.5 mm vs 25.6 mm, P = .934), average number of cyclic loading cycles (3738 vs 3847, P = .552), average load to failure (348 N vs 371 N, P = .357), and number of catastrophic failures observed between the antegrade and retrograde fixation groups (3 in each). Practical equivalence between the 2 groups was calculated and the 2 groups were demonstrated to be practically equivalent (upper threshold P = .010). CONCLUSIONS: For this model of proximal pole scaphoid wrist fractures, antegrade and retrograde screw configuration have been proven to be equivalent in terms of biomechanical strength. With further clinical study, we hope surgeons will be able to make their decision for fixation technique based on approaches to bone grafting, concern for tenuous blood supply, and surgeon preference without fear of poor biomechanical properties. PMID- 29616588 TI - The Relationships of Intergroup Ideologies to Ethnic Prejudice: A Meta-Analysis. AB - This meta-analysis summarizes the results of research on the relationships of majority group members' endorsement of assimilation, colorblindness, multiculturalism, and the relative relationships of colorblindness and multiculturalism to ethnic prejudice. Random effects analyses found that assimilation was positively related to explicit prejudice ( g. = 0.80), multiculturalism was negatively related to both explicit ( g. = -0.26) and implicit prejudice ( g. = -0.19), and colorblindness was negatively related to explicit prejudice ( g. = -0.07). Multiculturalism was more closely associated with low prejudice than colorblindness ( g. = 0.15). Effect sizes varied as a function of methodology (experimental vs. correlational), country in which research was conducted (United States vs. other countries), and, in experimental studies of multiculturalism, type of prime used (abstract vs. concrete). Discussion points include methodological issues, groups used as targets of prejudice, national diversity norms, additional issues raised in the studies reviewed, and directions for future research. PMID- 29616589 TI - The DNA methylation landscape of enhancers in the guinea pig hippocampus. AB - AIM: To determine the state of methylation of DNA molecules in the guinea pig hippocampus that are associated with either poised or active enhancers. METHODS: We used sequential chromatin immunoprecipitation-bisulfite-sequencing with an antibody to H3K4me1 to map the state of methylation of DNA that is found within enhancers. Actively transcribing transcription start sites were mapped by chromatin immunoprecipitation-sequencing with an antibody to RNApolII-PS5. Total DNA methylation was mapped using reduced representation bisulfite sequencing. RESULTS: DNA that overlaps with H3K4me1 binding regions in the genome is heavily methylated. However, DNA molecules that are found in H3K4me1 chromatin are hypomethylated, while DNA found in enhancers that are associated with active transcription is further demethylated. Differential methylation in enhancers is spotted in single CGs, bimodal and corresponds to transcription factor binding sites. CONCLUSION: Our study delineates the DNA methylation status of H3K4 me1 bound regions in the hippocampus in active and inactive genes. PMID- 29616590 TI - DDR1 and DDR2 physical interaction leads to signaling interconnection but with possible distinct functions. AB - Discoidin domain receptors 1 and 2 (DDR1 and DDR2) are members of the tyrosine kinase receptors activated after binding with collagen. DDRs are implicated in numerous physiological and pathological functions such as proliferation, adhesion and migration. Little is known about the expression of the two receptors in normal and cancer cells and most of studies focus only on one receptor. Western blot analysis of DDR1 and DDR2 expression in different tumor cell lines shows an absence of high co-expression of the two receptors suggesting a deleterious effect of their presence at high amount. To study the consequences of high DDR1 and DDR2 co-expression in cells, we over-express the two receptors in HEK 293T cells and compare biological effects to HEK cells over-expressing DDR1 or DDR2. To distinguish between the intracellular dependent and independent activities of the two receptors we over-express an intracellular truncated dominant-negative DDR1 or DDR2 protein (DDR1DN and DDR2DN). No major differences of Erk or Jak2 activation are found after collagen I stimulation, nevertheless Erk activation is higher in cells co-expressing DDR1 and DDR2. DDR1 increases cell proliferation but co-expression of DDR1 and DDR2 is inhibitory. DDR1 but not DDR2 is implicated in cell adhesion to a collagen I matrix. DDR1, and DDR1 and DDR2 co-expression inhibit cell migration. Moreover a DDR1/DDR2 physical interaction is found by co immunoprecipitation assays. Taken together, our results show a deleterious effect of high co-expression of DDR1 and DDR2 and a physical interaction between the two receptors. PMID- 29616591 TI - A qualitative analysis of the role of emotions in different patterns of long-term weight loss. AB - OBJECTIVE: To explore participant perspectives of the impact emotions have on weight loss. DESIGN: A qualitative design gathered data through semi-structured interviews with participants in a weight management programme. The interview addresses the following research questions: (1) how do individuals working to lose weight perceive the impact emotions have on their long-term success, and (2) what strategies do more or less successful participants use to regulate their emotions? Researchers conducted and transcribed the interviews then completed content analysis to create and organise themes. RESULTS: Two broad themes emerged through the interviews with 21 participants: emotional impact and emotional regulation. Further subthemes captured emotions blocking action toward goals, strategies for regulating emotions (e.g. exercise, food) and the need for new strategies to regulate emotions. Themes were also split in to three groups based on weight outcomes: regainer, moderate success (3-6% loss) and large success (>7% loss). More successful participants, compared to regainers, shared being aware of the impact of their emotions and made efforts to develop healthy regulation strategies. CONCLUSIONS: Emotional awareness and regulation play an important role in participant's weight management experience. Taking time to build emotional awareness and strategies to manage emotions is important to participants in weight management. PMID- 29616592 TI - Attitudes of intensive care and emergency physicians in Australia with regard to the organ donation process: A qualitative analysis. AB - Specialized hospital physicians have direct capacity to impact Australia's sub optimal organ donation rates because of their responsibility to identify and facilitate donation opportunities. Australian physicians' attitudes toward this responsibility are examined. A total of 12 intensive care unit and three emergency department physicians were interviewed using a constructionist grounded theory and situational analysis approach. A major theme emerged, related to physicians' conflicts of interest in maintaining patients'/next-of-kin's best interests and a sense of duty-of-care in this context. Two sub-themes related to this main theme were identified as follows: (1) discussions about organ donation and who is best to carry these out and (2) determining whether organ donation is part of end-of-life care; including the avoidance of non-therapeutic ventilation; and some reluctance to follow clinical triggers in the emergency department. Overall, participants indicated strong support for organ donation but would not consider it part of end-of-life care, representing a major obstacle to the support of potential donation opportunities. Findings have implications for physician education and training. Continued efforts are needed to integrate the potential for organ donation into end-of-life care within intensive care units and emergency departments. PMID- 29616593 TI - Understanding the pros and cons of organ donation decision-making: Decisional balance and expressing donation intentions among African Americans. AB - Increasing public commitment to organ donation is critical to improving donor kidney availability for end-stage renal disease patients desiring transplant. This study surveyed ( N = 1339) African Americans, measuring perceived pros relative to cons of organ donation, to evaluate an existing Transtheoretical Model decisional balance scale and associations between decisional balance and expressing donation intentions. Findings supported the existing scale structure. More positive decisional balance ratios were associated with 1.76 times the odds of expressing intentions (95% confidence interval = 1.52-2.04). Pros were more strongly linked to donation intentions than cons. Greater understanding of organ donation decision-making is valuable for informing interventions that encourage donation. PMID- 29616594 TI - The protective function of noncoding DNA in genome defense of eukaryotic male germ cells. AB - Peripheral and abundant noncoding DNA has been hypothesized to protect the genome and the central protein-coding sequences against DNA damage in somatic genome. In the cytosol, invading exogenous nucleic acids may first be deactivated by small RNAs encoded by noncoding DNA via mechanisms similar to the prokaryotic CRISPR Cas system. In the nucleus, the radicals generated by radiation in the cytosol, radiation energy and invading exogenous nucleic acids are absorbed, blocked and/or reduced by peripheral heterochromatin, and damaged DNA in heterochromatin is removed and excluded from the nucleus to the cytoplasm through nuclear pore complexes. To further strengthen the hypothesis, this review summarizes the experimental evidence supporting the protective function of noncoding DNA in the genome of male germ cells. Based on these data, this review provides evidence supporting the protective role of noncoding DNA in the genome defense of sperm genome through similar mechanisms to those of the somatic genome. PMID- 29616595 TI - Dynamics analysis of a predator-prey system with harvesting prey and disease in prey species. AB - In this paper, a predator-prey system with harvesting prey and disease in prey species is given. In the absence of time delay, the existence and stability of all equilibria are investigated. In the presence of time delay, some sufficient conditions of the local stability of the positive equilibrium and the existence of Hopf bifurcation are obtained by analysing the corresponding characteristic equation, and the properties of Hopf bifurcation are given by using the normal form theory and centre manifold theorem. Furthermore, an optimal harvesting policy is investigated by applying the Pontryagin's Maximum Principle. Numerical simulations are performed to support our analytic results. PMID- 29616596 TI - Decoding and modelling of time series count data using Poisson hidden Markov model and Markov ordinal logistic regression models. AB - Hidden Markov models are stochastic models in which the observations are assumed to follow a mixture distribution, but the parameters of the components are governed by a Markov chain which is unobservable. The issues related to the estimation of Poisson-hidden Markov models in which the observations are coming from mixture of Poisson distributions and the parameters of the component Poisson distributions are governed by an m-state Markov chain with an unknown transition probability matrix are explained here. These methods were applied to the data on Vibrio cholerae counts reported every month for 11-year span at Christian Medical College, Vellore, India. Using Viterbi algorithm, the best estimate of the state sequence was obtained and hence the transition probability matrix. The mean passage time between the states were estimated. The 95% confidence interval for the mean passage time was estimated via Monte Carlo simulation. The three hidden states of the estimated Markov chain are labelled as 'Low', 'Moderate' and 'High' with the mean counts of 1.4, 6.6 and 20.2 and the estimated average duration of stay of 3, 3 and 4 months, respectively. Environmental risk factors were studied using Markov ordinal logistic regression analysis. No significant association was found between disease severity levels and climate components. PMID- 29616597 TI - Malignant Solitary Fibrous Tumor Metastatic to Widely Invasive Hurthle Cell Thyroid Carcinoma: A Distinct Tumor-to-Tumor Metastasis. AB - We illustrate a case of synchronous malignant solitary fibrous tumor of the thoracic cavity, and widely invasive thyroid Hurthle cell carcinoma. The Hurthle cell carcinoma was found to harbor distinct areas of malignant solitary fibrous tumor. This is a unique case of tumor-to-tumor metastasis that, to the best of our knowledge, has not been previously reported. PMID- 29616598 TI - Knowledge, Beliefs, and Behaviors Related to Palliative Care Delivery Among Pediatric Oncology Health Care Providers. AB - The care of pediatric patients with cancer and their families is complex and rapidly evolving. Despite significant advances in outcomes, symptoms of the disease and complications of therapy continue to cause suffering that may improve with the involvement of pediatric palliative care (PPC) services. This descriptive study responds to the observation of great variability in PPC utilization within pediatric oncology. Data collected from 156 health care professionals (nurses, advanced practice professionals, and physicians) from a statewide hematology alliance evaluates the knowledge, beliefs, and perceived barriers to PPC involvement. Data analysis reveals significant variability when comparing respondents from professional roles and practice environments. Despite progress in PPC availability, care delivery remains incongruent with current recommendations. Knowledge gained from this study emphasizes the important role for all health care providers in advocating for support of PPC programs, educating the public, and committing to intentional involvement of PPC services while caring for pediatric oncology patients. PMID- 29616600 TI - Communication Between Obstetricians and Pediatricians. PMID- 29616601 TI - Does neutrophil to lymphocyte ratio demonstrate deterioration in renal function? AB - INTRODUCTION: Chronic kidney disease (CKD) is a major health issue worldwide, which leads to end-stage renal failure and cardiovascular events. Neutrophil to lymphocyte ratio (NLR) is a surrogate marker of inflammation and has been widely studied in malignancies, hypertension, heart diseases, and vascular diseases. In this study, we aimed to investigate if NLR represents renal reserve and function after partial or radical nephrectomy. METHODS: We conducted a retrospective study consists of patients who had undergone radical/partial nephrectomy in our hospital and/or who admitted to urology and nephrology clinics as an outpatient. Patients were divided into four groups: Group 1 (n = 46): Healthy controls; Group 2 (n = 50): Patients who had undergone unilateral partial nephrectomy; Group 3 (n = 46): Patients who had gone unilateral nephrectomy; Group 4 (n = 82): Patients who had CKD. RESULTS: The mean NLR of each group was as follows: Group 1: 2.14 +/- 0.73; Group 2: 3.52 +/- 3.74; Group 3: 3.64 +/- 3.52, and Group 4: 3.53 +/- 2.30. NLR was lower in Group 1 compared to other groups but statistically significant difference was observed only between Group 1 (control) and Group 4 (CKD), 2.14 +/- 0.73 versus 3.53 +/- 2.30 (p = .005). In non parametric correlation analysis NLR was found negatively correlated with GFR and positively correlated CKD stage (p = .028 for both correlations). CONCLUSIONS: The NLR may constitute a practical predictor of CKD besides Cr in patients who had undergone partial or radical nephrectomy. PMID- 29616602 TI - Correlates of nursing care burden among institutionalized patients with dementia. AB - : ABSTRACTBackground:The stress associated with care of patients with dementia has led to high nursing staff turnover. This study aims to explore patient factors that are related to nursing burden. METHODS: The present study examined nursing care burden related to 55 institutionalized dementia patients using the Modified Nursing Care Assessment Scale (M-NCAS). Cognition was assessed with the Severe Impairment Battery (SIB), activities of daily living (ADLs) were measured with the Alzheimer's Disease Functional Assessment of Change Scale (ADFACS), aggression was measured with the Aggressive Behavior Scale (ABS), and the Charlson Comorbidity Index (CCI) was used to assess medical comorbidity. Finally, the Dementia Cognitive Fluctuation Scale (DCFS) was used to assess the presence and severity of cognitive fluctuations (CFs). Linear regression models were used to assess their relationships with nursing care burden. RESULTS: The mean age of the patients was 90.41 years (SD=2.84) and 89.10% were males. ADFACS total score (B = 0.36, beta = 0.42, p = 0.002) and ABS score (B = 2.933, beta = 0.37, p = 0.002) significantly predicted the M-NCAS Attitude score. ABS score was the only significant predictor of M-NCAS Strain score (B = 2.57, beta = 0.35, p = 0.009). CONCLUSIONS: In the long-term care setting, aggressive behavior plays an important role in both subjective and objective nursing burden, while impaired ADLs increase the objective burden for nursing staff. PMID- 29616603 TI - Snack food as a modulator of human resting-state functional connectivity. AB - OBJECTIVE: To elucidate the mechanisms of how snack foods may induce non homeostatic food intake, we used resting state functional magnetic resonance imaging (fMRI), as resting state networks can individually adapt to experience after short time exposures. In addition, we used graph theoretical analysis together with machine learning techniques (support vector machine) to identifying biomarkers that can categorize between high-caloric (potato chips) vs. low caloric (zucchini) food stimulation. METHODS: Seventeen healthy human subjects with body mass index (BMI) 19 to 27 underwent 2 different fMRI sessions where an initial resting state scan was acquired, followed by visual presentation of different images of potato chips and zucchini. There was then a 5-minute pause to ingest food (day 1=potato chips, day 3=zucchini), followed by a second resting state scan. fMRI data were further analyzed using graph theory analysis and support vector machine techniques. RESULTS: Potato chips vs. zucchini stimulation led to significant connectivity changes. The support vector machine was able to accurately categorize the 2 types of food stimuli with 100% accuracy. Visual, auditory, and somatosensory structures, as well as thalamus, insula, and basal ganglia were found to be important for food classification. After potato chips consumption, the BMI was associated with the path length and degree in nucleus accumbens, middle temporal gyrus, and thalamus. CONCLUSION: The results suggest that high vs. low caloric food stimulation in healthy individuals can induce significant changes in resting state networks. These changes can be detected using graph theory measures in conjunction with support vector machine. Additionally, we found that the BMI affects the response of the nucleus accumbens when high caloric food is consumed. PMID- 29616604 TI - UNTANGLING, UNBUNDLING, AND MOVING FORWARD: FRAMING HEALTH TECHNOLOGY REASSESSMENT IN THE CHANGING CONCEPTUAL LANDSCAPE. AB - OBJECTIVES: Health technology reassessment (HTR) is a policy process to manage health technologies throughout their lifecycle and ensure their ongoing optimal use. However, within an ever-evolving field, HTR is only one of many concepts associated with the optimization of health technologies. There is limited understanding of how other concepts and processes might differ and/or be interrelated. This study aims to describe the concepts underlying the various technology optimization processes and to reconcile their relationships within the HTR process. METHODS: A synthesis of the literature on approaches to HTR was completed. An inductive synthesis approach was completed to catalogue common concepts and themes. Expert stakeholders were consulted to develop a schematic to diagrammatically depict the relationships among concepts and frame them within the HTR process. RESULTS: A practical schematic was developed. Common concepts and themes were organized under six major domains that address the following discussion questions: (i) what is the value of the existing technology?; (ii) what is the current utilization gap?; (iii) what are the available tools and resources?; (iv) what are the levers for change?; (v) what is the desired outcome?; and (vi) who are the foundational actors? CONCLUSIONS: Using these six questions to frame the issues faced by HTR will advance the common understanding of HTR, as well as improve implementation of HTR initiatives. These questions will clearly identify the process required to move forward within a complex healthcare system. PMID- 29616605 TI - Withdrawal of 'Assessing Efficacy of Lipid in Unstable, Non-Last Overdose Patients - RETRACTION'. PMID- 29616607 TI - Non-pharmacological interventions for persons with dementia: what are they and how should they be studied? AB - The publication of four papers concerning non-pharmacological interventions for persons with dementia heralds progress in the science of dementia care. The four papers are very diverse in focus and methodology, and include a study of the impact of a visual arts program on quality of life, communication, and well-being by Windle et al. (2017); an overview of systematic reviews of pharmacological and non-pharmacological interventions for the treatment of behavioral and psychological symptoms of dementia by Dyer et al. (2017); a systematic review of the efficacy of intervention in people with Lewy body dementia by Morrin et al. (2017); and a protocol of the Behavior and Evolution of Young Onset Dementia part two (BEYOND-II) study, an intervention study aimed at improvement in the management of neuropsychiatric symptoms in institutionalized people with young onset dementia by van Duinen-van den IJssel et al. (2017). PMID- 29616606 TI - Streptococcal group A, C and G pharyngitis in school children: a prospective cohort study in Southern India. AB - Diagnosing streptococcal pharyngitis in children on the basis of clinical appearance and throat culture is complicated by high colonisation rates and by the ability of other pathogens to cause clinically similar disease. To characterise the epidemiology of Lancefield Group A, C and G beta-haemolytic streptococcus (GAS, GCS and GGS, respectively) in children, we conducted a 2-year prospective study of 307 school children between 7 and 11 years old. GGS and GAS were commonly identified organisms both for silent streptococcal colonisation and symptomatic sore throat, while GCS was uncommonly found. Streptococcal culture positivity at the time of clinical pharyngitis was estimated to reflect true streptococcal pharyngitis in only 26% of instances, with the frequency varying from 54% for children rarely colonised to 1% for children frequently colonised. Numerous GAS emm types were identified, including several types previously associated with severe pharyngitis (e.g. emm types 1, 3 and 28). No severe complications were seen in any child. These data suggest that the clinical diagnosis of streptococcal pharyngitis is likely to remain difficult and that treatment decisions will remain clouded by uncertainty. There remains a need for organism-specific rapid point-of-care streptococcal diagnostic tests and tests that can distinguish between streptococcal colonisation and disease. PMID- 29616609 TI - Job vacancy at the European Centre for Disease Prevention and Control. PMID- 29616608 TI - Candida auris: epidemiological situation, laboratory capacity and preparedness in European Union and European Economic Area countries, 2013 to 2017. AB - During 2013-2017, 620 cases of Candida auris were reported in the European Union/European Economic Area - 466 (75.2%) colonisations, 110 (17.7%) bloodstream infections, 40 (6.5%) other infections and four cases (0.6%) of unknown colonisation/infection status - the majority from four large outbreaks. Survey results showed that several countries lacked laboratory capacity and/or information on the occurrence of cases at national level. To prevent further spread, adequate laboratory capacity and infection control preparedness is required in Europe. PMID- 29616610 TI - A case of respiratory toxigenic diphtheria: contact tracing results and considerations following a 30-year disease-free interval, Catalonia, Spain, 2015. AB - In May 2015, following a 30-year diphtheria-free interval in Catalonia, an unvaccinated 6-year-old child was diagnosed with diphtheria caused by toxigenic Corynebacterium diphtheriae. After a difficult search for equine-derived diphtheria antitoxin (DAT), the child received the DAT 4 days later but died at the end of June. Two hundred and seventeen contacts were identified in relation to the index case, and their vaccination statuses were analysed, updated and completed. Of these, 140 contacts underwent physical examination and throat swabs were taken from them for analysis. Results were positive for toxigenic C. diphtheriae in 10 contacts; nine were asymptomatic vaccinated children who had been in contact with the index case and one was a parent of one of the nine children. Active surveillance of the 217 contacts was initiated by healthcare workers from hospitals and primary healthcare centres, together with public health epidemiological support. Lack of availability of DAT was an issue in our case. Such lack could be circumvented by the implementation of an international fast-track procedure to obtain it in a timely manner. Maintaining primary vaccination coverage for children and increasing booster-dose immunisation against diphtheria in the adult population is of key importance. PMID- 29616613 TI - In the national epidemiological bulletins - a selection from recent issues. PMID- 29616614 TI - Rise and fall of outbreak-specific clone inside endemic pulsotype of Salmonella 4,[5],12:i:-; insights from high-resolution molecular surveillance in Emilia Romagna, Italy, 2012 to 2015. AB - Background and aimEpidemiology of human non-typhoid salmonellosis is characterised by recurrent emergence of new clones of the pathogen over time. Some clonal lines of Salmonella have shaped epidemiology of the disease at global level, as happened for serotype Enteritidis or, more recently, for Salmonella 4,[5],12:i:-, a monophasic variant of serotype Typhimurium. The same clonal behaviour is recognisable at sub-serotype level where single outbreaks or more generalised epidemics are attributable to defined clones. The aim of this study was to understand the dynamics of a clone of Salmonella 4,[5],12:i:- over a 3 year period (2012-15) in a province of Northern Italy where the clone caused a large outbreak in 2013. Furthermore, the role of candidate outbreak sources was investigated and the accuracy of multilocus variable-number tandem repeat analysis (MLVA) was evaluated. Methods: we retrospectively investigated the outbreak through whole genome sequencing (WGS) and further monitored the outbreak clone for 2 years after its conclusion. Results: The study showed the transient nature of the clone in the population, possibly as a consequence of its occasional expansion in a food-processing facility. We demonstrated that important weaknesses characterise conventional typing methods applied to clonal pathogens such as Salmonella 4,[5],12:i:-, namely lack of accuracy for MLVA and inadequate resolution power for PFGE to be reliably used for clone tracking. Conclusions: The study provided evidence for the remarkable prevention potential of whole genome sequencing used as a routine tool in systems that integrate human, food and animal surveillance. PMID- 29616611 TI - Dominant influenza A(H3N2) and B/Yamagata virus circulation in EU/EEA, 2016/17 and 2017/18 seasons, respectively. AB - We use surveillance data to describe influenza A and B virus circulation over two consecutive seasons with excess all-cause mortality in Europe, especially in people aged 60 years and older. Influenza A(H3N2) virus dominated in 2016/17 and B/Yamagata in 2017/18. The latter season was prolonged with positivity rates above 50% among sentinel detections for at least 12 weeks. With a current west east geographical spread, high influenza activity might still be expected in eastern Europe. PMID- 29616615 TI - Assessment of bacterial contamination of lipstick using pyrosequencing. AB - As soon as they are exposed to the environment, cosmetics become contaminated with microorganisms, and this contamination accumulates with increased use. In this study, we employed pyrosequencing to investigate the diversity of bacteria found on lipstick. Bacterial DNA was extracted from 20 lipstick samples and mixed in equal ratios for pyrosequencing analysis. As a result, 105 bacterial genera were detected, four of which (Leifsonia, Methylobacterium, Streptococcus, and Haemophilus) were predominant in 92% of the 19,863 total sequence reads. Potentially pathogenic genera such as Staphylococcus, Pseudomonas, Escherichia, Salmonella, Corynebacterium, Mycobacterium, and Neisseria accounted for 27.6% of the 105 genera. The most commonly identified oral bacteria belonged to the Streptococcus genus, although other oral genera such as Actinomyces, Fusobacterium, Porphyromonas, and Lactobacillus were also detected. PMID- 29616616 TI - Non-comedogenic and non-acnegenic claim substantiation. AB - There are currently two methods to evaluate comedogenecity. One is the inexpensive human model developed by Mills and Kligman and modified by others. The second is the more costly human clinical trial, which is the gold standard for comedogenesis and to which the human model is compared. The qualification of each method to support the comedogenecity claim is evaluated and contrasted. PMID- 29616618 TI - The antiwrinkle and antimelanogenic effects of the nonedible part of Sorghum bicolor (L.) Moench and their augmentation by fermentation. AB - Sorghum [Sorghum bicolor (L.) Moench] is a major cereal crop. Despite the wide cultivation of sorghum, its stalks are used as hay and silage. The plant has numerous bioactive compounds including cosmeceutical ingredients. Thus, we investigated the antimelanogenic and SSE that is prepared from the stalk of Sorghum bicolor L. (SSE) after ethanol (EtOH) extraction. Based on the antioxidant capacity, antityrosinase activity, and suppression of the protein expression levels of matrix metalloproteinase (MMP)-1, -2, and -3 in human neonatal foreskin HDF-N cells, a 50% EtOH extraction of SSEs showed antimelanogenic and antiwrinkle potential. To enrich the cosmeceutical potential of SSE, a fermentation process was applied to SSE with the use of the fungus Aspergillus oryzae NK ( f SSE). On additional fermentation, the cosmeceutical potential of SSE increased with further enhancement of antityrosinase activity and suppression of MMP-1, -2, and -3 protein expression. SSE contains p-coumaric acid, and its level was enriched by the fermentation process. Collectively, SSE and its fermented product can serve as good ingredients in new cosmeceutical compounds. PMID- 29616617 TI - Formulation of chitosan patch incorporating Artocarpus altilis heartwood extract for improving hyperpigmentation. AB - Artocarpus altilis heartwood extract contains the bioactive compound artocarpin which exhibits melanogenesis inhibitory activity. However, the extract has poor solubility which affects the skin permeability of the compound. A chitosan hydrogel patch incorporating A. altilis heartwood extract was formulated to enhance the delivery of an amount of artocarpin sufficient for depigmenting the skin. The extract was prepared as an o/w microemulsion before blending with an aqueous solution of chitosan. The hydrogel patch was formulated by blending in a 1:1 ratio by weight of 4% w/w chitosan solution and 0.04% w/w extract microemulsion which provides optimal values of the mechanical properties of the patch. The release of artocarpin from the formulated patch (artocarpin content, 0.07 mg/cm2) exhibited two phases; the rapid rate (0-15 min) averaged 0.73 ug/min/mm2, and the slow rate (15-240 min) averaged 0.02 ug/min/mm2. The formulated patches significantly improved the hyperpigmented area of the subjects after 3 weeks of application. No adverse events were observed. The results indicate that the formulated chitosan hydrogel patch delivers an effective amount of incorporated artocarpin depigmenting action. PMID- 29616619 TI - Letter to the editor. PMID- 29616620 TI - Noninvasive measurement of advanced glycation end-products in the facial skin: New data for skin aging studies. AB - Using skin autofluorescence (SAF) as a marker of advanced glycation end-products (AGEs) has been extensively studied in the last decade since the introduction of the noninvasive in vivo measurement technique. Data have shown the level of skin AGEs increases with chronological age in healthy human beings, and this increase is substantially higher in age-matched diabetic patients. In skin research, glycation with the accompanying accumulation of skin AGEs has been regarded as one of the primary skin aging mechanisms that contribute to skin wrinkling and the loss of skin elasticity. To date, the totality of SAF data reported in literature has been obtained from measurements on the arm, and noninvasive measurement of facial skin AGE accumulation would add great value to skin aging research. In this study, we report the levels of facial and forearm skin AGEs in 239 men and women of 21-65 year of age. Significantly lower levels of AGEs were detected in the facial skin than in the forearm skin from the young Caucasian groups, and the difference was much larger for men than for women. The rate of change in skin AGE level over age was found to be about 50% higher in men than in women, which further highlights the gender difference. A statistically significant correlation between the levels of skin AGE and facial wrinkling was also observed. The facial skin AGE data may provide new insight into skin aging research. PMID- 29616621 TI - Two randomized studies to evaluate the cooling sensation, consumer liking, and tolerability of a skin disinfectant spray. AB - The aim of these two clinical studies was to evaluate the sensory characteristics and irritation potential of a prototype disinfectant spray (containing 0.13% w/v benzalkonium chloride and a cooling agent) in subjects with experimental wounds. The pilot study was a single center, "replicated latinClinicalTrials.ClinicalTrials. square design," randomized and double-blinded study. The pivotal study was a single center, randomized, controlled, crossover, double-blinded study, following a direct comparison test design of the study products. The experimental wounds were generated using sequential tape strippings of the forearm skin before product application. The test product was compared with the currently marketed BACTROBAN(r) disinfectant spray, negative control (0.9% w/v saline), and positive control (70% w/v isopropyl alcohol, pilot study only). The pilot study was intended to inform the study design and sample size for the pivotal study. The pilot study demonstrated that the positive control product delivered significantly more irritancy (stinging /burning sensory) than the negative control product on the experimental wound, which verified the integrity of the wound model. The results of the pivotal study suggested that the prototype formulation delivered significantly more cooling sensation than both BACTROBAN(r) disinfectant spray and negative control at 3 and 5 min after product application, and overall for a 15-min period after application. No statistically significant differences in product liking were observed between the prototype disinfectant spray and the BACTROBAN(r) disinfectant spray or negative control. The prototype disinfectant spray, BACTROBAN(r) disinfectant spray, and control products were well-tolerated in these studies. PMID- 29616622 TI - Development of a preclinical surfactant skin penetration assay to reflect exposure times typical of consumer use. AB - Mixed surfactant and surfactant-polymer compositions have been reported to decrease surfactant deposition onto and penetration into the skin relative to single surfactant compositions, potentially improving the mildness of the product. Previous workers in this area [see Moore et al., J. Cosmet. Sci.54:29-46 (2003), and subsequent publications] employed a procedure in which excised porcine skin was exposed to a surfactant solution containing radiolabeled sodium dodecyl sulfate (14C-SDS) for 5 h. We have developed an improved SDS penetration assay using excised human skin that reflects typical consumer exposure times for rinse-off products. Using the new protocol, we were able to see a significant decrease in 14C-SDS penetration from a sodium lauryl sulfate (SLS)/polyethylene oxide composition applied to excised skin for either 2 or 10 min, as compared to SLS only. Furthermore, differences between the SDS penetration patterns on porcine skin and human skin were seen with a second SLS/polymer system; consequently, we do not recommend porcine skin for routine mildness screening by 14C-SDS penetration. PMID- 29616623 TI - Color profiles and stability of acylated and nonacylated anthocyanins as novel pigment sources in a lipstick model: A viable alternative to synthetic colorants. AB - Cosmetics, such as lipstick, can affect an individual's perception of attractiveness and morale. Consumer concern with the safety of synthetic colorants has made the need for alternative natural color sources increasingly urgent. Our goal was to evaluate the feasibility of anthocyanin (ACN) extracts as colorants in lipstick formulations. Lipstick formulations were colored with ACN rich materials. Accelerated environmental testing typical of the cosmetic industry were used: incubation at 20 degrees , 37 degrees , and 45 degrees C for 12 weeks and temperature abuse cycles between 20 degrees /37 degrees C or -20 degrees /20 degrees C. Color (CIELab) and total monomeric ACN (pH-differential) changes were monitored to determine shelf stability of the product. All formulations exhibited acceptable color for lipsticks. Shelf stability was determined to exceed 2 year based on the accelerated testing conditions. Formulations containing cyanidin as their main ACN were the most stable (elderberry, purple corn, and purple sweet potato). ACNs could be used as suitable alternatives to synthetic colorants in lipid-based topical formulations. PMID- 29616624 TI - Invasive strategy and frailty in very elderly patients with acute coronary syndromes. AB - AIMS: Current guidelines recommend an early invasive strategy in patients with non-ST-segment elevation acute coronary syndromes (NSTEACS). The role of an invasive strategy in frail elderly patients remains controversial. The aim of this substudy was to assess the impact of an invasive strategy on outcomes according to the degree of frailty in these patients. METHODS AND RESULTS: The LONGEVO-SCA registry included unselected NSTEACS patients aged >=80 years. A geriatric assessment, including frailty, was performed during hospitalisation. During the admission, we evaluated the impact of an invasive strategy on the incidence of cardiac death, reinfarction or new revascularisation at six months. From 531 patients included, 145 (27.3%) were frail. Mean age was 84.3 years. Most patients underwent an invasive strategy (407/531, 76.6%). Patients undergoing an invasive strategy were younger and had a lower proportion of frailty (23.3% vs. 40.3%, p<0.001). The incidence of cardiac events was more common in patients managed conservatively, after adjusting for confounding factors (sub-hazard ratio [sHR] 2.32, 95% confidence interval [CI]: 1.26-4.29, p=0.007). This association remained significant in non-frail patients (sHR 3.85, 95% CI: 2.13-6.95, p=0.001), but was not significant in patients with established frailty criteria (sHR 1.40, 95% CI: 0.72-2.75, p=0.325). The interaction invasive strategy-frailty was significant (p=0.032). CONCLUSIONS: An invasive strategy was independently associated with better outcomes in very elderly patients with NSTEACS. This association was different according to frailty status. PMID- 29616625 TI - Plaque burden influences accurate classification of fibrous cap atheroma by in vivo optical coherence tomography in a porcine model of advanced coronary atherosclerosis. AB - AIMS: In vivo validation of coronary optical coherence tomography (OCT) against histology and the effects of plaque burden (PB) on plaque classification remain unreported. We aimed to investigate this in a porcine model with human-like coronary atherosclerosis. METHODS AND RESULTS: Five female Yucatan D374Y-PCSK9 transgenic hypercholesterolaemic minipigs were implanted with a coronary shear modifying stent to induce advanced atherosclerosis. OCT frames (n=201) were obtained 34 weeks after implantation. Coronary arteries were perfusion-fixed, serially sectioned and co-registered with OCT using a validated algorithm. Lesions were adjudicated using the Virmani classification and PB assessed from histology. OCT had a high sensitivity, but modest specificity (92.9% and 74.6%), for identifying fibrous cap atheroma (FCA). The reduced specificity for OCT was due to misclassification of plaques with histologically defined pathological intimal thickening (PIT) as FCA (46.1% of the frames with histological PIT were misclassified). PIT lesions misclassified as FCA by OCT had a statistically higher PB than in other OCT frames (median 32.0% versus 13.4%; p<0.0001). Misclassification of PIT lesions by OCT occurred when PB exceeded approximately 20%. CONCLUSIONS: Compared with histology, in vivo OCT classification of FCA had high sensitivity but reduced specificity due to misclassification of PITs with high PB. PMID- 29616626 TI - Coronary Vasospastic Angina: A Rare Case of Ergonovine Positivity and Curative Bilateral Cardiac Sympathectomy. PMID- 29616627 TI - Lumen Boundaries Extracted from Coronary Computed Tomography Angiography on Computed Fractional Flow Reserve (FFRCT): Validation with Optical Coherence Tomography. AB - AIMS: To evaluate the accuracy of minimal lumen area (MLA) by coronary computed tomography angiography (cCTA) and its impact on fractional flow reserve (FFRCT). METHODS AND RESULTS: Fifty-seven patients (118 lesions, 72 vessels) who underwent cCTA and optical coherence tomography (OCT) were enrolled. OCT and cCTA were co registered and MLAs were measured with both modalities. FFROCT was calculated using OCT-updated models with cCTA-based lumen geometry replaced by OCT-derived geometry. Lesions were grouped by Agatston score (AS) and minimum lumen diameter (MLD) using the OCT catheter and guide wire size (1.0 mm) as a threshold. For all lesions, the average absolute difference between cCTA and OCT MLA was 0.621+/ 0.571 mm2. Pearson correlation coefficients between cCTA and OCT MLAs in lesions with low-intermediate and high AS were 0.873 and 0.787, respectively (both p<0.0001). Irrespective of AS score, excellent correlations were observed for MLA (r=0.839, p<0.0001) and FFR comparisons (r=0.918, p<0.0001) in lesions with MLD>=1.0 mm but not for lesions with MLD<1.0 mm. CONCLUSIONS: The spatial resolution of cCTA or calcification does not practically limit the accuracy of lumen boundary identification by cCTA or FFRCT calculations for MLD>=1.0 mm. The accuracy of cCTA MLA could not be adequately assessed for lesions with MLD<1.0 mm. PMID- 29616628 TI - Pressure wire assessment of jailed balloon technique efficacy in a patient with complex bifurcated lesion. PMID- 29616629 TI - Novel percutaneous suture-mediated patent foramen ovale closure technique: early results of the NobleStitch EL Italian Registry. AB - AIMS: The aim of this study was to assess the efficacy of a novel percutaneous "deviceless" suture-mediated patent foramen ovale (PFO) closure system. METHODS AND RESULTS: Between June 2016 and October 2017, a prospective registry aimed at assessing the safety and efficacy of the NobleStitch EL (HeartStitch, Fountain Valley, CA, USA) suture-based PFO closure system was carried out at 12 sites in Italy. Among 200 consecutive patients evaluated, 192 were considered suitable for suture-mediated PFO closure (44+/-13 years, 114 female). Suture of the septum with the NobleStitch EL system was carried out successfully in 186 (96%) patients. Median fluoroscopy time was 16.1 (13.0-22.5) minutes and contrast volume 200 (150-270) ml. At 206+/-130 days follow-up, contrast transthoracic echocardiography with the Valsalva manoeuvre revealed no RLS (grade 0) in 139 (75%) patients and RLS grade <=1 in 166 (89%) patients. Significant RLS was present in 20 (11%) patients (grade 2 and 3 in 11 and nine patients, respectively). There were no device-related complications. CONCLUSIONS: The early results of this first Italian registry indicate that the suture-mediated "deviceless" closure of PFO is feasible in the majority of septal anatomies, and provides an effective closure of PFO comparable to traditional devices with a good safety profile at medium-term follow-up. PMID- 29616630 TI - The antivenom efficacy against a viper bite without medical treatment for 3 days: a case report. AB - Snakebites can be deadly, depending on the course of extremely serious hemorrhagic complications in the absence of antivenom, which remains the only specific and effective treatment, if it is introduced in time. We report the case of a young patient of 18 years, bitten by a snake and receiving only tradition care until admission to intensive care 3 days later, with advanced bleeding and inflammation; four vials of FAV-Africa antivenom were administered and resulted in dramatic improvement in his condition. This result confirms the empirical concept that delay in management should under no circumstances exclude the administration of antivenom. PMID- 29616631 TI - Revisiting Ebola, a quiet river in the heart of Africa. AB - In 1995, 20 years after the first known Ebola outbreak, one of us (JPG) wrote an editorial about Ebola Virus Disease that captured the knowledge and attitudes toward viral diseases of that time and discussed the future of viruses in our world. Now, 21 years later, in the wake of the West African Ebola pandemic of 2013-2016, and after 22 other Ebola outbreaks, we revisit the article to determine if knowledge, attitudes, and practices have changed. We conclude that the necessary infrastructures (surveillance, financial, treatment/preventative health) have improved with each outbreak, and knowledge of the virus (vaccines, therapies, diagnostics) has increased. However, the global reach of the virus has also increased due to expanded means of global transportation. Furthermore, the knowledge of the virus that has increased with each outbreak has not translated into the necessary marginal increase in preparedness; we do not seem to be learning from our mistakes. PMID- 29616632 TI - 2nd Doctors Without Borders Pediatric Days, Dakar December 15-16, 2017. PMID- 29616633 TI - Preparation needed for the social dimensions of epidemics in Africa: Experience from a training session in Conakry. AB - After the Ebola outbreak in West Africa (2013-2016), preparedness is on the agenda of health institutions. However, key questions remain about the scope of preparedness and activities related to the socio-cultural dimension of epidemics. A multidisciplinary short-course Infectious Diseases and Anthropology in West Africa (MIAA) was held at CERFIG, Conakry, in November 2017. Its evaluation provides some answers to key questions, such as who should be trained, and what its objectives, pedagogical contents, and methods should be. PMID- 29616634 TI - Intoxication par la tetrodotoxine. PMID- 29616635 TI - Elevation de l'incidence de Talaromyces marneffei. PMID- 29616636 TI - Hepatite E dans les camps. PMID- 29616637 TI - Diarrhees chez l'enfant des bidonvilles. PMID- 29616638 TI - Prevalence elevee de Plasmodium vivax. PMID- 29616639 TI - Sickle-cell disease with an eruptive appearance? What is your diagnosis? AB - Lupus is an autoimmune disease of the connective tissues, relatively frequent in the black population, and with a marked female prevalence. Clinical polymorphisms explain the diverse and varied nature of the clinical forms that are sources of diagnostic aberrations. This disease can be associated with various diseases. Here we report an unusual association with AS hemoglobinopathy. PMID- 29616640 TI - Treatment of elephantiasis of the leg by fasciotomy and lymphangiectomy with skin preservation in a resource-limited setting: a case report and review. AB - The author reports the surgical management of a patient with elephantiasis of the leg in the Democratic Republic of Congo. A fasciotomy and lymphangiectomy with skin preservation, combined with compression therapy, resulted in significant cosmetic, functional, and social improvement. Although challenging in a resource limited setting, development of surgical management may make it possible to reduce beliefs that elephantiasis is incurable or due to witchcraft and may reduce time to consultation. PMID- 29616641 TI - Snake Bites by Bothrops lanceolatus in Martinique. AB - Bothrops lanceolatus, a member of the Viperidae family and Crotalinae subfamily, is the only snake causing envenomation in Martinique, which is the only place it exists in the world. Any bite by this snake may result in severe thrombotic complications including cerebral, pulmonary, and myocardial infarction and affecting the patient's vital or functional prognosis. The exact composition of the venom as well as the mechanisms of toxicity involved are still debated today. The first specific antivenom immunotherapy (AVI), Bothrofav1, manufactured in 1991, reduced mortality and morbidity significantly. In 2004, however, an increase in the number of cases of Bothrops lanceolatus envenomation-induced ischemic strokes despite early AVI administration, raised questions about its effectiveness and encouraged the development of a second AVI, Bothrofav2, which became available in February 2011. Causes of the failures with the first AVI remain hypothetical, and the effectiveness of the second is under evaluation. This article reviews the published data available on this rare envenomation, present in one of our French overseas departments and discusses its fascinating scientific and medical issues. PMID- 29616642 TI - Persistence of the cholera epidemic in the Tillabery district (Niger): epidemiological analysis of determining factors. AB - To analyze the determinants of the persistence of the cholera epidemic in Tillabery to obtain a durable solution. Case-control study conducted in three health centers in June 2013 in Tillabery. Cholera cases were confirmed by laboratory testing or epidemiologically linked with a confirmed index case. Controls were individuals with no history of diarrhea, of the same sex, from the same village and with an age difference that did not exceed five years. A logistic regression model was used to analyze the appearance of cholera according to the determining factors. The analysis showed significant association between the occurrence of cholera and variables related to behavior. The adjusted OR confirm higher risks of cholera for persons in households with more than five inhabitants (crude OR = 1.55 95 % CI (1.06 to 2.28) and adjusted OR 95 % CI 2.68 (1.79 to 4.56)), or in contact with a person with diarrhea (crude OR = 1.86 95% CI (1.26 to 2.75) and adjusted OR = 1.61 95% CI (1.5 to 2.68)), and who report not washing their hands after defecation (crude OR = 3.44 95% CI (2.20 to 5.41) and adjusted OR = 2.76 95% CI (1.73 to 3.79)). This study concludes that the Tillabery cholera victims are primarily those with hazardous hygienic practices. Niger must define operational recommendations to limit the continuance of cholera in certain river areas, particularly in the Tillabery. PMID- 29616643 TI - Medecine et Sante Tropicales: Prospects. PMID- 29616644 TI - Etiological, therapeutic and prognostic particularities of primary biliary peritonitis in tropical environments. AB - To describe the etiological, therapeutic, and prognostic aspects of primary biliary peritonitis in Burkina Faso. This retrospective study reviewed records of all patients admitted for primary biliary peritonitis at Tenkodogo Regional Hospital (Burkina Faso) from 2010 through 2016. Cases of secondary biliary peritonitis have been excluded. Thirty patients were identified. Their average age was 26.5 years. Fourteen patients were under 12 years of age. The reasons for consultation were dominated by abdominal pain (in all cases) and bile-induced vomiting (in 22 cases). Seven patients had a general condition classified in stage 2 of the World Health Organization classification, 18 in stage 3, and 5 in stage 4. The etiologies of peritonitis were acute typhoidal cholecystitis, which predominated (27 cases), and gallstones (3 cases). The surgical approach was a laparotomy in all cases. Intraoperative observation showed an inflamed and perforated gallbladder in 24 cases; gangrene was noted in 6 cases. Treatment consisted of cholecystectomy and peritoneal lavage, associated with antibiotic therapy. The post-operative period was complicated by septicemia in 12 cases. Fourteen patients died, for a mortality rate of 46.7 %. In rural Burkina Faso, primary biliary peritonitis occurs in young subjects. Its cause is most often acute cholecystitis due to Salmonella typhi. Mortality is very high. PMID- 29616645 TI - State of the fight against informal market of medicines in Togo: approaches and limitations. AB - The extent of medicines sales and consumption in the informal market in Togo raises many ethical and public health issues. In order to report on the situation of public action in the fight against this practice, we conducted a qualitative survey from 15 to 25 February 2016 in the commune of Lome and in the Maritime Region among the actors of control system and resource people in the general population. This was supplemented by an analysis of Togo's pharmaceutical and health policy documents and a literature review on the illicit drug market issues relating to public health, political science, the social sciences applied to health. In spite of the existence of national and international tools, household poverty, cultural self-medication, ignorance of the population concerning the health risks of informal market medicines, weak political commitment, weakness regulation and enforcement, corruption, constitute obstacles to the success of actions to combat this practice. PMID- 29616646 TI - Morbidity and mortality in HIV-infected children on antiretroviral therapy in Togo. AB - the aim of this study was to evaluate the mortality and morbidity of HIV-infected children on highly active antiretroviral treatment (HAART) in Togo. this is a retrospective study of HIV-infected children on HAART in the 25 largest centers of HIV/AIDS care in Togo. the study included 1861 children (sex-ratio=0.99). Among them, 35.6 % were in WHO clinical stages 3 or 4 at the beginning of HAART. The most common opportunistic infections were coughing and pneumonia (37.1 %), gastroenteritis (11.3 %), various bacterial infections (10.4 %), and pruritus (10.4 %). The incidence of death was estimated at 4.5 per 100 person-years. Mortality was highest during the first year of antiretroviral therapy. The survival rate at 12 months of ART was 92.6 %. Children who began HAART at WHO clinical stage 4 had a significantly lower survival rate than the others (P<0.0001). The presence of a side effect of HAART (P=0.041), and hospitalization (P<0.001) were significantly associated with death in these children. although the new recommendations for medical care require early initiation of HAART, the improved performance of programs to prevent maternal-infant transmission remains crucial in reducing morbidity and mortality of children on HAART in Togo. PMID- 29616647 TI - Epidemiology of malignant hemopathies recorded in hospitals in Cameroon. AB - Data about malignant blood diseases are sparse in Cameroon. Their epidemiology was studied in patients at the General Hospital of Douala (GHD) and the Yaounde Central Hospital (CHY) from 2004 through 2014. The variables we studied were social and demographic (age, sex, occupation, marital status), clinical (reasons for consultation, clinical signs, year of diagnosis), and biological (blood count, myelogram and blood smear, immunophenotyping, biopsy, and cytogenetics). In all, 4409 files were reviewed and 454 cases identified, documented and confirmed (248 in GHD and 206 in CHY). The prevalence of malignant blood diseases was 10.4%. The patients' mean age was 44.3 +/- 19 [range : 1-80] years and the M/F sex ratio 1.4/1. In 32.2% of the cases, the patient consulted because of a tumor. The most frequent malignant blood diseases, in decreasing order, were non Hodgkin's lymphoma (31.1%), chronic myeloid leukemia (21.4%), chronic lymphoid leukemia (12.6%), multiple myeloma (11.2%), acute lymphoblastic leukemia (7.4%), and acute myeloblastic leukemia (6.4%). Their incidence by age group showed that acute lymphoblastic leukemia was most common among children (20%), and chronic myeloid leukemia among young adults (28.9%). The main hemogram abnormalities were anemia (73.7%), hyperleukocytosis (57.3%), and thrombopenia (39.2%). Various types of malignant blood diseases thus exist in the hospital environment in Cameroon, and their forms are underdiagnosed. PMID- 29616648 TI - Respiratory health of women selling cassava, corn and soybean flour in Lumbumbashi, Democratic Republic of the Congo. AB - The aim of this study was to determine the prevalence of respiratory complaints in Congolese women selling grain flours in Lubumbashi. The study enrolled 370 women, including 183 cassava, corn and soybean flour selling women (exposed group) and 187 tax collectors in municipal markets (control group) in Lubumbashi, DRC. A standardized respiratory health questionnaire was used, and a lung function test performed with the use of peak flow-meters. The prevalence of respiratory complaints was markedly higher in dust-exposed women than controls. In addition, peak expiratory flow rate (PEFR) was significantly lower in the exposed group than in controls (342.46 +/- 65.62 vs. 410.89 +/- 70.91, respectively ; P<0.05). After adjustment for age and education level, women involved in cassava, corn and soybean flour selling business were more likely to develop respiratory complaints ad disorders as compared to controls. PMID- 29616649 TI - Description of 48 cases of multiple myeloma seen in the hematology laboratory of the CHU-Joseph Ravoahangy Andrianavalona, Antananarivo, Madagascar. AB - Monoclonal gammopathies are common abnormalities and their incidence increases with age. They are detected in roughly 3 % of people older over 50 years and up to 7 % of those over 70 years. Multiple myeloma (MM) is characterized by the proliferation of plasma cells within the bone marrow and excess secretion of monoclonal immunoglobulins. In Madagascar, late performance of biological examinations such as serum protein electrophoresis overestimates MM rates. We studied 54 patient records between March 2009 and January 2015 in the biology laboratory of the Joseph Ravoahangy Andrianavalona university hospital in Antananarivo (Madagascar). Monoclonal gammopathy was associated with multiple myeloma in most cases (88.9 %). Patients' median age was 64.2 years. Men were slightly more affected than women. It is discovered most frequently due to bone symptoms (83.3 %), and anemia is always present. Monoclonal gammopathy is mostly IgG. The bone marrow study showed medullary plasmacytosis. This disease appears most often in the elderly and has a slight male predominance. Bone marrow cytology is mandatory for diagnosis. PMID- 29616650 TI - Pediatric angiostrongyliasis. AB - Angiostrongyliasis, the leading cause worldwide of eosinophilic meningitis, is an emergent disease due to Angiostrongylus cantonensis larvae, transmitted accidentally to humans. Contamination of children usually occurs by direct contact with an infected mollusk. Eosinophilic meningoencephalitis is the major clinical feature of this parasitic infection in humans. It is usually benign for adults, but more severe for children. Clinical symptoms usually combine fever, meningitis, and neurological signs (somnolence, moaning, hypotonia, convulsions, and increased intracranial pressure). Presumptive diagnosis of human angiostrongyliasis is based on epidemiologic characteristics, clinical symptoms, medical history, and laboratory findings, in particular, hypereosinophilia in blood and cerebrospinal fluid. Treatment is based on corticosteroids associated with anthelmintics. This work reviews the diagnosis and treatment of this life threatening (especially in children) parasitic disease and the need for preventive action. PMID- 29616651 TI - Knowledge and practice of Togolese women concerning cervical cancer. AB - OBJECTIVE: To identify the determinants of the knowledge and practice of Togolese women concerning cervical cancer. METHODS: This cross-sectional study with a descriptive and analytical focus took place in Togo during the four-month period from May to August 2016 and surveyed women aged 18 to 60 living in the Lome municipal area for at least 12 months. Sampling of the intervention zones was based on reasoned choice depending on the availability of health structures in the area. Once in the field, the health centers were taken as landmarks, and the individual living closest to the center was the first to be surveyed. The snowball technique was adopted. All data were entered and analyzed by Epi Info version 7.2 and Excel 2016. Bivariate (chi-2) and multivariate (logistic regression) analyses were performed to study potential associations between different variables. RESULTS: We interviewed 207 women, whose mean age was 31.7 years (+/-10.7). Of the 65.5 % (95 % CI = 58.6-72.0) of respondents who had heard of cervical cancer, 2.9 % (95 % CI = 0.6-5.2) knew HPV infection is a risk factor. Of the 70 women seeing a gynecologist-obstetrician, only 23.2 % (95 % CI = 13.0-34.9) had been screened for cervical cancer. More than half of our respondents had a history (96.1 %) of voluntary interruption of pregnancy, or miscarriage, infection and gynecological and obstetric surgery. The proportion of women with both an obstetric history and screening was 9.7 % (95 % CI = 6.0 14.5). The leading reason for not being screened among our respondents was a fear of pelvic examination (frequency: 11.9%, 95% CI = 7.2-16.5). CONCLUSION: Women seeing a gynecologist and/or with a high educational level are more likely to be informed about cervical cancer and have a greater likelihood of screening. PMID- 29616652 TI - Risk factors for in-hospital maternal mortality in the region of Maradi, Niger (2008-2010: A retrospective study of 7 regional maternity units. AB - In the Maradi region, despite multiple efforts to reduce maternal mortality the in-hospital maternal mortality ratio (HMMR) remains high. We sought to determine the factors related to maternal mortality in seven maternity units in this region. A retrospective study reviewed records of deliveries from January, 2008, through December, 2010. Data for all maternal deaths were collected. The Chi2 test was used to determine the significance of differences between groups for the different variables. Statistical significance was defined as P < 0.05. Data were analyzed with Epi Info(c) 3.5.1. The in-hospital maternal mortality ratio (HMMR) was 2,512 per 100,000 live births. Women aged 14 to 19 years were most affected, accounting for 27.1 % of deaths. In all, 93 (27.4 %) women died during their pregnancy. Direct obstetric causes accounted for 53.61 % of these deaths, and indirect causes 46.39 %. The bivariate analysis showed that age 14 to19 years (Chi2 = 64.69; P = 0.00000178); great multiparity (Chi2 = 64.69; P = 0.00000124), primiparity (Chi2 = 18.82; P = 0.000016), the third trimester of pregnancy (Chi2 = 10.43; P = 0.0054) were significantly associated with maternal death. It is therefore necessary to strengthen women's awareness about the risks of early pregnancy and the immediate use of health services. PMID- 29616653 TI - Accessibility of cesarean deliveries in Benin. AB - To be used effectively, emergency obstetric and neonatal care must be available and accessible. This study sought to measure the accessibility of cesarean deliveries in Benin. Cross-sectional study of randomly selected women in each of the 12 obstetrics departments in Benin. Geographical accessibility was measured by estimating the distance between the parturientes residence and the hospital. Financial accessibility was the average direct cost of the cesarean delivery -the sum of medical and non-medical costs. The functionality of the referral system was assessed according to the conditions of referral of women referred for cesareans. The mean distance between women's homes and the hospital was 20.2 +/- 22.3 kilometers. Of the 579 women, 63.0 % were referred from a peripheral health center to a hospital; the referral conditions were completed in the obstetric record for only half of them. The data sheet for the referral was completed for only 34.4 %; venous access had been placed in 28.5 %, and the patient was accompanied by medical personnel in only 1.7% of cases. The average direct cost of the cesarean to families was 36,782 +/- 30,859 FCFA. Cesarean deliveries are now more accessible financially due to the policy of free access, but they remains geographically inaccessible, because of the long distances to be covered and the poor organization of referrals to ensure continuity of care. PMID- 29616654 TI - Evaluation of the use of Home Emergency in a Sub-Sahara African hospital: Example of the Hospital Principal in Dakar. AB - Overloaded emergency departments are common around the world. This prospective, descriptive, and analytical study evaluates the reasons for emergency room use and describes the severity of the patients' conditions and how they reach the emergency department. It took place at the emergency department of the principal hospital of Dakar (the Armed Forces Teaching Hospital) over a one-week period (from August 23 to August 30, 2016) and included a sample of 219 patients of both sexes aged 15 years and older. Data were collected about social and demographic characteristics, reasons for choosing the emergency department rather than other care, time of day, day of the week, accessibility, means of transport, diagnosis, and severity. More than half of patients (55 %) were men, with a mean age of 42 +/- 18. Only 10 % of patients lived within 5 km of the hospital. Most (84.5 %) came from the Dakar region and lived between 5 and 35 km from the hospital. Most patients reached the hospital by their own means (83 %). Only 2 % were transported by the public emergency ambulance service. The reasons for choosing the emergency unit were the opportunity for additional tests in 41.1 % of cases ; the desire to be hospitalized in 26.9 % ; fear of death in 26.5 %, no waiting list in 14.2 %, and lack of money in 11 % of cases. Patients in truly serious condition accounted for only 5 % of cases. Most (88 %) returned home after stabilization, 12 % were hospitalized, and 0.5 % died. Good practices, good organization, and improved complementarity between public, private, and emergency services are needed to reduce the use of the latter. PMID- 29616655 TI - [Patient Safety and the Increasing Complexity of Modern Healthcare]. PMID- 29616656 TI - [The way to public health: Health-related prevention and health promotio]. PMID- 29616657 TI - [Diabetes is a challenge: A ten year follow up of people with diabetes]. AB - INTRODUCTION: Diabetes is a chronic disease often with serious and costly complications. Therefore well organised diabetes care is needed. The purpose was to research outcome of treatment on biological parameters in people with type one and two diabetes in one primary care over ten years and compare with international guidelines. MATERIAL AND METHODS: Retrospective cohort study, information was gathered from medical records at Sudurnes Health Center, in the years 2005, 2010 and 2015. The sample was persons listed in diabetes unit in beginning of 2005. One measurement for every participant each of the three years was used (n=113). Biological parameters were analysed and compared to international guidelines and attendance to clinic examined. RESULTS: HbA1c level was 7.22% in 2005 but increased significantly to 7.56% in 2015. Diastolic blood pressure decreased significantly to 2015. Most achieved international guidelines in HbA1c goals in 2005 (51%), HDL in 2010 (43.8%), LDL in 2015 (41.9%) TG, in 2010 (79.8%), BMI in 2015 (44.2%), systolic blood pressure in 2010 (63.4%) and diastolic blood pressure in 2015 (74.2%). BMI was around 32 kg/m2 in all three years. In 2015, association was found between neuropathic symptoms and higher HbA1c level. Documentation regarding diabetes complications became much better in 2015 when a new form for electronic documentation was launched. CONCLUSION: Tighter blood glucose control is needed to lessen risk of complications, as well as to reduce lipid and bloodpressure leves closer to international guidelines. Improving documentation is important. PMID- 29616658 TI - [Gout - a treatable condition]. AB - Gout is a disabling and common arthritis with increasing prevalence. Without treatment the disease can cause permanent joint damage. It is commonly associated with the metabolic syndrome but can also be related to a number of life threatening diseases and their treatments. Gout is often misdiagnosed and its long-term management is suboptimal despite the availability of effective treatments. Recently The American College of Rheumatology (ACR) and European League against Rheumatism (EULAR) released common guidelines for the diagnosis of gout and EULAR updated their guidelines for management. There is increased emphasis on preventive treatment, both with lifestyle modifications and pharmacotherapy. It is important to educate patients about the disease and the existence of effective treatment options, how to manage an acutely inflamed joint and why it is important to lower serum urate. When a patient is diagnosed with gout he should be screened for associated comorbidities. It is important to treat to-target and lower serum urate over a long period of time to induce permanent remission of gouty arthritis. PMID- 29616659 TI - Introduction of a hybrid treatment delivery system used for quality assurance in multi-catheter interstitial brachytherapy. AB - Multi-catheter interstitial brachytherapy (iBT) is a treatment option for breast cancer patients after breast conserving surgery. Typically, only a few additional quality interventions after the first irradiation have been introduced to ensure the planned treatment delivery. Therefore, the purpose of this study is to show the possibilities of an electromagnetic tracking (EMT) system integrated into the afterloader for quality assurance (QA) in high-dose rate (HDR) iBT of patients with breast cancer. The hybrid afterloader system equipped with an electromagnetic sensor was used for all phantom and patient measurements. Phantom measurements were conducted to estimate the quality of different evaluation schemes. After a coherent point drift registration of the EMT traces to the reconstructed catheters based on computed tomograms the dwell positions (DP) were defined. Different fitting and interpolation methods were analyzed for the reconstruction of DPs. All estimated DPs were compared to the DPs defined in treatment planning. Until now, the implant geometry of 20 patients treated with HDR brachytherapy was acquired and explored. Regarding the reconstruction techniques, both fitting and interpolation were able to detect manually introduced shifts and swaps. Nonetheless, interpolation showed superior results (RMSE = 1.27 mm), whereas fitting seemed to be more stable to distortion and motion. The EMT system proved to be beneficial for QA in brachytherapy and furthermore, clinical feasibility was proven. PMID- 29616660 TI - Evolutionary pruning of transfer learned deep convolutional neural network for breast cancer diagnosis in digital breast tomosynthesis. AB - Deep learning models are highly parameterized, resulting in difficulty in inference and transfer learning for image recognition tasks. In this work, we propose a layered pathway evolution method to compress a deep convolutional neural network (DCNN) for classification of masses in digital breast tomosynthesis (DBT). The objective is to prune the number of tunable parameters while preserving the classification accuracy. In the first stage transfer learning, 19 632 augmented regions-of-interest (ROIs) from 2454 mass lesions on mammograms were used to train a pre-trained DCNN on ImageNet. In the second stage transfer learning, the DCNN was used as a feature extractor followed by feature selection and random forest classification. The pathway evolution was performed using genetic algorithm in an iterative approach with tournament selection driven by count-preserving crossover and mutation. The second stage was trained with 9120 DBT ROIs from 228 mass lesions using leave-one-case-out cross-validation. The DCNN was reduced by 87% in the number of neurons, 34% in the number of parameters, and 95% in the number of multiply-and-add operations required in the convolutional layers. The test AUC on 89 mass lesions from 94 independent DBT cases before and after pruning were 0.88 and 0.90, respectively, and the difference was not statistically significant (p > 0.05). The proposed DCNN compression approach can reduce the number of required operations by 95% while maintaining the classification performance. The approach can be extended to other deep neural networks and imaging tasks where transfer learning is appropriate. PMID- 29616661 TI - Shell feature: a new radiomics descriptor for predicting distant failure after radiotherapy in non-small cell lung cancer and cervix cancer. AB - Distant failure is the main cause of human cancer-related mortalities. To develop a model for predicting distant failure in non-small cell lung cancer (NSCLC) and cervix cancer (CC) patients, a shell feature, consisting of outer voxels around the tumor boundary, was constructed using pre-treatment positron emission tomography (PET) images from 48 NSCLC patients received stereotactic body radiation therapy and 52 CC patients underwent external beam radiation therapy and concurrent chemotherapy followed with high-dose-rate intracavitary brachytherapy. The hypothesis behind this feature is that non-invasive and invasive tumors may have different morphologic patterns in the tumor periphery, in turn reflecting the differences in radiological presentations in the PET images. The utility of the shell was evaluated by the support vector machine classifier in comparison with intensity, geometry, gray level co-occurrence matrix-based texture, neighborhood gray tone difference matrix-based texture, and a combination of these four features. The results were assessed in terms of accuracy, sensitivity, specificity, and AUC. Collectively, the shell feature showed better predictive performance than all the other features for distant failure prediction in both NSCLC and CC cohorts. PMID- 29616662 TI - Monte Carlo proton dose calculations using a radiotherapy specific dual-energy CT scanner for tissue segmentation and range assessment. AB - Proton beam ranges derived from dual-energy computed tomography (DECT) images from a dual-spiral radiotherapy (RT)-specific CT scanner were assessed using Monte Carlo (MC) dose calculations. Images from a dual-source and a twin-beam DECT scanner were also used to establish a comparison to the RT-specific scanner. Proton ranges extracted from conventional single-energy CT (SECT) were additionally performed to benchmark against literature values. Using two phantoms, a DECT methodology was tested as input for Geant4 MC proton dose calculations. Proton ranges were calculated for different mono-energetic proton beams irradiating both phantoms; the results were compared to the ground truth based on the phantom compositions. The same methodology was applied in a head-and neck cancer patient using both SECT and dual-spiral DECT scans from the RT specific scanner. A pencil-beam-scanning plan was designed, which was subsequently optimized by MC dose calculations, and differences in proton range for the different image-based simulations were assessed. For phantoms, the DECT method yielded overall better material segmentation with >86% of the voxel correctly assigned for the dual-spiral and dual-source scanners, but only 64% for a twin-beam scanner. For the calibration phantom, the dual-spiral scanner yielded range errors below 1.2 mm (0.6% of range), like the errors yielded by the dual source scanner (<1.1 mm, <0.5%). With the validation phantom, the dual-spiral scanner yielded errors below 0.8 mm (0.9%), whereas SECT yielded errors up to 1.6 mm (2%). For the patient case, where the absolute truth was missing, proton range differences between DECT and SECT were on average in -1.2 +/- 1.2 mm (-0.5% +/- 0.5%). MC dose calculations were successfully performed on DECT images, where the dual-spiral scanner resulted in media segmentation and range accuracy as good as the dual-source CT. In the patient, the various methods showed relevant range differences. PMID- 29616663 TI - 4D-PET reconstruction using a spline-residue model with spatial and temporal roughness penalties. AB - 4D reconstruction of dynamic positron emission tomography (dPET) data can improve the signal-to-noise ratio in reconstructed image sequences by fitting smooth temporal functions to the voxel time-activity-curves (TACs) during the reconstruction, though the optimal choice of function remains an open question. We propose a spline-residue model, which describes TACs as weighted sums of convolutions of the arterial input function with cubic B-spline basis functions. Convolution with the input function constrains the spline-residue model at early time-points, potentially enhancing noise suppression in early time-frames, while still allowing a wide range of TAC descriptions over the entire imaged time course, thus limiting bias. Spline-residue based 4D-reconstruction is compared to that of a conventional (non-4D) maximum a posteriori (MAP) algorithm, and to 4D reconstructions based on adaptive-knot cubic B-splines, the spectral model and an irreversible two-tissue compartment ('2C3K') model. 4D reconstructions were carried out using a nested-MAP algorithm including spatial and temporal roughness penalties. The algorithms were tested using Monte-Carlo simulated scanner data, generated for a digital thoracic phantom with uptake kinetics based on a dynamic [18F]-Fluromisonidazole scan of a non-small cell lung cancer patient. For every algorithm, parametric maps were calculated by fitting each voxel TAC within a sub region of the reconstructed images with the 2C3K model. Compared to conventional MAP reconstruction, spline-residue-based 4D reconstruction achieved >50% improvements for five of the eight combinations of the four kinetics parameters for which parametric maps were created with the bias and noise measures used to analyse them, and produced better results for 5/8 combinations than any of the other reconstruction algorithms studied, while spectral model-based 4D reconstruction produced the best results for 2/8. 2C3K model-based 4D reconstruction generated the most biased parametric maps. Inclusion of a temporal roughness penalty function improved the performance of 4D reconstruction based on the cubic B-spline, spectral and spline-residue models. PMID- 29616664 TI - From the volcano effect to banding: a minimal model for bacterial behavioral transitions near chemoattractant sources. AB - Sharp chemoattractant (CA) gradient variations near food sources may give rise to dramatic behavioral changes of bacteria neighboring these sources. For instance, marine bacteria exhibiting run-reverse motility are known to form distinct bands around patches (large sources) of chemoattractant such as nutrient-soaked beads while run-and-tumble bacteria have been predicted to exhibit a 'volcano effect' (spherical shell-shaped density) around a small (point) source of food. Here we provide the first minimal model of banding for run-reverse bacteria and show that, while banding and the volcano effect may appear superficially similar, they are different physical effects manifested under different source emission rate (and thus effective source size). More specifically, while the volcano effect is known to arise around point sources from a bacterium's temporal differentiation of signal (and corresponding finite integration time), this effect alone is insufficient to account for banding around larger patches as bacteria would otherwise cluster around the patch without forming bands at some fixed radial distance. In particular, our model demonstrates that banding emerges from the interplay of run-reverse motility and saturation of the bacterium's chemoreceptors to CA molecules and our model furthermore predicts that run reverse bacteria susceptible to banding behavior should also exhibit a volcano effect around sources with smaller emission rates. PMID- 29616665 TI - Comments on "Clinical ethics and the role of clinical ethics committees: proposal for a revival" by Petrini and Ricciardi. Letter. PMID- 29616666 TI - From dissemination to Citizen Science. Editorial. PMID- 29616667 TI - Healthcare organizational performance: why changing the culture really matters. Commentary. AB - An organization may be considered as having three components: a structure, systems and culture. Culture is the most difficult part of the organization to affect. After all, culture has the key role in impacting and improving organizational performance. The leadership of an organization and its key operations are paramount in shaping the culture. Leadership and organizational culture are inextricably intertwined. They are two sides of the same coin. Culture is a medium through which leadership travels and impacts organizational performance. If leaders are to fulfil the challenges of the 21st century, they must first understand the dynamics of culture and their role as sculptors through behavioural and cognitive ways. PMID- 29616668 TI - General principles and practice of the ethics of public health surveillance: comments on the situation in Italy. Commentary. AB - The "WHO Guidelines on ethical issues in public health surveillance" were published shortly after the Italian Presidency of the Council of Ministers published a Decree (3rd March, 2017) regarding surveillance systems and registries. The WHO document is a comprehensive framework of international import that forms a compendium of ethical principles to underlie public health surveillance. Although the Italian Decree is in line with the guidelines it contains no reference to mechanisms to ensure ethical surveillance, which instead are recommended in the WHO document. Ethics Committees would appear the most suitable candidates to fill this role. PMID- 29616669 TI - The PIPER WEEKEND study. Children's and adults satisfaction regarding paediatric pain in Italian Emergency Department. AB - BACKGROUND: Despite pain being a crucial aspect of urgent-emergency care, the attention of healthcare workers towards this symptom in the Emergency Department (ED) is still inadequate. The aims of this study were to assess children's and their adults accompanier's satisfaction regarding pain management in Italian ED, considering healthcare workers' attention to the symptom as well as the appropriateness and efficacy of treatments received. METHODS: Questionnaires were administered face-to-face by trained interviewers over the period of one weekend in 29 Italian ED. The questionnaires were addressed to children 3-16 years old, assigned a green code at triage, and their adult accompaniers. RESULTS: Overall, 1581 questionnaires were administered (923 to parents or caregivers, 658 to children). The reported level of attention to pain by the care team was high (57.20%) as was the adults' satisfaction with the pain management (95.01%); a high level of satisfaction was related to the healthcare workers' attention to pain. According to the adults, 73.56% of the healthcare professionals collected accurate information about pain; this was confirmed by the children. Pain was managed by a doctor-and-nurse team in less than half the cases (43.77%). Therapy efficacy was reportedly poor: only 14.01% of children were pain-free when leaving the ED. CONCLUSIONS: Despite increasing understanding of pain and the availability of guidelines and effective analgesics, efficient pain relief in paediatric patients in the ED remains an unfulfilled goal: half of children with pain did not receive any treatments. Therefore the quality of pain management in the ED needs to be improved. PMID- 29616670 TI - Development and cross-validation of predictive equation for estimating total body lean in children. AB - AIM: To develop and cross-validate a predictive equation for estimating lean body mass (LBM) in children, based on bioelectrical impedance analysis (BIA) and anthropometric parameters, and to compare our equation with other predictive methods. METHODS: We evaluated body composition of 155 children (age 5-14 years) by BIA and dual energy X-ray absorptiometry (DXA). Children were divided in two groups: developing set and cross-validation set. Statistical analysis as multiple regression and Bland-Altman methods were performed. RESULTS: From developing set (105 children) a predictive LBM (kg) equation was created. From the cross validated set (35 children), our equation was seen to agree with LBM (kg) by DXA. On the contrary, LBM predicted by Schaefer's equation and BIA did not agree with the criterion measure. CONCLUSIONS: This cross-validated equation can be useful in epidemiological studies and also in clinical practice, permitting a better definition and follow up of children's body composition. PMID- 29616671 TI - Bed rest after cardiovascular implantable electronic device placement: systematic review and meta-analysis. AB - BACKGROUND: Bed rest is prescribed for all patients after cardiovascular implantable electronic device (CIED) placement but to a varied extent. Different clinical protocols exist. AIM: To assess the effects of different lengths of bed rest on complications and patient comfort after CIED implantation. METHODS: We searched MEDLINE, EMBASE, Cochrane Database of Systematic Reviews, CINAHL, SCOPUS. We included randomized and quasi-randomized controlled trials. Two of the authors independently selected trials, assessed the risk of bias, and extracted data. RESULTS: We included 2 RCTs. There was no evidence that shorter bed rest was more harmful than longer bed rest in terms of lead displacement (RR 0.681, 95% CI [0.063, 7.332]) and hematoma (RR 1.642, 95% CI [0.282, 9.560]). None of the studies reported the assessment of bleeding, back pain, or urinary discomfort. CONCLUSIONS: Shorter periods of bed rest appear to be as safe as longer ones. However, to confirm these results, further larger trials are needed. PMID- 29616672 TI - Erythrocyte phenotype in a pregnant woman of Sri Lanka. Description of the case and complications related to communication problems. AB - BACKGROUND: The Bombay phenotype is a rare genetic trait which is characterized by the absence of A, B and H antigens on red cells as well as in body secretions. The serum shows the presence of antibodies against antigen H. Patients with this rare blood type are not easily transfusable. We had observed a woman aged 18, at the 20th week of pregnancy, native of Sri Lanka, with an IgG and IgM class anti H. We report the case and the clinical issues arisen. MATERIALS AND METHODS: The determination of ABO, Rh[D] group, the indirect antiglobulin test (IAT) were performed in tube techniques and in neutral gel microcolumn. Detection for antibodies was performed using ID-Card LISS-Coombs microtubes, in solid phase and with tube techniques. For molecular analysis, the FUT1 and FUT2 genes were sequenced using BigDye terminator v1.1. The study of FUT2 gene was performed after extraction of mRNA using Qiagen kit RNase and then reverse-transcribed into cDNA. RESULTS: The Bombay phenotype was confirmed by serological and molecular analysis techniques. The patient, in collaboration with a cultural mediator, was informed of her immunohaematological condition and a program of assistance was proposed to her. Unfortunately the patient did not return for the next visit, despite of a telephone reminder. During childbirth a haemorrhage occurred and a request of compatible blood for an urgent transfusion arrived at our transfusion service. Fortunately, the haemorrhage was arrested and the patient didn't need to have any transfusions. CONCLUSION: This case emphasizes the need for an efficient management of rare blood types that are more and more frequent as a result of migration. It is necessary to organize, in strategic points of the national territory, reference centres with better diagnostic capabilities and implement freezing of red blood cells with rare phenotype for diagnostic and therapeutical use. Communication issues are as well important in dealing with this emerging phenomenon. PMID- 29616673 TI - Knowledge of sexually transmitted infections and sex-at-risk among Italian students of health professions. Data from a one-month survey. AB - AIM: The aim of the study was to evaluate the knowledge and behavioral risks associated with sexually transmitted infections (STIs) among the students of health professions at the University of Palermo divided into two age groups (18 22 years and 23-27 years). MATERIALS AND METHODS: A self-administered questionnaire was distributed. The questionnaire is structured in three parts in addition to an introduction to socio-demographic information. The first part investigates the quality of information provided by public institutions on the subject, the second part the knowledge of contraceptive methods used to reduce the risk of contagion and the third part the knowledge of STIs and HPV vaccination. A multivariable logistic regression model was used and adjusted Odds Ratios (aOR) are presented. RESULTS: The sample was represented by 1022 respondents (70.8% females, 61.5% aged 18-22 years). In multivariate analyses males have a greater risk of not knowing HPV vaccine (aOR 3.52, 95% CI 2.26 5.49). The 18-22 age group has a higher risk than the 23-27 age group to think of being not sufficiently informed to avoid contagion (aOR 3.92, 95% CI 2.18-7.06), never having STIs specific tests (aOR 2.90, 95% CI 2.21-3.80), not knowing HPV vaccine (aOR 1.86, 95% CI 1.13-3.07) and not knowing that it can be administered to males (aOR 2.63, 95% CI 1.96-3.53). CONCLUSIONS: Based on our findings, it is necessary to implement sexual education programs for the improvement of knowledge in terms of STIs and the promotion of health. Future studies are needed to assess the effectiveness and cost of education programs that should also be addressed to young adults who do not attend university. PMID- 29616674 TI - Costs and effectiveness of influenza vaccination: a systematic review. AB - BACKGROUND: Seasonal influenza can cause a significant public health burden. Vaccination is proposed as the most effective measure to prevent influenza and related undesired outcomes. OBJECTIVE: To estimate the efficiency of influenza vaccination. METHODS: A literature review of economic evaluations of influenza vaccinations, published over the last 5 years, was performed using MEDLINE (through PubMed), Web of Science and Scopus. RESULTS: 935 papers were identified and 30 were selected, including studies performed in different population subgroups: general population, children, adults, elderly, pregnant women and high risk patients. Twenty-one studies were performed in Europe and in US. The majority of the studies were carried out on elderly patients and children. All except one were cost-effectiveness analyses and reported influenza vaccination as a cost-saving or cost-effective intervention. CONCLUSIONS: Vaccination strategies are economically favourable in a range of countries and sub-groups of patients. PMID- 29616675 TI - Self-directed continuing medical education at the point-of-care: implications for cost and value. AB - PURPOSE: There is a growing interest in the use of point-of-care clinical decision support resources as a form of continuing medical education (CME). This paper models various cost and value outcomes that might emerge from the use of a clinical decision support tool (BMJ Best Practice) as CME. METHODS: BMJ Best Practice is the clinical decision support tool of the BMJ. Healthcare professionals can use it to do self-directed CME. We modeled the use of clinical decision support as a component of CME and evaluated the potential impact of this use on costs. RESULTS: High users of self-directed CME at the point-of-care can reduce the cost of their CME. This is mainly by saving on the costs of external CME meetings. CONCLUSIONS: Healthcare professionals should consider using a blend of self-directed CME and face-to-face education to ensure that their CME activities offer maximum value for a given cost. PMID- 29616676 TI - Certification and evaluation of the clinical ethics consultant. A proposal for Italy. AB - Clinical ethics, as a sub-discipline of bioethics, is subject to growing professionalization in North America, Europe and elsewhere. Since the goal of clinical ethics is the identification, analysis and resolution of ethical dilemmas and conflicts in health care settings, specific competencies for practitioners and criteria to evaluate them are strongly needed. Regarding clinical ethics consultation (CEC) many efforts have been made by American clinical ethicists and scholars to delineate the core knowledge and skills to perform it, to settle specific professional responsibilities and tasks and to identify the fundamental training and quality requirements that candidates and actual professionals should satisfy in order to serve as ethics consultants. Starting from the analysis of two meaningful international experiences, the one American and the other German, the paper discusses the process of certification of the clinical ethics consultant and encourages its implementation in the Italian context trying to outline a model which is suited to it. PMID- 29616677 TI - Influenza vaccine effectiveness in an Italian elderly population during the 2016 2017 season. AB - Interim analyses of the 2016-17 influenza vaccine effectiveness showed variable results depending on timing of the analysis and geographical setting. We conducted a population-based retrospective cohort study based on the analysis of health-related administrative data to assess the effectiveness of the 2016-17 influenza vaccine among the elderly population of a north-eastern Italian area. Data on 64854 subjects >=65 years of age were analyzed up to April 30, 2017. The influenza vaccine was administered to 53% of the elderly population. No significant effect was observed on the likelihood of Emergency department visits, hospitalizations, or deaths from pneumonia and influenza. PMID- 29616678 TI - Species identification of crested gibbons (Nomascus) in captivity in China using karyotyping- and PCR-based approaches. AB - Gibbons and siamangs (Hylobatidae) are well-known for their rapid chromosomal evolution, which has resulted in high speciation rate within the family. On the other hand, distinct karyotypes do not prevent speciation, allowing interbreeding between individuals in captivity, and the unwanted hybrids are ethically problematic as all gibbon species are endangered or critically endangered. Thus, accurate species identification is crucial for captive breeding, particularly in China where studbooks are unavailable. Identification based on external morphology is difficult, especially for hybrids, because species are usually similar in appearance. In this study, we employed G-banding karyotyping and fluorescence in situ hybridization (FISH) as well as a PCR-based approach to examine karyotypic characteristics and identify crested gibbons of the genus Nomascus from zoos and nature reserves in China. We characterized and identified five karyotypes from 21 individuals of Nomascus. Using karyotypes and mitochondrial and nuclear genes, we identified three purebred species and three hybrids, including one F2 hybrid between N. gabriellae and N. siki. Our results also supported that N. leucogenys and N. siki shared the same inversion on chromosome 7, which resolves arguments from previous studies. Our results demonstrated that both karyotyping and DNA-based approaches were suitable for identifying purebred species, though neither was ideal for hybrid identification. The advantages and disadvantages of both approaches are discussed. Our results further highlight the importance of animal ethics and welfare, which are critical for endangered species in captivity. PMID- 29616679 TI - Variations in diet composition of sympatric Trachypithecus francoisi and Macaca assamensis in the limestone habitats of Nonggang, China. AB - Comparative studies of sympatric species are essential for understanding behavioral and ecological adaptation as well as the mechanisms that can reduce resource competition to allow coexistence. Francois' langurs (Trachypithecus francoisi) and Assamese macaques (Macaca assamensis) are sympatric primate species found in the limestone seasonal rainforests of Nonggang Nature Reserve, southwestern Guangxi, China. To explore their different adaptation strategies, we collected data on diet using scan sampling at 15-min intervals. Our results revealed that Francois' langurs showed a more flexible diet composition than Assamese macaques. Francois' langurs increased dietary diversity and mature leaf consumption in response to seasonal scarcity of preferred young leaves and fruits, whereas Assamese macaques relied heavily on young bamboo leaves (Indocalamus calcicolus) in most months. These variations reflect the differences in digestive physiology, morphology, and the temporal and spatial distribution of food resources. PMID- 29616680 TI - Comparison of T Helper Cell Patterns in Primary Open-Angle Glaucoma and Normal Pressure Glaucoma. AB - BACKGROUND HSP60-related immunological activities are found in normal-pressure glaucoma (NPG) patients, in whom an elevated intraocular pressure (IOP) found in primary open-angle glaucoma (POAG) is not observed. HSP60 was found in POAG and NPG patients, while anti-HSP60 level was mainly found to be higher in NPG patients. The purpose of this study was to compare the percentages of Th cells and levels of related cytokines, attempting to provide evidence to explain this discrepancy. MATERIAL AND METHODS Blood samples from POAG, NPG, and normal control (NC) groups were collected and peripheral blood monocytes were isolated and cultured with or without the stimulation of HSP60. Flow cytometry and enzyme linked immunosorbent assay were used to assess the percentages of Th1, Th2, Th17, and Treg cells, as well as HSP60 antibody levels and related cytokine levels, before and after culture. RESULTS Significantly higher titers of anti-HSP60 were observed only in NPG patients. Comparable Th1 and Th2 cell frequencies, IL-4 level, and IFN-gamma level were found in POAG and NPG patients, while higher Treg cell frequency was only found in POAG patients. After culturing with HSP60, increased Th2 frequencies and decreased Th1 frequencies were observed in the POAG, NPG, and NC groups, while increased Treg frequency was only identified in the POAG and NC groups. CONCLUSIONS Different Th cell patterns were observed among POAG, NPG, and NC groups. Lack of induction of Treg cells and imbalance of the pro-inflammatory and anti-inflammatory response patterns of Th cells exist in some NPG patients. PMID- 29616681 TI - [Influenza vaccination coverage (2011-2014) in healthcare workers from two health departments of the Valencian Community and hospital services more vulnerable to the flu.] AB - OBJECTIVE: Health care workers can transmit influenza to patients in health centers, therefore its vaccination is considered a preventive measure first order. The objective of this study was to know the coverage of vaccination against seasonal influenza in health professionals in two health departments of the Valencian Community (Torrevieja and Elx- Crevillent), in the seasons 2011-12, 2012-13 and 2013-14. METHODS: TA cross-sectional descriptive study was carried out to determine the coverage of influenza vaccination through the Nominal Vaccine Registry (NVR) of the Conselleria de Sanitat de la Generalitat Valenciana. The services with the highest risk of contagion were detected through requests for PCR analysis in patients suspected of influenza during the 2013-14 season. RESULTS: A total of 2035 health professionals were surveyed who achieved an average vaccination coverage of 27.2% in the 2013-14 season, showing an upward trend from the 2011-12 season. Significant differences were observed between professional categories and, practitioners presented the lowest coverage. A total of 192 PCR requests were recorded in both departments. The services which concentrate a greater number of requests were: Internal Medicine (n = 100), urgency service (n = 37), intensive care unit (n = 25) and Pediatrics ( n=154); The influenza vaccination coverage of these services in the 2013-14 seasons was 27.0%, 32.3%, 34.3% and 25.3%, respectively. CONCLUSIONS: Although they show an upward trend, vaccination coverage is low in health care personnel. Nurses are the best vaccinated. It would be appropriate to implement immunization strategies aimed specifically at services that, because of their activity, pose a greater risk to the patient. PMID- 29616682 TI - Corrigendum: Arabidopsis aldehyde dehydrogenase 10 family members confer salt tolerance through putrescine-derived 4-aminobutyrate (GABA) production. AB - This corrects the article DOI: 10.1038/srep35115. PMID- 29616683 TI - Macrophages: Running on empty. PMID- 29616684 TI - Allergy: An alarmin cut. PMID- 29616685 TI - Germinal centres: An exit strategy for B cells. PMID- 29616686 TI - Determination of quantum yields of semiconductor nanocrystals at the single emitter level via fluorescence correlation spectroscopy. AB - Comparing the photoluminescence (PL) properties of ensembles of nanocrystals like semiconductor quantum dots (QDs) with single particle studies is of increasing interest for many applications of these materials as reporters in bioimaging studies performed under very dilute conditions or even at the single particle level. Particularly relevant is here the PL quantum yield (PhiF), which determines the signal size together with the reporter's molar extinction coefficient and is a direct measure for nanocrystal quality, especially for the inorganic surface passivation shell and its tightness, which can be correlated also with nanocrystal stability and the possible release of heavy metal ions. Exemplarily for red and green emitting CdTe nanocrystals, we present a method for the determination of PhiF of nanoparticle dispersions at ultralow concentration compared to cuvette measurements using fluorescence correlation spectroscopy (FCS), a single molecule method, and compared to molecular dyes with closely matching spectral properties and known PhiF. Our results underline the potential of this approach, provided that material-inherent limitations like ligand- and QD specific aggregation affecting particle diffusion and QD drawbacks such as their complex and power-dependent blinking behavior are properly considered as shown here. PMID- 29616687 TI - CoMn2O4 embedded in MnOOH nanorods as a bifunctional catalyst for oxygen reduction and oxygen evolution reactions. AB - CoMn2O4 embedded in MnOOH nanorods (CoMn2O4-MnOOH NRs) was prepared using a two step hydrothermal method involving the oxidation of Mn by Co species in preformed MnOOH NRs. The as-prepared CoMn2O4-MnOOH NRs exhibit an expectably remarkable performance for the ORR and the OER, indicating their great potential for widespread application in fuel cells and metal-air batteries. PMID- 29616688 TI - Plasmons in N-doped graphene nanostructures tuned by Au/Ag films: a time dependent density functional theory study. AB - The energy resonance point of the prominent peak of the absorption spectrum of nitrogen-doped graphene is in the ultraviolet region. This limits its application as a co-catalyst in renewable hydrogen evolution through photocatalytic water splitting in the visible light region. It is well known that noble metal films show active absorption in the visible region due to the existence of the unique feature known as surface plasmon resonance. Here we report tunable plasmons in nitrogen-doped graphene nanostructures using noble metal (Au/Ag) films. The energy resonance point of the prominent peak of the composite nanostructure is altered by changing the separation space of two-layered nanostructures. We found the strength of the absorption spectrum of the composite nanostructure is much stronger than the isolated N-doped graphene monolayer. When the separation space is decreased, the prominent peak of the absorption spectrum is red-shifted to the visible light region. Moreover, currents of several microamperes exist above the surface of the N-doped graphene and Au film composite nanostructure. In addition, the field enhancement exceeds 1000 when an impulse excitation polarized in the armchair-edge direction (X-axis) when the separation space is decreased to 3 A and is close to 100 when an impulse excitation polarized in the zigzag-edge direction (Y-axis). The N-doped graphene and noble metal film composite nanostructure is a good candidate material as a co-catalyst in renewable hydrogen production by photocatalytic water splitting in the visible light region. PMID- 29616689 TI - Kinetics in the real world: linking molecules, processes, and systems. AB - Unravelling elementary steps, reaction pathways, and kinetic mechanisms is key to understanding the behaviour of many real-world chemical systems that span from the troposphere or even interstellar media to engines and process reactors. Recent work in chemical kinetics provides detailed information on the reactive changes occurring in chemical systems, often on the atomic or molecular scale. The optimisation of practical processes, for instance in combustion, catalysis, battery technology, polymerisation, and nanoparticle production, can profit from a sound knowledge of the underlying fundamental chemical kinetics. Reaction mechanisms can combine information gained from theory and experiments to enable the predictive simulation and optimisation of the crucial process variables and influences on the system's behaviour that may be exploited for both monitoring and control. Chemical kinetics, as one of the pillars of Physical Chemistry, thus contributes importantly to understanding and describing natural environments and technical processes and is becoming increasingly relevant for interactions in and with the real world. PMID- 29616690 TI - Atomically resolved calcium phosphate coating on a gold substrate. AB - Some articles have revealed that the electrodeposition of calcium phosphate (CaP) coatings entails a precursor phase, similarly to biomineralization in vivo. The chemical composition of the initial layer and its thickness are, however, still arguable, to the best of our knowledge. Moreover, while CaP and electrodeposition of metal coatings have been studied utilizing atom-probe tomography (APT), the electrodeposition of CaP ceramics has not been heretofore studied. Herein, we present an investigation of the CaP deposition on a gold substrate. Using APT and transmission electron microscopy (TEM) it is found that a mixture of phases, which could serve as transient precursor phases to hydroxyapatite (HAp), can be detected. The thickness of these phases is tens of nanometers, and they consist of amorphous CaP (ACP), dibasic calcium phosphate dihydrate (DCPD), and octacalcium phosphate (OCP). This demonstrates the value of using atomic-resolved characterization techniques for identifying the precursor phases. It also indicates that the kinetics of their transformation into the more stable HAp is not too fast to enable their observation. The coating gradually displays higher Ca/P atomic ratios, a porous nature, and concomitantly a change in its density. PMID- 29616692 TI - Simultaneous assembly of van der Waals heterostructures into multiple nanodevices. AB - van der Waals heterostructures (vdWH) are made of different two-dimensional (2D) layers stacked on top of each other, forming a single material with unique properties that differ from those of the individual 2D constituent layers, and that can be modulated through the interlayer interaction. These hetero-materials can be artificially made by mechanical stamping, solution processing or epitaxial growth. Alternatively, franckeite has been recently described as an example of a naturally-occurring vdWH that can be exfoliated down to nanometer thicknesses. Research on vdWHs has so far been limited to manually exfoliated and stamped individual devices. Here, a scalable and fast method to fabricate vdWH nanodevices from liquid phase exfoliated nanoflakes is reported. The transport and positioning of the flakes into localized submicrometer structures is achieved simultaneously in multiple devices via a dielectrophoretic process. The complex vdWH is preserved after dielectrophoresis and the properties of the resulting field-effect transistors are equivalent to those fabricated via mechanical exfoliation and stamping. The combination of liquid phase exfoliation and dielectrophoretic assembly is particularly suited for the study of vdWHs and applications where large-scale fabrication is required. PMID- 29616691 TI - Kinetic analysis of tautomer forms of aromatic-urea compounds with acetate ions: solvent effect of excited state intermolecular proton transfer. AB - In this paper, we report the solvent effect of excited state intermolecular proton transfer (ESIPT) reactions of urea compounds in the presence of tetrabutylammonium acetate (TBAAc). We prepared anthracene-urea compounds (9An and 2An), a pyrene-urea compound (Py) and an anthracene-diurea compound (9,10An), which have alkylsulfonyl groups to improve their solubility in various organic solvents. We investigated the solvent effects of the ESIPT reaction using absorption, fluorescence, and 1H NMR spectroscopy along with fluorescence decay measurements in dimethyl sulfoxide (DMSO), acetonitrile (MeCN), tetrahydrofuran (THF) and toluene. The tautomer fluorescence of 9An showed remarkable solvent dependence on the spectral red-shift compared with 2An, Py and 9,10An. As a result of the detailed spectroscopic investigations with regard to the solvent including kinetic analysis of the ESIPT for 9AnAcO-, we revealed that the energy gap between the normal and tautomer forms in the excited state depended on the hydrogen bond acceptor basicity (beta), which is one of the Kamlet-Taft solvent parameters. Finally, we discovered that the tautomer structures of aromatic-urea compounds were stabilized by hydrogen bond interactions. PMID- 29616693 TI - A copper/O2-mediated direct sp3 C-H/N-H cross-dehydrogen coupling reaction of acylated amines and N-aryl glycine esters. AB - A copper salt-catalyzed cross-dehydrogenative coupling reaction between N-aryl glycine esters and acylated amines has been developed. The reaction proceeded effectively under an oxygen atmosphere without the use of peroxide agents. This simple protocol allows for the preparation of a series of new compounds in a moderate to excellent yield via the CDC reaction of a wide range of N-aryl glycine derivatives with acylated amines, which are of great interest in the field of medicinal chemistry. A plausible mechanism involving the formation of an iminium ion intermediate, followed by coupling with acylated amines was proposed after some control experiments were conducted. PMID- 29616694 TI - Enhancing the luminescence efficiency of silicon-nanocrystals by interaction with H+ ions. AB - The emission of silicon nanocrystals (Si-NCs), synthesized by pulsed laser ablation in water, was investigated on varying the pH of the solution. These samples emit MUs decaying orange photoluminescence (PL) associated with radiative recombination of quantum-confined excitons. Time-resolved spectra reveal that both the PL intensity and the lifetime increase by a factor of ~20 when the pH decreases from 10 to 1 thus indicating that the emission quantum efficiency increases by inhibiting nonradiative decay rates. Infrared (IR) absorption and electron paramagnetic resonance (EPR) experiments allow addressing the origin of defects on which the excitons nonradiatively recombine. The linear correlation between the PL and the growth of SiH groups demonstrates that H+ ions passivate the nonradiative defects that are located in the interlayer between the Si-NC core and the amorphous SiO2 shell. PMID- 29616700 TI - Editorial: Prevention of Alzheimer's Disease in Chinese Populations: Status, Challenges and Directions. PMID- 29616701 TI - Diabetes Mellitus and Cognitive Decline - Prevention Should Not Be Delayed! PMID- 29616702 TI - Identifying Better Outcome Measures to Improve Treatment of Agitation in Dementia: A Report from the EU/US/CTAD Task Force. AB - For the second time in the past 3 years, the EU-US CTAD Task Force addressed challenges related to designing clinical trials for agitation in dementia, which is one of the most disruptive aspects of the condition for both patients and caregivers. Six recommendations emerged from the Task Force meeting: 1 - Operationalizing agitation criteria established by the IPA; 2 - Combining clinician- and caregiver-derived outcomes as primary outcome measures; 3 - Using global ratings to define clinically meaningful effects and power studies; 4 - Improving the accuracy of caregiver reports by better training and education of caregivers; 5 - Employing emerging technologies to collect near real-time behavioral data; and 6 - Utilizing innovative trial designs and increasing the use of biomarkers to maximize the productivity of clinical trials for neuropsychiatric symptoms. PMID- 29616703 TI - Biomarker and Clinical Trial Design Support for Disease-Modifying Therapies: Report of a Survey of the EU/US: Alzheimer's Disease Task Force. AB - BACKGROUND: Disease-modifying therapies are urgently needed for the treatment of Alzheimer's disease (AD). The European Union/United States (EU/US) Task Force represents a broad range of stakeholders including biopharma industry personnel, academicians, and regulatory authorities. OBJECTIVES: The EU/US Task Force represents a community of knowledgeable individuals who can inform views of evidence supporting disease modification and the development of disease-modifying therapies (DMTs). We queried their attitudes toward clinical trial design and biomarkers in support of DMTs. DESIGN/SETTING/PARTICIANTS: A survey of members of the EU/US Alzheimer's Disease Task Force was conducted. Ninety-three members (87%) responded. The details were analyzed to understand what clinical trial design and biomarker data support disease modification. MEASUREMENTS/RESULTS/CONCLUSIONS: Task Force members favored the parallel group design compared to delayed start or staggered withdrawal clinical trial designs to support disease modification. Amyloid biomarkers were regarded as providing mild support for disease modification while tau biomarkers were regarded as providing moderate support. Combinations of biomarkers, particularly combinations of tau and neurodegeneration, were regarded as providing moderate to marked support for disease modification and combinations of all three classes of biomarkers were regarded by a majority as providing marked support for disease modification. Task Force members considered that evidence derived from clinical trials and biomarkers supports clinical meaningfulness of an intervention, and when combined with a single clinical trial outcome, nearly all regarded the clinical trial design or biomarker evidence as supportive of disease modification. A minority considered biomarker evidence by itself as indicative of disease modification in prevention trials. Levels of evidence (A,B,C) were constructed based on these observations. CONCLUSION: The survey indicates the view of knowledgeable stakeholders regarding evidence derived from clinical trial design and biomarkers in support of disease modification. Results of this survey can assist in designing clinical trials of DMTs. PMID- 29616704 TI - Minimizing the Sample Sizes of Clinical Trials on Preclinical and Early Symptomatic Stage of Alzheimer Disease. AB - BACKGROUND: Clinical trials of investigational drugs for Alzheimer disease (AD) increasingly focus on the prodromal (symptomatic) stage of the illness and now its preclinical (asymptomatic) stage. Sensitive and specific cognitive and functional endpoints are needed to track subtle cognitive and functional changes in the early and preclinical stages to minimize sample sizes in these trials. OBJECTIVES: To identify informative items in a standard clinical assessment protocol and a psychometric battery that are predictive of onset of dementia symptom. DESIGN: Longitudinal retrospective study. SETTING: Washington University (WU) Knight Alzheimer Disease Research Center (ADRC). PARTICIPANTS: A total of 735 individuals at least 65 years old and cognitively normal at baseline from a longitudinal clinical cohort at the WU Knight ADRC. MEASUREMENTS: The annual clinical assessment included a wide spectrum of functional and cognitive domains; a comprehensive psychometric battery was completed about 2 weeks after the clinical evaluation. Psychometricians are blinded to the results of the clinical evaluation and to the prior performance of the participants on the psychometric tests. RESULTS: The mean age at baseline of the 735 participants was 74.30 and 62.31% were female. 240 individuals developed prodromal dementia symptoms (consistent with mild cognitive impairment due to AD and with very mild AD dementia) during longitudinal follow-up (mean follow-up=6.79 years). Among a total of 562 items in the clinical and cognitive assessments under analysis, 292 (52%) were identified as informative because their longitudinal changes were predictive of symptomatic onset. When these items were used to form the functional and cognitive composites, the longitudinal rates of changes were free of a learning effect and captured subtle longitudinal progression prior to symptomatic onset. The rates of change were much greater right after the symptomatic onset than those from the functional and cognitive composites formed using non-informative items. Although the sample sizes for prevention trials (prior to symptomatic onset) using the informative items still yield large numbers, the sample sizes for early treatment trial (after symptomatic onset) was much smaller than those derived from all the items or from the non-informative items alone. CONCLUSIONS: The antecedent longitudinal changes in nearly half of the items in a clinical assessment protocol and a comprehensive cognitive battery did not show statistically significant ability to predict the dementia symptom onset, and hence may be non-informative to track the preclinical functional and cognitive progression of AD. The remaining items, on the other hand, captured some of the preclinical changes prior to the symptom onset, but performed much better right after the symptom onset. Currently ongoing prevention trials on preclinical AD of elderly individuals may need to re-assess the sample sizes and statistical power. PMID- 29616705 TI - A Literature Review of Methodologies Used in Randomized Clinical Trials of Agitation in Alzheimer's Disease. AB - Agitation is a common and burdensome symptom associated with Alzheimer's disease (AD). This is a narrative literature review of the designs and methods used in randomized clinical trials of agitation in patients with AD; sources range from published, to completed but not published, to ongoing studies in the past 10 years. Selection for review included blinded, randomized trials conducted to assess the effect of a pharmacological intervention for which agitation in patients with AD was among the prespecified end points. Key criteria for exclusion included open-label studies, trials of dementia not specific to AD, or mixed populations of AD and unspecified dementia. A search of PubMed and clinicaltrials.gov databases identified 36 trials for which agitation was among the prespecified end points: 18 were published trials and 18 were completed but not published or ongoing. There was significant heterogeneity among AD studies in terms of diagnostic criteria, assessment of severity of disease and agitation, sample size and powering assumptions, treatment duration, patient age and cognitive status, and outcomes measurements. Few studies used a mitigation strategy for placebo response. Accumulating evidence suggests that it is important to consider the following in trial design: thresholds for baseline severity of agitation and AD; use of prespecified accepted criteria to define agitation; and use of standardized, validated tools to measure treatment effects during a trial. Adoption of these design strategies might help improve signal detection and bring us closer to identifying the most appropriate, effective, and safe treatments for agitation in patients with AD. PMID- 29616706 TI - The Integrated Alzheimer's Disease Rating Scale (iADRS) Findings from the EXPEDITION3 Trial. AB - The Integrated Alzheimer's Disease (AD) Rating Scale (iADRS) is a composite tool that combines scores from the AD Assessment Scale-Cognitive subscale (ADAS-Cog) and the AD Cooperative Study - instrumental Activities of Daily Living (ADCS iADL). It demonstrates acceptable psychometric properties, and is effective in capturing both disease progression and separation of placebo and active drug effect. We assessed the performance of iADRS in the solanezumab EXPEDITION3 study, an 80-week, placebo-controlled study of individuals with mild AD dementia. A statistically significant difference between placebo and active drug was observed for iADRS score change from baseline at Week 28 (p=0.028) through Week 80 (p=0.015). Across the Phase 3 solanezumab trials, iADRS was the only tool that consistently differentiated between solanezumab and placebo groups. These findings suggest that the iADRS is a useful integrated measurement tool for treatment trials of individuals with mild AD dementia. PMID- 29616707 TI - Adherence to the Mediterranean Diet Is not Related to Beta-Amyloid Deposition: Data from the Women's Healthy Ageing Project. AB - BACKGROUND: Research has indicated the neuroprotective potential of the Mediterranean diet. Adherence to the Mediterranean diet has shown preventative potential for Alzheimer's disease incidence and prevalence, yet few studies have investigated the impact of Mediterranean diet adherence on the hallmark protein; beta-amyloid. OBJECTIVES: To investigate the association between Mediterranean diet adherence and beta-amyloid deposition in a cohort of healthy older Australian women. DESIGN: This study was a cross-sectional investigation of participants from the longitudinal, epidemiologically sourced Women's Healthy Ageing Project which is a follow-up of the Melbourne Women's Midlife Health Project. SETTING: Assessments were conducted at the Centre for Medical Research, Royal Melbourne Hospital in Melbourne, Australia. F-18 Florbetaben positron emission tomography scanning was conducted at the Austin Centre for PET in Victoria, Australia. PARTICIPANTS: One hundred and eleven Women's Healthy Ageing Project participants were included in the study. MEASUREMENTS: Mediterranean diet adherence scores for all participants were calculated from the administration of a validated food frequency questionnaire constructed by the Cancer Council of Victoria. Beta-amyloid deposition was measured using positron emission tomography standardised uptake value ratios. RESULTS: Gamma regression analysis displayed no association between Mediterranean diet adherence and beta-amyloid deposition. This result was consistent across APOE-epsilon4 +/- cohorts and with the inclusion of covariates such as age, education, body mass index and cognition. CONCLUSIONS: This study found no association between adherence to the Mediterranean diet and beta-amyloid deposition in a cohort of healthy Australian women. PMID- 29616708 TI - Strong Relationship between Malnutrition and Cognitive Frailty in the Singapore Longitudinal Ageing Studies (SLAS-1 and SLAS-2). AB - BACKGROUND: Physical frailty is well known to be strongly associated with malnutrition, but the combined impact of physical frailty and cognitive impairment among non-demented older persons (cognitive frailty) on malnutrition prevalence is not well documented. DESIGN: Cross-sectional cohort study. SETTING AND PARTICIPANTS: Community-dwelling older Singaporeans aged >=55y (n=5414) without dementia in the Singapore Longitudinal Ageing Study (SLAS-1 and SLAS-2). MEASUREMENTS: The Mini Nutritional Assessment - short form (MNA-SF) and Nutrition Screening Initiative (NSI) Determine Checklist were used to determine their nutritional status. Participants were categorized as cognitive normal (CN) or cognitive impaired (CI) by Mini Mental State Examination (MMSE<=23), as pre-frail (PF) (score=1-2) or frail (F) (score=3-5) using Fried's criteria, and as cognitive pre-frail (PF+CI) or cognitive frail (F+CI). RESULTS: The prevalence of cognitive frailty was 1.6%, and cognitive pre-frailty was 5.5% (total, 7.1%). The prevalence of MNA malnutrition was 2.4%, and NSI high nutritional risk was 6.3%. The prevalence of MNA malnutrition was lowest among Robust-CN and highest among Frail-CI (0.5% in Robust-CN, 0.6% in Robust-CI, 2.8% in Pre-frail-CN, 7.3% in Pre frail-CI, 15.4% in Frail-CN, and 23.1% in Frail-CI). Similarly, the prevalence of NSI high nutritional risk was lowest in Robust-CN (3.7%) and highest in Frail-CI (13.6%). Adjusted for sociodemographic and health status, pre-frailty/frailty-CI versus Robust-CN was associated with the highest odds ratio of association with MNA malnutrition (OR=8.16, p<0.001), although not the highest with NSI high nutritional risk (OR=1.48, p=0.017). CONCLUSIONS: An extraordinary high prevalence of malnutrition was observed among older adults with cognitive frailty who should be specially targeted for active intervention. PMID- 29616709 TI - Development of Azeliragon, an Oral Small Molecule Antagonist of the Receptor for Advanced Glycation Endproducts, for the Potential Slowing of Loss of Cognition in Mild Alzheimer's Disease. AB - Increasing evidence supports the role of the Receptor for Advanced Glycation Endproducts (RAGE) in the pathology of Alzheimer's disease. Azeliragon (TTP488) is an orally bioavailable small molecule inhibitor of RAGE in Phase 3 development as a potential treatment to slow disease progression in patients mild AD. Preclinical studies in animal models of AD (tgAPPSwedish/London) have shown azeliragon to decrease Abeta plaque deposition; reduce total Abeta brain concentration while increasing plasma Abeta levels; decreases sAPPbeta while increasing sAPPalpha; reduce levels of inflammatory cytokines; and slow cognitive decline and improve cerebral blood flow. In the Phase 2b study, 18-months treatment in patients with mild-to-moderate AD indicated a baseline to endpoint change in ADAS-cog of 3.1 points in favor of drug. A greater magnitude of effect was evident in the sub-group of patients with mild AD (MMSE 21-26) with a baseline to endpoint change of 4 points on the ADAS-cog in favor of azeliragon and a 1 point change in CDR-sb in favor of drug. Azeliragon 5 mg/day delayed time to cognitive deterioration (7-point change in ADAS-cog from baseline, logrank p=0.0149). Based on promising results from the Phase 2b study, a Phase 3 registration program (STEADFAST) is being conducted under a Special Protocol Assessment from FDA. The ongoing Phase 3 program, if successful may demonstrate azeliragon can slow cognitive decline in mild AD patients. PMID- 29616710 TI - Letter to editor: Nanorobots the Future of Neurology: A Perspective on Alzheimer's Disease. PMID- 29616711 TI - Suicidal risk, hopelessness and depression in patients with schizophrenia and internalized stigma. AB - BACKGROUND: Internalized stigma has negative consequences on subjective and objective aspects of the recovery in people diagnosed with mental disorders. Despite its relevance, it has been poorly studied in patients with schizophrenia. METHODS: A sample of 71 outpatients with a diagnosis of schizophrenia who attended Psychosocial Rehabilitation Centers of Gran Canaria, Spain, were evaluated. We assessed the prevalence of internalized stigma and its possible association with sociodemographic, clinical, psychological and psychopathological variables, as well as suicidal behaviour and suicidal ideation. RESULTS: 21.1% of the patients had internalized stigma. Internalized stigma was associated with higher prevalence of suicidal ideation during the last year, higher number of suicide attempts, higher current suicidal risk, worse self-compassion, higher self-esteem, higher scores on depression, higher prevalence of depression and higher hopelessness. After multivariate analysis, hopelessness and the existence of depression were independently associated with internalized stigma, although depression showed trend towards significance. CONCLUSIONS: The association between internalized stigma and higher hopelessness, depression and higher suicidal risk suggests the necessity to systematically assess internalized stigma in patients with schizophrenia, and to intervene to reduce it. PMID- 29616712 TI - Anxiety, hospital fears and conduct and behavioral alterations during pediatric hospitalization. AB - INTRODUCTION: A hospital admission is an experience capable of generating emotional and behavioral alterations at any age. This study pretends to analyze the response of anxiety, fears and/or behavioral alterations in pediatric patients exposed to a conventional non-surgical hospital admission and the existing relationship between these responses and certain modulating variables. Metodology. Design of cohorts. Data collection was carried out in three stages (M1: at admission; M2: at discharge; M3: 2 weeks after discharge), on a 30 patient sample between the ages of 6 to 15 years and 30 caregivers. A comparison was made on the mean of the repeated measurements (Student t) of the respond variables and their correlation (Pearson’s Coefficient Correlation) with modulating variables. RESULTS: The results of the intra-subject analysis showed significance in terms of anxiety levels state in patients in M1 versus M3 (t=3.93, p<.0001, d=0.69) and the magnitude of the total behavioral alterations registered in M1 versus M3 (t=-5.02, p<.0001, d=0.60). It was observed that a significant relationship between modulating variables of patients (anxiety risk) and of the caregiver (anxiety character state, strategy of confrontation) and the variables of response of the anxiety and behavioral alterations of the patient. CONCLUSIONS: Exposure of a conventional non-surgical hospital admission may have negative consequences at an emotional and behavioral level in children, present far beyond the hospital admission. Certain variables, from the patient and the caregiver, are psychological vulnerability factors before a hospitalization process. PMID- 29616713 TI - Mental health in displaced children by armed conflict - National Mental Health Survey Colombia 2015. AB - INTRODUCTION: The armed conflict in Colombia is considered one of the most violent in Latin America. Children as a vulnerable population are most affected, increasing their risk of developing mental problems such as anxiety disorder and post-traumatic stress disorder. OBJECTIVES: To determine the prevalence of the most frequent mental problems in the Colombian children affected by armed conflict. METHODOLOGY: A cross-sectional study, using data from the National Mental Health Survey 2015. With children aged 7 to 11 years, in whom the RQC, PCL and DISC-IV-P (3.0.1) were applied. RESULTS: We described information on 100 displaced children between 7 and 11 years old due to armed conflict, being a representative sample at national level. It was found that 98.7% of this population is at school, as well as 17.8% in poverty. Mental illnesses were asked according to their appearance in the last 12 months, these were: anxiety disorder 6.5% (CI 95% 2.7-14.7) in displaced population, compared to 1.8% (CI 95% 1.1-3.1) in non-displaced; High score for post-traumatic stress was 13.2% (CI 95% 3.9 36.4) in displaced persons and 6.6% (CI 95% 4.0-10.7) in nondisplaced persons. CONCLUSIONS: Children affected by armed conflict have greater risk of presenting some mental illnesses such as anxiety disorder and post-traumatic stress, evidencing the situation of vulnerability in which they are. PMID- 29616714 TI - Clinical profile of inpatients referred to a consultation-liaison psychiatry service: an observational study assessing changes over a 10-yearperiod. AB - OBJECTIVE: Previous research has described the characteristics of Consultation liaison psychiatry (CLP) services over one or more years. The aim of this paper was to examine the patterns of a large sample of patients receiving CLP service over a 10-year-period (2005–2014) and to determine the possible changes over time of the clinical practice. The sample size of our study, the duration of the observation period and the application of standardized operating procedures for acquiring and coding data, will provide more robust evidence than has been reported by most similar studies published in the last years. METHODS: Longitudinal observational and descriptive study. Data were collected prospectively with standardized operating procedures on consecutive inpatient consultation requests to the University Clinical Hospital of Barcelona CLP service. RESULTS: 9,808 psychiatric consultation were requested (referral rate=2.2%). The referrals to our CLP service were requested mainly by medical units. The most frequent psychiatric diagnoses were alcohol-related disorders, delirium and adjustment disorders. The mean percentage of patients treated with psychopharmacologic drugs was 81.6%. The mean length of the hospital stays of patients with psychiatric comorbidity referred to our CLP service was significantly longer than that of all the admissions to the hospital during that period. Most of the studied variables remained constant over the 10-year-period. However, some somatic diagnoses at admission, reasons for referral and recommendations of psychotropic drugs presented significant changes. CONCLUSIONS: Despite the continuous evolution and changes of several factors in the last two decades, like the health care systems, the clinical practice of CLP services has been quite stable over time. However, our results support the idea of a non static specialty. PMID- 29616715 TI - Serotonin syndrome versus neuroleptic malignant syndrome: a case report. PMID- 29616716 TI - Treatment of Delayed Post-Hypoxic Leukoencephalopathy as a complication of carbon monoxide poisoning with risperidone and hyperbaric oxygen therapy. PMID- 29616717 TI - The chick model system: a distinguished past and a great future. AB - When I was asked by the Chief Editor of the Int. J. Dev. Biol. to consider editing a Special Issue about "the chick", I was first hesitant, because I had already edited such an issue for another journal in 2004 (Mech. Dev. volume 121), when the sequence of the chick genome was first released (Stern, 2004, 2005). But at the same time I was surprised that this journal, well known for its Special Issues of which many have become important historical and literary land-marks to the developmental biology literature, had not yet produced a volume on what is probably the oldest developmental model system. Despite this, it is often forgotten that much of what we know (or think we know) about human developmental events is due to extrapolation from chick embryological studies. PMID- 29616718 TI - Chick midgut morphogenesis. AB - The gastrointestinal tract is an essential system of organs required for nutrient absorption. As a simple tube early in development, the primitive gut is patterned along its anterior-posterior axis into discrete compartments with unique morphologies relevant to their functions in the digestive process. These morphologies are acquired gradually through development as the gut is patterned by tissue interactions, both molecular and mechanical in nature, involving all three germ layers. With a focus on midgut morphogenesis, we review work in the chick embryo demonstrating how these molecular signals and mechanical forces sculpt the developing gut tube into its mature form. In particular, we highlight two mechanisms by which the midgut increases its absorptive surface area: looping and villification. Additionally, we review the differentiation and patterning of the intestinal mesoderm into the layers of smooth muscle that mechanically drive peristalsis and the villification process itself. Where relevant, we discuss the mechanisms of chick midgut morphogenesis in the context of experimental data from other model systems. PMID- 29616719 TI - A snail tale and the chicken embryo. AB - Some 25 years ago, a clone was identified that contained the chicken Slug sequences (now called Snail2 ). How could we anticipate at that time how much the chick embryo would help us to understand the ins and outs of cell migration during development and in disease? Indeed, the chick embryo helped us identify Snail2 as the first transcription factor that could induce the epithelial mesenchymal transition (EMT), key for the migration of embryonic and cancer cells. PMID- 29616720 TI - Chick muscle development. AB - Striated muscle is the most abundant tissue in the body of vertebrates and it forms, together with the skeleton, the locomotory system required both for movement and the creation of the specific body shape of a species. Research on the embryonic development of muscles has a long tradition both in classical embryology and in molecular developmental biology. While the gene networks regulating muscle development have been discovered mostly in the mouse through genetics, our knowledge on cell lineages, muscle morphogenesis and tissue interactions regulating their formation is to a large extent based on the use of the avian model. This review highlights present knowledge of the development of skeletal muscle in vertebrate embryos. Special focus will be placed on the contributions from chicken and quail embryo model systems. PMID- 29616721 TI - Early hematopoietic and vascular development in the chick. AB - The field of hematopoietic and vascular developmental research owes its origin to the chick embryo. Many key concepts, such as the hematopoietic stem cell, hemangioblast and hemogenic endothelium, were first proposed in this model organism. Genetically tractable models have gradually replaced the chick in the past two decades. However, advances in comparative genomics, transcriptomics and promoteromics promise a re-emergence of the chick embryo as a powerful model for hematopoietic/vascular research. This review summarizes the current status of our understanding of early blood/vascular development in the chick, focusing primarily on the processes of primitive hematopoiesis and early vascular network formation in the extraembryonic and lateral plate mesoderm territories. Emphasis is given to ontological and molecular association between the blood and endothelial cells and to the evolutionary relationship between the hemangioblasts, common precursors for the blood and endothelial lineages, and the coelomic epithelial lining cells. Links between early blood/vascular development and later definitive hematopoiesis are also discussed. Finally, potential applications of the chick model for comparative and omics-level studies of the blood/vascular system are highlighted. PMID- 29616722 TI - The early development of germ cells in chicken. AB - Primordial germ cells (PGCs) are the founder cells for mature gametes, the vehicles by which individuals transmit genetic and epigenetic information to later generations. Since the 19th century, avian species (chickens in particular) have been widely used for germ cell research. Previous studies have used chicken PGCs for a variety of research applications, including as a model for studies focusing on germline development. Other applications of chicken PGCs, including conservation efforts for avian species and methods of producing transgenic birds, have further reinforced the importance of these cells. However, much remains to be revealed about the origin and role of PGCs during their development in the chicken. Here, we provide a comprehensive review of chicken PGCs, focusing in particular upon their initial profiles and physiological changes during development as regulated by environmental factors and/or intrinsic mechanisms. We also emphasise sex-dependent differences in PGC development after settlement within the gonads, as well as future applications for avian PGCs. PMID- 29616723 TI - An obsession with the chick. AB - This paper provides a brief account of some aspects of the career of Ruth Bellairs using selected examples from her research publications, with the emphasis being placed on the early stages of chick embryo development, and in particular, on cell migration. Topics include the role of Hensen's node, the vitelline membrane, the structure and segmentation of somites, the tail bud and the Wolffian duct. Her research approach has involved embryo culture, experimental surgery, transmission and scanning electron microscopy, time-lapse filming and immunostaining techniques. PMID- 29616724 TI - Sex determination and gonadal sex differentiation in the chicken model. AB - Our understanding of avian sex determination and gonadal development is derived primarily from the studies in the chicken. Analysis of gynandromorphic chickens and experimental chimeras indicate that sexual phenotype is at least partly cell autonomous in the chicken, with sexually dimorphic gene expression occurring in different tissue and different stages. Gonadal sex differentiation is just one of the many manifestations of sexual phenotype. As in other birds, the chicken has a ZZ male: ZW female sex chromosome system, in which the male is the homogametic sex. Most evidence favours a Z chromosome dosage mechanism underling chicken sex determination, with little evidence of a role for the W chromosome. Indeed, the W appears to harbour a small number of genes that are un-related to sexual development, but have been retained because they are dosage sensitive factors. As global Z dosage compensation is absent in birds, Z-linked genes may direct sexual development in different tissues (males having on average 1.5 to 2 times the expression level of females). In the embryonic gonads, the Z-linked DMRT1 gene plays a key role in testis development. Beyond the gonads, other combinations of Z-linked genes may govern sexual development, together with a role for sex steroid hormones. Gonadal DMRT1 is thought to activate other players in testis development, namely SOX9 and AMH, and the recently identified HEMGN gene. DMRT1 also represses ovarian pathway genes, such as FOXL2 and CYP19A1. A lower level of DMRT1 expression in the female gonads is compatible with activation of the ovarian pathway. Some outstanding questions include how the key testis and ovary genes, DMRT1 and FOXL2, are regulated. In addition, confirmation of the central role of these genes awaits genome editing approaches. PMID- 29616725 TI - Cell biological mechanisms regulating chick neurogenesis. AB - Signalling pathways that regulate neural progenitor proliferation and neuronal differentiation have been identified. However, we know much less about how transduction of such signals is regulated within neuroepithelial cells to direct cell fate choice during mitosis and subsequent neuronal differentiation. Here we review recent advances in the experimentally amenable chick embryo, which reveal that this involves association of signalling pathway components with cell biological entities, including mitotic centrosomes and ciliary structures. This includes changing centrosomal localization of protein kinase A, which regulates Sonic hedgehog signalling and so neural progenitor status, and Mindbomb1, a mediator of Notch ligand activation, which promotes Notch signalling in neighbouring cells, and so is active in presumptive neurons. We further review cell biological events that underlie the later step of neuronal delamination, during which a newborn neuron detaches from its neighbouring cells and undergoes a process known as apical abscission. This involves inter-dependent actin and microtubule dynamics and includes dissociation of the centrosome from the ciliary membrane, which potentially alters the signalling repertoire of this now post mitotic cell. Open questions and future directions are discussed along with technological advances which improve accuracy of gene manipulation, monitoring of protein dynamics and quantification of cell biological processes in living tissues. PMID- 29616726 TI - Segmentation of the chick central and peripheral nervous systems. AB - The chick embryo has provided a prominent model system for the study of segmental patterning in the nervous system. During early development, motor and sensory axon growth cones traverse the anterior/rostral half of each somite, so avoiding the developing vertebral components and ensuring separation of spinal nerves from vertebral bones. A glycoprotein expressed on the surface of posterior half-somite cells confines growth cones to the anterior half-somites by a contact repulsive mechanism. Hindbrain segmentation is also a conspicuous feature of chick brain development. We review how its contemporary analysis was initiated in the chick embryo, and the advantages the chick system continues to provide in its detailed elucidation at both molecular and neural circuit levels. PMID- 29616727 TI - Insights into neural crest development from studies of avian embryos. AB - The neural crest is a multipotent and highly migratory cell type that contributes to many of the defining features of vertebrates, including the skeleton of the head and most of the peripheral nervous system. 150 years after the discovery of the neural crest, avian embryos remain one of the most important model organisms for studying neural crest development. In this review, we describe aspects of neural crest induction, migration and axial level differences, highlighting what is known about the underlying gene regulatory mechanisms. Past and emerging technologies continue to improve the resolution with which we can examine important questions of neural crest development, with modern avian molecular embryology continuing to make important contributions. PMID- 29616728 TI - A life in Science with the avian embryo. AB - My career in research was a second thought. I first (during 8 years) worked as a secondary school teacher and after 4-5 years, during which my two daughters were born, I found a way to escape from what was to be a lifetime job. For two years, my initiation to research was limited to the free time left by my teaching duties. This period of time was a bit "complicated" but not enough to prevent me to realize that research was really what I wanted to do for the rest of my life... And this was when I became acquainted with the chick embryo. This companionship later became extended to another representative of the avian world: the quail (Coturnix coturnix japonica). I recall in the following lines a survey of scientific stories that came out from my association with these precious animals, ... not without a feeling of gratitude. PMID- 29616729 TI - Specification of sensory placode progenitors: signals and transcription factor networks. AB - Sensory placodes contribute to much of the sensory nervous system in the vertebrate head. They give rise to parts of the eye, ear and nose, as well as to the sensory ganglia that innervate the face, tongue, oesophagus and visceral tissues. Despite their diversity, during development placodes arise from a population of common progenitor cells, which are first specified at the border of the neural plate. The chick has been particularly instrumental in dissecting the timing of these events, and recent evidence has highlighted the close relationship of placode progenitors and precursors for neural crest cells and the central nervous system. This review focuses on the induction of placode progenitors by localised signalling events, and the transcriptional networks that lead to their specification. PMID- 29616730 TI - Developmental studies of avian brain organization. AB - Avian brain organization or brain Bauplan is identical with that of vertebrates in general. This essay visits avian studies that contained advances or discussions about brain organization, trying to explain critically what they contributed. In order to start from a specific background, the new prevailing paradigm as regards brain organization, the prosomeric model, is presented first. Next a brief historic survey is made of how ideas on this topic evolved from the start of modern neuromorphology at the end of the 19th century. Longitudinal zonal organization with or without transverse segmentation (neuromeres) was the first overall concept applied to the brain. The idea of neuromeric structure later decayed in favour of a columnar model. This emphasized functional correlations rather than causal developmental content, assimilating forebrain functions to hindbrain ones. Though it became prevalent in the post-world-war period of neuroscience, in the last decades of the 20th century advances in molecular biology allowed developmental genes to be mapped, and it became evident that gene expression patterns support the old neuromeric model rather than the columnar one. This was also corroborated by modern experimental approaches (fate mapping and analysis of patterning). PMID- 29616732 TI - General principles of spinal motor circuit development: early contributions from research on avian embryos. AB - Birds and mammals, both being amniotes, share many common aspects of development. Thus our understanding of how limb-innervating mammalian spinal motor circuits develop was greatly influenced by the use of the avian embryo (chick/quail) to bring about experimental perturbations to identify basic underlying mechanisms. These included embryonic surgery, the application of drugs to influence activity or molecular interactions, and the ability to observe motor behavior and make physiological recordings in intact developing embryos. This article will review some of these contributions, highlighting several areas including the acquisition of motoneuron subtype identity and target selection, as well as the role of spontaneous rhythmic activity in circuit development. PMID- 29616731 TI - Sonic hedgehog in vertebrate neural tube development. AB - The formation and wiring of the vertebrate nervous system involves the spatially and temporally ordered production of diverse neuronal and glial subtypes that are molecularly and functionally distinct. The chick embryo has been the experimental model of choice for many of the studies that have led to our current understanding of this process, and has presaged and informed a wide range of complementary genetic studies, in particular in the mouse. The versatility and tractability of chick embryos means that it remains an important model system for many investigators in the field. Here we will focus on the role of Sonic hedgehog (Shh) signaling in coordinating the diversification, patterning, growth and differentiation of the vertebrate nervous system. We highlight how studies in chick led to the identification of the role Shh plays in the developing neural tube and how subsequent work, including studies in the chick and the mouse revealed details of the cell intrinsic programs controlling cell fate determination. We compare these mechanisms at different rostral-caudal positions along the neuraxis and discuss the particular experimental attributes of the chick that facilitated this work. PMID- 29616733 TI - Pluripotency in avian species. AB - Pluripotency defines the ability of a cell to self-renew and to differentiate into all embryonic lineages both in vitro and in vivo. This definition was first established mainly with the mouse model and the establishment of mouse embryonic stem cells (ESCs) in the 1980's and extended later on to other species including non-human primates and humans. Similarly, chicken ESCs were derived and established in vitro from pregastrulating embryos leading to cells with unique properties at molecular, epigenetic and developmental levels. By comparing the properties of murine, mammalian and avian ESCs and of the more recently discovered induced pluripotential stem (iPS)-derived cells generated in all of these species, avian specificities start to emerge including specific molecular genes, epigenetic mark profiles and original developmental properties. Here, we present common, but also avian-specific elements that contribute to defining avian pluripotency. PMID- 29616734 TI - Illuminating the chicken model through genetic modification. AB - After decades of research investment, techniques for the robust and efficient modification of the chicken genome are now with us. The biology of the chicken has provided many challenges, as have the methods by which transgenes can be readily, stably and functionally integrated into the genome. Now that these obstacles have been surmounted and the chicken has been 'updated' to a cutting edge modern model organism, a future as a central and versatile model in developmental biology beckons. In this review, we describe recent advances in genetic modification of the chicken and some of the many transgenic models developed for the elucidation of the mechanisms of embryogenesis. PMID- 29616735 TI - Chicken genomics. AB - As one of the most economically important species and a unique model organism for biological and medical research, the chicken represents the first non-mammalian amniotic species to have its genome sequenced; and so far, the chicken reference genome represents the best assembled and annotated avian genome. Since the release of the first draft genome sequence, the chicken genome assembly has improved greatly in coverage, contiguity and accuracy owing to the continuous efforts made by the chicken genomics community to generate extensive new data using novel sequencing technologies. Transcriptome sequencing, especially the recent effort to characterise full-length transcripts in chicken tissues, has provided key insights into the complexity of structure and function of the chicken genome. In this article, we review the progress in chicken genome assembly and annotation, and recent advances in comparative genomics in birds. Limitations of current data and plans of research are also discussed. PMID- 29616736 TI - From soil mechanics to chick development. AB - Here, I provide some recollections of my life, starting as a civil engineer in South Africa and how I gradually became interested in biology, particularly pattern formation. In retrospect, I think that my decision to work on chick embryos to study limb development back in 1966 turned out to be the right one. The principles discovered in these 50 years, both by my collaborators and by other colleagues, have established the principles of how the limb develops in higher vertebrates, including humans. PMID- 29616737 TI - Staging tables for avian embryos: a little history. AB - Absolute time elapsed since fertilization, or hours' incubation, is not a good measure of the precise degree of development of an embryo because there is considerable variation. The chick embryo benefits from a detailed, well defined staging system introduced by Hamburger and Hamilton in 1951, perhaps the most precise and detailed available for any species. This paper briefly reviews the background and legacy of this table, including the remarkable work of its predecessors, Mathias Duval and Franz Keibel. It also begs the question of why the mouse embryo still lacks a similarly precise classification. PMID- 29616738 TI - Contributions of the chick embryo and experimental embryology to understanding the cellular mechanisms of neurulation. AB - The chick embryo has served as a workhorse for experimental embryological studies designed to elucidate mechanisms underlying neurulation, the process that forms the neural tube, the rudiment of the entire adult central nervous system. Early chick embryos developing in whole-embryo culture can be readily manipulated in cut-and-paste-type experiments, and this attribute makes this model system unparalleled for studying the morphogenesis of embryos and their organ rudiments. How the chick embryo and experimental embryology have contributed to our understanding of critical events of neurulation are summarized. PMID- 29616739 TI - Michael Abercrombie: contact inhibition of locomotion and more. AB - Michael Abercrombie is regarded as one of the principal pioneers of cell biology. Although Abercrombie began his career as an experimental embryologist, working on the avian organizer with C. H. Waddington, questions on how cells in culture migrate and interact dominated his career. Whilst studying the social behaviour of chick heart embryonic fibroblasts, Abercrombie identified a phenomenon whereby colliding cells collapse their protrusions towards the cell-cell contact upon a collision, preventing their continued migration. The cells then form protrusions away from the contact and, space permitting, migrate away from each other. This behaviour is now referred to as 'contact inhibition of locomotion' and has been identified within embryology as the driving force behind the directional migration of the neural crest and the dispersion patterning of haemocytes and Cajal-Retzius neurons. Furthermore, its loss between collisions of cancer cells and healthy cells is associated with metastasis. In this review we begin with an overview of Abercrombie's life and highlight some of his key publications. We then discuss Abercrombie's discovery of contact inhibition of locomotion, the roles which cell-cell adhesions, cell-matrix adhesions and the cytoskeleton play in facilitating this phenomenon, and the importance of contact inhibition of locomotion within the living organism. PMID- 29616740 TI - Somite formation in the chicken embryo. AB - Somites are epithelial blocks of paraxial mesoderm that define the vertebrate embryonic segments. They are responsible for imposing the metameric pattern observed in many tissues of the adult such as the vertebrae, and they give rise to most of the axial skeleton and skeletal muscles of the trunk. Due to its easy accessibility in the egg, the chicken embryo has provided an ideal model to study somite development. Somites were first described in the chicken embryo by Malpighi in the 17th century, soon after the invention of the microscope. Most of the major concepts relating to somite segmentation and differentiation result from studies performed in the chicken embryo (Brand-Saberi and Christ, 2000). In this review, we will discuss how studies on somites in avian embryos have contributed to our understanding of key developmental processes such as segmentation, control of bilateral symmetry or axis regionalization. PMID- 29616741 TI - Avian models and the study of invariant asymmetry: how the chicken and the egg taught us to tell right from left. AB - While the external vertebrate body plan appears bilaterally symmetrical with respect to anterior-posterior and dorsal-ventral axes, the internal organs are arranged with a striking and invariant left-right asymmetry. This laterality is important for normal body function, as alterations manifest as numerous human birth defect syndromes. The left-right axis is set up very early during embryogenesis by an initial and still poorly understood break in bilateral symmetry, followed by a cascade of molecular events that was discovered 20 years ago in the chick embryo model. This gene regulatory network leads to activation of the pitx2 gene on the left side of the embryo which ultimately establishes asymmetric organogenesis of the heart, gut, brain, and other organs. In this review, we highlight the crucial contributions of the avian model to the discovery of the differential transcriptional cascades operating on the Left and Right sides, as well as to the physiological events operating upstream of asymmetric gene expression. The chick was not only instrumental in the discovery of mechanisms behind left-right patterning, but stands poised to facilitate inroads into the most fundamental aspects that link asymmetry to the rest of evolutionary developmental biology. PMID- 29616742 TI - Coordination between body growth and tissue growth: Wolffian duct elongation and somitogenesis proceed in harmony with axial growth. AB - During embryogenesis, different tissues develop coordinately, and this coordination is often in harmony with body growth. Recent studies allow us to understand how this harmonious regulation is achieved at the levels of inter cellular, inter-tissue, and tissue-body relationships. Here, we present an overview of recently revealed mechanisms by which axial growth (tail growth) drives a variety of morphogenetic events, with a focus on the coordinated progression between Wolffian (nephric) duct elongation and somitogenesis. We also discuss how we can relate this coordination to the events occurring during limb bud outgrowth, since the limb buds and tail bud are appendage anlagen acquired during vertebrate evolution, both of which undergo massive elongation/outgrowth. PMID- 29616743 TI - The chick limb: embryology, genetics and teratology. AB - The chick embryo has a long history in investigations of vertebrate limb development because of the ease with which its limbs can be experimentally manipulated. Early studies elucidated the fundamental embryology of the limb and identified the key signalling regions that govern its development. The chick limb became a leading model for exploring the concept of positional information and understanding how patterns of differentiated cells and tissues develop in vertebrate embryos. When developmentally important molecules began to be identified, experiments in chick limbs were crucial for bridging embryology and molecular biology. The embryological mechanisms and molecular basis of limb development are largely conserved in mammals, including humans, and uncovering these molecular networks provides links to clinical genetics. We emphasise the important contributions of naturally occurring chick mutants to elucidating limb embryology and identifying novel developmentally important genes. In addition, we consider how the chick limb has been used to study mechanisms involved in teratogenesis with a focus on thalidomide. These studies on chick embryos have given insights into how limb defects can be caused by both genetic changes and chemical insults and therefore are of great medical significance. PMID- 29616744 TI - Craniofacial development: discoveries made in the chicken embryo. AB - The aim of this review is to highlight some of the key contributions to our understanding of craniofacial research from work carried out with the chicken and other avian embryos. From the very first observations of neural crest cell migration to the fusion of the primary palate, the chicken has proven indispensable in facilitating craniofacial research. In this review we will look back to the premolecular studies where "cut and paste" grafting experiments mapped the fate of cranial neural crest cells, the role of different tissue layers in patterning the face, and more recently the contribution of neural crest cells to jaw size and identity. In the late 80's the focus shifted to the molecular underpinnings of facial development and, in addition to grafting experiments, various chemicals and growth factors were being applied to the face. The chicken is above all else an experimental model, inviting hands-on manipulations. We describe the elegant discoveries made by directly controlling signaling either in the brain, in the pharyngeal arches or in the face itself. We cover how sonic hedgehog (Shh) signals to the face and how various growth factors regulate facial prominence identity, growth and fusion. We also review abnormal craniofacial development and how several type of spontaneous chicken mutants shed new light on diseases affecting the primary cilium in humans. Finally, we bring out the very important role that the bird beak has played in understanding amniote evolution. The chicken, duck and quail have been and will continue to be used as experimental models to explore the evolution of jaw diversity and the morphological constraints of the vertebrate face. PMID- 29616745 TI - In-situ analysis of mast cells and dendritic cells in coronary atherosclerosis in chronic kidney disease (CKD). AB - AIMS: Mast cells (MC) and dendritic cells (DC) have immune modulatory function and can influence T-cell activity. Both cell types have been found in atherosclerotic plaques and are thought to play an important role for plaque stability. Compared to matched segments of the non-renal population, patients with chronic kidney disease (CKD) show a more pronounced and more aggressive course of atherosclerosis with higher plaque calcification and significantly higher complications rates. It was the aim of this study to analyze the number and localization of MCs and DCs, macrophages, T- and B-cells as well as the expression of markers of inflammation such as CRP and NFkappaB in calcified and non-calcified atherosclerotic plaques of patients with CKD and control patients. METHODS: Fifty coronary atherosclerotic plaques from patients with endstage CKD (CKD, n=25) and control (n=25) patients were categorized according to the Stary classification and investigated using immunohistochemistry (markers for MC, DC, T, B, macrophage and NFkappaB). Expression was analyzed separately for the complete plaque area as well as for the different plaque subregions and correlations were analyzed. RESULTS: We found only very few DCs and MCs per lesion area with slightly increased numbers in calcified plaques. MCs per plaque area were significantly more frequent in CKD than in control patients and this was independent of plaque calcification. MCs were most frequently found in the shoulder and basis of the plaque. DCs per plaque area were significantly less in calcified plaques of CKD compared to control patients. In control, but not in CKD patients, DCs were significantly more frequent in calcified than in non-calcified plaques. Within the plaques DCs were similarly distributed between all 4 subregions. CONCLUSIONS: Coronary atherosclerotic plaques of CKD patients showed a significantly higher number of MCs whereas DCs were less frequent compared to control patients particularly if plaques were calcified. These findings might indicate a potential proinflammatory role of MCs, but not of DCs in atherosclerotic lesions of CKD patients, adding another characteristic of advanced atherosclerosis in these patients. PMID- 29616746 TI - Interleukin 21 treatment in a murine model as a novel potential cytokine immunotherapy for colon cancer. AB - BACKGROUND: Interleukin 21 (IL-21), which belongs to the common gamma-chain (gammac) family, is a novel tumor suppressor that has been shown to affect T-cell proliferation, survival and function. However, the role of IL-21 in colon cancer remains unclear. OBJECTIVES: We sought to determine whether IL-21 could inhibit the progression of colon cancer in mice; we also explored the mechanisms underlying the immunological effects of IL-21 in colon cancer. MATERIAL AND METHODS: Exogenous IL-21 protein was expressed to treat tumor-bearing mice and the production of cytokine interleukin 4, interferon gamma and lambda from CD4+ T, CD8+ T, and NK cells were measured, along with the survival times of these tumor-bearing mice. RESULTS: Interleukin 21 promoted the secretion of interferon gamma from the CD4+ T, CD8+ T and NK cells and it enhanced the production of interferon lambda by the NK cells. More importantly, IL-21 treatment significantly enhanced antitumor effects in favor of tumor eradication. We also found that CD8+ T and NK cells are necessary for the antitumor immune responses elicited by IL-21. CONCLUSIONS: Interleukin 21 is a powerful tool for activating CD8+ T cells and NK cells which exhibit potent cytolytic effector functions and should therefore be exploited for anticancer immunotherapy. Our findings support the development of a novel cytokine immunotherapy against colon cancer. PMID- 29616747 TI - Awareness and attitudes towards clinical trials among Polish oncological patients who had never participated in a clinical trial. AB - BACKGROUND: Participation in a clinical trial significantly shortens waiting time associated with receiving specialist care. Furthermore, it may be the case that, through clinical trials, subjects can access medicines that are not typically available in Poland. OBJECTIVES: The aim of this study was to determine the opinions of oncological patients about clinical trials. MATERIAL AND METHODS: The research has been carried out during the years 2014-2016. A proprietary questionnaire consisting of 10 closed, single and multiple choice questions about awareness and perceptions of clinical trials, and 5 questions concerning demographic information was used. A group of 256 patients with cancer (54% women, 46% men), aged 21-77 years, was surveyed. RESULTS: Respondents were statistically more likely to decide to participate in a clinical trial as oncological patients than the healthy volunteers (Pearson's chi2 test p = 0.00006). The desire to qualify for clinical trials in no way depends on the knowledge of side effects (Pearson's chi2 test p = 0.16796). CONCLUSIONS: Our study found that the patients' awareness about clinical trials varied. However, a positive attitude towards research was visible. The main identified barriers to clinical trial participation were fear of possible side effects. Most patients regarded clinical trials as useful, and considered that they are conducted to introduce new treatment/new drug. PMID- 29616748 TI - Electrocardiographic T-wave parameters in families with long QT syndrome. AB - BACKGROUND: T-wave parameters, especially the Tpeak-Tend interval (TpTe), reflect the total dispersion of repolarization, whose amplification may lead to the development of life-threatening ventricular arrhythmias observed in the long QT syndrome (LQTS). OBJECTIVES: The study attempted to evaluate QT, QTp (Q-Tpeak) and TpTe (Tpeak-Tend) intervals in unaffected and affected blood relatives of children with clinically confirmed LQTS as well as to determine whether the values of these repolarization parameters may be used in clinical practice. MATERIAL AND METHODS: The study group included 47 affected blood relatives (27 LQTS1 and 20 LQTS2) and 68 unaffected family members without clinically confirmed LQTS symptoms. The TpTe, QT and QTp intervals were measured manually in the lead V5 of standard ECGs and corrected using Bazett's and Fridericia's formulas. RESULTS: The RR, QT, QTp and TpTe intervals with their corrected values were significantly longer (p < 0.0001) in the affected subjects than in the unaffected subjects and, similarly, in LQTS1 and LQTS2 patients compared with the unaffected family members. The TpTe interval in LQTS2 showed only a tendency to be longer compared to LQTS1, but did not reach statistical significance (p = 0.0933). For affected blood relatives, only the TpTe interval (p < 0.0409) and QT interval, corrected with Bazett's (p < 0.0393) and Fridericia's (p < 0.0495) formulas, enabled differentiation between LQTS1 (mean TpTe = 103 +/-15) and LQTS2 women (mean TpTe = 106 +/-17). Moreover, there were statistically significant differences (p < 0.05) in the TpTe interval between the 6 sex subgroups: unaffected women and men as well as women and men with LQTS1 and LQTS2. CONCLUSIONS: The electrocardiographic Tpeak-Tend parameter, in addition to the QT interval, is helpful in identifying affected blood relatives of children with LQTS, particularly for the group of LQTS1 and LQTS2 women. Further studies are required to assess the clinical importance of the TpTe interval in families with long QT syndrome. PMID- 29616749 TI - Impact of selected magnetic fields on the therapeutic effect in patients with lumbar discopathy: A prospective, randomized, single-blinded, and placebo controlled clinical trial. AB - BACKGROUND: Interdisciplinary physical therapy together with pharmacological treatment constitute conservative treatment strategies related to low back pain (LBP). There is still a lack of high quality studies aimed at an objective evaluation of physiotherapeutic procedures according to their effectiveness in LBP. OBJECTIVES: The aim of this study is to carry out a prospective, randomized, single-blinded, and placebocontrolled clinical trial to evaluate the effectiveness of magnetic fields in discopathy-related LBP. MATERIAL AND METHODS: A group of 177 patients was assessed for eligibility based on inclusion and exclusion criteria. In the end, 106 patients were randomly assigned into 5 comparative groups: A (n = 23; magnetic therapy: 10 mT, 50 Hz); B (n = 23; magnetic therapy: 5 mT, 50 Hz); C (n = 20; placebo magnetic therapy); D (n = 20; magnetic stimulation: 49.2 MUT, 195 Hz); and E (n = 20; placebo magnetic stimulation). All patients were assessed using tests for pain intensity, degree of disability and range of motion. Also, postural stability was assessed using a stabilographic platform. RESULTS: In this study, positive changes in all clinical outcomes were demonstrated in group A (p < 0.05). The most effective clinical effect was observed for pain reduction (p < 0.05), improvement of the range of motion (p < 0.05) and functional ability of the spine (p <0.05). It is also worth noting that the effects in the majority of the measured indicators were mostly short-term (p > 0.05). CONCLUSIONS: It was determined that the application of magnetic therapy (10 mT, 50 Hz, 20 min) significantly reduces pain symptoms and leads to an improvement of functional ability in patients with LBP. PMID- 29616750 TI - Comparison of two models of inflammatory bowel disease in rats. AB - BACKGROUND: There is a need for experimental animal models for inflammatory bowel diseases (IBD), but no proposed model has been unanimously accepted. OBJECTIVES: The aim of this study was to develop 2 affordable models of IBD in rats and to compare them. MATERIAL AND METHODS: We produced IBD in rats using either dextran sodium sulfate (DSS) or 2, 4, 6-trinitrobenzene sulfonic acid (TNBS). The requirements for experimental models were: a predictable clinical course, histopathology and inflammation similar to human ulcerative colitis (UC) and Crohn's disease (CD). The effect of acute administration of DSS and TNBS on oxidative stress (as measured by the assessment of glutathione peroxidase - GPx) was verified. The activity of whole blood GPx was measured using a commercially available Randox kit (Crumlin, UK). RESULTS: The administration of DSS increased GPx activity compared to the control and TNBS-treated groups, but not to a statistically significant degree. Histological examination of the colonic mucosa following the administration of DSS showed multifocal erosions with minimal to mild inflammatory infiltrate, mainly by polymorphonuclear cells (PMN), lymphocytes and plasma cells. For TNBS-induced colitis, the histological changes manifested as multifocal areas of ulcerative colitis with mild to severe inflammatory infiltrate. Whole blood GPx values displayed a direct dependence on the chemical agent used. Our results show a correlation between histopathology, proinflammatory state and oxidative stress. CONCLUSIONS: The experimental DSSor TNBS-induced bowel inflammation used in this study corresponds to human IBD and is reproducible with characteristics indicative of acute inflammation in the case of the protocols mentioned. PMID- 29616751 TI - MiR-181a inhibits human trabecular meshwork cell apoptosis induced by H2O2 through the suppression of NF-kappaB and JNK pathways. AB - BACKGROUND: The trabecular meshwork (TM) plays a critical role in the outflow of aqueous humor. OBJECTIVES: In this study, we aimed to investigate the effect of miR-181a on H2O2-induced apoptosis in TM cells. MATERIAL AND METHODS: Human primary explant-derived TM cells were cultured in fibroblast medium and then treated with different concentrations of H2O2 for 2 h. We used a series of methods to carry out the research, such as MTT assay, quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR), apoptosis assay, and western blot methodology. RESULTS: The apoptosis assay and qRT-PCR showed that H2O2 induced apoptosis and cell viability were suppressed in a dose-dependent manner in TM cells. After the TM cells were treated with H2O2, miR-181a expression was significantly lower. The overexpression of miR-181a enhanced TM cells' viability, while the knockdown of miR-181a inhibited viability of cells. The overexpression of miR-181a suppressed TM cell apoptosis, while the knockdown of miR-181a induced apoptosis. H2O2 activated the nuclear factor-kappaB (NF-kappaB) and c-Jun N terminal kinase (JNK) pathways and induced cell apoptosis, while the overexpression of miR-181a suppressed both pathways and decreased the rate of apoptosis. CONCLUSIONS: In conclusion, this study indicated that miR-181a could improve the survival rate of TM cells after H2O2 treatment by blocking the NF kappaB and JNK signaling pathways. These findings might provide novel therapeutic opportunities in the treatment of glaucoma. PMID- 29616752 TI - Adrenal hemorrhage: A single center experience and literature review. AB - BACKGROUND: Adrenal hemorrhage (AH) is a rare condition that can lead to acute adrenal insufficiency and may be fatal. The risk factors of AH include focal adrenal lesion, abdominal trauma and anticoagulation therapy. The clinical manifestation of AH varies widely; the symptoms may be related to adrenal insufficiency or may reflect multiple organ failure. However, in many cases, the course of AH is asymptomatic. OBJECTIVES: The study is a retrospective analysis of 23 cases of AH, whose aim is to discuss the etiology and the management of selected patients, as well as a literature review. MATERIAL AND METHODS: The paper presents a retrospective analysis of 23 patients with AH confirmed by radiological and/or pathological examination. Epidemiological data, the results of laboratory tests, and radiological and pathological examinations were included in the analysis. RESULTS: The risk factors of AH were not established in 13 patients, 5 patients had experienced a trauma prior to AH diagnosis, 1 patient was diagnosed with sepsis, 2 patients had concomitant neoplastic disease, and in 2 patients, 2 risk factors were present. Among patients who required emergency admission, 5 patients were hospitalized due to acute abdominal pain, 1 patient due to sepsis and 1 patient due to symptoms of active endocrinopathy. In the remaining patients, diagnostic procedures were prompted by the detection of adrenal incidentaloma (AI). A total of 40% of patients underwent surgical treatment due to the magnitude of AH or clinical and laboratory evidence of overt endocrinopathy. In the remaining patients, conservative treatment and further observation was recommended. In 34.8% of these patients, follow-up examinations revealed a gradual regression. CONCLUSIONS: It seems that there is a need to distinguish patients with AH who do not require surgical intervention. Follow-up radiological examination is necessary to reassess the lesion. The patients in whom shrinkage of the tumor can be observed are likely not to require surgical treatment. PMID- 29616753 TI - Isobolographic additivity among lacosamide, lamotrigine and phenobarbital in a mouse tonic-clonic seizure model. AB - BACKGROUND: Epilepsy is a serious neurological disease affecting about 1% of people worldwide (65 million). Seizures are controllable with antiepileptic drugs (AEDs) in about 70% of epilepsy patients, however, there remains about 30% of patients inadequately medicated with these AEDs, who need a satisfactory control of their seizure attacks. For these patients, one of the treatment options is administration of 2 or 3 AEDs in combination. OBJECTIVES: To determine the anticonvulsant effects of a combination of 3 selected AEDs (i.e., lacosamide - LCM, lamotrigine - LTG and phenobarbital - PB) at the fixed-ratio of 1:1:1 in a mouse maximal electroshock-induced (tonic-clonic) seizure model by using isobolographic analysis. MATERIAL AND METHODS: Seizure activity was evoked in adult male albino Swiss mice by a current (sinewave, 25 mA, 500 V, 50 Hz, 0.2 s stimulus duration) delivered via auricular electrodes. Type I isobolographic analysis was used to detect interaction for the 3-drug combination. RESULTS: With type I isobolographic analysis, the combination of LCM, LTG and PB (at the fixed ratio of 1:1:1) exerted additive interaction in the mouse maximal electroshock induced (tonic-clonic) seizure model. CONCLUSIONS: The combination of LCM with LTG and PB produced additive interaction in the mouse tonicclonic seizure model, despite various molecular mechanisms of action of the tested AEDs. PMID- 29616754 TI - Venous insufficiency: Differences in the content of trace elements. A preliminary report. AB - BACKGROUND: Venous insufficiency is still a serious clinical problem. The exact cause and molecular mechanisms of this disease are still unknown. In this study, we try to identify whether there is a difference in the level of trace elements between healthy and pathological veins. Our results show that insufficient veins have different levels of some trace elements: magnesium, calcium, manganese, and silicon compared to control samples. This study could lead to a better understanding of the molecular causes of venous insufficiency and may help to develop better methods of treatment. OBJECTIVES: Nowadays, venous diseases are a very common clinical phenomenon. Venous insufficiency is thought to be one of the most common vein diseases. The exact mechanisms of its etiology are still unknown, although from a clinical point of view some risk factors include gender, age, changing hormone levels, heredity, and standing or sitting for long periods. An imbalance in trace elements could also play a crucial role in the development and/or progression of venous insufficiency. MATERIAL AND METHODS: The trace element content in varicose vein walls and in normal vein walls was measured using an inductively coupled plasma-optical emission spectrometer (ICP-OES) after sample mineralization. Statistical analysis (the Mann-Whitney U test and the Friedman ANOVA) was performed to compare insufficient veins to controls (healthy veins). RESULTS: This study found statistically significant higher magnesium (Mg) ion levels in varicose veins compared to controls (p = 0.0067) and differences close to statistical significance in calcium (Ca), manganese (Mn), and silicon (Si) ion levels. CONCLUSIONS: The results obtained could indicate oxidative stress occurring in chronic venous insufficiency as well as free radical neutralization pathways due to superoxide dismutase (SOD) activity with Mg, Mn and copper (Cu) ion involvement. Our results are consistent with literature data and are preliminary in nature. PMID- 29616755 TI - Anaesthesia and Sedation for the Autistic Patient. AB - Autism is a disability that affects how a person communicates andrelates to the world around them. Patients on the autisticspectrum may be referred to a Special Care Dentistry service to bemanaged under sedation or general anaesthetic, as their visit tothe dentist can be stressful and disruptive to their routine. As it is aspectrum disorder, each patient needs to be assessed individuallyin order to determine whether sedation or general anaestheticwould be appropriate for them. Some autistic patients may havegood verbal communication and mild learning difficulties, andmay be able to tolerate treatment under local anaesthetic withbehavioural management alone. On the other end of thespectrum, patients with severe autism and learning difficultiesmay not permit the dentist to even examine them and will requirea general anaesthetic. There will also be patients on the autisticspectrum who are suitable for conscious sedation depending ontheir level of learning difficulty and cooperation. Oral andtransmucosal sedation can also be useful for providing presedationto a patient to facilitate venous access. In order tominimise distress to the patient, it is important that adequatesedation, anaesthesia and analgesia are achieved both perioperativelyand post-operatively. PMID- 29616756 TI - The Clinical Management of the Gagging Patient. AB - A pronounced gag reflex can be a burden for patients and dentistsalike. It can limit the capability of a patient to undergo dentaltreatment and complicate the dentist's ability to providetreatment. Understanding the somatic and psychological basis ofan overactive gag reflex is key to providing treatment. The firsttechniques involved should be local measures to reduce anxiety.Further techniques can be used if this proves fruitless. Localanaesthetic, conscious sedation, acupuncture, hypnosis and TENSare techniques that have been suggested in the literature toovercome a pronounced gag reflex. This paper will explore theaetiology of the gag reflex and the many suggested approaches tothe management of a patient with a pronounced gag reflex.Understanding the causes and having a working knowledge of themanagement approaches will help dentists overcome gag reflexesin the treatment of these patients. PMID- 29616757 TI - The Role of General Anaesthesia in Special Care & Paediatric Dentistry; Inclusion Criteria and Clinical Indications. AB - Dental practitioners dealing with children and individuals withspecial needs can be supported by the provision of generalanaesthesia for the most challenging patients in situations whereother options are insufficient. The availability of generalanaesthesia will further the aim of extending access to the widestrange of dental care to the greatest number of patients regardlessof disability, age or phobia. The objective is to ensure patients havea pain-free and healthy mouth, and any necessary treatment in themost appropriate setting related to their specific needs. A strictlyindividual and holistic approach is required when evaluating therisk versus benefit of proceeding with general anaesthesia fordelivery of dental treatment particularly for children and specialneeds individuals. It is vitally important to consider and address allrelevant factors specific to this particular group of patientsincluding assessment of capacity, validity of consent, and anyspecific medical, social and behavioural issues. The other sedationmodalities must be always taken into consideration.This article emphasises the crucial decision-making role of dentistsin the referral process for dental treatment under generalanaesthesia and the need for multidisciplinary co-operationbetween dental practitioners, community and hospital services. PMID- 29616758 TI - Behaviour Management of Children Presenting in the Emergency Department with OMFS Problems. AB - Introduction: This paper is a summary of three case reports of patients treatedby Oral and Maxillofacial (OMFS) Dental Foundation Trainees(DF2s) at a busy London paediatric Accident and Emergency (A&E)department. Discussion: Behavioural management for paediatric patients is challenging.The authors discuss various non pharmacological behaviouralmanagement methods as stand-alone techniques or as an adjunctto drugs (sedation or anaesthesia). They highlight three caseswhere a dedicated Play-Specialist is employed to assist treatmentundertaken in an acute hospital setting. Here we discuss optionsavailable to clinicians for behaviour management as well as threecase scenarios detailing the use of Play-Specialists alongsideconventional pharmacological and non-pharmacologicalmethods. Conclusion: Through implementing appropriate behavioural managementmethods (with or without drugs), optimal patient care can beachieved. The benefit of having a specialist solely trained inengaging with children, with respect to their behaviouraltendencies, is demonstrated, highlighting their value in an acutesetting. PMID- 29616759 TI - How Memorial Hermann's Online Payments Are Boosting Patient Loyalty and Revenue. AB - The Houston-based health system has implemented new workflows and technology in 14 of its hospitals and across its care delivery network to make the payment process more patient-friendly and build consumer loyalty. PMID- 29616760 TI - Coding for Prolonged Office Visits. AB - If a provider spends longer than expected on a patient office visit, how can this time be captured and accounted for in payment? PMID- 29616761 TI - Investments in Patient Access Education Pay Strong Dividends. AB - Registration staff play a significant role in patient satisfaction and revenue cycle performance. PMID- 29616762 TI - Does Your Revenue Cycle Staff Measure Up? AB - Centura Health's metrics reflect staff work quality as well as overall revenue cycle performance. PMID- 29616763 TI - Cash flow disruptions can plague patient accounting system conversions. AB - Preparation is key to limiting revenue dips. PMID- 29616764 TI - Patient Loan Program Supports Expansion, Increases Staff Efficiency. AB - Novant Health's zero-interest loan program allows patients to add new healthcare service fees to existing balances. PMID- 29616765 TI - New Respiratory Failure Coding Affects Payments. AB - Differences between ICD-9 and ICD-10 don't appear significant until healthcare organizations drill down to the specifics. PMID- 29616766 TI - As Uninsured Rate Drops, Affordability Challenges Grow. AB - Hospitals are facing growing financial pressure from insured patient's affordability challenges, according to recent poll results. PMID- 29616767 TI - How Brookwood Baptist Health Survived a Vendor Switch and Maintained Strong Revenue. AB - Extensive testing and strong analytics helped one Alabama health system stay on top of collections when it converted to a new EHR. PMID- 29616768 TI - Managing CMS Overpayments. AB - Although CMS previously had general requirements for reporting and repaying overpayments, a new rule "puts statutory form and teeth behind it", says Thomas Flynn, Hackensack Meridian Health. PMID- 29616769 TI - Vetting Patient Accounts for Better Experiences and Financial Outcomes. AB - Trinitas Regional Medical Center generated more than $1 million by identifying missed billing opportunities. PMID- 29616770 TI - How St. Francis Hospital Increased Collection with Automated Patient Pricing. AB - Part of the hospital's strategy is to focus on small balances that make a big impact on the bottom line. PMID- 29616771 TI - Getting a Handle on Staff Turnover. AB - Keep staff turnover in the single digits for peak performance. PMID- 29616773 TI - Discharge Summaries and Clinical Coding: Wait or Risk? AB - The risk of denials and recovery audits climbs when coders finalize cases without discharge summaries. PMID- 29616772 TI - Using Analytics to Understand Denials-and Fix Problems. AB - Revenue cycle departments should be able to see how patient type, payers, and DRGs drive denial increases. PMID- 29616774 TI - Collaborating with Competitors to Provide Charity Care. AB - By using the same income threshold for charity care eligibility across health system partners, one system isn't being favored because of its generous charity care policy. PMID- 29616775 TI - Tearing Down the Walls of Revenue Cycle Silos. AB - Data evolution is forcing revenue cycle silos to crumble. And that's a good thing. PMID- 29616777 TI - Preparing for Premium Increases in the ACA Marketplace. AB - Hospitals and health systems can examine how exchange plan choices and premium trends will impact uncompensated care costs. PMID- 29616776 TI - Air Pollution and Glucose Metabolism: An Analysis in Non-Diabetic Participants of the Heinz Nixdorf Recall Study. AB - BACKGROUND: Despite the importance of understanding the connection between air pollution exposure and diabetes, studies investigating links between air pollution and glucose metabolism in nondiabetic adults are limited. OBJECTIVE: We aimed to estimate the association of medium-term air pollution exposures with blood glucose and glycated hemoglobin A1c (HbA1c) among nondiabetics. METHODS: This study included observations from nondiabetic participants (nobs=7,108) of the population-based Heinz Nixdorf Recall study at baseline (2000-2003) and follow-up examination (2006-2008). Daily fine particulate matter (aerodynamic diameter<=2.5 MUm, PM2.5; aerodynamic diameter<=10 MUm, PM10), accumulation mode particle number (PNAM), and nitrogen dioxide (NO2) exposures were estimated at participants' residences using the spatiotemporal European Air Pollution Dispersion (EURAD) chemistry transport model. We evaluated the associations between medium-term air pollution exposures (28- and 91-d means) and glucose metabolism measures using mixed linear regression and adjusting for season, meteorology, and personal characteristics. A range of other exposure windows (1-, 2-, 3-, 7-, 14-, 45-, 60-, 75-, 105-, 120-, and 182-d means) were also evaluated to identify potentially relevant biological windows. RESULTS: We observed positive associations between PM2.5 and PNAM exposures and blood glucose levels [e.g., 28-d PM2.5: 0.91 mg/dL (95% CI: 0.38, 1.44) per 5.7 MUg/m3]. PM2.5, PM10, and PNAM exposures were positively associated with HbA1c [e.g., 91-d PM2.5: 0.07 p.p. (95% CI: 0.04, 0.10) per 4.0 MUg/m3]. Mean exposures during longer exposure windows (75- to 105-d) were most strongly associated with HbA1c, whereas 7- to 45 d exposures were most strongly associated with blood glucose. NO2 exposure was not associated with blood glucose or with HbA1c. CONCLUSIONS: Medium-term PM and PNAM exposures were positively associated with glucose measures in nondiabetic adults. These findings indicate that reducing ambient air pollution levels may decrease the risk of diabetes. https://doi.org/10.1289/EHP2561. PMID- 29616778 TI - Actions to Take Now in Response to CMS's FY17 OPPS Final Rule. AB - Once change to the OPPS rule eliminates the L1 modifier for unrelated laboratory tests, which will now be packaged with other services. PMID- 29616779 TI - Personalizing the Payment Process Builds Patient Satisfaction. AB - Messages specific to balance due amounts allow hospitals to tailor wording and payment options based on high or low balances. PMID- 29616780 TI - New Hypertension Category Offers Specificity. AB - Physicians must indicate a diagnosis for hypertension as coders cannot code from vital sign data. PMID- 29616781 TI - Early View of Off-Campus Hospital Department Medicare Payments. AB - Although off-campus departments account for a small percentage of outpatient revenue, the number could be underreported. PMID- 29616782 TI - Registration Academy Improves Performance. AB - St. Joseph Health started its curriculum design by asking patient access leaders what a perfect training program would cover. PMID- 29616783 TI - Cultivating Homegrown Inpatient Auditors. AB - By training coders who already are on staff, hospitals leverage institutional knowledge and build career paths. PMID- 29616784 TI - Coding for Conscious Sedation. AB - Conscious sedation codes are based on time intervals and patient age. PMID- 29616785 TI - Inorganic Nano-Targeted Drugs Delivery System and Its Application of Platinum Based Anticancer Drugs. AB - As one of the most important anticancer drugs, cisplatin and its analogues have been widely used in chemotherapy regimens of various tumors. However, a series of side effects and resistance/cross-resistance have been becoming the main obstacles which limit their application and effectiveness. Recent researches suggest that inorganic nano-materials which act as targeted drug delivery carriers of platinum-based anticancer drugs not only enhance the antitumor activity of platinum-based drugs, but also reduce the side effects and resistance. The nano-targeted drugs delivery system provides a new strategy in clinical application of platinum-based anticancer drugs. This review will focus on recent advances in inorganic nano-carriers for platinum-based targeted drugs delivery system. PMID- 29616786 TI - Nanocrystals Technology for Improving Bioavailability of Poorly Soluble Drugs: A Mini-Review. AB - Nanocrystals technology for water insoluble drugs delivery has been expanding exponentially, as a robust approach, over the last ten years. Drug nanocrystals are sub-micron colloidal dispersion system of pure drug nanoparticles. Compared to the traditional pharmaceutical dosage forms, nano-crystals formulation presented many extraordinary properties such as enhanced dissolution rate and saturation solubility, high drug loading, excellent reproducibility of oral absorption, improved proportionality of dose-bioavailability, and increased patient compliance. This review explains the bioavailability improving mechanism in drug delivery to present the state-of-art nanocrystals. The physically stable nanocrystals with appropriate particle size and zeta potential could be prepared by screening of stabilizing agents. The marketed nanocrystal products and drug safety issues about the technology are also discussed. Moreover, the perspectives and challenges about improving nanocrystals investigated in this review could provide guidance for further study. Thus, this article could serve as a reference for optimizing the bioavailability of a specific drug candidate. PMID- 29616787 TI - Nano-Ionic Solid State Resistive Memories (Re-RAM): A Review. AB - Nano-ionic devices based on modest to fast ion conductors as active materials intrigued a revolution in the field of nano solid state resistive memories (the so-called Re-RAM) ever since HP labs unveiled the first solid state memristor device based on titanium dioxide (TiO2). This has brought impetus to the practical implementation of fourth missing element called "Memristor" correlating charge (q) and flux (phi) based on the conceptual thought by Chua in 1971 completing a missing gap between the passive electronic components (R, C and L). It depicts various functional features as memory element in terms of ionic charge transport in solid state by virtue of external electric flux variations. Consequently, a new avenue has been found by manipulating the ionic charge carriers creating a fast switching resistive random access memory (Re-RAM) or the so-called Memristors. The recent research has led to low power, faster switching speed, high endurance and high retention time devices that can be scaled down the order of few nanometers dimension and the 3D stacking is employed that significantly reduces the die area. This review is organized to provide the progress hitherto accomplished in the materials arena to make memristor devices with respect to current research attempts, different stack structures of ReRAM cells using various materials as well as the application of memristive system. Different synthesis approaches to make nano-ionic conducting metal oxides, the fabrication methods for ReRAM cells and its memory performance are reviewed comprehensively. PMID- 29616788 TI - Cationic Organochalcogen with Monomer/Excimer Emissions for Dual-Color Live Cell Imaging and Cell Damage Diagnosis. AB - Studies on the development of fluorescent organic molecules with different emission colors for imaging of organelles and their biomedical application are gaining lots of focus recently. Here, we report two cationic organochalcogens 1 and 2, both of which exhibit very weak green emission (Phi1 = 0.12%; Phi2 = 0.09%) in dilute solution as monomers, but remarkably enhanced green emission upon interaction with nucleic acids and large red-shifted emission in aggregate state by the formation of excimers at high concentration. More interestingly, the monomer emission and excimer-like emission can be used for dual color imaging of different organelles. Upon passively diffusing into cells, both probes selectively stain nucleoli with strong green emission upon 488 nm excitation, whereas upon 405 nm excitation, a completely different stain pattern by staining lysosomes (for 1) or mitochondria (for 2) with distinct red emission is observed because of the highly concentrated accumulation in these organelles. Studies on the mechanism of the accumulation in lysosomes (for 1) or mitochondria (for 2) found that the accumulations of the probes are dependent on the membrane permeabilization, which make the probes have great potential in diagnosing cell damage by sensing lysosomal or mitochondrial membrane permeabilization. The study is demonstrative, for the first time, of two cationic molecules for dual-color imaging nucleoli and lysosomes (1)/mitochondria (2) simultaneously in live cell based on monomer and excimer-like emission, respectively, and more importantly, for diagnosing cell damage. PMID- 29616789 TI - ZnO Nanorod Array Modified PVDF Membrane with Superhydrophobic Surface for Vacuum Membrane Distillation Application. AB - The vacuum membrane distillation (VMD) is a promising technology for lots of applications. To solve the membrane fouling and wetting problems, in this paper, a novel ZnO nanorods 1 H,1 H,2 H,2 H-perfluorodecyltriethoxysilane (PDTS) modified poly(vinylidene fluoride) (PVDF) membrane with a micro/nanoscale hierarchical structure and a superhydrophobic surface has been prepared and applied to the VMD process for distilling highly salty water, for the first time. Among these, a pyrolysis-adhesion method is created to obtain the ZnO seeds and fasten them on the PVDF substrate firmly. The novel modified membrane shows a stable superhydrophobic surface with a water contact angle of 152 degrees , easy cleaning property, excellent thermal and mechanical stability, because of the Cassie's state caused by pocketing much air in the hydrophobized ZnO nanorods, the low surface energy of PDTS coating, and the strong adhesion between ZnO nanorods and PVDF membrane, which has built an ideal structure for VMD application. After 8 h VMD of 200 g L-1 NaCl solution, compared to the virgin PVDF membrane, the novel membrane shows a similar permeate flux but a much higher quality permeated liquid because of its unique antifouling and antiwetting caused by the several microns gap between the feed and the membrane. Due to its easy cleaning property, the novel membrane also exhibits an excellent reusability. PMID- 29616790 TI - Novel Tadalafil Derivatives Ameliorates Scopolamine-Induced Cognitive Impairment in Mice via Inhibition of Acetylcholinesterase (AChE) and Phosphodiesterase 5 (PDE5). AB - On the basis of the drug-repositioning and redeveloping strategy, first generation dual-target inhibitors of acetylcholinesterase (AChE) and phosphodiesterase 5 (PDE5) have been recently reported as a potentially novel therapeutic method for the treatment of Alzheimer's disease (AD), and the lead compound 2 has proven this method was feasible in AD mouse models. In this study, our work focused on exploring alternative novel tadalafil derivatives (3a-s). Among the 19 analogues, compound 3c exhibited good selective dual-target AChE/PDE5 inhibition and good blood-brain barrier (BBB) permeability. Moreover, its citrate (3c.Cit) possessed improved water solubility and good effects against scopolamine-induced cognitive impairment with inhibition of cortical AChE activities and enhancement of cAMP response element-binding protein (CREB) phosphorylation ex vivo. PMID- 29616791 TI - On the Stability of NaO2 in Na-O2 Batteries. AB - Na-O2 batteries are regarded as promising candidates for energy storage. They have higher energy efficiency, rate capability, and chemical reversibility than Li-O2 batteries; in addition, sodium is cheaper and more abundant compared to lithium. However, inconsistent observations and instability of discharge products have inhibited the understanding of the working mechanism of this technology. In this work, we have investigated a number of factors that influence the stability of the discharge products. By means of in operando powder X-ray diffraction study, the influence of oxygen, sodium anode, salt, solvent, and carbon cathode were investigated. The Na metal anode and an ether-based solvent are the main factors that lead to the instability and decomposition of NaO2 in the cell environment. This fundamental insight brings new information on the working mechanism of Na-O2 batteries. PMID- 29616792 TI - Facile and Scalable Flow-Induced Deposition of Organosilica on Porous Polymer Supports for Reverse Osmosis Desalination. AB - The fabrication of a continuous and uniform organosilica membrane on a porous polymer substrate was achieved via a facile and technologically scalable flow induced deposition (FD) approach. The uniformity of the thickness of an organosilica separation layer on a polymer surface with a large area was improved significantly via this two-step FD approach. Meanwhile, the optimal concentration of the organosilica used in membrane preparation was also investigated. This polymer-supported organosilica layered-hybrid membrane showed a high level of NaCl rejection (97.5-99%) in the reverse osmosis desalination of a 2000 ppm NaCl solution at an operating pressure of 3 MPa. This membrane also exhibited good stability and flexibility when rolled into a curvature radius of 11 mm. PMID- 29616793 TI - Co3O4/MnO2/Hierarchically Porous Carbon as Superior Bifunctional Electrodes for Liquid and All-Solid-State Rechargeable Zinc-Air Batteries. AB - The design of efficient, durable, and affordable catalysts for oxygen reduction reaction (ORR) and oxygen evolution reaction (OER) is very indispensable in liquid-type and flexible all-solid-state zinc-air batteries. Herein, we present a high-performance bifunctional catalyst with cobalt and manganese oxides supported on porous carbon (Co3O4/MnO2/PQ-7). The optimized Co3O4/MnO2/PQ-7 exhibited a comparable ORR performance with commercial Pt/C and a more superior OER performance than all of the other prepared catalysts, including commercial Pt/C. When applied to practical aqueous (6.0 M KOH) zinc-air batteries, the Co3O4/MnO2/porous carbon hybrid catalysts exhibited exceptional performance, such as a maximum discharge peak power density as high as 257 mW cm-2 and the most stable charge-discharge durability over 50 h with negligible deactivation to date. More importantly, a series of flexible all-solid-state zinc-air batteries can be fabricated by the Co3O4/MnO2/porous carbon with a layer-by-layer method. The optimal catalyst (Co3O4/MnO2/PQ-7) exhibited an excellent peak power density of 45 mW cm-2. The discharge potentials almost remained unchanged for 6 h at 5 mA cm-2 and possessed a long cycle life (2.5 h@5 mA cm-2). These results make the optimized Co3O4/MnO2/PQ-7 a promising cathode candidate for both liquid-type and flexible all-solid-state zinc-air batteries. PMID- 29616794 TI - Controllable Synthesis of Ni xSe (0.5 <= x <= 1) Nanocrystals for Efficient Rechargeable Zinc-Air Batteries and Water Splitting. AB - The development of earth-abundant, highly active, and corrosion-resistant electrocatalysts to promote the oxygen reduction reaction (ORR) and oxygen and hydrogen evolution reactions (OER/HER) for rechargeable metal-air batteries and water-splitting devices is urgently needed. In this work, Ni xSe (0.5 <= x <= 1) nanocrystals with different crystal structures and compositions have been controllably synthesized and investigated as potential electrocatalysts for multifunctional ORR, OER, and HER in alkaline conditions. A novel hot-injection process at ambient pressure was developed to control the phase and composition of a series of Ni xSe by simply adjusting the added molar ratio of the nickel resource to triethylenetetramine. Electrochemical analysis reveals that Ni0.5Se nanocrystalline exhibits superior OER activity compared to its counterparts and is comparable to RuO2 in terms of the low overpotential required to reach a current density of 10 mA cm-2 (330 mV), which may benefit from the pyrite-type crystal structure and Se enrichment in Ni0.5Se. For the ORR and HER, Ni0.75Se nanoparticles achieve the best performance including lower overpotentials and larger apparent current densities. Further investigations demonstrate that Ni0.75Se could not only provide an enhanced electrochemical active area but also facilitate electron transfer during the electrocatalytic process, thus contributing to the remarkable catalytic activity. As a practical application, the Ni0.75Se electrode enables rechargeable Zn-air battery with a considerable performance including a long cycling lifetime (200 cycles), high specific capacity (609 mA h g-1 based on the consumed Zn), and low overpotential (0.75 V) at 10 mA cm-2. Meanwhile, the water-splitting cell setup with an anode of Ni0.5Se for the HER and a cathode of Ni0.75Se for the OER exhibits a considerable performance with low decay in activity of 12.9% under continuous polarization for 10 h. These results suggest the promising potential of nickel selenide nanocrystals as earth-abundant and high-performance electrocatalysts for metal air batteries and alkaline water splitting. PMID- 29616795 TI - Three-Dimensional Hierarchical MoS2 Nanosheets/Ultralong N-Doped Carbon Nanotubes as High-Performance Electromagnetic Wave Absorbing Material. AB - Here, we report a simple method to grow thin MoS2 nanosheets (NSs) on the ultralong nitrogen-doped carbon nanotubes through anion-exchange reaction. The MoS2 NSs are grown on ultralong nitrogen-doped carbon nanotube surfaces, leading to an interesting three-dimensional hierarchical structure. The fabricated hybrid nanotubes have a length of approximately 100 MUm, where the MoS2 nanosheets have a thickness of less than 7.5 nm. The hybrid nanotubes show excellent electromagnetic wave attenuation performance, with the effective absorption bandwidth of 5.4 GHz at the thicknesses of 2.5 mm, superior to the pure MoS2 nanosheets and the MoS2 nanosheets grown on the short N-doped carbon nanotube surfaces. The experimental results indicate that the direct growth of MoS2 on the ultralong nitrogen-doped carbon nanotube surfaces is a key factor for the enhanced electromagnetic wave attenuation property. The results open the avenue for the development of ultralong transition metal dichalcogenides for electromagnetic wave absorbers. PMID- 29616796 TI - Synergetic Effects of Multifunctional Composites with More Efficient Polysulfide Immobilization and Ultrahigh Sulfur Content in Lithium-Sulfur Batteries. AB - A high sulfur loading cathode is the most crucial component for lithium-sulfur batteries (LSBs) to obtain considerable energy density for commercialization applications. The major challenges associated with high sulfur loading electrodes are poor material utilization caused via the nonconductivity of the charged product (S) and the discharged product (Li2S), poor stability arisen from dissolution of lithium polysulfides (LiPSs) into most organic electrolytes and pulverization, and structural damage of the electrode caused by large volumetric expansion. A multifunctional synergistic composite enables ultrahigh sulfur content for advanced LSBs, which comprises the sulfur particle encapsulated with an ion-selective polymer with conductive carbon nanotubes and dispersed around Magneli phase Ti4O7 (MS-3) by the bottom-up method. The ion-selective polymer provides a physical shield and electrostatic repulsion against the shuttling of polysulfides with negative charge, whereas it can permit the transmission of lithium ion (Li+) through the polymer membrane, and the carbon nanotubes twined around the sulfur promote electronic conductivity and sulfur utilization as well as strong chemical adsorption of LiPSs by means of Ti4O7. Because of this hierarchical construction, the cathode possesses a lofty final sulfur loading of 72% and large sulfur areal mass loading of 3.56 mg cm-2, which displays the large areal specific capacity of 4.22 mA h cm-2. In the same time, it can provide excellent cyclic performance with the corresponding capacity attenuation ratio of 0.08% per cycle at 0.5 C after 300 cycles. Especially, while sulfur areal mass loading is sharply enhanced to 5.11 mg cm-2, the MS-3 composite exhibits a large initial areal capacity of 5.04 mA h cm-2 and still keeps a high reversible capacity of 696 mA h g-1 at 300th cycle even at a 1.0 C. The design of high sulfur content cathodes is a viable approach for boosting practical commercialized application of LSBs. PMID- 29616797 TI - Facile Amplification of Solution-State Surface-Enhanced Raman Scattering of Small Molecules Using Spontaneously Formed 3D Nanoplasmonic Wells. AB - Surface-enhanced Raman scattering (SERS) has recently been considered as one of the most promising tools to directly analyze small molecules without labels, owing to advantages in sensitivity, specificity, and speed. However, collecting reproducible SERS signals from small molecules on substrates or in solutions is challenging because of random molecular adsorption on surfaces and laser-induced molecular convection in solutions. Herein, we report a novel and efficient way to collect SERS signals from solution samples using three-dimensional nanoplasmonic wells spontaneously formed by interfacial reactions between liquid polydimethylsiloxane (PDMS) and small droplets of metal ion solutions (e.g., HAuCl4 and AgNO3). A SERS signal is easily maximized at the center near the bottom of the well due to spherical feature of the fabricated wells and electromagnetic field enhancement by the metallic nanoparticles (e.g., Au and Ag) integrated on their surfaces. Through the systematic control over the volume, concentration, and composition of the metal ion solution, optical functions of the nanoplasmonic wells were optimized for SERS, which was further amplified by exploiting the plasmonic couplings with colloidal nanoparticles. By using the optimized nanoplasmonic wells and the detection protocol, we successfully obtained intrinsic spectra of biomolecules (e.g., adenine, glucose, amyloid beta) and toxic environmental molecules (e.g., 1,1'-diethyl-2,2'-cyanine iodide and chloromethyliothiazolinone/methylisothiazolinone) as well as Raman active molecules, such as rhodamine 6G and 1,2-bis(4-pyridyl)ethylene at a low concentrations down to the picomolar level. Our detection platform provides a powerful way to develop highly sensitive sensors and high-throughput analyzing protocols for fieldwork applications as well as diagnosing diseases. PMID- 29616798 TI - Polyelectrolyte Binder for Sulfur Cathode To Improve the Cycle Performance and Discharge Property of Lithium-Sulfur Battery. AB - To achieve the higher capacity and the better cycle performance of the lithium sulfur (L-S) batteries, a copolymer electrolyte prepared via emulsifier-free emulsion polymerization was used as the binder for the sulfur cathode in this study. This polyelectrolyte binder has uniform dispersion and good Li+ conductivity in the cathode that can improve the kinetics of sulfur electrochemical reactions. As a result, the capacity and cycle performance of the battery are improved evidently when the cell is discharged to 1.8 V. Moreover, when the cell is discharged to 1.5 V, the difficult deposition of Li2S2 will take place easily at 1.75 V, and the difficult transformation from solid Li2S2 to solid Li2S will progress smoothly and completely during the voltage range of 1.55 1.75 V, too. The capacity of this L-S battery discharged to 1.5 V is as much as 1700 mAh g-1, which is very close to the theoretical value of sulfur cathode. The knowledge acquired in this study is valuable not only for the design of an efficient new polyelectrolyte binder for sulfur cathode but also the discovery that the discharge degree is the main fact that limits the capacity to reach its theoretical value. PMID- 29616799 TI - Investigation of the Na Storage Property of One-Dimensional Cu2- xSe Nanorods. AB - In this study, one-dimensional Cu2- xSe nanorods synthesized by a simple water evaporation-induced self-assembly approach are served as the anode material for Na-ion batteries for the first time. Cu2- xSe electrodes express outstanding electrochemical properties. The initial discharge capacity is 149.3 mA h g-1 at a current density of 100 mA g-1, and the discharge capacity can remain at 106.2 mA h g-1 after 400 cycles. Even at a high current density of 2000 mA g-1, the discharge capacity of the Cu2- xSe electrode still remains at 62.8 mA h g-1, showing excellent rate performance. Owing to the excellent electronic conductivity and one-dimensional structure of Cu2- xSe, the Cu2- xSe electrodes manifest fast Na+ ion diffusion rate. Moreover, detailed Na+ insertion/extraction mechanism is further investigated by ex situ measurements and theoretical calculations. PMID- 29616800 TI - First-Principles Study of Lithium Cobalt Spinel Oxides: Correlating Structure and Electrochemistry. AB - Embedding a lithiated cobalt oxide spinel (Li2Co2O4, or LiCoO2) component or a nickel-substituted LiCo1- xNi xO2 analogue in structurally integrated cathodes such as xLi2MnO3.(1- x)LiM'O2 (M' = Ni/Co/Mn) has been recently proposed as an approach to advance the performance of lithium-ion batteries. Here, we first revisit the phase stability and electrochemical performance of LiCoO2 synthesized at different temperatures using density functional theory calculations. Consistent with previous studies, we find that the occurrence of low- and high temperature structures (i.e., cubic lithiated spinel LT-LiCoO2; or Li2Co2O4 ( Fd3 m) vs trigonal-layered HT-LiCoO2 ( R3 m), respectively) can be explained by a small difference in the free energy between these two compounds. Additionally, the observed voltage profile of a Li/LiCoO2 cell for both cubic and trigonal phases of LiCoO2, as well as the migration barrier for lithium diffusion from an octahedral (Oh) site to a tetrahedral site (Td) in Fd3 m LT-Li1- xCoO2, has been calculated to help understand the complex electrochemical charge/discharge processes. A search of LiCo xM1- xO2 lithiated spinel (M = Ni or Mn) structures and compositions is conducted to extend the exploration of the chemical space of Li-Co-Mn-Ni-O electrode materials. We predict a new lithiated spinel material, LiNi0.8125Co0.1875O2 ( Fd3 m), with a composition close to that of commercial, layered LiNi0.8Co0.15Al0.05O2, which may have the potential for exploitation in structurally integrated, layered spinel cathodes for next-generation lithium-ion batteries. PMID- 29616801 TI - Comparison of Protein Hydrolysis Catalyzed by Bovine, Porcine, and Human Trypsins. AB - Based on trypsin specificity (for lysines and arginines), trypsins from different sources are expected to hydrolyze a given protein to the same theoretical maximum degree of hydrolysis (DHmax,theo). This is in contrast with experiments. Using alpha-lactalbumin and beta-casein, this study aims to reveal if the differences among experimental DHmax (DHmax,exp) by bovine, porcine, and human trypsins are due to their secondary specificity. Peptide analysis showed that ~78% of all the cleavage sites were efficiently hydrolyzed by porcine trypsin, and ~47 and ~53% were efficiently hydrolyzed by bovine and human trypsins, respectively. These differences were explained by the enzyme secondary specificity, that is, their sensitivities to the amino acids around the cleavage sites. The DHmax predictions based on the secondary specificity were 4 times closer to the DHmax,exp than the predictions based on trypsin specificity alone (DHmax,theo). Proposed preliminary relations between binding sites and trypsin secondary specificity allow DHmax,exp estimations of tryptic hydrolysis of other proteins. PMID- 29616802 TI - Semirigid Tripodal Ligand Based Uranyl Coordination Polymer Isomers Featuring 2D Honeycomb Nets. AB - We report five novel uranyl coordination polymers, [(CH3)2NH2]UO2(BTPCA) (1), [(CH3)2NH2]UO2(BTPCA) (2), [(CH3)2NH2]2[UO2(BTPCA)][UO2(BTPCA)].(H2O)5.5 (3), [(CH3)2NH2]2(UO2)2(BTPCA)2.(H2O)3 (4), and [(CH3)2NH2]UO2(BTPCA) (5), by the utilization of semirigid ligand 1,1',1"-(benzene-1,3,5-triyl)tripiperidine-4 carboxylic acid (H3BTPCA) and uranyl nitrate through solvothermal reactions. Single-crystal X-ray diffraction analysis reveals that the five compounds share a similar structure composition and local coordination mode to the exclusion of disordered water or DMF molecules. Each UO2(COO)3- motif is connected to six neighboring units through three BTPCA3- ligands, generating an infinite uranyl honeycomb (6, 3) net. The structures of all the five compounds consist of 2D honeycomb nets of various degrees of distortions, which are induced by the flexibility of piperidine rings. The dimethylamine cations and solvent molecules fill in the space between layers. Therefore, these five compounds are isomers in a broad sense. Notably, both compounds 3 and 4 possess 2-fold interpenetrated structures. For compound 5, the distance between the neighboring 2D honeycomb nets is 7.253 A. This is the largest distance between the 2D honeycomb nets in uranyl-based coordination polymers, to the best of our knowledge. In addition, compounds 1, 2, and 4 are also characterized by infrared spectroscopy (IR), thermogravimetric analysis (TG), powder X-ray diffraction (PXRD), and luminescence properties. PMID- 29616803 TI - Unmasking the Mechanism of Structural Para- to Ferroelectric Phase Transition in (NH4)2SO4. AB - New nontoxic and biocompatible ferroelectric materials are a subject undergoing intense study. One of the most promising research branches is focused on H-bonded organic or hybrid ferroelectrics. The engineering of these materials is based on mimicking the phase transition mechanisms of the well-known inorganic ferroelectrics. In our study, a coupled experimental and theoretical methodology was used for a precise investigation of the ferroelectric phase transition mechanism in ammonium sulfate (AS). A series of single-crystal X-ray diffraction measurements were performed in the temperature range between 273 and 163 K. The detailed inspection of the obtained static structural data, in the above mentioned temperature range, allowed us to reveal dynamical effects at the ferroelectric phase transition. Accurate analysis of all geometrical features within the obtained crystal structures was carried out. The results were discussed in the view of previously discovered physical properties. X-ray studies were complemented by the use of quantum theory of atoms in molecules calculations and Hirshfeld surface analysis. Valence shell charge concentration analysis allowed us to find the subtle changes between charge density distribution within SO42- in para- and ferroelectric phases. H-bond interactions, geometrically classified in both AS phases, were all confirmed by the appropriate critical points. The interaction energies were estimated for the structures at 273, 233, 213, 183, and 163 K. Correlation between the geometrical approach and the results of theoretical calculations enabled us to discover the differences in interaction equilibrium between the AS phases. The mechanism of the phase transition originates from the disruption of the vibrational lattice mode between sulfate anions. Our studies resolved the problem, which was under discussion for more than 60 years. PMID- 29616804 TI - Molecular Machine Powered Surface Programmatic Chain Reaction for Highly Sensitive Electrochemical Detection of Protein. AB - A bipedal molecular machine powered surface programmatic chain reaction was designed for electrochemical signal amplification and highly sensitive electrochemical detection of protein. The bipedal molecular machine was built through aptamer-target specific recognition for the binding of one target protein with two DNA probes, which hybridized with surface-tethered hairpin DNA 1 (H1) via proximity effect to expose the prelocked toehold domain of H1 for the hybridization of ferrocene-labeled hairpin DNA 2 (H2-Fc). The toehold-mediated strand displacement reaction brought the electrochemical signal molecule Fc close to the electrode and meanwhile released the bipedal molecular machine to traverse the sensing surface by the surface programmatic chain reaction. Eventually, a large number of duplex structures of H1-H2 with ferrocene groups facing to the electrode were formed on the sensor surface to generate an amplified electrochemical signal. Using thrombin as a model target, this method showed a linear detection range from 2 pM to 20 nM with a detection limit of 0.76 pM. The proposed detection strategy was enzyme-free and allowed highly sensitive and selective detection of a variety of protein targets by using corresponding DNA based affinity probes, showing potential application in bioanalysis. PMID- 29616805 TI - Reduction of Werner Syndrome Protein Enhances G:C -> A:T Transition by O6 Methylguanine in Human Cells. AB - O6-Methylguanine ( O6-MeG) is a damaged base produced by methylating reagents. The Werner syndrome protein (WRN) is a cancer-related human DNA helicase. The effects of WRN reduction on O6-MeG-caused mutagenesis were assessed by an siRNA mediated knockdown in human U2OS cells, using a shuttle plasmid with a single O6 MeG base in the supF gene. The plasmid DNA was replicated in the cells, isolated, and electroporated into an Escherichia coli indicator strain. The lowered amount of WRN increased the frequency of mutations induced by O6-MeG, mainly G:C -> A:T substitution. The increased mutation rate suggested that the cancer-related WRN suppresses the G:C -> A:T substitution by O6-MeG in human cells. PMID- 29616806 TI - Dynamic Covalent Metathesis in the C?C/C?N Exchange between Knoevenagel Compounds and Imines. AB - Fast and reversible dynamic covalent C?C/C?N exchange takes place without catalyst in nonpolar solvents between barbiturate-derived Knoevenagel (Kn) compounds and imines. A detailed study of the reaction indicates that it proceeds by an associative organo-metathesis mechanism involving the formation of a four membered ring azetidine intermediate by addition of the imine C?N group to the C?C bond of the Kn compound. This intermediate could be generated cleanly and stabilized at low temperature by condensation of the o,p-dinitrophenyl Kn derivative with the cyclic imine 1-azacyclohexene. It was characterized by extensive NMR and mass spectrometric studies. The process described represents a genuine dynamic covalent organo-metathesis through a four-membered ring adduct as intermediate. It paves the way for the exploration of a wide set of dynamic systems involving (strongly) polarized C?C bonds and various imines, extending also into covalent dynamic polymers and polymolecular assemblies. PMID- 29616807 TI - Electronic Structure and Reactivity of One-Electron-Oxidized Copper(II) Bis(phenolate)-Dipyrrin Complexes. AB - The sterically hindered bis(phenol)-dipyrrin ligands HLH3 and PhLH3 were reacted with 1 equiv of copper(II) under ambient conditions to produce the copper radical complexes [Cu(HL)] and [Cu(PhL)]. Their X-ray crystal structures show relatively short C-O bond distances (mean bond distances of 1.287 and 1.291 A), reminiscent of mixed pyrrolyl-phenoxyl radical species. Complexes [Cu(HL)] and [Cu(PhL)] exhibit rich electronic spectra, with an intense near-IR (NIR) band (epsilon > 6 mM-1 cm-1) at 1346 and 1321 nm, respectively, assigned to a ligand-to-ligand charger-transfer transition. Both show a reversible oxidation wave ( E1/21,ox = 0.05 and 0.04 V), as well as a reversible reduction wave ( E1/21,red = -0.40 and 0.56 V versus ferrocenium/ferrocene, respectively). The cations ([Cu(HL)]+ and [Cu(PhL)]+) and anions ([Cu(HL)]- and [Cu(PhL)]-) were generated. They all display an axial ( S = 1/2) signal with a copper hyperfine structure in their electron paramagnetic resonance spectra, consistent with ligand-centered redox processes in both reduction and oxidation. Complex [Cu(HL)](SbF6) was cocrystallized with [Cu(HL)]. Oxidation is accompanied by a slight contraction of both the C-O bonds (mean bond distance of 1.280 A) and the C-C bonds connecting the peripheral rings to the dipyrrin. The cations show vis-NIR bands of up to 1090 nm due to their quinoidal nature. The anions do not show a significant band above 700 nm, in agreement with their bis(phenolate)-dipyrrin character. The radical complexes efficiently catalyze the aerobic oxidation of benzyl alcohol, 1 phenylethanol, and unactivated 2-phenylethanol in basic conditions. PMID- 29616808 TI - Ru(II)-Catalyzed C-H Aminocarbonylation of N-(Hetero)aryl-7-azaindoles with Isocyanates. AB - The ruthenium(II)-catalyzed C-H aminocarbonylation of N-(hetero)aryl-7-azaindoles with isocyanates is described. The excellent site selectivity at the ortho position within the N-(hetero)aryl ring was observed to provide ortho-amidated N (hetero)aryl-7-azaindoles under the mild reaction conditions. The resulting 7 azaindole derivatives can be readily transformed into 7-azaindoles containing carboxylic acid and alkyl amine functional groups. PMID- 29616809 TI - beta-Lactam Biotransformations Activate Innate Immunity. AB - Antibiotics are widely prescribed to treat bacterial infections, but many of these drugs also affect patient immune responses. While the molecular mechanisms regulating these diverse immunomodulatory interactions are largely unknown, recent studies support two primary models: (1) antibiotics can alter immune function by directly interacting with human targets; and/or (2) antibiotics can indirectly affect immune responses via alteration of the human microbiota composition. Here, we describe results that could support a third model in which a nonimmunostimulatory antibiotic can be biotransformed by human microbiota members into an immunostimulatory product that lacks antibacterial activity. Specifically, we identified, characterized, and semisynthesized new biotransformation products derived from the beta-lactams amoxicillin and ampicillin, antibiotics regularly prescribed in the clinic. The drug metabolism products were identified in bacterial cultures harboring beta-lactamase, a common resistance determinant. One of the amoxicillin biotransformation products activated innate immunity, as assessed by NF-kappaB signaling in human leukemic monocytes, whereas amoxicillin itself exhibited no effect. Amoxicillin has previously been shown to have minimal long-term impact on human microbiota composition in clinical trial studies. Taken together, our results could support a broader immunomodulatory mechanism whereby antibiotics could indirectly regulate immune function in a stable, microbiome-dependent manner. PMID- 29616810 TI - P-Stereogenic and Non-P-Stereogenic Ir-MaxPHOX in the Asymmetric Hydrogenation of N-Aryl Imines. Isolation and X-ray Analysis of Imine Iridacycles. AB - A small library of Ir-MaxPHOX catalysts has been applied to the asymmetric hydrogenation of N-aryl imines. A structure-activity analysis of the three-chiral center MaxPHOX ligand has been performed. Using complex 1b, the hydrogenation of N-aryl imines took place with up to 96% enantiomeric excess at atmospheric pressure of hydrogen and low temperature. The impact of the stereochemical information at the phosphorus center is small with respect to the selectivity, but large with respect the catalyst activity. Non-P-stereogenic analogs of MaxPHOX were also synthesized and tested, but they provided lower selectivity. The selectivity observed could be explained by taking into account that the actual catalysts were cyclometalated imine complexes formed in situ. [IrHCl(MaxPHOX)(imine)] complexes 9 and 10 were synthesized and characterized by X-ray crystallography. These complexes, via chloride abstraction, provided the active catalytic species with the same levels of selectivity. Finally, the influence of the counterion on the catalyst performance was also studied. PMID- 29616811 TI - Triazine-Based Cationic Leaving Group: Synergistic Driving Forces for Rapid Formation of Carbocation Species. AB - A new triazine-based cationic leaving group has been developed for the acid catalyzed alkylation of O- and C-nucleophiles. There are two synergistic driving forces, namely, stable C?O bond formation and charge-charge repulsive effects, involved in the rapid generation of the carbocation species in the presence of trifluoromethanesulfonic acid (~200 mol %). Considerable rate acceleration of benzylation, allylation, and p-nitrobenzylation was observed as compared to the reactions with less than 100 mol % of the acid catalyst. The triazine-based leaving group showed superior p-nitrobenzylation yield and stability in comparison to common leaving groups, trichloroacetimidate and bromide. A plausible reaction mechanism (the cationic leaving group pathway) was proposed on the basis of mechanistic and kinetic studies, NMR experiments, and calculations. PMID- 29616812 TI - Bioactive alpha-Pyrone Derivatives from the Endolichenic Fungus Dothideomycetes sp. EL003334. AB - Two new alpha-pyrones, dothideopyrones E (1) and F (2), were isolated from a culture of the endolichenic fungus Dothideomycetes sp. EL003334. Their structures were elucidated by spectroscopic data analysis. Their absolute configurations were established by the modified Mosher's method. Compound 2 inhibited nitric oxide (NO) production with IC50 values of 15.0 +/- 2.8 MUM in lipopolysaccharide (LPS)-induced BV2 cells. Compound 2 diminished the protein expression levels of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Additionally, 2 decreased the mRNA expression levels of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha), interleukin (IL) 1beta, and IL-6. PMID- 29616813 TI - Conjugation of Specifically Developed Antibodies for High- and Low-Molecular Weight Glutenins with Fluorescent Quantum Dots as a Tool for Their Detection in Wheat Flour Dough. AB - The importance of gluten proteins, gliadins and glutenins, is well-known in the quality of wheat products. To gain more specific information about the role of glutenins in wheat dough, the two major subunits of glutenin, high- and low molecular-weight (HMW and LMW) glutenins, were extracted, isolated, and identified by mass spectrometry. Antibodies for HMW and LMW glutenins were developed using the proteomic information on the characterized glutenin subunits. The antibodies were found to be specific to each subunit by western immunoblots and were then conjugated to quantum dots (QDs) using site-click conjugation, a new method to keep antibody integrity. A fluorescence-link immunosorbent assay tested the successful QD conjugation. The QD-conjugated antibodies were applied to dough samples, where they recognized glutenin subunits and were visualized using a confocal laser scanning microscope. PMID- 29616814 TI - Isolation of Imaqobactin, an Amphiphilic Siderophore from the Arctic Marine Bacterium Variovorax Species RKJM285. AB - The amphiphilic siderophore imaqobactin was isolated from the Arctic bacterium Variovorax sp. RKJM285, a strain isolated from marine sediment collected from an inlet near Clyde River, Nunavut, Canada. The 2D structure of imaqobactin was determined by a combination of LC-HRMS, MS/MS, and NMR spectroscopic methods. The absolute configuration of the depsipeptide core was determined by Marfey's analysis, and the relative configuration of the 4,7-diamino-3-hydroxy-2 methylheptanoic acid moiety was determined by NOESY and selective NOE experiments. The photoreductive properties of imaqobactin were tested and are discussed. Initial tests for antimicrobial and cytotoxic activity of imaqobactin were also performed, identifying moderate antimicrobial activity. PMID- 29616815 TI - Diastereoselective Synthesis of an Advanced Intermediate of Thapsigargin and Other 6,12-Guaianolides Using a RCEYM Strategy. AB - A new and flexible approach toward the synthesis of 6,12-guaianolide anticancer drugs such as trilobolides or thapsigargin has been developed that could be applied to the preparation of analogues with a modified ring system. The synthesis starts from commercial 2-methylcyclopentane-1,3-dione, only relying on diastereoselective reactions for the construction of the stereogenic centers at C1, C3, C6, and C10 and features a high-yielding ring-closing enyne metathesis (RCEYM) step for the formation of the [5,7] bicyclic core. PMID- 29616816 TI - Real-World Emission Factors of Gaseous and Particulate Pollutants from Marine Fishing Boats and Their Total Emissions in China. AB - Pollutants from fishing boats have generally been neglected worldwide, and there is an acute shortage of measured emission data, especially in China. Therefore, on-board measurements of pollutants emitted from 12 different fishing boats in China (including gill net, angling, and trawler boats) were carried out in this study to investigate emission factors (EFs), characteristics and total emissions. The average EFs for CO2, CO, NO x, PM, and SO2 were 3074 +/- 55.9, 50.6 +/- 31.7, 54.2 +/- 30.7, 9.54 +/- 2.24, and 5.94 +/- 6.38 g (kg fuel)-1, respectively, which were higher than those from previous studies of fishing boats. When compared to medium-speed and slow-speed engine vessels, high-speed engines on fishing boats had higher CO EFs but lower NO x EFs. Notably, when fishing boats were in low-load conditions, they always had higher EFs of CO, PM, and NO2 compared to other operating modes. The estimated results showed that emissions from motor-powered fishing boats in China in 2012 (232, 379, and 61.8 kt CO, NO x and PM) accounted for 10.7%, 10.9%, and 19.3% of the total CO, NO x and PM emitted from nonroad mobile sources, which means significant contribution of fishing boats to air pollution, especially in southern China areas. PMID- 29616817 TI - Supramolecular Encapsulation and Bioactivity Modulation of a Halonium Ion by Cucurbit[ n]uril ( n = 7, 8). AB - This is the first time that cucurbit[7]uril and cucurbit[8]uril have been demonstrated to serve as synthetic receptors for a halonium guest species, diphenyleneiodonium, modulating its bioactivities and alleviating its cardiotoxicity, which further expands the onium family of guest molecules for the cucurbit[ n]uril family and provides new insights for halonium-cucurbit[ n]uril host-guest chemistry and its potential applications in pharmaceutical chemistry. PMID- 29616819 TI - Repair Activity of trans-Resveratrol toward 2'-Deoxyguanosine Radicals. AB - In the present study, the repair activity of trans-resveratrol toward 2' deoxyguanosine (dGuo) radicals in polar and nonpolar solvents was studied using density functional theory. The hydrogen transfer/proton coupled electron transfer and single electron transfer (SET) mechanisms between trans-resveratrol and dGuo radicals were considered. Taking into consideration the molar fraction of neutral trans-resveratrol (ROH) and anionic trans-resveratrol (RO-), the overall rate constants for repairing dGuo-radicals by trans-resveratrol are 9.94 * 108 and 2.01 * 109 dm3 mol-1 s-1 in polar and nonpolar solvents, respectively, and the overall rate constant of repairing cation radical (dGuo*+) by trans-resveratrol via an SET mechanism is 7.17 * 109 dm3 mol-1 s-1. The repair activity of RO- toward dGuo-radicals is better than that of ROH, but the repair activity of ROH toward dGuo*+ is better than that of RO-. Unfortunately, neither ROH nor RO- can repair the 2'-deoxyribose radicals of dGuo. It can therefore be concluded that trans-resveratrol is an effective antioxidant for repairing base radicals of dGuo and dGuo*+. The study can help us understand the repair activity of trans resveratrol toward dGuo radicals. PMID- 29616818 TI - Magnetic Sponge Behavior via Electronic State Modulations. AB - A reversible magnetic change in response to external stimuli is a desired function of molecular magnetic materials. The magnetic change induced by a change in the intrinsic spin is significant because the magnetic change is inevitable and could become drastic. In this study, we demonstrate a reversible magnetic change closely associated with electronic state modulations, as well as structural modifications realized by solvation/desolvation cycles of a magnetic sponge. The compound was a D2A-type layered magnet, [{Ru2(O2CPh-2,3,5 Cl3)4}2(TCNQMe2)].4DCM (1; 2,3,5-Cl3PhCO2- = 2,3,5-trichlorobenzoate; TCNQMe2 = 2,5-dimethyl-7,7,8,8-tetracyanoquinodimethane; DCM = dichloromethane), where [Ru2(O2CPh-2,3,5-Cl3)4] ([Ru2II,II]) is an electron donor (D) and TCNQMe2 is an electron acceptor (A). Compound 1 had a one-electron-transferred, charge-ordered state with a [{Ru2II,II}-TCNQMe2*--{Ru2II,III}+] (1e-I) formula. Strong intralayer antiferromagnetic couplings between [Ru2II,II] with S = 1 or [Ru2II,III]+ with S = 3/2 and TCNQMe2*- with S = 1/2, as well as ferromagnetic interlayer interactions, induced long-range ferrimagnetic ordering at Tc = 101 K. Interstitial DCM molecules were located between layers, and these were gradually eliminated under vacuum at 80 degrees C to form a solvent-free compound (1-dry) without loss of crystallinity. The electronic state of 1-dry thermally fluctuated and eventually provided a charge-disproportionate disordered state, with a [{Ru2}0.5+-TCNQMe21.5--{Ru2II,III}+] (1.5e-I) formula as the ground state. The Tc in 1-dry was 34 K because of the presence of diamagnetic TCNQMe22- in some parts of the framework. A large Tc variation with Delta Tc ~ 70 K was switchable; switching was achieved by charge-state modulations accompanied by subtle structural modifications in solvation/desolvation treatments. PMID- 29616820 TI - Effect of Oil Hydrophobicity on the Adsorption and Rheology of beta-Lactoglobulin at Oil-Water Interfaces. AB - The adsorption of protein layers at oil-water interfaces is critical to the formation and stability of various emulsions in, for example, technical applications as well as in biological lipid storage. Effects of ionic strength, pH, temperature, and pretreatments of the proteins are well-known. However, the oil phase has been regarded as exchangeable and its role in protein adsorption has been widely ignored. Herein, the influence of systematically selected oil interfaces of high purity on the formation and properties of beta-lactoglobulin (beta-lg) adsorption layers was evaluated. Droplet profile tensiometry and interfacial rheometry were employed to determine the adsorption kinetics and dilatational and interfacial shear moduli. We show that depending on the molecular size, flexibility, hydrophobicity, polarity, and polarizability of the oils, globular proteins adsorb distinctively. Stronger interactions of polar oils with the hydrophilic exterior of the native beta-lg lead to decelerated protein unfolding. This results in lower surface pressures and slower formation of viscoelastic networks. In addition, polar oils interact stronger with the protein network by hydrophilic bonding and thereby act as softening agents. The observed effects of hydrophobic subphases on the adsorbed protein layers provide knowledge, which promotes higher reproducibility in rheological studies and precise tailoring of interfacial films for enhanced formation and stability of emulsions. PMID- 29616821 TI - Carbamoyl Radicals via Photoredox Decarboxylation of Oxamic Acids in Aqueous Media: Access to 3,4-Dihydroquinolin-2(1 H)-ones. AB - The first visible-light-mediated photoredox oxidative approach for generating carbamoyl radicals from oxamic acids is disclosed. Reaction of the generated carbamoyl radicals with electron-deficient alkenes opens efficient access to 3,4 dihydroquinolin-2(1 H)-ones under mild conditions through a sequence of intermolecular radical addition, cyclization, and aromatization. The process is compatible with a variety of oxamic acids and electron-deficient alkenes, and a wide variety of 3,4-dihydroquinolin-2(1 H)-ones were prepared. PMID- 29616822 TI - The future of image-guided radiotherapy-is image everything? AB - MR-based image-guided (IG) radiotherapy via all-in-one MR treatment units (MR linacs) is one of the hottest topics in contemporary radiotherapy research. From ingenious engineering solutions to complex physical problems, researchers have developed machines with the promise of superior image quality, and all the advantages this may confer. Benefits include better tumour visualisation, online adaptation and the potential for image biomarker-based personalised RT. However, it is important to remember that the technical challenges are real. In many instances, they are skillfully managed rather than abolished, a point illustrated by the wide variety of MR-linac designs. The proposed benefits also deserve careful inspection. Better visibility of the primary tumour on an IG scan cannot be bad, but does not automatically equate to better IG, which often depends on a more generalised match to daily anatomy. MR-linac will undoubtedly be a rich milieu to search for IMBs, but these will need to be carefully validated, and similar work with CT-based biomarkers using existing, cheaper, and more widely available hardware is currently ongoing. Online adaptation is an attractive concept, but practicalities are complex, and more work is required to understand which patients will benefit from plan adaptation, and when. Finally, the issue of cost cannot be overlooked, nor can the research community's responsibilities to global healthcare inequalities. MR-linac is an exciting and ingenious technology, which merits both investment and research. It may not, however, have the future to itself. PMID- 29616823 TI - Odontoid fracture depicted on a panoramic radiograph. AB - A traumatic odontoid fracture was depicted incidentally on a panoramic radiograph of a 73-year-old male patient. This brief note sheds light on the importance of following a systematic visual interrogation of panoramic radiographs, ensuring all anatomic structures are carefully assessed and incidental findings are not overlooked. PMID- 29616824 TI - Thermostable xylanase inhibits and disassembles Pseudomonas aeruginosa biofilms. AB - Pseudomonas aeruginosa biofilms are problematic and play a critical role in the persistence of chronic infections because of their ability to tolerate antimicrobial agents. In this study, various cell-wall degrading enzymes were investigated for their ability to inhibit biofilm formation of two P. aeruginosa strains, PAO1 and PA14. Xylanase markedly inhibited and detached P. aeruginosa biofilms without affecting planktonic growth. Xylanase treatment broke down extracellular polymeric substances and decreased the viscosity of P. aeruginosa strains. However, xylanase treatment did not change the production of pyochelin, pyocyanin, pyoverdine, the Pseudomonas quinolone signal, or rhamnolipid. In addition, the anti-biofilm activity of xylanase was thermally stable for > 100 days at 45 degrees C. Also, xylanase showed anti-biofilm activity against one methicillin-resistance Staphylococcus aureus and two Escherichia coli strains. PMID- 29616825 TI - An experimental test to reveal negative side-effects of high treatability information on preventative health behaviour. AB - OBJECTIVES: When the course of a disease can be positively changed by health professionals the disease can be indicated as 'highly treatable'. This 'high treatability information' (HTI) may have negative side-effects on people's preventative motivation. This study examined the effects of HTI regarding skin cancer on preventative motivation. DESIGN: This study employed a 2 (high treatability (HTI) versus low treatability (LTI)) * 2 (high versus low susceptibility)-experiment with a hanging control group. (family) History and self-efficacy were assessed as moderators. Participants (N = 309) were randomly assigned to one of the five conditions. MAIN OUTCOME MEASURES: The main outcome was intention to engage in preventative actions regarding skin cancer. RESULTS: HTI significantly lowered the intention compared to LTI, under the condition of high susceptibility in people with low self-efficacy. In addition, in people with a (family) history of skin cancer, HTI significantly lowered the intention compared to the no-information group. CONCLUSION: HTI regarding skin cancer can cause a drop in the preventative motivation. The effects can be conceptualised as negative side-effects of HTI. As substantial proportions of the general population have a (family) history of skin cancer or low self-efficacy, the side effects may be widespread, possibly increasing the incidence of skin cancer. PMID- 29616826 TI - Linalool loaded on glutathione-modified gold nanoparticles: a drug delivery system for a successful antimicrobial therapy. AB - In the present study, antimicrobial activity of Linalool loaded on Glutathione modified Gold nanoparticles prepared by novel method was investigated. The aim of this study is to evaluate the antimicrobial activity of Linalool-gold nanoparticles (LIN-GNPs) against Gram's positive bacteria Staphylococcus aureus, Gram's negative bacteria Escherichia coli, and against Leishmania tropica. Gold nanoparticles were synthesized using the chemical method. Colour change, UV-Vis spectrum, FTIR and SEM confirmed the characterization of gold nanoparticles and LIN-GNPs. The antibacterial study was including agar well diffusion method, MIC, MBC. The mode of action was determined by cellular material release assay, SEM and AO/EtBr for ROS detection. Anti-parasitic activity was evaluated using MTT assay. FTIR spectral analysis investigated that Linalool was loaded on gold nanoparticles. SEM showed that the Gold nanoparticles and LIN-GNPs were generally found to be spherical in shape and the size was ranged 5-11 nm for GNPs and 15-20 nm for LIN-GNPs. The results of antibacterial activity demonstrated that Linalool alone had low activity against gram-positive and gram-negative bacteria. While the results showed that gram-positive bacteria were more effective by LIN-GNPs. LIN-GNPs acted on the bacterial cell membrane, resulting in loss of integrity and increased permeability of cell wall and stimulated ROS production that leads to damage of bacterial nucleic acid. The anti-parasitic activity results indicated the high activity of LIN-GNPs on L. tropica compared with Linalool and Gold nanoparticles. These results proved that LIN-GNPs have great potential as antimicrobial activity and could be used as a developing strategy for a successful antimicrobial therapeutic agent. PMID- 29616827 TI - Dietary fats and cardiovascular health: a summary of the scientific evidence and current debate. AB - This narrative review summarises the main studies of the role of the different fatty acids in coronary heart disease (CHD) and cardiovascular disease (CVD) risk and the current scientific debate on dietary recommendations. Reduction and substitution of the saturated fatty acids (SFAs) with the polyunsaturated fatty acids (PUFAs) are still the main dietary recommendation to prevent CHD and CVD. In the last few years, however, the strength of the scientific evidence underlying this dietary advice has been questioned. Recent investigations reappraise the previously declared deleterious role of the SFAs and reduce the positive role of PUFAs, mainly the omega-6, whereas the role of monounsaturated fatty acids (MUFAs) remains unclear. In contrast, the negative effects of trans fatty acids (TFAs) seem stronger than previously thought. Finally, criticisms have emerged from a dietary recommendation approach focussed on individual components rather than on wide food items and eating habits. PMID- 29616829 TI - Chronic testosterone administration improves cardiac contractility and has a beneficial effect on the haemostatic system by enhancing fibrinolytic activity and inducing hypocoagulation in healthy rats. AB - This study investigated the effects of chronic supraphysiological dose of testosterone propionate administration cardiovascular function in rats from the perspective of haemostatic function including platelet functions, coagulation, and fibrinolysis. Testosterone significantly enhanced cardiac contractility by enhancing LVSP (10%), dp/dtmax (36.7%), dp/dtmin (14.6%) without altering heart rate, diastolic function, and serum lipid profile. While it has no effect on platelets count, thromboxane B2 levels, and platelet aggregation, testosterone significantly enhanced bleeding time and increased circulatory and thoracic aorta mRNA and protein levels of tPA (46.5%, 58.2%, and 74.3%, respectively) and significantly decreased those of PAI-1 (29.3%, 26.4%, and 32.8%, respectively). While there were no significant changes in PT and aPTT, mRNA and protein levels of prothrombin and factor VII were downregulated in the livers of the testosterone-treated rats (57.7% and 64.9%, respectively). Overall, chronic testosterone administration in rats may act as a cardio-protective agent by modulating haemostasis in rats. PMID- 29616828 TI - Zinc binding groups for histone deacetylase inhibitors. AB - Zinc binding groups (ZBGs) play a crucial role in targeting histone deacetylase inhibitors (HDACIs) to the active site of histone deacetylases (HDACs), thus determining the potency of HDACIs. Due to the high affinity to the zinc ion, hydroxamic acid is the most commonly used ZBG in the structure of HDACs. An alternative ZBG is benzamide group, which features excellent inhibitory selectivity for class I HDACs. Various ZBGs have been designed and tested to improve the activity and selectivity of HDACIs, and to overcome the pharmacokinetic limitations of current HDACIs. Herein, different kinds of ZBGs are reviewed and their features have been discussed for further design of HDACIs. PMID- 29616830 TI - CGRP - a target for acute therapy in migraine: Clinical data. AB - Background A better understanding of the mechanisms underlying the migraine attack has reinforced the concept that migraine is a complex brain disease, and has paved the way for the development of new migraine specific acute treatments. In recent years, targeting the calcitonin gene-related peptide and its receptors has been one of the most promising pharmacological strategies for both acute and preventive treatment of migraine. Findings Randomized double-blind placebo controlled trials have demonstrated the superiority of small molecule calcitonin gene-related peptide receptor antagonists (gepants) over placebo in treating acute migraine attacks measured as the two-hour pain free endpoint. Gepants also improved migraine associated symptoms, such as nausea, photophobia and phonophobia. Two of the class have had their development stopped because of hepatotoxicity, which is emerging as being due to metabolites. Gepants have a good tolerability and can be safely used in patients with stable cardiovascular disease. Conclusion Exciting results have been obtained targeting the calcitonin gene-related peptide pathway to abort acute migraine attacks, thus reinforcing the relevance of mechanism-based treatments specific for migraine. PMID- 29616831 TI - Identifying clinically relevant sliding hiatal hernias: a population-based endoscopy study. AB - OBJECTIVES: The clinical relevance of small to moderate sliding hiatal hernias is controversial. The aims of the present study were to (1) investigate which symptoms are associated with sliding hiatal hernias and (2) define the length of a sliding hiatal hernia at which gastrointestinal symptoms occur. METHODS: A study population representative of the general Swedish population answered a questionnaire regarding gastrointestinal symptoms and was investigated with an upper endoscopy. The length of any sliding hiatal hernia was measured. RESULTS: Only reflux-related symptoms were associated with length of the hiatal hernia (acid regurgitation OR 1.46, CI 1.19-1.79, heartburn OR 1.27, CI 1.05-1.54), and the association did not become significant until an axial hiatal hernia length of 2 cm. CONCLUSIONS: Only reflux symptoms could be attributed to sliding hiatal hernias. Hiatal hernias less than 2 cm should be considered clinically insignificant. PMID- 29616832 TI - Effectiveness of the Wheelchair Skills Training Program: a systematic review and meta-analysis. AB - OBJECTIVE: To conduct a systematic review synthesizing the evidence for the effectiveness of the Wheelchair Skills Training Program (WSTP). DATA SOURCES: We searched PubMed, the Cochrane Library, CINAHL and Embase databases, as well as grey literature, up to 10 October 2017. STUDY SELECTION: Randomized controlled trials (RCTs) assessing the effectiveness of the WSTP. DATA EXTRACTION: Two independent reviewers screened articles and extracted data. Methodological quality was assessed using Cochrane's Risk of Bias Tool. DATA SYNTHESIS: Meta analyses (including sub-group analyses) were conducted for the Wheelchair Skills Test (WST) and WST Questionnaire (WST-Q) total capacity scores. We qualitatively assessed retention, WST/WST-Q subtotal and individual-skill capacity scores and other identified outcomes. The quality of evidence was determined using the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach. Thirteen articles (581 participants) were included for analysis. The level of evidence was of moderate quality. The WSTP increased the post-training WST/WST-Q total capacity scores by 14.0% (95% CI: 7.4, 20.8; p < .0001) compared to no treatment, standard care or educational controls, a relative increase over baseline of 21.2%. Subgroup analyses showed that training was more effective for new wheelchair users. Retention of training effects was suggested by the absence of significant declines between tests post-training and at follow-up. The WSTP was found to have positive effects on some other outcomes. No serious adverse events were reported. CONCLUSIONS: There is moderate quality evidence that the WSTP is a safe intervention that has a clinically meaningful effect on WST/WST-Q capacity scores and some other outcomes. Implications for rehabilitation A systematic review and meta-analysis of 13 randomized controlled trials on a total of 581 participants, using the Wheelchair Skills Training Program (WSTP) as the intervention, found that the WSTP increased Wheelchair Skills Test (WST) and WST Questionnaire (WST-Q) total capacity scores by 21.2% relative to baseline. Subgroup analyses showed that training was more effective for new wheelchair users. The WSTP was found to have positive effects on some other outcomes and no serious adverse events were reported. The WSTP warrants cautious implementation in clinical and educational settings. PMID- 29616833 TI - Single pot synthesized gold nanoparticles using Hippophae rhamnoides leaf and berry extract showed shape-dependent differential nanobiotechnological applications. AB - A facile one-pot green synthesis of gold nanoparticles (AuNPs) with different geometries was achieved using an underutilized Himalayan bioresource Hippophae rhamnoides. Aqueous leaf (LE) and berry extracts (BE) showed rapid synthesis of monodispersed spherical LEAuNPs (27 +/- 3.2 nm) and anisotropic BEAuNPs (55 +/- 4.5 nm) within 2 and 15 min, respectively. The Fourier-transform infrared (FTIR) spectroscopy showed involvement of polyphenolics/flavonoids in AuNPs reduction. LE AuNPs (IC50 49 ug) exhibited higher antioxidant potential than BE AuNPs (IC50 57 ug). Both BE nanotriangles and LE nanospheres exhibited cytotoxicity against Jurkat cell lines. These nanocatalysts also exhibited effective (80-99%) reductive degradation of structurally different carcinogenic azo dyes. Kinetic studies revealed that BE nanotriangles exhibited higher catalytic efficiency (14 67%) than LE nanospheres suggesting shape-dependent regulation of biological activities. The gas chromatography-mass spectrometry (GC-MS) analysis confirmed conversion of toxic methyl orange dye to non-toxic intermediates. Probable degradation mechanism involving adsorption and catalytic reduction of azo bonds was proposed. The present synthesis protocol provided a facile and energy saving procedure for rapid synthesis of highly stable nanoparticles with significant antioxidant and anticancer potential. This is the first report of H. rhamnoides mediated green synthesis of multipurpose AuNPs as antioxidant, anticancer and nanocatalytic agents for treatment of dye contaminated waste water and future therapeutic applications. PMID- 29616834 TI - Omitting cardiophrenic lymph nodes in the treatment of patients with Hodgkin lymphoma via modified involved-site radiation therapy. AB - Cardiophrenic lymph nodes (CPLNs) are occasionally involved in Hodgkin lymphoma (HL). We characterized the incidence of CPLN involvement among 169 HL patients and evaluated outcomes after treatment with omission of the CPLN region from the involved-site radiation therapy (ISRT) field. Three types of RT fields were used: standard (S)-ISRT, reduced-dose (RD)-ISRT (lower dose to CPLNs, standard to other sites), or modified (M)-ISRT (omission of CPLNs). CPLNs were involved at diagnosis in 29 patients (17%). Of the 20 patients who received RT after complete response to chemotherapy, 4(20%) received S-ISRT, 8(40%) RD-ISRT, and 8(40%) M ISRT. The four-year progression-free survival was 94.7%. One relapse occurred at a non-CPLN site after RD-ISRT. The mean heart dose and volume of the heart that received 25 Gy was higher for S-ISRT patients compared to M-ISRT (p = .043 and p = .025, respectively). Re-planning the M-ISRT cases as S-ISRT resulted in significant increase in cardiac doses. PMID- 29616835 TI - Lessons learned from the implementation of non-invasive fetal RHD screening. AB - INTRODUCTION: In the fight against hemolytic disease of the fetus and newborn, pregnant RhD negative women are offered antenatal and postnatal anti-D immunoglobulin prophylaxis to prevent the development of antibodies against the fetal D antigen. Antenatal prophylaxis has traditionally been provided to all D negative pregnant women, as the fetal RhD type remains unknown until birth. With noninvasive prenatal testing of cell-free DNA, predicting the fetal RhD type has become highly feasible based on analysis of the fetal RHD gene. Fetal RHD screening can guide targeted antenatal prophylaxis, treating only women who carry an RhD positive fetus, thereby avoiding the unnecessary treatment of approximately 40% of the RhD negative women. Areas covered: Areas covered are the current clinical practice, performance, and challenges of fetal RHD screening, and relevant issues for its implementation. Expert commentary: Fetal RHD screening is highly accurate, with sensitivities of 99.9%, as reported from clinical programs. From gestational week 10, sensitivities are approximately 99%. Despite challenges in assay design, low levels of cell-free fetal DNA in the maternal plasma, and concerns regarding implementation and medical necessity, the clinical experience with fetal RHD screening and targeted prophylaxis has generated encouraging results, and its future widespread use is expected. PMID- 29616836 TI - Normal tissue damage: its importance, history and challenges for the future. AB - Sir Oliver Scott, a philanthropist and radiation biologist and, therefore, the epitome of a gentleman and a scholar, was an early Director of the BECC Radiobiology Research Unit at Mount Vernon. His tenure preceded that of Jack Fowler, with both contributing to basic, translational and clinical thought and application in radiation across the globe. With respect to this review, Fowler's name in particular has remained synonymous with the use of models, both animal and mathematical, that assess and quantify the biological mechanisms that underlie radiation-associated normal tissue toxicities. An understanding of these effects is critical to the optimal use of radiation therapy in the clinic; however, the role that basic sciences play in clinical practice has been undergoing considerable change in recent years, particularly in the USA, where there has been a growing emphasis on engineering and imaging to improve radiation delivery, with empirical observations of clinical outcome taking the place of models underpinned by evidence from basic science experiments. In honour of Scott and Fowler's work, we have taken this opportunity to review how our respective fields of radiation biology and radiation physics have intertwined over the years, affecting the clinical use of radiation with respect to normal tissue outcomes. We discuss the past and current achievements, with the hope of encouraging a revived interest in physics and biology as they relate to radiation oncology practice, since, like Scott and Fowler, we share the goal of improving the future outlook for cancer patients. PMID- 29616837 TI - Outcome of Ph negative myeloproliferative neoplasms transforming to accelerated or leukemic phase. AB - Myeloproliferative neoplasms (MPN) are chronic disorders that can sometimes evolve into accelerated or leukemic phases. We retrospectively identified 122 patients with such blastic phases. The overall median survival was four months: 10.2 months for patients treated with intensive treatments compared to three months for best supportive care (p = .005). Azacytidine, intensive chemotherapies, or allogeneic stem cell transplantation gave the highest median survivals with 9, 10.2, and 19.4 months, respectively. Accelerated phases (AP) had a longer median survival compared to acute leukemia (4.8 months vs. 3.1 months; p = .02). In this retrospective and observational study, we observe that the longest survivals are seen in patients eligible for intensive treatments. Azacytidine shows interesting results in patients non-fit for intensive chemotherapy. Supportive care should probably be restricted to elderly patients and those with unfavorable karyotype. An early diagnosis of AP could also result in a better survival rate. PMID- 29616838 TI - Why all randomised controlled trials produce biased results. AB - BACKGROUND: Randomised controlled trials (RCTs) are commonly viewed as the best research method to inform public health and social policy. Usually they are thought of as providing the most rigorous evidence of a treatment's effectiveness without strong assumptions, biases and limitations. OBJECTIVE: This is the first study to examine that hypothesis by assessing the 10 most cited RCT studies worldwide. DATA SOURCES: These 10 RCT studies with the highest number of citations in any journal (up to June 2016) were identified by searching Scopus (the largest database of peer-reviewed journals). RESULTS: This study shows that these world-leading RCTs that have influenced policy produce biased results by illustrating that participants' background traits that affect outcomes are often poorly distributed between trial groups, that the trials often neglect alternative factors contributing to their main reported outcome and, among many other issues, that the trials are often only partially blinded or unblinded. The study here also identifies a number of novel and important assumptions, biases and limitations not yet thoroughly discussed in existing studies that arise when designing, implementing and analysing trials. CONCLUSIONS: Researchers and policymakers need to become better aware of the broader set of assumptions, biases and limitations in trials. Journals need to also begin requiring researchers to outline them in their studies. We need to furthermore better use RCTs together with other research methods. Key messages RCTs face a range of strong assumptions, biases and limitations that have not yet all been thoroughly discussed in the literature. This study assesses the 10 most cited RCTs worldwide and shows that trials inevitably produce bias. Trials involve complex processes - from randomising, blinding and controlling, to implementing treatments, monitoring participants etc. - that require many decisions and steps at different levels that bring their own assumptions and degree of bias to results. PMID- 29616839 TI - The cultivable bacterial flora of the esophagus in subjects with esophagitis. AB - BACKGROUND: The healthy human esophagus is colonized by bacteria similar to that of the oral mucosa. However, little is known about the microbiome of the esophagus in esophagitis or the possible role of bacteria in the inflammatory response. AIM: To survey bacterial diversity and compare the microbiome of the esophagus in subjects with gastro-esophageal reflux disease (GERD) and eosinophilic esophagitis (EoE). MATERIAL AND METHODS: Seventeen subjects diagnosed with GERD and 10 with EoE underwent endoscopic examination with brush sampling and biopsies from the oral cavity, upper and lower esophagus. The samples were cultivated on agar plates, and bacterial growth was identified to the genus or species level and semi-quantified. RESULTS: Significantly higher numbers of bacterial groups or species were found in specimens from the lower esophagus in subjects with EoE compared to subjects with GERD (median 4 (range 1 7) vs. 2 (range 0-6), p < .0014). Sixteen vs. 14 different bacterial groups or species were found in subjects with GERD and EoE, respectively, mostly in sparse or very sparse amounts. Alfa-streptococci (viridans streptococci) were the most common bacteria in both groups. Streptococci were present in all of the EoE subjects but only in approximately 75% in lower esophagus of the GERD-subjects, regardless of the sampling method. CONCLUSION: Subjects with GERD had significantly less bacterial diversity in both oral and esophageal samples than EoE-subjects. Whether this discrepancy might be explained by an effect on the protective mucosal biofilm by the acidic content of the reflux in subjects with GERD remains unclear. PMID- 29616840 TI - Decitabine in combination with G-CSF, low-dose cytarabine and aclarubicin is as effective as standard dose chemotherapy in the induction treatment for patients aged from 55 to 69 years old with newly diagnosed acute myeloid leukemia. AB - We retrospectively studied 87 patients aged from 55 to 69 years old with acute myeloid leukemia (AML) who received decitabine in combination with G-CSF, low dose cytarabine and aclarubicin (DCAG) or standard dose chemotherapy as induction therapy. Patients receiving DCAG had a similar overall response rate (ORR) (p = .6105) and complete remission (CR) rate (p = .3615) compared to those undergoing standard induction. The median overall survival (OS) and relapse-free survival (RFS) was also similar between the two groups although more 'older' (aged from 60 to 69 years old) and 'unfit' patients underwent DCAG regimen. Notably, patients in DCAG group experienced significantly fewer infections (75 versus 100%, p = .001). Moreover recovery of platelet count was significantly more rapid in DCAG group. Thus we speculate DCAG is possibly a feasible and safe treatment regimen for the relatively older patients with AML and is as effective as standard induction. PMID- 29616841 TI - Outcome of patients with acute undifferentiated leukemia after allogeneic hematopoietic stem cell transplantation. PMID- 29616842 TI - The discovery and development of aclidinium bromide for the treatment of chronic obstructive pulmonary disease. AB - INTRODUCTION: Bronchodilators, including long-acting muscarinic receptor antagonists (LAMAs), are a mainstay of the pharmacological treatment of chronic obstructive pulmonary disease (COPD). LAMAs act as bronchodilators principally by antagonizing airway smooth muscle cells M3 muscarinic receptors. Aclidinium bromide is a twice-daily LAMA which was developed to improve on the efficacy and/or safety of previous LAMAs. Area covered: Herein, the authors present the pharmacotherapeutic role of aclidinium in COPD and point out unmet need in this research area. The following aspects are covered: a) the discovery and medicinal chemistry of aclidinium bromide; b) an overview of the market; c) its mechanism of action; d) its pharmacokinetic/pharmacodynamic profile derived from pre clinical studies; e) the clinical studies which led to its licensing; f) the evidence from meta-analyses; g) the aclidinium/formoterol fixed dose combination for COPD and h) priorities in this area of research. Expert opinion: Aclidinium bromide has the pharmacological properties, safety and efficacy profile and inhaler characteristics which makes it a valuable therapeutic option for pharmacological management of patients with COPD. Due to its rapid biotransformation into inactive metabolites, aclidinium is potentially one of the safest LAMAs. Further head-to-head randomized clinical trials are required to define efficacy and safety of aclidinium when compared to once-daily LAMAs. The clinical relevance of airway anti-remodeling effects of aclidinium has to be defined. PMID- 29616844 TI - Assessment of synergistic effect of combining hyperthermia with irradiation and calcium carbonate nanoparticles on proliferation of human breast adenocarcinoma cell line (MCF-7 cells). AB - The present study was undertaken to evaluate the synergistic effect of combining hyperthermia with irradiation and calcium carbonate nanoparticles (CC NPs) on proliferation of MCF-7 cells. The cells were randomly allocated to 19 groups: one negative control, three positive controls and 15 treatment groups. MCF-7 cells were treated with three concentrations of CC NPs (50, 100 and 150 MUg/mL), gamma radiation (200 cGy), hyperthermia (41 degrees C for 1 h) and three concentrations of doxorubicin (200, 400 and 800 nm) and incubated at 37 degrees C for 24 h. Then the cell viability, the percentage of apoptosis and the levels of caspase-3, -8 and -9 proteins were measured. The results indicated that the combination group (150 ug/mL CC NPs + thermoradiotherapy) had a significant (p < .001) decrease in cell viability (48.65 +/- 4.8%) and a significant (p < .001) increase in apoptosis percentage (45 +/- 1.63%) of MCF-7 cells, as compared with the negative control and most of the other treatment groups. Moreover, a significant (p < .05) increase was observed in the activity of caspase-3 and caspase-9. Our findings revealed that CC NPs in combination with irradiation and hyperthermia could significantly reduce the cell viability and enhance the apoptosis of the MCF-7 breast cancer cells, the same as doxorubicin anti-cancer drug. PMID- 29616843 TI - Phase 1 trial of ibrutinib and carfilzomib combination therapy for relapsed or relapsed and refractory multiple myeloma. AB - This phase 1, dose-finding study investigated ibrutinib and carfilzomib +/- dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma (>=2 lines of therapy including bortezomib and an immunomodulatory agent). Of 43 patients enrolled, 74% were refractory to bortezomib and 23% had high-risk cytogenetics. No dose-limiting toxicities were observed. The recommended phase 2 dose was ibrutinib 840 mg and carfilzomib 36 mg/m2 with dexamethasone. The most common >= grade 3 (>10%) treatment-emergent adverse events were hypertension, anemia, pneumonia, fatigue, diarrhea, and thrombocytopenia. Overall response rate was 67% (very good partial response, 21%; stringent complete response, 2%), with an additional 9% minimal response. Median progression-free survival was 7.2 months and was not inferior in refractory nor high-risk patients. Median overall survival was not reached. Ibrutinib plus carfilzomib demonstrated encouraging responses with a manageable safety profile in this advanced population. PMID- 29616845 TI - Lateralizing Calcaneal Osteotomies and Their Effect on Calcaneal Alignment: A Three-Dimensional Digital Model Analysis. AB - BACKGROUND: Few authors have directly compared multiple types of lateralizing calcaneal osteotomies (LCOs) in terms of their ability to achieve deformity correction. The aim of this research was to use a digital model of a varus hindfoot to compare 4 different LCOs in terms of deformity correction and amount of tuberosity lateralization required. The authors hypothesis was that osteotomies involving a wedge resection would achieve greater correction with less lateralization. METHODS: A weightbearing computed tomographic scan of a patient with a varus hindfoot deformity was used to construct a 3-dimensional digital model of the hindfoot, preserving weightbearing alignment. Four different LCOs were modeled: a standard oblique osteotomy, a Dwyer osteotomy, a modified Dwyer osteotomy involving lateralization in addition to wedge resection, and a Malerba Z-type osteotomy with wedge resection and lateralization. Incremental corrections were performed with each osteotomy type, and amount of correction was assessed with a vertical hindfoot angle and measurement of the lateral translation of the most inferior aspect of the calcaneus. Calcaneal length and osteotomy contact surface area were also measured. RESULTS: The modified Dwyer osteotomy led to the greatest improvements in the vertical hindfoot angle and lateral translation, followed by the Malerba osteotomy. The standard and Malerba osteotomies allowed the most preservation of calcaneal length; the Malerba and Dwyer osteotomies had the greatest contact surface area. CONCLUSION: LCOs that involve wedge resection as well as lateralization were able to achieve the greatest correction of hindfoot varus. CLINICAL RELEVANCE: For the surgical treatment of cavovarus foot deformities, osteotomies with wedge resection in addition to lateralization enable more powerful correction. PMID- 29616847 TI - Switching from all-trans retinoic acid to arsenic trioxide for newly diagnosed acute promyelocytic leukemia. PMID- 29616848 TI - AML with MDS-related changes and blasts of mixed lineage: time for a new provisional entity? PMID- 29616849 TI - Multiple myeloma - a cure within reach. PMID- 29616846 TI - Specific Transcriptome Changes Associated with Blood Pressure Reduction in Hypertensive Patients After Relaxation Response Training. AB - OBJECTIVE: Mind-body practices that elicit the relaxation response (RR) have been demonstrated to reduce blood pressure (BP) in essential hypertension (HTN) and may be an adjunct to antihypertensive drug therapy. However, the molecular mechanisms by which the RR reduces BP remain undefined. DESIGN: Genomic determinants associated with responsiveness to an 8-week RR-based mind-body intervention for lowering HTN in 13 stage 1 hypertensive patients classified as BP responders and 11 as nonresponders were identified. RESULTS: Transcriptome analysis in peripheral blood mononuclear cells identified 1771 genes regulated by the RR in responders. Biological process- and pathway-based analysis of transcriptome data demonstrated enrichment in the following gene categories: immune regulatory pathways and metabolism (among downregulated genes); glucose metabolism, cardiovascular system development, and circadian rhythm (among upregulated genes). Further in silico estimation of cell abundance from the microarray data showed enrichment of the anti-inflammatory M2 subtype of macrophages in BP responders. Nuclear factor-kappaB, vascular endothelial growth factor, and insulin were critical molecules emerging from interactive network analysis. CONCLUSIONS: These findings provide the first insights into the molecular mechanisms that are associated with the beneficial effects of the RR on HTN. PMID- 29616850 TI - The relationship between erectile dysfunction severity, mean platelet volume and vitamin D levels. AB - BACKGROUND: The aim of this study was to evaluate the relationship between mean platelet volume (MPV) and vitamin D levels according to ED severity. METHODS: Between October 2015 and September 2017, patients who applied to the andrology outpatient clinic with an ED complaint were retrospectively reviewed. Patients with diabetes, hypertension, hyperlipidemia, malignancy, late-onset hypogonadism and smokers were not included in the study. The International Erectile Function Index-Erectile Function (IIEF-EF) questionnaire was used to assess the levels of erectile function. According to this scoring system, patients were divided into two groups. IIEF score: between 17 and 25 = mild ED (Group 1) and IIEF score between 16 and 0 = moderate-severe ED (Group 2). Blood samples of the patients were taken from antecubital vein and MPV and 25-hydroxyvitamin D [25(OH)D] levels were evaluated. RESULTS: Ninety patients were included in the study (Group 1: n = 41, Group 2: n = 49). The mean age of the patients was 41.07 +/- 8.56 and the mean body mass index (BMI) was 27.59 +/- 3.91. 25(OH)D levels were found to be statistically lower in Group 2 (18.85 +/- 6.09; 13.98 +/- 7.10; p = .001). MPV levels were found to be statistically higher in Group 2 (10.05 +/- 0.81; 10.78 +/ 1.16; p = .001). Correlation between IIEF-EF scores and 25(OH)D levels was positive (p = .03, r = 0.22). There was negative correlation between IIEF-EF scores and MPV and between 25(OH)D levels and MPV levels [p = .003 for IIEF EF/MPV, p = .04, r = -0.23 for 25(OH)D/MPV]. CONCLUSION: There is a significant positive correlation between ED severity and 25(OH)D levels and there is a significant negative correlation between ED severity and MPV levels. PMID- 29616852 TI - Rituximab addition to chemotherapy in real world patients with chronic lymphocytic leukemia: effective in first line but indication of lack of efficacy in subsequent lines of therapy. PMID- 29616851 TI - Distinct transcriptomic and exomic abnormalities within myelodysplastic syndrome marrow cells. AB - To provide biologic insights into mechanisms underlying myelodysplastic syndromes (MDS) we evaluated the CD34+ marrow cells transcriptome using high-throughput RNA sequencing (RNA-Seq). We demonstrated significant differential gene expression profiles (GEPs) between MDS and normal and identified 41 disease classifier genes. Additionally, two main clusters of GEPs distinguished patients based on their major clinical features, particularly between those whose disease remained stable versus patients who transformed into acute myeloid leukemia within 12 months. The genes whose expression was associated with disease outcome were involved in functional pathways and biologic processes highly relevant for MDS. Combined with exomic analysis we identified differential isoform usage of genes in MDS mutational subgroups, with consequent dysregulation of distinct biologic functions. This combination of clinical, transcriptomic and exomic findings provides valuable understanding of mechanisms underlying MDS and its progression to a more aggressive stage and also facilitates prognostic characterization of MDS patients. PMID- 29616853 TI - Clonal shifts in MDS - from SF3B1 to EZH2. PMID- 29616854 TI - The effectiveness of interferon-alpha combined with imatinib in patient with chronic myeloid leukemia harboring T315I BCR-ABL1 mutation. PMID- 29616855 TI - Clinically defined subgroups of mycosis fungoides display differing histopathological features at initial biopsy. AB - Most patients with mycosis fungoides (MF) remain in early disease stages but some progress to tumor stage. The individual course of the disease cannot be predicted. We wanted to assess the clinical and histological characteristics of the first available biopsy. An end-of-spectrum approach with two groups was used, comparing MF remaining long-term stable in T1a ('MF stable') and MF with later tumor development or present T3 stage ('MF tumor'). The clinical and histomorphological features of the initial skin biopsy were compared. Patients in the 'MF tumor' group presented initially with higher disease stages. The first biopsies of 'MF tumor' patients showed significantly higher infiltrate density and depth, more large cells and a higher proliferative index. In summary, long term stable MF seems to differ in clinical and histopathological parameters from MF with T3 evolution/presence already at the time point of the initial biopsy. Our findings might indicate a predetermined biologic behavior. PMID- 29616856 TI - Oncogene-induced senescence: a potential breakpoint mechanism against malignant transformation in plasma cell disorders. AB - Oncogene-induced senescence (OIS) is a cellular tumor-suppressive mechanism present in several premalignant conditions. Here, we analyze the possible impact of OIS on malignant transformation in plasma cell disorders. Tumor samples from 125 patients with different disease stages were analyzed immunohistochemically for expression of senescence markers. Protein expression of cyclin-dependent kinase inhibitor p21Cip1/Waf1 was significantly higher in smoldering multiple myeloma (SMM) compared to monoclonal gammopathy of undetermined significance (MGUS) (p = .02) or symptomatic multiple myeloma (MM) (p = .005). SMM plasma cells expressing p21Cip1/Waf1 were negative for Ki67, consistent with senescence. While p27Kip1 was highly expressed in healthy controls, MGUS and SMM, expression decreased significantly in MM (p = .02). SMM plasma cells displayed a mutually exclusive expression of p21Cip1/Waf1/p27Kip1 suggesting compensatory mechanisms of senescence. In conclusion, we found markers of cellular senescence differentially expressed in SMM compared to MGUS and MM supporting the hypothesis of OIS as a breakpoint mechanism against malignant transformation in plasma cell disorders. PMID- 29616857 TI - Pilot trial of K562/GM-CSF whole-cell vaccination in MDS patients. AB - Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoietic stem cell malignancies. Currently, approved drugs are given with non-curative intent as the only known cure is allogeneic bone marrow transplantation, which relies on the donor's immune system driving an allogeneic effect. Previous efforts to harness the endogenous immune system have been less successful. We present the results of a pilot study of K562/GM-CSF (GVAX) whole-cell vaccination in MDS patients. The primary objective of safety was met as there were no serious adverse events. One patient had a decrease in transfusion requirements and another demonstrated hematologic improvement suggesting a signal for clinical activity. In vitro correlative studies indicated biological effects on immune cells following vaccination. Although only a pilot study, results are encouraging that an immunotherapeutic approach with a whole-cell vaccine may be feasible in MDS patients. PMID- 29616858 TI - Role of Yin Yang-1 (YY1) in the transcription regulation of the multi-drug resistance (MDR1) gene. AB - Resistance to chemotherapy hinders the successful treatment of acute lymphoblastic leukemia (ALL). The multi-drug resistance-1 (MDR1/ABCB1) gene encodes P-glycoprotein (P-gp), which plays an important role in chemoresistance; however, its transcriptional regulation remains unclear. We investigated the role of YY1 in the regulation of MDR1 and its relation to ALL outcomes. Analysis of the MDR1 promoter revealed four putative YY1-binding sites, which we analyzed using a reporter system and ChIP analysis. YY1 silencing resulted in the inhibition of MDR1 expression and function. The clinical roles of YY1 and MDR1 expression were evaluated in children with ALL. Expression of both proteins was increased in ALL patients compared to controls. We identified a positive correlation between YY1 and MDR1 expression. High levels of YY1 were associated with decreased overall survival. Our results demonstrated that YY1 regulates the transcription of MDR1. Therefore, YY1 may serve as a useful prognostic and/or therapeutic target. PMID- 29616859 TI - Expression of functional folate receptors in multiple myeloma. AB - Receptor-targeted delivery of imaging and therapeutic agents has emerged as an attractive strategy to diagnosis and treat many diseases including cancer. One of the most well-studied receptors for targeted therapies is the folate receptor (FR) family. FR-alpha and FR-beta are present on many cancers with little expression in normal tissues; leading to the testing of at least six folate targeted drugs in human clinical trials for various cancers. However, the expression of FR in blood cancers has not been fully explored with no reports of FR expression in myelomas. Herein, we report the expression of both FR-alpha and FR-beta on CD138 + plasma cells isolated from patients with multiple myeloma. In addition, all-trans retinoic acid was shown to increase the levels of FR-alpha and FR-beta in two myeloma cell lines. Altogether, this data suggests that folate targeted therapies for the treatment of multiple myeloma warrants further investigation. PMID- 29616860 TI - Targeting HAUSP in both p53 wildtype and p53-mutant tumors. AB - Inhibition of Mdm2 function is a validated approach to restore p53 activity for cancer therapy; nevertheless, inhibitors of Mdm2 such as Nutlin-3 have certain limitations, suggesting that additional targets in this pathway need to be further elucidated. Our finding that the Herpesvirus-Associated Ubiquitin Specific Protease (HAUSP, also called USP7) interacts with the p53/Mdm2 protein complex, was one of the first examples that deubiquitinases (DUBs) exhibit a specific role in regulating protein stability. Here, we show that inhibitors of HAUSP and Nutlin-3 can synergistically activate p53 function and induce p53 dependent apoptosis in human cancer cells. Notably, HAUSP can also target the N Myc oncoprotein in a p53-independent manner. Moreover, newly synthesized HAUSP inhibitors are more potent than the commercially available inhibitors to suppress N-Myc activities in p53 mutant cells for growth suppression. Taken together, our study demonstrates the utility of HAUSP inhibitors to target cancers in both a p53-depdentent and -independent manner. PMID- 29616862 TI - R. J. Michael Fry (8/7/1924-24/11/2017). PMID- 29616861 TI - Case studies investigating genetic heterogeneity between anatomically distinct bone marrow compartments in acute myeloid leukemia. PMID- 29616863 TI - Maintenance azacitidine after myeloablative allogeneic hematopoietic cell transplantation for myeloid malignancies. AB - Allogeneic hematopoietic cell transplantation (HCT) is a curative option for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), but carries a high risk of relapse. This retrospective review evaluates the effectiveness of maintenance azacitidine in high-risk AML and MDS patients to reduce the probability of relapse. Twenty-five patients who received maintenance azacitidine were matched to historical controls in a two-to-one ratio based on diagnosis, donor type, conditioning regimen intensity, and age. Over 90% of patients received myeloablative conditioning. There was no difference in time to hematologic relapse, overall survival, or non-relapse mortality. Maintenance therapy was stopped early in 72% of patients due to graft-versus-host-disease, relapse, infection, and intolerance (13 of 25 patients received less than 4 cycles). There was a trend towards higher toxicity in the azacitidine group. The use of prophylactic azacitidine following myeloablative allogeneic HCT outside a clinical trial cannot be recommended at this time. PMID- 29616864 TI - A phase-1 study of dasatinib plus all-trans retinoic acid in acute myeloid leukemia. AB - Src family kinases (SFKs) are hyperactivated in acute myeloid leukemia (AML). SFKs impede the retinoic acid receptor, and SFK inhibitors enhance all-trans retinoic acid (ATRA)-mediated cellular differentiation in AML cell lines and primary blasts. To translate these findings into the clinic, we undertook a phase I dose-escalation study of the combination of the SFK inhibitor dasatinib and ATRA in patients with high-risk myeloid neoplasms. Nine subjects were enrolled: six received 70 mg dasatinib plus 45 mg/m2 ATRA daily, and three received 100 mg dasatinib plus 45 mg/m2 ATRA daily for 28 days. Headache and QTc prolongations were the only two grade 3 adverse events observed. No significant clinical responses were observed. We conclude that the combination of 70 mg dasatinib and 45 mg/m2 ATRA daily is safe with acceptable toxicity. Our results provide the safety profile for further investigations into the clinical efficacy of this combination therapy in myeloid malignancies. PMID- 29616865 TI - Single-agent panobinostat for relapsed/refractory diffuse large B-cell lymphoma: clinical outcome and correlation with genomic data. A phase 2 study of the Fondazione Italiana Linfomi. AB - We investigated panobinostat 40 mg three times weekly in 35 adult patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). Overall response rate and complete response were 17.1% and 11.4%, respectively. Median progression free survival (PFS) and overall survival were 2.4 and 7.6 months, respectively. Calculated 12, 24 and 36 months PFS were 26%, 11% and 11%, respectively. Four patients who achieved a sustained CR, continued receiving panobinostat for an overall period of 44, 48, 50, 62 months. Thrombocytopenia grade 3 (5 patients) and 4 (24 patients) represented the main toxic effect, causing dose reduction or treatment suspension in 19 patients. Genomic analysis was unable to identify any relationship between mutations and response; TP53 mutation appeared not to impact the clinical outcome. Overall, panobinostat has a modest activity in R/R DLBCL patients, however it can induce very long lasting responses in some cases. Thrombocytopenia frequently limits the use of this agent. PMID- 29616866 TI - Changes in abdominal wall thickness during laparoscopy: implications for the use of magnetic assisted surgery. AB - INTRODUCTION: Recently, magnetic solutions have been proposed to minimize surgical invasiveness. These are comprised of deployable instruments containing magnets which are inserted into the abdominal cavity through a single access point. The manipulation of the internal elements occurs via magnets held on the external surface of the abdominal wall. This technology relies on the magnetic force between the magnets, which is inversely related to the abdominal wall thickness (AWT). The aim of this study was to establish the expected change in AWT from before and after initiation of pneumoperitoneum. MATERIAL AND METHODS: Patients scheduled for laparoscopic procedures were assessed by ultrasound for AWT immediately before and during laparoscopy. Change of AWT during laparoscopy was calculated. Statistical analysis was performed using Student's t-test. RESULTS: Thirty-two patients undergoing various laparoscopic procedures were included. Twenty patients were male (62.5%) and ten were morbidly obese (31%). Mean age was 51 years (range 18-76) and average BMI was 28.1 kg/m2 (range 19.0 41.0). AWT decreased on average by 15.6% once pneumoperitoneum was initiated in both obese and non-obese patients (p = .01). CONCLUSION: Our data suggest that following preoperative assessment of AWT with abdominal wall ultrasound, more patients than expected might be candidates for the use of trans-abdominal magnetic devices. PMID- 29616868 TI - Frontline treatment of diffuse large B-cell lymphoma in elderly: a systematic review of clinical trials in post-rituximab era. AB - Treatment of diffuse large B cell lymphoma (DLBCL) remains challenging in elderly population and systematic reviews are lacking in this area. Medline and Cochrane Register of Controlled Trials in addition to conference proceedings were searched for therapeutic clinical trials on frontline treatment of DLBCL in adults >=60 in post-rituximab era. Forty-one out of 713 reviewed papers met our inclusion criteria. Six cycles of rituximab, cyclophosphamide, vincristine, prednisone (R CHOP) administered every 21 d remain the standard treatment for fit elderly, with no role for maintenance rituximab. For individuals >=80, the strongest evidence favors rituximab/ofatumumab-miniCHOP. Numerous alternative approaches including the use of liposomal anthracyclines, dose and regimen adjustment to frailty/comorbidity score, brief duration regimens, and consolidative radioimmunotherapy have produced promising outcomes and could be considered for R CHOP inappropriate elderly. Phase III randomized trials studying the efficacy of liposomal vincristine, extended-exposure rituximab, and lenalidomide plus R-CHOP are ongoing. PMID- 29616869 TI - Hodgkin lymphoma presenting with paraneoplastic myasthenia: a case report. PMID- 29616867 TI - Long non-coding regulatory RNAs in sponges and insights into the origin of animal multicellularity. AB - How animals evolved from a single-celled ancestor over 700 million years ago is poorly understood. Recent transcriptomic and chromatin analyses in the sponge Amphimedon queenslandica, a morphologically-simple representative of one of the oldest animal phyletic lineages, have shed light on what innovations in the genome and its regulation underlie the emergence of animal multicellularity. Comparisons of the regulatory genome of this sponge with those of more complex bilaterian model species and even simpler unicellular relatives have revealed that fundamental changes in genome regulatory complexity accompanied the evolution of animal multicellularity. Here, we review and discuss the results of these recent investigations by specifically focusing on the contribution of long non-coding RNAs to the evolution of the animal regulatory genome. PMID- 29616870 TI - The influence of lymphoid reconstitution kinetics on clinical outcomes in allogeneic stem cell transplantation. AB - Lymphoid recovery following myeloablative stem cell transplantation (SCT) displays a logistic pattern of exponential growth followed by a plateau. Within this logistic framework, lymphoid recovery is characterized by the parameters R (slope of ascent), a (time of maximal rate of ascent) and K (plateau), the 'steady-state' lymphocyte count. A retrospective analysis of allogeneic SCT performed from 2008 to 2013 was undertaken to compare lymphoid recovery and clinical outcomes in 131 patients with acute myelogenous leukemia, acute lymphocytic leukemia, and myelodysplastic syndromes. Using Prism software, a logistic curve was successfully fit to the absolute lymphocyte count recovery in all patients. Patients were classified according to the magnitude and rate of lymphoid recovery; pattern A achieved an absolute lymphocyte counts (ALC) of >1000/MUL by day 45, pattern B an ALC 500 < x < 1000/MUL, and pattern C an ALC <500/MUL. Pattern A was characterized by a higher mean K (p < .0001) compared with patterns B and C. Patients with patterns B and C were more likely to have mixed T cell chimerism at 90 d following SCT (p = .01). There was a trend towards improved survival (and relapse-free survival) in those with pattern A and B at 1 year compared to pattern C (p = .073). There was no difference in cGVHD (p = .42) or relapse (p = .45) between pattern types. Cytomegalovirus (CMV), aGVHD, and all relapse were heralded by deviation from logistic behavior. Pattern C patients were more likely to require donor lymphocyte infusion (DLI) (p = .017). Weaning of tacrolimus post-transplant was associated with a second, separate logistic expansion in some patients. This study demonstrated that lymphoid reconstitution follows a prototypical logistic recovery and that pattern observed correlates with T cell chimerism and need for DLI, and may influence survival. PMID- 29616871 TI - DCEP as a bridge to ongoing therapies for advanced relapsed and/or refractory multiple myeloma. AB - There is limited data describing dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP) in relapsed refractory multiple myeloma (RRMM). We reviewed 65 patients with RRMM receiving DCEP between 2005 and 2017 in two Melbourne Hospitals. Patients had received a mean of three prior treatment lines (range, 1 11). The mean number of cycles of DCEP was two (range, 1-4). Overall response rate (ORR) was 55% whilst 19% achieved MR and SD. Median overall survival (OS) was 9.6 months. Those bridged to autologous stem cell transplant (ASCT) had significantly improved OS compared to those who were not (median 32.8 vs. 10.7 months, p=.0004). Significant treatment-related mortality (TRM) was observed (9.7%), mostly attributable to grade 3-4 neutropenia and febrile neutropenia. Mandatory use of G-CSF is, therefore, warranted to prevent septic complications. In heavily pretreated RRMM, DCEP is an effective bridge to definitive therapy but in the absence of the latter, its value is questionable. PMID- 29616872 TI - The impact of traffic sign deficit on road traffic accidents in Nigeria. AB - This study assesses the impact of traffic sign deficit on road traffic accidents in Nigeria. The participants were 720 commercial vehicle drivers. While simple random sampling was used to select 6 out of 137 federal highways, stratified random sampling was used to select six categories of commercial vehicle drivers. The study used qual-dominant mixed methods approach comprising key informant interviews; group interviews; field observation; policy appraisal and secondary literature on traffic signs. Result shows that the failure of government to provide and maintain traffic signs in order to guide road users through the numerous accident black spots on the highways is the major cause of road accidents in Nigeria. The study argues that provision and maintenance of traffic signs present opportunity to promoting safety on the highways and achieving the sustainable development goals. PMID- 29616873 TI - Identifying the factors behind fatal and non-fatal road crashes: a case study of Lahore, Pakistan. AB - The study identifies the factors behind fatal and non-fatal road crashes in Lahore, Pakistan, by investigating 461 reported cases to Traffic Police Lahore that occurred during January-November 2014. Road crashes are categorized into fatal and non-fatal crashes and, because of the binary nature of the dependent variable, logistic regression is used to identify the factors behind these crashes. As a follow-up, discriminant analysis is employed to classify the factors related to fatal and non-fatal crashes. The logistic regression results reveal that females are at higher risk of fatalities than male drivers. Among vehicle types, rickshaws and cars are more involved in fatal accidents because both are growing at large on roads. Long trucks and trailers are also involved in fatal accidents, mainly because of their huge size and drivers' risky driving behaviours. It is also noted that risk of fatalities is higher in case where two vehicles bumped each other. Speeding and overloading are the common behaviours resulting in fatal crashes. Better urban transport systems and strict compliance with traffic rules and regulations may improve road safety in Pakistan. PMID- 29616875 TI - Injury control: using novel analytic methods to enhance advocacy and policy response. PMID- 29616876 TI - A framework for medical power in two case studies of health policymaking in India and Niger. AB - Medical professionals influence health policymaking but the power they exercise is not well understood in low- and middle-income countries. We explore medical power in national health policymaking for child survival in Niger (late 1990s 2012) and emergency medicine specialisation in India (early 1990s-2015). Both case studies used document review, in-depth interviews and non-participant observation; combined analysis traced policy processes and established theoretical categories around power to build a conceptual framework of medical power in health policymaking. Medical doctors, mainly specialists, utilised their power to shape policy differently in each case. In Niger, a small, connected group of paediatricians pursued a policy of task-shifting after a powerful non medical actor, the country's president, shifted the debate by enacting broad health systems improvements. In India, a more fragmented group of specialists prioritised tertiary-level healthcare policies likely to benefit only a small subset of the population. Compared to high-income settings, medical power in these cases was channelled and expressed with greater variability in the profession's ability to organise and influence policymaking. Taken together, both cases provide evidence that a concentration of medical power in health policymaking can result in the medicalisation of public health issues. PMID- 29616877 TI - Promoting youth occupant restraint based on need. AB - Motor vehicle crashes are a leading cause of death for youth. Appropriate occupant protection significantly reduces these preventable injuries. Secondary field observation survey records were studied to identify populations that would most likely benefit from youth occupant protection programs. Multivariate regression analysis showed that drivers of youth between 4 and 14 years were in need of programs promoting youth and driver occupant restraint use. When these drivers were using seat belts, it was 35 times more likely they had youth occupants in safety restraints. A focus on pickup truck drivers may also give these programs greater efficacy in increasing youth restraint use. This study was limited to a single state, but the approach should be transferable to other jurisdictions where youth occupant protection field observation studies are conducted. PMID- 29616874 TI - Porphyromonas gingivalis traffics into endoplasmic reticulum-rich-autophagosomes for successful survival in human gingival epithelial cells. AB - Porphyromonas gingivalis, an opportunistic pathogen usurps gingival epithelial cells (GECs) as primary intracellular niche for its colonization in the oral mucosa. However, the precise characterization of the intracellular trafficking and fate of P. gingivalis in GECs remains incomplete. Therefore, we employed high resolution three-dimensional-transmission-electron-microscopy to determine the subcellular location of P. gingivalis in human primary GECs upon invasion. Serial sections of infected-GECs and their tomographic reconstruction depicted ER-rich double-membrane autophagosomal-vacuoles harboring P. gingivalis. Western-blotting and fluorescence confocal microscopy showed that P. gingivalis significantly induces LC3-lipidation in a time-dependent-manner and co-localizes with LC3, ER lumen-protein Bip, or ER-tracker, which are major components of the phagophore membrane. Furthermore, GECs that were infected with FMN-green-fluorescent transformant-strain (PgFbFP) and selectively permeabilized by digitonin showed rapidly increasing large numbers of double-membrane-vacuolar-P. gingivalis over 24 hours of infection with a low-ratio of cytosolically free-bacteria. Moreover, inhibition of autophagy using 3-methyladenine or ATG5 siRNA significantly reduced the viability of intracellular P. gingivalis in GECs as determined by an antibiotic-protection-assay. Lysosomal marker, LAMP-1, showed a low-degree colocalization with P. gingivalis (~20%). PgFbFP was used to investigate the fate of vacuolar- versus cytosolic-P. gingivalis by their association with ubiquitin binding-adaptor-proteins, NDP52 and p62. Only cytosolic-P. gingivalis had a significant association with both markers, which suggests cytosolically-free bacteria are likely destined to the lysosomal-degradation pathway whereas the vacuolar-P. gingivalis survives. Therefore, the results reveal a novel mechanism for P. gingivalis survival in GECs by harnessing host autophagy machinery to establish a successful replicative niche and persistence in the oral mucosa. PMID- 29616878 TI - Integrating Competing Demands of Osmoregulatory and Thermoregulatory Homeostasis. AB - Mammals are characterized by a stable core body temperature. When maintenance of core temperature is challenged by ambient or internal heat loads, mammals increase blood flow to the skin, sweat and/or pant, or salivate. These thermoregulatory responses enable evaporative cooling at moist surfaces to dissipate body heat. If water losses incurred during evaporative cooling are not replaced, body fluid homeostasis is challenged. This article reviews the way mammals balance thermoregulation and osmoregulation. PMID- 29616879 TI - Physiology in Perspective: Seeking Solutions to Biological Questions. PMID- 29616882 TI - Leptospira spp. in the Oral Cavity of Urban Brown Rats ( Rattus norvegicus) from Vancouver, Canada-Implications for Rat-Rat and Rat-Human Transmission. AB - We tested the urine and saliva of 137 wild rats ( Rattus norvegicus) from Vancouver, Canada, for the presence of Leptospira spp. Only one saliva sample was found positive and two were suspect, all from urine-positive rats ( n=81), indicating that active shedding of leptospires in saliva is unlikely to occur. PMID- 29616881 TI - THE USE OF KETAMINE-XYLAZINE OR BUTORPHANOL-AZAPERONE-MEDETOMIDINE TO IMMOBILIZE AMERICAN BLACK BEARS ( URSUS AMERICANUS). AB - Wildlife anesthetic protocols must offer rapid inductions and recoveries, be physiologically safe, and be minimally regulated. With this in mind, we evaluated differences in induction and recovery times and physiological parameters in 33 American black bears ( Ursus americanus) anesthetized with ketamine-xylazine (KX) or immobilized with a commercial drug combination of butorphanol, azaperone, and medetomidine (BAM). Dose was based on mass estimated from field observations. Bears were housed at Appalachian Bear Rescue, Townsend, Tennessee, US, or free ranging within the Great Smoky Mountains National Park (Tennessee and North Carolina, US) and chemically immobilized for management purposes. From 11 April to 29 June 2016, we immobilized bears with injection via pole syringe or disposable dart projected from an air-powered dart rifle. Once immobilized, we measured each bear's temperature, respiration (breaths/min), heart rate (beats/min), hemoglobin oxygen saturation (via pulse oximetry), arterial blood gases, and mass (kg). We found no differences in the induction parameters, partial pressures of CO2, and rectal temperatures. The BAM-treated bears had lower heart and respiratory rates that led to lower hemoglobin oxygen saturation levels (from blood gas analysis, SaO2). The SaO2 after treatment with BAM (91.1+/ 0.8%) was lower than with KX (93.4+/-0.9%). After handling, we reversed KX treated bears with a x=0.2+/-0.02 mg/kg yohimbine and BAM-treated bears with x=1.5+/-0.1 mg/kg atipamezole and 0.8+/-0.1 mg/kg naltrexone. We found no differences in the recovery times to increased respiration and to the bear assuming a head-up position. The BAM-treated bears stood and recovered quicker than did KX-treated animals. Based on our observations, BAM appears to offer safe, predictable immobilizations with fewer drawbacks and faster recovery times than KX-treated bears. PMID- 29616883 TI - Leukocyte Reference Intervals for Free-Ranging Hummingbirds in Northern California, USA. AB - Hummingbirds are specialized nectarivores and important ecological pollinators that are the focus of conservation efforts as well as scientific investigations of metabolism and flight dynamics. Despite their importance, basic information is lacking about hummingbird blood cells. We aimed to establish reference intervals for total and differential leukocyte counts from healthy free-ranging hummingbirds in northern California. Hummingbirds were captured in four counties in spring and summer of 2012. A drop of blood was used to prepare smears for total white blood cell estimate and 200-cell differential leukocyte counts. Reference Value Advisor was used for descriptive statistics and calculation of reference intervals. Blood smears from 42 Anna's Hummingbirds ( Calypte anna) and 33 Black-chinned Hummingbirds ( Archilochus alexandri) were included. The only significant differences in leukocyte counts were due to age, and juvenile hummingbirds had significantly higher lymphocyte counts than adult hummingbirds ( P<0.0001). These reference intervals provide robust baseline data to evaluate health status and disease in free-ranging hummingbirds. PMID- 29616880 TI - Is Adenosine Action Common Ground for NREM Sleep, Torpor, and Other Hypometabolic States? AB - This review compares two states that lower energy expenditure: non-rapid eye movement (NREM) sleep and torpor. Knowledge on mechanisms common to these states, and particularly on the role of adenosine in NREM sleep, may ultimately open the possibility of inducing a synthetic torpor-like state in humans for medical applications and long-term space travel. To achieve this goal, it will be important, in perspective, to extend the study to other hypometabolic states, which, unlike torpor, can also be experienced by humans. PMID- 29616884 TI - Characteristics and potential human health hazards of charged aerosols generated by high-voltage power lines. AB - We investigated the characteristics of charged aerosols produced by high-voltage power lines (HVPLs) to explore the effects on respiratory disease incidence among those who handle HVPLs. Charged aerosol currents and charged aerosol concentrations were measured over 24 h at 12 sites. Aerosol current effective levels were 2.7 times higher compared to exposed and control sites. This pattern of relative enhancement at exposed sites was seen consistently in all measurements and the difference was 1.7 higher at exposed sites. Correlation analysis among all important variables revealed strong positive correlations between currents and concentration, currents and magnetic field, humidity and concentration, and humidity and particles of 10 um or less (PM10), while negative correlations were observed between charged aerosol concentrations and wind velocity and between wind velocity and humidity. Estimated production of charged aerosols from HVPLs found that people who work with HVPLs are highly likely to be exposed to charged aerosols. PMID- 29616885 TI - Egg-Hatching Mechanism of Human Liver Fluke, Opisthorchis viverrini: A Role For Leucine Aminopeptidases From the Snail Host, Bithynia siamensis goniomphalos. AB - The human liver fluke Opisthorchis viverrini (Platyhelminthes, Trematoda, Digenea) uses snails of the genus Bithynia as first intermediate host. Peculiarly among trematodes, the eggs of O. viverrini hatch within the digestive tract of its snail host. It remains uncertain whether hatching in this species is mediated through mechanical fracture of the eggshell or by digestion with specific digestive enzymes. This study aimed to characterize enzymes with specific inhibitors and factors involved in the hatching activity of O. viverrini eggs. For measuring egg hatching in vivo, 50 O. viverrini mature eggs were fed to individual Bithynia siamensis goniomphalos snails at various temperature conditions for 24 hr. Ex vivo, mature eggs were incubated with crude snail extract and commercial leucine aminopeptidase (LAP). Egg-hatching of O. viverrini was temperature dependent, with optimal hatching occurring at 24-28 C, with a peak of hatching of 93.54% in vivo and 30.55% ex vivo occurring at these temperatures. Ex vivo hatching rates increased to 45.87% under anaerobic conditions at 28 C. Some 22.70% and 16.21% of heat-killed eggs also hatched within the snail digestive tract and snail extract, respectively, indicating that host molecules are involved in the hatching response. Most eggs hatch in the anterior regions of the digestive tract. Hatching was completely inhibited in the presence of bestatin, an inhibitor of LAP, but not in the presence of phosphatase inhibitors. Bestatin inhibition of hatching was reversible. Finally, egg hatching could be induced by addition of a porcine LAP. The results indicate that this digenean utilizes both LAP of the snail host and movement of miracidia for hatching. PMID- 29616886 TI - Effect of unifocal versus multifocal lenses on cervical spine posture in patients with presbyopia. AB - SIGNIFICANCE: There are many environmental considerations which may or may not lead to the development of faulty cervical mechanics. The design of near-vision lenses could contribute to the development of such cervical dysfunction and consequently neck pain. Decision-making regarding the proper type of lens prescription seems important for presbyopic individuals. PURPOSE: To investigate the effect of unifocal and multifocal lenses on cervical posture. METHODS: Thirty subjects (18 females and 12 males) participated in the study with an age range from 40 to 64 years. Each subject wore consequently both unifocal and multifocal lenses randomly while reading. Lateral cervical spine X-ray films were taken for each subject during each lens wearing. X-ray films were analyzed with digital software (AutoCAD 2D version 22) to measure segmental angles of the cervical vertebrae (occiput/C1, C1/C2, C2/C3, C3/C4, C4/C5, C5/C6, C6/C7, C3/C7, C0/C3, and occiput/C7). RESULTS: Higher significant extension angles were observed in the segments C0/C7, C1/C2, C5/C6, C6/C7 and C3/C7 (p < 0.05) during multifocal lens wearing, in contrast to higher flexion angles between C3/C4 and C4/C5 (p < 0.05) when wearing unifocal lenses. CONCLUSION: Multifocal lens spectacles produce increased extension in the cervical vertebrae angles when compared with the use of unifocal lenses. PMID- 29616887 TI - Upper limb muscle activation during sports video gaming of persons with spinal cord injury. AB - OBJECTIVE: Video gaming as a therapeutic tool has largely been studied within the stroke population with some benefits reported in upper limb motor performance, balance, coordination, and cardiovascular status. To date, muscle activation of upper limb muscles in persons with spinal cord injuries (SCI) has not been studied during video game play. In this paper, we provide descriptive and comparative data for muscle activation and strength during gaming for players with tetraplegia and paraplegia, as well as, compare these results with data from traditional arm exercises (ie, biceps curl and shoulder press) with light weights which are commonly prescribed for a home program. PARTICIPANTS: Fourteen individuals with chronic SCI (9 tetraplegia, 5 paraplegia). DESIGN: We measured upper limb muscle activation with surface electromyography (EMG) during Wii Sports video game play. Muscle activation was recorded from the playing arm during 4 selected games and normalized to a maximum voluntary contraction (MVC). OUTCOME MEASURES: Heart rate and upper limb motion were recorded simultaneously with EMG. Wilcoxon signed rank tests were used to analyze differences in muscle activation between participants with paraplegia versus tetraplegia and compare gaming with traditional arm exercises with light weights. A Friedman 2-way analysis of variance identified key muscle groups active during game play. RESULTS: Overall muscle activation across the games was not different between those with paraplegia and tetraplegia. Heart rate during video game play for tennis and boxing were on average 10 to 20 beats/minute above resting heart rate. The magnitude of EMG was relatively greater for traditional arm exercises with light weights compared with game play. CONCLUSION: The selected Wii games were able to elicit upper extremity muscle activation and elevated heart rates for individuals with SCI that may be used to target therapeutic outcomes. PMID- 29616888 TI - Listened to, but not heard! The failure to represent the public in genetically modified food policies. AB - 'In the mid-1990s, a mismatch was addressed between European genetically modified food policy, which focused primarily on risks and economic prospects, and public anxieties, which also included other concerns, and there was a development in European food policy toward the inclusion of what were referred to as "ethical aspects." Using parliamentary debates in Denmark in 2002 and 2015 as a case, this article examines how three storylines of concern that were visible in public discourse at the time were represented by the decision makers in parliament. It shows that core public concerns raising fundamental questions about genetically modified foods, and in particular their perceived unnaturalness, were not considered in the parliamentary debates. It is suggested that the failure of the parliament to represent the public may undermine the legitimacy of politicians and lead to disillusionment with parliamentary government. PMID- 29616889 TI - Farmers prevailing perception profiles regarding GM crops: A classification proposal. AB - Genetically modified organisms have been at the centre of a major public controversy, involving different interests and actors. While much attention has been devoted to consumer views on genetically modified food, there have been few attempts to understand the perceptions of genetically modified technology among farmers. By investigating perceptions of genetically modified organisms among Brazilian farmers, we intend to contribute towards filling this gap and thereby add the views of this stakeholder group to the genetically modified debate. A comparative analysis of our data and data from other studies indicate there is a complex variety of views on genetically modified organisms among farmers. Despite this diversity, we found variations in such views occur within limited parameters, concerned principally with expectations or concrete experiences regarding the advantages of genetically modified crops, perceptions of risks associated with them, and ethical questions they raise. We then propose a classification of prevailing profiles to represent the spectrum of perceptions of genetically modified organisms among farmers. PMID- 29616891 TI - Carnobacterium antarcticum sp. nov., a psychrotolerant, alkaliphilic bacterium isolated from sandy soil in Antarctica. AB - A novel, alkaliphilic, psychrotolerant, facultative anaerobe, designated CP1T, was isolated from sandy soil near the Davis Station in Antarctica. The short-rod shaped cells displayed Gram-positive staining and did not form spores. Strain CP1T was able to grow at temperatures between 4 and 36 degrees C, pH 6.0-9.5, and in the presence of up to 5.0 % (w/v) NaCl. 16S rRNA gene and multilocus (pheS, rpoA, and atpA) sequence analysis revealed Carnobacterium mobile DSM 4848T and Carnobacterium iners LMG 26642T as the closest relatives (97.4 and 97.1 % 16S rRNA gene sequence similarity, respectively). The genomic G+C content was 38.1 mol%, and DNA-DNA hybridization with DSM 4848T revealed 32.4+/-3.4 % similarity. The major fatty acid components were C14 : 0 and C16 : 1omega9c. The cell wall contained meso-diaminopimelic acid and was of peptidoglycan type A1gamma. Based on physiological, genotypic and biochemical characteristics, strain CP1T represents a novel species of the genus Carnobacterium for which the name Carnobacterium antarcticum sp. nov. is proposed. The type strain is CP1T (=DSM 103363T=CGMCC 1.15643T). PMID- 29616890 TI - S-Allyl-L-cysteine sulfoxide, a garlic odor precursor, suppresses elevation in blood ethanol concentration by accelerating ethanol metabolism and preventing ethanol absorption from gut. AB - Alcoholic beverages are enjoyed together with meals worldwide, but their excessive intake is associated with an increased risk of various diseases. We investigated whether S-allyl-L-cysteine sulfoxide (ACSO), a sulfuric odor precursor of garlic, suppresses elevation in plasma ethanol concentration by accelerating ethanol metabolism and preventing ethanol absorption from the gut in rats. ACSO and garlic extract with a high ACSO content (Garlic-H) suppressed elevation in concentrations of ethanol and acetaldehyde in plasma and promoted the activities of alcohol dehydrogenase and aldehyde dehydrogenase. However, ACSO and Garlic-H did not affect plasma acetate so much. Furthermore, we examined the change in plasma ethanol concentration by injecting ACSO or Garlic-H into the ligated stomach or jejunum together with ethanol solution. ACSO and Garlic-H suppressed the absorption of ethanol from the stomach and jejunum, but suppression in the jejunum was less than in the stomach. In conclusion, ACSO inhibits ethanol absorption and accelerates ethanol metabolism. PMID- 29616892 TI - Mapping the nuclear localization signal in the matrix protein of potato yellow dwarf virus. AB - The ability of the matrix (M) protein of potato yellow dwarf virus (PYDV) to remodel nuclear membranes is controlled by a di-leucine motif located at residues 223 and 224 of its primary structure. This function can be uncoupled from that of its nuclear localization signal (NLS), which is controlled primarily by lysine and arginine residues immediately downstream of the LL motif. In planta localization of green fluorescent protein fusions, bimolecular fluorescence complementation assays with nuclear import receptor importin-alpha1 and yeast based nuclear import assays provided three independent experimental approaches to validate the authenticity of the M-NLS. The carboxy terminus of M is predicted to contain a nuclear export signal, which is belived to be functional, given the ability of M to bind the Arabidopsis nuclear export receptor 1 (XPO1). The nuclear shuttle activity of M has implications for the cell-to-cell movement of PYDV nucleocapsids, based upon its interaction with the N and Y proteins. PMID- 29616893 TI - Acidovorax kalamii sp. nov., isolated from a water sample of the river Ganges. AB - A Gram-stain-negative, rod-shaped, aerobic, straw yellow, motile strain, designated KNDSW-TSA6T, belonging to the genus Acidovorax, was isolated from a water sample of the river Ganges, downstream of the city of Kanpur, Uttar Pradesh, India. Cells were aerobic, non-endospore-forming and motile with single polar flagella. It differed from its phylogenetically related strains by phenotypic characteristics such as hydrolysis of urea, gelatin, casein and DNA, and the catalase reaction. The major fatty acids were C16 : 1omega7c/C16 : 1omega6c, C16 : 0 and C18 : 1omega7c/C18 : 1omega6c. Phylogenetic analysis based on 16S rRNA and housekeeping genes (gyrb, recA and rpoB gene sequences), confirmed its placement within the genus Acidovorax as a novel species. Strain KNDSW-TSA6T showed highest 16S rRNA sequence similarity to Acidovorax soli BL21T (98.9 %), Acidovorax delafieldii ATCC 17505T (98.8 %), Acidovorax temperans CCUG 11779T (98.2 %), Acidovorax caeni R-24608T (97.9 %) and Acidovorax radicis N35T (97.6 %). The digital DNA-DNA hybridization and average nucleotide identity values calculated from whole genome sequences between strain KNDSW-TSA6T and the two most closely related strains A. soli BL21T and A. delafieldii ATCC 17505T were below the threshold values of 70 and 95 % respectively. Thus, the data from the polyphasic taxonomic analysis clearly indicates that strain KNDSW-TSA6T represents a novel species, for which the name Acidovorax kalamii sp. nov. is proposed. The type strain is Acidovorax kalamii (=MTCC 12652T=KCTC 52819T=VTCC-B 910010T). PMID- 29616895 TI - Ceftriaxone-resistant Salmonella Typhi carries an IncI1-ST31 plasmid encoding CTX M-15. AB - PURPOSE: Ceftriaxone is the drug of choice for typhoid fever and the emergence of resistant Salmonella Typhi raises major concerns for treatment. There are an increasing number of sporadic reports of ceftriaxone-resistant S. Typhi and limiting the risk of treatment failure in the patient and outbreaks in the community must be prioritized. This study describes the use of whole genome sequencing to guide outbreak identification and case management. METHODOLOGY: An isolate of ceftriaxone-resistant S. Typhi from the blood of a child taken in 2000 at the Popular Diagnostic Center, Dhaka, Bangladesh was subjected to whole genome sequencing, using an Illumina NextSeq 500 and analysis using Geneious software.Results/Key findings. Comparison with other ceftriaxone-resistant S. Typhi revealed an isolate from the Democratic Republic of the Congo in 2015 as the closest relative but no evidence of an outbreak. A plasmid belonging to incompatibility group I1 (IncI1-ST31) which included blaCTX-M-15 (ceftriaxone resistance) associated with ISEcp-1 was identified. High similarity (90 %) was seen with pS115, an IncI1 plasmid from S. Enteritidis, and with pESBL-EA11, an incI1 plasmid from E. coli (99 %) showing that S. Typhi has access to ceftriaxone resistance through the acquisition of common plasmids. CONCLUSIONS: The transmission of ceftriaxone resistance from E. coli to S. Typhi is of concern because of clinical resistance to ceftriaxone, the main stay of typhoid treatment. Whole genome sequencing, albeit several years after the isolation, demonstrated the success of containment but clinical trials with alternative agents are urgently required. PMID- 29616894 TI - Bacillus alkalilacus sp. nov., isolated from a sediment sample from a lake in India. AB - An aerobic, endospore-forming, haloalkali-tolerant, Gram-stain-positive, motile, rod-shaped bacterium, designated strain AK73T, was isolated from a sediment sample collected from Sambhar lake, Jaipur, Rajasthan, India. Colonies were circular, 1-2 mm in diameter, glossy, smooth, yellowish and convex with an entire margin after 48 h growth on marine agar at pH 9 and 37 degrees C. Growth occurred at 15-42 degrees C, 0-10 % (w/v) NaCl and at a pH range of 7-12. Strain AK73T was positive for catalase and arginine dihydrolase 2 activities, hydrolysis of Tweens 20, 40 and 80, and negative for esculinase, caseinase, gelatinase, beta galactosidase, lipase (Tween 60) and urease activities. The fatty acids were dominated by branched iso-, anteiso-, saturated fatty acids with a high abundance of iso-C15 : 0, anteiso-C15 : 0, C16 : 0 and anteiso-C17 : 0; MK-7 was the major menaquinone. The cell-wall peptidoglycan contained meso-diaminopimelic acid as the diagnostic diamino acid. The polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, one unidentified aminophospholipid, four unidentified phospholipids and three unidentified lipids. The DNA G+C content of strain AK73T was 54 mol%. Analysis based on comparative 16S rRNA gene sequence analysis indicated that Bacillus alcalophilus was the nearest phylogenetic neighbour, with a pair-wise sequence similarity of 96.0 %. Phylogenetic analysis showed that strain AK73T formed a separate lineage but was loosely associated with a peripheral cluster of organisms that contained Bacillus gibsonii, Bacillus murimartini and Bacillus plakortidis with similarity values of 93.6, 93.5 and 93.4 %, respectively. Based on its phenotypic characteristics and on phylogenetic inference, strain AK73T represents a novel species of the genus Bacillus, for which the name Bacillus alkalilacus sp. nov. is proposed. The type strain is AK73T (=JCM 32184T=MTCC 12637T=KCTC 33880T). PMID- 29616897 TI - Singleton Low Birthweight Rates, by Race and Hispanic Origin: United States, 2006 2016. AB - Low birthweight (LBW) is among the leading causes of infant death in the United States (1). LBW infants are also more likely to have health problems (2). After reaching its highest level in four decades, the LBW rate among all births declined from 2006 to 2014 (3,4), but the trend reversed in 2015 and 2016 when the LBW rate increased (4), moving further away from the Healthy People 2020 goal of reducing LBW rates to 7.8% of live births (5). This report shows trends in LBW, moderately low birthweight (MLBW), and very low birthweight (VLBW) by race and Hispanic origin from 2006 to 2016 for singleton births only, as rates of multiple births can impact LBW rates (4,6). PMID- 29616898 TI - Receipt of a Sexual Risk Assessment From a Doctor or Medical Care Provider in the Past Year Among Women and Men Aged 15-44 With Recent Sexual Activity. AB - Objective-Using 2011-2015 data from the National Survey of Family Growth (NSFG), this report examines by selected characteristics the percentage of women and men aged 15-44 in the United States with recent sexual activity who received a sexual risk assessment from a doctor or other medical care provider in the past year. PMID- 29616899 TI - Use of the National Health Interview Survey Linked to Medicaid Analytic eXtract Data to Identify Children With Medicaid-covered Births. AB - Objective-This report illustrates the use of National Health Interview Survey (NHIS) data linked to Medicaid Analytic eXtract (MAX) data to identify children whose births were covered by Medicaid, as indicated in MAX data, among those participating in NHIS in early childhood, and briefly describes their selected health characteristics. PMID- 29616896 TI - Distinct evolutionary patterns of Neisseria meningitidis serogroup B disease outbreaks at two universities in the USA. AB - Neisseria meningitidis serogroup B (MnB) was responsible for two independent meningococcal disease outbreaks at universities in the USA during 2013. The first at University A in New Jersey included nine confirmed cases reported between March 2013 and March 2014. The second outbreak occurred at University B in California, with four confirmed cases during November 2013. The public health response to these outbreaks included the approval and deployment of a serogroup B meningococcal vaccine that was not yet licensed in the USA. This study investigated the use of whole-genome sequencing(WGS) to examine the genetic profile of the disease-causing outbreak isolates at each university. Comparative WGS revealed differences in evolutionary patterns between the two disease outbreaks. The University A outbreak isolates were very closely related, with differences primarily attributed to single nucleotide polymorphisms/insertion deletion (SNP/indel) events. In contrast, the University B outbreak isolates segregated into two phylogenetic clades, differing in large part due to recombination events covering extensive regions (>30 kb) of the genome including virulence factors. This high-resolution comparison of two meningococcal disease outbreaks further demonstrates the genetic complexity of meningococcal bacteria as related to evolution and disease virulence. PMID- 29616900 TI - Main Reasons for Never Testing for HIV Among Women and Men Aged 15-44 in the United States, 2011-2015. AB - This report presents the percentage of men and women aged 15-44 in the United States who have never been tested for HIV outside of blood or blood product donation based on 2011-2015 data from the National Survey of Family Growth (NSFG). Additionally, this report describes the main reasons reported for having never been tested for HIV. Data are shown by selected demographic characteristics and HIV risk-related behaviors. PMID- 29616901 TI - Issues in Developing a Surveillance Case Definition for Nonfatal Suicide Attempt and Intentional Self-harm Using International Classification of Diseases, Tenth Revision, Clinical Modification (ICD-10-CM) Coded Data. AB - Suicide and intentional self-harm are among the leading causes of death in the United States. To study this public health issue, epidemiologists and researchers often analyze data coded using the International Classification of Diseases (ICD). Prior to October 1, 2015, health care organizations and providers used the clinical modification of the Ninth Revision of ICD (ICD-9-CM) to report medical information in electronic claims data. The transition in October 2015 to use of the clinical modification of the Tenth Revision of ICD (ICD-10-CM) resulted in the need to update methods and selection criteria previously developed for ICD-9 CM coded data. This report provides guidance on the use of ICD-10-CM codes to identify cases of nonfatal suicide attempts and intentional self-harm in ICD-10 CM coded data sets. ICD-10-CM codes for nonfatal suicide attempts and intentional self-harm include: X71-X83, intentional self-harm due to drowning and submersion, firearms, explosive or thermal material, sharp or blunt objects, jumping from a high place, jumping or lying in front of a moving object, crashing of motor vehicle, and other specified means; T36-T50 with a 6th character of 2 (except for T36.9, T37.9, T39.9, T41.4, T42.7, T43.9, T45.9, T47.9, and T49.9, which are included if the 5th character is 2), intentional self-harm due to drug poisoning (overdose); T51-T65 with a 6th character of 2 (except for T51.9, T52.9, T53.9, T54.9, T56.9, T57.9, T58.0, T58.1, T58.9, T59.9, T60.9, T61.0, T61.1, T61.9, T62.9, T63.9, T64.0, T64.8, and T65.9, which are included if the 5th character is 2), intentional self-harm due to toxic effects of nonmedicinal substances; T71 with a 6th character of 2, intentional self-harm due to asphyxiation, suffocation, strangulation; and T14.91, Suicide attempt. Issues to consider when selecting records for nonfatal suicide attempts and intentional self-harm from ICD-10-CM coded administrative data sets are also discussed. PMID- 29616902 TI - A View from the Other Side of the Consultation Desk. AB - In this reflection on being both a physician and a patient, I consider the events that happened to me as a patient with cancer and how this will change my practice as a doctor in the future. PMID- 29616903 TI - Sinonasal Ewing Sarcoma: A Case Report and Literature Review. AB - INTRODUCTION: Ewing sarcoma (ES) of the sinonasal tract and associated primitive neuroectodermal tumors are rare. To our knowledge, only 10 case reports of sinonasal ES of the nose or paranasal sinuses have been reported. Furthermore, there has been only 1 case of sinonasal ES arising from the middle turbinate. Recommended management of sinonasal ES stems from the management of its osseous counterpart, ES, but treatment with surgery, radiotherapy, and chemotherapy is varied. Five-year survival rates vary from 21% to 70%, with the lower rates representing patients presenting with metastatic disease. CASE PRESENTATION: A 26 year-old man presented with persistent left-sided nasal obstruction. Endoscopy demonstrated a friable mass in the left nasal cavity originating from the middle turbinate with extension into the nasopharynx, confirmed with computed tomography and magnetic resonance imaging. There was no evidence of metastatic disease on positron emission tomography-computed tomography. Histopathologic results were consistent with sinonasal ES. The result of fluorescent in situ hybridization was positive for the EWS gene translocation. A multidisciplinary tumor board evaluated the patient. The patient then underwent neoadjuvant chemotherapy, followed by definitive endoscopic surgical resection and postoperative radiotherapy. DISCUSSION: Our literature review found more involvement of the maxillary and ethmoid sinuses compared with the nasal cavity, and that the role of radiation and surgical approach was varied. ES of the sinonasal tract is a rare entity with high mortality, but few standardized treatment protocols exist. Further study and evidence-based treatment protocols are needed. This article outlines the role of relevant imaging, a multidisciplinary team approach, and the optimal timing of surgery, chemotherapy, and radiation. PMID- 29616904 TI - Does a Relationship Exist Between Lower Body Power and Balance Scores Among Older Adults? AB - CONTEXT: Falls are the second-leading cause of unintentional injury and death worldwide. OBJECTIVE: To determine if a relationship exists between lower body power scores and center of pressure (CoP) and limits of stability (LoS) scores. METHODS: A one-shot case study design (n = 13) was selected for the investigation. All participants were assessed stability scores via computerized posturography to determine CoP and LoS balance scores. Participants stood on a perturbed surface with their eyes open and closed. An experimental stair ramp with a switch mat timing device was used to determine lower body power scores in watts. RESULTS: There was a strong correlation (r = 0.725, p = 0.005) between the posterior (LoS) plane and relative peak power. An intraclass R revealed a strong correlation among the three trials (R = 0.831) performed on the stair ramp. CONCLUSION: Muscle power output and LoS scores have moderate to strong correlations with balance scores in older adults. PMID- 29616905 TI - Low Cancer Risk of South Asians: A Brief Report. AB - CONTEXT: South Asians (ancestry in India, Pakistan, Bangladesh, or Sri Lanka) may have lower cancer risk than other racial-ethnic groups. OBJECTIVE: To supplement published cohort data suggesting low cancer risk in South Asians. DESIGN: Logistic regression models with 7 covariates to study cancer mortality through 2012 in 273,843 persons (1117 South Asians) with baseline examination data from 1964 to 1985. MAIN OUTCOME MEASURE: Cancer mortality. RESULTS: Through 2012, death was attributed to cancer in 28,031 persons, of which 1555 were Asians, including 32 South Asians. The all-Asian vs white adjusted odds ratio was 1.0, and the South Asian vs white odds ratio was 0.5 (p < 0.001). In separate regressions, South Asians were at lower risk than blacks, Chinese, Filipinos, Japanese, or other Asians. The South Asian-white disparity was concentrated in men but was generally similar when strata of smoking, body mass index, baseline age, and date of death were compared. CONCLUSION: These data support the observation that compared with whites and other Asian groups, South Asians, especially men, have a lower risk of cancer. PMID- 29616906 TI - Diagnostic Pathway of Oral Cavity Cancer in an Integrated Health Care System. AB - CONTEXT: Survival for patients with oral cavity squamous cell carcinoma (OCSCC) has remained relatively stagnant despite advances in treatment. Few studies have examined why advanced-stage disease is diagnosed in 40% of patients with OCSCC nationally. OBJECTIVE: To characterize the diagnostic pathway of OCSCC in an integrated health care system. DESIGN: Retrospective study of patients with OCSCC (2007-2010). MAIN OUTCOME MEASURES: Referral patterns and demographic, clinical, and tumor characteristics associated with time to diagnosis (diagnostic interval). RESULTS: Of 247 patients, 167 (68%) had early-stage (I/II) disease, 86 (35%) were referred by dentists, and 70 (28%) had a history of premalignancy. The median time (interquartile range) from symptom onset to care sought from a primary care physician (patient interval), from primary care physician to otolaryngologist, and from otolaryngologist to diagnosis was 8.6 (4.0-25.8), 1.0 (0.6-3.1), 0.0 (0.0-3.0) weeks, respectively. These intervals did not differ by demographic characteristics, clinical factors, or tumor stage. Prolonged diagnostic intervals were observed among patients with premalignant lesions. CONCLUSION: The patient interval was the largest component of the total diagnostic interval. The subsequent professional workup proceeded relatively efficiently. Prolonged diagnostic interval in patients with premalignant lesions may reflect the natural history of malignant transformation rather than a delay in diagnosis. However, nearly one-fourth of these cases were diagnosed at an advanced stage; closer surveillance may represent an opportunity for diagnosis at an earlier stage. Surveillance for premalignant lesions and facilitating referrals from dentists may expedite the diagnosis and treatment of OCSCC. Further investigation is warranted. PMID- 29616907 TI - A Practical Guide for Physicians and Health Care Workers to Reduce Their Carbon Footprint in Daily Clinical Work. AB - With Earth Overshoot Day having recently passed, there is no space for complacency regarding taking care of our planet. On August 2, 2017, humanity used nature's resource budget for the entire year. For decades, we have lived far beyond our means by overexploiting natural resources and spewing pollution, such as microplastics and industrial chemicals, into our environment. On the other hand, public awareness of human-induced climate change has also increased since the 1980s. The frequent media coverage about extreme weather conditions and natural disasters, such as Hurricane Irma in 2017, serves as an important reminder that anthropogenic climate change is happening now.Adverse health conditions associated with climate change include an increased prevalence of diseases and disorders. Although we all contribute to this development, as physicians we also have the privileged duty to protect global human health. Therefore, we should make every effort to cut down our own carbon footprint and adapt a more sustainable lifestyle.The aim of this commentary is to provide feasible tips and strategies to effectively reduce one's individual carbon footprint, with a special focus on daily clinical and hospital work. Not only are these strategies easy to implement in daily clinical routine, but most of them are associated with important health benefits. PMID- 29616908 TI - Glioblastoma Multiforme in a Patient with Multiple Myeloma: A Case Report and Literature Review. AB - INTRODUCTION: Lenalidomide is an immunomodulatory drug approved by the US Food and Drug Administration in 2006 for the treatment of multiple myeloma. In 2012, the Food and Drug Administration issued a statement warning physicians of the increased risk with lenalidomide treatment of the following secondary primary malignancies: Acute myelogenous leukemia, myelodysplastic syndromes, and Hodgkin lymphoma. The statement did not mention glioblastoma multiforme, a Grade 4 astrocytoma, or other high-grade astrocytomas that have been reported on rare occasions in the setting of multiple myeloma. CASE PRESENTATION: A 72-year-old man, who had been in complete remission from multiple myeloma for 1 year after treatment that included lenalidomide, presented with confusion, headache, nausea and vomiting, and recurrent falls. A magnetic resonance image of his brain revealed a mass that on stereotactic biopsy was found to be glioblastoma multiforme. DISCUSSION: We present the seventh reported case of high-grade astrocytoma as a second primary malignancy in multiple myeloma and the first reported occurrence of glioblastoma multiforme after the use of lenalidomide in multiple myeloma. This report adds to the pool of cases that reveal associations between use of lenalidomide and increased risk of developing secondary primary high-grade astrocytomas in multiple myeloma. PMID- 29616909 TI - One Leader's Journey Toward Empanelment. AB - Empanelment is an important step toward managing population health. Achieving empanelment in a fee-for-service world necessitates organizational support for panel size measurement and creativity regarding use of panel size to inform access decisions. Empanelment efforts and access must be balanced to create sustainable, high-quality care models and to improve practitioner and patient experiences. PMID- 29616910 TI - The Case for Including Adverse Childhood Experiences in Child Maltreatment Education: A Path Analysis. AB - CONTEXT: The lifelong, negative consequences of exposure to adverse childhood experiences (ACEs) for individuals and their families are well established. OBJECTIVE: To demonstrate the importance of including ACE information in child maltreatment education curricula using path analysis. DESIGN: Survey data examined the impact of child maltreatment education programs and knowledge about ACEs on medical practitioners' reporting habits and ability to detect maltreatment. A path diagram distinguished between the direct impact of education programs on outcome measures and the indirect effect that is mediated through knowledge of ACEs. MAIN OUTCOME MEASURES: Medical practitioners' ability to detect child maltreatment and their number of referrals to Child Protective Services (CPS). RESULTS: The optimized path diagram (chi2SB(3) = 3.9, p = 0.27; RMSEA-SB = 0.017; R2 = 0.21, where SB is Satorra-Bentler coefficient and RMSEA is root-mean-square error of approximation) revealed the mediating variable "knowledge about ACEs" as the strongest structural effect (SB-beta = 0.34) on the number of CPS referrals. It was almost twice as high as the second strongest effect of formal education programs (SB-beta = 0.19). For workplace training programs, the total effect when including knowledge of ACEs was almost double as strong as the direct effect alone. Even when previous child maltreatment education was controlled for, practitioners familiar with the consequences of ACEs were significantly more likely to recognize and to report abuse to CPS. CONCLUSION: This study documented the importance of specialized training programs on ACEs, and the essential role ACE knowledge plays in the effectiveness of provider education programs. PMID- 29616911 TI - The Rural Inpatient Mortality Study: Does Urban-Rural County Classification Predict Hospital Mortality in California? AB - CONTEXT: Evidence suggests an association between rurality and decreased life expectancy. OBJECTIVE: To determine whether rural hospitals have higher hospital mortality, given that very sick patients may be transferred to regional hospitals. DESIGN: In this ecologic study, we combined Medicare hospital mortality ratings (N = 1267) with US census data, critical access hospital classification, and National Center for Health Statistics urban-rural county classifications. Ratings included mortality for coronary artery bypass grafting, stroke, chronic obstructive pulmonary disease, heart attack, heart failure, and pneumonia across 277 California hospitals between July 2011 and June 2014. We used generalized estimating equations to evaluate the association of urban-rural county classifications on mortality ratings. MAIN OUTCOME MEASURES: Unfavorable Medicare hospital mortality rating "worse than the national rate" compared with "better" or "same." RESULTS: Compared with large central "metro" (metropolitan) counties, hospitals in medium-sized metro counties had 6.4 times the odds of rating "worse than the national rate" for hospital mortality (95% confidence interval = 2.8-14.8, p < 0.001). For hospitals in small metro counties, the odds of having such a rating were 3.7 times greater (95% confidence interval = 0.7 23.4, p = 0.12), although not statistically significant. Few ratings were provided for rural counties, and analysis of rural counties was underpowered. CONCLUSION: Hospitals in medium-sized metro counties are associated with unfavorable Medicare mortality ratings, but current methods to assign mortality ratings may hinder fair comparisons. Patient transfers from rural locations to regional medical centers may contribute to these results, a potential factor that future research should examine. PMID- 29616912 TI - ECG Diagnosis: Accelerated Idioventricular Rhythm. PMID- 29616913 TI - Meditation and Mindfulness: A Call to Action in Elevating Primary Care. AB - Mindfulness meditation has vast physiologic benefits that can reduce physician burnout and improve physician well-being. Collective meditation and mindfulness practices with organized continuity among physician groups can synergistically elevate the practice of primary care by fostering creativity and innovation needed for sustainable solutions. A cohesive frontline physician voice rooted in higher purpose cultivated by meditation and mindfulness practices in a platform directly linked to quality improvement can lead to meaningful change in primary care for all. PMID- 29616914 TI - Association of Inflammatory Markers with Disease Progression in Patients with Metastatic Melanoma Treated with Immune Checkpoint Inhibitors. AB - INTRODUCTION: We investigated the effect of inflammatory biomarkers (neutrophil, platelet, and lymphocyte counts) on risk of progression in patients with metastatic melanoma treated with an immune checkpoint inhibitor targeting programmed cell death protein-1 (PD-1). METHODS: This retrospective cohort study included 108 patients with malignant melanoma treated with an anti-PD-1 checkpoint inhibitor from August 2014 through December 2015. The outcome was disease progression noted on imaging or clinical examination. Follow-up began on the date of initiation of anti-PD-1 therapy and ended on the date of progression, disenrollment, death of causes other than malignant melanoma, or the end of the study in February 2017. RESULTS: The median time from initiating therapy with an anti-PD-1 checkpoint inhibitor (nivolumab or pembrolizumab) to the end of follow up was 118 days. After adjustment, baseline neutrophil and platelet counts were associated with progression. The hazard ratio (HR) for neutrophil counts >= 5501/MUL vs <= 3900/MUL was 2.3 (95% confidence interval [CI] = 1.2-4.6, p < 0.05). For platelet counts >= 304,000 vs <= 215,000/MUL, the HR was 2.0 (CI = 1.0 3.9, p < 0.05). For lymphocyte counts >= 1716/MUL vs <= 1120/MUL, the HR was 0.5 (CI = 0.2-1.0, p = 0.05). CONCLUSION: For patients with metastatic melanoma treated with nivolumab or pembrolizumab, higher neutrophil or platelet counts, or lower lymphocyte counts, are associated with higher risk of progression. For these patients, we recommend more frequent assessment for progression and closer follow-up, especially for patients with substantial comorbidities or poor physical performance. PMID- 29616915 TI - Refractory Hypoxemia in a Patient with Submassive Pulmonary Embolism and an Intracardiac Shunt: A Case Report and Review of the Literature. AB - INTRODUCTION: Acute pulmonary embolism is the third leading cause of cardiovascular death. Management options include anticoagulation with or without thrombolysis. Concurrent persistent hypoxemia should be a clue to the existence of an intracardiac shunt. CASE PRESENTATION: A 46-year-old man experienced acute hypoxemic respiratory failure requiring mechanical ventilation after anesthesia induction for elective hip arthroplasty. He was found to have submassive bilateral pulmonary emboli with acute right ventricular dysfunction and a coexisting patent foramen ovale with right-to-left shunt. He remained profoundly hypoxemic despite catheter-directed thrombolysis. He underwent surgical embolectomy with partial endarterectomy, resulting in clinical improvement. DISCUSSION: The management of acute submassive pulmonary embolism is undertaken on an individualized basis because of the wide spectrum of clinical presentations. In this report we review the literature and discuss the evidence behind the management of cases of acute pulmonary embolism complicated by hypoxemia from a patent foramen ovale. In a case of acute pulmonary embolism complicated by refractory hypoxemia from an intracardiac shunt, adjunctive therapies in addition to anticoagulation and thrombolysis must be considered. PMID- 29616916 TI - Effects of Treatment-Associated Increases in Fruit and Vegetable Intake on the Consumption of Other Food Groups and Weight Through Self-Regulatory Processes. AB - CONTEXT: Increased intake of fruits and vegetables (FV) may be useful for weight loss. OBJECTIVE: This study was designed to evaluate the effects of changes in FV intake on the overall diet and to determine if self-regulation affects the association between changes in FV intake and weight. METHODS: Women with obesity (N = 74, mean age = 47.7 years) participating in a year-long behavioral weight loss treatment were assessed regarding changes in consumption of various food groups, physical activity, and eating self-regulation over 6, 12, and 24 months. RESULTS: FV intake change significantly predicted changes in weight and consumption of dairy and bread products and sweets. The only other notable relationships were among changes in sweets, bread, and dairy consumption over 24 months. Over 6, 12, and 24 months, changes in self-regulation significantly mediated the FV intake-weight change relationship. The overall mediation models were significant (R2 values = 0.19, 0.13, and 0.32, respectively). A reciprocal relationship between changes in FV intake and self-regulation also was found. Significant increases in physical activity outputs did not influence weight changes. CONCLUSION: Findings supported a relationship between FV intake and weight loss occurring through self-regulatory skills. Associations between FV intake and reduced consumption of other food groups provided data useful for improving the architecture of behavioral weight-loss treatments and the foci of medical practitioners' helping methods. PMID- 29616917 TI - Naloxone Distribution and Training for Patients with High-Risk Opioid Use in a Veterans Affairs Community-Based Primary Care Clinic. AB - CONTEXT: Naloxone distribution has historically been implemented in a community based, expanded public health model; however, there is now a need to further explore primary care clinic-based naloxone delivery to effectively address the nationwide opioid epidemic. OBJECTIVE: To create a general medicine infrastructure to identify patients with high-risk opioid use and provide 25% of this population with naloxone autoinjector prescription and training within a 6 month period. DESIGN: The quality improvement study was conducted at an outpatient clinic serving 1238 marginally housed veterans with high rates of comorbid substance use and mental health disorders. Patients at high risk of opioid-related adverse events were identified using the Stratification Tool for Opioid Risk Management and were contacted to participate in a one-on-one, 15 minute, hands-on naloxone training led by nursing staff. MAIN OUTCOME MEASURES: The number of patients identified at high risk and rates of naloxone training/distribution. RESULTS: There were 67 patients identified as having high risk opioid use. None of these patients had been prescribed naloxone at baseline. At the end of the intervention, 61 patients (91%) had been trained in the use of naloxone. Naloxone was primarily distributed by licensed vocational nurses (42/61, 69%). CONCLUSION: This study demonstrates the feasibility of high-risk patient identification and of a primary care-based and nursing-championed naloxone distribution model. This delivery model has the potential to provide access to naloxone to a population of patients with opioid use who may not be engaged in mental health or specialty care. PMID- 29616918 TI - Part of the research family. AB - eLife is publishing a collection of articles and interviews with scientists who are parents to explore how to get the best of both worlds. PMID- 29616919 TI - Looking for the best of both worlds. AB - Research institutions could do more to support scientists who are pregnant or have young children. PMID- 29616920 TI - Correction: Type III CRISPR-Cas systems can provide redundancy to counteract viral escape from type I systems. PMID- 29616921 TI - Association of Spilberger anxiety scale with nutritional attitudes, Mediterranean diet adoption and anthropometric characteristics in a sample of young adults. PMID- 29616922 TI - Moderate hyperhomocysteinemia along with increased levels of B12 in a 21-y boy with the Sanfilippo syndrome in poor nutritional status. PMID- 29616923 TI - Evaluation of diet quality and hyperemesis gravidarum in pregnant women according to income. PMID- 29616924 TI - Neuroprotective role of nutrients and prevalence of primary open angle glaucoma. PMID- 29616925 TI - Association of nutritional and socioeconomic factors with blood lipid levels in children aged 3-14 years old suffering from familial hypercholesterolemia. PMID- 29616926 TI - Dietary flavonoid intake and erectile dysfunction among young men of reproductive age. PMID- 29616927 TI - A clinical audit of nutritional screening and support of hospitalized patients with hematologic diseases. PMID- 29616928 TI - Postoperative C-reactive protein to albumin ratio as a diagnostic tool for predicting complications after abdominal surgery. PMID- 29616929 TI - Levels of obesity and adoption of Mediterranean diet in primary school children in areas of Attica with low socio-economic indicators. PMID- 29616930 TI - Adherence to the Mediterranean diet and metabolic parameters in patients with chronic kidney disease stage 5. PMID- 29616931 TI - Selenium supplementation and Hashimoto's thyroiditis: An update. PMID- 29616932 TI - A review of the use of neurotrophic agents as a conservative treatment of carpal tunnel syndrome. PMID- 29616933 TI - Cardiometabolic disease staging system in retired professional soccer players. PMID- 29616934 TI - Baseline characteristics of patients attending an obesity clinic for dietary intervention. PMID- 29616935 TI - Application and evaluation of a specifically designed, school based educational programme, focusing on promoting healthy eating behaviors in toddlers, based on traditional Greek farytails. PMID- 29616936 TI - Dietary compliance to hypocaloric diet and weight reduction in obese men and women. PMID- 29616937 TI - Water intake study in correlation with social and psychological factors in elderly people. PMID- 29616938 TI - Evaluation of orthorexia among dietetics students. PMID- 29616939 TI - Nutritional supplements, special diets and alternative therapies use among adults with different physical activity level in two cities of Greece and UK. PMID- 29616940 TI - Assessment to Mediterranean diet and quality of life in oncology patients. PMID- 29616941 TI - Microbiological/chemical quality of meals in the school-based program on food aid and healthy nutrition promotion - DIATROFI: The linkage with hygiene practices observed during inspections in food suppliers' facilities. PMID- 29616942 TI - Single and combined effects of inflammatory markers on diabetes development; the mediating role of obesity: 10-year follow up of the Attica study. PMID- 29616943 TI - Malnutrition risk, depression and weight status among HIV positive patients under HAART. PMID- 29616944 TI - Commandaria sweet wine melanoidins as functional food ingredient: Exploring antioxidant, antimicrobial and anti-hypertensive potential. PMID- 29616945 TI - Effects of a weight-loss Mediterranean lifestyle intervention on obstructive sleep apnea: Preliminary results of a randomized controlled clinical trial. PMID- 29616946 TI - Screening for nutrition risk in adults outpatients with inflammatory bowel disease: Results from a multicenter study in Greece and the United Kingdom. PMID- 29616947 TI - Knowledge and practices on healthy eating among breast cancer patients on chemotherapy. PMID- 29616948 TI - Dietary patterns in NAFLD and their interaction with polymorphisms in PNPLA3 and TM6SF2 genes. PMID- 29616949 TI - Nutrition therapy practices applied on severe burn patients: Results from the INS 2014 survey. PMID- 29616950 TI - J-shaped relationship between habitual coffee consumption and 10-year (2002-2012) cardiovascular disease incidence: The ATTICA study. PMID- 29616951 TI - Associations between food group consumption and follicular fluid follistatin levels in subfertile women undergoing in-vitro fertilization treatment. PMID- 29616952 TI - Metabolomic analysis of amino acids in inflammatory bowel disease (IBD): The role in disease management. PMID- 29616953 TI - The epidemic of overweight and central obesity in Greek students living in the islands: Results from the EYZHN program 2014-2015. PMID- 29616954 TI - Relationship between dietary habits and assisted reproduction outcome: A study among infertile Greek women undergoing in-vitro fertilization treatment. PMID- 29616955 TI - Prevalence of childhood hypertension and hypertension phenotypes by weight status and waist circumference: The healthy growth study. PMID- 29616956 TI - A clinical trial on the efficacy of a Mediterranean diet enriched with fatty fish in the management of paediatric asthma: Preliminary results. PMID- 29616957 TI - Diabetes risk assessment of cardiovascular free individuals, through the calculation and evaluation of a lifestyle index; results of the 10-year follow up of the Attica study. PMID- 29616958 TI - Associations between the Mediterranean diet and sleep in the elderly. PMID- 29616959 TI - Assessment of phase angle by bioelectric impedance analysis and its association with length of hospital stay in patients with pancreatic cancer undergoing pancreaticoduodenectomy. PMID- 29616960 TI - Prevalence of sarcopenia and diagnostic ability assessment of widely available methods of muscle mass and performance estimation in cirrhotic patients. PMID- 29616961 TI - Dietary intake of macronutrients and micronutrients, among the Greek population: HEL-NHANES 2013-2015. PMID- 29616962 TI - Associations between dietary patterns and obstructive sleep apnea severity. PMID- 29616964 TI - Nutritional assessment in gastrointestinal oncology patients undergoing chemotherapy. PMID- 29616963 TI - Nutritional status and objective assessment of functional status in patients with neoplastic diseases receiving antineoplastic therapy: Preliminary results. PMID- 29616965 TI - Air pollution during pregnancy and childhood obesity risk: Potential protective effect of diet. PMID- 29616966 TI - Estimation of the relationship between restrictive nutritional behaviors and body composition in adolescence and early adulthood. PMID- 29616967 TI - Mediterranean diet adherence and nutritional assessment of Cypriot primary schoolchildren. PMID- 29616968 TI - Adherence to the Mediterranean diet and lifestyle characteristics of university students in Cyprus: A cross-sectional survey. PMID- 29616969 TI - Decrease of hypoglycaemic episodes of children and adolescents with Type 1 diabetes after participation in a summer camp. PMID- 29616970 TI - The association of physical activity to blood cholesterol levels and blood pressure. PMID- 29616971 TI - The orthodontic evaluation at the service of nutrition science: Preventing and promoting human health during childhood and adolescence. PMID- 29616972 TI - The effects of vitamin D deficiency on uterine contractile protein expression. PMID- 29616973 TI - The incidence of unintentional underfeeding in ICU patients: A 12-month observational study. PMID- 29616974 TI - Assessment of nutritional status and conformity with Mediterranean diet of family caregivers of Alzheimer's disease patients. PMID- 29616975 TI - Role of electron back action on photons in hybridizing double-layer graphene plasmons with localized photons. AB - In this paper, we deal with the electromagnetic coupling between an incident surface-plasmon-polariton wave and relativistic electrons in two graphene layers. Our previous investigation was limited to single-layer graphene (Iurov et al 2017 Phys. Rev. B 96 081408). However, the present work, is both an expanded and extended version of this previous Phys. Rev. B paper after having included very detailed theoretical formalisms and extensive comparisons of results from either one or two graphene layers embedded in a dielectric medium. The additional retarded Coulomb interaction between two graphene layers will compete with the coupling between the single graphene layer and the surface of a conductor. Consequently, some distinctive features, such as triply-hybridized absorption peaks and a new acoustic-like graphene plasmon mode within the anticrossing region, have been found for the double-layer graphene system. Physically, our theory is self-consistent, in comparison with a commonly adopted perturbative theory, for studying hybrid light-plasmon modes and the electron back action on photons. Instead of usual radiation or grating-deflection field coupling, a surface-plasmon-polariton localized field coupling is introduced with completely different dispersion relations for radiative (small wave numbers) and evanescent (large wave numbers) field modes. Technically, the exactly calculated effective scattering matrix for this theory can be employed to construct an effective medium theory in order to improve the accuracy of the well-known finite difference time-domain method for solving Maxwell's equations numerically. Practically, the predicted triply-hybridized absorption peaks can excite polaritons only, giving rise to a possible polariton-condensation based laser. PMID- 29616976 TI - Improving the analysis of near-infrared spectroscopy data with multivariate classification of hemodynamic patterns: a theoretical formulation and validation. AB - OBJECTIVE: The statistical analysis of functional near infrared spectroscopy (fNIRS) data based on the general linear model (GLM) is often made difficult by serial correlations, high inter-subject variability of the hemodynamic response, and the presence of motion artifacts. In this work we propose to extract information on the pattern of hemodynamic activations without using any a priori model for the data, by classifying the channels as 'active' or 'not active' with a multivariate classifier based on linear discriminant analysis (LDA). APPROACH: This work is developed in two steps. First we compared the performance of the two analyses, using a synthetic approach in which simulated hemodynamic activations were combined with either simulated or real resting-state fNIRS data. This procedure allowed for exact quantification of the classification accuracies of GLM and LDA. In the case of real resting-state data, the correlations between classification accuracy and demographic characteristics were investigated by means of a Linear Mixed Model. In the second step, to further characterize the reliability of the newly proposed analysis method, we conducted an experiment in which participants had to perform a simple motor task and data were analyzed with the LDA-based classifier as well as with the standard GLM analysis. MAIN RESULTS: The results of the simulation study show that the LDA-based method achieves higher classification accuracies than the GLM analysis, and that the LDA results are more uniform across different subjects and, in contrast to the accuracies achieved by the GLM analysis, have no significant correlations with any of the demographic characteristics. Findings from the real-data experiment are consistent with the results of the real-plus-simulation study, in that the GLM analysis results show greater inter-subject variability than do the corresponding LDA results. SIGNIFICANCE: The results obtained suggest that the outcome of GLM analysis is highly vulnerable to violations of theoretical assumptions, and that therefore a data-driven approach such as that provided by the proposed LDA-based method is to be favored. PMID- 29616977 TI - Low-loss integrated electrical surface plasmon source with ultra-smooth metal film fabricated by polymethyl methacrylate 'bond and peel' method. AB - External light sources are mostly employed to functionalize the plasmonic components, resulting in a bulky footprint. Electrically driven integrated plasmonic devices, combining ultra-compact critical feature sizes with extremely high transmission speeds and low power consumption, can link plasmonics with the present-day electronic world. In an effort to achieve this prospect, suppressing the losses in the plasmonic devices becomes a pressing issue. In this work, we developed a novel polymethyl methacrylate 'bond and peel' method to fabricate metal films with sub-nanometer smooth surfaces on semiconductor wafers. Based on this method, we further fabricated a compact plasmonic source containing a metal insulator-metal (MIM) waveguide with an ultra-smooth metal surface on a GaAs based light-emitting diode wafer. An increase in propagation length of the SPP mode by a factor of 2.95 was achieved as compared with the conventional device containing a relatively rough metal surface. Numerical calculations further confirmed that the propagation length is comparable to the theoretical prediction on the MIM waveguide with perfectly smooth metal surfaces. This method facilitates low-loss and high-integration of electrically driven plasmonic devices, thus provides an immediate opportunity for the practical application of on-chip integrated plasmonic circuits. PMID- 29616978 TI - A study on dynamic model of steady-state visual evoked potentials. AB - OBJECTIVE: Significant progress has been made in the past two decades to considerably improve the performance of steady-state visual evoked potential (SSVEP)-based brain-computer interface (BCI). However, there are still some unsolved problems that may help us to improve BCI performance, one of which is that our understanding of the dynamic process of SSVEP is still superficial, especially for the transient-state response. APPROACH: This study introduced an antiphase stimulation method (antiphase: phase [Formula: see text]), which can simultaneously separate and extract SSVEP and event-related potential (ERP) signals from EEG, and eliminate the interference of ERP to SSVEP. Based on the SSVEP signals obtained by the antiphase stimulation method, the envelope of SSVEP was extracted by the Hilbert transform, and the dynamic model of SSVEP was quantitatively studied by mathematical modeling. The step response of a second order linear system was used to fit the envelope of SSVEP, and its characteristics were represented by four parameters with physical and physiological meanings: one was amplitude related, one was latency related and two were frequency related. This study attempted to use pre-stimulation paradigms to modulate the dynamic model parameters, and quantitatively analyze the results by applying the dynamic model to further explore the pre-stimulation methods that had the potential to improve BCI performance. MAIN RESULTS: The results showed that the dynamic model had good fitting effect with SSVEP under three pre stimulation paradigms. The test results revealed that the parameters of SSVEP dynamic models could be modulated by the pre-stimulation baseline luminance, and the gray baseline luminance pre-stimulation obtained the highest performance. SIGNIFICANCE: This study proposed a dynamic model which was helpful to understand and utilize the transient characteristics of SSVEP. This study also found that pre-stimulation could be used to adjust the parameters of SSVEP model, and had the potential to improve the performance of SSVEP-BCI. PMID- 29616979 TI - Ultrahigh-power supercapacitors based on highly conductive graphene nanosheet/nanometer-sized carbide-derived carbon frameworks. AB - In order to develop energy storage devices with high power performance, electrodes should hold well-defined pathways for efficient ionic and electronic transport. Herein, we demonstrate a highly conductive graphene nanosheet/nanometer-sized carbide-derived carbon framework (hcGNS/nCDC). In this architecture, nCDC possesses short transport paths for electrolyte ions, thus ensuring the rapid ions transportation. The excellent electrical conductivity of hcGNS can reduce the electrode internal resistance for the supercapacitor and thus endows the hcGNS/nCDC composite electrodes with excellent electronic transportation performance. Electrochemical measurements show that the cyclic voltammogram of hcGNS/nCDC can maintain a rectangular-like shape with the increase of the scan rate from 5 mV s-1 to 20 V s-1, and the specific capacitance retention is up to 51% even at a high scan rate of 20 V s-1, suggesting ultrahigh power performance, which, to the best of our knowledge, is among the best power performances reported so far for the carbon materials. Furthermore, the hcGNS/nCDC composite also shows an excellent cycling stability (no drop in its capacitance occurs even after 10000 cycles). This work demonstrates the advantage in the ultrahigh power performance for the framework having both short transport pathways for electrolyte ions and high electrical conductivity. PMID- 29616980 TI - Direct atomic fabrication and dopant positioning in Si using electron beams with active real-time image-based feedback. AB - Semiconductor fabrication is a mainstay of modern civilization, enabling the myriad applications and technologies that underpin everyday life. However, while sub-10 nanometer devices are already entering the mainstream, the end of the Moore's law roadmap still lacks tools capable of bulk semiconductor fabrication on sub-nanometer and atomic levels, with probe-based manipulation being explored as the only known pathway. Here we demonstrate that the atomic-sized focused beam of a scanning transmission electron microscope can be used to manipulate semiconductors such as Si on the atomic level, inducing growth of crystalline Si from the amorphous phase, reentrant amorphization, milling, and dopant front motion. These phenomena are visualized in real-time with atomic resolution. We further implement active feedback control based on real-time image analytics to automatically control the e-beam motion, enabling shape control and providing a pathway for atom-by-atom correction of fabricated structures in the near future. These observations open a new epoch for atom-by-atom manufacturing in bulk, the long-held dream of nanotechnology. PMID- 29616981 TI - Effect of the shell material and confinement type on the conversion efficiency of core/shell quantum dot nanocrystal solar cells. AB - In this study, the effects of the shell material and confinement type on the conversion efficiency of core/shell quantum dot nanocrystal (QDNC) solar cells have been investigated in detail. For this purpose, the conventional, i.e. original, detailed balance model, developed by Shockley and Queisser to calculate an upper limit for the conversion efficiency of silicon p-n junction solar cells, is modified in a simple and effective way to calculate the conversion efficiency of core/shell QDNC solar cells. Since the existing model relies on the gap energy ([Formula: see text]) of the solar cell, it does not make an estimation about the effect of QDNC materials on the efficiency of the solar cells, and gives the same efficiency values for several QDNC solar cells with the same [Formula: see text]. The proposed modification, however, estimates a conversion efficiency in relation to the material properties and also the confinement type of the QDNCs. The results of the modified model show that, in contrast to the original one, the conversion efficiencies of different QDNC solar cells, even if they have the same [Formula: see text], become different depending upon the confinement type and shell material of the core/shell QDNCs, and this is crucial in the design and fabrication of the new generation solar cells to predict the confinement type and also appropriate QDNC materials for better efficiency. PMID- 29616982 TI - A fast intracortical brain-machine interface with patterned optogenetic feedback. AB - OBJECTIVE: The development of brain-machine interfaces (BMIs) brings new prospects to patients with a loss of autonomy. By combining online recordings of brain activity with a decoding algorithm, patients can learn to control a robotic arm in order to perform simple actions. However, in contrast to the vast amounts of somatosensory information channeled by limbs to the brain, current BMIs are devoid of touch and force sensors. Patients must therefore rely solely on vision and audition, which are maladapted to the control of a prosthesis. In contrast, in a healthy limb, somatosensory inputs alone can efficiently guide the handling of a fragile object, or ensure a smooth trajectory. We have developed a BMI in the mouse that includes a rich artificial somatosensory-like cortical feedback. APPROACH: Our setup includes online recordings of the activity of multiple neurons in the whisker primary motor cortex (vM1) and delivers feedback simultaneously via a low-latency, high-refresh-rate, spatially structured photo stimulation of the whisker primary somatosensory cortex (vS1), based on a mapping obtained by intrinsic imaging. MAIN RESULTS: We demonstrate the operation of the loop and show that mice can detect the neuronal spiking in vS1 triggered by the photo-stimulations. Finally, we show that the mice can learn a behavioral task relying solely on the artificial inputs and outputs of the closed-loop BMI. SIGNIFICANCE: This is the first motor BMI that includes a short-latency, intracortical, somatosensory-like feedback. It will be a useful platform to discover efficient cortical feedback schemes towards future human BMI applications. PMID- 29616983 TI - Upper stimulation threshold for retinal ganglion cell activation. AB - OBJECTIVE: The existence of an upper threshold in electrically stimulated retinal ganglion cells (RGCs) is of interest because of its relevance to the development of visual prosthetic devices, which are designed to restore partial sight to blind patients. The upper threshold is defined as the stimulation level above which no action potentials (direct spikes) can be elicited in electrically stimulated retina. APPROACH: We collected and analyzed in vitro recordings from rat RGCs in response to extracellular biphasic (anodic-cathodic) pulse stimulation of varying amplitudes and pulse durations. Such responses were also simulated using a multicompartment model. MAIN RESULTS: We identified the individual cell variability in response to stimulation and the phenomenon known as upper threshold in all but one of the recorded cells (n = 20/21). We found that the latencies of spike responses relative to stimulus amplitude had a characteristic U-shape. In silico, we showed that the upper threshold phenomenon was observed only in the soma. For all tested biphasic pulse durations, electrode positions, and pulse amplitudes above lower threshold, a propagating action potential was observed in the distal axon. For amplitudes above the somatic upper threshold, the axonal action potential back-propagated in the direction of the soma, but the soma's low level of hyperpolarization prevented action potential generation in the soma itself. SIGNIFICANCE: An upper threshold observed in the soma does not prevent spike conductance in the axon. PMID- 29616984 TI - Effectiveness of different rescanning techniques for scanned proton radiotherapy in lung cancer patients. AB - Non-small cell lung cancer (NSCLC) is a tumour type thought to be well-suited for proton radiotherapy. However, the lung region poses many problems related to organ motion and can for actively scanned beams induce severe interplay effects. In this study we investigate four mitigating rescanning techniques: (1) volumetric rescanning, (2) layered rescanning, (3) breath-sampled (BS) layered rescanning, and (4) continuous breath-sampled (CBS) layered rescanning. The breath-sampled methods will spread the layer rescans over a full breathing cycle, resulting in an improved averaging effect at the expense of longer treatment times. In CBS, we aim at further improving the averaging by delivering as many rescans as possible within one breathing cycle. The interplay effect was evaluated for 4D robustly optimized treatment plans (with and without rescanning) for seven NSCLC patients in the treatment planning system RayStation. The optimization and final dose calculation used a Monte Carlo dose engine to account for the density heterogeneities in the lung region. A realistic treatment delivery time structure given from the IBA ScanAlgo simulation tool served as basis for the interplay evaluation. Both slow (2.0 s) and fast (0.1 s) energy switching times were simulated. For all seven studied patients, rescanning improves the dose conformity to the target. The general trend is that the breath sampled techniques are superior to layered and volumetric rescanning with respect to both target coverage and variability in dose to OARs. The spacing between rescans in our breath-sampled techniques is set at planning, based on the average breathing cycle length obtained in conjunction with CT acquisition. For moderately varied breathing cycle lengths between planning and delivery (up to 15%), the breath-sampled techniques still mitigate the interplay effect well. This shows the potential for smooth implementation at the clinic without additional motion monitoring equipment. PMID- 29616985 TI - Recording characteristics of electrical impedance-electromyography needle electrodes. AB - OBJECTIVE: Needle EMG remains the standard clinical test for neuromuscular disease (NMD) assessment, but it only characterizes myofiber membrane depolarization. On the other hand, electrical impedance provides non-electrically active structural and compositional data of tissues. Here, we designed a prototype of needle electrode integrating electrical impedance and EMG measurement capabilities, the so-called I-EMG needle electrode. APPROACH: We use finite element method models to study the impedance recording characteristics of I-EMG needle electrodes. The simulated electrical and mechanical design specifications are then manufactured to create a prototype of an I-EMG needle electrode. We pilot these new needle electrodes by conducting in vivo impedance measurements with muscle at rest on healthy wild-type (wt, n = 5) and muscular dystrophy (mdx, n = 5) mice. Comparisons between wt and mdx mice are performed using Mann-Whitney test, two-tailed, p < 0.05. The electrical characterization of the EMG electrode in the developed I-EMG needles was performed in vitro on saline solution and through EMG detection in wt animal at rest and during voluntary contractions. RESULTS: Muscle impedance demonstrate good repeatability (p < 0.05 and p < 0.005 for resistance and reactance at 50 kHz, respectively) and agreement between different I-EMG needles. Impedance data allows us to discriminate between mdx and wt muscle (p < 0.05 and p < 0.005 for resistance and reactance at 10 kHz, respectively). EMG broadband noise power and peak amplitude using the I-EMG needle were similar to that of a commercial monopolar EMG needle. EMG recordings using the I-EMG needle measured electrical activity similar to a standard monopolar needle with muscle at rest and during voluntary contraction. SIGNIFICANCE: Needle I-EMG technology may offer the opportunity to enhance the diagnostic capability and quantification of NMD beyond that possible with either impedance or EMG techniques separately. Ultimately, needle I-EMG could serve as a new bedside tool to assess NMD without increasing the complexity or duration of the EMG test. PMID- 29616986 TI - Homogeneous growth of TiO2-based nanotubes on nitrogen-doped reduced graphene oxide and its enhanced performance as a Li-ion battery anode. AB - The pursuit of a promising replacement candidate for graphite as a Li-ion battery anode, which can satisfy both engineering criteria and market needs has been the target of researchers for more than two decades. In this work, we have investigated the synergistic effect of nitrogen-doped reduced graphene oxide (NrGO) and nanotubular TiO2 to achieve high rate capabilities with high discharge capacities through a simple, one-step and scalable method. First, nanotubes of hydrogen titanate were hydrothermally grown on the surface of NrGO sheets, and then converted to a mixed phase of TiO2-B and anatase (TB) by thermal annealing. Specific surface area, thermal gravimetric, structural and morphological characterizations were performed on the synthesized product. Electrochemical properties were investigated by cyclic voltammetry and cyclic charge/discharge tests. The prepared anode showed high discharge capacity of 150 mAh g-1 at 1 C current rate after 50 cycles. The promising capacity of synthesized NrGO-TB was attributed to the unique and novel microstructure of NrGO-TB in which long nanotubes of TiO2 have been grown on the surface of NrGO sheets. Such architecture synergistically reduces the solid-state diffusion distance of Li+ and increases the electronic conductivity of the anode. PMID- 29616987 TI - The crystal structure of [Fe2(PIMIC6)(AnthCO2)(CH3CN)].[Fe2(PIMIC6)(AnthCO2)(CH3CN)0.9(CH2Cl2)0.1].[Fe2(PI IC6)(AnthCO2)(OH2)].0.75CH3CN: a crystallographer's nightmare or a fascinating case of disorder? AB - Refinement of large crystal structures as well as that of disordered structures can be challenging. If both features come together, structure refinement has the potential of becoming a crystallographer's nightmare. Here, the refinement of the large and highly disordered structure of [Fe2(PIMIC6)(AnthCO2)(CH3CN)].[Fe2(PIMIC6)(AnthCO2)(CH3CN)0.9(CH2Cl2)0.1].[Fe2(PI IC6)(AnthCO2)(OH2)].0.75CH3CN [(1), PIMIC6 is a phenol-imine-based macrocycle, AnthCO2 is an anthracene acid anion] is described and discussed. A total of 5311 parameters had to be refined to generate a model that allows for 14 400 possible arrangements of (1) in the asymmetric unit, making this structure one of the most complex structures in the Cambridge Structural Database to date. All disorders are exceptionally well resolved and exhaustive parameterizing affords a refinement model that is unique with respect to the detail of disorder refinement. PMID- 29616988 TI - Crystal growth, structure and characterization of Er6B4O15 as self-activated eye safe laser material within the near-infrared waveband. AB - A new rare-earth borate Er6B4O15 was synthesized by a solid-state reaction technique. The crystal was obtained by a flux method. Single-crystal X-ray diffraction analysis revealed that the crystal structure is composed of ErO6 polyhedra sharing edges and BO3 groups. The absorption, near-infrared fluorescence spectra and the fluorescence decay curve of Er: 4I13/2 energy level in the Er6B4O15 crystal were measured at room temperature. The absorption peak was located at 977 nm with absorption cross section of 1.16 * 10-21 cm2 and a full width at half-maximum (FWHM) of 16 nm, which is very suitable for commercial 980 nm laser diode pumping. A maximum emission peak at 1560 mm with a broad FWHM of 64 nm was observed in this crystal because of the Er3+ transition 4I13/2 >4I15/2, while the emission cross section was calculated to be 8.53 * 10-20 cm2. These results imply that the Er6B4O15 crystal is a promising candidate material for the achievement of an eye-safe near-infrared wavelength laser. PMID- 29616989 TI - A method for visualization of the variation of noncovalent interactions in crystal structures of conformational polymorphs. AB - A method for clear visualization of the variation of noncovalent interactions in crystal structures of conformational polymorphs is developed and introduced. The first stage of the method establishes the characteristics of all, without exception, noncovalent interactions in all crystal structures under discussion. This is possible using a strict and objective method of construction of Voronoi Dirichlet polyhedra within the framework of the stereoatomic model of crystal structures. The second stage of the method then involves plotting of diagrams, showing the relation between parameters characterizing interatomic interactions and chosen geometric parameters of molecules. Application of the title method to highly polymorphic systems of ROY and flufenamic acid allows several imperceptible features of real crystal structures to be revealed and determines the value of different types of interactions in their conformational polymorphs. The method is universal as it can be readily adapted to any system of crystal structures in which noncovalent interactions change as a function of any parameters. Employment of the title method along with quantum chemical calculations offers opportunities for the correlation of potential energy of crystalline materials with noncovalent interactions in their structures, which is a giant step forward towards a more complete understanding of the relationship between the structure and properties of compounds. PMID- 29616990 TI - Aromaticity of benzene derivatives: an exploration of the Cambridge Structural Database. AB - The harmonic oscillator model of aromaticity (HOMA) index, one of the most popular aromaticity indices for solid-state benzene rings in the Cambridge Structural Database (CSD), has been analyzed. The histograms of HOMA for benzene, for benzene derivatives with one formyl, nitro, amino or hydroxy group as well as the histograms for the derivatives with two formyl, nitro, amino or hydroxy groups in ortho, meta and para positions were investigated. The majority of the substituted benzene derivatives in the CSD are characterized by a high value of HOMA, indicating fully aromatic character; however, the distribution of the HOMA value from 1 to about 0 indicates decreasing aromaticity down to non-aromatic character. Among the benzene derivatives investigated, a significant decrease in aromaticity can be related to compounds with diamino and dinitro groups in the meta position. PMID- 29616991 TI - Revisiting the I{?overline {?bf 1}} structures of high-temperature Ca-rich plagioclase feldspar - a single-crystal neutron and X-ray diffraction study. AB - The I{?overline 1} structures of four natural Ca-rich plagioclase feldspars formed at high temperature were analysed using single-crystal neutron and X-ray diffraction. The neutron time-of-flight Laue diffractometer at the ORNL Spallation Neutron Source (Tennessee, USA) combined with a single-crystal X-ray diffraction instrument were able to reveal some new details about these already intensively studied structures. The split oxygen atoms refined from the neutron diffraction data show the underlying mechanism of Ca-Na ordering and the anisotropic P{?overline 1} ordering along the c-axis. The compositional ranges covered by the samples studied are quite rare for I{?overline 1} structures. The incommensurately modulated e2 structure of some plagioclase samples can easily be confused with an I{?overline 1} structure from the diffraction pattern, which puts some previously published I{?overline 1} structures into question. An incomplete phase diagram for Ca-rich plagioclase feldspar is proposed to explain the rarity of the I{?overline 1} structure in this compositional range, and a time-temperature-transformation diagram for the composition ~An66 is provided accordingly. PMID- 29616992 TI - Ionic network analysis of tectosilicates: the example of coesite at variable pressure. AB - The method of ionic network analysis [Thomas (2017). Acta Cryst. B73, 74-86] is extended to tectosilicates through the example of coesite, the high-pressure polymorph of SiO2. The structural refinements of Cernok et al. [Z. Kristallogr. (2014), 229, 761-773] are taken as the starting point for applying the method. Its purpose is to predict the unit-cell parameters and atomic coordinates at (p-T X) values in-between those of diffraction experiments. The essential development step for tectosilicates is to define a pseudocubic parameterization of the O4 cages of the SiO4 tetrahedra. The six parameters aPC, bPC, cPC, alphaPC, betaPC and gammaPC allow a full quantification of the tetrahedral structure, i.e. distortion and enclosed volume. Structural predictions for coesite require that two separate quasi-planar networks are defined, one for the silicon ions and the other for the O4 cage midpoints. A set of parametric curves is used to describe the evolution with pressure of these networks and the pseudocubic parameters. These are derived by fitting to the crystallographic data. Application of the method to monoclinic feldspars and to quartz and cristobalite is discussed. Further, a novel two-parameter quantification of the degree of tetrahedral distortion is described. At pressures in excess of ca 20.45 GPa it is not possible to find a self-consistent solution to the parametric curves for coesite, pointing to the likelihood of a phase transition. PMID- 29616993 TI - Hydrocerussite-related minerals and materials: structural principles, chemical variations and infrared spectroscopy. AB - White lead or basic lead carbonate, 2PbCO3.Pb(OH)2, the synthetic analogue of hydrocerussite Pb3(OH)2(CO3)2, has been known since antiquity as the most frequently used white paint. A number of different minerals and synthetic materials compositionally and structurally related to hydrocerussite have been described within the last two decades. Herein, a review is given of general structural principles, chemical variations and IR spectra of the rapidly growing family of hydrocerussite-related minerals and synthetic materials. Only structures containing a hydroxo- and/or oxo-component, i.e. which are compositionally directly related with hydrocerussite and 'white lead', are reviewed in detail. An essential structural feature of all the considered phases is the presence of electroneutral [PbCO3]0 cerussite-type layers or sheets. Various interleaved sheets can be incorporated between the cerussite-type sheets. Different sheets are stacked into two-dimensional blocks separated by the stereochemically active 6s2 lone electron pairs on Pb2+ cations. Minerals and synthetic materials described herein, together with a number of still hypothetical members, constitute a family of modular structures. Hydrocerussite, abellaite and grootfonteinite can be considered to constitute a merotype family of structures. The remaining hydrocerussite-related structures discussed are built on similar principles, but are more complex. Structural architectures of somersetite and slag phase from Lavrion, Attica, Greece, are unique for oxysalt mineral structures in general. Thus, the whole family of hydrocerussite-related phases can be denoted as a plesiotype family of modular structures. The crystal structures of hydrocerussite from Merehead quarry, Somerset, England, and of its synthetic analogue, both determined from single crystals, are reported here for the first time. The results of the infrared (IR) spectroscopy show that this method is useful for distinguishing several different minerals related to hydrocerussite and their synthetic analogues. PMID- 29616994 TI - Accurate and precise lattice parameters of H2O and D2O ice Ih between 1.6 and 270 K from high-resolution time-of-flight neutron powder diffraction data. AB - Accurate and precise lattice parameters for D2O and H2O varieties of hexagonal ice (ice Ih, space group P63/mmc) have been obtained in the range 1.6 to 270 K. Precision of the lattice parameters (~0.0002% in a and 0.0004% in c for D2O, 0.0008% in a and 0.0015% in c for H2O) is ensured by use of the time-of-flight method on one of the longest primary neutron flight-path instruments in the world, the High-Resolution Powder Diffractometer at the ISIS neutron source. These data provide a more precise description of the negative thermal expansion of the material at low temperatures than the previous synchrotron 'gold standard' [Rottger et al. (1994). Acta Cryst. B50, 644-648], including the region below 10 K where the lattice parameters saturate. The volume expansivity of both isotopologues turns negative below 59-60 K, in excellent agreement with a recent dilatometry study. The axial expansivities are highly isotropic (differing by < 1% in D2O ice Ih). Furthermore, the c/a ratio of different D2O ice samples exhibit a statistically significant dispersion of ~0.015% below 150 K that appears to depend on the thermal history of the sample, which disappears on warming above 150 K. Similarly, H2O ice exhibits a 'kink' in the c/a ratio at ~115 K. The most plausible explanation is a freezing-in of the molecular reorientation process on cooling and subsequent relaxation on warming. PMID- 29616995 TI - Phase transitions in ferroelectric 4-aminopyridinium tetrachloroantimonate(III) - revisited. AB - New X-ray diffraction studies on the crystal structure of ferroelectric [4 NH2C5H4NH][SbCl4] indicate that in the broad temperature range from 240 to 304 K covering the three intermediate phases, the crystal structure is modulated. Phase II is incommensurately modulated with modulation vector q = betab*, beta varying from 0.60 to 0.66 and monoclinic C2/c(0beta0)s0 superspace group. Ferroelectric phase III is commensurate with q = 2?over 3b* and Cc(0beta0)0 symmetry. Polar phase IV is incommensurately modulated with beta varying from 0.66 to 0.70 and Cc(0beta0)0 superspace group. In all phases only first-order satellites are observed along the b* direction. Two types of periodic deformation are present in the structure of modulated phases. The 4-aminopyridinium cations are subjected to occupation modulation whereas [SbCl4]-n chains are displacively modulated. The paraelectric-ferroelectric phase transition is an example of the incommensurate commensurate transition of the lock-in type. A new mechanism for this transformation is proposed. PMID- 29616996 TI - Crystal structure, phase transition and structural deformations in iron borate (Y0.95Bi0.05)Fe3(BO3)4 in the temperature range 90-500 K. AB - An accurate X-ray diffraction study of (Y0.95Bi0.05)Fe3(BO3)4 single crystals in the temperature range 90-500 K was performed on a laboratory diffractometer and used synchrotron radiation. It was established that the crystal undergoes a diffuse structural phase transition in the temperature range 350-380 K. The complexity of localization of such a transition over temperature was overcome by means of special analysis of systematic extinction reflections by symmetry. The transition temperature can be considered to be Tstr ? 370 K. The crystal has a trigonal structure in the space group P3121 at temperatures of 90-370 K, and it has a trigonal structure in the space group R32 at 375-500 K. There is one type of chain formed by the FeO6 octahedra along the c axis in the R32 phase. When going into the P3121 phase, two types of nonequivalent chains arise, in which Fe atoms are separated from the Y atoms by a different distance. Upon lowering the temperature from 500 to 90 K, a distortion of the Y(Bi)O6, FeO6, B(2,3)O3 coordination polyhedra is observed. The distances between atoms in helical Fe chains and Fe-O-Fe angles change non-uniformly. A sharp jump in the equivalent isotropic displacement parameters of O1 and O2 atoms within the Fe-Fe chains and fluctuations of the equivalent isotropic displacement parameters of B2 and B3 atoms were observed in the region of structural transition as well as noticeable elongation of O1, O2, B2, B3, Fe1, Fe2 atomic displacement ellipsoids. It was established that the helices of electron density formed by Fe, O1 and O2 atoms may be structural elements determining chirality, optical activity and multiferroicity of rare-earth iron borates. Compression and stretching of these helices account for the symmetry change and for the manifestation of a number of properties, whose geometry is controlled by an indirect exchange interaction between iron cations that compete with the thermal motion of atoms in the structure. Structural analysis detected these changes as variations of a number of structural characteristics in the c unit-cell direction, that is, the direction of the helices. Structural results for the local surrounding of the atoms in (Y0.95Bi0.05)Fe3(BO3)4 were confirmed by EXAFS and Mossbauer spectroscopies. PMID- 29616997 TI - Crystal structures of alkali metal (Group 1) citrate salts. AB - The crystal structures of 16 new alkali metal citrates were determined using powder and/or single crystal techniques. These structures and 12 previously determined citrate structures were optimized using density functional techniques. The central portion of a citrate ion is fairly rigid, while the conformations of the terminal carboxylate groups exhibit no preferences. The citrate-metal bonding is ionic. Trends in metal-citrate coordination are noted. The energy of an O H...O hydrogen bond is proportional to the square root of the H...acceptor Mulliken overlap population, and a correlation between the hydrogen bond energy and the H...acceptor distance was developed: E (kJ mol-1) = 137.5 (5) - 45.7 (8) (H...A, A). The hydrogen bond contribution to the crystal energy ranges from 62.815 to 627.6 kJ mol-1 citrate-1 and comprises ~5 to 30% of the crystal energy. The general order of ionization of the three carboxylic acid groups of citric acid is: central, terminal, terminal, although there are a few exceptions. Comparisons of the refined and DFT-optimized structures indicate that crystal structures determined using powder diffraction data may not be as accurate as single-crystal structures. PMID- 29616999 TI - lncRNA UCA1 Is a Novel Regulator in Cardiomyocyte Hypertrophy through Targeting the miR-184/HOXA9 Axis. AB - Cardiac hypertrophy is closely associated with a series of cardiovascular diseases, including heart failure and sudden death in particular. An in-depth comprehension of the pathogenesis of cardiac hypertrophy will improve the diagnosis and therapy of cardiac hypertrophy. It has been acknowledged that long noncoding RNAs/microRNAs (lncRNAs/miRNAs) are crucial regulators in diverse biological processes, including various cardiovascular diseases, in multiple manners. Nevertheless, the biological roles of lncRNA UCA1 and miR-184 in cardiac hypertrophy are scarcely reported. In this paper, qRT-PCR analysis exhibited that lncRNA UCA1 was highly expressed in mice heart treated with transverse aortic constriction (TAC) and the cardiomyocytes treated with phenylephrine (PE). On the contrary, miR-184 was downregulated under the same conditions. In addition, it was deduced that lncRNA UCA1 was reversely related with miR-184 in PE-triggered hypertrophic cardiomyocytes, confirmed by the Spearman correlation analysis. The knockdown of UCA1 or the overexpression of miR-184 lessened the enlarged surface area of cardiomyocytes and the elevated expressions of fetal genes (ANP and BNP) induced by PE. Later, it was determined that miR-184 was a direct target of UCA1, whereas the mRNA HOXA9 was a target of miR-184. Rescue assays indicated that UCA1 promoted the progression of cardiac hypertrophy through competitively binding with miR-184 to enhance the expression of HOXA9. PMID- 29617000 TI - Statins and New-Onset Diabetes in Cardiovascular and Kidney Disease Cohorts: A Meta-Analysis. AB - BACKGROUND: Statins have long been prescribed for the primary and secondary prevention of cardiovascular disease (CVD) and kidney disease. Their benefits and efficacy are widely accepted in current clinical practice, but like any other therapeutic agents, they have adverse effects. One of the emerging concerns with statin therapy is the development of new-onset diabetes mellitus (NODM), a dreaded risk factor for CVD and kidney disease and widely viewed as CVD equivalent. Accumulating evidence indicates that NODM is a consequence of statin use. METHODS: We conducted a meta-analysis of studies reporting on associations between NODM and statin use. Based on strict exclusion criteria, a total of 11 studies were selected. Their data were analyzed using Comprehensive Meta Analysis(r) statistical software and reported as odds ratios (OR) with 95% confidence intervals (CI). RESULTS: The cumulative fixed effect for use of statin therapy and incident NODM was an OR of 1.61 (95% CI 1.55-1.68, p < 0.001). Our results suggest that statin therapy is associated with NODM, such that there is a small but significant risk of NODM among patients receiving statin for CVD prevention therapy. However, this high-risk population also has other diabetes risk factors (such as obesity and hypertension) contributing to the development of NODM. CONCLUSIONS: It is imperative that patients on statin therapy be monitored carefully for NODM. However, it can be argued that the risk of statin therapy is offset by the multitude of cardiovascular and kidney-protective effects provided by such an important and highly effective therapeutic agent. PMID- 29617001 TI - Personalized Statin Therapy and Coronary Atherosclerotic Plaque Burden in Asymptomatic Low/Intermediate-Risk Individuals. AB - BACKGROUND: Current guidelines for the primary prevention of atherosclerotic cardiovascular disease are based on the estimation of a predicted 10-year cardiovascular disease risk and the average relative risk reduction estimates from statin trials. In the clinical setting, however, decision-making is better informed by the expected benefit for the individual patient, which is typically lacking. Consequently, a personalized statin benefit approach based on absolute risk reduction over 10 years (ARR10 benefit threshold >=2.3%) has been proposed as a novel approach. However, how this benefit threshold relates with coronary plaque burden in asymptomatic individuals with low/intermediate cardiovascular disease risk is unknown. AIMS: In this study, we compared the predicted ARR10 obtained in each individual with plaque burden detected by coronary computed tomography angiography. METHODS AND RESULTS: Plaque burden (segment volume score, segment stenosis score, and segment involvement score) was assessed in prospectively recruited asymptomatic subjects (n = 70; 52% male; median age 56 years [interquartile range 51-64 years]) with low/intermediate Framingham risk score (< 20%). The expected ARR10 with statin in the entire cohort was 2.7% (1.5 4.6%) with a corresponding number needed to treat over 10 years of 36 (22-63). In subjects with an ARR10 benefit threshold >=2.3% (vs. < 2.3%), plaque burden was significantly higher (p = 0.02). CONCLUSION: These findings suggest that individuals with higher coronary plaque burden are more likely to get greater benefit from statin therapy even among asymptomatic individuals with low cardiovascular risk. PMID- 29617002 TI - The Role of Dendritic and Endothelial Cells in Cardiorenal Syndrome. AB - BACKGROUNDS: Dendritic cells (DCs) are antigen-presenting cells that play a central role in innate and adaptive immune responses; however, the cross talk between cardiac and renal DCs in cardiorenal syndrome (CRS) has not yet been fully elucidated. In this setting, endothelial cells (ECs) also contribute to immune responses. SUMMARY: DC and EC activation and dysfunction have a central role in the pathogenesis of CRS. Regarding immune responses in CRS, it is unknown whether ECs may serve as antigen-presenting cells or act synergistically with DCs to actively participate in innate and adaptive immune responses. This review first focuses on the burden of concomitant heart and renal DCs in the context of CRS; it examines what is known of DCs in animal models, and proposes a central role for DCs in all types of CRS. Second, this review briefly describes the role of ECs in the context of CRS. Key Messages: Understanding the role of DCs and ECs in immune response could lead to the development of novel therapies for the prevention and treatment of CRS. PMID- 29617003 TI - The Effect of Mitochondrial Complex I-Linked Respiration by Isoflurane Is Independent of Mitochondrial Nitric Oxide Production. AB - BACKGROUND: Anesthetic preconditioning (APC) of the myocardium is mediated in part by reversible alteration of mitochondrial function. Nitric oxide (NO) inhibits mitochondrial respiration and may mediate APC-induced cardioprotection. In this study, the effects of isoflurane on different states of mitochondrial respiration during the oxidation of complex I-linked substrates and the role of NO were investigated. METHODS: Mitochondria were isolated from Sprague-Dawley rat hearts. Respiration rates were measured polarographically at 28oC with a computer controlled Clark-type O2 electrode in the mitochondria (0.5 mg/mL) with complex I substrates glutamate/malate (5 mM). Isoflurane (0.25 mM) was administered before or after adenosine diphosphate (ADP)-initiated state 3 respiration. The NO synthase (NOS) inhibitor L-N5-(1-iminoethyl)-ornithine (L-NIO, 10 MUM) and the NO donor S-nitroso-N-acetylpenicillamine (SNAP, 1 MUM) were added before or after the addition of ADP. RESULTS: Isoflurane administered in state 2 increased state 2 respiration and decreased state 3 respiration. This attenuation of state 3 respiration by isoflurane was similar when it was given during state 3. L-NIO did not alter mitochondrial respiration or the effect of isoflurane. SNAP only, added in state 3, decreased state 3 respiration and enhanced the isoflurane-induced attenuation of state 3 respiration. CONCLUSION: Isoflurane has clearly distinguishable effects on different states of mitochondrial respiration during the oxidation of complex I substrates. The uncoupling effect during state 2 respiration and the attenuation of state 3 respiration may contribute to the mechanism of APC-induced cardioprotection. These effects of isoflurane do not depend on endogenous mitochondrial NO, as the NOS inhibitor L-NIO did not alter the effects of isoflurane on mitochondrial respiration. PMID- 29617004 TI - Impact of Chronic Kidney Disease on Cardiovascular and Renal Events in Patients Undergoing Percutaneous Coronary Intervention with Everolimus-Eluting Stent: Risk Stratification with C-Reactive Protein. AB - BACKGROUND: Chronic kidney disease (CKD) and inflammation play critical roles in atherosclerosis. There is limited evidence regarding the relationship between CKD and patients receiving second-generation drug-eluting stents for coronary artery disease. OBJECTIVE: This study aimed to investigate the effect of CKD on cardiovascular and renal events in patients undergoing percutaneous coronary intervention (PCI) with everolimus-eluting stents (EES). METHODS: We analyzed 504 consecutive patients with stable angina pectoris and significant coronary artery stenosis treated with EES. CKD was defined as an estimated glomerular filtration rate < 60 mL/min/1.73 m2 before coronary angiography. The primary outcome was the occurrence of major adverse renal and cardiovascular events (MARCE) including cardiac death, revascularization, heart failure, cerebral infarction, worsening renal function > 25% from baseline, and renal replacement therapy at 1 year. RESULTS: Patients were divided into the a MARCE (n = 126) and a non-MARCE (n = 378) group. The incidence of CKD was 51% in all subjects (including those on hemodialysis) and was significantly higher in the MARCE group than in the non MARCE group (p = 0.00001). Multivariate logistic regression analysis identified that CKD was independently associated with MARCE (adjusted odds ratio 2.03, 95% confidence interval 1.21-3.39, p = 0.007). Patients were divided into four groups based on CKD and C-reactive protein (CRP) level prior to initial coronary angiography. Cox proportional hazards analysis revealed that patients with CKD and high CRP (>=0.3 mg/dL) had the worst prognosis (hazard ratio 4.371, 95% confidence interval 2.634-7.252, p = 0.00001) compared to patients without CKD and with low CRP. CONCLUSION: CKD combined with CRP predicted more clinical events in patients undergoing PCI with EES. PMID- 29617005 TI - High Right Ventricular Stroke Work Index Is Associated with Worse Kidney Function in Patients with Heart Failure with Preserved Ejection Fraction. AB - BACKGROUND: In patients with heart failure with preserved ejection fraction (HFpEF), worse kidney function is associated with worse overall cardiac mechanics. Right ventricular stroke work index (RVSWI) is a parameter of right ventricular function. The aim of our study was to determine the relationship between RVSWI and glomerular filtration rate (GFR) in patients with HFpEF. METHOD: This was a single-center cross-sectional study. HFpEF is defined as patients with documented heart failure with ejection fraction > 50% and pulmonary wedge pressure > 15 mm Hg from right heart catheterization. RVSWI (normal value 8 12 g/m/beat/m2) was calculated using the formula: RVSWI = 0.0136 * stroke volume index * (mean pulmonary artery pressure - mean right atrial pressure). Univariate and multivariate linear regression analysis was performed to study the correlation between RVSWI and GFR. RESULT: Ninety-one patients were included in the study. The patients were predominantly female (n = 64, 70%) and African American (n = 61, 67%). Mean age was 66 +/- 12 years. Mean GFR was 59 +/- 35 mL/min/1.73 m2. Mean RVSWI was 11 +/- 6 g/m/beat/m2. Linear regression analysis showed that there was a significant independent inverse relationship between RVSWI and GFR (unstandardized coefficient = -1.3, p = 0.029). In the subgroup with combined post and precapillary pulmonary hypertension (Cpc-PH) the association remained significant (unstandardized coefficient = -1.74, 95% CI 3.37 to -0.11, p = 0.04). CONCLUSION: High right ventricular workload indicated by high RVSWI is associated with worse renal function in patients with Cpc-PH. Further prospective studies are needed to better understand this association. PMID- 29617007 TI - Pediatric tuberculosis detection using trained African giant pouched rats. AB - BACKGROUND: Tuberculosis (TB) diagnosis in children is a challenge with up to 94% of children with TB treated empirically in TB high-burden countries. Therefore, new diagnostic tests are needed for TB diagnosis. We determined the performance of trained rats in the diagnosis of pediatric TB and whether they can improve detection rate compared to the standard of care. METHODS: Presumptive TB patients in 24 TB clinics in Tanzania were tested. Samples indicated as TB-positive by rats underwent confirmation by concentrated smear microscopy. TB yield of bacteriologically confirmed pediatric TB patients (<=5 years) was compared with yield of standard of care. RESULTS: Sputum samples from 55,148 presumptive TB patients were tested. Nine hundred eighty-two (1.8%) were the children between 1 and 5 years. Clinics detected 34 bacteriologically positive children, whereas rats detected additional 23 children yielding 57 bacteriologically TB-positive children. Rats increased pediatric TB detection by 67.6%. Among 1-14-year-old children, clinics detected 331 bacteriologically positive TB whereas rats found the additional 208 children with TB that were missed by clinics. Relative increase in TB case detection by rats decreased with the increase in age (P<0.0001). CONCLUSION: Trained rats increase pediatric TB detection significantly and could help address the pediatric TB diagnosis challenges. Further determination of accuracy of rats involving other sample types is still needed. PMID- 29617006 TI - Relevance of B-Lines on Lung Ultrasound in Volume Overload and Pulmonary Congestion: Clinical Correlations and Outcomes in Patients on Hemodialysis. AB - BACKGROUND: Volume overload in patients on hemodialysis (HD) is an independent risk factor for cardiovascular mortality. B-lines detected on lung ultrasound (BLUS) assess extravascular lung water. This raises interest in its utility for assessing volume status and cardiovascular outcomes. METHODS: End-stage renal disease patients on HD at the Island Rehab Center being older than 18 years were screened. Patients achieving their dry weight (DW) had a lung ultrasound in a supine position. Scores were classified as mild (0-14), moderate (15-30), and severe (>30) for pulmonary congestion. Patients with more than 60 were further classified as very severe. Patients were followed for cardiac events and death. RESULTS: 81 patients were recruited. 58 were males, with a mean age of 59.7 years. 44 had New York Heart Association (NYHA) class 1, 24 had class 2, and 13 had class 3. In univariate analysis, NYHA class was associated with B-line classes (<0.001) and diastolic dysfunction (0.002). In multivariate analysis, NYHA grade strongly correlated with B-line classification (0.01) but not with heart function (0.95). 71 subjects were followed for a mean duration of 1.19 years. 9 patients died and 20 had an incident cardiac event. A Kaplan-Meier survival analysis demonstrated an interval decrease in survival times in all cause mortality and cardiac events with increased BLUS scores (p = 0.0049). Multivariate Cox regression analysis showed the independent predictive value of BLUS class for mortality and cardiac events with a heart rate of 2.98 and 7.98 in severe and very severe classes, respectively, compared to patients in the mild class (p = 0.025 and 0.013). CONCLUSION: At DW, BLUS is an independent risk factor for death and cardiovascular events in patients on HD. PMID- 29617008 TI - Erratum: Incisional Negative Pressure Wound Therapy for Prevention of Wound Healing Complications Following Reduction Mammaplasty: Erratum. AB - [This corrects the article DOI: 10.1097/GOX.0000000000001560.]. PMID- 29617009 TI - Correction: Differentiation of quantitative CT imaging phenotypes in asthma versus COPD. AB - [This corrects the article DOI: 10.1136/bmjresp-2017-000252.]. PMID- 29617010 TI - Commentary: Is Life Extension Today a Faustian Bargain? PMID- 29617011 TI - Methodical bias for comparison of periodontal ligament injection and local infiltration anesthesia for routine extractions in the maxilla. PMID- 29617013 TI - One-step assembly of CuMo2S3 nanocrystals for the synergistic effect of photothermal therapy and photodynamic therapy. AB - In this study, we fabricated a novel PVP conjugated CuMo2S3 nanocrystal, which can be used as an efficient photosensitizer. The CuMo2S3 nanocrystals were synthesized via a facile one-pot reflux method and exhibited high biocompatibility, strong NIR absorbance, low cytotoxicity, high stability, high photothermal conversion efficiency, and effective generation of reactive oxygen species (ROS). Moreover, the combined treatments of photodynamic therapy (PDT) and photothermal therapy (PTT) generated by the CuMo2S3 nanocrystals under NIR irradiation drastically inhibited tumor growth. Thus, CuMo2S3 nanocrystals have a great potential for synergistic effect of PDT and PTT. PMID- 29617012 TI - Corrigendum: Broad Impairment of Natural Killer Cells From Operationally Tolerant Kidney Transplanted Patients. AB - [This corrects the article on p. 1721 in vol. 8, PMID: 29312288.]. PMID- 29617014 TI - Freestanding chi3-borophene nanoribbons: a density functional theory investigation. AB - Experimental observation of borophene nanoribbons (BNRs) motivated us to carry out a comprehensive investigation on BNRs, decomposed from a chi3 sheet, using density functional theory. Our results show that the stability and also the electrical and magnetic properties of the ribbons are strongly dependent on the edge configurations. We have studied two categories of ribbon: XBNRs and YBNRs. The first one is a nonmagnetic metal with armchair shaped edges, while YBNRs can be magnetic or nonmagnetic depending on the edge shape. YBNRs have four different edge types and we show that two of them are magnetic (a- and b-type edges) while the other two are nonmagnetic (c- and d-type edges). There are 10 distinct configurations possible by arranging the different edges of YBNRs. 10 percent of YBNRs are polarized asymmetrically at the edges, leading to the loss of degeneracy of the spin-up and spin-down bands in the antiferromagnetic configuration. 40 percent of YBNRs have one magnetic edge and can be promising candidates for spintronic applications due to the separation of the spin in the real space in addition to the energy space. Electronic transmission properties of the ribbons were also studied and we found that transmission channels are suppressed at the edges of XBNRs due to electron localization. PMID- 29617016 TI - Light induced damage and repair in nucleic acids and proteins: general discussion. PMID- 29617017 TI - Study of the electronic structure of electron accepting cyano-films: TCNQversusTCNE. AB - In this article, we perform systematic research on the electronic structure of two closely related organic electron acceptor molecules (TCNQ and TCNE), which are of technological interest due to their outstanding electronic properties. These studies have been performed from the experimental point of view by the use electron spectroscopies (XPS and UPS) and supported theoretically by the use of ab-initio DFT calculations. The cross-check between both molecules allows us to identify the characteristic electronic features of each part of the molecules and their contribution to the final electronic structure. We can describe the nature of the band gap of these materials, and we relate this with the appearance of the shake-up features in the core level spectra. A band bending and energy gap reduction of the aforementioned electronic structure in contact with a metal surface are seen in the experimental results as well in the theoretical calculations. This behavior implies that the TCNQ thin film accepts electrons from the metal substrate becoming a Schottky n-junction. PMID- 29617015 TI - Quantitative analysis of zero-field splitting parameter distributions in Gd(iii) complexes. AB - The magnetic properties of paramagnetic species with spin S > 1/2 are parameterized by the familiar g tensor as well as "zero-field splitting" (ZFS) terms that break the degeneracy between spin states even in the absence of a magnetic field. In this work, we determine the mean values and distributions of the ZFS parameters D and E for six Gd(iii) complexes (S = 7/2) and critically discuss the accuracy of such determination. EPR spectra of the Gd(iii) complexes were recorded in glassy frozen solutions at 10 K or below at Q-band (~34 GHz), W band (~94 GHz) and G-band (240 GHz) frequencies, and simulated with two widely used models for the form of the distributions of the ZFS parameters D and E. We find that the form of the distribution of the ZFS parameter D is bimodal, consisting roughly of two Gaussians centered at D and -D with unequal amplitudes. The extracted values of D (sigmaD) for the six complexes are, in MHz: Gd-NO3Pic, 485 +/- 20 (155 +/- 37); Gd-DOTA/Gd-maleimide-DOTA, -714 +/- 43 (328 +/- 99); iodo-(Gd-PyMTA)/MOMethynyl-(Gd-PyMTA), 1213 +/- 60 (418 +/- 141); Gd-TAHA, 1361 +/- 69 (457 +/- 178); iodo-Gd-PCTA-[12], 1861 +/- 135 (467 +/- 292); and Gd PyDTTA, 1830 +/- 105 (390 +/- 242). The sign of D was adjusted based on the Gaussian component with larger amplitude. We relate the extracted P(D) distributions to the structure of the individual Gd(iii) complexes by fitting them to a model that superposes the contribution to the D tensor from each coordinating atom of the ligand. Using this model, we predict D, sigmaD, and E values for several additional Gd(iii) complexes that were not measured in this work. The results of this paper may be useful as benchmarks for the verification of quantum chemical calculations of ZFS parameters, and point the way to designing Gd(iii) complexes for particular applications and estimating their magnetic properties a priori. PMID- 29617018 TI - The role of charge in 1,2,3-triazol(ium)-based halogen bonding activators. AB - The influence of charge on the performance of monocationic and dicationic triazol(ium)-based halogen bond donors was investigated. Next to the activity in a halide abstraction benchmark reaction, halogen bonding was also evaluated via X ray structural analyses and isothermal titration calorimetry. PMID- 29617019 TI - A missing member of conjugated N-heterocycles: realizing pyrido[1,2-alpha]azepine by reacting ruthenium alkenylcarbene complex with alkyne. AB - Despite the excellent chemical properties of N-heterocycles, pyrido[1,2 alpha]azepine remains elusive due to its potential antiaromaticity and lability. Herein, we demonstrate the synthesis and characterization of the first bicyclic pyrido[1,2-alpha]azepine that leverages the coordination to the ruthenium center to promote the stability of N-bridged bicycle. PMID- 29617020 TI - Simultaneous neutron powder diffraction and microwave dielectric studies of ammonia absorption in metal-organic framework systems. AB - Ammonia absorption has been investigated in metal-organic frameworks (UiO-67, HKUST-1 and CPO-27-Co) using custom-built apparatus that allows simultaneous neutron powder diffraction (NPD), microwave dielectric characterisation and out gas mass spectroscopy of solid-state materials during ammonia adsorption. Deuterated ammonia was flowed through the sample and absorption monitored using mass flow meters and mass spectroscopy. Argon gas was then flowed through the ammoniated sample to cause ammonia desorption. Changes in structure found from NPD measurements were compared to changes in dielectric characteristics to differentiate physisorbed and metal-coordinated ammonia, as well as determine decomposition of sample materials. The results of these studies allow the identification of materials with useful ammonia storage properties and provides a new metric for the measurement of gas absorption within mesoporous solids. PMID- 29617021 TI - Bionanophotonics: general discussion. PMID- 29617022 TI - Photocrosslinking between nucleic acids and proteins: general discussion. PMID- 29617025 TI - Correction: Clickable glutathione using tetrazine-alkene bioorthogonal chemistry for detecting protein glutathionylation. AB - Correction for 'Clickable glutathione using tetrazine-alkene bioorthogonal chemistry for detecting protein glutathionylation' by Dilini N. Kekulandara et al., Org. Biomol. Chem., 2016, 14, 10886-10893. PMID- 29617031 TI - Addressing Alzheimer's Disease in Asian American and Pacific Islander Older Adults: An Action Guide for Service Providers. PMID- 29617034 TI - Interdisciplinary Collaboration in Medication-Related Falls Prevention in Older Adults. AB - The older adult population continues to steadily increase. Largely attributed to longer life spans and aging of the Baby Boomer generation, continued growth of this population is expected to affect a multitude of challenging public health concerns. Specifically, falls in older adults are prevalent but overlooked concerns. Health care providers are well-positioned to provide valuable interventions in this aspect. An interdisciplinary, team-based approach of health care providers is required to maximize falls prevention through patient-centered and collaborative care. The current article highlights the implications of inappropriate medication use and the need to improve care coordination to tackle this public health issue affecting older adults. [Journal of Gerontological Nursing, 44(4), 11-15.]. PMID- 29617035 TI - Effects of Patient Care Unit Design and Technology on Nurse and Patient Care Technician Communication. AB - The current study described RN and patient care technician (PCT) communication in centralized and hybrid decentralized workstation designs using hands-free communication technology and infrared locator badge technology to facilitate communication. New construction of an oncology unit provided the opportunity to compare staff communication in two different workstation designs. Observations and questionnaires compared nurse and PCT communication in the two-unit designs. Descriptive statistics were used to analyze the differences. The hybrid decentralized unit had increased use of hands-free communication technology and hallway communication by nurses and PCTs, and increased patient room communication by nurses. Perceptions of communication between nurses and PCTs and congruency of priorities for care were similar for both units. The locator badge technology had limited adoption. Replacement of nurse workstations with new construction or remodeling impact staff communication patterns, necessitating that nurse leaders understand the impact of design and technology on communication. [Journal of Gerontological Nursing, 44(4), 17-22.]. PMID- 29617036 TI - Ethanol ablation for refractory bile leakage after complex hepatectomy. AB - BACKGROUND: Only a few reports exist on the use of ethanol ablation for posthepatectomy bile leakage. The aim of this study was to assess the value of ethanol ablation in refractory bile leakage. METHODS: Medical records of consecutive patients who underwent a first hepatobiliary resection with bilioenteric anastomosis between 2007 and 2016 were reviewed retrospectively, with special attention to bile leakage and ethanol ablation therapy. Bile leakage was graded as A/B1/B2 according to the International Study Group of Liver Surgery definition. Absolute ethanol was injected into the target bile duct during fistulography. RESULTS: Of the 609 study patients, 237 (38.9 per cent) had bile leakage, including grade A in 33, grade B1 in 18 and grade B2 in 186. Left trisectionectomy was more often associated with grade B2 bile leakage than other types of hepatectomy (P < 0.001). Of 186 patients with grade B2 bile leakage, 31 underwent ethanol ablation therapy. Ethanol ablation was started a median of 34 (range 15-122) days after hepatectomy. The median number of treatments was 3 (1 7), and the total amount of ethanol used was 15 (3-71) ml. Complications related to ethanol ablation included transient fever (27 patients) and mild pain (13). Following ethanol ablation, bile leakage resolved in all patients and drains were removed. The median interval between the first ablation and drain removal was 28 (1-154) days. CONCLUSION: Ethanol ablation is safe and effective, and may be a treatment option for refractory bile leakage. PMID- 29617037 TI - Final-impression techniques and materials for making complete and removable partial dentures. AB - BACKGROUND: Edentulism is relatively common and is often treated with the provision of complete or partial removable dentures. Clinicians make final impressions of complete dentures (CD) and removable partial dentures (RPD) using different techniques and materials. Applying the correct impression technique and material, based on an individual's oral condition, improves the quality of the prosthesis, which may improve quality of life. OBJECTIVES: To assess the effects of different final-impression techniques and materials used to make complete dentures, for retention, stability, comfort, and quality of life in completely edentulous people.To assess the effects of different final-impression techniques and materials used to make removable partial dentures, for stability, comfort, overextension, and quality of life in partially edentulous people. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 22 November 2017), the Cochrane Central Register of Controlled Trials (CENTRAL) (Cochrane Register of Studies, to 22 November 2017), MEDLINE Ovid (1946 to 22 November 2017), and Embase Ovid (21 December 2015 to 22 November 2017). The US National Institutes of Health Trials Registry (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. No restrictions were placed on language or publication status when searching the electronic databases, however the search of Embase was restricted by date due to the Cochrane Centralised Search Project to identify all clinical trials and add them to CENTRAL. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing different final-impression techniques and materials for treating people with complete dentures (CD) and removable partial dentures (RPD). For CD, we included trials that compared different materials or different techniques or both. In RPD for tooth-supported conditions, we included trials comparing the same material and different techniques, or different materials and the same technique. In tooth- and tissue-supported RPD, we included trials comparing the same material and different dual-impression techniques, and different materials with different dual-impression techniques. DATA COLLECTION AND ANALYSIS: Two review authors independently, and in duplicate, screened studies for eligibility, extracted data, and assessed the risk of bias for each included trial. We expressed results as risk ratios (RR) for dichotomous outcomes, and as mean differences (MD) or standardised mean differences (SMD) for continuous outcomes, with 95% confidence intervals (CI), using the random-effects model. We constructed 'Summary of findings' tables for the main comparisons and outcomes (participant-reported oral health-related quality of life, quality of the denture, and denture border adjustments). MAIN RESULTS: We included nine studies in this review. Eight studies involved 485 participants with CD. We assessed six of the studies to be at high risk of bias, and two to be at low risk of bias. We judged one study on RPD with 72 randomised participants to be at high risk of bias.Overall, the quality of the evidence for each comparison and outcome was either low or very low, therefore, results should be interpreted with caution, as future research is likely to change the findings.Complete denturesTwo studies compared the same material and different techniques (one study contributed data to a secondary outcome only); two studies compared the same technique and different materials; and four studies compared different materials and techniques.One study (10 participants) evaluated two stage-two step, Biofunctional Prosthetic system (BPS) using additional silicone elastomer compared to conventional methods, and found no evidence of a clear difference for oral health-related quality of life, or quality of the dentures (denture satisfaction). The study reported that BPS required fewer adjustments. We assessed the quality of the evidence as very low.One study (27 participants) compared selective pressure final-impression technique using wax versus polysulfide elastomeric (rubber) material. The study did not measure quality of life or dentures, and found no evidence of a clear difference between interventions in the need for adjustments (RR 0.81, 95% CI 0.38 to 1.70). We assessed the quality of the evidence as very low.One study compared two stage-two step final impression with alginate versus silicone elastomer. Oral health related quality of life measured by the OHIP-EDENT seemed to be better with silicone (MD 7.20, 95% CI 2.71 to 11.69; 144 participants). The study found no clear differences in participant-reported quality of the denture (comfort) after a two-week 'confirmation' period, but reported that silicone was better for stability and chewing efficiency. We assessed the quality of the evidence as low.Three studies compared single-stage impressions with alginate versus two stage-two step with elastomer (silicone, polysulfide, or polyether) impressions. There was no evidence of a clear difference in the OHIP-EDENT at one month (MD 0.05, 95% CI -2.37 to 2.47; two studies, 98 participants). There was no evidence of a clear difference in participant-rated general satisfaction with dentures at six months (MD 0.00, 95% CI -8.23 to 8.23; one study, 105 participants). We assessed the quality of the evidence as very low.One study compared single-stage alginate versus two stage-two step using zinc-oxide eugenol, and found no evidence of a clear difference in OHIP-EDENT (MD 0.50, 95% CI -2.67 to 3.67; 39 participants), or general satisfaction (RR 3.15, 95% CI 0.14 to 72.88; 39 participants) at six months. We assessed the quality of the evidence as very low.Removable partial denturesOne study randomised 72 participants and compared altered-cast technique versus one-piece cast technique. The study did not measure quality of life, but reported that most participants were satisfied with the dentures and there was no evidence of any clear difference between groups for general satisfaction at one-year follow-up (low-quality evidence). There was no evidence of a clear difference in number of intaglio adjustments at one year (RR 1.43, 95% CI 0.61 to 3.34) (very low-quality evidence). AUTHORS' CONCLUSIONS: We conclude that there is no clear evidence that one technique or material has a substantial advantage over another for making complete dentures and removable partial dentures. Available evidence for the relative benefits of different denture fabrication techniques and final-impression materials is limited and is of low or very low quality. More high-quality RCTs are required. PMID- 29617038 TI - Contrasting effects of landscape composition on crop yield mediated by specialist herbivores. AB - Landscape composition not only affects a variety of arthropod-mediated ecosystem services, but also disservices, such as herbivory by insect pests that may have negative effects on crop yield. Yet, little is known about how different habitats influence the dynamics of multiple herbivore species, and ultimately their collective impact on crop production. Using cabbage as a model system, we examined how landscape composition influenced the incidence of three specialist cruciferous pests (aphids, flea beetles, and leaf-feeding Lepidoptera), lepidopteran parasitoids, and crop yield across a gradient of landscape composition in New York, USA. We expected that landscapes with a higher proportion of cropland and lower habitat diversity would lead to an increase in pest pressure of the specialist herbivores and a reduction in crop yield. However, results indicated that neither greater cropland area nor lower landscape diversity influenced pest pressure or yield. Rather, pest pressure and yield were best explained by the presence of non-crop habitats (i.e., meadows) in the landscape. Specifically, cabbage was infested with fewer Lepidoptera in landscapes with a higher proportion of meadows likely resulting from increased parasitism. Conversely, cabbage was infested with more flea beetles and aphids as the proportion of meadows in the landscape increased, suggesting that these pests benefit from non-crop habitats. Furthermore, path analysis confirmed that these landscape-mediated effects on pest populations can have either positive or negative cascading effects on crop yield. Our findings illustrate how different pest species within the same cropping system show contrasting responses to landscape composition with respect to both the direction and spatial scale of the relationship. Such tradeoffs resulting from the complex interaction between multiple-pests, natural enemies, and landscape composition must be considered, if we are to manage landscapes for pest suppression benefits. PMID- 29617039 TI - Closure of gastrointestinal incisions using skin staples alone and in combination with suture in 29 cats. AB - OBJECTIVE: To report the use of skin staples alone, and in combination with sutures, for closure of gastrointestinal incisions in cats and to describe outcomes. MATERIALS AND METHODS: Retrospective study of cats that underwent gastrotomy, jejunotomy, jejunal or colonic anastomosis using skin staples alone or in combination with sutures to close the enteric wounds at one referral hospital between 2001 and 2016. Data regarding patient signalment, duration of clinical signs, indication for surgery, diagnosis, haematological and biochemical values, surgical time, procedure, complications and outcome were collected. All the gastrotomies and some of the large intestine incisions were closed in a hybrid technique using two layers (monofilament suture and skin staples). All the small intestine and some of the large intestinal incisions were closed in a single layer using skin staples. RESULTS: Twenty-nine cats were included in the study. Indications for surgery included foreign body (14/29), neoplasia (6/29) and idiopathic megacolon (9/29). Overall, 26 of 29 (~90%) of cases survived to discharge. One cat had postoperative cardiopulmonary arrest, and 2/29 cats were euthanased at the owner's request. There was no evidence of incisional dehiscence in any case. CLINICAL SIGNIFICANCE: Skin staplers are safe, reliable, affordable and effective for closure of gastrointestinal incisions in cats. We found skin staples can be a useful tool in closure of gastrotomies and large intestinal resection and anastomosis procedures in cats. PMID- 29617040 TI - Melatonin levels in human diabetic dental pulp tissue and its effects on dental pulp cells under hyperglycaemic conditions. AB - AIM: To investigate melatonin (MEL) levels in human dental pulp tissue (hDP) in type 2 diabetic (T2D) participants and the underlying molecular mechanisms of its effects in human dental pulp cells (hDPCs) under hyperglycaemia. METHODOLOGY: The study included 16 healthy and 16 T2D participants who underwent vital pulp extirpation for hDP and four healthy participants undergoing third molar extraction for hDPCs analyses. MTT and NRU were used as tests for cytotoxicity. The pulp tissue levels of MEL, inducible NO synthase (iNOS) and superoxide dismutase (SOD) activity, as well as iNOS, histone acetyltransferase p300 (p300) and SOD activity levels in hDPCs incubated with MEL (0.1 and 1.0 mmol L-1 ) under normoglycaemia and hyperglycaemia were measured by enzyme-linked immunosorbent assay. Comparisons between the two groups were made by unpaired t-tests or Mann Whitney test whilst the chi-square test was used for dichotomous variables. To compare more groups, the Kruskal-Wallis test with Dunn's multiple comparison was used, whilst Spearman correlation was used to assess association between two variables. RESULTS: Melatonin was decreased (124.30 +/- 21.6 vs. 240.0 +/- 19.1 pg mL-1 , P < 0.01), whilst iNOS levels increased (0.92 +/- 0.08 vs. 0.32 +/- 0.09 ng mL-1 , P < 0.01) in hDP from T2D compared to nondiabetic participants. In hDPCs, MEL (0.1 and 1.0 mmol L-1 ) had no cytotoxicity. Incubation with 1.0 mmol L-1 of MEL (24 h) decreased hyperglycaemia-induced increases of iNOS (0.34 +/- 0.01 ng mL-1 vs. 0.40 +/- 0.01 ng mL-1 , P < 0.01) and p300 (11.59 +/- 0.58 ng mL 1 vs. 16.12 +/- 0.39 ng mL-1 , P < 0.01), and also, increased SOD activity (87.11 +/- 3.10% vs. 68.56 +/- 3.77%, P < 0.01) to the levels comparable to the normoglycaemic; iNOS and p300 protein expression levels showed strong positive correlation under hyperglycaemia (Spearman r = 0.8242, P < 0.001). CONCLUSION: Type 2 diabetic participants had decreased MEL in hDP. At pharmacological concentrations, MEL is not cytotoxic for hDPCs and normalizes iNOS and SOD activity levels in hyperglyceamic hDPCs suggesting its antioxidant and protective effects in human dental pulp tissue under hyperglycaemia. PMID- 29617041 TI - Direct binding and internalization of diverse extracellular nucleic acid species through the collagenous domain of class A scavenger receptors. AB - Nucleic acids are potential pathogen-associated or danger-associated molecular patterns that modulate immune responses and the development of autoimmune disorders. Class A scavenger receptors (SR-As) are a diverse group of pattern recognition receptors that recognize a variety of polyanionic ligands including nucleic acids. While SR-As are important for the recognition and internalization of extracellular dsRNA, little is known about extracellular DNA, despite its association with chronic infections and autoimmune disorders. In this study, we investigated the specificity of and requirement for SR-As in binding and internalizing different species, sequences and lengths of nucleic acids. We purified recombinant coiled-coil/collagenous and scavenger receptor cysteine-rich (SRCR) domains that have been implicated as potential ligand-binding domains. We detected a direct interaction of RNA and DNA species with the coiled coil/collagenous domain, but not the SRCR domain. Despite the presence of additional surface receptors that bind nucleic acids, SR-As were found to be sufficient for nucleic acid binding and uptake in A549 human lung epithelial cells. Moreover, these findings suggest that the coiled-coil/collagenous domain of SR-As is sufficient to bind nucleic acids independent of species, sequence or length. PMID- 29617042 TI - Use of a Gastroschisis Feeding Guideline to Improve Standardization of Care and Patient Outcomes at an Urban Children's Hospital. AB - BACKGROUND: This study examined clinical outcomes associated with the use of a gastroschisis-specific (GS) feeding advancement guideline. METHODS: We performed a retrospective study of all simple gastroschisis babies (N = 65) treated between June 2009June 2015. We compared patients treated on a postintestinal surgery guideline using either a 1-day (1D) or 3-day (3D) feeding advancement from August 2009-August 2013 with infants treated on a GS guideline from September 2013-June 2015. RESULTS: Patients in the 2 groups were similar in sex, race, gestational age, weight, and comorbidities. Median time to full enteral nutrition (EN) was 11 days for the 1D group, 22 days for the 3D group, and 18 days for the GS group (P < .01). However, lengths of stay and estimated weight gain per day were similar among the groups. A total of 3 infants (10%) in the 1D group developed necrotizing enterocolitis compared with none in the 3D or GS groups. Control chart analysis showed reduced variation in median time to full EN in the GS group when compared with the 1D and 3D groups. Guideline adherence was significantly better with the GS guideline when compared with the 1D or 3D guidelines (94% vs 72% vs 90%; P < .01). CONCLUSION: A GS protocol yielded reduced variation in median time to full EN, significant improvement in percent adherence to the guideline, and zero cases of necrotizing enterocolitis. Weight gain and lengths of stay were not adversely affected by slower feeds. PMID- 29617043 TI - A novel type of +2-base pair frameshift CALR mutation in a patient with myeloproliferative neoplasm. AB - Somatic CALR mutations have been identified in the majority of JAK2 mutation negative essential thrombocythaemia (ET) and primary myelofibrosis. Almost all CALR mutations have been reported to typically generate a +1-base pair (bp) frameshift in the open reading frame. Here, we describe an ET patient with a +2 bp frameshift CALR mutation. A 41-year-old man was admitted because of headache, and diagnosed as JAK2-negative ET. After 4 years, his disease progressed to post ET myelofibrosis, and CALR mutation analysis demonstrated a +2-bp frameshift CALR mutation caused by two different CALR mutations, c.1139_1151del and c.1211_1215delinsTTGA, on the same allele. The resultant mutant protein sequence shared 19 amino acids with those from type 1 and type 2 CALR mutations, but the downstream C-terminal sequences were different. To our knowledge, CALR double mutations causing +2-bp frameshift are extremely rare. Identification of this novel type of CALR mutation has potential implications for better understanding of CALR oncogenesis. PMID- 29617044 TI - PCSK9 plays a novel immunological role in oxidized LDL-induced dendritic cell maturation and activation of T cells from human blood and atherosclerotic plaque. AB - BACKGROUND: Activated T cells and dendritic cells (DCs) occur in atherosclerotic plaques. Proprotein convertase subtilisin kexin 9 (PCSK9) targets the LDL receptor (LDLR) and results in increased LDL levels. We here investigate immune effects of PCSK9 on OxLDL induced DC maturation and T-cell activation. METHODS: T cells were isolated from carotid specimens of patients undergoing carotid endarterectomy or from peripheral blood of healthy individuals. Human peripheral blood monocytes were differentiated into DCs. Naive T cells were cocultured with pretreated DCs. The effects of PCSK9 and its inhibition by silencing were studied. RESULTS: OxLDL induced PCSK9 in DCs and promoted DC maturation with increased expressions of CD80, CD83, CD86 and HLA-DR and the scavenger receptors LOX-1 and CD36. T cells exposed to OxLDL-treated DCs proliferated and produced IFN-gamma and IL-17, thus with polarization to Th1 and/or Th17 subsets. Silencing of PCSK9 reversed the OxLDL effects on DCs and T cells. DC maturation was repressed, and the production of TNF-alpha, IL-1beta and IL-6 was limited, while TGF-beta and IL-10 secretion and T regulatory cells were induced. OxLDL induced miRNA let-7c, miR-27a, miR-27b, miR-185. Silencing PCSK9 repressed miR-27a and to a lesser extent let-7c. PCSK9 silencing enhanced SOCS1 expression induced by OxLDL. Experiments on T cells from carotid atherosclerotic plaques or healthy individuals showed similar results. CONCLUSIONS: We demonstrate immunological effects of PCSK9 in relation to activation and maturation of DCs and plaque T cells by OxLDL, a central player in atherosclerosis. This may directly influence atherosclerosis and cardiovascular disease, independent of LDL lowering. PMID- 29617045 TI - Confinement of Metal-N-Heterocyclic Carbene Complexes to Control Reactivity in Catalytic Reactions. AB - Confinement of a metal complex is a promising way to induce reactivity modulation and selectivity. Combining this principle with the properties of N-heterocyclic carbenes (NHC) used as ligands is therefore of great interest. NHCs metal complexes have been encapsulated in polymeric structures (metal-organic frameworks, metal organic polymers and porous organic polymers), and in molecular containers (capsules, cages or cavitands). This confinement induced reactivity change, on and off switching of reactions, substrate selection, stereoselectivity, regioselectivity, and product distribution variation. The syntheses and the influence of confinement on reactivity will be discussed in this Minireview. PMID- 29617046 TI - The predictability of genomic changes underlying a recent host shift in Melissa blue butterflies. AB - Despite accumulating evidence that evolution can be predictable, studies quantifying the predictability of evolution remain rare. Here, we measured the predictability of genome-wide evolutionary changes associated with a recent host shift in the Melissa blue butterfly (Lycaeides melissa). We asked whether and to what extent genome-wide patterns of evolutionary change in nature could be predicted (i) by comparisons among instances of repeated evolution and (ii) from SNP * performance associations in a laboratory experiment. We delineated the genetic loci (SNPs) most strongly associated with host use in two L. melissa lineages that colonized alfalfa. Whereas most SNPs were strongly associated with host use in none or one of these lineages, we detected a an approximately twofold excess of SNPs associated with host use in both lineages. Similarly, we found that host-associated SNPs in nature could also be partially predicted from SNP * performance (survival and weight) associations in a laboratory rearing experiment. But the extent of overlap, and thus degree of predictability, was somewhat reduced. Although we were able to predict (to a modest extent) the SNPs most strongly associated with host use in nature (in terms of parallelism and from the experiment), we had little to no ability to predict the direction of evolutionary change during the colonization of alfalfa. Our results show that different aspects of evolution associated with recent adaptation can be more or less predictable and highlight how stochastic and deterministic processes interact to drive patterns of genome-wide evolutionary change. PMID- 29617047 TI - Review shows that Icelandic society is taking firmer steps to tackle the diverse forms of child abuse and neglect that its children are exposed to. AB - AIM: This review examined and summarised the research published on child abuse in Iceland, which was mainly in the country's native language, to make the findings more accessible to English speakers. It specifically focused on child rearing and the physical, emotional and sexual abuse, neglect and intrafamilial conflicts suffered by children at the hands of their parents and other carers. METHOD: The review drew on published research, books and reports and compared the findings with Nordic research and global estimates of child abuse. RESULTS: Qualitative and quantitative research revealed that the prevalence of different forms of child abuse, child neglect and intra-familial conflicts in Iceland was similar to, or higher than, global and Nordic estimates. Younger respondents reported less physical abuse than older respondents, but higher levels of emotional abuse. Legislation, greater awareness, public debates and research on child abuse in Iceland have contributed to the growing recognition of the negative consequences of child abuse and strengthened support for prevention strategies. CONCLUSION: Icelandic children have reportedly experienced diverse forms of child abuse and neglect from their parents and other carers. Diverse initiatives have been put in place that underline the urgent need to tackle such behaviour. PMID- 29617049 TI - Parents of children referred to a sleep laboratory for disordered breathing reported anxiety, daytime sleepiness and poor sleep quality. AB - AIM: We evaluated the impact that having a child with sleep-disordered breathing had on their parents, including their own sleep quality. METHODS: Questionnaires were completed by 96 parents of 86 children referred for a sleep study or control of continuous positive airway pressure (CPAP) or noninvasive ventilation (NIV) at the sleep laboratory of the Necker Hospital, Paris, France, between October 2015 and January 2016. The questionnaires evaluated anxiety and depression, family functioning, the parents' quality of life, daytime sleepiness and sleep quality. RESULTS: The children had a mean age of seven +/-five years and most of the responses (79%) came from their mothers. These showed that 26% of parents showed moderate-to-severe anxiety, 8% moderate-to-severe depression, 6% complex family cohesion, 59% moderate-to-severe daytime sleepiness and 54% poor sleep quality. Anxiety was higher in mothers than in fathers (p < 0.001). The questionnaire scores did not differ according to the child's age, the results of the sleep studies or the CPAP or NIV treatment. The symptoms seem to be more commonly related to the child's underlying disease than their sleep-disordered breathing. CONCLUSION: The parents of children referred to a sleep laboratory reported frequent anxiety, daytime sleepiness and poor sleep quality. PMID- 29617048 TI - Pseudosarcomatous myofibroblastic proliferations of the genitourinary tract are genetically different from nodular fasciitis and lack USP6, ROS1 and ETV6 gene rearrangements. AB - AIMS: Pseudosarcomatous myofibroblastic proliferations of the genitourinary tract have a debatable relationship with inflammatory myofibroblastic tumour (generally lacking ALK rearrangement); however, they share several overlapping features with nodular fasciitis of soft tissue. As rearrangement of the USP6 gene has been recently recognised as a recurrent alteration in soft tissue nodular fasciitis, and several other alternative gene fusions have been recently recognised in inflammatory myofibroblastic tumour, the aim of this study was to investigate whether USP6, ROS1 or ETV6 rearrangements were present in these lesions (12 cases). METHODS AND RESULTS: Fluorescence in-situ hybridisation analysis was performed by the use of bacterial artificial chromosome-derived break-apart probes against USP6, ROS1, and ETV6. Two cases with adequate genetic material from recent paraffin tissue blocks were also tested by use of a solid tumour gene fusion detection assay via next-generation sequencing, targeting >50 known genes involved in recurrent fusions. None of the genitourinary pseudosarcomatous myofibroblastic proliferations was found to harbour USP6 (0/12), ROS1 (0/8) or ETV6 (0/7) rearrangements, and no gene fusions were detected in two cases studied by sequencing. CONCLUSIONS: Despite overlap in histological and immunohistochemical features between pseudosarcomatous myofibroblastic proliferation and nodular fasciitis, these tumours lack the recently recognised USP6 rearrangements that occur in nodular fasciitis, as well as alternative fusions found in ALK-negative inflammatory myofibroblastic tumours. At present, this diagnosis remains based primarily on clinical, histological and immunohistochemical features. PMID- 29617050 TI - Transient antagonism of anti-CD20 monoclonal antibodies and PI3K inhibitor idelalisib in DLBCL cell lines. AB - INTRODUCTION: PI3K inhibitors are evaluated for relapsed and refractory Diffuse large B-cell lymphoma (DLBCL) patients. OBJECTIVE: As rituximab has shown to influence B-cell receptor (BCR) signaling, we investigated the interaction of anti-CD20 antibody rituximab and the new type II glycoengineered anti-CD20 antibody obinutuzumab in combination with the PI3K delta inhibitor idelalisib. METHODS: Established DLBCL cell lines were treated with either rituximab or obinutuzumab alone or in combination with PI3K delta inhibitor idelalisib. RESULTS: Rituximab and to a lesser extent obinutuzumab monotherapy resulted in a temporary upregulation of p-Akt, p42/44, and p38 signaling pathways. Idelalisib reduced p-Akt expression. Rituximab antagonized the p-Akt downregulation at early time points, while obinutuzumab did not interfere with idelalisib's effects. In cell growth analysis, early antagonism could also be detected. CONCLUSION: The combination of idelalisib with CD antibodies shows an initial antagonism of rituximab but not obinutuzumab in downregulation of PI3K-signaling targets. PMID- 29617051 TI - Management of adrenal emergencies in educated patients with adrenal insufficiency A prospective study. AB - OBJECTIVE: To evaluate the management of adrenal emergencies (AE) requiring parenteral glucocorticoid (GC) treatment in patients with chronic adrenal insufficiency (AI). DESIGN: Prospective, multicentre, questionnaire-based study. PATIENTS AND MEASUREMENTS: Participating patients (n = 150) with chronic AI were provided with a questionnaire on the management of emergency situations, which had to be completed and sent back in case of an AE. In addition, patients were contacted by phone on a regular basis. RESULTS: Fifty-nine AE in 39 patients were documented. The time interval from contact to arrival of a medical professional was 20 minutes (1-240). In total, in 43 AE, patients received parenteral GC by a medical professional. The time interval between showing the emergency card and GC injection by a medical professional was 60 minutes (5-360). A total of 26 patients administered GC by self-injection. The time from the beginning of symptoms to GC injection was significantly shorter in case of self-injection (self-injection vs injection by medical professional; 85 minutes [20-280] vs 232.5 minutes [1-3135]; P < .001). After self-injection, 62% of the patients were treated outpatient, compared to 27% of the patients after exclusive injection by a medical professional (P = .008). To improve the emergency management, most of the patients (84%) indicated a need for an easier way of self-injection. CONCLUSION: While management of AE by both patients and medical professionals still shows high variability, patients profit from the option of self-injection. Patient care, including education of patients and health-professionals, as well as the way of GC administration, needs further optimization. PMID- 29617052 TI - Retinopathy of prematurity screening at >=30 weeks: urinary NTpro-BNP performance. AB - AIM: Urinary N-terminal B-type natriuretic peptide NTproBNP levels are associated with the development of retinopathy of prematurity (ROP) in infants <30 weeks of gestation. The incidence of ROP in more mature infants who meet other ROP screening criteria is very low. We therefore aimed to test whether urinary NTproBNP predicted ROP development in these infants. METHODS: Prospective observational study in 151 UK infants >=30 + 0 weeks of gestation but also <32 weeks of gestation and/or <1501 g, to test the hypothesis that urinary NTproBNP levels on day of life (DOL) 14 and 28 were able to predict ROP development. RESULTS: Urinary NTproBNP concentrations on day 14 and day 28 of life did not differ between infants with and without ROP (medians 144 vs 128 mcg/mL, respectively, p = 0.86 on DOL 14 and medians 117 vs 94 mcg/mL, respectively, p = 0.64 on DOL28). CONCLUSION: The association previously shown for infants <30 completed weeks between urinary NTproBNP and the development of ROP was not seen in more mature infants. Urinary NTproBNP does not appear helpful in rationalising direct ophthalmoscopic screening for ROP in more mature infants, and may suggest a difference in pathophysiology of ROP in this population. PMID- 29617053 TI - Efficacy and safety of rivaroxaban compared to enoxaparin in treatment of cancer associated venous thromboembolism. AB - BACKGROUND: Low molecular weight heparin (LMWH) is the guideline-endorsed treatment for cancer-associated venous thromboembolism (cVTE). Study objectives were to compare the efficacy and safety of rivaroxaban and enoxaparin in cVTE. METHODS: Using a cohort study design, consecutive patients with cVTE (3/1/2013 7/31/2016), enrolled in the Mayo Thrombophilia Clinic Direct Oral Anticoagulants Registry, were compared to contemporary cancer patients receiving enoxaparin. The cumulative incidence of venous thromboembolism (VTE) recurrence, major and clinically relevant non-major bleeding, and survival were assessed at 3 and 12 months. RESULTS: Ninety-eight patients received rivaroxaban (51% female, mean age 63 +/- 12 years) and 168 enoxaparin (34.5% female, mean age 62 +/- 15 years). The most common cancers included gastrointestinal/pancreatic, genitourinary and hematologic cancers. More than half of patients had pulmonary emboli at presentation. More than half had metastases, and two-thirds were receiving chemotherapy. At 3 months, there were no differences in VTE recurrence (rivaroxaban 1.0% vs enoxaparin 4.2%; P = .15), major bleeding (rivaroxaban 5.1% vs enoxaparin 3.6%; P = .55), or all-cause mortality (rivaroxaban 4.1% vs enoxaparin 8.9%; P = .14). At 12 months, these outcomes did not differ by treatment strategy. CONCLUSION: The results of this "real-world" experience with cVTE suggest that rivaroxaban may offer a safe and effective alternative to LMWH. PMID- 29617054 TI - Activation of voltage-gated sodium current and inhibition of erg-mediated potassium current caused by telmisartan, an antagonist of angiotensin II type-1 receptor, in HL-1 atrial cardiomyocytes. AB - Telmisartan (TEL) is a non-peptide blocker of angiotensin II type-1 (AT1 ) receptor. However, the mechanisms through which this drug interacts directly with ion currents in hearts remain largely unclear. Herein, we aim to investigate the effects of TEL the on ionic currents and membrane potential of murine HL-1 cardiomyocytes. In whole-cell recordings, addition of TEL stimulated the peak and late components of voltage-gated Na+ currents (INa ) with different potencies. The EC50 values required to achieve the stimulatory effect of this drug on peak and late INa were 0.2 and 1.2 MUmol/L, respectively, and the current-voltage relationship of peak INa shifted toward less-depolarized potentials during exposure to TEL. Telmisartan not only increased peak INa but also prolonged the inactivation time course of late INa . Amiodarone (Amio) or ranolazine (Ran), but not angiotensin II, could reverse TEL-mediated effects. The drug enhanced the recovery rate of INa inactivation and exerted an inhibitory effect on erg mediated K+ and L-type Ca2+ currents. In whole-cell current-clamp recordings, addition of the drug resulted in prolongation of the duration of action potentials (APs) in a dose-dependent manner in HL-1 cells; Amio or Ran could reverse this increase in AP durations. Telmisartan-mediated prolongation of AP was attenuated in KCNH2 siRNA-transfected HL-1 cells. In cultured smooth muscle cells of the human coronary artery, TEL enhanced INa amplitudes and slowed current inactivation. Stimulation by TEL of INa in HL-1 cells did not simply increase current magnitude but altered current kinetics, thereby suggesting state dependent activation. Telmisartan may have greater affinity to the open/inactivated state than to the resting state residing in NaV channels. Collectively, TEL-mediated stimulation of INa and inhibition of IK(erg) could be an important ionic mechanism underlying the increased cell excitability of HL-1 cells; these actions, however, cannot be entirely explained by its blockade of AT1 receptor. PMID- 29617055 TI - Development of a large-volume human-derived adipose acellular allogenic flap by perfusion decellularization. AB - In reconstructive surgery, transfer of patients' tissue (autologous flaps) is routinely used to repair large soft tissue defects caused by surgery, trauma, chronic diseases, or malformations; unfortunately, this strategy is not always possible and often creates a secondary defect in the donor site of the tissue. Tissue-engineered synthetic flaps are currently unable to repair clinically relevant, large-volume defects; allogenic flaps from cadaveric donors could provide a ready-to-use biological alternative if treated with methods to avoid the immune-rejection of the donor's cells. Here, we describe the successful decellularization of a large (> 800 cc) human-derived adipose flap through a perfusion apparatus; we demonstrate the complete removal of the immunogenic cellular components of the flap with the retention of its structural components and vascular network. Our aim is to obtain a universally compatible, off-the shelf acellular allogenic flap that could be recellularized with cells from recipient patients to provide a tissue-engineered allogenic/autologous alternative for reconstruction of large-volume soft-tissue defects. PMID- 29617056 TI - Predictable information in neural signals during resting state is reduced in autism spectrum disorder. AB - The neurophysiological underpinnings of the nonsocial symptoms of autism spectrum disorder (ASD) which include sensory and perceptual atypicalities remain poorly understood. Well-known accounts of less dominant top-down influences and more dominant bottom-up processes compete to explain these characteristics. These accounts have been recently embedded in the popular framework of predictive coding theory. To differentiate between competing accounts, we studied altered information dynamics in ASD by quantifying predictable information in neural signals. Predictable information in neural signals measures the amount of stored information that is used for the next time step of a neural process. Thus, predictable information limits the (prior) information which might be available for other brain areas, for example, to build predictions for upcoming sensory information. We studied predictable information in neural signals based on resting-state magnetoencephalography (MEG) recordings of 19 ASD patients and 19 neurotypical controls aged between 14 and 27 years. Using whole-brain beamformer source analysis, we found reduced predictable information in ASD patients across the whole brain, but in particular in posterior regions of the default mode network. In these regions, epoch-by-epoch predictable information was positively correlated with source power in the alpha and beta frequency range as well as autocorrelation decay time. Predictable information in precuneus and cerebellum was negatively associated with nonsocial symptom severity, indicating a relevance of the analysis of predictable information for clinical research in ASD. Our findings are compatible with the assumption that use or precision of prior knowledge is reduced in ASD patients. PMID- 29617057 TI - Antigen-specific Helios- , Neuropilin-1- Tregs induce apoptosis of autoreactive B cells via PD-L1. AB - Regulatory T cells (Tregs) maintain self-tolerance and prevent autoimmunity by controlling autoreactive T cells. We recently demonstrated in vivo that Tregs can directly suppress auto-reactive B cells via programmed death ligand 1 (PD-L1) that ligated PD-1 on B cells and caused them to undergo apoptosis. Here, we asked whether this mechanism is utilized by thymus-derived natural Tregs and/or by peripheral lymphoid tissue-induced Tregs. We first demonstrated that antigen specific PD-L1-expressing Tregs were induced in the draining lymph node of autoantigen-expressing tissue and characterized them by their lack of the transcription factor Helios and of the surface marker Neuropilin-1 (Nrp-1). Next, we established an in vitro co-culture system to study the interaction between B cells and Treg subsets under controlled conditions. We found that Nrp- Treg, but not Nrp+ Treg suppressed autoreactive B cells, whereas both were able to suppress T-helper cells. Such suppression was antigen-specific and was facilitated by PD L1/PD-1-induced apoptosis. Furthermore, it required physical cell contact and was MHC II-restricted, providing an explanation for the antigen-specificity of peripherally-induced Tregs. These findings identify a role for peripherally induced Helios- Nrp-1- inducible Treg in controlling peripheral B-cell tolerance against tissue auto-antigens. PMID- 29617058 TI - Multicenter, randomized controlled, observer-blinded study of a nitric oxide generating treatment in foot ulcers of patients with diabetes-ProNOx1 study. AB - The aim of this multicenter, prospective, observer-blinded, parallel group, randomized controlled trial was to assess the safety and efficacy of EDX110, a nitric oxide generating medical device, in the treatment of diabetic foot ulcers in a patient group reflecting "real world" clinical practice compared against optimal standard care. Participants were recruited from ten hospital sites in multidisciplinary foot ulcer clinics. The ulcers were full thickness, with an area of 25-2,500 mm2 and either a palpable pedal pulse or ankle brachial pressure index > 0.5. Infected ulcers were included. Treatment lasted 12 weeks, or until healed, with a 12-week follow-up period. Both arms were given optimal debridement, offloading and antimicrobial treatment, the only difference being the fixed used of EDX110 as the wound dressing in the EDX110 group. 135 participants were recruited with 148 ulcers (EDX110-75; Control-73), 30% of which were clinically infected at baseline. EDX110 achieved its primary endpoint by attaining a median Percentage Area Reduction of 88.6% compared to 46.9% for the control group (p = 0.016) at 12 weeks in the intention-to-treat population. There was no significant difference between wound size reduction achieved by EDX110 after 4 weeks and the wound size reduction achieved in the control group after 12 weeks. EDX110 was well tolerated. Thirty serious adverse events were reported (12 in the EDX110 group, of which 4 were related to the ulcer; 18 in the control group, of which 10 were related and 1 possibly related to the ulcer), with significant reduction in serious adverse events related to the ulcer in EDX group. There was no significant difference in adverse events. This study, in a real world clinical foot ulcer population, demonstrates the ability of EDX110 to improve healing, as measured by significantly reducing the ulcer area, compared to current best clinical practice. PMID- 29617059 TI - Aldo-keto reductases-mediated cytotoxicity of 2-deoxyglucose: A novel anticancer mechanism. AB - 2-Deoxyglucose (2DG) is a non-metabolizable glucose analog currently in clinical trials to determine its efficacy in enhancing the therapeutic effects of radiotherapy and chemotherapy of several types of cancers. It is thought to preferentially kill cancer cells by inhibiting glycolysis because cancer cells are more dependent on glycolysis for their energy needs than normal cells. However, we found that the toxicity of 2DG in cancer cells is mediated by the enzymatic activities of AKR1B1 and/or AKR1B10 (AKR1Bs), which are often overexpressed in cancer cells. Our results show that 2DG kills cancer cells because, in the process of being reduced by AKR1Bs, depletion of their cofactor NADPH leads to the depletion of glutathione (GSH) and cell death. Furthermore, we showed that compounds that are better substrates for AKR1Bs than 2DG are more effective than 2DG in killing cancer cells that overexpressed these 2 enzymes. As cancer cells can be induced to overexpress AKR1Bs, the anticancer mechanism we identified can be applied to treat a large variety of cancers. This should greatly facilitate the development of novel anticancer drugs. PMID- 29617060 TI - Prospective real-world analysis of OnabotulinumtoxinA in chronic migraine post National Institute for Health and Care Excellence UK technology appraisal. AB - BACKGROUND AND PURPOSE: The National Institute for Health and Care Excellence (NICE) in the UK recommends the use of OnabotulinumtoxinA (BoNTA, Botox(r) ) in the management of chronic migraine (CM) following specific guidelines within the National Health Service. In view of the lack of data on the efficacy of this therapy following implementation of these guidelines in clinical practice and on the evaluation of guidance compliance, we aimed to evaluate the effectiveness and safety of BoNTA in patients with CM following the NICE guidelines. METHODS: This was a prospective real-life audit study. RESULTS: After two treatments, 127 of 200 patients (63.5%) obtained at least a 30% reduction in headache days. Those who continued the treatment up to 3 years reported a stable beneficial effect compared with baseline. Amongst responders, 68 patients (53.5%) were reclassified as episodic migraineurs. A total of 57 of these patients (83.8%) converted to an episodic migraine pattern at 6-month follow-up. The majority of those whose migraine became episodic after BoNTA extended the treatment intervals beyond 3 months (range 4-8 months) before noticing any worsening of headache. We observed no significant differences in the efficacy measures in patients treated with 155 U BoNTA compared with those treated with >155 U BoNTA. CONCLUSIONS: When administered according to the NICE guidance, BoNTA produced a clinically meaningful effect in the long-term management of CM with and without medication overuse headache. Treatment discontinuation when CM becomes episodic may be useful in clinical practice to identify those who may benefit from extended treatment intervals. Our clinical experience indicates a lack of additional benefit from using the 'follow-the-pain' paradigm. PMID- 29617061 TI - Internet addiction and attention-deficit-hyperactivity disorder: Effects of anxiety, depression and self-esteem. AB - BACKGROUND: Attention-deficit-hyperactivity disorder (ADHD) is one of the most common neurodevelopmental disorders of childhood. Behavioral disinhibition, poor neurocognitive skills and immediate reward preference in children with ADHD have been suggested as risk factors for Internet addiction (IA). The aim of the present study was therefore to investigate the relationship between IA and depression, anxiety, and self-esteem in adolescents with ADHD, and to identify the features of Internet use that predict IA. METHODS: We studied 111 patients with ADHD aged 12-18 years, and 108 healthy controls. The ADHD patients and controls were asked to complete a sociodemographic data form, the Internet Addiction Scale (IAS), Children's Depression Inventory, Childhood Screening Scale for Anxiety in Children, and the Rosenberg Self-Esteem Scale. RESULTS: IAS total score in the adolescents with ADHD was significantly higher than in the control group. Compared with the control group, the ADHD group depression scale score was significantly higher, and self-esteem score significantly lower (P < 0.05 for both). There was no difference between the groups in anxiety score. IAS score had a positive correlation with depression and anxiety scores, and a negative correlation with self-esteem score. CONCLUSION: The relationship between IA scale score and depression, anxiety and self-esteem scale scores were similar in the ADHD and the control group. In addition, IAS subscale and total scores were significantly higher in the ADHD group than the control group, even after controlling for the effects of self-esteem, depression and anxiety scores. Thus, ADHD is thought to be an independent risk factor for depression, anxiety and self esteem, and, hence, for IA. PMID- 29617062 TI - Radiofrequency Thermocoagulation of the Ganglion Impar for Coccydynia Management: Long-Term Effects. AB - OBJECTIVE: To investigate the short- and long-term effects of ganglion impar radiofrequency thermocoagulation (RFT) treatment in patients with chronic coccydynia. METHODS: We retrospectively analyzed the medical records of patients who underwent RFT of the ganglion impar between 2009 and 2011. Pain intensity visual numeric scale (VNS) scores and Euroqol 5D (EQ-5D) index scores were recorded pre-intervention and post-intervention at the first, sixth, and twelfth months. The differences between pre-procedural VNS scores and post-procedural VNS scores at the first, sixth, and twelfth months were evaluated. The success of the intervention was recorded as the percentage difference between the pre intervention VNS scores and post-intervention VNS scores at the first, sixth, and twelfth months. RESULTS: The mean age of the patients, including 11 females (55%) and 8 males (45%), was 48.7 +/- 14.3 years. The average follow-up duration was 17.3 +/- 2.9 months. Statistically significant differences were observed between the pre- and post-procedure VNS scores (P < 0.0001). Improvements in VNS scores were correlated with improvements in EQ-5D index scores. Mid-term (sixth month) and long-term (twelfth month) evaluations after the intervention revealed that 67.4% and 61.1% of the patients had successful outcomes, respectively. CONCLUSION: Our data suggested that RFT of the ganglion impar in patients with chronic coccydynia resulted in effective outcomes, and patients who responded to RFT had significantly lower post-RFT pain scores. PMID- 29617063 TI - Hypocrellin B-loaded, folate-conjugated polymeric micelle for intraperitoneal targeting of ovarian cancer in vitro and in vivo. AB - Photodynamic therapy (PDT) is considered an innovative and attractive modality to treat ovarian cancer. In the present study, a biodegradable polymer poly (ethylene glycol) (PEG)-poly (lactic acid)(PLA)-folate (FA-PEG-PLA) was prepared in order to synthesize an active-targeting, water-soluble and pharmacomodulated photosensitizer nanocarrier. Drug-loading content, encapsulation efficiency, in vitro and in vivo release were characterized, in which hypocrellin B (HB)/FA-PEG PLA micelles had a high encapsulation efficiency and much slower control release for drugs compared to free drugs (P < .05). To evaluate the targeting ability of the HB/FA-PEG-PLA micelles, a cellular uptake study in vitro was carried out, which showed significantly enhanced uptake of HB/FA-PEG-PLA micelles in SKOV3 (FR+) compared to A2780 cancer cells (FR-). The enhanced uptake of HB/FA-PEG-PLA micelles to cancer cells resulted in a more effective post-PDT killing of SKOV3 cells compared to plain micelles and free drugs. Binding and uptake of HB/FA-PEG PLA micelles by SKOV3 cells were also observed in vivo after ip injection of folate-targeted micelles in tumor-bearing ascitic ovarian cancer animals. Drug levels in ascitic tumor tissues were increased 20-fold (P < .001), which underscored the effect of a regional therapy approach with folate targeting. Furthermore, the HB-loaded micelles were mainly distributed in kidney and liver (the main clearance organs) in biodistribution. These results showed that our newly developed PDT photosensitizer HB/FA-PEG-PLA micelles have a high drug loading capacity, good biocompatibility, controlled drug release, and enhanced targeting and antitumor effect, which is a potential approach to future targeting ovarian cancer therapy. PMID- 29617064 TI - Treatment of Complicated Grief in Survivors of Suicide Loss: A HEAL Report. AB - OBJECTIVE: Suffering associated with complicated grief (CG) is profound. Because suicide loss survivors are susceptible to developing CG, identifying effective treatments for suicide loss survivors with CG is a high priority. This report provides data on the acceptability and effectiveness of antidepressant medication and complicated grief therapy (CGT), a CG-targeted psychotherapy, for suicide loss survivors with CG identified by an Inventory of Complicated Grief score >= 30. METHODS: This is a secondary analysis of data collected from March 2010 to September 2014 for a 4-site, double-blind, placebo-controlled randomized trial comparing the effectiveness of antidepressant medication alone or in combination with CGT for participants with CG (score >= 30 on the Inventory of Complicated Grief) who were bereaved by suicide (SB; n = 58), accident/homicide (A/H; n = 74), or natural causes (NC; n = 263). Using mode of death as a grouping factor, we evaluated acceptability of treatments by comparing 12-week medication and 16 session CGT completion; we evaluated effectiveness by comparing response at week 20, defined by a score of 1 or 2 on the Complicated Grief Clinical Global Impressions-Improvement scale (CG-CGI-I), and additional secondary response measures. RESULTS: Among participants receiving medication alone, SB medication completion rates (36%) were lower than rates for A/H (54%) and NC (68%; chi2 = 11.76, P < .01). SB medication completion rates were much higher for SB individuals receiving CGT (82%; chi2 = 12.45, P < .001) than for SB individuals receiving medication alone. CGT completion rates were similar in the 3 groups (SB = 74%, A/H = 64%, NC = 77%; chi2 = 2.48, P = .29). For SB participants receiving CGT, CG-CGI-I response rates were substantial (64%), but lower compared to the other groups (A/H = 93%, NC = 84%; chi2 = 8.00, P < .05). However, on all other outcomes, changes from baseline for SB participants were comparable to those for A/H and NC participants, including number and severity of grief symptoms, suicidal ideation, and grief-related impairment, avoidance, and maladaptive beliefs. CONCLUSIONS: These results raise concern about the acceptability of medication alone as a treatment for complicated grief in treatment-seeking suicide-bereaved adults. In contrast, CGT is an acceptable and promising treatment for suicide-bereaved individuals with complicated grief. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01179568. PMID- 29617065 TI - Relationships Between Self-Injurious Behaviors, Pain Reactivity, and beta Endorphin in Children and Adolescents With Autism. AB - OBJECTIVE: Autism and certain associated behaviors including self-injurious behaviors (SIB) and atypical pain reactivity have been hypothesized to result from excessive opioid activity. The objective of this study was to examine the relationships between SIB, pain reactivity, and beta-endorphin levels in autism. METHODS: Study participants were recruited between 2007 and 2012 from day care centers and included 74 children and adolescents diagnosed with autism (according to DSM-IV-TR, ICD-10, and CFTMEA) and intellectual disability. Behavioral pain reactivity and SIB were assessed in 3 observational situations (parents at home, 2 caregivers at day care center, a nurse and child psychiatrist during blood drawing) using validated quantitative and qualitative scales. Plasma beta endorphin concentrations were measured in 57 participants using 2 different immunoassay methods. RESULTS: A high proportion of individuals with autism displayed SIB (50.0% and 70.3% according to parental and caregiver observation, respectively). The most frequent types of SIB were head banging and hand biting. An absence or decrease of overall behavioral pain reactivity was observed in 68.6% and 34.2% of individuals with autism according to parental and caregiver observation, respectively. Those individuals with hyporeactivity to daily life accidental painful stimuli displayed higher rates of self-biting (P < .01, parental evaluation). No significant correlations were observed between beta endorphin level and SIB or pain reactivity assessed in any of the 3 observational situations. CONCLUSIONS: The absence of any observed relationships between beta endorphin level and SIB or pain reactivity and the conflicting results of prior opioid studies in autism tend to undermine support for the opioid theory of autism. New perspectives are discussed regarding the relationships found in this study between SIB and hyporeactivity to pain. PMID- 29617067 TI - The Role of Polymers in the Synthesis of Noble Metal Nanoparticles: A Review. AB - Lately, many efforts have been devoted to finding more efficient methods to prepare metal nanoparticles with controlled shapes and sizes, low polydispersity, high purity and good stability in a specific dispersion medium. Therefore, it is highly desired to develop synthetic routes that can contribute to tune the properties of metal nanoparticles for their potential applications in diverse scientific and technological fields. Thus, the application of polymers in the synthesis of metal nanoparticles has attracted great interest due to the better understanding of the parameters involved in the stabilization processes of metal nanoparticles. In addition, the use of polymers in the chemical reduction of metal ions in solution has also attracted much attention recently. Thus, this field of research is growing in importance because it would be possible, for example, to prepare hybrid nanocomposites by using non-toxic reagents and simplified synthetic routes. However, control of the shape, improvement of the size distribution and establishing correlations between polymer structure and characteristics of noble metal nanoparticles are still challenging tasks that should be considered in the synthesis processes in order to obtain hybrid nanomaterials with desirable properties. PMID- 29617066 TI - The Mixed Opioid Receptor Antagonist Naltrexone Mitigates Stimulant-Induced Euphoria: A Double-Blind, Placebo-Controlled Trial of Naltrexone. AB - OBJECTIVE: Supratherapeutic doses of methylphenidate activate MU-opioid receptors, which are linked to euphoria. This study assessed whether naltrexone, a mixed MU-opioid antagonist, may attenuate the euphoric effects of stimulants, thereby minimizing their abuse potential in subjects with attention deficit/hyperactivity disorder (ADHD). METHODS: We conducted a 6-week, double blind, placebo-controlled, randomized clinical trial of naltrexone in adults with DSM-IV ADHD receiving open treatment with a long-acting formulation of methylphenidate (January 2013 to June 2015). Spheroidal Oral Drug Absorption System methylphenidate (SODAS-MPH) was administered twice daily, was titrated to ~1 mg/kg/d over 3 weeks, and was continued for 3 additional weeks depending on response and adverse effects. Subjects were adults with ADHD preselected for having experienced euphoria with an oral test dose of 60 mg of immediate-release methylphenidate (IR-MPH). The primary outcome measure was Question 2 (Liking a Drug Effect) on the Drug Rating Questionnaire, Subject version, which was assessed after oral test doses of 60 mg of IR-MPH were administered after the third and sixth weeks of treatment with SODAS-MPH. RESULTS: Thirty-seven subjects who experienced stimulant-induced (mild) euphoria at a baseline visit were started in the open trial of SODAS-MPH and randomized to naltrexone 50 mg/d or placebo. Thirty-one subjects completed through week 3, and 25 completed through week 6. Naltrexone significantly diminished the euphoric effect of IR-MPH during the heightened-risk titration phase (primary outcome; first 3 weeks) (chi2 = 5.07, P = .02) but not the maintenance phase (weeks 4-6) (chi2 = 0.22, P = .64) of SODAS-MPH treatment. CONCLUSIONS: Preclinical findings are extended to humans showing that naltrexone may mitigate stimulant-associated euphoria. Our findings provide support for further studies combining opioid receptor antagonists with stimulants to reduce abuse potential. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01673594. PMID- 29617068 TI - The Preparation of C-Reactive Protein Immunosensor Based on Amino Graphene and Hollow Silver Platinum Nanomaterials. AB - A novel and sensitive nonenzymatic sandwich-type electrochemical immunosensor was developed for the detection of C-reactive protein. The catalytic activity of Ag/Pt nanomaterials that possessed an intrinsic enzyme catalytic activity similar to that of horseradish peroxidase (HRP) was utilized as a label to improve the stability and sensitivity using amino graphene as an immobilization matrix. Comparing with the common methods of using HRP as labels for electrochemical detection, Ag/Pt nanoparticles might have longer lifetime than that of enzymes. As far as know, there is no other report using Ag/Pt as catalytic labels for electrocatalyzed reduction of H2O2 to fabricate the amperometric immunosensor. Under the optimized experimental conditions, the detection range of the sensor is from 0.5 ng/mL to 140 ng/mL with a linear correlation coefficient of 0.9934 and the detection limit of 0.17 ng/mL at 3sigma . The sensor has good stability, reproducibility and high sensitivity. Therefore, the immunosensor is promising for applications in point-of-care diagnostics. PMID- 29617069 TI - 'Folate-Conjugated Phosphorescent Silica Nanoparticles for Bioimaging and Cancer Cell Targeting. AB - Besides their superior photophysical properties, phosphorescent transition-metal complexes have some drawbacks for biological applications because of their poor solubility in aqueous solutions and toxicity. In order to avoid the biological environmental impacts on their optical function and solve the problems of water solubility and toxicity in sensing and bioimaging, two biocompatible organic/inorganic hybrid phosphorescent nanoprobes (Ir-MSN) by using mesoporous silica nanoparticles (MSN) as carriers and an iridium(III) complex as signaling unit were prepared in the present study. In addition, folic acid (FA) was covalently attached to them to endow the particles with characteristic of tumor targeting. The photophysical properties, cell staining and tumor cell targeting functions of FA-ligated Ir-MSN were investigated. These results demonstrated that such a design strategy of phosphorescent nanoprobes is an effective way to develop excellent phosphorescent cellular probes for living cell applications. PMID- 29617072 TI - Re: Dipyridamole reduces penile apoptosis in a rat model of post-prostatectomy erectile dysfunction. PMID- 29617073 TI - Changes observed in prostate biopsy practices in an inner city hospital with a high risk patient population following the 2012 uspstf psa screening recommendations. AB - INTRODUCTION: We compared characteristics of patients undergoing prostate biopsy in a high-risk inner city population before and after the 2012 USPSTF recommendation against PSA based prostate cancer screening to determine its effect on prostate biopsy practices. MATERIALS AND METHODS: This was a retrospective study including patients who received biopsies after an abnormal PSA measurement from October 2008-December 2015. Patients with previously diagnosed prostate cancer were excluded. Chi-square tests of independence, two sample t-tests, Mann-Whitney U tests, and Fisher's exact tests were performed. RESULTS: There were 202 and 208 patients in the pre-USPSTF and post-USPSTF recommendation cohorts, respectively. The post-USPSTF cohort had higher median PSA (7.8 versus 7.1ng/mL, p=0.05), greater proportion of patients who were black (96.6% versus 90.5%, p=0.01), and greater percentage of biopsy cores positive for disease (58% versus 29.5%, p<0.001). Multivariable analysis supported that the increase in PSA was independent of the increase in the proportion of patients who were black. The proportion of patients who were classified as D'Amico intermediate and high-risk disease increased in the post-USPSTF cohort and approached statistical significance (70.1% versus 58.8%, p=0.12). CONCLUSIONS: Our study suggests that the USPSTF recommendations may have led to na increase in pre-biopsy PSA as well as greater volume of disease. Also, a greater proportion of patients were being classified with intermediate or high risk disease. While the clinical significance of these findings is unknown, what the data suggests is somewhat troubling. Future research should further examine these changes in a larger cohort as well as resultant long-term outcomes. PMID- 29617075 TI - Vitamin C inhibits crystallization of struvite from artificial urine in the presence of Pseudomonas aeruginosa. AB - BACKGROUND: Formation of struvite stones is associated with urinary tract infection by urease-producing bacteria. Biogenic crystal growth in natural and synthetic materials is regulated by the action of inhibitors, ranging from small ions, molecules to large macromolecules. MATERIALS AND METHODS: We report the dynamics of in vitro crystallization of struvite in presence of vitamin C in synthetic urine using single diffusion gel growth technique. Sodium metasilicate gel of specific gravity 1.05 and the aqueous solution of ammonium dihydrogen phosphate were used as the medium for growing the struvite crystals. The crystallization process was induced by a urease positive struvite stone associated Pseudomonas aeruginosa to mimic the infection leading to stone formation. The grown crystals were characterized by ATR-FTIR and powder XRD. The surface morphology was analysed through FE-SEM for comparison between treatments. RESULTS: We observed decrease in number, dimension, and growth rate of struvite crystals with the increasing concentrations of vitamin C. Crystals displayed well defined faces and dendritic morphology of struvite in both control and biogenic systems. CONCLUSION: The results strongly suggest that, vitamin C can modulate the formation of struvite crystals in the presence of uropathogenic bacteria. PMID- 29617076 TI - Completely endophytic renal tumor: A laparoscopic approach. AB - Kidney cancer is the third most common urologic malignancy and a 2% annual increase in the incidence has occurred over the past two decades, largely because of the increased utilization of imaging. The majority of these tumors are small, so the indications for nephron-sparing surgery and for minimally invasive surgery are continually expanding. Complex kidney lesions, such as those completely endophytic, are still a challenge even for experienced surgeons. Our objective is to demonstrate the operative technique for laparoscopic partial nephrectomy with the aid of intra-operative ultrasound in a man with a totally endophytic renal lesion. Case: A 52 years old man, asymptomatic, with incidental renal mass of 2.9 cm, completely endophytic (R.E.N.A.L score 9p) submitted to partial laparoscopic nephrectomy. Surgical time was 2 hours, with 20 minutes of ischemia. Pathological anatomy confirmed tumor of clear cells T1a, free margins. PMID- 29617074 TI - Evaluation of urodynamic parameters after sling surgery in men with post prostatectomy urinary incontinence. AB - OBJECTIVE: To evaluate urodynamic alterations after sub-urethral sling surgery (SSU) in patients with post-prostatectomy urinary incontinence (PPUI). MATERIALS AND METHODS: We evaluated data of 22 patients submitted to radical prostatectomy (RP) or transurethral resection of prostate (TURP) that presented post-surgical urinary incontinence and were treated with SSU implant in a pilot study previously performed in our institution. METHODS: Those patients with PPUI were evaluated by urodynamic exam (UD) before and after surgery, and the parameters were compared, including uroflow, cystometry and micturition study. Exclusion criteria included patients without pre-operatory urodynamic study, those with urethral stenosis, those not healed of prostate cancer, patients without clinical conditions to be submitted to urodynamic study and those with severe neurological diseases or that refused to sign the consent form. Results were analyzed statistically by Fisher, Wilcoxon or Mann-Whitney tests. RESULTS: During free uroflow, none parameters showed any statistical significant differences. During cystometry, there were also no statistical differences and the same was observed at pressure versus flow study; the exception was at maximal flow detrusor pressure (PdetQmax), that was lower at post-operatory (p=0.028). In relation to the presence of urinary dysfunctions associated to PPUI, we observed a significant reduction of detrusor overactivity (p=0.035) in relation to pre operatory period. CONCLUSION: SSU surgery significantly reduced detrusor overactivity and PdetQMax; however, there were no alterations of other evaluated urodynamic parameters. PMID- 29617077 TI - Robotic adenomectomy using a laparoscopic dissector. AB - INTRODUCTION: Only few reports are known about the use of robotic surgery for prostate benign enlargement. The robotic surgery can be improved by laparoscopic tricks. We show a video of robotic adenomectomy where a laparoscopic dissector is used to help create the plan between prostatic capsule and adenoma. MATERIALS AND METHODS: A 62 years old male had severe urinary flow outlet obstruction. Medical therapy was not effective. Ultrasound detected a 92gr enlarged prostate with a large middle lobe. Robotic assisted adenomectomy was scheduled. The procedure followed this sequence: opening of Retzius space, superficial suture of the Dorsal vein complex, horizontal cistotomy. The plan was created with electrocautery and blunt dissection with the laparoscopic dissector. Haemostatic sutures were placed between prostate fossa and the posterior bladder neck and closure of the cistotomy. RESULTS: Whole operation time was 160 minutes, with a blood loss of 80cc. There was no perioperative or post-operative complication. Catheter was removed after 4 days. Post-operatory uroflowmetry shows a peak flow of 30ml/sec. Pathological examination is negative for tumor. After 60 days IPSS was 8. CONCLUSION: Robotic prostate adenomectomy using the laparoscopic dissector is a safe and effective minimally invasive treatment for benign prostatic enlargement. It is a novel technique to find and dissect the plane between prostatic adenoma and capsule. This could be one more use of laparoscopic technology to improve surgical outcomes in robotic field. PMID- 29617078 TI - Complete supine percutaneous nephrolithotomy with GoPro(r). Ten steps for success. AB - OBJECTIVE: To show a video of a complete supine Percutaneous Nephrolithotomy (csPCNL) performed for the treatment of a staghorn calculus, from the surgeon's point of view. The procedure was recorded with a GoPro(r) camera, demonstrating the ten essential steps for a successful procedure. MATERIALS AND METHODS: The patient was a 38 years-old woman with 2.4cm of left kidney lower pole stone burden who presented with 3 months of lumbar pain and recurrent urinary tract infections. She had a previous diagnosis of polycystic kidney disease and chronic renal failure stage 2. CT scan showed two 1.2cm stones in the lower pole (Guy's Stone Score 2). She had a previous ipsilateral double J insertion due to an obstructive pyelonephritis. The csPCNL was uneventful with a single access in the lower pole. The surgeon had a Full HD GoPro Hero 4 Session(r) camera mounted on his head, controlled by the surgical team with a remote control. All of the mains steps were recorded. Informed consent was obtained prior to the procedure. RESULTS: The surgical time was 90 minutes. Hemoglobin drop was 0.5g/dL. A post operative CT scan was stone-free. The patient was discharged 36 hours after surgery. The camera worked properly and didn't cause pain or muscle discomfort to the surgeon. The quality of the recorded movie was excellent. CONCLUSION: GoPro(r) camera proved to be a very interesting tool to document surgeries without interfering with the procedure and with great educational potential. More studies should be conducted to evaluate the role of this equipment. PMID- 29617079 TI - Effect of phyllanthus niruri on metabolic parameters of patients with kidney stone: a perspective for disease prevention. AB - : Phyllanthus niruri (P.niruri) or stone breaker is a plant commonly used to reduce stone risk, however, clinical studies on this issue are lacking. OBJECTIVE: To prospectively evaluate the effect of P. niruri on the urinary metabolic parameters of patients with urinary lithiasis. MATERIALS AND METHODS: We studied 56 patients with kidney stones <10mm. Clinical, metabolic, and ultrasonography assessment was conducted before (baseline) the use of P. niruri infusion for 12-weeks (P. niruri) and after a 12-week (wash out) Statistical analysis included ANOVA for repeated measures and Tukey's/McNemar's test for categorical variables. Significance was set at 5%. RESULTS: Mean age was 44+/-9.2 and BMI was 27.2+/-4.4kg/m2. Thirty-six patients (64%) were women. There were no significant changes in all periods for anthropometric and several serum measurements, including total blood count, creatinine, uric acid, sodium, potassium, calcium, urine volume and pH; a significant increase in urinary potassium from 50.5+/-20.4 to 56.2+/-21.8 mg/24-hour (p=0.017); magnesium/creatinine ratio 58+/-22.5 to 69.1+/-28.6mg/ gCr24-hour (p=0.013) and potassium/creatinine ratio 39.3+/-15.1 to 51.3+/-34.7mg/gCr24- hour (p=0.008) from baseline to wash out. The kidney stones decreased from 3.2+/-2 to 2.0+/-2per patient (p<0.001). In hyperoxaluria patients, urinary oxalate reduced from 59.0+/ 11.7 to 28.8+/-16.0mg/24-hour (p=0.0002), and in hyperuricosuria there was a decrease in urinary uric acid from 0.77+/-0.22 to 0.54+/-0.07mg/24-hour (p=0.0057). CONCLUSIONS: P.niruri intake is safe and does not cause significant adverse effects on serum metabolic parameters. It increases urinary excretion of magnesium and potassium caused a significant decrease in urinary oxalate and uric acid in patients with hyperoxaluria and hyperuricosuria. The consumption of P.niruri contributed to the elimination of urinary calculi. PMID- 29617080 TI - The protective effect of Papaverine and Alprostadil in rat testes after ischemia and reperfusion injury. AB - OBJECTIVE: To investigate the effect of papaverine and alprostadil on testicular torsion-detorsion injury in rats. MATERIALS AND METHODS: A total of 40 male Wistar-Albino rats were used in this study. Four hours of right testicular torsion was applied to each group, excluding sham operated group. The torsion detorsion (T/D), T/D + papaverine and T/D + alprostadil groups received saline, papaverine and alprostadil at the same time as surgical detorsion, respectively. At 14 days after the surgical detorsion, ischaemic changes and the degree of damage were evaluated with Cosentino scoring and the Johnson tubular biopsy score (JTBS). RESULTS: JTBS was determined as 8.8+/-2.7 in the Sham group, 5.08+/-1.9 in the T/ D+papaverine group, 5.29+/-2.3 in the T/D +alprostadil group and 2.86+/ 1.9 in the TD group. The JTBS was determined to be statistically significantly high in both the T/D + papaverine group and the T/D + alprostadil group compared to the T/D group (p=0.01, p=0.009). In the T/D + papaverine group, 3 (43 %) testes were classified as Cosentino 2, 3 (43%) as Cosentino 3 and 1 (14 %) as Cosentino 4. In the T/D +alprostadil group, 5 (50 %) testes were classified as Cosentino 2, 3 (30 %) as Cosentino 3 and 2 (20%) as Cosentino 4. CONCLUSION: The present study indicated that spermatic cord administration of alprostadil and papaverine showed a protective effect against ischemia/reperfusion injury after right-side testes torsion and histological changes were decreased after testicular ischemia reperfusion injury. PMID- 29617081 TI - Comparing the short - term outcomes and complications of monopolar and bipolar transurethral resection of bladder tumors in patients with coronary artery disese: a prospective, randomized, controlled study. AB - INTRODUCTION: To compare the perioperative outcomes and complications of monopolar and bipolar transurethral resection of bladder tumors (TURBT) in patients with coronary artery disease (CAD). MATERIALS AND METHODS: A total of 90 CAD patients with newly diagnosed bladder cancer who underwent TURBT were randomized into monopolar TURBT (M-TURBT) and bipolar TURBT (B-TURBT) groups. Primary outcome was safety of the procedures including obturator jerk, bladder perforation, clot retention, febrile urinary tract infection and TUR syndrome. The secondary outcome was the efficacy of TURBT procedures, including complete tumor resection, sampling of the deep muscle tissue and sampling of the qualified tissues without any thermal damage. RESULTS: Mean ages of the patients in M-TURBT and B-TURBT groups were 71.36+/-7.49 and 73.71+/-8.15 years, respectively (p=0.157). No significant differences were found between M-TURBT and B-TURBT groups regarding complete tumor resection (76.2% vs. 87.5%, p=0.162) and muscle tissue sampling rates (71.4% vs. 64.6%,p=0.252). Obturator jerk was detected in 16.7% of the patients in M-TURBT group and 2.1% in B-TURBT group (p=0.007). No statistically significant differences were found between the groups regarding intraoperative and postoperative complications. CONCLUSIONS: Both monopolar and bipolar systems can be used safely and effectively during TURBT procedure in CAD patients. Due to the more frequently seen obturator jerk in M-TURBT than B-TURBT, careful surgical approach is needed during M-TURBT. PMID- 29617083 TI - Retroperitoneal laparoscopic nephroureterectomy with distal and intramural ureter resection for a tuberculous non - functional kidney. AB - OBJECTIVE: To evaluate the safety and feasibility of total retroperitoneal laparoscopic nephroureterectomy with urinary-bladder junction resection for a tuberculous non-functional kidney. MATERIALS AND METHODS: A total of 27 individuals diagnosed with unilateral non-functional kidney secondary to tuberculosis were treated between June 2011 and June 2015. All patients had normal renal function on the contralateral side and underwent the standard four drug anti-tuberculosis treatment for at least four weeks before surgery. Total retroperitoneal laparoscopic nephroureterectomy was performed in all patients, and the urinary-bladder junction of distal ureter was managed using different auto-suture techniques. RESULTS: Nineteen male and 8 female patients with an average age of 47.3 years (range, 36-64 years) underwent surgery. All the operations were successfully performed without conversion. The median operative time was 109.3 min (range, 75-138 min), the median blood loss was 157.5 mL (range, 70-250 mL), and the median hospitalization time was 3.7 days (range, 3-6 days). No serious perioperative complications occurred. Anti-tuberculosis chemotherapy was prescribed to all patients, with the entire course of treatment lasting six months. No recurrence of tuberculosis of the bladder or the contralateral kidney was observed during the median follow-up period of 26.7 months (range, 6-54 months). CONCLUSION: Retroperitoneal laparoscopic nephroureterectomy with urinary-bladder junction resection is a safe and feasible approach for the treatment of tuberculous non-functional kidneys. PMID- 29617082 TI - Evaluation of apoptosis indexes in currently used oral alpha-blockers in prostate: a pilot study. AB - OBJECTIVES: Apoptosis effect of oral alpha-blockers is known in the prostate. Apoptosis index of silodosin has not been proved, yet. Aims are to present apoptosis index of silodosin in prostate and to compare this with other currently used alpha-blocker's apoptosis indexes together with their clinical effects. MATERIALS AND METHODS: Benign prostatic hyperplasia (BPH) patients were enrolled among those admitted to urology outpatient clinic between June 2014 and June 2015. Study groups were created according to randomly prescribed oral alpha blocker drugs as silodosin 8mg (Group 1; n=24), tamsulosin 0.4mg (Group 2; n=30), alfuzosin 10mg (Group 3; n=25), doxazosin 8mg (Group 4; n=22), terazosin 5mg (Group 5; n=15). Patients who refused to use any alpha-blocker drug were included into Group 6 as control group (n=16). We investigated apoptosis indexes of the drugs in prostatic tissues that were taken from patient's surgery (transurethral resection of prostate) and/or prostate biopsies. Immunochemical dyeing, light microscope, and Image Processing and Analysis in Java were used for evaluations. Statistical significant p was p<0.05. RESULTS: There were 132 patients with mean follow-up of 4.2+/-2.1 months. Pathologist researched randomly selected 10 areas in each microscope set. Group 1 showed statistical significant difference apoptosis index in immunochemical TUNEL dyeing and image software (p<0.001). Moreover, we determined superior significant development in parameters as uroflowmetry, quality of life scores, and international prostate symptom score in Group 1. CONCLUSIONS: Silodosin has higher apoptosis effect than other alpha blockers in prostate. Thus, clinic improvement with silodosin was proved by histologic studies. Besides, static factor of BPH may be overcome with creating apoptosis. PMID- 29617084 TI - Functional outcomes and quality of life after transobturatory slings: hand - made vs. commercial slings. AB - Surgical correction is the most efficient treatment for stress urinary incontinence (SUI), and transobturator sling (TO) has optimal results. The high cost of commercially available sling kits makes it difficult the access in most Brazilian public health services. Hand-made polypropylene slings, on the other hand, have been previously reported. The aim of the present study was to compare the effectiveness and safety of commercial vs. hand-made polypropylene mesh slings. Data from 57 women who underwent consecutive TO sling surgery to treat SUI were pros-pectively collected between 2012 and 2014, and divided in two groups for further comparison. In Group-1, 31 women underwent surgery with commercial slings. In Group-2, 26 women underwent hand-made polypropylene slings. Women were compared according to epidemiological data, perioperative evaluation, quality of life, urodynamic study, cure and complication rates. Results were objectively (stress test with Valsalva maneuver, with at least 200mL vesical repletion) and subjectively evaluated by the Patient Global Impression of Improvement(PGI-I), Visual Analog Scale (VAS) and ICIQ-SF. Success was defined as PGI-I, VAS and negative stress test. Group-1 (n=31) and Group-2 (n=26) had a mean age of 60 vs. 58years (p=0.386). All de-mographic data were similar. The mean VLPP was 75.6cmH2O vs. 76.6cmH2O (p=0.88). The mean follow-up was 24.3 vs. 21.5months (p=0.96). Success rates were 74.2% vs. 80.2% (p=0.556), with ICIQ-SF variation of 12.6 vs.15.5 (p=0.139) and PGI-I of 71% vs. 80% (p=0.225). There was only one major complication (urethrovaginal fistula in Group-1). In conclusion, handmade and commercial slings have similar effectiveness and safety. The manufacture technique has important key-points stated in the present manuscript. PMID- 29617092 TI - Impact of Economic Trends and Disparities on South Carolina Children's Health and Well-being: An Analysis of the 2016 KIDS COUNT Profile. PMID- 29617085 TI - The role of bladder diverticula in the prevalence of acute urinary retention in patients with BPH who are candidates to surgery. AB - INTRODUCTION: The urinary bladder diverticula (BD) secondary to benign prostatic hyperplasia (BPH) is a complication that can lead to urinary stasis, stone, urinary tract infection (UTI) and tumors. It's role in acute urinary retention (AUR) is not totally understood. OBJECTIVES: To determine the effect of BD size on AUR rates in patients with BPH candidates to surgery. SUBJECTS AND METHODS: We performed a retrospective cohort study of 47 patients with BPH and BD who underwent BPH surgery associated to complete bladder diverticulectomy from 2006 to 2016. We analyzed risk factors for AUR in patients with BD using univariate, multivariate and correlation analysis. RESULTS: There was a difference in the size of the diverticula, with 6.8 cm vs. 4.5 cm among patients with and without AUR respectively (p=0.005). The ROC curve showed a correlation between the size of BD and the risk of AUR. The value of 5.15 cm presented a sensitivity of 73% and a specificity of 72%. The area under the curve was 0.75 (p=0.01). Comparing groups with BD >5.0 cm vs. <=5.0 cm, the AUR incidence was 74% and 27.8% respectively with an OR of 2.65 (1.20-5.85) (p=0.005). In the multivariate analysis, only the size of the diverticula reached statistical significance (p=0.012). CONCLUSIONS: The diameter of BD is an independent risk factor for AUR in patients with BPH and BD who are candidates to surgery. A diameter greater than 5.15 cm increases the risk of AUR. PMID- 29617093 TI - The Impact of the Clinical Nurse Leader (CNL) on quality patient outcomes. PMID- 29617094 TI - Synthesis and Characterization of Methylene Blue-Containing Silica-Coated Magnetic Nanoparticles for Photodynamic Therapy. AB - Superparamagnetic iron oxide nanoparticles (SPIONs), with appropriate surface coating, are commonly used for biomedical applications such as photodynamic therapy (PDT). This work describes the preparation and characterization of methylene blue (MB)-containing silica-coated SPIONs. Upon exposure to light, MB reacts with molecular oxygen and generates singlet oxygen (1O2) which is cytotoxic and causes irreversible damage to tumor tissues. In this work, SPIONs were synthesized by co-precipitation and coated with a single/double silica layer. The photoactive molecule MB was entrapped in the silica layer deposited on the surface of SPIONs, leading to the formation of hybrid nanomaterials composed of a magnetic core and silica layer. The nanocomposite exhibited magnetic behavior at room temperature due to the presence of its Fe3O4 core. Structural and morphological characterizations were performed by X-ray diffraction (XRD), Fourier transformed infrared (FTIR), SQUID magnetic measurements, ultraviolet visible spectroscopy, scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS), and dynamic light scattering. The results showed the presence of a crystalline Fe3O4 magnetic core and amorphous silica phases. Kinetic measurements revealed 1O2 generation by the nanoparticles upon irradiation with visible light (lambda = 532 nm or lambda = 633 nm). The results highlight the potential uses of SPIONs coated with MB-entrapped silica for PDT, whereby a sustained and localized generation of 1O2 was successfully achieved. PMID- 29617095 TI - Dual Effect of Curcumin/BMP-2 Loaded in HA/PLL Hydrogels on Osteogenesis In Vitro and In Vivo. AB - In the present study, we evaluated the potential of poly-l-lysine/hyaluronic acid (HA/PLL) hydrogels containing curcumin (CUR) and bone morphogenetic protein-2 (BMP-2) as bone tissue regeneration scaffolds. Hydrogels HP-1~2 were formed by amide bonds via the condensation reactions between 0.02 MUmol HA and 0.06-0.12 MUmol poly-l-lysine . hydrobromide (PLL . HBr). Physical, chemical, and thermal analyses revealed that the amount of PLL . HBr significantly influenced hydrogel properties. Based on an In Vitro MG-63 cell proliferation test, HP-1~2 were cytocompatible, and all hydrogels containing different amounts of CUR and BMP-2, except for HA0.02/PLL0.06/CUR20/BMP-2100 (HPCB-4), resulted in cell proliferation above 80%. An In Vitro release test showed that CUR and BMP-2 were consistently released from HA0.02/PLL0.06/CUR15 (HPC), HA0.02/PLL0.06/BMP-2100 (HPB), HA0.02/PLL0.06/CUR15/BMP-210 , 50 , or 100 (HPCB-1~3), and HA0.02/PLL0.06/CUR10 or 20/BMP-2100 (HPCB-4~5) for 7 and 28 days, respectively. In Vitro ALP activity and calcium deposition and In Vivo micro-computed tomography (micro-CT) tests demonstrated the potential application of HPCB-3 as bone tissue regeneration scaffolds, suggesting that bone tissue regeneration can be optimized by controlling the amounts of CUR and BMP-2. PMID- 29617096 TI - Monodisperse, Self-Activated Luminescent, and Mesoporous Silica Nanospheres for Drug Delivery. AB - Monodisperse mesoporous silica nanospheres with novel self-activated luminescence have been fabricated by a modified templating sol-gel method followed by heat treatment, without introducing any rare earth or transition metal ions as activators. The SEM, TEM, and N2 adsorption/desorption isotherms results show that the as-obtained mesoporous silica nanospheres exhibit well-defined morphology, good dispersion, high specific surface area and pore volume. MTT assay indicates that the sample exhibits no obvious cytotoxicity against the A549, HeLa, and MCF-7 cells, which make it suitable to be utilized as a drug carrier. Under ultraviolet excitation, the sample exhibits an intense blue emission. Interestingly, the photoluminescence intensity of the IBU drug loaded system increases with the increase of cumulatively released IBU. Due to the relationship between the luminescence properties and drug release behavior, the as-obtained luminescent drug carrier may be potential as a probe for monitoring or detecting the drug release process. PMID- 29617097 TI - Dual Ligands-Capped Gold Nanorod as a Localized Surface Plasmon Resonance Transducer for Label-Free Detection of O-GlcNAcylated Proteins. PMID- 29617098 TI - Porous Prussian Blue Nanocubes as Photothermal Ablation Agents for Efficient Cancer Therapy. AB - Nanomaterial-based photothermal agents have attracted great attention as near infrared laser driven ablation agents for tumor therapy. In this work, Prussian blue nanocubes with porous interior were synthesized via controlled chemical etching method and successfully applied for efficient photothermal ablation of tumor cells in vitro. Monodispersed porous Prussian blue nanocubes (115.4+/-4.7 nm) were produced through a controlled self-etching reaction in the presence of polyvinylpyrrolidone (PVP). Owing to the strong absorbance in near infrared (NIR) region, the resulted porous Prussian blue nanocubes could lead to more than 80% death of Hela cells after being treated with nanocubes of concentration as low as 100 MUg mL-1. Compared to the traditional solid Prussian blue nanoparticles, these porous nanocubes can provide extra space for encapsulating anti-cancer drugs in their porous interior. It is anticipated that these porous Prussian blue nanocubes can be applied as an enabling platform to develop the next generation of multifunctional drug carrier for cancer treatments. PMID- 29617099 TI - A Second-Generation Proteasome Inhibitor and Doxorubicin Modulates IL-6, pSTAT-3 and NF-kB Activity in MDA-MB-231 Breast Cancer Cells. AB - Triple-Negative Breast Cancer (TNBC) has a poor prognosis due to lack of targeted therapy. Doxorubicin (DOX) has failed for multiple reasons, including development of multi-drug resistance, induction of inflammation (IL-6 secretion) and long term toxicities. DOX is also known to have off target proteasomal activation, justifying the concept of combining it with a proteasomal inhibitor. Our study investigated the therapeutic potential of an irreversible proteasome inhibitor carfilzomib (CARF) alone or in combination with DOX in two TNBC cell lines (MDA MB-231 and MDA-MB-468). CARF was as effective in inhibiting mitosis in vitro for both cell lines in comparison to DOX alone. CARF performed similar to DOX in inhibiting apoptosis but had better results in reducing proliferation. Further studies in MDA-MB-231 cells demonstrated that CARF also inhibited pro inflammatory IL-6 secretion and NF kappaB transcriptional activity while DOX stimulated both IL-6 and NF kappa-B activity. The reduction of IL-6 while using CARF highlights its therapeutic potential and ability to enhance current clinical drug regimens. Furthermore, exogenous administration of IL-6 potentiated NF Kappa B transcriptional activity, pSTAT3 (Tyr705) and JAK inflammatory signaling as well as cell proliferation in CARF- or DOX-treated MDA-MB-231 cells. In vivo, CARF treatment resulted in reduced serum IL-6 compared to treatment with DOX in female SCID-NOD mice with MDA-MB-231 cell tumor. A combinational approach using DOX and CARF presents a clinical potential for better efficacy, reduced proliferation, apoptosis, anti-angiogenesis, and less cardiac dysfunction when compared to current treatments using standalone DOX. PMID- 29617100 TI - Graphene Oxide Induces Toxicity and Alters Energy Metabolism and Gene Expression in Ralstonia solanacearum. AB - Graphene oxide (GO) is a promising material for development as an antibacterial, phytoprotective agent due to its contact-based antibacterial activity induced by its physical and chemical properties. However, the mechanism underlying the antibacterial effect of GO has yet to be elucidated. In the current study, we investigated the effects of GO on the phytopathogen R. solanacearum at the molecular level with a specific focus on energy metabolism. Under controlled conditions, the bacteriostatic and bactericidal actions of GO were investigated with respect to concentration, treatment time and rotation speed. Transmission electron microscopy (TEM) and destabilization assays revealed that GO caused injury to bacterial cell membrane structures. Furthermore, adenosine triphosphate (ATP) levels decreased after exposure to sheets of GO, while malondialdehyde levels significantly increased, indicating the occurrence of lipid oxidation. A series of genes related to bacterial virulence, motility and oxidative stress were selected to evaluate the molecular mechanism underlying GO's effects on R. solanacearum. Using quantitative reverse transcription polymerase chain reaction (RT-qPCR), we showed that in the presence of GO, the expression levels of genes involved in virulence and motility were down regulated, with the exception of popA. The phcA, hrpB and flgG genes were significantly downregulated by 2.61-, 3.45- and 4.22-fold, respectively. Conversely, the expression levels of sodB, oxyR and dps, three important oxidative stress genes, were upregulated by 1.82-, 2.17-, and 3.79-fold, respectively. These findings confirmed that cell membrane damage and oxidative stress were responsible for the antibacterial actions of GO, in addition to disturbances to energy metabolism processes. PMID- 29617101 TI - Comparative Cytotoxicity induced by Zinc Oxide Nanoparticles in Human Prostate Cells. AB - Despite increasing biomedical applications of zinc oxide nanoparticles (ZnO NPs), there is a lack of information concerning the biological effects of ZnO NPs on human cells. The purpose of this study was to assess the comparative cytotoxicity in human prostate cells (PC-3 and RWPE-1) exposure to 20-nm ZnO NPs. Exposure to concentrations from 0 to 50 MUg/mL of ZnO NPs reduced cell viability of PC-3 cells in a dose- and time-dependent manner; whereas it did not affect RWPE-1 cells. A dose-dependent increase in LDH leakage and intracellular reactive oxygen species was observed in PC-3 cells but not in RWPE-1 cells exposure to ZnO NPs at concentrations of 8 ~ 50 MUg/mL for 24 h (P < 0.05). That the percentage of apoptotic cells increased significantly was observed in PC-3 cells induced by ZnO NPs at 10 MUg/mL exposure for 8 h. Our results showed that ZnO NPs induced in vitro preferential cytotoxicity in the human prostate cancer cells. We indicated that the different cytotoxicity of ZnO NPs is likely due to the different cell nanoparticle interaction and response behavior rather than to hydrodynamic sizes of particles. It is suggested that ZnO NPs are expected to find a very promising targeting therapeutic application for human prostate cancer. PMID- 29617102 TI - Toxicity Evaluation of Iron Oxide (Fe3O4) Nanoparticles on Human Neuroblastoma Derived SH-SY5Y Cell Line. AB - Several studies suggest that Iron Oxide nanoparticles may arrive to central nervous system independently of the route of administration. Actually, evidences indicate that the presence iron oxide nanoparticles into nervous system are linked to several neurodegenerative diseases. In this regard, our goal was to assess in vitro PolyVinylPirrolidone coated Iron Oxide nanoparticles, diameter of 20 nm, neuro-toxicity and their mechanism of action, which was fixed over the human neuronal cell line SH-SY5Y. Inducted biological effects were evaluated after 4-48 hours at crescents doses 1-100 MUg/mL using the following endpoints: (i) Membrane integrity: Nanoparticles have produced no effect over cellular membrane for every dose and time evaluated; (ii) Mitochondrial activity: Starting at 10 MUg/mL with a decrease of cellular vitality of 35%, and a maximum decrease of 45% at highest dose (100 MUg/mL); (iii) Cellular morphology: Cells have evidenced no alteration after 48 hours of exposure; (iv) Cellular uptake: Dose time dependent accumulation has observed: blue spots have been found at 10 MUg/mL and over. Concluding, mitochondria are apparently the target: considering that the toxic effect produced by PolyVinylPirrolidone coated Iron Oxide nanoparticles after 48 hours of exposure in a dose-time dependent manner was evident. PMID- 29617103 TI - Immobilization of Glucose Oxidase on a Carbon Nanotubes/Dendrimer-Ferrocene Modified Electrode for Reagentless Glucose Biosensing. AB - Ferrocene-grafted dendrimer was covalently linked to the surface of a carbon nanotubes (CNTs)-chitosan (CS) nanocomposite modified electrode for immobilizing high-content glucose oxidase (GOx), which resulted in the successful development a novel reagentless glucose biosensor. Electrochemical impedance spectroscopy, cyclic voltammetry, and amperometry were used to characterize the preparation process and the enzymatically catalytic response of this biosensor. Due to the excellent electron transfer acceleration of the CNTs and the high-content loading of the GOx biomolecule and ferrocene mediator on the electrode matrix, this biosensor showed excellent analytical performance such as fast response time less than 10 s, wide linear range from 0.02 to 2.91 mM and low detection limit down to 7.5 MUM as well as satisfactory stability and reproducibility toward the amperometric glucose determination. In addition, satisfactory result was obtained when it was used for the glucose measurements in human blood samples. Thus this biosensor provides great potentials for practical applications. PMID- 29617104 TI - Aerosol-Assisted Rapid Fabrication of a Heterogeneous Organopalladium Catalyst with Hierarchical Bimodal Pores. AB - Heterogeneous organometallic catalysts with well-defined active sites and hierarchical pores hold tremendous promise for efficient and eco-friendly chemical processes. However, the simple and scalable preparation of these materials remains difficult to date, which has hampered a more broad application scope. Herein, we reported a low-cost, rapid, and scalable aerosol-assisted assembly approach for the synthesis of a well-defined PdDPP (PdCl2(PPh2(CH2)2))_ complex-containing benzene-bridged organosilica-based catalyst with a hierarchical bimodal micro-macroporous structure. This novel material was realized by using Pd(II) organometallic silane (Pd[PPh2(CH2)2Si(OEt)3]2Cl2) as the active species, organosilane 1,4-bis(triethoxysilyl)benzene (Ph[Si(OEt)3]2) as the silicate scaffold and the surfactant cetyltrimethylammonium bromide and the inorganic salt NaCl as the dual templates on a home-built aerosol spraying instrument. Multiple techniques including X-ray photoelectron spectroscopy and solid-state NMR spectra revealed that the organopalladium complex with a well defined molecular configuration of major trans model and minor cis model existed in the phenyl-functionalized silica material. As expected, it efficiently promoted a variety of important carbon-carbon cross-coupling transformations including Tsuji-Trost, Sonogashira, and Suzuki reactions in pure water without the assistance of any additives. In comparison with the homogeneous catalyst PdCl2(PPh2CH3)2, it even exhibited enhanced activity and selectivity in some cases owing to the unique confinement effect and the shape selectivity generated from the hierarchical porous structure. Meanwhile, it was easily recycled and reused eight times without the loss of its activity. PMID- 29617105 TI - Injection of Spin-Polarized Electrons into a AlGaN/GaN Device from an Electrochemical Cell: Evidence for an Extremely Long Spin Lifetime. AB - Spin-polarized electrons are injected from an electrochemical cell through a chiral self-assembled organic monolayer into a AlGaN/GaN device in which a shallow two-dimensional electron gas (2DEG) layer is formed. The injection is monitored by a microwave signal that indicates a coherent spin lifetime that exceeds 10 ms at room temperature. The signal was found to be magnetic field independent; however, it depends on the current of the injected electrons, on the length of the chiral molecules, and on the existence of 2DEG. PMID- 29617106 TI - Piezoelectric Property of a Tetragonal (Ba,Ca)(Zr,Ti)O3 Single Crystal and Its Fine-Domain Structure. AB - A tetragonal (Ba,Ca)(Zr,Ti)O3 (BCZT) single crystal was grown by a flux method, and the piezoelectric coefficient ( d33) was characterized. The piezoelectric response was proved to be associated with polarization extension, which was successfully used to explain the variation in d33*. From the intrinsic aspect, the compositional effect on Landau free-energy profiles was discussed, showing an "extender" nature of the as-grown crystal and the increasing tendency of structural instability toward the morphotropic phase boundary. From the extrinsic aspect, the evolution of domain structure under various external fields (electric and temperature) was studied, revealing that the fine-domain structure of the as grown BCZT single crystal was stable to E-field and temperature. The results manifest possibilities of further improving the piezoelectric property of the BCZT single crystal, which requires optimization of the crystal growth technique in future work. PMID- 29617107 TI - A Kind of Coordination Complex Cement for the Self-Assembly of Superstructure. AB - Not like the macroscopic building materials, the controllable assembly of blocks into superstructure has not been conquered in microscale, especially for the ordinary particles with shape defects and weak surface activities. Here, a facile route of assembling particles into superstructures utilizing Mo-polydopamine complex as the binder and curing agent is established. A side-by-side adsorption and growth mechanism in a water/ethanol system is derived, and the factors influencing the final structures are verified. This system is suitable to assemble superstructures from particles of different shapes such as nanospheres, nanocubes, nanorods, and hollow spheres in the range from 10 to 500 nm in size. And after high temperature and etching treatment, the generated MoO2/N/C frameworks with superpore structures derived from different blocks exhibit a high structural plasticity and potential application as multifunctional carriers for energy storage. Rather than the obtained system, our work assembles superstructures from various building blocks and explores more valuable complex cements for superstructures construction. PMID- 29617108 TI - Facets Matching of Platinum and Ferric Oxide in Highly Efficient Catalyst Design for Low-Temperature CO Oxidation. AB - Rational design of supported noble metal is of great importance for highly efficient heterogeneous catalysts. On the basis of the distinct adsorption characteristics of noble metal and transition-metal oxides toward O2 and CO, the overall catalytic performance of CO oxidation reaction could be further modified by controlling the surface property of the materials to achieve optimal adsorption activity. Here, we studied the influence of facets matching between both platinum and ferric oxide support on CO conversion efficiency. It shows that the activities of four catalysts rank following the order of Pt{100}/alpha Fe2O3{104} > Pt{100}/alpha-Fe2O3{001} > Pt{111}/alpha-Fe2O3{001} > Pt{111}/alpha Fe2O3{104}. The strong metal-support interaction and adsorption energy varying with matched enclosed surface are demonstrated by density functional theory based on the projected d-band density of states. Compared with the other three cases, the combination of Pt{100} and alpha-Fe2O3{104} successfully weakens CO poisoning and provides proper active sites for O2 adsorption. It reveals that the facets matching could be a practicable approach to design catalysts with enhanced catalytic performance. PMID- 29617109 TI - Targeted Brain Delivery of Rabies Virus Glycoprotein 29-Modified Deferoxamine Loaded Nanoparticles Reverses Functional Deficits in Parkinsonian Mice. AB - Excess iron deposition in the brain often causes oxidative stress-related damage and necrosis of dopaminergic neurons in the substantia nigra and has been reported to be one of the major vulnerability factors in Parkinson's disease (PD). Iron chelation therapy using deferoxamine (DFO) may inhibit this nigrostriatal degeneration and prevent the progress of PD. However, DFO shows very short half-life in vivo and hardly penetrates the blood brain barrier (BBB). Hence, it is of great interest to develop DFO formulations for safe and efficient intracerebral drug delivery. Herein, we report a polymeric nanoparticle system modified with brain-targeting peptide rabies virus glycoprotein (RVG) 29 that can intracerebrally deliver DFO. The nanoparticle system penetrates the BBB possibly through specific receptor-mediated endocytosis triggered by the RVG29 peptide. Administration of these nanoparticles significantly decreased iron content and oxidative stress levels in the substantia nigra and striatum of PD mice and effectively reduced their dopaminergic neuron damage and as reversed their neurobehavioral deficits, without causing any overt adverse effects in the brain or other organs. This DFO-based nanoformulation holds great promise for delivery of DFO into the brain and for realizing iron chelation therapy in PD treatment. PMID- 29617110 TI - Electrochromic Molecular Imprinting Sensor for Visual and Smartphone-Based Detections. AB - Electrochromic effect and molecularly imprinted technology have been used to develop a sensitive and selective electrochromic sensor. The polymeric matrices obtained using the imprinting technology are robust molecular recognition elements and have the potential to mimic natural recognition entities with very high selectivity. The electrochromic behavior of iridium oxide nanoparticles (IrOx NPs) as physicochemical transducer together with a molecularly imprinted polymer (MIP) as recognition layer resulted in a fast and efficient translation of the detection event. The sensor was fabricated using screen-printing technology with indium tin oxide as a transparent working electrode; IrOx NPs where electrodeposited onto the electrode followed by thermal polymerization of polypyrrole in the presence of the analyte (chlorpyrifos). Two different approaches were used to detect and quantify the pesticide: direct visual detection and smartphone imaging. Application of different oxidation potentials for 10 s resulted in color changes directly related to the concentration of the analyte. For smartphone imaging, at fixed potential, the concentration of the analyte was dependent on the color intensity of the electrode. The electrochromic sensor detects a highly toxic compound (chlorpyrifos) with a 100 fM and 1 mM dynamic range. So far, to the best of our knowledge, this is the first work where an electrochromic MIP sensor uses the electrochromic properties of IrOx to detect a certain analyte with high selectivity and sensitivity. PMID- 29617111 TI - Highly Sensitive Multifilament Fiber Strain Sensors with Ultrabroad Sensing Range for Textile Electronics. AB - Highly stretchable fiber strain sensors are one of the most important components for various applications in wearable electronics, electronic textiles, and biomedical electronics. Herein, we present a facile approach for fabricating highly stretchable and sensitive fiber strain sensors by embedding Ag nanoparticles into a stretchable fiber with a multifilament structure. The multifilament structure and Ag-rich shells of the fiber strain sensor enable the sensor to simultaneously achieve both a high sensitivity and largely wide sensing range despite its simple fabrication process and components. The fiber strain sensor simultaneously exhibits ultrahigh gauge factors (~9.3 * 105 and ~659 in the first stretching and subsequent stretching, respectively), a very broad strain-sensing range (450 and 200% for the first and subsequent stretching, respectively), and high durability for more than 10 000 stretching cycles. The fiber strain sensors can also be readily integrated into a glove to control a hand robot and effectively applied to monitor the large volume expansion of a balloon and a pig bladder for an artificial bladder system, thereby demonstrating the potential of the fiber strain sensors as candidates for electronic textiles, wearable electronics, and biomedical engineering. PMID- 29617112 TI - Control of Synaptic Plasticity Learning of Ferroelectric Tunnel Memristor by Nanoscale Interface Engineering. AB - Brain-inspired computing is an emerging field, which intends to extend the capabilities of information technology beyond digital logic. The progress of the field relies on artificial synaptic devices as the building block for brainlike computing systems. Here, we report an electronic synapse based on a ferroelectric tunnel memristor, where its synaptic plasticity learning property can be controlled by nanoscale interface engineering. The effect of the interface engineering on the device performance was studied. Different memristor interfaces lead to an opposite virgin resistance state of the devices. More importantly, nanoscale interface engineering could tune the intrinsic band alignment of the ferroelectric/metal-semiconductor heterostructure over a large range of 1.28 eV, which eventually results in different memristive and spike-timing-dependent plasticity (STDP) properties of the devices. Bidirectional and unidirectional gradual resistance modulation of the devices could therefore be controlled by tuning the band alignment. This study gives useful insights on tuning device functionalities through nanoscale interface engineering. The diverse STDP forms of the memristors with different interfaces may play different specific roles in various spike neural networks. PMID- 29617113 TI - Automated High-Throughput Synthesis of Protein-Loaded Polyanhydride Nanoparticle Libraries. AB - The development of high-throughput techniques and combinatorial libraries can facilitate rapid synthesis and screening of biomaterial-based nanocarriers for drug and vaccine delivery. This study describes a high-throughput method using an automated robot for synthesizing polyanhydride nanoparticles encapsulating proteins. Polyanhydrides are a class of safe and biodegradable polymers that have been widely used as drug and vaccine delivery vehicles. The robot contains a multiplexed homogenizer and has the capacity to handle parallel streams of monomer or polymer solutions to synthesize polymers and/or nanoparticles. Copolymer libraries were synthesized using the monomers sebacic acid, 1,6-bis( p carboxyphenoxy)hexane, and 1,8-bis( p-carboxyphenoxy)-3,6-dioxactane and compared to conventionally synthesized copolymers. Nanoparticle libraries of varying copolymer compositions encapsulating the model antigen ovalbumin were synthesized using flash nanoprecipitation. The amount of the surfactant Span 80 was varied to test its effect on protein encapsulation efficiency as well as antigen release kinetics. It was observed that, although the amount of surfactant did not significantly affect protein release rate, its presence enhanced protein encapsulation efficiency. Protein burst and release kinetics from conventionally and combinatorially synthesized nanoparticles were similar even though particles synthesized using the high-throughput technique were smaller. Finally, it was demonstrated that the high-throughput method could be adapted to functionalize the surface of particle libraries to aid in the design and screening of targeted drug and vaccine delivery systems. These results suggest that the new high throughput method is a viable alternative to conventional methods for synthesizing and screening protein and vaccine delivery vehicles. PMID- 29617114 TI - High-Capacity Mg-Organic Batteries Based on Nanostructured Rhodizonate Salts Activated by Mg-Li Dual-Salt Electrolyte. AB - A magnesium battery is a promising candidate for large-scale transportation and stationary energy storage due to the security, low cost, abundance, and high volumetric energy density of a Mg anode. But there are still some obstacles retarding the wide application of Mg batteries, including poor kinetics of Mg-ion transport in lattices and low theoretical capacity in inorganic frameworks. A Mg Li dual-salt electrolyte enables kinetic activation by dominant intercalation of Li-ions instead of Mg-ions in cathode lattices without the compromise of a stable Mg anode process. Here we propose a Mg-organic battery based on a renewable rhodizonate salt ( e. g., Na2C6O6) activated by a Mg-Li dual-salt electrolyte. The nanostructured organic system can achieve a high reversible capacity of 350 400 mAh/g due to the existence of high-density carbonyl groups (C?O) as redox sites. Nanocrystalline Na2C6O6 wired by reduced graphene oxide enables a high rate performance of 200 and 175 mAh/g at 2.5 (5 C) and 5 A/g (10 C), respectively, which also benefits from a high intrinsic diffusion coefficient (10 12-10-11 cm2/s) and pesudocapacitance contribution (>60%) of Na2C6O6 for Li-Mg co intercalation. The suppressed exfoliation of C6O6 layers by a firmer non-Li pinning via Na-O-C or Mg-O-C and a dendrite-resistive Mg anode lead to a long term cycling for at least 600 cycles. Such an extraordinary capacity/rate performance endows the Mg-Na2C6O6 system with high energy and power densities up to 525 Wh/kg and 4490 W/kg (based on active cathode material), respectively, exceeding the level of high-voltage insertion cathodes with typical inorganic structures. PMID- 29617115 TI - Tunable Rh2(II,II) Light Absorbers as Excited-State Electron Donors and Acceptors Accessible with Red/Near-Infrared Irradiation. AB - A series of dirhodium(II,II) paddlewheeel complexes of the type cis-[Rh2(MU DTolF)2(MU-L)2][BF4]2, where DTolF = N,N'-di( p-tolyl)formamidinate and L = 1,8 naphthyridine (np), 2-(pyridin-2-yl)-1,8-naphthyridine (pynp), 2-(quinolin-2-yl) 1,8-naphthyridine (qnnp), and 2-(1,8-naphthyridin-2-yl)quinoxaline (qxnp), were synthesized and characterized. These molecules feature new tridentate ligands that concomitantly bridge the dirhodium core and cap the axial positions. The complexes absorb light strongly throughout the ultraviolet/visible range and into the near-infrared region and exhibit relatively long-lived triplet excited-state lifetimes. Both the singlet and triplet excited states exhibit metal/ligand-to ligand charge transfer (ML-LCT) in nature as determined by transient absorption spectroscopy and spectroelectrochemistry measurements. When irradiated with low energy light, these black dyes are capable of undergoing reversible bimolecular electron transfer both to the electron acceptor methyl viologen and from the electron donor p-phenylenediamine. Photoinduced charge transfer in the latter was inaccessible with previous Rh2(II,II) complexes. These results underscore the fact that the excited state of this class of molecules can be readily tuned for electron-transfer reactions upon simple synthetic modification and highlight their potential as excellent candidates for p- and n-type semiconductor applications and for improved harvesting of low-energy light to drive useful photochemical reactions. PMID- 29617116 TI - Large-Scale Validation of Mixed-Solvent Simulations to Assess Hotspots at Protein Protein Interaction Interfaces. AB - The ability to target protein-protein interactions (PPIs) with small molecule inhibitors offers great promise in expanding the druggable target space and addressing a broad range of untreated diseases. However, due to their nature and function of interacting with protein partners, PPI interfaces tend to extend over large surfaces without the typical pockets of enzymes and receptors. These features present unique challenges for small molecule inhibitor design. As such, determining whether a particular PPI of interest could be pursued with a small molecule discovery strategy requires an understanding of the characteristics of the PPI interface and whether it has hotspots that can be leveraged by small molecules to achieve desired potency. Here, we assess the ability of mixed solvent molecular dynamic (MSMD) simulations to detect hotspots at PPI interfaces. MSMD simulations using three cosolvents (acetonitrile, isopropanol, and pyrimidine) were performed on a large test set of 21 PPI targets that have been experimentally validated by small molecule inhibitors. We compare MSMD, which includes explicit solvent and full protein flexibility, to a simpler approach that does not include dynamics or explicit solvent (SiteMap) and find that MSMD simulations reveal additional information about the characteristics of these targets and the ability for small molecules to inhibit the PPI interface. In the few cases were MSMD simulations did not detect hotspots, we explore the shortcomings of this technique and propose future improvements. Finally, using Interleukin-2 as an example, we highlight the advantage of the MSMD approach for detecting transient cryptic druggable pockets that exists at PPI interfaces. PMID- 29617117 TI - Sustainable Hydrogels Based on Lignin-Methacrylate Copolymers with Enhanced Water Retention and Tunable Material Properties. AB - Synthesizing lignin-based copolymers would valorize a major coproduct stream from pulp and paper mills and biorefineries as well as reduce the dependence on petrochemical-based consumer goods. In this study, we used organosolv lignin isolated from hybrid poplar ( Populus trichocarpa * P. deltoides) to generate lignin-containing methacrylate hydrogels. The copolymer hydrogels were synthesized by first grafting 2-hydroxyethyl methacrylate (HEMA) onto lignin (OSLH) via esterification and then by free radical polymerization of OSLH with excess HEMA. The copolymer hydrogels were prepared with different stoichiometric ratios of OSLH (e.g., 0, 10, 20, and 40 wt %) with respect to HEMA. Copolymerization with OSLH led to an increase in cross-linking density, which in turn enhanced the hydrogel's material properties; we report up to 39% improvement in water retention, 20% increase in thermostability, and up to a 3 order increase in magnitude of the storage modulus ( G'). The copolymer's properties, such as water retention and glass transition temperature, could be tuned by altering the percent functionalization of lignin OH groups and the ratio of OSLH to HEMA. PMID- 29617118 TI - Feedback-Induced Temporal Control of "Breathing" Polymersomes To Create Self Adaptive Nanoreactors. AB - Here we present the development of self-regulated "breathing" polymersome nanoreactors that show temporally programmable biocatalysis induced by a chemical fuel. pH-sensitive polymersomes loaded with horseradish peroxidase (HRP) and urease were developed. Addition of an acidic urea solution ("fuel") endowed the polymersomes with a transient size increase and permeability enhancement, driving a temporal "ON" state of the HRP enzymatic catalysis; subsequent depletion of fuel led to shrinking of the polymersomes, resulting in the catalytic "OFF" state. Moreover, the nonequilibrium nanoreactors could be reinitiated several cycles as long as fuel was supplied. This feedback-induced temporal control of catalytic activity in polymersome nanoreactors provides a platform for functional nonequilibrium systems as well as for artificial organelles with precisely controlled adaptivity. PMID- 29617119 TI - Combined Effects of Surface Charge and Pore Size on Co-Enhanced Permeability and Ion Selectivity through RGO-OCNT Nanofiltration Membranes. AB - Nanofiltration (NF) has received much attention for wastewater treatment and desalination. However, NF membranes generally suffer from the trade-off between permeability and selectivity. In this work, the coenhancement of permeability and ion selectivity was achieved through tuning the surface charge and pore size of oxidized carbon nanotube (OCNT) intercalated reduced graphene oxide (RGO) membranes. With the increase of OCNT content from 0 to 83%, the surface charge and the pore size were increased. The permeability increased to 10.6 L m-2 h-1 bar-1 and rejection rate reached 78.1% for Na2SO4 filtration at a transmembrane pressure of 2 bar, which were 11.8 and 1.3 times higher than those of pristine RGO membrane. The composite membrane also showed 11.1 times higher permeability (11.1 L m-2 h-1 bar-1) and 2.9 times higher rejection rate (35.3%) for NaCl filtration. The analyses based on Donnan steric pore model suggest that the increased permeability is attributed to the combined effects of enlarged pore size and increased surface charge, while the enhanced ion selectivity is mainly dependent on the electrostatic interaction between the membrane and target ions. This finding provides a new insight for the development of high-performance NF membranes in water treatment and desalination. PMID- 29617120 TI - Metal Organic Framework with Coordinatively Unsaturated Sites as Efficient Fenton like Catalyst for Enhanced Degradation of Sulfamethazine. AB - A novel Fenton-like catalyst, metal organic framework MIL-100(Fe) with FeII/FeIII mixed-valence coordinatively unsaturated iron center (CUS-MIL-100(Fe)), was synthesized, characterized, and used for the degradation of sulfamethazine (SMT). The catalytic performance of CUS-MIL-100(Fe) was investigated on the basis of various parameters, including initial pH, H2O2 concentration, catalyst dosage, and initial SMT concentration. The results showed that CUS-MIL-100(Fe) could effectively degrade SMT, with almost 100% removal efficiency within 180 min (52.4% mineralization efficiency), under the reaction conditions of pH 4.0, 20 mg L-1 SMT, 6 mM H2O2, and 0.5 g L-1 catalyst. Moreover, CUS-MIL-100(Fe) displayed a higher catalytic activity than that of MIL-100(Fe) for SMT degradation. Combined with the physical-chemical characterization, the enhanced catalytic activity can be ascribed to the incorporation of FeII and FeIII CUSs (coordinatively unsaturated metal sites), the large specific surface area, as well as the formation of mesopores. Furthermore, CUS-MIL-100(Fe) exhibited a good stability and reusability. The possible catalytic mechanism of CUS-MIL-100(Fe) was tentatively proposed. PMID- 29617121 TI - Metal Composition and Polyethylenimine Doping Capacity Effects on Semiconducting Metal Oxide-Polymer Blend Charge Transport. AB - Charge transport and film microstructure evolution are investigated in a series of polyethylenimine (PEI)-doped (0.0-6.0 wt%) amorphous metal oxide (MO) semiconductor thin film blends. Here, PEI doping generality is broadened from binary In2O3 to ternary (e.g., In+Zn in IZO, In+Ga in IGO) and quaternary (e.g., In+Zn+Ga in IGZO) systems, demonstrating the universality of this approach for polymer electron doping of MO matrices. Systematic comparison of the effects of various metal ions on the electronic transport and film microstructure of these blends are investigated by combined thin-film transistor (TFT) response, AFM, XPS, XRD, X-ray reflectivity, and cross-sectional TEM. Morphological analysis reveals that layered MO film microstructures predominate in PEI-In2O3, but become less distinct in IGO and are not detectable in IZO and IGZO. TFT charge transport measurements indicate a general coincidence of a peak in carrier mobility (MUpeak) and overall TFT performance at optimal PEI doping concentrations. Optimal PEI loadings that yield MUpeak values depend not only on the MO elemental composition but also, equally important, on the metal atomic ratios. By investigating the relationship between the MO energy levels and PEI doping by UPS, it is concluded that the efficiency of PEI electron-donation is highly dependent on the metal oxide matrix work function in cases where film morphology is optimal, as in the IGO compositions. The results of this investigation demonstrate the broad generality and efficacy of PEI electron doping applied to electronically functional metal oxide systems and that the resulting film microstructure, morphology, and energy level modifications are all vital to understanding charge transport in these amorphous oxide blends. PMID- 29617122 TI - Pd(II)-NHDC-Functionalized UiO-67 Type MOF for Catalyzing Heck Cross-Coupling and Intermolecular Benzyne-Benzyne-Alkene Insertion Reactions. AB - A novel palladium N-heterocyclic bis-carbene dicarboxylate ligand (Pd-NHDC-H2L) was successfully synthesized. In addition, an Pd-NHDC-containing UiO-67 type MOF (UiO-67-Pd-NHDC) was prepared on the basis of a size-matched ligand mixture of biphenyl-4,4'-dicarboxylic acid/Pd-NHDC-H2L (9/1) and ZrCl4 under solvothermal conditions. The obtained UiO-67-Pd-NHC MOF can be a highly heterogeneous catalyst to promote Heck cross-coupling and intermolecular benzyne-benzyne-alkene insertion reactions. PMID- 29617123 TI - Rerouting of Metabolism into Desired Cellular Products by Nutrient Stress: Fluxes Reveal the Selected Pathways in Cyanobacterial Photosynthesis. AB - Boosting cellular growth rates while redirecting metabolism to make desired products are the preeminent goals of gene engineering of photoautotrophs, yet so far these goals have been hardly achieved owing to lack of understanding of the functional pathways and their choke points. Here we apply a 13C mass isotopic method (INST-MFA) to quantify instantaneous fluxes of metabolites during photoautotrophic growth. INST-MFA determines the globally most accurate set of absolute fluxes for each metabolite from a finite set of measured 13C-isotopomer fluxes by minimizing the sum of squared residuals between experimental and predicted mass isotopomers. We show that the widely observed shift in biomass composition in cyanobacteria, demonstrated here with Synechococcus sp. PCC 7002, favoring glycogen synthesis during nitrogen starvation is caused by (1) increased flux through a bottleneck step in gluconeogenesis (3PG -> GAP/DHAP), and (2) flux overflow through a previously unrecognized hybrid gluconeogenesis-pentose phosphate (hGPP) pathway. Our data suggest the slower growth rate and biomass accumulation under N starvation is due to a reduced carbon fixation rate and a reduced flux of carbon into amino acid precursors. Additionally, 13C flux from alpha-ketoglutarate to succinate is demonstrated to occur via succinic semialdehyde, an alternative to the conventional TCA cycle, in Synechococcus 7002 under photoautotrophic conditions. We found that pyruvate and oxaloacetate are synthesized mainly by malate dehydrogenase with minimal flux into acetyl coenzyme A via pyruvate dehydrogenase. Nutrient stress induces major shifts in fluxes into new pathways that deviate from historical metabolic pathways derived from model bacteria. PMID- 29617124 TI - Terahertz HgTe Nanocrystals: Beyond Confinement. AB - We report the synthesis of nanocrystals with an optical feature in the THz range. To do so, we develop a new synthetic procedure for the growth of HgTe, HgSe, and HgS nanocrystals, with strong size tunability from 5 to 200 nm. This is used to tune the absorption of the nanocrystals all over the infrared range up to terahertz (from 2 to 65 MUm for absorption peak and even 200 MUm for cutoff wavelength). The interest for this procedure is not limited to large sizes since for small objects we demonstrate low aggregation and good shape control (i.e., spherical object) while using nonexpansive and simple mercury halogenide precursors. By integrating these nanocrystals into an electrolyte-gated transistor, we evidence a change of carrier density from p-doped to n-doped as the confinement is vanishing. PMID- 29617125 TI - Quantitative Characterization of Translational Riboregulators Using an in Vitro Transcription-Translation System. AB - Riboregulators are short RNA sequences that, upon binding to a ligand, change their secondary structure and influence the expression rate of a downstream gene. They constitute an attractive alternative to transcription factors for building synthetic gene regulatory networks because they can be engineered de novo. However, riboregulators are generally designed in silico and tested in vivo, which provides little quantitative information about their performances, thus hindering the improvement of design algorithms. Here we show that a cell-free transcription-translation (TX-TL) system provides valuable information about the performances of in silico designed riboregulators. We first propose a simple model that provides a quantitative definition of the dynamic range of a riboregulator. We further characterize two types of translational riboregulators composed of a cis-repressed (cr) and a trans-activating (ta) strand. At the DNA level we demonstrate that high concentrations of taDNA poisoned the activator until total shut off, in agreement with our model, and that relative dynamic ranges of riboregulators determined in vitro are in agreement with published in vivo data. At the RNA level, we show that this approach provides a fast and simple way to measure dissociation constants of functional riboregulators, in contrast to standard mobility-shift assays. Our method opens the route for using cell-free TX-TL systems for the quantitative characterization of functional riboregulators in order to improve their design in silico. PMID- 29617126 TI - Long-Term Feeding of Elemental Sulfur Alters Microbial Community Structure and Eliminates Mercury Methylation Potential in Sulfate-Reducing Bacteria Abundant Activated Sludge. AB - This study reported a novel observation that the long-term cultivation of sulfur reducing bacteria (S0RB) from a sulfate-reducing bacteria (SRB)-abundant seeding sludge with elemental sulfur feeding significantly shaped the microbial community structure and eliminated the mercury methylation potential in the S0RB-enriched sludge. In this study, the enrichments of SRB and S0RB from activated sludge were obtained through long-term cultivations. Subsequently, the batch tests showed that approximately 5000 MUg/L Hg (II) was completely removed from the solution by both the SRB-enriched and S0RB-enriched sludge. Extremely low or no MeHg production was observed in the S0RB-enriched sludge (less than the limit of detection, 0.01 MUg/L), while 1.49 MUg/L MeHg accumulated in the SRB-enriched sludge. Other batch tests using the sludge samples from a replication of the cultivation showed that the methylation capability of the S0RB-enriching sludge gradually diminished to a negligible level over a 6 month cultivation time. However, some mercury-methylation-related bacteria were present in the enrichment of S0RB such as Geobacter. The absence of MeHg in the S0RB-enriched sludge may be attributed to the dissolved organic matter (DOM) instead of the sulfur- and sulfate-reduction pathway or MeHg demethylation when exposed to Hg (II). The cultivated S0RB could be used for mercury-contaminated wastewater treatment without MeHg concern. PMID- 29617127 TI - Unraveling the Chemical Nature of the 3D "Hollow" Hybrid Halide Perovskites. AB - The newly introduced class of 3D halide perovskites, termed "hollow" perovskites, has been recently demonstrated as light absorbing semiconductor materials for fabricating lead-free perovskite solar cells with enhanced efficiency and superior stability. Hollow perovskites derive from three-dimensional (3D) AMX3 perovskites ( A = methylammonium (MA), formamidinium (FA); M = Sn, Pb; X = Cl, Br, I), where small molecules such as ethylenediammonium cations ( en) can be incorporated as the dication without altering the structure dimensionality. We present in this work the inherent structural properties of the hollow perovskites and expand this class of materials to the Pb-based analogues. Through a combination of physical and spectroscopic methods (XRD, gas pycnometry, 1H NMR, TGA, SEM/EDX), we have assigned the general formula (A)1- x( en) x(M)1-0.7 x(X)3 0.4 x to the hollow perovskites. The incorporation of en in the 3D perovskite structure leads to massive M and X vacancies in the 3D [ MX3] framework, thus the term hollow. The resulting materials are semiconductors with significantly blue shifted direct band gaps from 1.25 to 1.51 eV for Sn-based perovskites and from 1.53 to 2.1 eV for the Pb-based analogues. The increased structural disorder and hollow nature were validated by single crystal X-ray diffraction analysis as well as pair distribution function (PDF) analysis. Density functional theory (DFT) calculations support the experimental trends and suggest that the observed widening of the band gap is attributed to the massive M and X vacancies, which create a less connected 3D hollow structure. The resulting materials have superior air stability, where in the case of Sn-based hollow perovskites it exceeds two orders of temporal magnitude compared to the conventional full perovskites of MASnI3 and FASnI3. The hollow perovskite compounds pose as a new platform of promising light absorbers that can be utilized in single junction or tandem solar cells. PMID- 29617128 TI - Processive Degradation of Crystalline Cellulose by a Multimodular Endoglucanase via a Wirewalking Mode. AB - Processive hydrolysis of crystalline cellulose by cellulases is a critical step for lignocellulose deconstruction. The classic Trichoderma reesei exoglucanase TrCel7A, which has a closed active-site tunnel, starts each processive run by threading the tunnel with a cellulose chain. Loop regions are necessary for tunnel conformation, resulting in weak thermostability of fungal exoglucanases. However, endoglucanase CcCel9A, from the thermophilic bacterium Clostridium cellulosi, comprises a glycoside hydrolase (GH) family 9 module with an open cleft and five carbohydrate-binding modules (CBMs) and hydrolyzes crystalline cellulose processively. How CcCel9A and other similar GH9 enzymes bind to the smooth surface of crystalline cellulose to achieve processivity is still unknown. Our results demonstrate that the C-terminal CBM3b and three CBMX2s enhance productive adsorption to cellulose, while the CBM3c adjacent to the GH9 is tightly bound to 11 glucosyl units, thereby extending the catalytic cleft to 17 subsites, which facilitates decrystallization by forming a supramodular binding surface. In the open cleft, the strong interaction forces between substrate binding subsites and glucosyl rings enable cleavage of the hydrogen bonds and extraction of a single cellulose chain. In addition, subsite -4 is capable of drawing the chain to its favored location. Cellotetraose is released from the open cleft as the initial product to achieve high processivity, which is further hydrolyzed to cellotriose, cellobiose and glucose by the catalytic cleft of the endoglucanase. On this basis, we propose a wirewalking mode for processive degradation of crystalline cellulose by an endoglucanase, which provides insights for rational design of industrial cellulases. PMID- 29617129 TI - Classical Example of Total Kinetic and Thermodynamic Control: The Diels-Alder Reaction between DMAD and Bis-furyl Dienes. AB - A rare example of chemospecificity in the tandem Diels-Alder reaction of activated alkynes and bis-dienes has been revealed. The reaction between bis furyl dienes and DMAD occurs at 25-80 degrees C and leads to kinetically controlled "pincer" adducts, 4a,8a-disubstituted 1,4:5,8-diepoxynaphthalenes. On the contrary, only thermodynamically controlled "domino" adducts (2,3 disubstituted 1,4:5,8-diepoxynaphthalenes) are formed in the same reaction at 140 degrees C. The "pincer" adducts can be transformed to the "domino" adducts at heating. The rate constants for reactions of both types were calculated using dynamic 1H NMR spectroscopy. PMID- 29617131 TI - A Computational Study of the Ionic Liquid-Induced Destabilization of the Miniprotein Trp-Cage. AB - Fundamental understanding of protein stability away from physiological conditions is important due to its evolutionary implications and relevance to industrial processing and storage of biological materials. The molecular mechanisms of stabilization/destabilization by environmental perturbations are incompletely understood. We use replica-exchange molecular dynamics simulations and thermodynamic analysis to investigate the effects of ionic liquid-induced perturbations on the folding/unfolding thermodynamics of the Trp-cage miniprotein. We find that ionic liquid-induced denaturation resembles cold unfolding, where the unfolded states are populated by compact, partially folded structures in which elements of the secondary structure are conserved, while the tertiary structure is disrupted. Our simulations show that the intrusion of ions and water into Trp-cage's hydrophobic core is facilitated by the disruption of its salt bridge and 310-helix by specific ion-residue interactions. Despite the swelling and widening of the hydrophobic core, however, Trp-cage's alpha-helix remains stable. We further show that ionic liquid disrupts protein-protein and protein-water hydrogen bonds while favoring the formation of ion-protein bonds, shifting the equilibrium of conformational states and promoting denaturation near room temperature. PMID- 29617130 TI - Structure and Dynamics of DNA and RNA Double Helices Obtained from the CCG and GGC Trinucleotide Repeats. AB - Expansions of both GGC and CCG sequences lead to a number of expandable, trinucleotide repeat (TR) neurodegenerative diseases. Understanding of these diseases involves, among other things, the structural characterization of the atypical DNA and RNA secondary structures. We have performed molecular dynamics simulations of (GCC) n and (GGC) n homoduplexes in order to characterize their conformations, stability, and dynamics. Each TR has two reading frames, which results in eight nonequivalent RNA/DNA homoduplexes, characterized by CpG or GpC steps between the Watson-Crick base pairs. Free energy maps for the eight homoduplexes indicate that the C-mismatches prefer anti-anti conformations, while G-mismatches prefer anti-syn conformations. Comparison between three modifications of the DNA AMBER force field shows good agreement for the mismatch free energy maps. The mismatches in DNA-GCC (but not CCG) are extrahelical, forming an extended e-motif. The mismatched duplexes exhibit characteristic sequence-dependent step twist, with strong variations in the G-rich sequences and the e-motif. The distribution of Na+ is highly localized around the mismatches, especially G-mismatches. In the e-motif, there is strong Na+ binding by two G(N7) atoms belonging to the pseudo GpC step created when cytosines are extruded and by extrahelical cytosines. Finally, we used a novel technique based on fast melting by means of an infrared laser pulse to classify the relative stability of the different DNA-CCG and -GGC homoduplexes. PMID- 29617132 TI - Stimuli-Responsive Functionalization Strategies to Spatially and Temporally Control Surface Properties: Michael vs Diels-Alder Type Additions. AB - Stimuli-responsive self-assembled monolayers (SAMs) are used to confer switchable physical, chemical, or biological properties to surfaces through the application of external stimuli. To obtain spatially and temporally tunable surfaces, we present microcontact printed SAMs of a hydroquinone molecule that are used as a dynamic interface to immobilize different functional molecules either via Diels Alder or Michael thiol addition reactions upon the application of a low potential. In spite of the use of such reactions and the potential applicability of the resulting surfaces in different fields ranging from sensing to biomedicine through data storage or cleanup, a direct comparison of the two functionalization strategies on a surface has not yet been performed. Although the Michael thiol addition requires molecules that are commercial or easy to synthesize in comparison with the cyclopentadiene derivatives needed for the Diels-Alder reaction, the latter reaction produces more homogeneous coverages under similar experimental conditions. PMID- 29617133 TI - Milieu-Initiated Inversion of the Aqueous Polyproline II/beta Propensity in the Alanine Tripeptide: Aggregation Origin of the Onset of Amyloid Formation. AB - Extending our earlier analogous study of the alanine dipeptide (ADP), we have now analyzed the effect of the external environment on the polyproline II (P) and beta relative energies, the P/beta propensity, of the alanine tripeptide (ATP). Ab initio calculations of ATP(H2O)19 and ATP(H2O)19(HCl) exhibit the same propensity inversion as in ADP: in the pure water case the PP conformation is favored while the addition of the HCl molecule results in the betabeta conformation being of lower energy. A comparison, following an intermediate insertion and departure of an HCl molecule, shows that the energy of a hydrogen bonded (H2O)19betaATP::betaATP(H2O)19 structure is lower than that of the sum of two separate PP systems, i.e., that the aggregated state of the peptide is favored. This arises from the basic physical response to their total environmental influences. Questions about quantitative results from molecular dynamics simulations, obviously needed to analyze longer chains and other side chains, are addressed via rigid water calculations. The desirability of basing studies of amyloid formation on our proposed alternative milieu-folding paradigm is discussed. PMID- 29617134 TI - Exploring Chimeric Calix[4]tetrolarene Molecular Scaffolds: Theoretical Investigations. AB - The structure and spectral characteristics of the chimeric mixture of calixarene and pyrogallolarene (usually referred to as calix[4]tetrolarene) and its derivatives are studied employing the M06-2X-based density functional theory. Different conformers, viz., cone, partial cone, 1,2-alternate, and 1,3-alternate, were identified as the stationary point structures on their potential energy surfaces. Among these, the symmetric C4 v cone conformer is found to be energetically favorable, which can be attributed to the cyclic array of hydrogen bonding network in the calix[4]tetrolarene or its thia analogue. The substitution of methoxy groups at the upper rims of calix[4]tetrol- and thicalix[4]tetrol arenes significantly influences the cooperative hydrogen-bonding network and conformational behavior of these hosts. The methoxy-substituted macrocycles show lowering in symmetry from C4 v to C2 v, engendering the pinched cone conformer to be the lowest energy structure. The enhanced solubility of the modified calix[4]tetrolarene macrocycles has been further explained from diminutive cooperative hydrogen bonding in its top rim compared to the pyrogallolarene, which is evidenced from the quantum theory of atoms in molecule and noncovalent interaction reduce density gradient method. Discernibly, the underlying cooperative hydrogen bonding emerges its signature in the characteristic vibrational patterns of the calixarene-based molecular scaffolds. The chemical shift parameters in their 1H NMR spectra have further been characterized. PMID- 29617135 TI - Discovery of Novel Dual Mechanism of Action Src Signaling and Tubulin Polymerization Inhibitors (KX2-391 and KX2-361). AB - The discovery of potent, peptide site directed, tyrosine kinase inhibitors has remained an elusive goal. Herein we describe the discovery of two such clinical candidates that inhibit the tyrosine kinase Src. Compound 1 is a phase 3 clinical trial candidate that is likely to provide a first in class topical treatment for actinic keratosis (AK) with good efficacy and dramatically less toxicity compared to existing standard therapy. Compound 2 is a phase 1 clinical trial candidate that is likely to provide a first in class treatment of malignant glioblastoma and induces 30% long-term complete tumor remission in animal models. The discovery strategy for these compounds iteratively utilized molecular modeling, along with the synthesis and testing of increasingly elaborated proof of concept compounds, until the final clinical candidates were arrived at. This was followed with mechanism of action (MOA) studies that revealed tubulin polymerization inhibition as the second MOA. PMID- 29617136 TI - BACE1: Now We Can See You. AB - No in vivo imaging biomarker currently exists for BACE, a drug target for Alzheimer's disease (AD). A strategy aiming to find a novel brain-penetrant positron emission tomography (PET) radiotracer for BACE1 led to the discovery of a highly potent and selective aminothiazine inhibitor, PF-06684511. This scaffold has been now evaluated as BACE1 PET radiotracer ([18F]PF-06684511) after labeling with fluorine-18 (18F), allowing its evaluation in non-human primates (NHP) as the first a brain-penetrant PET radiotracer for imaging BACE1 in vivo. PMID- 29617138 TI - Continuous Tuning of Organic Phosphorescence by Diluting Triplet Diffusion at the Molecular Level. AB - Organic long-persistent phosphorescent materials are advantageous due to the cost effectiveness and easy processability. The organic phosphorescence is achieved by the long-lived triplet excitons, and the challenges are recognized regarding the various nonradiative pathways to quench the emission lifetime. Taming long-lived phosphorescence is generally engaged with the charge-transfer or exciton diffusion in molecular stacking to stabilize triplet excitons or form a photoinduced ionized state. Herein, we elucidate that the triplet-diffusion can cause a significant quenching that is not thermally activated by using a system of perfluorinated organic complexes. Hence, we suggest a coevaporation technique to dilute a single phosphorescence-emitting molecule with another optically inactive molecule to suppress the diffusion-induced quenching, tuning the phosphorescence lifetime and spectral features continuously. The work successfully suggests a general semitheoretical method of quantifying the population equilibrium to elucidate the loss mechanisms for organic phosphorescence. PMID- 29617137 TI - Physical Origin of Thermostabilization by a Quadruple Mutation for the Adenosine A2a Receptor in the Active State. AB - The G protein-coupled receptors (GPCRs) form a large, physiologically important family of membrane proteins and are currently the most attractive targets for drug discovery. We investigate the physical origin of thermostabilization of the adenosine A2a receptor (A2aR) in the active state, which was experimentally achieved by another research group using the four point mutations: L48A, A54L, T65A, and Q89A. The investigation is performed on the basis of our recently developed physics-based free-energy function (FEF), which has been quite successful for the thermodynamics of GPCRs in the inactive state. The experimental condition for solving the wild-type and mutant crystal structures was substantially different from that for comparing their thermostabilities. Therefore, all-atom molecular dynamics simulations are necessitated, which also allows us to account for the structural fluctuations of the membrane protein. We show that the quadruple mutation leads to the enlargement of the solvent-entropy gain upon protein folding. The solvent is formed by hydrocarbon groups constituting nonpolar chains within the lipid bilayer, and the entropy is relevant to the thermal motion of the hydrocarbon groups. From an energetic point of view (e.g., in terms of protein intramolecular hydrogen bonds), the mutation confers no improvement upon the structural stability of A2aR. The reliability of our FEF and the crucial importance of the solvent-entropy effect have thus been demonstrated for a GPCR in the active state. We are now ready to identify thermostabilizing mutations of GPCRs not only in the inactive state but also in the active one. PMID- 29617139 TI - Direct Silyl-Heck Reaction of Chlorosilanes. AB - A nickel complex/Lewis acid combination effectively catalyzed the direct silyl Heck reaction of chlorosilanes, which are key raw materials in the organosilicon industry, to give synthetically important alkenylsilane products. Trichlorosilanes, dichlorosilanes, and monochlorosilanes underwent the silyl-Heck reaction to afford the corresponding alkenylsilanes in high yields. In the reactions of dichlorosilanes, a single substitution occurred to give monoalkenylsilanes in a highly selective manner. PMID- 29617140 TI - Construction of Unsymmetrical Triphenylenes from Electron-Rich Biphenyls and Diaryliodonium Salts via Copper-Catalyzed Multiple C-H Arylation. AB - An efficient protocol to synthesize unsymmetrical triphenylenes from electron rich biphenyls and diaryliodonium salts via Cu catalysis was developed. A variety of unsymmetrical triphenylenes with diversified functional groups were synthesized according to this method. This transformation went through multiple direct C-H arylations from easily produced starting materials with high step economy. The gram-scale synthesis of triphenylenes and their facile transformation into diverse functional organic molecules were illustrated. PMID- 29617141 TI - Palladium-Catalyzed Esterification of Carboxylic Acids with Aryl Iodides. AB - The first palladium-catalyzed esterification of carboxylic acids with aryl iodides is described. A palladium-based catalytic system consisting of IBnF (1,3 bis((pentafluorophenyl)methyl)imidazole-2-ylidene) ligand was found to significantly accelerate the aryl-O bond-forming esterification reaction. A series of aryl iodides and carboxylic acids undergoes a palladium-catalyzed coupling reaction to provide the corresponding aryl esters in moderate to good yields. In addition, sterically hindered aryl iodides and carboxylic acids were well-tolerated yielding the corresponding aryl esters. PMID- 29617142 TI - Double-Network Nanostructured Hydrogel-Derived Ultrafine Sn-Fe Alloy in Three Dimensional Carbon Framework for Enhanced Lithium Storage. AB - Tin-based alloys (Sn-M, M = Fe, Co, Ni, and Cu) have been considered as promising alternatives for graphite anode in advanced Li-ion batteries, but their practical application is hindered by huge volume change-induced poor cycle life. We propose here a facile inorganic-organic double-network nanostructured hydrogel-enabled methodology for uniformly immobilizing ultrafine Sn-M alloys in hierarchical carbon frameworks. The double-network nanostructured gel, consisting of three dimensional (3D) intertwined cyano-bridged Sn(IV)-Fe(II) inorganic gel and chitosan-glutaraldehyde organic polymer gel, can realize 3D space confinement in molecular scale and thus obtain ultrafine Sn-Fe alloy particles (average size ~2.7 nm) uniformly embedded in hierarchical 1D to 3D carbon framework. These unique structural features enable the Sn-Fe@C framework electrodes to exhibit long cycle life (516 mA h g-1 after 500 cycles at 0.1 A g-1) and high rate capability (491 and 270 mA h g-1 at 1 and 10 A g-1, respectively). This work provides new insight into controlled synthesis of ultrafine alloys in hierarchical 3D carbon frameworks for improving energy storage properties. PMID- 29617143 TI - Oxazolidinone-Mediated Sequence Determination of One-Bead One-Compound Cyclic Peptide Libraries. AB - A novel one-bead one-compound (OBOC) dual ring-opening/cleavage approach for cyclic peptide sequencing was developed. The method selectively modifies serine, cysteine, threonine, and/or glutamic acid to an oxazolidinone-derived moiety, thereby increasing the susceptibility of the modified peptide backbone toward hydrolysis. The resulting linear peptide was then sequenced in 1 min by tandem mass spectrometry on a quadrupole time-of-flight instrument incorporating two dimensional liquid chromatography and ion mobility spectrometry separation. To evaluate this approach, a library of cyclic peptides was successfully sequenced with 98% overall accuracy, demonstrating its robustness and broad substrate scope. PMID- 29617144 TI - Undulated Gold Nanoplatelet Superstructures: In Situ Growth of Hemispherical Gold Nanoparticles onto the Surface of Gold Nanotriangles. AB - Negatively charged flat gold nanotriangles, formed in a vesicular template phase and separated by an AOT-micelle-based depletion flocculation, were reloaded by adding a cationic polyelectrolyte, that is, a hyperbranched polyethylenimine (PEI). Heating the system to 100 degrees C in the presence of a gold chloride solution, the reduction process leads to the formation of gold nanoparticles inside the polymer shell surrounding the nanoplatelets. The gold nanoparticle formation is investigated by UV-vis spectroscopy, small-angle X-ray scattering, and dynamic light scattering measurements in combination with transmission electron microscopy. Spontaneously formed gold clusters in the hyperbranched PEI shell with an absorption maximum at 350 nm grow on the surface of the nanotriangles as hemispherical particles with diameters of ~6 nm. High-resolution micrographs show that the hemispherical gold particles are crystallized onto the {111} facets on the bottom and top of the platelet as well as on the edges without a grain boundary. Undulated gold nanoplatelet superstructures with special properties become available, which show a significantly modified performance in SERS-detected photocatalysis regarding both reactivity and enhancement factor. PMID- 29617145 TI - Cu(II)/Ag(I)-Catalyzed Cascade Reaction of Sulfonylhydrazone with Anthranils: Synthesis of 2-Aryl-3-sulfonyl Substituted Quinoline Derivatives. AB - In this paper, a Cu(II)/Ag(I)-catalyzed cascade reaction of anthranils with sulfonylhydrazone to construct 2-phenyl-3-sulfonyl disubstituted quinoline derivatives under mild conditions was studied. The mechanism study indicated that this reaction involves radical addition, and new C-C, C-N, and C-S bonds were constructed in one step. PMID- 29617146 TI - 1,5-O -> N Carbamoyl Snieckus-Fries-Type Rearrangement. AB - The reaction of o-lithiated O-aryl N,N-diethylcarbamates with (hetero)aromatic nitriles gives rise to functionalized salicylidene urea derivatives in high yields through a new 1,5-O -> N carbamoyl migration. This Snieckus-Fries-type rearrangement nicely complements previously known O -> C and O -> O related shifts. In addition, when dimethylmalononitrile is used as the electrophilic partner, the carbamoyl shift is preferred over the expected transnitrilation reaction. PMID- 29617147 TI - Prolinate Salt as a Catalyst in the syn-Selective, Asymmetric Mannich Reaction of Alkynyl Imine. AB - Prolinate salt is an efficient catalyst in the Mannich reaction of alkynyl imine and aldehyde, to afford synthetically useful chiral propargyl amine derivatives with excellent syn-selectivity and nearly perfect control of the absolute configuration. The counterion of the prolinate salt does not affect the enantioselectivity. This is a rare example, in which proline alkali metals, alkaline-earth metals, or ammonium salt show higher reactivity and better stereoselectivity than the parent proline. PMID- 29617148 TI - Characteristics and outcomes associated with 30-day readmissions following acute coronary syndrome 2000-2013: the Acute Coronary Syndrome Israeli Survey. AB - BACKGROUND: Readmissions following acute myocardial infarction are associated with poor outcomes and a heavy economic burden. There are few evidence-based data on the characteristics and outcomes of patients readmitted following acute coronary syndrome. We explored the incidence and outcomes of patients readmitted after an acute coronary syndrome in the past decade. METHODS: The study population comprised all acute coronary syndrome patients who were enrolled and prospectively followed up in the biennial Acute Coronary Syndrome Israeli Survey from 2000 to 2013. Multivariate analysis identified factors independently associated with readmission and long-term mortality. RESULTS: There were 13,010 study patients, of whom 556 (4.2%) had an unplanned readmission within 30 days of the index event. Stent thrombosis during the index hospitalisation (odds ratio (OR) 8.43; 95% confidence interval (CI) 4.11-16.07; P<0.001), female sex (OR 1.34; 95% CI 1.1-1.63; P=0.003), older age (>65 years; OR 1.28; 95% CI 1.06-1.55; P=0.011), and lack of dual-antiplatelet therapy (OR 1.52; 95% CI 1.25-1.86; P<0.001) were independently associated with readmission. Readmitted patients were less likely to have been treated with guideline-directed medical therapy during hospitalisation and at discharge, and were less likely to have undergone coronary angiography. A strong trend towards decline in readmission rates following acute coronary syndrome was observed between 2000 and 2013 ( P<0.001). However, the association between readmission and poor long-term outcome was more pronounced among patients readmitted during more recent years (2008-2013). CONCLUSIONS: Patients readmitted to hospital following acute coronary syndrome comprise an undertreated, high-risk cohort. Our findings indicate that despite a significant decline in readmission rates following acute coronary syndrome over the past decade, readmission within 30 days following acute coronary syndrome still portends a grave outcome. PMID- 29617149 TI - Effect of Surgical Weight Loss on Plantar Fasciitis and Healthcare Utilization. AB - BACKGROUND: Plantar fasciitis (PF) is known to be one of the most common causes of heel pain. Obesity is recognized as a significant factor in PF development, possibly due to increased mechanical loading of the foot as a result of excess weight. The benefit of bariatric surgery is documented for other comorbidities but not for PF. METHODS: Retrospective chart review of patients with a diagnosis of PF identified from a prospectively maintained database of the Cleveland Clinic Bariatric and Metabolic Institute. Age, gender, surgery, excess weight loss (EWL), body mass index (BMI), and healthcare utilization related to PF treatment were abstracted. Comparative analyses were stratified by surgery type. RESULTS: Two hundred twenty-eight (2.2%) from a total of 10,305 patients in our comprehensive bariatric program had a documented diagnosis of PF, of whom 163 underwent bariatric surgery and were included in the analysis. Eighty-five percent of patients were females, age was 52.2 +/- 9.9 years, and, pre intervention BMI was 45 +/- 7.7. Postoperatively BMI, and %EWL was 34.8 +/- 7.8 kg/m2 and 51.0 +/- 20.4%, respectively. One hundred and forty-six (90%) patients achieved resolution of PF and related symptoms. Mean number of treatment modalities used for PF in patients preoperatively was 1.9 +/- 1.0 (p=0.25) Post surgery, the number treatment modalities used per patient was reduced to 0.3 +/- 0.1 (p=0.01). CONCLUSION: We present new evidence suggesting that reductions in BMI after bariatric surgery may be associated with decreasing the numbers of visits for PF, and contribute to symptomatic improvement. PMID- 29617150 TI - "Experience Isn't Everything": How Emotion Affects the Relationship Between Experience and Cue Utilization. AB - OBJECTIVE: This research examined whether negative and positive arousal emotions modify the relationship between experience level and cue utilization among anesthetists. BACKGROUND: The capacity of a practitioner to form precise associations between clusters of features (e.g., symptoms) and events (e.g., diagnosis) and then act on them is known as cue utilization. A common assumption is that practice experience allows opportunities for cue acquisition and cue utilization. However, this relationship is often not borne out in research findings. This study investigates the role of emotional state in this relationship. METHOD: An online tool (EXPERTise 2.0) was used to assess practitioner cue utilization for tasks relevant to anesthesia. The experience of positive and negative arousal emotions in the previous three days was measured, and emotion clusters were generated. Experience was measured as the composite of practice years and hours of practice experience. The moderating role of emotion on the relationship between experience and cue utilization was examined. RESULTS: Data on 125 anesthetists (36% female) were included in the analysis. The predicted interaction between arousal emotions and the experience level emerged. In particular, post hoc analyses revealed that anxiety-related emotions facilitated the likelihood of high cue utilization in less experienced practitioners. CONCLUSION: The findings suggest a role for emotions in cue use and suggest a functional role for normal range anxiety emotions in a simulated work-relevant task. APPLICATION: This research illustrates the importance of understanding the potentially functional effects common negative arousal emotions may have on clinical performance, particularly for those with less experience. PMID- 29617151 TI - Detection of Nitrogen Content in Rubber Leaves Using Near-Infrared (NIR) Spectroscopy with Correlation-Based Successive Projections Algorithm (SPA). AB - Near-infrared spectroscopy is an efficient, low-cost technology that has potential as an accurate method in detecting the nitrogen content of natural rubber leaves. Successive projections algorithm (SPA) is a widely used variable selection method for multivariate calibration, which uses projection operations to select a variable subset with minimum multi-collinearity. However, due to the fluctuation of correlation between variables, high collinearity may still exist in non-adjacent variables of subset obtained by basic SPA. Based on analysis to the correlation matrix of the spectra data, this paper proposed a correlation based SPA (CB-SPA) to apply the successive projections algorithm in regions with consistent correlation. The result shows that CB-SPA can select variable subsets with more valuable variables and less multi-collinearity. Meanwhile, models established by the CB-SPA subset outperform basic SPA subsets in predicting nitrogen content in terms of both cross-validation and external prediction. Moreover, CB-SPA is assured to be more efficient, for the time cost in its selection procedure is one-twelfth that of the basic SPA. PMID- 29617152 TI - Comparison of Pre- and Postoperative Sleep Studies in Patients Undergoing Sphincter Pharyngoplasty. AB - OBJECTIVE: To determine if sphincter pharyngoplasty changes sleep study parameters on patients undergoing surgery for velopharyngeal insufficiency (VPI). DESIGN: Retrospective chart review on patients undergoing sphincter pharyngoplasty for VPI with pre- and postoperative polysomnography completed. SETTING: Institutional study at a tertiary pediatric hospital. PATIENTS: All patients who underwent sphincter pharyngoplasty over a 20-year period were reviewed; all patients with both pre- and postoperative sleep studies were collected for evaluation. INTERVENTIONS: Sphincter pharyngoplasty for patients with VPI. MAIN OUTCOME MEASURE: Sleep study parameters collected include apnea hypopnea index (AHI), obstructive and central apneas, hypopneas, and mixed events. The preoperative values were compared to postoperative values. RESULTS: There were 98 patients collected with sleep studies for review. Of these, 32 patients had both pre- and postoperative sleep studies. The AHI increased from 1.8 preoperatively to a postoperative value of 4.8 ( P = .004). The number of obstructive events per night went from 4.6 to 17.6 postoperatively ( P = .04). The number of hypopneas increased from 4.0 to 13.6 ( P = .003). The other parameters were not statistically different, central events decreased from 4.8 to 2.1 ( P = .086), and mixed events were essentially unchanged from 0.2 to 0.5 ( P = .17) events per night. CONCLUSIONS: Patients undergoing sphincter pharyngoplasty for VPI may experience an increase in their postoperative AHI, obstructive events per night, and hypopneas. Sleep studies should be performed both pre- and postoperatively to assess the need for intervention or change in management. PMID- 29617153 TI - Effects of inorganic nitrate and nitrite consumption on cognitive function and cerebral blood flow: A systematic review and meta-analysis of randomized clinical trials. AB - We conducted a systematic review and meta-analysis of randomized clinical trials examining the effect of inorganic nitrate or nitrite supplementation on cognitive function (CF) and cerebral blood flow (CBF). Two databases (PubMed, Embase) were searched for articles from inception until May 2017. Inclusion criteria were: randomized clinical trials; participants >18 years old; trials comparing a nitrate/nitrite intervention with a control. Thirteen and nine trials were included in the meta-analysis to assess CF and CBF, respectively. Random-effects models were used and the effect size described as standardized mean differences (SMDs). A total of 297 participants (median of 23 per trial) were included for CF; 163 participants (median of 16 per trial) were included for CBF. Nitrate/nitrite supplementation did not influence CF (SMD +0.06, 95% CI: -0.06, 0.18, P = 0.32) or CBF under resting (SMD +0.14, 95% CI: -0.13, 0.41, P = 0.31), or stimulated conditions (SMD + 0.23, 95% CI: -0.11, 0.56, P = 0.19). The meta regression showed an inverse association between duration of the intervention and CBF (P = 0.02) but no influence of age, BMI or dose (P < 0.05). Nitrate and nitrite supplementation did not modify CBF or CF. Further trials employing larger samples sizes and interventions with longer duration are warranted. PMID- 29617154 TI - N-terminal pro-brain natriuretic peptide and high-sensitivity troponin T exhibit additive prognostic value for the outcome of critically ill patients. AB - BACKGROUND: Patients treated at medical intensive care units suffer from various pathologies and often present with elevated troponin T (TnT) and N-terminal pro brain natriuretic peptide (NT-proBNP) levels. Both markers may reflect different forms of cardiac involvement in critical illness. Therefore, the aim of our study was to examine the synergistic prognostic potential of NT-proBNP and high sensitivity TnT (hs)TnT in unselected critically ill patients. METHODS: We included all consecutive patients admitted to our intensive care unit within one year, excluding those suffering from acute myocardial infarction or undergoing cardiac surgery and measured NT-proBNP and TnT plasma levels on the day of admission and 72 hours thereafter. RESULTS: Of the included 148 patients, 52% were male, mean age was of 64.2 +/- 16.8 years and 30-day mortality was 33.2%. Non-survivors showed significantly higher NT-proBNP and TnT plasma levels as compared with survivors ( p<0.01). An elevation of both markers exhibited an additive effect on mortality, as those with both NT-proBNP and TnT levels above the median had a 30-day mortality rate of 51.0%, while those with both markers below the median had a 16.7% mortality rate (hazard ratio 3.7). These findings were independent of demographic and clinical parameters ( p<0.05). CONCLUSIONS: Our findings regarding the individual predictive properties of NT-proBNP and TnT are in line with literature. However, we were able to highlight that they exhibit additive prognostic potential which exceeds their individual value. This might be attributed to a difference in underlying pathomechanisms and an assessment of synergistic risk factors. PMID- 29617155 TI - The Spectrum of the Universe. AB - Cosmic background (CB) radiation, encompassing the sum of emission from all sources outside our own Milky Way galaxy across the entire electromagnetic spectrum, is a fundamental phenomenon in observational cosmology. Many experiments have been conceived to measure it (or its constituents) since the extragalactic Universe was first discovered; in addition to estimating the bulk (cosmic monopole) spectrum, directional variations have also been detected over a wide range of wavelengths. Here we gather the most recent of these measurements and discuss the current status of our understanding of the CB from radio to gamma ray energies. Using available data in the literature, we piece together the sky averaged intensity spectrum and discuss the emission processes responsible for what is observed. We examine the effect of perturbations to the continuum spectrum from atomic and molecular line processes and comment on the detectability of these signals. We also discuss how one could, in principle, obtain a complete census of the CB by measuring the full spectrum of each spherical harmonic expansion coefficient. This set of spectra of multipole moments effectively encodes the entire statistical history of nuclear, atomic, and molecular processes in the Universe. PMID- 29617156 TI - Presentation of a Rare Lobulated Tongue Anomaly. AB - The presence of a bilobed tongue is a rare congenital malformation. There are multiple reports of a bifid anterior lobe; however, a case with complete separation of isolated anterior and posterior lobes has not been previously described. We report the case of a 2-year-old male, who presented with a V-shaped mandible and glossoptosis in the setting of respiratory distress and difficulty feeding, incidentally found to have a bilobed tongue with independent anterior and posterior lobes. PMID- 29617157 TI - Comparing the Open Trial - Selective Reminding Test results with the California Learning Verbal Test II in multiple sclerosis. AB - We compared the California Learning Verbal Test II (CVLT II) and the Open Trial Selective Reminding Test (OT-SRT) in assessing learning in persons with Multiple Sclerosis. One-hundred and twelve participants with multiple sclerosis performed the OT-SRT and the CVLT II on two different days. All participants completed additional cognitive tests assessing information processing speed (IPS), working memory (WM), and executive functions (EF). By definition, all participants were identified as having impaired learning on the OT-SRT (i.e., z score <-1.0); however, only 38 participants (33.9%) were identified as having impaired learning on the CVLT II (i.e., a z score <-1 total correct responses trials 1-5). The sample was thus divided into two groups, those who failed both tests (Fail-2) and those who failed only one (Fail-1). The Fail-2 group showed poorer performance on EF, WM and IPS in comparison with the Fail-1 group. On the CVLT II, the Fail-1 group showed a significantly greater improvement between trials 1 and 5, as compared with the Fail-2 group. However, the two groups performed similarly on the OT-SRT. Correlation analysis showed that EF is positively correlated with CVLT II learning slope but not with OT-SRT learning slope. The CVLT II and the OT SRT are not equivalent tests: while the CVLT II appears to be sensitive to overall cognitive dysfunction, the OT-SRT is more sensitive to focal learning and memory impairments. PMID- 29617158 TI - Effects of static magnetic fields on bone microstructure and mechanical properties in mice. AB - All the living organisms originate, evolve and live under geomagnetic field (GMF, 20-70 uT). With rapid development in science and technology, exposure to various static magnetic fields (SMFs) from natural and man-made sources remains a public environmental topic in consideration of its probable health risk for humans. Many animal studies related to health effect have demonstrated that SMF could improve bone formation and enhance bone healing. Moreover, most of the studies focused on local SMF generated by rod-type magnet. It was difficult to come to a conclusion that how SMF affected bone metabolism in mice. The present study employed hypomagnetic field (HyMF, 500 nT), and moderate SMF (MMF, 0.2 T) to systematically investigate the effects of SMF with continuous exposure on microstructure and mechanical properties of bone. Our results clearly indicated that 4-week MMF exposure did not affect bone biomechanical properties or bone microarchitecture, while HyMF significantly inhibited the growth of mice and elasticity of bone. Furthermore, mineral elements might mediate the biological effect of SMF. PMID- 29617159 TI - The Effect of Acute Hypovolemia on the Eye. AB - INTRODUCTION: To investigate the effects of acute hypovolemia induced by blood donation on the eye. Methods or Study Design: This prospective, observational study included a single eye from each of 48 healthy men between 20 and 40 years of age who had donated 500 ml of blood and 28 eyes of 28 healthy, age- and gender matched control subjects. The ocular parameters including ocular perfusion pressure (OPP), intraocular pressure (IOP), axial length (AL), central corneal thickness (CCT), choroidal and retinal thicknesses, and retinal nerve fiber layer (RNFL) were measured before blood donation and at 10 min and 1, 2, 3, and 4 h after blood donation. RESULTS: The mean OPP was significantly reduced following blood donation (baseline, 43.4 +/- 4.9 vs. 40.8 +/- 4.6 mmHg; p = 0.003). The mean subfoveal choroidal thickness (SFCT) was measured as 322.96 +/- 76.23, 291.63 +/- 77.85, 309.77 +/- 75.72, 312.31 +/- 75.98, 315.73 +/- 75.43, and 317.75 +/- 75.73 um before blood donation, at baseline, 10 min, and 1, 2, 3, and 4 h following donation, respectively [F(2.462, 115.731) = 22.618, p < 0.001]. In the control group, the SFCT was measured as 302.04 +/- 32.04, 301.43 +/- 35.16, 298.07 +/- 37.33, 298.96 +/- 39.17, 302.54 +/- 39.24, and 301.61 +/- 40.41 um at baseline, 10 min, and 1, 2, 3, and 4 h following donation, respectively [F(2.124, 57.340) = 0.592, p = 0.566]. There was no difference in AL, CCT, RNFL, retinal thicknesses, and IOP measurements performed before and after blood donation (p > 0.05). CONCLUSIONS: Acute hypovolemia caused a significant reduction in SFCT which persisted for 3 h. This study may pave way for better understanding of choroidal thickness changes in disease states. PMID- 29617160 TI - Corrigendum. PMID- 29617161 TI - Effects of Non-Driving Related Task Modalities on Takeover Performance in Highly Automated Driving. AB - OBJECTIVE: Aim of the study was to evaluate the impact of different non-driving related tasks (NDR tasks) on takeover performance in highly automated driving. BACKGROUND: During highly automated driving, it is allowed to engage in NDR tasks temporarily. However, drivers must be able to take over control when reaching a system limit. There is evidence that the type of NDR task has an impact on takeover performance, but little is known about the specific task characteristics that account for performance decrements. METHOD: Thirty participants drove in a simulator using a highly automated driving system. Each participant faced five critical takeover situations. Based on assumptions of Wickens's multiple resource theory, stimulus and response modalities of a prototypical NDR task were systematically manipulated. Additionally, in one experimental group, the task was locked out simultaneously with the takeover request. RESULTS: Task modalities had significant effects on several measures of takeover performance. A visual-manual texting task degraded performance the most, particularly when performed handheld. In contrast, takeover performance with an auditory-vocal task was comparable to a baseline without any task. Task lockout was associated with faster hands-on-wheel times but not altered brake response times. CONCLUSION: Results showed that NDR task modalities are relevant factors for takeover performance. An NDR task lockout was highly accepted by the drivers and showed moderate benefits for the first takeover reaction. APPLICATION: Knowledge about the impact of NDR task characteristics is an enabler for adaptive takeover concepts. In addition, it might help regulators to make decisions on allowed NDR tasks during automated driving. PMID- 29617163 TI - Heterogeneous Trajectories of Depression Symptoms in Latino Youth. AB - Latino youth are at greater risk for depression relative to youth of other ethnic groups. The course of depression among Latino children and adolescents, however, remains largely unexamined, along with family and cultural factors that can help explain dissimilar symptom paths. The present study used growth mixture modeling to map trajectories of depression symptoms and to examine youth and parent familism as predictors of these trajectories. Participants were 133 Latino 5th- to 7th-grade students (Mage = 12.4 years, SD = 0.91; 55.6% boys) and a subsample of their parents (n = 89). Youth reported on their depression symptoms at four time points, including two surveys (Time 1 and Time 3) and two in-person interviews (Time 2 and Time 4) over the course of 2 years. Familism reports were obtained from youth at Time 1 and from parents at Time 2. The trajectories identified include stable-low, recovery, and escalating, and only youth familism predicted membership in these trajectories. Relative to those in the recovery trajectory, youth reporting higher familism were more likely to belong to the stable-low trajectory. This study helps to highlight the heterogeneous course of depression among Latino youth and illustrates the importance of incorporating youth perspectives on family cultural values when considering their well-being. PMID- 29617162 TI - Dietary acculturation among black immigrant families living in Ottawa-a qualitative study. AB - The study explores the dietary acculturation process among first-generation immigrant families from sub-Saharan Africa or the Caribbean living in Ottawa (Canada). In-depth qualitative interviews were conducted with 12 mothers. The interaction between accelerating factors and other mediating factors resulted in a spiral of dietary changes triggered by immigration. The spiral evolved at different paces from traditional to acculturated and toward healthy or unhealthy diets and was hard to stop or to change in its direction once it started. Findings call for enhancing immigrant mothers' food access, food literacy and nutrition-related parenting skills, and their children's school food environment. PMID- 29617164 TI - Using Knowledge Wisely. PMID- 29617165 TI - Posttraumatic stress disorder after a first-ever intracerebral hemorrhage in the Chinese population: A pilot study. AB - The objective of this study was to reveal the prevalence, associated risk factors, and long-term outcomes of Posttraumatic stress disorder (PTSD) in patients after intracerebral hemorrhage (ICH). Consecutive patients admitted to our institute from January 2016 to September 2016 for a first-ever ICH were asked to participate in our study. PTSD was determined with Diagnostic and Statistical Manual of Mental Disorders (fifth edition; DSM-5), and questionnaires on mental and physical status were used. Patients were followed at 3 and 12 months after ICH. Sixty-four patients were eventually included for analysis. Compared with patients without PTSD, patients with PTSD were more likely to be female (67% vs. 29%, p = 0.01), and had higher rates of receiving minimally invasive surgery (MIS; 47% vs. 18%, p = 0.04). Patients with PTSD achieved higher IES-R scores, had more intense anxiety and depression, were more habitually use maladaptive coping strategies, and had poorer quality of life and worse stroke-related disability than those without PTSD. At 12-months follow-up, 6 of the 14 (43%) patients initially diagnosed with PTSD had self-recovered. ICH leads to increased PTSD risk in the Chinese population, especially those who are female, more severely disabled, or received MIS. PMID- 29617166 TI - Preoperative verbal memory problems and their clinical prognostic value in meningioma patients: A prospective study. AB - This study aimed to evaluate clinical utility of The Hopkins Verbal Learning Test Revised (HVLT-R) for assessment of preoperative memory function in meningioma patients and to investigate prognostic value of memory assessment in predicting outcomes after meningioma excision surgery. A total of 93 meningioma patients were assessed 2-3 days preoperatively using HVLT-R, and EORTC QLQ-30 and QLQ BN20. Functional outcome at discharge was evaluated using The Glasgow Outcome Scale. A sample of 95 healthy controls was matched to patients according to age, gender, and education. Meningioma patients demonstrated impaired working memory, delayed recall and recognition, flatter learning slope, and less effective acquisition. Location of meningioma was not related to any of the studied memory scores. Patients with left sided meningiomas more often produced false positive recognitions and demonstrated worse delayed recall when compared to patients with right sided, but not bilateral meningiomas. Verbal memory impairment was not associated with perceived health status. Functional outcome at discharge was predicted by tumor side, global health status score, and HVLT-R Cumulative learning score. Cumulative verbal learning impairment was associated with greater risk for poor functional outcome, indicating that cognitive impairment has added prognostic value beyond established prognostic indicators of meningioma patients. PMID- 29617167 TI - Sudden Infant Death Syndrome: A Global Public Health Issue and Nursing's Response. AB - Sudden unexplained death in infancy, including sudden infant death syndrome (SIDS), is a global public health challenge. Despite public health campaigns and efforts, SIDS remains the leading cause of postneonatal mortality in many developed countries. In this article, we review SIDS, describe nursing's unique professional position in addressing this problem, and explore how the principles of social justice can inform nursing's response. Motivated by nursing's ethical and moral obligations, the profession is called to take an active role in educating others regarding this phenomenon, to participate in research, and to develop or advocate for policy that aims to reduce the incidence of SIDS on an international scale. PMID- 29617168 TI - What neuropsychological functions best discriminate performance in adults post stroke? AB - This study aimed to develop a short version of an instrument to detect cognitive impairment in stroke patients, investigate which cognitive dimensions best discriminate between stroke patients and healthy adults and to graphically analyze the relationships among the neuropsychological variables and groups. This pilot study included 94 adults (49 post-stroke and 45 neurologically healthy) who answered the Brief Neuropsychological Assessment Battery NEUPSILIN for patients with expressive aphasia (NEUPSILIN-Af) to assess orientation, perception, memory, praxis, executive functions, oral language, and academic achievement (written language and arithmetic). The IRT Rasch model for dichotomous data indicated the exclusion of items that could not be used to discriminate performances. ROC curves indicated that only the orientation, oral language, academic achievement, and executive function dimensions could be used to differentiate between the clinical and healthy groups. Graphical analysis indicated that independently of the relation among variables, orientation and executive functions tasks are essentials in the neuropsychological assessments. This study contributes to the development of specific and sensitive neuropsychological instruments to assess stroke patients and to better understand the common deficits present in this clinical population. PMID- 29617169 TI - Verbal intelligence in bilinguals when measured in L1 and L2. AB - This study was aimed at studying the Verbal IQ in two groups of Spanish/English bilinguals: simultaneous and early sequential bilinguals. 48 Spanish/English bilinguals born in the U.S. or Latin American countries but moving to United States before the age of 10 were selected. The verbal subtests of the Wechsler Adult Intelligence Scale (English and Spanish) - Third Edition (WAIS-III) was administered. Overall, performance was significantly better in English for both groups of bilinguals. Verbal IQ difference when tested in Spanish and English was about one standard deviation higher in English for simultaneous bilinguals, and about half standard deviation for early sequential bilinguals. In both groups, Verbal IQ in English was about 100; considering the level of education of our sample (bachelor degree, on average), it can be assumed that Verbal IQ in English was lower than expected, suggesting that bilinguals may be penalized even when evaluated in the dominant language. PMID- 29617170 TI - Using the Structured Interview of Personality Organization for DSM-5 Level of Personality Functioning Rating Performed by Inexperienced Raters. AB - We argue that clinical information related to an object-relations model of personality pathology can be used by untrained and clinically inexperienced students to rate personality-disordered patients on the Level of Personality Functioning Scale (LPFS). To do so, 73 clinically inexperienced undergraduate students were asked to assess personality functioning of 10 female inpatients using the LPFS from audio recordings of the Structured Interview of Personality Organization (STIPO). LPFS ratings showed acceptable interrater reliability. Moreover, LPFS ratings were significantly associated with external measures of severity of personality pathology (number of DSM-IV-TR personality disorders) as assessed by experienced clinicians. Finally, the students' ratings were also associated with the level of personality organization as measured by experienced clinicians using the STIPO. Our findings confirm that untrained raters can reliably assess personality pathology by rating the LPFS based on material from the STIPO. Implications related to the use of the STIPO as a tool for the assessment of personality pathology according to the DSM-5 Alternative model are discussed. PMID- 29617172 TI - A case of exudative vitreoretinopathy and chorioretinal coloboma associated with microcephaly in a female with contiguous Xp11.3-11.4 deletion. AB - The constellation of signs including microcephaly, retinal colobomas, and exudative vitreo-retinopathy suggests a mutation of the KIF-11 gene on chromosome 10q. We report a female infant with these features but due, instead, to a contiguous gene deletion on chromosome Xp including the OMIM morbid genes CASK, KDM6A, NDP, MAOA, NYX, and DDX3X. The NDP deletion could account for the exudative retinopathy and the CASK deletion for the microcephaly, while CASK and KDM6A have both been associated with coloboma. This case highlights genetic heterogeneity for the clustering of these signs. PMID- 29617173 TI - Vaccine hesitancy - a potential threat to the achievements of vaccination programmes in Africa. AB - Vaccination programmes in Africa have made extraordinary progress over the last four decades. Yet, vaccine hesitancy threatens to erode these gains. Vaccine hesitancy is a continuum between vaccine acceptance and refusal. A growing number of people in Africa are delaying or refusing recommended vaccines for themselves or their children, even when safe and effective vaccines are available. This predisposes communities to infectious diseases, resulting in multiple disease outbreaks, ultimately consuming resources and costing lives. Vaccine hesitancy is currently receiving unprecedented global attention, however, there remains several knowledge gaps, particularly in Africa. The vast majority of research on this topic has been conducted in high income countries. Little is therefore known about the nature and causes of vaccine hesitancy in Africa, and evidence-based interventions in the region to address it are also limited. Moreover, tools to measure vaccine hesitancy are scarce, and none that exist have been validated in Africa. We discuss these knowledge gaps, and propose a research and capacity building agenda to better measure and overcome vaccine hesitancy in Africa. Ultimately, this is essential if we hope to enhance and sustain public demand for vaccination and preserve the tremendous achievements of vaccination programmes on the continent. PMID- 29617171 TI - Lenvatinib-induced renal failure: two first-time case reports and review of literature. AB - INTRODUCTION: Lenvatinib (LEN) is a multi-kinase anti-angiogenic drug recently approved in several cancers. LEN is not easily manageable due to its complex safety profile. Proteinuria and renal failure (RF) were reported among the most frequent LEN-induced adverse events (AEs), often leading to discontinuations or dose modifications. Understanding the pathogenesis of these AEs could ameliorate the management of LEN-induced renal toxicity. Areas covered: We present two cases of LEN-induced renal failure (LIRF) with different pathogenesis. 1) LIRF with severe proteinuria in a man treated for a metastatic papillary thyroid carcinoma. Kidney biopsy showed a glomerular damage secondary to LEN, having excluded other causes of RF. 2) LIRF without proteinuria in a woman with metastatic adenoid cystic carcinoma of minor salivary gland. A tubulointerstitial nephropathy was supposed by clinical evaluation and laboratory tests. Effective management was obtained by oral steroids without interrupting LEN. Expert opinion: The case 1 presented for the first time the histological picture of LIRF with a classical glomerular damage leading to secondary proteinuria and tubular failure. Case 2 showed an alternative LIRF pattern of likely tubulointerstitial injury without proteinuria. These reports reflect two sides of the same coin, both to be considered in case of LIRF. PMID- 29617174 TI - Prolonged follicular helper T cell responses in ME7 scrapie-infected mice. AB - We previously reported that mice intracerebrally inoculated with the mouse adapted scrapie strain ME7 have markedly diminished T zones in the spleen due to the decreased expression of CCL19 and CCL21. In addition, follicular dendritic cell networks in germinal centers were larger in ME7-infected spleens compared to uninfected spleens. As an extension of that study, we set out to determine how ME7 infection affects spleen structure and follicular helper T (Tfh) cell responses in mice. For this study, mice were intraperitoneally inoculated with brain homogenate of the ME7 inoculum and spleens were analyzed 50, 130, and 200 days after inoculation and compared with those from uninfected mice. The result showed that ME7- infected mice had increased Tfh cell responses which were maintained until end-stage prion disease. Although CD4 T cells decreased in white pulps, they increased in germinal centers, and expressed higher levels of the Tfh related genes, such as Bcl6, Il21, Cxcr5, Icos, and Pdcd1. In addition, ME7 infected spleens had increased numbers of CD4 memory T cells. These data indicate that although ME7 infection led to impaired splenic white pulp structure, CD4 memory T cells were increased and Tfh cell responses were required and prolonged to provide help for the replication and accumulation of pathogenic prion protein in germinal centers. PMID- 29617175 TI - Maximum likelihood approach suggests positive selection in platelet integrin alphaIIbbeta3 in mammalian species. AB - Platelet integrin alphaIIbbeta3 is crucial for platelet aggregation. Although structural and functional characteristics of this protein have been extensively studied, the evolutionary pattern studies of this protein complex in mammals are scarce. Here, we addressed this question using maximum likelihood approaches to identify codons that are evolving under positive selection. Likelihood of positive selection was estimated using CODEML implemented in PAML software applied to integrin alphaIIbbeta3 derived from nucleotide sequences of 10 different mammalian species. Four codons in mature alphaIIb-subunit (corresponding to residues 150, 184, 193, and 370) and three codons in mature beta3-subunit (corresponding to residues 129, 440, and 444) showed signs of positive selection with posterior probabilities over 95%. The different amino acids observed for each of the positively selected residues detected showed different physicochemical properties. These results open new research avenues to understand the physiological importance of specific residues and should allow for a better understanding of the function and the different interactions of each residue within the mature protein. PMID- 29617176 TI - Increased Platelet Content of SDF-1alpha is Associated with Worse Prognosis in Patients with Pulmonary Arterial Hypertension. AB - Inflammatory processes and platelet activity play an important role in the pathophysiology of pulmonary arterial hypertension (PAH). Enhanced IL-6 signaling and higher concentration of stromal-derived factor alpha (SDF-1) have been previously shown to be linked with prognosis in PAH. We hypothesized that platelets of PAH patients have higher content of IL-6 and SDF-1 and thus are involved in disease progression. We enrolled into study 22 PAH patients and 18 healthy controls. Patients with PAH presented significantly higher plasma concentrations and platelet contents of IL-6, sIL-6R, and SDF-1 than healthy subjects (platelet content normalized to protein concentration: IL-6 (0.85*10-10 [0.29 - 1.37] vs. 0.45*10-10 [0.19-0.65], sIL-6R 1.54*10-7 [1.32-2.21] vs. 1.14*10-7 [1.01-1.28] and SDF-1 (2.72*10-7 [1.85-3.23] vs. 1.70*10-7 [1.43-2.60], all p < 0.05). Patients with disease progression (death, WHO class worsening, or therapy escalation, n = 10) had a significantly higher platelet SDF-1/total platelet protein ratio (3.68*10-7 [2.45-4.62] vs. 1.69*10-7 [1.04-2.28], p = 0.001), with no significant differences between plasma levels. Kaplan-Meier analysis revealed that patients with higher platelet SDF-1/total platelet protein ratio had more frequently deterioration of PAH in the follow-up (15.24 +/- 4.26 months, log-rank test, p = 0.01). Concentrations of IL-6, sIL-6 receptor and SDF 1 in plasma and platelets are elevated in PAH patients. Higher content of SDF-1 in platelets is associated with poorer prognosis. Our study, despite of limitation due to small number of enrolled patients, suggests that activated platelets may be an important source of cytokines at the site of endothelial injury, but their exact role in the pathogenesis of PAH requires further investigation. PMID- 29617178 TI - Recruitment of feces donors among blood donors: Results from an observational cohort study. AB - As the use of fecal microbiota transplantation (FMT) has gained momentum, an increasing need for continuous access to healthy feces donors has developed. Blood donors constitute a healthy subset of the general population and may serve as an appropriate group for recruitment. In this study, we investigated the suitability of blood donors as feces donors. In a prospective cohort study, we recruited blood donors onsite at a public Danish blood bank. Following their consent, the blood donors underwent a stepwise screening process: First, blood donors completed an electronic pre-screening questionnaire to rule out predisposing risk factors. Second, eligible blood donors had blood and fecal samples examined. Of 155 blood donors asked to participate, 137 (88%) completed the electronic pre-screening questionnaire, 16 declined, and 2 were excluded. Of the 137 donors who completed the questionnaire, 79 (58%) were excluded mainly due to having an allergy, being overweight, or presenting gastrointestinal complaints. Among the remaining 58 (37%) donors, complete blood and feces screenings were obtained from 46 (79%). Of these 46 donors, 15 (33%) were excluded primarily due to abnormal blood results or the presence of apathogenic intestinal parasites. Overall, 31 (20%; 95% confidence interval 14-27%) of the 155 blood donors qualified as feces donors. In conclusion, blood donors constitute a suitable and motivated population for a continuous recruitment of voluntary feces donors. We found that a stepwise recruitment procedure was feasible and that 20% of the blood donors were eligible for feces donation. PMID- 29617177 TI - Challenges in conducting a community-based influenza vaccine trial in a rural community in northern India. AB - Evidence on influenza vaccine effectiveness from low and middle countries (LMICs) is limited due to limited institutional capacities; lack of adequate resources; and lack of interest by ministries of health for influenza vaccine introduction. There are concerns that the highest ethical standards will be compromised during trials in LMICs leading to mistrust of clinical trials. These factors pose regulatory and operational challenges to researchers in these countries. We conducted a community-based vaccine trial to assess the efficacy of live attenuated influenza vaccine and inactivated influenza vaccine in rural north India. Key regulatory challenges included obtaining regulatory approvals, reporting of adverse events, and compensating subjects for trial-related injuries; all of which were required to be completed in a timely fashion. Key operational challenges included obtaining audio-visual consent; maintaining a low attrition rate; and administering vaccines during a narrow time period before the influenza season, and under extreme heat. We overcame these challenges through advanced planning, and sustaining community engagement. We adapted the trial procedures to cope with field conditions by conducting mock vaccine camps; and planned for early morning vaccination to mitigate threats to the cold chain. These lessons may help investigators to confront similar challenges in other LMICs. PMID- 29617179 TI - Sclerostin and DKK1 Inhibition Preserves and Augments Alveolar Bone Volume and Architecture in Rats with Alveolar Bone Loss. AB - Alveolar bone is a mechanosensitive tissue that provides structural support for teeth. Alveolar bone loss is common with aging, menopause, tooth loss, and periodontitis and can lead to additional tooth loss, reduced denture fixation, and challenges in placing dental implants. The current studies suggest that sclerostin and DKK1, which are established osteocyte-derived inhibitors of bone formation, contribute to alveolar bone loss associated with estrogen ablation and edentulism in rats. Estrogen-deficient ovariectomized rats showed significant mandibular bone loss that was reversed by systemic administration of sclerostin antibody (SAB) alone and in combination with DKK1 antibody (DAB). Osteocytes in the dentate and edentulous rat maxilla expressed Sost (sclerostin) and Dkk1 (DKK1) mRNA, and molar extraction appeared to acutely increase DKK1 expression. In a chronic rat maxillary molar extraction model, systemic SAB administration augmented the volume and height of atrophic alveolar ridges, effects that were enhanced by coadministering DAB. SAB and SAB+DAB also fully reversed bone loss that developed in the opposing mandible as a result of hypo-occlusion. In both treatment studies, alveolar bone augmentation with SAB or SAB+DAB was accompanied by increased bone mass in the postcranial skeleton. Jaw bone biomechanics showed that intact sclerostin-deficient mice exhibited stronger and denser mandibles as compared with wild-type controls. These studies show that sclerostin inhibition, with and without DKK1 coinhibition, augmented alveolar bone volume and architecture in rats with alveolar bone loss. These noninvasive approaches may have utility for the conservative augmentation of alveolar bone. PMID- 29617180 TI - Use of trunk muscle training and neuromuscular electrical stimulation to reduce pain and disability in an older adult with chronic low back pain: A case report. AB - Among older adults, low back pain (LBP) is common, costly, and disabling. Trunk muscle training (TMT) and neuromuscular electrical stimulation (NMES) have both been found to be effective in reducing LBP, but studies among older adults have been limited. An 83-year-old female with left-sided chronic LBP participated in a randomized controlled trial consisting of supervised TMT and NMES to the paraspinal muscles two times per week for 12 weeks. She also participated in a home exercise program. At the end of the intervention, she reported reduced LBP and LBP-related disability per the modified Oswestry disability index (i.e., 60% at baseline to 40% at 12 weeks). Her Short Physical Performance Battery summary score improved from 4/12 at baseline to 10/12 at 12 weeks, while her Timed Up and Go test improved from 17.21 to 15.20 s and her Repetitive Trunk Rotation test from 2.72 to 1.93 s/right-left rotation. This case demonstrates a positive short term treatment response to TMT supplemented with NMES of the paraspinal muscles in an older adult with chronic LBP. A packaged intervention of TMT plus NMES may be a means of addressing not only LBP, but also impaired physical function and resultant disability. PMID- 29617181 TI - Examination of the British Columbia influenza prevention policy for healthcare workers: Phase 1 qualitative case study. AB - In August 2012, British Columbia became the first Canadian province to implement a province-wide Influenza Prevention Policy requiring all healthcare workers (HCWs) in residential and acute care facilities to either be immunized against influenza, or wear masks in patient care areas during the influenza season. This qualitative case study sought to understand the key facilitators and barriers involved in developing and implementing British Columbia's Influenza Prevention Policy. An explanatory qualitative case study approach was selected for this project. Data were collected through the review of 110 documents (policy and planning documents, implementation tools, press releases, communication materials, etc.), and through 7 focus groups with policy implementation team members (n = 48). Focus group interview transcripts were analyzed using Framework Analysis methods, and Prior's approach guided document analysis. Four themes were identified: (1) Clashing paradigms, (2) Policy implementation gaps, (3) Pathways of power, and (4) Personal impacts. Issues embedded in macro-, meso-, and micro level contexts, and planning across the province, were identified as critical to policy implementation. A province-wide approach with senior-level engagement and dedicated resources is critical in a province-wide influenza prevention policy for HCW. Recommendations to improve large-scale implementation of condition-of service influenza policies include: engaging stakeholders early, considering the complexity of political contexts, allotting time to plan appropriately, developing 'enforcement' plans, and providing education and skills to frontline providers. PMID- 29617182 TI - "...I've said I wish I was dead, you'd be better off without me": A systematic review of people's experiences of living with severe asthma. AB - OBJECTIVE: Our aim was to conduct a systematic review and synthesis of qualitative evidence exploring the lived experience of adults with severe asthma. DATA SOURCES: We searched MEDLINE via OvidSP, PsycINFO via OvidSP, PubMed, CINAHL, EMBASE, Sociological Abstracts, Google Scholar, the journals Qualitative Health Research and Qualitative Research, and a study of experiences of living with asthma by the Health Experiences Research group. STUDY SELECTIONS: Studies were included if they used qualitative methods and explored the subjective experiences of adults (>=18 years) with a clear diagnosis of severe asthma. RESULTS: From 575 identified studies, five met the inclusion criteria. Synthesis revealed an overarching theme of efforts that people living with severe asthma engage in to achieve personal control over their condition. Individuals 'strive for autonomy' through dealing with symptoms and treatment, acquiring knowledge, making decisions and reclaiming identity. CONCLUSION: This systematic review found a paucity of qualitative studies reporting on people's perspectives of living with severe asthma, and a focus on clinical rather than personal issues. Our synthesis reveals that severe asthma was disempowering, and a threat to identity and life roles. What was important to people living with severe asthma was striving to achieve a greater level of personal control over their condition, but these efforts received little support from their healthcare providers. Thus, more attention should be paid to understanding the self-management strategies and personal goals of people living with severe asthma. This may assist in designing interventions to better support patient self-management and improve health outcomes. PMID- 29617183 TI - Measuring trust in vaccination: A systematic review. AB - Vaccine acceptance depends on public trust and confidence in the safety and efficacy of vaccines and immunization, the health system, healthcare professionals and the wider vaccine research community. This systematic review analyses the current breadth and depth of vaccine research literature that explicitly refers to the concept of trust within their stated aims or research questions. After duplicates were removed, 19,643 articles were screened by title and abstract. Of these 2,779 were screened by full text, 35 of which were included in the final analysis. These studies examined a range of trust relationships as they pertain to vaccination, including trust in healthcare professionals, the health system, the government, and friends and family members. Three studies examined generalized trust. Findings indicated that trust is often referred to implicitly (19/35), rather than explicitly examined in the context of a formal definition or discussion of the existing literature on trust in a health context. Within the quantitative research analysed, trust was commonly measured with a single-item measure (9/25). Only two studies used validated multi-item measures of trust. Three studies examined changes in trust, either following an intervention or over the course of a pandemic. The findings of this review indicate a disconnect between the current vaccine hesitancy research and the wider health-related trust literature, a dearth in research on trust in low and middle-income settings, a need for studies on how trust levels change over time and investigations on how resilience to trust-eroding information can be built into a trustworthy health system. PMID- 29617185 TI - Long non-coding RNA metallothionein 1 pseudogene 3 promotes p2y12 expression by sponging miR-126 to activate platelet in diabetic animal model. AB - Platelet hyperaggregation and hypercoagulation are associated with increase of thrombogenic risk, especially in patients with type 2 diabetes (T2D). High activity of P2Y12 receptor is found in T2D patients, exposing such patients to a prothrombotic condition. P2Y12 is a promising target for antiplatelet, but due to P2Y12 receptor constitutive activation, the clinical practical phenomena such as "clopidogrel resistance" are commonly occurring. In this study, we investigate the role of lncRNA on platelet activation. By lncRNA array, we screened thousands of differentially expressed lncRNA in megakaryocytes from T2D patients and confirmed that lncRNA metallothionein 1 pseudogene 3 (MT1P3) was significantly upregulated in megakaryocytes from T2D patients than in healthy controls. And we further investigate the biofunction of MT1P3 on platelet activation and the regulatory mechanism on p2y12. MT1P3 was positively correlated with p2y12 mRNA levels and promoted p2y12 expression by sponging miR-126. Knockdown of MT1P3 by siRNA reduced p2y12 expression, inhibiting platelet activation and aggregation in diabetes animal model. In conclusion, our findings identify MT1P3 as a key regulator in platelet activation by increasing p2y12 expression through sponging miR-126 under T2D condition. These findings may provide a new insight for managing platelet hyperactivity-related diseases. PMID- 29617184 TI - Targeting interleukin-22 for cancer therapy. AB - Interleukin-22 (IL-22) is a member of IL-10 family of cytokines. IL-22 induces proliferative and anti-apoptotic signaling pathways and production of anti microbial molecules that enhance tissue regeneration and host defense. IL-22 has also been identified as a cancer-promoting cytokine since deregulation of the IL 22-IL-22R1 system is linked to different cancer entities including lung, breast, gastric, pancreatic and colon cancers. T cells and innate lymphoid cells are the main cellular sources of IL-22. Expression of its specific receptor IL-22R1 is restricted to the non-hematopoietic cells which makes the IL-22-IL-22R1 pathway an attractive target for anti-cancer therapy. For development of such therapies, a better understanding of IL-22 regulation in the tumor microenvironment is needed. We could recently decipher how cancer cells promote IL-22 production by memory T cells via induction of IL-1. Here we will discuss how this knowledge might contribute to developing therapies disregulating the IL-22 pathway for cancer immunotherapy. PMID- 29617186 TI - DETERMINING RAPTOR SPECIES AND TISSUE SENSITIVITY FOR IMPROVED WEST NILE VIRUS SURVEILLANCE. AB - Raptors are a target sentinel species for West Nile virus (WNV) because many are susceptible to WNV disease, they are easily sighted because of their large size, and they often occupy territories near human settlements. Sick and dead raptors accumulate at raptor and wildlife rehabilitation clinics. However, investigations into species selection and specimen type for efficient detection of WNV are lacking. Accordingly, we evaluated dead raptors from north-central Colorado, US and southeast Wyoming, US over a 4-yr period. Nonvascular mature feathers ("quill"), vascular immature feathers ("pulp"), oropharyngeal swabs, cloacal swabs, and kidney samples were collected from raptor carcasses at the Rocky Mountain Raptor Program in Colorado from 2013 through 2016. We tested the samples using real-time reverse transcriptase-PCR. We found that 11% (53/482) of raptor carcasses tested positive for WNV infection. We consistently detected positive specimens during a 12-wk span between the second week of July and the third week of September across all years of the study. We detected WNV RNA most frequently in vascular feather pulp from Cooper's Hawk ( Accipiter cooperii). North American avian mortality surveillance for WNV using raptors can obviate necropsies by selecting Cooper's Hawk and Red-tailed Hawk ( Buteo jamaicensis) as sentinels and targeting feather pulp as a substrate for viral detection. PMID- 29617187 TI - BATS RECOVERING FROM WHITE-NOSE SYNDROME ELEVATE METABOLIC RATE DURING WING HEALING IN SPRING. AB - Host responses to infection with novel pathogens are costly and require trade offs among physiologic systems. One such pathogen is the fungus Pseudogymnoascus destructans (Pd) that causes white-nose syndrome (WNS) and has led to mass mortality of hibernating bats in eastern North America. Although infection with Pd does not always result in death, we hypothesized that bats that survive infection suffer significant consequences that negatively impact the ability of females to reproduce. To understand the physiologic consequences of surviving infection with Pd, we assessed differences in wing damage, mass-specific resting metabolic rate, and reproductive rate between little brown myotis ( Myotis lucifugus) that survived a winter in captivity after inoculation with Pd (WNS survivors) and comparable, uninfected bats. Survivors of WNS had significantly more damaged wing tissue and displayed elevated mass-specific metabolic rates compared with Pd-uninfected bats after emergence from hibernation. The WNS survivors and Pd-uninfected bats did not significantly differ in their reproductive capacity, at least in captivity. However, our metabolic data demonstrated greater energetic costs during spring in WNS survivors compared with uninfected bats, which may have led to other consequences for postpartum fitness. We suggest that, after surviving the energetic constraints of winter, temperate hibernating bats infected with Pd faced a second energetic bottleneck after emerging from hibernation. PMID- 29617188 TI - Mechanisms of antimicrobial resistance among hospital-associated pathogens. AB - INTRODUCTION: The introduction of antibiotics revolutionized medicine in the 20th century permitting the treatment of once incurable infections. Widespread use of antibiotics, however, has led to the development of resistant organisms, particularly in the healthcare setting. Today, the clinician is often faced with pathogens carrying a cadre of resistance determinants that severely limit therapeutic options. The genetic plasticity of microbes allows them to adapt to stressors via genetic mutations, acquisition or sharing of genetic material and modulation of genetic expression leading to resistance to virtually any antimicrobial used in clinical practice. Areas covered: This is a comprehensive review that outlines major mechanisms of resistance in the most common hospital associated pathogens including bacteria and fungi. Expert commentary: Understanding the genetic and biochemical mechanisms of such antimicrobial adaptation is crucial to tackling the rapid spread of resistance, can expose unconventional therapeutic targets to combat multidrug resistant pathogens and lead to more accurate prediction of antimicrobial susceptibility using rapid molecular diagnostics. Clinicians making treatment decisions based on the molecular basis of resistance may design therapeutic strategies that include de escalation of broad spectrum antimicrobial usage, more focused therapies or combination therapies. These strategies are likely to improve patient outcomes and decrease the risk of resistance in hospital settings. PMID- 29617190 TI - Bile acid oxidation by Eggerthella lenta strains C592 and DSM 2243T. AB - Strains of Eggerthella lenta are capable of oxidation-reduction reactions capable of oxidizing and epimerizing bile acid hydroxyl groups. Several genes encoding these enzymes, known as hydroxysteroid dehydrogenases (HSDH) have yet to be identified. It is also uncertain whether the products of E. lenta bile acid metabolism are further metabolized by other members of the gut microbiota. We characterized a novel human fecal isolate identified as E. lenta strain C592. The complete genome of E. lenta strain C592 was sequenced and comparative genomics with the type strain (DSM 2243) revealed high conservation, but some notable differences. E. lenta strain C592 falls into group III, possessing 3alpha, 3beta, 7alpha, and 12alpha-hydroxysteroid dehydrogenase (HSDH) activity, as determined by mass spectrometry of thin layer chromatography (TLC) separated metabolites of primary and secondary bile acids. Incubation of E. lenta oxo-bile acid and iso bile acid metabolites with whole-cells of the high-activity bile acid 7alpha dehydroxylating bacterium, Clostridium scindens VPI 12708, resulted in minimal conversion of oxo-derivatives to lithocholic acid (LCA). Further, Iso chenodeoxycholic acid (iso-CDCA; 3beta,7alpha-dihydroxy-5beta-cholan-24-oic acid) was not metabolized by C. scindens. We then located a gene encoding a novel 12alpha-HSDH in E. lenta DSM 2243, also encoded by strain C592, and the recombinant purified enzyme was characterized and substrate-specificity determined. Genomic analysis revealed genes encoding an Rnf complex (rnfABCDEG), an energy conserving hydrogenase (echABCDEF) complex, as well as what appears to be a complete Wood-Ljungdahl pathway. Our prediction that by changing the gas atmosphere from nitrogen to hydrogen, bile acid oxidation would be inhibited, was confirmed. These results suggest that E. lenta is an important bile acid metabolizing gut microbe and that the gas atmosphere may be an important and overlooked regulator of bile acid metabolism in the gut. PMID- 29617189 TI - Cumulative Burden of Morbidity Among Testicular Cancer Survivors After Standard Cisplatin-Based Chemotherapy: A Multi-Institutional Study. AB - Purpose In this multicenter study, we evaluated the cumulative burden of morbidity (CBM) among > 1,200 testicular cancer survivors and applied factor analysis to determine the co-occurrence of adverse health outcomes (AHOs). Patients and Methods Participants were <= 55 years of age at diagnosis, finished first-line chemotherapy >= 1 year previously, completed a comprehensive questionnaire, and underwent physical examination. Treatment data were abstracted from medical records. A CBM score encompassed the number and severity of AHOs, with ordinal logistic regression used to assess associations with exposures. Nonlinear factor analysis and the nonparametric dimensionality evaluation to enumerate contributing traits procedure determined which AHOs co-occurred. Results Among 1,214 participants, approximately 20% had a high (15%) or very high/severe (4.1%) CBM score, whereas approximately 80% scored medium (30%) or low/very low (47%). Increased risks of higher scores were associated with four cycles of either ifosfamide, etoposide, and cisplatin (odds ratio [OR], 1.96; 95% CI, 1.04 to 3.71) or bleomycin, etoposide, and cisplatin (OR, 1.44; 95% CI, 1.04 to 1.98), older attained age (OR, 1.18; 95% CI, 1.10 to 1.26), current disability leave (OR, 3.53; 95% CI, 1.57 to 7.95), less than a college education (OR, 1.44; 95% CI, 1.11 to 1.87), and current or former smoking (OR, 1.28; 95% CI, 1.02 to 1.63). CBM score did not differ after either chemotherapy regimen ( P = .36). Asian race (OR, 0.41; 95% CI, 0.23 to 0.72) and vigorous exercise (OR, 0.68; 95% CI, 0.52 to 0.89) were protective. Variable clustering analyses identified six significant AHO clusters (chi2 P < .001): hearing loss/damage, tinnitus (OR, 16.3); hyperlipidemia, hypertension, diabetes (OR, 9.8); neuropathy, pain, Raynaud phenomenon (OR, 5.5); cardiovascular and related conditions (OR, 5.0); thyroid disease, erectile dysfunction (OR, 4.2); and depression/anxiety, hypogonadism (OR, 2.8). Conclusion Factors associated with higher CBM may identify testicular cancer survivors in need of closer monitoring. If confirmed, identified AHO clusters could guide the development of survivorship care strategies. PMID- 29617191 TI - Alpha-galactosylceramide (alphaGalCer) enhances vaccine-induced protection in a model of ricin intoxication. AB - Alpha-galactosylceramide (alphaGalCer) is a glycolipid derived from a marine sponge that is a potent activator of both mouse and human invariant natural killer T (iNKT) cells. For that reason, alphaGalCer is a promising vaccine adjuvant that has been shown to improve both humoral and cellular immunity when co-administered with various vaccines, including candidate vaccines for biodefense. In the current study, we tested the effectiveness of alphaGalCer as an adjuvant for the clinically-relevant ricin toxin subunit vaccine, RiVax. alphaGalCer had a potent adjuvant effect, as shown by a rapid onset of anti-ricin IgG titers, accelerated development of serum toxin-neutralizing activity, and enhanced protection from lethal ricin challenge in a mouse model. These results underscore the potential of alphaGalCer to augment the protective immune response to a vaccine designed to counteract ricin toxin, a fast-acting biothreat agent. PMID- 29617192 TI - Optical clearing of the pancreas for visualization of mature beta-cells and vessels in mice. AB - Glucose metabolism is regulated by insulin, which is produced from beta-cells in the pancreas. Because insulin is secreted into vessels in response to blood glucose, vascular structures of the pancreas, especially the relationship between vessels and beta-cells, are important for physiological and pathological glucose metabolism. Here, we developed a system to visualize vessels surrounding mature beta-cells expressing transcription factor MafA in a three-dimensional manner. Optical clearing of the pancreas prevented light scattering of fluorescence driven by the bacterial artificial chromosome (BAC)-mafA promoter in beta-cells. Reconstruction of confocal images demonstrated mature beta-cells and the glomerular-like structures of beta-cell vasculatures labeled with DyLight 488 conjugated lectin in normal mice as well as in low-dose streptozotocin-injected diabetes model mice with reduced beta-cell mass. This technological innovation of organ imaging can be used to investigate morphological changes in vascular structures during transplantation, regeneration and diabetes development. PMID- 29617193 TI - The Effect of CHAMP on Physical Activity and Lesson Context in Preschoolers: A Feasibility Study. AB - PURPOSE: This feasibility study compared the effects of 2 movement programs, traditional and mastery climate (i.e., the Children's Health Activity Motor Program [CHAMP]), on lesson context and children's physical activity (PA) levels. A secondary aim was to examine sex differences in PA levels in both programs. METHOD: Seventy-two preschoolers served as participants and were assigned to a movement program. Physical activity levels and lesson context were assessed with the System for Observing Fitness Instruction Time. RESULTS: Preschoolers in CHAMP spent more time walking (p < .05, d = 3.3), more time in moderate-to-vigorous PA (MVPA; p < .05, d = 3.6), and less time standing (p < .05, d = 3.8) compared with those in a traditional movement program. Boys in both programs spent less time standing (p < .05, d = 4.8) and more time in vigorous activity (p < .05, d = 5.8) and MVPA (p < .05, d = 4.4) compared with girls. During CHAMP, children spent less time engaged in management and knowledge (p < .05, d = 1.4, and p < .001, d = 0.9, respectively) and more time in skill practice (p < .05, d = 1.5). CONCLUSION: The findings support that participation in CHAMP elicits more MVPA in preschool-age children compared with a traditional movement program. The Children's Health Activity Motor Program provided children with more class time devoted to skill practice. The program appears to be an innovative approach that is beneficial for PA engagement and could contribute positively to children's health. PMID- 29617194 TI - The Intersectionality of Stigmas among Key Populations of Older Adults Affected by HIV: a Thematic Analysis. AB - OBJECTIVES: The present study examined the intersectionality of stigma across varying groups of older persons living with HIV (PWH). METHODS: Four focus groups of older PWH (gay/bisexual men, heterosexual men, heterosexual and bisexualwomen, and Spanish-speaking) were audio-recorded and transcribed. Inductive thematic text analysis was used to identify qualitative themes. RESULTS: Five major themes emerged from the data: 1) disclosure of HIV status; 2) types of stigma experienced; 3) discrimination experienced; 4) other outcomes associated with experiencing stigma; and 5) influence of aging on social isolation experienced due to stigma. Findings indicate women did not suffer from the intersection of stigmas. Other groups suffered from the intersection of stigma due to HIV status and age (gay/bisexual males); HIV status and perceived stigma of sexual orientation or drug use (heterosexual males); and HIV status and culture/ethnicity (Spanish-speaking). CONCLUSIONS: Results indicate that many at risk groups, including heterosexual men, homosexual men, and Spanish-speaking individuals, experience an intersection of stigma between aging and their sexuality, HIV status, or real or perceived drug use. CLINICAL IMPLICATIONS: Results highlight the need for HIV support, especially social support, to address intersection of stigmas for unique groups of individuals disproportionately affected by HIV. PMID- 29617195 TI - Natural tissue concentrations in adult Ambystoma maculatum and larval DNA damage from exposure to arsenic and chromium. AB - Arsenic (As) and chromium (Cr) are two contaminants that are detected in aquatic and terrestrial habitats. Using the spotted salamander, Ambystoma maculatum, to assess impacts from these contaminants may be advantageous as adults live and breed in such environments. Adult amphibians typically exhibit elevated tissue concentrations of contaminants present in their environment, while larval stages were found to exhibit increased sensitivity to pollutants. From January through March of 2015, during the spring breeding season, 5 adults and approximately 32 egg masses were collected from a local breeding site. Field levels of As and Cr ranged from 5.99 to 8.88 ug/L and 1.45 to 2 ug/L, respectively, while mean adult As tissue concentrations were 56.74 ug/g dry weight for heart, 0.92 ug/g for liver, and 1.21 ug/g for tail tissue. Mean tissue concentrations for Cr were 87.64 ug/g for heart, 1.47 ug/g for liver, and 6.92 ug/g for tail. Developing larvae that were collected from the field and exposed in a lab setting for 12 d to 0.2 or 20 mg/L of either As or Cr displayed little DNA damage attributed to As, but marked damage due to exposure to 20 mg/L Cr when assessed using the comet assay. Exposure to a mixture of either 0.25:0.1 or 25:10 mg/L As and Cr resulted in significant DNA damage at the lower concentration of 0.25:0.1 mg/L. As adult spotted salamanders were found to possess high concentrations of these contaminants in cardiac tissue, and larvae were shown to be susceptible to DNA damage from increased exposures, assessing impacts and potential declines of amphibian populations exposed to As and Cr is needed. PMID- 29617196 TI - Promoting Healthy Menu Choices in Fast Food Restaurant Advertising: Influence of Perceived Brand Healthiness, Brand Commitment, and Health Consciousness. AB - Fast food restaurants have increasingly turned to healthier choices to counter criticisms of nutritionally poor menu offerings and to differentiate themselves from the competition. However, research has yet to specifically investigate how consumers respond to advertisements for these healthier foods. To address this knowledge gap, two experiments were conducted to examine how perceived brand healthiness, brand commitment, and health consciousness influence responses to nutrient-content claimed print advertisements for healthy foods. Findings indicate that consumer responsiveness varies across the three factors but is more positive for advertisements placed by perceivably healthy restaurant brands, and that brand commitment and health consciousness play significant roles in affecting how consumer respond to such advertising. Several theoretical and managerial implications of the findings are discussed. PMID- 29617197 TI - Diagnosis or Diagnosing? From Symptoms to a Phenomenological-Psychoanalytic Stance on the Patient's World. AB - While on the one hand therapists can count on a number of codified and standardized diagnostic procedures, on the other hand it is hard to believe that in their daily work therapists slavishly follow these standardized procedures. In a clinical assessment, the diagnosis seems to be the outcome of a naive and fuzzy process that is strongly influenced by personal training, by, theoretical models, and by one's masters as well as the experience gained in the field. What happens inside the no man's land of the clinical encounter? Can we identify some landmarks in these "amoeboid" exploratory moves? This paper addresses diagnosis not only as a noun or name ("diagnosis"), but also as a verb ("diagnosing"), arguing that a diagnostic space opens up thanks to an oscillatory state of mind that emerges at the intersection of different ways of looking "through" the symptom. PMID- 29617199 TI - Hiding in Plain Sight: Appreciating the Significance of Women's Secondary Psychosexuality. AB - Women's psychosexuality remains an underdeveloped area in mainstream psychoanalysis. The paper argues for psychoanalytic recognition of women's secondary psychosexual development, that is, an extended developmental vantage point that includes women's pubertal and reproductive experiences. The author's arguments are illustrated through in-depth interview data from a research project that was conducted with mothers from thirty to sixty years old. The author proposes that women are subjected to at least three types of psychological conflict related to their secondary psychosexual events and processes. As a consequence of this, significant psychological challenge is encountered, but also the potential for substantial psychological growth. The three groupings of conflict have been formulated as Bodily evacuations: Continence versus incontinence; Bodily unpredictability: Plasticity versus constancy; and Bodily prohibitions: Social policing versus personal agency. Menstruation and lactation are discussed in relation to these three categories of conflict. PMID- 29617201 TI - Some Thoughts on Self-Disclosure. AB - This paper explores the pros and cons of self-disclosure and self revelation in the analyst. It takes as its starting point a paper by Jeffrey Stern that shows a mixed but generally positive outcome of an incident of self-disclosure. The trend in more recent times has been toward somewhat more self-disclosure, with modern analysts' views on a continuum. The author discusses an example from his own practice, in which he delayed self-disclosure for some time, but did reveal facts about himself, and how this had a mostly positive outcome. He concludes by distinguishing self-disclosure that entails stating facts about self from self revelation, when the analyst tells his feelings about some specifics from his own life or in the patient's disclosure. Such revelation is not likely to be beneficial to the therapeutic alliance in its early stages, but may be of value as the analytic relationship and trust develop over longer time. PMID- 29617203 TI - Get Out: A Study of Interracial Dynamics in an Unrepaired and Unrepentant America A Modern Day Racial Horror. PMID- 29617202 TI - The Psychoanalyst's Resistance to the Task of Proof. AB - Freud's letters and papers indicate that his emotions interfered with his endeavor to justify his theories to an unsympathetic public. His example suggests that a psychoanalyst who wishes to prove the validity of psychoanalysis to critics may experience strong and unpalatable emotions that in turn stimulate defense mechanisms, such as avoidance of proving activities. While Freud habitually observed the public's resistance to psychoanalytic ideas, he overlooked the possibility of his own resistance to presenting them. Those who are interested in pursuing scientific validation of psychoanalytic theories and efficacy may wish to consider whether psychoanalysts' emotional resistances have contributed to the psychoanalytic community's halting approach to validation and the presentation of proof. PMID- 29617204 TI - Services, Stigma, and Discrimination: Perceptions of African Descendant Men Living with HIV/AIDS in Brazil and in the United States. AB - This study aimed to give voice to 13 men of African descent from Salvador, Brazil, and East Texas, United States, living with HIV/AIDS regarding their perceptions on accessibility of services, and the stigma and discrimination they experience. Phenomenological research using in-depth interviews was used as methodology. Five themes emerged from the data analysis: perception of positive health, services and accessibility, not disclosing HIV status is a way to be protected, health professionals untrained in treating people living with HIV/AIDS, being of African descent increases discrimination in both countries, education would decrease stigma and discrimination. This study addresses how stigma and discrimination experienced by these men violate their human rights, and the need of policies to mitigate these practices. PMID- 29617205 TI - A Novel Method to Extend a Partial-Body CT for the Reconstruction of Dose to Organs beyond the Scan Range. AB - Epidemiological investigation is an important approach to assessing the risk of late effects after radiotherapy, and organ dosimetry is a crucial part of such analysis. Computed tomography (CT) images, if available, can be a valuable resource for individualizing the dosimetry, because they describe the specific anatomy of the patient. However, CT images acquired for radiation treatment planning purposes cover only a portion of the body near the target volume, whereas for epidemiology, the interest lies in the more distant normal tissues, which may be located outside the scan range. To address this challenge, we developed a novel method, called the Anatomically Predictive Extension (APE), to extend a partial-body CT image stack using images of a computational human phantom matched to the patient based on their height and weight. To test our method, we created five APE phantoms from chest and abdominal images extracted from the chest-abdomen-pelvis (CAP) CT scans of five patients. Organ doses were calculated for simple chest and prostate irradiations that were planned on the reference computational phantom (assumed patient geometry if no CT images are available), APE phantoms (patient-phantom hybrid given a partial-body patient CT) and full patient CAP CT scans (ground truth). The APE phantoms and patient CAP CT scans resulted in nearly identical dosimetry for those organs that were fully included in the partial-body CT used to construct the APE. The calculated doses to these same organs in the reference phantoms differed by up to 20% and 52% for the chest and prostate cases, respectively. For organs outside the scan coverage, the reference phantom showed, on average, dose differences of 31% (chest case) and 41% (prostate case). For the APE phantoms, these values were 26% (chest) and 17% (prostate). The APE method combines patient and phantom images to improve organ dosimetry both inside and outside the scan range. We intend to use the APE method for estimating dose for organs peripheral to the treatment fields; however, this method is quite generalizable with many potential applications. PMID- 29617206 TI - The Identification of Reasons, Solutions, and Techniques Informing a Theory-Based Intervention Targeting Recreational Sports Participation. AB - PURPOSE: This study is the 3rd piece of formative research utilizing the theory of planned behavior to inform the development of a behavior change intervention. Focus groups were used to identify reasons for and solutions to previously identified key beliefs in addition to potentially effective behavior change techniques. METHOD: A purposive sample of 22 first-year undergraduate students (n = 8 men; Mage = 19.8 years, SD = 1.3 years) attending a university in the North of England was used. Focus groups were audio-recorded; recordings were transcribed verbatim, analyzed thematically, and coded for recurrent themes. RESULTS: The data revealed 14 reasons regarding enjoyment, 11 reasons for friends' approval, 11 reasons for friends' own participation, 14 reasons for the approval of family members, and 10 solutions to time constraints. Twelve distinct techniques were suggested to attend to these reasons and solutions. CONCLUSION: This qualitative research will be used to inform the development of a theory based intervention to increase students' participation in university recreational sports. PMID- 29617207 TI - Impact of Balance Confidence on Daily Living Activities of Older People with Knee Osteoarthritis with Regard to Balance, Physical Function, Pain, and Quality of Life - A Preliminary Report. AB - OBJECTIVES: The objective of this study was to explore the impact of balance confidence on different activities of daily living (ADL) in older people with knee osteoarthritis (OA). METHODS: Forty-seven consecutive participants with knee OA were included in this cross-sectional study. They were divided according to the results of the Activities-specific Balance Confidence (ABC) Scale into a group with a low level of confidence in physical functioning (ABC < 50, n = 22) and a group with moderate and high levels of confidence (ABC >= 50, n = 25). RESULTS: In the ABC < 50 group, the effect of pain on ADL, the physician's global assessment of the disease, and the Western Ontario and McMaster Universities Osteoarthritis Index scores were significantly higher, while quality of life (Short form-36) was lower compared to the ABC >= 50 group. No significant difference was found between the two groups regarding the static and dynamic balance measurements. CONCLUSIONS: Older people with knee OA who were less confident in their daily physical activities had more physical difficulties and a greater effect of pain on ADL, lower quality of life, and a higher physician's global assessment, but no differences were obtained in balance tests. CLINICAL IMPLICATIONS: In people with knee OA, decreased balance confidence is associated with more physical difficulties, an increased effect of pain on ADL, and lower quality of life. An improved awareness of decreased balance confidence may lead to more effective management of older people with knee OA by improving their mobility and QOL through rehabilitation. Furthermore, future research in that direction is warranted. PMID- 29617208 TI - Analysis of Prehospital Scene Times and Interventions on Mortality Outcomes in a National Cohort of Penetrating and Blunt Trauma Patients. AB - BACKGROUND: Recent studies have suggested improved outcomes in victims of penetrating trauma managed with shorter prehospital times and limited interventions. The purpose of the current study was to perform an outcome analysis of patients transported following penetrating and blunt traumatic injuries. METHODS: We performed a descriptive retrospective analysis of the 2014 National Emergency Medical Services Information System (NEMSIS) public release research data set for patients presenting after acute traumatic injury. RESULTS: A total of 2,018,141 patient encounters met criteria, of which 3.9% were penetrating trauma. Prehospital cardiac arrest occurred in 0.5% blunt and 4.2% penetrating trauma patients. Emergency department (ED) mortality was higher in penetrating than blunt trauma patients (4.1% vs. 0.8%). Scene times were 18.1 +/- 36.5 minutes for blunt and 16.0 +/- 45.3 minutes for penetrating trauma. Mean scene time for blunt trauma patients who died in the ED was 24.9 +/- 58.0 minutes compared with 18.8 +/- 38.5 minutes for those admitted; for penetrating trauma, scene times were 17.9 +/- 23.5 and 13.4 +/- 11.6 minutes, respectively. Mean number of procedures performed for blunt trauma patients who died in the ED was 6.5 +/- 4.3 compared with 3.1 +/- 2.3 for those who survived until admission; for penetrating trauma, the numbers of procedures performed were 5.7 +/- 3.4 and 2.6 +/- 2.0, respectively. CONCLUSIONS: Although less frequent than blunt trauma, penetrating trauma is associated with significantly higher prehospital and ED mortality. Increased scene time and number of procedures was associated with greater mortality for both blunt and penetrating trauma. Further study is required to better understand any causal relationships between prehospital times and interventions and patient outcomes. PMID- 29617209 TI - Differences in the Stimulus Accommodative Convergence/Accommodation Ratio using Various Techniques and Accommodative Stimuli. AB - PURPOSE: To investigate differences in the stimulus accommodative convergence/accommodation (AC/A) ratio using various techniques and accommodative stimuli, and to describe a method for determining the stimulus AC/A ratio. METHODS: A total of 81 subjects with a mean age of 21 years (range, 20-23 years) were enrolled. The relationship between ocular deviation and accommodation was assessed using two methods. Ocular deviation was measured by varying the accommodative requirement using spherical plus/minus lenses to create an accommodative stimulus of 10.00 diopters (D) (in 1.00 D steps). Ocular deviation was assessed using the alternate prism cover test in method 1 at distance (5 m) and near (1/3 m), and the major amblyoscope in method 2. The stimulus AC/A ratios obtained using methods 1 and 2 were calculated and defined as the stimulus AC/A ratios with low and high accommodation, respectively, using the following analysis method. The former was calculated as the difference between the convergence response to an accommodative stimulus of 3 D and 0 D, divided by 3. The latter was calculated as the difference between the convergence response to a maximum (max) accommodative stimulus with distinct vision of the subject and an accommodative stimulus of max minus 3.00 D, divided by 3. RESULTS: The median stimulus AC/A ratio with low accommodation (1.0 Delta/D for method 1 at distance, 2.0 Delta/D for method 1 at near, and 2.7 Delta/D for method 2) differed significantly among the measurement methods (P < 0.01). Differences in the median stimulus AC/A ratio with high accommodation (4.0 Delta/D for method 1 at distance, 3.7 Delta/D for method 1 at near, and 4.7 Delta/D for method 2) between method 1 at distance and method 2 were statistically significant (P < 0.05), while method 1 at near was not significantly different compared with other methods. CONCLUSIONS: Differences in the stimulus AC/A ratio value were significant according to measurement technique and accommodative stimuli. However, differences caused by measurement technique may be reduced by using a high accommodative stimulus during measurements. PMID- 29617210 TI - Effect of omega-3 fatty acids supplementation during pregnancy on lung function in preschoolers: a clinical trial. AB - RATIONALE: Prenatal omega-3 fatty acids improve alveolarization, diminish inflammation, and improve pulmonary growth, but it is unclear whether these outcomes translate into improved postnatal lung function. OBJECTIVE: We assessed the effect of prenatal supplementation with docosahexaenoic acid (DHA) on offspring lung function through 60 months of age. METHODS: We included a cohort of 772 Mexican preschoolers whose mothers participated in a clinical trial (NCT00646360) of supplementation with DHA or a placebo from week 18-22 of gestation through delivery. MEASUREMENTS: The children were followed after birth and anthropometric measurements and forced oscillation tests were performed at 36, 48, and 60 months of age. The effect of DHA was tested using a longitudinal mixed effect models. RESULTS: Overall, mean (Standard Deviation) of the measurements of respiratory system resistance and respiratory system reactance at 6, 8, and 10 Hz during follow up period were 11.3 (2.4), 11.1 (2.4), 10.3 (2.2) and -5.2 (1.6), -4.8 (1.7), -4.6 (1.6), respectively. There were no significant differences in pulmonary function by treatment group. DHA did not affect the average lung function or the trajectories through 60 months. CONCLUSIONS: Prenatal DHA supplementation did not influence pulmonary function in this cohort of Mexican preschoolers. PMID- 29617211 TI - Systemic inflammatory status is associated with increased platelet reactivity in the early period after acute coronary syndromes. AB - Systemic inflammation measured by high-sensitivity C reactive protein (CPR) is associated with increased risk of major adverse cardiovascular events (MACE). Recent clinical trials targeting CPR showed a reduction in MACE after an acute coronary syndrome (ACS). Inflammation could be linked to high platelet reactivity (HPR), which is an independent predictor of MACE in patients with ACS. We aimed to evaluate the impact of 1-month C-reactive Protein (CRP) levels on HPR in patients enrolled in the GEPRESS study. We measured CRP and platelet reactivity index (PRI) at 30 days follow-up. PRI was assessed with vasodilator stimulated phosphoprotein (VASP) phosphorylation assay at the same timepoint. HPR was defined as PRI >50%. Of the 1042 patients included in the GEPRESS study, 756 (75%) had both VASP and CRP data at 30 days follow-up. HPR was found in 61 (49.1%) patients with CRP >1 mg/L and 233 (36.4%) patients with CRP <=1 mg/L, p = 0.012. After adjustment for covariates, we found a direct gradient of effect between CRP and HPR; the inclusion of CRP significantly increased the discrimination of HPR regression model. This is the first study showing that residual HPR is more likely to occur in patients with CRP >1 mg/L at 1 month after non-ST elevation-ACS and this may contribute to the unfavorable outcome observed in such patients. PMID- 29617212 TI - Physical Education Preservice Teachers' Perceptions About Preparation for Comprehensive School Physical Activity Programs. AB - PURPOSE: Physical educators may be the responsible people for implementing comprehensive school physical activity programs (CSPAPs) in schools. However, it is unclear whether physical education teacher education (PETE) programs provide the relevant learning opportunities to preservice teachers for CSPAP implementation. The purpose of this study was to understand preservice teachers' perspectives and experiences of CSPAP preparation in their PETE programs. METHOD: Fourteen PETE students from 6 different universities participated and shared their experiences in PETE programs. Data were collected through a short survey, 1 formal interview, field images, document gathering, and an additional survey to follow up the interview. Descriptive statistics, constant comparison, and analytic induction techniques were used to analyze the data. RESULTS: Participants' familiarity with CSPAPs was related to positive opinions about the role of physical educators in CSPAPs. Three common themes were revealed: (a) introducing CSPAP via courses, (b) the lack of programwide hands-on experiences for CSPAP, and (c) limited preparation for social skills with stakeholders. Participants' perceptions of the role of physical educators as physical activity leaders had been expanded during their training. CONCLUSION: The participating PETE programs integrated CSPAP components in the existing courses to introduce CSPAP, while there was a lack of sufficient practical opportunities to learn how to implement (aspects of) a CSPAP. Participants felt they were insufficiently prepared to promote and implement expanded physical activity programming beyond physical education classes in schools. The majority of the PETE preservice teachers wanted more practical CSPAP experiences in their programs. PMID- 29617213 TI - Child-Parent Relationship Therapy with Extra-Familial Abused Children. AB - Sexual abuse by a perpetrator outside of the family is the most prevalent form of child sexual abuse. It is associated with serious consequences for both the child and his family. Surprisingly, however, the issue of extra-familial sexual abuse has received very little research and clinical attention. The purpose of the current study was to explore the effectiveness of Child-Parent Relationship Therapy (CPRT), which uses nondirective play therapy tools, among parents of extra-familial abused children and their parents. In order to do so, data was collected from 51 parents who participated in CPRT, at three points in time: pretreatment stage, at the beginning of the first meeting; and in the post treatment stage. The data included the parents' reports via three questionnaires: Parenting Stress Inventory (PSI), Compassion Fatigue Self-Test (CFST), Child Behavior Checklist (CBCL). Overall, the results indicated a decrease in internalizing and externalizing symptoms among the children, as well as in parenting stress and in parental secondary trauma symptoms. This study contributes to the literature on interventions with victims of extra-familial child abuse and their parents. Specifically, the results highlight the benefits and importance of involving both parents and children in therapeutic interventions for victims of extra-familial child sexual abuse, with particular emphasis on the benefits of Child-Parent Relationship Therapy. PMID- 29617214 TI - Individual Differences Influencing Immediate Effects of Internal and External Focus Instructions on Children's Motor Performance. AB - PURPOSE: A large pool of evidence supports the beneficial effect of an external focus of attention on motor skill performance in adults. In children, this effect has been studied less and results are inconclusive. Importantly, individual differences are often not taken into account. We investigated the role of working memory, conscious motor control, and task-specific focus preferences on performance with an internal and external focus of attention in children. METHODS: Twenty-five children practiced a golf putting task in both an internal focus condition and external focus condition. Performance was defined as the average distance toward the hole in 3 blocks of 10 trials. Task-specific focus preference was determined by asking how much effort it took to apply the instruction in each condition. In addition, working memory capacity and conscious motor control were assessed. RESULTS: Children improved performance in both the internal focus condition and external focus condition (np2 = .47), with no difference between conditions (np2 = .01). Task-specific focus preference was the only factor moderately related to the difference between performance with an internal focus and performance with an external focus (r = .56), indicating better performance for the preferred instruction in Block 3. CONCLUSION: Children can benefit from instruction with both an internal and external focus of attention to improve short-term motor performance. Individual, task-specific focus preference influenced the effect of the instructions, with children performing better with their preferred focus. The results highlight that individual differences are a key factor in the effectiveness in children's motor performance. The precise mechanisms underpinning this effect warrant further research. PMID- 29617215 TI - Phrenic long-term depression evoked by intermittent hypercapnia is modulated by serotonergic and adrenergic receptors in raphe nuclei. AB - Intermittent hypercapnia evokes prolonged depression of phrenic nerve activity (phrenic long-term depression, pLTD). This study was undertaken to investigate the role of 5-HT and alpha2-adrenergic receptors in the initiation of pLTD. Adult male urethane-anesthetized, vagotomized, paralyzed, and mechanically ventilated Sprague-Dawley rats were exposed to a protocol of acute intermittent hypercapnia (AIHc; 5 episodes of 15% CO2 in air, each episode lasting 3 min). The experimental group received microinjection of the selective 5-HT1A receptor agonist 8-hydroxy-2-(dipropylamino)tetralin hydrobromide (8-OH-DPAT), the broad spectrum 5-HT antagonist methysergide, or the alpha2-adrenergic antagonist yohimbine, whereas the control group received microinjection of 0.9% saline into the caudal raphe region. Peak phrenic nerve activity (pPNA) and burst frequency ( f) were analyzed during baseline (T0), during 5 hypercapnic episodes (THc1-THc5), and at 15, 30, and 60 min after the end of the last hypercapnic episode. In the control group, pPNA decreased 60 min after the end of the last hypercapnic episode compared with baseline values, i.e., pLTD developed ( P = 0.023). In the 8-OH-DPAT group, pPNA significantly decreased at T15, T30, and T60 compared with baseline values, i.e., pLTD developed ( P = 0.01). In the methysergide and yohimbine groups, AIHc did not evoke significant changes of the pPNA at T15, T30, and T60 compared with baseline values. In conclusion, activation of 5-HT1A receptors accentuated induction of pLTD, whereas blockade of alpha2-adrenergic receptors prevented development of pLTD following AIHc in anesthetized rats. These results suggest that chemical modulation of 5-HT and alpha2-adrenergic receptors in raphe nuclei affects hypercapnia-induced pLTD, offering important insights in understanding the mechanisms involved in development of respiratory plasticity. NEW & NOTEWORTHY Hypercapnia is a concomitant feature of many breathing disorders, including obstructive sleep apnea. In this study, acute intermittent hypercapnia evoked development of phrenic long-term depression (pLTD) 60 min after the last hypercapnic episode that was preserved if the selective 5-HT1A receptor agonist 8-hydroxy-2-(dipropylamino)tetralin hydrobromide was microinjected in the caudal raphe region before the hypercapnic stimulus. This study highlights that both 5-HT and adrenergic receptor activation is needed for induction of pLTD in urethane-anesthetized rats following intermittent hypercapnia exposure. PMID- 29617216 TI - Effect of standing posture on inhibitory postsynaptic potentials in gastrocnemius motoneurons. AB - This study examined the task dependence of sensory inputs on motoneuron excitability by comparing the inhibitory postsynaptic potential (IPSP) evoked by stimulation of the sural nerve between a standing postural task (Free Standing) and a comparable voluntary isometric contraction performed in a supine position (Lying Supine). We hypothesized that there would be a smaller IPSP in standing than in the supine position, based on the task dependence of the ankle plantarflexor activity on the standing task. Ten healthy participants participated in a total of 15 experiments. Single motor unit (MU) firings were recorded with both intramuscular fine-wire electrodes and high-density surface electromyography. Participants maintained the MU discharge at 6-8 Hz in Free Standing or Lying Supine while the right sural nerve was stimulated at random intervals between 1 and 3 s. To evaluate the reflex response, the firing times of the discriminated MUs were used to construct peristimulus time histograms and peristimulus frequencygrams. The sural nerve stimulation resulted in weaker inhibition in Free Standing than in Lying Supine. This finding is discussed in relation to the putative activation of persistent inward currents in standing posture and the task-dependent advantages of overriding inhibitory synaptic inputs to the plantarflexors to maintain the standing posture. NEW & NOTEWORTHY The task-dependent modulation of sensory inputs on motoneuron excitability in standing is not well understood. Evoking an inhibitory postsynaptic potential (IPSP) resulted in a smaller IPSP in gastrocnemius motoneurons in standing than in the supine position. Mildly painful sensory inputs produced weaker motoneuron inhibition in standing, suggesting an imperative to maintain ankle plantarflexion activity for the task of upright stance. PMID- 29617217 TI - Emphasizing the "positive" in positive reinforcement: using nonbinary rewarding for training monkeys on cognitive tasks. AB - Nonhuman primates constitute an indispensable model system for studying higher brain functions at the neurophysiological level. Studies involving these animals elucidated the neuronal mechanisms of various cognitive and executive functions, such as visual attention, working memory, and decision-making. Positive reinforcement training (PRT) constitutes the gold standard for training animals on the cognitive tasks employed in these studies. In the laboratory, PRT is usually based on application of a liquid reward as the reinforcer to strengthen the desired behavior and absence of the reward if the animal's response is wrong. By trial and error, the monkey may adapt its behavior and successfully reduce the number of error trials, and eventually learn even very sophisticated tasks. However, progress and success of the training strongly depend on reasonable error rates. If errors get too frequent, they may cause a drop in the animal's motivation to cooperate or its adaptation to high error rates and poor overall performance. We introduce in this report an alternative training regime to minimize errors and base the critical information for learning on graded rewarding. For every new task rule, the feedback to the animal is provided by different amounts of reward to distinguish the desired, optimal behavior from less optimal behavior. We applied this regime in different situations during training of visual attention tasks and analyzed behavioral performance and reaction times to evaluate its effectiveness. For both simple and complex behaviors, graded rewarding was found to constitute a powerful technique allowing for effective training without trade-off in accessible task difficulty or task performance. NEW & NOTEWORTHY Laboratory training of monkeys usually builds on providing a fixed amount of reward for the desired behavior, and no reward otherwise. We present a nonbinary, graded reward schedule to emphasize the positive, desired behavior and to keep errors on a moderate level. Using data from typical training situations, we demonstrate that graded rewards help to effectively guide the animal by success rather than errors and provide a powerful new tool for positive reinforcement training. PMID- 29617218 TI - Computational model of brain-stem circuit for state-dependent control of hypoglossal motoneurons. AB - In patients with obstructive sleep apnea (OSA), the pharyngeal muscles become relaxed during sleep, which leads to a partial or complete closure of upper airway. Experimental studies suggest that withdrawal of noradrenergic and serotonergic drives importantly contributes to depression of hypoglossal motoneurons and, therefore, may contribute to OSA pathophysiology; however, specific cellular and synaptic mechanisms remain unknown. In this new study, we developed a biophysical network model to test the hypothesis that, to explain experimental observations, the neuronal network for monoaminergic control of excitability of hypoglossal motoneurons needs to include excitatory and inhibitory perihypoglossal interneurons that mediate noradrenergic and serotonergic drives to hypoglossal motoneurons. In the model, the state-dependent activation of the hypoglossal motoneurons was in qualitative agreement with in vivo data during simulated rapid eye movement (REM) and non-REM sleep. The model was applied to test the mechanisms of action of noradrenergic and serotonergic drugs during REM sleep as observed in vivo. We conclude that the proposed minimal neuronal circuit is sufficient to explain in vivo data and supports the hypothesis that perihypoglossal interneurons may mediate state-dependent monoaminergic drive to hypoglossal motoneurons. The population of the hypothesized perihypoglossal interneurons may serve as novel targets for pharmacological treatment of OSA. NEW & NOTEWORTHY In vivo studies suggest that during rapid eye movement sleep, withdrawal of noradrenergic and serotonergic drives critically contributes to depression of hypoglossal motoneurons (HMs), which innervate the tongue muscles. By means of a biophysical model, which is consistent with a broad range of empirical data, we demonstrate that the neuronal network controlling the excitability of HMs needs to include excitatory and inhibitory interneurons that mediate noradrenergic and serotonergic drives to HMs. PMID- 29617219 TI - Mu-oscillation changes related to the development of anticipatory postural control in children and adolescents. AB - Anticipatory postural adjustments (APAs) cancel the destabilizing effects of movement on posture. Across development, the maturation of APAs is characterized by an accurate adjustment of the timing parameters of electromyographic (EMG) response. The study aimed at investigating the maturation of cortical oscillations involved in the improvement of APAs efficiency. Thirty-six healthy participants (8-16 yr) performed the bimanual load-lifting task in which subjects are instructed to lift a load, placed on the left forearm, with the right hand. EMG data were acquired over the biceps brachii on the postural arm to the determine EMG response onset. Electroencephalographic signals were analyzed in the time-frequency domain by convolution with complex Gaussian Morlet wavelets. Electrophysiological signature of APAs in children and adolescents consisted of a mu-rhythm desynchronization over the sensorimotor cortex contralateral to the postural arm. Across development, the mu-rhythm desynchronization was characterized by a progressive shift forward of the onset of the desynchronization, lower amplitude, and velocity. These changes occurred along with an alteration of the timing of the EMG response, as shown by an earlier onset of the flexor inhibition with increasing age. The maturational changes in the Mu-oscillations might sustain the development of APAs. A possible role of the Mu-oscillation in the generation of postural command is discussed. NEW & NOTEWORTHY Across development, our study showed a progressive shift forward of the parameters of the mu-rhythm desynchronization. These changes occurred along with an alteration of the timing parameters of the electromyographic response, as shown by an earlier onset of the flexor inhibition with increasing age. The progressive development of APAs during childhood and adolescence might therefore be sustained by maturational electrophysiological changes that include mu-rhythm oscillation modifications in the postural sensorimotor cortex. PMID- 29617220 TI - The Association of Dietary and Urinary Sodium With Bone Mineral Density and Risk of Osteoporosis: A Systematic Review and Meta-Analysis. AB - OBJECTIVE: Although some earlier studies have indicated an association between dietary/urinary sodium and bone mass density (BMD), bone mass content (BMC), and the risk of osteoporosis (OS), findings are still conflicting. The aim of this study was to summarize the relation of dietary/urinary sodium with BMD, BMC, and the risk of OS. METHODS: We conducted a systematic search up to April 2017 in PubMed/MEDLINE, SCOPUS, and Web of Science to find relevant studies. Articles with cross-sectional and cohort designs in which odds ratios (ORs), correlations (r), or beta coefficients were reported for the association between dietary/urinary sodium and OS, BMD, or BMC were included. RESULTS: Pooling 11 effect sizes with a total of 39,065 people showed that higher sodium consumption significantly increased the risk of OS (OR = 1.20; 95% confidence interval [CI], 1.02-1.41; p = 0.026), with high heterogeneity among studies (I2 = 68.0%; p = 0.001). Subgroup analyses showed significantly higher risk of OS in premenopausal women (OR = 1.31; 95% CI, 1.01-1.69; p = 0.036), in participants with a mean age older than 50 years (OR = 1.15; 95% CI, 1.04-1.28; p = 0.005), in dietary sodium intake subgroup (OR = 1.45; 95% CI, 1.19-1.77; p < 0.001), and in individuals with adjustment for energy (OR = 1.77; 95% CI, 1.38-2.27; p < 0.001). The correlation coefficients showed no significant association between urinary sodium and BMD (r = -0.46; 95% CI, -0.74 to -0.18; p = 0.02). CONCLUSIONS: We found a positive association between sodium intake and the risk of OS, while no association was found with urinary sodium. Furthermore, there was no significant correlation between sodium intake and BMD. Due to high heterogeneity in this research, more studies are suggested. PMID- 29617221 TI - The Effects of Mindfulness-Based Interventions on Diabetes-Related Distress, Quality of Life, and Metabolic Control Among Persons with Diabetes: A Meta Analytic Review. AB - Mindfulness-based interventions (MBIs) have improved psychological outcomes for multiple chronic health conditions, including diabetes. A meta-analytic review of the literature was conducted on all located studies (n = 14) investigating MBIs that targeted diabetes-related distress (DRD) and diabetes-related outcomes among people with Type 1 and Type 2 diabetes. PsychInfo, PubMed, Medline, and Web of Science were searched for MBIs that were designed to improve DRD and other secondary outcomes, including quality of life and measures of metabolic control. A meta-analysis of these outcomes uncovered small-to-moderate effect sizes for intervention studies measuring pretreatment to posttreatment changes in DRD and metabolic control among treatment group participants. However, the pretreatment to follow-up comparisons for DRD and metabolic control were small and unreliable. For control groups, all pre-treatment to post-treatment and pre-treatment to follow-up comparisons were unreliable for all outcomes. A moderate effect size for treatment-control comparisons was found for intervention studies measuring quality of life outcomes at posttreatment, but not at follow-up comparisons. All other effect sizes for treatment-control comparisons were unreliable. Limitations and implications for MBIs among individuals with diabetes are discussed. PMID- 29617222 TI - Year of reckoning for women in science. PMID- 29617223 TI - Turkish Medical Association-detained for peace. PMID- 29617224 TI - Stroke-acting FAST at all ages. PMID- 29617225 TI - Mentoring women in medicine: a personal perspective. PMID- 29617226 TI - Offline: Welcome to the new Age of Romanticism. PMID- 29617227 TI - National Health Protection Scheme revealed in India. PMID- 29617228 TI - Health under austerity in Greece. PMID- 29617229 TI - A global girl gang. PMID- 29617230 TI - Robin West breaks gender barriers in US football and baseball. PMID- 29617231 TI - Art and oncology: one life. PMID- 29617232 TI - Reducing health disparities: Bar Ilan Medical School's care transition service. PMID- 29617233 TI - Protecting Rohingya: lives, minds, and the future. PMID- 29617234 TI - Health equity in Israel. PMID- 29617235 TI - Health equity in Israel. PMID- 29617236 TI - Health equity in Israel. PMID- 29617237 TI - Health equity in Israel - Authors' reply. PMID- 29617238 TI - Inequalities in non-communicable diseases in Israel. PMID- 29617239 TI - Shared values cannot redress the occupier-occupied imbalance. PMID- 29617240 TI - Inequalities in non-communicable diseases in Israel - Authors' reply. PMID- 29617241 TI - Women's health in Israel. PMID- 29617242 TI - Medical ethics in Israel - Author's reply. PMID- 29617243 TI - Medical ethics in Israel. PMID- 29617244 TI - Deaths of children and women in Gaza hostilities. PMID- 29617245 TI - Deaths of children and women in Gaza hostilities - Authors' reply. PMID- 29617247 TI - Examining humanitarian principles in changing warfare. PMID- 29617248 TI - What's next for Indigenous health in Australia? PMID- 29617249 TI - Asthma in US children. PMID- 29617250 TI - Amending the EU Withdrawal Bill: a safeguard for health. PMID- 29617251 TI - Primary care research: a call for papers. PMID- 29617252 TI - Offline: Apostasy against the public health elites. PMID- 29617253 TI - CDC faces leadership changes, potential spending cuts. PMID- 29617254 TI - Yemeni health under relentless pressure. PMID- 29617255 TI - End of a cholera epidemic in South Sudan declared. PMID- 29617256 TI - Schizophrenia. PMID- 29617257 TI - Life behind bars. PMID- 29617259 TI - Medical 3D printing and the physician-artist. PMID- 29617258 TI - Gabriel Leung: working for a healthier Hong Kong. PMID- 29617261 TI - Germany's contribution to global health. PMID- 29617262 TI - Dengue vaccination: a more balanced approach is needed. PMID- 29617263 TI - Germany needs to catch up in global health research. PMID- 29617264 TI - Germany must invest in its global health academic workforce. PMID- 29617265 TI - Germany's expanding role in global health. PMID- 29617266 TI - Germany's expanding role in global health. PMID- 29617267 TI - Germany's expanding role in global health - Authors' reply. PMID- 29617268 TI - Antidiabetic and renoprotective effect of Anogeissus acuminata leaf extract on experimentally induced diabetic nephropathy. AB - Background Diabetic nephropathy is the leading cause of end-stage renal disease. Hyperglycemia, oxidative stress, and inflammation are some of the mechanisms involved in renal damage. Anogeissus acuminata (AA) is used in India as an antidiabetic agent and has potent antioxidant activity. However, it has never been evaluated for its effect on diabetic nephropathy. Hence, in the present study we aimed to evaluate its effect on streptozotocin-induced diabetes mellitus and its renal complications. Methods Diabetes mellitus was induced by injecting streptozotocin, 50 mg/kg, i.p. in rats fasted for 6 h. Rats with hyperglycemia were treated with extracts of AA for 8 weeks at doses of 100 and 300 mg/kg, orally. Human NPH insulin (4 IU/kg, s.c.) was used as standard treatment. Plasma glucose levels (at weeks 1, 2, 4, and 8) and oxidative stress parameters (at weeks 2 and 4) were assessed. Effect on diabetic nephropathy was evaluated by recording the urinary volume, urinary protein excretion, kidney weights, serum creatinine, and blood urea nitrogen levels at week 8. Results Methanolic extract of AA leaves produced statistically significant (p<0.05) hypoglycemic and antioxidant effect. It also resulted in improved urinary function, reflected by better urinary volume and reduced protein excretion in urine. AA treatment could prevent the elevation of serum creatinine and blood urea nitrogen level in a dose dependent manner. Kidney hypertrophy could be attenuated remarkably, as reflected by the significantly lower kidney weight (KW) per 100 g body weight (p<0.05). Conclusions AA leaf extract attenuated the development of diabetic nephropathy and also demonstrated antidiabetic and antioxidant action. PMID- 29617270 TI - Implementation of physiological fluids to provide insight into the characterization, fate, and biological interactions of silver nanoparticles. AB - Silver nanoparticles (AgNPs) are being increasingly utilized in consumer and medical applications. However, there remains conflicting reports on their safety, which are evaluated through a combination of in vitro and in vivo exposure models. These discrepancies may arise, in part, due to the inherent differences between cell-based and animal systems. It is well established that nanotoxicological effects are highly dependent on the unique physicochemical properties and behavior of the particle set, including size, surface chemistry, agglomeration, and ionic dissolution. However, recent studies have identified that these properties vary as a function of exposure environment; providing a rationale for the contradictory results between in vitro and in vivo assessments. Artificial physiological fluids are emerging as a powerful tool as they allow for the characterization of NPs in an environment which they would likely encounter in vivo, in addition to having the experimental advantages of flexibility and consistency. Here, we demonstrated that the utilization of artificial fluids provided a mechanism to assess AgNP behavior and induced bioresponses in environments that they would likely encounter in vivo. AgNPs were introduced within an alveolar-based exposure model, which included alveolar epithelial (A549) cells incubated within artificial alveolar fluid (AF). Additionally, the particles underwent extensive characterization within both AF and lysosomal fluid, which the AgNPs would encounter following cellular internalization. Following incubation in physiological environments AgNP properties were significantly modified versus a traditional media environment, including alterations to both extent of agglomeration and rate of ionic dissolution. Moreover, when A549s were exposed to AgNPs in AF, the cells displayed lower cytotoxicity and stress rates, corresponding to a fluid-dependent drop in silver ion production. This work highlights the need for enhanced in vitro models that more closely mimic in vivo exposure environments in order to capture true NP behaviors and cellular interactions. PMID- 29617269 TI - Complementary and alternative medicine usage and its determinant factors among Iranian infertile couples. AB - Background The aim of this study was to determine the status of utilizing some complementary and alternative medicine techniques in infertile couples. Methods This was a cross-sectional study conducted on 250 infertile couples referred to a hospital in Kerman using convenience sampling. A researcher-made questionnaire was used to study the prevalence and user satisfaction of complementary and alternative medicines. Results Results indicated that 49.6% of the infertile couples used at least one of the complementary and alternative medicines during the past year. Most individuals used spiritual techniques (71.8% used praying and 70.2% used Nazr) and medicinal plants (54.8%). Safety is the most important factor affecting the satisfaction of infertile couples with complementary treatments (couples think that such treatments are safe (54.8%)). Discussion Concerning high prevalence of complementary and alternative treatments in infertile couples, incorporating such treatments into the healthcare education and promoting the awareness of infertile individuals seem crucial. PMID- 29617271 TI - Lattice QCD and heavy ion collisions: a review of recent progress. AB - In the last few years, numerical simulations of Quantum chromodynamics on the lattice have reached a new level of accuracy. A wide range of thermodynamic quantities is now available in the continuum limit and for physical quark masses. This allows a comparison with measurements from heavy ion collisions for the first time. Furthermore, calculations of dynamical quantities are also becoming available. The combined effort from first principles and experiment allows us to gain an unprecedented understanding of the properties of quark-gluon plasma. I will review the state-of-the-art results from lattice simulations and connect them to the experimental information from the relativistic heavy ion collider and the large hadron collider. PMID- 29617272 TI - Prediction of Protein-Protein Interactions from Amino Acid Sequences Based on Continuous and Discrete Wavelet Transform Features. AB - Protein-protein interactions (PPIs) play important roles in various aspects of the structural and functional organization of cells; thus, detecting PPIs is one of the most important issues in current molecular biology. Although much effort has been devoted to using high-throughput techniques to identify protein-protein interactions, the experimental methods are both time-consuming and costly. In addition, they yield high rates of false positive and false negative results. In addition, most of the proposed computational methods are limited in information about protein homology or the interaction marks of the protein partners. In this paper, we report a computational method only using the information from protein sequences. The main improvements come from novel protein sequence representation by combing the continuous and discrete wavelet transforms and from adopting weighted sparse representation-based classifier (WSRC). The proposed method was used to predict PPIs from three different datasets: yeast, human and H. pylori. In addition, we employed the prediction model trained on the PPIs dataset of yeast to predict the PPIs of six datasets of other species. To further evaluate the performance of the prediction model, we compared WSRC with the state-of-the art support vector machine classifier. When predicting PPIs of yeast, humans and H. pylori dataset, we obtained high average prediction accuracies of 97.38%, 98.92% and 93.93% respectively. In the cross-species experiments, most of the prediction accuracies are over 94%. These promising results show that the proposed method is indeed capable of obtaining higher performance in PPIs detection. PMID- 29617275 TI - A Serendipitous Journey Leading to My Love of Dendritic Patterns and Chemistry. AB - As the oldest of four Midwestern boys who were offsprings of an accountant and a housewife, each with less than a formal high school degree, we were blessed to have such parents.[...]. PMID- 29617273 TI - Binding Interactions of Zinc Cationic Porphyrin with Duplex DNA: From B-DNA to Z DNA. AB - Recognition of unusual left-handed Z-DNA by specific binding of small molecules is crucial for understanding biological functions in which this particular structure participates. Recent investigations indicate that zinc cationic porphyrin (ZnTMPyP4) is promising as a probe for recognizing Z-DNA due to its characteristic chiroptical properties upon binding with Z-DNA. However, binding mechanisms of the ZnTMPyP4/Z-DNA complex remain unclear. By employing time resolved UV-visible absorption spectroscopy in conjunction with induced circular dichroism (ICD), UV-vis, and fluorescence measurements, we examined the binding interactions of ZnTMPyP4 towards B-DNA and Z-DNA. For the ZnTMPyP4/Z-DNA complex, two coexisting binding modes were identified as the electrostatic interaction between pyridyl groups and phosphate backbones, and the major groove binding by zinc(II) coordinating with the exposed guanine N7. The respective contribution of each mode is assessed, allowing a complete scenario of binding modes revealed for the ZnTMPyP4/Z-DNA. These interaction modes are quite different from those (intercalation and partial intercalation modes) for the ZnTMPyP4/B-DNA complex, thereby resulting in explicit differentiation between B-DNA and Z-DNA. Additionally, the binding interactions of planar TMPyP4 to DNA were also investigated as a comparison. It is shown that without available virtual orbitals to coordinate, TMPyP4 binds with Z-DNA solely in the intercalation mode, as with B-DNA, and the intercalation results in a structural transition from Z-DNA to B ZNA. These results provide mechanistic insights for understanding ZnTMPyP4 as a probe of recognizing Z-DNA and afford a possible strategy for designing new porphyrin derivatives with available virtual orbitals for the discrimination of B DNA and Z-DNA. PMID- 29617276 TI - Toxicity Thresholds Based on EDTA Extractable Nickel and Barley Root Elongation in Chinese Soils. AB - The uncertainty in the risk assessment of trace metal elements in soils when total metal contents are used can be decreased by assessing their availability and/or extractability when the soils have a high background value or different sources of trace metal elements. In this study, the added water-soluble nickel (Ni) toxicity to barley root elongation was studied in 17 representative Chinese soil samples with and without artificial rainwater leaching. The extractability of added Ni in soils was estimated by three sequential extractions with ethylenediaminetetraacetic acid (EDTA). The results showed that the effective concentration of EDTA extractable Ni (EC50), which caused 50% inhibition of barley root elongation, ranged from 46 to 1019 mg/kg in unleached soils and 24 to 1563 mg/kg in leached soils. Regression models for EDTA extractable Ni and total Ni added to soils against soil properties indicated that EDTA extractable Ni was significantly correlated with the total Ni added to soils and that pH was the most important control factor. Regression models for toxicity thresholds based on EDTA extractable Ni against soil properties showed that soil citrate dithionate extractable Fe was more important than soil pH in predicting Ni toxicity. These results can be used to accurately assess the risk of contaminated soils with high background values and/or different Ni sources. PMID- 29617274 TI - Identification and Characterization of the MADS-Box Genes and Their Contribution to Flower Organ in Carnation (Dianthus caryophyllus L.). AB - Dianthus is a large genus containing many species with high ornamental economic value. Extensive breeding strategies permitted an exploration of an improvement in the quality of cultivated carnation, particularly in flowers. However, little is known on the molecular mechanisms of flower development in carnation. Here, we report the identification and description of MADS-box genes in carnation (DcaMADS) with a focus on those involved in flower development and organ identity determination. In this study, 39 MADS-box genes were identified from the carnation genome and transcriptome by the phylogenetic analysis. These genes were categorized into four subgroups (30 MIKCc, two MIKC*, two Malpha, and five Mgamma). The MADS-box domain, gene structure, and conserved motif compositions of the carnation MADS genes were analysed. Meanwhile, the expression of DcaMADS genes were significantly different in stems, leaves, and flower buds. Further studies were carried out for exploring the expression of DcaMADS genes in individual flower organs, and some crucial DcaMADS genes correlated with their putative function were validated. Finally, a new expression pattern of DcaMADS genes in flower organs of carnation was provided: sepal (three class E genes and two class A genes), petal (two class B genes, two class E genes, and one SHORT VEGETATIVE PHASE (SVP)), stamen (two class B genes, two class E genes, and two class C), styles (two class E genes and two class C), and ovary (two class E genes, two class C, one AGAMOUS-LIKE 6 (AGL6), one SEEDSTICK (STK), one B sister, one SVP, and one Malpha). This result proposes a model in floral organ identity of carnation and it may be helpful to further explore the molecular mechanism of flower organ identity in carnation. PMID- 29617277 TI - Geometrical Structures and Electronic Properties of Ga6 and Ga5X (X = B, C, N, O, F, Al, Si, P, S, Cl) Clusters. AB - Based on the unbiased CALYPSO (Crystal structure Analysis by Particle Swarm Optimization) structure searching method in combination with density functional theory (DFT), the geometrical structures and electronic properties are investigated theoretically for Ga6 and Ga5X (X = B, C, N, O, F, Al, Si, P, S, Cl) clusters. The PBE0 exchange-correlation functional and the 6-311G(d) basis set is carried out to determine global minima on potential energy surfaces. The relative stabilities of the clusters are examined by the binding energies and substitution reaction. Following the predictions of the Jellium model, the Ga5B cluster with the 18 valence electrons is the most stable structure. At last, with the obtained lowest energy structures, some physical properties such as electrons transfer, molecular orbitals, and total and partial densities of states are discussed, respectively. PMID- 29617278 TI - Effect of Storage Conditions on the Long-Term Stability of Bactericidal Effects for Laser Generated Silver Nanoparticles. AB - Silver nanoparticles (AgNPs) are widely used as antibacterial agents, but their antibacterial durability and the influence by storage conditions have not been thoroughly investigated. In this study, AgNPs were produced using a picosecond laser and stored under three different conditions: daylight, dark and cold (4 degrees C). The antibacterial effects of the laser AgNPs were examined against Escherichia coli in either a 14-day interval (frequent air exposure) or a 45-day interval (less frequent air exposure) using a well-diffusion method until the antibacterial effects disappeared. Results showed that the antibacterial activity of the laser generated AgNPs lasted 266 to 405 days. Frequent air exposure increased particle oxidation as measured by high-angle annular dark-field detector for scanning transmission electron microscopy (HAADF-STEM) and X-ray energy dispersive (EDX) spectroscopy, and reduced the antibacterial duration by about 13 weeks. Compared to the chemically produced AgNPs, the antibacterial effect of the laser AgNPs lasted over 100 days longer when tested in the 45-day interval, but was susceptible to oxidation when frequently exposed to the air. The laser generated AgNPs had lower antibacterial activity when stored in cold compared to that stored at room temperature. This study demonstrated the long lasting antibacterial durability of the laser generated AgNPs. Such information could help design future medical applications for the AgNPs. PMID- 29617279 TI - Discovery of Novel Enhancers of Isoniazid Toxicity in Mycobacterium tuberculosis. AB - The number of effective first-line antibiotics for the treatment of Mycobacterium tuberculosis infection is strongly limited to a few drugs. Due to emerging resistance against those drugs, second- and third-line antibiotics have been established in therapy with certain problems and also increasing mycobacterial resistance. An alternative to such novel drugs or combined therapeutic regimes which may reduce resistance development is finding enhancers of mycobacterial drug effectiveness, especially enhancers that counteract causative resistance mechanisms. Such enhancers may reduce the extracellular drug efflux mediated by bacterial efflux pumps and thus enhance the intracellular drug toxicity. We developed novel 1,4-dihydropyridines (DHPs) as potential efflux pump inhibitors with some determined P-gp affinities. The influence on the antituberculotic drug toxicity has been investigated for three prominent antituberculotic drugs. Exclusive and selective toxicity enhancing effects have been detected for isoniazid (INH) which could be related to certain substituent effects of the 1,4 DHPs. So, structure-dependent activities have been found. Thus, promising enhancers could be identified and a suggested efflux pump inhibition is discussed. PMID- 29617281 TI - Effect of Potassium Chlorate on the Treatment of Domestic Sewage by Achieving Shortcut Nitrification in a Constructed Rapid Infiltration System. AB - A constructed rapid infiltration (CRI) system is a new type of sewage biofilm treatment technology, but due to its anaerobic zone it lacks the carbon sources and the conditions for nitrate retention, and its nitrogen removal performance is very poor. However, a shortcut nitrification–denitrification process presents distinctive advantages, as it saves oxygen, requires less organic matter, and requires less time for denitrification compared to conventional nitrogen removal methods. Thus, if the shortcut nitrification–denitrification process could be applied to the CRI system properly, a simpler, more economic, and efficient nitrogen removal method will be obtained. However, as its reaction process shows that the first and the most important step of achieving shortcut nitrification–denitrification is to achieve shortcut nitrification, in this study we explored the feasibility to achieve shortcut nitrification, which produces nitrite as the dominant nitrogen species in effluent, by the addition of potassium chlorate (KClO3) to the influent. In an experimental CRI test system, the effects on nitrogen removal, nitrate inhibition, and nitrite accumulation were studied, and the advantages of achieving a shortcut nitrification–denitrification process were also analysed. The results showed that shortcut nitrification was successfully achieved and maintained in a CRI system by adding 5 mM KClO3 to the influent at a constant pH of 8.4. Under these conditions, the nitrite accumulation percentage was increased, while a lower concentration of 3 mM KClO3 had no obvious effect. The addition of 5mM KClO3 in influent presumably inhibited the activity of ammonia-oxidizing bacteria (AOB) and nitrite-oxidizing bacteria (NOB), but inhibition of nitrite-oxidizing bacteria (NOB) was so strong that it resulted in a maximum nitrite accumulation percentage of up to over 80%. As a result, nitrite became the dominant nitrogen product in the effluent. Moreover, if the shortcut denitrification process will be achieved in the subsequent research, it could save 60.27 mg CH3OH per litre of sewage in the CRI system compared with the full denitrification process. PMID- 29617280 TI - Oropouche Fever: A Review. AB - Oropouche fever is an emerging zoonotic disease caused by Oropouche virus (OROV), an arthropod transmitted Orthobunyavirus circulating in South and Central America. During the last 60 years, more than 30 epidemics and over half a million clinical cases attributed to OROV infection have been reported in Brazil, Peru, Panama, Trinidad and Tobago. OROV fever is considered the second most frequent arboviral febrile disease in Brazil after dengue fever. OROV is transmitted through both urban and sylvatic transmission cycles, with the primary vector in the urban cycle being the anthropophilic biting midge Culicoides paraensis. Currently, there is no evidence of direct human-to-human OROV transmission. OROV fever is usually either undiagnosed due to its mild, self-limited manifestations or misdiagnosed because its clinical characteristics are similar to dengue, chikungunya, Zika and yellow fever, including malaria as well. At present, there is no specific antiviral treatment, and in the absence of a vaccine for effective prophylaxis of human populations in endemic areas, the disease prevention relies solely on vector control strategies and personal protection measures. OROV fever is considered to have the potential to spread across the American continent and under favorable climatic conditions may expand its geographic distribution to other continents. In view of OROV's emergence, increased interest for formerly neglected tropical diseases and within the One Health concept, the existing knowledge and gaps of knowledge on OROV fever are reviewed. PMID- 29617282 TI - Inhibiting TRK Proteins in Clinical Cancer Therapy. AB - Gene rearrangements resulting in the aberrant activity of tyrosine kinases have been identified as drivers of oncogenesis in a variety of cancers. The tropomyosin receptor kinase (TRK) family of tyrosine receptor kinases is emerging as an important target for cancer therapeutics. The TRK family contains three members, TRKA, TRKB, and TRKC, and these proteins are encoded by the genes NTRK1, NTRK2, and NTRK3, respectively. To activate TRK receptors, neurotrophins bind to the extracellular region stimulating dimerization, phosphorylation, and activation of downstream signaling pathways. Major known downstream pathways include RAS/MAPK/ERK, PLCγ, and PI3K/Akt. While being rare in most cancers, TRK fusions with other proteins have been well-established as oncogenic events in specific malignancies, including glioblastoma, papillary thyroid carcinoma, and secretory breast carcinomas. TRK protein amplification as well as alternative splicing events have also been described as contributors to cancer pathogenesis. For patients harboring alterations in TRK expression or activity, TRK inhibition emerges as an important therapeutic target. To date, multiple trials testing TRK inhibiting compounds in various cancers are underway. In this review, we will summarize the current therapeutic trials for neoplasms involving NTKR gene alterations, as well as the promises and setbacks that are associated with targeting gene fusions. PMID- 29617283 TI - Regulation of Bicarbonate Secretion in Marine Fish Intestine by the Calcium Sensing Receptor. AB - In marine fish, high epithelial intestinal HCO3− secretion generates luminal carbonate precipitates of divalent cations that play a key role in water and ion homeostasis. The present study was designed to expose the putative role for calcium and the calcium-sensing receptor (CaSR) in the regulation of HCO3− secretion in the intestine of the sea bream (Sparus aurata L.). Effects on the expression of the CaSR in the intestine were evaluated by qPCR and an increase was observed in the anterior intestine in fed fish compared with unfed fish and with different regions of intestine. CaSR expression reflected intestinal fluid calcium concentration. In addition, anterior intestine tissue was mounted in Ussing chambers to test the putative regulation of HCO3− secretion in vitro using the anterior intestine. HCO3− secretion was sensitive to varying calcium levels in luminal saline and to calcimimetic compounds known to activate/block the CaSR i.e., R 568 and NPS-2143. Subsequent experiments were performed in intestinal sacs to measure water absorption and the sensitivity of water absorption to varying luminal levels of calcium and calcimimetics were exposed as well. It appears, that CaSR mediates HCO3− secretion and water absorption in marine fish as shown by responsiveness to calcium levels and calcimimetic compounds. PMID- 29617285 TI - A State-of-the-Art Review on Soil Reinforcement Technology Using Natural Plant Fiber Materials: Past Findings, Present Trends and Future Directions. AB - Incorporating sustainable materials into geotechnical applications increases day by day due to the consideration of impacts on healthy geo-environment and future generations. The environmental issues associated with conventional synthetic materials such as cement, plastic-composites, steel and ashes necessitate alternative approaches in geotechnical engineering. Recently, natural fiber materials in place of synthetic material have gained momentum as an emulating soil-reinforcement technique in sustainable geotechnics. However, the natural fibers are innately different from such synthetic material whereas behavior of fiber-reinforced soil is influenced not only by physical-mechanical properties but also by biochemical properties. In the present review, the applicability of natural plant fibers as oriented distributed fiber-reinforced soil (ODFS) and randomly distributed fiber-reinforced soil (RDFS) are extensively discussed and emphasized the inspiration of RDFS based on the emerging trend. Review also attempts to explore the importance of biochemical composition of natural-fibers on the performance in subsoil reinforced conditions. The treatment methods which enhances the behavior and lifetime of fibers, are also presented. While outlining the current potential of fiber reinforcement technology, some key research gaps have been highlighted at their importance. Finally, the review briefly documents the future direction of the fiber reinforcement technology by associating bio mediated technological line. PMID- 29617284 TI - T2 Magnetic Resonance Assay: Overview of Available Data and Clinical Implications. AB - Invasive candidiasis is a common healthcare-associated infection with a high mortality rate that can exceed 60% in cases of septic shock. Blood culture performance is far from ideal, due to the long time to positivity and suppression by antifungal agents. The T2 Magnetic Resonance (T2MR) assay is an FDA-approved qualitative molecular diagnostic method that can detect and speciate the 5 most common Candida spp.; namely, Candida albicans, Candida glabrata, Candida parapsilosis, Candida tropicalis, and Candida krusei, in approximately 5 h. In a multicenter clinical trial that included both a prospective and a contrived arm to represent the full range of clinically relevant concentrations of Candida spp., T2MR demonstrated a sensitivity and specificity of 91.1% and 98.1%, respectively. The utility of T2MR in candidemia depends on the prevalence of disease in each clinical setting. In intensive care units and other high prevalence settings, the incorporation of T2MR in diagnostic algorithms is very appealing. T2MR is expected to allow timely initiation of antifungal therapy and help with anti-fungal stewardship. In low-prevalence settings, the positive predictive value of T2MR might not be enough to justify initiation of antifungal treatment in itself. The performance of T2MR has not been studied in cases of deep-seated candidiasis. Despite some promising evidence in published clinical trials, further studies are needed to determine the performance of T2MR in invasive candidiasis without candidemia. Overall, experience with T2MR in everyday clinical practice is evolving but, in the right setting, this technology is expected to provide "actionable information" for the management of patients evaluated for candidemia. PMID- 29617287 TI - Antioxidant Activities and Caffeic Acid Content in New Zealand Asparagus (Asparagus officinalis) Roots Extracts. AB - Asparagus officinalis are perennial plants that require re-planting every 10–20 years. The roots are traditionally mulched in the soil or treated as waste. The A. officinalis roots (AR) contain valuable bioactive compounds that may have some health benefiting properties. The aim of this study was to investigate the total polyphenol and flavonoid contents (TPC and TFC, respectively) and antioxidant (2,2-diphenyl-1-picrylhydrazyl (DPPH), Oxygen Radical Absorbance Capacity (ORAC) and Ferric Reducing/Antioxidant Power (FRAP) assays) activities of New Zealand AR extract. The antioxidant activity decreased with a longer extraction time. PMID- 29617286 TI - Acetylcholinesterase Inhibition and Antioxidant Activity of N-trans Caffeoyldopamine and N-trans-Feruloyldopamine. AB - Phenolic acids and their derivatives found in nature are well-known for their potential biological activity. In this study, two amides derived from trans caffeic/ferulic acid and dopamine were synthesized and characterized by Fourier transform infrared spectroscopy (FTIR), mass spectrometry, proton and carbon-13 nuclear magnetic resonance spectroscopy. The compounds were tested for the inhibition of acetylcholinesterase (AChE) from Electrophorus electricus and for antioxidant activity by scavenging 2,2-diphenyl-1-pycrylhydrazyl free radical (DPPH•) and 2,2′-azinobis(3-ethylbenzothiazoline-6-sulphonic acid) radical cation (ABTS•+), reducing ferric ions, and ferrous ions chelation. N trans-Feruloyldopamine displayed the highest inhibitory effect on AChE with half maximal inhibitory concentration (IC50) values of 8.52 μM. In addition, an in silico study was done to determine the most favorable AChE cluster with the synthesized compounds. Further, these clusters were investigated for binding positions at the lowest free binding energy. Both synthesized hydroxycinnamates were found to be better antioxidants than the parent acids in in vitro tests applied. N-trans-Caffeoyldopamine showed the best antioxidant activity in the three tested methods—against non-biological stable free radicals IC50 5.95 μM for DPPH•, 0.24 μM for the ABTS•+ method, and for reducing power (ascorbic acid equivalent (AAE) 822.45 μmol/mmol)—while for chelation activity against Fe2+ ions N-trans-feruloyldopamine had slightly better antioxidant activity (IC50 3.17 mM). PMID- 29617288 TI - Rapid Determination of Thiabendazole Pesticides in Rape by Surface Enhanced Raman Spectroscopy. AB - Thiabendazole is widely used in sclerotium blight, downy mildew and black rot prevention and treatment in rape. Accurate monitoring of thiabendazole pesticides in plants will prevent potential adverse effects to the Environment and human health. Surface Enhanced Raman Spectroscopy (SERS) is a highly sensitive fingerprint with the advantages of simple operation, convenient portability and high detection efficiency. In this paper, a rapid determination method of thiabendazole pesticides in rape was conducted combining SERS with chemometric methods. The original SERS were pretreated and the partial least squares (PLS) was applied to establish the prediction model between SERS and thiabendazole pesticides in rape. As a result, the SERS enhancing effect based on silver Nano substrate was better than that of gold Nano-substrate, where the detection limit of thiabendazole pesticides in rape could reach 0.1 mg/L. Moreover, 782, 1007 and 1576 cm−1 could be determined as thiabendazole pesticides Raman characteristic peaks in rape. The prediction effect of thiabendazole pesticides in rape was the best ( R p 2 = 0.94, RMSEP = 3.17 mg/L) after the original spectra preprocessed with 1st-Derivative, and the linear relevance between thiabendazole pesticides concentration and Raman peak intensity at 782 cm−1 was the highest (R2 = 0.91). Furthermore, five rape samples with unknown thiabendazole pesticides concentration were used to verify the accuracy and reliability of this method. It was showed that prediction relative standard deviation was 0.70–9.85%, recovery rate was 94.71–118.92% and t value was −1.489. In conclusion, the thiabendazole pesticides in rape could be rapidly and accurately detected by SERS, which was beneficial to provide a rapid, accurate and reliable scheme for the detection of pesticides residues in agriculture products. PMID- 29617289 TI - A Developed NK-92MI Cell Line with Siglec-7neg Phenotype Exhibits High and Sustainable Cytotoxicity against Leukemia Cells. AB - Altered sialic acid processing that leads to upregulation of cell surface sialylation is recognized as a key change in malignant tissue glycosylation. This cancer-associated hypersialylation directly impacts the signaling interactions between tumor cells and their surrounding microenvironment, especially the interactions mediated by immune cell surface sialic acid-binding immunoglobulin like lectins (Siglecs) to relay inhibitory signals for cytotoxicity. First, we obtained a Siglec-7neg NK-92MI cell line, NK-92MI-S7N, by separating a group of Siglec-7neg cell population from an eight-month-long-term NK-92MI in vitro culture by fluorescence-activated cell sorting (FACS). The effect of Siglec-7 loss on NK-92MI-S7N cells was characterized by the cell morphology, proliferation, and cytotoxic activity via FACS, MTS assay, cytotoxic assay, and natural killer (NK) degranulation assay. We found the expression levels of Siglec 7 in NK-92MI were negatively correlated with NK cytotoxicity against leukemia cells. This NK-92MI-S7N cell not only shared very similar phenotypes with its parental cells but also possessed a high and sustainable killing activity. Furthermore, this Siglec-7neg NK line was unexpectedly capable of eliminating a NK-92MI-resistant leukemia cell, THP-1, through enhancing the effector-target interaction. In this study, a NK cell line with high and sustainable cytotoxicity was established and this cell may provide a potential application in NK-based treatment for leukemia patients. PMID- 29617290 TI - Micro-Capillary Coatings Based on Spiropyran Polymeric Brushes for Metal Ion Binding, Detection, and Release in Continuous Flow. AB - Micro-capillaries, capable of light-regulated binding and qualitative detection of divalent metal ions in continuous flow, have been realised through functionalisation with spiropyran photochromic brush-type coatings. Upon irradiation with UV light, the coating switches from the passive non-binding spiropyran form to the active merocyanine form, which binds different divalent metal ions (Zn2+, Co2+, Cu2+, Ni2+, Cd2+), as they pass through the micro capillary. Furthermore, the merocyanine visible absorbance spectrum changes upon metal ion binding, enabling the ion uptake to be detected optically. Irradiation with white light causes reversion of the merocyanine to the passive spiropyran form, with simultaneous release of the bound metal ion from the micro-capillary coating. PMID- 29617292 TI - An In-Vitro Optical Sensor Designed to Estimate Glycated Hemoglobin Levels. AB - The purpose of this research was to design an optical sensor for evaluating glycated hemoglobin (HbA1c) percentages in hemoglobin. The A1c sensors available in the market use invasive methods, while our device offers the possibility of non-invasive monitoring of HbA1c levels in diabetic patients. A prototype is assembled using two light emitting diodes with peak emission wavelengths of 535 nm and 593 nm, a photodiode, and a microcontroller. The proposed sensor measures the transmitted intensity in the form of an output voltage. We devise an approach to estimate the percentage of HbA1c in hemoglobin for a given solution. This estimation is based on the relative change in absorbance due to change in path length and molar absorption coefficients of hemoglobin and HbA1c, at the two wavelengths. We calculate the molar absorption coefficient of HbA1c at 535 nm and 593 nm wavelengths using the sensor, which is performed by a multiple variable regression analysis algorithm fed through the microcontroller. Specifically, the sensor output voltage with respect to the sample concentration is fitted to an exponentially decaying equation model. We used a commercial chemical assay called Control FD Glycohemoglobin A1c with known percentage HbA1c levels to verify our device measurements. PMID- 29617293 TI - Wide-Baseline Stereo-Based Obstacle Mapping for Unmanned Surface Vehicles. AB - This paper proposes a wide-baseline stereo-based static obstacle mapping approach for unmanned surface vehicles (USVs). The proposed approach eliminates the complicated calibration work and the bulky rig in our previous binocular stereo system, and raises the ranging ability from 500 to 1000 m with a even larger baseline obtained from the motion of USVs. Integrating a monocular camera with GPS and compass information in this proposed system, the world locations of the detected static obstacles are reconstructed while the USV is traveling, and an obstacle map is then built. To achieve more accurate and robust performance, multiple pairs of frames are leveraged to synthesize the final reconstruction results in a weighting model. Experimental results based on our own dataset demonstrate the high efficiency of our system. To the best of our knowledge, we are the first to address the task of wide-baseline stereo-based obstacle mapping in a maritime environment. PMID- 29617291 TI - Interplay of Viral Infection, Host Cell Factors and Tumor Microenvironment in the Pathogenesis of Nasopharyngeal Carcinoma. AB - Undifferentiated nasopharyngeal carcinoma (NPC) is strongly associated with Epstein-Barr virus (EBV) infection. In addition, heavy infiltration of leukocytes is a common characteristic of EBV-associated NPC. It has long been suggested that substantial and interactive impacts between cancer and stromal cells create a tumor microenvironment (TME) to promote tumorigenesis. The coexistence of tumor infiltrating lymphocytes with EBV-infected NPC cells represents a distinct TME which supports immune evasion and cancer development from the early phase of EBV infection. Intracellularly, EBV-encoded viral products alter host cell signaling to facilitate tumor development and progression. Intercellularly, EBV-infected cancer cells communicate with stromal cells through secretion of cytokines and chemokines, or via release of tumor exosomes, to repress immune surveillance and enhance metastasis. Although high expression of miR-BARTs has been detected in NPC patients, contributions of these more recently discovered viral products to the establishment of TME are still vaguely defined. Further investigations are needed to delineate the mechanistic linkage of the interplay between viral and host factors, especially in relation to TME, which can be harnessed in future therapeutic strategies. PMID- 29617294 TI - Synthesized Mammography: Clinical Evidence, Appearance, and Implementation. AB - Digital breast tomosynthesis (DBT) has improved conventional mammography by increasing cancer detection while reducing recall rates. However, these benefits come at the cost of increased radiation dose. Synthesized mammography (s2D) has been developed to provide the advantages of DBT with nearly half the radiation dose. Since its F.D.A. approval, multiple studies have evaluated the clinical performance of s2D. In clinical practice, s2D images are not identical to conventional 2D images and are designed for interpretation with DBT as a complement. This article reviews the present literature to assess whether s2D is a practical alternative to conventional 2D, addresses the differences in mammographic appearance of findings, and provides suggestions for implementation into clinical practice. PMID- 29617295 TI - The Effects of Deoxynivalenol and Zearalenone on the Pig Large Intestine. A Light and Electron Microscopy Study. AB - The contamination of feed with mycotoxins results in reduced growth, feed refusal, immunosuppression, and health problems. Deoxynivalenol (DON) and zearalenone (ZEN) are among the most important mycotoxins. The aim of the study was to examine the effects of low doses of these mycotoxins on the histological structure and ultrastructure of the large intestine in the pig. The study was performed on 36 immature gilts of mixed breed (White Polish Big × Polish White Earhanging), which were divided into four groups administrated per os with ZEN at 40 µg/kg BW, DON at 12 µg/kg BW, a mixture of ZEN (40 µg/kg BW) and DON (12 µg/kg BW) or a placebo. The pigs were killed by intravenous overdose of pentobarbital after one, three, and six weeks of treatment. The cecum, ascending and descending colon samples were prepared for light and electron microscopy. Administration of toxins did not influence the architecture of the mucosa and submucosa in the large intestine. ZEN and ZEN + DON significantly decreased the number of goblet cells in the cecum and descending colon. The mycotoxins changed the number of lymphocytes and plasma cells in the large intestine, which usually increased in number. However, this effect differed between the intestine segments and toxins. Mycotoxins induced some changes in the ultrastructure of the mucosal epithelium. They did not affect the expression of proliferative cell nuclear antigen and the intestinal barrier permeability. The obtained results indicate that mycotoxins especially ZEN may influence the defense mechanisms of the large intestine. PMID- 29617296 TI - Macrophage Populations in Visceral Adipose Tissue from Pregnant Women: Potential Role of Obesity in Maternal Inflammation. AB - Obesity is associated with inflammatory changes and accumulation and phenotype polarization of adipose tissue macrophages (ATMs). Obese pregnant women have alterations in adipose tissue composition, but a detailed description of macrophage population is not available. In this study, we characterized macrophage populations in visceral adipose tissue (VAT) from pregnant women with normal, overweight, and obese pregestational weight. Immunophenotyping of macrophages from VAT biopsies was performed by flow cytometry using CD45 and CD14 as markers of hematopoietic and monocyte linage, respectively, while HLA-DR, CD11c, CD163, and CD206 were used as pro- and anti-inflammatory markers. Adipocyte number and size were evaluated by light microscopy. The results show that pregnant women that were overweight and obese during the pregestational period had adipocyte hypertrophy. Two different macrophage populations in VAT were identified: recruited macrophages (CD45+CD14+), and a novel population lacking CD45, which was considered to be a resident macrophages subset (CD45−CD14+). The number of resident HLA−DRlow/− macrophages showed a negative correlation with body mass index (BMI). Both resident and recruited macrophages from obese women expressed higher CD206 levels. CD11c expression was higher in resident HLA-DR+ macrophages from obese women. A strong correlation between CD206 and CD11c markers and BMI was observed. Our findings show that being overweight and obese in the pregestational period is associated with adipocyte hypertrophy and specific ATMs populations in VAT. PMID- 29617297 TI - The Combinational Use of CRISPR/Cas9 and Targeted Toxin Technology Enables Efficient Isolation of Bi-Allelic Knockout Non-Human Mammalian Clones. AB - Recent advances in genome editing systems such as clustered regularly interspaced short palindromic repeats/CRISPR-associated protein-9 nuclease (CRISPR/Cas9) have facilitated genomic modification in mammalian cells. However, most systems employ transient treatment with selective drugs such as puromycin to obtain the desired genome-edited cells, which often allows some untransfected cells to survive and decreases the efficiency of generating genome-edited cells. Here, we developed a novel targeted toxin-based drug-free selection system for the enrichment of genome-edited cells. Cells were transfected with three expression vectors, each of which carries a guide RNA (gRNA), humanized Cas9 (hCas9) gene, or Clostridium perfringens-derived endo-β-galactosidase C (EndoGalC) gene. Once EndoGalC is expressed in a cell, it digests the cell-surface α-Gal epitope, which is specifically recognized by BS-I-B4 lectin (IB4). Three days after transfection, these cells were treated with cytotoxin saporin-conjugated IB4 (IB4SAP) for 30 min at 37 °C prior to cultivation in a normal medium. Untransfected cells and those weakly expressing EndoGalC will die due to the internalization of saporin. Cells transiently expressing EndoGalC strongly survive, and some of these surviving clones are expected to be genome-edited bi-allelic knockout (KO) clones due to their strong co-expression of gRNA and hCas9. When porcine α-1,3 galactosyltransferase gene, which can synthesize the α-Gal epitope, was attempted to be knocked out, 16.7% and 36.7% of the surviving clones were bi allelic and mono-allelic knockout (KO) cells, respectively, which was in contrast to the isolation of clones in the absence of IB4SAP treatment. Namely, 0% and 13.3% of the resulting clones were bi-allelic and mono-allelic KO cells, respectively. A similar tendency was seen when other target genes such as DiGeorge syndrome critical region gene 2 and transforming growth factor-β receptor type 1 gene were targeted to be knocked out. Our results indicate that a combination of the CRISPR/Cas9 system and targeted toxin technology using IB4SAP allows efficient enrichment of genome-edited clones, particularly bi-allelic KO clones. PMID- 29617298 TI - Lectin-Binding Specificity of the Fertilization-Relevant Protein PDC-109 by Means of Surface Plasmon Resonance and Carbohydrate REcognition Domain EXcision-Mass Spectrometry. AB - Seminal plasma proteins are relevant for sperm functionality and some appear responsible for establishing sperm interactions with the various environments along the female genital tract towards the oocyte. In recent years, research has focused on characterizing the role of these proteins in the context of reproductive biology, fertility diagnostics and treatment of related problems. Herein, we focus on the main protein of bovine seminal plasma, PDC-109 (BSP-A1/ A2), which by virtue of its lectin properties is involved in fertilization. By means of surface plasmon resonance, the interaction of PDC-109 with a panel of the most relevant glycosidic epitopes of mammals has been qualitatively and quantitatively characterized, and a higher affinity for carbohydrates containing fucose has been observed, in line with previous studies. Additionally, using the orthogonal technique of Carbohydrate REcognition Domain EXcision-Mass Spectrometry (CREDEX-MS), the recognition domain of the interaction complexes between PDC-109 and all fucosylated disaccharides [(Fuc-α1,(3,4,6)-GlcNAc)] has been defined, revealing the specific glycotope and the peptide domain likely to act as the PDC-109 carbohydrate binding site. PMID- 29617300 TI - On the Lateral Compressive Behavior of Empty and Ex-Situ Aluminum Foam-Filled Tubes at High Temperature. AB - In this research work, the effect of lateral loading (LL) on the crushing performance of empty tubes (ETs) and ex situ aluminum foam-filled tubes (FFTs) was investigated at 300 °C. The cylindrical thin-walled steel tube was filled with the closed-cell aluminum alloy foam that compressed under quasi-static loading conditions. During the compression test, the main mechanical properties of the ETs improved due to the interaction effect between the cellular structure of the foam and the inner wall of the empty tube. In addition, the initial propagated cracks on the steel tubes reduced considerably as a result of such interaction. Furthermore, the obtained results of the LL loading were compared with the axial loading (AL) results for both ETs and FFTs at the same temperature. The findings indicated that the application of loading on the lateral surface of the composite causes the lower mechanical properties of both ETs and FFTs in comparison with the axial loading conditions. PMID- 29617299 TI - A Comparison of the Effects of FATTY ACID DESATURASE 7 and HYDROPEROXIDE LYASE on Plant-Aphid Interactions. AB - The spr2 mutation in tomato (Solanum lycopersicum), which disrupts function of FATTY ACID DESATURASE 7 (FAD7), confers resistance to the potato aphid (Macrosiphum euphorbiae) and modifies the plant’s C6 volatile profiles. To investigate whether C6 volatiles play a role in resistance, HYDROPEROXIDE LYASE (HPL), which encodes a critical enzyme in C6 volatile synthesis, was silenced in wild-type tomato plants and spr2 mutants. Silencing HPL in wild-type tomato increased potato aphid host preference and reproduction on 5-week old plants but had no influence on 3-week old plants. The spr2 mutation, in contrast, conferred strong aphid resistance at both 3 and 5 weeks, and silencing HPL in spr2 did not compromise this aphid resistance. Moreover, a mutation in the FAD7 gene in Arabidopsis thaliana also conferred resistance to the green peach aphid (Myzus persicae) in a genetic background that carries a null mutation in HPL. These results indicate that HPL contributes to certain forms of aphid resistance in tomato, but that the effects of FAD7 on aphids in tomato and Arabidopsis are distinct from and independent of HPL. PMID- 29617301 TI - An Ecological Study on the Spatially Varying Relationship between County-Level Suicide Rates and Altitude in the United States. AB - Suicide is a serious but preventable public health issue. Several previous studies have revealed a positive association between altitude and suicide rates at the county level in the contiguous United States. We assessed the association between suicide rates and altitude using a cross-county ecological study design. Data on suicide rates were obtained from a Web-based Injury Statistics Query and Reporting System (WISQARS), maintained by the U.S. National Center for Injury Prevention and Control (NCIPC). Altitude data were collected from the United States Geological Survey (USGS). We employed an ordinary least square (OLS) regression to model the association between altitude and suicide rates in 3064 counties in the contiguous U.S. We conducted a geographically weighted regression (GWR) to examine the spatially varying relationship between suicide rates and altitude after controlling for several well-established covariates. A significant positive association between altitude and suicide rates (average county rates between 2008 and 2014) was found in the dataset in the OLS model (R2 = 0.483, p < 0.001). Our GWR model fitted the data better, as indicated by an improved R2 (average: 0.62; range: 0.21–0.64) and a lower Akaike Information Criteria (AIC) value (13,593.68 vs. 14,432.14 in the OLS model). The GWR model also significantly reduced the spatial autocorrelation, as indicated by Moran’s I test statistic (Moran’s I = 0.171; z = 33.656; p < 0.001 vs. Moran’s I = 0.323; z = 63.526; p < 0.001 in the OLS model). In addition, a stronger positive relationship was detected in areas of the northern regions, northern plain regions, and southeastern regions in the U.S. Our study confirmed a varying overall positive relationship between altitude and suicide. Future research may consider controlling more predictor variables in regression models, such as firearm ownership, religion, and access to mental health services. PMID- 29617303 TI - 3D Laser Scanner for Underwater Manipulation. AB - Nowadays, research in autonomous underwater manipulation has demonstrated simple applications like picking an object from the sea floor, turning a valve or plugging and unplugging a connector. These are fairly simple tasks compared with those already demonstrated by the mobile robotics community, which include, among others, safe arm motion within areas populated with a priori unknown obstacles or the recognition and location of objects based on their 3D model to grasp them. Kinect-like 3D sensors have contributed significantly to the advance of mobile manipulation providing 3D sensing capabilities in real-time at low cost. Unfortunately, the underwater robotics community is lacking a 3D sensor with similar capabilities to provide rich 3D information of the work space. In this paper, we present a new underwater 3D laser scanner and demonstrate its capabilities for underwater manipulation. In order to use this sensor in conjunction with manipulators, a calibration method to find the relative position between the manipulator and the 3D laser scanner is presented. Then, two different advanced underwater manipulation tasks beyond the state of the art are demonstrated using two different manipulation systems. First, an eight Degrees of Freedom (DoF) fixed-base manipulator system is used to demonstrate arm motion within a work space populated with a priori unknown fixed obstacles. Next, an eight DoF free floating Underwater Vehicle-Manipulator System (UVMS) is used to autonomously grasp an object from the bottom of a water tank. PMID- 29617305 TI - The Cost of Youth Suicide in Australia. AB - Suicide is the leading cause of death among Australians between 15 and 24 years of age. This study seeks to estimate the economic cost of youth suicide (15–24 years old) for Australia using 2014 as a reference year. The main outcome measure is monetized burden of youth suicide. Costs, in 2014 AU$, are measured and valued as direct costs, such as coronial inquiry, police, ambulance, and funeral expenses; indirect costs, such as lost economic productivity; and intangible costs, such as bereavement. In 2014, 307 young Australians lost their lives to suicide (82 females and 225 males). The average age at time of death was 20.4 years, representing an average loss of 62 years of life and close to 46 years of productive capacity. The average cost per youth suicide is valued at $2,884,426, including $9721 in direct costs, $2,788,245 as the value of lost productivity, and $86,460 as the cost of bereavement. The total economic loss of youth suicide in Australia is estimated at $22 billion a year (equivalent to US$ 17 billion), ranging from $20 to $25 billion. These findings can assist decision makers understand the magnitude of adverse outcomes associated with youth suicide and the potential benefits to be achieved by investing in effective suicide prevention strategies. PMID- 29617304 TI - The Pathological Spectrum of Systemic Anaplastic Large Cell Lymphoma (ALCL). AB - Anaplastic large cell lymphoma (ALCL) represents a group of malignant T-cell lymphoproliferations that share morphological and immunophenotypical features, namely strong CD30 expression and variable loss of T-cell markers, but differ in clinical presentation and prognosis. The recognition of anaplastic lymphoma kinase (ALK) fusion proteins as a result of chromosomal translocations or inversions was the starting point for the distinction of different subgroups of ALCL. According to their distinct clinical settings and molecular findings, the 2016 revised World Health Organization (WHO) classification recognizes four different entities: systemic ALK-positive ALCL (ALK+ ALCL), systemic ALK-negative ALCL (ALK− ALCL), primary cutaneous ALCL (pC-ALCL), and breast implant associated ALCL (BI-ALCL), the latter included as a provisional entity. ALK is rearranged in approximately 80% of systemic ALCL cases with one of its partner genes, most commonly NPM1, and is associated with favorable prognosis, whereas systemic ALK− ALCL shows heterogeneous clinical, phenotypical, and genetic features, underlining the different oncogenesis between these two entities. Recognition of the pathological spectrum of ALCL is crucial to understand its pathogenesis and its boundaries with other entities. In this review, we will focus on the morphological, immunophenotypical, and molecular features of systemic ALK+ and ALK− ALCL. In addition, BI-ALCL will be discussed. PMID- 29617302 TI - Nanotechnology for Cancer Therapy Based on Chemotherapy. AB - Chemotherapy has been widely applied in clinics. However, the therapeutic potential of chemotherapy against cancer is seriously dissatisfactory due to the nonspecific drug distribution, multidrug resistance (MDR) and the heterogeneity of cancer. Therefore, combinational therapy based on chemotherapy mediated by nanotechnology, has been the trend in clinical research at present, which can result in a remarkably increased therapeutic efficiency with few side effects to normal tissues. Moreover, to achieve the accurate pre-diagnosis and real-time monitoring for tumor, the research of nano-theranostics, which integrates diagnosis with treatment process, is a promising field in cancer treatment. In this review, the recent studies on combinational therapy based on chemotherapy will be systematically discussed. Furthermore, as a current trend in cancer treatment, advance in theranostic nanoparticles based on chemotherapy will be exemplified briefly. Finally, the present challenges and improvement tips will be presented in combination therapy and nano-theranostics. PMID- 29617306 TI - Development of Colorectal-Targeted Dietary Supplement Tablets Containing Natural Purple Rice Bran Oil as a Colorectal Chemopreventive. AB - Colorectal cancer occurs due to various factors. The important risks are dietary lifestyle and inflammatory bowel diseases, such as Crohn’s disease and ulcerative colitis. It has been found that the inhibitory enzyme cyclooxygenase-2 (COX-2) in the colorectal region can potentially reduce the risk of colorectal cancer. The present study investigated rice bran oil from natural purple rice bran, which exhibits antioxidant and anti-inflammatory activity. This study aimed to evaluate the bioactive compound content of natural purple rice bran oil (NPRBO) derived from native Thai purple rice and the anti-inflammatory activity of NPRBO in colorectal cancer cells, and to develop a colorectal delivery platform in the form of film-coated tablets. NPRBO from the rice bran of five different Thai purple rice cultivars, namely Khao’ Gam Leum-Phua (KGLP), Khao’ Gam Boung (KGB), Khao’ Gam Thor (KGT), Khao’ Gam Pah E Kaw (KGPEK), and Khao’ Niaw Dam (KND), were extracted using the supercritical carbon dioxide extraction technique. The amount of γ-oryzanol (ORY), tocotrienols, and tocopherols present in NPRBOs and the in vitro anti inflammatory activity of NPRBO were investigated. The highest anti-inflammatory NPRBO was transformed into a dry and free-flowing powder by liquisolid techniques. Then, it was compressed into core tablets and coated with Eudragit®L100 and Eudragit® NE30D. The in vitro release study of the film coated NPRBO tablets was performed in three-phase simulated gastrointestinal media. The cultivar KGLP was superior to the other samples in terms of the ORY, tocotrienol and tocopherol contents and anti-inflammatory activity. Aerosil® was the most suitable absorbent for transforming NPRBO into a free-flowing powder and was used to prepare the NPRBO core tablets. The in vitro KGLP-NPRBO film coated tablet release profile showed that no ORY was released at gastric pH while 85% of ORY was released at pH 7.4 after 6 h; this would be expected to occur in the colorectal area. Therefore, this study demonstrates the potential of KGLP NPRBO to prevent colorectal cancer via a specific colorectal dietary supplement delivery system. PMID- 29617307 TI - GFRA1: A Novel Molecular Target for the Prevention of Osteosarcoma Chemoresistance. AB - The glycosylphosphatidylinositol-linked GDNF (glial cell derived neurotrophic factor) receptor alpha (GFRA), a coreceptor that recognizes the GDNF family of ligands, has a crucial role in the development and maintenance of the nervous system. Of the four identified GFRA isoforms, GFRA1 specifically recognizes GDNF and is involved in the regulation of proliferation, differentiation, and migration of neuronal cells. GFRA1 has also been implicated in cancer cell progression and metastasis. Recent findings show that GFRA1 can contribute to the development of chemoresistance in osteosarcoma. GFRA1 expression was induced following treatment of osteosarcoma cells with the popular anticancer drug, cisplatin and induction of GFRA1 expression significantly suppressed apoptosis mediated by cisplatin in osteosarcoma cells. GFRA1 expression promotes autophagy by activating the SRC-AMPK signaling axis following cisplatin treatment, resulting in enhanced osteosarcoma cell survival. GFRA1-induced autophagy promoted tumor growth in mouse xenograft models, suggesting a novel function of GFRA1 in osteosarcoma chemoresistance. PMID- 29617308 TI - A Systematic Study of RNAi Effects and dsRNA Stability in Tribolium castaneum and Acyrthosiphon pisum, Following Injection and Ingestion of Analogous dsRNAs. AB - RNA interference (RNAi) effects in insects are highly variable and may be largely dependent upon the stability of introduced double-stranded RNAs to digestion by nucleases. Here, we report a systematic comparison of RNAi effects in susceptible red flour beetle (Tribolium castaneum) and recalcitrant pea aphid (Acyrthosiphon pisum) following delivery of dsRNAs of identical length targeting expression of V type ATPase subunit E (VTE) and inhibitor of apoptosis (IAP) genes. Injection and ingestion of VTE and IAP dsRNAs resulted in up to 100% mortality of T. castaneum larvae and sustained suppression (>80%) of transcript levels. In A. pisum, injection of VTE but not IAP dsRNA resulted in up to 65% mortality and transient suppression (ca. 40%) of VTE transcript levels. Feeding aphids on VTE dsRNA reduced growth and fecundity although no evidence for gene suppression was obtained. Rapid degradation of dsRNAs by aphid salivary, haemolymph and gut nucleases contrasted with stability in T. castaneum larvae where it appears that exo-nuclease activity is responsible for relatively slow digestion of dsRNAs. This is the first study to directly compare RNAi effects and dsRNA stability in receptive and refractory insect species and provides further evidence that dsRNA susceptibility to nucleases is a key factor in determining RNAi efficiency. PMID- 29617309 TI - The Mycotox Charter: Increasing Awareness of, and Concerted Action for, Minimizing Mycotoxin Exposure Worldwide. AB - Mycotoxins are major food contaminants affecting global food security, especially in low and middle-income countries. The European Union (EU) funded project, MycoKey, focuses on “Integrated and innovative key actions for mycotoxin management in the food and feed chains” and the right to safe food through mycotoxin management strategies and regulation, which are fundamental to minimizing the unequal access to safe and sufficient food worldwide. As part of the MycoKey project, a Mycotoxin Charter (charter.mycokey.eu) was launched to share the need for global harmonization of mycotoxin legislation and policies and to minimize human and animal exposure worldwide, with particular attention to less developed countries that lack effective legislation. This document is in response to a demand that has built through previous European Framework Projects—MycoGlobe and MycoRed—in the previous decade to control and reduce mycotoxin contamination worldwide. All suppliers, participants and beneficiaries of the food supply chain, for example, farmers, consumers, stakeholders, researchers, members of civil society and government and so forth, are invited to sign this charter and to support this initiative. PMID- 29617311 TI - Special Issue: NextGen Materials for 3D Printing. AB - Only a handful of materials are well-established in three-dimensional (3D) printing and well-accepted in industrial manufacturing applications. However, recent advances in 3D printable materials have shown potential for enabling numerous novel applications in the future. This special issue, consisting of 2 reviews and 10 research articles, intends to explore the possible materials that could define next-generation 3D printing. PMID- 29617310 TI - Protective Effects of Ellagitannin-Rich Strawberry Extracts on Biochemical and Metabolic Disturbances in Rats Fed a Diet High in Fructose. AB - The present study compares the effects of two dietary strawberry extracts rich in monomeric (ME) or dimeric (DE) ellagitannins (ETs) on gastrointestinal, blood and tissue biomarkers in Wistar rats fed high-fructose diets. Both strawberry extracts beneficially affect the antioxidant status and lipid profile of the liver and serum. The ME extract shows a greater ability to inhibit lipid peroxidation in kidneys, more effectively decreases serum and liver triglycerides, and exerts greater anti-inflammatory effects in blood serum than the DE extract. The DE extract significantly reduces the activity of microbial enzymes in the cecum. These effects might be associated with higher cecum and urine levels of ET metabolites in rats fed with ME than in rats fed with DE. In conclusion, the diet-induced fructose-related disturbances observed in biochemical parameters are regulated by both extracts; nevertheless, the beneficial effects of the ME extract are mostly associated with systemic parameters, while those of the DE extracts are associated with local microbial activity. PMID- 29617312 TI - Metabolomic Profiling of the White, Violet, and Red Flowers of Rhododendron schlippenbachii Maxim. AB - Rhododendron schlippenbachii Maxim. is a garden plant that is also used for natural medicines as a consequence of the biological activities of its diverse metabolites. We accordingly profiled two anthocyanins and 40 primary and secondary metabolites in the three different colored flowers. The major anthocyanins found in the flowers were cyanidins. The red flowers exhibited the highest accumulation of anthocyanins (1.02 ± 0.02 mg/g dry weight). Principal component analysis was applied to the GC-TOFMS data. The levels of key tricarboxylic acid cycle intermediates in red flowers, such as succinic acid, fumaric acid, and malic acid, were found to be highly significantly different (p < 0.0001) from those in the flowers of other colors. In this study, we aimed to determine metabolite interactions and phenotypic variation among white, violet, and red flowers of R. schlippenbachii by using gas chromatography time-of-flight mass spectrometry (GC-TOFMS) and high-performance liquid chromatography (HPLC). PMID- 29617313 TI - The Relationship of Health Beliefs with Information Sources and HPV Vaccine Acceptance among Young Adults in Korea. AB - Despite the HPV vaccine’s efficacy in preventing cervical cancer, its coverage rates among Asians are very low. To increase immunization coverage among these populations, understanding the psychological factors that affect HPV acceptability is critical. To this end, this study examined the relationships between multidimensional health beliefs and HPV vaccine acceptance, and what information sources effectively foster HPV vaccination-related health beliefs. Data were collected using a survey of 323 undergraduate students in Korea. Results showed that perceived susceptibility, perceived severity, perceived benefits, and perceived vaccine safety concerns predicted vaccine acceptance. Multiple dimensions of perceived barriers showed differing impacts on vaccine acceptance. In addition, interpersonal information sources were effective in boosting various health beliefs for HPV vaccination. The Internet also was effective in reducing social barriers, but the effects were opposite to those of social media. Theoretical and practical implications are discussed. PMID- 29617314 TI - Menaquinone Content of Cheese. AB - Vitamin K2 (menaquinone) concentrations were measured in a wide range of cheeses and the effects of fat content, ripening and origin of the cheeses were investigated. Moreover, the menaquinone content of cheese was compared with that of other foods known to contain vitamin K2. It was found that cheese and curd are the most important sources of long-chain menaquinones in the Western diet and, in general, hard cheeses are richer in menaquinones than soft cheeses. However, the actual menaquinone content varies substantially and is dependent on the type of cheese, the time of ripening, the fat content and the geographic area where the cheeses are produced. Given the fact that poor vitamin K status has been mentioned as a risk factor for cardiovascular disease and mortality, while there is no clear evidence for adverse cardiovascular effects of dairy fats, cheese should be considered as a recommendable component in a heart-healthy diet. PMID- 29617315 TI - Facile Synthesis of Nitrogen and Oxygen Co-Doped Clews of Carbon Nanobelts for Supercapacitors with Excellent Rate Performance. AB - Facile synthesis of carbon materials with high heteroatom content, large specific surface area (SSA) and hierarchical porous structure is critical for energy storage applications. In this study, nitrogen and oxygen co-doped clews of carbon nanobelts (NCNBs) with hierarchical porous structures are successfully prepared by a carbonization and subsequent activation by using ladder polymer of hydroquinone and formaldehyde (LPHF) as the precursor and ammonia as the activating agent. The hierarchical porous structures and ultra-high SSA (up to 2994 m2 g−1) can effectively facilitate the exchange and transportation of electrons and ions. Moreover, suitable heteroatom content is believed to modify the wettability of the carbon material. The as-prepared activated NCNBs-60 (the NCNBs activated by ammonia at 950 °C for 60 min) possess a high capacitance of 282 F g−1 at the current density of 0.25 A g−1, NCNBs-45 (the NCNBs are activated by ammonia at 950 °C for 45 min) and show an excellent capacity retention of 50.2% when the current density increase from 0.25 to 150 A g−1. Moreover, the NCNBs-45 electrode exhibits superior electrochemical stability with 96.2% capacity retention after 10,000 cycles at 5.0 A g−1. The newly prepared NCNBs thus show great potential in the field of energy storage. PMID- 29617316 TI - Study of Photochemical Cytosine to Uracil Transition via Ultrafast Photo-Cross Linking Using Vinylcarbazole Derivatives in Duplex DNA. AB - Gene therapies, including genome editing, RNAi, anti-sense technology and chemical DNA editing are becoming major methods for the treatment of genetic disorders. Techniques like CRISPR-Cas9, zinc finger nuclease (ZFN) and transcription activator-like effector-based nuclease (TALEN) are a few such enzymatic techniques. Most enzymatic genome editing techniques have their disadvantages. Thus, non-enzymatic and non-invasive technologies for nucleic acid editing has been reported in this study which might possess some advantages over the older methods of DNA manipulation. 3-cyanovinyl carbazole (CNVK) based nucleic acid editing takes advantage of photo-cross-linking between a target pyrimidine and the CNVK to afford deamination of cytosine and convert it to uracil. This method previously required the use of high temperatures but, in this study, it has been optimized to take place at physiological conditions. Different counter bases (inosine, guanine and cytosine) complementary to the target cytosine were used, along with derivatives of CNVK (NH2VK and OHVK) to afford the deamination at physiological conditions. PMID- 29617317 TI - The Political Economy of Health Co-Benefits: Embedding Health in the Climate Change Agenda. AB - A complex, whole-of-economy issue such as climate change demands an interdisciplinary, multi-sectoral response. However, evidence suggests that human health has remained elusive in its influence on the development of ambitious climate change mitigation policies for many national governments, despite a recognition that the combustion of fossil fuels results in pervasive short- and long-term health consequences. We use insights from literature on the political economy of health and climate change, the science–policy interface and power in policy-making, to identify additional barriers to the meaningful incorporation of health co-benefits into climate change mitigation policy development. Specifically, we identify four key interrelated areas where barriers may exist in relation to health co-benefits: discourse, efficiency, vested interests and structural challenges. With these insights in mind, we argue that the current politico-economic paradigm in which climate change is situated and the processes used to develop climate change mitigation policies do not adequately support accounting for health co-benefits. We present approaches for enhancing the role of health co-benefits in the development of climate change mitigation policies to ensure that health is embedded in the broader climate change agenda. PMID- 29617318 TI - Public Health and Unconventional Oil and Gas Extraction Including Fracking: Global Lessons from a Scottish Government Review. AB - Unconventional oil and gas extraction (UOGE) including fracking for shale gas is underway in North America on a large scale, and in Australia and some other countries. It is viewed as a major source of global energy needs by proponents. Critics consider fracking and UOGE an immediate and long-term threat to global, national, and regional public health and climate. Rarely have governments brought together relatively detailed assessments of direct and indirect public health risks associated with fracking and weighed these against potential benefits to inform a national debate on whether to pursue this energy route. The Scottish government has now done so in a wide-ranging consultation underpinned by a variety of reports on unconventional gas extraction including fracking. This paper analyses the Scottish government approach from inception to conclusion, and from procedures to outcomes. The reports commissioned by the Scottish government include a comprehensive review dedicated specifically to public health as well as reports on climate change, economic impacts, transport, geology, and decommissioning. All these reports are relevant to public health, and taken together offer a comprehensive review of existing evidence. The approach is unique globally when compared with UOGE assessments conducted in the USA, Australia, Canada, and England. The review process builds a useful evidence base although it is not without flaws. The process approach, if not the content, offers a framework that may have merits globally. PMID- 29617320 TI - Waist Circumference Is an Anthropometric Parameter That Identifies Women with Metabolically Unhealthy Phenotypes. AB - Metabolically healthy (MH) and metabolically unhealthy (MUH) phenotypes can be present in any subject independently of their body mass index (BMI). However, factors related to the presence of these phenotypes are poorly understood. Therefore, the aim of this cross-sectional study is to describe the prevalence and characteristics associated with the MH and MUH phenotypes in Mexican subjects with different BMI categories. Anthropometric and biochemical parameters were evaluated after 12 h of fasting. HMW (High Molecular Weight) adiponectin and insulin levels were measured by ELISA (enzyme-linked immunosorbent assay). A total of 345 subjects were included, of which, 73.9% were women. The prevalence of the MH phenotype was 69.9%, 46.7%, and 19% in normal weight, overweight, and obesity, respectively. ROC (receiver operating characteristic) curve analysis showed that the waist circumference demonstrated a statistical significance (p < 0.01) in detecting the MUH phenotype in each BMI group only in women. Furthermore, subjects with lower HMW adiponectin levels showed a 2.1 increased risk of presenting the MUH phenotype. In conclusion, in this Mexican population, waist circumference was an anthropometric parameter that identified women with the MUH phenotype in all BMI categories and hypoadiponectinemia was a risk factor for the presence of this phenotype. PMID- 29617319 TI - Biosensing Based on Nanoparticles for Food Allergens Detection. AB - Food allergy is one of the major health threats for sensitized individuals all over the world and, over the years, the food industry has made significant efforts and investments to offer safe foods for allergic consumers. The analysis of the concentration of food allergen residues in processing equipment, in raw materials or in the final product, provides analytical information that can be used for risk assessment as well as to ensure that food-allergic consumers get accurate and useful information to make their food choices and purchasing decisions. The development of biosensors based on nanomaterials for applications in food analysis is a challenging area of growing interest in the last years. Research in this field requires the combined efforts of experts in very different areas including food chemistry, biotechnology or materials science. However, the outcome of such collaboration can be of significant impact on the food industry as well as for consumer’s safety. These nanobiosensing devices allow the rapid, selective, sensitive, cost-effective and, in some cases, in-field, online and real-time detection of a wide range of compounds, even in complex matrices. Moreover, they can also enable the design of novel allergen detection strategies. Herein we review the main advances in the use of nanoparticles for the development of biosensors and bioassays for allergen detection, in food samples, over the past few years. Research in this area is still in its infancy in comparison, for instance, to the application of nanobiosensors for clinical analysis. However, it will be of interest for the development of new technologies that reduce the gap between laboratory research and industrial applications. PMID- 29617322 TI - Hydroxyapatite and Other Calcium Phosphates for the Conservation of Cultural Heritage: A Review. AB - The present paper reviews the methods and the performance of in situ formation of calcium phosphates (CaP) for the conservation of materials belonging to cultural heritage. The core idea is to form CaP (ideally hydroxyapatite, HAP, the most stable CaP at pH > 4) by reaction between the substrate and an aqueous solution of a phosphate salt. Initially proposed for the conservation of marble and limestone, the treatment has been explored for a variety of different substrates, including sandstones, sulphated stones, gypsum stuccoes, concrete, wall paintings, archaeological bones and paper. First, the studies aimed at identifying the best treatment conditions (e.g., nature and concentration of the phosphate precursor, solution pH, treatment duration, ionic and organic additions to the phosphate solution, mineralogical composition of the new CaP phases) are summarized. Then, the treatment performance on marble and limestone is reviewed, in terms of protective and consolidating effectiveness, compatibility (aesthetic, microstructural and physical) and durability. Some pilot applications in real case studies are also reported. Recent research aimed at extending the phosphate treatment to other substrates is then illustrated. Finally, the strengths of the phosphate treatment are summarized, in comparison with alternative products, and some aspects needing future research are outlined. PMID- 29617321 TI - Exosome-Mediated Transfer of Cancer Cell Resistance to Antiestrogen Drugs. AB - Exosomes are small vesicles which are produced by the cells and released into the surrounding space. They can transfer biomolecules into recipient cells. The main goal of the work was to study the exosome involvement in the cell transfer of hormonal resistance. The experiments were performed on in vitro cultured estrogen dependent MCF-7 breast cancer cells and MCF-7 sublines resistant to SERM tamoxifen and/or biguanide metformin, which exerts its anti-proliferative effect, at least in a part, via the suppression of estrogen machinery. The exosomes were purified by differential ultracentrifugation, cell response to tamoxifen was determined by MTT test, and the level and activity of signaling proteins were determined by Western blot and reporter analysis. We found that the treatment of the parent MCF-7 cells with exosomes from the resistant cells within 14 days lead to the partial resistance of the MCF-7 cells to antiestrogen drugs. The primary resistant cells and the cells with the exosome-induced resistance were characterized with these common features: decrease in ERα activity and parallel activation of Akt and AP-1, NF-κB, and SNAIL1 transcriptional factors. In general, we evaluate the established results as the evidence of the possible exosome involvement in the transferring of the hormone/metformin resistance in breast cancer cells. PMID- 29617323 TI - Parameter Estimation of Multiple Frequency-Hopping Signals with Two Sensors. AB - This paper essentially focuses on parameter estimation of multiple wideband emitting sources with time-varying frequencies, such as two-dimensional (2-D) direction of arrival (DOA) and signal sorting, with a low-cost circular synthetic array (CSA) consisting of only two rotating sensors. Our basic idea is to decompose the received data, which is a superimposition of phase measurements from multiple sources into separated groups and separately estimate the DOA associated with each source. Motivated by joint parameter estimation, we propose to adopt the expectation maximization (EM) algorithm in this paper; our method involves two steps, namely, the expectation-step (E-step) and the maximization (M step). In the E-step, the correspondence of each signal with its emitting source is found. Then, in the M-step, the maximum-likelihood (ML) estimates of the DOA parameters are obtained. These two steps are iteratively and alternatively executed to jointly determine the DOAs and sort multiple signals. Closed-form DOA estimation formulae are developed by ML estimation based on phase data, which also realize an optimal estimation. Directional ambiguity is also addressed by another ML estimation method based on received complex responses. The Cramer-Rao lower bound is derived for understanding the estimation accuracy and performance comparison. The verification of the proposed method is demonstrated with simulations. PMID- 29617325 TI - Recent Advances in Attention Bias Modification for Substance Addictions. AB - Research on attentional bias modification has increased since 2014. A recent meta analysis demonstrates evidence for bias modification for substance disorders, including alcohol and tobacco use disorders. Several pharmacological trials have shown that pharmacological agents can attenuate and modify such attentional bias. The pharmacological trials that have appeared to date have produced mixed results, which has clinical implications. Developments in Internet and mobile technologies have transformed how attention bias modification is currently being achieved. There remains great potential for further research that examines the efficacy of technology-aided attention bias interventions. PMID- 29617324 TI - Betalains in Some Species of the Amaranthaceae Family: A Review. AB - Natural pigments are largely distributed in the plant kingdom. They belong to diverse groups, with distinct biochemical pathways. Betalains with colours that range from yellow to red-violet can de divided into two main subgroups: betaxanthins and betacyanins. These types of pigments are confined into 13 families of the order Caryophyllales and in some genera of higher fungi (Amanita muscaria, Hygrocybe and Hygrophorus). The Amaranthaceae family includes diverse genera in which betalains are present: Alternanthera, Amaranthus, Beta, Chenopodium, Celosia and Gomphrena. The biosynthesis of betalains and their general biological properties were reviwed in the present work. In addition, the types of betalains present in some species of the aforementioned genera, their stability and production, as well as biological attributes, were reviewed. PMID- 29617326 TI - Ubiquitin System. AB - Ever since the discovery of ubiquitin in 1975[...]. PMID- 29617328 TI - A Two-Step Process of Nitrous Oxide before Carbon Dioxide for Humanely Euthanizing Piglets: On-Farm Trials. AB - Current methods of euthanizing piglets are raising animal welfare concerns. Our experiment used a novel two-step euthanasia method, using nitrous oxide (N2O) for six minutes and then carbon dioxide (CO2) on compromised 0- to 7-day-old piglets. A commercial euthanasia chamber was modified to deliver two euthanasia treatments: the two-step method using N2O then CO2 (N2O treatment) or only CO2 (CO2 treatment). In Experiment 1, 18 piglets were individually euthanized. In Experiment 2, 18 groups of four to six piglets were euthanized. In the N2O treatment, piglets lost posture, indicating the onset of losing consciousness, before going into CO2 where they showed heavy breathing and open-mouth breathing; whereas piglets in the CO2 treatment did not lose posture until after exhibiting these behaviors (p ≤ 0.004). However, piglets in the N2O treatment took longer to lose posture compared to the CO2 treatment (p < 0.001). Piglets in the N2O treatment displayed more behavioral signs of stress and aversion: squeals/minute (p = 0.004), escape attempts per pig (p = 0.021), and righting responses per pig (p = 0.084) in a group setting. In these regards, it cannot be concluded that euthanizing piglets for 6 min with N2O and then CO2 is more humane than euthanizing with CO2 alone. PMID- 29617327 TI - Applications of Cancer Cell-Specific Aptamers in Targeted Delivery of Anticancer Therapeutic Agents. AB - Aptamers are single-stranded oligonucleotides that specifically bind and interact with their corresponding targets, including proteins and cells, through unique three-dimensional structures. Numerous aptamers have been developed to target cancer biomarkers with high specificity and affinity, and some are employed as versatile guiding ligands for cancer-specific drug delivery and anti-cancer therapeutics. In this review, we list the aptamers that target tumor surface biomarkers and summarize the representative applications of aptamers as agonists and antagonists that activate anti-cancer and inactivate pro-cancer biomarkers, respectively. In addition, we describe applications of aptamer-drug or aptamer oligonucleotide conjugates that can deliver therapeutic agents, including small interfering RNAs, micro RNAs, short hairpin RNAs, and chemotherapeutic molecules, to cancer cells. Moreover, we provide examples of aptamer- conjugated nano vehicles, in which cancer-targeting oligonucleotide aptamers are conjugated with nano-vehicles such as liposomes, micelles, polymeric nanoparticles, and quantum dots. Conjugation of aptamers with anti-cancer drugs and nano-vehicles will facilitate innovative applications of aptamer-based cancer therapeutics. PMID- 29617329 TI - Synthesis and Anticandidal Activity of New Imidazole-Chalcones. AB - In the present work, 15 new 1-(4-(1H-imidazol-1-yl)phenyl)-3-(4 substituedphenyl)prop-2-en-1-one derivatives (3a–3o) were synthesized to evaluate their antifungal activity. Structures of newly synthesized imidazole derivatives (3a–3o) were characterized by IR, 1H-NMR, 13C-NMR, and LCMSMS spectroscopic methods. The anticandidal activity of compounds (3a–3o) against C. albicans (ATCC 24433), C. krusei (ATCC 6258), C. parapsilosis (ATCC 22019), and C. glabrata (ATCC 90030) was elucidated according to the EUCAST definitive (EDef 7.1) method. Consistent with the activity studies, 3a–3d were found to be more potent derivatives with their MIC50 values (0.78 µg/mL–3.125 µg/mL) against Candida strains. Compound 3c indicated similar antifungal activity to ketoconazole against all Candida species and was evaluated as the most active derivative in the series. Effects of the most potent derivatives 3a–3d on ergosterol biosynthesis were observed by LC-MS-MS method, which is based on quantification of the ergosterol level in C. krusei. Moreover, these compounds were subjected to a cytotoxicity test for the preliminary toxicological profiles and were found as non-cytotoxic. Furthermore, docking studies for the most active derivative 3c were performed to evaluate its binding modes on lanosterol 14-α-demethylase. In addition to in vitro tests, docking studies also revealed that Compound 3c is a potential ergosterol biosynthesis inhibitor. PMID- 29617331 TI - Joint Center Estimation Using Single-Frame Optimization: Part 1: Numerical Simulation. AB - The biomechanical models used to refine and stabilize motion capture processes are almost invariably driven by joint center estimates, and any errors in joint center calculation carry over and can be compounded when calculating joint kinematics. Unfortunately, accurate determination of joint centers is a complex task, primarily due to measurements being contaminated by soft-tissue artifact (STA). This paper proposes a novel approach to joint center estimation implemented via sequential application of single-frame optimization (SFO). First, the method minimizes the variance of individual time frames’ joint center estimations via the developed variance minimization method to obtain accurate overall initial conditions. These initial conditions are used to stabilize an optimization-based linearization of human motion that determines a time-varying joint center estimation. In this manner, the complex and nonlinear behavior of human motion contaminated by STA can be captured as a continuous series of unique rigid-body realizations without requiring a complex analytical model to describe the behavior of STA. This article intends to offer proof of concept, and the presented method must be further developed before it can be reasonably applied to human motion. Numerical simulations were introduced to verify and substantiate the efficacy of the proposed methodology. When directly compared with a state-of the-art inertial method, SFO reduced the error due to soft-tissue artifact in all cases by more than 45%. Instead of producing a single vector value to describe the joint center location during a motion capture trial as existing methods often do, the proposed method produced time-varying solutions that were highly correlated (r > 0.82) with the true, time-varying joint center solution. PMID- 29617330 TI - Fermented Food and Non-Communicable Chronic Diseases: A Review. AB - Fermented foods represent a significant fraction of human diets. Although their impact on health is positively perceived, an objective evaluation is still missing. We have, therefore, reviewed meta-analyses of randomized controlled trials (RCT) investigating the relationship between fermented foods and non transmissible chronic diseases. Overall, after summarizing 25 prospective studies on dairy products, the association of fermented dairy with cancer was found to be neutral, whereas it was weakly beneficial, though inconsistent, for specific aspects of cardio-metabolic health, in particular stroke and cheese intake. The strongest evidence for a beneficial effect was for yoghurt on risk factors of type 2 diabetes. Although mechanisms explaining this association have not been validated, an increased bioavailability of insulinotropic amino acids and peptides as well as the bacterial biosynthesis of vitamins, in particular vitamin K2, might contribute to this beneficial effect. However, the heterogeneity in the design of the studies and the investigated foods impedes a definitive assessment of these associations. The literature on fermented plants is characterized by a wealth of in vitro data, whose positive results are not corroborated in humans due to the absence of RCTs. Finally, none of the RCTs were specifically designed to address the impact of food fermentation on health. This question should be addressed in future human studies. PMID- 29617333 TI - A Predictive Model Has Identified Tick-Borne Encephalitis High-Risk Areas in Regions Where No Cases Were Reported Previously, Poland, 1999-2012. AB - During 1999-2012, 77% of the cases of tick-borne encephalitis (TBE) were recorded in two out of 16 Polish provinces. However, historical data, mostly from national serosurveys, suggest that the disease could be undetected in many areas. The aim of this study was to identify which routinely-measured meteorological, environmental, and socio-economic factors are associated to TBE human risk across Poland, with a particular focus on areas reporting few cases, but where serosurveys suggest higher incidence. We fitted a zero-inflated Poisson model using data on TBE incidence recorded in 108 NUTS-5 administrative units in high risk areas over the period 1999-2012. Subsequently we applied the best fitting model to all Polish municipalities. Keeping the remaining variables constant, the predicted rate increased with the increase of air temperature over the previous 10-20 days, precipitation over the previous 20-30 days, in forestation, forest edge density, forest road density, and unemployment. The predicted rate decreased with increasing distance from forests. The map of predicted rates was consistent with the established risk areas. It predicted, however, high rates in provinces considered TBE-free. We recommend raising awareness among physicians working in the predicted high-risk areas and considering routine use of household animal surveys for risk mapping. PMID- 29617332 TI - Rapid Identification of Intact Staphylococcal Bacteriophages Using Matrix Assisted Laser Desorption Ionization-Time-of-Flight Mass Spectrometry. AB - Staphylococcus aureus is a major causative agent of infections associated with hospital environments, where antibiotic-resistant strains have emerged as a significant threat. Phage therapy could offer a safe and effective alternative to antibiotics. Phage preparations should comply with quality and safety requirements; therefore, it is important to develop efficient production control technologies. This study was conducted to develop and evaluate a rapid and reliable method for identifying staphylococcal bacteriophages, based on detecting their specific proteins using matrix-assisted laser desorption ionization time-of flight mass spectrometry (MALDI-TOF MS) profiling that is among the suggested methods for meeting the regulations of pharmaceutical authorities. Five different phage purification techniques were tested in combination with two MALDI-TOF MS matrices. Phages, either purified by CsCl density gradient centrifugation or as resuspended phage pellets, yielded mass spectra with the highest information value if ferulic acid was used as the MALDI matrix. Phage tail and capsid proteins yielded the strongest signals whereas the culture conditions had no effect on mass spectral quality. Thirty-seven phages from Myoviridae, Siphoviridae or Podoviridae families were analysed, including 23 siphophages belonging to the International Typing Set for human strains of S. aureus, as well as phages in preparations produced by Microgen, Bohemia Pharmaceuticals and MB Pharma. The data obtained demonstrate that MALDI-TOF MS can be used to effectively distinguish between Staphylococcus-specific bacteriophages. PMID- 29617334 TI - Decision-Making and Environmental Implications under Cap-and-Trade and Take-Back Regulations. AB - To reduce carbon emissions during production and realize the recycling of resources, the government has promulgated carbon cap-and-trade regulation and take-back regulation separately. This paper firstly analyses the manufacturing, remanufacturing and collection decisions of a monopoly manufacturer under cap-and trade regulation and take-back regulation conditions, and then explores the environmental impact (i.e., carbon emissions) of both carbon regulation and more stringent take-back regulation. Finally, numerical examples are provided to illustrate the theoretical results. The results indicate that it will do good for the environment once the cap-and-trade regulation is carried out. We also conclude that government’s supervision of carbon trading price plays an important role in reducing the environmental impact. Furthermore, unexpectedly, we prove that if emissions intensity of a remanufactured (vis-á-vis new) product is sufficiently high, the improvement of collection and remanufacturing targets might lead to the deterioration of environment. PMID- 29617335 TI - Association between Four-Level Categorisation of Indoor Exposure and Perceived Indoor Air Quality. AB - The aim of this study was to develop and test a tool for assessing urgency of indoor air quality (IAQ) measures. The condition of the 27 buildings were investigated and results were categorized. Statistical test studied the differences between the categories and the employees’ complaints about their work environment. To study the employees’ experiences of the work premises, a validated indoor air (IA) questionnaire was used. This study reveals a multifaceted problem: many factors affecting IAQ may also affect perceived IAQ, making it difficult to separate the impurity sources and ventilation system deficiencies affecting to employee experiences. An examination of the relationship between the categories and perceived IAQ revealed an association between the mould odour perceived by employees and mould detected by the researcher. A weak link was also found between the assessed categories and environmental complaints. However, we cannot make far-reaching conclusions regarding the assessed probability of abnormal IA exposure in the building on the basis of employee experiences. According to the results, categorising tool can partly support the assessment of the urgency for repairs when several factors that affect IAQ are taken into account. PMID- 29617336 TI - Single Nucleotide Polymorphisms in HMGB1 Correlate with Lung Cancer Risk in the Northeast Chinese Han Population. AB - Lung cancer is the principal cause of cancer-associated deaths. HMGB1 has been reported to be associated with tumorigenesis. This study aimed to investigate the relationship between rs1412125 and rs1360485 polymorphisms in HMGB1 and the risk and survival of lung cancer. 850 cases and 733 controls were included. Logistic regression analysis and survival analysis were performed to investigate the association between SNPs and the risk and survival of lung cancer. Crossover analysis was used to analyze the interaction between SNPs and tobacco exposure. Results indicated that rs1412125 polymorphism was associated with lung cancer risk, especially with the risk of lung adenocarcinoma and small cell lung cancer. Carriers with CT and CC genotypes had a decreased risk of lung cancer (CT + CC vs.TT: adjusted OR = 0.736, p = 0.004). Similar results were obtained in the stratification analysis for non-smokers and female population. For rs1360485 polymorphism, AG and GG genotypes could decrease the risk of lung adenocarcinoma and female lung cancer by 0.771-fold and 0.789-fold. However, no significant interaction between polymorphisms and tobacco exposure or association between SNPs and the survival of lung cancer was observed. This study indicated polymorphisms in HMGB1 may be a novel biomarker for female lung adenocarcinoma risk. PMID- 29617337 TI - The Coaching on Lifestyle (CooL) Intervention for Overweight and Obesity: A Longitudinal Study into Participants' Lifestyle Changes. AB - Combined lifestyle interventions (CLIs) can be effective in reducing weight and improving lifestyle-related behaviours but it is unclear how CLIs can best be implemented in practice in order to achieve sustained lifestyle changes. The Coaching on Lifestyle programme (CooL) is a CLI in the Netherlands, in which professional lifestyle coaches counsel adults and children (and/or their parents) who are obese or at high risk of obesity to achieve a sustained healthier lifestyle. The CooL intervention consists of group and individual sessions addressing the topics of physical activity, dietary behaviours, sleep and stress. Our longitudinal one-group pre-post study aimed to identify lifestyle changes among participants (adults, children and their parents) at 8 and 18 months after initiation. We assessed constructs ranging from motivation and behaviour-specific cognitions to behaviours and health outcomes. Positive and sustained changes among adults were found regarding perceived autonomy, motivation, perceived barriers, lifestyle behaviours, quality of life and weight. Among children and their parents, few improvements were found regarding behaviours and quality of life. CooL has been successful in coaching adult participants towards sustained behavioural change during the intervention period. Mixed results and smaller effect sizes were found for children and their parents. PMID- 29617338 TI - A Fiber Optic Interferometric Sensor Platform for Determining Gas Diffusivity in Zeolite Films. AB - Fiber optic interferometer (FOI) sensors have been fabricated by directly growing pure-silica MFI-type zeolite (i.e., silicalite) films on straight-cut endfaces of single-mode communication optical fibers. The FOI sensor has been demonstrated for determining molecular diffusivity in the zeolite by monitoring the temporal response of light interference from the zeolite film during the dynamic process of gas adsorption. The optical thickness of the zeolite film depends on the amount of gas adsorption that causes the light interference to shift upon loading molecules into the zeolitic channels. Thus, the time-dependence of the optical signal reflected from the coated zeolite film can represent the adsorption uptake curve, which allows computation of the diffusivity using models derived from the Fick’s Law equations. In this study, the diffusivity of isobutane in silicalite has been determined by the new FOI sensing method, and the results are in good agreement with literature values obtained by various conventional macroscopic techniques. The FOI sensor platform, because of its robustness and small size, could be useful for studying molecular diffusion in zeolitic materials under conditions that are inaccessible to the existing techniques. PMID- 29617339 TI - Environmental Sustainability and Mold Hygiene in Buildings. AB - Environmental sustainability is one of the key issues in building management. In Hong Kong, one of the initiatives is to reduce the operation hours of air conditioning in buildings to cut down energy consumption. In this study, we reported a mold contamination case in a newly refurbished laboratory, in which the air-conditioner was switched from 24- to 18-h mode after refurbishment. In order to prevent mold recurrence, the air-conditioner was switched back to 24-h mode in the laboratory. During the mold investigation, visible mold patches in the laboratory were searched and then cultured, counted and identified. Building and environmental conditions were recorded, and used to deduce different causes of mold contamination. Eight contaminated sites including a wall, a bench, some metal and plastic surfaces and seven types of molds including two Cladosporium spp., two Aspergillus spp., one Rhizopus sp., one Trichoderma sp., and one Tritirachium sp. were identified. Cladosporium spp. were the most abundant and frequently found molds in the laboratory. The contaminated areas could have one to five different species on them. Based on the mold and environmental conditions, several scenarios causing the mold contamination were deduced, and different mold control measures were discussed to compare them with the current solution of using 24-h air-conditioning to control mold growth. This study highlights the importance of mold hygiene in sustainable building management. PMID- 29617340 TI - Robust Stride Segmentation of Inertial Signals Based on Local Cyclicity Estimation. AB - A novel approach for stride segmentation, gait sequence extraction, and gait event detection for inertial signals is presented. The approach operates by combining different local cyclicity estimators and sensor channels, and can additionally employ a priori knowledge on the fiducial points of gait events. The approach is universal as it can work on signals acquired by different inertial measurement unit (IMU) sensor types, is template-free, and operates unsupervised. A thorough evaluation was performed with two datasets: our own collected FRIgait dataset available for open use, containing long-term inertial measurements collected from 57 subjects using smartphones within the span of more than one year, and an FAU eGait dataset containing inertial data from shoe-mounted sensors collected from three cohorts of subjects: healthy, geriatric, and Parkinson’s disease patients. The evaluation was performed in controlled and uncontrolled conditions. When compared to the ground truth of the labelled FRIgait and eGait datasets, the results of our evaluation revealed the high robustness, efficiency (F-measure of about 98%), and accuracy (mean absolute error MAE in about the range of one sample) of the proposed approach. Based on these results, we conclude that the proposed approach shows great potential for its applicability in procedures and algorithms for movement analysis. PMID- 29617341 TI - Spatiotemporal Local-Remote Senor Fusion (ST-LRSF) for Cooperative Vehicle Positioning. AB - Vehicle positioning plays an important role in the design of protocols, algorithms, and applications in the intelligent transport systems. In this paper, we present a new framework of spatiotemporal local-remote sensor fusion (ST-LRSF) that cooperatively improves the accuracy of absolute vehicle positioning based on two state estimates of a vehicle in the vicinity: a local sensing estimate, measured by the on-board exteroceptive sensors, and a remote sensing estimate, received from neighbor vehicles via vehicle-to-everything communications. Given both estimates of vehicle state, the ST-LRSF scheme identifies the set of vehicles in the vicinity, determines the reference vehicle state, proposes a spatiotemporal dissimilarity metric between two reference vehicle states, and presents a greedy algorithm to compute a minimal weighted matching (MWM) between them. Given the outcome of MWM, the theoretical position uncertainty of the proposed refinement algorithm is proven to be inversely proportional to the square root of matching size. To further reduce the positioning uncertainty, we also develop an extended Kalman filter model with the refined position of ST-LRSF as one of the measurement inputs. The numerical results demonstrate that the proposed ST-LRSF framework can achieve high positioning accuracy for many different scenarios of cooperative vehicle positioning. PMID- 29617342 TI - Identification and In Silico Characterization of a Genetically Distinct Avian Rotavirus D Capsid Gene, VP7. AB - Rotavirus D (RV-D) is gaining importance as a cause of gastroenteritis and runting and stunting syndrome (RSS) in poultry. To date, information is scarce on the molecular analysis of RV-D isolates worldwide. In this study, the VP7 gene, a major constituent of outer capsid structural protein, from a RV-D isolate (UKD48) obtained from Uttarakhand state was analyzed. Phylogenetically, the RV-D isolate was found to be closely related to a South Korean strain, and the nucleotide percent identity varied from 80.4–84.2% with other RV-D strains available globally. Furthermore, domain investigation within 21 aligned amino acid sequences of the VP7 gene affirmed that this gene has several domains: a conserved glycosylation site (N–I–T) having an important role in protein folding; a N-terminal signal peptide (“ITG”) for endoplasmic reticulum retention; and two hydrophobic sites for elucidating transmembrane portions, antigenic structures, and so forth. The findings suggest that the VP7 gene of the Indian RV-D isolate is genetically distinct from those of other avian RV-Ds. Although biological evidence is still needed to prove the functional characteristics of these domains in outer capsid structural proteins, the present study adds new knowledge and derives the need for further investigation. PMID- 29617343 TI - Postharvest Monitoring of Tomato Ripening Using the Dynamic Laser Speckle. AB - The dynamic laser speckle (biospeckle) method was tested as a potential tool for the assessment and monitoring of the maturity stage of tomatoes. Two tomato cultivars—Admiro and Starbuck—were tested. The process of climacteric maturation of tomatoes was monitored during a shelf life storage experiment. The biospeckle phenomena were captured using 640 nm and 830 nm laser light wavelength, and analysed using two activity descriptors based on biospeckle pattern decorrelation—C4 and ε. The well-established optical parameters of tomatoes skin were used as a reference method (luminosity, a*/b*, chroma). Both methods were tested with respect to their prediction capabilities of the maturity and destructive indicators of tomatoes—firmness, chlorophyll and carotenoids content. The statistical significance of the tested relationships were investigated by means of linear regression models. The climacteric maturation of tomato fruit was associated with an increase in biospckle activity. Compared to the 830 nm laser wavelength the biospeckle activity measured at 640 nm enabled more accurate predictions of firmness, chlorophyll and carotenoids content. At 640 nm laser wavelength both activity descriptors (C4 and ε) provided similar results, while at 830 nm the ε showed slightly better performance. The linear regression models showed that biospeckle activity descriptors had a higher correlation with chlorophyll and carotenoids content than the a*/b* ratio and luminosity. The results for chroma were comparable with the results for both biospeckle activity indicators. The biospeckle method showed very good results in terms of maturation monitoring and the prediction of the maturity indices of tomatoes, proving the possibility of practical implementation of this method for the determination of the maturity stage of tomatoes. PMID- 29617344 TI - A Key Gene, PLIN1, Can Affect Porcine Intramuscular Fat Content Based on Transcriptome Analysis. AB - Intramuscular fat (IMF) content is an important indicator for meat quality evaluation. However, the key genes and molecular regulatory mechanisms affecting IMF deposition remain unclear. In the present study, we identified 75 differentially expressed genes (DEGs) between the higher (H) and lower (L) IMF content of pigs using transcriptome analysis, of which 27 were upregulated and 48 were downregulated. Notably, Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated that the DEG perilipin-1 (PLIN1) was significantly enriched in the fat metabolism-related peroxisome proliferator-activated receptor (PPAR) signaling pathway. Furthermore, we determined the expression patterns and functional role of porcine PLIN1. Our results indicate that PLIN1 was highly expressed in porcine adipose tissue, and its expression level was significantly higher in the H IMF content group when compared with the L IMF content group, and expression was increased during adipocyte differentiation. Additionally, our results confirm that PLIN1 knockdown decreases the triglyceride (TG) level and lipid droplet (LD) size in porcine adipocytes. Overall, our data identify novel candidate genes affecting IMF content and provide new insight into PLIN1 in porcine IMF deposition and adipocyte differentiation. PMID- 29617345 TI - Structural Health Monitoring in Composite Structures by Fiber-Optic Sensors. AB - Fiber-optic sensors cannot measure damage; to get information about damage from strain measurements, additional strategies are needed, and several alternatives are available in the existing literature. This paper discusses two independent procedures. The first is based on detecting new strains appearing around a damage spot. The structure does not need to be under loads, the technique is very robust, and damage detectability is high, but it requires sensors to be located very close to the damage, so it is a local technique. The second approach offers wider coverage of the structure; it is based on identifying the changes caused by damage on the strain field in the whole structure for similar external loads. Damage location does not need to be known a priori, and detectability is dependent upon the sensor's network density, the damage size, and the external loads. Examples of application to real structures are given. PMID- 29617346 TI - Effective Delivery of Arsenic Trioxide to HPV-Positive Cervical Cancer Cells Using Optimised Liposomes: A Size and Charge Study. AB - Despite the success of arsenic trioxide (ATO) in treating haematological malignancies, its potential to treat solid tumours has not been fully exploited, owing to its dose-limiting toxicity and poor pharmacokinetics. In order to overcome this hurdle, liposomal encapsulation of the drug with different surface charges (neutral, negative, and positive) and sizes (100, 200 and 400 nm) were synthesised and tested on human papilloma virus (HPV)-positive HeLa and HPV negative HT-3 cervical cancer cell lines. Two epithelial cell lines-human keratinocytes (HK) and human colon cells (CRL-1790)-were used as controls. The synthesised liposomes were tested for their physico-chemical characteristics, drug loading efficiency, and toxicity on the studied cell lines. Neutral liposomes of 100 nm in size were the chosen formulation for delivering ATO into the studied cells, as they showed the least intrinsic cytotoxicity and the highest loading efficiency. The findings demonstrated that the optimised formulation of liposomes was an effective drug delivery method for HPV-infected cervical cancer cells. Furthermore, the toxicity vs. uptake ratio was highest for HeLa cells, while a reduced or minimal toxic effect was observed for non-HPV infected cervical cancer cells and control cells. These findings may provide a promising therapeutic strategy for effectively managing cervical cancers. PMID- 29617347 TI - Flavonoid 8-O-Glucuronides from the Aerial Parts of Malva verticillata and Their Recovery Effects on Alloxan-Induced Pancreatic Islets in Zebrafish. AB - Malva verticillata (Cluster mallow), a leafy vegetable that has been popular in East Asia for a long time, has also been used in herbal teas and medicines. The aqueous fraction of the aerial parts of Malva verticillata, exhibiting a very high quantity of flavonoids compared to the EtOAc and n-BuOH fractions, exhibited significant recovery effects on pancreatic islets damaged by alloxan in zebrafish larvae. Thus, the bioactive components responsible for this anti-diabetic activity were investigated. A new flavonoid glucuronide (1) and five known flavonoids were isolated from the aqueous fraction. Based on several spectroscopic methods, compound 1 was identified to be nortangeretin-8-O-beta-D glucuronide, and was named malvaflavone A. The A-ring of compound 1 had a 5,6,7,8 tetrahydroxy moiety, which rarely occurs in plant systems. Also 8-O-glucuronide attached to the flavonoid moiety was rarely occurred in plant system. Compounds 1, 3, 4, and 6 significantly improved the pancreatic islet size in zebrafish at 0.1 MUM, and compounds 1 and 6 were found to block beta-cell K+ channels in experiments with diazoxide. In ABTS, ORAC, and SOD assays, compounds 1-5 exhibited high anti-oxidant activities compared with quercetin and BHA (positive controls), indicating that the 8-O-glucuronide attached to the flavonoid moiety is a key structure for the expression of anti-oxidant activity. This is the first report of the isolation of compounds 1-6 from M. verticillata as well evaluated for anti-diabetic and anti-oxidant ativities. PMID- 29617348 TI - A Student's t Mixture Probability Hypothesis Density Filter for Multi-Target Tracking with Outliers. AB - In multi-target tracking, the outliers-corrupted process and measurement noises can reduce the performance of the probability hypothesis density (PHD) filter severely. To solve the problem, this paper proposed a novel PHD filter, called Student's t mixture PHD (STM-PHD) filter. The proposed filter models the heavy tailed process noise and measurement noise as a Student's t distribution as well as approximates the multi-target intensity as a mixture of Student's t components to be propagated in time. Then, a closed PHD recursion is obtained based on Student's t approximation. Our approach can make full use of the heavy-tailed characteristic of a Student's t distribution to handle the situations with heavy tailed process and the measurement noises. The simulation results verify that the proposed filter can overcome the negative effect generated by outliers and maintain a good tracking accuracy in the simultaneous presence of process and measurement outliers. PMID- 29617349 TI - Toenail Chromium Concentration and Metabolic Syndrome among Korean Adults. AB - Although in vivo and in vitro studies have shown that chromium has protective effects against metabolic diseases, few studies have examined this association in humans. The present study examined chronic chromium (Cr) exposure among Koreans based on the measurement of toenail Cr concentrations, and analyzed the associations between toenail Cr concentrations and metabolic syndrome (MetS) and its components. We conducted a cross-sectional analysis using baseline data from the prospective cohort study in the Yeungnam area of South Korea that included 232 men and 268 women. Toenail Cr concentration was quantified by neutron activation analysis, and metabolic biomarker levels were obtained through medical examinations. The odd ratios (OR) of prevalent MetS and its components in correlation with Cr concentrations were calculated using multivariable logistic regression. After multiple confounding variables were adjusted for, participants with higher concentrations of Cr had a prevalence rate of MetS similar to those with lower concentrations (OR, 1.84; 95% confidence interval, 0.65-5.23). Our results do not support an association between long-term exposure to Cr and a lower prevalence of MetS in Koreans, whose Cr concentrations are relatively low compared to those of populations in Europe and the United States. PMID- 29617350 TI - Co-Ingestion of Rice Bran Soymilk or Plain Soymilk with White Bread: Effects on the Glycemic and Insulinemic Response. AB - The regular consumption of soy products is associated with inverse incidence of type 2 diabetes, and there has been an increasing interest in the glycemia reducing potential of rice bran and its components. In this study, we investigated whether consuming soymilk with the addition of rice bran (fiber) can reduce the glycemic response of a carbohydrate meal. Seventeen healthy Asian men (BMI: 18.5-29 kg/m2) participated in this randomized crossover trial. On four occasions, they consumed white bread (two times) and white bread with two different soymilks differing in protein and rice bran content. Blood samples were taken to measure glucose and insulin response over a period of 3 hours. Taking the glycemic index (GI) value of white bread as a reference value of 100, the GI of white bread when co-ingested with rice bran soymilk (RBS) was 83.1 (+/-7.7) and sugar-free soymilk (SFS) was 77.5 (+/-10.1), both were lower than white bread (p < 0.05). The insulin response of both soymilk treatments was similar to white bread (p > 0.05). The glucose/insulin ratio of RBS and SFS were respectively 43.1 (+/- 6.1) and 60.0 (+/- 17.0) and were lower (p < 0.05) than white bread (123.5 +/- 21.1) during the first 30 min. In conclusion, co-ingestion of low amounts of soy protein with a carbohydrate meal stimulated early-phase insulin secretion and thereby increased blood glucose clearance effectiveness. Furthermore, rice bran fortified soymilk reduced the glycemic response similarly to soymilk with a greater dose of soy protein. Rice bran and its components offer therapeutic potential for glycemic and insulinemic control. PMID- 29617351 TI - The Nuts and Bolts of Food Immunotherapy: The Future of Food Allergy. AB - Food allergies are on the rise and have a major impact on the quality of life of the food allergic child and their family. Currently, the mainstream treatment for food allergies is strict avoidance and elimination of the allergenic food(s) from the patient's diet in order to prevent an allergic reaction. However, recent advances in research have presented new therapeutic options for food allergic patients that are potentially becoming promising alternatives to traditional treatment. Food immunotherapy is the most popular of these new emerging interventions and has been studied intensively over the last decade for various foods. In this review, we discuss this exciting new development that is aspiring to become part of the mainstream therapy for food allergy. PMID- 29617352 TI - Loss of ISWI Function in Drosophila Nuclear Bodies Drives Cytoplasmic Redistribution of Drosophila TDP-43. AB - Over the past decade, evidence has identified a link between protein aggregation, RNA biology, and a subset of degenerative diseases. An important feature of these disorders is the cytoplasmic or nuclear aggregation of RNA-binding proteins (RBPs). Redistribution of RBPs, such as the human TAR DNA-binding 43 protein (TDP 43) from the nucleus to cytoplasmic inclusions is a pathological feature of several diseases. Indeed, sporadic and familial forms of amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar degeneration share as hallmarks ubiquitin-positive inclusions. Recently, the wide spectrum of neurodegenerative diseases characterized by RBPs functions' alteration and loss was collectively named proteinopathies. Here, we show that TBPH (TAR DNA-binding protein-43 homolog), the Drosophila ortholog of human TDP-43 TAR DNA-binding protein-43, interacts with the arcRNA hsromega and with hsromega-associated hnRNPs. Additionally, we found that the loss of the omega speckles remodeler ISWI (Imitation SWI) changes the TBPH sub-cellular localization to drive a TBPH cytoplasmic accumulation. Our results, hence, identify TBPH as a new component of omega speckles and highlight a role of chromatin remodelers in hnRNPs nuclear compartmentalization. PMID- 29617354 TI - Radiation-Induced Gene Expression Changes in High and Low Grade Breast Cancer Cell Types. AB - BACKGROUND: There is extensive scientific evidence that radiation therapy (RT) is a crucial treatment, either alone or in combination with other treatment modalities, for many types of cancer, including breast cancer (BC). BC is a heterogeneous disease at both clinical and molecular levels, presenting distinct subtypes linked to the hormone receptor (HR) status and associated with different clinical outcomes. The aim of this study was to assess the molecular changes induced by high doses of ionizing radiation (IR) on immortalized and primary BC cell lines grouped according to Human epidermal growth factor receptor (HER2), estrogen, and progesterone receptors, to study how HR status influences the radiation response. Our genomic approach using in vitro and ex-vivo models (e.g., primary cells) is a necessary first step for a translational study to describe the common driven radio-resistance features associated with HR status. This information will eventually allow clinicians to prescribe more personalized total doses or associated targeted therapies for specific tumor subtypes, thus enhancing cancer radio-sensitivity. METHODS: Nontumorigenic (MCF10A) and BC (MCF7 and MDA-MB-231) immortalized cell lines, as well as healthy (HMEC) and BC (BCpc7 and BCpcEMT) primary cultures, were divided into low grade, high grade, and healthy groups according to their HR status. At 24 h post-treatment, the gene expression profiles induced by two doses of IR treatment with 9 and 23 Gy were analyzed by cDNA microarray technology to select and compare the differential gene and pathway expressions among the experimental groups. RESULTS: We present a descriptive report of the substantial alterations in gene expression levels and pathways after IR treatment in both immortalized and primary cell cultures. Overall, the IR-induced gene expression profiles and pathways appear to be cell line dependent. The data suggest that some specific gene and pathway signatures seem to be linked to HR status. CONCLUSIONS: Genomic biomarkers and gene signatures of specific tumor subtypes, selected according to their HR status and molecular features, could facilitate personalized biological-driven RT treatment planning alone and in combination with targeted therapies. PMID- 29617353 TI - Teleosts Genomics: Progress and Prospects in Disease Prevention and Control. AB - Genome wide studies based on conventional molecular tools and upcoming omics technologies are beginning to gain functional applications in the control and prevention of diseases in teleosts fish. Herein, we provide insights into current progress and prospects in the use genomics studies for the control and prevention of fish diseases. Metagenomics has emerged to be an important tool used to identify emerging infectious diseases for the timely design of rational disease control strategies, determining microbial compositions in different aquatic environments used for fish farming and the use of host microbiota to monitor the health status of fish. Expounding the use of antimicrobial peptides (AMPs) as therapeutic agents against different pathogens as well as elucidating their role in tissue regeneration is another vital aspect of genomics studies that had taken precedent in recent years. In vaccine development, prospects made include the identification of highly immunogenic proteins for use in recombinant vaccine designs as well as identifying gene signatures that correlate with protective immunity for use as benchmarks in optimizing vaccine efficacy. Progress in quantitative trait loci (QTL) mapping is beginning to yield considerable success in identifying resistant traits against some of the highly infectious diseases that have previously ravaged the aquaculture industry. Altogether, the synopsis put forth shows that genomics studies are beginning to yield positive contribution in the prevention and control of fish diseases in aquaculture. PMID- 29617355 TI - Specific Chemical and Genetic Markers Revealed a Thousands-Year Presence of Toxic Nodularia spumigena in the Baltic Sea. AB - In the Baltic Sea, diazotrophic cyanobacteria have been present for thousands of years, over the whole brackish water phase of the ecosystem. However, our knowledge about the species composition of the cyanobacterial community is limited to the last several decades. In the current study, the presence of species-specific chemical and genetic markers in deep sediments were analyzed to increase the existing knowledge on the history of toxic Nodularia spumigena blooms in the Baltic Sea. As chemical markers, three cyclic nonribosomal peptides were applied: the hepatotoxic nodularin, which in the sea was detected solely in N. spumigena, and two anabaenopeptins (AP827 and AP883a) characteristic of two different chemotypes of this species. From the same sediment samples, DNA was isolated and the gene involved in biosynthesis of nodularin, as well as the phycocyanin intergenic spacer region (PC-IGS), were amplified. The results of chemical and genetic analyses proved for the first time the thousands-year presence of toxic N. spumigena in the Baltic Sea. They also indicated that through all this time, the same two sub-populations of the species co-existed. PMID- 29617356 TI - Clostridium Bacteria and Autism Spectrum Conditions: A Systematic Review and Hypothetical Contribution of Environmental Glyphosate Levels. AB - Nowadays, there seems to be a consensus about the multifactorial nature of autism spectrum disorders (ASD). The literature provides hypotheses dealing with numerous environmental factors and genes accounting for the apparently higher prevalence of this condition. Researchers have shown evidence regarding the impact of gut bacteria on neurological outcomes, altering behavior and potentially affecting the onset and/or severity of psychiatric disorders. Pesticides and agrotoxics are also included among this long list of ASD-related environmental stressors. Of note, ingestion of glyphosate (GLY), a broad-spectrum systemic herbicide, can reduce beneficial bacteria in the gastrointestinal tract microbiota without exerting any effects on the Clostridium population, which is highly resistant to this herbicide. In the present study, (i) we performed a systematic review to evaluate the relationship between Clostridium bacteria and the probability of developing and/or aggravating autism among children. For that purpose, electronic searches were performed on Medline/PubMed and Scielo databases for identification of relevant studies published in English up to December 2017. Two independent researches selected the studies and analyzed the data. The results of the present systematic review demonstrate an interrelation between Clostridium bacteria colonization of the intestinal tract and autism. Finally, (ii) we also hypothesize about how environmental GLY levels may deleteriously influence the gut-brain axis by boosting the growth of Clostridium bacteria in autistic toddlers. PMID- 29617357 TI - Cyclic Guanosine Monophosphate (cGMP)-Dependent Protein Kinase II Blocks Epidermal Growth Factor (EGF)/Epidermal Growth Factor Receptor (EGFR)-Induced Biological Effects on Osteosarcoma Cells. AB - BACKGROUND The present work was performed to detect the potential inhibitory effect of cyclic guanosine monophosphate (cGMP)-dependent protein kinase II (PKG II) on epidermal growth factor (EGF) receptor-induced biological activity and related signal cascades in osteosarcoma cells. MATERIAL AND METHODS We transfected the osteosarcoma MG-63 cell line with an adenoviral vector encoding PKG II cDNA (Ad-PKGII) and incubated the transfected cells with 250 MUM 8-pCPT cGMP to activate the PKG II. We stimulated the MG-63 cells with100 ng/ml EGF, and then detected their proliferation using a CCK-8 assay. Transwell assay was used to examine MG-63 cell migration; and Western blot analysis was used to detect expression of matrix metalloproteinase 9 (MMP-9) and activation of ERK and Akt. RESULTS Stimulating cells by 100 ng/ml EGF promoted MG-63 cell proliferation and migration, ERK and Akt phosphorylation, and MMP-9 expression. These effects of EGF were inhibited in MG-63 cells infected with Ad-PKGII and incubated with 8 pCPT-cGMP. CONCLUSIONS Our results demonstrate that Ad-PKGII infection significantly inhibited EGF-induced proliferation and migration, as well as the associated-signal cascades; which indicates that PKG II might be a potential anti cancer factor. PMID- 29617358 TI - What exactly is 'N' in cell culture and animal experiments? AB - Biologists determine experimental effects by perturbing biological entities or units. When done appropriately, independent replication of the entity intervention pair contributes to the sample size (N) and forms the basis of statistical inference. If the wrong entity-intervention pair is chosen, an experiment cannot address the question of interest. We surveyed a random sample of published animal experiments from 2011 to 2016 where interventions were applied to parents and effects examined in the offspring, as regulatory authorities provide clear guidelines on replication with such designs. We found that only 22% of studies (95% CI = 17%-29%) replicated the correct entity intervention pair and thus made valid statistical inferences. Nearly half of the studies (46%, 95% CI = 38%-53%) had pseudoreplication while 32% (95% CI = 26% 39%) provided insufficient information to make a judgement. Pseudoreplication artificially inflates the sample size, and thus the evidence for a scientific claim, resulting in false positives. We argue that distinguishing between biological units, experimental units, and observational units clarifies where replication should occur, describe the criteria for genuine replication, and provide concrete examples of in vitro, ex vivo, and in vivo experimental designs. PMID- 29617359 TI - Sexual dimorphism of sleep regulated by juvenile hormone signaling in Drosophila. AB - Sexually dimorphic phenotypes are a universal phenomenon in animals. In the model animal fruit fly Drosophila, males and females exhibit long- and short-sleep phenotypes, respectively. However, the mechanism is still a mystery. In this study, we showed that juvenile hormone (JH) is involved in regulation of sexually dimorphic sleep in Drosophila, in which gain of JH function enlarges differences of the dimorphic sleep phenotype with higher sleep in males and lower sleep in females, while loss of JH function blurs these differences and results in feminization of male sleep and masculinization of female sleep. Further studies indicate that germ cell-expressed (GCE), one of the JH receptors, mediates the response in the JH pathway because the sexually dimorphic sleep phenotypes cannot be rescued by JH hormone in a gce deletion mutant. The JH-GCE regulated sleep dimorphism is generated through the sex differentiation-related genes -fruitless (fru) and doublesex (dsx) in males and sex-lethal (sxl), transformer (tra) and doublesex (dsx) in females. These are the "switch" genes that separately control the sleep pattern in males and females. Moreover, analysis of sleep deprivation and circadian behaviors showed that the sexually dimorphic sleep induced by JH signals is a change of sleep drive and independent of the circadian clock. Furthermore, we found that JH seems to also play an unanticipated role in antagonism of an aging-induced sleep decrease in male flies. Taken together, these results indicate that the JH signal pathway is critical for maintenance of sexually dimorphic sleep by regulating sex-relevant genes. PMID- 29617360 TI - Toxicological and pharmacological assessment of AGEN1884, a novel human IgG1 anti CTLA-4 antibody. AB - CTLA-4 and CD28 exemplify a co-inhibitory and co-stimulatory signaling axis that dynamically sculpts the interaction of antigen-specific T cells with antigen presenting cells. Anti-CTLA-4 antibodies enhance tumor-specific immunity through a variety of mechanisms including: blockade of CD80 or CD86 binding to CTLA-4, repressing regulatory T cell function and selective elimination of intratumoral regulatory T cells via an Fcgamma receptor-dependent mechanism. AGEN1884 is a novel IgG1 antibody targeting CTLA-4. It potently enhanced antigen-specific T cell responsiveness that could be potentiated in combination with other immunomodulatory antibodies. AGEN1884 was well-tolerated in non-human primates and enhanced vaccine-mediated antigen-specific immunity. AGEN1884 combined effectively with PD-1 blockade to elicit a T cell proliferative response in the periphery. Interestingly, an IgG2 variant of AGEN1884 revealed distinct functional differences that may have implications for optimal dosing regimens in patients. Taken together, the pharmacological properties of AGEN1884 support its clinical investigation as a single therapeutic and combination agent. PMID- 29617361 TI - A real-time PCR tool for the surveillance of zoonotic Onchocerca lupi in dogs, cats and potential vectors. AB - The ocular onchocercosis is caused by the zoonotic parasite Onchocerca lupi (Spirurida: Onchocercidae). A major hindrance to scientific progress is the absence of a reliable diagnostic test in affected individuals. Microscopic examination of skin snip sediments and the identification of adults embedded in ocular nodules are seldom performed and labour-intensive. A quantitative real time PCR (qPCR) assay was herein standardized for the detection of O. lupi DNA and the results compared with microscopic examination and conventional PCR (cPCR). The specificity of qPCR and cPCR was assessed by processing the most common filarial nematodes infecting dogs, skin samples from O. lupi infected (n = 35 dogs) or uninfected animals (n = 21 dogs; n = 152 cats) and specimens of potential insect vector (n = 93 blackflies; n = 59 mosquitoes/midges). The analytical sensitivity of both assays was assessed using 10-fold serial dilutions of DNA from adult specimen and from a pool of microfilariae. The qPCR on skin samples revealed an analytical specificity of 100% and a sensitivity up to 8 x 10 1 fg/2MUl O. lupi adult-DNA and up to 3.6 x 10-1 pg/2MUl of mfs-DNA (corresponding to 1 x 10-2 mfs/2MUl). Only 9.5% O. lupi-infected skin samples were positive for cPCR with a sensitivity of 8 x 10-1 pg/2MUl of DNA. Out of 152 blackflies and mosquitoes/midges, eight specimens experimentally infected (n = 1 S. erythrocephalum; n = 1 S. ornatum; n = 6 Simulium sp.) were positive by qPCR. The qPCR assay herein standardized represents an important step forward in the diagnosis of zoonotic onchocercosis caused by O. lupi, especially for the detection and quantification of low number of mfs. This assay provides a fundamental contribution for the establishment of surveillance strategies aiming at assessing the presence of O. lupi in carnivores and in insect species acting as potential intermediate hosts. The O. lupi qPCR assay will enable disease progress monitoring as well as the diagnosis of apparently clinical healthy dogs and cats. PMID- 29617362 TI - A novel approach to improve immune effector responses post transplant by restoration of CCL21 expression. AB - Chemotherapy or chemoradiotherapy conditioning regimens required for bone marrow transplantation (BMT) cause significant morbidity and mortality as a result of insufficient immune surveillance mechanisms leading to increased risks of infection and tumor recurrence. Such conditioning causes host stromal cell injury, impairing restoration of the central (thymus) and peripheral (spleen and lymph node) T cell compartments and slow immune reconstitution. The chemokine, CCL21, produced by host stromal cells, recruits T- and B-cells that provide lymphotoxin mediated instructive signals to stromal cells for lymphoid organogenesis. Moreover, T- and B-cell recruitment into these sites is required for optimal adaptive immune responses to pathogens and tumor antigens. Previously, we reported that CCL21 was markedly reduced in secondary lymphoid organs of transplanted animals. Here, we utilized adenoviral CCL21 gene transduced dendritic cells (DC/CCL21) given by footpad injections as a novel approach to restore CCL21 expression in secondary lymphoid organs post transplant. CCL21 expression in secondary lymphoid organs reached levels of naive controls and resulted in increased T cell trafficking to draining lymph nodes (LNs). An increase in both lymphoid tissue inducer cells and the B cell chemokine CXCL13 known to be important in LN formation was observed. Strikingly, only mice vaccinated with DC/CCL21 loaded with bacterial, viral or tumor antigens and not recipients of DC/control adenovirus loaded cells or no DCs had a marked increase in the systemic clearance of pathogens (bacteria; virus) and leukemia cells. Because DC/CCL21 vaccines have been tested in clinical trials for patients with lung cancer and melanoma, our studies provide the foundation for future trials of DC/CCL21 vaccination in patients receiving pre-transplant conditioning regimens. PMID- 29617363 TI - Pre-exposure to 50 Hz-electromagnetic fields enhanced the antiproliferative efficacy of 5-fluorouracil in breast cancer MCF-7 cells. AB - Resistance to 5-fluorouracil (5-FU) and its induced immune suppression have prevented its extensive application in the clinical treatment of breast cancer. In this study, the combined effect of 50 Hz-EMFs and 5-FU in the treatment of breast cancer was explored. MCF-7 and MCF10A cells were pre-exposed to 50 Hz-EMFs for 0, 2, 4, 8 and 12 h and then treated with different concentrations of 5-FU for 24 h; cell viability was analyzed by MTT assay and flow cytometry. After pre exposure to 50 Hz-EMFs for 12 h, apoptosis and cell cycle distribution in MCF-7 and MCF10A cells were detected via flow cytometry and DNA synthesis was measured by EdU incorporation assay. Apoptosis-related and cell cycle-related gene and protein expression levels were monitored by qPCR and western blotting. Pre exposure to 50 Hz-EMFs for 12 h enhanced the antiproliferative effect of 5-FU in breast cancer cell line MCF-7 in a dose-dependent manner but not in normal human breast epithelial cell line MCF10A. Exposure to 50 Hz-EMFs had no effect on apoptosis and P53 expression of MCF-7 and MCF10A cells, whereas it promoted DNA synthesis, induced entry of MCF-7 cells into the S phase of cell cycle, and upregulated the expression levels of cell cycle-related proteins Cyclin D1 and Cyclin E. Considering the pharmacological mechanisms of 5-FU in specifically disrupting DNA synthesis, this enhanced inhibitory effect might have resulted from the specific sensitivity of MCF7 cells in active S phase to 5-FU. Our findings demonstrate the enhanced cytotoxic activity of 5-FU on MCF7 cells through promoting entry into the S phase of the cell cycle via exposure to 50 Hz EMFs, which provides a novel method of cancer treatment based on the combinatorial use of 50 Hz-EMFs and chemotherapy. PMID- 29617364 TI - Refractoriness of Sergentomyia schwetzi to Leishmania spp. is mediated by the peritrophic matrix. AB - BACKGROUND: The peritrophic matrix (PM) is an acellular chitin-containing envelope which in most blood sucking insects encloses the ingested blood meal and protects the midgut epithelium. Type I PM present in sand flies and other blood sucking batch feeders is secreted around the meal by the entire midgut in response to feeding. Here we tested the hypothesis that in Sergentomyia schwetzi the PM creates a physical barrier that prevents escape of Leishmania parasites from the endoperitrophic space. METHODOLOGY/PRINCIPAL FINDINGS: Morphology and ultrastructure of the PM as well the production of endogenous chitinase in S. schwetzi were compared with three sand fly species, which are natural vectors of Leishmania. Long persistence of the PM in S. schwetzi was not accompanied by different morphology or decreased production of chitinase. To confirm the role of the PM in refractoriness of S. schwetzi to Leishmania parasites, culture supernatant from the fungus Beauveria bassiana containing chitinase was added to the infective bloodmeal to disintegrate the PM artificially. In females treated with B. bassiana culture supernatants the PM was weakened and permeable, lacking multilayered inner structure; Leishmania colonized the midgut and the stomodeal valve and produced metacyclic forms. In control females Leishmania infections were lost during defecation. CONCLUSIONS/SIGNIFICANCE: Persistence of the PM till defecation of the bloodmeal represents an important factor responsible for refractoriness of S. schwetzi to Leishmania development. Leishmania major as well as L. donovani promastigotes survived defecation and developed late-stage infections only in females with PM disintegrated artificially by B. bassiana culture supernatants containing exogenous chitinase. PMID- 29617365 TI - PTEN suppresses axon outgrowth by down-regulating the level of detyrosinated microtubules. AB - Inhibition of the phospholipid phosphatase and tumor suppressor PTEN leads to excessive polarized cell growth during directed cell migration and neurite outgrowth. These processes require the precise regulation of both the actin and microtubule cytoskeleton. While PTEN is known to regulate actin dynamics through phospholipid modulation, whether and how PTEN regulates microtubule dynamics is unknown. Here, we show that depletion of PTEN leads to elevated levels of stable and post-translationally modified (detyrosinated) microtubules in fibroblasts and developing neurons. Further, PTEN depletion enhanced axon outgrowth, which was rescued by reducing the level of detyrosinated microtubules. These data demonstrate a novel role of PTEN in regulating the microtubule cytoskeleton. They further show a novel function of detyrosinated microtubules in axon outgrowth. Specifically, PTEN suppresses axon outgrowth by down-regulating the level of detyrosinated microtubules. Our results suggest that PTEN's role in preventing excessive cell growth in cancerous and neurodevelopmental phenotypes is partially exerted by stabilization and detyrosination of the microtubule cytoskeleton. PMID- 29617366 TI - Cross sectional associations of screen time and outdoor play with social skills in preschool children. AB - Screen time and physical activity behaviours develop during the crucial early childhood period (0-5 years) and impact multiple health and developmental outcomes, including psychosocial wellbeing. Social skills, one component of psychosocial wellbeing, are vital for children's school readiness and future mental health. This study investigates potential associations of screen time and outdoor play (as a proxy for physical activity) with social skills. Cross sectional data were available for 575 mothers with a child (54% boys) aged 2-5 years. Mothers reported their child's screen time, outdoor play time and social skills (Adaptive Social Behavior Inventory; ASBI). Multiple linear regression analyses assessed associations of screen and outdoor play time (Model 1) and compliance with screen time and physical activity recommendations (Model 2) with three ASBI subscales. Boys and girls spent a mean of 2.0 and 2.2 hours per day in screen time, and 3.3 and 2.9 hours per day in outdoor play, respectively. Girls scores for express and comply skills were significantly higher than boys (p<0.005). After applying the Benjamini-Hochberg Procedure to adjust for multiple associations, children's television/DVD/video viewing was inversely associated with their compliant scores (B = -0.35 95% CI -0.26, -0.14; p = 0.001) and outdoor play time was positively associated with both expressive (B = 0.20 95% CI 0.07, 0.34; p = 0.004) and compliant (B = 0.22 95% CI 0.08, 0.36; p = 0.002) scores. Findings indicate that television/DVD/video viewing may be adversely, and outdoor play favourably, associated with preschool children's social skills. Future research is required to identify the direction of causation and explore potential mechanisms of association. PMID- 29617368 TI - Reducing negative affect and increasing rapport improve interracial mentorship outcomes. AB - Research suggests that interracial mentoring relationships are strained by negative affect and low rapport. As such, it stands to reason that strategies that decrease negative affect and increase rapport should improve these relationships. However, previous research has not tested this possibility. In video-chats (Studies 1 and 2) and face-to-face meetings (Study 3), we manipulated the degree of mutual self-disclosure between mentees and mentors, a strategy that has been shown to reduce negative affect and increase rapport. We then measured negative affect and rapport as mediators, and mentee performance (quality of speech delivered; Studies 1 and 3) and mentor performance (warmth and helpfulness; Studies 2 and 3) as key outcomes. Results revealed that increased self-disclosure decreased negative affect and increased rapport for both mentees and mentors. Among mentees, decreased negative affect predicted better performance (Studies 1 and 3). Among mentors, increased rapport predicted warmer feedback (Studies 2 and 3). These effects remained significant when we meta analyzed data across studies (Study 4), and also revealed the relationship of rapport to more helpful feedback. Findings suggest that affect and rapport are key features in facilitating positive outcomes in interracial mentoring relationships. PMID- 29617367 TI - Gene set analysis of post-lactational mammary gland involution gene signatures in inflammatory and triple-negative breast cancer. AB - BACKGROUND: Epidemiological studies have found that triple-negative breast cancer (TNBC) and TN inflammatory breast cancer (IBC) are associated with lower frequency and duration of breast-feeding compared to non-TNBC and non-TN IBC, respectively. Limited breast-feeding could reflect abrupt or premature involution and contribute to a "primed" stroma that is permissive to the migration of cancer cells typical of IBC. We hypothesized that gene expression related to abrupt mammary gland involution after forced weaning may be enriched in the tissues of IBC patients and, if so, provide a potential correlation between limited breast feeding and the development of aggressive breast cancer. METHODS: We utilized the Short Time-series Expression Miner (STEM) program to cluster significant signatures from two independent studies that analyzed gene expression at multiple time-points of mouse mammary gland involution. Using 10 significant signatures, we performed gene ontology analysis and gene set enrichment analysis (GSEA) on training and validation sets from human breast cancer gene expression data to identify specific genes that are enriched in IBC compared to non-IBC and in TN compared to non-TN in IBC and non-IBC groups. RESULTS: Examining the combined data, we identified 10 involution gene clusters (Inv1-10) that share time dependent regulation after forced weaning. Inv5 was the only cluster significantly enriched in IBC in the training and validation set (nominal p values <0.05) and only by unadjusted p-values (FDR q-values 0.26 and 0.46 respectively). Eight genes in Inv5 are upregulated in both the training and validation sets in IBC. Combining the training and validation sets, both Inv5 and Inv6 have nominal p-values <0.05 and q-values 0.39 and 0.20, respectively. The time course for both clusters includes genes that change within 12 hours after forced weaning. CONCLUSIONS: Results from this in silico study suggest correlation between molecular events during abrupt involution and aggressive breast cancer. Specifically, candidate genes from Inv5 merit functional investigation regarding the role of limited breast-feeding in IBC development. PMID- 29617369 TI - A novel decision tree classification based on post-pruning with Bayes minimum risk. AB - Pruning is applied in order to combat over-fitting problem where the tree is pruned back with the goal of identifying decision tree with the lowest error rate on previously unobserved instances, breaking ties in favour of smaller trees with high accuracy. In this paper, pruning with Bayes minimum risk is introduced for estimating the risk-rate. This method proceeds in a bottom-up fashion converting a parent node of a subtree to a leaf node if the estimated risk-rate of the parent node for that subtree is less than the risk-rates of its leaf. This paper proposes a post-pruning method that considers various evaluation standards such as attribute selection, accuracy, tree complexity, and time taken to prune the tree, precision/recall scores, TP/FN rates and area under ROC. The experimental results show that the proposed method produces better classification accuracy and its complexity is not much different than the complexities of reduced-error pruning and minimum-error pruning approaches. The experiments also demonstrate that the proposed method shows satisfactory performance in terms of precision score, recall score, TP rate, FP rate and area under ROC. PMID- 29617370 TI - Metabolic and hormonal adaptation in Bubalus bubalis around calving and early lactation. AB - Pregnancy and lactation are physiological periods that result in an increased metabolic demand that, if not satisfied, could provoke a threat to homeostasis. In this study changes in the values of Non-Esterified Fatty Acids (NEFA) and beta hydroxybutyrate (BHB), glucose, insulin, thyroid hormones, milk composition and yield were investigated in buffaloes during the late pregnancy and early lactation. From a total of 50 buffaloes, blood samples were collected -7+/-5 days before expected calving; +7+/-5; +30+/-5 and +50+/-5 days post-partum; milk samples were collected at the same post-partum time points. On serum samples, the values of Non-Esterified Fatty Acids (NEFA), beta-hydroxybutyrate (BHB), glucose, insulin, Triiodothyronine (T3), Thyroxine (T4) and Thyroid-stimulating hormone (TSH) were evaluated. On milk, fat %, protein %, lactose %, somatic cells score (SCS), milk yield and daily milk production (DMP) were assessed. Peripartum period significantly influenced all studied parameters (P<0.05). Milk constituents and productivity statistically changed throughout monitoring period (P<0.005). Milk yield resulted positively correlated with insulin and TSH values, negatively correlated with NEFA and BHB. Insulin was negatively correlated with lactose % and positively correlated with SCS. The obtained results showed that the peripartum period and lactation are accompanied by marked changes in some biochemical variables and in the thyroid hormones values in Italian Mediterranean Buffaloes. Moreover, the relationship found between TSH values and milk yield seems to suggest a possible role of thyroid gland on the maintenance of lactogenesis. This study underlines the importance of monitoring the hormonal status of buffalo during the transition period in order to understand when adjustments of regulatory mechanisms break through physiological limits predisposing the buffalo to metabolic problems. PMID- 29617371 TI - Critical diversity: Divided or united states of social coordination. AB - Much of our knowledge of coordination comes from studies of simple, dyadic systems or systems containing large numbers of components. The huge gap 'in between' is seldom addressed, empirically or theoretically. We introduce a new paradigm to study the coordination dynamics of such intermediate-sized ensembles with the goal of identifying key mechanisms of interaction. Rhythmic coordination was studied in ensembles of eight people, with differences in movement frequency ('diversity') manipulated within the ensemble. Quantitative change in diversity led to qualitative changes in coordination, a critical value separating regimes of integration and segregation between groups. Metastable and multifrequency coordination between participants enabled communication across segregated groups within the ensemble, without destroying overall order. These novel findings reveal key factors underlying coordination in ensemble sizes previously considered too complicated or 'messy' for systematic study and supply future theoretical/computational models with new empirical checkpoints. PMID- 29617372 TI - Trends in the relative prevalence of genital ulcer disease pathogens and association with HIV infection in Johannesburg, South Africa, 2007-2015. AB - BACKGROUND: In South Africa, treatment of genital ulcer disease (GUD) occurs in the context of syndromic management. GUD aetiological studies have been conducted in Johannesburg since 2007. We report on GUD pathogen prevalence, sero-prevalence of STI co-infections and aetiological trends among GUD patients presenting to a community-based primary healthcare facility in Johannesburg over a 9-year period. METHODS AND FINDINGS: GUD surveys were conducted from January to April each year. Consecutive genital ulcers were sampled from consenting adults. Swab-extracted DNA was tested by multiplex real-time PCR assays for herpes simplex virus (HSV), Treponema pallidum (TP), Haemophilus ducreyi (HD) and Chlamydia trachomatis (CT). HSV-positive DNA extracts were further subtyped into HSV-1 and HSV-2 using a commercial PCR assay; CT-positive extracts were tested with an in-house PCR assay specific for serovars L1-L3 (lymphogranuloma venereum). Sera were tested for HIV, HSV-2, and syphilis co-infections. Giemsa-stained ulcer smears were screened for Klebsiella granulomatis by microscopy. Data were analysed with STATATM version 14. Of 771 GUD specimens, 503 (65.2%) had a detectable pathogen: HSV 468 (60.7%); TP 30 (3.9%); CT L1-3 7 (0.9%); HD 4 (0.5%). No aetiological agents were detected in 270 (34.8%) ulcer specimens. Seroprevalence rates were as follows: HIV 61.7%; HSV-2 80.2% and syphilis 5.8%. There was a strong association between GUD pathogen detection and HIV seropositivity (p < 0.001); 68% of cases caused by HSV were co-infected with HIV. There was a significant decline in the relative prevalence of ulcer-derived HSV over time, predominantly from 2013-2015 (p-value for trend = 0.023); and a trend towards a decrease in the HIV seropositivity rate (p-value for trend = 0.209). CONCLUSIONS: HSV remains the leading cause of pathogen-detectable GUD in South Africa. The prevalence of HIV co-infection among GUD patients is high, underlining the importance of linkage to universal HIV testing and treatment in primary healthcare settings. PMID- 29617373 TI - Emotional reactivity to daily life stress in spousal caregivers of people with dementia: An experience sampling study. AB - INTRODUCTION: Caregivers differ in their emotional response when facing difficult situations during the caregiving process. Individual differences in vulnerabilities and resources could play an exacerbating or buffering role in caregivers' reactivity to daily life stress. This study examines which caregiver characteristics modify emotional stress reactivity in dementia caregivers. METHODS: Thirty caregivers collected momentary data, as based on the experience sampling methodology, to assess (1) appraised subjective stress related to events and minor disturbances in daily life, and (2) emotional reactivity to these daily life stressors, conceptualized as changes in negative affect. Caregiver characteristics (i.e. vulnerabilities and resources) were administered retrospectively. RESULTS: Caregivers who more frequently used the coping strategies 'seeking distraction', 'seeking social support', and 'fostering reassuring thoughts' experienced less emotional reactivity towards stressful daily events. A higher educational level and a higher sense of competence and mastery lowered emotional reactivity towards minor disturbances in daily life. No effects were found for age, gender, and hours of care and contact with the person with dementia. DISCUSSION: Caregiver resources can impact emotional reactivity to daily life stress. Interventions aimed at empowerment of caregiver resources, such as sense of competence, mastery, and coping, could help to reduce stress reactivity in dementia caregivers. PMID- 29617374 TI - Genome-wide association studies reveal that members of bHLH subfamily 16 share a conserved function in regulating flag leaf angle in rice (Oryza sativa). AB - As a major component of ideal plant architecture, leaf angle especially flag leaf angle (FLA) makes a large contribution to grain yield in rice. We utilized a worldwide germplasm collection to elucidate the genetic basis of FLA that would be helpful for molecular design breeding in rice. Genome-wide association studies (GWAS) identified a total of 40 and 32 QTLs for FLA in Wuhan and Hainan, respectively. Eight QTLs were commonly detected in both conditions. Of these, 2 and 3 QTLs were identified in the indica and japonica subpopulations, respectively. In addition, the candidates of 5 FLA QTLs were verified by haplotype-level association analysis. These results indicate diverse genetic bases for FLA between the indica and japonica subpopulations. Three candidates, OsbHLH153, OsbHLH173 and OsbHLH174, quickly responded to BR and IAA involved in plant architecture except for OsbHLH173, whose expression level was too low to be detected; their overexpression in plants increased rice leaf angle. Together with previous studies, it was concluded that all 6 members in bHLH subfamily 16 had the conserved function in regulating FLA in rice. A comparison with our previous GWAS for tiller angle (TA) showed only one QTL had pleiotropic effects on FLA and TA, which explained low similarity of the genetic basis between FLA and TA. An ideal plant architecture is expected to be efficiently developed by combining favorable alleles for FLA from indica with favorable alleles for TA from japonica by inter-subspecies hybridization. PMID- 29617375 TI - Gender-transformative Bandebereho couples' intervention to promote male engagement in reproductive and maternal health and violence prevention in Rwanda: Findings from a randomized controlled trial. AB - BACKGROUND: Rigorous evidence of the effectiveness of male engagement interventions, particularly on how these interventions impact relationship power dynamics and women's decision-making, remains limited. This study assessed the impact of the Bandebereho gender-transformative couples' intervention on impact on multiple behavioral and health-related outcomes influenced by gender norms and power relations. METHODS: We conducted a multi-site randomised controlled trial in four Rwandan districts with expectant/current fathers and their partners, who were randomised to the intervention (n = 575 couples) or control group (n = 624 couples). Primary outcomes include women's experience of physical and sexual IPV, women's attendance and men's accompaniment at ANC, modern contraceptive use, and partner support during pregnancy. At 21-months post-baseline, 1123 men and 1162 partners were included in intention to treat analysis. Generalized estimating equations with robust standard errors were used to fit the models. FINDINGS: The Bandebereho intervention led to substantial improvements in multiple reported outcomes. Compared to the control group, women in the intervention group reported: less past-year physical (OR 0.37, p<0.001) and sexual IPV (OR 0.34, p<0.001); and greater attendance (IRR 1.09, p<0.001) and male accompaniment at antenatal care (IRR 1.50, p<0.001); and women and men in the intervention group reported: less child physical punishment (women: OR 0.56, p = 0.001; men: OR 0.66, p = 0.005); greater modern contraceptive use (women: OR 1.53, p = 0.004; men: OR 1.65, p = 0.001); higher levels of men's participation in childcare and household tasks (women: beta 0.39, p<0.001; men: beta 0.33, p<0.001); and less dominance of men in decision-making. CONCLUSIONS: Our study strengthens the existing evidence on male engagement approaches; together with earlier studies our findings suggest that culturally adapted gender-transformative interventions with men and couples can be effective at changing deeply entrenched gender inequalities and a range of health-related behavioral outcomes. TRIAL REGISTRATION: ClinicalTrials.gov NCT02694627. PMID- 29617376 TI - Brain Tumor promotes axon growth across the midline through interactions with the microtubule stabilizing protein Apc2. AB - Commissural axons must cross the midline to establish reciprocal connections between the two sides of the body. This process is highly conserved between invertebrates and vertebrates and depends on guidance cues and their receptors to instruct axon trajectories. The DCC family receptor Frazzled (Fra) signals chemoattraction and promotes midline crossing in response to its ligand Netrin. However, in Netrin or fra mutants, the loss of crossing is incomplete, suggesting the existence of additional pathways. Here, we identify Brain Tumor (Brat), a tripartite motif protein, as a new regulator of midline crossing in the Drosophila CNS. Genetic analysis indicates that Brat acts independently of the Netrin/Fra pathway. In addition, we show that through its B-Box domains, Brat acts cell autonomously to regulate the expression and localization of Adenomatous polyposis coli-2 (Apc2), a key component of the Wnt canonical signaling pathway, to promote axon growth across the midline. Genetic evidence indicates that the role of Brat and Apc2 to promote axon growth across the midline is independent of Wnt and Beta-catenin-mediated transcriptional regulation. Instead, we propose that Brat promotes midline crossing through directing the localization or stability of Apc2 at the plus ends of microtubules in navigating commissural axons. These findings define a new mechanism in the coordination of axon growth and guidance at the midline. PMID- 29617377 TI - Inositol 1,4,5-trisphosphate 3-kinase A overexpressed in mouse forebrain modulates synaptic transmission and mGluR-LTD of CA1 pyramidal neurons. AB - Inositol 1,4,5-trisphosphate 3-kinase A (IP3K-A) regulates the level of the inositol polyphosphates, inositol trisphosphate (IP3) and inositol tetrakisphosphate to modulate cellular signaling and intracellular calcium homeostasis in the central nervous system. IP3K-A binds to F-actin in an activity dependent manner and accumulates in dendritic spines, where it is involved in the regulation of synaptic plasticity. IP3K-A knockout mice exhibit deficits in some forms of hippocampus-dependent learning and synaptic plasticity, such as long term potentiation in the dentate gyrus synapses of the hippocampus. In the present study, to further elucidate the role of IP3K-A in the brain, we developed a transgenic (Tg) mouse line in which IP3K-A is conditionally overexpressed approximately 3-fold in the excitatory neurons of forebrain regions, including the hippocampus. The Tg mice showed an increase in both presynaptic release probability of evoked responses, along with bigger synaptic vesicle pools, and miniature excitatory postsynaptic current amplitude, although the spine density or the expression levels of the postsynaptic density-related proteins NR2B, synaptotagmin 1, and PSD-95 were not affected. Hippocampal-dependent learning and memory tasks, including novel object recognition and radial arm maze tasks, were partially impaired in Tg mice. Furthermore, (R,S)-3,5-dihydroxyphenylglycine induced metabotropic glutamate receptor long-term depression was inhibited in Tg mice and this inhibition was dependent on protein kinase C but not on the IP3 receptor. Long-term potentiation and depression dependent on N-methyl-d-aspartate receptor were marginally affected in Tg mice. In summary, this study shows that overexpressed IP3K-A plays a role in some forms of hippocampus-dependent learning and memory tasks as well as in synaptic transmission and plasticity by regulating both presynaptic and postsynaptic functions. PMID- 29617379 TI - Climate variability and cultural eutrophication at Walden Pond (Massachusetts, USA) during the last 1800 years. AB - Recent shifts in the ecological condition of Walden Pond, MA, are of potentially wide interest due to the lake's importance as a cultural, historical, and recreational resource in addition to its scientific value as an indicator of local and global environmental change. Algal microfossils in six sediment cores document changes in hydroclimate and trophic status of the lake during the last 1800 years and extend two previous sediment core records of shorter length. Low percentages of planktonic diatoms in the longest cores (WAL-3, WAL-15) indicate shallowing and/or greater water clarity associated with a relatively arid interval during the Medieval Climate Anomaly, ca. A.D. 1150-1300, Cultural eutrophication of the lake since the A.D. 1920s caused diatoms in the genera Asterionella and Synedra to increase in relative abundance at the expense of Cyclotella, Discostella, and the chrysophyte alga Mallomonas allorgei. Percentages of Asterionella and Synedra have remained fairly stable since A.D. 2000 when a previous sediment core study was conducted, but scaled chrysophytes have become more numerous. These findings suggest that, although mitigation efforts have curtailed anthropogenic nutrient inputs to Walden Pond, the lake has not returned to the pre-impact condition described by Henry David Thoreau and may become increasingly vulnerable to further changes in water quality in a warmer and possibly wetter future. PMID- 29617378 TI - Degenerate Pax2 and Senseless binding motifs improve detection of low-affinity sites required for enhancer specificity. AB - Cells use thousands of regulatory sequences to recruit transcription factors (TFs) and produce specific transcriptional outcomes. Since TFs bind degenerate DNA sequences, discriminating functional TF binding sites (TFBSs) from background sequences represents a significant challenge. Here, we show that a Drosophila regulatory element that activates Epidermal Growth Factor signaling requires overlapping, low-affinity TFBSs for competing TFs (Pax2 and Senseless) to ensure cell- and segment-specific activity. Testing available TF binding models for Pax2 and Senseless, however, revealed variable accuracy in predicting such low affinity TFBSs. To better define parameters that increase accuracy, we developed a method that systematically selects subsets of TFBSs based on predicted affinity to generate hundreds of position-weight matrices (PWMs). Counterintuitively, we found that degenerate PWMs produced from datasets depleted of high-affinity sequences were more accurate in identifying both low- and high-affinity TFBSs for the Pax2 and Senseless TFs. Taken together, these findings reveal how TFBS arrangement can be constrained by competition rather than cooperativity and that degenerate models of TF binding preferences can improve identification of biologically relevant low affinity TFBSs. PMID- 29617380 TI - From SNPs to pathways: Biological interpretation of type 2 diabetes (T2DM) genome wide association study (GWAS) results. AB - Genome-wide association studies (GWAS) have become a common method for discovery of gene-disease relationships, in particular for complex diseases like Type 2 Diabetes Mellitus (T2DM). The experience with GWAS analysis has revealed that the genetic risk for complex diseases involves cumulative, small effects of many genes and only some genes with a moderate effect. In order to explore the complexity of the relationships between T2DM genes and their potential function at the process level as effected by polymorphism effects, a secondary analysis of a GWAS meta-analysis is presented. Network analysis, pathway information and integration of different types of biological information such as eQTLs and gene environment interactions are used to elucidate the biological context of the genetic variants and to perform an analysis based on data visualization. We selected a T2DM dataset from a GWAS meta-analysis, and extracted 1,971 SNPs associated with T2DM. We mapped 580 SNPs to 360 genes, and then selected 460 pathways containing these genes from the curated collection of WikiPathways. We then created and analyzed SNP-gene and SNP-gene-pathway network modules in Cytoscape. A focus on genes with robust connections to pathways permitted identification of many T2DM pertinent pathways. However, numerous genes lack literature evidence of association with T2DM. We also speculate on the genes in specific network structures obtained in the SNP-gene network, such as gene-SNP gene modules. Finally, we selected genes relevant to T2DM from our SNP-gene pathway network, using different sources that reveal gene-environment interactions and eQTLs. We confirmed functions relevant to T2DM for many genes and have identified some-LPL and APOB-that require further validation to clarify their involvement in T2DM. PMID- 29617382 TI - Measuring CO2 and CH4 with a portable gas analyzer: Closed-loop operation, optimization and assessment. AB - The use of cavity ring-down spectrometer (CRDS) based portable greenhouse gas analyzers (PGAs) in closed-loop configuration to measure small sample volumes (< 1 l) for CH4 and CO2 concentrations is increasing and offers certain advantages over conventional measurement methods in terms of speed as well as the ability to measure directly in field locations. This first systematic assessment of the uncertainties, problems and issues associated with achieving reliable and repeatable measurement with this technique presents the adaptation, measurement range, calibration and maintenance, accuracy and issues of efficient operation, for one example instrument. Regular open-loop calibration, a precise loop volume estimate, leak free system, and a high standard of injection practices are necessary for accurate results. For 100 MUl injections, measured values ranging from 4.5 to 9 x104 ppm (CH4), and 1000 ppm to 1 x106 ppm (CO2) are possible with uncertainties +/-5.9% and +/-3.0%, respectively, beyond 100 ppm CH4 correction may be necessary. Uncertainty arising from variations water vapour content and atmospheric pressure are small (0.24% and -0.9% to +0.5%, respectively). With good practice, individual operator repeatability of 1.9% (CH4) and 2.48% (CO2) can be achieved. Between operator injection error was around 3% for both gases for four operators. Slow syringe plunger operation (> 1s) is recommended; generally delivered more (ca. 3-4%) sample into the closed instrument loop than did rapid operation. Automated value retrieval is recommended; we achieved a 3 to 5-fold time reduction for each injection cycle (ca. <2 min), and operator reading, recording, and digitization errors are eliminated. PMID- 29617381 TI - Prevention of colonic neoplasia with polyethylene glycol: A short term randomized placebo-controlled double-blinded trial. AB - : Chemoprevention represents an attractive modality against colorectal cancer (CRC) although widespread clinical implementation of promising agents (e.g. aspirin/NSAIDS) have been stymied by both suboptimal efficacy and concerns over toxicity. This highlights the need for better agents. Several groups, including our own, have reported that the over-the-counter laxative polyethylene glycol (PEG) has remarkable efficacy in rodent models of colon carcinogenesis. In this study, we undertook the first randomized human trial to address the role of PEG in prevention of human colonic neoplasia. This was a double-blind, placebo controlled, three-arm trial where eligible subjects were randomized to 8g PEG 3350 (n = 27) or 17g PEG-3350 (n = 24), or placebo (n = 24; maltodextrin) orally for a duration of six months. Our initial primary endpoint was rectal aberrant crypt foci (ACF) but this was changed during protocol period to rectal mucosal epidermal growth factor receptor (EGFR). Of the 87 patients randomized, 48 completed study primary endpoints and rectal EGFR unchanged PEG treatment. Rectal ACF had a trend suggesting potentially reduction with PEG treatment (pre-post change 1.7 in placebo versus -0.3 in PEG 8+ 17g doses, p = 0.108). Other endpoints (proliferation, apoptosis, expression of SNAIL and E-cadherin), previously noted to be modulated in rodent models, appeared unchanged with PEG treatment in this clinical trial. We conclude that PEG was generally well tolerated with the trial failing to meet primary efficacy endpoints. However, rectal ACFs demonstrated a trend (albeit statistically insignificant) for suppression with PEG. Moreover, all molecular assays including EGFR were unaltered with PEG underscoring issues with lack of translatability of biomarkers from preclinical to clinical trials. This data may provide the impetus for future clinical trials on PEG using more robust biomarkers of chemoprevention. TRIAL REGISTRATION: ClinicalTrials.gov NCT00828984. PMID- 29617383 TI - Biometric recognition via texture features of eye movement trajectories in a visual searching task. AB - Biometric recognition technology based on eye-movement dynamics has been in development for more than ten years. Different visual tasks, feature extraction and feature recognition methods are proposed to improve the performance of eye movement biometric system. However, the correct identification and verification rates, especially in long-term experiments, as well as the effects of visual tasks and eye trackers' temporal and spatial resolution are still the foremost considerations in eye movement biometrics. With a focus on these issues, we proposed a new visual searching task for eye movement data collection and a new class of eye movement features for biometric recognition. In order to demonstrate the improvement of this visual searching task being used in eye movement biometrics, three other eye movement feature extraction methods were also tested on our eye movement datasets. Compared with the original results, all three methods yielded better results as expected. In addition, the biometric performance of these four feature extraction methods was also compared using the equal error rate (EER) and Rank-1 identification rate (Rank-1 IR), and the texture features introduced in this paper were ultimately shown to offer some advantages with regard to long-term stability and robustness over time and spatial precision. Finally, the results of different combinations of these methods with a score-level fusion method indicated that multi-biometric methods perform better in most cases. PMID- 29617384 TI - A group of Populus trichocarpa DUF231 proteins exhibit differential O acetyltransferase activities toward xylan. AB - Wood represents the most abundant biomass produced by plants and one of its major components is acetyl xylan. Acetylation in xylan can occur at O-2 or O-3 of a xylosyl residue, at both O-2 and O-3 of a xylosyl residue, and at O-3 of a xylosyl residue substituted at O-2 with glucuronic acid. Acetyltransferases responsible for the regiospecific acetylation of xylan in tree species have not yet been characterized. Here we report the biochemical characterization of twelve Populus trichocarpa DUF231-containing proteins, named PtrXOATs, for their roles in the regiospecific acetylation of xylan. The PtrXOAT genes were found to be differentially expressed in Populus organs and among them, PtrXOAT1, PtrXOAT2, PtrXOAT9 and PtrXOAT10 exhibited the highest level of expression in stems undergoing wood formation. Activity assays of recombinant proteins demonstrated that all twelve PtrXOAT proteins were able to transfer acetyl groups from acetyl CoA onto a xylohexaose acceptor with PtrXOAT1, PtrXOAT2, PtrXOAT3, PtrXOAT11 and PtrXOAT12 having the highest activity. Structural analysis of the PtrXOAT catalyzed reaction products using 1H NMR spectroscopy revealed that PtrXOAT1, PtrXAOT2 and PtrXOAT3 mediated 2-O- and 3-O-monoacetylation and 2,3-di-O acetylation of xylosyl residues and PtrXOAT11 and PtrXOAT12 only catalyzed 2-O- and 3-O-monoacetylation of xylosyl residues. Of the twelve PtrXOATs, only PtrXOAT9 and PtrXOAT10 were capable of transferring acetyl groups onto the O-3 position of 2-O-glucuronic acid-substituted xylosyl residues. Furthermore, when expressed in the Arabidopsis eskimo1 mutant, PtrXOAT1, PtrXAOT2 and PtrXOAT3 were able to rescue the defects in xylan acetylation. Together, these results demonstrate that the twelve PtrXOATs are acetyltransferases with different roles in xylan acetylation in P. trichocarpa. PMID- 29617385 TI - Anthocyanin bio-fortified colored wheat: Nutritional and functional characterization. AB - Colored wheat, rich in anthocyanins, has created interest among the breeders and baking industry. This study was aimed at understanding the nutritional and product making potential of our advanced, high yielding and regionally adapted colored wheat lines. Our results indicated that our advanced colored wheat lines exhibited higher anthocyanin content and antioxidant activity than donor wheat lines and it varied in the order of white=30 mg/24h) were evaluated with linear regression analyses and multinomial logistic regression analyses, respectively. RESULTS: After adjustment for potential confounders, each extra hour of total physical activity was associated with a more favorable kidney function (betaeGFR = 2.30 (95%CI = 1.46; 3.14)), whereas each extra hour of sedentary behavior was associated with a more adverse kidney function (betaeGFR = -0.71 (-1.08; -0.35)). Also, compared to individuals with the lowest levels of total physical activity, individuals with the highest levels had less kidney damage (OR15-<30mg/24h = 0.63 (0.41; 0.96), OR>=30mg/24h = 0.84 (0.53; 1.35). An extra hour of sedentary behavior was associated with more kidney damage (OR15-<30 mg/24h = 1.11 (1.01; 1.22), OR>=30 mg/24h = 1.10 (0.99; 1.22)). Further, a highly sedentary pattern was associated with a more adverse kidney function, but no association was seen with kidney damage. CONCLUSIONS: Physical activity and sedentary behavior were associated with kidney function and kidney damage. Additionally, sedentary behavior patterns were associated with kidney function. Causal studies are required to examine whether this indeed implicates that prevention strategies should focus not only on increasing physical activity, but on reducing sedentary behavior as well. PMID- 29617429 TI - Providers' perceptions of communication with patients in primary healthcare in Rwanda. AB - BACKGROUND: Delivery of effective healthcare is contingent on the quality of communication between the patient and the healthcare provider. Little is known about primary healthcare providers' perceptions of communication with patients in Rwanda. AIM: To explore providers' perceptions of patient-provider communication (PPC) and analyse the ways in which providers present and reflect on communication practice and problems. METHODS: Qualitative, in-depth, semi structured interviews with nine primary health care providers. An abductive analysis supplemented by the framework method was applied. A narrative approach allowed the emergence of archetypical narratives on PPC. RESULTS: Providers shared rich reflections on the importance of proper communication with patients and appeared committed to making their interaction work optimally. Still, providers had difficulty critically analysing limitations of their communication in practice. Reported communication issues included lack of communication training as well as time and workload issues. Two archetypes of narratives on PPC issues and practice emerged and are discussed. CONCLUSION: While providers' narratives put patients at the centre of care, there were indications that patient-provider communication training and practice need further development. In depth exploration of highlighted issues and adapted strategies to tackle communication drawbacks are prerequisites to improvement. This study contributes to the advancement of knowledge related to communication between the patient and the provider in a resource-limited setting. PMID- 29617430 TI - Screening potential reference genes for quantitative real-time PCR analysis in the oriental armyworm, Mythimna separata. AB - The oriental armyworm, Mythimna separata, is a major insect pest in China and other Asian countries. Unfortunately, suitable reference genes for quantitative real-time PCR (qRT-PCR) have not been previously identified in M. separata for normalizing target gene expression. In this study, we evaluated the expression stability of eight candidate genes (18S, ACT, EF1-alpha, GAPDH, RPS7, RPS13, RPL32 and TUB) in M. separata using the comparative DeltaCt method, BestKeeper, Normfinder geNorm and ReFinder, a comprehensive software platform. The results indicated that the appropriate reference gene varied depending on the experimental conditions. We found that ACTIN, EF1-alpha and TUB were optimal for different developmental stages; TUB, RPS13 and EF1-alpha showed the most stable expresssion in different tissues; RPS13 and 18S were the best reference genes for monitoring expression under high temperature conditions; TUB, RPS13 and RPS7 exhibited the most stable expression under larval-crowding conditions; RPS7, EF1 alpha, RPL32 and GAPDH were the best for pesticide exposure experiments. This study provides tools for reliable normalization of qRT-PCR data and forms a foundation for functional studies of target gene expression in M. separata. PMID- 29617431 TI - Membrane permeabilizing amphiphilic peptide delivers recombinant transcription factor and CRISPR-Cas9/Cpf1 ribonucleoproteins in hard-to-modify cells. AB - Delivery of recombinant proteins to therapeutic cells is limited by a lack of efficient methods. This hinders the use of transcription factors or Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR) ribonucleoproteins to develop cell therapies. Here, we report a soluble peptide designed for the direct delivery of proteins to mammalian cells including human stem cells, hard-to modify primary natural killer (NK) cells, and cancer cell models. This peptide is composed of a 6x histidine-rich domain fused to the endosomolytic peptide CM18 and the cell penetrating peptide PTD4. A less than two-minute co-incubation of 6His-CM18-PTD4 peptide with spCas9 and/or asCpf1 CRISPR ribonucleoproteins achieves robust gene editing. The same procedure, co-incubating with the transcription factor HoxB4, achieves transcriptional regulation. The broad applicability and flexibility of this DNA- and chemical-free method across different cell types, particularly hard-to-transfect cells, opens the way for a direct use of proteins for biomedical research and cell therapy manufacturing. PMID- 29617432 TI - Vitamin K2 improves proliferation and migration of bovine skeletal muscle cells in vitro. AB - Skeletal muscle function is highly dependent on the ability to regenerate, however, during ageing or disease, the proliferative capacity is reduced, leading to loss of muscle function. We have previously demonstrated the presence of vitamin K2 in bovine skeletal muscles, but whether vitamin K has a role in muscle regulation and function is unknown. In this study, we used primary bovine skeletal muscle cells, cultured in monolayers in vitro, to assess a potential effect of vitamin K2 (MK-4) during myogenesis of muscle cells. Cell viability experiments demonstrate that the amount of ATP produced by the cells was unchanged when MK-4 was added, indicating viable cells. Cytotoxicity analysis show that MK-4 reduced the lactate dehydrogenase (LDH) released into the media, suggesting that MK-4 was beneficial to the muscle cells. Cell migration, proliferation and differentiation was characterised after MK-4 incubation using wound scratch analysis, immunocytochemistry and real-time PCR analysis. Adding MK 4 to the cells led to an increased muscle proliferation, increased gene expression of the myogenic transcription factor myod as well as increased cell migration. In addition, we observed a reduction in the fusion index and relative gene expression of muscle differentiation markers, with fewer complex myotubes formed in MK-4 stimulated cells compared to control cells, indicating that the MK 4 plays a significant role during the early phases of muscle proliferation. Likewise, we see the same pattern for the relative gene expression of collagen 1A, showing increased gene expression in proliferating cells, and reduced expression in differentiating cells. Our results also suggest that MK-4 incubation affect low density lipoprotein receptor-related protein 1 (LRP1) and the low-density lipoprotein receptor (LDLR) with a peak in gene expression after 45 min of MK-4 incubation. Altogether, our experiments show that MK-4 has a positive effect on muscle cell migration and proliferation, which are two important steps during early myogenesis. PMID- 29617433 TI - A high content, high throughput cellular thermal stability assay for measuring drug-target engagement in living cells. AB - Determining and understanding drug target engagement is critical for drug discovery. This can be challenging within living cells as selective readouts are often unavailable. Here we describe a novel method for measuring target engagement in living cells based on the principle of altered protein thermal stabilization / destabilization in response to ligand binding. This assay (HCIF CETSA) utilizes high content, high throughput single cell immunofluorescent detection to determine target protein levels following heating of adherent cells in a 96 well plate format. We have used target engagement of Chk1 by potent small molecule inhibitors to validate the assay. Target engagement measured by this method was subsequently compared to target engagement measured by two alternative methods (autophosphorylation and CETSA). The HCIF-CETSA method appeared robust and a good correlation in target engagement measured by this method and CETSA for the selective Chk1 inhibitor V158411 was observed. However, these EC50 values were 23- and 12-fold greater than the autophosphorylation IC50. The described method is therefore a valuable advance in the CETSA method allowing the high throughput determination of target engagement in adherent cells. PMID- 29617434 TI - Transcription factor compensation during mammary gland development in E2F knockout mice. AB - The E2F transcription factors control key elements of development, including mammary gland branching morphogenesis, with several E2Fs playing essential roles. Additional prior data has demonstrated that loss of individual E2Fs can be compensated by other E2F family members, but this has not been tested in a mammary gland developmental context. Here we have explored the role of the E2Fs and their ability to functionally compensate for each other during mammary gland development. Using gene expression from terminal end buds and chromatin immunoprecipitation data for E2F1, E2F2 and E2F3, we noted both overlapping and unique mammary development genes regulated by each of the E2Fs. Based on our computational findings and the fact that E2Fs share a common binding motif, we hypothesized that E2F transcription factors would compensate for each other during mammary development and function. To test this hypothesis, we generated RNA from E2F1-/-, E2F2-/- and E2F3+/- mouse mammary glands. QRT-PCR on mammary glands during pregnancy demonstrated increases in E2F2 and E2F3a in the E2F1-/- mice and an increase in E2F2 levels in E2F3+/- mice. During lactation we noted that E2F3b transcript levels were increased in the E2F2-/- mice. Given that E2Fs have previously been noted to have the most striking effects on development during puberty, we hypothesized that loss of individual E2Fs would be compensated for at that time. Double mutant mice were generated and compared with the single knockouts. Loss of both E2F1 and E2F2 revealed a more striking phenotype than either knockout alone, indicating that E2F2 was compensating for E2F1 loss. Interestingly, while E2F2 was not able to functionally compensate for E2F3+/- during mammary outgrowth, increased E2F2 expression was observed in E2F3+/- mammary glands during pregnancy day 14.5 and lactation day 5. Together, these findings illustrate the specificity of E2F family members to compensate during development of the mammary gland. PMID- 29617436 TI - Correction: Clinical and inflammatory characteristics of Asthma-COPD overlap in workers with occupational asthma. AB - [This corrects the article DOI: 10.1371/journal.pone.0193144.]. PMID- 29617435 TI - Evaluation of survival of patients with hepatocellular carcinoma: A comparative analysis of prognostic systems. AB - BACKGROUND AND AIM: There are several prognostic systems that address different aspects of the patient and the tumour and can guide the management of patients with hepatocellular carcinoma (HCC). This study aimed to evaluate and compare the eight staging systems for a group of patients in a public service in Brazil. METHODS: Patients with HCC were retrospectively analysed between 2000 and 2012. The prognostic systems Okuda, The Cancer of the Liver Italian Program (CLIP), the Chinese University Prognostic Index (CUPI), Groupe d'Etude et de Traitement du Carcinome Hepatocellulaire (GRETCH), the modified TNM-based Japan Integrated Score (JIS) combined with alpha-fetoprotein and Child-Turcotte-Pugh (CTP), the TNM system, and the Barcelona Clinic Liver Cancer Classification (BCLC) were applied to these patients and compared through model fit measurements, likelihood scores, and the Akaike Information Criterion (AIC). RESULTS: A total of 247 patients were studied. The average survival time was 60 months. The TNM, Okuda, CLIP, GRETCH, modified JIS, and BCLC systems were well correlated with one another and individually important to the prediction of survival among the patients studied. However, in the statistical analysis, the CUPI delivered the best predictive performance (AIC = 566; log-likelihood = -281,240). CONCLUSION: Although the CUPI system was demonstrated to be the most appropriate HCC staging system for the studied population, the choice of an ideal system is a controversial subject, and future studies with larger numbers of patients are necessary for the validation of the CUPI system as the method of choice for other populations. PMID- 29617437 TI - Patient-nominated supporters as facilitators for engagement in HIV care in a referral hospital in Peru: A retrospective cohort study. AB - Patient-nominated supporters can potentially improve the continuum of HIV care. We retrospectively determined factors associated with having a patient-nominated supporter among people living with HIV (PLWH), and its association with retention in care and viral suppression. We analysed registries of adults evaluated by social workers (n = 1345) at a referral hospital in Peru between 2011-2014. Nondisclosure of HIV status was associated with lacking supporters (aPR: 5.41, 95% CI: 3.83-7.64). Retention in care was 76.4% and 34.2% after one and two years of enrolment, respectively. PLWH with supporters were more likely to be retained in care after two years (aRR = 1.36, 95% CI: 1.02-1.81), but not after one year (aRR = 1.10, 95% CI: 0.98-1.23) compared to PLWH without supporters. Having supporters who were parents or friends was associated with an increased probability of being retained in care after one and two years of enrolment. Viral suppression after one year of enrolment was 58.7%. Having a supporter was not associated with viral suppression (aRR = 1.18, 95% CI: 0.99-1.41), but PLWH with supporters were more likely to have viral load measurements (p = 0.005). Patient nominated supporters appear beneficial for engagement in HIV care; these benefits may be related to the nature of their relationship with PLWH. PMID- 29617439 TI - Correction: Five decades on: Use of historical weaning size data reveals that a decrease in maternal foraging success underpins the long-term decline in population of southern elephant seals (Mirounga leonina). AB - [This corrects the article DOI: 10.1371/journal.pone.0173427.]. PMID- 29617438 TI - Lipoatrophy/lipohypertrophy outcomes after antiretroviral therapy switch in children in the UK/Ireland. AB - BACKGROUND: Following widespread use of stavudine, a thymidine analogue, in antiretroviral therapy (ART) over the past three decades, up to a third of children developed lipoatrophy (LA) and/or lipohypertrophy (LH). Following phasing-out of stavudine, incidence of newly-diagnosed LA and LH declined dramatically. However, the natural history of existing cases should be explored, particularly with prolonged protease inhibitor exposure. METHODS: The Collaborative HIV Paediatric Study (CHIPS) is a multicentre cohort study of most HIV-infected children in the United Kingdom and Ireland. Those on ART with a LA/LH assessment recorded in 2003-2011 were included. Assessments were completed annually by consultant physicians. Using the 0-3 grading system, LA or LH was defined as grade 2 or 3. Resolution was defined as return to grade 1 or 0 in all body regions. RESULTS: Of 1345 children followed for median (IQR) 5.5 (2.9, 8.2) years after ART initiation, 30 developed LA and 27 developed LH, all at least 2 years after ART initiation. Median age at LA diagnosis was 11 (10, 13) years and at LH diagnosis was 13 (11, 15) years. Children with LA were more likely white (p<0.0001); lower height-for-age z-score at ART initiation (p = 0.02); initiated ART earlier (p = 0.04), with longer ART exposure (p = 0.04). Children with LH were similar to those without. Analysis of individual drugs revealed that LA was associated with greater duration of exposure to stavudine and didanosine; while LH was associated with greater duration of exposure to stavudine and ritonavir (given alone or in combination with another protease inhibitor). Median time in follow-up following ART switch was 2.8 (1.9, 4.9) and 2.5 (1.6, 4.7) years respectively. Resolution occurred in 10 (30%) of LA cases (median time to resolution 2.3 [1.8, 3.6] years) and 3 (11%) of LH cases (median time to resolution 2.0 [1.7, 2.1] years). CONCLUSIONS: Prevalence of LA and LH were low, with some resolution noted, especially for LA. More long-term data are needed. PMID- 29617442 TI - Correction: A FRET-based biosensor for measuring Galpha13 activation in single cells. AB - [This corrects the article DOI: 10.1371/journal.pone.0193705.]. PMID- 29617440 TI - The impact of serotype-specific vaccination on phylodynamic parameters of Streptococcus pneumoniae and the pneumococcal pan-genome. AB - In the United States, the introduction of the heptavalent pneumococcal conjugate vaccine (PCV) largely eliminated vaccine serotypes (VT); non-vaccine serotypes (NVT) subsequently increased in carriage and disease. Vaccination also disrupts the composition of the pneumococcal pangenome, which includes mobile genetic elements and polymorphic non-capsular antigens important for virulence, transmission, and pneumococcal ecology. Antigenic proteins are of interest for future vaccines; yet, little is known about how the they are affected by PCV use. To investigate the evolutionary impact of vaccination, we assessed recombination, evolution, and pathogen demographic history of 937 pneumococci collected from 1998-2012 among Navajo and White Mountain Apache Native American communities. We analyzed changes in the pneumococcal pangenome, focusing on metabolic loci and 19 polymorphic protein antigens. We found the impact of PCV on the pneumococcal population could be observed in reduced diversity, a smaller pangenome, and changing frequencies of accessory clusters of orthologous groups (COGs). Post PCV7, diversity rebounded through clonal expansion of NVT lineages and inferred in-migration of two previously unobserved lineages. Accessory COGs frequencies trended toward pre-PCV7 values with increasing time since vaccine introduction. Contemporary frequencies of protein antigen variants are better predicted by pre PCV7 values (1998-2000) than the preceding period (2006-2008), suggesting balancing selection may have acted in maintaining variant frequencies in this population. Overall, we present the largest genomic analysis of pneumococcal carriage in the United States to date, which includes a snapshot of a true vaccine-naive community prior to the introduction of PCV7. These data improve our understanding of pneumococcal evolution and emphasize the need to consider pangenome composition when inferring the impact of vaccination and developing future protein-based pneumococcal vaccines. PMID- 29617441 TI - PD-1/PD-L1 expression in a series of intracranial germinoma and its association with Foxp3+ and CD8+ infiltrating lymphocytes. AB - One histopathological characteristic of intracranial germinoma is abundant tumor infiltrating lymphocytes (TILs) showing a two-cell pattern with large undifferentiated tumor cells. The programmed cell death 1 (PD-1)/programmed cell death 1 ligand (PD-L) axis has recently been recognized as an anti-tumor immune system. To evaluate intratumor immune status in intracranial germinoma, we examined expressions of PD-1 and PD-L1 (clone 28-8) and subtypes of TILs. Expressions of PD-1 and PD-L1 were detected immunohistochemically in 25 formalin fixed, paraffin-embedded tumor specimens from 24 patients with intracranial germinoma consisting of 22 primary and 3 recurrent tumors. To evaluate subtypes of TILs, quantification of lymphocytes with CD3, CD8, CD4, and Foxp3 was performed. Statistical analyses were performed among PD-1, PD-L1 and subtypes of TILs. In 25 tumor tissue, expressions of PD-1 in TILs and PD-L1 in tumor cells were identified in 96% (24/25) and 92% (23/25), respectively. Expression of PD-1 was associated with CD3+ TIL density. Expression of PD-1 correlated with Foxp3+ TIL density and CD8+ TIL density, but not with CD4+ TIL density. Furthermore, expression of PD-1 correlated strongly with Foxp3+/CD4+ ratio. Taken together, increase of PD-1+ expression is associated with accumulation of Foxp3+ and CD8+ TILs. These findings intimate that PD-1/PD-L1 axis might shape the immune infiltration suggesting a modulation of the immune response and subsequent tumor growth in intracranial germinoma. Anti-PD-1 and anti-PD-L1 are potential immune therapeutic strategies in intracranial germinoma. PMID- 29617443 TI - Changes in serum levels of autotaxin with direct-acting antiviral therapy in patients with chronic hepatitis C. AB - Sustained virological response (SVR) rates have increased remarkably since the introduction of direct-acting antiviral agents (DAAs) for chronic hepatitis C. Autotaxin (ATX) is a secreted enzyme converting lysophosphatidylcholine to lysophosphatidic acid and a newly established biomarker for liver fibrosis. Interferon-free DAA regimens for chronic hepatitis C could improve liver stiffness in SVR patients according to several non-invasive evaluation methods, but the clinical response and significance of ATX in this context have not yet been defined. We therefore investigated sequential serum ATX levels at baseline, 4 weeks after the start of treatment, and 24 weeks after treatment in 159 hepatitis C virus (HCV)-infected patients who received DAA therapy. Other non invasive fibrosis markers (aspartate aminotransferase-to-platelet ratio and FIB-4 index) were examined as well. Baseline median ATX levels were comparable between the 144 patients who achieved a SVR and the 15 who did not (1.54 vs. 1.62 mg/L), but median ATX levels became significantly decreased during and after DAA therapy in the SVR group only (from 1.54 to 1.40 and 1.31 mg/L, respectively; P < 0.001). ATX was significantly decreased between baseline and 4 weeks of treatment in overall, male, and female SVR patients (all P < 0.001). In subjects with low necroinflammatory activity in the liver (i.e., alanine aminotransferase < 30 U/L), ATX levels were significantly reduced from baseline to 4 weeks of treatment and remained low (P < 0.001) in patients with a SVR. Thus, interferon-free DAA therapy was associated with a significant decrease in serum ATX levels in patients achieving a SVR, suggesting early regression of liver fibrosis in addition to inflammation treatment. PMID- 29617444 TI - Ambient but not local lactate underlies neuronal tolerance to prolonged glucose deprivation. AB - Neurons require a nearly constant supply of ATP. Glucose is the predominant source of brain ATP, but the direct effects of prolonged glucose deprivation on neuronal viability and function remain unclear. In sparse rat hippocampal microcultures, neurons were surprisingly resilient to 16 h glucose removal in the absence of secondary excitotoxicity. Neuronal survival and synaptic transmission were unaffected by prolonged removal of exogenous glucose. Inhibition of lactate transport decreased microculture neuronal survival during concurrent glucose deprivation, suggesting that endogenously released lactate is important for tolerance to glucose deprivation. Tandem depolarization and glucose deprivation also reduced neuronal survival, and trace glucose concentrations afforded neuroprotection. Mass cultures, in contrast to microcultures, were insensitive to depolarizing glucose deprivation, a difference attributable to increased extracellular lactate levels. Removal of local astrocyte support did not reduce survival in response to glucose deprivation or alter evoked excitatory transmission, suggesting that on-demand, local lactate shuttling is not necessary for neuronal tolerance to prolonged glucose removal. Taken together, these data suggest that endogenously produced lactate available globally in the extracellular milieu sustains neurons in the absence of glucose. A better understanding of resilience mechanisms in reduced preparations could lead to therapeutic strategies aimed to bolster these mechanisms in vulnerable neuronal populations. PMID- 29617445 TI - Comparison of six fit algorithms for the intra-voxel incoherent motion model of diffusion-weighted magnetic resonance imaging data of pancreatic cancer patients. AB - The intravoxel incoherent motion (IVIM) model for diffusion-weighted imaging (DWI) MRI data bears much promise as a tool for visualizing tumours and monitoring treatment response. To improve the currently poor precision of IVIM, several fit algorithms have been suggested. In this work, we compared the performance of two Bayesian IVIM fit algorithms and four other IVIM fit algorithms for pancreatic cancer imaging. DWI data were acquired in 14 pancreatic cancer patients during two MRI examinations. Three different measures of performance of the fitting algorithms were assessed: (i) uniqueness of fit parameters (Spearman's rho); (ii) precision (within-subject coefficient of variation, wCV); and (iii) contrast between tumour and normal-appearing pancreatic tissue. For the diffusivity D and perfusion fraction f, a Bayesian fit (IVIM-Bayesian-lin) offered the best trade-off between tumour contrast and precision. With the exception for IVIM-Bayesian-lin, all algorithms resulted in a very poor precision of the pseudo-diffusion coefficient D* with a wCV of more than 50%. The pseudo-diffusion coefficient D* of the Bayesian approaches were, however, significantly correlated with D and f. Therefore, the added value of fitting D* was considered limited in pancreatic cancer patients. The easier implemented least squares fit with fixed D* (IVIM-fixed) performed similar to IVIM-Bayesian-lin for f and D. In conclusion, the best performing IVIM fit algorithm was IVM-Bayesian-lin, but an easier to implement least squares fit with fixed D* performs similarly in pancreatic cancer patients. PMID- 29617446 TI - MiR-29b affects the secretion of PROG and promotes the proliferation of bovine corpus luteum cells. AB - The regulatory role of miRNAs has been explored in ovarian cells, and their effects on gonadal development, apoptosis, ovulation, steroid production and corpus luteum (CL) development have been revealed. In this study, we analyzed the expression of miR-29b at different stages of bovine CL development and predicted the target genes of miR-29b. We confirmed that miR-29b reduces the expression of the oxytocin receptor (OXTR), affects progesterone (PROG) secretion and regulates the function of the CL. RT-PCR showed that the expression of miR-29b was significantly higher in functional CL phases than in the regressed CL phase. Immunohistochemistry showed that OXTR was expressed in both large and small CL cells and was mainly located in the cell membrane and cytoplasm of these cells. We analyzed the expression levels of OXTR and found that transfection with a miR 29b mimic decreased OXTR expression, but transfection with the inhibitor had a limited effect on the expression of the OXTR protein. At the same time, the secretion of PROG was significantly increased in the miR-29b mimic-transfected group. We also analyzed the effect of miR-29b on the apoptosis of CL cells. Finally, we found that miR-29b could promote the proliferation of bovine CL cells. In conclusion, we found that miR-29b reduces the expression of OXTR and can promote PROG secretion and the proliferation of CL cells via OXTR. PMID- 29617447 TI - Increased visceral tissue perfusion with heated, humidified carbon dioxide insufflation during open abdominal surgery in a rodent model. AB - Tissue perfusion during surgery is important in reducing surgical site infections and promoting healing. This study aimed to determine if insufflation of the open abdomen with heated, humidified (HH) carbon dioxide (CO2) increased visceral tissue perfusion and core body temperature during open abdominal surgery in a rodent model. Using two different rodent models of open abdominal surgery, visceral perfusion and core temperature were measured. Visceral perfusion was investigated using a repeated measures crossover experiment with rodents receiving the same sequence of two alternating treatments: exposure to ambient air (no insufflation) and insufflation with HH CO2. Core body temperature was measured using an independent experimental design with three treatment groups: ambient air, HH CO2 and cold, dry (CD) CO2. Visceral perfusion was measured by laser speckle contrast analysis (LASCA) and core body temperature was measured with a rectal thermometer. Insufflation with HH CO2 into a rodent open abdominal cavity significantly increased visceral tissue perfusion (2.4 perfusion units (PU)/min (95% CI 1.23-3.58); p<0.0001) compared with ambient air, which significantly reduced visceral blood flow (-5.20 PU/min (95% CI -6.83- -3.58); p<0.0001). Insufflation of HH CO2 into the open abdominal cavity significantly increased core body temperature (+1.15 +/- 0.14 degrees C) compared with open cavities exposed to ambient air (-0.65 +/- 0.52 degrees C; p = 0.037), or cavities insufflated with CD CO2 (-0.73 +/- 0.33 degrees C; p = 0.006). Abdominal visceral temperatures also increased with HH CO2 insufflation compared with ambient air or CD CO2, as shown by infrared thermography. This study reports for the first time the use of LASCA to measure visceral perfusion in open abdominal surgery and shows that insufflation of open abdominal cavities with HH CO2 significantly increases visceral tissue perfusion and core body temperature. PMID- 29617448 TI - Ranking of osteogenic potential of physical exercises in postmenopausal women based on femoral neck strains. AB - The current study aimed to assess the potential of different exercises triggering an osteogenic response at the femoral neck in a group of postmenopausal women. The osteogenic potential was determined by ranking the peak hip contact forces (HCFs) and consequent peak tensile and compressive strains at the superior and inferior part of the femoral neck during activities such as (fast) walking, running and resistance training exercises. Results indicate that fast walking (5 6 km/h) running and hopping induced significantly higher strains at the femoral neck than walking at 4 km/h which is considered a baseline exercise for bone preservation. Exercises with a high fracture risk such as hopping, need to be considered carefully especially in a frail elderly population and may therefore not be suitable as a training exercise. Since superior femoral neck frailness is related to elevated hip fracture risk, exercises such as fast walking (above 5 km/h) and running can be highly recommended to stimulate this particular area. Our results suggest that a training program including fast walking (above 5 km/h) and running exercises may increase or preserve the bone mineral density (BMD) at the femoral neck. PMID- 29617449 TI - Assessment of veins in T2*-weighted MR angiography predicts infarct growth in hyperacute ischemic stroke. AB - BACKGROUND AND PURPOSE: T2*-weighted magnetic resonance angiography (SWAN) detects hemodynamic insufficiency as hypointense areas in medullary or cortical veins. We therefore investigated whether SWAN can help predict ischemic penumbra like lesions in patients with acute ischemic stroke (AIS). MATERIALS AND METHODS: Magnetic resonance imaging (MRI) records-including SWAN, diffusion-weighted imaging (DWI), and magnetic resonance angiography (MRA)-of consecutive patients with major vessel occlusion within 6 h from AIS onset were analyzed. Acute recanalization was defined as an arterial occlusive lesion score of 2-3. A modified Alberta Stroke Program Early CT Score (mASPECTS) was used to evaluate ischemic areas revealed by SWAN and DWI. SWAN- and DWI-based mASPECTSs were calculated, and correlations between DWI-SWAN mismatches with final infarct lesions or clinical outcomes were evaluated. RESULTS: Among the 35 patients included in this study, we confirmed cardioembolic stroke in 26, atherothrombotic stroke in 4, and unknown stroke etiology in 5. Overall, recanalization was achieved in 23 patients, who showed a higher follow-up DWI-based mASPECTS and lower modified Rankin Scale (mRS) score at 90 days than patients without recanalization. Initial SWAN- and follow-up DWI-based mASPECTSs were significantly higher for atherothrombotic stroke than for cardioembolic stroke. Of 12 patients without recanalization, DWI-SWAN mismatch was significantly correlated with infarct growth. Patients with recanalization showed no such correlation. In the assessment of clinical outcome, follow-up DWI-based mASPECTS and patient's age were significantly correlated with mRS at 90 days after stroke. A multivariate logistic regression analysis revealed that the follow-up DWI-based mASPECTS was independently associated with a favorable outcome 90 days after stroke. CONCLUSIONS: For patients with AIS, DWI-SWAN mismatch might show penumbra like lesions that would predict infarct growth without acute recanalization. Assessment of ischemic lesions from the venous side appears to be useful for considering the etiology and revascularization therapy. PMID- 29617450 TI - Limb remote ischemic conditioning of the recipient protects the liver in a rat model of arterialized orthotopic liver transplantation. AB - BACKGROUND: Ischemic-reperfusion (IR) injury still represents a major concern in clinical transplantation, especially in the era of extreme organ shortage and extended criteria donor organs. In the present study we aimed to investigate the hepatoprotective effects of remote ischemic conditioning (RIC) in a rat model of arterialized orthotopic liver transplantation (OLT). METHODS: Male Lewis rats were used (n = 144 / 72 OLT cases; 240-340g) as donors and recipients. Livers were flushed and stored in 4 degrees C HTK-solution for 8h before implantation. Recipients were randomly allocated into three experimental groups: RIC 1, RIC 2, Control. In RIC 1, RIC 2 groups, RIC was applied in the recipient before hepatectomy or after reperfusion (4x5-5min IR via clamping the infrarenal aorta), respectively. Animals were sacrificed at 1, 3, 24, 168h post-reperfusion (n = 6 recipient/group/time point). Hepatocellular injury, graft circulation, serum cytokines, tissue redox-stress and adenosine-triphosphate (ATP) levels have been assessed. Additional markers were analyzed, using Western blotting and reverse transcription polymerase chain reaction. RESULTS: RIC 1 group showed significantly (p<0.05) improved portal venous and microcirculation flow as well as velocity. RIC has significantly reduced tissue injury according to the serum levels of transaminases and results of histopathological evaluation. Reduced TUNEL-staining (p<0.01 RIC 1-2 vs. Control) and elevated pBAD/BAD ratio was detected in the RIC groups (p<0.01 RIC 1 vs. Control). Supporting findings were obtained from measurements of serum IL-10 as well as tissue malondialdehyde and ATP levels. Hemoxygenase-1 (HO-1) mRNA-expression was significantly higher in RIC 1 compared to Control (p<0.05 RIC 1 vs. Control). CONCLUSION: These results suggest that RIC might confer potent protection against the detrimental effects of IR injury including tissue damage, apoptosis, graft circulation, inflammation, tissue energetic status in OLT. HO-1 overexpression might play an orchestrating role in RIC mediated organ protection. An earlier intervention (RIC 1 protocol) was more effective than remote conditioning after graft reperfusion. PMID- 29617451 TI - Integrative multi-platform meta-analysis of gene expression profiles in pancreatic ductal adenocarcinoma patients for identifying novel diagnostic biomarkers. AB - Applying differentially expressed genes (DEGs) to identify feasible biomarkers in diseases can be a hard task when working with heterogeneous datasets. Expression data are strongly influenced by technology, sample preparation processes, and/or labeling methods. The proliferation of different microarray platforms for measuring gene expression increases the need to develop models able to compare their results, especially when different technologies can lead to signal values that vary greatly. Integrative meta-analysis can significantly improve the reliability and robustness of DEG detection. The objective of this work was to develop an integrative approach for identifying potential cancer biomarkers by integrating gene expression data from two different platforms. Pancreatic ductal adenocarcinoma (PDAC), where there is an urgent need to find new biomarkers due its late diagnosis, is an ideal candidate for testing this technology. Expression data from two different datasets, namely Affymetrix and Illumina (18 and 36 PDAC patients, respectively), as well as from 18 healthy controls, was used for this study. A meta-analysis based on an empirical Bayesian methodology (ComBat) was then proposed to integrate these datasets. DEGs were finally identified from the integrated data by using the statistical programming language R. After our integrative meta-analysis, 5 genes were commonly identified within the individual analyses of the independent datasets. Also, 28 novel genes that were not reported by the individual analyses ('gained' genes) were also discovered. Several of these gained genes have been already related to other gastroenterological tumors. The proposed integrative meta-analysis has revealed novel DEGs that may play an important role in PDAC and could be potential biomarkers for diagnosing the disease. PMID- 29617452 TI - A sibling method for identifying vQTLs. AB - The propensity of a trait to vary within a population may have evolutionary, ecological, or clinical significance. In the present study we deploy sibling models to offer a novel and unbiased way to ascertain loci associated with the extent to which phenotypes vary (variance-controlling quantitative trait loci, or vQTLs). Previous methods for vQTL-mapping either exclude genetically related individuals or treat genetic relatedness among individuals as a complicating factor addressed by adjusting estimates for non-independence in phenotypes. The present method uses genetic relatedness as a tool to obtain unbiased estimates of variance effects rather than as a nuisance. The family-based approach, which utilizes random variation between siblings in minor allele counts at a locus, also allows controls for parental genotype, mean effects, and non-linear (dominance) effects that may spuriously appear to generate variation. Simulations show that the approach performs equally well as two existing methods (squared Z score and DGLM) in controlling type I error rates when there is no unobserved confounding, and performs significantly better than these methods in the presence of small degrees of confounding. Using height and BMI as empirical applications, we investigate SNPs that alter within-family variation in height and BMI, as well as pathways that appear to be enriched. One significant SNP for BMI variability, in the MAST4 gene, replicated. Pathway analysis revealed one gene set, encoding members of several signaling pathways related to gap junction function, which appears significantly enriched for associations with within-family height variation in both datasets (while not enriched in analysis of mean levels). We recommend approximating laboratory random assignment of genotype using family data and more careful attention to the possible conflation of mean and variance effects. PMID- 29617453 TI - The cultivable autochthonous microbiota of the critically endangered Northern bald ibis (Geronticus eremita). AB - The critically endangered Northern bald ibis (Geronticus eremita) is a migratory bird that became extinct in Europe centuries ago. Since 2014, the Northern bald ibis is subject to an intensive rehabilitation and conservation regime aiming to reintroduce the bird in its original distribution range in Central Europe and concurrently to maintain bird health and increase population size. Hitherto, virtually nothing is known about the microbial communities associated with the ibis species; an information pivotal for the veterinary management of these birds. Hence, the present study was conducted to provide a baseline description of the cultivable microbiota residing in the Northern bald ibis. Samples derived from the choana, trachea, crop and cloaca were examined employing a culturomic approach in order to identify microbes at each sampling site and to compare their frequency among age classes, seasonal appearances and rearing types. In total, 94 microbial species including 14 potentially new bacterial taxa were cultivated from the Northern bald ibis with 36, 58 and 59 bacterial species isolated from the choana, crop and cloaca, respectively. The microbiota of the Northern bald ibis was dominated by members of the phylum Firmicutes, followed by Proteobacteria, Actinobacteria, Bacteroidetes and Fusobacteria, altogether phylotypes commonly observed within avian gut environments. Differences in relative abundances of various microbial taxa were evident among sample types indicating mucosa-specific colonisation properties and tissue tropism. Besides, results of the present study indicate that the composition of microbiota was also affected by age, season (environment) and rearing type. While the prevalence of traditional pathogenic microbial species was extremely low, several opportunists including Clostridium perfringens toxotype A were frequently present in samples indicating that the Northern bald ibis may represent an important animal reservoir for these pathogens. In summary, the presented study provides a first inventory of the cultivable microbiota residing in the critically endangered Northern bald ibis and represents a first step in a wider investigation of the ibis microbiome with the ultimate goal to contribute to the management and survival of this critically endangered bird. PMID- 29617454 TI - Case-based surveillance of measles in Sicily during 2012-2017: The changing molecular epidemiology and implications for vaccine strategies. AB - Following the indication of the World Health Organization, a national plan for the elimination of measles was approved in Italy and this included the improvement of the molecular surveillance of measles viruses and the interruption of indigenous transmission of the disease. Nevertheless, large outbreaks continue to occur in almost all regions of the country, including Sicily. Here we describe the epidemiology and molecular dynamics of measles viruses as a result of the measles surveillance activity carried out by the "Reference Laboratory for Measles and Rubella" in Sicily over a 5-year period. Biological samples of 259 suspected measles cases were tested for viral RNA detection and a total of 223 (86.1%) were classified as laboratory confirmed. The median age of confirmed measles cases was 21.0 years and about half of them were adults aged 19 years and older. Overall, one-third of the patients showed clinical complications and these latter were more common among adults than children (44.9% vs. 25.7%). The vast majority of measles cases were unvaccinated (94.2%, n = 210). The phylogenetic analysis of 221 measles virus nucleotide sequences revealed sporadic detections of genotypes D4 and H1, while endemic circulation of genotypes D8 and B3 was documented. Genotype D8 was associated with epidemics occurred between 2013 and 2016, whereas genotype B3 was more recently introduced into Sicily characterizing the current measles outbreak. The results of this study confirm the autochthonous co-circulation of viral variants belonging to different genotypes during the study period, and emphasizes the need of measles surveillance programmes in order to investigate the viral dynamics, the pathways of disease transmission, and to eventually adapt the development of successfull vaccine formulations. PMID- 29617455 TI - The ecological footprint of Acca sellowiana domestication maintains the residual vertebrate diversity in threatened highlands of Atlantic Forest. AB - Past and contemporary human actions are causing numerous changes in patterns and processes at various ecosystem scales and trophic levels, including unintended downstream changes, such as species interactions. In its native range Acca sellowiana (Feijoa) combines some characteristics of human interactions: incipient domestication, restricted to subtropical Atlantic Forest highlands, associated with the threatened conifer Araucaria angustifolia (Araucaria), within a domesticated landscape with anthropogenic forest patches, and provides fruit at a time of resource shortage (Araucaria seeds-pinhao). We quantify the trophic relationships between Feijoa and vertebrates, and evaluate the influences on interactions caused by environmental variations, Feijoa domestication evidences, spatial distance and fruit availability. In four sites within protected areas, we selected 28 focal individuals of Feijoa (seven/site) and collected three temporal replicas between 2015 and 2016, when we measured productivity and frugivory via 45-second videos taken with camera traps. Using ecological network, rarefaction curves and variation partitioning analyses, we evaluate the frugivory network topology, the spatiotemporal structure of communities in relation to fruit availability and the influence of predictive variables on frugivory. We found a large spatiotemporal variation in productivity of Feijoa and that 20 species consumed Feijoa fruits, with a species degree of 2.8 (+/-5.7) and average Feijoa degree of 14.4 (+/-10.1), in a modular network with intermediary connectance. Rarefaction curves showed that richness and the independent records are congruent with the fruit amount. Variation partitioning showed that, for the focal individuals, canopy area, green coverage, patch size and distance to water influenced frugivory, and the Feijoa domestication influenced significantly the mammalian frugivory. Feijoa is an important resource that provides food during the time of year when Pinhao is absent, and attracts frugivores, maintain the residual diversity of vertebrates contributing to the structure of communities in highlands. Our insights allowed us to evaluate the magnitude of the interactions between vertebrates and an incipient domesticated tree, in a cultural landscape and highly threatened environment, under a basal foodweb approach with implications for bottom-up and top-down forces. The results contribute to understanding animal-plant relationships, including concepts that can be replicated for other sessile prey and mobile predators in any region or habitat under different gradients of management. Thus, this work shows how human actions can change not only patterns of distribution and abundance but also the diversity and direction of interspecific interactions among species. PMID- 29617456 TI - Epidemiological links between tuberculosis cases identified twice as efficiently by whole genome sequencing than conventional molecular typing: A population-based study. AB - BACKGROUND: Patients with Mycobacterium tuberculosis isolates sharing identical DNA fingerprint patterns can be epidemiologically linked. However, municipal health services in the Netherlands are able to confirm an epidemiological link in only around 23% of the patients with isolates clustered by the conventional variable number of tandem repeat (VNTR) genotyping. This research aims to investigate whether whole genome sequencing (WGS) is a more reliable predictor of epidemiological links between tuberculosis patients than VNTR genotyping. METHODS: VNTR genotyping and WGS were performed in parallel on all Mycobacterium tuberculosis complex isolates received at the Netherlands National Institute for Public Health and the Environment in 2016. Isolates were clustered by VNTR when they shared identical 24-loci VNTR patterns; isolates were assigned to a WGS cluster when the pair-wise genetic distance was <= 12 single nucleotide polymorphisms (SNPs). Cluster investigation was performed by municipal health services on all isolates clustered by VNTR in 2016. The proportion of epidemiological links identified among patients clustered by either method was calculated. RESULTS: In total, 535 isolates were genotyped, of which 25% (134/535) were clustered by VNTR and 14% (76/535) by WGS; the concordance between both typing methods was 86%. The proportion of epidemiological links among WGS clustered cases (57%) was twice as common than among VNTR clustered cases (31%). CONCLUSION: When WGS was applied, the number of clustered isolates was halved, while all epidemiologically linked cases remained clustered. WGS is therefore a more reliable tool to predict epidemiological links between tuberculosis cases than VNTR genotyping and will allow more efficient transmission tracing, as epidemiological investigations based on false clustering can be avoided. PMID- 29617459 TI - Importance of triggers and veto-barriers for the implementation of sanitation in informal peri-urban settlements - The case of Cochabamba, Bolivia. AB - An estimated 2.4 billion people lack access to improved sanitation which has devastating consequences for human health and the environment. Understanding what constitute sanitation demand is crucial for accelerating the spread of improved sanitation. This study aims to understand the adoption mechanisms for improved sanitation. An informal peri-urban settlement in Cochabamba, Bolivia was selected as a case study to understand adoption patterns. Various qualitative methods of data collection and analysis were employed. The findings showed that pour-flush toilets was the only preferred sanitation alternative at the study site. An adoption framework for waterborne toilets was developed based on diffusion of innovation theory. Factors that influence adoption were identified. Some functioned as triggers and initiated adoption, whereas some factors blocked adoption and constituted veto-barriers. Most factors were connected to the individual household situation and its members, but neighborhood development also affected pour-flush adoption. Based on adoption time the residents were divided into the following adoption groups: first adopters, early majority, late majority, laggards and non-adopters. Each adoption group followed its own adoption route with specific characteristics and respective triggers or veto barriers. We argue that the strong demand for waterborne toilets in peri-urban areas need to be recognized and the developed framework could be used for customizing sanitation improvement programs for certain target groups. PMID- 29617458 TI - Performance of QuantiFERON-TB Gold Plus for detection of latent tuberculosis infection in pregnant women living in a tuberculosis- and HIV-endemic setting. AB - We evaluated the performance of QuantiFERON-TB Gold Plus (QFT-Plus), which includes two Mycobacterium tuberculosis antigen formulations (TB1 and TB2), for detection of latent tuberculosis infection during pregnancy. Eight-hundred-twenty nine Ethiopian pregnant women (5.9% HIV-positive) were tested with QFT-Plus, with bacteriological sputum analysis performed for women with clinically suspected tuberculosis and HIV-positive women irrespective of clinical presentation. QFT Plus read-out was categorized according to the conventional cut-off (0.35 IU/ml) for both antigen formulations. In addition, we analysed the distribution of QFT Plus results within a borderline zone (0.20-0.70 IU/ml), and interferon-gamma response in relation to HIV infection and gestational age. Two-hundred-seventy seven women (33%) were QFT-Plus-positive (HIV-positive 16/49 [33%]; HIV-negative 261/780 [33%]). There was a strong agreement between the two antigen formulations (kappa = 0.92), with discordant results in 29 cases (3.5%). Whereas discordant QFT-Plus results were rare in pregnancy, several results with both TB1 and TB2 within the borderline range were observed (11/49 [22%] vs. 43/780 [5.5%] in HIV positive and HIV-negative women, respectively; p<0.0001). HIV-positive women had lower absolute interferon-gamma levels (TB1: 0.47 vs. 2.16 IU/ml; p<0.001, TB2: 0.49 vs. 2.24 IU/ml, p<0.001, considering results >=0.20 IU/ml) compared to HIV negative women. QFT-Plus-positive women who submitted samples at later stages of pregnancy had lower mitogen- (p<0.001) but higher TB-antigen-specific (p = 0.031 for TB1, p = 0.061 for TB2) interferon-gamma response. Considering their lower capacity to produce TB-specific interferon-gamma, a lower cut-off level for defining QFT-Plus-positivity may be considered in HIV-positive pregnant women. PMID- 29617457 TI - SUR1-TRPM4 channel activation and phasic secretion of MMP-9 induced by tPA in brain endothelial cells. AB - BACKGROUND: Hemorrhagic transformation is a major complication of ischemic stroke, is linked to matrix metalloproteinase-9 (MMP-9), and is exacerbated by tissue plasminogen activator (tPA). Cerebral ischemia/reperfusion is characterized by SUR1-TRPM4 (sulfonylurea receptor 1-transient receptor potential melastatin 4) channel upregulation in microvascular endothelium. In humans and rodents with cerebral ischemia/reperfusion (I/R), the SUR1 antagonist, glibenclamide, reduces hemorrhagic transformation and plasma MMP-9, but the mechanism is unknown. We hypothesized that tPA induces protease activated receptor 1 (PAR1)-mediated, Ca2+-dependent phasic secretion of MMP-9 from activated brain endothelium, and that SUR1-TRPM4 is required for this process. METHODS: Cerebral I/R, of 2 and 4 hours duration, respectively, was obtained using conventional middle cerebral artery occlusion. Immunolabeling was used to quantify p65 nuclear translocation. Murine and human brain endothelial cells (BEC) were studied in vitro, without and with NF-kappaB activation, using immunoblot, zymography and ELISA, patch clamp electrophysiology, and calcium imaging. Genetic and pharmacological manipulations were used to identify signaling pathways. RESULTS: Cerebral I/R caused prominent nuclear translocation of p65 in microvascular endothelium. NF-kappaB-activation of BEC caused de novo expression of SUR1-TRPM4 channels. In NF-kappaB-activated BEC: (i) tPA caused opening of SUR1-TRPM4 channels in a plasmin-, PAR1-, TRPC3- and Ca2+-dependent manner; (ii) tPA caused PAR1-dependent secretion of MMP-9; (iii) tonic secretion of MMP-9 by activated BEC was not influenced by SUR1 inhibition; (iv) phasic secretion of MMP-9 induced by tPA or the PAR1-agonist, TFLLR, required functional SUR1-TRPM4 channels, with inhibition of SUR1 decreasing tPA-induced MMP-9 secretion. CONCLUSIONS: tPA induces PAR1-mediated, SUR1-TRPM4-dependent, phasic secretion of MMP-9 from activated brain endothelium. PMID- 29617460 TI - Loss of HAI-2 in mice with decreased prostasin activity leads to an early-onset intestinal failure resembling congenital tufting enteropathy. AB - Prostasin (CAP1/PRSS8) is a glycosylphosphatidylinositol (GPI)-anchored serine protease that is essential for epithelial development and overall survival in mice. Prostasin is regulated primarily by the transmembrane serine protease inhibitor, hepatocyte growth factor activator inhibitor (HAI)-2, and loss of HAI 2 function leads to early embryonic lethality in mice due to an unregulated prostasin activity. We have recently reported that critical in vivo functions of prostasin can be performed by proteolytically-inactive or zymogen-locked variants of the protease. Here we show that the zymogen form of prostasin does not bind to HAI-2 and, as a result, loss of HAI-2 does not affect prenatal development and survival of mice expressing only zymogen-locked variant of prostasin (Prss8 R44Q). Indeed, HAI-2-deficient mice homozygous for R44Q mutation (Spint2-/ ;Prss8R44Q/R44Q) are born in the expected numbers and do not exhibit any obvious developmental abnormality at birth. However, postnatal growth in these mice is severely impaired and they all die within 4 to 7 days after birth due to a critical failure in the development of small and large intestines, characterized by a widespread villous atrophy, tufted villi, near-complete loss of mucin producing goblet cells, loss of colonic crypt structure, and bleeding into the intestinal lumen. Intestines of Spint2-/-;Prss8R44Q/R44Q mice showed altered expression of epithelial junctional proteins, including reduced levels of EpCAM, E-cadherin, occludin, claudin-1 and -7, as well as an increased level of claudin 4, indicating that the loss of HAI-2 compromises intestinal epithelial barrier function. Our data indicate that the loss of HAI-2 in Prss8R44Q/R44Q mice leads to development of progressive intestinal failure that at both histological and molecular level bears a striking resemblance to human congenital tufting enteropathy, and may provide important clues for understanding and treating this debilitating human disease. PMID- 29617461 TI - Adaptive differentiation of Festuca rubra along a climate gradient revealed by molecular markers and quantitative traits. AB - Species response to climate change is influenced by predictable (selective) and unpredictable (random) evolutionary processes. To understand how climate change will affect present-day species, it is necessary to assess their adaptive potential and distinguish it from the effects of random processes. This will allow predicting how different genotypes will respond to forecasted environmental change. Space for time substitution experiments are an elegant way to test the response of present day populations to climate variation in real time. Here we assess neutral and putatively adaptive variation in 11 populations of Festuca rubra situated along crossed gradients of temperature and moisture using molecular markers and phenotypic measurements, respectively. By comparing population differentiation in putatively neutral molecular markers and phenotypic traits (QST-FST comparisons), we show the existence of adaptive differentiation in phenotypic traits and their plasticity across the climatic gradient. The observed patterns of differentiation are due to the high genotypic and phenotypic differentiation of the populations from the coldest (and wettest) environment. Finally, we observe statistically significant covariation between markers and phenotypic traits, which is likely caused by isolation by adaptation. These results contribute to a better understanding of the current adaptation and evolutionary potential to face climate change of a widespread species. They can also be extrapolated to understand how the studied populations will adjust to upcoming climate change without going through the lengthy process of phenotyping. PMID- 29617462 TI - Doxorubicin chemotherapy affects the intracellular and interstitial free amino acid pools in skeletal muscle. AB - Skeletal muscle (SM) health and integrity is dependent on the dynamic balance between protein synthesis and degradation, and central to this process is the availability of amino acids (AA) in the amino pool. While Doxorubicin (DOX) remains one of the most widely used chemotherapeutic agents for the treatment of solid and hematological malignancies, little is known of the effect of the drug on SM, particularly its effect on the availability of amino acids in the tissue. The purpose of this study was to examine the effect of DOX administration on vascular, interstitial and intracellular concentrations of AA in SM of the rat up to 8 days after the administration of a 1.5 or 4.5 mg/kg i.p. dose of DOX. In the plasma, total amino acids (TAA) were significantly increased compared to control where greater (P<0.05) concentrations were observed following the 1.5 mg/kg dose compared to the 4.5 mg/kg dose. Compared to control, the 1.5 mg/kg dose resulted in an increase (P<0.05) in interstitial TAA whereas the 4.5 mg/kg resulted in a sustained decrease (P<0.05). Intracellular TAA, essential amino acids (EAA) and branched-chain amino acids (BCAA) where significantly increased in each muscle group analyzed, following the 1.5 and 4.5 mg/kg doses compared to control. This study provides important insight into the amino acid response following DOX chemotherapy and presents a substantial foundation for future studies focused on reducing SM damage and recovery by targeting amino acid metabolism. PMID- 29617463 TI - Mice harboring pathobiont-free microbiota do not develop intestinal inflammation that normally results from an innate immune deficiency. AB - BACKGROUND: Inability to maintain a stable and beneficial microbiota is associated with chronic gut inflammation, which classically manifests as colitis but may more commonly exist as low-grade inflammation that promotes metabolic syndrome. Alterations in microbiota, and associated inflammation, can originate from dysfunction in host proteins that manage the microbiota, such as the flagellin receptor TLR5. That the complete absence of a microbiota (i.e. germfree conditions) eliminates all evidence of inflammation in TLR5-deficient mice demonstrates that this model of gut inflammation is microbiota-dependent. We hypothesize that such microbiota dependency reflects an inability to manage pathobionts, such as Adherent-Invasive E. coli (AIEC). Herein, we examined the extent to which microbiota mismanagement and associated inflammation in TLR5 deficient mice would manifest in a limited and pathobiont-free microbiota. For this purpose, WT and TLR5-deficient mice were generated and maintained with the 8 member consortium of bacteria referred to as "Altered Schaedler Flora" (ASF). Such ASF animals were subsequently inoculated with AIEC reference strain LF82. Feces were assayed for bacterial loads, fecal lipopolysaccharide and flagellin loads, fecal inflammatory marker lipocalin-2 and microbiota composition. RESULTS: Relative to similarly maintained WT mice, mice lacking TLR5 (T5KO) did not display low-grade intestinal inflammation nor metabolic syndrome under ASF conditions. Concomitantly, the ASF microbial community was similar between WT and T5KO mice, while inoculation with AIEC strain LF82 resulted in alteration of the ASF community in T5KO mice compared to WT control animals. AIEC LF82 inoculation in ASF T5KO mice resulted in microbiota components having elevated levels of bioactive lipopolysaccharide and flagellin, a modest level of low-grade inflammation and increased adiposity. CONCLUSIONS: In a limited-complexity pathobiont-free microbiota, loss of the flagellin receptor TLR5 does not impact microbiota composition nor its ability to promote inflammation. Addition of AIEC to this ecosystem perturbs microbiota composition, increases levels of lipopolysaccharide and flagellin, but only modestly promotes gut inflammation and adiposity, suggesting that the phenotypes previously associated with loss of this innate immune receptor require disruption of complex microbiota. PMID- 29617468 TI - Utilization of food outlets and intake of minimally processed and ultra-processed foods among 7 to 14-year-old schoolchildren. A cross-sectional study. AB - BACKGROUND: Access to food retailers is an environmental determinant that influences what people consume. This study aimed to test the association between the use of food outlets and schoolchildren's intake of minimally processed and ultra-processed foods. DESIGN AND SETTING: This was a cross-sectional study conducted in public and private schools in Florianopolis, state of Santa Catarina, southern Brazil, from September 2012 to June 2013. METHODS: The sample consisted of randomly selected clusters of schoolchildren aged 7 to 14 years, who were attending 30 schools. Parents or guardians provided socioeconomic and demographic data and answered questions about use of food outlets. Dietary intake was surveyed using a dietary recall questionnaire based on the previous day's intake. The foods or food groups were classified according to the level of processing. Negative binomial regression was used for data analysis. RESULTS: We included 2,195 schoolchildren in the study. We found that buying foods from snack bars or fast-food outlets was associated with the intake frequency of ultra processed foods among 11-14 years old in an adjusted model (incidence rate ratio, IRR: 1.11; 95% confidence interval, CI: 1.01;1.23). Use of butchers was associated with the intake frequency of unprocessed/minimally processed foods among children 11-14 years old in the crude model (IRR: 1.11; 95% CI: 1.01;1.22) and in the adjusted model (IRR: 1.11; 95% CI: 1.06;1.17). CONCLUSIONS: Use of butchers was associated with higher intake of unprocessed/minimally processed foods while use of snack bars or fast-food outlets may have a negative impact on schoolchildren's dietary habits. PMID- 29617469 TI - Foot health and quality of life among university students: cross-sectional study. AB - BACKGROUND: Foot problems are believed to reduce quality of life and are increasingly present. Even among young adults of university age, untreated foot problems can lead to postural and mobility problems. Accordingly, our aim here was to determine the relationship between foot health and quality of life and general health among male and female university students. DESIGN AND SETTING: Observational cross-sectional quantitative study conducted at the Podiatric Medicine and Surgery Clinic of the University of Coruna, Ferrol, Spain. METHODS: A sample of 112 participants of median age 22 years came to a health center, where self-reported data were registered, including professional activity, and scores obtained through the Foot Health Status Questionnaire (FHSQ) were compared. RESULTS: In Section One of the FHSQ, the university students recorded lower scores of 66.66 in the footwear domain and 60 in the general foot health domain and higher scores of 84.37 in the foot pain domain and 93.75 in the foot function domain. In Section Two, they obtained lower scores of 60 in the overall health domain and 62.50 in the vigor domain and higher scores of 100 in the physical activity and 87.50 in the social capacity domain. Differences between males and females were evaluated using the Wilcoxon rank-sum test, which showing statistical significance (P < 0.05) regarding the dimensions of footwear and general foot health. CONCLUSIONS: These university students' quality of life relating to foot health was poor. This appears to be associated with the university period, regardless of gender. PMID- 29617470 TI - APPLICABILITY OF A GENERIC QUESTIONNAIRE FOR QUALITY OF LIFE ASSESSMENT FOR ASTHMATIC CHILDREN. AB - OBJECTIVE: To determine the applicability of the generic instrument Pediatric Quality of Life Inventory (PedsQL 4.0) to assess health-related quality of life of asthmatic children compared to the specific instrument Pediatric Asthma Quality of Life Questionnaire (PAQLQ). METHODS: This research involved the evaluation of 30 children aged seven to eleven years, who had been diagnosed with asthma for at least six months prior to research. Both quality of life questionnaires were applied to children by an interviewer over the period of one day. Data were analyzed using the Statistical Package for the Social Sciences (SPSS) 20.0, with significance level set at 5%. RESULTS: No differences in quality of life was found when genders were compared. Asthmatic children classified as practitioners and non-practitioners of physical activity had different scores in the physical health-related domain (PedsQL 4.0). The scores of children with different levels of asthma severity and control were significantly different in two out of three domains evaluated by PAQLQ. When assessed by PedsQL 4.0, no significant difference was observed as to quality of life of children with different levels of asthma control and severity. Quality of life measurements of asthmatic children by PedsQL 4.0 and PAQLQ instruments had a moderate and significant correlation (r=0.415, p=0.02). CONCLUSIONS: PedsQL 4.0 could distinguish children practicing different levels of physical activity, but it was not sensitive enough to distinguish health-related quality of life among children with different levels of asthma severity and control. PMID- 29617471 TI - HYPOPHOSPHATEMIC RICKETS: CASE REPORT. AB - OBJECTIVE: Early diagnosis and immediate treatment of hypophosphatemic rickets is of utmost importance as it may prevent subsequent sequelae. This report aims at warning pediatricians to consider the presence of the disease. CASE DESCRIPTION: Description of the metabolic profile, creatinine clearance, nutritional status, weight and body structure of a patient who presented the clinical-laboratorial characteristics of hypophosphatemic rickets and was followed in an outpatient clinic for tubulopathies over the period of 12 months. The patient had been bedridden for some time, was dependent on mechanical ventilation and presented an altered metabolic bone condition. Treatment was phosphate (initial: 65 mg/kg/day and final: 24,2 mg/kg/day), calcium (initial: 127 mg/kg/day, final: 48,4 mg/kg/day) and calcitriol (initial: 0.06 mcg/kg/day, final: 0.03 mcg/kg/day). The patient improved, evolving into spontaneous breathing and walking unaided. Laboratory results: calcium (mg/dL) initial 7.1, final 10.1; phosphate (mg/dL) initial 1.7 final 3.2; magnesium (mg/dL) initial 1.5 final 2.1, parathyroid hormone (pg/l) initial 85.8, final 52.7, alkaline phosphatase (UI/l) initial 12660, final 938; there was also improvement in weight/structural development (Z score: H/A initial: -6.05, final -3.64; W/A: initial -2.92, final -1.57) with presence of transitory gallstones. Creatinine clearance (mL/min/1.73m2bsa) was constant. The medication improved his laboratory results and nutritional status, but the patient did not return for two years for follow-up and, during this period, his condition has noticeably deteriorated. COMMENTS: Early diagnosis and follow-up are essential in dealing with this pathology. PMID- 29617472 TI - PHYSICAL EDUCATION CLASSES AND HEALTH OUTCOMES IN BRAZILIAN STUDENTS. AB - OBJECTIVE: To analyze the association between participation and physical activity during Physical Education classes with health outcomes in Brazilian students. METHODS: 681 Brazilian students (50.5% female) aged 10 to 17 years participated in this cross-sectional study. Independent variables analyzed were participation and physical activity during Physical Education classes, both assessed using a self-report questionnaire. The outcomes were: cardiorespiratory fitness (20-meter Shuttle Run test), muscle strength (Push-up test), overweight and obesity (body mass index) and high blood pressure. Statistical analysis was conducted by Poisson regression to estimate the prevalence ratio (PR) and 95% confidence intervals (95%CI) adjusted for confounding variables (age, sex, parental education, physical activity and sedentary behavior), considering the complex sample design. RESULTS: Participation in Physical Education classes was not associated with any of the studied variables. Being active during Physical Education classes was associated with achieving health related criteria for cardiorespiratory fitness (PR=1.34, 95%CI 1.16-1.55) and muscle strength (PR=1.36, 95%CI 1.09-1.71). The same did not occur for overweight (PR=1.04, 95%CI 0.95-1.14), obesity (PR=1.02, 95%CI 0.91-1.05), or high blood pressure (PR=0.98, 95%CI 0.90-1.06). CONCLUSIONS: Students who reported being active during classes presented a higher likelihood to achieve the health criteria for cardiorespiratory fitness and muscle strength. However, classes traditionally offered in Brazil do not protect students from overweight, obesity, or high blood pressure. PMID- 29617473 TI - EXERCISE TOLERANCE, PULMONARY FUNCTION, RESPIRATORY MUSCLE STRENGTH, AND QUALITY OF LIFE IN CHILDREN AND ADOLESCENTS WITH RHEUMATIC HEART DISEASE. AB - OBJECTIVE: Despite the high prevalence of rheumatic heart disease in Brazil, the occurrence of functional impairment in children and adolescents with rheumatic heart disease is not clear. The aim of this study was to evaluate exercise tolerance, respiratory muscle strength, lung function, and quality of life of children and adolescents with rheumatic heart disease. METHODS: Cross-sectional study, conducted from August to December 2014 with children and adolescents with rheumatic heart disease aged 8 to 16 years. The participants, after completing the socioeconomic, clinical, and quality of life questionnaires were tested by spirometry, manovacuometry and in a 6-minute walk test. The variables and their reference values were compared using the paired Student's t-test. Comparisons between predicted and observed walking distance were done also by Student's t test, consdiering the categorization of the participants. Correlations between these differences and quantitative variables were assessed by Pearson's coefficient, being significant p<0.05. RESULTS: All 56 participants had a walked distance lower than predicted (p<0.001). The differences between predicted and observed distances were positively correlated with the baseline heart rate (r=0.3545; p=0.007). Expiratory muscle strength was also lower than the predicted values (p<0,001). Regarding quality of life assessment, the mean scores were 70, 77 and 67% for general, physical, and psychosocial aspects, respectively. CONCLUSIONS: Children and adolescents with rheumatic heart disease have reduced exercise tolerance, which is related to their higher baseline heart rate; they also show impaired expiratory strength and quality of life. PMID- 29617474 TI - VITAMIN A DEFICIENCY IN BRAZILIAN CHILDREN AND ASSOCIATED VARIABLES. AB - OBJECTIVE: To analyze the variables associated with vitamin A deficiency (VAD) in Brazilian children aged 6 to 59 months, considering a hierarchical model of determination. METHODS: This is part of the National Survey on Demography and Health of Women and Children, held in 2006. Data analysis included 3,417 children aged from six to 59 months with retinol data. Vitamin A deficiency was defined as serum retinol <0.7 mol/L. Univariate and multiple Poisson regression analysis were performed, with significance level set at 5%, using a hierarchical model of determination that considered three conglomerates of variables: those linked to the structural processes of community (socioeconomic-demographic variables); to the immediate environment of the child (maternal variables, safety and food consumption); and individual features (biological characteristics of the child). Data were expressed in prevalence ratio (PR). RESULTS: After adjustment for confounding variables, the following remained associated with VAD: living in the Southeast [PR=1,59; 95%CI 1,19-2,17] and Northeast [PR=1,56; 95%CI 1,16-2,15]; in urban area [RP=1,31; 95%CI 1,02-1,72]; and mother aged >=36 years [RP=2,28; 95%CI 1,37-3,98], the consumption of meat at least once in the last seven days was a protective factor [PR=0,24; 95%CI 0,13-0,42]. CONCLUSIONS: The main variables associated with VAD in the country are related to structural processes of society and to the immediate, but not individual, environment of the child. PMID- 29617475 TI - ULTRASONOGRAPHIC MARKERS OF CARDIOVASCULAR DISEASE RISK IN OBESE CHILDREN. AB - OBJECTIVE: To evaluate whether the obesity alters ultrasonographical markers of metabolic and cardiovascular disease risk in children. METHODS: A cross-sectional study evaluated 80 children aged between 6 and 10 years, comparing 40 obese with 40 normal children. The following parameters were assessed: weight; height; body mass index; arterial blood pressure; body fat; basal metabolic rate; HDL cholesterol, LDL-cholesterol and total cholesterol; fasting insulin and glucose; quantitative insulin sensitivity check index (QUICKI); homeostasis model of assessment - insulin resistance (HOMA-IR); basal diameter of the brachial artery; brachial artery flow mediated dilation (FMD) and of pulsatility index change (PI C). RESULTS: Significant differences were observed between obese vs. non-obese children: systolic blood pressure (97.7+/-8.4 vs. 89.0+/-5.8 mmHg; p<0.01), diastolic blood pressure (64.3+/-7.9 vs. 52.9+/-5.1 mmHg; p<0.01), proportion of body fat (45.1+/-5.9 vs. 21.3+/-6.0%; p<0.01), basal metabolic rate (1216.1+/ 102.1 vs. 1072.9+/-66.4 Kcal; p<0.01), total cholesterol (164.7+/-25.2 vs. 153.4+/-15.8 mg/dL; p=0.03), fasting insulin (7.1+/-5.2 vs. 2.8+/-1.8 pIU/mL; p<0.01), HOMA-IR (1.5+/-1.1 vs. 0.6+/-0.4; p<0.01), basal diameter of the brachial artery (2.5+/-0.3 vs. 2.1+/-0.3 mm; p<0.01); PI-C (-15.5+/-27.2 vs. 31.9+/-15.5%; p<0.01), decreased QUICKI (0.4+/-0.05 vs. 0.4+/-0.03; p<0.01), and FMD (6.6+/-3.2 vs. 15.6+/-7.3%; p<0.01). CONCLUSIONS: Obesity worsens ultrasonographical and laboratorial markers of metabolic and cardiovascular disease risk in children. PMID- 29617477 TI - [Social practices in the medicalization and humanization of prenatal care]. AB - The study's main objective is to analyze how discourses of medicalization and humanization reconnect in primary healthcare and shape prenatal care for pregnant women provided by family health teams. This was a single and integrated case study with multiple analytical units and a qualitative approach. A total of 17 focus groups were performed, in which 47 health professionals were heard (14 physicians, 19 nurses, and 14 dentists), members of 17 family health teams in 16 municipalities in the South of Brazil. The empirical material was analyzed from the perspective of Foucauldian discourse analysis. The family health teams, adopting general practice, reported difficulties in conducting prenatal care, evoking and bolstering the discourse of obstetric medicalization that their practice should supposedly offset. The discourse officially adopted by humanization, prioritized in the generalist model of prenatal care, continues to function as a complementary discourse to that of medicalization and specialization, which prevails in the practices reported by the teams. The emphasis on humanized care for pregnant women tests the limits of professional territories and assumes the renegotiation of competencies. Efforts at collaboration between the family health teams and obstetricians have not proved very successful in this specific case. PMID- 29617476 TI - ACUTE LOWER RESPIRATORY INFECTION IN GUARANI INDIGENOUS CHILDREN, BRAZIL. AB - OBJECTIVE: To describe the clinical profile and treatment of Brazilian Guarani indigenous children aged less than five years hospitalized for acute lower respiratory infection (ALRI), living in villages in the states from Rio de Janeiro to Rio Grande do Sul. METHODS: Of the 234 children, 23 were excluded (incomplete data). The analysis was conducted in 211 children. Data were extracted from charts by a form. Based on record of wheezing and x-ray findings, ALRI was classified as bacterial, viral and viral-bacterial. A bivariate analysis was conducted using multinomial regression. RESULTS: Median age was 11 months. From the total sample, the ALRI cases were classified as viral (40.8%), bacterial (35.1%) and viral-bacterial (24.1%). It was verified that 53.1% of hospitalizations did not have clinical-radiological-laboratorial evidence to justify them. In the multinomial regression analysis, the comparison of bacterial and viral-bacterial showed the likelihood of having a cough was 3.1 times higher in the former (95%CI 1.11-8.70), whereas having chest retractions was 61.0% lower (OR 0.39, 95%CI 0.16-0.92). Comparing viral with viral-bacterial, the likelihood of being male was 2.2 times higher in the viral (95%CI 1.05-4.69), and of having tachypnea 58.0% lower (OR 0.42, 95%CI 0.19-0.92). CONCLUSIONS: Higher proportion of viral processes was identified, as well as viral-bacterial co-infections. Coughing was a symptom indicative of bacterial infection, whereas chest retractions and tachypnea showed viral-bacterial ALRI. Part of the resolution of non-severe ALRI still occurs at hospital level; therefore, we concluded that health services need to implement their programs in order to improve indigenous primary care. PMID- 29617478 TI - Revisiting the P-36 oil rig accident 15 years later: from management of incidental and accidental situations to organizational factors. AB - The accident with the P-36 oil rig in the Campos Basin in Rio de Janeiro State, Brazil, was one of the petroleum industry's worst international disasters. Based on this specific case, the article aims to (a) verify the role of the human dimension in the reliability of highly complex systems, with a focus on the management of incidental and accidental situations with the potential to lead to large-scale accidents. The analysis should help (b) shed light on some of the organizational factors that can increase the risk level in offshore activities, beyond the so-called immediate causes. The methodology involves mainly document research (especially the reports produced by Petrobras, ANP/DPC, and CREA-RJ) and interviews with three professionals that worked on the P-36 rig. The results indicate that the management of incidental and accidental situations in which emergency decisions are made should take advantage of contribution by the workforce, who can identify gaps in the process and discuss them with managers. This involves shared and more flexible decisions and collective analysis of risk situations. The findings also suggest that certain organizational factors contributed to the accident, corroborating domestic and international studies of major accidents and pointing to the need for a shift in the focus adopted by oil companies' management. PMID- 29617479 TI - Prevalence and characteristics of adverse drug events in Brazil. AB - The aim of this study was to describe the prevalence of adverse drug events (ADEs) and associated factors reported by users of medicines in Brazil. This was a cross-sectional population-based study conducted from September 2013 to February 2014 with data from the Brazilian National Survey on Access, Use, and Promotion of Rational Use of Medicines (PNAUM). The study included all individuals that reported the use of medicines and identified, among them, all those reporting at least one problem with the medicine's use. A descriptive analysis was performed to estimate ADE prevalence and 95% confidence intervals (95%CI) among the target variables. Crude and adjusted prevalence ratios were calculated using Poisson regression to investigate factors associated with ADEs. Overall ADE prevalence in Brazil was 6.6% (95%CI: 5.89-7.41), and after multivariate analysis, higher prevalence was associated with female gender, residence in the Central and Northeast regions, consumption of more medicines, "bad" self-rated health, and self-medication. The drugs most frequently reported with ADEs were fluoxetine, diclofenac, and amitriptyline. The most frequent ADEs were somnolence, epigastric pain, and nausea. Most reported ADEs were mild, avoidable, and associated with medicines used frequently by the population. The study provided knowledge on the size of the problem with use of medicines in Brazil. PMID- 29617480 TI - [Trends in the use of medical and dental services and associations with educational level and private health plan coverage in Brazil, 1998-2013]. AB - The public-private mix in the Brazilian health system favors double coverage of health services for individuals with private health plans and may aggravate inequities in the use of services. The aim of this study was to describe trends in the use of medical and dental services and associations with schooling and private health coverage. Data were obtained from a national household survey with representative samples in the years 1998, 2003, 2008, and 2013. The study described trends in the use of health services by adults, adjusted by private health coverage, years of schooling, sex, and age. There was an upward trend in the use of health services in adults without a private plan and among adults with a private plan the trend in use varied in a non-linear way. The medical service presented alternation in use over the years and the dental service showed a tendency to decline after 2003. It is necessary to monitor trends in private health coverage and the use of health services to assist government in regulating private plans and avoid increasing inequities among citizens in access to and use of health services. PMID- 29617481 TI - Immigration, global health, and human rights. PMID- 29617482 TI - Bacillus cereus as the main casual agent of foodborne outbreaks in Southern Brazil: data from 11 years. AB - Foodborne diseases are a global concern. In Brazil, the most prevalent pathogen found in foodborne outbreaks is Salmonella sp. (14.4%), followed by Staphylococcus aureus (7.7%), Escherichia coli (6.5%), and Bacillus cereus (3.1%). With the aim to perform a regional detailed analysis of foodborne intoxication, we analyzed 253 outbreaks' profile reports to Food Surveillance team of the General Secretariat of Health Surveillance of Porto Alegre, Rio Grande do Sul State, between 2003 and 2013. In contrast to what was most notified in Brazil, in Porto Alegre the main outbreak agent identified was Bacillus cereus (32.2%) and, based on the patient symptoms, most cases were linked to enterotoxin production. The majority of the outbreaks were linked to the ingestion of food containing cereals or sauces poorly kept at environment temperature during the stock or preparation. We believe that, due to the compulsory use of pasteurized eggs in our city, Salmonella sp. outbreaks are less important here. PMID- 29617483 TI - [Intimate partner violence: treatment profile in urgent and emergency care services in Brazilian state capitals, 2014]. AB - The study aimed to describe the treatment profile for victims of intimate partner violence in urgent and emergency care services in the Brazilian Unified National Health System (SUS) and to investigate differences between the sexes. A descriptive study was performed with data from a survey performed by the System for Surveillance of Accidents and Violence (VIVA Survey), conducted in 86 urgent and emergency care services in 25 state capitals in 2014. All 506 cases of intimate partner violence were included, with 69.9% female victims and 65% from 20 to 39 years of age. Black individuals predominated (70% of females and 82.8% of males, p = 0.005). Lack of paid work was more frequent in female victims (50.4%) compared to males (24.1%), while alcohol consumption was more frequent in males (47.9%) compared to females (21.9%) (p < 0.001). The most common means of aggression against female victims was physical force or beating (70.9%), followed by use of sharp objects (14.5%), while for male victims it was sharp objects (48.7%), followed by physical force or beating (31.6%). Male individuals were identified as the aggressors by 97.6% of the female victims and 11.8% of the males (p < 0.001). The victim's residence was the main site of violence (69.6% of female victims and 74.4% of males; p = 0.622). Most victims were females, while most aggressors were males. Differences between the sexes may reflect cultural patterns and emphasize the need to investigate gender in addition to biological sex. PMID- 29617484 TI - [Trends and factors associated with food insecurity in Brazil: the National Household Sample Survey, 2004, 2009, and 2013]. AB - The aim of this study was to analyze trends and factors associated with food insecurity in Brazil in 2004, 2009, and 2013, using microdata from the National Household Sample Survey (PNAD). Food insecurity was assessed using the Brazilian Food Insecurity Scale. Independent variables were selected from a conceptual model of determination of food insecurity, which was also used in the elaboration of multiple generalized linear models. The results show a downward trend in food insecurity prevalence from 2004 to 2013, especially for moderate and severe food insecurity, from 17% in 2004 (95%CI: 15.7-18.4) to 7.9% in 2013 (95%CI: 7.2-8.7). Despite important decreases in the prevalence of moderate and severe food insecurity, regardless of the level of determination, the population strata with the lowest prevalence in 2004 showed the largest relative reduction. As for factors associated with moderate and severe food insecurity, they remained the same in the ten years covered by the PNAD survey, namely: the North and Northeast regions, urban areas with inadequate sanitation, household density > 2 persons per bedroom, <= 4 household durable consumer goods, and households headed by females, individuals < 60 years, and non-whites, <= 4 years of schooling, and being unemployed. From 2004 to 2013, the prevalence of Brazilian households with moderate and severe food insecurity dropped by half, but from the perspective of equity the advances occurred unequally and were lower in strata with greater social, economic, and demographic vulnerability. PMID- 29617485 TI - [Hypertriglyceridemic waist phenotype: associated factors and comparison with other cardiovascular and metabolic risk indicators in the ELSA-Brasil study]. AB - This study's objectives were to estimate the prevalence of hypertriglyceridemic waist (HTW) phenotype in participants in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil), identify associated risk factors, and compare with other cardiovascular and metabolic risk indicators. This was a cross-sectional study with baseline data from a cohort of public employees. HTW is defined as the simultaneous presence of increased waist circumference (WC) (>= 80cm for women, >= 90cm for men according to the International Diabetes Federation - IDF; and >= 88cm for women, >= 102cm for men according to the U.S. National Cholesterol Education Program - NCEP) and hypertriglyceridemia. Associations between independent variables and HTW were tested with multivariate logistic regression models. HTW was also compared to other cardiovascular and metabolic risk indicators by means of correlation tests, kappa index, sensitivity, and specificity. After exclusions, 12,811 participants were analyzed. Prevalence of HTW ranged from 24.7% (IDF) to 13.3% (NCEP). HTW was associated with age, excessive alcohol consumption, former smoking, low HDL, non-high HDL, and increased C-reactive protein, independently of gender or the criterion used to define HTW. HTW was associated with cardiovascular risk indicators, especially metabolic syndrome. The high prevalence of HTW and its association with cardiovascular risk indicators, especially metabolic syndrome, supports its use as a cardiometabolic risk screening tool in clinical practice. PMID- 29617486 TI - [Structure of primary healthcare units for treating persons with diabetes: Cycles I and II of the Brazilian National Program to Improve Access and Quality]. AB - The objective was to describe the necessary structure for treating diabetes patients in the primary healthcare system, as evaluated in Cycles I and II of the Brazilian National Program for the Improvement of Access and Quality (PMAQ) in 2012 and 2014, according to the municipalities' characteristics. A descriptive study was used to assess primary care units whose teams participated in Cycles I and II of the PMAQ in 2012 and 2014. The study used variables from Module I of the external evaluation of the PMAQ that addresses the primary care units' structure. Materials (150kg scale, sphygmomanometer, adult stethoscope, tape measure, blood glucose monitor, monofilament packs, ophthalmoscope, and capillary blood glucose strips); medicines (NPH and regular insulin, glyburide, and metformin); and physical space (clinical consultation room, pharmacy, reception/waiting room, and meeting room). All the medicines and the reception/waiting room increased by more than 10p.p. from 2012 to 2014. The prevalence rates for adequate structure of materials, medicines, and physical space in the primary care units were higher in 2014. Adequate structure increased as follows: for materials, from 3.9% to 7.8%, for medicines, from 31.3% to 49.9%, for physical space, from 15.3% to 23.3%. Municipalities with more than 300,000 inhabitants, higher Human Development Index (HDI), and lower coverage of the Family Health Strategy (FHS) showed higher prevalence rates for adequate primary care units. Units that adhered to Cycles I and II of the PMAQ showed improvement in their structures. However, there was a low prevalence of primary care units with adequate structures, besides differences in the services' structure according to population size, HDI, and FHS coverage. PMID- 29617487 TI - [Oral health care in the Xingu Indigenous Park, Brazil, from 2004 to 2013: an analysis based on evaluation indicators]. AB - In 2011, the Brazilian National Oral Health Policy redefined its model of care for indigenous peoples, recommending the use of epidemiology and follow-up of the impact of activities using adequate indicators. The current study aimed to analyze trends in these indicators, proposed by the Brazilian Ministry of Health, in the Xingu Indigenous Park, Brazil, from 2004 to 2013. This was a quantitative study using secondary data from the Xingu Special Indigenous Health District and the Xingu Project of the Federal University of Sao Paulo. The coverage rate for first dental visit exceeded 60% in all the years analyzed except 2009 and 2010 (44.7% and 53.4%, respectively). The basic dental treatment indicator showed a significant increase, from 44.9% to 79.9%, between 2006 and 2008. The proportion of tooth extractions decreased from 24.3% in 2004 to 3.8% in 2011. Mean coverage of supervised collective toothbrushing showed the highest variation (1.2 to 23.3%). Access to oral health showed good coverage, and the indicator for completed treatment showed a higher percentage when compared to other indigenous peoples during the same period. Better performance on the tooth extractions indicator may have been due to the change in focus of care through partnerships with universities, although the indicators for supervised toothbrushing suggest the need to prioritize preventive measures. Changes in indigenous healthcare management, with weakening or absence of partnerships, may have negatively influenced the program's indicators. PMID- 29617488 TI - [School feeding and the establishment of school identities: from meals for the poor to the right to food]. AB - This essay aims to analyze school feeding as a practice contributing to the establishment of school identities. The point of departure is a nonsystematic review of publications on school feeding and identities in Brazil's public schools. The discussion begins with the persistence of paternalistic discourses and practices that reduce school feeding to food for the poor, observed in the studies. The meanings in this paternalistic approach suggest that it appears to function as a power mechanism to brand the schoolchildren with an identify of poverty and inferiority. This understanding is situated in the prevailing power relations in schools, in the exercise of disciplinary power and its potential to produce identities, as well as the practices of resistance resulting from such power in the school feeding context. The schoolchildren are also agents of their own identity processes, considering that their relations with school feeding involve processes not only of subordination but also of resistance and active identity-building, combining the traditional with the modern, the local with the global, among other aspects. Even the ambiguities in this scenario are signs of a paradigm shift in the planning and practice of school feeding, raising elements to analyze it: on the one hand, as a device for the maintenance of social inequalities, and on the other, efforts and actions to support school feeding as an essential right and factor for emancipatory identities. PMID- 29617489 TI - Longitudinal Study on the Lifestyle and Health of University Students (ELESEU): design, methodological procedures, and preliminary results. AB - Admission to a university may cause significant changes in the pattern of exposure to health risks. The aim of this paper is to describe the study design and methodological procedures adopted in the Longitudinal Study on the Lifestyle and Health of University Students (ELESEU). This study examines a dynamic cohort of full-time students at a public university in the State of Mato Grosso, Brazil. This research, which started in 2015, will have four years of follow-up and is scheduled to end in 2018. A self-administered questionnaire is applied, containing questions regarding demographic and socioeconomic characteristics, and information on health conditions and risk factors such as lifestyle, perceived stress, symptoms of depression, body image, risk behaviors for eating disorders, self-assessment of health and diet quality, and other issues related to nutrition and health. Anthropometric and blood pressure measurements are also recorded. Two 24-hour dietary recalls and cholesterol, triglycerides, and glucose capillary measurements are collected in 50% of the students. In 2015, 495 participants (82.6% of the eligible students) were assessed in the baseline study. Of these, 348 (70.3%) were followed up in 2016. In 2016, 566 participants were included in the cohort (81% of the eligible students). This study will help to identify the factors that might influence changes in the nutritional, health, and metabolic status of young adults during college life. PMID- 29617490 TI - Multiculturality skills, health care and communication disorders. PMID- 29617491 TI - The impact of decongestive physical therapy and elastic bandaging on the control of pain in patients with venous ulcers. AB - OBJECTIVE: to evaluate pain in individuals with venous ulcers treated with elastic bandage and decongestant physical therapy. METHODS: we studied 90 patients, divided into three groups with 30 patients each: a group treated with elastic bandage and decongestant physical therapy; a group treated with elastic bandage; and a group treated only with primary dressing according to tissue type and presence of exudate. We used the Pain Numerical Scale to quantify pain intensity and the McGill Pain Questionnaire for pain qualitative assessment. RESULTS: in the first evaluation, all patients who participated in the study reported intense pain. In the fifth evaluation, the majority of patients treated with elastic bandaging and decongestant physical therapy did not report pain; the majority of patients in the elastic bandage group reported mild pain; and most patients treated only with primary dressing reported mild to moderate pain. During all five assessments using the McGill questionnaire, most patients in the elastic bandaging and primary dressing groups used descriptors of the sensory, affective, evaluative and miscellaneous groups to describe their pain. However, in the fourth and fifth evaluations, most patients who received decongestant physical therapy combined with elastic bandaging treatment did not use any of the descriptors. CONCLUSION: patients treated with decongestant physical therapy and elastic bandage presented pain improvement from the third evaluation performed on. PMID- 29617492 TI - Influence of advanced age on postoperative outcomes and total loss following breast reconstruction: a critical assessment of 560 cases. AB - OBJECTIVE: to evaluate the role of age in the risk of postoperative complications in patients submitted to unilateral breast reconstruction after mastectomy, with emphasis on total reconstruction loss. METHODS: we conducted a retrospective study of patients submitted to breast reconstruction, whose variables included: oncological and reconstruction data, postoperative complications, including loss of reconstruction and complications of surgical wound. We divided the patients into two groups, according to the classification of the Brazilian National Elderly Policy and the Statute of the Elderly: young (age <60 years) and elderly (60 years or more). We also grouped them according to the World Health Organization classification: young people (age <44 years), middle age (45-59 years); elderly (age 60-89 years) and extreme advanced age (90 years or older). We applied the surgical risk classification of the American Society of Anesthesiologists to investigate the role of the preoperative physical state as a possible predictor of complications. RESULTS: of the 560 patients operated on, 94 (16.8%) were 60 years of age or older. We observed a local complication rate of 49.8%, the majority being self-limited. The incidences of necrosis, infection and dehiscence were 15.5%, 10.9% and 9.3%, respectively. Patients older than 60 years presented a chance of complication 1.606 times greater than the younger ones. Forty-five (8%) patients had loss of the reconstruction; there was no statistically significant difference in the mean age of the patients who presented this result or not (p=0.321). CONCLUSION: in selected patients, breast reconstruction can be considered safe; most documented complications were limited and could be treated conservatively. PMID- 29617493 TI - Pectoralis major myocutaneous flap in Head And Neck Surgery reconstructions: critical analysis. AB - OBJECTIVE: to evaluate the results of the use of the pectoralis major flap in the reconstruction of head and neck surgeries. METHODS: we conducted a retrospective study with data bank analysis and review of medical records of patients with head and neck cancer operated at the Discipline of Head and Neck Surgery, Surgery Department, Sao Paulo Holy Home of Mercy, using the pectoralis major flap for reconstruction, in a period of 16 years. We analyzed age, gender, primary site of neoplasia, clinical staging, preoperative radiotherapy (RT) and complications, classified as major and minor. RESULTS: the series comprised 92 patients, of whom 86 (93.5%) were men; the mean age was 61.39 (+/-11.35) years; the most common primary sites were the mouth, in 35 cases (38%), oropharynx, in 21 (22.8%), and larynx, in 18 cases (19.6%). The majority of patients were in stage IV (88/92, 95.6%) and only four (4.3%) had preoperative RT. The overall complication rate was 48.9%, but only 6.5%, characterized as major complications. In the univariate statistical analysis, we found no factors related to the occurrence of complications. Only the primary neoplasm site presented marginal significance (p = 0.06). CONCLUSION: the pectoralis major flap is safe, with few complete and effective losses in reconstructions in head and neck surgeries, with low rates of major complications, being an option to be considered. PMID- 29617494 TI - Transcatheter Aortic Valve Replacement: The Experience of One Brazilian Health Care Center. AB - OBJECTIVE: Transcatheter aortic valve replacement has been an alternative to invasive treatment for symptomatic severe aortic stenosis in high risk patients. The primary endpoint was 30-day and 1-year mortality from any cause. Secondary endpoints were to compare the clinical and echocardiographic variation pre-and post- transcatheter aortic valve replacement, and the occurrence of complications throughout a 4-year follow-up period. METHODS: This prospective cohort, nestled to a multicenter study (Registro Brasileiro de Implante de Bioprotese por Cateter), describes the experience of a public tertiary center in transcatheter aortic valve replacement. All patients who underwent this procedure between October 2011 and February 2016 were included. RESULTS: Fifty-eight patients underwent transcatheter aortic valve replacement. The 30-day all-cause mortality was 5.2% (n=3) and after 1 year was 17.2% (n=10). A significant improvement in New York Heart Association functional classification was observed when comparing pre-and post- transcatheter aortic valve replacement (III or IV 84.4% versus 5.8%; P<0.001). A decline in peak was observed (P<0.001) and mean (P<0.001) systolic transaortic gradient. The results of peak and mean post-implant transaortic gradient were sustained after one year (P=0.29 and P=0.36, respectively). Left ventricular ejection fraction did not change significantly during follow-up (P=0.41). The most frequent complications were bleeding (28.9%), the need for permanent pacemaker (27.6%) and acute renal injury (20.6%). CONCLUSION: Mortality and complications in this study were consistent with worldwide experience. Transcatheter aortic valve replacement had positive clinical and hemodynamic results, when comparing pre-and post-procedure, and the hemodynamic profile of the prosthesis was sustained throughout follow-up. PMID- 29617496 TI - Cardiopulmonary Bypass and Cancer Dissemination: A Logical But Unlikely Association. PMID- 29617495 TI - Early Clinical Results of Perceval Sutureless Aortic Valve in 139 Patients: Freeman Experience. AB - OBJECTIVE: The aim of this retrospective study is to evaluate the safety and performance of the Perceval sutureless valve in patients undergoing aortic valve replacement. We report the 30-day clinical outcomes of 139 patients. METHODS: From January 2014 to December 2016, 139 patients underwent sutureless aortic valve replacement. Their operation notes, National Adult Cardiac Surgery Database and perioperative transoesophageal echocardiography findings were studied retrospectively. RESULTS: Ninety-two patients underwent isolated aortic valve replacement (group A) with Perceval valve and 47 patients had combined procedures of aortic valve replacement and coronary artery bypass grafting (group B). The patients received a size S (n=23), M (n=39), L (n=42) or XL (n=35) prosthesis. Perceval valve was successfully implanted in 135 (97.1%) patients. Mean cross clamping time and bypass time were 40 and 63 minutes for isolated cases, while 68 and 107 minutes for combined cases. Three (2.1%) patients died within 30 days. Four patients suffered stroke and 5 patients went into acute renal failure. Median intensive care unit and hospital stay was 2 and 8.5, respectively. Four valves were explanted due to significant paravalvular leak after surgery. Five patients had permanent pacemaker as a result of complete heart block and mean postoperative drainage was 295 mL for isolated case and 457 mL for combined cases. The mean gradient across Perceval valve was 12.5 mmHg while its effective orifice area was 1.5 cm2. CONCLUSION: Early postoperative results showed that Perceval valve is safe. Further follow up is needed to evaluate the long-term outcome with this bioprosthesis. PMID- 29617497 TI - OPCABG for Moderate CIMR in Elderly Patients: a Superior Option? AB - OBJECTIVE: To compare the early and late outcomes of off-pump coronary artery bypass grafting and coronary artery bypass graft + mitral valve repair in elderly patients with moderate chronic ischemic mitral regurgitation. METHODS: One hundred and fifty elderly (age > 70 years) patients with moderate chronic ischemic mitral regurgitation who underwent off-pump coronary artery bypass grafting (n=95) or coronary artery bypass graft + mitral valve repair (n=55) between January 2007 and December 2014 were studied. They were subdivided according to presence or absence of high operative risk. Peri-operative variables and early operative outcomes were retrospectively studied. Survival, mitral regurgitation grade, and functional outcomes were prospectively analysed. RESULTS: Both groups were comparable in terms of age (P=0.23), sex (P=0.74), left ventricle ejection fraction (P=0.6) and preoperative functional class (P=0.52). The mean number of grafts for off-pump coronary artery bypass grafting group was 3.14 and coronary artery bypass graft + mitral valve repair was 3.21. Off-pump coronary artery bypass grafting group had statistically significant better early operative outcomes i.e perioperative blood transfusions, intraaortic balloon pump usage, arrhythmias, renal dysfunction, liver dysfunction, sepsis, mean hours of ventilation, intensive care unit stay and operative mortality. On a prospective follow up of 5+/-2.33 years (1-9 years), coronary artery bypass graft + mitral valve repair in low operative risk subgroup had better improvements in mitral regurgitation grade than off-pump coronary artery bypass grafting. Both groups had similar improvements in functional class and cumulative survival was also comparable (63.2% vs. 54.5%). CONCLUSION: Off-pump coronary artery bypass grafting is a safer alternative to coronary artery bypass graft + mitral valve repair with better early operative outcomes and comparable late survival and functional outcomes in elderly patients with moderate chronic ischemic mitral regurgitation, especially those with higher operative risk. PMID- 29617498 TI - Long-Term Results of Mitral Valve Repair. AB - INTRODUCTION: Current guidelines state that patients with severe mitral regurgitation should be treated in reference centers with a high reparability rate, low mortality rate, and durable results. OBJECTIVE: To analyze our global experience with the treatment of organic mitral regurgitation from various etiologies operated in a single center. METHODS: We evaluated all surgically treated patients with organic mitral regurgitation from 2004-2017. Patients were evaluated clinically and by echocardiography every year. We determined early and late survival rates, valve related events and freedom from recurrent mitral regurgitation and tricuspid regurgitation. Valve failure was defined as any mitral regurgitation >= moderate degree or the need for reoperation for any reason. RESULTS: Out of 133 patients with organic mitral regurgitation, 125 (93.9%) were submitted to valve repair. Mean age was 57+/-15 years and 52 patients were males. The most common etiologies were degenerative disease (73 patients) and rheumatic disease (34 patients). Early mortality was 2.4% and late survival was 84.3% at 10 years, which are similar to the age- and gender-matched general population. Only two patients developed severe mitral regurgitation, and both were reoperated (95.6% at 10 years). Freedom from mitral valve failure was 84.5% at 10 years, with no difference between degenerative and rheumatic valves. Overall, late >= moderate tricuspid regurgitation was present in 34% of the patients, being more common in the rheumatic ones. The use of tricuspid annuloplasty abolished this complication. CONCLUSION: We have demonstrated that mitral regurgitation due to organic mitral valve disease from various etiologies can be surgically treated with a high repair rate, low early mortality and long term survival that are comparable to the matched general population. Concomitant treatment of atrial fibrillation and tricuspid valve may be important adjuncts to optimize long-term results. PMID- 29617500 TI - External Validation of European System for Cardiac Operative Risk Evaluation II (EuroSCORE II) for Risk Prioritization in an Iranian Population. AB - INTRODUCTION: The European System for Cardiac Operative Risk Evaluation II (EuroSCORE II) is a prediction model which maps 18 predictors to a 30-day post operative risk of death concentrating on accurate stratification of candidate patients for cardiac surgery. OBJECTIVE: The objective of this study was to determine the performance of the EuroSCORE II risk-analysis predictions among patients who underwent heart surgeries in one area of Iran. METHODS: A retrospective cohort study was conducted to collect the required variables for all consecutive patients who underwent heart surgeries at Emam Reza hospital, Northeast Iran between 2014 and 2015. Univariate and multivariate analysis were performed to identify covariates which significantly contribute to higher EuroSCORE II in our population. External validation was performed by comparing the real and expected mortality using area under the receiver operating characteristic curve (AUC) for discrimination assessment. Also, Brier Score and Hosmer-Lemeshow goodness-of-fit test were used to show the overall performance and calibration level, respectively. RESULTS: Two thousand five hundred eight one (59.6% males) were included. The observed mortality rate was 3.3%, but EuroSCORE II had a prediction of 4.7%. Although the overall performance was acceptable (Brier score=0.047), the model showed poor discriminatory power by AUC=0.667 (sensitivity=61.90, and specificity=66.24) and calibration (Hosmer-Lemeshow test, P<0.01). CONCLUSION: Our study showed that the EuroSCORE II discrimination power is less than optimal for outcome prediction and less accurate for resource allocation programs. It highlights the need for recalibration of this risk stratification tool aiming to improve post cardiac surgery outcome predictions in Iran. PMID- 29617499 TI - Mortality Predictors in the Surgical Treatment of Active Infective Endocarditis. AB - INTRODUCTION: Active infective endocarditis is associated with high morbidity and mortality. Surgery is indicated in high-risk conditions, and the main determinants of mortality in surgical treatment should be evaluated. OBJECTIVE: To identify mortality predictors in the surgical treatment of active infective endocarditis in a long-term follow-up. METHODS: This prospective observational study involved 88 consecutive patients diagnosed with active infective endocarditis, who underwent surgery between January 2005 and December 2015. Fifty eight (65.9%) patients were male, the mean age was 50.87+/-16.15 years. A total of 31 (35.2%) patients had a history of rheumatic fever; 48 (54.5%) had had heart surgery with prosthetic valve implantation; 45 (93.8%) had biological prosthetic valve endocarditis and 3 (6.3%) mechanical prosthetic valve; 40 (45.5%) patients had the disease in their native valve. The mean EuroSCORE II was 8.9+/-6.5%, and the main surgical indication was refractory heart failure in 38 (43.2%) patients. A total of 68 bioprosthesis (36 aortic, 32 mitral) and 29 mechanical prostheses (12 aortic, 17 mitral) were implanted and three mitral valve plasties performed. A total of 25 (28.4%) patients underwent double or triple valve procedures. Aortic annulus reconstruction by abscess was performed in 18 (20.5%) and six (6.81%) patients had combined procedure. The mean surgery time was 359+/-97.6 minutes. RESULTS: The overall survival in up to a 10-year follow-up period was 79.5%. In the univariate analysis, the main mortality predictors were positive blood cultures (P=0.003), presence of typical microorganisms (P=0.008), most frequently Streptococcus viridans (12 cases; 25%); C-reactive protein (hazard ratio [HR] 1.034, 95% confidence interval [CI] 1.000 to 1.070, P=0.04); creatinine clearance (HR 0.977, 95% CI 0.962 to 0.993, P=0.005); length of surgery: every five minutes multiplies the chance of death 1.005-fold (HR 1.005, 95% CI 1.001 to 1.009, P=0.0307); age (HR 1.060, 95% CI 1.026 to 1.096, P=0.001); and EuroSCORE II (HR 1.089, 95% CI 1.030 to 1.151, P=0.003). CONCLUSION: A positive blood culture with typical microorganism, C-reactive protein, age, EuroSCORE II, total surgical time and the presence of postoperative complications were the major predictors of mortality and significantly impacted survival in up to a 10-year follow-up period. PMID- 29617501 TI - CABG and Preoperative use of Beta-Blockers in Patients with Stable Angina are Associated with Better Cardiovascular Survival. AB - OBJECTIVE: In contrast to unstable angina, optimal therapy in patients with stable angina is debated. Our aim was to evaluate the outcomes of patients with stable angina scheduled for isolated coronary artery bypass grafts and the effect of preoperative use of beta-blockers. Overall and cardiovascular survivals were our primary outcome. Operative mortality and postoperative complications along with subgroup analysis of diabetic patients were our secondary outcomes. METHODS: Retrospective evaluation of patients with stable angina scheduled for isolated coronary artery bypass grafts was included. Pre- and postoperative variables were extracted from the institution database. Survival was obtained from the National Registry. RESULTS: We included 282 patients with stable angina, with a mean age of 65.6+/-9.5 years. 26.6% were female and 38.7% had diabetes. Three-vessel disease was present in 76.6% of patients. Previous beta-blocker treatment was evident in 69.9% of patients. 10-year overall survival in the whole population was 60.5% (95% confidence interval [CI]: 50.3-70.7%). Operative mortality during the study period was 3.5%. Patients with preoperative use of beta-blocker therapy had better overall survival (9.0 years, 95%CI: 8.6-9.5) than those without treatment (7.9 years, 95%CI: 7.1-8.8 years; P=0.048). Predictors for overall survival were: hypertension, diabetes, and age. Predictors for cardiovascular survival in diabetic patients were: beta-blocker use, gender, and age. CONCLUSION: Coronary artery bypass grafts surgery in patients with stable angina carries low operative mortality, postoperative complications, and excellent long term cardiovascular survival. The preoperative use of beta-blockers in diabetic patients is associated with better cardiovascular survival after coronary artery bypass grafts. PMID- 29617502 TI - The Frequency of Infective Endocarditis in Candida Bloodstream Infections: a Retrospective Study in a Child Hospital. AB - INTRODUCTION: Fungal endocarditis is reported less frequently than bacterial endocarditis, with an incidence of 0-12% of the total pediatric infective endocarditis. OBJECTIVE: In this study, the incidence of infective endocarditis in Candida bloodstream infections in a tertiary hospital during the periods of 2007 and 2016 was reviewed. METHODS: Patients with positive blood or catheter cultures in terms of Candida spp. during the study period of January 2007 and January 2016 were analyzed in terms of Candida infective endocarditis. Infective endocarditis was defined according to the modified Duke criteria. The outcome, possible associated predisposing factors for Candida endocarditis were determined. RESULTS: 221 patients and 256 attacks with positive blood or catheter cultures in terms of Candida were included in the study. The most common Candida species was Candida parapsilosis, isolated in 157 (61.3%) attacks, followed by Candida albicans in 70 (27.3%). Neurological diseases (23%), hemato-oncological diseases (12.1%), previously known heart diseases (8.2%), inborn errors of metabolism (9%) were common comorbidities. Twelve (5.4%) patients had a previous history of cardiac surgery. Among the 221 patients, Candida endocarditis was present in only two (0.9%) of them. CONCLUSION: Although Candida infective endocarditis is an uncommon but frequently fatal infection in pediatrics, echocardiography should be performed routinely for patients with positive blood or catheter cultures in terms of Candida. Prompt and effective antimicrobial therapy might prevent cardiac surgery in selected cases, however this could not be a general rule for all patients. PMID- 29617503 TI - Postoperative Bleeding Following Preoperative Clopidogrel Administration in Patients with Haemoglobin Level Above 110 g/L Undergoing Urgent CABG. AB - INTRODUCTION: Patients with acute coronary syndrome usually receive dual antiplatelet therapy (DAPT) (usually clopidogrel + aspirin) prior to coronary catheterization, and approximately 10% of these patients require coronary artery bypass grafting (CABG). DAPT has favorable effects on prevention of thrombus formation, but it can have deleterious effects on surgical hemostasis. Anaemia, if present, gives additional risk to such patients. The aim of this study was to examine if DAPT affects postoperative bleeding in patients with haemoglobin levels above 110 g/L, who underwent urgent or emergent CABG, less than five days after stopping DAPT therapy. METHODS: Data were collected prospectively on 122 CABG patients, operated by a surgical team from March 2008 to August 2013. Patients were stratified into two groups: group 1 received DAPT within 5 days of CABG (n=65), and group 2 where DAPT was discontinued for more than 5 days prior to CABG (n=57). All patients were diagnosed with acute coronary syndrome preoperatively, and all of them had haemoglobin levels above 110 g/L. Patients who needed reoperation, combined procedures, or off-pump revascularization were excluded. RESULTS: There was no hospital mortality. Mean chest tube losses after the surgical revascularization did not differ significantly, but group 1 received a higher quantity of transfused red blood cells and platelets. CONCLUSION: Urgent and emergent surgical revascularization using extracorporeal circulation in patients with acute coronary syndrome whose preoperative haemoglobin levels are above 110 g/L is a safe and effective procedure. We suggest that, where indicative, one may perform CABG in less than 5 days after the clopidogrel discontinuation. PMID- 29617504 TI - Hemolysis and Inflammatory Response to Extracorporeal Circulation during On-Pump CABG: Comparison between Roller and Centrifugal Pump Systems. AB - OBJECTIVE: To compare the perioperative incidence rates of hemolysis and inflammatory response in patients undergoing coronary artery bypass grafting with the two main types of cardiopulmonary bypass, centrifugal and roller pumps, and establish correlations among hemolytic and inflammatory changes. METHODS: This was a prospective, randomized trial of 60 patients assigned to either roller pump (G1, n=30) or centrifugal pump (G2, n=30) bypass. Markers of hemolysis (serum haptoglobin, lactate dehydrogenase [LDH]) and inflammation (interleukin [IL]1beta, IL-6, and TNF-alpha) were measured and analyzed. RESULTS: There was no significant between-group difference in the variables of interest. In G1, there was a positive association with IL-6 and TNF-alpha (P<0.01 and P<0.05, respectively). In G2, there was a positive association with LDH in the postoperative period (P<0.5). At 24h post-cardiopulmonary bypass, there were positive associations between LDH and IL-1beta (P<0.05), LDH and TNF-alpha (P<0.01), haptoglobin and TNF-alpha (P<0.05), and LDH and TNF-alpha (P<0.01) in G1, and between LDH and IL-6 (P<0.01), LDH and TNF-alpha (P<0.01), and LDH and IL 6 (P<0.01) in G2. CONCLUSION: There were no significant between-group differences in markers of hemolysis or inflammation. IL-6 and TNF-alpha were positively associated with duration of cardiopulmonary bypass in G1, while LDH was positively associated with duration of cardiopulmonary bypass in G2. The rate of significant associations between markers of hemolysis and inflammation was higher in the roller pump group (G1). REGISTRATION NUMBER: ReBEC (RBR-92b9dg). PMID- 29617505 TI - Evaluation of the Effects of Atorvastatin and Ischemic Postconditioning Preventing on the Ischemia and Reperfusion Injury: Experimental Study in Rats. AB - INTRODUCTION: Reperfusion injury leads to systemic morphological and functional pathological alterations. Some techniques are already estabilished to attenuate the damage induced by reperfusion. Ischemic preconditioning is one of the standard procedures. In the last 20 years, several experimental trials demonstrated that the ischemic postconditioning presents similar effectiveness. Recently experimental trials demonstrated that statins could be used as pharmacological preconditioning. METHODS: 41 Wistar rats (Rattus norvegicus albinus) were distributed in 5 groups: Ischemia and Reperfusion (A), Ischemic Postconditioning (B), Statin (C), Ischemic Postconditioning + Statins (D) and SHAM (E). After euthanasia, lungs, liver, kidneys and ileum were resected and submitted to histopathological analysis. RESULTS: The average of lung parenchymal injury was A=3.6, B=1.6, C=1.2, D=1.2, E=1 (P=0.0029). The average of liver parenchymal injury was A=3, B=1.5, C=1.2, D=1.2, E = 0 (P<0.0001). The average of renal parenchymal injury was A=4, B=2.44, C=1.22, D=1.11, E=1 (P<0.0001). The average of intestinal parenchymal injury was A=2, B=0.66, C=0, D=0, E=0 (P=0.0006). The results were submitted to statistics applying Kruskal-Wallis test, estabilishing level of significance P<0.05. CONCLUSION: Groups submitted to ischemic postconditioning, to pre-treatment with statins and both methods associated demonstrated less remote reperfusion injuries, compared to the group submitted to ischemia and reperfusion without protection. PMID- 29617506 TI - Chronic Chagas Cardiomyopathy Patients and Resynchronization Therapy: a Survival Analysis. AB - INTRODUCTION: Chagas disease represents an important health problem with socioeconomic impacts in many Latin-American countries. It is estimated that 20% to 30% of the people infected by Trypanosoma cruzi will develop chronic Chagas cardiomyopathy (CCC), which is generally accompanied by heart failure (HF). Cardiac resynchronization therapy (CRT) may be indicated for patients with HF and electromechanical dysfunctions. OBJECTIVE: The primary endpoint of this study was to analyze the response to CRT in patients with CCC, while the secondary endpoint was to estimate the survival rates of CRT responder patients. METHODS: This is an observational, cross-sectional and retrospective study. The records of 50 patients with CRT pacing devices implanted between June 2009 and March 2017 were analyzed. For statistical analyses, Pearson's correlation was used along with Student's t-test, and survival was analyzed using the Kaplan-Meier method. A P value of <0.05 was considered significant. RESULTS: Out of 50 patients, 56% were male, with a mean age of 63.4+/-13.3 years and an average CRT duration of 61.2+/ 21.7 months. The mean QRS duration was 150.12+/-12.4 ms before and 116.04+/-2.2 ms after the therapy (P<0.001). The mean left ventricular ejection fractions (LVEF) were 29+/-7% and 39.1+/-12.2% before and after CRT, respectively (P<0.001). A total of 35 (70%) patients had a reduction of at least one New York Heart Association (NYHA) functional class after six months of therapy (P=0.014). The survival rate after 72 months was 45%. CONCLUSION: This study showed clinical improvement and a nonsignificant survival rate in patients with CCC after the use of CRT. PMID- 29617507 TI - Closure of Patent Foramen Ovale versus Medical Therapy after Cryptogenic Stroke: Meta-Analysis of Five Randomized Controlled Trials with 3440 Patients. AB - OBJECTIVE: We aimed to determine whether patent foramen ovale closure reduces the risk of stroke, also assessing some safety outcomes. INTRODUCTION: The clinical benefit of closing a patent foramen ovale after a cryptogenic stroke has been an open question for several decades, so that it is necessary to review the current state of published medical data in this regard. METHODS: MEDLINE, EMBASE, CENTRAL/CCTR, SciELO, LI-LACS, Google Scholar and reference lists of relevant articles were searched for randomized controlled trials that reported any of the following outcomes: stroke, death, major bleeding or atrial fibrillation. Five studies fulfilled our eligibility criteria and included 3440 patients (1829 for patent foramen ovale closure and 1611 for medical therapy). RESULTS: The risk ratio (RR) for stroke in the "device closure" group compared with the "medical therapy" showed a statistically significant difference between the groups, favouring the "device closure" group (RR 0.400; 95% CI 0.183-0.873, P=0.021). There was no statistically significant difference between the groups regarding the safety outcomes death and major bleeding, but we observed an increase in the risk of atrial fibrillation in the "device closure group (RR 4.000; 95% CI 2.262 7.092, P<0.001). We also observed that the larger the proportion of effective closure, the lower the risk of stroke. CONCLUSION: This meta-analysis found that stroke rates are lower with percutaneously implanted device closure than with medical therapy alone, being these rates modulated by the rates of effective closure. PMID- 29617508 TI - The Role of Heart Team Approach in Penetrating Cardiac Trauma: Case Report and Review of the Literature. AB - Penetrating cardiac trauma has been increasing in clinical experience and is joined to important morbidity and mortality. A case of a 38-year-old female with history of postpartum depression was reported, admitted to our department for cardiac tamponade due to penetrating self-inflicted multiple stab wound of the chest complicated by rupture of anterior left ventricular wall and traumatic ventricular septal defect. Following the unstable hemodynamic instability, a combined therapeutic strategy was chosen: surgery and transcatheter implantation to correct free wall ventricle damage and traumatic ventricular septal defect, respectively. PMID- 29617509 TI - A Rare Cause of Abdominal Pain in Childhood: Cardiac Angiosarcoma. AB - Cardiac angiosarcomas are extremely rare in childhood, they are rapidly progressive tumours that often present themselves as diagnostic dilemmas, resulting in delayed diagnosis. Also, extracardiac manifestations, including abdominal pain, are extremely rare in patients with intracardiac tumors. We herein present the case of a 15-year-old girl who presented with abdominal pain. Echocardiography and thoracic computed tomography showed right atrial mass. The patient underwent surgery, chemotherapy, and radiotherapy. Eight months after treatment, abdominal recurrence was detected. The abdominal mass was resected, and radiotherapy and new chemotherapy protocol were given. The present case illustrates a rare case of primary cardiac angiosarcoma posing a diagnostic dilemma in an adolescent girl. PMID- 29617510 TI - Symptomatic Aortic Paravalvular Leak: Percutaneous Treatment with Amplatzer Vascular Plug III Device as an Alternative to Surgery. AB - A significant prosthetic paravalvular leak is an uncommon and severe postsurgical complication correlated to the occurrence of congestive heart failure and hemolytic anemia. Percutaneous treatment has become an attractive and effective proposal to relieve symptoms and reduce complications in patients whose high rate of morbidity/mortality precludes a new surgery. This is the case of an 81-year old patient with a history of biological aortic valve replacement seeking medical help due to heart failure and hemolytic anemia, with a prosthetic paravalvular regurgitation jet and high surgical mortality according to EuroSCORE II. PMID- 29617512 TI - Error in Article Title. PMID- 29617511 TI - ORBITA Trial: Redefining the Role of Intervention in the Treatment of Stable Coronary Disease? PMID- 29617513 TI - Safety of Estradiol Treatment in Perimenopausal Asymptomatic Women. PMID- 29617514 TI - Early Intervention Service for Young People With Psychosis: Saving Young Lives. PMID- 29617516 TI - Safety of Estradiol Treatment in Perimenopausal Asymptomatic Women-Reply. PMID- 29617515 TI - Development of White Matter Circuitry in Infants With Fragile X Syndrome. AB - Importance: Fragile X syndrome (FXS) is a genetic neurodevelopmental disorder and the most common inherited cause of intellectual disability in males. However, there are no published data on brain development in children with FXS during infancy. Objective: To characterize the development of white matter at ages 6, 12, and 24 months in infants with FXS compared with that of typically developing controls. Design, Setting, and Participants: Longitudinal behavioral and brain imaging data were collected at 1 or more time points from 27 infants with FXS and 73 typically developing controls between August 1, 2008, and June 14, 2016, at 2 academic medical centers. Infants in the control group had no first- or second degree relatives with intellectual or psychiatric disorders, including FXS and autism spectrum disorder. Main Outcomes and Measures: Nineteen major white matter pathways were defined in common atlas space based on anatomically informed methods. Diffusion parameters, including fractional anisotropy, were compared between groups using linear mixed effects modeling. Fiber pathways showing group differences were subsequently examined in association with direct measures of verbal and nonverbal development. Results: There were significant differences in the development of 12 of 19 fiber tracts between the 27 infants with FXS (22 boys and 5 girls) and the 73 infants in the control group (46 boys and 27 girls), with lower fractional anisotropy in bilateral subcortical-frontal, occipital-temporal, temporal-frontal, and cerebellar-thalamic pathways, as well as 4 of 6 subdivisions of the corpus callosum. For all 12 of these pathways, there were significant main effects between groups but not for the interaction of age * group, indicating that lower fractional anisotropy was present and stable from age 6 months in infants with FXS. Lower fractional anisotropy values in the uncinate fasciculi were correlated with lower nonverbal developmental quotient in the FXS group (left uncinate, F = 10.06; false discovery rate-corrected P = .03; right uncinate, F = 21.8; P = .004). Conclusions and Relevance: The results substantiate in human infants the essential role of fragile X gene expression in the early development of white matter. The findings also suggest that the neurodevelopmental effects of FXS are well established at 6 months of age. PMID- 29617517 TI - Association of an Early Intervention Service for Psychosis With Suicide Rate Among Patients With First-Episode Schizophrenia-Spectrum Disorders. AB - Importance: Patients with schizophrenia have a substantially higher suicide rate than the general public. Early intervention (EI) services improve short-term outcomes. However, little is known about the association of EI with suicide reduction in the long term. Objective: To examine the association of a 2-year EI service with suicide reduction in patients with first-episode schizophrenia spectrum (FES) disorders during 12 years and the risk factors for early and late suicide. Design, Setting, and Participants: This historical control study compared 617 consecutive patients with FES who received the 2-year EI service in Hong Kong between July 1, 2001, and June 30, 2003, with 617 patients with FES who received standard care (SC) between July 1, 1998, and June 30, 2001, matched individually. Clinical information was systematically retrieved for the first 3 years of clinical care for both groups. The details of death were collected up to 12 years from presentation to the services. Data analysis was performed from October 30, 2016, to August 18, 2017. Main Outcomes and Measures: Suicide rate during 12 years was the primary measure. The association of the EI service with the suicide rates during years 1 through 3 and years 4 through 12 were explored separately. Results: The main analysis included 1234 patients, with 617 in each group (mean [SD] age at baseline, 21.2 [3.4] years in the EI group and 21.3 [3.4] years in the SC group; 318 male [51.5%] in the EI group and 322 [52.2%] in the SC group). The suicide rates were 7.5% in the SC group and 4.4% in the EI group (McNemar chi2 = 5.55, P = .02). Patients in the EI group had significantly better survival (propensity score-adjusted hazard ratio, 0.57; 95% CI, 0.36-0.91; P = .02), with the maximum association observed in the first 3 years. The number of suicide attempts was an indicator of early suicide (1-3 years). Premorbid occupational impairment, number of relapses, and poor adherence during the initial 3 years were indicators of late suicide (4-12 years). Conclusions and Relevance: This study suggests that the EI service may be associated with reductions in the long-term suicide rate. Suicide at different stages of schizophrenia was associated with unique risk factors, highlighting the importance of a phase-specific service. PMID- 29617518 TI - Prevalence and Correlates of Skin Cancer Screening Among Indoor Tanners and Nontanners. AB - Importance: The US Food and Drug Administration recommends that indoor tanners (ITs) be screened regularly for skin cancer (SC). Objective: To investigate the association between indoor tanning and SC screening. Design, Setting, and Participants: The 2015 National Health Interview Survey was a multistage, clustered, cross-sectional design with 30 352 US adults participating. The response rate for the sample adult data used in this study was 55.20% after excluding 1099 individuals who reported a history of SC and 2221 individuals with unknown SC screening or indoor tanning history. To examine the independent correlates of screening, we conducted multiple logistic regressions separately for ITs and nontanners (NTs), simultaneously including all preselected variables of interest as potential predictors. Formal interaction analyses were also performed to determine if the covariate effects differed significantly between ITs and NTs. Exposures: Indoor tanning as well as sociodemographic, health care, and SC risk and sun protection factors. Main Outcomes and Measures: The primary outcome was self-reported full-body SC screening by a physician. Univariable and multivariable analyses were conducted to determine the secondary outcome, correlates of SC screening among ITs and NTs. Results: A total of 15 777 participants (51.98%) were female, and 23 823 (78.49%) were white; 4987 (16.43%) of the sample had indoor tanned, and 1077 (21.59%) of these had tanned last year. A total of 1505 ITs (30.18%) and 4951 NTs (19.52%) had been screened for SC. Correlates of screening for ITs and NTs were older age (ITs: odds ratio [OR], 4.29 [95% CI, 2.72-6.76]; NTs, OR, 5.14 [95% CI, 4.01-6.58], age >=65 years vs 18 29 years), higher income (ITs: OR, 2.08 [95% CI, 1.50-2.88]; NTs: OR, 1.79 [95% CI, 1.51-2.12]; >$100 000 vs $0-34 999), seeking online health information (ITs, OR, 0.71 [95% CI. 0.56-0.91; NTs, OR, 0.65 [95% CI, 0.58-0.72], for not looking up health info online), family history of melanoma (ITs: OR, 1.92 [95% CI, 1.26 2.93]; NTs: OR, 1.58 [95% CI, 1.21-2.05]) or SC (ITs: OR, 1.59 [95% CI, 1.17 2.17; NTs: OR, 1.61 [95% CI, 1.33-1.94]), very high SPF sunscreen use (ITs: OR, 0.57 [95% CI, 0.42-0.78]; NTs: OR, 0.71 [95% CI, 0.61-0.82], use of SPF of 1-14 vs SPF of >50), and receipt of a professional spray-on tan (ITs: OR, 0.60 [ 95% CI, 0.41-0.88]; NTs: OR, 0.51 [95% CI, 0.32-0.81], for not receiving a salon spray-on tan). Correlates for NTs only were white race (blacks: OR, 0.45 [95% CI, 0.37-0.54], others: OR, 0.40 [95% CI, 0.33-0.48]), non-Hispanic ethnicity (Hispanics: OR, 0.42 [95% CI, 0.36-0.50]), email use (no email: OR, 0.67 [95% CI, 0.56-0.80]), having a usual clinic/or physician's office (no usual place: OR, 0.56 [95% CI, 0.40-0.78]), emergency department visits (OR, 1.20 [95% CI, 1.06 1.35]), having had a previous cancer diagnosis (no cancer diagnosis: OR, 0.67 [95% CI, 0.57-0.79]), not being worried about medical bills (OR, 1.37 [95% CI, 1.15-1.63] vs very worried), sun protection (rarely/never: OR, 0.43 [95% CI, 0.34 0.56]), and sunless self-tanning (not using: OR, 0.62 [95% CI, 0.47-0.83]). Conclusions and Relevance: Few ITs have been screened for SC, although SC rates are higher than among NTs. It is not surprising that SC screening is associated with SC risk factors (eg, family history of SC and age) among ITs. However, some unscreened ITs may be putting themselves at even greater risk of SC by also being more likely to use low SPF sunscreen than ITs who have been screened for SC. PMID- 29617519 TI - Consanguineous Marriage and the Psychopathology of the Progeny of First-Cousin Couples. PMID- 29617520 TI - Tips for Analyzing Large Data Sets From the JAMA Surgery Statistical Editors. PMID- 29617521 TI - Practical Guide to Surgical Data Sets: National Surgical Quality Improvement Program (NSQIP) and Pediatric NSQIP. PMID- 29617522 TI - Acute Coronary Syndrome in a 44-Year-Old Woman. PMID- 29617524 TI - Prevalence of Delusional Infestation-A Population-Based Study. PMID- 29617523 TI - Effects of Sacubitril/Valsartan on Physical and Social Activity Limitations in Patients With Heart Failure: A Secondary Analysis of the PARADIGM-HF Trial. AB - Importance: Health-related quality of life (HRQL) of patients with heart failure is markedly reduced compared with that in patients with other chronic diseases, demonstrating substantial limitations in physical and social activities. In the Prospective Comparison of ARNI With an ACE-Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial, sacubitril/valsartan improved overall HRQL compared with enalapril, as determined by the Kansas City Cardiomyopathy Questionnaire (KCCQ). Objective: To examine the effects of sacubitril/valsartan on physical and social activities. Design, Setting, and Participants: The PARADIGM-HF trial was a randomized, double-blind, active treatment-controlled clinical trial performed from December 8, 2009, to March 31, 2014, in 8399 patients with New York Heart Association class II to IV disease and a left ventricular ejection fraction of 40% or less at 1043 centers in 38 countries. Data analysis was performed from August 1, 2017, to December 25, 2017. Interventions: Sacubitril/valsartan, 200 mg twice daily, or enalapril, 10 mg twice daily. Main Outcomes and Measures: Patients completed HRQL assessments using the KCCQ at randomization, 4-month, 8-month, and annual visits. The effect of sacubitril/valsartan on components of the physical and social limitation sections of the KCCQ at 8 months and longitudinally and related biomarkers and clinical outcomes were studied. Results: At baseline, 7618 of 8399 patients (90.7%) (mean [SD] age, 64 [11] years; 5987 [78.6%] male and 1631 [21.4%] female) completed the initial KCCQ assessment. Patients reported the greatest limitations at baseline in jogging and sexual relationships. Patients receiving sacubitril/valsartan had significantly better adjusted change scores in most physical and social activities at 8 months and during 36 months compared with those receiving enalapril. The largest improvement over enalapril was in household chores (adjusted change score difference, 2.35; 95% CI, 1.19-3.50; P < .001) and sexual relationships (adjusted change score difference, 2.72; 95% CI, 0.97-4.46; P = .002); both persisted through 36 months (overall change score difference, 1.69 [95% CI, 0.78-2.60], P < .001; and 2.36 [95% CI, 1.01-3.71], P = .001, respectively). Conclusions and Relevance: In patients with heart failure with reduced ejection fraction, sacubitril/valsartan significantly improved nearly all KCCQ physical and social activities compared with enalapril, with the largest responses in household chores and sexual relationships. In addition to reduced likelihood of cardiovascular death, all-cause mortality, and heart failure hospitalization, sacubitril/valsartan may improve limitations in common activities in these patients. Trial Registration: clinicaltrials.gov Identifier: NCT01035255. PMID- 29617525 TI - A Checklist to Elevate the Science of Surgical Database Research. PMID- 29617526 TI - Practical Guide to Surgical Data Sets: Military Health System Tricare Encounter Data. PMID- 29617527 TI - Association of Hidradenitis Suppurativa With T Helper 1/T Helper 17 Phenotypes: A Semantic Map Analysis. AB - Importance: In spite of progress in understanding the mechanisms underlying hidradenitis suppurativa (HS) as an inflammatory skin disease, there is still a demand for an overview on immunopathogenesis of HS. Objective: To demonstrate the importance of the type 1/type 17 immune response in lesional HS skin by drawing a semantic connectivity map. Design, Setting, and Participants: Single-center case series of 24 patients with HS. Association of HS with T helper 1/T helper 17 (TH1/TH17) phenotype was assessed using semantic map analysis. Main Outcomes and Measures: Association of HS with TH1/TH17 phenotype. Results: The analysis was performed on 24 lesional HS biopsy samples from untreated patients with HS (16 [67%] female; median age, 36.5 years [range, 21-51 years]) with a mean (SD) Hurley stage of 2.29 (0.62) and 9 punch biopsy samples from healthy controls (6 [67%] female; median age, 43 years [range, 23-66 years]). The map shows a clustering of all TH1/TH17-associated cytokines (interleukin 17 [IL-17], interferon gamma, IL-12, IL-23, IL-32, IL-1beta, tumor necrosis factor) around overall lesional inflammation. Tumor necrosis factor, IL-12, and IL-17 are even directly connected via interferon gamma. In contrast, IL-13, a TH2-associated cytokine, was inversely correlated with the presence of TH1/TH17-associated cytokines, further highlighting the importance of the TH1/TH17 cytokines in HS pathogenesis. Conclusions and Relevance: These findings suggest that HS may be a TH1/TH17-driven inflammatory skin disease. PMID- 29617528 TI - Atorvastatin in Combination With Narrowband UV-B in Adult Patients With Active Vitiligo: A Randomized Clinical Trial. PMID- 29617529 TI - Indoor Tanners as a Priority Population for Skin Cancer Screening. PMID- 29617530 TI - Task Shifting in Dermatology-A Call to Action-Reply. PMID- 29617532 TI - Task Shifting in Dermatology-A Call to Action. PMID- 29617531 TI - Consanguineous Marriage and the Psychopathology of Progeny: A Population-wide Data Linkage Study. AB - Importance: Approximately 1 in 10 children worldwide are born to consanguineous parents. The literature on consanguinity and mental health of progeny is scarce despite the fact that many of the factors associated with consanguineous unions are also associated with mental health. Objective: To investigate if children of consanguineous parents are at increased risk of common mood disorders or psychoses. Design, Setting, and Participants: This investigation was a retrospective population-wide cohort study of all individuals born in Northern Ireland between January 1, 1971, and December 31, 1986, derived from the Child Health System data set and linked to nationwide administrative data sources on prescription medication and death records. Data from the Child Health System data set identified all 447 452 births delivered to mothers residing in Northern Ireland between 1971 and 1986. The final data set comprised 363 960 individuals, alive and residing in Northern Ireland in 2014, with full data on all variables. The dates of analysis were June 1 to October 31, 2017. Main Outcomes and Measures: Degree of parental consanguinity was assessed from questions asked of the parents during routine health visitor house calls within 2 weeks of the child's birth. Potential mental ill health was estimated by receipt of psychotropic medication in 2010 to 2014. Ever or never use was used for the main analysis, with sensitivity analyses using a cutoff of at least 3 months' prescriptions. Receipt of antidepressant or anxiolytic medications was used as a proxy for common mood disorders, whereas receipt of antipsychotic medications was used as a proxy indicator of psychoses. Results: Of the 363 960 individuals (52.5% [191 102] male), 609 (0.2%) were born to consanguineous parents. After full adjustment for factors known to be associated with poor mental health, multilevel logistic regression models found that children of first-cousin consanguineous parents were more than 3 times as likely to be in receipt of antidepressant or anxiolytic medications (odds ratio, 3.01; 95% CI, 1.24-7.31) and more than twice as likely to be in receipt of antipsychotic medication (odds ratio, 2.13; 95% CI, 1.29-3.51) compared with children of nonrelated parents. Conclusions and Relevance: A child of consanguineous parents is at increased risk of common mood disorders and psychoses. PMID- 29617533 TI - Practical Guide to Surgical Data Sets: Healthcare Cost and Utilization Project National Inpatient Sample (NIS). PMID- 29617534 TI - Practical Guide to Surgical Data Sets: Society of Thoracic Surgeons (STS) National Database. PMID- 29617537 TI - Practical Guide to Surgical Data Sets: Society for Vascular Surgery Vascular Quality Initiative (SVS VQI). PMID- 29617536 TI - Practical Guide to Surgical Data Sets: National Trauma Data Bank (NTDB). PMID- 29617538 TI - Practical Guide to Surgical Data Sets: Metabolic and Bariatric Surgery Accreditation and Quality Program (MBSAQIP). PMID- 29617541 TI - Practical Guide to Surgical Data Sets: Medicare Claims Data. PMID- 29617542 TI - Practical Guide to Surgical Data Sets: National Cancer Database (NCDB). PMID- 29617535 TI - Association of Methylation Signals With Incident Coronary Heart Disease in an Epigenome-Wide Assessment of Circulating Tumor Necrosis Factor alpha. AB - Importance: Tumor necrosis factor alpha (TNF-alpha) is a proinflammatory cytokine with manifold consequences for mammalian pathophysiology, including cardiovascular disease. A deeper understanding of TNF-alpha biology may enhance treatment precision. Objective: To conduct an epigenome-wide analysis of blood derived DNA methylation and TNF-alpha levels and to assess the clinical relevance of findings. Design, Setting, and Participants: This meta-analysis assessed epigenome-wide associations in circulating TNF-alpha concentrations from 5 cohort studies and 1 interventional trial, with replication in 3 additional cohort studies. Follow-up analyses investigated associations of identified methylation loci with gene expression and incident coronary heart disease; this meta-analysis included 11 461 participants who experienced 1895 coronary events. Exposures: Circulating TNF-alpha concentration. Main Outcomes and Measures: DNA methylation at approximately 450 000 loci, neighboring DNA sequence variation, gene expression, and incident coronary heart disease. Results: The discovery cohort included 4794 participants, and the replication study included 816 participants (overall mean [SD] age, 60.7 [8.5] years). In the discovery stage, circulating TNF-alpha levels were associated with methylation of 7 cytosine-phosphate-guanine (CpG) sites, 3 of which were located in or near DTX3L-PARP9 at cg00959259 (beta [SE] = -0.01 [0.003]; P = 7.36 * 10-8), cg08122652 (beta [SE] = -0.008 [0.002]; P = 2.24 * 10-7), and cg22930808(beta [SE] = -0.01 [0.002]; P = 6.92 * 10-8); NLRC5 at cg16411857 (beta [SE] = -0.01 [0.002]; P = 2.14 * 10-13) and cg07839457 (beta [SE] = -0.02 [0.003]; P = 6.31 * 10-10); or ABO, at cg13683939 (beta [SE] = 0.04 [0.008]; P = 1.42 * 10-7) and cg24267699 (beta [SE] = -0.009 [0.002]; P = 1.67 * 10-7), after accounting for multiple testing. Of these, negative associations between TNF-alpha concentration and methylation of 2 loci in NLRC5 and 1 in DTX3L 14 PARP9 were replicated. Replicated TNF-alpha-linked CpG sites were associated with 9% to 19% decreased risk of incident coronary heart disease per 10% higher methylation per CpG site (cg16411857: hazard ratio [HR], 0.86; 95% CI, 0.78-1.95; P = .003; cg07839457: HR, 0.89; 95% CI, 0.80-0.94; P = 3.1 * 10-5; cg00959259: HR, 0.91; 95% CI, 0.84-0.97; P = .002; cg08122652: HR, 0.81; 95% CI, 0.74-0.89; P = 2.0 * 10-5). Conclusions and Relevance: We identified and replicated novel epigenetic correlates of circulating TNF-alpha concentration in blood samples and linked these loci to coronary heart disease risk, opening opportunities for validation and therapeutic applications. PMID- 29617543 TI - Practical Guide to Surgical Data Sets: Veterans Affairs Surgical Quality Improvement Program (VASQIP). PMID- 29617544 TI - Practical Guide to Surgical Data Sets: Surveillance, Epidemiology, and End Results (SEER) Database. PMID- 29617546 TI - Calculated decisions: Parkland formula for burns PMID- 29617545 TI - Deployment of carboxymethyl cellulose sheets to prevent esophageal stricture after full circumferential endoscopic submucosal dissection: A porcine model. AB - BACKGROUND AND AIM: Esophageal stricture is a serious adverse event secondary to extensive endoscopic submucosal dissection (ESD). The present study aimed to investigate the efficacy of carboxymethyl cellulose (CMC) sheets for the prevention of esophageal stricture after full circumferential ESD in an animal model. METHODS: Fourteen porcine models were randomized into a control group (n = 7) and a CMC group (n = 7). Five-centimeter-long circumferential esophageal ESD was carried out at a distance of 40 to 45 cm from the incisors in all models. In the CMC group, CMC sheets were placed over the mucosal defect completely after ESD, whereas the control group underwent routine ESD only. Endoscopic examination was conducted after the first and second week post-ESD. Esophageal specimens were harvested during post-mortem and were evaluated for macroscopic and histological appearance. Blood serum levels of four pro-inflammatory or profibrotic cytokines were measured quantitatively. RESULTS: The CMC group had better food tolerability during the second week post-ESD. The CMC group showed a significantly lower esophageal mucosal stricture rate compared to the control group. Histological assessments showed less fibrosis in the submucosal layer, milder damage to the muscularis propria, and enhanced re-epithelization in the CMC group. Serum transforming growth factor beta 1 levels were significantly lower in the CMC group post-ESD. CONCLUSION: Deployment of CMC sheets on the mucosal defect appears to be a promising method for preventing esophageal strictures after extensive ESD. PMID- 29617547 TI - Supramolecular Hydrogels Based on MPEG-Grafted Hyaluronic Acid and alpha-CD Containing HP-beta-CD/Simvastatin Enhance Osteogenesis In Vivo. AB - Simvastatin (SIM) accelerates new bone formation both in vitro and In Vivo by enhancing the expression of recombinant human bone morphogenetic protein-2 (rhBMP 2). In this study, we evaluated the effect of water-solubility of SIM on new bone formation by preparing two types of supramolecular hydrogels: pseudopolyrotaxanes (PPRXs) based on metoxy polyethyleneglycol-grafted hyaluronic acid (MPEG-g-HA) and alpha-cyclodextrin (alpha-CD) containing water-soluble hydroxypropyl beta cyclodextrin/simvastatin inclusion complex (HP-beta-CD-ic-SIM; MPEG-g-HA/alpha CD/HP-beta-CD-ic-SIM) or only SIM (MPEG-g-HA/alpha-CD/SIM). As compared to MPEG-g HA/alpha-CD/SIM, SIM was more rapidly released from MPEG-g-HA/alpha-CD/HP-beta CD-ic-SIM in a sustained manner owing to increased water-solubility. New bone actively formed at the calvarial defect site in a rabbit model 4 weeks after implantation, as examined by micro computed tomography (micro CT), hematoxylin and eosin (H&E) staining, and Goldner's trichrome staining. The results showed that the water-solubility of SIM plays a significant role in enhancing new bone formation in vivo. PMID- 29617548 TI - Calculated decisions: King's College Criteria for Acetaminophen Toxicity PMID- 29617549 TI - The Importance of Calcium Ions in Poly-A RNA Mediated Tobacco Mosaic Virus-Like Rod Formation. AB - Due to its well-understood structural and chemical features, Tobacco mosaic virus (TMV) has attracted interest as a template for producing a variety of novel nanostructured materials and devices. However, for TMV based nanotechnology to reach its potential, controlling the size of TMV rods without using infectious native RNA is a key issue. Here, we re-examine the interactions of TMV coat protein (CP) with poly A RNA. Our results confirm that poly A RNA can induce virus-like rod formation through interactions with the coat protein. In addition, we show that calcium ions have an important role in stabilizing such rods, a previously unknown interaction that enhances the reliability of poly A induced assembly. PMID- 29617550 TI - Calculated decisions: Acetaminophen Overdose and N-Acetylcysteine (NAC) Dosing PMID- 29617552 TI - Cassie-Levitated Droplets for Distortion-Free Low-Energy Solid-Liquid Interactions. AB - Despite the rapid advent of superomniphobic materials, there is a lack of methodologies to accurately investigate the ultralow-energy interactions taking place on these interfaces. For instance, universally employed models such as the pendant droplet often fail to provide representative information on the wetting properties of superomniphobic surfaces. The delicate balance between the forces acting at the droplet-surface and droplet-needle interfaces can easily result in heavily distorted droplet profiles. Here, we introduce a Cassie-levitating droplet model which overcomes the limitations of the pendant droplet model, allowing a distortion-free assessment of the interactions between super(amphi)omniphobic materials and low surface tension liquids. Comparative analysis in wetting of low surface tension fluids such as hexadecane (~27.47 mN/m) on superamphiphobic surfaces via the Cassie-levitating and pendant droplet models reveals up to 70 degrees (800%) deviations in the estimated contact angle hysteresis. A theoretical framework is developed to assess experimentally observed profile distortions against ideal gravity-induced sagging of droplet shapes during dynamic droplet expansion and contraction cycles. Notably, pendant droplets resulted in up to 50% distortion while the Cassie-levitating ones achieved less than just 10%. We believe that the Cassie-levitating droplet model bears ample potential for the characterization of the rapidly emerging family of superomniphobic materials, setting the basis for their future engineering in numerous emerging applications. PMID- 29617553 TI - Rupture of Lipid Membranes Induced by Amphiphilic Janus Nanoparticles. AB - The surface coatings of nanoparticles determine their interaction with biomembranes, but studies have been limited almost exclusively to nanoparticles with a uniform surface chemistry. Although nanoparticles are increasingly made with complex surface chemistries to achieve multifunctionalities, our understanding of how a heterogeneous surface coating affects particle-biomembrane interaction has been lagging far behind. Here we report an investigation of this question in an experimental system consisting of amphiphilic "two-faced" Janus nanoparticles and supported lipid membranes. We show that amphiphilic Janus nanoparticles at picomolar concentrations induce defects in zwitterionic lipid bilayers. In addition to revealing the various effects of hydrophobicity and charge in particle-bilayer interactions, we demonstrate that the Janus geometry the spatial segregation of hydrophobicity and charges on particle surface-causes nanoparticles to bind more strongly to bilayers and induce defects more effectively than particles with uniformly mixed surface functionalities. We combine experiments with computational simulation to further elucidate how amphiphilic Janus nanoparticles extract lipids to rupture intact lipid bilayers. This study provides direct evidence that the spatial arrangement of surface functionalities on a nanoparticle, rather than just its overall surface chemistry, plays a crucial role in determining how it interacts with biological membranes. PMID- 29617551 TI - Organohalogens Naturally Biosynthesized in Marine Environments and Produced as Disinfection Byproducts Alter Sarco/Endoplasmic Reticulum Ca2+ Dynamics. AB - Contemporary sources of organohalogens produced as disinfection byproducts (DBPs) are receiving considerable attention as emerging pollutants because of their abundance, persistence, and potential to structurally mimic natural organohalogens produced by bacteria that serve signaling or toxicological functions in marine environments. Here, we tested 34 organohalogens from anthropogenic and marine sources to identify compounds active toward ryanodine receptor (RyR1), known toxicological targets of non-dioxin-like polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs). [3H]Ryanodine ([3H]Ry) binding screening (<=2 MUM) identified 10 highly active organohalogens. Further analysis indicated that 2,3-dibromoindole (14), tetrabromopyrrole (31), and 2,3,5-tribromopyrrole (34) at 10 MUM were the most efficacious at enhancing [3H]Ry binding. Interestingly, these congeners also inhibited microsomal sarcoplasmic/endoplasmic reticulum (SR/ER) Ca2+ ATPase (SERCA1a). Dual SERCA1a inhibition and RyR1 activation triggered Ca2+ efflux from microsomal vesicles with initial rates rank ordered 31 > 34 > 14. Hexabromobipyrroles (25) enhanced [3H]Ry binding moderately with strong SERCA1a inhibition, whereas pyrrole (24), 2,3,4-tribromopyrrole (26), and ethyl-4-bromopyrrole-2-carboxylate (27) were inactive. Of three PBDE derivatives of marine origin active in the [3H]Ry assay, 4'-hydroxy-2,3',4,5',6-pentabromodiphenyl ether (18) was also a highly potent SERCA1a inhibitor. Molecular targets of marine organohalogens that are also DBPs of emerging environmental concern are likely to contribute to their toxicity. PMID- 29617554 TI - Small Titanium-Based MOFs Prepared with the Introduction of Tetraethyl Orthosilicate and Their Potential for Use in Drug Delivery. AB - Metal-organic frameworks (MOFs) have attracted much attention in the areas of biomedicine and medicine owing to their versatile porous structure. However, the oversize and high cellular toxicity of some metal-based MOF particles have hindered their development. Therefore, a series of small Ti-based MOFs are prepared with the introduction of tetraethyl orthosilicate (TEOS) into the reaction system. Compared with the Ti-based MOFs prepared by traditional methods, the size of the Ti-based MOFs prepared with this method is decreased by 42.78%. Meanwhile, the good biocompatibility of the prepared Ti-based MOF particles toward the L929 cell lines is proven using CCK-8 assays. Furthermore, the controlled release property of the Ti-based MOFs is evaluated by using ibuprofen (IBU) as a model drug. The amount of drug loaded in the samples is shown to be approximately 10%, and approximately 95% of the IBU is released from the MOFs after exposure to PBS for 24 h. We conclude that the size-decreased Ti-based MOFs prepared with the introduction of TEOS into the reaction systems are potential drug carriers in terms of their good biocompatibility and effective performance in the controlled release of a drug. PMID- 29617555 TI - Fluorescent Polymersomes with Aggregation-Induced Emission. AB - Fluorescent polymersomes are interesting systems for cell/tissue imaging and in vivo study of drug distribution and delivery. We report on bright fluorescent polymersomes with aggregation-induced emission self-assembled by a series of tetraphenylethylene (TPE)-containing amphiphilic biodegradable block copolymers, where the hydrophilic block is a polyethylene glycol and hydrophobic block is a TPE-substituted trimethylenecarbonate polymer P(TPE-TMC). Their self-assemblies in water were prepared by nanoprecipitation using dioxane or tetrahydrofuran as co-solvent, and the self-assembling processes were studied in detail by cryo electron microscopy, dynamic light scattering, and spectrofluorometer. The polymersomes are formed via the closure of bilayer lamellae self-assembled first by amphiphilic block copolymers. The polymersome membrane affords a nanosize bright fluorescent system with self-assembly induced emission in the thickness scale of 10-15 nm. The control of the whole size of polymersome is achieved by the choice of co-solvent for self-assembling and by the design of a suitable hydrophilic/hydrophobic ratio of block copolymers. These polymersomes can be potentially used as a stable fluorescent tool to monitor the transportation and distribution of drugs and bioconjugates in living cells. PMID- 29617556 TI - A Dual-Targeting Delivery System for Effective Genome Editing and In Situ Detecting Related Protein Expression in Edited Cells. AB - One of critical steps in genome editing by CRISPR-Cas9 is to deliver the CRISPR Cas9 system into targeted cells. In this study, we developed a dual-targeting delivery system based on polymer/inorganic hybrid nanoparticles to realize highly efficient genome editing in targeted tumor cells as well as in situ detection on the related protein expression in edited cells. The CRISPR-Cas9 plasmid for CDK11 knockout was encapsulated in the core of the delivery system composed of protamine sulfate, calcium carbonate, and calcium phosphate by coprecipitation, and functional derivatives of carboxymethyl chitosan (biotinylated carboxymethyl chitosan with biotin ligands and aptamer-incorporated carboxymethyl chitosan with AS1411 ligands) were decorated on the nanovector surface by electrostatic interactions to form the dual-targeting delivery system. On the basis of the tumor cell targeting capability of biotin and AS1411 ligands as well as the nuclear targeting of AS1411, the dual-targeting system can deliver the CRISPR Cas9 plasmid into the nuclei of tumor cells to realize highly efficient genome editing, resulting in a dramatic decrease (>90%) in CDK11 protein together with the significant downregulation of other proteins involved in tumor development, including an ~90% decrease in MMP-9, >40% decrease in VEGF, and ~70% decrease in survivin. Using the same vector, molecular beacons can be easily delivered to edited cell nuclei to in situ detect the mRNA level of related proteins (p53 and survivin as typical examples) and mRNA distribution in subcellular organelles. Our strategy can realize effective genome editing and in situ detection on related protein expression simultaneously. PMID- 29617558 TI - Friction and Wear Reduction in Copper with a Gradient Nano-grained Surface Layer. AB - A gradient nano-grained (GNG) surface layer is fabricated on a commercial-purity Cu sample, in which a significant reduction in the coefficient of friction and the wear loss is obtained compared to the coarse-grained and the nano-grained counterparts. A novel mild ploughing mechanism without subsurface damage has been identified in the GNG sample, giving rise to a much reduced wear rate. Sliding induced surface deformation brings about the unique inhomogeneous substructure in the GNG Cu: the topmost layer persists with nanograins without being oxidized, underneath which deformation is well accommodated by grain coarsening adjacent to the dynamic recrystallization layer. Both subsurface structural evolution and stress field model confirm that sliding-induced strain localization is suppressed, which is responsible for the superior friction and wear behaviors of the GNG Cu. PMID- 29617557 TI - Computational Analysis for the Rational Design of Anti-Amyloid Beta (Abeta) Antibodies. AB - Alzheimer's disease (AD) is a neurodegenerative disorder that lacks effective treatment options. Anti-amyloid beta (Abeta) antibodies are the leading drug candidates to treat AD, but the results of clinical trials have been disappointing. Introducing rational mutations into anti-Abeta antibodies to increase their effectiveness is a way forward, but the path to take is unclear. In this study, we demonstrate the use of computational fragment-based docking and MMPBSA binding free energy calculations in the analysis of anti-Abeta antibodies for rational drug design efforts. Our fragment-based docking method successfully predicts the emergence of the common EFRH epitope. MD simulations coupled with MMPBSA binding free energy calculations are used to analyze scenarios described in prior studies, and we computationally introduce rational mutations into PFA1 to predict mutations that can improve its binding affinity toward the pE3-Abeta3 8 form of Abeta. Two out of our four proposed mutations are predicted to stabilize binding. Our study demonstrates that a computational approach may lead to an improved drug candidate for AD in the future. PMID- 29617559 TI - Fabrication and Thermoelectric Properties of n-Type CoSb2.85Te0.15 Using Selective Laser Melting. AB - We report a nonequilibrium fabrication method of n-type CoSb2.85Te0.15 skutterudites using selective laser melting (SLM) technology. A powder of CoSb2.85Te0.15 was prepared by self-propagating high-temperature synthesis (SHS) and served as the raw material for the SLM process. The effect of SLM processing parameters such as the laser power and scanning speed on the quality of the forming CoSb2.85Te0.15 thin layers was systematically analyzed, and the optimal processing window for SLM was determined. A brief postannealing at 450 degrees C for 4 h, following the SLM process, has resulted in a phase-pure CoSb2.85Te0.15 bulk material deposited on a Ti substrate. The Seebeck coefficient of the annealed SLM prepared bulk material is close to that of the sample prepared by the traditional sintering method, and its maximum ZT value reached 0.56 at 823 K. Moreover, a Ti-Co-Sb ternary compound transition layer of about 70 MUm in thickness was found at a dense interface between CoSb2.85Te0.15 and the Ti substrate. The contact resistivity was measured as 37.1 MUOmegacm2. The results demonstrate that SLM, coupled with postannealing, can be used for fabrication of incongruently melting skutterudite compounds on heterogeneous substrates. This lays an important foundation for the follow-up research utilizing energy efficient SHS and SLM processes in rapid printing of thermoelectric modules. PMID- 29617560 TI - 3D Anionic Silicate Covalent Organic Framework with srs Topology. AB - The synthesis of 3D covalent organic frameworks (COFs) adopting novel topologies is challenging, and so far 3D COFs have only been reported for nets based on building blocks with tetrahedral geometry. We demonstrate the targeted synthesis of an anionic 3D COF crystallizing in a three-coordinated srs net by exploiting a recently developed linkage for the formation of anionic silicate COFs based on hypercoordinate silicon nodes. The framework, named SiCOF-5, was synthesized by reticulating dianionic hexacoordinate [SiO6]2- nodes with triangular triphenylene building blocks and adopts a two-fold interpenetrated srs-c net with an overall composition of Na2[Si(C18H6O6)] (where C18H6O6 is triphenylene-2,3,6,7,10,11 hexakis(olate)). A key requirement for the crystallization of SiCOF-5 was the careful control over the nucleation and growth rate by gradual generation of the silicon source during the course of the reaction. PMID- 29617561 TI - Plant Induced Changes to Rhizosphere Characteristics Affecting Supply of Cd to Noccaea caerulescens and Ni to Thlaspi goesingense. AB - Changes in soil rhizosphere properties after growing the Cd hyperaccumulator Noccaea caerulescens and the Ni hyperaccumulator Thlaspi goesingense were investigated. Dissolved organic carbon content increased in the rhizosphere, but there were no significant changes in the solution concentrations of Cd and Ni. Concentrations of these metals extracted by NH4Cl and EDTA decreased in the rhizosphere, as did DGT-measured concentrations, indicating a depletion of labile metal in the solid phase. The results could be explained by the increased DOC in the rhizosphere maintaining a higher proportion of the labile metal in solution through complexation, with the overall depletion of metals only manifest in the solid phase. The DGT induced fluxes in soils and sediments (DIFS) model was used to provide key kinetic information on soil processes and labile pool size. These data showed that the more limited metal supply in the rhizosphere after the growth of hyperaccumulators was due to both depletion of the solid phase pool and a lower rate constant of supply from solid phase to solution. The effect on the rate constant, which could be rationalized by the plant sequentially accessing and consuming the more labile pools of metal, was most marked for Cd, which had the highest accumulation factors. PMID- 29617562 TI - Interface Effects on the Ionic Conductivity of Doped Ceria-Yttria-Stabilized Zirconia Heterostructures. AB - Multilayered heterostructures of Ce0.85Sm0.15O2-delta and Y0.16Zr0.92O2-delta of a high crystallographic quality were fabricated on (001)-oriented MgO single crystal substrates. Keeping the total thickness of the heterostructures constant, the number of ceria-zirconia bilayers was increased while reducing the thickness of each layer. At each interface Ce was found primarily in the reduced, 3+ oxidation state in a layer extending about 2 nm from the interface. Concurrently, the conductivity decreased as the thickness of the layers was reduced, suggesting a progressive confinement of the charge transport along the YSZ layers. The comparative analysis of the in-plane electrical characterization suggests that the contribution to the total electrical conductivity of these interfacial regions is negligible. For the smallest layer thickness of 2 nm the doped ceria layers are electrically insulating and the ionic transport only occurs through the zirconia layers. This is explained in terms of a reduced mobility of the oxygen vacancies in the highly reduced ceria. PMID- 29617563 TI - Protein Surface Structural Recognition in Inactive Areas: A New Immobilization Strategy for Acetylcholinesterase. AB - This work reported a new method of design for the immobilization of acetylcholinesterase (AChE) based on its molecular structure to improve its sensitivity and stability. The immobilization binding site on the surface of AChE was determined using MOLCAD's multi-channel functionality. Then, 11 molecules ((+)-catechin, (-)-epicatechin, (-)-gallocatechin, hesperetin, naringenin, quercetin, taxifolin, (-)-epicatechin gallate, flupirtine, atropine, and hyoscyamine) were selected from the ZINC database (about 50 000 molecules) as candidate affinity ligands for AChE. The fluorescence results showed that the binding constant Kb between AChE and the ligands ranged from 0.01344 * 104 to 4.689 * 104 M-1 and there was one independent class of binding site for the ligands on AChE. The AChE-ligand binding free energy ranged from -12.14 to -26.65 kJ mol-1. Naringenin, hesperetin, and quercetin were the three most potent immobilized affinity ligands. In addition, it was confirmed that the binding between the immobilized ligands only occurred at a single site, located in an inactive area on the surface of AChE, and did not affect the enzymatic activity as shown through a competition experiment and enzyme assay. This method based on protein surface structural recognition with high sensitivity and stability can be used as a generic approach for design of the enzyme immobilization and biosensor development. PMID- 29617564 TI - Method-Unifying View of Loop-Formation Kinetics in Peptide and Protein Folding. AB - Protein folding can be described as a probabilistic succession of events in which the peptide chain forms loops closed by specific amino acid residue contacts, herein referred to as loop nodes. To measure loop rates, several photophysical methods have been introduced where a pair of optically active probes is incorporated at selected chain positions and the excited probe undergoes contact quenching (CQ) upon collision with the second probe. The quenching mechanisms involved triplet-triplet energy transfer, photoinduced electron transfer, and collision-induced fluorescence quenching, where the fluorescence of Dbo, an asparagine residue conjugated to 2,3-diazabicyclo[2.2.2]octane, is quenched by tryptophan. The discrepancy between the loop rates afforded from these three CQ techniques has, however, remained unresolved. In analyzing this discrepancy, we now report two short-distance FRET methods where Dbo acts as an energy acceptor in combination with tryptophan and naphtylalanine, two donors with largely different fluorescence lifetimes of 1.3 and 33 ns, respectively. Despite the different quenching mechanisms, the rates from FRET and CQ methods were, surprisingly, of comparable magnitude. This combination of FRET and CQ data led to a unifying physical model and to the conclusion that the rate of loop formation in folding reactions varies not only with the kind and number of residues that constitute the chain but also in particular with the size and properties of the residues that constitute the loop node. PMID- 29617565 TI - Generalized Electrodiffusion Equation with Fractality of Space-Time: Experiment and Theory. AB - Physical and technological principles of formation of clathrate structures for supramolecular electronics are given in this paper. It has been established that supramolecular nature of the "host-guest" conjunction, in general, and hierarchical architecture of the corresponding clathrates, in particular, provide realization of such an extraordinary effect as an optically or a magnetically controlled phenomenon of colossal "negative capacity" with a predicted frequency interval of manifestation, magnitude, and multiplicity. For the first time, the experimental confirmation of the behavior of the electretized fractal clathrate GaSe?beta-CD?FeSO4?? as a dissipative element, which accumulates inductive energy, is demonstrated. A general approach for obtaining the generalized transport equations with fractional derivatives by using the Liouville equation with fractional derivatives for a system of classical particles and the Zubarev nonequilibrium statistical operator method within Renyi statistics is presented. New non-Markovian electrodiffusion equations for ions in a spatially heterogeneous medium with the fractal structure and a generalized Cattaneo-type diffusion equation taking into account the fractality of space-time are obtained. The model of subdiffusion impedance based on the Cattaneo equation with fractional derivatives is applied to multilayer nanostructures. Nyquist diagrams for different valuses of the parameter tau (delay time of a flow relative to a concentration gradient) and the subdiffusion coefficient Dalpha are calculated. PMID- 29617566 TI - Simultaneous Printing of Two Inks by Contact Lithography. AB - Microcontact printing (MUCP) is a valuable technique used to fabricate complex patterns on surfaces for applications such as sensors, cell seeding, self assembled monolayers of proteins and nanoparticles, and micromachining. The process is very precise but is typically confined to depositing a single type of ink per print, which limits the complexity of using multifunctionality patterns. Here we describe a process by which two inks are printed concomitantly in a single operation to create an alternating pattern of hydrophobic and hydrophilic characteristics. The hydrophobic ink, PDMS, is deposited by evaporation on the noncontact region, while the hydrophilic polyelectrolyte is transferred on contact. We demonstrate that there is no gap between the two patterns using an optical-electrochemical method. We describe some potential applications of this method, including layer-by-layer deposition of polyelectrolytes for sensors and creation of a scaffold for cell culture. PMID- 29617567 TI - Asymmetric Total Synthesis of Cyclocitrinol. AB - The first and asymmetric total synthesis of cyclocitrinol, an unusual C25 steroid, has been accomplished in a linear sequence of 18 steps from commercially available compound 11. The synthetically challenging bicyclo[4.4.1] A/B ring system with a strained bridgehead (anti-Bredt) double bond of cyclocitrinol was constructed efficiently and diastereoselectively via a type II intramolecular [5 + 2] cycloaddition. PMID- 29617568 TI - Electrochemical Control of pH in Nanoliter Volumes. AB - The electrochemical management of the proton concentration in miniaturized dimensions opens the way to control and parallelize multistep chemical reactions, but still it faces many challenges linked to the efficient proton generation and control of their diffusion. Here we present a device operated electrochemically that demonstrates the control of the pH in a cell of ~140 nL. The device comprises a microfluidic reactor integrated with a pneumatic mechanism that allows the exchange of reagents and the isolation of protons to decrease the effect of their diffusion. We monitored the pH with a fluorescence marker and calculated the final value from the redox currents. We demonstrate a large pH amplitude control from neutral pH values beyond the fluorescence marker range at pH 5. On the basis of the calculations from the Faradaic currents, the minimum pH reached should undergo pH ~ 0.9. The pH contrast between neutral and acid pH cells can be maintained during periods longer than 15 min with an appropriate design of a diffusion barrier. PMID- 29617569 TI - Plasma-Induced, Self-Masking, One-Step Approach to an Ultrabroadband Antireflective and Superhydrophilic Subwavelength Nanostructured Fused Silica Surface. AB - In this work, antireflective and superhydrophilic subwavelength nanostructured fused silica surfaces have been created by one-step, self-masking reactive ion etching (RIE). Bare fused silica substrates with no mask were placed in a RIE vacuum chamber, and then nanoscale fluorocarbon masks and subwavelength nanostructures (SWSs) automatically formed on these substrate after the appropriate RIE plasma process. The mechanism of plasma-induced self-masking SWS has been proposed in this paper. Plasma parameter effects on the morphology of SWS have been investigated to achieve perfect nanocone-like SWS for excellent antireflection, including process time, reactive gas, and pressure of the chamber. Optical properties, i.e., antireflection and optical scattering, were simulated by the finite difference time domain (FDTD) method. Calculated data agree well with the experiment results. The optimized SWS show ultrabroadband antireflective property (up to 99% from 500 to 1360 nm). An excellent improvement of transmission was achieved for the deep-ultraviolet (DUV) range. The proposed low-cost, highly efficient, and maskless method was applied to achieve ultrabroadband antireflective and superhydrophilic SWSs on a 100 mm optical window, which promises great potential for applications in the automotive industry, goggles, and optical devices. PMID- 29617570 TI - Ion Permeability of a Microtubule in Neuron Environment. AB - Microtubules, constituted by end-to-end negatively charged alpha- and beta tubulin dimers, are long, hollow, pseudohelical cylinders with internal and external diameters of about 16 and 26 nm, respectively, and widely exist in cell cytoplasm, neuron axons, and dendrites. Although their structural functions in physiological processes, such as cell mitosis, cell motility, and motor protein transport, have been widely accepted, their role in neuron activity remains attractively elusive. Here we show a new function of microtubules: they can generate instant response to a calcium pulse because of their specific permeability for ions. Our comprehensive simulations from all-atom molecular dynamics to potential of mean force and continuum modeling reveal that K+ and Na+ ions can permeate through the nanopores in the microtubule wall easily, while Ca2+ ions are blocked by the wall with a much higher free energy barrier. These cations are adsorbed to the surfaces of the wall with affinity decreasing in the sequence Ca2+, Na+, and K+. As a result, when the concentration of Ca2+ ions increases outside the microtubule during neuronal excitation, K+ and Na+ ions will be driven into the microtubule, triggering subsequent axial ion redistribution within the microtubule. The results shed light on the possibility of the ion-permeable microtubules being involved in neural signal processing. PMID- 29617571 TI - Direct Identification of Surface Defects and Their Influence on the Optical Characteristics of Upconversion Nanoparticles. AB - Core-shell structure is an obvious concept to suppress surface-related deactivations in lanthanide-doped upconversion nanoparticles (UCNPs). However, no direct observation of atomic-scale surface restoration, which can improve the upconversion photoluminescence, has been reported. Here, we use aberration corrected high-angle annular dark field scanning transmission electron microscopy to study the surface condition of KLu2F7:Yb3+,Er3+ bare core UCNPs. Due to the very thin and uniform thickness of the UCNPs, we observe unambiguously that the recovery from surface defects enhances upconversion photoluminescence. Furthermore, the realization of dominant green lasing emission under pulsed laser excitation confirms the high crystallinity of the UCNPs. PMID- 29617572 TI - Toward beta-Secretase-1 Inhibitors with Improved Isoform Selectivity. AB - BACE1 is responsible for the first step in APP proteolysis, leading to toxic Abeta production, and has been indicated to play a key role in the pathogenesis of Alzheimer's disease. The related isoform BACE2 is thought to be involved in processing of the pigment cell-specific melanocyte protein. To avoid potential effects on pigmentation, we investigated the feasibility for developing isoform selective BACE1 inhibitors. Cocrystal structures of 47 compounds were analyzed and clustered according to their selectivity profiles. Selective BACE1 inhibitors were found to exhibit two distinct conformational features proximal to the flap and the S3 subpocket. Several new molecules were designed and tested to make use of this observation. The combination of a pyrimidinyl C-ring and a methylcyclohexyl element resulted in lead molecule 28, which exhibited ~50-fold selectivity. Compared to a nonselective BACE1/2 inhibitor, 28 showed significantly less inhibition of PMEL processing in human melanocytes, indicating good functional selectivity of this inhibitor class. PMID- 29617573 TI - Reply to Rambaud et al.: Do We Really Doubt Extracorporeal Membrane Oxygenation Efficacy in Pediatric Acute Respiratory Distress Syndrome? PMID- 29617575 TI - Do We Really Doubt Extracorporeal Membrane Oxygenation Efficacy in Pediatric Acute Respiratory Distress Syndrome? PMID- 29617574 TI - Circulating and Tumor Myeloid-derived Suppressor Cells in Resectable Non-Small Cell Lung Cancer. AB - RATIONALE: Myeloid-derived suppressor cell (MDSC) expansion has been found to play a role in disease progression in patients with cancer. However, the characteristics of MDSCs in lung cancer are poorly understood. OBJECTIVES: We prospectively investigated MDSCs and inflammatory factors in tumor and peripheral blood samples from patients with resectable non-small cell lung cancer and studied their correlations with the disease prognosis. METHODS: A complex analysis of MDSC subsets and inflammatory mediators was performed using flow cytometry and a Bio-Plex assay. MEASUREMENTS AND MAIN RESULTS: A significant increase in the frequency of circulating monocytic (M)-MDSCs was observed in the patients with non-small cell lung cancer compared with the healthy donors (HDs). Moreover, the frequencies of M- and polymorphonuclear (PMN)-MDSCs were higher in tumors than in the peripheral blood of the same patients. This accumulation was associated with elevated concentrations of inflammatory mediators involved in MDSC migration to and activation in the tumor microenvironment. An analysis of the MDSC immunosuppressive pattern showed increased programmed death-ligand 1 expression on circulating cells from patients compared with HDs. Tumor PMN-MDSCs displayed higher programmed death-ligand 1 expression levels than the same cells in the peripheral blood. The frequency of CCR5 (C-C chemokine receptor 5) expression on circulating M-MDSCs was significantly higher in the patients than in the HDs. Clinical data analysis revealed negative correlations between recurrence-free survival and the frequencies of PMN-MDSCs and CCR5+ M-MDSCs in the circulation but not in tumors. CONCLUSIONS: Our findings suggest that the level of MDSCs in the peripheral blood but not in tumor tissues predicts recurrence after surgery. PMID- 29617576 TI - Current understanding on pharmacokinetics, clinical efficacy and safety of progestins for treating pain associated to endometriosis. AB - INTRODUCTION: Endometriosis is a chronic estrogen and progestogen responsive inflammatory disease associated with pain symptoms and infertility. The medical therapy of endometriosis aims to induce decidualization within the hormonally dependent ectopic endometrium, and it is often administered to ameliorate women' pain symptoms or to prevent post-surgical disease recurrence. A variety of progestins have been used in monotherapy for the medical management of women with endometriosis. Areas covered: This review aims to offer the reader a complete overview of pharmacokinetic (PK) and clinical efficacy of progestins for the treatment of endometriosis. Expert opinion: Each progestin has a distinct PK parameters and pharmacodynamics affinity not only for progesterone receptor, but also for other steroid receptors, such as estrogen, androgen, and glucocorticoid. Moreover, progestins can also be delivered in different formulations. All these characteristics influence their final biological effect. Randomized, controlled, non-blinded studies support the use of oral progestin-only treatment for pelvic pain associated with endometriosis. Currently, the only two progestins approved by Food and Drug Administration (FDA) for the treatment of endometriosis are norethindrone acetate (NETA) and depot medroxyprogesterone acetate (DMPA). PMID- 29617577 TI - Ultrasound Guidance for Pleural-Catheter Placement. PMID- 29617578 TI - The Key Role of Epigenetics in Human Disease Prevention and Mitigation. PMID- 29617579 TI - Hand, Foot, and Mouth Disease in an Adult. PMID- 29617580 TI - Promise and Reality of Price Transparency. PMID- 29617581 TI - Groin Hernia Surgery in Low-Resource Settings - A Problem Still Unsolved. PMID- 29617582 TI - PCI Strategies in Acute Myocardial Infarction with Cardiogenic Shock. PMID- 29617583 TI - Inventing a New Model of Hypertension Care for Black Men. PMID- 29617584 TI - Cousin Pam. PMID- 29617586 TI - Bouveret's Syndrome. PMID- 29617585 TI - Outpatient Talc Administration by Indwelling Pleural Catheter for Malignant Effusion. AB - BACKGROUND: Malignant pleural effusion affects more than 750,000 persons each year across Europe and the United States. Pleurodesis with the administration of talc in hospitalized patients is the most common treatment, but indwelling pleural catheters placed for drainage offer an ambulatory alternative. We examined whether talc administered through an indwelling pleural catheter was more effective at inducing pleurodesis than the use of an indwelling pleural catheter alone. METHODS: Over a period of 4 years, we recruited patients with malignant pleural effusion at 18 centers in the United Kingdom. After the insertion of an indwelling pleural catheter, patients underwent drainage regularly on an outpatient basis. If there was no evidence of substantial lung entrapment (nonexpandable lung, in which lung expansion and pleural apposition are not possible because of visceral fibrosis or bronchial obstruction) at 10 days, patients were randomly assigned to receive either 4 g of talc slurry or placebo through the indwelling pleural catheter on an outpatient basis. Talc or placebo was administered on a single-blind basis. Follow-up lasted for 70 days. The primary outcome was successful pleurodesis at day 35 after randomization. RESULTS: The target of 154 patients undergoing randomization was reached after 584 patients were approached. At day 35, a total of 30 of 69 patients (43%) in the talc group had successful pleurodesis, as compared with 16 of 70 (23%) in the placebo group (hazard ratio, 2.20; 95% confidence interval, 1.23 to 3.92; P=0.008). No significant between-group differences in effusion size and complexity, number of inpatient days, mortality, or number of adverse events were identified. No significant excess of blockages of the indwelling pleural catheter was noted in the talc group. CONCLUSIONS: Among patients without substantial lung entrapment, the outpatient administration of talc through an indwelling pleural catheter for the treatment of malignant pleural effusion resulted in a significantly higher chance of pleurodesis at 35 days than an indwelling catheter alone, with no deleterious effects. (Funded by Becton Dickinson; EudraCT number, 2012-000599-40 .). PMID- 29617587 TI - 4-Year Follow-up in a Child with a Total Autologous Tracheal Replacement. PMID- 29617588 TI - More on Ofatumumab for TTP. PMID- 29617589 TI - Change in Overweight from Childhood to Early Adulthood and Risk of Type 2 Diabetes. AB - BACKGROUND: Childhood overweight is associated with an increased risk of type 2 diabetes in adulthood. We investigated whether remission of overweight before early adulthood reduces this risk. METHODS: We conducted a study involving 62,565 Danish men whose weights and heights had been measured at 7 and 13 years of age and in early adulthood (17 to 26 years of age). Overweight was defined in accordance with Centers for Disease Control and Prevention criteria. Data on type 2 diabetes status (at age >=30 years, 6710 persons) were obtained from a national health registry. RESULTS: Overweight at 7 years of age (3373 of 62,565 men; 5.4%), 13 years of age (3418 of 62,565; 5.5%), or early adulthood (5108 of 62,565; 8.2%) was positively associated with the risk of type 2 diabetes; associations were stronger at older ages at overweight and at younger ages at diagnosis of type 2 diabetes. Men who had had remission of overweight before the age of 13 years had a risk of having type 2 diabetes diagnosed at 30 to 60 years of age that was similar to that among men who had never been overweight (hazard ratio, 0.96; 95% confidence interval [CI], 0.75 to 1.21). As compared with men who had never been overweight, men who had been overweight at 7 and 13 years of age but not during early adulthood had a higher risk of type 2 diabetes (hazard ratio, 1.47; 95% CI, 1.10 to 1.98), but their risk was lower than that among men with persistent overweight (hazard ratio [persistently overweight vs. never overweight], 4.14; 95% CI, 3.57 to 4.79). An increase in body-mass index between 7 years of age and early adulthood was associated with an increased risk of type 2 diabetes, even among men whose weight had been normal at 7 years of age. CONCLUSIONS: Childhood overweight at 7 years of age was associated with increased risks of adult type 2 diabetes only if it continued until puberty or later ages. (Funded by the European Union.). PMID- 29617590 TI - Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer. PMID- 29617591 TI - Stream of Consciousness. PMID- 29617592 TI - Bedside Computer Vision - Moving Artificial Intelligence from Driver Assistance to Patient Safety. PMID- 29617593 TI - A Science-Driven Model of Community Collaboration to Improve Youth Outcomes. PMID- 29617594 TI - Embracing the School Start Later Movement: Adolescent Sleep Deprivation as a Public Health and Social Justice Problem. PMID- 29617595 TI - Local Health Departments' Role in Nonprofit Hospitals' Community Health Needs Assessment. PMID- 29617596 TI - Causal Thinking as a Critical Tool for Eliminating Social Inequalities in Health. PMID- 29617597 TI - Drug Purchasing Strategies to Treat People With Hepatitis C in the Criminal Justice System. PMID- 29617598 TI - Health, Social Movements, and Australian Immigration Detention. PMID- 29617600 TI - Don't Tear Slums Down; Help Them Unslum! PMID- 29617599 TI - Public Health Conditions for Successful Broad-Scale Integration of HIV and HCV Screening in Emergency Departments. PMID- 29617601 TI - Let's Require the "T-Word". PMID- 29617602 TI - Contagion and Public Health in Switzerland: Wilhelm Ost, MD (1853-1922), Polizeiarzt. PMID- 29617603 TI - Cause and Association: Missing the Forest for the Trees. PMID- 29617605 TI - AJPH Global News. PMID- 29617604 TI - Neural Tube Defects and Folic Acid Food Fortification in Europe. PMID- 29617606 TI - US Immigration: A Shrinking Vision of Belonging and Deserving. PMID- 29617607 TI - Moving Beyond the Cause Constraint: A Public Health of Consequence, May 2018. PMID- 29617608 TI - The C-Word: The More We Discuss It, the Less Dirty It Sounds. PMID- 29617609 TI - How Medicaid Can Strengthen the National Response to the Opioid Epidemic. PMID- 29617610 TI - Where Your Electronics Go to Die. PMID- 29617611 TI - On the Prophylaxis of Infectious Childhood Diseases. PMID- 29617612 TI - Antitransgender Political Backlash Threatens Health and Access to Care. PMID- 29617613 TI - Inheritance and Health: What Really Matters? PMID- 29617614 TI - Provoking Us to Thoughtfully, but Urgently, Move Public Health Ahead. PMID- 29617615 TI - Maximizing the Impact of Tobacco 21 Laws Across the United States. PMID- 29617616 TI - The Role of US Mayors and Health Commissioners in Combatting Health Disparities. PMID- 29617617 TI - A Typology of Nonfinancial Conflict in Population Health Research. PMID- 29617619 TI - Not All Influences on Science Are Conflicts of Interest. PMID- 29617618 TI - Can Tobacco Cessation Quitlines Improve the Use of Dental Health Care? PMID- 29617620 TI - News From The Nation's Health. PMID- 29617621 TI - Data Are Not Enough-Hurray For Causality! PMID- 29617622 TI - Start With the "C-Word," Follow the Roadmap for Causal Inference. PMID- 29617624 TI - Long noncoding RNA LINC00152 as a novel predictor of lymph node metastasis and survival in human cancer: a systematic review and meta-analysis. AB - BACKGROUND: LINC00152, a novel long noncoding RNA (lncRNA), was identified as an oncogene involved various cancers. This study was designed to explore the clinical significance and prognosis role of LINC00152. METHODS: Eligible studies were recruited by a systematic search in PubMed, Web of Science, and Embase up to August 23, 2017. Odds ratios (ORs), hazard ratios (HRs) and 95% confidence interval (95% CI) were pooled using Review Manager 5.3 and STATA 12.0. RESULT: A total of 10 studies with 913 patients were included to evaluate the association between LINC00152 expression and clinicopathological factors, overall survival (OS) and disease-free survivals (DFS). The results indicated that the expression level of LINC00152 was positively correlated with tumor size (OR = 5.19, 95% CI: 2.33-11.52, p < .0001), TNM stage (OR = 3.12, 95% CI: 1.77-5.51, p < .0001) and lymph node metastasis (OR = 3.41, 95% CI: 2.13-5.48, p < .00001). Moreover, elevated LINC00152 could predict unfavorable OS with pooled HR of 1.66 (95% CI: 1.29-2.13, p < .0001) and poor DFS (HR = 2.13, 95% CI: 1.39-3.25, p = .0005) in cancer patients. CONCLUSION: LINC00152 was correlated with advanced clinicopathological features and poor prognosis as a novel predictive biomarker in various cancers. PMID- 29617625 TI - Call for more transparency in manufacturers declarations on serum indices: On behalf of the Working Group for Preanalytical Phase (WG-PRE), European Federation of Clinical Chemistry and Laboratory Medicine (EFLM). AB - The presence of interfering substances like free hemoglobin, bilirubin or lipids compromises sample quality and potentially affects laboratory analysis and test results. Recently, the use of serum indices for objectively assessing sample quality has become commonplace and many preanalytical platforms, as well as clinical chemistry and coagulation analyzers, are now equipped with this analytical feature. Nevertheless, some important drawbacks remain in this practice, mainly pertaining the measurement procedure, the approach for reporting interference data, the definition of objective thresholds of interference after which test results may be biased, and the lack of harmonized practices for describing how interference cut-offs have been identified. Therefore, this document aims to discuss these important caveats and propose some reliable solutions that may be adopted by manufacturers for increasing worldwide harmonization of serum indices. PMID- 29617626 TI - Synthetic approaches to access acortatarins, shensongines and pollenopyrroside; potent antioxidative spiro-alkaloids with a naturally rare morpholine moiety. AB - Pyrrole spiroketal alkaloids (PSAs) are a class of novel natural products that have been recently disclosed. Acortatarin A and acortatarin B, two potent antioxidative spiroalkaloids with a naturally rare morpholine moiety, are important members of this class. These spiroalkaloids are isolated from Acorus tatarinowii, Brassica campestris, Capparis spinose, bread crust, Xylaria nigripes and medicine Shensong Yangxin and could inhibit significantly the reactive oxygen species (ROS) production in high-glucose-induced mesangial cells in a time- and dose-dependent manner. Hence, these natural products are promising starting points for the formation of new therapeutics to medicate cardiovascular diseases, cancer, diabetic complications, and other diseases in which ROS are implicated. The impressive structure combined with an interesting pharmacological activity prompted synthetic chemists to construct an asymmetric synthetic strategy that could be used to access structural derivatives in addition to the larger quantities of natural products required for further biological investigations. This review summarizes the current state of the literature regarding with the synthesis of acortatarin A and B and its other family members viz. shensongine A, B and C, and pollenopyrroside A. The present review discusses the pros and cons of synthetic methodologies, which would be beneficial for further developments in the synthetic methodologies. Hopefully, this struggle pushes the reader's mind to consider new perspectives, think differently and forge new connections. PMID- 29617627 TI - Cytotoxic carbazole alkaloid derivatives from the leaves and stems of Murraya microphylla. AB - Four new carbazole alkaloid derivatives, including a pair of enantiomers of the heterodimers of carbazole and phenylpropanoid (1a/1b) and two rare polyprenylated carbazole alkaloids (2, 3), together with 19 known analogues (4-22), were isolated from the leaves and stems of Murraya microphylla. Their structures were established by UV, IR, 1D/2D NMR, and HRESIMS data analysis, and their absolute configurations were determined by comparison of experimental and calculated ECD data and the ECD exciton coupling method. All the isolates were evaluated for their cytotoxicities against HepG2, Du145, HCT-116, and HeLa tumor cell lines. Compounds 7 and 11 exhibited obvious cytotoxic effects on four cancer cell lines in a dose-dependent manner. PMID- 29617628 TI - A Retentive Memory of Tetrachloroethene Respiration in Sulfurospirillum halorespirans - involved Proteins and a possible link to Acetylation of a Two Component Regulatory System. AB - : Organohalide respiration (OHR), comprising the reductive dehalogenation of halogenated organic compounds, is subject to a unique memory effect and long-term transcriptional downregulation of the involved genes in Sulfurospirillum multivorans. Gene expression ceases slowly over approximately 100 generations in the absence of tetrachloroethene (PCE). However, the molecular mechanisms of this regulation process are not understood. We show here that Sulfurospirillum halorespirans undergoes the same type of regulation when cultivated without chlorinated ethenes for a long period of time. In addition, we compared the proteomes of S. halorespirans cells cultivated in the presence of PCE with those of cells long- and short-term cultivated with nitrate as the sole electron acceptor. Important OHR-related proteins previously unidentified in S. multivorans include a histidine kinase, a putative quinol dehydrogenase membrane protein, and a PCE-induced porin. Since for some regulatory proteins a posttranslational regulation of activity by lysine acetylations is known, we also analyzed the acetylome of S. halorespirans, revealing that 32% of the proteome was acetylated in at least one condition. The data indicate that the response regulator and the histidine kinase of a two-component system most probably involved in induction of PCE respiration are highly acetylated during short-term cultivation with nitrate in the absence of PCE. SIGNIFICANCE: The so far unique long-term downregulation of organohalide respiration is now identified in a second species suggesting a broader distribution of this regulatory phenomenon. An improved protein extraction method allowed the identification of proteins most probably involved in transcriptional regulation of OHR in Sulfurospirillum spp. Our data indicate that acetylations of regulatory proteins are involved in this extreme, sustained standby-mode of metabolic enzymes in the absence of a substrate. This first published acetylome of Epsilonproteobacteria might help to study other ecologically or medically important species of this clade. PMID- 29617629 TI - Effects of Interleukin-6 on posterior capsular opacification. AB - The purpose of this work was to determine the effects of interleukin-6 (IL-6) on the development of posterior capsular opacification (PCO) in vitro and in vivo. Western blot and real-time PCR were used to test the IL-6-induced epithelial mesenchymal transition (EMT) marker alpha-smooth muscle actin (alpha-SMA), the extracellular matrix (ECM) markers fibronectin (Fn) and type I collagen (COL-1), transforming growth factor beta2 (TGF-beta2), and the activation and role of the JAK/STAT3 signaling pathway in human lens epithelial cells (HLECs). Immunocytofluorescence staining was performed to detect gp130 and IL-6Ralpha expression in HLECs. Rat PCO models were then established to examine the impact of STAT3 knockdown by shRNA adeno-associated virus on PCO development, and immunohistochemical staining was performed to detect the expression of Fn in the anterior and posterior capsule in vivo. We found that IL-6 promotes the expression of Fn, COL-1, TGF-beta2, p-JAK2 and p-STAT3 in HLECs but exerts little effect on alpha-SMA. The JAK/STAT3 inhibitor WP1066 effectively suppressed the IL 6-induced expression of Fn and COL-1 in lens epithelial cells. STAT3 knockdown effectively inhibited the development of PCO in rats and significantly reduced the expression of Fn in the anterior and posterior capsule. These data suggest that IL-6 contributes to the development of PCO by promoting TGF-beta2 activation and ECM synthesis through a JAK/STAT3 signaling-dependent mechanism. Furthermore, inhibiting JAK/STAT3 signaling effectively impairs both PCO development in rats and ECM synthesis in the lens capsule. PMID- 29617630 TI - Insights into the mode of action of 1,2,6,7-tetraoxaspiro [7.11] nonadecane (N 89) against adult Schistosoma mansoni worms. AB - Control of morbidity associated with schistosomiasis via chemotherapy largely relies on the drug praziquantel. Repeated therapy with praziquantel has created concerns about the possible selection of resistant worms and necessitated the search for novel drugs to treat schistosomiasis. Here, a murine model was infected with Schistosoma mansoni and treated with oral 1,2,6,7-tetraoxaspiro [7.11] nonadecane (N-89), which caused a significant reduction in fecundity and egg burden and reduced morbidity when administered at 5-weeks post-infection. The analysis showed that the mode of action occurred through the ingestion of activated N-89 by the worms, and that there was no direct external effect on the S. mansoni worms. Ultrastructural analysis of the treated worms showed disruptions in the gut lumen and the presence of large volumes of material, suggestive of undigested blood meals or red blood cells. In addition, there were reduced vitelline cells in female worms and damage to sub-tegmental musculature in male worms. Eggs recovered from the treated mice showed both damage to the eggs and the production of immature eggs. Expression of mRNA responsible for gut and digestive function and egg production was also significantly affected by N-89 treatment, whereas control genes for musculature showed no significant changes. Thus, N-89 drastically affected the total digestive function and egg production of S. mansoni worms. Physiological processes requiring heme uptake such as egg production and eggshell formation were subsequently affected, suggesting that the compound could be a possible therapeutic drug candidate for schistosomiasis control. PMID- 29617631 TI - Metabolic process of raffinose family oligosaccharides during cold stress and recovery in cucumber leaves. AB - Raffinose family oligosaccharides (RFOs) accumulate under stress conditions in many plants and have been suggested to act as stress protectants. To elucidate the metabolic process of RFOs under cold stress, levels of RFOs, and related carbohydrates, the expression and activities of main metabolic enzymes and their subcellular compartments were investigated during low-temperature treatment and during the recovery period in cucumber leaves. Cold stress induced the accumulation of stachyose in vacuoles, galactinol in vacuoles and cytosol, and sucrose and raffinose in vacuoles, cytosol, and chloroplasts. After cold stress removal, levels of these sugars decreased gradually in the respective compartments. Among four galactinol synthase genes (CsGS), CsGS1 was not affected by cold stress, while the other three CsGSs were up-regulated by low temperature. RNA levels of acid-alpha-galactosidase (GAL) 3 and alkaline-alpha-galactosidase (AGA) 2 and 3, and the activities of GAL and AGA, were up-regulated after cold stress removal. GAL3 protein and GAL activity were exclusively located in vacuoles, whereas AGA2 and AGA 3 proteins were found in cytosol and chloroplasts, respectively. The results indicate that RFOs, which accumulated during cold stress in different subcellular compartments in cucumber leaves, could be catabolized in situ by different galactosidases after stress removal. PMID- 29617632 TI - Development of chicken and fish muscle protein - Water partition coefficients predictive models for ionogenic and neutral organic chemicals. AB - Muscle protein was one of critical accumulation protein for anthropogenic chemicals. However, few predictive models were constructed for muscle protein up to now. In addition, some ionizable chemicals classes e.g. sulfonates were not successfully modeled in previously models, indicating considerable work would be needed. The major objective of this study was to develop quantitative structure activity relationship (QSAR) models for predicting the muscle protein-water partition coefficient (logKMP/w) of chicken and fish. In the modeling, the n octanol/water distribution coefficient (logD), functional groups, atom-centred fragments and chemical form adjusted descriptors were used to construct the models. The application domain of the derived models was defined by the Euclidean distance-based method and Williams plot. The modeling results indicated that the determination coefficient (R2), leave-one out cross validation Q2 (Q2LOO) and bootstrapping coefficient (Q2BOOT) of the QSAR models for chicken and fish were 0.882 and 0.929, 0.844 and 0.906, 0.779 and 0.792, respectively, implying the models had good goodness-of-fit and robustness. The coefficient determination (R2EXT) and external validation coefficient (Q2EXT) of the validation set for the two models were 0.874 and 0.937, 0.869 and 0.915, respectively, indicating the models had good predictive ability. The predictor variables selected to construct the logKMP/w models of chicken and fish included logD, the function groups, and the fraction of the ionized species (deltaI). Considering the molecular descriptors used here can be calculated from their molecular structures directly, the developed models could be easily used to fill the logKMP/w data gap for other chemicals within the applicability domain. PMID- 29617633 TI - Reducing racial/ethnic tobacco cessation disparities via cognitive behavioral therapy: Design of a dualsite randomized controlled trial. AB - : Racial/ethnic disparities in tobacco cessation are such that U.S. minorities have greater difficulty quitting compared to White non-Hispanics. Group differences in distress (i.e., perceived stress and depressive symptoms) may contribute to cessation disparities. The allostasis model of health suggests that the toll of chronic stress experienced by racial/ethnic minorities may lead to dysregulation of the physiological stress system and drug use. Previous research suggests that group cognitive behavioral therapy (CBT) for tobacco cessation addresses distress as a modifiable mechanism and has the potential to reduce/eliminate disparities. The present study is a dualsite randomized controlled trial aimed at evaluating the efficacy of group CBT in eliminating racial/ethnic differences in smoking cessation and distress. The study utilizes a [2 (intervention: group CBT or group general health education [GHE]) * 3 (race/ethnicity: African American/Black, Hispanic, White)] factorial design by randomizing 225 adult smokers from the community. Both interventions provide eight counseling sessions and eight weeks of nicotine patch therapy. Assessments occur at the end-of-therapy, and at 3-, 6-, and 12-months. Generalized longitudinal mixed modeling will be used to test our primary abstinence outcome, biochemically-confirmed 7-day point prevalence abstinence at 12-months. We hypothesize that group CBT will reduce or eliminate racial/ethnic differences in perceived stress, depressive symptoms, and smoking cessation compared to group GHE. We also hypothesize that reductions in physiological distress, assessed by salivary cortisol, will mediate racial/ethnic group differences in smoking cessation, particularly among racial/ethnic minorities. This study has implications for eliminating disparities in psychosocial factors related to tobacco use and cessation. TRIAL REGISTRATION: Clinicaltrials.govNCT02511236. Registered on July 27, 2015. PMID- 29617635 TI - Eating the Beast: Dietary Protein and Anticancer Immunity. AB - Studies on the impact of diet on cancer progression have predominantly focused on the metabolic demands of the tumor. In this issue of Cell Metabolism, Rubio Patino et al. (2018) examine how a small reduction in dietary protein effectively commandeers the adaptive immune response to attack the tumor, highlighting a role for endoplasmic reticulum stress. PMID- 29617634 TI - Surgical weight-loss to improve functional status trajectories following total knee arthroplasty: SWIFT trial: Rationale, design, and methods. AB - Total Knee Arthroplasty (TKA, also known as total knee replacement) is a highly effective surgical intervention for the restoration of physical function and improving quality of life in patients with disabling knee osteoarthritis. Recent data suggest that obesity is a major risk factor in the pathogenesis and progression of knee osteoarthritis, with increases in body mass index (BMI, kg/m2) directly correlating with the prevalence of knee osteoarthritis. However, recent data also suggest that there are increased risks associated with TKAs when performed in patients with morbid obesity (BMI > 40 kg/m2). Patients with morbid obesity are routinely referred for weight management prior to surgery. Many of these patients fail to meet the recommended weight loss goals prior to TKA, potentially making them ineligible for surgery or placing them at increased risk for sub-optimal outcomes. Thus, the purpose of this study is to examine the potential therapeutic impact and long-term outcomes of surgically induced weight loss on TKA outcomes. Specifically, these outcomes will include measures of physical function, mobility, and indices of joint function at 1 and 2 years post TKA compared between extremely obese patients who undergo TKA (Control group, n = 150) and those with TKA performed ~1 year after bariatric surgery (Test group, n = 150). An additional primary endpoint will be the percent of bariatric patients that negate or delay the need for TKA. Secondary endpoints include perioperative outcomes after TKA. PMID- 29617636 TI - Without Adaptive Immunity, There's a Cost to Responding STAT. AB - The relative contributions of innate and adaptive immune mechanisms in responding to the intestinal microbiota during ontogeny are largely unknown. A recent study in Nature by Mao et al. (2018) elegantly dissects the role of each cell type in the intestine and further describes the metabolic cost to innate immunity. PMID- 29617637 TI - Fighting for Resources: Who Started the Battle? Who Is Winning It? AB - Several vacuolar bacteria and parasites, such as Legionella, Chlamydia, and Toxoplasma, have been reported to grow associated with host mitochondria. The reason behind this phenomenon remains elusive. In this issue of Cell Metabolism, Pernas et al. (2018) propose that fusion of host mitochondria limits the availability of fatty acids needed for Toxoplasma gondii replication. PMID- 29617638 TI - Senescence Elicits Stemness: A Surprising Mechanism for Cancer Relapse. AB - Cellular senescence is traditionally viewed as a permanent form of cell cycle arrest that restrains tumorigenesis. In a recent study in Nature, however, Milanovic et al. (2018) challenge this conventional view, showing that senescence can counterintuitively promote cancer stemness and tumor aggressiveness. This finding suggests that attacking senescence can be exploited in cancer therapy. PMID- 29617639 TI - Adipose Tissue Flexes Its Muscles. AB - How brown and beige adipocytes activate UCP1-dependent thermogenesis has been studied in great detail. In Cell Metabolism, Tharp et al. (2018) have recently added another interesting dimension to this by demonstrating that actinomyosin mediated elasticity regulates the thermogenic capacity of UCP1+ adipocytes, opening up new ways by which UCP1-dependent thermogenesis can be stimulated. PMID- 29617640 TI - RNA-Targeted Therapeutics. AB - RNA-targeted therapies represent a platform for drug discovery involving chemically modified oligonucleotides, a wide range of cellular RNAs, and a novel target-binding motif, Watson-Crick base pairing. Numerous hurdles considered by many to be impassable have been overcome. Today, four RNA-targeted therapies are approved for commercial use for indications as diverse as Spinal Muscular Atrophy (SMA) and reduction of low-density lipoprotein cholesterol (LDL-C) and by routes of administration including subcutaneous, intravitreal, and intrathecal delivery. The technology is efficient and supports approaching "undruggable" targets. Three additional agents are progressing through registration, and more are in clinical development, representing several chemical and structural classes. Moreover, progress in understanding the molecular mechanisms by which these drugs work has led to steadily better clinical performance and a wide range of mechanisms that may be exploited for therapeutic purposes. Here we summarize the progress, future challenges, and opportunities for this drug discovery platform. PMID- 29617641 TI - Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1. AB - Glucagon-like peptide-1 (GLP-1) released from gut enteroendocrine cells controls meal-related glycemic excursions through augmentation of insulin and inhibition of glucagon secretion. GLP-1 also inhibits gastric emptying and food intake, actions maximizing nutrient absorption while limiting weight gain. Here I review the circuits engaged by endogenous versus pharmacological GLP-1 action, highlighting key GLP-1 receptor (GLP-1R)-positive cell types and pathways transducing metabolic and non-glycemic GLP-1 signals. The role(s) of GLP-1 in the benefits and side effects associated with bariatric surgery are discussed and actions of GLP-1 controlling islet function, appetite, inflammation, and cardiovascular pathophysiology are highlighted. Refinement of the risk-versus benefit profile of GLP-1-based therapies for the treatment of diabetes and obesity has stimulated development of orally bioavailable agonists, allosteric modulators, and unimolecular multi-agonists, all targeting the GLP-1R. This review highlights established and emerging concepts, unanswered questions, and future challenges for development and optimization of GLP-1R agonists in the treatment of metabolic disease. PMID- 29617642 TI - The Science and Translation of Lactate Shuttle Theory. AB - Once thought to be a waste product of anaerobic metabolism, lactate is now known to form continuously under aerobic conditions. Shuttling between producer and consumer cells fulfills at least three purposes for lactate: (1) a major energy source, (2) the major gluconeogenic precursor, and (3) a signaling molecule. "Lactate shuttle" (LS) concepts describe the roles of lactate in delivery of oxidative and gluconeogenic substrates as well as in cell signaling. In medicine, it has long been recognized that the elevation of blood lactate correlates with illness or injury severity. However, with lactate shuttle theory in mind, some clinicians are now appreciating lactatemia as a "strain" and not a "stress" biomarker. In fact, clinical studies are utilizing lactate to treat pro inflammatory conditions and to deliver optimal fuel for working muscles in sports medicine. The above, as well as historic and recent studies of lactate metabolism and shuttling, are discussed in the following review. PMID- 29617643 TI - AIDA Selectively Mediates Downregulation of Fat Synthesis Enzymes by ERAD to Retard Intestinal Fat Absorption and Prevent Obesity. AB - The efficiency of intestinal absorption of dietary fat constitutes a primary determinant accounting for individual vulnerability to obesity. However, how fat absorption is controlled and contributes to obesity remains unclear. Here, we show that inhibition of endoplasmic-reticulum-associated degradation (ERAD) increases the abundance of triacylglycerol synthesis enzymes and fat absorption in small intestine. The C2-domain protein AIDA acts as an essential factor for the E3-ligase HRD1 of ERAD to downregulate rate-limiting acyltransferases GPAT3, MOGAT2, and DGAT2. Aida-/- mice, when grown in a thermal-neutral condition or fed high-fat diet, display increased intestinal fatty acid re-esterification, circulating and tissue triacylglycerol, accompanied with severely increased adiposity without enhancement of adipogenesis. Intestine-specific knockout of Aida largely phenocopies its whole-body knockout, strongly indicating that increased intestinal TAG synthesis is a primary impetus to obesity. The AIDA mediated ERAD system may thus represent an anti-thrifty mechanism impinging on the enzymes for intestinal fat absorption and systemic fat storage. PMID- 29617644 TI - A Transcriptional Circuit Filters Oscillating Circadian Hormonal Inputs to Regulate Fat Cell Differentiation. AB - Glucocorticoid and other adipogenic hormones are secreted in mammals in circadian oscillations. Loss of this circadian oscillation pattern correlates with obesity in humans, raising the intriguing question of how hormone secretion dynamics affect adipocyte differentiation. Using live, single-cell imaging of the key adipogenic transcription factors CEBPB and PPARG, endogenously tagged with fluorescent proteins, we show that pulsatile circadian hormone stimuli are rejected by the adipocyte differentiation control system. In striking contrast, equally strong persistent signals trigger maximal differentiation. We identify the mechanism of how hormone oscillations are filtered as a combination of slow and fast positive feedback centered on PPARG. Furthermore, we confirm in mice that flattening of daily glucocorticoid oscillations significantly increases the mass of subcutaneous and visceral fat pads. Together, our study provides a molecular mechanism for why stress, Cushing's disease, and other conditions for which glucocorticoid secretion loses its pulsatility may lead to obesity. PMID- 29617646 TI - Mitochondria Restrict Growth of the Intracellular Parasite Toxoplasma gondii by Limiting Its Uptake of Fatty Acids. AB - How intracellular pathogens acquire essential non-diffusible host metabolites and whether the host cell counteracts the siphoning of these nutrients by its invaders are open questions. Here we show that host mitochondria fuse during infection by the intracellular parasite Toxoplasma gondii to limit its uptake of fatty acids (FAs). A combination of genetics and imaging of FA trafficking indicates that Toxoplasma infection triggers lipophagy, the autophagy of host lipid droplets (LDs), to secure cellular FAs essential for its proliferation. Indeed, Toxoplasma FA siphoning and growth are reduced in host cells genetically deficient for autophagy or triglyceride depots. Conversely, Toxoplasma FA uptake and proliferation are increased in host cells lacking mitochondrial fusion, required for efficient mitochondrial FA oxidation, or where mitochondrial FA oxidation is pharmacologically inhibited. Thus, mitochondrial fusion can be regarded as a cellular defense mechanism against intracellular parasites, by limiting Toxoplasma access to host nutrients liberated by lipophagy. PMID- 29617645 TI - Mitochondria Bound to Lipid Droplets Have Unique Bioenergetics, Composition, and Dynamics that Support Lipid Droplet Expansion. AB - Mitochondria associate with lipid droplets (LDs) in fat-oxidizing tissues, but the functional role of these peridroplet mitochondria (PDM) is unknown. Microscopic observation of interscapular brown adipose tissue reveals that PDM have unique protein composition and cristae structure and remain adherent to the LD in the tissue homogenate. We developed an approach to isolate PDM based on their adherence to LDs. Comparison of purified PDM to cytoplasmic mitochondria reveals that (1) PDM have increased pyruvate oxidation, electron transport, and ATP synthesis capacities; (2) PDM have reduced beta-oxidation capacity and depart from LDs upon activation of brown adipose tissue thermogenesis and beta oxidation; (3) PDM support LD expansion as Perilipin5-induced recruitment of mitochondria to LDs increases ATP synthase-dependent triacylglyceride synthesis; and (4) PDM maintain a distinct protein composition due to uniquely low fusion fission dynamics. We conclude that PDM represent a segregated mitochondrial population with unique structure and function that supports triacylglyceride synthesis. PMID- 29617648 TI - A Pseudo-Kinase Double Act. AB - Pragmin is a catalytically inactive pseudo-kinase that is important in regulating cellular growth and adhesion. In this issue of Structure, Lecointre et al. (2018) present the structure of Pragmin, illustrating a dimerization domain flanking its pseudo-kinase domain that is important for Pragmin-mediated activation of the non receptor tyrosine kinase CSK. PMID- 29617649 TI - Choosing the Best Enzyme Complex Structure Made Easy. AB - In this issue of Structure, Tyzack et al. (2018) present a study of enzyme-ligand complexes in the PDB and show that the molecular similarity of bound and cognate ligands can be used to choose the most biologically appropriate complex structure for analysis when multiple structures are available. PMID- 29617647 TI - The Factor Inhibiting HIF Asparaginyl Hydroxylase Regulates Oxidative Metabolism and Accelerates Metabolic Adaptation to Hypoxia. AB - Animals require an immediate response to oxygen availability to allow rapid shifts between oxidative and glycolytic metabolism. These metabolic shifts are highly regulated by the HIF transcription factor. The factor inhibiting HIF (FIH) is an asparaginyl hydroxylase that controls HIF transcriptional activity in an oxygen-dependent manner. We show here that FIH loss increases oxidative metabolism, while also increasing glycolytic capacity, and that this gives rise to an increase in oxygen consumption. We further show that the loss of FIH acts to accelerate the cellular metabolic response to hypoxia. Skeletal muscle expresses 50-fold higher levels of FIH than other tissues: we analyzed skeletal muscle FIH mutants and found a decreased metabolic efficiency, correlated with an increased oxidative rate and an increased rate of hypoxic response. We find that FIH, through its regulation of oxidation, acts in concert with the PHD/vHL pathway to accelerate HIF-mediated metabolic responses to hypoxia. PMID- 29617650 TI - Unexpected Specificity of a Trypsin-like Enzyme. AB - In this issue of Structure, Stach et al. (2018) describe the properties of SplE, a trypsin-like enzyme from Staphylococcus aureus. They report, on the basis of biochemical and structural studies, the unusual specificity requiring the presence of histidine in the P1 subsite of its substrate. PMID- 29617651 TI - Loss of Dnmt3a Immortalizes Hematopoietic Stem Cells In Vivo. AB - Somatic mutations in DNMT3A are recurrent events across a range of blood cancers. Dnmt3a loss of function in hematopoietic stem cells (HSCs) skews divisions toward self-renewal at the expense of differentiation. Moreover, DNMT3A mutations can be detected in the blood of aging individuals, indicating that mutant cells outcompete normal HSCs over time. It is important to understand how these mutations provide a competitive advantage to HSCs. Here we show that Dnmt3a-null HSCs can regenerate over at least 12 transplant generations in mice, far exceeding the lifespan of normal HSCs. Molecular characterization reveals that this in vivo immortalization is associated with gradual and focal losses of DNA methylation at key regulatory regions associated with self-renewal genes, producing a highly stereotypical HSC phenotype in which epigenetic features are further buttressed. These findings lend insight into the preponderance of DNMT3A mutations in clonal hematopoiesis and the persistence of mutant clones after chemotherapy. PMID- 29617653 TI - Removing 4E-BP Enables Synapses to Refine without Postsynaptic Activity. AB - Throughout the developing nervous system, considerable synaptic re-organization takes place as postsynaptic neurons extend dendrites and incoming axons refine their synapses, strengthening some and eliminating others. It is well accepted that these processes rely on synaptic activity; however, the mechanisms that lead to this developmental reorganization are not fully understood. Here, we explore the regulation of cap-dependent translation, a mechanism known to play a role in synaptic growth and plasticity. Using sympathetic ganglia in alpha3 nicotinic acetylcholine receptor (nAChR)-knockout (KO) mice, we establish that electrophysiologically silent synapses between preganglionic axons and postsynaptic sympathetic neurons do not refine, and the growth of dendrites and the targeting of synapses on postsynaptic neurons are impaired. Remarkably, genetically removing 4E-BP, a suppressor of cap-dependent translation, from these alpha3 nAChR-KO mice largely restores these features. We conclude that synaptic connections can re-organize and refine without postsynaptic activity during post natal development when 4E-BP-regulated cap-dependent translation is enhanced. PMID- 29617652 TI - Multifaceted Impact of MicroRNA 493-5p on Genome-Stabilizing Pathways Induces Platinum and PARP Inhibitor Resistance in BRCA2-Mutated Carcinomas. AB - BRCA1/2-mutated ovarian cancers (OCs) are defective in homologous recombination repair (HRR) of double-strand breaks (DSBs) and thereby sensitive to platinum and PARP inhibitors (PARPis). Multiple PARPis have recently received US Food and Drug Administration (FDA) approval for treatment of OCs, and resistance to PARPis is a major clinical problem. Utilizing primary and recurrent BRCA1/2-mutated carcinomas from OC patients, patient-derived lines, and an in vivo BRCA2-mutated mouse model, we identified a microRNA, miR-493-5p, that induced platinum/PARPi resistance exclusively in BRCA2-mutated carcinomas. However, in contrast to the most prevalent resistance mechanisms in BRCA mutant carcinomas, miR-493-5p did not restore HRR. Expression of miR-493-5p in BRCA2-mutated/depleted cells reduced levels of nucleases and other factors involved in maintaining genomic stability. This resulted in relatively stable replication forks, diminished single-strand annealing of DSBs, and increased R-loop formation. We conclude that impact of miR 493-5p on multiple pathways pertinent to genome stability cumulatively causes PARPi/platinum resistance in BRCA2 mutant carcinomas. PMID- 29617654 TI - Identification of CDC25 as a Common Therapeutic Target for Triple-Negative Breast Cancer. AB - CDK4/6 inhibitors are effective against cancer cells expressing the tumor suppressor RB1, but not RB1-deficient cells, posing the challenge of how to target RB1 loss. In triple-negative breast cancer (TNBC), RB1 and PTEN are frequently inactivated together with TP53. We performed kinome/phosphatase inhibitor screens on primary mouse Rb/p53-, Pten/p53-, and human RB1/PTEN/TP53 deficient TNBC cell lines and identified CDC25 phosphatase as a common target. Pharmacological or genetic inhibition of CDC25 suppressed growth of RB1-deficient TNBC cells that are resistant to combined CDK4/6 plus CDK2 inhibition. Minimal cooperation was observed in vitro between CDC25 antagonists and CDK1, CDK2, or CDK4/6 inhibitors, but strong synergy with WEE1 inhibition was apparent. In accordance with increased PI3K signaling following long-term CDC25 inhibition, CDC25 and PI3K inhibitors effectively synergized to suppress TNBC growth both in vitro and in xenotransplantation models. These results provide a rationale for the development of CDC25-based therapies for diverse RB1/PTEN/TP53-deficient and proficient TNBCs. PMID- 29617655 TI - PTCD1 Is Required for 16S rRNA Maturation Complex Stability and Mitochondrial Ribosome Assembly. AB - The regulation of mitochondrial RNA life cycles and their roles in ribosome biogenesis and energy metabolism are not fully understood. We used CRISPR/Cas9 to generate heart- and skeletal-muscle-specific knockout mice of the pentatricopeptide repeat domain protein 1, PTCD1, and show that its loss leads to severe cardiomyopathy and premature death. Our detailed transcriptome-wide and functional analyses of these mice enabled us to identify the molecular role of PTCD1 as a 16S rRNA-binding protein essential for its stability, pseudouridylation, and correct biogenesis of the mitochondrial large ribosomal subunit. We show that impaired mitoribosome biogenesis can have retrograde signaling effects on nuclear gene expression through the transcriptional activation of the mTOR pathway and upregulation of cytoplasmic protein synthesis and pro-survival factors in the absence of mitochondrial translation. Taken together, our data show that impaired assembly of the mitoribosome exerts its consequences via differential regulation of mitochondrial and cytoplasmic protein synthesis. PMID- 29617656 TI - Impaired Spermatogenesis, Muscle, and Erythrocyte Function in U12 Intron Splicing Defective Zrsr1 Mutant Mice. AB - The U2AF35-like ZRSR1 has been implicated in the recognition of 3' splice site during spliceosome assembly, but ZRSR1 knockout mice do not show abnormal phenotypes. To analyze ZRSR1 function and its precise role in RNA splicing, we generated ZRSR1 mutant mice containing truncating mutations within its RNA recognition motif. Homozygous mutant mice exhibited severe defects in erythrocytes, muscle stretch, and spermatogenesis, along with germ cell sloughing and apoptosis, ultimately leading to azoospermia and male sterility. Testis RNA sequencing (RNA-seq) analyses revealed increased intron retention of both U2- and U12-type introns, including U12-type intron events in genes with key functions in spermatogenesis and spermatid development. Affected U2 introns were commonly found flanking U12 introns, suggesting functional cross-talk between the two spliceosomes. The splicing and tissue defects observed in mutant mice attributed to ZRSR1 loss of function suggest a physiological role for this factor in U12 intron splicing. PMID- 29617657 TI - Transgenerational Sterility of Piwi Mutants Represents a Dynamic Form of Adult Reproductive Diapause. AB - Environmental stress can induce adult reproductive diapause, a state of developmental arrest that temporarily suspends reproduction. Deficiency for C. elegans Piwi protein PRG-1 results in strains that reproduce for many generations but then become sterile. We found that sterile-generation prg-1/Piwi mutants typically displayed pronounced germ cell atrophy as L4 larvae matured into 1-day old adults. Atrophied germlines spontaneously reproliferated across the first days of adulthood, and this was accompanied by fertility for day 2-4 adults. Sterile day 5 prg-1 mutant adults remained sterile indefinitely, but providing an alternative food source could restore their fertility. Our data imply that late generation prg-1 mutants experience a dynamic form of adult reproductive diapause, promoted by stress response, cell death, and RNAi pathways, where delayed fertility and reproductive quiescence represent parallel adaptive developmental outcomes. This may occur in response to a form of "heritable stress" that is transmitted by gametes and epigenetic in nature. PMID- 29617663 TI - Brv1 Is Required for Drosophila Larvae to Sense Gentle Touch. AB - How we sense touch is fundamental for many physiological processes. However, the underlying mechanism and molecular identity for touch sensation are largely unknown. Here, we report on defective gentle-touch behavioral responses in brv1 loss-of-function Drosophila larvae. RNAi and Ca2+ imaging confirmed the involvement of Brv1 in sensing touch and demonstrated that Brv1 mediates the mechanotransduction of class III dendritic arborization neurons. Electrophysiological recordings further revealed that the expression of Brv1 protein in HEK293T cells gives rise to stretch-activated cation channels. Purified Brv1 protein reconstituted into liposomes were found to sense stretch stimuli. In addition, co-expression studies suggested that Brv1 amplifies the response of mechanosensitive ion channel NOMPC (no mechanoreceptor potential C) to touch stimuli. Altogether, these findings demonstrate a molecular entity that mediates the gentle-touch response in Drosophila larvae, providing insights into the molecular mechanisms of touch sensation. PMID- 29617658 TI - Machine Learning Detects Pan-cancer Ras Pathway Activation in The Cancer Genome Atlas. AB - Precision oncology uses genomic evidence to match patients with treatment but often fails to identify all patients who may respond. The transcriptome of these "hidden responders" may reveal responsive molecular states. We describe and evaluate a machine-learning approach to classify aberrant pathway activity in tumors, which may aid in hidden responder identification. The algorithm integrates RNA-seq, copy number, and mutations from 33 different cancer types across The Cancer Genome Atlas (TCGA) PanCanAtlas project to predict aberrant molecular states in tumors. Applied to the Ras pathway, the method detects Ras activation across cancer types and identifies phenocopying variants. The model, trained on human tumors, can predict response to MEK inhibitors in wild-type Ras cell lines. We also present data that suggest that multiple hits in the Ras pathway confer increased Ras activity. The transcriptome is underused in precision oncology and, combined with machine learning, can aid in the identification of hidden responders. PMID- 29617659 TI - Spatial Organization and Molecular Correlation of Tumor-Infiltrating Lymphocytes Using Deep Learning on Pathology Images. AB - Beyond sample curation and basic pathologic characterization, the digitized H&E stained images of TCGA samples remain underutilized. To highlight this resource, we present mappings of tumor-infiltrating lymphocytes (TILs) based on H&E images from 13 TCGA tumor types. These TIL maps are derived through computational staining using a convolutional neural network trained to classify patches of images. Affinity propagation revealed local spatial structure in TIL patterns and correlation with overall survival. TIL map structural patterns were grouped using standard histopathological parameters. These patterns are enriched in particular T cell subpopulations derived from molecular measures. TIL densities and spatial structure were differentially enriched among tumor types, immune subtypes, and tumor molecular subtypes, implying that spatial infiltrate state could reflect particular tumor cell aberration states. Obtaining spatial lymphocytic patterns linked to the rich genomic characterization of TCGA samples demonstrates one use for the TCGA image archives with insights into the tumor-immune microenvironment. PMID- 29617661 TI - Integrated Genomic Analysis of the Ubiquitin Pathway across Cancer Types. AB - Protein ubiquitination is a dynamic and reversible process of adding single ubiquitin molecules or various ubiquitin chains to target proteins. Here, using multidimensional omic data of 9,125 tumor samples across 33 cancer types from The Cancer Genome Atlas, we perform comprehensive molecular characterization of 929 ubiquitin-related genes and 95 deubiquitinase genes. Among them, we systematically identify top somatic driver candidates, including mutated FBXW7 with cancer-type-specific patterns and amplified MDM2 showing a mutually exclusive pattern with BRAF mutations. Ubiquitin pathway genes tend to be upregulated in cancer mediated by diverse mechanisms. By integrating pan-cancer multiomic data, we identify a group of tumor samples that exhibit worse prognosis. These samples are consistently associated with the upregulation of cell-cycle and DNA repair pathways, characterized by mutated TP53, MYC/TERT amplification, and APC/PTEN deletion. Our analysis highlights the importance of the ubiquitin pathway in cancer development and lays a foundation for developing relevant therapeutic strategies. PMID- 29617671 TI - Shp-2 Is Dispensable for Establishing T Cell Exhaustion and for PD-1 Signaling In Vivo. AB - In chronic infection and cancer, T cells acquire a dysfunctional state characterized by the expression of inhibitory receptors. In vitro studies implicated the phosphatase Shp-2 downstream of these receptors, including PD-1. However, whether Shp-2 is responsible in vivo for such dysfunctional responses remains elusive. To address this, we generated T cell-specific Shp-2-deficient mice. These mice did not show differences in controlling chronic viral infections. In this context, Shp-2-deleted CD8+ T lymphocytes expanded moderately better but were less polyfunctional than control cells. Mice with Shp-2-deficient T cells also showed no significant improvement in controlling immunogenic tumors and responded similarly to controls to alpha-PD-1 treatment. We therefore showed that Shp-2 is dispensable in T cells for globally establishing exhaustion and for PD-1 signaling in vivo. These results reveal the existence of redundant mechanisms downstream of inhibitory receptors and represent the foundation for defining these relevant molecular events. PMID- 29617670 TI - Manipulating Hippocampal Place Cell Activity by Single-Cell Stimulation in Freely Moving Mice. AB - Learning critically depends on the ability to rapidly form and store non overlapping representations of the external world. In line with their postulated role in episodic memory, hippocampal place cells can undergo a rapid reorganization of their firing fields upon contextual manipulations. To explore the mechanisms underlying such global remapping, we juxtacellularly stimulated 42 hippocampal neurons in freely moving mice during spatial exploration. We found that evoking spike trains in silent neurons was sufficient for creating place fields, while in place cells, juxtacellular stimulation induced a rapid remapping of their place fields to the stimulus location. The occurrence of complex spikes was most predictive of place field plasticity. Our data thus indicate that plasticity-inducing stimuli are able to rapidly bias place cell activity, simultaneously suppressing existing place fields. We propose that such competitive place field dynamics could support the orthogonalization of the hippocampal map during global remapping. PMID- 29617660 TI - Genomic, Pathway Network, and Immunologic Features Distinguishing Squamous Carcinomas. AB - This integrated, multiplatform PanCancer Atlas study co-mapped and identified distinguishing molecular features of squamous cell carcinomas (SCCs) from five sites associated with smoking and/or human papillomavirus (HPV). SCCs harbor 3q, 5p, and other recurrent chromosomal copy-number alterations (CNAs), DNA mutations, and/or aberrant methylation of genes and microRNAs, which are correlated with the expression of multi-gene programs linked to squamous cell stemness, epithelial-to-mesenchymal differentiation, growth, genomic integrity, oxidative damage, death, and inflammation. Low-CNA SCCs tended to be HPV(+) and display hypermethylation with repression of TET1 demethylase and FANCF, previously linked to predisposition to SCC, or harbor mutations affecting CASP8, RAS-MAPK pathways, chromatin modifiers, and immunoregulatory molecules. We uncovered hypomethylation of the alternative promoter that drives expression of the DeltaNp63 oncogene and embedded miR944. Co-expression of immune checkpoint, T regulatory, and Myeloid suppressor cells signatures may explain reduced efficacy of immune therapy. These findings support possibilities for molecular classification and therapeutic approaches. PMID- 29617662 TI - Driver Fusions and Their Implications in the Development and Treatment of Human Cancers. AB - Gene fusions represent an important class of somatic alterations in cancer. We systematically investigated fusions in 9,624 tumors across 33 cancer types using multiple fusion calling tools. We identified a total of 25,664 fusions, with a 63% validation rate. Integration of gene expression, copy number, and fusion annotation data revealed that fusions involving oncogenes tend to exhibit increased expression, whereas fusions involving tumor suppressors have the opposite effect. For fusions involving kinases, we found 1,275 with an intact kinase domain, the proportion of which varied significantly across cancer types. Our study suggests that fusions drive the development of 16.5% of cancer cases and function as the sole driver in more than 1% of them. Finally, we identified druggable fusions involving genes such as TMPRSS2, RET, FGFR3, ALK, and ESR1 in 6.0% of cases, and we predicted immunogenic peptides, suggesting that fusions may provide leads for targeted drug and immune therapy. PMID- 29617673 TI - Mitochondrial Complex I Inhibitors Expose a Vulnerability for Selective Killing of Pten-Null Cells. AB - A hallmark of advanced prostate cancer (PC) is the concomitant loss of PTEN and p53 function. To selectively eliminate such cells, we screened cytotoxic compounds on Pten-/-;Trp53-/- fibroblasts and their Pten-WT reference. Highly selective killing of Pten-null cells can be achieved by deguelin, a natural insecticide. Deguelin eliminates Pten-deficient cells through inhibition of mitochondrial complex I (CI). Five hundred-fold higher drug doses are needed to obtain the same killing of Pten-WT cells, even though deguelin blocks their electron transport chain equally well. Selectivity arises because mitochondria of Pten-null cells consume ATP through complex V, instead of producing it. The resulting glucose dependency can be exploited to selectively kill Pten-null cells with clinically relevant CI inhibitors, especially if they are lipophilic. In vivo, deguelin suppressed disease in our genetically engineered mouse model for metastatic PC. Our data thus introduce a vulnerability for highly selective targeting of incurable PC with inhibitors of CI. PMID- 29617672 TI - Increased RNA Editing May Provide a Source for Autoantigens in Systemic Lupus Erythematosus. AB - RNA-editing mechanisms, which induce nucleotide substitution in the RNA, increase transcript and protein diversities. Editing dysregulation has been shown to lead to grave outcomes, and transcriptome-wide aberrant RNA editing has been found in tumors. However, little is known about the involvement of editing in other diseases. Systemic lupus erythematosus (SLE) is a multisystemic autoimmune disease characterized by a loss of tolerance for autoantigens from various tissues and the production of multiple autoantibodies. Here, we show that blood samples from individuals with SLE have abnormally high levels of RNA editing, some of which affect proteins and potentially generate novel autoantigens. We suggest that elevated RNA editing, either by ADARs or APOBECs, may be involved in the pathophysiology of SLE, as well as in other autoimmune diseases, by generating or increasing the autoantigen load, a key requisite for the progression of autoimmunity. PMID- 29617675 TI - Neonatal Subventricular Zone Neural Stem Cells Release Extracellular Vesicles that Act as a Microglial Morphogen. AB - Subventricular zone (SVZ) neural stem cells (NSCs) are the cornerstone of the perinatal neurogenic niche. Microglia are immune cells of the nervous system that are enriched in the neonatal SVZ. Although microglia regulate NSCs, the extent to which this interaction is bi-directional is unclear. Extracellular vesicles (EVs) are cell-derived particles that encase miRNA and proteins. Here, we demonstrate that SVZ NSCs generate and release EVs. Neonatal electroporated fluorescent EV fusion proteins were released by NSCs and subsequently cleared from the SVZ. EVs were preferentially targeted to microglia. Small RNA sequencing identified miRNAs within the EVs that regulate microglia physiology and morphology. EVs induced a transition to a CD11b/Iba1 non-stellate microglial morphology. The transition accompanied a microglial transcriptional state characterized by Let-7-regulated cytokine release and a negative feedback loop that controlled NSC proliferation. These findings implicate an NSC-EV-microglia axis and provide insight to normal and pathophysiological brain development. PMID- 29617674 TI - Adolescent Nicotine Exposure Alters GABAA Receptor Signaling in the Ventral Tegmental Area and Increases Adult Ethanol Self-Administration. AB - Adolescent smoking is associated with pathological drinking later in life, but the biological basis for this vulnerability is unknown. To examine how adolescent nicotine exposure influences subsequent ethanol intake, nicotine was administered during adolescence or adulthood, and responses to alcohol were measured 1 month later. We found that adolescent, but not adult, nicotine exposure altered GABA signaling within the ventral tegmental area (VTA) and led to a long-lasting enhancement of alcohol self-administration. We detected depolarizing shifts in GABAA reversal potentials arising from impaired chloride extrusion in VTA GABA neurons. Alterations in GABA signaling were dependent on glucocorticoid receptor activation and were associated with attenuated dopaminergic neuron responses to alcohol in the lateral VTA. Importantly, enhancing chloride extrusion in adolescent nicotine-treated animals restored VTA GABA signaling and alcohol self administration to control levels. Taken together, this work suggests that adolescent nicotine exposure increases the risk profile for increased alcohol drinking in adulthood. PMID- 29617677 TI - The mTOR Kinase Inhibitor CZ415 Inhibits Human Papillary Thyroid Carcinoma Cell Growth. AB - BACKGROUND/AIM: Mammalian target of rapamycin (mTOR) plays an important role in papillary thyroid carcinoma (PTC) cell progression. CZ415 is a novel, highly efficient and specific mTOR kinase inhibitor. The current study tested the potential anti-tumor activity of CZ415 in human PTC cells. METHODS: The established (TPC-1 cell line) and primary human PTC cells were treated with CZ415. Cell survival and growth were tested by Cell Counting Kit-8 assay and BrdU ELISA assay, respectively. Cell apoptosis was tested by caspase-3/-9 activity assay, Hoechst-33342 staining assay and single-stranded DNA ELISA assay. Cell cycle progression was tested by propidium iodide-FACS assay. The mTOR signaling was tested by Western blotting assay and co-immunoprecipitation assay. The mouse xenograft tumor model was applied to study the effect of CZ415 in vivo. RESULTS: In cultured human PTC cells, treatment with CZ415 at nM concentrations significantly inhibited cell survival and growth. CZ415 induced apoptosis activation and cell cycle arrest in human PTC cells. CZ415 disrupted assembling of mTORC1 (mTOR-Raptor association) and mTORC2 (mTOR-Rictor-GbetaL association) in TPC-1 cells, which led to de-phosphorylation of the mTORC1 substrates (S6K1 and 4E-BP1) and the mTORC2 substrate AKT (Ser-473). Further studies show that the autophagy inhibitor 3-methyladenine (3-MA) or Beclin-1 shRNA aggravated CZ415 induced cytotoxicity against PTC cells. In vivo, CZ415 oral administration inhibited TPC-1 xenograft tumor growth in mice. CONCLUSION: Our results show that mTOR blockage by CZ415 inhibits PTC cell growth in vitro and in vivo. PMID- 29617676 TI - Glycosylation of Human IgA Directly Inhibits Influenza A and Other Sialic-Acid Binding Viruses. AB - Immunoglobulin A (IgA) plays an important role in protecting our mucosal surfaces from viral infection, in maintaining a balance with the commensal bacterial flora, and in extending maternal immunity via breast feeding. Here, we report an additional innate immune effector function of human IgA molecules in that we demonstrate that the C-terminal tail unique to IgA molecules interferes with cell surface attachment of influenza A and other enveloped viruses that use sialic acid as a receptor. This antiviral activity is mediated by sialic acid found in the complex N-linked glycans at position 459. Antiviral activity was observed even in the absence of classical antibody binding via the antigen binding sites. Our data, therefore, show that the C-terminal tail of IgA subtypes provides an innate line of defense against viruses that use sialic acid as a receptor and the role of neuraminidases present on these virions. PMID- 29617678 TI - Increased Asics Expression via the Camkii-CREB Pathway in a Novel Mouse Model of Trigeminal Pain. AB - BACKGROUND/AIMS: Migraine is a disabling condition that severely impacts socioeconomic function and quality of life. The focus of this study was to develop a mouse model of trigeminal pain that mimics migraine. METHODS: After undergoing dural cannulation surgery, mice were treated with repeated dural doses of an acidic solution to induce trigeminal pain. RESULTS: The method elicited intermittent, head-directed wiping and scratching as well as the expression of both the c-FOS gene in the spinal trigeminal nucleus caudalis and calcitonin gene related peptide (CGRP) in the periaqueductal grey matter. Interestingly, the acid induced trigeminal pain behaviour was inhibited by amiloride, an antagonist of acid-sensing ion channels (ASICs), but not by AMG-9810, an inhibitor of transient receptor potential cation channel V1(TRPV1). In addition, the relative mRNA and protein expression levels of ASIC1a and ASIC3 were increased in the acid-induced trigeminal nociceptive pathways. Furthermore, blocking CaMKII with KN-93 significantly reduced the acid-induced trigeminal pain behaviour and c-FOS gene expression. CONCLUSION: The data suggested that chronic intermittent administration of an acidic solution to mice resulted in trigeminal hypersensitivity and that dural acid-induced trigeminal pain behaviour in mice may mechanistically mimic migraine. The observations here identify an entirely novel treatment strategy for migraine. PMID- 29617680 TI - The Role of Crush Cytology in the Diagnosis of Large-Intestine Lesions with Correlation on Histopathology. AB - OBJECTIVE: To study the efficacy of colonoscopic crush cytology as a convenient and near-accurate method to evaluate colonic neoplasms. STUDY DESIGN: Retrospective and cross-sectional. The original cytologic diagnoses were correlated with a histology report on 100 cases sent to the cytology laboratory over 2 years. RESULTS: Of the 100 cases, 25 were nonmalignant. Of the 75 malignant lesions, 72 could be identified as positive for malignancy on cytology. The false-positives consisted of 6 adenomas and 1 case of ulcerative colitis. Thus, sensitivity and specificity of cytology are 96 and 63.2%, respectively. Of the 6 adenomas diagnosed as malignant, 4 showed high-grade dysplasia, and the other 2 showed superficial ulceration with low-grade dysplasia on histopathology. The ulcerative colitis case showed widespread ulcers and regenerative/reparative features on biopsy. The 3 adenocarcinomas diagnosed s benign on cytology showed an occasional malignant cell with thickened nuclear borders and prominent central nucleoli. CONCLUSIONS: With careful attention to the cytomorphology, coupled with good clinical and endoscopic correlation, crush cytology of the large intestine is a reliable diagnostic tool. It categorizes lesions as malignant and benign with a high sensitivity, positive predictive value, and negative predictive value. Adenomas and reparative/regenerative changes seen in inflammatory bowel disease are major pitfalls in the cytology diagnosis of malignancy that may be averted by informing the endoscopic findings and clinical history. Cytology diagnosis saves time and gives proper feedback to the gastroenterologist. PMID- 29617679 TI - Simvastatin Attenuates Neurogenetic Damage and Improves Neurocongnitive Deficits Induced by Isoflurane in Neonatal Rats. AB - BACKGROUND/AIMS: Isoflurane inhibited neurogenesis and induced subsequent neurocognitive deficits in developing brain. Simvastatin exerts neuroprotection in a wide range of brain injury models. In the present study, we investigated whether simvastatin could attenuate neurogenetic inhibition and cognitive deficits induced by isoflurane exposure in neonatal rats. METHODS: Sprague-Dawley rats at postnatal day (PND) 7 and neural stem cells (NSCs) were treated with either gas mixture, isoflurane, or simvastatin 60 min prior to isoflurane exposure, respectively. The rats were decapitated at PND 8 and PND 10 for detection of neurogenesis in the subventricular zone (SVZ) and subgranular zone (SGZ) of the hippocampus by immunostaining. NSC proliferation, viability and apoptosis were assessed by immunohistochemistry, CCK-8 and TUNEL, respectively. The protein expressions of caspase-3, p-Akt and p-GSK-3beta both in vivo and vitro were assessed by western blotting. Cognitive functions were assessed by Morris Water Maze test and context fear conditioning test at the adult. RESULTS: Isoflurane exposure inhibited neurogenesis in the SVZ and SGZ, decreased NSC proliferation and viability, promoted NSC apoptosis and led to late cognitive deficits. Furthermore, isoflurane increased caspase-3 expression and decreased protein expressions of p-Akt and p-GSK-3beta both in vivo and in vitro. Pretreatment with simvastatin attenuated isoflurane-elicited changes in NSCs and cognitive function. Co-treatment with LY294002 reversed the effect of simvastatin on NSCs in vitro. CONCLUSION: We for the first time showed that simvastatin, by upregulating Akt/GSK-3beta signaling pathway, alleviated isoflurane-induced neurogenetic damage and neurocognitive deficits in developing rat brain. PMID- 29617682 TI - Phenalen-1-One-Mediated Antimicrobial Photodynamic Therapy and Chlorhexidine Applied to a Novel Caries Biofilm Model. AB - Antimicrobial photodynamic therapy (aPDT) may be useful as a supportive antimicrobial measure for caries-active subjects. In this study, the antimicrobial efficacy of aPDT with a phenalen-1-one photosensitizer was evaluated in a novel in vitro biofilm model comprising Actinomyces naeslundii, Actinomyces odontolyticus, and Streptococcus mutans and was compared to chlorhexidine. The proposed biofilm model allows high-throughput screening for antimicrobial efficacy while exhibiting a differentiated response to different antimicrobial approaches. While chlorhexidine 0.2% showed a reduction of ~4 log10 for all species, aPDT led to a more pronounced reduction of S. mutans (2.8 log10) than of Actinomyces spp. (1.2 or 1.3 log10). A similar effect was also observed in monospecies biofilms. Therefore, aPDT may be more effective against S. mutans than against Actinomyces spp. when in biofilms, and this antimicrobial approach merits further investigations. PMID- 29617681 TI - MiR-19b-3p Regulates MAPK1 Expression in Embryonic Fibroblasts from the Great Tit (Parus Major) Under Hypoxic Conditions. AB - BACKGROUND/AIMS: Genomic adaptations to high altitudes have been well studied in the last several years; however, the roles of microRNAs (miRNAs), which are essential modulators of a variety of genes and key cellular processes, have rarely been explored. Here, we explored the interactions between miRNAs and their target genes as an adaptation to high altitude in an avian species, the great tit (Parus major), which is widely distributed across the Eurasian continent at altitudes between 4500 m and sea level. Because the MAPK signaling pathway plays a crucial role in the hypoxia response in the great tit, we chose MAPK1 as a target candidate gene. METHODS: We established a great tit embryonic fibroblast line and subsequently studied the relationship between miRNA-19b-3p and MAPK1 in normoxia and hypoxia groups. Meanwhile, the great tit embryonic fibroblasts (GEFs) were treated or transfected with miR-19b-3p mimics, inhibitors, or si MAPK1, and their proliferation was subsequently assessed using the MTT assay. The expression of the miRNAs and MAPK1 was measured by real-time PCR and Western blotting. RESULTS: We identified 14 miRNAs in the cardiac tissues of great tits that are related to hypoxia adaptation. MAPK1 binds only to miR-19b-3p of the 14 miRNAs predicted by both TargetScan and miRanda software. Specifically, we validated the computational prediction of miR-19b-3p binding to the 3'UTR of MAPK1 using a luciferase reporter assay. Our results show that miR-19b-3p promotes GEFs proliferation and up-regulates MAPK1 expression. Moreover, miR-19b 3p mimics and MAPK1 knockdown induce GEFs apoptosis and regulate the cell cycle under hypoxic conditions. CONCLUSIONS: Our study is the first to describe an important miRNA-mediated regulatory mechanism of high altitude adaptation in a non-model wild songbird and highlights the importance of studies on miRNA mediated mechanisms of hypoxic adaptations in other animals. PMID- 29617664 TI - Genomic and Molecular Landscape of DNA Damage Repair Deficiency across The Cancer Genome Atlas. AB - DNA damage repair (DDR) pathways modulate cancer risk, progression, and therapeutic response. We systematically analyzed somatic alterations to provide a comprehensive view of DDR deficiency across 33 cancer types. Mutations with accompanying loss of heterozygosity were observed in over 1/3 of DDR genes, including TP53 and BRCA1/2. Other prevalent alterations included epigenetic silencing of the direct repair genes EXO5, MGMT, and ALKBH3 in ~20% of samples. Homologous recombination deficiency (HRD) was present at varying frequency in many cancer types, most notably ovarian cancer. However, in contrast to ovarian cancer, HRD was associated with worse outcomes in several other cancers. Protein structure-based analyses allowed us to predict functional consequences of rare, recurrent DDR mutations. A new machine-learning-based classifier developed from gene expression data allowed us to identify alterations that phenocopy deleterious TP53 mutations. These frequent DDR gene alterations in many human cancers have functional consequences that may determine cancer progression and guide therapy. PMID- 29617683 TI - MiR-140 Expression Regulates Cell Proliferation and Targets PD-L1 in NSCLC. AB - BACKGROUND/AIMS: Programmed death ligand1(PD-L1) plays a role in the development and progression of non-small cell lung cancer (NSCLC). This study aimed to identify miRNA(s) that are responsible for regulation of expression of PD-L1 in NSCLC, and to investigate the role of PD-L1 in regulation of the cell cycle in NSCLC. METHODS: We predicted the target miRNA of PD-L1, which was miR-140, using the online tools TargetScan and miBase. In NSCLC cells obtained from clinical specimens, in addition to A549 and NCI-H1650 cell cultures, western blots were used to detect the level of expression of proteins, while real-time PCR was used to determine the level of expression of PD-L1, miR-140, cyclin E, and beta-actin. Transfection with miR-140 mimics, miR-140 inhibitors, and PD-L1 siRNA were conducted using commercial kits. To determine whether miR-140 directly binds PD L1, a luciferase reporter gene with wild type or mutated PD-L1 was used. Cell viability was measured with the MTT assay, and PI staining was used for cell cycle analysis. RESULTS: We found low expression of miR-140 and high expression of PD-L1 and cyclin E in NSCLC cells. Over-expression of miR-140 suppressed the expression of PD-L1 by directly binding its 3' UTR, and was also associated with decreased expression of cyclin E and inhibition of cellular proliferation in A549 and NCI-H1650 cells. Inhibition of PD-L1, in the absence of manipulations to miR 140, also decreased the expression of cyclin E. CONCLUSION: We conclude that miR 140 directly suppresses PD-L1 and inhibits the miR-140/PD-L1/cyclin E pathway in NSCLC. PMID- 29617684 TI - Characteristics of Mild Cognitive Impairment Using the Thai Version of the Consortium to Establish a Registry for Alzheimer's Disease Tests: A Multivariate and Machine Learning Study. AB - BACKGROUND: The Consortium to Establish a Registry for Alzheimer's Disease (CERAD) developed a neuropsychological battery (CERAD-NP) to screen patients with Alzheimer's dementia. Mild cognitive impairment (MCI) has received attention as a pre-dementia stage. OBJECTIVES: To delineate the CERAD-NP features of MCI and their clinical utility to externally validate MCI diagnosis. METHODS: The study included 60 patients with MCI, diagnosed using the Clinical Dementia Rating, and 63 normal controls. Data were analysed employing receiver operating characteristic analysis, Linear Support Vector Machine, Random Forest, Adaptive Boosting, Neural Network models, and t-distributed stochastic neighbour embedding (t-SNE). RESULTS: MCI patients were best discriminated from normal controls using a combination of Wordlist Recall, Wordlist Memory, and Verbal Fluency Test. Machine learning showed that the CERAD features learned from MCI patients and controls were not strongly predictive of the diagnosis (maximal cross-validation 77.2%), whilst t-SNE showed that there is a considerable overlap between MCI and controls. CONCLUSIONS: The most important features of the CERAD-NP differentiating MCI from normal controls indicate impairments in episodic and semantic memory and recall. While these features significantly discriminate MCI patients from normal controls, the tests are not predictive of MCI. PMID- 29617665 TI - Molecular Characterization and Clinical Relevance of Metabolic Expression Subtypes in Human Cancers. AB - Metabolic reprogramming provides critical information for clinical oncology. Using molecular data of 9,125 patient samples from The Cancer Genome Atlas, we identified tumor subtypes in 33 cancer types based on mRNA expression patterns of seven major metabolic processes and assessed their clinical relevance. Our metabolic expression subtypes correlated extensively with clinical outcome: subtypes with upregulated carbohydrate, nucleotide, and vitamin/cofactor metabolism most consistently correlated with worse prognosis, whereas subtypes with upregulated lipid metabolism showed the opposite. Metabolic subtypes correlated with diverse somatic drivers but exhibited effects convergent on cancer hallmark pathways and were modulated by highly recurrent master regulators across cancer types. As a proof-of-concept example, we demonstrated that knockdown of SNAI1 or RUNX1-master regulators of carbohydrate metabolic subtypes modulates metabolic activity and drug sensitivity. Our study provides a system level view of metabolic heterogeneity within and across cancer types and identifies pathway cross-talk, suggesting related prognostic, therapeutic, and predictive utility. PMID- 29617686 TI - Trend Analysis of Studies on Water Fluoridation Related to Dental Caries in PubMed. AB - Water fluoridation has been cited as one of the top 10 public health achievements of the 20th century. Herein, we analyzed water fluoridation articles related to dental caries published in PubMed between 1950 and 2016 using informetrics and linguistic methods to investigate trends in the studies. To this aim, queries such as "dental caries and (water fluoridation or fluoridated water)," "dental caries and (fluoride or fluoridation)," and "dental caries" were submitted to PubMed to retrieve information about articles on water fluoridation within the area of dental caries and fluoride - their titles, abstracts, publication dates, author affiliations, and publication journals. This article information was then collected by an automatic web crawler and examined through informetrics and linguistic analyses. It was found that the number of articles concerned with water fluoridation and dental caries was 3,381 and declined over time after 1970. The articles were published by 750 journals - most notably, Community Dentistry and Oral Epidemiology and Caries Research. With regard to the geographic distribution of the authors, Europe and North America, especially the USA and UK, accounted for 59.9% of the articles published during the years 1987 to 2015, though there was a sharp increase in the number of authors in Oceania and Asia in recent years. In the titles and abstracts of the articles, "community" and "fluorosis" were mentioned more frequently than the other key terms selected in this study, regardless of the period examined. Our findings may allow one to assess how the research on water fluoridation has evolved over the past several decades. PMID- 29617685 TI - Incidence of Antibiotic-Related Rash in Children with Epstein-Barr Virus Infection and Evaluation of the Frequency of Confirmed Antibiotic Hypersensitivity. AB - BACKGROUND: The incidence of rash after aminopenicillin treatment in children with Epstein-Barr Virus (EBV) infection was reported to be 80-100%. A few recent studies suggested that the incidence may be much lower during EBV infection. There are no clear data on the incidence of true drug hypersensitivity among these patients. The aim of this study is to determine the incidence of rash and antibiotic allergy after antibiotic treatment in children with EBV infection. METHODS: Drug hypersensitivity was investigated in antibiotic-treated patients with a positive EBV IgM who developed a rash between 2013 and 2016. RESULTS: During the study period, 221 children were diagnosed with EBV infection, and 120 (54.3%) patients were treated with antibiotics during disease. Rash developed in 41 (41/221, 18.6%) patients, and 20 of them (total 120; 16.6%) were treated with antibiotics (most frequently aminopenicillins: 72.5%), and 21 of them (total 101, 20.8%) were not treated with antibiotics (p = 0.43). For 10 of the 20 antibiotic treated patients with a rash, parents did not consent to an allergy workup. Three of the 10 patients who were tested for drug allergy were proven to have amoxicillin-clavulanate hypersensitivity (30%). Five of the patients without workup reacted after reuse of the suspected drug for infection treatment. CONCLUSION: In this study, the incidence of drug hyper-sensitivity was much lower than previously reported. Some of the reactions that occur during infectious mononucleosis are transient, and some are true drug hypersensitivity reactions. Thus, these patients should be evaluated with allergy tests before these drugs are used again after EBV infection. PMID- 29617687 TI - Hemeoxygenase-1 Suppresses IL-1beta-Induced Apoptosis Through the NF-kappaB Pathway in Human Degenerative Nucleus Pulposus Cells. AB - BACKGROUND/AIMS: Nucleus pulposus cell (NPC) apoptosis is the main factor in intervertebral disc degeneration (IDD); thus, inhibiting the excessive apoptosis of nucleus pulposus cells may be a potential way to alleviate IDD. The effect of Hemeoxygenase-1 (HO-1) on human NPC apoptosis has never been reported. Our study aimed to investigate the effect and mechanism of HO-1 on apoptosis in human degenerative NPCs. METHODS: Nucleus pulposus tissues were collected from patients with lumbar vertebral fracture (LVF) and IDD. The expression of HO-1 and P65 in intervertebral discs was determined using immunohistochemistry and western blot analysis. Apoptosis of human nucleus pulposus cells was quantified by flow cytometric analysis. A recombinant lentiviral vector overexpressing HO-1 and HO-1 siRNA was used to promote or silence the expression of HO-1 in nucleus pulposus cells. The NF-kappaB inhibitor PDTC was used to inhibit the NF-kappaB pathway. RESULTS: Our study demonstrated that compared with normal samples, IDD samples showed down-regulation of HO-1 expression and up-regulation of P65 expression. Overexpression of HO-1 inhibited the increase in nucleus pulposus cell apoptosis after IL-1beta treatment and simultaneously inhibited the expression of p-P65. Furthermore, after treatment with PDTC, the number of apoptotic cells was significantly decreased with or without overexpression of HO-1. CONCLUSION: HO-1 might play a significant role in IDD, and HO-1 protected degenerative human NPCs against apoptosis induced by IL-1beta through the NF-kappaB pathway. These findings would aid in the development of novel therapeutic approaches for IDD treatment. PMID- 29617688 TI - Big Data for Public Health Policy-Making: Policy Empowerment. AB - Digitization is considered to radically transform healthcare. As such, with seemingly unlimited opportunities to collect data, it will play an important role in the public health policy-making process. In this context, health data cooperatives (HDC) are a key component and core element for public health policy making and for exploiting the potential of all the existing and rapidly emerging data sources. Being able to leverage all the data requires overcoming the computational, algorithmic, and technological challenges that characterize today's highly heterogeneous data landscape, as well as a host of diverse regulatory, normative, governance, and policy constraints. The full potential of big data can only be realized if data are being made accessible and shared. Treating research data as a public good, creating HDC to empower citizens through citizen-owned health data, and allowing data access for research and the development of new diagnostics, therapies, and public health policies will yield the transformative impact of digital health. The HDC model for data governance is an arrangement, based on moral codes, that encourages citizens to participate in the improvement of their own health. This then enables public health institutions and policymakers to monitor policy changes and evaluate their impact and risk on a population level. PMID- 29617689 TI - Clinical Decision-Making when Treating Diabetic Macular Edema Patients with Dexamethasone Intravitreal Implants. AB - Diabetes mellitus (DM) is a metabolic disease frequently associated with comorbidities that include diabetic macular edema (DME). The current medical approach to treating DME involves intravitreal injections with either anti vascular endothelial growth factors or steroids. However, the burden associated with intravitreal injections and DM-derived complications is high, underlining the need to find optimal treatment regimens. In this article we describe the considerations we apply when treating DME patients with dexamethasone intravitreal implants (Ozurdex(r)), particularly those that influence the clinical decision-making process during the follow-up period. These considerations are based both on the available medical literature and on our clinical experience following the use of these implants in this type of patient, the goal being to optimize the number of injections and the clinical outcome of this therapy. We also provide a general overview of the pathophysiology of DME, highlighting the inflammatory component as a rationale to use steroids in these patients. PMID- 29617691 TI - Reply. PMID- 29617694 TI - Soluble Receptor for Advanced Glycation End Products (sRAGE) is Up-Regulated in Multiple Sclerosis Patients Treated with Interferon beta-1a. AB - BACKGROUND/AIMS: Multiple sclerosis (MS) is a chronic inflammatory disorder of the central nervous system. Considering the role of immune system in its pathogenesis, researchers have focused on evaluation of the expression of immune related genes or proteins in MS patients. Among proteins whose participation in inflammatory process has been documented is the receptor for advanced glycation end products (RAGE). METHODS: In the present study, we compared RAGE transcript levels by means of quantitative real-time PCR as well as the serum level of soluble RAGE (sRAGE) by means of enzyme- linked immunosorbent assay (ELISA) in 50 IFNbeta-1a responsive relapsing-remitting MS patients when compared with age and sex-matched healthy subjects. RESULTS: Elevated expression of RAGE as well as higher levels of sRAGE were detected in IFN-beta responsive MS patients compared with the controls. A significant inverse correlation between sRAGE plasma concentrations and the expanded disability status scale (EDSS) was also detected in which each unit of increase in sRAGE level resulted in a 0.308 unit decrease in EDSS. CONCLUSION: Considering the stable clinical state of the MS patients in this study and their response to IFNbeta-1a, the elevated levels of sRAGE in patients compared with healthy subjects could be related to the effects of this kind of treatment. PMID- 29617690 TI - Thrombin Generation in Vitreous and Subretinal Fluid of Patients with Retinal Detachment. AB - PURPOSE: To measure prothrombin fragments (F1+2) and thrombin-antithrombin complex (TAT) in vitreous and subretinal fluid (SRF) of rhegmatogenous retinal detachment (RRD) patients and to validate and further specify our earlier finding of increased thrombin activity in patients with proliferative vitreoretinopathy (PVR). METHODS: F1+2 and TAT were measured in 31 vitreous and 16 SRF samples using the Enzygnost(r) immunoassays. RESULTS: We found significant levels of F1+2 and TAT in the vitreous of all patients with RRD compared to patients with macular hole or macular pucker. However, there was no significant difference between patients who would develop PVR in the future, had established PVR, and patients with uncomplicated RRD both in vitreous concentrations of F1+2 (Kruskal Wallis p = 0.963) and TAT (p = 0.516). CONCLUSION: The analysis of F1+2 and TAT confirmed significant thrombin generation in both vitreous and SRF of patients with RRD. An imbalance between the thrombin regulation mechanisms TAT and alpha2 macroglobulin possibly explains the difference from our previous findings. PMID- 29617698 TI - Pseudomonas aeruginosa and Klebsiella pneumoniae Adaptation to Innate Immune Clearance Mechanisms in the Lung. AB - Many different species of gram-negative bacteria are associated with infection in the lung, causing exacerbations of chronic obstructive pulmonary disease, cystic fibrosis (CF), and ventilator-associated pneumonias. These airway pathogens must adapt to common host clearance mechanisms that include killing by antimicrobial peptides, antibiotics, oxidative stress, and phagocytosis by leukocytes. Bacterial adaptation to the host is often evident phenotypically, with increased extracellular polysaccharide production characteristic of some biofilm-associated organisms. Given the relatively limited repertoire of bacterial strategies to elude airway defenses, it seems likely that organisms sharing the same ecological niche might also share common strategies to persistently infect the lung. In this review, we will highlight some of the major factors responsible for the adaptation of Pseudomonas aeruginosa to the lung, addressing how growth in biofilms enables persistent infection, relevant to, but not limited to, the pathogenesis of infection in CF. In contrast, we will discuss how carbapenem resistant Klebsiella pneumoniae evade immune clearance, an organism often associated with ventilator-associated pneumonia and health-care-acquired pneumonias, but not a typical pathogen in CF. PMID- 29617697 TI - Proteomic Profiling of Diffuse Large B-Cell Lymphomas. AB - OBJECTIVE: The aim of this study was to identify differences in proteome profiles of diffuse large B-cell lymphoma (DLBCL) of nongerminal center (non-GC) versus GC type in the search for new markers and drug targets. METHODS: Six DLBCL, with 3 repeats for each, were used for the initial study by proteomics: 3 non-GC and 3 GC DLBCL cases. For immunohistochemistry, tissue microarrays were made from 31 DLBCL samples: 16 non-GC de novo lymphomas and 15 GC cases (11 transformed from follicular lymphomas and 4 de novo GC lymphomas). Proteome profiling was performed by two-dimensional gel electrophoresis and MALDI-TOF mass spectrometry. RESULTS: Ninety-one proteins were found differentially expressed in non-GC compared to GC type. The Cytoscape tool was used for systemic analysis of proteomics data, revealing 19 subnetworks representing functions affected in non GC versus GC types of DLBCL. CONCLUSION: A validation study of 3 selected proteins (BiP/Grp78, Hsp90, and cyclin B2) showed the enhanced expression in non GC DLBCL, supporting the proteomics data. PMID- 29617696 TI - VR-10 Thrombospondin-1 Synthetic Polypeptide's Impact on Rhesus Choroid-Retinal Endothelial Cells. AB - BACKGROUND/AIMS: This study aimed to investigate the effects of the VR-10 TSP-1 synthetic polypeptide on cytokines and the proliferation and migration of endothelial cells, as well as exploring a new method for anti-ocular neoangiogenesis. METHODS: We measured the proliferation of RF/6A cells by an MTT assay and investigated the migration of RF/6A cells by a Transwell chamber assay. We examined the mRNA transcript levels of TGF-beta2, VEGF, PEDF, Bcl-2 and FasL in RF/6A cells by RT-PCR and evaluated the expression of Fas and caspase-3 proteins in RF/6A cells by western blot analysis. RESULTS: 1. TSP-1 (1 ug/ml) and synthetic peptide VR-10 (0.1 ug/ml, 1 ug/ml and 10 ug/ml) inhibited the proliferation of RF/6A cells in a time and dose-dependent way. 2. TSP-1 and synthetic peptide VR-10 could inhibit the migration of RF/6A cells in a Transwell chamber (P < 0.001). It was demonstrated that 10 ug/ml synthetic peptide VR-10 had the strongest effect. 3. The expression of TGF-beta2 mRNA in RF/6A cells increased after treatment with 1 ug/ml TSP-1 (P < 0.0001). However, there was no significant difference between the synthetic peptide VR-10 and the control group (P > 0.05). Expression of PEDF mRNA in RF/6A cells was increased after treatment with 1 ug/ml TSP-1 and synthetic peptide VR-10. We demonstrated that 10 ug/ml synthetic peptide VR-10 had the strongest effect (P < 0.001). There were significant differences between groups (P < 0.001). Expression of TGF-beta2 mRNA in RF/6A cells increased after treatment with 1 ug/ml TSP-1 (P = 0.000). There was no significant difference between the synthetic peptide VR-10 and the control group (P > 0.05). PEDF mRNA expression in RF/6A cells decreased after 1 ug/ml TSP 1 and synthetic peptide VR-10 therapy, among which 10 ug/ml synthetic peptide VR 10 demonstrated the strongest effect (P < 0.001). There were significant differences between groups (P < 0.001), except for the 1 ug/ml synthetic peptide VR-10 and 1 ug/ml synthetic peptide VR-10 groups (P = 0.615). 4. Compared with the control group, FasL mRNA expression was significantly increased in the 10 ug/ml synthetic peptide VR-10 treatment group; however, Bcl-2 mRNA expression was decreased. 5. Western blotting showed that RF/6A cells in the control group mainly expressed the 32 kD procaspase-3 forms. For the 10 ug/ml synthetic peptide, VR-10 treatment group, it showed decreased expression of procaspase-3 (32 kD) and concomitant increased expression of its shorter pro apoptotic forms (20 kD). Compared with the control group, Fas protein expression significantly increased in the 10 ug/ml synthetic peptide VR-10 treatment group. CONCLUSIONS: Synthetic peptide VR-10 had an inhibitory action on the proliferation and migration of RF/6A cells. VR-10 inhibited angiogenesis by its combined actions, which included up-regulating the expression of an anti-angiogenesis gene, namely, pigment epithelium-derived factor (PEDF), down-regulating the expression of the pro-angiogenic vascular endothelial growth factor (VEGF), and mediated endothelial cell apoptosis. PMID- 29617692 TI - Prognostic Significance of LncRNA PVT1 and Its Potential Target Gene Network in Human Cancers: a Comprehensive Inquiry Based Upon 21 Cancer Types and 9972 Cases. AB - BACKGROUND/AIMS: Whether the level of long noncoding RNA plasmacytoma variant translocation 1 gene (lncRNA PVT1) expression influences the clinical development and outcome of human cancers has not been thoroughly elucidated to date. Inconsistencies still exist regarding the associations between PVT1 and the clinicopathological features, including patient survival data. Additionally, the regulatory mechanism of PVT1 among human cancers remains unclear. METHODS: we conducted a comprehensive inquiry to verify the implication of PVT1 expression in cancer patients by conducting a meta-analysis of 19 selected studies and The Cancer Genome Atlas (TCGA) database to examine the relationship between PVT1 expression and both the prognosis and clinicopathological features of cancer patients using STATA 12.0. In addition, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses of the potential mRNA target genes of PVT1 gathered from TANRIC and Multi Experiment Matrix (MEM) were performed. RESULTS: The level of PVT1 expression in tumor tissues was higher than in paired non-cancer tissues and was significantly associated with a poorer prognosis in cancer patients. Additionally, overexpression of PVT1 was significantly correlated with histological differentiation, tumor (T) classification, lymph node (N) classification and TNM stages. Furthermore, a total of 462 validated target genes were identified, and the GO and KEGG analyses demonstrated that the validated targets of PVT1 were significantly enriched in several pathways, including the GnRH signaling pathway, the Cytokine-cytokine receptor interaction pathway, the Inflammatory mediator regulation of TRP channels pathway, and the Neuroactive ligand-receptor interaction pathway. CONCLUSION: PVT1 may serve as a potential biomarker associated with the progression and prognosis of human cancers. PMID- 29617699 TI - Abnormal Expression of PICT-1 and Its Codon 389 Polymorphism Is a Risk Factor for Human Endometrial Cancer. AB - OBJECTIVE: The protein interacting with carboxyl terminus-1 (PICT-1) gene has been implicated as a tumor suppressor gene, and its alterations have been reported in several cancers. This study investigated the association of PICT-1 alterations with endometrial carcinogenesis. METHODS: We analyzed the entire coding region of the PICT-1 gene using polymerase chain reaction-single-strand conformation polymorphism and DNA sequencing to examine PICT-1 mutations in endometrial cancer. Western blotting and immunohistochemical staining were performed to analyze the protein expression and cellular localization of PICT-1 in endometrial cancer cell lines and patient samples. RESULTS: The codon 389 polymorphism of PICT-1 increased the risk of endometrial cancer. Interestingly, 2 of 13 endometrial cancers somatically acquired this mutation compared to normal counterparts. Immunohistochemical staining revealed lower levels of PICT-1 in samples from atypical endometrial hyperplasia and endometrial cancer tissues compared to normal endometrial tissues (p < 0.01). This decrease in PICT-1 expression was significantly correlated with histological grade and lymph node metastasis (p < 0.05). CONCLUSIONS: The findings of this study suggest that disruption of PICT-1 protein expression and codon 389 polymorphism can contribute to the pathogenesis or neoplastic progression of endometrial cancer. PMID- 29617693 TI - The Protective Effects of the A/ZJU01/ PR8/2013 Split H7N9 Avian Influenza Vaccine Against Highly Pathogenic H7N9 in BALB/c Mice. AB - BACKGROUND/AIMS: Since the first case of novel H7N9 infection was reported, China has experienced five epidemics of H7N9. During the fifth wave, a highly pathogenic H7N9 strain emerged. In order to assess whether the H7N9 vaccine based on A/Zhejiang/DTID-ZJU01/2013(H7N9) was effective in protecting against highly pathogenic H7N9, we conducted this study. METHODS: Groups of mice were immunized twice by intraperitoneal injection with 500 ul of either split vaccine alone or MF59-adjuvanted vaccine. Serum was collected 2 weeks after the second vaccine booster. The hemagglutinin inhibition test was conducted on vaccine seed and highly pathogenic H7N9 to evaluate the neutralization of highly pathogenic H7N9. We also immunized mice and challenged them with highly pathogenic H7N9. Mice were observed for illness, weight loss, and death at 1 week and 2 weeks post infection. Then, the mice were sacrificed and lungs were removed. Antibody responses were assessed and pathological changes in the lung tissue were evaluated. RESULTS: The ability of serum to neutralize highly pathogenic H7N9 was reduced. In mice, highly pathogenic H7N9 was more virulent than A/Zhejiang/DTID ZJU01/2013(H7N9). After challenge with highly pathogenic H7N9, all mice died while mice challenged with A/Zhejiang/DTID-ZJU01/2013(H7N9) all recovered. The A/ZJU01/PR8/2013 split H7N9 avian influenza vaccine was able to protect against infection with highly pathogenic H7N9 in mice, with or without MF59. Moreover, H7N9 vaccine adjuvanted with MF59 produced high antibody levels, which lead to better protection. CONCLUSIONS: The A/ZJU01/PR8/2013 split H7N9 avian influenza vaccine based on A/Zhejiang/DTID-ZJU01/2013(H7N9) is effective in protecting against highly pathogenic H7N9. H7N9 vaccine adjuvanted with MF59 offers better protection against infection with highly pathogenic H7N9. In order to make the H7N9 vaccine applicable to humans, further clinical trials are required to evaluate MF59 adjuvanted vaccine. Meanwhile, the vaccine strain should be updated based on the highly pathogenic H7N9 gene sequence. PMID- 29617701 TI - Isolation and Characterization of a Lytic Bacteriophage (vB_PmiS-TH) and Its Application in Combination with Ampicillin against Planktonic and Biofilm Forms of Proteus mirabilis Isolated from Urinary Tract Infection. AB - Proteus mirabilis is one of the most common causes of urinary tract infection (UTI), particularly in patients undergoing long-term catheterization. Phage vB_PmiS-TH was isolated from wastewater with high lytic activity against P. mirabilis (TH) isolated from UTI. The phage had rapid adsorption, a large burst size (~260 PFU per infected cell), and high stability at a wide range of temperatures and pH values. As analyzed by transmission electron microscopy, phage vB_PmiS-TH had an icosahedral head of ~87 * 62 nm with a noncontractile tail about 137 nm in length and 11 nm in width. It belongs to the family Siphoviridae. Combination of the phage vB_PmiS-TH with ampicillin had a higher removal activity against planktonic cells of P. mirabilis (TH) than the phage or the antibiotic alone. Combination of the phage at a multiplicity of infection of 100 with a high dose of ampicillin (246 ug/mL) showed the highest biofilm removal activity after 24 h. This study demonstrates that using a combination of phage and antibiotic could be significantly more effective against planktonic and biofilm forms of P. mirabilis (TH). PMID- 29617700 TI - Vasoactive Intestinal Peptide Protects Salivary Glands against Structural Injury and Secretory Dysfunction via IL-17A and AQP5 Regulation in a Model of Sjogren Syndrome. AB - OBJECTIVE: Sjogren syndrome (SS) is an autoimmune disease involving exocrine glands. Currently, drugs that can improve both abnormal immunity and exocrine gland function are needed. The study aimed to investigate the effect and mechanism of vasoactive intestinal peptide (VIP) on the immune response and exocrine gland function in SS. METHODS: We investigated the effects of VIP on the immune response and secretory function of submandibular glands using NOD mice, and analyzed the expression of IL-17A and AQP5 (aquaporin 5). The submandibular gland cells from healthy 8-day-old Sprague-Dawley rats were used to observe the influence of VIP on AQP5 expression. RESULTS: Our study shows that treatment with VIP in an SS mouse model could not only reduce the immune injury to exocrine glands but also improve the secretory function of these glands. Furthermore, VIP was shown to improve the abnormal immune status by downregulating IL-17A expression in the exocrine glands. It also enhanced the secretory function of exocrine glands by upregulating AQP5 expression. CONCLUSIONS: Using a model of SS, we found that VIP could not only modulate the immune response but also affect exocrine gland function, and that these therapeutic effects were associated with IL-17A and AQP5 regulation. PMID- 29617695 TI - Topical Treatment of Skin Injury Inflicted in Mice by X-Ray Irradiation. AB - BACKGROUND/AIMS: There is no treatment, without side effects, efficiently preventing or curing skin burns, caused by radiotherapy. A new experimental topical treatment protocol was assessed in mice receiving orthovoltage X-rays at an equivalent dose to that applied to human breast cancer patients in conventional radiotherapy. METHODS: SKH-HR2 female hairless mice were irradiated on their dorsum with a total dose of 4,300 cGy during a 1-month period (20 fractions). The treatment group received a combination of 3 topical products, an oil-in-water cream, a gel containing Pinus halepensis bark aqueous extract, and an ointment containing olive oil extract of the marine isopod Ceratothoa oestroides. The positive control group was treated with a conventionally used commercial gel, whereas the negative control group did not receive any topical treatment. Skin alterations were evaluated by macroscopic examinations, measurements of transepidermal water loss (TEWL), melanin content, erythema intensity, hydration, and histopathology assessment. RESULTS: Sixty days after radiation, TEWL and hydration values were abnormal and elements of acute, chronic, and granulomatous inflammation were present in all cases. The severest damage was detected in the deeper dermis. Treatment showed a comparatively beneficial effect on chronic and granulomatous inflammation while positive control was beneficial on acute inflammation. CONCLUSION: Skin anti-inflammatory treatment was the most effective but must be applied for several months. Further preclinical studies should be conducted, assimilating a human cancer radiation therapeutic schema with the aim of optimizing skin inflammation treatment. PMID- 29617666 TI - Systematic Analysis of Splice-Site-Creating Mutations in Cancer. AB - For the past decade, cancer genomic studies have focused on mutations leading to splice-site disruption, overlooking those having splice-creating potential. Here, we applied a bioinformatic tool, MiSplice, for the large-scale discovery of splice-site-creating mutations (SCMs) across 8,656 TCGA tumors. We report 1,964 originally mis-annotated mutations having clear evidence of creating alternative splice junctions. TP53 and GATA3 have 26 and 18 SCMs, respectively, and ATRX has 5 from lower-grade gliomas. Mutations in 11 genes, including PARP1, BRCA1, and BAP1, were experimentally validated for splice-site-creating function. Notably, we found that neoantigens induced by SCMs are likely several folds more immunogenic compared to missense mutations, exemplified by the recurrent GATA3 SCM. Further, high expression of PD-1 and PD-L1 was observed in tumors with SCMs, suggesting candidates for immune blockade therapy. Our work highlights the importance of integrating DNA and RNA data for understanding the functional and the clinical implications of mutations in human diseases. PMID- 29617667 TI - Somatic Mutational Landscape of Splicing Factor Genes and Their Functional Consequences across 33 Cancer Types. AB - Hotspot mutations in splicing factor genes have been recently reported at high frequency in hematological malignancies, suggesting the importance of RNA splicing in cancer. We analyzed whole-exome sequencing data across 33 tumor types in The Cancer Genome Atlas (TCGA), and we identified 119 splicing factor genes with significant non-silent mutation patterns, including mutation over representation, recurrent loss of function (tumor suppressor-like), or hotspot mutation profile (oncogene-like). Furthermore, RNA sequencing analysis revealed altered splicing events associated with selected splicing factor mutations. In addition, we were able to identify common gene pathway profiles associated with the presence of these mutations. Our analysis suggests that somatic alteration of genes involved in the RNA-splicing process is common in cancer and may represent an underappreciated hallmark of tumorigenesis. PMID- 29617702 TI - Expression and Clinical Implication of Autophagy-Associated Protein p62 in Osteosarcoma. AB - PURPOSE: Recent studies highlight the role of autophagy in cancer tumorigenesis, recurrence, metastasis, and chemoresistance. p62 is an adapter protein that is crucial for the autophagy pathway. In this study, we will describe the expression of p62 and its correlation with clinic prognosis in osteosarcoma. METHODS: Western blot was used to test the expression of p62 in osteosarcoma cell lines (U2OS, KHOS, MG63, Saos-2, U2OSR2, KHOSR2, and 143B). A tissue microarray (TMA) was analyzed by immunohistochemistry to determine the expression levels of p62 in osteosarcoma patients and evaluate any correlation between p62 and clinical characteristics in osteosarcoma patients. RESULTS: p62 was expressed differently in all cell lines. The TMA also showed differential expression in osteosarcoma tissues. Seventy-five of 79 (94.9%) patient tissues exhibited p62 immunostaining, ranging from no staining (4 of 97, 5.1%) to 1+ staining (40 of 79, 50.6%), 2+ staining (17 of 79, 21.5%), and 3+ staining (18 of 79, 22.8%). The low staining (1+) was classified as the p62 weak group (50.6%), the medium staining (2+) and intense staining (3+) were classified as the p62 strong group (44.3%). Analyzing the clinical data of the osteosarcoma TMA, we found that the 5-year survival rate of patients with weak p62 expression was significantly lower than that of the patients with strong p62 expression (p = 0.0165). Furthermore, the decreased p62 expression may be associated with higher metastatic and chemoresistant rates in osteosarcoma patients. CONCLUSION: Our results suggest that p62 may be an effective predictor of prognosis and a potential target for therapy in osteosarcoma. PMID- 29617669 TI - The Cancer Genome Atlas Comprehensive Molecular Characterization of Renal Cell Carcinoma. AB - Renal cell carcinoma (RCC) is not a single disease, but several histologically defined cancers with different genetic drivers, clinical courses, and therapeutic responses. The current study evaluated 843 RCC from the three major histologic subtypes, including 488 clear cell RCC, 274 papillary RCC, and 81 chromophobe RCC. Comprehensive genomic and phenotypic analysis of the RCC subtypes reveals distinctive features of each subtype that provide the foundation for the development of subtype-specific therapeutic and management strategies for patients affected with these cancers. Somatic alteration of BAP1, PBRM1, and PTEN and altered metabolic pathways correlated with subtype-specific decreased survival, while CDKN2A alteration, increased DNA hypermethylation, and increases in the immune-related Th2 gene expression signature correlated with decreased survival within all major histologic subtypes. CIMP-RCC demonstrated an increased immune signature, and a uniform and distinct metabolic expression pattern identified a subset of metabolically divergent (MD) ChRCC that associated with extremely poor survival. PMID- 29617668 TI - Pan-Cancer Analysis of lncRNA Regulation Supports Their Targeting of Cancer Genes in Each Tumor Context. AB - Long noncoding RNAs (lncRNAs) are commonly dysregulated in tumors, but only a handful are known to play pathophysiological roles in cancer. We inferred lncRNAs that dysregulate cancer pathways, oncogenes, and tumor suppressors (cancer genes) by modeling their effects on the activity of transcription factors, RNA-binding proteins, and microRNAs in 5,185 TCGA tumors and 1,019 ENCODE assays. Our predictions included hundreds of candidate onco- and tumor-suppressor lncRNAs (cancer lncRNAs) whose somatic alterations account for the dysregulation of dozens of cancer genes and pathways in each of 14 tumor contexts. To demonstrate proof of concept, we showed that perturbations targeting OIP5-AS1 (an inferred tumor suppressor) and TUG1 and WT1-AS (inferred onco-lncRNAs) dysregulated cancer genes and altered proliferation of breast and gynecologic cancer cells. Our analysis indicates that, although most lncRNAs are dysregulated in a tumor specific manner, some, including OIP5-AS1, TUG1, NEAT1, MEG3, and TSIX, synergistically dysregulate cancer pathways in multiple tumor contexts. PMID- 29617703 TI - Effects of ovarian hormone loss on neuritic plaques and autophagic flux in the brains of adult female APP/PS1 double-transgenic mice. AB - Epidemiologic studies have demonstrated that women account for two-thirds of Alzheimer's disease (AD) cases, for which the decline in circulating gonadal hormone is considered to be one of the major risk factors. In addition, ovarian hormone deficiency may affect beta-amyloid (Abeta) deposition, which has a close relationship with autophagic flux. In this study, we investigated the impact of short-term or long-term ovarian hormone deprivation on two mouse models, the non transgenic (wild-type) and the APP/PS1 double-transgenic AD (2*TgAD) model. Autophagy-related proteins (Beclin1, LC3, and p62) and lysosome-related proteins were detected to evaluate Abeta deposition and autophagy. Our results showed that in the group with short-term depletion of ovarian hormones by ovariectomy (ovx), Beclin1, Cathepsin B (Cath-B), and LAMP1 levels were significantly decreased, while the levels of LC3-II and p62 were increased. In the long-term group, however, there was a sharp decline in Beclin1, LC3-II, Cath-B, and LAMP1 expression but not in p62 expression which is increased. It is worthwhile to note that the occurrence of neuritic plaque-induced ovarian hormone loss increased both the Abeta level and neuritic plaque deposition in 2*TgAD mice. Therefore, autophagy may play an important role in the pathogenesis of female AD, which is also expected to help post-menopausal patients with AD. PMID- 29617705 TI - Declining Financial Capacity in Mild Cognitive Impairment: A Six-Year Longitudinal Study. AB - Objective: To investigate financial skill decline over a 6-year period in persons with mild cognitive impairment (MCI) presumed due to Alzheimer's disease (AD). Methods: Study participants were cognitively normal (CN) older adults (n = 82) and adults with MCI (n = 91) based on consensus conference diagnosis. Participants completed baseline and up to six annual follow-up assessments that included standardized financial skills measurement (Financial Capacity Instrument; FCI; nine FCI domain and two global scores). We examined FCI change over time using mixed-model repeated measures analysis adjusted for baseline age and follow-up duration. Results: At baseline, the CN group performed better than the MCI group across both global and seven domain scores. Group * Time interaction effects (all p's <.02) were found for all global and domain scores. The largest interaction effects were observed for complex domains of Financial Conceptual Knowledge, Checkbook Management, Bank Statement Management, and Bill Payment (all p's <.0001). Annualized decline in the MCI group's global scores, calculated in relation to CN group performance, was 10-17% over the initial 3 year time span and 22-24% at 6 years. Decline in FCI domain scores ranged from 6% (Knowledge of Assets/Estate) to 22% (Investment Decision-Making) at 3 year follow up, and from 15% (Basic Monetary Skills) to 37% (Financial Judgment) at 6 year follow-up. Conclusions: Over a 6-year period, persons with MCI demonstrated significant declines in multiple financial skills and in particular financial judgment. The findings highlight the importance of ongoing oversight by family members and clinicians of financial skills and activities in persons with MCI. PMID- 29617707 TI - Changes in Body Mass Index and Physical Activity Predict Changes in Vitality During a Weight Loss Trial in Breast Cancer Survivors. AB - Background: Breast cancer survivors rank fatigue (e.g., decreased vitality) as their number one concern affecting quality of life. Excess adiposity is associated with decreased vitality in breast cancer survivors, yet weight loss intervention trials report inconsistent effects on this parameter. Methods: This is a secondary analysis of the Exercise and Nutrition to Enhance Recovery and Good Health for You trial, in which 692 overweight or obese breast cancer survivors <=5 years from diagnosis, initiated weight loss interventions, and completed assessments semi-annually for 2 years. Assessments included the Godin Leisure-Time Exercise Questionnaire and the SF-36 MOS vitality subscale as an inverse measure of fatigue. Multilevel structural equation models estimated the direct effects of physical activity on vitality and indirect effects through body mass index (BMI) changes. Results: Within-person findings show that at assessments with greater physical activity, BMI was significantly lower (B = 0.07, p < 0.001) and vitality was higher (B = 0.22, p < 0.001). However, there was no direct relationship between lower BMI and higher vitality (B = -0.11, p = 0.262) after controlling for the relationship of physical activity with BMI and physical activity with vitality. The between-person indirect effect of physical activity change through BMI change to vitality was significant (B = 0.03, p < 0.001). Participants whose physical activity was above the mean (B = 0.37, p < 0.001) and whose BMI was below the mean (B = -1.05, p < 0.001) were more likely to report greater vitality. Conclusion: Improvements in vitality are primarily associated with increases in physical activity rather than BMI changes in this trial. Vitality was lower among survivors with higher BMI, although within individual changes in BMI had no effect on vitality. Physical activity and weight loss share mechanistic links to vitality with physical activity potentially increasing (e.g., in an additive or synergistic manner) the effect of BMI reduction on vitality. PMID- 29617706 TI - Perseverative Cognitions and Stress Exposure: Comparing Relationships With Psychological Health Across a Diverse Adult Sample. AB - Background: Both exposure to stress and perseverative cognitions (PCs)-repetitive cognitive representations of real or imagined stressors-are linked with poor psychological health. Yet, stress exposure and PCs are correlated, thus potentially obscuring any unique effects. Purpose: The purpose of this paper is to concurrently test associations between stress exposure and PCs and psychological health to examine the independent relationship of each with psychological health. Moreover, we examined whether these relationships are similar across sex, age, and race. Methods: An adult community sample (n = 302) completed a measure of stress exposure, three PCs scales, and questionnaires assessing self-reported psychological health, including emotional well-being, vitality, social functioning, role limitations due to personal problems, subjective well-being, depressive symptoms, and poor sleep quality. Results: Structural equation modeling was used to test a model in which both stress exposure and PCs predict psychological health. PCs consistently predicted all the psychological health outcomes, but stress was largely unrelated to the outcomes despite bivariate correlations suggesting a relationship. A follow-up model identified indirect effects of stress exposure on psychological health via PCs. Results were fairly consistent regardless of one's sex, age, or race. Conclusions: PCs robustly predicted all of the psychological health outcomes, intimating PCs as a common pathway to poor psychological health. Results have implications for stress interventions, including the need to address PCs after experiencing stress. PMID- 29617704 TI - Expectancy Effects on Self-Reported Attention-Deficit/Hyperactivity Disorder Symptoms in Simulated Neurofeedback: A Pilot Study. AB - Objective: Expectancy is a psychological factor that can impact treatment effectiveness. Research on neurofeedback for attention-deficit/hyperactivity disorder (ADHD) suggests expectancy may contribute to treatment outcomes, though evidence for expectancy as an explanatory factor is sparse. This pilot study investigated the effects of expectancies on self-reported ADHD symptoms in simulated neurofeedback. Method: Forty-six adults who were concerned that they had ADHD expected to receive active neurofeedback, but were randomly assigned to receive a placebo with false feedback indicating attentive (positive false feedback) or inattentive (negative false feedback) states. Effects of the expectancy manipulation were measured on an ADHD self-report scale. Results: Large expectancy effects were found, such that individuals who received positive false feedback reported significant decreases in ADHD symptoms, whereas individuals who received negative false feedback reported significant increases in ADHD symptoms. Conclusions: Findings suggest that expectancy should be considered as an explanatory mechanism for ADHD symptom change in response to neurofeedback. PMID- 29617708 TI - A Systematic Review of the Neuropsychological Sequelae of People Diagnosed with Anti N-Methyl-D-Aspartate Receptor Encephalitis in the Acute and Chronic Phases. AB - Objective: A systematic review was conducted to investigate the emerging cognitive profile for people diagnosed with anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis. Method: Ten papers met the review criteria including five neuropsychological case studies and five case series; three of the 10 studies used matched controls. The cognitive functioning of 54 participants (46 female: eight male) was studied. Paper quality assessment was undertaken and outcomes summarized. Neuropsychological results during the acute phase (<=12 months) and chronic phase (>12 months) were extracted and a narrative review of the papers' findings undertaken. Results: A range of neuropsychological test batteries were used across the studies, administered between one and four times. The review revealed difficulties with memory, particularly delayed verbal memory, and executive functioning. This may be consistent with the role of NMDA receptors in the limbic system, specifically the hippocampus, which are thought to be essential to aspects of learning and memory. Conclusions: To date, there is a paucity of high quality neuropsychological and psychological research concerning the impact of anti-NMDAR encephalitis on cognitive function and psychosocial wellbeing, both of adults and particularly of those under 18 years. Significant limitations of the literature reviewed include lack of attention to pre-morbid functioning, insufficient rationale for neuropsychological battery choice, use of samples of convenience, and limited translation of neuropsychological findings into rehabilitation. Limitations of this review include exclusive focus on an adult population and the necessity of a narrative review given the methodological diversity in studies making up the evidence base. PMID- 29617711 TI - Predictors of Alcohol Withdrawal Readmissions. AB - Aims: Hospital readmissions serve as a major benchmark for the quality of care and alcohol withdrawal (AW) may lead to multiple hospitalizations and readmissions. We sought to evaluate readmission rates and predictors of having AW related readmissions in a nationally representative sample. Short summary: In a nationally representative sample, AW readmission within 30 days and multiple readmissions during the year were high and were particularly predicted by discharge against medical advice (AMA), comorbid psychosis, comorbid depression, poor socioeconomic status, comorbid drug abuse and alcohol-related medical disease. Methods: Subjects from the 2013 Nationwide Readmissions Database (NRD) with AW as a primary or secondary diagnosis. Cross-sectional and retrospective analyses were performed using regression methods appropriate for the NRD complex sampling design. The outcome measures were AW-related readmission, 30-day readmission and multiple readmissions. Results: In 2013, 393,118 discharges involved ICD-9 coding for AW and 41.5% of these included AW as the primary discharge diagnosis. The rate of AW-related readmission in 2013, as estimated from first-quarter index events, was 58.8% (95% confidence interval (CI) 57.5 60.1), with an average of 1.8 readmissions (95% CI 1.7-1.9). The 30-day readmission rate, estimated from January-November index events, was 19.7% (95% CI 19.0-20.4). The strongest independent predictors of yearly, 30-day and multiple readmission were discharged AMA and comorbid psychotic disorder. Conclusion: AW readmission within 30 days and multiple readmissions during the year were common and were particularly predicted by AMA discharge and comorbid psychotic disorder. While these and other factors can help identify high-risk patients, further study to determine causal mechanisms may aid efforts to improve both the outcomes and costs associated with acute AW treatment. PMID- 29617710 TI - Negative association of antibiotics on clinical activity of immune checkpoint inhibitors in patients with advanced renal cell and non-small-cell lung cancer. AB - Background: The composition of gut microbiota affects antitumor immune responses, preclinical and clinical outcome following immune checkpoint inhibitors (ICI) in cancer. Antibiotics (ATB) alter gut microbiota diversity and composition leading to dysbiosis, which may affect effectiveness of ICI. Patients and methods: We examined patients with advanced renal cell carcinoma (RCC) and non-small-cell lung cancer (NSCLC) treated with anti-programmed cell death ligand-1 mAb monotherapy or combination at two academic institutions. Those receiving ATB within 30 days of beginning ICI were compared with those who did not. Objective response, progression-free survival (PFS) determined by RECIST1.1 and overall survival (OS) were assessed. Results: Sixteen of 121 (13%) RCC patients and 48 of 239 (20%) NSCLC patients received ATB. The most common ATB were beta-lactam or quinolones for pneumonia or urinary tract infections. In RCC patients, ATB compared with no ATB was associated with increased risk of primary progressive disease (PD) (75% versus 22%, P < 0.01), shorter PFS [median 1.9 versus 7.4 months, hazard ratio (HR) 3.1, 95% confidence interval (CI) 1.4-6.9, P < 0.01], and shorter OS (median 17.3 versus 30.6 months, HR 3.5, 95% CI 1.1-10.8, P = 0.03). In NSCLC patients, ATB was associated with similar rates of primary PD (52% versus 43%, P = 0.26) but decreased PFS (median 1.9 versus 3.8 months, HR 1.5, 95% CI 1.0-2.2, P = 0.03) and OS (median 7.9 versus 24.6 months, HR 4.4, 95% CI 2.6-7.7, P < 0.01). In multivariate analyses, the impact of ATB remained significant for PFS in RCC and for OS in NSCLC. Conclusion: ATB were associated with reduced clinical benefit from ICI in RCC and NSCLC. Modulatation of ATB related dysbiosis and gut microbiota composition may be a strategy to improve clinical outcomes with ICI. PMID- 29617709 TI - What Happens After Treatment? Long-Term Effects of Continued Substance Use, Psychiatric Problems and Help-Seeking on Social Status of Alcohol-Dependent Individuals. AB - Purpose: We examined whether alcohol-dependent individuals with sustained substance use or psychiatric problems after completing treatment were more likely to experience low social status and whether continued help-seeking would improve outcomes. Short summary: Ongoing alcohol, drug and psychiatric problems after completing treatment were associated with increased odds of low social status (unemployment, unstable housing and/or living in high-poverty neighborhood) over 7 years. The impact of drug problems declined over time, and there were small, delayed benefits of AA attendance on social status. Method: Alcohol-dependent individuals sampled from public and private treatment programs (N = 491; 62% male) in Northern California were interviewed at treatment entry and 1, 3, 5 and 7 years later. Random effects models tested relationships between problem severity (alcohol, drug and psychiatric problems) and help-seeking (attending specialty alcohol/drug treatment and Alcoholics Anonymous, AA) with low social status (unemployment, unstable housing and/or living in a high-poverty neighborhood) over time. Results: The proportion of participants experiencing none of the indicators of low social status increased between baseline and the 1 year follow-up and remained stable thereafter. Higher alcohol problem scores and having any drug and/or psychiatric problems in the years after treatment were associated with increased odds of low social status over time. An interaction of drug problems with time indicated the impact of drug problems on social status declined over the 7-year period. Both treatment-seeking and AA attendance were associated with increased odds of low social status, although lagged models suggested there were small, delayed benefits of AA attendance on improved social status over time. Conclusion: Specialty addiction treatment alone was not sufficient to have positive long-term impacts on social status and social integration of most alcohol-dependent people. PMID- 29617713 TI - Bevacizumab may improve quality of life, but not overall survival in glioblastoma: an epidemiological study. AB - Background: The vascular endothelial growth factor antibody bevacizumab (Avastin(r)), received approval for the treatment of recurrent glioblastoma in many countries including the USA and Switzerland, but not the European Union, in 2009. Here, we explored the hypothesis that the approval of bevacizumab improved outcome with glioblastoma on a population level. Patients and methods: The prognostic significance of epidemiological, molecular genetic, and clinical data including treatment for glioblastoma patients diagnosed from 2010 to 2014 in the Canton of Zurich, Switzerland, was retrospectively analyzed using log-rank test and Cox proportional hazards models. Data were compared with data for the years 2005-2009. Results: In total, 310 glioblastoma patients were identified in the years 2010-2014. Median overall survival was 13.5 months for patients with known isocitrate dehydrogenase (IDH) wild-type (wt) (IDH1R132H-non-mutant) tumors (N = 248), compared with 11.3 months for IDH wt patients (P = 0.761) before (2005 2009). In the IDH wt cohort, bevacizumab use at any time increased from 19% in 2005-2009 to 49% in 2010-2014. Multivariate analysis did not identify bevacizumab exposure at any time to be associated with survival. Yet, upon the second-line treatment, baseline doses of corticosteroids were reduced by more than half in 83% of patients on bevacizumab compared with 48% of the patients treated with bevacizumab-free regimens (P = 0.007). Conclusion: This epidemiological study of a small, but clinically well-annotated patient cohort fails to support the assumption that the strong increase of bevacizumab use since 2010 improved survival in glioblastoma although clinical benefit associated with decreased steroid use may have been achieved. PMID- 29617712 TI - Oral bisphosphonate use and lung cancer incidence among postmenopausal women. AB - Background: Bisphosphonates are common medications for the treatment of osteoporosis in older populations. Several studies, including the Women's Health Initiative (WHI), have found inverse associations of bisphosphonate use with risk of breast and endometrial cancer, but little is known about its association with other common malignancies. The objective of this study was to evaluate the association of bisphosphonate use on the incidence of lung cancer in the WHI. Patients and methods: The association between oral bisphosphonate use and lung cancer risk was examined in 151 432 postmenopausal women enrolled into the WHI in 1993-1998. At baseline and during follow-up, participants completed an inventory of regularly used medications including bisphosphonates. Results: After a mean follow-up of 13.3 years, 2511 women were diagnosed with incident lung cancer. There was no evidence of a difference in lung cancer incidence between oral bisphosphonate users and never users (adjusted hazard ratio = 0.91; 95% confidence intervals, 0.80-1.04; P = 0.16). However, an inverse association was observed among those who were never smokers (hazard ratio = 0.57, 95% confidence interval, 0.39-0.84; P < 0.01). Conclusion: In this large prospective cohort of postmenopausal women, oral bisphosphonate use was associated with significantly lower lung cancer risk among never smokers, suggesting bisphosphonates may have a protective effect against lung cancer. Additional studies are needed to confirm our findings. PMID- 29617714 TI - Transcriptome profiling of genes involving in carotenoid biosynthesis and accumulation between leaf and root of carrot (Daucus carota L.). AB - Carrot provides abundant carotenoid for human diet and is one of the most widely cultivated root vegetables in the world. However, the absence of the tissue specific transcriptome of carrots hampers the investigation of the association of secondary metabolic mechanism with the different tissue types. In this study, we obtained 46,119,008/48,414,508 raw reads and 45,394,846/47,887,648 clean reads from the carrot leaf and root, respectively. Moreover, alpha- and beta-carotene were found to accumulate in both tissues. Then, using Trinity assembly into contigs and mapped back to contigs, these reads were assembled to 56,267 and 62,427 leaf and root unigenes, respectively, after Ns removal and paired-end extension. In addition, a total of 18,354 DEGs were found between the carrot leaf and root unigenes, and 99 of these DEGs were found to be involved in carotenoid biosynthesis as revealed by integrated function annotation. In the carotenoid pathway DEGs, DcPSY1, DcZ-ISO, DcCISO2, DcLBCY, DcLECY, DcZEP1, DcZEP2, DcVDE1, DcVDE2, DcNSY1, DcNSY2, DcA8H-CYP707A1.2, DcAAO3a, DcCCD4, and DcMAX1 were expressed dramatically in the carrot leaf compared with in the root. This result was consistent with the results from the quantitative real-time PCR analysis of DEG expression profiles. Moreover, 67 more carotenoid biosynthesis-related genes were found in this transcriptome database. Most of these DEGs were up-regulated in the carrot leaf compared with those in the root. The expression of DEGs may be related to the higher carotenoid pathway flux in the carrot leaf than in the root. These results will help to further understand the carotenoid biosynthesis in carrot. PMID- 29617715 TI - New horizons in systemic anti-cancer therapy in older people. AB - Cancer is a disease associated with ageing. Increased life expectancy means that cancer in older adults is becoming an increasingly common problem. There are unique issues to consider when making decisions about cancer treatment in older populations. Unfortunately, however, this group is still under-represented in clinical trials for new cancer therapies meaning there are less evidence-based data to guide management. This article aims to look at how we can optimise the cancer treatment for older patients with a focus on systemic anti-cancer therapy and addressing particular issues around patient selection, improving treatment tolerance and use of newer agents with different toxicity profiles. PMID- 29617716 TI - Corrigendum: Screening for At-Risk Alcohol Consumption in Primary Care: A Randomized Evaluation of Screening Approaches. PMID- 29617717 TI - Adding a new analytical procedure with clinical interpretation in the tool box of survival analysis. PMID- 29617718 TI - Genetic counselling in the era of genomic medicine. AB - Background: Genomic technology can now deliver cost effective, targeted diagnosis and treatment for patients. Genetic counselling is a communication process empowering patients and families to make autonomous decisions and effectively use new genetic information. The skills of genetic counselling and expertise of genetic counsellors are integral to the effective implementation of genomic medicine. Sources of data: Original papers, reviews, guidelines, policy papers and web-resources. Areas of agreement: An international consensus on the definition of genetic counselling. Genetic counselling is necessary for implementation of genomic medicine. Areas of controversy: Models of genetic counselling. Growing points: Genomic medicine is a growing and strategic priority for many health care systems. Genetic counselling is part of this. Areas timely for developing research: An evidence base is necessary, incorporating implementation and outcome research, to enable health care systems, practitioners, patients and families to maximize the utility (medically and psychologically) of the new genomic possibilities. PMID- 29617719 TI - Platelet-Rich Plasma, Adipose Tissue, and Scar Modulation. AB - Level of Evidence: 4. PMID- 29617720 TI - A decade of genome-wide association studies for coronary artery disease: the challenges ahead. AB - In this review, we summarize current knowledge on the genetics of coronary artery disease, based on 10 years of genome-wide association studies. The discoveries began with individual studies using 200K single nucleotide polymorphism arrays and progressed to large-scale collaborative efforts, involving more than a 100 000 people and up to 40 Mio genetic variants. We discuss the challenges ahead, including those involved in identifying causal genes and deciphering the links between risk variants and disease pathology. We also describe novel insights into disease biology based on the findings of genome-wide association studies. Moreover, we discuss the potential for discovery of novel treatment targets through the integration of different layers of 'omics' data and the application of systems genetics approaches. Finally, we provide a brief outlook on the potential for precision medicine to be enhanced by genome-wide association study findings in the cardiovascular field. PMID- 29617721 TI - Gender, Work, and Health. PMID- 29617722 TI - PCSK9 regulates expression of scavenger receptors and ox-LDL uptake in macrophages. AB - Aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) has been shown to influence macrophage biology and modulate atherogenesis. We conducted this study to examine the regulation of scavenger receptors (SRs) (LOX-1, SRA, and CD36) and oxidized liporoptein cholesterol (ox-LDL) uptake in macrophages by PCSK9. Methods and results: Treatment of mouse peritoneal macrophages with tumour necrosis factor alpha (TNF-alpha) resulted in concentration-dependent modest, but significant, increase in PCSK9 expression. Importantly, treatment of TNF-alpha primed macrophages with recombinant murine PCSK9 increased the expression of LOX 1, SRA, and CD36 2-5 fold, and enhanced ox-LDL uptake by ~five-fold. The increase in LOX-1 was much greater than in SRA or CD36. PCSK9 inhibition (by siRNA transfection or use of macrophages from PCSK9-/- mice) reduced the expression of SRs (LOX-1 ? SRA or CD36). Ox-LDL uptake in response to PCSK9 was also inhibited in macrophages from LOX-1-/- mice (P < 0.05 vs. macrophages from SRA-/- and CD36 /- mice). Upregulation of PCSK9 by cDNA transfection induced intense ox-LDL uptake which was inhibited by co-transfection of cells with siRNA LOX-1 (P < 0.05 vs. siRNA SRA or siRNA CD36). Further, TNF-alpha-mediated PCSK9 upregulation and subsequent expression of SRs and ox-LDL uptake were reduced in macrophages from gp91phox-/-, p47phox-/- and p22phox-/- mice (vs. macrophages from wild-type mice). Conclusions: This study shows that in an inflammatory milieu, elevated levels of PCSK9 potently stimulate the expression of SRs (principally LOX-1) and ox-LDL uptake in macrophages, and thus contribute to the process of atherogenesis. PMID- 29617723 TI - Perceptual unity in the split brain: the role of subcortical connections. PMID- 29617724 TI - Nanopore sequencing technology and tools for genome assembly: computational analysis of the current state, bottlenecks and future directions. AB - Nanopore sequencing technology has the potential to render other sequencing technologies obsolete with its ability to generate long reads and provide portability. However, high error rates of the technology pose a challenge while generating accurate genome assemblies. The tools used for nanopore sequence analysis are of critical importance, as they should overcome the high error rates of the technology. Our goal in this work is to comprehensively analyze current publicly available tools for nanopore sequence analysis to understand their advantages, disadvantages and performance bottlenecks. It is important to understand where the current tools do not perform well to develop better tools. To this end, we (1) analyze the multiple steps and the associated tools in the genome assembly pipeline using nanopore sequence data, and (2) provide guidelines for determining the appropriate tools for each step. Based on our analyses, we make four key observations: (1) the choice of the tool for basecalling plays a critical role in overcoming the high error rates of nanopore sequencing technology. (2) Read-to-read overlap finding tools, GraphMap and Minimap, perform similarly in terms of accuracy. However, Minimap has a lower memory usage, and it is faster than GraphMap. (3) There is a trade-off between accuracy and performance when deciding on the appropriate tool for the assembly step. The fast but less accurate assembler Miniasm can be used for quick initial assembly, and further polishing can be applied on top of it to increase the accuracy, which leads to faster overall assembly. (4) The state-of-the-art polishing tool, Racon, generates high-quality consensus sequences while providing a significant speedup over another polishing tool, Nanopolish. We analyze various combinations of different tools and expose the trade-offs between accuracy, performance, memory usage and scalability. We conclude that our observations can guide researchers and practitioners in making conscious and effective choices for each step of the genome assembly pipeline using nanopore sequence data. Also, with the help of bottlenecks we have found, developers can improve the current tools or build new ones that are both accurate and fast, to overcome the high error rates of the nanopore sequencing technology. PMID- 29617725 TI - Corrigendum. PMID- 29617727 TI - A survey and evaluation of Web-based tools/databases for variant analysis of TCGA data. AB - The Cancer Genome Atlas (TCGA) is a publicly funded project that aims to catalog and discover major cancer-causing genomic alterations with the goal of creating a comprehensive 'atlas' of cancer genomic profiles. The availability of this genome wide information provides an unprecedented opportunity to expand our knowledge of tumourigenesis. Computational analytics and mining are frequently used as effective tools for exploring this byzantine series of biological and biomedical data. However, some of the more advanced computational tools are often difficult to understand or use, thereby limiting their application by scientists who do not have a strong computational background. Hence, it is of great importance to build user-friendly interfaces that allow both computational scientists and life scientists without a computational background to gain greater biological and medical insights. To that end, this survey was designed to systematically present available Web-based tools and facilitate the use TCGA data for cancer research. PMID- 29617728 TI - Commentary on: The Top 100 Social Media Influencers in Plastic Surgery on Twitter: Who Should You Be Following? PMID- 29617726 TI - No association between circulating concentrations of vitamin D and risk of lung cancer: an analysis in 20 prospective studies in the Lung Cancer Cohort Consortium (LC3). AB - Background: There is observational evidence suggesting that high vitamin D concentrations may protect against lung cancer. To investigate this hypothesis in detail, we measured circulating vitamin D concentrations in prediagnostic blood from 20 cohorts participating in the Lung Cancer Cohort Consortium (LC3). Patients and methods: The study included 5313 lung cancer cases and 5313 controls. Blood samples for the cases were collected, on average, 5 years before lung cancer diagnosis. Controls were individually matched to the cases by cohort, sex, age, race/ethnicity, date of blood collection, and smoking status in five categories. Liquid chromatography coupled with tandem mass spectrometry was used to separately analyze 25-hydroxyvitamin D2 [25(OH)D2] and 25-hydroxyvitamin D3 [25(OH)D3] and their concentrations were combined to give an overall measure of 25(OH)D. We used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for 25(OH)D as both continuous and categorical variables. Results: Overall, no apparent association between 25(OH)D and risk of lung cancer was observed (multivariable adjusted OR for a doubling in concentration: 0.98, 95% CI: 0.91, 1.06). Similarly, we found no clear evidence of interaction by cohort, sex, age, smoking status, or histology. Conclusion: This study did not support an association between vitamin D concentrations and lung cancer risk. PMID- 29617729 TI - Statin use linked with a decrease in the conversion from high-grade prostatic intraepithelial neoplasia (HGPIN) to prostate cancer. AB - The roles of obesity, metabolic dysregulation and systemic inflammation to advance prostate carcinogenesis are unclear. This study investigates metabolic and inflammatory factors in the transition from high-grade prostatic intraepithelial neoplasia (HGPIN) to prostate cancer (PC). We prospectively followed 160 men diagnosed with HGPIN at biopsy and therefore at high-risk and clinically monitored for PC. Analyses investigated body mass index (BMI), waist circumference, waist-hip ratio (WHR), height, fat mass, lean mass percent body fat, NSAIDs, statins, metformin, diabetes, hypertension, hypercholesterolemia representing metabolic dysregulation on the risk of a PC diagnosis during follow up. Systemic inflammation was estimated through measurement of 13 plasma cytokine levels. Statin use was significantly linked with overall PC at follow-up [odds ratio (OR) = 0.45, (0.23, 0.91), P = 0.03], with a somewhat stronger link with high-grade [OR = 0.39, (0.15, 1.04), P = 0.06] PC compared with low-grade PC [OR = 0.50, (0.23, 1.12), P = 0.09]. Non-statin cholesterol-lowering medications, BMI, WHR, diabetes, hypertension and percent body fat were not significantly associated with PC. Although blood IL-12p70, IL-2 and IL-1beta levels were significantly lower among statin users, inflammatory markers were not significantly linked with PC and did not explain the observed relationship between statins and lower PC risk. In summary, this prospective study of HGPIN patients at high risk for PC finds that statin use was significantly associated with reduced risk of PC detection at follow-up. Systemic markers of inflammation did not mediate this association, suggesting that statins affect PC progression through alternative pathways. PMID- 29617730 TI - Ovarian cancer therapeutic potential of glutamine depletion based on GS expression. AB - Amino acids (AAs) are biologically important nutrient compounds necessary for the survival of any cell. Of the 20 AAs, cancer cells depend on the uptake of several extracellular AAs for survival. However, which extracellular AA is indispensable for the survival of cancer cells and the molecular mechanism involved have not been fully defined. In this study, we found that the reduction of cell survival caused by glutamine (Gln) depletion is inversely correlated with the expression level of glutamine synthetase (GS) in ovarian cancer (OVC) cells. GS expression was downregulated in 45 of 316 OVC cases (14.2%). The depletion of extracellular Gln by treatment with l-asparaginase, in addition to inhibiting Gln uptake via the knockdown of a Gln transporter, led to the inhibition of cell growth in OVC cells with low expression of GS (GSlow-OVC cells). Furthermore, the re-expression of GS in GSlow-OVC cells induced the inhibition of tumor growth in vitro and in vivo. Thus, these findings provide novel insight into the development of an OVC therapy based on the requirement of Gln. PMID- 29617731 TI - Predicting serious rare adverse reactions of novel chemicals. AB - Motivation: Adverse drug reactions (ADRs) are one of the main causes of death and a major financial burden on the world's economy. Due to the limitations of the animal model, computational prediction of serious and rare ADRs is invaluable. However, current state-of-the-art computational methods do not yield significantly better predictions of rare ADRs than random guessing. Results: We present a novel method, based on the theory of 'compressed sensing' (CS), which can accurately predict serious side-effects of candidate and market drugs. Not only is our method able to infer new chemical-ADR associations using existing noisy, biased and incomplete databases, but our data also demonstrate that the accuracy of CS in predicting a serious ADR for a candidate drug increases with increasing knowledge of other ADRs associated with the drug. In practice, this means that as the candidate drug moves up the different stages of clinical trials, the prediction accuracy of our method will increase accordingly. Availability and implementation: The program is available at https://github.com/poleksic/side-effects. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29617734 TI - Reply to Walker et al. PMID- 29617732 TI - A new approach for comprehensively describing heterogametic sex chromosomes. AB - Notwithstanding the rapid developments in sequencing techniques, Y and W sex chromosomes have still been mostly excluded from whole genome sequencing projects due to their high repetitive DNA content. Therefore, Y and W chromosomes are poorly described in most species despite their biological importance. Several methods were developed for identifying Y or W-linked sequences among unmapped scaffolds. However, it is not enough to discover functional regions from short unmapped scaffolds. Here, we provide a new and simple strategy based on k-mer comparison for comprehensive analysis of the W chromosome in Bombyx mori. Using this novel method, we effectively assembled de novo 1281 W-derived genome contigs (totaling 1.9 Mbp), and identified 156 W-linked transcript RNAs and 345 W-linked small RNAs. This method will help in the elucidation of mechanisms of sexual development and exploration of W chromosome biological functions, and provide insights into the evolution of sex chromosomes. Moreover, we showed this method can be employed in identifying heterogametic sex chromosomes (W and Y chromosomes) in many other species where genomic information is still scarce. PMID- 29617735 TI - Direct-Acting Antivirals and Hepatitis C: The Ethics of Price and Rationing by Genotype. PMID- 29617733 TI - Reflux after esophagectomy with gastric conduit reconstruction in the posterior mediastinum for esophageal cancer: original questionnaire and EORTC QLQ-C30 survey. AB - Reflux following an esophagectomy with gastric conduit reconstruction in the posterior mediastinum is a clinically significant problem. In this study, we investigated the frequency and impact of reflux on the quality of life (QOL) among 158 patients who underwent an esophagectomy for esophageal cancer using an original questionnaire and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Version 3.0 (EORTC QLQ-C30). Reflux frequency was assessed using the original questionnaire. The number of patients who complained of reflux every day, two or three times a week, once a week, or less than once a week was 16 (10.1%), 21 (13.3%), 26 (16.5%), and 60 (38.0%), respectively. Out of 35 patients (22.2%) reported no reflux symptoms. Patients were divided into two groups: those with reflux >= once/week (63 patients) and those with low frequency of symptoms (95 patients). Time elapsed following surgery was the only factor to influence reflux frequency. Reflux frequency decreased within two years of surgery; however, the frequency plateaued after more than two years. QOL was assessed using the EORTC QLQ-C30. The >= once/week reflux group had a significantly lower global health status score than the low frequency reflux group (59.6 +/- 24.2 vs. 70.8 +/- 20.7; P = 0.007). In addition, the >= once/week reflux group had a significantly lower social functioning score than the low-frequency reflux group (81.6 +/- 24.1 vs. 88.4 +/- 19.8; P = 0.035). Regarding symptoms, the >= once/week reflux group had significantly higher scores for fatigue, nausea, and vomiting, dyspnea and insomnia compared to the low frequency reflux group (fatigue: 42.4 +/- 21.9 vs. 28.9 +/- 18.4, P < 0.001; nausea and vomiting: 17.3 +/- 17.1 vs. 4.9 +/- 10.6, P < 0. 001; dyspnea: 29.2 +/ 26.0 vs. 21.7 +/- 26.8, P = 0.043; insomnia: 22.2 +/- 31.1 vs. 10.5 +/- 21.7, P = 0.015). Thus, reflux after an esophagectomy was associated with a lower QOL. PMID- 29617736 TI - Cytomegalovirus DNAemia Burden and Mortality Following Allogeneic Hematopoietic Stem Cell Transplantation: An Area Under a Curve-Based Investigational Approach. PMID- 29617737 TI - Efficacy and Safety of Ivermectin Against Trichuris trichiura in Preschool-aged and School-aged Children: A Randomized Controlled Dose-finding Trial. AB - Background: Although trichuriasis affects millions of children worldwide, recommended drugs lack efficacy and new treatment options are urgently needed. Ivermectin has promising potential to complement the anthelminthic armamentarium. Methods: A randomized placebo-controlled trial was conducted in rural Cote d'Ivoire to provide evidence on the efficacy and safety of ascending oral ivermectin dosages in preschool-aged children (PSAC) and school-aged children (SAC) infected with Trichuris trichiura. The primary outcome was the cure rate (CR) for T. trichiura infection, and the secondary outcomes were safety, egg reduction rates (ERRs) against T. trichiura infection, and CRs and ERRs against other soil-transmitted helminth species. Results: A total of 126 PSAC and 166 SAC were included in an available case analysis. In PSAC, efficacy against T. trichiura did not differ between 200 ug/kg ivermectin and placebo treatment arm, as expressed in CRs (20.9% [95% confidence interval {CI}, 11.9%-52.8%] vs 19.5% [10.4%-49.9%]) and geometric mean ERRs (78.6% [60.1%-89.5%] vs 68.2% [40.5% 84.8%]). In SAC, the highest administered ivermectin dose of 600 ug/kg had a low CRs (12.2% [95% CI, 4.8%-32.3%]) and moderate ERRs (66.3% [43.8%-80.2%]). Only mild adverse events and no organ toxicity, based on serum biomarkers, was observed. Conclusion: Ivermectin can be administered safely to PSAC with trichuriasis. Given the low efficacy of ivermectin monotherapy against T. trichiura infection, further research should investigate the optimal drug combinations and dosages with ivermectin against soil-transmitted helminthiasis. Clinical Trials Registration: ISRCTN15871729 (www.isrctn.com). PMID- 29617738 TI - Reply to Chou and Trautner. PMID- 29617740 TI - Emotional Body Odors as Context: Effects on Cardiac and Subjective Responses. AB - Many studies have indicated that the chemical cues from body odors (BOs) of donors experiencing negative emotions can influence the psychophysiological and behavioral response of the observers. However, these olfactory cues have been used mainly as contextual information for processing visual stimuli. Here, for the first time, we evaluate how emotional BO affects the emotional tone of a subsequent BO message. Axillary sweat samples were taken from 20 donors in 3 separate sessions while they watched fear, disgust, or neutral videos. In a double-blind experiment, we assessed the cardiac and subjective responses from 69 participants who were either exposed to negative emotional or neutral BOs. Our results showed a reduced cardiac parasympathetic activity (HF%)-indicating increased stress-when participants smelled the emotional BOs before the neutral BOs, compared to when they smelled neutral followed by emotional BOs. The intensity of the neutral odor also increased following the exposure to both negative BOs. These findings indicate that BOs contain an emotion-dependent chemical cue that affects the perceiver both at the physiological and subjective levels. PMID- 29617739 TI - Results From a Randomized, Placebo-Controlled Clinical Trial of a RBX2660-A Microbiota-Based Drug for the Prevention of Recurrent Clostridium difficile Infection. AB - Background: Despite advancements, recurrent Clostridium difficile infections (CDI) remain an urgent public health threat with insufficient response rates to currently approved antibiotic therapies. Microbiota-based treatments appear effective, but rigorous clinical trials are required to optimize dosing strategies and substantiate long-term safety. Methods: This randomized, double blind, placebo-controlled phase 2B trial enrolled adults with 2 or more CDI recurrences to receive: 2 doses of RBX2660, a standardized microbiota-based drug (group A); 2doses of placebo (group B); or 1 dose of RBX2660 followed by 1 dose of placebo (group C). Efficacy was defined as prevention of recurrent CDI for 8 weeks following treatment. Participants who had a recurrence within 8 weeks were eligible to receive up to 2 open-label RBX2660 doses. The primary endpoint was efficacy for group A compared to group B. Secondary endpoints included the efficacy of group C compared to group B, combined efficacy in the blinded and open-label phases, and safety for 24 months. Results: The efficacy for groups A, B, and C were 61%, 45%, and 67%, respectively. The primary endpoint was not met (P = .152). One RBX2660 dose (group C) was superior to placebo (group B; P = .048), and the overall efficacy (including open-label response) for RBX2660 treated participants was 88.8%. Adverse events did not differ significantly among treatment groups. Conclusions: One, but not 2, doses of RBX2660 was superior to placebo in this randomized, placebo-controlled trial. These data provide important insights for a larger phase 3 trial and continued clinical development of RBX2660. Clinical Trials Registration: NCT02299570. PMID- 29617741 TI - Efficacy and Safety of short courses of antibiotic therapy for bacteremia caused by Enterobacteriaceae. PMID- 29617742 TI - A Statewide Antibiotic Stewardship Collaborative to Improve the Diagnosis and Treatment of Urinary Tract and Skin and Soft Tissue Infections. AB - Background: Colorado hospitals participated in a statewide collaborative to improve the management of inpatient urinary tract infections (UTIs) and skin and soft tissue infections (SSTIs). We evaluated the effects of the intervention on diagnostic accuracy and antibiotic use. Methods: The main collaborative outcomes were proportion of UTI diagnoses that met criteria for symptomatic UTI; exposure to fluoroquinolones (UTI only); duration of therapy (UTIs and SSTIs); and exposure to antibiotics with broad gram-negative activity (SSTIs only). Outcomes were compared between pre-intervention and intervention periods overall and by hospital. Secondary analyses were changes in outcome trends by time series analysis. Results: Twenty-six hospitals, including 9 critical access hospitals, participated in the collaborative. Data were reported for 4060 UTIs and 1759 SSTIs. Between the pre-intervention and intervention periods, the proportion of diagnosed UTIs that met criteria for symptomatic UTI was similar (51% vs 54%, respectively; P = .10), exposure to fluoroquinolones declined (49% vs 41%; P < .001), and the median duration of therapy was unchanged (7 vs 7 days; P = .99). Among SSTIs, exposure to antibiotics with broad gram-negative activity declined (61% vs 53%; P = .001) and the median duration of therapy declined (11 vs 10 days; P = .03). There was substantial variation in performance among hospitals. By time series analysis, only the declining trend of fluoroquinolone use was significant (P = .03). Conclusions: The collaborative model is a feasible approach to engage hospitals in a common antibiotic stewardship intervention. Performance improvement was observed for several outcomes but varied substantially by hospital. PMID- 29617743 TI - Head orthosis therapy in positional plagiocephaly: longitudinal 3D-investigation of long-term outcomes, compared with untreated infants and with a control group. AB - Background: As there are very few long-term studies on the effects of head orthosis on deformational plagiocephaly (DP), we investigated the outcomes of patients, including facial symmetry and dental occlusion. Methods: Forty-five infants with DP [cranial vault asymmetry index (CVAI) > 3.5 per cent] were divided into two groups: one treated with head orthosis (32 infants) and another without (13 infants). Another group without head asymmetry (CVAI <= 3.5 per cent) served as control. Using 3D-stereophotogrammetry, cranial asymmetry was analysed using symmetry-related variables [CVAI, posterior cranial asymmetry index (PCAI), and ear offset]. Data acquisition was performed before (T1) and at the end of treatment (T2), and at the age of 4 years (T3) for the treated group and at T1 and T3 for the remaining groups. Parameters of facial symmetry and dental occlusion were assessed at T3 for infants with DP. Results: Symmetry-related variables (?T1-T3) improved significantly more in the treated than the control group, whereas these parameters did not differ significantly between the untreated and control group. Comparing the treated and untreated groups between T1 and T3, the reduction in the asymmetry at the treated group was significantly higher for the CVAI and PCAI. In follow-up, the untreated group showed higher incidences of facial asymmetries than the treated group. Seventy-five per cent of all lateral crossbites found in patients with DP were contralateral to the posterior flattening. Limitations: Due to ethical reasons, the investigation is a non-randomized study. Parameters of facial symmetry were only assed for the treated and untreated groups. Conclusion: Head orthosis therapy in patients with DP leads to significantly better long-term outcomes. Facial asymmetries are more frequent in patients with DP who do not receive this treatment. PMID- 29617744 TI - Natural history of eosinophilic esophagitis: a systematic review of epidemiology and disease course. AB - Eosinophilic esophagitis is a chronic immune-mediated esophageal disorder. For its timely diagnosis, clinicians must recognize common symptoms, and understand differences in symptoms across patient groups. The aim of this study is to systematically review the epidemiology and natural history of eosinophilic esophagitis. The MEDLINE, Embase, and Cochrane databases were searched from 1974 to February 2017 for studies describing the epidemiology and natural history of eosinophilic esophagitis. Congress abstracts from 2014 to 2016 were also searched. Search results were screened against predetermined inclusion/exclusion criteria by two independent reviewers, and data extraction was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta Analyses guidelines. Of 1376 articles identified, 47 met the inclusion criteria: 20 on epidemiology and 27 on natural history. Incidence and prevalence of eosinophilic esophagitis varied widely across North America and Europe, and increased over time. Incidence increased 131-fold in the Netherlands (1996-2010), 20-fold in Denmark (1997-2006), and 5.1-fold in Calgary, Canada (2004-2008). The most commonly reported symptoms were emesis and abdominal pain in children, and dysphagia and food impaction in adults. Age at diagnosis was 5.9-12.0 years in children, and approximately 30 years in adults. Time between symptom onset and diagnosis was 1.2-3.5 years in children and 3.0-8.0 years in adults. Diagnostic delay was associated with an increased risk of endoscopic features of fibrostenosis. Symptoms of eosinophilic esophagitis differed significantly by age and race. In conclusion, there is an increasing incidence and prevalence of eosinophilic esophagitis. The considerable delay between symptom onset and diagnosis suggests that clinicians do not readily recognize the disease, which may have important clinical ramifications. PMID- 29617746 TI - Thoracoabdominal pressure gradient and gastroesophageal reflux: insights from lung transplant candidates. AB - Advanced lung disease is associated with gastroesophageal reflux disease (GERD). The thoracoabdominal pressure gradient (TAPG) facilitates gastroesophageal reflux, but the effects of TAPG on gastroesophageal reflux in patients with pulmonary disease have not been well defined. Patients diagnosed with end-stage lung disease are expected to have the most extreme derangement in respiratory mechanics. The aim of this study is to explore the relationship between TAPG and reflux in lung transplant (LTx) candidates. We reviewed LTx recipients who underwent pretransplant esophageal high-resolution manometry and a 24-hour pH study. Patients were excluded if they were undergoing redo LTx, had manometric hiatal hernia, or had previously undergone foregut surgery. TAPG was defined as the intra-abdominal pressure minus the intrathoracic pressure during inspiration. Adjusted TAPG was calculated by the TAPG minus the resting lower esophageal sphincter (LES) pressure (LESP). Twenty-two patients with normal esophageal function tests (i.e., normal esophageal motility with neither manometric hiatal hernia nor pathological reflux on 24-hour pH monitoring) were selected as the pulmonary disease-free control group. In total, 204 patients underwent LTx between January 2015 and December 2016. Of these, 77 patients met inclusion criteria. We compared patients with obstructive lung disease (OLD, n = 33; 42.9%) and those with restrictive lung disease (RLD, n = 42; 54.5%). 2/77 patients (2.6%) had pulmonary arterial hypertension. GERD was more common in the RLD group than in the OLD group (24.2% vs. 47.6%, P = 0.038). TAPG was similar between the OLD group and the controls (14.2 vs. 15.3 mmHg, P = 0.850); however, patients in the RLD group had significantly higher TAPG than the controls (24.4 vs. 15.3 mmHg, P = 0.002). Although TAPG was not correlated with GERD, the adjusted TAPG correlated with reflux in all 77 patients with end-stage lung disease (DeMeester score, rs = 0.256, P = 0.024; total reflux time, rs = 0.259, P = 0.023; total number of reflux episodes, rs = 0.268, P = 0.018). Additionally, pathological reflux was seen in 59.1% of lung transplant candidates with adjusted TAPG greater than 0 mmHg (i.e., TAPG exceeding LESP); GERD was seen in 30.9% of patients who had an adjusted TAPG <= 0 mmHg. In summary, TAPG varies based on the underlying cause of lung disease. Higher adjusted TAPG increases pathological reflux, even if patients have normal antireflux anatomy and physiology (i.e., no hiatal hernia and manometrically normal LES function). Adjusted TAPG may provide further insights into the pathophysiology of GERD. PMID- 29617745 TI - TISSUES 2.0: an integrative web resource on mammalian tissue expression. AB - Abstract: Physiological and molecular similarities between organisms make it possible to translate findings from simpler experimental systems-model organisms into more complex ones, such as human. This translation facilitates the understanding of biological processes under normal or disease conditions. Researchers aiming to identify the similarities and differences between organisms at the molecular level need resources collecting multi-organism tissue expression data. We have developed a database of gene-tissue associations in human, mouse, rat and pig by integrating multiple sources of evidence: transcriptomics covering all four species and proteomics (human only), manually curated and mined from the scientific literature. Through a scoring scheme, these associations are made comparable across all sources of evidence and across organisms. Furthermore, the scoring produces a confidence score assigned to each of the associations. The TISSUES database (version 2.0) is publicly accessible through a user-friendly web interface and as part of the STRING app for Cytoscape. In addition, we analyzed the agreement between datasets, across and within organisms, and identified that the agreement is mainly affected by the quality of the datasets rather than by the technologies used or organisms compared. Database URL: http://tissues.jensenlab.org/ PMID- 29617748 TI - CORRIGENDUM FOR "Sex- and Age-Specific Impact of ERK Loss Within the Pituitary Gonadotrope in Mice". PMID- 29617747 TI - Reply to letter: obesity and esophagectomy for esophageal cancer: is it only the high BMI that defines prognosis? PMID- 29617749 TI - Phenology of Honey Bee Swarm Departure in New Jersey, United States. AB - Departure of swarms from honey bee (Apis mellifera Linnaeus (Hymenoptera: Apidae)) nests is an important reproductive event for wild honey bee colonies and economically costly in managed bee colonies. The seasonal timing of swarm departure varies regionally and annually, creating challenges for honey bee management and emphasizing the potential for swarming behavior to be affected by plant-pollinator phenological mismatch. In this study, we first document variability in the timing of swarm departure across the large and heterogeneous geographical area of New Jersey over 4 years using 689 swarm-cluster observations. Second, hypothesizing that honey bee colonies adaptively tune the timing of swarm departure to match floral food-resource availability, we predicted that growing degree-days could be used to account for regional and annual variability. To test this idea, we used local weather records to determine the growing degree-day on which each swarm cluster was observed and tested for differences among climate regions and years. The state-wide mean swarm cluster date was May 15 (+/- 0.6 d), with moderate but significant differences among the state's five climate regions and between years. Use of degree-day information suggests that local heat accumulation can account for some climate-region differences in swarm-departure timing. Annual variation existed on a scale of only several days and was not accounted for by growing degree-days, suggesting little adaptive tuning of swarm-departure timing with respect to local heat accumulation. PMID- 29617751 TI - Behavioral Evidence for Host Transitions in Plant, Plant Parasite, and Insect Interactions. AB - Specialized herbivorous insects have the ability to transition between host plant taxa, and considering the co-evolutionary history between plants and the organisms utilizing them is important to understanding plant insect interactions. We investigated the role of a pine tree parasite, dwarf mistletoe (Arceuthobium spp.) M. Bieb. Santalales: Viscaceae, in mediating interactions between Neophasia (Lepidoptera: Pieridae) butterflies and pine trees, the butterflies' larval hosts. Mistletoe is considered the butterflies' ancestral host, and the evolutionary transition to pine may have occurred recently. In Arizona, United States, we studied six sites in pine forest habitats: three in Neophasia menapia (Felder and R. Felder, 1859) habitat and three in Neophasia terlooii Behr, 1869 habitat. Each site contained six stands of trees that varied in mistletoe infection severity. Butterfly behavior was observed and ranked at each stand. Volatile compounds were collected from trees at each site and analyzed using gas chromatography-mass spectroscopy. Female butterflies landed on or patrolled around pine trees (i.e., interacted) more than males, and N. terlooii interacted more with pine trees than N. menapia. Both butterfly species interacted more with tree stands harboring greater mistletoe infection, and N. terlooii interacted more with heavily infected tree stands than did N. menapia. The influence of mistletoe on Neophasia behavior may be mediated by differences in tree volatiles resulting from mistletoe infection. Volatile profiles significantly differed between infected and uninfected pine trees. The role of mistletoe in mediating butterfly interactions with pines has implications for conservation biology and forest management, and highlights the importance of understanding an organism's niche in an evolutionary context. PMID- 29617752 TI - Muscle layer thickness affects the peroral endoscopic myotomy procedure complexity. AB - Esophageal motility disorders can cause severe dysphagia, regurgitation, and/or noncardiac chest pain due to a lack of coordinated esophageal motility function. However, the clinical significance of esophageal muscle layer thickness remains unclear. The aims of this study are to elucidate the clinical significance of esophageal muscle layer thickness in patients with esophageal motility disorders who undergo peroral endoscopic myotomy (POEM), and to identify predictors of a longer POEM procedure time. Seventy-four consecutive patients with esophageal motility disorders who underwent POEM procedures at Kobe University Hospital from April 2015 to December 2016 were prospectively recruited into this study. First, we investigated the associations between the thickness of the esophageal muscular layer and clinical parameters. There were no significant differences, except in the POEM procedure time, between the patients with esophageal muscle layer thickness values of >=1.5 mm (group A) and <1.5 mm (group B). However, the relative frequency of a longer POEM procedure time (>=78 min) was significantly higher in group A than in group B (66.7% vs. 19.5, P < 0.0001). Next, independent clinical factors that were related to longer POEM procedures were investigated. Multivariate logistic regression analysis with stepwise selection demonstrated that a thick esophageal muscle layer and the length of myotomy were an independent predictor of a longer POEM procedure (odds ratio: 13.9 and 12.0, respectively). Our results indicate that preoperative endoscopic ultrasonography evaluations can help to predict the technical complexity of POEM procedures. PMID- 29617754 TI - Effects of Adult Feeding and Overwintering Conditions on Energy Reserves and Flight Performance of Emerald Ash Borer (Coleoptera: Buprestidae). AB - Emerald ash borer, Agrilus planipennis Fairmaire (Coleoptera: Buprestidae), an invasive beetle from Asia, spreads through human-mediated movement and active flight. The effects of adult feeding and overwintering conditions on A. planipennis energy reserves (e.g., lipid, glycogen, and sugars) and flight are poorly understood. We conjectured that the potential energetic demands associated with the production of cryoprotectants might affect dispersal capacity and partially explain slower spread of A. planipennis in Minnesota than in the other states. Two studies sought to measure the effects of adult feeding on lipid content and flight capacity. Adult A. planipennis were fed shamel ash, Fraxinus uhdei Wenzig, leaves for 0-20 d after emergence, and half were flown on a custom flight mill for 24 h, before being frozen for comparative lipid analysis with a control group. The second study compared the effects of adult feeding on energy reserves and flight capacity of A. planipennis that were originally from St. Paul, Minnesota but overwintered in infested logs placed in Grand Rapids, Minnesota (low winter temperature, -34 degrees C) or St. Paul, Minnesota (-26.3 degrees C). Live adults consumed foliage at a constant rate, but lipid content (percentage of fresh mass) did not change with increases in feeding or flight. Adult glycogen content declined with flight and increased only slightly with feeding. Overwintering location affected survival rates but not energy reserves or flight capacity. These results suggest that the flight capacity of A. planipennis is largely determined before emergence, with no differences in energy reserves after cryoprotectant investment. PMID- 29617753 TI - An Examination of Appetite and Disordered Eating in Active Crohn's Disease. AB - Background: Crohn's disease [CD] patients suffer from nutritional deficiencies when in active disease. We aim to examine calorific intake, macronutrient choice, and disordered eating behaviour in patients with active CD. Methods: CD patients with matched healthy volunteers [HV] were recruited. Active disease was defined by faecal calprotectin >250 ug/g, C-reactive protein 83.8 +/- 47.1 mg/dL, or active disease seen on endoscopy or imaging. Symptoms were quantified by Harvey Bradshaw Index [HBI]. Calorific intake was assessed by 24-h dietary recall. Disordered eating was assessed using validated questionnaires: Binge Eating Scale [BES]; Power of Food Scale [PFS]; Control of Eating Questionnaire [CoEQ]; Dutch Eating Behaviour Questionnaire [DEBQ]; and Three Factor Eating Questionnaire [TFEQ]. Results: Totals of 30 CD (18 male[M]:12 female [F], age 32.3 +/- 2.19 years, body mass index [BMI] 24.9 +/- 0.8) and 31 matched HV [19 M:12 F, age 32.8 +/- 2.0 years, BMI 24.7 +/- 0.5] were recruited. Mean faecal calprotectin was 1032.5 +/- 176 ug/g, C-reactive protein 8.38 +/- 4.71 mg/dL, and HBI 4.8 +/- 1. There were no significant differences in calorific intake between groups. Protein intake was lower in the CD cohort [p = 0.03]. Hospital Anxiety and Depression score was higher [p = 0.01] and CoEQ-Positive Mood [p = 0.001] lower in CD. CD patients were characterised by higher BES [p = 0.01] and lower CoEQ Craving Control [p = 0.027], with greater craving for Sweet [p = 0.043] and Savoury [p = 0.021] foods. PFS food Present [p = 0.005], DEBQ Emotional [p =< 0.001], and External Eating [p = 0.022] were significantly higher than among HV. Conclusions: Reduced protein consumption and more prevalent disordered eating behaviour traits were present in CD. Greater binge eating and decreased control of cravings may be attributed to lower mood and higher anxiety observed. Patients may benefit from stronger psychological support with firm dietetic advice for healthy eating. PMID- 29617755 TI - Soft- and hard-tissue changes following treatment of Class II division 1 malocclusion with Activator versus Trainer: a randomized controlled trial. AB - Background: Increased awareness on the role of oral functions in the aetiology of Class II deformities has led to the wide spread of myofunctional training appliances as easy and possibly effective treatment for children with Class II malocclusion but their efficacy is yet to be proven. Objectives: To evaluate soft and hard-tissue changes following 12 months of Class II division 1 treatment in growing patients with a conventional functional appliance (a modified Activator) versus a myofunctional Trainer system (T4K(r)). Setting and sample population: Department of Orthodontics, Dental School. Participants, study design, and methods : Sixty Class II division 1 children (8-12 years old) were recruited from primary schools and were distributed randomly into two equal groups. Randomization was based on a computer-generated sequence of random numbers. Data analysis included: the Activator group (28 patients, mean age = 10.6 +/- 1.3 years); the T4K(r) group (26 patients, mean age = 10.3 +/- 1.4 years). Skeletal, dentoalveolar, and soft tissues changes were assessed using standardized lateral cephalograms collected before and after 12 months of treatment. No blinding was applied in this trial. Results: Improvement in the Class II skeletal and dentofacial characteristics were significantly greater in the Activator group when compared with the T4K(r) group. The improvement was evident in a significant decrease in the skeletal angle ANB with Activator (x- = -1.89 +/- 1.12) compared to T4K(r) (x- = -0.9 +/- 1.01) (P = 0.01), a significant greater increase in the facial convexity angle with Activator (x- = 2.61 +/- 3.71) more than T4K(r) (x- = 0.2 +/- 2.51) (P = 0.04), and a significant reduction in the overjet (x- = -3.0 +/- 2.3 mm) compared to (x- = -1.5 +/- 1.9 mm; P = 0.01) with Activator versus T4k(r), respectively (P = 0.001). Limitations: This study was a short-term study (12-month follow-up). Conclusions: The results of the current study indicated that the Activator was more effective than the T4K(r) in treating Class II division 1 growing patients. Registration: The trial was not registered in any major database of clinical trials. Protocol: The protocol was not published before the commencement of the trial but can be given upon request. PMID- 29617750 TI - Colectomy Rates in Ulcerative Colitis are Low and Decreasing: 10-year Follow-up Data From the Swiss IBD Cohort Study. AB - Objectives: Previous population-based studies in patients with ulcerative colitis [UC] revealed variable colectomy rates and colectomy-associated risk factors. Over the past two decades, a decrease in colectomy rates was observed. We assessed risk factors and colectomy rates over time in UC in the Swiss Inflammatory Bowel Disease Cohort Study [SIBDCS]. Methods: Prospectively collected SIBDCS data, including disease history, baseline characteristics at enrolment, and course of disease, were retrospectively analysed. Cumulative and adjusted annual colectomy rates were calculated. Results: Among 1245 UC patients analysed [54.6% male], 114 [9.2%] underwent colectomy. We observed 5-, 10-, 15-, and 20-year cumulative colectomy rates after diagnosis of 4.1%, 6.4%, 10.4%, and 14.4% of patients, respectively. Male sex (odds ratio [OR] 1.54; p = 0.035), pancolitis at diagnosis [OR = 2.16; p = 0.005], younger age at diagnosis [OR 0.89 per 5 years of age; p = 0.006] and presence of extraintestinal manifestations [EIM] [OR 2.30; p < 0.001] were risk factors for undergoing colectomy. We did not observe a significant protective effect of smoking on colectomy risk [OR 0.64; p = 0.106]. The majority of colectomies were performed within first 10 years of disease onset, with a rapidly decreasing colectomy rate after 15 years. In patients diagnosed after 2003, colectomy was performed much earlier during and individual's disease course. Nevertheless, we found a significantly decreasing trend in yearly colectomy rates over time after 2005. Conclusions: Crude and adjusted colectomy rates in Swiss UC patients were lower than those reported previously in the literature, and decreased over time. PMID- 29617757 TI - Editorial: Changing of the Guard-A New Editor for Epidemiologic Reviews. PMID- 29617756 TI - Tweets and Transformative Technologies: Enabling Our Endocrine Future. PMID- 29617758 TI - Does headgear treatment in young children affect the maxillary canine eruption path? AB - Objective: To test whether early headgear (HG) treatment and space conditions in the dental arch affect the eruption pathway of the maxillary canines in young children with mixed dentition. Subjects and methods: Data from two randomized controlled trials studying the effects of early HG treatment were pooled, yielding a study sample comprising 99 children (38 girls and 61 boys, mean age 7.6 years) with Angle Class II occlusion. Fifty-one children were treated with HG and 48 children served as an untreated control group (CG). Digital 3D models and panoramic radiographs were taken before (T0) and after (T1) treatment, and changes in the maxillary canine eruption angle and interdental spaces were measured at T0 and T1. A paired samples t-test was used to assess changes in maxillary canine angulation, and an independent samples t-test was used to evaluate the effect of HG treatment on spacing in the dental arch. Associations between intra-arch space conditions and changes in maxillary canine angulation were estimated with linear regression models. Results: The eruption pattern of the permanent canine was significantly more vertical in the HG group than in the CG. The linear regression models showed a statistically significant association among the intercanine distance, crowding in the anterior part of the maxilla, and changes in the maxillary canine eruption angle. The maxillary canine eruption pattern changed significantly more to a vertical direction in spaced dental arches than in crowded dental arches in the HG group. Conclusion: This study shows that early HG treatment in children with Angle Class II occlusion may change the eruption pattern of permanent maxillary canines to a more vertical direction. This change appears to be related to space conditions in the maxillary arch, especially in the intercanine region, with more effect in children with spaced dental arches than in children with crowded dental arches. PMID- 29617759 TI - Regulation of Gene Expression by Thyroid Hormone in Primary Astrocytes: Factors Influencing the Genomic Response. AB - Astrocytes mediate the action of thyroid hormone in the brain on other neural cells through the production of the active hormone triiodothyronine (T3) from its precursor thyroxine. T3 has also many effects on the astrocytes in vivo and in culture, but whether these actions are directly mediated by transcriptional regulation is not clear. In this work, we have analyzed the genomic response to T3 of cultured astrocytes isolated from the postnatal mouse cerebral cortex using RNA sequencing. Cultured astrocytes express relevant genes of thyroid hormone metabolism and action encoding type 2 deiodinase (Dio2), Mct8 transporter (Slc16a2), T3 receptors (Thra1 and Thrb), and nuclear corepressor (Ncor1) and coactivator (Ncoa1). T3 changed the expression of 668 genes (4.5% of expressed genes), of which 117 were responsive to T3 in the presence of cycloheximide. The Wnt and Notch pathways were downregulated at the posttranscriptional level. Comparison with the effect of T3 on astrocyte-enriched genes in mixed cerebrocortical cultures isolated from fetal cortex revealed that the response to T3 is influenced by the degree of astrocyte maturation and that, in agreement with its physiological effects, T3 promotes the transition between the fetal and adult patterns of gene expression. PMID- 29617760 TI - First endocardial mapping of the left ventricle using the AdvisorTM HD Grid Catheter in a patient with a mitral valve clip. PMID- 29617761 TI - Refining the Ambush Hypothesis: Evidence That GC- and AT-Rich Bacteria Employ Different Frameshift Defence Strategies. AB - Stop codons are frequently selected for beyond their regular termination function for error control. The "ambush hypothesis" proposes out-of-frame stop codons (OSCs) terminating frameshifted translations are selected for. Although early indirect evidence was partially supportive, recent evidence suggests OSC frequencies are not exceptional when considering underlying nucleotide content. However, prior null tests fail to control amino acid/codon usages or possible local mutational biases. We therefore return to the issue using bacterial genomes, considering several tests defining and testing against a null. We employ simulation approaches preserving amino acid order but shuffling synonymous codons or preserving codons while shuffling amino acid order. Additionally, we compare codon usage in amino acid pairs, where one codon can but the next, otherwise identical codon, cannot encode an OSC. OSC frequencies exceed expectations typically in AT-rich genomes, the +1 frame and for TGA/TAA but not TAG. With this complex evidence, simply rejecting or accepting the ambush hypothesis is not warranted. We propose a refined post hoc model, whereby AT-rich genomes have more accidental frameshifts, handled by RF2-RF3 complexes (associated with TGA/TAA) and are mostly +1 (or -2) slips. Supporting this, excesses positively correlate with in silico predicted frameshift probabilities. Thus, we propose a more viable framework, whereby genomes broadly adopt one of the two strategies to combat frameshifts: preventing frameshifting (GC-rich) or permitting frameshifts but minimizing impacts when most are caught early (AT-rich). Our refined framework holds promise yet some features, such as the bias of out-of-frame sense codons, remain unexplained. PMID- 29617762 TI - Pressure gradient vs. flow relationships to characterize the physiology of a severely stenotic aortic valve before and after transcatheter valve implantation. AB - Aims: Echocardiography and tomographic imaging have documented dynamic changes in aortic stenosis (AS) geometry and severity during both the cardiac cycle and stress-induced increases in cardiac output. However, corresponding pressure gradient vs. flow relationships have not been described. Methods and results: We recruited 16 routine transcatheter aortic valve implantations (TAVI's) for graded dobutamine infusions both before and after implantation; 0.014" pressure wires in the aorta and left ventricle (LV) continuously measured the transvalvular pressure gradient (DeltaP) while a pulmonary artery catheter regularly assessed cardiac output by thermodilution. Before TAVI, DeltaP did not display a consistent relationship with transvalvular flow (Q). Neither linear resistor (median R2 0.16) nor quadratic orifice (median R2 < 0.01) models at rest predicted stress observations; the severely stenotic valve behaved like a combination. The unitless ratio of aortic to left ventricular pressures during systolic ejection under stress conditions correlated best with post-TAVI flow improvement. After TAVI, a highly linear relationship (median R2 0.96) indicated a valid valve resistance. Conclusion: Pressure loss vs. flow curves offer a fundamental fluid dynamic synthesis for describing aortic valve pathophysiology. Severe AS does not consistently behave like an orifice (as suggested by Gorlin) or a resistor, whereas TAVI devices behave like a pure resistor. During peak dobutamine, the ratio of aortic to left ventricular pressures during systolic ejection provides a 'fractional flow reserve' of the aortic valve that closely approximates the complex, changing fluid dynamics. Because resting assessment cannot reliably predict stress haemodynamics, 'valvular fractional flow' warrants study to explain exertional symptoms in patients with only moderate AS at rest. PMID- 29617764 TI - Whole human heart histology to validate electroanatomical voltage mapping in patients with non-ischaemic cardiomyopathy and ventricular tachycardia. AB - Aims: Electroanatomical voltage mapping (EAVM) is an important diagnostic tool for fibrosis identification and risk stratification in non-ischaemic cardiomyopathy (NICM); currently, distinct cut-offs are applied. We aimed to evaluate the performance of EAVM to detect fibrosis by integration with whole heart histology and to identify the fibrosis pattern in NICM patients with ventricular tachycardias (VTs). Methods and results: Eight patients with NICM and VT underwent EAVM prior to death or heart transplantation. EAVM data was projected onto slices of the entire heart. Pattern, architecture, and amount of fibrosis were assessed in transmural biopsies corresponding to EAVM sites. Fibrosis pattern in NICM biopsies (n = 507) was highly variable and not limited to mid-wall/sub-epicardium. Fibrosis architecture was rarely compact, but typically patchy and/or diffuse. In NICM, biopsies without abnormal fibrosis unipolar voltage (UV) and bipolar voltage (BV) showed a linear association with wall thickness (WT). The amount of viable myocardium showed a linear association with both UV and BV. Accordingly, any cut-off to delineate fibrosis performed poorly. An equation was generated calculating the amount of fibrosis at any location, given WT and UV or BV. Conclusion: Considering the linear relationships between WT, amount of fibrosis and both UV and BV, the search for any distinct voltage cut-off to identify fibrosis in NICM is futile. The amount of fibrosis can be calculated, if WT and voltages are known. Fibrosis pattern and architecture are different from ischaemic cardiomyopathy and findings on ischaemic substrates may not be applicable to NICM. PMID- 29617766 TI - Narrative Interest Standard: A Novel Approach to Surrogate Decision-Making for People With Dementia. AB - Dementia is a common neurodegenerative process that can significantly impair decision-making capacity as the disease progresses. When a person is found to lack capacity to make a decision, a surrogate decision-maker is generally sought to aid in decision-making. Typical bases for surrogate decision-making include the substituted judgment standard and the best interest standard. Given the heterogeneous and progressive course of dementia, however, these standards for surrogate decision-making are often insufficient in providing guidance for the decision-making for a person with dementia, escalating the likelihood of conflict in these decisions. In this article, the narrative interest standard is presented as a novel and more appropriate approach to surrogate decision-making for people with dementia. Through case presentation and ethical analysis, the standard mechanisms for surrogate decision-making for people with dementia are reviewed and critiqued. The narrative interest standard is then introduced and discussed as a dementia-specific model for surrogate decision-making. Through incorporation of elements of a best interest standard in focusing on the current benefit-burden ratio and elements of narrative to provide context, history, and flexibility for values and preferences that may change over time, the narrative interest standard allows for elaboration of an enriched context for surrogate decision-making for people with dementia. More importantly, however, a narrative approach encourages the direct contribution from people with dementia in authoring the story of what matters to them in their lives. PMID- 29617763 TI - beta-Cell Autophagy in Diabetes Pathogenesis. AB - Nearly 100 years have passed since Frederick Banting and Charles Best first discovered and purified insulin. Their discovery and subsequent improvements revolutionized the treatment of diabetes, and the field continues to move at an ever-faster pace with respect to unique treatments for both type 1 and type 2 diabetes. Despite these advances, we still do not fully understand how apoptosis of the insulin-producing beta-cells is triggered, presenting a challenge in the development of preventative measures. In recent years, the process of autophagy has generated substantial interest in this realm due to discoveries highlighting its clear role in the maintenance of cellular homeostasis. As a result, the number of studies focused on islet and beta-cell autophagy has increased substantially in recent years. In this review, we will discuss what is currently known regarding the role of beta-cell autophagy in type 1 and type 2 diabetes pathogenesis, with an emphasis on new and exciting developments over the past 5 years. Further, we will discuss how these discoveries might be translated into unique treatments in the coming years. PMID- 29617765 TI - Draft genome of the Peruvian scallop Argopecten purpuratus. AB - Background: The Peruvian scallop, Argopecten purpuratus, is mainly cultured in southern Chile and Peru was introduced into China in the last century. Unlike other Argopecten scallops, the Peruvian scallop normally has a long life span of up to 7 to 10 years. Therefore, researchers have been using it to develop hybrid vigor. Here, we performed whole genome sequencing, assembly, and gene annotation of the Peruvian scallop, with an important aim to develop genomic resources for genetic breeding in scallops. Findings: A total of 463.19-Gb raw DNA reads were sequenced. A draft genome assembly of 724.78 Mb was generated (accounting for 81.87% of the estimated genome size of 885.29 Mb), with a contig N50 size of 80.11 kb and a scaffold N50 size of 1.02 Mb. Repeat sequences were calculated to reach 33.74% of the whole genome, and 26,256 protein-coding genes and 3,057 noncoding RNAs were predicted from the assembly. Conclusions: We generated a high quality draft genome assembly of the Peruvian scallop, which will provide a solid resource for further genetic breeding and for the analysis of the evolutionary history of this economically important scallop. PMID- 29617767 TI - An unique case of congenital varices of the four pulmonary veins. PMID- 29617769 TI - Seeing Dementia: Two Radically Different Views. PMID- 29617768 TI - Improving the annotation of the Heterorhabditis bacteriophora genome. AB - Background: Genome assembly and annotation remain exacting tasks. As the tools available for these tasks improve, it is useful to return to data produced with earlier techniques to assess their credibility and correctness. The entomopathogenic nematode Heterorhabditis bacteriophora is widely used to control insect pests in horticulture. The genome sequence for this species was reported to encode an unusually high proportion of unique proteins and a paucity of secreted proteins compared to other related nematodes. Findings: We revisited the H. bacteriophora genome assembly and gene predictions to determine whether these unusual characteristics were biological or methodological in origin. We mapped an independent resequencing dataset to the genome and used the blobtools pipeline to identify potential contaminants. While present (0.2% of the genome span, 0.4% of predicted proteins), assembly contamination was not significant. Conclusions: Re prediction of the gene set using BRAKER1 and published transcriptome data generated a predicted proteome that was very different from the published one. The new gene set had a much reduced complement of unique proteins, better completeness values that were in line with other related species' genomes, and an increased number of proteins predicted to be secreted. It is thus likely that methodological issues drove the apparent uniqueness of the initial H. bacteriophora genome annotation and that similar contamination and misannotation issues affect other published genome assemblies. PMID- 29617770 TI - Screening of 2A peptides for polycistronic gene expression in yeast. AB - A complexity of pathway expression in yeast compared to prokaryotes is the need for separate promoters and terminators for each gene expressed. Single transcript expression and separated protein production is possible via the use of 2A viral peptides, but detailed characterization to assess their suitability and applications is needed. The present work aimed to characterize multiple 2A peptide sequences to determine suitability for metabolic engineering applications in Saccharomyces cerevisiae. We screened 22 peptides placed between fluorescent protein sequences. Cleaving efficiency was calculated by western blot intensity of bands corresponding to the cleaved and uncleaved forms of the reporter. Three out of the 22 sequences showed high cleavage efficiency: 2A peptide from Equine rhinitis B virus (91%), Porcine teschovirus-1 (85%) and Operophtera brumata cypovirus-18 (83%). Furthermore, expression of the released protein was comparable to its monocistronic expression. As a proof-of-concept, the triterpene friedelin was successfully produced in the same yeast strain by expressing its synthase with the truncated form of HMG1 linked by the 2A peptide of ERBV-1, with production titers comparable to monocistronic expression (via separate promoters). These results suggest that these peptides could be suitable for expression and translation of multiple proteins in metabolic engineering applications in S. cerevisiae. PMID- 29617771 TI - Real-time DNA barcoding in a rainforest using nanopore sequencing: opportunities for rapid biodiversity assessments and local capacity building. AB - Background: Advancements in portable scientific instruments provide promising avenues to expedite field work in order to understand the diverse array of organisms that inhabit our planet. Here, we tested the feasibility for in situ molecular analyses of endemic fauna using a portable laboratory fitting within a single backpack in one of the world's most imperiled biodiversity hotspots, the Ecuadorian Choco rainforest. We used portable equipment, including the MinION nanopore sequencer (Oxford Nanopore Technologies) and the miniPCR (miniPCR), to perform DNA extraction, polymerase chain reaction amplification, and real-time DNA barcoding of reptile specimens in the field. Findings: We demonstrate that nanopore sequencing can be implemented in a remote tropical forest to quickly and accurately identify species using DNA barcoding, as we generated consensus sequences for species resolution with an accuracy of >99% in less than 24 hours after collecting specimens. The flexibility of our mobile laboratory further allowed us to generate sequence information at the Universidad Tecnologica Indoamerica in Quito for rare, endangered, and undescribed species. This includes the recently rediscovered Jambato toad, which was thought to be extinct for 28 years. Sequences generated on the MinION required as few as 30 reads to achieve high accuracy relative to Sanger sequencing, and with further multiplexing of samples, nanopore sequencing can become a cost-effective approach for rapid and portable DNA barcoding. Conclusions: Overall, we establish how mobile laboratories and nanopore sequencing can help to accelerate species identification in remote areas to aid in conservation efforts and be applied to research facilities in developing countries. This opens up possibilities for biodiversity studies by promoting local research capacity building, teaching nonspecialists and students about the environment, tackling wildlife crime, and promoting conservation via research-focused ecotourism. PMID- 29617772 TI - Providers' Perceptions and Training Needs for Counseling Adolescents Undergoing Voluntary Medical Male Circumcision. AB - Background: The majority of individuals who seek voluntary medical male circumcision (VMMC) services in sub-Saharan Africa are adolescents (ages 10-19 years). However, adolescents who obtain VMMC services report receiving little information on human immunodeficiency virus (HIV) prevention and care. In this study, we assessed the perceptions of VMMC facility managers and providers about current training content and their perspectives on age-appropriate adolescent counseling. Methods: Semistructured in-depth interviews were conducted with 33 VMMC providers in Tanzania (n = 12), South Africa (n = 9), and Zimbabwe (n = 12) and with 4 key informant facility managers in each country (total 12). Two coders independently coded the data thematically using a 2-step process and Atlas.ti qualitative coding software. Results: Providers and facility managers discussed limitations with current VMMC training, noting the need for adolescent-specific guidelines and counseling skills. Providers expressed hesitation in communicating complete sexual health information-including HIV testing, HIV prevention, proper condom usage, the importance of knowing a partner's HIV status, and abstinence from sex or masturbation during wound healing-with younger males (aged <15 years) and/or those assumed to be sexually inexperienced. Many providers revealed that they did not assess adolescent clients' sexual experience and deemed sexual topics to be irrelevant or inappropriate. Providers preferred counseling younger adolescents with their parents or guardians present, typically focusing primarily on wound care and procedural information. Conclusions: Lack of training for working with adolescents influences the type of information communicated. Preconceptions hinder counseling that supports comprehensive HIV preventive behaviors and complete wound care information, particularly for younger adolescents. PMID- 29617773 TI - Females' Peer Influence and Support for Adolescent Males Receiving Voluntary Medical Male Circumcision Services. AB - Background: While female involvement in voluntary medical male circumcision (VMMC) has been studied among adults, little is known about the influence of adolescent females on their male counterparts. This study explored adolescent females' involvement in VMMC decision making and the postoperative wound healing process in South Africa, Tanzania, and Zimbabwe. Methods: Across 3 countries, 12 focus group discussions were conducted with a total of 90 adolescent females (aged 16-19 years). Individual in-depth interviews were conducted 6-10 weeks post VMMC with 92 adolescent males (aged 10-19 years). Transcribed and translated qualitative data were coded into categories and subcategories by 2 independent coders. Results: Adolescent female participants reported being supportive of male peers' decisions to seek VMMC, with the caveat that some thought VMMC gives males a chance to be promiscuous. Regardless, females from all countries expressed preference for circumcised over uncircumcised sexual partners. Adolescent females believed VMMC to be beneficial for the sexual health of both partners, viewed males with a circumcised penis as more attractive than uncircumcised males, used their romantic relationships with males or the potential for sex as leveraging points to convince males to become circumcised, and demonstrated supportive attitudes in the wound-healing period. Interviews with males confirmed that encouragement from females was a motivating factor in seeking VMMC. Conclusions: Adolescent female participants played a role in convincing young males to seek VMMC and remained supportive of the decision postprocedure. Programs aiming to increase uptake of VMMC and other health-related initiatives for adolescent males should consider the perspective and influence of adolescent females. PMID- 29617774 TI - Adolescent Male Circumcision for HIV Prevention in High Priority Countries: Opportunities for Improvement. AB - Global experts recognize the need to transform conventional models of healthcare to create adolescent responsive health systems. As countries near 80% coverage of voluntary medical male circumcision (VMMC) for those aged 15-49 years, prioritization of younger men becomes critical to VMMC sustainability. This special supplement reporting 9 studies focusing on adolescent VMMC programming and services comes at a critical time. Eight articles report how well adolescents are reached with the World Health Organization's minimum package for comprehensive human immunodeficiency virus (HIV) prevention in South Africa, Zimbabwe, and Tanzania, analyzing motivation, counseling, wound healing, parental involvement, female peer support, quality of in-service communication, and providers' perceptions, and one presents models for achieving high VMMC coverage by 2021. One important finding is that adolescent boys, especially the youngest, experience gaps in their comprehension of key elements in the World Health Organization's minimum package. Although parents, counselors, and providers are involved and supportive, they are inadequately prepared to counsel youth, partly owing to discomfort with adolescent sexuality. At the country level, deliberately prioritizing young adolescents (aged 10-14 years) is likely to achieve national coverage targets more quickly and cost-effectively than continuing to focus on older, harder-to-reach men. The studies in this supplement point to areas where VMMC programs are achieving successes and they reveal areas for improvement. Given that prioritizing adolescents will be the best means of achieving sustainable VMMC for HIV prevention for the foreseeable future, applying the lessons learned here will increase the effectiveness of VMMC programs. PMID- 29617775 TI - Age Differences in Perceptions of and Motivations for Voluntary Medical Male Circumcision Among Adolescents in South Africa, Tanzania, and Zimbabwe. AB - Background: The World Health Organization (WHO) and the Joint United Nations Programme on HIV/AIDS (UNAIDS) have set a Fast-Track goal to achieve 90% coverage of voluntary medical male circumcision (VMMC) among boys and men aged 10-29 years in priority settings by 2021. We aimed to identify age-specific facilitators of VMMC uptake among adolescents. Methods: Younger (aged 10-14 years; n = 967) and older (aged 15-19 years; n = 559) male adolescents completed structured interviews about perceptions of and motivations for VMMC before receiving VMMC counseling at 14 service provision sites across South Africa, Tanzania, and Zimbabwe. Adjusted prevalence ratios (aPRs) were estimated using multivariable modified Poisson regression models with generalized estimating equations and robust standard errors. Results: The majority of adolescents reported a strong desire for VMMC. Compared with older adolescents, younger adolescents were less likely to cite protection against human immunodeficiency virus (HIV) or other sexually transmitted infections (aPR, 0.77; 95% confidence interval [CI], .66 .91) and hygienic reasons (aPR, 0.55; 95% CI, .39-.77) as their motivation to undergo VMMC but were more likely to report being motivated by advice from others (aPR, 1.88; 95% CI, 1.54-2.29). Although most adolescents believed that undergoing VMMC was a normative behavior, younger adolescents were less likely to perceive higher descriptive norms (aPR, 0.79; .71-.89), injunctive norms (aPR, 0.86; 95% CI, .73-1.00), or anticipated stigma for being uncircumcised (aPR, 0.79; 95% CI, .68-.90). Younger adolescents were also less likely than older adolescents to correctly cite that VMMC offers men and boys partial HIV protection (aPR, 0.73; 95% CI, .65-.82). Irrespective of age, adolescents' main concern about undergoing VMMC was pain (aPR, 0.95; 95% CI, .87-1.04). Among younger adolescents, fear of pain was negatively associated with desire for VMMC (aPR, 0.89; 95% CI, .83-.96). Conclusions: Age-specific strategies are important to consider to generate sustainable demand for VMMC. Programmatic efforts should consider building on the social norms surrounding VMMC and aim to alleviate fears about pain. PMID- 29617776 TI - Counseling Received by Adolescents Undergoing Voluntary Medical Male Circumcision: Moving Toward Age-Equitable Comprehensive Human Immunodeficiency Virus Prevention Measures. AB - Background: The minimum package of voluntary medical male circumcision (VMMC) services, as defined by the World Health Organization, includes human immunodeficiency virus (HIV) testing, HIV prevention counseling, screening/treatment for sexually transmitted infections, condom promotion, and the VMMC procedure. The current study aimed to assess whether adolescents received these key elements. Methods: Quantitative surveys were conducted among male adolescents aged 10-19 years (n = 1293) seeking VMMC in South Africa, Tanzania, and Zimbabwe. We used a summative index score of 8 self-reported binary items to measure receipt of important elements of the World Health Organization recommended HIV minimum package and the US President's Emergency Plan for AIDS Relief VMMC recommendations. Counseling sessions were observed for a subset of adolescents (n = 44). To evaluate factors associated with counseling content, we used Poisson regression models with generalized estimating equations and robust variance estimation. Results: Although counseling included VMMC benefits, little attention was paid to risks, including how to identify complications, what to do if they arise, and why avoiding sex and masturbation could prevent complications. Overall, older adolescents (aged 15-19 years) reported receiving more items in the recommended minimum package than younger adolescents (aged 10-14 years; adjusted beta, 0.17; 95% confidence interval [CI], .12-.21; P < .001). Older adolescents were also more likely to report receiving HIV test education and promotion (42.7% vs 29.5%; adjusted prevalence ratio [aPR], 1.53; 95% CI, 1.16 2.02) and a condom demonstration with condoms to take home (16.8% vs 4.4%; aPR, 2.44; 95% CI, 1.30-4.58). No significant age differences appeared in reports of explanations of VMMC risks and benefits or uptake of HIV testing. These self reported findings were confirmed during counseling observations. Conclusions: Moving toward age-equitable HIV prevention services during adolescent VMMC likely requires standardizing counseling content, as there are significant age differences in HIV prevention content received by adolescents. PMID- 29617777 TI - Adolescent Wound-Care Self-Efficacy and Practices After Voluntary Medical Male Circumcision-A Multicountry Assessment. AB - Background: Adolescent boys (aged 10-19 years) constitute the majority of voluntary medical male circumcision (VMMC) clients in sub-Saharan Africa. They are at higher risk of postoperative infections compared to adults. We explored adolescents' wound-care knowledge, self-efficacy, and practices after VMMC to inform strategies for reducing the risks of infectious complications postoperatively. Methods: Quantitative and qualitative data were collected in South Africa, Tanzania, and Zimbabwe between June 2015 to September 2016. A postprocedure survey was conducted approximately 7-10 days after VMMC among male adolescents (n = 1293) who had completed a preprocedure survey; the postprocedure survey assessed knowledge of proper wound care and wound-care self-efficacy. We also conducted in-depth interviews (n = 92) with male adolescents 6-10 weeks after the VMMC procedure to further explore comprehension of providers' wound care instructions as well as wound-care practices, and we held 24 focus group discussions with randomly selected parents/guardians of the adolescents. Results: Adolescent VMMC clients face multiple challenges with postcircumcision wound care owing to factors such as forgetting, misinterpreting, and disregarding provider instructions. Although younger adolescents stated that parental intervention helped them overcome potential hindrances to wound care, parents and guardians lacked crucial information on wound care because most had not attended counseling sessions. Some older adolescents reported ignoring symptoms of infection and not returning to the clinic for review when an adverse event had occurred. Conclusions: Increased involvement of parents/guardians in wound-care counseling for younger adolescents and in wound-care supervision, alongside the development of age-appropriate materials on wound care, are needed to minimize postoperative complications after VMMC. PMID- 29617778 TI - Scaling Up Voluntary Medical Male Circumcision for Human Immunodeficiency Virus Prevention for Adolescents and Young Adult Men: A Modeling Analysis of Implementation and Impact in Selected Countries. AB - Background: The new World Health Organization and Joint United Nations Programme on HIV/AIDS strategic framework for voluntary medical male circumcision (VMMC) aims to increase VMMC coverage among males aged 10-29 years in priority settings to 90% by 2021. We use mathematical modeling to assess the likelihood that selected countries will achieve this objective, given their historical VMMC progress and current implementation options. Methods: We use the Decision Makers' Program Planning Toolkit, version 2, to examine 4 ambitious but feasible scenarios for scaling up VMMC coverage from 2017 through 2021, inclusive in Lesotho, Malawi, Mozambique, Namibia, South Africa, Swaziland, Tanzania, Uganda, and Zimbabwe. Results: Tanzania is the only country that would reach the goal of 90% VMMC coverage in 10- to 29-year-olds by the end of 2021 in the scenarios assessed, and this was true in 3 of the scenarios studied. Mozambique, South Africa, and Lesotho would come close to reaching the objective only in the most ambitious scenario examined. Conclusions: Major changes in VMMC implementation in most countries will be required to increase the proportion of circumcised 10- to 29-year-olds to 90% by the end of 2021. Scaling up VMMC coverage in males aged 10 29 years will require significantly increasing the number of circumcisions provided to 10- to 14-year-olds and 15- to 29-year-olds. PMID- 29617779 TI - Parental Communication, Engagement, and Support During the Adolescent Voluntary Medical Male Circumcision Experience. AB - Background: Voluntary medical male circumcision (VMMC) is one of few opportunities in sub-Saharan Africa to engage male adolescents in the healthcare system. Limited data are available on the level of parental communication, engagement, and support adolescents receive during the VMMC experience. Methods: We conducted 24 focus group discussions with parents/guardians of adolescents (N = 192) who agreed to be circumcised or were recently circumcised in South Africa, Tanzania, and Zimbabwe. In addition, male adolescents (N = 1293) in South Africa (n = 299), Tanzania (n = 498), and Zimbabwe (n = 496) were interviewed about their VMMC experience within 7-10 days postprocedure. We estimated adjusted prevalence ratios (aPRs) using multivariable Poisson regression with generalized estimating equations and robust standard errors. Results: Parents/guardians noted challenges and gaps in communicating with their sons about VMMC, especially when they did not accompany them to the clinic. Adolescents aged 10-14 years were significantly more likely than 15- to 19-year-olds to report that their parent accompanied them to a preprocedure counseling session (56.5% vs 12.5%; P < .001). Among adolescents, younger age (aPR, 0.86; 95% confidence interval [CI], .76-.99) and rural setting (aPR, 0.34; 95% CI, .13-.89) were less likely to be associated with parental-adolescent communication barriers, while lower socioeconomic status (aPR, 1.37; 95% CI, 1.00-1.87), being agnostic (or of a nondominant religion; aPR, 2.87; 95% CI, 2.21-3.72), and living in South Africa (aPR, 2.63; 95% CI, 1.29-4.73) were associated with greater perceived barriers to parental-adolescent communication about VMMC. Parents/guardians found it more difficult to be involved in wound care for older adolescents than for adolescents <15 years of age. Conclusions: Parents play a vital role in the VMMC experience, especially for younger male adolescents. Strategies are needed to inform parents completely throughout the VMMC adolescent experience, whether or not they accompany their sons to clinics. PMID- 29617780 TI - Perceived Quality of In-Service Communication and Counseling Among Adolescents Undergoing Voluntary Medical Male Circumcision. AB - Background: Experience with providers shapes the quality of adolescent health services, including voluntary medical male circumcision (VMMC). This study examined the perceived quality of in-service communication and counseling during adolescent VMMC services. Methods: A postprocedure quantitative survey measuring overall satisfaction, comfort, perceived quality of in-service communication and counseling, and perceived quality of facility-level factors was administered across 14 VMMC sites in South Africa, Tanzania, and Zimbabwe. Participants were adolescent male clients aged 10-14 years (n = 836) and 15-19 years (n = 457) and completed the survey 7 to 10 days following VMMC. Adjusted prevalence ratios (aPRs) were estimated by multivariable modified Poisson regression with generalized estimating equations and robust variance estimation to account for site-level clustering. Results: Of 10- to 14-year-olds and 15- to 19-year-olds, 97.7% and 98.7%, respectively, reported they were either satisfied or very satisfied with their VMMC counseling experience. Most were also very likely or somewhat likely (93.6% of 10- to 14-year olds and 94.7% of 15- to 19-year olds) to recommend VMMC to their peers. On a 9-point scale, the median perceived quality of in-service (counselor) communication was 9 (interquartile range [IQR], 8-9) among 15- to 19-year-olds and 8 (IQR, 7-9) among 10- to 14-year-olds. The 10 to 14-year-olds were more likely than 15- to 19-year-olds to perceive a lower quality of in-service (counselor) communication (score <7; 21.5% vs. 8.2%; aPR, 1.61 [95% confidence interval, 1.33-1.95]). Most adolescents were more comfortable with a male rather than female counselor and provider. Adolescents of all ages wanted more discussion about pain, wound care, and healing time. Conclusions: Adolescents perceive the quality of in-service communication as high and recommend VMMC to their peers; however, many adolescents desire more discussion about key topics outlined in World Health Organization guidance. PMID- 29617781 TI - Impact of Counseling Received by Adolescents Undergoing Voluntary Medical Male Circumcision on Knowledge and Sexual Intentions. AB - Background: Little is known regarding the impact of counseling delivered during voluntary medical male circumcision (VMMC) services on adolescents' human immunodeficiency virus (HIV) knowledge, VMMC knowledge, or post-VMMC preventive sexual intentions. This study assessed the effect of counseling on knowledge and intentions. Methods: Surveys were conducted with 1293 adolescent clients in 3 countries (South Africa, n = 299; Tanzania, n = 498; Zimbabwe, n = 496). Adolescents were assessed on HIV and VMMC knowledge-based items before receiving VMMC preprocedure counseling and at a follow-up survey approximately 10 days postprocedure. Sexually active adolescents were asked about their sexual intentions in the follow-up survey. Prevalence ratios (PRs) and 95% confidence intervals (CIs) were calculated by modified Poisson regression models with generalized estimating equations and robust variance estimators. Results: Regarding post-VMMC HIV prevention knowledge, older adolescents were significantly more likely than younger adolescents to know that a male should use condoms (age 10-14 years, 41.1%; 15-19 years, 84.2%; aPR, 1.38 [95% CI, 1.19 1.60]), have fewer sex partners (age 10-14 years, 8.1%; age 15-19 years, 24.5%; aPR, 2.10 [95% CI, 1.30-3.39]), and be faithful to one partner (age 10-14 years, 5.7%; age 15-19 years, 23.2%; aPR, 2.79 [95% CI, 1.97-3.97]) to further protect himself from HIV. Older adolescents demonstrated greater improvement in knowledge in most categories, differences that were significant for questions regarding number of sex partners (aPR, 2.01 [95% CI, 1.18-3.44]) and faithfulness to one partner post-VMMC (aPR, 3.28 [95% CI, 2.22-4.86]). However, prevention knowledge levels overall and HIV risk reduction sexual intentions among sexually active adolescents were notably low, especially given that adolescents had been counseled only 7-10 days prior. Conclusions: Adolescent VMMC counseling needs to be improved to increase knowledge and postprocedure preventive sexual intentions. PMID- 29617782 TI - Epicardial permanent pacemaker implantation in the retrosternal space of a 2.3-kg infant. AB - Permanent pacemaker implantation in small infants can be challenging because of patient size and expected somatic growth. In our case, we used the retrosternal space as a generator pocket for an extremely low-birth-weight premature baby with autoantibody-associated congenital heart block born to a systemic lupus erythematosus mother. PMID- 29617783 TI - A practical tool for maximal information coefficient analysis. AB - Background: The ability of finding complex associations in large omics datasets, assessing their significance, and prioritizing them according to their strength can be of great help in the data exploration phase. Mutual information-based measures of association are particularly promising, in particular after the recent introduction of the TICe and MICe estimators, which combine computational efficiency with superior bias/variance properties. An open-source software implementation of these two measures providing a complete procedure to test their significance would be extremely useful. Findings: Here, we present MICtools, a comprehensive and effective pipeline that combines TICe and MICe into a multistep procedure that allows the identification of relationships of various degrees of complexity. MICtools calculates their strength assessing statistical significance using a permutation-based strategy. The performances of the proposed approach are assessed by an extensive investigation in synthetic datasets and an example of a potential application on a metagenomic dataset is also illustrated. Conclusions: We show that MICtools, combining TICe and MICe, is able to highlight associations that would not be captured by conventional strategies. PMID- 29617784 TI - The influence of different inflow configurations on computational fluid dynamics in a novel three-leaflet mechanical heart valve prosthesis. AB - OBJECTIVES: A novel mechanical heart valve was developed with a special focus on avoiding anticoagulation. Computational fluid dynamics were used for the research design. Here, the effect of different anatomical inflow geometries on flow characteristics is evaluated. METHODS: Flow and pressure simulations were performed on a novel 3-leaflet mechanical heart valve in a fully open position at 2 flow rates related to the peak and end-systolic flow. The computational fluid dynamics model was designed according to 4 different (1 cylindrical, 3 conical with increasing diameter) anatomical configurations of the left ventricular outflow tract derived from an inverse heart model. RESULTS: With increasing inflow diameter, the flow velocity decreased for both flow rates, from 1543 mm/s in cylindrical configuration to 1475 mm/s in conical configuration for a flow rate of 18 l/min. However, there was no further decrease for the inflow diameters 38 and 48 mm. The velocity profile became broader with increasing inflow diameter and the maximal pressure decreased. At the leading edge, velocity almost stagnated, while the pressure increased and the reflection point moved downstream. No occurrence of dead space was observed with the different configurations and flow rates. CONCLUSIONS: An analysis of different anatomical inflow configurations by computational fluid dynamic simulations showed a more homogenous velocity profile and lower flow velocity values with increasing inflow diameter up to 38 mm in this novel 3-leaflet mechanical heart valve. PMID- 29617785 TI - Extended bronchoplasty for locally advanced left lower lobe lung cancer: surgical technique and outcomes. AB - Extended bronchoplasty combined with left lower lobectomy plus lingulectomy can be indicated for some locally advanced left lower lobe cancers to avoid pneumonectomy, but its outcome has not been well studied. We retrospectively analysed the surgical outcomes of 10 patients since 2008, when we introduced this procedure. The median age was 67 years (range 42-80). Squamous cell carcinoma was the most common histology. The indication for this procedure was bulky or extranodal metastasis in an interlobar node in 9 patients and massive tumour invasion to the lingula in 1 patient. Bronchoplasty was performed by a sleeve (n = 7) or deep-wedge (n = 3) resection of the left main and superior division bronchi, according to the type of tumour extension. One of the sleeve cases resulted in anastomotic kinking and was converted to left pneumonectomy intraoperatively, but no postoperative morbidity or mortality was observed. Locoregional recurrence was not found with a median follow-up of 31 months (range 13-83). This type of extended bronchoplasty can be a safe alternative to left pneumonectomy for left lower lobe cancers invading an interlobar node or lingula in which R0 resection is difficult by a simple or standard sleeve left lower lobectomy. PMID- 29617786 TI - Reply to Gimenez et al. PMID- 29617787 TI - Diagnosis and Treatment of Neurocysticercosis: 2017 Clinical Practice Guidelines by the Infectious Diseases Society of America (IDSA) and the American Society of Tropical Medicine and Hygiene (ASTMH). PMID- 29617789 TI - Does oesophageal stenosis have any impact on survival of oesophageal cancer patients? AB - A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was 'Does oesophageal stenosis have any impact on survival of oesophageal cancer patients?'. A total of 542 papers were found using the reported search, of which 8 cohort studies represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Most of these studies defined stenosis as failure to cross the tumour at endoscopic ultrasonography. Seven studies demonstrated that oesophageal cancer patients with stenosis had significantly poorer survival than those without, while 2 studies found that oesophageal stenosis was also a predictor of poor recurrence-free survival. We conclude that oesophageal stenosis is a predictor of poor prognosis in patients with oesophageal cancer. PMID- 29617791 TI - Beating-heart aortic arch surgery in neonates and infants. AB - OBJECTIVES: Aortic arch repair has been shifted from deep hypothermia plus circulatory arrest to cerebral perfusion at tepid temperatures. A step forward is a simultaneous brain-coronary perfusion, allowing beating-heart arch surgery. METHODS: A 'Y' cannula from the arterial line delivers oxygenated blood to brain and heart. The arch is repaired on a beating heart at 25 degrees C. Intracardiac repair is performed after running cardioplegia through the root line. Fifty patients are classified into 3 groups: A, Norwood (8 neonates); B, aortic arch (14 children) and C, aortic arch plus intracardiac repair (28 patients). Associated anomalies in Group C are as follows: ventricular septal defect (10), arterial switch (5), atrial septal defect (4), cor triatriatum (3), aortic commissurotomy (2), comprehensive repair (2), ostium primum (1) and Yasui (1). RESULTS: The mean bypass time was 161 +/- 54.44 (range 93-312) min. Mean brain coronary perfusion was 37.26 +/- 10.54 (18-60) min. Mean coronary ischaemia was 31 +/- 32.40 (0-160) min. The heart was not arrested in Group B patients. Follow up was complete for a mean of 30 (1-48) months. Four patients died in the postoperative period. Two required angioplasty for recoarctation. CONCLUSIONS: Selective brain-coronary perfusion is feasible and easy to switch to conventional cardioplegia delivery. Coronary ischaemia can be notably reduced and even 0 min in isolated arch surgery. PMID- 29617790 TI - m6ASNP: a tool for annotating genetic variants by m6A function. AB - Background: Large-scale genome sequencing projects have identified many genetic variants for diverse diseases. A major goal of these projects is to characterize these genetic variants to provide insight into their function and roles in diseases. N6-methyladenosine (m6A) is one of the most abundant RNA modifications in eukaryotes. Recent studies have revealed that aberrant m6A modifications are involved in many diseases. Findings: In this study, we present a user-friendly web server called "m6ASNP" that is dedicated to the identification of genetic variants that target m6A modification sites. A random forest model was implemented in m6ASNP to predict whether the methylation status of an m6A site is altered by the variants that surround the site. In m6ASNP, genetic variants in a standard variant call format (VCF) are accepted as the input data, and the output includes an interactive table that contains the genetic variants annotated by m6A function. In addition, statistical diagrams and a genome browser are provided to visualize the characteristics and to annotate the genetic variants. Conclusions: We believe that m6ASNP is a very convenient tool that can be used to boost further functional studies investigating genetic variants. The web server "m6ASNP" is implemented in JAVA and PHP and is freely available at [60]. PMID- 29617792 TI - Evaluating intimal hyperplasia under clinical conditions. AB - OBJECTIVES: Open arterial revascularization using venous segments is frequently associated with the development of intimal hyperplasia (IH), leading to severe restenosis and graft failure. The lack of treatment to prevent this pathology is a major problem. Therefore, we generated a new porcine model, which closely mimics the clinical development of human IH, to test the therapeutic potential of candidate drugs. METHODS: A patch of jugular vein was sutured to the right common carotid artery of pigs, to expose the vein to haemodynamic conditions of the arterial bed. Four weeks after surgery, the operated vessels which received no further treatment (the control group) were compared with (i) contralateral, non operated vessels (the healthy group); (ii) vessels of pigs that received a perivascular application of a drug-free microparticle gel (the placebo group) and (iii) vessels of pigs that perioperatively received the same gel loaded with 10 mg atorvastatin (the atorvastatin group). RESULTS: When compared with non operated vessels, all operated segments displayed a sizable IH which was thicker in the venous patch than in the host artery. These alterations were associated with a thickening of the intima layer of both vessels in the absence of inflammation. The intima/media ratio has been significantly increased by 2000 fold in the vein patches. Perivascular application of atorvastatin did not prevent IH formation. However, the drug increased the adventitial neovascularization in the operated vessels. CONCLUSIONS: The novel porcine model allows for monitoring IH formation under haemodynamic conditions which mimic clinical situations. It should facilitate the screening of innovative treatments to prevent restenosis. PMID- 29617793 TI - The effect of biologic factors and adjunctive therapies on orthodontically induced inflammatory root resorption: a systematic review and meta-analysis. AB - Objective: Biologic factors and adjunctive therapies are known to affect the degree of orthodontically induced inflammatory root resorption (OIIRR). However, a systematic overall assessment of their impact on OIIRR has not previously been reported. We, therefore, aimed to systematically assess effects on OIIRR of biologic factors and adjunctive therapies in human and animal subjects. Methods: A comprehensive search strategy was performed for all major electronic databases. Two reviewers independently selected studies, undertook data extraction and assessed the risk of bias for all included studies according to a pre-specified protocol inspired by Cochrane and the PRISMA guidelines. Eligible studies compared the effect of intervention(s) in an experimental and a control group. Results: A total of 9 human and 36 animal trials met the inclusion criteria. Where appropriate, random-effect meta-analyses were carried out to determine the outcome measure OIIRR. The random-effect meta-analysis demonstrated that OIIRR was inhibited by fluoride (ES = -2.08 [-3.02, -1.14]), thyroxine (ES = -1.91 [ 3.20, -0.61]), and steroids (ES = -2.79 [-4.26, -1.33]). In contrast, corticotomy (ES = 0.38 [0.05, 0.71]) significantly enhanced OIIRR. Conclusion: In animals, administration of fluoride, thyroxine and steroids decreased OIIRR, whereas corticotomy increased OIIRR. In general, the effect on OIIRR increased with higher dosage and/or exposure time. Despite methodological limitations of the included studies, this systematic review provides an important overview of the effect of biologic factors and adjunctive therapies on OIIRR. PMID- 29617794 TI - Reproductive intentions and use of reproductive health care among female survivors of childhood cancer. AB - STUDY QUESTION: Do female childhood cancer survivors (CCSs) express a decreased desire to have children and do they use reproductive health care more often compared to women without a history of cancer? SUMMARY ANSWER: Overall, no difference was found in the desire to have children between CCSs and controls, whereas CCSs consult a fertility specialist more often, at a younger age, and sooner after their first attempt at conceiving. WHAT IS KNOWN ALREADY: Female CCSs may face a shorter than anticipated reproductive window as a result of their cancer treatment. Little is known about their desire to have children and use of reproductive health care, especially in relation to their former cancer treatment. STUDY DESIGN, SIZE, DURATION: This study is part of the DCOG LATER VEVO study, a nationwide retrospective cohort study on female fertility in Dutch CCSs. In total, 1749 CCSs and 1673 controls were invited for the study. Data collection took place between January 2008 and May 2014. PARTICIPANTS/MATERIALS, SETTING, METHODS: Data on the desire to have children and use of reproductive health care were collected by questionnaire. The control group consisted of sisters from CCSs and females from the general population. In total, 1106 (63%) CCSs and 818 (49%) controls completed the questionnaire. MAIN RESULTS AND THE ROLE OF CHANCE: Overall, no difference was found in the desire to have children between CCSs and controls (86% and 89%, respectively). However, survivors of a CNS tumour were less likely to desire children and CCSs without biological children at time of study were more likely to report that their desire to have children was unfulfilled because of medical reasons (9%), compared to controls (1%). In total, 12% of CCSs ever consulted a fertility specialist compared to 10% of controls (OR = 1.7, 95% CI: 1.3-2.4). Mean (SD) age at time of their first visit was 27.7 (4.4) years for CCSs and 29.9 (3.9) years for controls (P < 0.01). In total, 43% of CCSs consulted a fertility specialist within 12 months after they had started trying to achieve a pregnancy, compared to 27% of controls. Risk factors for consulting a fertility specialist included a previous diagnosis of renal tumour, leukaemia, lymphoma or a CNS tumour, and treatment with alkylating chemotherapy, gonadotoxic radiotherapy or both. In total, 70% of CCSs reported a female factor as cause of subfertility compared to 34% of controls (OR = 4.5, 95% CI: 2.3-8.7) and in this specific group, CCSs seemed more likely to use fertility treatment (OR = 2.9, 95% CI: 1.0-8.2). LIMITATIONS, REASONS FOR CAUTION: Because of the low number of CCSs who used fertility treatment, we were not able to look at specific diagnoses and treatment types associated with using fertility treatment. Nevertheless, we were able to identify diagnostic- and treatment related risk factors for consulting a fertility specialist. Details regarding consultations with a fertility specialist and fertility treatment were based on self-report and may therefore be subject to recall bias. WIDER IMPLICATIONS OF THE FINDINGS: Decisions about parenthood affect all CCSs. It's important to evaluate reproductive intentions and function timely after cancer treatment, so CCSs can be adequately counselled regarding family planning and fertility treatment. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the Dutch Cancer Society (Grant no. VU 2006-3622) and the Children Cancer Free Foundation (Project no. 20). TRIAL REGISTRATION NUMBER: NTR2922. PMID- 29617796 TI - Primary cardiac synovial sarcoma: an asymptomatic patient 8 years after the primary surgery. AB - Primary cardiac synovial sarcoma is an extremely rare disease. Its prognosis is poor with a median survival time of 24 months, even when adequate and timely treatment is given. This case reports a 61-year-old woman presenting with primary cardiac synovial sarcoma with an 8-year survival time following surgical and adjuvant chemotherapy. PMID- 29617795 TI - Team dynamics within quality improvement teams: a scoping review. AB - Purpose: This scoping review examines what is known about the processes of quality improvement (QI) teams, particularly related to how teams impact outcomes. The aim is to provide research-informed guidance for QI leaders and to inform future research questions. Data sources: Databases searched included: MedLINE, EMBASE, CINAHL, Web of Science and SCOPUS. Study selection: Eligible publications were written in English, published between 1999 and 2016. Articles were included in the review if they examined processes of the QI team, were related to healthcare QI and were primary research studies. Studies were excluded if they had insufficient detail regarding QI team processes. Data extraction: Descriptive detail extracted included: authors, geographical region and health sector. The Integrated (Health Care) Team Effectiveness Model was used to synthesize findings of studies along domains of team effectiveness: task design, team process, psychosocial traits and organizational context. Results of data synthesis: Over two stages of searching, 4813 citations were reviewed. Of those, 48 full-text articles are included in the synthesis. This review demonstrates that QI teams are not immune from dysfunction. Further, a dysfunctional QI team is not likely to influence practice. However, a functional QI team alone is unlikely to create change. A positive QI team dynamic may be a necessary but insufficient condition for implementing QI strategies. Conclusions: Areas for further research include: interactions between QI teams and clinical microsystems, understanding the role of interprofessional representation on QI teams and exploring interactions between QI team task, composition and process. PMID- 29617797 TI - Distributed deep learning networks among institutions for medical imaging. AB - Objective: Deep learning has become a promising approach for automated support for clinical diagnosis. When medical data samples are limited, collaboration among multiple institutions is necessary to achieve high algorithm performance. However, sharing patient data often has limitations due to technical, legal, or ethical concerns. In this study, we propose methods of distributing deep learning models as an attractive alternative to sharing patient data. Methods: We simulate the distribution of deep learning models across 4 institutions using various training heuristics and compare the results with a deep learning model trained on centrally hosted patient data. The training heuristics investigated include ensembling single institution models, single weight transfer, and cyclical weight transfer. We evaluated these approaches for image classification in 3 independent image collections (retinal fundus photos, mammography, and ImageNet). Results: We find that cyclical weight transfer resulted in a performance that was comparable to that of centrally hosted patient data. We also found that there is an improvement in the performance of cyclical weight transfer heuristic with a high frequency of weight transfer. Conclusions: We show that distributing deep learning models is an effective alternative to sharing patient data. This finding has implications for any collaborative deep learning study. PMID- 29617798 TI - Inpatient burden of esophageal cancer and analysis of factors affecting in hospital mortality and length of stay. AB - Esophageal cancer (EC) continues to be a major source of morbidity and mortality in the United States. However, there has been a relative dearth of research into hospital utilization in patients with EC. This study examines temporal trends in hospital admissions, length of stay (LOS), mortality, and costs associated with EC. In addition, we also analyzed factors associated with inpatient mortality and LOS. We interrogated National Inpatient Sample (NIS), a large registry of inpatient data, to retrieve information about various demographic and factors associated with hospital stay in patients who were admitted for EC between the years 1998 and 2013 in the United States. After examining trends over time, multivariate analysis was performed to identify factors associated with LOS and mortality. During 1998-2013, 538,776 hospital stays with principal diagnosis of EC were reviewed. Number of hospital stays and inpatient charges increased by 397 per year (+/-67.8; P < 0.0001) and $3,033 per patient per year (+/-135; <0.0001) respectively. Mortality and LOS decreased by 0.23% per year (+/-0.03; P < 0.0001) and 0.07 days per year (+/-0.006; P < 0.0001) respectively. Multiple factors associated with LOS and mortality were outlined. Despite overall increase in hospital utilization with respect to number of admissions and inpatient charges, inpatient mortality and LOS associated with EC declined. Factors associated with inpatient mortality and LOS may help drive clinical decision-making and influence healthcare or hospital policy. PMID- 29617799 TI - Adipose tissue-specific responses reveal an important role of lipogenesis during heat stress adaptation in pigs1. AB - Elevated ambient temperature causes heat stress in pigs, resulting in reduced animal performance. To better understand tissue responses to heat stress in pigs, we conducted a study in which pigs were subjected to four treatments: acute (24 h) heat stress (AHS) at 35 degrees C +/- 1 ambient temperature, chronic (7 d) heat stress at 35 degrees C +/- 1 (HS) or normal ambient temperature (20 degrees C+/- 1) for 7 d with ad-libitum feeding (Con) or with pair-feeding to the feed intake (FI) of the HS pigs (PF). Heat stress decreased FI by approximately 36% and 64% in HS and AHS treatments respectively, compared with Con (P < 0.01). Concentration of free fatty acids (FFA) was elevated in AHS compared to HS (P = 0.031). Serum insulin concentration was lower in PF than Con (P = 0.045). Blood urea nitrogen (BUN) concentration was elevated in HS compared with Con and PF (P = 0.008), but lower (P < 0.021) in AHS compared to HS. In the subcutaneous adipose tissue, the mRNA and protein abundance of PCK1 were higher (P < 0.05) in the HS treatment than Con and PF, and also higher (P < 0.05) in HS than AHS. However, there was no difference in GK mRNA between Con, PF, and HS, although its expression was lower (P = 0.003) in AHS vs. HS. Protein abundance of the ER stress marker, CCAT/enhancer-binding homologous protein (CHOP), was higher in PF than Con (P < 0.05), and higher (P = 0.033) in HS than AHS in subcutaneous fat. In mesenteric fat, PCK1 mRNA was higher (P < 0.001) in the HS than Con and PF treatments. Additionally, expression of PCK1 was lower (P = 0.039) in AHS vs. HS. Expression of PCK1 was downregulated (P < 0.05) in the liver of PF pigs compared to other treatments, but most other genes measured were not affected by treatment in the liver and muscle tissues. These results confirm that heat stress induces a robust adipose tissue response in favor of increased lipid storage. This indicates that adipose tissue might play an important role in heat stress adaptation. PMID- 29617802 TI - Tetralogy of Fallot with critical biventricular dysfunction: is surgical correction achievable? AB - We describe the case of a 32-month-old patient from a developing country with tetralogy of Fallot associated with a severe biventricular dysfunction. This association is rare but makes the surgical strategy complex and potentially contraindicated. An acute severe hypoxic episode led us to perform palliative rescue intervention involving the placement of an undersized systemic-to pulmonary shunt. This surgery was well tolerated and allowed a fast and impressive recovery of the ventricular function, making complete repair possible. PMID- 29617801 TI - Influence of Electron-Holes on DNA Sequence-Specific Mutation Rates. AB - Biases in mutation rate can influence molecular evolution, yielding rates of evolution that vary widely in different parts of the genome and even among neighboring nucleotides. Here, we explore one possible mechanism of influence on sequence-specific mutation rates, the electron-hole, which can localize and potentially trigger a replication mismatch. A hole is a mobile site of positive charge created during one-electron oxidation by, for example, radiation, contact with a mutagenic agent, or oxidative stress. Its quantum wavelike properties cause it to localize at various sites with probabilities that vary widely, by orders of magnitude, and depend strongly on the local sequence. We find significant correlations between hole probabilities and mutation rates within base triplets, observed in published mutation accumulation experiments on four species of bacteria. We have also computed hole probability spectra for hypervariable segment I of the human mtDNA control region, which contains several mutational hotspots, and for heptanucleotides in noncoding regions of the human genome, whose polymorphism levels have recently been reported. We observe significant correlations between hole probabilities, and context-specific mutation and substitution rates. The correlation with hole probability cannot be explained entirely by CpG methylation in the heptanucleotide data. Peaks in hole probability tend to coincide with mutational hotspots, even in mtDNA where CpG methylation is rare. Our results suggest that hole-enhanced mutational mechanisms, such as oxidation-stabilized tautomerization and base deamination, contribute to molecular evolution. PMID- 29617803 TI - Genome-wide association study for feed efficiency traits using SNP and haplotype models. AB - Feed costs comprise the majority of variable expenses in beef cattle systems making feed efficiency an important economic consideration within the beef industry. Due to the expense of recording individual feed-intake phenotypes, a genomic-enabled approach could be advantageous toward improving this economically relevant trait complex. A genome-wide association study (GWAS) was performed using 748 crossbred steers and heifers representing seven sire breeds with phenotypes for ADG and ADFI. Animals were genotyped with the BovineSNP50v2 BeadChip containing approximately 54,000 SNP. Both traits were analyzed using univariate SNP-based (BayesC) and haplotype-based (BayesIM) models and jointly using BayesIM to perform a bivariate GWAS. For BayesIM, a hidden Markov model (HMM) of haplotype segments of variable length was built where haplotypes were mapped to clusters based on local similarity. The estimated HMM was then used to assign haplotype cluster genotypes, instead of SNP genotypes, as latent covariates in a Bayesian mixture model. The number of haplotype clusters at each location was assumed to be either 8 (BayesIM8) or 16 (BayesIM16). A total of three univariate analyses for each trait and two bivariate analyses were performed. Posterior SD (PSD) for ADG were 0.28 (0.08), 0.37 (0.11), 0.37 (0.11), 0.35 (0.11), and 0.35 (0.12) for BayesC, BayesIM8, BayesIM16, BayesIM8 bivariate, and BayesIM16 bivariate, respectively. ADFI PSD were 0.30 (0.07), 0.44 (0.13), 0.42 (0.12), 0.38 (0.10), and 0.38 (0.10) for the same models. The top 1% of 1-Mb windows that explained the largest fraction of genetic variation in common between univariate SNP and haplotype models ranged from 24% to 40% and from 20% to 32% for ADG and ADFI, respectively. Spearmen rank correlations between molecular breeding values from SNP and haplotype-based models in the training data were similar for both traits (>0.96) suggesting that either model would lead to similar rankings of animals, although resolution of potential QTL appeared to be greater for BayesIM. PMID- 29617800 TI - Plastid Transcript Editing across Dinoflagellate Lineages Shows Lineage-Specific Application but Conserved Trends. AB - Dinoflagellates are a group of unicellular protists with immense ecological and evolutionary significance and cell biological diversity. Of the photosynthetic dinoflagellates, the majority possess a plastid containing the pigment peridinin, whereas some lineages have replaced this plastid by serial endosymbiosis with plastids of distinct evolutionary affiliations, including a fucoxanthin pigment containing plastid of haptophyte origin. Previous studies have described the presence of widespread substitutional RNA editing in peridinin and fucoxanthin plastid genes. Because reports of this process have been limited to manual assessment of individual lineages, global trends concerning this RNA editing and its effect on the biological function of the plastid are largely unknown. Using novel bioinformatic methods, we examine the dynamics and evolution of RNA editing over a large multispecies data set of dinoflagellates, including novel sequence data from the peridinin dinoflagellate Pyrocystis lunula and the fucoxanthin dinoflagellate Karenia mikimotoi. We demonstrate that while most individual RNA editing events in dinoflagellate plastids are restricted to single species, global patterns, and functional consequences of editing are broadly conserved. We find that editing is biased toward specific codon positions and regions of genes, and generally corrects otherwise deleterious changes in the genome prior to translation, though this effect is more prevalent in peridinin than fucoxanthin lineages. Our results support a model for promiscuous editing application subsequently shaped by purifying selection, and suggest the presence of an underlying editing mechanism transferred from the peridinin-containing ancestor into fucoxanthin plastids postendosymbiosis, with remarkably conserved functional consequences in the new lineage. PMID- 29617804 TI - Feasibility of transcatheter aortic valve implantation in patients with coronary heights <=7 mm: insights from the transcatheter aortic valve implantation Karlsruhe (TAVIK) registry. AB - OBJECTIVES: Transcatheter aortic valve implantation (TAVI) in patients with low coronary heights is generally denied but is not impossible. Information about these high-risk procedures is sparse. METHODS: Since May 2008, data of more than 3000 patients who had TAVI were prospectively collected in the institutional TAVI Karlsruhe registry. Characteristics, peri- and postoperative outcome of patients with low coronary heights of <=7 mm were analysed according to the Valve Academic Research Consortium-2. RESULTS: Eighty-six patients with an average coronary height of 6.4 +/- 1.1 mm (mean age 81.0 +/- 5.3 years, logistic EuroSCORE I 19.6 +/- 13.3%) were treated. TAVI was performed in 72 transfemoral (83.7%) and 14 transapical (16.3%) cases using 44 CoreValve/Evolut R (51.2%), 21 Sapien XT/S3 (24.4%), 14 ACURATE (16.3%), 5 Lotus (5.8%) and 2 Portico (2.3%) prostheses. Ten procedures were valve-in-valve (VinV) TAVI (VinV, 11.6%). The 72-h, 30-day, 1 year and follow-up (3.0 +/- 1.6 years) mortality rates were 2.3%, 8.0%, 10.5% and 26.7%, respectively. Within 30 days, 4 cardiac deaths and 3 non-cardiac deaths occurred (4.7% and 3.5%). Three coronary obstructions (3.5%) occurred-2 during VinV TAVI. One patient was connected to extracorporeal circulation that could not be weaned later due to an unsuccessful percutaneous coronary intervention. Another patient, the only conversion (1.2%), required delayed surgical valve replacement. The third patient died of right heart failure after aortic dissection. The procedural success rate was 95.3%. VinV procedures were associated with increased follow-up deaths (P < 0.001; hazard ratio 7.96). CONCLUSIONS: Coronary-related complications in TAVI procedures in patients with coronary heights <=7 mm occurred less frequently, but once they occurred, they were serious. These TAVI procedures are feasible, with a high procedural success rate, but meticulous preoperative planning should be mandatory. In VinV procedures, the follow-up mortality rate is increased; therefore, we do not recommend these procedures. PMID- 29617805 TI - Relationship between chemical composition of native forage and nutrient digestibility by Tibetan sheep on the Qinghai-Tibetan Plateau. AB - To better utilize native pasture at the high altitude region, three-consecutive year feeding experiments and a total of seven metabolism trials were conducted to evaluate the impact of three forage stages of maturity on the chemical composition, nutrient digestibility, and energy metabolism of native forage in Tibetan sheep on the Qinghai-Tibetan Plateau (QTP). Forages were harvested from June to July, August to October, and November to December of 2011 to 2013, corresponding to the vegetative, bloom, and senescent stages of the annual forages. Twenty male Tibetan sheep were selected for each study and fed native forage ad libitum. The digestibility of DM, OM, CP, NDF, ADF, DE, DE/GE, and ME/GE were greatest (P < 0.01) from the vegetative stage, intermediate (P < 0.01) from the bloom stage, and least (P < 0.01) from the senescent stage. Nutrient digestibility and energy parameters correlated positively (linear, 0.422 to 0.778; quadratic, 0.568 to 0.815; P < 0.01) with the CP content of forage but correlated negatively with the content of NDF (linear, 0.343 to 0.689; quadratic, 0.444 to 0.777; P <= 0.02), ADF (linear, 0.563 to 0.766; quadratic, 0.582 to 0.770; P < 0.01), and ether extract (EE, linear, 0.283 to 0.574; quadratic, 0.366 to 0.718; P <= 0.04) of forage. For each predicted variable, the prediction of DMI expressed as grams per kilogram of BW (g/kg BW.d) yielded a greater R2 value (0.677 to 0.761 vs. 0.616 to 0.711) compared with the equations of DMI expressed as g/kg metabolic BW by step-wise regression. The results suggest that parameters of forage CP, NDF, and ADF content were most closely related to nutrient digestibility. Contrary to previous studies, in this study, ADF content had a greater linear relationship (0.766 vs. 0.563 to 0.732) with OM digestibility than the other parameters of nutrient digestibility. The quadratic relationship between forage CP content and CP digestibility indicates that when forage CP content exceeds the peak point (9.7% DM in the present study), increasing forage CP content could decrease CP digestibility when Tibetan sheep were offered native forage alone on the QTP. Additionally, using the forage CP, EE, NDF, and ADF content to predict DMI (g/kg BW.d) yielded the best fit equation for Tibetan sheep living in the northeast portion of the QTP. PMID- 29617806 TI - Overexpression screen reveals transcription factors involved in lipid accumulation in Yarrowia lipolytica. AB - Yarrowia lipolytica is a non-conventional oleaginous yeast that displays high lipid titers and yields; its production capacity holds significant promise for industrial biolipid applications. While its lipid metabolism has been widely studied, little is known about its transcriptional regulatory network. Deciphering the role of transcriptional regulators is crucial for understanding lipid accumulation, a complex phenomenon. To identify the transcription factors involved in lipid metabolism, we developed a systematic overexpression approach for 148 putative transcription factors. Analyses of overexpressing transformants revealed that 38 had an impact on lipid accumulation under at least one of the growth conditions tested. For most of these factors, our results provide the first experimentally determined functional annotation. Our data suggest that the regulation network differs depending on the carbon source, which is critical information when carrying out industrial bioprocesses. These results will therefore help guide further rational metabolic engineering for improving biolipid production by Y. lipolytica. Moreover, this work has created the largest collection of Y. lipolytica overexpressing strains to date, which will be useful in phenotype screening. PMID- 29617807 TI - Effects of feeding monensin to bred heifers fed in a drylot on nutrient and energy balance. AB - The objective of this study was to determine if feeding monensin would improve diet digestion, energy and nitrogen balance in bred heifers receiving a limit-fed corn stalk-based diet. Sixteen pregnant Meat Animal Research Center (MARC) III composite heifers were used in a 161-d completely randomized design. Heifers were randomly assigned to one of two treatments, no monensin (CON) or 150 mg/d monensin (MON), with eight heifers in each treatment group. Heifers were limit fed a corn stalk-based diet at 100% of MEm requirements. Effects of monensin on energy and nitrogen balance were determined via total fecal and urine collections and open-circuit respiration calorimetry. Total fecal and urine collection occurred on d 14, 42, and 161 of monensin feeding, and calorimetry measurements were made on d 0, 3, 14, 28, 42, and 161 of monensin feeding. DMI was not different (P = 0.94) for CON and MON heifers and, by design, increased (P < 0.01) from d 14 to d 161 of the trial to account for increasing fetal growth requirements. No differences (P = 0.91) in GE intake were observed between CON and MON heifers, and DE and ME intakes did not differ (P > 0.58) with monensin inclusion. DM, OM, NDF, and ADF digestion did not differ (P > 0.52) between treatments. Fecal, methane, urinary, and heat energy losses were not different (P > 0.16) for MON and CON heifers. Methane production was not different between treatments when expressed as daily liters of methane (P = 0.40); however, MON heifers produced 7% less (P = 0.03) methane per day than CON heifers when expressed as liters of methane produced on a metabolic body weight (MBW) basis. Furthermore, monensin had no effect (P = 0.36) on overall retained energy (RE). Nitrogen intake and excretion was not different (P > 0.13) between treatment groups. Results of this experiment indicate that adding monensin to limit-fed, corn stalk-based diets may not have a large effect on the energy and nitrogen balance of confined heifers. PMID- 29617809 TI - Experimental Enteric Bacterial Infections in Pigs. PMID- 29617808 TI - Novel aspects of the assembly and activation of inflammasomes with focus on the NLRC4 inflammasome. AB - Inflammasomes are multiprotein structures that activate caspase-1, support secretion of pro-inflammatory cytokines, IL-1beta and IL-18, and also induce inflammatory programmed cell death, termed pyoptosis. Inflammasomes are activated in response to the detection of endogenous and microbially derived danger signals and are mediated by several classes of inflammasome-forming sensors. These include several nucleotide-binding proteins of the NOD-like receptor (NLR) family, including NLRP1, NLRP3 and NLRC4, as well as the proteins Absent in Melanoma 2 (AIM2) and Pyrin. Mutations in genes encoding some of these sensors have been found to be associated with gain-of-function monogenetic inflammatory disorders in humans. Genetic, biochemical and structural studies have begun to demonstrate how these proteins sense danger signals and to shed light on the step by-step processes that are necessary for the assembly of inflammasomes, in both physiologic responses to pathogens and potentially in autoinflammatory conditions. Recent biochemical studies of pro-caspase-1 and an adapter protein known as ASC suggest that inflammasomes act to initiate self-generating effector filaments responsible for activating caspase-1 and initiating downstream signaling. These studies have suggested a model of molecular events from sensor activation to inflammasome formation that may describe processes that are universal to inflammasome formation. PMID- 29617810 TI - Two Groups of Cocirculating, Epidemic Clostridiodes difficile Strains Microdiversify through Different Mechanisms. AB - Clostridiodes difficile strains from the NAPCR1/ST54 and NAP1/ST01 types have caused outbreaks despite of their notable differences in genome diversity. By comparing whole genome sequences of 32 NAPCR1/ST54 isolates and 17 NAP1/ST01 recovered from patients infected with C. difficile we assessed whether mutation, homologous recombination (r) or nonhomologous recombination (NHR) through lateral gene transfer (LGT) have differentially shaped the microdiversification of these strains. The average number of single nucleotide polymorphisms (SNPs) in coding sequences (NAPCR1/ST54 = 24; NAP1/ST01 = 19) and SNP densities (NAPCR1/ST54 = 0.54/kb; NAP1/ST01 = 0.46/kb) in the NAPCR1/ST54 and NAP1/ST01 isolates was comparable. However, the NAP1/ST01 isolates showed 3* higher average dN/dS rates (8.35) that the NAPCR1/ST54 isolates (2.62). Regarding r, whereas 31 of the NAPCR1/ST54 isolates showed 1 recombination block (3,301-8,226 bp), the NAP1/ST01 isolates showed no bases in recombination. As to NHR, the pangenome of the NAPCR1/ST54 isolates was larger (4,802 gene clusters, 26% noncore genes) and more heterogeneous (644 +/- 33 gene content changes) than that of the NAP1/ST01 isolates (3,829 gene clusters, ca. 6% noncore genes, 129 +/- 37 gene content changes). Nearly 55% of the gene content changes seen among the NAPCR1/ST54 isolates (355 +/- 31) were traced back to MGEs with putative genes for antimicrobial resistance and virulence factors that were only detected in single isolates or isolate clusters. Congruently, the LGT/SNP rate calculated for the NAPCR1/ST54 isolates (26.8 +/- 2.8) was 4* higher than the one obtained for the NAP1/ST1 isolates (6.8 +/- 2.0). We conclude that NHR-LGT has had a greater role in the microdiversification of the NAPCR1/ST54 strains, opposite to the NAP1/ST01 strains, where mutation is known to play a more prominent role. PMID- 29617813 TI - CORRIGENDUM FOR "Juvenile-Specific Burst Firing of Terminal Nerve GnRH3 Neurons Suggests Novel Functions in Addition to Neuromodulation". PMID- 29617811 TI - Patterns of Population Variation in Two Paleopolyploid Eudicot Lineages Suggest That Dosage-Based Selection on Homeologs Is Long-Lived. AB - Genes that are inherently subject to strong selective constraints tend to be overretained in duplicate after polyploidy. They also continue to experience similar, but somewhat relaxed, constraints after that polyploidy event. We sought to assess for how long the influence of polyploidy is felt on these genes' selective pressures. We analyzed two nested polyploidy events in Brassicaceae: the At-alpha genome duplication that is the most recent polyploidy in the model plant Arabidopsis thaliana and a more recent hexaploidy shared by the genus Brassica and its relatives. By comparing the strength and direction of the natural selection acting at the population and at the species level, we find evidence for continued intensified purifying selection acting on retained duplicates from both polyploidies even down to the present. The constraint observed in preferentially retained genes is not a result of the polyploidy event: the orthologs of such genes experience even stronger constraint in nonpolyploid outgroup genomes. In both the Arabidopsis and Brassica lineages, we further find evidence for segregating mildly deleterious variants, confirming that the population-level data uncover patterns not visible with between-species comparisons. Using the A. thaliana metabolic network, we also explored whether network position was correlated with the measured selective constraint. At both the population and species level, nodes/genes tended to show similar constraints to their neighbors. Our results paint a picture of the long-lived effects of polyploidy on plant genomes, suggesting that even yesterday's polyploids still have distinct evolutionary trajectories. PMID- 29617812 TI - Postruminal digestion of starch infused into the abomasum of heifers with or without exogenous amylase administration. AB - The effect of an exogenous amylase on postruminal digestion of starch infused into the abomasum of cattle was studied. Four rumen-cannulated heifers were fed 5.5 kg DM/d of a diet without starch, and assigned randomly to a crossover design. The experiment consisted of 2 periods lasting 23 d each with 10 d for adaptation to the diet followed by 13 d of abomasal infusion and sample collection. During the first 3 d of each infusion phase, isotonic saline solution was infused (1 liter/h) for measurement of baseline values in feces, followed by daily infusions of 880 g DM corn starch (1 kg/10 liters of water) without or with the addition of 2% of amylase. Titanium dioxide (10 g/d) was ruminally administered for estimation of fecal excretion. Digestion of starch in small intestine was calculated as the difference between the amounts of infused starch, disappeared from hindgut and fecal excretion. The apparent disappearance of starch from the hindgut was estimated based on the increment of microbial nitrogen (N) excretion due to starch infusion (1 g microbial N/100 g fermented starch) compared to baseline values. The concentration of purine bases in feces was used to estimate excretion of microbial N. Microbial N excretion increased with starch infusion (P < 0.05) but was not influenced by amylase (P = 0.81). Starch disappearance from the small intestine was not improved by amylase (P = 0.78) and averaged 85%. Amylase affected neither blood concentration of glucose (P = 0.80) nor of insulin (P = 0.26), but glucagon was lower without (P < 0.0001) than with amylase. The infusion of starch increased fecal excretion of total VFA (acetate, propionate, and butyrate) by 53% (P < 0.05), which indicates increased carbohydrate fermentation in the hindgut and incomplete digestion of starch in the small intestine. However, the excretion of total VFA was not affected by amylase (P = 0.66). Lactate excretion was higher at the second day of starch infusion (P < 0.05) without than with amylase, which suggests lower flow of starch from the small intestine to the hindgut due to a possible effect of amylase addition in animals not adapted to starch digestion. However, lactate excretion returned near to baseline values within 2 d, which was probably due to increase of lactate-utilizing bacteria and the adaptation of the microbial population in the hindgut. Further studies with higher starch levels and addition of amylase are recommended. PMID- 29617815 TI - Resistance to Dolutegravir-A Chink in the Armor? PMID- 29617814 TI - A Respiratory Syncytial Virus Vaccine Based on the Small Hydrophobic Protein Ectodomain Presented With a Novel Lipid-Based Formulation Is Highly Immunogenic and Safe in Adults: A First-in-Humans Study. AB - Background: Respiratory syncytial virus infection can cause lower respiratory tract infection in older adults comparable to influenza, but no vaccines are available. Methods: This was a randomized, observer-blinded, first-in-humans study of a novel synthetic RSV antigen based on the ectodomain of the small hydrophobic glycoprotein (SHe) of RSV subgroup A, formulated with either the lipid and oil-based vaccine platform DepoVax (DPX-RSV[A]) or alum (RSV[A]-Alum), in healthy, 50-64-year-old individuals. Two dose levels (10 or 25 ug) of SHe with each formulation were compared to placebo. A booster dose was administered on day 56. Results: There was no indication that the vaccine was unsafe. Mild pain, drowsiness, and muscles aches were the most common solicited adverse events (AEs), and the frequencies of the AEs did not increase after dose 2. Robust anti SHe-specific immune responses were demonstrated in the DPX-RSV(A) 10-MUg and 25 MUg groups (geometric mean titer, approximately 10-fold and 100-fold greater than that of placebo at days 56 and 236, respectively), and responses were sustained in the DPX-RSV(A) 25-MUg group at day 421. Responses to the RSV(A)-Alum vaccines were very low. Conclusions: A novel antigen from the SH protein of RSV, formulated in a lipid and oil-based vaccine platform, was highly immunogenic, with sustained antigen-specific antibody responses, and had an acceptable safety profile. PMID- 29617816 TI - Immunization With a Novel Human Type 5 Adenovirus-Vectored Vaccine Expressing the Premembrane and Envelope Proteins of Zika Virus Provides Consistent and Sterilizing Protection in Multiple Immunocompetent and Immunocompromised Animal Models. AB - Background: Zika virus (ZIKV) infection may be associated with severe complications and disseminated via both vector-borne and nonvector-borne routes. Adenovirus-vectored vaccines represent a favorable controlling measure for the ZIKV epidemic because they have been shown to be safe, immunogenic, and rapidly generable for other emerging viral infections. Evaluations of 2 previously reported adenovirus-vectored ZIKV vaccines were performed using nonlethal animal models and/or nonepidemic ZIKV strain. Methods: We constructed 2 novel human adenovirus 5 (Ad5)-vectored vaccines containing the ZIKV premembrane-envelope (Ad5-Sig-prM-Env) and envelope (Ad5-Env) proteins, respectively, and evaluated them in multiple nonlethal and lethal animal models using epidemic ZIKV strains. Results: Both vaccines elicited robust humoral and cellular immune responses in immunocompetent BALB/c mice. Dexamethasone-immunosuppressed mice vaccinated with either vaccine demonstrated robust and durable antibody responses and significantly lower blood and tissue viral loads than controls (P < .05). Similar findings were also observed in interferon-alpha/beta receptor-deficient A129 mice. In both of these immunocompromised animal models, Ad5-Sig-prM-Env vaccinated mice had significantly (P < .05) higher titers of anti-ZIKV-specific neutralizing antibody titers and lower (undetectable) viral loads than Ad5-Env vaccinated mice. The close correlation between the neutralizing antibody titer and viral load helped to explain the better protective effect of Ad5-Sig-prM-Env than Ad5-Env. Anamnestic response was absent in Ad5-Sig-prM-Env-vaccinated A129 mice. Conclusions: Ad5-Sig-prM-Env provided sterilizing protection against ZIKV infection in mice. PMID- 29617817 TI - Decreased PECAM1-mediated TGF-beta1 expression in the mid-secretory endometrium in women with recurrent implantation failure. AB - STUDY QUESTION: Is recurrent implantation failure (RIF) associated with decreased expression of platelet and endothelial cell adhesion molecule 1 (PECAM1) and transforming growth factor beta1 (TGF-beta1) in the endometrium during the implantation window? SUMMARY ANSWER: The present study demonstrates that the expression of PECAM1 and TGF-beta1 is significantly decreased in the mid secretory endometrium in women with RIF, which may account for embryo implantation failure. WHAT IS KNOWN ALREADY: RIF has become a bottleneck issue that hampers the improvement of pregnancy rates in IVF-embryo transfer (IVF-ET). The causes of RIF are complex and may involve the dysregulation of various growth factors, metabolites, and inflammatory cytokines. At present, the precise pathogenesis of RIF has not been elucidated. STUDY DESIGN, SIZE, DURATION: This was a prospective case-control study. Endometrial tissue samples were obtained from January 2014 to December 2016 from two groups of women who had undergone IVF (RIF group, 22 women who underwent >=3 ETs including a total of >=4 good-quality embryos without pregnancy, control group, 18 women who conceived in their first treatment cycle). At the same time, samples were obtained from 18 women with infertility secondary to tubal factor in the early proliferative, late proliferative and mid-secretory phases of the menstrual cycle (n = 6 per group). Samples used for isolation of primary human endometrial epithelial cells and stromal cells (HEECs and HESCs) were collected in December 2017 from six women with infertility secondary to tubal factor. PARTICIPANTS/MATERIALS, SETTING, METHODS: We investigated gene expression using integrative whole genome expression microarray analysis, including differentially expressed gene screening, principal component analysis, and functional enrichment analysis. RT qPCR, western blotting, immunohistochemistry, immunofluorescence co-localization analysis and short hairpin RNA (shRNA) plasmid transfection in Ishikawa cell line, HEECs and HESCs were used to investigate the expression of PECAM1 and TGF beta1. MAIN RESULTS AND THE ROLE OF CHANCE: Integrative data mining of whole genome expression profiles identified cell adhesion as a key regulator in RIF. Database retrieval and literature review screened several novel cell adhesion related genes that might participate in embryo implantation, which include PECAM1, intercellular adhesion molecule 2 (ICAM2), integrin subunit beta2 (ITGB2), selectin P (SELP) and TEK receptor tyrosine kinase (TEK). Among these targets, the mRNA and protein levels of PECAM1 were significantly lower in the RIF group than those in the control group. During the menstrual cycles of women with secondary infertility, the protein expression level of PECAM1 was the lowest in early proliferative phase, slightly increased in late proliferative phase and was the highest in mid-secretory phase. While the expression level of HOXA10, an endometrial receptivity marker, kept at a low level in early proliferative phase and increased in late proliferative phase, then maintained at a high level in the mid-secretory phase. Furthermore, TGF-beta1, mediated by PECAM1, was also decreased significantly in the RIF group. Using shRNA-based approach, we demonstrated that the depletion of PECAM1 significantly decreased the expression of TGF-beta1 in Ishikawa cells, as well as in primary HEECs and HESCs. These results indicated that PECAM1 and TGF-beta1 might play a pivotal role in modulating endometrial receptivity. LIMITATIONS REASONS FOR CAUTION: Although we have shown that PECAM1 and TGF-beta1 were down-regulated in the women with RIF, the molecular mechanism of the effect of the factors on the endometrial receptivity remain unclear. WIDER IMPLICATIONS OF THE FINDINGS: Our findings provide insight into the contribution of PECAM1 and TGF-beta1 in regulating implantation, which could be used to develop potential therapeutic methods for RIF. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by grants from the National Natural Science Foundation of China (Nos. 81771656 and 81370763), Special fund for clinical research of the Chinese Medical Association (No. 16020480664), and the Merck Serono China Research Fund for Fertility Agreement. The authors have no competing interests. PMID- 29617818 TI - FSHB -211 G>T is a major genetic modulator of reproductive physiology and health in childbearing age women. AB - STUDY QUESTION: Are the genetic variants FSHB -211 G>T (rs10835638), FSHR c.2039 A>G (Asn680Ser, rs6166) and FSHR -29 G>A (rs1394205) associated with serum FSH, LH and anti-Mullerian hormone (AMH) levels in reproductive age women, their menstrual cycle parameters and risk of infertility? SUMMARY ANSWER: Only the FSHB -211 G>T variant was a major genetic determinant of serum gonadotropin levels in both, eumenorrheic healthy women and female infertility patients, and the T allele carrier status was enriched among idiopathic infertility cases. WHAT IS KNOWN ALREADY: There are accumulating data on common genetic variants modulating reproductive parameters and fertility potential. FSHB -211 G>T represents the strongest acknowledged genetic factor contributing to male circulating gonadotropins levels. Respective data in women are limited and the two previously published studies have reached conflicting results. In addition, previous studies have consistently associated FSHR c.2039 A>G (but not FSHR -29 G>A) with female serum FSH level. STUDY DESIGN, SIZE, DURATION: The study aimed to test robust and clinically meaningful genetic effects (if present) of the FSHB -211 G>T, FSHR c.2039 A>G and FSHR -29 G>A variants on female basal FSH, LH and AMH levels, and linked reproductive parameters. Genetic association testing was performed in two independent and clinically different study groups (i) eumenorrheic healthy women without known fertility problems (n = 169; 27.6 +/- 6.1 years) and (ii) female partners of infertile couples (n = 186; 32.4 +/- 4.7 years). The study groups were compared for allelic and genotypic distributions of the analysed variants. PARTICIPANTS/MATERIALS, SETTING, METHODS: All participants were recruited during the HAPPY PREGNANCY study (2013-2015) at the Women's Clinic, Tartu University Hospital, Estonia. Serum FSH, LH and AMH were measured in the follicular phase (Days 2-6) of the menstrual cycle. All three single nucleotide polymorphisms (SNPs) were genotyped by PCR and Taqman allelic discrimination assay. The effect of the analysed variants on hormonal measurements and menstrual cycle data was assessed using linear regression under additive and recessive models adjusted by age, BMI and smoking status. Results of the two subgroups were combined in a meta analysis applying the fixed effects model. Restricted maximum likelihood analysis was applied to estimate the proportion of total phenotypic variance of analysed reproductive parameters, explainable by the tested genetic variants. In case control analysis, genetic association with infertility status was tested using Fisher's exact test and logistic regression adjusted by age, BMI and smoking status. MAIN RESULTS AND THE ROLE OF CHANCE: In both study groups, T-allele of the FSHB -211 G>T was associated with significantly higher serum levels of FSH and LH. Results of the meta-analysis (additive genetic model) remained significant after Bonferroni correction for multiple testing: FSH, T-allele effect 0.80 IU/L, P = 1.2 * 10-3; LH, 1.58 IU/L, P = 1.8*10-8. A more pronounced effect of T-allele of the FSHB -211 G>T on circulating LH was identified as a driving factor to increased LH/FSH ratio (meta-analysis, P = 4.7 * 10-3). In healthy women, the FSHB -211 G>T variant was estimated to explain 3.5 and 7.1% of the total variance of the measured serum FSH and LH levels, respectively. The corresponding numbers for the infertility patients were 1.6 and 10.5%. Women with idiopathic infertility compared to controls exhibited a doubled T-allele frequency (23.6 versus 12.4%; P = 8.9 * 10-3) and a >3-fold excess of TT homozygotes (5.6 versus 1.8%; P = 3.5 * 10-2). The only association of the FSHR c.2039 A>G was detected with serum FSH levels in eumenorrheic healthy women, explaining 3.9% of the total parameter variance (G-allele effect 0.56 IU/L, P = 4.6 * 10-3). In the study group of healthy reproductive age women, the highest serum FSH levels were detected among the FSHB -211 T-allele carriers with the FSHR c.2039 GG-genotype (median 7.7 IU/L). In contrast, the lowest hormone concentrations were measured for the women carrying the combination of the FSHB 211 GG- and the FSHR c.2039 AA-homozygosity (median 5.8 IU/L, P = 9.6 * 10-3). None of the analysed reproductive parameters was associated with the FSHR -29 G>A variant. In our study groups, the tested polymorphisms did not reach significant associations with serum AMH measurements, menstrual cycle length or age at menarche. LIMITATIONS, REASONS FOR CAUTION: Small sample size and the design involving two clinical groups with different reproductive histories may have limited the capacity to replicate the associations with the age at menarche and length of menstrual cycle, initially reported in large genome-wide association studies. Small sample size may have also affected the accuracy in estimating the contribution of the tested variants to the total phenotypic variance of measured gonadotropin concentrations. The group of eumenorrheic healthy women had its limitations as a control to estimate the true effect of analysed genetic variants on individual's fertility potential as the recruitment strategy had been targeted mostly towards younger women, who may not yet have planned to conceive a child by this age. WIDER IMPLICATIONS OF THE FINDINGS: We propose that like in men, also in women the FSHB -211 G>T represents a key genetic modulator of circulating gonadotropin, leading to various possible downstream effects on reproductive physiology. This claim is strongly supported by the reports of genome-wide association studies on various female reproductive traits and diseases. In perspective, FSHB -211 G>T may have a diagnostic value in fertility clinics to detect female patients with genetically inherited elevated basal FSH and LH levels. STUDY FUNDING/COMPETING INTEREST(S): The study was supported by Estonian Science Foundation Grant (ETF9030 for M.L.); Institutional Research Grant (IUT34 12 for M.L.) and European Union through the European Regional Development Fund (project HAPPY PREGNANCY, 3.2.0701.12-0047; for M.L. and K.R.). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the article. We have no competing interests to declare. TRAIL REGISTRATION NUMBER: Not applicable. PMID- 29617819 TI - Impact of valve type on outcomes after redo mitral valve replacement in patients aged 50 to 69 years. AB - OBJECTIVES: Little data are available with regard to valve selections in redo valvular surgery. We investigated the impact of valve types on late outcomes after redo mitral valve replacement (MVR). METHODS: We retrospectively reviewed 66 patients aged 50-69 (mean age 62.2 +/- 5.1) years who underwent redo MVR over the past 25 years. In redo MVR, 46 (69.7%) redo procedures were the 1st redo valvular surgeries, 16 (24.2%) were 2nd redos, 3 (4.5%) were 3rd redos and 1 was a 4th (1.5%) redo. We classified 66 patients into 2 groups: mechanical MVR group (M-MVR, n = 44) and biological MVR group (B-MVR, n = 22). The mean follow-up period was 8.2 +/- 6.3 years. RESULTS: Hospital mortality rates were 3.3% in M MVR and 9.7% in B-MVR (P = 0.3328). Survival rates in M-MVR and B-MVR at 5 and 10 years were 93.0 +/- 4.8% vs 76.0 +/- 10.5% and 77.6 +/- 9.1% vs 51.3 +/- 13.7%, respectively (log-rank test, P = 0.0072). Late death occurred in 7 patients in M MVR and 9 in B-MVR. Freedom rates from valve-related events in M-MVR and B-MVR at 5 and 10 years were 100.0 +/- 0.0% vs 76.5 +/- 10.3% and 93.3 +/- 6.4% vs 52.4 +/ 13.6%, respectively (log-rank test, P < 0.0001). No bleeding and thromboembolic events were observed in M-MVR, whereas gastrointestinal bleeding (n = 1), subarachnoid haemorrhage (n = 1) and cerebral infarction (n = 2) were observed in B-MVR. A predictor of late death was a biological valve in redo MVR (P = 0.0206, hazard ratio = 3.402, 95% confidence interval 1.207-9.591). CONCLUSIONS: It would seem that redo MVR using a mechanical valve was associated with better early and late outcomes in this age group. PMID- 29617820 TI - Fecal Incontinence in Inflammatory Bowel Disease: A Systematic Review and Meta Analysis. AB - Background: Understanding of the prevalence, pathophysiology, and management of fecal incontinence (FI) in inflammatory bowel disease (IBD) patients without an ileal pouch anal anastomosis (IPAA) is suboptimal. We conducted a systematic review and meta-analysis on the prevalence, pathophysiology, and management of primary FI in IBD patients without IPAA. Methods: We searched MEDLINE, EMBASE, and Cochrane Database of Systematic Reviews (1966 through March 2017) for studies on the prevalence, physiology, or management of FI in IBD patients without IPAA. A random effects model was used to calculate pooled prevalence rates and odds ratio (OR) with 95% confidence interval (CI). Heterogeneity was assessed with I2 statistics, Cochran Q statistic, and sensitivity analyses. Results: Seventeen studies were included. Six studies evaluated the prevalence of FI in 4671 IBD patients. There was significant heterogeneity among the studies, but the pooled prevalence of FI among case-control studies was homogeneous at 24% (95% CI 18% 30%, I2 = 50.6%, P = 0.16). FI was more common among IBD patients than non-IBD controls (OR = 7.73; 95% CI 6.26 to 9.84). Therapeutic options were poorly evaluated in uncontrolled studies. Surgery was effective in 70% of patients (7/10), sacral nerve stimulation was effective in 100% of patients (5/5), and 41.6% of patients (5/12) reported subjective improvement in FI with percutaneous tibial nerve stimulation. Conclusions: FI is prevalent in IBD patients without IPAA, and more common than non-IBD controls. Additional controlled studies are warranted to further identify effective therapeutic interventions for FI in IBD. 10.1093/ibd/izx109_video1izx109_Video_15760611117001. PMID- 29617821 TI - Development of a Psychosocial Risk Screener for Siblings of Children With Cancer: Incorporating the Perspectives of Parents. AB - Objective: Although many siblings experience distress after a child's cancer diagnosis, their psychosocial functioning is seldom assessed in clinical oncology settings. One barrier to systematic sibling screening is the lack of a validated, sibling-specific screening instrument. Thus, this study developed sibling specific screening modules in English and Spanish for the Psychosocial Assessment Tool (PAT), a well-validated screener of family psychosocial risk. Methods: A purposive sample of English- and Spanish-speaking parents of children with cancer (N = 29) completed cognitive interviews to provide in-depth feedback on the development of the new PAT sibling modules. Interviews were transcribed verbatim, cleaned, and analyzed using applied thematic analysis. Items were updated iteratively according to participants' feedback. Data collection continued until saturation was reached (i.e., all items were clear and valid). Results: Two sibling modules were developed to assess siblings' psychosocial risk at diagnosis (preexisting risk factors) and several months thereafter (reactions to cancer). Most prior PAT items were retained; however, parents recommended changes to improve screening format (separately assessing each sibling within the family and expanding response options to include "sometimes"), developmental sensitivity (developing or revising items for ages 0-2, 3-4, 5-9, and 10+ years), and content (adding items related to sibling-specific social support, global assessments of sibling risk, emotional/behavioral reactions to cancer, and social ecological factors such as family and school). Conclusions: Psychosocial screening requires sibling-specific screening items that correspond to preexisting risk (at diagnosis) and reactions to cancer (several months after diagnosis). Validated, sibling-specific screeners will facilitate identification of siblings with elevated psychosocial risk. PMID- 29617822 TI - HIV-1 Resistance Dynamics in Patients With Virologic Failure to Dolutegravir Maintenance Monotherapy. AB - Background: A high genetic barrier to resistance to the integrase strand transfer inhibitor (INSTI) dolutegravir has been reported in vitro and in vivo. We describe the dynamics of INSTI resistance-associated mutations (INSTI-RAMs) and mutations in the 3'-polypurine tract (3'-PPT) in relation to virologic failure (VF) observed in the randomized Dolutegravir as Maintenance Monotherapy for HIV-1 study (DOMONO, NCT02401828). Methods: From 10 patients with VF, plasma samples were collected before the start of cART and during VF, and were used to generate Sanger sequences of integrase, the 5' terminal bases of the 3' long terminal repeat (LTR), and the 3'-PPT. Results: Median human immunodeficiency virus RNA load at VF was 3490 copies/mL (interquartile range 1440-4990 copies/mL). INSTI RAMs (S230R, R263K, N155H, and E92Q+N155H) were detected in 4 patients, no INSTI RAMs were detected in 4 patients, and sequencing of the integrase gene was unsuccessful in 2 patients. The time to VF ranged from 4 weeks to 72 weeks. In 1 patient, mutations developed in the highly conserved 3'-PPT. No changes in the terminal bases of the 3'-LTR were observed. Conclusions: The genetic barrier to resistance is too low to justify dolutegravir maintenance monotherapy because single INSTI-RAMs are sufficient to cause VF. The large variation in time to VF suggests that stochastic reactivation of a preexisting provirus containing a single INSTI-RAM is the mechanism for failure. Changes in the 3'-PPT point to a new dolutegravir resistance mechanism in vivo. Clinical Trials Registration: NCT02401828. PMID- 29617823 TI - Detecting Specific Resource Use by Drosophila suzukii (Diptera: Drosophilidae) Using Gut Content Analysis. AB - Drosophila suzukii Matsumura (Diptera: Drosophilidae) is an invasive, highly polyphagous pest of soft-skinned fruits throughout much of the world. A better understanding of the ecology of adult flies, including their nutritional resources, is needed to advance ecologically based management approaches. In this study, we evaluate the capability of polymerase chain reaction-based gut content analysis to detect a known food resource from DNA extracted from laboratory reared flies. Using strawberry as a focal host and available DNA primers, we validated that DNA from this host could be detected for up to 7 d post consumption. With the development of specific primers for additional hosts, we expect that this technique will enable researchers to better understand how D. suzukii adults use, and move between, nutritional resources. PMID- 29617825 TI - Estimation of the cumulative cancer risk of female children attributable to radiocaesium in soil in an evacuation zone, prior to their return. AB - The Fukushima Daiichi accident highlighted the difficulty in making good decisions regarding post-accident actions for the protection of members of the public. Discussions are continuing between the authorities and the residents about 'how safe is safe'. Although governmental officials have argued that 20 mSv per year is a safe level of exposure, many residents have expressed strong doubts, and one of their major concerns is the greater health risk of radiation exposure for children. For settling this controversy, the author has demonstrated risk projections for cancer mortality of female children (0 to 18 years old) resulting from four different levels of radiocaesium deposits on the ground. The results showed that, for female children, the cumulative lifetime attributable risk of cancer mortality due to 18-years external radiation exposure from radiocaesium in soil would be 0.9% for 134Cs and 2.4% for 137Cs for an initial annual dose of 20 mGy/year; when the initial dose was 5 mGy/year, the cumulative lifetime cancer risk would be 0.2% and 0.6% for 134Cs and 137Cs, respectively. These results indicate the critical importance of accurate information about the composition and behavior of major radionuclides released to the environment, as well as precise dose monitoring and risk coefficients, for proper decision-making regarding protective actions for members of the public. PMID- 29617824 TI - The S230R Integrase Substitution Associated With Virus Load Rebound During Dolutegravir Monotherapy Confers Low-Level Resistance to Integrase Strand Transfer Inhibitors. AB - Background: Dolutegravir (DTG) is an integrase strand-transfer inhibitor (INSTI) used for treatment of human immunodeficiency virus (HIV)-infected individuals. Owing to its high genetic barrier to resistance, DTG has been clinically investigated as maintenance monotherapy to maintain viral suppression and to reduce complication and healthcare costs. Our study aims to explain the underlying mechanism related to the emergence of a S230R substitution in patients who experienced virologic failure while using DTG monotherapy. Methods: We evaluated the effect of the S230R substitution in regard to integrase enzyme activity, viral infectivity, replicative capacity, and susceptibility to different INSTIs by biochemical and cell-based assays. Results: The S230R substitution conferred a 63% reduction in enzyme efficiency. S230R virus was 1.29 fold less infectious than wild-type virus but could replicate in PM1 cells without significant delay. Resistance levels against DTG, cabotegravir, raltegravir, and elvitegravir in tissue culture were 3.85-, 3.72-, 1.52-, and 1.21-fold, respectively, in virus with the S230R substitution. Conclusions: Our data indicate that the S230R substitution is comparable to the previously reported R263K substitution in some respects. Virologic failure during DTG monotherapy can occur through the development of the S230R or R263K mutation, without the need for high-level DTG resistance. PMID- 29617827 TI - Erratum to: "For as Long as Necessary: Examining 30 years of MSD's Focus on Achieving Elimination of Onchocerciasis and Lymphatic Filariasis". PMID- 29617826 TI - Long-term outcomes of total arch replacement with the non-frozen elephant trunk technique for Stanford Type A acute aortic dissection. AB - OBJECTIVES: Arch repair using the frozen elephant trunk (FET) technique has been utilized to treat Type A acute aortic dissection. In contrast, the long-term outcomes of the non-FET technique focus on the thrombosed false lumen (FL), and distal aortic reoperation rates remain unclear. The goal of our study was to investigate the efficacy and long-term outcomes of the non-FET technique as the benchmark. METHODS: We reviewed 518 patients with Type A acute aortic dissection in the last 20 years. Among them, 139 hospital survivors (61 +/- 12 years) who had undergone total arch replacement with the non-FET technique were enrolled. A total of 86% (120/139) of patients had a patent FL at the descending aorta preoperatively. The median follow-up period was 41 (1-219) months. RESULTS: No spinal cord ischaemia and new entry tear formation were observed. Postoperative FL thrombosis of the entire descending aorta was obtained in 47% (66/139) and in 39% (47/120) of patients who had a patent FL preoperatively. Freedom from dissection-related distal reoperation rates at 1, 3, 5 and 10 years were 87%, 83%, 81% and 78%, respectively. The results of multivariate analysis indicated that the predictors of a dissection-related reoperation were connective tissue disease [hazard ratio (HR) 4.6, P = 0.006], re-entry at the superior mesenteric artery (HR 2.9, P = 0.04), unachieved primary entry resection (HR 5.3, P = 0.001) and preoperative maximum descending aortic diameter >=38 mm (HR 11.6, P < 0.001). CONCLUSIONS: Total arch replacement with the non-FET technique was safe and reliable from the viewpoint of spinal cord ischaemia. Further comparative studies between the FET and the non-FET techniques are required. PMID- 29617828 TI - Genomics of Parallel Ecological Speciation in Lake Victoria Cichlids. AB - The genetic basis of parallel evolution of similar species is of great interest in evolutionary biology. In the adaptive radiation of Lake Victoria cichlid fishes, sister species with either blue or red-back male nuptial coloration have evolved repeatedly, often associated with shallower and deeper water, respectively. One such case is blue and red-backed Pundamilia species, for which we recently showed that a young species pair may have evolved through "hybrid parallel speciation". Coalescent simulations suggested that the older species P. pundamilia (blue) and P. nyererei (red-back) admixed in the Mwanza Gulf and that new "nyererei-like" and "pundamilia-like" species evolved from the admixed population. Here, we use genome scans to study the genomic architecture of differentiation, and assess the influence of hybridization on the evolution of the younger species pair. For each of the two species pairs, we find over 300 genomic regions, widespread across the genome, which are highly differentiated. A subset of the most strongly differentiated regions of the older pair are also differentiated in the younger pair. These shared differentiated regions often show parallel allele frequency differences, consistent with the hypothesis that admixture-derived alleles were targeted by divergent selection in the hybrid population. However, two-thirds of the genomic regions that are highly differentiated between the younger species are not highly differentiated between the older species, suggesting independent evolutionary responses to selection pressures. Our analyses reveal how divergent selection on admixture-derived genetic variation can facilitate new speciation events. PMID- 29617829 TI - Genetic Environment of cry1 Genes Indicates Their Common Origin. AB - Although in Bacillus thuringiensis the cry genes coding for the insecticidal crystal proteins are plasmid-borne and are usually associated with mobile genetic elements, several aspects related to their genomic organization, diversification, and transmission remain to be elucidated. Plasmids of B. thuringiensis and other members of the Bacillus cereus group (n = 364) deposited in GenBank were screened for the presence of cry1 genes, and their genetic environment was analyzed using a comparative bioinformatic approach. The cry1 genes were identified in 27 B. thuringiensis plasmids ranging from 64 to 761 kb, and were predominantly associated with the ori44, ori60, or double orf156/orf157 and pXO1-16/pXO1-14 replication systems. In general, the cry1 genes occur individually or as a part of an insecticidal pathogenicity island (PAI), and are preceded by genes coding for an N-acetylmuramoyl-l-alanine amidase and a putative K+(Na+)/H+ antiporter. However, except in the case of the PAI, the latter gene is disrupted by the insertion of IS231B. Similarly, numerous mobile elements were recognized in the region downstream of cry1, except for cry1I that follows cry1A in the PAI. Therefore, the cassette involving cry1 and these two genes, flanked by transposable elements, named as the cry1 cassette, was the smallest cry1-carrying genetic unit recognized in the plasmids. Conservation of the genomic environment of the cry1 genes carried by various plasmids strongly suggests a common origin, possibly from an insecticidal PAI carried by B. thuringiensis megaplasmids. PMID- 29617830 TI - Detecting Signatures of Positive Selection along Defined Branches of a Population Tree Using LSD. AB - Identifying the genomic basis underlying local adaptation is paramount to evolutionary biology, and bears many applications in the fields of conservation biology, crop, and animal breeding, as well as personalized medicine. Although many approaches have been developed to detect signatures of positive selection within single populations and population pairs, the increasing wealth of high throughput sequencing data requires improved methods capable of handling multiple, and ideally large number of, populations in a single analysis. In this study, we introduce LSD (levels of exclusively shared differences), a fast and flexible framework to perform genome-wide selection scans, along the internal and external branches of a given population tree. We use forward simulations to demonstrate that LSD can identify branches targeted by positive selection with remarkable sensitivity and specificity. We illustrate a range of potential applications by analyzing data from the 1000 Genomes Project and uncover a list of adaptive candidates accompanying the expansion of anatomically modern humans out of Africa and their spread to Europe. PMID- 29617831 TI - Leaf dorsoventrality as a paramount factor determining spectral performance in field-grown wheat under contrasting water regimes. AB - The effects of leaf dorsoventrality and its interaction with environmentally induced changes in the leaf spectral response are still poorly understood, particularly for isobilateral leaves. We investigated the spectral performance of 24 genotypes of field-grown durum wheat at two locations under both rainfed and irrigated conditions. Flag leaf reflectance spectra in the VIS-NIR-SWIR (visible near-infrared-short-wave infrared) regions were recorded in the adaxial and abaxial leaf sides and at the canopy level, while traits providing information on water status and grain yield were evaluated. Moreover, leaf anatomical parameters were measured in a subset of five genotypes. The spectral traits studied were more affected by the leaf side than by the water regime. Leaf dorsoventral differences suggested higher accessory pigment content in the abaxial leaf side, while water regime differences were related to increased chlorophyll, nitrogen, and water contents in the leaves in the irrigated treatment. These variations were associated with anatomical changes. Additionally, leaf dorsoventral differences were less in the rainfed treatment, suggesting the existence of leaf side-specific responses at the anatomical and biochemical level. Finally, the accuracy in yield prediction was enhanced when abaxial leaf spectra were employed. We concluded that the importance of dorsoventrality in spectral traits is paramount, even in isobilateral leaves. PMID- 29617832 TI - Challenges constraining insulin access in Nepal-a country with no local insulin production. AB - Background: Nepal is facing an increasing burden of diabetes and relies almost entirely on insulin imported through India. Methods: We employed a modified version of the WHO/Health Action International standard survey to assess insulin availability and prices, along with qualitative interviews with insulin retailers (pharmacists) and wholesalers in the Kathmandu Valley, Nepal. Results: The mean availability of the two human insulins listed on the 2011 Nepal Essential Medicine List were 14.3% and 42.85% in the surveyed private- and public-sector pharmacies, respectively, compared with the WHO target of 80% availability. The median consumer price of human insulin cartridges, analogue insulin cartridges and pens was, respectively, 2.1, 4.6 and 5.3 times that of human insulin vials (US$5.54). The insulin cartridges made in India were less expensive (p<0.001) than those made elsewhere. The lowest-paid worker would need to spend between 3 and 17 days' wages to purchase a monthly insulin supply out of pocket. Conclusion: Insulin access is limited in Kathmandu owing to low availability and the highly unaffordable price. Insulin access could improve with the government exploring additional suppliers, pooling insulin tenders, auditing insulin utilization and developing independent prescribing guidelines. Furthermore, there is a need to educate physicians and develop a consensus statement on insulin initiation to curb the growing analogue use and promote rational use. PMID- 29617833 TI - Comparison of objective measures and patients' perceptions of quality of services in government health facilities in the Democratic Republic of Congo. AB - Objective: Examine the relationship between patients' perceptions of quality and the objective level of quality at government health facilities, and determine whether the pre-existing attitudes and beliefs of patients regarding health services interfere with their ability to accurately assess quality of care. Design: Cross-sectional, visit-level analysis. Setting: Three regions (Nord Ubangi, Kasai/Kasai-Central and Maniema/Tshopo) of the Democratic Republic of Congo. Participants: Data related to the inpatient and outpatient visits to government health facilities made by all household members who were included in the survey was used for the analysis. Data were collected from patients and the facilities they visited. Main Outcome Measures: Patients' perceptions of the level of quality related to availability of drugs and equipment; patient centeredness and safety serve compared with objective measures of quality. Results: Objective measures and patient perceptions of the drug supply were positively associated (beta = 0.16, 95% CI = 0.03, 0.28) and of safety were negatively associated (beta = -0.12, 95% CI = -0.23, -0.01). Several environmental factors including facility type, region and rural/peri-urban setting were found to be significantly associated with respondents' perceptions of quality across multiple outcomes. Conclusions: Overall, patients are not particularly accurate in their assessments of quality because their perceptions are impacted by their expectations and prior experience. Future research should examine whether improving patients' knowledge of what they should expect from health services, and the transparency of the facility's quality data can be a strategy for improving the accuracy of patients' assessments of the quality of the health services, particularly in low-resourced settings. PMID- 29617834 TI - Differential Evolution of Antiretroviral Restriction Factors in Pteropid Bats as Revealed by APOBEC3 Gene Complexity. AB - Bats have attracted attention in recent years as important reservoirs of viruses deadly to humans and other mammals. These infections are typically nonpathogenic in bats raising questions about innate immune differences that might exist between bats and other mammals. The APOBEC3 gene family encodes antiviral DNA cytosine deaminases with important roles in the suppression of diverse viruses and genomic parasites. Here, we characterize pteropid APOBEC3 genes and show that species within the genus Pteropus possess the largest and most diverse array of APOBEC3 genes identified in any mammal reported to date. Several bat APOBEC3 proteins are antiviral as demonstrated by restriction of retroviral infectivity using HIV-1 as a model, and recombinant A3Z1 subtypes possess strong DNA deaminase activity. These genes represent the first group of antiviral restriction factors identified in bats with extensive diversification relative to homologues in other mammals. PMID- 29617835 TI - Patient and transplant outcome in infants starting renal replacement therapy before 2 years of age. AB - Background: Despite major technical improvements in the care of children requiring renal replacement therapy (RRT) before 2 years of age, the management of those patients remains challenging and transplantation is generally delayed until the child weighs 10 kg or is 2 years old. In this national cohort study, we studied patient and graft survival in children starting RRT before 2 years of age to help clinicians and parents when deciding on RRT initiation and transplantation management. Methods: All children starting RRT before 24 months of age between 1992 and 2012 in France were included through the national Renal Epidemiology and Information Network (REIN) registry. The primary endpoints were patient survival on dialysis and 10-year graft survival. Results: A total of 224 patients were included {62% boys, median age 10.5 months [interquartile range (IQR) 5.8-15.6]}. The 10-year survival rate was 84% (IQR 77-89). Suffering from extrarenal comorbidities was the only factor significantly associated with both an increased risk of death on dialysis [hazard ratio 5.9 (95% confidence interval 1.8-19.3)] and a decreased probability of being transplanted. During follow-up, 174 renal transplantations were performed in 171 patients [median age at first transplantation 30.2 (IQR 21.8-40.7) months]. The 10-year graft survival was 74% (IQR 67-81). Factors associated with graft loss in multivariate analysis were the time spent on dialysis before transplantation, donor/recipient height ratio with an increased risk for both small and tall donors and presenting two human leucocyte antigen-antigen D-related mismatches. Conclusions: This study confirms the good outcome of children starting RRT before 2 years of age. The main question remains when and how to transplant those children. Our study provides data on the optimal morphological and immunological matching in order to help clinicians in their decisions. PMID- 29617837 TI - Leaf-rolling in maize crops: from leaf scoring to canopy-level measurements for phenotyping. AB - Leaf rolling in maize crops is one of the main plant reactions to water stress that can be visually scored in the field. However, leaf-scoring techniques do not meet the high-throughput requirements needed by breeders for efficient phenotyping. Consequently, this study investigated the relationship between leaf rolling scores and changes in canopy structure that can be determined by high throughput remote-sensing techniques. Experiments were conducted in 2015 and 2016 on maize genotypes subjected to water stress. Leaf-rolling was scored visually over the whole day around the flowering stage. Concurrent digital hemispherical photographs were taken to evaluate the impact of leaf-rolling on canopy structure using the computed fraction of intercepted diffuse photosynthetically active radiation, FIPARdif. The results showed that leaves started to roll due to water stress around 09:00 h and leaf-rolling reached its maximum around 15:00 h (the photoperiod was about 05:00-20:00 h). In contrast, plants maintained under well watered conditions did not show any significant rolling during the same day. A canopy-level index of rolling (CLIR) is proposed to quantify the diurnal changes in canopy structure induced by leaf-rolling. It normalizes for the differences in FIPARdif between genotypes observed in the early morning when leaves are unrolled, as well as for yearly effects linked to environmental conditions. Leaf level rolling score was very strongly correlated with changes in canopy structure as described by the CLIR (r2=0.86, n=370). The daily time course of rolling was characterized using the amplitude of variation, and the rate and the timing of development computed at both the leaf and canopy levels. Results obtained from eight genotypes common between the two years of experiments showed that the amplitude of variation of the CLIR was the more repeatable trait (Spearman coefficient rho=0.62) as compared to the rate (rho=0.29) and the timing of development (rho=0.33). The potential of these findings for the development of a high-throughput method for determining leaf-rolling based on aerial drone observations are considered. PMID- 29617839 TI - Outcomes of aortic valve replacement via partial upper sternotomy versus conventional aortic valve replacement in obese patients. AB - OBJECTIVES: Excellent outcomes after minimally invasive aortic valve replacement (mini-AVR) have been reported. Therefore, mini-AVR has become a popular treatment option in many cardiac surgery centres. However, whether obese patients particularly benefit from mini-AVR remains unclear. The aim of the present study was to evaluate outcomes of AVR performed through partial upper sternotomy compared to AVR through a full sternotomy (full-AVR) in obese patients. METHODS: We retrospectively reviewed the medical records of all patients who underwent isolated AVR at our institution, and 217 consecutive obese [body mass index (BMI) >30 kg/m2] patients were identified. Outcomes of the mini-AVR group were compared with the full-AVR group. RESULTS: One hundred and twenty-six patients underwent mini-AVR and 91 patients had full-AVR. The mean age and BMI were 69.8 +/- 10.4 years and 32.6 +/- 3.1 kg/m2 in the mini-AVR group compared to 70.0 +/- 10.5 years and 33.1 +/- 3.0 kg/m2 in the full-AVR group. Mortality, myocardial infarction, stroke, renal failure and surgical site infections were equivalent. Mini-AVR was associated with decreased ventilation time [6 h (minimum, min 3 h; maximum, max 76 h) vs 8 h (min 3 h; max 340 h); P = 0.004], shorter intensive care unit (ICU) stay [2 days (min 1 day; max 25 days) vs 4 days (min 1 day; max 35 days); P = 0.031] and reduced transfusion requirements (26.5% vs 56.0%; P = 0.004). Total duration of hospital stay as well as postoperative pain levels were comparable. CONCLUSIONS: Patient safety was not affected by mini-AVR. Significant benefits in terms of decreased transfusion requirements, ventilator times and ICU times were found in the mini-AVR group. Consequently, mini-AVR, performed through partial upper sternotomy, should also be routinely offered to obese patients. PMID- 29617838 TI - Improving immediate newborn care practices in Philippine hospitals: impact of a national quality of care initiative 2008-2015. AB - Objective: To determine whether intrapartum and newborn care practices improved in 11 large hospitals between 2008 and 2015. Design: Secondary data analysis of observational assessments conducted in 11 hospitals in 2008 and 2015. Setting: Eleven large government hospitals from five regions in the Philippines. Participants: One hundred and seven randomly sampled postpartum mother-baby pairs in 2008 and 106 randomly sampled postpartum mothers prior to discharge from hospitals after delivery. Interventions: A national initiative to improve quality of newborn care starting in 2009 through development of a standard package of intrapartum and newborn care services, practice-based training, formation of multidisciplinary hospital working groups, and regular assessments and meetings in hospitals to identify actions to improve practices, policies and environments. Quality improvement was supported by policy development, health financing packages, health facility standards, capacity building and health communication. Main outcome measures: Sixteen intrapartum and newborn care practices. Results: Between 2008 and 2015, initiation of drying within 5 s of birth, delayed cord clamping, dry cord care, uninterrupted skin-to-skin contact, timing and duration of the initial breastfeed, and bathing deferred until 6 h after birth all vastly improved (P<0.001). The proportion of newborns receiving hygienic cord handling and the hepatitis B birth dose decreased by 11-12%. Except for reduced induction of labor, inappropriate maternal care practices persisted. Conclusions: Newborn care practices have vastly improved through an approach focused on improving hospital policies, environments and health worker practices. Maternal care practices remain outdated largely due to the ineffective didactic training approaches adopted for maternal care. PMID- 29617836 TI - Met Receptor Tyrosine Kinase and Chemoprevention of Oral Cancer. AB - Background: We have previously shown that gene expression profiles of oral leukoplakia (OL) may improve the prediction of oral cancer (OC) risk. To identify new targets for prevention, we performed a systematic survey of transcripts associated with an increased risk of oral cancer and overexpressed in OC vs normal mucosa (NM). Methods: We used gene expression profiles of 86 patients with OL and available outcomes from a chemoprevention trial of OC and NM. MET expression was evaluated using immunohistochemistry in 120 OL patients, and its association with OC development was tested in multivariable analysis. Sensitivity to pharmacological Met inhibition was tested invitro in premalignant and OC cell lines (n = 33) and invivo using the 4-NQO model of oral chemoprevention (n = 20 mice per group). All statistical tests were two-sided. Results: The overlap of 693 transcripts associated with an increased risk of OC with 163 transcripts overexpressed in OC compared with NM led to the identification of 23 overlapping transcripts, including MET. MET overexpression in OL was associated with a hazard ratio of 3.84 (95% confidence interval = 1.59 to 9.27, P = .003) of developing OC. Met activation was found in OC and preneoplastic cell lines. Crizotinib activity in preneoplastic and OC cell lines was comparable. ARQ 197 was more active in preneoplastic compared with OC cell lines. In the 4-NQO model, squamous cell carcinoma, dysplasia, and hyperkeratosis were observed in 75.0%, 15.0%, and 10.0% in the control group, and in 25.0%, 70.0%, and 5.0% in the crizotinib group (P < .001). Conclusion: Together, these data suggest that MET activation may represent an early driver in oral premalignancy and a target for chemoprevention of OC. PMID- 29617840 TI - Bioefficacy of Insect Growth Regulators Against Aedes albopictus (Diptera: Culicidea) From Sarawak, Malaysia: A Statewide Survey. AB - The susceptibility status of Aedes albopictus (Skuse; Diptera: Culicidea) larvae collected from 13 districts in Sarawak state, Malaysia was evaluated against five insect growth regulators (IGRs) namely, methoprene, pyriproxyfen, diflubenzuron, cyromazine, and novaluron. Field populations of Ae. albopictus were susceptible to methoprene, pyriproxyfen, cyromazine and novaluron with resistance ratios (RRs) ranging from 0.19-0.38, 0.05-0.14, 0.50-0.95, and 0.75-1.00, respectively. Nevertheless, tolerance towards diflubenzuron (0.33-1.33) was observed in this study. In general, these IGRs exhibited promising results and can be used as alternative control agents against field populations of Ae. albopictus in Sarawak, Malaysia. PMID- 29617842 TI - Long-term follow-up of a combined rituximab and cyclophosphamide regimen in renal anti-neutrophil cytoplasm antibody-associated vasculitis. PMID- 29617843 TI - In vivo evaluation of EGFRvIII mutation in primary glioblastoma patients via complex multiparametric MRI signature. AB - Background: Epidermal growth factor receptor variant III (EGFRvIII) is a driver mutation and potential therapeutic target in glioblastoma. Non-invasive in vivo EGFRvIII determination, using clinically acquired multiparametric MRI sequences, could assist in assessing spatial heterogeneity related to EGFRvIII, currently not captured via single-specimen analyses. We hypothesize that integration of subtle, yet distinctive, quantitative imaging/radiomic patterns using machine learning may lead to non-invasively determining molecular characteristics, and particularly the EGFRvIII mutation. Methods: We integrated diverse imaging features, including the tumor's spatial distribution pattern, via support vector machines, to construct an imaging signature of EGFRvIII. This signature was evaluated in independent discovery (n = 75) and replication (n = 54) cohorts of de novo glioblastoma, and compared with the EGFRvIII status obtained through an assay based on next-generation sequencing. Results: The cross-validated accuracy of the EGFRvIII signature in classifying the mutation status in individual patients of the independent discovery and replication cohorts was 85.3% (specificity = 86.3%, sensitivity = 83.3%, area under the curve [AUC] = 0.85) and 87% (specificity = 90%, sensitivity = 78.6%, AUC = 0.86), respectively. The signature was consistent with EGFRvIII+ tumors having increased neovascularization and cell density, as well as a distinctive spatial pattern involving relatively more frontal and parietal regions compared with EGFRvIII- tumors. Conclusions: An imaging signature of EGFRvIII was found, revealing a complex, yet distinct macroscopic glioblastoma phenotype. By non-invasively capturing the tumor in its entirety, the proposed methodology can assist in evaluating the tumor's spatial heterogeneity, hence overcoming common spatial sampling limitations of tissue-based analyses. This signature can preoperatively stratify patients for EGFRvIII-targeted therapies, and potentially monitor dynamic mutational changes during treatment. PMID- 29617841 TI - Applications for alpha-lactalbumin in human nutrition. AB - alpha-Lactalbumin is a whey protein that constitutes approximately 22% of the proteins in human milk and approximately 3.5% of those in bovine milk. Within the mammary gland, alpha-lactalbumin plays a central role in milk production as part of the lactose synthase complex required for lactose formation, which drives milk volume. It is an important source of bioactive peptides and essential amino acids, including tryptophan, lysine, branched-chain amino acids, and sulfur containing amino acids, all of which are crucial for infant nutrition. alpha Lactalbumin contributes to infant development, and the commercial availability of alpha-lactalbumin allows infant formulas to be reformulated to have a reduced protein content. Likewise, because of its physical characteristics, which include water solubility and heat stability, alpha-lactalbumin has the potential to be added to food products as a supplemental protein. It also has potential as a nutritional supplement to support neurological function and sleep in adults, owing to its unique tryptophan content. Other components of alpha-lactalbumin that may have usefulness in nutritional supplements include the branched-chain amino acid leucine, which promotes protein accretion in skeletal muscle, and bioactive peptides, which possess prebiotic and antibacterial properties. This review describes the characteristics of alpha-lactalbumin and examines the potential applications of alpha-lactalbumin for human health. PMID- 29617844 TI - Platform trials arrive on time for glioblastoma. PMID- 29617845 TI - A Small-Molecule CD4-Mimetic Compound Protects Bone Marrow-Liver-Thymus Humanized Mice From HIV-1 Infection. AB - Background: Small-molecule CD4-mimetic compounds (CD4mc) inhibit human immunodeficiency virus (HIV-1) entry by blocking binding to the CD4 receptor and by premature triggering of the viral envelope glycoprotein (Env) spike. Methods: The efficacy of a CD4mc in protecting bone marrow-liver-thymus (BLT) humanized mice from vaginal HIV-1 challenge was evaluated. Results: Intravaginal application of the CD4mc JP-III-48, either before or simultaneously with virus challenge, protected BLT humanized mice from HIV-1JR-CSF infection in a dose- dependent manner. Conclusion: The direct antiviral effects of a CD4mc prevent HIV 1 infection in a murine model of sexual transmission. PMID- 29617846 TI - eResearch in acute kidney injury: a primer for electronic health record research. AB - Acute kidney injury (AKI) has a significant impact on patient morbidity and mortality as well as overall health care costs. eResearch, which integrates information technology and information management to optimize research strategies, provides a perfect platform for necessary ongoing AKI research. With the recent adoption of a widely accepted definition of AKI and near-universal use of electronic health records, eResearch is becoming an important tool in AKI research. Conducting eResearch in AKI should ideally be based on a relatively uniform methodology. This article is the first of its kind to describe a methodology for pursuing eResearch specific to AKI and includes an illustrative database example for critically ill patients. We discuss strategies for using serum creatinine and urine output in large databases to identify and stage AKI and ways to interpolate missing values and validate data. Issues specific to the pediatric population include variation in serum creatinine with growth, varied severity of illness scoring systems and medication dosage based on weight. Many of these same strategies used to optimize AKI eResearch can be applicable to real time AKI alerts with potential integration of additional clinical variables. PMID- 29617847 TI - Firm Efficiency and Returns-to-Scale in the Honey Bee Pollination Services Industry. AB - While the demand for pollination services have been increasing, continued declines in honey bee, Apis mellifera L. (Hymenoptera: Apidae), colonies have put the cropping sector and the broader health of agro-ecosystems at risk. Economic factors may play a role in dwindling honey bee colony supply in the United States, but have not been extensively studied. Using data envelopment analysis (DEA), we measure technical efficiency, returns to scale, and factors influencing the efficiency of those apiaries in the northern Rocky Mountain region participating in the pollination services market. We find that, although over 25% of apiaries are technically efficient, many experience either increasing or decreasing returns to scale. Smaller apiaries (under 80 colonies) experience increasing returns to scale, but a lack of available financing may hinder them from achieving economically sustainable colony levels. Larger apiaries (over 1,000 colonies) experience decreasing returns to scale. Those beekeepers may have economic incentivizes to decrease colony numbers. Using a double bootstrap method, we find that apiary location and off-farm employment influence apiary technical efficiency. Apiaries in Wyoming are found to be more efficient than those in Utah or Montana. Further, engagement in off-farm employment increases an apiary's technical efficiency. The combined effects of efficiency gains through off-farm employment and diseconomies of scale may explain, in part, the historical decline in honey bee numbers. PMID- 29617848 TI - Surgery for Glioblastoma in Light of Molecular Markers: Impact of Resection and MGMT Promoter Methylation in Newly Diagnosed IDH-1 Wild-Type Glioblastomas. AB - BACKGROUND: Previous studies addressing the influence of surgery on the outcome of patients with glioblastomas (GBM) have not addressed molecular markers. The value of surgery versus the tumor's major biological markers remains unclear. OBJECTIVE: We investigate the extent of resection as a prognosticator for patients with newly diagnosed primary GBM with the incorporation of molecular diagnostics as per the updated WHO 2016 diagnostic criteria for GBM. METHODS: Patients with newly diagnosed GBM who underwent resection were prospectively included within a database. We analyzed patients with newly diagnosed GBM and excluded patients who presented with IDH1 R132H mutations. Gross total resection (GTR) was defined as complete removal of enhancing disease. RESULTS: One hundred seventy-five patients were included within the analysis. One hundred four patients (59.4%) had GTR, 71 patients (40.6%) had subtotal or partial resection. Eighty patients (45.7%) displayed O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation, 95 patients (54.3%) showed no MGMT promoter methylation. In Cox regression analysis, MGMT promoter methylation (hazard ratio [HR] 1.55; 95% confidence interval [CI], 1.01-2.19; P = .0133) and GTR (HR 1.48; 95% CI, 1.06 2.07; P = .0206) were significantly associated with favorable progression-free survival. MGMT promoter methylation (HR 2.13; 95% CI, 1.45-3.12; P = .0001) and GTR (HR 1.81; 95% CI, 1.24-2.63; P = .002) were associated with favorable overall survival (OS). Of other risk factors analyzed, age (>60 vs <= 60 yr) was significantly associated with progression-free survival (HR 1.60; 95% CI, 1.14 2.24; P = .006) and OS (HR 2.19; 95% CI, 1.51-3.19; P < .0001). CONCLUSION: GTR and MGMT promoter methylation are independent prognosticators for improved overall and progression-free survival in a homogeneous cohort of newly diagnosed patients with IDH wild-type glioblastoma. PMID- 29617849 TI - Mosquito Saliva: The Hope for a Universal Arbovirus Vaccine? AB - Arthropod-borne viruses (arboviruses) are taxonomically diverse causes of significant morbidity and mortality. In recent decades, important mosquito-borne viruses such as West Nile, chikungunya, dengue, and Zika have re-emerged and spread widely, in some cases pandemically, to cause serious public health emergencies. There are no licensed vaccines against most of these viruses, and vaccine development and use has been complicated by the number of different viruses to protect against, by subtype and strain variation, and by the inability to predict when and where outbreaks will occur. A new approach to preventing arboviral diseases is suggested by the observation that arthropod saliva facilitates transmission of pathogens, including leishmania parasites, Borrelia burgdorferi, and some arboviruses. Viruses carried within mosquito saliva may more easily initiate host infection by taking advantage of the host's innate and adaptive immune responses to saliva. This provides a rationale for creating vaccines against mosquito salivary proteins, rather than against only the virus proteins contained within the saliva. As proof of principle, immunization with sand fly salivary antigens to prevent leishmania infection has shown promising results in animal models. A similar approach using salivary proteins of important vector mosquitoes, such as Aedes aegypti, might protect against multiple mosquito borne viral infections. PMID- 29617850 TI - Assessment of T1 Slope Minus Cervical Lordosis and C2-7 Sagittal Vertical Axis Criteria of a Cervical Spine Deformity Classification System Using Long-Term Follow-up Data After Multilevel Posterior Cervical Fusion Surgery. AB - BACKGOUND: Recently, previous research proposed a cervical spine deformity (CSD) classification using a modified Delphi approach. However, C2-C7 sagittal vertical axis (SVA) and T1 slope minus C2-C7 lordosis (TS-CL) cut-off values for moderate and severe disability were based on expert opinion. OBJECTIVE: To investigate the validity of a CSD classification system. METHODS: From 2007 to 2012, 30 consecutive patients with a minimum 5-yr follow-up having 3- or more level posterior cervical fusion met inclusion criteria. The following radiographic parameters were measured: C0-C2 lordosis, C2-C7 lordosis, C2-C7 SVA, T1 slope, and TS-CL. Pearson correlation coefficients were calculated between pairs of radiographic measures and health-related quality of life. RESULTS: Average follow up period was 7.3 yr. C2-C7 SVA positively correlated with neck disability index (NDI) scores (r = 0.554). Regression models predicted a threshold C2-C7 SVA value of 40.8 mm and 70.6 mm correlated with moderate and severe disability based on the NDI score, respectively. The TS-CL had positive correlation with C2-C7 SVA and NDI scores (r = 0.841 and r = 0.625, respectively). Regression analyses revealed that a C2-C7 SVA value of 40 mm and 70 mm corresponded to a TS-CL value of 20 degrees and 25 degrees , respectively. CONCLUSION: Regression models predicted a threshold C2-C7 SVA (value of 40.8 mm and 70.6 mm) and TS-CL (value of 20 degrees and 25 degrees ) correlated with moderate and severe disability based on the NDI, respectively. The cut-off value C2-C7 SVA and TS-CL modifier of the CSD classification can be revised accordingly. PMID- 29617851 TI - Effects of Nutrition Intervention on Total and Cancer Mortality: 25-Year Post trial Follow-up of the 5.25-Year Linxian Nutrition Intervention Trial. AB - Background: A beneficial effect of supplementation with selenium, vitamin E, and beta-carotene was observed on total and cancer mortality in a Chinese population, and it endured for 10 years postintervention, but longer durability is unknown. Methods: A randomized, double-blind, placebo-controlled trial was conducted in Linxian, China, from 1986 to 1991; 29 584 residents age 40 to 69 years received daily supplementations based on a factorial design: Factors A (retinol/zinc), B (riboflavin/niacin), C (vitamin C/molybdenum), and/or D (selenium/vitamin E/beta carotene), or placebo for 5.25 years, and followed for up 25 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the intervention effects on mortalities were estimated using Cox proportional hazards models. Results: Through 2016, the interventions showed no effect on total mortality. The previously reported protective effect of Factor D against total mortality was lost 10 years postintervention. The protective effect of Factor D for gastric cancer was attenuated (HR = 0.93, 95% CI = 0.85 to 1.01), but a newly apparent protective effect against esophageal cancer was found for Factor B (HR = 0.92, 95% CI = 0.85 to 1.00, two-sided P = .04). Other protective/adverse associations were observed for cause-specific mortalities. Protective effects were found in people younger than age 55 years at baseline against non-upper gastrointestinal cancer death for Factor A (HR = 0.80, 95% CI = 0.69 to 0.92) and against death from stroke for Factor C (HR = 0.89, 95% CI = 0.82 to 0.96). In contrast, increased risk of esophageal cancer was found when the intervention began after age 55 years for Factors C (HR = 1.16, 95% CI = 1.04 to 1.30) and D (HR = 1.20, 95% CI = 1.07 to 1.34). Conclusions: Multiyear nutrition intervention is unlikely to have a meaningful effect on mortality more than a decade after supplementation ends, even in a nutritionally deprived population. Whether sustained or repeat intervention would provide longer effects needs further investigation. PMID- 29617852 TI - Anterior Cervical Foraminotomy: 2-Dimensional Operative Video. AB - We provide a step-by-step technique guide for performing anterior cervical foraminotomy in this video. An illustrative case was presented with detailed narration and a discussion of surgical nuances. Anterior cervical foraminotomy can be an effective treatment strategy for patients with unilateral cervical radiculopathy without the need for cervical spine fusion. Spine surgeons should be familiar with technique and use it as a motion-preserving surgical option in treating isolated cervical radiculopathy. There is no identifying information in this video. A patient consent was obtained for publishing of the material included in the video. PMID- 29617853 TI - Smoking among adults with and without disabilities in the UK. AB - Background: The health risks of cigarette smoking are well established. As a result, reducing cigarette smoking is a key concern for public health agencies. Little is known about rates of smoking among adults with disabilities. Methods: Secondary analysis of data collected in Waves 2 and 7 of 'Understanding Society', an annual household panel study. Results: Age and gender adjusted odds ratios (AORs) of adults with disabilities smoking increased significantly from 1.41 (1.33-1.49) in 2010-12 to 1.57 (1.45-1.70) in 2015-17 (P = 0.032). AORs of adults with disabilities smoking 20 or more cigarettes a day increased non-significantly from 1.83 (1.66-2.02) in 2010-12 to 1.90 (1.65-2.20) in 2015-17. These changes were evident for both men and women and across age groups. Additionally adjusting these estimates to take account of between group differences in socioeconomic position significantly reduced the AORs for both smoking outcomes. Changes over time in AORs reflected a more rapid decline in smoking among participants without a disability. Conclusions: Adults with disabilities are more likely than their peers to smoke. Public health agencies and practitioners may wish to consider what reasonable adjustments may need to be made to policies and interventions to ensure that they are effective for adults with disabilities. PMID- 29617854 TI - Microsurgical Treatment of Bowhunter's Syndrome: 3-Dimensional Operative Video. AB - We present the case of a 56-yr-old previously healthy male who presented with an approximately 1-yr history of intermittent dizziness, near syncope, and holocephalic headaches when turning his head to the left side for a prolonged period of time. He had a distant history of a previous anterior cervical discectomy and fusion at the C6-7 level. He was neurologically intact. Static, dynamic, and vascular imaging confirmed hypoplasia of the right vertebral artery and dominance of the left vertebral artery that completely filled the posterior circulation. Dynamic imaging confirmed compression of the left vertebral artery just above the C5-6 disc space on full head rotation to the left. After an anterior cervical exposure, we dissected lateral to the C5-6 disc space to the transverse process. The anterior tubercle was identified, and a Doppler ultrasound was used to insonate the vertebral artery above the level of compression. The anterior wall of the transverse foramen was thinned with a high speed drill under constant irrigation and Kerrison rongeurs used to expose the vertebral artery at the site of compression. Importantly, the fibrotic band at, above, and below the level of compression was also dissected and removed. The patient tolerated the procedure well, and was discharged from the hospital 2 d after surgery with no neurological deficits and with complete relief of his preoperative symptoms. Because his symptoms completely resolved and have not recurred, no postoperative imaging was performed. The etiology, presentation, and microsurgical treatment of this rare disease are discussed.All appropriate patient consents were obtained for this submission.(c) 2017 Department of Neurosurgery, Emory University Hospital. Used with permission.All Figures used with permission as above. PMID- 29617855 TI - Endoscopic Resection of an Intraventricular Tumor With Second Window Indocyanine Green: 2-Dimensional Operative Video. AB - A 26-year-old woman presented to our clinic with years of headaches and mental clouding. She had a nonfocal neurological examination including benign ophthalmological examination. Head computed tomography and brain magnetic resonance imaging (MRI) demonstrated asymmetry of the lateral ventricles due to a lesion arising from the foramen of Monro. At the top of our differential diagnosis were choroid plexus tumor and colloid cyst. We offered the patient treatment via an endoscopic approach. Here, we demonstrate the feasibility of using tumor-localizing dyes such as indocyanine green (ICG) in conjunction with endoscopes equipped with lasers to localize and treat intraventricular lesions. While ICG is FDA approved, the technique presented here is investigational and the dye is being used off-label. The laser-equipped endoscope is also being used off-label. To treat the ventricular asymmetry, we performed an endoscopic septostomy between the frontal horns of the lateral ventricles. For our tumor localizing dye technique, we injected the patient with ICG 24 hours before the planned surgery. We were able to clearly visualize the lesion at the foramen of Monro as it was intensely fluorescent. The dye also appeared to localize to the presumably normal choroid plexus. We resected the lesion endoscopically and permanent pathology revealed that the lesion was a choroid plexus papilloma. The postoperative MRI showed improvement in her ventricular asymmetry and complete resection of the enhancing lesion at the foramen of Monro. The patient recovered well and was uneventfully discharged. She was seen in follow-up and has had improvement in her headaches.Consent for surgery was obtained from the patient. Consent for publication of the operative video was also obtained from the patient. PMID- 29617856 TI - Hen genetic strain and extended cold storage influence on physical egg quality from cage-free aviary housing system. AB - In the United States, there is an increase in need for cage-free eggs in retail and food manufacturing sectors. Understanding the impact of cage-free systems and the corresponding management on egg quality is pertinent as the U.S. industry adapts existing housing and builds new cage-free housing structures. A study was conducted comparing 2 brown shell and 2 white shell hen strains housed in a cage free aviary system. Each set of eggs were placed in cold storage and assessed at 0, 2, 4, 8, and 12 wk. Eggs were collected at 21, 31, 42, and 60 wk of hen age. A full profile of physical quality measurements was conducted on up to 18 intact eggs for each hen strain/egg storage/hen age combination. Egg weight increased approximately 10 g for brown shell and 14 g for white shell eggs as hens aged. Many of the properties monitored were significantly impacted by all 3 main effects (hen strain, egg storage, and hen age) resulting in 3-way interactions. A brown and a white shell strain had stronger shells (44 N; P < 0.0001) than the remaining brown and white shell strains (42 N and 39 N, respectively). The current study also determined volume of shell, total length, maximum width, and percent length at maximum width to more accurately indicate egg shape than shape index. One brown shell strain produced eggs with the most consistent shape characteristics over the hen ages monitored. White shell eggs from the cage-free aviary housing produced the highest whole-egg total solids between 31 to 60 wk of hen age, whereas brown shell eggs resulted in the most consistent level of whole egg total solids (22-23.5%). The brown and white shell strains in the current study produce cage-free aviary eggs with distinctive physical quality attributes. The outcomes from this study can be utilized by the U.S. egg industry in planning management strategies and market placement of cage-free eggs. PMID- 29617857 TI - FIC proteins: from bacteria to humans and back again. AB - During the last decade, FIC proteins have emerged as a large family comprised of a variety of bacterial enzymes and a single member in animals. The air de famille of FIC proteins stems from a domain of conserved structure, which catalyzes the post-translational modification of proteins (PTM) by a phosphate-containing compound. In bacteria, examples of FIC proteins include the toxin component of toxin/antitoxin modules, such as Doc-Phd and VbhT-VbhA, toxins secreted by pathogenic bacteria to divert host cell processes, such as VopS, IbpA and AnkX, and a vast majority of proteins of unknown functions. FIC proteins catalyze primarily the transfer of AMP (AMPylation), but they are not restricted to this PTM and also carry out other modifications, for example by phosphocholine or phosphate. In a recent twist, animal FICD/HYPE was shown to catalyze both AMPylation and de-AMPylation of the endoplasmic reticulum BIP chaperone to regulate the unfolded protein response. FICD shares structural features with some bacterial FIC proteins, raising the possibility that bacteria also encode such dual activities. In this review, we discuss how structural, biochemical and cellular approaches have fertilized each other to understand the mechanism, regulation and function of FIC proteins from bacterial pathogens to humans. PMID- 29617858 TI - Candida tropicalis affects the virulence profile of Candida albicans: an in vitro and in vivo study. AB - Candida albicans and Candida tropicalis are commensal microorganisms occurring in the oral cavity of approximately 50%-70% of healthy individuals. However, these microbes can become pathogenic through changes in the environment or weakened host immune system. Thus, the aim of this investigation was to evaluate the interaction between species of the genus Candida in the biofilm formation, filamentation, gene expression and virulence in Galleria mellonella. Coincubation of C. albicans with C. tropicalis cells after 48 h resulted in significant reduction of biofilm formation by decreasing viable cell counts, metabolic activity and hyphal growth. The C. albicans genes (BCR1, CPH1, EFG1, UME6, HWP1, ALS3, SAP5 and PLB2) were quantified by quantitative real-time polymerase chain reaction and most of genes were downregulated. Regarding in vivo assay, the groups that the larvae received C. albicans and C. tropicalis had a significant survival increase compared to the control group of C. albicans (P = 0.0001) in agreement with the in vitro results. In conclusion, C. tropicalis colonization was associated with a decrease in the growth of C. albicans, suggesting an antagonistic relation between these two species. Therefore, C. tropicalis by reducing C. albicans virulence profile may limit the ability of this pathogenic fungus to cause infection. PMID- 29617859 TI - Human lung epithelial cells support human metapneumovirus persistence by overcoming apoptosis. AB - Human metapneumovirus (hMPV) has been identified as a major cause of lower respiratory tract infection in children. Epidemiological and molecular evidence has highlighted an association between severe childhood respiratory viral infection and chronic lung diseases, such as asthma and chronic obstructive pulmonary disease. Currently, animal models have demonstrated the ability of hMPV to persist in vivo suggesting a role of the virus in asthma development in children. However, mechanisms involved in hMPV persistence in the respiratory tract are not yet understood. In the present study we monitored hMPV infection in human alveolar epithelial A549 cells in order to understand if the virus is able to persist in these cells upon acute infection. Our data show that hMPV initially induces an apoptotic process in A549 cells through poly (ADP-ribose) polymerase 1 cleavage, caspase-3/7 activation and Wee1 activity. The hMPV-infected cells were then able to overcome the apoptotic pathway and cell cycle arrest in G2/M by expressing B-cell lymphoma 2 and to acquire a reservoir cell phenotype with constant production of infectious virus. These findings provide evidence of the ability of hMPV to persist in alveolar epithelial cells and help in understanding the mechanisms responsible for hMPV persistence in the human respiratory tract. PMID- 29617860 TI - Whole-genome sequencing based characterization of antimicrobial resistance in Enterococcus. AB - Whole-genome sequencing (WGS) has transformed our understanding of antimicrobial resistance, yielding new insights into the genetics underlying resistance. To date, most studies using WGS to study antimicrobial resistance have focused on gram-negative bacteria in the family Enterobacteriaceae, such as Salmonella spp. and Escherichia coli, which have well-defined resistance mechanisms. In contrast, relatively few studies have been performed on gram-positive organisms. We sequenced 197 strains of Enterococcus from various animal and food sources, including 100 Enterococcus faecium and 97 E. faecalis. From analyzing acquired resistance genes and known resistance-associated mutations, we found that resistance genotypes correlated with resistance phenotypes in 96.5% of cases for the 11 drugs investigated. Some resistances, such as those to tigecycline and daptomycin, could not be investigated due to a lack of knowledge of mechanisms underlying these phenotypes. This study showed the utility of WGS for predicting antimicrobial resistance based on genotype alone. PMID- 29617861 TI - The application of Iberoamerican study of adverse events (IBEAS) methodology in Brazilian hospitals. AB - Objective: To assess the prevalence of adverse events (AE) and to investigate its association with factors related to the patient and to hospital admission. Design: Cross-sectional study. Setting: Four general hospitals located in the southeastern region of Brazil. Participants: All patients admitted to the participating hospitals at the time of the study were surveyed. Intervention: The methodology was based on the Iberoamerican study of adverse events, a two-stage medical record review. Main Outcome Measure: Medical records were screened for AE only in the day (24-h) immediately before the review process, independently of the admission date. Results: A total of 695 admissions were examined. Prevalence was 12.8%. Almost 43% of AE were preventable. More than 60% of patients with an event prolonged hospital stay. In final regression model, urgent admission (OR: 2.68; Confidence Interval (CI) 95%: 1.53-4.69), submission to a procedure (odds ratio (OR): 2.41; CI 95%: 1.33-4.39), presence of central venous catheter (OR: 2.25; CI 95%: 1.14-4.41) and immunosuppressive therapy (OR: 3.41; CI 95%: 1.57 7.40) were statistically associated with AE. Conclusions: Our results indicate that around 1.3 AE happen in each 10 hospital admissions in Brazil. As patient safety continues to be a Public Health concern worldwide and mainly in developing countries, this would indicate the potential use of prevalence measures for monitoring patient safety in Brazilian context. PMID- 29617862 TI - Generation of tumor antigen-specific murine CD8+ T cells with enhanced anti-tumor activity via highly efficient CRISPR/Cas9 genome editing. AB - Immunotherapies have led to the successful development of novel therapies for cancer. However, there is increasing concern regarding the adverse effects caused by non-tumor-specific immune responses. Here, we report an effective strategy to generate high-avidity tumor-antigen-specific CTLs, using Cas9/single-guide RNA (sgRNA) ribonucleoprotein (RNP) delivery. As a proof-of-principle demonstration, we selected the gp100 melanoma-associated tumor antigen, and cloned the gp100 specific high-avidity TCR from gp100-immunized mice. To enable rapid structural dissection of the TCR, we developed a 3D protein structure modeling system for the TCR/antigen-major histocompatibility complex (pMHC) interaction. Combining these technologies, we efficiently generated gp100-specific PD-1(-) CD8+ T cells, and demonstrated that the genetically engineered CD8+ T cells have high avidity against melanoma cells both in vitro and in vivo. Our methodology offers computational prediction of the TCR response, and enables efficient generation of tumor antigen-specific CD8+ T cells that can neutralize tumor-induced immune suppression leading to a potentially powerful cancer therapeutic. PMID- 29617863 TI - Characterizing the acute heat stress response in gilts: I. Thermoregulatory and production variables. AB - Identifying traits associated with susceptibility or tolerance to heat stress (HS) is a prerequisite for developing strategies to improve efficient pork production during the summer months. Study objectives were to determine the relationship between the thermoregulatory and production responses to acute HS in pigs. Prepubertal gilts (n = 235; 77.9 +/- 1.2 kg BW) were exposed to a thermoneutral (TN) period (P1, 24 h; 21.9 +/- 0.5 degrees C, 62 +/- 13% RH; fed ad libitum) followed immediately by a subsequent acute HS period (P2, 24 h; 29.7 +/- 1.3 degrees C, 49 +/- 8% RH; fed ad libitum). Rectal temperature (TR), skin temperature (TS), and respiration rate (RR) were monitored and BW and feed intake (FI) were determined. All pigs had increased TR, TS, and RR (0.80 degrees C, 5.65 degrees C, and 61.2 bpm, respectively; P < 0.01) and decreased FI and BW (29% and 1.10 kg, respectively; P < 0.01) during P2 compared to P1. Interestingly, body temperature indices did not explain variation in FI during P2 (R2 <= 0.02). Further, the percent change in BW during P2 was only marginally explained by each body temperature index (R2 <= 0.06) or percent change in FI (R2 = 0.14). During HS, TR was strongly correlated with P1 TR (r = 0.72, P < 0.01), indicating a pig's body temperature during TN conditions predicts the severity of hyperthermia during HS. Additionally, the change in TR (DeltaTR, HS TR - TN TR) was larger in pigs retrospectively classified as susceptible (SUS) as compared to tolerant (TOL) pigs (1.05 vs. 0.51 degrees C, respectively; P < 0.01). In summary, thermoregulatory responses and production variables during acute HS are only marginally related. Further, changes in BW and FI were unexpectedly poorly correlated during acute HS (r = 0.34; P < 0.01). Collectively, suboptimal growth is largely independent on the thermoregulatory response and hypophagia during acute HS. Consequently, incorporating solely body temperature indices into a genetic index is likely insufficient for substantial progress in selecting HS tolerant pigs. PMID- 29617864 TI - Rumen bacterial community structure impacts feed efficiency in beef cattle. AB - The importance of the rumen microbiota on nutrient cycling to the animal is well recognized; however, our understanding of the influence of the rumen microbiome composition on feed efficiency is limited. The rumen microbiomes of two large animal cohorts (125 heifers and 122 steers) were characterized to identify specific bacterial members (operational taxonomic units [OTUs]) associated with feed efficiency traits (ADFI, ADG, and G:F) in beef cattle. The heifer and steer cohorts were fed a forage-based diet and a concentrate-based diet, respectively. A rumen sample was obtained from each animal via esophageal tubing and bacterial community composition was determined through 16S rRNA gene sequencing of the V4 region. Based on a regression approach that used individual performance measures, animals were classified into divergent feed efficiency groups. Within cohort, an extreme set of 16 animals from these divergent groups was selected as a discovery population to identify differentially abundant OTUs across the rumen bacterial communities. The remaining samples from each cohort were selected to perform forward stepwise regressions using the differentially abundant OTUs as explanatory variables to distinguish predictive OTUs for the feed efficiency traits and to quantify the OTUs collective impact on feed efficiency phenotypes. OTUs belonging to the families Prevotellaceae and Victivallaceae were present across models for heifers, whereas OTUs belonging to the families Prevotellaceae and Lachnospiraceae were present across models for steers. Within the heifer cohort, models explained 19.3%, 25.3%, and 19.8% of the variation for ADFI, ADG, and G:F, respectively. Within the steer cohort, models explained 27.7%, 32.5%, and 26.9% of the variation for ADFI, ADG, and G:F, respectively. Overall, this study suggests a substantial role of the rumen microbiome on feed efficiency responses. PMID- 29617865 TI - Adipose tissue-specific responses reveal an important role of lipogenesis during heat stress adaptation in pigs. AB - Elevated ambient temperature causes heat stress in pigs, resulting in reduced animal performance. To better understand tissue responses to heat stress in pigs, we conducted a study in which pigs were subjected to four treatments: acute (24 h) heat stress (AHS) at 35 degrees C +/- 1 ambient temperature, chronic (7 d) heat stress at 35 degrees C +/- 1 (HS) or normal ambient temperature (20 degrees C+/- 1) for 7 d with ad-libitum feeding (Con) or with pair-feeding to the feed intake (FI) of the HS pigs (PF). Heat stress decreased FI by approximately 36% and 64% in HS and AHS treatments respectively, compared with Con (P < 0.01). Concentration of free fatty acids (FFA) was elevated in AHS compared to HS (P = 0.031). Serum insulin concentration was lower in PF than Con (P = 0.045). Blood urea nitrogen (BUN) concentration was elevated in HS compared with Con and PF (P = 0.008), but lower (P < 0.021) in AHS compared to HS. In the subcutaneous adipose tissue, the mRNA and protein abundance of PCK1 were higher (P < 0.05) in the HS treatment than Con and PF, and also higher (P < 0.05) in HS than AHS. However, there was no difference in GK mRNA between Con, PF, and HS, although its expression was lower (P = 0.003) in AHS vs. HS. Protein abundance of the ER stress marker, CCAT/enhancer-binding homologous protein (CHOP), was higher in PF than Con (P < 0.05), and higher (P = 0.033) in HS than AHS in subcutaneous fat. In mesenteric fat, PCK1 mRNA was higher (P < 0.001) in the HS than Con and PF treatments. Additionally, expression of PCK1 was lower (P = 0.039) in AHS vs. HS. Expression of PCK1 was downregulated (P < 0.05) in the liver of PF pigs compared to other treatments, but most other genes measured were not affected by treatment in the liver and muscle tissues. These results confirm that heat stress induces a robust adipose tissue response in favor of increased lipid storage. This indicates that adipose tissue might play an important role in heat stress adaptation. PMID- 29617866 TI - Serotonin induces parathyroid hormone-related protein in goat mammary gland. AB - During lactation, large amounts of calcium are exported from the mammary gland into milk to ensure skeletal growth of the offspring. Recent studies revealed that serotonin (5-HT) is essential to stimulate skeletal calcium resorption for milk synthesis. Our objective was to explore the correlation between circulating 5-HT and serum calcium and parathyroid hormone-related protein (PTHrP) concentrations around parturition in dairy goats. We also investigated the effect of 5-HT on PTHrP expression in cultured primary goat mammary epithelial cells (GMEC). Blood samples of multiparous Guanzhong dairy goats were collected on day 5 to 3 postpartum for analysis of serum concentrations of calcium, 5-HT, and PTHrP. Results revealed that from day -3 to 0 postpartum serum calcium and 5-HT concentrations decreased progressively, but serum PTHrP concentration only had a sharp drop in the postpartum period sampled. Correlation analysis of circulating 5-HT and serum calcium and PTHrP concentrations on day 1 and 2 postpartum revealed that low serum 5-HT concentration was positively correlated with serum total calcium or PTHrP concentration. By knocking down tryptophan hydroxylase-1 (TPH1) or adding 5-hydroxytryptophan (5-HTP) to decrease or increase the levels of 5-HT in GMEC, we observed that 5-HTP increased PTHrP expression in a dose dependent manner and siTPH1 decreased PTHrP protein expression. Furthermore, 5-HT increased mRNA abundance of calcium-sensing receptor (CaSR) in a dose-dependent manner and decreased the expression of plasma membrane Ca2+ ATPase-1 (PMCA1). Taken together, 5-HT seems to induce PTHrP expression in goat mammary cells during and after parturition. These findings suggest that increasing 5-HT biosynthesis could be a potential therapeutic target for prevention of hypocalcemia in dairy goats. PMID- 29617867 TI - Weaning disrupts intestinal antioxidant status, impairs intestinal barrier and mitochondrial function, and triggers mitophagy in piglets. AB - In the present study, we investigated the influence of weaning on antioxidant status, intestinal integrity, mitochondrial function, and the mitophagy level in piglets (weaned at 21 d) during the 1 wk after weaning. The redox status was measured by antioxidant enzymes activities, related genes expression, and malondialdehyde (MDA) content in jejunum. The intestinal barrier function was assessed by the Ussing chamber and expression of tight junction proteins in the jejunum. The function of intestine mitochondria was measured by mitochondrial DNA (mtDNA) content and activities of mitochondria oxidative phosphorylation complexes. The levels of light chain 3-1 (LC3-I), light chain 3-II (LC3-II), PTEN induced putative kinase 1 (PINK1), and Parkin were determined to investigate whether mitophagy is involved in the weaning process. The results showed that, as compared with the preweaning phase (d 0), weaning suppressed (P < 0.05) the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) on d 3 and d 7 postweaning, decreased (P < 0.05) the expression of copper and zinc superoxide dismutase (Cu/Zn-SOD), manganese-containing superoxide dismutase (Mn SOD) on d 3 postweaning, declined (P < 0.05) the level of glutathione peroxidase 1 (GPX-1) and glutathione peroxidase 4 (GPX-4) on d 3 and d 7 postweaning, and increased (P < 0.05) MDA content in jejunum on d 3 and d 7 postweaning. The jejunal transepithelial electrical resistance and levels of occludin, claudin-1, and zonula occludens-1 on d 3 and d 7 postweaning were reduced (P < 0.05), and paracellular flux of fluorescein isothiocyanatedextran (4 kDa) on d 3 and d 7 postweaning was increased (P < 0.05). Weaning induced mitochondrial dysfunction, as demonstrated by decreased (P < 0.05) content of mtDNA on d 3 and d 7 postweaning and declined (P < 0.05) activities of mitochondria complexes (I, II, III, IV) in jejunum on d 1, d 3, and d 7 postweaning. Weaning led to an increased (P < 0.05) expression level of mitophagy-related proteins, PINK1 and Parkin, in the intestinal mitochondria, as well as an enhancement (P < 0.05) of the ratio of LC3-II to LC3-I content in the jejunal mucosa on d 1, d 3, and d 7 postweaning. These results suggest that weaning disrupted intestinal oxidative balance, and this imbalance may impair intestinal barrier and mitochondrial function and trigger mitophagy in piglets. PMID- 29617869 TI - Changes in Brain Structural Networks and Cognitive Functions in Testicular Cancer Patients Receiving Cisplatin-Based Chemotherapy. AB - Background: Cisplatin-based chemotherapy may have neurotoxic effects within the central nervous system. The aims of this study were 1) to longitudinally investigate the impact of cisplatin-based chemotherapy on whole-brain networks in testicular cancer patients undergoing treatment and 2) to explore whether possible changes are related to decline in cognitive functioning. Methods: Sixty four newly orchiectomized TC patients underwent structural magnetic resonance imaging (T1-weighted and diffusion-weighted imaging) and cognitive testing at baseline prior to further treatment and again at a six-month follow-up. At follow up, 22 participants had received cisplatin-based chemotherapy (CT) while 42 were in active surveillance (S). Brain structural networks were constructed for each participant, and network properties were investigated using graph theory and longitudinally compared across groups. Cognitive functioning was evaluated using standardized neuropsychological tests. All statistical tests were two-sided. Results: Compared with the S group, the CT group demonstrated altered global and local brain network properties from baseline to follow-up as evidenced by decreases in important brain network properties such as small-worldness (P = .04), network clustering (P = .04), and local efficiency (P = .02). In the CT group, poorer overall cognitive performance was associated with decreased small worldness (r = -0.46, P = .04) and local efficiency (r = -0.51, P = .02), and verbal fluency was associated with decreased local efficiency (r = -0.55, P = .008). Conclusions: Brain structural networks may be disrupted following treatment with cisplatin-based chemotherapy. Impaired brain networks may underlie poorer performance over time on both specific and nonspecific cognitive functions in patients undergoing chemotherapy. To the best of our knowledge, this is the first study to longitudinally investigate changes in structural brain networks in a cancer population, providing novel insights regarding the neurobiological mechanisms of cancer-related cognitive impairment. PMID- 29617868 TI - Responses in the rumen microbiome of Bos taurus and indicus steers fed a low quality rice straw diet and supplemented protein. AB - Bos indicus typically perform better than Bos taurus when consuming a low-quality diet; however, the response to supplementation is generally greater in B. taurus. The underlying mechanisms supporting these responses have not been fully elucidated. Characterization of differences in rumen prokaryotic populations and their functional role in the two subspecies may provide additional insight. Ten cannulated steers (5 Angus and 5 Brahman) were used in concurrent 5 * 5 Latin squares. Animals were offered ad libitum access to rice straw (4.7% CP). Treatments consisted of an unsupplemented control diet and two levels (50 or 120 mg N/kg BW) of isonitrogenous supplements (30% CP), that were either high (H; 74%) or low (L; 26%) in undegradable intake protein. Rumen samples were collected at 0 and 4 h postfeeding and separated into liquid and solid fractions. Rumen bacterial taxa were sequenced utilizing a Roche 454 platform based on the 16s rRNA gene. At 97% sequence similarity, 97,826 operational taxonomic units were identified, which included 24 phyla, 108 families, and 255 genera. Analysis included SAS PROC mixed model, QIIME, and PICRUSt. Across all samples, Bacteroidetes and Firmicutes accounted for 65% and 28% of total bacterial abundance, respectively. The families Prevotellaceae (P = 0.05) and Ruminococcaceae (P = 0.004) and the genera Prevotellaceae (family; P = 0.003) within the phyla Bacteroidetes differed significantly in relative abundance with added protein when compared to the control. Consistent differences in the relative abundance of family and genus taxa between B. indicus and B. taurus suggest roles the symbiotic rumen microbiome may have in the capacity of B. indicus to utilize low-quality forage over a range of supplement types and levels including (Prevotella, Ruminococcus [family], Sphingobacteriaceae [family], Bacteroidales [order], Pontibacter, Bacteroides, Succiclasticum, Barnesiella, and Xylanibacter). Overall bacterial community diversity differences across parameters were limited. Rice straw is recalcitrant to bacterial digestion because of high levels of silica in the epidermis making this straw more resistant to bacterial attachment. Thus, this analysis represents the bacterial diversity and function of the rumen under conditions depleted CP, recalcitrant fiber matrix and restricted digestibility which appear to limit the microbial population to those capable of attaching and digesting complexed structural carbohydrates, resulting in reduced plasticity, and more evenness in diversity across parameters. PMID- 29617870 TI - Wave Change of Intraoperative Transcranial Motor-Evoked Potentials During Corrective Fusion for Syndromic and Neuromuscular Scoliosis. AB - BACKGROUND: There is little information on intraoperative neuromonitoring during correction fusion surgery for syndromic scoliosis. OBJECTIVE: To investigate intraoperative TcMEPs and conditions (body temperature and blood pressure) for syndromic scoliosis. METHODS: The subjects were 23 patients who underwent 25 surgeries for corrective fusion using TcMEP. Patients were divided into groups based on a decrease (DA+) or no decrease (DA-) of the amplitude of the TcMEP waveform of >=70%. The groups were compared for age, sex, disease, type of surgery, fusion area, operation time, estimated blood loss, body temperature, blood pressure, Cobb angle, angular curve (Cobb angle/number of vertebra), bending flexibility, correction rate, and recovery. RESULTS: The mean Cobb angles before and after surgery were 85.2 degrees and 29.1 degrees , giving a correction rate of 68.2%. There were 16 surgeries (64.0%) with intraoperative TcMEP wave changes. The DA+ and DA- groups had similar intraoperative conditions, but the short angular curve differed significantly between these groups. Amplitude deterioration occurred in 4 cases during first rod placement, in 8 during rotation, and in 3 during second rod placement after rotation. Seven patients had complete loss of TcMEP. However, most TcMEP changes recovered after pediclectomy or decreased correction. The preoperative angular curve differed significantly between patients with and without TcMEP changes (P < .05). CONCLUSION: Intraoperative TcMEP wave changes occurred in 64.0% of surgeries for corrective fusion, and all but one of these changes occurred during the correction procedure. The angular curve was a risk factor for intraoperative motor deficit. PMID- 29617872 TI - Nonpharmacological Management of Pain: Convergence in Priorities Fuels the Drive for More Evidence. PMID- 29617871 TI - Clinical and Laboratory Predictors of Shiga Toxin-Producing Escherichia coli Infection in Children With Bloody Diarrhea. AB - Objectives: Children with acute bloody diarrhea are at risk of being infected with Shiga toxin-producing Escherichia coli (STEC) and of progression to hemolytic uremic syndrome. Our objective was to identify clinical and laboratory factors associated with STEC infection in children who present with acute bloody diarrhea. Methods: We performed a prospective cohort study of consecutive children younger than 18 years who presented with acute (<2-week duration) bloody diarrhea between August 1, 2013, and August 1, 2014. We excluded patients with a chronic gastrointestinal illness and/or an obvious noninfectious source of bloody stool. We obtained a standardized history and study laboratory tests, performed physical examinations, and recorded patient outcomes. Results: Of the 135 eligible patients, 108 were enrolled; 27 declined consent. The median patient age was 3 years, and 56% were male. Ten (9%) patients tested positive for STEC (E coli O157:H7, n = 8; E coli O111, n = 1; E coli O103, n = 1), and 62 had negative stool culture results. Children infected with STEC were older (8.5 vs 3 years, respectively) (P < .001) and more likely to have abdominal tenderness (83% vs 17%, respectively) than those in the other groups. D-Dimer concentrations had a 70% sensitivity and 55% specificity for differentiating children with STEC from those with another cause of bloody diarrhea and 75% sensitivity and 70% specificity in differentiating children with a bacterial etiology from those with negative stool culture results. Conclusion: Clinical assessment and laboratory data cannot reliably exclude the possibility that children with bloody diarrhea have an STEC infection and are at consequent risk of developing hemolytic uremic syndrome. Abnormal D-dimer concentrations (>0.5 MUg/mL) were insufficiently sensitive and specific for distinguishing patients with STEC from those with another bacterial cause of bloody diarrhea. However, this marker might be useful in identifying children whose bloody diarrhea is caused by a bacterial enteric pathogen. PMID- 29617874 TI - Avoiding the Major Causes of Death: Does Childhood Misfortune Reduce the Likelihood of Being Disease Free in Later Life? AB - Objectives: Although previous research reveals the detrimental effects of early misfortune on the development of chronic diseases in later life, few studies have investigated its effects on remaining disease free. This study draws on cumulative inequality theory to investigate whether experiencing childhood misfortune reduces the likelihood of remaining disease free over time. Methods: This study utilizes five waves of data from the Health and Retirement Study to test whether five domains of childhood misfortune predict being disease free at baseline (2004) and developing disease over time (2004-2012). Results: Respondents reporting risky parental behaviors during childhood were less likely to be disease free at baseline and had an increased risk of disease onset over time, the latter driven by having a guardian who smoked in combination with more pack-years smoked in adulthood. Furthermore, we find that adult resources, i.e. wealth, help to mitigate the noxious effects of other misfortunes, notably poor socioeconomic conditions. Discussion: Consistent with cumulative inequality theory, these findings reveal that experiencing multiple types of misfortune during childhood decreases the likelihood of remaining disease free in later life, but engaging in health behaviors, such as physical activity, can help to ameliorate some of the noxious effects of early misfortune. PMID- 29617873 TI - A multi-landing pad DNA integration platform for mammalian cell engineering. AB - Engineering mammalian cell lines that stably express many transgenes requires the precise insertion of large amounts of heterologous DNA into well-characterized genomic loci, but current methods are limited. To facilitate reliable large-scale engineering of CHO cells, we identified 21 novel genomic sites that supported stable long-term expression of transgenes, and then constructed cell lines containing one, two or three 'landing pad' recombination sites at selected loci. By using a highly efficient BxB1 recombinase along with different selection markers at each site, we directed recombinase-mediated insertion of heterologous DNA to selected sites, including targeting all three with a single transfection. We used this method to controllably integrate up to nine copies of a monoclonal antibody, representing about 100 kb of heterologous DNA in 21 transcriptional units. Because the integration was targeted to pre-validated loci, recombinant protein expression remained stable for weeks and additional copies of the antibody cassette in the integrated payload resulted in a linear increase in antibody expression. Overall, this multi-copy site-specific integration platform allows for controllable and reproducible insertion of large amounts of DNA into stable genomic sites, which has broad applications for mammalian synthetic biology, recombinant protein production and biomanufacturing. PMID- 29617875 TI - Genetic Analysis of Reemerging GII.P16-GII.2 Noroviruses in 2016-2017 in China. AB - Background: During 2016-2017, the previously rare GII.P16-GII.2 norovirus suddenly emerged as the predominant genotype causing gastroenteritis outbreaks in China and other countries. Its origin, phylodynamics, and mechanism behind the predominance remain unclear. Methods: Bayesian phylogenetic analyses were performed on 180 full capsid and 150 polymerase sequences of 2016-2017 GII.P16 GII.2 noroviruses in China, and those for all publicly available GII.P16 and GII.2 sequences. Saliva-based histo-blood group antigen (HBGA) binding assays and crystal structural analysis were conducted by using the P proteins of 2016-2017 GII.P16-GII.2 noroviruses. Results: The reemerging GII.P16-GII.2 norovirus showed a rapid genetic diversification after its emergence in 2012-2013. The antigenicity and HBGA binding profile of the early 2016-2017 and pre-2016 GII.2 noroviruses were similar. A further variant with a single Val256Ile mutation and the conventionally orientated Asp382 in the VP1 protein showed an expanded HBGA binding spectrum. Mutations on the surface of polymerase that could alter its function were seen, which may help to accelerate the VP1 gene evolution to 5.5 * 10-3 substitutions per site per year. This virus can be traced back to Pearl River Delta, China. Conclusions: Our findings provide new insights into GII.2 norovirus epidemics and highlight the necessity of enhanced global surveillance for potential epidemics of rare-genotype noroviruses. PMID- 29617877 TI - Paediatric renal hydatid cyst. PMID- 29617876 TI - A novel method for improved accuracy of transcription factor binding site prediction. AB - Identifying transcription factor (TF) binding sites (TFBSs) is important in the computational inference of gene regulation. Widely used computational methods of TFBS prediction based on position weight matrices (PWMs) usually have high false positive rates. Moreover, computational studies of transcription regulation in eukaryotes frequently require numerous PWM models of TFBSs due to a large number of TFs involved. To overcome these problems we developed DRAF, a novel method for TFBS prediction that requires only 14 prediction models for 232 human TFs, while at the same time significantly improves prediction accuracy. DRAF models use more features than PWM models, as they combine information from TFBS sequences and physicochemical properties of TF DNA-binding domains into machine learning models. Evaluation of DRAF on 98 human ChIP-seq datasets shows on average 1.54-, 1.96- and 5.19-fold reduction of false positives at the same sensitivities compared to models from HOCOMOCO, TRANSFAC and DeepBind, respectively. This observation suggests that one can efficiently replace the PWM models for TFBS prediction by a small number of DRAF models that significantly improve prediction accuracy. The DRAF method is implemented in a web tool and in a stand-alone software freely available at http://cbrc.kaust.edu.sa/DRAF. PMID- 29617878 TI - Role of TGFbeta Signaling in Maternal Ethanol-Induced Fetal Articular Cartilage Dysplasia and Adult Onset of Osteoarthritis in Male Rats. AB - Based on our previous findings that prenatal ethanol exposure in offspring increased susceptibility to adult osteoarthritis, this study aimed to further investigate the direct toxicity of ethanol on fetal articular cartilage development. Rat bone marrow-derived stroma cells were capsulated in alginate beads, incubated in a chondrogenic differentiation medium, and cultured for 4 weeks with ethanol treatment at concentrations of 0, 4, 20, and 100 mM. Pregnant rats were treated with ethanol (4 g/kg/day) from gestational days (GDs) 9 to 20. At GD20 and postnatal weeks 2, 6, and 12, 8 male offspring were sacrificed, and 8 male offspring rats of 8-weeks old in each group were treated with or without intraarticular injection of papain for 4 weeks to verify the susceptibility of adult osteoarthritis. Ethanol treatment resulted in poor differentiation of bone marrow-derived stroma cells to chondrocytes and suppressed the expression of the transforming growth factor-beta (TGFbeta)-smad2/3-Sox9 signaling pathway. In animal experiments, the shape of articular cartilage in the ethanol treatment group was more disordered than that of the control group, the matrix was not deep, and the cartilage was thin, which showed poor cartilage development. The TGFbeta signaling pathway in the ethanol treatment group was persistently low at all time points. After intraarticular injection of papain, histological analyses, and the Mankin score revealed increased cartilage destruction in the ethanol treatment group. Ethanol caused articular cartilage dysplasia that was programmed in adulthood via a low-functional TGFbeta signaling pathway, and the tolerance of this articular cartilage to external stimuli was significantly decreased. PMID- 29617879 TI - Prevalence and Significance of Substitutions in the Fusion Protein of Respiratory Syncytial Virus Resulting in Neutralization Escape From Antibody MEDI8897. AB - Background: Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infection among infants and young children. To date, no vaccine is approved for the broad population of healthy infants. MEDI8897, a potent anti RSV fusion antibody with extended serum half-life, is currently under clinical investigation as a potential passive RSV vaccine for all infants. As a ribonucleic acid virus, RSV is prone to mutation, and the possibility of viral escape from MEDI8897 neutralization is a potential concern. Methods: We generated RSV monoclonal antibody (mAb)-resistant mutants (MARMs) in vitro and studied the effect of the amino acid substitutions identified on binding and viral neutralization susceptibility to MEDI8897. The impact of resistance-associated mutations on in vitro growth kinetics and the prevalence of these mutations in currently circulating strains of RSV in the United States was assessed. Results: Critical residues identified in MARMs for MEDI8897 neutralization were located in the MEDI8897 binding site defined by crystallographic analysis. Substitutions in these residues affected the binding of mAb to virus, without significant impact on viral replication in vitro. The frequency of natural resistance-associated polymorphisms was low. Conclusions: Results from this study provide insights into the mechanism of MEDI8897 escape and the complexity of monitoring for emergence of resistance. PMID- 29617880 TI - Changes in expression of special AT-rich sequence binding protein 1 and phosphatase and tensin homologue in kidneys of diabetic rats during ageing. PMID- 29617881 TI - FDG-PET diagnoses of sporadic Creutzfeldt-Jakob disease: radiology-pathology correlation. PMID- 29617882 TI - Protect us from poor-quality medical research. AB - Much of the published medical research is apparently flawed, cannot be replicated and/or has limited or no utility. This article presents an overview of the current landscape of biomedical research, identifies problems associated with common study designs and considers potential solutions. Randomized clinical trials, observational studies, systematic reviews and meta-analyses are discussed in terms of their inherent limitations and potential ways of improving their conduct, analysis and reporting. The current emphasis on statistical significance needs to be replaced by sound design, transparency and willingness to share data with a clear commitment towards improving the quality and utility of clinical research. PMID- 29617883 TI - Risk for adverse pregnancy outcome in axial spondyloarthritis and rheumatoid arthritis: disease activity matters. AB - Objective: To analyse pregnancy outcome and delivery mode in patients with RA and axial spondyloarthritis (axSpA) in relation to disease activity and anti rheumatic drugs. Methods: Patients with RA and axSpA were compared with age matched healthy controls (HCs) with respect to pregnancy outcome and delivery mode. Disease activity (DAS28, ASDAS, CRP) and medication use of patients was assessed once at each trimester. ORs with 95% CI were calculated with univariate and multivariate regression models. Results: We analysed 244 pregnancies, of which 96 occurred in patients with RA, 78 in patients with axSpA and 70 in HCs. The adjusted analysis showed that pregnant women with RA and axSpA had a higher risk of pregnancy complications (gestational diabetes, preeclampsia, infection, preterm premature rupture of membranes), small for gestational age infants and preterm deliveries (all P < 0.05). Active disease was a predictor for preterm delivery in both RA [odds ratio (OR) = 3.9, 95% CI: 1.25, 12.15] and axSpA (OR = 13.8, 95% CI: 1.33, 143.94). Regarding delivery mode, most patients had vaginal deliveries. However, women with RA revealed an increased risk of caesarean section compared with HC (P < 0.05), which was not seen in patients with axSpA. Conclusion: Our findings show that disease activity of RA and axSpA during pregnancy influences pregnancy outcome. To allow for successful pregnancy a treatment strategy that targets inactive disease beyond conception should be followed. PMID- 29617884 TI - Rituximab versus the modified Ponticelli regimen in the treatment of primary membranous nephropathy: a Health Economic Model. AB - Background: Membranous nephropathy is among the most common causes of nephrotic syndrome worldwide, with a high healthcare burden. Treatment using the modified Ponticelli regimen (mPR) has remained the standard of care for decades, but newer therapies such as rituximab offer promising results with reduced side effects. The cost of this treatment, however, is perceived as a barrier to widespread use, especially in resource limited healthcare systems. Methods: We developed a decision-analytic model to estimate the cost-effectiveness of rituximab versus the mPR from the perspective of the National Health Service in the UK over a 1 year, 5 year and lifetime horizon. Primary outcome is the cost-effectiveness of rituximab versus mPR at 5 years post-treatment. Secondary outcomes are cost effectiveness at 1 and 10 years post-treatment and over a lifetime. Results: At 1 year post-treatment, rituximab therapy dominates mPR. At 5 years post-treatment, rituximab therapy is cheaper than the Ponticelli regimen but at a loss of 0.014 quality-adjusted life years (QALYs) with an incremental cost-effectiveness ratio (ICER) of L95 494.13. Over a lifetime, rituximab remains the cheaper option with an incremental cost of -L5251.03 but with a reduced quality of life (incremental QALY of -0.512) giving an ICER of L10 246.09. Conclusions: Our analysis indicates that rituximab has the potential to be a cost-effective treatment in the short and medium terms despite the high single-dose cost. This evaluation suggests that further research is warranted and highlights the need for a high-quality clinical trial to confirm the efficacy and cost-effectiveness of rituximab versus the current standard of care. PMID- 29617885 TI - Can findings on peripheral blood smear differentiate leptospirosis from other infections? A preliminary comparative study. AB - Background: Blood smear changes have never been investigated as a potential tool to aid in the diagnosis of leptospirosis. Methods: Blood smears prepared from patients with leptospirosis, dengue and sepsis within the first 5 days of illness were reported by haematologists blinded to the diagnosis. Results: A total of 20, 28 and 22 patients with leptospirosis, dengue and sepsis, respectively, were analysed. Neutrophil leucocytosis, toxic changes in neutrophils, left shift, reactive lymphocytes, target cells and thrombocytopaenia were seen in 60%, 70%, 40%, 70%, 50% and 65% of the leptospirosis patients, respectively. The combination of reactive lymphocytes with toxic neutrophils or neutrophil leucocytosis was highly suggestive of leptospirosis. Conclusions: Peripheral blood smear findings may be helpful in differentiating leptospirosis from other common acute febrile illnesses. PMID- 29617886 TI - Factors associated with food insecurity among older homeless adults: results from the HOPE HOME study. AB - Background: The US homeless population is aging. Older adults and those living in poverty are at a high risk of food insecurity. Methods: We conducted a cross sectional analysis of baseline data from a population-based study of 350 homeless adults aged >=50. We assessed food security and receipt of food assistance. We used multivariable logistic regression to examine factors associated with very low food security. Results: The majority of the cohort was male and African American. Over half (55.4%) met criteria for food insecurity, 24.3% reported very low food security. Half (51.7%) reported receiving monetary food assistance. In the multivariable model, those who were primarily sheltered in the prior 6 months, (multi-institution users [AOR = 0.44, 95% CI: 0.22-0.86]) had less than half the odds of very low food security compared with those who were unsheltered. Depressive symptoms (AOR = 3.01, 1.69-5.38), oral pain (AOR = 2.15, 1.24-3.74) and cognitive impairment (AOR = 2.21, 1.12-4.35) were associated with increased odds of very low food security. Conclusions: Older homeless adults experience a high prevalence of food insecurity. To alleviate food insecurity in this population, targeted interventions must address specific risk groups. PMID- 29617887 TI - E-cigarettes: Comparing the Possible Risks of Increasing Smoking Initiation with the Potential Benefits of Increasing Smoking Cessation. AB - Introduction: The public health community is divided regarding electronic cigarettes. Skeptics emphasize potential vaping-induced increases in smoking among children and possible health hazards for adults. Enthusiasts consider e cigarettes much less dangerous than smoking and believe they increase adult smoking cessation. We compare potential health benefits and costs to put these two perspectives in context. Methods: Using a dynamic model that tracks the US adult population's smoking status and smoking-related deaths over time, we simulate the effects of vaping-induced smoking initiation and cessation on life years saved or lost to the year 2070. The base case assumes that vaping annually increases smoking initiation by 2% and smoking cessation by 10%. Sensitivity analyses raise the initiation rate increase to 6% while decreasing the cessation rate increase to 5%. Sensitivity analyses also test vaping's reducing the health benefits of quitting smoking by 10%. Results: With base-case assumptions, the population gains almost 3.3 million life-years by 2070. If all people who quit smoking by vaping lose 10% of the benefit of quitting smoking, the net life-year gain falls to 2.4 million. Under worst-case assumptions, in which vaping increases smoking initiation by 6% and cessation by 5%, and vaping-induced quitters lose 10% of the health benefits, the population gains over 580,000 life years. Conclusion: Potential life-years gained as a result of vaping-induced smoking cessation are projected to exceed potential life-years lost due to vaping induced smoking initiation. These results hold over a wide range of plausible parameters. Implications: Our analysis strongly suggests that the upside health benefit associated with e-cigarettes, in terms of their potential to increase adult smoking cessation, exceeds their downside risk to health as a result of their possibly increasing the number of youthful smoking initiators. Public messaging and policy should continue to strive to reduce young people's exposure to all nicotine and tobacco products. But they should not do so at the expense of limiting such products' potential to help adult smokers to quit. PMID- 29617888 TI - Parental Smoking and Adult Offspring's Smoking Behaviors in Ethnic Minority Groups: An Intergenerational Analysis in the HELIUS Study. AB - Introduction: To understand smoking behaviors among ethnic minority groups, studies have largely focused on societal factors, with little attention to family influences. Yet studies among majority groups have identified parental smoking as an important risk factor. It is unknown whether this applies to ethnic minority groups. We investigated the association between parental smoking and adult offspring's smoking behaviors among ethnic minority groups with an immigrant background. Methods: We used data from the Healthy Life in an Urban Setting study from Amsterdam (the Netherlands) from January 2011 to December 2015. The sample consisted of 2184 parent-offspring pairs from South-Asian Surinamese, African Surinamese, Turkish, Moroccan, and Ghanaian origin. We collected self-reported smoking data: current status, duration of exposure to parental smoking, number of daily cigarettes, heavy smoking ( > 10 cigarettes/day), and nicotine dependency (using the Fagerstrom Test). Analyses were stratified by offspring's age, cohabitation with parent, education (parent/offspring), offspring's cultural orientation, and gender concordance within pairs. Logistic regression was used. Results: Overall, parental smoking was associated with offspring's smoking behaviors (eg, current smoking: odds ratio 2.33; 95% confidence interval 1.79 3.03), with little ethnic variation. We found dose-response associations between exposure to parental smoking and offspring's smoking. The associations were similar across different strata but stronger in gender-concordant pairs (3.16; 2.12-4.51 vs. 1.73; 1.15-2.59 in gender-discordant pairs; p-value for interaction .017). Conclusions: Parental smoking is associated with offspring's smoking behaviors in ethnic minority groups across different strata but particularly in gender-concordant pairs. Similar to majority groups, family influences matter to smoking behaviors in ethnic minority groups. Implications: Our findings have deepened our understanding of smoking behaviors among ethnic minority groups. Future studies should simultaneously consider societal factors and parental influences, to comprehensively understand their impact on smoking among ethnic minority groups. Also, smoking patterns among family members should be addressed in individual counselling, irrespective of ethnicity. PMID- 29617889 TI - Insomnia in Alcohol-Dependent Patients: Prevalence, Risk Factors and Acamprosate Effect: An Individual Patient Data Meta-Analysis. AB - Aims: The prevalence of insomnia ranges from 36% to 91% in alcohol-dependent patients and may persist after alcohol withdrawal. Acamprosate has been shown to decrease insomnia in abstinent patients. Based on a large clinical trial database, the aim of the present study is to assess the efficacy of acamprosate in reducing insomnia, and if indeed it does reduce insomnia, to better understand its action mechanism. Short Summary: The aim of the study is to confirm the efficacy of acamprosate to reduce insomnia using an individual patient data meta analysis. Twelve studies were found including 3508 patients. After a 6-month follow-up, the mean insomnia decrease over baseline was -26% and -45% for the placebo and acamprosate groups, respectively (P < 0.001). Methods: An individual patient data meta-analysis selected all the randomized trials of acamprosate in which insomnia was documented. Our main endpoint was insomnia change after a 6 month follow-up, measured by the validated Short Sleep Index (SSI) derived from the Hamilton Depression and Anxiety Scale. The meta-analysis was conducted using a two-level multilevel (patient/trial) mixed model with random treatment effect, random study effect and adjusting for baseline severity covariates. Results: Twelve studies were found including 3508 patients, 59.8% of whom were suffering from insomnia (95% CI 58.1-61.4). Psychiatric history, severe addiction, living alone and abnormal gamma-GT levels were found to be the risk factors of insomnia. After 6 months, the mean SSI decrease over baseline was -26% and -45% for placebo and acamprosate, respectively (treatment effect = 19%, 12.5-25.5; P < 0.001). By using a univariate mediation model, we found that the mediating effect of abstinence on insomnia accounted for 55.7% of the overall effect of acamprosate on insomnia reduction. Conclusions: Insomnia is prevalent among alcohol-dependent patients. It decreases spontaneously with abstinence but more frequently with acamprosate treatment. PMID- 29617890 TI - Quantification of Subdural Electrode Shift Between Initial Implantation, Postimplantation Computed Tomography, and Subsequent Resection Surgery. AB - BACKGROUND: Subdural electrodes are often implanted for localization of epileptic regions. Postoperative computed tomography (CT) is typically acquired to locate electrode positions for planning any subsequent surgical resection. Electrodes are assumed to remain stationary between CT acquisition and resection surgery. OBJECTIVE: To quantify subdural electrode shift that occurred between the times of implantation (Crani 1), postoperative CT acquisition, and resection surgery (Crani 2). METHODS: Twenty-three patients in this case series undergoing subdural electrode implantation were evaluated. Preoperative magnetic resonance and postoperative CT were acquired and coregistered, and electrode positions were extracted from CT. Intraoperative positions of electrodes and the cortical surface were digitized with a coregistered stereovision system. Movement of the exposed cortical surface was also tracked, and change in electrode positions was calculated relative to both the skull and the cortical surface. RESULTS: In the 23 cases, average shift of electrode positions was 8.0 +/- 3.3 mm between Crani 1 and CT, 9.2 +/- 3.7 mm between CT and Crani 2, and 6.2 +/- 3.0 mm between Crani 1 and Crani 2. The average cortical shift was 4.7 +/- 1.4 mm with 2.9 +/- 1.0 mm in the lateral direction. The average shift of electrode positions relative to the cortical surface between Crani 1 and Crani 2 was 5.5 +/- 3.7 mm. CONCLUSION: The results show that electrodes shifted laterally not only relative to the skull, but also relative to the cortical surface, thereby displacing the electrodes from their initial placement on the cortex. This has significant clinical implications for resection based upon seizure activity and functional mapping derived from intracranial electrodes. PMID- 29617891 TI - Comparing indigenous mortality across urban, rural and very remote areas: a systematic review and meta-analysis. AB - Background: It remains unclear how indigenous mortality varies between residential areas. We conducted a systematic review and meta-analysis on mortality patterns in urban, rural and very remote areas for the adult and infant indigenous populations of Australia, Canada, New Zealand and the USA. Methods: A literature search was performed using major online electronic publication repositories. Studies presenting indigenous mortality or disease incidence/prevalence in urban, rural or very remote areas were included. Indigenous mortality and disease incidence/prevalence in both urban and very remote areas were compared with those in rural areas. Studies that reported number of deaths or disease incidences along with population were included in the meta-analysis. Results: Thirty-one studies were included with data from Australia (n=19), Canada (n=3), New Zealand (n=1) and the USA (n=8). Indigenous adult all cause mortality, cervical cancer mortality, trauma mortality and incidence of myocardial infarction were all significantly lower in urban areas compared with rural areas. Likewise, indigenous adult cardiovascular mortality and renal disease mortality were significantly lower in very remote areas compared with rural areas, while indigenous infant all-cause mortality showed no significant difference in urban, rural or very remote areas. Conclusions: Urban areas consistently experienced lower adult indigenous mortality compared with rural areas, as did some very remote areas. Indigenous infants, however, experience similar mortality rates across all residential areas. PMID- 29617892 TI - Medical knowledge related to Rocky Mountain spotted fever in Sonora, Mexico. AB - Background: Rocky Mountain spotted fever (RMSF) is a tick-borne disease with a high case-fatality rate unless diagnosed promptly and treated timely with doxycycline. Physician knowledge about presentation and treatment can improve outcomes of RMSF in endemic regions, such as Sonora in northern Mexico, where RMSF has caused 1348 non-fatal cases and 247 deaths from 2003 to 2016. Methods: A cross-sectional study was conducted with 343 physicians working in medical facilities in Sonora, Mexico. A 25-item questionnaire explored physician knowledge of clinical, epidemiological and preventive aspects of RMSF. Results: Only 62% of physicians agreed that doxycycline should be used as the first choice treatment for children under 8 years with suspected RMSF. Additionally, 40% of primary care physicians correctly identified the time to initiate doxycycline, and 32% correctly identified the case-fatality rate of untreated RMSF in all patients. Conclusions: Inadequate medical knowledge may adversely affect how patients infected with Rickettsia rickettsii are diagnosed and treated. Educational programs that improve the risk perception and medical knowledge about RMSF should be targeted at physicians most likely to have initial contact with diseased patients. PMID- 29617893 TI - Serum Cortisol and Cortisone as Potential Biomarkers of Partial 11beta Hydroxysteroid Dehydrogenase Type 2 Deficiency. AB - BACKGROUND: Pathogenic variations in HSD11B2 gene triggers the apparent mineralocorticoid excess syndrome (AME). There is scarce information regarding the phenotypes of subjects carrying heterozygous pathogenic variants in HSD11B2 gene. We investigated if serum cortisol/cortisone (F/E) ratio and cortisone are useful for identifying partial 11betaHSD2 deficiency in those heterozygous subjects. METHODS: We studied two patients diagnosed with AME and their families carrying either D223N or R213C mutation. We also evaluated 32 healthy control subjects (13 children and 19 adults) to obtain normal references ranges for all measured variables. Case 1: A boy carrying D223N mutation in HSD11B2 gene and Case 2: A girl carrying R213C mutation. We assessed serum F/E ratio and cortisone by HPLC-MS/MS, aldosterone, plasma-renin-activity(PRA), electrolytes, and HSD11B2 genetic analyses. RESULTS: The normal values (median [interquartile range]) in children for serum F/E and cortisone (ug/dl) were 2.56 [2.21-3.69] and 2.54 [2.35 2.88], and in adults were 4.42 [3.70-4.90] and 2.23 [1.92-2.57], respectively. Case 1 showed a very high serum F/E 28.8 and low cortisone 0.46 ug/dl. His mother and sister were normotensives and heterozygous for D223N mutation with high F/E (13.2 and 6.0, respectively) and low cortisone (2.0 and 2.2, respectively). Case 2 showed a very high serum F/E 175 and suppressed cortisone 0.11 ug/dl. Her parents and sister were heterozygous for the R213C mutation with normal phenotype, but high F/E and low cortisone. Heterozygous subjects showed normal aldosterone, PRA, but lower fractional excretion of sodium and urinary Na/K ratio than controls. CONCLUSION: Serum F/E ratio and cortisone allow to identify partial 11betaHSD2 deficiencies, as occurs in heterozygous subjects, who would be susceptible to develop arterial hypertension. PMID- 29617894 TI - Factors Associated With Hypertension Control in US Adults Using 2017 ACC/AHA Guidelines: National Health and Nutrition Examination Survey 1999-2016. AB - BACKGROUND: Factors and trends associated with hypertension control (BP < 130/80 mm Hg) and mean blood pressure (BP) among hypertensive adults (BP >=1 30/80 mm Hg or medicated for hypertension). METHOD: Data on 22,911 hypertensive US adults from the 1999-2016 National Health and Nutrition Examination Survey. RESULTS: For men, hypertension control prevalence increased from 8.6% in 1999-2000 to 16.2% in 2003-2004 (P < 0.001), and continued the increasing trend afterwards to 23.2% in 2011-2012 (P < 0.001) and then plateaued. For women, hypertension control prevalence increased from 1999-2000 to 2009-2010 (10.8-26.3%, P < 0.001) and then plateaued. For men with hypertension, systolic BP decreased from 1999-2000 to 2011-2012 (135.7-132.8 mm Hg, P < 0.001) and then increased to 135.3 mm Hg in 2015-2016 (P < 0.001). For women with hypertension, systolic BP decreased from 1999-2000 to 2009-2010 (139.7-131.9 mm Hg; P < 0.001) and then increased to 134.4 mm Hg in 2015-2016 (P = 0.003). Diastolic BP decreased from 1999-2000 to 2015 2016 (men: 79.1-75.5 mm Hg and women: 76.4-73.7 mm Hg, P < 0.001 for both). In 2011-2016, hypertension control was 22.0% for men and 25.2% for women. The adjusted prevalence ratio (PR) of hypertension control were lower for non Hispanic black men and women (PR = 0.72, 95% confidence interval (CI) = 0.61 0.86; PR = 0.83, 95% CI = 0.70-0.99, respectively; non-Hispanic white (NHW) as reference), Hispanic and non-Hispanic Asian men (PR = 0.70, 95% CI = 0.54-0.92; PR = 0.59, 95% CI = 0.39-0.86; respectively; NHW as reference). CONCLUSION: Hypertension control significantly increased from 1999-2000 to 2011-2012 (men) and 2009-2010 (women) and then plateaued. About a quarter of US adults with hypertension were controlled in 2011-2016. PMID- 29617895 TI - Risk Factors for Orthostatic Hypotension: Differences Between Elderly Men and Women. AB - BACKGROUND: Orthostatic hypotension (OH) occurs when mechanisms regulating blood pressure (BP) levels after standing-up are altered. It is unclear how prevalence and risk factors for OH are different between sexes. We aimed to investigate sex differences in prevalence and risk factors for OH elderly individuals. METHODS: We included 882 participants from Maracaibo Aging Study. OH was a sustained reduction of >=20 mm Hg in systolic BP, >=10 mm Hg in diastolic BP, or both, after 3 minutes of changing positions from supine to standing. Multivariable logistic regression models were used to examine the relationships among risk factors for OH in men and women considering interaction sex-term and stratified by sex. RESULTS: The mean age was 66.7 +/- 8.5 years, being similar by sex. Women and men 55-74 years had similar prevalence of OH+ (18.5% vs. 20.9%, respectively). After 75 years, the proportion of women with OH+ was lower than men (11% vs. 30%, respectively). Hypertension, specifically systolic BP >=140 mm Hg, and high pulse pressure (PP) were related with OH+ accounted by interaction sex-term, while diastolic BP >=90 mm Hg, antihypertensive treatment, body mass index (BMI), diabetes mellitus and age were not. Systolic BP >=140 mm Hg increases the risk of OH only among women, while BMI showed an inverse association in both sexes. CONCLUSIONS: Although the prevalence of OH is similar in both sexes, there are different risk factors associated by sex. Systolic BP >=140 mm Hg was associated with increased risk of OH only with women while BMI was a protective factor for OH in men and women. PMID- 29617897 TI - For a sound use of health care data in epidemiology: evaluation of a calibration model for count data with application to prediction of cancer incidence in areas without cancer registry. AB - There is a growing interest in using health care (HC) data to produce epidemiological surveillance indicators such as incidence. Typically, in the field of cancer, incidence is provided by local cancer registries which, in many countries, do not cover the whole territory; using proxy measures from available nationwide HC databases would appear to be a suitable approach to fill this gap. However, in most cases, direct counts from these databases do not provide reliable measures of incidence. To obtain accurate incidence estimations and prediction intervals, these databases need to be calibrated using a registry based gold standard measure of incidence. This article presents a calibration model for count data developed to predict cancer incidence from HC data in geographical areas without cancer registries. First, the ratio between the proxy measure and incidence is modeled in areas with registries using a Poisson mixed model that allows for heterogeneity between areas (calibration stage). This ratio is then inverted to predict incidence from the proxy measure in areas without registries. Prediction error admits closed-form expression which accounts for heterogeneity in the ratio between areas. A simulation study shows the accuracy of our method in terms of prediction and coverage probability. The method is further applied to predict the incidence of two cancers in France using hospital data as the proxy measure. We hope this approach will encourage sound use of the usually imperfect information extracted from HC data. PMID- 29617896 TI - An Evaluation of Function of Multicopy Noncoding RNAs in Mammals Using ENCODE/FANTOM Data and Comparative Genomics. AB - Mammalian diversification has coincided with a rapid proliferation of various types of noncoding RNAs, including members of both snRNAs and snoRNAs. The significance of this expansion however remains obscure. While some ncRNA copy number expansions have been linked to functionally tractable effects, such events may equally likely be neutral, perhaps as a result of random retrotransposition. Hindering progress in our understanding of such observations is the difficulty in establishing function for the diverse features that have been identified in our own genome. Projects such as ENCODE and FANTOM have revealed a hidden world of genomic expression patterns, as well as a host of other potential indicators of biological function. However, such projects have been criticized, particularly from practitioners in the field of molecular evolution, where many suspect these data provide limited insight into biological function. The molecular evolution community has largely taken a skeptical view, thus it is important to establish tests of function. We use a range of data, including data drawn from ENCODE and FANTOM, to examine the case for function for the recent copy number expansion in mammals of six evolutionarily ancient RNA families involved in splicing and rRNA maturation. We use several criteria to assess evidence for function: conservation of sequence and structure, genomic synteny, evidence for transposition, and evidence for species-specific expression. Applying these criteria, we find that only a minority of loci show strong evidence for function and that, for the majority, we cannot reject the null hypothesis of no function. PMID- 29617898 TI - Assessment of the Kidney Donor Profile Index in a European cohort. AB - Background: Recently, transplant societies have had to change their allocation policies to counter global organ shortages. However, strategies differ significantly and long-term outcomes and cross-regional applicability remain to be evaluated. Methods: Therefore, we retrospectively analysed the Kidney Donor Profile Index (KDPI) of 987 adult kidney transplants at our centre using data from the Organ Procurement and Transplantation Network (OPTN) as a reference. Results: In our cohort, the median KDPI was 66%, with a higher proportion of >85% KDPI kidneys compared with the US cohort (32.3% versus 9.2%). Among elderly patients (>=65 years of age), 62% received >95% KDPI kidneys, which were primarily allocated within the Eurotransplant Senior Program (ESP). After 10 years, the rate of death-censored graft survival was 70.5%. Recipients of >85% KDPI kidneys were significantly older, demonstrating higher mortality, poorer graft survival and lower estimated glomerular filtration rate. Patients receiving >=99% KDPI kidneys had a satisfactory 5-year death-censored graft survival (72.9%). The 5-year survival rate of patients living with a functioning graft exceeded the matched OPTN data in the whole KDPI range, despite a higher proportion of elderly recipients. Multivariate analysis revealed KDPI as an independent risk factor for graft loss (hazard ratio 1.14/10%, P < 0.001), although C-statistics of 0.62 indicated limited discriminative ability for individuals. Conclusion: The analysis demonstrated KDPI as a potentially useful tool for donor quality assessment in a European cohort. Most importantly, our analysis revealed acceptable outcomes even for very high KDPI kidneys. PMID- 29617899 TI - In ovo applications in poultry: A review,. AB - The various methods employed for the in ovo administration of different materials for promoting the health and productivity of poultry are discussed in this review article. The amnion has proven to be an effective site for injection and the timing of in ovo injection has commonly occurred at transfer. However, the volumes and dosages or concentrations of the materials administered vary depending on bird type, egg size, timing and site of injection, incubation system and regimen, and the type of material. Both manual and automated injections have been shown to be effective. Nevertheless, commercial application mandates automation. Materials described in the literature over the past 20 years or more for in ovo use in avian species include vaccines, drugs, hormones, competitive exclusion cultures and prebiotics, and supplemental nutrients. Vaccines approved for in ovo delivery include those for Marek's disease, infectious bursal disease, fowl pox, Newcastle disease, and coccidiosis. Some of the materials listed above have been shown to be viable candidates for enhancing immunity and for promoting embryonic and posthatch development. Several reports have indicated that probiotics may be effectively used to fight intestinal bacterial infections, and folic aid, as well as egg white protein and various amino acids, including L arginine, L-lysine, L-histidine, HMB, and threonine alone or in combination, have been shown to benefit embryonic development or posthatch performance. Furthermore, CpG oligodeoxynucleotides, vitamins C and E, and thyme and savory have the potential to enhance immunity, carbohydrates can be used to increase tissue glycogen stores, and creatine can be used to promote muscle growth. Trace minerals and vitamin D3 have shown potential to improve bone strength, and potassium chloride may be an effective alternative electrolyte in vaccine diluent. The in ovo application of these and other materials will continue to expand and provide further benefits to the poultry industry. PMID- 29617900 TI - Development and application of a SYBR green real-time PCR for detection of the emerging avian leukosis virus subgroup K. AB - Avian leukosis virus subgroup K (ALV-K) is an emerging ALV tumor virus of chickens. We developed a SYBR green-based real-time polymerase chain reaction (PCR) assay for the rapid and economical detection of ALV-K in chicken flocks. The assay was specific for ALV-K and did not cross-react with other ALV subgroup or avian influenza virus, Newcastle disease virus, or Marek's Disease virus. The method was 100 times more sensitive than conventional PCR and 10 times more sensitive than the enzyme-linked immunosorbent assay (ELISA) for the P27 antigen. The assay was also more sensitive than conventional PCR in tests of 86 clinical plasma samples. DF-1 tissue culture cells infected with 1 TCID50 ALV-K particle were identified as negative using ELISA but tested positive with the real-time PCR method. The viral loads in organs and tissues in infected chickens were highest in kidney, lungs, and glandular stomach, and these results matched ELISA findings. PMID- 29617901 TI - The use of two staining methods for identification of spermatozoon structure in roosters. AB - Many of the methods used to stain semen result in very pronounced coloring of the sperm, but unfortunately they do not distinguish their individual structures, which play a key role in the fertilization process. Hence the aim of this study was to identify sperm structures using two staining techniques in the semen of roosters from breeding flocks. The subject of the study was the sperm of roosters from a Ross 308 breeding flock. To capture the differences in the dimensions of sperm subjected to the effect of different chemical substances in dyes, microscope slides were stained by two techniques: with an AgNO3 solution and by a differential method (eosin-nigrosin test). Assessment was made of the degree of coloration and the number of details that could be identified in the morphological structure of the sperm. The use of AgNO3 allowed accurate identification of the acrosome, nucleus, and midpiece, which were visible in the slides stained with eosin-nigrosin, but only in dead spermatozoa. The AGNO3 staining technique used in this study reveals the cell nucleus within the head and can be an alternative method to analysis with a scanning electron microscope. This staining technique can be used to stain sperm structures that cannot be seen in other methods of slide preparation, which means that it can be considered for routine use in assessing the fertility of roosters in breeder flocks. PMID- 29617902 TI - Differential Expression of P450 Genes and nAChR Subunits Associated With Imidacloprid Resistance in Laodelphax striatellus (Hemiptera: Delphacidae). AB - Imidacloprid is a key insecticide used for controlling sucking insect pests, including the small brown planthopper (Laodelphax striatellus, Fallen) (Hemiptera: Delphacidae), an important agricultural pest of rice. A strain of L. striatellus (YN-ILR) developed 21-fold resistance when selected with imidacloprid on a susceptible YN strain. An in vitro study on piperonyl butoxide synergism indicated that enhanced detoxification mediated by cytochrome P450s contributed to imidacloprid resistance to some extent, and multiple P450 genes showed altered expression in the imidacloprid-resistant YN-ILR strain compared with the susceptible YN strain (CYP425B1-CYP6BD10 had 1.51- to 11.45-fold higher expression, CYP4CE2-CYP4DD1V2 had 0.12- to 0.57-fold lower expression). While there were no mutations in target nicotinic acetylcholine receptor (nAChR) genes, subunits of Lsalpha1, Lsbeta1, and Lsbeta3 in the YN-ILR strain showed 3.86-, 4.39-, and 2.59-fold higher expression and Lsa8 displayed 0.38-fold lower expression than the YN strain. Moreover, 21-fold moderate imidacloprid resistance in individuals of L. striatellus did not produce a fitness cost. The findings suggest that L. striatellus has the capacity to develop resistance to imidacloprid through P450 detoxification and potential target nAChR expression changes, and moderate imidacloprid resistance was not associated with a fitness cost. PMID- 29617903 TI - Spermatogonial stem cells. AB - Spermatogonial stem cells (SSCs) are the most primitive spermatogonia in the testis and have an essential role to maintain highly productive spermatogenesis by self-renewal and continuous generation of daughter spermatogonia that differentiate into spermatozoa, transmitting genetic information to the next generation. Since the 1950s, many experimental methods, including histology, immunostaining, whole-mount analyses, and pulse-chase labeling, had been used in attempts to identify SSCs, but without success. In 1994, a spermatogonial transplantation method was reported that established a quantitative functional assay to identify SSCs by evaluating their ability to both self-renew and differentiate to spermatozoa. The system was originally developed using mice and subsequently extended to nonrodents, including domestic animals and humans. Availability of the functional assay for SSCs has made it possible to develop culture systems for their ex vivo expansion, which dramatically advanced germ cell biology and allowed medical and agricultural applications. In coming years, SSCs will be increasingly used to understand their regulation, as well as in germline modification, including gene correction, enhancement of male fertility, and conversion of somatic cells to biologically competent male germline cells. PMID- 29617904 TI - Response to the Letter: Methodological Concerns About a Systematic Review and Meta-analysis of Maternal Active Smoking during Pregnancy and Low Birth Weight. PMID- 29617905 TI - Microvascular Decompression of Facial Nerve and Pexy of the Left Vertebral Artery for Left Hemifacial Spasm: 3-Dimensional Operative Video. AB - A 73-yr-old man presented with intractable left hemifacial spasm of 4 yr duration. Brain magnetic resonance imaging showed significant compression of left facial nerve by the left vertebral artery (VA) and anterior inferior cerebellar artery (AICA).The patient underwent a left retrosigmoid craniotomy and a microvascular decompression of the cranial nerve (CN) VII. Intraoperatively, we found that the distal AICA had a protracted subarcuate extradural course.1 This was relieved by intra/extradural dissection. The left VA and the AICA loop were compressing the root exit zone of CN VII. The VA was mobilized, and pexy into the petrosal dura was done with 8-0 nylon sutures (Ethilon Nylon Suture, Ethicon Inc, a subsidiary of Johnson & Johnson, Somerville, New Jersey). Once this was done, the lateral spread disappeared.2 The AICA loop was decompressed with 2 pieces of Teflon felt (Bard PTFE felt, Bard peripheral Vascular Inc, a subsidiary of CR Bard Inc, Temp, Arizona). After this, wave V of the brainstem auditory evoked potential (BAEP) disappeared completely, with no recovery despite the application of the nicardipine on the internal auditory artery (IAA). The IAA appeared to be stretched by the microvascular decompression. Arachnoidal dissection was done to release the CN VIII and an additional felt piece was placed to elevate the AICA loop; the BAEP recovered completely. The patient had a complete disappearance of the hemifacial spasm postoperatively, and hearing was unchanged.This 3-D video shows the technical nuances of performing a vertebropexy, release of the AICA from its extradural subarcuate course, and the surgical maneuvers in the event of an unexpected change in neuromonitoring response. The suture technique of vertebropexy is preferred to a loop technique, to avoid kinking of the VA.3Informed consent was obtained from the patient prior to the surgery that included videotaping of the procedure and its distribution for educational purposes. All relevant patient identifiers have also been removed from the video and accompanying radiology slides. PMID- 29617906 TI - Congenital Dermal Sinus and Limited Dorsal Myeloschisis: "Spectrum Disorders" of Incomplete Dysjuction Between Cutaneous and Neural Ectoderms. AB - BACKGROUND: The existence of tethering tracts in spinal dysraphism, other than congenital dermal sinus (CDS), has been recognized and has been summated into an integrated concept of limited dorsal myeloschisis (LDM). OBJECTIVE: To elucidate the underlying embryology of LDM in relation to CDS by focusing on the pathological features of special cases of tethering tracts. METHODS: Out of 389 spinal dysraphism patients who were operated on from 2010 to 2016, 5 patients who had tethering tracts composed of both CDS and LDM (or "probable LDM" if only fibrous tissue was found) were identified. Their clinical presentation, radiological images, operative findings, and pathology were thoroughly reviewed. RESULTS: Three nonsaccular-type patients harbored stalks in which the squamous epithelial lined sinus (CDS) was found in the distal portion, and fibroneural (LDM) or fibrous (probable LDM) tissue in the proximal part. Two patients had saccular lesions, and a stalk was found inside the sac, connecting a small pit on the skin to the spinal cord. The tracts were pathologically identical to a CDS. CONCLUSION: This study reports the coexistence of CDS and LDM (or probable LDM) components. These unique cases support the hypothesis that the CDS and LDM are among a spectrum of an anomaly that is caused by failure of complete dysjunction between cutaneous and neural ectoderms. Neurosurgeons should be aware of the possibility of coexisting "CDS" components in cases suggestive of LDM. In such cases, not only untethering but also meticulous removal of the squamous epithelium is critical. PMID- 29617907 TI - Reply to Pasqualotto and Sukiennik. PMID- 29617908 TI - Mobilization of the Anterior Inferior Cerebellar Artery When Firmly Adherent to the Petrous Dura Mater-A Technical Nuance in Retromastoid Transmeatal Vestibular Schwannoma Surgery: 3-Dimensional Operative Video. AB - The anterior inferior cerebellar artery (AICA) usually runs loosely within the cerebellopontine cistern; in rare cases, however, it is firmly adherent to the petrous dura mater.1,2 Recognizing this variation is particularly important in vestibular schwannoma surgery via the retrosigmoid transmeatal approach to prevent the high morbidity associated with vascular injury. This video demonstrates a surgical technique to effectively mobilize the AICA when firmly adherent to the petrous dura mater. A 39-year-old man presented with a history of progressive right-sided hearing loss without facial weakness or other associated symptoms3. Magnetic resonance imaging (MRI) demonstrated an intracanalicular lesion, suggestive of vestibular schwannoma. During follow-up, audiometry confirmed a further slight deterioration of hearing and repeated MRI demonstrated tumor growth (T2 according to Hannover classification). Since the patient opted against radiosurgery, a retrosigmoid transmeatal approach under continuous intraoperative monitoring was performed in supine position. Following drainage of cerebrospinal fluid and exposure of the cerebellopontine cistern, the AICA was found to be firmly adherent to the petrous dura mater. Both structures were elevated conjointly and displaced medially for safe drilling of the inner auditory canal, sufficient exposure, and complete excision of the vestibular schwannoma. The patient had an excellent recovery, hearing and facial function were preserved, and no secondary neurological deficits noted.The patient consented to publication of this anonymized video. PMID- 29617909 TI - Maternal Nicotine Exposure Leads to Augmented Expression of the Antioxidant Adipose Tissue Triglyceride Lipase Long-Term in the White Adipose of Female Rat Offspring. AB - Globally, approximately 10%-25% of women smoke during pregnancy. Since nicotine is highly addictive, women may use nicotine-containing products like nicotine replacement therapies for smoking cessation, but the long-term consequences of early life exposure to nicotine remain poorly defined. Our laboratory has previously demonstrated that maternal nicotine exposed (MNE) rat offspring exhibit hypertriglyceridemia due to increased hepatic de novo lipogenesis. Hypertriglyceridemia may also be attributed to impaired white adipose tissue (WAT) lipid storage; however, the effects of MNE on WAT are not completely understood. We hypothesize that nicotine-induced alterations in adipose function (eg, lipid storage) underlie dyslipidemia in MNE adults. Female 6-month-old rats exposed to nicotine during gestation and lactation exhibited significantly decreased visceral adipocyte cell area by 40%, attributed, in part, to a 3-fold increase in adipose triglyceride lipase (ATGL) protein expression compared with vehicle. Given ATGL has antioxidant properties and in utero nicotine exposure promotes oxidative stress in various tissues, we next investigated if there was evidence of increased oxidative stress in MNE WAT. At both 3 weeks and 6 months, MNE offspring expressed 37%-48% higher protein levels of superoxide dismutase-1 and -2 in WAT. Since oxidative stress can induce inflammation, we examined the inflammatory profile of WAT and found increased expression of cytokines (interleukin-1beta, tumor necrosis factor alpha, and interleukin-6) by 44%-61% at 6 months. Collectively, this suggests that the expression of WAT ATGL may be induced to counter MNE-induced oxidative stress and inflammation. However, higher levels of ATGL would further promote lipolysis in WAT, culminating in impaired lipid storage and long-term dyslipidemia. PMID- 29617911 TI - OnTrack: development and feasibility of a smartphone app designed to predict and prevent dietary lapses. AB - Given that the overarching goal of weight loss programs is to remain adherent to a dietary prescription, specific moments of nonadherence known as "dietary lapses" can threaten weight control via the excess energy intake they represent and by provoking future lapses. Just-in-time adaptive interventions could be particularly useful in preventing dietary lapses because they use real-time data to generate interventions that are tailored and delivered at a moment computed to be of high risk for a lapse. To this end, we developed a smartphone application (app) called OnTrack that utilizes machine learning to predict dietary lapses and deliver a targeted intervention designed to prevent the lapse from occurring. This study evaluated the feasibility, acceptability, and preliminary effectiveness of OnTrack among weight loss program participants. An open trial was conducted to investigate subjective satisfaction, objective usage, algorithm performance, and changes in lapse frequency and weight loss among individuals (N = 43; 86% female; body mass index = 35.6 kg/m2) attempting to follow a structured online weight management plan for 8 weeks. Participants were adherent with app prompts to submit data, engaged with interventions, and reported high levels of satisfaction. Over the course of the study, participants averaged a 3.13% weight loss and experienced a reduction in unplanned lapses. OnTrack, the first Just-in time adaptive intervention for dietary lapses was shown to be feasible and acceptable, and OnTrack users experienced weight loss and lapse reduction over the study period. These data provide the basis for further development and evaluation. PMID- 29617910 TI - Sleep characteristics and inflammatory biomarkers among midlife women. AB - Study Objectives: Research suggests that sleep disturbances are associated with elevated levels of inflammation. Some evidence indicates that women may be particularly vulnerable; increased levels of inflammatory biomarkers with sleep disturbances are primarily observed among women. Midlife, which encompasses the menopause transition, is typically reported as a time of poor sleep. We tested whether poorer objectively measured sleep characteristics were related to a poorer inflammatory profile in midlife women. Methods: Two hundred ninety-five peri- and postmenopausal women aged 40-60 completed 3 days of wrist actigraphy, physiologic hot flash monitoring, questionnaires (e.g. Berlin sleep apnea risk questionnaire], and a blood draw for the assessment of inflammatory markers, including C-reactive protein (CRP), interleukin-6 (IL-6), and von Willebrand factor (VWF) antigen. Associations of objective (actigraphy) sleep with inflammatory markers were tested in regression models. Sleep efficiency was inverse log transformed. Covariates included age, race/ethnicity, education, body mass index, sleep apnea risk, homeostatic model assessment (a measure of insulin resistance), systolic blood pressure, low-density lipoprotein cholesterol, and physical activity. Results: In separate models controlling for age, race/ethnicity, and education, lower sleep efficiency was associated with higher IL-6 [b(SE) = .02 (.10), p = .003] and VWF [b(SE) = .02 (.08), p = .002]. More minutes awake after sleep onset was associated with higher VWF [b(SE) = .12 (.06), p = .01]. Findings persisted in multivariable models. Conclusions: Lower sleep efficiency and more minutes awake after sleep onset were independently associated with higher circulating levels of VWF. Lower sleep efficiency was associated with higher circulating levels of IL-6. These findings suggest that sleep disturbances are associated with greater circulating inflammation in midlife women. PMID- 29617913 TI - Striking Racial/Ethnic Disparities in Liver Cancer Incidence Rates and Temporal Trends in California, 1988-2012. AB - Background: Hepatocellular carcinoma (HCC) is characterized by disparate risk patterns by race/ethnicity. We examined HCC incidence patterns and temporal trends among detailed racial/ethnic populations, including disaggregated Asian American subgroups. Methods: Using data from the population-based California Cancer Registry, we identified 41 929 invasive HCC cases diagnosed during 1988 2012. Patients were grouped into mutually exclusive racial/ethnic groups of non Hispanic (NH) white, NH black, Hispanic, and NH Asian/Pacific Islander (API), as well as Asian subgroups of Chinese, Filipino, Japanese, Korean, Vietnamese, Cambodian, Laotian, and South Asian. Age-adjusted and age-specific incidence rates by sex, race/ethnicity, and time period were calculated. The average annual percent change (AAPC) in incidence rates was estimated using joinpoint regression. All estimates were provided with the 95% confidence intervals (CIs). Results: Aggregated NH API had higher HCC risk than NH whites, NH blacks, and Hispanics. When disaggregated, Southeast Asians (Vietnamese, Cambodians, and Laotians) had overall HCC incidence rates eight to nine times higher than NH whites and more than twice that of other ethnic Asians. Statistically significant rising temporal trends of HCC were found in NH whites, NH blacks, and Hispanics, especially those older than age 50 years. Overall HCC risk declined in Chinese males (AAPC = -1.3%, 95% CI = -2.0 to -0.6), but rose in Filipino (AAPC = +1.2%, 95% CI = 0.3 to 2.1) and Japanese males (AAPC = +3.0%, 95% CI = 0.4 to 5.6) and Vietnamese (AAPC = +4.5%, 95% CI = 0.7 to 8.5) and Laotian (+3.4%, 95% CI = 0.1 to 6.8) females. Conclusions: Our findings provide valuable information for the identification of at-risk ethnic subgroups of Asian Americans while underscoring the importance of disaggregating ethnic populations in cancer research. PMID- 29617912 TI - Impact of Antiretroviral Regimens on Cerebrospinal Fluid Viral Escape in a Prospective Multicohort Study of Antiretroviral Therapy-Experienced Human Immunodeficiency Virus-1-Infected Adults in the United States. AB - Background: Cerebrospinal fluid (CSF) viral escape occurs in 4%-20% of human immunodeficiency virus (HIV)-infected adults, yet the impact of antiretroviral therapy (ART) on CSF escape is unclear. Methods: A prospective study of 1063 participants with baseline plasma viral load (VL) <=400 copies/mL between 2005 and 2016. The odds ratio (OR) for ART regimens (protease inhibitor with nucleoside reverse transcriptase inhibitor [PI + NRTI] vs other ART) and CSF escape was estimated using mixed-effects models. Results: Baseline mean age was 46 years, median plasma VL, and CD4 count were 50 copies/mL, and 424 cells/MUL, respectively. During median follow-up of 4.4 years, CSF escape occurred in 77 participants (7.2%). PI + NRTI use was an independent predictor of CSF escape (OR, 3.1; 95% confidence interval, 1.8-5.0) in adjusted analyses and models restricted to plasma VL <=50 copies/mL (P < .001). Regimens that contained atazanavir (ATV) were a stronger predictor of CSF viral escape than non-ATV PI + NRTI regimens. Plasma and CSF M184V/I combined with thymidine-analog mutations were more frequent in CSF escape vs no escape (23% vs 2.3%). Genotypic susceptibility score-adjusted central nervous system (CNS) penetration effectiveness (CPE) values were calculated for CSF escape with M184V/I mutations (n = 34). Adjusted CPE values were low (<5) for CSF in 27 (79%), indicating suboptimal CNS drug availability. Conclusions: PI + NRTI regimens are independent predictors of CSF escape in HIV-infected adults. Reduced CNS ART bioavailability may predispose to CSF escape in patients with M184V/I mutations. PMID- 29617915 TI - Erratum. PMID- 29617916 TI - Alcohol and Drug Use Among Older Adults: Associations with Widowhood, Relationship Quality, and Physical Health. PMID- 29617914 TI - Effect of Dietary Non-phytate Phosphorus Levels on the Diversity and Structure of Cecal Microbiota in Meat Duck from 1 to 21 d of age. AB - The study was conducted to distinguish the effect of dietary non-phytate phosphorus (NPP) levels on the community diversity and structure of the cecal microbiota in meat duck based on 16S rDNA high-throughput sequencing. In total, 525 1-d-old ducklings were fed diets (105 ducklings, 7 pens of 15 ducklings, on each diet) containing five levels of NPP (0.22, 0.34, 0.40, 0.46, and 0.58%) for 21 days. The results showed that dietary NPP levels linearly and quadratically increased (P < 0.05) 21 d body weight, 1 to 21 d feed intake and NPP intake, and contrarily, linearly decreased (P < 0.05) beta-diversity of cecal microbial population in ducks. beta-diversity analyses showed that microbiota clustering based on dietary NPP levels occured, with 0.22% NPP groups distinctly different from the 0.46% and 0.58% NPP group samples. Moreover, dietary NPP levels could change the relative abundance of the phylum Proteobacteria (linear, P < 0.05), genera Eubacterium coprostanoligenes (quadratic, P < 0.05), Ruminococcaceae UCG 014 (quadratic, P < 0.05) and Subdoligrannulum (linear, P < 0.05), and Lachnospiraceae family (quadratic, P < 0.05) in cecal microbiota of ducks. Increasing the dietary NPP level influenced the cecal microbiota and positively affected the growth of meat ducks. PMID- 29617917 TI - Management of hypercalcaemia-induced heart failure using mechanical circulatory support. AB - Acute heart failure is associated with high morbidity and mortality. Heart failure is caused by various conditions, including electrolyte imbalances. We report a rare case of hypercalcaemia-induced acute heart failure complicated by cardiogenic shock. Mechanical circulatory support was used successfully in this patient until calcium homeostasis was restored. PMID- 29617918 TI - Mortality Among Mothers Whose Children Were Taken Into Care by Child Protection Services: A Discordant Sibling Analysis. AB - This study examines whether mothers who had a child taken into care by child protection services have higher mortality rates compared with rates seen in their biological sisters who did not have a child taken into care. We conducted this retrospective cohort study using linkable administrative data from 3,948 mothers whose oldest child was born in Manitoba, Canada, between April 1, 1992, and March 31, 2015. These mothers were from 1,974 families in which one sister had a child taken into care and one sister did not. We computed rate differences and hazard ratios of all-cause, avoidable, and unavoidable mortality. There were an additional 24 deaths per 10,000 person-years among mothers who had had a child taken into care. Mothers who had a child taken into care had higher rates of mortality due to avoidable causes (hazard ratio = 3.46; 95% confidence interval: 1.41, 8.48) and unavoidable causes (hazard ratio = 2.92; 95% confidence interval: 1.01, 8.44). The number of children taken into care did not affect mortality rates among mothers with at least 1 child taken into care. The higher mortality rates-particularly avoidable mortality-among mothers who had a child taken into care indicate a need for more specific interventions for these mothers. PMID- 29617919 TI - Combined Nasoseptal and Inferior Turbinate Flap for Reconstruction of Large Skull Base Defect After Expanded Endonasal Approach: Operative Technique. AB - BACKROUND: Increasing indications for endoscopic endonasal approaches have led neurosurgeons to develop new reconstruction techniques for larger skull base defects. Vascularized grafts have been a great adjunction to reduce the rate of cerebrospinal fluid leak and can also be used to cover exposed critical structures such as the internal carotid artery. The nasoseptal flap and the inferior or middle turbinate flap are thus widely used in endoscopic skull base surgery, but may be insufficient for very large defects. OBJECTIVE: To present a new mucosal flap used to cover large skull base defects in which the mucosa of the inferior turbinate, inferior meatus, nasal floor, and nasal septum is harvested in 1 piece keeping both vascular pedicles intact (inferior turbinate and septal arteries). METHODS: We describe a surgical technique to harvest a combined inferior turbinate-nasoseptal flap. RESULTS: Technical pearls and surgical pitfalls are described through 2 clinical cases in which the nasoseptal mucosa was partially damaged during a previous surgery, rendering the nasoseptal flap insufficient by itself. The flap is harvested thanks to 2 mucosal cuts: a first circular cut around the choanal arch and the junction between the hard and the soft palate, and a second one combining classical cuts of the nasoseptal flap and the inferior turbinate flap. CONCLUSION: The inferior turbinate-nasoseptal flap can be a useful alternative in patients whose septal mucosa was partially damaged and/or with very large postoperative skull base defects. PMID- 29617920 TI - Invited Commentary: The Microbiome and Population Health-Considerations for Enhancing Study Design and Data Analysis in Observational and Interventional Epidemiology. AB - Measurement and characterization of the human microbiome in large population based human studies has recently become a reality secondary to technological advances in high-throughput DNA sequencing. These advances bring new challenges and knowledge gaps for study planning, data analysis, and interpretation that are novel to large-scale epidemiologic studies. In this issue of the Journal, Sinha et al. (Am J Epidemiol. 2018;187(6):1282-1290) have provided data with which to inform statistical power and sample size requirements for microbiome studies in population-based settings. This work serves as a helpful starting point for study planning while also serving as a springboard for discussion regarding additional considerations for improving microbiome research. This commentary emphasizes the importance of selecting microbiome metrics appropriate for the biological hypothesis under investigation, as well as the need for new analytical tools that can better capitalize on the unique yet rich information contained in microbiome data sets. PMID- 29617921 TI - Causal Model of the Association of Social Support With Antepartum Depression: A Marginal Structural Modeling Approach. AB - We used marginal structural models to evaluate associations of social support with antepartum depression in late pregnancy, if everyone had had high social support both before pregnancy and during early pregnancy, compared with having low social support at one of the 2 time points or low social support at both time points. In 2012-2014, pregnant Peruvian women (n = 3,336) were recruited into a prospective cohort study (at a mean gestational age of 9 weeks). A follow-up interview (n = 2,279) was conducted (at 26-28 weeks of gestation). Number of available support providers and satisfaction with social support were measured using Sarason Social Support Questionnaire-6. Depression was measured using the Edinburgh Postnatal Depression Scale. Low number of support providers at both time points was associated with increased risk of depression (odds ratio = 1.62, 95% confidence interval: 1.12, 2.34). The association for low satisfaction at both time points was marginally significant (odds ratio = 1.41, 95% confidence interval: 0.99, 1.99). Depression risk was not significantly higher for women who reported high social support at one of the 2 time points. Our study reinforces the importance of assessing social support before and during pregnancy and underscores the need for future interventions targeted at increasing the number of support providers to prevent antepartum depression. PMID- 29617922 TI - Diversity of Chlamydia trachomatis in Trachoma-Hyperendemic Communities Treated With Azithromycin. AB - Prior studies have theorized that low chlamydial genetic diversity following mass azithromycin treatments for trachoma may create a population bottleneck that prevents the return of infection, but little empirical evidence exists to support this hypothesis. In this study, a single mass azithromycin distribution was administered to 21 communities in the Gurage Zone of Ethiopia in 2003. All children aged 1-5 years had conjunctival swabs performed before treatment and 2 and 6 months after treatment. All swabs positive for Chlamydia trachomatis at 2 months underwent typing of the gene encoding the major outer membrane protein (ompA) of C. trachomatis, as did the same number of swabs per community from the pretreatment and 6-month visits. Diversity of ompA types, expressed as the reciprocal of Simpson's index, was calculated for each community. In total, 15 ompA types belonging to the A and B genovars were identified. The mean diversity was 2.11 (95% confidence interval: 1.79, 2.43) before treatment and 2.16 (95% confidence interval: 1.76, 2.55) 2 months after treatment (P = 0.78, paired t test). Diversity of ompA was not associated with the prevalence of ocular chlamydia (P = 0.76) and did not predict subsequent changes in the prevalence of ocular chlamydia (P = 0.32). This study found no evidence to support the theory that ompA diversity is associated with transmission of ocular chlamydia. PMID- 29617923 TI - Breastfeeding And Childhood Wheeze: Age-Specific Analyses And Longitudinal Wheezing Phenotypes As Complimentary Approaches To The Analysis Of Cohort Data. AB - Systematic reviews suggest that breastfeeding is associated with a lower risk of asthma, although marked heterogeneity exists. Using UK Millennium Cohort Study data (n = 10,126 children born 2000-2001), we examined the association between breastfeeding duration and wheezing in the past year, first at each age-group separately (age 9 months, 3, 5, 7 and 11 years) and then as a longitudinal wheezing phenotype: 'early transient' (wheezing any time up to age 5 but not thereafter); 'late onset' (any time from age 7 but not beforehand); 'persistent' (any time up to age 5 and any time from age 7). The association between breastfeeding and wheeze varied by age (interaction two-sided P = 0.0003). For example, breastfeeding for 6-9 months was associated with lower odds of wheezing at age 9 months, 3, and 5 years, but less so at age 7 and 11 years (adjusted odds ratios 0.73, 0.78, 0.79, 0.84, 1.06 respectively). There was a strong dose response relationship for breastfeeding per month and early transient wheeze (adjusted linear trend OR 0.961, 95% CI: 0.942, 0.980), but no clear trend for late onset or persistent wheeze. Our results identified heterogeneity in the association between breastfeeding and wheezing according to age at wheezing and wheezing phenotype. PMID- 29617924 TI - Invited Commentary: Gaze Aversion and Unnoticed Phenomena. AB - Child abuse is a social phenomenon that has been underresearched and undersupported. The scale of the problem is large, with over 3 million US children reported for abuse or neglect each year. An estimated 15% of confirmed victims may be placed in out-of-home care to ensure their safety. Studies have not previously examined the impact of losing a child into foster care on maternal health and mortality. Family and maternal risk factors, such as teen pregnancy, intimate partner violence, or drug and alcohol abuse, have been well documented as risk factors for maltreatment. The findings of Wall-Wieler et al. (Am J Epidemiol. 2018;187(6):1182-1188) are not so much unexpected as they are surprising in that the impact of foster care on maternal health has heretofore been largely unexamined. The innovative use of maternal sisters with children not in foster care as controls provides a powerful control for family genetics, and family environment with likely common early life experiences, in the mortality of the mothers whose children were removed. With over 3 million children reported for suspected maltreatment each year, the related health and social outcomes for both children and their families require more careful examination using public health methods. PMID- 29617925 TI - Sutureless and Rapid-Deployment Aortic Valve Replacement International Registry (SURD-IR): early results from 3343 patients. AB - OBJECTIVES: The Sutureless and Rapid-Deployment Aortic Valve Replacement International Registry (SURD-IR) was established by a consortium of 18 research centres-the International Valvular Surgery Study Group (IVSSG)-to overcome limitations of the literature and provide adequately powered evidence on sutureless and rapid-deployment aortic valves replacement (SURD-AVR). METHODS: Data from 3343 patients undergoing SURD-AVR over a 10-year period (2007-2017) were collected in the registry. The mean age of the patients was 76.8 +/- 6.7 years, with 36.4% being 80 years or older. The average logistic EuroSCORE was 11.3 +/- 9.7%. RESULTS: Isolated SURD-AVR was performed in 70.7% (n = 2362) of patients using full sternotomy (35.3%) or less invasive approaches (64.8%). Overall hospital mortality was 2.1%, being 1.4% in patients who had isolated SURD AVR and 3.5% in those who had concomitant procedures (P < 0.001). When considering baseline risk profile, mortality rate was 0.8% and 1.9% in low risk (logistic EuroSCORE <10%) isolated SURD-AVR and combined SURD-AVR, respectively, and 2.2% and 3.7% in higher risk patients (logistic EuroSCORE >=10%). Postoperative neurological complications included stroke (2.8%) and transient ischaemic attack (1.1%). New atrioventricular block requiring pacemaker occurred in 10.4% of the patients. The rate of pacemaker implantation significantly decreased over time [from 17.2% (2007-2008) to 5.4% (2016); P = 0.02]. CONCLUSIONS: Our findings showed that SURD-AVR is a safe and effective alternative to conventional aortic valve replacement and is associated with excellent clinical outcomes. Further adequately powered statistical analyses from the retrospective and prospective SURD-IR will allow for the development of high quality evidence-based clinical guidelines for SURD-AVR. PMID- 29617926 TI - Translational science matters: forging partnerships between biomedical and behavioral science to advance the public's health. AB - The prevention and effective treatment of many chronic diseases such as cardiovascular disease, cancer and diabetes are dependent on behaviors such as not smoking, adopting a physically-active lifestyle, eating a healthy diet, and adhering to prescribed medical and behavioral regimens. Yet adoption and maintenance of these behaviors pose major challenges for individuals, their families and communities, as well as clinicians and health care systems. These challenges can best be met through the integration of the biomedical and behavioral sciences that is achieved by the formation of strategic partnerships between researchers and practitioners in these disciplines to address pressing clinical and public health problems. The National Institutes of Health has supported a number of clinical trials and research initiatives that demonstrate the value of biomedical and behavioral science partnerships in translating fundamental discoveries into significant improvements in health outcomes. We review several such examples of collaborations between biomedical and behavioral researchers, describe key initiatives focused on advancing a transdisciplinary translational perspective, and outline areas which require insights, tools and findings from both the biomedical and behavioral sciences to advance the public's health. PMID- 29617927 TI - Estimating Counterfactual Risk Under Hypothetical Interventions in the Presence of Competing Events: Crystalline Silica Exposure and Mortality From 2 Causes of Death. AB - Exposure to silica has been linked to excess risk of lung cancer and nonmalignant respiratory disease mortality. In this study we estimated risk for both these outcomes in relation to occupational silica exposure as well as the reduction in risk that would result from hypothetical interventions on exposure in a cohort of exposed workers. Analyses were carried out using data from an all-male study population consisting of 2,342 California diatomaceous earth workers regularly exposed to crystalline silica and followed between 1942 and 2011. We estimated subdistribution risk for each event under the natural course and interventions of interest using the parametric g-formula to adjust for healthy-worker survivor bias. The risk ratio for lung cancer mortality, comparing an intervention in which a theoretical maximum exposure limit was set at 0.05 mg/m3 (the current US regulatory limit) with the observed exposure concentrations, was 0.86 (95% confidence interval: 0.63, 1.22). The corresponding risk ratio for nonmalignant respiratory disease mortality was 0.69 (95% confidence interval: 0.52, 0.93). Our findings suggest that risks from both outcomes would have been considerably lower if historical silica exposures in this cohort had not exceeded current regulatory limits. PMID- 29617928 TI - DeFine: deep convolutional neural networks accurately quantify intensities of transcription factor-DNA binding and facilitate evaluation of functional non coding variants. AB - The complex system of gene expression is regulated by the cell type-specific binding of transcription factors (TFs) to regulatory elements. Identifying variants that disrupt TF binding and lead to human diseases remains a great challenge. To address this, we implement sequence-based deep learning models that accurately predict the TF binding intensities to given DNA sequences. In addition to accurately classifying TF-DNA binding or unbinding, our models are capable of accurately predicting real-valued TF binding intensities by leveraging large scale TF ChIP-seq data. The changes in the TF binding intensities between the altered sequence and the reference sequence reflect the degree of functional impact for the variant. This enables us to develop the tool DeFine (Deep learning based Functional impact of non-coding variants evaluator, http://define.cbi.pku.edu.cn) with improved performance for assessing the functional impact of non-coding variants including SNPs and indels. DeFine accurately identifies the causal functional non-coding variants from disease associated variants in GWAS. DeFine is an effective and easy-to-use tool that facilities systematic prioritization of functional non-coding variants. PMID- 29617930 TI - Impact of CAR Agonist Ligand TCPOBOP on Mouse Liver Chromatin Accessibility. AB - Activation of the nuclear receptor and transcription factor CAR (Nr1i3) by its specific agonist ligand TCPOBOP (1, 4-bis[2-(3, 5-dichloropyridyloxy)]benzene) dysregulates hundreds of genes in mouse liver and is linked to male-biased hepatocarcinogenesis. To elucidate the genomic organization of CAR-induced gene responses, we investigated the distribution of TCPOBOP-responsive RefSeq coding and long noncoding RNA (lncRNA) genes across the megabase-scale topologically associating domains (TADs) that segment the genome, and which provide a structural framework that functionally constrains enhancer-promoter interactions. We show that a subset of TCPOBOP-responsive genes cluster within TADs, and that TCPOBOP-induced genes and TCPOBOP-repressed genes are often found in different TADs. Further, using DNase-seq and DNase hypersensitivity site (DHS) analysis, we identified several thousand genomic regions (DeltaDHS) where short-term exposure to TCPOBOP induces localized changes (increases or decreases) in mouse liver chromatin accessibility, many of which cluster in TADs together with TCPOBOP responsive genes. Sites of chromatin opening were highly enriched nearby genes induced by TCPOBOP and chromatin closing was highly enriched nearby genes repressed by TCPOBOP, consistent with TCPOBOP-responsive DeltaDHS serving as enhancers and promoters that positively regulate CAR-responsive genes. Gene expression changes lagged behind chromatin opening or closing for a subset of TCPOBOP-responsive DeltaDHS. DeltaDHS that were specifically responsive to TCPOBOP in male liver were significantly enriched for genomic regions with a basal male bias in chromatin accessibility; however, the male-biased response of hepatocellular carcinoma-related genes to TCPOBOP was not associated with a correspondingly male-biased DeltaDHS response. These studies elucidate the genome wide organization of CAR-responsive genes and of the thousands of associated genomic sites where TCPOBOP exposure induces both rapid and persistent changes in chromatin accessibility. PMID- 29617931 TI - Robotic mitral valve replacements with bioprosthetic valves in 52 patients: experience from a tertiary referral hospital. AB - OBJECTIVES: Robotic mitral valve replacement (MVR) emerged in the late 1990s as an alternative approach to conventional sternotomy. With the increased use of bioprosthetic valves worldwide and strong patient desire for minimally invasive procedures, the safety and feasibility of robotic MVRs with bioprosthetic valves require investigation. METHODS: Between January 2013 and May 2017, 52 consecutive patients underwent robotic MVRs using the da Vinci Si surgical system (Intuitive Surgical Inc., Sunnyvale, CA, USA). Their mean age was 55.1 +/- 13.8 years, and mean EuroSCORE II was 2.25% +/- 1.25%. Among the enrolled patients, 32 (61.5%) patients presented with preoperative atrial fibrillation, 6 (11.5%) patients had experienced embolic stroke and 5 (9.6%) patients had undergone previous cardiac surgery. The operations were performed using cardiopulmonary bypass (CPB) under an arrested heart status. RESULTS: Five porcine valves and 47 bovine valves were implanted. A total of 38 (73.1%) patients received concomitant cardiac procedures, including 26 Cox-maze IV procedures, 12 tricuspid valve repairs and 5 atrial septal defect repairs. The mean aortic cross-clamp and CPB times were 141.3 +/- 34.3 min and 217.1 +/- 42.0 min, respectively. There was no operative mortality. During the mean follow-up of 29 +/- 15 months, no prosthesis degeneration was noted. The average left atrial dimension exhibited a significant decrease from 51.4 +/- 11.5 mm to 42.6 +/- 10.1 mm. CONCLUSIONS: Robotic MVR with bioprosthetic valves is safe, feasible and reproducible. Mid-term results are encouraging. Both aortic cross-clamp and CPB times can be improved with experience. PMID- 29617932 TI - Building online genomics applications using BioPyramid. AB - Summary: BioPyramid is a Python package, which serves as a scaffold for building an online application for the exploration of gene expression data. It is designed for bioinformaticians wishing to quickly share transformed data and interactive analyses with collaborators. Current R-based tools similarly address the need to quickly share 'omics'-data in an exploratory format, but these are generally small-scale, single-dataset solutions. Biopyramid is written in Python pyramid framework and scalable to address longer-term or more complex projects. It contains a number of components designed to reduce the time and effort in building such an application from scratch, including gene annotation, dataset models and visualization tools. Availability and implementation: Freely available at http://github.com/jarny/biopyramid. Implemented in python and javascript. PMID- 29617933 TI - A qualitative study of female caregiving spouses' experiences of intimate relationships as cognition declines in Parkinson's disease. AB - Background: the complex and progressive nature of Parkinson's disease (PD) and cognitive impairment may necessitate a care provider, a role which is frequently undertaken by a spouse. Providing and receiving care related to dementia impacts on a couple's partnership and may result in decreased intimacy and relationship satisfaction. Objective: to explore the changes in long-term intimate relationships in Parkinson's-related dementia, as perceived by spouses providing care to their partners. Methods: participants were identified using purposive sampling. Twelve female spouses whose partners had PD and mild cognitive impairment (PD-MCI), PD dementia (PDD) or dementia with Lewy bodies (DLB) completed semi-structured face-to-face interviews. Transcribed data were analysed using inductive thematic analysis. The consolidated criteria for reporting qualitative research (COREQ) were applied. Results: couples' relationship satisfaction, intimacy and communication had already reduced in the mild cognitive impairment stage of PD, but the decline in these domains was markedly greater with the emergence of dementia. Increased spousal care responsibilities resulted in partners spending more time together, but feeling emotionally more distanced. Several participants' roles transitioned from spouse to caregiver and they reported feelings of frustration, resentment, anger, sadness and a worry for the future. Cognitive impairment was significantly harder to accept, manage and cope with than the motor symptoms of PD. Spouses acknowledged their marital commitments and exhibited acceptance, adjustment, resilience and various coping strategies. Conclusion: this is the first study exploring relationship satisfaction in Parkinson's-related dementia and has provided valuable insight into the changing patterns of intimate relationships. PMID- 29617934 TI - Steroid refractory dermatomyositis following combination dabrafenib and trametinib therapy. PMID- 29617935 TI - Pre-Bombing Population Density in Hiroshima and Nagasaki: Its Measurement and Impact on Radiation Risk Estimates in the Life Span Study of Atomic Bomb Survivors. AB - In the Life Span Study of atomic bomb survivors, differences in urbanicity between high-dose and low-dose survivors could confound the association between radiation dose and adverse outcomes. We obtained data on the pre-bombing population distribution in Hiroshima and Nagasaki, and quantified the impact of adjustment for population density on radiation risk estimates for mortality (1950 2003) and incident solid cancer (1958-2009). Population density ranged from 4,671 14,378 and 5,748-19,149 people/km2 in urban regions of Hiroshima and Nagasaki, respectively. Radiation risk estimates for solid cancer mortality were attenuated by 5.1%, but those for all-cause mortality and incident solid cancer were unchanged. There was no overall association between population density and adverse outcomes, but there was evidence that the association between density and mortality differed by age at exposure. Among survivors 10-14 years old in 1945, there was a positive association between population density and risk of all-cause mortality (relative risk, 1.053 per 5,000 people/km2 increase, 95% confidence interval: 1.027, 1.079) and solid cancer mortality (relative risk, 1.069 per 5,000 people/km2 increase, 95% confidence interval: 1.025, 1.115). Our results suggest that radiation risk estimates from the Life Span Study are not sensitive to unmeasured confounding by urban-rural differences. PMID- 29617936 TI - De novo haplotype reconstruction in viral quasispecies using paired-end read guided path finding. AB - Motivation: RNA virus populations contain different but genetically related strains, all infecting an individual host. Reconstruction of the viral haplotypes is a fundamental step to characterize the virus population, predict their viral phenotypes and finally provide important information for clinical treatment and prevention. Advances of the next-generation sequencing technologies open up new opportunities to assemble full-length haplotypes. However, error-prone short reads, high similarities between related strains, an unknown number of haplotypes pose computational challenges for reference-free haplotype reconstruction. There is still much room to improve the performance of existing haplotype assembly tools. Results: In this work, we developed a de novo haplotype reconstruction tool named PEHaplo, which employs paired-end reads to distinguish highly similar strains for viral quasispecies data. It was applied on both simulated and real quasispecies data, and the results were benchmarked against several recently published de novo haplotype reconstruction tools. The comparison shows that PEHaplo outperforms the benchmarked tools in a comprehensive set of metrics. Availability and implementation: The source code and the documentation of PEHaplo are available at https://github.com/chjiao/PEHaplo. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29617938 TI - Identification and function of FAR protein family genes from a transcriptome analysis of Aphelenchoides besseyi. AB - Motivation: The rice white tip nematode (RWTN) Aphelenchoides besseyi is a migratory plant parasitic nematode that infects the aboveground parts of plants. Fatty acid- and retinoid-binding (FAR) proteins are nematode-specific proteins that are involved in many important biological processes. Genes encoding FAR proteins have been identified in many species of nematodes, which indicated that nematodes may produce more than one type of FAR protein. The main goal of this study is to find new molecular targets including new far genes that will help control RWTN, and reduce the economic damage caused by RWTN. Results: Two RWTN populations with different levels of pathogenicity and reproduction were sequenced and analyzed with next-generation sequencing. 17 087 transcripts were annotated using six databases and 1696 differentially expressed genes (DEGs) were identified between the two RWTN populations. Seven new Ab-far genes were identified from the transcriptome data of the two RWTN populations which is the first to identify multiple far genes in plant parasitic nematodes. This study is the first to identify far genes in the nervous system of nematodes and the first to report a transcriptome sequencing analysis of different RWTN populations. The results help elucidate the genes related to parasitism and pathogenicity and also contribute to the identification of new target genes and development of new methods to control RWTN. Availability and implementation: Our data are publicly available at Sequence Read Archive (SRA) database and GenBank database. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29617937 TI - Efficient analysis of large-scale genome-wide data with two R packages: bigstatsr and bigsnpr. AB - Motivation: Genome-wide datasets produced for association studies have dramatically increased in size over the past few years, with modern datasets commonly including millions of variants measured in dozens of thousands of individuals. This increase in data size is a major challenge severely slowing down genomic analyses, leading to some software becoming obsolete and researchers having limited access to diverse analysis tools. Results: Here we present two R packages, bigstatsr and bigsnpr, allowing for the analysis of large scale genomic data to be performed within R. To address large data size, the packages use memory-mapping for accessing data matrices stored on disk instead of in RAM. To perform data pre-processing and data analysis, the packages integrate most of the tools that are commonly used, either through transparent system calls to existing software, or through updated or improved implementation of existing methods. In particular, the packages implement fast and accurate computations of principal component analysis and association studies, functions to remove single nucleotide polymorphisms in linkage disequilibrium and algorithms to learn polygenic risk scores on millions of single nucleotide polymorphisms. We illustrate applications of the two R packages by analyzing a case-control genomic dataset for celiac disease, performing an association study and computing polygenic risk scores. Finally, we demonstrate the scalability of the R packages by analyzing a simulated genome-wide dataset including 500 000 individuals and 1 million markers on a single desktop computer. Availability and implementation: https://privefl.github.io/bigstatsr/ and https://privefl.github.io/bigsnpr/. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29617939 TI - FaStore: a space-saving solution for raw sequencing data. AB - Motivation: The affordability of DNA sequencing has led to the generation of unprecedented volumes of raw sequencing data. These data must be stored, processed and transmitted, which poses significant challenges. To facilitate this effort, we introduce FaStore, a specialized compressor for FASTQ files. FaStore does not use any reference sequences for compression and permits the user to choose from several lossy modes to improve the overall compression ratio, depending on the specific needs. Results: FaStore in the lossless mode achieves a significant improvement in compression ratio with respect to previously proposed algorithms. We perform an analysis on the effect that the different lossy modes have on variant calling, the most widely used application for clinical decision making, especially important in the era of precision medicine. We show that lossy compression can offer significant compression gains, while preserving the essential genomic information and without affecting the variant calling performance. Availability and implementation: FaStore can be downloaded from https://github.com/refresh-bio/FaStore. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29617940 TI - Intraosseous Versus Intravenous Access in Pediatric Septic Shock Patients Admitted to Alexandria University Pediatric Intensive Care Unit. AB - The cornerstone of emergency management of sepsis is early, goal-directed therapy. The purpose of this study was to evaluate the effect of intraosseous (IO) vs. intravenous (IV) access for resuscitation of patients with septic shock admitted to pediatric intensive care unit. This prospective interventional randomized clinical trial study was conducted on 60 patients with septic shock who need rapid administration of fluids and drugs; 30 cases were randomly chosen for IO vascular access, while the other 30 were selected for IV access. The IO route was successfully secured in all cases with a significant shorter time of vascular access insertion, shorter length of stay and reduction in mortality in IO group vs. IV group (p = 0.001, 0.045, 0.002, respectively). In pediatric emergencies, as in case of shock, the use of IO route is recommended to get rapid vascular access as soon as possible, as it revealed better outcome. PMID- 29617941 TI - A reference peptide database for proteome quantification based on experimental mass spectrum response curves. AB - Motivation: Mass spectrometry (MS) based quantification of proteins/peptides has become a powerful tool in biological research with high sensitivity and throughput. The accuracy of quantification, however, has been problematic as not all peptides are suitable for quantification. Several methods and tools have been developed to identify peptides that response well in mass spectrometry and they are mainly based on predictive models, and rarely consider the linearity of the response curve, limiting the accuracy and applicability of the methods. An alternative solution is to select empirically superior peptides that offer satisfactory MS response intensity and linearity in a wide dynamic range of peptide concentration. Results: We constructed a reference database for proteome quantification based on experimental mass spectrum response curves. The intensity and dynamic range of over 2 647 773 transitions from 121 318 peptides were obtained from a set of dilution experiments, covering 11 040 gene products. These transitions and peptides were evaluated and presented in a database named SCRIPT MAP. We showed that the best-responder (BR) peptide approach for quantification based on SCRIPT-MAP database is robust, repeatable and accurate in proteome-scale protein quantification. This study provides a reference database as well as a peptides/transitions selection method for quantitative proteomics. Availability and implementation: SCRIPT-MAP database is available at http://www.firmiana.org/responders/. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29617942 TI - Cloning and characterization of the UePrf1 gene in Ustilago esculenta. AB - Ustilago esculenta, an obligate parasite of Zizania latifolia, is a typical dimorphic fungus which induces host stem swelling and inhibits host inflorescence development, but is not found in host leaves. Previous studies have shown that dimorphic switching is essential for fungal pathogenicity and is regulated by protein kinase A and mitogen-activated protein kinase (MAPK) signaling pathways that are integrated by Prf1 in Ustilago maydis. In this study we identified a Prf1 homolog in U. esculenta, designated UePrf1, encoding 830 amino acids with a conserved high mobility group domain located between amino acids 124 and 195. UePrf1 was upregulated during the mating process, which induces dimorphism in U. esculenta. In vitro, UePrf1 mutants showed defects in the mating process, including cell fusion and hyphal growth. UePrf1 mutants also show reduced expression of a genes, even during the cell fusion process. Additionally, the defect in hyphal growth of the UeKpp2 and UeKpp6 mutants (MAPK signaling pathway mutants) was partially counteracted by UePrf1 overexpression, along with induced b gene expression. These results provide evidence that UePrf1 is a key factor coordinating dimorphism in U. esculenta and suggest a conserved role for UePrf1 in the regulation of the a and b genes. PMID- 29617943 TI - Efficient simulation of intrinsic, extrinsic and external noise in biochemical systems. PMID- 29617944 TI - PhenotypeSimulator: A comprehensive framework for simulating multi-trait, multi locus genotype to phenotype relationships. AB - Motivation: Simulation is a critical part of method development and assessment. With the increasing sophistication of multi-trait and multi-locus genetic analysis techniques, it is important that the community has flexible simulation tools to challenge and explore the properties of these methods. Results: We have developed PhenotypeSimulator, a comprehensive phenotype simulation scheme that can model multiple traits with multiple underlying genetic loci as well as complex covariate and observational noise structure. This package has been designed to work with many common genetic tools both for input and output. We describe the underlying components of this simulation tool and illustrate its use on an example dataset. Availability and implementation: PhenotypeSimulator is available as a well documented R/CRAN package and the code is available on github: https://github.com/HannahVMeyer/PhenotypeSimulator. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29617945 TI - Intracranial Neoplasms in the First Year of Life: Results of a Third Cohort of Patients From a Single Institution. AB - BACKGROUND: Brain tumors in the first year of life are rare and their management remains challenging. OBJECTIVE: To report on the contemporary management of brain tumors in infants with reference to previous series from our institution. METHODS: Retrospective cohort study design. Electronic/paper case note review of all brain tumors diagnosed at our institution in children aged <1 yr since the publication of our previous series. RESULTS: Ninety-eight patients were seen. The most common presentations were with vomiting and macrocrania, at a median age of 184 d. Sixty-two percent of tumors were supratentorial. Ninety-one patients underwent 230 procedures; 7 patients had no surgery. One hundred eighteen operations were directly on brain tumors (biopsy 37, subtotal resection 47, gross total resection 34). Ninety-one cerebrospinal fluid diversions, 9 endoscopic procedures, and 13 preoperative embolizations were performed. Operative mortality was 4.4%. Tumor types in order of frequency were choroid plexus papillomas (CPP, 17), primitive neuroectodermal tumor (12), atypical teratoid/rhabdoid tumor (10), high-grade glioma (9), optic glioma (9), ependymoma (8), low-grade glioma (6), pilocytic astrocytoma (6), choroid plexus carcinoma (5), and teratoma (5), with 11 miscellaneous tumors. Survival was 93% at 1 mo (91/98), 64% at 1 yr (61/95), 44% at 5 yr (32/73), 28% at 10 yr (16/58). No patients with CPP or low-grade glioma died. Five-year survival rates were lowest for anaplastic ependymoma, primitive neuroectodermal tumor, and atypical teratoid/rhabdoid tumor. Seventy seven percent of children reaching school age were in mainstream schooling. CONCLUSION: Overall survival from neonatal brain tumors remains similar to previous series; analysis of tumor subtypes reveals improvements for CPP and gliomas. Despite increasing operative intervention, operative mortality continues to decline for this group of challenging patients. PMID- 29617946 TI - Long-term selection of chickens for body weight alters muscle satellite cell behaviors. AB - Muscle satellite cells (SC) are resident stem-like cells that play an integral role in skeletal muscle growth and repair. Understanding how SC maintain their identities and dynamic properties is critical to animal growth. However, the genetic and environmental factors governing SC behaviors and the underpinning mechanisms remain unknown. To explore whether genetic selection influences SC behaviors, we used 2 lines of chickens selected for over 50 generations with over a 10-fold difference in body weight at 56 d of age-the Virginia high weight selection (HWS) and low weight selection (LWS) lines. To study these 2 lines, we performed both in vivo and in vitro experiments. In vivo, we studied the abundance of SC in normal physiological settings and tested their functional roles in muscle regeneration using a muscle injury model. In vitro, we isolated SC from chicken skeletal muscle and assayed their ability to proliferate and differentiate under cultured conditions. Immunohistochemical staining of breast muscle (pectoralis major) revealed that muscle fibers from HWS chickens possessed more SC than those from LWS. Further analysis showed that the SC pool from HWS muscles contained a higher percentage of activated SC compared to that of LWS. When isolated SC from HWS and LWS muscles were cultured, HWS SC exhibited greater abilities to proliferate and differentiate than those SC from LWS. To test whether the observed in vitro differences in SC properties could be confirmed in vivo, we subjected chicken breast muscle to barium chloride to induce muscle injury and regeneration. Consistent with in vitro data, breast muscle in HWS chicken experienced a faster and more robust recovery than that of LWS, as evidenced by quicker regeneration and larger muscle fiber size. Taken together, these findings suggest divergent selection for body weight not only results in correlated responses in SC number, but also changes SC growth kinetics. Further dissection of the molecular mechanism will aid the identification of the target molecules for growth intervention in chickens. PMID- 29617947 TI - Relationship of Lipids and Lipid-Lowering Medications With Cognitive Function: The Multi-Ethnic Study of Atherosclerosis. AB - Studies on the relationship of cholesterol concentrations and lipid-lowering medications with dementia risk have yielded inconsistent findings. Therefore, we investigated the association of lipid concentrations and lipid-lowering medications with cognitive function in the Multi-Ethnic Study of Atherosclerosis across 3 different cognitive domains assessed by means of the Cognitive Abilities Screening Instrument (CASI; version 2), the Digit Symbol Coding (DSC) Test, and the Digit Span (DS) Test in 2010-2012. After adjustment for sociodemographic and confounding factors, including concentrations of other lipids and use of lipid lowering medication, higher total cholesterol, low-density lipoprotein cholesterol, and non-high-density-lipoprotein cholesterol concentrations were modestly associated with higher DS Test scores. None of the lipid parameters were associated with CASI or DSC Test scores. Similarly, changes in lipid concentrations were not associated with any cognitive function test score. Using treatment effects model analysis and after adjusting for confounding factors, including lipid concentrations, the use of any lipid-lowering medication, especially statins, was associated with higher scores on the CASI and backward DS tests but not on the DSC and forward DS tests. Our study does not support a robust association between lipid concentrations and cognitive function or between the use of lipid-lowering medication, especially statins, and worse cognitive function. PMID- 29617948 TI - 2017 Articles of the Year, Reviewers of the Year, and Figure of the Year. PMID- 29617949 TI - RE: "Deployment And Preterm Birth Among US Army Soldiers". PMID- 29617950 TI - Reactome Pengine: a web-logic API to the Homo sapiens reactome. AB - Summary: Existing ways of accessing data from the Reactome database are limited. Either a researcher is restricted to particular queries defined by a web application programming interface (API) or they have to download the whole database. Reactome Pengine is a web service providing a logic programming-based API to the human reactome. This gives researchers greater flexibility in data access than existing APIs, as users can send their own small programs (alongside queries) to Reactome Pengine. Availability and implementation: The server and an example notebook can be found at https://apps.nms.kcl.ac.uk/reactome-pengine. Source code is available at https://github.com/samwalrus/reactome-pengine and a Docker image is available at https://hub.docker.com/r/samneaves/rp4/. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29617951 TI - Non-mumps Viral Parotitis During the 2014-2015 Influenza Season in the United States. AB - Background: During the 2014-2015 US influenza season, 320 cases of non-mumps parotitis (NMP) among residents of 21 states were reported to the Centers for Disease Control and Prevention (CDC). We conducted an epidemiologic and laboratory investigation to determine viral etiologies and clinical features of NMP during this unusually large occurrence. Methods: NMP was defined as acute parotitis or other salivary gland swelling of >2 days duration in a person with a mumps- negative laboratory result. Using a standardized questionnaire, we collected demographic and clinical information. Buccal samples were tested at the CDC for selected viruses, including mumps, influenza, human parainfluenza viruses (HPIVs) 1-4, adenoviruses, cytomegalovirus, Epstein-Barr virus (EBV), herpes simplex viruses (HSVs) 1 and 2, and human herpes viruses (HHVs) 6A and 6B. Results: Among the 320 patients, 65% were male, median age was 14.5 years (range, 0-90), and 67% reported unilateral parotitis. Commonly reported symptoms included sore throat (55%) and fever (48%). Viruses were detected in 210 (71%) of 294 NMP patients with adequate samples for testing, >=2 viruses were detected in 37 samples, and 248 total virus detections were made among all samples. These included 156 influenza A(H3N2), 42 HHV6B, 32 EBV, 8 HPIV2, 2 HPIV3, 3 adenovirus, 4 HSV-1, and 1 HSV-2. Influenza A(H3N2), HHV6B, and EBV were the most frequently codetected viruses. Conclusions: Our findings suggest that, in addition to mumps, clinicians should consider respiratory viral (influenza) and herpes viral etiologies for parotitis, particularly among patients without epidemiologic links to mumps cases or outbreaks. PMID- 29617953 TI - Featured Article: Interpersonal Stressors and Resources as Predictors of Adolescent Adjustment Following Traumatic Brain Injury. AB - Objective: The present study sought to examine adolescents' perceptions of their interpersonal stressors and resources across parent, sibling, friend, and school relationships, and the longitudinal associations with self-reported adjustment after traumatic brain injury (TBI) over a 12-month period. Methods: We examined the main effects of stressors and resources on internalizing and externalizing symptoms in 152 adolescents who had sustained complicated mild-to-severe TBI. We also investigated the conjoint effects of stressors and resources and the moderating effects of TBI severity with stressors and resources on outcomes. Results: High stressors consistently predicted worse adjustment. High resources were generally only associated with fewer internalizing symptoms. Main effects were qualified by interactions between school stressors and resources in predicting externalizing symptoms and between friend stressors and resources in predicting internalizing and externalizing symptoms. For school stressors, the effects of resources on externalizing symptoms functioned as a buffer. In comparison, the buffering effects of friend resources on internalizing and externalizing symptoms disappeared at moderate-to-high levels of friend stress. Moderating effects of TBI severity were also observed, such that as family resources increased, only adolescents with complicated mild-to-moderate TBI, but not those with severe TBI, experienced decreases in internalizing and eternalizing symptoms. Conclusion: Interpersonal stressors and social support have important implications for adolescent adjustment after TBI. Adolescents with low levels of school resources, with high levels of friend stress, and who sustain severe TBI are at greatest risk for difficulties with adjustment. PMID- 29617954 TI - AGORA: organellar genome annotation from the amino acid and nucleotide references. AB - Summary: Next-generation sequencing (NGS) technologies have led to the accumulation of high-throughput sequence data from various organisms in biology. To apply gene annotation of organellar genomes for various organisms, more optimized tools for functional gene annotation are required. Almost all gene annotation tools are mainly focused on the chloroplast genome of land plants or the mitochondrial genome of animals. We have developed a web application AGORA for the fast, user-friendly and improved annotations of organellar genomes. Annotator for Genes of Organelle from the Reference sequence Analysis (AGORA) annotates genes based on a basic local alignment search tool (BLAST)-based homology search and clustering with selected reference sequences from the NCBI database or user-defined uploaded data. AGORA can annotate the functional genes in almost all mitochondrion and plastid genomes of eukaryotes. The gene annotation of a genome with an exon-intron structure within a gene or inverted repeat region is also available. It provides information of start and end positions of each gene, BLAST results compared with the reference sequence and visualization of gene map by OGDRAW. Availability and implementation: Users can freely use the software, and the accessible URL is https://bigdata.dongguk.edu/gene_project/AGORA/. The main module of the tool is implemented by the python and php, and the web page is built by the HTML and CSS to support all browsers. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29617952 TI - Risk Factors for Human Papillomavirus Infection and Abnormal Cervical Cytology Among Perinatally Human Immunodeficiency Virus-Infected and Uninfected Asian Youth. AB - Background: Infection with high-risk human papillomavirus (HR-HPV) may be higher in perinatally human immunodeficiency virus (HIV)-infected (PHIV) than HIV uninfected (HU) adolescents because of long-standing immune deficiency. Methods: PHIV and HU females aged 12-24 years in Thailand and Vietnam were matched by age group and lifetime sexual partners. At enrollment, blood, cervical, vaginal, anal, and oral samples were obtained for HPV-related testing. The Wilcoxon and Fisher exact tests were used for univariate and logistic regression for multivariate analyses. Results: Ninety-three PHIV and 99 HU adolescents (median age 19 [18-20] years) were enrolled (June 2013-July 2015). Among PHIV, 94% were currently receiving antiretroviral therapy, median CD4 count was 593 (392-808) cells/mm3, and 62% had a viral load <40 copies/mL. Across anogenital compartments, PHIV had higher rates of any HPV detected (80% vs 60%; P = .003) and any HR-HPV (60% vs 43%, P = .02). Higher proportions of PHIV had abnormal Pap smears (eg, atypical squamous cells of unknown significance [ASC-US], 12% vs 14%; low-grade squamous intraepithelial neoplastic lesions, 19% vs 1%). After adjusting for ever being pregnant and asymptomatic sexually transmitted infections (STI) at enrollment, PHIV were more likely to have HR-HPV than HU (odds ratio, 2.02; 95% confidence interval, 1.09-3.77; P = .03). Conclusions: Perinatal HIV infection was associated with a higher risk of HR-HPV and abnormal cervical cytology. Our results underscore the need for HPV vaccination for PHIV adolescents and for prevention and screening programs for HPV and other STIs. PMID- 29617955 TI - Duration of Zika Viremia in Serum. PMID- 29617956 TI - Microglia activation in Niemann-Pick disease, type C1 is amendable to therapeutic intervention. AB - Niemann-Pick disease, type C1 (NPC1) is a neurodegenerative disorder with limited treatment options. NPC1 is associated with neuroinflammation; however, attempts to therapeutically target neuroinflammation in NPC1 have had mixed success. We show here that NPC1 neuroinflammation is characterized by an atypical microglia activation phenotype. Specifically, Npc1-/- microglia demonstrated altered morphology, reduced levels of lineage markers and a shift toward glycolytic metabolism. Treatment with 2-hydroxypropyl-beta-cyclodextrin (HPbetaCD), a drug currently being studied in a phase 2b/3 clinical trial, reversed all microglia associated defects in Npc1-/- animals. In addition, impairing microglia mediated neuroinflammation by genetic deletion of IRF8 led to decreased symptoms and increased lifespan. We identified CD22 as a marker of dysregulated microglia in Npc1 mutant mice and subsequently demonstrated that elevated cerebrospinal fluid levels of CD22 in NPC1 patients responds to HPbetaCD administration. Collectively, these data provide the first in-depth analysis of microglia function in NPC1 and suggest possible new therapeutic approaches. PMID- 29617957 TI - Influenza-Associated Parotitis During the 2014-2015 Influenza Season in the United States. AB - Background: During the 2014-2015 influenza season in the United States, 256 cases of influenza-associated parotitis were reported from 27 states. We conducted a case-control study and laboratory investigation to further describe this rare clinical manifestation of influenza. Methods: During February 2015-April 2015, we interviewed 50 cases (with parotitis) and 124 ill controls (without parotitis) with laboratory-confirmed influenza; participants resided in 11 states and were matched by age, state, hospital admission status, and specimen collection date. Influenza viruses were characterized using real-time polymerase chain reaction and next-generation sequencing. We compared cases and controls using conditional logistic regression. Specimens from additional reported cases were also analyzed. Results: Cases, 73% of whom were aged <20 years, experienced painful (86%), unilateral (68%) parotitis a median of 4 (range, 0-16) days after onset of systemic or respiratory symptoms. Cases were more likely than controls to be male (76% vs 51%; P = .005). We detected influenza A(H3N2) viruses, genetic group 3C.2a, in 100% (32/32) of case and 92% (105/108) of control specimens sequenced (P = .22). Influenza B and A(H3N2) 3C.3 and 3C.3b genetic group virus infections were detected in specimens from additional cases. Conclusions: Influenza associated parotitis, as reported here and in prior sporadic case reports, seems to occur primarily with influenza A(H3N2) virus infection. Because of the different clinical and infection control considerations for mumps and influenza virus infections, we recommend clinicians consider influenza in the differential diagnoses among patients with acute parotitis during the influenza season. PMID- 29617958 TI - Reply to Fontaine. PMID- 29617959 TI - Reduction in All-Cause Acute Otitis Media in Children <3 Years of Age in Primary Care Following Vaccination With 10-Valent Pneumococcal Haemophilus influenzae Protein-D Conjugate Vaccine: A Whole-Population Study. AB - Background: The 10-valent pneumococcal conjugate vaccine (PHiD-CV10) was introduced in Iceland in 2011, without catch-up. The aim of this study was to estimate vaccine impact (VI) on acute otitis media (AOM). Methods: In this whole population study, all primary care visits due to AOM from 2005 to 2015 in children <3 years of age were included. Birth cohorts were grouped as vaccine noneligible (VNEC) or vaccine eligible (VEC). Crude incidence rates (IRs) were compared between the VNEC and VEC. A Cox regression model for repeated events was used to model the individual-level data. VI was calculated as (hazard ratio [HR] 1) * 100%. Results: Included were 53150 children, with 140912 person-years of follow-up and 58794 AOM episodes. Both IR and the mean number of episodes differed significantly between VNEC and VEC; 43 compared to 38 episodes per 100 person-years and 1.61 episodes per child compared to 1.37. IR was significantly reduced in all age brackets, with the largest reduction in children <4 months of age (40% [95% confidence interval {CI}, 31%-49%). The VI on all-cause AOM was 22% (95% CI, 12%-31%). The impact was mediated through its effect on the first (HR, 0.84 [95% CI, .82-.86]) and second (HR, 0.95 [95% CI, .93-.98]) episodes. Conclusions: The impact of PHiD-CV10 on all-cause AOM was considerable, mediated mainly by preventing the first two episodes of AOM. A decrease in the IR of AOM in children too young to receive direct vaccine protection was demonstrated, suggesting herd effect. PMID- 29617960 TI - Is Parotitis One More Complication of Influenza? The Ongoing Challenge of Determining Causal Associations. PMID- 29617961 TI - Reply to van Laarhoven et al. PMID- 29617962 TI - Assessment of the minimal available phosphorus needs of laying hens: Implications for phosphorus management strategies. AB - The oversupply of dietary phosphorus (P) leads to increased feed costs and discharge of excessive P to the environment, thus directly impacting the sustainability of egg production practices. The present study was conducted to better define the minimal available P needs of laying hens. Fifty-six Lohmann white laying hens were individually caged and fed one of 7 diets with graded levels of available P (0.15, 0.20, 0.25, 0.30, 0.35, 0.40, or 0.45%) for 12 weeks. Records were maintained for body weight, feed intake, and egg production during the experimental period. Blood and egg samples were collected and digestibility studies conducted at wk 6 and 12 of the experiment. At the end of the experiment, tibia characteristics and expression of the P transporters in the small intestine and kidney were determined. Lowering dietary available P from 0.45 to 0.15% generally reduced plasma P concentrations (P < 0.01), but hen productive performance, plasma calcium, parathyroid hormone and other constituents, tibia bone mineral density and content, tibia ash percentage, and mRNA abundance of the small intestine, and kidney type II sodium/phosphate cotransporter were not different among treatments. Specific gravity and eggshell thickness tended to increase with reducing dietary P (P < 0.05). Total P intake, excretion, and retention net amount decreased (P < 0.01) with reducing dietary P, but its retention rate (of intake) remained unchanged. Furthermore, changing dietary P did not affect calcium retention rate and net deposition of total P and calcium in eggs. These data indicate that reducing dietary available P up to 0.15% is adequate to maintain health and performance of layers. As such, this minimal available P estimate should serve as a benchmark for the assessment of P contents of commercial laying hen rations, with the goal of enhancing the sustainability of egg production. PMID- 29617963 TI - Detecting hidden batch factors through data-adaptive adjustment for biological effects. AB - Motivation: Batch effects are one of the major source of technical variations that affect the measurements in high-throughput studies such as RNA sequencing. It has been well established that batch effects can be caused by different experimental platforms, laboratory conditions, different sources of samples and personnel differences. These differences can confound the outcomes of interest and lead to spurious results. A critical input for batch correction algorithms is the knowledge of batch factors, which in many cases are unknown or inaccurate. Hence, the primary motivation of our paper is to detect hidden batch factors that can be used in standard techniques to accurately capture the relationship between gene expression and other modeled variables of interest. Results: We introduce a new algorithm based on data-adaptive shrinkage and semi-Non-negative Matrix Factorization for the detection of unknown batch effects. We test our algorithm on three different datasets: (i) Sequencing Quality Control, (ii) Topotecan RNA Seq and (iii) Single-cell RNA sequencing (scRNA-Seq) on Glioblastoma Multiforme. We have demonstrated a superior performance in identifying hidden batch effects as compared to existing algorithms for batch detection in all three datasets. In the Topotecan study, we were able to identify a new batch factor that has been missed by the original study, leading to under-representation of differentially expressed genes. For scRNA-Seq, we demonstrated the power of our method in detecting subtle batch effects. Availability and implementation: DASC R package is available via Bioconductor or at https://github.com/zhanglabNKU/DASC. Contact: zhanghan@nankai.edu.cn or zhandonl@bcm.edu. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29617964 TI - Hippocampal Subcellular Organelle Proteomic Alteration of Copper-Treated Mice. AB - Copper neurotoxicity has been implicated in multiple neurological diseases. However, there is a lack of deep understanding on copper neurotoxicity, especially for low-dose copper exposure. In this study, we investigated the effects of chronic, low-dose copper treatment (0.13 ppm copper chloride in drinking water) on hippocampal mitochondrial and nuclear proteome in mice by 2 dimensional fluorescence difference gel electrophoresis coupled with MALDI-TOF MS/MS. Behavioral tests revealed that low-dose copper caused spatial memory impairment, DNA oxidative damage as well as loss of synaptic proteins. Proteomic analysis revealed modulation of 31 hippocampal mitochondrial proteins (15 increased and 16 decreased), and 46 hippocampal nuclear proteins (18 increased and 28 decreased) in copper-treated versus untreated mice. Bioinformatic analysis indicated that these differentially expressed proteins are mainly involved energy metabolism (NDUV1, COX5B, IDH3A, and PGAM1), synapses (complexin-2, synapsin-2), DNA damage (PDIA3), apoptosis (GRP75), and oxidative stress (SODC, PRDX3). Among these differentially expressed proteins, synapsin-2, a synaptic-related protein, was found to be significantly decreased as confirmed by Western-blot analysis. In addition, we found that superoxide dismutase [Cu-Zn] (SODC), a copper ion target protein, was identified to be decreased in copper-treated mice versus untreated mice. We also found that stathmin (STMN1), a microtubule-destabilizing neuroprotein, was significantly decreased in hippocampal nuclei of copper-treated mice versus untreated mice. Taken together, we conclude that low-dose copper exposure causes spatial memory impairment and perturbs multiple biological/pathogenic processes by dysregulating the mitochondrial and nuclear proteome, particularly the proteins related to respiratory chain, synaptic vesicle fusion, axonal/neurtic integrity, and oxidative stress. The change of STMN1 and SODC may represent early novel biomarkers of copper neurotoxicity. PMID- 29617965 TI - Cost-effectiveness of Preventive Therapy for Tuberculosis With Isoniazid and Rifapentine Versus Isoniazid Alone in High-Burden Settings. AB - Background: A short-course regimen of 3 months of weekly rifapentine and isoniazid (3HP) has recently been recommended by the World Health Organization as an alternative to at least 6 months of daily isoniazid (isoniazid preventive therapy [IPT]) for prevention of tuberculosis (TB). The contexts in which 3HP may be cost-effective compared to IPT among people living with human immunodeficiency virus are unknown. Methods: We used a Markov state transition model to estimate the incremental cost-effectiveness of 3HP relative to IPT in high-burden settings, using a cohort of 1000 patients in a Ugandan HIV clinic as an emblematic scenario. Cost-effectiveness was expressed as 2017 US dollars per disability-adjusted life year (DALY) averted from a healthcare perspective over a 20-year time horizon. We explored the conditions under which 3HP would be considered cost-effective relative to IPT. Results: Per 1000 individuals on antiretroviral therapy in the reference scenario, treatment with 3HP rather than IPT was estimated to avert 9 cases of TB and 1 death, costing $9402 per DALY averted relative to IPT. Cost-effectiveness depended strongly on the price of rifapentine, completion of 3HP, and prevalence of latent TB. At a willingness to pay of $1000 per DALY averted, 3HP is likely to be cost-effective relative to IPT only if the price of rifapentine can be greatly reduced (to approximately $20 per course) and high treatment completion (85%) can be achieved. Conclusions: 3HP may be a cost-effective alternative to IPT in high-burden settings, but cost effectiveness depends on the price of rifapentine, achievable completion rates, and local willingness to pay. PMID- 29617967 TI - Older drugs with infantile evidence: the illustrative example of loop diuretics. PMID- 29617968 TI - Tetralogy of Fallot with aortopulmonary window and interrupted aortic arch: multimodality imaging in a rare association. PMID- 29617969 TI - News From the Foundation for Physical Therapy. PMID- 29617966 TI - MechRNA: prediction of lncRNA mechanisms from RNA-RNA and RNA-protein interactions. AB - Motivation: Long non-coding RNAs (lncRNAs) are defined as transcripts longer than 200 nt that do not get translated into proteins. Often these transcripts are processed (spliced, capped and polyadenylated) and some are known to have important biological functions. However, most lncRNAs have unknown or poorly understood functions. Nevertheless, because of their potential role in cancer, lncRNAs are receiving a lot of attention, and the need for computational tools to predict their possible mechanisms of action is more than ever. Fundamentally, most of the known lncRNA mechanisms involve RNA-RNA and/or RNA-protein interactions. Through accurate predictions of each kind of interaction and integration of these predictions, it is possible to elucidate potential mechanisms for a given lncRNA. Results: Here, we introduce MechRNA, a pipeline for corroborating RNA-RNA interaction prediction and protein binding prediction for identifying possible lncRNA mechanisms involving specific targets or on a transcriptome-wide scale. The first stage uses a version of IntaRNA2 with added functionality for efficient prediction of RNA-RNA interactions with very long input sequences, allowing for large-scale analysis of lncRNA interactions with little or no loss of optimality. The second stage integrates protein binding information pre-computed by GraphProt, for both the lncRNA and the target. The final stage involves inferring the most likely mechanism for each lncRNA/target pair. This is achieved by generating candidate mechanisms from the predicted interactions, the relative locations of these interactions and correlation data, followed by selection of the most likely mechanistic explanation using a combined P-value. We applied MechRNA on a number of recently identified cancer-related lncRNAs (PCAT1, PCAT29 and ARLnc1) and also on two well-studied lncRNAs (PCA3 and 7SL). This led to the identification of hundreds of high confidence potential targets for each lncRNA and corresponding mechanisms. These predictions include the known competitive mechanism of 7SL with HuR for binding on the tumor suppressor TP53, as well as mechanisms expanding what is known about PCAT1 and ARLn1 and their targets BRCA2 and AR, respectively. For PCAT1-BRCA2, the mechanism involves competitive binding with HuR, which we confirmed using HuR immunoprecipitation assays. Availability and implementation: MechRNA is available for download at https://bitbucket.org/compbio/mechrna. Supplementary information: Supplementary data are available at Bioinformatics online. PMID- 29617970 TI - Opening Up the Black Box of Peer Review. PMID- 29617971 TI - Chronic Musculoskeletal Pain is a Nervous System Disorder... Now What? PMID- 29617972 TI - On "Diagnosis of Upper Quadrant Lymphedema Secondary to Cancer: Clinical Practice Guideline from the Oncology Section of the American Physical Therapy Association." Levenhagen K, Davies C, Perdomo M, Ryans K, Gilchrist L. Phys Ther. 2017;97:729-745. PMID- 29617973 TI - Moving Students Toward Movement: "Situational Analysis of Physical Therapist Clinical Instructors' Facilitation of Students' Emerging Embodiment of Movement in Practice." Covington K, Barcinas SJ. Phys Ther. 2017;97:603-614. PMID- 29617975 TI - Neuromarker Levels Also Predict Mortality in Adult Tuberculous Meningitis. PMID- 29617974 TI - Association between layer-specific global longitudinal strain and adverse outcomes following acute coronary syndrome. AB - Aims: To investigate the prognostic value of layer-specific global longitudinal strain (GLS) in predicting heart failure (HF) and cardiovascular death (CD) following acute coronary syndrome (ACS). Methods and results: In this retrospective study, 465 ACS patients underwent transthoracic echocardiography following percutaneous coronary intervention (PCI). The primary endpoint was the composite of HF and/or CD with a median follow-up time of 4.6 (0.2-6.3) years. During follow-up 199 patients (42.7%) suffered HF and/or CD (176 developed HF and 38 suffered CD). Absolute endomyocardial global longitudinal strain (GLSendo) (12% vs. 17%, P < 0.001), GLS (11% vs. 14%, P < 0.001), and epimyocardial global longitudinal strain (GLSepi) (9% vs. 13%, P < 0.001) were all reduced in patients with an adverse outcome. In multivariable Cox regressions, which included clinical baseline characteristics and conventional echocardiographic measurements, GLS obtained from all layers remained independently associated with the composite outcome; GLSendo [hazard ratio: 1.19 (1.10-1.28), P < 0.001, per 1% decrease], GLS [hazard ratio 1.24 (1.14-1.35), P < 0.001, per 1% decrease], and GLSepi [hazard ratio 1.26 (1.15-1.39), P < 0.001, per 1% decrease]. No other echocardiographic measures remained independently associated with the composite outcome in these models. Finally, GLS and GLSepi provided incremental prognostic information on the risk of developing the composite endpoint, when added to all other clinical and echocardiographic measures [adding GLS (c-statistics: 0.76 vs. 0.74, P = 0.048) or adding GLSepi (c-statistics: 0.76 vs. 0.74, P = 0.039)]. Conclusion: In ACS patients, layer-specific strain provides independent prognostic information regarding risk of developing HF and/or CD. Furthermore, only GLS and GLSepi provided incremental prognostic information when added to all other significant predictors. PMID- 29617976 TI - The effects of tenapanor on serum fibroblast growth factor 23 in patients receiving hemodialysis with hyperphosphatemia. AB - Background: Elevated serum fibroblast growth factor 23 (FGF23) is strongly associated with cardiovascular risk and mortality. Tenapanor, an inhibitor of gastrointestinal sodium/hydrogen exchanger isoform 3, decreased serum phosphate in a randomized, double-blind, placebo-controlled Phase 2 trial (ClinicalTrials.gov identifier NCT02081534) of patients receiving hemodialysis with hyperphosphatemia. Here, we report a secondary analysis of effects on serum FGF23 during that study. Methods: After 1-3 weeks of washout of phosphate binders, 162 patients were randomized to receive 4 weeks of treatment with placebo or one of six tenapanor regimens (3 or 30 mg once daily, or 1, 3, 10 or 30 mg twice daily). Intact FGF23 concentrations were determined from serum samples collected at screening, post-washout and end of treatment, assayed in duplicate in a single batch at the end of the study. Results: After phosphate binder washout, serum FGF23 concentrations increased in all groups [range of geometric means: 1430-2605 pg/mL before, to 2601-6294 pg/mL after washout (P < 0.001 for all patients analyzed as a single group)]. Serum FGF23 concentrations subsequently decreased in tenapanor-treated patients (2030-3563 pg/mL), whereas they increased further in placebo-treated patients (6930 pg/mL). In an analysis of covariance, FGF23 decreased by 9.1-27.9% in tenapanor-treated patients and increased by 21.9% in placebo-treated patients (P <= 0.001-0.04). Conclusions: Following a marked increase in serum FGF23 in response to withdrawal of phosphate binders, tenapanor significantly decreased serum FGF23 in patients receiving hemodialysis with hyperphosphatemia. Further studies are required to explore the long-term effects of controlling FGF23 with tenapanor. PMID- 29617977 TI - Aortic sarcoidosis complicated by a pulmonary artery aneurysm. AB - A 76-year-old woman, who had a history of ocular sarcoidosis, was incidentally found to have a huge pulmonary artery aneurysm, along with aortic, mitral and tricuspid valve insufficiency. She underwent pulmonary artery plication along with surgeries for 3 valves. A specimen of the slightly enlarged ascending aorta revealed the involvement of sarcoidosis in the aortic wall. The systemic granulomatous inflammation process of sarcoidosis possibly affected the valvular and vascular pathology. Herein, we report a rare case of aortic sarcoidosis complicated by a pulmonary artery aneurysm. PMID- 29617978 TI - Pectus excavatum causing dynamic right ventricular outflow tract obstruction: increased obstruction during expiration and decreased during inspiration. PMID- 29617979 TI - Early structural valve deterioration of the Mitroflow biological valve prosthesis. PMID- 29617980 TI - Physical activity is associated with higher sleep efficiency in the general population: the CoLaus study. AB - Study Objectives: To evaluate the association of objective physical activity (PA) and sedentary behavior (SB) with sleep duration and quality. Methods: Cross sectional study including 2649 adults (53.5% women, 45-86 years) from the general population. Proportions of time spent in PA and SB were measured using 14 day accelerometry. Low PA and high SB statuses were defined as the lowest and highest tertile of each behavior. "Inactive," "Weekend warrior," and "Regularly active" weekly patterns were also defined. Sleep parameters were derived from the accelerometer and validated questionnaires. Results: High PA, relative to low PA, was associated with higher sleep efficiency (76.6 vs. 73.8%, p < 0.01) and lower likelihood of evening chronotype [relative-risk ratio (RR) and 95% CI: 0.71 (0.52; 0.97)]. Similar associations were found for low SB relative to high SB. "Weekend warriors" relative to "Inactives," had higher sleep efficiency [76.4 vs. 73.9%, p < 0.01] and lower likelihood of evening chronotype [RR: 0.63 (0.43; 0.93)]. "Regularly actives," relative to "Inactives," had higher sleep efficiency [76.7 vs. 73.9%, p < 0.01] and tended to have less frequently an evening chronotype [RR: 0.75 (0.54; 1.04), p = 0.09]. No associations were found for PA and SB with sleep duration, daytime sleepiness, insomnia, and risk of sleep apnea (after adjustment for body mass index). Conclusions: High PA and low SB individuals, even if they do not sleep longer, have higher sleep efficiency and have less frequently an evening chronotype. PMID- 29617981 TI - Impact of statin therapy on coronary plaque burden and composition assessed by coronary computed tomographic angiography: a systematic review and meta-analysis. AB - Aim: To clarify the potential role of coronary computed tomographic angiography (CCTA) in assessing the remodelling impact of statin therapy on plaque burden and compositions. Methods and results: A systematic literature review and meta analysis were conducted to examine the effect of statin therapy on different plaque volumes assessed by serial CCTA. Twelve studies were included with a mean (+/-standard deviation) follow-up period of 14.5 +/- 9.5 months. Data on plaque volume were pooled using weighted mean difference method. Available data on a total of 199 intensive statin therapy receivers, 404 moderate statin therapy receivers and 189 controls (mean age = 62 +/- 5 years, male gender = 78%) were meta-analysed. Intensive statin therapy reduced total plaque volume (TPV) by 20.87 [95% confidence interval (CI) -31.17, -10.56; P < 0.001] mm3, while moderate statin therapy reduced it by -1.67 (95% CI -9.99, 6.65; P = 0.69) mm3. In contrast TPV increased significantly in controls by 14.96 (95% CI 5.28, 24.64; P = 0.002) mm3. Percents of mean volume regression were -3.6% and -0.7% in intensive and moderate statin receivers, respectively, vs. +5.8% progression in controls. Statin therapy decreased non-calcified plaque volume by -7.62 (95% CI 17.38, 2.13; P = 0.124) mm3 and low attenuation plaque volume by -5.84 (95% CI 8.02, -3.66; P < 0.001) mm3. In statin therapy receivers, calcified plaque volume increased by 11.83 (95% CI 3.37, 20.29; P = 0.006) mm3 and calcium signal intensity increased by 21.99 (95% CI 9.2, 34.8; P < 0.001) Hounsfield units. Conclusions: Initial studies demonstrated CCTA's possible role in evaluating the effect of statin therapy on plaque volume and composition. Further studies are warranted to delineate the mechanisms behind plaque changes. PMID- 29617983 TI - Breakthrough Invasive Fungal Infections on Isavuconazole Prophylaxis and Treatment: What Is Happening in the Real-World Setting? PMID- 29617982 TI - Gepotidacin for the Treatment of Uncomplicated Urogenital Gonorrhea: A Phase 2, Randomized, Dose-Ranging, Single-Oral Dose Evaluation. AB - Background: In this phase 2 study, we evaluated the efficacy and safety of oral gepotidacin, a novel triazaacenaphthylene bacterial type II topoisomerase inhibitor, for the treatment of uncomplicated urogenital gonorrhea. Methods: Adult participants with suspected urogenital gonorrhea were enrolled and completed baseline (day 1) and test-of-cure (days 4-8) visits. Pretreatment and posttreatment urogenital swabs were collected for Neisseria gonorrhoeae (NG) culture and susceptibility testing. Pharyngeal and rectal swab specimens were collected if there were known exposures. Participants were stratified by gender and randomized 1:1 to receive a 1500-mg or 3000-mg single oral dose of gepotidacin. Results: The microbiologically evaluable population consisted of 69 participants, with NG isolated from 69 (100%) urogenital, 2 (3%) pharyngeal, and 3 (4%) rectal specimens. Microbiological eradication of NG was achieved by 97%, 95%, and 96% of participants (lower 1-sided exact 95% confidence interval bound, 85.1%, 84.7%, and 89.1%, respectively) for the 1500-mg, 3000-mg, and combined dose groups, respectively. Microbiological cure was achieved in 66/69 (96%) urogenital infections. All 3 failures were NG isolates that demonstrated the highest observed gepotidacin minimum inhibitory concentration of 1 ug/mL and a common gene mutation. At the pharyngeal and rectal sites, 1/2 and 3/3 NG isolates, respectively, demonstrated microbiological cure. There were no treatment-limiting adverse events for either dose. Conclusions: This study demonstrated that single, oral doses of gepotidacin were >=95% effective for bacterial eradication of NG in adult participants with uncomplicated urogenital gonorrhea. Clinical Trials Registration: NCT02294682. PMID- 29617984 TI - Activity and diversity of methane-oxidizing bacteria along a Norwegian sub-Arctic glacier forefield. AB - Methane (CH4) is one of the most abundant greenhouse gases in the atmosphere and identification of its sources and sinks is crucial for the reliability of climate model outputs. Although CH4 production and consumption rates have been reported from a broad spectrum of environments, data obtained from glacier forefields are restricted to a few locations. We report the activities of methanotrophic communities and their diversity along a chronosequence in front of a sub-Arctic glacier using high-throughput sequencing and gas flux measurements. CH4 oxidation rates were measured in the field throughout the growing season during three sampling times at eight different sampling points in combination with laboratory incubation experiments. The overall results showed that the methanotrophic community had similar trends of increased CH4 consumption and increased abundance as a function of soil development and time of year. Sequencing results revealed that the methanotrophic community was dominated by a few OTUs and that a short term increase in CH4 concentration, as performed in the field measurements, altered slightly the relative abundance of the OTUs. PMID- 29617985 TI - Effect of Potato virus Y Presence in Solanum tuberosum (Solanales: Solanaceae) and Chenopodium album on Aphid (Hemiptera: Aphididae) Behavior. AB - This study establishes the effect of Potato Virus Y (PVY; Potyvirus) in potatoes, Solanum tuberosum L. (Solanales: Solanaceae) and in common-lambs' quarter Chenopodium album L. (Amaranthaceae) on Macrosiphum euphorbiae Thomas (Hemiptera: Aphididae) and Myzus persicae Sulzer (Hemiptera: Aphididae) behavior, host preference, transmission, and fitness under field and laboratory studies. In the field, several weeds, besides C. album, were collected, including: Sisymbrium altissimum L. (Brassicaceae), Erodium cicutarium L., Lactuca serriola L., Solanum sarrachoides Sendtner (Solanaceae), and S. dulcamara L. (Solanaceae). All weeds were serologically tested for the presence of PVY. From all weeds collected, 2.3 and 34% of C. album and S. sarrachoides, respectively, were PVY-positive. From those positive samples, 72% of the PVY found were PVYN; the remaining 28% was PVYO. In addition, several aphid species were collected from those weeds: Ovatus crataegarious Walker, Macrosiphum euphorbiae (Hemiptera: Aphididae), Hyalopterus pruni Geoffroy (Hemiptera: Aphididae), Rophalosiphum madis Fitch, and 'others aphid' species were collected. The highest number of aphids were collected in E. cicutarium, followed by S. dulcamara, L. serriola, S. altissimum, and C. album. In laboratory studies, PVY-infected C. album does not induce the production of aphids. Moreover, M. persicae did not appear to have a strong preference for either healthy or PVY-infected potato plant, but they did develop a preference for infected plants after prolonged feeding. M. persicae and M. euphorbiae transmitted PVY from C. album to S. tuberosum, 44 and 37.5 % of the time. Future research should seek to identify not only other sources and prevalence of PVY in the field but vector relationships. In insect-pathogen complex continues to persist in solanaceous field crops around the world. PMID- 29617987 TI - Presence of Aedes and Anopheles mosquito larvae is correlated to bacteria found in domestic water-storage containers. AB - Water-storage containers are common in households where access to water is scarce and often act as breeding sites for vector mosquitoes. Bacteria in these containers may be important for attracting or repelling ovipositing mosquitoes. We hypothesized that bacterial community composition in water-storage containers would represent either inhibitory or suitable environmental conditions for mosquito larvae. To investigate this, we characterized the bacterial community composition in water-storage containers and correlated these communities to Aedes and Anopheles larval densities. Water samples were collected over two years from 13 containers in an Indian village and analyzed by high throughput 16S rRNA gene amplicon sequencing. Comparisons of bacterial community composition between water with and without mosquito larvae showed that Xanthomonadaceae, Comamonadaceae and Burkholderiaceae were more common (P < 0.05) in absence of larvae, while Lachnospiraceae, Synechococcaceae, Alcaligenaceae and Cryomorphaceae were more common (P < 0.05) in presence of larvae. Indicator analysis identified operational taxonomic units designated as CL500-29 marine group (Acidimicrobiaceae) and FukuN101 (Microbacteriaceae) for absence and presence of larvae, respectively. These results contribute to the understanding of which bacteria, directly or indirectly, can be linked to absence or presence of mosquitoes around households and set the basis for potential measures to be taken against these vector mosquitoes. PMID- 29617986 TI - Fermentation products in the cystic fibrosis airways induce aggregation and dormancy-associated expression profiles in a CF clinical isolate of Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is a well-known dominant opportunistic pathogen in cystic fibrosis (CF) with a wide range of metabolic capacities. However, P. aeruginosa does not colonize the airways alone, and benefits from the metabolic products of neighboring cells-especially volatile molecules that can travel between different parts of the airways easily. Here, we present a study that investigates the metabolic, gene expression profiles and phenotypic responses of a P. aeruginosa clinical isolate to fermentation products lactic acid and 2,3-butanediol, metabolites that are produced by facultative anaerobic members of the CF polymicrobial community and potential biomarkers of disease progression. Although previous studies have successfully investigated the metabolic and transcriptional profiles of P. aeruginosa, most have used common lab reference strains that may differ in important ways from clinical isolates. Using transcriptomics and metabolomics with gas chromatography time of flight mass spectrometry, we observe that fermentation products induce pyocyanin production along with the expression of genes involved in P. aeruginosa amino acid utilization, dormancy and aggregative or biofilm modes of growth. These findings have important implications for how interactions within the diverse CF microbial community influence microbial physiology, with potential clinical consequences. PMID- 29617988 TI - Myocardial native T1 and extracellular volume with healthy ageing and gender. AB - Aims: To determine how native myocardial T1 and extracellular volume (ECV) change with age, both to understand aging and to inform on normal reference ranges. Methods and results: Ninety-four healthy volunteers with no a history or symptoms of cardiovascular disease or diabetes underwent cardiovascular magnetic resonance at 1.5 T. Mid-ventricular short axis native and post-contrast T1 maps by Shortened MOdified Look-Locker Inversion-recovery (ShMOLLI), MOdified Look-Locker Inversion Recovery (MOLLI) [pre-contrast: 5s(3s)3s, post-contrast: 4s(1s)3s(1s)2s] and saturation recovery single-shot acquisition (SASHA) were acquired and ECV by these three techniques were derived for the mid anteroseptum. Mean age was 50 +/- 14 years (range 20-76), male 52%, with no age difference between genders (males 51 +/- 14 years; females 49 +/- 15 years, P = 0.55). Quoting respectively ShMOLLI, MOLLI, SASHA throughout, mean myocardial T1 was 957 +/- 30 ms, 1025 +/- 38 ms, 1144 +/- 45 ms (P < 0.0001) and ECV 28.4 +/- 3.0% [95% confidence interval (CI) 27.8-29.0], 27.3 +/- 2.7 (95% CI 26.8-27.9), 24.1 +/- 2.9% (95% CI 23.5-24.7) (P < 0.0001), with all values higher in females for all techniques (T1 +18 ms, +35 ms, +51 ms; ECV +2.7%, +2.6%, +3.4%). Native myocardial T1 reduced slightly with age (R2 = 0.042, P = 0.048; R2 = 0.131, P < 0.0001-on average by 8-11 ms/decade-but not for SASHA (R2 = 0.033 and P = 0.083). ECV did not change with age (R2 = 0.003, P = 0.582; R2 = 0.002, P = 0.689; R2 = 0.003, P = 0.615). Heart rate decreased slightly with age (R2 = 0.075, coefficient = -0.273, P = 0.008), but there was no relationship between age and other blood T1 influences (haematocrit, iron, high density lipoprotein cholesterol). Conclusion: Gender influences native T1 and ECV with women having a higher native T1 and ECV. Native T1 measured by MOLLI and ShMOLLI was slightly lower with increasing age but not with SASHA and ECV was independent of age for all techniques. PMID- 29617989 TI - Knowledge of venomous snakes, snakebite first aid, treatment, and prevention among clinicians in northern Nigeria: a cross-sectional multicentre study. AB - Background: Snakebite envenoming causes considerable morbidity and mortality in northern Nigeria. The clinician's knowledge of snakebite impacts outcome. We assessed clinicians' knowledge of snakebite envenoming to highlight knowledge and practice gaps for possible intervention to improve snakebite outcomes. Methods: This was a cross-sectional multicentre study of 374 doctors selected from the accident and emergency, internal medicine, family medicine/general outpatient, paediatrics and surgery departments of nine tertiary hospitals in northern Nigeria using a multistage sampling technique. A self-administered questionnaire was used to assess their sociodemographics, knowledge of common venomous snakes, snakebite first aid, snake antivenom treatment and prevention. Results: The respondents' mean age was 35.6+/-5.8 y. They were predominantly males (70.6%) from urban hospitals (71.9%), from the northwest region (35.3%), in family medicine/general outpatient departments (33.4%), of <10 years working experience (66.3%) and had previous experience in snakebite management (78.3%). Although their mean overall knowledge score was 70.2+/-12.6%, only 52.9% had an adequate overall knowledge score. Most had adequate knowledge of snakebite clinical features (62.3%), first aid (75.7%) and preventive measures (97.1%), but only 50.8% and 25.1% had adequate knowledge of snake species that caused most injuries/deaths and anti-snake venom treatment, respectively. Overall knowledge predictors were >=10 y working experience (odd ratio [OR] 1.72 [95% confidence interval {CI} 1.07 to 2.76]), urban hospital setting (OR 0.58 [95% CI 0.35 to 0.96]), surgery department (OR 0.44 [95% CI 0.24 to 0.81]), northwest/north central region (OR 2.36 [95% CI 1.46 to 3.82]) and previous experience in snakebite management (OR 2.55 [95% CI 1.49 to 4.36]). Conclusions: Overall knowledge was low. Improvements in overall knowledge may require clinicians' exposure to snakebite management and training of accident and emergency clinicians in the region. PMID- 29617990 TI - Structure and dynamics of microbiomes associated with the marine sponge Tedania sp. during its life cycle. AB - Tedania sp. is a dominant sponge that is ubiquitous along the southeast coast of China. High-throughput sequencing and transmission electron microscopy were used to describe a detailed profile of sponge-associated microbiomes at seven life stages: adult, embryo-containing spawning adult, embryo, pre-competent larva at 2 h and 4 h, competent larva at 8 h and post-larva within 1-2h after settlement, as well as the surrounding seawater. Among a total of 15098 operational taxonomic units (OTUs), 13 were present exclusively in all stages of the sponge life cycle and could thus be identified as sponge-specific bacteria. Many OTUs were shared between the sponge and seawater, though abundance differed. The relative abundance of beta-Proteobacteria associated with sponges was much higher than found in seawater. The microbiomes from each life stage also exhibited a characteristic distribution. Synechococcales dominated in adults, and Enterobacteriaceae was prominent in larvae. The competent larva was notable, with sharp increases in the total OTUs, diversity indices, richness estimates and unique OTUs. Some bacterial groups that were rare in other sponge stages and seawater, such as Clostridia (5.6%), were markedly more abundant in competent larvae. In conclusion, this work greatly advances our understanding of the dynamics and persistence of the sponge-microbe association. PMID- 29617991 TI - Letter responding to Screening for atrial fibrillation: a European Heart Rhythm Association (EHRA) consensus document endorsed by the Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), and Societad Latinoamericana de Estimulation Cardiaca y Electrofisiologia (SOLAECE). PMID- 29617992 TI - Advancing a unified, global effort to address health disadvantages associated with migration, ethnicity and race. PMID- 29617993 TI - Navigation of lead extraction-is it possible? Impact of preprocedural electrocardiogram-triggered computed tomography on navigation of lead extraction. AB - OBJECTIVES: As the number of transvenous lead extractions continues to increase, preprocedural protocols for this procedure must be assessed. The objective of this study was to determine whether an electrocardiogram (ECG)-triggered computed tomography (Et-CT) with three-dimensional (3D) reconstructions could aid lead extractors in choosing the optimal tools to improve procedural success and avoid complications. METHODS: In this study, 31 patients scheduled for transvenous lead extraction underwent a preprocedural Et-CT between January 2016 and May 2017. Both 3D-reconstructions and the two-dimensional files were reviewed for possible lead adhesions, calcifications, migrations or perforations. RESULTS: Mean age was 46.7 +/- 14.0 years. Seventy-one percent of patients were men, and 29.0% had undergone prior cardiac surgery. Indications for extraction included infection (n = 18, 58.1%), lead dysfunction (n = 8, 25.8%), upgrade (n = 3, 9.7%), severe tricuspid regurgitation (n = 1, 3.2%) and superior vena cava occlusion (n = 1, 3.2%). Eighteen patients had an implantable cardioverter defibrillator (58.1%). Sixty-eight of 70 targeted leads were extracted with a mean of 2.2 leads per patient and an average lead age of 109.3 +/- 58.7 months. Et-CT files supported transvenous lead extraction by revealing possible adhesions in 16 patients, 5 perforations and 2 venous occlusions. Lead extraction was performed using the excimer laser, mechanical tools and femoral snares. Complete procedural success was achieved in 93.5% (n = 29) of cases. Clinical success was 100%, and intraoperative mortality was 0%. CONCLUSIONS: A preprocedural Et-CT with 3D reconstructions can help to visualize lead alignment and identify abnormalities that may foreshadow procedural difficulties. A preprocedural Et-CT may therefore aid lead extractors in choosing the optimal extraction tool and strategy. PMID- 29617994 TI - Reply to Nardi et al. PMID- 29617995 TI - Unravelling the socioeconomic gradient in the incidence of catastrophic health care expenditure: a comment. PMID- 29617996 TI - Response to a comment on 'Unravelling the socioeconomic gradient in the incidence of catastrophic health care expenditure'. PMID- 29617997 TI - Effect of ethanol and butanol on autotrophic growth of model homoacetogens. AB - Research efforts aimed at increasing ethanol and butanol productivity from syngas are currently gaining attention. For most model carboxydotrophic bacteria, production rates, yields and maximum product titres have been studied in detail, but little is known on alcohol toxicity in these bacteria. The aim of this work was to investigate the inhibitory effects of ethanol and butanol on the growth of Clostridium ljungdahlii PETC, C. carboxidivorans P7, and 'Butyribacterium methylotrophicum DSM3468'. Experiments to determine inhibitory effects due to product accumulation were carried out using a synthetic mixture of CO:CO2:H2 as a substrate. These conditions were chosen to mimic gaseous effluents of biomass and waste gasification plants. Inhibition effects were recorded as changes in growth parameters. No significant inhibition was observed for ethanol at concentrations below 15 g/L. The three species exhibited higher sensitivity to butanol. Half inhibition constants for butanol could be estimated for P7 (IC50 = 4.12 g/L), DSM3468 (IC50 = 1.79 g/L), and PETC (IC50 = 9.75 g/L). In conclusion, at least for the tested strains, alcohol toxicity is not an immediate handicap for increasing alcohol production of the tested homoacetogenic strains. PMID- 29617998 TI - Genome-wide association analyses identify new loci influencing intraocular pressure. AB - Elevated intraocular pressure (IOP) is a significant risk factor for glaucoma, the leading cause of irreversible blindness worldwide. While previous studies have identified numerous genetic variants associated with IOP, these loci only explain a fraction of IOP heritability. Recently established of biobank repositories have resulted in large amounts of data, enabling the identification of the remaining heritability for complex traits. Here, we describe the largest genome-wide association study of IOP to date using participants of European ancestry from the UK Biobank. We identified 671 directly genotyped variants that are significantly associated with IOP (P < 5 * 10-8). In addition to 103 novel loci, the top ranked novel IOP genes are LMX1B, NR1H3, MADD and SEPT9. We replicated these findings in an external population and examined the pleiotropic nature of these loci. These discoveries not only further our understanding of the genetic architecture of IOP, but also shed new light on the biological processes underlying glaucoma. PMID- 29617999 TI - The association between diabetes and depressive symptoms varies by quality of diabetes care across Europe. AB - Background: Depressive symptoms are more common in adults with diabetes and may arise from the physical and psychosocial burden of disease. Better quality of diabetes care may be associated with a reduced disease burden and fewer depressive symptoms. Methods: This cross-sectional study included 34 420 participants from 19 countries in the European Social Survey Round 7 (2014-2015). Countries were grouped into quartiles based on their quality of diabetes care as measured in the Euro Diabetes Index 2014. Individual-level depressive symptoms were measured using the 8-item Center for Epidemiologic Studies-Depression Scale. Negative binomial regression was used to compare the number of depressive symptoms between adults with and without diabetes in each quartile of diabetes care quality. Analyses included adjustment for covariates and survey weights. Results: In countries with the highest quality of diabetes care, having diabetes was associated with only a 3% relative increase in depressive symptoms (95% CI 1.00-1.05). In countries in the second, third and fourth (lowest) quartiles of diabetes care quality, having diabetes was associated with a 13% (95% CI 1.08 1.17), 13% (1.08-1.19) and 22% (1.14-1.31) relative increase in depressive symptoms, respectively. Conclusion: The association between diabetes and depressive symptoms appears stronger in European countries with lower quality of diabetes care. Potential pathways for this association include the financial aspects of diabetes care, access to services and differential exposure to the social determinants of heath. Further research is needed to unpack these mechanisms and improve the quality of life of people with diabetes across Europe. PMID- 29618000 TI - Effect of the clarification pH of sorghum juice on the composition of essential nutrients for fermentation. AB - The growing demand to replace fossil fuels with renewable alternatives has generated an urgent and imminent global need to find new non-fossil sources. Sweet sorghum is widely recognized as a highly promising biomass energy crop with the particular potential to complement sugarcane for ethanol production. Our aim in this study was to evaluate the influence of pH during the clarification process on the composition of essential nutrients in the sorghum juice and observe how this affects the efficiency of the ethanol fermentation process. We found that a higher pH directly affected residual concentrations of key nutrients (P, Ca, Zn and Mn) and consequently the efficiency of ethanol fermentation. In conclusion, we recommend a clarification procedure at pH 6-6.5 in order not to significantly affect nutritional parameters important for the yeast fermentation process. PMID- 29618001 TI - Body Fluid Processing Workspace Quality Improvement Initiative in a High-Volume Reference Laboratory. AB - Objectives: In a clinical laboratory, the design of the workspace directs the workflow and significantly affects the productivity of clinical laboratory scientists (CLS). With the chronic shortage of CLS, a well-designed workspace is essential to take full advantage of available staff, especially in high-volume laboratories. Methods: Through the use of quality improvement tools, a manual body fluid testing workspace was redesigned to address weaknesses in the layout that led to excessive physical steps taken by staff. Results: System engineering tools such as a fishbone diagram, spaghetti diagrams, Plan-Do-Study-Act cycles, and a counterbalance measure were all used in a CLS-led quality improvement initiative to redesign a workspace in the manual body fluid processing area of a clinical laboratory at Mayo Clinic. Conclusions: After the redesign, physical steps taken and time to process body fluids were reduced by an average of 40% and 32%, respectively, demonstrating the utility of quality improvement tools in clinical laboratory settings. PMID- 29618002 TI - Response to authors re commentary: Renewed controversy over cardiovascular risk with non-steroidal anti-inflammatory drugs. PMID- 29618003 TI - Cohort Profile: The Pregnancy and Neonatal Diabetes Outcomes in Remote Australia (PANDORA) Study. PMID- 29618004 TI - The antidepressant tianeptine reverts synaptic AMPA receptor defects caused by deficiency of CDKL5. AB - Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5) gene cause a complex neurological disorder, characterized by infantile seizures, impairment of cognitive and motor skills and autistic features. Loss of Cdkl5 in mice affects dendritic spine maturation and dynamics but the underlying molecular mechanisms are still far from fully understood. Here we show that Cdkl5 deficiency in primary hippocampal neurons leads to deranged expression of the alpha-amino-3 hydroxy-5-methyl-4-iso-xazole propionic acid receptors (AMPA-R). In particular, a dramatic reduction of expression of the GluA2 subunit occurs concomitantly with its hyper-phosphorylation on Serine 880 and increased ubiquitination. Consequently, Cdkl5 silencing skews the composition of membrane-inserted AMPA-Rs towards the GluA2-lacking calcium-permeable form. Such derangement is likely to contribute, at least in part, to the altered synaptic functions and cognitive impairment linked to loss of Cdkl5. Importantly, we find that tianeptine, a cognitive enhancer and antidepressant drug, known to recruit and stabilise AMPA Rs at the synaptic sites, can normalise the expression of membrane inserted AMPA Rs as well as the number of PSD-95 clusters, suggesting its therapeutic potential for patients with mutations in CDKL5. PMID- 29618005 TI - The sub-coronary Ross-Konno procedure in children: a word of caution for use in infants. PMID- 29618006 TI - Dysfunction of Serotonergic and Dopaminergic Neuronal Systems in the Antidepressant-Resistant Impairment of Social Behaviors Induced by Social Defeat Stress Exposure as Juveniles. AB - Background: Extensive studies have been performed on the role of monoaminergic neuronal systems in rodents exposed to social defeat stress as adults. In the present study, we investigated the role of monoaminergic neuronal systems in the impairment of social behaviors induced by social defeat stress exposure as juveniles. Methods: Juvenile, male C57BL/6J mice were exposed to social defeat stress for 10 consecutive days. From 1 day after the last stress exposure, desipramine, sertraline, and aripiprazole were administered for 15 days. Social behaviors were assessed at 1 and 15 days after the last stress exposure. Monoamine turnover was determined in specific regions of the brain in the mice exposed to the stress. Results: Stress exposure as juveniles induced the impairment of social behaviors in adolescent mice. In mice that showed impairment of social behaviors, turnover of serotonin and dopamine, but not noradrenaline, was decreased in specific brain regions. Acute and repeated administration of desipramine, sertraline, and aripiprazole failed to attenuate the impairment of social behaviors, whereas repeated administration of a combination of sertraline and aripiprazole showed additive attenuating effects. Conclusions: These findings suggest that social defeat stress exposure as juveniles induces the treatment resistant impairment of social behaviors in adolescents through dysfunction in the serotonergic and dopaminergic neuronal systems. The combination of sertraline and aripiprazole may be used as a new treatment strategy for treatment-resistant stress-related psychiatric disorders in adolescents with adverse juvenile experiences. PMID- 29618007 TI - Subphenotype meta-analysis of testicular cancer genome-wide association study data suggests a role for RBFOX family genes in cryptorchidism susceptibility. AB - STUDY QUESTION: Can subphenotype analysis of genome-wide association study (GWAS) data from subjects with testicular germ cell tumor (TGCT) provide insight into cryptorchidism (undescended testis, UDT) susceptibility? SUMMARY ANSWER: Suggestive intragenic GWAS signals common to UDT, TGCT case-case and TGCT case control analyses occur in genes encoding RBFOX RNA-binding proteins (RBPs) and their neurodevelopmental targets. WHAT IS KNOWN ALREADY: UDT is a strong risk factor for TGCT, but while genetic risk factors for TGCT are well-known, genetic susceptibility to UDT is poorly understood and appears to be more complex. STUDY DESIGN, SIZE, DURATION: We performed a secondary subphenotype analysis of existing GWAS data from the Testicular Cancer Consortium (TECAC) and compared these results with our previously published UDT GWAS data, and with data previously acquired from studies of the fetal rat gubernaculum. PARTICIPANTS/MATERIALS, SETTING, METHODS: Studies from the National Cancer Institute (NCI), United Kingdom (UK) and University of Pennsylvania (Penn) that enrolled white subjects were the source of the TGCT GWAS data. We completed UDT subphenotype case-case (TGCT/UDT vs TGCT/non-UDT) and case-control (TGCT/UDT vs control), collectively referred to as 'TECAC' analyses, followed by a meta analysis comprising 129 TGCT/UDT cases, 1771 TGCT/non-UDT cases, and 3967 unaffected controls. We reanalyzed our UDT GWAS results comprising 844 cases and 2718 controls by mapping suggestive UDT and TECAC signals (defined as P < 0.001) to genes using Ingenuity Pathway Analysis (IPA(r)). We compared associated pathways and enriched gene categories common to all analyses after Benjamini Hochberg multiple testing correction, and analyzed transcript levels and protein expression using qRT-PCR and rat fetal gubernaculum confocal imaging, respectively. MAIN RESULTS AND THE ROLE OF CHANCE: We found suggestive signals within 19 genes common to all three analyses, including RBFOX1 and RBFOX3, neurodevelopmental paralogs that encode RBPs targeting (U)GCATG-containing transcripts. Ten of the 19 genes participate in neurodevelopment and/or contribute to risk of neurodevelopmental disorders. Experimentally predicted RBFOX gene targets were strongly overrepresented among suggestive intragenic signals for the UDT (117 of 628 (19%), P = 3.5 * 10-24), TECAC case-case (129 of 711 (18%), P = 2.5 * 10-27) and TECAC case-control (117 of 679 (17%), P = 2 * 10 21) analyses, and a majority of the genes common to all three analyses (12 of 19 (63%), P = 3 * 10-9) are predicted RBFOX targets. Rbfox1, Rbfox2 and their encoded proteins are expressed in the rat fetal gubernaculum. Predicted RBFOX targets are also enriched among transcripts differentially regulated in the fetal gubernaculum during normal development (P = 3 * 10-31), in response to in vitro hormonal stimulation (P = 5 * 10-45) and in the cryptorchid LE/orl rat (P = 2 * 10-42). LARGE SCALE DATA: GWAS data included in this study are available in the database of Genotypes and Phenotypes (dbGaP accession numbers phs000986.v1.p1 and phs001349.v1p1). LIMITATIONS, REASONS FOR CAUTION: These GWAS data did not reach genome-wide significance for any individual analysis. UDT appears to have a complex etiology that also includes environmental factors, and such complexity may require much larger sample sizes than are currently available. The current methodology may also introduce bias that favors false discovery of larger genes. WIDER IMPLICATIONS OF THE FINDINGS: Common suggestive intragenic GWAS signals suggest that RBFOX paralogs and other neurodevelopmental genes are potential UDT risk candidates, and potential TGCT susceptibility modifiers. Enrichment of predicted RBFOX targets among differentially expressed transcripts in the fetal gubernaculum additionally suggests a role for this RBP family in regulation of testicular descent. As RBFOX proteins regulate alternative splicing of Calca to generate calcitonin gene-related peptide, a protein linked to development and function of the gubernaculum, additional studies that address the role of these proteins in UDT are warranted. STUDY FUNDING/COMPETING INTEREST(S): The Eunice Kennedy Shriver National Institute for Child Health and Human Development (R01HD060769); National Center for Research Resources (P20RR20173), National Institute of General Medical Sciences (P20GM103464), Nemours Biomedical Research, the Testicular Cancer Consortium (U01CA164947), the Intramural Research Program of the NCI, a support services contract HHSN26120130003C with IMS, Inc., the Abramson Cancer Center at Penn, National Cancer Institute (CA114478), the Institute of Cancer Research, UK and the Wellcome Trust Case-Control Consortium (WTCCC) 2. None of the authors reports a conflict of interest. PMID- 29618009 TI - Constructing lightweight and flexible pipelines using Plugin-Based Microbiome Analysis (PluMA). AB - Motivation: Software pipelines have become almost standardized tools for microbiome analysis. Currently many pipelines are available, often sharing some of the same algorithms as stages. This is largely because each pipeline has its own source language and file formats, making it typically more economical to reinvent the wheel than to learn and interface to an existing package. We present Plugin-Based Microbiome Analysis (PluMA), which addresses this problem by providing a lightweight back end that can be infinitely extended using dynamically loaded plugin extensions. These can be written in one of many compiled or scripting languages. With PluMA and its online plugin pool, algorithm designers can easily plug-and-play existing pipeline stages with no knowledge of their underlying implementation, allowing them to efficiently test a new algorithm alongside these stages or combine them in a new and creative way. Results: We demonstrate the usefulness of PluMA through an example pipeline (P M16S) that expands an obesity study involving gut microbiome samples from the mouse, by integrating multiple plugins using a variety of source languages and file formats, and producing new results. Availability and implementation: Links to github repositories for the PluMA source code and P-M16S, in addition to the plugin pool are available from the Bioinformatics Research Group (BioRG) at: http://biorg.cis.fiu.edu/pluma. PMID- 29618008 TI - Variable rescue of microtubule and physiological phenotypes in mdx muscle expressing different miniaturized dystrophins. AB - Delivery of miniaturized dystrophin genes via adeno-associated viral vectors is one leading approach in development to treat Duchenne muscular dystrophy. Here we directly compared the functionality of five mini- and micro-dystrophins via skeletal muscle-specific transgenic expression in dystrophin-deficient mdx mice. We evaluated their ability to rescue defects in the microtubule network, passive stiffness and contractility of skeletal muscle. Transgenic mdx mice expressing the short dystrophin isoform Dp116 served as a negative control. All mini- and micro-dystrophins restored elevated detyrosinated alpha-tubulin and microtubule density of mdx muscle to values not different from C57BL/10, however, only mini dystrophins restored the transverse component of the microtubule lattice back to C57BL/10. Passive stiffness values in mdx muscles expressing mini- or micro dystrophins were not different from C57BL/10. While all mini- and micro dystrophins conferred significant protection from eccentric contraction-induced force loss in vivo and ex vivo compared to mdx, removal of repeats two and three resulted in less protection from force drop caused by eccentric contraction ex vivo. Our data reveal subtle yet significant differences in the relative functionalities for different therapeutic constructs of miniaturized dystrophin in terms of protection from ex vivo eccentric contraction-induced force loss and restoration of an organized microtubule lattice. PMID- 29618010 TI - Hypoglycemic Exposure and Risk of Asymptomatic Hypoglycemia in Type 1 Diabetes Assessed by Continuous Glucose Monitoring. AB - Context: Recurrent hypoglycemia promotes impaired awareness, resulting in an increased risk for asymptomatic hypoglycemia. However, there are no firm data on the frequency of hypoglycemia in daily life needed to initiate this vicious cycle or the role of asymptomatic hypoglycemia. Objective: To explore the association between hypoglycemic exposure and proportion of asymptomatic hypoglycemia and relation to risk for severe hypoglycemia. Design: Prospective observational trial. Setting: Outpatient clinic. Patients: One hundred fifty-three unselected patients with type 1 diabetes mellitus (T1D). Intervention: Six days of blinded continuous glucose monitoring and recording of hypoglycemia symptoms. Main Outcome Measure: Proportion of asymptomatic hypoglycemic events (glucose level <=70 mg/dL). Results: Patients were grouped by the number of hypoglycemic events during the recording period (group 1: one event; group 2: two to three events; group 3: four to six events; group 4: seven or more events), and fractions of asymptomatic events were calculated. Across the four groups, the fraction of asymptomatic hypoglycemia increased: 57% in group 1, 61% in group 2, 65% in group 3, and 80% in group 4 (P < 0.001). Higher fraction of asymptomatic hypoglycemia was positively associated with risk for severe hypoglycemia (incidence rate ratio, 1.3; 95% confidence interval, 1.1 to 1.5; P = 0.003). Group 4 consisted of patients characterized by classic risk factors of severe hypoglycemia (longer duration of diabetes, lower hemoglobin A1c, and more frequent impaired awareness of hypoglycemia). Conclusions: Patients with T1D with hypoglycemic rates corresponding to daily exposure had an increased fraction of asymptomatic events, which was positively associated with risk for severe hypoglycemia; therefore, such patients deserve particular attention in clinical practice. PMID- 29618011 TI - Effects of Diazoxide-Mediated Insulin Suppression on Glucose and Lipid Metabolism in Nondiabetic Obese Men. AB - Context: It has been suggested that stimulation of lipolysis by diazoxide (DZX) mediated insulin suppression may be useful in treating obesity. However, the optimal dose to promote lipolysis without causing hyperglycemia is unknown. Objective: To assess the effects of DZX in nondiabetic obese men on lipid and glucose metabolism. Design: Double-blind, placebo (PL)-controlled, 6-month trial in men with a body mass index of 30 to 37.5 kg/m2 treated with a combination of caloric restriction, a standardized exercise program, and DZX or PL dose escalation. Results: The mean maximal tolerated dose of DZX was 422 +/- 44 mg/d (range, 200 to 700 mg/d). Dose-limiting events were edema (n = 11), hyperglycemia (n = 6), and nausea (n = 2). After dose reduction to a level free of clinical side effects, DZX treatment was associated with a markedly greater decrease in fasting insulin levels than PL (-72.3 +/- 3.5% vs -23.0 +/- 12.6%; P < 0.001) and a significant improvement of blood pressure and plasma lipid levels. The decline in insulin levels occurred at the cost of a small increase in plasma glucose (0.6 +/- 0.2 mmol/L vs -0.1 +/- 0.1 mmol/L; P = 0.04) and hemoglobin A1C (0.2 +/- 0.1% vs 0.0 +/- 0.1%; P = 0.17). Conclusion: In nondiabetic obese men, insulin levels can be reduced up to 70% without major metabolic side effects. The marked intersubject variation in maximal tolerated dose indicates that DZX dose titration needs to be individualized. PMID- 29618012 TI - Dopamine Modulates the Efficiency of Sensory Evidence Accumulation During Perceptual Decision Making. AB - Background: Perceptual decision making is the process through which available sensory information is gathered and processed to guide our choices. However, the neuropsychopharmacological basis of this important cognitive function is largely elusive. Yet, theoretical considerations suggest that the dopaminergic system may play an important role. Methods: In a double-blind, randomized, placebo controlled study design, we examined the effect of methylphenidate in 2 dosages (0.25 mg/kg and 0.5 mg/kg body weight) in separate groups of healthy young adults. We used a moving dots task in which the coherency of the direction of moving dots stimuli was manipulated in 3 levels (5%, 15%, and 35%). Drift diffusion modelling was applied to behavioral data to capture subprocesses of perceptual decision making. Results: The findings show that only the drift rate (v), reflecting the efficiency of sensory evidence accumulation, but not the decision criterion threshold (a) or the duration of nondecisional processes (Ter), is affected by methylphenidate vs placebo administration. Compared with placebo, administering 0.25 mg/kg methylphenidate increased v, but only in the 35% coherence condition. Administering 0.5 mg/kg methylphenidate did not induce modulations. Conclusions: The data suggest that dopamine selectively modulates the efficacy of evidence accumulation during perceptual decision making. This modulation depends on 2 factors: (1) the degree to which the dopaminergic system is modulated using methylphenidate (i.e., methylphenidate dosage) and (2) the signal-to-noise ratio of the visual information. Dopamine affects sensory evidence accumulation only when dopamine concentration is not shifted beyond an optimal level and the incoming information is less noisy. PMID- 29618013 TI - FGF21 Is Associated with Metabolic Effects and Treatment Response in Depressed Bipolar II Disorder Patients Treated with Valproate. AB - Background: Patients with bipolar disorder are at high risk of metabolic disturbance after mood stabilizer treatment. However, the mediators linking the two conditions remain unknown. In this study, we investigated whether fibroblast growth factor-21 (FGF21) was associated with metabolic effects and treatment response in depressed bipolar disorder patients. Methods: We recruited 78 community-dwelling controls and 137 bipolar disorder patients; the latter were interviewed using the Chinese Version of the Modified Schedule of Affective Disorder and Schizophrenia-Life Time. Upon study entry, the bipolar disorder patients were all in a major depressive status, with 17-item Hamilton Depression Rating Scale (HDRS) scores >15. They received valproate (500-1000 mg daily) for 12 weeks, and fluoxetine 20 mg daily was permitted to treat depressive symptoms. Fasting plasma level of FGF21, lipid profiles, and body weight were collected at baseline and after 12 weeks of treatment. Results: At baseline, the demographic characteristics, FGF21 level, and metabolic indices did not differ significantly between the controls and bipolar disorder patients. After 12 weeks of treatment, the FGF21 level (167.7+/-122.0 to 207.1+/-162.3 pg/mL, P=.001), body weight and waist circumference had increased significantly (P<.001 and P=.028, respectively). Moreover, the change in FGF21 level was significantly correlated with the changes in HDRS score (r=0.393, P=.002), total cholesterol (r=-0.344, P=.008), and low-density lipoprotein (r=-0.347, P=.007). Conclusions: The central and peripheral mediating effects of FGF21 on bipolar disorder depression treatment might be opposite. High peripheral FGF21 levels might link regulation of metabolic effect and resistance to treatment in bipolar disorder. PMID- 29618014 TI - Glutathione, the Major Redox Regulator, in the Prefrontal Cortex of Individuals at Clinical High Risk for Psychosis. AB - Introduction: Oxidative stress and glutathione dysregulation have been implicated in the etiology of schizophrenia. To date, most in vivo studies have investigated alterations in cerebral glutathione levels in patients in which the disorder is already established; however, whether oxidative stress actually predates the onset of psychosis remains unknown. In the current study, we investigated cerebral glutathione levels of antipsychotic-naive individuals at clinical high risk for psychosis. As exploratory analyses, we also investigated the associations between cerebral glutathione levels and peripheral glutathione peroxidase activity and clinical and neuropsychological measures. Methods: Glutathione levels were measured in the medial prefrontal cortex of 30 clinical high risk (n=26 antipsychotic naive) and 26 healthy volunteers using 3T proton magnetic resonance spectroscopy. Each participant was assessed for glutathione peroxidase activity in plasma and genotyped for the glutamate cysteine ligase catalytic subunit polymorphism. Results: No significant differences were observed in glutathione levels between clinical high risk and healthy volunteers in the medial prefrontal cortex (F(1,54)=0.001, P =0.98). There were no significant correlations between cerebral glutathione levels and clinical and neuropsychological measures. Similarly, no significant differences were found in peripheral glutathione peroxidase activity between clinical high risk and healthy volunteers (F(1,37)=0.15, P =0.70). However, in clinical high risk, we observed a significant effect of lifetime history of cannabis use on glutathione peroxidase activity (F(1,23)=7.41, P =0.01). Discussion: The lack of significant differences between antipsychotic naive clinical high risk and healthy volunteers suggests that alterations in glutathione levels in medial prefrontal cortex are not present in the clinical high risk state. PMID- 29618015 TI - High Fear of Disease Occurrence Is Associated With Low Quality of Life in Patients With Multiple Endocrine Neoplasia Type 1: Results From the Dutch MEN1 Study Group. AB - Objective: Multiple endocrine neoplasia type 1 (MEN1) is a hereditary disease characterized by a high risk of developing primary hyperparathyroidism, duodenopancreatic neuroendocrine tumors, and pituitary tumors (PITs). It is unclear if having MEN1 leads to psychological distress because of fear of disease occurrence (FDO), thereby potentially affecting quality of life. Design: A cross sectional study was performed using the Dutch MEN1 cohort. All patients received the Cancer Worry Scale (a score >=14 reflects high FDO), the Medical Outcomes Study 36-item Short-Form Health Survey (SF-36), and questions on sociodemographic and medical history. Results: A total of 227 of 285 (80%) eligible patients with MEN1 completed the questionnaire. The mean (+/- standard deviation) age was 47 +/ 15 years. Overall, patients experienced an FDO of 15.1 +/- 4.7, with 58% of patients having a score >=14. This is higher than reported in previous studies assessing fear of cancer recurrence in different cancer populations (31% to 52%). Adjusted for age and sex, the FDO score was negatively associated with almost all SF-36 subscales. In multivariable analysis, the diagnosis of a PIT, a pancreatic neuroendocrine tumor, and not being employed were associated with FDO (P < 0.05). Patients had higher FDO scores for their family members than for themselves. Conclusion: The majority of patients with MEN1 have FDO for themselves and even more for their relatives. This psychological distress is associated with a lower health-related quality of life. Therefore, in the medical care for MEN1, emphasis should also be placed on FDO and quality of life. PMID- 29618017 TI - Resuscitation skills after Helping Babies Breathe training: a comparison of varying practice frequency and impact on retention of skills in different types of providers. AB - Background: Helping Babies Breathe (HBB), a basic neonatal resuscitation curriculum, improves early neonatal mortality in low-resource settings. Our goal was to determine retention of resuscitation skills by different cadres of providers using the approved HBB Spanish translation in a rural clinic and community hospital in Honduras. Methods: Twelve clinic and 37 hospital providers were trained in 1 d HBB workshops and followed from July 2012 to February 2014. Resuscitation skills were evaluated by objective structured clinical evaluations (OSCEs) at regular intervals. Clinic providers practiced monthly, whereas hospital providers were randomized to monthly practice for 6 months vs three consecutive practices at 3, 5 and 6 months. Results: In the rural clinic, follow up OSCE assessment showed rapid loss of skills by 1 month after HBB training. For all providers, repeated monthly testing resulted in improvements and maintenance of OSCE performance. In the community hospital, over all time points, the group with monthly OSCEs had 2.9 greater odds of passing compared with the group who practiced less frequently. Physicians were found to have 4.3 times greater odds of passing compared with nurses. Conclusions: Rapid loss of resuscitation skills occurs after an initial training. Repeated practice leads to retention of skills in all types of providers. Further investigation is warranted to determine the clinical correlation of neonatal outcomes after HBB training. PMID- 29618016 TI - Short-Term Repeatability of Insulin Resistance Indexes in Older Adults: The Atherosclerosis Risk in Communities Study. AB - Context: The homeostatic model assessment of insulin resistance (HOMA-IR) and triglyceride (TG)/high-density lipoprotein cholesterol (HDL-C) ratio (TG/HDL-C) are insulin resistance indexes routinely used in clinical and population-based studies; however, their short-term repeatability is not well characterized. Objective: To quantify the short-term repeatability of insulin resistance indexes and their analytes, consisting of fasting glucose and insulin for HOMA-IR and TG and HDL-C for TG/HDL-C. Design: Prospective cohort study. Participants: A total of 102 adults 68 to 88 years old without diabetes attended an initial examination and repeated examination (mean, 46 days; range, 28 to 102 days). Blood samples were collected, processed, shipped, and assayed following a standardized protocol. Main Outcome Measures: Repeatability was quantified using the intraclass correlation coefficient (ICC) and within-person coefficient of variation (CV). Minimum detectable change (MDC95) and minimum detectable difference with 95% confidence (MDD95) were quantified. Results: For HOMA-IR, insulin, and fasting glucose, the ICCs were 0.70, 0.68, and 0.70, respectively; their respective within-person CVs were 30.4%, 28.8%, and 5.6%. For TG/HDL-C, TG, and HDL-C, the ICCs were 0.80, 0.68, and 0.91, respectively; their respective within-person CVs were 23.0%, 20.6%, and 8.2%. The MDC95 was 2.3 for HOMA-IR and 1.4 for TG/HDL-C. The MDD95 for a sample of n = 100 was 0.8 for HOMA-IR and 0.6 for TG/HDL-C. Conclusions: Short-term repeatability was fair to good for HOMA-IR and excellent for TG/HDL-C according to suggested benchmarks, reflecting the short-term variability of their analytes. These measurement properties can inform the use of these indexes in clinical and population-based studies. PMID- 29618018 TI - Patterns of plant and animal protein intake are strongly associated with cardiovascular mortality: the Adventist Health Study-2 cohort. AB - Background: Current evidence suggests that plant and animal proteins are intimately associated with specific large nutrient clusters that may explain part of their complex relation with cardiovascular health. We aimed at evaluating the association between specific patterns of protein intake with cardiovascular mortality. Methods: We selected 81 337 men and women from the Adventist Health Study-2. Diet was assessed between 2002 and 2007, by using a validated food frequency questionnaire. Dietary patterns based on the participants' protein consumption were derived by factor analysis. Cox regression analysis was used to estimate multivariate-adjusted hazard ratios (HRs) adjusted for sociodemographic and lifestyle factors and dietary components. Results: There were 2276 cardiovascular deaths during a mean follow-up time of 9.4 years. The HRs for cardiovascular mortality were 1.61 [98.75% confidence interval (CI), 1.12 2.32; P trend < 0.001] for the 'Meat' protein factor and 0.60 (98.75% CI, 0.42 0.86; P trend < 0.001) for the 'Nuts & Seeds' protein factor (highest vs lowest quintile of factor scores). No significant associations were found for the 'Grains', 'Processed Foods' and 'Legumes, Fruits & Vegetables' protein factors. Additional adjustments for the participants' vegetarian dietary pattern and nutrients related to cardiovascular disease outcomes did not change the results. Conclusions: Associations between the 'Meat' and 'Nuts & Seeds' protein factors and cardiovascular outcomes were strong and could not be ascribed to other associated nutrients considered to be important for cardiovascular health. Healthy diets can be advocated based on protein sources, preferring low contributions of protein from meat and higher intakes of plant protein from nuts and seeds. PMID- 29618019 TI - Differential Expression of Synapsin I and II upon Treatment by Lithium and Valproic Acid in Various Brain Regions. AB - Introduction: Due to the heterogeneity of psychiatric illnesses and overlapping mechanisms, patients with psychosis are differentially responsive to pharmaceutical drugs. In addition to having therapeutic effects for schizophrenia and bipolar disorder, antipsychotics and mood stabilizers have many clinical applications and are used unconventionally due to their direct and indirect effects on neurotransmitters. Synapsins, a family of neuronal phosphoproteins, play a key regulatory role in neurotransmitter release at synapses. In this study, we investigated the effects of mood stabilizers, lithium, and valproic acid on synapsin gene expression in the rat brain. Methods: Intraperitoneal injections of saline, lithium, and valproic acid were administered to male Sprague Dawley rats twice daily for 14 d, corresponding to their treatment group. Following decapitation and brain tissue isolation, mRNA was extracted from various brain regions including the hippocampus, striatum, prefrontal cortex, and frontal cortex. Results: Biochemical analysis revealed that lithium significantly increased gene expression of synapsin I in the striatum, synapsin IIa in the hippocampus and prefrontal cortex, and synapsin IIb in the hippocampus and striatum. Valproic acid significantly increased synapsin IIa in the hippocampus and prefrontal cortex, as well as synapsin IIb in the hippocampus and striatum. Conclusion: These significant changes in synapsin I and II expression may implicate a common transcription factor, early growth response 1, in its mechanistic pathway. Overall, these results elucidate mechanisms through which lithium and valproic acid act on downstream targets compared with antipsychotics and provide deeper insight on the involvement of synaptic proteins in treating neuropsychiatric illnesses. PMID- 29618021 TI - Persistence of Diabetes and Hypertension After Multimodal Treatment of Acromegaly. AB - Context: Diabetes and hypertension are frequent comorbidities of acromegaly. Objective: To analyze the course of diabetes and hypertension at diagnosis and after multimodal therapy in a large cohort of patients with acromegaly. Design and Setting: Retrospective study at a tertiary care center. Patients and Methods: A total of 522 patients with acromegaly treated according to a preestablished protocol. Main Outcome Measures: Prevalence of diabetes and hypertension and its relationship with biochemical indices of acromegalic control. Results: The cohort was stratified according to disease activity upon last visit to clinic: (1) surgical remission (n = 122), (2) pharmacologically controlled (n = 92), (3) active disease (n = 148), (4) insulinlike growth factor (IGF)-1 discordance (n = 64), and (5) growth hormone (GH) discordance (n = 96). The prevalence of diabetes and hypertension at diagnosis was 30% and 37%, respectively, and did not change upon the last visit (30.6% and 38%). Both comorbidities were more prevalent at diagnosis and on the last visit than in the general population. Diabetes was less prevalent on the last visit in patients who achieved surgical remission than in those who persisted with active disease (25% vs 40%, P = 0.01). Upon multivariate analysis, diabetes was associated with an IGF-1 at diagnosis >2* upper limit of normal, with the persistence of active acromegaly, the presence of hypertension upon the last visit, with the presence of a macroadenoma, and with female sex. Conclusion: Our findings underscore the importance of an integral approach when managing these patients, focusing not only on the control of GH and IGF-1 levels but also on the timely diagnosis and the specific treatment of each comorbidity. PMID- 29618020 TI - Cumulative Burden of Depression and All-Cause Mortality in Women Living With Human Immunodeficiency Virus. AB - Background: Research linking depression to mortality among people living with human immunodeficiency virus (PLWH) has largely focused on binary "always vs never" characterizations of depression. However, depression is chronic and is likely to have cumulative effects on mortality over time. Quantifying depression as a cumulative exposure may provide a better indication of the clinical benefit of enhanced depression treatment protocols delivered in HIV care settings. Methods: Women living with HIV (WLWH), naive to antiretroviral therapy, from the Women's Interagency HIV Study were followed from their first visit in or after 1998 for up to 10 semiannual visits (5 years). Depressive symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D) scale. An area under-the-curve approach was used to translate CES-D scores into a time-updated measure of cumulative days with depression (CDWD). We estimated the effect of CDWD on all-cause mortality using marginal structural Cox proportional hazards models. Results: Overall, 818 women contributed 3292 woman-years over a median of 4.8 years of follow-up, during which the median (interquartile range) CDWD was 366 (97-853). Ninety-four women died during follow-up (2.9 deaths/100 woman years). A dose-response relationship was observed between CDWD and mortality. Each additional 365 days spent with depression increased mortality risk by 72% (hazard ratio, 1.72; 95% confidence interval, 1.34-2.20). Conclusions: In this sample of WLWH, increased CDWD elevated mortality rates in a dose-response fashion. More frequent monitoring and enhanced depression treatment protocols designed to reduce CDWD may interrupt the accumulation of mortality risk among WLWH. PMID- 29618022 TI - Methyl-isoeugenol, a Highly Attractive Male Lure for the Cucurbit Flower Pest Zeugodacus diversus (Coquillett) (syn. Bactrocera diversa) (Diptera: Tephritidae: Dacinae). AB - Effective male fruit fly attractants, such as cue lure (CL) and methyl eugenol (ME), are important in the monitoring and management of pest species through lure and kill techniques of trapping and male annihilation. However, some species are only weakly responsive to these lures, making their detection and control difficult. Zeugodacus diversus (Coquillett), a pest of cucurbit flowers in Asia, is weakly attracted to ME. Recently in Australia and Papua New Guinea, the eugenol analogues isoeugenol, methyl-isoeugenol, and dihydroeugenol were found to be effective attractants for species with a weak response to ME and CL, as well as several nonresponsive species. Additionally, studies from the early 1900s indicated that Z. diversus was attracted to isoeugenol. To determine if these eugenol analogues may be more effective attractants for Z. diversus, we field tested them in Bangladesh in comparison to ME, as well as CL and zingerone. Z. diversus was significantly more attracted to all three eugenol analogues than ME, with it most attracted to methyl-isoeugenol. Its attraction to methyl-isoeugenol was 49 times greater than its attraction to ME (respective means 23.58 flies/trap/day (FTD) and 0.48 FTD). Z. diversus was also consistently trapped at methyl-isoeugenol at all trap clearances including when populations were low, whereas it was only trapped at ME at 6 out of the 13 clearances. This study demonstrates that methyl-isoeugenol is a highly attractive lure for Z. diversus and would be a valuable inclusion as an attractant in monitoring and male annihilation programs. PMID- 29618023 TI - Dynamic Modeling of Crimean Congo Hemorrhagic Fever Virus (CCHFV) Spread to Test Control Strategies. AB - Crimean Congo hemorrhagic fever is a zoonotic disease which has emerged or re emerged recently in Eastern Europe and Turkey. The causative agent is a virus, mainly transmitted by ticks of the species Hyalomma marginatum (Koch, 1844, Ixodida, Amblyommidae). To test potential scenarios for the control of pathogen spread, a dynamic mechanistic model has been developed that takes into account the major processes involved in tick population dynamics and pathogen spread. The tick population dynamics model represents both abiotic (meteorological variables) and biotic (hare and cattle densities) factors in the determination of processes (development, host finding, and mortality). The infection model consists of an SIRS model for the host part whereas a lifelong infectiousness was considered for ticks. The model was first applied to a zone in Central Anatolia (Turkey). Simulated dynamics represent the average reported level of infection in vectors and hosts. A sensitivity analysis to parameter value has been carried out and highlighted the role of transstadial transmission as well as acquisition of the pathogen by immature stages. Applying the model to different sites of Turkey shows different patterns in the dynamics of acarological risk (number of infectious questing adults). This model was thereafter used to test control strategies. Simulation results indicate that acaricide treatments and decrease in hare density could have valuable effects when combined, either on the acarological risk or on the prevalence in cattle. The kind of model we have developed provides insight into the ability of different strategies to prevent and control disease spread. PMID- 29618025 TI - Erratum to "Comparative Oviposition Site Selection in Containers by Aedes aegypti and Aedes albopictus (Diptera: Culicidae) from Florida". PMID- 29618024 TI - A novel long non-coding RNA Myolinc regulates myogenesis through TDP-43 and Filip1. AB - Myogenesis is a complex process required for skeletal muscle formation during embryonic development and for regeneration and growth of myofibers in adults. Accumulating evidence suggests that long non-coding RNAs (lncRNAs) play key roles in regulating cell fate decision and function in various tissues. However, the role of lncRNAs in the regulation of myogenesis remains poorly understood. In this study, we identified a novel muscle-enriched lncRNA called 'Myolinc (AK142388)', which we functionally characterized in the C2C12 myoblast cell line. Myolinc is predominately localized in the nucleus, and its levels increase upon induction of the differentiation. Knockdown of Myolinc impairs the expression of myogenic regulatory factors and formation of multi-nucleated myotubes in cultured myoblasts. Myolinc also regulates the expression of Filip1 in a cis-manner. Similar to Myolinc, knockdown of Filip1 inhibits myogenic differentiation. Furthermore, Myolinc binds to TAR DNA-binding protein 43 (TDP-43), a DNA/RNA binding protein that regulates the expression of muscle genes (e.g. Acta1 and MyoD). Knockdown of TDP-43 inhibits myogenic differentiation. We also show that Myolinc-TDP-43 interaction is essential for the binding of TDP-43 to the promoter regions of muscle marker genes. Finally, we show that silencing of Myolinc inhibits skeletal muscle regeneration in adult mice. Altogether, our study identifies a novel lncRNA that controls key regulatory networks of myogenesis. PMID- 29618026 TI - Nitric Oxide Fumigation for Control of Spotted Wing Drosophila (Diptera: Drosophilidae) in Strawberries. AB - Nitric oxide (NO) fumigation was conducted to determine the efficacy of controlling spotted wing drosophila (SWD), Drosophila suzukii Matsumura (Diptera: Drosophilidae), in strawberries and the effects on postharvest quality of strawberries under ultralow oxygen conditions at 2 degrees C. Eight-hour fumigations with 1.0 and 3.0% NO were tested against different life stages of the insect to determine an effective treatment, and a 16-h fumigation was tested to determine the impact on strawberry quality. Complete control of eggs and larvae in strawberries was achieved in an 8-h fumigation with 3.0% NO, and the treatment achieved 98.8% mortality of pupae. The first and second instars were more susceptible to NO and were completely controlled with 1.0% NO fumigation. The 16 h fumigation treatment with 3.0% NO had no negative impact on strawberry quality as there were no significant differences from the control in berry damage score. The NO fumigation, however, significantly reduced mold 2 wk after fumigation, indicating that NO fumigation had potential to preserve strawberry quality. The results of this study demonstrated that NO fumigation is effective for control of SWD and safe to strawberries, and therefore, NO fumigation has potential to control SWD on harvested strawberries. PMID- 29618027 TI - Continuous Glucose Monitoring Efficacy in Routine Use. PMID- 29618028 TI - Hepatic Production of Fibroblast Growth Factor 23 in Autosomal Dominant Polycystic Kidney Disease. AB - Context: The bone-derived hormone fibroblast growth factor (FGF) 23 controls phosphate homeostasis and urinary phosphate excretion. FGF23 plasma levels increase in the early stage of renal insufficiency to prevent hyperphosphatemia. Recent evidence suggests that this increase has effects on cardiac and immune cells that compromise patients' health. Patients with autosomal dominant polycystic kidney disease (ADPKD) have been reported to have higher FGF23 concentrations than other patients with similar renal function. The significance of this finding has remained unknown. Methods and Results: Analyzing the FGF23 plasma levels in 434 patients with ADPKD and 355 control subjects with a measured glomerular filtration rate (mGFR) between 60 and 120 mL/min per 1.73 m2, we confirmed that patients with ADPKD had higher FGF23 plasma concentrations than controls. Remarkably, this difference did not translate into renal phosphate leakage. Using different assays for FGF23, we found that this discrepancy was explained by a predominant increase in the cleaved C-terminal fragment of FGF23, which lacks phosphaturic activity. We found that FGF23 plasma concentration independently correlated with the severity of cystic liver disease in ADPKD. We observed that, in contrast to control liver tissues, the cystic liver from patients with ADPKD markedly expressed FGF23 messenger RNA and protein. In line with this finding, the surgical reduction of polycystic liver mass was associated with a decrease in FGF23 plasma levels independently of any modification in mGFR, phosphate, or iron status. Conclusion: Our findings demonstrate that severely polycystic livers produce FGF23 and increase levels of circulating FGF23 in patients with ADPKD. PMID- 29618030 TI - Response to A. Matikas et al. PMID- 29618031 TI - Prolonged endogenous fibrinolysis predicts reduced survival after acute coronary syndromes. PMID- 29618029 TI - The role of FREM2 and FRAS1 in the development of congenital diaphragmatic hernia. AB - Congenital diaphragmatic hernia (CDH) has been reported twice in individuals with a clinical diagnosis of Fraser syndrome, a genetic disorder that can be caused by recessive mutations affecting FREM2 and FRAS1. In the extracellular matrix, FREM2 and FRAS1 form a self-stabilizing complex with FREM1, a protein whose deficiency causes sac CDH in humans and mice. By sequencing FREM2 and FRAS1 in a CDH cohort, and searching online databases, we identified five individuals who carried recessive or double heterozygous, putatively deleterious variants in these genes which may represent susceptibility alleles. Three of these alleles were significantly enriched in our CDH cohort compared with ethnically matched controls. We subsequently demonstrated that 8% of Frem2ne/ne and 1% of Fras1Q1263*/Q1263* mice develop the same type of anterior sac CDH seen in FREM1 deficient mice. We went on to show that development of sac hernias in FREM1 deficient mice is preceded by failure of anterior mesothelial fold progression resulting in the persistence of an amuscular, poorly vascularized anterior diaphragm that is abnormally adherent to the underlying liver. Herniation occurs in the perinatal period when the expanding liver protrudes through this amuscular region of the anterior diaphragm that is juxtaposed to areas of muscular diaphragm. Based on these data, we conclude that deficiency of FREM2, and possibly FRAS1, are associated with an increased risk of developing CDH and that loss of the FREM1/FREM2/FRAS1 complex, or its function, leads to anterior sac CDH development through its effects on mesothelial fold progression. PMID- 29618032 TI - Nehal N. Mehta MD MSCE. PMID- 29618033 TI - Petr Widimsky MD DrSc FESC. PMID- 29618034 TI - The value of Guidelines in everyday clinical practice. PMID- 29618035 TI - Rapidly getting resuscitation skills to the patient with out-of-hospital cardiac arrest. PMID- 29618037 TI - The Need for Systematic Reviews in Oncology. PMID- 29618036 TI - Quantification of aortic stiffness and wall stress in healthy volunteers and abdominal aortic aneurysm patients using time-resolved 3D ultrasound: a comparison study. AB - Aims: Using non-invasive 3D ultrasound, peak wall stress (PWS) and aortic stiffness can be evaluated, which may provide additional criteria in abdominal aortic aneurysm (AAA) risk assessment. In this study, these measures were determined in both young and age-matched individuals, and AAA patients while its relation to age, maximum diameter, and growth was assessed statistically. Methods and results: Time-resolved 3D-US data were acquired for 30 volunteers and 65 AAA patients. The aortic geometry was segmented, and tracked over the cardiac cycle using 3D speckle tracking to characterize the wall motion. Wall stress analysis was performed using finite element analysis. Model parameters were optimized until the model output matched the measured 3D displacements. A significant increase in aortic stiffness was measured between the age-matched volunteers [median 0.58, interquartile range (IQR) 0.48-0.71 kPa?m] and the small AAA patients (median 1.84, IQR 1.38-2.46 kPa?m; P < 0.001). In addition, an increase in aortic stiffness was evaluated between the small (30-39 mm) and large (>=50 mm) AAAs (median 2.72, IQR 1.99-3.14 kPa?m; P = 0.01). The 99th percentile wall stress showed a positive correlation with diameter (rho = 0.73, P < 0.001), and significant differences between age-matched volunteers and AAA patients. Conclusion: The AAA pathology causes an early and significant increase in aortic stiffness of the abdominal aorta, even after correcting for the expected effect of ageing and differences in arterial pressure. Moreover, some AAAs revealed relatively high PWS, although the maximum diameter was below the threshold for surgical repair. Using the current method, these measures become available during follow-up, which could improve AAA rupture risk assessment. PMID- 29618038 TI - Healthy dying: time for health promotion to get serious. PMID- 29618039 TI - In vitro synergy with fluconazole plus doxycycline or tigecycline against clinical Candida glabrata isolates. AB - Candida species, traditionally viewed as opportunistic agents, are increasingly seen as a cause of infection in hospitalized patients. Treatment options are limited to a few classes of drugs. Increased resistance, especially by Candida glabrata, is problematic. We investigated the interaction between fluconazole and doxycycline or tigecycline, using clinically unique blood culture C. glabrata isolates. Eighteen isolates were screened using an Etest(r) MIC:MIC synergy method. With the doxycycline plus fluconazole combination, 28% of isolates showed synergy; tigecycline plus fluconazole showed 94% synergy. No antagonism was seen. The mechanisms of these interactions are unclear. Further research is warranted to assess clinical utility. PMID- 29618040 TI - Corrigendum: Is 8% O2 more normoxic than 21% O2 for long-term in vitro cultures of human primary term cytotrophoblasts? PMID- 29618041 TI - Prospective Study of Cancer Genetic Variants: Variation in Rate of Reclassification by Ancestry. AB - Background: In germline genetic testing, variants from understudied ancestries have been disproportionately classified as being of uncertain significance. We hypothesized that the rate of variant reclassification likewise differs by ancestry. Methods: Nonbenign variants in actionable genes were collected from consenting subjects undergoing genetic testing at two Southern California sites from September 1996 through December 2016. Variant reclassifications were recorded as they were received, until February 2017 or reclassification to benign. Excluding duplicate variants (same ancestry, laboratory, classification), generalized linear models for the hereditary breast cancer genes (BRCA1/2) and other variants investigated whether rate of reclassification differed for seven categories of ancestry compared with non-Hispanic European. Models took into account laboratory, year, gene, sex, and current classification (handled as a time-dependent covariate) and were adjusted for multiple hypothesis testing. Results: Among 1483 nonbenign variants, 693 (46.7%) involved BRCA1/2. Overall, 268 (18.1%) variants were reclassified at least once. Few (9.7%) reclassified variants underwent a net upgrade in pathogenicity. For BRCA1/2 variants, reclassification rates varied by ancestry and increased over time, more steeply for ancestries with lower initial rates (African, Ashkenazi, Chinese) than for ancestries whose initial rates were high (Middle Eastern) or similar to non Hispanic European (non-Chinese Asian, Native American, Hispanic). In contrast, reclassification rates of non-BRCA1/2 variants did not vary over time but were elevated for most minority ancestries except non-Chinese Asian and Native American. Conclusions: For nonbenign variants in cancer-related genes, the rates at which reclassifications are issued vary by ancestry in ways that differ between BRCA1/2 and other genes. PMID- 29618042 TI - In vivo prediction of the carcass fatness using live body measurements in Pekin ducks. AB - The purpose of this study was to evaluate the correlation between live body measurements and several fat traits in Pekin ducks, and ultimately to formulate multiple regression equations for the in vivo estimation of the carcass fatness of Pekin ducks. Several traits were measured in a total of 208 Pekin ducks aged 6 wk (107 males and 101 females). All ducks were weighed and measured for a set of body measurements including live body weight, body slope length, breast muscle thickness, skin fat thickness, chest width, keel length, and neck length. The breast muscle thickness and skin fat thickness was measured using B-scan sonography. Carcass information, including eviscerated weight, subcutaneous fat with skin weight, and abdominal fat weight, was collected after slaughter. Our results revealed that sex effects on most traits were significant (P < 0.05), and that the weight of subcutaneous fat with skin was significantly correlated with live body weight (r = 0.57 to 0.71, P < 0.01). Four additional traits of males were closely correlated with the weight of subcutaneous fat with skin, namely breast muscle thickness (r = 0.20, P < 0.01), skin fat thickness (r = 0.43, P < 0.01), chest width (r = 0.24, P < 0.01), and neck length (r = 0.20, P < 0.05). The abdominal fat weight, percentage of fat, and percentage of subcutaneous fat with skin of ducks were significantly correlated with live body weight (r = 0.38 to 0.43, P < 0.01), and skin fat thickness (r = 0.38 to 0.49, P < 0.01). These traits provided the basis for constructing regression equations to predict weight (or percentage) of subcutaneous fat and abdominal fat with high values of coefficients of multiple correlation (R) between the dependent variable and the independent variables. Two equations were verified to be applicable in other duck groups, with high accuracy, as more than 80% of estimated values were within the margin of error (<10%), compared with the actual values. PMID- 29618043 TI - RE: Receptor Conversion in Distant Breast Cancer Metastases: A Systematic Review and Meta-analysis. PMID- 29618044 TI - Analysis of 'sensitive' periods of fetal and child growth. AB - Background: Birth weight and weight gain in infancy and early childhood are commonly studied as risk factors for later cardiometabolic diseases. In this study, we explore methods for quantifying weight gain during different age periods and for comparing the magnitude of the associations with later blood pressure. Methods: Based on data from a birth cohort study nested within a large cluster-randomized trial with repeated measures of weight from birth to 16 years of age, we compared the results of four analytic approaches to assess sensitive periods of growth in relation to blood pressure at age 16 years. Results: Approaches based on z-scores of weight or weight gain velocity (both standardized for age and sex) or on regression-based conditional weight standardized residuals yielded more coherent results than an approach based on absolute weight gain velocity. Weight gain standardized by sex and age was positively associated with blood pressure at 16 years at all postnatal age periods, but the magnitude of association was larger during adolescence (11.5-16 years) than during earlier intervals (0-3 months, 3-12 months, 1-6.5 years or 6.5-11.5 years). Conclusions: Standardization of weight and weight gain by age and sex, or regression-based standardized residuals based on conditional weight, reflects relative gain and thus accounts for the rapid weight gains normally observed in early infancy and puberty. Adolescence appears to be a more sensitive period for relative weight gain effects on later blood pressure than earlier periods, even those of similar duration. PMID- 29618045 TI - The developmental transcriptome atlas of the spoon worm Urechis unicinctus (Echiurida: Annelida). AB - Background: Echiurida is one of the most intriguing major subgroups of annelida because, unlike most other annelids, echiurids lack metameric body segmentation as adults. For this reason, transcriptome analyses from various developmental stages of echiurid species can be of substantial value for understanding precise expression levels and the complex regulatory networks during early and larval development. Results: A total of 914 million raw RNA-Seq reads were produced from 14 developmental stages of Urechis unicinctus and were de novo assembled into contigs spanning 63,928,225 bp with an N50 length of 2700 bp. The resulting comprehensive transcriptome database of the early developmental stages of U. unicinctus consists of 20,305 representative functional protein-coding transcripts. Approximately 66% of unigenes were assigned to superphylum-level taxa, including Lophotrochozoa (40%). The completeness of the transcriptome assembly was assessed using benchmarking universal single-copy orthologs; 75.7% of the single-copy orthologs were presented in our transcriptome database. We observed 3 distinct patterns of global transcriptome profiles from 14 developmental stages and identified 12,705 genes that showed dynamic regulation patterns during the differentiation and maturation of U. unicinctus cells. Conclusions: We present the first large-scale developmental transcriptome dataset of U. unicinctus and provide a general overview of the dynamics of global gene expression changes during its early developmental stages. The analysis of time course gene expression data is a first step toward understanding the complex developmental gene regulatory networks in U. unicinctus and will furnish a valuable resource for analyzing the functions of gene repertoires in various developmental phases. PMID- 29618046 TI - Draft genome assembly of the Bengalese finch, Lonchura striata domestica, a model for motor skill variability and learning. AB - Background: Vocal learning in songbirds has emerged as a powerful model for sensorimotor learning. Neurobehavioral studies of Bengalese finch (Lonchura striata domestica) song, naturally more variable and plastic than songs of other finch species, have demonstrated the importance of behavioral variability for initial learning, maintenance, and plasticity of vocalizations. However, the molecular and genetic underpinnings of this variability and the learning it supports are poorly understood. Findings: To establish a platform for the molecular analysis of behavioral variability and plasticity, we generated an initial draft assembly of the Bengalese finch genome from a single male animal to 151* coverage and an N50 of 3.0 MB. Furthermore, we developed an initial set of gene models using RNA-seq data from 8 samples that comprise liver, muscle, cerebellum, brainstem/midbrain, and forebrain tissue from juvenile and adult Bengalese finches of both sexes. Conclusions: We provide a draft Bengalese finch genome and gene annotation to facilitate the study of the molecular-genetic influences on behavioral variability and the process of vocal learning. These data will directly support many avenues for the identification of genes involved in learning, including differential expression analysis, comparative genomic analysis (through comparison to existing avian genome assemblies), and derivation of genetic maps for linkage analysis. Bengalese finch gene models and sequences will be essential for subsequent manipulation (molecular or genetic) of genes and gene products, enabling novel mechanistic investigations into the role of variability in learned behavior. PMID- 29618047 TI - Single-molecule, full-length transcript sequencing provides insight into the extreme metabolism of the ruby-throated hummingbird Archilochus colubris. AB - Background: Hummingbirds oxidize ingested nectar sugars directly to fuel foraging but cannot sustain this fuel use during fasting periods, such as during the night or during long-distance migratory flights. Instead, fasting hummingbirds switch to oxidizing stored lipids that are derived from ingested sugars. The hummingbird liver plays a key role in moderating energy homeostasis and this remarkable capacity for fuel switching. Additionally, liver is the principle location of de novo lipogenesis, which can occur at exceptionally high rates, such as during premigratory fattening. Yet understanding how this tissue and whole organism moderates energy turnover is hampered by a lack of information regarding how relevant enzymes differ in sequence, expression, and regulation. Findings: We generated a de novo transcriptome of the hummingbird liver using PacBio full length cDNA sequencing (Iso-Seq), yielding 8.6Gb of sequencing data, or 2.6M reads from 4 different size fractions. We analyzed data using the SMRTAnalysis v3.1 Iso-Seq pipeline, then clustered isoforms into gene families to generate de novo gene contigs using Cogent. We performed orthology analysis to identify closely related sequences between our transcriptome and other avian and human gene sets. Finally, we closely examined homology of critical lipid metabolism genes between our transcriptome data and avian and human genomes. Conclusions: We confirmed high levels of sequence divergence within hummingbird lipogenic enzymes, suggesting a high probability of adaptive divergent function in the hepatic lipogenic pathways. Our results leverage cutting-edge technology and a novel bioinformatics pipeline to provide a first direct look at the transcriptome of this incredible organism. PMID- 29618048 TI - Mammalian genomic regulatory regions predicted by utilizing human genomics, transcriptomics, and epigenetics data. AB - Genome sequences for hundreds of mammalian species are available, but an understanding of their genomic regulatory regions, which control gene expression, is only beginning. A comprehensive prediction of potential active regulatory regions is necessary to functionally study the roles of the majority of genomic variants in evolution, domestication, and animal production. We developed a computational method to predict regulatory DNA sequences (promoters, enhancers, and transcription factor binding sites) in production animals (cows and pigs) and extended its broad applicability to other mammals. The method utilizes human regulatory features identified from thousands of tissues, cell lines, and experimental assays to find homologous regions that are conserved in sequences and genome organization and are enriched for regulatory elements in the genome sequences of other mammalian species. Importantly, we developed a filtering strategy, including a machine learning classification method, to utilize a very small number of species-specific experimental datasets available to select for the likely active regulatory regions. The method finds the optimal combination of sensitivity and accuracy to unbiasedly predict regulatory regions in mammalian species. Furthermore, we demonstrated the utility of the predicted regulatory datasets in cattle for prioritizing variants associated with multiple production and climate change adaptation traits and identifying potential genome editing targets. PMID- 29618049 TI - 10KP: A phylodiverse genome sequencing plan. AB - Understanding plant evolution and diversity in a phylogenomic context is an enormous challenge due, in part, to limited availability of genome-scale data across phylodiverse species. The 10KP (10,000 Plants) Genome Sequencing Project will sequence and characterize representative genomes from every major clade of embryophytes, green algae, and protists (excluding fungi) within the next 5 years. By implementing and continuously improving leading-edge sequencing technologies and bioinformatics tools, 10KP will catalogue the genome content of plant and protist diversity and make these data freely available as an enduring foundation for future scientific discoveries and applications. 10KP is structured as an international consortium, open to the global community, including botanical gardens, plant research institutes, universities, and private industry. Our immediate goal is to establish a policy framework for this endeavor, the principles of which are outlined here. PMID- 29618050 TI - Control of mRNA decapping by autoinhibition. AB - 5' mediated cytoplasmic RNA decay is a conserved cellular process in eukaryotes. While the functions of the structured core domains in this pathway are well studied, the role of abundant intrinsically disordered regions (IDRs) is lacking. Here we reconstitute the Dcp1:Dcp2 complex containing a portion of the disordered C-terminus and show its activity is autoinhibited by linear interaction motifs. Enhancers of decapping (Edc) 1 and 3 cooperate to activate decapping by different mechanisms: Edc3 alleviates autoinhibition by binding IDRs and destabilizing an inactive form of the enzyme, whereas Edc1 stabilizes the transition state for catalysis. Both activators are required to fully stimulate an autoinhibited Dcp1:Dcp2 as Edc1 alone cannot overcome the decrease in activity attributed to the C-terminal extension. Our data provide a mechanistic framework for combinatorial control of decapping by protein cofactors, a principle that is likely conserved in multiple 5' mRNA decay pathways. PMID- 29618051 TI - Landscape Physiognomy Influences Abundance of the Lone Star Tick, Amblyomma americanum (Ixodida: Ixodidae), in Ozark Forests. AB - The lone star tick, Amblyomma americanum Linnaeus (Ixodida: Ixodidae), is emerging as an important human disease vector in the United States. While some recent studies have modeled broad-scale (regional or county-level) distribution patterns of A. americanum, less is known about how local-scale habitat characteristics drive A. americanum abundance. Such local-scale information is vital to identify targets for tick population control measures within land management units. We investigated how habitat features predict host-seeking A. americanum adult and nymph abundance within a 12-ha oak-hickory forest plot in the Missouri Ozarks. We trapped ticks using CO2-baited traps at 40 evenly spaced locations for three 24-h periods during the summer of 2015, and we measured biotic and abiotic variables surrounding each location. Of 2,008 A. americanum captured, 1,009 were nymphs, and 999 were adults. We observed spatial heterogeneity in local tick abundance (min = 0 ticks, max = 112 ticks, mean = 16.7 ticks per trap night). Using generalized linear mixed models, we found that both nymphs and adults had greater abundance in valleys as well as on northern facing aspects. Moreover, nymph abundance was negatively related to temperature variance, while adult abundance had a negative relationship with elevation. These results demonstrate that managers in this region may be able to predict local tick abundance through simple physiognomic factors and use these parameters for targeted management action. PMID- 29618052 TI - Letter responding to Screening for atrial fibrillation: a European Heart Rhythm Association (EHRA) consensus document endorsed by the Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), and Societad Latinoamericana de Estimulation Cardiaca y Electrofisiologia (SOLAECE)-Authors' reply. PMID- 29618053 TI - G-Anchor: a novel approach for whole-genome comparative mapping utilizing evolutionary conserved DNA sequences. AB - Background: Cross-species whole-genome sequence alignment is a critical first step for genome comparative analyses, ranging from the detection of sequence variants to studies of chromosome evolution. Animal genomes are large and complex, and whole-genome alignment is a computationally intense process, requiring expensive high-performance computing systems due to the need to explore extensive local alignments. With hundreds of sequenced animal genomes available from multiple projects, there is an increasing demand for genome comparative analyses. Results: Here, we introduce G-Anchor, a new, fast, and efficient pipeline that uses a strictly limited but highly effective set of local sequence alignments to anchor (or map) an animal genome to another species' reference genome. G-Anchor makes novel use of a databank of highly conserved DNA sequence elements. We demonstrate how these elements may be aligned to a pair of genomes, creating anchors. These anchors enable the rapid mapping of scaffolds from a de novo assembled genome to chromosome assemblies of a reference species. Our results demonstrate that G-Anchor can successfully anchor a vertebrate genome onto a phylogenetically related reference species genome using a desktop or laptop computer within a few hours and with comparable accuracy to that achieved by a highly accurate whole-genome alignment tool such as LASTZ. G-Anchor thus makes whole-genome comparisons accessible to researchers with limited computational resources. Conclusions: G-Anchor is a ready-to-use tool for anchoring a pair of vertebrate genomes. It may be used with large genomes that contain a significant fraction of evolutionally conserved DNA sequences and that are not highly repetitive, polypoid, or excessively fragmented. G-Anchor is not a substitute for whole-genome aligning software but can be used for fast and accurate initial genome comparisons. G-Anchor is freely available and a ready-to use tool for the pairwise comparison of two genomes. PMID- 29618054 TI - Influence of Residual Disease Following Surgical Resection in Newly Diagnosed Glioblastoma on Clinical, Neurocognitive, and Patient Reported Outcomes. AB - BACKGROUND: The influence of subtotal resection (STR) on neurocognitive function (NCF), quality of life, and symptom burden in glioblastoma is unknown. If bevacizumab preferentially benefits patients with STR is unknown. OBJECTIVE: To examine these uncertainties. METHODS: NCF and patient reported outcomes (PRO) were prospectively collected in NRG Oncology RTOG 0525 and 0825. Changes in NCF and PRO measures from baseline to prespecified times were examined by Wilcoxon test, and mixed effects longitudinal modeling, to assess differences between patients who received STR vs gross-total resection. Changes were also compared among STR patients on 0825 receiving placebo vs bevacizumab to assess for a preferential therapeutic effect. Overall survival between STR and gross-total resection patients was compared using the Kaplan-Meier method. RESULTS: A total of 427 patients were eligible with STR present in 37%. At baseline, patients with STR had worse NCF, worse MD Anderson Symptom Inventory Brain Tumor Neurological Factor ratings (P = .004), and European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (P = .002). Longitudinal multivariate analysis associated STR with worse NCF (Hopkins Verbal Learning Test Revised Delayed Recognition [P = .048], Trail Making Test Part A [P = .035], and Controlled Oral Word Association [P = .049]). One hundred eighty-three STR patients from 0825 were analyzed (89 bevacizumab, 94 placebo); bevacizumab failed to demonstrate improvement in select NCF or PRO measures. CONCLUSION: STR patients had worse NCF and PROs before therapy. During adjuvant therapy, STR patients had worse objective NCF, despite accounting for tumor location. STR did not result in a detriment to OS. The addition of bevacizumab did not preferentially improve PRO or NCF outcomes in STR patients. PMID- 29618055 TI - Malignancy Index Using Intraoperative Flow Cytometry is a Valuable Prognostic Factor for Glioblastoma Treated With Radiotherapy and Concomitant Temozolomide. AB - BACKGROUND: Intraoperative prediction of radiochemosensitivity is desirable for improving the clinical management of glioblastoma (GBM) patients. We have previously developed an original technique for intraoperative flow cytometry (iFC) and defined a malignancy index (MI). OBJECTIVE: To determine whether MI correlates with prognosis in GBM patients who underwent the standard treatment protocol of radiotherapy and temozolomide administration. METHODS: The current study included 102 patients with GBM that had been newly diagnosed from 2010 to 2015 who underwent our iFC analysis and received the standard treatment protocol. We evaluated MI values in each patient, then statistically analyzed the relationship between MI and prognosis using survival analysis that include other clinicopathological factors (age, sex, Karnofsky performance status [KPS], extent of resection, second-line bevacizumab, O6-methylguanine-DNA methyltransferase [MGMT] status, MIB-1 labeling index, and mutation of the isocitrate dehydrogenase 1 gene [IDH1]). RESULTS: Log-rank test revealed that age, KPS, extent of resection, MGMT status, IDH1 mutation, and high MI (>=26.3%) significantly correlated with overall survival. Multivariate analysis with Cox regression modeling identified MI as the most significant prognostic factor (hazard ratio = 2.246; 95% confidence interval = 1.347-3.800; P = .0019). MI showed strong correlation with IDH1 mutation status in chi-square test (P = .0023). In addition, log-rank test revealed that MI affects overall survival more strongly in patients with IDH1 wildtype than those with IDH1 mutant. CONCLUSION: MI from an iFC study may help predict the prognosis in patients with GBM who receive the standard treatment. Survival can be related to sensitivity to radio-chemotherapy. PMID- 29618056 TI - Cohort Profile: The Haematological Malignancy Research Network (HMRN); a UK population-based patient cohort. PMID- 29618057 TI - LSD1 mediates metabolic reprogramming by glucocorticoids during myogenic differentiation. AB - The metabolic properties of cells are formed under the influence of environmental factors such as nutrients and hormones. Although such a metabolic program is likely initiated through epigenetic mechanisms, the direct links between metabolic cues and activities of chromatin modifiers remain largely unknown. In this study, we show that lysine-specific demethylase-1 (LSD1) controls the metabolic program in myogenic differentiation, under the action of catabolic hormone, glucocorticoids. By using transcriptomic and epigenomic approaches, we revealed that LSD1 bound to oxidative metabolism and slow-twitch myosin genes, and repressed their expression. Consistent with this, loss of LSD1 activity during differentiation enhanced the oxidative capacity of myotubes. By testing the effects of various hormones, we found that LSD1 levels were decreased by treatment with the glucocorticoid dexamethasone (Dex) in cultured myoblasts and in skeletal muscle from mice. Mechanistically, glucocorticoid signaling induced expression of a ubiquitin E3 ligase, JADE-2, which was responsible for proteasomal degradation of LSD1. Consequently, in differentiating myoblasts, chemical inhibition of LSD1, in combination with Dex treatment, synergistically de-repressed oxidative metabolism genes, concomitant with increased histone H3 lysine 4 methylation at these loci. These findings demonstrated that LSD1 serves as an epigenetic regulator linking glucocorticoid action to metabolic programming during myogenic differentiation. PMID- 29618059 TI - 'Co-operation and Communism cannot work side by side': Organized Consumers and the Early Cold War in Britain. AB - This article contributes to a better understanding of labour anti-communism in Britain through an exploration of the evolution of ideas and attitudes within the co-operative movement during the early Cold War. It demonstrates that the period witnessed an increasingly rigid separation of co-operation from communism and argues that this separation made it harder for activists within the co-operative movement to imagine a total or utopian alternative to capitalism. Drawing particularly on a close reading of the co-operative press as well as other sources, the study is divided into three main parts. The first section discusses sympathy among co-operators for the achievements of the Soviet Union, which increased during the war against fascism. The article then moves on to consider the continuing dialogue between British co-operators and their counterparts in European communist states and how international tensions shaped co-operators' views. The final major section explores the hardening of attitude towards communism after Marshall Aid was declared in June 1947, and underlines the role played by figures such as A. V. Alexander and Jack Bailey who worked with the Information Research Department at the Foreign Office to spread anti-communism within the movement. The conclusion reflects, more speculatively, on what implications this shift may have had for the medium and long-term decline of co operation and the hegemony of capitalist consumerism post-war. PMID- 29618058 TI - A transcriptional factor B paralog functions as an activator to DNA damage responsive expression in archaea. AB - Previously it was shown that UV irradiation induces a strong upregulation of tfb3 coding for a paralog of the archaeal transcriptional factor B (TFB) in Sulfolobus solfataricus, a crenarchaea. To investigate the function of this gene in DNA damage response (DDR), tfb3 was inactivated by gene deletion in Sulfolobus islandicus and the resulting Deltatfb3 was more sensitive to DNA damage agents than the original strain. Transcriptome analysis revealed that a large set of genes show TFB3-dependent activation, including genes of the ups operon and ced system. Furthermore, the TFB3 protein was found to be associated with DDR gene promoters and functional dissection of TFB3 showed that the conserved Zn-ribbon and coiled-coil motif are essential for the activation. Together, the results indicated that TFB3 activates the expression of DDR genes by interaction with other transcriptional factors at the promoter regions of DDR genes to facilitate the formation of transcription initiation complex. Strikingly, TFB3 and Ced systems are present in a wide range of crenarchaea, suggesting that the Ced system function as a primary DNA damage repair mechanism in Crenarchaeota. Our findings further suggest that TFB3 and the concurrent TFB1 form a TFB3-dependent DNA damage-responsive circuit with their target genes, which is evolutionarily conserved in the major lineage of Archaea. PMID- 29618060 TI - Tn and STn are members of a family of carbohydrate tumor antigens that possess carbohydrate-carbohydrate interactions. AB - The mucin-type O-glycome in cancer aberrantly expresses the truncated glycans Tn (GalNAcalpha1-Ser/Thr) and STn (Neu5Acalpha2,6GalNAcalpha1-Ser/Thr). However, the role of Tn and STn in cancer and other diseases is not well understood. Our recent discovery of the self-binding properties (carbohydrate-carbohydrate interactions, CCIs) of Tn (Tn-Tn) and STn (STn-STn) provides a model for their possible roles in cellular transformation. We also review evidence that Tn and STn are members of a larger family of glycan tumor antigens that possess CCIs, which may participate in oncogenesis. PMID- 29618062 TI - 45,X/46,XY Mosaicism Presenting With Isolated Unilateral Cryptorchidism and a Normal Blood Karyotype. AB - Context: 45,X/46,XY mosaicism is a disorder of sex development leading to abnormal gonadal development and to unpredictable genital phenotype, growth, and pubertal development. Case Description: A 2-year-old male presented with a right impalpable testis. Blood karyotype was 46,XY. A laparoscopy performed for right orchidopexy revealed a right streak gonad with Mullerian structures, whereas on the left side, a normal descended testis was present. The karyotype of the removed gonad was 45,X/46,XY. The child grew along the second centile, within the midparental height (MPH) range, until the time of puberty, when linear growth worsened due to a lack of a pubertal growth spurt, and growth hormone (GH) therapy was initiated. He developed spontaneous puberty (13 years of age) and showed normal pubertal progression. However, from the age of 15 years, he had low normal testosterone, raised follicle-stimulating hormone, and reduction of inhibin B, possibly suggestive of declining testicular function. His final height was -2.24 standard deviation score (SDS) (-2.4 SDS at GH start; MPH -1.6 SDS). Conclusions: Our case describes a mild male phenotype associated with 45,X/46,XY mosaicism characterized by unilateral cryptorchidism, spontaneous onset of puberty, and normal blood karyotype. The case illustrates the difficulties inherent in making a diagnosis of 45,X/46,XY mosaicism when there is no genital ambiguity and makes the point that growth and testicular impairment may occur, mostly manifesting during adolescence. An early diagnosis is crucial to initiate careful monitoring for growth and pubertal disorders, increased tumor risk, and fertility issues commonly seen in these children. PMID- 29618061 TI - Histone deacetylation promotes transcriptional silencing at facultative heterochromatin. AB - It is important to accurately regulate the expression of genes involved in development and environmental response. In the fission yeast Schizosaccharomyces pombe, meiotic genes are tightly repressed during vegetative growth. Despite being embedded in heterochromatin these genes are transcribed and believed to be repressed primarily at the level of RNA. However, the mechanism of facultative heterochromatin formation and the interplay with transcription regulation is not understood. We show genome-wide that HDAC-dependent histone deacetylation is a major determinant in transcriptional silencing of facultative heterochromatin domains. Indeed, mutation of class I/II HDACs leads to increased transcription of meiotic genes and accumulation of their mRNAs. Mechanistic dissection of the pho1 gene where, in response to phosphate, transient facultative heterochromatin is established by overlapping lncRNA transcription shows that the Clr3 HDAC contributes to silencing independently of SHREC, but in an lncRNA-dependent manner. We propose that HDACs promote facultative heterochromatin by establishing alternative transcriptional silencing. PMID- 29618063 TI - Endoscopic port access surgery for isolated atrioventricular valve endocarditis. AB - OBJECTIVES: Our goal was to report the clinical and echocardiographic outcomes of endoscopic port access surgery for isolated active and convalescent atrioventricular valve endocarditis (AVVE). METHODS: Our current surgical team performed endoscopic port access surgery in 66 consecutive patients with isolated AVVE (mean age, 65.5 +/- 12.7 years, 37.9% women, mean EuroSCORE II 31.2 +/- 24.9%, 45.5% prosthetic AVVE, Staphylococcus aureus 22.2%), between 1 May 2004 and 31 July 2015. Isolated mitral valve endocarditis was present in 53 (80.4%) patients, including 11 (16.7%) with periannular abscesses. RESULTS: Procedures performed included mitral valve repair (n = 15, 22.7%) and left ventricular septal myomectomy (n = 1, 1.5%). Reasons for sternotomy conversion (n = 6, 9.1%) included lung adhesions (n = 3, 4.5%). The mean cardiopulmonary bypass and ischaemic times were 167.2 +/-48.7 and 112.6 +/- 33.3 min, respectively. In hospital morbidities included revision for bleeding (n = 6, 9.1%). The 30-day survival rate was 87.9%. Causes of in-hospital deaths (n = 12) included low cardiac output syndrome (n = 3, 4.5%). Age, critical preoperative status and EuroSCORE II score predicted deaths individually at the 5% level of significance. The Kaplan-Meier analyses (mean 63.2 +/- 42.5 months) for survival and freedom from AVVE reintervention at 10 years were 69.4% and 98.4%, respectively. Of the mid-term survivors (n = 50, 93.9% complete), 94.0% (n = 47) classified as New York Heart Association (NYHA) II or less with no mitral valve regurgitation greater than Grade I. CONCLUSIONS: Complex atrioventricular valve surgery in the context of AVVE can be endoscopically performed in experienced centres and should not deter surgeons from offering patients with AVVE the potential benefits of minimally invasive cardiac surgery. PMID- 29618064 TI - Subcellular distribution of endogenous malectin under rest and stress conditions is regulated by ribophorin I. AB - Malectin is a newly discovered endoplasmic reticulum (ER)-resident lectin, which specifically recognizes Glc2Man9GlcNAc2 on newly synthesized glycoproteins. We have previously demonstrated that malectin forms a complex with ribophorin I for selective retention of misfolded glycoproteins inside the cell. Here, we showed that ribophorin I also functions to regulate the subcellular localization of malectin under various conditions. Even though malectin does not contain an ER retention signal motif, we found that endogenous malectin mainly localizes in the ER, which is disrupted upon suppression of ribophorin I, leading to its movement from ER to Golgi. In contrast, under ER-stress conditions, malectin mainly localizes in the Golgi, which is restored to ER localization by overexpression of ribophorin I. These results indicate that the subcellular localization of malectin is accurately regulated by the expression level of ribophorin I, which will provide further insights into the understanding of the function of malectin. PMID- 29618065 TI - In Reply: Big Data Research in Neurosurgery: A Critical Look at this Popular New Study Design. PMID- 29618066 TI - Pulmonary vein obstruction after primary sutureless pericardial repair of a total anomalous pulmonary venous connection. AB - Total anomalous pulmonary venous connection is a rare congenital heart disease. The development of pulmonary venous obstruction is one of the major risk factors for poor outcomes after surgical repair. Sutureless pericardial repair for a total anomalous pulmonary venous connection was introduced to decrease the risk of pulmonary venous obstruction after surgical repair, and favourable outcomes have been reported. Herein, we report the case of an infant with a total anomalous pulmonary venous connection who developed pulmonary venous obstruction after primary sutureless pericardial repair. PMID- 29618067 TI - Local Cortisol Elevation Contributes to Endometrial Insulin Resistance in Polycystic Ovary Syndrome. AB - Context: Endometrial insulin resistance (IR) may account for the endometrial dysfunction in polycystic ovary syndrome (PCOS). The underlying mechanism remains to be elucidated. Objective: To investigate whether the abundance of 11beta hydroxysteroid dehydrogenases (11beta-HSDs) 1 and 2 and cortisol as well as the insulin signaling pathway are altered in PCOS endometrium and to clarify the relationship between endometrial IR and local cortisol. Design: We measured cortisol and cortisone concentrations, 11beta-HSD1 and 11beta-HSD2, and core insulin signaling molecules in endometrial biopsies collected from non-PCOS and PCOS with or without IR patients on the seventh day after human chorionic gonadotropin injection. We also studied the effects of cortisol on glucose uptake and the insulin signaling pathway in primary cultured endometrial epithelial cells (EECs). Results: The cortisol concentration was elevated, whereas 11beta HSD2 expression was diminished in endometrial biopsies obtained from PCOS with IR patients compared with those from non-PCOS and PCOS without IR patients. The implantation rate was relatively impaired and the endometrial insulin signaling pathway was defective in PCOS with IR patients. In addition, cortisol attenuated insulin-stimulated glucose uptake in EECs, which was mediated by inhibition of Akt phosphorylation and glucose transporter type 4 translocation via induction of phosphatase and tensin homolog deleted on chromosome ten (PTEN). Conclusions: Decreased oxidation of cortisol and defects of insulin signaling in endometrium were observed in PCOS with IR patients. The excessive cortisol level, derived from the reduction of 11beta-HSD2, might contribute to the development of endometrial IR by inhibiting the insulin signaling pathway via induction of PTEN expression in EECs. PMID- 29618068 TI - Occipital Artery to Posterior Cerebral Artery Bypass Using Descending Branch of the Lateral Circumflex Femoral Artery Graft for Treatment of Fusiform, Unruptured Posterior Cerebral Artery Aneurysm: 3-Dimensional Operative Video. AB - Posterior cerebral artery (PCA) aneurysms can be technically challenging lesions due to the intricacy of perforating branches and the relationship to cranial nerves and the brainstem. Fusiform aneurysms of the perimesencephalic segment of the PCA are a rare finding which does not favor direct clip occlusion or reconstruction. In such cases, proximal parent vessel occlusion is an option for aneurysm treatment. Extracranial-intracranial (EC-IC) bypass can be used to revascularize beyond the lesion when considering proximal occlusion. Based on previous literature for occipital artery (OA) bypass and the time-consuming dissection required for OA harvest, an interposition graft was chosen. The descending branch of the lateral circumflex femoral artery (DLCFA) is a good alternative interposition graft with a diameter that is favorable for revascularizing smaller, more distal vessels.This 3-dimensional video presents the case of a 26-year-old female with severe headaches who was found to have unruptured, fusiform aneurysmal dilatations of the PCA. Given the patient's youth and the morphology of the aneurysms, an EC-IC bypass with proximal occlusion was recommended. The DLCFA was used as an interposition graft. The left OA was found to be a suitable donor. A subtemporal approach was used to access the PCA for proximal occlusion. An occipital interhemispheric approach was performed to isolate a suitable recipient segment of the ipsilateral PCA branch for microvascular end-to-side anastomosis. Postoperative catheter angiography showed significant thrombosis of the fusiform aneurysms and a patent EC-IC bypass. Postoperative magnetic resonance imaging showed no infarcts and the patient was discharged neurologically intact.The patient was consented for inclusion in a prospective institutional review board (IRB) approved database from which this IRB approved retrospective report was performed. The consent for intraoperative video and picture use was also obtained.Images in the video between 0:49 and 1:11, (c) University of Southern California Neurorestoration Center. Used with permission, all rights reserved. PMID- 29618069 TI - Genetic diversity and antifungal susceptibility of Candida albicans isolated from Iranian patients. AB - A total of 105 independent Candida albicans strains isolated from patients in Iran were investigated. According to CLSI documents M27-A3 and M27-S4, the 24 h geometric mean MICs of caspofungin, itraconazole, and fluconazole were 0.27, 3.19, and 11.91 MUg/ml, respectively. Microsatellites analysis of CEF3, CAIII, LOC4 Loci identified 93 different allelic genotypes clustered apart into six different clades. Antifungal susceptibility was not linked with the source of isolation and the corresponding genotype of C. albicans strains. PMID- 29618070 TI - Congenital Dermal Sinus and Limited Dorsal Myeloschisis: "Spectrum Disorders" of Incomplete Dysjuction Between Cutaneous and Neural Ectoderms. AB - BACKGROUND: The existence of tethering tracts in spinal dysraphism, other than congenital dermal sinus (CDS), has been recognized and has been summated into an integrated concept of limited dorsal myeloschisis (LDM). OBJECTIVE: To elucidate the underlying embryology of LDM in relation to CDS by focusing on the pathological features of special cases of tethering tracts. METHODS: Out of 389 spinal dysraphism patients who were operated on from 2010 to 2016, 5 patients who had tethering tracts composed of both CDS and LDM (or "probable LDM" if only fibrous tissue was found) were identified. Their clinical presentation, radiological images, operative findings, and pathology were thoroughly reviewed. RESULTS: Three nonsaccular-type patients harbored stalks in which the squamous epithelial lined sinus (CDS) was found in the distal portion, and fibroneural (LDM) or fibrous (probable LDM) tissue in the proximal part. Two patients had saccular lesions, and a stalk was found inside the sac, connecting a small pit on the skin to the spinal cord. The tracts were pathologically identical to a CDS. CONCLUSION: This study reports the coexistence of CDS and LDM (or probable LDM) components. These unique cases support the hypothesis that the CDS and LDM are among a spectrum of an anomaly that is caused by failure of complete dysjunction between cutaneous and neural ectoderms. Neurosurgeons should be aware of the possibility of coexisting "CDS" components in cases suggestive of LDM. In such cases, not only untethering but also meticulous removal of the squamous epithelium is critical. PMID- 29618071 TI - Image Guidance for Ventricular Shunt Surgery: An Analysis of Ventricular Size and Proximal Revision Rates. AB - BACKGROUND: Image guidance is a promising technology that could lead to lower rates of premature shunt failure by decreasing the rate of inaccurate proximal catheter placement. OBJECTIVE: To perform a detailed radiographic analysis of ventricular size using 3 well-described methods and compare proximal revision rates. METHODS: Our shunt surgery research database was queried to identify procedures (new placement or revision) where frameless stereotactic electromagnetic neuronavigation was used (January 2010-June 2016). A randomly selected cohort of surgeries done without image guidance during the same time period served as the comparison group. A radiographic analysis utilizing the following indices was used to classify ventricular size: bifrontal, bicaudate, and frontal-occipital horn ratio. The primary outcome was shunt failure due specifically to proximal catheter malfunction at 90 and 180 days. RESULTS: A total of 108 stereotactic and 95 free-hand cases were identified. Overall, there was no difference in ventricular size between the 2 groups. Neuronavigation yielded improved accuracy rates (73% grade 1; P < .001). Although there was no statistically significant difference in proximal revision rates when all patients were analyzed, there was a clinically beneficial reduction in the 90- and 180-day failure rates across all radiographic indices in children with small-to-moderate ventricular sizes when using image guidance. CONCLUSION: Electromagnetic neuronavigation results in more accurate placement of catheters, but did not result in an overall reduction in proximal shunt failure at 90 and 180 days after the index surgery. However, subgroup analysis suggests a clinically important benefit in those patients with harder to cannulate ventricles. PMID- 29618072 TI - Surgical cut down for vascular access with conscious sedation for transcatheter aortic valve replacement: the best of both worlds? AB - OBJECTIVES: Despite the established efficacy of transcatheter aortic valve replacement for aortic valve replacement, vascular complications remain a major cause of procedural morbidity and mortality. In this study, we evaluate the use of femoral artery cut down with conscious sedation and report outcomes and complications associated with this approach. METHODS: Our study included 282 patients undergoing transcatheter aortic valve replacement with conscious sedation and surgical cut down for femoral access between 2015 and 2017. Data were prospectively recorded in the local institutional database and were retrospectively accessed. Descriptive statistics are presented, and a Kaplan Meier time-to-event plot was used to estimate 1-year survival. RESULTS: The mean age of the patients was 82.7 +/- 7.31 years and consisted of 146 (52%) women. Echocardiographic data demonstrated a severe aortic stenosis with a mean area of 0.65 +/- 0.16 cm2 and a mean gradient of 48.9 +/- 13.3 mmHg. STS-PROM for the cohort was 7.2%, representing an intermediate risk group. Six (2.2%) patients died within 30 days after transcatheter aortic valve replacement. Major vascular complications occurred in 2 (0.7%) patients and minor vascular complications occurred in 6 (2.2%) patients in our cohort. Wound complications were observed in 2 (0.7%) patients. CONCLUSIONS: We demonstrate that the use of conscious sedation and surgical cut down for femoral arterial access resulted in a major vascular complication rate of less than 1% and low in-hospital mortality rates without any significant increase in wound complications. PMID- 29618073 TI - Anterolateral Approach for Central Thoracic Disc Prolapse-Surgical Strategies Used to Tackle Differing Operative Findings: 3-Dimensional Operative Video. AB - Thoracic disc prolapses causing cord compression can be challenging. For compressive central disc protrusions, a posterior approach is not suitable due to an unacceptable level of cord manipulation. An anterolateral transthoracic approach provides direct access to the disc prolapse allowing for decompression without disturbing the spinal cord. In this video, we describe 2 cases of thoracic myelopathy from a compressive central thoracic disc prolapse. In both cases, informed consent was obtained. Despite similar radiological appearances of heavy calcification, intraoperatively significant differences can be encountered. We demonstrate different surgical strategies depending on the consistency of the disc and the adherence to the thecal sac. With adequate exposure and detachment from adjacent vertebral bodies, soft discs can be, in most instances, separated from the theca with minimal cord manipulation. On the other hand, largely calcified discs often present a significantly greater challenge and require thinning the disc capsule before removal. In cases with significant adherence to dura, in order to prevent cord injury or cerebrospinal fluid leak a thinned shell can be left, providing total detachment from adjacent vertebrae can be achieved. Postoperatively, the first patient, with a significantly calcified disc, developed a transient left leg weakness which recovered by 3-month follow-up. This video outlines the anatomical considerations and operative steps for a transthoracic approach to a central disc prolapse, whilst demonstrating that computed tomography appearances are not always indicative of potential operative difficulties. PMID- 29618074 TI - Letter: Epidural Steroid Injection-Induced Menorrhagia: An Under-recognized Complication Associated With a Common Spinal Intervention. PMID- 29618075 TI - Thoracoscopic rebiopsy to detect the T790M mutation after postoperative recurrence. AB - After pulmonary resection for non-small-cell lung cancer, some patients with postoperative recurrence and mutated epidermal growth factor receptor (EGFR) subsequently receive EGFR-tyrosine kinase inhibitors (EGFR-TKIs). Osimertinib may be efficacious if those patients become resistant to the 1st-line EGFR-TKI because of the T790M mutation. We recently performed thoracoscopic rebiopsy to detect the T790M mutation in 4 patients who became resistant to the 1st-line EGFR TKI treatment for postoperative recurrence. Our limited experience suggests that thoracoscopic biopsy is associated with limited morbidity, can help detect the T790M mutation and may improve the management of select patients with acquired resistance to the 1st-line EGFR-TKIs. PMID- 29618076 TI - Age and Body Size Influence Sperm Quantity in Male Aedes albopictus (Diptera: Culicidae) Mosquitoes. AB - Aedes albopictus (Skuse) (Diptera: Culicidae) is a vector of several arboviruses impacting human health, including dengue, chikungunya, and potentially Zika. Vector control strategies that deploy modified males into the field are in use or under development and require a solid understanding of male biology; unfortunately, there has been limited effort to understand male Ae. albopictus reproductive biology, including sperm production and capacity. We tested whether body size and age affect spermatogenesis in Ae. albopictus. In general, older and larger males produced more sperm than their younger or smaller counterparts. Large males continued spermatogenesis well after 10-d post-eclosion (dpe), augmenting their reserves by 39%. By contrast, small males stopped producing sperm at 10 dpe. These results contribute to a deeper understanding of Ae. albopictus reproductive physiology. We discuss the usefulness of these findings in the context of Ae. albopictus life history and their utility in optimizing male mosquito release strategies. PMID- 29618077 TI - N-Ethyl Pentylone (Ephylone) Intoxications: Quantitative Confirmation and Metabolite Identification in Authentic Human Biological Specimens. AB - N-ethyl pentylone (ephylone) has been identified as the most recent novel stimulant to emerge into the arena of evolving novel psychoactive substances (NPS). Due to its novelty, information regarding case reports with associated quantitative confirmations, biotransformation pathways, and identified unique metabolites will assist the scientific community in understanding the implications of the emergence and risks associated with N-ethyl pentylone use. Authentic blood specimens (n = 26) submitted as part of toxicological death investigations or drugged driving casework tested positive for N-ethyl pentylone, and were quantitatively analyzed by liquid chromatography tandem mass spectrometry (LC-MS-MS). N-ethyl pentylone concentrations ranged from 12 to 1,200 ng/mL, with mean (+/-standard deviation) and median concentrations of 313 (+/ 366) and 125 ng/mL, respectively, excluding one case measured at 50,000 ng/mL. N ethyl pentylone was often found in combination with other drugs of abuse and NPS, include a variety of novel opioids including fentanyl analogs. Oral fluid specimens (n = 5), collected from recreational drug users at a dance music festival, were quantitatively analyzed using LC-MS-MS. Concentrations ranged from 12.6 to 1,377 ng/mL. Additional analysis was performed to characterize the metabolic profile of N-ethyl pentylone using human liver microsomes (HLM), followed by confirmation of the presence of the proposed metabolites in a subset of the blood specimens and oral fluid specimens. Metabolomic analysis was performed using a liquid chromatograph quadrupole time-of-flight mass spectrometer (LC-QTOF), followed by data processing using MetabolitePilotTM software. In vivo verification of in vitro HLM-generated metabolites resulted in the confirmation of four metabolites. Reduction of the beta-ketone to an alcohol resulted in the most prominent metabolite found in the authentic specimens, and its uniqueness to N-ethyl pentylone leads to this metabolite being an appropriate biomarker to determine N-ethyl pentylone ingestion. This is the first study to report N-ethyl pentylone concentrations and to characterize the metabolic profile of N-ethyl pentylone. PMID- 29618078 TI - Simultaneous Time-concentration Analysis of Soman and VX Adducts to Butyrylcholinesterase and Albumin by LC-MS-MS. AB - A sensitive method for the purification and determination of two protein adducts, organophosphorus (OP)-BChE and OP-albumin adducts, in a single sample using a simultaneous sample preparation method was developed and validated using liquid chromatography-tandem mass spectrometry. First, we isolated O-ethyl S-2 diisopropylaminoethyl methyl phosphonothiolate (VX) and O-pinacolyl methylphosphonofluoridate (soman, GD)-BChE adducts using an immunomagnetic separation (IMS) method and the HiTrapTM Blue affinity column was subsequently used to isolate and purify VX and GD-albumin adducts from the plasma of rhesus monkeys exposed to nerve agents. Additionally, we examined the time-concentration profiles of two biomarkers, VX and GD-nonapeptides and VX and GD-tyrosines, derived from OP-BChE and OP-albumin adducts up to 8 weeks after exposure. Based on the results, we determined that VX and GD-tyrosine is more suitable than VX and GD-nonapeptide as a biomarker owing to its longevity. This integrated approach is expected to be applicable for the quantification of other OP-BChE and OP-albumin adducts in human plasma, thus serving as a potential generic assay for exposure to nerve agents. PMID- 29618080 TI - Corrigendum to "Isolation and Characterization of Novel Polymorphic Microsatellite Markers for Cimex hemipterus F. (Hemiptera: Cimicidae)". PMID- 29618079 TI - Effects of Massage in Reducing the Pain and Anxiety of the Cardiac Surgery Critically Ill-a Randomized Controlled Trial. AB - Objective: To evaluate the effectiveness of hand massage on the pain and anxiety of the cardiac surgery critically ill. Design: A three-arm randomized controlled trial. Setting: This study was conducted in a medical-surgical intensive care unit in Canada. Subjects: Adult patients who underwent elective cardiac surgery, who were able to speak French/English and to self-report symptoms, without a high risk of postoperative complications were eligible. Methods: Patients were randomly allocated to standard care plus either two 20-minute hand massages (experimental), two 20-minute hand holdings (active control), or two 20-minute rest periods (passive control/standard care). Pain intensity, pain unpleasantness, anxiety, muscle tension, and vital signs were evaluated before, after, and 30 minutes later for each intervention. Results: From the 83 patients recruited, 60 were randomized (20 massage, 19 hand holding, 21 standard care). After controlling for baseline scores, the massage group reported significantly lower pain intensity, pain unpleasantness, and anxiety for the first data collection set compared with both hand holding and standard care (analysis of covariance, P < 0.02), with an average decrease of two points on a 0-10 scale. No statistically significant differences were noted between hand holding and standard care for any of the symptoms. Similar results were observed for the second data collection set (N = 43). Patients had decreased muscle tension post massage. Vital signs did not differ significantly between groups. Conclusions: Findings suggest that a 20-minute hand massage in addition to routine postoperative pain management can concomitantly reduce pain intensity, pain unpleasantness, and anxiety by two points on average on a 0-10 scale. PMID- 29618081 TI - Origin of Syrinx Fluid in Syringomyelia: A Physiological Study. AB - BACKGROUND: The origin of syrinx fluid is controversial. OBJECTIVE: To elucidate the mechanisms of syringomyelia associated with cerebrospinal fluid pathway obstruction and with intramedullary tumors, contrast transport from the spinal subarachnoid space (SAS) to syrinx was evaluated in syringomyelia patients. METHODS: We prospectively studied patients with syringomyelia: 22 with Chiari I malformation and 16 with SAS obstruction-related syringomyelia before and 1 wk after surgery, and 9 with tumor-related syringomyelia before surgery only. Computed tomography-myelography quantified dye transport into the syrinx before and 0.5, 2, 4, 6, 8, 10, and 22 h after contrast injection by measuring contrast density in Hounsfield units (HU). RESULTS: Before surgery, more contrast passed into the syrinx in Chiari I malformation-related syringomyelia and spinal obstruction-related syringomyelia than in tumor-related syringomyelia, as measured by (1) maximum syrinx HU, (2) area under the syrinx concentration-time curve (HU AUC), (3) ratio of syrinx HU to subarachnoid cerebrospinal fluid (CSF; SAS) HU, and (4) AUC syrinx/AUC SAS. More contrast (AUC) accumulated in the syrinx and subarachnoid space before than after surgery. CONCLUSION: Transparenchymal bulk flow of CSF from the subarachnoid space to syrinx occurs in Chiari I malformation-related syringomyelia and spinal obstruction-related syringomyelia. Before surgery, more subarachnoid contrast entered syringes associated with CSF pathway obstruction than with tumor, consistent with syrinx fluid originating from the subarachnoid space in Chiari I malformation and spinal obstruction-related syringomyelia and not from the subarachnoid space in tumor related syringomyelia. Decompressive surgery opened subarachnoid CSF pathways and reduced contrast entry into syringes associated with CSF pathway obstruction. PMID- 29618083 TI - Borderline Personality Disorder Features Are Associated with Concurrent Pain Related Disability in a Chronic Pain Sample. AB - Objective: To determine whether core features of borderline personality disorder are associated with increased rates of being on disability benefits due to chronic pain conditions. Subjects: A total of 147 patients currently in treatment for chronic pain at a multimodal chronic pain clinic. Methods: We tested for a concurrent relationship between borderline personality disorder features and employment status using self-report measures. Results: Borderline personality disorder features were associated with increased likelihood of currently being on disability due to pain conditions (odds ratio [OR] = 23.13, 95% confidence interval [CI] = 1.68-318.73), on disability due to other conditions (OR = 33.65, 95% CI = 2.15-526.13), and unemployed (OR = 20.14, 95% CI = 1.38-294.93), even while controlling for pain severity and interference, depression, and trait anxiety. A follow-up analysis revealed that these associations were due to the negative relationships facet of borderline personality disorder features. Conclusions: Borderline personality disorder features, particularly negative relationships, are associated with increased rates of pain disability, general disability, and unemployment in a chronic pain sample. Future research should examine mechanisms by which the maladaptive interpersonal behaviors and cognitions of borderline personality disorder might result in worse long-term employment outcomes of chronic pain. PMID- 29618082 TI - Subjective value representations during effort, probability and time discounting across adulthood. AB - Every day, humans make countless decisions that require the integration of information about potential benefits (i.e. rewards) with other decision features (i.e. effort required, probability of an outcome or time delays). Here, we examine the overlap and dissociation of behavioral preferences and neural representations of subjective value in the context of three different decision features (physical effort, probability and time delays) in a healthy adult life span sample. While undergoing functional neuroimaging, participants (N = 75) made incentive compatible choices between a smaller monetary reward with lower physical effort, higher probability, or a shorter time delay versus a larger monetary reward with higher physical effort, lower probability, or a longer time delay. Behavioral preferences were estimated from observed choices, and subjective values were computed using individual hyperbolic discount functions. We found that discount rates were uncorrelated across tasks. Despite this apparent behavioral dissociation between preferences, we found overlapping subjective value-related activity in the medial prefrontal cortex across all three tasks. We found no consistent evidence for age differences in either preferences or the neural representations of subjective value across adulthood. These results suggest that while the tolerance of decision features is behaviorally dissociable, subjective value signals share a common representation across adulthood. PMID- 29618084 TI - The rationale for Janus kinase inhibitors for the treatment of spondyloarthritis. AB - The pathogenesis of SpA is multifactorial and involves a range of immune cell types and cytokines, many of which utilize Janus kinase (JAK) pathways for signaling. In this review, we summarize the animal and pre-clinical data that have demonstrated the effects of JAK blockade on the underlying molecular mechanisms of SpA and provide a rationale for JAK inhibition for the treatment of SpA. We also review the available clinical trial data evaluating JAK inhibitors tofacitinib, baricitinib, peficitinib, filgotinib and upadacitinib in PsA, AS and related inflammatory diseases, which have demonstrated the efficacy of these agents across a range of SpA-associated disease manifestations. The available clinical trial data, supported by pre-clinical animal model studies demonstrate that JAK inhibition is a promising therapeutic strategy for the treatment of SpA and may offer the potential for improvements in multiple articular and extra articular disease manifestations of PsA and AS. PMID- 29618085 TI - Reassessing Free-Testosterone Calculation by Liquid Chromatography-Tandem Mass Spectrometry Direct Equilibrium Dialysis. AB - Context: Assessment of free testosterone (FT) might help evaluate androgen status in patients with borderline total testosterone (T) and/or altered sex hormone binding globulin (SHBG) levels. However, the validity of different methods to measure FT is debatable. Methods: Serum from 183 women and 146 men was analyzed using equilibrium dialysis (ED), with FT directly measured by liquid chromatography-tandem mass spectrometry. FT calculation was re-evaluated for the mass action law-based equation according to Vermeulen (cFT-V), empirical equations according to Ly (cFT-L), and a proposed calculation based on a multistep, dynamic, allosteric model according to Zakharov (cFT-Z). Results: FT level analyzed by ED [median,13 pmol/L (1.2% of T) in women; 248 pmol/L (1.5% of T) in men] was strongly inversely correlated to SHBG level, significantly to albumin level in women, and only weakly to SHBG level in men. The median [percentile (p) range, 2.5 to 97.5] ratios of calculated FT (cFT) over ED-FT (from European Male Aging Study samples) were 1.19 (0.9 to 1.47), 1.00 (0.69 to 1.42), and 2.05 (1.26 to 3.26) for cFT-V, cFT-L, and cFT-Z, respectively. The ratio for cFT-V was not significantly affected by SHBG, T, or albumin levels (rho range, 0.17 to -0.01); ratios for cFT-L and cFT-Z were affected (P < 0.05 and P < 0.001, respectively) and strongly correlated with SHBG levels (rho = 0.72 and 0.75, respectively). Rank correlations between cFT% and ED-FT% (for men) were 0.62, 0.74, and 0.89 for cFT-Z, cFT-L, and cFT-V, respectively. Conclusion: FT results by direct ED confirm prior FT data from indirect ED and ultrafiltration methodologies. Calculations have inherent limitations, with clinically important differences among evaluated equations: cFT-V, although overestimating FT level, appears the most robust approximation, largely independent of SHBG, albumin, and T levels. PMID- 29618086 TI - Inflammatory phenotypes in the intestine of poultry: not all inflammation is created equal. AB - The intestinal tract harbors a diverse community of microbes that have co-evolved with the host immune system. Although many of these microbes execute functions that are critical for host physiology, the host immune system must control the microbial community so that the dynamics of this interdependent relationship is maintained. To facilitate host homeostasis, the immune system ensures that the microbial load is tolerated, but anatomically contained, while remaining reactive to microbial invasion. Inflammation is the most prevalent manifestation of host defense in reaction to alterations in tissue homeostasis and is elicited by innate immune receptors that recognize and detect infection, host damage, and danger signaling molecules that activate a highly regulated network of immunological and physiological events for the purpose of maintaining homeostasis and restoring functionality. The efficacy, duration, and consequences of an inflammatory response is dependent upon the type of trigger that is recognized by the innate immune receptors. Further, because of different triggers, there are multiple phenotypes of inflammation. Physiological inflammation is the homeostatic balance between tolerance of the microbiota and the reactivity to pathogen invasion. Pathologic inflammation is usually an acute response that involves the host response to toxins and infection often resulting in collateral damage to surrounding tissue and increased metabolic energy use. Metabolic inflammation is a chronic low-grade inflammation generated by excessive nutrient intake and the metabolic surplus fosters metabolic dysfunction by integrating signals from both the immune and metabolic systems. Sterile inflammation is a low grade chronic inflammation, in the absence of an infection, in response to chemical, physical, and metabolic stimuli. With a sterile inflammatory response, the stimulus persists without being eliminated suggesting that collateral damage is the cause of the disease. The common denominator with all intestinal inflammatory phenotypes is the central role of the gut microbiota whether it be microbial balance and diversity of microbial metabolic production or microbial turnover. PMID- 29618087 TI - Extensive and systematic rewiring of histone post-translational modifications in cancer model systems. AB - Histone post-translational modifications (PTMs) generate a complex combinatorial code that regulates gene expression and nuclear functions, and whose deregulation has been documented in different types of cancers. Therefore, the availability of relevant culture models that can be manipulated and that retain the epigenetic features of the tissue of origin is absolutely crucial for studying the epigenetic mechanisms underlying cancer and testing epigenetic drugs. In this study, we took advantage of quantitative mass spectrometry to comprehensively profile histone PTMs in patient tumor tissues, primary cultures and cell lines from three representative tumor models, breast cancer, glioblastoma and ovarian cancer, revealing an extensive and systematic rewiring of histone marks in cell culture conditions, which includes a decrease of H3K27me2/me3, H3K79me1/me2 and H3K9ac/K14ac, and an increase of H3K36me1/me2. While some changes occur in short term primary cultures, most of them are instead time-dependent and appear only in long-term cultures. Remarkably, such changes mostly revert in cell line- and primary cell-derived in vivo xenograft models. Taken together, these results support the use of xenografts as the most representative models of in vivo epigenetic processes, suggesting caution when using cultured cells, in particular cell lines and long-term primary cultures, for epigenetic investigations. PMID- 29618089 TI - A Rare Ultrasonographic Finding in Pudendal Neuralgia: Posteriorly Prolapsed Cervix. PMID- 29618088 TI - Cell-wall synthesis and ribosome maturation are co-regulated by an RNA switch in Mycobacterium tuberculosis. AB - The success of Mycobacterium tuberculosis relies on the ability to switch between active growth and non-replicating persistence, associated with latent TB infection. Resuscitation promoting factors (Rpfs) are essential for the transition between these states. Rpf expression is tightly regulated as these enzymes are able to degrade the cell wall, and hence potentially lethal to the bacterium itself. We have identified a regulatory element in the 5' untranslated region (UTR) of rpfB. We demonstrate that this element is a transcriptionally regulated RNA switch/riboswitch candidate, which appears to be restricted to pathogenic mycobacteria, suggesting a role in virulence. We have used translation start site mapping to re-annotate the RpfB start codon and identified and validated a ribosome binding site that is likely to be targeted by an rpfB antisense RNA. Finally, we show that rpfB is co-transcribed with ksgA and ispE downstream. ksgA encodes a universally conserved methyltransferase involved in ribosome maturation and ispE encodes an essential kinase involved in cell wall synthesis. This arrangement implies co-regulation of resuscitation, cell wall synthesis and ribosome maturation via the RNA switch. PMID- 29618090 TI - Finding the Signal in the Noise in the Serologic Diagnosis of Flavivirus Infections. PMID- 29618093 TI - Burn Survivor Quality of Life and Barriers to Support Program Participation. AB - After a serious burn, re-entry into family life, society, and work can be incredibly difficult. Support services such as professional counseling and peer support play a key role for recovering survivors. Herein, we sought to identify support service participation rates, barriers to participation, and quality of life (QOL) among burn survivors treated at a regional burn center. A survey of burn survivors over 18 years old treated for a burn for 5 days or greater between 2006 and 2016 were invited to participate in a survey. The three-part survey contained sections covering demographics, questions regarding support program (SP) awareness, needs and participation, and QOL surveys. Univariate and multivariate regression analyses were performed to identify factors related to SP participation and QOL scores. Nine hundred sixty-eight patients were eligible; 150 responses were received. Over one third (40, 31%) of the responding survivors wanted support, but only half of those (23, 17%) participated in SPs. Distance and awareness of the available programs were two barriers to participation. Those attending SPs were more likely to have had larger burns (OR = 3.7, P = 0.05) and visible burns (OR = 7.5, P = 0.031). Lower scores on selected QOL scales were associated with burns more than 30%, visible burns, female gender, time from burn, and age group. A sizable number of burn survivors want SPs. However, access to these services and advertising their existence are hurdles to overcome. Future burn survivor SPs should focus on psychosocial stresses identified in the QOL assessments. PMID- 29618091 TI - Longitudinal Analysis of Antibody Cross-neutralization Following Zika Virus and Dengue Virus Infection in Asia and the Americas. AB - Background: The 4 dengue virus serotypes (DENV1-4) and Zika virus (ZIKV) are related mosquito-borne flaviviruses of major importance globally. While monoclonal antibodies and plasma from DENV-immune donors can neutralize or enhance ZIKV in vitro and in small-animal models, and vice versa, the extent, duration, and significance of cross-reactivity in humans remains unknown, particularly in flavivirus-endemic regions. Methods: We studied neutralizing antibodies to ZIKV and DENV1-4 in longitudinal serologic specimens collected through 3 years after infection from people in Latin America and Asia with laboratory-confirmed DENV infections. We also evaluated neutralizing antibodies to ZIKV and DENV1-4 in patients with Zika through 6 months after infection. Results: In patients with Zika, the highest neutralizing antibody titers were to ZIKV, with low-level cross-reactivity to DENV1-4 that was greater in DENV-immune individuals. We found that, in primary and secondary DENV infections, neutralizing antibody titers to ZIKV were markedly lower than to the infecting DENV and heterologous DENV serotypes. Cross-neutralization was greatest in early convalescence, then ZIKV neutralization decreased, remaining at low levels over time. Conclusions: Patterns of antibody cross-neutralization suggest that ZIKV lies outside the DENV serocomplex. Neutralizing antibody titers can distinguish ZIKV from DENV infections when all viruses are analyzed simultaneously. These findings have implications for understanding natural immunity and vaccines. PMID- 29618095 TI - Case Report: Double Oberlin Nerve Transfer to Restore Elbow Flexion Following C5 C6 Avulsion Injury. AB - BACKGROUND AND IMPORTANCE: The use of nerve transfers to restore nerve function following traumatic avulsion injuries has been described, though there is still a paucity in the literature documenting technique and long-term outcomes for these procedures. The double Oberlin nerve transfer involves transferring fascicles from the median and ulnar nerves to the musculocutaneous nerve to restore elbow flexion in patients with a C5-C6 avulsion injury. The purpose of this case report is to present our indications and technique for a double Oberlin transfer in addition to exhibiting video footage at follow-up time points documenting the incremental improvement in elbow flexion following the injury. CLINICAL PRESENTATION: The patient is a 25-yr old, left-hand dominant male who presented 5 mo following a motor vehicle accident. He had 0/5 biceps muscle strength on the left with a computed tomography myelogram that demonstrated pseudomeningoceles from C2-C3 to C7-T1 with root avulsions of C5 and C6. He was subsequently indicated for a double Oberlin nerve transfer to restore elbow flexion. CONCLUSION: In this case report, we present our technique and outcomes for a double Oberlin transfer with restoration of elbow flexion at 1-yr follow-up for a patient with traumatic brachial plexus injury. We believe that the double Oberlin transfer serves as a safe and effective method to restore elbow flexion in this patient population. PMID- 29618094 TI - Clustering of Schizotypal Features in Unaffected First-Degree Relatives of Schizophrenia Patients. AB - Meehl conceptualized schizotypy as the phenotypic manifestations of a neural integrative defect resulting from a schizophrenia diathesis. The majority of schizotypy studies recruited subjects from the general population and revealed a multidimensional construct. This 2-phase investigation first examined the clustering of schizotypy in 194 unaffected relatives of schizophrenia patients using the Chapman Psychosis Proneness scales and then directly compared the cognitive profiles of negative schizotypal individuals and positive schizotypal individuals with schizophrenia patients and controls. In the first phase, cluster analysis categorized 194 unaffected relatives of schizophrenia patients into positive schizotypy (n = 33), negative schizotypy (n = 66), mixed schizotypy (n = 27), and low schizotypy (n = 64). Positive schizotypal participants showed more self-report pleasure experiences than negative schizotypal participants, replicating earlier cluster analytic findings. In the second phase, 27 negative schizotypal individuals, 18 positive schizotypal individuals, 19 schizophrenia patients, and 29 controls were recruited. Although the groups were matched in terms of age, gender, and IQ, they differed significantly in cognitive profiles. While schizophrenia patients exhibited the broadest cognitive impairments, negative schizotypal participants exhibited visual memory, working memory, and verbal fluency impairments, and positive schizotypal participants exhibited logical memory, visual memory, working memory, and theory-of-mind impairments. Among people with familial risk of schizophrenia, individuals exhibiting positive rather than negative schizotypal features resembled schizophrenia patients in cognitive profiles. Using the psychometric-familial method to identify schizotypy, our findings support the heterogeneity of schizotypy as well as the potential utility of the positive schizotypy dimension in genetically high-risk individuals to predict the risk of developing schizophrenia. PMID- 29618096 TI - Utilizing Mutual Information Analysis to Explore the Relationship Between Gray and White Matter Structural Pathologies in Schizophrenia. AB - Schizophrenia has been characterized as a neurodevelopmental disorder, with structural brain abnormalities reported at all stages. However, at present, it remains unclear whether gray and white matter abnormalities represent related or independent pathologies in schizophrenia. In this study, we present findings from an integrative analysis exploring the morphological relationship between gray and white matter in 45 schizophrenia participants and 49 healthy controls. We utilized mutual information (MI), a measure of how much information two variables share, to assess the morphological dependence between gray and white matter in three segments of the corpus callsoum, and the gray matter regions these segments connect: (1) the genu and the left and right rostral middle frontal gyrus (rMFG), (2) the isthmus and the left and right superior temporal gyrus (STG), (3) the splenium and the left and right lateral occipital gyrus (LOG). We report significantly reduced MI between white matter tract dispersion of the right hemispheric callosal connections to the STG and both cortical thickness and area in the right STG in schizophrenia patients, despite a lack of group differences in cortical thickness, surface area, or dispersion. We believe that this reduction in morphological dependence between gray and white matter may reflect a possible decoupling of the developmental processes that shape morphological features of white and gray matter early in life. The present study also demonstrates the importance of studying the relationship between gray and white matter measures, as opposed to restricting analyses to gray and white matter measures independently. PMID- 29618098 TI - Impact of cognitive behavioral therapy for insomnia disorder on sleep and comorbid symptoms in military personnel: a randomized clinical trial. AB - Study Objectives: To compare the efficacy of cognitive behavioral therapy for insomnia (CBTi) disorder and a Control condition on reducing insomnia and comorbid symptoms in a sample of active duty military personnel. Methods: Randomized clinical trial of 151 active duty US Army personnel at Fort Hood, Texas. Results: This study replicated Original (n = 66) findings (CBTi outperformed Control) in a follow-on sample (n = 85) on diary-assessed sleep efficiency (d = 1.04), total sleep time (d = 0.38), sleep latency (d = -0.93), number of awakenings (d = -0.56), wake time after sleep onset (d = -0.91), sleep quality (d = 1.00), and the Insomnia Severity Index (d = -1.36) in active duty soldiers. CBTi also outperformed Control in the combined sample (N = 151) on four of the five subscales of the Multidimensional Fatigue Inventory (d = -0.32 to 0.96) and the mental health subscale on the Veterans RAND 12-Item Health Survey (d = 0.37). Exploratory analyses also showed CBTi outperformed Control on nicotine (d = -0.22) and caffeine (d = -0.47) use reduction. Significant within group differences were found for both groups on depression, anxiety, and posttraumatic stress disorder symptoms, but there was no group by time interaction for these symptoms or for use of hypnotics or alcohol. Conclusions: CBTi was an effective treatment for insomnia and comorbid symptoms including daytime fatigue, general mental health, nicotine, and caffeine use. Clinical Trial Registration: Clinicaltrials.gov; Identifier: NCT01549899; "Comparing Internet and In-Person Brief Cognitive Behavioral Therapy of Insomnia". PMID- 29618097 TI - Alignment Modulates Ancestral Sequence Reconstruction Accuracy. AB - Accurate reconstruction of ancestral states is a critical evolutionary analysis when studying ancient proteins and comparing biochemical properties between parental or extinct species and their extant relatives. It relies on multiple sequence alignment (MSA) which may introduce biases, and it remains unknown how MSA methodological approaches impact ancestral sequence reconstruction (ASR). Here, we investigate how MSA methodology modulates ASR using a simulation study of various evolutionary scenarios. We evaluate the accuracy of ancestral protein sequence reconstruction for simulated data and compare reconstruction outcomes using different alignment methods. Our results reveal biases introduced not only by aligner algorithms and assumptions, but also tree topology and the rate of insertions and deletions. Under many conditions we find no substantial differences between the MSAs. However, increasing the difficulty for the aligners can significantly impact ASR. The MAFFT consistency aligners and PRANK variants exhibit the best performance, whereas FSA displays limited performance. We also discover a bias towards reconstructed sequences longer than the true ancestors, deriving from a preference for inferring insertions, in almost all MSA methodological approaches. In addition, we find measures of MSA quality generally correlate highly with reconstruction accuracy. Thus, we show MSA methodological differences can affect the quality of reconstructions and propose MSA methods should be selected with care to accurately determine ancestral states with confidence. PMID- 29618099 TI - Surgical Treatment of Extratemporal Epilepsy: Results and Prognostic Factors. AB - BACKGROUND: Surgery is a widely accepted option for the treatment of pharmacoresistant epilepsies of extratemporal origin. OBJECTIVE: To analyze clinical and epileptological results and to provide prognostic factors influencing seizure outcome. METHODS: This retrospective single-center study comprises a consecutive series of 383 patients, most of whom had an identifiable lesion on MRI, who underwent resective surgery for extratemporal epilepsy. Data including diagnostic modalities, surgical treatment, histopathology, prognostic factors, and epileptological outcome were analyzed. RESULTS: Resective procedures were located as follows: frontal (n = 183), parietal (n = 44), occipital (n = 24), and insular (n = 24). In 108 cases resection included more than 1 lobe. Histopatholological evaluation revealed focal cortical dysplasias (n = 178), tumors (n = 110), cavernomas (n = 27), gliosis (n = 42), and nonspecific findings (n = 36). A distinct epileptogenic lesion was detected in 338 (88.7%) patients. After a mean follow-up of 54 mo, 227 (62.5%) patients remained free from disabling seizures (Engel class I), and 178 (49%) were completely seizure free (Engel class Ia). There was no perioperative mortality. Permanent morbidity was encountered in 46 cases (11.8%). The following predictors were significantly associated with excellent seizure outcome (Engel I): lesion visible on magnetic resonance imaging (MRI; P = .02), noneloquent location (P = .01), complete resection of the lesion (P = .001), absence of epileptic activity postoperatively (P = .001), circumscribed histological findings (P = .001), lower age at surgery (P = .008), and shorter duration of epilepsy (P = .02). CONCLUSION: Surgical treatment of extratemporal epilepsy provides satisfying epileptological results with an acceptable morbidity. Best results can be achieved in younger patients with circumscribed MRI lesions, which can be resected completely. PMID- 29618100 TI - New Legal Landscapes: (Re)Constructing the Boundaries of Mental Capacity Law. AB - This article explores the development of law and policy relating to mental capacity law, situating this within the context of the binaries that have driven this development. Whilst the story of this historical development is well worn, considering it through this lens allows some of the previously hidden problematic consequences of these binaries to come to the fore in our debates. The article will expose these issues through considering the binary between capacity and incapacity, and the interlinked binaries of empowerment/protection and autonomy/paternalism underpinning policies and debate in this area. It will be shown that the struggles around the boundaries of this framework are becoming more pressing given the United Nations Convention on the Rights of Persons with Disabilities (UNCRPD), which presents a more fluid and potentially transformative framework for thinking about the legal subject in this context. There is here a danger, however, that we may end up falling too easily into seeing these issues through our current framework and in turn missing the opportunity to realise the potential of the UNCRPD. The article will disrupt and denaturalise the 'given ness' of these conceptual boundaries, drawing on theoretical insights that seek to foreground relationality and the dynamic nature and processes of law. This opens the space in which to reimagine alternative trajectories for legal and ethical responses to take, and to provoke new conceptual pathways. PMID- 29618102 TI - Comparative Safety and Efficacy of Modified TICI 2b and TICI 3 Reperfusion in Acute Ischemic Strokes Treated With Mechanical Thrombectomy. AB - BACKGROUND: Mechanical thrombectomy (MT) is the current standard of care for acute ischemic stroke (AIS) patients with emergent large-vessel occlusions (ELVO). Successful reperfusion of ELVO is traditionally defined by modified Thrombolysis in Cerebral Infarction (mTICI) grades of 2b or 3. OBJECTIVE: To evaluate the comparative safety and efficacy of mTICI 2b and mTICI 3 reperfusion in AIS patients treated with MT. METHODS: Consecutive ELVO patients who underwent MT at 6 high-volume centers were included in this analysis. Standard safety (3-mo mortality, symptomatic intracranial hemorrhage [sICH]) and efficacy (absolute and relative reduction in NIHSS-scores during hospitalization, functional-improvement [shift analysis in mRS-scores], and functional-independence [mRS-scores of 0-2] at 3-mo) were compared between patients who had mTICI 2b and mTICI 3 reperfusion post MT. RESULTS: A total of 416 ELVO patients achieved successful reperfusion with mTICI 2b (n = 216) and mTICI 3 (n = 200) following MT. The mTICI 3 group had significantly (P < .05) greater absolute (11 vs 9 points) and relative (77% vs 63%) reduction in NIHSS-scores during hospitalization, lower sICH (6% vs 12%), and higher 3-mo functional-independence (55% vs 44%) rates. Successful reperfusion with mTICI 3 was independently (P < .05) associated with greater absolute and relative reduction in NIHSS-scores during hospitalization as well as higher odds of 3-mo functional improvement (common odds ratios: 1.67; 95% confidence interval: 1.10-2.56) and functional independence (odds ratio: 2.08; 95% confidence interval: 1.22-3.53) in multivariable regression models adjusting for confounders. CONCLUSION: Successful reperfusion with mTICI 3 was associated with greater neurological improvement during hospitalization and better 3-mo functional outcomes in comparison to mTICI 2b reperfusion. PMID- 29618101 TI - Impact of intranasal oxytocin on interoceptive accuracy in alcohol users: An attentional mechanism? AB - Interoception, i.e. the perception and appraisal of internal bodily signals, is related to the phenomenon of craving, and is reportedly disrupted in alcohol use disorders. The hormone oxytocin influences afferent transmission of bodily signals and, through its potential modulation of craving, is proposed as a possible treatment for alcohol use disorders. However, oxytocin's impact on interoception in alcohol users remains unknown.Healthy alcohol users (N = 32) attended two laboratory sessions to perform tests of interoceptive ability (heartbeat tracking: attending to internal signals and, heartbeat discrimination: integrating internal and external signals) after intranasal administration of oxytocin or placebo. Effects of interoceptive accuracy, oxytocin administration and alcohol intake, were tested using mixed-effects models.On the tracking task, oxytocin reduced interoceptive accuracy, but did not interact with alcohol consumption. On the discrimination task, we found an interaction between oxytocin administration and alcohol intake: Oxytocin, compared to placebo, increased interoceptive accuracy in heavy drinkers, but not in light social drinkers.Our study does not suggest a pure interoceptive impairment in alcohol users but instead potentially highlights reduced flexibility of internal and external attentional resource allocation. Importantly, this impairment seems to be mitigated by oxytocin. This attentional hypothesis needs to be explicitly tested in future research. PMID- 29618103 TI - The Neurologic Assessment in Neuro-Oncology (NANO) Scale as an Assessment Tool for Survival in Patients With Primary Glioblastoma. AB - BACKGROUND: The Neurologic Assessment in Neuro-Oncology (NANO) scale is a standardized objective metric designed to measure neurological function in neuro oncology. Current neuroradiological evaluation guidelines fail to use specific clinical criteria for progression. OBJECTIVE: To determine if the NANO scale was a reliable assessment tool in glioblastoma (GBM) patients and whether it correlated to survival. METHODS: Our group performed a retrospective review of all patients with newly diagnosed GBM from January 1, 2010, through December 31, 2012, at our institution. We applied the NANO scale, Karnofsky performance score (KPS), Eastern Cooperative Oncology Group (ECOG) scale, Macdonald criteria, and the Response Assessment in Neuro-Oncology (RANO) criteria to patients at the time of diagnosis as well as at 3, 6, and 12 mo. RESULTS: Initial NANO score was correlated with overall survival at time of presentation. NANO progression was correlated with decreased survival in patients at 6 and 12 mo. A decrease in KPS was associated with survival at 3 and 6 mo, an increase in ECOG score was associated only at 3 mo, and radiological evaluation (RANO and Macdonald) was correlated at 3 and 6 mo. Only the NANO scale was associated with patient survival at 1 yr. NANO progression was the only metric that was linked to decreased overall survival when compared to RANO and Macdonald at 6 and 12 mo. CONCLUSION: The NANO scale is specific to neuro-oncology and can be used to assess patients with glioma. This retrospective analysis demonstrates the usefulness of the NANO scale in glioblastoma. PMID- 29618104 TI - Tissue Metabolic Changes Drive Cytokine Responses to Mycobacterium tuberculosis. AB - Cellular metabolism can influence host immune responses to Mycobacterium tuberculosis. Using a systems biology approach, differential expression of 292 metabolic genes involved in glycolysis, glutathione, pyrimidine, and inositol phosphate pathways was evident at the site of a human tuberculin skin test challenge in patients with active tuberculosis infection. For 28 metabolic genes, we identified single nucleotide polymorphisms that were trans-acting for in vitro cytokine responses to M. tuberculosis stimulation, including glutathione and pyrimidine metabolism genes that alter production of Th1 and Th17 cytokines. Our findings identify novel therapeutic targets in host metabolism that may shape protective immunity to tuberculosis. PMID- 29618105 TI - Physician Time Burden Associated with Querying Prescription Drug Monitoring Programs. AB - Objective: Prescription drug monitoring programs (PDMPs) enable prescribers to review patient prescription histories, and their use is mandatory in many states. We estimated the cost of physicians retrieving PDMP patient reports compared with a model where a delegate (i.e., administrative staff) retrieves reports. Methods: We performed a cost analysis with a one-year time horizon, from the perspective of physicians' employers. We obtained specialty-specific estimates of controlled substance prescribing frequency from the National Ambulatory Medical Care Survey, 2012-2014. We defined three PDMP usage cases based on the frequency of queries: comprehensive (before every Schedule II-IV controlled substance prescription), selective (before new Schedule II-IV prescriptions and every six months for continuing medications), and minimal (before new Schedule II or III prescriptions and annually for continuing medications). Results: The delegate model was less costly for all specialties in the comprehensive usage case and most specialties in the selective usage case, and it was similar to physician model costs in the minimal usage case. Estimated annual costs of the physician model to a large health care system (1,000 full-time equivalent physicians) were $1.6 million for comprehensive usage, $1.1 million for selective usage, and $645,313 for minimal usage. The delegate model was less costly in the comprehensive (savings of $907,283) and selective usage cases (savings of $156,216). Conclusions: Relying on delegates vs physicians to retrieve reports is less costly in most cases. Automation and integration of PDMP data into electronic health records may reduce costs further. Physicians, health care systems, and states should collaborate to streamline access to PDMPs. PMID- 29618106 TI - Contribution of Intrasellar Pressure Elevation to Headache Manifestation in Pituitary Adenoma Evaluated With Intraoperative Pressure Measurement. AB - BACKGROUND: Headache frequently occurs in patients with pituitary adenoma and is reported in large as well as small adenomas. However, the exact mechanism of headache derived from pituitary adenoma remains unknown. OBJECTIVE: To evaluate the contribution of intrasellar pressure (ISP) to headache manifestation by using intraoperative ISP measurement. METHODS: The records of 108 patients who had first-time transsphenoidal surgery for pituitary adenoma were reviewed retrospectively. Measurement of intraoperative ISP was undergone using intracranial pressure monitoring sensors and compared with radiological assessment. RESULTS: Among 30 patients with headache, 29 (96.7%) presented with significant headache (Headache Impact Score-6, 50 or greater). Intraoperative ISP measurement was conducted successfully in all cases, and revealed higher ISP in patients with headache (35.6 +/- 9.2 mm Hg) than in those without headache (15.8 +/- 5.2 mm Hg). The ISP reduction after sella floor decompression was greater in patients with headache than that in patients without headache. In patients with headache, the frequency of invasion into the cavernous sinus or sphenoid sinus was significantly lower, and the diameter of the foramen at the diaphragm sellae was narrower. In addition, intratumoral cyst or hematoma was more common in patients with headache. Postoperatively, headache was either diminished or improved in 28 patients (93.3%). CONCLUSION: Headache in patients with pituitary adenomas associated with ISP elevation, results from compromised dural integrity at the sella and intratumoral hemorrhage. The increased stretch force of the sella dura may be a notable etiology of headache in patients with pituitary adenoma. PMID- 29618107 TI - Incidence and Time of Onset of Osseous Pseudoprogression in Patients With Metastatic Spine Disease From Renal Cell or Prostate Carcinoma After Treatment With Stereotactic Body Radiation Therapy. AB - BACKGROUND: Tumor osseous pseudoprogression (PP), defined as an imaging-based transient increase in tumor size following treatment, was recently described in patients with spinal metastases following stereotactic body radiation therapy. Distinguishing PP from true tumor progression is critical. OBJECTIVE: To describe the incidence, time of onset, and time range of PP following stereotactic body radiation therapy in patients treated for spinal metastases from either prostate cancer (PC) or renal cell carcinoma (RCC), and associated predictive factors. METHODS: A retrospective study was conducted on our institution's cancer database from 2009 to 2015. Selection was based on single level, no prior radiation or surgery, >=2 follow-up spine magnetic resonance imaging (MRI), and metastases arising from either PC or RCC. Gross tumor volume was contoured on pre- and up to 5 posttreatment MRIs. Patients were sorted into groups depending on gross tumor volume response: PP, non-PP, or progressive disease. Clinical and dosimetric variables were compared using either Fisher's exact test or Kruskal-Wallis analyses. RESULTS: Forty-three spinal segments from 31 patients were analyzed. RCC and PC patients showed similar incidence of PP (~37%). Whether the primary was lytic or sclerotic was a significant predictive factor with more PP in the lytic group (P = .0208). There was a trend of earlier PP onset in RCC (within 6 18 mo) as compared to PC; however, PC segments showed more time-confined presentation of PP (9-12 mo). CONCLUSION: There was a higher incidence of PP in lytic compared to sclerotic primary tumor type. PP in spinal metastatic sites may have variable presentations depending on the primary cancer. PMID- 29618108 TI - Onion Hybrid Seed Production: Relation with Nectar Composition and Flower Traits. AB - Onion (Allium cepa L.) is one of the main vegetable crops. Pollinators are required for onion seed production, being honeybees the most used. Around the world, two types of onion varieties are grown: open pollinated (OP) and hybrids. Hybrids offer numerous advantages to growers, but usually have lower seed yields than OP cultivars, which in many cases compromise the success of new hybrids. As pollination is critical for seed set, understanding the role of floral rewards and attractants to pollinator species is the key to improve crop seed yield. In this study, the correlation of nectar-analyzed compounds, floral traits, and seed yield under open field conditions in two experimental sites was determined. Nectar composition was described through the analysis of sugars, phenol, and alkaloid compounds. Length and width of the style and tepals of the flowers were measured to describe floral traits. Floral and nectar traits showed differences among the studied lines. For nectar traits, we found a significant influence of the environment where plants were cultivated. Nonetheless, flower traits were not influenced by the experimental sites. The OP and the male-sterile lines (MSLs) showed differences in nectar chemical composition and floral traits. In addition, there were differences between and within MSLs, some of which were correlated with seed yield, bringing the opportunity to select the most productive MSL, using simple determinations of morphological characters like the length of the style or tepals size. PMID- 29618109 TI - Patient Values and Preferences Regarding Opioids for Chronic Noncancer Pain: A Systematic Review. AB - Objective: Shared-care decision-making between patients and clinicians involves making trade-offs between desirable and undesirable consequences of management strategies. Although patient values and preferences should provide the basis for these trade-offs, few guidelines consider the relevant evidence when formulating recommendations. To inform a guideline for use of opioids in patients with chronic noncancer pain, we conducted a systematic review of studies exploring values and preferences of affected patients toward opioid therapy. Methods: We searched MEDLINE, CINAHL, EMBASE, and PsycINFO from the inception of each database through October 2016. We included studies examining patient preferences for alternative approaches to managing chronic noncancer pain and studies that assessed how opioid-using chronic noncancer pain patients value alternative health states and their experiences with treatment. We compiled structured summaries of the results. Results: Pain relief and nausea and vomiting were ranked as highly significant outcomes across studies. When considered, the adverse effect of personality changes was rated as equally important. Constipation was assessed in most studies and was an important outcome, secondary to pain relief and nausea and vomiting. Of only two studies that evaluated addiction, both found it less important to patients than pain relief. No studies examined opioid overdose, death, or diversion. Conclusions: Our findings suggest that the adverse effects of opioids, especially nausea and vomiting, may reduce or eliminate any net benefit of opioid therapy unless pain relief is significant (>2 points on a 10-point scale). Further research should investigate patient values and preferences regarding opioid overdose, diversion, and death. PMID- 29618110 TI - Identification of Myofascial Trigger Points in Breast Cancer Survivors with Upper Limb Pain: Interrater Reliability. AB - Objective: Despite the increasing awareness of the contribution of myofascial dysfunctions to upper limb pain in breast cancer survivors, reliability of the identification of myofascial trigger points (MTPs) in this population has not yet been investigated. Therefore, the aim of the present study was to investigate the interrater reliability of the identification of MTPs by palpation at the upper limb region in breast cancer survivors with upper limb pain. Design: Interrater reliability study. Setting: University Hospitals Leuven, Belgium. Subjects: Thirty breast cancer survivors with pain at the upper limb region. Methods: Nine muscles (upper trapezius, levator scapulae, infraspinatus, supraspinatus, teres major and minor, subscapularis, pectoralis major, and scalene muscles) at the operated side were examined. The weighted kappa (WK) coefficient and Absolute Agreement with 95% confidence intervals were calculated. Results: Moderate agreement was found for all examined upper limb muscles (WK = 0.41-0.60), except for the trapezius muscle, for which the agreement was almost perfect (WK = 0.83), and the supraspinatus muscle (WK = 0.23), for which the agreement was only fair. Conclusions: For most muscles, moderate interrater reliability for the identification of MTPs by palpation in breast cancer survivors with upper limb pain was found. Therefore, we concluded that the identification of MTPs by palpation may add to the diagnosis of the myofascial pain syndrome in breast cancer survivors. PMID- 29618111 TI - Letter: Big Data Research in Neurosurgery: A Critical Look at This Popular New Study Design. PMID- 29618112 TI - Critical Care in the Military Health System: A Survey-Based Summary of Critical Care Services. AB - Introduction: Critical care is an important component of in-patient and combat casualty care, and it is a major contributor to U.S. healthcare costs. Regular exposure to critically ill and injured patients may directly contribute to wartime skills retention for military caregivers. Data describing critical care services in the Military Health System (MHS), however, is lacking. This study was undertaken to describe MHS critical care services, their resource utilization, and differences in care practices amongst military treatment facilities (MTFs). Materials and Methods: Twenty-six MTFs representing 38 adult critical care services or intensive care units (ICUs) were surveyed. The survey collected information about organizational structure, resourcing, and unit characteristics at the time of a concurrent 24-h point-prevalence survey designed to describe patient characteristics and staffing in these facilities. The survey was anonymous and protected health information was not collected. We analyzed the data according to high capacity centers (HCCs) (>=200 beds) and low capacity centers (LCCs) (<200 beds). Differences between HCCs and LCCs were compared using Fisher's exact test. Results: Seventeen MTFs (7 HCCs and 10 LCCs), representing 27 ICUs, responded to the survey. This was a 65% response rate for MTFs and a 71% response rate for services/ICUs. HCCs reported more closed vs. open ICUs; more dedicated critical care services (i.e., medical and surgical ICUs vs. mixed ICUs); fewer respiratory therapists available, but more with certification; more total nursing staff and more critical care certified nurses; the use of subjectively more effective protocols (10.5 vs. 6.7 protocols/unit or service); higher utilization of an ICU daily rounds checklist (65% vs. 0%); and less consistency of clinician type participation during multidisciplinary rounds. ICU leadership structure was similar among the institutions. The majority of respondents were unable to provide summary APACHE II scores, but HCCs were more likely to submit this information than LCCs. Most centers perform multidisciplinary rounds daily, but they are more likely to be run by a physician credentialed in critical care at HCCs (85% vs. 59%, p < 0.05). 67% of respondents reported mortality rates <5%. The two services that reported mortality rates greater than 10% were both LCCs. Conclusion: This is the first comprehensive report about MHS critical care services. Despite notable variability in data reporting, an important finding itself, this study highlights notable differences in organizational structure and resourcing between HCCs and LCCs within the MHS. The clinical implication of these differences (i.e., impact on patient outcomes) of these differences require further study. Better understanding of MHS critical care services may improve enterprise decision-making about these services which could ultimately improve care of combat casualties. PMID- 29618113 TI - Surgical Resection of Intramedullary Epidermoid Cyst: 2-Dimensional Operative Video. AB - Intramedullary epidermoid cysts are extremely rare lesions. Preoperative diagnosis can be challenging due to non-specific imaging futures. We illustrate the case of a 32-year-old man who presented with a symptomatic intramedullary mass, which at surgery proved to be an epidermoid cyst. The spinal cord was decompressed by removing the pearl-white keratin material, although the capsule, which was tenaciously adherent to the surrounding spinal cord parenchyma, was only partially removed. In this video, we illustrate the salient surgical points for the resection of this very unusual intramedullary lesion. PMID- 29618115 TI - Melanoma Screening and Mortality. PMID- 29618114 TI - Management of a Previously Coiled Anterior Cerebral Artery Aneurysm in a Child: 3 Dimensional Operative Video. AB - We present the case of an 11-yr-old male who originally presented to an outside hospital with subarachnoid hemorrhage. He was discovered at that time to have a ruptured right A1-A2 junction anterior cerebral artery aneurysm just proximal to the anterior communicating artery. He underwent endovascular coiling at the outside center. While recovering at a rehabilitation center, he had a rehemorrhage and acute neurological decline. He was transferred to our service, where he underwent surgical exploration and clip reconstruction of what appeared to be a pseudoaneurysm. After a frontotemporal exposure, the right A1 segment was identified at the carotid bifurcation and followed medially. The aneurysm was significantly larger than on the original angiogram and the wall of the aneurysm was extraordinarily thin, consistent with a pseudoaneurysm. A small portion of the gyrus rectus was removed to expose the A2 segments and the remainder of the large, partially thrombosed and coiled sac of the aneurysm. Thrombus and the previously placed coils were removed in a piecemeal fashion. Two fenestrated clips were used to reconstruct the right A1, with the blades used to bring together normal tissue on the ventral surface to create a new lumen. A Doppler ultrasound was used to insunate both A1s and A2s to confirm patency. Intraoperative cerebral angiogram showed complete obliteration of the aneurysm and excellent reconstruction of the anterior cerebral complex.The patient did very well and was neurologically intact on discharge.All appropriate patient consents were obtained for this submission. PMID- 29618116 TI - Critical Role of the Right VLPFC in Emotional Regulation of Social Exclusion: A tDCS Study. AB - There is abundant evidence suggesting that the right ventrolateral prefrontal cortex (rVLPFC) plays an important role in down-regulating the emotional response to social exclusion. However, a causal relationship between rVLPFC function and explicit emotional regulation is not clear in the context of social exclusion. This study employed anodal tDCS to activate rVLPFC while participants used emotional regulation to reappraise pictures of social exclusion. Forty-four participants were randomly assigned to an active tDCS group or a sham group. Both groups viewed social exclusion images under two conditions: in the no-reappraisal condition, participants were instructed to passively view social exclusion images; in the reappraisal condition, they reappraised the images to down regulate negative emotional responses. Compared to sham stimulation, anodal tDCS over the rVLPFC resulted in less negative emotion ratings, and produced significantly smaller pupil diameter in the reappraisal, compared to no reappraisal block. The tDCS also led to longer fixation durations to rejectees and shorter fixation durations to rejecters. Taken together, these findings suggest a causal role for rVLPFC in down-regulation of negative emotions produced by social exclusion. The current study has implications for clinical interventions targeting emotional regulation deficits. PMID- 29618117 TI - Dissociable Contributions of the Prefrontal Cortex in Group-Based Cooperation. AB - The success of our political institutions, environmental stewardship, and evolutionary fitness all hinge on our ability to prioritize collective-interest over self-interest. Despite considerable interest in the neuro-cognitive processes that underlie group cooperation, the evidence to date is inconsistent. Several papers support models of prosocial restraint, while more recent work supports models of prosocial intuition. We evaluate these competing models using a sample of lesion patients with damage to brain regions previously implicated in intuition and deliberation. Compared to matched control participants (brain damaged and healthy controls), we found that patients with dorsolateral prefrontal cortex (dlPFC) damage were less likely to cooperate in a modified public goods game, whereas patients with ventromedial prefrontal cortex (vmPFC) damage were more likely to cooperate. In contrast, we observed no association between cooperation and amygdala damage relative to controls. These findings suggest that the dlPFC, rather than the vmPFC or amygdala, plays a necessary role in group-based cooperation. These findings suggest cooperation does not solely rely on intuitive processes. Implications for models of group cooperation are discussed. PMID- 29618119 TI - External Ventricular Drain Placement Accuracy and Safety When Done by Midlevel Practitioners. AB - BACKGROUND: External ventricular drains (EVDs) measure intracranial pressure, divert cerebrospinal fluid, and allow for orthotropic administration of pharmacologic agents. Currently, neurosurgeons and neurosurgery residents are the primary practitioners placing EVDs. Due to the urgency of neurosurgical pathologies and the lack of qualified residents at most hospitals, midlevel practitioner (MLP) placement of EVDs would be advantageous. OBJECTIVE: To assess the accuracy and complication rates of MLP and neurosurgeon EVD placement. METHODS: This was a retrospective cohort of all patients with an EVD placed between January 2012 and September 2016 at a level 1 trauma center. We compared safety and accuracy of EVD placement between neurosurgeons and MLPs. RESULTS: MLP first attempted EVD placement in 238 patients and senior neurosurgeon first attempted EVD placement in 70 subjects. There was no significant difference between accuracy of placement within the ventricle (87.4% vs 90.0%, P = .5557), hemorrhage rate (5.9% vs 4.3%, P = .77), or infection rate (0.8% vs 1.4%, P = .5399) for placement attempted by an MLP compared with a neurosurgeon, respectively. CONCLUSION: MLPs perform EVD placement safely with no significant difference in accuracy of placement or complication rates compared with placement by senior neurosurgeons. This may allow for earlier management of elevated intracranial pressure and access to care where previously unavailable; leading to improved patient outcomes. PMID- 29618120 TI - In Reply: Intracranial Connections of the Vertebral Venous Plexus: Anatomic Study With Application to Neurosurgical and Endovascular Procedures at the Craniocervical Junction. PMID- 29618118 TI - Neural mechanisms of the rejection-aggression link. AB - Social rejection is a painful event that often increases aggression. However, the neural mechanisms of this rejection-aggression link remain unclear. A potential clue may be that rejected people often recruit the ventrolateral prefrontal cortex's (VLPFC) self-regulatory processes to manage the pain of rejection. Using functional MRI, we replicated previous links between rejection and activity in the brain's mentalizing network, social pain network and VLPFC. VLPFC recruitment during rejection was associated with greater activity in the brain's reward network (i.e. the ventral striatum) when individuals were given an opportunity to retaliate. This retaliation-related striatal response was associated with greater levels of retaliatory aggression. Dispositionally aggressive individuals exhibited less functional connectivity between the ventral striatum and the right VLPFC during aggression. This connectivity exerted a suppressing effect on dispositionally aggressive individuals' greater aggressive responses to rejection. These results help explain how the pain of rejection and reward of revenge motivate rejected people to behave aggressively. PMID- 29618121 TI - Precision medicine using different biological DMARDs based on characteristic phenotypes of peripheral T helper cells in psoriatic arthritis. AB - Objectives: We sought to investigate the selection of specific biological DMARDs (bDMARDs) based on characteristic lymphocyte phenotypes for treating PsA. Methods: Of 64 patients with PsA resistant to MTX, 26 underwent bDMARDs therapy selected according to phenotypic differences in peripheral helper T cells on 8 colour flow cytometry. The efficacies of this strategic treatment and the standard treatment administered to the other 38 patients were evaluated at 6 months. Results: The 26 patients with PsA in the strategic treatment group were classified into the following four types based on peripheral blood analysis: (i) CXCR3+CCR6-CD38+HLA-DR+ activated Th1 cell-predominant type, (ii) CXCR3-CCR6+ CD38+HLA-DR+ activated Th17 cell-predominant type, (iii) Th1/Th17-high type and (iv) Th1/Th17-low type. Accordingly, ustekinumab was administered to the activated Th1 cell-predominant patients, secukinumab to the activated Th17 cell predominant patients, secukinumab or TNF inhibitor to the Th1/Th17-high patients, and TNF inhibitor to the Th1/Th17-low patients. After 6 months of strategic treatment, there was a significant decrease in simplified disease activity index (SDAI) (from 16.2 to 3.52), DAS28 (ESR) (from 4.13 to 2.27) and psoriasis area and severity index (from 8.36 to 2.40). Low disease activity by SDAI was achieved in 24 (92.3%) of the 26 patients. The rate of low disease activity achievement according to SDAI at 6 months was significantly higher in the strategic bDMARDs treatment group compared with that of the standard bDMARDs treatment group. Conclusion: Strategic treatment in which different bDMARDs were selected according to phenotypic differences in helper T cells showed significantly higher efficacy than standard bDMARD therapy, indicating the value of precision medicine. PMID- 29618122 TI - DDX49 is an RNA helicase that affects translation by regulating mRNA export and the levels of pre-ribosomal RNA. AB - Among the proteins predicted to be a part of the DExD box RNA helicase family, the functions of DDX49 are unknown. Here, we characterize the enzymatic activities and functions of DDX49 by comparing its properties with the well studied RNA helicase, DDX39B. We find that DDX49 exhibits a robust ATPase and RNA helicase activity, significantly higher than that of DDX39B. DDX49 is required for the efficient export of poly (A)+ RNA from nucleus in a splicing-independent manner. Furthermore, DDX49 is a resident protein of nucleolus and regulates the steady state levels of pre-ribosomal RNA by regulating its transcription and stability. These dual functions of regulating mRNA export and pre-ribosomal RNA levels enable DDX49 to modulate global translation. Phenotypically, DDX49 promotes proliferation and colony forming potential of cells. Strikingly, DDX49 is significantly elevated in diverse cancer types suggesting that the increased abundance of DDX49 has a role in oncogenic transformation of cells. Taken together, this study shows the physiological role of DDX49 in regulating distinct steps of mRNA and pre-ribosomal RNA metabolism and hence translation and potential pathological role of its dysregulation, especially in cancers. PMID- 29618123 TI - Hydroxychloroquine-induced retinal toxicity in an asymptomatic patient. PMID- 29618124 TI - Microsurgical Resection of a Large Intraventricular Trigonal Tumor: 3-Dimensional Operative Video. AB - A 62-yr-old woman presented with incidentally detected left trigonal mass by magnetic resonance imaging (MRI) performed during workup for left-sided hearing loss and vertigo of 5-yr duration. Due to persistent dizziness, headache, and progressive enlargement of the tumor in follow-up scans, operation was planned. Because the tumor extended superiorly, a superior parietal lobule approach was selected.She underwent a left parietal craniotomy. A strip electrode was used to localize the motor and sensory regions, and neuronavigation was used to confirm the entry site. A small transsulcal corticotomy was performed posterior to a large cortical vein. The tumor was pinkish in color with a well-defined capsule. It was centrally debulked by using curettes, pituitary forceps, and the ultrasonic aspirator. Tumoral blood supply from the choroid plexus and the posterior choroidal vessels were cauterized and divided. Additional blood supply coming from the anterior choroidal vessels was also found and cauterized. After circumferential dissection of the tumor capsule, the tumor was removed completely. The pathology indicated WHO Grade I meningioma. The patient had mild expressive and receptive aphasia postoperatively, but improved progressively. The postoperative MRI showed total resection with no evidence of brain injury. At 3 mo follow-up, the speech was normal; she was independent for all daily activities, but had not yet returned to work (Karnofsky score 80).This 3-D video shows the technical nuances of microsurgical resection of an intraventricular tumor through a narrow brain corridor.Informed consent was obtained from the patient prior to the surgery that included videotaping of the procedure and its distribution for educational purposes. All relevant patient identifiers have also been removed from the video and accompanying radiology slides. PMID- 29618126 TI - Colon cancer incidence rates in the world from the Cancer Incidence in Five Continents XI. PMID- 29618125 TI - Distributed affective space represents multiple emotion categories across the human brain. AB - The functional organization of human emotion systems as well as their neuroanatomical basis and segregation in the brain remains unresolved. Here, we used pattern classification and hierarchical clustering to characterize the organization of a wide array of emotion categories in the human brain. We induced 14 emotions (6 'basic', e.g. fear and anger; and 8 'non-basic', e.g. shame and gratitude) and a neutral state using guided mental imagery while participants' brain activity was measured with functional magnetic resonance imaging (fMRI). Twelve out of 14 emotions could be reliably classified from the haemodynamic signals. All emotions engaged a multitude of brain areas, primarily in midline cortices including anterior and posterior cingulate gyri and precuneus, in subcortical regions, and in motor regions including cerebellum and premotor cortex. Similarity of subjective emotional experiences was associated with similarity of the corresponding neural activation patterns. We conclude that different basic and non-basic emotions have distinguishable neural bases characterized by specific, distributed activation patterns in widespread cortical and subcortical circuits. Regionally differentiated engagement of these circuits defines the unique neural activity pattern and the corresponding subjective feeling associated with each emotion. PMID- 29618127 TI - Online Ratings of Neurosurgeons: An Examination of Web Data and its Implications. AB - BACKGROUND: Patient satisfaction ratings are increasingly used for hospital rankings, referral base and physician reimbursement. As such, online physician rating websites (PRWs) are quickly becoming a topic of interest. OBJECTIVE: To analyze the distribution of neurosurgeons' ratings on the 3 most widely used PRWs, and examine factors associated with positive and negative ratings. METHODS: We used a key term search to identify board-certified neurosurgeons on 3 widely used PRWs: RateMD.com, Healthgrades.com, and Vitals.com. Data were collected on average rating and number of ratings. Demographic, training-related and practice related data, as well as location of practice, and place of training were also collected. RESULTS: Data was non-normally distributed (P < .001 for all 3). Having fewer reviews was associated with higher variance in ratings between PRWs for a given surgeon (odds ratio 0.99, P = .001). All surgeons below the 25th percentile with respect to the number of reviews that had been written about them were eliminated. Of the remaining surgeons (n = 3054), the median composite score was 4.11 out of 5, interquartile range (3.69, 4.44). Surgeons had higher median modified composite scores if they were fellowship-trained (P = .0001) or graduated from a top 25 medical school (P = .0117), but not if they graduated from a top 25 residency (P = .1056). Surgeons located in major cities had higher median composite scores (P = .0025). CONCLUSION: Online ratings for neurosurgeons must be evaluated in context. Median ratings are generally high, but variable between websites. Median scores also vary among regions and practice settings. Higher scores were associated with ranking of medical school, recent graduation, and fellowship training completion. PMID- 29618129 TI - Assessing Health Outcomes Among Veterans of Project SHAD (Shipboard Hazard and Defense). PMID- 29618128 TI - Anti-DFS70 autoantibodies in undifferentiated connective tissue diseases subjects: what's on the horizon? AB - Objective: The main objective was to determine the prevalence of anti-dense fine speckled (DFS70) antibodies in a stable population of undifferentiated connective tissue disease (UCTD) to better define their potential role. Methods: Immunological and clinical records of 91 long-standing UCTD patients were studied. DFS pattern was determined using the IIF ANA test on HEp-2 cells and anti-DFS70 antibodies were tested by chemiluminescence assay and by DFS70 line immunoassay. Results: Twelve (13.2%) of 91 serum samples were positive for anti DFS70 antibodies by chemiluminescence assay and line immunoassay. There was no statistical significance between the prevalence of anti-ENA and anti-DNA autoantibodies in patients with and without anti-DFS70 antibodies. No differences were found in the clinical characteristics of both groups. The presence of the anti-DFS70 antibodies was related to the younger age class. Conclusion: The high prevalence of anti-DFS70 antibodies in the UCTD patients suggested the potential role of these autoantibodies as a marker in the evolution of UCTD to CTD. PMID- 29618130 TI - 131I DOSE ESTIMATION FROM INTAKE OF TAP WATER IN THE EARLY PHASE AFTER FUKUSHIMA DAIICHI NUCLEAR POWER PLANT ACCIDENT. AB - In March 2011, the Fukushima Daiichi Nuclear Power Plant Accident occurred and a large amount of radionuclides was released. To study its effect, we estimated the internal exposure due to intake of tap water in the early phase after the accident. As the number of measured values of tap water following the accident was limited, 131I concentration in tap water was estimated by 1-compartment model using the deposition amount of radionuclides calculated by an atmospheric transport, dispersion and deposition simulation. The internal doses for the evacuees were estimated by assuming representative evacuation patterns, and the internal doses for the non-evacuees were estimated for each municipal government. In the evacuation areas, the maximum of thyroid equivalent dose of 1- and 10-year old children and adults were 22, 11 and 4.7 mSv, respectively. The maximum of thyroid equivalent dose of those three groups in the non-evacuation areas were 9.5, 4.7 and 2.0 mSv, respectively. PMID- 29618132 TI - Systemic Exercise-Induced Hypoalgesia Following Isometric Exercise Reduces Conditioned Pain Modulation. AB - Objective: Physically active individuals show greater conditioned pain modulation (CPM) compared with less active individuals. Understanding the effects of acute exercise on CPM may allow for a more targeted use of exercise in the management of pain. This study investigated the effects of acute isometric exercise on CPM. In addition, the between-session and within-session reliability of CPM was investigated. Design: Experimental, randomized crossover study. Setting: Laboratory at Marquette University. Subjects: Thirty healthy adults (19.3+/-1.5 years, 15 males). Methods: Subjects underwent CPM testing before and after isometric exercise (knee extension, 30% maximum voluntary contraction for three minutes) and quiet rest in two separate experimental sessions. Pressure pain thresholds (PPTs) at the quadriceps and upper trapezius muscles were assessed before, during, and after ice water immersions. Results: PPTs increased during ice water immersion (i.e., CPM), and quadriceps PPT increased after exercise (P < 0.05). CPM decreased similarly following exercise and quiet rest (P > 0.05). CPM within-session reliability was fair to good (intraclass correlation coefficient [ICC] = 0.43-0.70), and the between-session reliability was poor (ICC = 0.20 0.35). Due to the variability in the systemic exercise-induced hypoalgesia (EIH) response, participants were divided into systemic EIH responders (N = 9) and nonresponders (N = 21). EIH responders experienced attenuated CPM following exercise (P = 0.03), whereas the nonresponders showed no significant change (P > 0.05). Conclusions: Isometric exercise decreased CPM in individuals who reported systemic EIH, suggesting activation of shared mechanisms between CPM and systemic EIH responses. These results may improve the understanding of increased pain after exercise in patients with chronic pain and potentially attenuated CPM. PMID- 29618131 TI - RESIDENTIAL EXPOSURE TO EXTREMELY LOW FREQUENCY ELECTRIC AND MAGNETIC FIELDS IN THE CITY OF RAMALLAH-PALESTINE. AB - This study was focused on the measurement of residential exposure to power frequency (50-Hz) electric and magnetic fields in the city of Ramallah-Palestine. A group of 32 semi-randomly selected residences distributed amongst the city were under investigations of fields variations. Measurements were performed with the Spectrum Analyzer NF-5035 and were carried out at one meter above ground level in the residence's bedroom or living room under both zero and normal-power conditions. Fields' variations were recorded over 6-min and some times over few hours. Electric fields under normal-power use were relatively low; ~59% of residences experienced mean electric fields <10 V/m. The highest mean electric field of 66.9 V/m was found at residence R27. However, electric field values were log-normally distributed with geometric mean and geometric standard deviation of 9.6 and 3.5 V/m, respectively. Background electric fields measured under zero power use, were very low; ~80% of residences experienced background electric fields <1 V/m. Under normal-power use, the highest mean magnetic field (0.45 MUT) was found at residence R26 where an indoor power substation exists. However, ~81% of residences experienced mean magnetic fields <0.1 MUT. Magnetic fields measured inside the 32 residences showed also a log-normal distribution with geometric mean and geometric standard deviation of 0.04 and 3.14 MUT, respectively. Under zero-power conditions, ~7% of residences experienced average background magnetic field >0.1 MUT. Fields from appliances showed a maximum mean electric field of 67.4 V/m from hair dryer, and maximum mean magnetic field of 13.7 MUT from microwave oven. However, no single result surpassed the ICNIRP limits for general public exposures to ELF fields, but still, the interval 0.3-0.4 MUT for possible non-thermal health impacts of exposure to ELF magnetic fields, was experienced in 13% of the residences. PMID- 29618134 TI - Melanin-concentrating hormone-expressing neurons adjust slow-wave sleep dynamics to catalyze paradoxical (REM) sleep. AB - Study Objectives: Experimental studies over the last 15 years established a role in sleep of the tuberal hypothalamic neurons that express melanin-concentrating hormone (MCH). Controversies still remain regarding their actual contribution to both slow-wave sleep (SWS) and paradoxical sleep (PS also known as REM sleep) or PS alone. Methods: To address this point, we compared effects of chemogenetic activation and inhibition of MCH neurons on SWS and PS amounts and EEG rhythmic activities in transgenic Pmch-cre mice. Results: In agreement with recently reported optogenetic data, the activation of MCH neurons invariably facilitates PS onset and maintenance. Our chemogenetic experiments further disclose that the ultradian rhythm of SWS is also notably related to the activity of MCH neurons. We observed that the mean duration of SWS episodes is significantly extended when MCH neurons are inhibited. Conversely, when they were excited, SWS bouts were drastically shortened and depicted substantial changes in delta rhythmic activities in electroencephalographic recording likely reflecting a deeper SWS. Conclusions: According to these original findings, we propose that when MCH neurons are physiologically recruited, SWS depth is increased and the extinction of SWS episodes is accelerated, two joint physiological processes strengthening the probability for natural SWS to PS transition and likely facilitating PS onset. PMID- 29618135 TI - Outcomes of 40 Nonsyndromic Sagittal Craniosynostosis Patients as Adults: A Case Control Study With 26 Years of Postoperative Follow-up. AB - BACKGROUND: While sagittal synostosis is the most common craniosynostosis, long term follow-up of these patients is lacking. OBJECTIVE: To evaluate the results of surgical management of those patients with sagittal synostosis who attain adulthood. METHODS: An outcome study of surgically treated isolated sagittal synostosis patients operated between 1977 and 1998 was conducted at the Craniofacial Center of Oulu University Hospital, Oulu, Finland with an average follow-up time of 26.5 yr. Patients' socioeconomic situation, satisfaction with their own facial appearance and attractiveness as rated by 2 independent panels was evaluated and compared to controls. RESULTS: The self-satisfaction with the patients' own appearance scored a mean of 75 mm on a visual analog scale of 100 mm between the patients and 76 mm with the control group. The subjective satisfaction of the patients with their own appearance failed to correlate with the rating of their appearance by the panels. The panels rated the patients' appearance to be on average 6 to 7 mm out of 100 mm visual analog scale less attractive than the controls. Data on socioeconomic situation, including marital status, housing, education, employment of the patients, and controls are presented. CONCLUSION: Isolated sagittal synostosis patients treated surgically were as happy with their facial appearance as were individuals in an age and gender-matched control group. Two independent panels found the patients' appearance to be only somewhat less attractive. Analysis of the socioeconomic situation and general health revealed that patients equaled that of controls. PMID- 29618136 TI - The role of ultrasound-defined tenosynovitis and synovitis in the prediction of rheumatoid arthritis development. AB - Objectives: Tenosynovitis (TS) is common in early arthritis. However, the value of US-defined TS in predicting RA development is unclear. We assessed the predictive utility of US-defined TS alongside US-defined synovitis and clinical and serological variables in a prospective cohort of early arthritis patients. Methods: One hundred and seven patients with clinically apparent synovitis of one or more joint and symptom duration ?3 months underwent baseline clinical, laboratory and US assessment of 19 bilateral joint sites and 16 bilateral tendon compartments. Diagnostic outcome was determined after 18 months, applying the 2010 ACR/EULAR classification criteria for RA. The predictive values of US defined TS for persistent RA were compared with those of US-defined synovitis, clinical and serological variables. Results: A total of 4066 US joint sites and 3424 US tendon compartments were included in the analysis. Forty-six patients developed persistent RA, 17 patients developed non-RA persistent disease and 44 patients had resolving disease at follow-up. US-defined TS in at least one tendon compartment at baseline was common in all groups (RA 85%, non-RA persistent disease 71% and resolving 70%). On multi-variate analysis, US-defined digit flexor TS provided independent predictive data over and above the presence of ACPA and US-defined joint synovitis. Conclusion: US-defined digit flexor TS provided independent predictive data for persistent RA development in patients with early arthritis. The predictive utility of this tendon site should be further assessed in a larger cohort; investigators designing imaging-based predictive algorithms for RA development should include this tendon component as a candidate variable. PMID- 29618137 TI - Diagnostic Investigation of Lesions Associated with Succinate Dehydrogenase Defects. AB - The mitochondrial enzyme succinate dehydrogenase (SDH) acts as a tumor suppressor. Biallelic inactivation of one of the genes encoding for SDH subunits (collectively named SDHx) leads to complete loss of the protein function and the development of diverse group of tumors. Pheochromocytomas-paragangliomas are the prime example of hereditary tumors caused by SDH deficiency. In this review, we discuss the roles of imaging examinations, and illustrate new insights into genotype-imaging phenotype relationships. PMID- 29618138 TI - Duodenocolonic Fistula As A Rare Complication of Intestinal Burkitt Lymphoma in a Three-Year-Old Boy. AB - BACKGROUND: Burkitt lymphoma (BL) in children often presents with abdominal localization. Intestinal perforations have been described mainly during treatment. We report on a three-year-old patient with abdominal BL who was diagnosed with a duodenocolonic fistula. CASE REPORT: A three-year-old boy presented with diarrhea, crampy abdominal pain, and a four-week history of loss of appetite and weight. Ultrasound and MRI detected a colonic tumor forming a duodenocolonic fistula which was verified by gastroduodenoscopy. A surgical biopsy revealed BL. The stage III BL with low LDH was treated with four courses of BFM-type short-pulse chemotherapy. After two courses of chemotherapy the patient developed a mechanic ileus. A segmental resection of a short segment of the colon at the right flexure carrying the residual tumor mass with cicatricial stenosis and fistula followed by colonic end to end anastomosis and covering of the fistula by omentum major were carried out without complication. 15 days after surgery, two additional courses of chemotherapy could be administrated and the boy is in ongoing remission and free of any symptoms with a follow-up interval of 18 months. CONCLUSIONS: Duodeonocolonic fistula at presentation in a child with abdominal BL is extremely rare. Delayed surgery after size of the tumor bulk has been reduced by chemotherapy might represent a risk adapted approach. However, due to limited experience with duodenocolonic fistulas even in larger pediatric lymphoma trials any decision has to be based on the problems to be faced in individual cases. PMID- 29618139 TI - Factors Affecting Acceptance of Hospital Information Systems Based on Extended Technology Acceptance Model: A Case Study in Three Paraclinical Departments. AB - OBJECTIVE: Regardless of the acceptance of users, information and communication systems can be considered as a health intervention designed to improve the care delivered to patients. This study aimed to determine the adoption and use of the extended Technology Acceptance Model (TAM2) by the users of hospital information system (HIS) in paraclinical departments including laboratory, radiology, and nutrition and to investigate the key factors of adoption and use of these systems. MATERIALS AND METHODS: A standard questionnaire was used to collect the data from nearly 253 users of these systems in paraclinical departments of eight university hospitals in two different cities of Iran. A total of 202 questionnaires including valid responses were used in this study (105 in Urmia and 97 in Khorramabad). The data were processed using LISREL and SPSS software and statistical analysis technique was based on the structural equation modeling (SEM). RESULTS: It was found that the original TAM constructs had a significant impact on the staffs' behavioral intention to adopt HIS in paraclinical departments. The results of this study indicated that cognitive instrumental processes (job relevance, output quality, result demonstrability, and perceived ease of use), except for result demonstrability, were significant predictors of intention to use, whereas the result revealed no significant relationship between social influence processes (subjective norm, voluntariness, and image) and the users' behavioral intention to use the system. CONCLUSION: The results confirmed that several factors in the TAM2 that were important in previous studies were not significant in paraclinical departments and in government-owned hospitals. The users' behavior factors are essential for successful usage of the system and should be considered. It provides valuable information for hospital system providers and policy makers in understanding the adoption challenges as well as practical guidance for the successful implementation of information systems in paraclinical departments. PMID- 29618140 TI - [The S3 Guidelines Psychosocial Therapies in Severe Mental Illness - The Update]. PMID- 29618141 TI - Erratum to: Knee Pain and the Use of Various Types of Footwear-A Review. PMID- 29618142 TI - Preoperative Hyponatremia Is Associated with Reoperation and Prolonged Length of Hospital Stay following Total Knee Arthroplasty. AB - Hyponatremia is a risk factor for adverse surgical outcomes, but limited information is available on the prognosis of hyponatremic patients who undergo total knee arthroplasty (TKA). The purpose of this investigation was to compare the incidence of major morbidity (MM), 30-day readmission, 30-day reoperation, and length of hospital stay (LOS) between normonatremic and hypontremic TKA patients.The American College of Surgeons National Surgical Quality Improvement Program database was used to identify all primary TKA procedures. Hyponatremia was defined as <135 mEq/L and normonatremia as 135 to 145 mEq/L; hypernatremic patients (>145 mEq/L) were excluded. Multivariable logistic regression was used to determine the association between hyponatremia and outcomes after adjusting for demographics and comorbidities. An alpha level of 0.002 was used and calculated using the Bonferroni correction. Our final analysis included 88,103 patients of which 3,763 were hyponatremic and 84,340 were normonatremic preoperatively. In our multivariable models, hyponatremic patients did not have significantly higher odds of experiencing an MM (odds ratio [OR]: 1.05; 99% confidence interval [CI] 0.93-1.19) or readmission (OR: 1.12; 99% CI: 1-1.24). However, patients with hyponatremia did experience significantly greater odds for reoperation (OR: 1.24; 99% CI: 1.05-1.46) and longer hospital stay (OR: 1.15; 99% CI: 1.09-1.21). We found that hyponatremic patients undergoing TKA had increased odds of reoperation and prolonged hospital stay. Preoperative hyponatremia may be a modifiable risk factor for adverse outcomes in patients undergoing TKA, and additional prospective studies are warranted to determine whether preoperative correction of hyponatremia can prevent complications. PMID- 29618143 TI - Efficacy and Safety of Hylan versus Hyaluronic Acid in the Treatment of Knee Osteoarthritis. AB - The purpose of this study was to use meta-analytic approach to compare the efficacy and safety of intraarticular hylan and hyaluronic acid (HA) for knee osteoarthritis (OA) treatment. We searched PubMed, Embase, and the Cochrane databases through July 2017 to identify Level I randomized controlled trials (RCTs) that evaluated clinical efficacy and safety of hylan compared with HA for knee OA. The primary outcomes were Visual Analogue Scale (VAS) for pain and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain, and WOMAC function scores. In each study and for the outcome measures (VAS for pain, WOMAC pain, function and stiffness scores, and Lequesne score), we calculated the treatment effect from the difference between the preintervention and postintervention changes in the hylan and HA groups. Twenty-one RCTs involving 3,058 patients were included. Pooled analysis suggested that compared with HA, hylan was associated with similar pain relief and function improvement in patients with knee OA (VAS for pain: mean difference [MD], -3.04; 95% confidence interval [CI], -9.13 to 3.04; p = 0.33; I2 = 76%. WOMAC pain score: MD, 0.23; 95% CI, -0.25 to 0.70; p = 0.35; I2 = 0%. WOMAC function score: MD, -0.47; 95% CI, 6.81 to 5.88; p = 0.88; I2 = 84%). No significant difference was found comparing the patients with treatment-related adverse events. The relationship was robust in sensitivity analysis and consistent in most of the subgroup analyses. As to the primary outcomes (WOMAC pain, function scores, VAS for pain), the difference between hylan and HA did not reach the previously reported minimum clinically important difference (MCID) values (-13.4 for VAS for pain, -2.0 for WOMAC pain score, -7.7 for WOMAC function score). Our meta-analysis showed that there were no statistically and clinically significant differences in pain relief and function improvement between hylan and HA injections for knee OA treatment. In view of its higher costs, we discourage the use of hylan in patients with knee OA in clinical practice. The level of evidence is I, meta-analysis of Level I studies. PMID- 29618144 TI - Five-Strand Hamstring Autograft in Primary Anterior Cruciate Ligament Reconstruction. AB - The purpose of this study was to describe our surgical technique of using five strand hamstring autograft with interference screw fixation in primary anterior cruciate ligament (ACL) reconstruction and to report the early postoperative outcomes of this technique. Patients who underwent primary ACL reconstruction using five-strand hamstring autografts with interference screw fixation between December 2014 and June 2016 were included in this study. The five-strand configuration was used in these patients because the four-strand configuration produced a graft diameter of less than 8 mm. Subjective questionnaires, including the Knee Injury and Osteoarthritis Outcome Score (KOOS) and the Lysholm Score, were administered preoperatively, as well as at 1- and 2-year follow-ups. Paired t-test was used to compare the pre- and postoperative outcome scores. The study group comprised 25 patients. There were no intraoperative complications. The mean follow-up period was 17.8 months (12-24). There were 19 males and 6 females. The median age was 24 years (16-41), and median body mass index was 23.9 (18.5-30.2). The median diameter of the five-strand graft was 9 mm (8-10 mm), with a mean of 9.06 +/- 0.60 mm. This was associated with a median graft length of 90 mm (80-100 mm). The postoperative Lysholm, KOOS symptoms, KOOS Pain, KOOS daily function, KOOS sports function, KOOS quality of life, and Short Form-36 Physical Component Summary scores improved significantly compared with the preoperative scores. The use of the five-strand hamstring graft with interference screw fixation in primary ACL reconstruction is associated with significant improvements in patient reported outcomes in the early postoperative period. The five-strand graft technique is a useful means of increasing graft diameter when faced with an undersized hamstring graft. PMID- 29618145 TI - Reliability of Intraoperative Knee Range of Motion Measurements by Goniometer Compared with Robot-Assisted Arthroplasty. AB - Accurate measurement of knee range of motion (ROM) is critical to predict the outcomes of knee surgery and prognosis. We investigated the reliability of knee ROM measurements by goniometer compared with robotic system. Fifty-three patients with medial osteoarthritis who were planning to undergo unicompartmental knee arthroplasty (UKA) with robotic UKA were prospectively enrolled. During the operation, knee ROM measurement was performed in both flexion and extension before and after insertion of the implant using both a goniometer and robotic system. The intraclass correlation coefficient (ICC) of extension measured by the goniometer and robotic system showed good agreement; however, the ICC of flexion did not show good agreement. During passive flexion, the mean values measured before insertion of the implant were significantly lower by goniometer (134.6 +/- 6.43) than by robot (145.4 +/- 6.80; p = 0.017); likewise, the mean values after insertion of the implant were significantly lower by goniometer (138.6 +/- 6.07) than by robotic system (147.0 +/- 6.60; p = 0.045). A goniometer can underestimate knee ROM measurements compared with robotic system, especially in flexion. Orthopaedic surgeons should be cautious when measuring the flexion angle with a goniometer. PMID- 29618146 TI - Comparison of the Leg-Length Change between Opening- and Closing-Wedge High Tibial Osteotomy: A Systematic Review and Meta-Analysis. AB - The aim of this meta-analysis was to compare the effects of closing-wedge (CW) and opening-wedge (OW) high tibial osteotomies (HTOs) on the change in leg length. Our hypotheses were that leg length will increase after OW HTO and decrease after CW HTO, and the magnitude of the change in leg length would be negligible in both techniques. Multiple databases including MEDLINE, Embase, and Cochrane were searched for studies comparing the change in leg length after HTO with that before HTO. After testing for publication bias and heterogeneity, we aggregated variables by using the random-effects model. The weighted mean differences of leg length were estimated before and after OW and CW HTOs with 95% confidence intervals (CIs). Four studies that analyzed 127 OW HTOs and 175 CW HTOs were included in this meta-analysis. Leg length increased by 6.96 mm after OW HTO (95% CI: -3.43 to 17.36) and decreased by 1.95 mm after CW HTO (95% CI: 10.89 to 7). Additionally, the change in leg length after OW HTO had a positive correlation with the degree of correction. The leg length increased after OW HTO, and the increase was sufficiently large to cause clinical concerns. The change in leg length after CW HTO was negligible despite the decrease in length. Therefore, CW HTO seems to be a better treatment option than OW HTO if a large correction is required. PMID- 29618147 TI - Where is the Target Point to Prevent Cortical Hinge Fracture in Medial Closing Wedge Distal Femoral Varus Osteotomy? AB - The purpose of this study was to investigate whether the location of the hinge affects the incidence of hinge fracture during medial closing-wedge distal femoral varus osteotomy (DFVO). Twenty knees from 10 fresh-frozen human cadavers (mean age, 75 +/- 17 years) were used to perform uniplanar medial closing-wedge DFVO with a 7-mm wedge. Each specimen was randomly assigned to either group A (supracondylar hinge) or group B (lateral condylar hinge). The incidence of hinge fracture and stability was compared between both groups after uniplanar medial closing-wedge DFVO. In group A, 8 of 10 knees had a lateral cortex fracture during closure of the osteotomy gap, and all fractured knees were unstable. Two knees with an intact lateral cortical hinge showed stability under manual valgus and varus forces. After intentional breakage of the lateral cortical hinge, both knees were found to be unstable under the same force. In group B, 2 of 10 knees had a lateral cortex fracture, and 8 knees had no fractures. All specimens were found to be stable under manual valgus and varus forces. After intentional breakage of the lateral cortical hinge in group B, 2 knees were unstable, while 8 knees remained stable. This study showed a significantly higher incidence of lateral cortical hinge fracture and instability in group A than in group B during closure of the osteotomy gap. PMID- 29618148 TI - Previous History of Breast Cancer Increases Rates of Pulmonary Embolism and Costs after Total Knee Arthroplasty: An Evaluation of 185,114 Matched Patients. AB - Risk factors for adverse events after total knee arthroplasty (TKA) relating to malignancy have not been well studied. Thus, the purpose of this study was to conduct a retrospective case-control outcome and cost analysis after TKA in this population. Patients with a history of breast cancer (BrCa) were identified based on the International Classification of Disease 9th revision codes. An age- and sex-matched cohort was also identified of patients without a history of BrCa. Complications, length of stay, comorbidity burden, and reimbursements were tracked at 90 days. Each cohort comprised 92,557 patients. Length of stay was similar between cohorts (p = 0.627). Comorbidity status and incidence of pulmonary embolism (PE), lower extremity ultrasound, and chest computed tomography (CT) use were higher in patients with a history of BrCa (p < 0.05 for all). Control patients had a lower incidence of acute myocardial infarction (0.14 vs. 0.21%; p < 0.001). Surgical complications were similar. The 90-day reimbursements were greater in patients with a history of BrCa (US$13,990 vs. US$13,033 for controls; p = 0.021). Surgeons should be aware of the increased risk of PE after TKA in patients with a history of BrCa as well as increased 90 day costs, which warrant great attention. PMID- 29618149 TI - Ankle and Hindfoot Symptoms after Medial Open Wedge High Tibial Osteotomy. AB - Medial open wedge high tibial osteotomy (MOWHTO) is a commonly performed procedure for symptomatic medial compartment osteoarthritis (OA). However, little is known about its effects on ipsilateral ankle or hindfoot. The aim of our study was to determine the incidence of ankle or hindfoot problems after MOWHTO and examine its association with radiological indices. Thirty-five knees (32 patients) undergoing navigated MOWHTO were evaluated for the presence of new onset ankle or hindfoot symptoms after surgery. Pre- and postoperative hip-knee ankle (HKA) angle, medial proximal tibial angle (MPTA), and tibial plafond inclination (TPI) were measured and compared on standing lower limb alignment radiographs. The mean postoperative change in HKA angle, MPTA, and TPI was 8.8 degrees , 7.0 degrees , and 8.4 degrees , respectively. New-onset unexplained ankle or hindfoot symptoms were seen in 20% of the cases after surgery. Postoperative change in TPI was significantly greater in symptomatic patients as compared with asymptomatic ones (12.8 degrees +/- 4.9 degrees vs. 8.1 degrees +/- 4.8 degrees , p = 0.03). The odds ratio (OR) for developing ankle or hindfoot symptoms in cases with >= 10 degrees change in TPI postoperatively was 10.8 (p = 0.04). Ankle or hindfoot symptoms were successfully managed with conservative treatment in all cases. PMID- 29618150 TI - A Meta-Analysis Comparing Liposomal Bupivacaine and Traditional Periarticular Injection for Pain Control after Total Knee Arthroplasty. AB - Liposomal bupivacaine is a novel method for pain control after total knee arthroplasty (TKA), but recent studies showed no advantage for patients undergoing TKA compared with traditional periarticular injection (PAI). The purpose of this analysis was to compare the clinical outcomes between liposomal bupivacaine treatment and traditional PAI. We retrospectively reviewed data from 16 clinical trials in published databases from their inception to June 2017. The primary outcome was postoperative Visual Analogue Scale (VAS) score and secondary outcomes included opiate usage, narcotic consumption, range of motion, and length of stay. Nine randomized controlled trials and seven nonrandomized controlled trials involving 924 liposomal bupivacaine cases and 1,293 traditional PAI cases were eligible for inclusion in the meta-analysis. No differences were detected in most of the clinical outcomes, except for postoperative VAS within 12 hours and length of stay. This analysis showed that liposomal bupivacaine is not associated with significant improvement in postoperative pain control or other outcomes in TKA compared with PAI. PMID- 29618151 TI - Procoagulant State in Current and Former Anabolic Androgenic Steroid Abusers. AB - BACKGROUND: Anabolic androgenic steroid (AAS) abusers are considered at increased risk of cardiovascular morbidity and mortality. We hypothesized that current and former AAS abuse would induce a procoagulant shift in the haemostatic balance. METHODS: Men 18 to 50 years of age were included as current AAS abusers, former AAS abusers or controls. Morning blood samples were collected after overnight fasting. Thrombin generation (lag time, time to peak, peak height, and endogenous thrombin potential [ETP]) and coagulation factor II (prothrombin), VII and X, antithrombin, protein C, free protein S and tissue factor pathway inhibitor (TFPI) were assessed. Groups were compared by ANOVA or Kruskal-Wallis test and probabilities were corrected for multiple comparisons. Associations were evaluated using linear regression models. RESULTS: ETP was increased around 15% in current (n = 37) and former (n = 33) AAS abusers compared with controls (n = 30; p < 0.001). Prothrombin and factor X were increased >=10% in AAS abusers and prothrombin was a predictor of ETP (p < 0.0005). Lag time and time to peak were increased 10 to 30% in current AAS abusers (p < 0.001) and associated with higher concentrations of TFPI, antithrombin, protein C and protein S (p < 0.0005; = 0.005). Multivariate linear regression, with all coagulation inhibitors as covariates, identified TFPI to be independently associated with lag time and time to peak (p < 0.0005). CONCLUSION: Thrombin generation is augmented in current and former AAS abusers, reflecting a procoagulant state, with altered concentrations of coagulation proteins. Prospective studies are needed to clarify whether these findings translate into an increased thrombotic risk in AAS abusers potentially even after cessation. PMID- 29618152 TI - Altered Plasma Clot Properties and Trauma-Related Venous Thromboembolism despite Thromboprophylaxis. AB - BACKGROUND: Prothrombotic clot phenotype may characterize patients developing deep vein thrombosis (DVT) despite pharmacological thromboprophylaxis. We studied the role of fibrin clot properties and its potential determinants in individuals who experienced DVT after lower limb injury. METHODS: In a case-control study, we assessed 50 patients who developed DVT despite prophylactic use of low molecular-weight heparins (the failed thromboprophylaxis group) after a lower limb injury, and three age- and sex-matched control groups, 50 patients each: (1) patients with trauma-related DVT without prior thromboprophylaxis; (2) individuals with unprovoked DVT; (3) patients without history of DVT (the no-DVT controls). Fibrin clot properties, along with thrombin concentration and alpha2 antiplasmin, were assessed following 3 months of anticoagulation in all DVT patients. RESULTS: Compared with the no-DVT controls, the failed thromboprophylaxis group exhibited denser fibrin networks (12.8% lower clot permeability [Ks], p = 0.0008) and impaired fibrinolysis (46.2% longer clot lysis time [CLT], p = 0.0001 and 8% lower rate of D-dimer release from clots, p = 0.0008). In the unprovoked DVT, similar Ks and 14.9% shorter CLT (p = 0.02) were reported compared with the failed thromboprophylaxis group. The failed thromboprophylaxis patients had higher odds of having elevated peak thrombin generation (>241.5 nM, 90th percentile in the no-DVT controls; odds ratio [OR]: 3.62; 95% confidence interval [CI], 1.86-7.06; p = 0.002), and higher odds of having elevated alpha2-antiplasmin (>115.05%; OR: 3.38; 95% CI, 1.64-6.98; p = 0.001). CONCLUSION: Patients who experienced DVT despite thromboprophylaxis following lower limb trauma display a strongly prothrombotic fibrin clot phenotype, including increased clot density and hypofibrinolysis associated with higher plasma alpha2-antiplasmin. PMID- 29618153 TI - Activation of Endoplasmic Reticulum Stress and Unfolded Protein Response in Congenital Factor VII Deficiency. AB - Congenital factor (F) VII deficiency is a bleeding disorder caused by a heterogeneous pattern of mutations in the F7 gene. Protein misfolding due to mutations is a strong candidate mechanism to produce the highly represented type I FVII deficiency forms, characterized by a concomitant deficiency of FVII antigen and activity. Misfolded proteins can accumulate within the endoplasmic reticulum (ER) causing ER stress with subsequent activation of the unfolded protein response (UPR). So far, there are limited data on this important issue in FVII deficiency. In this study, we chose as candidate FVII model mutations, the p.Q160R, p.I289del and p.A354V-p.P464Hfs, which are all associated with severe to moderate type I FVII deficiency. In vitro expression of the recombinant (r) mutants rFVII-160R, rFVII-289del or rFVII-354V-464Hfs, which are characterized by either amino acid substitution, deletion, or by an extended carboxyl terminus, demonstrated inefficient secretion of the mutant proteins, probably caused by intracellular retention and association with ER chaperones. Both ER stress and UPR were activated following expression of all FVII mutants, with the highest response for rFVII-289del and rFVII-354V-464Hfs. These data unravel new knowledge on pathogenic mechanisms leading to FVII deficiency, and support the investigation of pharmaceutical modulators of ER stress and UPR as therapeutic agents. PMID- 29618154 TI - Low Plasma ADAMTS13 Activity Is Associated with Coagulopathy, Endothelial Cell Damage and Mortality after Severe Paediatric Trauma. AB - Decrease of plasma activity of ADAMTS13, a metalloenzyme that cleaves von Willebrand factor (VWF) and prevents adhesion and aggregation of platelets, has been reported early after onset of systemic inflammation resulting from infections and after severe trauma. Here, we determined whether trauma-induced systemic (sterile) inflammation would be associated with a reduction of plasma ADAMTS13 activity in paediatric patients and its association with disease severity and outcome. Paediatric patients (n = 106) with severe trauma at a level 1 paediatric trauma centre between 2014 and 2016 were prospectively enrolled. Blood samples were collected upon arrival and at 24 hours and analysed for plasma levels of ADAMTS13 activity, VWF antigen, collagen binding activity, human neutrophil peptides (HNP) 1-3, coagulation abnormalities, endothelial glycocalyx damage and clinical outcome. Plasma samples were also collected for similar measurements from 52 healthy paediatric controls who underwent elective minor surgery. The median age of patients was 9 years with 81% sustaining blunt trauma. The median injury severity score was 22 and the mortality rate was 11%. Plasma levels of ADAMTS13 activity were significantly lower and plasma levels of VWF antigen and HNP 1-3 proteins were significantly higher for paediatric trauma patients on admission and at 24 hours when compared with controls. Finally, the lowest plasma ADAMTS13 activity was found in patients who died from their injuries. We conclude that relative plasma deficiency of ADAMTS13 activity may be associated with more severe traumatic injury, significant endothelial glycocalyx damage, coagulation abnormalities and mortality after severe trauma in paediatric patients. PMID- 29618155 TI - Von Willebrand Factor Aggravates Hepatic Ischemia-Reperfusion Injury by Promoting Neutrophil Recruitment in Mice. AB - Hepatic ischaemia-reperfusion (I/R) injury is a serious liver damage that critically influences the clinical outcome of liver surgery or transplantation. Since recent studies indicated the critical involvement of von Willebrand factor (VWF) in reperfusion injuries of brain and myocardium, we hypothesized that VWF dependent thrombotic or inflammatory responses also play a role in hepatic I/R injury. Using a mouse model of hepatic I/R injury, we explored the functional relevance of the VWF-ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) axis in this pathologic condition. Time course studies during hepatic I/R revealed significantly lower alanine aminotransferase (ALT) values, as well as greater hepatic blood flow, in VWF gene deleted (KO) mice in comparison with wild-type (WT) mice. Histological analysis revealed a significantly lesser extent of neutrophil infiltration and hepatocellular necrosis in liver tissues of VWF-KO mice. Human recombinant ADAMTS13 significantly improved the impairment in ALT values and hepatic blood flow and decreased neutrophil infiltration within the liver tissue of WT mice. Real-time intravital imaging successfully visualized significantly reduced leukocyte-vessel wall interactions in I/R liver of VWF-KO mice. Taken together, our results indicate that VWF promotes neutrophil recruitment in ischaemic mouse liver, critically aggravating reperfusion injury, and suggest that functional regulation of VWF by ADAMTS13 represents a promising therapeutic option for hepatic I/R injury. PMID- 29618156 TI - ADAMTS-13 Activity Predicts Outcome in Acute Ischaemic Stroke Patients Undergoing Endovascular Treatment. AB - BACKGROUND: Endovascular treatment improves outcome in patients with acute ischaemic stroke due to large vessel occlusion in general. But outcome in some of these patients is jeopardized by recanalization failure or bleeding. OBJECTIVES: This study aimed to determine a possible association of mediators of inflammation and haemostasis (C-reactive protein, interleukin-6, matrix metalloproteinase-9, monocyte chemoattractant protein-1, asymmetric dimethylarginine [ADMA], symmetric dimethylarginine, von Willebrand factor and a disintegrin and metalloproteinase with a thrombospondin type 1 motif 13 [ADAMTS-13]) with the post-intervention grade of reperfusion, complications and clinical outcome in patients who underwent endovascular treatment of ischaemic stroke. PATIENTS/METHODS: Forty one patients with acute ischaemic stroke due to large vessel occlusion were prospectively enrolled into the study. Peripheral venous blood was taken prior to treatment and 24 hours and 3, 7 and 90 days after symptom onset. The post intervention grade of reperfusion was determined using the modified Treatment in Cerebral Infarction (mTICI) score. Clinical outcome on day 90 was assessed using the modified Rankin's scale (mRS). RESULTS: Low ADAMTS-13 activity (p = 0.009) and missing of statin therapy (p = 0.038) on admission were independently associated with unfavourable outcome (mRS: 5-6). Patients with unsuccessful reperfusion (mTICI: 0-1) showed higher ADMA levels on admission (p = 0.018). However, this association could not be confirmed in the binary logistic regression analysis. CONCLUSION: Low ADAMTS-13 activity is a predictor of unfavourable outcome in patients with ischaemic stroke undergoing endovascular therapy. Further studies are warranted to elucidate the clinical and potential therapeutic role of ADAMTS-13 in acute ischaemic stroke. PMID- 29618157 TI - Angiopoietin-2 and Survival in Peripheral Artery Disease Patients. AB - Survival of peripheral arterial disease (PAD) patients increased over the last decade due to increased use of secondary preventive medication and rapid revascularization of PAD patients. Angiogenetic markers such as vascular endothelial growth factor (VEGF), angiopoietin-2 (Ang-2) and its receptor Tie-2 might be useful markers to assess the residual risk for mortality in PAD patients. The aim of this study was to evaluate angiogenetic markers for the prediction of mortality in a PAD cohort. For this purpose, 366 patients (mean age: 69 +/- 10 years) with PAD Fontaine stage I or II were included and followed up over a 5-year study period. Serum Ang-2, Tie-2 and VEGF levels were measured by bead-based multiplex assay. All-cause mortality and major cardiovascular events (MACE) including all-cause death, non-fatal stroke and non-fatal myocardial infarction were analysed by Kaplan-Meier and Cox regression analyses after 5 years. Ang-2 was associated with Tie-2 (R = 0.151, p = 0.006) and VEGF levels (R = 0.160, p = 0.002). However, only Ang-2 was linked to all all-cause mortality in PAD patients (hazard ratio [HR]: 1.55 [1.23-2.15], p = 0.008) even after adjustment for age and gender, haemoglobin A1c, low-density lipoprotein cholesterol, systolic blood pressure and glomerular filtration rate (HR: 1.44 [1.03-2.00], p = 0.032). Furthermore, an association of Ang-2 and MACE in PAD patients (HR: 1.36 (1.03-1.78), p = 0.028) was found. This result implies that Ang-2 might be used as an additional marker to stratify PAD patients to predict poor mid-term life expectancy. PMID- 29618158 TI - Erratum to: Thromboelastometry and platelet function during acclimatisation to high altitude. PMID- 29618160 TI - Comparing Non-Vitamin K Antagonist Oral Anticoagulants (NOACs) to Different Coumadins: The Win-Win Scenarios. PMID- 29618159 TI - Early P2Y12 Inhibitors Escalation in Primary PCI Patients: Insights from the RENOVAMI Registry. AB - BACKGROUND: Early escalation from clopidogrel to new generation P2Y12 inhibitors is common practice in patients with ST-elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (pPCI). Real-world data about this strategy, however, are limited. METHODS: From 2012 to 2015, 1,057 consecutive STEMI patients treated with pPCI in an Italian hub-and-spoke network were prospectively included in an observational registry (RENOVAMI, ClinicalTrials.gov Identifier: NCT01760382). We compared the prevalence, predictive factors and in-hospital outcomes of patients escalated to a new generation P2Y12 inhibitor within the first 24 hours from pPCI with those continuing on admission antiplatelet therapy. RESULTS: In the first 24 hours after pPCI, 165 patients (15.6%) were escalated from clopidogrel to a new generation P2Y12 inhibitor, while de-escalation to clopidogrel was occasional (19 patients, 1.8%) and switch between new generation P2Y12 inhibitors was rare (8 patients, 0.8%, all from ticagrelor to prasugrel). Drug eluting stent use (adjusted odds ratio [OR], 2.19, 95% confidence interval [CI], 1.55-3.08, p = 0.0002) and impaired renal function (adjusted OR, 0.19, 95% CI, 0.05-0.77, p = 0.02) were the only independent predictive factors for the decision to escalate. After adjustment for potential confounders, escalation did not predict in hospital outcomes, whereas the overall use of new generation P2Y12 inhibitors was correlated with a better in-hospital survival (adjusted hazard ratio, 0.47, 95% CI, 0.25-0.91, p = 0.03). Moreover, escalation did not influence bleeding rates. CONCLUSIONS: In this prospective registry of STEMI patients treated with pPCI and contemporary antiplatelet therapy, early escalation to a new generation P2Y12 inhibitor appeared safe and did not significantly affect in-hospital bleeding rates. PMID- 29618161 TI - Risk of Thromboembolic Events without Oral Anticoagulation at 90 Days after Surgical Aortic Valve Replacement with a Bioprosthesis. PMID- 29618162 TI - Renal Impairment, Recurrent Venous Thromboembolism and Bleeding in Cancer Patients with Acute Venous Thromboembolism-Analysis of the CATCH Study. AB - OBJECTIVE: This article assesses the impact of renal impairment (RI) on the efficacy and safety of anticoagulation in patients with cancer-associated thrombosis from the Comparison of Acute Treatments in Cancer Hemostasis (CATCH) study (NCT01130025). MATERIALS AND METHODS: Renal function was assessed using the Modification of Diet in Renal Disease equation in patients with cancer associated thrombosis who received either tinzaparin (175 IU/kg) once daily or warfarin for 6 months, in an open-label, randomized, multi-centre trial with blinded adjudication of outcomes. Associations between baseline RI (glomerular filtration rate [GFR] <60 mL/min/1.73m2) and recurrent symptomatic or incidental venous thromboembolism (VTE), clinically relevant bleeding (CRB), major bleeding and death were assessed using Fisher's exact test. RESULTS: Baseline-centralized GFR data were available for 864 patients (96% of study population). RI was found in 131 patients (15%; n = 69 tinzaparin). Recurrent VTE occurred in 14% of patients with and 8% of patients without RI (relative risk [RR] 1.74; 95% confidence interval [CI] 1.06, 2.85), CRB in 19% and 14%, respectively (RR 1.33; 95% CI 0.90, 1.98), major bleeding in 6.1% and 2.0%, respectively (RR 2.98; 95% CI 1.29, 6.90) and mortality rate was 40% and 34%, respectively (RR 1.20; 95% CI 0.94, 1.53). Patients with RI on tinzaparin showed no difference in recurrent VTE, CRB, major bleeding or mortality rates versus those on warfarin. CONCLUSION: RI in patients with cancer-associated thrombosis on anticoagulation was associated with a statistically significant increase in recurrent VTE and major bleeding, but no significant increase in CRB or mortality. No differences were observed between long-term tinzaparin therapy and warfarin. PMID- 29618163 TI - Differential diagnosis between a granuloma and radicular cyst: effectiveness of magnetic resonance imaging. AB - AIM: To investigate the diagnostic reliability and accuracy of magnetic resonance imaging (MRI) to differentiate periapical lesions of endodontic origin and to compare the results with histopathological information. METHODOLOGY: The radiolucent periapical jaw lesions of 34 patients, which were surgically enucleated, were investigated by two radiologists using MRI, based on the same six criteria, to categorize the lesions as granulomas, radicular cysts or others. After apicoectomies, two oral pathologists (blinded to the radiologist's diagnoses) analysed all specimens by referring to seven specific parameters and diagnosed the specimens as granulomas, radicular cysts or other conditions. The inter-rater agreements between the radiologists and pathologists in terms of MRI and histological diagnoses, respectively, along with the discriminant power of the adopted criteria and the accuracy of the MRI assessments compared with the histopathological results, were calculated. Cohen's kappa test was adopted to examine inter-rater agreement between the two radiologists and two pathologists. Guttman's lambda coefficient (lambda6 ) was used to evaluate the internal consistency of the items used for the differential diagnosis by radiologists. The accuracy resulted from a receiver operator characteristic (ROC) analysis. RESULTS: A strong inter-rater reliability was observed between the two radiologists (k-statistic = 0.86, P = 0.0001) and the two pathologists (k statistic = 0.88, P = 0.0001). The internal consistency of the diagnostic items was 0.605 for cysts and 0.771 for granulomas. The accuracy (true positives plus true negatives) of the radiologists was greater than that of the pathologists based on analysis (area under the curve = 0.87 and 0.91, respectively). CONCLUSIONS: The reliability and accuracy of MRI were high and comparable to histopathological reliability, highlighting the usefulness of this noninvasive technique as a pre-treatment diagnostic method for periapical endodontic lesions. PMID- 29618165 TI - Small arteries stay stiff for a longer period following vibration exercises in combination with blood flow restriction. AB - PURPOSE: The aim of this study was to assess the effect of isometric exercises performed during whole-body vibration (WBV) with and without blood flow restriction (BFR) on arterial elasticity and hemodynamic variables. METHODS: Eight male subjects performed static upper body (UB) and lower body (LB) exercises on a vibration platform with and without BFR. During BFR sessions, BFR cuffs were placed on the arms or legs and inflated to a target pressure. Exercises consisted of eight 45-s sets for UB, and ten 1-min sets for LB. Arterial elasticity and hemodynamic variables were assessed before, at 10 min and 40 min postexercise. Repeated measures ANOVA was used to test the mean differences in related variables. RESULTS: A significant condition (BFR versus no BFR) main effect was detected for small arterial elasticity (P<0.05). For heart rate (HR), there were significant time (P<0.01), condition (P = 0.02) and body (P = 0.04) main effects during exercise and condition (P<0.04) and time (P<0.01) main effects following exercise. Significantly lower values in systemic vascular resistance were detected at 10 min post compared to 40 min post (P<0.02) and UB compared to LB (P = 0.02). CONCLUSIONS: Results showed that small arteries stayed stiffer for a longer period of time after vibration exercises with BFR and BFR placed a greater demand on cardiovascular system. Findings also indicated that the type of exercises performed and/or the measurement location are very important and should be taken into account when examining arterial response. PMID- 29618164 TI - Dissecting genomic hotspots underlying seed protein, oil, and sucrose content in an interspecific mapping population of soybean using high-density linkage mapping. AB - The cultivated [Glycine max (L) Merr.] and wild [Glycine soja Siebold & Zucc.] soybean species comprise wide variation in seed composition traits. Compared to wild soybean, cultivated soybean contains low protein, high oil, and high sucrose. In this study, an interspecific population was derived from a cross between G. max (Williams 82) and G. soja (PI 483460B). This recombinant inbred line (RIL) population of 188 lines was sequenced at 0.3* depth. Based on 91 342 single nucleotide polymorphisms (SNPs), recombination events in RILs were defined, and a high-resolution bin map was developed (4070 bins). In addition to bin mapping, quantitative trait loci (QTL) analysis for protein, oil, and sucrose was performed using 3343 polymorphic SNPs (3K-SNP), derived from Illumina Infinium BeadChip sequencing platform. The QTL regions from both platforms were compared, and a significant concordance was observed between bin and 3K-SNP markers. Importantly, the bin map derived from next-generation sequencing technology enhanced mapping resolution (from 1325 to 50 Kb). A total of five, nine, and four QTLs were identified for protein, oil, and sucrose content, respectively, and some of the QTLs coincided with soybean domestication-related genomic loci. The major QTL for protein and oil were mapped on Chr. 20 (qPro_20) and suggested negative correlation between oil and protein. In terms of sucrose content, a novel and major QTL were identified on Chr. 8 (qSuc_08) and harbours putative genes involved in sugar transport. In addition, genome-wide association using 91 342 SNPs confirmed the genomic loci derived from QTL mapping. A QTL based haplotype using whole-genome resequencing of 106 diverse soybean lines identified unique allelic variation in wild soybean that could be utilized to widen the genetic base in cultivated soybean. PMID- 29618166 TI - Homo and hetero dimerisation of the human guanylate-binding proteins hGBP-1 and hGBP-5 characterised by affinities and kinetics. AB - The human guanylate-binding proteins (hGBPs) exhibit diverse antipathogenic and tumour-related functions which make them key players in the innate immune response. The isoforms hGBP-1 to hGBP-5 form homomeric complexes and localise to specific cellular compartments. Upon heteromeric interactions, hGBPs are able to guide each other to their specific compartments. Thus, homo- and heteromeric interactions allow the hGBPs to build a network within the cell which might be important for their diverse biological functions. We characterised homomeric complexes of hGBPs in vitro and presented most recently that nonprenylated hGBP-1 and hGBP-5 form dimers as highest oligomeric species while farnesylated hGBP-1 is able to form polymers. We continued to work on the biochemical characterisation of the heteromeric interactions between hGBPs and present here results for nonprenylated hGBP-1 and hGBP-5. Multiangle light scattering identified the GTP dependent heteromeric complex as dimer. Also hGBP-5's tumour-associated splice variant (hGBP-5ta) was able to form a hetero dimer with hGBP-1. Intriguingly, both hGBP-5 splice variants were able to induce domain rearrangements within hGBP 1. We further characterised the homo and hetero dimers with Forster resonance energy transfer-based experiments. This allowed us to obtain affinities and kinetics of the homo and hetero dimer formation. Furthermore, we identified that the LG domains of hGBP-1 and hGBP-5 build an interaction site within the hetero dimer. Our in vitro study provides mechanistic insights into the homomeric and heteromeric interactions of hGBP-1 and hGBP-5 and present useful strategies to characterise the hGBP network further. PMID- 29618169 TI - Seasonal associations with novel climates for North American migratory bird populations. AB - Determining the implications of global climate change for highly mobile taxa such as migratory birds requires a perspective that is spatiotemporally comprehensive and ecologically relevant. Here, we document how passerine bird species that migrate within the Western Hemisphere (n = 77) are associated with projected novel climates across the full annual cycle. Following expectations, highly novel climates occurred on tropical non-breeding grounds and the least novel climates occurred on temperate breeding grounds. Contrary to expectations, highly novel climates also occurred within temperate regions during the transition from breeding to autumn migration. This outcome was caused by lower inter-annual climatic variability occurring in combination with stronger warming projections. Thus, migrants are projected to encounter novel climates across the majority of their annual cycle, with a pronounced peak occurring when juveniles are leaving the nest and preparing to embark on their first migratory journey, which may adversely affect their chances of survival. PMID- 29618168 TI - Higher chlorzoxazone clearance in obese children compared with nonobese peers. AB - AIMS: To test the in vivo activity of Cytochrome P450 (CYP) 2E1 in obese children vs. nonobese children, aged 11-18 years. Secondly, whether the activity of CYP2E1 in these patients is associated with NALFD, diabetes or hyperlipidaemia. METHODS: Seventy children were divided into groups by body mass index (BMI) standard deviation score (SDS). All children received 250 mg oral chlorzoxazone (CLZ) as probe for CYP2E1 activity. Thirteen blood samples and 20-h urine samples were collected per participant. RESULTS: Obese children had an increased oral clearance and distribution of CLZ, indicating increased CYP2E1 activity, similar to obese adults. The mean AUC0-infinity value of CLZ was decreased by 46% in obese children compared to nonobese children. The F was was increased twofold in obese children compared to nonobese children, P < 0.0001. Diabetic biomarkers were significantly increased in obese children, while fasting blood glucose and Hba1c levels were nonsignificant between groups. Liver fat content was not associated with CLZ Cl. CONCLUSION: Oral clearance of CLZ was increased two-fold in obese children vs. nonobese children aged 11-18 years. This indicates an increased CYP2E1 activity of clinical importance, and dose adjustment should be considered for CLZ. PMID- 29618167 TI - Recombinant protein susceptibility to proteolysis in the plant cell secretory pathway is pH-dependent. AB - Cellular engineering approaches have been proposed to mitigate unintended proteolysis in plant protein biofactories, involving the design of protease activity-depleted environments by gene silencing or in situ inactivation with accessory protease inhibitors. Here, we assessed the impact of influenza virus M2 proton channel on host protease activities and recombinant protein processing in the cell secretory pathway of Nicotiana benthamiana leaves. Transient co expression assays with M2 and GFP variant pHluorin were first conducted to illustrate the potential of proton export from the Golgi lumen to promote recombinant protein yield. A fusion protein-based system involving protease sensitive peptide linkers to attach inactive variants of tomato cystatin SlCYS8 was then designed to relate the effects of M2 on protein levels with altered protease activities in situ. Secreted versions of the cystatin fusions transiently expressed in leaf tissue showed variable 'fusion to free cystatin' cleavage ratios, in line with the occurrence of protease forms differentially active against the peptide linkers in the secretory pathway. Variable ratios were also observed for the fusions co-expressed with M2, but the extent of fusion cleavage was changed for several fusions, positively or negatively, as a result of pH increase in the Golgi. These data indicating a remodelling of endogenous protease activities upon M2 expression confirm that the stability of recombinant proteins in the plant cell secretory pathway is pH-dependent. They suggest, in practice, the potential of M2 proton channel to modulate the stability of protease-susceptible secreted proteins in planta via a pH-related, indirect effect on host resident proteases. PMID- 29618170 TI - Climate change and an invasive, tropical milkweed: an ecological trap for monarch butterflies. AB - While it is well established that climate change affects species distributions and abundances, the impacts of climate change on species interactions has not been extensively studied. This is particularly important for specialists whose interactions are tightly linked, such as between the monarch butterfly (Danaus plexippus) and the plant genus Asclepias, on which it depends. We used open-top chambers (OTCs) to increase temperatures in experimental plots and placed either nonnative Asclepias curassavica or native A. incarnata in each plot along with monarch larvae. We found, under current climatic conditions, adult monarchs had higher survival and mass when feeding on A. curassavica. However, under future conditions, monarchs fared much worse on A. curassavica. The decrease in adult survival and mass was associated with increasing cardenolide concentrations under warmer temperatures. Increased temperatures alone reduced monarch forewing length. Cardenolide concentrations in A. curassavica may have transitioned from beneficial to detrimental as temperature increased. Thus, the increasing cardenolide concentrations may have pushed the larvae over a tipping point into an ecological trap; whereby past environmental cues associated with increased fitness give misleading information. Given the ubiquity of specialist plant herbivore interactions, the potential for such ecological traps to emerge as temperatures increase may have far-reaching consequences. PMID- 29618171 TI - Percutaneous vertebroplasty for osteoporotic vertebral compression fracture. AB - BACKGROUND: Percutaneous vertebroplasty remains widely used to treat osteoporotic vertebral fractures although our 2015 Cochrane review did not support its role in routine practice. OBJECTIVES: To update the available evidence of the benefits and harms of vertebroplasty for treatment of osteoporotic vertebral fractures. SEARCH METHODS: We updated the search of CENTRAL, MEDLINE and Embase and trial registries to 15 November 2017. SELECTION CRITERIA: We included randomised and quasi-randomised controlled trials (RCTs) of adults with painful osteoporotic vertebral fractures, comparing vertebroplasty with placebo (sham), usual care, or another intervention. As it is least prone to bias, vertebroplasty compared with placebo was the primary comparison. Major outcomes were mean overall pain, disability, disease-specific and overall health-related quality of life, patient reported treatment success, new symptomatic vertebral fractures and number of other serious adverse events. DATA COLLECTION AND ANALYSIS: We used standard methodologic procedures expected by Cochrane. MAIN RESULTS: Twenty-one trials were included: five compared vertebroplasty with placebo (541 randomised participants), eight with usual care (1136 randomised participants), seven with kyphoplasty (968 randomised participants) and one compared vertebroplasty with facet joint glucocorticoid injection (217 randomised participants). Trial size varied from 46 to 404 participants, most participants were female, mean age ranged between 62.6 and 81 years, and mean symptom duration varied from a week to more than six months.Three placebo-controlled trials were at low risk of bias and two were possibly susceptible to performance and detection bias. Other trials were at risk of bias for several criteria, most notably due to lack of participant and personnel blinding.Compared with placebo, high- to moderate quality evidence from five trials (one with incomplete data reported) indicates that vertebroplasty provides no clinically important benefits with respect to pain, disability, disease-specific or overall quality of life or treatment success at one month. Evidence for quality of life and treatment success was downgraded due to possible imprecision. Evidence was not downgraded for potential publication bias as only one placebo-controlled trial remains unreported. Mean pain (on a scale zero to 10, higher scores indicate more pain) was five points with placebo and 0.6 points better (0.2 better to 1 better) with vertebroplasty, an absolute pain reduction of 6% (2% better to 10% better, minimal clinical important difference is 15%) and relative reduction of 9% (3% better to14% better) (five trials, 535 participants). Mean disability measured by the Roland Morris Disability Questionnaire (scale range zero to 23, higher scores indicate worse disability) was 14.2 points in the placebo group and 1.7 points better (0.3 better to 3.1 better) in the vertebroplasty group, absolute improvement 7% (1% to 14% better), relative improvement 10% better (3% to 18% better) (three trials, 296 participants).Disease-specific quality of life measured by the Quality of Life Questionnaire of the European Foundation for Osteoporosis (QUALEFFO) (scale zero to 100, higher scores indicating worse quality of life) was 62 points in the placebo group and 2.75 points (3.53 worse to 9.02 better) in the vertebroplasty group, absolute change: 3% better (4% worse to 9% better), relative change: 5% better (6% worse to 15% better (two trials, 175 participants). Overall quality of life (European Quality of Life (EQ5D), zero = death to 1 = perfect health, higher scores indicate greater quality of life) was 0.38 points in the placebo group and 0.05 points better (0.01 better to 0.09 better) in the vertebroplasty group, absolute improvement: 5% (1% to 9% better), relative improvement: 18% (4% to 32% better) (three trials, 285 participants). In one trial (78 participants), 9/40 (or 225 per 1000) people perceived that treatment was successful in the placebo group compared with 12/38 (or 315 per 1000; 95% CI 150 to 664) in the vertebroplasty group, RR 1.40 (95% CI 0.67 to 2.95), absolute difference: 9% more reported success (11% fewer to 29% more); relative change: 40% more reported success (33% fewer to 195% more).Moderate-quality evidence (low number of events) from seven trials (four placebo, three usual care, 1020 participants), up to 24 months follow-up, indicates we are uncertain whether vertebroplasty increases the risk of new symptomatic vertebral fractures (70/509 (or 130 per 1000; range 60 to 247) observed in the vertebroplasty group compared with 59/511 (120 per 1000) in the control group; RR 1.08 (95% CI 0.62 to 1.87)).Similarly, moderate-quality evidence (low number of events) from five trials (three placebo, two usual care, 821 participants), indicates uncertainty around the risk of other serious adverse events (18/408 or 76 per 1000, range 6 to 156) in the vertebroplasty group compared with 26/413 (or 106 per 1000) in the control group; RR 0.64 (95% CI 0.36 to 1.12). Notably, serious adverse events reported with vertebroplasty included osteomyelitis, cord compression, thecal sac injury and respiratory failure.Our subgroup analyses indicate that the effects did not differ according to duration of pain <= 6 weeks versus > 6 weeks. Including data from the eight trials that compared vertebroplasty with usual care in a sensitivity analyses altered the primary results, with all combined analyses displaying considerable heterogeneity. AUTHORS' CONCLUSIONS: Based upon high- to moderate-quality evidence, our updated review does not support a role for vertebroplasty for treating acute or subacute osteoporotic vertebral fractures in routine practice. We found no demonstrable clinically important benefits compared with placebo (sham procedure) and subgroup analyses indicated that the results did not differ according to duration of pain <= 6 weeks versus > 6 weeks.Sensitivity analyses confirmed that open trials comparing vertebroplasty with usual care are likely to have overestimated any benefit of vertebroplasty. Correcting for these biases would likely drive any benefits observed with vertebroplasty towards the null, in keeping with findings from the placebo-controlled trials.Numerous serious adverse events have been observed following vertebroplasty. However due to the small number of events, we cannot be certain about whether or not vertebroplasty results in a clinically important increased risk of new symptomatic vertebral fractures and/or other serious adverse events. Patients should be informed about both the high- to moderate-quality evidence that shows no important benefit of vertebroplasty and its potential for harm. PMID- 29618173 TI - Sedation in Pediatric Esophagogastroduodenoscopy. AB - Pediatric esophagogastroduodenoscopy (EGD) has become an established diagnostic and therapeutic modality in pediatric gastroenterology. Effective sedation strategies have been adopted to improve patient tolerance during pediatric EGD. For children, safety is a fundamental consideration during this procedure as they are at a higher risk of severe adverse events from procedural sedation compared to adults. Therefore, a detailed risk evaluation is required prior to the procedure, and practitioners should be aware of the benefits and risks associated with sedation regimens during pediatric EGD. In addition, pediatric advanced life support by endoscopists or immediate intervention by anesthesiologists should be available in the event that severe adverse events occur during pediatric EGD. PMID- 29618174 TI - Diagnosis of Malignant Biliary Stricture: More is Better. PMID- 29618175 TI - Foreign Body Ingestion in Children. AB - Foreign body (FB) ingestion in children is common and most children are observed to be between 6 months and 3 years of age. Although most FBs in the gastrointestinal tract pass spontaneously without complications, endoscopic or surgical removal may be required in a few children. Thus, FB ingestion presents a significant clinical difficulty in pediatric gastroenterological practice. Parameters that need to be considered regarding the timing of endoscopic removal of ingested FBs in children are the children's age or body weight, the clinical presentation, time lapse since ingestion, time of last meal, type as well as size and shape of the FB, and its current location in the gastrointestinal tract. Esophageal button batteries require emergency removal regardless of the presence of symptoms because they can cause serious complications. Coins, magnets, or sharp FBs in the esophagus should be removed within 2 hours in symptomatic and within 24 hours in asymptomatic children. Among those presenting with a single or multiple magnets and a metallic FB that have advanced beyond the stomach, symptomatic children need a consultation with a pediatric surgeon for surgery, and asymptomatic children may be followed with serial X-rays to assess progression. Sharp or pointed, and long or large and wide FBs located in the esophagus or stomach require endoscopic removal. PMID- 29618176 TI - Endoscopic Ultrasound Real-Time Elastography in Liver Disease. PMID- 29618177 TI - Pediatric Colonoscopy: The Changing Patterns and Single Institutional Experience Over a Decade. AB - The safety and effectiveness of pediatric colonoscopy for lower gastrointestinal tract diseases have been established in Korea for about 30 years. Both diagnostic and therapeutic colonoscopies have had many advances in terms of operator skill and experience and are now being performed by most pediatric gastroenterologists. Pediatric colonoscopy is different in many aspects from that of adults, such as expected diagnoses, patient management, bowel preparation, selection criteria for sedation, and instrument selection. In this review, the author presents practical information on pediatric colonoscopy, the author's experiences, and the changes in colonoscopy practices over a decade in a tertiary hospital in Korea. PMID- 29618178 TI - Identification and Expression Patterns of fvexpl1, an Expansin-Like Protein Encoding Gene, Suggest an Auxiliary Role in the Stipe Morphogenesis of Flammulina velutipes. AB - Expansins are cell wall proteins that mediate cell wall loosening and promote specific tissue and organ morphogenesis in plants and in some microorganisms. Unlike plant expansins, the biological functions of fungal expansin-like proteins have rarely been discussed. In the present study, an expansin-like protein encoding fvexpl1 gene, was identified from Flammulina velutipes by using local BLAST. It consisted of five exons with a total length of 822 bp. The deduced protein FVEXPL1 contained 274 amino acids with a predicted molecular mass and isoelectric point of 28,589 Da and pH 4.93, respectively. The first 19 amino acids from the N terminal are the signal peptide. Phylogenetic analysis and multiple protein alignment indicated FVEXPL1 was an expansin-like protein. The expression level of fvexpl1 gene in the stipe was significantly higher than that in the mycelia, primordia, and cap. However, the expression level of fvexpl1 gene was significantly higher in the fast elongation region of the stipe as compared with the slow elongation region. Expression analysis indicated that fvexpl1 gene might have an auxiliary role in the stipe morphogenesis of F. velutipes. PMID- 29618179 TI - Non-Benzoquinone Geldanamycin Analog, WK-88-1, Induces Apoptosis in Human Breast Cancer Cell Lines. AB - Heat shock protein 90 (Hsp90) is treated as a molecular therapeutic target for the prevention and treatment of cancer. Geldanamycin (GA) was the first identified natural Hsp90 inhibitor, but hepatotoxicity has limited its clinical application. Nevertheless, a new GA analog (WK-88- 1) with the non-benzoquinone skeleton, obtained from genetically engineered Streptomyces hygroscopicus, was found to have anticancer activity against two human breast cancer cell lines. WK 88-1 produced concentration-dependent inhibition of cell proliferation, cell cycle arrest, and apoptosis in estrogen receptor (ER)-positive MCF-7 and ER negative MDA-MB-231 cell lines. Detailed analysis showed that WK-88-1 downregulated some key cell cycle molecules (CDK1 and cyclin B1) and lead to G2/M cell cycle arrest. Further studies also showed that WK-88-1 could induce human breast cancer cell apoptosis by downregulating Hsp90 client proteins (Akt, p-Akt, IKK, c-Raf, and Bcl-2), decreasing the ATP level, increasing reactive oxygen species production, and lowering the mitochondrial membrane potential. Meanwhile, we discovered that WK-88-1 significantly decreased the levels of Her-2 and ER alpha in MCF-7 cells but not in MDA-MB-231 cells. In addition, WK-88-1 significantly increased caspase-3, -8, and -9 activities and the cleavage of PARP in a concentration-dependent manner (with the exception of caspase-3 and PARP in MCF-7 cells). Taken together, our preliminary results suggest that WK-88-1 has the potential to play a role in breast cancer therapy. PMID- 29618180 TI - Comparative Analysis of Gut Microbial Communities in Children under 5 Years Old with Diarrhea. AB - Diarrhea is a global disease with a high morbidity and mortality rate in children. In this study, 25 fecal samples were collected from children under 5 years old. Seven samples had been taken from healthy children without diarrhea and marked as the healthy control group; eight samples had been sampled from children with diarrhea caused by dyspepsia and defined as the non-infectious group; and ten samples had been taken from children with diarrhea induced by intestinal infections and identified as the infectious group. We detected the microbial communities of samples by using high-throughput sequencing of 16S rRNA genes. The proportion of aerobic and facultative anaerobic microbes in samples of the infectious group was much higher than in the non-infectious group. In addition, the relative abundance of Enterococcus in the healthy control group was significantly higher than in the non-infectious group and infectious group. This can be used as a potential diagnostic biomarker for diarrhea. PMID- 29618181 TI - Preparation of Interface-Assembled Carbonyl Reductase and Its Application in the Synthesis of S-Licarbazepine in Toluene/Tris-HCl Buffer Biphasic System. AB - In this study, interface-assembled carbonyl reductase (IACR) was prepared and used in the synthesis of S-licarbazepine in a toluene/Tris-HCl biphasic system. The carbonyl reductase (CR) was conjugated with polystyrene to form a surfactant like structure at the interface of the toluene/Tris-HCl biphasic system. The interface-assembled efficiency of IACR reached 83% when the CR (180 U/mg) and polystyrene concentration were 8 * 102 g/ml and 3.75 * 103 g/ml, respectively. The conversion reached 95.6% and the enantiometric excess of S-licarbazepine was 98.6% when 3.97 * 106 nmol/l oxcarbazepine was converted by IACR using 6% ethanol as a co-substrate in toluene/Tris-HCl (12.5:10) at 30 degrees C and 43 *g for 6 h. IACR could be reused efficiently five times. PMID- 29618182 TI - Accuracy of Imputation of Microsatellite Markers from BovineSNP50 and BovineHD BeadChip in Hanwoo Population of Korea. AB - Until now microsatellite (MS) have been a popular choice of markers for parentage verification. Recently many countries have moved or are in process of moving from MS markers to single nucleotide polymorphism (SNP) markers for parentage testing. FAO-ISAG has also come up with a panel of 200 SNPs to replace the use of MS markers in parentage verification. However, in many countries most of the animals were genotyped by MS markers till now and the sudden shift to SNP markers will render the data of those animals useless. As National Institute of Animal Science in South Korea plans to move from standard ISAG recommended MS markers to SNPs, it faces the dilemma of exclusion of old animals that were genotyped by MS markers. Thus to facilitate this shift from MS to SNPs, such that the existing animals with MS data could still be used for parentage verification, this study was performed. In the current study we performed imputation of MS markers from the SNPs in the 500-kb region of the MS marker on either side. This method will provide an easy option for the labs to combine the data from the old and the current set of animals. It will be a cost efficient replacement of genotyping with the additional markers. We used 1,480 Hanwoo animals with both the MS data and SNP data to impute in the validation animals. We also compared the imputation accuracy between BovineSNP50 and BovineHD BeadChip. In our study the genotype concordance of 40% and 43% was observed in the BovineSNP50 and BovineHD BeadChip respectively. PMID- 29618183 TI - Editor's Introduction to This Issue (G&I 16:1, 2018). PMID- 29618185 TI - Estimation of the Genetic Substitution Rate of Hanwoo and Holstein Cattle Using Whole Genome Sequencing Data. AB - Despite the importance of mutation rate, some difficulties exist in estimating it. Next-generation sequencing (NGS) data yields large numbers of single nucleotide polymorphisms, which can make it feasible to estimate substitution rates. The genetic substitution rates of Hanwoo and Holstein cattle were estimated using NGS data. Our main findings was to calculate the gene's substitution rates. Through estimation of genetic substitution rates, we found: diving region of altered substitution density exists. This region may indicate a boundary between protected and unprotected genes. The protected region is mainly associated with the gene ontology terms of regulatory genes. The genes that distinguish Hanwoo from Holstein in terms of substitution rate predominantly have gene ontology terms related to blood and circulatory system. This might imply that Hanwoo and Holstein evolved with dissimilar mutation rates and processes after domestication. The difference in meat quality between Hanwoo and Holstein could originate from differential evolution of the genes related to these blood and circulatory system ontology terms. PMID- 29618184 TI - System-Wide Expression and Function of Olfactory Receptors in Mammals. AB - Olfactory receptors (ORs) in mammals are generally considered to function as chemosensors in the olfactory organs of animals. They are membrane proteins that traverse the cytoplasmic membrane seven times and work generally by coupling to heterotrimeric G protein. The OR is a G protein-coupled receptor that binds the guanine nucleotide-binding Galphaolf subunit and the Gbetagamma dimer to recognize a wide spectrum of organic compounds in accordance with its cognate ligand. Mammalian ORs were originally identified from the olfactory epithelium of rat. However, it has been recently reported that the expression of ORs is not limited to the olfactory organ. In recent decades, they have been found to be expressed in diverse organs or tissues and even tumors in mammals. In this review, the expression and expected function of olfactory receptors that exist throughout an organism's system are discussed. PMID- 29618186 TI - Predictors of abnormal brain computed tomography findings in patients with acute altered mental status in the emergency department. AB - OBJECTIVE: Brain computed tomography (CT) is commonly performed to diagnose acute altered mental status (AMS), a critically important symptom in many serious diseases. However, negative CT results are common, which result in unnecessary CT use. Therefore, this study aimed to determine the clinical factors associated with positive CT findings. METHODS: Patients with acute AMS selected from an emergency department-based registry were retrospectively evaluated. Patients with non-traumatic and noncommunicable diseases on initial presentation and with Glasgow Comal Scale scores of <15 were included in the study. RESULTS: Among the 367 brain CT results of patients with AMS during the study period, 146 (39.8%) were positive. In a multivariate analysis, the presence of focal neurologic deficit (odds ratio [OR], 132.6; 95% confidence interval [CI], 37.8 to 464.6), C reactive protein level <2 mg/dL (OR, 3.9; 95% CI, 1.4 to 10.6), and Glasgow Comal Scale score <9 (OR, 2.4; 95% CI, 1.2 to 4.8) were significantly associated with positive brain CT results. CONCLUSION: The presence of focal neurologic deficit, initial Glasgow Comal Scale score of <9, and initial C-reactive protein levels of <2 mg/dL can facilitate the selection of brain CT to diagnose patients with acute AMS in the emergency department. PMID- 29618187 TI - Effect of alcohol use on emergency department length of stay among minimally injured patients based on mechanism of injury: multicenter observational study. AB - OBJECTIVE: This study aimed to evaluate the effect of alcohol use on emergency department (ED) length of stay (LOS) among minimally injured patients by mechanism of injury. METHODS: This was a retrospective study of injury surveillance data for injured patients (except poisoning), aged over 18 years, discharged home from the ED, and treated at seven academic EDs in Korea during 2008 to 2012. Patients were divided into alcohol-related and alcohol-unrelated groups based on self-report. We used multivariable quantile regression models for the analysis and adjusted covariates including age, sex, consciousness status, severity of injury, emergency medical service use, the season, day and time of visit, and hospital. To determine if there were different effects of alcohol use across mechanism of injury, all analyses were stratified by each mechanism. RESULTS: Among 192,200 patients, 95,807 patients were analyzed. The number of participants in the alcohol-related group was 16,249 (17.0%). In the multivariable quantile regression model, the alcohol-related group had significantly longer ED LOS at the 10th (7 minutes; 95% confidence interval [CI], 6 to 8), 50th (21 minutes; 95% CI, 19 to 23), and 90th (81 minutes; 95% CI, 74 to 87) percentiles when compared to the alcohol-unrelated group. The effect of alcohol use on increased ED LOS was most prominent in motor vehicle injuries. CONCLUSION: We found that alcohol use was associated with increased emergency ED LOS. Furthermore, if we limited our attention to the effect of alcohol use on the number of patients, the burden of alcohol use on the ED would have been underestimated. PMID- 29618188 TI - Is it possible to reduce intra-hospital transport time for computed tomography evaluation in critically ill cases using the Easy Tube Arrange Device? AB - OBJECTIVE: Patients are often transported within the hospital, especially in cases of critical illness for which computed tomography (CT) is performed. Since increased transport time increases the risks of complications, reducing transport time is important for patient safety. This study aimed to evaluate the ability of our newly invented device, the Easy Tube Arrange Device (ETAD), to reduce transport time for CT evaluation in cases of critical illness. METHODS: This prospective randomized control study included 60 volunteers. Each participant arranged five or six intravenous fluid lines, monitoring lines (noninvasive blood pressure, electrocardiography, central venous pressure, arterial catheter), and therapeutic equipment (O2 supply device, Foley catheter) on a Resusci Anne mannequin. We measured transport time for the CT evaluation by using conventional and ETAD method. RESULTS: The median transport time for CT evaluation was 488.50 seconds (95% confidence interval [CI], 462.75 to 514.75) and, 503.50 seconds (95% CI, 489.50 to 526.75) with 5 and 6 fluid lines using the conventional method and 364.50 seconds (95% CI, 335.00 to 388.75), and 363.50 seconds (95% CI, 331.75 to 377.75) with ETAD (all P<0.001). The time differences were 131.50 (95% CI, 89.25 to 174.50) and 148.00 (95% CI, 116.00 to 177.75) (all P<0.001). CONCLUSION: The transport time for CT evaluation was reduced using the ETAD, which would be expected to reduce the complications that may occur during transport in cases of critical illness. PMID- 29618189 TI - Cervical collar makes difficult airway: a simulation study using the LEMON criteria. AB - OBJECTIVE: Endotracheal intubation is extremely difficult to perform in patients wearing a cervical collar for a head and neck injury. Therefore, we analyzed actual measurements using the look externally, evaluate 3-3-2, Mallampati score, obstruction, and neck mobility (LEMON) criteria before and after cervical collar application to investigate the causes of a difficult airway. METHODS: This simulation study was performed in 76 healthy volunteers. We measured the mouth opening, modified Mallampati classification, and neck extension before and after cervical collar application. RESULTS: The mean inter-incisor distance significantly decreased from 4.3 to 2.6 cm (P<0.001). Fifty-seven participants classified as I and II were newly classified as III and IV according to the modified Mallampati classification after cervical collar application (16% to 91%). The angles of neck extension significantly decreased from 44 degrees to 22 degrees after cervical collar application (P<0.001). Before cervical collar application, our simulations predicted that 14 of 76 participants (18%) would have a difficult airway, whereas after cervical collar application, 76 of 76 (100%) were predicted to have a difficult airway. CONCLUSION: All values for the LEMON criteria (mouth opening, modified Mallampati classification, and neck extension) worsened significantly after cervical collar application. Additionally, a difficult airway was predicted in all participants after cervical collar application. PMID- 29618190 TI - Pre-hospital i-gel blind intubation for trauma: a simulation study. AB - OBJECTIVE: This study aimed to evaluate the efficacy of i-gel blind intubation (IGI) as a rescue device for definitive airway management in ground intubation for pre-hospital trauma patients. METHODS: A prospective randomized crossover study was conducted with 18 paramedics to examine intubation performance of two blind intubation techniques through a supraglottic airway devices (IGI and laryngeal mask airway Fastrach), compared with use of a Macintosh laryngoscope (MCL). Each intubation was conducted at two levels of patient positions (ground- and stretcher-level). Primary outcomes were the intubation time and the success rate for intubation. RESULTS: The intubation time (sec) of each intubation technique was not significantly different between the two positions. In both patient positions, the intubation time of IGI was shortest among the three intubation techniques (17.9+/-5.2 at the ground-level and 16.9+/-3.8 at the stretcher-level). In the analysis of cumulative success rate and intubation time, IGI was the fastest to reach 100% success among the three intubation techniques regardless of patient position (all P<0.017). The success of intubation was only affected by the intubation technique, and IGI achieved more success than MCL (odds ratio, 3.6; 95% confidence interval, 1.1 to 11.6; P=0.03). CONCLUSION: The patient position did not affect intubation performance. Additionally, the intubation time with blind intubation through supraglottic airway devices, especially with IGI, was significantly shorter than that with MCL. PMID- 29618191 TI - Delayed massive hemothorax requiring surgery after blunt thoracic trauma over a 5 year period: complicating rib fracture with sharp edge associated with diaphragm injury. AB - Delayed massive hemothorax requiring surgery is relatively uncommon and can potentially be life-threatening. Here, we aimed to describe the nature and cause of delayed massive hemothorax requiring immediate surgery. Over 5 years, 1,278 consecutive patients were admitted after blunt trauma. Delayed hemothorax is defined as presenting with a follow-up chest radiograph and computed tomography showing blunting or effusion. A massive hemothorax is defined as blood drainage >1,500 mL after closed thoracostomy and continuous bleeding at 200 mL/hr for at least four hours. Five patients were identified all requiring emergency surgery. Delayed massive hemothorax presented 63.6+/-21.3 hours after blunt chest trauma. All patients had superficial diaphragmatic lacerations caused by the sharp edge of a broken rib. The mean preoperative chest tube drainage was 3,126+/-463 mL. We emphasize the high-risk of massive hemothorax in patients who have a broken rib with sharp edges. PMID- 29618193 TI - A novel method to cease traumatic urethral bleeding. AB - Urethral bleeding due to trauma is a well-studied and often self-limiting condition. However, existing evidence regarding effective management of massive hemorrhage is limited. Intermittent penile compression and continuous perineal pressure are methods commonly used to control urethral bleeding. Nevertheless, these methods are not mentioned in the literature as specific treatment for this condition, and are rather learned by physicians via word of mouth. Sometimes these methods are ineffective and difficult for the patient to tolerate. This paper explains a new method implemented on a young man with massive urethral bleeding due to iatrogenic trauma, which was unresponsive to standard management. For this patient, the bleeding was controlled by gradually inflating the balloon of the catheter up to 4 mL. Given its safety and efficiency in controlling bleeding in this patient, it seems this new technique should be considered in cases of massive hemorrhage unresponsive to routine treatment. PMID- 29618192 TI - Incidence and characteristics of major bleeding among rivaroxaban users with renal disease and nonvalvular atrial fibrillation. AB - OBJECTIVE: Patients with nonvalvular atrial fibrillation (AF) and renal disease (RD) who receive anticoagulation therapy appear to be at greater risk of major bleeding (MB) than AF patients without RD. As observed in past studies, anticoagulants are frequently withheld from AF patients with RD due to concerns regarding bleeding. The objective of this study was to evaluate the incidence and pattern of MB in those with RD, as compared to those without RD, in a population of rivaroxaban users with nonvalvular AF. METHODS: Electronic medical records of over 10 million patients from the Department of Defense Military Health System were queried to identify rivaroxaban users with nonvalvular AF. A validated algorithm was used to identify MB-related hospitalizations. RD was defined through diagnostic codes present within 6 months prior to the bleeding date for MB cases and end of study participation for non-MB patients. Data were collected on patient characteristics, comorbidities, MB management, and outcomes. RESULTS: Overall, 44,793 rivaroxaban users with nonvalvular AF were identified. RD was present among 6,921 patients (15.5%). Patients with RD had a higher rate of MB than those without RD, 4.52 per 100 person-years versus 2.54 per 100 person years, respectively. The fatal bleeding outcome rate (0.09 per 100 person-years) was identical between those with and without RD. CONCLUSION: In this post marketing study of 44,793 rivaroxaban users with nonvalvular AF, RD patients experienced a higher MB rate than those without RD. The higher rate of MB among those with RD may be due to the confounding effects of comorbidities. PMID- 29618195 TI - Inter-rater variability in the interpretation of the head impulse test results. PMID- 29618194 TI - Quality improvement activity for improving pain management in acute extremity injuries in the emergency department. AB - OBJECTIVE: The aim of this study was to investigate the effectiveness of a quality improvement activity for pain management in patients with extremity injury in the emergency department (ED). METHODS: This was a retrospective interventional study. The patient group consisted of those at least 19 years of age who visited the ED and were diagnosed with International Classification of Diseases codes S40-S99 (extremity injuries). The quality improvement activity consisted of three measures: a survey regarding activities, education, and the triage nurse's pain assessment, including change of pain documentation on electronic medical records. The intervention was conducted from January to April in 2014 and outcome was compared between May and August in 2013 and 2014. The primary outcome was the rate of analgesic prescription, and the secondary outcome was the time to analgesic prescription. RESULTS: A total of 1,739 patients were included, and 20.3% of 867 patients in the pre-intervention period, and 28.8% of 872 patients in the post-intervention period received analgesics (P< 0.001). The prescription rate of analgesics for moderate-to-severe injuries was 36.4% in 2013 and 44.5% in 2014 (P=0.026). The time to analgesics prescription was 116.6 minutes (standard deviation 225.6) in 2013 and 64 minutes (standard deviation 75.5) in 2014 for all extremity injuries. The pain scoring increased from 1.4% to 51.6%. CONCLUSION: ED-based quality improvement activities including education and change of pain score documentation can improve the rate of analgesic prescription and time to prescription for patients with extremity injury in the ED. PMID- 29618196 TI - The course of intracranial pressure after antipyretic therapy in acute brain injury. AB - BACKGROUND: The present study was performed to evaluate intracranial pressure (ICP) variations after antipyretic therapy and their relationship to ICP at baseline (ICPbas) in acute brain injury (ABI) patients. METHODS: We completed a retrospective analysis on data derived from 2 previously published prospective observational studies. The first study involved 32 ABI patients and was performed to elucidate the cerebral and hemodynamic effects of intravenous (IV) paracetamol. The second study involved 30 ABI patients and was performed to investigate cerebral and hemodynamic effects of intramuscular IM diclofenac sodium (DCF). Overall patient population was divided into 2 groups: 1) Group A (G A) when ICPbas was <= 15 mmHg and 2) Group B (G-B) when ICPbas was > 15 mmHg. The main objective was to evaluate if ICPbas affects the time course of ICP after antipyretics administration. RESULTS: Data from 62 ABI patients were analyzed. We failed to observe a significant change in ICP after antipyretic treatment in the overall group of patients (P1 = 0.486). A significant difference, however, was found between the two groups (P2 < 0.001). We observed that in the G-A, ICP increased in response to antipyretic administration, whereas in the G-B, ICP decreased. These opposite responses are reflected in the statistically significant interaction (P3 < 0.001). CONCLUSIONS: Variation in ICP after antipyretic therapy is influenced by ICPbas. Specifically, patients with ICPbas <= 15 mmHg showed a significant increase in ICP after antipyretic therapy, while a significant reduction in ICP was observed in patients with ICPbas > 15 mmHg. PMID- 29618197 TI - Fluorescence-assisted surgery in the interhemispheric transcallosal approach for thalamic lesions. PMID- 29618198 TI - A Parallel Approach to 7-(Hetero)arylpyrazolo[1,5- a]pyrimidin-5-ones. AB - A modular, two-pot assembly of 7-arylpyrazolo[1,5- a]pyrimidones from aryl/heteroaryl halides and aminopyrazoles in library format was developed. Sonogashira coupling of aryl bromides with triethyl orthopropiolate, followed by in situ orthoester hydrolysis, provides access to beta-aryl ynoates, which undergo regioselective cyclocondensation with aminopyrazoles. The ability to vary the C7 vector of 7-arylpyrazolo[1,5- a]pyrimidones in two steps using readily available (hetero)aryl halides significantly enhances synthetic access to this challenging vector. PMID- 29618199 TI - Sc3+ (or HClO4) Activation of a Nonheme FeIII-OOH Intermediate for the Rapid Hydroxylation of Cyclohexane and Benzene. AB - [Fe(beta-BPMCN)(CH3CN)2]2+ (1, BPMCN = N,N' -bis(pyridyl-2-methyl)- N,N' dimethyl- trans-1,2-diaminocyclo-hexane) is a relatively poor catalyst for cyclohexane oxidation by H2O2 and cannot perform benzene hydroxylation. However, addition of Sc3+ activates the 1/H2O2 reaction mixture to be able to hydroxylate cyclohexane and benzene within seconds at -40 degrees C. A metastable S = 1/2 FeIII-(eta1-OOH) intermediate 2 is trapped at -40 degrees C, which undergoes rapid decay upon addition of Sc3+ at rates independent of [substrate] but linearly dependent on [Sc3+]. HClO4 elicits comparable reactivity as Sc3+ at the same concentration. We thus postulate that these additives both facilitate O-O bond heterolysis of 2 to form a common highly electrophilic FeV?O oxidant that is comparably reactive to the fastest nonheme high-valent iron-oxo oxidants found to date. PMID- 29618200 TI - Intranasally Administered S100A9 Amyloids Induced Cellular Stress, Amyloid Seeding, and Behavioral Impairment in Aged Mice. AB - Amyloid formation and neuroinflammation are major features of Alzheimer's disease pathology. Proinflammatory mediator S100A9 was shown to act as a link between the amyloid and neuroinflammatory cascades in Alzheimer's disease, leading together with Abeta to plaque formation, neuronal loss and memory impairment. In order to examine if S100A9 alone in its native and amyloid states can induce neuronal stress and memory impairment, we have administered S100A9 species intranasally to aged mice. Single and sequential immunohistochemistry and passive avoidance behavioral test were conducted to evaluate the consequences. Administered S100A9 species induced widespread cellular stress responses in cerebral structures, including frontal lobe, hippocampus and cerebellum. These were manifested by increased levels of S100A9, Bax, and to a lesser extent activated caspase-3 immunopositive cells. Upon administration of S100A9 fibrils, the amyloid oligomerization was observed in the brain tissues, which can further exacerbate cellular stress. The cellular stress responses correlated with significantly increased training and decreased retention latencies measured in the passive avoidance test for the S100A9 treated animal groups. Remarkably, the effect size in the behavioral tests was moderate already in the group treated with native S100A9, while the effect sizes were large in the groups administered S100A9 amyloid oligomers or fibrils. The findings demonstrate the brain susceptibility to neurotoxic damage of S100A9 species leading to behavioral and memory impairments. Intranasal administration of S100A9 species proved to be an effective method to study amyloid induced brain dysfunctions, and S100A9 itself may be postulated as a target to allay early stage neurodegenerative and neuroinflammatory processes. PMID- 29618201 TI - Controllable Self-Assembly of Macrocycles in Water for Isolating Aromatic Hydrocarbon Isomers. AB - A series of purely organic macrocycles and catenanes can be self-assembled by condensing a cationic bisaldehyde compound with a series of dihydrazide linkers in weakly acidic water. On one hand, the macrocycles could be generated as the predominant products under the condition of low concentration or less polar media. In the presence of a guest template, these macrocycles could even be obtained in close to quantitative yields, allowing them to be isolated as pure solid products without the need for chromatographic purification. On the other hand, [2]catenanes could be obtained as the major products in more concentrated solutions or more polar media where hydrophobic effects are enhanced. Once purified, both macrocycles and catenanes exhibit remarkable kinetic stability in both the solid state and neutral aqueous solution at room temperature. By means of selective host-guest recognition, one of the macrocyclic products is capable of resolving a pair of hydrocarbon isomers, namely phenanthrene and anthracene, which have similar properties and can hardly be separated by commonly used approaches. PMID- 29618202 TI - Au-Catalyzed Intermolecular [2+2] Cycloadditions between Chloroalkynes and Unactivated Alkenes. AB - The [2+2] cycloaddition is a versatile strategy for the synthesis of strained cyclobutenes of high synthetic value. In this study, two efficient intermolecular [2+2] cycloadditions between two different types of chloroalkynes and unactivated alkene are realized with gold catalysis. Of significance is that the reaction works with challenging monosubstituted unactivated alkenes, which is unprecedented in gold catalysis and scarcely documented in other metal catalyzed/promoted reactions; moreover, the reaction exhibits excellent regioselectivities, which are much better than those reported in literature. With 1,2-disubstituted unactivated alkenes, the reaction is largely stereospecific. The cyclobutene products can be prepared in nearly gram scale and readily undergo further reactions including various cross-coupling reactions using the C(sp2)-Cl and/or C(sp2)-SPh bond, which in turn substantially broaden the scope of accessible cyclobutenes and enhance the synthetic utility of this bimolecular reaction. PMID- 29618203 TI - Rational Design of Multifunctional Polymeric Nanoparticles Based on Poly(l histidine) and d-alpha-Vitamin E Succinate for Reversing Tumor Multidrug Resistance. AB - A multifunctional nanoparticulate system composed of methoxy poly(ethylene glycol)-poly(l-histidine)-d-alpha-vitamin E succinate (MPEG-PLH-VES) copolymers for encapsulation of doxorubicin (DOX) was elaborated with the aim of circumventing the multidrug resistance (MDR) in breast cancer treatment. The MPEG PLH-VES nanoparticles (NPs) were subsequently functionalized with biotin motif for targeted drug delivery. The MPEG-PLH-VES copolymer exerts no obvious effect on the P-gp expression level of MCF-7/ADR but exhibited a significant influence on the loss of mitochondrial membrane potential, the reduction of intracellular ATP level, and the inhibition of P-gp ATPase activity of MCF-7/ADR cells. The constructed MPEG-PLH-VES NPs exhibited an acidic pH-induced increase on particle size in aqueous solution. The DOX-encapsulated MPEG-PLH-VES/biotin-PEG-VES (MPEG PLH-VES/B) NPs were characterized to possess high drug encapsulation efficiency of approximate 90%, an average particle size of approximately 130 nm, and a pH responsive drug release profile in acidic milieu. Confocal laser scanning microscopy (CLSM) investigations revealed that the DOX-loaded NPs resulted in an effective delivery of DOX into MCF-/ADR cells and a notable carrier-facilitated escape from endolysosomal entrapment. Pertaining to the in vitro cytotoxicity evaluation, the DOX-loaded MPEG-PLH-VES/B NPs resulted in more pronounced cytotoxicity to MCF-/ADR cells compared with DOX-loaded MPEG-PLH-VES NPs and free DOX solution. In vivo imaging study in MCF-7/ADR tumor-engrafted mice exhibited that the MPEG-PLH-VES/B NPs accumulated at the tumor site more effectively than MPEG-PLH-VES NPs due to the biotin-mediated active targeting effect. In accordance with the in vitro results, DOX-loaded MPEG-PLH-VES/B NPs showed the strongest inhibitory effect against the MCF-7/ADR xenografted tumors with negligible systemic toxicity, as evidenced by the histological analysis and change of body weight. The multifunctional MPEG-PLH-VES/B nanoparticulate system has been demonstrated to provide a promising strategy for efficient delivery of DOX into MCF-7/ADR cancerous cells and reversing MDR. PMID- 29618205 TI - Design, Synthesis, and Herbicidal Activity of Pyrimidine-Biphenyl Hybrids as Novel Acetohydroxyacid Synthase Inhibitors. AB - The issue of weed resistance to acetohydroxyacid synthase (EC 2.2.1.6, AHAS) inhibitors has become one of the largest obstacles for the application of this class of herbicides. In a continuing effort to discover novel AHAS inhibitors to overcome weed resistance, a series of pyrimidine-biphenyl hybrids (4aa-bb and 5aa ah) were designed and synthesized via a scaffold hopping strategy. Among these derivatives, compounds 4aa ( Ki = 0.09 MUM) and 4bb ( Ki = 0.02 MUM) displayed higher inhibitory activities against Arabidopsis thaliana AHAS than those of the controls bispyribac ( Ki = 0.54 MUM) and flumetsulam ( Ki = 0.38 MUM). Remarkably, compounds 4aa, 4bb, 5ah, and 5ag exhibited excellent postemergence herbicidal activity and a broad spectrum of weed control at application rates of 37.5-150 g of active ingredient (ai)/ha. Furthermore, 4aa and 4bb showed higher herbicidal activity against AHAS inhibitor-resistant Descurainia sophia, Ammannia arenaria, and the corresponding sensitive weeds than that of bispyribac at 0.94 0.235 g ai/ha. Therefore, the pyrimidine-biphenyl motif and lead compounds 4aa and 4bb have great potential for the discovery of novel AHAS inhibitors to combat AHAS-inhibiting herbicide-resistant weeds. PMID- 29618206 TI - Cation Dynamics Governed Thermal Properties of Lead Halide Perovskite Nanowires. AB - Metal halide perovskite (MHP) nanowires such as hybrid organic-inorganic CH3NH3PbX3 (X = Cl, Br, I) have drawn significant attention as promising building blocks for high-performance solar cells, light-emitting devices, and semiconductor lasers. However, the physics of thermal transport in MHP nanowires is still elusive even though it is highly relevant to the device thermal stability and optoelectronic performance. Through combined experimental measurements and theoretical analyses, here we disclose the underlying mechanisms governing thermal transport in three different kinds of lead halide perovskite nanowires (CH3NH3PbI3, CH3NH3PbBr3 and CsPbBr3). It is shown that the thermal conductivity of CH3NH3PbBr3 nanowires is significantly suppressed as compared to that of CsPbBr3 nanowires, which is attributed to the cation dynamic disorder. Furthermore, we observed different temperature-dependent thermal conductivities of hybrid perovskites CH3NH3PbBr3 and CH3NH3PbI3, which can be attributed to accelerated cation dynamics in CH3NH3PbBr3 at low temperature and the combined effects of lower phonon group velocity and higher Umklapp scattering rate in CH3NH3PbI3 at high temperature. These data and understanding should shed light on the design of high-performance MHP based thermal and optoelectronic devices. PMID- 29618204 TI - NRVS Studies of the Peroxide Shunt Intermediate in a Rieske Dioxygenase and Its Relation to the Native FeII O2 Reaction. AB - The Rieske dioxygenases are a major subclass of mononuclear nonheme iron enzymes that play an important role in bioremediation. Recently, a high-spin FeIII (hydro)peroxy intermediate (BZDOp) has been trapped in the peroxide shunt reaction of benzoate 1,2-dioxygenase. Defining the structure of this intermediate is essential to understanding the reactivity of these enzymes. Nuclear resonance vibrational spectroscopy (NRVS) is a recently developed synchrotron technique that is ideal for obtaining vibrational, and thus structural, information on Fe sites, as it gives complete information on all vibrational normal modes containing Fe displacement. In this study, we present NRVS data on BZDOp and assign its structure using these data coupled to experimentally calibrated density functional theory calculations. From this NRVS structure, we define the mechanism for the peroxide shunt reaction. The relevance of the peroxide shunt to the native FeII/O2 reaction is evaluated. For the native FeII/O2 reaction, an FeIII-superoxo intermediate is found to react directly with substrate. This process, while uphill thermodynamically, is found to be driven by the highly favorable thermodynamics of proton-coupled electron transfer with an electron provided by the Rieske [2Fe-2S] center at a later step in the reaction. These results offer important insight into the relative reactivities of FeIII-superoxo and FeIII-hydroperoxo species in nonheme Fe biochemistry. PMID- 29618207 TI - Palladium-Catalyzed Carbene Migratory Insertion and Trapping with Sulfinic Acid Salts toward Allylic Sulfones. AB - Allylic sulfones were synthesized with excellent selectivity and good yield via Pd-catalyzed cross-coupling of vinyl iodide with N-tosylhydrazone. This process involves palladium carbene migratory insertion/trapping with sulfinic acid salts. For the previous Pd-catalyzed N-tosylhydrazone cross-coupling, sulfinic acid salt is generated as a byproduct. In this transformation, the diazo compound and the sulfinic acid salt, which are all generated from N-tosylhydrazone, were used as cross-coupling partner. PMID- 29618208 TI - Discovery of Novel Schizocommunin Derivatives as Telomeric G-Quadruplex Ligands That Trigger Telomere Dysfunction and the Deoxyribonucleic Acid (DNA) Damage Response. AB - Telomeric G-quadruplex targeting and telomere maintenance interference are emerging as attractive strategies for anticancer therapies. Here, a novel molecular scaffold is explored for telomeric G-quadruplex targeting. A series of novel schizocommunin derivatives was designed and synthesized as potential telomeric G-quadruplex ligands. The interaction of telomeric G-quadruplex DNA with the derivatives was explored by biophysical assay. The cytotoxicity of the derivatives toward cancer cell lines was evaluated by the methyl thiazolyl tetrazolium (MTT) assay. Among the derivatives, compound 16 showed great stabilization ability toward telomeric G-quadruplex DNA and good cytotoxicity toward cancer cell lines. Further cellular experiments indicated that 16 could induce the formation of telomeric G-quadruplex in cells, triggering a DNA damage response at the telomere and causing telomere dysfunction. These effects ultimately provoked p53-mediated cell cycle arrest and apoptosis, and suppressed tumor growth in a mouse xenograft model. Our work provides a novel scaffold for the development of telomeric G-quadruplex ligands. PMID- 29618209 TI - Flavonols and Carotenoids in Yellow Petals of Rose Cultivar ( Rosa 'Sun City'): A Possible Rich Source of Bioactive Compounds. AB - Rose flowers have received increasing interest as rich sources of bioactive compounds. The composition of flavonols and carotenoids in yellow petals of Rosa 'Sun City' was determined by high-performance liquid chromatography coupled with photodiode array and mass spectrometric detectors (HPLC-PDA-MS). In total, 19 flavonols and 16 carotenoids were identified, some of which were first discovered in rose petals. Significant changes were observed in their profiles during seven blooming stages. Total flavonol contents showed the highest levels at stage 2 (S2; 1152.29 MUg/g, FW). Kaempferol 7- O-glucoside and kaempferol 3- O-rhamnoside were the predominant individual flavonols. Total carotenoid concentration was highest at S4 (142.71 MUg/g, FW). Violaxanthins with different geometrical configurations appeared as the major carotenoids across all blooming stages. These results indicated that 'Sun City' petals are rich sources of flavonols and carotenoids. Moreover, it is important to choose the appropriate harvest time on the basis of the targeted compounds. PMID- 29618211 TI - Curriculum Vitae of Benjamin Widom. PMID- 29618210 TI - Chirality-Dependent Electron Spin Filtering by Molecular Monolayers of Helicenes. AB - The interaction of low-energy photoelectrons with well-ordered monolayers of enantiopure helical heptahelicene molecules adsorbed on metal surfaces leads to a preferential transmission of one longitudinally polarized spin component, which is strongly coupled to the helical sense of the molecules. Heptahelicene, composed of only carbon and hydrogen atoms, exhibits only a single helical turn but shows excess in longitudinal spin polarization of about P Z = 6 to 8% after transmission of initially balanced left- and right-handed spin polarized electrons. Insight into the electronic structure, that is, the projected density of states, and the spin-dependent electron scattering in the helicene molecule is gained by using spin-resolved density functional theory calculations and a model Hamiltonian approach, respectively. Our results support the semiclassical picture of electronic transport along a helical pathway under the influence of spin-orbit coupling induced by the electrostatic molecular potential. PMID- 29618212 TI - Tribute to Benjamin Widom. PMID- 29618213 TI - Publications of Benjamin Widom. PMID- 29618214 TI - Scientific Autobiography of Benjamin Widom. PMID- 29618215 TI - Colleagues of Benjamin Widom. PMID- 29618217 TI - Spotlights: Volume 9, Issue 7. PMID- 29618216 TI - Coherence from Light Harvesting to Chemistry. PMID- 29618218 TI - NIH Toolbox(r) Emotion Batteries for Children: Factor-Based Composites and Norms. AB - The recently released National Institutes of Health Toolbox (NIHTB) batteries for neurological and behavioral function were designed to serve as standardized, common measures in clinical and epidemiological research. The current study aimed to examine constructs assessed by the self-report and parental proxy-report scales in the NIHTB Emotion Battery (NIHTB-EB) for Children by using factor analyses on data from the U.S. national normative sample of 2,916 English speaking children. This battery contains 31 scales designed to assess both positive and negative aspects of social and emotional functioning that are considered developmentally relevant at each of three age ranges (3-7, 8-12, and 13-17 years). Results revealed four similar self-report factors for ages 8 to 12 years and 13 to 17 years. Proxy reports for ages 3 to 7 years revealed three factors, and for ages 8 to 12 years two factors. Based on the standardization sample data, age- and gender-corrected norms are presented for all NIHTB-EB individual scales and factor-based composites. PMID- 29618220 TI - The Physical Properties of Ceramides in Membranes. AB - Ceramides are sphingolipids containing a sphingosine or a related base, to which a fatty acid is linked through an amide bond. When incorporated into a lipid bilayer, ceramides exhibit a number of properties not shared by almost any other membrane lipid: Ceramides ( a) are extremely hydrophobic and thus cannot exist in suspension in aqueous media; ( b) increase the molecular order (rigidity) of phospholipids in membranes; ( c) give rise to lateral phase separation and domain formation in phospholipid bilayers; ( d) possess a marked intrinsic negative curvature that facilitates formation of inverted hexagonal phases; ( e) make bilayers and cell membranes permeable to small and large (i.e., protein-size) solutes; and ( f) promote transmembrane (flip-flop) lipid motion. Unfortunately, there is hardly any link between the physical studies reviewed here and the mass of biological and clinical studies on the effects of ceramides in health and disease. PMID- 29618221 TI - "Sacred Pause" in the ICU: Evaluation of a Ritual and Intervention to Lower Distress and Burnout. AB - BACKGROUND: Increased exposure to deaths in the intensive care unit (ICU) generate grief among ICU staff, which remains unresolved most of the time. Unresolved grief becomes cumulative and presents a risk factor for burnout. "sacred pause" is a ritual performed at patient's death to honor the lost life and recognize the efforts of the health-care team. OBJECTIVE: To study the impact of the ritual of sacred pause on the attitudes and behaviors of the ICU physicians and nurses. METHODS: Ten-question online anonymous survey was sent to ICU physicians and nurses in the medical ICU of a tertiary care hospital in July 2017. RESULTS: Thirty-four ICU team members completed the survey including 12 physicians and 22 nurses. Seventy sacred pause rituals were performed from July 2016 to June 2017. Seventy-nine percent respondents believed that the ritual brought closure and helped them overcome the feelings of disappointment, grief, distress, and failure after the death of their patient in ICU. Seventy-three percent agreed that the ritual has instilled and encouraged a sense of team effort. Eighty-two percent responded that the ritual makes their efforts feel appreciated. Many felt that the ritual should be a universal phenomenon in all ICUs. Only 55% respondents felt that the practice has a potential to decrease ICU burnout, many of them (42%) were undecided. CONCLUSION: Sacred pause brings closure, prevents cumulative grief and distress, builds resilience, promotes team effort, and improves professional satisfaction of ICU team. It may lower burnout syndrome in ICU, but further studies are warranted. PMID- 29618222 TI - Adolescent Sugar-Sweetened Beverage Intake is Associated With Parent Intake, Not Knowledge of Health Risks. AB - PURPOSE:: To examine associations of adolescent sugar-sweetened beverage (SSB) intake with parent SSB intake and parent and adolescent knowledge of SSB-related health risks. DESIGN:: Quantitative, cross-sectional. SETTING:: 2014 SummerStyles survey. SUBJECTS:: Nine hundred and ninety parent and adolescent (12-17 years) pairs. MEASURES:: The outcome was self-reported adolescent intake (0, >0 to <1, or >=1 time/day) of SSBs (soda, fruit drinks, sports/energy drinks, other SSBs). The exposures were self-reported parent SSB intake (0, >0 to <1, >=1 to <2, or >=2 times/day) and parent and adolescent knowledge of SSB-related health risks (weight gain, diabetes, and dental caries). ANALYSIS:: Separate multinomial logistic regression models were used to estimate adjusted odds ratios (aORs) for adolescent SSB intake >=1 time/day (ref: 0 times/day), according to (1) parent SSB intake and (2) parent and (3) adolescent knowledge. RESULTS:: About 31% of adolescents consumed SSBs >=1 time/day, and 43.2% of parents consumed SSBs >=2 times/day. Adolescent and parent knowledge that SSB intake is related to health conditions ranged from 60.7% to 80.4%: weight gain (75.0% and 80.4%, respectively), diabetes (60.7% and 71.4%, respectively), and dental caries (77.5% and 72.9%, respectively). In adjusted models, adolescent SSB intake >=1 time/day was associated with parent intake >=2 times/day (aOR = 3.30; 95% confidence interval = 1.62-6.74) but not with parent or adolescent knowledge of health risks. CONCLUSION:: Parental SSB intake may be an important factor in understanding adolescent behavior; knowledge of SSB-related health conditions alone may not influence adolescent SSB behavior. PMID- 29618223 TI - Structural DNA Nanotechnology: Artificial Nanostructures for Biomedical Research. AB - Structural DNA nanotechnology utilizes synthetic or biologic DNA as designer molecules for the self-assembly of artificial nanostructures. The field is founded upon the specific interactions between DNA molecules, known as Watson Crick base pairing. After decades of active pursuit, DNA has demonstrated unprecedented versatility in constructing artificial nanostructures with significant complexity and programmability. The nanostructures could be either static, with well-controlled physicochemical properties, or dynamic, with the ability to reconfigure upon external stimuli. Researchers have devoted considerable effort to exploring the usability of DNA nanostructures in biomedical research. We review the basic design methods for fabricating both static and dynamic DNA nanostructures, along with their biomedical applications in fields such as biosensing, bioimaging, and drug delivery. PMID- 29618219 TI - Behavioral Variability and Phenotypic Diversity in Bacterial Chemotaxis. AB - Living cells detect and process external signals using signaling pathways that are affected by random fluctuations. These variations cause the behavior of individual cells to fluctuate over time (behavioral variability) and generate phenotypic differences between genetically identical individuals (phenotypic diversity). These two noise sources reduce our ability to predict biological behavior because they diversify cellular responses to identical signals. Here, we review recent experimental and theoretical advances in understanding the mechanistic origin and functional consequences of such variation in Escherichia coli chemotaxis-a well-understood model of signal transduction and behavior. After briefly summarizing the architecture and logic of the chemotaxis system, we discuss determinants of behavior and chemotactic performance of individual cells. Then, we review how cell-to-cell differences in protein abundance map onto differences in individual chemotactic abilities and how phenotypic variability affects the performance of the population. We conclude with open questions to be addressed by future research. PMID- 29618224 TI - Advances in Multicompartment Mesoporous Silica Micro/Nanoparticles for Theranostic Applications. AB - Mesoporous silica nanoparticles (MSNs) are promising functional nanomaterials for a variety of biomedical applications, such as bioimaging, drug/gene delivery, and cancer therapy. This is due to their low density, low toxicity, high biocompatibility, large specific surface areas, and excellent thermal and mechanical stability. The past decade has seen rapid advances in the development of MSNs with multiple compartments. These include hierarchical porous structures and core-shell, yolk-shell, and Janus structured particles for efficient diagnosis and therapeutic applications. We review advances in this area, covering the categories of multicompartment MSNs and their synthesis methods, with an emphasis on hierarchical structures and the incorporation of multiple functions. We classify multicompartment mesoporous silica micro/nanostructures, ranging from core-shell and yolk-shell structures to Janus and raspberry-like nanoparticles, and discuss their synthesis methods. We review applications of these multicompartment MSNs, including bioimaging, targeted drug/gene delivery, chemotherapy, phototherapy, and in vitro diagnostics. We also highlight the latest trends and new opportunities. PMID- 29618226 TI - The effect of rectus muscle re-approximation at cesarean delivery on pain perceived after operation: a randomized control trial. AB - BACKGROUND: Cesarean section rate has increased dramatically worldwide but there is still debate about the optimum operative technique of cesarean section. OBJECTIVE: The purpose of this study was to assess the effect of rectus muscle reapproximation at cesarean delivery on the postoperative pain. METHODS: This study was a prospective, double-blind, randomized controlled trial. It included 280 primigravidas, with a singleton pregnancy, who underwent elective lower segment cesarean section at term. The patients were randomly allocated into two equal groups; Group (A): undergoing rectus muscle reapproximation, and Group (B): not undergoing rectus muscle reapproximation. Postoperative pain was assessed by visual analogue scale (VAS) from 0 (no pain) to 100 (maximum pain). Postoperative analgesia, operative time, changes in hemoglobin level, length of hospital stay, and occurrence of postoperative complication were also assessed. RESULTS: Postoperative pain score at the end of the first 24 hours and at the end of the next 24 hours were significantly higher among the group of rectus muscle reapproximation (a difference in VAS pain score of: 5, 95% confidence interval: 0.1-11, p value: .02) and (a difference of 1, 95% confidence interval: 0.1-2.9, p value: .01), respectively. As regards the narcotic use in the first 24 hours after cesarean section, in the form of injections of meperidine 50 mg, it was significantly higher among the group of rectus muscle closure (a difference of 10 mg, 95% confidence interval 3-21.7 mg, p value: .02). While in the next 24 hours, the NSAIDs use, in the form of diclofenac sodium injection, was significantly higher among the group of rectus muscle reapproximation (a difference of 10 mg, 95% confidence interval 3.7-31.7 mg, p value: .02). CONCLUSIONS: Rectus muscle reapproximation among women undergoing primary caesarian section is associated with significant increase in the postoperative pain and analgesic requirements. PMID- 29618225 TI - The examination of vegetable- and mineral oil-based inks' effects on print quality: Green printing effects with different oils. AB - INTRODUCTION: Printing inks oil selection is related to the desired nature of the varnish in the ink production. Petroleum-derived mineral oils and vegetable oils can be used in offset inks. METHODS: In this study, the behaviors of vegetable- and mineral oil-based inks on uncoated and coated paper surfaces were investigated in terms of printability. Solid tone test prints were done with offset printing of these inks. Print gloss of the printed samples was measured and a light fastness test was implemented on these samples in order to determine the resistance to fading. Absorption behavior and contact angles of the ink printed films on the test papers were measured with the sessile water drop method depending on time, and surface energies were calculated. RESULTS: On both paper types, linseed-soybean oil-based vegetable ink gave the highest brightness value. The lowest print gloss results on the paper were obtained from soybean oil-based inks. The lowest color change was recorded with mineral oil-based inks on gloss coated papers. According to the ink-film-surface relation, when the contact angle is high, surface energy decreases and the absorbency of the ink-film is lower. CONCLUSIONS: In this study, the behaviors of vegetable- and mineral oil-based inks on different paper surfaces, and the effect on the quality of printability as well as differences, have been evaluated, taking environmental and health factors into consideration. PMID- 29618228 TI - Shoulder and elbow injuries in soccer goalkeepers versus field players in the National Collegiate Athletic Association, 2009-2010 through 2013-2014. AB - OBJECTIVES: Examination of the incidence of shoulder and elbow injuries in the collegiate soccer player population is limited, as is comparison between goalkeepers and field players. We hypothesized that goalkeepers would have a higher incidence of shoulder and elbow injuries than field players. Furthermore, we sought to determine the incidence of shoulder and elbow injuries among National Collegiate Athletic Association (NCAA) soccer players, and to determine injury risk factors. METHODS: The NCAA Injury Surveillance Program database was analyzed for injuries to NCAA men's and women's soccer players during the 2009 2010 through 2013-2014 academic years. The incidence of injury was calculated per 10,000 athletic exposures (AE) for goalkeepers versus field players, activity, and injury characteristics, and compared using univariate analysis and risk ratios to determine injury risk factors. RESULTS: While the overall incidence of shoulder and elbow injuries in soccer players was 2.7/10,000AE [95% CI 2.62 2.78], the incidence among goalkeepers was 4.6-fold higher (8.3 vs. 1.8/10,000AE, p < 0.0001). Goalkeepers had significantly higher incidences of injury in practice (21.3-fold) and in the preseason (16.1-fold) than field players. Women goalkeepers were disproportionately affected, with injury incidences 7.7-fold higher than women field players, and 1.9-fold higher than male goalkeepers. Acromioclavicular joint injuries, rotator cuff tears/sprains, and elbow and shoulder instability constituted the majority of the goalkeeper injuries. CONCLUSIONS: Shoulder and elbow injuries in NCAA soccer players are significantly more common in goalkeepers than field players. Incidence varies widely by position and injury, with a number of associated risk factors. Soccer players sustaining these injuries, along with their coaches and medical providers, may benefit from this injury data to best manage expectations and outcomes. Soccer governing bodies may use this to track injury incidence and response to preventative measures. PMID- 29618227 TI - Improved drug loading via spray drying of a chalcone implant for local treatment of cutaneous leishmaniasis. AB - Current chemotherapy of cutaneous leishmaniasis (CL), even the mildest forms, encompasses multiple and painful injections with toxic drugs that cause systemic adverse effects. Recently, we showed the promising use of poly(lactic-co-glycolic acid) (PLGA) microparticles loaded with an antileishmanial nitrosylated chalcone (CH8) for effective, safe, local, and single-dose treatment of CL. Here, we proposed to optimize the delivery system by increasing the CH8 loading in PLGA microparticles using spray drying instead of emulsification-solvent evaporation. The effect of solvent composition and polymeric matrix changes on thermal properties, loading efficiency, particle size, morphology, and spatial drug distribution of the CH8-loaded microparticles was evaluated. The results showed that spray drying allowed a higher CH8 content (18% w/w), as contrasting with the previous solvent evaporation technique that maximally incorporated 7.8% of CH8. In vitro studies on 96-hour incubation with L. amazonensis-infected macrophages showed that entrapment in spray-dried PLGA microparticles rendered CH8 safer, preserved its antileishmanial activity, and did not affect its antioxidant properties. PMID- 29618229 TI - Effects of soybean lipid infusion on triglyceride and unbound free fatty acid levels in preterm infants. AB - OBJECTIVE: To determine the plasma triglyceride (TG) and unbound free fatty acid (FFAu) levels in infants treated with increasing dosages of soybean lipid, intralipid (IL), infusion. STUDY DESIGN: TG and FFAu levels were measured in 78 preterm infants (BW 500-2000 g; GA 23-34 weeks) using the fluorescent probe ADIFAB2 and enzymatic method. RESULTS: The infants' BW was 1266.2 +/- 440.7 g and GA 28.8 +/- 3.1 weeks. TG levels were 77.4 +/- 50 mg/dL, 140.2 +/- 188 mg/dL (p < .04 compared to levels during low dose IL infusion) and 135.6 +/- 118 mg/dL (p < .004), respectively during increased IL rates. FFAu levels were 17.7 +/- 13 nM, 47.3 +/- 102.8 nM (p = .07) and 98 +/- 234 nM (p = .03). TG levels correlated with IL dose, the rate of IL administration, and FFAu levels. TG and FFAu levels were higher in infants below 28 weeks' gestation Conclusions: Increasing dosage of IL is associated with increasing levels of TG and FFAu, especially in infants below 29 weeks of gestation. The increased level of FFAu suggests inefficient cellular utilization. PMID- 29618230 TI - Combination of Adenomyoma and Adenomyomatous Hyperplasia of the Ampullary System: A First Case Report. AB - Adenomyoma and adenomyomatous hyperplasia are benign tumor-like lesions that rarely involve the major or minor duodenal papilla. We report the case of a 73 year-old patient who underwent a cephalic duodenopancreatectomy due to clinical and radiological evidence of underlying malignant neoplasm. The histopathology results revealed the unusual association of a major duodenal papilla adenomyoma and an adenomyomatous hyperplasia of the minor papilla. Because of their resemblance to pancreatic malignancy, the diagnosis of these lesions is particularly challenging. In most cases, it is established postoperatively, after histopathological examination of the surgical specimen. PMID- 29618231 TI - Corrigendum. AB - Keuthen, N.J., Tung, E.S., Woods, D.W., Franklin, M.E., Altenburger, E.M., Pauls, D.L., & Flessner, C.A. (2015). Replication study of the Milwaukee inventory for subtypes of trichotillomania-adult version in a clinically-characterized sample. Behavior Modification. 39(4):580-599. DOI: 10.1177/0145445515580533 The authors regret that there is an error in the first paragraph of page 595. It should read as follows and the changes are shown in bold. "Thus, strategies likely to enhance awareness (e.g., stimulus control and habit reversal) would now be primarily appropriate for those with low scores on the Intention scale. In summary, pullers with high scores on the Emotion scale and high scores on the Intention scale would likely benefit most with ACT or DBT. Pullers with low scores on the Intention scale and low scores on the Emotion scale would likely profit most from treatment beginning with stimulus control and habit reversal." PMID- 29618232 TI - Functional Outcomes 6 Months After Severe Traumatic Brain Injury Following Admission Into Intensive Care Unit: A Cohort Study in Two Tertiary Hospitals. AB - Severe traumatic brain injury (TBI) survivors show physical and functional improvements but continue to have cognitive and psychosocial problems throughout recovery. However, the functional outcome of severe TBI in Malaysia is unknown. The objective of this study is to measure the functional outcomes of severe TBI within 6 months post-injury. A cohort study was done on 33 severe TBI survivors. The Glasgow Outcome Scale-Extended (GOSE) was used in this study. The mean age of the participants was 31.79 years (range: 16-73 years). The logistic regression model was statistically significant, chi2(5, N = 33) = 29.09, p < .001. The length of stay (LOS) in incentive care unit ( p = .049, odds ratio = 6.062) and duration on ventilator ( p = .048, odds ratio = 0.083) were good predictors of the functional outcomes. Future research should focus on larger sample size of severe TBI in Malaysia. PMID- 29618233 TI - Using Commercial Physical Activity Trackers for Health Promotion Research: Four Case Studies. AB - BACKGROUND: Wearable physical activity (PA) trackers are becoming increasingly popular for intervention and assessment in health promotion research and practice. The purpose of this article is to present lessons learned from four studies that used commercial PA tracking devices for PA intervention or assessment, present issues encountered with their use, and provide guidelines for determining which tools to use. METHOD: Four case studies are presented that used PA tracking devices (iBitz, Zamzee, FitBit Flex and Zip, Omron Digital Pedometer, Sensewear Armband, and MisFit Flash) in the field-two used the tools for intervention and two used the tools as assessment methods. RESULTS: The four studies presented had varying levels of success with using PA devices and experienced several issues that impacted their studies, such as companies that went out of business, missing data, and lost devices. Percentage ranges for devices that were lost were 0% to 29% and was 0% to 87% for those devices that malfunctioned or lost data. CONCLUSIONS: There is a need for low-cost, easy-to use, accurate PA tracking devices to use as both intervention and assessment tools in health promotion research related to PA. PMID- 29618234 TI - Patient safety culture in obstetrics and gynecology and neonatology units: the nurses' and the midwives' opinion. AB - BACKGROUND: Patients treated in health care facilities that provide services in the fields of obstetrics, gynecology, and neonatology are especially vulnerable. Large multidisciplinary teams of physicians, multiple invasive and noninvasive diagnostic and therapeutic procedures, and the use of advanced technologies increase the probability of adverse events. The evaluation of knowledge about patient safety culture among nurses and midwives working in such units and the identification of critical areas at a health care institution would reduce the number of adverse events and improve patient safety. The aim of the study was to evaluate the opinion of nurses and midwives working in clinical departments that provide services in the fields of obstetrics, gynecology, and neonatology about patient safety culture and to explore potential predictors for the overall perception of safety. METHODS: We used the Hospital Survey on Patient Safety Culture (HSOPSC) to evaluate nurses' and midwives' opinion about patient safety issues. The overall response rate in the survey was 100% (n = 233). RESULTS: The analysis of the dimensions of safety on the unit level showed that the respondents' most positive evaluations were in the Organizational Learning - Continuous Improvement (73.2%) and Feedback and Communication about Error (66.8%) dimensions, and the most negative evaluations in the Non-punitive Response to Error (33.5%) and Staffing (44.6%) dimensions. On the hospital level, the evaluation of the safety dimensions ranged between 41.4 and 56.8%. The percentage of positive responses in the outcome dimensions Frequency of Events Reported was 82.4%. We found a significant association between the outcome dimension Frequency of Events Reported and the Hospital Management Support for Patient Safety and Feedback and Communication about Error Dimensions. CONCLUSIONS: On the hospital level, the critical domains in health care facilities that provide services in the fields of obstetrics, gynecology, and neonatology were Teamwork Across Hospital Units, and on the unit level - Communication Openness, Teamwork Within Units, Non-punitive Response to Error, and Staffing. The remaining domains were seen as having a potential for improvement. PMID- 29618235 TI - Integrative Review of the Relationship Between Sleep Disturbances and Episodic Memory in Older Adults. AB - Impaired episodic memory in older adults has been linked to many factors. One of these factors is sleep disturbances, which are reported by more than 50% of older adults. The relationship between episodic memory and sleep disturbances remains unclear, however, because of the multiple types of measures of sleep and episodic memory used in previous studies. The purpose of this integrative literature review was to integrate and compare findings on this relationship in adults aged 65 years. An electronic search was conducted in PubMed, Cumulative Index to Nursing and Allied Health Literature, PsychINFO, and Medline for material published from the inception of the databases to December 2016. The literature search produced 13 data-based, peer-reviewed, and primary research articles that met eligibility criteria. The synthesized results from these articles provide evidence that older adults with 6-8 hr of self-reported total sleep time had better episodic memory than older adults with <=5 hr or >=9 hr of total sleep time. Shorter length and lower percentage of slow-wave sleep were associated with reduced episodic memory in older adults, but the results were controversial. Selection of different measurements and inconsistent variables across studies increased the difficulty of synthesizing and comparing the results. The diversity of covariates controlled in the included articles raise questions regarding which covariates should be controlled in such studies of sleep and episodic memory in older adults. The numerous study limitations were thus major barriers to understanding the relationship between sleep disturbances and episodic memory. PMID- 29618236 TI - Designing a new biosensor "DNA ELISA" to detect Escherichia coli using genomic DNA and comparison of this method to PCR-ELISA. AB - In this experiment, DNA-ELISA biosensor was introduced, bearing the ability to detect specific bacteria in about 4 h. This is a more rapid system in comparison to conventional methods, like colony counting method. Moreover, this method does not require any amplification and directly detects genomic DNA of bacteria, giving a lower limit to the sensitivity of 40,000 bacteria. In this study, two specific probes capture (biotin labelled) and detector (dig labelled), were used against special regions of 16s rRNA gene of Escherichia coli ATCC 25922. The capture probe has the ability to trap the target bacterial DNA from a pool of other kinds of bacteria under specific conditions. The detector probe then was used to hybridize to the genome of trapped bacteria. The detection proceeds by adding HRP-anti dig enzyme and its substrate, ABTS to emit light. Light absorbance is measured for verifying the detection. PMID- 29618237 TI - Transition from paediatric to adult healthcare for young people with cystic fibrosis: Parents' information needs. AB - Parents of young people with cystic fibrosis (YPWCF) play an important role during the transition from paediatric to adult health services. There is limited evidence on parental information needs and the extent to which they are met. An online survey was conducted targeting a finite population of 190 parents of YPWCF in Ireland. Fifty-nine parents responded (31% response rate). Parents reported the need for more general preparation and timing of the transfer, more information regarding the differences between adult and child health services and how their child will self-manage his/her illness in the future. Most parents received information on the timing of transfer and new healthcare providers but reported being insufficiently informed about their legal status relating to medical confidentiality for their adult child and community resources available for their child after transition to adult health services. The findings highlight the importance of information and preparation for caregivers as well as young people to promote successful transition to adult healthcare. Providing parents with clear information and anticipatory guidance are simple changes in practice that may lead to improvements in transition experiences. PMID- 29618238 TI - The importance of environment: Neighborhood characteristics and parent perceptions of child health. AB - Andersen's Behavioral Model of Health Services Use acknowledges the importance of community and environment in how individuals utilize health-care services. This article questions whether and how environment influences perceptions of health, specifically parents' perceptions of their children's health. Based on data from the 2011-2012 US National Survey of Children's Health, this study investigates how parents' views of their neighborhoods (such as safety, social support, amenities, and detracting elements) shape perceptions of their child's health. Furthermore, the analysis considers how these relationships are similar or different for minority populations. Using ordinal logistic regression, this study demonstrates that neighborhood characteristics influence parents' perceptions of their children's health. Parents who report their neighborhoods as safe, supportive, and having desirable amenities perceive their children to be healthier. Parents living in neighborhoods possessing detracting elements report their children's health as worse. These findings are largely consistent for minority and nonminority neighborhoods. The findings of this study convey the importance of environments to how parents view the health of their children. Improving safety and strengthening social supports within neighborhoods could help to address health concerns. As well, health-care organizations and public health offices should launch initiatives in disadvantaged neighborhoods to address health concerns and disparities. PMID- 29618239 TI - Perspectives of Community Co-Researchers About Group Dynamics and Equitable Partnership Within a Community-Academic Research Team. AB - Equitable partnership processes and group dynamics, including individual, relational, and structural factors, have been identified as key ingredients to successful community-based participatory research partnerships. The purpose of this qualitative study was to investigate the key aspects of group dynamics and partnership from the perspectives of community members serving as co-researchers. Semistructured, in-depth interviews were conducted with 15 Latino immigrant co researchers from an intervention project with Latinos Unidos por la Salud (LU Salud), a community research team composed of Latino immigrant community members and academic investigators working in a health research partnership. A deductive framework approach guided the interview process and qualitative data analysis. The LU-Salud co-researchers described relationships, personal growth, beliefs/identity motivation (individual dynamics), coexistence (relational dynamics), diversity, and power/resource sharing (structural dynamics) as key foundational aspects of the community-academic partnership. Building on existing CBPR and team science frameworks, these findings demonstrate that group dynamics and partnership processes are fundamental drivers of individual-level motivation and meaning making, which ultimately sustain efforts of community partners to engage with the research team and also contribute to the achievement of intended research outcomes. PMID- 29618240 TI - Understanding the Relationship Between Female Sex Workers and Their Intimate Partners: Lessons and Initial Findings From Participatory Research in North Karnataka, South India. AB - While traditional HIV prevention programs with female sex workers (FSWs) in Karnataka, India, have focused on reducing HIV transmission between FSWs and clients through increased condom use, these programs have not fully addressed the transmission risk between FSWs and their nonpaying intimate partners (IPs). Condom use is infrequent and violence is recurrent in these relationships: Furthermore, there is little evidence on the precise nature of FSW-IP relationships. Our study addresses this knowledge gap to inform HIV programs targeted at FSWs. A series of workshops, using participatory tools, was held to explore FSW-IP relationships; 31 FSWs and 37 IPs participated. Three aspects of FSW-IP relationships were examined: how FSWs and IPs understand and interpret their relationships, factors influencing condom use, and the role of violence and its consequences. FSWs wish to be perceived as their IPs' wives, while IPs expect their FSW partners to accept their dominance in the relationship. Nonuse of condoms signals fidelity and elevates the status of the relationship almost to that of marriage, which helps FSWs enter the category of "good" (married) women. Tolerating and accepting violence in these relationships is normative, as in other marital relationships; IPs justify violence as necessary to establish and maintain their power within the relationship. Both FSWs and IPs value their relationships despite the high degree of risk posed by low condom use and high levels of violence. Implications for program design include addressing current norms around masculinity and gender roles, and improving communication within relationships. PMID- 29618241 TI - Lung adenocarcinoma during pregnancy: clinical case and literature review. AB - Lung cancer during pregnancy is a very rare disease with less than 70 cases published to date. Information about specific lung cancer as adenocarcinoma is even more limited. Genetic techniques can detect oncogene mutations which seem to be more frequent among cases of lung cancer in pregnant women and could determine both the treatment and prognosis. We present a recent case seen at our hospital and a literature review. PMID- 29618242 TI - Load transfer of nanocomposite film on aluminum substrate. AB - INTRODUCTION: Nanocomposite films have attracted much attention in recent years. Depending on the composition of the film and fabrication method, a large range of applications has been employed for nanocomposite films. METHOD: In this study, nanocomposite films reinforced with multi-walled carbon nanotubes (MWCNTs) were deposited on the aluminum substrate through hot press processing. A shear lag model and Euler beam theory were employed to evaluate the stress distribution and load carrying capability of the nanocomposite film subjected to tensile load and bending moment. RESULTS: The influence of MWCNT on the Young's modulus and load carrying capability of the nanocomposite film was investigated through a parametric study. The theoretical predictions were verified by comparison with experimental tests. A close agreement with difference less than 6% was achieved between the theoretical prediction and experimental measurements. CONCLUSIONS: The Young's modulus and load transfer of the nanocomposite film reinforced with MWCNTs increases with the increase of the MWCNT loading. Compared to the neat epoxy film, nanocomposite film with 1 wt % of MWCNT exhibits an increase of 20% in both the Young's modulus and load carrying capability. PMID- 29618243 TI - Preparation and thermal insulation performance of cast-in-situ phosphogypsum wall. AB - INTRODUCTION: The mass accumulation of phosphogypsum has caused serious environmental pollution, which has become a worldwide problem. Gypsum is a kind of green building material, which is lighter, has better heat and sound insulation performance, and is easier to recycle compared to cement. The application of cast-in-situ phosphogypsum wall could consume a large amount of pollutant, and improve the efficiency of building construction. METHODS: The preparation and thermal insulation performance of cast-in-situ phosphogypsum wall were investigated. The property of phosphogypsum-fly ash-lime (PFL) triad cementing materials, the adaptability of retarders and superplasticizers, and the influences of vitrified microsphere as aggregates were explored. Thus, the optimum mix was proposed. Thermal insulation performance tests and ANSYS simulation of this material was carried out. RESULTS: Optimal structures based on heat channels and the method of calculation determining related parameters were proposed, which achieved a 12.3% reduction in the heat transfer coefficient of the wall. CONCLUSION: With good performance, phosphogypsum could be used in cast in-situ walls. This paper provides the theoretical basis for the preparation and energy-saving application of phosphogypsum in the walls of buildings. PMID- 29618244 TI - Study on buffer characteristics of air cushion used as hip protector. AB - INTRODUCTION: In order to develop a good hip protector to prevent in the elderly hip fracture as a result of a fall, we studied the buffer characteristics of sponges and air cushions. METHODS: The buffer rate of material was defined, and the absorption ability of the material to instantaneous impact was evaluated. An experimental device was developed and used to measure the buffer rates of sponges and leak-allowed air cushions with orifice(s). RESULTS: According to the experimental results, the buffer rate largely depended on the hardness of the sponge materials, and on the total area of the orifice(s) for the leak-allowed air cushions. Compared with the sponge with correct hardness and thickness, the buffer characteristic of the air cushion seems slightly inferior. CONCLUSIONS: Nevertheless, the air cushion's overall performance, including the better buffer rate, ultra-lightness, flexibility, and low cost, makes it a potentially useful material for hip protectors and other sport protectors. PMID- 29618245 TI - Magnetic and dielectric properties of Ca-substituted BiFeO3 nanoferrites by the sol-gel method. AB - BACKGROUND: A multiferroic material can simultaneously show two or more basic magnetic properties, including ferromagnetism, antiferromagnetism, and ferroelectricity. BiFeO3 is a multiferroic material with a rhombohedral distorted perovskite structure. Doping can reduce the volatility of Bi and greatly improve the magnetoelectric properties of BiFeO3. METHODS: To investigate the influence of the doping content we used the following analytical methods: X-ray powder diffraction (XRD), scanning electron microscopy (SEM), microwave network analysis (PNA-N5244A), and the Superconducting Quantum Interference Device (Quantum Design MPMS) test. RESULTS: With the increase of Ca2+ concentration in the solution, the grain size of Bi1- xCa xFeO3 becomes smaller, showing the role of Ca2+ ions as the dopant for fine grains. The calcination temperatures are the major causes for the saturated magnetization. The residual magnetization ( Mr) and the coercive force ( Hc) decrease linearly with the increase of x value, and due to the effect of Ca2+ substitution at Bi3+ sites, which causes the valence change of Fe and/or the oxygen vacancies. CONCLUSIONS: The XRD result indicates that the diffraction peak emerges with the increase of Ca2+ and the main diffraction peak achieves a high angle. The best calcining temperature is 600 degrees C, and the morphology is very dependent on the calcining temperature. PMID- 29618246 TI - Microstructure and optical properties of ZnO nanorods prepared by anodic arc plasma method. AB - INTRODUCTION: A one-dimensional ZnO nanostructure is a versatile and multifunctional n-type semiconductor. In this paper, ZnO nanorods were successfully prepared by the anodic arc plasma method in an oxidizing atmosphere. METHODS: The composition, morphology, crystal microstructure, and optical properties of ZnO nanorods were characterized by using X-ray diffraction (XRD), high-resolution transmission electron microscopy (HRTEM) and the corresponding selected-area electron diffraction (SAED), X-ray energy dispersive spectrometry (XEDS), ultraviolet-visible (UV-VIS) spectroscopy, Raman scattering spectrum (Raman), and photoluminescence spectrum (PL). RESULTS: The experiment results show that ZnO nanorods synthesized by this method possess hexagonal wurtzite crystal structure with good crystallization, no other impurity phases are observed, the crystalline size is about 18 nm, and the lattice constant distortion occurs compared to that of bulk ZnO. The morphology of the sample is a rod-like shape, the length ranges from 100 nm to 300 nm, the average diameter is approximately 20 nm, and the aspect ratio is relatively high. The UV-VIS absorption spectrum occurs red shift, The Raman spectrum further demonstrates that the major peaks are assigned to ZnO optical vibrational modes, and the PL spectrum exhibits coexistence properties of ultraviolet (UV) and green emission. CONCLUSIONS: The results prove that ZnO nanorods with hexagonal wurtzite crystal structure were successfully prepared by the anodic arc plasma method in an oxidizing atmosphere. PMID- 29618247 TI - Preparation and Application of a New Crosslinked Polyammonium as a Shale Inhibitor. AB - BACKGROUND: Despite the fact that a number of traditional shale inhibitors have been utilized widely in drilling operations, the same additive may be unfavorable for different drilling due to environmental protection requirements which limit scales of use. Hence, a series of polyammonium compounds was prepared from dimethylamine, epichlorohydrin, and melamine (DEM). METHODS: To concentrate our efforts, we used both standard and extra methods to investigate the inhibitive properties of a melamine crosslinking agent using mud balls immersion tests, linear expansion measurements, laser particle distribution measurements, thermogravimetric analysis, and scanning electron microscopy. RESULTS: The anti swelling rate of DEM-8 reached up to 92.3% when its concentration reached 0.8%. DEM-8 has strong inhibitive capability to bentonite hydration swelling. DEM-8 can affect the bentonite particle size at a large scale. It may adsorb on the surface of clay through hydrogen bonds and electrostatic interaction by an anchoring effect and a hydrophobic effect. CONCLUSIONS: Compared with a blank solution, DEM 8 displays high inhibitive ability against the hydration and swelling of clay. The mud ball is more stable in DEM-8 solution and its swelling degree is very low compared with that of the control test. The inhibition mechanism of DEM-8 to shale can be deduced in that hydrogen bonding, ion exchange, and anchoring effect help to control the hydration and swelling. PMID- 29618248 TI - Surface-enhanced Raman scattering investigation of bovine serum albumin by Au nanoparticles with different sizes. AB - BACKGROUND: Surface-enhanced Raman scattering (SERS) has become a useful spectroscopic tool for studying biomolecule structures. The main types of plasmonic substrates used in biological systems are Au nanoparticles (AuNPs), whose surface plasmon resonance depends on the nanoparticle size, morphology, particle interspace, and so on. METHODS: In this study, AuNP colloids with different sizes were synthesized and used as the sensors to probe SERS signals of different biomarkers and biomolecules. RESULTS: The results showed that an AuNP colloid of ~50 nm had excellent SERS effects in probing various molecules, and could be preserved for about 3 months with excellent repeatability and reproducibility (RSD <5%) in terms of the probed signal intensity (rhodamine 6G and crystal violet). Meanwhile, the fabricated AuNPs were applied to study the SERS signals and structural information of bovine serum albumin (BSA) in aqueous solution. It was found that SERS could rapidly provide the structural information and vibration characteristics of BSA. CONCLUSION: It was concluded that biocompatible AuNP colloid may be a promising biosensor in the rapid and label free detection of biological systems. PMID- 29618250 TI - Stress analysis of sandwich composite beam induced by piezoelectric layer. AB - INTRODUCTION: Smart structures equipped with piezoelectric devices to sense and actuate the structure could be used in many engineering applications. To explore the smart structure further and apply it to more complex structures, some problems are critical to be concerned. Among them, delamination due to the high stress is an important issue since its serious effect on the strength and stiffness of the composite structure. METHOD: In this investigation, a piezoelectric layer is embedded into the host structure to form a sandwich composite structure. The piezoelectric layer is subjected to an electric voltage, yielding the bending effect on the sandwich composite structure. A theoretical model based on the Euler beam theory and interfacial continuity is presented to determine the stresses of the sandwich composite beam caused by the piezoelectric layer. RESULTS: The influences of the embedded depth and Young's modulus of the piezoelectric layer on the stress distribution of the sandwich composite beam are investigated through a parametric study. The analytical solutions are verified by the finite element method. Good agreement is achieved between the present approach and the finite element method. CONCLUSIONS: Numerical analysis indicates that the maximum tensile stresses in the top and bottom layers are decreasing with the increase of the embedded depth, while the maximum compressive stress in the lead zirconate titanate layer is increasing with the increase of the embedded depth. Both the top and bottom layers are subjected to tensile stress and increasing with the increase of the Young's modulus ratio, while the piezoelectric layer is subjected to compressive stress and increasing with the increase of the Young's modulus ratio. PMID- 29618249 TI - The influence of Ca substitution on LaFeO3 nanoparticles in terms of structural and magnetic properties. AB - BACKGROUND: The nanocrystalline structure of La1 -xCa xFeO3 was prepared by a sol gel method involving an auto-combustion process. The incorporation of rare-earths in LaFeO3 induces strain in magnetic properties, especially in terms of the following parameters: replacement amount, oxygen partial pressure, and calcination temperature. METHODS: To determine the effects of the amount of Ca2+ ion doping agent and the calcination temperature on the microstructure, particle morphology, and magnetic properties of LaFeO3 crystal, we performed the following respective analytical methods: X-ray powder diffraction, Fourier-transform infrared (FT-IR) spectroscopy, scanning electron microscopy, and vibrating sample magnetometer tests. RESULTS: The orthorhombic structure of LaFeO3 perovskite did not change even when it was doped with Ca2+ ions, and its space group continued to be Pnma (No.62). FT-IR spectra confirmed that the main band appearing at 568 cm-1 is due to the antisymmetric stretching vibration of Fe-O-Fe bonds in FeO6. The introduction of Ca inhibits the growth of grains but the morphology of particles is improved. With an increasing concentration of Ca2+ ions, magnetic behavior of the samples also witnessed an increasing trend in a proportionate manner. With an increase in calcination temperature, the enclosed area of the magnetic hysteresis curve of the sample reduced remarkably. CONCLUSIONS: The growth of nanoparticles can be restrained with an increase of Ca content that is used as doping agent. The magnetic behavior of La1 -xCa xFeO3 tilts towards G type antiferromagnetism; the magnetic orientation is achieved from the super exchange interaction of Fe3+ ions with oxygen ions. PMID- 29618251 TI - Effects of diffusion process on potential induced degradation of silicon solar cells. AB - BACKGROUND: Potential induced degradation (PID) has recently been identified as one of the most important degradation mechanisms for silicon solar cells. It is widely considered that PID is closely related with the manufacture and application period of solar modules. METHODS: In this study, the effects of diffusion sheet resistance on PID were verified and explained by testing the emitter doping profile, the minority carrier lifetime, the emitter saturation current, the electrical performance of different cells, and the PID process. RESULTS: With increasing sheet resistance of cells, the depth and saturation current density of the emitter both decreased, and the cell efficiency increased, whereas the PID phenomenon became serious. CONCLUSIONS: It was found that higher sheet resistance or thinner P-N junction could lead to higher PID sensitivity. Therefore, more attention should be paid to PID phenomenon as the photovoltaic industry develops in the direction of high sheet resistance. PMID- 29618252 TI - Nonlinear dynamic analysis and hypernormal form of truss core sandwich plates. AB - INTRODUCTION: Truss core material, which is a new type of ultra-light material with comprehensive properties, is used in the aerospace industry. The aim of this paper is to investigate the dynamic behavior of three-dimensional Kagome sandwich plates with truss core under transverse and in-plane excitation in the case of 1:1 internal resonance. METHODS: Firstly, the averaged equation is obtained by means of the method of multiple scales. Then, the nonlinear system is analyzed applying the theory of normal form. Eventually, we analyze the dynamic behavior, mainly periodic motions, for the truss core sandwich panels by using numerical simulation. RESULTS: Numerical results are presented here for the nonlinear dynamic behavior of the model of truss core sandwich plates, which provides theoretical guidance to vibration control. CONCLUSIONS: Considerable insight has been gained concerning the sign of parameter of the model controlled by material property. PMID- 29618253 TI - Surface modification of bacterial cellulose aerogels by ARGET ATRP. AB - INTRODUCTION: Bacterial cellulose (BC) aerogels have received more and more attention due to their renewability, biodegradability and other excellent properties in recent years. Modification of BC aerogels using different methods would expand their applications. However, many problems exist for these modifications, such as a low grafting ratio, the larger dosage of metal catalyst required and so on. Activator regeneration by electron transfer (ARGET) for atom transfer radical polymerization (ATRP) is a novel ATRP method which could significantly reduce the amount of metal catalyst required and achieve a high grafting ratio. METHODS: Novel nanostructured BC aerogels containing epoxy groups were prepared by the ARGET ATRP method. BC aerogels were functionalized with initiating sites by reaction with 2-bromoisobutyryl bromide (BiBBr), and followed by ARGET ATRP reaction with glycidyl methacrylate (GMA) which was catalyzed by copper(II) bromide (CuBr2) and N,N,N',N,'N"-pentamethyldiethylenetriamine (PMDETA), and then reduced by vitamin C. BC aerogels containing epoxy groups (BC g-PGMA) were obtained after freeze-drying. The influence factors of the solvent ratio of N,N-dimethyl formamide (DMF)/toluene, monomer concentration, the concentration of CuBr2, the molar ratio of vitamin C (Vc)/CuBr2,reaction temperature and time on the grafting ratio were investigated. RESULTS: The results showed that the optimal DMF and toluene volume ratio was 2:1, the optimal monomer and CuBr2 concentration were 2 mol/l and 1.5 mmol/l. The optimal molar ratio of PMDETA/CuBr2 and Vc/CuBr2 were 4:1 and 1:1. The optimal reaction temperature and time were 60 degrees C and 9 h. Scanning electron microscopy (SEM) images showed that GMA was strongly adhered onto the surface and inside of the BC pellicle. CONCLUSIONS: GMA was self-grown on the BC surface and achieved the high grafting ratio of 1052.7% under optimal conditions. The BC-g-PGMA aerogels containing the epoxy groups will provide wider application prospects in drug release, enzyme fixed, functional materials and other fields. PMID- 29618254 TI - Synthesis of magnetic Fe3O4 micro/nanospheres in organic solvent. AB - INTRODUCTION: Micro/nanostructured materials have attracted a great deal of attention, and many strategies have been developed to fabricate micro/nanostructured materials. METHODS: Amine-functionalized micro/nanostructured Fe3O4 with different sizes was synthesized conveniently in organic media. The chemical structures of as-synthesized products were characterized by FTIR, TEM, SEM, and XRD. RESULTS: The ligand binds to the Fe3O4 core by hydrogen bond between the oxygen atom on the surface of Fe3O4 and the hydrogen atom in molecular ethylenediamine. Their magnetic properties were also investigated. CONCLUSIONS: First, there is no need to control the reaction under a nitrogen atmosphere, and just one salt is used as an iron source. The growth and the surface modification of Fe3O4 crystalline nucleation happen at the same time. Second, monodispersed Fe3O4 micro/nanospheres were prepared without additional surfactant or external magnetic fields. Third, this method is preferred compared with the conventional organic phase method, as the reaction condition is milder and less pollutant will be produced. PMID- 29618255 TI - Mechanical property research of different materials for supporting rings. AB - INTRODUCTION: Supporting rings are becoming more widely applied as an assistant structural support. However, during the engineering design and optimization process, many tests are necessary to understand the mechanical properties of different materials and the different section shape for supporting rings. METHODS: The key problem is to measure the radial force caused by elongation under the axes' pressure. This cannot be measured directly through the use of sensors. The previous, simple method was to position a transfer bar into the hole on the supported wall, or use a strain gauge, which changes the contact boundary. A new method called the "semi-ring method" is proposed. RESULTS: The problem can be solved well and the feasibility of this method is shown from an example of its application. CONCLUSIONS: An innovative method is applied in test of mechanical performance for PTFE and butyl rubber material adopted in four kinds of section shape structure supporting rings. The results and analysis can provide some beneficial references for structure design. PMID- 29618256 TI - Study on electromagnetic characteristics of the magnetic coupling resonant coil for the wireless power transmission system. AB - BACKGROUND: The resonant coil design is taken as the core technology in the magnetic coupling resonant wireless power transmission system, which achieves energy transmission by the coupling of the resonant coil. This paper studies the effect of the resonant coil on energy transmission and the efficiency of the system. Combining a two-coil with a three-coil system, the optimum design method for the resonant coil is given to propose a novel coil structure. METHODS: First, the co-simulation methods of Pspice and Maxwell are used. When the coupling coefficient of the resonant coil is different, the relationship between system transmission efficiency, output power, and frequency is analyzed. When the self inductance of the resonant coil is different, the relationship between the performance and frequency of the system transmission is analyzed. Then, two-coil and three-coil structure models are built, and the parameters of the magnetic field of the coils are calculated and analyzed using the finite element method. In the end, a dual E-type simulation circuit model is used to optimize the design of the novel resonance coil. RESULTS: The co-simulation results show that the coupling coefficients of the two-coil, three-coil, and novel coil systems are 0.017, 0.17 and 0.0126, respectively. The power loss of the novel coil is 16.4 mW. CONCLUSIONS: There is an obvious improvement in the three-coil system, which shows that the magnetic leakage of the field and the energy coupling are relatively small. The new structure coil has better performance, and the load loss is lower; it can improve the system output power and transmission efficiency. PMID- 29618257 TI - Preparation of anticoagulant PyC biomaterials with super-hydrophobic surface. AB - INTRODUCTION: Pyrolytic carbon (PyC) is a kind of biomaterial which is chemically inert and has excellent biocompatibility. In order to obtain a super-hydrophobic PyC surface to improve anticoagulation and inhibit thrombus, this study prepares grating pair structure, microhole array structure, helix structure on PyC surface by nanoseconds laser etching. METHODS: Rod-like ZnO film and ball-like ZnO film are prepared on the PyC surface by the hydrothermal method; polyvinyl pyrrolidone (PVP) nanofiber film and PVP/TiO2 complex nanofiber film are prepared on the PyC surface by the electrospinning method; the PyC surface is silanized. Finally, surface microstructure and surface energy are characterized by scanning electron microscopy and contact angle meter (OCA20, German DataPhysics Co.). RESULTS: The periodical microstructures are formed respectively by nanoseconds laser etching. The surface roughness is increased by the hydrothermal and electrospinning method. CONCLUSIONS: Through infiltration experiment on rough and smooth PyC surfaces, rough PyC surface with microstructure is super-hydrophobic and has greater than 150 degrees contact angle, which decreases blood flow resistance and inhibits thrombus. PMID- 29618258 TI - Numerical study on rupture process of fiber-reinforced composites. AB - INTRODUCTION: This study aims to investigate the strength characteristics of fiber composites under uniaxial tensile stress. METHODS: A tensile failure finite element model based on fracture mechanics was built for fiber composites. The principal stress concentration-release-transfer evolution and the crack propagation of the composites under the conditions of equal single fiber width, unequal quantity, and equal total fiber width and unequal quantity were discussed. RESULTS: The tensile strength of the composites increased with fiber quantity when the width of each single fiber was equal. CONCLUSIONS: The tensile strength of the composites increased with fiber quantity when the total width of the composite fiber was equal. PMID- 29618260 TI - Mix design of asphalt mixture used for the waterproof and anti-cracking layer in the rainy area of South China. AB - INTRODUCTION: In this study, the asphalt mixture (porosity <2%) was tested for use between the upper and middle layers of the asphalt pavement to improve its interlayer structure and to enhance its related waterproof and anti-cracking ability. METHODS: Considering the weather characteristics and traffic conditions in Jiangxi Province, appropriate raw materials were selected. Based on the technical indexes of the raw materials, expected porosity (<2%), and AC-5 standard for the asphalt mixture, experiments were conducted to determine the best gradation range of the waterproof and anti-cracking layer, and to obtain the optimum amount of the asphalt and fiber used based on Marshall tests. RESULTS: The high-temperature rutting test, low-temperature cracking test, and water stability test were conducted to evaluate the pavement performance of the waterproof and anti-cracking layer. CONCLUSIONS: A waterproof and anti-cracking layer was added between the upper and middle layers of the asphalt pavement, which has excellent performance for avoiding cracks and water damage. PMID- 29618259 TI - Effects of quartz on crystallization behavior of mold fluxes and microstructural characteristics of flux film. AB - BACKGROUND: Mold fluxes are mainly prepared using cement clinker, quartz, wollastonite, borax, fluorite, soda ash and other mineral materials. Quartz, as one of the most common and essential materials, was chosen for this study to analyze itseffects on crystallization temperature, critical cooling rate, crystal incubation time, crystallization ratio and phases of flux film. METHODS: We used the research methods of process mineralogy with the application of the single hot thermocouple technique, heat flux simulator, polarizing microscope, X-ray diffraction, etc. Results: By increasing the quartz content from 16 mass% to 24 mass%, the crystallization temperature, critical cooling rate and crystallization ratio of flux film decreased, and the crystal incubation time was extended. Meanwhile, the mineralogical structure of the flux film changed, with a large amount of wollastonite precipitation and a significant decrease in the cuspidine content until it reached zero. This showed a steady decline in the heat transfer control capacity of the flux film. CONCLUSIONS: The reason for the results above is that, by increasing the quartz content, the silicon-oxygen tetrahedron network structure promoted a rise in viscosity and restrained ion migration, inhibiting crystal nucleation and growth, leading to the weakening of the crystallization and a decline in the crystallization ratio. PMID- 29618261 TI - Preparation and properties studies of UV-curable silicone modified epoxy resin composite system. AB - INTRODUCTION: Modified epoxy suitable for ultraviolet (UV) curing is prepared by using organic silicon toughening. The curing kinetics of the composite are studied by dielectric analysis (DEA), and the two-phase compatibility of the composite is studied by scanning electron microscopy (SEM). METHODS: The tensile properties, heat resistance, and humidity resistance of the cured product are explored by changing the composition ratio of the silicone and the epoxy resin. RESULTS: SEM of silicone/epoxy resin shows that the degree of cross-linking of the composites decreases with an increase of silicone resin content. Differential thermal analysis indicates that the glass transition temperature and the thermal stability of the composites decrease gradually with an increase of silicone resin content. The thermal degradation rate in the high temperature region, however, first decreases and then increases. In general, after adding just 10%-15% of the silicone resin and exposing to light for 15 min, the composite can still achieve a better curing effect. CONCLUSIONS: Under such conditions, the heat resistance of the cured product decreases a little. The tensile strength is kept constant so that elongation at breakage is apparently improved. The change rate after immersion in distilled water at 60 degrees C for seven days is small, which shows excellent humidity resistance. PMID- 29618262 TI - Study on super-long deep-hole drilling of titanium alloy. AB - INTRODUCTION: In this study, the super-long deep-hole drilling of a titanium alloy was investigated. METHODS: According to material properties of the titanium alloy, an experimental approach was designed to study three issues discovered during the drilling process: the hole-axis deflection, chip morphology, and tool wear. RESULTS: Based on the results of drilling experiments, crucial parameters for the super-long deep-hole drilling of titanium alloys were obtained, and the influences of these parameters on quality of the alloy's machining were also evaluated. CONCLUSIONS: Our results suggest that the developed drilling process is an effective method to overcome the challenge of super-long deep-hole drilling on difficult-to-cut materials. PMID- 29618263 TI - A thermodynamic and kinetic study of trace iron removal from aqueous cobalt sulfate solutions using Monophos resin. AB - BACKGROUND: High purity cobalt has many important applications, such as magnetic recording media, magnetic recording heads, optoelectronic devices, magnetic sensors, and integrated circuits, etc. To produce 5N or higher purity cobalt in an electro-refining process, one of the challenges is to effectively reduce the Fe content of aqueous cobalt salt solution before electrolysis. This paper describes thermodynamic and kinetic investigations of the Fe adsorption process of a new sulfonated monophosphonic resin with the trade mark Monophos. METHODS: Five cobalt sulfate solutions of different Co concentrations were prepared. Fe ions were removed from the solutions by ion exchange method using Monophos resin. Chemical analysis was carried out using a Perkin Elmer ICP-OES. RESULTS: The initial Fe concentrations of about 0.9-2.0 mg/L can be reduced to about 0.3-0.8 mg/L, which is equivalent to an Fe removal rate of 60-67%. The Langmuir isothermal adsorption model applies well to the Fe removal process. A second order type based on McKay equation fits better with experimental data than other kinetic models. The kinetic curve can be divided into two sections. For t < 30 min, particle diffusion may act as the controlling step, whereas chemical reaction may control the Fe adsorption process in the section t > 30 min. CONCLUSIONS: Monophos resin is effective for the removal of trace Fe from cobalt sulfate solution. This ion exchange process obeys the Langmuir isothermal adsorption model and the McKay equation of second-order kinetics. PMID- 29618264 TI - Interfacial damage identification of steel and concrete composite beams based on piezoceramic wave method. AB - INTRODUCTION: Steel-concrete composite structures are playing an increasingly important role in economic construction because of a series of advantages of great stiffness, good seismic performance, steel material saving, cost efficiency, convenient construction, etc. However, in service process, due to the long-term effects of environmental impacts and dynamic loading, interfaces of a composite structure might generate debonding cracks, relative slips or separations, and so on, lowering the composite effect of the composite structure. METHODS: In this paper, the piezoceramics (PZT) are used as transducers to perform experiments on interface debonding slips and separations of composite beams, respectively, aimed at proposing an interface damage identification model and a relevant damage detection innovation method based on PZT wave technology. RESULTS: One part of various PZT patches was embedded in concrete as "smart aggregates," and another part of the PZT patches was pasted on the surface of the steel beam flange, forming a sensor array. CONCLUSIONS: A push-out test for four specimens was carried out and experimental results showed that, under the action of the external loading, the received signal amplitudes will increasingly decrease with increase of debonding slips along the interface. The proposed signal energy-based interface damage detection algorithm is highly efficient in surface state evaluations of composite beams. PMID- 29618265 TI - The Perspective of Older Men With Depression on Suicide and Its Prevention in Primary Care. AB - BACKGROUND: Suicide rates in older men are higher than in the general population, yet their utilization of mental health services is lower. AIMS: This study aimed to describe: (a) what primary care providers (PCPs) can do to prevent late-life suicide, and (b) older men's attitudes toward discussing suicide with a PCP. METHOD: Thematic analysis of interviews focused on depression and suicide with 77 depressed, low-socioeconomic status, older men of Mexican origin, or US-born non Hispanic whites recruited from primary care. RESULTS: Several themes inhibiting suicide emerged: it is a problematic solution, due to religious prohibition, conflicts with self-image, the impact on others; and, lack of means/capacity. Three approaches to preventing suicide emerged: talking with them about depression, talking about the impact of their suicide on others, and encouraging them to be active. The vast majority, 98%, were open to such conversations. An unexpected theme spontaneously arose: "What prevents men from acting on suicidal thoughts?" CONCLUSION: Suicide is rarely discussed in primary care encounters in the context of depression treatment. Our study suggests that older men are likely to be open to discussing suicide with their PCP. We have identified several pragmatic approaches to assist clinicians in reducing older men's distress and preventing suicide. PMID- 29618266 TI - Suicide Rates in Evacuation Areas After the Fukushima Daiichi Nuclear Disaster. AB - BACKGROUND: Associations between nuclear disasters and suicide have been examined to a limited extent. AIM: To clarify the suicide rates in evacuation areas after the nuclear disaster in Fukushima, which occurred in March 2011. METHOD: This descriptive study used monthly data from vital statistics between March 2009 and December 2015. Suicide rates in areas to which evacuation orders had been issued, requiring across-the-board, compulsory evacuation of residents from the entire or part of municipalities, were obtained and compared with the national average. RESULTS: Male suicide rates in evacuation areas increased significantly immediately after the disaster, and then began to increase again 4 years after the disaster. Female suicide rates declined slightly during the first year and then increased significantly over the subsequent 3-year period. Moreover, male rates in areas where evacuation orders were issued for the total area declined over the course of approximately 2 years, but then began to increase thereafter. Analysis by age revealed postdisaster male rates in evacuation areas decreased for those aged 50-69 years and increased for those aged <= 29 years and >= 70 years. LIMITATIONS: The number of suicides among females and the female population in the evacuation area was small. CONCLUSION: Our findings suggest the need to keep in mind that, when providing post-disaster mental health services, suicide rates can eventually increase even if they initially decrease. PMID- 29618267 TI - A Multidimensional Theory of Suicide. AB - BACKGROUND: Theory is the foundation of science; this is true in suicidology. Over decades of studies of suicide notes, Leenaars developed a multidimensional model of suicide, with international (crosscultural) studies and independent verification. AIM: To corroborate Leenaars's theory with a psychological autopsy (PA) study, examining age and sex of the decedent, and survivor's relationship to deceased. METHOD: A PA study in Norway, with 120 survivors/informants was undertaken. Leenaars' theoretical-conceptual (protocol) analysis was undertaken of the survivors' narratives and in-depth interviews combined. RESULTS: Substantial interjudge reliability was noted (kappa = .632). Overall, there was considerable confirmatory evidence of Leenaars's intrapsychic and interpersonal factors in suicide survivors' narratives. Differences were found in the age of the decedent, but not in sex, nor in the survivor's closeness of the relationship. Older deceased people were perceived to exhibit more heightened unbearable intrapsychic pain, associated with the suicide. CONCLUSION: Leenaars's theory has corroborative verification, through the decedents' suicide notes and the survivors' narratives. However, the multidimensional model needs further testing to develop a better evidence-based way of understanding suicide. PMID- 29618268 TI - Reporting on Suicide Between 1819 and 1944. AB - BACKGROUND: Suicide rates increased substantially in many countries during the 19th century. Little is known about news coverage on suicide in this period and its relationship to suicide rates. AIMS: To test whether there was a covariation between the quantity of reporting and suicide rates and whether the press relied on sensational reporting. METHOD: A content analysis of Austrian news coverage between 1819 and 1944 was conducted and compared with contemporary findings. RESULTS: There were similar corresponding troughs and peaks in both time series, indicative of covariation. The analysis revealed that variations in the quantity of reporting predicted the following year's suicide rates, a pattern consistent with a long-term Werther effect. Conversely, suicide rates did not predict future values of the quantity of reporting. Furthermore, the press substantially overrepresented "vivid" firearm suicides compared with other more "pallid" methods such as drowning, indicative of sensational reporting. LIMITATIONS: The causal order of the quantity of reporting and suicide rates should be interpreted with caution. CONCLUSION: The press may have contributed to the establishment of suicide as a mass phenomenon in the 19th century. The contemporary comparison is indicative of temporal stability. PMID- 29618269 TI - Importance of Messages for a Suicide Prevention Media Campaign. AB - BACKGROUND: A suicide prevention media campaign aimed at family members and friends may be one useful population-level suicide prevention strategy for Australia. However, currently there is limited evidence of what messages would be acceptable and appropriate for inclusion. AIMS: This expert consensus study aimed to identify messages that experts with lived experience of suicide risk and suicide prevention professionals believed were most important to include in such a suicide prevention campaign. METHOD: Using an online survey method, 127 participants with lived experience (lived experience group) and 33 suicide prevention professionals (suicide prevention professionals group) rated 55 statements, drawn from an earlier Delphi study, from very low priority to very high priority for inclusion in a suicide prevention campaign. RESULTS: There was significant agreement within and between the two participant groups on the most highly rated messages for inclusion. The mostly highly rated messages were that family members or friends should ask directly about suicidal thoughts and intentions, listen to responses without judgment, and tell the person at risk that they care and want to help. LIMITATIONS: We restricted ratings to just one round and may therefore have limited the level of consensus achieved. Use of a predefined set of suicide prevention messages might also have prevented us from identifying other important messages. Lived experience participants were drawn from one source and this might bias their responses through exposure to common suicide prevention messages that influence their points of view. CONCLUSION: There is substantial agreement between professionals and people with lived experience on the most important messages to include in a suicide prevention campaign. These most highly rated messages could be adopted in a suicide prevention media campaign. PMID- 29618270 TI - Associations of Tabloid Newspaper Use With Endorsement of Suicide Myths, Suicide Related Knowledge, and Stigmatizing Attitudes Toward Suicidal Individuals. AB - BACKGROUND: Educating the public about suicide is an important component of suicide prevention. So far, little is known about whether common misconceptions of suicide are related to individual tabloid newspaper use. AIMS: This study aimed to investigate associations of time spent reading tabloids with endorsement of suicide myths, suicide-related knowledge, and with stigmatizing attitudes toward suicidal individuals. METHOD: In this cross-sectional online survey, we assessed suicide-related knowledge and stigmatizing attitudes toward suicidal individuals among 456 study participants in Austria together with their endorsement of five common suicide myths (e.g., "suicidal individuals do not communicate their intent"). Furthermore, we assessed participants' time spent reading tabloids. RESULTS: Multivariate analyses controlling for gender, age, education, and the time spent reading broadsheet newspapers and watching television indicated that participants' time spent reading tabloids was associated with higher endorsement of suicide myths as well as with a lower level of suicide-related knowledge and a higher level of stigmatizing attitudes toward suicidal individuals. LIMITATIONS: Due to the study's cross-sectional design, causality concerning these associations could not be assessed. CONCLUSION: The present findings confirm that readers of tabloids are an important target group for suicide education efforts. PMID- 29618271 TI - Harmful or Helpful? A Systematic Review of How Those Bereaved Through Suicide Experience Research Participation. AB - BACKGROUND: Many of the bereaved through suicide are interested in participating in postvention studies. However, there is a contradiction between the positive experiences of research participation and concerns raised by ethical boards. AIMS: To review studies on the experience of research participation by those bereaved through suicide, including initial contact with the study and its short- and long-term impacts. METHOD: Systematic searches in Embase, Medline, PsycINFO, as well as Google Scholar identified 12 papers reporting on 11 studies. RESULTS: The majority (73-100%) of study participants evaluated participation positively, and would recommend it to others (90-100%), as it was related to altruism, social support, and personal growth. A minority experienced participation as negative (2 10%) or upsetting (5-22%) due to feelings of guilt or painful memories. However, having a painful experience does not preclude seeing it as helpful. LIMITATIONS: Most studies concerned face-to-face psychological autopsy studies, and only two studies included a control group. CONCLUSION: Research applying standardized measures may enhance our understanding of the factors germane to (non )participation and to the likelihood of a positive/negative research experience. Vigilant recruitment and providing optimum care for participants are indicated. Further research may continue to improve participant safety and the research design of suicide bereavement studies. PMID- 29618272 TI - Does fortification of pasteurized donor human milk increase the incidence of necrotizing enterocolitis among preterm neonates? A randomized controlled trial. AB - OBJECTIVE: To compare the effect of fortified pasteurized donor human milk (PDHM) versus unfortified PDHM on the incidence of necrotizing enterocolitis (NEC) and immediate outcome among preterm neonates. METHODS: This randomized controlled trial (RCT) conducted in a tertiary care teaching hospital, south India included 80 healthy preterm neonates randomized to two groups (Group A and B). Neonates in Group A and B were fed with fortified PDHM and unfortified PDHM, respectively. Neonates in both groups were managed uniformly as per standard NICU protocol. The primary outcome was the incidence of NEC and the secondary outcomes included severity of NEC, incidence of sepsis, mortality, duration of hospital stay, number of days to reach full enteral feeds and weight gain. Neonates were followed up for 28 days or discharge whichever was earlier. RESULTS: The baseline maternal and neonatal characteristics in both groups were comparable. There was no increase in incidence of NEC in fortified PDHM group compared to unfortified PDHM group (2.5 versus 7.5%, p = .31). Severity of NEC, incidence of sepsis, mortality, duration of hospital stay, number of days to reach full enteral feeds and weight gain were also similar in both groups. CONCLUSIONS: Standard fortification of PDHM does not increase the incidence of NEC among preterm neonates. PMID- 29618274 TI - Usability testing of an mHealth device for swallowing therapy in head and neck cancer survivors. AB - The objective of this study was to conduct the first patient usability testing of a mobile health (mHealth) system for in-home swallowing therapy. Five participants with a history of head and neck cancer evaluated the mHealth system. After completing an in-application (app) tutorial with the clinician, participants were asked to independently complete five tasks: pair the device to the smartphone, place the device correctly, exercise, interpret progress displays, and close the system. Quantitative and qualitative methods were used to evaluate the effectiveness, efficiency, and satisfaction with the system. Critical changes to the app were found in three of the tasks, resulting in recommendations for the next iteration. These issues were related to ease of Bluetooth pairing, placement of device, and interpretation of statistics. Usability testing with patients identified issues that were essential to address prior to implementing the mHealth system in subsequent clinical trials. Of the usability methods used, video observation (synced screen capture with videoed gestures) revealed the most information. PMID- 29618273 TI - Cost-effectiveness of cladribine tablets, alemtuzumab, and natalizumab in the treatment of relapsing-remitting multiple sclerosis with high disease activity in England. AB - AIMS: Cladribine tablets were the first oral short-course treatment approved for highly active relapsing multiple sclerosis (MS). The Association of British Neurologists guidelines currently recommend two infusion therapies, alemtuzumab and natalizumab, to treat high disease activity relapsing remitting MS (HDA RRMS). This analysis assessed the cost-effectiveness of cladribine tablets in HDA RRMS compared with alemtuzumab and natalizumab, from the perspective of the National Health Service (NHS) in England. MATERIALS AND METHODS: A cohort-based Markov model with 11 health states (10 Expanded Disability Status Scale [EDSS] plus death) was developed. Transition matrices from the British Columbia registry were used to model the natural history of EDSS. The treatment effect on EDSS was modelled using hazard ratios for 6-month confirmed disability progression from an indirect treatment comparison (ITC). Relapses and drug-related adverse events were modeled via annualized relapse rates and event probabilities, with associated costs and quality-adjusted life year (QALY) losses. Utilities were derived from trials and the literature, and costs from NHS and literature sources. Uncertainty was assessed via probabilistic and deterministic sensitivity analyses. RESULTS: Cladribine tablets were dominant (i.e., less costly and more effective) vs alemtuzumab and natalizumab in pairwise comparisons, and the dominant strategy in fully incremental analyses. Incremental cost was driven largely by drug acquisition and administration costs, and incremental QALY gain largely by differences in delayed EDSS progression. Cladribine tablets had a 93% probability of being cost-effective at a threshold of GBP 30,000 per QALY gained, and remained dominant across the scenario analyses tested. The greatest influence on results was the treatment effect on disability progression derived from the ITC. LIMITATIONS: Uncertainty over the efficacy of DMT beyond trial durations. In line with other comparative effectiveness analyses, the network meta-analysis informing this cost-effectiveness analysis was associated with a degree of uncertainty. No treatment switching analyses were undertaken. CONCLUSIONS: Cladribine tablets are a cost-effective alternative to alemtuzumab and natalizumab in the treatment of HDA-RRMS from the perspective of the NHS in England. PMID- 29618275 TI - Experiences of Nigerian Internationally Educated Nurses Transitioning to United States Health Care Settings. AB - INTRODUCTION: Successful transition to practice of internationally educated nurses (IENs) can critically affect quality of care. The aim of this study was to characterize the facilitators and barriers to transition of Nigerian IENs (NIENs) to the United States health care setting. METHOD: Using a descriptive phenomenology approach, 6 NIENs were interviewed about their transitional experiences in the United States. Thematic methods were used for data analysis. RESULTS: The three major themes identified from the participants' stories were "fear/anger and disappointment" (FAD), "road/journey to success/overcoming challenges" (RJO), and "moving forward" (MF). The FAD theme predominated, including experiences of racism, bullying, and inequality. The RJO theme included resilience, and the MF theme encompassed personal growth. DISCUSSION: NIENs face personal and organizational barriers to adaptation, especially fear, anger and disappointment. Future research should seek to develop a model for optimal adaptation that focuses on improving both personal and organizational facilitators and decreasing barriers. PMID- 29618276 TI - Perceived Barriers to Managing Medications and Solutions to Barriers Suggested by Bhutanese Former Refugees and Service Providers. AB - INTRODUCTION: The purpose of this study was to explore perceived barriers to managing medications and potential solutions to such barriers among Bhutanese former refugees and service providers in Tasmania, Australia. METHOD: Thirty Bhutanese former refugees and service providers recruited through community health programs participated in a community-based participatory research design. Data were elicited through a structured focus group process and analyzed using content analysis. RESULTS: Perceived barriers to managing medications included language barriers, low health literacy, and culturally unresponsive interactions with services. Themes identifying potential solutions to barriers referred to the functional health literacy of individuals (providing reassurance, checking understanding, and involving support networks) and creating supportive health care environments (consistent service providers, culturally responsive care, assistance navigating services, using trained interpreters). DISCUSSION: Creating environments conducive to interactive and critical health literacy about medications is as important for culturally congruent care as supporting the functional health literacy of individuals. PMID- 29618277 TI - Spinal Fluid Cytokine Levels and Single-Photon Emission Computed Tomography Findings in Complex Febrile Seizures. AB - In this study, the authors assessed cerebrospinal fluid cytokine levels and single-photon emission computed tomography (SPECT) findings in complex febrile seizures. This study included 23 Japanese patients with complex febrile seizures. Twenty patients underwent SPECT and 12 underwent analysis of cerebrospinal fluid cytokine levels (interleukin [IL]-6, interleukin-10, interleukin-17, interleukin 1beta, tumor necrosis factor-alpha, and interferon-gamma); 9 patients underwent both studies. Cerebrospinal fluid cytokine levels were compared between the current complex febrile seizure patients and 30 patients with acute encephalopathy. In 17 of 20 patients, SPECT findings revealed areas of hypoperfusion, including the frontal (5), occipital (4), and lobular (4) regions, overlapping with other areas. Relative to patients with acute encephalopathy, those with complex febrile seizures exhibited significantly lower cerebrospinal fluid interleukin-6, interleukin-1beta, tumor necrosis factor-alpha, and interleukin-10 levels and significantly higher interleukin-17 levels. As patients with complex febrile seizures frequently exhibit abnormal SPECT findings, cerebrospinal fluid interleukin-17 levels might provide a valid biomarker to discriminate complex febrile seizures and acute encephalopathy, regardless of SPECT findings. PMID- 29618278 TI - Automated Preparation of MS-Sensitive Fluorescently Labeled N-Glycans with a Commercial Pipetting Robot. AB - N-Glycan analysis is routinely performed for biotherapeutic protein characterization. A recently introduced N-glycan analysis kit using RapiFluor-MS (RFMS) labeling provides time savings over reductive amination labeling methods while also providing enhanced fluorescence (FLR) and mass spectrometry (MS) responses. This article demonstrates the semiautomation of this kit using an Andrew Alliance pipetting robot that promises further gains in productivity. This robotic platform uses standard manual pipettors and an optically guided arm to facilitate the automation of manual procedures. The manual RFMS protocol includes two heating and cooling steps during protein denaturation and de-N-glycosylation. However, the current Andrew Alliance automated platform cannot move reaction tubes to and from different heating blocks. As a result, samples prepared using the automated procedure remain in a computer-controlled Peltier effect heating block, requiring reoptimization of denaturation and de-N-glycosylation temperatures. Using hydrophilic interaction liquid chromatography to monitor the RFMS-labeled glycan profiles, the authors demonstrated the reproducibility of the automated protocol with percent relative standard deviations (RSDs) of 9%-19% for the total area and 0.8%-20% for the relative areas of major and minor glycoforms. Overall, the automated platform presented here proves to be a convenient and reliable solution for N-glycan preparation and analysis. PMID- 29618279 TI - Long-term maintenance treatment of ulcerative colitis in eastern India: a 15-year follow-up. AB - Clinical data of 65 histologically documented ulcerative colitis patients from January 2001 to December 2013 were prospectively recorded till June 2017 and analysed to determine the outcome of long-term maintenance treatment. Drugs used were 5-aminosalicylates, steroids and azathioprine. Primary outcome measure was relapse. Though 73.8% patients relapsed, most occurred within the first five years with mild to moderate severity and were easily controlled with the same medicines. None had progressive disease; drug discontinuation was possible in six cases. Side effects of drugs were negligible. Rates of surgery, colon cancer, complications and disease-related death were very low. Longer disease duration, azathioprine discontinuation and 5-aminosalicylate use in dose < 2.4 g/d were positively associated with relapses. Biologics were not used in any patient. We conclude that long-term effective use of low-cost drugs in India may obviate the need for newer more expensive drugs. PMID- 29618280 TI - Progressive resistance exercise training and changes in resting-state functional connectivity of the caudate in persons with multiple sclerosis and severe fatigue: A proof-of-concept study. AB - Fatigue is one of the most disabling symptoms of multiple sclerosis (MS). While progressive resistance training (PRT) has been shown to reduce fatigue in persons with MS, it is not clear why these reductions occur. One hypothesis is that PRT may induce functional changes to the caudate, a region highly implicated in MS fatigue. The aim of the current study was to study the effects of PRT on overall fatigue impact and resting-state functional connectivity of the caudate in persons with MS reporting severe fatigue. Participants were semi-randomly assigned to either a 16-week home-based PRT (n = 5) or stretching control (n = 5) condition. Both groups demonstrated reductions in overall fatigue impact (main effect of time: F = .84, d = .65). Significant group * time interactions were found, with the PRT group demonstrating post-training increases in functional connectivity between the caudate and left inferior parietal (F = 66.0, p < .001), bilateral frontal (both p < .001), and right insula (F = 21.8, p = .002) regions compared to the stretching group. Furthermore, greater post-training increases in functional connectivity between the caudate and left inferior parietal region were associated with greater decreases in cognitive fatigue (r = -.52) specifically. This study provides initial evidence for the caudate as a potential neural substrate for the beneficial effects of PRT on fatigue in persons with MS. PMID- 29618281 TI - Melatonin-independent Photoperiodic Entrainment of the Circannual TSH Rhythm in the Pars Tuberalis of the European Hamster. AB - Adaptation of biological rhythms to a seasonal environment in circannual mammals is achieved via the synchronization of intrinsic circannual rhythms to the external year by photoperiod. In mammals, the photoperiodic information is integrated to seasonal physiology via the pineal hormone melatonin regulation of pars tuberalis (PT) TSHbeta expression and its downstream control of hypothalamic dio2 gene expression. In the circannual European hamster, however, photoperiodic entrainment of the circannual clock is possible in pinealectomized animals. The present study explores whether the TSHbeta expression in the PT and the downstream hypothalamic pathways are regulated by photoperiod in European hamsters in the absence of melatonin. All animals were kept on an accelerated photoperiodic regime, which compressed the natural year to a 6-month cycle. Sham operated European hamsters and half of the pinealectomized European hamsters entrained their annual cycle in reproduction, body weight, and activity pattern to this cycle, whereas the other half of the pinealectomized animals followed only each second cycle. In all animals, PT TSHbeta and hypothalamic dio2 expressions were higher in hamsters displaying a summer physiological state than in those in winter state. Moreover, in agreement with their seasonal state, reproductive animals (summer state) showed higher expression of rfrp and lower expression of kiss1-genes encoding central regulators of the reproductive axis than those animals in reproductive quiescence (winter state), indicating the hypothalamic integration of the photoperiodic signal even in pinealectomized animals. The appropriate occurrence of a well-characterized activity pattern indicative of a so-called sensitive phase to short photoperiod suggested that the SCN constructs the melatonin-independent photoperiodic message. This message is sufficient to entrain the circannual rhythm in TSHbeta expression in the PT and the downstream hypothalamic neuroendocrine pathway through a yet unknown pathway. These results reinforce the hypothesis that the PT is the site for the integration of circannual and photoperiodic information. PMID- 29618283 TI - Review of the Role of the Pharmacist in Reducing Hospital Readmissions. AB - Hospital readmissions remain a public health concern despite progress in reducing and preventing its occurrence. Among strategies that have been implemented to reduce readmission most involves medication management. Our objective was to evaluate the effectiveness of interventions involving pharmacists to reduce hospital readmissions. PubMed and Google Scholar were searched for primary literature from January 1990 to July 2016 with search terms such as "hospital readmission," and "Pharmacist," or "Pharmacy," or "medications." Studies with an abstract in English which highlighted a pharmacist involvement based on the type of intervention, country of origin, type of study, and findings were summarized. The outcomes of these interventions to reduce hospital readmissions were mixed. Of the 29 studies, 16 (55%) showed a statistically significant reduction in readmissions ranging from 3.3% to 30%. Most of the interventions focused mainly on patient education postdischarge (8) or in addition to medication reconciliation predischarge (9). There were no studies from Africa or Asia but mainly from the United States (72%). Although multiple factors contribute to hospital readmission, this review highlights the important role pharmacists can play singularly and as part of interdisciplinary teams. Most effective interventions often involved medication review and patient education postdischarge. PMID- 29618282 TI - Neuroprotective effect of Citrus kawachiensis (Kawachi Bankan) peels, a rich source of naringin, against global cerebral ischemia/reperfusion injury in mice. AB - Cerebral ischemia/reperfusion is known to induce the generation of reactive oxygen species and inflammatory responses. Numerous studies have demonstrated that naringin (NGIN) has anti-oxidant and anti-inflammatory properties. We previously reported that Citrus kawachiensis contains a large quantity of NGIN in its peel. In the present study, we orally (p.o.) administered dried peel powder of C. kawachiensis to mice of a transient global ischemia model and found in the hippocampus region that it 1) suppressed neuronal cell death, 2) reversed the reduction in the level of phosphorylated calcium-calmodulin-dependent protein kinase II, 3) had the tendency to reverse the reduction in the level of glutathione, and 4) blocked excessive activation of microglia and astrocytes. These results suggested that the dried peel powder of C. kawachiensis had a neuroprotective effect against ischemic brain via anti-oxidative and anti inflammatory effects. We also showed that these effects of the dried peel powder were more powerful than those obtained with a comparable amount of NGIN alone. PMID- 29618284 TI - Toward an Integrative Theory of Thalamic Function. AB - The thalamus has long been suspected to have an important role in cognition, yet recent theories have favored a more corticocentric view. According to this view, the thalamus is an excitatory feedforward relay to or between cortical regions, and cognitively relevant computations are exclusively cortical. Here, we review anatomical, physiological, and behavioral studies along evolutionary and theoretical dimensions, arguing for essential and unique thalamic computations in cognition. Considering their architectural features as well as their ability to initiate, sustain, and switch cortical activity, thalamic circuits appear uniquely suited for computing contextual signals that rapidly reconfigure task relevant cortical representations. We introduce a framework that formalizes this notion, show its consistency with several findings, and discuss its prediction of thalamic roles in perceptual inference and behavioral flexibility. Overall, our framework emphasizes an expanded view of the thalamus in cognitive computations and provides a roadmap to test several of its theoretical and experimental predictions. PMID- 29618285 TI - Evolution of New miRNAs and Cerebro-Cortical Development. AB - The noncoding portion of the genome, including microRNAs, has been fertile evolutionary soil for cortical development in primates. A major contribution to cortical expansion in primates is the generation of novel precursor cell populations. Because miRNA expression profiles track closely with cell identity, it is likely that numerous novel microRNAs have contributed to cellular diversity in the brain. The tools to determine the genomic context within which novel microRNAs emerge and how they become integrated into molecular circuitry are now in hand. PMID- 29618286 TI - Neuronal Activity-Dependent Control of Postnatal Neurogenesis and Gliogenesis. AB - The addition of new neurons and oligodendroglia in the postnatal and adult mammalian brain presents distinct forms of gray and white matter plasticity. Substantial effort has been devoted to understanding the cellular and molecular mechanisms controlling postnatal neurogenesis and gliogenesis, revealing important parallels to principles governing the embryonic stages. While during central nervous system development, scripted temporal and spatial patterns of neural and glial progenitor proliferation and differentiation are necessary to create the nervous system architecture, it remains unclear what driving forces maintain and sustain postnatal neural stem cell (NSC) and oligodendrocyte progenitor cell (OPC) production of new neurons and glia. In recent years, neuronal activity has been identified as an important modulator of these processes. Using the distinct properties of neurotransmitter ionotropic and metabotropic channels to signal downstream cellular events, NSCs and OPCs share common features in their readout of neuronal activity patterns. Here we review the current evidence for neuronal activity-dependent control of NSC/OPC proliferation and differentiation in the postnatal brain, highlight some potential mechanisms used by the two progenitor populations, and discuss future studies that might advance these research areas further. PMID- 29618287 TI - Comparison of total ionic strength adjustment buffers III and IV in the measurement of fluoride concentration of teas. AB - BACKGROUND: Tea is the second most consumed drink in the UK and a primary source of hydration; it is an important source of dietary fluoride (F) for consumers and also abundant in aluminium (Al). Varying ranges of F concentrations in teas have been reported worldwide which may be, in part, due to differences in analytical techniques used to measure this ion. AIM: The effect of using total ionic adjustment buffers (TISAB) III or IV when measuring F concentration of black teas available in the UK was investigated and compared. Based on this evaluation, the effects of three different infusion times, 1 min, 10 min and 1 h, caffeine content and tea form on the F contents of the tea samples were investigated. METHODS: The F concentrations of 47 tea samples were measured directly using a fluoride ion-selective electrode (F-ISE), TISAB III and IV and infusion times of 1 min, 10 min and 1 h. RESULTS: Mean (SD) F concentration of tea samples for all infusion times was statistically significantly higher ( p < 0.001) measured by TISAB IV (4.37 (2.16) mg/l) compared with TISAB III (3.54 (1.65) mg/l). A statistically significant positive correlation ( p < 0.001) was found between Al concentration (mg/l) and differences in F concentration (mg/l) measured using the two TISABs; the difference in F concentration measured by the two TISABs increased with the magnitude of Al concentration. CONCLUSION: Due to higher concentrations of F and Al in teas and their complexing potential, use of TISAB IV facilitates more accurate measurement of F concentration when using an F-ISE and a direct method. PMID- 29618289 TI - Testing equality of means in partially paired data with incompleteness in single response. AB - In testing differentially expressed genes between tumor and healthy tissues, data are usually collected in paired form. However, incomplete paired data often occur. While extensive statistical researches exist for paired data with incompleteness in both arms, hardly any recent work can be found on paired data with incompleteness in single arm. This paper aims to fill this gap by proposing some new methods, namely, P-value pooling methods and a nonparametric combination test. Simulation studies are conducted to investigate the performance of the proposed methods in terms of type I error and power at small to moderate sample sizes. A real data set from The Cancer Genome Atlas (TCGA) breast cancer study is analyzed using the proposed methods. PMID- 29618288 TI - Upregulation of MiR-212 Inhibits Migration and Tumorigenicity and Inactivates Wnt/beta-Catenin Signaling in Human Hepatocellular Carcinoma. AB - BACKGROUND: MicroRNAs are involved in hepatocellular carcinoma metastasis, a principal cause of hepatocellular carcinoma-related death in patients worldwide. MiR-212 is a microRNA that has been identified in several types of cancers and is postulated to influence cell signaling and subsequent malignant pathogenesis. Despite emerging reports suggesting that miR-212 plays a significant role in the onset, progression, and migration of these types of malignant tumors, its involvement in the development of hepatocellular carcinoma has not been fully elucidated. MATERIALS AND METHODS: Quantitative reverse transcription polymerase chain reaction, wound healing, transwell migration and invasion assays, Western blotting, and xenograft tumor growth models were performed to test the expression levels and functions of miR-212 in hepatocellular carcinoma. Luciferase reporter assay, quantitative reverse transcription polymerase chain reaction, Western blotting, and immunohistochemistry were used to identify and verify the target of miR-212. RESULTS: In this study, we identify significant repression of miR-212 in hepatocellular carcinoma and demonstrate that overexpression of miR-212 inhibits the migration of hepatocellular carcinoma cells in vitro and in vivo. Furthermore, we identify forkhead box M1, whose expression is inversely related to that of miR-212, as a direct target of miR-212. Additionally, reexpression of forkhead box M1 rescues the miR-212-mediated inhibition of cell migration. We observed that inhibition of miR-212 activates forkhead box M1 but inhibits the Wnt/beta-catenin pathway by suppressing Wnt, LEF-1, c-Myc, and nuclear beta catenin. Finally, in vivo studies confirmed the inhibitory effect of miR-212 on hepatocellular carcinoma growth. CONCLUSION: Our present findings indicate that miR-212 is a potential prognostic biomarker of hepatocellular carcinoma and that the miR-212/forkhead box M1 regulatory axis may represent a new therapeutic objective for hepatocellular carcinoma treatment. PMID- 29618290 TI - Shared parameter models for joint analysis of longitudinal and survival data with left truncation due to delayed entry - Applications to cystic fibrosis. AB - Many longitudinal studies observe time to occurrence of a clinical event such as death, while also collecting serial measurements of one or more biomarkers that are predictive of the event, or are surrogate outcomes of interest. Joint modeling can be used to examine the relationship between the biomarker and the event, and also as a way of adjusting analyses of the biomarker for non-ignorable dropout. In settings such as registry studies, an additional complexity is caused when follow-up of subjects is delayed, referred to as left-truncation of follow up in the survival analysis setting. If not adjusted for, this can cause bias in estimation of parameters of the survival distribution for the clinical event and in parameters of the longitudinal outcome such as the profile or rate of change over time because subjects may die or have the clinical event before follow-up starts. This paper illustrates how a broad class of shared parameter models can be used to jointly model a time to event outcome along with a longitudinal marker using available nonlinear mixed modeling software, when follow-up times are left truncated. Methods are applied to jointly model survival and decline in lung function in cystic fibrosis patients. PMID- 29618291 TI - Bilateral versus ipsilesional cortico-subcortical activity patterns in stroke show hemispheric dependence. AB - Background Understanding of interhemispheric interactions in stroke patients during motor control is an important clinical neuroscience quest that may provide important clues for neurorehabilitation. In stroke patients bilateral overactivation in both hemispheres has been interpreted as a poor prognostic indicator of functional recovery. In contrast, ipsilesional patterns have been linked with better motor outcomes. Aim We investigated the pathophysiology of hemispheric interactions during limb movement without and with contralateral restraint, to mimic the effects of constraint-induced movement therapy. We used neuroimaging to probe brain activity with such a movement-dependent interhemispheric modulation paradigm. Methods We used a functional magnetic resonance imaging block design during which the plegic/paretic upper limb was recruited/mobilized to perform unilateral arm elevation, as a function of presence versus absence of contralateral limb restriction (n = 20, with balanced left/right lesion sites). Results Analysis of 10 right hemispheric stroke participants yielded bilateral sensorimotor cortex activation in all movement phases in contrast with the unilateral dominance seen in the 10 left hemispheric stroke participants. Superimposition of contralateral restriction led to a prominent shift from activation to deactivation response patterns, in particular in cortical and basal ganglia motor areas in right hemispheric stroke. Left hemispheric stroke was, in general, characterized by reduced activation patterns, even in the absence of restriction, which induced additional cortical silencing. Conclusion The observed hemispheric-dependent activation/deactivation shifts is novel and these pathophysiological observations suggest short-term neuroplasticity that may be useful for hemisphere-tailored neurorehabilitation. PMID- 29618292 TI - Treat fast but abandon time from ischemic stroke onset as a criterion for treatment: The DAWN and DEFUSE-3 trials. PMID- 29618293 TI - Deficiencies of Magnesium Replacement in the Critically Ill. PMID- 29618294 TI - A Research Note on the Influence of Relationship Length and Sex on Preferences for Altruistic and Cooperative Mates. AB - Previous literature suggests that altruism may have evolved as a sexually selectable trait. Recent research suggests that women seek altruistic traits for long-term, not short-term relationships, as altruism can serve as an honest signal of one's character. We tested this hypothesis by asking 102 participants to complete a modified version of Buss's Mate Preferences Questionnaire. We found that women placed higher importance on altruism in a mate compared to men, and this preference was greater when seeking a long-term mate, compared to a short term mate. We also found that although women placed greater importance on cooperativeness in a mate compared to men, this preference was not influenced by whether they were seeking a short-term or a long-term mate. We successfully replicate previous literature exploring the role of altruism in mate choice. PMID- 29618295 TI - Activation of Yeast Mitochondrial Translation: Who Is in Charge? AB - Mitochondrial genome has undergone significant reduction in a course of evolution; however, it still contains a set of protein-encoding genes and requires translational machinery for their expression. Mitochondrial translation is of the prokaryotic type with several remarkable differences. This review is dedicated to one of the most puzzling features of mitochondrial protein synthesis, namely, the system of translational activators, i.e., proteins that specifically regulate translation of individual mitochondrial mRNAs and couple protein biosynthesis with the assembly of mitochondrial respiratory chain complexes. The review does not claim to be a comprehensive analysis of all published data; it is rather focused on the idea of the "core component" of the translational activator system. PMID- 29618296 TI - Retrograde Signaling as a Mechanism of Yeast Adaptation to Unfavorable Factors. AB - Mitochondria perform many essential functions in eukaryotic cells. Being the main producers of ATP and the site of many catabolic and anabolic reactions, they participate in intracellular signaling, proliferation, aging, and formation of reactive oxygen species. Mitochondrial dysfunction is the cause of many diseases and even cell death. The functioning of mitochondria in vivo is impossible without interaction with other cellular compartments. Mitochondrial retrograde signaling is a signaling pathway connecting mitochondria and the nucleus. The major signal transducers in the yeast retrograde response are Rtg1p, Rtg2p, and Rtg3p proteins, as well as four additional negative regulatory factors - Mks1p, Lst8p, and two 14-3-3 proteins (Bmh1/2p). In this review, we analyze current information on the retrograde signaling in yeast that is regarded as a stress or homeostatic response mechanism to changes in various metabolic and biosynthetic activities that occur upon mitochondrial dysfunction. We also discuss relations between retrograde signaling and other signaling pathways in the cell. PMID- 29618297 TI - Influence of a Single Point Mutation in the Constant Domain of the Bence-Jones Protein bif on Its Aggregation Properties. AB - Multiple myeloma nephropathy occurs due to the aggregate formation by monoclonal immunoglobulin light chains (Bence-Jones proteins) in kidneys of patients with multiple myeloma. The mechanism of amyloid deposit formation is still unclear. Earlier, the key role in the fibril formation has been assigned to the variable domains that acquired amyloidogenic properties as a result of somatic mutations. However, fibril formation by the Bence-Jones protein BIF was found to be the function of its constant domain. The substitution of Ser177 by Asn in the constant domain of the BIF protein is most likely an inherited than a somatic mutation. To study the role of this mutation in amyloidogenesis, the recombinant Bence-Jones protein BIF and its mutant with the N177S substitution typical for the known immunoglobulin Ckappa allotypes Km1, Km1,2, and Km3 were isolated. The morphology of aggregates formed by the recombinant proteins under conditions similar to those occurring during the protein transport in bloodstream and its filtration into the renal glomerulus, in the distal tubules, and in the proximal renal tubules was analyzed by atomic force microscopy. The nature of the aggregates formed by BIF and its N177S mutant during incubation for 14 days at 37 degrees C strongly differed and depended on both pH and the presence of a reducing agent. BIF formed fibrils at pH 7.2, 6.5, and 10.1, while the N177S mutant formed fibrils only at alkaline pH 10.1. The refolding of both proteins in the presence of 5 mM dithiothreitol resulted in the formation of branched structures. PMID- 29618298 TI - Negative Cooperativity in the Interaction of Prostaglandin H Synthase-1 with the Competitive Inhibitor Naproxen Can Be Described as the Interaction of a Non competitive Inhibitor with Heterogeneous Enzyme Preparation. AB - The kinetic mechanism of the interaction of nonsteroidal anti-inflammatory drugs (NSAIDs) with their main pharmacological target, prostaglandin H synthase (PGHS), has not yet been established. We showed that inhibition of PGHS-1 from sheep vesicular glands by naproxen (a representative of NSAIDs) demonstrates a non competitive character with respect to arachidonic acid and cannot be described within a framework of the commonly used kinetic schemes. However, it can be described by taking into account the negative cooperativity of naproxen binding to the cyclooxygenase active sites of the PGHS-1 homodimer (the first naproxen molecule forms a more stable complex (K1 = 0.1 uM) with the enzyme than the second naproxen molecule (K2 = 9.2 uM)). An apparent non-competitive interaction of PGHS-1 with naproxen is due to slow dissociation of the enzyme-inhibitor complexes. The same experimental data could also be described using commonly accepted kinetic schemes, assuming that naproxen interacts was a mixture of two enzyme species with the inhibition constants Kalpha = 0.05 uM and Kbeta = 18.3 uM. Theoretical analysis and numerical calculations show that the phenomenon of kinetic convergence of these two models has a general nature: when K2 >> K1, the kinetic patterns (for transient kinetics and equilibrium state) generated by the cooperative model could be described by a scheme assuming the presence of two enzyme forms with the inhibition constants Kalpha = K1/2, Kbeta = 2.K2. When K2 << K1, the cooperative model can be presented as a scheme with two inhibitor molecules simultaneously binding to the enzyme with the observed inhibition constant K (K = K1.K2). The assumption on the heterogeneity of the enzyme preparation in relation to its affinity to the inhibitor can be used instead of the assumption on the negative cooperativity of the enzyme-inhibitor interactions for convenient and easy practical description of such phenomena in enzymology, biotechnology, pharmacology, and other fields of science. PMID- 29618299 TI - Comparison of Methods of Detection of Exceptional Sequences in Prokaryotic Genomes. AB - Many proteins need recognition of specific DNA sequences for functioning. The number of recognition sites and their distribution along the DNA might be of biological importance. For example, the number of restriction sites is often reduced in prokaryotic and phage genomes to decrease the probability of DNA cleavage by restriction endonucleases. We call a sequence an exceptional one if its frequency in a genome significantly differs from one predicted by some mathematical model. An exceptional sequence could be either under- or over represented, depending on its frequency in comparison with the predicted one. Exceptional sequences could be considered biologically meaningful, for example, as targets of DNA-binding proteins or as parts of abundant repetitive elements. Several methods to predict frequency of a short sequence in a genome, based on actual frequencies of certain its subsequences, are used. The most popular are methods based on Markov chain models. But any rigorous comparison of the methods has not previously been performed. We compared three methods for the prediction of short sequence frequencies: the maximum-order Markov chain model-based method, the method that uses geometric mean of extended Markovian estimates, and the method that utilizes frequencies of all subsequences including discontiguous ones. We applied them to restriction sites in complete genomes of 2500 prokaryotic species and demonstrated that the results depend greatly on the method used: lists of 5% of the most under-represented sites differed by up to 50%. The method designed by Burge and coauthors in 1992, which utilizes all subsequences of the sequence, showed a higher precision than the other two methods both on prokaryotic genomes and randomly generated sequences after computational imitation of selective pressure. We propose this method as the first choice for detection of exceptional sequences in prokaryotic genomes. PMID- 29618300 TI - Comparative Action of Cardiotonic Steroids on Intracellular Processes in Rat Cortical Neurons. AB - Binding to Na+,K+-ATPase, cardiotonic steroids (CTS) activate intracellular signaling cascades that affect gene expression and regulation of proliferation and apoptosis in cells. Ouabain is the main CTS used for studying these processes. The effects of other CTS on nervous tissue are practically uncharacterized. Previously, we have shown that ouabain affects the activation of mitogen-activated protein kinases (MAP kinases) ERK1/2, p38, and JNK. In this study, we compared the effects of digoxin and bufalin, which belong to different subclasses of CTS, on primary culture of rat cortical cells. We found that CTS toxicity is not directly related to the degree of Na+,K+-ATPase inhibition, and that bufalin and digoxin, like ouabain, are capable of activating ERK1/2 and p38, but with different concentration and time profiles. Unlike bufalin and ouabain, digoxin did not decrease JNK activation after long-term incubation. We concluded that the toxic effect of CTS in concentrations that inhibit less than 80% of Na+,K+-ATPase activity is related to ERK1/2 activation as well as the complex profile of MAP kinase activation. A direct correlation between Na+,K+-ATPase inhibition and the degree of MAP kinase activation is only observed for ERK1/2. The different action of the three CTS on JNK and p38 activation may indicate that it is associated with intracellular signaling cascades triggered by protein protein interactions between Na+,K+-ATPase and various partner proteins. Activation of MAP kinase pathways by these CTS occurs at concentrations that inhibit Na+,K+-ATPase containing the alpha1 subunit, suggesting that these signaling cascades are realized via alpha1. The results show that the signaling processes in neurons caused by CTS can differ not only because of different inhibitory constants for Na+,K+-ATPase. PMID- 29618301 TI - 2,5-Diketopiperazines: A New Class of Poly(ADP-ribose)polymerase Inhibitors. AB - We show for the first time that natural 2,5-diketopiperazines (cyclic dipeptides) can suppress the activity of the important anticancer target poly(ADP ribose)polymerase (PARP). Cyclo(L-Ala-L-Ala) and cyclo(L-Ala-D-Ala) can interact with the key residues of the PARP-1 active site, as demonstrated using docking and molecular dynamics simulations. One of the amide groups of cyclo(L-Ala-L-Ala) and cyclo(L-Ala-D-Ala) forms hydrogen bonds with the Gly863 residue, while the second amide group can form a hydrogen bond with the catalytic residue Glu988, and the side chain can make a hydrophobic contact with Ala898. Newly identified diketopiperazine inhibitors are promising basic structures for the design of more effective inhibitors of PARP family enzymes. The piperazine core with two chiral centers provides many opportunities for structural optimization. PMID- 29618302 TI - Presence of Old Individuals in a Population Accelerates and Optimizes the Process of Selection: in silico Experiments. AB - One of the important components of the concept of aging-phenoptosis (programmed aging) is the notion of aging as an accelerator of evolution having the rank of subconcept. For many reasons, the main being the problematic experimental testing of evolutionary hypotheses, verification of the above-mentioned subconcept can be based primarily on analysis of the internal inconsistency of heuristic models and their correspondence to undisputedly observed facts. To illustrate the acceleration mechanism, and most importantly to structure the evolutionary process in communities that include naturally weakened individuals, V. P. Skulachev offered in 2003 a conceptual model that he later called a "fable about hares". Despite its simplicity, this model has undoubted internal logic. The natural trend in the development of conceptual models is their translation into the language of mathematics. The purpose of the present work was to create a variation of the known multi-agent model "predator-prey" that would allow us to "see" how the presence in the prey population of naturally weakened (old) members stimulates the selection of individuals with traits whose adaptive potential is not devaluated with age. The model (http://homebear.ru/PD) was developed on the Java platform, version 6, NetBeans development environment 8.2. Statistical analysis and preparation of illustrative materials were carried out using environment R, version 3.4.1. The results of numerical experiments set using our model correspond in principle to the provisions of the heuristic model of Skulachev and, consequently, confirm the absence in it of logical contradictions. PMID- 29618303 TI - Myoglobin: Oxygen Depot or Oxygen Transporter to Mitochondria? A Novel Mechanism of Myoglobin Deoxygenation in Cells (review). AB - In this review, we shortly summarize the data of our studies (and also corresponding studies of other authors) on the new mechanism of myoglobin (Mb) deoxygenation in a cell, according to which Mb acts as an oxygen transporter, and its affinity for the ligand, like in other transporting proteins, is regulated by the interaction with the target, in our case, mitochondria (Mch). We firstly found that contrary to previously formulated and commonly accepted concepts, oxymyoglobin (MbO2) deoxygenation occurs only via interaction of the protein with respiring mitochondria (low pO2 values are necessary but not sufficient for this process to proceed). Detailed studies of the mechanism of Mb-Mch interaction by various physicochemical methods using natural and artificial bilayer phospholipid membranes showed that: (i) the rate of MbO2 deoxygenation in the presence of respiring Mch fully coincides with the rate of O2 uptake by mitochondria from a solution irrespectively of their state (native coupled, freshly frozen, or FCCP uncoupled), i.e. it is determined by the respiratory activity of Mch; (ii) Mb nonspecifically binds to membrane phospholipids of the outer mitochondrial membrane, while any Mb-specific protein or phospholipid sites on it are lacking; (iii) oxygen uptake by Mch from a solution and the uptake of Mb-bound oxygen are two different processes, as their rates are differently affected by proteins (e.g. lysozyme) that compete with MbO2 for binding to the mitochondrial membrane; (iv) electrostatic forces significantly contribute to the Mb-membrane interactions; the dependence of these interactions on ionic strength is provided by the local electrostatic interactions between anionic groups of phospholipids (the heads) and invariant Lys and Arg residues near the Mb heme pocket; (v) interactions of Mb with phospholipid membranes promote conformational changes in the protein, primarily in its heme pocket, without significant alterations in the protein secondary and tertiary structures; and (vi) Mb-membrane interactions lead to decrease in the affinity of myoglobin for O2, which could be monitored by the increase in the MbO2 autooxidation rate under aerobic conditions and under anaerobic ones, by the shift in the MbO2/Mb(2) equilibrium towards the ligand free protein. The decrease in the affinity of Mb for the ligand should facilitate O2 dissociation from MbO2 at physiological pO2 values in cells. PMID- 29618304 TI - Editorial: Breaking the Discovery Impasse (part 1): A Case for Deep Learning. PMID- 29618305 TI - Pro-inflammatory Cytokines: Cellular and Molecular Drug Targets for Glucocorticoid-induced-osteoporosis via Osteocyte. AB - Glucocorticoids are widely used to treat varieties of allergic and autoimmune diseases, however, long-term application results in glucocorticoid-induced osteoporosis (GIOP). Inflammatory cytokines: tumor necrosis factor-alpha (TNF alpha) and interleukin-6 (IL-6) play important regulatory roles in bone metabolism, but their roles in GIOP remain largely unknown. Osteocytes can modulate the formation and function of both osteoblasts and osteoclasts, directly via gap junctions, or indirectly by transferring molecule signaling. Apoptotic osteocytes release RANKL, HMGB1 and pro-inflammatory cytokines to stimulate osteoclastogenesis. Moreover, osteocytes can secrete FGF23 to regulate bone metabolism. Exposure to high levels of GCs can drive osteocyte apoptosis and influence gap junctions, leading to bone loss. GCs treatment is regarded to produce more FGF23 to inhibit bone mineralization. GCs also disrupt the vascular to decrease osteocyte feasibility and mineral appositional rate, resulting in a decline in bone strength. Apoptotic bodies from osteocytes induced by GCs treatment can enhance production of TNF-alpha and IL-6. On the other hand, TNF alpha and IL-6 show synergistic effects by altering osteocytes signaling towards osteoclasts and osteoblasts. In addition, TNF-alpha can induce osteocyte apoptosis and attribute to a worsened bone quality in GCs. IL-6 and osteocytes may interact with each other. Therefore, we hypothesize that GCs regulate osteocyteogenesis through TNF-alpha and IL-6, which are highly expressed around osteocyte undergoing apoptosis. In the present review, we summarized the roles of osteocytes in regulating osteoblasts and osteoclasts. Furthermore, the mechanism of GCs altered relationship between osteocytes and osteoblasts/osteoclasts. In addition, we discussed the roles of TNF-alpha and IL-6 in GIOP by modulating osteocytes. Lastly, we discussed the possibility of using pro-inflammatory signaling pathway as therapeutic targets to develop drugs for GIOP. PMID- 29618307 TI - Safety and Efficacy of Adenovirus Carrying Hepatocyte Growth Factor Gene by Percutaneous Endocardial Injection for Treating Post-infarct Heart Failure: A Phase IIa Clinical Trial. AB - OBJECTIVE: Our previous phase I clinical trial has confirmed the safety of Adenovirus carrying Hepatocyte Growth Factor gene (Ad-HGF) by intracoronary administration for treating severe coronary artery disease. This study was performed to evaluate the safety and efficacy of Ad-HGF by percutaneous endocardial injection for treating post-infarct heart failure. METHODS: A total of 30 patients (15 in the experimental group and 15 in the control group) with postinfarct heart failure who were not indicated to revascularization and had received the optimal standardized medication therapy were included in the study. Percutaneous endocardial Ad-HGF gene transfer was injected with a catheter-based intramyocardial delivery system in the experimental group. Safety parameters were measured and compared between baseline and follow-ups in the experimental group. The Mean Difference (MD) of efficacy parameters from baseline to 6-month follow up was measured in both groups and compared with each other. RESULTS: No one suffered from serious adverse events in the experimental group during the 6-month follow-up. The experimental group revealed significant lower left ventricular end diastolic dimension (LVDd) (68.5 vs. 65.8 MD: -2.69+/-1.08, P=0.03) and higher LVEF of both echocardiograph (35.2 vs. 39.3, MD: 4.05+/-0.86, P=0.0005) and single photon emission computed tomography (27.7 vs. 30.6, MD: 2.9+/-0.8, P=0.003) in the 6-month follow-up than that in the baseline, but the control group did not (P>0.05). Compared to the control group, the experimental group showed significant improvement ranges of lower LVDd (2.6 vs. -2.69, MD: -5.3+/ 1.4, P=0.0009) and higher echocardiographic LVEF (-2 vs. 4.05, MD: 6.1+/-1.6, P=0.0008) from baseline to 6-month follow-up. CONCLUSION: Percutaneous endocardial administration of Ad-HGF is safe and potentially efficient in improving LVEF and lowering LVDd of patients with post-infarct heart failure. PMID- 29618309 TI - Genetics and Gene Therapy of Anderson-Fabry Disease. AB - Fabry's disease is a genetic disorder of X-linked inheritance caused by mutations in the alpha galactosidase A gene resulting in deficiency of this lysosomal enzyme. The progressive accumulation of glycosphingolipids, caused by the inadequate enzymatic activity, is responsible of organ dysfunction and thus of clinical manifestations. In the presence of a high clinical suspicion, a careful physical examination and specific laboratory tests are required, finally diagnosis of Fabry's disease is confirmed by the demonstration of absence or reduced alpha-galactosidase A enzyme activity in hemizygous men and gene typing in heterozygous females; in fact the performance of enzymatic activity assay alone in women is inconclusive. Measurement of the biomarkers Gb3 and Lyso Gb3 in biological specimens may facilitate diagnosis. Because of its multisystemic involvement Fabry's disease may present a large spectrum of clinical manifestations as acroparesthesias, hypohidrosis, angiokeratomas, signs and symptoms of cardiac, renal, cerebrovascular involvement (renal insufficiency, proteinuria, left ventricular hypertrophy, strokes). Enzyme replacement therapy with recombinant alpha- galactosidase A is actually the specific therapy for Fabry disease. Early beginning of this treatment has shown beneficial effects in particular in cardiac and renal disease, a less efficacy it has been reported in central nervous system involvement. ERT has shown to be associated to a significant reduction of Gb3 accumulation in several tissues, in particular heart and kidney; moreover it improves pain related quality of life. Next generation lysosomal storage disorder treatment is based on new strategic approaches as stem cell based therapy, pharmacological chaperones, viral gene therapy; concerning Fabry's disease, it has been recently addressed to great interest this last innovative method, that is to say viral gene therapy, for delivering recombination enzyme into main involved tissues; promising results have been reported in animal models. Great efforts have been made and are still required in this field in order to make available a more effective, safer, advantageous therapeutic strategy for patients with Fabry's disease. PMID- 29618310 TI - Genetics and Gene Therapy in Hunter Disease. AB - Mucopolysaccharidosis type II or Hunter syndrome is an X-linked lysosomal storage disease caused by a mutation in the gene encoding the lysosomal enzyme iduronate 2-sulfatase. The consequent enzyme deficiency causes a progressive, multisystem accumulation of glycosaminoglycans, which is the cause of the clinical manifestations involving also Central Nervous System for patients with the severe form of disease. The limits of the currently available therapies for Hunter syndrome, hematopoietic stem cell transplantation and recombinant enzyme replacement therapy, mainly regarding brain achievement, have encouraged several studies which recognized gene therapy as a potential therapeutic option for this condition. In vitro studies firstly aimed at the demonstration that viral vector- mediated IDS gene expression could lead to high levels of enzyme activity in transduced cells. The encouraging results obtained allowed the realization of many preclinical studies investigating the utilization of gene therapy vectors in animal models of Mucopolysaccharidosis II, together with a phase I clinical trial approved for Hunter patients affected by the mild form of the disease. Together to in vivo studies in which recombinant vectors are directly administered, systematically or by direct injection into Central Nervous System, also ex vivo gene therapy, consisting in transplantation of autologous hematopoietic stem cells, modified in vitro, into the animal or patient, has been tested. A wider clinical application of the results obtained so far is essential to ensure that gene therapy can be definitively validated as a therapeutic option available and usable for this rare but life-threatening disorder. PMID- 29618311 TI - Predicting Factors affecting Glucose Monitoring Treatment Satisfaction and Drug Attitude Inventory (Adherence) among Patients with Type 2 Diabetes Mellitus; Cross-sectional Observational Study. AB - OBJECTIVES: The study aimed to explore the predictors affecting patient satisfaction to glucose monitoring system (GMSS) and drug attitude inventory (DAI) / treatment adherence among type 2 diabetes mellitus patients. METHODS: Cross-sectional observational study design was used to conduct this study. Subjective assessments were made by questionnaires and objective data was collected from the patients' medication profiles registered to diabetic clinics. Patients were recruited from five different public hospitals of Hyderabad region, India. A total of 430 patients completed for analysis. The predictors to GMSS dimensions and adherence status were analyzed with Wilks's lambda effect and multivariate generalized linear model (GLM/MANOVA). RESULTS: Study population consisted of 64.4% males and 35.6% females, age mean +/- SD (43.3+/-11.42) years, majority of the study of participants were in between 40-60 years of age (53.3%). Majority of participants were considered healthy on BMI scale (67.2%), in contrast 234 (54.4%) reported high glycemic index with Hb1Ac (> 7.5%). Descriptive distribution pattern showed 241 (56.1%) participants were moderately satisfied with the current monitoring system. However, 157 (36.5%) reported poor satisfaction to GMSS scale score. Findings showed that low mean score of openness and worthwhileness are reported among nonadherent participants. Behavioral burden significantly high among nonadherent patients then adherents. However, emotional burden showed no effect on treatment adherence. CONCLUSION: This study found high rates of poor glucose monitoring system satisfaction along with low-to-poor treatment adherence among T2DM patients. Individual characteristics and clinical parameters significantly and positively predict the variance of GMSS and DAI among patients' with T2DM. PMID- 29618308 TI - Genetics and Therapies for GM2 Gangliosidosis. AB - Tay-Sachs disease, caused by impaired beta-N-acetylhexosaminidase activity, was the first GM2 gangliosidosis to be studied and one of the most severe and earliest lysosomal diseases to be described. The condition, associated with the pathological build-up of GM2 ganglioside, has acquired almost iconic status and serves as a paradigm in the study of lysosomal storage diseases. Inherited as a classical autosomal recessive disorder, this global disease of the nervous system induces developmental arrest with regression of attained milestones; neurodegeneration progresses rapidly to cause premature death in young children. There is no effective treatment beyond palliative care, and while the genetic basis of GM2 gangliosidosis is well established, the molecular and cellular events, from diseasecausing mutations and glycosphingolipid storage to disease manifestations, remain to be fully delineated. Several therapeutic approaches have been attempted in patients, including enzymatic augmentation, bone marrow transplantation, enzyme enhancement, and substrate reduction therapy. Hitherto, none of these stratagems has materially altered the course of the disease. Authentic animal models of GM2 gangliodidosis have facilitated in-depth evaluation of innovative applications such as gene transfer, which in contrast to other interventions, shows great promise. This review outlines current knowledge pertaining the pathobiology as well as potential innovative treatments for the GM2 gangliosidoses. PMID- 29618312 TI - The Nutritional Characteristics of the Hypotensive WASHOKU-modified DASH Diet: A Sub-analysis of the DASH-JUMP Study. AB - BACKGROUND: We developed a WASHOKU-modified DASH diet named DASH-JUMP. We previously reported the hypotensive effect of the DASH-JUMP diet in Japanese participants with untreated high-normal Blood Pressure (BP) or stage 1 hypertension. OBJECTIVE: We aim to introduce the DASH-JUMP diet worldwide as a new lifestyle medicine. Accordingly, we prospectively assessed the nutritional characteristics of the DASH-JUMP diet. METHODS: Participants were treated with the DASH-JUMP diet for 2 months. Then, for 4 months after the intervention, they consumed their usual diets. We conducted a nutritional survey using the FFQg nutrient questionnaire at baseline and after 1, 2, 3, and 6 months. We received completed questionnaires from 55 participants (28 men and 27 women; mean age 54.2 +/- 8.0 years) and analyzed them. RESULTS: The DASH-JUMP diet is rich in green yellow vegetables, seaweed, milk, and mushrooms, while it has low contents of meat, eggs, confectionery, oils and fats, pickles, shellfish boiled in sweetened soy sauce, and fruits. Nutrients significantly associated with the observed change in systolic BP were niacin (P = 0.005) and carbohydrate (P = 0.033). The results of the FFQg questionnaire revealed that participants who had an increased BP at 1 month after ceasing the intervention had eating habits that broadly imitated the DASH-JUMP diet at 4 months after ceasing the intervention. Therefore, the systolic and diastolic BP values at 4 months after ceasing the intervention decreased significantly compared to those at baseline. CONCLUSION: The DASH-JUMP diet may represent a new lifestyle medicine for reducing hypertension. PMID- 29618313 TI - Sodium-glucose Cotransporter 2 Inhibitors: The Impact on Development and Progression of Heart Failure. AB - BACKGROUND: Available hypoglycemic-agents enable physicians to achieve consistent glycemic-control, but effects on cardiovascular-outcomes have been marginal or questionable. SGLT-2 inhibitors emerged as a novel antidiabetic drug class with remarkable cardiovascular benefits, and significant improvement in the prevention and progression of HF. OBJECTIVE: The purpose of this article is to critically review the effect of SGLT-2 inhibitors on HFoutcomes and the potential underlying mechanisms. METHOD: We conducted a thorough review of the literature. The studies addressing the impact of SGLT-2 inhibitors on HF and potential underlying mechanisms were identified. Additionally, we reviewed the references of the identified original papers. RESULTS: The EMPA-REG OUTCOME trial was the first cardiovascular safety study of this drug class that assessed among other outcomes, the impact of SGLT-2 inhibition on HF. Empagliflozin was associated with significant reductions of the risks for hospitalization or death from HF in patients with- and without-HF. Similar benefits were noted from a large-cohort study assessing the effect of SGLT-2 inhibitors on HF-outcomes in real-life. Potential mechanisms include the SGLT-2 inhibitors-induced lowering of blood pressure, the decrease in visceral obesity and the amelioration of arterial stiffness. Improvements of left ventricular mass and diastolic dysfunction may also be implicated in the manifestation of HF-benefits. Lastly, the SGLT-2 inhibitors-related higher ketones bioavailability might offer a better "fuel" to the myocardium. CONCLUSION: The pleiotropic effects of SGLT-2 inhibitors seem to be translated in significant improvement of HF-related outcomes. On-going trials will provide further information on the impact of these agents in various high- and low-risk populations. PMID- 29618314 TI - The prevalence of terraced treescapes in analyses of phylogenetic data sets. AB - BACKGROUND: The pattern of data availability in a phylogenetic data set may lead to the formation of terraces, collections of equally optimal trees. Terraces can arise in tree space if trees are scored with parsimony or with partitioned, edge unlinked maximum likelihood. Theory predicts that terraces can be large, but their prevalence in contemporary data sets has never been surveyed. We selected 26 data sets and phylogenetic trees reported in recent literature and investigated the terraces to which the trees would belong, under a common set of inference assumptions. We examined terrace size as a function of the sampling properties of the data sets, including taxon coverage density (the proportion of taxon-by-gene positions with any data present) and a measure of gene sampling "sufficiency". We evaluated each data set in relation to the theoretical minimum gene sampling depth needed to reduce terrace size to a single tree, and explored the impact of the terraces found in replicate trees in bootstrap methods. RESULTS: Terraces were identified in nearly all data sets with taxon coverage densities < 0.90. They were not found, however, in high-coverage-density (i.e., >= 0.94) transcriptomic and genomic data sets. The terraces could be very large, and size varied inversely with taxon coverage density and with gene sampling sufficiency. Few data sets achieved a theoretical minimum gene sampling depth needed to reduce terrace size to a single tree. Terraces found during bootstrap resampling reduced overall support. CONCLUSIONS: If certain inference assumptions apply, trees estimated from empirical data sets often belong to large terraces of equally optimal trees. Terrace size correlates to data set sampling properties. Data sets seldom include enough genes to reduce terrace size to one tree. When bootstrap replicate trees lie on a terrace, statistical support for phylogenetic hypotheses may be reduced. Although some of the published analyses surveyed were conducted with edge-linked inference models (which do not induce terraces), unlinked models have been used and advocated. The present study describes the potential impact of that inference assumption on phylogenetic inference in the context of the kinds of multigene data sets now widely assembled for large-scale tree construction. PMID- 29618315 TI - Variance explained by whole genome sequence variants in coding and regulatory genome annotations for six dairy traits. AB - BACKGROUND: There are an exceedingly large number of sequence variants discovered through whole genome sequencing in most populations, including cattle. Deciphering which of these affect complex traits is a major challenge. In this study we hypothesize that variants in some functional classes, such as splice site regions, coding regions, DNA methylated regions and long noncoding RNA will explain more variance in complex traits than others. Two variance component approaches were used to test this hypothesis - the first determines if variants in a functional class capture a greater proportion of the variance, than expected by chance, the second uses the proportion of variance explained when variants in all annotations are fitted simultaneously. RESULTS: Our data set consisted of 28.3 million imputed whole genome sequence variants in 16,581 dairy cattle with records for 6 complex trait phenotypes, including production and fertility. We found that sequence variants in splice site regions and synonymous classes captured the greatest proportion of the variance, explaining up to 50% of the variance across all traits. We also found sequence variants in target sites for DNA methylation (genomic regions that are found be highly methylated in bovine placentas), captured a significant proportion of the variance. Per sequence variant, splice site variants explain the highest proportion of variance in this study. The proportion of variance captured by the missense predicted deleterious (from SIFT) and missense tolerated classes was relatively small. CONCLUSION: The results demonstrate using functional annotations to filter whole genome sequence variants into more informative subsets could be useful for prioritization of the variants that are more likely to be associated with complex traits. In addition to variants found in splice sites and protein coding genes regulatory variants and those found in DNA methylated regions, explained considerable variation in milk production and fertility traits. In our analysis synonymous variants captured a significant proportion of the variance, which raises the possible explanation that synonymous mutations might have some effects, or more likely that these variants are miss-annotated, or alternatively the results reflect imperfect imputation of the actual causative variants. PMID- 29618316 TI - AceTree: a major update and case study in the long term maintenance of open source scientific software. AB - BACKGROUND: AceTree, a software application first released in 2006, facilitates exploration, curation and editing of tracked C. elegans nuclei in 4-dimensional (4D) fluorescence microscopy datasets. Since its initial release, AceTree has been continuously used to interact with, edit and interpret C. elegans lineage data. In its 11 year lifetime, AceTree has been periodically updated to meet the technical and research demands of its community of users. This paper presents the newest iteration of AceTree which contains extensive updates, demonstrates the new applicability of AceTree in other developmental contexts, and presents its evolutionary software development paradigm as a viable model for maintaining scientific software. RESULTS: Large scale updates have been made to the user interface for an improved user experience. Tools have been grouped according to functionality and obsolete methods have been removed. Internal requirements have been changed that enable greater flexibility of use both in C. elegans contexts and in other model organisms. Additionally, the original 3-dimensional (3D) viewing window has been completely reimplemented. The new window provides a new suite of tools for data exploration. CONCLUSION: By responding to technical advancements and research demands, AceTree has remained a useful tool for scientific research for over a decade. The updates made to the codebase have extended AceTree's applicability beyond its initial use in C. elegans and enabled its usage with other model organisms. The evolution of AceTree demonstrates a viable model for maintaining scientific software over long periods of time. PMID- 29618318 TI - A simulation study investigating power estimates in phenome-wide association studies. AB - BACKGROUND: Phenome-wide association studies (PheWAS) are a high-throughput approach to evaluate comprehensive associations between genetic variants and a wide range of phenotypic measures. PheWAS has varying sample sizes for quantitative traits, and variable numbers of cases and controls for binary traits across the many phenotypes of interest, which can affect the statistical power to detect associations. The motivation of this study is to investigate the various parameters which affect the estimation of statistical power in PheWAS, including sample size, case-control ratio, minor allele frequency, and disease penetrance. RESULTS: We performed a PheWAS simulation study, where we investigated variations in statistical power based on different parameters, such as overall sample size, number of cases, case-control ratio, minor allele frequency, and disease penetrance. The simulation was performed on both binary and quantitative phenotypic measures. Our simulation on binary traits suggests that the number of cases has more impact on statistical power than the case to control ratio; also, we found that a sample size of 200 cases or more maintains the statistical power to identify associations for common variants. For quantitative traits, a sample size of 1000 or more individuals performed best in the power calculations. We focused on common genetic variants (MAF > 0.01) in this study; however, in future studies, we will be extending this effort to perform similar simulations on rare variants. CONCLUSIONS: This study provides a series of PheWAS simulation analyses that can be used to estimate statistical power for some potential scenarios. These results can be used to provide guidelines for appropriate study design for future PheWAS analyses. PMID- 29618317 TI - New insights into the phylogenetics and population structure of the prairie falcon (Falco mexicanus). AB - BACKGROUND: Management requires a robust understanding of between- and within species genetic variability, however such data are still lacking in many species. For example, although multiple population genetics studies of the peregrine falcon (Falco peregrinus) have been conducted, no similar studies have been done of the closely-related prairie falcon (F. mexicanus) and it is unclear how much genetic variation and population structure exists across the species' range. Furthermore, the phylogenetic relationship of F. mexicanus relative to other falcon species is contested. We utilized a genomics approach (i.e., genome sequencing and assembly followed by single nucleotide polymorphism genotyping) to rapidly address these gaps in knowledge. RESULTS: We sequenced the genome of a single female prairie falcon and generated a 1.17 Gb (gigabases) draft genome assembly. We generated maximum likelihood phylogenetic trees using complete mitochondrial genomes as well as nuclear protein-coding genes. This process provided evidence that F. mexicanus is an outgroup to the clade that includes the peregrine falcon and members of the subgenus Hierofalco. We annotated > 16,000 genes and almost 600,000 high-quality single nucleotide polymorphisms (SNPs) in the nuclear genome, providing the raw material for a SNP assay design featuring > 140 gene-associated markers and a molecular-sexing marker. We subsequently genotyped ~ 100 individuals from California (including the San Francisco East Bay Area, Pinnacles National Park and the Mojave Desert) and Idaho (Snake River Birds of Prey National Conservation Area). We tested for population structure and found evidence that individuals sampled in California and Idaho represent a single panmictic population. CONCLUSIONS: Our study illustrates how genomic resources can rapidly shed light on genetic variability in understudied species and resolve phylogenetic relationships. Furthermore, we found evidence of a single, randomly mating population of prairie falcons across our sampling locations. Prairie falcons are highly mobile and relatively rare long-distance dispersal events may promote gene flow throughout the range. As such, California's prairie falcons might be managed as a single population, indicating that management actions undertaken to benefit the species at the local level have the potential to influence the species as a whole. PMID- 29618319 TI - nQuire: a statistical framework for ploidy estimation using next generation sequencing. AB - BACKGROUND: Intraspecific variation in ploidy occurs in a wide range of species including pathogenic and nonpathogenic eukaryotes such as yeasts and oomycetes. Ploidy can be inferred indirectly - without measuring DNA content - from experiments using next-generation sequencing (NGS). We present nQuire, a statistical framework that distinguishes between diploids, triploids and tetraploids using NGS. The command-line tool models the distribution of base frequencies at variable sites using a Gaussian Mixture Model, and uses maximum likelihood to select the most plausible ploidy model. nQuire handles large genomes at high coverage efficiently and uses standard input file formats. RESULTS: We demonstrate the utility of nQuire analyzing individual samples of the pathogenic oomycete Phytophthora infestans and the Baker's yeast Saccharomyces cerevisiae. Using these organisms we show the dependence between reliability of the ploidy assignment and sequencing depth. Additionally, we employ normalized maximized log- likelihoods generated by nQuire to ascertain ploidy level in a population of samples with ploidy heterogeneity. Using these normalized values we cluster samples in three dimensions using multivariate Gaussian mixtures. The cluster assignments retrieved from a S. cerevisiae population recovered the true ploidy level in over 96% of samples. Finally, we show that nQuire can be used regionally to identify chromosomal aneuploidies. CONCLUSIONS: nQuire provides a statistical framework to study organisms with intraspecific variation in ploidy. nQuire is likely to be useful in epidemiological studies of pathogens, artificial selection experiments, and for historical or ancient samples where intact nuclei are not preserved. It is implemented as a stand-alone Linux command line tool in the C programming language and is available at https://github.com/clwgg/nQuire under the MIT license. PMID- 29618320 TI - EnrichedHeatmap: an R/Bioconductor package for comprehensive visualization of genomic signal associations. PMID- 29618321 TI - Correction to: joint models for longitudinal and time-to-event data: a review of reporting quality with a view to meta-analysis. AB - Following publication of the original article [1] the authors reported that reference 15 (Cella et al.) had been incorrectly replaced with a duplicate of Brombin et al. during publication. PMID- 29618322 TI - Sequential tests for monitoring methods to detect elevated incidence - a simulation study. AB - BACKGROUND: Common cancer monitoring practice is seldom prospective and rather driven by public requests. This study aims to assess the performance of a recently developed prospective cancer monitoring method and the statistical tools used, in particular the sequential probability ratio test in regard to specificity, sensitivity, observation time and heterogeneity of size of the geographical unit. METHODS: A simulation study based on a predefined selection of cancer types, geographical unit and time period was set up. Based on the population structure of Lower Saxony the mean number of cases of three diagnoses were randomly assigned to the geographical units during 2008-2012. A two-stage monitoring procedure was then executed considering the standardized incidence ratio and sequential probability ratio test. Scenarios were constructed differing by the simulation of clusters, significance level and test parameter indicating a risk to be elevated. RESULTS: Performance strongly depended on the choice of the test parameter. If the expected numbers of cases were low, the significance level was not fully exhausted. Hence, the number of false positives was lower than the chosen significance level suggested, leading to a high specificity. Sensitivity increased with the expected number of cases and the amount of risk and decreased with the size of the geographical unit. CONCLUSIONS: The procedure showed some desirable properties and is ready to use for a few settings but demands adjustments for others. Future work might consider refinements of the geographical structure. Inhomogeneous unit size could be addressed by a flexible choice of the test parameter related to the observation time. PMID- 29618323 TI - A cost-effectiveness analysis of a community based CVD program in Sweden based on a retrospective register cohort. AB - BACKGROUND: Several large scale community-based cardiovascular disease prevention programs were initiated in the 80s, and one was the Vasterbotten Intervention Programme, Sweden. As an initial step in 1985, a pilot study was introduced in the Norsjo municipality that combined individual disease prevention efforts among the middle-aged population with community-oriented health promotion activities. All citizens at 30, 40, 50, and 60 years of age were invited to a physical examination combined with a healthy dialogue at the local primary health care centre. Vasterbotten Intervention Program is still running following the same lines and is now a part of the ordinary public health in the county. The purpose of this study is to estimate the costs of running Vasterbotten Intervention Programme from 1990 to 2006, versus the health gains and savings reasonably attributable to the program during the same time period. METHODS: A previous study estimated the number of prevented deaths during the period 1990-2006 which can be attributed to the programme. We used this estimate and calculated the number of QALYs gained, as well as savings in resources due to prevented non fatal cases during the time period 1990 to 2006. Costs for the programmes were based on previously published scientific articles as well as current cost data from the county council, who is responsible for the programme. RESULT: The cost per QALY gained from a societal perspective is SEK 650 (Euro 68). From a health care sector perspective, the savings attributable to the VIP exceeded its costs. CONCLUSION: Our analysis shows that Vasterbotten Intervention Programme is extremely cost-effective in relation to the Swedish threshold value (SEK 500000 per QALY gained or Euro 53,000 per QALY gained). Other research has also shown a favorable effect of Vasterbotten Intervention Programme on population health and the health gap. We therefore argue that all health care organizations, acting in settings reasonably similar to Sweden, have good incentive to implement programs like Vasterbotten Intervention Programme. PMID- 29618325 TI - Chylopericardium in a child with IgA nephropathy: a case report. AB - BACKGROUND: Chylopericardium effusion is characterized by the accumulation of milky effusion in the pericardium. It is often idiopathic but it can be secondary to trauma, chest radiation, tuberculosis and malignancy. If cardiac tamponade ensues, it becomes life-threatening. Herein we describe chylopericardium tamponade in a child with IgA nephropathy. To the best of our knowledge, this is the first reported case of chylopericardium tamponade in IgA nephropathy. CASE PRESENTATION: A 6 years old boy with IgA nephropathy presented with dyspnea, orthopnea, pretibial pitting edema, ascites and fever. Muffled heart sounds and hepatomegaly were also noted. Echocardiography and thoracic CT revealed that there was a large volume of hydropericardium. Moreover, the pericardial milky fluid by pericardiocentesis was analyzed and chylopericardium effusion was eventually confirmed. Pericardial drainage was continued and his diet was modified to low fat, rich MCT and high protein. Complete remission was achieved after 3 weeks of this combined treatment. CONCLUSION: Chylopericardial tamponade could be a rare and life-threatening complication of IgA nephropathy. Etiological analysis is critical for determining the therapeutic approach in patients with pericardial effusion. PMID- 29618324 TI - Chloroplast genome analyses and genomic resource development for epilithic sister genera Oresitrophe and Mukdenia (Saxifragaceae), using genome skimming data. AB - BACKGROUND: Epilithic sister genera Oresitrophe and Mukdenia (Saxifragaceae) have an epilithic habitat (rocky slopes) and a parapatric distribution in East Asia, which makes them an ideal model for a more comprehensive understanding of the demographic and divergence history and the influence of climate changes in East Asia. However, the genetic background and resources for these two genera are scarce. RESULTS: The complete chloroplast (cp) genomes of two Oresitrophe rupifraga and one Mukdenia rossii individuals were reconstructed and comparative analyses were conducted to examine the evolutionary pattern of chloroplast genomes in Saxifragaceae. The cp genomes ranged from 156,738 bp to 156,960 bp in length and had a typical quadripartite structure with a conserved genome arrangement. Comparative analysis revealed the intron of rpl2 has been lost in Heuchera parviflora, Tiarella polyphylla, M. rossii and O. rupifraga but presents in the reference genome of Penthorum chinense. Seven cp hotspot regions (trnH psbA, trnR-atpA, atpI-rps2, rps2-rpoC2, petN-psbM, rps4-trnT and rpl33-rps18) were identified between Oresitrophe and Mukdenia, while four hotspots (trnQ-psbK, trnR-atpA, trnS-psbZ and rpl33-rps18) were identified within Oresitrophe. In addition, 24 polymorphic cpSSR loci were found between Oresitrophe and Mukdenia. Most importantly, we successfully developed 126 intergeneric polymorphic gSSR markers between Oresitrophe and Mukdenia, as well as 452 intrageneric ones within Oresitrophe. Twelve randomly selected intergeneric gSSRs have shown that these two genera exhibit a significant genetic structure. CONCLUSIONS: In this study, we conducted genome skimming for Oresitrophe rupifraga and Mukdenia rossii. Using these data, we were able to not only assemble their complete chloroplast genomes, but also develop abundant genetic resources (cp hotspots, cpSSRs, polymorphic gSSRs). The genomic patterns and genetic resources presented here will contribute to further studies on population genetics, phylogeny and conservation biology in Saxifragaceae. PMID- 29618326 TI - A novel homozygous mutation in POLR3A gene causing 4H syndrome: a case report. AB - BACKGROUND: 4H syndrome is a congenital hypomyelinating leukodystrophy characterized by hypodontia, hypomyelination and hypogonadotropic hypogonadism belonging to the Pol III-related leukodystrophies which arise due to mutations in the POLR3A or POLR3B gene. The clinical presentation is of neurodevelopmental delay or regression with ataxia, dystonia, nystagmus, delayed deciduous dentition and abnormal order of eruption of teeth. MRI brain shows a characteristic hypomyelination pattern. Several mutations have been described in the implicated genes but there are no reports on mutations seen in patients from India. CASE PRESENTATION: We report a 11/2 year old girl, only child of a non-consanguinous couple who presented with delayed developmental milestones and delayed dentition. On physical examination she had downward slanting palpebral fissures, low set ears, smooth philtrum, hypodontia, prominent body hair and clitoromegaly. There was prominent horizontal nystagmus, hypertonia of both upper and lower limbs, exaggerated deep tendon jerks and flexor planter response. She had not attained complete head control and required support to sit. She showed absent waves on brainstem evoked response audiometry and her fundus examination showed bilateral optic atrophy with prolongation of P100 latencies on visual evoked potentials. MRI Brain showed hyperintensity of entire white matter with involvement of the internal and external capsule, frontal deep white matter and corpus callosum. Her karyotype was 46 XX and her endocrinal profile was unremarkable. Clinical exome sequencing identified an unreported mutation in the POLR3A gene. The same mutation was identified by Sanger sequencing in heterozygous state in both parents. The child is being managed with physiotherapy and developmental therapy. She has been provided with hearing aids and started on speech therapy. Parents were provided anticipatory guidance and genetic counselling about autosomal recessive nature of inheritance, risk of recurrence and need for follow-up. CONCLUSION: 4H syndrome is a rare congenital hypomyelinating leukodystrophy inherited as an autosomal recessive disorder due to mutations in the POLR3A and POLR3B gene. Delay or regression of milestones, abnormalities in dentition and endocrinal perturbations are its hallmark. A novel mutation in the POLR3A gene resulting in amino acid substitution of arginine for glutamine at codon 808 (p.R808Q) was detected in exon 18 in our case. PMID- 29618327 TI - Overweight adolescents' views on physical activity - experiences of participants in an internet-based intervention: a qualitative study. AB - BACKGROUND: Overweight and obese adolescents are reported to be less physically active than their peers. Research-based knowledge about their views may contribute to a better understanding of key factors that may foster or undermine motivation for physical activity, and provide knowledge for the future development of interventions. This paper explores experiences of physical activity among overweight adolescents, age 13-14 years, participants in Young & Active, a web-based controlled trial intervention to increase physical activity (ClinicalTrials.gov NCT01700309). The theoretical perspective is based on Self Determination Theory. METHODS: Two qualitative post-intervention research interviews, with a nine-month interval, were conducted with 21 adolescents, 15 girls and 6 boys to study short-term and long-term changes. The informants were recruited from a total of 84 participants from the Young & Active intervention group. Data were analyzed using qualitative content analysis. RESULTS: The participants associated physical activity with organized sports and physical education classes at school, and as a means of promoting good health and attractive bodies. A majority of the adolescents said that they experienced their health as poorer than other youths, and expressed worries about their fitness and future health. Mastering a physical activity, being together with friends and having fun promoted motivation to perform sports. Not mastering an activity, or not knowing the others made them less motivated. None of the adolescents highlighted the importance of informal active living when asked about their understanding and experiences of physical activity. Consistency was found between the first and second interviews. CONCLUSION: This study adds to limited research on overweight and obese adolescents' experiences of physical activity. The participants' views reflect opinions in society about physical activity, and its importance for health. Viewing physical activity as conducted within organized sports makes it necessary to look into how these are organized, structured and led, and what can be done to support self-esteem, autonomous motivation and participation. The ability to choose among available, affordable and desirable physical activities, together with friends, may promote participation and maintenance. PMID- 29618328 TI - Breast density and breast cancer-specific survival by detection mode. AB - BACKGROUND: Breast density is known to affect breast cancer risk and screening sensitivity, but it may also be associated with breast cancer survival. The interpretation of results from previous studies on breast density and survival is complicated by the association between detection mode and survival. Here, we studied the effect of breast density on breast cancer-specific survival for different detection modes (screen-detected, interval <= 24 or > 24 months, non participant). METHODS: Data from the Nijmegen (Dutch) breast cancer screening programme were used. Women diagnosed with invasive breast cancer between 1975 and 2011 were included. Breast density was assessed visually, based on a dichotomized Wolfe scale: 'fatty breasts' (<=25%) and 'dense breasts' (> 25%). Cox proportional hazard regression was used to obtain hazard ratios (HR). RESULTS: We identified 2742 eligible women, with a breast pattern available for 2233 women. A diagnosis of interval cancer (HR 2.06, 95% CI 1.62-2.61) led to a significantly increased risk of breast cancer death compared with screen-detected cancer. No significant cause-specific survival difference between women with dense and fatty breasts was observed (HR 0.94, 95% CI 0.77-1.15). The hazard was only higher for women with dense breasts among interval cancers <=24 m (HR 1.07, 95% CI 0.74 1.56). The hazard appeared to be lower for women with dense breasts than for women with fatty breasts among screen-detected (HR 0.77, 95% CI 0.53-1.11) and interval cancers > 24 m (HR 0.80, 95% CI 0.53-1.20). None of the effects were statistically significant. CONCLUSIONS: Detection mode is strongly associated with breast cancer death. No clear association is apparent between breast density and breast cancer death, regardless of detection mode. PMID- 29618329 TI - A randomized controlled trial to evaluate utilization of physical activity recommendations among patients of cardiovascular healthcare centres in Eastern Slovakia: study design and rationale of the AWATAR study. AB - BACKGROUND: Guidelines on modifiable risk factors regarding cardiological patients are poorly implemented in clinical practice perhaps due to low health literacy. Several digital tools for improving lifestyle and behavioural intervention were developed. Our primary aim is to evaluate the effectiveness of a digital exercise prescription tool on the adherence to physical activity recommendations among patients with cardiovascular diseases. METHODS: A randomized controlled trial will be realized in cooperation with Cardiovascular Health Centres in Eastern Slovakia. Patients recruited through their cardiologists, will be randomised at 1:1 ratio to the three-months' experimental condition or control condition. The experimental group will receive standard lifestyle consultation leading to individually optimized prescription of physical activity. The control group will receive standard, usual-cardio-care lifestyle counselling, also in the domain of physical activity. The digital system will be used for optimized exercise prescription. The primary outcome is a change in the patient's adherence to exercise recommendations. Data will be collected in both groups prior to consultation and after 3 months. DISCUSSION: This study protocol presents background and design of a randomized control trial to investigate the effectiveness of a digital system-provide exercise prescription tool on the adherence to physical activity recommendations. An optimized exercise prescription that better reflects patient's diagnosis, comorbidities and medication can have a significant impact on secondary prevention of cardiovascular disease. This trial can provide important evidence about the effectiveness of digital exercise guidance in everyday practice of cardiovascular healthcare. TRIAL REGISTRATION: The study was registered on 1st November, 2017 and is available online at ClinicalTrials.gov (ID: NCT03329053 ). PMID- 29618331 TI - Design, implementation and evaluation of a web-based computer-tailored intervention to prevent binge drinking in adolescents: study protocol. AB - BACKGROUND: Binge-drinking in adolescents is a highly prevalent healthcare problem that associates physical and mental health complications with community implications. This paper describes the design, implementation and evaluation of the first web-based computer tailored intervention aimed at the prevention of binge drinking in Spanish adolescents. METHODS: The Alerta Alcohol program is based on the I-Change Model. First, feedback from focus and Delphi groups are used for cultural adaptation and to obtain further information on the items to be included on the program. A pilot study is then conducted to assess feasibility and to identify strengths and weaknesses. Second, a Cluster Randomized Controlled Trial is conducted to test the effectiveness of Alerta Alcohol in students aged 16 to 18 years. The study is performed in 16 high schools from Andalusia (southern Spain), which are randomized either to the experimental or the control condition (EC and CC). The EC receives the Alerta Alcohol intervention, which consists of four sessions at school (baseline questionnaire, two sessions in three scenarios: at home, celebrations, and public places, and a final evaluation). The adolescents are provided with answers related to their views of each scenario; this information is used to provide highly specific feedback regarding their knowledge, risk perception, self-esteem, attitude, social influence, and self-efficacy. In addition, two booster sessions are given at home to reinforce the previous messages. The CC just completes the baseline and the final evaluation questionnaires and then they are allowed to receive the intervention as well (as a waiting list). Evaluation takes place after four months. The primary endpoint is binge drinking within 30 days prior to the evaluation and alcohol use in the previous week. It is expected that Alerta Alcohol reduce the prevalence of binge drinking by 10%. Follow up analyses are carried out to determine the differences in effectiveness according to the compliance of the program (quality of the implementation). DISCUSSION: The results are expected to be applicable and may incorporate improvements in the practice of the Healthcare and Education Systems. If the program proves to be effective, regional and eventual national implementation should be considered. TRIAL REGISTRATION: Trial registration number (ClinicalTrials.gov): NCT03288896 . This study was retrospectively registered on 19/09/2017. PMID- 29618330 TI - Filaria specific antibody response profiling in plasma from anti-retroviral naive Loa loa microfilaraemic HIV-1 infected people. AB - BACKGROUND: In West and Central Africa areas of endemic Loa loa infections overlap with regions of high prevalence of human immunodeficiency virus type 1 (HIV-1) infections. Because individuals in this region are exposed to filarial parasites from birth, most HIV-1 infected individuals invariably also have a history of filarial parasite infection. Since HIV-1 infection both depletes immune system and maintains it in perpetual inflammation, this can hamper Loa loa filarial parasite mediated immune modulation, leading to enhanced loaisis. METHODS: In this study we have assessed in plasma from asymptomatic anti retroviral (ARV) naive Loa loa microfilaraemic HIV-1 infected people the filarial antibody responses specific to a filariasis composite antigen consisting of Wbgp29-BmR1-BmM14-WbSXP. The antibody responses specific to the filariasis composite antigen was determined by enzyme linked immunosorbent assay (ELISA) in plasma from ARV naive Loa loa microfilaraemic HIV-1 infected participants. In addition the filarial antigen specific IgG antibody subclass profiles were also determined for both HIV-1 positive and negative people. RESULTS: Both Loa loa microfilaraemic HIV-1 positive and negative individuals showed significantly higher plasma levels of IgG1 (P < 0.0001), IgG2 (P < 0.0001) and IgM (P < 0.0001) relative to amicrofilaraemic participants. A significant increase in IgE (P < 0.0001) was observed exclusively in Loa loa microfilaraemic HIV-1 infected people. In contrast there was a significant reduction in the level of IgG4 (p < 0.0001) and IgG3 (P < 0.0001) in Loa loa microfilaraemic HIV-1 infected individuals. CONCLUSIONS: Loa loa microfilaraemia in ARV naive HIV-1 infected people through differential reduction of plasma levels of filarial antigen specific IgG3, IgG4 and a significant increase in plasma levels of filarial antigen specific IgE could diminish Loa loa mediated immune-regulation. This in effect can result to increase loaisis mediated immunopathology in antiretroviral naive HIV-1 infected people. PMID- 29618332 TI - Schizophrenia alters intra-network functional connectivity in the caudate for detecting speech under informational speech masking conditions. AB - BACKGROUND: Speech recognition under noisy "cocktail-party" environments involves multiple perceptual/cognitive processes, including target detection, selective attention, irrelevant signal inhibition, sensory/working memory, and speech production. Compared to health listeners, people with schizophrenia are more vulnerable to masking stimuli and perform worse in speech recognition under speech-on-speech masking conditions. Although the schizophrenia-related speech recognition impairment under "cocktail-party" conditions is associated with deficits of various perceptual/cognitive processes, it is crucial to know whether the brain substrates critically underlying speech detection against informational speech masking are impaired in people with schizophrenia. METHODS: Using functional magnetic resonance imaging (fMRI), this study investigated differences between people with schizophrenia (n = 19, mean age = 33 +/- 10 years) and their matched healthy controls (n = 15, mean age = 30 +/- 9 years) in intra-network functional connectivity (FC) specifically associated with target-speech detection under speech-on-speech-masking conditions. RESULTS: The target-speech detection performance under the speech-on-speech-masking condition in participants with schizophrenia was significantly worse than that in matched healthy participants (healthy controls). Moreover, in healthy controls, but not participants with schizophrenia, the strength of intra-network FC within the bilateral caudate was positively correlated with the speech-detection performance under the speech masking conditions. Compared to controls, patients showed altered spatial activity pattern and decreased intra-network FC in the caudate. CONCLUSIONS: In people with schizophrenia, the declined speech-detection performance under speech on-speech masking conditions is associated with reduced intra-caudate functional connectivity, which normally contributes to detecting target speech against speech masking via its functions of suppressing masking-speech signals. PMID- 29618333 TI - The kallikrein-Kinin system modulates the progression of colorectal liver metastases in a mouse model. AB - BACKGROUND: The Kallikrein-Kinin System (KKS) has been found to play a role in tumor progression in several cancers. The KKS metabolic cascade depends on signalling through two cross talking receptors; bradykinin receptor 1 (B1R) and bradykinin receptor 2 (B2R). Activation of the Kinin receptor is responsible for multiple pathophysiologic functions including increase of vascular permeability and induction of host inflammatory responses that exert diverse effects on tumor growth. METHODS: B1R and B2R expression on mouse and human CRC cell lines was investigated. Changes in tumor growth and progression was assessed in male CBA mice bearing colorectal liver metastases (CRLM) following treatment with B1R or B2R blockers. In vitro cultures of human SW-480 and mouse colorectal cancer (MoCR) cell lines were examined for changes in their proliferation and migration properties following treatment with B1R or B2R blockers. RESULTS: Both colorectal cancer cell lines tested strongly positive for B1R and B2R expression. Inhibition of both receptors retarded tumor growth but only B1R blockade significantly reduced tumor load and increased tumor apoptosis. Blockade of either receptor reduced tumor vascularization in vivo and significantly inhibited proliferation and migration of colorectal cancer cells in vitro. CONCLUSION: Taken together, the present study demonstrated that kinin receptor blockade inhibited tumor growth and reduced its invading properties suggesting that KKS manipulation could be a novel target in colorectal cancer therapy. PMID- 29618334 TI - The frail older person does not exist: development of frailty profiles with latent class analysis. AB - BACKGROUND: A fundamental issue in elderly care is targeting those older people at risk and in need of care interventions. Frailty is widely used to capture variations in health risks but there is no general consensus on the conceptualization of frailty. Indeed, there is considerable heterogeneity in the group of older people characterized as frail. This research identifies frailty profiles based on the physical, psychological, social and cognitive domains of functioning and the severity of the problems within these domains. METHODS: This research was a secondary data-analysis of older persons derived from The Older Person and Informal Caregiver Minimum Dataset. Selected respondents were 60 years and older (n = 43,704; 59.6% female). The following variables were included: self reported health, cognitive functioning, social functioning, mental health, morbidity status, and functional limitations. Using latent class analysis, the population was divided in subpopulations that were subsequently discussed in a focus group with older people for further validation. RESULTS: We distinguished six frailty profiles: relatively healthy; mild physically frail; psychologically frail; severe physically frail; medically frail and multi-frail. The relatively healthy had limited problems across all domains. In three profiles older people mostly had singular problems in either the physical or psychological domain and the severity of the problems differed. Two remaining profiles were multidimensional with a combination of problems that extended to the social and cognitive domains. CONCLUSIONS: Our research provides an empirical base for meaningful frailty profiles. The profiles showed specific patterns underlying the problems in different domains of functioning. The heterogeneous population of frail older people has differing needs and faces different health issues that should be considered to tailor care interventions. Evaluation research of these interventions should acknowledge the heterogeneity of frailty by profiling. PMID- 29618335 TI - Dog ownership, dog walking, and leisure-time walking among Taiwanese metropolitan and nonmetropolitan older adults. AB - BACKGROUND: This study examined the prevalence of dog ownership and dog walking and its association with leisure-time walking among metropolitan and nonmetropolitan older adults. METHODS: A telephone-based cross-sectional survey targeting Taiwanese older adults was conducted in November 2016. Data related to dog ownership, time spent dog walking (categorized as non-dog owner, non-dog walkers, and dog walkers), and sociodemographic variables were obtained from 1074 older adults. Adjusted binary logistic regression was then performed. RESULTS: In this sample, 12% of Taiwanese older adults owned a dog and 31% of them walked their dogs for an average of 232.13 min over 5.9 days/week (standard deviation = 2.03). Older adults living in nonmetropolitan areas were more likely to own a dog (14.7% vs. 9.1%) but less likely to walk their dog (25.9% vs. 39.6%) than were those living in metropolitan areas. Compared with non-dog owners, only older adults living in nonmetropolitan areas who were dog walkers achieved 150 min of leisure-time walking (odds ratio: 3.03, 95% confidence interval: 1.05-8.77), after adjustment for potential confounders. CONCLUSION: Older Taiwanese adults living in nonmetropolitan areas who owned and walked their dogs were more likely to achieve health-enhancing levels of leisure-time walking. Tailored physical activity interventions for promoting dog walking should be developed for older adults who are dog owners living in nonmetropolitan areas and who do not engage in dog walking. PMID- 29618336 TI - Pretreatment neutrophil to lymphocyte ratio in determining the prognosis of head and neck cancer: a meta-analysis. AB - BACKGROUND: Recent studies have reported a relationship between prognosis and neutrophil-to-lymphocyte ratio (NLR) in patients with head and neck cancer (HNC). As the results are still controversial, we conducted a meta-analysis of pretreatment NLR in peripheral blood and prognosis in HNC patients. METHODS: We retrieved articles from PubMed, Medline, Cochrane Library, Embase and Web of Science. A comparative analysis was conducted for the effect of pretreatment NLR in peripheral blood on overall survival (OS), progression-free survival, disease free survival (DFS), disease-specific survival, metastasis-free survival, and recurrence-free survival of HNC patients. The analysis applied the criteria for systematic reviews described in the Cochrane Handbook and was conducted using hazard ratios (HRs) to estimate effect size, and calculated by Stata/SE version 13.0. RESULTS: The meta-analysis included eligible cohort studies (5475 cases). The OS data indicated increased mortality risk in HNC patients with a high NLR (HR = 1.84, 95% confidence interval (CI): 1.53-2.23; P < 0.001; heterogeneity, I2 = 37.2%, P = 0.074). Analysis of subgroups stratified by NLR cutoff values revealed increased mortality risk and significantly shorter DFS in patients with high NLR compared to those with low NLR (HR = 2.18, 95% CI: 1.46-3.24; P < 0.001). Patients with high NLR had a higher probability of tumor recurrence after treatment than those with low NLR (HR = 1.63, 95% CI: 1.09-2.45; P = 0.017; heterogeneity, I2 = 68.7%; P = 0.022). The probability of distant metastasis following treatment was greater in patients with high compared with low NLR (HR = 1.92, 95% CI: 1.36-2.72; P < 0.001; heterogeneity, I2 = 0.0%; P = 0.614). Funnel plots of the meta-analysis results were stable, as shown by sensitivity analysis. No publication bias was detected by the Egger test (P = 0.135). CONCLUSIONS: HNC patients with elevated pretreatment NLR in peripheral blood have poor prognosis and are prone to local invasion and distant metastasis. NLR values are easily obtained from routinely collected blood samples and could assist clinicians to determine prognosis of HNC patients. PMID- 29618338 TI - Optimal dietary patterns designed from local foods to achieve maternal nutritional goals. AB - BACKGROUND: Achieving nutritional requirements for pregnant and lactating mothers in rural households while maintaining the intake of local and culture-specific foods can be a difficult task. Deploying a linear goal programming approach can effectively generate optimal dietary patterns that incorporate local and culturally acceptable diets. The primary objective of this study was to determine whether a realistic and affordable diet that achieves nutritional goals for rural pregnant and lactating women can be formulated from locally available foods in Tanzania. METHODS: A cross sectional study was conducted to assess dietary intakes of 150 pregnant and lactating women using a weighed dietary record (WDR), 24 h dietary recalls and a 7-days food record. A market survey was also carried out to estimate the cost per 100 g of edible portion of foods that are frequently consumed in the study population. Dietary survey and market data were then used to define linear programming (LP) model parameters for diet optimisation. All LP analyses were done using linear program solver to generate optimal dietary patterns. RESULTS: Our findings showed that optimal dietary patterns designed from locally available foods would improve dietary adequacy for 15 and 19 selected nutrients in pregnant and lactating women, respectively, but inadequacies remained for iron, zinc, folate, pantothenic acid, and vitamin E, indicating that these are problem nutrients (nutrients that did not achieve 100% of their RNIs in optimised diets) in the study population. CONCLUSIONS: These findings suggest that optimal use of local foods can improve dietary adequacy for rural pregnant and lactating women aged 19-50 years. However, additional cost effective interventions are needed to ensure adequate intakes for the identified problem nutrients. PMID- 29618337 TI - Gene co-expression networks in liver and muscle transcriptome reveal sex-specific gene expression in lambs fed with a mix of essential oils. AB - BACKGROUND: Essential oil (EO) dietary supplementation is a new strategy to improve animal health. EO compounds have antiparasitic, antimicrobial, antiviral, antimycotic, antioxidant and anti-inflammatory proprieties. Nutrigenomics investigations represent innovative approaches in understanding the relation between diet effect and gene expression related to the animal performance. Few nutrigenomics studies have used a high-throughput RNA-Sequencing (RNA-Seq) approach, despite great potential of RNA-Seq data in gene expression quantification and in co-expression network analyses. Our aim is to use the potential of RNA-Sequencing data in order to evaluate the effect of an EO supplementary diet on gene expression in both lamb liver and muscle. RESULTS: Using a treatment and sex interaction model, 13 and 4 differentially expressed genes were identified in liver and muscle respectively. Sex-specific differentially expressed (DE) genes were identified in both sexes. Using network based analysis, different clusters of co-expressed genes that were highly correlated to the diet were detected in males vs. females, in agreement with DE analysis. A total of five regulatory genes in liver tissue associated to EO diet were identified: DNAJB9, MANF, UFM1, CTNNLA1 and NFX1. Our study reveals a sex dependent effect of EO diet in both tissues, and an influence on the expression of genes mainly involved in immune, inflammatory and stress pathway. CONCLUSION: Our analysis suggests a sex-dependent effect of the EO dietary supplementation on the expression profile of both liver and muscle tissues. We hypothesize that the presence of EOs could have beneficial effects on wellness of male lamb and further analyses are needed to understand the biological mechanisms behind the different effect of EO metabolites based on sex. Using lamb as a model for nutrigenomics studies, it could be interesting to investigate the effects of EO diets in other species and in humans. PMID- 29618339 TI - Cathepsin K associates with lymph node metastasis and poor prognosis in oral squamous cell carcinoma. AB - BACKGROUND: Lymph node metastasis (LNM) is a major determinant of prognosis and treatment planning of oral squamous cell carcinoma (OSCC). Cysteine cathepsins constitute a family of proteolytic enzymes with known role in the degradation of the extracellular matrix. Involvement in pathological processes, such as inflammation and cancer progression, has been proved. The aim of the study was to discover the clinicopathological and prognostic implications of cathepsin K (CTSK) expression in oral squamous cell carcinoma. METHODS: Eighty-three patients with primary OSCC, treated surgically between 1996 and 2000, were included. Gene expression data were acquired from a previously reported study. Human papilloma virus (HPV) status was previously determined by an algorithm for HPV-16. CTSK Protein expression was semi-quantitatively determined by immunohistochemistry in tumor and stromal cells. Expression data were correlated with various clinicopathological variables. RESULTS: Elevated gene and protein expression of CTSK were strongly associated to LNM and perineural invasion (p < 0.01). Logistic regression analysis highlighted increased CTSK protein expression in tumor cells as the most significant independent factor of lymphatic metastasis (OR = 7.65, CI:2.31-23.31, p = 0.001). Survival analysis demonstrated CTSK protein expression in both stromal and tumor cells as significant indicators of poor 5-year disease specific survival (HR = 2.40, CI:1.05-5.50, p = 0.038 for stromal cells; HR = 2.79, CI:1.02-7.64, p = 0.045 for tumor cells). CONCLUSION: Upregulation of CTSK seems to be associated with high incidence of lymphatic spread and poor survival in OSCC. CTSK could therefore serve as a predictive biomarker for OSCC. PMID- 29618340 TI - 3D high-resolution anorectal manometry in patients with perianal fistulas: comparison with 3D-anal ultrasound. AB - BACKGROUND: Perianal fistula surgery can damage the anal sphincters which may cause faecal incontinence. By measuring regional pressures, 3D-HRAM potentially provides better guidance for surgical strategy in patients with perianal fistulas. The aim was to measure regional anal pressures with 3D-HRAM and to compare these with 3D-EUS findings in patients with perianal fistulas. METHODS: Consecutive patients with active perianal fistulas who underwent both 3D-EUS and 3D-HRAM at a clinic specialised in proctology were included. A group of 30 patients without fistulas served as controls. Data regarding demographics, complaints, previous perianal surgical procedures and obstetric history were collected. The mean and regional anal pressures were measured with 3D-HRAM. Fistula tract areas detected with 3D-EUS were analysed with 3D-HRAM by visual coding and the regional pressures of the corresponding and surrounding area of the fistula tract areas were measured. The study was granted by the VUmc Medical Ethical Committee. RESULTS: Forty patients (21 males, mean age 47) were included. Four patients had a primary fistula, 19 were previously treated with a seton/abscess drainage and 17 had a recurrence after previously performed fistula surgery. On 3D-HRAM, 24 (60%) fistula tract areas were good and 8 (20%) moderately visible. All but 7 (18%) patients had normal mean resting pressures. The mean resting pressure of the fistula tract area was significantly lower compared to the surrounding area (47 vs. 76 mmHg; p < 0.0001). Only 2 (5%) patients had a regional mean resting pressure < 10 mmHg of the fistula tract area. Using a Delta mean resting pressure >= 30 mmHg difference between fistula tract area and non-fistula tract area as alternative cut-off, 21 (53%) patients were identified. In 6 patients 3D-HRAM was repeated after surgery: a local pressure drop was detected in one patient after fistulotomy with increased complaints of faecal incontinence. CONCLUSIONS: Profound local anal pressure drops are found in the fistula tract areas in patients normal mean resting pressures. Fistulotomy may affect local sphincter pressure. This might influence surgical decision making in future. PMID- 29618342 TI - Metabolic syndrome and body shape predict differences in health parameters in farm working women. AB - BACKGROUND: Sufficient evidence associate body shape to detrimental lifestyle diseases including the metabolic syndrome (MetS). The prevalence of the MetS, as well as effects of the MetS and body shape on body composition, insulin-like growth factor-1 (IGF-1), C-reactive protein (CRP) and sex hormone parameters were investigated in a female farm worker population in the Western Cape. METHODS: Women between the ages of 20-60 years were classified according to the International Diabetes Federation's definition of the MetS. Assessments included body shape (android/gynoid), blood pressure, anthropometric, bioelectrical impedance analyses and blood analyses for fasting glucose and insulin, lipid profile, IGF-1, CRP, and sex hormone parameters. RESULTS: The prevalence of the MetS was 52%, with abdominal obesity 68.8%, hypertension 66.4% and low high density lipoprotein-cholesterol (HDL-c) levels (64.1%) being the more prevalent MetS risk factors. The MetS, irrespective of body shape, was found to be associated with body mass index (p < 0.01), fat mass (%) (p < 0.01), waist circumference (p < 0.001), HDL-c (p < 0.001), systolic blood pressure (p < 0.05) and diastolic blood pressure (p < 0.01). No significant differences were observed for IGF-1, CRP and sex hormone parameters. CONCLUSION: The prevalence of the MetS and its individual risk factors were found to be significantly high in this female farm worker population. Additionally, the study showed that the MetS, body shape and/or both could predict differences in body composition, physiological and biochemical parameters in women. PMID- 29618341 TI - Quantitative analysis of near-implant magnesium accumulation for a Si-containing coated AZ31 cage from a goat cervical spine fusion model. AB - BACKGROUND: Magnesium (Mg) released from Mg-based implants degradation is believed to be effective in improving osteogenesis, however, studies focusing on Mg-based interbody cages are limited and fusion success was never reported. As excessive Mg accumulation can inhibit new bone formation, this study is designed to explain the possible reasons for the fusion failure of Mg-based cages by analyzing the relationships between the intervertebral Mg accumulation and the resulting interbody fusion. METHODS: The experimental cage was consisted of magnesium alloy (AZ31) substrate and Silicon (Si) -containing coating. C3/C4 and C5/C6 of 24 goats were implanted with cage or autologous iliac crest bone graft (Control group), which were analyzed at 3, 6, 12, and 24 weeks post-operatively. Intervertebral Mg concentrations, Mg-related Calcium (Ca)/ Phosphorus (P) ratios, radiological evaluations and histological findings were recorded for analyzing the relationships between the three of cage corrosion, Mg accumulation, and interbody fusion. RESULTS: Intervertebral Mg levels were significantly increased after cage implantation, especially in the areas that were closer to the cages at 3 weeks post-operatively, and these increased concentrations could persist up to 12 weeks post-operatively, indicating a relatively rapid corrosion process. Significantly lower Mg levels were only found at 24 weeks post-operatively, but these levels were still higher than those of the control group. In addition, Mg was found to be widely distributed at the intervertebral space since high Mg concentrations could even be detected at the posterior boundary of the vertebral body. Under this Mg accumulation profile, interbody fusion was not achieved, as indicated by the decreased Ca/P ratios, low CT fusion scores and negative histological results. CONCLUSIONS: Intervertebral excessive Mg accumulation might be the primary reason for interbody fusion failure. Quantitative Mg analysis can offer insight into the association between cage degeneration and biological response. PMID- 29618343 TI - HIV prevalence among female sex workers in Guigang City, Guangxi, China: an 8 year consecutive cross-sectional study. AB - BACKGROUND: Female sex workers (FSW) are a population that are at high risk for HIV infection, and their HIV/AIDS knowledge levels and sexual behaviors are of concern. This study describes changes in HIV prevalence and factors associated among female sex workers in Guigang City, Guangxi, one of the highest HIV prevalence areas in China. METHODS: Data were derived from an annual cross sectional venue-based survey, 2008 to 2015, in the form of sentinel surveillance. The participants were recruited using cluster sampling. FSW aged 16 years and above who completed a questionnaire and HIV testing. Both descriptive and multi level analyses were used to explore factors associated with changes in HIV prevalence. RESULTS: Seven thousand four hundred ninety-six FSW were recruited in this study. HIV prevalence among FSW in Guigang City fell into two periods, one with an increasing trend (2008-2011) and one with a decline (2012-2015). Differences between these time periods included age, relationship status, HIV knowledge, consistent condom use, lifetime illicit drug use, history of sexually transmitted infection in the past year, HIV testing, receipt of a condom distribution and education program or HIV counseling and testing, and peer education services. CONCLUSIONS: Since 2012, a reduction in HIV prevalence among FSW in Guigang City has been observed. The decline of HIV prevalence was associated with coinciding changes in demographic characteristics of FSW, improvement of HIV knowledge and safer sexual behaviors, and a program that promotes condom use, HIV counseling & testing, and peer education. PMID- 29618344 TI - Introduction of a guide based on a femoral neck section for fixation with multiple screws: a cadaveric study. AB - BACKGROUND: The design and application of assisted instrumentation for internal fixation of femoral neck fractures with multiple screws are still evolving. A novel guide based on a femoral neck section was designed to improve the accuracy of screw placement, and its efficacy was evaluated. METHODS: A guide based on a femoral neck section was designed for assisted fixation of femoral neck fractures with multiple screws. Femoral specimens from 10 adults (20 femurs) underwent assisted internal fixation for a femoral neck fracture with 3 cannulated screws using the new guide technique or conventional technique. The accuracy of screw orientation and entry point, the accuracy of optimal screw positioning, and drilling attempts, operative time, and fluoroscopy time were recorded. RESULTS: Among all 20 specimens, 60 screws were inserted successfully. Screw parallelism, operative time, and fluoroscopy time showed no statistical difference between the new guide technique and conventional technique (P > 0.05). The accuracy of optimal screw positioning was determined by the contained screw area ratio, distance between screws, distance from the centre of the femoral neck section, distance between screws and the femoral neck cortex, and Drilling attempts were statistical significantly better (data in the first three were larger and in the latter two was smaller) with the new guide technique, than with conventional technique (P < 0.05). CONCLUSIONS: This new, two-dimensional, fluoroscopy assisted, percutaneous guide technique enables accurate and optimal screw positioning in internal fixation of femoral neck fractures, compared with conventional technique. PMID- 29618345 TI - Perceptions of a group of hospital pharmacists and other professionals of the implementation of clinical pharmacy at a high complexity public hospital in Brazil. AB - BACKGROUND: During the process of implementation of clinical pharmacy services, internal and external factors may favor or hinder the incorporation of care into the hospital routine. This study aimed to understand the perceptions of a group of hospital pharmacists and other professionals of the implementation of clinical pharmacy at a high complexity public hospital in Brazil. METHODS: A focus group with 16 pharmacists and interviews with tree key stakeholders including managers in the pharmaceutical, medical, and nursing profession were conducted to understand their perceptions of the implementation clinical pharmacy services in a high complexity public hospital in Brazil. The service proposal was presented to the selected participants before conducting the focus group. Professionals with an overview of the hospital and influence on the relevant departments for the implementation of clinical pharmacy at the institution were selected. Data collected were transcribed and analyzed using the Bardin Content Analysis technique. Data analyzed were systematized into categories and registration units. The methodology involves the organization and analysis of reported content to make inferences. RESULTS: The data obtained were divided into four categories: "Perception of the current situation", "Implementation expectations", "Barriers to implementation", "Implementation facilitators". Participants discussed the stagnation of clinical activities of the pharmaceutical profession in Brazil, a reality that results from a lack of clinical training in the country. Pharmacists expressed their expectations for changes in professional performance. According to the managers, such services would positively affect clinical outcomes for patients. Gaps in academic education, lack of knowledge, and poor communication skills were barriers reported in this study. Pharmacists' clinical experience has been reported to facilitate the provision of services. CONCLUSIONS: This study highlights factors that may influence the implementation of clinical pharmacy services in the institution analyzed, such as resistance, fear, and frustration as barriers, as well the experience in clinical pharmacy of some pharmacists in the institution was one of the facilitators most cited by participants. This knowledge may aid future planning for the implementation of clinical pharmacy in hospitals. PMID- 29618346 TI - Diagnosis and management of a mediastinal ectopic thyroid laying on the right bronchus: case report and review of literature. AB - BACKGROUND: The mediastinal ectopic thyroid is very rare, accounting for less than 1% of all cases of ectopic thyroid tissue. The differential diagnoses with other diseases such as lymphomas, thymic tumors and dermoid cysts is mandatory, in fact each one, needs different management and treatment. CASE PRESENTATION: Here, we discuss a rare case of mediastinal ectopic thyroid presenting with a paratracheal mass laying on the right bronchus without symptoms. A 63-year-old male presented with an abnormal well-defined mass along the right paratracheal side, detected by chest x-ray. The CT scan confirmed the presence of a 6 * 8 cm heterogeneously enhanced mass, located behind the superior vena cava and left brachiocephalic artery, reaching azygos vein and right bronchus, without a mass effect. Taking into account the clinical importance of a mediastinal mass, we removed it surgically, through a double surgical approach consisting in a classical transverse cervicotomy for the left thyroid lobe, followed then by a longitudinal sternal splitting to remove the mediastinal mass and complete the thyroidectomy. CONCLUSIONS: In case of mediastinal masses, the surgical excision is recommended, presenting the double advantage to clarify the diagnosis and to treat the pathology. As demonstrated in this case, a mediastinal ectopic thyroid should be taken into account in the differential diagnosis, considering its clinical importance. PMID- 29618347 TI - Undergraduate medical students' perceptions and intentions regarding patient safety during clinical clerkship. AB - BACKGROUND: The purpose of this study was to examine undergraduate medical students' perceptions and intentions regarding patient safety during clinical clerkships. METHODS: Cross-sectional study administered in face-to-face interviews using modified the Medical Student Safety Attitudes and Professionalism Survey (MSSAPS) from three colleges of medicine in Korea. We assessed medical students' perceptions of the cultures ('safety', 'teamwork', and 'error disclosure'), 'behavioural intentions' concerning patient safety issues and 'overall patient safety'. Confirmatory factor analysis and Spearman's correlation analyses was performed. In total, 194(91.9%) of the 211 third-year undergraduate students participated. RESULTS: 78% of medical students reported that the quality of care received by patients was impacted by teamwork during clinical rotations. Regarding error disclosure, positive scores ranged from 10% to 74%. Except for one question asking whether the disclosure of medical errors was an important component of patient safety (74%), the percentages of positive scores for all the other questions were below 20%. 41.2% of medical students have intention to disclose it when they saw a medical error committed by another team member. CONCLUSIONS: Many students had difficulty speaking up about medical errors. Error disclosure guidelines and educational efforts aimed at developing sophisticated communication skills are needed. This study may serve as a reference for other institutions planning patient safety education in their curricula. Assessing student perceptions of safety culture can provide clerkship directors and clinical service chiefs with information that enhances the educational environment and promotes patient safety. PMID- 29618348 TI - Liraglutide downregulates hepatic LDL receptor and PCSK9 expression in HepG2 cells and db/db mice through a HNF-1a dependent mechanism. AB - BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9), a major regulator of cholesterol homeostasis, is associated with glucose metabolism. Liraglutide, a glucagon-like peptide-1 receptor agonist, can increase insulin secretion in a glucose-dependent manner and lower blood glucose. We aimed to investigate the relationship between liraglutide and PCSK9. METHODS: At the cellular level, the expressions of PCSK9 and hepatocyte nuclear factor 1 alpha (HNF1alpha) protein in HepG2 cells stimulated by liraglutide was examined using Western blot. Seven-week old db/db mice and wild type (WT) mice were administered either liraglutide (200 MUg/kg) or equivoluminal saline subcutaneously, twice daily for 7 weeks. Fasting glucose level, food intake and body weight were measured every week. After the 7-week treatment, the blood was collected for lipid and PCSK9 levels detection and the liver was removed from the mice for oil red O staining, immunohistochemical analysis, immunofluorescence test and Western bolt. RESULTS: Firstly, liraglutide suppressed both PCSK9 and HNF1alpha expression in HepG2 cells in a time and concentration dependent manner. Secondly, liraglutide induced weight loss in WT and db/db mice, decreased serum PCSK9, glucose and lipid levels and improved hepatic accumulation in db/db but not WT mice. Thirdly, liraglutide reduced both hepatic PCSK9 and low-density lipoprotein receptor (LDLR) expression with a decrease in HNF1alpha in db/db mice but not in WT mice. CONCLUSIONS: Liraglutide suppressed PCSK9 expression through HNF1alpha dependent mechanism in HepG2 cells and db/db mice, and decreased LDLR possibly via PCSK9-independent pathways in db/db mice. PMID- 29618349 TI - 3D printing-based minimally invasive cannulated screw treatment of unstable pelvic fracture. AB - BACKGROUND: Open reduction and internal fixation of pelvic fractures could restore the stability of the pelvic ring, but there were several problems. Minimally invasive closed reduction cannulated screw treatment of pelvic fractures has lots advantages. However, how to insert the cannulated screw safely and effectively to achieve a reliable fixation were still hard for orthopedist. Our aim was to explore the significance of 3D printing technology as a new method for minimally invasive cannulated screw treatment of unstable pelvic fracture. METHODS: One hundred thirty-seven patients with unstable pelvic fractures from 2014 to 2016 were retrospectively analyzed. Based on the usage of 3D printing technology for preoperative simulation surgery, they were assigned to 3D printing group (n = 65) and control group (n = 72), respectively. These two groups were assessed in terms of operative time, intraoperative fluoroscopy, postoperative reduction effect, fracture healing time, and follow-up function. The effect of 3D printing technology was evaluated through minimally invasive cannulated screw treatment. RESULTS: There was no significant difference in these two groups with respect to general conditions, such as age, gender, fracture type, time from injury to operation, injury cause, and combined injury. Length of surgery and average number of fluoroscopies were statistically different for 3D printing group and the control group (p < 0.01), i.e., 58.6 vs. 72.3 min and 29.3 vs. 37 min, respectively. Using the Matta radiological scoring systems, the reduction was scored excellent in 21/65 cases (32.3%) and good in 30/65 cases (46.2%) for the 3D printing group, versus 22/72 cases (30.6%) scored as excellent and 36/72 cases (50%) as good for the control group. On the other hand, using the Majeed functional scoring criteria, there were 27/65 (41.5%) excellent and 26/65 (40%) good cases for the 3D printing group in comparison to 30/72 (41.7%) and 28/72 (38.9%) cases for the control group, respectively. This suggests no significant difference between these two groups about the function outcomes. CONCLUSION: Full reduction and proper fixation of the pelvic ring and reconstruction of anatomical morphology are of great significance to patients' early functional exercise and for the reduction of long-term complications. This retrospective study has demonstrated the 3D printing technology as a potential approach for improving the diagnosis and treatment of pelvic fractures. TRIAL REGISTRATION: The study was retrospectively registered at the Chinese Clinical Trial Registry, number: ChiCTR TRC-17012798, trial registration date: 26 Sept. 2017. PMID- 29618350 TI - Impaction of lower third molars and their association with age: radiological perspectives. AB - BACKGROUND: Third molars are the most commonly impacted teeth, and their extraction is the most commonly performed procedure in oral and maxillofacial surgery. The aim of the present study is to describe the pattern of mandibular third molar impaction and to define the most appropriate age for prophylactic extraction of mandibular third molar teeth. METHODS: A total of 1198 orthopantomographs (OPGs) with 1810 impacted lower third molars were reviewed by two authors. The pattern of eruption in relation to patient's age was examined using standard radiographic points and angles. Statistical analysis was performed using SPSS for Windows release 16.0 (SPSS Inc., Chicago, IL, USA). RESULTS: In patients older than 20 years, vertical pattern of impaction was the most common (21.4%); while in young patients; horizontal impaction was more common (21.3%). Furthermore, there was a constant pattern of increase in Pell-Gregory ramus class 1 with increasing age, as the prevalence of class 1 was 0% at age 18 years compared to 54.9% at the age of 26 years. CONCLUSION: Frequency of vertical impaction of lower third molars was seen more at an older age (> 20 years) in this study, with an increase in the retromolar space. Late extraction of mandibular third molar teeth (i.e. after the age of 20) is therefore recommended when prophylactic extraction is considered. PMID- 29618351 TI - Hospitalization outcomes in patients with schizophrenia after switching to lurasidone or quetiapine: a US claims database analysis. AB - BACKGROUND: This study compared hospital admission rates among adult patients with schizophrenia who switched to antipsychotic monotherapy with lurasidone or quetiapine. METHODS: This retrospective cohort study used U.S.-based Truven Health MarketScan(r) Medicaid Multi-State Database (April 2010 through December 2012) and MarketScan(r) Commercial Claims and Encounters Database (April 2010 through October 2013). Continuous enrollment for 6-months before and after medication initiation was required. Treatment episodes ended after 6-months post lurasidone or quetiapine initiation, a 60-day treatment gap, or initiation of another antipsychotic. Length of treatment episodes (i.e., treatment duration) was compared using a t-test. All-cause, mental-health, and schizophrenia-related hospitalization rates, as well as costs, were compared between lurasidone- and quetiapine-treated patients using multivariable generalized linear models that adjusted for background characteristics. RESULTS: Quetiapine (n = 435) compared to lurasidone (n = 238) treatment was associated with increased all-cause (21% vs 13%, p < 0.05) and mental health-related hospitalizations (20% vs 12%, p < 0.05), but similar rates of schizophrenia-related hospitalizations (14% vs. 10%, p = 0.14). After adjusting for baseline covariates, quetiapine had 64% higher likelihood of all-cause hospitalizations (OR [odds ratio] = 1.64, 95% confidence interval [CI] 1.05-2.57, p = 0.03), 74% higher likelihood of mental health related hospitalizations (OR = 1.74, 95% CI 1.11-2.75, p = 0.02), and a similar likelihood of schizophrenia-related hospitalization (OR = 1.35, 95% CI 0.82-2.22, p = 0.24). For those with hospital admissions, adjusted all-cause admission costs were higher for quetiapine when compared with lurasidone in both the Medicaid ($22,036 vs. $15,424, p = 0.17) and commercial populations ($23,490 vs. $20,049, p = 0.61). These differences were not significant. The length of treatment episodes was significantly shorter for quetiapine than lurasidone (115.4 vs 123.1 days, p < 0.05). CONCLUSIONS: In this retrospective claims database study, patients with schizophrenia who were switched to lurasidone had significantly fewer all-cause and mental health-related hospitalizations and similar rates of schizophrenia-related hospitalization compared with those switched to quetiapine. Patients switching to lurasidone had a significantly longer treatment duration rate than those switching to quetiapine. These results may reflect differences in efficacy or tolerability between lurasidone and quetiapine. PMID- 29618352 TI - Government and public health responses to e-cigarettes in New Zealand: vapers' perspectives. AB - BACKGROUND: The New Zealand (NZ) government is to lift the ban on the sale of nicotine for use in electronic cigarettes (e-cigarettes). METHODS: Using a naturalistic approach, we sought to understand how the current law was experienced by e-cigarette users (vapers). Twenty-nine vapers were interviewed by telephone, between May and September 2016, using a semi-structured interview schedule. Open-ended questions covered: initiating vaping, the experience of stopping smoking, technical problems encountered, reasons for vaping, acceptability of vaping, addiction to vaping and advice given to smokers about vaping. The audio recordings were transcribed and then independently coded using a general inductive thematic analysis. RESULTS: This paper presents the main theme which was that vapers employed a range of reactionary strategies to the ban on the sale of nicotine e-liquid in NZ. These included lobbying government, spreading the word, establishing vaper support groups, helping people stop smoking by switching to vaping and advocating for e-cigarettes to be incorporated into smoking cessation practice. CONCLUSIONS: Vapers' experience and observations form a popular or lay epidemiology--one that identified that e-cigarettes were helping people stop smoking and could thus deliver public health benefits. Public health researchers and workers, and government fears about vaping, and proposals to strengthen restrictions contributed to the growth of the vaper community who reacted by forming self-help groups and providing alternative cessation support to smokers. For a significant switch from smoking to vaping to occur, the health sector needs to have a change of attitude towards vaping that is positive, and the public needs evidence-based information on vaping. A first step could be for the health sector to collaborate with the vaping community to reorient current tobacco control and cessation practice to encourage smokers to switch to less harmful smoke-free alternatives to smoking. PMID- 29618353 TI - Efficacy of virtual block objects in reducing the lung dose in helical tomotherapy planning for cervical oesophageal cancer: a planning study. AB - BACKGROUND: Intensity-modulated radiotherapy is useful for cervical oesophageal carcinoma (CEC); however, increasing low-dose exposure to the lung may lead to radiation pneumonitis. Nevertheless, an irradiation technique that avoids the lungs has never been examined due to the high difficulty of dose optimization. In this study, we examined the efficacy of helical tomotherapy that can restrict beamlets passing virtual blocks during dose optimization computing (block plan) in reducing the lung dose. METHODS: Fifteen patients with CEC were analysed. The primary/nodal lesion and prophylactic nodal region with adequate margins were defined as the planning target volume (PTV)-60 Gy and PTV-48 Gy, respectively. Nineteen plans per patient were made and compared (total: 285 plans), including non-block and block plans with several shapes and sizes. RESULTS: The most appropriate block model was semi-circular, 8 cm outside of the tracheal bifurcation, with a significantly lower lung dose compared to that of non-block plans; the mean lung volumes receiving 5 Gy, 10 Gy, 20 Gy, and the mean lung dose were 31.3% vs. 48.0% (p < 0.001), 22.4% vs. 39.4% (p < 0.001), 13.2% vs. 16.0% (p = 0.028), and 7.1 Gy vs. 9.6 Gy (p < 0.001), respectively. Both the block and non-block plans were comparable in terms of the homogeneity and conformity indexes of PTV-60 Gy: 0.05 vs. 0.04 (p = 0.100) and 0.82 vs. 0.85 (p = 0.616), respectively. The maximum dose of the spinal cord planning risk volume increased slightly (49.4 Gy vs. 47.9 Gy, p = 0.002). There was no significant difference in the mean doses to the heart and the thyroid gland. Prolongation of the delivery time was less than 1 min (5.6 min vs. 4.9 min, p = 0.010). CONCLUSIONS: The block plan for CEC could significantly reduce the lung dose, with acceptable increment in the spinal dose and a slightly prolonged delivery time. PMID- 29618354 TI - Isobolographic analysis of co-administration of two plant-derived antiplasmodial drug candidates, cryptolepine and xylopic acid, in Plasmodium berghei. AB - BACKGROUND: Increasing resistance to current anti-malarial therapies requires a renewed effort in searching for alternative therapies to combat this challenge, and combination therapy is the preferred approach to address this. The present study confirms the anti-plasmodial effects of two compounds, cryptolepine and xylopic acid and the relationship that exists in their combined administration determined. METHODS: Anti-plasmodial effect of cryptolepine (CYP) (3, 10, 30 mg kg-1) and xylopic acid (XA) (3, 10, 30 mg kg-1) was evaluated in Plasmodium berghei-infected male mice after a 6-day drug treatment. The respective doses which produced 50% chemosuppression (ED50) was determined by iterative fitting of the log-dose responses of both drugs. CYP and XA were then co-administered in a fixed dose combination of their ED50s (1:1) as well as different fractions of these combinations (1/2, 1/4, 1/8, 1/16 and 1/32) to find the experimental ED50 (Zexp). The nature of interaction between cryptolepine and xylopic acid was determined by constructing an isobologram to compare the Zexp with the theoretical ED50 (Zadd). Additionally, the effect of cryptolepine/xylopic acid co administration on vital organs associated with malarial parasiticidal action was assessed. RESULTS: The Zadd and Zexp were determined to be 12.75 +/- 0.33 and 2.60 +/- 0.41, respectively, with an interaction index of 0.2041. The Zexp was significantly (P < 0.001) below the additive isobole indicating that co administration of cryptolepine and xylopic acid yielded a synergistic anti plasmodial effect. This observed synergistic antiplasmodial effect did not have any significant deleterious effect on the kidney, liver and spleen. However, the testis were affected at high doses. CONCLUSION: The co-administration of cryptolepine and xylopic acid produces synergistic anti-malarial effect with minimal toxicity. PMID- 29618355 TI - Lactococcus lactis provides an efficient platform for production of disulfide rich recombinant proteins from Plasmodium falciparum. AB - BACKGROUND: The production of recombinant proteins with proper conformation, appropriate post-translational modifications in an easily scalable and cost effective system is challenging. Lactococcus lactis has recently been identified as an efficient Gram positive cell factory for the production of recombinant protein. We and others have used this expression host for the production of selected malaria vaccine candidates. The safety of this production system has been confirmed in multiple clinical trials. Here we have explored L. lactis cell factories for the production of 31 representative Plasmodium falciparum antigens with varying sizes (ranging from 9 to 90 kDa) and varying degree of predicted structural complexities including eleven antigens with multiple predicted structural disulfide bonds, those which are considered difficult-to-produce proteins. RESULTS: Of the 31 recombinant constructs attempted in the L. lactis expression system, the initial expression efficiency was 55% with 17 out of 31 recombinant gene constructs producing high levels of secreted recombinant protein. The majority of the constructs which failed to produce a recombinant protein were found to consist of multiple intra-molecular disulfide-bonds. We found that these disulfide-rich constructs could be produced in high yields when genetically fused to an intrinsically disorder protein domain (GLURP-R0). By exploiting the distinct biophysical and structural properties of the intrinsically disordered protein region we developed a simple heat-based strategy for fast purification of the disulfide-rich protein domains in yields ranging from 1 to 40 mg/l. CONCLUSIONS: A novel procedure for the production and purification of disulfide-rich recombinant proteins in L. lactis is described. PMID- 29618357 TI - Quantifying malaria endemicity in Ethiopia through combined application of classical methods and enzyme-linked immunosorbent assay: an initial step for countries with low transmission initiating elimination programme. AB - BACKGROUND: In the context of reduced transmission of malaria, it is essential to re-evaluate and determine the level of transmission as it guides re-orientation of control measures which is appropriate to local disease epidemiology. However, little is known about level of malaria transmission in Ethiopia. The present study aimed to investigate the level of malaria transmission through combined application of classical methods and enzyme-linked immunosorbent assay (EIA) in low transmission settings of Ethiopia. METHODS: This study was conducted in June 2016 on 763 apparently healthy children 2-9 years of age. Children were recruited from ten sites representing different malaria transmission settings in Ethiopia. Splenomegaly rate, infection rate and EIA antibody test were used to determine endemicity. The data were analysed using SPSS 21.0 and Stata 12.0. RESULTS: The overall prevalence of malaria parasitaemia was 2.49% (95% CI 1.38-3.59) and 2.36% (95% CI 1.28-3.44) as detected using rapid diagnostic test and microscopy, respectively. Plasmodium falciparum accounted for 62.63% of the infections. The prevalence of parasitaemia significantly varied by altitude and localities; the highest (5.8%) in areas below 1500 m above sea level. Overall, splenomegaly rate was 1.70% (95% CI 0.78-0.2.66%), making the overall malaria transmission hypoendemic. Infection rate was higher among males (2.7%), but rate of splenomegaly was higher in females. Incongruent with spleen rate and parasitaemia, EIA showed a higher level of cumulative exposure to malaria with spatially localized and highly heterogeneous transmission. Overall, 126 (18.75%, 95% CI 15.79-21.71) of the children were positive for total malaria antibodies with significant variations with altitude, age and sex; the higher in areas of < 1500 m asl (25.8%), children >= 5 years (22.1%) and among males (20.9%). CONCLUSIONS: Splenomegaly and parasitaemia are not good measures to show variations in the levels of malaria transmission in reduced and/or low endemic settings. The malaria antibody (i.e. serological) test seems to be a good measure of malaria endemicity showing greater degree of heterogeneity and localized risk of transmission. Thus, malaria elimination efforts need to be supported with serological indicators to identify patterns of foci of transmission to set priorities for interventions. PMID- 29618356 TI - In vitro maturation of oocytes from excised ovarian tissue in a patient with autoimmune ovarian insufficiency possibly associated with Epstein-Barr virus infection. AB - BACKGROUND: Some reports show that it is possible to isolate immature oocytes from human ovarian tissue retrieved by a cortex biopsy or ovariectomy of non stimulated ovaries and mature them in vitro. The mature oocytes can be vitrified and stored for in vitro fertilization, which, along with ovarian tissue cryopreservation, is mostly practiced in young cancer patients to preserve their fertility. There is much less data on this new approach in women with a natural ovarian insufficiency, which can be caused by different factors, including viral infection. In this case report this advanced methodology was used in a young patient suffering from ovarian insufficiency which was possibly associated with Epstein-Barr virus and infectious mononucleosis (glandular fever). METHODS: This case report included a 27-year-old patient who attended our infertility clinic because of ovarian failure as a part of autoimmune polyendocrinopathy that occurred after Epstein-Barr virus infection, which has rarely been reported until now. Although antral follicles were observed in her ovaries by ultrasound monitoring, she was amenorrhoeic with menopausal concentrations of follicle stimulating hormone (FSH) and without mature follicles. Therefore, a small biopsy of ovarian cortex tissue was performed using laparoscopy to retrieve immature oocytes. The retrieved oocytes were matured in vitro, cryopreserved, and stored for in vitro fertilization and potential pregnancy. RESULTS: Four immature, germinal vesicle (GV) oocytes were found and removed from tissue, denuded mechanically by a pipette, and matured in vitro in a maturation medium with added FSH and hCG as well as in co-culture with cumulus cells, which were retrieved by their denudation. Three oocytes matured in vitro to the metaphase II (MII) stage and were vitrified for in vitro fertilization along with ovarian tissue cryopreservation. CONCLUSION: Our results show that Epstein-Barr infection is possibly associated with autoimmune ovarian failure. The devastating impact on fertility in such disorder can be successfully avoided by in vitro maturation of oocytes from excised ovarian tissue. PMID- 29618358 TI - Clinical and molecular characterization of 112 single-center patients with Neurofibromatosis type 1. AB - BACKGROUND: The aim of this retrospective study was to define clinical and molecular characteristics of a large sample of neurofibromatosis type 1 (NF1) patients, as well as to evaluate mutational spectrum and genotype-phenotype correlation. NF1 is a relatively common neurogenetic disorder (1:2500-1:3000 individuals). It is caused by mutations of the NF1 gene on chromosome 17ql1.2, with autosomal dominant pattern of inheritance and wide phenotypical variability. Cafe-au-lait spots (CALs), cutaneous and/or subcutaneous neurofibromas (CNFs/SCNFs), skinfold freckling, skeletal abnormalities, Lisch nodules of the iris and increased risk of learning and intellectual disabilities, as well as tumors of the nervous system and other organs are its main clinical features. METHODS: The preliminary group collected 168 subjects with clinical suspicion of NF1. They were evaluated following the National Institutes of Health (NIH) criteria for NF1, revised by Gutmann et al. 1997, integrated for 67 of them by molecular testing. According to these references, 112 of 168 patients were diagnosed as NF1. The sample was characterized by an equal sex ratio (57 males, 55 females) and age distribution ranging from 10 days to 60 years of age (mean age, 13 years). RESULTS: A wide spectrum of clinical features has been observed in our patients. Mutational analysis resulted positive in 51 cases (76%). Twenty four mutations detected in our cohort have not been reported to date. CONCLUSIONS: This study may contribute to a better definition of genotypic and phenotypic features of NF1 patients, with respect to further insights into the clinical characterization of the disease. In addition, an amplification of the spectrum of mutations in the NF1 gene has been documented. PMID- 29618359 TI - Women's perspectives on antenatal breast expression: a cross-sectional survey. AB - BACKGROUND: The practice of antenatal breast expression (ABE) has been proposed as a strategy to promote successful breastfeeding. Although there has been some focus on the evaluation of the effects of ABE in promotion of breastfeeding, little or no evidence exists on women's experiences of ABE or opinions on ABE, particularly amongst overweight or obese women. METHODS: This study aimed to explore women's knowledge, practices and opinions of ABE, and any differences within the overweight and obese subgroups. A cross-sectional survey was undertaken using an online questionnaire distributed by a maternity user group representative via social media. Quantitative data were analysed using Chi-square and Fisher's exact tests in SPSS. Simple thematic analysis was used for the qualitative data. RESULTS: A total of 688 responses were analysed; the sample represented a group of breastfeeding mothers, of whom 64.5% had heard of ABE, 8.2% had been advised to do ABE, and 14.2% had undertaken ABE. Of the women who had been advised to do ABE, 67.9% had complied. Most participants (58.6%) were unsure if ABE was a good idea; however 80.9% would consider doing ABE if it was found to be helpful to prepare for breastfeeding. Women in the overweight or obese subgroups were significantly more likely to have heard of ABE (p < 0.001), and positive opinion of ABE also increased with higher BMI groups. The qualitative data demonstrated participants felt ABE may be beneficial when mother or baby have medical problems, and in preparation for breastfeeding, but highlighted their concerns that it may interfere with nature and be harmful, and that they wanted more information and knowledge about ABE. CONCLUSIONS: Amongst women who have breastfed, many have heard of ABE, compliance with advice to undertake ABE is relatively high, and ABE is considered an acceptable practice. Further investigation into the benefits and safety of ABE is warranted, to address the needs of childbearing women for evidence-based information about this practice. If the evidence base is established, overweight and obese pregnant women could be an important target group for this intervention. PMID- 29618360 TI - Physical activity and sedentary behavior in preschoolers: a longitudinal assessment of trajectories and determinants. AB - BACKGROUND: Despite physical activity (PA) being recognized as a critically important factor for good physical and mental health already early in life and throughout the life course, prospective data on activity behavior during the preschool years remains scarce. This study examined trajectories and determinants of levels and change in total PA (TPA), moderate-to-vigorous PA (MVPA) and sedentary behavior (SB) in a representative sample of Swiss preschoolers. METHODS: Data were drawn from the Swiss Preschoolers' Health Study (SPLASHY), a multi-site prospective cohort study including 555 children (53% boys) aged 2-to-6 years at baseline. A follow-up was conducted after 12 months. Activity behavior was measured using accelerometers. Information on 35 potential determinants from different socio-ecological domains was either directly measured or parent reported. Trajectories of TPA, MVPA and SB over time were described for boys and girls. Linear mixed models were used to investigate factors that predicted levels and change in TPA, MVPA and SB. RESULTS: All children were sufficiently physically active according to published recommendations for preschoolers. Trajectory profiles revealed a marked increase in TPA and MVPA in boys and girls whereas SB remained fairly stable over time. Mixed modeling demonstrated that variables most relevant to determining PA levels were sex, age and activity temperament (all positively associated). Together with gross motor skills, birth weight, family structure (only for TPA) and season (only for MVPA), these factors accounted for 26 and 32% of total variance explained in TPA and MVPA, respectively. Activity temperament emerged as the strongest determinant of SB (negative association) and explained with sex, season and family structure 20% of total variance in SB. The presence of older siblings was the only factor that predicted change in PA over time. CONCLUSIONS: In this healthy physically active cohort of preschoolers, non-modifiable individual-level factors had the greatest influence on PA. The limited success of this and previous studies to identify modifiable determinants and the finding that most preschoolers were sufficiently active suggest that future attempts should provide insights into how preschoolers' activity levels can be maintained and fostered to prevent subsequent harmful declines attributable, amongst others, to educational transitions. Thus, good-quality longitudinal studies are needed. TRIAL REGISTRATION: Current Controlled Trials ISRCTN41045021 (date of registration: 21.03.14). PMID- 29618361 TI - The prevalence change of hyperlipidemia and hyperglycemia and the effectiveness of yearly physical examinations: an eight-year study in Southwest China. AB - BACKGROUND: The aim of this study was to investigate the prevalence changes of hyperlipidemia and hyperglycemia from 2009 to 2016 and the effectiveness of yearly physical examinations to hyperlipidemia and hyperglycemia prevention in Chengdu. METHODS: A total of 794 residents (499 males) who have undergone annual health check-ups for 8 consecutive years (from 2009 to 2016) in Chengdu, a city in southwest China were selected as the follow-up group, 7226 residents in 2009 and 75,068 residents in 2016 who underwent health examinations in the same hospital were chosen to be the contemporary control group. The concentration of fasting serum triglyceride(TG), total cholesterol(TC), low density lipoprotein cholesterol(LDL-C), high density lipoprotein cholesterol (HDL-C) and glucose were measured and compared among these groups. RESULTS: There was a clear rise in the prevalence of hypercholesterolemia and hyperglycemia from 2009 to 2016 (p < 0.05). The follow-up group didn't show difference in levels of serum lipids and glucose compared with the general population after an 8-years' consecutive physical examination (p > 0.05), the follow-up cohort in the 8th year exhibited significant increases in serum total cholesterol and glucose compared with the 1st year (p < 0.05). CONCLUSION: The prevalence of hypercholesterolemia and hyperglycemia were increased significantly from 2009 to 2016. Annual physical examination didn't show a positive effect in the prevention of hypercholesterolemia and hyperglycemia. Health education should be improved to ensure the fulfillment of the preventive objective of yearly physical examination. PMID- 29618362 TI - Genetic analysis of Wnt/PCP genes in neural tube defects. AB - BACKGROUND: Mouse homozygous mutants in Wnt/planar cell polarity (PCP) pathway genes have been shown to cause neural tube defects (NTDs) through the disruption of normal morphogenetic processes critical to neural tube closure (NTC). Knockout mice that are heterozygotes of single PCP genes likely fail to produce NTD phenotypes, yet damaging variants detected in human NTDs are almost always heterozygous, suggesting that other deleterious interacting variants are likely to be present. Nonetheless, the Wnt/PCP pathway remains a genetic hotspot. Addressing these issues is essential for understanding the genetic etiology of human NTDs. METHODS: We performed targeted next-generation sequencing (NGS) on 30 NTD-predisposing Wnt/PCP pathway genes in 184 Chinese NTD cases. We subsequently replicated our findings for the CELSR1 gene in an independent cohort of 292 Caucasian NTD samples from the USA. Functional validations were confirmed using in vitro assays. RESULTS: CELSR1, CELSR2 and CELSR3 genes were significantly clustered with rare driver coding mutations (q-value< 0.05) demonstrated by OncodriveCLUST. During the validation stage, the number of rare loss of function (LoF) variants in CELSR1 was significantly enriched in NTDs compared with the LoF counts in the ExAC database (p < 0.001). Functional studies indicated compound heterozygote variants of CELSR2 p.Thr2026Met and DVL3 p.Asp403Asn result in down regulation of PCP signals. CONCLUSIONS: These data indicate rare damaging variants of the CELSR genes, identified in ~ 14% of NTD cases, are expected to be driver genes in the Wnt/PCP pathway. Compound damaging variants of CELSR genes and other Wnt/PCP genes, which were observed in 3.3% of the studied NTD cohort, are also expected to amplify these effects at the pathway level. PMID- 29618363 TI - Alitretinoin reduces erythema in inherited ichthyosis. AB - BACKGROUND: Acitretin is the main retinoid used to treat severe inherited ichthyosis. Alternatives may be considered if it results ineffective or there are side-effects, or for women of childbearing age. Our objective is evaluation of the effects and tolerance of alitretinoin. An observational retrospective multicentric study was designed to analyse patients with inherited ichthyosis treated by alitretinoin. RESULTS: A total of 13 patients were included, 11 of whom were receiving acitretin at inclusion. The main reason for switching to alitretinoin was a desire for pregnancy, but also because of side-effects or unsatisfactory efficacy. Starting dose was 10 mg/day, increased to 20 or 30 mg/day. Alitretinoin seemed to be more effective than acitretin at reducing erythema, but was less effective at reducing scaling or hyperkeratosis. Global efficacy was considered low for two patients, moderate for nine, and high for two. Treatment was well-tolerated, except for one patient who presented with benign intracranial hypertension leading to discontinuation of treatment. CONCLUSIONS: Alitretinoin may be suitable for hereditary ichthyosis with prominent erythema, especially for women of childbearing age. PMID- 29618364 TI - Exploring attitudes toward physician-assisted death in patients with life limiting illnesses with varying experiences of palliative care: a pilot study. AB - BACKGROUND: On February 6th, 2015, the Supreme Court of Canada ruled that competent adults suffering intolerably from a grievous and irremediable medical condition have the right to the assistance of a physician in ending their own lives, an act known as physician-assisted death, and later defined as medical assistance in dying, allowing for provision by a physician or a nurse practitioner. As of June 6th, 2016, this is no longer illegal across Canada. There is strong support amongst the general population for physician-assisted death, however there is no recent data on the attitudes of terminally ill patients. Our main objective was to gain information on terminally ill patients' general and personal attitudes toward physician-assisted death. METHODS: This is an exploratory pilot study. We surveyed three groups of patients with life limiting diagnoses: one with new referrals to palliative care; one with no palliative care involvement; and one with prior and ongoing management by a palliative care team. Respondents were surveyed twice, approximately two weeks apart, and rated their general attitudes toward physician-assisted death and the hypothetical consideration of physician-assisted death for oneself on a five point Likert scale at baseline and follow-up. Respondents with new referrals to palliative care were surveyed before and after palliative care consultation. This study was approved by The Western University Health Sciences Research Ethics Board and Lawson Health Research Institute. RESULTS: We surveyed 102 participants, 70 of whom completed both surveys (31% dropout rate). Participants in all groups predominantly responded between somewhat agree (4 on a 5-point Likert scale) and strongly agree (5 on the Likert scale) when asked about their general attitude toward physician-assisted death. Patients with prior palliative care involvement reported the highest average ratings of hypothetical consideration of physician-assisted death for oneself on a 5-point Likert scale (3.4 at baseline; 3.9 at follow-up), followed by patients with a new palliative consultation (3.2 at baseline; 3.3 at follow-up), and patients with no palliative involvement (2.6 at baseline; 2.9 at follow-up). CONCLUSIONS: Given the preliminary results of this pilot study, we can conclude that terminally ill patients generally agree that physician-assisted death should be available to patients with life-limiting illnesses. Furthermore, descriptive data show a trend for higher hypothetical consideration of physician-assisted death in those patients with prior and ongoing palliative care involvement than patients without palliative involvement. Responses in all groups remained fairly consistent over the two-week period. PMID- 29618366 TI - Bisphosphonate therapy for spinal osteoporosis in Hajdu-Cheney syndrome - new data and literature review. AB - BACKGROUND: Hajdu-Cheney syndrome (HCS) (#OMIM 102500) is a rare, autosomal dominant condition that presents in early childhood. It is caused by mutations in the terminal exon of NOTCH2, which encodes the transmembrane NOTCH2 receptor. This pathway is involved in the coupled processes of bone formation and resorption. The skeletal features of HCS include acro-osteolysis of the digits and osteoporosis commonly affecting vertebrae and long bones. Fractures are a prominent feature and are associated with significant morbidity. There is no specific treatment, but with both acro-osteolysis and generalized osteoporosis, it is possible that anti-resorptive treatment might be of benefit. However, to date only a few case reports have evaluated the effectiveness of bisphosphonate treatment. METHODS: We describe the clinical features, treatment regimens and response to bisphosphonate treatment in 7 newly described patients aged 6-39 with HCS, and pooled the data with that from 8 previously published cases (a total of 17 courses of treatment in 15 individuals). RESULTS: The mean lumbar spine bone mineral density (BMD) z-score before treatment was - 2.9 (SD 1.2). In 14 courses of treatment (82%), there was an increase in BMD with bisphosphonate treatment, but the impact (in terms of change in spinal BMD z-score) appeared to be less with advancing age (p = 0.01). There was no evidence that acro-osteolysis was prevented. CONCLUSIONS: Although individual response is variable and age-related, the data support a role for bisphosphonates in preventing or treating spinal osteoporosis in HCS, but bone loss from the lumbar spine may be rapid after cessation. PMID- 29618365 TI - Apolipoprotein E4 impairs spontaneous blood brain barrier repair following traumatic brain injury. AB - BACKGROUND: Traumatic Brain Injury (TBI) is a major cause of disability and mortality, to which there is currently no comprehensive treatment. Blood Brain Barrier (BBB) dysfunction is well documented in human TBI patients, yet the molecular mechanisms that underlie this neurovascular unit (NVU) pathology remains unclear. The apolipoprotein-E (apoE) protein has been implicated in controlling BBB integrity in an isoform dependent manner, via suppression of Cyclophilin A (CypA)-Matrix metallopeptidase-9 (MMP-9) signaling cascades, however the contribution of this pathway in TBI-induced BBB permeability is not fully investigated. METHODS: We exposed C57Bl/6 mice to controlled cortical impact and assessed NVU and BBB permeability responses up to 21 days post-injury. We pharmacologically probed the role of the CypA-MMP-9 pathway in BBB permeability after TBI using Cyclosporin A (CsA, 20 mg/kg). Finally, as the apoE4 protein is known to be functionally deficient compared to the apoE3 protein, we used humanized APOE mice as a clinically relevant model to study the role of apoE on BBB injury and repair after TBI. RESULTS: In C57Bl/6 mice there was an inverse relationship between soluble apoE and BBB permeability, such that damaged BBB stabilizes as apoE levels increase in the days following TBI. TBI mice displayed acute pericyte loss, increased MMP-9 production and activity, and reduced tight junction expression. Treatment with the CypA antagonist CsA in C57Bl/6 mice attenuates MMP-9 responses and enhances BBB repair after injury, demonstrating that MMP-9 plays an important role in the timing of spontaneous BBB repair after TBI. We also show that apoe mRNA is present in both astrocytes and pericytes after TBI. We report that APOE3 and APOE4 mice have similar acute BBB responses to TBI, but APOE3 mice display faster spontaneous BBB repair than APOE4 mice. Isolated microvessel analysis reveals delayed pericyte repopulation, augmented and sustained MMP-9 expression at the NVU, and impaired stabilization of Zonula Occludens-1, Occludin and Claudin-5 expression at tight junctions in APOE4 mice after TBI compared to APOE3 mice. CONCLUSIONS: These data confirm apoE as an important modulator of spontaneous BBB stabilization following TBI, and highlights the APOE4 allele as a risk factor for poor outcome after TBI. PMID- 29618367 TI - The use of driving endonuclease genes to suppress mosquito vectors of malaria in temporally variable environments. AB - BACKGROUND: The use of gene drive systems to manipulate populations of malaria vectors is currently being investigated as a method of malaria control. One potential system uses driving endonuclease genes (DEGs) to spread genes that impose a genetic load. Previously, models have shown that the introduction of DEG bearing mosquitoes could suppress or even extinguish vector populations in spatially-heterogeneous environments which were constant over time. In this study, a stochastic spatially-explicit model of mosquito ecology is combined with a rainfall model which enables the generation of a variety of daily precipitation patterns. The model is then used to investigate how releases of a DEG that cause a bias in population sex ratios towards males are affected by seasonal or random rainfall patterns. The parameters of the rainfall model are then fitted using data from Bamako, Mali, and Mbita, Kenya, to evaluate release strategies in similar climatic conditions. RESULTS: In landscapes with abundant resources and large mosquito populations the spread of a DEG is reliable, irrespective of variability in rainfall. This study thus focuses mainly on landscapes with low density mosquito populations where the spread of a DEG may be sensitive to variation in rainfall. It is found that an introduced DEG will spread into its target population more reliably in wet conditions, yet an established DEG will have more impact in dry conditions. In strongly seasonal environments, it is thus preferable to release DEGs at the onset of a wet season to maximize their spread before the following dry season. If the variability in rainfall has a substantial random component, there is a net increase in the probability that a DEG release will lead to population extinction, due to the increased impact of a DEG which manages to establish in these conditions. For Bamako, where annual rainfall patterns are characterized by a long dry season, it is optimal to release a DEG at the start of the wet season, where the population is growing fastest. By contrast release timing is of lower importance for the less seasonal Mbita. CONCLUSION: This analysis suggests that DEG based methods of malaria vector control can be effective in a wide range of climates. In environments with substantial temporal variation in rainfall, careful timing of releases which accounts for the temporal variation in population density can substantially improve the probability of mosquito suppression or extinction. PMID- 29618368 TI - Increased B3GALNT2 in hepatocellular carcinoma promotes macrophage recruitment via reducing acetoacetate secretion and elevating MIF activity. AB - BACKGROUND: Hepatocellular carcinoma (HCC) ranks as the sixth most prevalent cancer and the third leading cause of tumor-related death, so it is urgently needed to discover efficient markers and targets for therapy. beta-1,3-N acetylgalactosaminyltransferase II (B3GALNT2) belongs to the beta-1,3 glycosyltransferases (b3GT) family and has been reported to regulate development of both normal and tumor tissues. However, studies on the functions of B3GALNT2 in cancer are quite limited. Here we investigated the potential role of B3GALNT2 in HCC progression. METHODS: Western blot, qPCR, and immunohistochemistry assays were performed to quantify the relative expression of B3GALNT2 in HCC. The functions of B3GALNT2 in tumor progression were evaluated in HCC cell lines and nude mice. Metabolomics analysis was applied to detect alternatively expressed small molecules. Enzyme activity assays were employed to determine the tautomerase activity of macrophage inhibitory factor (MIF). RESULTS: For expression analysis, higher levels of B3GALNT2 were observed in tumor tissues compared with adjacent normal tissues, and upregulation of B3GALNT2 correlated with increased tumor size and worse overall survival. Changing levels of B3GALNT2 did not influence cell viability in vitro but promoted tumor growth via enhancing macrophage recruitment in vivo. Furthermore, acetoacetate was identified as a key molecule in B3GALNT2-mediated macrophage recruitment. Mechanistically, B3GALNT2 downregulated expression of enzymes involved in acetoacetate-related metabolism, and reduction of acetoacetate revived MIF activity, thus promoting macrophage recruitment. CONCLUSIONS: This study evaluated B3GALNT2 as a tumor marker in HCC and revealed functions of B3GALNT2 in metabolic transformation and microenvironmental remodeling in HCC. Mechanistically, B3GALNT2 reduced expression of some metabolic enzymes and thus downregulated levels of secreted acetoacetate. This relieved the activity of MIF and enhanced macrophage recruitment to promote tumor growth. PMID- 29618369 TI - Clinical characteristics of headache in Italian adolescents aged 11-16 years: a cross-sectional questionnaire school-based study. AB - BACKGROUND: The purpose of this study was to determine headache characteristics, impact on daily activities and medication attitudes among a large sample of adolescents in Italy. METHODS: Secondary school classes were randomly selected from a national stratified multistage sampling. Data regarding socio-familial factors, headache characteristics, impact on daily activities and medication use were recorded with an anonymous multiple-choice questionnaire. RESULTS: The survey involved 2064 adolescents. 1950 questionnaires were considered for analysis. Study population included 944 males (48.4%) and 1006 females (51.6%), aged between 11 and 16 years (mean 13.5 +/- 1.87). Headache prevalence was 65.9%. Mean age at headache onset was 8.33 years. 9.8% suffered from headache > 1/week, 14.3% > 1/month, 24.2% monthly and 17.7% less than monthly. The mean duration of a headache episode was less than 30 min in 32.9%, 1 hour in 28.1%, 2 hours in 19.3% and several hours in 19.5%. Pain intensity was moderate in 52.2% and severe in 9.5%. School represented the main trigger factor (67%). Impact on daily activities was noted in 57.5%. 69.2% of adolescents reported the use of pain relievers. Up to 5.7% declared self-medication, while only 20.6% followed a physician's prescription. Female adolescents experienced headache more frequently (70.2% vs 60%) and more intensely than male peers. Girls had a higher family history of headache, could more frequently identify a trigger factor, and were more affected into their daily activities than boys. CONCLUSIONS: Population based studies of headache disorders are important, as they inform needs assessment and underpin service policy for a disease that is a public-health priority. Headache has a high prevalence among adolescents and carries a significant burden in terms of impact on daily activities and use of medication. Furthermore, underdiagnose is common, while trigger factors are often detectable. Special consideration should be given to female adolescents and self-medication attitudes. PMID- 29618370 TI - Myeloperoxidase level and inflammatory markers and lipid and lipoprotein parameters in stable coronary artery disease. AB - BACKGROUND: Myeloperoxidase (MPO) impairing endothelial functions. We investigated whether increasing concentration of myeloperoxidase (MPO) and inflammatory markers induce progression and incident acute coronary syndrome (ACS) in stable coronary artery disease (SCAD) patients. Therefore, the concentration of MPO, lipids, lipoproteins (apo(apolipoprotein) AI, apoB, lipoprotein associated phospholipase A2 (LpPLA2) level), inflammatory markers (high sensitivity C-reactive protein (hsCRP), tumor necrosis factor-alpha (TNF alpha), interleukine-6 (IL-6) concentration) were examined. METHODS: This study concerned 67 SCAD patients divided into groups: all patients, patients with MPO < 200 ng/ml, MPO 200-300 ng/ml, MPO > 300 ng/ml concentration and 15 controls. ApoAI, apoB and hsCRP levels were examined using the immunonephelometric method, and MPO, LpPLA2, IL-6, TNF-alpha concentration was performed by using Quantikine ELISA kit R&D Systems. RESULTS: In the all patients, and in group with MPO 200 300 ng/ml TC, LDL-C, nonHDL-C, LpPLA2 concentration and TC/HDL-C, LDL-C/HDL-C ratios were insignificant, and significantly higher concentration of TG, apoB, MPO, inflammatory markers and TG/HDL-C, MPO/apoAI, MPO/HDL-C ratios but HDL-C, apoAI level and HDL-C/apoAI ratio were significantly reduced. In the group of patients with MPO < 200 ng/ml, level of TC, LDL-C, nonHDL-C, apoAI, apoAII, LpPLA2 and MPO and LDL-C/HDL-C ratio were in-significant, HDL-C was decreased but apoB, TG, inflammatory markers, apoB/apoAI, TG/HDL-C, MPO/apoAI, MPO/HDL-C ratio were significantly increased. In the group of patients with MPO > 300 ng/ml concentration of TC, LDL-C, nonHDL-C, apoAII, LpPLA2 and LDL-C/HDL-C ratios were not significant, but HDL-C and apoAI concentrations were significantly decreased. The concentrations of TG, apoB, MPO and inflammatory markers and TG/HDL-C, MPO/apoAI, MPO/HDL-C ratios were significantly increased compared to the controls. The apoAI concentration was significantly decreased and the concentration of MPO and hsCRP as well as MPO/apoAI and MPO/HDL-C ratios were significantly higher as compared to the group of patients with MPO < 200 ng/ml. Spearman's correlation test showed a positive correlation between MPO concentration and MPO/apoAI and MPO/HDL-C ratios in all patients and MPO < 200 ng/ml, MPO 200-300 ng/ml. The patients with MPO > 300 ng/ml showed a positive correlation between the concentration of MPO and the level of hsCRP and IL-6, and a negative correlation between MPO/apoAI ratio and the concentration of HDL-C, apoAI and apoAII. CONCLUSION: The results suggest that moderate dyslipidemia and dyslipoproteinemia deepening of inflammation, and inflammation slowly induce increase MPO concentration which decrease apoAI and HDL-C level and disturb HDLs function. The increasing MPO level and MPO/HDL-C, MPO/apoAI ratios can differentiate the SCAD patients at the risk of acute coronary syndrome (ACAD) and stroke. PMID- 29618371 TI - S100A12 concentrations and myeloperoxidase activities are increased in the intestinal mucosa of dogs with chronic enteropathies. AB - BACKGROUND: Intestinal mucosal S100A12 and myeloperoxidase (MPO) are inflammatory biomarkers in humans with inflammatory bowel disease (IBD). However, these biomarkers have not been studied in the intestinal mucosa of dogs with chronic enteropathies (CE), even though dogs with CE have increased S100A12 concentrations in feces and serum. This study investigated mucosal S100A12 concentrations and MPO activities in both dogs with CE and healthy Beagles. ELISA (S100A12 concentrations) and spectrophotometric methods (MPO activity) were used. The associations of both biomarkers with canine IBD activity index (CIBDAI), histopathologic findings, clinical outcome, and serum albumin concentrations were also investigated. We studied intestinal mucosal samples originating from different intestinal regions of 40 dogs with CE and 18 healthy Beagle dogs (duodenum, ileum, colon, and cecum). RESULTS: Compared with healthy Beagles, mucosal S100A12 concentrations in dogs with CE were significantly higher in the duodenum (p < 0.0001) and colon (p = 0.0011), but not in the ileum (p = 0.2725) and cecum (p = 0.2194). Mucosal MPO activity of dogs with CE was significantly higher in the duodenum (p < 0.0001), ileum (p = 0.0083), colon (p < 0.0001), and cecum (p = 0.0474). Mucosal S100A12 concentrations in the duodenum were significantly higher if the inflammatory infiltrate consisted mainly of neutrophils (p = 0.0439) or macrophages (p = 0.037). Mucosal S100A12 concentrations also showed a significant association with the severity of total histopathological injury and epithelial injury in the colon (p < 0.05). Mucosal MPO activity showed a significant association (p < 0.05) with the severity of total histopathological injury, epithelial injury, and eosinophil infiltration in the duodenum. There was no significant association of both biomarkers with CIBDAI or clinical outcome. CONCLUSIONS: This study showed that both mucosal S100A12 concentrations and MPO activities are significantly increased in the duodenum and colon of dogs with CE; mucosal MPO was also increased in the ileum and cecum. Future research should focus on assessing the clinical utility of S100A12 and MPO as diagnostic markers in dogs with CE. PMID- 29618372 TI - Prehospital triage of patients diagnosed with perforated peptic ulcer or peptic ulcer bleeding: an observational study of patients calling 1-1-2. AB - BACKGROUND: Triage systems are used in emergency medical services to systematically prioritize prehospital resources according to individual patient conditions. Previous studies have shown cases of preventable deaths in emergency medical services even when triage systems are used, indicating a potential undertriage among some conditions. The aim of this study was to investigate the triage level among patients diagnosed with perforated peptic ulcer (PPU) or peptic ulcer bleeding (PUB). METHODS: In a three-year period in Central Denmark Region, all patients hospitalized within 24 h after a 1-1-2 emergency call and who subsequently received either a PPU or a PUB (hereinafter combined and referred to as PPU/PUB) or a First Hour Quintet (FHQ: respiratory failure, stroke, trauma, cardiac chest pain, and cardiac arrest) diagnosis were investigated. A modified Poisson regression was used to estimate the relative risk of receiving the highest and lowest prehospital response level. Also, a linear regression analysis was used to estimate the relative risk of 30-day mortality. RESULTS: Of 8658 evaluated patients, 263 were diagnosed with PPU/PUB. After adjusting for relevant confounding variables, patients diagnosed with PPU/PUB were less likely to receive ambulance transportation compared to patients diagnosed with stroke, RR = 1.41 (CI: 1.28-1.56); trauma, RR = 1.28 (CI: 1.15 1.42); cardiac chest pain, RR = 1.47 (CI: 1.33-1.62); and cardiac arrest, RR = 1.44 (CI: 1.31-1.42). Among patients diagnosed with PPU/PUB, 6.5% (CI: 3.3-9.7) did not receive ambulance transportation. The proportion of patients not receiving ambulance transportation was higher among patients diagnosed with PPU/PUB compared to patients diagnosed with an FHQ diagnosis. The 30-day mortality rate among patients diagnosed with PPU/PUB was 7.8% (CI: 4.2-11.1). This was lower than the 30-day mortality rate among patients diagnosed with respiratory failure (P = 0.010), stroke (P = 0.001), and cardiac arrest (P < 0.001), but comparable to the 30-day mortality among patients diagnosed with cardiac chest pain (P = 0.080) and trauma (P = 0.281). CONCLUSION: Among patients calling 1-1-2, fewer patients diagnosed with PPU/PUB received ambulance transportation than patients diagnosed with FHQ diagnoses, despite a high mortality among patients diagnosed with PPU/PUB. PMID- 29618373 TI - Genetic variation associated with increased insecticide resistance in the malaria mosquito, Anopheles coluzzii. AB - BACKGROUND: Malaria mortality rates in sub-Saharan Africa have declined significantly in recent years as a result of increased insecticide-treated bed net (ITN) usage. A major challenge to further progress is the emergence and spread of insecticide resistance alleles in the Anopheles mosquito vectors, like An. coluzzii. A non-synonymous mutation in the para voltage-gated sodium channel gene reduces pyrethroid-binding affinity, resulting in knockdown resistance (kdr). Metabolic mechanisms of insecticide resistance involving detoxification genes like cytochrome P450 genes, carboxylesterases, and glutathione S transferases are also important. As some gene activity is tissue-specific and/or environmentally induced, gene regulatory variation may be overlooked when comparing expression from whole mosquito bodies under standard rearing conditions. RESULTS: We detected complex insecticide resistance in a 2014 An. coluzzii colony from southern Mali using bottle bioassays. Additional bioassays involving recombinant genotypes from a cross with a relatively susceptible 1995 An. coluzzii colony from Mali confirmed the importance of kdr and associated increased permethrin resistance to the CYP9K1 locus on the X chromosome. Significant differential expression of CYP9K1 was not observed among these colonies in Malpighian tubules. However, the P450 gene CYP6Z1 was overexpressed in resistant individuals following sublethal permethrin exposure and the carboxylesterase gene COEAE5G was constitutively overexpressed. CONCLUSIONS: The significant P450-related insecticide resistance observed in the 2014 An. coluzzii colony indicates that ITNs treated with the P450 inhibitor piperonyl butoxide (PBO) would be more effective in this region. The known insecticide resistance gene CYP6Z1 was differentially expressed exclusively in the context of sublethal permethrin exposure, highlighting the importance of tissue-specificity and environmental conditions in gene expression studies. The increased activity of the carboxylesterase COEAE5G in the resistant An. coluzzii colony suggests resistance to other insecticides like organophosphates. Additional gene expression studies involving other tissues (e.g. fat body) would provide a more comprehensive view of genes underlying metabolic insecticide resistance in An. coluzzii from Mali. Identifying genetic markers linked to these regulatory alleles is an important next step that would substantially improve insecticide resistance surveillance and population genetic studies in this important vector species. PMID- 29618375 TI - Association of spring-summer hydrology and meteorology with human West Nile virus infection in West Texas, USA, 2002-2016. AB - BACKGROUND: The emergence of West Nile virus (WNV) in the Western Hemisphere has motivated research into the processes contributing to the incidence and persistence of the disease in the region. Meteorology and hydrology are fundamental determinants of vector-borne disease transmission dynamics of a region. The availability of water influences the population dynamics of vector and host, while temperature impacts vector growth rates, feeding habits, and disease transmission potential. Characterization of the temporal pattern of environmental factors influencing WNV risk is crucial to broaden our understanding of local transmission dynamics and to inform efforts of control and surveillance. METHODS: We used hydrologic, meteorological and WNV data from west Texas (2002-2016) to analyze the relationship between environmental conditions and annual human WNV infection. A Bayesian model averaging framework was used to evaluate the association of monthly environmental conditions with WNV infection. RESULTS: Findings indicate that wet conditions in the spring combined with dry and cool conditions in the summer are associated with increased annual WNV cases. Bayesian multi-model inference reveals monthly means of soil moisture, specific humidity and temperature to be the most important variables among predictors tested. Environmental conditions in March, June, July and August were the leading predictors in the best-fitting models. CONCLUSIONS: The results significantly link soil moisture and temperature in the spring and summer to WNV transmission risk. Wet spring in association with dry and cool summer was the temporal pattern best-describing WNV, regardless of year. Our findings also highlight that soil moisture may be a stronger predictor of annual WNV transmission than rainfall. PMID- 29618374 TI - Transient reduction of DNA methylation at the onset of meiosis in male mice. AB - BACKGROUND: Meiosis is a specialized germ cell cycle that generates haploid gametes. In the initial stage of meiosis, meiotic prophase I (MPI), homologous chromosomes pair and recombine. Extensive changes in chromatin in MPI raise an important question concerning the contribution of epigenetic mechanisms such as DNA methylation to meiosis. Interestingly, previous studies concluded that in male mice, genome-wide DNA methylation patters are set in place prior to meiosis and remain constant subsequently. However, no prior studies examined DNA methylation during MPI in a systematic manner necessitating its further investigation. RESULTS: In this study, we used genome-wide bisulfite sequencing to determine DNA methylation of adult mouse spermatocytes at all MPI substages, spermatogonia and haploid sperm. This analysis uncovered transient reduction of DNA methylation (TRDM) of spermatocyte genomes. The genome-wide scope of TRDM, its onset in the meiotic S phase and presence of hemimethylated DNA in MPI are all consistent with a DNA replication-dependent DNA demethylation. Following DNA replication, spermatocytes regain DNA methylation gradually but unevenly, suggesting that key MPI events occur in the context of hemimethylated genome. TRDM also uncovers the prior deficit of DNA methylation of LINE-1 retrotransposons in spermatogonia resulting in their full demethylation during TRDM and likely contributing to the observed mRNA and protein expression of some LINE-1 elements in early MPI. CONCLUSIONS: Our results suggest that contrary to the prevailing view, chromosomes exhibit dynamic changes in DNA methylation in MPI. We propose that TRDM facilitates meiotic prophase processes and gamete quality control. PMID- 29618376 TI - Pseudoprogression manifesting as recurrent ascites with anti-PD-1 immunotherapy in urothelial bladder cancer. AB - BACKGROUND: Immunotherapies targeting the PD-1 checkpoint pathway have recently gained regulatory approval in numerous cancer types. With the widespread use of immune checkpoint therapies, varying patterns of responses and immune-related adverse events are being observed. CASE PRESENTATION: In this case, we highlight a patient who developed recurrent, large-volume ascites, while simultaneously having a 49% reduction in peritoneal tumor lesion size by RECIST criteria. Sampling of the fluid revealed high levels of IL-6 and IL-15. Cytology revealed no malignant cells on 4 separate paracenteses over a period of 6 weeks. Cell counts revealed that 45% of cells were lymphocytes, and further analysis was performed by fluorescence-activated cell sorting (FACS). The majority of lymphocytes were CD8+, of which 78% were PD-1+ and 43% were HLA-DR+ indicating an activated phenotype. CONCLUSIONS: In summary, treatment with anti-PD-1 therapy may result in pseudoprogression manifested by ascitic fluid accumulation due to the influx of activated T cells. Since worsening of ascites is typically associated with disease progression, it is important to consider the possibility of pesudoprogression in such patients undergoing therapy with immune checkpoint inhibitors. PMID- 29618377 TI - Proteomic analysis of protein interactions between Eimeria maxima sporozoites and chicken jejunal epithelial cells by shotgun LC-MS/MS. AB - BACKGROUND: Eimeria maxima initiates infection by invading the jejunal epithelial cells of chicken. However, the proteins involved in invasion remain unknown. The research of the molecules that participate in the interactions between E. maxima sporozoites and host target cells will fill a gap in our understanding of the invasion system of this parasitic pathogen. METHODS: In the present study, chicken jejunal epithelial cells were isolated and cultured in vitro. Western blot was employed to analyze the soluble proteins of E. maxima sporozoites that bound to chicken jejunal epithelial cells. Co-immunoprecipitation (co-IP) assay was used to separate the E. maxima proteins that bound to chicken jejunal epithelial cells. Shotgun LC-MS/MS technique was used for proteomics identification and Gene Ontology was employed for the bioinformatics analysis. RESULTS: The results of Western blot analysis showed that four proteins bands from jejunal epithelial cells co-cultured with soluble proteins of E. maxima sporozoites were recognized by the positive sera, with molecular weights of 70, 90, 95 and 130 kDa. The co-IP dilutions were analyzed by shotgun LC-MS/MS. A total of 204 proteins were identified in the E. maxima protein database using the MASCOT search engine. Thirty-five proteins including microneme protein 3 and 7 had more than two unique peptide counts and were annotated using Gene Ontology for molecular function, biological process and cellular localization. The results revealed that of the 35 annotated peptides, 22 (62.86%) were associated with binding activity and 15 (42.86%) were involved in catalytic activity. CONCLUSIONS: Our findings provide an insight into the interaction between E. maxima and the corresponding host cells and it is important for the understanding of molecular mechanisms underlying E. maxima invasion. PMID- 29618378 TI - Feline gastrointestinal parasitism in Greece: emergent zoonotic species and associated risk factors. AB - BACKGROUND: Feline gastrointestinal parasitism constitutes an issue of concern for veterinarians since parasites are widespread and affect animals' health and welfare. Furthermore, some of these pathogens have zoonotic potential. To provide detailed data on the current epizootiology of feline endoparasitism, a multicentric survey was conducted during 2016. METHODS: Faeces from 1150 cats were collected from all regions of Greece and examined by sedimentation and flotation techniques. Possible risk factors including gender, age, ownership status, living conditions and co-infections with other parasites were assessed using binary regression models for each one of the most prevalent parasites. RESULTS: The overall gastrointestinal parasite prevalence in cats was 50.7%. The study population consisted of cats of both sexes, different age groups, ownership status and living conditions. A total of 10 gastrointestinal parasitic species were detected and up to 5 different parasites were isolated in the same faecal sample. The most frequently identified parasites were Toxocara cati (n = 278; 24.2%), followed by Cystoisospora spp. (n = 189; 16.4%), Ancylostomatidae (n = 186; 16.2%), Aelurostrongylus abstrusus (n = 40; 3.5%), Giardia spp. (n = 26; 2.3%), Joyeuxiella pasqualei (n = 14; 1.2%), Capillaria aerophila (n = 8; 0.7%), Dipylidium caninum (n = 3; 0.2%), Toxascaris leonina (n = 2; 0.1%) and Troglostrongylus brevior (n = 2; 0.1%). The occurrence of co-infections was 11.6%. Concerning risk factors, the likelihood of T. cati infection was higher for female cats living outdoors and for cats being infected with Cystoisospora spp. In the same frame, young, stray, male and free of A. abstrusus cats were more likely to be infected with Cystoisospora spp. Correspondingly, stray, infected with Giardia spp. but free of Cystoisospora spp. cats were more likely to be infected with Ancylostomatidae. Regarding A. abstrusus infection, a higher probability was reported for cats living outdoors and for cats free of Cystoisospora spp., while Giardia spp. infections were more common in young and co-infected with Ancylostomatidae animals. CONCLUSIONS: The prevalence of parasitized cats in Greece was high and thus consideration should be paid to control the risk factors, to implement targeted preventive antiparasitic treatments and educate cat owners on the value of prevention for the health and welfare of their cats. PMID- 29618380 TI - Coordinated responses to individual tumor antigens by IgG antibody and CD8+ T cells following cancer vaccination. AB - BACKGROUND: One of today's greatest hurdles for cancer immunotherapy is the absence of information regarding which tumor antigens are already recognized by patients receiving immunotherapies, and whether those therapies then boost or generate an immune response against tumor proteins. For CD8+ T cells in particular, patient-specific immune recognition and responses at the level of individual tumor antigens are rarely characterized. Because of this, some immunologists have turned to serum antibodies as an alternative measure of antigen-specific anti-tumor immunity. In this work, we sought to simultaneously interrogate serum IgG and CD8+ T cell recognition of individual tumor antigens to determine whether antigen-specific serum IgG antibodies provide a window into the behavior of antigen-specific CD8+ T cell responses. Using antibody-based assays to evaluate immune response repertoires and focus T cell antigen exploration could afford substantial advantages for discovering and monitoring the anti cancer immune responses of patients enrolled on clinical trials. METHODS: We vaccinated female BALB/c mice with a novel combination of an autophagosome enriched vaccine derived from 4T1 mammary carcinoma along with poly-I:C adjuvant, then screened serum for IgG binding to arrays of 15mer peptides containing known mutation sites in 4T1. Simultaneously, we primed CD8+ T cell cultures from these same animals with 8-11mer peptides derived from these antigens. These primed T cells were then stimulated to measure recognition of the peptides or live 4T1 cells by IFNgamma release. RESULTS: Vaccinated animals demonstrate increases in antigen-specific CD8+ T cell recognition of 4T1 tumor cells and peptides. For proteins confirmed in 4T1 cells and vaccine by mass spectrometry, there is a correlation between this increased CD8+ T cell IFNgamma release and serum IgG binding to individual peptide antigens. CONCLUSIONS: These results suggest it is possible to observe some features of a patient's antigen-specific T cell repertoire via an antibody surrogate, which has implications for tumor antigen discovery and clinical monitoring of antigen-specific anti-tumor immunity. PMID- 29618381 TI - Efficacy of PD-1 & PD-L1 inhibitors in older adults: a meta-analysis. AB - BACKGROUND: Immune checkpoint inhibitors targeting PD-1/PD-L1 pathway demonstrated promising activities in variety of malignancies, however little is known regarding their efficacy in adults aged >=65 years. METHODS: We conducted a systematic review and a study-level meta-analysis to explore efficacy of ICIs based on age, younger vs older than 65 years. We included in this analysis randomized controlled phase II or III studies in patients with metastatic solid tumors that compared efficacy of PD-1 or PD-L1 inhibitors to a non-PD-1/PD-L1 inhibitor. Aggregated estimates of overall survival (OS) and progression-free survival (PFS) are based on random/mixed effects (RE) models to allow for heterogeneity between the studies. RESULTS: Initial search identified 53 articles, 17 were randomized controlled trials that compared nivolumab, pembrolizumab or atezolizumab to chemotherapy or targeted therapy. Only 9 trials reported hazard ratiios (HR) for OS based on age and were included in this meta analysis. Out of those studies seven reported HR for PFS but only 4 studies included subgroup-analysis based on age for PFS. The overall estimated random effects HR for death was 0.64 with 95% CI of 0.54-0.76 in patients >=65 years vs. 0.68 with 95% CI of 0.61-0.75 in patients < 65 years. The overall estimated random-effects for HR for progression was 0.74 with 95% CI of 0.60-0.92 in patients >=65 years vs. 0.73 with 95% CI of 0.61-0.88 in patients < 65 years. CONCLUSIONS: PD-1 (nivolumab and pembrolizumab) and PD-L1 (atezolizumab) inhibitors had comparable efficacy in adults younger vs >= 65 years. PMID- 29618379 TI - Molecular evidence for new sympatric cryptic species of Aedes albopictus (Diptera: Culicidae) in China: A new threat from Aedes albopictus subgroup? AB - BACKGROUND: Aedes (Stegomyia) albopictus (Skuse) is an indigenous species and the predominant vector of dengue fever in China. Understanding of genetic diversity and structure of the mosquito would facilitate dengue prevention and vector control. Sympatric cryptic species have been identified in the Ae. albopictus subgroup in Southeast Asia; however, little is known about the presence and distribution of cryptic species in China. This study aimed to examine the genetic diversity, evaluate potential new cryptic sibling species, and assess the prevalence of Wolbachia infections in field populations. METHODS: Aedes adult female specimens were collected from five provinces in southern and central China during 2015-2016. Morphological identification was performed under dissection microscope. The mitochondrial DNA cytochrome c oxidase subunit 1 (cox1, DNA barcoding) locus and the ribosomal DNA internal transcribed spacer region 2 (ITS2) marker were used to examine the genetic variation, evaluate cryptic sibling species, and population structure in the field populations. Screening for the presence of Wolbachia was performed using multiplex PCR. RESULTS: A total of 140 individual specimens with morphological characteristics similar to Ae. albopictus were sequenced for DNA barcoding. Among these, 129 specimens (92.1%) were confirmed and identified as Ae. albopictus. The remaining 11 specimens, from 2 provinces, were identified as 2 distinct sequence groups, which were confirmed by ITS2 marker sequencing, suggesting the existence of potential cryptic species of Ae. albopictus. In Ae. albopictus, we found significant genetic differentiation and population structure between populations collected from different climate zones. Medium to high frequencies of Wolbachia infections were observed in natural Ae. albopictus populations, whereas Wolbachia was infrequent or absent in cryptic species populations. CONCLUSIONS: Our findings highlight the population differentiation by climate zone and the presence of novel, cryptic Aedes species in China. The low prevalence of Wolbachia infections in cryptic species populations could reflect either a recent invasion of Wolbachia in Ae. albopictus or different host immune responses to this symbiont in the cryptic species. The study provides useful information for vector control and host symbiont coevolution. Further study is needed to investigate the potential for arbovirus infection and disease transmission in the emerged cryptic species. PMID- 29618382 TI - Hyperparasitaemia during clinical malaria episodes in infants aged 0-24 months and its association with in utero exposure to Plasmodium falciparum. AB - OBJECTIVE: Existing information has shown that infants who are prenatally exposed to P. falciparum are susceptible to subsequent malaria infections. However, the effect of prenatal exposure to P. falciparum on parasite density during clinical malaria episodes has not been fully elucidated. This study is a component of a prospective cohort study for which initial results have been published. This component was designed to determine the effect of prenatal exposure to P. falciparum on parasite density during clinical malaria episodes in the first 24 months of life. A total of 215 infants were involved and monitored for clinical malaria episodes defined by fever (>= 37 degrees C) and parasitaemia. The geometric mean parasite counts between exposed and unexposed infants were compared using independent samples t test. The effect of in utero exposure to P. falciparum on parasite density was assessed using binary logistic regression. RESULTS: The geometric mean parasite count per ul of blood during clinical malaria episodes in exposed infants was 24,889 (95% CI 18,286-31,490) while in unexposed infants it was 14,035 (95% CI 12,111-15,960), P < 0.05. Prenatal exposure to P. falciparum was associated with hyperparasitaemia during clinical malaria episodes (OR 7.04, 95% CI 2.31-21.74), while other factors were not significantly associated (P > 0.05). PMID- 29618383 TI - High-efficiency promoter-driven coordinated regulation of multiple metabolic nodes elevates lipid accumulation in the model microalga Phaeodactylum tricornutum. AB - BACKGROUND: Microalgal metabolic engineering holds great promise for the overproduction of a wide range of commercial bioproducts. It demands simultaneous manipulation of multiple metabolic nodes. However, high-efficiency promoters have been lacking. RESULTS: Here we report a strong constitutive promoter Pt211 in expressing multiple target genes in oleaginous microalga Phaeodactylum tricornutum. Pt211 was revealed to contain significant cis-acting elements. GUS reporter and principal genes glycerol-3-phosphate acyltransferase (GPAT) and diacylglycerol acyltransferase 2 (DGAT2) involved in triacylglycerol biosynthesis were tested under driven of Pt211 in P. tricornutum. GUS staining and qPCR analysis showed strong GUS expression. DGAT2 and GPAT linked with a designed 2A sequence exhibited higher transcript abundances than WT, while algal growth and photosynthesis were not impaired. CONCLUSION: The total lipid content increased notably by 2.6-fold compared to WT and reached up to 57.5% (dry cell weight). Overall, our findings report a strong promoter and a strategy for coordinated manipulation of complex metabolic pathways. PMID- 29618384 TI - Self-reported domain-specific and accelerometer-based physical activity and sedentary behaviour in relation to psychological distress among an urban Asian population. AB - BACKGROUND: The interpretation of previous studies on the association of physical activity and sedentary behaviour with psychological health is limited by the use of mostly self-reported physical activity and sedentary behaviour, and a focus on Western populations. We aimed to explore the association of self-reported and devise-based measures of physical activity and sedentary behaviour domains on psychological distress in an urban multi-ethnic Asian population. METHODS: From a population-based cross-sectional study of adults aged 18-79 years, data were used from an overall sample (n = 2653) with complete self-reported total physical activity/sedentary behaviour and domain-specific physical activity data, and a subsample (n = 703) with self-reported domain-specific sedentary behaviour and accelerometry data. Physical activity and sedentary behaviour data were collected using the Global Physical Activity Questionnaire (GPAQ), a domain-specific sedentary behaviour questionnaire and accelerometers. The Kessler Screening Scale (K6) and General Health Questionnaire (GHQ-12) were used to assess psychological distress. Logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals, adjusted for socio-demographic and lifestyle characteristics. RESULTS: The sample comprised 45.0% men (median age = 45.0 years). The prevalence of psychological distress based on the K6 and GHQ-12 was 8.4% and 21.7%, respectively. In the adjusted model, higher levels of self reported moderate-to-vigorous physical activity (MVPA) were associated with significantly higher odds for K6 (OR = 1.47 [1.03-2.10]; p-trend = 0.03) but not GHQ-12 (OR = 0.97 [0.77-1.23]; p-trend = 0.79), when comparing the highest with the lowest tertile. Accelerometry-assessed MVPA was not significantly associated with K6 (p-trend = 0.50) nor GHQ-12 (p-trend = 0.74). The highest tertile of leisure-time physical activity, but not work- or transport-domain activity, was associated with less psychological distress using K6 (OR = 0.65 [0.43-0.97]; p trend = 0.02) and GHQ-12 (OR = 0.72 [0.55-0.93]; p-trend = 0.01). Self-reported sedentary behaviour was not associated with K6 (p-trend = 0.90) and GHQ-12 (p trend = 0.33). The highest tertile of accelerometry-assessed sedentary behaviour was associated with significantly higher odds for K6 (OR = 1.93 [1.00-3.75]; p trend = 0.04), but not GHQ-12 (OR = 1.34 [0.86-2.08]; p-trend = 0.18). CONCLUSIONS: Higher levels of leisure-time physical activity and lower levels of accelerometer-based sedentary behaviour were associated with lower psychological distress. This study underscores the importance of assessing accelerometer-based and domain-specific activity in relation to mental health, instead of solely focusing on total volume of activity. PMID- 29618385 TI - Endoscopic management of maxillary sinus inverted papilloma attachment sites to minimize disease recurrence. AB - BACKGROUND: Inverted papillomas (IPs) are benign neoplasms, most commonly arising from the mucosal lining of the maxillary sinus. IPs can have single or multifocal sites of attachment. Although pedicle location is an important factor to consider in surgical planning, it is less clear whether the location or number of IP attachment sites hold any prognostic value. Herein, we aimed to determine the prognostic significance of the number and location of attachment sites of IPs originating from the maxillary sinus when managed by a pure endoscopic approach. METHODS: This was a single-center, single-surgeon retrospective chart review. Patients with maxillary sinus IPs who were managed by endoscopic approaches only, from January 1, 2010 to June 30, 2016, were identified. Demographic data, operative technique, number and location of IP attachment sites, follow-up duration, recurrence, and presence of malignant transformation were captured. RESULTS: Twenty-eight maxillary IP patients (61% males) were included, with a mean age of 54.9 (standard deviation (SD): 16.5) years. Approximately 36% of patients were referred from other institutions for management of recurrent IPs after failing previous surgical treatment. All patients were managed with an endoscopic approach, and all required an endoscopic medial maxillectomy to facilitate access to the maxillary sinus. At a mean follow-up of 31.1 (SD: 22.6) months, there were no recurrences identified. IPs with single (46%) and multifocal (54%) attachments were predominately to the medial and lateral walls. Maxillary IPs with multifocal attachments most frequently involved 2-3 walls of the sinus. Osteitis (36%) was commonly seen. CONCLUSION: IPs originating from the maxillary sinus frequently had multifocal attachments, but this did not impact disease recurrence. Despite the surgical challenges of accessing all of the maxillary sinus walls, IPs originating from the maxillary sinus can be effectively managed via a pure endoscopic approach. PMID- 29618388 TI - Psychotic traits in musicians. AB - The association of music with madness is very longstanding. But is it more than myth, and if so what is the nature of this relationship? We tested the hypotheses that musicians possess greater schizotypy and symptoms of bipolar disorder. A total of 102 musicians were found to have greater positive and negative schizotypal traits when compared to matched norms on the shortened Oxford Liverpool Inventory of Feelings and Experiences. Based on the Mood Disorder Questionnaire, 10.8% of musicians also met criteria for lifetime bipolar disorder. Rock musicians appeared to have greater symptoms than those performing in other musical genres. PMID- 29618389 TI - Barriers and Facilitators for Guidelines with Depression and Anxiety in Parkinson's Disease or Dementia. AB - ABSTRACTOur primary objective was to understand the barriers and facilitators associated with the implementation of high-quality clinical practice guidelines (CPGs) for depression and anxiety in patients with dementia or Parkinson's disease (PD). We conducted focus groups or interviews with participants experiencing dementia or PD, their caregivers, and physicians in Calgary, Alberta, and applied the theoretical domains framework and behaviour change wheel to guide data collection and perform a framework analysis. Thirty-three physicians and seven PD patients/caregivers participated. We report barriers and facilitators to the implementation of guideline recommendations for diagnosis, management, and the use of the guidelines. An overarching theme was the lack of evidence for depression or anxiety disorders in dementia or PD, which was prominent for anxiety versus depression. Patients noted difficulties with communicating symptoms and accessing services. Although guidelines are available, physicians have difficulty implementing certain recommendations due primarily to a lack of evidence regarding efficacy. PMID- 29618387 TI - Deregulation of the spindle assembly checkpoint is associated with paclitaxel resistance in ovarian cancer. AB - BACKGROUND: Ovarian cancer is the leading gynecologic cancer diagnosed in North America and because related symptoms are not disease specific, this often leads to late detection, an advanced disease state, and the need for chemotherapy. Ovarian cancer is frequently sensitive to chemotherapy at diagnosis but rapid development of drug resistance leads to disease progression and ultimately death in the majority of patients. RESULTS: We have generated paclitaxel resistant ovarian cell lines from their corresponding native cell lines to determine driver mechanisms of drug resistance using gene expression arrays. These paclitaxel resistant ovarian cells demonstrate: (1) Increased IC50 for paclitaxel and docetaxel (10 to 75-fold) and cross-resistance to anthracyclines (2) Reduced cell apoptosis in the presence of paclitaxel (3) Gene depletion involving mitotic regulators BUB1 mitotic checkpoint serine/threonine kinase, cyclin BI (CCNB1), centromere protein E (CENPE), and centromere protein F (CENPF), and (4) Functional data validating gene depletion among mitotic regulators. CONCLUSIONS: We have generated model systems to explore drug resistance in ovarian cancer, which have revealed a key pathway related to the spindle assembly checkpoint underlying paclitaxel resistance in ovarian cell lines. PMID- 29618386 TI - LncRNAs regulate the cytoskeleton and related Rho/ROCK signaling in cancer metastasis. AB - Some of the key steps in cancer metastasis are the migration and invasion of tumor cells; these processes require rearrangement of the cytoskeleton. Actin filaments, microtubules, and intermediate filaments involved in the formation of cytoskeletal structures, such as stress fibers and pseudopodia, promote the invasion and metastasis of tumor cells. Therefore, it is important to explore the mechanisms underlying cytoskeletal regulation. The ras homolog family (Rho) and Rho-associated coiled-coil containing protein serine/threonine kinase (ROCK) signaling pathway is involved in the regulation of the cytoskeleton. Moreover, long noncoding RNAs (lncRNAs) have essential roles in tumor migration and guide gene regulation during cancer progression. LncRNAs can regulate the cytoskeleton directly or may influence the cytoskeleton via Rho/ROCK signaling during tumor migration. In this review, we focus on the regulatory association between lncRNAs and the cytoskeleton and discuss the pathways and mechanisms involved in the regulation of cancer metastasis. PMID- 29618390 TI - On the Origin of Extended Resolution in Kelvin Probe Force Microscopy with a Worn Tip Apex. AB - In this work we analyzed the effect of the atomic force microscopy probe tip apex shape on Kelvin Probe Force Microscopy (KPFM) potential sensitivity and spatial resolution. It was found that modification of the apex shape from spherical to planar upon thinning of the conductive coating leads to enhanced apex contribution to the total electrostatic force between the probe and the sample. The effect results in extended potential sensitivity and spatial resolution of KPFM. Experimental results were supported by calculations. PMID- 29618391 TI - Provider payment to primary care physicians in China: background, challenges, and a reform framework. AB - AIM: To provide a framework for provider payment reform for primary care physicians in China. BACKGROUND: Primary health care is central to health system reform and payment incentives have significant consequences for the equity and efficiency of it. METHODS: This paper describes the special payments system for public primary health institutions and the subsequent internal salary remuneration to primary care physicians in China. Based on an analysis of the major challenges, we suggest a reform framework including the pattern of governance, and payments to primary health institutions and employed physicians. FINDINGS: A mixed system of input-based and output-based payments to institutions would probably be appropriate under a long-term and relational contract with the government. It was also advised that internal remuneration is provided by a basic salary plus a bonus based on performance, and an extra-regional allowance. We hope that the results can be used to shift the passive budgeting of in-house staff within the public primary health institutions toward strategic purchasing. PMID- 29618392 TI - Peer support for mental illness in India: an underutilised resource. PMID- 29618393 TI - Review: Genomics of bull fertility. AB - Fertility is one of the most economically important traits in both beef and dairy cattle production; however, only female fertility is typically subjected to selection. Male and female fertility have only a small positive genetic correlation which is likely due to the existence of a relatively small number of genetic variants within each breed that cause embryonic and developmental losses. Genomic tools have been developed that allow the identification of lethal recessive loci based upon marker haplotypes. Selection against haplotypes harbouring lethal alleles in conjunction with selection to improve female fertility will result in an improvement in male fertility. Genomic selection has resulted in a two to fourfold increase in the rate of genetic improvement of most dairy traits in US Holstein cattle, including female fertility. Considering the rapidly increasing rate of adoption of high-throughput single nucleotide polymorphism genotyping in both the US dairy and beef industries, genomic selection should be the most effective of all currently available approaches to improve male fertility. However, male fertility phenotypes are not routinely recorded in natural service mating systems and when artificial insemination is used, semen doses may be titrated to lower post-thaw progressively motile sperm numbers for high-merit and high-demand bulls. Standardization of sperm dosages across bull studs for semen distributed from young bulls would allow the capture of sire conception rate phenotypes for young bulls that could be used to generate predictions of genetic merit for male fertility in both males and females. These data would allow genomic selection to be implemented for male fertility in addition to female fertility within the US dairy industry. While the rate of use of artificial insemination is much lower within the US beef industry, the adoption of sexed semen in the dairy industry has allowed dairy herds to select cows from which heifer replacements are produced and cows that are used to produce terminal crossbred bull calves sired by beef breed bulls. Capture of sire conception rate phenotypes in dairy herds utilizing sexed semen will contribute data enabling genomic selection for male fertility in beef cattle breeds. As the commercial sector of the beef industry increasingly adopts fixed-time artificial insemination, sire conception rate phenotypes can be captured to facilitate the development of estimates of genetic merit for male fertility within US beef breeds. PMID- 29618395 TI - Novel Indicators for Enhancing the Clinical Outcome Metrics of Antimicrobial Stewardship Programs. PMID- 29618394 TI - Comparison of Predictors and Mortality Between Bloodstream Infections Caused by ESBL-Producing Escherichia coli and ESBL-Producing Klebsiella pneumoniae. AB - OBJECTIVETo compare the epidemiology, clinical characteristics, and mortality of patients with bloodstream infections (BSI) caused by extended-spectrum beta lactamase (ESBL)-producing Escherichia coli (ESBL-EC) versus ESBL-producing Klebsiella pneumoniae (ESBL-KP) and to examine the differences in clinical characteristics and outcome between BSIs caused by isolates with CTX-M versus other ESBL genotypesMETHODSAs part of the INCREMENT project, 33 tertiary hospitals in 12 countries retrospectively collected data on adult patients diagnosed with ESBL-EC BSI or ESBL-KP BSI between 2004 and 2013. Risk factors for ESBL-EC versus ESBL-KP BSI and for 30-day mortality were examined by bivariate analysis followed by multivariable logistic regression.RESULTSThe study included 909 patients: 687 with ESBL-EC BSI and 222 with ESBL-KP BSI. ESBL genotype by polymerase chain reaction amplification of 286 isolates was available. ESBL-KP BSI was associated with intensive care unit admission, cardiovascular and neurological comorbidities, length of stay to bacteremia >14 days from admission, and a nonurinary source. Overall, 30-day mortality was significantly higher in patients with ESBL-KP BSI than ESBL-EC BSI (33.7% vs 17.4%; odds ratio, 1.64; P=.016). CTX-M was the most prevalent ESBL subtype identified (218 of 286 polymerase chain reaction-tested isolates, 76%). No differences in clinical characteristics or in mortality between CTX-M and non-CTX-M ESBLs were detected.CONCLUSIONSClinical characteristics and risk of mortality differ significantly between ESBL-EC and ESBL-KP BSI. Therefore, all ESBL-producing Enterobacteriaceae should not be considered a homogeneous group. No differences in outcomes between genotypes were detected.CLINICAL TRIALS IDENTIFIERClinicalTrials.gov. Identifier: NCT01764490.Infect Control Hosp Epidemiol 2018;39:660-667. PMID- 29618396 TI - Corticosteroids for a sore throat. AB - Article chosenHayward GN, Hay AD, Moore MV, et al. Effect of oral dexamethasone without immediate antibiotics vs. placebo on acute sore throats in adults: a randomized clinical trial. JAMA 2017;317(15):1535-43. PMID- 29618397 TI - Nursing Home Physicians Discuss Caring for Elderly Residents: An Exploratory Study. AB - ABSTRACTDespite the increasing complexity of nursing home care, the role of physicians caring for residents is largely unexplored. This international, exploratory study sought to learn about physicians' roles, responsibilities, and tasks as well as investigate the unique qualities of medical practice in nursing homes. We conducted interviews with 18 physicians, who reported making important contributions to the quality of resident care, including clarifying the goals of care, working to reduce unnecessary medication and hospitalization, as well as contributing to staff education. Nursing home practice involved physicians in networks of relations that were instrumental to the quality of medical care and physicians' job satisfaction. The importance of these relationships disrupts the oft-drawn boundary between the medical and the social, suggesting that good medical practice depends on good social practice. Reflecting the exploratory nature of the study, we recommend research to better understand and support the relational dimensions of nursing home medicine. PMID- 29618398 TI - A Simple Vortex-Assisted Magnetic Dispersive Solid Phase Microextraction System for Preconcentration and Separation of Triazine Herbicides from Environmental Water and Vegetable Samples Using Fe3O4@MIL-100(Fe) Sorbent. AB - A vortex-assisted magnetic dispersive solid phase microextraction coupled with high-performance liquid chromatography has been developed for the extraction and determination of triazine herbicides by using magnetic metal organic frameworks [Fe3O4@MIL-100(Fe)] in environmental water and vegetable samples. The Fe3O4@MIL 100(Fe) composite has been characterized by using X-ray diffraction spectroscopy, tunneling electron microscopy, thermogravimetric measurement, and Brunauer-Emmett Teller analysis. The method is based on the sorption of triazine herbicides on Fe3O4@MIL-100(Fe) because of the complex formation between iron oxide nanoparticles and triazine herbicides beside pi-pi interactions between organic parts of Fe3O4@MIL-100(Fe) and triazine herbicides. The experimental parameters for the preconcentration of triazine herbicides, such as the type and volume of the eluent, pH, time of the sorption and desorption, and the amount of the sorbent, were optimized. Under the optimized conditions, the method was linear over the concentration range of 0.0061 to 70 ng/mL for each triazine herbicide, and the correlation coefficients ranged from 0.9988 to 0.9997. The limit of detection of the method at a signal-to-noise ratio of 3 was 2.0 to 5.3 ng/mL. The relative standard deviations for inter- and intraday assays were in the range of 5.8 to 10.2% and 3.8 to 6.3%, respectively. PMID- 29618399 TI - The Validation of the RIDA(r)QUICK Gliadin for AOAC Research Institute. AB - RIDA(r)QUICK Gliadin is an immuno-chromatographic test for the detection of gluten in foods, on surfaces, and in Cleaning-in-Place (CIP) waters. This test kit has been adopted as Final Action AOAC INTERNATIONAL Official Methods of AnalysisSM 2015.16 for gluten in corn products. The assay is based on the monoclonal antibody R5, which recognizes gluten in wheat, barley, and rye. Four different surfaces were contaminated with a gliadin material and analyzed by a direct swabbing of the surface with the dip-stick. The outcome was an LOD95% concentration of the assay between 1.6 and 3.0 MUg/100 cm2 gluten. For CIP waters that contain cleansing reagents, 100% positive results were obtained for minimum gluten concentration between 50 and 100 ng/mL. If the CIP water does not contain these reagents, the minimum detectable gluten level is 10 ng/mL. The independent validation study consisted of a method comparison study of recovery from a CIP solution and from a stainless-steel surface. The test kit was evaluated at six different concentration levels for both matrices, with 20 or 30 replicates per concentration level. The probability of detection was calculated for each contamination level. Additionally, the LOD95% concentration was estimated for each matrix analyzed. PMID- 29618400 TI - Studies on Antimicrobial Activity and Kinetics of Inhibition by Plant Products in India (1990-2016). AB - The antimicrobial activity of herbal extracts or plant isolates has usually been evaluated in India using different antimicrobial susceptibility testing methods generally based on diffusion and dilution. There are different analytical approaches for the reliable evaluation of antimicrobial activity ascribed to medicinal plants against selected pathogenic microorganisms. Obtained results may provide scientific bases for the selective use of these natural plants as healing drugs, crop-protecting pesticides, or shelf-life-extending solutions. In general, antimicrobial susceptibility methodologies involve in vivo and in vitro studies; at present, the in vitro evaluation of antibacterial activity appears more popular. Diffusion methods have some limitations, although they are extensively used to determine the susceptibility of organisms isolated from specimen samples to applied antimicrobials and vice versa. Dilution methods are preferred in the case of more precise antimicrobial activity estimation, in terms of minimum inhibitory concentration. With regard to the inherent antimicrobial nature of herbal compositions, herbs, and herbal extracts, Indian researchers have evaluated the reliability of these antimicrobial agents against selected pathogens and have shown them to be effective. Researchers have also tried to establish linear regression correlation analyses on the basis of available inhibition results. This research is still evolving, and interesting results may be expected in the future. PMID- 29618401 TI - A Novel Genetic Determination of a Lectin Gene in Iraqi Acinetobacter baumannii Isolates and Use of Purified Lectin as an Antibiofilm Agent. AB - BACKGROUND: Lectin was initially called hemagglutinin or agglutinin because of its capacity to agglutinate human as well as human erythrocytes. They are a heterogeneous group of proteins or glycoproteins of nonimmune origin. Because of their chemical properties, they have become a useful tool in several fields such as immunology, cell biology, molecular biology, membrane structure, pharmacology, cancer research, clinical chemistry, and genetic engineering. OBJECTIVE: The wide applications of lectins users urged the need to isolate lectins from a new strain of bacteria can produce new and high yield of lectin because the current production of lectin from Pseudomonas spp. is very expensive. The goal of this study was to screen the ability of Acinetobacter baumannii isolates to produce lectin and detection of its phenotypic and genotypic profiles and detection of lectin ability to inhibit ofbiofilm formation. METHODS: Fifty-one isolates from different sources were collected and detected genetically by using the recA gene. Phenotypic detection of lectin by using semi-quantitative analysis and quantitative analysis in microtiter plate. Genotypic detection of lectin by designed lec gene and used PCR technique. The lectin was extracted by using glass beads and purified by chromatographyic technique followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis for determination the molecular size of lectin and finally detection the spectrum of biofilm inhibition by the purified lectin toward biofilm producers. RESULTS: Of 51 A. baumannii isolates, 17 (33.3%) have been found to produce lectin. Ten of 17 were sequenced, of which 2 were submitted and tested by the gene bank National Center for Biotechnology Information (NCBI), and accession numbers (KX766405.1 and KX766406.1) were obtained. These 17 isolates were phenotypically and genotypically positive for lectin and showed different lec gene expression in semi-quantitative and quantitative analysis. The activities ranged between 4-128 U/mL. Lectin purified by ammonium sulfate precipitation was used to inhibit biofilm formation. We found reduction at three different types of bacteria ranging from 26% for Klebsiella pneumonia, 46.7% for P. stutzeri and 53% for A. baumannii. These results suggested that lectin has a promising application as an antibiofilm agent to combat the growing number of multidrug-resistant pathogen-associated infections. CONCLUSIONS: Lectin has been detected recently in A. baumannii, but the genetic property of this lectin has not yet been fully studied. In our study, we determined the presence of the lectin gene (lec gene) in A. baumannii by using PCR technique, and lec PCR products were identified with various source of isolation and sequenced to screening for epidemiology and submitted to the gene bank NCBI under accession number (KX766405.1 and KX766406.1). HIGHLIGHTS: A. baumannii has an ability to produce lectin protein; Lec gene was detected in A. baumannii, and the sequence was recorded under accession number KX766405.1 and KX766406.1.; Lectin was extracted by glass beads and purified by chromatographyic technique; Lectin had strong effect against biofilm formation. PMID- 29618402 TI - Evaluation of the iQ-Check(r)Salmonella II Assay in Select Foods: Collaborative Study, First Action 2017.06. AB - The iQ-Check Salmonella II Real-Time PCR test kit utilizes Salmonella-specific oligonucleotide probes and primers for the rapid and specific detection of Salmonella species in select food types. The alternative method was evaluated by using 375 g test portions in an unpaired study design for two matrices, milk chocolate and dry dog food. Each matrix was compared with the U.S. Food and Drug Administration Chapter 5 Salmonella reference method. Fourteen technicians from 12 laboratories, including academia and industry, located within the United States and Canada participated in the collaborative study. Three levels of contamination were evaluated for each matrix: an uninoculated control level (0 CFU/test portion), a low inoculum level (0.2-2 CFU/test portion), and a high inoculum level (2-5 CFU/test portion). The statistical analysis was conducted according to the Probability of Detection (POD) statistical model. The results obtained for the low inoculum level test portions produced a difference in the candidate presumptive and confirmatory results (dLPOD) value with a 95% confidence interval of -0.05, (-0.15, 0.06) for the milk chocolate and 0.10, ( 0.01, 0.21) for the dry dog food. The dLPOD results indicate an equivalence between the candidate method and reference method for the matrices evaluated, and the method demonstrated acceptable interlaboratory reproducibility as determined in the collaborative evaluation. False positive and false negative rates were determined for each matrix and produce values of <2%. Based on the data generated, the method demonstrated acceptable interlaboratory reproducibility data and statistical analysis. PMID- 29618403 TI - Determination of Ethanol in Kombucha, Juices, and Alcohol-Free Beer by EnzytecTMLiquid Ethanol: Single-Laboratory Validation, First Action 2017.07. AB - EnzytecTM Liquid Ethanol is an enzymatic test for the determination of ethanol in kombucha, juices, and alcohol-free beer. The kit contains two components in a ready-to-use format. Quantification is based on the catalytic activity of alcohol dehydrogenase, which oxidizes ethanol to acetaldehyde and converts NAD+ to NADH. Measurement is performed in 3 mL cuvettes at 340 nm within 20 min. Samples with alcohol contents around 0.5% alcohol by volume need to be diluted 1:20 or 1:50 with water before measurement. Acetaldehyde interferes at concentrations higher than 3000 mg/L, whereas sulfite interferes at concentrations higher than 300 mg/L. The linear measurement range is from 0.03 up to 0.5 g/L ethanol, whereas LOD and LOQ are 1.9 and 3.3 mg/L ethanol, respectively. Kombucha with concentrations between 2.85 and 5.82 g/L showed relative repeatability standard deviation around 1%, whereas juices were below 2%. Results from a reproducibility experiment revealed that at a concentration of 0.1 g/L, the RSDR was at 2.5%, whereas at higher concentrations between 0.2 and 0.3 g/L, coefficients around 1% were obtained. Trueness was checked by using Cerilliant aqueous ethanol solutions and beer with concentration of 0.4 and 4 g/L (BCR-651 and BCR-652). Spiking of kombucha and juice samples resulted in recoveries between 95% and 104%. Acceptable stability was found for the whole test kit under accelerated conditions at 37 degrees C for 2 weeks. The kit is also not susceptible to short freezing-thawing cycles and harsh transport conditions. PMID- 29618404 TI - Antimicrobial Substances for Food Packaging Products: The Current Situation. AB - Antimicrobial substances are widely used in many anthropic activities, including sanitary and military services for the human population. These compounds are also known to be used in food production, agricultural activities, and partially correlated industrial sectors. However, there are concerns regarding the link between the abuse of antimicrobial agents in these ambits and the possible detection of antibiotic-resistant microorganisms. Modern food and beverage products are generally found on the market as prepackaged units, with several exceptions. Consequently, positive and negative features of a specific food or beverage should be considered as the result of the synergic action of different components, including the container (or the assembled sum of packaging materials). At present, the meaning of food container also includes the creation and development of new packaging materials that are potentially able to interact with the contained food. "Active" packaging systems can be realized with antimicrobial substances. On the other hand, a careful evaluation of risks and advantages correlated with antimicrobial agents is needed because of possible negative and/or unexpected failures. PMID- 29618406 TI - Direct Comparison of Cavity Ring Down Spectrometry and Isotope Ratio Mass Spectrometry for Detection of Sugar Adulteration in Honey Samples. AB - In the last several years, economically motivated adulteration (EMA) of foods including honey has received increased attention. The addition of inexpensive sweeteners such as high fructose corn syrup or cane sugar to honey is still encountered despite scientific methods that can routinely detect this type of adulteration. The standard method for detection of these adulterants utilizes isotope ratio mass spectrometry (IRMS); however, this technique requires an elevated degree of technical knowledge for operation as well as a high cost for purchase and maintenance. Cavity ring down spectroscopy (CRDS) has demonstrated potential for this type of analysis and is less expensive with simpler operation. This study evaluates CRDS for the detection of low-cost sweeteners added to honey and compares the performance of CRDS to IRMS. Several honey samples were analyzed, and the advantages and limitations specific to CRDS were evaluated. Overall, the results indicate that CRDS provides a performance comparable to the benchmark technique IRMS for EMA honey analysis. PMID- 29618405 TI - The Validation of the Sample6 DETECTTM HT/L for AOAC Research Institute. AB - BACKGROUND: Listeria spp. are an important foodborne human pathogen because of their ability to cause disease and high mortality in individuals, particularly pregnant women, neonates, the elderly, immunocompromised individuals, and children. The Sample6 DETECTTM HT/L Kit is a semi-automated qualitative pathogen detection system designed to detect Listeria spp. (L. monocytogenes, L. innocua, L. ivanovii, L. seeligeri, L. welshimeri, and L. marthii) in environmental samples using the Sample6 BioIlluminationTM technology. OBJECTIVE: The study was done to evaluate the Sample6 DETECT HT/L Kit. The assay was evaluated for inclusivity, exclusivity, robustness, product consistency, and stability, and a matrix study of one environmental surface. METHODS: The performance of the Sample6 DETECT HT/L was compared with U.S. Food and Drug Administration reference culture method for Listeria using an unpaired study design. RESULTS: The Sample6 DETECT HT/L assay correctly identified all 50 inclusivity isolates and correctly excluded all 30 nontarget strains evaluated. The assay was not affected by minor variations in incubation temperature and time, or sample volume. Results across three production lots spanning the shelf life of the assay were consistent. In the matrix study, the Sample6 DETECT HT/L for Listeria correctly identified each test portion for the presence or absence of Listeria, and there were no statistically significant differences between candidate and reference method results. CONCLUSIONS: The data collected in this study demonstrate that the Sample6 DETECT HT/L assay is a reliable method for the detection of Listeria spp. on stainless-steel environmental surfaces after 22 h of enrichment. PMID- 29618407 TI - Enhanced Methane Yield by Codigestion of Sewage Sludge with Microalgae and Catering Waste Leachate. AB - The codigestion of different wastes is a promising concept to improve methane generation during anaerobic processes. However, the anaerobic codigestion of catering waste leachate with algal biomass and sewage sludge has not been studied to date. The present study investigated methane generation by the anaerobic codigestion of different mixtures of catering waste leachate, microalgal biomass, and sewage sludge. Codigestion of waste mixture containing equal ratios of three substrates had 39.31% higher methane yield than anaerobic digestion of raw sludge. This was possibly because of a proliferation of methanogens during the codigestion period, induced by multiphase digestion of different wastes with different degrees of digestibility. Therefore, codigestion of catering waste leachate, microalgal biomass, and sewage sludge appears to be an efficient technology for energy conversion from waste resources. The scientific application of this codigestion technology with these three substrates may play a role in solving important environmental issues of waste management. PMID- 29618408 TI - ? AB - This is a review of cognitive abilities in major depression, which is associated with attention problems, memory deficit and wide impairment in executive functions. Depressed patients show two major cognitive biases: excessive processing of negatively valenced emotional stimuli; and increased self-focus. Both of these biases help to facilitate the integration of negative self-related information in depressed patients and to maintain their negative mood. Brain imaging studies suggest that this cognitive impairment is characterized by abnormal cooperation between the cognitive and limbic networks involved in cognitive control and self-referential processing. In general, depression is a disorder of multiple networks with emotional, cognitive and emotional symptoms. Among these symptoms, cognition is a major determinant of functional and social outcomes. PMID- 29618409 TI - [Acute severe colitis]. AB - Acute severe colitis is a potentially life-threatening medical and surgical emergency requiring hospitalization and intensive monitoring. The diagnosis of severe acute colitis is based on clinical and biological criteria. Colectomy should be discussed at each stage of management and is indicated immediately in case of complications. Thromboembolic prevention with low molecular weight heparin is essential in any patient with severe acute colitis. The first-line medical treatment is intravenous corticosteroid at a dose of 0.8mg/kg/day of prednisone equivalent. In case of failure, a second line of medical treatment can be attempted in the absence of complications. The two possible treatments are infliximab and ciclosporin. PMID- 29618410 TI - [Long term outcomes after bariatric and metabolic surgery]. AB - At long (=5 years) and very long term (=10 years) bariatric and metabolic surgery (BMS) is the only treatment that allows a significant and durable weight loss concomitant with a control of the different obesity related diseases. Regardless of the surgical technique, BMS significantly decrease long-term mortality (-30% at 15 years). The maximum weight loss is reached at postoperative year 2. Beyond, a weight regain and is usually observed in all procedures. The variability of long-term outcomes underlines the importance of multidisciplinary care throughout follow-up. In 2017, Roux-en-Y-gastric bypass and sleeve gastrectomy were the most popular bariatric procedures and seem to have comparable long-term outcomes. PMID- 29618411 TI - An appeal from fellows. PMID- 29618413 TI - Telomere length and early trauma in schizophrenia. AB - BACKGROUND: Childhood trauma is emerging as a risk factor for schizophrenia, but its mechanism with respect to etiology is unknown. One possible pathway is through leucocyte telomere length (LTL) shortening, a measure of cellular aging associated with trauma. This study examined early trauma and LTL shortening in schizophrenia and considered sex effects. METHODS: The early trauma inventory (ETI) was administered to 48 adults with DSM-5 schizophrenia and 18 comparison participants. LTL was measured using qPCR. OUTCOMES: Cases had significantly more global trauma (F=4.10, p<0.01) and traumatic events (F=11.23, p<0.001), but case and control groups had similar LTL (1.91+/-0.74 and 1.83+/-0.62: p=0.68). The association of early trauma and LTL differed by sex in cases and controls (Fisher's R: Z<0.05). Significant negative associations were shown in male cases and, conversely, in female controls. For example, physical punishment was associated LTL shortening in males' cases (r=-0.429, p<01). Only female controls showed significant telomere shortening in association with early trauma. INTERPRETATION: This data confirms the substantial excess of early trauma among schizophrenia cases. There were significant sex-differences in the relationship of the trauma to LTL, with only male cases showing the expected shortening. There were converse sex effects in the control group. Mean LTL was notably similar in cases and controls, despite the trauma-related shortening in male cases, cigarette smoking, older age and chronic illness of the cases. Factors may lengthen LTL in some schizophrenia cases. The converse sex differences in the cases are consistent with findings defective sexual differentiation in schizophrenia, consistent with other findings in the field. PMID- 29618412 TI - Loss of endothelial nitric oxide synthase exacerbates intestinal and lung injury in experimental necrotizing enterocolitis. AB - BACKGROUND: Necrotizing enterocolitis (NEC) continues to be a devastating condition among preterm infants. Nitric oxide, which is synthesized in the intestine by endothelial nitric oxide synthase (eNOS), acts as a potent vasodilator and antioxidant within the mesentery and may play a role in prevention of NEC. We hypothesized that loss of endothelial nitric oxide would worsen both intestinal and associated lung injury and increase local and systemic inflammation during experimental NEC. METHODS: NEC was induced in five-day-old wild type (WT) and eNOS-knockout (eNOSKO) mouse pups. Experimental groups (n=10) were formula fed and subjected to intermittent hypoxic and hypothermic stress, while control groups (n=10) remained with their mother to breastfeed. Pups were monitored by daily clinical assessment. After sacrifice on day nine, intestine and lung were assessed for injury, and cytokines were measured in tissue homogenates by ELISA. Data were compared with Mann-Whitney, and p<0.05 was significant. RESULTS: Each NEC group was compared to its respective strain's breastfed control to facilitate comparisons between the groups. Both NEC groups were significantly sicker than their breastfed controls. eNOSKO NEC animals had a median clinical assessment score of 3 (IQR=1-5), and the WT NEC animal's median score was 3 (IQR=2-5). Despite similar clinical scores, intestinal injury was significantly worse in the eNOSKO NEC groups compared to WT NEC groups (median injury scores of 3.25 (IQR=2.25-3.625) and 2 (IQR=1-3), respectively (p=0.0474). Associated lung injury was significantly worse in the eNOSKO NEC group as compared to the WT NEC group (median scores of 8.5 (IQR=6.75-11.25) and 6.5 (IQR=5-7.5), respectively, p=0.0391). Interestingly, cytokines in both tissues were very different between the two groups, with varying effects noted for each cytokine (IL-6, IL-1beta, VEGF, and IL-12) in both tissues. CONCLUSION: Nitric oxide from eNOS plays a key role in preventing the development of NEC. Without eNOS function, both intestinal and lung injuries are more severe, and the inflammatory cascade is significantly altered. Further studies are needed to determine how eNOS-derived nitric oxide facilitates these beneficial effects. PMID- 29618414 TI - Systematic review of economic evaluations of the 23-valent pneumococcal polysaccharide vaccine (PPV23) in individuals 60 years of age or older. AB - OBJECTIVES: To systematically review the economic evaluations of 23-valent pneumococcal polysaccharide vaccine (PPV23) in adults aged >=60 years to inform the development of local studies through the discussion of parameters and assumptions that influence the results of the analyses. METHODS: We searched the MEDLINE, Excerpta Medica, Cochrane Library, Latin-American and Caribbean Health Sciences Literature (LILACS), Brazilian Regional Library of Medicine, National Health Service Economic Evaluation, and Centre for Reviews and Dissemination-as well as the Scopus citation index and the Web of Science for full economic evaluations of PPV23 published up to March 2016. Two independent reviewers screened the articles for relevance and extracted the data. Main study characteristics and methods (clinical and epidemiological data, cost and incremental cost-effectiveness ratios (ICERs) were extracted and compared. Costs were updated to 2016 international dollars. RESULTS: Twenty-seven studies published from 1980 to 2016 were reviewed. Most studies were conducted in Europe and the USA; three studies were conducted in Latin America (Brazil, 2; Colombia, 1). In addition to the scenario comparing the vaccination with the PPV23 to non vaccination, three studies also compared PPV23 to pneumococcal conjugate 13 valent vaccine (PCV13). All studies used static models. Most used a lifetime (44.4%) or 5-6 year's time horizon (33.3%). Only three studies considered herd protection from children immunization with PCV13 in the model. Most studies considered PPV23 cost-effective (less than US$50,000 per LYG or QALY) and sometimes cost-saving (results ranging from cost-saving to US$84,636/QALY). The estimates of disease burden, the efficacy/effectiveness of PPV23, and the effects of herd protection from childhood immunization had most influence on the results. CONCLUSIONS: Well-designed cost-effectiveness studies of PPV23 that represent the current epidemiological scenario and reduce uncertainty related to efficacy/effectiveness are extremely relevant to informing the decision-making process. PMID- 29618415 TI - The International Reach of Actas Dermo-Sifiliograficas. PMID- 29618416 TI - Thank You, Dr David Netscher. PMID- 29618417 TI - Emerging Strategies on Adjuvant Therapies for Nerve Recovery. AB - Current strategies for promoting faster and more effective peripheral nerve healing have utilized a wide variety of techniques and approaches. Nerve grafts, conduits, and stem cell therapy all have their respective advantages. However, there are still some difficulties in attaining complete functional recovery with a single treatment modality. The utilization of adjuvant treatments, in combination with current standard-of-care methods, offers the potential to improve patient outcomes. This paper highlights the current landscape of adjuvant treatments for enhancing peripheral nerve repair and regeneration. PMID- 29618418 TI - The Retinaculum Flap for Dorsal Fixation of Distal Radius Fractures. AB - In spite of the more popular volar approach for plating of distal radius fractures (DRFs), there are still indications for dorsal plating and even combined dorsovolar plating in complex DRFs. Dorsal plating carries a concern for complications such as tenosynovitis, extensor tendon adhesions, and delayed extensor tendon ruptures. These risks can be minimized by use of modern low profile plates and the use of an extensor retinaculum flap to cover the distal plate and screws. We describe the technique of the dorsal retinaculum flap for dorsal plating of DRFs. PMID- 29618419 TI - Proximal Row Carpectomy Using Decellularized Dermal Allograft. AB - Wrist arthritis is a common problem. When managed early, motion-sparing procedures can be performed with successful outcomes. Proximal row carpectomy (PRC) has demonstrated good functional results and high patient satisfaction with up to 20-year follow-up. The majority of patients with longer follow-up have, however, exhibited radiographic signs of progressive degeneration of the radiocapitate space. Although radiographic changes have not been shown to correlate with wrist pain and function, it remains a concern and questions the durability of the radiocapitate articulation with continued patient follow-up, especially those who underwent the original procedure at a younger age. Several modifications have been proposed and used to address this concern, including radiocapitate arthroplasty, with either distal radius hemiarthroplasty or tissue interposition grafts. Theoretical benefits to these adjuncts include minimizing wear and preserving the radiocapitate articulation as well as expanding the utility of a PRC even in the setting of a wrist with arthritis of the capitate head. We describe our surgical technique for managing radiocarpal arthritis with PRC and decellularized dermal allograft. Dermal matrix allografts have proved to be a safe adjunct in various orthopedic procedures, including those in the wrist and hand. This technique adds another surgical option for the treatment of radiocarpal arthritis and expands the indications for PRC to include select patients with degeneration of the capitate head. PMID- 29618420 TI - More Pain Than Expected After Losing a Finger. PMID- 29618421 TI - Awareness of medication related falls and preferred interventions among the elderly. AB - Falls are a major problem among the elderly and can lead to serious injury. Adults older than 65 years suffer the greatest number of severe falls. This study aims to evaluate the knowledge and perception of medication related falls as well as preferred medication related fall prevention programs in the local population. A cross-sectional survey was conducted among the elderly patients in a tertiary hospital. A total of 86 patients (n=86) were interviewed. Approximately 23.3% (20 patients) of the elderly had a history of falls over the past 6 months. Majority of the elderly considered falls as a major concern (80 patients, 93%) and is preventable (55 patients, 64%). Patients with a medical condition reported a significantly greater number of falls within the past 6 months (p<0.001). Approximately 69% (59 patients) of the elderly were aware of their medication and associated risk of falls. In patients that were unaware of medication associated risk of falls, 81.5% (22 patients) had a potentially inappropriate medication preferred preventive interventions for medication related falls were related to strength and training programs (37 patients, 43%). The knowledge of falls, medication related falls and intervention strategies in the elderly were minimal. PMID- 29618422 TI - Pharmacoeconomic analysis of treatment of patients infected with hepatitis C virus. AB - Hepatitis C infection imposes a high economic burden globally. It has been estimated that in 2012, the healthcare cost of Hepatitis C virus (HCV) was $6.5 billion. Furthermore, it has been projected that the cost will reach at $9.1 billion by the year 2024.Frequency of hepatitis C in Pakistan is significantly higher (4.5%) when compared to the populations like India (0.7%), Nepal (1.0), Myanmar (2.5%), Iran (0.8%), China (1%) and Afghanistan (1.1%). The current standard of care for chronic infection with hepatitis C virus is 24 or 48 weeks of therapy with Pegylated interferon-alfa-2a (Peg INF) +Ribavirin (RV) or Interferon alfa-2a (INF) + RV. The objective of this study was to determine that which combination is more effective and the gain in sustained virologic response (SVR) is worth the incremental cost. In total 84 patients were enrolled who received current standard treatment of care for chronic infection with HCV either 24 or 48 weeks of therapy with Peg INF + RV or INF + RV. A pharmacoeconomic analysis was done including fixed and variable cost (comprising concomitant therapies, emergency visits and hospital admissions) of both treatment regimens were calculated and compared with the SVR accomplished by the patients. It was concluded that the Peg INF + RV is cost effective as compared with conventional INF + RV for the treatment of adult patients infected with HCV genotype 3a under a varied array of possibilities regarding treatment costs and effectiveness. PMID- 29618423 TI - Pharmacological activities of Justicia adhatoda. AB - The current study focused on the pharmacological activities of Justicia adhatoda; including antibacterial, antifungal, phytotoxic, cytotoxic, haemagglutination, insecticidal, in vitro antiglycation, DPPH antioxidant and anti-termite. The crude methanolic extract (Crd. Met. Ext) showed 46.4 % antibacterial activity against M. morganii while the n-hexane fraction showed good (71.4%) and moderate (55.1%) activity against M. morganii and A. baumannii respectively. The EtOAc and aqueous fractions, in most of the cases, showed low to no activity against the selected bacterial pathogens, against A. niger, T. harzianum, A. parasiticus and V. dahliae. The Crd. Met. Ext and fractions showed low activity, against P. notatum and P. digitatum, Crd. Met. Ext. and all fractions were inactive. The percent growth regulation, in case of phytotoxic activity, by Crd. Met. Ext was 25 and 16.6, n-hexane fraction 16.6, 16.6 and 0, CHCl3 25, 8.33 and 0 % and EtOAc fractions 8.33, 8.33 and 0% at 1000 and 100 and 10ug/ml respectively. The aqueous fraction was inactive at all the test concentrations. The results of brine shrimp cytotoxic activity for Crd. Met. Ext was 13.33% and n-hexane fraction 20% at 1000, ug/ml respectively. All of the other fractions showed low to no activity at different test concentrations. All of the test samples were inactive against RBC's of the blood groups at all concentration indicating that the selected plant lack phytolectins and haemagglutination activity. The Crd. Met. Ext and various fraction showed low activity against the test insects i.e. C. pulicaria, C. chinensis and T. castaneum. The absorbance value of plant extract for anti glycation activity at various concentration were: 0.08, 0.067, 0.053 and 0.04 in comparison with Aminoguanidine 0.04, 0.035, 0.03 and 0.02 respectively at 10, 50, 90 and 130MUl. The DPPH radical scavenging activities were proportional to the concentration of the fractions, as the concentration of these increased, the percent scavenging activity also increased. The CHCl3 and EtOAc fractions killed all the termites in 24 hours while Crd. Met. Ext, n-hexane and aqueous fractions took 2-3 days. PMID- 29618424 TI - Formulation of nanoparticles ribosome inactivating proteins from Mirabilis jalapa L. (RIP MJ) conjugated AntiEpCAM antibody using low chain chitosan-pectin and cytotoxic activity against breast cancer cell line. AB - Ribosome Inactivating Proteins (RIPs) isolated from Mirabilis jalapa L. (MJ protein) leaves showed high cytotoxic effect on malignant. Chitosan nanoparticles have frequently been used in protein delivery applications. The aim of this study was to develop targeted drug delivery system of RIP MJ for breast cancer therapy with chitosan nanoparticles conjugated antiEpCAM antibody. RIP MJ nanoparticles were prepared using low viscous chitosan and pectin using polyelectrolit complex method, followed by conjugation process with antiEpCAM antibody. Characterization of this formula was then carried out for its entrapment efficiency, particles size, zeta potential, morphology using transmission electron microscope (TEM) and cytotoxic assay against T47D and Vero cell line. The optimal concentration of MJ protein; low viscous chitosan; pectin for preparing AntiEpCAM conjugated of RIP MJ nanoparticles was 0.1%; 0.01%;1% (m/v) respectively and showed satisfactory formula with the average particle size of 376.8+/-105.2nm, polydispersity index (PI) 0.401, zeta potential 43,71 mV, high entrapment efficiency 98,97+/-0,12%. Transmission electron microscope (TEM) imaging showed a spherical and homogenous structure for nanoparticles. The in vitro cytotoxicity analysis showed that RIP MJ nanoparticle had more cytotoxic effect compared to unformulated RIP against T47D cell-lines. AntiEpCAM conjugated RIP MJ nanoparticles however, increased cytotoxic effect of RIPs on Vero cell-lines not for T47D cell-lines. Chitosan Pectin nanoparticles suitable for delivering protein to target cancer cells. PMID- 29618426 TI - Anticataleptic activity of Zamzam water in chlorpromazine induced animal model of Parkinson disease. AB - Parkinsonism is characterized by rest tremor, inflexibility, balance debilitation, slow motion and dementia. It is known to be caused by the deficiency of dopaminergic neurons in nigrostriatal pathway. Different studies propose that oxidative burden may be included in the apoptotic process in parkisnons disease. Zamzam water being alkaline in composition may diminish the oxidative stress and hence relieve the symptoms. Therefore, the purpose of this study was to explore the neuroprotective effect of zamzam water in chlorpromazine induced animal model of Parkinsonism. Results revealed that zamzam water did not show significant anticataleptic effect after 21 days as compared to chlorpromazine treated group. However, after 30 days of giving zamzam water showed highly significant decrease (p<0.001) in cataleptic score as compared to chlorpromazine treated group that is negative control. After 30 days of dosing, cataleptic scores by zamzam water were closer to standard drug but standard drug (levodopa/carbidopa) still showed better results than zamzam water. Results from histopathological study of rat's brain also revealed regenerative changes by zamzam treated water when compared with negative control. This regenerative change after zamzam water treatment might play a positive role in future if administered continuously. These results also suggest that zamzam water can be used in combination with standard drug to produce synergistic effect in the management of parkinsons disease. PMID- 29618425 TI - Cytotoxic, embryotoxic, insecticidal and anti-microbial activities of standardized Areca catechu nut. AB - The study was aimed at evaluating various biological actions of widely consumed Areca catechu nut. The nut's ethanolic extract exhibited cytotoxicity (lung cancer cell line), embryotoxicity (chick embryo), phytotoxicity (Lemna minor), insecticidal (Rhyzopertha dominica), anti-bacterial (Pseudomonas aeruginosa), anti-fungal (Microsporum canis) and mitogenic (human blood lymphocytes) actions. The standardization results revealed presence of 1.7 MU g arecoline per mg of extract. In conclusion, the Areca nut is endowed with both harmful and beneficial biological actions. Keeping in view its wide consumption and ease of availability, the aforesaid information should be channelized for health and agricultural benefits. PMID- 29618427 TI - Amelioration of methylmercury induced neural damage by essential oil of Selinum vaginatum (Edgew) C. B. Clarke. AB - Methylmercury (MeHg), an organometallic contaminant is a well spotted cause for a series of disorders, especially in the central nervous system. As there is no proper treatment, Selinum vaginatum (Edgew) C. B. Clarke, a traditional medicinal plant, is taken in the present study for assessing its neuroprotective effect against MeHg induced toxicity using rat brain mitochondrial fractions. The results of 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide dye (MTT) assay indicated that there was a reduction in the mitochondrial viability in MeHg treated sample and IC50 value recorded was 2.5ug/ml. Biochemical analysis showed that there was a significant inhibition of glutathione levels (GSH) and catalase activity and an elevation of thiobarbituric acid reactive substances (TBARS) levels in MeHg treated sample. These changes were prevented by co-incubation with essential oil extracted from Selinum vaginatum. The GSH reduction caused by MeHg is restored by essential oil, endorsing its chelating effect, an important molecular mechanism of defense against oxidative injury. Some of the major compounds are detected in Gas chromatography-mass spectrometry (GC-MS) analysis of essential oil, which could be accountable for its neuroprotection against MeHg. PMID- 29618428 TI - Decreased activity of glutathione peroxidase with oral ferrous iron administration: A cause of oxidative stress. AB - Iron deficiency anemia (IDA) during pregnancy not only results in the disturbance of hematological parameters but has been found to be an additional cause of oxidative stress (OS). Moreover, oral iron for IDA during pregnancy has been found to worsen the condition. Present study aims to detect any alteration in glutathione peroxidase (GSH-Px) activity as an enzymatic anti-oxidant and its association with oral iron supplements. For study, 40 anemic pregnant women were prescribed with 200mg ferrous sulphate for 12 weeks (wks). A significant improvement in hemoglobin (Hb) and serum ferritin concentration (SFC) was seen after treatment (p<0.05). In contrast to the values for hematological parameters, GSH-PX was found to be same for control and anemic groups before iron supplements (p>0.05). A significant decrease in GSH-PX levels of anemic women was seen after iron therapy when compared with both the initial values and the control group (p<0.05). We found a positive association between oral iron administration and OS. Our results showed a strong association between oral iron supplements and SFC which supports the iron overload theory. It is therefore concluded that OS is associated with oral iron supplements during pregnancy. PMID- 29618429 TI - Assessing the efficacy of aqueous garlic extract, sodium nitrite and sodium thiosulfate against prolonged oral cyanide exposure in rabbits. AB - This study was aimed to compare the efficacy of aqueous garlic extract, sodium nitrite (SNT), sodium thiosulfate (STS) and hydroxocobalamin against oral cyanide exposure in rabbits. For this purpose, forty two adult male rabbits were divided randomly into 7 groups of 6 animals (A-G) each. Rabbits in group A were offered feed only and served as negative control, while the rabbits in group B received feed plus potassium cyanide (KCN) at 3mg/kg orally and were kept as positive control. Animals in group C received feed, KCN and intraperitoneal injection (IP) of aqueous garlic extract at 500mg/kg. Rabbits in group D were given feed, KCN and IP injection of STS at 600mg/kg. Members in group E received feed, KCN and IP injection of both aqueous garlic extract at 500mg/kg and SNT at 20mg/kg. Animals in group F were given feed, KCN and IP injection of both STS at 600mg/kg and SNT at 20mg/kg, while the rabbits in group G received feed, KCN and IP injection of hydroxocobalamin at 300mg/kg. The treatments were given to respective groups for 40 days. The efficacy of the antidotes was measured on the basis of changes in biochemical profile of rabbits in each group. In this study, hydroxocobalamin was found to be significantly more effective cyanide (CNI) antidote than garlic, STS, SNT plus garlic extract, or SNT and STS, either alone or in combination. A combination of SNT and garlic extract was the second most effective CNI antidote. The efficacy of garlic alone was significantly higher than STS alone or in combination with SNT. The efficacy of combined SNT and STS was superior to STS alone in treating rabbits with CNI toxicity. In conclusion, aqueous garlic extract alone or in combination with STS can effectively be used against cyanide toxicity. PMID- 29618430 TI - Anti-proliferative and anti-inflammatory activities of entophytic Penicillium crustosum from Phoenix dactylifer. AB - Natural sources have been and will remain an inspiration source for modern chemistry. The current study investigates the antiproliferative and anti inflammatory action of the ethyl acetate fraction of Penicillium crustosum from Phoenix dactylifera. This paper reports the isolation of P. crustosum from leaves of P. dactylifera and the antiproliferative activities of ethyl acetate fraction on cancer cells. To reach this goal, the anti-proliferation and cytotoxicity effects were evaluated by MTT and LDH assay respectively. The quantitative real time PCR technique was used to investigate IL-6 and IL-8 gene expression. Our results revealed higher anti-proliferative activity against HepG2 (82MUg/ml) than MCF7 (126MUg/ml) and inhibited the migration of the cell lines. The ethyl acetate fraction significantly altered LDH levels and reduced IL-6 transcript expression on MCF7 cell line but not in HepG2 cell line which could be specific anti inflammatory drug in breast cancer cell line. These results suggest that Phoenix dactylifera extract has a potent anti-proliferative and anti-inflammatory action. Further investigation to isolate the active compounds and mode of action is required. PMID- 29618431 TI - Investigation of Staphylococcus aureus, prevailing in the environment of Khyber Teaching Hospital, Peshawar, Pakistan. AB - The hospital environment plays an important role in the spread of microorganisms, including multi drug resistant (MDR) strains. Patients can acquire Methicillin Resistant Staphylococcus aureus (MRSA) which can reside in the clinical setup that are not cleaned and can spread through air droplets, bed clothing, and healthcare workers. The purpose of this study was to investigate the prevalence of S. aureus in the Khyber Teaching Hospital (KTH). A total of 200 samples were collected from the floor, walls, air and inanimate objects in different wards of the KTH, during May 2012 to September 2012. These samples were screened for the recovery of S. aureus. Recovered organisms were subjected to susceptibility testing and investigated for the detection of various toxin and antibiotic resistance genes by Polymerase Chain Reaction (PCR). A total of 64 samples yielded S. aureus, out of which 37 (57.81%) were proved as MRSA. No isolate was found resistant to Vancomycin, however 81.25% of the isolates were found susceptible to Linezolid and Amikacin. The susceptibility to Fusidic acid, Chloramphenicol, Rifampicin, Doxycycline and Meropenem was observed as 79.69%, 76.56%, 75.00, 73.44% and 68.75% respectively. The frequency of sea, seb and sec genes were 56.25%, 43.75% and 12.5% in the recovered isolates. Erm C was more prevalent (28.12 %) than the ermA and ermB. The prevalence of pvl in MRSA was 21.62 % which is less than 33.33% in the MSSA isolates. S. aureus and especially MRSA are frequently prevalent in the KTH. Therefore, every immune-compromised patient is prone to infections caused by S. aureus. This will lead to high morbidity/mortality rate, prolong hospital stay and add extra cost to the health system. PMID- 29618432 TI - Effects of single administration of apomorphine on memory and monoamine metabolism: A dose related study. AB - In the present study, we have monitored dose dependent effects of apomorphine on learning and memory. Behavioral sensitization and craving, which develop upon repeated treatment with dopamine receptor agonist apomorphine, are major limitations of the therapeutic use of apomorphine in Parkinson's patients. Effects of single (intraperitoneal) injection of apomorphine at different doses (i.e., 0.5, 1.0, & 2.0 mg/ml/kg) on locomotion in a familiar environment (Skinner's box) and memory in Morris water maze were investigated. Results show significantly enhanced activity in Skinner's box in a dose dependant manner. Low dose (0.5 mg/ml/kg) of apomorphine impaired both short- as well as long-term memory while both high and moderate doses of the drug (1.0, & 2.0 mg/ml/kg) enhanced the cognitive profile in rats. However, the memory-enhancing effects of apomorphine at moderate (1.0 mg/ml/kg) dose were more pronounced as compared to high (2.0 mg/ml/kg) dose of the drug. Rats were decapitated on day 2. Whole brains of rats were collected and stored at -70 degrees C. Biogenic amines (i.e., 5-Hydroxytryptamine; 5-HT and dopamine) and metabolites (i.e., Dihydroxyphenylacetic acid; DOPAC, Homovanillic acid; HVA & 5-Hydroxyindoleacetic acid; 5HIAA) were estimated by reverse phase High Performance Liquid Chromatography with electrochemical detector (HPLC-EC). Both low (0.5mg/ml/kg) as well as moderate (1.0mg/ml/kg) dose of apomorphine increased levels of dopamine, DOPAC, HVA, 5-HT and 5-HIAA. Whereas, high (4.0 mg/kg) dose of apomorphine increased levels of dopamine, DOPAC and HVA, while decreased 5-HT and 5-HIAA levels. Results would be helpful in elucidating memory enhancing effects of apomorphine at different doses and its implication for extending therapeutics in cognitive disorders. PMID- 29618433 TI - SDS-PAGE and 2-DE protein profiles of Ganoderma lucidum from different origins. AB - Ganoderma lucidum (Chizhi in Chinese) is one of the most valuable and widely used medicinal fungi in traditional Chinese medicines (TCMs). Most of previous studies were focused on the triterpenoids and polysaccharides of G. lucidum, whereas less attention had been paid on the protein, which is another bioactive compound in it. In the present study, protein maps of fourteen G. lucidum samples were comprehensively analyzed by sodium dodecyl sulfate - polyacrylamide gel electrophoresis (SDS-PAGE) and two-dimensional electrophoresis (2-DE). The results indicated that there were significant differences in protein profiles of G. lucidum samples from different origins. Furthermore, previous reported bioactive proteins from the fruiting bodies of G. lucidum, were mainly distributed in 4 taxa (A, B, C and D) based on their molecular weights on the 2 DE maps. The proteins should be considered as marker for the quality control of G. lucidum, because the proteomic variation may affect on their pharmacological activities. PMID- 29618434 TI - Formulation and in vitro evaluation of directly compressed controlled release tablets designed from the Co-precipitates. AB - Controlled release dosage forms provide sustained therapeutics effects for prolonged period of time and improve patient compliance. In present study, controlled release co-precipitates of Metoprolol Tartrate and Losartan Potassium were prepared by solvent evaporation method using polymers such as Eudragit RL 100 and Carbopol 974PNF and controlled release tablets were directly compressed into tablets. In-vitro dissolution of controlled release co-precipitates were performed by USP Method-II (paddle method) and tablets were evaluated by USP Method-I (rotating basket method) in phosphate buffer (PH 6.8) using pharma test dissolution apparatus. The temperature was maintained constant at 37+/-1.0 degrees C and the rotation speed of paddle and basket was kept constant at 100rpm. Drug release mechanisms were determined by applying Power Law kinetic model. The difference and similarity of dissolution profiles test formulations with reference standards were also determined by applying difference factor (f1) and similarity factor (f2). The results showed that the controlled release co precipitates with polymer Eudragit RL 100 of both the drug extended the drug release rates for 10 hours and those having polymer Carbopol 974P NF extended the drug release rates for 12 hours. The controlled release tablets prepared from controlled release co-precipitates extended the drugs release up to 24 hours with both the polymers. The drug was released by all tests anomalous non fickian mechanism except F1 and F5 do not follow Power Law. The f1 and f2 values obtained were not in acceptable limits except F15 whose values were in acceptable limits. It is concluded from the present study that polymers (Eudragit RL 100 and Carbopol 974P NF) can be efficiently used in development of controlled release dosage forms having predictable kinetics. PMID- 29618435 TI - Alpha-tocopherol ameliorates nephrotoxicity associated with the use of colistin in rabbits. AB - The alarming rise in the rate of multi drug resistant, life threatening gram negative infections has brought renaissance in the use of Colistin for last two decades. The major constraint in its utilization is its nephrotoxicity. Therefore it is being underused which is favoring the development of resistance. This study assesses the prevention of nephrotoxicity associated with high and low toxic doses of Colistin by alpha-tocopherol. Thirty rabbits were randomly divided into five groups. Baseline serum urea, creatinine and electrolytes were estimated. A loading dose of colistin was given in the form of infusion followed by I.M injections for six days. In the preventive groups alpha-tocopherol was additionally given orally for two weeks. Rabbits were sacrificed 24 hours after the last dose. The kidney slides graded and statistically analyzed using "chi square". The results of serum analysis were compared using one way analysis of variance followed by post hoc tukey test. There was marked nephrotoxicity in high toxic group where as in low toxic group mild nephrotoxicity was evident. Alpha tocopherol attenuated the renal insult in both the toxic groups. As damage induced by colistin is oxidative in nature, thus it was concluded that the protection offered by alpha- tocopherol is due to its antioxidant activity. PMID- 29618436 TI - Comparison efficacy of Curosurf and Survanta in preterm infants with respiratory distress syndrome. AB - This study aim was to compare the therapeutic efficacy of Curosurf and Survanta in preterm infants which were admitted into NICU. In this interventional study, 150 preterm infants divided randomly in two groups (75 in Survanta and 75 in Curosurf). Data analyzed by statistical methods in SPSS.19. The significance level was considered to be P<0.05.There were no statistically significant differences in gestational age, birth weight, mortality rate, pneumothorax, Brunch-Pulmonary Dysplasia (BPD), Intra Ventricular Hemorrhage (IVH) and the mean duration of hospitalization between two groups. But in repeating dose of Survanta group with 67.7% was higher than Curosurf group with 32.3% (p=0.043) and in mean duration of ventilation Survanta group with 8 days was lower than Curosurf group with 10.5 days (P=0.001). Results showed in treatment of RDS in preterm infants each of two groups had similar side-effects but the need for repeated doses in Curosurf group and need for ventilation in Survanta group is less than others. PMID- 29618437 TI - Cyclic voltammetric studies of Gemifloxacin using Gold electrode in presence of Britton-Robinson Buffer. AB - The electrochemical study of the Gemifloxacin has been conducted using cyclic voltammetry technique at gold electrode. Gemifloxacin is antibacterial compound. In present study the electrochemical parameters of Gemifloxacin were determined in (0.04M) Britton Robinson Buffer as a supporting electrolyte at different pH ranging from 2-6 pH. This buffer was selected according to the appropriate solubility of these pharmaceutical compounds. Voltammograms of Gemifloxacin have been recorded at six different scan rates of 20, 100, 200, 300, 400 and 500mV/s. Different electrochemical parameters such as peak potential (Ep), peak current (Ip), transfer coefficient (alpha), number of electron (nalpha), diffusion coefficient (D), and heterogeneous rate constant (K0) were determined. Moreover, diagnostics tests have also been applied to define the electrochemical behavior of Gemifloxacin showed quasi reversible redox process with two electron transfers at the electrode. PMID- 29618438 TI - Assessment of environmental impact on physico-chemical parameters and heavy metals content of bovine milk available in Malir District. AB - This work designed to investigate the physico-chemical properties (pH, conductivity, salinity, TDS, DO and specific gravity) and level of essential heavy metals (Fe, Cu and Zn) and deleterious metal (Cd) were analyzed in fresh bovine milk samples available for the consumers of Malir District, Karachi. Results of most of the samples revealed that the magnitude of conductivity below the range of reference. The concentrations of metals were determined after wet digestion of samples using atomic absorption spectroscopy. The ranges of average concentrations of Fe, Cu, Zn and Cd were found as 0.262-1.104mg/l, 0.001 2.740mg/l, 2.800-5.600mg/l and 0.001-0.034mg/l in identical order. Approximately 54% samples were noticed as highly contaminated with Cd. PMID- 29618439 TI - Drug-target network of taxanes revealed by data mining. AB - Taxanes, mainly group paclitaxel and docetaxel, are amongst the most promising anticancer agents that are widely used for a variety of tumor types. It is a great challenge to gain a quick overview of the molecular mechanisms of taxanes, owning to the massive amounts of data have been produced. Network pharmacology will be a powerful tool to uncover the drug-targets network of taxanes. In this study, drug-targets network of paclitaxel and docetaxel were constructed via STITCH by database mining, and its topological parameters and important nodes were analyzed. All will provide a systematic understanding for molecular mechanisms of pacltaxel and docetaxel in a quick and visual way. PMID- 29618440 TI - Synergistic potential of Zingiber officinale and Curcuma longa to ameliorate diabetic-dyslipidemia. AB - To find the cure of world's one of the leading morbid and mortal disorders; diabetes mellitus and its most prevalent complication, 'diabetic-dyslipidemia', is one of the leading health challenges of 21st century. The use of phytomedicine is a glimmer of hope in this scenario. Studies of current decade have shown that methanolic extracts of Zingiber officinale and Curcuma longa have highly effective therapeutic potentials against the aforesaid disorders, however, which of the extracts has more potential is still unclear. Furthermore, synergistic effect of the extracts has never been studied. Forty-eight Albino adult rats of either sex were randomly divided into eight groups. A-D groups were containing healthy rats while E-H groups were of induced diabetic-dyslipidemic rats. For forty-two days, rats of each group were given either distilled water or Zingiber officinale methanolic extract (ZOME) or Curcuma longa methanolic extract (CLME) or ZOME+CLME therapies at dose rate of 300mg/100 mL dist. H2O/kg body wt/day. FPG and lipid profiles were estimated before and after the trial, and were statistically analyzed by one-way ANOVA along with Post-hoc Tukey's multiple comparison tests. Although, ZOME and CLME significantly (P<0.05) lowered fasting plasma glucose (FPG) levels and controlled lipid profiles in diabetic dyslipidemic rats; yet, synergistic therapy of both extracts (ZOME+CLME) most significantly (P<0.05) controlled all parameters of diabetic-dyslipidemia (78.00+/-1.06mg/dL FPG, 62.00+/-0.58mg/dL TG, 66.50+/-0.76mg/dL cholesterol, 32.00+/-0.36mg/dL HDL, 22.43+/-0.64 mg/dL LDL, and 12.40+/-0.12mg/dL VLDL). Our findings may be useful to formulate new medicines having multiple potentials to control diabetes mellitus, dyslipidemia, and diabetic-dyslipidemia. PMID- 29618441 TI - Phytochemical screening and antibacterial potential of Artemisia absinthium L., Swertia chirayita and Sphaeranthus indicus. AB - Utilization of herbs for medicinal purpose started in the early history of mankind several thousand years ago. In this study, some plants that are used for lowering cholesterol level in local areas of Pakistan, such as Artemisia absinthium L., Swertia chirayita and Sphaeranthus indicus were screened for their phytochemical and antibacterial properties. For this purpose, these plants were extracted in different solvents i.e. ethanol, hexane and ethyl acetate. Phytochemcial analysis unveiled the existence of different bioactive compounds in these extracts. Presence of sugars was further confirmed by performing TLC. Antibacterial activity was determined against indicated bacterial strains, among all extracts Gul-e-mundi had maximum inhibition zone (23mm). DPPH free radical assay revealed the significant antioxidative potential of all the extracts where Gul-e-mundi showed maximum potential i.e., 83%. Plant extracts were also showing anti-proliferative activity on root tips of Allium cepa and Gul-e-mundi was observed to have maximum antimitotic activity i.e. 5%. GC-MS analysis revealed that oleic acid and linoleic acid were the compounds responsible for imparting antibacterial potential to Gul-e-mundi. In conclusion, among all the tested extracts Gul-e-mundi had maximum antibacterial, antioxidative and antimitotic potential. For future studies, phytochemcials responsible for these activities can be isolated and modified for pharmacological purpose. PMID- 29618442 TI - Potential action of Rumex vesicarius (L.) against potassium dichromate and gentamicin induced nephrotoxicity in experimental rats. AB - To determine the ameliorative potential of the active fraction from different extracts of Rumex vesicarius against potassium dichromate and gentamicin induced nephrotoxicity in experimental rats and its possible mechanism of action. Both sex wistar rats were divided into 6 groups (n=6/group) were fed with a control, potassium dichromate and gentamicin supplemented with different extracts at the doses of 200 and 400mg/kg respectively. Oral administration of EERV offered a significant (p<0.01 and p<0.001) dose dependent protection against PD and GN induced nephrotoxicity. Potassium dichromate and gentamicin nephrotoxicity assessed in terms of body weight, kidney weight, creatinine, urea, uric acid, BUN, albumin and total protein. Thus the present study revealed that EERV phytochemical constituents play an important role in protection against kidney damage. PMID- 29618443 TI - Labeling of epirubicin with technetium-99m: Optimization, biodistribution and scintigraphic imaging in tumor bearing mice. AB - Epirubicin is an antineoplastic agent of anthracycline antibiotic, used for treating a variety of tumor types such as lymphoma, cancer of the breast, lung, ovary and stomach. The objective of this work was to demonstrate direct radiolabeling of epirubicin with 99mTc, quality control, biological characterization and scientigraphic evaluation in tumor bearing mice. The 99mTc epirubicin labeling was optimized by varying the amounts of ligand 100-350MUg, stannous chloride dihydride 20-50MUg and pH range 2-10 by using NaOH or HCl. The radiochemical purity of 99mTc-epirubicin was evaluated by chromatographic techniques (Whatman No. 3 paper and ITLC-SG). HPLC analyses were performed to check purity of epirubicin and radiochemical purity of labeled 99mTc- epirubicin. Biodistribution and scintigraphic imaging of 99mTc-epirubicin was performed in normal and tumor bearing mice at various time intervals. The optimum conditions ensuring 99mTc-epirubicin labeling yield as high as 99% by adding 35MUg SnCl2.2H2O, 200MUg of ligand at pH 6 for 30 min at room temperature (25 degrees C+/-2 degrees C). HPLC of 99mTc-epirubicin shows about 99% binding of the compound with technetium-99m. Electrophoresis study indicated the neutral nature of 99mTc-epirubicin. Biodistribution data and scintigraphic results showed that 99mTc-epirubicin accumulated in the liver as well as in tumor with significant uptake and excellent retention. 99mTc-epirubicin shows good stability in human serum. In vitro and in vivo studies revealed the significantly uptake of 99mTc epirubicin in the tumor, and also indicating the efficiency of 99mTc-epirubicin as a tumor diagnostic agent. PMID- 29618444 TI - The genetic and chemical diversity in three original plants of licorice, Glycyrriza uralensis Fisch., Glycyrrhiza inflata Bat. and Glycyrrhiza glabra L. AB - Licorice is one of the most frequently used Chinese herbs, mainly containing triterpenoids and flavonoids. Three original plants, Glycyrrhiza glabra L., Glycyrrhiza uralensis Fisch., and Glycyrrhiza inflata Bat., are defined as licorice in Chinese pharmacopeia. In this study, 40 G. uralensis samples (Group A), 60 G. glabra samples (Group B, C and D) and 40 G. inflata samples (Group E and F), were used as plant materials, the genetic diversity of samples were determined by gene sequencing technology and the chemotypic diversity were detected by HPLC. The chemotypic diversity analysis showed that contents of triterpenoids in G. glabra (isoglycyrrhizin: 2.483+/-0.0671 mg?g-1, glycyrrhizin: 34.660+/-0.8591 mg?g-1) were obviously higher than that in G. uralensis and G. inflata. However, the contents of flavonoids (liquiritin: 21.996+/-0.6396 mg?g-1, isoliquiritin: 4.556+/-0.1252 mg?g-1, liquiritigenin: 0.623+/-0.0200 mg?g-1, isoliquiritigenin: 0.281+/-0.008 mg?g-1) in G. uralensis were higher than that in G. glabra and G. inflata. And contents of triterpenoids and flavonoids were both lowest in G. inflata. The genetic diversity analysis showed that the psbA-trnH intergenic regions on chloroplast DNA sequences were same in the same species, and significantly different between any two species. These findings will lay a solid foundation for the identification and quality control of licorice. Furthermore, recently the activity of isoglycyrrhizin has attracted more and more attentions and researches. The HPLC method established in this paper for the simultaneous assay of isoglycyrrhizin and glycyrrhizin will be helpful for the screening of superior quality licorice with a high content of isoglycyrrhizin. PMID- 29618445 TI - Assessment of children immunization pattern in Children Hospital Lahore, Pakistan. AB - The basic aim is to assess immunization pattern of children up to 15 months of age. A cross-sectional study was conducted on 100 immunized children in Children hospital Lahore, Pakistan. Single dose 0.05ml to 0.1ml of BCG was recommended at the time of birth. Three doses of 0.5ml of Pneumococcal vaccine was given, coupled with the Penta-valent vaccine was given at 6 week, 10 week and 14 weeks of age. Two doses 0.5ml of measles vaccine was given at 9 & 15 months. Respondent's sex, age and the vaccinated children against diseases were analyzed in the form of percentages and frequency tables through statistical analysis in the software called SPSS version 16.0. Female children immunization against various diseases was less in number. The results concluded that by informing community about the problem of ailment and the real significance of vaccinations, we are able to maintain and develop greater immunization coverage and as a result, more lives of children were saved. PMID- 29618446 TI - Effects of Qibaipingfei capsules on pulmonary vascular relaxation through KATP channel activation by the NO/cGMP signaling pathway. AB - This research explores the effects of Qibaipingfei (QBPF) capsules on pulmonary vascular relaxation in vitro and the relationship of the ATP-sensitive K+ (KATP) channel and nitric oxide (NO) pathway. Vasodilator effects of QBPF (0.125-2 g/kg) on rat pulmonary artery rings were observed using a multi-wire myograph system. The maximum relaxation (Emax) of QBPF was detected following treatment involving endothelial denudation, Nomega-nitro-L-arginine methyl ester (L-NAME), 1H-[1,2,4] oxadiazolo[4,3-alpha]quinoxalin-1-one (ODQ), or glyburide (GLYB). Furthermore, rat models of phlegm and blood stasis syndrome combined with chronic obstructive pulmonary disease (COPD) were established using compound factors. KIR6.1 and SUR2B protein expression was analyzed by western blotting. After 9,11-dideoxy-11 alpha],9-alpha]-epoxy-methanoprostaglandinF2alpha (U46619) was used to pre constrict endothelium-intact pulmonary artery rings, QBPF induced the effects of concentration-dependent relaxation at a concentration for 50% of maximal effect (EC50) of 0.56 g/L and Emax of 84.30% +/- 6.27%. After the endothelium was denuded, the vasodilator effects reduced significantly (P<0.01). QBPF-induced relaxation was inhibited by L-NAME, ODQ, and GLYB (P<0.01). The vasodilator effect was also attenuated in the model group (Emax=62.63%+/-10.02, EC50 = 0.72 g/L, P<0.01). In comparison with expression in the control group, SUR2B protein expression was down-regulated in the model group (P<0.01) but no significant difference was detected in KIR6.1 protein expression between the groups (P>0.05). QBPF and nicorandil (Nic) treatment up-regulated SUR2B KATP channel expression (P<0.05). QBPF induces endothelial-dependent relaxation in pulmonary artery rings in vitro, through a mechanism that potentially activates the KATP channel in pulmonary vascular smooth muscles via the NO-cyclic GMP (cGMP)-dependent pathway. PMID- 29618447 TI - Analgesic, anti-inflammatory and diuretic activities of Cicer arietinum L. AB - Analgesic, anti-inflammatory and diuretic activities of the methanol extract of two varieties of Cicer arietinum viz black or Desi and white or Kabuli were tested in the doses of 200 and 400 mg/kg. For analgesic effect of the extracts, acetic acid induced writhing, tail immersion and hot plate tests were employed in mice. The anti-inflammatory activity was carried out by carrageenan induced inflammation in rats, whereas the diuretic action was determined using metabolic cages for rats. Animals were divided into six groups (n=7): (1) Control (2) Standard (3) MECAB 200 (4) MECAB 400 (5) MECAW 200 (6) MECAW 400. All extracts and standard drugs were administered orally. Acute oral toxicity of the extracts was also checked in mice up to 2000mg/kg dose, which showed a favorable safety. Significant analgesic and anti-inflammatory effects were observed. The results of diuretic activity were significant at 12th and 24th hrs. Therefore, it is concluded that the methanol extracts of the seeds of Cicer arietinum have analgesic, anti-inflammatory and diuretic potential. PMID- 29618448 TI - Free radical scavenging activity of Telfairia occidentalis extracts and their effects on iron-sulphate induced lipid per oxidation. AB - Non-enzymic natural antioxidants of plant origin are known to play a key role in inflammation linked with free radicals and oxidative stress. This study investigates the free radical scavenging activity of various Telfairia occidentalis leaves extracts in relation to their inhibitory effects on lipid peroxidation. The extracts markedly exhibited antioxidants activity especially the ethyl acetate (EE) and chloroform (CE) extract which scavenged 1,1-diphenyl-2 picryhydraxyl (DPPH) radicals significantly (p<0.05) by 76.34 and 76.62% respectively at 600MU/ml with minimum effects (53.34%) obtained with the methanol (ME) extract. Similarly the extracts scavenged iron/EDTA/H2O2 induced hydroxyl radical formation in a dose-dependent manner as the ME, EE and CE extracts scavenged the radicals at 300ug/ml by 40.55, 24.23 and 19.64% respectively. Interestingly, ME, EE and CE extracts inhibited iron-induced lipid per oxidation significantly (P<0.05) by 93.56, 76.24 and 70.54% respectively at 300ug/ml. Phytochemical analysis showed the presence of phenols and flavonoids at 2.58, 1.98, 3.24 and 0.840, 0.300, 0.400mg/g garlic acid and quercetin equivalence at 300 MUg/ml concentrations respectively. Bioactive constituents of the leaves extracts shows antioxidants potentials, radical scavenging and inhibitory effects on lipid per oxidation which were highly expressed in methanol extract and may be a template for drug discovery. PMID- 29618449 TI - Pharmacophoric screening of newly synthesized isoniazid derivatives and their antimycobacterial activity. AB - Mycobacterium tuberculosis is clinically recognized as a causative agent of Tuberculosis. Keeping in view, this study was endeavored to screen our previously synthesized seventeen INH analogues for their antimycobacterial potential using proportion method. During this process, INH and all the seventeen compounds were examined at different concentrations of 0.05, 0.1 and 0.2MUg/mL which were prepared using Lowenstein-Jensen (LJ) base. For drug susceptibility test, three Mycobacterial strains ATCC H37Rv, known INH-sensitive and INH-resistant strains were selected, sub-cultured on LJ Medium and serial diluted to achieve 1:10, 1:100, 1:1000 and 1:10000 from calibrated bacterial suspension Mcfarland No. 1. Dilutions of 1:100 and 1:10000 were added to drug free medium and 1:100 bacterial suspension was added to each of the test concentrations and finally incubated for 4-6 weeks at 37 degrees C. It was observed that only compounds II and XI were active against MTb. Compounds III, IX and X also showed activity but were less potent. Ligand Scout 3.02[il_10] was used to perform pharmacophore-based screening where important pharmacophoric features were identified in the structures of these compounds which could be related to their observed antimycobacterial activity. PMID- 29618450 TI - Evaluation of phytochemical and in vitro antioxidant activity of water and acetone extracts of selected vegetables. AB - The aim of this study was to determine antioxidant activity of Brassica oleracea (Cabbage), Brassica rapa (Turnip) and Raphanus sativus (Radish). All of the three selected vegetables were ultrasonically extracted in water and acetone. The antioxidant activity was determined by DPPH and H2O2. Highest phenolic, flavonoid and flavonol contents were found among water extract of Raphanus sativus, Brassica oleracea and Brassica rapa respectively. Highest %age of DPPH inhibition was exhibited by water extract of Brassica rapa and highest OH? radical scavenging activity was shown by water extract of Raphanus sativus. PMID- 29618451 TI - Analgesic and anti-inflammatory activities of fixed oil of Macrotyloma uniflorum (Lam.) Verdc. in mice and rats. AB - Macrotyloma uniflorum commonly known as horse gram or kulthi bean is grown as a pulse for livestock and human consumption. The beans contain about 1.3% fat, 18% protein, 15% carbohydrate along with vitamins and minerals. In traditional medicine it is used as antihyperglycemic, antioxidant, antihypertensive and diuretic. Other important medicinal uses include treatment of renal stones, obesity, piles, oedema and fever. The present study evaluated analgesic (by acetic acid induced writhing, hot plate and tail flick tests in mice) and anti inflammatory (carrageenan induced paw edema in rats) activities of Macrotyloma uniflorum fixed oil (MUFO). Four groups were included in study: Group-I: Normal Saline Control (2ml/kg), Group-II: MUFO (2ml/kg), Group-III: MUFO (4ml/kg), and Group-IV: Standard Acetyl salicylic acid (ASA 300mg/kg). All results were significant however delayed onset of action was observed in tail flick and paw edema tests. Acute oral toxicity of the oil was also checked in mice and was found safe upto 4ml/kg dose, as no signs of toxicity and mortality were observed. It is concluded that Macrotyloma uniflorum fixed oil may possess analgesic and anti-inflammatory activity which can be related with a peripheral mechanism of action. PMID- 29618452 TI - Short Communication - Synthesis of drug metal complexes and their influence on human platelet aggregation. AB - During the past few decades the emergence of inorganic medicinal chemistry has been developed novel therapeutic agents. Researcher's perseverance in this branch of chemistry has led them to explore further valuable chemical spaces by synthesizing metal complexes already known pharmacological agents for their potential use. However, it is in its early stage, this methodology has demonstrated metal complexes with better bioactivities than the parent ligand molecules. In this study, transition metal complexes of pyrazinamide (PZ), isoniazid (INH), fluconazole (FCZ), metformin (dimethylbiguanide, DMBG) and losartan potassium (LS-K) were selected to evaluate for their possible anti platelets aggregation in the light of reports on divalent and trivalent cations like calcium, copper, manganese, magnesium, and cadmium may influence the process of thrombocytic activity and aggregation. The required evaluation was carried out on human plasma through an APACT 4004 platelet aggregation analyzer. Arachidonic acid (ADP) was used to gauge any alteration in platelet shape and aggregation process. The parent drugs showed some anti-platelets aggregation, however, their metal complexes demonstrated better efficacy. PMID- 29618453 TI - Report - Susceptibility of avian pathogenic Escherichia coli from Zoo birds in Indonesia to antibiotics and disinfectants. AB - Antibiotic resistance in avian pathogenic Escherichia coli (APEC) is a common problem in the Indonesian poultry industry. Zoo birds have been postulated as sentinels, reservoirs, and potential spreaders of antibiotic resistance, although much is still unknown about the strains of zoo birds. Disinfection can reduce the infection burden. However, little is known about the presence of resistance against these products. Sixty one APEC strains were isolated from Indonesian zoo birds. The resistance to different classes of antibiotics as well as the minimum inhibitory concentrations (MIC) and minimum bactericidal concentrations (MBC) of five disinfectants most often used in the poultry industry was determined. Resistance to tetracycline (42.6%), sulfonamides (24.5%), ampicillin (22.9%), gentamicin (19.6), nalidixic acid (18.03%) and streptomycin (16.3%) was high, but resistance to other tested antibiotics was low and none of the isolates were resistant to extended spectrum beta-lactamase (ESBL) producers. Sixteen strains (26.2%) were found positive for multi drug resistance. The MIC of the disinfectants for the APEC strains showed normal distribution, indicating that there was no acquired resistance. MBCs were similar to MICs using the broth dilution method, showing the bactericidal effect of the disinfectants. Phenotypic resistance to commonly used disinfectants could not be found, indicating that the current use of disinfectants in the zoo and aviaries did not select for resistance. Significantly high resistance rates against commonly used antibiotics in Indonesian zoos is worrisome and indicates that widespread use of antibiotics could have negative implications for animal health and the environment. Proper use of antibiotics and surveillance programs to monitor antimicrobial resistance in pathogenic bacteria are warranted. PMID- 29618454 TI - Development of Whole Slide Imaging on Smartphones and Evaluation With ThinPrep Cytology Test Samples: Follow-Up Study. AB - BACKGROUND: The smartphone-based whole slide imaging (WSI) system represents a low-cost and effective alternative to automatic scanners for telepathology. In a previous study, the development of one such solution, named scalable whole slide imaging (sWSI), was presented and analyzed. A clinical evaluation of its iOS version with 100 frozen section samples verified the diagnosis-readiness of the produced virtual slides. OBJECTIVE: The first aim of this study was to delve into the quantifying issues encountered in the development of an Android version. It should also provide insights into future high-resolution real-time feedback medical imaging apps on Android and invoke the awareness of smartphone manufacturers for collaboration. The second aim of this study was to further verify the clinical value of sWSI with cytology samples. This type is different from the frozen section samples in that they require finer detail on the cellular level. METHODS: During sWSI development on Android, it was discovered that many models do not support uncompressed camera pixel data with sufficient resolution and full field of view. The proportion of models supporting the optimal format was estimated in a test on 200 mainstream Android models. Other factors, including slower processing speed and camera preview freezing, also led to inferior performance of sWSI on Android compared with the iOS version. The processing speed was mostly determined by the central processing unit frequency in theory, and the relationship was investigated in the 200-model simulation experiment with physical devices. The camera preview freezing was caused by the lag between triggering photo capture and resuming preview. In the clinical evaluation, 100 ThinPrep cytology test samples covering 6 diseases were scanned with sWSI and compared against the ground truth of optical microscopy. RESULTS: Among the tested Android models, only 3.0% (6/200) provided an optimal data format, meeting all criteria of quality and efficiency. The image-processing speed demonstrated a positive relationship with the central processing unit frequency but to a smaller degree than expected and was highly model-dependent. The virtual slides produced by sWSI on Android and iOS of ThinPrep cytology test samples achieved similar high quality. Using optical microscopy as the ground truth, pathologists made a correct diagnosis on 87.5% (175/200) of the cases with sWSI virtual slides. Depending on the sWSI version and the pathologist in charge, the kappa value varied between .70 and .82. All participating pathologists considered the quality of the sWSI virtual slides in the experiment to be adequate for routine usage. CONCLUSIONS: Limited by hardware and operating system support, the performance of sWSI on mainstream Android smartphones did not fully match the iOS version. However, in practice, this difference was not significant, and both were adequate for digitizing most of the sample types for telepathology consultation. PMID- 29618455 TI - Juvenile hormone reveals mosaic developmental programs in the metamorphosing optic lobe of Drosophila melanogaster. AB - The development of the adult optic lobe (OL) of Drosophila melanogaster is directed by a wave of ingrowth of the photoreceptors over a 2-day period at the outset of metamorphosis, which is accompanied by the appearance of the pupal specific transcription factor Broad-Z3 (Br-Z3) and expression of early drivers in OL neurons. During this time, there are pulses of ecdysteroids that time the metamorphic events. At the outset, the transient appearance of juvenile hormone (JH) prevents precocious development of the OL caused by the ecdysteroid peak that initiates pupariation, but the artificial maintenance of JH after this time misdirects subsequent development. Axon ingrowth, Br-Z3 appearance and the expression of early drivers were unaffected, but aspects of later development such as the dendritic expansion of the lamina monopolar neurons and the expression of late drivers were suppressed. This effect of the exogenous JH mimic (JHM) pyriproxifen is lost by 24 h after pupariation. Part of this effect of JHM is due to its suppression of the appearance of ecdysone receptor EcR-B1 that occurs after pupation and during early adult development. PMID- 29618457 TI - STOPS trial versus Costa et al: a more accurate analysis. PMID- 29618456 TI - Functional domains of the FSHD-associated DUX4 protein. AB - Aberrant expression of the full-length isoform of DUX4 (DUX4-FL) appears to underlie pathogenesis in facioscapulohumeral muscular dystrophy (FSHD). DUX4-FL is a transcription factor and ectopic expression of DUX4-FL is toxic to most cells. Previous studies showed that DUX4-FL-induced pathology requires intact homeodomains and that transcriptional activation required the C-terminal region. In this study, we further examined the functional domains of DUX4 by generating mutant, deletion, and fusion variants of DUX4. We compared each construct to DUX4 FL for (i) activation of a DUX4 promoter reporter, (ii) expression of the DUX4-FL target gene ZSCAN4, (iii) effect on cell viability, (iv) activation of endogenous caspases, and (v) level of protein ubiquitination. Each construct produced a similarly sized effect (or lack of effect) in each assay. Thus, the ability to activate transcription determined the extent of change in multiple molecular and cellular properties that may be relevant to FSHD pathology. Transcriptional activity was mediated by the C-terminal 80 amino acids of DUX4-FL, with most activity located in the C-terminal 20 amino acids. We also found that non-toxic constructs with both homeodomains intact could act as inhibitors of DUX4-FL transcriptional activation, likely due to competition for promoter sites.This article has an associated First Person interview with the first author of the paper. PMID- 29618458 TI - Keeping athletes on the field: preventing primary and secondary ACL injuries. PMID- 29618459 TI - Diagnosing Cervical Neoplasia in Rural Brazil Using a Mobile Van Equipped with In Vivo Microscopy: A Cluster-Randomized Community Trial. AB - Cervical cancer is a leading cause of death in underserved areas of Brazil. This prospective randomized trial involved 200 women in southern/central Brazil with abnormal Papanicolaou tests. Participants were randomized by geographic cluster and referred for diagnostic evaluation either at a mobile van upon its scheduled visit to their local community, or at a central hospital. Participants in both arms underwent colposcopy, in vivo microscopy, and cervical biopsies. We compared rates of diagnostic follow-up completion between study arms, and also evaluated the diagnostic performance of in vivo microscopy compared with colposcopy. There was a 23% absolute and 37% relative increase in diagnostic follow-up completion rates for patients referred to the mobile van (102/117, 87%) compared with the central hospital (53/83, 64%; P = 0.0001; risk ratio = 1.37, 95% CI, 1.14-1.63). In 229 cervical sites in 144 patients, colposcopic examination identified sites diagnosed as cervical intraepithelial neoplasia grade 2 or more severe (CIN2+; 85 sites) with a sensitivity of 94% (95% CI, 87%-98%) and specificity of 50% (95% CI, 42%-58%). In vivo microscopy with real-time automated image analysis identified CIN2+ with a sensitivity of 92% (95% CI, 84%-97%) and specificity of 48% (95% CI, 40%-56%). Women referred to the mobile van were more likely to complete their diagnostic follow-up compared with those referred to a central hospital, without compromise in clinical care. In vivo microscopy in a mobile van provides automated diagnostic imaging with sensitivity and specificity similar to colposcopy. Cancer Prev Res; 11(6); 359-70. (c)2018 AACR. PMID- 29618460 TI - A System-Level Approach to Improve the Uptake of Antiestrogen Preventive Therapy among Women with Atypical Hyperplasia and Lobular Cancer In Situ. AB - Background: The low uptake of antiestrogen preventive therapy among women at high risk of developing breast cancer remains a challenge. We implemented a performance improvement program to increase the uptake of preventive therapy among women with atypical hyperplasia (AH) and lobular cancer in situ (LCIS).Methods: A performance improvement program was implemented at the MD Anderson Cancer Center (Houston, TX), November 2015 to February 2017, for patients with a new (<6 months) or existing (>=6 months) diagnosis of AH/LCIS. The program consisted of an audit of eligible women who were recommended and prescribed preventive therapy and the provision of clinical performance feedback to providers. The baseline uptake of preventive therapy was estimated from patients enrolled in a high-risk breast cohort.Results: Baseline uptake of preventive therapy was 44%. The program registered 408 patients with a new (n = 87) or existing diagnosis (n = 321) of AH/LCIS; mean age was 57 and 71% were non Hispanic white. Ninety-eight percent of patients received a recommendation for preventive therapy. The overall prescribing of preventive therapy to patients with a new or existing diagnosis was 82% (monthly range, 40%-100%; Ptrend = 0.76) and 48% (monthly range, 27%-57%; Ptrend < 0.01), respectively. Adherence among patients with a new or existing diagnosis was 76% and 48% (P < 0.01) at 6 months, respectively.Conclusion: A system-level approach improved the uptake of preventive therapy. Identifying women at the time of diagnosis of AH/LCIS and offering a strong recommendation are key components for improving acceptance and adherence with preventive therapy. Cancer Prev Res; 11(5); 295-302. (c)2018 AACR. PMID- 29618461 TI - Lessons from the Crypt: HMGA1-Amping up Wnt for Stem Cells and Tumor Progression. AB - High mobility group A1 (HMGA1) chromatin remodeling proteins are enriched in aggressive cancers and stem cells, although their common function in these settings has remained elusive until now. Recent work in murine intestinal stem cells (ISC) revealed a novel role for Hmga1 in enhancing self-renewal by amplifying Wnt signaling, both by inducing genes expressing Wnt agonist receptors and Wnt effectors. Surprisingly, Hmga1 also "builds" a stem cell niche by upregulating Sox9, a factor required for differentiation to Paneth cells; these cells constitute an epithelial niche by secreting Wnt and other factors to support ISCs. HMGA1 is also highly upregulated in colon cancer compared with nonmalignant epithelium and SOX9 becomes overexpressed during colon carcinogenesis. Intriguingly, HMGA1 is overexpressed in diverse cancers with poor outcomes, where it regulates developmental genes. Similarly, HMGA1 induces genes responsible for pluripotency and self-renewal in embryonic stem cells. These findings demonstrate that HMGA1 maintains Wnt and other developmental transcriptional networks and suggest that HMGA1 overexpression fosters carcinogenesis and tumor progression through dysregulation of these pathways. Studies are now needed to determine more precisely how HMGA1 modulates chromatin structure to amplify developmental genes and how to disrupt this process in cancer therapy. Cancer Res; 78(8); 1890-7. (c)2018 AACR. PMID- 29618463 TI - Stone RM, Manley PW, Larson RA, Capdeville R. Midostaurin: its odyssey from discovery to approval for treating acute myeloid leukemia and advanced systemic mastocytosis. Blood Adv. 2017;2(4):444-453. PMID- 29618465 TI - Association of Metformin with Breast Cancer Incidence and Mortality in Patients with Type II Diabetes: A GRADE-Assessed Systematic Review and Meta-analysis. AB - Background: Preclinical data suggest that metformin may reduce breast cancer incidence and improve cancer prognosis. However, the current evidence in observational studies is inconclusive. A systematic review and meta-analysis was conducted to assess the effect of metformin on the incidence of breast cancer and all-cause mortality in patients with type II diabetes (T2D).Methods: A literature search was performed on Medline, EMBASE, and the Cochrane library from inception to November 2016. Outcomes were incidence of breast cancer and all-cause mortality. Risk of bias and overall certainty of evidence was assessed using the Newcastle-Ottawa Scale and Grading of Recommendations Assessment, Development, and Evaluation (GRADE), respectively. Meta-analyses were performed using the most fully adjusted ORs or HRs and 95% confidence intervals (95% CI) as effect measures.Results: A total of 12 observational studies were included for breast cancer incidence and 11 studies for all-cause mortality. No significant association was found between metformin exposure and incidence of breast cancer (OR = 0.93; 95% CI, 0.85-1.03; I2 = 35%). A 45% risk reduction was observed for all-cause mortality (HR = 0.55; 95% CI, 0.44-0.70; I2 = 81%). Presence of publication bias is strongly suspected for both outcomes using Egger's funnel plots.Conclusions: The use of metformin may improve overall survival in patients with T2D and breast cancer. No effect of metformin on the incidence of breast cancer was observed. Interpretation of results is limited by the observational nature of the studies and resulting biases.Impact: Clinical trials are warranted to determine the role of metformin in breast cancer risk reduction and prognosis. Cancer Epidemiol Biomarkers Prev; 27(6); 627-35. (c)2018 AACR. PMID- 29618462 TI - Allogeneic hematopoietic stem cell transplantation for severe, refractory juvenile idiopathic arthritis. AB - Patients with juvenile idiopathic arthritis (JIA) can experience a severe disease course, with progressive destructive polyarthritis refractory to conventional therapy with disease-modifying antirheumatic drugs including biologics, as well as life-threatening complications including macrophage activation syndrome (MAS). Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative immunomodulatory strategy for patients with such refractory disease. We treated 16 patients in 5 transplant centers between 2007 and 2016: 11 children with systemic JIA and 5 with rheumatoid factor-negative polyarticular JIA; all were either refractory to standard therapy, had developed secondary hemophagocytic lymphohistiocytosis/MAS poorly responsive to treatment, or had failed autologous HSCT. All children received reduced toxicity fludarabine-based conditioning regimens and serotherapy with alemtuzumab. Fourteen of 16 patients are alive with a median follow-up of 29 months (range, 2.8-96 months). All patients had hematological recovery. Three patients had grade II-IV acute graft versus-host disease. The incidence of viral infections after HSCT was high, likely due to the use of alemtuzumab in already heavily immunosuppressed patients. All patients had significant improvement of arthritis, resolution of MAS, and improved quality of life early following allo-HSCT; most importantly, 11 children achieved complete drug-free remission at the last follow-up. Allo-HSCT using alemtuzumab and reduced toxicity conditioning is a promising therapeutic option for patients with JIA refractory to conventional therapy and/or complicated by MAS. Long-term follow-up is required to ascertain whether disease control following HSCT continues indefinitely. PMID- 29618466 TI - Maternal immunization increases nestling energy expenditure, immune function, and fledging success in a passerine bird. AB - Female birds transfer maternally derived antibodies (matAb) to their nestlings, via the egg yolk. These antibodies are thought to provide passive protection, and allow nestlings to avoid the costs associated with mounting an innate immune response. To test whether there is an energetic benefit to nestlings from receiving matAb, we challenged adult female tree swallows (Tachycineta bicolor) prior to clutch initiation with either lipopolysaccharide (LPS) or saline (Control). Following hatching, one half of each female's nestlings were immunized on day 8 post-hatch with LPS or saline, and the 4-h post-immunization nestling metabolic rate (MR) was measured. There was no difference in either LPS-reactive antibodies or total Ig levels between offspring of immunized and non-immunized mothers on day 6 or 14 post-hatch, possibly reflecting a relatively short half life of matAbs in altricial birds. Additionally, we found no evidence that nestlings from LPS-immunized mothers could avoid the growth suppression that may result from activation of an inflammatory response. Unexpectedly, we found that control nestlings from LPS mothers had higher resting MR than control nestlings of control mothers. We attribute the increased MR to the costs associated with a general non-specific enhancement of immune function in nestlings from LPS immunized mothers. Consistent with enhanced immune function, nestlings of immunized mothers had a more robust inflammatory response to phytohaemagglutinin and higher fledging success. Our results suggest that maternal antigen exposure pre-laying can result in increased fitness for both mothers and offspring, depending on food availability. PMID- 29618468 TI - Tumour lysis in newborn: spontaneous or secondary to antenatal steroids? AB - Malignancies are rare in the early neonatal period. Common congenital tumours include malignant teratoma and neuroblastomas. Tumour lysis syndrome is a serious condition usually seen after commencement of chemotherapy for a malignancy. Rare case reports of spontaneous tumour lysis have been reported though not in the newborn period. We report here an instance of tumour lysis syndrome in a newborn with congenital rhabdoid tumour, where the cause was either spontaneous or related to antenatal steroid exposure. PMID- 29618467 TI - Subtle Perturbations of the Maize Methylome Reveal Genes and Transposons Silenced by Chromomethylase or RNA-Directed DNA Methylation Pathways. AB - DNA methylation is a chromatin modification that can provide epigenetic regulation of gene and transposon expression. Plants utilize several pathways to establish and maintain DNA methylation in specific sequence contexts. The chromomethylase (CMT) genes maintain CHG (where H = A, C or T) methylation. The RNA-directed DNA methylation (RdDM) pathway is important for CHH methylation. Transcriptome analysis was performed in a collection of Zea mays lines carrying mutant alleles for CMT or RdDM-associated genes. While the majority of the transcriptome was not affected, we identified sets of genes and transposon families sensitive to context-specific decreases in DNA methylation in mutant lines. Many of the genes that are up-regulated in CMT mutant lines have high levels of CHG methylation, while genes that are differentially expressed in RdDM mutants are enriched for having nearby mCHH islands, implicating context-specific DNA methylation in the regulation of expression for a small number of genes. Many genes regulated by CMTs exhibit natural variation for DNA methylation and transcript abundance in a panel of diverse inbred lines. Transposon families with differential expression in the mutant genotypes show few defining features, though several families up-regulated in RdDM mutants show enriched expression in endosperm tissue, highlighting the potential importance for this pathway during reproduction. Taken together, our findings suggest that while the number of genes and transposon families whose expression is reproducibly affected by mild perturbations in context-specific methylation is small, there are distinct patterns for loci impacted by RdDM and CMT mutants. PMID- 29618469 TI - Surprising cause of a hoarse voice. PMID- 29618470 TI - Relationship Between Changes in Fat and Lean Depots Following Weight Loss and Changes in Cardiovascular Disease Risk Markers. AB - BACKGROUND: Gluteofemoral fat mass has been associated with improved cardiovascular disease risk factors. It is not clear if loss of this protective fat during weight loss partially negates the effect of loss of visceral fat. The aim of this study was to examine regional fat loss in a large weight-loss cohort from one center and to determine if fat loss in the leg and total lean tissue loss is harmful. METHODS AND RESULTS: We combined the data from 7 of our previously published 3-month weight-loss studies and examined the relationship between regional fat and lean tissue loss and changes in cardiovascular disease risk factors in 399 participants. At baseline, leg fat was positively associated with high-density lipoprotein cholesterol in women and inversely with fasting triglyceride level in both sexes. Abdominal lean tissue was also related to systolic blood pressure in men. Changes in regional fat and lean tissue were positively associated with changes in glucose, insulin, total cholesterol, triglycerides, low-density lipoprotein cholesterol and systolic and diastolic blood pressure (r=0.11-0.22, P<0.05) with leg fat and arm lean tissue dominating in multivariate regression. After adjustment for total weight or total fat change, these relationships disappeared except for a positive relationship between arm and lean leg mass loss and changes in triglycerides and systolic blood pressure. CONCLUSIONS: Loss of leg fat and leg lean tissue was directly associated with beneficial changes in cardiovascular disease risk markers. Loss of lean tissue may not have an adverse effect on cardiovascular disease risk, and measures to retain lean tissue during weight loss may not be necessary. PMID- 29618471 TI - American-Style Football and Cardiovascular Health. PMID- 29618472 TI - Angiotensin II Type 1 Receptor Autoantibodies in Postural Tachycardia Syndrome. AB - BACKGROUND: Both the adrenergic and renin-angiotensin systems contribute to orthostatic circulatory homeostasis, which is impaired in postural orthostatic tachycardia syndrome (POTS). Activating autoantibodies to the alpha1-adrenergic and beta1/2-adrenergic receptors have previously been found in sera from patients with POTS. We hypothesized that patients with POTS might also harbor activating autoantibodies to the angiotensin II type 1 receptor (AT1R) independently of antiadrenergic autoimmunity. This study examines a possible pathophysiological role for AT1R autoantibodies in POTS. METHODS AND RESULTS: Serum immunoglobulin G from 17 patients with POTS, 6 patients with recurrent vasovagal syncope, and 10 normal controls was analyzed for the ability to activate AT1R and alter AT1R ligand responsiveness in transfected cells in vitro. Of 17 subjects with POTS, 12 demonstrated significant AT1R antibody activity in immunoglobulin G purified from their serum. No significant AT1R antibody activity was found in the subjects with vasovagal syncope or healthy subjects. AT1R activation by POTS immunoglobulin G was specifically blocked by the AT1R blocker losartan. Moreover, POTS immunoglobulin G significantly shifted the angiotensin II dosage response curve to the right, consistent with an inhibitory effect. All subjects with POTS were positive for one or both autoantibodies to the AT1R and alpha1-adrenergic receptor. CONCLUSIONS: Most patients with POTS harbor AT1R antibody activity. This supports the concept that AT1R autoantibodies and antiadrenergic autoantibodies, acting separately or together, may exert a significant impact on the cardiovascular pathophysiological characteristics in POTS. PMID- 29618473 TI - IL-23R Deficiency Does Not Impact Atherosclerotic Plaque Development in Mice. AB - BACKGROUND: Interleukin-23 (IL-23) has been implicated in inflammatory and autoimmune diseases by skewing CD4+ T helper cells towards a pathogenic Th17 phenotype. In this study we investigated the presence of IL-23 receptor (IL-23R) expressing cells in the atherosclerotic aorta and evaluated the effect of IL-23R deficiency on atherosclerosis development in mice. METHODS AND RESULTS: We used heterozygous Ldlr-/-Il23reGFP/WT knock-in mice to identify IL-23R-expressing cells by flow cytometry and homozygous Ldlr-/-Il23reGFP/eGFP (Ldlr-/-Il23r-/- ) mice to investigate the effect of lack of IL-23R in atherosclerosis. We demonstrate the presence of relatively rare IL-23R-expressing cells in lymphoid tissue and aorta (~0.1-1% IL23R+ cells of all CD45+ leukocytes). After 10 weeks on a high-fat diet, production of IL-17, but not interferon-gamma, by CD4+ T cells and other lymphocytes was reduced in Ldlr-/-Il23r-/- compared with Ldlr-/- controls. However, Ldlr-/- and Ldlr-/-Il23r-/- mice had equivalent amounts of aortic sinus and descending aorta lesions. Adoptive transfer of IL-23R-deficient CD4+ T cells to lymphopenic Ldlr-/-Rag1-/- resulted in dramatically reduced IL-17 producing T cells but did not reduce atherosclerosis, compared with transfer of IL-23R-sufficient CD4+ T cells. CONCLUSIONS: These data demonstrate that loss of IL-23R does not affect development of experimental atherosclerosis in LDLr deficient mice, despite a role for IL-23 in differentiation of IL-17-producing T cells. PMID- 29618475 TI - Novel Measure of Local Impedance Predicts Catheter-Tissue Contact and Lesion Formation. AB - BACKGROUND: Coupling between the ablation catheter and myocardium is critical to resistively heat tissue with radiofrequency ablation. The objective of this study was to evaluate whether a novel local impedance (LI) measurement on an ablation catheter identifies catheter-tissue coupling and is predictive of lesion formation. METHODS AND RESULTS: LI was studied in explanted hearts (n=10 swine) and in vivo (n=10; 50-70 kg swine) using an investigational electroanatomic mapping system that measures impedance from an ablation catheter with mini electrodes incorporated in the distal electrode (Rhythmia and IntellaNav MiFi OI, Boston Scientific). Explanted tissue was placed in a warmed (37 degrees C) saline bath mounted on a scale, and LI was measured 15 mm away from tissue to 5 mm of catheter-tissue compression at multiple catheter angles. Lesions were created with 31 and 50 W for 5 to 45 seconds (n=90). During in vivo evaluation of LI, measurements of myocardium (n=90) and blood pool (n=30) were guided by intracardiac ultrasound while operators were blinded to LI data. Lesions were created with 31 and 50 W for 45 seconds in the ventricles (n=72). LI of myocardium (119.7 Omega) was significantly greater than that of blood pool (67.6 Omega; P<0.01). Models that incorporate LI drop (DeltaLI) to predict lesion size had better performance than models that incorporate force-time integral (R2=0.75 versus R2=0.54) and generator impedance drop (R2=0.82 versus R2=0.58). Steam pops displayed a significantly higher starting LI and larger DeltaLI compared with successful radiofrequency applications (P<0.01). CONCLUSIONS: LI recorded from miniature electrodes provides a valuable measure of catheter-tissue coupling, and DeltaLI is predictive of lesion formation during radiofrequency ablation. PMID- 29618474 TI - Cruciferous and Total Vegetable Intakes Are Inversely Associated With Subclinical Atherosclerosis in Older Adult Women. AB - BACKGROUND: Dietary patterns rich in fruits and vegetables are considered to reduce atherosclerotic disease presentation and are reported to be inversely associated with subclinical measures of atherosclerosis, such as carotid artery intima-media thickness (IMT) and plaque. However, the effect of vegetable intake alone, and relationships to specific types of vegetables containing different phytochemical profiles, is important. The aim of this study was to investigate the associations of total vegetable intake and specific vegetables grouped according to phytochemical constituents with common carotid artery IMT (CCA-IMT) and carotid plaque severity in a cohort of older adult women (aged >=70 years). METHODS AND RESULTS: Total vegetable intake was calculated at baseline (1998) using a validated food frequency questionnaire. Vegetable types included cruciferous, allium, yellow/orange/red, leafy green, and legumes. In 2001, CCA IMT (n=954) and carotid focal plaque (n=968) were assessed using high-resolution B-mode carotid ultrasonography. Mean (SD) total vegetable intake was 199.9 (78.0) g/d. Women consuming >=3 servings of vegetables each day had ~4.6% to 5.0% lower mean CCA-IMT (P=0.014) and maximum CCA-IMT (P=0.004) compared with participants consuming <2 servings of vegetables. For each 10 g/d higher in cruciferous vegetable intake, there was an associated 0.006 mm (0.8%) lower mean CCA-IMT (P<0.01) and 0.007 mm (0.8%) lower maximum CCA-IMT (P<0.01). Other vegetable types were not associated with CCA-IMT (P>0.05). No associations were observed between vegetables and plaque severity (P>0.05). CONCLUSIONS: Increasing vegetables in the diet with a focus on consuming cruciferous vegetables may have benefits for the prevention of subclinical atherosclerosis in older adult women. CLINICAL TRIAL REGISTRATION: URL: http://www.anzctr.org.au. Unique identifier: ACTRN12615000750583. PMID- 29618476 TI - Differentiating Ventricular From Supraventricular Arrhythmias Using the Postpacing Interval After Failed Antitachycardia Pacing. AB - BACKGROUND: Implantable cardioverter defibrillator arrhythmia discrimination algorithms often are unable to discriminate ventricular from supraventricular arrhythmias. We sought to evaluate whether the response to antitachycardia pacing (ATP) in patients with an implantable cardioverter defibrillator could further discriminate ventricular from supraventricular arrhythmias in patients receiving ATP. METHODS AND RESULTS: All episodes of ventricular or supraventricular tachycardia where ATP was delivered in patients enrolled in RAFT (Cardiac Resynchronization Therapy for Mild-to-Moderate Heart Failure Trial) were included. RAFT randomized 1798 patients with New York Heart Association class II/III heart failure, left ventricular ejection fraction <=30%, and QRS duration of >=120 ms to a implantable cardioverter defibrillator+/-cardiac resynchronization therapy. The tachycardia cycle lengths (TCLs) before and after the delivery of ATP and the postpacing intervals were assessed. Overall, 10 916 ATP attempts were reviewed for 8150 tachycardia episodes in 924 patients. After excluding tachycardias where ATP terminated the episode or where the specific mechanism of the tachycardia was uncertain, we analyzed 3676 ATP attempts delivered for 2046 tachycardia episodes in 541 patients. A shorter difference between postpacing interval and TCL (PPI-TCL) was more likely to be associated with ventricular tachycardia than with supraventricular tachyarrhythmia (138.1+/ 104.2 versus 277.4+/-126.9 ms; p<0.001). Analysis of the receiver operator curve for the PPI-TCL revealed an area under the curve of 0.803 (p<0.001; 95% confidence interval, 0.784-0.822). The majority of tachycardias with a PPI-TCL >360 ms were supraventricular with a PPI-TCL value of <=360 ms having a sensitivity of 97.4% and specificity of 28.3% for ventricular tachycardia. CONCLUSIONS: The ATP response, specifically the PPI-TCL, can further discriminate ventricular from supraventricular arrhythmias in patients with implantable cardioverter defibrillators when the currently available discriminators fail. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00251251. PMID- 29618477 TI - Characteristics of Ice Impedance Recorded From a Ring Electrode Placed at the Anterior Surface of the Cryoballoon: Novel Approach to Define Ice Formation and Pulmonary Vein Isolation. AB - BACKGROUND: The success of cryoablation of the pulmonary vein isolation (PVI) is dependent on transmural and circumferential ice formation. We hypothesize that rising impedance recorded from a ring electrode placed 2 mm from the cryoballoon signifies ice formation covering the balloon surface and indicates ice expansion. The impedance level enables titration of the cryoapplication time to avoid extracardiac damage while ensuring PVI. METHODS AND RESULTS: In 12 canines, a total of 57 pulmonary veins were targeted for isolation. Two cryoapplications were delivered per vein with a minimum of 90 and maximum of 180-second duration. Cryoapplication was terminated on reaching a 500 Omega change from baseline. Animals recovered 38+/-6 days post-procedure, and veins were assessed electrically for isolation. Heart tissue was histologically analyzed. Extracardiac structures were examined for damage. PVI was achieved in 100% of the veins if the impedance reached 500 Omega in <90 seconds with freeze time of 90 seconds. When 500 Omega was reached >90 to 180 seconds (142.60+/-29.3 seconds), 90% PVI was achieved. When the final impedance was between 200 and 500 Omega with 180 seconds of freeze time, PVI was achieved in 86.8%. For impedance of <200 Omega, PVI was achieved in 14%. No extracardiac damage was recorded. CONCLUSIONS: Impedance rise of 500 Omega at <90 seconds with freeze time of 90 seconds resulted in 100% PVI. Impedance measurements from the nose of the balloon is a direct measure of ice formation on the balloon. It provides real-time feedback on the quality of the ablation and defines the cryoapplication termination time based on ice formation, limiting ice expansion to extracardiac tissues. PMID- 29618480 TI - A pain in the neck: Grisel's syndrome. PMID- 29618478 TI - NADPH oxidase activation regulates apoptotic neutrophil clearance by murine macrophages. AB - The phagocyte reduced NAD phosphate (NADPH) oxidase generates superoxide, the precursor to reactive oxygen species (ROS) that has both antimicrobial and immunoregulatory functions. Inactivating mutations in NADPH oxidase alleles cause chronic granulomatous disease (CGD), characterized by enhanced susceptibility to life-threatening microbial infections and inflammatory disorders; hypomorphic NADPH oxidase alleles are associated with autoimmunity. Impaired apoptotic cell (AC) clearance is implicated as an important contributing factor in chronic inflammation and autoimmunity, but the role of NADPH oxidase-derived ROS in this process is incompletely understood. Here, we demonstrate that phagocytosis of AC (efferocytosis) potently activated NADPH oxidase in mouse peritoneal exudate macrophages (PEMs). ROS generation was dependent on macrophage CD11b, Toll-like receptor 2 (TLR2), TLR4, and myeloid differentiation primary response 88 (MyD88), and was also regulated by phosphatidylinositol 3-phosphate binding to the p40 phox oxidase subunit. Maturation of efferosomes containing apoptotic neutrophils was significantly delayed in CGD PEMs, including acidification and acquisition of proteolytic activity, and was associated with slower digestion of apoptotic neutrophil proteins. Treatment of wild-type macrophages with the vacuolar-type H+ ATPase inhibitor bafilomycin also delayed proteolysis within efferosomes, showing that luminal acidification was essential for efficient digestion of efferosome proteins. Finally, cross-presentation of AC-associated antigens by CGD PEMs to CD8 T cells was increased. These studies unravel a key role for the NADPH oxidase in the disposal of ACs by inflammatory macrophages. The oxidants generated promote efferosome maturation and acidification that facilitate the degradation of ingested ACs. PMID- 29618479 TI - Comparable outcomes of patients eligible vs ineligible for SWOG leukemia studies. AB - Patients may be deemed ineligible for a clinical trial for reasons that do not directly impact efficacy or safety. We identified reasons for ineligibility and compared outcomes of ineligible with eligible patients treated on Southwest Oncology Group (SWOG) Leukemia Committee protocols. Patients enrolled in SWOG phase 2, 2/3, or 3 protocols open since 2005 were analyzed for eligibility status, reasons for ineligibility, baseline characteristics, Eastern Cooperative Oncology Group (ECOG) performance status (PS), serious adverse events (SAEs), complete remission (CR) status, and overall survival. A total of 2361 patients were enrolled in the 13 included studies. Of these, 247 (10%) were deemed ineligible; 78 were excluded from analyses, and 169 were included. Of the 169 included in analyses, 60% (101/169) were excluded due to missing baseline documentation. Baseline characteristics comparing ineligible to eligible patients were similar, with the exception of ECOG PS for S0325 (P = .02) and S0530 (P = .002). In multivariable analyses, neither the proportion of patients with ECOG PS >= 2 (P = .12) nor the rate of grade 5 SAEs (P = .62) differed between groups. There was no difference in survival between eligible and ineligible patients (P = .25), and CR rates were similar, with the exception of S0325 (P < .001) and S0703 (P = .004). The findings of this study suggest that nonessential eligibility criteria can be less restrictive, thus expanding patient enrollment and avoiding protocol deviations. The clinical trials included in this study were registered at www.clincialtrials.gov as #NCT00085709, #NCT00066794, #NCT00070499, #NCT00109837, #NCT00093418, #NCT00492856, #NCT00337168, #NCT00352365, #NCT00658814, #NCT00792948, #NCT00945815, #NCT00840177, and #NCT01522976. PMID- 29618481 TI - Question 2: Is there a role for Montelukast in the management of viral-induced wheeze in preschool children? PMID- 29618482 TI - 40 years of fabricated or induced illness (FII): where next for paediatricians? Paper 1: epidemiology and definition of FII. PMID- 29618483 TI - For debate: Forty years of fabricated or induced illness (FII): where next for paediatricians? Paper 2: Management of perplexing presentations including FII. PMID- 29618484 TI - Evaluating the process and outcomes of child death review in the Solomon Islands. AB - While maternal and perinatal mortality auditing has been strongly promoted by the World Health Organization (WHO), there has been very limited promotion or evaluation of child death auditing in low/middle-income settings. In 2017, a standardised child death review process was introduced in the paediatric department of the National Hospital in Honiara, Solomon Islands. We evaluated the process and outcomes of child death reviews. The child death auditing process was assessed through systematic observations made at each of the weekly meetings using the following standards for evaluation: (1) adapted WHO tools for paediatric auditing; (2) the five stages of the audit cycle; (3) published principles of paediatric audit; and (4) WHO and Solomon Islands national clinical standards of Hospital Care for Children. Thirty-three child death review meetings were conducted over 6 months, reviewing 66 neonatal and child deaths. Some areas of the process were satisfactory and other areas were identified for improvement. The latter included use of a more systematic classification of causes of death, inclusion of social risk factors and community problems in the modifiable factors and more follow-up with implementation of action plans. Areas for improvement were in communication, clinical assessment and treatment, availability of laboratory tests, antenatal clinic attendance and equipment for high dependency neonatal and paediatric care. Many of the changes recommended by audit require a quality improvement team to implement. Child death auditing can be done in resource-limited settings and yield useful information of gaps which are linked to preventable deaths; however, using the data to produce meaningful changes in practice is the greatest challenge. Audit is an iterative and evolving process that needs a structure, tools, evaluation, and needs to be embedded in the culture of a hospital as part of overall quality improvement, and requires a quality improvement team to follow-up and implement action plans. PMID- 29618485 TI - Ultrasound guidance for internal jugular vein cannulation in PICU: a randomised controlled trial. AB - OBJECTIVE: We investigated whether ultrasound guidance was advantageous over the anatomical landmark technique when performed by inexperienced paediatricians. DESIGN: Randomised controlled trial. SETTING: A paediatric intensive care unit of a teaching hospital. PATIENTS: 80 children (aged 28 days to <14 years). INTERVENTIONS: Internal jugular vein cannulation with ultrasound guidance in real time or the anatomical landmark technique. MAIN OUTCOME MEASURES: Success rate, success rate on the first attempt, success rate within three attempts, puncture time, number of attempts required for success and occurrence of complications. RESULTS: We found a higher success rate in the ultrasound guidance than in the control group (95% vs 61%, respectively; p<0.001; relative risk (RR)=0.64, 95% CI (CI) 0.50 to 0.83). Success on the first attempt was seen in 95% and 34% of venous punctures in the US guidance and control groups, respectively (p<0.001; RR=0.35, 95% CI 0.23 to 0.54). Fewer than three attempts were required to achieve success in 95% of patients in the US guidance group but only 44% in the control group (p<0.001; RR=0.46, 95% CI 0.32 to 0.66). Haematomas, inadvertent arterial punctures, the number of attempts and the puncture time were all significantly lower in the ultrasound guidance than in the control group (p<0.015 for all). CONCLUSIONS: Critically ill children may benefit from the ultrasound guidance for internal jugular cannulation, even when the procedure is performed by operators with limited experience. TRIAL REGISTRATION NUMBER: RBR-4t35tk. PMID- 29618486 TI - Optical mapping reveals a higher level of genomic architecture of chained fusions in cancer. AB - Genomic rearrangements are common in cancer, with demonstrated links to disease progression and treatment response. These rearrangements can be complex, resulting in fusions of multiple chromosomal fragments and generation of derivative chromosomes. Although methods exist for detecting individual fusions, they are generally unable to reconstruct complex chained events. To overcome these limitations, we adopted a new optical mapping approach, allowing megabase length genome maps to be reconstructed and rearranged genomes to be visualized without loss of integrity. Whole-genome mapping (Bionano Genomics) of a well studied highly rearranged liposarcoma cell line resulted in 3338 assembled consensus genome maps, including 72 fusion maps. These fusion maps represent 112.3 Mb of highly rearranged genomic regions, illuminating the complex architecture of chained fusions, including content, order, orientation, and size. Spanning the junction of 147 chromosomal translocations, we found a total of 28 Mb of interspersed sequences that could not be aligned to the reference genome. Traversing these interspersed sequences using short-read sequencing breakpoint calls, we were able to identify and place 399 sequencing fragments within the optical mapping gaps, thus illustrating the complementary nature of optical mapping and short-read sequencing. We demonstrate that optical mapping provides a powerful new approach for capturing a higher level of complex genomic architecture, creating a scaffold for renewed interpretation of sequencing data of particular relevance to human cancer. PMID- 29618488 TI - SULFATION PATHWAYS: Steroid sulphatase inhibition via aryl sulphamates: clinical progress, mechanism and future prospects. AB - Steroid sulphatase is an emerging drug target for the endocrine therapy of hormone-dependent diseases, catalysing oestrogen sulphate hydrolysis to oestrogen. Drug discovery, developing the core aryl O-sulphamate pharmacophore, has led to steroidal and non-steroidal drugs entering numerous clinical trials, with promising results in oncology and women's health. Steroidal oestrogen sulphamate derivatives were the first irreversible active-site-directed inhibitors and one was developed clinically as an oral oestradiol pro-drug and for endometriosis applications. This review summarizes work leading to the therapeutic concept of sulphatase inhibition, clinical trials executed to date and new insights into the mechanism of inhibition of steroid sulphatase. To date, the non-steroidal sulphatase inhibitor Irosustat has been evaluated clinically in breast cancer, alone and in combination, in endometrial cancer and in prostate cancer. The versatile core pharmacophore both imbues attractive pharmaceutical properties and functions via three distinct mechanisms of action, as a pro-drug, an enzyme active-site-modifying motif, likely through direct sulphamoyl group transfer, and as a structural component augmenting activity, for example by enhancing interactions at the colchicine binding site of tubulin. Preliminary new structural data on the Pseudomonas aeruginosa arylsulphatase enzyme suggest two possible sulphamate-based adducts with the active site formylglycine as candidates for the inhibition end product via sulphamoyl or sulphonylamine transfer, and a speculative choice is suggested. The clinical status of sulphatase inhibition is surveyed and how it might develop in the future. Also discussed are dual-targeting approaches, development of 2-substituted steroidal sulphamates and non-steroidal derivatives as multi-targeting agents for hormone independent tumours, with other emerging directions. PMID- 29618487 TI - Integrated analysis sheds light on evolutionary trajectories of young transcription start sites in the human genome. AB - Understanding the molecular mechanisms and evolution of the gene regulatory system remains a major challenge in biology. Transcription start sites (TSSs) are especially interesting because they are central to initiating gene expression. Previous studies revealed widespread transcription initiation and fast turnover of TSSs in mammalian genomes. Yet, how new TSSs originate and how they evolve over time remain poorly understood. To address these questions, we analyzed ~200,000 human TSSs by integrating evolutionary (inter- and intra-species) and functional genomic data, particularly focusing on evolutionarily young TSSs that emerged in the primate lineage. TSSs were grouped according to their evolutionary age using sequence alignment information as a proxy. Comparisons of young and old TSSs revealed that (1) new TSSs emerge through a combination of intrinsic factors, like the sequence properties of transposable elements and tandem repeats, and extrinsic factors such as their proximity to existing regulatory modules; (2) new TSSs undergo rapid evolution that reduces the inherent instability of repeat sequences associated with a high propensity of TSS emergence; and (3) once established, the transcriptional competence of surviving TSSs is gradually enhanced, with evolutionary changes subject to temporal (fewer regulatory changes in younger TSSs) and spatial constraints (fewer regulatory changes in more isolated TSSs). These findings advance our understanding of how regulatory innovations arise in the genome throughout evolution and highlight the genomic robustness and evolvability in these processes. PMID- 29618489 TI - Beyond "Asian": Specific East and Southeast Asian Races or Ethnicities Associated With Jaundice Readmission. AB - OBJECTIVES: Clinical practice guidelines have recognized "Asian" and "East Asian" as risk factors for newborn jaundice and readmission. We sought to identify more detailed and specific, parent-identified races or ethnicities associated with jaundice readmission. METHODS: We conducted a case control study of 653 newborn infants born (2014-2016) at a West-Coast, urban hospital to examine specific parent-described races or ethnicities that are associated with newborn hospital readmissions for hyperbilirubinemia. Parent-reported race or ethnicity was abstracted from the California Newborn Screening Test. RESULTS: Our sample included 105 infants readmitted for jaundice (cases) and 548 infants as controls. In the full cohort, 66 infants (10.1%) were Coombs positive, 39 infants (6.0%) were born before 37 weeks' gestational age, and 405 infants (62.0%) were born to first-time mothers. The parents described the 653 infants using 45 unique races and ethnicities. In a multivariable model that controlled for Coombs positivity, gestational age <37 weeks, and primiparity, infants described as "Far East Asian" (odds ratio [OR] = 3.17; 95% confidence interval [CI] = 1.94-5.18) or "Southeast Asian" (OR = 3.17; 95% CI = 1.66-6.08) had increased risk for jaundice readmission. Infants described as Southeast Asian (eg, Laotian, Cambodian, Indonesian, Vietnamese, and Filipino) and Far East Asian (eg, Chinese, Korean, Taiwanese, Japanese, and Mongolian) had an increased risk of readmission. Finally, we did not find an association between South Asian (OR = 0.79; 95% CI = 0.33-1.92) race or ethnicity and risk of jaundice readmission. CONCLUSIONS: In this study, we help clarify and move beyond the term "Asian" as a risk factor for readmission due to hyperbilirubinemia. PMID- 29618491 TI - JASN this Month: Something Old, Something New. PMID- 29618490 TI - Uhrf1 regulates germinal center B cell expansion and affinity maturation to control viral infection. AB - The production of high-affinity antibody is essential for pathogen clearance. Antibody affinity is increased through germinal center (GC) affinity maturation, which relies on BCR somatic hypermutation (SHM) followed by antigen-based selection. GC B cell proliferation is essentially involved in these processes; it provides enough templates for SHM and also serves as a critical mechanism of positive selection. In this study, we show that expression of epigenetic regulator ubiquitin-like with PHD and RING finger domains 1 (Uhrf1) was markedly up-regulated by c-Myc-AP4 in GC B cells, and it was required for GC response. Uhrf1 regulates cell proliferation-associated genes including cdkn1a, slfn1, and slfn2 by DNA methylation, and its deficiency inhibited the GC B cell cycle at G1 S phase. Subsequently, GC B cell SHM and affinity maturation were impaired, and Uhrf1 GC B knockout mice were unable to control chronic virus infection. Collectively, our data suggest that Uhrf1 regulates GC B cell proliferation and affinity maturation, and its expression in GC B cells is required for virus clearance. PMID- 29618492 TI - Autophagy regulates testosterone synthesis by facilitating cholesterol uptake in Leydig cells. AB - Testosterone is indispensable for sexual development and maintaining male characteristics, and deficiency of this hormone results in primary or late-onset hypogonadism (LOH). Testosterone is primarily produced in Leydig cells, where autophagy has been reported to be extremely active. However, the functional role of autophagy in testosterone synthesis remains unknown. In this study, we show that steroidogenic cell-specific disruption of autophagy influenced the sexual behavior of aging male mice because of a reduction in serum testosterone, which is similar to the symptoms of LOH. The decline in testosterone was caused mainly by a defect in cholesterol uptake in autophagy-deficient Leydig cells. Further studies revealed that once autophagic flux was disrupted, Na+/H+ exchanger regulatory factor 2 (NHERF2) accumulated in Leydig cells, resulting in the down regulation of scavenger receptor class B, type I (SR-BI) and eventually leading to insufficient cholesterol supply. Collectively, these results reveal that autophagy promotes cholesterol uptake into Leydig cells by eliminating NHERF2, suggesting that dysfunction of autophagy might be causal in the loss of testosterone production in some patients. PMID- 29618494 TI - Does free or lower cost smoking cessation medication stimulate quitting? Findings from the International Tobacco Control (ITC) Netherlands and UK surveys. AB - OBJECTIVE: To investigate whether mentioning free or lower cost smoking cessation medication as a trigger for thinking about quitting is related to higher medication use, more quit attempts and quit success, and whether these associations are modified by education and income. METHODS: Data were derived from the 2013 and 2014 surveys of the International Tobacco Control Netherlands (n=1164) and UK (n=768) cohort. Logistic regression analyses were used to assess associations between mentioning in 2013 that free/lower cost smoking cessation medication was a trigger for thinking about quitting smoking and the use of medication, quit attempts and smoking cessation in 2014. RESULTS: 37.0% of smokers in the UK and 24.9% of smokers in the Netherlands mentioned free/lower cost medication as a trigger for thinking about quitting. Smokers who mentioned this trigger were more likely to have used cessation medication during a quit attempt both in the UK (OR=4.19, p<0.001) and in the Netherlands (OR=2.14, p=0.033). The association between mentioning free/lower cost medication as a trigger for thinking about quitting and actual quit attempts was significant in the UK (OR=1.45, p=0.030), but not in the Netherlands (OR=1.10, p=0.587). There was no significant association with quit success. Associations did not differ across income and education groups. CONCLUSION: Free/lower cost smoking cessation medication may increase the use of cessation medication and stimulate quit attempts among smokers with low, moderate and high education and income. PMID- 29618495 TI - Fibrinogen does not relate to cardiovascular or muscle manifestations in COPD: cross-sectional data from the ERICA study. AB - Cardiovascular and skeletal muscle manifestations constitute important comorbidities in COPD, with systemic inflammation proposed as a common mechanistic link. Fibrinogen has prognostic role in COPD. We aimed to determine whether aortic stiffness and quadriceps weakness are linked in COPD, and whether they are associated with the systemic inflammatory mediator-fibrinogen. Aortic pulse wave velocity (aPWV), quadriceps maximal volitional contraction (QMVC) force and fibrinogen were measured in 729 patients with stable, Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages II-IV COPD. The cardiovascular and muscular manifestations exist independently (P=0.22, chi2). Fibrinogen was not associated with aPWV or QMVC (P=0.628 and P=0.621, respectively), making inflammation, as measured by plasma fibrinogen, an unlikely common aetiological factor. PMID- 29618493 TI - Time matters in multiple sclerosis: can early treatment and long-term follow-up ensure everyone benefits from the latest advances in multiple sclerosis? PMID- 29618496 TI - Cell-centred meta-analysis reveals baseline predictors of anti-TNFalpha non response in biopsy and blood of patients with IBD. AB - OBJECTIVE: Although anti-tumour necrosis factor alpha (anti-TNFalpha) therapies represent a major breakthrough in IBD therapy, their cost-benefit ratio is hampered by an overall 30% non-response rate, adverse side effects and high costs. Thus, finding predictive biomarkers of non-response prior to commencing anti-TNFalpha therapy is of high value. DESIGN: We analysed publicly available whole-genome expression profiles of colon biopsies obtained from multiple cohorts of patients with IBD using a combined computational deconvolution-meta-analysis paradigm which allows to estimate immune cell contribution to the measured expression and capture differential regulatory programmes otherwise masked due to variation in cellular composition. Insights from this in silico approach were experimentally validated in biopsies and blood samples of three independent test cohorts. RESULTS: We found the proportion of plasma cells as a robust pretreatment biomarker of non-response to therapy, which we validated in two independent cohorts of immune-stained colon biopsies, where a plasma cellular score from inflamed biopsies was predictive of non-response with an area under the curve (AUC) of 82%. Meta-analysis of the cell proportion-adjusted gene expression data suggested that an increase in inflammatory macrophages in anti TNFalpha non-responding individuals is associated with the upregulation of the triggering receptor expressed on myeloid cells 1 (TREM-1) and chemokine receptor type 2 (CCR2)-chemokine ligand 7 (CCL7) -axes. Blood gene expression analysis of an independent cohort, identified TREM-1 downregulation in non-responders at baseline, which was predictive of response with an AUC of 94%. CONCLUSIONS: Our study proposes two clinically feasible assays, one in biopsy and one in blood, for predicting non-response to anti-TNFalpha therapy prior to initiation of treatment. Moreover, it suggests that mechanism-driven novel drugs for non responders should be developed. PMID- 29618497 TI - Distal versus proximal intestinal short-chain fatty acid release in man. PMID- 29618498 TI - Impact of thiopurines on the natural history and surgical outcome of ulcerative colitis: a cohort study. AB - OBJECTIVE: Thiopurines are used as maintenance therapy in ulcerative colitis (UC), but whether these drugs influence the natural history of the disease is unknown. We aimed to assess the effect of thiopurines in terms of colectomy, hospital admission, progression in disease extent and anti-tumour necrosis factor (TNF) therapy within 10 years from initiation. DESIGN: Patients diagnosed with UC within the Orebro University Hospital catchment area, during 1963-2010, who initiated thiopurines (n=253) were included. To overcome the risk of confounding by indication, we compared patients who stopped treatment within 12 months because of an adverse reaction (n=76) with patients who continued therapy or discontinued due to other reasons (n=177) and assessed long-term outcomes using Cox regression with adjustment for potential confounding factors. RESULTS: The cumulative probability of colectomy within 10 years was 19.5% in tolerant patients compared with 29.0% in intolerant (adjusted HR 0.49; 95% CI 0.21 to 0.73). The probability of hospital admission was 34.0% in tolerant versus 56.2% in intolerant patients (adjusted HR 0.36; 95% CI 0.23 to 0.56). The risk for progression in disease extent was 20.4% in tolerant patients compared with 48.8% in intolerant (adjusted HR 0.47; 95% CI 0.21 to 1.06). Within 10 years, 16.1% of tolerant and 27.5% of intolerant patients received anti-TNF therapy (adjusted HR 0.49; 95% CI 0.26 to 0.92). CONCLUSION: Based on the novel approach of comparing patients tolerant and intolerant to thiopurines, we reveal that thiopurines have a profound beneficial impact of the natural history and long-term colectomy rates of UC. PMID- 29618499 TI - Comparison of an In Vitro Diagnostic Next-Generation Sequencing Assay with Sanger Sequencing for HIV-1 Genotypic Resistance Testing. AB - The ability of next-generation sequencing (NGS) technologies to detect low frequency HIV-1 drug resistance mutations (DRMs) not detected by dideoxynucleotide Sanger sequencing has potential advantages for improved patient outcomes. We compared the performance of an in vitro diagnostic (IVD) NGS assay, the Sentosa SQ HIV genotyping assay for HIV-1 genotypic resistance testing, with Sanger sequencing on 138 protease/reverse transcriptase (RT) and 39 integrase sequences. The NGS assay used a 5% threshold for reporting low-frequency variants. The level of complete plus partial nucleotide sequence concordance between Sanger sequencing and NGS was 99.9%. Among the 138 protease/RT sequences, a mean of 6.4 DRMs was identified by both Sanger and NGS, a mean of 0.5 DRM was detected by NGS alone, and a mean of 0.1 DRM was detected by Sanger sequencing alone. Among the 39 integrase sequences, a mean of 1.6 DRMs was detected by both Sanger sequencing and NGS and a mean of 0.15 DRM was detected by NGS alone. Compared with Sanger sequencing, NGS estimated higher levels of resistance to one or more antiretroviral drugs for 18.2% of protease/RT sequences and 5.1% of integrase sequences. There was little evidence for technical artifacts in the NGS sequences, but the G-to-A hypermutation was detected in three samples. In conclusion, the IVD NGS assay evaluated in this study was highly concordant with Sanger sequencing. At the 5% threshold for reporting minority variants, NGS appeared to attain a modestly increased sensitivity for detecting low-frequency DRMs without compromising sequence accuracy. PMID- 29618500 TI - Comparison of Manual and Fully Automated AIX1000 Rapid Plasma Reagin Assays for Laboratory Diagnosis of Syphilis. AB - The analytical performance of the AIX1000 system, a fully automated and recently FDA-cleared rapid plasma reagin (RPR) system, was evaluated by comparison to a manual RPR test in a traditional syphilis testing algorithm. A total of 1,028 consecutive serum samples submitted for syphilis testing to the University of North Carolina Hospitals Clinical Immunology Laboratory were tested per each manufacturer's instructions. Among those samples, 996 were nonreactive and 20 were reactive using both the ASI RPR card system and the AIX1000 system. Of the 12 discrepant specimens, 11 were AIX1000 reactive and ASI card nonreactive whereas 1 specimen was ASI card reactive and AIX1000 nonreactive. The sensitivity and specificity of the manual ASI card were 76.0% and 99.8%, respectively, while the sensitivity and specificity of the AIX100 were 100.0% and 99.4%, respectively (sensitivity P = 0.03). Among the 20 concordant reactive specimens, 68.4% of the titers agreed within +/-1 dilution between methods. Reproducibility testing of the AIX1000 system demonstrated qualitative and semiquantitative (within +/-1 dilution) agreement between specimens tested on different days of 96.0% and 76.0%, respectively, and 100.0% agreement between replicates within the same run. One of 24 samples analyzed under other disease conditions was reactive on both the AIX1000 system and the ASI card. Overall, the fully automated AIX1000 system demonstrated significantly enhanced sensitivity and specificity similar to that of the manual ASI RPR card test, making the AIX1000 system suitable for the laboratory diagnosis of syphilis in a clinical laboratory setting. PMID- 29618501 TI - Use of External Quality Control Material for HIV-1 RNA Testing To Assess the Comparability of Data Generated in Separate Laboratories and the Stability of HIV 1 RNA in Samples after Prolonged Storage. AB - The National Institute of Allergy and Infectious Diseases (NIAID) AIDS Clinical Trials Group (ACTG) stores specimens from its clinical trials in a biorepository and permits the use of these specimens for nonprotocol exploratory studies, once the studies for the original protocol are concluded. We sought to assess the comparability of the data generated from real-time HIV-1 RNA testing during two clinical trials with the data generated from the retesting of different aliquots of the same samples after years of storage at -80 degrees C. Overall, there was 92% agreement in the data generated for 1,570 paired samples (kappa statistic = 0.757; 95% confidence interval [CI], 0.716 to 0.797), where samples were tested in one laboratory using the microwell plate (MWP) version of the Roche HIV-1 Monitor test within 1 to 37 days of collection and retested in another laboratory using the Cobas version of the assay after a median of 6.7 years of storage (range, 5.7 to 8.6 years). Historical external quality control data submitted to the NIAID Virology Quality Assurance program (VQA) by client laboratories using the same two versions of the Monitor assay were used to differentiate between systematic differences in the assays to evaluate the stability of HIV-1 RNA in the stored samples. No significant loss of RNA was noted in samples containing either a low concentration (<50 copies/ml) or a high concentration (>=50 copies/ml) of HIV-1 RNA (P = 0.10 and P = 0.90, respectively) regardless of the time in storage. These data confirm the quality of the plasma samples in the ACTG biorepository following long-term storage. PMID- 29618502 TI - Group B Streptococcus Vaginal Carriage in Pregnant Women as Deciphered by Clustered Regularly Interspaced Short Palindromic Repeat Analysis. AB - We evaluated the diversity of group B Streptococcus (GBS) vaginal carriage populations in pregnant women. For this purpose, we studied each isolate present in a primary culture of a vaginal swab using a new approach based on clustered regularly interspaced short palindromic repeats (CRISPR) locus analysis. To evaluate the CRISPR array composition rapidly, a restriction fragment length polymorphism (RFLP) analysis was performed. For each different pattern observed, the CRISPR array was sequenced and capsular typing and multilocus sequence typing (MLST) were performed. A total of 970 isolates from 10 women were analyzed by CRISPR-RFLP. Each woman carrying GBS isolates presented one to five specific "personal" patterns. Five women showed similar isolates with specific and unique restriction patterns, suggesting the carriage of a single GBS clone. Different patterns were observed among isolates from the other five women. For three of these, CRISPR locus sequencing highlighted low levels of internal modifications in the locus backbone, whereas there were high levels of modifications for the last two women, suggesting the carriage of two different clones. These two clones were closely related, having the same ancestral spacer(s), the same capsular type and, in one case, the same ST, but showed different antibiotic resistance patterns in pairs. Eight of 10 women were colonized by a single GBS clone, while two of them were colonized by two strains, leading to a risk of selection of more virulent and/or more-resistant clones during antibiotic prophylaxis. This CRISPR analysis made it possible to separate isolates belonging to a single capsular type and sequence type, highlighting the greater discriminating power of this approach. PMID- 29618503 TI - Defining and Evaluating a Core Genome Multilocus Sequence Typing Scheme for Genome-Wide Typing of Clostridium difficile. AB - Clostridium difficile, recently renamed Clostridioides difficile, is the most common cause of antibiotic-associated nosocomial gastrointestinal infections worldwide. To differentiate endogenous infections and transmission events, highly discriminatory subtyping is necessary. Today, methods based on whole-genome sequencing data are increasingly used to subtype bacterial pathogens; however, frequently a standardized methodology and typing nomenclature are missing. Here we report a core genome multilocus sequence typing (cgMLST) approach developed for C. difficile Initially, we determined the breadth of the C. difficile population based on all available MLST sequence types with Bayesian inference (BAPS). The resulting BAPS partitions were used in combination with C. difficile clade information to select representative isolates that were subsequently used to define cgMLST target genes. Finally, we evaluated the novel cgMLST scheme with genomes from 3,025 isolates. BAPS grouping (n = 6 groups) together with the clade information led to a total of 11 representative isolates that were included for cgMLST definition and resulted in 2,270 cgMLST genes that were present in all isolates. Overall, 2,184 to 2,268 cgMLST targets were detected in the genome sequences of 70 outbreak-associated and reference strains, and on average 99.3% cgMLST targets (1,116 to 2,270 targets) were present in 2,954 genomes downloaded from the NCBI database, underlining the representativeness of the cgMLST scheme. Moreover, reanalyzing different cluster scenarios with cgMLST were concordant to published single nucleotide variant analyses. In conclusion, the novel cgMLST is representative for the whole C. difficile population, is highly discriminatory in outbreak situations, and provides a unique nomenclature facilitating interlaboratory exchange. PMID- 29618504 TI - Kaptive Web: User-Friendly Capsule and Lipopolysaccharide Serotype Prediction for Klebsiella Genomes. AB - As whole-genome sequencing becomes an established component of the microbiologist's toolbox, it is imperative that researchers, clinical microbiologists, and public health professionals have access to genomic analysis tools for the rapid extraction of epidemiologically and clinically relevant information. For the Gram-negative hospital pathogens such as Klebsiella pneumoniae, initial efforts have focused on the detection and surveillance of antimicrobial resistance genes and clones. However, with the resurgence of interest in alternative infection control strategies targeting Klebsiella surface polysaccharides, the ability to extract information about these antigens is increasingly important. Here we present Kaptive Web, an online tool for the rapid typing of Klebsiella K and O loci, which encode the polysaccharide capsule and lipopolysaccharide O antigen, respectively. Kaptive Web enables users to upload and analyze genome assemblies in a web browser. The results can be downloaded in tabular format or explored in detail via the graphical interface, making it accessible for users at all levels of computational expertise. We demonstrate Kaptive Web's utility by analyzing >500 K. pneumoniae genomes. We identify extensive K and O locus diversity among 201 genomes belonging to the carbapenemase-associated clonal group 258 (25 K and 6 O loci). The characterization of a further 309 genomes indicated that such diversity is common among the multidrug-resistant clones and that these loci represent useful epidemiological markers for strain subtyping. These findings reinforce the need for rapid, reliable, and accessible typing methods such as Kaptive Web. Kaptive Web is available for use at http://kaptive.holtlab.net/, and the source code is available at https://github.com/kelwyres/Kaptive-Web. PMID- 29618506 TI - Biochemical and molecular characterisation of neurological Wilson disease. AB - BACKGROUND: To identify biochemical and genetic features that characterise neurological Wilson disease as a distinct disease subgroup. METHODS: Detailed biochemical profiles and genotypic characteristics of neurological (86 patients) and hepatic subgroups (233 patients) from 368 unrelated Korean families were analysed. RESULTS: Compared with patients in the hepatic subgroup, patients in the neurological subgroup had a later age at onset, a higher proportion with Kayser-Fleischer rings and higher serum creatinine levels, and a lower proportion with favourable outcome (62% vs 80%, P<0.016). At diagnosis, the neurological subgroup had lower serum ceruloplasmin (3.1+/-2.1 mg/dL vs 4.2+/-3.2 mg/dL, P<0.001), total copper (26.4+/-13.8 ug/dL vs 35.8+/-42.4 ug/dL, P=0.005), free copper (17.2+/-12.5 ug/dL vs 23.5+/-38.2 ug/dL, P=0.038) and urinary copper (280.9+/-162.9 ug/day vs 611.1+/-1124.2 ug/day, P<0.001) levels. Serum aspartate aminotransferase, alanine aminotransferase, gamma glutamyltransferase and total bilirubin levels, as well as prothrombin time, were also lower in the neurological subgroup. Liver cirrhosis was more common but mostly compensated in the neurological subgroup. Frameshift, nonsense or splice-site ATP7B mutations and mutations in transduction or ATP hinge domains (2.4% vs 23.1%, P=0.006) were less common in the neurological subgroup. CONCLUSION: The neurological subgroup had distinct clinical, biochemical and genetic profiles. Further studies are required to identify the factors, with or without association with copper metabolism, underlying the neurological presentation for which treatment needs to be targeted to improve the clinical outcome of this subgroup. PMID- 29618505 TI - Incorporation of IgG Depletion in a Neutralization Assay Facilitates Differential Diagnosis of Zika and Dengue in Secondary Flavivirus Infection Cases. AB - Zika virus (ZIKV) has emerged as a major global public health concern due to its link as a causative agent of human birth defects. Laboratory diagnosis of suspected ZIKV infections by serological testing of specimens collected a week or more after symptom onset primarily relies on detection of anti-ZIKV-specific IgM antibodies by enzyme-linked immunosorbent assay coupled with detection of ZIKV specific neutralizing antibody by neutralization tests. A definitive diagnosis based on serological assays is possible during primary ZIKV infections; however, due to the cross-reactivity of antibodies elicited during flaviviral infections, a definitive diagnosis is not always possible, especially among individuals who have previously been exposed to closely related flaviviruses, such as dengue virus (DENV). Here, we investigated the neutralizing IgM antibody profiles of 33 diagnostic specimens collected from individuals with suspected primary and secondary flaviviral infections acquired when visiting areas experiencing active ZIKV transmission in 2015 and 2016. Specimens collected between 1 day and 3 months postexposure were tested for ZIKV and dengue virus type 1 (DENV1) and type 2 (DENV2) by the plaque reduction neutralization test (PRNT) before and after IgG depletion. We found that IgG depletion prior to neutralization testing had little effect in differentiating samples from individuals with secondary infections taken less than 3 weeks postexposure; however, IgG depletion significantly reduced the cross-reactive neutralizing antibody titers and increased the percentage of cases discernible by PRNT from 15.4% (95% confidence interval [CI], 4.3 to 42.2%) to 76.9% (95% CI, 49.7 to 91.8%) for samples collected between roughly 3 and 12 weeks postexposure. These results highlight the potential of IgG depletion to improve the specificity of PRNT for better confirmation and differential diagnosis of flavivirus infections. PMID- 29618508 TI - A Sephin1-insensitive tripartite holophosphatase dephosphorylates translation initiation factor 2alpha. AB - The integrated stress response (ISR) is regulated by kinases that phosphorylate the alpha subunit of translation initiation factor 2 and phosphatases that dephosphorylate it. Genetic and biochemical observations indicate that the eIF2alphaP-directed holophosphatase, a therapeutic target in diseases of protein misfolding, is comprised of a regulatory subunit, PPP1R15, and a catalytic subunit, protein phosphatase 1 (PP1). In mammals, there are two isoforms of the regulatory subunit, PPP1R15A and PPP1R15B, with overlapping roles in the essential function of eIF2alphaP dephosphorylation. However, conflicting reports have appeared regarding the requirement for an additional co-factor, G-actin, in enabling substrate-specific dephosphorylation by PPP1R15-containing PP1 holoenzymes. An additional concern relates to the sensitivity of the holoenzyme to the [(o-chlorobenzylidene)amino]guanidines Sephin1 or guanabenz, putative small-molecule proteostasis modulators. It has been suggested that the source and method of purification of the PP1 catalytic subunit and the presence or absence of an N-terminal repeat-containing region in the PPP1R15A regulatory subunit might influence the requirement for G-actin and sensitivity of the holoenzyme to inhibitors. We found that eIF2alphaP dephosphorylation by PP1 was moderately stimulated by repeat-containing PPP1R15A in an unphysiological low ionic strength buffer, whereas stimulation imparted by the co-presence of PPP1R15A and G-actin was observed under a broad range of conditions, low and physiological ionic strength, regardless of whether the PPP1R15A regulatory subunit had or lacked the N-terminal repeat-containing region and whether it was paired with native PP1 purified from rabbit muscle or recombinant PP1 purified from bacteria. Furthermore, none of the PPP1R15A-containing holophosphatases tested were inhibited by Sephin1 or guanabenz. PMID- 29618509 TI - Dimerization of p15RS mediated by a leucine zipper-like motif is critical for its inhibitory role on Wnt signaling. AB - We previously demonstrated that p15RS, a newly discovered tumor suppressor, inhibits Wnt/beta-catenin signaling by interrupting the formation of beta catenin.TCF4 complex. However, it remains unclear how p15RS helps exert such an inhibitory effect on Wnt signaling based on its molecular structure. In this study, we reported that dimerization of p15RS is required for its inhibition on the transcription regulation of Wnt-targeted genes. We found that p15RS forms a dimer through a highly conserved leucine zipper-like motif in the coiled-coil terminus domain. In particular, residues Leu-248 and Leu-255 were identified as being responsible for p15RS dimerization, as mutation of these two leucines into prolines disrupted the homodimer formation of p15RS and weakened its suppression of Wnt signaling. Functional studies further confirmed that mutations of p15RS at these residues results in diminishment of its inhibition on cell proliferation and tumor formation. We therefore concluded that dimerization of p15RS governed by the leucine zipper-like motif is critical for its inhibition of Wnt/beta catenin signaling and tumorigenesis. PMID- 29618507 TI - Further delineation of the MECP2 duplication syndrome phenotype in 59 French male patients, with a particular focus on morphological and neurological features. AB - The Xq28 duplication involving the MECP2 gene (MECP2 duplication) has been mainly described in male patients with severe developmental delay (DD) associated with spasticity, stereotypic movements and recurrent infections. Nevertheless, only a few series have been published. We aimed to better describe the phenotype of this condition, with a focus on morphological and neurological features. Through a national collaborative study, we report a large French series of 59 affected males with interstitial MECP2 duplication. Most of the patients (93%) shared similar facial features, which evolved with age (midface hypoplasia, narrow and prominent nasal bridge, thick lower lip, large prominent ears), thick hair, livedo of the limbs, tapered fingers, small feet and vasomotor troubles. Early hypotonia and global DD were constant, with 21% of patients unable to walk. In patients able to stand, lower limbs weakness and spasticity led to a singular standing habitus: flexion of the knees, broad-based stance with pseudo-ataxic gait. Scoliosis was frequent (53%), such as divergent strabismus (76%) and hypermetropia (54%), stereotypic movements (89%), without obvious social withdrawal and decreased pain sensitivity (78%). Most of the patients did not develop expressive language, 35% saying few words. Epilepsy was frequent (59%), with a mean onset around 7.4 years of age, and often (62%) drug-resistant. Other medical issues were frequent: constipation (78%), and recurrent infections (89%), mainly lung. We delineate the clinical phenotype of MECP2 duplication syndrome in a large series of 59 males. Pulmonary hypertension appeared as a cause of early death in these patients, advocating its screening early in life. PMID- 29618510 TI - Mg2+ binding triggers rearrangement of the IM30 ring structure, resulting in augmented exposure of hydrophobic surfaces competent for membrane binding. AB - The "inner membrane-associated protein of 30 kDa" (IM30), also known as "vesicle inducing protein in plastids 1" (Vipp1), is found in the majority of photosynthetic organisms that use oxygen as an energy source, and its occurrence appears to be coupled to the existence of thylakoid membranes in cyanobacteria and chloroplasts. IM30 is most likely involved in thylakoid membrane biogenesis and/or maintenance, and has recently been shown to function as a membrane fusion protein in presence of Mg2+ However, the precise role of Mg2+ in this process and its impact on the structure and function of IM30 remains unknown. Here, we show that Mg2+ binds directly to IM30 with a binding affinity of ~1 mm Mg2+ binding compacts the IM30 structure coupled with an increase in the thermodynamic stability of the proteins' secondary, tertiary, and quaternary structures. Furthermore, the structural alterations trigger IM30 double ring formation in vitro because of increased exposure of hydrophobic surface regions. However, in vivo Mg2+-triggered exposure of hydrophobic surface regions most likely modulates membrane binding and induces membrane fusion. PMID- 29618511 TI - Structural and functional delineation of aerobactin biosynthesis in hypervirulent Klebsiella pneumoniae. AB - Aerobactin, a citryl-hydroxamate siderophore, is produced by a number of pathogenic Gram-negative bacteria to aid in iron assimilation. Interest in this well-known siderophore was reignited by recent investigations suggesting that it plays a key role in mediating the enhanced virulence of a hypervirulent pathotype of Klebsiella pneumoniae (hvKP). In contrast to classical opportunistic strains of K. pneumoniae, hvKP causes serious life-threatening infections in previously healthy individuals in the community. Multiple contemporary reports have confirmed fears that the convergence of multidrug-resistant and hvKP pathotypes has led to the evolution of a highly transmissible, drug-resistant, and virulent "super bug." Despite hvKP harboring four distinct siderophore operons, knocking out production of only aerobactin led to a significant attenuation of virulence. Herein, we continue our structural and functional studies on the biosynthesis of this crucial virulence factor. In vivo heterologous production and in vitro reconstitution of aerobactin biosynthesis from hvKP was carried out, demonstrating the specificity, stereoselectivity, and kinetic throughput of the complete pathway. Additionally, we present a steady-state kinetic analysis and the X-ray crystal structure of the second aerobactin synthetase IucC, as well as describe a surface entropy reduction strategy that was employed for structure determination. Finally, we show solution X-ray scattering data that support a unique dimeric quaternary structure for IucC. These new insights into aerobactin assembly will help inform potential antivirulence strategies and advance our understanding of siderophore biosynthesis. PMID- 29618513 TI - The full-length cytochrome P450 enzyme CYP102A1 dimerizes at its reductase domains and has flexible heme domains for efficient catalysis. AB - The cytochrome P450 enzyme CYP102A1 from Bacillus megaterium is a highly efficient hydroxylase of fatty acids, and there is a significant interest in using CYP102A1 for biotechnological applications. Here, we used size-exclusion chromatography-multiangle light scattering (SEC-MALS) analysis and negative-stain EM to investigate the molecular architecture of CYP102A1. The SEC-MALS analysis yielded a homogeneous peak with an average molecular mass of 235 +/- 5 kDa, consistent with homodimeric CYP102A1. The negative-stain EM of dimeric CYP102A1 revealed four distinct lobes, representing the two heme and two reductase domains. Two of the lobes were in close contact, whereas the other two were often observed apart and at the ends of a U-shaped configuration. The overall dimension of the dimer was ~130 A. To determine the identity of the lobes, we FLAG-tagged the N or C terminus of CYP102A1 to visualize additional densities in EM and found that anti-FLAG Fab could bind only the N-tagged P450. Single-particle analysis of this anti-Flag Fab-CYP102A1 complex revealed additional density in the N terminally tagged heme domains, indicating that the heme domains appear flexible, whereas the reductase domains remain tightly associated. The effects of truncation on CYP102A1 dimerization, identification of cross-linked sites by peptide mapping, and molecular modeling results all were consistent with the dimerization of the reductase domain. We conclude that functional CYP102A1 is a compact globular protein dimerized at its reductase domains, with its heme domains exhibiting multiple conformations that likely contribute to the highly efficient catalysis of CYP102A1. PMID- 29618512 TI - Cyclase-associated protein 1 (CAP1) is a prenyl-binding partner of Rap1 GTPase. AB - Rap1 proteins are members of the Ras subfamily of small GTPases involved in many biological responses, including adhesion, cell proliferation, and differentiation. Like all small GTPases, they work as molecular allosteric units that are active in signaling only when associated with the proper membrane compartment. Prenylation, occurring in the cytosol, is an enzymatic posttranslational event that anchors small GTPases at the membrane, and prenyl binding proteins are needed to mask the cytoplasm-exposed lipid during transit to the target membrane. However, several of these proteins still await discovery. In this study, we report that cyclase-associated protein 1 (CAP1) binds Rap1. We found that this binding is GTP-independent, does not involve Rap1's effector domain, and is fully contained in its C-terminal hypervariable region (HVR). Furthermore, Rap1 prenylation was required for high-affinity interactions with CAP1 in a geranylgeranyl-specific manner. The prenyl binding specifically involved CAP1's C-terminal hydrophobic beta-sheet domain. We present a combination of experimental and computational approaches, yielding a model whereby the high-affinity binding between Rap1 and CAP1 involves electrostatic and nonpolar side-chain interactions between Rap1's HVR residues, lipid, and CAP1 beta-sheet domain. The binding was stabilized by the lipid insertion into the beta-solenoid whose interior was occupied by nonpolar side chains. This model was reminiscent of the recently solved structure of the PDEdelta-K-Ras complex; accordingly, disruptors of this complex, e.g. deltarasin, blocked the Rap1-CAP1 interaction. These findings indicate that CAP1 is a geranylgeranyl-binding partner of Rap1. PMID- 29618514 TI - Activation of stimulator of interferon genes (STING) induces ADAM17-mediated shedding of the immune semaphorin SEMA4D. AB - Stimulator of interferon genes (STING) is an endoplasmic reticulum-resident membrane protein that mediates cytosolic pathogen DNA-induced innate immunity and inflammatory responses in host defenses. STING is activated by cyclic di nucleotides and is then translocated to the Golgi apparatus, an event that triggers STING assembly with the downstream enzyme TANK-binding kinase 1 (TBK1). This assembly leads to the phosphorylation of the transcription factor interferon regulatory factor 3 (IRF3), which in turn induces expression of type-I interferon (IFN) and chemokine genes. STING also mediates inflammatory responses independently of IRF3, but these molecular pathways are largely unexplored. Here, we analyzed the RAW264.7 macrophage secretome to comprehensively identify proinflammatory factors released into the extracellular medium upon STING activation. In total, we identified 1299 proteins in macrophage culture supernatants, of which 23 were significantly increased after STING activation. These proteins included IRF3-dependent cytokines, as well as previously unknown targets of STING, such as the immune semaphorin SEMA4D/CD100, which possesses proinflammatory cytokine-like activities. Unlike for canonical cytokines, the expression of the SEMA4D gene was not up-regulated. Instead, upon STING activation, membrane-bound SEMA4D was cleaved into a soluble form, suggesting the presence of a post-translational shedding machinery. Importantly, the SEMA4D shedding was blocked by TMI-1, an inhibitor of the sheddase ADAM metallopeptidase domain 17 (ADAM17) but not by the TBK1 inhibitor BX795. These results suggest that STING activates ADAM17 and that this activation produces soluble proinflammatory SEMA4D independently of the TBK1/IRF3-mediated transcriptional pathway. PMID- 29618515 TI - Staphylopine, pseudopaline, and yersinopine dehydrogenases: A structural and kinetic analysis of a new functional class of opine dehydrogenase. AB - Opine dehydrogenases (ODHs) from the bacterial pathogens Staphylococcus aureus, Pseudomonas aeruginosa, and Yersinia pestis perform the final enzymatic step in the biosynthesis of a new class of opine metallophores, which includes staphylopine, pseudopaline, and yersinopine, respectively. Growing evidence indicates an important role for this pathway in metal acquisition and virulence, including in lung and burn-wound infections (P. aeruginosa) and in blood and heart infections (S. aureus). Here, we present kinetic and structural characterizations of these three opine dehydrogenases. A steady-state kinetic analysis revealed that the three enzymes differ in alpha-keto acid and NAD(P)H substrate specificity and nicotianamine-like substrate stereoselectivity. The structural basis for these differences was determined from five ODH X-ray crystal structures, ranging in resolution from 1.9 to 2.5 A, with or without NADP+ bound. Variation in hydrogen bonding with NADPH suggested an explanation for the differential recognition of this substrate by these three enzymes. Our analysis further revealed candidate residues in the active sites required for binding of the alpha-keto acid and nicotianamine-like substrates and for catalysis. This work reports the first structural kinetic analyses of enzymes involved in opine metallophore biosynthesis in three important bacterial pathogens of humans. PMID- 29618517 TI - ARL11 regulates lipopolysaccharide-stimulated macrophage activation by promoting mitogen-activated protein kinase (MAPK) signaling. AB - ADP-ribosylation factor-like GTPase 11 (ARL11) is a cancer-predisposing gene that has remained functionally uncharacterized to date. In this study, we report that ARL11 is endogenously expressed in mouse and human macrophages and regulates their activation in response to lipopolysaccharide (LPS) stimulation. Accordingly, depletion of ARL11 impaired both LPS-stimulated pro-inflammatory cytokine production by macrophages and their ability to control intracellular replication of Salmonella. LPS-stimulated activation of extracellular signal regulated kinase (ERK) and p38 mitogen-activated protein kinase (MAPK) was substantially compromised in Arl11-silenced macrophages. In contrast, increased expression of ARL11 led to constitutive ERK1/2 phosphorylation, resulting in macrophage exhaustion. Finally, we found that ARL11 forms a complex with phospho ERK in macrophages within minutes of LPS stimulation. Taken together, our findings establish ARL11 as a novel regulator of ERK signaling in macrophages, required for macrophage activation and immune function. PMID- 29618518 TI - C-terminal domain small phosphatase-like 2 promotes epithelial-to-mesenchymal transition via Snail dephosphorylation and stabilization. AB - The epithelial-to-mesenchymal transition (EMT) is a cellular reprogramming process converting epithelial cells into mesenchymal cell morphology. Snail is a critical regulator of EMT by both suppressing epithelial gene expression and promoting mesenchymal gene expression. Expression and activity of Snail are tightly controlled at transcriptional and post-translational levels. It has previously been reported that Snail undergoes phosphorylation and ubiquitin dependent proteasome degradation. Here, we report nuclear phosphatase SCP4/CTDSPL2 acts as a novel Snail phosphatase. SCP4 physically interacts with and directly dephosphorylates Snail. SCP4-mediated dephosphorylation of Snail suppresses the ubiquitin-dependent proteasome degradation of Snail and consequently enhances TGFbeta-induced EMT. The knockdown of SCP4 in MCF10A mammary epithelial cells leads to attenuated cell migration. Collectively, our finding demonstrates that SCP4 plays a critical role in EMT through Snail dephosphorylation and stabilization. PMID- 29618516 TI - The proinflammatory protein HMGB1 is a substrate of transglutaminase-2 and forms high-molecular weight complexes with autoantigens. AB - High-mobility group box 1 (HMGB1) is a chromatin-associated protein that, in response to stress or injury, translocates from the nucleus to the extracellular milieu, where it functions as an alarmin. HMGB1's function is in part determined by the complexes (HMGB1c) it forms with other molecules. However, structural modifications in the HMGB1 polypeptide that may regulate HMGB1c formation have not been previously described. In this report, we observed high-molecular weight, denaturing-resistant HMGB1c in the plasma and peripheral blood mononuclear cells of individuals with systemic lupus erythematosus (SLE) and, to a much lesser extent, in healthy subjects. Differential HMGB1c levels were also detected in mouse tissues and cultured cells, in which these complexes were induced by endotoxin or the immunological adjuvant alum. Of note, we found that HMGB1c formation is catalyzed by the protein-cross-linking enzyme transglutaminase-2 (TG2). Cross-link site mapping and MS analysis revealed that HMGB1 can be cross linked to TG2 as well as a number of additional proteins, including human autoantigens. These findings have significant functional implications for studies of cellular stress responses and innate immunity in SLE and other autoimmune disease. PMID- 29618519 TI - Genetic diversity and drivers of dwarfism in extinct island emu populations. AB - Australia's iconic emu (Dromaius novaehollandiae novaehollandiae) is the only living representative of its genus, but fossil evidence and reports from early European explorers suggest that three island forms (at least two of which were dwarfs) became extinct during the nineteenth century. While one of these-the King Island emu-has been found to be conspecific with Australian mainland emus, little is known about how the other two forms-Kangaroo Island and Tasmanian emus-relate to the others, or even the size of Tasmanian emus. We present a comprehensive genetic and morphological analysis of Dromaius diversity, including data from one of the few definitively genuine Tasmanian emu specimens known. Our genetic analyses suggest that all the island populations represent sub-populations of mainland Dnovaehollandiae Further, the size of island emus and those on the mainland appears to scale linearly with island size but not time since isolation, suggesting that island size-and presumably concomitant limitations on resource availability-may be a more important driver of dwarfism in island emus, though its precise contribution to emu dwarfism remains to be confirmed. PMID- 29618520 TI - Positive biodiversity-productivity relationships in forests: climate matters. AB - While it is widely acknowledged that forest biodiversity contributes to climate change mitigation through improved carbon sequestration, conversely how climate affects tree species diversity-forest productivity relationships is still poorly understood. We combined the results of long-term experiments where forest mixtures and corresponding monocultures were compared on the same site to estimate the yield of mixed-species stands at a global scale, and its response to climatic factors. We found positive mixture effects on productivity using a meta analysis of 126 case studies established at 60 sites spread across five continents. Overall, the productivity of mixed-species forests was 15% greater than the average of their component monocultures, and not statistically lower than the productivity of the best component monoculture. Productivity gains in mixed-species stands were not affected by tree age or stand species composition but significantly increased with local precipitation. The results should guide better use of tree species combinations in managed forests and suggest that increased drought severity under climate change might reduce the atmospheric carbon sequestration capacity of natural forests. PMID- 29618521 TI - Extreme diversity in the songs of Spitsbergen's bowhead whales. AB - Almost all mammals communicate using sound, but few species produce complex songs. Two baleen whales sing complex songs that change annually, though only the humpback whale (Megaptera novaeangliae) has received much research attention. This study focuses on the other baleen whale singer, the bowhead whale (Balaena mysticetus). Members of the Spitsbergen bowhead whale population produced 184 different song types over a 3-year period, based on duty-cycled recordings from a site in Fram Strait in the northeast Atlantic. Distinct song types were recorded over short periods, lasting at most some months. This song diversity could be the result of population expansion, or immigration of animals from other populations that are no longer isolated from each other by heavy sea ice. However, this explanation does not account for the within season and annual shifting of song types. Other possible explanations for the extraordinary diversity in songs could be that it results either from weak selection pressure for interspecific identification or for maintenance of song characteristics or, alternatively, from strong pressure for novelty in a small population. PMID- 29618522 TI - Correction to 'Estimating maximum bite performance in Tyrannosaurus rex using multi-body dynamics'. PMID- 29618524 TI - Blocking IL-2 Signal In Vivo with an IL-2 Antagonist Reduces Tumor Growth through the Control of Regulatory T Cells. AB - IL-2 is critical for peripheral tolerance mediated by regulatory T (Treg) cells, which represent an obstacle for effective cancer immunotherapy. Although IL-2 is important for effector (E) T cell function, it has been hypothesized that therapies blocking IL-2 signals weaken Treg cell activity, promoting immune responses. This hypothesis has been partially tested using anti-IL-2 or anti-IL 2R Abs with antitumor effects that cannot be exclusively attributed to lack of IL 2 signaling in vivo. In this work, we pursued an alternative strategy to block IL 2 signaling in vivo, taking advantage of the trimeric structure of the IL-2R. We designed an IL-2 mutant that conserves the capacity to bind to the alphabeta chains of the IL-2R but not to the gammac-chain, thus having a reduced signaling capacity. We show our IL-2 mutein inhibits IL-2 Treg cell-dependent differentiation and expansion. Moreover, treatment with IL-2 mutein reduces Treg cell numbers and impairs tumor growth in mice. A mathematical model was used to better understand the effect of the mutein on Treg and E T cells, suggesting suitable strategies to improve its design. Our results show that it is enough to transiently inhibit IL-2 signaling to bias E and Treg cell balance in vivo toward immunity. PMID- 29618523 TI - Tuning T Cell Signaling Sensitivity Alters the Behavior of CD4+ T Cells during an Immune Response. AB - Intricate processes in the thymus and periphery help curb the development and activation of autoreactive T cells. The subtle signals that govern these processes are an area of great interest, but tuning TCR sensitivity for the purpose of affecting T cell behavior remains technically challenging. Previously, our laboratory described the derivation of two TCR-transgenic CD4 T cell mouse lines, LLO56 and LLO118, which recognize the same cognate Listeria epitope with the same affinity. Despite the similarity of the two TCRs, LLO56 cells respond poorly in a primary infection whereas LLO118 cells respond robustly. Phenotypic examination of both lines revealed a substantial difference in their surface of expression of CD5, which serves as a dependable readout of the self-reactivity of a cell. We hypothesized that the increased interaction with self by the CD5-high LLO56 was mediated through TCR signaling, and was involved in the characteristic weak primary response of LLO56 to infection. To explore this issue, we generated an inducible knock-in mouse expressing the self-sensitizing voltage-gated sodium channel Scn5a. Overexpression of Scn5a in peripheral T cells via the CD4-Cre promoter resulted in increased TCR-proximal signaling. Further, Scn5a-expressing LLO118 cells, after transfer into BL6 recipient mice, displayed an impaired response during infection relative to wild-type LLO118 cells. In this way, we were able to demonstrate that tuning of TCR sensitivity to self can be used to alter in vivo immune responses. Overall, these studies highlight the critical relationship between TCR-self-pMHC interaction and an immune response to infection. PMID- 29618525 TI - Crk Adaptor Proteins Regulate NK Cell Expansion and Differentiation during Mouse Cytomegalovirus Infection. AB - Natural killer cells are critical in the immune response to infection and malignancy. Prior studies have demonstrated that Crk family proteins can influence cell apoptosis, proliferation, and cell transformation. In this study, we investigated the role of Crk family proteins in mouse NK cell differentiation and host defense using a mouse CMV infection model. The number of NK cells, maturational state, and the majority of the NKR repertoire was similar in Crk x Crk-like (CrkL)-double-deficient and wild type NK cells. However, Crk family proteins were required for optimal activation, IFN-gamma production, expansion, and differentiation of Ly49H+ NK cells, as well as host defense during mouse CMV infection. The diminished function of Crk x CrkL-double-deficient NK cells correlated with decreased phosphorylation of STAT4 and STAT1 in response to IL-12 and IFN-alpha stimulation, respectively. Together, our findings analyzing NK cell specific Crk-deficient mice provide insights into the role of Crk family proteins in NK cell function and host defense. PMID- 29618527 TI - Double trouble: modelling the impact of low risk perception and high-risk sexual behaviour on chlamydia transmission. AB - Risk perception plays an important role in testing behaviour for sexually transmitted infections, but is rarely included in mathematical models exploring the impact of testing. We explored the impact of incorporating sexual behaviour (SB), risk perception (RP) and differential testing uptake in SB-RP groups on prevalence, using chlamydia as an example. We developed a pair model with a susceptible-infected-susceptible structure representing heterosexuals aged 16-26 years. The effect of testing on chlamydia prevalence was compared between a model with only SB (SB model) and a model with SB and RP (SB-RP model). In the SB-RP model, a scenario without differential testing uptake in SB-RP groups was compared to scenarios with differential testing uptake in SB-RP groups. Introducing testing into the SB-RP model resulted in a slightly smaller reduction in chlamydia prevalence (-38.0%) as compared to the SB model (-40.4%). In the SB RP model, the scenario without differential testing uptake in SB-RP groups overestimated the reduction in chlamydia prevalence (with 4.8%), especially in the group with high SB and low RP (19.8%). We conclude that mathematical models incorporating RP and differential testing uptake in SB-RP groups improve the impact assessment of testing and treatment on chlamydia prevalence. PMID- 29618528 TI - Evolution and mechanics of mixed phospholipid fibrinogen monolayers. AB - All mammals depend on lung surfactant (LS) to reduce surface tension at the alveolar interface and facilitate respiration. The inactivation of LS in acute respiratory distress syndrome (ARDS) is generally accompanied by elevated levels of fibrinogen and other blood plasma proteins in the alveolar space. Motivated by the mechanical role fibrinogen may play in LS inactivation, we measure the interfacial rheology of mixed monolayers of fibrinogen and dipalmitoylphosphatidylcholine (DPPC), the main constituent of LS, and compare these to the single species monolayers. We find DPPC to be ineffective at displacing preadsorbed fibrinogen, which gives the resulting mixed monolayer a strongly elastic shear response. By contrast, how effectively a pre-existing DPPC monolayer prevents fibrinogen adsorption depends upon its surface pressure. At low DPPC surface pressures, fibrinogen penetrates DPPC monolayers, imparting a mixed viscoelastic shear response. At higher initial DPPC surface pressures, this response becomes increasingly viscous-dominated, and the monolayer retains a more fluid, DPPC-like character. Fluorescence microscopy reveals that the mixed monolayers exhibit qualitatively different morphologies. Fibrinogen has a strong, albeit preparation-dependent, mechanical effect on phospholipid monolayers, which may contribute to LS inactivation and disorders such as ARDS. PMID- 29618530 TI - The Treatment of Mental Illness Is a Human Right. PMID- 29618529 TI - De novo synthetic biliprotein design, assembly and excitation energy transfer. AB - Bilins are linear tetrapyrrole chromophores with a wide range of visible and near visible light absorption and emission properties. These properties are tuned upon binding to natural proteins and exploited in photosynthetic light-harvesting and non-photosynthetic light-sensitive signalling. These pigmented proteins are now being manipulated to develop fluorescent experimental tools. To engineer the optical properties of bound bilins for specific applications more flexibly, we have used first principles of protein folding to design novel, stable and highly adaptable bilin-binding four-alpha-helix bundle protein frames, called maquettes, and explored the minimal requirements underlying covalent bilin ligation and conformational restriction responsible for the strong and variable absorption, fluorescence and excitation energy transfer of these proteins. Biliverdin, phycocyanobilin and phycoerythrobilin bind covalently to maquette Cys in vitro A blue-shifted tripyrrole formed from maquette-bound phycocyanobilin displays a quantum yield of 26%. Although unrelated in fold and sequence to natural phycobiliproteins, bilin lyases nevertheless interact with maquettes during co expression in Escherichia coli to improve the efficiency of bilin binding and influence bilin structure. Bilins bind in vitro and in vivo to Cys residues placed in loops, towards the amino end or in the middle of helices but bind poorly at the carboxyl end of helices. Bilin-binding efficiency and fluorescence yield are improved by Arg and Asp residues adjacent to the ligating Cys on the same helix and by His residues on adjacent helices. PMID- 29618531 TI - What is Truth? The Spiritual Quest of Forensic Psychiatry. AB - The search for truth is a foundational aim and value of forensic psychiatry. It is also a deeply spiritual exercise. It must, therefore, be possible to describe a spirituality of forensic psychiatry, which I attempt to begin in this article. This exploration opens with a discussion of spirituality and its contexts. I then examine the nature of vocation in its application to medicine, psychiatry and the law. This proceeds to a close evaluation of the attitudes and activities that I will argue occupy the groundwork of forensic practice and form pathways to truth: presence, empathy, compassion, and centering. I then examine some of the forces that harm the expression of truth in the courtroom, and the means for healing those injuries. Concern for the common good, an integral part of my own spirituality, arises repeatedly in this discussion. I conclude with thoughts on the search for truth, in our work and in ourselves, and an invitation to colleagues to imagine forensic psychiatry as a spiritual practice. My hope is that this endeavor will stimulate reflection among forensic clinicians and encourage further inquiry and explication. PMID- 29618532 TI - The Notion of Truth and Our Evolving Understanding of Sexual Harassment. AB - The notion of truth and its determination in legal proceedings is contingent on the cultural setting in which a claim is argued or disputed. Recent years have demonstrated a dramatic shift in the public dialogue concerning sexual harassment. This shift reflects changing cultural mores and standards in the workplace and society as a whole, particularly with respect to the validity of women's voices. The subjective reality experienced by victims of sexual harassment is inherently tied to the legal system's treatment of women throughout history. In determinations of truth, our understanding of which information and perspectives are relevant, and our expectations regarding the credibility of complainants and the accused, are undergoing a period of rapid change. The discourse surrounding the #MeToo movement suggests that the "reasonable-person" standard so often applied by courts is poorly suited to sexual-harassment litigation. As our understanding of what constitutes "severe," "pervasive," and "unwelcome" conduct continues to evolve, forensic psychiatrists must strive to uphold the values of respect for persons in the search for the truth. PMID- 29618533 TI - Truth as Humility Nourishing Compassion Through Wisdom. AB - Among the strengths of forensic psychiatry as a profession is its ability to support lively discussion of critical questions, such as how to characterize its own essence and whether it belongs to the practice of medicine. The American Academy of Psychiatry and the Law is fortunate that Michael Norko has taken the occasion of his presidential address to describe in depth the results of the advanced stage of his probing on a truly spiritual level the fundamental place of compassion in the practice of forensic psychiatry. In so doing, he casts inevitable light on the seamless connections binding forensic psychiatry and medicine, particularly the importance for both of practicing compassion in our search for truth. PMID- 29618526 TI - Opportunities and obstacles for deep learning in biology and medicine. AB - Deep learning describes a class of machine learning algorithms that are capable of combining raw inputs into layers of intermediate features. These algorithms have recently shown impressive results across a variety of domains. Biology and medicine are data-rich disciplines, but the data are complex and often ill understood. Hence, deep learning techniques may be particularly well suited to solve problems of these fields. We examine applications of deep learning to a variety of biomedical problems-patient classification, fundamental biological processes and treatment of patients-and discuss whether deep learning will be able to transform these tasks or if the biomedical sphere poses unique challenges. Following from an extensive literature review, we find that deep learning has yet to revolutionize biomedicine or definitively resolve any of the most pressing challenges in the field, but promising advances have been made on the prior state of the art. Even though improvements over previous baselines have been modest in general, the recent progress indicates that deep learning methods will provide valuable means for speeding up or aiding human investigation. Though progress has been made linking a specific neural network's prediction to input features, understanding how users should interpret these models to make testable hypotheses about the system under study remains an open challenge. Furthermore, the limited amount of labelled data for training presents problems in some domains, as do legal and privacy constraints on work with sensitive health records. Nonetheless, we foresee deep learning enabling changes at both bench and bedside with the potential to transform several areas of biology and medicine. PMID- 29618534 TI - Revisiting the False Confession Problem. AB - Despite the existence of important safeguards in our criminal legal system, innocent suspects often succumb to forceful and deceptive interrogation techniques. Among those over-represented members of the false confessor population are minors, people with cognitive and intellectual disabilities, and those with psychiatric disorders. Some of the confessions made by these at-risk populations can hardly be considered voluntary or reliable, but they are generally admitted at trial, regardless of their prejudicial effect. Forensic psychiatrists should become more involved in the overall process of evaluating confessions, not only testifying in courts, but also assisting policymakers in reforming the interrogation process and influencing the legal process. Thus, forensic psychiatrists may give their expert opinion by providing proper training to police interrogators and examining videotaped interrogations. In addition, forensic experts can be instrumental in contributing to three legal solutions that we propose to the false confession problem: a constitutional approach, an evidence law approach, and a jury instruction approach. Each of these approaches requires forensic psychiatrists to help judges and jurors understand the coercive nature of the interrogation process and its effect on suspects' behavior. PMID- 29618535 TI - Forensic Evaluations for Offenders With Dementia in Taiwan's Criminal Courts. AB - Dementia is an increasing world-wide health problem, and the association between dementia and adjudication of crimes has rarely been studied. The data in this study are described and analyzed by gender, psychiatric diagnosis, type of crime, and the acceptance rate by the courts of opinions tendered by forensic psychiatric examiners. The source data are derived from the databank of the Judicial Yuan (Judicial Department) of the Republic of China Law and Regulations Retrieval System. There was a male predominance of 85.1 percent. Larceny (42.6%) was the most frequent crime. There was also a high judicial acceptance rate of 91.5 percent of the professional opinions received from forensic psychiatric evaluators who examined defendants at the request of the courts. Psychiatrists play an important role in providing their professional opinions for the Taiwanese courts with regard to adjudication of evaluees with dementia. Most courts accepted psychiatrists' professional opinions about offenders with dementia, and the rate of acceptance was reflected in the judicial rulings of criminal responsibility. PMID- 29618537 TI - Linking Mental Disorder and Risk in Sexually Violent Person Assessments. AB - A common criticism of sexually violent person (SVP) laws is that psychiatric commitment has been co-opted to continue the incarceration of dangerous criminals, not dangerous individuals with mental illness. This opinion may have credence because some forensic clinicians use a "silo" approach (i.e., diagnosing based on historical criminal behavior rather than current symptomatology, and formulating risk for future sexual violence based on actuarial scores rather than characteristics and features of the mental condition). A silo process fosters a missing link; namely, the absence of a nexus between the mental condition and risk. This approach violates the necessary predicate for involuntary civil commitment, that the symptoms of an individual's current mental disorder be linked to and support a present sexual danger to others. In this article, we provide a brief overview of SVP statutes; describe how the silo approach compromises accurate diagnosis and identification of relevant risk factors; and present actual and fictitious cases illustrating the presence and absence of the missing link. PMID- 29618536 TI - Court-Ordered Evaluations From a Mental Health Court. AB - Mental health courts (MHCs) have been in existence for more than 20 years, but little is known about the demographics, clinical features, and court outcomes of MHC defendants court-ordered for competence to stand trial (CST) evaluations. We examined these items in defendants who underwent CST evaluations for the Marion County, IN, MHC. The MHC defendants were significantly more likely than defendants referred from other courts to be male, black, unemployed, and on disability, and have a history of prior arrests and psychiatric treatment. MHC defendants found incompetent to stand trial (ICST) were significantly more likely to have a psychotic disorder and a high school education than MHC defendants found CST, and they were significantly less likely to have a mood disorder, to be on psychiatric medication, or to cooperate in forensic interviews. Evaluator concordance of primary diagnoses was linked to concordance of CST opinion. There were no significant differences in the outcome of charges between CST and ICST MHC defendants. This study highlights several important findings. First, evaluator concordance of diagnoses is linked to evaluator concordance of opinion. Second, the Marion County MHC functioned in a non-adversarial manner by not discriminating against defendants who were found ICST at the time of final judgment. PMID- 29618538 TI - Using Technology to Improve the Objectivity of Criminal Responsibility Evaluations. AB - Criminal responsibility (or insanity) evaluations require forensic clinicians to reconstruct a defendant's decision-making abilities, behavioral control, and emotional state at the time of the criminal act. Forensic evaluators are ultimately tasked to evaluate whether an individual had the capacity to understand right from wrong, and in some jurisdictions, determine whether the defendant lacked substantial capacity to conform his behavior to the requirements of the law as a result of a threshold condition (e.g., mental illness). Insanity evaluations are inherently complex, because they require the clinician to determine someone's mental state at some point in the past (weeks, months, or even years). Recent research on insanity evaluations underscores significant problems with the reliability and validity of these evaluations. However, technological advances including social media (e.g., Facebook and Twitter), mandating that law enforcement videotape interrogations, and the use of body and dashboard cameras can aid clinicians in improving the precision and quality of insanity evaluations. This article discusses practical guidelines and ethics related concerns regarding the use of technology to improve the objectivity of criminal responsibility evaluations. PMID- 29618539 TI - Sexsomnia as a Defense in Repeated Sex Crimes. AB - Sexsomnia and related sexual behaviors during sleep may be diagnosed in individuals accused of sex crimes. Although sexsomnia is now formally recognized in the DSM-5, the variable presentation of such behaviors and the possibility of malingering in medicolegal situations can cause challenges for forensic evaluators and legal professionals alike. Review of the literature reveals a paucity of cases involving allegations of repeated incidents due to abnormal sexual behaviors or experiences in sleep. It is important for experts involved in such cases to understand how the courts have responded to sexsomnia defenses involving diverse alleged incidents. The authors review the case law and discuss methods of examining evaluees with suspected sexsomnia in cases of alleged sexual assault. PMID- 29618540 TI - Mental Condition Requirement in Competency to Stand Trial Assessments. AB - In Ohio, a criminal defendant is incompetent to stand trial only if "a present mental condition" renders him unable to understand the nature and objectives of the proceedings against him or to assist in his defense. Some forensic mental health evaluators have treated the mental-condition requirement as synonymous with, or similar to, the psychiatric condition required in the state's insanity criteria, which requires a "severe mental disease or defect." Yet the term mental condition does not appear in other areas of the state's criminal code or in the state's definition of a mental illness for purposes of civil commitment. Moreover, Ohio's adjudicative competency statute does not explain what conditions or symptoms constitute a mental condition sufficient to render a defendant incompetent. This article is a review of the mental condition requirement in competence to stand trial laws, using Ohio as an example, and how this term has been interpreted (or misinterpreted) by mental health evaluators and the legal system. Suggestions for practicing forensic evaluators are offered. PMID- 29618541 TI - Understanding Tattoos in Medicolegal Assessments. AB - Tattoos have held different meanings throughout history, with particular significance in cultural, social, and clinical contexts. Psychiatrists have long been interested in understanding the relevance of the tattooed body in a clinical or forensic evaluation and in settling on interpretive models that hold reliable value. Some studies have indicated that tattoos may be associated with markers of high-risk behaviors, mental illness diagnosis, and personality disorders. We attempt to provide an updated and comprehensive guide for forensic evaluators, so they can incorporate the observation of tattoos into their assessments with a review of the scientific literature that supports the interpretations and places them in context. The association between tattoos and risk, mental health, or behavioral implications is not as clear or linear as one might initially imagine, and mental health professionals should have a sophisticated understanding of the practice. PMID- 29618542 TI - AAPL Practice Resource for the Forensic Evaluation of Psychiatric Disability. AB - Full Document: Anfang SA, Gold LH, Meyer DJ: AAPL practice resource for the forensic evaluation of psychiatric disability. Journal of the American Academy of Psychiatry and the Law Online Supplement 2018, 46 (1). Available at: http://www.jaapl.org/content/46/1_Supplement. PMID- 29618543 TI - Analytical Transparency and Reproducibility in Human Neuroimaging Studies. PMID- 29618544 TI - c-Jun in Schwann Cells: Stay Away from Extremes. PMID- 29618545 TI - A Dynamical System Framework for Theorizing Preparatory Inhibition. PMID- 29618546 TI - Attention Selectively Gates Afferent Signal Transmission to Area V4. AB - Selective attention allows focusing on only part of the incoming sensory information. Neurons in the extrastriate visual cortex reflect such selective processing when different stimuli are simultaneously present in their large receptive fields. Their spiking response then resembles the response to the attended stimulus when presented in isolation. Unclear is where in the neuronal pathway attention intervenes to achieve such selective signal routing and processing. To investigate this question, we tagged two equivalent visual stimuli by independent broadband luminance noise and used the spectral coherence of these behaviorally irrelevant signals with the field potential of a local neuronal population in male macaque monkeys' area V4 as a measure for their respective causal influences. This new experimental paradigm revealed that signal transmission was considerably weaker for the not-attended stimulus. Furthermore, our results show that attention does not need to modulate responses in the input populations sending signals to V4 to selectively represent a stimulus, nor do they suggest a change of the V4 neurons' output gain depending on their feature similarity with the stimuli. Our results rather imply that selective attention uses a gating mechanism comprising the synaptic "inputs" that transmit signals from upstream areas into the V4 neurons. A minimal model implementing attention dependent routing by gamma-band synchrony replicated the attentional gating effect and the signals' spectral transfer characteristics. It supports the proposal that selective interareal gamma-band synchrony subserves signal routing and explains our experimental finding that attention selectively gates signals already at the level of afferent synaptic input.SIGNIFICANCE STATEMENT Depending on the behavioral context, the brain needs to channel the flow of information through its networks of massively interconnected neurons. We designed an experiment that allows to causally assess routing of information originating from an attended object. We found that attention "gates" signals at the interplay between afferent fibers and the local neurons. A minimal model demonstrated that coherent gamma-rhythmic activity (~60 Hz) between local neurons and their afferent-providing input neurons can realize the gating. Importantly, the attended signals did not need to be amplified already in an earlier processing stage, nor did they get amplified by a simple output response modulation. The method provides a useful tool to study mechanisms of dynamic network configuration underlying cognitive processes. PMID- 29618547 TI - Frequency dependence shapes the adaptive landscape of imperfect Batesian mimicry. AB - Despite more than a century of biological research on the evolution and maintenance of mimetic signals, the relative frequencies of models and mimics necessary to establish and maintain Batesian mimicry in natural populations remain understudied. Here we investigate the frequency-dependent dynamics of imperfect Batesian mimicry, using predation experiments involving artificial butterfly models. We use two geographically distinct populations of Adelpha butterflies that vary in their relative frequencies of a putatively defended model (Adelpha iphiclus) and Batesian mimic (Adelpha serpa). We found that in Costa Rica, where both species share similar abundances, Batesian mimicry breaks down, and predators more readily attack artificial butterfly models of the presumed mimic, A. serpa By contrast, in Ecuador, where A. iphiclus (model) is significantly more abundant than A. serpa (mimic), both species are equally protected from predation. Our results provide compelling experimental evidence that imperfect Batesian mimicry is frequency-dependent on the relative abundance of models and mimics in natural populations, and contribute to the growing body of evidence that complex dynamics, such as seasonality or the availability of alternative prey, influence the evolution of mimetic traits. PMID- 29618548 TI - Revealing hidden insect-fungus interactions; moderately specialized, modular and anti-nested detritivore networks. AB - Ecological networks are composed of interacting communities that influence ecosystem structure and function. Fungi are the driving force for ecosystem processes such as decomposition and carbon sequestration in terrestrial habitats, and are strongly influenced by interactions with invertebrates. Yet, interactions in detritivore communities have rarely been considered from a network perspective. In the present study, we analyse the interaction networks between three functional guilds of fungi and insects sampled from dead wood. Using DNA metabarcoding to identify fungi, we reveal a diversity of interactions differing in specificity in the detritivore networks, involving three guilds of fungi. Plant pathogenic fungi were relatively unspecialized in their interactions with insects inhabiting dead wood, while interactions between the insects and wood decay fungi exhibited the highest degree of specialization, which was similar to estimates for animal-mediated seed dispersal networks in previous studies. The low degree of specialization for insect symbiont fungi was unexpected. In general, the pooled insect-fungus networks were significantly more specialized, more modular and less nested than randomized networks. Thus, the detritivore networks had an unusual anti-nested structure. Future studies might corroborate whether this is a common aspect of networks based on interactions with fungi, possibly owing to their often intense competition for substrate. PMID- 29618549 TI - The role of ecological factors in shaping bat cone opsin evolution. AB - Bats represent one of the largest and most striking nocturnal mammalian radiations, exhibiting many visual system specializations for performance in light-limited environments. Despite representing the greatest ecological diversity and species richness in Chiroptera, Neotropical lineages have been undersampled in molecular studies, limiting the potential for identifying signatures of selection on visual genes associated with differences in bat ecology. Here, we investigated how diverse ecological pressures mediate long-term shifts in selection upon long-wavelength (Lws) and short-wavelength (Sws1) opsins, photosensitive cone pigments that form the basis of colour vision in most mammals, including bats. We used codon-based likelihood clade models to test whether ecological variables associated with reliance on visual information (e.g. echolocation ability and diet) or exposure to varying light environments (e.g. roosting behaviour and foraging habitat) mediated shifts in evolutionary rates in bat cone opsin genes. Using additional cone opsin sequences from newly sequenced eye transcriptomes of six Neotropical bat species, we found significant evidence for different ecological pressures influencing the evolution of the cone opsins. While Lws is evolving under significantly lower constraint in highly specialized high-duty cycle echolocating lineages, which have enhanced sonar ability to detect and track targets, variation in Sws1 constraint was significantly associated with foraging habitat, exhibiting elevated rates of evolution in species that forage among vegetation. This suggests that increased reliance on echolocation as well as the spectral environment experienced by foraging bats may differentially influence the evolution of different cone opsins. Our study demonstrates that different ecological variables may underlie contrasting evolutionary patterns in bat visual opsins, and highlights the suitability of clade models for testing ecological hypotheses of visual evolution. PMID- 29618550 TI - Abundance-dependent effects of neighbourhood dissimilarity and growth rank reversal in a neotropical forest. AB - Why tropical forests harbour an exceptional number of species with striking differences in abundances remains an open question. We propose a theoretical framework to address this question in which rare species may have different extirpation risks depending on species ranks in tree growth and sensitivities to neighbourhood interactions. To evaluate the framework, we studied tree growth and its responses to neighbourhood dissimilarity (ND) in traits and phylogeny for 146 species in a neotropical forest. We found that tree growth was positively related to ND, and common species were more strongly affected by ND than rare species, which may help delay dominance of common species. Rare species grew more slowly at the community-wide average ND than common species. But rare species grew faster when common species tended to dominate locally, which may help reduce extirpation risk of rare species. Our study highlights that tree growth rank among species depends on their responses to neighbourhood interactions, which can be important in fostering diversity maintenance in tropical forests. PMID- 29618552 TI - Correction to 'The genetic basis and enigmatic origin of melanic polymorphism in pomarine skuas (Stercorarius pomarinus)'. PMID- 29618551 TI - Computer simulations show that Neanderthal facial morphology represents adaptation to cold and high energy demands, but not heavy biting. AB - Three adaptive hypotheses have been forwarded to explain the distinctive Neanderthal face: (i) an improved ability to accommodate high anterior bite forces, (ii) more effective conditioning of cold and/or dry air and, (iii) adaptation to facilitate greater ventilatory demands. We test these hypotheses using three-dimensional models of Neanderthals, modern humans, and a close outgroup (Homo heidelbergensis), applying finite-element analysis (FEA) and computational fluid dynamics (CFD). This is the most comprehensive application of either approach applied to date and the first to include both. FEA reveals few differences between H. heidelbergensis, modern humans, and Neanderthals in their capacities to sustain high anterior tooth loadings. CFD shows that the nasal cavities of Neanderthals and especially modern humans condition air more efficiently than does that of H. heidelbergensis, suggesting that both evolved to better withstand cold and/or dry climates than less derived Homo We further find that Neanderthals could move considerably more air through the nasal pathway than could H. heidelbergensis or modern humans, consistent with the propositions that, relative to our outgroup Homo, Neanderthal facial morphology evolved to reflect improved capacities to better condition cold, dry air, and, to move greater air volumes in response to higher energetic requirements. PMID- 29618554 TI - Letter by Lapin et al Regarding Article, "PROMIS GH (Patient-Reported Outcomes Measurement Information System Global Health) Scale in Stroke: A Validation Study". PMID- 29618553 TI - Stroke Among Young West Africans: Evidence From the SIREN (Stroke Investigative Research and Educational Network) Large Multisite Case-Control Study. AB - BACKGROUND AND PURPOSE: Stroke in lower and middle-income countries affects a young and productive age group. Data on factors associated with stroke in the young are sorely lacking from lower and middle-income countries. Our objective is to characterize the nature of stroke and its risk factors among young West Africans aged <50 years old. METHODS: The SIREN (Stroke Investigative Research and Educational Network) is a multicenter, case-control study involving 15 sites in Nigeria and Ghana. Cases included adults aged >=18 years with computed tomography/magnetic resonance imaging-confirmed stroke. Controls were age-and gender-matched stroke-free adults recruited from the communities in catchment areas of cases. Comprehensive evaluation for vascular, lifestyle, and psychosocial factors was performed. We used conditional logistic regression to estimate odds ratios and population attributable risks with 95% confidence intervals. RESULTS: Five hundred fifteen (24.3%) out of 2118 cases enrolled were <50 years old. Among subjects <50 years old, hemorrhagic stroke proportion was 270 (52.5%) versus 245 (47.5%) for ischemic strokes. Etiologic subtypes of ischemic strokes included large artery atherosclerosis (40.0%), small vessel disease (28.6%), cardioembolism (11.0%), and undetermined (20.4%). Hypertension (91.7%), structural lesions (3.4%), and others (4.9%) were causally associated with hemorrhagic stroke. Six topmost modifiable factors associated with stroke in descending order of population attributable risk (95% confidence interval) were hypertension: 88.7% (82.5%-94.8%), dyslipidemia: 48.2% (30.6%-65.9%), diabetes mellitus: 22.6% (18.7%-26.5%), low green vegetable consumption: 18.2% (-6.8% 43.2%), stress: 14.5% (4.9%-24.1%), and cardiac disease: 8.4% (5.8%-11.1%). CONCLUSIONS: The high and rising burden of stroke among young Africans should be curtailed via aggressive, population-wide vascular risk factor control. PMID- 29618556 TI - Stroke Literature Synopses: Clinical Science. PMID- 29618555 TI - Basic and Translational Research in Intracerebral Hemorrhage: Limitations, Priorities, and Recommendations. PMID- 29618557 TI - Thrombectomy for M1-Middle Cerebral Artery Occlusion: Angiographic Aspect of the Arterial Occlusion and Recanalization: A Preliminary Observation. AB - BACKGROUND AND PURPOSE: Despite the recent technical evolution of the endovascular treatment of acute ischemic stroke, late and incomplete recanalization can be achieved after several maneuvers but with a potentially higher risk of futile reperfusion and complications, such as clot fragmentation. The aim of this article is to investigate the impact of the angiographic phenotype of M1-middle cerebral artery occlusions, classified as regular and irregular in aspect, on the results of treatment by stent retrievers (SRs) or contact aspiration (CA). METHODS: From January to April 2016, 84 consecutive patients, admitted for acute ischemic stroke with a middle cerebral artery occlusion, were treated by endovascular therapy. Among them, 60 patients (26M, 34F, median age, 70.5; interquartile range, 58.5-80.0) were treated by SR (25/60, 41.7%) or CA (35/60, 58.3%) as a first-line approach in 2 experienced centers. Patients' characteristics, timing, and procedural data were prospectively recorded and compared between the 2 study subgroups (regular and irregular phenotype). RESULTS: A regular phenotype at the occlusion site was observed in 24 patients (40%). Among these, successful recanalization after the first-line strategy (Thrombolysis in Cerebral Infarction 2b-3) was achieved in 100% of patients treated by CA and in only 33.3% of patients treated by SR (P=0.001). For irregular phenotypes, SR achieved Thrombolysis in Cerebral Infarction 2b-3 in 73.9% and CA, in 38.5% (P=0.036) of cases. Among regular phenotype patients, the average number of maneuvers was 1.3 (median, 1; range 1-3) with first-line CA and 2.7 (median, 3; range 1-5) with first-line SR (P=0.008). CONCLUSIONS: The angiographic phenotype of the occlusion site may be associated with a different response to SR and CA in this preliminary experience. PMID- 29618559 TI - Inhibition of IP6K1 suppresses neutrophil-mediated pulmonary damage in bacterial pneumonia. AB - The significance of developing host-modulating personalized therapies to counteract the growing threat of antimicrobial resistance is well-recognized because such resistance cannot be overcome using microbe-centered strategies alone. Immune host defenses must be finely controlled during infection to balance pathogen clearance with unwanted inflammation-induced tissue damage. Thus, an ideal antimicrobial treatment would enhance bactericidal activity while preventing neutrophilic inflammation, which can induce tissue damage. We report that disrupting the inositol hexakisphosphate kinase 1 (Ip6k1) gene or pharmacologically inhibiting IP6K1 activity using the specific inhibitor TNP [N2 (m-(trifluoromethyl)benzyl) N6-(p-nitrobenzyl)purine] efficiently and effectively enhanced host bacterial killing but reduced pulmonary neutrophil accumulation, minimizing the lung damage caused by both Gram-positive and Gram-negative bacterial pneumonia. IP6K1-mediated inorganic polyphosphate (polyP) production by platelets was essential for infection-induced neutrophil-platelet aggregate (NPA) formation and facilitated neutrophil accumulation in alveolar spaces during bacterial pneumonia. IP6K1 inhibition reduced serum polyP levels, which regulated NPAs by triggering the bradykinin pathway and bradykinin-mediated neutrophil activation. Thus, we identified a mechanism that enhances host defenses while simultaneously suppressing neutrophil-mediated pulmonary damage in bacterial pneumonia. IP6K1 is, therefore, a legitimate therapeutic target for such disease. PMID- 29618558 TI - Unmet Needs and Challenges in Clinical Research of Intracerebral Hemorrhage. PMID- 29618560 TI - A bioengineered retinal pigment epithelial monolayer for advanced, dry age related macular degeneration. AB - Retinal pigment epithelium (RPE) dysfunction and loss are a hallmark of non neovascular age-related macular degeneration (NNAMD). Without the RPE, a majority of overlying photoreceptors ultimately degenerate, leading to severe, progressive vision loss. Clinical and histological studies suggest that RPE replacement strategies may delay disease progression or restore vision. A prospective, interventional, U.S. Food and Drug Administration-cleared, phase 1/2a study is being conducted to assess the safety and efficacy of a composite subretinal implant in subjects with advanced NNAMD. The composite implant, termed the California Project to Cure Blindness-Retinal Pigment Epithelium 1 (CPCB-RPE1), consists of a polarized monolayer of human embryonic stem cell-derived RPE (hESC RPE) on an ultrathin, synthetic parylene substrate designed to mimic Bruch's membrane. We report an interim analysis of the phase 1 cohort consisting of five subjects. Four of five subjects enrolled in the study successfully received the composite implant. In all implanted subjects, optical coherence tomography imaging showed changes consistent with hESC-RPE and host photoreceptor integration. None of the implanted eyes showed progression of vision loss, one eye improved by 17 letters and two eyes demonstrated improved fixation. The concurrent structural and functional findings suggest that CPCB-RPE1 may improve visual function, at least in the short term, in some patients with severe vision loss from advanced NNAMD. PMID- 29618562 TI - Cardiac differentiation of pluripotent stem cells and implications for modeling the heart in health and disease. AB - Cellular models comprising cardiac cell types derived from human pluripotent stem cells are valuable for studying heart development and disease. We discuss transcriptional differences that define cellular identity in the heart, current methods for generating different cardiomyocyte subtypes, and implications for disease modeling, tissue engineering, and regenerative medicine. PMID- 29618563 TI - Erratum for the Research Article: "Constitutive and TNFalpha-inducible expression of chondroitin sulfate proteoglycan 4 in glioblastoma and neurospheres: Implications for CAR-T cell therapy" by S. Pellegatta, B. Savoldo, N. Di Ianni, C. Corbetta, Y. Chen, M. Patane, C. Sun, B. Pollo, S. Ferrone, F. DiMeco, G. Finocchiaro, G. Dotti. PMID- 29618561 TI - Battery-free, wireless sensors for full-body pressure and temperature mapping. AB - Thin, soft, skin-like sensors capable of precise, continuous measurements of physiological health have broad potential relevance to clinical health care. Use of sensors distributed over a wide area for full-body, spatiotemporal mapping of physiological processes would be a considerable advance for this field. We introduce materials, device designs, wireless power delivery and communication strategies, and overall system architectures for skin-like, battery-free sensors of temperature and pressure that can be used across the entire body. Combined experimental and theoretical investigations of the sensor operation and the modes for wireless addressing define the key features of these systems. Studies with human subjects in clinical sleep laboratories and in adjustable hospital beds demonstrate functionality of the sensors, with potential implications for monitoring of circadian cycles and mitigating risks for pressure-induced skin ulcers. PMID- 29618566 TI - Opioid overdose and misuse in post-surgical opioid-naive -patients. PMID- 29618565 TI - Pharmacokinetics of rifapentine and rifampin in a rabbit model of tuberculosis and correlation with clinical trial data. AB - In clinical trials of two rifamycin antibiotics (rifampin and rifapentine) for treating tuberculosis (TB), patients with cavitary lung lesions did not appear to derive benefit from rifapentine. Rifapentine was found not to outperform rifampin, despite a lower minimum inhibitory concentration against Mycobacterium tuberculosis in mouse models of TB. To understand these findings, we have developed a rabbit model of TB that reliably develops lung cavities with features similar to those of patients with pulmonary cavitary TB. After single or multiple doses of rifampin or rifapentine that produced human-equivalent plasma exposures, rabbits were sacrificed at different time points after dosing. We measured site of-disease drug pharmacokinetics and tissue drug distribution. We used pharmacokinetic-pharmacodynamic (PK/PD) modeling to estimate drug penetration into different types of tubercular lesions. Both drugs penetrated rabbit lung cellular lesions, as well as the fibrotic cavity wall of cavitary lesions (penetration coefficients >=1 compared to plasma). For the necrotic liquefied material inside cavitary lesions known as caseum (which contains high numbers of bacteria), the penetration coefficient was 1.0 for rifampin but only 0.25 for rifapentine. When estimates of site-of-disease drug PK were substituted into clinical PK/PD models, the relationship between site-of-action exposure and sputum culture conversion was significant (P < 10-7). We propose that poor penetration of rifapentine into lung cavitary lesions explains, in part, why rifapentine doses required to improve treatment outcomes in two phase 2 clinical trials were four times higher in TB patients with large cavities compared to TB patients without cavitary lung disease. PMID- 29618568 TI - Co-dydramol - specify the strength. PMID- 29618567 TI - More recommendations to minimise exposure to ? valproate in pregnancy. PMID- 29618564 TI - Postnatal Zika virus infection is associated with persistent abnormalities in brain structure, function, and behavior in infant macaques. AB - The Zika virus (ZIKV) epidemic is associated with fetal brain lesions and other serious birth defects classified as congenital ZIKV syndrome. Postnatal ZIKV infection in infants and children has been reported; however, data on brain anatomy, function, and behavioral outcomes following infection are absent. We show that postnatal ZIKV infection of infant rhesus macaques (RMs) results in persistent structural and functional alterations of the central nervous system compared to age-matched controls. We demonstrate ZIKV lymphoid tropism and neurotropism in infant RMs and histopathologic abnormalities in the peripheral and central nervous systems including inflammatory infiltrates, astrogliosis, and Wallerian degeneration. Structural and resting-state functional magnetic resonance imaging (MRI/rs-fMRI) show persistent enlargement of lateral ventricles, maturational changes in specific brain regions, and altered functional connectivity (FC) between brain areas involved in emotional behavior and arousal functions, including weakened amygdala-hippocampal connectivity in two of two ZIKV-infected infant RMs several months after clearance of ZIKV RNA from peripheral blood. ZIKV infection also results in distinct alterations in the species-typical emotional reactivity to acute stress, which were predicted by the weak amygdala-hippocampal FC. We demonstrate that postnatal ZIKV infection of infants in this model affects neurodevelopment, suggesting that long-term clinical monitoring of pediatric cases is warranted. PMID- 29618569 TI - Evidence for mosquito repellents in preventing malaria. PMID- 29618570 TI - Retinoids: EMA updated warnings. PMID- 29618571 TI - Omega-3 fatty acid supplements and cardiovascular disease. PMID- 29618572 TI - Influence of Diabetes on Trends in Perioperative Cardiovascular Events. AB - OBJECTIVE: Patients undergoing noncardiac surgery frequently have diabetes mellitus (DM) and an elevated risk of cardiovascular disease. It is unknown whether temporal declines in the frequency of perioperative major adverse cardiovascular and cerebrovascular events (MACCEs) apply to patients with DM. RESEARCH DESIGN AND METHODS: Patients >=45 years of age who underwent noncardiac surgery from January 2004 to December 2013 were identified using the U.S. National Inpatient Sample. DM was identified using ICD-9 diagnosis codes. Perioperative MACCEs (in-hospital all-cause mortality, acute myocardial infarction, or acute ischemic stroke) by DM status were evaluated over time. RESULTS: The final study sample consisted of 10,581,621 hospitalizations for major noncardiac surgery; DM was present in ~23% of surgeries and increased over time (P for trend <0.001). Patients with DM experienced MACCEs in 3.3% of surgeries vs. 2.8% of surgeries for patients without DM (P < 0.001). From 2004 to 2013, the odds of perioperative MACCEs after multivariable adjustment increased by 6% (95% CI 2-9) for DM patients, compared with an 8% decrease (95% CI -10 to 6) for patients without DM (P for interaction <0.001). Trends for individual end points were all less favorable for patients with DM versus those without DM. CONCLUSIONS: In an analysis of >10.5 million noncardiac surgeries from a large U.S. hospital admission database, perioperative MACCEs were more common among patients with DM versus those without DM. Perioperative MACCEs increased over time and individual end points were all less favorable for patients with DM. Our findings suggest that a substantial unmet need exists for strategies to reduce the risk of perioperative cardiovascular events among patients with DM. PMID- 29618574 TI - New Pioglitazone Metabolites and Absence of Opened-Ring Metabolites in New N Substituted Thiazolidinedione. AB - Thiazolidinediones (TZDs) are drugs used to treat type 2 diabetes mellitus; however, several safety concerns remain regarding the available drugs in this class. Therefore, the search for new TZD candidates is ongoing; metabolism studies play a crucial step in the development of new candidates. Pioglitazone, one of the most commonly used TZDs, and GQ-11, a new N-substituted TZD, were investigated in terms of their metabolic activity in rat and human liver microsomes to assess their metabolic stability and investigate their metabolites. Methods for preparation of samples were based on liquid-liquid extraction and protein precipitation. Quantitation was performed using liquid chromatography (LC)-tandem mass spectrometry, and the metabolite investigation was performed using ultraperformance LC coupled to a hybrid quadrupole-time of flight mass spectrometer. The predicted intrinsic clearance of GQ-11 was 70.3 and 46.1 ml/kg per minute for rats and humans, respectively. The predicted intrinsic clearance of pioglitazone was 24.1 and 15.9 ml/kg per minute for rats and humans, respectively. The pioglitazone metabolite investigation revealed two unpublished metabolites (M-D and M-A). M-A is a hydration product and may be related to the mechanism of ring opening and the toxicity of pioglitazone. The metabolites of GQ 11 are products of oxidation; no ring-opening metabolite was observed for GQ-11. In conclusion, under the same experimental conditions, a ring-opening metabolite was observed only for pioglitazone. The resistance of GQ-11 to the ring opening is probably related to N-substitution in the TZD ring. PMID- 29618573 TI - The Risk of Acute Pancreatitis After Initiation of Dipeptidyl Peptidase 4 Inhibitors: Testing a Hypothesis of Subgroup Differences in Older U.S. Adults. AB - OBJECTIVE: To examine whether dipeptidyl peptidase 4 inhibitors (DPP-4I) increase acute pancreatitis risk in older patients and whether the association varies by age, sex, and history of cardiovascular disease (CVD). RESEARCH DESIGN AND METHODS: We conducted a cohort study of DPP-4I initiators versus thiazolidinedione (TZD) or sulfonylurea initiators using U.S. Medicare beneficiaries, 2007-2014. Eligible initiators were aged 66 years or older without history of pancreatic disease or alcohol-related diseases. Patients were followed up for hospitalization due to acute pancreatitis and censored at 90 days after treatment changes. Weighted Cox models were used to estimate the hazard ratio (HR) for acute pancreatitis. Analyses were performed overall as well as within subgroups defined by age, sex, and CVD history. RESULTS: We found no increased risk of acute pancreatitis comparing 49,374 DPP-4I initiators to 132,223 sulfonylurea initiators (weighted HR 1.01; 95% CI 0.83-1.24) and comparing 57,301 DPP-4I initiators to 32,612 TZD initiators (weighted HR 1.11; 95% CI 0.76-1.62). Age and sex did not modify the association. Among patients with CVD, acute pancreatitis incidence was elevated in initiators of DPP-4I and sulfonylurea (2.3 and 2.4 per 1,000 person-years, respectively) but not in TZD initiators (1.5). Among patients with CVD, higher risk of acute pancreatitis was observed with DPP 4I compared with TZD (weighted HR 1.84; 95% CI 1.02-3.35) but not compared with sulfonylurea. CONCLUSIONS: Our study provides evidence that DPP-4I is not associated with an increased risk of acute pancreatitis in older adults overall. The positive association observed in patients with CVD could be due to chance or bias but merits further investigation. PMID- 29618575 TI - Predicting Antitumor Effect of Deoxypodophyllotoxin in NCI-H460 Tumor-Bearing Mice on the Basis of In Vitro Pharmacodynamics and a Physiologically Based Pharmacokinetic-Pharmacodynamic Model. AB - Antitumor evaluation in tumor-bearing mouse is time- and energy-consuming. We aimed to investigate whether in vivo antitumor efficacy could be predicted on the basis of in vitro pharmacodynamics using deoxypodophyllotoxin (DPT), an antitumor candidate in development, as a model compound. Proliferation kinetics of monolayer-cultivated NCI-H460 cells under various DPT concentrations were quantitatively investigated and expressed as calibration curves. Koch two-phase natural growth model combined with sigmoid Emax model, i.e., dM/dt = 2lambda0lambda1M/(lambda1 + 2lambda0M) - Emax C gamma /(EC50gamma + C gamma ).M, was introduced to describe cell proliferation (M) against time under DPT treatment (C). Estimated in vitro pharmacodynamic parameters were: EC50, 8.97 nM; Emax , 0.820 day-1, and gamma, 7.13. A physiologically based pharmacokinetic model including tumor compartment was introduced to predict DPT disposition in plasma, tumor tissue, and main normal tissues of NCI-H460 tumor-bearing mice following a single dose. The in vivo pharmacodynamic model and parameters were assumed the same as the in vitro ones, and linked with simulated tumor pharmacokinetic profiles by a physiologically based pharmacokinetic (PBPK) model to build a PBPK-pharmacodynamic (PBPK-PD) model. After natural growth parameters (lambda0 and lambda1) were estimated, the objective in this study was to predict with the PBPK-PD model the tumor growth in NCI-H460 tumor-bearing mice during multidose DPT treatment, a use of the model similar to what others have reported. In our work, the model was successfully applied to predict tumor growth in SGC 7901 tumor-bearing mice. The resulting data indicated that in vivo antitumor efficacy might be predicted on the basis of in vitro cytotoxic assays via a PBPK PD model approach. We demonstrated that the approach is reasonable and applicable and may facilitate and accelerate anticancer candidate screening and dose regimen design in the drug discovery process. PMID- 29618577 TI - Androgen receptor moonlighting in the prostate cancer microenvironment. AB - Androgen receptor (AR) signaling is vital for the normal development of the prostate and is critically involved in prostate cancer (PCa). AR is not only found in epithelial prostate cells but is also expressed in various cells in the PCa-associated stroma, which constitute the tumor microenvironment (TME). In the TME, AR is expressed in fibroblasts, macrophages, lymphocytes and neutrophils. AR expression in the TME was shown to be decreased in higher-grade and metastatic PCa, suggesting that stromal AR plays a protective role against PCa progression. With that, the functionality of AR in stromal cells appears to deviate from the receptor's classical function as described in PCa cells. However, the biological action of AR in these cells and its effect on cancer progression remains to be fully understood. Here, we systematically review the pathological, genomic and biological literature on AR actions in various subsets of prostate stromal cells and aim to better understand the consequences of AR signaling in the TME in relation to PCa development and progression. PMID- 29618579 TI - Infolding of the Venus P-Valve After Transcatheter Pulmonary Valve Implantation. PMID- 29618578 TI - PET response assessment in apatinib-treated radioactive iodine-refractory thyroid cancer. AB - This work evaluated the use of the positron emission tomography (PET)/computed tomography (CT) technique to assess the early therapeutic response and predict the prognosis of patients with radioactive iodine-refractory differentiated thyroid cancer (RAIR-DTC) who underwent apatinib therapy. Standardised uptake value (SUV), metabolic tumour volume (MTV) and total lesion glycolysis (TLG), derived from 18F-FDG PET/CT and SUV from 68Ga-NOTA-PRGD2 PET/CT were evaluated. Tumour response was evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1. Sixteen of 20 patients achieved partial response (PR) and four of 20 had stable disease (SD) after apatinib therapy. Six progression-free survival (PFS) events occurred. A strong correlation was observed between the best change in the sum of the longest diameters of target lesions (DeltaCT%) and 18F-FDG PET/CT indices after the completion of the first treatment cycle (DeltaMTV% (P = 0.0019), DeltaTLG% (P = 0.0021) and DeltaSUVmax% (P = 0.0443)). A significant difference in PFS was observed between patients with DeltaMTV% <-45% and >=-45% (P = 0.0019) and between patients with DeltaTLG% <-80% and >=-80% (P = 0.0065). Ten of 11 patients presented a decrease in SUVmax on 68Ga-NOTA-PRGD2 PET/CT after two cycles of apatinib therapy and showed PR, whereas one patient presenting an increase in SUVmax only showed SD as the best response. When a cut off value of the target/background ratio at -20% was used, two PFS curves showed a significant difference (P = 0.0016). Hence, early assessment by 18F-FDG and 68Ga-NOTA-PRGD2 PET/CT was effective in the prediction and evaluation of RAIR-DTC treated with apatinib. PMID- 29618580 TI - Oxidative Stress Inhibits Healthy Adipose Expansion Through Suppression of SREBF1 Mediated Lipogenic Pathway. AB - Recent studies have emphasized the association of adipose oxidative stress (Fat reactive oxygen species [ROS]) with the pathogenesis of metabolic disorders in obesity. However, the causal roles of Fat ROS in metabolic disturbances in vivo remain unclear because no mouse model has been available in which oxidative stress is manipulated by targeting adipocytes. In this research, we generated two models of Fat ROS-manipulated mice and evaluated the metabolic features in diet induced obesity. Fat ROS-eliminated mice, in which Cat and Sod1 were overexpressed in adipocytes, exhibited adipose expansion with decreased ectopic lipid accumulation and improved insulin sensitivity. Conversely, Fat ROS augmented mice, in which glutathione was depleted specifically in adipocytes, exhibited restricted adipose expansion associated with increased ectopic lipid accumulation and deteriorated insulin sensitivity. In the white adipose tissues of these mice, macrophage polarization, tissue fibrosis, and de novo lipogenesis were significantly changed. In vitro approaches identified KDM1A-mediated attenuation of sterol-regulatory element-binding transcription factor 1 (SREBF1) transcriptional activities as the underlying mechanism for the suppression of de novo lipogenesis by oxidative stress. Thus, our study uncovered the novel roles of Fat ROS in healthy adipose expansion, ectopic lipid accumulation, and insulin resistance, providing the possibility for the adipocyte-targeting antioxidant therapy. PMID- 29618581 TI - Causes and Predictors of 30-Day Readmission in Patients With Acute Myocardial Infarction and Cardiogenic Shock. AB - BACKGROUND: Acute myocardial infarction (AMI) occurs as a result of irreversible damage to cardiac myocytes secondary to lack of blood supply. Cardiogenic shock complicating AMI has significant associated morbidity and mortality, and data on postdischarge outcomes are limited. METHODS AND RESULTS: We derived the study cohort of patients with AMI and cardiogenic shock from the 2013 to 2014 Healthcare Cost and Utilization Project National Readmission Database. Incidence, predictors, and causes of 30-day readmissions were analyzed. From 43 212 index admissions for AMI with cardiogenic shock, 26 016 (60.2%) survived to discharge and 5277 (20.2% of survivors) patients were readmitted within 30 days. More than 50% of these readmissions occurred within first 10 days. Cardiac causes accounted for 42% of 30-day readmissions (heart failure 20.6%; acute coronary syndrome 11.6%). Among noncardiac causes, respiratory (11.4%), infectious (9.4%), medical or surgical care complications (6.3%), gastrointestinal/hepatobiliary (6.5%), and renal causes (4.8%) were most common. Length of stay >=8 days (odds ratio [OR], 2.04; 95% confidence interval [CI], 1.70-2.44; P<0.01), acute deep venous thrombosis (OR, 1.26; 95% CI, 1.08-1.48; P<0.01), liver disease (OR, 1.25; 95% CI, 1.03-1.50; P=0.02), systemic thromboembolism (OR, 1.21; 95% CI, 1.02-1.44; P=0.02), peripheral vascular disease (OR, 1.16; 95% CI, 1.07-1.27; P<0.01), diabetes mellitus (OR, 1.16; 95% CI, 1.08-1.24; P<0.01), long-term ventricular assist device implantation (OR, 1.77; 95% CI, 1.23-2.55; P<0.01), intraaortic balloon pump use (OR, 1.10; 95% CI, 1.02-1.18; P<0.01), performance of coronary artery bypass grafting (OR, 0.85; 95% CI, 0.77-0.93; P<0.01), private insurance (OR, 0.72; 95% CI, 0.64-0.80; P<0.01), and discharge to home (OR, 0.85; 95% CI, 0.73-0.98; P=0.03) were among the independent predictors of 30-day readmission. CONCLUSIONS: In-hospital mortality and 30-day readmission in cardiogenic shock complicating AMI are significantly elevated. Patients are readmitted mainly for noncardiac causes. Identification of high-risk factors may guide interventions to improve outcomes within this population. PMID- 29618582 TI - Uropathogens and Pyuria in Children With Neurogenic Bladders. AB - : : media-1vid110.1542/5727212324001PEDS-VA_2017-3006Video Abstract BACKGROUND: A recent study revealed that specific uropathogens are associated with lower odds of pyuria in a general pediatrics population. Children with neurogenic bladders who require clean intermittent catheterization (CIC) frequently have pyuria. Our objective with this study was to determine if an association exists between pyuria and type of uropathogen in CIC-dependent children. METHODS: We obtained urinalysis and urine culture results from electronic medical records from January 2008 through December 2014 for patients <=18 years of age with neurogenic bladders managed at a single institution. Cultures without concurrent urinalyses were excluded from analysis, as were cultures that yielded no growth, fungal growth, or growth of unidentified mixed organisms. We used logistic regression to determine the association of pyuria and leukocyte esterase with specific uropathogens. RESULTS: We included 2420 cultures in this analysis. The growth of Enterococcus on urine culture was associated with lower odds of both pyuria and leukocyte esterase. In contrast, the growth of more than 100 000 colony-forming units per milliliter of Proteus mirabilis was associated with increased odds of both pyuria and leukocyte esterase, and the growth of Pseudomonas aeruginosa was associated with increased odds of leukocyte esterase but not pyuria. Certain etiologies of neurogenic bladder, such as bladder exstrophy and cloacal malformations, were also associated with increased odds of pyuria compared with neurogenic bladder due to myelomeningocele. CONCLUSIONS: In children with neurogenic bladders who require CIC, Enterococcus may grow in urine culture without pyuria or positive leukocyte esterase. Accordingly, urine cultures should be obtained in symptomatic children, regardless of urinalysis results. PMID- 29618583 TI - Reducing Electrolyte Testing in Hospitalized Children by Using Quality Improvement Methods. AB - BACKGROUND AND OBJECTIVES: Despite studies indicating a high rate of overuse, electrolyte testing remains common in pediatric inpatient care. Frequently repeated electrolyte tests often return normal results and can lead to patient harm and increased cost. We aimed to reduce electrolyte testing within a hospital medicine service by >25% within 6 months. METHODS: We conducted an improvement project in which we targeted 6 hospital medicine teams at a large academic children's hospital system by using the Model for Improvement. Interventions included standardizing communication about the electrolyte testing plan and education about the costs and risks associated with overuse of electrolyte testing. Our primary outcome measure was the number of electrolyte tests per patient day. Secondary measures included testing charges and usage rates of specific high-charge panels. We tracked medical emergency team calls and readmission rates as balancing measures. RESULTS: The mean baseline rate of electrolyte testing was 2.0 laboratory draws per 10 patient days, and this rate decreased by 35% after 1 month of initial educational interventions to 1.3 electrolyte laboratory draws per 10 patient days. This change has been sustained for 9 months and could save an estimated $292 000 in patient-level charges over the course of a year. Use of our highest-charge electrolyte panel decreased from 67% to 22% of testing. No change in rates of medical emergency team calls or readmission were found. CONCLUSIONS: Our improvement intervention was associated with significant and rapid reduction in electrolyte testing and has not been associated with unintended adverse events. PMID- 29618584 TI - Leflunomide Increases Hepatic Exposure to Methotrexate and Its Metabolite by Differentially Regulating Multidrug Resistance-Associated Protein Mrp2/3/4 Transporters via Peroxisome Proliferator-Activated Receptor alpha Activation. AB - Methotrexate (MTX) is the gold standard drug for the treatment of rheumatoid arthritis (RA), and it is frequently combined with leflunomide (LEF) to enhance its clinical efficacy. However, this combination can exacerbate liver toxicity, and the underlying mechanism has not yet been clarified. We investigated whether LEF affects the pharmacokinetics of MTX and its primary toxic metabolite, 7 hydroxyl methotrexate (7OH MTX), in mice. LEF significantly increased the plasma concentration (area under the plasma concentration-time curve) of MTX and 7OH MTX (2.4 and 4.5 times, respectively), decreased their bile excretion, and increased their accumulation in the liver and kidneys. When we investigated the effect of LEF on the MTX absorption, distribution, metabolism, and excretion process, we found that LEF had little effect on liver aldehyde oxidase and 7OH MTX formation. However, LEF significantly decreased the expression of the apical efflux transporter multidrug resistance-associated protein 2 (Mrp2) and increased that of the basolateral efflux transporters Mrp3/4, except there was no significant change in Mrp4 protein expression. Mrp2/3/4 alteration changed the distribution of MTX and 7OH MTX in plasma and tissues. Further studies suggested that LEF indirectly activated peroxisome proliferator-activated receptor alpha (PPARalpha), which was likely responsible for the Mrp2/3/4 alteration in the liver. The MTX plasma concentration change induced by LEF was reversed by the PPARalpha-specific antagonist GW6471. These results may partially explain the exacerbated liver toxicity caused by combination treatment with MTX and LEF and may raise concerns regarding the risk of potential drug-drug interactions between PPARalpha agonists and Mrp substrates in the clinic. PMID- 29618585 TI - Correctors of the Major Cystic Fibrosis Mutant Interact through Membrane-Spanning Domains. AB - The most common cystic fibrosis causing mutation is deletion of phenylalanine at position 508 (F508del), a mutation that leads to protein misassembly with defective processing. Small molecule corrector compounds: VX-809 or Corr-4a (C4) partially restores processing of the major mutant. These two prototypical corrector compounds cause an additive effect on F508del/cystic fibrosis transmembrane conductance regulator (CFTR) processing, and hence were proposed to act through distinct mechanisms: VX-809 stabilizing the first membrane-spanning domain (MSD) 1, and C4 acting on the second half of the molecule [consisting of MSD2 and/or nucleotide binding domain (NBD) 2]. We confirmed the effect of VX-809 in enhancing the stability of MSD1 and showed that it also allosterically modulates MSD2 when coexpressed with MSD1. We showed for the first time that C4 stabilizes the second half of the CFTR protein through its action on MSD2. Given the allosteric effect of VX-809 on MSD2, we were prompted to test the hypothesis that the two correctors interact in the full-length mutant protein. We did see evidence supporting their interaction in the full-length F508del-CFTR protein bearing secondary mutations targeting domain:domain interfaces. Disruption of the MSD1:F508del-NBD1 interaction (R170G) prevented correction by both compounds, pointing to the importance of this interface in processing. On the other hand, stabilization of the MSD2:F508del-NBD1 interface (by introducing R1070W) led to a synergistic effect of the compound combination on the total abundance of both the immature and mature forms of the protein. Together, these findings suggest that the two correctors interact in stabilizing the complex of MSDs in F508del-CFTR. PMID- 29618586 TI - Zika virus infection in the returning traveller: what every neurologist should know. AB - Zika virus has been associated with a wide range of neurological complications. Neurologists in areas without current active transmission of the virus may be confronted with Zika-associated neurological disease, as a large number of returning travellers with Zika virus infection have been reported and the virus continues to spread to previously unaffected regions. This review provides an overview of Zika virus-associated neurological disease and aims to support neurologists who may encounter patients returning from endemic areas. PMID- 29618587 TI - Dynamics of cortical domains in early Drosophila development. AB - Underlying the plasma membrane of eukaryotic cells is an actin cortex that includes actin filaments and associated proteins. A special feature of all polarized and epithelial cells are cortical domains, each of which is characterized by specific sets of proteins. Typically, an epithelial cell contains apical, subapical, lateral and basal domains. The domain-specific protein sets contain evolutionarily conserved proteins, as well as cell-type specific factors. Among the conserved proteins are, the Par proteins, Crumbs complex and the lateral proteins Scribbled and Discs large 1. Organization of the plasma membrane into cortical domains is dynamic and depends on cell type, differentiation and developmental stage. The dynamics of cortical organization is strikingly visible in early Drosophila embryos, which increase the number of distinct cortical domains from one, during the pre-blastoderm stage, to two in syncytial blastoderm embryos, before finally acquiring the four domains that are typical for epithelial cells during cellularization. In this Review, we will describe the dynamics of cortical organization in early Drosophila embryos and discuss the processes and mechanisms underlying cortical remodeling. PMID- 29618576 TI - Options and Limitations in Clinical Investigation of Bacterial Biofilms. AB - Bacteria can form single- and multispecies biofilms exhibiting diverse features based upon the microbial composition of their community and microenvironment. The study of bacterial biofilm development has received great interest in the past 20 years and is motivated by the elegant complexity characteristic of these multicellular communities and their role in infectious diseases. Biofilms can thrive on virtually any surface and can be beneficial or detrimental based upon the community's interplay and the surface. Advances in the understanding of structural and functional variations and the roles that biofilms play in disease and host-pathogen interactions have been addressed through comprehensive literature searches. In this review article, a synopsis of the methodological landscape of biofilm analysis is provided, including an evaluation of the current trends in methodological research. We deem this worthwhile because a keyword oriented bibliographical search reveals that less than 5% of the biofilm literature is devoted to methodology. In this report, we (i) summarize current methodologies for biofilm characterization, monitoring, and quantification; (ii) discuss advances in the discovery of effective imaging and sensing tools and modalities; (iii) provide an overview of tailored animal models that assess features of biofilm infections; and (iv) make recommendations defining the most appropriate methodological tools for clinical settings. PMID- 29618588 TI - Sleep-Active Neurons: Conserved Motors of Sleep. AB - Sleep is crucial for survival and well-being. This behavioral and physiological state has been studied in all major genetically accessible model animals, including rodents, fish, flies, and worms. Genetic and optogenetic studies have identified several neurons that control sleep, making it now possible to compare circuit mechanisms across species. The "motor" of sleep across animal species is formed by neurons that depolarize at the onset of sleep to actively induce this state by directly inhibiting wakefulness. These sleep-inducing neurons are themselves controlled by inhibitory or activating upstream pathways, which act as the "drivers" of the sleep motor: arousal inhibits "sleep-active" neurons whereas various sleep-promoting "tiredness" pathways converge onto sleep-active neurons to depolarize them. This review provides the first overview of sleep-active neurons across the major model animals. The occurrence of sleep-active neurons and their regulation by upstream pathways in both vertebrate and invertebrate species suggests that these neurons are general and ancient components that evolved early in the history of nervous systems. PMID- 29618589 TI - Functional Imaging and Optogenetics in Drosophila. AB - Understanding how activity patterns in specific neural circuits coordinate an animal's behavior remains a key area of neuroscience research. Genetic tools and a brain of tractable complexity make Drosophila a premier model organism for these studies. Here, we review the wealth of reagents available to map and manipulate neuronal activity with light. PMID- 29618592 TI - Tread Lightly Interpreting Polygenic Tests of Selection. PMID- 29618593 TI - A Genetic Screen for Pre-mRNA Splicing Mutants of Arabidopsis thaliana Identifies Putative U1 snRNP Components RBM25 and PRP39a. PMID- 29618594 TI - Cell Biology of the Mitochondrion. PMID- 29618591 TI - Biology in Bloom: A Primer on the Arabidopsis thaliana Model System. AB - Arabidopsis thaliana could have easily escaped human scrutiny. Instead, Arabidopsis has become the most widely studied plant in modern biology despite its absence from the dinner table. Pairing diminutive stature and genome with prodigious resources and tools, Arabidopsis offers a window into the molecular, cellular, and developmental mechanisms underlying life as a multicellular photoautotroph. Many basic discoveries made using this plant have spawned new research areas, even beyond the verdant fields of plant biology. With a suite of resources and tools unmatched among plants and rivaling other model systems, Arabidopsis research continues to offer novel insights and deepen our understanding of fundamental biological processes. PMID- 29618596 TI - Alternative Splicing of FOXP3 Controls Regulatory T Cell Effector Functions and Is Associated With Human Atherosclerotic Plaque Stability. AB - RATIONALE: Regulatory T (Treg) cells suppress immune responses and have been shown to attenuate atherosclerosis. The Treg cell lineage-specification factor FOXP3 (forkhead box P3) is essential for Treg cells' ability to uphold immunologic tolerance. In humans, FOXP3 exists in several different isoforms, however, their specific role is poorly understood. OBJECTIVE: To define the regulation and functions of the 2 major FOXP3 isoforms, FOXP3fl and FOXP3Delta2, as well as to establish whether their expression is associated with the ischemic atherosclerotic disease. METHODS AND RESULTS: Human primary T cells were transduced with lentiviruses encoding distinct FOXP3 isoforms. The phenotype and function of these cells were analyzed by flow cytometry, in vitro suppression assays and RNA-sequencing. We also assessed the effect of activation on Treg cells isolated from healthy volunteers. Treg cell activation resulted in increased FOXP3 expression that predominantly was made up of FOXP3Delta2. FOXP3Delta2 induced specific transcription of GARP (glycoprotein A repetitions predominant), which functions by tethering the immunosuppressive cytokine TGF (transforming growth factor)-beta to the cell membrane of activated Treg cells. Real-time polymerase chain reaction was used to determine the impact of alternative splicing of FOXP3 in relation with atherosclerotic plaque stability in a cohort of >150 patients that underwent carotid endarterectomy. Plaque instability was associated with a lower FOXP3Delta2 transcript usage, when comparing plaques from patients without symptoms and patients with the occurrence of recent (<1 month) vascular symptoms including minor stroke, transient ischemic attack, or amaurosis fugax. No difference was detected in total levels of FOXP3 mRNA between these 2 groups. CONCLUSIONS: These results suggest that activated Treg cells suppress the atherosclerotic disease process and that FOXP3Delta2 controls a transcriptional program that acts protectively in human atherosclerotic plaques. PMID- 29618590 TI - Wingless Signaling: A Genetic Journey from Morphogenesis to Metastasis. AB - This FlyBook chapter summarizes the history and the current state of our understanding of the Wingless signaling pathway. Wingless, the fly homolog of the mammalian Wnt oncoproteins, plays a central role in pattern generation during development. Much of what we know about the pathway was learned from genetic and molecular experiments in Drosophila melanogaster, and the core pathway works the same way in vertebrates. Like most growth factor pathways, extracellular Wingless/Wnt binds to a cell surface complex to transduce signal across the plasma membrane, triggering a series of intracellular events that lead to transcriptional changes in the nucleus. Unlike most growth factor pathways, the intracellular events regulate the protein stability of a key effector molecule, in this case Armadillo/beta-catenin. A number of mysteries remain about how the "destruction complex" destabilizes beta-catenin and how this process is inactivated by the ligand-bound receptor complex, so this review of the field can only serve as a snapshot of the work in progress. PMID- 29618598 TI - Routine Assessment and Promotion of Physical Activity in Healthcare Settings: A Scientific Statement From the American Heart Association. AB - Physical inactivity is one of the most prevalent major health risk factors, with 8 in 10 US adults not meeting aerobic and muscle-strengthening guidelines, and is associated with a high burden of cardiovascular disease. Improving and maintaining recommended levels of physical activity leads to reductions in metabolic, hemodynamic, functional, body composition, and epigenetic risk factors for noncommunicable chronic diseases. Physical activity also has a significant role, in many cases comparable or superior to drug interventions, in the prevention and management of >40 conditions such as diabetes mellitus, cancer, cardiovascular disease, obesity, depression, Alzheimer disease, and arthritis. Whereas most of the modifiable cardiovascular disease risk factors included in the American Heart Association's My Life Check - Life's Simple 7 are evaluated routinely in clinical practice (glucose and lipid profiles, blood pressure, obesity, and smoking), physical activity is typically not assessed. The purpose of this statement is to provide a comprehensive review of the evidence on the feasibility, validity, and effectiveness of assessing and promoting physical activity in healthcare settings for adult patients. It also adds concrete recommendations for healthcare systems, clinical and community care providers, fitness professionals, the technology industry, and other stakeholders in order to catalyze increased adoption of physical activity assessment and promotion in healthcare settings and to contribute to meeting the American Heart Association's 2020 Impact Goals. PMID- 29618599 TI - Triglyceride-Rich Lipoprotein Cholesterol and Risk of Cardiovascular Events Among Patients Receiving Statin Therapy in the TNT Trial. AB - BACKGROUND: Mendelian randomization data suggest that the genetic determinants of lifetime higher triglyceride-rich lipoprotein-cholesterol (TRL-C) are causally related to cardiovascular disease and therefore a potential therapeutic target. The relevance of TRL-C among patients receiving statins is unknown. We assessed the relationship between TRL-C and cardiovascular risk, and whether this risk was modifiable among patients receiving statins in the TNT trial (Treating to New Targets). METHODS: Patients with coronary heart disease and low-density lipoprotein cholesterol (LDL-C) 130 to 250 mg/dL entered an 8-week run-in phase with atorvastatin 10 mg/d (ATV10). After this period, participants with LDL-C <130 mg/dL entered the randomized phase with ATV10 (n=5006) versus atorvastatin 80 mg/d (ATV80, n=4995). The primary end point was coronary heart disease death, nonfatal myocardial infarction, resuscitated cardiac arrest, or stroke (major adverse cardiovascular events [MACE]). TRL-C was calculated as total cholesterol minus high-density lipoprotein cholesterol minus LDL-C. The effect of atorvastatin on TRL-C was assessed during the run-in phase (ATV10) and randomized phase (ATV80 versus ATV10). The risk of MACE was assessed across quintiles (Q) of baseline TRL-C (and, for comparison, by baseline triglycerides and non-high density lipoprotein cholesterol) during the randomized period. Last, the association between TRL-C changes with atorvastatin and cardiovascular risk was assessed by multivariate Cox regression. RESULTS: ATV10 reduced TRL-C 10.7% from an initial TRL-C of 33.9+/-16.6 mg/dL. ATV80 led to an additional 15.4% reduction. Cardiovascular risk factors positively correlated with TRL-C. Among patients receiving ATV10, higher TRL-C was associated with higher 5-year MACE rates (Q1=9.7%, Q5=13.8%; hazard ratio Q5-versus-Q1, 1.48; 95% confidence interval, 1.15-1.92; P-trend<0.0001). ATV80 (versus ATV10) did not significantly alter the risk of MACE in Q1-Q2, but significantly reduced risk in Q3-Q5 (relative risk reduction, 29%-41%; all P<0.0250), with evidence of effect modification ( P-homogeneity=0.0053); results were consistent for triglycerides ( P-homogeneity=0.0101) and directionally similar for non-high-density lipoprotein cholesterol ( P-homogeneity=0.1387). Last, in adjusted analyses, a 1 SD percentage reduction in TRL-C with atorvastatin resulted in a significant lower risk of MACE (hazard ratio, 0.93; 95% confidence interval, 0.86-1.00; P=0.0482) independent of the reduction in LDL-C and of similar magnitude to that per 1 SD lowering in LDL-C (hazard ratio, 0.89; 95% confidence interval, 0.83-0.95; P=0.0008). CONCLUSIONS: The present post hoc analysis from TNT shows that increased TRL-C levels are associated with an increased cardiovascular risk and provides evidence for the cardiovascular benefit of lipid lowering with statins among patients who have coronary heart disease with high TRL-C. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00327691. PMID- 29618597 TI - Regulation of Vascular Calcification by Growth Hormone-Releasing Hormone and Its Agonists. AB - RATIONALE: Vascular calcification (VC) is a marker of the severity of atherosclerotic disease. Hormones play important roles in regulating calcification; estrogen and parathyroid hormones exert opposing effects, the former alleviating VC and the latter exacerbating it. To date no treatment strategies have been developed to regulate clinical VC. OBJECTIVE: The objective of this study was to investigate the effect of growth hormone-releasing hormone (GHRH) and its agonist (GHRH-A) on the blocking of VC in a mouse model. METHODS AND RESULTS: Young adult osteoprotegerin-deficient mice were given daily subcutaneous injections of GHRH-A (MR409) for 4 weeks. Significant reductions in calcification of the aortas of MR409-treated mice were paralleled by markedly lower alkaline phosphatase activity and a dramatic reduction in the expression of transcription factors, including the osteogenic marker gene Runx2 and its downstream factors, osteonectin and osteocalcin. The mechanism of action of GHRH A was dissected in smooth muscle cells isolated from human and mouse aortas. Calcification of smooth muscle cells induced by osteogenic medium was inhibited in the presence of GHRH or MR409, as evidenced by reduced alkaline phosphatase activity and Runx2 expression. Inhibition of calcification by MR409 was partially reversed by MIA602, a GHRH antagonist, or a GHRH receptor-selective small interfering RNA. Treatment with MR409 induced elevated cytosolic cAMP and its target, protein kinase A which in turn blocked nicotinamide adenine dinucleotide phosphate oxidase activity and reduced production of reactive oxygen species, thus blocking the phosphorylation of nuclear factor kappaB (p65), a key intermediate in the ligand of receptor activator for nuclear factor-kappa B Runx2/alkaline phosphatase osteogenesis program. A protein kinase A-selective small interfering RNA or the chemical inhibitor H89 abolished these beneficial effects of MR409. CONCLUSIONS: GHRH-A controls osteogenesis in smooth muscle cells by targeting cross talk between protein kinase A and nuclear factor kappaB (p65) and through the suppression of reactive oxygen species production that induces the Runx2 gene and alkaline phosphatase. Inflammation-mediated osteogenesis is thereby blocked. GHRH-A may represent a new pharmacological strategy to regulate VC. PMID- 29618600 TI - Outdoor air pollution, exhaled 8-isoprostane and current asthma in adults: the EGEA study. AB - Associations between outdoor air pollution and asthma in adults are still scarce, and the underlying biological mechanisms are poorly understood. Our aim was to study the associations between 1) long-term exposure to outdoor air pollution and current asthma, 2) exhaled 8-isoprostane (8-iso; a biomarker related to oxidative stress) and current asthma, and 3) outdoor air pollution and exhaled 8-iso.Cross sectional analyses were conducted in 608 adults (39% with current asthma) from the first follow-up of the French case-control and family study on asthma (EGEA; the Epidemiological study of the Genetic and Environmental factors of Asthma). Data on nitrogen dioxide, nitrogen oxides, particulate matter with a diameter <=10 and <=2.5 um (PM10 and PM2.5), road traffic, and ozone (O3) were from ESCAPE (European Study of Cohorts for Air Pollution Effects) and IFEN (French Institute for the Environment) assessments. Models took account of city and familial dependence.The risk of current asthma increased with traffic intensity (adjusted (a)OR 1.09 (95% CI 1.00-1.18) per 5000 vehicles per day), with O3 exposure (aOR 2.04 (95% CI 1.27-3.29) per 10 ug.m-3) and with exhaled 8-iso concentration (aOR 1.50 (95% CI 1.06-2.12) per 1 pg.mL-1). Among participants without asthma, exhaled 8-iso concentration increased with PM2.5 exposure (adjusted (a)beta 0.23 (95% CI 0.005-0.46) per 5 ug.m-3), and decreased with O3 and O3-summer exposures (abeta -0.20 (95% CI -0.39- -0.01) and abeta -0.52 (95% CI -0.77- -0.26) per 10 ug.m-3, respectively).Our results add new insights into a potential role of oxidative stress in the associations between outdoor air pollution and asthma in adults. PMID- 29618602 TI - "Evolution of respiratory function in Duchenne muscular dystrophy from childhood to adulthood." Antonella LoMauro, Marianna Romei, Sandra Gandossini, Riccardo Pascuzzo, Simone Vantini, Maria Grazia D'Angelo and Andrea Aliverti. Eur Respir J 2018; 51: 1701418. PMID- 29618603 TI - Adding an invasive procedure will not necessarily change treatment or outcome of NSCLC patients with preoperative clinical N1 disease. PMID- 29618601 TI - Promoting respiratory public health through epigenetics research: an ERS Environment Health Committee workshop report. PMID- 29618604 TI - HypAir FeNO: an electrochemical sensor. PMID- 29618605 TI - Vicarious breathlessness: an inferential perceptual learned transposition process that may not be inconsequential to either patient or caregiver. PMID- 29618606 TI - Adding an invasive procedure will not necessarily change treatment or outcome of NSCLC patients with preoperative clinical N1 disease. PMID- 29618607 TI - Chronic thromboembolic pulmonary hypertension after acute pulmonary embolism: to screen or not to screen? PMID- 29618608 TI - Identifying early pulmonary arterial hypertension in patients with systemic sclerosis. PMID- 29618609 TI - Molecular structural diversity of mitochondrial cardiolipins. AB - Current strategies used to quantitatively describe the biological diversity of lipids by mass spectrometry are often limited in assessing the exact structural variability of individual molecular species in detail. A major challenge is represented by the extensive isobaric overlap present among lipids, hampering their accurate identification. This is especially true for cardiolipins, a mitochondria-specific class of phospholipids, which are functionally involved in many cellular functions, including energy metabolism, cristae structure, and apoptosis. Substituted with four fatty acyl side chains, cardiolipins offer a particularly high potential to achieve complex mixtures of molecular species. Here, we demonstrate how systematically generated high-performance liquid chromatography-mass spectral data can be utilized in a mathematical structural modeling approach, to comprehensively analyze and characterize the molecular diversity of mitochondrial cardiolipin compositions in cell culture and disease models, cardiolipin modulation experiments, and a broad variety of frequently studied model organisms. PMID- 29618610 TI - Roll maneuvers are essential for active reorientation of Caenorhabditis elegans in 3D media. AB - Locomotion of the nematode Caenorhabditis elegans is a key observable used in investigations ranging from behavior to neuroscience to aging. However, while the natural environment of this model organism is 3D, quantitative investigations of its locomotion have been mostly limited to 2D motion. Here, we present a quantitative analysis of how the nematode reorients itself in 3D media. We identify a unique behavioral state of C. elegans-a roll maneuver-which is an essential component of 3D locomotion in burrowing and swimming. The rolls, associated with nonzero torsion of the nematode body, result in rotation of the plane of dorsoventral body undulations about the symmetry axis of the trajectory. When combined with planar turns in a new undulation plane, the rolls allow the nematode to reorient its body in any direction, thus enabling complete exploration of 3D space. The rolls observed in swimming are much faster than the ones in burrowing; we show that this difference stems from a purely hydrodynamic enhancement mechanism and not from a gait change or an increase in the body torsion. This result demonstrates that hydrodynamic viscous forces can enhance 3D reorientation in undulatory locomotion, in contrast to known hydrodynamic hindrance of both forward motion and planar turns. PMID- 29618611 TI - FAM210A is a novel determinant of bone and muscle structure and strength. AB - Osteoporosis and sarcopenia are common comorbid diseases, yet their shared mechanisms are largely unknown. We found that genetic variation near FAM210A was associated, through large genome-wide association studies, with fracture, bone mineral density (BMD), and appendicular and whole body lean mass, in humans. In mice, Fam210a was expressed in muscle mitochondria and cytoplasm, as well as in heart and brain, but not in bone. Grip strength and limb lean mass were reduced in tamoxifen-inducible Fam210a homozygous global knockout mice (TFam210a-/- ), and in tamoxifen-inducible Fam210 skeletal muscle cell-specific knockout mice (TFam210aMus-/- ). Decreased BMD, bone biomechanical strength, and bone formation, and elevated osteoclast activity with microarchitectural deterioration of trabecular and cortical bones, were observed in TFam210a-/- mice. BMD of male TFam210aMus-/- mice was also reduced, and osteoclast numbers and surface in TFam210aMus-/- mice increased. Microarray analysis of muscle cells from TFam210aMus-/- mice identified candidate musculoskeletal modulators. FAM210A, a novel gene, therefore has a crucial role in regulating bone structure and function, and may impact osteoporosis through a biological pathway involving muscle as well as through other mechanisms. PMID- 29618613 TI - The labyrinth of human variation. PMID- 29618612 TI - Interrelated role of Klotho and calcium-sensing receptor in parathyroid hormone synthesis and parathyroid hyperplasia. AB - The pathogenesis of parathyroid gland hyperplasia is poorly understood, and a better understanding is essential if there is to be improvement over the current strategies for prevention and treatment of secondary hyperparathyroidism. Here we investigate the specific role of Klotho expressed in the parathyroid glands (PTGs) in mediating parathyroid hormone (PTH) and serum calcium homeostasis, as well as the potential interaction between calcium-sensing receptor (CaSR) and Klotho. We generated mouse strains with PTG-specific deletion of Klotho and CaSR and dual deletion of both genes. We show that ablating CaSR in the PTGs increases PTH synthesis, that Klotho has a pivotal role in suppressing PTH in the absence of CaSR, and that CaSR together with Klotho regulates PTH biosynthesis and PTG growth. We utilized the tdTomato gene in our mice to visualize and collect PTGs to reveal an inhibitory function of Klotho on PTG cell proliferation. Chronic hypocalcemia and ex vivo PTG culture demonstrated an independent role for Klotho in mediating PTH secretion. Moreover, we identify an interaction between PTG expressed CaSR and Klotho. These findings reveal essential and interrelated functions for CaSR and Klotho during parathyroid hyperplasia. PMID- 29618615 TI - Physiological constraints on marine mammal body size. PMID- 29618614 TI - Cell contraction induces long-ranged stress stiffening in the extracellular matrix. AB - Animal cells in tissues are supported by biopolymer matrices, which typically exhibit highly nonlinear mechanical properties. While the linear elasticity of the matrix can significantly impact cell mechanics and functionality, it remains largely unknown how cells, in turn, affect the nonlinear mechanics of their surrounding matrix. Here, we show that living contractile cells are able to generate a massive stiffness gradient in three distinct 3D extracellular matrix model systems: collagen, fibrin, and Matrigel. We decipher this remarkable behavior by introducing nonlinear stress inference microscopy (NSIM), a technique to infer stress fields in a 3D matrix from nonlinear microrheology measurements with optical tweezers. Using NSIM and simulations, we reveal large long-ranged cell-generated stresses capable of buckling filaments in the matrix. These stresses give rise to the large spatial extent of the observed cell-induced matrix stiffness gradient, which can provide a mechanism for mechanical communication between cells. PMID- 29618616 TI - Change in Topoisomerase 1-Positive Circulating Tumor Cells Affects Overall Survival in Patients with Advanced Breast Cancer after Treatment with Etirinotecan Pegol. AB - Purpose: Preplanned exploratory analyses were performed to identify biomarkers in circulating tumor cells (CTC) predictive of response to the topoisomerase 1 inhibitor etirinotecan pegol (EP).Experimental Design: The BEACON trial treated patients with metastatic breast cancer (MBC) with EP or treatment of physician's choice (TPC). Blood from 656 of 852 patients (77%) was processed with ApoStream to enrich for CTCs. A multiplex immunofluorescence assay measured expression of candidate response biomarkers [topoisomerase 1 (Top1), topoisomerase 2 (Top2), Ki67, RAD51, ABCG2, gammaH2AX, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)] in CTCs. Patients were classified as Top1 low (Top1Lo) or Top1 high (Top1Hi) based on median CTC Top1 expression. Correlation of CTC biomarker expression at baseline, cycle 2 day 1 (C2D1), and cycle 4 day 1 with overall survival (OS) was investigated using Cox regression and Kaplan-Meier analyses.Results: Overall, 98% of samples were successfully processed, of which 97% had detectable CTCs (median, 47-63 CTCs/mL; range, 0-2,020 CTCs/mL). Top1, Top2, and TUNEL expression was detected in 52% to 90% of samples; no significant associations with OS were observed in pretreatment samples for either group. EP treated patients with low C2D1Top1+ CTCs had improved OS compared with those with higher positivity (14.1 months vs. 11.0 months, respectively; HR, 0.7; P = 0.02); this difference was not seen in TPC-treated patients (HR, 1.12; P = 0.48). Patients whose CTCs decreased from Top1Hi to Top1Lo at C2D1 had the greatest OS benefit from EP (HR, 0.57; P = 0.01).Conclusions: CTC Top1 expression following EP treatment may identify patients with MBC most likely to have an OS benefit. Clin Cancer Res; 24(14); 3348-57. (c)2018 AACR. PMID- 29618617 TI - Risk Assessment after Neoadjuvant Chemotherapy in Luminal Breast Cancer Using a Clinicomolecular Predictor. AB - Purpose: This study aimed to evaluate a modified EPclin test (mEPclin), a combination of EndoPredict (EP) score, post-neoadjuvant pathologic tumor size and nodal status, for predicting the risk of distance recurrence after neoadjuvant chemotherapy (NACT) in patients with residual estrogen receptor (ER) positive/HER2-negative breast cancer. We also compared the prognostic power of the mEPclin with that of the CPS-EG score.Experimental Design: A total of 428 formalin-fixed, paraffin-embedded tumor samples from GeparTrio and GeparQuattro studies were evaluated for mRNA expression of eight cancer-related and three reference genes. The mEPclin score was computed using a modified algorithm and predefined cut-off values were used to classify each patient at low or high risk. Primary endpoint was disease-free survival (DFS).Results: A higher continuous mEPclin score was significantly associated with increased risk of relapse [HR, 2.16; 95% confidence interval (CI), 1.86-2.51; P < 0.001] and death (HR, 2.28; 95% CI, 1.90-2.75; P < 0.001). Similarly, patients classified at high risk by dichotomous mEPclin showed significantly poorer DFS and overall survival compared with those at low risk. In contrast with CPS-EG, the mEPclin remained significantly prognostic for DFS in multivariate analysis (HR, 2.13; 95% CI, 1.73 2.63; P < 0.001). Combining CPS-EG and other clinicopathological variables with mEPclin yielded a significant improvement of the prognostic power for DFS versus without mEPclin (c-indices: 0.748 vs. 0.660; P < 0.001).Conclusions: The mEPclin score independently predicted the risk of distance recurrence and provided additional prognostic information to the CPS-EG score to assess more accurately the prognosis after NACT in the luminal non-pCR patient population. Therefore, this approach can be used to select patients for additional post-neoadjuvant therapies. Clin Cancer Res; 24(14); 3358-65. (c)2018 AACR. PMID- 29618618 TI - Inositol Trisphosphate Receptor Type 3-mediated Enhancement of EGFR and MET Cotargeting Efficacy in Non-Small Cell Lung Cancer Detected by 18F fluorothymidine. AB - Purpose: Our aim was to test whether imaging with 18F-fluorothymidine (18F-FLT) PET/CT was able to detect the combined effects of EGFR and MET inhibitors in oncogene-driven non-small cell lung cancer (NSCLC) and to elucidate the mechanisms underlying the enhanced efficacy of drug combination.Experimental Design: NSCLC cells bearing MET amplification (H1993 and H820) were treated with EGFR and MET inhibitors either alone or in combination and then tested for cell viability and inhibition of signaling. Nude mice bearing H1993 tumors underwent 18F-FLT PET/CT scan before and after treatment with erlotinib and crizotinib alone or in combination (1:1 ratio) and posttreatment changes of 18F-FLT uptake in tumors were determined. The role of inositol trisphosphate receptor type 3 (IP3R3) in mediating the combined action of EGFR and MET inhibitors was tested by transfecting NSCLC cells with IP3R3-targeted siRNA.Results: Imaging studies showed a significant reduction of 18F-FLT uptake in response to combined treatment with EGFR and MET inhibitors that was higher than that obtained with single agents (ANOVA, F-ratio = 6.215, P = 0.001). Imaging findings were confirmed by analysis of surgically excised tumors. Levels of IP3R3 were significantly reduced in both cells and tumors after treatment with crizotinib, whereas EGFR inhibitors caused a reduction of IP3R3 interaction with K-Ras mainly through dephosphorylation of serine residues of K-Ras.Conclusions: Our findings indicate that 18F-FLT PET/CT is able to detect the enhanced efficacy of EGFR and MET inhibitors in oncogene-driven NSCLC and that such enhancement is mediated by IP3R3 through its interaction with K-Ras. Clin Cancer Res; 24(13); 3126-36. (c)2018 AACR. PMID- 29618621 TI - Cholinergic forebrain density loss in Parkinson disease: More than just cognitive changes. PMID- 29618619 TI - Prevalent Homozygous Deletions of Type I Interferon and Defensin Genes in Human Cancers Associate with Immunotherapy Resistance. AB - Purpose: Homozygous deletions play important roles in carcinogenesis. The genome wide screening for homozygously deleted genes in many different cancer types with a large number of patient specimens representing the tumor heterogeneity has not been done.Experimental Design: We performed integrative analyses of the copy number profiles of 10,759 patients across 31 cancer types from The Cancer Genome Atlas project.Results: We found that the type-I interferon, alpha-, and beta defensin genes were homozygously deleted in 19 cancer types with high frequencies (7%-31%, median = 12%; interquartile range = 10%-16.5%). Patients with homozygous deletion of interferons exhibited significantly shortened overall or disease-free survival time in a number of cancer types, whereas patients with homozygous deletion of defensins did not significantly associate with worse overall or disease-free survival. Gene expression analyses suggested that homozygous deletion of interferon and defensin genes could activate genes involved in oncogenic and cell-cycle pathways but repress other genes involved in immune response pathways, suggesting their roles in promoting tumorigenesis and helping cancer cells evade immune surveillance. Further analysis of the whole exomes of 109 patients with melanoma demonstrated that the homozygous deletion of interferon (P = 0.0029, OR = 11.8) and defensin (P = 0.06, OR = 2.79) genes are significantly associated with resistance to anti-CTLA4 immunotherapy.Conclusions: Our analysis reveals that the homozygous deletion of interferon and defensin genes is prevalent in human cancers, and importantly this feature can be used as a novel prognostic biomarker for immunotherapy resistance. Clin Cancer Res; 24(14); 3299-308. (c)2018 AACR. PMID- 29618620 TI - Orthoxenografts of Testicular Germ Cell Tumors Demonstrate Genomic Changes Associated with Cisplatin Resistance and Identify PDMP as a Resensitizing Agent. AB - Purpose: To investigate the genetic basis of cisplatin resistance as efficacy of cisplatin-based chemotherapy in the treatment of distinct malignancies is often hampered by intrinsic or acquired drug resistance of tumor cells.Experimental Design: We produced 14 orthoxenograft transplanting human nonseminomatous testicular germ cell tumors (TGCT) in mice, keeping the primary tumor features in terms of genotype, phenotype, and sensitivity to cisplatin. Chromosomal and genetic alterations were evaluated in matched cisplatin-sensitive and their counterpart orthoxenografts that developed resistance to cisplatin in nude mice.Results: Comparative genomic hybridization analyses of four matched orthoxenografts identified recurrent chromosomal rearrangements across cisplatin resistant tumors in three of them, showing gains at 9q32-q33.1 region. We found a clinical correlation between the presence of 9q32-q33.1 gains in cisplatin refractory patients and poorer overall survival (OS) in metastatic germ cell tumors. We studied the expression profile of the 60 genes located at that genomic region. POLE3 and AKNA were the only two genes deregulated in resistant tumors harboring the 9q32-q33.1 gain. Moreover, other four genes (GCS, ZNF883, CTR1, and FLJ31713) were deregulated in all five resistant tumors independently of the 9q32 q33.1 amplification. RT-PCRs in tumors and functional analyses in Caenorhabditis elegans (C. elegans) indicate that the influence of 9q32-q33.1 genes in cisplatin resistance can be driven by either up- or downregulation. We focused on glucosylceramide synthase (GCS) to demonstrate that the GCS inhibitor DL-threo PDMP resensitizes cisplatin-resistant germline-derived orthoxenografts to cisplatin.Conclusions: Orthoxenografts can be used preclinically not only to test the efficiency of drugs but also to identify prognosis markers and gene alterations acting as drivers of the acquired cisplatin resistance. Clin Cancer Res; 24(15); 3755-66. (c)2018 AACR. PMID- 29618622 TI - Automated DWI analysis can identify patients within the thrombolysis time window of 4.5 hours. AB - OBJECTIVE: To develop an automated model based on diffusion-weighted imaging (DWI) to detect patients within 4.5 hours after stroke onset and compare this method to the visual DWI-FLAIR (fluid-attenuated inversion recovery) mismatch. METHODS: We performed a subanalysis of the "DWI-FLAIR mismatch for the identification of patients with acute ischemic stroke within 4.5 hours of symptom onset" (PRE-FLAIR) and the "AX200 for ischemic stroke" (AXIS 2) trials. We developed a prediction model with data from the PRE-FLAIR study by backward logistic regression with the 4.5-hour time window as dependent variable and the following explanatory variables: age and median relative DWI (rDWI) signal intensity, interquartile range (IQR) rDWI signal intensity, and volume of the core. We obtained the accuracy of the model to predict the 4.5-hour time window and validated our findings in an independent cohort from the AXIS 2 trial. We compared the receiver operating characteristic curve to the visual DWI-FLAIR mismatch. RESULTS: In the derivation cohort of 118 patients, we retained the IQR rDWI as explanatory variable. A threshold of 0.39 was most optimal in selecting patients within 4.5 hours after stroke onset resulting in a sensitivity of 76% and specificity of 63%. The accuracy was validated in an independent cohort of 200 patients. The predictive value of the area under the curve of 0.72 (95% confidence interval 0.64-0.80) was similar to the visual DWI-FLAIR mismatch (area under the curve = 0.65; 95% confidence interval 0.58-0.72; p for difference = 0.18). CONCLUSIONS: An automated analysis of DWI performs at least as good as the visual DWI-FLAIR mismatch in selecting patients within the 4.5-hour time window. PMID- 29618624 TI - Mass migration of stroke populations: For better or worse, away they go. PMID- 29618623 TI - Interfacility transfers for US ischemic stroke and TIA, 2006-2014. AB - OBJECTIVE: To investigate changes in emergency department (ED) transfers for ischemic stroke (IS) and TIA. METHODS: We performed a retrospective observational study using the US Nationwide Emergency Department Sample to identify changes in interfacility ED transfers for IS and TIA from the perspective of the transferring ED (2006-2014). We calculated nationwide transfer rates and individual ED transfer rates for IS/TIA by diagnosis and hospital characteristics. Hospital-level fractional logistic regression examined changes in transfer rates over time. RESULTS: The population-estimated number of transfers for IS/TIA increased from 22,576 patient visits in 2006 to 54,485 patient visits in 2014 (p trend < 0.001). The rate of IS/TIA transfer increased from 3.4 (95% confidence interval [CI] 3.0-3.8) in 2006 to 7.6 (95% CI 7.2-7.9) in 2014 per 100 ED visits. Among individual EDs, mean transfer rates for IS/TIA increased from 8.2 per 100 ED visits (median 2.0, interquartile range [IQR] 0 10.2) to 19.4 per 100 ED visits (median 8.1, IQR 1.1-33.3) (2006-2014) (p trend < 0.001). Transfers were more common among IS. Transfer rates were greatest among rural (adjusted odds ratio [AOR] 3.05, 95% CI 2.56-3.64) vs urban/teaching and low-volume EDs (AOR 7.49, 95% CI 6.58-8.53, 1st vs 4th quartile). The adjusted odds of transfer for IS/TIA increased threefold (2006-2014). CONCLUSIONS: Interfacility ED transfers for IS/TIA more than doubled from 2006 to 2014. Further work should determine the necessity of IS/TIA transfers and seek to optimize the US stroke care system. PMID- 29618625 TI - Getting serious about the early-life epilepsies: Lessons from the world of pediatric oncology. AB - Early-life epilepsies represent a group of many individually rare and often complex developmental brain disorders associated with lifelong devastating consequences and high risk for early mortality. The quantity and quality of evidence needed to guide the evaluation and treatment to optimize outcomes of affected children is minimal; most children are treated within an evidence-free practice zone based solely on anecdote and lore. The remarkable advances in diagnostics and therapeutics are implemented haphazardly with no systematic effort to understand their effects and value. This stands in stark contrast to the evidence-rich practice of the Children's Oncology Group, where standard of care treatments are identified through rigorous, multicenter research studies, and the vast majority of patients are treated on protocols developed from that research. As a consequence, overall mortality for childhood cancers has declined from ~90% in the 1950s to ~20% today. The situations of these 2 rare disease specialties are contrasted, and some suggestions for moving early-life epilepsy onto a fast track for success are offered. Chief amongst these is that early-life epilepsy should be treated with the same urgency as pediatric cancer. The best diagnostics and evidence-based treatments should be used in a systematic fashion right from the start, not after the child and family have been subjected to the ravages of the disorder for months or years. This will require unity and cooperation among physicians, researchers, and institutions across state and national borders. PMID- 29618626 TI - Demoralization in Parkinson disease. AB - OBJECTIVE: To determine the prevalence and associated features of demoralization in Parkinson disease (PD). METHODS: Participants with PD and controls were prospectively recruited from outpatient movement disorder clinics and the community. Demoralization was defined as scoring positively on the Diagnostic Criteria for Psychosomatic Research, Demoralization questionnaire or Kissane Demoralization Scale score >=24. Depression was defined as Patient Health Questionnaire-9 score >=10. Forward stepwise logistic regression was used to determine the odds of having demoralization in the overall, control, and PD cohorts. RESULTS: Demoralization occurred in 18.1% of 94 participants with PD and 8.1% of 86 control participants (p = 0.05). These 2 groups were otherwise comparable in age, sex, education, economics, race, and marital status. Although demoralization was highly associated with depression, there were individuals with one and not the other. Among participants with PD, 7 of 19 (36.8%) depressed individuals were not demoralized, and 5 of 17 (29.4%) demoralized individuals were not depressed. In the overall cohort, having PD (odds ratio 2.60, 95% confidence interval 1.00-6.80, p = 0.051) was associated with demoralization, along with younger age and not currently being married. In the PD cohort, younger age and Unified Parkinson's Disease Rating Scale, part III score (per score 1) were associated with demoralization (odds ratio 1.06, 95% confidence interval 1.01-1.12, p = 0.02). CONCLUSIONS: Demoralization is common in PD and is associated with motor dysfunction. In demoralization, there is a prominent inability to cope, making it somewhat distinct from depression. Treatment approaches are also different, making it important to identify demoralization in patients with PD. PMID- 29618627 TI - Baseline symptoms and basal forebrain volume predict future psychosis in early Parkinson disease. AB - OBJECTIVE: Determining baseline predictors of future psychosis in Parkinson disease (PD) may identify those at risk for more rapidly progressive disease, i.e., a more malignant PD subtype. METHODS: This cohort study evaluated 423 patients with newly diagnosed PD collected as part of the Parkinson's Progression Markers Initiative. Psychotic symptoms were assessed with the Movement Disorders Society-Unified Parkinson Disease Rating Scale item 1.2, which assesses hallucinations and psychosis over the past week. At baseline, participants completed the Scales for Outcomes in Parkinson's Disease-Autonomic, the REM Sleep Behavior Disorder (RBD) Screening Questionnaire, and the Epworth Sleepiness Scale. Cholinergic nucleus 4 (Ch4) density was calculated for 228 participants with PD and 101 healthy controls. RESULTS: Multivariate logistic regression adjusted for age and sex found that greater autonomic symptoms (p = 0.002), RBD (p = 0.021), and excessive daytime sleepiness (EDS) (p = 0.003) at baseline were associated with increased risk of reporting psychotic symptoms on >=2 occasions. Having 2 or 3 of these baseline symptoms was associated with lower Ch4 density (p = 0.007). In a logistic regression model adjusted for age and sex, higher Ch4 gray matter density was associated with lower risk of reporting psychotic symptoms on >=2 occasions (odds ratio 0.96 [for an increase in density of 1 unit], p = 0.03). CONCLUSIONS: This study confirms that RBD, EDS, and greater autonomic symptom burden are associated with greater risk of future psychotic symptoms in PD. Reduced Ch4 density at baseline is associated with future psychotic symptoms and a greater burden of RBD, EDS, and autonomic symptoms. PMID- 29618628 TI - Aluminum-Activated Malate Transporters Can Facilitate GABA Transport. AB - Plant aluminum-activated malate transporters (ALMTs) are currently classified as anion channels; they are also known to be regulated by diverse signals, leading to a range of physiological responses. Gamma-aminobutyric acid (GABA) regulation of anion flux through ALMT proteins requires a specific amino acid motif in ALMTs that shares similarity with a GABA binding site in mammalian GABAA receptors. Here, we explore why TaALMT1 activation leads to a negative correlation between malate efflux and endogenous GABA concentrations ([GABA]i) in both wheat (Triticum aestivum) root tips and in heterologous expression systems. We show that TaALMT1 activation reduces [GABA]i because TaALMT1 facilitates GABA efflux but GABA does not complex Al3+ TaALMT1 also leads to GABA transport into cells, demonstrated by a yeast complementation assay and via 14C-GABA uptake into TaALMT1-expressing Xenopus laevis oocytes; this was found to be a general feature of all ALMTs we examined. Mutation of the GABA motif (TaALMT1F213C) prevented both GABA influx and efflux, and resulted in no correlation between malate efflux and [GABA]i We conclude that ALMTs are likely to act as both GABA and anion transporters in planta. GABA and malate appear to interact with ALMTs in a complex manner to regulate each other's transport, suggestive of a role for ALMTs in communicating metabolic status. PMID- 29618629 TI - Targeted Recruitment of the Basal Transcriptional Machinery by LNK Clock Components Controls the Circadian Rhythms of Nascent RNAs in Arabidopsis. AB - The rhythms of steady-state mRNA expression pervade nearly all circadian systems. However, the mechanisms behind the rhythmic transcriptional synthesis and its correlation with circadian expression remain fully unexplored, particularly in plants. Here, we discovered a multifunctional protein complex that orchestrates the rhythms of transcriptional activity in Arabidopsis thaliana The expression of the circadian oscillator genes TIMING OF CAB EXPRESSION1/PSEUDO-RESPONSE REGULATOR1 and PSEUDO-RESPONSE REGULATOR5 initially relies on the modular function of the clock-related factor REVEILLE8: its MYB domain provides the DNA binding specificity, while its LCL domain recruits the clock components, NIGHT LIGHT-INDUCIBLE AND CLOCK-REGULATED proteins (LNKs), to target promoters. LNKs, in turn, specifically interact with RNA Polymerase II and the transcript elongation FACT complex to rhythmically co-occupy the target loci. The functional interaction of these components is central for chromatin status, transcript initiation, and elongation as well as for proper rhythms in nascent RNAs. Thus, our findings explain how genome readout of environmental information ultimately results in rhythmic changes of gene expression. PMID- 29618630 TI - EAR1 Negatively Regulates ABA Signaling by Enhancing 2C Protein Phosphatase Activity. AB - The reversible phosphorylation of proteins by kinases and phosphatases is an antagonistic process that modulates many cellular functions. Protein phosphatases are usually negatively regulated by inhibitor proteins. During abscisic acid (ABA) signaling, these inhibitor proteins comprise PYR1/PYL/RCAR ABA receptors, which inhibit the core negative regulators, the clade A type 2C protein phosphatases (PP2Cs). However, it is not known whether these PP2Cs are positively regulated by other proteins. Here, we identified an Arabidopsis thaliana ear1 (enhancer of aba co-receptor1) mutant that exhibits pleiotropic ABA hypersensitive phenotypes. EAR1 encodes an uncharacterized protein that is conserved in both monocots and dicots. EAR1 interacts with the N-terminal inhibition domains of all six PP2Cs, ABA INSENSITIVE1 (ABI1), ABI2, HYPERSENSITIVE TO ABA1 (HAB1), HAB2, ABA-HYPERSENSITIVE GERMINATION1 (AHG1), and AHG3, during ABA signaling and enhances the activity of PP2Cs both in vitro and in vivo. ABA treatment caused EAR1 to accumulate in the nucleus. These results indicate that EAR1 is a negative regulator of ABA signaling that enhances the activity of PP2Cs by interacting with and releasing the N-terminal autoinhibition of these proteins. PMID- 29618631 TI - The YTH Domain Protein ECT2 Is an m6A Reader Required for Normal Trichome Branching in Arabidopsis. AB - Methylations at position N6 of internal adenosines (m6As) are the most abundant and widespread mRNA modifications. These modifications play crucial roles in reproduction, growth, and development by controlling gene expression patterns at the posttranscriptional level. Their function is decoded by readers that share the YTH domain, which forms a hydrophobic pocket that directly accommodates the m6A residues. While the physiological and molecular functions of YTH readers have been extensively studied in animals, little is known about plant readers, even though m6As are crucial for plant survival and development. Viridiplantae contains high numbers of YTH domain proteins. Here, we performed comprehensive evolutionary analysis of YTH domain proteins and demonstrated that they are highly likely to be actual readers with redundant as well as specific functions. We also show that the ECT2 protein from Arabidopsis thaliana binds to m6A containing RNAs in vivo and that this property relies on the m6A binding pocket carried by its YTH domain. ECT2 is cytoplasmic and relocates to stress granules upon heat exposure, suggesting that it controls mRNA fate in the cytosol. Finally, we demonstrate that ECT2 acts to decode the m6A signal in the trichome and is required for their normal branching through controlling their ploidy levels. PMID- 29618632 TI - Adenylyl cyclase A mRNA localized at the back of cells is actively translated in live chemotaxing Dictyostelium. AB - Dictyostelium discoideum cells transport adenylyl cyclase A (ACA)-containing vesicles to the back of polarized cells to relay exogenous cAMP signals during chemotaxis. Fluorescence in situ hybridization (FISH) experiments showed that ACA mRNA is also asymmetrically distributed at the back of polarized cells. By using the MS2 bacteriophage system, we now visualize the distribution of ACA mRNA in live chemotaxing cells. We found that the ACA mRNA localization is not dependent on the translation of the protein product and requires multiple cis-acting elements within the ACA-coding sequence. We show that ACA mRNA is associated with actively translating ribosomes and is transported along microtubules towards the back of cells. By monitoring the recovery of ACA-YFP after photobleaching, we observed that local translation of ACA-YFP occurs at the back of cells. These data represent a novel functional role for localized translation in the relay of chemotactic signals during chemotaxis. PMID- 29618634 TI - Mice harbouring an oculodentodigital dysplasia-linked Cx43 G60S mutation have severe hearing loss. AB - Given the importance of connexin43 (Cx43, encoded by GJA1) function in the central nervous system and sensory organ processing, we proposed that it would also be crucial in auditory function. To that end, hearing was examined in two mouse models of oculodentodigital dysplasia that globally express GJA1 mutations resulting in mild or severe loss of Cx43 function. Although Cx43I130T/+ mutant mice, with ~50% Cx43 channel function, did not have any hearing loss, Cx43G60S/+ mutant mice, with ~20% Cx43 channel function, had severe hearing loss. There was no evidence of inner ear sensory hair cell loss, suggesting that the mechanism for Cx43-linked hearing loss lies downstream in the auditory pathway. Since evidence suggests that Cx26 function is essential for hearing and may be protective against noise-induced hearing loss, we challenged Cx43I130T/+ mice with a loud noise and found that they had a similar susceptibility to noise induced hearing loss to that found in controls, suggesting that decreased Cx43 function does not sensitize the mice for environmentally induced hearing loss. Taken together, this study suggests that Cx43 plays an important role in baseline hearing and is essential for auditory processing.This article has an associated First Person interview with the first author of the paper. PMID- 29618633 TI - Seh1 targets GATOR2 and Nup153 to mitotic chromosomes. AB - In metazoa, the Nup107 complex (also known as the nucleoporin Y-complex) plays a major role in formation of the nuclear pore complex in interphase and is localised to kinetochores in mitosis. The Nup107 complex shares a single highly conserved subunit, Seh1 (also known as SEH1L in mammals) with the GATOR2 complex, an essential activator of mTORC1 kinase. mTORC1/GATOR2 has a central role in the coordination of cell growth and proliferation. Here, we use chemical genetics and quantitative chromosome proteomics to study the role of the Seh1 protein in mitosis. Surprisingly, Seh1 is not required for the association of the Nup107 complex with mitotic chromosomes, but it is essential for the association of both the GATOR2 complex and nucleoporin Nup153 with mitotic chromosomes. Our analysis also reveals a role for Seh1 at human centromeres, where it is required for efficient localisation of the chromosomal passenger complex (CPC). Furthermore, this analysis detects a functional interaction between the Nup107 complex and the small kinetochore protein SKAP (also known as KNSTRN). PMID- 29618635 TI - Removal of sialic acid from bull sperm decreases motility and mucus penetration ability but increases zona pellucida binding and polyspermic penetration in vitro. AB - This study tested the hypothesis that sperm sialic acid (Sia) is required to reach the site of fertilization, and that successful fertilization requires recognition of Sia from both the sperm and oocyte to occur. In addition, it has recently been reported that Siglecs (Sia-binding-immunoglobulin-like lectins) are present on the sperm surface. Thus, the possibility that the recognition of oocyte Sia was sperm-Siglec-mediated was also addressed. Sperm exposed to neuraminidase (NMase) exhibited lower overall and progressive motility, which translated to a decreased ability to swim through cervical mucus from cows in oestrus. In addition, when either sperm or cumulus-oocyte complexes (COCs) were treated with NMase, a decrease in cleavage and blastocyst rate was observed. However, incubation of sperm with increasing concentrations of anti-Siglec-2, -5, -6 and -10 antibodies prior to fertilization had no effect on their fertilizing ability. Interestingly, treatment with NMase increased the number of sperm bound to the ZP but also the rate of polyspermic fertilization. Flow cytometry analysis revealed no differences in the percentage of capacitated or acrosome-reacted sperm. These results suggest that Sia are required to reach the site of fertilization but need to be removed for sperm-oocyte interaction. However, fine regulation is needed to avoid abnormal fertilization which can lead to impaired embryo development. PMID- 29618636 TI - Single-cell profiling screen identifies microtubule-dependent reduction of variability in signaling. AB - Populations of isogenic cells often respond coherently to signals, despite differences in protein abundance and cell state. Previously, we uncovered processes in the Saccharomyces cerevisiae pheromone response system (PRS) that reduced cell-to-cell variability in signal strength and cellular response. Here, we screened 1,141 non-essential genes to identify 50 "variability genes". Most had distinct, separable effects on strength and variability of the PRS, defining these quantities as genetically distinct "axes" of system behavior. Three genes affected cytoplasmic microtubule function: BIM1, GIM2, and GIM4 We used genetic and chemical perturbations to show that, without microtubules, PRS output is reduced but variability is unaffected, while, when microtubules are present but their function is perturbed, output is sometimes lowered, but its variability is always high. The increased variability caused by microtubule perturbations required the PRS MAP kinase Fus3 and a process at or upstream of Ste5, the membrane-localized scaffold to which Fus3 must bind to be activated. Visualization of Ste5 localization dynamics demonstrated that perturbing microtubules destabilized Ste5 at the membrane signaling site. The fact that such microtubule perturbations cause aberrant fate and polarity decisions in mammals suggests that microtubule-dependent signal stabilization might also operate throughout metazoans. PMID- 29618637 TI - Interaction of 2',3'-cAMP with Rbp47b Plays a Role in Stress Granule Formation. AB - 2',3'-cAMP is an intriguing small molecule that is conserved among different kingdoms. 2',3'-cAMP is presumably produced during RNA degradation, with increased cellular levels observed especially under stress conditions. Previously, we observed the presence of 2',3'-cAMP in Arabidopsis (Arabidopsis thaliana) protein complexes isolated from native lysate, suggesting that 2',3' cAMP has potential protein partners in plants. Here, affinity purification experiments revealed that 2',3'-cAMP associates with the stress granule (SG) proteome. SGs are aggregates composed of protein and mRNA, which enable cells to selectively store mRNA for use in response to stress such as heat whereby translation initiation is impaired. Using size-exclusion chromatography and affinity purification analyses, we identified Rbp47b, the key component of SGs, as a potential interacting partner of 2',3'-cAMP. Furthermore, SG formation was promoted in 2',3'-cAMP-treated Arabidopsis seedlings, and interactions between 2',3'-cAMP and RNA-binding domains of Rbp47b, RRM2 and RRM3, were confirmed in vitro using microscale thermophoresis. Taken together, these results (1) describe novel small-molecule regulation of SG formation, (2) provide evidence for the biological role of 2',3'-cAMP, and (3) demonstrate an original biochemical pipeline for the identification of protein-metabolite interactors. PMID- 29618638 TI - Large Crown Root Number Improves Topsoil Foraging and Phosphorus Acquisition. AB - Suboptimal phosphorus (P) availability is a primary constraint to plant growth on Earth. We tested the hypothesis that maize (Zea mays) genotypes with large crown root number (CN) will have shallower rooting depth and improved P acquisition from low-P soils. Maize recombinant inbred lines with contrasting CN were evaluated under suboptimal P availability in greenhouse mesocosms and the field. Under P stress in mesocosms, the large-CN phenotype had 48% greater root respiration, 24% shallower rooting depth, 32% greater root length density in the topsoil, 37% greater leaf P concentration, 48% greater leaf photosynthesis, 33% greater stomatal conductance, and 44% greater shoot biomass than the small-CN phenotype. Under P stress in the field, the large-CN phenotype had 32% shallower rooting depth, 51% greater root length density in the topsoil, 44% greater leaf P concentration, 18% greater leaf photosynthesis, 21% greater stomatal conductance, 23% greater shoot biomass at anthesis, and 28% greater yield than the small-CN phenotype. These results support the hypothesis that large CN improves plant P acquisition from low-P soils by reducing rooting depth and increasing topsoil foraging. The large-CN phenotype merits consideration as a selection target to improve P capture in maize and possibly other cereal crops. PMID- 29618639 TI - Hospital-level care coordination strategies associated with better patient experience. AB - BACKGROUND: Patient experience is a key measure of hospital quality and is increasingly contained in value-based payment programmes. Understanding whether strategies aimed at improving care transitions are associated with better patient experience could help clinical leaders and policymakers seeking to improve care across multiple dimensions. OBJECTIVE: To determine the association of specific hospital care coordination and transition strategies with patient experience. DESIGN: We surveyed leadership at 1600 acute care hospitals and categorised respondents into three groups based on the strategies used: low-strategy (bottom quartile of number of strategies), mid-strategy (quartiles 2 and 3) and high strategy (highest quartile). We used linear regression models to examine the association between use of these strategies and performance on measures of patient experience from the Hospital Consumer Assessment of Healthcare Providers and Systems survey. RESULTS: We achieved a 62% response rate. High-strategy hospitals reported using 7.7 strategies on average usually or always on their patient populations, while mid-strategy and low-strategy hospitals reported using 5.0 and 2.3 strategies, respectively. Compared with low-strategy hospitals, high strategy hospitals had a higher overall rating (+2.23 percentage points (pp), P<0.001), higher recommendation score (+2.5 pp, P<0.001), and higher satisfaction with discharge process (+1.35 pp, P=0.01) and medication communication (+1.44 pp, P=0.002). Mid-strategy hospitals had higher scores than low-strategy hospitals except for discharge satisfaction. Patient-facing strategies, like sharing discharge summaries with patients prior to discharge, using discharge coordinators and calling patients 48 hours after discharge, were each individually associated with a higher overall hospital rating, and higher satisfaction with discharge process and medication communication. CONCLUSIONS: Hospitals with greater reported use of care coordination and transition strategies have better patient experience than hospitals with fewer reported strategies. Strategies that most directly involve patients have the strongest association with better experience. PMID- 29618640 TI - Porcine Deltacoronavirus Engages the Transmissible Gastroenteritis Virus Functional Receptor Porcine Aminopeptidase N for Infectious Cellular Entry. AB - Identification of cellular receptors used by coronavirus (CoV) entry into the host cells is critical to an understanding of pathogenesis and to development of intervention strategies. The fourth CoV genus, Deltacoronavirus, evolutionarily related to the Gammacoronavirus, has just been defined recently. In the current study, we demonstrate that porcine aminopeptidase N (pAPN) acts as a cross-genus CoV functional receptor for both enteropathogenic porcine deltacoronovirus (PDCoV) and alphacoronovirus (AlphaCoV) (transmissible gastroenteritis virus [TGEV]) based upon three lines of evidence. First, the soluble S1 protein of PDCoV bound to the surface of target porcine cell lines known to express pAPN as efficiently as TGEV-S1, which could be blocked by soluble pAPN pretreatment. Second, both PDCoV-S1 and TGEV-S1 physically recognized and interacted with pAPN by coimmunoprecipitation in pAPN cDNA-transfected cells and by dot blot hybridization assay. Finally, exogenous expression of pAPN in refractory cells conferred susceptibility to PDCoV-S1 binding and to PDCoV entry and productive infection. PDCoV-S1 appeared to have a lower pAPN-binding affinity and likely consequent lower infection efficiency in pAPN-expressing refractory cells than TGEV-S1, suggesting that there may be differences between these two viruses in the virus-binding regions in pAPN. This study paves the way for dissecting the molecular mechanisms of PDCoV-host interactions and pathogenesis as well as facilitates future vaccine development and intervention strategies against PDCoV infection.IMPORTANCE The emergence of new human and animal coronaviruses is believed to have occurred through interspecies transmission that is mainly mediated by a species-specific receptor of the host. Among the four genera of the Coronavirinae, a couple of functional receptors for the representative members in the genera Alphacoronavirus and Betacoronavirus have been identified, whereas receptors for Gammacoronavirus and Deltacoronavirus, which are believed to originate from birds, are still unknown. Porcine coronaviruses, including the newly discovered porcine deltacoronavirus (PDCoV) associated with diarrhea in newborn piglets, have posed a serious threat to the pork industry in Asia and North America. Here, we report that PDCoV employs the alphacoronavirus TGEV functional receptor porcine aminopeptidase N (pAPN) for cellular entry, demonstrating the usage of pAPN as a cross-genus CoV functional receptor. The identification of the PDCoV receptor provides another example of the expanded host range of CoV and paves the way for further investigation of PDCoV-host interaction and pathogenesis. PMID- 29618641 TI - Ac102 Participates in Nuclear Actin Polymerization by Modulating BV/ODV-C42 Ubiquitination during Autographa californica Multiple Nucleopolyhedrovirus Infection. AB - As a virus-encoded actin nucleation promoting factor (NPF), P78/83 induces actin polymerization to assist in Autographa californica multiple nucleopolyhedrovirus (AcMNPV) propagation. According to our previous study, although P78/83 actively undergoes ubiquitin-independent proteasomal degradation, AcMNPV encodes budded virus/occlusion derived virus (BV/ODV)-C42 (C42), which allows P78/83 to function as a stable NPF by inhibiting its degradation during viral infection. However, whether there are other viral proteins involved in regulating P78/83-induced actin polymerization has yet to be determined. In this study, we found that Ac102, an essential viral gene product previously reported to play a key role in mediating the nuclear accumulation of actin during AcMNPV infection, is a novel regulator of P78/83-induced actin polymerization. By characterizing an ac102 knockout bacmid, we demonstrated that Ac102 participates in regulating nuclear actin polymerization as well as the morphogenesis and distribution of capsid structures in the nucleus. These regulatory effects are heavily dependent on an interaction between Ac102 and C42. Further investigation revealed that Ac102 binds to C42 to suppress K48-linked ubiquitination of C42, which decreases C42 proteasomal degradation and consequently allows P78/83 to function as a stable NPF to induce actin polymerization. Thus, Ac102 and C42 form a regulatory cascade to control viral NPF activity, representing a sophisticated mechanism for AcMNPV to orchestrate actin polymerization in both a ubiquitin-dependent and ubiquitin independent manner.IMPORTANCE Actin is one of the most functionally important proteins in eukaryotic cells. Morphologically, actin can be found in two forms: a monomeric form called globular actin (G-actin) and a polymeric form called filamentous actin (F-actin). G-actin can polymerize to form F-actin, and nucleation promoting factor (NPF) is the initiator of this process. Many viral pathogens harness the host actin polymerization machinery to assist in virus propagation. Autographa californica multiple nucleopolyhedrovirus (AcMNPV) induces actin polymerization in host cells. P78/83, a viral NPF, is responsible for this process. Previously, we identified that BV/ODV-C42 (C42) binds to P78/83 and protects it from degradation. In this report, we determined that another viral protein, Ac102, is involved in modulating C42 ubiquitination and, consequently, ensures P78/83 activity as an NPF to initiate actin polymerization. This regulatory cascade represents a novel mechanism by which a virus can harness the cellular actin cytoskeleton to assist in viral propagation. PMID- 29618642 TI - Ortervirales: New Virus Order Unifying Five Families of Reverse-Transcribing Viruses. PMID- 29618643 TI - Comparison of Uncleaved and Mature Human Immunodeficiency Virus Membrane Envelope Glycoprotein Trimers. AB - The mature envelope glycoprotein (Env) spike on the surfaces of human immunodeficiency virus type 1 (HIV-1)-infected cells and virions is derived from proteolytic cleavage of a trimeric gp160 glycoprotein precursor. In these studies, we compared the conformations of cleaved and uncleaved membrane Envs with truncated cytoplasmic tails to those of stabilized soluble gp140 SOSIP.664 Env trimers. Deletion of the gp41 cytoplasmic tail did not significantly affect the sensitivity of viruses with the HIV-1AD8 Env to inhibition by antibodies or a CD4-mimetic compound. After glutaraldehyde fixation and purification from membranes, a cleaved Env exhibited a hydrodynamic radius of ~10 nm and an antibody-binding profile largely consistent with that expected based on virus neutralization sensitivity. The purified cleaved Env trimers exhibited a hollow architecture with a central void near the trimer axis. Uncleaved Env, cross linked and purified in parallel, exhibited a hydrodynamic radius similar to that of the cleaved Env. However, the uncleaved Env was recognized by poorly neutralizing antibodies and appeared by negative-stain electron microscopy to sample multiple conformations. Compared with membrane Envs, stabilized soluble gp140 SOSIP.664 Env trimers appear to be more compact, as reflected in their smaller hydrodynamic radii and negative-stain electron microscopy structures. The antigenic features of the soluble gp140 SOSIP.664 Env trimers differed from those of the cleaved membrane Env, particularly in gp120 V3 and some CD4-binding-site epitopes. Thus, proteolytic maturation allows the membrane-anchored Env to achieve a conformation that retains functional metastability but masks epitopes for poorly neutralizing antibodies.IMPORTANCE The entry of human immunodeficiency virus type 1 (HIV-1) into host cells is mediated by the envelope glycoprotein (Env) spike on the surface of the virus. Host antibodies elicited during natural HIV-1 infection or by vaccination can potentially recognize the Env spike and block HIV-1 infection. However, the changing shape of the HIV-1 Env spike protects the virus from antibody binding. Understanding the shapes of natural and man-made preparations of HIV-1 Envs will assist the development of effective vaccines against the virus. Here, we evaluate the effects of several Env modifications commonly used to produce Env preparations for vaccine studies and the determination of structure. We found that the cleavage of the HIV-1 Env precursor helps Env to assume its natural shape, which resists the binding of many commonly elicited antibodies. Stabilized soluble Envs exhibit more compact shapes but expose some Env elements differently than the natural Env. PMID- 29618645 TI - Feline Herpesvirus 1 US3 Blocks the Type I Interferon Signal Pathway by Targeting Interferon Regulatory Factor 3 Dimerization in a Kinase-Independent Manner. AB - As a prevalent agent in cats, feline herpesvirus 1 (FHV-1) infection contributes to feline respiratory disease and acute and chronic conjunctivitis. FHV-1 can successfully evade the host innate immune response and persist for the lifetime of the cat. Several mechanisms of immune evasion by human herpesviruses have been elucidated, but the mechanism of immune evasion by FHV-1 remains unknown. In this study, we screened for FHV-1 open reading frames (ORFs) responsible for inhibiting the type I interferon (IFN) pathway with an IFN-beta promoter reporter and analysis of IFN-beta mRNA levels in HEK 293T cells and the Crandell-Reese feline kidney (CRFK) cell line, and we identified the Ser/Thr kinase US3 as the most powerful inhibitor. Furthermore, we found that the anti-IFN activity of US3 depended on its N terminus (amino acids 1 to 75) and was independent of its kinase activity. Mechanistically, the ectopic expression of US3 selectively inhibited IFN regulatory factor 3 (IRF3) promoter activation. Furthermore, US3 bound to the IRF association domain (IAD) of IRF3 and prevented IRF3 dimerization. Finally, US3-deleted recombinant FHV-1 and US3-repaired recombinant FHV-1 (rFHV-dUS3 and rFHV-rUS3, respectively) were constructed. Compared with wild-type FHV-1 and rFHV-rUS3, infection with rFHV-dUS3 induced large amounts of IFN-beta in vitro and in vivo More importantly, US3 deletion significantly attenuated virulence, reduced virus shedding, and blocked the invasion of trigeminal ganglia. These results indicate that FHV-1 US3 efficiently inhibits IFN induction by using a novel immune evasion mechanism and that FHV-1 US3 is a potential regulator of neurovirulence.IMPORTANCE Despite widespread vaccination, the prevalence of FHV-1 remains high, suggesting that it can successfully evade the host innate immune response and infect cats. In this study, we screened viral proteins for inhibiting the IFN pathway and identified the Ser/Thr kinase US3 as the most powerful inhibitor. In contrast to other members of the alphaherpesviruses, FHV-1 US3 blocked the host type I IFN pathway in a kinase independent manner and via binding to the IRF3 IAD and preventing IRF3 dimerization. More importantly, the depletion of US3 attenuated the anti-IFN activity of FHV-1 and prevented efficient viral replication in vitro and in vivo Also, US3 deletion significantly attenuated virulence and blocked the invasion of trigeminal ganglia. We believe that these findings not only will help us to better understand the mechanism of how FHV-1 manipulates the host IFN response but also highlight the potential role of US3 in the establishment of latent infection in vivo. PMID- 29618644 TI - Molecular Basis of Unusually High Neutralization Resistance in Tier 3 HIV-1 Strain 253-11. AB - Understanding the mechanisms used by HIV-1 to evade antibody neutralization may contribute to the design of a high-coverage vaccine. The tier 3 virus 253-11 is poorly neutralized by subtype-matched and subtype C sera, even compared to other tier 3 viruses, and is also recognized poorly by V3/glycan-targeting monoclonal antibodies (MAbs). We found that sequence polymorphisms in the V3 loop and N linked glycosylation sites contribute only minimally to the high neutralization resistance of 253-11. Interestingly, the 253-11 membrane-proximal external region (MPER) is rarely recognized by sera in the context of the wild-type virus but is commonly recognized in the context of an HIV-2 chimera, suggesting steric or kinetic hindrance of binding to MPER in the native envelope (Env). Mutations in the 253-11 MPER, which were previously reported to increase the lifetime of the prefusion Env conformation, affected the resistance of 253-11 to antibodies targeting various epitopes on HIV-1 Env, presumably destabilizing its otherwise stable, closed trimer structure. To gain insight into the structure of 253-11, we constructed and crystallized a recombinant 253-11 SOSIP trimer. The resulting structure revealed that the heptad repeat helices in gp41 are drawn in close proximity to the trimer axis and that gp120 protomers also showed a relatively compact disposition around the trimer axis. These observations give substantial insight into the molecular features of an envelope spike from a tier 3 virus and into possible mechanisms that may contribute to its unusually high neutralization resistance.IMPORTANCE HIV-1 isolates that are highly resistant to broadly neutralizing antibodies could limit the efficacy of an antibody-based vaccine. We studied 253-11, which is highly resistant to commonly elicited neutralizing antibodies. To further understand its resistance, we made mutations that are known to delay fusion and thus increase the time that the virus spends in the open conformation following CD4 binding. Interestingly, we found that these mutations affect the 253-11 envelope (Env) spike before CD4 binding, presumably by destabilizing the trimer structure. To gain further information about the structure of the 253-11 Env trimer, we generated a recombinant 253-11 SOSIP trimer. The crystal structure of the SOSIP trimer revealed that the gp41 helices and the gp120 protomers were drawn in toward the center of the molecule compared to most solved HIV-1 Env structures. These observations provide insight into the distinct molecular features of a tier 3 envelope spike. PMID- 29618646 TI - Functional Relevance of the Transmembrane Domain and Cytoplasmic Tail of the Pseudorabies Virus Glycoprotein H for Membrane Fusion. AB - Herpesvirus membrane fusion depends on the core fusion machinery, comprised of glycoproteins B (gB) and gH/gL. Although gB structurally resembles autonomous class III fusion proteins, it strictly depends on gH/gL to drive membrane fusion. Whether the gH/gL complex needs to be membrane anchored to fulfill its function and which role the gH cytoplasmic (CD) and transmembrane domains (TMD) play in fusion is unclear. While the gH CD and TMD play an important role during infection, soluble gH/gL of herpes simplex virus 1 (HSV-1) seems to be sufficient to mediate cell-cell fusion in transient assays, arguing against an essential contribution of the CD and TMD. To shed more light on this apparent discrepancy, we investigated the role of the CD and TMD of the related alphaherpesvirus pseudorabies virus (PrV) gH. For this purpose, we expressed C-terminally truncated and soluble gH and replaced the TMD with a glycosylphosphatidylinositol (gpi) anchor. We also generated chimeras containing the TMD and/or CD of PrV gD or HSV-1 gH. Proteins were characterized in cell-based fusion assays and during virus infection. Although truncation of the CD resulted in decreased membrane fusion activity, the mutant proteins still supported replication of gH-negative PrV, indicating that the PrV gH CD is dispensable for viral replication. In contrast, PrV gH lacking the TMD, membrane-anchored via a lipid linker, or comprising the PrV gD TMD were nonfunctional, highlighting the essential role of the gH TMD for function. Interestingly, despite low sequence identity, the HSV-1 gH TMD could substitute for the PrV gH TMD, pointing to functional conservation.IMPORTANCE Enveloped viruses depend on membrane fusion for virus entry. While this process can be mediated by only one or two proteins, herpesviruses depend on the concerted action of at least three different glycoproteins. Although gB has features of bona fide fusion proteins, it depends on gH and its complex partner, gL, for fusion. Whether gH/gL prevents premature fusion or actively triggers gB-mediated fusion is unclear, and there are contradictory results on whether gH/gL function requires stable membrane anchorage or whether the ectodomains alone are sufficient. Our results show that in pseudorabies virus gH, the transmembrane anchor plays an essential role for gB mediated fusion while the cytoplasmic tail is not strictly required. PMID- 29618648 TI - A non-envelopment role for the ESCRT-III complex during HCMV infection. AB - Secondary envelopment of human cytomegalovirus (HCMV) occurs through a mechanism that is poorly understood. Many enveloped viruses utilize the endosomal sorting complexes required for transport (ESCRTs) for viral budding and envelopment. Although there are conflicting reports on the role of the ESCRT AAA-ATPase protein VPS4 in an HCMV infection, VPS4 may act in an envelopment role similar to its function during other viral infections. Because VPS4 is normally recruited by the ESCRT-III complex, we hypothesized that ESCRT-III subunits would also be required for HCMV infection. We investigated the role of ESCRT-III, the core ESCRT scission complex, during the late stages of infection. We show that inducible expression of dominant-negative ESCRT-III subunits during infection blocks endogenous ESCRT function, but does not inhibit virus production. We also show that HCMV forms enveloped intracellular and extracellular virions in the presence of dominant-negative ESCRT-III subunits, suggesting that ESCRT-III is not involved in the envelopment of HCMV. We also found that similar to ESCRT-III, inducible expression of a dominant-negative form of VPS4A did not inhibit the envelopment of virions or reduce virus titers. Thus, HCMV does not require the ESCRTs for secondary envelopment. However, we found that ESCRT-III subunits are required for efficient virus spread. This suggests a role for ESCRT-III during the spread of HCMV that is independent of viral envelopment.IMPORTANCE Human cytomegalovirus (HCMV) is a prevalent opportunistic pathogen in the human population. HCMV infection in neonatal and immunocompromised patients can cause severe and possibly life-threatening complications in these at-risk patients. It is important to define mechanisms of the viral replication cycle to identify potential targets for new therapies. Secondary envelopment, or acquisition of the membrane envelope, of HCMV is a mechanism that needs further study. Using an inducible fibroblast system to carefully control for the toxicity associated with blocking ESCRT-III function, this study determines that the ESCRT proteins are not required for viral envelopment. However, the study does discover a non envelopment role for the ESCRT-III complex in the efficient spread of the virus. Thus, this study advances our understanding of an important process essential for the replication of HCMV. PMID- 29618647 TI - Identification of the RNA Pseudoknot within the 3' End of the Porcine Reproductive and Respiratory Syndrome Virus Genome as a Pathogen-Associated Molecular Pattern To Activate Antiviral Signaling via RIG-I and Toll-Like Receptor 3. AB - Once infected by viruses, cells can detect pathogen-associated molecular patterns (PAMPs) on viral nucleic acid by host pattern recognition receptors (PRRs) to initiate the antiviral response. Porcine reproductive and respiratory syndrome virus (PRRSV) is the causative agent of porcine reproductive and respiratory syndrome (PRRS), characterized by reproductive failure in sows and respiratory diseases in pigs of different ages. To date, the sensing mechanism of PRRSV has not been elucidated. Here, we reported that the pseudoknot region residing in the 3' untranslated regions (UTR) of the PRRSV genome, which has been proposed to regulate RNA synthesis and virus replication, was sensed as nonself by retinoic acid-inducible gene I (RIG-I) and Toll-like receptor 3 (TLR3) and strongly induced type I interferons (IFNs) and interferon-stimulated genes (ISGs) in porcine alveolar macrophages (PAMs). The interaction between the two stem-loops inside the pseudoknot structure was sufficient for IFN induction, since disruption of the pseudoknot interaction powerfully dampened the IFN induction. Furthermore, transfection of the 3' UTR pseudoknot transcripts in PAMs inhibited PRRSV replication in vitro Importantly, the predicted similar structures of other arterivirus members, including equine arteritis virus (EAV), lactate dehydrogenase-elevating virus (LDV), and simian hemorrhagic fever virus (SHFV), also displayed strong IFN induction activities. Together, in this work we identified an innate recognition mechanism by which the PRRSV 3' UTR pseudoknot region served as PAMPs of arteriviruses and activated innate immune signaling to produce IFNs that inhibit virus replication. All of these results provide novel insights into innate immune recognition during virus infection.IMPORTANCE PRRS is the most common viral disease in the pork industry. It is caused by PRRSV, a positive single-stranded RNA virus, whose infection often leads to persistent infection. To date, it is not yet clear how PRRSV is recognized by the host and what is the exact mechanism of IFN induction. Here, we investigated the nature of PAMPs on PRRSV and the associated PRRs. We found that the 3' UTR pseudoknot region of PRRSV, which has been proposed to regulate viral RNA synthesis, could act as PAMPs recognized by RIG-I and TLR3 to induce type I IFN production to suppress PRRSV infection. This report is the first detailed description of pattern recognition for PRRSV, which is important in understanding the antiviral response of arteriviruses, especially PRRSV, and extends our knowledge on virus recognition. PMID- 29618649 TI - Brain large artery lymphocytic inflammation and Human Immunodeficiency Virus related brain arterial remodeling. AB - The pathogenesis of increased stroke risk in Human Immunodeficiency Virus (HIV) remains unclear. Our study investigated the relationship between adventitial and intimal CD3+ T cells and brain arterial remodeling that potentially contributes to HIV-related vasculopathy and stroke. Large brain arteries from 84 HIV+ cases and 78 HIV- cases were analyzed to determine interadventitial and luminal diameters, intimal and wall thickness, percentage stenosis, and presence of atherosclerosis. Immunohistochemical analysis was performed to detect and visually score CD3, a pan T cell marker, in the intima and adventitia. Our study showed that adventitial CD3+ T cells are lower among persons with HIV, especially if CD4<200, though intimal CD3+ T cells did not differ by HIV status. Among those with HIV but CD4<200 at time of death, intimal CD3+ T cells were associated with hypertrophic outward remodeling, while among those with HIV and CD4>200 or HIV- controls, intimal CD3+ T cells were associated with hypertrophic inward remodeling. We conclude that intimal lymphocytic inflammation is involved in brain arterial remodeling that may contribute to HIV-related cerebrovascular pathology.IMPORTANCE Although mortality from Human Immunodeficiency Virus (HIV) has decreased with the use of combination antiretroviral therapies, there is now an increased risk of cardiovascular and cerebrovascular disease associated with HIV. Thus, there is a need to understand the pathogenesis of stroke in HIV infection. Our study examines how lymphocytic inflammation in brain arteries may contribute to increased cerebral vasculopathy. With this understanding, our study can potentially help direct future therapies to target and prevent brain arterial remodeling processes associated with HIV. PMID- 29618651 TI - Large scale complete genome sequencing and phylodynamic analysis of eastern equine encephalitis virus reveal source-sink transmission dynamics in the United States. AB - Eastern equine encephalitis virus (EEEV) has a high case-fatality rate in horses and humans, and Florida has been hypothesized to be the source of EEEV epidemics for the northeastern U.S. To test this hypothesis, we sequenced complete genomes of 433 EEEV strains collected within the U.S. from 1934 to 2014. Phylogenetic analysis suggested EEEV evolves relatively slowly and that transmission is enzootic in Florida, characterized by higher genetic diversity and long-term local persistence. In contrast, EEEV in New York and Massachusetts were characterized by lower genetic diversity, multiple introductions, and shorter local persistence. Our phylogeographic analysis supported a source-sink model in which Florida is the major source of EEEV compared to the other localities sampled. In sum, this study revealed the complex epidemiological dynamics of EEEV in different geographic regions in the U.S., and provided general insights into the evolution and transmission of other avian mosquito-borne viruses in this region.IMPORTANCE Eastern equine encephalitis virus (EEEV) infections are severe in horses and humans on the east coast of the United States with over 90% mortality rate in horses, approximately 33% mortality rate in humans, and significant brain damage in most human survivors. However, little is known about the evolutionary characteristics of EEEV due to the lack of genome sequences. By generating large collection of publicly-available complete genome sequences, this study comprehensively determined the evolution of the virus, described the epidemiological dynamics of EEEV in different states in the U.S., and identified Florida as one of the major sources. These results may have important implications for the control and prevention of other mosquito-borne viruses in the Americas. PMID- 29618652 TI - The metalloproteinase-proteoglycans ADAMTS7 and ADAMTS12 provide an innate, tendon-specific protective mechanism against heterotopic ossification. AB - Heterotopic ossification (HO) is a significant clinical problem with incompletely resolved mechanisms. Here, the secreted metalloproteinases ADAMTS7 and ADAMTS12 are shown to comprise a unique proteoglycan class that protects against a tendency toward HO in mouse hindlimb tendons, menisci, and ligaments. Adamts7 and Adamts12 mRNAs were sparsely expressed in murine forelimbs but strongly coexpressed in hindlimb tendons, skeletal muscle, ligaments, and meniscal fibrocartilage. Adamts7-/- Adamts12-/- mice, but not corresponding single-gene mutants, which demonstrated compensatory upregulation of the intact homolog mRNA, developed progressive HO in these tissues after 4 months of age. Adamts7-/- Adamts12-/- tendons had abnormal collagen fibrils, accompanied by reduced levels of the small leucine-rich proteoglycans (SLRPs) biglycan, fibromodulin, and decorin, which regulate collagen fibrillogenesis. Bgn-/0 Fmod-/- mice are known to have a strikingly similar hindlimb HO to that of Adamts7-/- Adamts12-/- mice, implicating fibromodulin and biglycan reduction as a likely mechanism underlying HO in Adamts7-/- Adamts12-/- mice. Interestingly, degenerated human biceps tendons had reduced ADAMTS7 mRNA compared with healthy biceps tendons, which expressed both ADAMTS7 and ADAMTS12. These results suggest that ADAMTS7 and ADAMTS12 drive an innate pathway protective against hindlimb HO in mice and may be essential for human tendon health. PMID- 29618650 TI - Simian Immunodeficiency Virus Vif and Human APOBEC3B Interactions Resemble Those between HIV-1 Vif and Human APOBEC3G. AB - Several members of the APOBEC3 DNA cytosine deaminase family can potently inhibit Vif-deficient human immunodeficiency virus type 1 (HIV-1) by catalyzing cytosine deamination in viral cDNA and impeding reverse transcription. HIV-1 counteracts restriction with the virally encoded Vif protein, which targets relevant APOBEC3 proteins for proteasomal degradation. HIV-1 Vif is optimized for degrading the restrictive human APOBEC3 repertoire, and, in general, lentiviral Vif proteins specifically target the restricting APOBEC3 enzymes of each host species. However, simian immunodeficiency virus SIVmac239 Vif elicits a curiously wide range of APOBEC3 degradation capabilities that include degradation of several human APOBEC3s and even human APOBEC3B, a non-HIV-1-restricting APOBEC3 enzyme. To better understand the molecular determinants of the interaction between SIVmac239 Vif and human APOBEC3B, we analyzed an extensive series of mutants. We found that SIVmac239 Vif interacts with the N-terminal domain of human APOBEC3B and, interestingly, that this occurs within a structural region homologous to the HIV-1 Vif interaction surface of human APOBEC3G. An alanine scan of SIVmac239 Vif revealed several residues required for human APOBEC3B degradation activity. These residues overlap HIV-1 Vif surface residues that interact with human APOBEC3G and are distinct from those that engage APOBEC3F or APOBEC3H. Overall, these studies indicate that the molecular determinants of the functional interaction between human APOBEC3B and SIVmac239 Vif resemble those between human APOBEC3G and HIV-1 Vif. These studies contribute to the growing knowledge of the APOBEC-Vif interaction and may help guide future efforts to disrupt this interaction as an antiviral therapy or exploit the interaction as a novel strategy to inhibit APOBEC3B-dependent tumor evolution.IMPORTANCE Primate APOBEC3 proteins provide innate immunity against retroviruses such as HIV and SIV. HIV-1, the primary cause of AIDS, utilizes its Vif protein to specifically counteract restrictive human APOBEC3 enzymes. SIVmac239 Vif exhibits a much wider range of anti-APOBEC3 activities that includes several rhesus macaque enzymes and extends to multiple proteins in the human APOBEC3 repertoire, including APOBEC3B. Understanding the molecular determinants of the interaction between SIVmac239 Vif and human APOBEC3B adds to existing knowledge on the APOBEC3-Vif interaction and has potential to shed light on what processes may have shaped Vif functionality over evolutionary time. An intimate understanding of this interaction may also lead to a novel cancer therapy because, for instance, creating a derivative of SIVmac239 Vif that specifically targets human APOBEC3B could be used to suppress tumor genomic DNA mutagenesis by this enzyme, slow ongoing tumor evolution, and help prevent poor clinical outcomes. PMID- 29618653 TI - The inflammasome potentiates influenza/Staphylococcus aureus superinfection in mice. AB - Secondary bacterial respiratory infections are commonly associated with both acute and chronic lung injury. Influenza complicated by bacterial pneumonia is an effective model to study host defense during pulmonary superinfection due to its clinical relevance. Multiprotein inflammasomes are responsible for IL-1beta production in response to infection and drive tissue inflammation. In this study, we examined the role of the inflammasome during viral/bacterial superinfection. We demonstrate that ASC-/- mice are protected from bacterial superinfection and produce sufficient quantities of IL-1beta through an apoptosis-associated speck like protein containing CARD (ASC) inflammasome-independent mechanism. Despite the production of IL-1beta by ASC-/- mice in response to bacterial superinfection, these mice display decreased lung inflammation. A neutrophil elastase inhibitor blocked ASC inflammasome-independent production of IL-1beta and the IL-1 receptor antagonist, anakinra, confirmed that IL-1 remains crucial to the clearance of bacteria during superinfection. Delayed inhibition of NLRP3 during influenza infection by MCC950 decreases bacterial burden during superinfection and leads to decreased inflammatory cytokine production. Collectively, our results demonstrate that ASC augments the clearance of bacteria, but can also contribute to inflammation and mortality. ASC should be considered as a therapeutic target to decrease morbidity and mortality during bacterial superinfection. PMID- 29618654 TI - Exosomal Tat protein activates latent HIV-1 in primary, resting CD4+ T lymphocytes. AB - Replication competent HIV-1 persists in a subpopulation of CD4+ T lymphocytes despite prolonged antiretroviral treatment. This residual reservoir of infected cells harbors transcriptionally silent provirus capable of reigniting productive infection upon discontinuation of antiretroviral therapy. Certain classes of drugs can activate latent virus but not at levels that lead to reductions in HIV 1 reservoir size in vivo. Here, we show the utility of CD4+ receptor targeting exosomes as an HIV-1 latency reversal agent (LRA). We engineered human cellular exosomes to express HIV-1 Tat, a protein that is a potent transactivator of viral transcription. Preparations of exosomal Tat-activated HIV-1 in primary, resting CD4+ T lymphocytes isolated from antiretroviral-treated individuals with prolonged periods of viral suppression and led to the production of replication competent HIV-1. Furthermore, exosomal Tat increased the potency of selected LRA by over 30-fold in terms of HIV-1 mRNA expression, thereby establishing it as a potentially new class of biologic product with possible combinatorial utility in targeting latent HIV-1. PMID- 29618655 TI - IL-27 gene therapy induces depletion of Tregs and enhances the efficacy of cancer immunotherapy. AB - Tumor-induced expansion of Tregs is a significant obstacle to cancer immunotherapy. However, traditional approaches to deplete Tregs are often inefficient, provoking autoimmunity. We show here that administration of IL-27 expressing recombinant adeno-associated virus (AAV-IL-27) significantly inhibits tumor growth and enhances T cell responses in tumors. Strikingly, we found that AAV-IL-27 treatment causes rapid depletion of Tregs in peripheral blood, lymphoid organs, and - most pronouncedly - tumor microenvironment. AAV-IL-27-mediated Treg depletion is dependent on IL-27 receptor and Stat1 in Tregs and is a combined result of CD25 downregulation in Tregs and inhibition of IL-2 production by T cells. In combination with a GM-CSF vaccine, AAV-IL-27 treatment not only induced nearly complete tumor rejection, but also resulted in amplified neoantigen specific T cell responses. AAV-IL-27 also dramatically increased the efficacy of anti-PD-1 therapy, presumably due to induction of PD-L1 in T cells and depletion of Tregs. Importantly, AAV-IL-27 therapy did not induce significant adverse events, partially due to its induction of IL-10. In a plasmacytoma mouse model, we found that IL-10 was required for AAV-IL-27-mediated tumor rejection. Thus, our study demonstrates the potential of AAV-IL-27 as an independent cancer therapeutic and as an efficient adjuvant for cancer immunotherapy. PMID- 29618656 TI - Ontogeny and reversal of brain circuit abnormalities in a preclinical model of PCOS. AB - Androgen excess is a hallmark of polycystic ovary syndrome (PCOS), a prevalent yet poorly understood endocrine disorder. Evidence from women and preclinical animal models suggests that elevated perinatal androgens can elicit PCOS onset in adulthood, implying androgen actions in both PCOS ontogeny and adult pathophysiology. Prenatally androgenized (PNA) mice exhibit a robust increase of progesterone-sensitive GABAergic inputs to gonadotropin-releasing hormone (GnRH) neurons implicated in the pathogenesis of PCOS. It is unclear when altered GABAergic wiring develops in the brain, and whether these central abnormalities are dependent upon adult androgen excess. Using GnRH-GFP-transgenic mice, we determined that increased GABA input to GnRH neurons occurs prior to androgen excess and the manifestation of reproductive impairments in PNA mice. These data suggest that brain circuit abnormalities precede the postpubertal development of PCOS traits. Despite the apparent developmental programming of circuit abnormalities, long-term blockade of androgen receptor signaling from early adulthood rescued normal GABAergic wiring onto GnRH neurons, improved ovarian morphology, and restored reproductive cycles in PNA mice. Therefore, androgen excess maintains changes in female brain wiring linked to PCOS features and the blockade of androgen receptor signaling reverses both the central and peripheral PNA-induced PCOS phenotype. PMID- 29618657 TI - 17-beta Estradiol regulates proglucagon-derived peptide secretion in mouse and human alpha- and L cells. AB - Clinical and experimental data indicate a beneficial effect of estrogens on energy and glucose homeostasis associated with improved insulin sensitivity and positive effects on insulin secretion. The aim of the study was to investigate the impact of estrogens on proglucagon-producing cells, pancreatic alpha cells, and enteroendocrine L cells. The consequences of sexual hormone deprivation were evaluated in ovariectomized mice (ovx). Ovx mice exhibited impaired glucose tolerance during oral glucose tolerance tests (OGTT), which was associated with decreased GLP-1 intestinal and pancreatic secretion and content, an effect that was reversed by estradiol (E2) treatment. Indeed, E2 increased oral glucose induced GLP-1 secretion in vivo and GLP-1 secretion from primary culture of mouse and human alpha cells through the activation of all 3 estrogen receptors (ERs), whereas E2-induced GLP-1 secretion from mouse and human intestinal explants occurred only by ERbeta activation. Underlying the implication of ERbeta, its selective agonist WAY20070 was able to restore glucose tolerance in ovx mice at least partly through plasma GLP-1 increase. We conclude that E2 directly controls both alpha- and L cells to increase GLP-1 secretion, in addition to its effects on insulin and glucagon secretion, highlighting the potential beneficial role of the estrogenic pathway and, more particularly, of ERbeta agonists to prevent type 2 diabetes. PMID- 29618658 TI - Pancreatic cancer therapy with combined mesothelin-redirected chimeric antigen receptor T cells and cytokine-armed oncolytic adenoviruses. AB - Pancreatic ductal adenocarcinoma (PDA) is characterized by its highly immunosuppressive tumor microenvironment (TME) that limits T cell infiltration and induces T cell hypofunction. Mesothelin-redirected chimeric antigen receptor T cell (meso-CAR T cell) therapy has shown some efficacy in clinical trials but antitumor efficacy remains modest. We hypothesized that combined meso-CAR T cells with an oncolytic adenovirus expressing TNF-alpha and IL-2 (Ad5/3-E2F-D24-TNFa IRES-IL2, or OAd-TNFa-IL2) would improve efficacy. OAd-TNFa-IL2 enhanced the antitumor efficacy of meso-CAR T cells in human-PDA-xenograft immunodeficient mice and efficacy was associated with robustly increased tumor-infiltrating lymphocytes (TILs), enhanced and prolonged T cell function. Mice treated with parental OAd combined with meso-CAR T developed tumor metastasis to the lungs even if primary tumors were controlled. However, no mice treated with combined OAd-TNFa-IL2 and meso-CAR T died of tumor metastasis. We also evaluated this approach in a syngeneic mouse tumor model by combining adenovirus expressing murine TNF-alpha and IL-2 (Ad-mTNFa-mIL2) and mouse CAR T cells. This approach induced significant tumor regression in mice engrafted with highly aggressive and immunosuppressive PDA tumors. Ad-mTNFa-mIL2 increased both CAR T cell and host T cell infiltration to the tumor and altered host tumor immune status with M1 polarization of macrophages and increased dendritic cell maturation. These findings indicate that combining cytokine-armed oncolytic adenovirus to enhance the efficacy of CAR T cell therapy is a promising approach to overcome the immunosuppressive TME for the treatment of PDA. PMID- 29618659 TI - Mesenchymal TNFR2 promotes the development of polyarthritis and comorbid heart valve stenosis. AB - Mesenchymal TNF signaling is etiopathogenic for inflammatory diseases such as rheumatoid arthritis and spondyloarthritis (SpA). The role of Tnfr1 in arthritis has been documented; however, Tnfr2 functions are unknown. Here, we investigate the mesenchymal-specific role of Tnfr2 in the TnfDeltaARE mouse model of SpA in arthritis and heart valve stenosis comorbidity by cell-specific, Col6a1-cre driven gene targeting. We find that TNF/Tnfr2 signaling in resident synovial fibroblasts (SFs) and valvular interstitial cells (VICs) is detrimental for both pathologies, pointing to common cellular mechanisms. In contrast, systemic Tnfr2 provides protective signaling, since its complete deletion leads to severe deterioration of both pathologies. SFs and VICs lacking Tnfr2 fail to acquire pathogenic activated phenotypes and display increased expression of antiinflammatory cytokines associated with decreased Akt signaling. Comparative RNA sequencing experiments showed that the majority of the deregulated pathways in TnfDeltaARE mesenchymal-origin SFs and VICs, including proliferation, inflammation, migration, and disease-specific genes, are regulated by Tnfr2; thus, in its absence, they are maintained in a quiescent nonpathogenic state. Our data indicate a pleiotropy of Tnfr2 functions, with mesenchymal Tnfr2 driving cell activation and arthritis/valve stenosis pathogenesis only in the presence of systemic Tnfr2, whereas nonmesenchymal Tnfr2 overcomes this function, providing protective signals and, thus, containing both pathologies. PMID- 29618660 TI - Transcriptomics and machine learning predict diagnosis and severity of growth hormone deficiency. AB - BACKGROUND: The effect of gene expression data on diagnosis remains limited. Here, we show how diagnosis and classification of growth hormone deficiency (GHD) can be achieved from a single blood sample using a combination of transcriptomics and random forest analysis. METHODS: Prepubertal treatment-naive children with GHD (n = 98) were enrolled from the PREDICT study, and controls (n = 26) were acquired from online data sets. Whole blood gene expression was correlated with peak growth hormone (GH) using rank regression and a random forest algorithm tested for prediction of the presence of GHD and in classification of GHD as severe (peak GH <4 MUg/l) and nonsevere (peak >=4 MUg/l). Performance was assessed using area under the receiver operating characteristic curve (AUC-ROC). RESULTS: Rank regression identified 347 probe sets in which gene expression correlated with peak GH concentrations (r = +/- 0.28, P < 0.01). These 347 probe sets yielded an AUC-ROC of 0.95 for prediction of GHD status versus controls and an AUC-ROC of 0.93 for prediction of GHD severity. CONCLUSION: This study demonstrates highly accurate diagnosis and disease classification for GHD using a combination of transcriptomics and random forest analysis. TRIAL REGISTRATION: NCT00256126 and NCT00699855. FUNDING: Merck and the National Institute for Health Research (CL-2012-06-005). PMID- 29618661 TI - Comprehensive immunoproteogenomic analyses of malignant pleural mesothelioma. AB - We generated a comprehensive atlas of the immunologic cellular networks within human malignant pleural mesothelioma (MPM) using mass cytometry. Data-driven analyses of these high-resolution single-cell data identified 2 distinct immunologic subtypes of MPM with vastly different cellular composition, activation states, and immunologic function; mass spectrometry demonstrated differential abundance of MHC-I and -II neopeptides directly identified between these subtypes. The clinical relevance of this immunologic subtyping was investigated with a discriminatory molecular signature derived through comparison of the proteomes and transcriptomes of these 2 immunologic MPM subtypes. This molecular signature, representative of a favorable intratumoral cell network, was independently associated with improved survival in MPM and predicted response to immune checkpoint inhibitors in patients with MPM and melanoma. These data additionally suggest a potentially novel mechanism of response to checkpoint blockade: requirement for high measured abundance of neopeptides in the presence of high expression of MHC proteins specific for these neopeptides. PMID- 29618662 TI - Human MAIT cells exit peripheral tissues and recirculate via lymph in steady state conditions. AB - Mucosal-associated invariant T cells (MAIT cells) recognize bacterial metabolites as antigen and are found in blood and tissues, where they are poised to contribute to barrier immunity. Recent data demonstrate that MAIT cells located in mucosal barrier tissues are functionally distinct from their blood counterparts, but the relationship and circulation of MAIT cells between blood and different tissue compartments remains poorly understood. Previous studies raised the possibility that MAIT cells do not leave tissue and may either be retained or undergo apoptosis. To directly address if human MAIT cells exit tissues, we collected human donor-matched thoracic duct lymph and blood and analyzed MAIT cell phenotype, transcriptome, and T cell receptor (TCR) diversity by flow cytometry and RNA sequencing. We found that MAIT cells were present in the lymph, despite being largely CCR7- in the blood, thus indicating that MAIT cells in the lymph migrated from tissues and were capable of exiting tissues to recirculate. Importantly, MAIT cells in the lymph and blood had highly overlapping clonotype usage but distinct transcriptome signatures, indicative of differential activation states. PMID- 29618663 TI - Advances, challenges, and opportunities in extracellular RNA biology: insights from the NIH exRNA Strategic Workshop. AB - Extracellular RNA (exRNA) has emerged as an important transducer of intercellular communication. Advancing exRNA research promises to revolutionize biology and transform clinical practice. Recent efforts have led to cutting-edge research and expanded knowledge of this new paradigm in cell-to-cell crosstalk; however, gaps in our understanding of EV heterogeneity and exRNA diversity pose significant challenges for continued development of exRNA diagnostics and therapeutics. To unravel this complexity, the NIH convened expert teams to discuss the current state of the science, define the significant bottlenecks, and brainstorm potential solutions across the entire exRNA research field. The NIH Strategic Workshop on Extracellular RNA Transport helped identify mechanistic and clinical research opportunities for exRNA biology and provided recommendations on high priority areas of research that will advance the exRNA field. PMID- 29618664 TI - Macrophage microRNA-150 promotes pathological angiogenesis as seen in age-related macular degeneration. AB - Macrophage aging is pathogenic in diseases of the elderly, including age-related macular degeneration (AMD), a leading cause of blindness in older adults. However, the role of microRNAs, which modulate immune processes, in regulating macrophage dysfunction and thereby promoting age-associated diseases is underexplored. Here, we report that microRNA-150 (miR-150) coordinates transcriptomic changes in aged murine macrophages, especially those associated with aberrant lipid trafficking and metabolism in AMD pathogenesis. Molecular profiling confirmed that aged murine macrophages exhibit dysregulated ceramide and phospholipid profiles compared with young macrophages. Of translational relevance, upregulation of miR-150 in human peripheral blood mononuclear cells was also significantly associated with increased odds of AMD, even after controlling for age. Mechanistically, miR-150 directly targets stearoyl-CoA desaturase-2, which coordinates macrophage-mediated inflammation and pathologic angiogenesis, as seen in AMD, in a VEGF-independent manner. Together, our results implicate miR-150 as pathogenic in AMD and provide potentially novel molecular insights into diseases of aging. PMID- 29618665 TI - B lymphocytes confer immune tolerance via cell surface GARP-TGF-beta complex. AB - GARP, a cell surface docking receptor for binding and activating latent TGF-beta, is highly expressed by platelets and activated Tregs. While GARP is implicated in immune invasion in cancer, the roles of the GARP-TGF-beta axis in systemic autoimmune diseases are unknown. Although B cells do not express GARP at baseline, we found that the GARP-TGF-beta complex is induced on activated human and mouse B cells by ligands for multiple TLRs, including TLR4, TLR7, and TLR9. GARP overexpression on B cells inhibited their proliferation, induced IgA class switching, and dampened T cell-independent antibody production. In contrast, B cell-specific deletion of GARP-encoding gene Lrrc32 in mice led to development of systemic autoimmune diseases spontaneously as well as worsening of pristane induced lupus-like disease. Canonical TGF-beta signaling more readily upregulates GARP in Peyer patch B cells than in splenic B cells. Furthermore, we demonstrated that B cells are required for the induction of oral tolerance of T cell-dependent antigens via GARP. Our studies reveal for the first time to our knowledge that cell surface GARP-TGF-beta is an important checkpoint for regulating B cell peripheral tolerance, highlighting a mechanism of autoimmune disease pathogenesis. PMID- 29618666 TI - Peptide vaccine immunotherapy biomarkers and response patterns in pediatric gliomas. AB - Low-grade gliomas (LGGs) are the most common brain tumor affecting children. We recently reported an early phase clinical trial of a peptide-based vaccine, which elicited consistent antigen-specific T cell responses in pediatric LGG patients. Additionally, we observed radiologic responses of stable disease (SD), partial response (PR), and near-complete/complete response (CR) following therapy. To identify biomarkers of clinical response in peripheral blood, we performed RNA sequencing on PBMC samples collected at multiple time points. Patients who showed CR demonstrated elevated levels of T cell activation markers, accompanied by a cytotoxic T cell response shortly after treatment initiation. At week 34, patients with CR demonstrated both IFN signaling and Poly-IC:LC adjuvant response patterns. Patients with PR demonstrated a unique, late monocyte response signature. Interestingly, HLA-V expression, before or during therapy, and an early monocytic hematopoietic response were strongly associated with SD. Finally, low IDO1 and PD-L1 expression before treatment and early elevated levels of T cell activation markers were associated with prolonged progression-free survival. Overall, our data support the presence of unique peripheral immune patterns in LGG patients associated with different radiographic responses to our peptide vaccine immunotherapy. Future clinical trials, including our ongoing phase II LGG vaccine immunotherapy, should monitor these response patterns. PMID- 29618667 TI - Evaluation of the broad-spectrum lytic capability of bacteriophage cocktails against various Salmonella serovars and their effects on weaned pigs infected with Salmonella Typhimurium. AB - The broad-spectrum lytic capability of Salmonella bacteriophages against various Salmonella species was evaluated to determine their potential as an alternative for antibiotics, and the safety and preventive effects of the bacteriophages were assessed on mice and pigs. Four bacteriophage cocktails were prepared using 13 bacteriophages, and the lytic capability of the four bacteriophage cocktails was tested using Salmonella reference strains and field isolates. Bacteriophage cocktail C (SEP-1, SGP-1, STP-1, SS3eP-1, STP-2, SChP-1, SAP-1, SAP-2; >=109 pfu/ml) showed the best lytic activity against the Salmonella reference strains (100% of 34) and field isolates (92.5% of 107). Fifty mice were then orally inoculated with bacteriophage cocktail C to determine the distribution of bacteriophages in various organs, blood and feces. The effects of bacteriophages on Salmonella infection in weaned pigs (n=15) were also evaluated through an experimental challenge with Salmonella Typhimurium after treatment with bacteriophage cocktail C. All mice exhibited distribution of the bacteriophages in all organs, blood and feces until 15 days post infection (dpi). After 35 dpi, bacteriophages were not detected in any of these specimens. As demonstrated in a pig challenge study, treatment with bacteriophage cocktail C reduced the level of Salmonella shedding in feces. The metagenomic analyses of these pig feces also revealed that bacteriophage treatment decreased the number of species of the Enterobacteriaceae family without significant disturbance to the normal fecal flora. This study showed that bacteriophages effectively controlled Salmonella in a pig challenge model and could be a good alternative for antibiotics to control Salmonella infection. PMID- 29618668 TI - Establishment of a Madin-Darby bovine kidney cell line expressing anchorless bovine prion protein. AB - Enzyme-linked immunosorbent assay (ELISA) performed using extensively purified bacterially expressed bovine prion protein (PrP) shows decreased cross reactivity. We generated a transduced Madin-Darby bovine kidney (MDBK) cell line continuously expressing glycosylphosphatidylinositol (GPI)-anchorless bovine PrP (designated as MDBK ?GPI protein) by using a lentiviral expression system. The present study also described the method for purifying bovine PrP through sequential culturing without the need for complex purification protocol. Our results showed that the purified bovine PrP could be used as an immunogen for developing anti-PrP monoclonal antibodies. Together, our results suggest that the new GPI-anchorless bovine PrP and its purification method can be used for performing basic studies for employing a cell-based approach. PMID- 29618669 TI - Identification of Two Phenanthrene Derivatives from Australasian Allied Species in Genus Dendrobium. AB - Genus Dendrobium (Orchidaceae) contains numerous species. Phylogenetic analyses based on morphological characteristics and DNA sequences indicated that this genus is divided into two major groups: Asian and Australasian clades. On the other hand, little is known about the phytochemical differences and similarities among the species in each clade. In this study, we selected 18 Dendrobium species (11 from the Asian clade and 7 from the Australasian clade) and constructed HPLC profiles, arrays composed of relative intensity of the chromatographic peaks. Next, orthogonal partial least square discriminant analysis (OPLS-DA) was applied to the profile matrix to classify Dendrobium species into the Asian and Australasian clades in order to identify the peaks that significantly contribute to the class separation. In the end, two phenanthrenes, 4,9-dimethoxyphenanthrene 2,5-diol 1 and 1,5-dimethoxyphenanthrene-2,7-diol 2, which contributed to the class separation, were isolated from the HPLC peaks. The existence of 2 was limited to the genetically related Australasian species. PMID- 29618670 TI - Usage of continuous glucose monitoring (CGM) for detecting an unrecognized hypoglycemia and management of glucocorticoid replacement therapy in adult patients with central hypoadrenalism. AB - Patients with adrenal insufficiency require appropriate glucocorticoid replacement therapy; however, reliable biological parameters for optimizing glucocorticoid supplementation are limited. The physician has to rely primarily on clinical judgment, carefully taking into account signs and symptoms potentially suggestive of over- or under-replacement. We have found that some patients who are viewed as receiving sufficient doses of glucocorticoids occasionally exhibit morning headache or morning discomfort, which may be caused by unrecognized nocturnal hypoglycemia. Our aim in this study was to evaluate the usefulness of continuous glucose monitoring (CGM) for detecting unrecognized hypoglycemia and optimizing glucocorticoid replacement therapy in adult patients with central hypoadrenalism. Six patients with central hypoadrenalism of various etiologies were included in this study. All patients exhibited occasional morning headache or discomfort. We performed CGM to measure plasma glucose levels in all patients, and CGM identified unrecognized hypoglycemia episodes at midnight and early in the morning in five patients (83%). The CGM findings were used to fine tune the dosing and regimens of glucocorticoid replacement and to re-evaluate glucose levels to avoid further unrecognized hypoglycemic events. This optimization of hydrocortisone supplementation prevented additional nocturnal hypoglycemia incidences in all cases. The addition of L-thyroxine with hydrocortisone continued to provide favorable glycemic control. Occasional symptoms also improved after maintenance in all patients. These findings demonstrated that CGM may represent a powerful tool for identifying unrecognized hypoglycemia and for optimizing supplementary hormones in patients with central hypoadrenalism, thereby improving their quality of life. PMID- 29618671 TI - Prognostic value of the 8th tumor-node-metastasis classification for follicular carcinoma and poorly differentiated carcinoma of the thyroid in Japan. AB - Follicular thyroid carcinoma (FTC), a form of differentiated thyroid carcinoma, is the second most common malignancy arising from thyroid follicular cells. Recently, the tumor-node-metastasis (TNM) classification for differentiated thyroid carcinoma was revised from the 7th to the 8th edition. The diagnostic criteria for poorly differentiated carcinoma (PDC) were also updated in the latest World Health Organization (WHO) classification. In this study, we investigated whether these changes are appropriate for accurately predicting prognosis. Three hundred and twenty-nine patients diagnosed with postoperative pathologically confirmed FTC, who underwent initial surgery at our hospital between 1984 and 2004, were enrolled. For this study, patients were re-evaluated and diagnosed with FTC (N = 285) or PDC (N = 44) without typical nuclear findings of papillary thyroid carcinoma. For FTC, the 8th TNM classification was a more accurate predictor of prognosis than the 7th TNM classification. In the 8th TNM classification, cause-specific survival became significantly poorer from Stage I to IVB. The cause-specific survival of PDC based on the latest WHO classification was worse than, but did not significantly differ from, that of PDC based only on the former WHO classification. For PDC, neither of the TNM classifications could accurately predict prognosis. Taken together, we conclude that (1) the 8th TNM classification more accurately reflects the prognosis of FTC than the 7th TNM classification; (2) PDC based on the former WHO classification should be retained, at least in Japan; and (3) the TNM classification may not be suitable for predicting the prognosis of PDC. PMID- 29618672 TI - Sweet Preference Associated with the Risk of Hypercholesterolemia Among Middle Aged Women in Korea. AB - AIMS: Sweet preference has been reported to be associated with various health problems. This study examined the influence of sweet taste preference on the risk of dyslipidemia in Korean middle-aged women. METHODS: The study selected 3,609 middle-aged women from the Korean Genome and Epidemiology Study (KoGES) and classified them into two groups on the basis of whether or not they preferred sweet taste. Dietary intake was analyzed using a semiquantitative food frequency questionnaire. Serum lipid profiles and anthropometric variables were measured. RESULTS: Subjects who preferred the sweet taste had significantly higher intakes of sugar products and sweet drink than those who did not prefer the sweet taste. Subjects who preferred the sweet taste showed higher carbohydrate and fat intake and less fiber intake than those who did not prefer the sweet taste. The serum concentrations of total cholesterol and low-density lipoprotein (LDL) cholesterol were significantly higher in subjects who preferred the sweet taste than those who did not prefer. Furthermore, subjects who preferred the sweet taste showed a significantly higher odds ratio (OR) for hypercholesterolemia (OR 1.22; 95% CI (1.01-1.45)) and hyper-LDL cholesterolemia (OR 1.33; 95% CI (1.11-1.60)) than those who did not prefer the sweet taste. CONCLUSION: Our results suggested that preference for sweet taste may increase the consumption of sugar products and sweet drinks, which is partially linked to the risk of hypercholesterolemia and hyper-LDL cholesterolemia in Korean middle-aged women. PMID- 29618674 TI - Detection of novel adenovirus in sick pigeons. AB - This study reports a novel adenovirus that was found circulating in pigeons in China. Nucleotide homology analysis of the hexon gene showed a nucleotide similarity of 79.0 and 70.9% with PiAd-2 variant A and PiAd-1, respectively. Phylogenetic analysis suggested that the identified virus, together with PiAd-2 variant, constitutes a monophyletic group (proposed as Pigeon Aviadenovirus B) in the genus Aviadenovirus. The present study contributes to the understanding of the epidemiology, ecology, and taxonomy of adenoviruses in pigeons. PMID- 29618675 TI - Prevalence of Escherichia coli Resistant to Beta-Lactam Antibiotics among Patients with Chronic Obstructive Pulmonary Disease and Urinary Tract Infection. AB - Urinary tract infection (UTI), which is typically caused by Escherichia coli (E. coli), is an insufficiently recognized co-morbidity among patients with chronic obstructive pulmonary disease (COPD). Adequate treatment can be complicated by resistance of the causative pathogen to beta-lactam antibiotics, which often produce beta-lactamase enzymes that destroy the antibiotic. The beta-lactamase family of enzymes is extremely diverse, including different types of enzyme and mutant forms. In this study, we analyzed 580 patients with COPD (236 females and 344 males) and thus found 218 patients with co-morbid UTIs, including 58 patients with UTI caused by E. coli (38 females and 20 males). We also investigated cases of uncomplicated symptomatic and asymptomatic UTI caused by E. coli and the presence of resistance to beta-lactam antibiotics among those patients. The E. coli strains resistant to beta-lactam antibiotics were selected for their ability to grow on selective media, before DNA microarrays were applied for specific identification of three beta-lactamase gene types (i.e., TEM, SHV and CTX-M). Overall, 83% of E. coli strains responsible for UTIs in COPD patients carried extended-spectrum beta-lactamase genes. The most prevalent were those producing CTX-M, with CTX-M-15 being predominant. The rare CTX-M-27 and TEM-15 genes were also detected in two samples. Three samples contained several extended-spectrum beta-lactamase genes simultaneously (CTX-M-15 or CTX-M-14 plus SHV-5 or TEM-15). This high prevalence of resistant E. coli strains necessitates rational antibiotic selection when treating UTI to prevent COPD exacerbations. Additionally, antibiotic therapy should be aligned with and adapted to existing and potential COPD co-morbidities. PMID- 29618676 TI - Mitochondrial dysfunction in cumulus-oocyte complexes increases cell-free mitochondrial DNA. AB - This study examined the concentration of cell-free mitochondrial DNA (cf-mtDNA) in porcine follicular fluid (FF) and explored whether the cfDNA level in the culture medium could reflect mitochondrial dysfunction in cumulus cell-oocyte complexes (COCs). cfDNA concentration was higher in the fluid of small-sized follicles, compared to that in larger follicles. The length of cfDNA ranged from short (152 bp) to long (1,914 bp) mtDNA in FF, detected by polymerase chain reaction (PCR). cfDNA concentration in FF significantly correlated with the mtDNA copy number in FF but not with the number of one-copy gene (nuclear DNA) in FF. When the COCs were treated with the mitochondrial uncoupler, namely carbonyl cyanide m-chlorophenyl hydrazone (CCCP), for 2 h and incubated for 42 h, subsequent real-time PCR detected significantly higher amount of cf-mtDNA, compared to nuclear cfDNA, in the spent culture medium. The mtDNA number and viability of cumulus cells and oocytes remained unchanged. When the oocytes were denuded from the cumulus cells following CCCP treatment, PCR detected very low levels of cfDNA in the spent culture medium of the denuded oocytes. In contrast, CCCP treatment of granulosa cells significantly increased the amount of cf-mtDNA in the spent culture medium, without any effect on other markers, including survival rate, apoptosis of cumulus cells, and lactate dehydrogenase levels. Thus, cf-mtDNA was present in FF in a wide range of length, and mitochondrial dysfunction in COCs increased the active secretion of cf-mtDNA in the cultural milieu. PMID- 29618677 TI - Impact of lifestyle intervention on dry eye disease in office workers: a randomized controlled trial. AB - OBJECTIVES: To evaluate the effects of a 2-month lifestyle intervention for dry eye disease in office workers. METHODS: Prospective interventional study (randomized controlled study). Forty-one middle-aged Japanese office workers (men, 22; women, 19; 39.2+/-8.0 years) with definite and probable dry eye disease were enrolled and randomized to an intervention group (n = 22) and a control group (n = 19). The intervention aimed at modifying diet, increasing physical activity, and encouraging positive thinking. The primary outcome was change in dry eye disease diagnoses. Secondary outcome was change in disease parameters, including dry eye symptoms, as assessed using the Dry Eye-Related Quality of Life Score, corneal and conjunctival staining scores, tear break-up time, and Schirmer test results. RESULTS: A total of 36 participants (intervention group, 17; control group, 19) completed the study. The number of definite dry eye disease diagnoses decreased from four to none (p =.05), and the dry eye symptom score showed a significant decrease in the intervention group (p =.03). In contrast, the corneal and conjunctival staining scores, tear break-up time, and Schirmer test results did not differ significantly between groups. CONCLUSIONS: The 2 month lifestyle intervention employed in this study improved dry eye disease status among office workers, with a considerable decrease in subjective symptoms. Lifestyle intervention may be a promising management option for dry eye disease, although further investigation of long-term effects are required. PMID- 29618678 TI - The acute effect of exposure to noise on cardiovascular parameters in young adults. AB - OBJECTIVE: In this study, an experiment was conducted to examine whether noise exposure produced acute changes in cardiovascular responses, and whether these responses differed based on psycho-acoustic parameters to noises of low to high intensity. METHODS: Thirty healthy subjects were enrolled. Three industrial noises were binaurally presented with a supra-aural earphone. The sound levels of noise were <55, 75, and 90 dB. Each noise was continued for 20 min and the electrocardiogram was simultaneously recorded. RESULTS: The results showed a statistically significant increase in systolic blood pressure (SBP) at the 90 dB sound level. The study estimated a blood pressure increase of 0.85 mmHg/10 dB and 0.71 mmHg/10 dB in SBP and diastolic blood pressure (DBP), respectively. These results suggest that exposure to noise, particularly high-frequency noise, negatively impacts blood pressure. The tonality and fluctuation strength of noise especially impacts systolic blood pressure. CONCLUSIONS: The psycho-acoustic parameters of noise should be considered when evaluating the impact of noise exposure. PMID- 29618679 TI - Low Risk of Pulmonary Vein Stenosis After Contemporary Atrial Fibrillation Ablation - Lessons From Repeat Procedures After Radiofrequency Current, Cryoballoon, and Laser Balloon. AB - BACKGROUND: The incidence of pulmonary vein stenosis (PVS) after AF ablation following contemporary procedures remains unclear. We compared the incidence of PVS/narrowing (PVS/N) after PV isolation (PVI) for (1) 3-D mapping-guided wide area encircling irrigated radiofrequency current (RFC) ablation; (2) first-third generation big cryoballoon (CB1-3) ablation; and (3) laser balloon (LB) ablation.Methods and Results:All patients undergoing a second procedure between January 2012 and November 2016 were subgrouped according to index ablation (PVI): RFC; CB; or LB. PVS/N was classified using PV diameter ratio (second/index procedure) on selective PV angiogram performed before ablation: mild, 25-49%; moderate, 50-74%; or severe, >=75%. A total of 344 patients (1,362 PV) were analyzed (RFC, n=211; 840 PV; CB1, n=21; 82 PV; CB2,3, n=64; 250 PV; LB, n=48; 190 PV). In the LB group, 45 patients (94%) were treated with dose >=8.5 W. Second procedures were performed on average 14.9+/-14.1 months after the index procedure. Mild PVS/N was observed in 18.4%, 9.5% and 3.6% of PV in the LB, RFC and CB groups, respectively (P<0.01). Moderate PVS was recognized in 2 PV (0.1%; RFC, LB). Severe PVS was never observed, and no PV intervention/surgery was required. CONCLUSIONS: The risk for significant PVS is low after RFC/CB. The incidence of mild PVS/N was highest after standard-dose LB ablation and lowest after high-dose CB ablation. PMID- 29618680 TI - Is There Any Impact of ST Re-elevation on Patients With Acute Myocardial Infarction Following Reperfusion Therapy? PMID- 29618682 TI - ? PMID- 29618681 TI - Role of Tissue Factor in Vascular Failure. PMID- 29618683 TI - [MALT lymphoma with t (X;14) (p11.2;q32) developing during the course of cutaneous leukocytoclastic angitis]. AB - A 73-year-old man with left parotid gland swelling over 2 months was referred to our hospital in March 201X. Purpura on the lower legs had been recurrent for >20 years. Biopsy of the parotid gland demonstrated diffuse infiltration of abnormal lymphocytes that were negative for CD10 and positive for CD19, CD20, and kappa chain. The Ki-67 positivity was <10%; lymphoepithelial lesions were observed. The patient was diagnosed with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). Chromosome analysis revealed t (X;14) (p11.2;q32), and fluorescence in situ hybridization (FISH) of metaphase spreads showed three signals of the immunoglobulin heavy chain (IGH) gene on the derivative chromosomes X and 14, besides the normal chromosome 14. CT findings of parotid glands were suggestive of Sjogren syndrome, and biopsy of the purpura on the leg demonstrated leukocytoclastic vasculitis. In the literature, only seven patients with lymphoma and t (X;14) translocation have been reported. Of these, five patients had MALT lymphoma, one had nodal marginal zone lymphoma, and one had diffuse large B-cell lymphoma. In all patients, lymphoma evolved from previous autoimmune diseases. It is suggested that MALT lymphoma with the t (X;14) translocation forms a new entity of lymphoma. PMID- 29618684 TI - [Successful treatment with thalidomide-combined therapy in an amyloidosis complicated multiple myeloma patient refractory to bortezomib, lenalidomide, and pomalidomide]. AB - A 77-year-old man suffering from back and arm pain was referred for anemia to the hospital by an orthopedic clinic. Serum examination of the patient revealed monoclonal IgA, and he consulted the Sapporo Medical University Hospital, where he was diagnosed with multiple myeloma complicated with AL amyloidosis. He was then enrolled for a randomized double-blind study aimed to compare between melphalan-prednisone (MP) and thalidomide-melphalan-prednisone (MPT) treatments, which revealed the patient to be in the MP arm. This treatment induced a temporary partial response. After progression, he was treated with three variable combinations: 1) bortezomib and MP, 2) lenalidomide and dexamethasone, and 3) pomalidomide and dexamethasone. However, none of these treatments provided a stable response. Further, thalidomide in combination with bortezomib and dexamethasone was provided as the fifth-line treatment. After four cycles of this treatment, he achieved VGPR that lasted for 11 months. Our case report suggests that because there is a lack of a standard strategy for MM that is refractory to several agents, treatment should be selected on the basis of previous treatments and general condition of patients. PMID- 29618685 TI - [Splenic diffuse red pulp small B-cell lymphoma diagnosed by splenectomy initially mimicking hairy cell leukemia-Japanese variant]. AB - A 62-year-old man presented to the hospital with thrombocytopenia, and splenomegaly was detected. His blood films prepared by natural air drying revealed medium-sized lymphocytes with unevenly distributed large and small villous projections. The cytoplasm was basophilic, nuclei were oval with clumped chromatin, and nucleoli were absent in most cells. Immune phenotypes CD19+, CD20+, CD11c+, FMC7+, IgM+, and Igkappa+ were detected. TRAP stain appeared negative, IgH JH chain genes were monoclonally rearranged, and BRAF V600E mutation was not detected. On the basis of these findings, hairy cell leukemia Japanese variant (HCL-JV) was strongly suspected. The patient was followed up for >4 years without treatment. However, because thrombocytopenia and splenomegaly gradually progressed, splenectomy was performed. Microscopic examination confirmed that the splenic white pulp was atrophic. Moreover, infiltrates comprising small-to-medium-sized atypical lymphocytes with inconspicuous nucleoli were predominantly detected in the congested red pulp. On the basis of these results and immune histochemical findings, the patient was diagnosed with splenic diffuse red pulp small B-cell lymphoma (SDRPL). Here we discussed whether the aforementioned diseases (HCL-JV and SDRPL) are the same; however, further accumulation of cases is essential to draw a definite conclusion. PMID- 29618686 TI - [Giant hemophilic pseudotumors in brothers with non-severe hemophilia B]. AB - Hemophilic pseudotumors can occur in patients with hemophilia because of recurrent bleeding and poor hemostasis. A man in his 30s with hemophilia B and human immunodeficiency virus/hepatitis C virus co-infection complicated by liver cirrhosis presented with a large pseudotumor in the left iliopsoas muscle. However, resting to stop bleeding was difficult with his daily work. Osteolytic changes in the left ilium progressed over 8 years. A large osteolytic pseudotumor in the pelvis was also incidentally identified in his younger brother during his 30s. The same mutations in F9 (p. Arg294Gln, hemizygous mutation) associated with a non-severe phenotype were detected in both brothers. The clinical courses of the brothers suggested that large pseudotumors can occur in patients with non severe hemophilia and underline the importance of patient education. PMID- 29618687 TI - [Successful cord blood transplantation in a patient with adult-onset common variable immunodeficiency]. AB - Common variable immunodeficiency (CVID) is the most frequently diagnosed congenital immunodeficiency and is characterized by dysfunctional antibody production. It often occurs at the age of >=10 years. Here we reported a case of a 46-year-old man confirmed with adult-onset CVID. He was effectively treated with cord blood transplant (CBT). The patient was observed with repeated upper respiratory infection a few years back and was referred to our department owing to a marked decrease in neutrophil counts and progression of anemia. Laboratory tests confirmed hypogammaglobulinemia, but no autoantibodies were detected. Bone marrow aspiration showed a hypocellular marrow with predominantly mature lymphocytes. T-cell receptor excision circle assay revealed a reduction in T-cell neogenesis. Further, multicolor flow cytometry analysis revealed a low differentiation of B cells; subsequently, CVID was confirmed in the patient. The patient had a severe clinical course and therefore, received CBT for the treatment. After the transplantation, the hematopoiesis was restored and the serum immunoglobulin levels returned to normal. The patient exhibited a favorable clinical course. Nevertheless, there is no precise definition to establish the disease concept of CVID. Also, most of the potential cases are predominantly reported in adults. Therefore, further data on cases with CVID should be accumulated to establish the diagnostic criteria as well as treatment modalities. PMID- 29618688 TI - [Human herpesvirus-6 pneumonitis following autologous peripheral blood stem cell transplantation]. AB - A-46-year-old man was diagnosed with peripheral T cell lymphoma, not otherwise specified. He achieved a complete remission after pirarubicin, cyclophosphamide, vincristine, and prednisolone (THP-COP) therapy and successful autologous peripheral blood stem-cell transplantation (AutoSCT). However, 6 months post AutoSCT, he complained of fever. Chest computed tomography of the patient displayed bilateral interstitial pneumonitis. Human herpesvirus-6 (HHV-6) DNA was detected in his bronchoalveolar lavage fluid. Therefore, the patient was confirmed for HHV-6 pneumonitis. The treatment with foscarnet was effective, and no relapse was noticed in the patient. Besides, we have experienced pneumonitis of unknown origin in some patients after autologous or allogeneic stem-cell transplantations. Moreover, most of the above patients were clinically diagnosed using serum or plasma markers. Therefore, examining respiratory symptoms after AutoSCT would enable a more accurate diagnosis as well as treatment of patients with HHV-6 pneumonitis. PMID- 29618689 TI - [Osteonecrosis developing after rituximab-containing chemotherapy for Waldenstrom macroglobulinemia]. AB - A 71-year-old woman presented with fever, weight loss, and anemia because of recurrent Waldenstrom macroglobulinemia (WM) with cryoglobulinemia. Treatment with five cycles of doxorubicin, vincristine, cyclophosphamide, and prednisolone (CHOP) therapy was initiated, which resulted in insufficient improvement in anemia. Hence, a combination of rituximab and CHOP therapy was subsequently initiated. The patient complained of lumbago and lower leg pain on day 4 of the chemoimmunotherapy. X-ray findings for the affected sites were unremarkable, and the patient's symptoms gradually and spontaneously subsided. Rituximab monotherapy was then administered, which resulted in the deterioration of her symptoms. Magnetic resonance imaging revealed osteonecrosis of the bilateral distal ends of the femur, and proximal and distal ends of the tibia. This is the first case of lower leg osteonecrosis complicating chemoimmunotherapy for WM. Osteonecrosis may be an unusual adverse effect of rituximab therapy for WM. Tumor lysis by rituximab may have contributed to the pathogenesis of this complication. MRI assessment should be considered when WM patients complain of bone pain following rituximab-containing chemotherapy. PMID- 29618690 TI - [Neutrophil recovery by eltrombopag treatment in a patient with adult-onset autoimmune neutropenia and immune thrombocytopenia]. AB - Adult-onset autoimmune neutropenia (AIN) is rarely self-limiting, unlike infant onset AIN. Although several therapeutic agents have been reported, including corticosteroids, more effective treatment options may exist. Here, we describe neutrophil recovery by eltrombopag in a 52-year-old male AIN patient with immune thrombocytopenia (ITP) who was referred to our hospital with severe neutropenia. Within a year of referral, he developed moderate thrombocytopenia. He was diagnosed with AIN and concurrent ITP, based on the detection of antineutrophil antibodies and bone marrow aspiration, respectively. Further platelet count reduction and the appearance of purpura prompted an initial treatment of 0.5 mg/kg prednisolone. Thrombocytopenia remission was prompt but transient, with platelet counts rapidly declining before initiating prednisolone tapering. Similarly, absolute neutrophil counts (ANCs), after a shorter recovery period, returned to the baseline level below 2*108/l. Further platelet reduction was prevented by eltrombopag administration. Intriguingly, the ANCs recovered following platelet recovery and remained above 5*108/l for > three months despite prednisolone dosage tapering. To our knowledge, this is the first report describing the effectiveness of eltrombopag in AIN. PMID- 29618691 TI - [MonoMAC syndrome patient developing myelodysplastic syndrome following persistent EBV infection]. AB - An 18-year-old man was diagnosed with Epstein-Barr virus (EBV) -associated hemophagocytic syndrome (HPS) and treated with prednisolone (PSL) at a previous hospital. During PSL tapering, the HPS symptoms reappeared, and the patient was referred to our hospital. Increased PSL improved the symptoms, but the EBV infection remained unresolved. At age 20, he was admitted to our hospital for newly developed pneumonia and diagnosed with myelodysplastic syndrome (refractory cytopenia with multilineage dysplasia) (MDS-RCMD; normal karyotype, IPSS: Int-1) by bone marrow examination. MDS remission was achieved following bone marrow transplantation from an unrelated donor, and he is currently alive without relapse. The patient's father had also been diagnosed with MDS when he was young and died from leukoencephalopathy at approximately 50 years old. These observations support a diagnosis of familial MDS. GATA2 mutation p.R230Hfs*44 was identified in both bone marrow and control cells (buccal swab) at MDS diagnosis, and he was diagnosed with monocytopenia and mycobacterial infection (MonoMAC) syndrome. Furthermore, an acquired STAG2 mutation (splicing site change, c.820 2A>G) in the bone marrow cells was also identified, which might contribute to MDS progression. PMID- 29618692 TI - [Transfusion independence achieved with pomalidomide therapy in a patient with primary myelofibrosis]. AB - Primary myelofibrosis (PMF) is commonly associated with anemia. IMiD(r) immunomodulatory drugs including thalidomide and lenalidomide have been shown to be effective in improving anemia associated with PMF. However, because of adverse events, their use has been restricted. Herein we report the case of a 67-year-old male patient with transfusion-dependent PMF treated with the immunomodulatory drug pomalidomide in a clinical trial. Significant improvements in anemia and thrombocytopenia were observed with pomalidomide, and the patient recovered from transfusion dependence for 8 months. Although phase 3 trial failed to show the superiority of pomalidomide over placebo, pomalidomide may have some benefit in selected patients with transfusion-dependent PMF. PMID- 29618694 TI - ? PMID- 29618693 TI - [Long-term remission with mogamulizumab monotherapy in a patient with refractory adult T-cell leukemia-lymphoma]. AB - A 73-year-old female with malaise, anorexia, and hydrodipsia was referred to our department. Peripheral blood tests revealed leukocytosis with 51% blast cells exhibiting flower-shaped nuclei. Flow-cytometry to detect tumor cells in peripheral blood indicated CD3+, CD4+, CD8-, and CD25- expression, but those in the lymph nodes expressed CD25+. Southern blots revealed clonal HTLV-1 provirus in the tumor cells, consistent with adult T-cell leukemia-lymphoma. Cytotoxic chemotherapy was ineffective, but eight cycles of mogamulizumab induced complete remission (CR). A relapse lesion appeared on the right breast but disappeared spontaneously. The patient has currently maintained CR for over five years. PMID- 29618695 TI - Clinical Impact of the Ankle-Brachial Index in Patients Undergoing Successful Percutaneous Coronary Intervention. AB - BACKGROUND: Several studies have reported a relationship between clinical outcomes and the ankle-brachial index (ABI) in different populations. However, the relationship in Japanese patients or in patients undergoing percutaneous coronary intervention (PCI) has not been examined well.Methods and Results:The subjects were 1,857 patients who underwent PCI from July 2007 to May 2010 and in whom the carotid and renal arteries and abdominal aorta were examined simultaneously by ultrasonography and ABI. We investigated the relationship between ABI and major adverse cardiovascular events (MACE: all-cause death, myocardial infarction, and stroke). The median follow-up was 1,322 days (interquartile range: 1,092-1,566 days). Patients with low (<0.9), borderline (0.9-1.0) and high ABI (>1.4) had significantly higher incidence of MACE at 4 years (31%, 15%, 10%, and 29% for the low, borderline, normal, and high groups, respectively; log-rank P<0.0001) and all-cause mortality at 4 years (22%, 12%, 6.9%, and 29%, respectively; P<0.0001) compared with the normal ABI group (1.0<=ABI<=1.4). The adjusted hazard ratios for MACE were 2.35 (1.72-3.20), 1.27 (0.89-1.80) and 1.87 (0.81-3.79) for low, borderline and high ABI, respectively. CONCLUSIONS: This study suggested that ABI provides additional information for cardiovascular disease risk stratification in Japanese patients undergoing PCI, even it is borderline ABI. PMID- 29618696 TI - Subclinical Leaflet Thrombosis in Transcatheter Aortic Valve Replacement Detected by Multidetector Computed Tomography - A Review of Current Evidence. AB - Subclinical leaflet thrombosis (SLT) following transcatheter aortic valve replacement (TAVR) has been increasingly recognized. SLT has the hallmark features of hypo-attenuated leaflet thickening (HALT) on multidetector computed tomography (MDCT), which may result in hypoattenuation affecting motion (HAM). The actual prevalence of this condition is uncertain, with limited observational registries. SLT has caught the attention of the cardiovascular community because of concerns regarding its clinical sequelae, specifically the potential increased incidence of cerebrovascular events. There are available, albeit sparse, data to suggest that when left untreated, SLT may lead to valve deterioration with potential hemodynamic compromise and potentially clinically overt prostheses thrombosis. Some clinicians have opted to treat patients with SLT with anticoagulation. Although anticoagulation may be a rational treatment option, little data exist on the safety and efficacy of this treatment. This is particularly important considering TAVR patients also have higher bleeding risk than the standard population. In this review, we aim to summarize the current evidence on SLT, explore its pathophysiological mechanism, discuss the current treatment options and future trials that may clarify the optimal antithrombotic strategies of SLT. PMID- 29618697 TI - Cutting Edge Science and Medicine of Adenosine in Patients With Heart Failure. PMID- 29618698 TI - Anticoagulation Therapy After Left Ventricular Assist Device Implantation. PMID- 29618700 TI - [Methods of coping with musculoskeletal pain among community-dwelling elderly individuals]. AB - Objectives Musculoskeletal pain impairs vital function and results in a requirement for long-term care. According to studies in other countries, a program that aims at reducing pain through instructions for pain-coping should be implemented. In Japan, a study on pain-coping has recently been initiated; however, the methods of coping with pain that are implemented by community dwelling elderly individuals have not been evaluated. This study aimed to clarify the methods currently used for coping with musculoskeletal pain and to examine their association with the state of pain among community-dwelling elderly individuals.Methods A survey was performed by sending questionnaires by mail to 2,281 community-dwelling elderly individuals. Responses were obtained from 1,835 people. The survey items consisted of questions about basic attributes and pain. A total of 16 questionnaire items regarding the methods of coping with pain were used for measuring pain-coping that community-dwelling elderly individuals use. The methods of coping with pain were classified into various types by factor analysis. The scores were calculated by type and their association with the state of pain was analyzed using one-way analysis of variance.Results As a result of the factor analysis, methods of coping with pain were classified into five categories: "treatment in hospitals," "daily active coping," "restriction of daily behavior," "self-therapy," and "rest." From one-way analysis of variance for the site of pain, there was a significant difference between the "treatment in hospitals" and "restriction of daily behavior" categories. Among both scores, a higher score was observed in subjects with pain in both the lower back and the knee, compared to those with only pain in the lower back or the knee. Among the number of the sites, there was a significant difference between the "treatment in hospitals," "restriction of daily behavior," and "self-therapy" categories; subjects exhibiting two or more sites of pain showed a higher score than those exhibiting one site of pain. For pain duration, there was a significant difference between the "treatment in hospitals," "restriction of daily behavior," and "self-therapy" categories; subjects who had experienced pain for 5 years or longer had a higher score than those who had experienced pain for less than 6 months.Conclusion We found that five types of methods of coping with pain ("treatment in hospitals," "daily active coping," "restriction of daily behavior," "self-therapy," and "rest") were used by community-dwelling elderly individuals and that "treatment in hospitals" and "restriction of daily behavior" were the most common strategies among elderly individuals with pain. PMID- 29618699 TI - Triterpenic Acids from Potentilla parvifolia and Their Protective Effects against Okadaic Acid Induced Neurotoxicity in Differentiated SH-SY5Y Cells. AB - Six triterpenic acids were separated and purified from the ethyl acetate extractive fraction of ethanol extracts of Potentilla parvifolia FISCH. using a variety of chromatographic methods. The neuroprotective effects of these triterpenoids were investigated in the present study, in which the okadaic acid induced neurotoxicity in human neuroblastoma SH-SY5Y cells were used as an Alzheimer's disease cell model in vitro. The cell model was established with all trans-retinoic acid (5 umol/L, 4 d) and okadaic acid (40 nmol/L, 6 h) treatments to induce tau phosphorylation and synaptic atrophy. Subsequently, the neuroprotective effects of these triterpenic acids were evaluated in vitro by this cell model. Results from the Western blot and morphology analysis suggested that compounds 3-6 had the better neuroprotective effects. Furthermore, we tested the level of mitochondrial reactive oxygen species and mitochondrial membrane potential of these compounds in SH-SY5Y cells by flow cytometry technology to investigate the potential neuroprotective mechanism of these compounds. All of the results indicated that maybe the mechanism of compounds 5 and 6 is to protect the cell from mitochondrial oxidative stress injuries. PMID- 29618701 TI - [Self-reported obituary columns in a local daily newspaper]. AB - Objectives To reveal the features of death and subsequent funeral services, we analyzed self-reported obituaries in The Shimotsuke, a local daily newspaper in Tochigi, Japan. In addition, the usefulness and disadvantages of such a database of deaths based on the obituaries were discussed.Method For a 5-year period, from January 2011 through December 2015, all the obituary columns in The Shimotsuke were computerized as a database and analyzed. Some results were compared with the vital statistics data in the corresponding period of time. Data analyzed were: dead persons' address (municipalities), name, sex, cause of death, age at death, date of death and funeral services, the chief mourner (Moshu), and so on.Results During the observed 5-year period, 69,793 deaths appeared in the columns, which were 67.6% of the all deaths in the vital statistics. No difference was observed in the proportions between the sexes in the published deaths in comparison with the vital statistics. In both sexes, the proportion was low in 0-9 years old, then high among 10-19 years, decreasing in 20s, and after then the proportion increased according to the age. The proportion was low in city areas, such as Utsunomiya and Oyama, and high in some cities and towns in the northern or eastern parts of Tochigi prefecture. The highest was in Motegi Town (88.0%), and the lowest was Nogi Town (38.0%), which is located in the southern-most part of the prefecture and is closest to the Tokyo metropolitan area. Almost all the funeral services were conducted within a week of the death, and no delays were observed to have been caused by the short supply of cremation services, which exists in large cities in Japan. In case where the chief mourner was a child, a parent, or a spouse of a child, the male sex was dominant. Analyses of death from senile decay, suicide, and homicide indicated that the accuracy of the published cause of death was low. The date of the funeral services was strongly influenced by superstitions in this country.Conclusions Observations of the self-reported obituaries in a local daily newspaper over five years revealed the situations of the deaths in the area that could not be observed using vital statistics. Despite limitations, the information was partially useful as a database. PMID- 29618702 TI - [Countermeasures for rubella outbreak among adults in Sumida city from April 2013 to March 2016]. PMID- 29618703 TI - [Subjective symptoms of outpatients with hypertension in Japan: Analysis of the Comprehensive Survey of Living Conditions (2010)]. PMID- 29618705 TI - Apolipoprotein A-1 Binding Protein Inhibits Inflammatory Signaling Pathways by Binding to Apolipoprotein A-1 in THP-1 Macrophages. AB - BACKGROUND: It has previously been demonstrated that apolipoprotein A-1 (apoA-1) binding protein (AIBP) promotes apoA-1 binding to ATP-binding cassette transporter A1 (ABCA1) and prevents ABCA1 protein degradation so as to inhibit foam cell formation. Because apoA-1 inhibits inflammatory signaling pathways, whether AIBP has an inhibitory effect on inflammatory signaling pathways in THP-1 derived macrophages is investigated.Methods and Results:Analysis of inflammation related gene expression indicated that AIBP decreased lipopolysaccharide (LPS) mediated macrophage inflammation. AIBP significantly prevented NF-kappaB nuclear translocation. Further, AIBP prevented the activation of mitogen-activated protein kinases (MAPKs), including p38 MAPK, extracellular-signal regulated kinase and c-Jun N-terminal kinase. AIBP decreased MyD88 expression at both mRNA and protein levels, but did not have any effect on TLR4 expression. Moreover, treatment with both AIBP and apoA-1 decreased the abundance of TLR4 in the lipid raft fraction. AIBP lacking 115-123 amino acids (?115-123), however, did not have such effects as described for intact AIBP. In addition, knockdown of ABCA1 inhibited the effects of AIBP on inflammatory factor secretion. CONCLUSIONS: These results suggest that AIBP inhibits inflammatory signaling pathways through binding to apoA-1 and stabilizing ABCA1, and subsequent alteration of lipid rafts and TLR4 in the cell membrane. PMID- 29618704 TI - Pinelliae Rhizoma Praeparatum Involved in the Regulation of Bile Acids Metabolism in Hepatic Injury. AB - Pinelliae Rhizoma Praeparatum (PRP) as traditional Chinese medicine had been used for hepatic diseases in combinative forms. However, the effect of PRP was not clear when used alone. So to explore the hepatoprotective/hepatotoxin of PRP is necessary. The activities of PRP were investigated in acetaminophen-induced hepatic injury mice. Liver function markers, hepatic oxidative stress markers were evaluated. Bile acids metabolic transports and nuclear factor erythroid 2 related factor 2 (Nrf2) were detected. As a drug for the treatment of liver diseases, PRP slightly restored the parameters towards normal in model mice only in low dosage, and also had no antioxidant activity and regulate Nrf2. Cholestasis was significantly elevated in model mice when pretreatment with routine or high dosage of PRP, but had no effect on normal mice. Bile salt export pump (Bsep) and multidrug resistance-associated protein 2 (Mrp2) in model mice were markedly increased when pretreatment with low dose PRP, but significantly decreased when pretreatment in routine or high dosage. Mrp3 was significantly induced in model mice after pretreatment of PRP. But the adjustment effect to bile acids transporters by PRP was not significant in normal mice. These results reveal that PRP has the different effects on bile acids transporter in hepatic injury mice, and therefore, the dosage of PRP need to be paid attention to when it is used in clinical hepatic injury. PMID- 29618706 TI - "Ikigai", Subjective Wellbeing, as a Modifier of the Parity-Cardiovascular Mortality Association - The Japan Collaborative Cohort Study. AB - BACKGROUND: Nulliparity is associated with an excess risk of cardiovascular disease (CVD). "Ikigai", subjective wellbeing in Japan, is associated with reduced risk of CVD. The impact of ikigai on the association between parity and the risk of CVD, however, has not been reported.Methods and Results:A total of 39,870 Japanese women aged 40-79 years without a history of CVD, cancer or insufficient information at baseline in 1988-1990, were enrolled and followed until the end of 2009. They were categorized into 7 groups according to parity number 0->=6. Using Cox regression hazard modeling, the associations between parity and mortality from stroke, coronary artery disease, and total CVD were investigated. During the follow-up period, 2,121 total CVD deaths were documented. No association was observed between parity and stroke and CVD mortality in women with ikigai, but there was an association in those without ikigai. The multivariable hazard ratios of stroke and total CVD mortality for nulliparous women without ikigai vs. those with 1 child were 1.87 (95% CI: 1.15 3.05) and 1.46 (95% CI: 1.07-2.01), respectively, and that for stroke mortality in high parity women without ikigai was 1.56 (95% CI: 1.00-2.45). CONCLUSIONS: Nulliparous or high parity women without ikigai had higher mortality from stroke and/or total CVD, suggesting that ikigai attenuated the association between parity and CVD mortality in Japanese women. PMID- 29618707 TI - Donor Polymorphisms in Genes Related to B-Cell Biology Associated With Antibody Mediated Rejection After Heart Transplantation. AB - BACKGROUND: Heart transplantation (HT) is a well-established lifesaving treatment for endstage cardiac failure. Antibody-mediated rejection (AMR) represents one of the main problems after HT because of its diagnostic complexity and the poor evidence for supporting treatments. Complement cascade and B-cells play a key role in AMR and contribute to graft damage. This study explored the importance of variants in genes related to complement pathway and B-cell biology in HT and AMR in donors and in donor-recipient pairs.Methods and Results:Genetic variants in 112 genes (51 complement and 61 B-cell biology genes) were analyzed on next generation sequencing in 28 donor-recipient pairs, 14 recipients with and 14 recipients without AMR. Statistical analysis was performed with SNPStats, R, and EPIDAT3.1. We identified one single nucleotide polymorphism (SNP) in donors in genes related to B-cell biology,interleukin-4 receptor subunitalpha (p.Ile75Val IL4Ralpha), which correlated with the development of AMR. Moreover, in the analysis of recipient-donor genotype discrepancies, we identified another SNP, in this case inadenosine deaminase(ADA; p.Val178(p=)), which was related to B-cell biology, associated with the absence of AMR. CONCLUSIONS: Donor polymorphisms and recipient-donor discrepancies in genes related to the biology of B-cells, could have an important role in the development of AMR. In contrast, no variants in donor or in donor-recipient pairs in complement pathways seem to have an impact on AMR. PMID- 29618708 TI - [Characteristics of health literacy, social capital, and health behavior acquired through experiences by health promotion volunteers]. AB - Objectives In order to promote health in the community, collaborative activities with community organizations are, in addition to individual health guidance, considered to be effective. Health promotion volunteers (HPVs) are now gaining attention as one such community organization. The purposes of this research were to clarify the characteristics of health literacy, social capital, and health behavior acquired through experience by HPVs and to obtain findings with which to examine ways to foster HPVs.Methods An anonymous, self-administered questionnaire survey was conducted through the postal system in a town with 87 currently active HPVs, 158 former HPVs who served between April 2009 and March 2015, and 299 people with no experience as HPVs. The respondents were 54 active HPVs (response rate, 62.1%); 69 former HPVs (43.7%); and 136 people with no experience (45.5%). Participants were asked about their sociodemographic characteristics; activity status as an HPV; self-rated health; whether they had undergone a medical examination (recently) or not; health literacy; social capital; health behaviors; etc.Results Health literacy, social capital, and health behavior scores of active HPVs showed no significant difference among the three groups. Many of the active HPVs felt that the work was "of help to the local government." The number of participants who tried to encourage others and who self-rated their health statuses as healthy in the active HPV group were significantly higher compared with the former HPVs and the group with no experience.Conclusion In fostering HPVs, it is necessary to support them in order to ensure that they proactively engage in activities promoting health. PMID- 29618709 TI - [Factors related to frequent emergency hospital refusal of ambulance transport calls]. AB - Purpose Among the factors that adversely affect the time needed for ambulance transport, one factor for which intervention is possible is the time it takes to choose a medical receiving facility. This research clarified the characteristics of the time, location, and severity of medical emergencies in which the choice of hospital was difficult.Methods The research covered a 1-year period from January 1 through December 31, 2014, investigating all incidents of ambulance transport for patients in Wakayama Prefecture, except for those involving pediatric patients, amounting to a total of 41,574 incidents. Of those, the number of referrals was missing in 129 cases and the remaining 41,445 incidents were analyzed. Cases with 4 or more referrals were adopted as an indicator of difficulty in choosing a hospital. Using binary logistic regression analysis, odds ratios (ORs) with 95% confidence intervals (CIs) were computed for the times and locations of emergency calls, and the degree of injury or illness. A comprehensive analysis was performed, and stratified analysis by Major Diagnostic Category (MDC) was performed, examining external injuries, burns, and poisoning; nervous system disorders; digestive system, liver, biliary tract, and pancreatic disorders; respiratory disorders; and circulatory system disorders.Results The distribution of numbers of referrals ranged from 1 to 12, and 79.6% of cases involved 1 referral, while cases with 4 or more referrals made up 3.5% of the total. In the overall analysis, for cases with 4 or more referrals, call times were examined using weekday working hours as a reference; all other times had high ORs (at 95%CI). The highest OR (95%CI) of 4.0 (3.2-5.0) was for late nights during weekends and holidays. Regarding the degree of injury or illness, using moderate and mild injuries as a reference, the number of referrals (3 times or fewer) was significantly lower for severe injuries and incidents of death (0.8;0.7-0.9). However, in the results of the stratified analysis by MDC, external injuries, burns, and poisoning; severe injury; and death each had an OR (95%CI) of 1.4 (1.0-1.8).Conclusion The relationship between the time, location, and severity of medical emergencies was examined using the number of referrals as an indicator of difficulty with hospital choice in ambulance transport. This research clarified that cases late at night during weekends and holidays, and moderate and mild injuries caused the most difficulty, and that the problems depended on the secondary medical district. PMID- 29618710 TI - [Predictors of social isolation among older people living in urban area: a prospective study]. AB - Objectives We aimed to investigate the predictors of social isolation among older people living in urban area.Methods A mail survey was sent out to 7,015 elderly subjects living in nine districts of Itabashi ward. At baseline (2012), 3,696 subjects and at follow-up (2014) 2,375 replied to the self-administered questionnaire. We defined social isolation as seeing friends or relatives less than two or three times a month. Gender, age, self-rated health, present illnesses, instrumental activities of daily living (IADL), frequency of going out, frequency of social participation, family structure, and perceived financial status were also investigated. A t-test, a chi-square test, and logistic regression analysis were conducted to examine the predictors of social isolation in a follow-up study.Results Of the 1,791 subjects who were analyzed for social isolation, 348 (19.4%) were found to be socially isolated in 2014. A multiple logistic regression analysis showed that men (adjusted odds ratio, 1.88; 95% confidence interval, 1.41-2.50) were significantly more likely to be isolated than women. Being older (1.03, 1.01-1.06) was also a significant predictor of isolation. Subjects who participated in group activities one to three times a month (1.62, 1.04-2.53) were significantly more likely to be isolated than those who participated in them more than once a week. Subjects who rated their financial status as low (1.67, 1.20-2.32) were more likely to be isolated than those who rated it as high. Subjects who were isolated (10.24, 7.60-13.81), and those who did not respond to questions about isolation (8.15, 3.76-17.67), were significantly more likely to be isolated than those who were not isolated at baseline. Among the subjects who were not isolated at baseline, being male (2.39, 1.57-3.64) and lower self-rated health (3.99, 1.33-11.94) were predictors of social isolation.Conclusion Participation in social activities is effective in preventing social isolation among elderly men living in urban area. PMID- 29618711 TI - [The development of an end-of-life-care system in small remote islands: the formulation and application of an "Office Procedure Manual for End-of-Life Care"]. PMID- 29618712 TI - Cytochrome P450-dependent drug oxidation activities in commercially available hepatocytes derived from human induced pluripotent stem cells cultured for 3 weeks. AB - Hepatocyte-like cells differentiated from human induced pluripotent stem (iPS) cells are of great interest for applications in pharmacological research. For drug metabolism testing, commercially available hepatocytes derived from human iPS cells are generally recommended to be used 1 week after seeding on plates. In this study, however, after 3-4 weeks of culture according to the manufacturer's instructions, human cytochrome P450 (P450) 2C9- and 2C19-dependent diclofenac 4' hydroxylation and omeprazole 5-hydroxylation activities of the iPS-derived hepatocytes had significantly increased above the activities at 1 week and had reached levels similar to those in HepaRG cells, a human hepatocyte-like cell line. This increase in activities was associated with increasing P450 2C9 and 2C19 mRNA levels. Human P450 3A4-dependent midazolam 1'/4-hydroxylation activities in the iPS-derived hepatocytes were also enhanced after 3 weeks of culture, but the levels were low compared with those of HepaRG cells. These results indicate that the induction of mRNA of typical P450s in human iPS-derived hepatocyte-like cells occurred after 3 weeks of normal culture conditions. However, the induction levels varied considerably depending on the pregnane X receptor pathway and/or the P450 isoform. Our findings that the hepatic functions of human iPS-derived hepatocytes were enhanced by 3 weeks of simple culture could facilitate the use of these cells for drug metabolism and toxicity testing. PMID- 29618713 TI - Development of an in vitro photosafety evaluation method utilizing intracellular ROS production in THP-1 cells. AB - Photoreactive compounds that may experience exposure to ultraviolet (UV) radiation can lead to the intracellular production of reactive oxygen species (ROS), which may cause phototoxic and photoallergenic responses. Here, we developed a novel in vitro photosafety assay and investigated whether it could be used to predict phototoxicity and photosensitivity by measuring changes in intracellular ROS production. THP-1 cells that had previously taken up 5-(and-6) carboxy-2',7'-difluorodihydrofluorescein diacetate (carboxy-H2DFFDA), a ROS sensitive fluorescent reagent, were exposed to photoreactive substances such as phototoxic and photoallergenic materials and then subjected to with UV-A irradiation (5 J/cm2). The fluorescence intensity was subsequently measured using a flow cytometer, and the intracellular ROS production was calculated. A statistically significant increase in ROS following treatment with photoreactive substances was observed in cells irradiated with UV-A. In contrast, no significant increase was observed for non-photoreactive substances in comparison to the control solution. Next, to confirm the impact of intracellular ROS on the photosensitive response, changes in CD86 and CD54 expression were measured following quencher addition during the photo human cell line activation test (photo h-CLAT). The results confirmed the reduction of CD86 and CD54 expression in response to photoallergenic substances following quencher addition. Together, these findings suggest that intracellular ROS production is involved in photosensitizing reactions. Therefore, we suggest that the developed method utilizing intracellular ROS production as an index may be useful as a novel in vitro evaluation tool for photoreactive substances. PMID- 29618714 TI - Nicotine and methyl vinyl ketone, major components of cigarette smoke extracts, increase protective amyloid-beta peptides in cells harboring amyloid-beta precursor protein. AB - The increased ratio of longer amyloid-beta (Abeta1-42)/shorter amyloid-beta (Abeta1-40) peptides, generated from amyloid precursor protein (APP), is known to promote the development of Alzheimer's disease (AD). To investigate the role of smoking in Abeta production, we determined the production of Abeta species in the presence of nicotine or methyl vinyl ketone (MVK), major components of cigarette smoke extracts, in Flp-InTM T-RExTM-293 (T-REx293) cells harboring a single copy of human APP. While treatment with nicotine or MVK did not affect the amount of APP, the levels of Abeta1-40 in the culture media were significantly increased. On the other hand, the levels of Abeta1-42 were unaltered by nicotine or MVK treatment. The Abeta1-42/Abeta1-40 ratio was therefore attenuated by cigarette smoke extracts. Similar results were obtained in T-REx293 cells harboring APP of Swedish- or London-type mutation linked to familial AD. T-REx293 cells expressed the nicotinic acetylcholine receptor (nAchR) and tubocurarine, an nAChR antagonist, completely blocked the effects of nicotine. Treatment with nicotine significantly elevated cellular levels of beta-secretase that cleaves APP prior to Abeta generation. Taken together, a protective role of nicotine against AD pathology was suggested by enhanced extracellular Abeta1-40 production, which may suppress Abeta fibrillogenesis. PMID- 29618715 TI - Comparing time-series of chemical concentrations in zebrafish (Danio rerio) embryos/larvae exposed to teratogens with different hydrophobicity; caffeine, sodium valproate, and diethylstilbestrol. AB - Developmental toxicity is an adverse developmental outcome, i.e., death, malformation, growth retardation, or functional deficiency. Recently, alternative methods of assessing developmental toxicity using zebrafish (Danio rerio) as a preliminary screening have attracted attention because of their low cost and high throughput. However, most toxicity evaluations have been based on a chemical concentration in an aqueous solution, and the chemical concentrations in embryos/larvae and their temporal behavior have in most cases been unclear, regardless of differences of chemical hydrophobicity. In the present study, we selected three teratogens with different hydrophobicities (caffeine, CA, log Kow 0.07; sodium valproate, VA, log Kow 0.26 (pH 7.4); and diethylstilbestrol, DES, log Kow 5.07), and we measured their concentrations in embryos/larvae exposed to these chemicals every 24 hr post-fertilization (hpf) until 144 hpf. Kinetic analysis based on a one-compartment fish model that yields first order kinetics for CA and VA revealed that concentrations of both CA and VA in embryos/larvae increased gradually and became saturated by around 100 hpf. In contrast, DES concentrations in embryos/larvae reached a maximum at 48 or 72 hpf and then decreased gradually. The present study suggests that the temporal pattern of chemical concentrations is a function of the hydrophobicity of the chemicals. PMID- 29618716 TI - Glutathione has a more important role than metallothionein-I/II against inorganic mercury-induced acute renal toxicity. AB - Inorganic mercury is a harmful heavy metal that causes severe kidney damage. Glutathione (GSH), a tripeptide comprising L-glutamic acid, glycine and L cysteine, and metallothionein (MT), a cysteine-rich and metal-binding protein, are biologically important protective factors for renal toxicity by inorganic mercury. However, the relationship between GSH and MT for the prevention of renal toxicity by inorganic mercury is unknown. We examined the sensitivity of the mice depleted in GSH by treatment with L-Buthionine-SR-sulfoximine (L-BSO), and MT I/II null mice genetically deleted for MT-I and MT-II, to inorganic mercury (HgCl2). Kidney damage was not induced in the wild-type mice treated with HgCl2 (30 umol/kg). In the MT-I/II null mice, renal toxicity was induced by HgCl2 at a dose of 30 umol/kg but not 1.0 umol/kg. All GSH-depleted mice of both strains were dead following the injection of HgCl2 (30 umol/kg). GSH-depleted wild-type mice treated with HgCl2 (1.0 umol/kg) developed kidney damage similar to MT-I/II null mice treated with HgCl2 (30 umol/kg). Moreover, renal toxicity induced by HgCl2 (1.0 umol/kg) was more severe in GSH-depleted MT-I/II null mice compared with GSH-depleted wild-type mice. The present study found that GSH and MT-I/II play cooperatively an important role in the detoxification of severe kidney damage caused by inorganic mercury. In addition, GSH may act as a primary protective factor against inorganic mercury-induced acute renal toxicity, because GSH-depleted mice were more sensitive to inorganic mercury than MT-I/II null mice. PMID- 29618717 TI - The profiles and networks of miRNA, lncRNA, mRNA, and circRNA in benzo(a)pyrene transformed bronchial epithelial cells. AB - Our aim was to demonstrate the significance of miRNA, lncRNA, and circRNA in the transformation of human bronchial epithelial cells induced by benzo(a)pyrene (BaP), and to investigate their regulatory networks. Hierarchical clustering, gene ontology (GO) analysis, Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis and network regulation analysis were used to analyze the high-throughput sequencing results of human bronchial epithelial cell line BEAS-2B and BaP transformed BEAS-2B cells (BEAS-2B-T). 76,191,786 and 3,431differentially expressed miRNA, lncRNA, mRNA and circRNA were detected, respectively; 43 miRNA, 48 lncRNA, 438 mRNA and 2,079 circRNA were up-regulated; 33 miRNA, 143 lncRNA, 348 mRNA and 1,352 circRNA were down-regulated. Through GO analysis, 257 biological process (BP) terms, 12 cell composition (CC) terms and 49 molecular function (MF) terms were found in differentially-expressed lncRNA; 143 BP terms, 32 CC terms, and 48 MF terms were found in differentially-expressed circRNA. Pathways of KEGG analysis of lncRNA and circRNA could be classified into the categories "human diseases" and "organism systems". From miRNA-circRNA, circRNA mRNA, and lncRNA-circRNA networks analysis, we found that mir-137, circ-RPS5, circ-ZNF292, circ-ERBB2IP, circ-SEMA3C, circ-IGF1R, circ-RTN4, APOC1, and CDKN2A may be of great significance for cell transformation. From the analysis of miRNA, lncRNA, mRNA, and circRNA networks, we found that PDGFRB, lncRNA RGMB-AS1, circ ZNF292 are associated with miR-138-5p. Our study shows that miRNA, lncRNA, and circRNA have a significant regulatory role in the transformation of human bronchial epithelial cell induced by BaP. PMID- 29618718 TI - The Effects of Left Ventricular Assist Device Support Level on the Biomechanical States of Aortic Valve. AB - BACKGROUND Although aortic valve disease caused by left ventricular assist device (LVAD) support has attracted more and more attention, the precise biomechanical effects of LVAD support level on the aortic valve are still unclear. MATERIAL AND METHODS A structural finite element models study was conducted using an ideal aortic valve geometric model. Four different study conditions were designed, according to the reduction of the open duration of the aortic valve. The isotropic hyperelastic constitutive equation was chosen to reflect the mechanical property of the leaflets. The distribution of the stress, strain, and transient dynamics of the leaflet were calculated. RESULTS Along with the increase of LVAD support level, the open duration of the aortic valve was also reduced by the increase of LVAD support (low support level case 0.23 seconds versus middle support level case 0.2 seconds versus high support level case 0.14 seconds). Moreover, along with the increase of support mode of LVAD, the von Mises stress in most leaflet areas was increased from the low stress level (0-0.4 MPa) to the middle region (0.4-0.8 MPa). Once the leaflets were continuously closed, the high stress level (larger than 0.8 MPa) was observed. In contrast, the support level of LVAD only had slight effects on the distribution of von Mises strain. According to the aforementioned results, maintaining the open duration of aortic valve longer than 0.2 seconds could achieve better performance of biomechanical states of leaflets. CONCLUSIONS This study could provide useful information on the determination of optimal LVAD support strategy. PMID- 29618719 TI - Cervical Esophagotomy for Foreign Body Extraction: A Case Report and Extensive Literature Review of the Last 20 Years. AB - BACKGROUND Voluntary and involuntary ingestion of foreign bodies is a common condition; in most cases they pass through the digestive tract, but sometimes they stop, creating emergency situations for the patient. We report a case of meat bolus with cartilaginous component impacted in the cervical esophagus, with a brief literature review. CASE REPORT A 64-year-old man came to our attention for retention in the cervical esophagus of a piece of meat accidentally swallowed during lunch. After a few attempts of endoscopic removal carried out previously in other hospitals, the patient has been treated by us with a cervical esophagotomy and removal of the foreign body, without any complications. We checked the database of PubMed, Scopus, and the Cochrane Library from January 2007 to January 2017 in order to verify the presence of randomized controlled trials, clinical trials, retrospective studies, and case series regarding the use of the cervical esophagotomy for the extraction of foreign bodies impacted in the esophagus. CONCLUSIONS The crucial point is to differentiate the cases that must be immediately treated from those requiring simple observation. Endoscopic treatment is definitely the first therapeutic option, but in case of failure of this approach, in our opinion, cervical esophagotomy could be a safe, easy, viable, durable approach for the extraction of foreign bodies impacted in the cervical esophagus. Our review does not have the purpose of providing definitive conclusions but is intended to represent a starting point for subsequent studies. PMID- 29618721 TI - Risk of thrombosis and mortality in inflammatory bowel disease. AB - OBJECTIVES: Patients with inflammatory bowel disease have a higher risk of thrombosis, which is associated with a higher morbidity and mortality. Most data about VTE are related to hospitalized patients with active disease, but several cases happen in the outpatient setting, and are not covered by current prophylaxis recommendation. As the knowledge of VTE in outpatients is still poor, the aim of this study is to evaluate the risk, clinical data and mortality of thrombosis in patients followed in our center, comparing our findings with the current prophylaxis recommendation. METHODS: The medical electronic chart of 1093 inflammatory bowel disease patients and their image exams were actively searched for words related to thrombosis, followed by charts reviewed to collect information about the event and data regarding clinical settings and thrombosis profile. RESULTS: Overall, 654 Crohn's and 439 Colitis patients were included. Thrombosis prevalence was 5.1%,and mortality rate was higher in patients who had suffered thrombosis (10.71% vs. 1.45%, OR 8.0). Half of them developed thrombosis in the outpatient setting, 52% of these had disease activity, 17% had recent hospitalization, and 10% had previous thrombosis. In 27% of cases, diagnosis was done by routine image exams, with no clinical symptoms or previous history of thrombosis. None of them had used thromboprophylaxis. However, a great majority of patients who had thrombosis during hospitalization used heparin prophylaxis. CONCLUSION: Inflammatory bowel disease patients who develop thrombosis have an increased mortality risk. A significant proportion of the events happened in patients without a clear thromboprophylaxis recommendation or in those receiving heparin prophylaxis. PMID- 29618720 TI - Anti-TNF and thiopurine therapy in pregnant IBD patients does not significantly alter a panel of B-cell and T-cell subsets in 1-year-old infants. AB - OBJECTIVES: Infants exposed to combination therapy with anti-tumor necrosis factor (anti-TNF) agents and thiopurines may exhibit increased infections at 1 year of age compared to unexposed infants. We hypothesized that this increased risk of infection is due to abnormal development of the newborn immune system. METHODS: We immunophenotyped B-cell and T-cell subsets using multiparameter flow cytometry in 1-year-old infants whose mothers were exposed to therapeutic agents for IBD. We analyzed samples from infants exposed to infliximab (IFX) or adalimumab (ADA) monotherapy (IFX/ADA, n = 11), certolizumab pegol (CZP) monotherapy (CZP, n = 4), IFX or ADA plus thiopurine combination therapy (IFX/ADA + IM, n = 4), and CZP plus thiopurine combination therapy (CZP + IM, n = 2). RESULTS: Percentages of B cells, CD4+ T helper cells, T regulatory cells (Tregs), and CD8+ cytotoxic T cells, were similar among the groups. Infants exposed to combination therapy (IFX/ADA + IM) exhibited trends toward fewer CD27+ B cells, switched memory B cells, plasmablasts, interferon gamma (IFNgamma)-producing CD4+ and CD8+ T cells, and CCR5+CD4+ T cells, but these did not reach statistical significance. CONCLUSIONS: Multiparameter immunophenotyping of major B-cell and T cell subsets suggests that the adaptive newborn immune system develops largely unaltered after exposure to combination therapy as compared to anti-TNF monotherapy. PMID- 29618722 TI - Incorporation of mutations in five genes in the revised International Prognostic Scoring System can improve risk stratification in the patients with myelodysplastic syndrome. AB - Gene mutations have not yet been included in the 2016 WHO classification and revised International Prognostic Scoring System (IPSS-R), which are now widely utilized to discriminate myelodysplastic syndrome (MDS) patients regarding risk of leukemia evolution and overall survival (OS). In this study, we aimed to investigate whether integration of gene mutations with other risk factors could further improve the stratification of MDS patients. Mutational analyses of 25 genes relevant to myeloid malignancies in 426 primary MDS patients showed that mutations of CBL, IDH2, ASXL1, DNMT3A, and TP53 were independently associated with shorter survival. Patients within each IPSS-R or 2016 WHO classification defined risk group could be stratified into two risk subgroups based on the mutational status of these five genes; patients with these poor-risk mutations had an OS shorter than others in the same risk group, but similar to those with the next higher risk category. A scoring system incorporating age, IPSS-R and five poor-risk mutations could divide the MDS patients into four risk groups (P < 0.001 for both OS and leukemia-free survival). In conclusion, integration of gene mutations in current IPSS-R improves the prognostication of MDS patients and may help identify high-risk patients for more aggressive treatment in IPSS-R lower risk group. PMID- 29618723 TI - Enhanced protection in mice induced by immunization with inactivated whole viruses compare to spike protein of middle east respiratory syndrome coronavirus. AB - The persistent public health threat of infection with Middle East respiratory syndrome coronavirus (MERS-CoV) highlights the need for an effective and safe MERS-CoV vaccine. In this study, we prepared and vaccinated mice with either a Spike (S) protein or inactivated whole MERS-CoV (IV) with a combined adjuvant (alum+CpG) as a vaccine formulation. Similar levels of the anti-S protein IgG response and neutralizing activity were induced by both the S protein and IV vaccines. In addition, immune responses against three other structural proteins, the envelope (E), membrane (M), and nucleocapsid (N) proteins, were also detected in sera of mice that received IV. No antigen-specific T-cell immunity was detected after vaccination based on the interferon-gamma ELISpot assay. Mice were transduced with Ad5-hDPP4 after the final immunization and were then challenged with MERS-CoV (1 * 105 plaque-forming units). Compared with the control group (adjuvant alone), mice immunized with the S protein or IV showed slightly lower pathological damage in the lung, as well as reduced antigen expression and lung virus titers. Mice that received IV formulations also showed increased protective immunity (almost no live virus was isolated from the lung). In conclusion, our data indicate that immunization with our IV formulation induced enhanced protection in mice compared to immunization with the S protein against MERS-CoV, which should be further tested in camels and clinical trials. PMID- 29618724 TI - Global dynamics of stage-specific transcription factor binding during thymocyte development. AB - In vertebrates, multiple transcription factors (TFs) bind to gene regulatory elements (promoters, enhancers, and silencers) to execute developmental expression changes. ChIP experiments are often used to identify where TFs bind to regulatory elements in the genome, but the requirement of TF-specific antibodies hampers analyses of tens of TFs at multiple loci. Here we tested whether TF binding predictions using ATAC-seq can be used to infer the identity of TFs that bind to functionally validated enhancers of the Cd4, Cd8, and Gata3 genes in thymocytes. We performed ATAC-seq at four distinct stages of development in mouse thymus, probing the chromatin accessibility landscape in double negative (DN), double positive (DP), CD4 single positive (SP4) and CD8 SP (SP8) thymocytes. Integration of chromatin accessibility with TF motifs genome-wide allowed us to infer stage-specific occupied TF binding sites within known and potentially novel regulatory elements. Our results provide genome-wide stage-specific T cell open chromatin profiles, and allow the identification of candidate TFs that drive thymocyte differentiation at each developmental stage. PMID- 29618725 TI - Looking for variable molecular markers in the chestnut gall wasp Dryocosmus kuriphilus: first comparison across genes. AB - The quick spread of the chestnut gall wasp Dryocosmus kuriphilus in Europe constitutes an outstanding example of recent human-aided biological invasion with dramatic economic losses. We screened for the first time a set of five nuclear and mitochondrial genes from D. kuriphilus collected in the Iberian Peninsula, and compared the sequences with those available from the native and invasive range of the species. We found no genetic variability in Iberia in none of the five genes, moreover, the three genes compared with other European samples showed no variability either. We recorded four cytochrome b haplotypes in Europe; one was genuine mitochondrial DNA and the rest nuclear copies of mitDNA (numts), what stresses the need of careful in silico analyses. The numts formed a separate cluster in the gene tree and at least two of them might be orthologous, what suggests that the invasion might have started with more than one individual. Our results point at a low initial population size in Europe followed by a quick population growth. Future studies assessing the expansion of this pest should include a large number of sampling sites and use powerful nuclear markers (e. g. Single Nucleotide Polymorphisms) to detect genetic variability. PMID- 29618727 TI - Rule-based modelling provides an extendable framework for comparing candidate mechanisms underpinning clathrin polymerisation. AB - Polymerisation of clathrin is a key process that underlies clathrin-mediated endocytosis. Clathrin-coated vesicles are responsible for cell internalization of external substances required for normal homeostasis and life -sustaining activity. There are several hypotheses describing formation of closed clathrin structures. According to one of the proposed mechanisms cage formation may start from a flat lattice buildup on the cellular membrane, which is later transformed into a curved structure. Creation of the curved surface requires rearrangement of the lattice, induced by additional molecular mechanisms. Different potential mechanisms require a modeling framework that can be easily modified to compare between them. We created an extendable rule-based model that describes polymerisation of clathrin molecules and various scenarios of cage formation. Using Global Sensitivity Analysis (GSA) we obtained parameter sets describing clathrin pentagon closure and the emergence/production and closure of large-size clathrin cages/vesicles. We were able to demonstrate that the model can reproduce budding of the clathrin cage from an initial flat array. PMID- 29618726 TI - Exome Sequencing Identifies Genetic Variants Associated with Circulating Lipid Levels in Mexican Americans: The Insulin Resistance Atherosclerosis Family Study (IRASFS). AB - Genome-wide association studies have identified numerous variants associated with lipid levels; yet, the majority are located in non-coding regions with unclear mechanisms. In the Insulin Resistance Atherosclerosis Family Study (IRASFS), heritability estimates suggest a strong genetic basis: low-density lipoprotein (LDL, h2 = 0.50), high-density lipoprotein (HDL, h2 = 0.57), total cholesterol (TC, h2 = 0.53), and triglyceride (TG, h2 = 0.42) levels. Exome sequencing of 1,205 Mexican Americans (90 pedigrees) from the IRASFS identified 548,889 variants and association and linkage analyses with lipid levels were performed. One genome-wide significant signal was detected in APOA5 with TG (rs651821, PTG = 3.67 * 10-10, LODTG = 2.36, MAF = 14.2%). In addition, two correlated SNPs (r2 = 1.0) rs189547099 (PTG = 6.31 * 10-08, LODTG = 3.13, MAF = 0.50%) and chr4:157997598 (PTG = 6.31 * 10-08, LODTG = 3.13, MAF = 0.50%) reached exome-wide significance (P < 9.11 * 10-08). rs189547099 is an intronic SNP in FNIP2 and SNP chr4:157997598 is intronic in GLRB. Linkage analysis revealed 46 SNPs with a LOD > 3 with the strongest signal at rs1141070 (LODLDL = 4.30, PLDL = 0.33, MAF = 21.6%) in DFFB. A total of 53 nominally associated variants (P < 5.00 * 10-05, MAF >= 1.0%) were selected for replication in six Mexican-American cohorts (N = 3,280). The strongest signal observed was a synonymous variant (rs1160983, PLDL = 4.44 * 10-17, MAF = 2.7%) in TOMM40. Beyond primary findings, previously reported lipid loci were fine-mapped using exome sequencing in IRASFS. These results support that exome sequencing complements and extends insights into the genetics of lipid levels. PMID- 29618728 TI - Association between DNA methylation in cord blood and maternal smoking: The Hokkaido Study on Environment and Children's Health. AB - Maternal smoking is reported to cause adverse effects on the health of the unborn child, the underlying mechanism for which is thought to involve alterations in DNA methylation. We examined the effects of maternal smoking on DNA methylation in cord blood, in 247 mother-infant pairs in the Sapporo cohort of the Hokkaido Study, using the Infinium HumanMethylation 450K BeadChip. We first identified differentially methylated CpG sites with a false discovery rate (FDR) of <0.05 and the magnitude of DNA methylation changes (|beta| >0.02) from the pairwise comparisons of never-smokers (Ne-S), sustained-smokers (Su-S), and stopped smokers (St-S). Subsequently, secondary comparisons between St-S and Su-S revealed nine common sites that mapped to ACSM3, AHRR, CYP1A1, GFI1, SHANK2, TRIM36, and the intergenic region between ANKRD9 and RCOR1 in Ne-S vs. Su-S, and one common CpG site mapping to EVC2 in Ne-S vs. St-S. Further, we verified these CpG sites and examined neighbouring sites using bisulfite next-generation sequencing, except for AHRR cg21161138. These changes in DNA methylation implicate the effect of smoking cessation. Our findings add to the current knowledge of the association between DNA methylation and maternal smoking and suggest future studies for clarifying this relationship in disease development. PMID- 29618729 TI - Apolipoprotein A-II induces acute-phase response associated AA amyloidosis in mice through conformational changes of plasma lipoprotein structure. AB - During acute-phase response (APR), there is a dramatic increase in serum amyloid A (SAA) in plasma high density lipoproteins (HDL). Elevated SAA leads to reactive AA amyloidosis in animals and humans. Herein, we employed apolipoprotein A-II (ApoA-II) deficient (Apoa2 -/- ) and transgenic (Apoa2Tg) mice to investigate the potential roles of ApoA-II in lipoprotein particle formation and progression of AA amyloidosis during APR. AA amyloid deposition was suppressed in Apoa2 -/- mice compared with wild type (WT) mice. During APR, Apoa2 -/- mice exhibited significant suppression of serum SAA levels and hepatic Saa1 and Saa2 mRNA levels. Pathological investigation showed Apoa2 -/- mice had less tissue damage and less inflammatory cell infiltration during APR. Total lipoproteins were markedly decreased in Apoa2 -/- mice, while the ratio of HDL to low density lipoprotein (LDL) was also decreased. Both WT and Apoa2 -/- mice showed increases in LDL and very large HDL during APR. SAA was distributed more widely in lipoprotein particles ranging from chylomicrons to very small HDL in Apoa2 -/- mice. Our observations uncovered the critical roles of ApoA-II in inflammation, serum lipoprotein stability and AA amyloidosis morbidity, and prompt consideration of therapies for AA and other amyloidoses, whose precursor proteins are associated with circulating HDL particles. PMID- 29618730 TI - Immunotoxicity of Silver Nanoparticles (AgNPs) on the Leukocytes of Common Bottlenose Dolphins (Tursiops truncatus). AB - Silver nanoparticles (AgNPs) have been extensively used and are considered as an emerging contaminant in the ocean. The environmental contamination of AgNPs is expected to increase greatly over time, and cetaceans, as the top ocean predators, will suffer the negative impacts of AgNPs. In the present study, we investigate the immunotoxicity of AgNPs on the leukocytes of cetaceans using several methods, including cytomorphology, cytotoxicity, and functional activity assays. The results reveal that 20 nm Citrate-AgNPs (C-AgNP20) induce different cytomorphological alterations and intracellular distributions in cetacean polymorphonuclear cells (cPMNs) and peripheral blood mononuclear cells (cPBMCs). At high concentrations of C-AgNP20 (10 and 50 MUg/ml), the time- and dose dependent cytotoxicity in cPMNs and cPBMCs involving apoptosis is demonstrated. C AgNP20 at sub-lethal doses (0.1 and 1 MUg/ml) negatively affect the functional activities of cPMNs (phagocytosis and respiratory burst) and cPBMCs (proliferative activity). The current study presents the first evidence of the cytotoxicity and immunotoxicity of AgNPs on the leukocytes of cetaceans and improves our understanding of environmental safety concerning AgNPs. The dose response data of AgNPs on the leukocytes of cetaceans are invaluable for evaluating the adverse health effects in cetaceans and for proposing a conservation plan for marine mammals. PMID- 29618731 TI - Plasmodium APC3 mediates chromosome condensation and cytokinesis during atypical mitosis in male gametogenesis. AB - The anaphase promoting complex/cyclosome (APC/C) is a highly conserved multi subunit E3 ubiquitin ligase that controls mitotic division in eukaryotic cells by tagging cell cycle regulators for proteolysis. APC3 is a key component that contributes to APC/C function. Plasmodium, the causative agent of malaria, undergoes atypical mitotic division during its life cycle. Only a small subset of APC/C components has been identified in Plasmodium and their involvement in atypical cell division is not well understood. Here, using reverse genetics we examined the localisation and function of APC3 in Plasmodium berghei. APC3 was observed as a single focus that co-localised with the centriolar plaque during asexual cell division in schizonts, whereas it appeared as multiple foci in male gametocytes. Functional studies using gene disruption and conditional knockdown revealed essential roles of APC3 during these mitotic stages with loss resulting in a lack of chromosome condensation, abnormal cytokinesis and absence of microgamete formation. Overall, our data suggest that Plasmodium utilises unique cell cycle machinery to coordinate various processes during endomitosis, and this warrants further investigation in future studies. PMID- 29618733 TI - Use of Soluble Extracellular Regions of MmpL (SERoM) as Vaccines for Tuberculosis. AB - The current vaccine for tuberculosis (TB) is a live attenuated strain of Mycobacterium bovis (BCG) and while effective at reducing the potential for disseminated TB in young children its disease protection rates in adults is highly variable while it confers little protection against latent TB. With these limitations a new vaccine is desperately needed. We investigated the efficacy of three members of the mycobacterial membrane protein Large (MmpL) family as potential subunit vaccines for TB. MmpLs are large, multifunctional integral membrane proteins, and as such are recalcitrant to purification. Here, we describe a strategy of producing synthetic antigens comprised of the soluble, extracellular regions of MmpL (SERoM)-1, MmpL8 and MmpL10 (SERoM-8 and 10 respectively) as potential vaccine candidates. SERoM-1 and SERoM-8 were determined to be highly immunogenic by IFN-gamma ELISpot assays, with 0.1% of all splenocytes from SERoM-1 vaccinated mice producing IFN-gamma when re-stimulated with MmpL1. A combined SERoM-1, -8 and -10 vaccine demonstrated significant protection against M. tuberculosis challenge in a murine model of TB, resulting in approximately 10-fold reduction in bacterial numbers following challenge in both the lungs and spleens compared to adjuvant only vaccinated mice. These protective effects were comparable to that achieved with BCG. PMID- 29618732 TI - KoVariome: Korean National Standard Reference Variome database of whole genomes with comprehensive SNV, indel, CNV, and SV analyses. AB - High-coverage whole-genome sequencing data of a single ethnicity can provide a useful catalogue of population-specific genetic variations, and provides a critical resource that can be used to more accurately identify pathogenic genetic variants. We report a comprehensive analysis of the Korean population, and present the Korean National Standard Reference Variome (KoVariome). As a part of the Korean Personal Genome Project (KPGP), we constructed the KoVariome database using 5.5 terabases of whole genome sequence data from 50 healthy Korean individuals in order to characterize the benign ethnicity-relevant genetic variation present in the Korean population. In total, KoVariome includes 12.7M single-nucleotide variants (SNVs), 1.7M short insertions and deletions (indels), 4K structural variations (SVs), and 3.6K copy number variations (CNVs). Among them, 2.4M (19%) SNVs and 0.4M (24%) indels were identified as novel. We also discovered selective enrichment of 3.8M SNVs and 0.5M indels in Korean individuals, which were used to filter out 1,271 coding-SNVs not originally removed from the 1,000 Genomes Project when prioritizing disease-causing variants. KoVariome health records were used to identify novel disease-causing variants in the Korean population, demonstrating the value of high-quality ethnic variation databases for the accurate interpretation of individual genomes and the precise characterization of genetic variations. PMID- 29618734 TI - Carotenoid dynamics and lipid droplet containing astaxanthin in response to light in the green alga Haematococcus pluvialis. AB - The unicellular green alga Haematococcus pluvialis accumulates large amounts of the red ketocarotenoid astaxanthin to protect against environmental stresses. Haematococcus cells that accumulate astaxanthin in the central part (green-red cyst cells) respond rapidly to intense light by distributing astaxanthin diffusively to the peripheral part of the cell within 10 min after irradiation. This response is reversible: when astaxanthin-diffused cells were placed in the dark, astaxanthin was redistributed to the center of the cell. Although Haematococcus possesses several pigments other that astaxanthin, the subcellular distribution and content of each pigment remain unknown. Here, we analyzed the subcellular dynamics and localization of major pigments such as astaxanthin, beta carotene, lutein, and chlorophylls under light irradiation using time-lapse and label-free hyperspectral imaging analysis. Fluorescence microscopy and freeze fracture transmission electron microscopy showed that, preceding/following exposure to light, astaxanthin colocalized with lipid droplets, which moved from the center to the periphery through pathways in a chloroplast. This study revealed that photoresponse dynamics differed between astaxanthin and other pigments (chlorophylls, lutein, and beta-carotene), and that only astaxanthin freely migrates from the center to the periphery of the cell through a large, spherical, cytoplasm-encapsulating chloroplast as a lipid droplet. We consider this to be the Haematococcus light-protection mechanism. PMID- 29618735 TI - Source reconstruction of airborne toxics based on acute health effects information. AB - The intentional or accidental release of airborne toxics poses great risk to the public health. During these incidents, the greatest factor of uncertainty is related to the location and rate of released substance, therefore, an information of high importance for emergency preparedness and response plans. A novel computational algorithm is proposed to estimate, efficiently, the location and release rate of an airborne toxic substance source based on health effects observations; data that can be readily available, in a real accident, contrary to actual measurements. The algorithm is demonstrated by deploying a semi-empirical dispersion model and Monte Carlo sampling on a simplified scenario. Input data are collected at varying receptor points for toxics concentrations (C; standard approach) and two new types: toxic load (TL) and health effects (HE; four levels). Estimated source characteristics are compared with scenario values. The use of TL required the least number of receptor points to estimate the release rate, and demonstrated the highest probability (>90%). HE required more receptor points, than C, but with lesser deviations while probability was comparable, if not better. Finally, the algorithm assessed very accurately the source location when using C and TL with comparable confidence, but HE demonstrated significantly lower confidence. PMID- 29618736 TI - Circulating Levels of Inflammatory Proteins and Survival in Patients with Gallbladder Cancer. AB - Although inflammation is central to gallbladder cancer (GBC) development and proliferation, no study has systematically investigated circulating inflammatory proteins and patient survival. We aimed to examine whether the circulating levels of inflammatory proteins is associated with all-cause mortality among such patients. We recruited 134 patients with newly diagnosed with GBC from 1997 to 2001 in a population-based study in Shanghai and an independent set of 35 patients from 2012 to 2013 in Chile. Cox proportional hazards regression models adjusted for covariates were used to evaluate the hazard ratios (HRs) for death by serum levels of 49 inflammatory proteins (quartiles). Of 49 evaluable proteins, eight were significantly associated with overall survival. Seven were associated with a poorer survival, while the highest levels of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) were associated with an increase in survival (HR = 0.26, 95% CI = 0.14, 0.47). No substantial difference in the magnitude of the association was observed between early- and late-stages of GBC. Of seven proteins, five were validated in the patients from Chile. Reducing inflammation and targeting pathways associated with increased survival might improve GBC outcomes. The potential for using a TRAIL-related anticancer drug for GBC treatment merits further investigation. PMID- 29618739 TI - Nanoscale High-Tc YBCO/GaN Super-Schottky Diode. AB - We demonstrate a high-temperature nanoscale super-Schottky diode based on a superconducting tunnel junction of pulsed-laser-deposited YBCO on GaN thin films. A buffer-free direct growth of nanoscale YBCO thin films on heavily doped GaN was performed to realize a direct high-Tc superconductor-semiconductor junction. The junction shows strongly non-linear I-V characteristics, which have practical applications as a low-voltage super-Schottky diode for microwave mixing and detection. The V-shaped differential conductance spectra observed across the junction are characteristic of the c-axis tunneling into a cuprate superconductor with a certain disorder level. This implementation of the super-Schottky diode, supported by the buffer-free direct growth of nanoscale high-Tc thin films on semiconductors, paves the way for practical large-scale fabrication and integration of high-Tc-superconductor devices in future technologies. PMID- 29618737 TI - Genome-wide association study and meta-analysis identify loci associated with ventricular and supraventricular ectopy. AB - The genetic basis of supraventricular and ventricular ectopy (SVE, VE) remains largely uncharacterized, despite established genetic mechanisms of arrhythmogenesis. To identify novel genetic variants associated with SVE/VE in ancestrally diverse human populations, we conducted a genome-wide association study of electrocardiographically identified SVE and VE in five cohorts including approximately 43,000 participants of African, European and Hispanic/Latino ancestry. In thirteen ancestry-stratified subgroups, we tested multivariable adjusted associations of SVE and VE with single nucleotide polymorphism (SNP) dosage. We combined subgroup-specific association estimates in inverse variance weighted, fixed-effects and Bayesian meta-analyses. We also combined fixed effects meta-analytic t-test statistics for SVE and VE in multi-trait SNP association analyses. No loci reached genome-wide significance in trans-ethnic meta-analyses. However, we found genome-wide significant SNPs intronic to an apoptosis-enhancing gene previously associated with QRS interval duration (FAF1; lead SNP rs7545860; effect allele frequency = 0.02; P = 2.0 * 10-8) in multi trait analysis among European ancestry participants and near a locus encoding calcium-dependent glycoproteins (DSC3; lead SNP rs8086068; effect allele frequency = 0.17) in meta-analysis of SVE (P = 4.0 * 10-8) and multi-trait analysis (P = 2.9 * 10-9) among African ancestry participants. The novel findings suggest several mechanisms by which genetic variation may predispose to ectopy in humans and highlight the potential value of leveraging pleiotropy in future studies of ectopy-related phenotypes. PMID- 29618738 TI - Whole-genome sequencing of a large collection of Myroides odoratimimus and Myroides odoratus isolates and antimicrobial susceptibility studies. AB - The genus Myroides comprises several species of Gram-negative, non-motile, and non-fermenting bacteria, which have been regarded as non-pathogenic for decades. Multiple recent reports, however, underscore the pathogenic potential that Myroides sp. possesses for humans. These bacteria seem to be resistant to a wide range of antibiotics (including beta-lactams and aminoglycosides). Therefore, treatment options are limited. Knowledge of antimicrobial resistance, however, is based on only one meaningful comprehensive study and on data published from case reports. This lack of data motivated us to test 59 strains from our Myroides collection (43 M. odoratimimus and 16 M. odoratus) for resistance against 20 commonly used antibiotics. We also performed molecular analyses to reveal whether our bacteria harbor the genus-specific M. odoratimimus metallo-beta-lactamase (MUS-1) or the M. odoratus metallo beta-lactamase (TUS-1), and other beta lactamases, which may provide an explanation for the extended antimicrobial resistance. PMID- 29618740 TI - Traumatic Brain Injury Leads to Accelerated Atherosclerosis in Apolipoprotein E Deficient Mice. AB - Traumatic brain injury (TBI) has been associated with atherosclerosis and cardiovascular mortality in humans. However the causal relationship between TBI and vascular disease is unclear. This study investigated the direct role of TBI on vascular disease using a murine model of atherosclerosis. Apolipoprotein E deficient mice were placed on a western diet beginning at 10 weeks of age. Induction of TBI or a sham operation was performed at 14 weeks of age and mice were sacrificed 6 weeks later at 20 weeks of age. MRI revealed evidence of uniform brain injury in all mice subjected to TBI. There were no differences in total cholesterol levels or blood pressure between the groups. Complete blood counts and flow cytometry analysis performed on peripheral blood 6 weeks following TBI revealed a higher percentage of Ly6C-high monocytes in mice subjected to TBI compared to sham-treated mice. Mice with TBI also showed elevated levels of plasma soluble E-selectin and bone marrow tyrosine hydroxylase. Analysis of atherosclerosis at the time of sacrifice revealed increased atherosclerosis with increased Ly6C/G immunostaining in TBI mice compared to sham-treated mice. In conclusion, progression of atherosclerosis is accelerated following TBI. Targeting inflammatory pathways in patients with TBI may reduce subsequent vascular complications. PMID- 29618741 TI - Spin-orbit torque magnetometry by wide-field magneto-optical Kerr effect. AB - Magneto-optical Kerr effect (MOKE) is an efficient approach to probe surface magnetization in thin film samples. Here we present a wide-field MOKE technique that adopts a Kohler illumination scheme to characterize the current-induced damping-like spin-orbit torque (DL-SOT) in micron-sized and unpatterned magnetic heterostructures with perpendicular magnetic anisotropy. Through a current induced hysteresis loop shift analysis, we quantify the DL-SOT efficiency of a Ta based heterostructure with bar-shaped geometry, Hall-cross geometry, and unpatterned geometry to be |xi DL | ~ 0.08. The proposed wide-field MOKE approach therefore provides an instant and direct characterization of DL-SOT, without the need of any further interpretation on electrical signals. PMID- 29618742 TI - Early life stress induces long-term changes in limbic areas of a teleost fish: the role of catecholamine systems in stress coping. AB - Early life stress (ELS) shapes the way individuals cope with future situations. Animals use cognitive flexibility to cope with their ever-changing environment and this is mainly processed in forebrain areas. We investigated the performance of juvenile gilthead seabream, previously subjected to an ELS regime. ELS fish showed overall higher brain catecholaminergic (CA) signalling and lower brain derived neurotrophic factor (bdnf) and higher cfos expression in region-specific areas. All fish showed a normal cortisol and serotonergic response to acute stress. Brain dopaminergic activity and the expression of the alpha2Alpha adrenergic receptor were overall higher in the fish homologue to the lateral septum (Vv), suggesting that the Vv is important in CA system regulation. Interestingly, ELS prevented post-acute stress downregulation of the alpha2Alpha receptor in the amygdala homologue (Dm3). There was a lack of post-stress response in the beta2 adrenergic receptor expression and a downregulation in bdnf in the Dm3 of ELS fish, which together indicate an allostatic overload in their stress coping ability. ELS fish showed higher neuronal activity (cfos) post-acute stress in the hippocampus homologue (Dlv) and the Dm3. Our results show clear long-term effects on limbic systems of seabream that may compromise their future coping ability to environmental challenges. PMID- 29618743 TI - Vertical Transport Control of Electrical Charge Carriers in Insulator/Oxide Semiconductor Hetero-structure. AB - The technology for electrical current passing through an insulator thin-film between two electrodes is newly getting spotlights for substantial potentials toward advanced functional devices including a diode and a resistive switching device. However, depending on an electrode-limited conduction mechanisms of the conventional devices, a narrow processing window for a thickness of the insulator thin-film and an inability to control a magnitude and direction of the currents are challenges to overcome. Herein, we report a new approach to enable electrical charge carriers to pass stably through a relatively-thick insulator layer and to control a magnitude and polarity of the currents by applying an oxide semiconductor electrode in a metal/insulator/metal structure. We reveal that the electrical conduction in our devices follows a space charge-limited conduction mechanism which mainly depends on the charge carriers injected from contacts. Therefore, characteristics of the current including a current value and a rectification ratio of input signal are precisely controlled by electrical properties of the oxide semiconductor electrode. The unique current characteristics in metal/insulator/oxide semiconductor structures give extendable inspirations in electronic materials science, even a prominent solution for various technology areas of electronics. PMID- 29618744 TI - Network approach of the conformational change of c-Src, a tyrosine kinase, by molecular dynamics simulation. AB - Non-receptor tyrosine kinase c-Src plays a critical role in numerous cellular signalling pathways. Activation of c-Src from its inactive to the active state involves large-scale conformational changes, and is controlled by the phosphorylation state of two major phosphorylation sites, Tyr416 and Tyr527. A detailed mechanism for the entire conformational transition of c-Src via phosphorylation control of Tyr416 and Tyr527 is still elusive. In this study, we investigated the inactive-to-active conformational change of c-Src by targeted molecular dynamics simulation. Based on the simulation, we proposed a dynamical scenario for the activation process of c-Src. A detailed study of the conformational transition pathway based on network analysis suggests that Lys321 plays a key role in the c-Src activation process. PMID- 29618745 TI - Differences in DNA Methylation and Functional Expression in Lactase Persistent and Non-persistent Individuals. AB - In humans the expression of lactase changes during post-natal development, leading to phenotypes known as lactase persistence and non-persistence. Polymorphisms within the lactase gene (LCT) enhancer, in particular the -13910C > T, but also others, are linked to these phenotypes. We were interested in identifying dynamic mediators of LCT regulation, beyond the genotype at -13910C > T. To this end, we investigated two levels of lactase regulation in human intestinal samples obtained from New England children and adolescents of mixed European ancestry: differential expression of transcriptional regulators of LCT, and variations in DNA methylation, and their relation to phenotype. Variations in expression of CDX2, POU2F1, GATA4, GATA6, and HNF1alpha did not correlate with phenotype. However, an epigenome-wide approach using the Illumina Infinium HM450 bead chip identified a differentially methylated position in the LCT promoter where methylation levels are associated with the genotype at -13910C > T, the persistence/non-persistence phenotype and lactase enzymatic activity. DNA methylation levels at this promoter site and CpGs in the LCT enhancer are associated with genotype. Indeed, taken together they have a higher power to predict lactase phenotypes than the genotype alone. PMID- 29618746 TI - MiRNA-142-3p increases radiosensitivity in human umbilical cord blood mononuclear cells by inhibiting the expression of CD133. AB - This study is to explore the molecular regulation mechanism of CD133 which is associated with malignancy and poor prognosis of blood system diseases. CD133+HUCB-MNC (human umbilical cord blood mononuclear cells) and CD133-HUCB-MNC were isolated and amplificated from umbilical cord blood, and then were exposed to different doses of radiation and subjected to a clonogenic assay. CCK-8 kit was used to detect cell viability, Annexin V-FITC/PI cell apoptosis detection kit was used for the detection of apoptotic cells and the BrdU assay was performed by flow cytometry. The expression of protein was analyzed by western blots. The profile of miRNA expression in response to radiation was examined and validated by RT-PCR. miR-142-3p inhibited the expression of CD133 in umbilical cord blood mononuclear cells to increase radiosensitivity. CD133+HUCB-MNC cells were more radioresistant compared with CD133-HUCB-MNC cells. CD133+HUCB-MNC cells showed higher p-AKT and p-ERK levels after radiation. And miR-142-3p acted on 3'UTR of CD133 mRNA to inhibit CD133 expression. Moreover, miRNA-142-3p mimic increased radiosensitivity in CD133+HUCB-MNC cells. Our results elucidated a novel regulation pathway in hematopoietic stem cells and suggested a potential therapeutic approach for blood system diseases therapy. PMID- 29618747 TI - Arteriovenous blood metabolomics: An efficient method to determine the key metabolic pathway for milk synthesis in the intra-mammary gland. AB - The present study aimed to identify metabolic signature changes of the arteriovenous metabolome and the new metabolites that involved in mammary biological process during milk synthesis. GC/MS-based metabolomics profiling of arteriovenous plasma from 30 lactating dairy cows fed three diets identified a total of 144 metabolites. Phenylalanine and tyrosine, involved in aminoacyl-tRNA biosynthesis and phenylalanine metabolism, were shown higher expression in the artery than in the vein based on both GC/MS and targeted analysis for cows fed both alfalfa hay diet and rice straw diet. Mammary uptake or clearance of citric acid, stearic acid, oleic acid, fructose, beta-mannosylglycerate, 4 hydroxybutyrate, and D-talose were significantly correlated with milk performance or feed intake, indicating that these metabolites might be newly identified precursors or indicators of milk synthesis. This comprehensive assessment of metabolic changes in the arteriovenous metabolome will provide a fundamental understanding of the key metabolites involved in milk synthesis and shows implications of how metabolites from arteriovenous plasma across MG are involved in biological processes or physiological functions for milk synthesis. The newly identified metabolites from the present study provide potential new targeted insights into the study of physiological process for milk synthesis in the MG. PMID- 29618748 TI - Fingolimod therapy is not effective in a mouse model of spontaneous autoimmune peripheral polyneuropathy. AB - Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) is an autoimmune disorder, which causes progressive sensory and motor deficits and often results in severe disability. Knockout of the co-stimulatory protein CD86 in mice of the non-obese diabetic background (NoD.129S4-Cd86 tm1Shr /JbsJ) results in the development of a spontaneous autoimmune peripheral polyneuropathy (SAPP). We used this previously described transgenic model to study the effects of the sphingosine-1-phosphate receptor agonist fingolimod on SAPP symptoms, functional and electrophysiological characteristics. Compared to two control strains, knockout of CD86 in NOD mice (CD86-/- NOD) resulted in progressive paralysis with distinct locomotor deficits due to a severe sensory-motor axonal-demyelinating polyneuropathy as assessed by electrophysiological measurements. We started fingolimod treatment when CD86-/- NOD mice showed signs of unilateral hind limb weakness and continued at a dose of 1 mg/kg/day for eight weeks. We did not observe any beneficial effects of fingolimod regarding disease progression. In addition, fingolimod did not influence the functional outcome of CD86-/- NOD mice compared to vehicle treatment nor any of the electrophysiological characteristics. In summary, we show that fingolimod treatment has no beneficial effects in autoimmune polyneuropathy, which is in line with recent clinical data obtained in CIDP patients. PMID- 29618749 TI - Characterization of Chemosensory Responses on the Labellum of the Malaria Vector Mosquito, Anopheles coluzzii. AB - Anopheles gambiae coluzzii (An. coluzzii) uses olfaction to modulate a range of critical behaviors that are essential for survival and reproduction; most notably, host preference and selection underlie its vectorial capacity for human malaria. As is the case for all mosquitoes, An. coluzzii has three specialized peripheral olfactory appendages-the antennae, maxillary palps and labella-which are used to detect and orient in response to a large variety of olfactory cues. Of these, neither the molecular nor the physiological significance of the labellum have been thoroughly characterized despite suggestions that labial derived odorant reception is critical for close-range host attraction. Here we report global chemoreceptor transcriptome profiles together with a systematic electrophysiological analysis of labial T2 sensilla, and associated behavioral responses of female An. coluzzii. Single sensillum recordings of the T2 sensilla revealed robust responses to odorants previously associated with human sweat and oviposition sites and identified a 10-component blend that elicited attraction in a dual-choice landing bioassay designed to mimic host seeking in which non-blood fed females were significantly more attracted to the labial-responsive odorant blend as compared to gravid females. Taken together, these data suggest that, in An. coluzzii, olfactory responses derived from the labellum contribute to host seeking. PMID- 29618750 TI - Evolution of Sex Determination Loci in Atlantic Salmon. AB - Teleost fish exhibit a remarkable diversity in the control of sex determination, offering the opportunity to identify novel differentiation mechanisms and their ecological consequences. Here, we perform GWAS using 4715 fish and 46,501 SNP to map sex determination to three separate genomic locations in Atlantic salmon (Salmo salar). To characterize each, whole genome sequencing was performed to 30 fold depth of coverage using 20 fish representing each of three identified sex lineages. SNP polymorphism reveals male fish carry a single copy of the male specific region, consistent with an XX/XY or male heterogametric sex system. Haplotype analysis revealed deep divergence between the putatively ancestral locus on chromosome 2, compared with loci on chromosomes 3 and 6. Haplotypes in fish carrying either the chromosome 3 or 6 loci were nearly indistinguishable, indicating a founding event that occurred following the speciation event that defined Salmo salar from other salmonids. These findings highlight the evolutionarily fluid state of sex determination systems in salmonids, and resolve to the sequence level differences in animals with divergent sex lineages. PMID- 29618751 TI - Design of Boron Doped C2N-C3N Coplanar Conjugated Heterostructure for Efficient HER Electrocatalysis. AB - Hydrogen evolution reaction (HER) via the electrocatalytic reduction of water on metal-free catalysts may become a promising method for a sustainable energy supply in the future. However, compared with noble metals or transition metals, the carbon-based metal-free electrocatalysts show poor activity. Here, a novel coplanar metal-free catalyst (C2N-C3N) was designed for the first time to achieve better efficiency for electron transfer and water reduction. Through the DFT calculations, we discovered that the unique coplanar C2N-C3N structure can promote the directional transfer of electrons from C3N to C2N under the drive of built-in electric potential in the pi-conjugated plane. To achieve higher performance in HER, the single atom doping by the substitution of boron is carried out. Remarkably, after the boron is doped, the barrier in the Tafel step decreases from 2.35 eV to 0.86 eV. Our results indicate that the novel B-doped coplanar C2N-C3N structure is a promising metal-free catalyst for HER. PMID- 29618752 TI - IMSindel: An accurate intermediate-size indel detection tool incorporating de novo assembly and gapped global-local alignment with split read analysis. AB - Insertions and deletions (indels) have been implicated in dozens of human diseases through the radical alteration of gene function by short frameshift indels as well as long indels. However, the accurate detection of these indels from next-generation sequencing data is still challenging. This is particularly true for intermediate-size indels (>=50 bp), due to the short DNA sequencing reads. Here, we developed a new method that predicts intermediate-size indels using BWA soft-clipped fragments (unmatched fragments in partially mapped reads) and unmapped reads. We report the performance comparison of our method, GATK, PINDEL and ScanIndel, using whole exome sequencing data from the same samples. False positive and false negative counts were determined through Sanger sequencing of all predicted indels across these four methods. The harmonic mean of the recall and precision, F-measure, was used to measure the performance of each method. Our method achieved the highest F-measure of 0.84 in one sample, compared to 0.56 for GATK, 0.52 for PINDEL and 0.46 for ScanIndel. Similar results were obtained in additional samples, demonstrating that our method was superior to the other methods for detecting intermediate-size indels. We believe that this methodology will contribute to the discovery of intermediate-size indels associated with human disease. PMID- 29618753 TI - Nonlinear inelastic electron scattering from Au nanostructures induced by localized surface plasmon resonance. AB - Nonlinear electron scattering is a recently-discovered physical process observed during the localized plasmonic excitation of Ag nanostructures on graphite surface. In the present work, nonlinear electron scattering phenomena is experimentally verified on Au nanostructures by measuring inelastic scattering of electrons field-emitted from tungsten tip. The relative intensity of the electron energy-loss peak associated with the plasmonic excitation of Au shows again to increase nonlinearly with the electric field generated by the tip-sample bias, demonstrating the generality of nonlinear electron scattering process in plasmonic system. Compared to the nonlinear electron scattering phenomena observed on Ag nanostructures, the nonlinear term for Au nanostructures is about 1 to 2 orders of magnitude smaller, which is in consistent with the field enhancement factor of Au and Ag nanostructures from both the surface-enhanced Raman spectroscopy experiments and the theoretical calculations. PMID- 29618754 TI - Long-term response of forest productivity to climate change is mostly driven by change in tree species composition. AB - Climate change affects ecosystem functioning directly through impacts on plant physiology, resulting in changes of global productivity. However, climate change has also an indirect impact on ecosystems, through changes in the composition and diversity of plant communities. The relative importance of these direct and indirect effects has not been evaluated within a same generic approach yet. Here we took advantage of a novel approach for disentangling these two effects in European temperate forests across a large climatic gradient, through a large simulation-based study using a forest succession model. We first showed that if productivity positively correlates with realized tree species richness under a changed climate, indirect effects appear pivotal to understand the magnitude of climate change impacts on forest productivity. We further detailed how warmer and drier conditions may affect the diversity-productivity relationships (DPRs) of temperate forests in the long term, mostly through effects on species recruitment, ultimately enhancing or preventing complementarity in resource use. Furthermore, losing key species reduced the strength of DPRs more severely in environments that are becoming climatically harsher. By disentangling direct and indirect effects of climate change on ecosystem functioning, these findings explain why high-diversity forests are expected to be more resilient to climate change. PMID- 29618755 TI - Tensile behavior of Cu-coated Pd40Cu30Ni10P20 metallic glassy wire. AB - Catastrophic brittle fracture of monolithic metallic glass (MG) hinders engineering application of MGs. Although many techniques has been tried to enhance tensile ductility of metallic glasses, the enhancement is quite limited. Here, we show the effect of electrodeposited Cu coating on tensile plasticity enhancement of Pd40Cu30Ni10P20 MG wires, with different volume fractions of copper coatings (R), from 0% to 97%. With increasing R, tensile elongation is enhanced to 7.1%. The plasticity enhancement is due to confinement of the Cu coatings, which lead to multiple and secondary shear bands, according to SEM investigations. In addition, the SEM images also show that the patterns on the fracture surface of the Cu-coated MG wires vary with volume fraction of the Cu coatings. The size of shear offset decreases with increasing R. The viscous fingerings on the fracture surface of monolithic MG wire changes into dimples on the fracture surface of Cu coated MG wires with R of 90% and 97%. The electrodeposition technique used in this work provides a useful way to enhance plasticity of monolithic MGs under tensile loading at room temperature. PMID- 29618756 TI - Differences in the accumulation of phosphorus between vegetative cells and heterocysts in the cyanobacterium Nodularia spumigena. AB - The cyanobacterium Nodularia spumigena is a species that frequently forms blooms in the Baltic Sea. Accumulation of the vital nutrient phosphorus (P) apparently plays an important role in the ability of this and other cyanobacteria to grow even when dissolved inorganic phosphorus is depleted. However, until now, this has not been studied in N. spumigena at the cellular level. Therefore, in this study, phosphorus incorporation and distribution in cyanobacterial filaments over time was examined by scanning electron microscopy in combination with energy dispersive X-ray analysis (SEM/EDX) and nanoscale secondary ion mass spectrometry (NanoSIMS). Immediately after phosphate addition to a phosphorus-depleted population, the phosphate concentration decreased in the water while intracellular polyphosphate accumulated. Microscopically, phosphorus in form of polyphosphate granules was stored preferentially in vegetative cells, whereas heterocysts remained low in intracellular phosphorus. This information is an essential step towards understanding the phosphorus dynamics of this species and demonstrates that the division of tasks between vegetative cells and heterocysts is not restricted to nitrogen fixation. PMID- 29618757 TI - Exploring the capabilities of monochromated electron energy loss spectroscopy in the infrared regime. AB - Monochromated electron energy loss spectroscopy (EELS) is one of the leading techniques to study materials properties that correspond to low (<5 eV) energy losses (i.e. band-gaps, plasmons, and excitons) with nanoscale spatial resolution. Recently a new generation of monochromators have become available, opening regimes and unlocking excitations that were previously unobservable in the electron microscope. The capabilities of these new instruments are still being explored, and here we study the effect of monochromation on various aspects of EELS analysis in the infrared (<1 eV) regime. We investigate the effect of varying levels of monochromation on energy resolution, zero-loss peak (ZLP) tail reduction, ZLP tail shape, signal-to-noise-ratio, and spatial resolution. From these experiments, the new capabilities of monochromated EELS are shown to be highly promising for the future of localized spectroscopic analysis. PMID- 29618758 TI - Development and application of new composite grouting material for sealing groundwater inflow and reinforcing wall rock in deep mine. AB - With cement, bentonite, water glass, J85 accelerator, retarder and water as raw materials, a new composite grouting material used to seal groundwater inflow and reinforce wall rock in deep fractured rock mass was developed in this paper. Based on the reaction mechanism of raw material, the pumpable time, stone rate, initial setting time, plastic strength and unconfined compressive strength of multi-group proportion grouts were tested by orthogonal experiment. Then, the optimum proportion of composite grouting material was selected and applied to the grouting engineering for sealing groundwater inflow and reinforcing wall rock in mine shaft lining. The results show the mixing proportion of the maximum pumpable time, maximum stone rate and minimum initial setting time of grout are AK4BK1CK4DK2, AK3BK1CK1DK4 and AK3BK3CK4DK1, respectively. The mixing proportion of the maximum plastic strength and unconfined compressive strength of grouts concretion bodies are AK1BK1CK1DK3 and AK1BK1CK1DK1, respectively. Balanced the above 5 indicators overall and determined the optimum proportion of grouts: bentonite-cement ratio of 1.0, water-solid ratio of 3.5, accelerator content of 2.9% and retarder content of 1.45%. This new composite grouting material had good effect on the grouting engineering for sealing groundwater inflow and reinforcing wall rock in deep fractured rock mass. PMID- 29618759 TI - Soil pH and plant diversity shape soil bacterial community structure in the active layer across the latitudinal gradients in continuous permafrost region of Northeastern China. AB - In the permafrost region of northeastern China, vegetation and soil environment have showed response to permafrost degradation triggered by global warming, but the corresponding variation of the soil microbial communities remains poorly investigated. Here, a field investigation in the continuous permafrost region was conducted to collect 63 soil samples from 21 sites along a latitudinal gradient to assess the distribution pattern of microbial communities and their correlation with environmental factors. High-throughput Illumina sequencing revealed that bacterial communities were dominated by Proteobacteria, Acidobacteria, Bacteroidetes and Actinobacteria. Both microbial richness and phylogenetic diversity decreased initially and then increased as the latitude increased. UniFrac analysis of microbial communities detected significant differences among latitudes. Variation partitioning analysis and structural equation models revealed that environmental variables, including geographic factors, plant community factors and soil physicochemical factors, all played non-negligible roles in affecting the microbial community structures directly or indirectly. Redundancy analysis and boosted regression tree analysis further highlighted the influences of soil pH and plant richness on microbial community compositions and diversity patterns. Taken together, these results suggest that the distribution pattern of soil microbial communities shows distinct changes along the latitudinal gradients in northeastern China and is predominantly mediated by soil pH and plant diversity. PMID- 29618760 TI - Association between optical coherence tomography based retinal microvasculature characteristics and myocardial infarction in young men. AB - Incident myocardial infarction (MI) is a leading cause of adult mortality in the United States. However, because MI has a relatively low incidence in the young population, little information exists on the disease in younger adults. Because the retina has the unique quality that its vasculature is readily and noninvasively visible, the retina is frequently studied to evaluate correlations between vessels and cardiovascular diseases. In the current study, we evaluated the retinal microvasculature of patients who had experienced an MI before 50 years of age (n = 53 subjects) and age- and sex-matched patients who had not experienced an MI (n = 53 patients). We used circular optical coherence tomography (OCT) scans to image peripapillary venules and arterioles. The diameter of each vessel was measured and the respective arterial-venous ratio (AVR) was calculated. We did not detect any significant differences between MI and control subjects in retinal vessel calibre or AVR. PMID- 29618762 TI - Flat-Field Super-Resolution Localization Microscopy with a Low-Cost Refractive Beam-Shaping Element. AB - Super-resolution single-molecule localization microscopy, often referred to as PALM/STORM, works by ensuring that fewer than one fluorophore in a diffraction limited volume is emitting at any one time, allowing the observer to infer that the emitter is located at the center of the point-spread function. This requires careful control over the incident light intensity in order to control the rate at which fluorophores are switched on; if too many fluorophores are activated, their point-spread functions overlap, which impedes efficient localization. If too few are activated, the imaging time is impractically long. There is therefore considerable recent interest in constructing so-called 'top-hat' illumination profiles that provide a uniform illumination over the whole field of view. We present the use of a single commercially-available low-cost refractive beamshaping element that can be retrofitted to almost any existing microscope; the illumination profile created by this element demonstrates a marked improvement in the power efficiency of dSTORM microscopy, as well as a significant reduction in the propensity for reconstruction artifacts, compared to conventional Gaussian illumination. PMID- 29618763 TI - Cancer incidence surrounding the former Apollo nuclear facility 1990-2010. AB - Environmental radiation releases from a nuclear fuel fabrication facility in Apollo, Pennsylvania may have exposed the surrounding population to ionizing radiation. This study characterizes cancer incidence in the population living near the nuclear facility between 1990 and 2010. Cancer incidence in the minor civil divisions surrounding the Apollo facility was compared to a standard population of the state of Pennsylvania adjusted for calendar year, age, sex, and race. Bias due to residential misclassification was considered by adjustment of case count. We also evaluated whether birth cohort effects or changes in population distribution over time affected the standardized incidence rate ratio (SIR). From 1990 to 2010, the observed rate of cancer incidence among males in the Apollo area was 1.56 (95% CI 1.47-1.66) times the expected cancer rate, and among females was 1.38 (95% CI 1.30-1.47) times the expected cancer rate. Accounting for residential misclassification, the SIR for males and females combined was 1.16 (95% CI 1.10-1.21). Residents who were members of earlier birth cohorts had similar SIRs to those born later. This research suggests that cancer incidence among the population surrounding the former Apollo nuclear facility is greater than expected based on statewide rates. PMID- 29618761 TI - QIL1-dependent assembly of MICOS complex-lethal mutation in C19ORF70 resulting in liver disease and severe neurological retardation. AB - Seven subunits of the mitochondrial contact site and cristae junction (CJ) organizing system (MICOS) in humans have been recently described in function and structure. QIL1 (also named MIC13) is a small complex that is crucial for the maintenance and assembling of MICOS. A novel mutation of an essential splice site in the C19orf70 gene encoding QIL1 induces severe mitochondrial encephalopathy, hepatopathy and lactate acidosis consistent with psychomotor retardation. In addition, bilateral kidney stones were observed. Disassembly of MICOS complex subunits displays lack of MIC10-MIC26-MIC27-QIL1 subcomplex, resulting in aberrant cristae structure and a loss of cristae junctions and contact sites. In liver and muscle tissue, the activity of the respiratory chain complexes (OXPHOS) was severely impaired. Defects in MICOS complex do not only affect mitochondrial architecture, but also mitochondrial fusion, metabolic signalling, lipid trafficking and cellular electric homeostasis. PMID- 29618764 TI - Temporal trends and developmental patterns of plasma polybrominated diphenyl ether concentrations over a 15-year period between 1998 and 2013. AB - Polybrominated diphenyl ethers (PBDEs) were used extensively as flame retardants in furniture containing polyurethane foam until they were phased out of use, beginning in 2004. We examined temporal changes in plasma PBDE concentrations from 1998 to 2013 and characterized patterns of exposure over the early lifecourse among 334 children (903 samples) between birth and 9 years. We examined time trends by regressing PBDE concentration on year of sample collection in age-adjusted models and characterized developmental trajectories using latent class growth analysis (LCGA). Controlling for age, BDE-47 concentrations decreased 5% (95% confidence interval (CI): -9, -2) per year between 1998 and 2013. When considering only postnatal samples, this reduction strengthened to 13% (95% CI: -19, -9). Findings for BDE-99, 100 and 153 were similar, except that BDE-153 decreased to a lesser extent when both prenatal and postnatal samples were considered (-2%, 95% CI: -7, 0). These findings suggest that, on average, pentaBDE body burdens have decreased since the 2004 phase-out of these chemicals. When examining developmental period, PBDE concentrations peaked during toddler years for the majority of children, however, our observation of several unique trajectories suggests that a single measure may not accurately reflect exposure to PBDEs throughout early life. PMID- 29618765 TI - Associations between genetic polymorphisms of membrane transporter genes and prognosis after chemotherapy: meta-analysis and finding from Seoul Breast Cancer Study (SEBCS). AB - Membrane transporters can be major determinants of the pharmacokinetic profiles of anticancer drugs. The associations between genetic variations of ATP-binding cassette (ABC) and solute carrier (SLC) genes and cancer survival were investigated through a meta-analysis and an association study in the Seoul Breast Cancer Study (SEBCS). Including the SEBCS, the meta-analysis was conducted among 38 studies of genetic variations of transporters on various cancer survivors. The population of SEBCS consisted of 1338 breast cancer patients who had been treated with adjuvant chemotherapy. A total of 7750 SNPs were selected from 453 ABC and/or SLC genes typed by an Affymetrix 6.0 chip. ABCB1 rs1045642 was associated with poor progression-free survival in a meta-analysis (HR = 1.33, 95% CI: 1.07 1.64). ABCB1, SLC8A1, and SLC12A8 were associated with breast cancer survival in SEBCS (Pgene < 0.05). ABCB1 rs1202172 was differentially associated with survival depending on the chemotherapy (Pinteraction = 0.035). Our finding provides suggestive associations of membrane transporters on cancer survival. PMID- 29618766 TI - Molecular characterization of the first saltwater crocodilepox virus genome sequences from the world's largest living member of the Crocodylia. AB - Crocodilepox virus is a large dsDNA virus belonging to the genus Crocodylidpoxvirus, which infects a wide range of host species in the order Crocodylia worldwide. Here, we present genome sequences for a novel saltwater crocodilepox virus, with two subtypes (SwCRV-1 and -2), isolated from the Australian saltwater crocodile. Affected belly skins of juvenile saltwater crocodiles were used to sequence complete viral genomes, and perform electron microscopic analysis that visualized immature and mature virions. Analysis of the SwCRV genomes showed a high degree of sequence similarity to CRV (84.53% and 83.70%, respectively), with the novel SwCRV-1 and -2 complete genome sequences missing 5 and 6 genes respectively when compared to CRV, but containing 45 and 44 predicted unique genes. Similar to CRV, SwCRV also lacks the genes involved in virulence and host range, however, considering the presence of numerous hypothetical and or unique genes in the SwCRV genomes, it is completely reasonable that the genes encoding these functions are present but not recognized. Phylogenetic analysis suggested a monophyletic relationship between SwCRV and CRV, however, SwCRV is quite distinct from other chordopoxvirus genomes. These are the first SwCRV complete genome sequences isolated from saltwater crocodile skin lesions. PMID- 29618767 TI - Response to Correspondence by Fakhr-Movahedi et al. PMID- 29618768 TI - Correspondence: "Determinants of resilience among people who sustained spinal cord injury from the 2015 earthquake in Nepal". PMID- 29618769 TI - Roquefortine J, a novel roquefortine alkaloid, from the deep-sea-derived fungus Penicillium granulatum MCCC 3A00475. AB - Chemical investigation on the deep-sea-derived fungus Penicillium granulatum MCCC 3A00475 led to the isolation of a previously undescribed (roquefortine J, 1) and four known (2-5) roquefortine alkaloids, along with six ergosterol analogues (6 11). The planar structure of 1 was established mainly on the basis of extensive analysis of its 1D, 2D NMR, and HRESIMS spectra. The absolute configuration of 1 was determined by comparison of the calculated and experimental electronic circular dichroism spectra. Compounds 5, 6, and 7 exhibited potent anti proliferative effects against HepG2 tumor cells with IC50 values of 7.0, 8.6, and 8.2 MUM, respectively. PMID- 29618770 TI - Reclassification of Nocardia species based on whole genome sequence and associated phenotypic data. AB - Type strains of 72 validated Nocardia species were phylogenetically analyzed based on the multilocus sequence analysis (MLSA) concatenated atpD-groL1-groL2 recA-rpoA-secY-sodA-ychF. Furthermore, their similarity based on digital DNA-DNA hybridization (dDDH) was calculated. Nocardia soli, Nocardia cummidelens and Nocardia salmonicida, Nocardia nova and Nocardia elegans, Nocardia exalbida and Nocardia gamkensis, and Nocardia coubleae and Nocardia ignorata formed coherent clades, respectively. Moreover, each set showed over 70% relatedness by dDDH and shared common phenotypic characteristics. Therefore, we propose a reclassification of Nocardia soli and Nocardia cummidelens as a later heterotypic synonym of Nocardia salmonicida, Nocardia elegans as a later heterotypic synonym of Nocardia nova, Nocardia gamkensis as a later heterotypic synonym of Nocardia exalbida, and Nocardia coubleae as a later heterotypic synonym of Nocardia ignorata. PMID- 29618771 TI - Small molecule detection with aptamer based lateral flow assays: Applying aptamer C-reactive protein cross-recognition for ampicillin detection. AB - Aptamer-based lateral flow assays (LFAs) are an emerging field of aptamer applications due to numerous potential applications. When compared to antibodies, potential advantages like cost effectiveness or lower batch to batch variations are evident. The development of LFAs for small molecules, however, is still challenging due to several reasons, primarily linked to target size and accessible interaction sites. In small molecule analysis, however, aptamers in many cases are preferable since immunogenicity is not required and they may exhibit even higher target selectivity. We report the first cross-recognition of a small molecule (ampicillin) and a protein (C-reactive protein), predicted by in silico analysis, then experimentally confirmed - using two different aptamers. These features can be exploited for developing an aptamer-based LFA for label free ampicillin detection, functioning also for analysis in milk extract. Most importantly, the principal setup denotes a novel, transferable and versatile general approach for detection of small molecules using competitive LFAs, unlikely to be generally realized by aptamer-DNA-binding otherwise. PMID- 29618772 TI - Phosphorous fertilization alleviates drought effects on Alnus cremastogyne by regulating its antioxidant and osmotic potential. AB - Alnus cremastogyne, a broad-leaved tree endemic to south-western China, has both commercial and restoration importance. However, little is known of its morphological, physiological and biochemical responses to drought and phosphorous (P) application. A randomized experimental design was used to investigate how drought affected A. cremastogyne seedlings, and the role that P applications play in these responses. Drought had significant negative effects on A. cremastogyne growth and metabolism, as revealed by reduced biomass (leaf, shoot and root), leaf area, stem diameter, plant height, photosynthetic rate, leaf relative water content, and photosynthetic pigments, and a weakened antioxidative defence mechanism and high lipid peroxidation level. However, the reduced leaf area and enhanced osmolyte (proline and soluble sugars) accumulation suggests drought avoidance and tolerance strategies in this tree. Applying P significantly improved the leaf relative water content and photosynthetic rate of drought stressed seedlings, which may reflect increased anti-oxidative enzyme (superoxide dismutase, catalase and peroxidase) activities, osmolyte accumulation, soluble proteins, and decreased lipid peroxidation levels. However, P had only a slight or negligible effect on the well-watered plants. A. cremastogyne is sensitive to drought stress, but P facilitates and improves its metabolism primarily via biochemical and physiological rather than morphological adjustments, regardless of water availability. PMID- 29618773 TI - Anti-inflammatory effects in a mouse osteoarthritis model of a mixture of glucosamine and chitooligosaccharides produced by bi-enzyme single-step hydrolysis. AB - We developed a novel technique of bi-enzyme single-step hydrolysis, using recombinant chitosanase (McChoA) and exo-beta-D-glucosaminidase (AorCsxA) constructed previously in our lab, to degrade chitosan. The hydrolysis product was shown by HPLC, FTIR, and chemical analyses to be a mixture (termed "GC") composed primarily of glucosamine (80.00%) and chitooligosaccharides (9.80%). We performed experiments with a mouse osteoarthritis (OA) model to evaluate the anti inflammatory effects of GC against OA. The three "GC groups" (which underwent knee joint damage followed by oral administration of GC at concentrations 40, 80, and 160 mg/kg.bw.d for 15 days) showed significantly downregulated serum expression of pre-inflammatory cytokines (IL-1beta, IL-6, TNF-alpha), and significant, dose-dependent enhancement of anti-inflammatory cytokine IL-2, in comparison with Model group. Levels of C-reactive protein, which typically rise in response to inflammatory processes, were significantly lower in the GC groups than in Model group. Thymus index and levels of immunoglobulins (IgG, IgA, IgM) were higher in the GC groups. Knee joint swelling was relieved and typical OA symptoms were partially ameliorated in the GC-treated groups. Our findings indicate that GC has strong anti-inflammatory effects and potential as a therapeutic agent against OA and other inflammatory diseases. PMID- 29618774 TI - Novel Approach for Enhanced Scandium and Titanium Leaching Efficiency from Bauxite Residue with Suppressed Silica Gel Formation. AB - The need of light weight alloys for future transportation industry puts Sc and Ti under a sudden demand. While these metals can bring unique and desired properties to alloys, lack of reliable sources brought forth a supply problem which can be solved by valorization of the secondary resources. Bauxite residue (red mud), with considerable Ti and Sc content, is a promising resource for secure supply of these metals. Due to drawbacks of the direct leaching route from bauxite residue, such as silica gel formation and low selectivity towards these valuable metals, a novel leaching process based on oxidative leaching conditions, aiming more efficient and selective leaching but also considering environmental aspects via lower acid consumption, was investigated in this study. Combination of hydrogen peroxide (H2O2) and sulfuric acid (H2SO4) was utilized as the leaching solution, where various acid concentrations, solid-to-liquid ratios, leaching temperatures and times were examined in a comparative manner. Leaching with 2.5 M H2O2: 2.5 M H2SO4 mixture at 90 degrees C for 30 min was observed to be the best leaching conditions with suppressed silica gel formation and the highest reported leaching efficiency with high S/L ratio for Sc and Ti; 68% and 91%; respectively. PMID- 29618775 TI - In vivo study of non-invasive effects of non-thermal plasma in pressure ulcer treatment. AB - According to high incidence and prevalence of pressure ulcers worldwide, the purpose of this study is using of non-thermal atmospheric plasma as a novel therapy for pressure ulcers. Cold plasma was produced by applying a high-voltage (5 kV) and high-frequency (25 kHz), to helium gas. Under general anesthesia and sterile conditions, two circular magnets were used to create pressure ulcers on the dorsal skin of adult rats. The wounds were divided randomly into control and plasma-treated groups. Animals in the plasma-treated group received plasma radiation for 5 days, each day 3 times and every time 60 s. Mechanical assays were performed to determine plasma effects on the mechanical strength of the repaired tissue. The results showed that mechanical strength of repaired wound in the plasma-treated group was significantly higher than that in the control group (p < 0.05). In addition, evidence from histological studies indicates a significantly accelerated wound re-epithelialization in comparison with the control group; angiogenesis and fibrosis (collagen synthesis) were also significantly increased and the inflammation phase of wound healing was shorter in the plasma-treated group. The plasma treatment also resulted in significant wound contraction and acceleration of wound healing. The findings of present study indicate the effects of cold plasma on pressure ulcer treatment. PMID- 29618776 TI - Chronic toxicity of amitraz, coumaphos and fluvalinate to Apis mellifera L. larvae reared in vitro. AB - The effects of chronic exposure to common acaricides on Apis mellifera survival, developmental rate and larval weight were tested in the laboratory. Larvae were reared in vitro and fed a diet containing amitraz: 1.5, 11, 25 and 46 mg/L; coumaphos: 1.8, 6, 8 and 25 mg/L; or fluvalinate: 0.1, 1, 2.4 and 6 mg/L. The dependent variables were compared for groups feeding on treated diets and control diets: positive control, 45 mg/L dimethoate; solvent control; and negative control. Bee survival decreased in the 46 mg/L amitraz and 25 mg/L coumaphos treatments but not in any fluvalinate treatment. Furthermore, the developmental rate decreased in individuals treated with 46 mg/L amitraz. In our study, larvae exposed to acaricides at concentrations similar to maximum residue in pollen and honey/nectar had no detectable change in survival or developmental rate. Given that pollen and honey/nectar represent only a small part of larval diet, we suggest that residues of amitraz, coumaphos and fluvalinate at the levels we tested are unlikely to impact immature worker bee survival in the field, though our data do not preclude any sublethal effects that may result from bee exposure to these compounds or possible synergisms when they co-occur in bee colonies. PMID- 29618777 TI - Three macrophage subsets are identified in the uterus during early human pregnancy. AB - Macrophages are crucial for a successful pregnancy, and malfunctions of decidual macrophages correlate with adverse pregnancy outcomes, such as spontaneous abortion and preeclampsia. Previously, decidual macrophages were often thought to be a single population. In the present study, we identified three decidual macrophage subsets, CCR2-CD11cLO (CD11clow, ~80%), CCR2-CD11cHI (CD11chigh, ~5%), and CCR2+CD11cHI (CD11chigh, 10-15%), during the first trimester of human pregnancy by flow cytometry analysis. CCR2-CD11cLO macrophages are widely distributed in the decidua, while CCR2-CD11cHI and CCR2+CD11cHI macrophages are primarily detected close to extravillous trophoblast cells according to immunofluorescence staining. According to RNA sequencing bioinformatics analysis and in vitro functional studies, these three subsets of macrophages have different phagocytic capacities. CCR2+CD11cHI macrophages have pro-inflammatory characteristics, while the CCR2-CD11cHI population is suggested to be anti oxidative and anti-inflammatory due to its high expression of critical heme metabolism-related genes, suggesting that these two subsets of macrophages maintain an inflammatory balance at the leading edge of trophoblast invasion to facilitate the clearance of pathogen infection as well as maintain the homeostasis of the maternal-fetal interface. The present study physiologically identifies three decidual macrophage subsets. Further clarification of the functions of these subsets will improve our understanding of maternal-fetal crosstalk in the maintenance of a healthy pregnancy. PMID- 29618778 TI - Dynamic interaction of local and transhemispheric networks is necessary for progressive intensification of hippocampal seizures. AB - The detailed mechanisms of progressive intensification of seizures often occurring in epilepsy are not well understood. Animal models of kindling, with progressive intensification of stimulation-induced seizures, have been previously used to investigate alterations in neuronal networks, but has been obscured by limited recording capabilities during electrical stimulations. Remote networks in kindling have been studied by physical deletions of the connected structures or pathways, inevitably leading to structural reorganisations and related adverse effects. We used optogenetics to circumvent the above-mentioned problems inherent to electrical kindling, and chemogenetics to temporarily inhibit rather than ablate the remote interconnected networks. Progressively intensifying afterdischarges (ADs) were induced by repetitive photoactivation of principal neurons in the hippocampus of anaesthetized transgenic mice expressing ChR2. This allowed, during the stimulation, to reveal dynamic increases in local field potentials (LFPs), which coincided with the start of AD intensification. Furthermore, chemogenetic functional inhibition of contralateral hippocampal neurons via hM4D(Gi) receptors abrogated AD progression. These findings demonstrate that, during repeated activation, local circuits undergo acute plastic changes with appearance of additional network discharges (LFPs), leading to transhemispheric recruitment of contralateral dentate gyrus, which seems to be necessary for progressive intensification of ADs. PMID- 29618779 TI - Circatrigintan instead of lunar periodicity of larval release in a brooding coral species. AB - Larval release by brooding corals is often assumed to display lunar periodicity. Here, we show that larval release of individual Stylophora pistillata colonies does not comply with the assumed tight entrainment by the lunar cycle, and can better be classified as a circatrigintan pattern. The colonies exhibited three distinct reproductive patterns, characterized by short intervals, long intervals and no periodicity between reproductive peaks, respectively. Cross correlation between the lunar cycle and larval release of the periodic colonies revealed an approximately 30-day periodicity with a variable lag of 5 to 10 days after full moon. The observed variability indicates that the lunar cycle does not provide a strict zeitgeber. Other factors such as water temperature and solar radiation did not correlate significantly with the larval release. The circatrigintan patterns displayed by S. pistillata supports the plasticity of corals and sheds new light on discussions on the fecundity of brooding coral species. PMID- 29618780 TI - Risk Factors for Avian Influenza H9 Infection of Chickens in Live Bird Retail Stalls of Lahore District, Pakistan 2009-2010. AB - This study was conducted to identify risk factors associated with AIV infections in live bird retail stalls (LBRS) in Lahore District, Pakistan. A cross-sectional survey of LBRS was conducted from December 2009-February 2010 using two-stage cluster sampling based on probability proportional to size. A total of 280 oropharyngeal swab sample pools were collected from 1400 birds in 8 clusters and tested by qRT-PCR for the matrix (M) gene of type A influenza virus and HA gene subtypes H9, H5 and H7. Thirty-four (34) samples were positive for the M gene, of which 28 were also positive for H9. No sample was found positive for H5 or H7. Data for 36 potential risk factors, collected by questionnaire, were analyzed by survey-weighted logistic regression and prevalence odds ratios (OR) for associated risk factors were calculated. A final multivariable model identified three risk factors for H9 infection in LRBS, namely obtaining birds from mixed sources (OR 2.28, CI95%: 1.4-3.7), keeping birds outside cages (OR 3.10, CI95%: 1.4-7.0) and keeping chicken breeds other than broilers (OR 6.27, CI95%: 1.7 23.2). Sourcing birds from dealers/wholesalers, keeping birds inside cages and avoiding mixing different breeds in cages could reduce the risk of H9 infections in LRBS. PMID- 29618781 TI - Recycling Waste Soot from Merchant Ships to Produce Anode Materials for Rechargeable Lithium-Ion Batteries. AB - In this study, the waste soot generated by ships was recycled to produce an active material for use in lithium-ion batteries (LIBs). Soot collected from a ship was graphitized by a heat treatment process and used as an anode active material. It was confirmed that the graphitized soot was converted into a highly crystalline graphite, and was found to form carbon nano-onions with an average diameter of 70 nm. The graphitized soot showed a high discharge capacity and an excellent cycle life, with a reversible capacity of 260 mAhg-1 even after 150 cycles at a rate of 1 C. This study demonstrates that the annealed soot with a unique graphitic multilayer structure has an electrochemical performance that renders it suitable as a candidate for the production of low-cost anode materials for use in LIBs. PMID- 29618782 TI - ETV2-TET1/TET2 Complexes Induce Endothelial Cell-Specific Robo4 Expression via Promoter Demethylation. AB - Although transcription factors regulating endothelial cell (EC)-specific gene expression have been identified, it is not known how those factors induce EC specificity. We previously reported that DNA hypomethylation of the proximal promoter elicits EC-specific expression of Roundabout4 (Robo4). However, the mechanisms establishing EC-specific hypomethylation of the Robo4 promoter remain unknown. In this study, we demonstrated that the hypermethylated Robo4 proximal promoter is demethylated as human iPS cells differentiate into endothelial cells. Reporter assays demonstrated that ETV2, an ETS family transcription factor, bound to ETS motifs in the proximal promoter and activated Robo4 expression. Immunoprecipitation demonstrated direct interaction between ETV2 and methylcytosine-converting enzymes TET1 and TET2. Adenoviral expression of ETV2 TET1/TET2 complexes demethylated the Robo4 promoter and induced Robo4 expression in non-ECs. In summary, we propose a novel regulatory model of EC-specific gene expression via promoter demethylation induced by ETV2-TET1/TET2 complexes during endothelial differentiation. PMID- 29618783 TI - Microwave index engineering for slow-wave coplanar waveguides. AB - Microwave index engineering has been investigated in order to properly design slow-wave coplanar waveguides suitable for a wide range of applications in microwave, photonics, plasmonics and metamaterials. The introduction and optimization of novel capacitive and inductive elements is proposed as a design approach to increase the microwave index while keeping the impedance close to 50 Omega to ensure the compatibility with external electronic devices. The contribution of inductive and capacitive elements and their influence on the performance of the slow-wave coplanar waveguide has been systematically analyzed. As a result, a microwave index as high as 11.6 has been experimentally demonstrated in a frequency range up to 40 GHz which is, to the best of our knowledge, the largest microwave index obtained so far in coplanar waveguides. PMID- 29618785 TI - Tunable Ampere phase plate for low dose imaging of biomolecular complexes. AB - A novel device that can be used as a tunable support-free phase plate for transmission electron microscopy of weakly scattering specimens is described. The device relies on the generation of a controlled phase shift by the magnetic field of a segment of current-carrying wire that is oriented parallel or antiparallel to the electron beam. The validity of the concept is established using both experimental electron holographic measurements and a theoretical model based on Ampere's law. Computer simulations are used to illustrate the resulting contrast enhancement for studies of biological cells and macromolecules. PMID- 29618784 TI - NRF2 regulates the glutamine transporter Slc38a3 (SNAT3) in kidney in response to metabolic acidosis. AB - Expression of the glutamine transporter SNAT3 increases in kidney during metabolic acidosis, suggesting a role during ammoniagenesis. Microarray analysis of Nrf2 knock-out (KO) mouse kidney identified Snat3 as the most significantly down-regulated transcript compared to wild-type (WT). We hypothesized that in the absence of NRF2 the kidney would be unable to induce SNAT3 under conditions of metabolic acidosis and therefore reduce the availability of glutamine for ammoniagenesis. Metabolic acidosis was induced for 7 days in WT and Nrf2 KO mice. Nrf2 KO mice failed to induce Snat3 mRNA and protein expression during metabolic acidosis. However, there were no differences in blood pH, bicarbonate, pCO2, chloride and calcium or urinary pH, ammonium and phosphate levels. Normal induction of ammoniagenic enzymes was observed whereas several amino acid transporters showed differential regulation. Moreover, Nrf2 KO mice during acidosis showed increased expression of renal markers of oxidative stress and injury and NRF2 activity was increased during metabolic acidosis in WT kidney. We conclude that NRF2 is required to adapt the levels of SNAT3 in response to metabolic acidosis. In the absence of NRF2 and SNAT3, the kidney does not have any major acid handling defect; however, increased oxidative stress and renal injury may occur. PMID- 29618786 TI - Toxigenic effects of two benthic diatoms upon grazing activity of the sea urchin: morphological, metabolomic and de novo transcriptomic analysis. AB - Diatoms are unicellular algae playing a key role as photosynthetic organisms in the world's ocean food webs. The chemical ecology of planktonic diatoms is well documented, but few studies have reported on the effects of benthic diatoms on their consumers, also due to difficulties in the collection, quantification and massive culturing of benthic species. Here for the first time we investigate the effects of feeding on two abundantly occurring benthic diatoms, Nanofrustulum shiloi and Cylindrotheca closterium, isolated from the leaves of the seagrass Posidonia oceanica, on the sea urchin Paracentrotus lividus. Adult P. lividus were fed for one month on diets of either one of the two diatoms and on the green alga Ulva rigida, used as a feeding control. By combining morphological, metabolomic and de novo transcriptomic approaches, we demonstrate toxigenic effect on embryos generated by females fed with these benthic diatoms. Furthermore, chemical analysis reveal the presence of polyunsaturated aldehydes only for N. shiloi, and a high production of other oxylipins (cytotoxic compounds on their grazers and on cancer cell lines) for both diatoms, including some additional peaks not correlated to the canonic oxylipins commonly observed in planktonic diatoms. These findings open new perspectives in the study of diatom secondary metabolites influencing their grazers. PMID- 29618787 TI - Prognostic value of serum vascular endothelial growth factor and hematological responses in patients with newly-diagnosed POEMS syndrome. PMID- 29618788 TI - DNMT3AR882-associated hypomethylation patterns are maintained in primary AML xenografts, but not in the DNMT3AR882C OCI-AML3 leukemia cell line. PMID- 29618789 TI - Altered DNA repair; an early pathogenic pathway in Alzheimer's disease and obesity. AB - Unrepaired DNA double-strand breaks (DSBs) are lethal. The present study compared the extent of DSBs, neuronal apoptosis, and status of two major DSB repair pathways - homologous combinational repair (HR) and nonhomologous end-joining (NHEJ) - in hippocampus of 5-6 month and 16-18 month-old wild-type and APP/PSEN1 mice fed control diet or high fat diet (60% fat from lard). We performed immunohistochemical staining and quantification for nuclear foci formation of gamma-H2AX for DSBs, RAD51, and 53BP1, which represent the functional status of HR and NHEJ, respectively. Increased gamma-H2AX and caspase-3 staining indicated greater DSBs and associated neuronal apoptosis in APP/PSEN1 mice at both ages studied. RAD51-positive foci were fewer in APP/PSEN1 indicating that HR processes may be diminished in these mice, although NHEJ (53BP1 staining) appeared unchanged. High fat diet in young wild-type mice led to similar changes to those observed in APP/PSEN1 mice (gamma-H2AX and caspase-3 staining, and fewer RAD51 positive foci). Overall, these data suggest that APP/PSEN1- and high fat diet associated early accumulation of DSBs and neuronal cell death, resulted at least in part, from inhibition of HR, one of the major DSB repair pathways. PMID- 29618790 TI - Identification of individual subjects on the basis of their brain anatomical features. AB - We examined whether it is possible to identify individual subjects on the basis of brain anatomical features. For this, we analyzed a dataset comprising 191 subjects who were scanned three times over a period of two years. Based on FreeSurfer routines, we generated three datasets covering 148 anatomical regions (cortical thickness, area, volume). These three datasets were also combined to a dataset containing all of these three measures. In addition, we used a dataset comprising 11 composite anatomical measures for which we used larger brain regions (11LBR). These datasets were subjected to a linear discriminant analysis (LDA) and a weighted K-nearest neighbors approach (WKNN) to identify single subjects. For this, we randomly chose a data subset (training set) with which we calculated the individual identification. The obtained results were applied to the remaining sample (test data). In general, we obtained excellent identification results (reasonably good results were obtained for 11LBR using WKNN). Using different data manipulation techniques (adding white Gaussian noise to the test data and changing sample sizes) still revealed very good identification results, particularly for the LDA technique. Interestingly, using the small 11LBR dataset also revealed very good results indicating that the human brain is highly individual. PMID- 29618793 TI - In-situ Cutting of Graphene into Short Nanoribbons with Applications to Ni-Zn Batteries. AB - Rechargeable Ni-Zn batteries, with high safety, low cost and nontoxicity, can be expected to compete with lithium-ion batteries for market share. However, the issue of dissolution of zinc electrode largely limit the battery cycle life and remains unsolved. We designed a kind of graphene-ZnO hybrid electrode in which in situ cutting of graphene into short nanoribbons can effectively anchor plenty of zinc atoms onto the surface of graphene. This not only thoroughly fixes the issue of dissolution of zinc electrode but also increases the specific surface areas of zinc and promotes chemical reaction rate of the charge-discharge processes. By performing experimental measurements, we found that the discharge capacity of the new designed Ni-Zn batteries can be as high as 2603 mAh/gZno, and the superior electrochemical performance can be kept in 10,000 test cycles, suggesting that the new developed in-situ cutting technique is very useful in electrochemical fields. PMID- 29618792 TI - Subcutaneous Ehrlich Ascites Carcinoma mice model for studying cancer-induced cardiomyopathy. AB - Cardiomyopathy is one of the characteristic features of cancer. In this study, we establish a suitable model to study breast cancer-induced cardiomyopathy in mice. We used Ehrlich Ascites Carcinoma cells to induce subcutaneous tumor in 129/SvJ mice and studied its effect on heart function. In Ehrlich Ascites Carcinoma bearing mice, we found significant reduction in left ventricle wall thickness, ejection fraction, and fractional shortening increase in left ventricle internal diameter. We found higher muscle atrophy, degeneration, fibrosis, expression of cell-adhesion molecules and cell death in tumor-bearing mice hearts. As observed in cancer patients, we found that mTOR, a key signalling molecule responsible for maintaining cell growth and autophagy was suppressed in this model. Tumor bearing mice hearts show increased expression and nuclear localization of TFEB and FoxO3a transcription factors, which are involved in the upregulation of muscle atrophy genes, lysosomal biogenesis genes and autophagy genes. We propose that Ehrlich Ascites Carcinoma induced tumor can be used as a model to identify potential therapeutic targets for the treatment of heart failure in patients suffering from cancer-induced cardiomyopathy. This model can also be used to test the adverse consequences of cancer chemotherapy in heart. PMID- 29618791 TI - Multimodal imaging including semiquantitative short-wavelength and near-infrared autofluorescence in achromatopsia. AB - Multimodal imaging provides insights into phenotype and disease progression in inherited retinal disorders. Congenital achromatopsia (ACHM), a cone dysfunction syndrome, has been long considered a stable condition, but recent evidence suggests structural progression. With gene replacement strategies under development for ACHM, there is a critical need for imaging biomarkers to define progression patterns and follow therapy. Using semiquantitative plots, near infrared (NIR-AF) and short-wavelength autofluorescence (SW-AF) were explored and correlated with clinical characteristics and retinal structure on optical coherence tomography (OCT). In sixteen ACHM patients with genetic confirmation (CNGA3, n = 8; CNGB3, n = 7; PDE6C, n = 1), semiquantitative plots allowed the detailed analysis of autofluorescence patterns, even in poorly fixating eyes. Twelve eyes showed perifoveal hyperautofluorescent rings on SW-AF, and 7 eyes had central hypoautofluorescent areas on NIR-AF, without association between these alterations (P = 0.57). Patients with central NIR-AF hypoautofluorescence were older (P = 0.004) and showed more advanced retinal alterations on OCT than those with normal NIR-AF (P = 0.051). NIR-AF hypoautofluorescence diameter was correlated to patient age (r = 0.63, P = 0.009), size of ellipsoid zone defect on OCT (r = 0.67, P = 0.005), but not to the size of SW-AF hyperautofluorescence (P = 0.27). These results demonstrate the interest of NIR-AF as imaging biomarker in ACHM, suggesting a relationship with age and disease progression. PMID- 29618794 TI - Pupillary Abnormalities with Varying Severity of Diabetic Retinopathy. AB - Our aim is to study the dynamics of pupillary abnormalities in varying severity of diabetic retinopathy. A non-interventional case-control study with 405 eyes of 244 subjects with diabetes, and 41 eyes of 26 subjects with no history of diabetes was done. Diabetes group was classified according to retinopathy severity: no retinopathy, mild non-proliferative diabetic retinopathy (NPDR), moderate NPDR, severe NPDR and proliferative diabetic retinopathy (PDR). After dark adaptation, pupil size and flashlight response were captured with an infrared camera. Baseline Pupil Diameter (BPD), Amplitude of Pupillary Constriction (APC), Velocity of Pupillary Constriction (VPC) and Velocity of Pupillary Dilatation (VPD). Compared to controls, mean BPD decreased with increasing severity of diabetic retinopathy. Mean APC in control group was 1.73 +/- 0.37 mm and reduced in mild NPDR (1.57 +/- 0.39, p = 1.000), moderate NPDR (1.51 +/- 0.44, p = 0.152) and found to be significant reduced in severe NPDR (1.43 +/- 0.48, p = 0.001) and PDR (1.29 +/- 0.43, p = 0.008). Compared to controls, mean VPC decreased progressively with increasing severity of retinopathy, with a maximal difference in the PDR group. Mean VPD as compared to the control group was significantly reduced in the no DR (p = 0.03), mild NPDR (p = 0.038), moderate NPDR (p = 0.05), PDR group (p = 0.02). We found pupillary dynamics are abnormal in early stages of diabetic retinopathy and progress with increasing retinopathy severity. PMID- 29618795 TI - Dynamic changes in Japan's prevalence of abnormal findings in cervical cervical cytology depending on birth year. AB - Japan's governmental recommendation of HPV vaccine has now been suspended for more than 4 years. In and before 2013, the targets of 20-year-old cervical cancer screening were females born in and before 1993, i.e., those who could not have received HPV vaccination because it was not yet publicly introduced. The targets during 2014-2019 are, or will be, those born in 1994-1999, i.e., those who came of age during a period with the highest HPV immunization rate. We analyzed the statistical data for each birth year, for the cumulative HPV vaccination rates achieved as of age 16, and for the corresponding results of cervical cancer screening at age 20. The rate of abnormal findings in cervical cytology increased slightly from 3.68% in 2010 (birth year: 1990) to 4.35% in 2013 (birth year: 1993); however, it dynamically dropped to 2.99% in 2014 (birth year: 1994) and 3.03% in 2015 (birth year: 1995). In total, the rate of abnormal findings in cervical cytology was 3.96% in 2010-2013, but significantly dropped to 3.01% in 2014-2015 (p = 0.014). This is the first description of dynamic changes occurring in the abnormal rate of cervical cancer screening as a result of positive changes in national HPV vaccination rates. PMID- 29618796 TI - Prognostic value of cancer antigen -125 for lung adenocarcinoma patients with brain metastasis: A random survival forest prognostic model. AB - Using random survival forest, this study was intended to evaluate the prognostic value of serum markers for lung adenocarcinoma patients with brain metastasis (BM), and tried to integrate them into a prognostic model. During 2010 to 2015, the patients were retrieved from two medical centers. Besides the Cox proportional hazards regression, the random survival forest (RSF) were also used to develop prognostic model from the group A (n = 142). In RSF of the group A, the factors, whose minimal depth were greater than the depth threshold or had a negative variable importance (VIMP), were firstly excluded. Subsequently, C-index and Akaike information criterion (AIC) were used to guide us finding models with higher prognostic ability and lower overfitting possibility. These RSF models, together with the Cox, modified-RPA and lung-GPA index were validated and compared, especially in the group B (CAMS, n = 53). Our data indicated that the KSE125 model (KPS, smoking, EGFR-20 (exon 18, 19 and 21) and Ca125) was the best in survival prediction, and performed well in internal and external validation. In conclusions, for lung adenocarcinoma patients with brain metastasis, a validated prognostic nomogram (KPS, smoking, EGFR-20 and Ca125) can more accurately predict 1-year and 2-year survival of the patients. PMID- 29618797 TI - Development of a characterised tool kit for the interrogation of NLRP3 inflammasome-dependent responses. AB - Inflammation is an established contributor to disease and the NLRP3 inflammasome is emerging as a potential therapeutic target. A number of small molecule inhibitors of the NLRP3 pathway have been described. Here we analysed the most promising of these inhibitor classes side by side to assess relative potency and selectivity for their respective putative targets. Assessed using ASC inflammasome-speck formation, and release of IL-1beta, in both human monocyte/macrophage THP1 cells and in primary mouse microglia, we compared the relative potency and selectivity of P2X7 inhibitors, inflammasome inhibitors (diarylsulfonylurea vs. the NBC series), and caspase-1 inhibitors. In doing so we are now able to provide a well characterised small molecule tool kit for interrogating and validating inflammasome-dependent responses with a range of nanomolar potency inhibitors against established points in the inflammasome pathway. PMID- 29618799 TI - S-Nitrosoglutathione Reductase Underlies the Dysfunctional Relaxation to Nitric Oxide in Preterm Labor. AB - Tocolytics show limited efficacy to prevent preterm delivery. In uterine smooth muscle cGMP accumulation following addition of nitric oxide (NO) has little effect on relaxation suggesting a role for protein S-nitrosation. In human myometrial tissues from women in labor at term (TL), or spontaneously in labor preterm (sPTL), direct stimulation of soluble guanylyl cyclase (sGC) fails to relax myometrium, while the same treatment relaxes vascular smooth muscle completely. Unlike term myometrium, effects of NO are not only blunted in sPTL, but global protein S-nitrosation is also diminished, suggesting a dysfunctional response to NO-mediated protein S-nitrosation. Examination of the enzymatic regulator of endogenous S-nitrosoglutathione availability, S-nitrosoglutathione reductase, reveals increased expression of the reductase in preterm myometrium associated with decreased total protein S-nitrosation. Blockade of S nitrosoglutathione reductase relaxes sPTL tissue. Addition of NO donor to the actin motility assay attenuates force. Failure of sGC activation to mediate relaxation in sPTL tissues, together with the ability of NO to relax TL, but not sPTL myometrium, suggests a unique pathway for NO-mediated relaxation in myometrium. Our results suggest that examining the action of S-nitrosation on critical contraction associated proteins central to the regulation of uterine smooth muscle contraction can reveal new tocolytic targets. PMID- 29618800 TI - A Rapid CRISPR/Cas-based Mutagenesis Assay in Zebrafish for Identification of Genes Involved in Thyroid Morphogenesis and Function. AB - The foregut endoderm gives rise to several organs including liver, pancreas, lung and thyroid with important roles in human physiology. Understanding which genes and signalling pathways regulate their development is crucial for understanding developmental disorders as well as diseases in adulthood. We exploited unique advantages of the zebrafish model to develop a rapid and scalable CRISPR/Cas based mutagenesis strategy aiming at the identification of genes involved in morphogenesis and function of the thyroid. Core elements of the mutagenesis assay comprise bi-allelic gene invalidation in somatic mutants, a non-invasive monitoring of thyroid development in live transgenic fish, complementary analyses of thyroid function in fixed specimens and quantitative analyses of mutagenesis efficiency by Illumina sequencing of individual fish. We successfully validated our mutagenesis-phenotyping strategy in experiments targeting genes with known functions in early thyroid morphogenesis (pax2a, nkx2.4b) and thyroid functional differentiation (duox, duoxa, tshr). We also demonstrate that duox and duoxa crispants phenocopy thyroid phenotypes previously observed in human patients with bi-allelic DUOX2 and DUOXA2 mutations. The proposed combination of efficient mutagenesis protocols, rapid non-invasive phenotyping and sensitive genotyping holds great potential to systematically characterize the function of larger candidate gene panels during thyroid development and is applicable to other organs and tissues. PMID- 29618798 TI - Differential expression of microRNAs and other small RNAs in muscle tissue of patients with ALS and healthy age-matched controls. AB - Amyotrophic lateral sclerosis is a late-onset disorder primarily affecting motor neurons and leading to progressive and lethal skeletal muscle atrophy. Small RNAs, including microRNAs (miRNAs), can serve as important regulators of gene expression and can act both globally and in a tissue-/cell-type-specific manner. In muscle, miRNAs called myomiRs govern important processes and are deregulated in various disorders. Several myomiRs have shown promise for therapeutic use in cellular and animal models of ALS; however, the exact miRNA species differentially expressed in muscle tissue of ALS patients remain unknown. Following small RNA-Seq, we compared the expression of small RNAs in muscle tissue of ALS patients and healthy age-matched controls. The identified snoRNAs, mtRNAs and other small RNAs provide possible molecular links between insulin signaling and ALS. Furthermore, the identified miRNAs are predicted to target proteins that are involved in both normal processes and various muscle disorders and indicate muscle tissue is undergoing active reinnervation/compensatory attempts thus providing targets for further research and therapy development in ALS. PMID- 29618801 TI - Respiration and the watershed of spinal CSF flow in humans. AB - The dynamics of human CSF in brain and upper spinal canal are regulated by inspiration and connected to the venous system through associated pressure changes. Upward CSF flow into the head during inspiration counterbalances venous flow out of the brain. Here, we investigated CSF motion along the spinal canal by real-time phase-contrast flow MRI at high spatial and temporal resolution. Results reveal a watershed of spinal CSF dynamics which divides flow behavior at about the level of the heart. While forced inspiration prompts upward surge of CSF flow volumes in the entire spinal canal, ensuing expiration leads to pronounced downward CSF flow, but only in the lower canal. The resulting pattern of net flow volumes during forced respiration yields upward CSF motion in the upper and downward flow in the lower spinal canal. These observations most likely reflect closely coupled CSF and venous systems as both large caval veins and their anastomosing vertebral plexus react to respiration-induced pressure changes. PMID- 29618802 TI - Integrative analysis of Multiple Sclerosis using a systems biology approach. AB - Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by inflammatory-demyelinating events in the central nervous system. Despite more than 40 years of MS research its aetiology remains unknown. This study aims to identify the most frequently reported and consistently regulated molecules in MS in order to generate molecular interaction networks and thereby leading to the identification of deregulated processes and pathways which could give an insight of the underlying molecular mechanisms of MS. Driven by an integrative systems biology approach, gene-expression profiling datasets were combined and stratified into "Non-treated" and "Treated" groups and additionally compared to other disease patterns. Molecular identifiers from dataset comparisons were matched to our Multiple Sclerosis database (MuScle; www.padb.org/muscle ). From 5079 statistically significant molecules, correlation analysis within groups identified a panel of 16 high-confidence genes unique to the naive MS phenotype, whereas the "Treated" group reflected a common pattern associated with autoimmune disease. Pathway and gene-ontology clustering identified the Interferon gamma signalling pathway as the most relevant amongst all significant molecules, and viral infections as the most likely cause of all down-stream events observed. This hypothesis-free approach revealed the most significant molecular events amongst different MS phenotypes which can be used for further detailed studies. PMID- 29618803 TI - Neurogenesis: News of no new neurons? PMID- 29618804 TI - Techniques: MEG in motion. PMID- 29618805 TI - Techniques: In a split sequence. PMID- 29618806 TI - Neural circuits: Balancing threats. PMID- 29618807 TI - Myelin: Wrapped up. PMID- 29618809 TI - Metacognitive ability predicts learning cue-stimulus associations in the absence of external feedback. AB - Learning how certain cues in our environment predict specific states of nature is an essential ability for survival. However learning typically requires external feedback, which is not always available in everyday life. One potential substitute for external feedback could be to use the confidence we have in our decisions. Under this hypothesis, if no external feedback is available, then the agents' ability to learn about predictive cues should increase with the quality of their confidence judgments (i.e. metacognitive efficiency). We tested and confirmed this novel prediction in an experimental study using a perceptual decision task. We evaluated in separate sessions the metacognitive abilities of participants (N = 65) and their abilities to learn about predictive cues. As predicted, participants with greater metacognitive abilities learned more about the cues. Knowledge of the cues improved accuracy in the perceptual task. Our results provide strong evidence that confidence plays an active role in improving learning and performance. PMID- 29618811 TI - Systemic lupus erythematosus: Escape of gut microbe to the liver drives autoimmunity. PMID- 29618810 TI - Multi-functional nano-adhesive releasing therapeutic ions for MMP-deactivation and remineralization. AB - Restoration of hard tissue in conjunction with adhesive is a globally challenging issue in medicine and dentistry. Common clinical therapies involving application of adhesive and substitute material for functional or anatomical recovery are still suboptimal. Biomaterials with bioactivity and inhibitory effects of enzyme mediated adhesive degradation can render a solution to this. Here, we designed a novel copper-doped bioactive glass nanoparticles (CuBGn) to offer multifunction: metalloproteinases (MMP) deactivation and remineralization and incorporated the CuBGn in resin-dentin adhesive systems, which showed most common failure of MMP mediated adhesive degradation among hard tissue adhesives, to evaluate proposed therapeutic effects. A sol-gel derived bioactive glass nanoparticles doping 10 wt% of Cu (Cu-BGn) for releasing Cu ions, which were well-known MMP deactivator, were successfully created and included in light-curing dental adhesive (DA), a filler-free co-monomer resin blend, at different concentrations (up to 2 wt%). These therapeutic adhesives (CuBGn-DA) showed enhanced (a)cellular bioactivity, cytocompatibility, microtensile bond strength and MMP deactivation-ability. In conclusion, the incorporation of Cu ions releasing nano-bioactive glass demonstrated multifunctional properties at the resin-dentin interface; MMP deactivation and remineralization, representing a suitable strategy to extend the longevity of adhesive-hard tissue (i.e. resin-dentin) interfaces. PMID- 29618808 TI - Fibrinogen in neurological diseases: mechanisms, imaging and therapeutics. AB - The blood coagulation protein fibrinogen is deposited in the brain in a wide range of neurological diseases and traumatic injuries with blood-brain barrier (BBB) disruption. Recent research has uncovered pleiotropic roles for fibrinogen in the activation of CNS inflammation, induction of scar formation in the brain, promotion of cognitive decline and inhibition of repair. Such diverse roles are possible in part because of the unique structure of fibrinogen, which contains multiple binding sites for cellular receptors and proteins expressed in the nervous system. The cellular and molecular mechanisms underlying the actions of fibrinogen are beginning to be elucidated, providing insight into its involvement in neurological diseases, such as multiple sclerosis, Alzheimer disease and traumatic CNS injury. Selective drug targeting to suppress the damaging functions of fibrinogen in the nervous system without affecting its beneficial effects in haemostasis opens a new fibrinogen therapeutics pipeline for neurological disease. PMID- 29618812 TI - A small peptide modulates stomatal control via abscisic acid in long-distance signalling. AB - Mammalian peptide hormones propagate extracellular stimuli from sensing tissues to appropriate targets to achieve optimal growth maintenance 1 . In land plants, root-to-shoot signalling is important to prevent water loss by transpiration and to adapt to water-deficient conditions 2, 3 . The phytohormone abscisic acid has a role in the regulation of stomatal movement to prevent water loss 4 . However, no mobile signalling molecules have yet been identified that can trigger abscisic acid accumulation in leaves. Here we show that the CLAVATA3/EMBRYO-SURROUNDING REGION-RELATED 25 (CLE25) peptide transmits water-deficiency signals through vascular tissues in Arabidopsis, and affects abscisic acid biosynthesis and stomatal control of transpiration in association with BARELY ANY MERISTEM (BAM) receptors in leaves. The CLE25 gene is expressed in vascular tissues and enhanced in roots in response to dehydration stress. The root-derived CLE25 peptide moves from the roots to the leaves, where it induces stomatal closure by modulating abscisic acid accumulation and thereby enhances resistance to dehydration stress. BAM receptors are required for the CLE25 peptide-induced dehydration stress response in leaves, and the CLE25-BAM module therefore probably functions as one of the signalling molecules for long-distance signalling in the dehydration response. PMID- 29618813 TI - Crystal structures of the gastric proton pump. AB - The gastric proton pump-the H+, K+-ATPase-is a P-type ATPase responsible for acidifying the gastric juice down to pH 1. This corresponds to a million-fold proton gradient across the membrane of the parietal cell, the steepest known cation gradient of any mammalian tissue. The H+, K+-ATPase is an important target for drugs that treat gastric acid-related diseases. Here we present crystal structures of the H+, K+-ATPase in complex with two blockers, vonoprazan and SCH28080, in the luminal-open state, at 2.8 A resolution. The drugs have partially overlapping but clearly distinct binding modes in the middle of a conduit running from the gastric lumen to the cation-binding site. The crystal structures suggest that the tight configuration at the cation-binding site lowers the pK a value of Glu820 sufficiently to enable the release of a proton even into the pH 1 environment of the stomach. PMID- 29618814 TI - Structure of photosynthetic LH1-RC supercomplex at 1.9 A resolution. AB - Light-harvesting complex 1 (LH1) and the reaction centre (RC) form a membrane protein supercomplex that performs the primary reactions of photosynthesis in purple photosynthetic bacteria. The structure of the LH1-RC complex can provide information on the arrangement of protein subunits and cofactors; however, so far it has been resolved only at a relatively low resolution. Here we report the crystal structure of the calcium-ion-bound LH1-RC supercomplex of Thermochromatium tepidum at a resolution of 1.9 A. This atomic-resolution structure revealed several new features about the organization of protein subunits and cofactors. We describe the loop regions of RC in their intact states, the interaction of these loop regions with the LH1 subunits, the exchange route for the bound quinone QB with free quinone molecules, the transport of free quinones between the inside and outside of the LH1 ring structure, and the detailed calcium-ion-binding environment. This structure provides a solid basis for the detailed examination of the light reactions that occur during bacterial photosynthesis. PMID- 29618815 TI - Distributed hepatocytes expressing telomerase repopulate the liver in homeostasis and injury. AB - Hepatocytes are replenished gradually during homeostasis and robustly after liver injury1, 2. In adults, new hepatocytes originate from the existing hepatocyte pool3-8, but the cellular source of renewing hepatocytes remains unclear. Telomerase is expressed in many stem cell populations, and mutations in telomerase pathway genes have been linked to liver diseases9-11. Here we identify a subset of hepatocytes that expresses high levels of telomerase and show that this hepatocyte subset repopulates the liver during homeostasis and injury. Using lineage tracing from the telomerase reverse transcriptase (Tert) locus in mice, we demonstrate that rare hepatocytes with high telomerase expression (TERTHigh hepatocytes) are distributed throughout the liver lobule. During homeostasis, these cells regenerate hepatocytes in all lobular zones, and both self-renew and differentiate to yield expanding hepatocyte clones that eventually dominate the liver. In response to injury, the repopulating activity of TERTHigh hepatocytes is accelerated and their progeny cross zonal boundaries. RNA sequencing shows that metabolic genes are downregulated in TERTHigh hepatocytes, indicating that metabolic activity and repopulating activity may be segregated within the hepatocyte lineage. Genetic ablation of TERTHigh hepatocytes combined with chemical injury causes a marked increase in stellate cell activation and fibrosis. These results provide support for a 'distributed model' of hepatocyte renewal in which a subset of hepatocytes dispersed throughout the lobule clonally expands to maintain liver mass. PMID- 29618816 TI - The evolutionary history of vertebrate RNA viruses. AB - Our understanding of the diversity and evolution of vertebrate RNA viruses is largely limited to those found in mammalian and avian hosts and associated with overt disease. Here, using a large-scale meta-transcriptomic approach, we discover 214 vertebrate-associated viruses in reptiles, amphibians, lungfish, ray finned fish, cartilaginous fish and jawless fish. The newly discovered viruses appear in every family or genus of RNA virus associated with vertebrate infection, including those containing human pathogens such as influenza virus, the Arenaviridae and Filoviridae families, and have branching orders that broadly reflected the phylogenetic history of their hosts. We establish a long evolutionary history for most groups of vertebrate RNA virus, and support this by evaluating evolutionary timescales using dated orthologous endogenous virus elements. We also identify new vertebrate-specific RNA viruses and genome architectures, and re-evaluate the evolution of vector-borne RNA viruses. In summary, this study reveals diverse virus-host associations across the entire evolutionary history of the vertebrates. PMID- 29618818 TI - Cryo-EM structure of the Blastochloris viridis LH1-RC complex at 2.9 A. AB - The light-harvesting 1-reaction centre (LH1-RC) complex is a key functional component of bacterial photosynthesis. Here we present a 2.9 A resolution cryo electron microscopy structure of the bacteriochlorophyll b-based LH1-RC complex from Blastochloris viridis that reveals the structural basis for absorption of infrared light and the molecular mechanism of quinone migration across the LH1 complex. The triple-ring LH1 complex comprises a circular array of 17 beta polypeptides sandwiched between 17 alpha- and 16 gamma-polypeptides. Tight packing of the gamma-apoproteins between beta-polypeptides collectively interlocks and stabilizes the LH1 structure; this, together with the short Mg-Mg distances of bacteriochlorophyll b pairs, contributes to the large redshift of bacteriochlorophyll b absorption. The 'missing' 17th gamma-polypeptide creates a pore in the LH1 ring, and an adjacent binding pocket provides a folding template for a quinone, Q P, which adopts a compact, export-ready conformation before passage through the pore and eventual diffusion to the cytochrome bc 1 complex. PMID- 29618817 TI - Fatal swine acute diarrhoea syndrome caused by an HKU2-related coronavirus of bat origin. AB - Cross-species transmission of viruses from wildlife animal reservoirs poses a marked threat to human and animal health 1 . Bats have been recognized as one of the most important reservoirs for emerging viruses and the transmission of a coronavirus that originated in bats to humans via intermediate hosts was responsible for the high-impact emerging zoonosis, severe acute respiratory syndrome (SARS) 2-10 . Here we provide virological, epidemiological, evolutionary and experimental evidence that a novel HKU2-related bat coronavirus, swine acute diarrhoea syndrome coronavirus (SADS-CoV), is the aetiological agent that was responsible for a large-scale outbreak of fatal disease in pigs in China that has caused the death of 24,693 piglets across four farms. Notably, the outbreak began in Guangdong province in the vicinity of the origin of the SARS pandemic. Furthermore, we identified SADS-related CoVs with 96-98% sequence identity in 9.8% (58 out of 591) of anal swabs collected from bats in Guangdong province during 2013-2016, predominantly in horseshoe bats (Rhinolophus spp.) that are known reservoirs of SARS-related CoVs. We found that there were striking similarities between the SADS and SARS outbreaks in geographical, temporal, ecological and aetiological settings. This study highlights the importance of identifying coronavirus diversity and distribution in bats to mitigate future outbreaks that could threaten livestock, public health and economic growth. PMID- 29618819 TI - Advanced maturation of human cardiac tissue grown from pluripotent stem cells. AB - Cardiac tissues generated from human induced pluripotent stem cells (iPSCs) can serve as platforms for patient-specific studies of physiology and disease1-6. However, the predictive power of these models is presently limited by the immature state of the cells1, 2, 5, 6. Here we show that this fundamental limitation can be overcome if cardiac tissues are formed from early-stage iPSC derived cardiomyocytes soon after the initiation of spontaneous contractions and are subjected to physical conditioning with increasing intensity over time. After only four weeks of culture, for all iPSC lines studied, such tissues displayed adult-like gene expression profiles, remarkably organized ultrastructure, physiological sarcomere length (2.2 um) and density of mitochondria (30%), the presence of transverse tubules, oxidative metabolism, a positive force-frequency relationship and functional calcium handling. Electromechanical properties developed more slowly and did not achieve the stage of maturity seen in adult human myocardium. Tissue maturity was necessary for achieving physiological responses to isoproterenol and recapitulating pathological hypertrophy, supporting the utility of this tissue model for studies of cardiac development and disease. PMID- 29618820 TI - Characterization of the 1S-2S transition in antihydrogen. AB - In 1928, Dirac published an equation 1 that combined quantum mechanics and special relativity. Negative-energy solutions to this equation, rather than being unphysical as initially thought, represented a class of hitherto unobserved and unimagined particles-antimatter. The existence of particles of antimatter was confirmed with the discovery of the positron 2 (or anti-electron) by Anderson in 1932, but it is still unknown why matter, rather than antimatter, survived after the Big Bang. As a result, experimental studies of antimatter3-7, including tests of fundamental symmetries such as charge-parity and charge-parity-time, and searches for evidence of primordial antimatter, such as antihelium nuclei, have high priority in contemporary physics research. The fundamental role of the hydrogen atom in the evolution of the Universe and in the historical development of our understanding of quantum physics makes its antimatter counterpart-the antihydrogen atom-of particular interest. Current standard-model physics requires that hydrogen and antihydrogen have the same energy levels and spectral lines. The laser-driven 1S-2S transition was recently observed 8 in antihydrogen. Here we characterize one of the hyperfine components of this transition using magnetically trapped atoms of antihydrogen and compare it to model calculations for hydrogen in our apparatus. We find that the shape of the spectral line agrees very well with that expected for hydrogen and that the resonance frequency agrees with that in hydrogen to about 5 kilohertz out of 2.5 * 1015 hertz. This is consistent with charge-parity-time invariance at a relative precision of 2 * 10 12-two orders of magnitude more precise than the previous determination 8 corresponding to an absolute energy sensitivity of 2 * 10-20 GeV. PMID- 29618821 TI - Accelerated increase in plant species richness on mountain summits is linked to warming. AB - Globally accelerating trends in societal development and human environmental impacts since the mid-twentieth century 1-7 are known as the Great Acceleration and have been discussed as a key indicator of the onset of the Anthropocene epoch 6 . While reports on ecological responses (for example, changes in species range or local extinctions) to the Great Acceleration are multiplying 8, 9 , it is unknown whether such biotic responses are undergoing a similar acceleration over time. This knowledge gap stems from the limited availability of time series data on biodiversity changes across large temporal and geographical extents. Here we use a dataset of repeated plant surveys from 302 mountain summits across Europe, spanning 145 years of observation, to assess the temporal trajectory of mountain biodiversity changes as a globally coherent imprint of the Anthropocene. We find a continent-wide acceleration in the rate of increase in plant species richness, with five times as much species enrichment between 2007 and 2016 as fifty years ago, between 1957 and 1966. This acceleration is strikingly synchronized with accelerated global warming and is not linked to alternative global change drivers. The accelerating increases in species richness on mountain summits across this broad spatial extent demonstrate that acceleration in climate-induced biotic change is occurring even in remote places on Earth, with potentially far ranging consequences not only for biodiversity, but also for ecosystem functioning and services. PMID- 29618822 TI - Combined maternal and postnatal high-fat diet leads to metabolic syndrome and is effectively reversed by resveratrol: a multiple-organ study. AB - This study aimed to study the impact of a combination of maternal and post weaning high-fat diets and whether resveratrol was beneficial. Sprague-Dawley dams were fed either chow or a high-fat diet, before mating, during pregnancy, and into lactation. At weaning, their offspring were randomly fed chow or a high fat diet. Four experimental groups were generated: CC (maternal/postnatal chow diet), HC (maternal high-fat/postnatal chow diet), CH (maternal chow/postnatal high-fat diet), and HH (maternal/postnatal high-fat diet). A fifth group consisted of HH plus resveratrol. The 4 month-old offspring of HH group had higher body weight, higher levels of plasma triglycerides, leptin, angiotensin I and angiotensin II and abnormal intraperitoneal glucose tolerance test results, which fulfilled the features of metabolic syndrome. The dysregulation of the renin-angiotensin system was seen in multiple organs. Sirtuin 1 expression/abundance was reduced by a maternal/postnatal high-fat diet, in all the organs examined. Resveratrol ameliorated most of the features of metabolic syndrome and molecular alterations. The administration of a high-fat diet in both periods showed interactive metabolic effects in the plasma and many organs. Our results suggest that a maternal high-fat diet sensitizes offspring to the adverse effects of subsequent high-fat intake on multiple organs. PMID- 29618823 TI - Oxygen Extraction Ratio (OER) as a Measurement of Hemodialysis (HD) Induced Tissue Hypoxia: A Pilot Study. AB - HD tissue hypoxia associates with organ dysfunctions. OER, the ratio between SaO2 and central-venous-oxygen-saturation, could estimate oxygen requirements during sessions, but no data are available. We evaluated OER behavior in 20 HD patients with permanent central venous catheter (CVC) as vascular access. Pre-HD OER (33.6 +/- 1.4%; M +/- SE) was higher than normal (range 20-30%). HD sessions increased OER to 39.2 +/- 1.5% (M +/- SE; p < 0.05) by 30' and to 47.4 +/- 1.5% (M +/- SE; p < 0.001) by end of treatment (delta 40%). During HD sessions of the long and short interdialytic intervals, OER values overlapped, suggesting no influence of patient's hydration status shifts. OER increased (p < 0.05) after 30' of isolated HD (zero ultrafiltration), but not during isolated ultrafiltration (zero dialysate flow), suggesting a role for blood-membrane-dialysate interaction, independent of volume reduction. In ten patients, individual variability of pre HD OER was low and repeatable (maximum calculated difference over time 6.6%), and negatively correlated with HD-induced OER increments (r = 0.860; p < 0.005), suggesting a decline in the adaptive response along with resting OER increments. In 30 prevalent patients, adjusted multivariate analysis showed that pre-HD OER (HR = 0.88, CI 0.79-0.99, p = 0.028) and percent HD-induced OER (HR = 1.04, CI 1.01-1.08, p = 0.015) were both associated with mortality, with threshold values respectively <32% and >40%. In HD patients with CVC as vascular access, OER is a cheap, easily measurable and repeatable parameter useful to assess intradialytic hypoxia, and a potential biomarker of HD related stress and morbidity, helpful to recognize patients at increased risk of mortality. PMID- 29618824 TI - Novel Chlamydia species isolated from snakes are temperature-sensitive and exhibit decreased susceptibility to azithromycin. AB - Chlamydia species have recently been recognized as emerging pathogens in snakes. However, isolation of novel snake chlamydiae is critical and their growth characteristics are largely unknown. In this study, two novel chlamydial species are described: Chlamydia serpentis and Chlamydia poikilothermis, isolated after attempts on 23 cloacal and choanal swabs from 18 PCR-positive captive snakes originating from different Swiss snake collections. Isolation success, growth curve and infectivity rates over a 48-hour time period were dependent on temperature (37 degrees C for C. serpentis, 28 degrees C for C. poikilothermis). C. serpentis and C. poikilothermis were sensitive to tetracycline and moxifloxacin during evaluation by in vitro antibiotic susceptibility assay but intermediate to resistant (2-4 MUg/ml) to azithromycin. Whole genome sequencing of the isolates provided proof of the novel species status, and gives insights into the evolution of these branches of genus Chlamydia. PMID- 29618825 TI - Investigation of GeSn Strain Relaxation and Spontaneous Composition Gradient for Low-Defect and High-Sn Alloy Growth. AB - Recent development of group-IV alloy GeSn indicates its bright future for the application of mid-infrared Si photonics. Relaxed GeSn with high material quality and high Sn composition is highly desirable to cover mid-infrared wavelength. However, its crystal growth remains a great challenge. In this work, a systematic study of GeSn strain relaxation mechanism and its effects on Sn incorporation during the material growth via chemical vapor deposition was conducted. It was discovered that Sn incorporation into Ge lattice sites is limited by high compressive strain rather than historically acknowledged chemical reaction dynamics, which was also confirmed by Gibbs free energy calculation. In-depth material characterizations revealed that: (i) the generation of dislocations at Ge/GeSn interface eases the compressive strain, which offers a favorably increased Sn incorporation; (ii) the formation of dislocation loop near Ge/GeSn interface effectively localizes defects, leading to the subsequent low-defect grown GeSn. Following the discovered growth mechanism, a world-record Sn content of 22.3% was achieved. The experiment result shows that even higher Sn content could be obtained if further continuous growth with the same recipe is conducted. This report offers an essential guidance for the growth of high quality high Sn composition GeSn for future GeSn based optoelectronics. PMID- 29618827 TI - NIPTmer: rapid k-mer-based software package for detection of fetal aneuploidies. AB - Non-invasive prenatal testing (NIPT) is a recent and rapidly evolving method for detecting genetic lesions, such as aneuploidies, of a fetus. However, there is a need for faster and cheaper laboratory and analysis methods to make NIPT more widely accessible. We have developed a novel software package for detection of fetal aneuploidies from next-generation low-coverage whole genome sequencing data. Our tool - NIPTmer - is based on counting pre-defined per-chromosome sets of unique k-mers from raw sequencing data, and applying linear regression model on the counts. Additionally, the filtering process used for k-mer list creation allows one to take into account the genetic variance in a specific sample, thus reducing the source of uncertainty. The processing time of one sample is less than 10 CPU-minutes on a high-end workstation. NIPTmer was validated on a cohort of 583 NIPT samples and it correctly predicted 37 non-mosaic fetal aneuploidies. NIPTmer has the potential to reduce significantly the time and complexity of NIPT post-sequencing analysis compared to mapping-based methods. For non-commercial users the software package is freely available at http://bioinfo.ut.ee/NIPTMer/ . PMID- 29618828 TI - Results of the radiation dose of head, body and tail of hippocampus in nasopharyngeal carcinoma patients treated with intensity modulated radiotherapy. AB - This study is to analyze the radiation dose of head, body and tail of hippocampus (HC) of nasopharyngeal carcinoma (NPC) patients treated with intensity modulated radiotherapy (IMRT). Evaluate cognitive function of patients with Wechsler adult intelligence scale-Chinese revised (WAIS-CR). HC were segmented into HC head (HH), HC body (HB) and HC tail (HT) and the indexes were then analyzed. WAIS-CR was tested before and 3months after radiotherapy. The mean radiation dose of left and right HC was (1147 +/- 976)cGy, (1011 +/- 602)cGy respectively. The radiation dose and the volume exposed in different dose of HH, HB and HT decreased in turn. For 5 patients, before and after radiotherapy, the regular-order score was 8.60 +/- 1.34, 8.0 +/- 1.00 (P = 0.43), while the reverse-order score was 5.80 +/- 0.84, 5.20 +/- 0.84 (P = 0.07). The radiation dose of HH, HB and HT was different, and the radiation dose of HH was the highest, which should be emphasized especially. PMID- 29618826 TI - A systems pharmacology-oriented discovery of a new therapeutic use of the TCM formula Liuweiwuling for liver failure. AB - Multiple components of traditional Chinese medicine (TCM) formulae determine their treatment targets for multiple diseases as opposed to a particular disease. However, discovering the unexplored therapeutic potential of a TCM formula remains challenging and costly. Inspired by the drug repositioning methodology, we propose an integrated strategy to feasibly identify new therapeutic uses for a formula composed of six herbs, Liuweiwuling. First, we developed a comprehensive systems approach to enrich drug compound-liver disease networks to analyse the major predicted diseases of Liuweiwuling and discover its potential effect on liver failure. The underlying mechanisms were subsequently predicted to mainly attribute to a blockade of hepatocyte apoptosis via a synergistic combination of multiple effects. Next, a classical pharmacology experiment was designed to validate the effects of Liuweiwuling on different models of fulminant liver failure induced by D-galactosamine/lipopolysaccharide (GalN/LPS) or thioacetamide (TAA). The results indicated that pretreatment with Liuweiwuling restored liver function and reduced lethality induced by GalN/LPS or TAA in a dose-dependent manner, which was partially attributable to the abrogation of hepatocyte apoptosis by multiple synergistic effects. In summary, the integrated strategy discussed in this paper may provide a new approach for the more efficient discovery of new therapeutic uses for TCM formulae. PMID- 29618830 TI - Evaluation of the TLR negative regulatory network in CVID patients. AB - Common variable immunodeficiency (CVID), a clinically symptomatic primary immunodeficiency disease (PID), is characterized by hypogammaglobulinemia leading to recurrent infections and various complications. Recently, some defects in the signaling of TLRs have been identified in CVID patients which led us to investigate the expression of TLR4 and 9 negative regulatory molecules and their upregulation status following their activation. Using TaqMan real-time PCR, SOCS1, TNFAIP3, RFN216, and IRAK-M transcripts among peripheral blood mononuclear cells (PBMCs) were measured with/without TLR4 and 9 activations. TLR4 and 9 were activated by lipopolysaccharide (LPS) and unmethylated CpG-oligodeoxynucleotide (CpG-ODN), respectively. Production of IFN-alpha and TNF-alpha cytokines, as a part of the functional response of mentioned TLRs, was also measured using ELISA. Deficient transcripts of IRAK-M and TNFAIP3 in unstimulated PBMCs and lower production of TNF-alpha and IFN-alpha after treatments were observed. Upregulation of RFN216 and TNFAIP3 after TLR9 activation was abnormal compared to healthy individuals. Significant correlations were found between abnormal IRAK-M and TNFAIP3 transcripts, and lymphadenopathy and inflammatory scenarios in patients, respectively. It seems that the transcriptional status of some negative regulatory molecules is disturbed in CVID patients, and this could be caused by the underlying pathogenesis of CVID and could involve complications like autoimmunity and inflammatory responses. PMID- 29618831 TI - Mechanism and medical implications of mammalian autophagy. AB - Autophagy is a highly conserved catabolic process induced under various conditions of cellular stress, which prevents cell damage and promotes survival in the event of energy or nutrient shortage and responds to various cytotoxic insults. Thus, autophagy has primarily cytoprotective functions and needs to be tightly regulated to respond correctly to the different stimuli that cells experience, thereby conferring adaptation to the ever-changing environment. It is now apparent that autophagy is deregulated in the context of various human pathologies, including cancer and neurodegeneration, and its modulation has considerable potential as a therapeutic approach. PMID- 29618829 TI - The genetic diversity within the 1.4 kb HLA-G 5' upstream regulatory region moderately impacts on cellular microenvironment responses. AB - The HLA-G 5'URR extending 1.4 kb from the ATG presents a unique set of regulatory elements among HLA genes. Several variable sites have been described that coincide with or are close to these elements, thus HLA-G 5'URR polymorphism might influence the HLA-G expression level. We cloned the ten most frequent HLA-G 5'URR haplotypes to evaluate their activity on a luciferase reporter gene in HLA-G+ cell lines (JEG-3/choriocarcinoma and FON+/melanoma). We also investigated associations between the plasma HLA-G (sHLA-G) levels and the HLA-G 5'URR variability in 157 healthy individuals. Cell lines were transfected with pGL3 Basic vector constructions containing HLA-G 5'URR sequences. The G010101a (in JEG 3) and G010101b (in FON+) haplotypes exhibited higher promoter activity, whereas the G010101d (in JEG-3) and G010102a (in FON+) haplotypes exhibited lower promoter activity. In the presence of HLA-G inducers (interferon-beta and progesterone) or repressors (cyclopamine) HLA-G promoter activity was modulated, but certain haplotypes exhibited differential responses. No strict association was observed between plasma sHLA-G levels and the 5'URR haplotypes or genotypes; however, the G010101b haplotype was underrepresented among HLA-G-negative plasmas. Therefore, the HLA-G 5'URR polymorphism may have an impact on the modulation of HLA-G gene expression, but alone provides a limited predictive value for sHLA-G levels in vivo. PMID- 29618832 TI - Prevalence, duration and risk factors for appendicular osteoarthritis in a UK dog population under primary veterinary care. AB - Osteoarthritis is the most common joint disease diagnosed in veterinary medicine and poses considerable challenges to canine welfare. This study aimed to investigate prevalence, duration and risk factors of appendicular osteoarthritis in dogs under primary veterinary care in the UK. The VetCompassTM programme collects clinical data on dogs attending UK primary-care veterinary practices. The study included all VetCompassTM dogs under veterinary care during 2013. Candidate osteoarthritis cases were identified using multiple search strategies. A random subset was manually evaluated against a case definition. Of 455,557 study dogs, 16,437 candidate osteoarthritis cases were identified; 6104 (37%) were manually checked and 4196 (69% of sample) were confirmed as cases. Additional data on demography, clinical signs, duration and management were extracted for confirmed cases. Estimated annual period prevalence (accounting for subsampling) of appendicular osteoarthritis was 2.5% (CI95: 2.4-2.5%) equating to around 200,000 UK affected dogs annually. Risk factors associated with osteoarthritis diagnosis included breed (e.g. Labrador, Golden Retriever), being insured, being neutered, of higher bodyweight and being older than eight years. Duration calculation trials suggest osteoarthritis affects 11.4% of affected individuals' lifespan, providing further evidence for substantial impact of osteoarthritis on canine welfare at the individual and population level. PMID- 29618834 TI - Adsorption and protective behavior of BTAH on the initial atmospheric corrosion process of copper under thin film of chloride solutions. AB - The initial corrosion process of copper and the corrosion resistance mechanism of Benzotriazole under chloride-containing thin electrolyte layer (TEL) was investigated. After theoretical calculation and experimental characterization, the forming process of [Cu(I)BTA]n film was chemically adsorbed on copper surface by Cu-N bond tightly; corrosion rate increased as TEL thickness decreased. Whilst, energy distribution plot of electrochemical noise provided the validity of corrosion type, and the purported corrosion energy (Ec) deduced from electrochemical noise was approximately proportion to corrosion rate (1/Rct) with and without the anticorrosion film, which denoted the feasibility to determine corrosion rate by nondestructive on-line monitoring electrochemical noise progress. PMID- 29618833 TI - Cyperenoic acid suppresses osteoclast differentiation and delays bone loss in a senile osteoporosis mouse model by inhibiting non-canonical NF-kappaB pathway. AB - Cyperenoic acid is a terpenoid isolated from the root of a medicinal plant Croton crassifolius with a wide range of biological activities. In this study, the effects of cyperenoic acid on osteoclast differentiation were investigated both in vitro and in vivo using receptor activator of nuclear factor-kappaB ligand (RANKL)-induced bone marrow-derived osteoclasts and senescence-accelerated mouse prone 6 (SAMP6). Cyperenoic acid significantly suppressed RANKL-induced osteoclast differentiation at the concentrations with no apparent cytotoxicity. The half maximum inhibitory concentration (IC50) for osteoclast differentiation was 36.69 MUM +/- 1.02. Cyperenoic acid treatment evidently reduced the expression of two key transcription factors in osteoclast differentiation, NFATc1 and c-Fos. Detailed signaling analysis revealed that cyperenoic acid did not affect MAPK pathways and canonical NF-kappaB pathway but impaired activation of p100/p52 in the non-canonical NF-kappaB pathway upon RANKL stimulation. Moreover, the expression of osteoclast-related genes, nfatc1, ctsk, irf8, acp5 and cfos were disrupted by cyperenoic acid treatment. The bone resorption activity by cyperenoic acid-treated osteoclasts were impaired. In a senile osteoporosis mouse model SAMP6, mice fed on diet supplemented with cyperenoic acid showed delay in bone loss, compared to the control. Taken together, plant-derived cyperenoic acid shows great potential as therapeutic agent for osteoporosis. PMID- 29618835 TI - N2-rich fluid in the vein-type Yangjingou scheelite deposit, Yanbian, NE China. AB - Nearly pure N2 fluid inclusions (Th (L) = -151~-168 degrees C; Th (V) = ~150.3 degrees C) were identified in W-mineralized quartz veins from the Yangjingou scheelite deposit, in the eastern Yanbian area, NE China. Other fluid inclusion populations include N2-CO2, NaCl-H2O +/- N2 and CO2 +/- N2-NaCl-H2O, but no hydrocarbons were detected. The host rocks are part of the Wudaogou Group metamorphic series, which mainly consist of Ca-rich mica schist. Subhedral sulfide minerals occur in early disseminated W-mineralized quartz veins, or have partially replaced early scheelite. ThN2 and ThN2-H2O indicate N2 fluid-trapping from 315 degrees C to 410 degrees C and from 80 MPa to 350 MPa. Oxygen and hydrogen isotopic data (deltaD = -74.90/00~-770/00, delta18O = 9.60/00~120/00, V SMOW) suggest that the mineralizing fluids were composed of mixed magmatic and metamorphic water, N2-rich inclusions (delta15N = -0.50/00 to 1.40/00) indicate fluid-rock interaction with metamorphic rocks. The N2-rich fluid was closely associated with scheelite precipitation. During thermal decomposition under high oxygen fugacity conditions, which occurred synchronously with metamorphism and magmatic activity, large amounts of N2 were liberated from NH4+-micas, which then accumulated in the parent fluid of the quartz scheelite veins. PMID- 29618836 TI - Outcomes of sphincterotomy for small pupil phacoemulsification. AB - PURPOSE: Sphincterotomy, an alternative to iris hooks or pupil stretching, is a technique that can aid in small pupil phacoemulsification. The incidence of post operative complications of this procedure, however, has not been studied. Our study evaluates the post-operative outcomes of phacoemulsification surgery with adjunctive pupillary sphincterotomy. METHODS: We conducted a retrospective review of case notes and Medisoft (r) electronic record of patients that had undergone simultaneous sphincterotomy, phacoemulsification and intraocular lens (IOL) implantation by a single surgeon between March 2012 and February 2017. Our main outcome measures were post-operative ocular hypertension (IOP > 21 mmHg), uveitis and cystoid macular oedema (CMO). RESULTS: A total of 114 eyes of 114 patients were included in this study. The mean age was 81.2 years (range: 26-100). All patients had uncomplicated surgery. Transient (<1 month) ocular hypertension developed in five (4%) eyes. Sustained ocular hypertension (>1 month) occurred in one (1%) eye, which had pre-existing glaucoma. All four (4%) eyes that developed a persistent uveitis (>1 month) resolved with topical therapy except for one eye with a history of uveitis. The 6 (5%) eyes that developed CMO had a history significant for uveitis (n = 4), diabetic macular oedema (n = 1) and epiretinal membrane (n = 1). All CMO maculae resolved to their baseline. CONCLUSION: The incidence of post-operative complications following uncomplicated phacoemulsification and IOL implantation with pupillary sphincterotomy is low. The most important predisposing factors for development of a complication are ocular co-morbidities such as glaucoma, uveitis and the presence of a macular pathology. PMID- 29618837 TI - Ventilator Dependence Risk Score for the Prediction of Prolonged Mechanical Ventilation in Patients Who Survive Sepsis/Septic Shock with Respiratory Failure. AB - We intended to develop a scoring system to predict mechanical ventilator dependence in patients who survive sepsis/septic shock with respiratory failure. This study evaluated 251 adult patients in medical intensive care units (ICUs) between August 2013 to October 2015, who had survived for over 21 days and received aggressive treatment. The risk factors for ventilator dependence were determined. We then constructed a ventilator dependence (VD) risk score using the identified risk factors. The ventilator dependence risk score was calculated as the sum of the following four variables after being adjusted by proportion to the beta coefficient. We assigned a history of previous stroke, a score of one point, platelet count less than 150,000/MUL a score of one point, pH value less than 7.35 a score of two points, and the fraction of inspired oxygen on admission day 7 over 39% as two points. The area under the curve in the derivation group was 0.725 (p < 0.001). We then applied the VD risk score for validation on 175 patients. The area under the curve in the validation group was 0.658 (p = 0.001). VD risk score could be applied to predict prolonged mechanical ventilation in patients who survive sepsis/septic shock. PMID- 29618838 TI - Opportunistic migration and habitat use of the giant mottled eel Anguilla marmorata (Teleostei: Elopomorpha). AB - Freshwater eels have fascinated biologists for centuries due to the spectacular long-distance migrations between their freshwater habitats and their spawning areas far out in the ocean. Although freshwater eels originated in the Indonesian region, remarkably little is known about the life history of tropical freshwater eels. The diverse migratory patterns and habitat choice between marine and freshwater environments by the giant mottled eel Anguilla marmorata Quoy & Gaimard, 1824 were examined by analysing the otolith strontium (Sr) and calcium (Ca) concentrations collected in Asian waters. The wide range of otolith Sr:Ca ratios indicated that the habitat use of A. marmorata was opportunistic among fresh, brackish, and marine waters. The present study first confirmed the occurrence of marine-resident eels that have never migrated into a freshwater habitat in A. marmorata. A. marmorata may have the same behavioural plasticity as temperate and other tropical anguillid species regarding whether to enter freshwater or to remain in estuarine and marine environments. Freshwater eels migrate flexibly among freshwater, brackish water, and seawater environments and it is now evident that their movement into freshwater is not an obligate migratory pathway but should be defined as an opportunistic catadromy, with marine and estuarine residents as ecophenotypes. PMID- 29618839 TI - Metformin adapts its cellular effects to bioenergetic status in a model of metabolic dysfunction. AB - Thermal injury induces a complex immunometabolic response, characterized by hyperglycemia, extensive inflammation and persistent hypermetabolism. It has been suggested that attenuation of the hypermetabolic response is beneficial for patient wellbeing. To that effect, metformin represents an attractive therapeutic agent, as its effects on glycemia, inflammation and bioenergetics can improve outcomes in burn patients. Therefore, we studied metformin and its effects on mitochondrial bioenergetics in a murine model of thermal injury. We set out to determine the impact of this agent on mitochondrial hypermetabolism (adult mice) and mitochondrial dysfunction (aged mice). Seahorse respirometry complimented by in-gel activity assays were used to elucidate metformin's cellular mechanism. We found that metformin exerts distinctly different effects, attenuating the hypermetabolic mitochondria of adult mice while significantly improving mitochondrial bioenergetics in the aged mice. Furthermore, we observed that these changes occur both with and without adenosine monophosphate kinase (AMPK) activation, respectively, and analyzed damage markers to provide further context for metformin's beneficial actions. We suggest that metformin has a dual role following trauma, acting via both AMPK-dependent and independent pathways depending on bioenergetic status. These findings help further our understanding of metformin's biomolecular effects and support the continued use of this drug in patients. PMID- 29618841 TI - Greater reductions in plasma aldosterone with aliskiren in hypertensive patients with higher soluble (Pro)renin receptor level. AB - The (pro)renin receptor is important in the regulation of the tissue renin angiotensin-aldosterone system. The benefits and safety of single-aliskiren treatment without other renin-angiotensin-aldosterone system inhibitors remain unclear. The serum level of the soluble form of the (pro)renin receptor is thought to be a biomarker reflecting the activity of the tissue renin-angiotensin aldosterone system. We investigated the effects of single renin-angiotensin aldosterone system blockade with aliskiren on renal and vascular functions and determined if serum level of the soluble (pro)renin receptor was a predictor of aliskiren efficacy in hypertensive patients with chronic kidney disease. Thirty nine essential hypertensive patients with chronic kidney disease in our outpatient clinic were randomly assigned to receive either aliskiren or amlodipine. The parameters associated with renal and vascular functions and indices of renin-angiotensin-aldosterone system components, including serum levels of the soluble form, were evaluated before and after 12-week and 24-week treatment. Blood pressure was not significantly different between the groups. No significant changes in serum levels were observed in the soluble (pro)renin receptor in either group. Urinary albumin, protein excretion, and cardio-ankle vascular index significantly decreased in the aliskiren group. In the aliskiren group, there was a significant negative correlation between the basal level of the soluble (pro)renin receptor and the change in plasma aldosterone concentration. Single renin-angiotensin-aldosterone system blockade with aliskiren showed renal and vascular protective effects independent of blood pressure reduction. Serum levels of the soluble (pro)renin receptor may indicate aldosterone production via the (pro)renin receptor in the adrenal gland. PMID- 29618840 TI - SMAD6 overexpression leads to accelerated myogenic differentiation of LMNA mutated cells. AB - LMNA gene encodes lamins A and C, two major components of the nuclear lamina, a network of intermediate filaments underlying the inner nuclear membrane. Most of LMNA mutations are associated with cardiac and/or skeletal muscles defects. Muscle laminopathies include Emery-Dreifuss Muscular Dystrophy, Limb-Girdle Muscular Dystrophy 1B, LMNA-related Congenital Muscular Dystrophy and Dilated Cardiomyopathy with conduction defects. To identify potential alterations in signaling pathways regulating muscle differentiation in LMNA-mutated myoblasts, we used a previously described model of conditionally immortalized murine myoblasts: H-2K cell lines. Comparing gene expression profiles in wild-type and Lmna?8-11 H-2K myoblasts, we identified two major alterations in the BMP (Bone Morphogenetic Protein) pathway: Bmp4 downregulation and Smad6 overexpression. We demonstrated that these impairments lead to Lmna?8-11 myoblasts premature differentiation and can be rescued by downregulating Smad6 expression. Finally, we showed that BMP4 pathway defects are also present in myoblasts from human patients carrying different heterozygous LMNA mutations. PMID- 29618842 TI - Publisher Correction: 2D MoS2 as an efficient protective layer for lithium metal anodes in high-performance Li-S batteries. AB - In the version of this Article originally published, a technical error in typesetting led to the traces in Fig. 3a being trimmed and made to overlap. The figure has now been corrected with the traces as supplied by the authors; the original and corrected Fig. 3a are shown below. Also, in the last paragraph of the section "Mechanistic study on Li diffusion in MoS2" the authors incorrectly included the term 'high-concentration' in the text "the Li diffusion will be dominated by high-concentration Li migration on the surface of T-MoS2 with a much smaller energy barrier (0.155 eV) to overcome". This term has now been removed from all versions of the Article. Finally, the authors have added an extra figure in the Supplementary Information (Supplementary Fig. 19) to show galvanostatic tests at 1 and 3 mA cm-2 for the MoS2-coated Li symmetric cells. The caption to Fig. 3 of the Article has been amended to reflect this, with the added wording "Galvanostatic tests at 1 and 3 mA cm-2 can be found in Supplementary Fig. 19." PMID- 29618843 TI - Rudhira/BCAS3 is essential for mouse development and cardiovascular patterning. AB - Rudhira/Breast Carcinoma Amplified Sequence 3 (BCAS3) is a cytoskeletal protein that promotes directional cell migration and angiogenesis in vitro and is implicated in human carcinomas and coronary artery disease. To study the role of Rudhira during development in vivo, we generated the first knockout mouse for rudhira and show that Rudhira is essential for mouse development. Rudhira null embryos die at embryonic day (E) 9.5 accompanied by severe vascular patterning defects in embryonic and extra-embryonic tissues. To identify the molecular processes downstream of rudhira, we analyzed the transcriptome of intact knockout yolk sacs. Genome-wide transcriptome analysis showed that Rudhira functions in angiogenesis and its related processes such as cell adhesion, extracellular matrix organization, peptidase activity and TGFbeta signaling. Since Rudhira is also expressed in endothelial cells (ECs), we further generated Tie2Cre-mediated endothelial knockout (CKO) of rudhira. CKO embryos survive to E11.5 and similar to the global knockout, display gross vascular patterning defects, showing that endothelial Rudhira is vital for development. Further, Rudhira knockdown ECs in culture fail to sprout in a spheroid-sprouting assay, strongly supporting its role in vascular patterning. Our study identifies an essential role for Rudhira in blood vessel remodeling and provides a mouse model for cardiovascular development. PMID- 29618844 TI - Dyslipidaemia: In vivo genome editing of ANGPTL3: a therapy for atherosclerosis? PMID- 29618845 TI - Comparing potential recharge estimates from three Land Surface Models across the Western US. AB - Groundwater is a major source of water in the western US. However, there are limited recharge estimates available in this region due to the complexity of recharge processes and the challenge of direct observations. Land surface Models (LSMs) could be a valuable tool for estimating current recharge and projecting changes due to future climate change. In this study, simulations of three LSMs (Noah, Mosaic and VIC) obtained from the North American Land Data Assimilation System (NLDAS-2) are used to estimate potential recharge in the western US. Modeled recharge was compared with published recharge estimates for several aquifers in the region. Annual recharge to precipitation ratios across the study basins varied from 0.01-15% for Mosaic, 3.2-42% for Noah, and 6.7-31.8% for VIC simulations. Mosaic consistently underestimates recharge across all basins. Noah captures recharge reasonably well in wetter basins, but overestimates it in drier basins. VIC slightly overestimates recharge in drier basins and slightly underestimates it for wetter basins. While the average annual recharge values vary among the models, the models were consistent in identifying high and low recharge areas in the region. Models agree in seasonality of recharge occurring dominantly during the spring across the region. Overall, our results highlight that LSMs have the potential to capture the spatial and temporal patterns as well as seasonality of recharge at large scales. Therefore, LSMs (specifically VIC and Noah) can be used as a tool for estimating future recharge rates in data limited regions. PMID- 29618846 TI - Biological sensing and control of emission dynamics of quantum dot bioconjugates using arrays of long metallic nanorods. AB - We study biological sensing using plasmonic and photonic-plasmonic resonances of arrays of ultralong metallic nanorods and analyze the impact of these resonances on emission dynamics of quantum dot bioconjugates. We demonstrate that the LSPRs and plasmonic lattice modes of such array can be used to detect a single self assembled monolayer of alkanethiol at the visible (550 nm) and near infrared (770 nm) range with well resolved shifts. We study adsorption of streptavidin-quantum dot conjugates to this monolayer, demonstrating that formation of nearly two dimensional arrays of quantum dots with limited emission blinking can lead to extra well-defined wavelength shifts in these modes. Using spectrally-resolved lifetime measurements we study the emission dynamics of such quantum dot bioconjugates within their monodispersed size distribution. We show that, despite their close vicinity to the nanorods, the rate of energy transfer from these quantum dots to nanorods is rather weak, while the plasmon field enhancement can be strong. Our results reveal that the nanorods present a strongly wavelength or size-dependent non-radiative decay channel to the quantum dot bioconjugates. PMID- 29618847 TI - Monte Carlo Bayesian inference on a statistical model of sub-gridcolumn moisture variability using high-resolution cloud observations. Part 1: Method. AB - A method is presented to constrain a statistical model of sub-gridcolumn moisture variability using high-resolution satellite cloud data. The method can be used for large-scale model parameter estimation or cloud data assimilation. The gridcolumn model includes assumed probability density function (PDF) intra-layer horizontal variability and a copula-based inter-layer correlation model. The observables used in the current study are Moderate Resolution Imaging Spectroradiometer (MODIS) cloud-top pressure, brightness temperature and cloud optical thickness, but the method should be extensible to direct cloudy radiance assimilation for a small number of channels. The algorithm is a form of Bayesian inference with a Markov chain Monte Carlo (MCMC) approach to characterizing the posterior distribution. This approach is especially useful in cases where the background state is clear but cloudy observations exist. In traditional linearized data assimilation methods, a subsaturated background cannot produce clouds via any infinitesimal equilibrium perturbation, but the Monte Carlo approach is not gradient-based and allows jumps into regions of non-zero cloud probability. The current study uses a skewed-triangle distribution for layer moisture. The article also includes a discussion of the Metropolis and multiple try Metropolis versions of MCMC. PMID- 29618848 TI - Monte Carlo Bayesian inference on a statistical model of sub-gridcolumn moisture variability using high-resolution cloud observations. Part 2: Sensitivity tests and results. AB - Part 1 of this series presented a Monte Carlo Bayesian method for constraining a complex statistical model of global circulation model (GCM) sub-gridcolumn moisture variability using high-resolution Moderate Resolution Imaging Spectroradiometer (MODIS) cloud data, thereby permitting parameter estimation and cloud data assimilation for large-scale models. This article performs some basic testing of this new approach, verifying that it does indeed reduce mean and standard deviation biases significantly with respect to the assimilated MODIS cloud optical depth, brightness temperature and cloud-top pressure and that it also improves the simulated rotational-Raman scattering cloud optical centroid pressure (OCP) against independent (non-assimilated) retrievals from the Ozone Monitoring Instrument (OMI). Of particular interest, the Monte Carlo method does show skill in the especially difficult case where the background state is clear but cloudy observations exist. In traditional linearized data assimilation methods, a subsaturated background cannot produce clouds via any infinitesimal equilibrium perturbation, but the Monte Carlo approach allows non-gradient-based jumps into regions of non-zero cloud probability. In the example provided, the method is able to restore marine stratocumulus near the Californian coast, where the background state has a clear swath. This article also examines a number of algorithmic and physical sensitivities of the new method and provides guidance for its cost-effective implementation. One obvious difficulty for the method, and other cloud data assimilation methods as well, is the lack of information content in passive-radiometer-retrieved cloud observables on cloud vertical structure, beyond cloud-top pressure and optical thickness, thus necessitating strong dependence on the background vertical moisture structure. It is found that a simple flow-dependent correlation modification from Riishojgaard provides some help in this respect, by better honouring inversion structures in the background state. PMID- 29618849 TI - CAMx Ozone Source Attribution in the Eastern United States using Guidance from Observations during DISCOVER-AQ Maryland. AB - A Comprehensive Air-Quality Model with Extensions (CAMx) version 6.10 simulation was assessed through comparison with data acquired during NASA's 2011 DISCOVER-AQ Maryland field campaign. Comparisons for the baseline simulation (CB05 chemistry, EPA 2011 National Emissions Inventory) show a model overestimate of NOy by +86.2% and an underestimate of HCHO by -28.3%. We present a new model framework (CB6r2 chemistry, MEGAN v2.1 biogenic emissions, 50% reduction in mobile NOx, enhanced representation of isoprene nitrates) that better matches observations. The new model framework attributes 31.4% more surface ozone in Maryland to electric generating units (EGUs) and 34.6% less ozone to on-road mobile sources. Surface ozone becomes more NOx-limited throughout the eastern United States compared to the baseline simulation. The baseline model therefore likely underestimates the effectiveness of anthropogenic NOx reductions as well as the current contribution of EGUs to surface ozone. PMID- 29618850 TI - Vertical variation of ice particle size in convective cloud tops. AB - A novel technique is used to estimate derivatives of ice effective radius with respect to height near convective cloud tops (dre /dz) from airborne shortwave reflectance measurements and lidar. Values of dre /dz are about -6 MUm/km for cloud tops below the homogeneous freezing level, increasing to near 0 MUm/km above the estimated level of neutral buoyancy. Retrieved dre /dz compares well with previously documented remote sensing and in situ estimates. Effective radii decrease with increasing cloud top height, while cloud top extinction increases. This is consistent with weaker size sorting in high, dense cloud tops above the level of neutral buoyancy where fewer large particles are present, and with stronger size sorting in lower cloud tops that are less dense. The results also confirm that cloud-top trends of effective radius can generally be used as surrogates for trends with height within convective cloud tops. These results provide valuable observational targets for model evaluation. PMID- 29618851 TI - Network Reconstruction From High-Dimensional Ordinary Differential Equations. AB - We consider the task of learning a dynamical system from high-dimensional time course data. For instance, we might wish to estimate a gene regulatory network from gene expression data measured at discrete time points. We model the dynamical system nonparametrically as a system of additive ordinary differential equations. Most existing methods for parameter estimation in ordinary differential equations estimate the derivatives from noisy observations. This is known to be challenging and inefficient. We propose a novel approach that does not involve derivative estimation. We show that the proposed method can consistently recover the true network structure even in high dimensions, and we demonstrate empirical improvement over competing approaches. Supplementary materials for this article are available online. PMID- 29618852 TI - Mapping in-vivo optic nerve head strains caused by intraocular and intracranial pressures. AB - Although it is well documented that abnormal levels of either intraocular (IOP) or intracranial pressure (ICP) can lead to potentially blinding conditions, such as glaucoma and papilledema, little is known about how the pressures actually affect the eye. Even less is known about potential interplay between their effects, namely how the level of one pressure might alter the effects of the other. Our goal was to measure in-vivo the pressure-induced stretch and compression of the lamina cribrosa due to acute changes of IOP and ICP. The lamina cribrosa is a structure within the optic nerve head, in the back of the eye. It is important because it is in the lamina cribrosa that the pressure induced deformations are believed to initiate damage to neural tissues leading to blindness. An eye of a rhesus macaque monkey was imaged in-vivo with optical coherence tomography while IOP and ICP were controlled through cannulas in the anterior chamber and lateral ventricle, respectively. The image volumes were analyzed with a newly developed digital image correlation technique. The effects of both pressures were highly localized, nonlinear and non-monotonic, with strong interactions. Pressure variations from the baseline normal levels caused substantial stretch and compression of the neural tissues in the posterior pole, sometimes exceeding 20%. Chronic exposure to such high levels of biomechanical insult would likely lead to neural tissue damage and loss of vision. Our results demonstrate the power of digital image correlation technique based on non invasive imaging technologies to help understand how pressures induce biomechanical insults and lead to vision problems. PMID- 29618853 TI - Associations Between Parent Emotional Arousal and Regulation and Adolescents' Affective Brain Response. AB - Parents' emotional functioning represents a central mechanism in the caregiving environment's influence on adolescent affective brain function. However, a paucity of research has examined links between parental emotional arousal and regulation and adolescents' affective brain function. Thus, the present study examined associations between parents' self-rated negative emotion, parent emotion regulation difficulties, and adolescent brain responsivity to negative and positive emotional stimuli. Participants included 64 12-14 year-old adolescents (31 females) and their female primary caregivers. Adolescents viewed negative, positive, and neutral emotional stimuli during an fMRI scanning session. Region of interest analyses showed that higher parent negative emotion was related to adolescents' greater ACC and vmPFC response to both negatively- and positively-valenced emotional stimuli; whereas, parent negative emotion was related to adolescents' greater amygdala response to negative emotional stimuli only. Furthermore, parent emotion regulation moderated the association between parent negative emotion and adolescents' brain response to negative emotional stimuli, such that parents with high negative emotion and high emotion regulation difficulties had adolescents with the greatest affective brain response. Findings highlight the importance of considering both parent emotional arousal and regulation in understanding the family affective environment and its relation to adolescent emotion-related brain development. PMID- 29618854 TI - Farewell, dear readers.... PMID- 29618855 TI - Dr. Kuldeep Singh Goleria: A True Karma Yogi. PMID- 29618856 TI - A learning module in hair restoration surgery: A simple and economic method to learn all steps of strip method of hair follicles harvesting and implantation. AB - Background: There is a global increase in demand for hair transplant as well as increasing demand for trained assistants and surgeons. It is a fact that permanent donor hair follicles are limited and any loss during learning is permanent and irreversible, so there is no place to learn and/or practice on a patient. Objective: To develop a learning module in hair restoration surgery to learn all steps of strip method of hair follicles harvesting and methods of implantation. Materials and Methods: In this learning module, the materials used are paper, pencil, plant leaf, foam and thread. The last step is on goat skin. Module has been divided into multiple steps. The first step is training of microsurgery position, the second step is training of movement at wrist using paper and pencil, the third step is strip harvesting and slivering on foam model, the fourth step is learning of follicle dissection on leaf model, the fifth step is thread follicle implantation on leaf bed. After practising on non-living model finally, all steps are practised on goatskin, starting from slivering, follicle dissection and implantation of goat follicles on leaf. Conclusion: This is very economical and user-friendly system to learn all steps of strip method of hair follicle harvesting and methods of implantation as well. The materials used are available around us and anyone can learn as well as train his or her technicians in very short time. PMID- 29618857 TI - Three component cartilage framework reconstruction for correction of post traumatic nasal septal collapse. AB - Background: Post-traumatic nasal septal collapse results in flat, broad, non projecting nose due to mid-vault collapse. These patients may have airway obstruction due to poorly supported internal valve. Traditional techniques like 'cantilever graft technique' or conventional 'L-graft technique' produce a rigid lobule as the single unit framework extends to the tip. These grafts also lack in internal valve support. Materials and Methods: Twelve patients with post traumatic nasal septal collapse were treated with three component cartilage framework technique in the past 3 years. The framework was reconstructed in three components-septal, columellar and dorsal onlay; using costal cartilage. If needed, upper lateral cartilage support grafts were also provided. Results: At 6 months' follow-up, all 12 patients were satisfied with the outcome. The nasal projection and dorsal definition were aesthetically pleasing, and there was free natural movement of the lobular part of the nose. One graft was revised for further improvement in outcome. Airway obstruction, when present was also relieved. Conclusion: This technique has distinct advantages over the conventional techniques as the framework of separate components maintains pliability of the lobule, supports the internal valve and offers good control of aesthetic needs. PMID- 29618858 TI - A comprehensive functional classification of cleft hand: The DAST concept. AB - Context: Phenotypic expressions of the congenital cleft hand are variable and might baffle even the experienced as to the choice of surgery. The morphological parameters defining the anomaly dictate not only the functional capacity of the anomalous hand but also the degree of possible surgical restoration. Despite a large number of classifying systems available, none encompass all the relevant issues. Aims: The purpose of this work is to present an all-inclusive and universally acceptable classification of the deformity which would graphically represent the entire gamut of possible presentations; principal and associated. Furthermore, based on such staging, the choice of surgical procedure and the stages of surgical intervention can be standardised to ensure the best results for the patient. Patients and Methods: This study is based on a series of 27 patients with a total of 38 cleft hands. Results and Conclusions: The necessity to include and to assess all determinants of function and complexity in these hands to standardise the choice of management, gave rise to the DAST system of classification; an acronym for all the morphological determinants of the anomaly (D = Digits missing, A = Associated anomalies in the hand, S = Site of cleft, T = Functional state of the Thumb). Numerical values were assigned to each component in increasing order of complexity. Score for each determinant as well as the aggregate score indicates the degree of complexity in a graphic manner. The DAST classification has a predictive value in choice of procedure and prognosticating surgical outcomes. PMID- 29618859 TI - A novel technique using a subcutaneously pedicled islanded prolabial flap for the secondary correction of bilateral cleft lip and nasal deformity. AB - Context: The bilateral cleft lip and nose deformity frequently requires lip revision surgery at the time of secondary rhinoplasty. The goal is to achieve an adequate philtrum with a well-shaped Cupid's bow, white roll alignment and a central vermilion tubercle. Aims: We have devised a new technique of using prolabial tissue tailored as an island of skin based on a subcutaneous pedicle for the secondary reconstruction of the philtral aesthetic unit in patients with bilateral cleft lip nasal deformity. Settings and Design: This technique was used in 21 patients from March 2012 to August 2015. All patients had undergone primary lip repair at other institutions and required lip revision with simultaneous rhinoplasty. Subjects and Methods: The objective criteria considered in the post operative evaluation by the authors included improvement of philtral ridge projection, symmetry of philtral column and nasal sill and white roll continuity. The ten individual parameters were given a score from 1 to 4 (with 1 = lowest and 4 = highest for each individual parameter) and the total score was rated as 31-40 = excellent, 21-30 = good, 11-20 = fair and 0-10 = Poor. The patients' overall satisfaction was assessed at 6 months postoperatively to record their impression of the aesthetic improvement after our procedure. Results: The follow-up period ranged from 6 months to 3 years. The prolabial flap had no post-operative complications. The authors' assessment judged 15 (71.4%) patients as having an excellent outcome and 6 (28.5%) patients as having a good outcome. All patients expressed subjective satisfaction with the post-operative appearance of their upper lip and rated their results as improved and overall satisfaction scoring was high. Conclusions: This technique is a new addition to the repertoire of procedures which already exist for the correction of bilateral cleft lip nose deformity. It is safe, reliable and has a good aesthetic outcome with no significant morbidity. PMID- 29618860 TI - A study the various clinical and electrophysiological parameters of severity of carpal tunnel syndrome, their correlation with post-operative recovery. AB - Objective: We aimed to study the various clinical and electrophysiological parameters of severity of carpal tunnel syndrome (CTS) and to see if the severity of CTS affects recovery after surgery. Patients and Methods: A prospective study of 35 patients suffering from CTS. Clinical severity was assessed using visual analogue scale and standard questionnaires such as Levine and Disabilities of Arm, Shoulder and Hand questionnaires. All the patients underwent electrophysiological evaluation to assess electrophysiological severity of CTS. According to modified Padua classification, they were classified into three groups, namely, minimal to mild, moderate and severe to extreme. All patients underwent Carpal tunnel release in our unit. The clinical assessment was repeated 3 months post-operatively. Results: Out of 33 patients, majority (65.7%) of the patients were suffering from moderately severe CTS. The clinical provocative tests were positive in majority of patients. Clinically and statistically significant (P < 0.001) improvement was seen in all clinical severity scores. However, it did not show any statistical correlation with electrophysiological severity of the disease when compared among the groups. There was no association of age, gender of the patient, body mass index, hand dominance, affected side of the patient, results of provocative tests and the presence or absence of thenar muscle atrophy when compared among the three severity groups (P > 0.05). Conclusions: Although pre-operative clinical scores of severity and electrophysiology have a diagnostic role in CTS, they do not correlate with post operative recovery and in turn fail to predict the extent of post-operative recovery before surgery. PMID- 29618861 TI - Evaluation of facial artery perforator-based flaps in reconstruction of facial defects. AB - Introduction: Several flaps have been described for reconstructing facial or oral defects. Flaps such as forehead and pectoralis major are often too bulky for small-to-moderate-sized defects, for which nasolabial flaps are often ideal. However, nasolabial flaps have limited mobility and reach and may need two stages, particularly for intraoral defects. According to recent literatures, facial artery provides numerous small cutaneous perforators, based on which skin flaps can be islanded, with greater mobility and reach for reconstruction of small-to-moderate-sized intraoral and facial defects in one stage. Our study aims to evaluate the reliability and versatility of facial artery perforator-based flaps in the reconstruction of such defects. Materials and Methods: A ethical committee-approved retrospective study was conducted on data of the patients attending our outpatient department between February 2014 and October 2015 with small-to-moderate-sized facial/oral lesions. The total sample size was 23. We studied the relation of flap survival with size of flap, route of inset and neck dissection, functional and aesthetic outcomes and feasibility of adjuvant therapy in cases of malignancies. Results and Analysis: A wide range of facial defects, especially intraoral defects, could be reconstructed in one stage using facial artery perforator-based flaps. The flaps were reliable. Complications included only partial skin loss of the flaps in a few cases. Complications were directly related to the length of the flaps and the route of inset. Functional and aesthetic outcomes were satisfactory and none of the flaps showed any significant post-radiotherapy changes. Conclusions: We concluded that facial artery perforator flap can be a simple, safe, versatile and one-stage alternative to the traditional flaps in the reconstruction of small-to-moderate-sized facial defects. Neck dissection can be safely done in the same sitting. PMID- 29618862 TI - Acetic acid dressings: Finding the Holy Grail for infected wound management. AB - Background: Wounds have since long, contributed majorly to the health-care burden. Infected long-standing non-healing wounds place many demands on the treating surgeon and are devastating for the patients physically, nutritionally, vocationally, financially, psychologically and socially. Acetic acid has long been included among agents used in the treatment of infected wounds. In this study, we have evaluated the use of acetic acid for topical application in the treatment of infected wounds. Materials and Methods: A total of 100 patients with infected wounds were treated with topical application of 1% acetic acid as dressing material after appropriate cleaning. A specimen of wound swab was collected before first application and further on days 3, 7, 10 and 14. Daily dressings of wounds were done similarly. Minimum inhibitory concentration (MIC) of acetic acid against various organisms isolated was determined. Results: The patients treated ranged between 9 and 60 years, with the mean age 33 years. Nearly 70% of patients were male. Aetiologies of wounds: infective 35, diabetic 25, trauma 20, burns 10, venous ulcers 5 and infected graft donor site 5. Various microorganisms isolated include Pseudomonas aeruginosa (40%), Staphylococcus aureus (2%), Acinetobacter (12%), Escherichia Coli (5%), Proteus mirabilis (3%), Klebsiella (18%), methicillin-resistant S. aureus (10%), Streptococcus (2%) and Enterococcus (1%), Citrobacter (1%). Few wounds (6%) also isolated fungi. About 28%, 64% and 8% of patients isolated no growth on culture after 7, 14 and 21 days, respectively. MIC of all isolated organisms was <=0.5%. Conclusion: pH of the wound environment plays a pivotal role in wound healing. Acetic acid with concentration of 1% has shown to be efficacious against wide range of bacteria as well as fungi, simultaneously accelerating wound healing. Acetic acid is non toxic, inexpensive, easily available and efficient topical agent for effective elimination of wound infections caused due to multi-drug resistant, large variety of bacteria and fungus. PMID- 29618863 TI - Ad hoc posterior tibial vessels perforator propeller flaps for the reconstruction of lower third leg soft- tissue defects. AB - Introduction: Lower third leg soft tissue defects with anatomical and pathological constraints are posing formidable challenges to reconstructive surgeon. Aim: This retrospective study was conducted to assess the effectiveness of ad hoc posterior tibial vessels perforator-propeller flaps for the reconstruction of small and medium sized soft tissue defects in the lower third leg. Patients and Methods: 22 patients (16 were males and 6 were females) were involved in this study between period of January 2012 and December 2016.We followed the protocol of initial non delineating exploratory incision made to find out single best perforator in all patients. All the defects in leg reconstructed with adhoc posterior tibial vessel propeller flaps. Results: All 22 flaps survived well. All in an average of 13 months follow up period, had pain free walking, with minimal scarring and acceptable aesthesis at the reconstruction sites with no need for any secondary procedure. Conclusion: With inability of preoperatively dopplering the perforators in the lower third leg region, the exploratory posterior nondelineating incision was used in all cases to secure the single best perforator for the propeller flaps. Thus adhoc posterior tibial vessel propeller flaps are dependable, easily adoptable for the reconstruction of soft tissue defects of the lower third leg region. PMID- 29618864 TI - The conundrum of deep vein thrombosis prophylaxis in burns in India and review of literature. AB - Objective: The aim is to assess the practice of deep vein thrombosis (DVT) prophylaxis among the plastic surgeons attending National Academy of Burns India Conference 2012 (NABICON 2012). Background: DVT prophylaxis in burns is a controversial issue as there is no consensus among the community of burn surgeons about the prevalence of DVT, the incidence of pulmonary embolism, the indications for DVT prophylaxis, dosage and duration of low molecular weight heparins (LMWH) and the complications related to DVT and LMWH. Methodology: A survey was conducted among plastic surgeons attending the NABICON 2012 held at New Delhi, by circulating a questionnaire. The respondents were divided into two groups based on whether burns constituted more than or less than 50% of their practice. The data thus collected were tabulated and analysed. Results: Almost 70% of all the respondents practice some form of DVT prophylaxis. There was significantly higher incidence of complications related to the use of LMWH among the surgeons whose practice of burns was >50%. There was no significant difference between the two groups in relation to the incidence and complication of DVT or recommendation of DVT prophylaxis. Conclusion: Majority of plastic surgeons practice DVT prophylaxis routinely and consider multiple criteria such as percentage of burns, age, lower limb involvement, the degree of burns and associated co-morbidities for starting the LMWH. PMID- 29618865 TI - Planning community-based intervention for speech for children with cleft lip and palate from rural South India: A needs assessment. AB - Background and Aim: A community-based rehabilitation programme, Sri Ramachandra University-Transforming Faces project, was initiated to provide comprehensive management of communication disorders in individuals with CLP in two districts in Tamil Nadu, India. This community-based programme aims to integrate hospital based services with the community-based initiatives and to enable long-term care. The programme was initiated in Thiruvannamalai (2005) district and extended to Cuddalore (2011). The aim of this study was to identify needs related to speech among children with CLP, enroled in the above community-based programme in two districts in Tamil Nadu, India. Design: This was a cross-sectional study. Participants and Setting: Ten camps were conducted specifically for speech assessments in two districts over a 12-month period. Two hundred and seventeen individuals (116 males and 101 females) >3 years of age reported to the camps. Methods: Investigator (SLP) collected data using the speech protocol of the cleft and craniofacial centre. Descriptive analysis and profiling of speech samples were carried out and reported using universal protocol for reporting speech outcomes. Fleiss' Kappa test was used to estimate inter-rater reliability. Results: In this study, inter-rater reliability between three evaluators revealed good agreement for the parameters: resonance, articulatory errors and voice disorder. About 83.8% (n = 151/180) of the participants demonstrated errors in articulation and 69% (n = 124/180) exhibited abnormal resonance. Velopharyngeal port functioning assessment was completed for 55/124 participants. Conclusion: This study allows us to capture a "snapshot" of children with CLP, living in a specific geographical location, and assist in planning intervention programmes. PMID- 29618866 TI - Journal club and post-graduate medical education. AB - A journal club is an educational meeting in which a group of individuals discuss published articles, to keep themselves abreast of new knowledge, promoting in them the awareness of current research findings, teaching them to critique and appraise research, and encourage them to utilize research in evidence based practice of the speciality. With so much of market driven research in journals the role of journal club becomes even more vital to differentiate a genuine recent advance from a clever but outright harmful rediscovery of the wheel which has been long discarded. Journal clubs can be department initiated or journal initiated and there are randomized control trials to prove that they improve reading habits, knowledge of epidemiology and statistics, and use of medical literature in practice. Choosing the journal club articles, assessing them and presenting them in the journal club meeting are all of vital importance and as a trainee advances in his training he/she is expected to imbibe the best from his seniors and peers in the club. I a journal club one is simply expected to summarize the research question, the methods, the results and the conclusions and not slavishly read through the article. It is the presenter's interpretation that is more important than actually rehashing the contents of the article. PMID- 29618867 TI - Nasal reconstruction with pre-laminated forehead flap. AB - Loss of nasal skin as well as loss of both lateral alar cartilages and vestibular lining with exposure of septum presents a grotesque deformity by itself, with further danger of loss of nasal bones and other cartilaginous structures leading to total loss of nose. The Goal of the treatment is to restore the skin cover as well as lining and cartilage support, restoring nose while avoiding the deformity. In an elderly patient with Spiritual restrictions, with diabetes and Hypertension, the treatment was needed to be carried out under local anesthesia as a daycare procedure. Forehead flap was pre-Laminated on forehead before the transfer to have all the three layers of nasal covering. Next the flap was transferred, customizing to recipient site. Finally pedicle was divided retaining the supratrochlear vessels, ensuring the vascularity of the reconstruction and retaining the ability to debulk/manipulate the flap later. PMID- 29618868 TI - Alveolar soft part sarcoma of the forearm. AB - Alveolar soft part sarcoma (ASPS) is a rare form of soft-tissue sarcoma arising from connective tissue. It is most often seen in adolescents and young adults and has high propensity for recurrence and metastasis. Clinically, it mimics haemangioma or arteriovenous malformations. In our case report, an 18-year-old female presented with markedly vascular tumour in the left forearm, for which excision biopsy was done. Histopathological report revealed ASPS. The patient was screened for metastasis. Ultrasound abdomen, computed tomography (CT) chest, CT brain and whole-body skeletal survey was done. The patient was found to have bilateral pulmonary metastasis. The patient was given 6 cycles of chemotherapy with adriamycin, cyclophosphamide and vincristine. There was no locoregional and pulmonary recurrence for 11 months after being treated by excision of the tumour followed by chemotherapy. PMID- 29618869 TI - New, small, needle holders: Their designs and usage techniques. PMID- 29618870 TI - A simple technique for temporary marking of the electrical stimulation points in brachial plexus injury patients. PMID- 29618871 TI - Bed pad as an alternative painless, comfortable and economical burn wound dressing. PMID- 29618872 TI - The use of corneal blade in hand surgery. PMID- 29618873 TI - Dumb-bell lipoma of finger digital flexor sheath: Unusual presentation. PMID- 29618874 TI - Bilateral Parotid Sialadenosis Associated with Long-Standing Bulimia: A Case Report and Literature Review. AB - Purpose: Bulimia is a common cause of sialadenosis. This paper presents a case of bilateral parotid sialadenosis associated with long-standing bulimia, and reviews the relevant literature and current treatment options. Methods and Results: A 32 year-old woman had severe bilateral parotid sialomegaly for the last 6 years, which had occurred secondary to bulimia nervosa, which she had since 14 years. Treatment with pilocarpine was unsuccessful, so she underwent bilateral conservative parotidectomy. This procedure not only improved the aesthetic appearance of the patient but also improved her social and work life and overall quality of life. Conclusions: Sialomegaly secondary to bulimia results in a major alteration of the aesthetics of a patient's face. Conservative measures are not enough in many cases, and parotidectomy may be the only viable option, as it can also significantly improve adherence to psychiatric treatment for bulimia, in addition to correcting the facial aesthetics. PMID- 29618875 TI - Role of Serratiopeptidase After Surgical Removal of Impacted Molar: A Systematic Review and Meta-analysis. AB - Background: Serratiopeptidase for pain, facial swelling and trismus associated with surgical removal of impacted molar is under investigation. However conclusive evidence on the use of serratiopeptidase is lacking. Hence a systematic review and meta-analysis of randomized controlled studies was carried out. Methods: Electronic databases were searched for eligible studies and necessary data extracted. The data were analysed using non-Cochrane mode in RevMan 5.0. 95% confidence interval (95% CI) was used to represent the deviation from the point estimate. The heterogeneity between the studies was assessed using Forest plot visually, I2 statistics and Chi square test with a statistical P value of <0.10 to indicate statistical significance. Random-effect models were used in case of moderate to severe heterogeneity. Results: Five studies were included for final review. Serratiopeptidase improved trismus better than corticosteroids with the MD, 95% as 4.42 [3.84, 5]. As regards to swelling, no significant difference was observed for serratiopeptidase when compared to corticosteroids. Paucity of studies precludes any conclusion for other outcome measures as well as for other comparator drugs. Conclusion: Serratiopeptidase could be used safely and effectively to improve trismus and facial swelling after surgical removal of impacted molar. PMID- 29618876 TI - Third Molar and Their Relationship with Caries on the Distal Surface of Second Molar: A Meta-analysis. AB - Purpose: The aim of this meta-analysis was to determine which characteristics of mandibular third molars (MTMs) are more often associated with an increase in the prevalence/incidence of caries on the distal surface of mandibular second molars (MSMs). Methods: Three electronic databases were analyzed: PubMed; OVID and the Virtual Health Library. Observational studies were included, and the risk of bias was assessed using The Newcastle-Ottawa Scale. The Comprehensive Meta-Analysis software program was used for meta-analysis. Results: Fifteen studies were included in this systematic review, and five were included in the meta-analysis. The distal surface of MSMs were more likely to exhibit caries in the following scenarios: when MTMs were found in the A position, rather than the C position (OR: 3.45, 95% CI: 2.28-5.22, p<0.001); when the horizontal position was compared with the vertical (OR: 8.12, 95% CI: 3.75-17.58, p<0.001) and distoangular (OR: 9.75, 95% CI: 3.49 - 27.25, p<0.001) positions; and when the mesioangular position was compared with the vertical (OR: 7.25, 95% CI: 3.48-15.10, p<0.001) and distoangular (OR: 9.54, 95% CI: 3.47 - 26.21, p<0.001) positions. Conclusion: The results of this study suggest that the presence of MTMs increases the incidence of caries on the distal surface of MSMs. Furthermore, caries on the distal surface of MSMs is more commonly associated with position A and horizontal and mesioangular mandibular molars. PMID- 29618877 TI - Infection, Alveolar Osteitis, and Adverse Effects Using Metronidazole in Healthy Patients Undergoing Third Molar Surgery: A Meta-analysis. AB - Purpose: The aim of this systematic review and meta-analysis was to evaluate the risk of surgical infection, alveolar osteitis, and adverse effects using systemic metronidazole in comparison with placebo in healthy patients undergoing third molar surgery. Materials and Methods: The eligible reports were identified from diverse science sources. Clinical trials meeting the inclusion and exclusion criteria and an acceptable Oxford Quality Score were included in this study. The evaluation of risk was done using the Risk Reduction Calculator and Review Manager 5.3., from the Cochrane Library. A significant risk reduction was assumed when the upper limit of the 95% confidence intervals was <1 and the lower limit did not cross zero (negative number) alongside a p value of <0.05 for the overall test. Data of 667 patients from five clinical trials were used for the assessment of risk. Results: Our analysis showed no reduction of the risk of infection or dry socket in patients receiving metronidazole compared to whom took placebo. Meanwhile, the adverse effects did not exhibit a difference between the studied groups. Conclusion: The routine use of systemic metronidazole to prevent surgical site infection and/or dry socket in healthy patients undergoing third molar surgery is not recommended. PMID- 29618878 TI - Facial Anthropometric Norms of the Young Iranian Population. AB - Introduction: Facial anthropometric measurement is considered an essential concern of surgeons, orthodontists, artists and forensic scientists. The aim of this study is to investigate facial anthropometric norms of the young Iranian population. Methods: The study participants consisted of 200 healthy Iranian students (100 males, 100 females) aged 18-25 years old. Twenty-three liner and four angular measurements were investigated twice by a dentist. Independent samples t test was used to compare indices between males and females and also between countries. A p value less than 0.05 was considered statistically significant. Results: It was found that the mean measurements of c'-sn' of both sides, nasolabial angle, trichion-gnathion, tragion-tragion and gnathion-gnathion were statistically greater in Iranian males than in females (p < 0.05). Comparing Iranian anthropometric norms with North American Whites, Malays, Turkish and African American women demonstrated that there were statistically significant differences in most anthropometric measurements between Iranians and other populations (p < 0.05). Conclusion: In Iranians, mean measurements of c'-sn' of the right and left sides, nasolabial angle, trichion-gnathion, tragion-tragion and gnathion-gnathion were greater in men than in women. Comparing Iranian males and females with different ethnicities indicated several interracial differences, which should be taken into consideration when dealing with patients or also practitioners originated in this region. PMID- 29618879 TI - Pediatric Facial Fractures: A 10-year Study. AB - Aims and Objectives: The aim of the study is to retrospectively analyse the incidence of facial fractures along with age, gender predilection, etiology, commonest site, associated dental injuries and any complications of paediatric patients operated in Craniofacial unit of SDM college of dental sciences and hospital. Materials and Methods: This retrospective study was conducted at the department of OMFS, SDM College of Dental Sciences, Dharwad from January 2003 December 2013. All the patients below 15 years of age were included in the study. Data were recorded for the cause of injury, age and gender distribution, frequency and type of injury, localization and frequency of soft tissue injuries, dentoalveolar trauma, facial bone fractures, complications, concomitant injuries and different treatment protocols. Results: A total of 68 cases of paediatric fracture were treated during these 10 years. Boys were commonly injured than girls with a ratio of 2.9:1, the commonest cause of trauma was fall (59 %), mandible was the commonest bone to be fractured (83 %), treatment protocols were dependant on the age, region and type of fracture but in most of the cases closed reduction was the choice of treatment, dental injuries were seen in 26 % patients and the commonest injury was avulsion. Conclusion: This study was done not only to analyse the different types of facial fractures and the pattern of fracture of paediatric cases admitted at this centre, but also to act as a contributional data which will help us to take preventive measures to avoid such injuries and make the appropriate treatment plan and execute it to achieve the pre-injury status of form and function. PMID- 29618880 TI - Evaluation of Teeth in Line of Mandibular Fractures Treated with Stable Internal Fixation. AB - Purpose: To determine whether retention or removal of teeth in line of mandibular fractures affects the incidence of postoperative complications. To evaluate the fate of teeth retained in mandibular fractures based on location of fracture line in relation to apical foramen and lateral periodontium of retained tooth. Method: 51 mandibular fracture sites in 39 patients were treated by open reduction and internal fixation using miniplates. Teeth in line of fracture were removed if showed extensive caries, excessive mobility of tooth, or root fracture. Accordingly patients were divided into two groups, group I tooth removed (15 sites) and group II tooth retained (36 sites). Teeth retained in fracture line were classified based on position of the fracture in relation to apical foramen and the lateral periodontium of involved tooth estimated from preoperative panoramic radiograph into four types. Postoperative periodic follow up done for 1 year and seen for incidence of postoperative complications and fate of tooth in line of fracture. Results: Out of 36 fracture sites in which teeth were retained 5 (13.89%) showed postoperative complications, and out of 15 fracture sites in which teeth were removed 3 (20%) showed postoperative complications. Out of 36 fracture sites in which tooth was retained we found in 3 cases fracture line passed through 2 adjacent teeth. Thus we had in total 39 teeth in fracture line out of them 26 required no treatment 9 required endodontic treatment and 4 teeth required extraction. Need for extraction and endodontic treatment was found more in type I and type III relation. Conclusion: There is an increased risk for postoperative complications when a tooth is removed, although it is not statistically significant. Evaluation of fate of retained teeth showed better prognosis of teeth in type II cases than type III and type I cases. Results of this study leads to conclusions that teeth associated with mandibular fractures need not be removed on prophylactic basis. PMID- 29618881 TI - Epidemiology and Risk Factors of Maxillofacial Injuries in Brazil, a 5-year Retrospective Study. AB - Aim: The etiology and epidemiology of maxillofacial injuries varies widely in different regions of the world due to socioeconomic status, cultural aspects in addition to road traffic and drug consumption. The aim of this study is to determine major causes and epidemiological characteristics of maxillofacial trauma in a 5-year period. Materials and methods: Reports of corporal trauma (n = 25,632) from 2007 to 2011 in the Department of Forensic Medicine were analyzed as to the presence of maxillofacial injuries. Data were submitted to Chi square test and to multivariate Poisson regression. Results: 3262 reports referred maxillofacial trauma. The majority were men (55.8%), single (68.9%), most of them white (75.7%). The average age was 28.9 years (SD = 8.42), and victims with age between 16 and 30 years old were the most affected (48.0%). Women comprised 44% of total sample, 67.8% (971) were single, 76% (1.076) white and 46% (691) aged between 16 and 30 years old. Middle third injuries were associated after adjustment with females (PR 1.05; 95% CI 1.01-1.11), non-white subjects (PR 1.06; 95% CI 1.01-1.12) and physical aggression (PR 1.07; 95% CI 1.02-1.13). Injuries in the oral region was more prevalent in men (PR 1.24; 95% CI 1.09-1.41), in those aged between 16 and 30 (PR 1.97; 95% CI 1.48-2.61) and in subjects with injuries caused by traffic accident (PR 1.21; 95% CI 1.02-1.44). The presence of injuries in the lower third of face remained associated in the final model only with traffic accident (PR 1.75; 95% CI 1.43-2.15). Conclusion: Health care practitioners must recognize vulnerable population and most prevalent sites of lesion to identify cases of violence. PMID- 29618882 TI - Techniques to Improve Reliability and Predictability of the Dorsal Pedicled Tongue Flap in Closure of Palatal Defects and Oronasal Fistulae. AB - Introduction: Despite the improvement in surgical techniques in cleft palate surgery, oronasal fistulas continue to remain a challenge, usually the result of residual palatal and alveolar clefts and post-palatoplasty defects. The tongue flap is an extremely versatile, sturdy, reliable and efficient means of closure of anterior as well as posterior, unilateral and bilateral palatal defects, effectively functionally obliterating the oronasal communication, owing much of its success to its highly vascular structure, good mobility, texture match, central location and low donor site morbidity. However, it has a few drawbacks. Flap dehiscence and detachment during the early postoperative period is a troublesome complication owing to tongue movements during normal activities such as speaking, swallowing, yawning and coughing. Aim: This article describes some of the methods which can be used to effectively alleviate these shortcomings. Methods: A protocol of immobilizing the tongue by tethering it to the maxillary teeth for the 3-week postoperative period, and also maintaining the patient on nasogastric feeding, until the patient is taken up for surgical separation the pedicle, was employed in all patients in this case series. Results: There was a successful and predictable take of the tongue flap at the donor site, namely the palatal/oronasal fistula with its successful closure, in all the patients. Conclusion: Treatment of the oronasal fistula using a two-layer closure using the nasal mucoperiosteum together with an anteriorly based dorsal tongue flap is an easy and efficient method, whose reliability can be further increased by avoiding a common complication, namely tongue flap detachment in the postoperative period brought on by movements of the tongue, by immobilizing the tongue by tethering it to the maxillary teeth and also maintaining the patient on nasogastric feeding for the 3-week postoperative period. PMID- 29618883 TI - What Surgical Education the Speciality Offers? Perception of Role of Oral and Maxillofacial Surgery by 1200 Healthcare Professionals, Students and the General Public in Hyderabad, India. AB - Aim: To investigate the perception of Oral and maxillofacial surgery by healthcare professionals, students and general public. Materials and Methods: A questionnaire form was created that listed ten clinical situations, and given by hand to 1200 individuals, divided into six groups: group 1, medical professionals; group 2, Specialties of dentistry; group 3, general dentists; group 4, medical students; group 5, dental students; and group 6, general public, each comprising 200 individuals. Respondents were asked to indicate who they would expect to treat them if they had one of the specified conditions listed in the questionnaire. We present the results and current awareness levels of this simple questionnaire. The present study addresses the common issue raised by many authors, 'What surgical education the speciality offers?' especially to medical professionals, medical students and general public to enhance an appropriate referral. Results: Most of the respondents in groups 2, 3 and 5 agreed that specific conditions listed in the questionnaire were within the domain of oral and maxillofacial surgery, but such response was not seen in groups 1, 4 and 6 (p < 0.001). An overall awareness level of oral and maxillofacial surgery was found to be 50.2%. Conclusion: The onus of creating and improving the awareness and perception of our specialty lies on oral and maxillofacial surgeon. Unified efforts at individual as well as global level will help achieve this goal. PMID- 29618884 TI - Simultaneous Occurrence of a Midline Sublingual Dermoid Cyst with Respiratory Epithelium and Submental Dermoid Cyst in a Paediatric Patient: A Case Report and Review of Literature. AB - Aim: To present the case of a simultaneously occuring sublingual dermoid cyst with respiratory epthelium and a submental dermoid cyst, and also to review literatures on the same. Methods: A complete examination, radiograph, MRI and excision biopsy of both lesions were carried out and diagnosis was arrived at histopathologically. Results: The histopathology of the submental swelling revealed orthokeratinized stratified squamous epithelium with underlying connective tissue consisting of dense irregularly arranged collagen fibres with fibroblasts along with chronic inflammatory cell infiltrate of lymphocytes and plasma cells. There was presence of sebaceous glands and sebum. Sublingual swelling showed non-keratinized stratified squamous epithelium with a fibrovascular connective tissue. Areas of pseudostratified ciliated columnar epithelium were also evident in some areas. Presence of sebaceous glands also seen. Based on these findings a confirmatory diagnosis of sublingual dermoid cyst with respiratory epithelium and submental dermoid cyst was made. Conclusion: This report throws light on midline lesions of the oral cavity and hopes to add this rare case into the current differential diagnosis of the same. PMID- 29618885 TI - Endoscopic Assisted Combined Transantral and Subciliary Approach in Treatment of Orbital Floor Fracture: A Case Report. AB - Management of orbital floor fracture remains the most debated topic in maxillofacial field. There are many approaches to reconstruct orbital floor fractures and restore orbital position and function, but many have the drawback of incomplete visualization, especially of the posterior part of the orbit. Pain, diplopia and enophthalmos are the most common presenting symptoms in patients who sustained orbital blow out fracture. The main aim in treating orbital fracture is to reduce the prolapsed orbital tissue and reconstruct the floor which will improve diplopia and enophthalmos. As minimally invasive surgical techniques are gaining popularity, it is possible to reconstruct the orbital fracture defects using endoscopes. Endoscopic assisted combined transantral and subciliary technique provides better surgical access and outcome in the treatment of orbital floor fracture. PMID- 29618886 TI - Scar Management After Surgical Repair of Lateral Facial Clefts. AB - The prevention of scar contracture after surgery is an important aspect of lateral facial cleft repair. Maintaining adequate mouth opening is essential for speech, expression, chewing, oral hygiene and psychosocial well-being. Although there have been extensive reviews of non-surgical microstomia management in patients with oral electrical burns, there have been no reports on the use of oral commissure splints to manage the surgical scar in patients with lateral facial clefts. The case study presented here will demonstrate the clinical use of cheek retractors to provide physical resistance to scar contracture. We recommend early rehabilitation with cheek retractors to minimize scar contracture and the negative sequelae of scarred tissues on the dentition after lateral facial cleft repair. PMID- 29618887 TI - Comparison of Ropivacaine 0.75 % and Lignocaine 2 % with 1:200,000 Adrenaline in Dental Extractions: Single Blind Clinical Trial. AB - Introduction: The aim of this study was to evaluate the efficacy, safety and clinical acceptability of the local anaesthetic agent ropivacaine 0.75 % in comparison with lignocaine 2 % with adrenaline 1:200,000 in minor oral surgical procedures. Methods: Forty-seven patients, who required bilateral extractions in a single arch, were included in this study. One hundred and sixty-six extractions were performed and all the patients were administered nerve blocks/infiltration. Pre and postoperative pulse, blood pressure, random blood sugar, electrocardiogram and partial oxygen pressure were recorded at specified time intervals. Pain score by visual analogue scale, onset of action and depth of anesthesia were also observed. Duration of anaesthesia was assessed by feeling of numbness and first sign of pain. Results: Statistical analysis revealed insignificant difference between both the groups in terms of pulse, blood pressure, random blood sugar, and partial oxygen pressure. The depth of anesthesia was evaluated by pain, comfort during the procedure with visual analog scale and showed no significant difference between the two groups. The onset of action for maxillary infiltration was 33.29 +/- 9.2 (ropivacaine), 32.12 +/- 6.8 s (2 % lignocaine with adrenaline 1:200,000) and for pterygomandibular nerve block was 181.0 +/- 87.5 (ropivacaine), 32.12 +/- 6.8 s (2 % lignocaine with adrenaline 1:200,000). Duration of anesthesia when compared was 411.7 +/- 66.11 min (ropivacaine) and 107.87 +/- 16.54 (2 % lignocaine with adrenaline 1:200,000). On maxillary buccal vestibule infiltration it was also observed that in ropivacaine group there was no requirement of palatal infiltration suggestive of good diffusion property. Conclusion: Ropivacaine is a safe, clinically acceptable long acting local anaesthetic agent with added advantage of effective diffusion property. Ethical Committee Approval Number: SDC/MISC/2013/239. PMID- 29618888 TI - Strain Distribution and Amount of Force Required During Pterygomaxillary Dysjunction: A Comparison of Pterygoid Versus Shark-fin Osteotome. AB - Objective: This study was conducted to compare the efficacy of Obwegeser's pterygoid osteotome and Laster shark-fin osteotome by measurement of strain adjacent to the pterygomaxillary suture and the amount of force required for dysjunction. Materials and Methods: Two popular instruments Obwegesser's pterygoid and shark-fin osteotome were tested on dry human skulls. The external force required for separation of the pterygomaxillary suture with these osteotomes was generated by an electronically controlled 'Instron' tester Bi-06 108. Tests were performed with pterygoid osteotome placed on one randomly chosen side and shark-fin osteotome on the other side of the same specimen. The amount of strain developed by each of these instruments was recorded using two strain gauges on the right and left lateral pterygoid plates. Results: [Table: see text]. Conclusion: Based on the distribution of strain, from this study, we conclude that Laster shark-fin osteotome is efficacious over Obwegeser's Pterygoid osteotome, in Le fort I osteotomy. PMID- 29618889 TI - Comparison of Efficacy of Transalveolar Screws and Conventional Dental Wiring Using Erich Arch Bar for Maxillomandibular Fixation in Mandibular Fractures. AB - Introduction: Maxillomandibular fixation is required in nearly all cases of facial fractures which can be achieved by conventional dental wiring techniques or newer methods using transalveolar screws. Material and Methods: A prospective randomized clinical study divided into two groups with thirty adult patients each with mandibular fractures was undertaken comparing the Maxillomandibular fixation technique using transalveolar screws and Erichs arch bar. Total time taken, rate of glove perforation, intraoperative and postoperative complications were noted in both the groups. Results: The time taken for maxillomandibular fixation in minutes and rate of glove perforation was found to be statistically significantly less for transalveolar group compared to arch bar group (p < 0.05). However, there was no significant difference found in the oral hygiene and gingival status using the Glass index and Gingival index. The rate of screw breakage (04.67%), wire breakage (05.12%), non-vitality due to iatrogenic dental damage (01.66%), soft tissue injury and tooth loss were some of the noted complications during the study. Conclusion: We found that transalveolar group offered advantages like less time taken with a definite decreased risk of percutaneous injury, while the iatrogenic complications like dental damage can be reduced by taking adequate precautions. PMID- 29618890 TI - Modified Le Fort III Osteotomy: Different Applications. AB - Summary: Based on the new concepts of the modified Le Fort III osteotomy (MLFIIIO), Three variations of this technique are implemented: (A) the modified osteotomy Le Fort III Champy (1980) technique to be described with the use of surgical guides, and subciliary approach or an transconjunctival approach. Excellent technique for horizontal advancement no further to 6 mm, without requiring any type of graft.. (B) The modified Le Fort III osteotomy in "Z": to solve horizontal (posterior anterior) problems of more than 6 mm without bone grafting. It is itself a modification of the technique described by Champy. (C) The modified Le Fort III osteotomy ascending: modified the original technique described by Bell and Epker with interpositional grafts, was modified by the called ascendant, making it higher in cases where the patient has an acceptable nasal bridge, but exorbitism the lateral wall of the orbit. Le Fort III osteotomy combined with a Le Fort I osteotomy and a front implant. Method: As pointed out in Part I for the modified oblique Le Fort III osteotomy, methods for the design of the osteotomy Le Fort III property will depend on the requirements of individual patients, and this has led us to design specific techniques for the deformity. Results: Patients have a right projection of the middle third, and protection of the eyeball. Conclusions: The techniques presented for the advancement of the middle third have excellent results with the ability to be tailored to each patient deformity. PMID- 29618891 TI - Arthroscopy of the Inferior Compartment of the Temporomandibular Joint: A New Perspective. AB - Objective: Arthroscopy of the temporomandibular joint (TMJ) has become a well standardized non-invasive procedure for the treatment of TMJ internal derangement (ID). Since the last 1980s, no clinical application for arthroscopy of the inferior compartment has been established because of the intrinsic difficulty of the technique and the believing of the absence of clinical relevance for treatment of ID. Methods: We report on a particular case in which arthroscopy of the inferior joint compartment together with the examination of the upper joint space was performed in a patient with ID of the TMJ. A 1.9 mm scope was used, while the technique for entering the inferior compartment is presented. Results: The presence of intense synovitis, fibrous adhesion, and pseudowall were observed in the inferior joint compartment, thus leading to the hypothesis of the more than likely influence of the status of the synovial lining within this space in the persistence of symptoms in recalcitrant patients with ID. Conclusion: We believe that this new insight could lead surgeons to a more complete use of this non-invasive procedure for the treatment of this entity. Level of Evidence: 4/5. PMID- 29618892 TI - Musculoskeletal Changes as a Sequel to Advancement Genioplasty: A Long-Term Cephalometric Prospective Study. AB - Aims: The aim of this study was to evaluate cephalometrically the stability of hard tissues and soft tissue changes of advancement genioplasty 2 years after surgery. Methods: A prospective study was conducted which comprised of 25 patients, who underwent advancement genioplasty alone with no other orthognathic surgical procedures. Immediate pre-operative, 6 months postoperative, and 2 years postoperative lateral cephalograms were compiled and assessed. Results: The mean surgical advancement planned was around 8 mm. Six months post-surgery, the relapse rate was 15% of the surgical advancement which was considerably reduced in the following 18 months to 7%. The ratio of soft tissue to bony advancement at pogonion was 0.9:1. There are significant alterations in the soft tissue profile in terms of decrease in the soft tissue thickness, facial convexity angle, deepened mentolabial sulcus and minimal increase in the lower lip height. Conclusion: Advancement genioplasty was considered as a relatively stable procedure, if adequate muscular pedicle and internal rigid fixation were maintained. The present study was of 2 years, and we can expect further changes in the hard and soft tissues, which are clinically irrelevant. PMID- 29618893 TI - Role of Panoramic Imaging and Cone Beam CT for Assessment of Inferior Alveolar Nerve Exposure and Subsequent Paresthesia Following Removal of Impacted Mandibular Third Molar. AB - Objectives: Pre-operative radiographic evaluation of impacted mandibular third molar and inferior alveolar canal (IAC) is important in preventing a possible nerve exposure and damage during surgical removal. The present study analysed the relation of the mandibular third molar with inferior alveolar canal using panoramic radiography (PAN) and cone beam CT (CBCT) and evaluated the radiographic features suggestive of IAN exposure and post-operative paresthesia. Materials and Methods: PAN and CBCT findings of 53 impacted mandibular third molars having a close relation with IAC undergoing extraction were analysed. Further, all cases were evaluated for any sensory loss in relation to IAN 1 week post-operatively. Results: The most common PAN feature was combination of darkening of roots (DR) and interruption of white line (IWL), seen in 35.86% (19) cases. The most common CBCT feature was thinning of lingual cortex in 81.14% (43) cases. The most common location of IAC in CBCT was inferior in 47.16% (25) cases, followed by buccal 26.41% (14). On comparison of PAN and CBCT findings, DR and IWL both exclusively 92.86% (13); 80% (12) cases and in combination 75% (15) were most commonly associated with thinning of lingual cortex. IAN exposure was seen in 7.55% (4) cases, and 3.77% (2) cases reported with paresthesia. Absence of corticalisation and IWL was associated with all cases of nerve exposure, inter radicular location of IAC seen in three out of the four cases. Cases with paresthesia had DR and deflection of roots (DEFR) with thinning of lingual cortex by roots. Conclusion: DR with DEFR or IWL in PAN as combination and inter radicular location of IAC with thinning of lingual cortex by root tips in CBCT are highly predictive of nerve exposure and subsequent paresthesia. PMID- 29618894 TI - Comparative Histomorphometric Evaluation of Healthy and Ankylosed Mandibular Condylar Process. AB - Background: Temporomandibular joint (TMJ) ankylosis is one of the most disruptive maladies afflicting the masticatory system. The characteristic feature is the formation of bony mass bridging condyle with glenoid fossa. The exact pathogenesis is, however, not completely understood. Purpose: To investigate and compare histomorphometric features of ankylosed condylar specimen with normal condylar process. Materials and Methods: Group I included 17 post-traumatic unilateral TMJ ankylosis patients managed by excision of ankylosed mass and interpositional arthroplasty. Group II included 13 condylar head fracture patients managed by surgical debridement. The bony specimens of both the groups were subjected to histomorphometric examination for assessment of percentage of bone in trabeculae area (%BONE), osteocyte cell density (OSTCD), the presence of inflammation and fibrosis. Results: The mean %BONE, OSTCD, %inflammation, %fibrosis was 60.4%, 340.9 mm2, 52.9 and 58.8% in group I and 29.6%, 202.6 mm2, 31 and 0% in group II. %BONE, OSTCD and fibrosis in cases of TMJ ankylosis were significantly higher than the controls while no significant difference was observed in the presence of inflammation. Conclusion: The persistence of joint inflammation following condylar head fracture causes aggressive reparative process leading to ankylosis. PMID- 29618896 TI - Cortical Bone Graft and GTR Membrane as "Ceiling Effect" in Alveolar Bone Grafting. AB - Background: In orofacial cleft deformity cases, bone grafting is a very essential step in reconstruction of the residual alveolar cleft defect. Material and Methods: Though various authors have put forth different techniques and graft sources for alveolar bone grafting, at our center, we have used iliac crest as the graft source and cortical bone graft with GTR membrane as "ceiling effect". Results: We have evaluated a series of cases of secondary alveolar bone grafting done with this technique by same surgeon at our center and have found great success. Conclusion: In this clinical paper, we describe our surgical technique and also the key points from surgeons experience to ensure a better result. PMID- 29618895 TI - Buccal Mucosal Epithelial Cells Downregulate CTGF Expression in Buccal Submucosal Fibrosis Fibroblasts. AB - Introduction: Oral submucosal fibrosis (OSMF) is a chronic debilitating fibrotic disease of the oral cavity and is a serious health hazard in south Asia and, increasingly, the rest of the world. The molecular basis behind various treatment modalities to treat OSMF still remains unclear. In this study, we have investigated the in vitro ability of the buccal mucosal cells to reduce the proliferation of the fibroblasts of the fibrotic area in co-culture of cells and also at the molecular levels to reduce the level of connective tissue growth factor (CTGF) in the OSMF fibroblasts (SMF-F). Materials and Methods: The study compares isolation, morphological and proliferation kinetics of SMF-F and BMF cells with and without co-culturing with BMEs. In addition, we have compared the mRNA expression levels of CTGF in SMF-F co-cultured BME and non-co-cultured SMF-F cells using validated real-time quantitative PCR (RT-qPCR) method. Results: The basic morphological characteristics of SMF-F were similar to BMF, but the former cells had higher proliferation rate in early passages compared to late passage state. We also observed that the CTGF expression levels in SMF-F under co-culture conditions of BME were consistently and significantly downregulated in all four different SMF-F-derived cells from four different patients. Conclusion: Rapid proliferation and collagen synthesis in SMF-F as against BMF cells are the factors that confirm the innate nature of fibrosis fibroblasts (SMF-F). Further, the CTGF expression level in SMF-F was significantly suppressed by BME in co culture conditions against controls (BMF). Considered together, this suggests that the cell therapeutic candidate of BME could be used in treating OSMF. PMID- 29618897 TI - A Simple and Effective Scalp Tourniquet for Controlling Scalp Hemorrhage. PMID- 29618898 TI - An Integrated Molecular Database on Indian Insects. AB - : MOlecular Database on Indian Insects (MODII) is an online database linking several databases like Insect Pest Info, Insect Barcode Information System (IBIn), Insect Whole Genome sequence, Other Genomic Resources of National Bureau of Agricultural Insect Resources (NBAIR), Whole Genome sequencing of Honey bee viruses, Insecticide resistance gene database and Genomic tools. This database was developed with a holistic approach for collecting information about phenomic and genomic information of agriculturally important insects. This insect resource database is available online for free at http://cib.res.in. Availability: http://cib.res.in/. PMID- 29618900 TI - Evaluation of in vitro chondrocytic differentiation: A stem cell research initiative at the King Abdulaziz University, Kingdom of Saudi Arabia. AB - Mesenchymal stem cells (MSCs) from various sources have been used in cartilage differentiation with variable success. Therefore, it is of interest to evaluate the in vitro differentiation potential of the hWJSCs derived from the human umbilical cords into chondrocytes at the stem cell research facility at the King Abdulaziz University. hWJSCs are an attractive choice for tissue engineering and regenerative medical applications including cartilage regeneration. We evaluated the hWJSCs using classical histological and cartilage related gene expression studies. Some of the known parameters were re-examined for consistency at the current laboratory conditions. Early passages (P1-P4) showed short fibroblastic morphology and high expression of MSC related surface markers namely CD29 (99.9%), CD44 (97.8%), CD73 (99.6%), CD90 (95.1%) and CD105 (98.9%). MTT assay showed time dependent increase in hWJSCs proliferation by 61.06% and 206.31% at 48h and 72h respectively. Toluidine blue histology showed that hWJSCs were successfully differentiated into chondrocytes in chondrocytic differentiation medium for 21 days. Differentiated hWJSCs also showed significantly increased expression of collagen type II, aggrecan and SOX9 compared to the undifferentiated control. It should be noted that the determination of the average cell yield, the population doubling time and histological staining wtih alcian blue and/or safronin O is required in future studies for improved evaluation of differentiation. Painless derivation, abundance of stem cells that are hypo-immunogenic and safety issues makes this method advantages to MSCs derived from other sources. PMID- 29618899 TI - Hypothetical endogenous SIV-like antigens in Mauritian cynomolgus macaques. AB - Simian immunodeficiency virus (SIV) infection of Mauritian cynomolgus macaques (MCMs) is an increasingly important nonhuman primate model for HIV vaccine research. We previously reported that in MCMs anti-SIV antibodies can be naturally developed without exogenous infection or vaccination, and that a vaccine targeting SIV protease cleavage sites (PCS) can cross-induce antibodies to non-PCS SIV antigens. We speculate that this is potentially caused by the existence of endogenous SIV-like antigens. External stimuli (such as environmental factors and vaccination) may induce expression of endogenous SIV like antigens to elicit these antibodies. Database and mass spectrometry analyses were conducted to search for such antigens. We identified endogenous SIV-like DNA sequences in cynomolgus macaque genome and non-PCS peptide homologous to SIV Env protein in PBMCs of a PCS-vaccinated monkey. Our preliminary insights suggest that endogenous SIV-like antigens may be one of the possible reasons for the natural and cross-inducible SIV antibodies in MCMs. PMID- 29618901 TI - Agemone mexicana flavanones; apposite inverse agonists of the beta2-adrenergic receptor in asthma treatment. AB - Asthma is an inflammatory disease of the airway that poses a major threat to human health. With increase industrialization in the developed and developing countries, the incidence of asthma is on the rise. The beta2-adrenergic receptor is an important target in designing anti-asthmatic drugs. The synthetic agonists of the beta2-adrenergic receptor used over the years proved effective, but with indispensable side effects, thereby limiting their therapeutic use on a long-term scale. Inverse agonists of this receptor, although initially contraindicated, had been reported to have long-term beneficial effects. Phytochemicals from Agemone mexicana were screened against the human beta2-adrenergic receptor in the agonist, inverse agonist, covalent agonist, and the antagonist conformations. Molecular docking of the phyto-constituents showed that the plant constituents bind better to the inverse agonist bound conformation of the protein, and revealed two flavanones; eriodictyol and hesperitin, with lower free energy (DeltaG) values and higher affinities to the inverse agonist bound receptor than the co-crystallized ligand. Eriodictyol and hesperitin bind with the glide score of -10.684 and - 9.958 kcal/mol respectively, while the standard compound ICI 118551, binds with glide score of -9.503 kcal/mol. Further interaction profiling at the protein orthosteric site and ADME/Tox screening confirmed the drug-like properties of these compounds. PMID- 29618903 TI - Simian Virus 40 Large T Antigen as a Model to Test the Efficacy of Flouroquinolones against Viral Helicases. AB - Simian virus 40 large T-antigen (SV40 LT-Ag) is a 708 amino acid nuclear phosphoprotein. Among many functions of LT-Ag is its ability to perform as an ATPase-helicase, catalyzing the unwinding of viral genome during replication. The LT-Ag has been employed in the studies of helicase structure and function, and has served as a model helicase for the screening of antiviral drugs that target viral helicase. In this study, using in vitro enzyme assays and in silico computer modeling, we screened a batch of 18 fluoroquinolones to assess their potential as antivirals by virtue of their inhibition of the LT-Ag helicase. We found all fluoroquinolones to be inhibitory to the helicase activity of LT-Ag. In our docking analysis, most of these tested drugs showed similarity in their interactions with LT-Ag. Our study shows the potential of fluoroquinolones as antiviral drugs and of SV40 LT-Ag as a model protein for screening drugs against viral helicases. PMID- 29618902 TI - Screening of Human Proteins for Fluoride and Aluminum Binding. AB - Previous studies showed that prolonged exposure to fluoride (F-) and aluminum (Al3+) ions is associated with numerous diseases including neurological disorders. They don't have any known biological function. But they can bind with proteins that interact with ions similar to them. Such unwanted interactions affect the normal biological function of the target proteins, as well as their downstream protein-protein interactions. Several studies show the detrimental effects posed by them including Alzheimer's disease. However, their target proteins have never been reported. Here, we have screened for the human protein targets subjected to F- and Al3+ interactions by using data-driven prediction tools. We have identified 20 different proteins that directly bind with them (10 interact with fluoride and 10 with aluminum). In addition, protein-protein interaction has been explored to find the proteins that indirectly interact with F- and Al3+. We have found 86 indirect targets for F- and 90 for Al3+. Furthermore, 19 common protein targets have been identified, including proteins (9 out of 19) associated with neurodegenerative disorders. However, wet lab experiments are beyond our scopes to validate the binding networks. Additional studies must be warranted. PMID- 29618904 TI - Current Opinions on Chemoresistance: An Overview. AB - Sub population of cancer cells, referred to as Cancer stem cells (CSCs) or tumor initiating cells, have enhanced metastatic potential that drives tumor progression. CSCs have been found to hold intrinsic resistance to present chemotherapeutic strategies. This resistance is attributed to DNA reparability, slower cell cycle and high levels of detoxifying enzymes. Hence, CSCs pose an obstacle against chemotherapy. The increasing prevalence of drug resistant cancers necessitates further research and treatment development. The current review presents the essential mechanisms that impart chemoresistance in CSCs as well as the epigenetic modifications that can induce drug resistance and considers how such epigenetic factors may contribute to the development of cancer progenitor cells, which are not killed by conventional cancer therapies. PMID- 29618906 TI - Mental Health in the Workplace: World Mental Health Day 2017. PMID- 29618905 TI - Quantitative Consensus in Systematic Reviews: Current and Future Challenges in Translational Science. AB - Translational science conceptualizes healthcare as a concerted set of processes that integrate research findings from the bench to the bedside. This model of healthcare is effectiveness-focused, patient-centered, and evidence-based, and yields evidence-based revisions of practice-based guidelines, which emerge from research synthesis protocols in comparative effectiveness research that are disseminated in systematic reviews. Systematic reviews produce qualitative and quantitative consensi of the best available evidence. The quantitative consensus is derived from meta-analysis protocols that are often achieved by probabilistic approach Bayesian statistical models. PMID- 29618907 TI - Green Tobacco Sickness: A Brief Review. AB - Green tobacco sickness (GTS) is the condition that mainly affects the tobacco harvesters. The condition is prevalent in Asian and South American tobacco harvesters. The present review was conducted to discuss the etiology, epidemiology, symptoms, and prevention of GTS. It is caused by the absorption of nicotine through the skin while the workers are engaged in handling the uncured tobacco leaves. The symptoms include nausea, vomiting, pallor, dizziness, headaches, increased perspiration, chills, abdominal pain, diarrhea, increased salivation, prostration, weakness, breathlessness, and occasional lowering of blood pressure. The prevalence of GTS varies from 8.2 to 47% globally. The use of personal protective equipment like water-resistant clothing, chemical-resistant gloves, plastic aprons, and rain-suits with boots should be used by the tobacco farmers to prevent its occurrence. An international-level awareness campaign has to be taken up and more stringent workers safety regulations have to be formulated. PMID- 29618908 TI - Compressed Air Working in Chennai During Metro Tunnel Construction: Occupational Health Problems. AB - Chennai metropolis has been growing rapidly. Need was felt of a metro rail system. Two corridors were planned. Corridor 1, of 23 km starting from Washermanpet to Airport. 14.3 km of this would be underground. Corridor 2, of 22 km starting from Chennai Central Railway station to St. Thomas Mount. 9.7 km of this would be underground. Occupational health centre's role involved selection of miners and assessing their fitness to work under compressed air. Planning and execution of compression and decompression, health monitoring and treatment of compression related illnesses. More than thirty five thousand man hours of work was carried out under compressed air pressure ranged from 1.2 to 1.9 bar absolute. There were only three cases of pain only ( Type I) decompression sickness which were treated with recompression. Vigilant medical supervision, experienced lock operators and reduced working hours under pressure because of inclement environmental conditions viz. high temperature and humidity, has helped achieve this low incident. Tunnelling activity will increase in India as more cities will soon opt for underground metro railway. Indian standard IS 4138 - 1977 " Safety code for working in compressed air" needs to be updated urgently keeping pace with modern working methods. PMID- 29618909 TI - Computer Use and Carpal Tunnel Syndrome: A Case-control Study. AB - Context: Carpal tunnel syndrome (CTS) is one of the musculoskeletal disorders that is often described as an occupational hazard, including occupations involving computer use. However, clear consensus is lacking as far as the association between the use of computer and risk of possible CTS is concerned. Aim: To assess the association between CTS and computer use. Settings and Design: A case-control study. Materials and Methods: A sample size of 411 (137 cases and 274 controls) was calculated using Epi Info (version 6). Thus, 137 confirmed cases of CTS and 274 controls (matched for age and sex) were studied using a structured questionnaire. Statistical Analysis Used: Odds ratio (OR) with 95% confidence interval was calculated between the two groups to analyze the association. For control of confounding factors, logistic regression analysis was done. Results: Current use of computer was found to be significantly higher in controls rather than cases (OR = 0.47, CI = 0.27-0.84, P = 0.009). Similarly, past use of computer was also found to be higher in controls. However, the difference was not statistically significant (OR = 0.38, CI = 0.11-1.35, P = 0.20). On applying logistic regression, variables found to be significantly associated with CTS were education (OR = 0.79, CI = 0.66-0.94, P = 0.01), obesity (OR = 3.11, 95%CI = 1.92-5.04, P = 0.00), and short stature (OR = 1.06, 95%CI = 1.02-1.1, P = 0.00). Although current use of computer (OR = 0.33, CI = 0.16-0.67, P = 0.00) was significantly associated with CTS in multivariate model, OR of value less than one does not indicate positive association between this variable and CTS. Conclusion: The study did not demonstrate any positive association between computer use and CTS. PMID- 29618910 TI - Shift Work and Quality of Personal, Professional, and Family Life among Health Care Workers in a Rehabilitation Center in Greece. AB - Context: Adverse work schedules and conditions may affect the physical, mental, and social wellbeing of workers, impairing quality of life and causing conflict between family and work roles. Aims: To compare quality of life, professional quality of life (ProQOL), and work/family conflict (WFC) between shift workers and nonshift workers and explore possible associations with demographic characteristics. Settings and Design: : A cross-sectional study was conducted in a rehabilitation center in Central Greece, recording demographic, occupational, and family characteristics. Materials and Methods: Participants answered the World Health Organization-5 Well-Being Index, the ProQOL questionnaire [compassion satisfaction (CS), and the burnout (BO) and secondary traumatic stress scales], and the WFC scale. Statistical Analysis Used: IBM Statistical Package for the Social Sciences version 19.0 for Windows. Results: Ninety-one employees (68.7% shift workers) participated, with mean age 33.5. Females reported higher compassion/satisfaction level (P = 0.031). Nursing profession was associated with higher levels of BO (P = 0.021), impact of work to family life (P = 0.008), and impact of family to work (FtW), and WFC (P = 0.008). Parenthood increased the impact of FtW (P = 0.008) and predispose to WFC (P = 0.023). In general, wellbeing was significantly correlated with CS (r = 0.368, P < 0.01), BO (r = -0.538, P < 0.01), and levels of WFC (P = 0.003). Work and family roles conflict was statistically significantly correlated with levels of BO (r = 0.497, P < 0.01), and CS (r = -0.288, P < 0.01). Conclusions: The interaction between general, professional, and family quality of life can guide interventions in the workplace in order to improve workers' quality of life and promote workers' health. PMID- 29618911 TI - Risk Assessment of Workers' Exposure to Volatile Organic Compounds in the Air of a Petrochemical Complex in Iran. AB - Context: Long-term exposure to volatile organic compounds (VOCs) affects the occupancies health in petrochemical complex. Objectives: The aim of this study is to apply the lifetime cancer risk (LCR) and hazard quotient (HQ) in occupational exposure to estimate the risk of VOCs in petrochemical complexes. Settings and Design: A cross-sectional study was conducted in the petrochemical complex of Iran for a period of 1 year. Materials and Methods: Sorbent tubes were used to obtain air samples from 169 workers at different petrochemical complexes in southern Iran. The compounds analyzed with gas chromatography equipped with a flame ionization detector (FID). Statistical Analysis Used: The data were analyzed by SPSS version 16. Comparison between the mean of pollutants concentration in personal samples was performed by one-way analysis of variance (ANOVA) test. Results: For all groups of workers, the results showed that exposure to carcinogenic compounds leads to LCR risks higher than 1 * 10-6. The mean of LCR for benzene is more than 10-4, and 53.3% of workers' exposed has a definite risk; the mean of LCR for workers exposed to ethyl benzene, epichlorohydrin, styrene, and trichloroethylene was between 10-4 and 10-6 and workers' exposure to these compounds was a probability risk for cancer. The mean of HQ was less than 1 for workers exposed to toluene, p-xylene, chlorobenzene, phenol, and methanol. Conclusions: The risk assessment with LCR showed that carcinogenic compounds are the main threat to workers' health and precautions should be taken to control workers' risk. PMID- 29618912 TI - Effort-Reward Imbalance and its Association with Health among Pluckers in a Tea Plantation in South India. AB - Context: Work-related stress is associated with cardiovascular diseases, musculoskeletal disorders, psychological ailments, and work-related injuries. Imbalance between high effort and low reward at work can lead to work stress among plantation workers. Aims: To assess the effort-reward imbalance (ERI) among pluckers in tea plantations in South India and its association on chronic health problems, substance abuses, and workplace injuries. Settings and Design: A cross sectional study was conducted among 346 tea pluckers from May to June 2015 in six selected tea plantations in Anamalai, South India. Patients and Methods: A short version of ERI questionnaire was used to assess the work-related stress among them. Along with ERI questionnaire, sociodemographic details, chronic diseases, substance abuses, and workplace injuries were ascertained. Statistical Analysis Used: Sociodemographic variables were described as frequency and measures of central tendency. Tests of association, such as Chi-square test, were applied. Results: Among the study population, 322 (93.1%) reported more effort, 23 (6.6%) reported more reward, and one (0.3%) had no imbalance between effort and reward. Those in older age group (>=51 years) experienced more effort compared to those in younger age group (<=50 years) (Fisher's exact = 21.905, P = 0.001). Educational status (Fisher's exact = 15.639, P = 0.027) and work experience (Fisher's exact = 23.122, P = 0.003) increased the effort rather than increasing the reward associated with work. No significant association was found between ERI and any chronic diseases, substance abuses, or injuries. Conclusions: Majority of pluckers in tea plantation experienced more effort compared to reward. PMID- 29618913 TI - Evaluation of Work-Related Musculoskeletal Disorders and Postural Stress of Female "Jari" Workers. AB - Aims: The present investigation was aimed to assess the postural stress and the prevalence of musculoskeletal disorders (MSDs) of the "Jari" (golden thread) workers. Settings and Design: This cross-sectional study was carried out on 156 female workers in different areas of the Purba Medinipur, Paschim Medinipur, and Howrah districts of West Bengal, India. Materials and Methods: The MSDs of the workers were evaluated by modified Nordic questionnaire method. The postural pattern during work was assessed by direct observation method. The posture of Jari workers has been analyzed by OWAS, REBA, and RULA methods. The joint angle in normal and working posture was observed. Results and Conclusions: The prevalence of MSDs was very high among the workers. The major locations of body pains in Jari workers were lower back, upper back, neck, wrist, thigh, and shoulder. The occurrence of MSDs was higher in lower and higher age group than that of the middle age group. The total work shift of the workers was approximately 13 h including rest pause. The dominant postures adopted by the workers were sitting on the floor with stretched legs, sitting on the floor with folded knees, and kneeling posture. From the results of the postural analysis, the postures of the Jari workers had been categorized as stressful. There were a significant deviation between normal standing angles and working angles. From the overall study, it may be concluded that adoption of stressful postures for longer duration might be the cause of MSDs in different body parts of the Jari workers. PMID- 29618914 TI - In-depth Analysis of Pattern of Occupational Injuries and Utilization of Safety Measures among Workers of Railway Wagon Repair Workshop in Jhansi (U.P.). AB - Context: Occupational injuries constitute a global health challenge, yet they receive comparatively modest scientific attention. Pattern of occupational injuries and its safety precautions among wagon repair workers is an important health issue, especially in developing countries like India. Aims: To assess the pattern of occupational injuries and utilization of safety measures among railway wagon repair workshop workers in Jhansi (U.P.). Settings and Design: Railway wagon repair workshop urban area, Jhansi (U.P). Occupation-based cross-sectional study. Patients and Methods: A cross-sectional study was conducted among 309 workers of railway workshop in Jhansi (U.P.) who were all injured during the study period of 1 year from July 2015 to June 2016. Baseline characteristics, pattern of occupational injuries, safety measures, and their availability to and utilization by the participants were assessed using a pretested structured questionnaire. Statistical Analysis Used: Data obtained were collected and analyzed statistically by simple proportions and Chi-square test. Results: The majority of studied workers aged between 38 and 47 years (n = 93, 30.6%) followed by 28-37 years (n = 79, 26%). Among the pattern of occupational injuries, laceration (28.7%) was most common followed by abrasion/scratch (21%). Safety shoes and hat were utilized 100% by all workers. Many of them had more than 5 years of experience (n = 237, 78%). Age group, education level, and utilization of safety measures were significantly associated with pattern of occupational injuries in univariate analysis (P < 0.05). Conclusions: Occupational injuries are high and utilization of safety measures is low among workers on railway wagon repair workshop, which highlights the importance of strengthening safety regulatory services toward this group of workers. Younger age group workers show a significant association with open wounds and surface wounds. As the education level of workers increases, the incidence of injuries decreases. Apart from shoes, hat, and gloves, regular utilization of other personal protective equipment was not seen. PMID- 29618915 TI - Exploring the Awareness Regarding E-waste and its Health Hazards among the Informal Handlers in Musheerabad Area of Hyderabad. AB - Introduction: Occupational Health hazards of handling and management of electronic waste is a nascent subject. Improper and unscientific handling of e waste can invite significant human and environmental health risks. Objective: To study the level of awareness about electronic waste and its health hazards amongst informal handlers in Musheerabad, Hyderabad. Methodology: Ethical approval and informed consents were obtained from Institutional Ethical Committee, University of Hyderabad and from the participants respectively before the commencement of study. This was a descriptive cross-sectional study conducted in randomly selected twenty-six waste handling centers from sixty of them in the locality. From each of the centers four handlers agedbetween 18 and 45 were randomly selected. Total of 104 handlers were interviewed using semi-structured schedule. Interviews were also conducted among 10 owners of such centres on the waste management practices. Results: About 72% of the handlers did not know the meaning of electronic waste and 71% were not aware of associated health risks, 85% did not use any protective gears, while 16% acknowledged health issues attributed to improper handling of e-waste, 77% felt their handling of e-waste was appropriate. Majority of center owners felt that informal e-waste handling does not pose any health risks, and reported that there was no awareness campaign by any agency as of then. Conclusion: This study highlights the need for awareness campaigns on proper e-waste management practices to ensure occupational safety among the waste handlers who belong to lower socio-economic strata. PMID- 29618916 TI - Sewage Pollution in Water Supply in Indore. AB - More than 20% of sewage waste is dumped untreated into Indore's water supply, while 80% of it's sewers are under-utilized or blocked. Such conditions may increase exposure to microbial pathogens and compromise water potability. This article reports an environmental risk assessment of Indore's Khan River based on existing literature, including hazard identification, dose-response and exposure assessment, identification of susceptible populations, risk characterization, and potential community-oriented management and communication approaches. PMID- 29618917 TI - Improving Workplace Ergonomics in Corporate Offices: A Comment on Madhwani et al. PMID- 29618918 TI - Head-to-Head Comparison of Three Virtual-Reality Robotic Surgery Simulators. AB - Background and Objectives: There are several different commercially available virtual-reality robotic simulators, but very little comparative data. We compared the face and content validity of 3 robotic surgery simulators and their pricing and availability. Methods: Fifteen participants completed one task on each of the following: dV-Trainer (dVT; Mimic Technologies, Inc., Seattle, Washington, USA), da Vinci Skills Simulator (dVSS; Intuitive Surgical Inc., Sunnyvale, California, USA), and RobotiX Mentor (RM; 3D Systems, Rock Hill, South Carolina, USA). Participants completed previously validated face and content validity questionnaires and a demographics questionnaire. Statistical analysis was then performed on the scores. Results: Participants had a mean age of 29.6 (range, 25 41) years. Most were surgical trainees, having performed a mean of 8.6 robotic primary surgeries. For face validity, ANOVA showed a significant difference favoring the dVSS over the dVT (P = .001), and no significant difference between the RM, dVSS, and dVT. Content validity revealed similar results, with a significant difference between the dVSS and dVT (P = .021), a trend toward a difference between the RM and dVT (P = .092), and no difference between the dVSS and RM (P = .99). Conclusion: All simulators demonstrated evidence of face and content validity, with significantly higher scores for the dVSS; it is also the least costly ($80,000 for the simulator), although it is frequently unavailable because of intra-operative use. The dVT and RM have similar face and content validity, are slightly more expensive, and are readily available. PMID- 29618919 TI - Umbilical Quilting Suture Technique during Single-Port Laparoscopic Surgery. AB - Background and Objectives: Single-port laparoscopic surgery (SPLS) is popular in the gynecological field, because it is less invasive and leaves a smaller scar. However, the postoperative shape of the umbilicus is often distorted due to the intensive procedures performed through the small opening. In this report, we describe a technique for forming a satisfactory umbilicus in SPLS. Methods: From March 2016 through April 2017, 32 patients were treated with SPLS by a single gynecologic surgeon. Group A (14 cases) underwent conventional umbilicus closure, and group B (18 cases) underwent a quilting suture technique. The umbilical shapes of each group were assessed by a plastic surgeon as was the patients' satisfaction. Evaluations were performed immediately after surgery and every month for 6 months thereafter. Results: The postoperative umbilical shape in group A showed features, such as loss of depression, disappearance of the central vertical line, and irregularly bulging tissue, whereas group B had a shape similar to that of the natural umbilicus and maintained its depression and vertical line. The average scores of the plastic surgeons' evaluations immediately after the operation were 10.4 for group A and 15.1 for group B. The final scores obtained 6 months after surgery were 15.2 and 17.8, respectively. The patients' satisfaction scores immediately after the operation were 4.9 for group A and 7.3 for group B. The scores increased gradually, to 8.1 and 9.2, respectively, at 6 months after surgery. Conclusion: Performing quilting sutures during wound closure in SPLS is effective for making an ideal umbilicus and ensuring patients' satisfaction. PMID- 29618920 TI - Vitreous levels of apolipoprotein A1 and retinol binding protein 4 in human rhegmatogenous retinal detachment associated with choroidal detachment. AB - Purpose: This study aims to quantify the concentration of apolipoprotein A1 (APOA1) and retinol binding protein (RBP4) expressed in the vitreous humors of patients with rhegmatogenous retinal detachment associated with choroidal detachment (RRDCD), rhegmatogenous retinal detachment (RRD), and idiopathic epimacular membrane (IEM). This study also aims to investigate the potential role of APOA1 and RBP4 as biomarkers of RRDCD. Methods: Enzyme-linked immunosorbent assay (ELISA) kits were used to obtain levels of APOA1 and RBP4 from the vitreous humor samples of 76 primary patients. These patients included 23 patients with RRDCD, 28 patients with RRD, and 24 patients with IEM. All patients were undergoing planned pars plana vitrectomy. The differences between the concentrations of the molecular biomarkers among different patient groups were analyzed using the Mann-Whitney U-test for nonparametric values and independent samples t-test or one-way ANOVA analysis for parametric data. The relationship between the molecular biomarkers, grades of proliferative vitreoretinopathy (PVR), and quadrants of retinal detachment were analyzed using nonparametric Spearman's rank correlation analysis. Results: The vitreous concentrations of APOA1 and RBP4 were statistically significantly higher in the RRDCD group compared to the RRD and IEM groups. Patients with severe PVR demonstrated a higher concentration of APOA1 and RBP4 compared to those with mild PVR, but this finding was not statistically significant. There was a statistically significant positive correlation between APOA1 and RBP4 in the RRDCD and RRD groups. Nonparametric Spearman's rank correlation analysis revealed that levels of APOA1 and RBP4 increased statistically significantly with an increasing number of detached retinal quadrants in the RRDCD and RRD groups. Conclusions: The findings of this study allude to the potential of APOA1 and RBP4 as specific biomarkers of RRDCD. The findings of this study may contribute to increased understanding regarding the role of APOA1 and RBP4 in RRDCD. PMID- 29618922 TI - In-depth interviews of patients with primary immunodeficiency who have experienced pump and rapid push subcutaneous infusions of immunoglobulins reveal new insights on their preference and expectations. AB - Purpose: Patients with primary immunodeficiency (PID) often receive immunoglobulin replacement therapy (IgRT). Physicians and patients have the choice between various methods of administration. For subcutaneous immunoglobulin infusions, patients may use an automated pump (P) or push the plunger of a syringe (rapid push [RP]). P infusions are performed once a week and last around 1 hour. RP decreases the duration of administration, but requires more frequent infusions. Patients and methods: Eight out of 30 patients (coming from a single center) who had participated in the cross-over, randomized, open-label trial comparing P and RP participated in a focus group or underwent in-depth interviews. Patients had a long history of home-based subcutaneous immunoglobulin using P. The trial suggested that RP had slightly greater interference on daily life than P, but similar efficacy and better cost-effectiveness. When asked about the delivery method they had preferred, around one-third of patients pointed out RP rather than P. In-depth interviews may reveal unforeseen reasons for patients' preferences. Results: Interviews underlined the complexity of the relationship that the patients maintain with their disease and IgRT. Even if they recognized the genetic nature of the disease and claimed PID was a part of them, patients tried not to be overwhelmed by the disease. IgRT by P was well integrated in patients' routine. By contrast, RP too frequently reminded the patients of their disease. In addition, some patients pointed out the difficulty of pushing the plunger due to the viscosity of the product. Coming back too frequently, RP was not perceived as time saving over a week. Long-lasting use of P could partly explain patients' reasonable reluctance to change to RP. Conclusion: In-depth interviews of PID patients highlighted unforeseen reasons for patients' preference that the physician needs to explore during the shared medical decision making process. PMID- 29618921 TI - PAX6 molecular analysis and genotype-phenotype correlations in families with aniridia from Australasia and Southeast Asia. AB - Purpose: Aniridia is a congenital disorder caused by variants in the PAX6 gene. In this study, we assessed the involvement of PAX6 in patients with aniridia from Australasia and Southeast Asia. Methods: Twenty-nine individuals with aniridia from 18 families originating from Australia, New Caledonia, Cambodia, Sri Lanka, and Bhutan were included. The PAX6 gene was investigated for sequence variants and analyzed for deletions with multiplex ligation-dependent probe amplification. Results: We identified 11 sequence variants and six chromosomal deletions, including one in mosaic. Four deleterious sequence variants were novel: p.(Pro81HisfsTer12), p.(Gln274Ter), p.(Ile29Thr), and p.(Met1?). Ocular complications were associated with a progressive loss of visual function as shown by a visual acuity <= 1.00 logMAR reported in 65% of eyes. The prevalence of keratopathy was statistically significantly higher in the Australasian cohort (78.6%) compared with the Southeast Asian cohort (9.1%, p=0.002). Variants resulting in protein truncating codons displayed limited genotype-phenotype correlations compared with other variants. Conclusions: PAX6 variants and deletions were identified in 94% of patients with aniridia from Australasia and Southeast Asia. This study is the first report of aniridia and variations in PAX6 in individuals from Cambodia, Sri Lanka, Bhutan, and New Caledonia, and the largest cohort from Australia. PMID- 29618923 TI - Patient preferences in the treatment of hemophilia A: impact of storage conditions on product choice. AB - Objectives: To gain insights into the usage of factor VIII (FVIII) products by patients diagnosed with moderate/severe hemophilia A, and to assess the impact and perceived importance of product storage. Methods: In this study, 200 patients diagnosed with moderate or severe hemophilia A across seven countries participated. Data were collected via a 30-minute, face-to-face interview in six countries and via a web-based survey in the seventh country. The questionnaire evaluated the effect of six features associated with FVIII products on the choice of the product; the structure and flow of data collection was designed to eliminate potential bias. Results: Two-thirds of the respondents were using recombinant FVIII products. Only 17% were generally dissatisfied with current FVIII products, whereas >40% of the respondents were dissatisfied with frequency of administration and storage issues when traveling. The majority noted restrictions in their daily activities, particularly travel and sports. Most of them (85%), stored their product in the refrigerator and of these, 88% believed that it should always be stored there. These patients were also less satisfied with the product overall, more concerned about storage temperature, more restricted in daily activities, and spent more time on preparation and injection compared with patients who stored their product at room temperature. Conjoint analysis revealed that origin of FVIII (plasma-derived vs recombinant) was the strongest driver of product choice among all respondents, followed by storage flexibility (temperature), reconstitution device, and administration frequency. In this study, we did not investigate the efficacy and safety of the product. Conclusion: Not refrigerating FVIII products was associated with greater patient satisfaction and less restriction on daily activities. If efficacy and safety are unaffected, then storing FVIII at room temperature might have a positive impact on product choice. Few patients were aware that FVIII can be stored without refrigeration, suggesting that health care professionals who treat hemophilia should communicate this aspect to the patient (depending on the labeled option); this approach might offer patients greater flexibility when traveling and require less time for reconstitution. PMID- 29618924 TI - Bio-based synthesis of silver nanoparticles from orange waste: effects of distinct biomolecule coatings on size, morphology, and antimicrobial activity. AB - Purpose: Despite the numerous reports on biological syntheses of silver nanoparticles (AgNPs), little is known about the composition of their capping agents, protein corona of plant extract-mediated synthesis, and their influence on the properties of AgNPs. Here, orange (Citrus sinensis) waste was utilized as a source of an extract for AgNP synthesis (the protein corona composition of which was elucidated), and also as a starting material for hesperidin and nanocellulose extraction, which were used for bio-based AgNP synthesis. A comparison of the results using the two methods of synthesis is presented. Methods: AgNPs were synthesized using orange (C. sinensis) peel extract (Or AgNPs) in a biological route, and using hesperidin (Hsd-AgNPs) and nanocellulose (extracted from oranges) in a green chemical route. Characterization of nanoparticles was carried out using zeta potential and hydrodynamic size measurements, transmission electron microscopy, and X-ray diffraction. Elucidation of proteins from protein corona was performed via ultra performance liquid chromatography-tandem mass spectrometer experiments. Antimicrobial activity was assessed via minimum inhibitory concentration assays against Xanthomonas axonopodis pv. citri (Xac), the bacterium that causes citric canker in oranges. Results: Or-AgNPs were not completely uniform in morphology, having a size of 48.1+/-20.5 nm and a zeta potential of -19.0+/-0.4 mV. Stabilization was performed mainly by three proteins, which were identified by tandem mass spectrometry (MS/MS) experiments. Hsd-AgNPs were smaller (25.4+/-12.5 nm) and had uniform morphology. Nanocellulose provided a strong steric and electrostatic ( 28.2+/-1.0 mV) stabilization to the nanoparticles. Both AgNPs presented roughly the same activity against Xac, with the minimum inhibitory concentration range between 22 and 24 MUg mL-1. Conclusion: Despite the fact that different capping biomolecules on AgNPs had an influence on morphology, size, and stability of AgNPs, the antibacterial activity against Xac was not sensitive to this parameter. Moreover, three proteins from the protein corona of Or-AgNPs were identified. PMID- 29618925 TI - Can community care workers deliver a falls prevention exercise program? A feasibility study. AB - Background: Almost half of older people receiving community care fall each year and this rate has not improved in the last decade. Falls prevention programs targeted at this group are uncommon, and expensively delivered by university trained allied health professionals. Purpose: To investigate the feasibility of community care workers delivering a falls prevention exercise program to older clients, at low or medium risk of falling, as part of an existing service provision. Patients and methods: Community care workers from 10 community care organizations participated in the training for, and delivery to their clients of, an 8-week evidence-based falls prevention exercise program. Community care workers included assessment staff (responsible for identifying the need for community care services through completing an assessment) and support workers (responsible for providing support in the home). Clients were surveyed anonymously at the completion of the intervention and workers participated in a semi-structured interview. Results: Twenty-five community care workers participated in the study. The falls prevention program was delivered to 29 clients, with an average age of 82.7 (SD: 8.72) years and consisting of 65.5% female. The intervention was delivered safely with no adverse events recorded, and the eligibility and assessment tools were completed by the majority of community care workers (93.1%). Assessment staff found it difficult to find time to deliver the intervention. Support workers were able to complete the intervention within their current service delivery period, with the initial assessment taking a small amount of additional time. Support workers reported enjoying the additional responsibility afforded by delivering the falls prevention program and seeing changes in their clients. The majority of clients (82%) reported enjoying the exercises, with 59% reporting that they felt it made a positive change in their health. Clients completed the exercises on average 4.8 (SD: 2.2) days per week. Conclusion: Community care workers who have completed appropriate training are able to deliver a falls prevention exercise program to their clients as part of their current services. Further research is required to determine whether the program reduces the rate of falls for community care clients and whether integration of a falls prevention program into an existing service is cost-effective. PMID- 29618926 TI - Superparamagnetic iron oxide nanoparticles modified with polyethylenimine and galactose for siRNA targeted delivery in hepatocellular carcinoma therapy. AB - Introduction: A safe and effective in vivo siRNA delivery system is a prerequisite for liver tumor treatment based on siRNA cancer therapeutics. Nanoparticles based on superparamagnetic iron oxide (SPIO) provide a promising delivery system. In this study, we aimed to explore a novel nanoparticle, which is composed of SPIO. Materials and methods: The particles have a core of iron oxide that is modified by galactose (Gal) and polyethylenimine (PEI), which act as shells, providing targeted delivery of therapeutic siRNA to the liver cancer. Gal-PEI-SPIO nanoparticles were synthesized, and the characteristics of the Gal PEI-SPIO encapsulated with siRNA were analyzed. Results: The particles remained nanoparticles and displayed negligible cytotoxicity when loaded with siRNA. In a serum stability assay, the Gal-PEI-SPIO nanoparticles could shield the siRNA from serum degradation and prolong the half-life of the siRNA in the system. Simultaneously, we found that the mixture could be efficiently taken up by Hepa1 6 cells in a flow cytometry assay. To study the anticancer effect, quantitative polymerase chain reaction and Western blotting were used to validate the silencing efficacy of the complexes in vitro. Subsequently, the nanoparticle mixtures were administered intravenously to tumor-bearing mice to explore the tissue distribution and the effect of the siRNA against cancer. We found that the nanoparticles could provide targeted siRNA delivery, accumulate easily in orthotopic tumors, enhance siRNA accumulation in the tumor tissues for 24 h and protect the siRNA from serum nuclease degradation in comparison with the control group. After these study procedures, the mice were sacrificed, and the tumors were removed to compare the tumor size and analyze the therapeutic effect on tumor growth. The tumor volume and the liver/body weight ratio were significantly reduced in the si-c-Met therapy groups. Additionally, the mRNA levels were also lower than those observed in the controls. Conclusion: Based on these results, we concluded that Gal-PEI-SPIO represents a promising and efficient platform for siRNA delivery in tumor therapy. PMID- 29618927 TI - Serum levels of GPER-1 in euthymic bipolar patients. AB - Introduction: Estrogen and its receptors have been suggested as playing a role in the pathogenesis of bipolar disorder (BD). Estrogen functions through the estrogen receptors alpha and beta and the recently discovered G-protein-coupled estrogen receptor-1 (GPER-1). The aim of this study was to evaluate serum GPER-1 levels in euthymic BD patients. Patients and methods: The study population consisted of 38 euthymic outpatients meeting the criteria for BD in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition and 35 age- and gender-matched healthy controls. Medical histories were obtained and physical examinations and laboratory tests conducted. Results: Serum GPER-1 levels were measured in both patients and controls and found to be significantly higher in the BD patients than in controls. These results were not influenced by the medications in use. Conclusion: The results of this study demonstrated that GPER 1 may play a role in BD pathophysiology. PMID- 29618928 TI - Comparison of ramosetron and ondansetron for the treatment of established postoperative nausea and vomiting after laparoscopic surgery: a prospective, randomized, double-blinded multicenter trial. AB - Background: Postoperative nausea and vomiting (PONV) is a common complication after surgery, which increases physical and psychological discomfort and delays recovery. The aim of this study was to test the hypothesis that ramosetron is comparable to ondansetron for the treatment of established PONV after laparoscopic surgery using a prospective, randomized, double-blinded, noninferiority study. Methods: Patients who had at least two risk factors of PONV and underwent laparoscopic surgery under general anesthesia were assessed for eligibility. Patients who developed PONV within the first 2 h after anesthesia received ondansetron (4 mg) or ramosetron (0.3 mg) intravenously in a randomized double-blind manner. Patients were then observed for 24 h after drug administration. The incidence of nausea and vomiting, severity of nausea, rescue antiemetic necessity, and adverse effects at 0-2 or 2-24 h after drug administration was evaluated. The primary endpoint was the rate of patients exhibiting a complete response, defined as no emesis and no further rescue antiemetic medication for 24 h after drug administration. Results: Among the 583 patients, 210 (36.0%) developed PONV and were randomized to either the ondansetron (n=105) or ramosetron (n=105) group. Patient's characteristics were similar between the groups. The complete response rate was 44.1% in the ondansetron group and 52.9% in the ramosetron group after 24 h of initial antiemetic administration. The incidence of adverse events was not different between the groups. Conclusion: We found evidence to support the noninferiority of ramosetron (0.3 mg) compared to ondansetron (4 mg) for the treatment of established PONV in moderate to high-risk patients undergoing laparoscopic surgery. PMID- 29618929 TI - Original endoscopic orbital decompression of lateral wall through hairline approach for Graves' ophthalmopathy: an innovation of balanced orbital decompression. AB - Background: Orbital decompression is an important surgical procedure for treatment of Graves' ophthalmopathy (GO), especially in women. It is reasonable for balanced orbital decompression of the lateral and medial wall. Various surgical approaches, including endoscopic transnasal surgery for medial wall and eye-side skin incision surgery for lateral wall, are being used nowadays, but many of them lack the validity, safety, or cosmetic effect. Patients and methods: Endoscopic orbital decompression of lateral wall through hairline approach and decompression of medial wall via endoscopic transnasal surgery was done to achieve a balanced orbital decompression, aiming to improve the appearance of proptosis and create conditions for possible strabismus and eyelid surgery afterward. From January 29, 2016 to February 14, 2017, this surgery was performed on 41 orbits in 38 patients with GO, all of which were at inactive stage of disease. Just before surgery and at least 3 months after surgery, Hertel's ophthalmostatometer and computed tomography (CT) were used to check proptosis and questionnaires of GO quality of life (QOL) were completed. Findings: The postoperative retroversion of eyeball was 4.18+/-1.11 mm (Hertel's ophthalmostatometer) and 4.17+/-1.14 mm (CT method). The patients' QOL was significantly improved, especially the change in appearance without facial scar. The only postoperative complication was local soft tissue depression at temporal region. Obvious depression occurred in four cases (9.76%), which can be repaired by autologous fat filling. Interpretation: This surgery is effective, safe, and cosmetic. Effective balanced orbital decompression can be achieved by using this original and innovative surgery method. The whole manipulation is safe and controllable under endoscope. The postoperative scar of endoscopic surgery through hairline approach is covered by hair and the anatomic structure of anterior orbit is not impacted. PMID- 29618930 TI - Symptoms Associated With Attention Deficit/Hyperactivity Disorder and Autism Spectrum Disorders in School-Aged Children Prenatally Exposed to Substances. AB - Prenatal exposure to substances may influence a child's neurodevelopment and impact on subsequent mental health. In a hospital-based population of school-aged children prenatally exposed to opiates and a number of illicit substances (n = 57), we evaluated mental health symptoms associated with attention deficit/hyperactivity disorder (ADHD) and autism spectrum disorders (ASD) using the Swanson, Nolan, and Pelham Questionnaire, revision IV (SNAP-IV) and the Autism Spectrum Screening Questionnaire (ASSQ) and compared the scores to a reference group which comprised children from the population-based Bergen Child Study (n = 171). Prenatally exposed children had significantly higher SNAP-IV scores associated with ADHD symptoms in both areas of inattention and hyperactivity/impulsivity and also reported a higher ASSQ score related to an increased number of symptoms associated with ASD, compared with the reference group. Of tested predictors of mental health outcomes in the exposed group, the intelligence quotient was a strong predictor of most mental health outcomes, and neonatal abstinence syndrome was a predictor of inattention. In conclusion, prenatally exposed children had more mental health symptoms associated with ADHD and ASD, compared with the reference group. PMID- 29618931 TI - Upregulated VEGFA and DLL4 act as potential prognostic genes for clear cell renal cell carcinoma. AB - Purpose: As a typical hypervascular tumor, clear cell renal cell carcinoma (ccRCC) is the most common type of RCC. This study was aimed to explore the prognostic genes for ccRCC, focusing on the roles of vascular endothelial growth factor A (VEGFA) and Delta-like ligand 4 (DLL4) in the disease. Materials and methods: The mRNA-sequencing data of kidney renal clear cell carcinoma (KIRC) were obtained from The Cancer Genome Atlas (TCGA) database, including 469 tumor samples and 68 adjacent normal samples. Using limma package, differentially expressed genes (DEGs) were analyzed by differential expression and subgroup analyses and confirmed using validation dataset GSE53757. Followed by enrichment analysis, protein-protein interaction (PPI) network analysis and protein subcellular localization were performed using multifaceted analysis tool for human transcriptome tool, and Cytoscape software and InnateDB database, respectively. Moreover, survival analysis was conducted to identify key prognosis associated genes. In addition, VEGFA and DLL4 levels were detected using real time quantitative PCR (qRT-PCR). Results: A total of 1,984 DEGs were screened in the KIRC tumor samples. VEGFA was located in extracellular space and could interact with placental growth factor (PGF) and angiopoietin 2 (ANGPT2) in the PPI network. Subgroup analysis suggested that VEGFA was significantly upregulated in stages I, II, and III ccRCC tumor samples. Survival analysis showed that TIMP1 was among the top four prognosis-associated genes. qRT-PCR analysis confirmed that the expression levels of DLL4 and VEGFA were significantly upregulated in tumor samples. Conclusion: VEGFA and DLL4 might be prognostic genes for ccRCC. Besides, PGF, ANGPT2, and TIMP1 might also be related to the prognosis of ccRCC patients. PMID- 29618932 TI - miR-1269 promotes cell survival and proliferation by targeting tp53 and caspase-9 in lung cancer. AB - Background and aim: Lung cancer is the leading cause of cancer death worldwide. In this study, we aim to elucidate the role of miR-1269 in the pathogenesis of lung cancer. Methods and results: From the results of analyses using The Cancer Genome Atlas (TCGA) database, we noted the expression of miR-1269 was increased in lung cancer tissue. miR-1269 expression was detected in both the normal adjacent lung tissue and in the tumorous lung tissue of lung cancer patients, and miR-1269 was more highly expressed in the tumors. High expression of miR-1269 correlated with patients' tumor stage and lymph node metastasis. A Cell Counting Kit-8 (CCK8) analysis and a cloning formation assay showed that overexpression of miR-1269 significantly promoted the growth of A549 cells, and that a lower expression of miR-1269 significantly increased cell apoptosis. We used the TargetScan 6.2 Database to predict the potential targets of miR-1269, and a luciferase activity assay was used to determine the direct interaction between miR-1269, tumor protein p53 (TP53), and caspase-9. Results from Western blots and real-time PCR showed that overexpression of miR-1269 significantly inhibited TP53 and caspase-9 expression. In addition, caspase-3 activity was found to decrease in a miR-1269 mimic group. The results showed that gene silencing of TP53 and caspase-9 significantly inhibited A549 cell growth and promoted cell apoptosis. The results also showed that the inhibition of miR-1269 and caspase-9 expression inhibited cell apoptosis. Immunohistochemistry (IHC) results demonstrated that TP53 and caspase-9 were expressed in low levels in tumor tissues, and that an inverse correlation exists between miR-1269 expression levels and TP53 or caspase 9 expression levels. Conclusion: These results demonstrate that miR-1269 promotes cell survival and proliferation by targeting TP53 and caspase-9 in lung cancer. PMID- 29618934 TI - Analysis of utilization patterns and associated costs of the breast imaging and diagnostic procedures after screening mammography. AB - Background: Little data exist on real-world patterns and associated costs of downstream breast diagnostic procedures following an abnormal screening mammography or clinical exam. Objectives: To analyze the utilization patterns in real-world clinical settings for breast imaging and diagnostic procedures, including the frequency and volume of patients and procedures, procedure sequencing, and associated health care expenditures. Materials and methods: Using medical claims from 2011 to 2015 MarketScan Commercial and Medicare Databases, adult females with breast imaging/diagnostic procedures (diagnostic mammography, ultrasound, molecular breast imaging, tomosynthesis, magnetic resonance imaging, or biopsy) other than screening mammography were selected. Continuous health plan coverage without breast diagnostic procedures was required for >=13 months before the first found breast diagnostic procedure (index event), with a 13-month post index follow-up period. Key outcomes included diagnostic procedure volumes, sequences, and payments. Results reported descriptively were projected to provide US national patient and procedure volumes. Results: The final sample of 875,526 patients was nationally projected to 12,394,432 patients annually receiving 8,732,909 diagnostic mammograms (53.3% of patients), 6,987,399 breast ultrasounds (42.4% of patients), and 1,585,856 biopsies (10.3% of patients). Following initial diagnostic procedures, 49.4% had second procedures, 20.1% followed with third procedures, and 10.0% had a fourth procedure. Mean (SD) costs for diagnostic mammograms of US$349 ($493), ultrasounds US$132 ($134), and biopsies US$1,938 ($2,343) contributed US$3.05 billion, US$0.92 billion, and US$3.07 billion, respectively, to annual diagnostic breast expenditures estimated at US$7.91 billion. Conclusion: The volume and expense of additional breast diagnostic testing, estimated at US$7.91 billion annually, underscores the need for technological improvements in the breast diagnostic landscape. PMID- 29618933 TI - Current perspectives on tree nut allergy: a review. AB - Tree nut (TN) allergy is common and often severe. It has become an important health concern as availability and consumption have increased. Prevalence varies by age and geographic region and appears to have increased in children. Accidental ingestion of TNs is common. Unfortunately, there is a lower likelihood of resolution of TN allergy, roughly 10%. TN-specific skin tests and serum immunoglobulin E levels can help aid in the diagnosis of TN allergy, but a careful medical history is important because a positive test in isolation is not typically diagnostic. Component-resolved diagnostic tests are being increasingly utilized and may improve accuracy. Management consists of strict avoidance of the causal nut(s) and prompt treatment of symptoms upon accidental exposure. A specific consideration with regard to the management of TN allergy is the decision to avoid all TNs or only the TNs to which a patient is clinically allergic. There are currently no data on the primary or secondary prevention of TN allergy. Treatment strategies are being evaluated. PMID- 29618935 TI - Metabolic profiling of follistatin overexpression: a novel therapeutic strategy for metabolic diseases. AB - Background: Follistatin (Fst) promotes brown adipocyte characteristics in adipose tissues. Methods: Abdominal fat volume (CT scan), glucose clearance (GTT test), and metabolomics analysis (mass spectrometry) of adipose tissues from Fst transgenic (Fst-Tg) and wild type (WT) control mice were analyzed. Oxygen consumption (Seahorse Analyzer) and lipidomics (gas chromatography) was analyzed in 3T3-L1 cells. Results: Fst-Tg mice show significant decrease in abdominal fat content, increased glucose clearance, improved plasma lipid profiles and significant changes in several conventional metabolites compared to the WT mice. Furthermore, overexpression of Fst in 3T3-L1 cells resulted in up regulation of key brown/beige markers and changes in lipidomics profiles. Conclusion: Fst modulates key factors involved in promoting metabolic syndrome and could be used for therapeutic intervention. PMID- 29618936 TI - Trace elements and oxidative stress in children with type 1 diabetes mellitus. AB - Background: The early imbalances of trace elements in type 1 diabetes (T1D) may cause disturbance of glucose metabolism and more oxidative stress that may enhance the development of insulin resistance and diabetic complications. We aim to evaluate the serum level of selenium (Se), zinc (Zn), magnesium (Mg), and copper (Cu), the degree of oxidative stress and evaluate their relations to glycemic control in children with T1D. Methods: A case-control study which included 100 diabetic children and 40 healthy children age, sex, and ethnicity matched as a control group. The diabetic children were divided into poor and good controlled patients according to glycosylated hemoglobin (A1c %). Studied children underwent history taking, clinical examination and laboratory measurement of serum Se, Zn, Mg, and Cu levels, erythrocyte reduced glutathione (GSH) and peroxidase enzyme activity (GPx). Results: Serum Se, Zn, Mg, Cu, erythrocyte GSH, and GPx were significantly lower in the diabetic group in comparison to the control group (P<0.05) and their levels were lower in poorly controlled patients compared to good controlled patients (P<0.05). The serum Se, Zn, Mg, erythrocyte GSH, and GPx showed a negative correlation with A1c %. The serum Se showed a positive correlation with erythrocyte GSH and GPx ([r=0.56, P<0.001], [r=0.78, P<0.001], respectively). Conclusion: Children with T1D, especially poorly controlled cases, had low serum Se, Zn, Mg, Cu, GSH, and GPx. Low serum Se in diabetic children may affect the erythrocyte GSH-GPx system. PMID- 29618938 TI - Bimodality treatment of patients with pelvic adenoid cystic carcinoma with photon intensity-modulated radiotherapy plus carbon ion boost: a case series. AB - Background: Treatment of patients with pelvic adenoid cystic carcinoma (ACC) remains a challenge owing to the rarity of the disease, the lack of data, and the relative radioresistance of these tumors. Case reports: This case series presents the results of three patients with recurrent or inoperable pelvic ACC treated with intensity-modulated radiotherapy (IMRT) plus carbon ion (C12) boost. Patients received C12 therapy at a dose of 3 Gray equivalents (GyE) (relative biological effectiveness [RBE]) per fraction up to 24 GyE RBE, followed by 50 GyE of photon IMRT in 25 fractions. Conclusion: IMRT plus C12 ion boost as a definitive or adjuvant treatment for pelvic ACCs seems to be a promising therapeutic option. No unexpected toxicity was detected and the observed toxicity remained consistently low. The initial treatment response is promising and similar to that experienced for head and neck ACCs. PMID- 29618940 TI - Langerhans cell histiocytosis with hemorrhagic uveitis and exudative retinal detachment. AB - Bilateral intraocular involvement in Langerhans cell histiocytosis (LCH) is uncommon. A 15-year-old boy presented with painless decreased vision in right and painful left red eye of 2 weeks duration. Visual acuity was 20/500 and 20/200, respectively. A fixed dilated pupil with exudative retinal detachment was present in the right eye and hemorrhagic iris nodules with hyphema and hypopyon were seen in the left eye. Intraocular pressure was 12 and 31 mmHg, respectively, in each eye. Ocular symptoms were preceded by fever with multiple skin rashes, subcutaneous nodules, and lymph node enlargement. The histopathological examination of skin and lymph node showed histiocytes positive for histiocytic S 100. He was treated with topical steroids and antiglaucoma eye drops along with intravenous vinblastine 6 mg and oral prednisolone (1 mg/kg). Hyphema and hypopyon were resolved, vision improved to 20/320 and 20/80, and intraocular pressure was under control. However, as multisystemic LCH has a poor prognosis, we were unable to save him. Hence, fatal conditions like LCH should also be considered in the differential diagnosis of any hemorrhagic uveitis. PMID- 29618937 TI - The impact of alpha-1 antitrypsin augmentation therapy on neutrophil-driven respiratory disease in deficient individuals. AB - Alpha-1 antitrypsin (AAT) is the most abundant serine protease inhibitor circulating in the blood. AAT deficiency (AATD) is an autosomal codominant condition affecting an estimated 3.4 million individuals worldwide. The clinical disease associated with AATD can present in a number of ways including COPD, liver disease, panniculitis and antineutrophil cytoplasmic antibody vasculitis. AATD is the only proven genetic risk factor for the development of COPD, and deficient individuals who smoke are disposed to more aggressive disease. Principally, AAT is a serine protease inhibitor; however, over the past number of years, the assessment of AAT as simply an antiprotease has evolved, and it is now recognized that AAT has significant anti-inflammatory properties affecting a wide range of cells, including the circulating neutrophil. PMID- 29618939 TI - SYK expression level distinguishes control from BRCA1-mutated lymphocytes. AB - Background: About 5%-10% of breast cancer and 10%-15% of ovarian cancer are hereditary. BRCA1 and BRCA2 are the most common germline mutations found in both inherited breast and ovarian cancers. Once these mutations are identified and classified, a course of action to reduce the risk of developing either ovarian or breast cancer - including surveillance and surgery - is carried out. Purpose: The purpose of the current research is to characterize the gene expression differences between healthy cells harboring a mutation in BRCA1/2 genes and normal cells. This will allow detection of candidate genes and help identify women who carry functional BRCA1/2 mutations, which cannot always be detected by the available sequencing methods, for example, carriers of mutations found in regulatory sequences of the genes. Materials and methods: Our cohort consisted of 50 healthy women, of whom 24 were individuals with BRCA1 or BRCA2 heterozygous mutations and 26 were non-carrier controls. RNA purified from non-irradiated lymphocytes of nine BRCA1/2 mutation carriers versus four control mutation negative individuals was utilized for RNA-Seq analysis. The selected RNA-Seq transcripts were validated, and the levels of spleen tyrosine kinase (SYK) mRNA were measured by using real-time quantitative polymerase chain reaction. Results: Differences in gene expression were found when comparing untreated lymphocytes of BRCA1/2 mutation carriers and controls. Among others, the SYK gene was identified as being differently expressed for BRCA1/2 mutation carriers. The expression level of SYK was significantly higher in untreated healthy lymphocytes of BRCA1 heterozygote carriers compared with controls, regardless of irradiation. In contrast to normal tissues, in cancerous breast tissues, the expression levels of the BRCA1 and SYK genes were not intercorrelated. Conclusion: Collectively, our observations demonstrate that SYK may prove to be a good candidate for better diagnosis, treatment, and prevention of BRCA1 mutation-associated breast cancer. PMID- 29618941 TI - Implementing a Social Knowledge Networking (SKN) system to enable meaningful use of an EHR medication reconciliation system. AB - Background: Despite the regulatory impetus toward meaningful use of electronic health record (EHR) Medication Reconciliation (MedRec) to prevent medication errors during care transitions, hospital adherence has lagged for one chief reason: low physician engagement, stemming from lack of consensus about which physician is responsible for managing a patient's medication list. In October 2016, Augusta University received a 2-year grant from the Agency for Healthcare Research and Quality to implement a Social Knowledge Networking (SKN) system for enabling its health system (AU Health) to progress from "limited use" of EHR MedRec technology to "meaningful use." The hypothesis is that SKN would bring together a diverse group of practitioners, to facilitate tacit knowledge exchange on issues related to EHR MedRec, which in turn is expected to increase practitioners' engagement in addressing those issues and enable meaningful use of EHR. The specific aims are to examine: 1) user-engagement in the SKN system, and 2) associations between "SKN use" and "meaningful use" of EHR. Methods: The 2 year project uses an exploratory mixed-method design and consists of three phases: 1) development; 2) SKN implementation; and 3) analysis. Phase 1, completed in May 2017, sought to identify a comprehensive set of issues related to EHR MedRec from practitioners directly involved in the MedRec process. This process facilitated development of a "Reporting Tool" on issues related to EHR MedRec, which, along with an existing "SKN/Discussion Tool," was integrated into the EHR at AU Health. Phase 2 (launched in June 2017) involves implementing the EHR-integrated SKN system over a 52-week period in inpatient and outpatient medicine units. Discussion: The prospective implementation design is expected to generate context-sensitive strategies for meaningful use and successful implementation of EHR MedRec and thereby make substantial contributions to the patient safety and risk management literature. From a health care policy perspective, if the hypothesis holds, federal vendors could be encouraged to incorporate SKN features into EHR systems. PMID- 29618942 TI - Genetic diversity of human respiratory syncytial virus isolated among children with acute respiratory infections in Southern Cameroon during three consecutive epidemic seasons, 2011-2013. AB - Background: Human respiratory syncytial virus (HRSV) is the main viral cause of severe lower respiratory tract disease in infants and young children. The aim of this study was to describe for the first time the genetic variability of HRSV in Cameroonian patients living in Yaounde for three consecutive epidemic seasons. Methods: HRSV-positive nasopharyngeal samples detected in children less than 15 years in Yaounde were collected from September 2011 to December 2013. Semi-nested RT-PCR, sequencing, and phylogenetic analyses of the second hypervariable region of the G gene were performed. Results: A total of 57 HRSV-positive samples were collected during the study period. Among these, 46 (80.7%) could be amplified in the G gene. HRSV group A (HRSV-A) and group B (HRSV-B) co-circulated in this population at 17.4 and 82.6%, respectively. HRSV-A strains clustered in the NA-1 genotype while HRSV-B strains clustered in the BA-9 genotype. HRSV-A strains accounted for 33.3% (2/6), 4.3% (1/23), and 29.4% (5/17) of the viruses isolated in 2011, 2012, and 2013, respectively. Conclusions: This study reports molecular epidemiology data of HRSV in Cameroon for the first time. Additional studies are required to clarify evolutionary patterns of HRSV throughout sub-Saharan Africa to support antiviral and vaccine development. PMID- 29618944 TI - Inflammation in Liver Diseases. PMID- 29618943 TI - A longitudinal examination of US teen childbearing and smoking risk. AB - BACKGROUND: Teenage motherhood and smoking have important health implications for youth in the United States and globally, but the link between teen childbearing and subsequent smoking is inadequately understood. The selection of disadvantaged young women into early childbearing and smoking may explain higher smoking levels among teen mothers, but teen motherhood may also shape subsequent smoking through compromised maternal depression or socioeconomic status, and race/ethnicity may condition these processes. OBJECTIVE: This study examines the relationship between US teen childbearing and subsequent daily smoking, accounting for prior smoking and selection processes related to social disadvantage. Analyses investigate whether socioeconomic status and depression in young adulthood explained any relationship between teen childbearing and daily smoking, as well as examining racial/ethnic heterogeneity in these processes. METHODS: Multivariate binary logistic regression analyses employ the National Longitudinal Study of Adolescent to Adult Health (Add Health; N = 7,529). RESULTS: The highest daily smoking prevalence occurred among non-Hispanic White teen mothers, with lower prevalence among Hispanic and non-Hispanic Black teen mothers. Compared to other women, teenage mothers are 2.5 times as likely to smoke daily in young adulthood. Their greater likelihood of daily smoking is due in part to selection and is also mediated by socioeconomic status in ways that differ by race/ethnicity. CONCLUSIONS: The findings suggest that preventing teen pregnancy or ameliorating its socioeconomic consequences may decrease daily smoking in this vulnerable population. Reducing teen smoking, especially during pregnancy, could improve teen, maternal, and infant health and thereby increase US health and longevity. CONTRIBUTION: This study provides new, nationally representative information about selection, mediation, and heterogeneity processes in the relationship between teen childbearing and subsequent smoking. PMID- 29618948 TI - microRNA-338-3p inhibits proliferation, migration, invasion, and EMT in osteosarcoma cells by targeting activator of 90 kDa heat shock protein ATPase homolog 1. AB - Background: Osteosarcoma (OS) is a rare, malignant bone tumor that primarily affects adolescents and has a high degree of malignancy and high incidence of recurrence and metastasis. Our study aimed to explore the role of miR-338-3p in OS cells. Methods: qRT-qPCR was performed to quantify miR-338-3p expression levels in OS tissue samples and in three common OS cell lines. MG-63 and Saos2 cells were separately transfected with miR-338-3p or NC mimics and miR-338-3p expression levels was determined by qRT-PCR. Cell proliferation was monitored using the Cell Counting Kit-8. Flow cytometer analysis was carried out to determine the distribution of cell cycle stages and apoptosis. Transwell assay was performed to measure the migratory and invasive capacities of MG-63 and Saos2 cells. The expression of Vimentin and E-cadherin was detected by western blot. Luciferase reporter assay, qRT-PCR and western blotting were performed to confirm the target of miR-338-3p. Results: Analysis by qRT-PCR revealed that miR-338-3p was downregulated in the tissue samples of 20 OS patients when compared with that in their matched adjacent non-tumor tissues. Furthermore, miR-338-3p was significantly downregulated in three common OS cell lines, namely, MG-63, Saos2, and HOS, when compared with that in the human osteoblast cell line hFOB1.19. Analysis by luciferase reporter assay, qRT-PCR, and western blotting revealed that activator of 90 kDa heat shock protein ATPase homolog 1 (AHSA1) is a direct target of miR-338-3p. miR-338-3p overexpression led to significant reduction in AHSA1 protein levels in MG63 and Saos2 cells. miR-338-3p overexpression reduced cell viability and migration and invasion behavior of MG63 and Saos2 cells. In addition, miR-338-3p overexpression suppressed epithelial-mesenchymal transition (EMT), induced a significant G1-phase arrest and did not affect the apoptosis in both MG-63 and Saos2 cells. Moreover, overexpression of AHSA1 reversed the inhibitory effect of miR-338-3p overexpression on proliferation, cell cycle, apoptosis, EMT, migration, and invasion of MG63 and Saos2 cells, thereby suggesting that miR-338-3p acts as a tumor suppressor in OS cells by targeting AHSA1. Conclusions: miR-338-3p/AHSA1 can serve as a potential therapeutic target for OS therapy. PMID- 29618949 TI - A cross-talk between integrin beta4 and epidermal growth factor receptor induces gefitinib chemoresistance to gastric cancer. AB - Background: Gastric cancer presents a major health burden worldwide. Therefore, many molecular targeting agents have been evaluated for treatment of gastric cancer. Gefitinib has shown anticancer activity against gastric cancer which work through inhibiting epidermal growth factor receptor (EGFR). However, the effect of gefitinib is limited due to its resistance. Therefore, understanding the mechanisms of gefitinib resistance is desperately needed to formulate novel strategies against gastric cancer. Here, we analyzed resistance mechanism from the crosstalk between EGFR and integrin beta4. Methods: Integrin beta4-expression vector or siRNA were used to analyze the functional effects of integrin beta4 on chemoresistance of gastric cancer cells to gefitinib. EGFR and integrin beta4 expression, proliferation and apoptosis of gastric cancer cells were assayed by indirect immunofluorescence, western blot, MTT and flow cytometry respectively. EGFR and integrin beta4 expression were also assayed on patient samples. Results: It was found that the integrin beta4 expression was increased in gefitinib resistant gastric cell line. The upregulated integrin beta4 expression was identified to promote gefitinib resistance and proliferation, and inhibit apoptosis, while downregulation of integrin beta4 was to inhibit gefitinib resistance and proliferation, and induce apoptosis. Moreover, the overexpression of integrin beta4 in SGC7901 cells resulted in the down-regulation of p-EGFR protein levels while down-regulation of integrin beta4, significantly resulted in overexpression of p-EGFR. The results of western blot from patients also showed there was obvious negative correlation between p-EGFR and integrin beta4 in gastric cancer patients. Conclusion: Considering the above results, it is concluded that the interaction of EGFR and integrin beta4 may change the sensitivity of gefitinib treatment. PMID- 29618950 TI - Tumor-suppressor role of miR-139-5p in endometrial cancer. AB - Background: Endometrial cancer (EC) is the fourth most common malignancy of the female genital tract worldwide. MicroRNAs are important gene regulators with critical roles in diverse biological processes, including tumorigenesis. Several study's show that miR-139-5p is involved in the tumorigenesis and metastasis of various cancers. However, its expression and potential biologic role in endometrial cancer remain to be determined. This study aimed to investigate the miR-139-5p expression and to analyze its function and underlying molecular mechanism in endometrial cancer. Methods: Expression of miR-139-5p was measured using qRT-PCR. The expression of HOXA10 was detected by Immunofluorescence staining in endometrial cancer tissues and adjacent normal tissues. CCK-8 and colony formation assays were used to assess the effect of miR-139-5p on ECC1 and Ishikawa cell line proliferation. Transwell migration assay was used to study the effect of miR-139-5p on EC cell migration. Luciferase reporter assay and western blot were used to confirm targeting of HOXA10 by miR-139-5p. Result: We demonstrated that miR-139-5p was down-regulated in human endometrial cancer compared to their matched adjacent non-tumor tissues. Overexpressed miR-139-5p significantly inhibited endometrial cancer cell viability and migration. Computational algorithm in combination with dual luciferase reporter assays identified HOXA10 as the target of miR-139-5p. HOXA10 expression was downregulated in endometrial cancer cells after miR-139-5p overexpression. The expression level of HOXA10 was significantly increased in endometrial cancer tissues, which was inversely correlated with miR-139-5p expression in clinical endometrial cancer tissues. Conclusion: These findings indicate that miR-139-5p targets the HOXA10 transcript and suppresses endometrial cancer cell growth and migration, suggesting that miR-139-5p acts as a tumor suppressive role in human endometrial cancer pathogenesis. PMID- 29618952 TI - Role of genetic variations of chitinase 3-like 1 in bronchial asthmatic patients. AB - Background: Single nucleotide polymorphisms (SNPs) in chitinase 3-like 1 (CHI3L1) are associated with bronchial severity and pulmonary function. CHI3L1 proteins are involved in both innate and adaptive immune responses; however, to date, the correlation of these SNPs and their age of onset of bronchial asthma has not been demonstrated. Methods: To address the role of these genetic variations, 390 patients with well-controlled bronchial asthma and living in Japan were recruited, genotyped, and had a pulmonary function test performed on them in this study. To analyze the concentration levels of CHI3L1 protein, bronchial lavage fluids were examined. Results: Forced expiratory volume in one second, %predicted (%FEV1), was significantly decreased in homozygotes of rs1214194 compared to heterozygotes and wild type. The age of onset of adult bronchial asthma was significantly younger in GG homozygotes of rs4950928 and AA homozygotes of rs1214194 than in the other two genotypes. The concentration of CHI3L1 protein in bronchial lavage fluid increased in both homozygotes of rs4950928 and rs1214194. Conclusions: Our study demonstrated that the homozygotes of rs4950928 and rs1214194 of CHI3L1 might predict an early onset of bronchial asthma and have the propensity to promote airway remodeling.Trial registration JMA-IIA00045 remodeling-ICS. PMID- 29618951 TI - Importance of hypersensitivity in adverse reactions to drugs in the elderly. AB - Background: The use of drugs in the elderly is very extensive because of the frequent occurrence of chronic diseases. Adverse drug reactions (ADRs) commonly occur in geriatric patients receiving multiple therapeutic regimens. In the literature, little attention has been given to ADRs in the elderly, and particularly to allergic reactions. Objective: The aim of the present study is to provide data on possible inappropriate prescriptions in the elderly in relation to allergic reactions and to identify a list of drugs which are likely inducers of allergic reactions. Methods: We retrospectively evaluated ADRs in patients referring to Immunoallergy Unit of Hospital Policlinico in Bari on the basis of Beers criteria. Among adverse reactions, hypersensitivity reactions were extracted and a comparison between different age groups was assessed. Results: Out of 823 patients with ADRs, in 30.6% hypersensitivity drug reactions (HDR) were diagnosed. Data about drug intake, comorbidities and clinical presentation were collected, aiming to identify possible risk factors. An evaluation of drugs most commonly involved was assessed. Conclusions: HDR are reported to represent 5 10% of all ADRs, while in our study population the prevalence was about 30%. This suggests the need to develop strategies to minimize the incidence of drug allergy in the elderly, as well to reduce the phenomenon of inappropriate prescriptions. PMID- 29618953 TI - DNA Area and NETosis Analysis (DANA): a High-Throughput Method to Quantify Neutrophil Extracellular Traps in Fluorescent Microscope Images. AB - Background: Neutrophil extracellular traps (NETs), extracellular structures composed of decondensed chromatin and antimicrobial molecules, are released in a process called NETosis. NETs, which are part of normal host defense, have also been implicated in multiple human diseases. Unfortunately, methods for quantifying NETs have limitations which constrain the study of NETs in disease. Establishing optimal methods for NET quantification holds the potential to further elucidate the role of NETs in normal and pathologic processes. Results: To better quantify NETs and NET-like structures, we created DNA Area and NETosis Analysis (DANA), a novel ImageJ/Java based program which provides a simple, semi automated approach to quantify NET-like structures and DNA area. DANA can analyze many fluorescent microscope images at once and provides data on a per cell, per image, and per sample basis. Using fluorescent microscope images of Sytox-stained human neutrophils, DANA quantified a similar frequency of NET-like structures to the frequency determined by two different individuals counting by eye, and in a fraction of the time. As expected, DANA also detected increased DNA area and frequency of NET-like structures in neutrophils from subjects with rheumatoid arthritis as compared to control subjects. Using images of DAPI-stained murine neutrophils, DANA (installed by an individual with no programming background) gave similar frequencies of NET-like structures as the frequency of NETs determined by two individuals counting by eye. Further, DANA quantified more NETs in stimulated murine neutrophils compared to unstimulated, as expected. Conclusions: DANA provides a means to quantify DNA decondensation and the frequency of NET-like structures using a variety of different fluorescent markers in a rapid, reliable, simple, high-throughput, and cost-effective manner making it optimal to assess NETosis in a variety of conditions. PMID- 29618954 TI - Treatment of Advanced Non-small-Cell Lung Cancer with Qi-Nourishing Essence Replenishing Chinese Herbal Medicine Combined with Chemotherapy. AB - Background: To evaluate the effect of qi-nourishing essence-replenishing Chinese herbal medicine combined with chemotherapy in survival of advanced non-small-cell lung cancer(NSCLC) patients with essence and qi deficiency. Methods: A prospective multi-centered randomized controlled study was conducted, and 266 advanced NSCLC patients were enrolled. 126 patients in control group received Vinorelbine plus cisplatin(NP) chemotherapy combined with symptom-oriented Chinese herbs medication(without qi-nourishing essence-replenishing herbs);140 patients in experimental group received NP chemotherapy combined with qi nourishing essence-replenishing Chinese herbal medication(Kangliu Zengxiao Decoction and modified Feiyanning Decoction, during and after chemotherapy respectively). Results: One patient in control and 2 in experimental group were excluded for failure to complete two cycles of chemotherapy. During follow-up, 17 and 7 patients in control and experimental group were excluded respectively(4 and 4 for taking Gefetinib after disease progression, 4 and 2 for receiving other chemotherapeutic regimens, 9 and 1 for lost to follow-up). 239 patients were included in the final analysis (131 in experimental group and 108 in control). Median overall survival in experimental group was significantly longer than control group (14.87vs.12.97 months,P = 0.027). In experimental and control group, 1-year, 3-year, 5-year, 7-year, and 9-year survival rates were 57% vs. 53%, 17% vs. 8%, 10% vs. 2%, 6% vs. 0%, and 6% vs. 0%, respectively. Conclusion: Qi-nourishing essence-replenishing Chinese herbal medicine combined with chemotherapy improves survival of advanced NSCLC patients with essence and qi deficiency. PMID- 29618955 TI - Content Is King: Databases Preserve the Collective Information of Science. AB - Databases store sequence information experimentally gathered to create resources that further science. In the last 20 years databases have become critical components of fields like proteomics where they provide the basis for large-scale and high-throughput proteomic informatics. Amos Bairoch, winner of the Association of Biomolecular Resource Facilities Frederick Sanger Award, has created some of the important databases proteomic research depends upon for accurate interpretation of data. PMID- 29618945 TI - Inducers of Senescence, Toxic Compounds, and Senolytics: The Multiple Faces of Nrf2-Activating Phytochemicals in Cancer Adjuvant Therapy. AB - The reactivation of senescence in cancer and the subsequent clearance of senescent cells are suggested as therapeutic intervention in the eradication of cancer. Several natural compounds that activate Nrf2 (nuclear factor erythroid derived 2-related factor 2) pathway, which is involved in complex cytoprotective responses, have been paradoxically shown to induce cell death or senescence in cancer. Promoting the cytoprotective Nrf2 pathway may be desirable for chemoprevention, but it might be detrimental in later stages and advanced cancers. However, senolytic activity shown by some Nrf2-activating compounds could be used to target senescent cancer cells (particularly in aged immune depressed organisms) that escape immunosurveillance. We herein describe in vitro and in vivo effects of fifteen Nrf2-interacting natural compounds (tocotrienols, curcumin, epigallocatechin gallate, quercetin, genistein, resveratrol, silybin, phenethyl isothiocyanate, sulforaphane, triptolide, allicin, berberine, piperlongumine, fisetin, and phloretin) on cellular senescence and discuss their use in adjuvant cancer therapy. In light of available literature, it can be concluded that the meaning and the potential of adjuvant therapy with natural compounds in humans remain unclear, also taking into account the existence of few clinical trials mostly characterized by uncertain results. Further studies are needed to investigate the therapeutic potential of those compounds that display senolytic activity. PMID- 29618956 TI - The intersection of extreme poverty and familial mental health in the United States. AB - Approximately 22% of children in the United States live in poverty, with high rates of caregiver depression and child disruptive behavior disorders (DBD). The current study aims to explore the relationships between living in extreme poverty and both child and parent mental health. Data are comprised of findings from the first effectiveness study of the 4Rs and 2Ss intervention, in addition to preliminary data from an implementation study currently underway (n = 484). Families with an annual income of less than $9,999 reported significantly greater child DBD scores and prevalence of clinically significant levels of caregiver depressive symptoms compared to income levels over $10,000. Findings support the recommendation for parental mental health to be attended to within the context of child mental health services. PMID- 29618957 TI - Systematic and Empirical Study of the Dependence of Polyphenol Recovery from Apricot Pomace on Temperature and Solvent Concentration Levels. AB - This work aims to study the impact of solvent mixture (between 0 and 50% ethanol/water mixture) and temperature (between 25 degrees C and 75 degrees C) levels on the solid-liquid extraction of phenolic compounds (quantity and bioactivity) from apricot pomace. Results show that the mean augmentation of 1% ethanol in the range [0-12%] enhances by three times the extraction of polyphenols compared to the same augmentation in the range [0-50%]. Similarly, the mean augmentation of 1 degrees Celcius in the range [0-25 degrees Celcius] enhances by two times the extraction of polyphenols compared to the same augmentation in the range [0-75 degrees Celcius]. Moreover, 1% of ethanol exhibited a greater impact on the phenolic compound extraction than 1 degrees Celsius. The response surface methodology showed that the optimal extraction condition was reached with 50% ethanol/water at 75 degrees C giving a total phenolic content (TPC) of 9.8 mg GAE/g DM, a flavonoids content (FC) of 8.9 mg CE/g DM, a tannin content (TC) of 4.72 mg/L, and an antiradical activity (AA) of 44%. High-performance liquid chromatography (HPLC) analysis showed that polyphenols were influenced by the selectivity of the solvent as well as the properties of each phenolic compound. Apricot pomace extracts could therefore be used as natural bioactive molecules for many industrial applications. PMID- 29618959 TI - Proficiency of First-Year Podiatric Medical Residents in the Use of Electronic Medical Records. AB - Objectives: The aim of this study was to survey podiatric residency directors to evaluate the proficiency of first-year podiatric medical residents in the use of electronic medical records and its potential impact on medical care. Methods: An online survey consisting of Likert-scale, multiple-choice, and open-ended questions was sent via email to 216 podiatric residency directors. Questions were directed toward the level of proficiency in electronic medical records expected at the beginning of residency training and the impact on patient care of residents' inexperience with electronic medical records. Results: A total of 54 of the 216 podiatric medical residency directors completed the survey. Results indicated that 70.3 percent of respondent directors expected a moderate level of proficiency in the use of electronic medical records; however, 35.2 percent indicated that less than 50 percent of the new residents had experience with electronic medical records prior to starting residency training. Only 51.5 percent of respondent directors felt that the new residents were successful or highly successful in using their hospital's electronic medical record upon arrival, but that figure increased to 98.2 percent upon completion of the first year of residency. Of importance, 29.7 percent of respondent directors reported that inexperience in electronic medical record use resulted in a more-than average to high impact on patient care, with open-ended responses including concerns about potential HIPAA violations, data breaches, or lost data. Conclusion: Residency directors deem it important that incoming first-year residents have a basic understanding of electronic medical records and related health informatics concepts; however, in-depth knowledge is not expected because of the high number of software programs available. Nonetheless, nearly one-third of respondents reported that inexperience in electronic medical record use does have a significant impact on patient care. PMID- 29618958 TI - The Development of a Minimum Data Set for an Infertility Registry. AB - Effective decision making in the healthcare setting is highly dependent on access to reliable and robust data and information. A minimum data set is a standard assessment instrument that is used during the data collection process to ensure that decision makers have access to a consistent set of information. The objective of the current study was to develop a minimum data set for infertility patients that can be employed as the basis for an infertility registry in Iran. A systematic review resulted in the identification of 2,501 articles and 17 patient forms from infertility centers that were relevant to the study objectives. Of these, 10 articles met all the inclusion and exclusion criteria, and 232 data elements were subsequently extracted from these papers. The data elements were classified by three experts and validated via two rounds of a Delphi technique. The accessibility of the data elements was then evaluated during a focus group discussion. Finally, 146 data elements were selected as the minimum data set. The proposed minimum data set could provide the basis for standardization of infertility treatments. Synchronizing the various data sets that are currently in use will be necessary to allow sharing of data across infertility registries. PMID- 29618960 TI - How Confounder Strength Can Affect Allocation of Resources in Electronic Health Records. AB - When electronic health record (EHR) data are used, multiple approaches may be available for measuring the same variable, introducing potentially confounding factors. While additional information may be gleaned and residual confounding reduced through resource-intensive assessment methods such as natural language processing (NLP), whether the added benefits offset the added cost of the additional resources is not straightforward. We evaluated the implications of misclassification of a confounder when using EHRs. Using a combination of simulations and real data surrounding hospital readmission, we considered smoking as a potential confounder. We compared ICD-9 diagnostic code assignment, which is an easily available measure but has the possibility of substantial misclassification of smoking status, with NLP, a method of determining smoking status that more expensive and time-consuming than ICD-9 code assignment but has less potential for misclassification. Classification of smoking status with NLP consistently produced less residual confounding than the use of ICD-9 codes; however, when minimal confounding was present, differences between the approaches were small. When considerable confounding is present, investing in a superior measurement tool becomes advantageous. PMID- 29618961 TI - Exploring Midwives' Need and Intention to Adopt Electronic Integrated Antenatal Care. AB - Documentation requirements for the Indonesian integrated antenatal care (ANC) program suggest the need for electronic systems to address gaps in existing paper documentation practices. Our goals were to quantify midwives' documentation completeness in a primary healthcare center, understand documentation challenges, develop a tool, and assess intention to use the tool. We analyzed existing ANC records in a primary healthcare center in Bangkalan, East Java, and conducted interviews with stakeholders to understand needs for an electronic system in support of ANC. Development of the web-based Electronic Integrated ANC (e-iANC) system used the System Development Life Cycle method. Training on the use of the system was held in the computer laboratory for 100 midwives chosen from four primary healthcare centers in each of five regions. The Unified Theory of Acceptance and Use of Technology (UTAUT) questionnaire was used to assess their intention to adopt e-iANC. The midwives' intention to adopt e-iANC was significantly influenced by performance expectancy, effort expectancy and facilitating conditions. Age, education level, and computer literacy did not significantly moderate the effects of performance expectancy and effort expectancy on adoption intention. The UTAUT results indicated that the factors that might influence intention to adopt e-iANC are potentially addressable. Results suggest that e-iANC might well be accepted by midwives. PMID- 29618962 TI - Development of Hospital-based Data Sets as a Vehicle for Implementation of a National Electronic Health Record. AB - Background: In developing countries such as Iran, international standards offer good sources to survey and use for appropriate planning in the domain of electronic health records (EHRs). Therefore, in this study, HL7 and ASTM standards were considered as the main sources from which to extract EHR data. Objective: The objective of this study was to propose a hospital data set for a national EHR consisting of data classes and data elements by adjusting data sets extracted from the standards and paper-based records. Method: This comparative study was carried out in 2017 by studying the contents of the paper-based records approved by the health ministry in Iran and the international ASTM and HL7 standards in order to extract a minimum hospital data set for a national EHR. Results: As a result of studying the standards and paper-based records, a total of 526 data elements in 174 classes were extracted. An examination of the data indicated that the highest number of extracted data came from the free text elements, both in the paper-based records and in the standards related to the administrative data. The major sources of data extracted from ASTM and HL7 were the E1384 and Hl7V.x standards, respectively. In the paper-based records, data were extracted from 19 forms sporadically. Discussion: By declaring the confidentiality of information, the ASTM standards acknowledge the issue of confidentiality of information as one of the main challenges of EHR development, and propose new types of admission, such as teleconference, tele-video, and home visit, which are inevitable with the advent of new technology for providing healthcare and treating diseases. Data related to finance and insurance, which were scattered in different categories by three organizations, emerged as the financial category. Documenting the role and responsibility of the provider by adding the authenticator/signature data element was deemed essential. Conclusion: Not only using well-defined and standardized data, but also adapting EHR systems to the local facilities and the existing social and cultural conditions, will facilitate the development of structured data sets. PMID- 29618963 TI - Value of Investment as a Key Driver for Prioritization and Implementation of Healthcare Software. AB - Health systems across the nation are recovering from massive financial and resource investments in electronic health record applications. In the midst of these recovery efforts, implementations of new care models, including accountable care organizations and population health initiatives, are underway. The shift from fee-for-service to fee-for-outcomes and fee-for-value payment models calls for care providers to work in new ways. It also changes how physicians are compensated and reimbursed. These changes necessitate that healthcare systems further invest in information technology solutions. Selecting which information technology (IT) projects are of most value is vital, especially in light of recent expenditures. Return-on-investment analysis is a powerful tool used in various industries to select the most appropriate IT investments. It has proven vital in selecting, justifying, and implementing software projects. Other financial metrics, such as net present value, economic value added, and total economic impact, also quantify the success of expenditures on information systems. This paper extends the concept of quantifying project value to include clinical outcomes and nonfinancial value as investment returns, applying a systematic approach to healthcare software projects. We term this inclusive approach Value of Investment. It offers a necessary extension for application in clinical settings where a strictly financial view may fall short in providing a complete picture of important benefits. This paper outlines the Value of Investment process and its attributes, and uses illustrative examples to explore the efficacy of this methodology within a midsized health system. PMID- 29618964 TI - Scaling estimates of vegetation structure in Amazonian tropical forests using multi-angle MODIS observations. AB - Detailed knowledge of vegetation structure is required for accurate modelling of terrestrial ecosystems, but direct measurements of the three dimensional distribution of canopy elements, for instance from LiDAR, are not widely available. We investigate the potential for modelling vegetation roughness, a key parameter for climatological models, from directional scattering of visible and near-infrared (NIR) reflectance acquired from NASA's Moderate Resolution Imaging Spectroradiometer (MODIS). We compare our estimates across different tropical forest types to independent measures obtained from: (1) airborne laser scanning (ALS), (2) spaceborne Geoscience Laser Altimeter System (GLAS)/ICESat, and (3) the spaceborne SeaWinds/QSCAT. Our results showed linear correlation between MODIS-derived anisotropy to ALS-derived entropy (r2= 0.54, RMSE=0.11), even in high biomass regions. Significant relationships were also obtained between MODIS derived anisotropy and GLAS-derived entropy (0.52<= r2<= 0.61; p<0.05), with similar slopes and offsets found throughout the season, and RMSE between 0.26 and 0.30 (units of entropy). The relationships between the MODIS-derived anisotropy and backscattering measurements (sigma0) from SeaWinds/QuikSCAT presented an r2 of 0.59 and a RMSE of 0.11. We conclude that multi-angular MODIS observations are suitable to extrapolate measures of canopy entropy across different forest types, providing additional estimates of vegetation structure in the Amazon. PMID- 29618966 TI - Integration of Nanobots Into Neural Circuits As a Future Therapy for Treating Neurodegenerative Disorders. AB - Recent neuroscientific research demonstrates that the human brain is becoming altered by technological devices. Improvements in biotechnologies and computer based technologies are now increasing the likelihood for the development of brain augmentation devices in the next 20 years. We have developed the idea of an "Endomyccorhizae like interface" (ELI) nanocognitive device as a new kind of future neuroprosthetic which aims to facilitate neuronal network properties in individuals with neurodegenerative disorders. The design of our ELI may overcome the problems of invasive neuroprosthetics, post-operative inflammation, and infection and neuroprosthetic degradation. The method in which our ELI is connected and integrated to neuronal networks is based on a mechanism similar to endomyccorhizae which is the oldest and most widespread form of plant symbiosis. We propose that the principle of Endomyccorhizae could be relevant for developing a crossing point between the ELI and neuronal networks. Similar to endomyccorhizae the ELI will be designed to form webs, each of which connects multiple neurons together. The ELI will function to sense action potentials and deliver it to the neurons it connects to. This is expected to compensate for neuronal loss in some neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease. PMID- 29618965 TI - Peptide Sharing Between Viruses and DLX Proteins: A Potential Cross-Reactivity Pathway to Neuropsychiatric Disorders. AB - The present study seeks to determine potential associations between viral infections and neuropsychiatric diseases. To address this issue, we investigated the peptide commonalities between viruses that have been related to psychiatric and neurological disorders-such as rubella, human immunodeficiency virus, and herpesviruses-and human distal-less homeobox (DLX) proteins expressed in developing brain-namely, DLX1, DLX2, DLX5, and DLX6. Peptide matching analyses revealed a high degree of pentapeptide sharing. From an immunological perspective, this overlap is relevant because pentapeptides are endowed with immunogenicity and antigenicity-that is, they are immune determinants. Moreover, infection-induced immune cross-reactions might have functional, spatial, and temporal implications related to the functions and expression patterns of DLX1 and DLX5 in the fetal and adult human brain. In sum, our data support the hypothesis that viral infections may be linked to neuropsychiatric diseases through autoimmune cross-reactions caused by molecular mimicry between viral proteins and brain-specific DLX self-antigens. PMID- 29618967 TI - Closing the Loop on Deep Brain Stimulation for Treatment-Resistant Depression. AB - Major depressive episodes are the largest cause of psychiatric disability, and can often resist treatment with medication and psychotherapy. Advances in the understanding of the neural circuit basis of depression, combined with the success of deep brain stimulation (DBS) in movement disorders, spurred several groups to test DBS for treatment-resistant depression. Multiple brain sites have now been stimulated in open-label and blinded studies. Initial open-label results were dramatic, but follow-on controlled/blinded clinical trials produced inconsistent results, with both successes and failures to meet endpoints. Data from follow-on studies suggest that this is because DBS in these trials was not targeted to achieve physiologic responses. We review these results within a technology-lifecycle framework, in which these early trial "failures" are a natural consequence of over-enthusiasm for an immature technology. That framework predicts that from this "valley of disillusionment," DBS may be nearing a "slope of enlightenment." Specifically, by combining recent mechanistic insights and the maturing technology of brain-computer interfaces (BCI), the next generation of trials will be better able to target pathophysiology. Key to that will be the development of closed-loop systems that semi-autonomously alter stimulation strategies based on a patient's individual phenotype. Such next-generation DBS approaches hold great promise for improving psychiatric care. PMID- 29618968 TI - Managing Clutter in a High Pulse Rate Echolocation System. AB - The use of echolocation for navigating in dense, cluttered environments is a challenge due to the need for rapid sampling of nearby objects in the face of delayed echoes from distant objects. In the wild, echolocating bats frequently encounter this situation when leaving the roost or while hunting. If long-delay echoes from a distant object are received after the next pulse is sent out, these "aliased" echoes appear as close-range phantom objects. Little is known about how bats cope with these situations. In this work, we demonstrate a novel strategy to manage aliasing in cases where a single target is actively being tracked at close range. This paper presents three reactive strategies for a high pulse-rate sonar system to combat aliased echoes: (1) changing the interpulse interval to move the aliased echoes away in time from the tracked target, (2) changing positions to create a geometry without aliasing, and (3) a phase-based, transmission beam shaping strategy to illuminate the target and not the aliasing object. PMID- 29618969 TI - Possible Role of Dorsolateral Prefrontal Cortex in Error Awareness: Single-Pulse TMS Evidence. AB - Background: Error awareness is essential to maintain an adaptive and goal directed behavior and is supposed to rely on the activity of the right dorsolateral prefrontal cortex (DLPFC). However, studies employing electrophysiological methods and functional resonance imaging (fMRI) do not allow to establish a causal relationship between error awareness and implicated brain structures. Objective: The study examined the causal relationship between DLPFC activity and error awareness in order to confirm the involvement of the right DLPFC in error awareness and to obtain temporal information about this process, namely when the activity of the right DLPFC is involved in error awareness. Methods: Three experiments with three different samples were conducted employing on-line Transcranial Magnetic Stimulation (TMS). A paired-pulse and a single pulse on-line TMS paradigm were employed respectively in Experiments 1 and 3, whereas in Experiment 2 a control test was conducted without TMS. In TMS experiments, the right DLPFC was stimulated, considering the left DLPFC and the Vertex as control sites. Results: Experiment 1 showed no effect of paired-pulse TMS over either right or left DLPFC on error awareness. In Experiment 3, independently from the time point during which TMS was delivered, results showed a significant effect of single-pulse TMS over the DLPFC on Stroop Awareness, without evidence for lateralization of the process. Conclusions: Results of the present study partially demonstrate the involvement of the DLPFC in error awareness. PMID- 29618970 TI - Corticotropin-Releasing Factor Receptors Modulate Oxytocin Release in the Dorsolateral Bed Nucleus of the Stria Terminalis (BNST) in Male Rats. AB - The neuropeptide oxytocin (OT) plays an important role in the regulation of social and anxiety-like behavior. Our previous studies have shown that OT neurons send projections from the hypothalamus to the dorsolateral bed nucleus of the stria terminalis (BNSTdl), a forebrain region critically involved in the modulation of anxiety-like behavior. Importantly, these OT terminals in the BNSTdl express presynaptic corticotropin releasing factor (CRF) receptor type 2 (CRFR2). This suggests that CRFR2 might be involved in the modulation of OT release. To test this hypothesis, we measured OT content in microdialysates collected from the BNSTdl of freely-moving male Sprague-Dawley rats following the administration of a selective CRFR2 agonist (Urocortin 3) or antagonist (Astressin 2B, As2B). To determine if type 1 CRF receptors (CRFR1) are also involved, we used selective CRFR1 antagonist (NBI35965) as well as CRF, a putative ligand of both CRFR1 and CRFR2. All compounds were delivered directly into the BNSTdl via reverse dialysis. OT content in the microdialysates was measured with highly sensitive and selective radioimmunoassay. Blocking CRFR2 with As2B caused an increase in OT content in BNSTdl microdialysates, whereas CRFR2 activation by Urocortin 3 did not have an effect. The As2B-induced increase in OT release was blocked by application of the CRFR1 antagonist demonstrating that the effect was dependent on CRFR1 transmission. Interestingly, CRF alone caused a delayed increase in OT content in BNSTdl microdialysates, which was dependent on CRF2 but not CRF1 receptors. Our results suggest that members of the CRF peptide family modulate OT release in the BNSTdl via a fine-tuned mechanism that involves both CRFR1 and CRFR2. Further exploration of mechanisms by which endogenous OT system is modulated by CRF peptide family is needed to better understand the role of these neuropeptides in the regulation of anxiety and the stress response. PMID- 29618971 TI - Novel Neurostimulation of Autonomic Pelvic Nerves Overcomes Bladder-Sphincter Dyssynergia. AB - The disruption of coordination between smooth muscle contraction in the bladder and the relaxation of the external urethral sphincter (EUS) striated muscle is a common issue in dysfunctional bladders. It is a significant challenge to overcome for neuromodulation approaches to restore bladder control. Bladder-sphincter dyssynergia leads to undesirably high bladder pressures, and poor voiding outcomes, which can pose life-threatening secondary complications. Mixed pelvic nerves are potential peripheral targets for stimulation to treat dysfunctional bladders, but typical electrical stimulation of pelvic nerves activates both the parasympathetic efferent pathway to excite the bladder, as well as the sensory afferent pathway that causes unwanted sphincter contractions. Thus, a novel pelvic nerve stimulation paradigm is required. In anesthetized female rats, we combined a low frequency (10 Hz) stimulation to evoke bladder contraction, and a more proximal 20 kHz stimulation of the pelvic nerve to block afferent activation, in order to produce micturition with reduced bladder-sphincter dyssynergia. Increasing the phase width of low frequency stimulation from 150 to 300 MUs alone was able to improve voiding outcome significantly. However, low frequency stimulation of pelvic nerves alone evoked short latency (19.9-20.5 ms) dyssynergic EUS responses, which were abolished with a non-reversible proximal central pelvic nerve cut. We demonstrated that a proximal 20 kHz stimulation of pelvic nerves generated brief onset effects at lower current amplitudes, and was able to either partially or fully block the short latency EUS responses depending on the ratio of the blocking to stimulation current. Our results indicate that ratios >10 increased the efficacy of blocking EUS contractions. Importantly, we also demonstrated for the first time that this combined low and high frequency stimulation approach produced graded control of the bladder, while reversibly blocking afferent signals that elicited dyssynergic EUS contractions, thus improving voiding by 40.5 +/- 12.3%. Our findings support advancing pelvic nerves as a suitable neuromodulation target for treating bladder dysfunction, and demonstrate the feasibility of an alternative method to non-reversible nerve transection and sub-optimal intermittent stimulation methods to reduce dyssynergia. PMID- 29618973 TI - Visual Maps Development: Reconsidering the Role of Retinal Efnas and Basic Principle of Map Alignment. PMID- 29618974 TI - The Automatic Proportionator Estimator Is Highly Efficient for Estimation of Total Number of Sparse Cell Populations. AB - Estimation of total number of a population of cells that are sparsely distributed in an organ or anatomically-defined region of interest represents a challenge for conventional stereological methods. In these situations, classic fractionator approaches that rely on systematic uniform random sampling are highly inefficient and, in many cases, impractical due to the intense sampling of the organ and tissue sections that is required to obtain sufficient counts for an acceptable level of precision. The proportionator, an estimator based on non-uniform sampling theory, marries automated image analysis with stereological principles and is the only estimator that provides a highly efficient and precise method to address these challenging quantification problems. In this paper, the practical considerations of the proportionator estimator and its implementation with ProportionatorTM software and digital slide imaging are reviewed. The power of the proportionator as a stereological tool is illustrated in its application to the estimation of the total number of a very rare (~50/vertebrae) and sparsely distributed population of osteoprogenitor cells in mouse vertebral body. The proportionator offers a solution to neuroscientists interested in quantifying total cell number of sparse cell populations in the central and peripheral nervous system where systematic uniform random sampling-based stereological estimators are impractical. PMID- 29618975 TI - Automatic Removal of Physiological Artifacts in EEG: The Optimized Fingerprint Method for Sports Science Applications. AB - Data contamination due to physiological artifacts such as those generated by eyeblinks, eye movements, and muscle activity continues to be a central concern in the acquisition and analysis of electroencephalographic (EEG) data. This issue is further compounded in EEG sports science applications where the presence of artifacts is notoriously difficult to control because behaviors that generate these interferences are often the behaviors under investigation. Therefore, there is a need to develop effective and efficient methods to identify physiological artifacts in EEG recordings during sports applications so that they can be isolated from cerebral activity related to the activities of interest. We have developed an EEG artifact detection model, the Fingerprint Method, which identifies different spatial, temporal, spectral, and statistical features indicative of physiological artifacts and uses these features to automatically classify artifactual independent components in EEG based on a machine leaning approach. Here, we optimized our method using artifact-rich training data and a procedure to determine which features were best suited to identify eyeblinks, eye movements, and muscle artifacts. We then applied our model to an experimental dataset collected during endurance cycling. Results reveal that unique sets of features are suitable for the detection of distinct types of artifacts and that the Optimized Fingerprint Method was able to correctly identify over 90% of the artifactual components with physiological origin present in the experimental data. These results represent a significant advancement in the search for effective means to address artifact contamination in EEG sports science applications. PMID- 29618976 TI - The Efficacy and Safety of Mainstream Medications for Patients With cDMARD-Naive Rheumatoid Arthritis: A Network Meta-Analysis. AB - Background: The mainstream medications for rheumatoid arthritis (RA) include conventional disease-modifying antirheumatic drugs (cDMARDs), which mostly are methotrexate (MTX), and biologic agents such as adalimumab (ADA), certolizumab (CZP), etanercept (ETN), golimumab (GOL), infliximab (IFX), and tocilizumab (TCZ). This network meta-analysis was aimed at evaluating the efficacy and safety of the medications above and interventions combining cDMARDs and biologic agents for patients with RA. Methods: PubMed, EMBASE, Cochrane Library, and ClinicalTrials.gov were searched systematically for eligible randomized controlled trials (RCTs). Outcomes concerning efficacy and safety were evaluated utilizing odds ratios (ORs) and 95% credible intervals (CrI). The outcomes of efficacy would be evaluated through remission and American College of Rheumatology (ACR) scores. The surface under the cumulative ranking curve (SUCRA) was calculated to rank each treatment on each index. Results: A total of 20 RCTs with 9,047 patients were included, and the efficacy and safety of the concerning interventions for RA were evaluated. Compared with cDMARDs alone, TCZ+MTX, ETN+MTX, IFX+MTX, TCZ, and ADA+MTX showed significant statistical advantage on ACR20, ACR50, and ACR70. Apart from that, as for remission, TCZ+MTX, IFX+MTX, TCZ, and CZP+MTX performed better compared to cDMARDs alone. The SUCRA ranking also indicated that TCZ+MTX was the intervention with best ranking in the entire four efficacy indexes followed by ETX+MTX and IFX+MTX. However, there was no obvious difference among these medications compared with cDMARDs when it comes to safety, which need more specific studies on that. Conclusion: TCZ+MTX was potentially the most recommended combination of medications for RA due to its good performance in all outcomes of efficacy. ETX+MTX and IFX+MTX, which also performed well, could be introduced as alternative treatments. However, considering the adverse events, the treatments concerning should be introduced with caution. PMID- 29618977 TI - Gut Microbiota-Regulated Pharmacokinetics of Berberine and Active Metabolites in Beagle Dogs After Oral Administration. AB - Berberine (BBR) is considered a multi-target drug that has significant advantages. In contrast to its significant pharmacological effects in clinic, the plasma level of BBR is very low. Our previous work revealed that dihydroberberine (dhBBR) could be an absorbable form of BBR in the intestine, and butyrate is an active metabolite that is generated by gut bacteria in rats. In this study, for the first time we describe gut microbiota-regulated pharmacokinetics in beagle dogs after oral administration of BBR by single (50 mg/kg) or multiple doses (50 mg/kg/d) for 7 days. GC-MS, GC, LC-MS/MS, and LC/MSn-IT-TOF were used to detect dhBBR, butyrate and BBR as well as its Phase I and II metabolites, respectively. The results showed that dhBBR was not detected in dog plasma but was excreted in small amounts in the feces of dogs examined on days 3 and 7. Butyrate was generated by gut bacteria and increased by 1.3- and 1.2-fold in plasma or feces, respectively, after 7 days of BBR treatment compared to the levels before treatment. Changes of intestinal bacterial composition were analyzed by 16S rRNA genes analysis. The results presented that dogs treated with BBR for 7 days increased both the abundance of the butyrate- and the nitroreductases- producing bacteria. We also identified chemical structures of the Phase I and II metabolites and analyzed their contents in beagle dogs. Eleven metabolites were detected in plasma and feces after BBR oral administration (50 mg/kg) to dogs, including 8 metabolites of Phase I and III metabolites of Phase II. The pharmacokinetic profile indicated that the concentration of BBR in plasma was low, with a Cmax value of 36.88 +/- 23.45 ng/mL. The relative content of glucuronic acid conjugates (M11) was higher than those of other metabolites (M1, M2, M12, and M14) in plasma. BBR was detected in feces, with high excreted amounts on day 3 (2625.04 +/- 1726.94 MUg/g) and day 7 (2793.43 +/- 488.10 MUg/g). In summary, this is the first study to describe gut microbiota-regulated pharmacokinetics in beagle dogs after oral administration of BBR, which is beneficial for discovery of drugs with poor absorption but good therapeutic efficacy. PMID- 29618978 TI - Is There a Potential of Misuse for Venlafaxine and Bupropion? AB - Objective: Traditionally, studies on the non-medical use of pharmaceutical products have focused on controlled substances; e.g., opiates/opioids; and benzodiazepines. Although both bupropion and venlafaxine have been reported as being misused, only anecdotal reports have been made available so far. Hence, the European Monitoring Agency (EMA) Adverse Drug Reactions (ADRs), misuse/abuse/dependence and withdrawal, venlafaxine- and bupropion-related, database was here analyzed. Methods: All EMA spontaneous reports relating to venlafaxine (2005-2016) and bupropion (2003-2016) notifications were here analyzed, to provide a descriptive analysis by source, gender, age, and type of report. The UK-based, 2000-2016, Yellow Card Scheme pharmacovigilance database, bupropion and venlafaxine withdrawal reports were compared as well with those pertaining to fluoxetine and paroxetine. Results: Out of 20,720 (bupropion) and 47,516 (venlafaxine) total number of ADRs, some 2,232 (10.8%), and 4,071 (8.5%) misuse/abuse/dependence ADRs were respectively associated with bupropion and venlafaxine. Conversely, bupropion withdrawal-related ADRs were here reported in 299/20,720 (1.44%) cases and in 914/47,516 (1.92%) cases for venlafaxine. Overall, all bupropion and venlafaxine misuse-/abuse-/dependence- and withdrawal ADRs were related to a respective number of 264 and 447 patients. According to the Proportional Reporting Ratio (PRR) computation, in comparison with venlafaxine bupropion resulted to be more frequently misused/abused (PRR: 1.50), but less frequently associated with both dependence (PRR: 0.92) and withdrawal (PRR: 0.77) issues. Yellow Card Scheme data suggested that paroxetine and venlafaxine, in comparison with fluoxetine and bupropion, were associated with higher number of withdrawal-related reports. Conclusions: The dopaminergic, stimulant-like, bupropion activities may be associated with its possible recreational value. Present data may confirm that the occurrence of a withdrawal syndrome may be a significant issue for venlafaxine-treated patients. PMID- 29618979 TI - Improvements in Attention and Cardiac Autonomic Modulation After a 2-Weeks Sprint Interval Training Program: A Fidelity Approach. AB - This study aimed to: (1) investigate the influence of a 2-weeks sprint interval training (SIT) program on aerobic capacity, cardiac autonomic control, and components of attention in young healthy university students; and (2) to ascertain whether training fidelity would influence these adaptations. One hundred and nine participants were divided into an experimental (EG) and control (CG) groups. The EG performed a SIT program that consisted of 6 sessions of 4 * 30 s "all-out" efforts on a cycle ergometer, interspersed with active rests of 4 min. The criterion for fidelity was achieving >90% of estimated maximum heart rate (HR) during sprint bouts. After analyses, the EG was divided into HIGH (n = 26) and LOW (n = 46) fidelity groups. Components of attention were assessed using the Attention Network Test (ANT). Aerobic capacity (VO2max) was estimated while the sum of skinfolds was determined. Autonomic control of HR was assessed by means of HR variability (HRV) and HR complexity at rest and during ANT. Both HIGH and LOW significantly increased aerobic capacity, vagal modulation before and during ANT, and executive control, and decreased body fatness after SIT (p < 0.05). However, only participants from HIGH showed an increase in HR complexity and accuracy in ANT when compared to LOW (p < 0.05). Two weeks of SIT improved executive control, body fatness, aerobic fitness, and autonomic control in university students with better results reported in those individuals who exhibited high fidelity. PMID- 29618972 TI - An Inflammation-Centric View of Neurological Disease: Beyond the Neuron. AB - Inflammation is a complex biological response fundamental to how the body deals with injury and infection to eliminate the initial cause of cell injury and effect repair. Unlike a normally beneficial acute inflammatory response, chronic inflammation can lead to tissue damage and ultimately its destruction, and often results from an inappropriate immune response. Inflammation in the nervous system ("neuroinflammation"), especially when prolonged, can be particularly injurious. While inflammation per se may not cause disease, it contributes importantly to disease pathogenesis across both the peripheral (neuropathic pain, fibromyalgia) and central [e.g., Alzheimer disease, Parkinson disease, multiple sclerosis, motor neuron disease, ischemia and traumatic brain injury, depression, and autism spectrum disorder] nervous systems. The existence of extensive lines of communication between the nervous system and immune system represents a fundamental principle underlying neuroinflammation. Immune cell-derived inflammatory molecules are critical for regulation of host responses to inflammation. Although these mediators can originate from various non-neuronal cells, important sources in the above neuropathologies appear to be microglia and mast cells, together with astrocytes and possibly also oligodendrocytes. Understanding neuroinflammation also requires an appreciation that non-neuronal cell-cell interactions, between both glia and mast cells and glia themselves, are an integral part of the inflammation process. Within this context the mast cell occupies a key niche in orchestrating the inflammatory process, from initiation to prolongation. This review will describe the current state of knowledge concerning the biology of neuroinflammation, emphasizing mast cell-glia and glia glia interactions, then conclude with a consideration of how a cell's endogenous mechanisms might be leveraged to provide a therapeutic strategy to target neuroinflammation. PMID- 29618980 TI - Moderate Modulation of Cardiac PGC-1alpha Expression Partially Affects Age Associated Transcriptional Remodeling of the Heart. AB - Aging is associated with a decline in cardiac function due to a decreased myocardial reserve. This adverse cardiac remodeling comprises of a variety of changes, including a reduction in mitochondrial function and a decline in the expression of the peroxisome proliferator-activated receptor gamma coactivator 1alpha (PGC-1alpha), a central regulator of mitochondrial biogenesis and metabolic adaptation in the myocardium. To study the etiological involvement of PGC-1alpha in cardiac aging, we used mouse models mimicking the modest down- and upregulation of this coactivator in the old and the exercised heart, respectively. Young mice with reduced cardiac expression of PGC-1alpha recapitulated part of the age-related impairment in mitochondrial gene expression, but otherwise did not aggravate the aging process. Inversely however, moderate overexpression of PGC-1alpha counteracts numerous key age-related remodeling changes, e.g., by improving blood pressure, age-associated apoptosis, and collagen accumulation, as well as in the expression of many, but not all cardiac genes involved in mitochondrial biogenesis, dynamics, metabolism, calcium handling and contractility. Thus, while the reduction of PGC-1alpha in the heart is insufficient to cause an aging phenotype, moderate overexpression reduces pathological remodeling of older hearts and could thereby contribute to the beneficial effects of exercise on cardiac function in aging. PMID- 29618981 TI - Influence of Endurance Training During Childhood on Total Hemoglobin Mass. AB - Elite endurance athletes are characterized by markedly increased hemoglobin mass (Hbmass). It has been hypothesized that this adaptation may occur as a response to training at a very young age. Therefore, the aim of this study was to monitor changes in Hbmass in children aged 8-14 years following systematic endurance training. In the first study, Hbmass, VO2max, and lean body mass (LBM) were measured in 17 endurance-trained children (13 boys and 4 girls; aged 9.7 +/- 1.3 years; training history 1.5+/-1.8 years; training volume 3.5 +/- 1.6 h) twice a year for up to 3.5 years. The same parameters were measured once in a control group of 18 age-matched untrained children. Hbmass and blood volume (BV) were measured using the optimized CO-rebreathing technique, VO2max by an incremental test on a treadmill, and LBM by skin-fold measurements. In the second pilot study, the same parameters were measured in 9 young soccer athletes (aged 7.8 +/- 0.2 years), and results were assessed in relation to soccer performance 2.5 years later. The increase in mean Hbmass during the period of study was 50% which was closely related to changes in LBM (r = 0.959). A significant impact of endurance training on Hbmass was observed in athletes exercising more than 4 h/week [+25.4 g compared to the group with low training volume (<2 h/week)]. The greatest effects were related to LBM (11.4 g.kg-1 LBM) and overlapped with the effects of age. A strong relationship was present between absolute Hbmass and VO2max (r = 0.939), showing that an increase of 1 g hemoglobin increases VO2max by 3.6 ml.min 1. Study 2 showed a positive correlation between Hbmass and soccer performance 2.5 years later at age 10.3 +/- 0.3 years (r = 0.627, p = 0.035). In conclusion, children with a weekly training volume of more than 4 h show a 7% higher Hbmass than untrained children. Although this training effect is significant and independent of changes in LBM, the major factor driving the increase in Hbmass is still LBM. PMID- 29618982 TI - Silencing the Odorant Binding Protein RferOBP1768 Reduces the Strong Preference of Palm Weevil for the Major Aggregation Pheromone Compound Ferrugineol. AB - In insects, perception of the environment-food, mates, and prey-is mainly guided by chemical signals. The dynamic process of signal perception involves transport to odorant receptors (ORs) by soluble secretory proteins, odorant binding proteins (OBPs), which form the first stage in the process of olfactory recognition and are analogous to lipocalin family proteins in vertebrates. Although OBPs involved in the transport of pheromones to ORs have been functionally identified in insects, there is to date no report for Coleoptera. Furthermore, there is a lack of information on olfactory perception and the molecular mechanism by which OBPs participate in the transport of aggregation pheromones. We focus on the red palm weevil (RPW) Rhynchophorus ferrugineus, the most devastating quarantine pest of palm trees worldwide. In this work, we constructed libraries of all OBPs and selected antenna-specific and highly expressed OBPs for silencing through RNA interference. Aggregation pheromone compounds, 4-methyl-5-nonanol (ferrugineol) and 4-methyl-5-nonanone (ferruginone), and a kairomone, ethyl acetate, were then sequentially presented to individual RPWs. The results showed that antenna-specific RferOBP1768 aids in the capture and transport of ferrugineol to ORs. Silencing of RferOBP1768, which is responsible for pheromone binding, significantly disrupted pheromone communication. Study of odorant perception in palm weevil is important because the availability of literature regarding the nature and role of olfactory signaling in this insect may reveal likely candidates representative of animal olfaction and, more generally, of molecular recognition. Knowledge of OBPs recognizing the specific pheromone ferrugineol will allow for designing biosensors for the detection of this key compound in weevil monitoring in date palm fields. PMID- 29618984 TI - Leptin Intake at Physiological Doses Throughout Lactation in Male Wistar Rats Normalizes the Decreased Density of Tyrosine Hydroxylase-Immunoreactive Fibers in the Stomach Caused by Mild Gestational Calorie Restriction. AB - Introduction: Gestational under nutrition in rats has been shown to decrease expression of sympathetic innervation markers in peripheral tissues of offspring, including the stomach. This has been linked to lower gastric secretion and decreased circulating levels of ghrelin. Considering the critical role of leptin intake during lactation in preventing obesity and reversing adverse developmental programming effects, we aimed to find out whether leptin supplementation may reverse the above mentioned alterations caused by mild gestational calorie restriction. Methods: Three groups of male rats were studied at a juvenile age (25 days old) and during adulthood (3 and 6 months old): the offspring of ad libitum fed dams (controls), the offspring of dams that were diet restricted (20%) from days 1 to 12 of gestation (CR), and CR rats supplemented with a daily oral dose of leptin (equivalent to 5 times the average amount they could receive each day from maternal milk) throughout lactation (CR-Leptin). The density of TyrOH-immunoreactive (TyrOH+) fibers and the levels of Tyrosine hydroxylase (TyrOH)-used as potential markers of functional sympathetic innervation-were measured in stomach. Plasma leptin and ghrelin levels were also determined. Results: Twenty five-day-old CR rats, but not CR-Leptin rats, displayed lower density of TyrOH+ fibers (-46%) and TyrOH levels (-47%) in stomach compared to controls. Alterations in CR animals were mitigated at 6 months of age, and differences were not significant. Adult CR-Leptin animals showed higher plasma ghrelin levels than CR animals, particularly at 3 months (+16%), and a lower leptin/ghrelin ratio (-28 and -37% at 3 and 6 months, respectively). Conclusion: Leptin intake during lactation is able to reverse the alterations in the density of TyrOH+ fibers in the stomach and normalize the increased leptin/ghrelin ratio linked to a mild gestational calorie restriction in rats, supporting the relevance of leptin as an essential nutrient during lactation. PMID- 29618983 TI - Perivascular Adipose Tissue as a Relevant Fat Depot for Cardiovascular Risk in Obesity. AB - Obesity is associated with increased risk of premature death, morbidity, and mortality from several cardiovascular diseases (CVDs), including stroke, coronary heart disease (CHD), myocardial infarction, and congestive heart failure. However, this is not a straightforward relationship. Although several studies have substantiated that obesity confers an independent and additive risk of all cause and cardiovascular death, there is significant variability in these associations, with some lean individuals developing diseases and others remaining healthy despite severe obesity, the so-called metabolically healthy obese. Part of this variability has been attributed to the heterogeneity in both the distribution of body fat and the intrinsic properties of adipose tissue depots, including developmental origin, adipogenic and proliferative capacity, glucose and lipid metabolism, hormonal control, thermogenic ability, and vascularization. In obesity, these depot-specific differences translate into specific fat distribution patterns, which are closely associated with differential cardiometabolic risks. The adventitial fat layer, also known as perivascular adipose tissue (PVAT), is of major importance. Similar to the visceral adipose tissue, PVAT has a pathophysiological role in CVDs. PVAT influences vascular homeostasis by releasing numerous vasoactive factors, cytokines, and adipokines, which can readily target the underlying smooth muscle cell layers, regulating the vascular tone, distribution of blood flow, as well as angiogenesis, inflammatory processes, and redox status. In this review, we summarize the current knowledge and discuss the role of PVAT within the scope of adipose tissue as a major contributing factor to obesity-associated cardiovascular risk. Relevant clinical studies documenting the relationship between PVAT dysfunction and CVD with a focus on potential mechanisms by which PVAT contributes to obesity-related CVDs are pointed out. PMID- 29618985 TI - The Complex Role of Store Operated Calcium Entry Pathways and Related Proteins in the Function of Cardiac, Skeletal and Vascular Smooth Muscle Cells. AB - Cardiac, skeletal, and smooth muscle cells shared the common feature of contraction in response to different stimuli. Agonist-induced muscle's contraction is triggered by a cytosolic free Ca2+ concentration increase due to a rapid Ca2+ release from intracellular stores and a transmembrane Ca2+ influx, mainly through L-type Ca2+ channels. Compelling evidences have demonstrated that Ca2+ might also enter through other cationic channels such as Store-Operated Ca2+ Channels (SOCCs), involved in several physiological functions and pathological conditions. The opening of SOCCs is regulated by the filling state of the intracellular Ca2+ store, the sarcoplasmic reticulum, which communicates to the plasma membrane channels through the Stromal Interaction Molecule 1/2 (STIM1/2) protein. In muscle cells, SOCCs can be mainly non-selective cation channels formed by Orai1 and other members of the Transient Receptor Potential-Canonical (TRPC) channels family, as well as highly selective Ca2+ Release-Activated Ca2+ (CRAC) channels, formed exclusively by subunits of Orai proteins likely organized in macromolecular complexes. This review summarizes the current knowledge of the complex role of Store Operated Calcium Entry (SOCE) pathways and related proteins in the function of cardiac, skeletal, and vascular smooth muscle cells. PMID- 29618986 TI - The Antioxidant Therapy: New Insights in the Treatment of Hypertension. AB - Reactive oxygen species (ROS) and reactive nitrogen species (RNS) play a key role in the regulation of the physiological and pathological signaling within the vasculature. In physiological conditions, a delicate balance between oxidants and antioxidants protects cells from the detrimental effects of ROS/RNS. Indeed, the imbalance between ROS/RNS production and antioxidant defense mechanisms leads to oxidative and nitrosative stress within the cell. These processes promote the vascular damage observed in chronic conditions, such as hypertension. The strong implication of ROS/RNS in the etiology of hypertension suggest that antioxidants could be effective in the treatment of this pathology. Indeed, in animal models of hypertension, the overexpression of antioxidants and the genetic modulation of oxidant systems have provided an encouraging proof of concept. Nevertheless, the translation of these strategies to human disease did not reach the expected success. This could be due to the complexity of this condition, whose etiology depends on multiple factors (smoking, diet, life styles, genetics, family history, comorbidities). Indeed, 95% of reported high blood pressure cases are deemed "essential hypertension," and at the molecular level, oxidative stress seems to be a common feature of hypertensive states. In this scenario, new therapies are emerging that could be useful to reduce oxidative stress in hypertension. It is now ascertained the role of Vitamin D deficiency in the development of essential hypertension and it has been shown that an appropriate high dose of Vitamin D significantly reduces blood pressure in hypertensive cohorts with vitamin D deficiency. Moreover, new drugs are emerging which have both antihypertensive action and antioxidant properties, such as celiprolol, carvedilol, nebivolol. Indeed, besides adrenergic desensitization, these kind of drugs are able to interfere with ROS/RNS generation and/or signaling, and are therefore considered promising therapeutics in the management of hypertension. In the present review we have dealt with the effectiveness of the antioxidant therapy in the management of hypertension. In particular, we discuss about Vitamin D and anti-hypertensive drugs with antioxidant properties. PMID- 29618987 TI - Cholinergic Submucosal Neurons Display Increased Excitability Following in Vivo Cholera Toxin Exposure in Mouse Ileum. AB - Cholera-induced hypersecretion causes dehydration and death if untreated. Cholera toxin (CT) partly acts via the enteric nervous system (ENS) and induces long lasting changes to enteric neuronal excitability following initial exposure, but the specific circuitry involved remains unclear. We examined this by first incubating CT or saline (control) in mouse ileal loops in vivo for 3.5 h and then assessed neuronal excitability in vitro using Ca2+ imaging and immunolabeling for the activity-dependent markers cFos and pCREB. Mice from a C57BL6 background, including Wnt1-Cre;R26R-GCaMP3 mice which express the fluorescent Ca2+ indicator GCaMP3 in its ENS, were used. Ca2+-imaging using this mouse model is a robust, high-throughput method which allowed us to examine the activity of numerous enteric neurons simultaneously and post-hoc immunohistochemistry enabled the neurochemical identification of the active neurons. Together, this provided novel insight into the CT-affected circuitry that was previously impossible to attain at such an accelerated pace. Ussing chamber measurements of electrogenic ion secretion showed that CT-treated preparations had higher basal secretion than controls. Recordings of Ca2+ activity from the submucous plexus showed that increased numbers of neurons were spontaneously active in CT-incubated tissue (control: 4/149; CT: 32/160; Fisher's exact test, P < 0.0001) and that cholinergic neurons were more responsive to electrical (single pulse and train of 20 pulses) or nicotinic (1,1-dimethyl-4-phenylpiperazinium (DMPP; 10 MUM) stimulation. Expression of the neuronal activity marker, pCREB, was also increased in the CT-treated submucous plexus neurons. c-Fos expression and spontaneous fast excitatory postsynaptic potentials (EPSPs), recorded by intracellular electrodes, were increased by CT exposure in a small subset of myenteric neurons. However, the effect of CT on the myenteric plexus is less clear as spontaneous Ca2+ activity and electrical- or nicotinic-evoked Ca2+ responses were reduced. Thus, in a model where CT exposure evokes hypersecretion, we observed sustained activation of cholinergic secretomotor neuron activity in the submucous plexus, pointing to involvement of these neurons in the overall response to CT. PMID- 29618988 TI - The Hyperglycemic Effect of Melatonin in the Chinese Mitten Crab, Eriocheir sinensis. AB - Melatonin has been identified in a variety of invertebrate species, but its function is not as well understood as in crustaceans. The effects of melatonin on hemolymph glucose levels and tissue carbohydrate metabolism in the Chinese mitten crab, Eriocheir sinensis, were fully investigated in this study. Moreover, whether the eyestalk (an important endocrine center in invertebrate species) involves in this process or not, also were clarified. Analysis revealed that eyestalk ablation, especially bilateral, caused a significant decrease in the hemolymph glucose level. Moreover, injection of melatonin induced hyperglycemia in a dose-dependent manner both in intact and ablated crabs. Based on the expression of CHH mRNA in the 10 different tissues, eyestalk, thoracic ganglion, intestinal tract and hemolymph were selected to estimate the effect of melatonin on the expression of CHH mRNA. Bilateral eyestalk ablation caused a significant increase in the expression of CHH mRNA in the thoracic ganglion, intestinal tract and hemolymph compared with the controls. In addition, injection of melatonin into intact or ablated crabs elevated the CHH mRNA level in the eyestalk, thoracic ganglion and intestinal tract tissues compared with controls. The hemolymph CHH mRNA after melatonin injection was elevated only in ablated crabs. Administration of melatonin resulted in a significant decrease in total carbohydrates and glycogen levels with an increase in phosphorylase activity levels in the hepatopancreas and muscle in intact and ablated crabs. Our findings demonstrated that melatonin can induce hyperglycemic effects in both intact and ablated crabs, suggesting that this effect is probably not mediated solely via eyestalk. PMID- 29618990 TI - Semantic Memory Organization in Japanese Patients With Schizophrenia Examined With Category Fluency. AB - Background: Disorganization of semantic memory in patients with schizophrenia has been studied by referring to their category fluency performance. Recently, data mining techniques such as singular value decomposition (SVD) analysis have been reported to be effective in elucidating the latent semantic memory structure in patients with schizophrenia. The aim of this study is to investigate semantic memory organization in patients with schizophrenia using a novel method based on data-mining approach. Method: Category fluency data were collected from 181 patients with schizophrenia and 335 healthy controls at the Department of Psychiatry, Osaka University. The 20 most frequently reported animals were chosen for SVD analysis. In the two-dimensional (2D) solution, item vectors (i.e., animal names) were plotted in the 2D space of each group. In the six-dimensional (6D) solution, inter-item similarities (i.e., cosines) were calculated among items. Cosine charts were also created for the six most frequent items to show the similarities to other animal items. Results: In the 2D spatial representation, the six most frequent items were grouped in the same clusters (i.e., dog, cat as pet cluster, lion, tiger as wild/carnivorous cluster, and elephant, giraffe as wild/herbivorous cluster) for patients and healthy adults. As for 6D spatial cosines, the correlations (Pearson's r) between 17 items commonly generated in the two groups were moderately high. However, cosine charts created for the three pairs from the six most frequent animals (dog-cat, lion tiger, elephant-giraffe) showed that pair-wise similarities between other animals were less salient in patients with schizophrenia. Discussion: Semantic memory organization in patients with schizophrenia, revealed by SVD analysis, did not appear to be seriously impaired in the 2D space representation, maintaining a clustering structure similar to that in healthy controls for common animals. However, the coherence of those animals was less salient in 6D space, lacking pair-wise similarities to other members of the animal category. These results suggests subtle but structural differences between the two groups. A data-mining approach by means of SVD analysis seems to be effective in evaluating semantic memory in patients with schizophrenia, providing both a visual representation and an objective measure of the structural alterations. PMID- 29618989 TI - Strongyle Infection and Gut Microbiota: Profiling of Resistant and Susceptible Horses Over a Grazing Season. AB - Gastrointestinal strongyles are a major threat to horses' health and welfare. Given that strongyles inhabit the same niche as the gut microbiota, they may interact with each other. These beneficial or detrimental interactions are unknown in horses and could partly explain contrasted susceptibility to infection between individuals. To address these questions, an experimental pasture trial with 20 worm-free female Welsh ponies (10 susceptible (S) and 10 resistant (R) to parasite infection) was implemented for 5 months. Fecal egg counts (FEC), hematological and biochemical data, body weight and gut microbiological composition were studied in each individual after 0, 24, 43, 92 and 132 grazing days. R and S ponies displayed divergent immunological profiles and slight differences in microbiological composition under worm-free conditions. After exposure to natural infection, the predicted R ponies exhibited lower FEC after 92 and 132 grazing days, and maintained higher levels of circulating monocytes and eosinophils, while lymphocytosis persisted in S ponies. Although the overall gut microbiota diversity and structure remained similar during the parasite infection between the two groups, S ponies exhibited a reduction of bacteria such as Ruminococcus, Clostridium XIVa and members of the Lachnospiraceae family, which may have promoted a disruption of mucosal homeostasis at day 92. In line with this hypothesis, an increase in pathobionts such as Pseudomonas and Campylobacter together with changes in several predicted immunological pathways, including pathogen sensing, lipid metabolism, and activation of signal transduction that are critical for the regulation of immune system and energy homeostasis were observed in S relative to R ponies. Moreover, S ponies displayed an increase in protozoan concentrations at day 92, suggesting that strongyles and protozoa may contribute to each other's success in the equine intestines. It could also be that S individuals favor the increase of these carbohydrate degrading microorganisms to enhance the supply of nutrients needed to fight strongyle infection. Overall, this study provides a foundation to better understand the mechanisms that underpin the relationship between equines and natural strongyle infection. The profiling of horse immune response and gut microbiota should contribute to the development of novel biomarkers for strongyle infection. PMID- 29618991 TI - Cue-Induced Brain Activation in Chronic Ketamine-Dependent Subjects, Cigarette Smokers, and Healthy Controls: A Task Functional Magnetic Resonance Imaging Study. AB - Background: Observations of drug-related cues may induce craving in drug dependent patients, prompting compulsive drug-seeking behavior. Sexual dysfunction is common in drug users. The aim of the study was to examine regional brain activation to drug (ketamine, cigarette smoking) associated cues and natural (sexual) rewards. Methods: A sample of 129 [40 ketamine use smokers (KUS), 45 non-ketamine use smokers (NKUS) and 44 non-ketamine use non-smoking healthy controls (HC)] participants underwent functional magnetic resonance imaging (fMRI) while viewing ketamine use related, smoking and sexual films. Results: We found that KUS showed significant increased activation in anterior cingulate cortex and precuneus in response to ketamine cues. Ketamine users (KUS) showed lower activation in cerebellum and middle temporal cortex compared with non-ketamine users (NKUS and HC) in response to sexual cues. Smokers (KUS and NKUS) showed higher activation in the right precentral frontal cortex in response to smoking cues. Non-ketamine users (NKUS and HC) showed significantly increased activation of cerebellum and middle temporal cortex while viewing sexual cues. Conclusion: These findings clearly show the engagement of distinct neural circuitry for drug-related stimuli in chronic ketamine users. While smokers (both KUS and NKUS) showed overlapping differences in activation for smoking cues, the former group showed a specific neural response to relevant (i.e., ketamine related) cues. In particular, the heightened response in anterior cingulate cortex may have important implications for how attentionally salient such cues are in this group. Ketamine users (KUS) showed lower activation in response to sexual cues may partly reflect the neural basis of sexual dysfunction. PMID- 29618992 TI - Fronto-Temporal Connectivity Predicts ECT Outcome in Major Depression. AB - Background: Electroconvulsive therapy (ECT) is arguably the most effective available treatment for severe depression. Recent studies have used MRI data to predict clinical outcome to ECT and other antidepressant therapies. One challenge facing such studies is selecting from among the many available metrics, which characterize complementary and sometimes non-overlapping aspects of brain function and connectomics. Here, we assessed the ability of aggregated, functional MRI metrics of basal brain activity and connectivity to predict antidepressant response to ECT using machine learning. Methods: A radial support vector machine was trained using arterial spin labeling (ASL) and blood-oxygen level-dependent (BOLD) functional magnetic resonance imaging (fMRI) metrics from n = 46 (26 female, mean age 42) depressed patients prior to ECT (majority right unilateral stimulation). Image preprocessing was applied using standard procedures, and metrics included cerebral blood flow in ASL, and regional homogeneity, fractional amplitude of low-frequency modulations, and graph theory metrics (strength, local efficiency, and clustering) in BOLD data. A 5-repeated 5 fold cross-validation procedure with nested feature-selection validated model performance. Linear regressions were applied post hoc to aid interpretation of discriminative features. Results: The range of balanced accuracy in models performing statistically above chance was 58-68%. Here, prediction of non responders was slightly higher than for responders (maximum performance 74 and 64%, respectively). Several features were consistently selected across cross validation folds, mostly within frontal and temporal regions. Among these were connectivity strength among: a fronto-parietal network [including left dorsolateral prefrontal cortex (DLPFC)], motor and temporal networks (near ECT electrodes), and/or subgenual anterior cingulate cortex (sgACC). Conclusion: Our data indicate that pattern classification of multimodal fMRI metrics can successfully predict ECT outcome, particularly for individuals who will not respond to treatment. Notably, connectivity with networks highly relevant to ECT and depression were consistently selected as important predictive features. These included the left DLPFC and the sgACC, which are both targets of other neurostimulation therapies for depression, as well as connectivity between motor and right temporal cortices near electrode sites. Future studies that probe additional functional and structural MRI metrics and other patient characteristics may further improve the predictive power of these and similar models. PMID- 29618993 TI - Categorizing Two Taiwanese Major Political Parties From Their Faces: The Influence of Provincial Appearance. AB - People go beyond the inferences afforded by a person's observable features to make guesses about personality traits or even social memberships such as political affiliations. The present study extended Hu et al. (2016) to further investigate the influence of provincial appearance on differentiating KMT (Kuomintang) and DPP (Democratic Progressive Party) candidates by headshot photos with three experiments. In Experiment 1 (Membership categorization task), participants categorized the photos from the pilot study (where the difference between the perceived age of KMT and DPP candidates was reduced) and divided into four blocks by their perceived age. We found that participants were able to distinguish KMT from DPP candidates significantly better than chance, even when the perceived age difference between the two parties was minimized. In Experiment 2 (Trait rating task), we asked young and middle-aged adults to rate six traits on candidate's photos. We found that "provincial appearance" is the core trait differentiating the two parties for both young and older participants, while "facial maturity" is another trait for older participants only. In Experiment 3 (Double categorization task), we asked participants to categorize the photos from the Exp. 1 on their membership (KMT or DPP) and on provincial appearance (mainlander or native Taiwanese) in two separate sessions. Results showed that young adults were likely to use the "provincial appearance" as the main characteristic cue to categorize candidates' political membership. In sum, our study showed that Taiwanese adults could categorize the two parties by their headshot photos when age cue was eliminated. Moreover, provincial appearance was the most critical trait for differentiating between KMT and DPP candidates, which may reflect a piece of significant history during the development of the two parties. PMID- 29618994 TI - Toward a Neuroscientific Understanding of Play: A Dimensional Coding Framework for Analyzing Infant-Adult Play Patterns. AB - Play during early life is a ubiquitous activity, and an individual's propensity for play is positively related to cognitive development and emotional well-being. Play behavior (which may be solitary or shared with a social partner) is diverse and multi-faceted. A challenge for current research is to converge on a common definition and measurement system for play - whether examined at a behavioral, cognitive or neurological level. Combining these different approaches in a multimodal analysis could yield significant advances in understanding the neurocognitive mechanisms of play, and provide the basis for developing biologically grounded play models. However, there is currently no integrated framework for conducting a multimodal analysis of play that spans brain, cognition and behavior. The proposed coding framework uses grounded and observable behaviors along three dimensions (sensorimotor, cognitive and socio emotional), to compute inferences about playful behavior in a social context, and related social interactional states. Here, we illustrate the sensitivity and utility of the proposed coding framework using two contrasting dyadic corpora (N = 5) of mother-infant object-oriented interactions during experimental conditions that were either non-conducive (Condition 1) or conducive (Condition 2) to the emergence of playful behavior. We find that the framework accurately identifies the modal form of social interaction as being either non-playful (Condition 1) or playful (Condition 2), and further provides useful insights about differences in the quality of social interaction and temporal synchronicity within the dyad. It is intended that this fine-grained coding of play behavior will be easily assimilated with, and inform, future analysis of neural data that is also collected during adult-infant play. In conclusion, here, we present a novel framework for analyzing the continuous time-evolution of adult-infant play patterns, underpinned by biologically informed state coding along sensorimotor, cognitive and socio-emotional dimensions. We expect that the proposed framework will have wide utility amongst researchers wishing to employ an integrated, multimodal approach to the study of play, and lead toward a greater understanding of the neuroscientific basis of play. It may also yield insights into a new biologically grounded taxonomy of play interactions. PMID- 29618995 TI - Brazil-Portugal Transcultural Adaptation of the UWES-9: Internal Consistency, Dimensionality, and Measurement Invariance. AB - The aim of this paper is to present a revision of international versions of the Utrecht Work Engagement Scale and to describe the psychometric properties of a Portuguese version of the UWES-9 developed simultaneously for Brazil and Portugal, the validity evidence related with the internal structure, namely, Dimensionality, measurement invariance between Brazil and Portugal, and Reliability of the scores. This is the first UWES version developed simultaneously for both countries, and it is an important instrument for understanding employees' work engagement in the organizations, allowing human resources departments to better use workforces, especially when they are migrants. A total of 524 Brazilian workers and 522 Portuguese workers participated in the study. Confirmatory Factor Analysis, group comparisons, and Reliability estimates were used. The use of workers who were primarily professionals or administrative support, according to ISCO-08, reinforced the need to collect data on other professional occupations. Confirmatory factor analysis showed acceptable fit for the UWES-9 original three-factor solution, and a second-order factor structure has been proposed that presented an acceptable fit. Full-scale invariance was obtained between the Portuguese and Brazilian samples, both for the original three-factor first-order and second-order models. Data revealed that Portuguese and Brazilian workers didn't show statistically significant differences in the work engagement dimensions. This version allows for direct comparisons of means and, consequently, for performance of comparative and cross-cultural studies between these two countries. PMID- 29618996 TI - Effects of Linguistic Labels on Visual Attention in Children and Young Adults. AB - Effects of linguistic labels on learning outcomes are well-established; however, developmental research examining possible mechanisms underlying these effects have provided mixed results. We used a novel paradigm where 8-year-olds and adults were simultaneously trained on three sparse categories (categories with many irrelevant or unique features and a single rule defining feature). Category members were either associated with the same label, different labels, or no labels (silent baseline). Similar to infant paradigms, participants passively viewed individual exemplars and we examined fixations to category relevant features across training. While it is well established that adults can optimize their attention in forced-choice categorization tasks without linguistic input, the present findings provide support for label induced attention optimization: simply hearing the same label associated with different exemplars was associated with increased attention to category relevant features over time, and participants continued to focus on these features on a subsequent recognition task. Participants also viewed images longer and made more fixations when images were paired with unique labels. These findings provide support for the claim that labels may facilitate categorization by directing attention to category relevant features. PMID- 29618997 TI - Executive Functions and Prosodic Abilities in Children With High-Functioning Autism. AB - Little is known about the relationship between prosodic abilities and executive function skills. As deficits in executive functions (EFs) and prosodic impairments are characteristics of autism, we examined how EFs are related to prosodic performance in children with high-functioning autism (HFA). Fifteen children with HFA (M = 7.4 years; SD = 1.12), matched to 15 typically developing peers on age, gender, and non-verbal intelligence participated in the study. The Profiling Elements of Prosody in Speech-Communication (PEPS-C) was used to assess prosodic performance. The Children's Color Trails Test (CCTT-1, CCTT-2, and CCTT Interference Index) was used as an indicator of executive control abilities. Our findings suggest no relation between prosodic abilities and visual search and processing speed (assessed by CCTT-1), but a significant link between prosodic skills and divided attention, working memory/sequencing, set-switching, and inhibition (assessed by CCTT-2 and CCTT Interference Index). These findings may be of clinical relevance since difficulties in EFs and prosodic deficits are characteristic of many neurodevelopmental disorders. Future studies are needed to further investigate the nature of the relationship between impaired prosody and executive (dys)function. PMID- 29618998 TI - Opposing Subjective Temporal Experiences in Response to Unpredictable and Predictable Fear-Relevant Stimuli. AB - Previous studies have found that the durations of fear-relevant stimuli were overestimated compared to those of neutral stimuli, even when the fear-relevant stimuli were only anticipated. The current study aimed to investigate the effect of the predictability of fear-relevant stimuli on sub-second temporal estimations. In Experiments 1a and 1b, a randomized design was employed to render the emotional valence of each trial unpredictable. In Experiments 2a and 2b, we incorporated a block design and a cueing paradigm, respectively, to render the emotional stimuli predictable. Compared with the neutral condition, the estimated blank interval was judged as being shorter under the unpredictable fear-relevant condition, while it was judged as being longer under the predictable fear relevant condition. In other words, the unpredictable and predictable fear relevant stimuli led to opposing temporal distortions. These results demonstrated that emotions modulate interval perception during different time processing stages. PMID- 29618999 TI - Temporal Audiovisual Motion Prediction in 2D- vs. 3D-Environments. AB - Predicting motion is essential for many everyday life activities, e.g., in road traffic. Previous studies on motion prediction failed to find consistent results, which might be due to the use of very different stimulus material and behavioural tasks. Here, we directly tested the influence of task (detection, extrapolation) and stimulus features (visual vs. audiovisual and three-dimensional vs. non-three dimensional) on temporal motion prediction in two psychophysical experiments. In both experiments a ball followed a trajectory toward the observer and temporarily disappeared behind an occluder. In audiovisual conditions a moving white noise (congruent or non-congruent to visual motion direction) was presented concurrently. In experiment 1 the ball reappeared on a predictable or a non predictable trajectory and participants detected when the ball reappeared. In experiment 2 the ball did not reappear after occlusion and participants judged when the ball would reach a specified position at two possible distances from the occluder (extrapolation task). Both experiments were conducted in three dimensional space (using stereoscopic screen and polarised glasses) and also without stereoscopic presentation. Participants benefitted from visually predictable trajectories and concurrent sounds during detection. Additionally, visual facilitation was more pronounced for non-3D stimulation during detection task. In contrast, for a more complex extrapolation task group mean results indicated that auditory information impaired motion prediction. However, a post hoc cross-validation procedure (split-half) revealed that participants varied in their ability to use sounds during motion extrapolation. Most participants selectively profited from either near or far extrapolation distances but were impaired for the other one. We propose that interindividual differences in extrapolation efficiency might be the mechanism governing this effect. Together, our results indicate that both a realistic experimental environment and subject specific differences modulate the ability of audiovisual motion prediction and need to be considered in future research. PMID- 29619000 TI - Developing Organizational Competences for Conflict Management: The Use of the Prisoner's Dilemma in Higher Education. AB - Interpersonal relationship require sophisticated competences of cohabitation. However, the availability of training tools to develop conflict management skills is limited and problematic. The prisoner's dilemma game (PDG), the most widely known example of game theory, a nonzero-sum game, has been used, in higher education, to provide students with an opportunity of active learning and for understanding counterintuitive concepts. It creates a condition of emotive, moral and decisional conflict in and between agents. This paper presents a case-study in higher education in which PDG was proposed to enhance organizational competences for conflict management, according to the psychoanalytic approach to organizational studies. The study aims to explore: (1) the significant characteristics of PDG used in an affective-emotional key in higher education; (2) the learning outcomes that PDG enables to activate in the participants in relation to the development of organizational skills for conflict management. Twenty students' reflective journals were analyzed using thematic analysis. Findings indicated that PDG is perceived as a useful device in students' learning experience, which is appreciated in relation to its concreteness, intensity and debriefing phase. Learning outcomes allow new meanings about conflict, by emphasizing its defensive, automatic and interpersonal dimension. This paper contributes to the understanding of PDG as a tool to develop competences in dealing with the challenges of conflict management, since it seems to favor the overcoming of the individualistic stereotype in conflict representation by highlighting the interdependence of social interaction. PMID- 29619001 TI - Intentional Observer Effects on Quantum Randomness: A Bayesian Analysis Reveals Evidence Against Micro-Psychokinesis. AB - Intentional effects of human observation on the output of quantum-based random number generators (tRNG) have been studied for decades now. This research has been known as micro-psychokinesis (micro-PK) and many studies in the field reported evidence for mentally induced non-random deviations from chance. A most recent meta-analysis from Bosch et al. (2006) revealed a very small and heterogeneous overall effect size that indicated a significant deviation from chance across studies. There remains doubt among the scientific community on the existence of micro-PK given: (i) the small and heterogenous effect; and (ii) the fact that several independent replication attempts of prominent studies failed to confirm the original results. The study presented here was intended to provide decisive evidence for or against the existence of micro-PK. An online experiment with 12,571 participants was conducted. The Bayesian analysis revealed strong evidence for H0 (BF01 = 10.07). Thus, micro-PK did not exist in the data. A closer inspection of the temporal change of the effect seemed to suggest a non random oscillative structure with a higher frequency than observed in simulated data. The possible role of entropy and the relation to the model of pragmatic information from von Lucadou (2015) is discussed. PMID- 29619002 TI - Eye Movements and Cognitive Strategy in a Fluid Intelligence Test: Item Type Analysis. AB - Eye movements help to infer the cognitive strategy that a person uses in fluid intelligence tests. However, intelligence tests demand different relations/rules tokens to be solved, such as rule direction, which is the continuation, variation or overlay of geometric figures in the matrix of the intelligence test. The aim of this study was to understand whether eye movements could predict the outcome of an intelligence test and in the rule item groups. Furthermore, we sought to identify which measure is best for predicting intelligence test scores and to understand if the rule item groups use the same strategy. Accordingly, 34 adults completed a computerized intelligence test with an eye-tracking device. The toggling rate, that is, the number of toggles on each test item equalized by the item latency explained 45% of the variance of the test scores and a significant amount of the rule tokens item groups. The regression analyses also indicated toggling rate as the best measure for predicting the score and that all the rule tokens seem to respect the same strategy. No correlation or difference were found between baseline pupil size and fluid intelligence. Wiener Matrizen-Test 2 was demonstrated to be a good instrument for the purpose of this study. Finally, the implications of these findings for an understanding of cognition are discussed. PMID- 29619004 TI - Protection of Oligodendrocytes Through Neuronal Overexpression of the Small GTPase Ras in Hyperoxia-Induced Neonatal Brain Injury. AB - Prematurely born infants are highly susceptible to various environmental factors, such as inflammation, drug exposure, and also high environmental oxygen concentrations. Hyperoxia induces perinatal brain injury affecting white and gray matter development. It is well known that mitogen-activated protein kinase signaling is involved in cell survival, proliferation, and differentiation. Therefore, we aim to elucidate cell-specific responses of neuronal overexpression of the small GTPase Ras on hyperoxia-mediated brain injury. Six-day-old (P6) synRas mice (neuronal Ras overexpression under the synapsin promoter) or wild type littermates were kept under hyperoxia (80% oxygen) or room air (21% oxygen) for 24 h. Apoptosis was analyzed by Western blot of cleaved Caspase-3 and neuronal and oligodendrocyte degeneration via immunohistochemistry. Short-term differentiation capacity of oligodendrocytes was assessed by quantification of myelin basic protein expression at P11. Long-lasting changes of hyperoxia-induced alteration of myelin structures were evaluated via transmission electron microscopy in young adult animals (P42). Western blot analysis of active Caspase 3 demonstrates a significant upregulation in wild-type littermates exposed to hyperoxia whereas synRas mice did not show any marked alteration of cleaved Caspase-3 protein levels. Immunohistochemistry revealed a protective effect of neuronal Ras overexpression on neuron and oligodendrocyte survival. Hyperoxia induced hypomyelination in wild-type littermates was restored in synRas mice. These short-term protective effects through promotion of neuronal survival translated into long-lasting improvement of ultrastructural alterations of myelin sheaths in mice with neuronal overexpression of Ras compared with hyperoxic wild type mice. Our data suggest that transgenic increase of neuronal Ras activity in the immature brain results in secondary protection of oligodendrocytes from hyperoxia-induced white matter brain injury. PMID- 29619003 TI - The Clinical Significance of O6-Methylguanine-DNA Methyltransferase Promoter Methylation Status in Adult Patients With Glioblastoma: A Meta-analysis. AB - Background and objective: Promoter status of O6-methylguanine-DNA methyltransferase (MGMT) has been widely established as a clinically relevant factor in glioblastoma (GBM) patients. However, in addition to varied therapy schedule, the prognosis of GBM patients is also affected by variations of age, race, primary or recurrent tumor. This study comprehensively investigated the association between MGMT promoter status and prognosis in overall GBM patients and in different GBM subtype including new diagnosed patients, recurrent patients and elderly patients. Methods: A comprehensive search was performed using PubMed, EMBASE, Cochrane databases to identify literatures (published from January 1, 2005 to April 1, 2017) that evaluated the associations between MGMT promoter methylation and prognosis of GBM patients. Results: Totally, 66 studies including 7,886 patients met the inclusion criteria. Overall GBM patients with a methylated status of MGMT receiving temozolomide (TMZ)-containing treatment had better overall survival (OS) and progression-free survival (PFS) [OS: hazard ratio (HR) = 0.46, 95% confidence interval (CI): 0.41-0.52, p < 0.001, Bon = 0.017; PFS: HR = 0.48, 95% CI 0.40-0.57, p < 0.001, Bon = 0.014], but no significant advantage on OS or PFS in GBM patients with TMZ-free treatment was observed (OS: HR = 0.97, 95% CI 0.91-1.03, p = 0.08, Bon = 1; PFS: HR = 0.76, 95% CI 0.57-1.02, p = 0.068, Bon = 0.748). These different impacts of MGMT status on OS were similar in newly diagnosed GBM patients, elderly GBM patients and recurrent GBM. Among patients receiving TMZ-free treatment, survival benefit in Asian patients was not observed anymore after Bonferroni correction (Asian OS: HR = 0.78, 95% CI 0.64-0.95, p = 0.02, Bon = 0.24, I2 = 0%; PFS: HR = 0.69, 95% CI 0.50-0.94, p = 0.02, Bon = 0.24). No benefit was observed in Caucasian receiving TMZ-free therapy regardless of Bonferroni adjustment. Conclusion: The meta-analysis highlights the universal predictive value of MGMT methylation in newly diagnosed GBM patients, elderly GBM patients and recurrent GBM patients. For elderly methylated GBM patients, TMZ alone therapy might be a more suitable option than radiotherapy alone therapy. Future clinical trials should be designed in order to optimize therapeutics in different GBM subpopulation. PMID- 29619006 TI - Mathematical Modeling of the Pituitary-Thyroid Feedback Loop: Role of a TSH-T3 Shunt and Sensitivity Analysis. AB - Despite significant progress in assay technology, diagnosis of functional thyroid disorders may still be a challenge, as illustrated by the vague upper limit of the reference range for serum thyrotropin (TSH). Diagnostical problems also apply to subjects affected by syndrome T, i.e., those 10% of hypothyroid patients who continue to suffer from poor quality of life despite normal TSH concentrations under substitution therapy with levothyroxine (L-T4). In this paper, we extend a mathematical model of the pituitary-thyroid feedback loop in order to improve the understanding of thyroid hormone homeostasis. In particular, we incorporate a TSH T3-shunt inside the thyroid, whose existence has recently been demonstrated in several clinical studies. The resulting extended model shows good accordance with various clinical observations, such as a circadian rhythm in free peripheral triiodothyronine (FT3). Furthermore, we perform a sensitivity analysis of the derived model, revealing the dependence of TSH and hormone concentrations on different system parameters. The results have implications for clinical interpretation of thyroid tests, e.g., in the differential diagnosis of subclinical hypothyroidism. PMID- 29619005 TI - Presence of Anxiety and Depression Symptoms Affects the First Time Treatment Efficacy and Recurrence of Benign Paroxysmal Positional Vertigo. AB - Objectives: To investigate the possible effects of anxiety and/or depression symptoms on the treatment outcomes and recurrence of benign paroxysmal positional vertigo (BPPV). Methods: This is a retrospective study conducted at a single institution. 142 consecutive patients diagnosed with idiopathic BPPV at the Department of Otology in Shengjing Hospital of China Medical University between October 2016 and July 2017 were retrospectively reviewed. 127 patients were finally included in this study. Zung self-rating anxiety scale (SAS) and Zung self-rating depression scale (SDS) were used to evaluate the presence of anxiety and/or depression, respectively, in our BPPV patients. A significant score (at or above 50 for SAS and 53 for SDS) represents the presence of clinically significant symptoms. Two-tailed Student's t-test, chi2 test, and logistic regression analysis were used as appropriate. A p value less than 0.05 was considered statistically significant. Results: The prevalence of anxiety and/or depression symptoms in BPPV patients in the present study was 49.61%. The effectiveness of the first time canalith repositioning maneuver (CRM) was 70.08%. With weekly follow-up treatments of CRM, the success rate increased to 97.64% by 1 month. The total recurrence rate at 6-month follow-up post-cure was 14.17%. Holding all other variables constant, patients with psychiatric symptoms (Relative-risk ratio: 3.160; p = 0.027) and patients with non-posterior semicircular canal (PSC) involvement (Relative-risk ratio: 7.828, p = 0.013) were more likely to experience residual dizziness (RD) even after effective CRM treatment. Psychiatric symptoms (Relative-risk ratio: 6.543; p = 0.001) and female gender (Relative-risk ratio: 4.563; p = 0.010) are risk factors for the failure of first time CRM. In addition, BPPV patients with psychiatric symptoms (Odds ratio: 9.184, p = 0.008) were significantly more likely to experience recurrences within the first 6 months after a successful maneuver. Conclusion: Anxiety-depression status significantly reduced the efficacy of the first time CRM and increased the risk for recurrence. Other factors, such as female gender and non-PSC involvement are also susceptible risk factors for BPPV patients to require multiple treatments and experience delayed recovery. A screening for psychiatric symptoms in BPPV patients and active treatment of these symptoms would benefit both physicians and patients in understanding and improving the prognosis of the disease and treatment options. PMID- 29619007 TI - Uric Acid Impairs Insulin Signaling by Promoting Enpp1 Binding to Insulin Receptor in Human Umbilical Vein Endothelial Cells. AB - High levels of uric acid (UA) are associated with type-2 diabetes and cardiovascular disease. Recent pieces of evidence attributed to UA a causative role in the appearance of diabetes and vascular damage. However, the molecular mechanisms by which UA induces these alterations have not been completely elucidated so far. Among the mechanisms underlying insulin resistance, it was reported the role of a transmembrane glycoprotein, named either ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) or plasma cell antigen 1, which is able to inhibit the function of insulin receptor (IR) and it is overexpressed in insulin-resistant subjects. In keeping with this, we stimulated human umbilical vein endothelial cells (HUVECs) with insulin and UA to investigate the effects of UA on insulin signaling pathway, testing the hypothesis that UA can interfere with insulin signaling by the activation of ENPP1. Cultures of HUVECs were stimulated with insulin, UA and the urate transporter SLC22A12 (URAT1) inhibitor probenecid. Akt and endothelial nitric oxide synthase (eNOS) phosphorylation levels were investigated by immunoblotting. ENPP1 binding to IR and its tyrosine phosphorylation levels were tested by immunoprecipitation and immunoblotting. UA inhibited insulin-induced Akt/eNOS axis. Moreover, UA induced ENPP1 binding to IR that resulted in an impairment of insulin signaling cascade. Probenecid reverted UA effects, suggesting that UA intracellular uptake is required for its action. In endothelial cells, UA directly interferes with insulin signaling pathway at receptor level, through ENPP1 recruitment. This evidence suggests a new molecular model of UA-induced insulin resistance and vascular damage. PMID- 29619008 TI - Initial Potassium Replacement in Diabetic Ketoacidosis: The Unnoticed Area of Gap. PMID- 29619009 TI - Extended Near-Infrared Optoacoustic Spectrometry for Sensing Physiological Concentrations of Glucose. AB - Glucose sensing is pursued extensively in biomedical research and clinical practice for assessment of the carbohydrate and fat metabolism as well as in the context of an array of disorders, including diabetes, morbid obesity, and cancer. Currently used methods for real-time glucose measurements are invasive and require access to body fluids, with novel tools and methods for non-invasive sensing of the glucose levels highly desired. In this study, we introduce a near infrared (NIR) optoacoustic spectrometer for sensing physiological concentrations of glucose within aqueous media and describe the glucose spectra within 850-1,900 nm and various concentration ranges. We apply the ratiometric and dictionary learning methods with a training set of data and validate their utility for glucose concentration measurements with optoacoustics in the probe dataset. We demonstrate the superior signal-to-noise ratio (factor of ~3.9) achieved with dictionary learning over the ratiometric approach across the wide glucose concentration range. Our data show a linear relationship between the optoacoustic signal intensity and physiological glucose concentration, in line with the results of optical spectroscopy. Thus, the feasibility of detecting physiological glucose concentrations using NIR optoacoustic spectroscopy is demonstrated, enabling the sensing glucose with +/-10 mg/dl precision. PMID- 29619010 TI - Thyroxine Treatment With Softgel Capsule Formulation: Usefulness in Hypothyroid Patients Without Malabsorption. AB - Background: Levothyroxine sodium (LT4) is the therapy of choice for hypothyroidism. In the last decade, new LT4 formulations, such as liquid and softgel capsules, became available. Even if some evidence has been reached in the efficacy of liquid LT4 in patients with suboptimal TSH on tablet LT4, the usefulness of softgel LT4 has been rarely studied. This study aimed at evaluating the effect of switching from tablet to softgel LT4 patients without increased need for LT4. TSH was used as proxy of LT4 bioavailability and effectiveness. Methods: During the period from April to August 2017, 19 patients on tablet LT4 treatment for hypothyroidism, mostly due to autoimmune thyroiditis, were enrolled. Subjects with causes of malabsorption or increased requirement of LT4 were previously excluded. Patients finally included were asked to switch from tablet to softgel LT4 formulation at unchanged dose and ingestion fashion (30 min before breakfast). TSH was measured with chemiluminescence immunoassays. Results: According to exclusion and inclusion criteria, 19 patients were finally selected. One of these had headache 4 days later and come back to tablet LT4, and 18 of them (16W/2M; mean age = 55 years; BMI 22.7 kg/m2) completed the study. They were treated with a median LT4 dose of 88 MUg/day and showed a median TSH value of 3.33 mIU/L. The rate of cases with TSH <= 4.0 mIU/L was 61.1% (11/18 cases). When patients were re-evaluated after 3 months of softgel LT4, we observed that TSH reached levels under 4.0 mIU/L in 16/18 (88.9%) patients, TSH was lower in 11 cases, and in 6 out of 7 patients with pre-switch TSH values over the normal range. Overall, TSH values on softgel LT4 (median 1.90 mIU/L) was significantly lower from that observed during tablet LT4 (p = 0.0039). Conclusion: These data show that hypothyroid patients with no proven malabsorption may have an improved TSH following 3 months from the switch from tablet to softgel LT4 preparation at unchanged dose. PMID- 29619011 TI - Spatiotemporal Changes of Cyanobacterial Bloom in Large Shallow Eutrophic Lake Taihu, China. AB - Lake Taihu is a large shallow eutrophic lake with frequent recurrence of cyanobacterial bloom which has high variable distribution in space and time. Based on the field observations and remote sensing monitoring of cyanobacterial bloom occurrence, in conjunction with laboratory controlled experiments of mixing effects on large colony formation and colonies upward moving velocity measurements, it is found that the small or moderate wind-induced disturbance would increase the colonies size and enable it more easily to overcome the mixing and float to water surface rapidly during post-disturbance. The proposed mechanism of wind induced mixing on cyanobacterial colony enlargement is associated with the presence of the extracellular polysaccharide (EPS) which increased the size and buoyancy of cyanobacteria colonies and promote the colonies aggregate at the water surface to form bloom. Both the vertical movement and horizontal migration of cyanobacterial colonies were controlled by the wind induced hydrodynamics. Because of the high variation of wind and current coupling with the large cyanobacterial colony formation make the bloom occurrence as highly mutable in space and time. This physical factor determining cyanobacterial bloom formation in the large shallow lake differ from the previously documented light-mediated bloom formation dynamics. PMID- 29619012 TI - Experimental Inoculation in Rats and Mice by the Giant Marseillevirus Leads to Long-Term Detection of Virus. AB - The presence of the giant virus of amoeba Marseillevirus has been identified at many different sites on the human body, including in the bloodstream of asymptomatic subjects, in the lymph nodes of a child with adenitis, in one adult with Hodgkin's disease, and in the pharynx of an adult. A high seroprevalence of the Marseillevirus has been recorded in the general population. Whether Marseillevirus can disseminate and persist within a mammal after entry remains unproven. We aimed to assess the ability of the virus to disseminate and persist into healthy organisms, especially in the lymphoid organs. Parenteral inoculations were performed by intraperitoneal injection (in rats and mice) or intravenous injection (in rats). Airway inoculation was performed by aerosolization (in mice). Dissemination and persistence were assessed by using PCR and amebal co-culture. Serologies were performed by immunofluorescent assay. Pathological examination was conducted after standard and immunohistochemistry staining. After intraperitoneal inoculation in mice and rats, Marseillevirus was detected in the bloodstream during the first 24 h. Persistence was noted until the end of the experiment, i.e., at 14 days in rats. After intravenous inoculation in rats, the virus was first detected in the blood until 48 h and then in deep organs with infectious virus detected until 14 and 21 days in the liver and the spleen, respectively. Its DNA was detected for up to 30 days in the liver and the spleen. After aerosolization in mice, infectious Marseillevirus was present in the lungs and nasal associated lymphoid tissue until 30 days post inoculation but less frequently and at a lower viral load in the lung than in the nasal associated lymphoid tissue. No other site of dissemination was found after aerosol exposure. Despite no evidence of disease being observed, the 30-day long persistence of Marseillevirus in rats and mice, regardless of the route of inoculation, supports the hypothesis of an infective potential of the virus in certain conditions. Its constant and long-term detection in nasal associated lymphoid tissue in mice after an aerosol exposure suggests the involvement of naso-pharyngeal associated lymphoid tissues in protecting the host against environmental Marseillevirus. PMID- 29619013 TI - Phosphorylation of the Bacillus subtilis Replication Controller YabA Plays a Role in Regulation of Sporulation and Biofilm Formation. AB - Bacillus subtilis cells can adopt different life-styles in response to various environmental cues, including planktonic cells during vegetative growth, sessile cells during biofilm formation and sporulation. While switching life-styles, bacteria must coordinate the progression of their cell cycle with their physiological status. Our current understanding of the regulatory pathways controlling the decision-making processes and triggering developmental switches highlights a key role of protein phosphorylation. The regulatory mechanisms that integrate the bacterial chromosome replication status with sporulation involve checkpoint proteins that target the replication initiator DnaA or the kinase phosphorelay controlling the master regulator Spo0A. B. subtilis YabA is known to interact with DnaA to prevent over-initiation of replication during vegetative growth. Here, we report that YabA is phosphorylated by YabT, a Ser/Thr kinase expressed during sporulation and biofilm formation. The phosphorylation of YabA has no effect on replication initiation control but hyper-phosphorylation of YabA leads to an increase in sporulation efficiency and a strong inhibition of biofilm formation. We also provide evidence that YabA phosphorylation affects the level of Spo0A-P in cells. These results indicate that YabA is a multifunctional protein with a dual role in regulating replication initiation and life-style switching, thereby providing a potential mechanism for cross-talk and coordination of cellular processes during adaptation to environmental change. PMID- 29619014 TI - Host and Aquatic Environment Shape the Amphibian Skin Microbiome but Effects on Downstream Resistance to the Pathogen Batrachochytrium dendrobatidis Are Variable. AB - Symbiotic microbial communities play key roles in the health and development of their multicellular hosts. Understanding why microbial communities vary among different host species or individuals is an important step toward understanding the diversity and function of the microbiome. The amphibian skin microbiome may affect resistance to the fungal pathogen Batrachochytrium dendrobatidis (Bd). Still, the factors that determine the diversity and composition of the amphibian skin microbiome, and therefore may ultimately contribute to disease resistance, are not well understood. We conducted a two-phase experiment to first test how host and environment shape the amphibian skin microbiome, and then test if the microbiome affects or is affected by Bd infection. Most lab experiments testing assembly of the amphibian skin microbiome so far have compared sterile to non sterile environments or heavily augmented to non-augmented frogs. A goal of this study was to evaluate, in an experimental setting, realistic potential drivers of microbiome assembly that would be relevant to patterns observed in nature. We tested effects of frog genetic background (2 source populations) and 6 natural lake water sources in shaping the microbiome of the frog Rana sierrae. Water in which frogs were housed affected the microbiome in a manner that partially mimicked patterns observed in natural populations. In particular, frogs housed in water from disease-resistant populations had greater bacterial richness than frogs housed in water from populations that died out due to Bd. However, in the experiment this difference in microbiomes did not lead to differences in host mortality or rates of pathogen load increase. Frog source population also affected the microbiome and, although none of the frogs in this study showed true resistance to infection, host source population had a small effect on the rate of pathogen load increase. This difference in infection trajectories could be due to the observed differences in the microbiome, but could also be due to other traits that differ between frogs from the two populations. In addition to examining effects of the microbiome on Bd, we tested the effect of Bd infection severity on the microbiome. Specifically, we studied a time series of the microbiome over the course of infection to test if the effects of Bd on the microbiome are dependent on Bd infection severity. Although limited to a small subset of frogs, time series analysis suggested that relative abundances of several bacterial phylotypes changed as Bd loads increased through time, indicating that Bd-induced disturbance of the R. sierrae microbiome is not a binary effect but instead is dependent on infection severity. We conclude that both host and aquatic environment help shape the R. sierrae skin microbiome, with links to small changes in disease resistance in some cases, but in this study the effect of Bd on the microbiome was greater than the effect of the microbiome on Bd. Assessment of the microbiome differences between more distantly related populations than those studied here is needed to fully understand the role of the microbiome in resistance to Bd. PMID- 29619015 TI - Colonization Dynamics of Cefotaxime Resistant Bacteria in Beef Cattle Raised Without Cephalosporin Antibiotics. AB - The emergence of infections caused by antimicrobial resistant microorganisms (ARMs) is currently one of the most important challenges to public health and medicine. Though speculated to originate at least partially from the overuse of antibiotics during food animal production, we hypothesized that cattle are exposed to ARMs in the environment. In this cohort study, a herd of beef calves with no previous exposure to antibiotics was followed during the first year of life in order to investigate the rate of colonization by bacteria resistant to the third-generation cephalosporin cefotaxime. Fecal samples were collected from the recto anal junction of cattle at the age of ~3, 6, 9, and 12 months and tested for cefotaxime resistant bacteria (CRB) and the presence of extended spectrum beta-lactamases (ESBLs). The colonization dynamics of CRB in calves (n = 188) was evaluated with samples collected from four periods using longitudinal statistical analyses. Colonization by CRB was a dynamic process with over 92% of the calves testing positive for CRB at least once during the first year of life. All isolates subjected to antimicrobial susceptibility test were resistant to at least four different antibiotics and carried multiple variants of the blaCTX-M genes. Metagenomic analysis revealed significant differences in microbiota of the calves with and without CRB colonization at different ages. This study provides evidence that colonization of beef calves by ARMs is a dynamic process that can occur in the absence of veterinary or agricultural use of antibiotics. PMID- 29619016 TI - Cyclic AMP Pathway Activation and Extracellular Zinc Induce Rapid Intracellular Zinc Mobilization in Candida albicans. AB - Zinc is an essential micronutrient, required for a range of zinc-dependent enzymes and transcription factors. In mammalian cells, zinc serves as a second messenger molecule. However, a role for zinc in signaling has not yet been established in the fungal kingdom. Here, we used the intracellular zinc reporter, zinbo-5, which allowed visualization of zinc in the endoplasmic reticulum and other components of the internal membrane system in Candida albicans. We provide evidence for a link between cyclic AMP/PKA- and zinc-signaling in this major human fungal pathogen. Glucose stimulation, which triggers a cyclic AMP spike in this fungus resulted in rapid intracellular zinc mobilization and this "zinc flux" could be stimulated with phosphodiesterase inhibitors and blocked via inhibition of adenylate cyclase or PKA. A similar mobilization of intracellular zinc was generated by stimulation of cells with extracellular zinc and this effect could be reversed with the chelator EDTA. However, zinc-induced zinc flux was found to be cyclic AMP independent. In summary, we show that activation of the cyclic AMP/PKA pathway triggers intracellular zinc mobilization in a fungus. To our knowledge, this is the first described link between cyclic AMP signaling and zinc homeostasis in a human fungal pathogen. PMID- 29619017 TI - An Overview of the Function and Maintenance of Sexual Reproduction in Dikaryotic Fungi. AB - Sexual reproduction likely evolved as protection from environmental stresses, specifically, to repair DNA damage, often via homologous recombination. In higher eukaryotes, meiosis and the production of gametes with allelic combinations different from parental type provides the side effect of increased genetic variation. In fungi it appears that while the maintenance of meiosis is paramount for success, outcrossing is not a driving force. In the subkingdom Dikarya, fungal members are characterized by existence of a dikaryon for extended stages within the life cycle. Such fungi possess functional or, in some cases, relictual, loci that govern sexual reproduction between members of their own species. All mating systems identified so far in the Dikarya employ a pheromone/receptor system for haploid organisms to recognize a compatible mating partner, although the paradigm in the Ascomycota, e.g., Saccharomyces cerevisiae, is that genes for the pheromone precursor and receptor are not found in the mating-type locus but rather are regulated by its products. Similarly, the mating systems in the Ascomycota are bipolar, with two non-allelic idiomorphs expressed in cells of opposite mating type. In contrast, for the Basidiomycota, both bipolar and tetrapolar mating systems have been well characterized; further, at least one locus directly encodes the pheromone precursor and the receptor for the pheromone of a different mating type, while a separate locus encodes proteins that may regulate the first locus and/or additional genes required for downstream events. Heterozygosity at both of two unlinked loci is required for cells to productively mate in tetrapolar systems, whereas in bipolar systems the two loci are tightly linked. Finally, a trade-off exists in wild fungal populations between sexual reproduction and the associated costs, with adverse conditions leading to mating. For fungal mammal pathogens, the products of sexual reproduction can be targets for the host immune system. The opposite appears true for phytopathogenic fungi, where mating and pathogenicity are inextricably linked. Here, we explore, compare, and contrast different strategies used among the Dikarya, both saprophytic and pathogenic fungi, and highlight differences between pathogens of mammals and pathogens of plants, providing context for selective pressures acting on this interesting group of fungi. PMID- 29619018 TI - S-Adenosyl-L-Homocysteine Hydrolase Inhibition by a Synthetic Nicotinamide Cofactor Biomimetic. AB - S-adenosyl-L-homocysteine (SAH) hydrolases (SAHases) are involved in the regulation of methylation reactions in many organisms and are thus crucial for numerous cellular functions. Consequently, their dysregulation is associated with severe health problems. The SAHase-catalyzed reaction is reversible and both directions depend on the redox activity of nicotinamide adenine dinucleotide (NAD+) as a cofactor. Therefore, nicotinamide cofactor biomimetics (NCB) are a promising tool to modulate SAHase activity. In the present in vitro study, we investigated 10 synthetic truncated NAD+ analogs against a SAHase from the root nodulating bacterium Bradyrhizobium elkanii. Among this set of analogs, one was identified to inhibit the SAHase in both directions. Isothermal titration calorimetry (ITC) and crystallography experiments suggest that the inhibitory effect is not mediated by a direct interaction with the protein. Neither the apo enzyme (i.e., deprived of the natural cofactor), nor the holo-enzyme (i.e., in the NAD+-bound state) were found to bind the inhibitor. Yet, enzyme kinetics point to a non-competitive inhibition mechanism, where the inhibitor acts on both, the enzyme and enzyme-SAH complex. Based on our experimental results, we hypothesize that the NCB inhibits the enzyme via oxidation of the enzyme-bound NADH, which may be accessible through an open molecular gate, leaving the enzyme stalled in a configuration with oxidized cofactor, where the reaction intermediate can be neither converted nor released. Since the reaction mechanism of SAHase is quite uncommon, this kind of inhibition could be a viable pharmacological route, with a low risk of off-target effects. The NCB presented in this work could be used as a template for the development of more potent SAHase inhibitors. PMID- 29619019 TI - Stable Regulation of Cell Cycle Events in Mycobacteria: Insights From Inherently Heterogeneous Bacterial Populations. AB - Model bacteria, such as E. coli and B. subtilis, tightly regulate cell cycle progression to achieve consistent cell size distributions and replication dynamics. Many of the hallmark features of these model bacteria, including lateral cell wall elongation and symmetric growth and division, do not occur in mycobacteria. Instead, mycobacterial growth is characterized by asymmetric polar growth and division. This innate asymmetry creates unequal birth sizes and growth rates for daughter cells with each division, generating a phenotypically heterogeneous population. Although the asymmetric growth patterns of mycobacteria lead to a larger variation in birth size than typically seen in model bacterial populations, the cell size distribution is stable over time. Here, we review the cellular mechanisms of growth, division, and cell cycle progression in mycobacteria in the face of asymmetry and inherent heterogeneity. These processes coalesce to control cell size. Although Mycobacterium smegmatis and Mycobacterium bovis Bacillus Calmette-Guerin (BCG) utilize a novel model of cell size control, they are similar to previously studied bacteria in that initiation of DNA replication is a key checkpoint for cell division. We compare the regulation of DNA replication initiation and strategies used for cell size homeostasis in mycobacteria and model bacteria. Finally, we review the importance of cellular organization and chromosome segregation relating to the physiology of mycobacteria and consider how new frameworks could be applied across the wide spectrum of bacterial diversity. PMID- 29619020 TI - Molecular Detection of Azole-Resistant Aspergillus fumigatus in Clinical Samples. AB - Aspergillus diseases are often caused by Aspergillus fumigatus. Azoles are the mainstay of therapy, but the management of aspergillosis is hampered by the emergence of azole resistance. Rapid detection of azole resistance might benefit treatment outcome by early treatment modifications. However, the yield of fungal culture in invasive aspergillosis is low and susceptibility testing requires several days to be completed. To overcome the low yield of fungal cultures and slow detection of resistance, it is possible to use molecular tools directly on clinical specimens in order to rapidly detect molecular markers of azole resistance. Molecular tools to detect resistant markers in the Cyp51A gene can be expected to be less sensitive compared to molecular tools to detect Aspergillus DNA as the Cyp51A gene is a single copy gene and the target for Aspergillus DNA is often a multi-copy gene. In this mini-review, we summarize the current molecular tools for detection of azole-resistant A. fumigatus directly in clinical material. Several in-house PCR assays have been applied directly on clinical material. Furthermore, two assays are commercial available; the AsperGenius and MycoGENIE. The amplification of resistance markers was successful in 70-100% of samples that were positive for Aspergillus DNA in BAL samples using the AsperGenius assay. Despite using several samples per patient, amplification of resistance markers was only successful in 33-57% of patients with Aspergillus DNA in blood. Furthermore, several sequence based methods have been applied with the benefit of the ability to detect other Cyp51A gene alterations. PMID- 29619021 TI - Validation of a Hypothesis: Colonization of Black Smokers by Hyperthermophilic Microorganisms. AB - Newly erupted black smokers (hydrothermal vent chimneys) are sterile during their formation, but house hyperthermophilic microorganisms in substantial amounts in later stages. No direct experimental data exist by which mechanisms hyperthermophiles colonize newly erupted black smokers, but a scenario was proposed recently how this might happen. Here we combine high temperature light microscopy with electron microscopy to show that two hyperthermophilic Archaea, namely Pyrococcus furiosus and Methanocaldococcus villosus are able to adhere onto authentic black smoker material (BSM). We especially are able to directly observe the adhesion process via video recordings taken at high temperatures. These data validate the hypothesis that hyperthermophiles are transferred by serendipitous water currents to the outside of newly formed black smokers and react within seconds to the there prevailing high temperatures by very fast movements. They scan the surface of the hydrothermal chimneys via a much slower zigzag seek-movement and adhere via their flagella at a suitable place, building up biofilms. PMID- 29619022 TI - Linking Microbial Community Structure and Function During the Acidified Anaerobic Digestion of Grass. AB - Harvesting valuable bioproducts from various renewable feedstocks is necessary for the critical development of a sustainable bioeconomy. Anaerobic digestion is a well-established technology for the conversion of wastewater and solid feedstocks to energy with the additional potential for production of process intermediates of high market values (e.g., carboxylates). In recent years, first generation biofuels typically derived from food crops have been widely utilized as a renewable source of energy. The environmental and socioeconomic limitations of such strategy, however, have led to the development of second-generation biofuels utilizing, amongst other feedstocks, lignocellulosic biomass. In this context, the anaerobic digestion of perennial grass holds great promise for the conversion of sustainable renewable feedstock to energy and other process intermediates. The advancement of this technology however, and its implementation for industrial applications, relies on a greater understanding of the microbiome underpinning the process. To this end, microbial communities recovered from replicated anaerobic bioreactors digesting grass were analyzed. The bioreactors leachates were not buffered and acidic pH (between 5.5 and 6.3) prevailed at the time of sampling as a result of microbial activities. Community composition and transcriptionally active taxa were examined using 16S rRNA sequencing and microbial functions were investigated using metaproteomics. Bioreactor fraction, i.e., grass or leachate, was found to be the main discriminator of community analysis across the three molecular level of investigation (DNA, RNA, and proteins). Six taxa, namely Bacteroidia, Betaproteobacteria, Clostridia, Gammaproteobacteria, Methanomicrobia, and Negativicutes accounted for the large majority of the three datasets. The initial stages of grass hydrolysis were carried out by Bacteroidia, Gammaproteobacteria, and Negativicutes in the grass biofilms, in addition to Clostridia in the bioreactor leachates. Numerous glycolytic enzymes and carbohydrate transporters were detected throughout the bioreactors in addition to proteins involved in butanol and lactate production. Finally, evidence of the prevalence of stressful conditions within the bioreactors and particularly impacting Clostridia was observed in the metaproteomes. Taken together, this study highlights the functional importance of Clostridia during the anaerobic digestion of grass and thus research avenues allowing members of this taxon to thrive should be explored. PMID- 29619023 TI - Functional Complement Analysis Can Predict Genetic Testing Results and Long-Term Outcome in Patients With Complement Deficiencies. AB - Background: Prevalence of complement deficiencies (CDs) is markedly higher in Slovenian primary immunodeficiency (PID) registry in comparison to other national and international PID registries. Objective: The purposes of our study were to confirm CD and define complete and partial CD in registered patients in Slovenia, to evaluate frequency of clinical manifestations, and to assess the risk for characteristic infections separately for subjects with complete and partial CD. Methods: CD was confirmed with genetic analyses in patients with C2 deficiency, C8 deficiency, and hereditary angioedema or with repeated functional complement studies and measurement of complement components in other CD. Results of genetic studies (homozygous subjects vs. heterozygous carriers) and complement functional studies were analyzed to define complete (complement below the level of heterozygous carriers) and partial CD (complement above the level of homozygous patients). Presence of characteristic infections was assessed separately for complete and partial CD. Results: Genetic analyses confirmed markedly higher prevalence of CD in Slovenian PID registry (26% of all PID) than in other national and international PID registries (0.5-6% of all PID). Complement functional studies and complement component concentrations reliably distinguished between homozygous and heterozygous CD carriers. Subjects with partial CD had higher risk for characteristic infections than previously reported. Conclusion: Results of our study imply under-recognition of CD worldwide. Complement functional studies and complement component concentrations reliably predicted risk for characteristic infections in patients with complete or partial CD. Vaccination against encapsulated bacteria should be advocated also for subjects with partial CD and not limited to complete CD. PMID- 29619024 TI - Extracellular NGFR Spacers Allow Efficient Tracking and Enrichment of Fully Functional CAR-T Cells Co-Expressing a Suicide Gene. AB - Chimeric antigen receptor (CAR)-T cell immunotherapy is at the forefront of innovative cancer therapeutics. However, lack of standardization of cellular products within the same clinical trial and lack of harmonization between different trials have hindered the clear identification of efficacy and safety determinants that should be unveiled in order to advance the field. With the aim of facilitating the isolation and in vivo tracking of CAR-T cells, we here propose the inclusion within the CAR molecule of a novel extracellular spacer based on the low-affinity nerve-growth-factor receptor (NGFR). We screened four different spacer designs using as target antigen the CD44 isoform variant 6 (CD44v6). We successfully generated NGFR-spaced CD44v6 CAR-T cells that could be efficiently enriched with clinical-grade immuno-magnetic beads without negative consequences on subsequent expansion, immuno-phenotype, in vitro antitumor reactivity, and conditional ablation when co-expressing a suicide gene. Most importantly, these cells could be tracked with anti-NGFR monoclonal antibodies in NSG mice, where they expanded, persisted, and exerted potent antitumor effects against both high leukemia and myeloma burdens. Similar results were obtained with NGFR-enriched CAR-T cells specific for CD19 or CEA, suggesting the universality of this strategy. In conclusion, we have demonstrated that the incorporation of the NGFR marker gene within the CAR sequence allows for a single molecule to simultaneously work as a therapeutic and selection/tracking gene. Looking ahead, NGFR spacer enrichment might allow good manufacturing procedures manufacturing of standardized CAR-T cell products with high therapeutic potential, which could be harmonized in different clinical trials and used in combination with a suicide gene for future application in the allogeneic setting. PMID- 29619025 TI - Mast Cells and Innate Lymphoid Cells: Underappreciated Players in CNS Autoimmune Demyelinating Disease. AB - Multiple sclerosis (MS) and its mouse model, experimental autoimmune encephalomyelitis, are autoimmune CNS inflammatory diseases. As a result of a breakdown in the relatively impermeable blood-brain barrier (BBB) in affected individuals, myelin-specific CD4+ and CD8+ T cells gain entry into the immune privileged CNS and initiate myelin, oligodendrocyte, and nerve axon destruction. However, despite the absolute requirement for T cells, there is increasing evidence that innate immune cells also play critical amplifying roles in disease pathogenesis. By modulating the character and magnitude of the myelin-reactive T cell response and regulating BBB integrity, innate cells affect both disease initiation and progression. Two classes of innate cells, mast cells and innate lymphoid cells (ILCs), have been best studied in models of allergic and gastrointestinal inflammatory diseases. Yet, there is emerging evidence that these cell types also exert a profound influence in CNS inflammatory disease. Both cell types are residents within the meninges and can be activated early in disease to express a wide variety of disease-modifying cytokines and chemokines. In this review, we discuss how mast cells and ILCs can have either disease promoting or -protecting effects on MS and other CNS inflammatory diseases and how sex hormones may influence this outcome. These observations suggest that targeting these cells and their unique mediators can be exploited therapeutically. PMID- 29619026 TI - Sexual Dimorphism of Immune Responses: A New Perspective in Cancer Immunotherapy. AB - Nowadays, several types of tumors can benefit from the new frontier of immunotherapy, due to the recent increasing knowledge of the role of the immune system in cancer control. Among the new therapeutic strategies, there is the immune checkpoint blockade (ICB), able to restore an efficacious antitumor immunity and significantly prolong the overall survival (OS) of patients with advanced tumors such as melanoma and non-small cell lung cancer (NSCLC). Despite the impressive efficacy of these agents in some patients, treatment failure and resistance are frequently observed. In this regard, the signaling governed by IFN type I (IFN-I) has emerged as pivotal in orchestrating host defense. This pathway displays different activation between sexes, thus potentially contributing to sexual dimorphic differences in the immune responses to immunotherapy. This perspective article aims to critically consider the immune signals, with particular attention to IFN-I, that may differently affect female and male antitumor responses upon immunotherapy. PMID- 29619027 TI - Predictive Virtual Infection Modeling of Fungal Immune Evasion in Human Whole Blood. AB - Bloodstream infections by the human-pathogenic fungi Candida albicans and Candida glabrata increasingly occur in hospitalized patients and are associated with high mortality rates. The early immune response against these fungi in human blood comprises a concerted action of humoral and cellular components of the innate immune system. Upon entering the blood, the majority of fungal cells will be eliminated by innate immune cells, i.e., neutrophils and monocytes. However, recent studies identified a population of fungal cells that can evade the immune response and thereby may disseminate and cause organ dissemination, which is frequently observed during candidemia. In this study, we investigate the so far unresolved mechanism of fungal immune evasion in human whole blood by testing hypotheses with the help of mathematical modeling. We use a previously established state-based virtual infection model for whole-blood infection with C. albicans to quantify the immune response and identified the fungal immune-evasion mechanism. While this process was assumed to be spontaneous in the previous model, we now hypothesize that the immune-evasion process is mediated by host factors and incorporate such a mechanism in the model. In particular, we propose, based on previous studies that the fungal immune-evasion mechanism could possibly arise through modification of the fungal surface by as of yet unknown proteins that are assumed to be secreted by activated neutrophils. To validate or reject any of the immune-evasion mechanisms, we compared the simulation of both immune evasion models for different infection scenarios, i.e., infection of whole blood with either C. albicans or C. glabrata under non-neutropenic and neutropenic conditions. We found that under non-neutropenic conditions, both immune-evasion models fit the experimental data from whole-blood infection with C. albicans and C. glabrata. However, differences between the immune-evasion models could be observed for the infection outcome under neutropenic conditions with respect to the distribution of fungal cells across the immune cells. Based on these predictions, we suggested specific experimental studies that might allow for the validation or rejection of the proposed immune-evasion mechanism. PMID- 29619028 TI - MAPK Phosphatase-1 Deficiency Exacerbates the Severity of Imiquimod-Induced Psoriasiform Skin Disease. AB - Persistent activation of mitogen-activated protein kinase (MAPK) is believed to be involved in psoriasis pathogenesis. MAPK phosphatase-1 (MKP-1) is an important negative regulator of MAPK activity, but the cellular and molecular mechanisms of MKP-1 in psoriasis development are largely unknown. In this study, we found that the expression of MKP-1 was decreased in the imiquimod (IMQ)-induced psoriasiform mouse skin. MKP-1-deficient (MKP-1-/-) mice were highly susceptible to IMQ induced skin inflammation, which was associated with increased production of inflammatory cytokines and chemokines. MKP-1 acted on both hematopoietic and non hematopoietic cells to regulate psoriasis pathogenesis. MKP-1 deficiency in macrophages led to enhanced p38 activation and higher expression of interleukin (IL)-1beta, CXCL2, and S100a8 upon R848 stimulation. Moreover, MKP-1 deficiency in the non-hematopoietic compartments led to an enhanced IL-22 receptor signaling and higher expression of CXCL1 and CXCL2 upon IMQ treatment. Collectively, our data suggest a critical role for MKP-1 in the regulation of skin inflammation. PMID- 29619029 TI - Anti-Type VII Collagen Antibodies Are Identified in a Subpopulation of Bullous Pemphigoid Patients With Relapse. AB - Bullous pemphigoid (BP) is an autoimmune bullous skin disease characterized by anti-BP180 and anti-BP230 autoantibodies (AAbs). Mucous membrane involvement is an uncommon clinical feature of BP which may evoke epidermolysis bullosa acquisita, another skin autoimmune disease characterized by anti-type VII collagen AAbs. We therefore evaluated the presence of anti-type VII collagen AAbs in the serum of BP patients with and without mucosal lesions at time of diagnosis and under therapy. Anti-BP180, anti-BP230, and anti-type VII collagen AAbs were measured by ELISA in the serum of unselected patients fulfilling clinical and histo/immunopathological BP criteria at baseline (n = 71) and at time of relapse (n = 24). At baseline, anti-type VII collagen AAbs were detected in 2 out of 24 patients with BP presenting with mucosal involvement, but not in patients without mucosal lesions (n = 47). At the time of relapse, 10 out of 24 BP patients either displayed a significant induction or increase of concentrations of anti-type VII collagen AAbs (P < 0.01), independently of mucosal involvement. Those 10 relapsing BP patients were also characterized by a sustained high concentration of anti-BP180 AAb, whereas the serum anti-BP230 AAb concentrations did not vary in BP patients with relapse according to the presence of anti-type VII collagen AAbs. Thus, our study showed that anti-type VII collagen along with anti-BP180 AAbs detection stratified BP patients at time of relapse, illustrating a still dysregulated immune response that could reflect a potential epitope spreading mechanism in those BP patients. PMID- 29619031 TI - Impact of Aging, Cytomegalovirus Infection, and Long-Term Treatment for Human Immunodeficiency Virus on CD8+ T-Cell Subsets. AB - Both healthy aging and human immunodeficiency virus (HIV) infection lead to a progressive decline in naive CD8+ T-cell numbers and expansion of the CD8+ T-cell memory and effector compartments. HIV infection is therefore often considered a condition of premature aging. Total CD8+ T-cell numbers of HIV-infected individuals typically stay increased even after long-term (LT) combination antiretroviral treatment (cART), which is associated with an increased risk of non-AIDS morbidity and mortality. The causes of these persistent changes in the CD8+ T-cell pool remain debated. Here, we studied the impact of age, CMV infection, and LT successful cART on absolute cell numbers in different CD8+ T cell subsets. While naive CD8+ T-cell numbers in cART-treated individuals (N = 38) increased to healthy levels, central memory (CM), effector memory (EM), and effector CD8+ T-cell numbers remained higher than in (unselected) age-matched healthy controls (N = 107). Longitudinal analysis in a subset of patients showed that cART did result in a loss of memory CD8+ T-cells, mainly during the first year of cART, after which memory cell numbers remained relatively stable. As CMV infection is known to increase CD8+ T-cell numbers in healthy individuals, we studied whether any of the persistent changes in the CD8+ T-cell pools of cART treated patients could be a direct reflection of the high CMV prevalence among HIV-infected individuals. We found that EM and effector CD8+ T-cell numbers in CMV+ healthy individuals (N = 87) were significantly higher than in CMV- (N = 170) healthy individuals. As a result, EM and effector CD8+ T-cell numbers in successfully cART-treated HIV-infected individuals did not deviate significantly from those of age-matched CMV+ healthy controls (N = 39). By contrast, CM T-cell numbers were quite similar in CMV+ and CMV- healthy individuals across all ages. The LT expansion of the CM CD8+ T-cell pool in cART-treated individuals could thus not be attributed directly to CMV and was also not related to residual HIV RNA or to the presence of HIV-specific CM T-cells. It remains to be investigated why the CM CD8+ T-cell subset shows seemingly irreversible changes despite years of effective treatment. PMID- 29619030 TI - Dopaminergic Stimulation of Myeloid Antigen-Presenting Cells Attenuates Signal Transducer and Activator of Transcription 3-Activation Favouring the Development of Experimental Autoimmune Encephalomyelitis. AB - The dual potential to promote tolerance or inflammation to self-antigens makes dendritic cells (DCs) fundamental players in autoimmunity. Previous results have shown that stimulation of dopamine receptor D5 (DRD5) in DCs potentiates their inflammatory behaviour, favouring the development of experimental autoimmune encephalomyelitis (EAE). Here, we aimed to decipher the underlying mechanism and to test its relevance in multiple sclerosis (MS) patients. Our data shows that DRD5-deficiency confined to DCs in EAE mice resulted in reduced frequencies of CD4+ T-cell subsets with inflammatory potential in the central nervous system, including not only Th1 and Th17 cells but also granulocyte-macrophage colony stimulating factor producers. Importantly, ex vivo depletion of dopamine from DCs resulted in a dramatic reduction of EAE severity, highlighting the relevance of an autocrine loop promoting inflammation in vivo. Mechanistic analyses indicated that DRD5-signalling in both mouse DCs and human monocytes involves the attenuation of signal transducer and activator of transcription 3-activation, a transcription factor that limits the production of the inflammatory cytokines interleukin (IL)-12 and IL-23. Furthermore, we found an exacerbated expression of all dopamine receptors in peripheral blood pro-inflammatory monocytes obtained from MS patients. These findings illustrate a novel mechanism by which myeloid antigen-presenting cells may trigger the onset of their inflammatory behaviour promoting the development of autoimmunity. PMID- 29619032 TI - An Autocrine TNFalpha-Tumor Necrosis Factor Receptor 2 Loop Promotes Epigenetic Effects Inducing Human Treg Stability In Vitro. AB - A crucial issue for Treg-based immunotherapy is to maintain a bona fide Treg phenotype as well as suppressive function during and after ex vivo expansion. Several strategies have been applied to harness Treg lineage stability. For instance, CD28 superagonist stimulation in vitro, in the absence of CD3 ligation, is more efficient in promoting Treg proliferation, and prevention of pro inflammatory cytokine expression, such as IL-17, as compared to CD3/CD28 stimulated Treg. Addition of the mTOR inhibitor rapamycin to Treg cultures enhances FOXP3 expression and Treg stability, but does impair proliferative capacity. A tumor necrosis factor receptor 2 (TNFR2) agonist antibody was recently shown to favor homogenous expansion of Treg in vitro. Combined stimulation with rapamycin and TNFR2 agonist antibody enhanced hypo-methylation of the FOXP3 gene, and thus promoting Treg stability. To further explore the underlying mechanisms of rapamycin and TNFR2 agonist-mediated Treg stability, we here stimulated FACS-sorted human Treg with a CD28 superagonist, in the presence of rapamycin and a TNFR2 agonist. Phenotypic analysis of expanded Treg revealed an autocrine loop of TNFalpha-TNFR2 underlying the maintenance of Treg stability in vitro. Addition of rapamycin to CD28 superagonist-stimulated Treg led to a high expression of TNFR2, the main TNFR expressed on Treg, and additional stimulation with a TNFR2 agonist enhanced the production of soluble as well as membrane-bound TNFalpha. Moreover, our data showed that the expression of histone methyltransferase EZH2, a crucial epigenetic modulator for potent Treg suppressor function, was enhanced upon stimulation with CD28 superagonist. Interestingly, rapamycin seemed to downregulate CD28 superagonist-induced EZH2 expression, which could be rescued by the additional addition of TNFR2 agonist antibody. This process appeared TNFalpha-dependent manner, since depletion of TNFalpha using Etanercept inhibited EZH2 expression. To summarize, we propose that an autocrine TNFalpha-TNFR2 loop plays an important role in endorsing Treg stability. PMID- 29619034 TI - Distinct Immunologic Properties of Soluble Versus Particulate Antigens. AB - Antigens in particulate form have distinct immunologic properties relative to soluble antigens. An understanding of the mechanisms and functional consequences of the distinct immunologic pathways engaged by these different forms of antigen is particularly relevant to the design of vaccines. It is also relevant regarding the use of therapeutic human proteins in clinical medicine that have been shown to aggregate, and perhaps as a result, elicit autoantibodies. PMID- 29619035 TI - Potential of Genomic Selection in Mass Selection Breeding of an Allogamous Crop: An Empirical Study to Increase Yield of Common Buckwheat. AB - To evaluate the potential of genomic selection (GS), a selection experiment with GS and phenotypic selection (PS) was performed in an allogamous crop, common buckwheat (Fagopyrum esculentum Moench). To indirectly select for seed yield per unit area, which cannot be measured on a single-plant basis, a selection index was constructed from seven agro-morphological traits measurable on a single plant basis. Over 3 years, we performed two GS and one PS cycles per year for improvement in the selection index. In GS, a prediction model was updated every year on the basis of genotypes of 14,598-50,000 markers and phenotypes. Plants grown from seeds derived from a series of generations of GS and PS populations were evaluated for the traits in the selection index and other yield-related traits. GS resulted in a 20.9% increase and PS in a 15.0% increase in the selection index in comparison with the initial population. Although the level of linkage disequilibrium in the breeding population was low, the target trait was improved with GS. Traits with higher weights in the selection index were improved more than those with lower weights, especially when prediction accuracy was high. No trait changed in an unintended direction in either GS or PS. The accuracy of genomic prediction models built in the first cycle decreased in the later cycles because the genetic bottleneck through the selection cycles changed linkage disequilibrium patterns in the breeding population. The present study emphasizes the importance of updating models in GS and demonstrates the potential of GS in mass selection of allogamous crop species, and provided a pilot example of successful application of GS to plant breeding. PMID- 29619033 TI - Triggering Receptor Expressed on Myeloid Cells-1 Signaling: Protective and Pathogenic Roles on Streptococcal Toxic-Shock-Like Syndrome Caused by Streptococcus suis. AB - Streptococcus suis infections can cause septic shock, which is referred to as streptococcal toxic-shock-like syndrome (STSLS). The disease is characterized by a severe inflammatory response, multiple organ failure, and high mortality. However, no superantigen that is responsible for toxic shock syndrome was detected in S. suis, indicating that the mechanism underlying STSLS is different and remains to be elucidated. Triggering receptor expressed on myeloid cells-1 (TREM-1), belonging to the Ig superfamily, is an activating receptor expressed on myeloid cells, and has been recognized as a critical immunomodulator in several inflammatory diseases of both infectious and non-infectious etiologies. In this review, we discuss the current understanding of the immunoregulatory functions of TREM-1 on acute infectious diseases and then highlight the crucial roles of TREM 1 on the development of STSLS. PMID- 29619036 TI - Long-Term Irrigation Affects the Dynamics and Activity of the Wheat Rhizosphere Microbiome. AB - The Inland Pacific Northwest (IPNW) encompasses 1. 6 million cropland hectares and is a major wheat-producing area in the western United States. The climate throughout the region is semi-arid, making the availability of water a significant challenge for IPNW agriculture. Much attention has been given to uncovering the effects of water stress on the physiology of wheat and the dynamics of its soilborne diseases. In contrast, the impact of soil moisture on the establishment and activity of microbial communities in the rhizosphere of dryland wheat remains poorly understood. We addressed this gap by conducting a three-year field study involving wheat grown in adjacent irrigated and dryland (rainfed) plots established in Lind, Washington State. We used deep amplicon sequencing of the V4 region of the 16S rRNA to characterize the responses of the wheat rhizosphere microbiome to overhead irrigation. We also characterized the population dynamics and activity of indigenous Phz+ rhizobacteria that produce the antibiotic phenazine-1-carboxylic acid (PCA) and contribute to the natural suppression of soilborne pathogens of wheat. Results of the study revealed that irrigation affected the Phz+ rhizobacteria adversely, which was evident from the significantly reduced plant colonization frequency, population size and levels of PCA in the field. The observed differences between irrigated and dryland plots were reproducible and amplified over the course of the study, thus identifying soil moisture as a critical abiotic factor that influences the dynamics, and activity of indigenous Phz+ communities. The three seasons of irrigation had a slight effect on the overall diversity within the rhizosphere microbiome but led to significant differences in the relative abundances of specific OTUs. In particular, irrigation differentially affected multiple groups of Bacteroidetes and Proteobacteria, including taxa with known plant growth-promoting activity. Analysis of environmental variables revealed that the separation between irrigated and dryland treatments was due to changes in the water potential (Psim) and pH. In contrast, the temporal changes in the composition of the rhizosphere microbiome correlated with temperature and precipitation. In summary, our long term study provides insights into how the availability of water in a semi-arid agroecosystem shapes the belowground wheat microbiome. PMID- 29619037 TI - Identification of Lipid Markers of Plasmopara viticola Infection in Grapevine Using a Non-targeted Metabolomic Approach. AB - The Oomycete Plasmopara viticola is responsible for downy mildew, which is one of the most damaging grapevine diseases. Due to the strictly biotrophic way of life of P. viticola, its metabolome is relatively poorly characterized. In this work, we have used a mass spectrometry-based non-targeted metabolomic approach to identify potential Plasmopara-specific metabolites. This has led to the characterization and structural elucidation of compounds belonging to three families of atypical lipids, which are not detected in healthy grapevine tissues. These lipids include ceramides and derivatives of arachidonic and eicosapentaenoic acid, most of which had not been previously described in Oomycetes. Furthermore, we show that these lipids can be detected in Plasmopara infected tissues at very early stages of the infection process, long before the appearance the first visible symptoms of the disease. Therefore, the potential use of these specific lipids as markers to monitor the development of P. viticola is discussed. PMID- 29619039 TI - Two TPL-Binding Motifs of ARF2 Are Involved in Repression of Auxin Responses. AB - Auxin signaling is finalized by activator auxin response factors (aARFs) that are released from Auxin/Indole-3-Acetic Acid (Aux/IAA) repressors and directly activate auxin-responsive genes. However, it remains to be answered how repressor ARFs (rARFs) exert their repression function. In this study, we assessed the molecular and biological functions of two putative co-repressor-binding motifs (EAR and RLFGI) of ARF2 (a rARF) in Arabidopsis thaliana. In the yeast two-hybrid assay, the EAR mutation moderately and the RLFGI mutation, or both motifs, almost completely disrupted the interaction between the co-repressor TOPLESS (TPL) and the repressive motifs-containing middle domain (MD) of ARF2. The ARF2-MD interacted not only with TPL but also with TPL homologs (TPRs). Root hair specific overexpression of rARFs (ARF1-4, 9-11, and 16) considerably inhibited root hair growth, suggesting that rARFs generally function as repressors in the auxin-responsive root hair single cell. Individual mutation of the ARF2 EAR or RLFGI motif slightly and both mutations greatly compromised ARF2-mediated inhibition of root hair growth and auxin-responsive gene expression. In addition, flowering time and seed size, two representative arf2 mutant phenotypes, were examined to assess the function of the repressive motifs in mutant complementation experiments. ARF2-mediated inhibition of flowering and seed growth was suppressed considerably by the individual mutation of EAR or RLFGI and almost completely by both mutations. These results suggest that EAR and RLFGI work together as major repressive motifs for ARF2 to recruit TPL/TPR co repressors and to exhibit its repressive biological functions. PMID- 29619038 TI - Optimized Use of Low-Depth Genotyping-by-Sequencing for Genomic Prediction Among Multi-Parental Family Pools and Single Plants in Perennial Ryegrass (Lolium perenne L.). AB - Ryegrass single plants, bi-parental family pools, and multi-parental family pools are often genotyped, based on allele-frequencies using genotyping-by-sequencing (GBS) assays. GBS assays can be performed at low-coverage depth to reduce costs. However, reducing the coverage depth leads to a higher proportion of missing data, and leads to a reduction in accuracy when identifying the allele-frequency at each locus. As a consequence of the latter, genomic relationship matrices (GRMs) will be biased. This bias in GRMs affects variance estimates and the accuracy of GBLUP for genomic prediction (GBLUP-GP). We derived equations that describe the bias from low-coverage sequencing as an effect of binomial sampling of sequence reads, and allowed for any ploidy level of the sample considered. This allowed us to combine individual and pool genotypes in one GRM, treating pool-genotypes as a polyploid genotype, equal to the total ploidy-level of the parents of the pool. Using simulated data, we verified the magnitude of the GRM bias at different coverage depths for three different kinds of ryegrass breeding material: individual genotypes from single plants, pool-genotypes from F2 families, and pool-genotypes from synthetic varieties. To better handle missing data, we also tested imputation procedures, which are suited for analyzing allele frequency genomic data. The relative advantages of the bias-correction and the imputation of missing data were evaluated using real data. We examined a large dataset, including single plants, F2 families, and synthetic varieties genotyped in three GBS assays, each with a different coverage depth, and evaluated them for heading date, crown rust resistance, and seed yield. Cross validations were used to test the accuracy using GBLUP approaches, demonstrating the feasibility of predicting among different breeding material. Bias-corrected GRMs proved to increase predictive accuracies when compared with standard approaches to construct GRMs. Among the imputation methods we tested, the random forest method yielded the highest predictive accuracy. The combinations of these two methods resulted in a meaningful increase of predictive ability (up to 0.09). The possibility of predicting across individuals and pools provides new opportunities for improving ryegrass breeding schemes. PMID- 29619040 TI - Oxygen Availability Influences Expression of Dickeya solani Genes Associated With Virulence in Potato (Solanum tuberosum L.) and Chicory (Cichorium intybus L.). AB - Dickeya solani is a Gram-negative necrotrophic, plant pathogenic bacterium able to cause symptoms in a variety of plant species worldwide. As a facultative anaerobe, D. solani is able to infect hosts under a broad range of oxygen concentrations found in plant environments. However, little is known about oxygen dependent gene expression in Dickeya spp. that might contribute to its success as a pathogen. Using a Tn5 transposon, harboring a promoterless gusA reporter gene, 146 mutants of D. solani IPO2222 were identified that exhibited oxygen-regulated expression of the gene into which the insertion had occurred. Of these mutants 114 exhibited higher expression under normal oxygen conditions than hypoxic conditions while 32 were more highly expressed under hypoxic conditions. The plant host colonization potential and pathogenicity as well as phenotypes likely to contribute to the ecological fitness of D. solani, including growth rate, carbon and nitrogen source utilization, production of pectinolytic enzymes, proteases, cellulases and siderophores, swimming and swarming motility and the ability to form biofilm were assessed for 37 strains exhibiting the greatest oxygen-dependent change in gene expression. Eight mutants expressed decreased ability to cause disease symptoms when inoculated into potato tubers or chicory leaves and three of these also exhibited delayed colonization of potato plants and exhibited tissue specific differences in gene expression in these various host tissues. The genes interrupted in these eight mutants encoded proteins involved in fundamental bacterial metabolism, virulence, bacteriocin and proline transport, while three encoded hypothetical or unknown proteins. The implications of environmental oxygen concentration on the ability of D. solani to cause disease symptoms in potato are discussed. PMID- 29619041 TI - Comparative Chloroplast Genomics of Gossypium Species: Insights Into Repeat Sequence Variations and Phylogeny. AB - Cotton is one of the most economically important fiber crop plants worldwide. The genus Gossypium contains a single allotetraploid group (AD) and eight diploid genome groups (A-G and K). However, the evolution of repeat sequences in the chloroplast genomes and the phylogenetic relationships of Gossypium species are unclear. Thus, we determined the variations in the repeat sequences and the evolutionary relationships of 40 cotton chloroplast genomes, which represented the most diverse in the genus, including five newly sequenced diploid species, i.e., G. nandewarense (C1-n), G. armourianum (D2-1), G. lobatum (D7), G. trilobum (D8), and G. schwendimanii (D11), and an important semi-wild race of upland cotton, G. hirsutum race latifolium (AD1). The genome structure, gene order, and GC content of cotton species were similar to those of other higher plant plastid genomes. In total, 2860 long sequence repeats (>10 bp in length) were identified, where the F-genome species had the largest number of repeats (G. longicalyx F1: 108) and E-genome species had the lowest (G. stocksii E1: 53). Large-scale repeat sequences possibly enrich the genetic information and maintain genome stability in cotton species. We also identified 10 divergence hotspot regions, i.e., rpl33 rps18, psbZ-trnG (GCC), rps4-trnT (UGU), trnL (UAG)-rpl32, trnE (UUC)-trnT (GGU), atpE, ndhI, rps2, ycf1, and ndhF, which could be useful molecular genetic markers for future population genetics and phylogenetic studies. Site-specific selection analysis showed that some of the coding sites of 10 chloroplast genes (atpB, atpE, rps2, rps3, petB, petD, ccsA, cemA, ycf1, and rbcL) were under protein sequence evolution. Phylogenetic analysis based on the whole plastomes suggested that the Gossypium species grouped into six previously identified genetic clades. Interestingly, all 13 D-genome species clustered into a strong monophyletic clade. Unexpectedly, the cotton species with C, G, and K-genomes were admixed and nested in a large clade, which could have been due to their recent radiation, incomplete lineage sorting, and introgression hybridization among different cotton lineages. In conclusion, the results of this study provide new insights into the evolution of repeat sequences in chloroplast genomes and interspecific relationships in the genus Gossypium. PMID- 29619043 TI - First Case Report of Prader-Willi-Like Syndrome in Colombia. AB - Background: Prader-Willi-like syndrome (PWLS) is believed to be caused by a variety of disruptions in genetic pathways both inside and outside of the genetic region implicated in PWS. By definition, PWLS does not demonstrate mutations in the 15q11-q13 region itself. It is a rare disorder whose clinical hallmarks include hypotonia, obesity, short extremities, and delayed development. This syndrome has been described in patients with 1p, 2p, 3p, 6q, and 9q chromosome abnormalities and in cases with maternal uniparental disomy of chromosome 14 and fragile X syndrome. Case presentation: In the present report, we describe a 9 year-old Colombian patient who demonstrated features of PWS and was ultimately diagnosed with PWLS after genetic analysis revealed a 14.97 Mb deletion of 6q16.1 q21. Conclusions: This is the first reported case of PWLS in Colombia and represents one of the largest documented 6q21 deletions. PMID- 29619042 TI - Ploidy Variation in Kluyveromyces marxianus Separates Dairy and Non-dairy Isolates. AB - Kluyveromyces marxianus is traditionally associated with fermented dairy products, but can also be isolated from diverse non-dairy environments. Because of thermotolerance, rapid growth and other traits, many different strains are being developed for food and industrial applications but there is, as yet, little understanding of the genetic diversity or population genetics of this species. K. marxianus shows a high level of phenotypic variation but the only phenotype that has been clearly linked to a genetic polymorphism is lactose utilisation, which is controlled by variation in the LAC12 gene. The genomes of several strains have been sequenced in recent years and, in this study, we sequenced a further nine strains from different origins. Analysis of the Single Nucleotide Polymorphisms (SNPs) in 14 strains was carried out to examine genome structure and genetic diversity. SNP diversity in K. marxianus is relatively high, with up to 3% DNA sequence divergence between alleles. It was found that the isolates include haploid, diploid, and triploid strains, as shown by both SNP analysis and flow cytometry. Diploids and triploids contain long genomic tracts showing loss of heterozygosity (LOH). All six isolates from dairy environments were diploid or triploid, whereas 6 out 7 isolates from non-dairy environment were haploid. This also correlated with the presence of functional LAC12 alleles only in dairy haplotypes. The diploids were hybrids between a non-dairy and a dairy haplotype, whereas triploids included three copies of a dairy haplotype. PMID- 29619044 TI - Observing atmospheric formaldehyde (HCHO) from space: validation and intercomparison of six retrievals from four satellites (OMI, GOME2A, GOME2B, OMPS) with SEAC4RS aircraft observations over the Southeast US. AB - Formaldehyde (HCHO) column data from satellites are widely used as a proxy for emissions of volatile organic compounds (VOCs) but validation of the data has been extremely limited. Here we use highly accurate HCHO aircraft observations from the NASA SEAC4RS campaign over the Southeast US in August-September 2013 to validate and intercompare six retrievals of HCHO columns from four different satellite instruments (OMI, GOME2A, GOME2B and OMPS) and three different research groups. The GEOS-Chem chemical transport model is used as a common intercomparison platform. All retrievals feature a HCHO maximum over Arkansas and Louisiana, consistent with the aircraft observations and reflecting high emissions of biogenic isoprene. The retrievals are also interconsistent in their spatial variability over the Southeast US (r=0.4-0.8 on a 0.5 degrees *0.5 degrees grid) and in their day-to-day variability (r=0.5-0.8). However, all retrievals are biased low in the mean by 20-51%, which would lead to corresponding bias in estimates of isoprene emissions from the satellite data. The smallest bias is for OMI-BIRA, which has high corrected slant columns relative to the other retrievals and low scattering weights in its air mass factor (AMF) calculation. OMI-BIRA has systematic error in its assumed vertical HCHO shape profiles for the AMF calculation and correcting this would eliminate its bias relative to the SEAC4RS data. Our results support the use of satellite HCHO data as a quantitative proxy for isoprene emission after correction of the low mean bias. There is no evident pattern in the bias, suggesting that a uniform correction factor may be applied to the data until better understanding is achieved. PMID- 29619046 TI - Formaldehyde production from isoprene oxidation across NOx regimes. AB - The chemical link between isoprene and formaldehyde (HCHO) is a strong, non linear function of NOx (= NO + NO2). This relationship is a linchpin for top-down isoprene emission inventory verification from orbital HCHO column observations. It is also a benchmark for overall photochemical mechanism performance with regard to VOC oxidation. Using a comprehensive suite of airborne in situ observations over the Southeast U.S., we quantify HCHO production across the urban-rural spectrum. Analysis of isoprene and its major first-generation oxidation products allows us to define both a "prompt" yield of HCHO (molecules of HCHO produced per molecule of freshly-emitted isoprene) and the background HCHO mixing ratio (from oxidation of longer-lived hydrocarbons). Over the range of observed NOx values (roughly 0.1 - 2 ppbv), the prompt yield increases by a factor of 3 (from 0.3 to 0.9 ppbv ppbv-1), while background HCHO increases by a factor of 2 (from 1.6 to 3.3 ppbv). We apply the same method to evaluate the performance of both a global chemical transport model (AM3) and a measurement constrained 0-D steady state box model. Both models reproduce the NOx dependence of the prompt HCHO yield, illustrating that models with updated isoprene oxidation mechanisms can adequately capture the link between HCHO and recent isoprene emissions. On the other hand, both models under-estimate background HCHO mixing ratios, suggesting missing HCHO precursors, inadequate representation of later-generation isoprene degradation and/or under-estimated hydroxyl radical concentrations. Detailed process rates from the box model simulation demonstrate a 3-fold increase in HCHO production across the range of observed NOx values, driven by a 100% increase in OH and a 40% increase in branching of organic peroxy radical reactions to produce HCHO. PMID- 29619045 TI - Why do Models Overestimate Surface Ozone in the Southeastern United States? AB - Ozone pollution in the Southeast US involves complex chemistry driven by emissions of anthropogenic nitrogen oxide radicals (NOx = NO + NO2) and biogenic isoprene. Model estimates of surface ozone concentrations tend to be biased high in the region and this is of concern for designing effective emission control strategies to meet air quality standards. We use detailed chemical observations from the SEAC4RS aircraft campaign in August and September 2013, interpreted with the GEOS-Chem chemical transport model at 0.25 degrees *0.3125 degrees horizontal resolution, to better understand the factors controlling surface ozone in the Southeast US. We find that the National Emission Inventory (NEI) for NOx from the US Environmental Protection Agency (EPA) is too high. This finding is based on SEAC4RS observations of NOx and its oxidation products, surface network observations of nitrate wet deposition fluxes, and OMI satellite observations of tropospheric NO2 columns. Our results indicate that NEI NOx emissions from mobile and industrial sources must be reduced by 30-60%, dependent on the assumption of the contribution by soil NOx emissions. Upper tropospheric NO2 from lightning makes a large contribution to satellite observations of tropospheric NO2 that must be accounted for when using these data to estimate surface NOx emissions. We find that only half of isoprene oxidation proceeds by the high-NOx pathway to produce ozone; this fraction is only moderately sensitive to changes in NOx emissions because isoprene and NOx emissions are spatially segregated. GEOS-Chem with reduced NOx emissions provides an unbiased simulation of ozone observations from the aircraft, and reproduces the observed ozone production efficiency in the boundary layer as derived from a regression of ozone and NOx oxidation products. However, the model is still biased high by 8+/-13 ppb relative to observed surface ozone in the Southeast US. Ozonesondes launched during midday hours show a 7 ppb ozone decrease from 1.5 km to the surface that GEOS-Chem does not capture. This bias may reflect a combination of excessive vertical mixing and net ozone production in the model boundary layer. PMID- 29619047 TI - The Role of C-Reactive Protein in the Early Prediction of Serious Pancreatic Fistula Development after Pancreaticoduodenectomy. AB - Introduction: Despite recent advances in surgical techniques, pancreatic fistulas are common. We aimed to determine the role of C-reactive protein in the prediction of clinically relevant fistula development. Materials and Methods: Data from patients who underwent pancreaticoduodenectomy between 2012 and 2015 is collected. Postoperative 1st, 3rd, and 5th day (POD1, POD3, and POD5) C-reactive protein (CRP) levels, postoperative pancreatic fistula (POPF) development, other complications, length of hospital stay, and mortality were recorded. Results: Of 117 patients, 43 patients (36.8%) developed complications (including fistulas). Of the patients developing fistulas, 21 (17.9%) had POPF A, 2 (1.7%) had POPF B, and 7 (6.0%) had POPF C. POD5 CRP and POD3 CRP were shown to be significantly correlated with mortality and development of clinically relevant POPF (p = 0.001 and p = 0.0001, resp.) and with mortality (p = 0.017), respectively. The development of clinically relevant POPFs (B and C) could be predicted with 90% sensitivity and 82.2% specificity by POD5 CRP cut-off level of 19 mg/dL and with 100% sensitivity and 63.6% specificity by the difference between POD5 and POD1 CRP cut-off level of >2.5 mg/dL. Conclusion: CRP levels can effectively predict the development of clinically relevant pancreatic fistulas. PMID- 29619048 TI - Efficacy of a Rinse Containing Sea Salt and Lysozyme on Biofilm and Gingival Health in a Group of Young Adults: A Pilot Study. AB - Objectives: To evaluate new mouth rinse containing sea salt, xylitol, and lysozyme on biofilm formation and gingival health in a group of young adults. Methods: The subjects were divided into two groups of 15 subjects each: control (A) and experimental group (B). The Turesky modification of Quigley-Hein plaque index was used to evaluate plaque scores while the presence or absence of gingival bleeding was used to determine gingival health. Measurements were done at baseline and at the end of the one-month trial period by one blinded examiner on six representative teeth. Group (A) maintained standardized oral health practices for the duration of the experiment. In addition, group (B) rinsed with a tablespoon of the provided sea salt mouth rinse for 30 seconds once in the morning and at night. After the 30-day trial period, subjects in both groups were reassessed as per baseline. Results. There were no statistically significant differences in the overall reduction from baseline in the mean plaque and gingivitis scores on all surfaces or on individual surfaces. Conclusion: Within the limitations of the study, rinsing with sea salt for thirty days did not affect the gingival and plaque scores in a group of young adults. PMID- 29619049 TI - The Effects of Storage Conditions on Lycopene Content and Color of Tomato Hot Pot Sauce. AB - Tomato hot pot sauce (THPS) at different storage temperatures (0, 25, and 37 degrees C) and with two kinds of packaging for 120 days was investigated in this study. High performance liquid chromatography was employed for detecting lycopene and 5-hydroxymethylfurfural (HMF). The changes of lycopene and HMF during storage were regressed with kinetic equation of both zero-order and first-order models, and the latter fitted better. The kinetic equation constant (k value) of lycopene or HMF at 37 degrees C was higher than that at 25 degrees C. The k value of lycopene of PET/PE (P1) packaged THPS was 1.60 times of that of PET/Al/EAA/PE (P2) packaged at 37 degrees C, while it was 2.12 times at 25 degrees C. The k value of HMF of P1 packaged THPS was 1.69 times of that of P2 packaged at 37 degrees C, while it was 1.01 times at 25 degrees C. Significant correlations between color index of L*, a*, and a*/b* and lycopene or HMF were found at storage temperature. Browning color was attributed to both Maillard reaction and degradation of lycopene. In conclusion, lower storage temperature and stronger oxygen barrier property of package could maintain color stability and extend shelf life. PMID- 29619050 TI - Time to PSA rise differentiates the PSA bounce after HDR and LDR brachytherapy of prostate cancer. AB - Purpose: To investigate the differences in prostate-specific antigen (PSA) bounce (PB) after high-dose-rate (HDR-BT) or low-dose-rate (LDR-BT) brachytherapy alone in prostate cancer patients. Materials and methods: Ninety-four patients with localized prostate cancer (T1-T2cN0), age ranged 50-81 years, were treated with brachytherapy alone between 2008 and 2010. Patients were diagnosed with adenocarcinoma, Gleason score <= 7. The LDR-BT total dose was 144-145 Gy, in HDR BT - 3 fractions of 10.5 or 15 Gy. The initial PSA level (iPSA) was assessed before treatment, then PSA was rated every 3 months over the first 2 years, and every 6 months during the next 3 years. Median follow-up was 3.0 years. Results: Mean iPSA was 7.8 ng/ml. In 58 cases, PSA decreased gradually without PB or biochemical failure (BF). In 24% of patients, PB was observed. In 23 cases (24%), PB was observed using 0.2 ng/ml definition; in 10 cases (11%), BF was diagnosed using nadir + 2 ng/ml definition. The HDR-BT and LDR-BT techniques were not associated with higher level of PB (26 vs. 22%, p = 0.497). Time to the first PSA rise finished with PB was significantly shorter after HDR-BT then after LDR-BT (median, 10.5 vs. 18.0 months) during follow-up. Predictors for PB were observed only after HDR-BT. Androgen deprivation therapy (ADT) and higher Gleason score decreased the risk of PB (HR = 0.11, p = 0.03; HR = 0.51, p = 0.01). The higher PSA nadir and longer time to PSA nadir increased the risk of PB (HR 3.46, p = 0.02; HR 1.04, p = 0.04). There was no predictors for PB after LDR-BT. Conclusions: HDR-BT and LDR-BT for low and intermediate risk prostate cancer had similar PB rate. The PB occurred earlier after HDR-BT than after LDR-BT. ADT and higher Gleason score decreased, and higher PSA nadir and longer time to PSA nadir increased the risk of PB after HDR-BT. PMID- 29619051 TI - A cold spot compensation technique using a combination of trans-rectal ultrasonography and intraoperative computed tomography for interstitial permanent prostate brachytherapy: a single-arm prospective trial. AB - Purpose: To evaluate the efficacy of a cold spot compensation technique using a combination of trans-rectal ultrasonography (TRUS) and computed tomography (CT) for permanent interstitial prostate brachytherapy. Material and methods: Sixty five patients were treated with the cold spot compensation technique using TRUS CT fusion. The prescribed dose was set at 145 Gy. The dose to 90% of prostate volume (D90) was planned to be within 195 Gy (134%) and 205 Gy (141%). After implantation using the conventional technique, additional seeds were implanted if cold spots were detected on TRUS-CT fusion images. Results: Cold spots were detected in 32 of 65 patients (49%) and were compensated by additional seeds. Median number of additional seeds was 3 (range, 1-5). A CT scan 1 month later revealed that the percentage of patients receiving an undesirably low D90 (160 180 Gy) was significantly reduced in the examination arm compared to historical controls. However, mean operation time was significantly longer in the examination arm (64 min) than in historical controls (49 min, p < 0.001). With median follow-up of 18 months (range, 9-24 months), no grade 3 or worse toxicity was encountered. Conclusion: The cold spot compensation technique using TRUS-CT fusion appears effective for patients receiving permanent interstitial prostate brachytherapy. PMID- 29619052 TI - Impact of brachytherapy technique (2D versus 3D) on outcome following radiotherapy of cervical cancer. AB - Purpose: The purpose of this study was to analyze the effect of 2D conventional brachytherapy (CBT) compared to 3D MRI-guided brachytherapy (IGBT) with and without the use of interstitial needles on local control, overall survival, and toxicity in patients treated for cervical cancer with radiation or chemoradiation. Material and methods: A retrospective analysis was performed of biopsy-proven FIGO IB-IVA cervical cancer patients, treated with primary radiation or chemoradiation, followed by brachytherapy (BT) between January 1997 and July 2016. Endpoints were local control, overall survival, and toxicity. Results: Of 126 patients included, 35 have been treated with CBT, 31 with IGBT without needles (IC), and 60 with IGBT with needles (ICIS). External beam radiotherapy (EBRT) had mostly been delivered concurrently with chemotherapy (weekly cisplatin). Overall local control was 93% after 1 year, and 88% after 3 years. Overall 3-year survival was 75%, and 5-year survival was 66%. The 3D technique (IGBT cohorts) showed a trend for an improved local control and overall survival (p = 0.05) compared to the 2D technique (CBT cohort). A decrease in toxicity was observed from 17% (2D cohort) to 12% (3D cohort). The use of interstitial needles was associated with a higher high-risk clinical target volume (HR-CTV) dose (11.3 Gy vs. 9.9 Gy) and a lower D2cc bladder dose (10.9 Gy vs. 14.7 Gy, both p < 0.01). Conclusions: In cervical cancer treatment, the use of a 3D brachytherapy technique (MRI-guided with or without interstitial needles) showed a trend towards an increased local control and improved overall survival with reduced toxicity, compared to the conventional 2D brachytherapy technique. The use of interstitial needles allowed dose sculpting, resulting in delivery of higher doses to the HR-CTV, while reducing radiation doses to organs at risk, such as the bladder. PMID- 29619053 TI - Dosimetric analysis of the effects of the bladder volume on organs at risk (OAR) in high-dose-rate intracavitary brachytherapy in carcinoma cervix - an institutional study. AB - Purpose: The purpose of this study was to establish a dosimetric correlation between the bladder volume and its effects on the dose received by the organs at risk (OARs) (urinary bladder, rectum, and sigmoid) during computed tomography (CT)-guided high-dose-rate (HDR) brachytherapy in carcinoma cervix, and to determine an optimum bladder volume to limit the dose to OARs. Material and methods: Seventy-five intracavitary applications in patients of carcinoma cervix (stage IIB, IIIA, IIIB, IVA) treated with external beam radiotherapy with concurrent chemotherapy followed by CT-based HDR intracavitary brachytherapy (tandem and ovoid type) at our institute between July 2014 to January 2016 were studied. The bladder volume at the time of imaging was noted and was correlated with the radiation dose received by bladder, rectum, and sigmoid colon. Results: Dose volume histogram (DVH) parameters of the bladder increases by elevating the volume of the bladder. Rectum dose does not follow a continuous increasing trend. It increases up to a bladder volume of 110 cc and then starts decreasing. The highest rectal dose observed was in the bladder volume, range 70-110 cc. The minimum doses were recorded when the bladder volume was > 170 cc. Sigmoid colon DVH parameters follow a similar trend as that of the rectum. Conclusions: A relationship exists between the volume of the OARs and the dose received by them. A bladder volume of about 70 cm3 or less proved better for achieving the prescribed dose limits of bladder, rectum, and sigmoid. The correlations between the bladder volume and the doses received by the OARs were not significant. PMID- 29619054 TI - Clinical analysis of speculum-based vaginal packing for high-dose-rate intracavitary tandem and ovoid brachytherapy in cervical cancer. AB - Purpose: Intra-vaginal packing is used to fix the applicator and displace organs at risk (OAR) during high-dose-rate intracavitary tandem and ovoid brachytherapy (HDR-ICB). We retain the speculum from applicator placement as a dual-function bladder and rectum retractor during treatment. Our objective is to review salient techniques for OAR displacement, share our packing technique, and determine the reduction in dose to OAR and inter-fraction variability of dose to OAR, associated with speculum-based vaginal packing (SBVP) in comparison to conventional gauze packing during HDR-ICB. Material and methods: We reviewed HDR ICB treatment plans for 45 patients, including 10 who underwent both conventional gauze packing and SBVP. Due to institutional inter-provider practice differences, patients non-selectively received either packing procedure. Packing was performed under conscious sedation, followed by cone beam computed tomography used for dosimetric planning. Maximum absolute and percent-of-prescription dose to the International Commission of Radiation Units bladder and rectal points in addition to D0.1cc, D1.0cc, and D2.0cc volumes of the bladder and rectum were analyzed and compared for each packing method using an independent sample t-test. Results: Of the 179 fractions included, 73% and 27% used SBVP and gauze packing, respectively. For patients prescribed 6 Gy to point A, SBVP was associated with reduced mean D0.1cc bladder dose, inter-fraction variability in D0.1cc bladder dose by 9.3% (p = 0.026) and 9.0%, respectively, and statistically equivalent rectal D0.1cc, D1.0cc, and D2.0cc. Patients prescribed 5.5 Gy or 5 Gy to point A after dose optimization, were less likely to benefit from SBVP. In the intra patient comparison, 80% of patients had reduction in at least one rectum or bladder parameter. Conclusions: In patients with conducive anatomy, SBVP is a cost-efficient packing method that is associated with improved bladder sparing and comparable rectal sparing relative to gauze packing during HDR-ICB without general anesthesia. PMID- 29619055 TI - Late G2 vagina toxicity in post-operative endometrial carcinoma is associated with a 68 Gy dose equivalent to 2 Gy per fraction(alpha/beta=3Gy) at 2 cm3 of vagina. AB - Purpose: To evaluate if the dose equivalent to 2 Gy per fraction (EQD2)(alpha/beta=3Gy) at 0.1 cm3, 1 cm3, and 2 cm3 of vagina in vaginal-cuff brachytherapy (VBT) (high-dose-rate [HDR] 192Ir-source) +/- external-beam irradiation (EBRT) is associated with toxicity in post-operative endometrial carcinoma (P-EC). Material and methods: From June 2014 till November 2015, 67 consecutive P-EC patients underwent VBT +/- EBRT; 44 patients received EBRT (median, 45 Gy; range, 44-50.4) + VBT (7 Gy), and 23 exclusive-VBT (6 Gy x 3 fractions). The upper 2.5 cm of vagina was delineated on computed tomography (CT). The active-length source was 2.5 cm, and the brachytherapy dose was prescribed at 5 mm from the applicator. D90, V100, and EQD2(alpha/beta=3Gy) at 0.1 cm3, 1 cm3, and 2 cm3 of the most exposed part of the vagina were calculated. Vaginal toxicity assessment was completed with a LENT-SOMA-objective-criteria. Statistics were done with the use of chi2 and Student's-t test. Results: The mean follow-up was 23.2 months (7.6-46.8). Median D90 was 7.8 Gy(alpha/beta=3Gy). Late toxicity: 8 G1 and 9 G2. Median EQD2(alpha/beta=3Gy) in vagina was 88.6 Gy (62.8 177.6) for 0.1 cm3, 72.4 Gy (57.1-130.4) for 1 cm3, and 69 Gy (53-113.4) for 2 cm3. Exclusive VBT vs. EBRT+VBT showed no differences in vaginal toxicity. There was no relationship between EQD2(alpha/beta=3Gy) at 0.1 cm3 and 1 cm3 of vagina with G1-G2 toxicity (p = 0.62 and p = 0.58, respectively). G2 toxicity was related to EQD2(alpha/beta=3Gy) at 2 cm3 (p = 0.03). EQD2(alpha/beta=3Gy) > 68 Gy caused G2 late toxicity in 20.5% patients. All patients presenting G2 toxicity received > 68 Gy EQD2(alpha/beta=3Gy). Conclusions: More than 68 Gy EQD2(alpha/beta=3Gy) at 2 cm3 was related to G2 toxicity in P-EC-VBT. Further studies including larger number of patients are needed to confirm these results. Patients receiving these doses should be informed of the risk of toxicity, with individualized treatment planning and follow-up to reduce G2 toxicity. PMID- 29619057 TI - Accelerated partial breast irradiation in a single 18 Gy fraction with high-dose rate brachytherapy: preliminary results. AB - Purpose: To evaluate the feasibility of acute and chronic toxicity in patients suitable for accelerated partial breast irradiation (APBI) in a single 18 Gy fraction with multicatheter high-dose-rate (HDR) brachytherapy, as well as cosmetic and oncological outcomes. Material and methods: Between September 2014 and March 2016, twenty consecutive patients with low-risk invasive and ductal carcinoma in situ were treated with interstitial multicatheter HDR brachytherapy in a single 18 Gy fraction. Results: Median age was 63.5 years (range, 51-79). Acute toxicity was observed in seven patients, while the pain during following days and hematoma were seen in four patients. With a median follow-up of 24 months, late toxicity was found in one patient with fat necrosis g2 and fibrosis g2 in another patient. The overall survival (OS) and locoregional control (LC) was 100%. Disease-free survival (DFS) and distant control was 95%. Good to excellent cosmetic outcomes were noted in 80% of patients and fair in 4 patients (20%). Conclusions: This is the first report in the medical literature that focuses on feasibility and acute and chronic toxicity, with a median follow-up of 24 months (range, 20-40). The protocol is viable and convenient. However, a longer follow-up is needed to know chronic toxicity and oncologic outcomes. PMID- 29619056 TI - Should molecular subtype be recommended as one of the selection criteria for accelerated partial breast irradiation? Preliminary results from an Asian cohort. AB - Purpose: The purpose of this study was to report clinical outcomes in patients treated with accelerated partial breast irradiation (APBI), stratified as per molecular subtype and American Society for Therapeutic Radiology and Oncology/Groupe Europeen de Curietherapie and European Society for Radiotherapy & Oncology (ASTRO/GEC-ESTRO) patient selection criteria in order to determine whether molecular subtype should be recommended as one of the selection criteria for APBI. Material and methods: 157 early-stage breast cancers patients, treated with APBI using multi-catheter interstitial brachytherapy with >= 6 months follow up were included. Molecular subtype was assigned based on estrogen/progesterone receptor (ER/PR), Her2neu and tumor grade. Patients were stratified into ASTRO and GEC-ESTRO risk groups, as per updated ASTRO consensus statement (CS) and GEC ESTRO recommendation, respectively. The Kaplan-Meier method was used to calculate the time to event data of clinical outcomes. Results: With a median follow-up of 35 months, local control (LC) and locoregional control (LRC) were not significantly different among the different molecular subtypes (p = 0.19, p = 0.41, respectively). None of the APBI guidelines predicted risk of local or locoregional recurrence. Re-analyzing the data by replacing ER status with molecular subtype in the ASTRO-CS did not show any significant difference in LC/LRC across the various categories. Her2neu subtype was associated with significantly lower disease-free survival, cause specific survival, and overall survival than the luminal subtypes. Conclusions: None of the mentioned APBI guidelines predicted local or locoregional recurrence risk in our study population. Additional follow-up will be needed to recommend inclusion of molecular subtype (or at least HER2 receptor status) in the patient selection criteria for APBI. PMID- 29619058 TI - Long-term outcome of high-dose-rate brachytherapy and perioperative brachytherapy in early mobile tongue cancer. AB - Purpose: To evaluate long-term outcome of high-dose-rate brachytherapy and perioperative brachytherapy in early mobile tongue cancer. Material and methods: Seventy-three patients with clinically staged T1/T2 N0 M0 of mobile tongue cancer were studied retrospectively. Between January 2000 and September 2010, 47 patients underwent high-dose-rate brachytherapy (HDR-BT) alone and 26 patients underwent perioperative brachytherapy (PB). Endpoints were overall survival, disease-free survival, loco-regional control, and late side effects. Results: Median age was 52 years and median follow-up was 74 months (range, 60-180). There were no local recurrences in the PB group. Overall survival at 6 years was 74.7% vs. 92.3% in HBR BT and PB group, respectively (p = 0.032). Disease-free survival at 6 years was 55.3% vs. 92.3% respectively in HDR-BT and PB (p = 0.002). Disease free survival at 6 years in tumor histologic grade 1/2 patients was 76.3 months versus 40% in grade 3 patients. Nodal recurrence-free rate at 6 years was 67.5% with HDR-BT only, and 96.2% with PB (p = 0.007). In HDR BT only group, nodal recurrence-free rate at 6 years in T1 patients was 89.8% versus 29.4% in T2 patients. 16% and 7% patients developed soft tissue necrosis and osteoradionecrosis, respectively. Multivariate Cox proportional hazards analysis revealed significant correlation of local recurrence with tumor grade (p = 0.029), nodal recurrence with T-stage (p = 0.007), and disease-free survival with age (p = 0.003) and T stage (p = 0.026). Conclusions: HDR-BT alone gives acceptable loco-regional control in T1 tumors. T2 stage tumors should not be treated by brachytherapy alone in view of high failure rates in nodal regions and should undergo either neck dissection or nodal irradiation. Perioperative brachytherapy is investigational and can be considered in patients who are at high-risk for local recurrence in patients undergoing surgery alone. PMID- 29619059 TI - A comparative assessment of inhomogeneity and finite patient dimension effects in 60Co and 192Ir high-dose-rate brachytherapy. AB - Purpose: To perform a comparative study of heterogeneities and finite patient dimension effects in 60Co and 192Ir high-dose-rate (HDR) brachytherapy. Material and methods: Clinically equivalent plans were prepared for 19 cases (8 breast, 5 esophagus, 6 gynecologic) using the Ir2.A85-2 and the Co0.A86 HDR sources, with a TG-43 based treatment planning system (TPS). Phase space files were obtained for the two source designs using MCNP6, and validated through comparison to a single source dosimetry results in the literature. Dose to water, taking into account the patient specific anatomy and materials (Dw,m), was calculated for all plans using MCNP6, with input files prepared using the BrachyGuide software tool to analyze information from DICOM RT plan exports. Results: A general TG-43 dose overestimation was observed, except for the lungs, with a greater magnitude for 192Ir. The distribution of percentage differences between TG-43 and Monte Carlo (MC) in dose volume histogram (DVH) indices for the planning target volume (PTV) presented small median values (about 2%) for both 60Co and 192Ir, with a greater dispersion for 192Ir. Regarding the organs at risk (OARs), median percentage differences for breast V50% were 3% (5%) for 60Co (192Ir). Differences in median skin D2cc were found comparable, with a larger dispersion for 192Ir, and the same applied to the lung D10cc and the aorta D2cc. TG-43 overestimates D2cc for the rectum and the sigmoid, with median differences from MC within 2% and a greater dispersion for 192Ir. For the bladder, the median of the difference is greater for 60Co (~2%) than for 192Ir (~0.75%), demonstrating however a greater dispersion again for 192Ir. Conclusions: The magnitude of differences observed between TG-43 based and MC dosimetry and their smaller dispersion relative to 192Ir, suggest that 60Co HDR sources are more amenable to the TG-43 assumptions in clinical treatment planning dosimetry. PMID- 29619060 TI - Reduction of applicator displacement in MR/CT-guided cervical cancer HDR brachytherapy by the use of patient hover transport system. AB - Purpose: To quantify the reduction of relative displacement between the implanted intracavitary applicator and the patient bony anatomy, due to the use of a hover transport system during the patient transports between the imaging table and the treatment table. Material and methods: The displacement of the applicator inside the patient was measured by comparing the distance between the tip of the tandem and the pubic bone on X-ray radiography images taken before and after moving a patient to magnetic resonance/computed tomography imaging. Displacements were evaluated for 27 fractions of treatment using hover transport and 185 fractions of treatment using manual transport. Results: The use of hover transport system reduced the percentage of fractions with displacements greater than 5 mm from 22.7% to 7.4%. The reduction of applicator displacement using hover transport is statistically significant, compared to the manual transport method (p-value 0.0086; mean displacement 3.41 mm [95% CI: 2.96-3.97] for manual transport, and 2.27 mm [95% CI: 1.71-2.97] for hover transport fractions). Conclusions: This study indicates that the hover transport system is effectively reducing displacement between tandem and patient bony anatomy during patient transports. The potential improvement in dosimetric accuracy due to this reduction warrants further study. PMID- 29619061 TI - The effect of tandem-ovoid titanium applicator on points A, B, bladder, and rectum doses in gynecological brachytherapy using 192Ir. AB - Purpose: The dosimetry procedure by simple superposition accounts only for the self-shielding of the source and does not take into account the attenuation of photons by the applicators. The purpose of this investigation is an estimation of the effects of the tandem and ovoid applicator on dose distribution inside the phantom by MCNP5 Monte Carlo simulations. Material and methods: In this study, the superposition method is used for obtaining the dose distribution in the phantom without using the applicator for a typical gynecological brachytherapy (superposition-1). Then, the sources are simulated inside the tandem and ovoid applicator to identify the effect of applicator attenuation (superposition-2), and the dose at points A, B, bladder, and rectum were compared with the results of superposition. The exact dwell positions, times of the source, and positions of the dosimetry points were determined in images of a patient and treatment data of an adult woman patient from a cancer center. The MCNP5 Monte Carlo (MC) code was used for simulation of the phantoms, applicators, and the sources. Results: The results of this study showed no significant differences between the results of superposition method and the MC simulations for different dosimetry points. The difference in all important dosimetry points was found to be less than 5%. Conclusions: According to the results, applicator attenuation has no significant effect on the calculated points dose, the superposition method, adding the dose of each source obtained by the MC simulation, can estimate the dose to points A, B, bladder, and rectum with good accuracy. PMID- 29619062 TI - Immediate type hypersensitivity and late phase reaction occurred consecutively in a patient receiving ethambutol and levofloxacin. AB - Background: We experienced a rare case of immediate type hypersensitivity and late phase reaction to anti-tubercular therapy consisting of ethambutol and levofloxacin, which occurred in close succession, giving the appearance of a single, continuous reaction to one drug. Case presentation: The patient was a man in his 70's who began therapy consisting of isoniazide, rifampicin, and ethambutol for pulmonary tuberculosis. Since the patient had a drug eruption within several hours after the start of his treatment, his reaction to ethambutol was assessed first among the three suspected drugs using an oral challenge test. Levofloxacin, which was not among the suspected drugs, was administered with ethambutol in order to avoid drug resistance resulting from the administration of a single drug. The patient experienced pruritus within 1 h. We observed a well defined, edematous erythema with induration, which persisted for several days after the patient received the two drugs. Next, skin tests were performed with ethambutol and levofloxacin. The skin reaction to ethambutol and levofloxacin consisted of two different types of allergic reaction, a immediate type reaction and phase reaction. Conclusion: This is the first report of a late phase reaction and immediate type hypersensitivity occurring in quick succession in the same patient. Subsequent skin tests were able to prove the presence of these two different types of allergic reactions. PMID- 29619063 TI - Bushenkangshuai Tablet Reduces Atherosclerotic Lesion by Improving Blood Lipids Metabolism and Inhibiting Inflammatory Response via TLR4 and NF-kappaB Signaling Pathway. AB - Bushenkangshuai tablet (BSKS) is a Chinese herbal compound which has been used for the treatment of cardiovascular and cerebrovascular diseases in China for decades. This study intends to explore the molecular mechanism of BSKS against atherosclerosis in ApoE-/- mice. ApoE-/- mice were fed with western-type diet for 6 weeks and then were given BSKS for 6 weeks. The results showed that BSKS attenuated the size of the atherosclerotic lesion, reduced visceral adipose content, and decreased blood lipids. We also found that BSKS promoted the expression of adiponectin and its receptors, inhibited the expression of Toll like receptor 4 and nuclear factor-kappa B, decreased the levels of interleukin-1 beta, monocyte chemotactic protein-1, and vascular cell adhesion molecule-1, and increased the levels of interleukin-10 and adiponectin. Our data provided evidence that BSKS exerted an antiatherosclerotic effect by lowering blood lipids and inhibiting inflammatory response via TLR4 and NF-kappaB signaling pathway. PMID- 29619064 TI - A Traditional Herbal Formula Xianlinggubao for Pain Control and Function Improvement in Patients with Knee and Hand Osteoarthritis: A Multicenter, Randomized, Open-Label, Controlled Trial. AB - Evidence of efficacy of a traditional herbal formula Xianlinggubao (XLGB) for treatment of osteoarthritis (OA) is limited. The present study was designed to evaluate the efficacy of XLGB in the management of patients with knee and hand OA. This was a multicenter, stratified, open-label, randomized controlled trial conducted at six centers in China. People aged 40 or above, diagnosed with OA of the knee or hand, were randomly assigned to the XLGB treatment group or watchful waiting control group. Main outcome measures were the changes in the numeric pain rating scales (NPRS) and the Western Ontario and McMaster Universities Arthritis Index (WOMAC) or the Australian/Canadian Osteoarthritis Hand Index (AUSCAN) scores, from baseline to 6 months. In total 534 patients (272 to XLGB and 262 to control group) received interventions. Participants in the XLGB group exhibited significant improvement in NPRS (P < 0.001) and WOMAC score (P < 0.001) or AUSCAN score (P < 0.001) compared to control group. Treatment with XLGB at current regime significantly reduced pain and improved function of the knee and hand in patients with OA over a 6-month period, implying that XLGB could be suggested as an alternative treatment for patients with knee or hand OA. PMID- 29619065 TI - Lycium barbarum Polysaccharide Promotes Maturation of Dendritic Cell via Notch Signaling and Strengthens Dendritic Cell Mediated T Lymphocyte Cytotoxicity on Colon Cancer Cell CT26-WT. AB - Lycium barbarum polysaccharide (LBP) is the major function component of Lycium barbarum L. and has been previously reported to induce the phenotypic and functional maturation of dendritic cells (DCs) as well as activating T lymphocytes. In the current study, the immunologic cytotoxicity promoting effect of LBP was assessed and the underlying mechanism was explored. The impact of LBP on the phenotype, maturation, and immunogenicity of DCs was assessed. The activity of Notch pathway which is involved in the regulation of LBP on DCs was detected. Afterwards, the influence of LBP on cytotoxicity of DC-mediated cytotoxicity T lymphocytes (CTLs) to CT26-WT colon cancer cells was further assessed. Administration of LBP induced the phenotypic and functional maturation of DCs. After being subjected to LBP, the expression of Notch and Jagged and Notch targets Hes1 and Hes5 was all upregulated. The cytotoxicity of DC-mediated CTLs was strengthened by administration of LBP. Additionally, cytotoxicity of DC mediated CTLs on CT26-WT colon cancer cells also increased with effector-target ratio. In conclusion, LBP could induce the phenotypic and functional maturation of DCs via Notch signaling and promote the cytotoxicity of DC-mediated CTLs, which could be employed as a promising adjuvant for cancer immunotherapy. PMID- 29619066 TI - Efficacy and Safety of the Injection of the Traditional Chinese Medicine Puerarin for the Treatment of Diabetic Peripheral Neuropathy: A Systematic Review and Meta Analysis of 53 Randomized Controlled Trials. AB - Objective: The injection of the traditional Chinese patent medicine puerarin has been widely used in the treatment of various diseases such as angina pectoris or ischemic stroke. We aim to evaluate the efficacy and safety of puerarin injection for the treatment of diabetic peripheral neuropathy (DPN). Methods: A systematic literature search was performed in seven medical databases from their inception until June 2017. 53 studies with RCTs, totaling 3284 patients, were included in this meta-analysis. The included studies were assessed by the Cochrane risk of bias and analyzed by Review Manager 5.3 software. Results: The meta-analysis showed that puerarin injection for the treatment of DPN was significantly better compared with the control group in terms of the total effective rate. The result showed that puerarin injection for the treatment of DPN can significantly increase the probability of sensory nerve conduction velocity (SNCV) and motor nerve conduction velocity (MNCV) of the median and peroneal nerves. Conclusions: This meta-analysis demonstrated that puerarin injection may be more effective and safe for the treatment of DPN. However, further and higher quality RCTs are required to prove its efficacy and provide meaningful evidence for clinical treatment due to the poor methodological quality. PMID- 29619067 TI - A Hop Extract Lifenol(r) Improves Postmenopausal Overweight, Osteoporosis, and Hot Flash in Ovariectomized Rats. AB - Objective: In order to assess the effectiveness of a hop extract (HE) for postmenopausal symptoms, the effects of Lifenol on ovariectomy-induced osteoporosis, hyperlipidemia, body weight increase, and hot flash were investigated in rats. Methods: Female Sprague-Dawley rats were ovariectomized and subjected to a daily scheduled exercise training (15 min at 15 m/min) or treated with HE (30 or 100 mg/kg, oral) or 17beta-estradiol (100 MUg/kg, intraperitoneal) for 12 weeks. Body and visceral fat weights, serum lipid profiles, osteoporotic parameters in serum, and femoral bones were analyzed. Separately, forced running induced dermal and rectal temperatures and blood flow velocity were measured in ovariectomized rats. Results: Ovariectomy increased blood lipids including triglycerides, total cholesterol, and low-density lipoproteins, leading to visceral fat accumulation and overweight. Estrogen depletion caused osteoporosis, displaying decreased femoral bone weight, bone mineral density and content, and blood phosphorus level. The disturbances in lipid metabolism and bone resorption were recovered by treatment with HE in a dose-dependent manner. In addition, HE treatment shortened the duration of forced running-induced alterations in skin and rectal temperatures by reducing blood flow velocity. Conclusion: The results indicate that HE attenuated overweight, osteoporosis, and hot flash in estrogen deficient animals by regulating blood lipid profile and fat accumulation, blood estrogen and bone resorption factors, and dermal blood flow. PMID- 29619068 TI - Astragalus membranaceus and Salvia miltiorrhiza Ameliorate Lipopolysaccharide Induced Acute Lung Injury in Rats by Regulating the Toll-Like Receptor 4/Nuclear Factor-Kappa B Signaling Pathway. AB - Astragalus membranaceus and Salvia miltiorrhiza (AM/SM) are well used in Traditional Chinese Medicines (TCM) for nourishing Qi and activating blood circulation method. From TCM theory, the pathogenesis of acute lung injury (ALI) was determined as Qi deficiency and blood stagnation. In this study, we are aiming to investigate the protective and therapeutic effects of AM/SM on a rat model of lipopolysaccharide- (LPS-) induced ALI in rats and to elucidate potential molecular mechanisms. ALI was induced by intratracheal instillation of LPS (5 mg/kg) in Sprague-Dawley rats. SM/AM was given orally before and after LPS administration. Results demonstrated that AM/SM attenuated lung histopathological changes induced by LPS, decreased wet/dry weight ratios and protein concentrations, and inhibited the production of tumor necrosis factor-alpha (TNF alpha) and interleukin-6 (IL-6) in BALF. Moreover, AM/SM significantly downregulated protein and mRNA expression of toll-like receptors 4 (TLR-4), interleukin-1 receptor-associated kinase-1 (IRAK-1), and nuclear factor-kappa B (NF-kappaB/p65). These findings suggest that AM/SM showed protective and therapeutic effects in LPS-induced ALI rat through modulating TLR-4 signaling pathways. Nourishing Qi and activating blood circulation may be a beneficial treatment for ALI. PMID- 29619069 TI - Piper retrofractum Vahl. Extract, as a PPARdelta and AMPK Activator, Suppresses UVB-Induced Photoaging through Mitochondrial Biogenesis and MMPs Inhibition in Human Dermal Fibroblasts and Hairless Mice. AB - Photoaging occurs by UVB-irradiation and involves production of reactive oxygen species (ROS) and overexpression of matrix metalloproteinases (MMPs), leading to extracellular matrix damage. Piper retrofractum Vahl. is used as a traditional medicine for antiflatulence, expectorant, sedative, and anti-irritant; however, its antiphotoaging effect has not yet been studied. The current study investigated the antiphotoaging effect of standardized Piper retrofractum extract (PRE) on UVB-damaged human dermal fibroblasts and hairless mouse skin. PRE treatment activated the peroxisome proliferator-activated receptor delta (PPARdelta) and the adenosine monophosphate-activated protein kinase (AMPK), consequently upregulating mitochondrial synthesis and reducing ROS production. Additionally, PRE inhibited MMPs expression via suppressing mitogen-activated protein kinase (MAPK) and activator protein-1 (AP-1). PRE downregulated UVB induced inflammatory reactions by inhibiting the nuclear factor-kappa B (NF kappaB) activity. PRE also enhanced transforming growth factor-beta (TGF-beta) and the Smad signaling pathway, thereby promoting procollagen gene transcription. Furthermore, oral administration of PRE (300 mg/kg/day) similarly regulated the signaling pathways and increased antioxidant enzyme expression, thus attenuating physiological deformations, such as wrinkle formation and erythema response. Collectively, these results suggest that PRE acts as a potent antiphotoaging agent via PPARdelta and AMPK activation. PMID- 29619070 TI - Use of Jianpi Jiedu Herbs in Patients with Advanced Colorectal Cancer: A Systematic Review and Meta-Analysis. AB - Objective: To systematically review the effect of invigorating Pi and detoxification (Jianpi Jiedu, (JPJD)) herbs in advanced colorectal cancer (CRC) patients receiving chemotherapy. Methods: Three English and four Chinese databases were searched. Literature was screened by EndNote X7 and data were analyzed by RevMan 5.2. Results: This review comprised 12 randomized clinical studies of 701 patients. The results showed that JPJD herbs improved the therapeutic effect on Chinese medicine symptoms [risk ratio (RR) = 1.59; 95% confidence interval (CI): 1.35~1.88] and Karnofsky performance score [RR = 2.07; 95% CI: 1.52~2.82] for advanced CRC patients receiving chemotherapy, lowered the Chinese medicine symptoms' score [weighted mean difference = -2.44; 95% CI: 3.23~-1.64], reduced the incidence of nausea and vomiting [RR = 0.23; 95% CI: 0.11~0.49], improved platelet at toxicity grades III-IV [odds ratio = 0.29; 95% CI: 0.12~0.74] and I-IV [RR = 0.65; 95% CI: 0.51~0.82], and improved white blood cell at toxicity grades III-IV [RR = 0.37; 95% CI: 0.23~0.58] and I-IV [RR = 0.69; 95% CI: 0.60~0.79]. However, the results showed no significant effect on tumor response. Conclusion: JPJD herbs can improve quality of life, relieve symptoms, and reduce adverse events of advanced CRC patients receiving chemotherapy. PMID- 29619071 TI - Quantifying Liver Stagnation Spleen Deficiency Pattern for Diarrhea Predominate Irritable Bowel Syndromes Using Multidimensional Analysis Methods. AB - Objective: This study aims to offer a new approach for quantifying severity of traditional Chinese medicine pattern with multidimensional analysis methods. Methods: A scale and theoretical models were constructed based on the definition of liver stagnation spleen deficiency pattern. Clinical data of 344 IBS-D patients from a cross-sectional study was used for feature validation of the model. Confirmatory factor analysis was used for evaluating the models. Also, multidimensional item response model was used for assessing multidimensional psychometric properties of the scale. Results: Detecting two latent traits, the Cronbach's alpha of the 9-item scale was 0.745. Multidimensional model was evaluated with significant goodness of fit indices while the unidimensional model was rejected. The multidimensional item response model showed all the items had adequate discrimination. Parameters presented adequate explanation regarding mental syndromes having high factor loading on the liver stagnation factor and abdominal discomfort syndromes highly related to the spleen deficiency factor. Test information function showed that scale demonstrated the highest discrimination power among patients with moderate to high level of severity. Conclusions: The application of the multidimensional analysis methods on the basis of theoretical model construction provides a useful and rational approach for quantifying the severity of traditional Chinese medicine patterns. PMID- 29619073 TI - Antipsoriatic Effects of Wannachawee Recipe on Imiquimod-Induced Psoriasis-Like Dermatitis in BALB/c Mice. AB - Psoriasis is a common immune-mediated chronic inflammatory skin disease characterized by thick and erythema raised plaques with adherent silvery scales. T-cells are activated via the IL-23/Th17 axis which is involved in psoriasis pathogenesis. Conventional treatments of psoriasis have adverse events that influence patients' adherence. Wannachawee Recipe (WCR) is Thai traditional medicine that is known to be effective for psoriasis patients; however, preclinical evidence is still lacking. This study investigated the therapeutic potential of WCR on antiproliferant activity using imiquimod- (IMQ-) induced psoriasis-like dermatitis in a mouse model. Psoriasis-like dermatitis was induced on the shaved dorsal skin and right ear pinna of BALB/c mice by topical application of IMQ for 15 consecutive days after which WCR was administered to the mice by oral gavage for 10 days. Phenotypical observations, histopathological examinations, and ELISA of skin and blood samples were conducted. WCR significantly ameliorated development of IMQ-induced psoriasis-like dermatitis and reduced levels of Th17 cytokines (IL-17A, IL-22, and IL-23) in both serum and dorsal skin. Histopathological findings showed a decrease in epidermal thickness and inflammatory T-cell infiltration in the WCR-treated groups. The WCR has pharmacological actions which regulate Th17 related cytokines suggesting that it is a potential alternative therapeutic strategy for psoriasis. PMID- 29619072 TI - A Network Pharmacology Approach to Uncover the Multiple Mechanisms of Hedyotis diffusa Willd. on Colorectal Cancer. AB - Background: As one of the most frequently diagnosed cancer diseases globally, colorectal cancer (CRC) remains an important cause of cancer-related death. Although the traditional Chinese herb Hedyotis diffusa Willd. (HDW) has been proven to be effective for treating CRC in clinical practice, its definite mechanisms have not been completely deciphered. Objective: The aim of our research is to systematically explore the multiple mechanisms of HDW on CRC. Methods: This study adopted the network pharmacology approach, which was mainly composed of active component gathering, target prediction, CRC gene collection, network analysis, and gene enrichment analysis. Results: The network analysis showed that 10 targets might be the therapeutic targets of HDW on CRC, namely, HRAS, PIK3CA, KRAS, TP53, APC, BRAF, GSK3B, CDK2, AKT1, and RAF1. The gene enrichment analysis implied that HDW probably benefits patients with CRC by modulating pathways related to cancers, infectious diseases, endocrine system, immune system, nervous system, signal transduction, cellular community, and cell motility. Conclusions: This study partially verified and predicted the pharmacological and molecular mechanism of HDW against CRC from a holistic perspective, which will also lay a foundation for the further experimental research and clinical rational application of HDW. PMID- 29619074 TI - Involvement of MrgprC in Electroacupuncture Analgesia for Attenuating CFA-Induced Thermal Hyperalgesia by Suppressing the TRPV1 Pathway. AB - Mas-related G-protein-coupled receptor C (MrgprC) plays an important role in modulating chronic inflammatory pain. Electroacupuncture (EA) has a satisfactory analgesic effect on chronic pain. This study aimed to investigate the involvement of MrgprC and its transient receptor potential vanilloid 1 (TRPV1) pathway in EA analgesia in chronic inflammatory pain. Chronic inflammatory pain was induced by subcutaneously injecting complete Freund's adjuvant (CFA) into the left hind paw. EA (2/100 Hz) stimulation was administered. MrgprC siRNAs were intrathecally administered to inhibit MrgprC expression, and bovine adrenal medulla 8-22 (BAM8 22) was used to activate MrgprC. The mechanical allodynia was decreased by EA significantly since day 3. The piled analgesic effect of EA was partially blocked by 6 intrathecal administrations of MrgprC siRNA. Both EA and BAM8-22 could downregulate the expression of TRPV1 and PKC in both the DRG and the SCDH. Both EA and BAM8-22 could also decrease the TRPV1 translocation and p-TRPV1 level in both the DRG and the SCDH. The effects of EA on PKCepsilon, TRPV1 translocation, and p-TRPV1 in both the DRG and the SCDH were reversed by MrgprC siRNA. The results indicated that MrgprC played crucial roles in chronic pain modulation and was involved in EA analgesia partially through the regulation of TRPV1 function at the DRG and SCDH levels. PMID- 29619075 TI - In vitro toxicological evaluation of surgical smoke from human tissue. AB - Background: Operating room personnel have the potential to be exposed to surgical smoke, the by-product of using electrocautery or laser surgical device, on a daily basis. Surgical smoke is made up of both biological by-products and chemical pollutants that have been shown to cause eye, skin and pulmonary irritation. Methods: In this study, surgical smoke was collected in real time in cell culture media by using an electrocautery surgical device to cut and coagulate human breast tissues. Airborne particle number concentration and particle distribution were determined by direct reading instruments. Airborne concentration of selected volatile organic compounds (VOCs) were determined by evacuated canisters. Head space analysis was conducted to quantify dissolved VOCs in cell culture medium. Human small airway epithelial cells (SAEC) and RAW 264.7 mouse macrophages (RAW) were exposed to surgical smoke in culture media for 24 h and then assayed for cell viability, lactate dehydrogenase (LDH) and superoxide production. Results: Our results demonstrated that surgical smoke-generated from human breast tissues induced cytotoxicity and LDH increases in both the SAEC and RAW. However, surgical smoke did not induce superoxide production in the SAEC or RAW. Conclusion: These data suggest that the surgical smoke is cytotoxic in vitro and support the previously published data that the surgical smoke may be an occupational hazard to healthcare workers. PMID- 29619077 TI - Risk factors for vitamin A and D deficiencies among children under-five in the state of Palestine. AB - Background: Vitamin A and D are essential for the proper growth and development of a child. Due to the complex political circumstances in the state of Palestine, research on micronutrient deficiency is scarce. Methods: The Palestinian Ministry of Health (MOH) and UNICEF conducted a national cross-sectional survey in 2013 after the implementation of various micronutrient supplementation and fortification programs. Risk factors for levels of vitamin A (n = 1054) and vitamin D (n = 150) were assessed among children aged 6 to 59 months using chi square tests and logistic regression with each of the outcome variables, vitamin A and D deficiencies. A child was considered to be deficient in vitamin A and D if he/she had a serum level < 1.05 MUmol/L and < 50 nmol/L respectively. Multiple logistic regression models were developed to identify independent risk factors for vitamin deficiencies. Results: The prevalence of vitamin A and D deficiency was 73.1% and 60.7% respectively. Children in Gaza were 1.34 (95%CI 0.78-2.31) and 1.96 times (95%CI 0.67-5.71) more likely to be deficient in vitamin A and D respectively compared to children in the West Bank. Anaemic children were 1.5 times more likely to be deficient in vitamin A (95%CI 1.08-2.10). Older children (> 1 year-old) were more likely to be deficient in vitamin D, and females were 2.72 times more likely to be deficient than males (95%CI 1.21-6.01). Results suggest no association between maternal education levels, feeding practices such as breastfeeding and complementary feeding and vitamin A and D deficiency. Although not reaching conventional levels of statistical significance, it was observed that children who received their vitamin drops from the MOH were more likely to have vitamin A and D deficiencies than those children receiving the supplements from the United Nations Relief and Works Agency for Palestine Refugees (UNRWA). Conclusions: Using these results, the MOH may consider specifically targeting at risk children to increase adherence to the full supplementation regimen. Further research into effective methods of service delivery by health service providers is needed including an in depth look at the UNRWA maternal counselling and supplement provision protocols. PMID- 29619076 TI - Immunogenicity of a Fap2 peptide mimotope of Fusobacterium nucleatum and its potential use in the diagnosis of colorectal cancer. AB - Background: The role of Fusobacterium nucleatum Fap2 protein in the development of colorectal cancer has recently been explained. Fap2, when bound to the human inhibitory receptor, TIGIT, inhibits the cytotoxic activity of natural killer (NK) cells against cancer cells, thus, allowing proliferation of the latter eventually leading to tumor growth. The aim of the study was to identify the immunogenicity of a peptide mimotope of the Fap2 protein and to determine the reactivity of colorectal cancer patients' sera against the mimotope. Methods: Immunogenic epitope of the Fap2 protein of F. nucleatum was selected using the B cell epitope prediction of the Immune Epitope Database and Analysis Resource (IEDB). The immunogenicity of the synthetic peptide mimotope of the Fap2 protein was determined in animal models and reactivity of colorectal cancer patients' sera against the mimotope was done by indirect ELISA. Results: Results show that the selected peptide mimotope, with sequence TELAYKHYFGT, of the outer membrane protein Fap2 of F. nucleatum is immunogenic. Increase in the absorbance readings of peptide-immunized rabbit sera was observed starting Week 1 which was sustained up to Week 10 in the indirect ELISA performed. Colorectal cancer cases (n = 37) were all reactive in an ELISA-based analysis using the mimotope as the capture antigen. Conclusions: In this study, we identified an immunogenic epitope of the Fap2 protein of the Fusobacterium nucleatum. We demonstrated the reactivity of serum of histopathologically confirmed CRC patients in a peptide-capture indirect ELISA which may serve as proof of concept for the development of CRC diagnostics. PMID- 29619079 TI - Liquid fuel generation from algal biomass via a two-step process: effect of feedstocks. AB - Background: In this study, a two-step processing method (hydrothermal liquefaction followed by catalytic upgrading) was used to produce upgraded bio oil. A comprehensive screening analysis of algal species, including four microalgae and four macroalgae, was conducted to bridge the gap between previous accounts of microalgae and macroalgae hydrothermal liquefaction and the upgrading process of the resulting crude bio-oils. Results: Hydrothermal liquefaction using eight algal biomasses was performed at 350 degrees C for 1 h. The microalgae always produced a higher crude bio-oil yield than the macroalgae due to their high lipid content, among which Schizochytrium limacinum provided the maximum crude bio-oil yield of 54.42 wt%. For microalgae, higher amounts of N in the biomass resulted in higher amounts of N in the crude bio-oil; however, contrary results were observed for the macroalgae. The crude bio-oils generated from both the microalgae and macroalgae were characterized as having a high viscosity, total acid number, and heteroatom content, and they were influenced by the biochemical compositions of the feedstocks. Next, all eight-crude bio-oils were treated at 400 degrees C for 2 h with 10 wt% Ru/C using tetralin as the hydrogen donor. The hydrogen source was provided after tetralin was transformed to naphthalene. All the upgraded bio-oils had higher energy densities and significantly lower N, O, and S contents and viscosities than their corresponding crude bio-oils. However, the H/C molar ratio of the upgraded bio-oils decreased due to the absence of external hydrogen relative to the crude bio-oils. The S content of the upgraded bio-oil produced from upgrading the Schizochytrium limacinum crude bio-oil was even close to the 50 ppm requirement of China IV diesel. Conclusions: Microalgae are better feedstocks than macroalgae for liquid fuel production. Biochemical components have a significant impact on the yield and composition of crude bio-oil. Tetralin does not perform as well as external hydrogen for controlling coke formation. The S content of the upgraded bio-oil can be reduced to 76 ppm for the crude bio-oil produced from Schizochytrium limacinum. Upgraded bio-oils have similar properties to those of naphtha and jet fuel. PMID- 29619078 TI - Feasibility of biodiesel production and CO2 emission reduction by Monoraphidium dybowskii LB50 under semi-continuous culture with open raceway ponds in the desert area. AB - Background: Compared with other general energy crops, microalgae are more compatible with desert conditions. In addition, microalgae cultivated in desert regions can be used to develop biodiesel. Therefore, screening oil-rich microalgae, and researching the algae growth, CO2 fixation and oil yield in desert areas not only effectively utilize the idle desertification lands and other resources, but also reduce CO2 emission. Results: Monoraphidium dybowskii LB50 can be efficiently cultured in the desert area using light resources, and lipid yield can be effectively improved using two-stage induction and semi continuous culture modes in open raceway ponds (ORPs). Lipid content (LC) and lipid productivity (LP) were increased by 20% under two-stage industrial salt induction, whereas biomass productivity (BP) increased by 80% to enhance LP under semi-continuous mode in 5 m2 ORPs. After 3 years of operation, M. dybowskii LB50 was successfully and stably cultivated under semi-continuous mode for a month during five cycles of repeated culture in a 200 m2 ORP in the desert area. This culture mode reduced the supply of the original species. The BP and CO2 fixation rate were maintained at 18 and 33 g m-2 day-1, respectively. Moreover, LC decreased only during the fifth cycle of repeated culture. Evaporation occurred at 0.9-1.8 L m-2 day-1, which corresponded to 6.5-13% of evaporation loss rate. Semi-continuous and two-stage salt induction culture modes can reduce energy consumption and increase energy balance through the energy consumption analysis of life cycle. Conclusion: This study demonstrates the feasibility of combining biodiesel production and CO2 fixation using microalgae grown as feedstock under culture modes with ORPs by using the resources in the desert area. The understanding of evaporation loss and the sustainability of semi-continuous culture render this approach practically viable. The novel strategy may be a promising alternative to existing technology for CO2 emission reduction and biofuel production. PMID- 29619080 TI - Characterization of a novel sugar transporter involved in sugarcane bagasse degradation in Trichoderma reesei. AB - Background: Trichoderma reesei is a saprophytic fungus implicated in the degradation of polysaccharides present in the cell wall of plants. T. reesei has been recognized as the most important industrial fungus that secretes and produces cellulase enzymes that are employed in the production of second generation bioethanol. A few of the molecular mechanisms involved in the process of biomass deconstruction by T. reesei; in particular, the effect of sugar transporters and induction of xylanases and cellulases expression are yet to be known. Results: In our study, we characterized a novel sugar transporter, which was previously identified by our group through in silico analysis of RNA-seq data. The novel T. reesei 69957-sugar transport system (Tr69957) is capable of transporting xylose, mannose, and cellobiose using a T. reesei 69957-sugar transport system in Saccharomyces cerevisiae. The deletion of Tr69957 in T. reesei affected the fungal growth and biomass accumulation, and the sugar uptake in the presence of mannose, cellobiose, and xylose. Molecular docking studies revealed that Tr69957 shows reduced protein-ligand binding energy for interactions towards disaccharides in comparison with monosaccharides. Furthermore, the deletion of Tr69957 affected the gene expression of cellobiohydrolases (cel7a and cel6a), beta-glucosidases (cel3a and cel1a), and xylanases (xyn1 and xyn2) in the cultures of parental and mutant strains in the presence of cellobiose and sugarcane bagasse (SCB). Conclusion: The transporter Tr69957 of T. reesei can transport cellobiose, xylose, and mannose, and can affect the expression of a few genes encoding enzymes, such as cellulases and xylanases, in the presence of SCB. We showed for the first time that a filamentous fungus (T. reesei) contains a potential mannose transporter that may be involved in the degradation of cellulose. PMID- 29619081 TI - Lignin from hydrothermally pretreated grass biomass retards enzymatic cellulose degradation by acting as a physical barrier rather than by inducing nonproductive adsorption of enzymes. AB - Background: Lignin is known to hinder efficient enzymatic conversion of lignocellulose in biorefining processes. In particular, nonproductive adsorption of cellulases onto lignin is considered a key mechanism to explain how lignin retards enzymatic cellulose conversion in extended reactions. Results: Lignin rich residues (LRRs) were prepared via extensive enzymatic cellulose degradation of corn stover (Zea mays subsp. mays L.), Miscanthus * giganteus stalks (MS) and wheat straw (Triticum aestivum L.) (WS) samples that each had been hydrothermally pretreated at three severity factors (log R0) of 3.65, 3.83 and 3.97. The LRRs had different residual carbohydrate levels-the highest in MS; the lowest in WS. The residual carbohydrate was not traceable at the surface of the LRRs particles by ATR-FTIR analysis. The chemical properties of the lignin in the LRRs varied across the three types of biomass, but monolignols composition was not affected by the severity factor. When pure cellulose was added to a mixture of LRRs and a commercial cellulolytic enzyme preparation, the rate and extent of glucose release were unaffected by the presence of LRRs regardless of biomass type and severity factor, despite adsorption of the enzymes to the LRRs. Since the surface of the LRRs particles were covered by lignin, the data suggest that the retardation of enzymatic cellulose degradation during extended reaction on lignocellulosic substrates is due to physical blockage of the access of enzymes to the cellulose caused by the gradual accumulation of lignin at the surface of the biomass particles rather than by nonproductive enzyme adsorption. Conclusions: The study suggests that lignin from hydrothermally pretreated grass biomass retards enzymatic cellulose degradation by acting as a physical barrier blocking the access of enzymes to cellulose rather than by inducing retardation through nonproductive adsorption of enzymes. PMID- 29619082 TI - Self-sustained enzymatic cascade for the production of 2,5-furandicarboxylic acid from 5-methoxymethylfurfural. AB - Background: 2,5-Furandicarboxylic acid is a renewable building block for the production of polyfurandicarboxylates, which are biodegradable polyesters expected to substitute their classical counterparts derived from fossil resources. It may be produced from bio-based 5-hydroxymethylfurfural or 5 methoxymethylfurfural, both obtained by the acidic dehydration of biomass-derived fructose. 5-Methoxymethylfurfural, which is produced in the presence of methanol, generates less by-products and exhibits better storage stability than 5 hydroxymethylfurfural being, therefore, the industrial substrate of choice. Results: In this work, an enzymatic cascade involving three fungal oxidoreductases has been developed for the production of 2,5-furandicarboxylic acid from 5-methoxymethylfurfural. Aryl-alcohol oxidase and unspecific peroxygenase act on 5-methoxymethylfurfural and its partially oxidized derivatives yielding 2,5-furandicarboxylic acid, as well as methanol as a by product. Methanol oxidase takes advantage of the methanol released for in situ producing H2O2 that, along with that produced by aryl-alcohol oxidase, fuels the peroxygenase reactions. In this way, the enzymatic cascade proceeds independently, with the only input of atmospheric O2, to attain a 70% conversion of initial 5-methoxymethylfurfural. The addition of some exogenous methanol to the reaction further improves the yield to attain an almost complete conversion of 5-methoxymethylfurfural into 2,5-furandicarboxylic acid. Conclusions: The synergistic action of aryl-alcohol oxidase and unspecific peroxygenase in the presence of 5-methoxymethylfurfural and O2 is sufficient for the production of 2,5-furandicarboxylic acid. The addition of methanol oxidase to the enzymatic cascade increases the 2,5-furandicarboxylic acid yields by oxidizing a reaction by-product to fuel the peroxygenase reactions. PMID- 29619083 TI - Engineering of E. coli inherent fatty acid biosynthesis capacity to increase octanoic acid production. AB - Background: As a versatile platform chemical, construction of microbial catalysts for free octanoic acid production from biorenewable feedstocks is a promising alternative to existing petroleum-based methods. However, the bio-production strategy has been restricted by the low capacity of E. coli inherent fatty acid biosynthesis. In this study, a combination of integrated computational and experimental approach was performed to manipulate the E. coli existing metabolic network, with the objective of improving bio-octanoic acid production. Results: First, a customized OptForce methodology was run to predict a set of four genetic interventions required for production of octanoic acid at 90% of the theoretical yield. Subsequently, all the ten candidate proteins associated with the predicted interventions were regulated individually, as well as in contrast to the combination of interventions as suggested by the OptForce strategy. Among these enzymes, increased production of 3-hydroxy-acyl-ACP dehydratase (FabZ) resulted in the highest increase (+ 45%) in octanoic acid titer. But importantly, the combinatorial application of FabZ with the other interventions as suggested by OptForce further improved octanoic acid production, resulting in a high octanoic acid-producing E. coli strain +fabZ DeltafadE DeltafumAC DeltaackA (TE10) (+ 61%). Optimization of TE10 expression, medium pH, and C:N ratio resulted in the identified strain producing 500 mg/L of C8 and 805 mg/L of total FAs, an 82 and 155% increase relative to wild-type MG1655 (TE10) in shake flasks. The best engineered strain produced with high selectivity (> 70%) and extracellularly (> 90%) up to 1 g/L free octanoic acid in minimal medium fed-batch culture. Conclusions: This work demonstrates the effectiveness of integration of computational strain design and experimental characterization as a starting point in rewiring metabolism for octanoic acid production. This result in conjunction with the results of other studies using OptForce in strain design demonstrates that this strategy may be also applicable to engineering E. coli for other customized bioproducts. PMID- 29619084 TI - Nondestructive and rapid determination of lignocellulose components of biofuel pellet using online hyperspectral imaging system. AB - Background: In the pursuit of sources of energy, biofuel pellet is emerging as a promising resource because of its easy storage and transport, and lower pollution to the environment. The composition of biomass has important implication for energy conversion processing strategies. Current standard chemical methods for biomass composition are laborious, time-consuming, and unsuitable for high throughput analysis. Therefore, a reliable and efficient method is needed for determining lignocellulose composition in biomass and so to accelerate biomass utilization. Here, near-infrared hyperspectral imaging (900-1700 nm) together with chemometrics was used to determine the lignocellulose components in different types of biofuel pellets. Partial least-squares regression and principal component multiple linear regression models based on whole wavelengths and optimal wavelengths were employed and compared for predicting lignocellulose composition. Results: Out of 216 wavelengths, 20, 10 and 17 were selected by the successive projections algorithm for cellulose, hemicellulose and lignin, respectively. Three simple and satisfactory prediction models were constructed, with coefficients of determination of 0.92, 0.84 and 0.71 for cellulose, hemicellulose and lignin, respectively. The relative parameter distributions were quantitatively visualized through prediction maps by transferring the optimal models to all pixels on the hyperspectral image. Conclusions: Hence, the overall results indicated that hyperspectral imaging combined with chemometrics offers a non-destructive and low-cost method for determining biomass lignocellulose components, which would help in developing a simple multispectral imaging instrument for biofuel pellets online measurement and improving the production management. PMID- 29619085 TI - Consolidated bioprocessing of butanol production from xylan by a thermophilic and butanologenic Thermoanaerobacterium sp. M5. AB - Background: Consolidated bioprocessing (CBP) has attracted increasing attention since it can accomplish hydrolytic enzymes production, lignocellulose degradation and microbial fermentation in one single step. Currently, biobutanol is mainly produced by mesophilic and solventogenic clostridia, such as Clostridium beijerinckii and C. acetobutylicum, which cannot directly utilize lignocellulose, an abundant, renewable and economic feedstock. Hence, metabolic construction or isolation of novel cellulolytic/hemicellulolytic and solventogenic bacteria to achieve direct butanol production from lignocellulose offers a promising alternative. Results: In this study, a newly isolated Thermoanaerobacterium sp. M5 could directly produce butanol from xylan through CBP at 55 degrees C via the butanol-ethanol pathway. Further genomic and proteomic analysis showed that the capabilities of efficient xylan degradation and butanol synthesis were attributed to the efficient expression of xylanase, beta-xylosidase and the bifunctional alcohol/aldehyde dehydrogenase (AdhE). Process optimization based on the characteristic of AdhE could further improve the final butanol titer to 1.17 g/L from xylan through CBP. Furthermore, a new co-cultivation system consisting of Thermoanaerobacterium sp. M5 which could release xylose from xylan efficiently and C. acetobutylicum NJ4 which possesses the capacity of high butanol production was established. This microbial co-cultivation system could improve the butanol titer to 8.34 g/L, representing the highest butanol titer from xylan through CBP. Conclusions: A newly thermophilic and butanogenic bacterium Thermoanaerobacterium sp. M5 was isolated and key enzymes responsible for butanol production were characterized in this study. High butanol titer was obtained from xylan through process optimization. In addition, the newly set up microbial co-cultivation system, consisting of Thermoanaerobacterium sp. M5 and C. acetobutylicum NJ4, achieved the highest butanol production from xylan compared with the reported co cultivation systems. PMID- 29619086 TI - Evolutionary engineering improves tolerance for medium-chain alcohols in Saccharomyces cerevisiae. AB - Background: Yeast-based chemical production is an environmentally friendly alternative to petroleum-based production or processes that involve harsh chemicals. However, many potential alcohol biofuels, such as n-butanol, isobutanol and n-hexanol, are toxic to production organisms, lowering the efficiency and cost-effectiveness of these processes. We set out to improve the tolerance of Saccharomyces cerevisiae toward these alcohols. Results: We evolved the laboratory strain of S. cerevisiae BY4741 to be more tolerant toward n hexanol and show that the mutations which confer tolerance occur in proteins of the translation initiation complex. We found that n-hexanol inhibits initiation of translation and evolved mutations in the alpha subunit of eIF2 and the gamma subunit of its guanine exchange factor eIF2B rescue this inhibition. We further demonstrate that translation initiation is affected by other alcohols such as n pentanol and n-heptanol, and that mutations in the eIF2 and eIF2B complexes greatly improve tolerance to these medium-chain alcohols. Conclusions: We successfully generated S. cerevisiae strains that have improved tolerance toward medium-chain alcohols and have demonstrated that the causative mutations overcome inhibition of translation initiation by these alcohols. PMID- 29619087 TI - Transcriptional and physiological data reveal the dehydration memory behavior in switchgrass (Panicum virgatum L.). AB - Background: Switchgrass (Panicum virgatum L.) is a model biofuel plant because of its high biomass, cellulose-richness, easy degradation to ethanol, and the availability of extensive genomic information. However, a little is currently known about the molecular responses of switchgrass plants to dehydration stress, especially multiple dehydration stresses. Results: Studies on the transcriptional profiles of 35-day-old tissue culture plants revealed 741 dehydration memory genes. Gene Ontology and pathway analysis showed that these genes were enriched in phenylpropanoid biosynthesis, starch and sucrose metabolism, and plant hormone signal transduction. Further analysis of specific pathways combined with physiological data suggested that switchgrass improved its dehydration resistance by changing various aspects of its responses to secondary dehydration stress (D2), including the regulation of abscisic acid (ABA) and jasmonic acid (JA) biosynthesis and signal transduction, the biosynthesis of osmolytes (l-proline, stachyose and trehalose), energy metabolism (i.e., metabolic process relating to photosynthetic systems, glycolysis, and the TCA cycle), and lignin biosynthesis. The transcriptional data and chemical substance assays showed that ABA was significantly accumulated during both primary (D1) and secondary (D2) dehydration stresses, whereas JA accumulated during D1 but became significantly less abundant during D2. This suggests the existence of a complicated signaling network of plant hormones in response to repeated dehydration stresses. A homology analysis focusing on switchgrass, maize, and Arabidopsis revealed the conservation and species-specific distribution of dehydration memory genes. Conclusions: The molecular responses of switchgrass plants to successive dehydration stresses have been systematically characterized, revealing a previously unknown transcriptional memory behavior. These results provide new insights into the mechanisms of dehydration stress responses in plants. The genes and pathways identified in this study will be useful for the genetic improvement of switchgrass and other crops. PMID- 29619088 TI - Novel optimization strategy for tannase production through a modified solid-state fermentation system. AB - Background: High amounts of insoluble substrates exist in the traditional solid state fermentation (SSF) system. The presence of these substrates complicates the determination of microbial biomass. Thus, enzyme activity is used as the sole index for the optimization of the traditional SSF system, and the relationship between microbial growth and enzyme synthesis is always ignored. This study was conducted to address this deficiency. All soluble nutrients from tea stalk were extracted using water. The aqueous extract was then mixed with polyurethane sponge to establish a modified SSF system, which was then used to conduct tannase production. With this system, biomass, enzyme activity, and enzyme productivity could be measured rationally and accurately. Thus, the association between biomass and enzyme activity could be easily identified, and the shortcomings of traditional SSF could be addressed. Results: Different carbon and nitrogen sources exerted different effects on microbial growth and enzyme production. Single-factor experiments showed that glucose and yeast extract greatly improved microbial biomass accumulation and that tannin and (NH4)2SO4 efficiently promoted enzyme productivity. Then, these four factors were optimized through response surface methodology. Tannase activity reached 19.22 U/gds when the added amounts of tannin, glucose, (NH4)2SO4, and yeast extract were 7.49, 8.11, 9.26, and 2.25%, respectively. Tannase activity under the optimized process conditions was 6.36 times higher than that under the initial process conditions. The optimized parameters were directly applied to the traditional tea stalk SSF system. Tannase activity reached 245 U/gds, which is 2.9 times higher than our previously reported value. Conclusions: In this study, a modified SSF system was established to address the shortcomings of the traditional SSF system. Analysis revealed that enzymatic activity and microbial biomass are closely related, and different carbon and nitrogen sources have different effects on microbial growth and enzyme production. The maximal tannase activity was obtained under the optimal combination of nutrient sources that enhances cell growth and tannase accumulation. Moreover, tannase production through the traditional tea stalk SSF was markedly improved when the optimized parameters were applied. This work provides an innovative approach to bioproduction research through SSF. PMID- 29619089 TI - Efficient whole cell biocatalyst for formate-based hydrogen production. AB - Background: Molecular hydrogen (H2) is an attractive future energy carrier to replace fossil fuels. Biologically and sustainably produced H2 could contribute significantly to the future energy mix. However, biological H2 production methods are faced with multiple barriers including substrate cost, low production rates, and low yields. The C1 compound formate is a promising substrate for biological H2 production, as it can be produced itself from various sources including electrochemical reduction of CO2 or from synthesis gas. Many microbes that can produce H2 from formate have been isolated; however, in most cases H2 production rates cannot compete with other H2 production methods. Results: We established a formate-based H2 production method utilizing the acetogenic bacterium Acetobacterium woodii. This organism can use formate as sole energy and carbon source and possesses a novel enzyme complex, the hydrogen-dependent CO2 reductase that catalyzes oxidation of formate to H2 and CO2. Cell suspensions reached specific formate-dependent H2 production rates of 71 mmol gprotein-1 h-1 (30.5 mmol gCDW-1 h-1) and maximum volumetric H2 evolution rates of 79 mmol L-1 h-1. Using growing cells in a two-step closed batch fermentation, specific H2 production rates reached 66 mmol gCDW-1 h-1 with a volumetric H2 evolution rate of 7.9 mmol L-1 h-1. Acetate was the major side product that decreased the H2 yield. We demonstrate that inhibition of the energy metabolism by addition of a sodium ionophore is suitable to completely abolish acetate formation. Under these conditions, yields up to 1 mol H2 per mol formate were achieved. The same ionophore can be used in cultures utilizing formate as specific switch from a growing phase to a H2 production phase. Conclusions: Acetobacterium woodii reached one of the highest formate-dependent specific H2 productivity rates at ambient temperatures reported so far for an organism without genetic modification and converted the substrate exclusively to H2. This makes this organism a very promising candidate for sustainable H2 production and, because of the reversibility of the A. woodii enzyme, also a candidate for reversible H2 storage. PMID- 29619091 TI - Dynamic development of metabolic syndrome and its risk prediction in Chinese population: a longitudinal study using Markov model. AB - Background: With the increasing prevalence of metabolic syndrome (MS), there is a need to track and predict the development of MS. In this study, we established a Markov model to explore the natural history and predict the risk of MS. Methods: A total of 21,777 Chinese individuals who had at least two consecutive health check-ups between 2010 and 2015 were studied. MS was defined using the Chinese Diabetes Society criteria. Twelve metabolic abnormal states (the no component state, four isolated component states, six 2-component states, and the MS state) were contained in each Markov chain. The transition probability was the mean of five probabilities for the transition between any two states in 2 consecutive years. Results: The dyslipidemia or overweight/obesity components were most likely to initiate the progress of MS in individuals aged 18-49. However, for individuals over 50 years old, the most likely initiating component of MS was dyslipidemia or hypertension. People who initially had dyslipidemia were most likely to develop the combined state of dyslipidemia with overweight/obesity before the age of 50, but after 50 years of age, the state of dyslipidemia merged with hypertension was the most common. Subjects (with the exception of males over 50 years of age who initially had an isolated state of hyperglycemia) who initially had an isolated state of overweight/obesity, hypertension, or hyperglycemia were most likely to develop a combination of one of these initial states with dyslipidemia. Males who initially had isolated hyperglycemia tended to develop hypertension after age 50. There was a greater chance for subjects who initially had an isolated hyperglycemia state or 2-component state that contained hyperglycemia to develop MS within 10 years compared to those who initially had other abnormal metabolic states. Conclusions: The occurrence of MS primarily began with overweight/obesity or dyslipidemia in people aged 18-49. However, for those over 50 years old, MS primarily initiated under the conditions of dyslipidemia or hypertension. When MS started under the conditions of overweight/obesity, hypertension or hyperglycemia, dyslipidemia tended to occur next. People who initially had isolated hyperglycemia or a 2-component state that contained hyperglycemia had a higher risk of developing MS than those with other initiating states. PMID- 29619092 TI - Science and biology drives the immune system to cure lung cancer patients: a revolution but not without challenges. PMID- 29619090 TI - Host-targeting therapies for hepatitis C virus infection: current developments and future applications. AB - Chronic hepatitis C virus (HCV) infection is a leading cause of chronic liver diseases and hepatocellular carcinoma (HCC) worldwide. In the past few years, anti-HCV therapies have undergone a revolution with the approval of multiple direct-acting antivirals (DAAs), which enable interferon-free treatments with considerable improvement of sustained virologic response in patients. Today, DAAs have become the standard of care for HCV therapy. However, several limitations remain, which include access to therapy, treatment failure in a subset of patients and persistent risk of HCC development following cure in patients with advanced fibrosis. By targeting conserved host proteins involved in the HCV life cycle, host-targeting agents (HTAs) offer opportunities for pan-genotypic antiviral approaches with a high barrier to drug resistance. Moreover, when applied in combination with DAAs, HTAs could improve the management of difficult to-treat patients by acting through a complementary mechanism of action. In this review, we summarize the different HTAs evaluated in preclinical and clinical development and discuss their potential role for anti-HCV therapies. PMID- 29619093 TI - Aromatase inhibitors are associated with a higher fracture risk than tamoxifen: a systematic review and meta-analysis. AB - Background: In this paper, our aim was to systematically evaluate published evidence of bone fracture risk associated with tamoxifen and aromatase inhibitors in women aged 65 and under, and diagnosed with nonmetastatic breast cancer. Methods: We comprehensively searched MEDLINE, EMBASE and CINAHL databases from January 1997 through May 2015, and reference lists of the selected articles to identify English-language randomized controlled trials and cohort studies of fracture risk. Two independent reviewers screened articles and assessed methodological quality using Risk of Bias assessment for randomized controlled trials and the Newcastle-Ottawa Scale for cohort studies. Fracture risk was estimated as pooled risk ratios using a random-effects model and inverse variance method. Results: Of 1926 identified articles, 21 independent studies fulfilled our selection criteria. Similar fracture risk was observed in women treated and not treated with tamoxifen [pooled risk ratio (RR) 0.95; 95% confidence interval (CI) 0.84-1.07]. A 35% (95% CI 1.21-1.51) higher fracture risk was observed in the aromatase inhibitor group compared with the tamoxifen group. A 17% (95% CI 1.07-1.28) higher fracture risk was observed in the aromatase inhibitor group than the no aromatase inhibitor group. Compared with the tamoxifen group, aromatase inhibitor-associated fracture risk increased by 33% (pooled RR 1.33; 95% CI 1.21-1.47) during the tamoxifen/aromatase inhibitor treatment period, but did not increase (pooled RR 0.99; 95% CI 0.72-1.37) during the post tamoxifen/aromatase inhibitor treatment period. Conclusions: Fracture risk is significantly higher in women treated with aromatase inhibitors, especially during the treatment period. Tamoxifen is not associated with lower fracture risk while tamoxifen could potentially preserve bone mass. Better osteoporosis management programs, especially during the treatment period, are needed for this group of women. PMID- 29619095 TI - Platelet-Rich Plasma in Reconstruction of Posterior Meatal Wall after Canal Wall Down Mastoidectomy. AB - Introduction Canal wall down (CWD) mastoidectomy has many drawbacks, including chronic otorrhea not responding to medications, granulations, dizziness on exposure to cold or hot water, and tendency of debris accumulation in the mastoid cavity, demanding periodic cleaning. Many of these problems can be solved by reconstruction of the posterior meatal wall (PMW). Objectives To assess the results of PMW reconstruction after CWD mastoidectomy for cholesteatoma using titanium mesh and platelet-rich plasma (PRP) mixed with bone pate. Methods This study was conducted with 20 patients that have atticoantral chronic suppurative otitis media. All cases were subjected to CWD mastoid surgery with complete elimination of the disease and reconstruction of the PMW by titanium mesh and the mixture of PRP with bone pate. All patients were exposed to a full preoperative evaluation and full postoperative assessment of the complications, the appearance of the external auditory canal contour, and the hearing gain expressed by the change of the air bone gap postoperatively. Results The PMW reconstructed by titanium mesh and the mixture of PRP with bone pate showed a smooth contour. During the follow-up of 12 to 36 months, the postoperative appearance of the external auditory canal contour was found to be smooth without hidden pouches, irregularities or stenosis in all cases. No granulation, foreign body reaction, or extrusion and/or displacement of the titanium mesh were registered. No facial palsy or recurrent cholesteatoma was reported. Conclusion The surgical reconstruction of the PMW using PRP, bone pate and titanium mesh after CWD mastoidectomy appears to be reliable without considerable complications, giving a smooth appearance to the PMW. PMID- 29619096 TI - Development and Administration of Chronic Suppurative Otitis Media Questionnaire 12 (COMQ-12) and Chronic Otitis Media Outcome Test-15 (COMOT-15) in Kannada. AB - Introduction It is essential to determine the quality of life among individuals with chronic suppurative otitis media (CSOM). However, there is limited literature on health-related quality of life measurements in Kannada-speaking individuals with CSOM. Objectives The present study attempted to translate and validate Chronic Suppurative Otitis Media Questionnaire-12 (COMQ-12) and Chronic Otitis Media Outcome Test-15 (COMOT-15) in Kannada. Method The English questionnaires were translated and back-translated, and they were later verified for content validity. The developed questionnaires were then administered to 100 individuals with CSOM for further validation. Results The results of the study showed that the translated questionnaires have good internal consistency for measuring quality of life among individuals with CSOM. The study also showed that Kannada-speaking individuals with CSOM show significant impairment in their health-related quality of life measures. Conclusions The impairments were more related to ear symptoms and psychological issues. However, test-retest reliability of the developed questionnaire and its further validation are essential. Thus, these questionnaires attempt to understand the problems of the individuals with CSOM from the patients' perspective and help clinicians provide the appropriate management. PMID- 29619094 TI - Foot osteoarthritis: latest evidence and developments. AB - Foot osteoarthritis (OA) is a common problem in older adults yet is under researched compared to knee or hand OA. Most existing studies focus on the first metatarsophalangeal joint, with evidence relating to midfoot OA being particularly sparse. Symptomatic radiographic foot OA affects 17% of adults aged 50 years and over. The first metatarsophalangeal joint is most commonly affected, followed by the second cuneometatarsal and talonavicular joints. Epidemiological studies suggest the existence of distinct first metatarsophalangeal joint and polyarticular phenotypes, which have differing clinical and risk factor profiles. There are few randomized controlled trials in foot OA. Existing trials provide some evidence of the effectiveness for pain relief of physical therapy, rocker sole shoes, foot orthoses and surgical interventions in first metatarsophalangeal joint OA and prefabricated orthoses in midfoot OA. Prospective epidemiological studies and randomized trials are needed to establish the incidence, progression and prognosis of foot OA and determine the effectiveness of both commonly used and more novel interventions. PMID- 29619097 TI - Pitch-Matching Accuracy and Temporal Auditory Processing. AB - Introduction Pitch-matching refers to the ability to vocally reproduce an acoustic model in a corresponding tone to the presented sound. This ability, which is dependent on pitch perception ability, can vary among individuals, and some are not able to sing in the correct tune or discriminate differences between tones. Objective To correlate pitch-matching accuracy and auditory processing in individuals without musical training. Methods A Pitch-Matching Test (vocal reproduction of synthesized and human voice sounds) and two commercially available tests of auditory temporal processing (the Pitch Pattern Sequence Test and the Random Gap Detection Test) were administered to all participants. A total of 62 college students of both genders, aged between 18 and 35 years old, were divided into 2 groups, according to their performances in the Pitch-Matching Test (the accurate match group and the inaccurate match group). Results In the Pitch Matching Test, both groups achieved better results when reproducing vocalized sounds. The accurate match group achieved a significantly higher pitch pattern sequence test performance. In the Random Gap Detection Test analysis, there were no differences between the two groups. The Pearson's chi-squared test showed a direct correlation between the Pitch-Matching Test and the Pitch Pattern Sequence Test. Conclusion The findings of this study suggest the existence of a significant relationship between temporal auditory processing and pitch-matching, through which accurate pitch-matching individuals perform better in the Pitch Pattern Sequence Test. Inaccurate pitch-matching individuals may be skilled at discriminating pitch, despite their poor performance in the Pitch-Matching Test. PMID- 29619098 TI - Short-Term Audiological Results of Diode Laser in Comparison with Manual Perforation in Stapes Surgery. AB - Introduction Diode laser is a new alternative in stapes surgery for otosclerosis. The present study is the first to compare the short-term results of the surgery performed using diode laser to those obtained through the conventional fenestration technique. Objective To use audiometry to establish a comparative analysis between the functional results obtained through surgery for otosclerosis using diode laser and the conventional technique. Method Audiometric evaluation of 12 patients submitted to stapes surgery for otosclerosis, using diode laser or conventional fenestration by needle and drills, between 2014 and 2015. Each group was composed of 6 patients. Pre and post-operative measures were compared for three months in both groups. The speech recognition threshold, the air and bone conduction threshold, as well as the gap between them at 500 Hz, 1 KHz, 2 KHz and 4 KHz were measured. Results Significant difference in bone conduction and SRT was observed when compared post and preoperative results in the diode group. However diode and conventional technique groups presented significant differences in air conduction and air-bone gap, suggesting that both can provide functional improvement. Conclusion Laser stapedotomy is a safe technique with good results. Both laser surgery and the conventional technique have improved the hearing of patients with a discreet advantage for the diode laser. Further prospective and randomized clinical trials are required to disclose all possible benefits of the stapes surgery using diode laser. PMID- 29619099 TI - The Impact of Deep Brain Stimulation on the Quality of Life and Swallowing in Individuals with Parkinson's Disease. AB - Introduction Deep brain stimulation (DBS) is an established treatment for Parkinson's disease (PD). However, there is little evidence regarding the effect of DBS on dysphagia. Objective To assess the swallowing and quality of life of individuals with PD before and after DBS surgery. Methods Our sample consisted of people who had undergone DBS surgery in a referral hospital in the state of Rio Grande do Sul, Brazil. The inclusion criteria were a diagnosis of PD and having undergone DBS surgery. A cognitive screening, through a questionnaire about depression and quality of life, was conducted. Evaluations of each patient's swallowing were performed before and after surgery. The assessment consisted of anamnesis, clinical assessment, the Functional Oral Intake Scale, clinical evaluation of swallowing, and the Hoehn and Yahr scale. Results The sample included 10 individuals, all male, with a mean age of 57.3 years (+/-4.7), a mean disease duration of 13.0 years (+/-2.4), and mean level education of 8.1 years (+/-4.0). In the clinical evaluation of the swallowing, a significant improvement after DBS was not observed. However, little changes in the signs and symptoms of dysphagia that had a positive impact on the quality of life were observed. Furthermore, there was no relation between the patients' motor subtype and swallowing pre- and post-DBS. Conclusion There was an improvement in the quality of life of the patients after DBS. However, the improvement in the clinical signs and symptoms of dysphagia did not cause an overall improvement in the swallowing function. PMID- 29619100 TI - Comparative Study Between Peristomal Patches in Patients with Definitive Tracheostomy. AB - Introduction To prevent or diminish pulmonary problems in laryngectomized patients, continuous use of a heat and moisture exchanger (HME) is recommended. Therefore, automatic speaking valves are also often combined with an HME to enable hands-free speech. In order to keep these devices in place, most commonly, peristomal patches are used. Objective This prospective clinical 2 * 2 crossover study aims at assessing the added value of a new patch for HME application, the Provox StabiliBase OptiDerm (SBO). The device combines the stable and conical base of the Provox StabiliBase with the skin-friendlier hydrocolloid Provox OptiDerm (OD) patch. Methods Thirty-two laryngectomized patients were included in this multicenter study. Participants were asked to compare SBO to OD, and to the patch they normally use. The primary outcome measure was patient preference. Results Overall, 60% of the participants had preference for their normally used patch, 23% preferred the SBO and 17% indicated no preference. When comparing the SBO to the OD, 43% preferred the SBO, 40% the OD and 17% had no preference. Conclusion Most patients preferred their normally used patch and SBO was favored by a subgroup. Provox StabiliBase OptiDerm seems to be a valuable addition to the existing patches and further increases patients' options for HME application. PMID- 29619101 TI - Frequency of Cervical Nodal Metastasis in Early-Stage Squamous Cell Carcinoma of the Tongue. AB - Introduction Oral cavity carcinoma is an aggressive tumor, with the tongue being one of the most common subsites of involvement. Surgery is a gold standard method of dealing with advanced-stage tumors. However, for early-stage carcinomas of the tongue, the management remains controversial. Several studies have indicated that early-stage cancers have a high chance of occult cervical node metastasis, which, if left untreated, can greatly affect the prognosis. Certain parameters can help identify patients with occult cervical node metastases, and can avoid unnecessary neck dissection in node negative patients. Tumor thickness is one such objective parameter. Objective To estimate the frequency of cervical lymph node metastasis in patients with early-stage, node-negative (N 0 ) squamous cell carcinoma of the tongue. Methods In-patient hospital data was reviewed from January 2013 until March 2014, and 78 patients who underwent primary resection of the tumor and neck dissection for biopsy-proven, early stage squamous cell carcinoma of the tongue were included. Data such as tumor thickness, tumor differentiation and presence of occult nodal metastasis in the surgical specimen were gathered from the histopathology reports. The frequency of subclinical cervical lymph node metastasis in patients with early-stage squamous cell carcinoma of the tongue was estimated. Results A total of 69% of the patients with tumor thicknesses > 5 mm had tumor metastases in the neck nodes, while 100% of the patients with tumor thicknesses < 5 mm had no neck nodal metastasis. Conclusion A tumor thickness > 5 mm is significantly associated with subclinical metastasis, and prophylactic neck dissection is warranted in such cases. PMID- 29619102 TI - Dynamic Slow Motion Video Endoscopy as an Adjunct to Impedance Audiometry in the Assessment of Eustachian Tube Function. AB - Introduction Eustachian tube (ET) dysfunction plays an important role not only in the pathophysiology of various middle ear disorders, but also in predicting the outcome of the treatment. As there is no single test that assesses both the anatomic and physiological functions of the ET, a combination of tympanometry and dynamic slow motion video endoscopy may improve the sensitivity of ET function assessment. Objective To find out if there is any correlation between dynamic slow motion nasal video endoscopy and impedance audiometry in assessing ET function in patients with middle ear diseases. Methods Ours was a descriptive study performed with 106 patients attending the Ear, Nose and Throat (ENT) Outpatient Department of a tertiary care center in South India with features suggestive of middle ear disease. All patients underwent impedance audiometry and dynamic slow motion nasal video endoscopy, and were graded based on the severity of the ET pathology. Results A total of 47 out of 97 patients with abnormal endoscopy findings also had abnormal impedance audiometry. The correlation was greater among the patients with higher grades of ET dysfunction. The endoscopy findings of 106 cases, when correlated with middle ear manometry, revealed that 56 cases showed complete agreement, and 50 cases showed disagreement. The nasal endoscopy results, when correlated with middle ear manometry studies by using McNemar's chi-squared (chi 2 ) test, showed a significant association between the 2 tests ( p = 0.017). Conclusion There is a significant alteration in middle ear pressure as the severity of the ET tube dysfunction increases. Impedance audiometry and nasal endoscopy provide a better measure of ET function. PMID- 29619103 TI - ENT Foreign Bodies: An Experience. AB - Introduction Ear, nose and throat (ENT) foreign bodies (FBs) are common occurrences, particularly among children. The proper recognition, study, and management of FBs are required to prevent complications. Their consequences are greatly variable, from mild disturbances that may not require hospitalization up to life-threatening complications. Objective To analyze the clinical spectrum of ENT FBs, the methods of removal, the outcomes and complications as seen in a tertiary referral hospital. Methods This hospital-based cross-sectional retrospective study was performed from July 2014 to June 2016. Patients with any type of ENT FBs, regardless of age, were included in the study; data was collected from 1,013 patients (572 males and 440 females) with a mean age of 12.5 years. Results Foreign bodies represented a large category among ENT emergencies (30%). Children were affected more frequently, particularly <= 6 years old. Swallowed FBs were the most common (53.6%), followed by aural FBs (24.68%), nasal FBs (19%), and inhaled FBs (2.6%). A total of 54.69% of ENT s were removed under general anesthesia (GA). Conclusion Foreign bodies (FB) in the ears, nose or throat are a common occurrence in otorhinolaryngology (ENT) emergency services. Children are the most affected age group. The commonest site of FB lodgment is in the throat. Ear, nose and throat FBs need to be properly managed to avoid complications. PMID- 29619104 TI - The Role of the Level of Interleukin-33 in the Therapeutic Outcomes of Immunotherapy in Patients with Allergic Rhinitis. AB - Introduction Allergic rhinitis (AR) affects up to 40% of the population and results in nasal itching, congestion, sneezing, and clear rhinorrhea. Objectives This study aimed to evaluate the changes in the clinical symptoms and in the level of serum interleukin (IL)-33 before and after pollen immunotherapy (IT) in patients with AR. Methods The total symptom score and the levels of total immunoglobulin E (IgE) and IL-33 were determined in the serum of 10 non-allergic healthy controls and 45 patients with AR who were equally divided into 3 groups: GI (patients did not receive IT), GII (patients had received IT for 6 months) and GIII (patients had received IT for 2 years). Results There was a significantly higher concentration of IgE and IL-33 in the serum of patients with AR than in that of non-allergic patients. Furthermore, serum level of IL-33 decreased significantly after pollen IT. But, there was no significant reduction in the serum level of IL-33 between GII and GIII patients. Conclusion Our results show a clinical improvement associated with a decrease in serum level of IL-33 after pollen IT. PMID- 29619105 TI - Assessment of Pulmonary Function before and after Sinus Surgery in Lung Transplant Recipients. AB - Introduction The association between sinus and lung diseases is well known. However, there are scarce studies regarding the effects of sinus surgery on pulmonary function in lung transplant recipients. The present study describes our experience with sinus surgery in lung transplant recipients with chronic rhinosinusitis. Objectives To assess the impact of sinus surgery for chronic rhinosinusitis on pulmonary function and on inpatient hospitalization days due to lower respiratory tract infection in lung transplant recipients. Methods A retrospective study conducted between 2006 and 2012 on a sample of lung transplant recipients undergoing sinus surgery for chronic rhinosinusitis. Pulmonary function, measured by forced vital capacity (FVC) and forced expiratory volume in the first second (FEV1), as well as inpatient hospitalization days due to lower respiratory tract infection, were compared 6 months before and 6 months after sinus surgery. Results The FEV1 values increased significantly, and the inpatient hospitalization days due to bronchopneumonia decreased significantly 6 months after sinus surgery. The preoperative and postoperative median FEV1 values were 2.35 and 2.68 respectively ( p = 0.0056 ). The median number of inpatient hospitalization days due to bronchopneumonia 6 months before and 6 months after surgery were 32.82 and 5.41 respectively ( p = 0.0013 ). Conclusion In this sample of lung transplant recipients with chronic rhinosinusitis, sinus surgery led to an improvement in pulmonary function and a decrease in inpatient hospitalization days due to bronchopneumonia. PMID- 29619106 TI - An Analysis of Anatomic Variations of the Sphenoid Sinus and Its Relationship to the Internal Carotid Artery. AB - Introduction The sphenoid sinus (SS) has a high variability; its anatomical relations and variations must be well understood prior to the expanded endoscopic surgery (EES) at the skull base via the endonasal transsphenoidal approach. A feared complication is injury to the internal carotid artery (ICA). Objective To evaluate the anatomic variations of the SS and its relationship to the ICA using computed tomography (CT). Methods Cross-sectional retrospective study. Analysis of 90 patients' CT scans on axial, coronal and sagittal planes with 1 mm slices, evaluating lateral and posterior extensions of pneumatization of the SS, deviation of the sphenoid septum, presence of septations and their relationship to the parasellar and paraclival segments of the internal carotid artery (psICA and pcICA, respectively). Results The association between the protrusions of the psICA and the pcICA was statistically significant ( p < 0.001), as was the association between the lateral extension of pneumatization of the SS and the protrusion of the psICA ( p = 0.014). The presence of the posterior extension of pneumatization of the SS and protrusion of the pcICA occurred in 46% of the cases. Deviation of the sphenoid septum in the direction of the pcICA was present in 14% and dehiscence of the pcICA was seen in 3.6% of the cases. Conclusion Using the CT scan to recognize the type of extensions of pneumatization of the SS, the deviation of the sphenoid septum, and the presence of septations is beneficial to identify accurately the ICA and to reduce the risk of injury to it. PMID- 29619107 TI - Unusual Presentation of Differentiated Thyroid Cancer Metastasis. AB - Introduction The rates of thyroid cancers are on a rise, especially well differentiated thyroid cancers. This could be partly due to newer diagnostic modalities, like high-resolution ultrasound, that can pick up smaller lesions. Differentiated thyroid cancers with distant metastases are not common, and even rarer is the initial presentation with complaints not related to the neck. Objectives The objective of this series was to study and report the unusual cases of patients with differentiated thyroid cancer with distant metastasis. There is a lack of data in the literature on these cases, and due to the rarity of such metastases, no definite treatment protocol has been defined. Methods A retrospective chart review of 1,200 cases of thyroid surgeries was performed. A total of 10 cases of well-differentiated thyroid cancer on the final histopathology exam that had initially presented with usual complaints to departments other than the Otolaryngology Department were identified. Results A total of 6 patients had papillary carcinoma, whereas 4 patients had follicular carcinoma on final the histopathology exam. Two patients presented with iliac crest lesions, 2 with vertebral lesions one each with parapharyngeal mass, supraclavicular mass, labia majora swelling and bleeding, lung, rib and neck of femur lesion. Conclusion There are still no specific guidelines on how to address these patients with differentiated thyroid cancer with distant metastasis (except for the cases of bone and lung lesions) and on which treatment should be offered in case of recurrence. More studies on the subject are required. PMID- 29619108 TI - The Effects of Experimental Intratympanic Steroid Administration on Organ of Corti Type 1 Spiral Ganglion. AB - Introduction It is unclear how effective is the intratympanic (IT) steroid treatment on organ of Corti type 1 spiral ganglion, its optimal dosage and frequency of administration. The effect of dexamethasone on cochlear functions in individuals with a normal hearing ability is also unknown. Objective The aim of this study was to evaluate, at the electrophysiological and ultrastructural levels, the effect of IT dexamethasone administration in guinea pigs with normal hearing on organ of Corti type 1 spiral ganglion. Methods A total of 20 guinea pigs ( n = 40 ears) whose hearing was detected to be normal by electrophysiological tests were included in the study and randomly divided into 6 groups. Four groups were considered study groups, while 2 groups were considered control groups. Dexamethasone was administered intratympanically in doses of 2 mg/mL and 4 mg/mL in the guinea pigs in the study groups. The animals in the control groups received physiological saline in equal doses as the study groups. All interventions were performed under general anesthesia, and the electrophysiological tests were repeated following the IT injections. Results No statistically significant differences were found among the groups when the IT injections were evaluated in terms of the electrophysiological measurements ( p > 0.05). The ultrastructural evaluation showed a cellular mitochondrial increase in the spiral ganglions of the cochlea in the groups in which dexamethasone was administered in a dose of 4 mg/mL. Conclusion According to the findings of this study, it can be suggested that the IT injection of dexamethasone is safe, and when applied in a dose of 4 mg/mL, it increases metabolic activity at the cellular level. PMID- 29619109 TI - Polysomnography Applied to Patients with Tinnitus: A Review. AB - Introduction Tinnitus has been defined as an "auditory phantom perception," meaning that tinnitus results from an abnormal activity within the nervous system, in the absence of any internal or external acoustic stimulation. About 10 to 15% of the adult population is affected by tinnitus, and a relevant percentage of tinnitus sufferers experience symptoms severe enough to significantly affect quality of life, including sleep disturbances, work impairment, and, in some cases, psychiatric distress. The self-rated complaints about tinnitus focus on emotional distress, auditory perceptual difficulties, and sleep disturbances. Objectives To evaluate the works that show sleep disorders in patients with tinnitus, and sleep disorders assessed by polysomnography. Data Synthesis We found four studies with polysomnography to assess sleep disorders in patients with tinnitus. The first study evaluated 80 patients who were military personnel without major psychiatric disturbances, and their tinnitus was associated with noise-induced permanent hearing. The second study was a prospective, case control, nonrandomized study of 18 patients affected by chronic tinnitus who were compared with a homogeneous control group consisting of 15 healthy subjects. The last work evaluated questionnaires mailed to patients before their initial appointment at the Oregon Health Sciences University Tinnitus Clinic between 1994 and 1997. These questionnaires requested information pertaining to insomnia, tinnitus severity, and loudness. Follow-up questionnaires were mailed to 350 patients 1 to 4 years (mean 5 +/- 2.3 years) after their initial appointment at the clinic. Conclusion There are few studies with polysomnography for the evaluation of patients with sleep disorders caused by tinnitus. This shows the need for more studies on this subject. PMID- 29619110 TI - Comparison of Bite Force with Locking Plates versus Non-Locking Plates in the Treatment of Mandibular Fractures: A Meta-Analysis. AB - Introduction Mandibular fractures represent a high percentage of all facial fractures, and the bite force is a fundamental parameter to measure the actual mandibular function and, subsequently, the masticatory efficiency and quality of life. Objectives The purpose of the present systematic review was to verify if there is any difference in the bite forces of patients with mandibular fractures fixed by locking or non-locking plates, testing the null hypothesis of no difference in this parameter. Data Synthesis A systematic review of the literature was conducted using four databases (PubMed, Virtual Health Library, Web of Science and Science Direct) without restrictions as to publication date or language. We found 3,039 abstracts, and selected 4 articles for this review. Conclusion The overall results show better performance in bite force for the locking plates when compared with the non-locking plates in the incisor region (mean deviation [MD]: 1.18; 95% confidence interval [95%CI]: 0.13-2.23), right molar region (MD: 4.71; 95%CI: 0.63-8.79) and left molar region (MD: 10.34; 95%CI: 4.55-16.13). Although the results of this study indicated a better bite force result with the locking plates, there is still no sufficient evidence to support this information safely. PMID- 29619112 TI - An Empirical Bayes Approach for Methylation Differentiation at the Single Nucleotide Resolution. AB - DNA methylation is an important epigenetic phenomenon that is associated with a variety of diseases, particularly cancers. Recent development of high throughput sequencing technology has enabled researchers to investigate the methylation rate at a single nucleotide resolution for any given sample. Testing for methylation rate equality or difference between two samples, however, is challenged by the small sample size observed at many sites across the genome. Fisher's exact test is typically used in this situation; however, it is conservative and it cannot be used to test for specific difference in methylation rate between two samples. In this paper, we propose an empirical Bayes approach that utilizes the genome-wide data as prior information for methylation differentiation between two samples. We show that this new approach is more powerful than Fisher's exact test. In addition, it can be used to test for any specific methylation difference while controlling the false discovery rate (FDR). The new method is applied to a real data set from a colon tumor study. PMID- 29619111 TI - Intratympanic Gentamicin for Intractable Meniere's Disease - A Review and Analysis of Audiovestibular Impact. AB - Introduction Intratympanic gentamicin regulates the symptoms in most patients with incapacitating Meniere's disease. The treatment protocols have changed over the years from medical labyrinthectomy to preservation of vestibular function. Objectives This study aims to review the audiovestibular response related to the effect of the drug in controlling vertigo. Data Synthesis Articles were identified by means of a search in the PubMed database using the key words Meniere and intratympanic or transtympanic gentamicin . Total 144 articles were reviewed after excluding those that were technical reports, those based on experimental animal studies, those that focused on outcomes other than vertigo (tinnitus or aural fullness), those with delivery methods other than tympanic membrane injection, and those with bilateral cases. If there was more than one article by the same author(s) or institution, only the most recent one matching the aforementioned criteria and those that were not overlapping were included. Conclusion Titration methods or multiple injections on a daily basis can be preferred if the patients have profound or non-serviceable hearing, since these methods have significant incidence of hearing loss. Treatment protocols with a frequency of injection not shorter than once a week, or those with injections on a monthly basis as "needed" provide the same level of vertigo control with better preservation of hearing. Caloric testing is not an ideal tool to analyze the correlation between vertigo control and the effect of gentamicin as compared with gain asymmetry of the vestibulo-ocular reflex. Vestibular-evoked myogenic potentials and the head thrust test are more reliable than other vestibular tests for the follow-up of patients undergoing gentamicin treatment. PMID- 29619113 TI - Analysis of circulating angiopoietin-like protein 3 and genetic variants in lipid metabolism and liver health: the DiOGenes study. AB - Background: Angiopoietin-like protein 3 (ANGPTL3), a liver-derived protein, plays an important role in the lipid and lipoprotein metabolism. Using data available from the DiOGenes study, we assessed the link with clinical improvements (weight, plasma lipid, and insulin levels) and changes in liver markers, alanine aminotransferase, aspartate aminotransferase (AST), adiponectin, fetuin A and B, and cytokeratin 18 (CK-18), upon low-calorie diet (LCD) intervention. We also examined the role of genetic variation in determining the level of circulating ANGPTL3 and the relation between the identified genetic markers and markers of hepatic steatosis. Methods: DiOGenes is a multicenter, controlled dietary intervention where obese participants followed an 8-week LCD (800 kcal/day, using a meal replacement product). Plasma ANGPTL3 and liver markers were measured using the SomaLogic (Boulder, CO) platform. Protein quantitative trait locus (pQTL) analyses assessed the link between more than four million common variants and the level of circulating ANGPTL3 at baseline and changes in levels during the LCD intervention. Results: Changes in ANGPTL3 during weight loss showed only marginal association with changes in triglycerides (nominal p = 0.02) and insulin (p = 0.04); these results did not remain significant after correcting for multiple testing. However, significant association (after multiple-testing correction) were observed between changes in ANGPTL3 and AST during weight loss (p = 0.004) and between ANGPTL3 and CK-18 (baseline p = 1.03 * 10-7, during weight loss p = 1.47 * 10-13). Our pQTL study identified two loci significantly associated with changes in ANGPTL3. One of these loci (the APOA4-APOA5-ZNF259-BUD13 gene cluster) also displayed significant association with changes in CK-18 levels during weight loss (p = 0.007). Conclusion: We clarify the link between circulating levels of ANGPTL3 and specific markers of liver function. We demonstrate that changes in ANGPLT3 and CK-18 during LCD are under genetic control from trans-acting variants. Our results suggest an extended function of ANGPTL3 in the inflammatory state of liver steatosis and toward liver metabolic processes. PMID- 29619115 TI - Cirrus cloud optical and microphysical property retrievals from eMAS during SEAC4RS using bi-spectral reflectance measurements within the 1.88 MUm water vapor absorption band. AB - Previous bi-spectral imager retrievals of cloud optical thickness (COT) and effective particle radius (CER) based on the Nakajima and King (1990) approach, such as those of the operational MODIS cloud optical property retrieval product (MOD06), have typically paired a non-absorbing visible or near-infrared wavelength, sensitive to COT, with an absorbing shortwave or midwave infrared wavelength sensitive to CER. However, in practice it is only necessary to select two spectral channels that exhibit a strong contrast in cloud particle absorption. Here it is shown, using eMAS observations obtained during NASA's SEAC4RS field campaign, that selecting two absorbing wavelength channels within the broader 1.88 MUm water vapor absorption band, namely the 1.83 and 1.93 MUm channels that have sufficient differences in ice crystal single scattering albedo, can yield COT and CER retrievals for thin to moderately thick single layer cirrus that are reasonably consistent with other solar and IR imager-based and lidar-based retrievals. A distinct advantage of this channel selection for cirrus cloud retrievals is that the below-cloud water vapor absorption minimizes the surface contribution to measured cloudy TOA reflectance, in particular compared to the solar window channels used in heritage retrievals such as MOD06. This reduces retrieval uncertainty resulting from errors in the surface reflectance assumption, as well as reduces the frequency of retrieval failures for thin cirrus clouds. PMID- 29619114 TI - Omega-3 fatty acid DHA modulates p53, survivin, and microRNA-16-1 expression in KRAS-mutant colorectal cancer stem-like cells. AB - Background: The presence of chemotherapy-resistant colorectal cancer stem cells (CCSCs) with KRAS mutation is thought to be one of the primary causes for treatment failure in colorectal cancer (CRC). P53, survivin, and microRNA-16-1 are challenging targets for anticancer drugs which are associated with chemoresistance in CRC. Yet, no p53-, survivin-, and microRNA-16-1-modulating drug with low toxicity but high efficacy against KRAS-mutant CCSCs have been approved for clinical application in CRC. Here, we investigated whether in vitro concentrations of DHA equal to human plasma levels, are able to modulate, Wt-p53, survivin, and microRNA-16-1 in CRC cells with stem cell-like properties. Methods: Wt-p53/KRAS-mutant CRC cells (HCT-116) with stem cell-like properties were treated with 100-, 150- and 200-MUM/L DHA, after which cell number, viability, growth inhibition, Wt-p53, survivin and microRNA-16-1 expression, caspase-3 activation and apoptotic-rate were evaluated by different cellular and molecular techniques. Results: After 24-, 48-, and 72-h treatments with 100- to 200-MUM/L DHA, growth inhibition- rates were measured to be 54.7% to 59.7%, 73.% to 75.8%, and 63.3% to 97.7%, respectively. Treatment for 48 h with indicated DHA concentrations decreased cell number and viability. In addition, we observed a decrease in both the transcript and protein levels of survivin followed by 1.3- to 1.7- and 1.1- to 4.7-fold increases in the Wt-p53 accumulation and caspase-3 activation levels respectively. Treatment with 100 and 150 MUM/L DHA increased microRNA-16-1 expression levels by 1.3- to 1.7-fold and enhanced the microRNA-16 1/survivin mRNA, p53/survivin, and caspase-3/survivin protein ratios by 1.7- to 1.8-, 1.3- to 2.6-, and 1.3- to 2-fold increases respectively. A decrease in the number of live cells and an increase in the number of apoptotic cells were also observed with increasing DHA concentrations. Conclusion: Wt-p53, survivin, and microRNA-16-1 appear to be promising molecular targets of DHA. Thus, DHA might represent an attractive anti-tumor agent directed against KRAS-mutant CCSCs. PMID- 29619116 TI - Uncertainties in cloud phase and optical thickness retrievals from the Earth Polychromatic Imaging Camera (EPIC). AB - This paper presents an investigation of the expected uncertainties of a single channel cloud optical thickness (COT) retrieval technique, as well as a simple cloud temperature threshold based thermodynamic phase approach, in support of the Deep Space Climate Observatory (DSCOVR) mission. DSCOVR cloud products will be derived from Earth Polychromatic Imaging Camera (EPIC) observations in the ultraviolet and visible spectra. Since EPIC is not equipped with a spectral channel in the shortwave or mid-wave infrared that is sensitive to cloud effective radius (CER), COT will be inferred from a single visible channel with the assumption of appropriate CER values for liquid and ice phase clouds. One month of Aqua MODIS daytime granules from April 2005 is selected for investigating cloud phase sensitivity, and a subset of these granules that has similar EPIC sun-view geometry is selected for investigating COT uncertainties. EPIC COT retrievals are simulated with the same algorithm as the operational MODIS cloud products (MOD06), except using fixed phase-dependent CER values. Uncertainty estimates are derived by comparing the single channel COT retrievals with the baseline bi-spectral MODIS retrievals. Results show that a single channel COT retrieval is feasible for EPIC. For ice clouds, single channel retrieval errors are minimal (< 2%) due to the particle size insensitivity of the assumed ice crystal (i.e., severely roughened aggregate of hexagonal columns) scattering properties at visible wavelengths, while for liquid clouds the error is mostly limited to within 10%, although for thin clouds (COT < 2) the error can be higher. Potential uncertainties in EPIC cloud masking and cloud temperature retrievals are not considered in this study. PMID- 29619117 TI - Instrumentation and Measurement Strategy for the NOAA SENEX Aircraft Campaign as Part of the Southeast Atmosphere Study 2013. AB - Natural emissions of ozone-and-aerosol-precursor gases such as isoprene and monoterpenes are high in the southeast of the US. In addition, anthropogenic emissions are significant in the Southeast US and summertime photochemistry is rapid. The NOAA-led SENEX (Southeast Nexus) aircraft campaign was one of the major components of the Southeast Atmosphere Study (SAS) and was focused on studying the interactions between biogenic and anthropogenic emissions to form secondary pollutants. During SENEX, the NOAA WP-3D aircraft conducted 20 research flights between 27 May and 10 July 2013 based out of Smyrna, TN. Here we describe the experimental approach, the science goals and early results of the NOAA SENEX campaign. The aircraft, its capabilities and standard measurements are described. The instrument payload is summarized including detection limits, accuracy, precision and time resolutions for all gas-and-aerosol phase instruments. The inter-comparisons of compounds measured with multiple instruments on the NOAA WP 3D are presented and were all within the stated uncertainties, except two of the three NO2 measurements. The SENEX flights included day- and nighttime flights in the Southeast as well as flights over areas with intense shale gas extraction (Marcellus, Fayetteville and Haynesville shale). We present one example flight on 16 June 2013, which was a daytime flight over the Atlanta region, where several crosswind transects of plumes from the city and nearby point sources, such as power plants, paper mills and landfills, were flown. The area around Atlanta has large biogenic isoprene emissions, which provided an excellent case for studying the interactions between biogenic and anthropogenic emissions. In this example flight, chemistry in and outside the Atlanta plumes was observed for several hours after emission. The analysis of this flight showcases the strategies implemented to answer some of the main SENEX science questions. PMID- 29619118 TI - Epigenetic modifications in KDM lysine demethylases associate with survival of early-stage NSCLC. AB - Background: KDM lysine demethylase family members are related to lung cancer clinical outcomes and are potential biomarkers for chemotherapeutics. However, little is known about epigenetic alterations in KDM genes and their roles in lung cancer survival. Methods: Tumor tissue samples of 1230 early-stage non-small cell lung cancer (NSCLC) patients were collected from the five independent cohorts. The 393 methylation sites in KDM genes were extracted from epigenome-wide datasets and analyzed by weighted random forest (Ranger) in discovery phase and validation dataset, respectively. The variable importance scores (VIS) for the sites in top 5% of both discovery and validation sets were carried forward for Cox regression to further evaluate the association with patient's overall survival. TCGA transcriptomic data were used to evaluate the correlation with the corresponding DNA methylation. Results: DNA methylation at sites cg11637544 in KDM2A and cg26662347 in KDM1A were in the top 5% of VIS in both discovery phase and validation for squamous cell carcinomas (SCC), which were also significantly associated with SCC survival (HRcg11637544 = 1.32, 95%CI, 1.16-1.50, P = 1.1 * 10 4; HRcg26662347 = 1.88, 95%CI, 1.37-2.60, P = 3.7 * 10-3), and correlated with corresponding gene expression (cg11637544 for KDM2A, P = 1.3 * 10-10; cg26662347 for KDM1A P = 1.5 * 10-5). In addition, by using flexible criteria for Ranger analysis followed by survival classification tree analysis, we identified four clusters for adenocarcinomas and five clusters for squamous cell carcinomas which showed a considerable difference of clinical outcomes with statistical significance. Conclusions: These findings highlight the association between somatic DNA methylation in KDM genes and early-stage NSCLC patient survival, which may reveal potential epigenetic therapeutic targets. PMID- 29619120 TI - Preoperative Ultrasonographic Evaluation for Malignancy of Soft-Tissue Sarcoma: A Retrospective Study. AB - Background: Ultrasonography is useful for distinguishing between benign and malignant soft-tissue tumors. However, no study has focused on its usefulness in the differential diagnosis between low-grade and high-grade soft-tissue sarcomas. We conducted a retrospective study to determine the usefulness of the parameters of ultrasonograph and to develop a practical scoring system for distinguishing between high-grade and low-grade sarcomas. Methods: Twenty-two cases of low-grade and 43 cases of high-grade malignant soft-tissue sarcoma were enrolled. Ultrasonography parameters including the longest diameter, depth of the tumor, echogenicity, tumor margin, and vascularity defined according to Giovagnorio's criteria were analyzed as factors to distinguish between the two types of sarcoma. Significant factors were entered into a multivariate model to define the scores for distinction according to the odds ratio. The usefulness of the score was analyzed via receiver operating characteristic analyses. Results: In univariate analysis, tumor margin, echogenicity, and vascularity were significantly different between low- and high-grade sarcomas. In the multivariate regression model, the odds ratio for high-grade vs. low-grade sarcoma was 8.8 for tumor margin, 69 for echogenicity, and 8.3 for vascularity. Scores for the risk factors were defined as follows: 1, ill-defined margin; 2, hypoechoic echogenicity; and 1, type IV in Giovagnorio's criteria. The sum of each score was confirmed by receiver operating characteristic analysis. The area under the curve was 0.95, with a cut-off score of 3, indicating that the scoring system was useful. Conclusion: The ultrasonography parameters of tumor margin, echogenicity, and vascularity are useful for distinguishing between low- and high-grade sarcomas. PMID- 29619119 TI - Dynamics of DNMT3A mutation and prognostic relevance in patients with primary myelodysplastic syndrome. AB - Background: DNMT3A gene mutation has been associated with poor prognosis in acute myeloid leukemia, but its clinical implications in myelodysplastic syndrome (MDS) and dynamic changes during disease progression remain controversial. Results: In this study, DNMT3A mutation was identified in 7.9% of 469 de novo MDS patients. DNMT3A-mutated patients had higher platelet counts at diagnosis, and patients with ring sideroblasts had the highest incidence of DNMT3A mutations, whereas those with multilineage dysplasia had the lowest incidence. Thirty-one (83.8%) of 37 DNMT3A-mutated patients had additional molecular abnormalities at diagnosis, and DNMT3A mutation was highly associated with mutations of IDH2 and SF3B1. Patients with DNMT3A mutations had a higher risk of leukemia transformation and shorter overall survival. Further, DNMT3A mutation was an independent poor prognostic factor irrespective of age, IPSS-R, and genetic alterations. The sequential study demonstrated that the original DNMT3A mutations were retained during follow-ups unless allogeneic hematopoietic stem cell transplantation was performed, while DNMT3A mutation was rarely acquired during disease progression. Conclusions: DNMT3A mutation predicts unfavorable outcomes in MDS and was stable during disease evolutions. It may thus be a potential biomarker to predict prognosis and monitor the treatment response. PMID- 29619121 TI - Intra-articular Fracture of the Distal part of the Triquetrum within the Pisotriquetral Joint: Case Report and Review of Literature. AB - Background: Intra-articular fractures of the distal part of the triquetrum within the pisotriquetral joint are uncommon, and can be associated with tears of the dorsal carpal ligaments, pisiform subluxation and/or FCU dislocation. Their diagnosis is difficult and requires a high clinical suspicion and a proper radiological examination including oblique wrist x-rays, computed tomography and MRI scan. These fractures can be delayed diagnosed due to late presentation thus leading to painful nonunion, persistent instability and late pisotriquetral arthritis. Case Report: We present a case of a 40-year-old male who complained about ulnarsided wrist pain after a fall on his extended wrist during bicycling. The diagnosis of triquetrum fracture was suspected on clinical examination and confirmed using standard and oblique radiographs and CT scan evaluation. He was immobilized in a short-arm cast for 6 weeks followed by a progressive return to wrist motion and subsequent strengthening for another 5 weeks. He reported complete resolution of pain and excellent wrist motion and function one year after the injury, demonstrating a Mayo score of 100. Conclusion: Isolated intra articular fractures of the triquetrum within the pisotriquetral joint are rare injuries and may constitute a subcategory of body fractures other than the dorsal cortical (chip), main body and volar lip avulsion fractures. Early clinical suspicion and proper imagine can lead to a successful outcome. PMID- 29619122 TI - Cervicothoracic Lordosis Can Influence Outcome After Posterior Cervical Spine Surgery. AB - Background: Previous studies on the correlation between cervical sagittal balance with improvement in quality of life showed significant results only for parameters of the anterior translation of the cervical spine (such as C2-C7 SVA). Objective: We test whether a new parameter, cervicothoracic lordosis, can predict clinical success in this type of surgery. Methods: The focused group involved patients who underwent surgical treatment of cervical degenerative disk disease by the posterior approach, due to myelopathy, radiculopathy or a combination of both. Neurologic deficit was measured before and after surgery with the Nurick Scale, postoperative quality of life, physical and mental components of SF-36 and NDI. Cervicothoracic lordosis and various sagittal balance parameters were also measured. Cervicothoracic lordosis was defined as the angle between: a) the line between the centroid of C2 and the centroid of C7; b) the line between the centroid of C7 and the centroid of T6. Correlations between postoperative quality of life and sagittal parameters were calculated. Results: Twenty-nine patients between 27 and 78 years old were evaluated. Surgery types were simple decompression (laminectomy or laminoforaminotomy) (3 patients), laminoplasty (4 patients) and laminectomy with fusion in 22 patients. Significant correlations were found for C2-C7 SVA and cervicothoracic lordosis. C2-C7 SVA correlated negatively with MCS (r=-0.445, p=0.026) and PCS (r=-0.405, p=0.045). Cervicothoracic lordosis correlated positively with MCS (r=0.554, p= 0.004) and PCS (r=0.462, p=0.020) and negatively with NDI (r=-0.416, p=0.031). Conclusion: The parameter cervicothoracic lordosis correlates with improvement of quality life after surgery for cervical degenerative disk disease by the posterior approach. PMID- 29619123 TI - Short-term Clinical Results of Manipulation Under Ultrasound-Guided Brachial Plexus Block in Patients with Idiopathic Frozen Shoulder and Diabetic Secondary Frozen Shoulder. AB - Purpose: This study examined the effectiveness of manipulation under ultrasound guided brachial plexus block in patients with recalcitrant idiopathic frozen shoulder and diabetic secondary frozen shoulder (diabetic frozen shoulder). Methods: Forty-four idiopathic frozen shoulders and 10 diabetic frozen shoulders with failed conservative treatment for at least 3 months were included in this study. The manipulation was performed under ultrasound-guided brachial plexus block and visual analogue scale, range of motion, and Constant scores were measured before manipulation and at the last follow-up examination. Results: No major complications were observed during the procedure. Sufficient improvement was not obtained in two patients during the procedure and to avoid complications, the procedure was discontinued and subsequently arthroscopic capsular release was performed. Visual analogue scale, range of motion towards all directions, and Constant scores were significantly improved after the manipulation in both the idiopathic frozen shoulder and diabetic frozen shoulder groups, however the diabetic group showed inferior results compared with those of the idiopathic group. Conclusion: This manipulation was effective and shortened the duration of symptoms in most of the idiopathic and diabetic frozen shoulders without major complications during the procedure. Diabetic frozen shoulder showed inferior clinical results and difficulty in recovery in range of motion, which indicated that diabetic frozen shoulder should be discussed as a different entity. PMID- 29619124 TI - The Value of Phenotypes in Knee Osteoarthritis Research. AB - Background: Over the past decade, phenotypes have been used to help categorize knee osteoarthritis patients relative to being subject to disease, disease progression, and treatment response. A review of potential phenotype selection is now appropriate. The appeal of using phenotypes is that they most rely on simple physical examination, clinically routine imaging, and demographics. The purpose of this review is to describe the panoply of phenotypes that can be potentially used in osteoarthritis research. Methods: A search of PubMed was used singularly to review the literature on knee osteoarthritis phenotypes. Results: Four phenotype assembly groups were based on physical features and noninvasive imaging. Demographics included metabolic syndrome (dyslipidemia, hypertension, obesity, and diabetes). Mechanical characteristics included joint morphology, alignment, the effect of injury, and past and present history. Associated musculoskeletal disorder characteristics included multiple joint involvement, spine disorders, neuromuscular diseases, and osteoporosis. With the knee as an organ, tissue characteristics were used to focus on synovium, meniscus, articular cartilage, patella fat pad, bone sclerosis, bone cysts, and location of pain. Discussion: Many of these phenotype clusters require further validation studies. There is special emphasis on knee osteoarthritis phenotypes due to its predominance in osteoarthritic disorders and the variety of tissues in that joint. More research will be required to determine the most productive phenotypes for future studies. Conclusion: The selection and assignment of phenotypes will take on an increasing role in osteoarthritis research in the future. PMID- 29619125 TI - Accuracy of a Self-monitoring Test for Identification and Monitoring of Age related Macular Degeneration: A Diagnostic Case-control Study. AB - Objective: To evaluate diagnostic accuracy of a new self-monitoring device using a Vernier hyperacuity alignment task. Method: A total of 11 wet Age-Related Macular Degeneration (AMD) patients and 9 controls contributing 37 eyes were consecutively enrolled into this prospective diagnostic case-control study at the retina centre of the Cantonal Hospital Lucerne, Switzerland. Vernier acuity testing (index test) and Optical Coherence Tomography (OCT, reference test) were performed in all participants. OCT scans were evaluated and graded by a retinal specialist masked to diagnosis and index test results. Candidate parameters of the index test to be used as the diagnostic statistic were identified using a bootstrap procedure. Ten parameters remaining were further assessed in univariate analyses. The overall Standard Deviation (SD) of absolute distances across all four axes of the Vernier acuity test provided the highest area under the Receiver Operating Characteristics (ROC) curve and was therefore selected. Results: Mean age of patients with wet AMD was 81.2 years (SD 4.99), mean numbers of letters were 67.4 (SD 14.1). The proportion of women was similar in both groups (controls: 88%, wet AMD: 72%). The area under the ROC curve was 0.87 (95% confidence interval CI: 0.75- 0.99) indicating excellent discrimination. Best accuracy was reached at a cut-off value of 0.64 with a sensitivity of 75% and a specificity of 94%. Conclusion: This diagnostic case-control study of a new screening device for AMD shows acceptable diagnostic accuracy. The promising preliminary data of this study call for further upstream evaluations in reasonably sized clinical studies. PMID- 29619126 TI - Effects of Early-Life Stress on Social and Anxiety-Like Behaviors in Adult Mice: Sex-Specific Effects. AB - Stressful events in an early postnatal period have critical implications for the individual's life and can increase later risk for psychiatric disorders. The aim of this study was to investigate the influence of early-life stress on the social behavior of adult male and female mice. C57Bl/6 mice were exposed to maternal separation (MS, 3 h once a day) or handling (HD, 15 min once a day) on postnatal day 2 through 14. Adult male and female mice were tested for social behavior in the social interaction test and for individual behavior in the plus-maze and open field tests. Female mice exposed to maternal separation had increased social behavior and increased anxiety. MS male mice had no changes in social behavior but had significantly disrupted individual behavior, including locomotor and exploratory activity. Handling had positive effects on social behavior in males and females and decreased anxiety in males. Our results support the hypothesis that brief separation of pups from their mothers (handling), which can be considered as moderate stress, may result in future positive changes in behavior. Maternal separation has deleterious effects on individual behavior and significant sex-specific effects on social behavior. PMID- 29619127 TI - Clinical Significance and Biological Role of HuR in Head and Neck Carcinomas. AB - Background: Hu-antigen R (HuR) is a posttranscriptional regulator of several target mRNAs, implicated in carcinogenesis. This review aims to present the current evidence regarding the biological role and potential clinical significance of HuR in head and neck carcinomas. Methods: The existing literature concerning HuR expression and function in head and neck carcinomas is critically presented and summarised. Results: HuR is expressed in the majority of the examined samples, showing higher cytoplasmic levels in malignant or premalignant cases. Moreover, HuR modulates several genes implicated in biological processes important for malignant transformation, growth, and invasiveness. HuR seems to be an adverse prognosticator in patients with OSCCs, whereas a correlation with a more aggressive phenotype is reported in several types of carcinomas. Conclusions: A consistent role of HuR in the carcinogenesis and progression of head and neck carcinomas is suggested; nevertheless, further studies are warranted to expand the present information. PMID- 29619128 TI - The Pathophysiological Mechanisms and the Quest for Biomarkers in Psoriasis, a Stress-Related Skin Disease. AB - Psoriasis is a physically, emotionally, and socially invalidating multifactorial disorder, with a significant impact on the patients' quality of life. Stress is one of the leading triggers for psoriasis and has been associated with disease onset and subsequent flare-ups, while the flare-ups by themselves often lead to psychological discomfort. The treatment of psoriasis is individualized, depending on the patients' measurable severity of illness, as well as the impact the skin condition has on patients' quality of life, as assessed by standardized questionnaires. The clinical scales used nowadays for measuring the severity of psoriasis are characterized by low reproducibility and high variability between examiners. Hence, there is a real need to identify objectively measurable biomarkers to standardize the assessment of the severity of psoriasis. We aim to review the pathophysiological mechanisms involved in psoriasis, focusing on the most critical advances in psoriasis biomarker discovery, pointing out those biomarkers which have also been studied in other stress-related conditions, thus emphasizing the relationship between psoriasis and stress. PMID- 29619129 TI - Sickle Cell Anemia Patients in Use of Hydroxyurea: Association between Polymorphisms in Genes Encoding Metabolizing Drug Enzymes and Laboratory Parameters. AB - This study investigated associations between SNPs in genes encoding metabolizing drug enzymes and laboratory parameters in sickle cell anemia patients under hydroxyurea (SCA-HU+). We evaluated hematologic and biochemical parameters by electronic methods and SNPs by PCR-RFLP and multiplex PCR in 35 SCA-HU+ patients and 67 SCA-HU- patients. The HbS, total cholesterol, lactate dehydrogenase, aspartate aminotransferase, total bilirubin and fractions levels, and leukocyte, eosinophil, monocyte, and erythroblast counts were reduced in SCA-HU+ patients (p < 0.05). Moreover, they presented higher HbF, C-reactive protein, and ferritin levels and elevated MCH and MCV values (p < 0.05). Genotype frequencies of variants GA + AA of MPO -463G>A and c1c2 + c2c2 of CYP2E1 -1293G>C/-1053C>T were higher in SCA-HU+ patients (p < 0.05). Independent associations were found between the variant A allele and lower total cholesterol, between c2 allele and low alpha-1 antitrypsin and between the null GSTT1 variant and high indirect and total bilirubin in SCA-HU+ patients. In SCA-HU- patients, independent associations were found between the variant A allele and high uric acid and between c2 allele and high urea. Our results suggest that SNPs MPO -463G>A, CYP2E1 -1293G>C/-1053C>T, and GSTT1 can be associated with alterations in lipid, inflammatory, renal, hemolytic, and hepatic profiles. However, further studies are needed to elucidate these associations. PMID- 29619130 TI - Copeptin as a Prognostic Marker in Acute Chest Pain and Suspected Acute Coronary Syndrome. AB - Background: In patients admitted with chest pain and suspected acute coronary syndrome (ACS), it is crucial to early identify those who are at higher risk of adverse events. The study aim was to assess the predictive value of copeptin in patients admitted to the emergency department with chest pain and nonconclusive ECG. Methods: Consecutive patients suspected for an ACS were enrolled prospectively. Copeptin and high-sensitive troponin T (hs-TnT) were measured at admission. Patients were followed up at six and 12 months for the occurrence of death and major adverse cardiac and cerebrovascular events (MACCE). Results: Among 154 patients, 11 patients died and 26 experienced MACCE. Mortality was higher in copeptin-positive than copeptin-negative patients with no difference in the rate of MACCE. Copeptin reached the AUC 0.86 (0.75-0.97) for prognosis of mortality at six and 0.77 (0.65-0.88) at 12 months. It was higher than for hs-TnT and their combination at both time points. Copeptin was a strong predictor of mortality in the Cox analysis (HR14.1 at six and HR4.3 at 12 months). Conclusions: Copeptin appears to be an independent predictor of long-term mortality in a selected population of patients suspected for an ACS. The study registration number is ISRCTN14112941. PMID- 29619131 TI - Maintenance of intestinal homeostasis by mucosal barriers. AB - Background: The intestine is inhabited by a tremendous number of microorganisms, which provide many benefits to nutrition, metabolism and immunity. Mucosal barriers by intestinal epithelial cells make it possible to maintain the symbiotic relationship between the gut microbiota and the host by separating them. Recent evidence indicates that mucosal barrier dysfunction contributes to the development of inflammatory bowel disease (IBD). In this review, we focus on the mechanisms by which mucosal barriers maintain gut homeostasis. Main text: Gut mucosal barriers are classified into chemical and physical barriers. Chemical barriers, including antimicrobial peptides (AMPs), are chemical agents that attack invading microorganisms, and physical barriers, including the mucus layer and the cell junction, are walls that physically repel invading microorganisms. These barriers, which are ingeniously modulated by gut microbiota and host immune cells, spatially segregate gut microbiota and the host immunity to avoid unnecessary immune responses to gut commensal microbes. Therefore, mucosal barrier dysfunction allows gut bacteria to invade gut mucosa, inducing excessive immune responses of the host immune cells, which result in intestinal inflammation. Conclusion: Gut mucosal barriers constructed by intestinal epithelial cells maintain gut homeostasis by segregating gut microbiota and host immune cells. Impaired mucosal barrier function contributes to the development of IBD. However, the mechanism by which the mucosal barrier is regulated by gut microbiota remains unclear. Thus, it should be further elucidated in the future to develop a novel therapeutic approach to IBD by targeting the mucosal barrier. PMID- 29619133 TI - Development and validation of a survey instrument to measure factors that influence pharmacist adoption of prescribing in Alberta, Canada. AB - Objective: Study objectives were to develop a questionnaire to assess factors influencing pharmacists' adoption of prescribing (i.e., continuing, adapting or initiating therapy), describe use of pre-incentive and mixed mode survey, and establish survey psychometric properties. Methods: Questions were developed based on prior qualitative research and Diffusion of Innovation theory. Expert review, cognitive testing, survey pilot, and main survey were used to test the questionnaire. Six content experts reviewed the questionnaire to establish face and content validity. Ten pharmacists from diverse practice settings were purposefully recruited for a cognitive interview to verify question readability. Content analysis was used to analyze the results. A pre-survey introduction letter with a monetary incentive was mailed via post to 100 (i.e. pilot) and 700 (i.e., main survey) randomly selected pharmacists. This was followed by an e-mail with a personalized link to the online questionnaire, e-mail reminders, and a telephone reminder if required. The psychometric properties of scales were evaluated with an exploratory factor analysis and Cronbach's alpha. Scale responses were described. Results: Engagement of six experts and ten pharmacists clarified definitions (e.g., prescribing), terminology, recall periods, and response options for the 34-item response scale. Fifty-six pharmacists completed the online pilot survey. Based on this data, ambiguous questions and routing issues were addressed. Three hundred and seventy-eight pharmacists completed the online main survey for a response rate of 54.6%. The factors analysis resulted in 27 questions in eight scales: (1) self-efficacy, (2) support from practice environment, (3) support from interprofessional relationship, (4) impact on professionalism, (5) impact on patient care), (6) prescribing beliefs, (7) technical use of electronic health record (EHR) and (8) patient care use of the EHR. Prescribing beliefs and technical use of the EHR scales had low reliability while the remaining six scales had strong evidence for reliability and validity. Conclusion: Through a multi-stage process, a survey instrument was developed to capture pharmacists' perceptions of prescribing influences. This questionnaire may support future research to develop interventions to enhance adoption of prescribing and enhance direct patient care by pharmacists. PMID- 29619132 TI - Aptamer-conjugated nanomaterials for specific cancer cell recognition and targeted cancer therapy. AB - Based on their unique advantages, increasing interest has been shown in the use of aptamers as target ligands for specific cancer cell recognition and targeted cancer therapy. Recently, the development of aptamer-conjugated nanomaterials has offered new therapeutic opportunities for cancer treatment with better efficacy and lower toxicity. We highlight some of the promising classes of aptamer conjugated nanomaterials for the specific recognition of cancer cells and targeted cancer therapy. Recent developments in the use of novel strategies that enable sensitive and selective cancer cell recognition are introduced. In addition to targeted drug delivery for chemotherapy, we also review how aptamer conjugated nanomaterials are being incorporated into emerging technologies with significant improvement in efficiency and selectivity in cancer treatment. PMID- 29619134 TI - Type B adverse drug reactions reported by an immunoallergology department. AB - Objective: Characterization of the adverse drug reactions (ADR) reported by the immunoallergology department (IAD), Centro Hospitalar de Sao Joao (Porto), to the Northern Pharmacovigilance Centre (NPC). Methods: An observational, descriptive and retrospective study was conducted, based in a spontaneous report system. Participants were all the patients from the IAD, with suspected ADR, reported to NPC by specialists after the study was completed. Results: Studied population had a median age of 41 years, with the predominance of the female gender (73.2%). Allergic rhinitis and asthma were the most frequent comorbidities. All studied ADR were type B, 89.6% were serious, 86.4% unexpected and 2.6% associated with drugs that presented less than 2 years in the market. The most represented drug classes were the non-steroidal anti-inflammatory drugs (NSAIDs) (52.6%) and antibiotics (25.2%). Skin symptoms represented 61.2% of the reported complaints. About 52.9% of these ADR occurred in less than one hour after intake. The most frequent ADR treatment at the time of the reaction was drug interruption (86.2%), followed by the prescription of anti-histamines (42.2%). Conclusions: Reported ADR to NPC by the Drug Alert Unit were mainly serious, unexpected, associated with NSAIDs and antibiotics and related with marketing authorization medicines older than two years. These results could be very useful to develop strategies to prevent the clinical and economic consequences of ADR. PMID- 29619135 TI - Satisfaction of patients receiving value added-services compared to traditional counter service for prescription refills in Malaysia. AB - Background: Patients' satisfaction is the key parameter to measure the quality of healthcare services. Value added-services (VAS) were introduced to improve the quality of medication deliveries and to reduce the waiting time at outpatient pharmacy. Objective: This study aimed to compare the satisfaction levels of patients receiving VAS and traditional counter service (TCS) for prescription refills in Port Dickson Hospital. Methods: A single-center, cross-sectional study was conducted in the outpatient pharmacy department of Port Dickson Hospital from 1 March to 30 June 2017. Systematic sampling method was utilized to recruit subjects into the study, except mail pharmacy in which universal sampling method was used. Data collection was done via telephone interviews for both groups. Results: There was 104 and 105 in TCS and VAS group respectively. The response rate was 99.5%. Overall, a significant higher total mean satisfaction score in VAS group was observed as compared to TCS group (43.39 versus 40.49, p=0.002). The same finding was observed after confounding factors were controlled (VAS=44.66, 95% CI 43.07:46.24 versus TCS=39.88, 95% CI 38.29:41.46; p<0.001). VAS respondents reported more satisfaction than TCS respondents for both general and technical aspects. Among the VAS offered, mail pharmacy service respondents showed highest total mean satisfaction score, but no significant different was seen between groups (p=0.064). Conclusion: VAS respondents were generally more satisfied than TCS respondents for prescription refills. A longitudinal study is necessary to examine the impact of other dimensions and other types of VAS on patients' satisfaction levels. PMID- 29619137 TI - Attitudes towards continuous professional development: a study of pharmacists in Lebanon. AB - Objective: To investigate the views and assess motivation, attitudes of pharmacists in Lebanon towards mandatory continuous education (CE), its transition to Continuous Professional Development (CPD), and identify barriers to participation in CPD. Methods: A cross-sectional observational study, conducted between February and May 2017, enrolled 591 pharmacists. The questionnaire used in this study was developed after an extensive literature review and based on previous similar studies in different countries. Results: Half of the pharmacists who completed the questionnaire agreed that all the factors that were mentioned in the questionnaire motivated completing CPD, whereas 55.4% felt confident that CPD meets their needs. 78.4% felt confident in their abilities to assess what they have learned. 71.6% felt confident in their abilities to assess what additional CPD activity may be necessary. The majority of the pharmacists agreed that accessibility of group learning activities (location/distance) (69.6%), job restrictions (76.3%) and lack of time (80.6%) were the most essential barriers against participation in CPD. Motivation was significantly and positively correlated with attitude (r= 0.718), but negatively correlated with barriers (r= 0.243). Attitude was significantly and negatively correlated with barriers (r= 0.120). Conclusion: Our findings contribute to informing the forward pathway for the profession. Attitude and motivation to CPD were positive in this study. Accessibility of group learning activities due to distance and location, job restrictions and lack of time were the major barriers to participation in CPD. Potential solutions can be sought to address these issues. PMID- 29619136 TI - Health literacy and knowledge in a cohort of Australian patients taking warfarin. AB - Objectives: To 1) characterise older patients taking warfarin, 2) assess these patients' level of warfarin knowledge, and 3) describe their strengths and limitations in health literacy, and 4) explore relationships between participants' characteristics, warfarin knowledge and health literacy. Methods: A warfarin knowledge questionnaire and Health Literacy Questionnaire (HLQ) were administered to older patients (aged >65 years, N=34) taking warfarin in an Australian general practice setting. Results: Key gaps in participant knowledge pertained to the consequences of an international normalized ratio (INR) being below the target INR range and safety issues such as when to seek medical attention. A limitation for participants with a lower level of health literacy was the ability to appraise health information. Patients who needed assistance in completing the HLQs had significantly lower warfarin knowledge scores (p=0.03). Overseas-born participants and those taking 5 or more long-term medications had lower HLQ scores for specific scales (p<0.05). Conclusion: In this study warfarin knowledge gaps and a limitation of health literacy amongst a small sample of older patients were identified. The findings suggest that education and resources may need to be tailored to the needs of older patients taking warfarin and their carers to address these knowledge gaps and limitations in health literacy. Patients who may need greater support include those that need assistance in completing the HLQ, are overseas-born, or are taking 5 or more long-term medications. PMID- 29619138 TI - An assessment of the impact of entrepreneurial skills of community pharmacists on pharmaceutical business performance in Jos metropolis, Nigeria. AB - Background: Community pharmacy has been a lucrative area of practice for pharmacists in Jos, Nigeria, until about the turn of the millennium where a decline in viability of the business has been observed. Objective: This study assessed the entrepreneurial skills of community pharmacists, the business performance of community pharmacies and the impact of their entrepreneurial skills on business performance. Methods: A cross sectional survey was conducted by administering a pretested questionnaire to 30 community pharmacists in Jos. An adaptation of the Bernelli model and the expanded Katz (1974)/Herron (1990) Skill Typology Model was used to assess nine entrepreneurial skills - product, organizational, industry, networking, leadership, executive, entrepreneurial, marketing and money skills; while sales growth, net profit and stock growth were used to assess business performance. Frequency distribution of results was presented, with further analysis done with the Epi-Info software using the chi square test of association. Result: The results from this study showed that community pharmacies in Jos do possess requisite entrepreneurial skills, but to varying extents. Product skills ranked highest while money skills and entrepreneurial skills ranked least, portraying a need for skills enhancement in these areas. Business performance was suboptimal, being rated as average or poor by 56.6% of respondents. However, most respondents (90%) still assessed their businesses as profitable. Money skills had a significant impact on business performance (P=0.03) and stock growth (P=0.04); while stock growth was significantly affected by leadership skills (P=0.002) and entrepreneurial skills (0.02). Net profit was significantly affected by industry skills (P=0.008). Conclusions: Community pharmacy business is still a profitable business venture in Jos though business performance is sub optimal. The entrepreneurial skills set of a community pharmacist set has an impact on business performance with money skills, leadership skills and entrepreneurial skills being most significant. This study recommended that entrepreneurial skills of community pharmacists in Nigeria are further developed to improve pharmaceutical business performance. PMID- 29619139 TI - Factors associated with smoking cessation success in Lebanon. AB - Objective: The objective is to assess factors associated with the success rate of smoking cessation among Lebanese smokers in a smoking cessation center. Methods: A cross-sectional data study, conducted between March 2014 and March 2016 in an outpatient smoking cessation center with 156 enrolled patients. The patient's nicotine dependence and motivation to quit smoking were evaluated according to the Fagerstrom Test for Nicotine Dependence and Richmond tests respectively. Results: The number of packs smoked per year decreased the odds of smoking cessation success (p=0.004, ORa=0.982, CI 0.97-0.994), while the compliance with the offered treatment increased the odds of success by 7.68 times (p<0.001, ORa=7.68, CI 3.438-17.187). Highly dependent and highly motivated smokers had more success in the quitting process compared to those with a lower dependence and motivation respectively. Conclusion: Our findings showed that many factors can influence smoking cessation, an experience described as difficult, most significantly the number of packs per year and compliance with the smoking cessation treatment. Moreover, although these outcomes are not representative of the entire Lebanese population, we believe that health authorities could utilize these results when implementing upcoming smoking cessations programs. All attempts at cessation should have a goal of reducing the number of packs smoked per year to improve the chances of ceasing into the future. PMID- 29619140 TI - Challenges and opportunities of clinical pharmacy services in Ethiopia: A qualitative study from healthcare practitioners' perspective. AB - Background: Currently, clinical pharmacists have in-depth therapeutic knowledge and scientific skills to act as drug therapy experts in healthcare settings. Objective: The aim of this study was to assess the opportunities and challenges of clinical pharmacy services from the health practitioners' perspective in University of Gondar (UOG) hospital Ethiopia. Methods: A qualitative study was performed using face-to-face in-depth interviews with health practitioners who were directly involved in clinical pharmacy services (clinical pharmacists, physicians, and nurses) in UOG hospital. Results: A total of 15 health professionals from various specialties were interviewed to express their views towards clinical pharmacists' competencies and identified challenges and opportunities regarding their clinical services. Based on interviewees report, the opportunities for clinical pharmacists includes acceptance of their clinical services among health specialties, new government policy and high patient load in hospital. However, inadequacy of service promotions, lack of continuity of clinical pharmacy services in wards, poor drug information services, lack of commitment, lack of confidence among clinical pharmacists, conflict of interest due to unclear scope of practice, and absence of cooperation with health workers were some of the challenges identified by the interviewees. Conclusion: We identified health professionals working in UOG hospital are receptive towards clinical pharmacy services, but identified some of the potential challenges that needed to be focused to strengthen and promote clinical pharmacy services. Further, the opportunities at hand also need to be utilized astutely to boost the services. PMID- 29619141 TI - Nigerian pharmacists' self-perceived competence and confidence to plan and conduct pharmacy practice research. AB - Background: Recent studies have revealed that pharmacists have interest in conducting research. However, lack of confidence is a major barrier. Objective: This study evaluated pharmacists' self-perceived competence and confidence to plan and conduct health-related research. Method: This cross sectional study was conducted during the 89th Annual National Conference of the Pharmaceutical Society of Nigeria in November 2016. An adapted questionnaire was validated and administered to 200 pharmacist delegates during the conference. Result: Overall, 127 questionnaires were included in the analysis. At least 80% of the pharmacists had previous health-related research experience. Pharmacist's competence and confidence scores were lowest for research skills such as: using software for statistical analysis, choosing and applying appropriate inferential statistical test and method, and outlining detailed statistical plan to be used in data analysis. Highest competence and confidence scores were observed for conception of research idea, literature search and critical appraisal of literature. Pharmacists with previous research experience had higher competence and confidence scores than those with no previous research experience (p<0.05). The only predictor of moderate-to-extreme self-competence and confidence was having at least one journal article publication during the last 5 years. Conclusion: Nigerian pharmacists indicated interest to participate in health-related research. However, self-competence and confidence to plan and conduct research were low. This was particularly so for skills related to statistical analysis. Training programs and building of Pharmacy Practice Research Network are recommended to enhance pharmacist's research capacity. PMID- 29619143 TI - Synthesis and Performance Evaluation of Pulse Electrodeposited Ni-AlN Nanocomposite Coatings. AB - This research work presents the microscopic analysis of pulse electrodeposited Ni AlN nanocomposite coatings using SEM and AFM techniques and their performance evaluation (mechanical and electrochemical) by employing nanoindentation and electrochemical methods. The Ni-AlN nanocomposite coatings were developed by pulse electrodeposition. The nickel matrix was reinforced with various amounts of AlN nanoparticles (3, 6, and 9 g/L) to develop Ni-AlN nanocomposite coatings. The effect of reinforcement concentration on structure, surface morphology, and mechanical and anticorrosion properties was studied. SEM and AFM analyses indicate that Ni-AlN nanocomposite coatings have dense, homogenous, and well defined pyramid structure containing uniformly distributed AlN particles. A decent improvement in the corrosion protection performance is also observed by the addition of AlN particles to the nickel matrix. Corrosion current was reduced from 2.15 to 1.29 MUA cm-2 by increasing the AlN particles concentration from 3 to 9 g/L. It has been observed that the properties of Ni-AlN nanocomposite coating are sensitive to the concentration of AlN nanoparticles used as reinforcement. PMID- 29619144 TI - Efficacy of Chitosan-Based Dressing for Control of Bleeding in Excisional Wounds. AB - Introduction: Excessive bleeding is a complication of wound debridement in patients receiving anticoagulation treatment. Chitosan is a linear, positively charged polysaccharide that has potential as a hemostatic topical dressing. This study examined the hemostatic efficacy of the chitosan based Opticell dressing (Medline Industries, Chicago, Ill) in heparinized rats with excisional wounds mimicking debridement. Methods: Three paired 12-mm excisional wounds were created on the dorsum of 600-g Sprague-Dawley rats 2 hours after intraperitoneal injection of heparin 800 IU/kg. Opticell or gauze dressings were applied with 3 seconds of gentle pressure. Results:Total Bleeding: The dressings were left in place until cessation of bleeding. Ten minutes was enough time for complete bleeding cessation in both groups. Gauze and Opticell were weighed before and after bleeding cessation, with the difference representing blood loss. Total blood loss was 627 +/- 47 mg/10 min with the standard gauze, but 247 +/- 47 mg/10 min with Opticell (P = .002 Mann-Whitney). N = 6 wounds per group. Rate of Bleeding: Gauze and Opticell dressings were removed and instantly replaced with 3 seconds of gentle pressure every minute until bleeding cessation. The removed dressings were weighed before and after application. There was less bleeding in the Opticell group at minutes 1, 2, and 3. Gauze: 183 +/- 40, 140 +/- 30, and 109 +/- 15 mg/min vs Opticell: 91 +/- 17, 54 +/- 8, and 57 +/- 11 mg/min). Analysis of variance, Tukey's test, P < .05. N = 12 wounds per group. Conclusion: Topical application of Opticell dressing with chitosan has hemostatic effects that could be a useful tool to control bleeding associated with wound debridement. PMID- 29619145 TI - Proper Controls to Electrochemically Evaluate Carotenoids using beta-Cyclodextrin Modified Surfaces. AB - We initially tested the electrochemical activity of beta-carotene and lutein at unmodified glassy carbon electrodes. We found good sensitivity (1 nA/MUM) at high, micromolar concentrations, but serum levels are at nanomolar concentrations. To enhance the electrochemical activity, we modified the sensor surface with beta-cyclodextrin, which has a hydrophobic core. Our goal was that the beta-carotene will be attracted to the beta-cyclodextrin core, increasing surface interaction and sensitivity. Instead we saw a decrease in electrochemical activity. Further investigation with a methylene blue mediator indicated two results. First, it is unlikely the beta-carotene strongly interacts with the beta cyclodextrin surface. And, second, the presence of a co-solvent or surfactant can greatly disrupt the surface beta-cyclodextrin activity. PMID- 29619146 TI - High-Fat Diet Increases HMGB1 Expression and Promotes Lung Inflammation in Mice Subjected to Mechanical Ventilation. AB - This study aims to evaluate the effects of a high-fat diet and mechanical ventilation on the pulmonary and systemic inflammatory response in C57BL/6 mice. Male C57BL/6 mice were divided into two groups: one received a standard diet, and the other received a high-fat diet. After 10 weeks, the groups were further divided into two groups each: control group (CG), mechanical ventilation group (MVG), diet group (DG), and diet mechanical ventilation group (DMVG). MVG and DMVG underwent mechanical ventilation for 60 minutes. All animals were euthanized for subsequent analysis. Animals receiving a high-fat diet presented higher body mass, adipose index, and greater adipocyte area. In the lung, the expression of HMGB1 was greater in DG and DMVG than in CG and MVG. CCL2 and IL-22 levels in MVG and DMVG were increased compared to those in CG and DG, whereas IL-10 and IL-17 were decreased. Superoxide dismutase activity was higher in MVG and DMVG than in CG. Catalase activity was lower in DG than in CG, and in MV groups, it was lower than that in CG and DG. MV and obesity promote inflammation and pulmonary oxidative stress in adult C57BL/6 mice. PMID- 29619147 TI - Translation and Cross-cultural Adaptation of the Hip Disability and Osteoarthritis Score into Persian Language: Reassessment of Validity and Reliability. AB - Background: This study aimed Persian translation and validation of the hip disability and osteoarthritis outcome score (HOOS) questionnaire. Methods: The study was carried out in two phases. First, we translated the HOOS according to acceptable guidelines. We assessed HOOS content convergent validity on 203 hip osteoarthritis patients using SF-36. Internal consistency was tested using Cronbach's alpha coefficient if each item removed and intraclass correlation coefficient (ICC) for the assessment of test-retest reproducibility. Results: Patients had mean (standard deviation) age of 39 (17). Test-retest ICC in whole was 0.95 (P = 0.014) showing excellent reliability. ICC was 0.92 for the "pain" subscale (P = 0.02), 0.81 for the "symptom" subscale (P = 0.002), 0.81 for the "function of daily living (FDL)" (P = 0.022), 0.88 for the "function of sports and recreational activities" (P = 0.006), but it was 0.62 (P = 0.1) for the "quality of life (QOL)." Cronbach's alpha was 0.92, 0.73, 0.97, 0.86, 0.80, and 0.80 for the pain, symptom, FDL, function of sports, QOL, and stiffness, respectively, showing good to excellent internal consistancy. Having SF-36 for the assessment of convergent validity, there was a strong correlation between total HOOS score and the physical component summary domain of SF-36 (r = 0.64, P = 0.0001), whereas the t correlation with the mental component summary domain was weak (r = 0.16, P = 0.04). Conclusions: The Persian version of the HOOS questionnaire is a valid (regarding physical not mental aspects) and reliable assessment tool in patients with hip osteoarthritis. PMID- 29619148 TI - Association of Serum 25-hydroxyvitamin D Levels and Liver Enzymes in a Nationally Representative Sample of Iranian Adolescents: The Childhood and Adolescence Surveillance and Prevention of Adult Noncommunicable Disease Study. AB - Background: Hypovitaminosis D is highly prevalent and has several adverse health effects. This study aims to assess the relationship of serum concentrations of 25 hydroxyvitamin D (25[OH] D) and liver enzymes in adolescents. Methods: This population-based cross-sectional survey was conducted among a nationally representative multistage sample of 1095 adolescents (52% boys), aged 10-18 years, living in different provinces of Iran. Serum 25(OH)D concentration <30 ng/mL was considered as hypovitaminosis D, and liver enzymes (alanine aminotransaminase [ALT] and aspartate aminotransaminase [AST]) of >40 U/L was considered as high level. To determine the association between serum 25(OH)D categories and elevated levels of liver enzymes, multiple regression models and linear regression analysis were applied, after adjustment for potential confounders. Odds ratios (95% confidence interval) of serum 25(OH)D and elevated liver enzymes were assessed by logistic regression analysis. Results: Higher rates of Vitamin D deficiency were documented among individuals with increased levels of liver enzymes. Compared to boys, median of 25(OH)D was lower in girls with elevated levels of liver function tests (12.75 vs. 25.60 ng/mL for ALT and 13 vs. 14.10 ng/mL for AST), with marginally significant gender differences regarding AST. Conclusions: We found a relatively high frequency of hypovitaminosis D among adolescents with abnormal liver function. Further prospective studies are needed to examine these associations from early life. PMID- 29619142 TI - Scholarly publishing depends on peer reviewers. AB - The peer-review crisis is posing a risk to the scholarly peer-reviewed journal system. Journals have to ask many potential peer reviewers to obtain a minimum acceptable number of peers accepting reviewing a manuscript. Several solutions have been suggested to overcome this shortage. From reimbursing for the job, to eliminating pre-publication reviews, one cannot predict which is more dangerous for the future of scholarly publishing. And, why not acknowledging their contribution to the final version of the article published? PubMed created two categories of contributors: authors [AU] and collaborators [IR]. Why not a third category for the peer-reviewer? PMID- 29619149 TI - Appendicular Skeletal Muscle Mass Reference Values and the Peak Muscle Mass to Identify Sarcopenia among Iranian Healthy Population. AB - Background: Sacopenia is a common problem in elderly with the adverse outcomes. The objective of this study was to estimate the peak appendicular skeletal muscle mass (ASM) and age of its attainment by sex among the Iranian population. Methods: A total of 691 men and women aged 18-94 years participated in this cross sectional, population-based study in Bushehr, Iran. ASM was measured by dual X ray absorptiometry. Cutoff points for men and women were established considering two standard deviations (SDs) below the mean values of the skeletal muscle index (SMI) for young reference groups. The relationship between ASM and age was described by the second-degree regression models. Two SDs below the mean SMIs of reference groups were as cutoff values of low muscle mass in Iranian population. Results: The peak ASM values were 21.35 +/- 0.12 Kg and 13.68 +/- 0.10 Kg, and the age at peak ASM were 26 (24-28) years and 34 (33-35) years for men and women, respectively. Mean and SD of SMI in those ages were 7.01 +/- 0.02 Kg/m2 and 5.44 +/- 0.02 Kg/m2 among men and women, respectively. Calculated cutoff values of low muscle mass among the Iranian population were 7.0 Kg/m2 and 5.4 Kg/m2 among men and women, respectively. Conclusions: Iranian reference values of SMI for both genders were similar to Asia Working Group for Sarcopenia recommendation and lower than the United States and European values. Further studies from different nations and the Middle East countries are needed to obtain reference values for populations, enabling the researchers for comparison and also more valid reports on sarcopenia prevalence. PMID- 29619150 TI - Effects of Mothers' Knowledge and Coping Strategies on the Glycemic Control of Their Diabetic Children in Egypt. AB - Background: This study aimed to examine the relationship between mothers' knowledge related to treatment management of type 1 diabetes (T1D), with perceptions of coping with diabetes-related stress and to examine the relationship between children's metabolic control and maternal coping. A cross sectional study was done among ninety-two mothers of T1D children. Methods: Data were collected using a structured questionnaire, Ways of coping questionnaire (WCQ), and Diabetes Knowledge questionnaire-24 (DKQ-24). Results: The most important predictors of the total knowledge scores among mothers were father education (P < 0.0001), followed by child age and sex (P < 0.0001), while the most important coping scales affected by total knowledge scores was accepting responsibility (P = 0.01). There were positive correlation between HBA1C and escape-avoidance and positive reappraisal coping scales (r = 0.24, P = 0.02 and r = 0.23, P = 0.02, respectively). Blood glucose level was the most important clinical characteristics affecting the use of seeking social support coping scale among mothers. Conclusions: Parents with more knowledge of diabetes and with better education were able to cope more effective and maintain a better glycemic control of their diabetic children. PMID- 29619151 TI - Musculoskeletal Disorders as Common Problems among Iranian Nurses: A Systematic Review and Meta-analysis Study. AB - Background: Considering the importance of musculoskeletal disorders (MSDs) as one of the health consequences of job stress among nurses and significant contradictions in prevalence in different parts of the body, this study was carried out to determine the prevalence of MSDs among Iranian nurses. Methods: All published studies from June 2000 until June 2015 were considered in reliable databases such as PubMed, Google Scholar, Google search, Scopus, ScienceDirect, and Persian databases such as SID, Iran Medex, and Magiran. These studies, after quality control, were entered into meta-analysis using the random effects model, a total of 41 papers were assessed between 2004 and 2015. Results: The prevalence rate of these disorders was 60.98%, 47.76%, 46.53%, 44.64%, 42.8%, 36.8%, 24.61%, and 17.5%, respectively, obtained for the back, neck, knees, upper back, ankles, shoulders, hands, hips, thighs, and elbows. Prevalence of MSDs will lead to high costs of medical, absenteeism from work, or even unemployment. Conclusions: Due to high prevalence of these disorders among Iranian nurses, providing effective training in the field of ergonomics and undergoing appropriate exercises are necessary to control it. PMID- 29619153 TI - Epidemiology of Handheld Cell Phone Use While Driving: A Study from a South Indian City. AB - Background: Using cell phones while driving contribute to distractions which can potentially cause minor or major road traffic injuries and also stress among other drivers. With this background, the study was done to ascertain the proportion of handheld cell phone use while driving among road users in Mysore city and also patterns of the use by the day of week, type of road, and type of vehicle. Methods: The study was conducted in Mysore, Karnataka, India. Four stretches of roads were observed thrice daily for 1 week. The total number of vehicles passing through the stretch and the number and characteristics of drivers using hand-held cell was noted. Pearson's Chi-square test was used to ascertain the significance of the difference in proportions. Results: The overall proportion of cell phone users was calculated as 1.41/100 vehicles. The observed use of handheld cell phones was 1.78 times higher on nonbusy roads than busy roads (Chi2 = 25.79, P < 0.0001). More than 50% of the handheld phone users were driving a two wheeler, the proportion being 50.5% in busy roads, and 67% in nonbusy roads. There was no difference in the proportion of cell phone use by time of the day or across different days of the week. Conclusions: The proportion of drivers who use cell phones is found to be relatively lower, and use of cell phones was higher on nonbusy roads. PMID- 29619152 TI - Comparison of Berlin Questionnaire, STOP-Bang, and Epworth Sleepiness Scale for Diagnosing Obstructive Sleep Apnea in Persian Patients. AB - Background: Obstructive sleep apnea (OSA) is a common disorder characterized by snoring, daytime sleepiness, fatigue, and repeated termination of airflow (apnea). Standard polysomnography (PSG) is diagnostic gold standard for OSA. PSG is expensive and not available everywhere. To identify the best OSA questionnaire for screening in Persian population, we compared Berlin, STOP-BANG, and Epworth Sleepiness Scale (ESS). Methods: In a cross-sectional study conducted on 400 adult patients suspected of OSA in Bamdad Respiratory Research Center, patients completed three questionnaires. For each questionnaire, patients were divided into high risk and low risk. Then, PSG was performed for all patients. According to PSG, patients categorized into without OSA (apnea-hypopnea index [AHI] <5), mild OSA (15> AHI >=5), moderate OSA (30> AHI >=15), and severe OSA (AHI >=30). Based on questionnaires and PSG results, predictive parameters for screening tests were calculated. Results: There were 234 (58.5%) males and 166 (41.5%) females in study population. Mean age of patients was 49.29 +/- 9.75 standard deviation years. There was significant association between age with OSA (P = 0.005) and between body mass index (BMI) and neck circumference, with moderate and severe OSA (P < 0.001). Sensitivities of Berlin, STOP-BANG, and ESS were 86.42%, 81.46%, and 59%, respectively. Specificities of Berlin, STOP-BANG, and ESS were 52.94%, 82.35%, and 76.47%, respectively. Conclusions: This study suggested that Berlin and STOP-BANG are more sensitive and accurate than ESS for OSA screening in Iran. PMID- 29619155 TI - 2017 Measles-Rubella Vaccination Campaign in India. PMID- 29619154 TI - Antihyperlipidemic Effect of Different Fractions Obtained from Teucrium polium Hydroalcoholic Extract in Rats. AB - Background: This study was aimed to screen the antihyperlipidemic effect of different fractions of Teucrium polium to obtain the most efficient herbal fraction for isolation of bioactive constituents responsible for hypolipidemic activity. Methods: Chloroform, butanol, and aqueous fractions were obtained from hydroalcoholic extract of T. polium aerial parts using partitioning process. To induce hyperlipidemia, dexamethasone (Dex) was injected 10 mg/kg/day (s.c.) for 8 days. In the test groups, animals received 50, 100 and 150 mg/kg of T. polium hydroalcoholic extract and different fractions orally simultaneously with Dex. Serum lipid profile and hepatic marker enzymes were evaluated using biochemical kits. Results: All treatments, especially chloroform and aqueous fractions, reversed serum lipid markers in hyperlipidemic rats. Maximum reduction in triglyceride (60.2%, P < 0.001) and maximum elevation in high-density lipoprotein (HDL) (35.0%, P < 0.01) was observed for chloroform fraction. Maximum cholesterol lowering effect (29.0%, P < 0.001) and maximum reduction in low-density lipoprotein were found for hydroalcoholic extract (72.9%, P < 0.001). Aqueous fraction improved all lipid markers at the highest dose. Butanol fraction decreased triglyceride at the lowest dose (43.9%, P < 0.001) and increased HDL (33%, P < 0.05) at the highest dose. There was a significant increase in alanine aminotransferase and aspartate aminotransferase levels in all tested groups compared to normal group (P < 0.001). Conclusions: This study showed strong antihyperlipidemic effect of various fractions derived from hydroalcoholic extract of T. polium. Chloroform and aqueous fractions may be worthy candidates for isolation of bioactive hypolipidemic constituents. However, possible hepatotoxicity should be considered for clinical application. PMID- 29619156 TI - Vitamin D Supplementation in Tunisian Pregnant Women: Needs More Evidence? PMID- 29619158 TI - A pilot trial of deferiprone in pantothenate kinase-associated neurodegeneration patients. AB - Pantothenate kinase-associated neurodegeneration (PKAN) is the most common form of neurodegeneration with brain iron accumulation, it is an autosomal recessive disease due to mutation in PANK 2 on chromosome 20, which causes the accumulation of iron in basal ganglia and production of free radicals that cause degeneration of the cells. Deferiprone is an iron chelator that was used in treatment of thalassemia patients, it can cross the blood-brain barrier and reverse the iron deposition in the brain. Five patients with genetically confirmed PKAN received 15 mg/kg deferiprone twice daily. All patients were examined at baseline, 12 and 18 months and magnetic resonance imaging (MRI) was done at the baseline and after 18 months. In our study qualitative evaluation of MRI showed that deferiprone was able to reduce the iron load in globus pallidus of all the patients and the results of clinical rating scales show that in four patients, there is an improvement in the first 12 months. The results of our paper show that deferiprone can prevent the progression of the disease. PMID- 29619157 TI - Glomerular Hyperfiltration as Predictor of Cardiometabolic Risk Factors among Children and Adolescents: The Childhood and Adolescence Surveillance and Prevention of Adult-V Study. AB - Background: The prevalence of glomerular hyperfiltration and chronic kidney disease is increasing worldwide in parallel with obesity hypertension epidemic. The effect of increases in glomerular filtrations (GFR) in children with metabolic syndrome has not been studied. The purpose of the present study is to investigate the relationship between GFR and cardiometabolic risk factors in a large sample of pediatric population. Methods: In this nationwide survey, 3800 participants were selected by cluster random sampling from 30 provinces in Iran. Anthropometric measures, biochemical, and clinical parameters were measured. We also measured estimated GFR (eGFR) using the recently modified Schwartz equations and other known cardiometabolic risk factors such as elevated total cholesterol, high low-density lipoprotein cholesterol (LDL-C), and obesity. Results: The response rate was 91.5% (n = 3843). The mean and standard deviation (SD) (Mean +/ SD) of eGFR for girls, boys, and total population were 96.71 +/- 19.46, 96.49 +/ 21.69, and 96.59 +/- 20 ml/min/1.73 m2, respectively. Overall, 38.7% of the participants did not have any cardiometabolic risk factor. In multivariate models, the risk of elevated systolic blood pressure (BP) (odds ratio [OR]: 1.48; 95% confidence interval [CI]: 1.08-2.02), elevated diastolic BP (OR: 1.48; 95% CI: 1.08-2.02), elevated LDL-C (OR: 1.35; 95% CI: 1.07-1.70), and obesity (OR: 1.70; 95%CI: 1.24-2.33) were significantly higher in participants with higher eGFR level than those with the lower level but not with low level of high-density lipoprotein cholesterol (OR: 0.72; 95% CI: 0.60-0.88). Conclusions: This study demonstrates an association between glomerular hyperfiltration and obesity related hypertension in a large sample of the Iranian pediatric population, independently of other classical risk factors. PMID- 29619159 TI - Depression and anxiety as determinants of health-related quality of life in patients with multiple sclerosis - United Arab Emirates. AB - To study the impact of depression and anxiety on health-related quality of life (HRQOL) in patients with multiple sclerosis (pwMS) in the UAE. All consecutive patients attending the MS clinic over a fourmonth period, October 2014 through February 2015, at Sheikh Khalifa Medical city (SKMC) were asked to complete The World Health Organization quality of life abbreviated scale (WHOQOL-BREF), the Patient Health Questionnaire nine-item (PHQ-9) depression scale, and Generalized Anxiety Disorder seven-item (GAD-7) scale. These last two scales were used to screen for depression and anxiety disorders respectively. The study looked at significant variables associated with HRQOL, using multivariate analysis. Eighty patients were enrolled in the study. Both anxiety and depression had a strong positive correlation with HRQOL in univariate analysis. However, depression was the strongest predictor of HRQOL in the patients using linear multi-regression analysis. Screening and timely treatment of both anxiety and depression in MS patients should be a recommended policy when managing pwMS to improve their optimal care and ensure better quality of life. PMID- 29619160 TI - Clinical features and electrocardiogram parameters in Parkinson's disease. AB - We investigated the relation between clinical features and electrocardiogram (ECG) parameters in patients with Parkinson's disease (PD). One hundred and fifty six PD patients were enrolled. Their clinical features [body mass index (BMI), age, disease duration, and disease stage] and ECG parameters [RR, PR, QRS, and QT intervals, and heart rate-corrected QT (QTc)] were analyzed. BMI was positively correlated with the PR and QRS intervals in patients with PD. The QRS interval was positively correlated with disease duration and Hoehn and Yahr stage, and the QT interval and QTc were positively correlated with age. Clinical features and ECG parameters are likely to be closely associated with each other. Several ECG parameters reflect autonomic dysfunction or disease progression. Clinicians should pay more attention to ECG parameters in the treatment of PD patients. PMID- 29619161 TI - Aneurysm treatment response prediction in follow up black blood magnetic resonance imaging. A case series study. AB - Black blood magnetic resonance imaging (MRI)is a promising imaging tool in predicting aneurysm rupture. Could it be also valuable in evaluating the treatment effect of endovascular and conservative treated aneurysms? Two patients were treated with stent and coil and one with Aspirine (ASS). Correlation of treatment response and contrast enhancement of the aneurysm wall is examined. In the first case stenting failed to treat the aneurysm and contrast enhancement in the wall did never subside during follow up black blood MRI. In the second case the aneurysm responded well to stenting and decreased in size, which was correlating significantly with attenuation of contrast enhancement in black blood MRI. In the third case the aneurysm responded to ASS treatment by decreasing in size as shown in follow up MR-angiography and the contrast enhancement in its wall decreased after 8 months of therapy. Black blood MRI seems to be a promising tool not only in predicting aneurysms at risk of rupture, but also in observing treatment responses after endovascular procedures or even Aspirine administration. When contrast enhancement decreases, aneurysm treatment seems to be successful as can be shown in decreasing size in the follow up angiography. PMID- 29619162 TI - CRISPR/Cas9-induced shank3b mutant zebrafish display autism-like behaviors. AB - Background: Human genetic and genomic studies have supported a strong causal role of SHANK3 deficiency in autism spectrum disorder (ASD). However, the molecular mechanism underlying SHANK3 deficiency resulting in ASD is not fully understood. Recently, the zebrafish has become an attractive organism to model ASD because of its high efficiency of genetic manipulation and robust behavioral phenotypes. The orthologous gene to human SHANK3 is duplicated in the zebrafish genome and has two homologs, shank3a and shank3b. Previous studies have reported shank3 morphants in zebrafish using the morpholino method. Here, we report the generation and characterization of shank3b mutant zebrafish in larval and adult stages using the CRISPR/Cas9 genome editing technique. Methods: CRISPR/Cas9 was applied to generate a shank3b loss-of-function mutation (shank3b-/- ) in zebrafish. A series of morphological measurements, behavioral tests, and molecular analyses were performed to systematically characterize the behavioral and molecular changes in shank3b mutant zebrafish. Results: shank3b-/- zebrafish exhibited abnormal morphology in early development. They showed reduced locomotor activity both as larvae and adults, reduced social interaction and time spent near conspecifics, and significant repetitive swimming behaviors. Additionally, the levels of both postsynaptic homer1 and presynaptic synaptophysin were significantly reduced in the adult brain of shank3b-deficient zebrafish. Conclusions: We generated the first inheritable shank3b mutant zebrafish model using CRISPR/Cas9 gene editing approach. shank3b-/- zebrafish displayed robust autism-like behaviors and altered levels of the synaptic proteins homer1 and synaptophysin. The versatility of zebrafish as a model for studying neurodevelopment and conducting drug screening will likely have a significant contribution to future studies of human SHANK3 function and ASD. PMID- 29619163 TI - Oxalyl amide assisted palladium-catalyzed synthesis of pyrrolidones via carbonylation of gamma-C(sp3)-H bonds of aliphatic amine substrates. AB - The first Pd-catalyzed regioselective gamma-carbonylation of oxalyl amide protected aliphatic amines with carbon monoxide leading to synthesis of pyrrolidones has been developed. Both gamma-methyl and cyclopropyl methylene C-H bonds are well activated to obtain the corresponding pyrrolidones in moderate to excellent yields. The role of 3-(trifluoromethyl)benzoic acid as an additive is critical as it helps in stabilizing the palladium intermediate formed during the catalytic cycle. The reaction scope is extended to benzylamine and allyl amine derivatives, thereby affording the corresponding products in good to excellent yields. PMID- 29619164 TI - A mitochondrial-targeted prodrug for NIR imaging guided and synergetic NIR photodynamic-chemo cancer therapy. AB - Nontoxic prodrugs, especially activated by tumor microenvironment, are urgently required for reducing the side effects of cancer therapy. And combination of chemo-photodynamic therapy prodrugs show effectively synergetic therapeutic efficiency, however, this goal has not been achieved in a single molecule. In this work, we developed a mitochondrial-targeted prodrug PNPS for near infrared (NIR) fluorescence imaging guided and synergetic chemo-photodynamic precise cancer therapy for the first time. PNPS contains a NIR photosensitizer (NPS) and an anticancer drug 5'-deoxy-5-fluorouridine (5'-DFUR). These two parts are linked and caged through a bisboronate group, displaying no fluorescence and very low cytotoxicity. In the presence of H2O2, the bisboronate group is broken, resulting in activation of NPS for NIR photodynamic therapy and activation of 5'-DFUR for chemotherapy. The activated NPS can also provide a NIR fluorescence signal for monitoring the release of activated drug. Taking advantage of the high H2O2 concentration in cancer cells, PNPS exhibits higher cytotoxicity to cancer cells than normal cells, resulting in lower side effects. In addition, based on its mitochondrial-targeted ability, PNPS exhibits enhanced chemotherapy efficiency compare to free 5'-DFUR. It also demonstrated a remarkably improved and synergistic chemo-photodynamic therapeutic effect for cancer cells. Moreover, PNPS exhibits excellent tumor microenvironment-activated performance when intravenously injected into tumor-bearing nude mice, as demonstrated by in vivo fluorescence imaging. Thus, PNPS is a promising prodrug for cancer therapy based on its tumor microenvironment-activated drug release, synergistic therapeutic effect and "turn-on" NIR imaging guide. PMID- 29619165 TI - De novo vesicle formation and growth: an integrative approach to artificial cells. AB - The assembly of artificial cells provides a novel strategy to reconstruct life's functions and shed light on how life emerged on Earth and possibly elsewhere. A major challenge to the development of artificial cells is the establishment of simple methodologies to mimic native membrane generation. An ambitious strategy is the bottom-up approach, which aims to systematically control the assembly of highly ordered membrane architectures with defined functionality. This perspective will cover recent advances and the current state-of-the-art of minimal lipid architectures that can faithfully reconstruct the structure and function of living cells. Specifically, we will overview work related to the de novo formation and growth of biomimetic membranes. These studies give us a deeper understanding of the nature of living systems and bring new insights into the origin of cellular life. PMID- 29619166 TI - Peptide/Cas9 nanostructures for ribonucleoprotein cell membrane transport and gene edition. AB - The discovery of RNA guided endonucleases has emerged as one of the most important tools for gene edition and biotechnology. The selectivity and simplicity of the CRISPR/Cas9 strategy allows the straightforward targeting and editing of particular loci in the cell genome without the requirement of protein engineering. However, the transfection of plasmids encoding the Cas9 and the guide RNA could lead to undesired permanent recombination and immunogenic responses. Therefore, the direct delivery of transient Cas9 ribonucleoprotein constitutes an advantageous strategy for gene edition and other potential therapeutic applications of the CRISPR/Cas9 system. The covalent fusion of Cas9 with penetrating peptides requires multiple incubation steps with the target cells to achieve efficient levels of gene edition. These and other recent reports suggested that covalent conjugation of the anionic Cas9 ribonucleoprotein to cationic peptides would be associated with a hindered nuclease activity due to undesired electrostatic interactions. We here report a supramolecular strategy for the direct delivery of Cas9 by an amphiphilic penetrating peptide that was prepared by a hydrazone bond formation between a cationic peptide scaffold and a hydrophobic aldehyde tail. The peptide/protein non-covalent nanoparticles performed with similar efficiency and less toxicity than one of the best methods described to date. To the best of our knowledge this report constitutes the first supramolecular strategy for the direct delivery of Cas9 using a penetrating peptide vehicle. The results reported here confirmed that peptide amphiphilic vectors can deliver Cas9 in a single incubation step, with good efficiency and low toxicity. This work will encourage the search and development of conceptually new synthetic systems for transitory endonucleases direct delivery. PMID- 29619167 TI - One-pass selective conversion of syngas to para-xylene. AB - The finite petroleum resources and environmental crisis compel the development of non-petroleum carbon resources by chemical transformation routes. Syngas (CO + H2) is a crucial junction point that exclusively bridges the non-petroleum carbon resources and other basic chemicals like alcohols, alkane/alkenes, etc. However, the one-pass conversion of syngas to value-added aromatics, especially para xylene, is still a big challenge. Here we presented a promising hybrid catalyst, named Cr/Zn-Zn/Z5@S1, to effectively realize the one-pass conversion of syngas to para-xylene. This hybrid catalyst exhibited enhanced activity on syngas conversion (CO conversion of 55.0%), good stability of catalyst lifetime and considerable selectivity of para-xylene (27.6% in the total products and 77.3% in xylene). The characterization and catalytic performance evaluation revealed that the well-designed core-shell Zn/Z5@S1 zeolite, as a vital part of this Cr/Zn Zn/Z5@S1 hybrid catalyst, substantially contributed to its extreme performance for the para-xylene one-pass precise synthesis from syngas. The concerted combination of two components in this hybrid catalyst can effectively depress the formation of unwanted by-products and facilitate the oriented synthesis of para xylene from syngas with unprecedented efficiency at the same time. PMID- 29619168 TI - A benzylic linker promotes methyltransferase catalyzed norbornene transfer for rapid bioorthogonal tetrazine ligation. AB - Site-specific alkylation of complex biomolecules is critical for late-stage product diversification as well as post-synthetic labeling and manipulation of proteins and nucleic acids. Promiscuous methyltransferases in combination with analogs of S-adenosyl-l-methionine (AdoMet) can functionalize all major classes of biomolecules. We show that benzylic moieties are transferred by Ecm1 with higher catalytic efficiency than the natural AdoMet. A relative specificity of up to 80% is achieved when a norbornene moiety is placed in para-position, enabling for the first time enzymatic norbornene transfer to specific positions in DNA and RNA- even in cell lysate. Subsequent tetrazine ligation of the stable norbornene moiety is fast, efficient, biocompatible and - in combination with an appropriate tetrazine - fluorogenic. PMID- 29619169 TI - A practical and scalable system for heteroaryl amino acid synthesis. AB - A robust system for the preparation of beta-heteroaryl alpha-amino acid derivatives has been developed using photoredox catalysis. This system operates via regiospecific activation of halogenated pyridines (or other heterocycles) and conjugate addition to dehydroalanine derivatives to deliver a wide range of unnatural amino acids. This process was conducted with good efficiency on large scale, the application of these conditions to amino ketone synthesis is shown, and a simple protocol is given for the preparation of enantioenriched amino acid synthesis, from a number of radical precursors. PMID- 29619170 TI - Efficient cross-effect dynamic nuclear polarization without depolarization in high-resolution MAS NMR. AB - Dynamic nuclear polarization (DNP) has the potential to enhance the sensitivity of magic-angle spinning (MAS) NMR by many orders of magnitude and therefore to revolutionize atomic resolution structural analysis. Currently, the most widely used approach to DNP for studies of chemical, material, and biological systems involves the cross-effect (CE) mechanism, which relies on biradicals as polarizing agents. However, at high magnetic fields (>=5 T), the best biradicals used for CE MAS-DNP are still far from optimal, primarily because of the nuclear depolarization effects they induce. In the presence of bisnitroxide biradicals, magic-angle rotation results in a reverse CE that can deplete the initial proton Boltzmann polarization by more than a factor of 2. In this paper we show that these depolarization losses can be avoided by using a polarizing agent composed of a narrow-line trityl radical tethered to a broad-line TEMPO. Consequently, we show that a biocompatible trityl-nitroxide biradical, TEMTriPol-1, provides the highest MAS NMR sensitivity at >=10 T, and its relative efficiency increases with the magnetic field strength. We use numerical simulations to explain the absence of depolarization for TEMTriPol-1 and its high efficiency, paving the way for the next generation of polarizing agents for DNP. We demonstrate the superior sensitivity enhancement using TEMTriPol-1 by recording the first solid-state 2D 13C-13C correlation spectrum at natural isotopic abundance at a magnetic field of 18.8 T. PMID- 29619171 TI - Surface electron dynamics in hematite (alpha-Fe2O3): correlation between ultrafast surface electron trapping and small polaron formation. AB - Spectroscopically following charge carrier dynamics in catalytic materials has proven to be a difficult task due to the ultrafast timescales involved in charge trapping and the lack of spectroscopic tools available to selectively probe surface electronic structure. Transient extreme ultraviolet reflection-absorption (XUV-RA) spectroscopy is able to follow surface electron dynamics due to its element, oxidation-state, and surface specificity, as well as the ultrafast time resolution which can be achieved with XUV pulses produced by high harmonic generation. Here, we use ultrafast XUV-RA spectroscopy to show that charge localization and small polaron formation in Fe2O3 occur within ~660 fs. The photoexcitation of hematite at 400 nm initially leads to an electronically delocalized ligand-to-metal charge transfer (LMCT) state, which subsequently evolves into a surface localized LMCT state. Comparison of the charge carrier dynamics for single and polycrystalline samples shows that the observed dynamics are negligibly influenced by grain boundaries and surface defects. Rather, correlation between experimental results and spectral simulations reveals that the lattice expansion during small polaron formation occurs on the identical time scale as surface trapping and represents the probable driving force for sub-ps electron localization to the hematite surface. PMID- 29619172 TI - Visualization of long-term Mg2+ dynamics in apoptotic cells using a novel targetable fluorescent probe. AB - Mg2+ plays important roles in many physiological processes. However, the underlying molecular mechanisms, especially in the apoptotic pathway, remain unclear due to the diffusion of Mg2+ probes, which hinders long-term imaging in specific organelles. We developed an immobilized Mg2+ probe, MGH, which is covalently conjugated with the HaloTag protein in various organelles. HaloTag coupled MGH enabled long-term imaging of intracellular local Mg2+ dynamics for 24 h. To exploit this remarkable property, MGH was applied to the investigation of intracellular Mg2+ dynamics during apoptosis. Time-lapse imaging revealed an increase in the Mg2+ concentration after apoptotic cell shrinkage. Combined imaging analyses of intracellular Mg2+ and ATP concentrations strongly suggested that this Mg2+ concentration increase was caused by the dissociation of Mg2+ from ATP, along with a decrease in the intracellular ATP concentration. Thus, this protein-coupled Mg2+ probe could be a new chemical tool to elucidate intracellular Mg2+ dynamics with high spatiotemporal resolution. PMID- 29619173 TI - Fluoro-substituted cyanine for reliable in vivo labelling of amyloid-beta oligomers and neuroprotection against amyloid-beta induced toxicity. AB - Alzheimer's disease (AD) is the most prevalent but still incurable neurodegenerative form of dementia. Early diagnosis and intervention are crucial for delaying the onset and progression of the disease. We herein report a novel fluoro-substituted cyanine, F-SLOH, which exhibits good Abeta oligomer selectivity with a high binding affinity, attributed to the synergistic effect of strong pi-pi stacking and intermolecular CH...O and CH...F interactions. The selectivity towards the Abeta oligomers in the brain was ascertained by in vitro labelling on tissue sections and in vivo labelling through the systemic administration of F-SLOH in 7 month APP/PS1 double transgenic (Tg) and APP/PS1/Tau triple Tg mouse models. F-SLOH also shows remarkably effective inhibition on Abeta aggregation and highly desirable neuroprotective effects against Abeta-induced toxicities, including the inhibition of ROS production and Ca2+ influx. Its excellent blood-brain barrier (BBB) penetrability and low bio toxicity further support its tremendous potential as a novel theranostic agent for both early diagnosis and therapy of AD. PMID- 29619174 TI - Bioinspired synthesis of pentacyclic onocerane triterpenoids. AB - The first chemical synthesis of pentacyclic onocerane triterpenoids has been achieved. A putative biomimetic tricyclization cascade is employed to forge a fused decalin-/oxepane ring system. The synthetic route proceeds to (+) cupacinoxepin in seven steps and to (+)-onoceranoxide in eight steps in the longest linear sequence, when starting from geranyl chloride and (+)-sclareolide. The bioinspired epoxypolyene cyclization is supported by computational and enzymatic studies. PMID- 29619175 TI - A matrix of heterobimetallic complexes for interrogation of hydrogen evolution reaction electrocatalysts. AB - Experimental and computational studies address key questions in a structure function analysis of bioinspired electrocatalysts for the HER. Combinations of NiN2S2 or [(NO)Fe]N2S2 as donors to (eta5-C5H5)Fe(CO)+ or [Fe(NO)2]+/0 generate a series of four bimetallics, gradually "softened" by increasing nitrosylation, from 0 to 3, by the non-innocent NO ligands. The nitrosylated NiFe complexes are isolated and structurally characterized in two redox levels, demonstrating required features of electrocatalysis. Computational modeling of experimental structures and likely transient intermediates that connect the electrochemical events find roles for electron delocalization by NO, as well as Fe-S bond dissociation that produce a terminal thiolate as pendant base well positioned to facilitate proton uptake and transfer. Dihydrogen formation is via proton/hydride coupling by internal S-H+...-H-Fe units of the "harder" bimetallic arrangements with more localized electron density, while softer units convert H-...H-via reductive elimination from two Fe-H deriving from the highly delocalized, doubly reduced [Fe2(NO)3]- derivative. Computational studies also account for the inactivity of a Ni2Fe complex resulting from entanglement of added H+ in a pinched -S delta-...H+... delta-S- arrangement. PMID- 29619176 TI - N-Heterocyclic carbenes on close-packed coinage metal surfaces: bis-carbene metal adatom bonding scheme of monolayer films on Au, Ag and Cu. AB - By means of scanning tunnelling microscopy (STM), complementary density functional theory (DFT) and X-ray photoelectron spectroscopy (XPS) we investigate the binding and self-assembly of a saturated molecular layer of model N heterocyclic carbene (NHC) on Cu(111), Ag(111) and Au(111) surfaces under ultra high vacuum (UHV) conditions. XPS reveals that at room temperature, coverages up to a monolayer exist, with the molecules engaged in metal carbene bonds. On all three surfaces, we resolve similar arrangements, which can be interpreted only in terms of mononuclear M(NHC)2 (M = Cu, Ag, Au) complexes, reminiscent of the paired bonding of thiols to surface gold adatoms. Theoretical investigations for the case of Au unravel the charge distribution of a Au(111) surface covered by Au(NHC)2 and reveal that this is the energetically preferential adsorption configuration. PMID- 29619177 TI - Direct structural identification of carbenium ions and investigation of host guest interaction in the methanol to olefins reaction obtained by multinuclear NMR correlations. AB - Probing and determining the intermediates formed during catalytic reactions in heterogeneous catalysis are strong challenges. Using 13C labelling and two dimensional 13C-13C through-bond NMR correlations, we directly reveal the structures of a range of carbenium ion species formed during the conversion of methanol to olefins on acidic H-ZSM-5 zeolite by mapping the carbon-carbon bond connectivities. Additionally, we use 13C-27Al and 29Si-13C through-space NMR experiments to probe the interactions between the confined carbon species (including carbenium ions) and the framework of the zeolite, which quantitatively provide an estimate for the carbon-aluminium and carbon-silicon distances, respectively. PMID- 29619179 TI - From cellulose to kerogen: molecular simulation of a geological process. AB - The process by which organic matter decomposes deep underground to form petroleum and its underlying kerogen matrix has so far remained a no man's land to theoreticians, largely because of the geological (Myears) timescale associated with the process. Using reactive molecular dynamics and an accelerated simulation framework, the replica exchange molecular dynamics method, we simulate the full transformation of cellulose into kerogen and its associated fluid phase under prevailing geological conditions. We observe in sequence the fragmentation of the cellulose crystal and production of water, the development of an unsaturated aliphatic macromolecular phase and its aromatization. The composition of the solid residue along the maturation pathway strictly follows what is observed for natural type III kerogen and for artificially matured samples under confined conditions. After expulsion of the fluid phase, the obtained microporous kerogen possesses the structure, texture, density, porosity and stiffness observed for mature type III kerogen and a microporous carbon obtained by saccharose pyrolysis at low temperature. As expected for this variety of precursor, the main resulting hydrocarbon is methane. The present work thus demonstrates that molecular simulations can now be used to assess, almost quantitatively, such complex chemical processes as petrogenesis in fossil reservoirs and, more generally, the possible conversion of any natural product into bio-sourced materials and/or fuel. PMID- 29619178 TI - Dendronic trimaltoside amphiphiles (DTMs) for membrane protein study. AB - The critical contribution of membrane proteins in normal cellular function makes their detailed structure and functional analysis essential. Detergents, amphipathic agents with the ability to maintain membrane proteins in a soluble state in aqueous solution, have key roles in membrane protein manipulation. Structural and functional stability is a prerequisite for biophysical characterization. However, many conventional detergents are limited in their ability to stabilize membrane proteins, making development of novel detergents for membrane protein manipulation an important research area. The architecture of a detergent hydrophobic group, that directly interacts with the hydrophobic segment of membrane proteins, is a key factor in dictating their efficacy for both membrane protein solubilization and stabilization. In the current study, we developed two sets of maltoside-based detergents with four alkyl chains by introducing dendronic hydrophobic groups connected to a trimaltoside head group, designated dendronic trimaltosides (DTMs). Representative DTMs conferred enhanced stabilization to multiple membrane proteins compared to the benchmark conventional detergent, DDM. One DTM (i.e., DTM-A6) clearly outperformed DDM in stabilizing human beta2 adrenergic receptor (beta2AR) and its complex with Gs protein. A further evaluation of this DTM led to a clear visualization of beta2AR Gs complex via electron microscopic analysis. Thus, the current study not only provides novel detergent tools useful for membrane protein study, but also suggests that the dendronic architecture has a role in governing detergent efficacy for membrane protein stabilization. PMID- 29619180 TI - Abnormal room temperature phosphorescence of purely organic boron-containing compounds: the relationship between the emissive behaviorand the molecular packing, and the potential related applications. AB - Purely organic materials with the characteristic of room-temperature phosphorescence (RTP) under ambient conditions demonstrate potential benefits in advanced optoelectronic applications. Exploration of versatile and efficient RTP compounds with low prices is full of challenges due to the slow intersystem crossing process and ultrafast deactivation of the active excited states of organic compounds. Here, a series of boron-containing phosphors were found to present RTP with long-lived lifetimes. Among these commercially available and cheap compounds, (4-methoxyphenyl)boronic acid (PBA-MeO) exhibits long-lived RTP, with a lifetime of 2.24 s, which is among the longest lifetimes of single component small molecules. Our extensive experiments illustrate that both a rigid conformation and expanded conjugation induced by molecular alignment contribute to the persistent RTP. Because of strong intermolecular interactions via hydrogen bonds, these arylboronic acids easily form crystals and are quite appropriate for anti-forgery materials. Subsequently, we develop a precise, speedy and convenient inkjet printing technology for the fabrication of optoelectronic displays. Furthermore, PBA-MeO is used as an additive to feed Bombyx mori silkworms and shows low toxicity over inorganic materials. Our findings may pave a new way for the development of RTP phosphors and promote their use in practical applications. PMID- 29619181 TI - Cancer-mitochondria-targeted photodynamic therapy with supramolecular assembly of HA and a water soluble NIR cyanine dye. AB - Mitochondria-targeted cancer therapies have proven to be more effective than other similar non-targeting techniques, especially in photodynamic therapy (PDT). Indocyanine dye derivatives, particularly IR-780, are widely known for their PDT utility. However, poor water solubility, dark toxicity, and photobleaching are limiting factors for these dyes, which otherwise show promise based on their good absorption in the near-infrared (NIR) region and mitochondria targeting ability. Herein, we introduce an indocyanine derivative (IR-Pyr) that is highly water soluble, exhibiting higher mitochondrial targetability and better photostability than IR-780. Furthermore, electrostatic interactions between the positively charged IR-Pyr and negatively charged hyaluronic acid (HA) were utilized to construct a micellar aggregate that is selective towards cancer cells. The cancer mitochondria-targeted strategy confirms high PDT efficacy as proved by in vitro and in vivo experiments. PMID- 29619183 TI - Rhodium-catalyzed asymmetric 1,4-addition reactions of aryl boronic acids with nitroalkenes: reaction mechanism and development of homogeneous and heterogeneous catalysts. AB - Asymmetric 1,4-addition reactions with nitroalkenes are valuable because the resulting chiral nitro compounds can be converted into various useful species often used as chiral building blocks in drug and natural product synthesis. In the present work, asymmetric 1,4-addition reactions of arylboronic acids with nitroalkenes catalyzed by a rhodium complex with a chiral diene bearing a tertiary butyl amide moiety were developed. Just 0.1 mol% of the chiral rhodium complex could catalyze the reactions and give the desired products in high yields with excellent enantioselectivities. The homogeneous catalyst thus developed could be converted to a reusable heterogeneous metal nanoparticle system using the same chiral ligand as a modifier, which was immobilized using a polystyrene derived polymer with cross-linking moieties, maintaining the same level of enantioselectivity. To our knowledge, this is the first example of asymmetric 1,4 addition reactions of arylboronic acids with nitroalkenes in a heterogeneous system. Wide substrate generality and high catalytic turnover were achieved in the presence of sufficient water without any additives such as KOH or KHF2 in both homogeneous and heterogeneous systems. Various insights relating to a rate limiting step in the catalytic cycle, the importance of water, role of the secondary amide moiety in the ligand, and active species in the heterogeneous system were obtained through mechanistic studies. PMID- 29619182 TI - Supramolecular catalyst functions in catalytic amount: cucurbit[8]uril accelerates the photodimerization of Brooker's merocyanine. AB - Supramolecular catalysis aims to modulate chemical reactions on both selectivity and rate by taking advantage of supramolecular chemistry. However, due to the effect of product inhibition, supramolecular catalysts are usually added in stoichiometric amounts. Herein, we report a supramolecular catalysis system in which 1% of the supramolecular catalyst, cucurbit[8]uril, is able to significantly accelerate the photodimerization of Brooker's merocyanine. This catalytic process is realized in a cyclic manner because the photodimerized product can be spontaneously replaced by monomeric reactants via competitive host guest complexation. Thus, a catalytic amount of cucurbit[8]uril is sufficient to accomplish photodimerization within 10 min. This line of research will enrich the field of supramolecular catalysis and allow the development of more efficient catalytic systems. PMID- 29619184 TI - A competing, dual mechanism for catalytic direct benzene hydroxylation from combined experimental-DFT studies. AB - A dual mechanism for direct benzene catalytic hydroxylation is described. Experimental studies and DFT calculations have provided a mechanistic explanation for the acid-free, Tp x Cu-catalyzed hydroxylation of benzene with hydrogen peroxide (Tp x = hydrotrispyrazolylborate ligand). In contrast with other catalytic systems that promote this transformation through Fenton-like pathways, this system operates through a copper-oxyl intermediate that may interact with the arene ring following two different, competitive routes: (a) electrophilic aromatic substitution, with the copper-oxyl species acting as the formal electrophile, and (b) the so-called rebound mechanism, in which the hydrogen is abstracted by the Cu-O moiety prior to the C-O bond formation. Both pathways contribute to the global transformation albeit to different extents, the electrophilic substitution route seeming to be largely favoured. PMID- 29619185 TI - Examining the role of protein structural dynamics in drug resistance in Mycobacterium tuberculosis. AB - Antimicrobial resistance represents a growing global health problem. The emergence of novel resistance mechanisms necessitates the development of alternative approaches to investigate the molecular fundamentals of resistance, leading ultimately to new strategies for counteracting them. To gain deeper insight into antibiotic-target interactions, the binding of the frontline anti tuberculosis drug isoniazid (INH) to a target enzyme, InhA, from Mycobacterium tuberculosis was studied using ultrafast two-dimensional infrared (2D-IR) spectroscopy and molecular simulations. Comparing wild-type InhA with a series of single point mutations, it was found that binding of the INH-NAD inhibitor to susceptible forms of the enzyme increased the vibrational coupling between residues located in the Rossmann fold co-factor binding site of InhA and suppressed dynamic fluctuations of the enzyme structure. The effect correlated with biochemical assay data, being reduced in the INH-resistant S94A mutant and absent in the biochemically-inactive P193A control. Molecular dynamics simulations and calculations of inter-residue couplings indicate that the changes in coupling and dynamics are not localised to the co-factor binding site, but permeate much of the protein. We thus propose that the resistant S94A mutation circumvents subtle changes in global structural dynamics caused by INH upon binding to the wild-type enzyme that may impact upon the formation of important protein-protein complexes in the fatty acid synthase pathway of M. tuberculosis. PMID- 29619186 TI - Bulk assembly of organic metal halide nanotubes. AB - The organic metal halide hybrids welcome a new member with a one-dimensional (1D) tubular structure. Herein we report the synthesis and characterization of a single crystalline bulk assembly of organic metal halide nanotubes, (C6H13N4)3Pb2Br7. In a metal halide nanotube, six face-sharing metal halide dimers (Pb2Br95-) connect at the corners to form rings that extend in one dimension, of which the inside and outside surfaces are coated with protonated hexamethylenetetramine (HMTA) cations (C6H13N4+). This unique 1D tubular structure possesses highly localized electronic states with strong quantum confinement, resulting in the formation of self-trapped excitons that give strongly Stokes shifted broadband yellowish-white emission with a photoluminescence quantum efficiency (PLQE) of ~7%. Having realized single crystalline bulk assemblies of two-dimensional (2D) wells, 1D wires, and now 1D tubes using organic metal halide hybrids, our work significantly advances the research on bulk assemblies of quantum-confined materials. PMID- 29619187 TI - Hexathioalkyl sumanenes: an electron-donating buckybowl as a building block for supramolecular materials. AB - Unlike planar aromatic compounds, bowl-shaped sumanene, which has concave and convex faces with different electrostatic potentials, tends to form a one dimensional columnar assembly without causing slip-stacking in the crystal. Here we report the first successful synthesis of liquid-crystalline (LC) sumanenes, which was brought about by the incorporation of six thioalkyl groups (R = SC6H13 or SC12H25) into the aromatic part of sumanene. In contrast to the case of the mesophase formation of corannulene, which requires the presence of many dendritic side chains, sumanene derivatives with simple alkyl chains can exhibit a remarkably high-order columnar LC mesophase over a wide temperature range. While non-substituted sumanene inherently behaves as an electron acceptor, hexathioalkyl versions, such as hexathiomethyl sumanene, show electron-donating properties, resulting in complexation with C60. Considering its unique shape, electronic properties, and self-assembly behavior, the electron-donating sumanene may represent a new building block for constructing supramolecular materials, both by itself and in combination with fullerene derivatives. PMID- 29619188 TI - Polyethyleneimine functionalized platinum superstructures: enhancing hydrogen evolution performance by morphological and interfacial control. AB - The electrocatalytic hydrogen evolution reaction (HER) is a highly promising green method for sustainable and efficient hydrogen production. So far, Pt nanocrystals are still the most active electrocatalysts for the HER in acidic media, although a tremendous search for alternatives has been done in the past decade. In this work, we synthesize polyethyleneimine (PEI) functionalized Pt superstructures (Pt-SSs@PEI) with tetragonal, hierarchical, and branched morphologies with a facile wet chemical reduction method. A series of physical characterizations are conducted to investigate the morphology, electronic structure, surface composition, and formation mechanism of Pt-SSs@PEI. Impressively, the as-prepared Pt-SSs@PEI show an unprecedented onset reduction potential (+64.6 mV vs. reversible hydrogen electrode) for the HER in strong acidic media due to the protonation of -NH2 groups in the PEI adlayers on the Pt surface, and they outperform all currently reported HER electrocatalysts. The work highlights a highly effective interface-engineering strategy for improving the electrocatalytic performance of Pt nanocrystals for the HER. PMID- 29619189 TI - Machine learning for quantum dynamics: deep learning of excitation energy transfer properties. AB - Understanding the relationship between the structure of light-harvesting systems and their excitation energy transfer properties is of fundamental importance in many applications including the development of next generation photovoltaics. Natural light harvesting in photosynthesis shows remarkable excitation energy transfer properties, which suggests that pigment-protein complexes could serve as blueprints for the design of nature inspired devices. Mechanistic insights into energy transport dynamics can be gained by leveraging numerically involved propagation schemes such as the hierarchical equations of motion (HEOM). Solving these equations, however, is computationally costly due to the adverse scaling with the number of pigments. Therefore virtual high-throughput screening, which has become a powerful tool in material discovery, is less readily applicable for the search of novel excitonic devices. We propose the use of artificial neural networks to bypass the computational limitations of established techniques for exploring the structure-dynamics relation in excitonic systems. Once trained, our neural networks reduce computational costs by several orders of magnitudes. Our predicted transfer times and transfer efficiencies exhibit similar or even higher accuracies than frequently used approximate methods such as secular Redfield theory. PMID- 29619190 TI - Observing enzyme ternary transition state analogue complexes by 19F NMR spectroscopy. AB - Ternary transition state analogue (TSA) complexes probing the isomerization of beta-d-glucose 1-phosphate (G1P) into d-glucose 6-phosphate (G6P) catalyzed by catalytically active, fluorinated (5-fluorotryptophan), beta-phosphoglucomutase (betaPGM) have been observed directly by 19F NMR spectroscopy. In these complexes MgF3- and AlF4- are surrogates for the transferring phosphate. However, the relevance of these metal fluorides as TSA complexes has been queried. The 1D 19F spectrum of a ternary TSA complex presented a molar equivalence between fluorinated enzyme, metal fluoride and non-isomerizable fluoromethylenephosphonate substrate analogue. Ring flips of the 5-fluoroindole ring remote from the active site were observed by both 19F NMR and X-ray crystallography, but did not perturb function. This data unequivocally demonstrates that the concentration of the metal fluoride complexes is equivalent to the concentration of enzyme and ligand in the TSA complex in aqueous solution. PMID- 29619191 TI - Elucidating the mechanism of the Ley-Griffith (TPAP) alcohol oxidation. AB - The Ley-Griffith reaction is utilized extensively in the selective oxidation of alcohols to aldehydes or ketones. The central catalyst is commercially available tetra-n-propylammonium perruthenate (TPAP, n-Pr4N[RuO4]) which is used in combination with the co-oxidant N-methylmorpholine N-oxide (NMO). Although this reaction has been employed for more than 30 years, the mechanism remains unknown. Herein we report a comprehensive study of the oxidation of diphenylmethanol using the Ley-Griffith reagents to show that the rate determining step involves a single alcohol molecule, which is oxidised by a single perruthenate anion; NMO does not appear in rate law. A key finding of this study is that when pure n Pr4N[RuO4] is employed in anhydrous solvent, alcohol oxidation initially proceeds very slowly. After this induction period, water produced by alcohol oxidation leads to partial formation of insoluble RuO2, which dramatically accelerates catalysis via a heterogeneous process. This is particularly relevant in a synthetic context where catalyst degradation is usually problematic. In this case a small amount of n-Pr4N[RuO4] must decompose to RuO2 to facilitate catalysis. PMID- 29619192 TI - Synthesis of poly(1,2-glycerol carbonate)-paclitaxel conjugates and their utility as a single high-dose replacement for multi-dose treatment regimens in peritoneal cancer. AB - Current chemotherapeutic dosing strategies are limited by the toxicity of anticancer agents and therefore rely on multiple low-dose administrations. As an alternative, we describe a novel sustained-release, biodegradable polymeric nanocarrier as a single administration replacement of multi-dose paclitaxel (PTX) treatment regimens. The first synthesis of poly(1,2-glycerol carbonate)-graft succinic acid-paclitaxel (PGC-PTX) is described, and its use enables high, controlled PTX loadings of up to 74 wt%. Moreover, the polymer backbone is composed of biocompatible building blocks-glycerol and carbon dioxide. When formulated as nanoparticles (NPs), PGC-PTX NPs exhibit PTX concentrations >15 mg mL-1, sub-100 nm diameters, narrow dispersity, storage stability for up to 6 months, and sustained and controlled PTX release kinetics over an extended period of 70 days. A safely administered single dose of PGC-PTX NPs contains more PTX than the median lethal dose of standard PTX. In murine models of peritoneal carcinomatosis, in which the clinical implementation of multi-dose intraperitoneal (IP) treatment regimens is limited by catheter-related complications, PGC-PTX NPs exhibit improved safety at high doses, tumor localization, and efficacy even after a single IP injection, with comparable curative effect to PTX administered as a multi-dose IP treatment regimen. PMID- 29619194 TI - Mono-N-protected amino acid ligands stabilize dimeric palladium(ii) complexes of importance to C-H functionalization. AB - Mono-protected amino acid (MPAA) ligands are used in a number of Pd-catalyzed C-H functionalization reactions. MPAAs have been proposed to bind to Pd(ii) via kappa2-(N,O) coordination, but such binding has not yet been experimentally validated. Herein, we report the synthesis and detailed characterization of a series of MPAA complexes prepared via cyclopalladation of dimethylbenzylamine in the presence of MPAAs. The isolated complexes exist as MU-carboxylato (MPAA) bridged dimers and feature potential M-M cooperativity and secondary sphere hydrogen bonding. Selective MPAA coordination and relay of stereochemistry, previously suggested to uniquely result from kappa2-(N,O) MPAA coordination, are both observed. The isolated MPAA complexes undergo C-C and C-X (X = Cl, Br, I) bond formation when treated with electrophiles used for catalytic C-H functionalization. Stoichiometric iodination of MPAA palladacycles was found to proceed via a dinuclear palladium species with one equivalent of iodine in the rate limiting transition structure, and the isolated complexes also served as viable precatalysts for catalytic C-H functionalization. Together, these results provide a number of insights into the reactivity of Pd-MPAA complexes relevant to C-H bond functionalization. PMID- 29619193 TI - Sensing iron availability via the fragile [4Fe-4S] cluster of the bacterial transcriptional repressor RirA. AB - Rhizobial iron regulator A (RirA) is a global regulator of iron homeostasis in many nitrogen-fixing Rhizobia and related species of alpha-proteobacteria. It belongs to the widespread Rrf2 super-family of transcriptional regulators and features three conserved Cys residues that characterise the binding of an iron sulfur cluster in other Rrf2 family regulators. Here we report biophysical studies demonstrating that RirA contains a [4Fe-4S] cluster, and that this form of the protein binds RirA-regulated DNA, consistent with its function as a repressor of expression of many genes involved in iron uptake. Under low iron conditions, [4Fe-4S] RirA undergoes a cluster conversion reaction resulting in a [2Fe-2S] form, which exhibits much lower affinity for DNA. Under prolonged low iron conditions, the [2Fe-2S] cluster degrades to apo-RirA, which does not bind DNA and can no longer function as a repressor of the cell's iron-uptake machinery. [4Fe-4S] RirA was also found to be sensitive to O2, suggesting that both iron and O2 are important signals for iron metabolism. Consistent with this, in vivo data showed that expression of RirA-regulated genes is also affected by O2. These data lead us to propose a novel regulatory model for iron homeostasis, in which RirA senses iron via the incorporation of a fragile iron-sulfur cluster that is sensitive to iron and O2 concentrations. PMID- 29619195 TI - Crystallophore: a versatile lanthanide complex for protein crystallography combining nucleating effects, phasing properties, and luminescence. AB - Macromolecular crystallography suffers from two major issues: getting well diffracting crystals and solving the phase problem inherent to large macromolecules. Here, we describe the first example of a lanthanide complex family named "crystallophore" (Xo4), which contributes to tackling both bottlenecks. This terbium complex, Tb-Xo4, is an appealing agent for biocrystallography, combining the exceptional phasing power of the Tb(iii) heavy atom with powerful nucleating properties, providing ready-to-use crystals for structure determination. Furthermore, protein/Tb-Xo4 co-crystals can be easily detected and discriminated from other crystalline by-products using luminescence. We demonstrate the potential of this additive for the crystallisation and structure determination of eight proteins, two of whose structures were unknown. PMID- 29619197 TI - Unveiling the role of boroxines in metal-free carbon-carbon homologations using diazo compounds and boronic acids. AB - By means of computational and experimental mechanistic studies the fundamental role of boroxines in the reaction between diazo compounds and boronic acids was elucidated. Consequently, a selective metal-free carbon-carbon homologation of aryl and vinyl boroxines using TMSCHN2, giving access to TMS-pinacol boronic ester products, was developed. PMID- 29619196 TI - Dual targeting of the cancer antioxidant network with 1,4-naphthoquinone fused Gold(i) N-heterocyclic carbene complexes. AB - To achieve a systems-based approach to targeting the antioxidant pathway, 1,4 naphthoquinone annulated N-heterocyclic carbene (NHC) [bis(1,3-dimesityl-4,5 naphthoquino-imidazol-2-ylidene)-gold(i)] [silver(i) dichloride] (1), [bis(1,3 dimesityl-4,5-naphthoquino-imidazol-2-ylidene)-gold(i)] chloride (2), and 1,3 dimesityl-4,5-naphthoquino-imidazol-2-ylidene)-gold(i) chloride (3)) were designed, synthesized, and tested for biological activity in a series of human cancer cell lines. The solution phase of complexes 1-3 were assigned using several spectroscopy techniques, including NMR spectroscopic analysis. Complexes 1 and 3 were further characterized by single crystal X-ray diffraction analysis. Electrochemical and spectroelectrochemical studies revealed that quinone reductions are reversible and that the electrochemically generated semiquinone and quinone dianions are stable under these conditions. Complex 1, containing two NHC-quinone moieties (to accentuate exogenous ROS via redox cycling) centered around a Au(i) center (to inactivate thioredoxin reductase (TrxR) irreversibly), was found to inhibit cancer cell proliferation to a much greater extent than the individual components (i.e., Au(i)-NHC alone or naphthoquinone alone). Treatment of A549 lung cancer cells with 1 produced a 27-fold increase in exogenous reactive oxygen species (ROS) which was found to localize to the mitochondria. The inhibition of TrxR, an essential mediator of ROS homeostasis, was achieved in the same cell line at low administrated concentrations of 1. TrxR inhibition by 1 was similar to that of auranofin, a gold(i) containing complex known to inhibit TrxR irreversibly. Complex 1 was found to induce cell death via an apoptotic mechanism as confirmed by annexin-V staining. Complex 1 was demonstrated to be efficacious in zebrafish bearing A549 xenografts. These results provide support for the suggestion that a dual targeting approach that involves reducing ROS tolerance while concurrently increasing ROS production can perturb antioxidant homeostasis, enhance cancer cell death in vitro, and reduce tumor burden in vivo, as inferred from preliminary zebra fish model studies. PMID- 29619198 TI - Self-assembly of noble metal nanoparticles into sub-100 nm colloidosomes with collective optical and catalytic properties. AB - Self-assembly at the nanoscale represents a powerful tool for creating materials with new structures and intriguing collective properties. Here, we report a novel strategy to synthesize nanoscale colloidosomes of noble metals by assembling primary metal nanoparticles at the interface of emulsion droplets formed by their capping agent. This strategy produces noble metal colloidosomes of unprecedentedly small sizes (<100 nm) in high yield and uniformity, which is highly desirable for practical applications. In addition, it enables the high tunability of the composition, producing a diversity of monometallic and bimetallic alloy colloidosomes. The colloidosomes exhibit interesting collective properties that are different from those of individual colloidal nanoparticles. Specifically, we demonstrate Au colloidosomes with well-controlled interparticle plasmon coupling and Au-Pd alloy colloidosomes with superior electrocatalytic performance, both thanks to the special structural features that arise from the assembly. We believe this strategy provides a general platform for producing a rich class of miniature colloidosomes that may have fascinating collective properties for a broad range of applications. PMID- 29619199 TI - Linking the structures, free volumes, and properties of ionic liquid mixtures. AB - The formation of ionic liquid (IL) mixtures has been proposed as an approach to rationally fine-tune the physicochemical properties of ILs for a variety of applications. However, the effects of forming such mixtures on the resultant properties of the liquids are only beginning to be understood. Towards a more complete understanding of both the thermodynamics of mixing ILs and the effect of mixing these liquids on their structures and physicochemical properties, the spatial arrangement and free volume of IL mixtures containing the common [C4C1im]+ cation and different anions have been systematically explored using small angle X-ray scattering (SAXS), positron annihilation lifetime spectroscopy (PALS) and 129Xe NMR techniques. Anion size has the greatest effect on the spatial arrangement of the ILs and their mixtures in terms of the size of the non polar domains and inter-ion distances. It was found that differences in coulombic attraction between oppositely charged ions arising from the distribution of charge density amongst the atoms of the anion also significantly influences these inter-ion distances. PALS and 129Xe NMR results pertaining to the free volume of these mixtures were found to strongly correlate with each other despite the vastly different timescales of these techniques. Furthermore, the excess free volumes calculated from each of these measurements were in excellent agreement with the excess volumes of mixing measured for the IL mixtures investigated. The correspondence of these techniques indicates that the static and dynamic free volume of these liquid mixtures are strongly linked. Consequently, fluxional processes such as hydrogen bonding do not significantly contribute to the free volumes of these liquids compared to the spatial arrangement of ions arising from their size, shape and coulombic attraction. Given the relationship between free volume and transport properties such as viscosity and conductivity, these results provide a link between the structures of IL mixtures, the thermodynamics of mixing and their physicochemical properties. PMID- 29619200 TI - Biomolecular conformational changes and ligand binding: from kinetics to thermodynamics. AB - The behaviour of biomolecular systems is governed by their thermodynamic and kinetic properties. It is thus important to be able to calculate, for example, both the affinity and rate of binding and dissociation of a protein-ligand complex, or the populations and exchange rates between distinct conformational states. Because these are typically rare events, calculating these properties from long molecular dynamics simulations remains extremely difficult. Instead, one often adopts a divide-and-conquer strategy in which equilibrium free-energy differences and the fastest state-to-state transition (e.g. ligand association or minor-to-major state conversion) are combined to estimate the slow rate (e.g. ligand dissociation) using a two-state assumption. Here we instead address these problems by using a previously developed method to calculate both the forward and backward rates directly from simulations. We then estimate the thermodynamics from the rates, and validate these values by independent means. We applied the approach to three systems of increasing complexity, including the association and dissociation of benzene to a fully buried cavity inside the L99A mutant variant of T4 lysozyme. In particular, we were able to determine both millisecond association and dissociation rates, and the affinity, of the protein-ligand system by directly observing dozens of rare events in atomic detail. Our approach both sheds light on the precision of methods for calculating kinetics and further provides a generally useful test for the internal consistency of kinetics and thermodynamics. We also expect our route to be useful for obtaining both the kinetics and thermodynamics at the same time in more challenging cases. PMID- 29619201 TI - Unequivocal determination of caulamidines A and B: application and validation of new tools in the structure elucidation tool box. AB - Ambiguities and errors in the structural assignment of organic molecules hinder both drug discovery and total synthesis efforts. Newly described NMR experimental approaches can provide valuable structural details and a complementary means of structure verification. The caulamidines are trihalogenated alkaloids from a marine bryozoan with an unprecedented structural scaffold. Their unique carbon and nitrogen framework was deduced by conventional NMR methods supplemented by new experiments that define 2-bond heteronuclear connectivities, reveal very long range connectivity data, or visualize the 35,37Cl isotopic effect on chlorinated carbons. Computer-assisted structural elucidation (CASE) analysis of the spectroscopic data for caulamidine A provided only one viable structural alternative. Anisotropic NMR parameters, specifically residual dipolar coupling and residual chemical shift anisotropy data, were measured for caulamidine A and compared to DFT-calculated values for the proposed structure, the CASE-derived alternative structure, and two energetically feasible stereoisomers. Anisotropy based NMR experiments provide a global, orthogonal means to verify complex structures free from investigator bias. The anisotropic NMR data were fully consistent with the assigned structure and configuration of caulamidine A. Caulamidine B has the same heterocyclic scaffold as A but a different composition and pattern of halogen substitution. Caulamidines A and B inhibited both wild type and drug-resistant strains of the malaria parasite Plasmodium falciparum at low micromolar concentrations, yet were nontoxic to human cells. PMID- 29619203 TI - A fluorenylidene-acridane that becomes dark in color upon grinding - ground state mechanochromism by conformational change. AB - We report mechanochromic color change controlled by conformational change (between folded and twisted conformers) of fluorenylidene-acridanes (FAs). FAs with four N-alkyl groups (methyl, ethyl, n-butyl and n-octyl) were synthesized via the Barton-Kellogg reaction of diazofluorene and electrophilic N-tert-butoxy carbonyl thioacridone, deprotection of the tert-butoxy carbonyl group gives fluorenylacridine, and alkylation on the nitrogen atom is done using alkyl tosylate or triflate. FAs were characterized by NMR, UV-vis absorption and photoluminescence spectroscopy, theoretical calculation, cyclic voltammetry, and powder and single-crystal X-ray analyses. The color and folded/twisted conformation of the FAs were changed by the choice of substituent on the nitrogen atom, physical state (solution or solid), and morphology (crystalline or amorphous). Grinding of N-methyl FA solids, using an agate mortar, caused the morphology to change from a crystalline to amorphous state, which induced a conformational change from the folded to the twisted conformer, and a mechanochromic color change from yellow to dark green. The reverse color change, along with a morphological and conformational change to the folded conformer, was performed by solvent vapor exposure (chloroform). The twisted and folded conformers showed ambipolar (hole/electron) and hole-only transport properties, respectively. PMID- 29619202 TI - Site-specific detection of protein secondary structure using 2D IR dihedral indexing: a proposed assembly mechanism of oligomeric hIAPP. AB - Human islet amyloid polypeptide (hIAPP) aggregates into fibrils through oligomers that have been postulated to contain alpha-helices as well as beta-sheets. We employ a site-specific isotope labeling strategy that is capable of detecting changes in dihedral angles when used in conjunction with 2D IR spectroscopy. The method is analogous to the chemical shift index used in NMR spectroscopy for assigning protein secondary structure. We introduce isotope labels at two neighbouring residues, which results in an increased intensity and positive frequency shift if those residues are alpha-helical versus a negative frequency shift in beta-sheets and turns. The 2D IR dihedral index approach is demonstrated for hIAPP in micelles for which the polypeptide structure is known, using pairs of 13C18O isotope labels L12A13 and L16V17, along with single labeled control experiments. Applying the approach to aggregation experiments performed in buffer, we show that about 27-38% of hIAPP peptides adopt an alpha-helix secondary structure in the monomeric state at L12A13, prior to aggregation, but not at L16V17 residues. At L16V17, the kinetics are described solely by the monomer and fiber conformations, but at L12A13 the kinetics exhibit a third state that is created by an oligomeric intermediate. Control experiments performed with a single isotope label at A13 exhibit two-state kinetics, indicating that a previously unknown change in dihedral angle occurs at L12A13 as hIAPP transitions from the intermediate to fiber structures. We propose a mechanism for aggregation, in which helices seed oligomer formation via structures analogous to leucine rich repeat proteins. PMID- 29619204 TI - The harpooning mechanism as evidenced in the oxidation reaction of the Al atom. AB - The harpooning mechanism has long been proposed for elementary reaction dynamics involving metals. It is characterized by an initial electron transfer (ET) process from the metal to the oxidant molecule. For the titled reaction Al + O2, the ET distance can be predicted to be 2.6 A by simply calculating the energy difference between the ionization energy of the Al atom and the electron affinity of the O2 molecule. Hereby we experimentally derived the maximum impact parameter bmax of 2.5 +/- 0.2 A for the titled reaction, in consistency with the predicted ET distance. This derivation of bmax was achieved by using the crossed molecular beam experiment at a collision energy of 507 cm-1 (i.e. 1.45 kcal mol-1) with a high resolution time-sliced ion velocity imaging detection of the state-selective AlO products based on the (1 + 1) resonance-enhanced multiphoton ionization. The small rotational constant of the AlO(X2Sigma+) radical (Be = 0.6413 cm-1) facilitated the formation of the AlO(v = 0) products in high rotational levels up to the energetically limited state, Nmax = 52, with an almost zero velocity mapping. Hence, in this extreme angular momentum disposal case, the collisional orbital angular momentum l was nearly completely channeled into the product rotational angular momentum as a consequence of the conservations of energy and angular momentum, offering a reaction system that breaks the restriction of kinematically favored mass combination in order to obtain information on the impact parameters. The present study yields the first direct derivation of bmax from the maximum rotational level of products under the experimental condition with the recoil energy E'T ~ 0. This, in turn, provides solid evidence in supporting the harpooning mechanism. PMID- 29619205 TI - Deformylation reaction-based probe for in vivo imaging of HOCl. AB - The detection of hypochlorous acid (HOCl) in vivo is vitally important because the local concentration of HOCl is highly correlated with some diseases such as atherosclerosis and rheumatoid arthritis. However, in vivo detection of HOCl remains a challenge due to the lack of a suitable probe. We report here a near infrared (NIR) emissive "turn-on" probe (FDOCl-1) based on a methylene blue derivative, which can quickly detect HOCl via a newly found deformylation mechanism. FDOCl-1 displays remarkable selectivity and sensitivity towards HOCl. The dramatic changes in colour and NIR emission were used to detect HOCl in vitro and in vivo in a mouse arthritis model. PMID- 29619207 TI - Awareness of diabetic retinopathy among people with diabetes in Jeddah, Saudi Arabia. AB - Background: Diabetic retinopathy (DR) is the most common microvascular complication of diabetes mellitus (DM) and the foremost cause of blindness. This study aimed to assess the level of awareness of DR and its related risk factors among patients with DM in Jeddah, Saudi Arabia. Methods: A cross-sectional study was conducted among patients with DM attending primary health care centers at the Ministry of Health in Jeddah. A structured, pretested, self-administered questionnaire was used to collect information on the sociodemographic and DM- and DR-related characteristics of the patients. Results: A total of 377 patients were enrolled. About 82.6% of the patients were aware that DM can affect their eyes, and they listed physicians, ophthalmologists, television, and family members as common sources of information on the topic. About 36% of the patients reported that their doctors had not advised them about it. More than half responded that they did not feel their vision to be affected by DM. More than 58% had never been diagnosed with DR. About 35% did not go to their eye checkups, even though around 59% thought that DR could lead to blindness. Of the 64% of patients whose DM was well controlled, 11% and 25% listed surgery and laser treatment, respectively, as available treatment options for DR. The following factors were found to be significant in relation to the subjects' awareness that DM can affect their eyes: the patients' perception of their doctors' advice about DR; the experience of having their vision affected by DM; the knowledge that DR may lead to blindness; the practice of going to eye checkups. Conclusions: Despite having good awareness about DM and its effects on eyes, the patients exhibited a relative lack of awareness about DR. Considering the association of DR with DM, its increasing magnitude is a potential burden on the community and health systems. PMID- 29619206 TI - Achieving efficient photodynamic therapy under both normoxia and hypoxia using cyclometalated Ru(ii) photosensitizer through type I photochemical process. AB - Photodynamic therapy (PDT) through the generation of singlet oxygen utilizing photosensitizers (PSs) is significantly limited under hypoxic conditions in solid tumors. So it is meaningful to develop effective PSs which can maintain excellent therapeutic effects under hypoxia. Here we reported a coumarin-modified cyclometalated Ru(ii) photosensitizer (Ru2), which exhibits lower oxidation potential and stronger absorption in the visible region than the coumarin-free counterpart. The evaluation of the PDT effect was performed under both normoxia and hypoxia. The results showed that Ru2 has a better therapeutic effect than the coumarin-free counterpart in in vitro experiments. Especially under hypoxia, Ru2 still retained an excellent PDT effect, which can be attributed to the direct charge transfer between the excited PS and an adjacent substrate through a type I photochemical process, forming highly-oxidative hydroxyl radicals to damage tumor cells. The anti-tumor activity of Ru2 was further proven to be effective in tumor bearing mice, and tumor growth was inhibited remarkably under PDT treatment. PMID- 29619208 TI - Conversion from insulin glargine U-100 to insulin glargine U-300 or insulin degludec and the impact on dosage requirements. AB - Background: We wanted to determine whether basal insulin requirements change when patients transition from insulin glargine U-100 (Gla-100) to insulin glargine U 300 (Gla-300) or insulin degludec. Methods: This study involved subjects seen in the University of Colorado Health Endocrine Clinic who were transitioned from Gla 100 to either Gla-300 (n = 95) or insulin degludec (n = 39). The primary outcome was the difference between baseline Gla-100 dose and dose of Gla-300 or insulin degludec prescribed after first follow-up visit within 1-12 months. Secondary outcomes included changes in glycemic control and empiric dose conversion from Gla-100 to Gla-300 or insulin degludec on the day of transition. Wilcoxon rank sum tests evaluated changes in insulin doses, and paired t tests assessed changes in glycemic control using GraphPad statistical software. Results: Median daily basal insulin dose increased for individuals transitioned from Gla-100 to Gla-300 from 30 [19-60 interquartile range (IQR)] units at baseline to 34.5 (19-70 IQR) units after follow up (p = 0.01). For patients transitioned to insulin degludec, dose changes from baseline to follow up were not significantly different (p = 0.56). At the time of transition, the prescribed dose of Gla-300 or insulin degludec did not significantly differ from the previous dose of Gla-100 (p = 0.73 and 0.28, respectively), indicating that empiric dose adjustments were not routinely prescribed. Conclusions: Patients who transitioned from Gla-100 to Gla 300 had increased basal insulin requirements between visits, while basal insulin requirements for those transitioned from Gla-100 to insulin degludec were not significantly different. PMID- 29399322 TI - Evaluation of predicted Medfly ( Ceratitis capitata) quarantine length in the United States utilizing degree-day and agent-based models. AB - Invasions by pest insects pose a significant threat to agriculture worldwide. In the case of Ceratitis capitata incursions on the US mainland, where it is not officially established, repeated detections are followed by quarantines and treatments to eliminate the invading population. However, it is difficult to accurately set quarantine duration because non-detection may not mean the pest is eliminated. Most programs extend quarantine lengths past the last fly detection by calculating the amount of time required for 3 generations to elapse under a thermal unit accumulation development model ("degree day"). A newer approach is to use an Agent-Based Simulation (ABS) to explicitly simulate population demographics and elimination. Here, predicted quarantine lengths for 11 sites in the continental United States are evaluated using both approaches. Results indicate a strong seasonality in quarantine length, with longer predictions in the second half of the year compared with the first; this pattern is more extreme in degree day predictions compared with ABS. Geographically, quarantine lengths increased with latitude, though this was less pronounced under the ABS. Variation in quarantine lengths for particular times and places was dramatically larger for degree day than ABS, generally spiking in the middle of the year for degree day and peaking in second half of the year for ABS. Analysis of 34 C. capitata quarantines from 1975 to 2017 in California shows that, for all but two, quarantines were started in the second half of the year, when degree day quarantine lengths are longest and have the highest uncertainty. For a set of hypothetical outbreaks based on these historical quarantines, the ABS produced significantly shorter quarantines than degree day calculations. Overall, ABS quarantine lengths were more consistent than degree day predictions, avoided unrealistically long values, and captured effects of rare events such as cold snaps. PMID- 29619209 TI - Contemporary approaches to the management of polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is a common disorder in women in their reproductive years and is characterized by androgen excess, ovulatory dysfunction, and polycystic ovarian morphology. It is also associated with several metabolic abnormalities, particularly insulin resistance and obesity, which play an important role in the pathophysiology of PCOS and, in particular, negatively influence ovarian function and fertility. This review article summarizes the available treatment for women with PCOS. Specifically, current and potentially new therapies are discussed. PMID- 29619211 TI - Quantifying bias in measuring insecticide-treated bednet use: meta-analysis of self-reported vs objectively measured adherence. AB - Background: Insecticide-treated bednets (ITNs) are recommended for use by 3.4 billion people at risk of malaria world-wide. Policy makers rely on measurements of ITN use to optimize malaria prevention efforts. Self-reports are the most common means of assessing ITN use, but self-reports may be biased in a way that reduces their reliability as a proxy for ITN adherence. This meta-analysis compared self-reported and two methods which are more objective measures of ITN use to explore whether self-reports overestimate actual ITN adherence. Methods: A comprehensive search of electronic databases and hand searching reference lists resulted in screening 2885 records and 202 articles were read in full. Sixteen articles with comparable data were chosen for the meta-analysis. Comparable data was defined as self-reported and objectively measured ITN use (observation of a mounted ITN or surprise visits confirming use) at the same unit of analysis, covering the same time period and same population. A random effects model was used to determine a weighted average risk difference between self-reported and objectively measured ITN use. Additional stratified analyses were conducted to explore study heterogeneity. Results: Self-reported ITN use is 8 percentage points (95% confidence interval CI: 3 to 13) higher than objectively measured ITN use, representing a 13.6% overestimation relative to the proportion measured as adherent to ITN use by objective measures. Wide variations in the discrepancies between self-reports and objective measures were unable to be explained using stratified analyses of variables including location, year of publication, seasonality and others. Conclusions: Self-reports overestimate ITN adherence relative to objectively measured ITN use by 13.6% and do so in an unpredictable manner that raises questions about the reliability of using self-reported ITN use alone as a surveillance tool and a guide for making policy decisions. PMID- 29619212 TI - Validity of maternal report of care-seeking for childhood illness. AB - Background: Accurate data on care-seeking for child illness are needed to improve public health programs and reduce child mortality. The accuracy of maternal report of care-seeking for child illness as collected through household surveys has not been validated. Methods: A 2016 survey compared reported care-seeking against a gold-standard of health care provider documented care-seeking events among a random sample of mothers of children <5 years in Southern Province, Zambia. Enrolled children were assigned cards with unique barcodes. Seventy-five health care providers were given smartphones with a barcode reader and instructed to scan the cards of participating children seeking care at the source, generating an electronic record of the care-seeking event. Additionally, providers gave all caregivers accessing care for a child <5 years provider specific tokens used to verify the point of care during the household survey. Reported care-seeking events were ascertained in each household using a questionnaire modeled off the Zambia Demographic and Health Survey (DHS) / Multiple Indicator Cluster Survey (MICS). The accuracy of maternal report of care seeking behavior was estimated by comparing care-seeking events reported by mothers against provider-documented events. Results: Data were collected on 384 children with fever, diarrhea, and/or symptoms of ARI in the preceding 2 weeks. Most children sought care from government facilities or community-based agents (CBAs). We found high sensitivity (Rural: 0.91, 95% confidence interval CI 0.84 0.95; Urban: 0.98, 95% CI 0.92-0.99) and reasonable specificity (Rural: 0.71, 95% CI 0.57-0.82; Urban: 0.76, 95% CI 0.62-0.85) of maternal report of care-seeking for child illness by type of provider. Maternal report of any care-seeking and seeking care from a skilled provider had slightly higher sensitivity and specificity. Seeking care from a traditional practitioner was associated with lower odds of accurately reporting the event, while seeking care from a government provider was associated with greater odds of accurate report. The measure resulted in a slight overestimation of true care-seeking behavior in the study population. Conclusions: Maternal report is a valid measure of care-seeking for child illness in settings with high utilization of public sector providers. The study findings were limited by the low diversity in care-seeking practices for child illness and the exclusion of shops. PMID- 29619213 TI - Pet owner and vet interactions: exploring the drivers of AMR. AB - Background: Antimicrobial resistance (AMR) is a growing public health problem across the world. As the negative consequences of AMR become apparent at local, national and international levels, more attention is being focussed on the variety of mechanisms by which AMR is potentiated. We explore how interactions between pet owners and veterinarians represent a key arena in which AMR-related behaviours can be shaped. Methods: In depth semi-structured interviews were carried out with pet owners (n = 23) and vets (n = 16) across the UK in 2017. A thematic analysis approach was taken, with inductively gathered data analysed deductively using a behavioural framework to identified key behaviours emerging from participant accounts which were amenable to change. Results: Interactions between vets and pet owners were characterised by misunderstandings and misconceptions around antibiotics by pet owners, and a lack of clarity about the positions and intentions of the other party. Vets and pet owners had differing perceptions of where pressure to prescribe antibiotics inappropriately originated. Vets perceived it was mostly pet owners who pushed for inappropriate antibiotics, whereas pet owners reported they felt it was vets that overprescribed. Low levels of understanding of AMR in general were apparent amongst pet owners and understandings with regard to AMR in pets specifically were almost non-existent in the sample. Conclusions: Improved use of antibiotics could be assisted by educating the pet owning public and by guideline development for companion animal vets, concurrent development of mandatory legislation, increased consultation time to facilitate better communication, development of vet training on antimicrobial therapy and stewardship led interactions with pet owners, and increased levels of knowledge of pet-related AMR amongst pet owners. PMID- 29619214 TI - Multiple drug resistance and biocide resistance in Escherichia coli environmental isolates from hospital and household settings. AB - Background: Antibiotic resistance of environmental Escherichia coli in hospitals could be increased due to extensive use of biocides resulting in serious infections. In this study, the prevalence of antibiotic resistance of environmental isolates of E. coli from hospitals and household settings were evaluated and compared. In addition, the association between biocide minimum inhibitory concentration (MIC) and multiple drug resistance (MDR) was investigated. Methods: Environmental samples were collected from different homes and hospitals in Amman, Jordan. The isolates were identified phenotypically and by PCR. Antibiotic susceptibility tests and MIC of selected biocides were performed on the isolates. Screening for blaCTX-M group 1 was also performed. Results: Of 21 E. coli strains isolated, 47.6% were MDR and 67.9% were phenotypically identified as extended spectrum beta-lactamase (ESBL) producers. The occurrence of these ESBL isolates was comparable between household and hospital settings (P > 0.05). The MIC values of the biocides tested against all isolates were well below the in-use concentration of biocides. Moreover, the MICs of biocides were comparable between isolates from households and those from hospitals (P > 0.05). No association was found between MDR and biocide MIC (P > 0.05). Most of ESBL isolates harboured blaCTX-M 1. Conclusions: The extensive use of biocides in hospitals is not associated with MDR nor does it affect the MIC of biocides against E.coli. PMID- 29619215 TI - Proteomic analysis of adipose tissue during the last weeks of gestation in pure and crossbred Large White or Meishan fetuses gestated by sows of either breed. AB - Background: The degree of adipose tissue development at birth may influence neonatal survival and subsequent health outcomes. Despite their lower birth weights, piglets from Meishan sows (a fat breed with excellent maternal ability) have a higher survival rate than piglets from Large White sows (a lean breed). To identify the main pathways involved in subcutaneous adipose tissue maturation during the last month of gestation, we compared the proteome and the expression levels of some genes at d 90 and d 110 of gestation in purebred and crossbred Large White or Meishan fetuses gestated by sows of either breed. Results: A total of 52 proteins in fetal subcutaneous adipose tissue were identified as differentially expressed over the course of gestation. Many proteins involved in energy metabolism were more abundant, whereas some proteins participating in cytoskeleton organization were reduced in abundance on d 110 compared with d 90. Irrespective of age, 24 proteins differed in abundance between fetal genotypes, and an interaction effect between fetal age and genotype was observed for 13 proteins. The abundance levels of proteins known to be responsive to nutrient levels such as aldolase and fatty acid binding proteins, as well as the expression levels of FASN, a key lipogenic enzyme, and MLXIPL, a pivotal transcriptional mediator of glucose-related stimulation of lipogenic genes, were elevated in the adipose tissue of pure and crossbred fetuses from Meishan sows. These data suggested that the adipose tissue of these fetuses had superior metabolic functionality, whatever their paternal genes. Conversely, proteins participating in redox homeostasis and apoptotic cell clearance had a lower abundance in Meishan than in Large White fetuses. Time-course differences in adipose tissue protein abundance were revealed between fetal genotypes for a few secreted proteins participating in responses to organic substances, such as alpha 2-HS-glycoprotein, transferrin and albumin. Conclusions: These results underline the importance of not only fetal age but also maternal intrauterine environment in the regulation of several proteins in subcutaneous adipose tissue. These proteins may be used to estimate the maturity grade of piglet neonates. PMID- 29619216 TI - Mutant IDH1 gliomas downregulate phosphocholine and phosphoethanolamine synthesis in a 2-hydroxyglutarate-dependent manner. AB - Background: Magnetic resonance spectroscopy (MRS) studies have identified elevated levels of the phospholipid precursor phosphocholine (PC) and phosphoethanolamine (PE) as metabolic hallmarks of cancer. Unusually, however, PC and PE levels are reduced in mutant isocitrate dehydrogenase 1 (IDHmut) gliomas that produce the oncometabolite 2-hydroxyglutarate (2-HG) relative to wild-type IDH1 (IDHwt) gliomas. The goal of this study was to determine the molecular mechanism underlying this unusual metabolic reprogramming in IDHmut gliomas. Methods: Steady-state PC and PE were quantified using 31P-MRS. To quantify de novo PC and PE synthesis, we used 13C-MRS and measured flux to 13C-PC and 13C-PE in cells incubated with [1,2-13C]-choline and [1,2-13C]-ethanolamine. The activities of choline kinase (CK) and ethanolamine kinase (EK), the enzymes responsible for PC and PE synthesis, were quantified using 31P-MR-based assays. To interrogate the role of 2-HG, we examined IDHwt cells incubated with 2-HG and, conversely, IDHmut cells treated with the IDHmut inhibitor AGI-5198. To examine the role of hypoxia-inducible factor 1-alpha (HIF-1alpha), we silenced HIF-1alpha using RNA interference. To confirm our findings in vivo and in the clinic, we studied IDHwt and IDHmut orthotopic tumor xenografts and glioma patient biopsies. Results: De novo synthesis of PC and PE was reduced in IDHmut cells relative to IDHwt. Concomitantly, CK activity and EK activity were reduced in IDHmut cells. Pharmacological manipulation of 2-HG levels established that 2-HG was responsible for reduced CK activity, EK activity, PC and PE. 2-HG has previously been reported to stabilize levels of HIF-1alpha, a known regulator of CK activity. Silencing HIF-1alpha in IDHmut cells restored CK activity, EK activity, PC and PE to IDHwt levels. Our findings were recapitulated in IDHmut orthotopic tumor xenografts and, most importantly, in IDHmut patient biopsies, validating our findings in vivo and in the clinic. Conclusions: This study identifies, to our knowledge for the first time, a direct role for 2-HG in the downregulation of CK and EK activity, and thereby, PC and PE synthesis in IDHmut gliomas. These results highlight the unusual reprogramming of phospholipid metabolism in IDHmut gliomas and have implications for the identification of MRS-detectable metabolic biomarkers associated with 2-HG status. PMID- 29619217 TI - Metabolomics of oncogene-specific metabolic reprogramming during breast cancer. AB - Background: The complex yet interrelated connections between cancer metabolism and oncogenic driver genes are relatively unexplored but have the potential to identify novel biomarkers and drug targets with prognostic and therapeutic value. The goal of this study was to identify global metabolic profiles of breast tumors isolated from multiple transgenic mouse models and to identify unique metabolic signatures driven by these oncogenes. Methods: Using mass spectrometry (GC-MS, LC MS/MS, and capillary zone electrophoresis (CZE)-MS platforms), we quantified and compared the levels of 374 metabolites in breast tissue from normal and transgenic mouse breast cancer models overexpressing a panel of oncogenes (PyMT, PyMT-DB, Wnt1, Neu, and C3-TAg). We also compared the mouse metabolomics data to published human metabolomics data already linked to clinical data. Results: Through analysis of our metabolomics data, we identified metabolic differences between normal and tumor breast tissues as well as metabolic differences unique to each initiating oncogene. We also quantified the metabolic profiles of the mammary fat pad versus mammary epithelium by CZE-MS/MS. However, the differences between the tissues did not account for the majority of the metabolic differences between the normal mammary gland and breast tumor tissues. Therefore, the differences between the cohorts were unlikely due to cellular heterogeneity. Of the mouse models used in this study, C3-TAg was the only cohort with a tumor metabolic signature composed of ten metabolites that had significant prognostic value in breast cancer patients. Gene expression analysis identified candidate genes that may contribute to the metabolic reprogramming. Conclusions: This study identifies oncogene-induced metabolic reprogramming within mouse breast tumors and compares the results to that of human breast tumors, providing a unique look at the relationship between and clinical value of oncogene initiation and metabolism during breast cancer. PMID- 29619219 TI - Examining the social status, risk factors and lifestyle changes of tuberculosis patients in Sri Lanka during the treatment period: a cross-sectional study. AB - Background: Tuberculosis (TB) is a major global health problem, commonly seen in underdeveloped countries. The probability of contracting the disease is significantly higher among the economically vulnerable and the socially disadvantaged. Risk factors associated with TB can also change over time. In the Sri Lankan context, no study has explored how these factors impact patients. Therefore, we aimed to explore social status, associated risk factors and lifestyle changes during the treatment period of TB patients attending a tertiary respiratory center in Colombo, Sri Lanka. Methods: The descriptive cross sectional study was conducted in 2011. The study population consisted of diagnosed tuberculosis patients above the age of 15 years. Patient records were retrieved from the TB patient registry for the Colombo district. Systematic sampling was used to identify patients to be invited to the study. An interviewer administered questionnaire was used for data collection. Data were collected on social status (example, level of education, employment, and income), associated risk factors (example, smoking and alcohol consumption, contact history, narcotic drug use) and lifestyle changes during treatment (example, employment status, social interactions). The analysis included a logistic regression model to explore the association between social status and risk factors. Results: The total number of patients included in the study was 425. Tuberculosis was found to be strongly prevalent among participants from the lower socio-economic status. It was also common in participants with a low level of education, unemployed, if employed, those who are engaged in unskilled employment and have low levels of income. Risk factors associated with the patients were smoking, alcohol consumptions, narcotic drug use, imprisonment, close contact history with active TB patients and chronic medical conditions. Changes in employment and the reduction of social-interactions were the main lifestyle changes of the participants occurred during the treatment period. The analysis also showed positive correlation between low-level social status and sputum smear infectivity, and use of dangerous drugs. Even after adjusting for confounders, tuberculosis negatively affected social interactions and income levels of participants from the low social status. Conclusion: Low socio-economic status negatively affected the lifestyle and social interactions of patients during the treatment period. Though competent treatment programs exist in Sri Lanka, it is still important to identify and mitigate risk factors associated with tuberculosis patients. A comprehensive multi-disciplinary approach considering patient lifestyle, and the implications of the disease and treatment on social interactions may strengthen the current preventive strategies. PMID- 29619218 TI - The burden and high prevalence of hypertension in Pakistani adolescents: a meta analysis of the published studies. AB - Background: Hypertension has been recognized as a global health concern for developing countries and is scarcely described in many of these countries. In Pakistan, few population-based surveys evaluated the prevalence of hypertension and there is no current nationally representative study (the latest nationwide survey was conducted more than two decades ago). Objective: The goal of the current study was to estimate the pooled prevalence of hypertension in Pakistani population using meta-analysis approach. Methods: We searched the published literature using PubMed, Google and Scopus supplemented by a manual search of bibliographies of retrieved articles for population studies providing estimates on the prevalence of hypertension between 1990 and 2017. Studies were included if they defined hypertension as >=140/90 mmHg and conducted in adults (>=15 years). From the extracted results, the heterogeneity index of the studies was determined using Chi-squared I2 tests and on the basis of heterogeneity, a fixed or random effect model was used to estimates the pooled prevalence of hypertension. Meta regression was performed to determine those factor of generating heterogeneity. Results: Of a total of 1240 articles, 18 studies comprising 42,618 participants met the eligibility criteria. The overall pooled prevalence of hypertension was 26.34% (25.93%, 26.75%). Subgroup analysis showed higher urban prevalence 26.61% (21.80%, 31.42%) than the rural dwellers 21.03% (10.18%, 31.87%). The prevalence by decade in 1990s was 19.55% (18.07%, 21.05%), in 2000s 23.95% (16.60%, 31.30%) and in 2010s 29.95% (24.13%, 35.77%). Similarly, the pooled prevalence was 24.99% (19.70%, 30.28%) in males and 24.76% (16.76%, 32.76%) in females. We recorded high burden of hypertension among the adult Pakistanis when compared to the data published in local and international journals 23.32% (18.9%, 27.74%) and 27.44% (20.97%, 33.91%). We also found differences in the prevalence of hypertension among small, medium and large studies. Conclusion: Comparing data from previous studies in Pakistan, we found a higher prevalence in urban areas and among males. The prevalence over time is likely to increase faster, further our results underscore the importance of good quality long-term studies that will help to understand hypertension better and implement effective prevention and management programs. PMID- 29619221 TI - Primary racemose hemangioma with bronchial-pulmonary arterial fistula. AB - Primary racemose hemangioma with bronchial-pulmonary arterial fistula is a very rare abnormality. We herein report an asymptomatic case of primary racemose hemangioma with no significant size change in 5 years. PMID- 29619220 TI - Development of the "Recovery from Eating Disorders for Life" Food Guide (REAL Food Guide) - a food pyramid for adults with an eating disorder. AB - Background: There is limited evidence to inform nutrition and dietetic interventions for individuals with eating disorders even though it is recommended as an essential part of multidisciplinary management. There is minimal guidance, an absence of standardised nutrition educational material, and no research on how best to educate patients on healthy eating and how to achieve nutrition adequacy. Therefore the REAL Food Guide was developed. Methods: The REAL Food Guide is a pyramid with four layers and key nutrition messages beside each layer that was conceived to address gaps in nutrition education and intervention for individuals with eating disorders. Written and verbal consumer feedback was obtained from consumers receiving treatment regarding the acceptability and usefulness of the REAL Food Guide. A unique database was developed to reflect the types of foods and realistic portion sizes that patients are likely to select. This database was used for nutrition modelling to assess the nutrition adequacy of three meal patterns (meat containing, vegetarian and semi-vegan) for both weight maintenance and weight regain. Each meal pattern was compared to the Nutrient Reference Values for Australia and New Zealand. Results: Nutritional analysis demonstrated nutritional adequacy of meal patterns for energy, macronutrients and most micronutrients when the recommended number of serves from the REAL Food Guide were assessed. All meal patterns were adequate in micronutrients except for the semi-vegan meal pattern that was inadequate in vitamin D. Feedback from individuals with eating disorders demonstrates the nutrition education tool was acceptable to them as they felt it was more helpful for their recovery than general nutrition guidelines. Conclusion: The REAL Food Guide is a comprehensive and user-friendly guide that clinicians can use to educate patients about components of a balanced and healthy diet. The guide can educate all eating disorder clinicians, including those who are new to the field, about the basics of nutrition. Clinicians using the guide can be confident that, if followed, patient's energy and nutritional requirements will be met and important nutrition education messages are reinforced, that are tailored to the beliefs and concerns of individuals with eating disorders. PMID- 29619222 TI - Laryngomalacia presenting as severe uncontrolled asthma. AB - Congenital laryngomalacia is the most common cause of stridor in infants and usually resolves without therapy by 12-18 months of age. However, a recent study found that laryngomalacia may leave structural and functional traces with increased risk of later respiratory symptoms, suggesting that late-onset laryngomalacia may represent long-term consequences of milder or even undiagnosed forms. Unusual cases demonstrated that inspiratory stridor developed subsequent to upper respiratory tract infections. The lack of airway hyperresponsiveness in adulthood also raised questions regarding the diagnosis of childhood asthma. Laryngomalacia should be distinguished from severe asthma. PMID- 29619223 TI - Respiratory exacerbation in a young adult with cystic fibrosis and tricuspid atresia. AB - Tricuspid atresia (TAt) is a complex congenital heart defect (CHD) characterized by the absence of the tricuspid valve and right ventricular hypoplasia requiring surgery in childhood, the Fontan procedure. We present a case of a 21-year-old male with TAt and cystic fibrosis (CF), who underwent a Fontan procedure in childhood, presenting to an adult CF clinic with severe deterioration in his respiratory status and multi-organ dysfunction associated with CF. This report describes problems associated with the management of a CF respiratory exacerbation and extrapulmonary manifestations of CF in the unique situation of a Fontan circulation, a circulation with absence of a subpulmonary ventricle and pulsatile pulmonary arterial blood flow where maintenance of systemic cardiac output is totally dependent on good respiratory function and low pulmonary artery pressures. PMID- 29619224 TI - Sperm aneuploidy and DNA fragmentation in unexplained recurrent pregnancy loss: a multicenter case-control study. AB - Background: Recurrent pregnancy loss (RPL) is defined as the loss of at least three pregnancies in the first trimester. Although the most common cause is embryo aneuploidy, and despite female checkup and couple karyotyping, in about 50% of cases RPL remain unexplained. Male implication has little been investigated and results are discordant. In this context, we conducted a multi center prospective case-control study to investigate male gamete implication in unexplained RPL. Methods: A total of 33 cases and 27 controls were included from three university hospitals. We investigated environmental and family factors with a detailed questionnaire and andrological examination, sperm characteristics, sperm DNA/chromatin status using the sperm chromatin structure assay (SCSA) and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and sperm aneuploidy using fluorescence in situ hybridization (FISH). The Mann-Whitney test and the Wilcoxon or Fisher exact tests were used. A non-parametric Spearman correlation was performed in order to analyze the relationship between various sperm parameters and FISH and sperm DNA fragmentation results. Results: We found significant differences between cases and controls in time to conceive, body mass index (BMI), family history of infertility and living environment. In cases, total sperm motility and the percentage of morphologically normal spermatozoa were significantly decreased. No difference was found between cases and controls in sperm DNA fragmentation or chromatin integrity. In cases, spermatozoa with aneuploidy, hyperhaploidy and chromosome 18 disomy were significantly increased. Conclusions: This prospective case-control study is one of the largest to examine environmental factors, sperm characteristics, sperm DNA fragmentation and chromatin, and chromosome anomalies in spermatozoa in relation to unexplained recurrent pregnancy loss. The originality of our study lies in the comprehensive andrological examination and search for risk factors and fertility history. Further studies are needed to confirm the links between unexplained RPL and a male family history of infertility or miscarriages. The increased sperm aneuploidy observed in unexplained RPL supports a male etiology. These data pave the way for further studies to demonstrate the value of preimplantation genetic screening in men with increased sperm aneuploidy whose partners experience unexplained RPL. PMID- 29619226 TI - Building a strong European alliance for personality disorder research and intervention. AB - People with personality disorders frequently face stigma, ignorance and pessimism regarding the treatability of their disorders. This is despite substantial progress that has been made in developing a number of effective evidence based psychotherapeutic treatments. However, expertise in how to systematically deliver these treatments in a sustainable way throughout Europe is largely lacking. To bridge the gap between evidence based treatments and their implementation in health services, the European Society for the Study of Personality Disorders is currently building a new alliance of experts to promote personality disorder scholarship, and to support the development of clinical expertise and systematic treatment implementation throughout Europe. The aim of this paper is to describe how the Society is currently using its interdisciplinary and international roster of experts to address the specific treatment and research needs of the European personality disorder field, particularly to countries in which expertise in the field is less developed. PMID- 29619225 TI - Recommendations for applying a multi-dimensional model of impulsive personality to diagnosis and treatment. AB - The UPPS-P Model of Impulsive Personality, a prominent model of impulsive personality derived from the Five Factor Model of Personality, is a multi dimensional model of impulsive personality that consists of negative urgency, lack of premeditation, lack of perseveration, sensation seeking, and positive urgency. The UPPS-P model has highlighted the importance of separating multidimensional traits due to the specificity of these traits corresponding to different risk behaviors. The goal of the current review paper is to make recommendations on how to apply the UPPS-P Model of Impulsive Personality, to diagnosis of and treatment for psychopathology. However, despite impulsivity being one of the most frequently used criteria for a number of clinical disorders, our review of the Diagnostic and Statistical Manual for Mental Disorders-5 found that the UPPS-P traits are not well represented in the diagnostic criteria, which we propose limits inferences about etiology and treatment targets. Additionally, research has largely focused on the importance of these traits for risk models; our review of the literature applying the UPPS-P traits to treatment processes and outcomes concluded that this area is not yet well studied. Here, we propose the specific application of the UPPS-P model to improve diagnosis and increase treatment effectiveness. PMID- 29619227 TI - Transcriptome profiling reveals regulatory mechanisms underlying corolla senescence in petunia. AB - The genetic regulatory mechanisms that govern natural corolla senescence in petunia are not well understood. To identify key genes and pathways that regulate the process, we performed a transcriptome analysis in petunia corolla at four developmental stages, including corolla fully opening without anther dehiscence (D0), corolla expansion, 2 days after anthesis (D2), corolla with initial signs of senescence (D4), and wilting corolla (D7). We identified large numbers of differentially expressed genes (DEGs), ranging from 4626 between the transition from D0 and D2, 1116 between D2 and D4, a transition to the onset of flower senescence, and 327 between D4 and D7, a developmental stage representing flower senescence. KEGG analysis showed that the auxin- and ethylene-related hormone biosynthesis and signaling transduction pathways were significantly activated during the flower development and highly upregulated at onset of flower senescence. Ethylene emission was detected at the D2 to D4 transition, followed by a large eruption at the D4 to D7 transition. Furthermore, large numbers of transcription factors (TFs) were activated over the course of senescence. Functional analysis by virus-induced gene silencing (VIGS) experiments demonstrated that inhibition of the expression of TFs, such as ethylene-related ERF, auxin-related ARF, bHLH, HB, and MADS-box, significantly extended or shortened flower longevity. Our data suggest that hormonal interaction between auxin and ethylene may play critical regulatory roles in the onset of natural corolla senescence in petunia. PMID- 29619228 TI - Genotyping-by-sequencing application on diploid rose and a resulting high-density SNP-based consensus map. AB - Roses, which have been cultivated for at least 5000 years, are one of the most important ornamental crops in the world. Because of the interspecific nature and high heterozygosity in commercial roses, the genetic resources available for rose are limited. To effectively identify markers associated with QTL controlling important traits, such as disease resistance, abundant markers along the genome and careful phenotyping are required. Utilizing genotyping by sequencing technology and the strawberry genome (Fragaria vesca v2.0.a1) as a reference, we generated thousands of informative single nucleotide polymorphism (SNP) markers. These SNPs along with known bridge simple sequence repeat (SSR) markers allowed us to create the first high-density integrated consensus map for diploid roses. Individual maps were first created for populations J06-20-14-3*"Little Chief" (J14-3*LC), J06-20-14-3*"Vineyard Song" (J14-3*VS) and "Old Blush"*"Red Fairy" (OB*RF) and these maps were linked with 824 SNPs and 13 SSR bridge markers. The anchor SSR markers were used to determine the numbering of the rose linkage groups. The diploid consensus map has seven linkage groups (LGs), a total length of 892.2 cM, and an average distance of 0.25 cM between 3527 markers. By combining three individual populations, the marker density and the reliability of the marker order in the consensus map was improved over a single population map. Extensive synteny between the strawberry and diploid rose genomes was observed. This consensus map will serve as the tool for the discovery of marker-trait associations in rose breeding using pedigree-based analysis. The high level of conservation observed between the strawberry and rose genomes will help further comparative studies within the Rosaceae family and may aid in the identification of candidate genes within QTL regions. PMID- 29619229 TI - Transcriptional analysis and histochemistry reveal that hypersensitive cell death and H2O2 have crucial roles in the resistance of tea plant (Camellia sinensis (L.) O. Kuntze) to anthracnose. AB - Anthracnose causes severe losses of tea production in China. Although genes and biological processes involved in anthracnose resistance have been reported in other plants, the molecular response to anthracnose in tea plant is unknown. We used the susceptible tea cultivar Longjing 43 and the resistant cultivar Zhongcha 108 as materials and compared transcriptome changes in the leaves of both cultivars following Colletotrichum fructicola inoculation. In all, 9015 and 8624 genes were differentially expressed between the resistant and susceptible cultivars and their controls (0 h), respectively. In both cultivars, the differentially expressed genes (DEGs) were enriched in 215 pathways, including responses to sugar metabolism, phytohormones, reactive oxygen species (ROS), biotic stimuli and signalling, transmembrane transporter activity, protease activity and signalling receptor activity, but DEG expression levels were higher in Zhongcha 108 than in Longjing 43. Moreover, functional enrichment analysis of the DEGs showed that hydrogen peroxide (H2O2) metabolism, cell death, secondary metabolism, and carbohydrate metabolism are involved in the defence of Zhongcha 108, and 88 key genes were identified. Protein-protein interaction (PPI) network demonstrated that putative mitogen-activated protein kinase (MAPK) cascades are activated by resistance (R) genes and mediate downstream defence responses. Histochemical analysis subsequently validated the strong hypersensitive response (HR) and H2O2 accumulation that occurred around the hyphal infection sites in Zhongcha 108. Overall, our results indicate that the HR and H2O2 are critical mechanisms in tea plant defence against anthracnose and may be activated by R genes via MAPK cascades. PMID- 29619230 TI - The grapevine kinome: annotation, classification and expression patterns in developmental processes and stress responses. AB - Protein kinases (PKs) have evolved as the largest family of molecular switches that regulate protein activities associated with almost all essential cellular functions. Only a fraction of plant PKs, however, have been functionally characterized even in model plant species. In the present study, the entire grapevine kinome was identified and annotated using the most recent version of the grapevine genome. A total of 1168 PK-encoding genes were identified and classified into 20 groups and 121 families, with the RLK-Pelle group being the largest, with 872 members. The 1168 kinase genes were unevenly distributed over all 19 chromosomes, and both tandem and segmental duplications contributed to the expansion of the grapevine kinome, especially of the RLK-Pelle group. Ka/Ks values indicated that most of the tandem and segmental duplication events were under purifying selection. The grapevine kinome families exhibited different expression patterns during plant development and in response to various stress treatments, with many being coexpressed. The comprehensive annotation of grapevine kinase genes, their patterns of expression and coexpression, and the related information facilitate a more complete understanding of the roles of various grapevine kinases in growth and development, responses to abiotic stress, and evolutionary history. PMID- 29619231 TI - Identification and substrate prediction of new Fragaria x ananassa aquaporins and expression in different tissues and during strawberry fruit development. AB - The newly identified aquaporin coding sequences presented here pave the way for further insights into the plant-water relations in the commercial strawberry (Fragaria x ananassa). Aquaporins are water channel proteins that allow water to cross (intra)cellular membranes. In Fragaria x ananassa, few of them have been identified hitherto, hampering the exploration of the water transport regulation at cellular level. Here, we present new aquaporin coding sequences belonging to different subclasses: plasma membrane intrinsic proteins subtype 1 and subtype 2 (PIP1 and PIP2) and tonoplast intrinsic proteins (TIP). The classification is based on phylogenetic analysis and is confirmed by the presence of conserved residues. Substrate-specific signature sequences (SSSSs) and specificity determining positions (SDPs) predict the substrate specificity of each new aquaporin. Expression profiling in leaves, petioles and developing fruits reveals distinct patterns, even within the same (sub)class. Expression profiles range from leaf-specific expression over constitutive expression to fruit-specific expression. Both upregulation and downregulation during fruit ripening occur. Substrate specificity and expression profiles suggest that functional specialization exists among aquaporins belonging to a different but also to the same (sub)class. PMID- 29619232 TI - Molecular markers reliably predict post-harvest deterioration of fresh-cut lettuce in modified atmosphere packaging. AB - Fresh-cut lettuce is popular, but highly perishable product. Genetic studies of two bi-parental populations derived from crossing parents with rapid and slow rates of deterioration showed that the deterioration rate is a heritable trait (broad spectrum heritability, H2 of 0.56-0.87). The major genetic determinant of the deterioration rate in both populations was the quantitative trait locus (QTL), qSL4, located on linkage group 4. This QTL explained 40-74% of the total phenotypic variation of the trait in the two populations. Saturating the qSL4 region with single-nucleotide (SNP) markers allowed detection of six haplotypes in a set of 16 lettuce accessions with different rates of deterioration. Three of the haplotypes were always associated with very rapid rates of deterioration, while the other three haplotypes were associated with slow rates of deterioration. Two SNPs located 53 bp apart were sufficient to separate the 16 accessions into two groups with different rates of deterioration. The accuracy of markers-trait association was subsequently tested on 350 plants from seven F2 families that originated from crossing parents with different rates of deterioration. The H2 of deterioration rate in these seven families ranged from 0.64 to 0.90. The SNP-based analysis accurately identified individuals with rapid, intermediate, and slow rates of deterioration in each family. Intermediate rate of deterioration was found in individuals having heterozygous alleles at qSL4, indicating an additive effect of the alleles. The assay can be used for fast, accurate, and reliable identification of deterioration rate after processing for salad. PMID- 29619233 TI - Vegan-mycoprotein concentrate from pea-processing industry byproduct using edible filamentous fungi. AB - Background: Currently around one billion people in the world do not have access to a diet which provides enough protein and energy. However, the production of one of the main sources of protein, animal meat, causes severe impacts on the environment. The present study investigates the production of a vegan-mycoprotein concentrate from pea-industry byproduct (PpB), using edible filamentous fungi, with potential application in human nutrition. Edible fungal strains of Ascomycota (Aspergillus oryzae, Fusarium venenatum, Monascus purpureus, Neurospora intermedia) and Zygomycota (Rhizopus oryzae) phyla were screened and selected for their protein production yield. Results: A. oryzae had the best performance among the tested fungi, with a protein yield of 0.26 g per g of pea processing byproduct from the bench scale airlift bioreactor cultivation. It is estimated that by integrating the novel fungal process at an existing pea processing industry, about 680 kg of fungal biomass attributing to about 38% of extra protein could be produced for each 1 metric ton of pea-processing byproduct. This study is the first of its kind to demonstrate the potential of the pea-processing byproduct to be used by filamentous fungi to produce vegan mycoprotein for human food applications. Conclusion: The pea-processing byproduct (PpB) was proved to be an efficient medium for the growth of filamentous fungi to produce a vegan-protein concentrate. Moreover, an industrial scenario for the production of vegan-mycoprotein concentrate for human nutrition is proposed as an integrated process to the existing PPI production facilities. PMID- 29619234 TI - Infantile spasms related to a 5q31.2-q31.3 microdeletion including PURA. AB - Recently, haploinsufficiency of PURA has been identified as an essential cause of 5q31.3 microdeletion syndrome, which is characterized by severe psychomotor developmental delay, epilepsy, distinctive features, and delayed myelination. A new 5q31.2-q31.3 microdeletion that included PURA was identified in a patient with infantile spasms. Approximately 50% of patients with PURA-related neurodevelopmental disorders exhibited epilepsy regardless of whether they harbor a 5q31.3 deletion or PURA mutation. Patients with the 5q31.3 deletion or a PURA mutation should be carefully monitored for epileptic seizures. PMID- 29619235 TI - iMETHYL: an integrative database of human DNA methylation, gene expression, and genomic variation. AB - We launched an integrative multi-omics database, iMETHYL (http://imethyl.iwate megabank.org). iMETHYL provides whole-DNA methylation (~24 million autosomal CpG sites), whole-genome (~9 million single-nucleotide variants), and whole transcriptome (>14 000 genes) data for CD4+ T-lymphocytes, monocytes, and neutrophils collected from approximately 100 subjects. These data were obtained from whole-genome bisulfite sequencing, whole-genome sequencing, and whole transcriptome sequencing, making iMETHYL a comprehensive database. PMID- 29619236 TI - Evaluation of the ISL1 gene in the pathogenesis of bladder exstrophy in a Swedish cohort. AB - Bladder exstrophy is a congenital closure defect of the urinary bladder with a profound effect on morbidity. Although the malformation is usually sporadic, a genetic background is supported by an increased recurrence risk in relatives, higher concordance rates in monozygotic twins and several associated chromosomal aberrations. Recently, the ISL1 gene was presented as a candidate gene for bladder exstrophy and epispadias complex (BEEC) development in two different studies. In our study, we screened for genetic variants in the ISL1 gene in DNA from 125 Swedish patients using Sanger sequencing and array-CGH analysis. In addition, we evaluated ISL1 expression in RNA of human bladder during embryonic and fetal weeks 5-10 relative to that in lung tissue (week 9). In total, 21 single-nucleotide variants were identified, including a potentially novel missense variant, c.137C>G p.(Ala46Gly), substituting a conserved amino acid. This variant was inherited from an unaffected mother. No structural variants were identified. RNA sequencing revealed ISL1 mRNA expression during the critical time frame of human bladder development. In conclusion, we did not detect any known or likely pathogenic variants in the ISL1 gene in 125 Swedish BEEC patients, indicating that variation in the ISL1 gene is not a common genetic mechanism of BEEC development in the Swedish population. PMID- 29619237 TI - Refining the clinical phenotype of Okur-Chung neurodevelopmental syndrome. AB - We describe an 8-year-old Japanese boy with a de novo recurrent missense mutation in CSNK2A1, c.593A>G, that is causative of Okur-Chung neurodevelopmental syndrome. He exhibited distinctive facial features, severe growth retardation with relative macrocephaly, and friendly, hyperactive behavior. His dysmorphic features might suggest a congenital histone modification defect syndrome, such as Kleefstra, Coffin-Siris, or Rubinstein-Taybi syndromes, which are indicative of functional interactions between the casein kinase II, alpha 1 gene and histone modification factors. PMID- 29619238 TI - Pelizaeus-Merzbacher disease can be a differential diagnosis in males presenting with severe neonatal respiratory distress and hypotonia. AB - Pelizaeus-Merzbacher disease (PMD; MIM #312080) is a rare X-linked recessive disorder. A male neonate presented with severe respiratory distress that required tracheostomy. After the appearance of nystagmus, PMD was suspected as a diagnosis for the patient, and a missense mutation, p.Phe51Val, was identified in PLP1, the gene responsible for PMD. PMD can be a differential diagnosis in a male neonate presenting severe respiratory distress. PMID- 29619239 TI - Novel compound heterozygous variants in the LARP7 gene in a patient with Alazami syndrome. AB - The LARP7 gene encodes a chaperone protein of the noncoding RNA 75 K, and mutations in this gene have been identified in patients with Alazami syndrome. Herein, we report another Japanese patient with Alazami syndrome and novel compound heterozygous variants in LARP7 (i.e., c.370delG, p.Glu124fs*38 and c.641_667+25del involving the splice donor site of intron 8). These findings provide further evidence that biallelic LARP7 defects cause the phenotype of Alazami syndrome. PMID- 29619240 TI - Comparison of PETINIA and LC-MS/MS for determining plasma mycophenolic acid concentrations in Japanese lung transplant recipients. AB - Background: Mycophenolic acid (MPA) treatment requires therapeutic drug monitoring to improve the outcome after organ transplantation. The aim of this study was to compare two methods, a particle enhanced turbidimetric inhibition immunoassay (PETINIA) and a reference liquid chromatography tandem mass spectrometry (LC-MS/MS) for determining plasma MPA concentrations from Japanese lung transplant recipients. Methods: Plasma MPA concentrations were determined from 20 Japanese lung transplant recipients using LC-MS/MS and the PETINIA on the Dimension Xpand Plus-HM analyzer. Results: The mean MPA concentration measured by PETINIA was significantly higher than that measured by LC-MS/MS (3.26 +/- 2.73 MUg/mL versus 2.82 +/- 2.71 MUg/mL, P < 0.0001). The result of the Passing Bablok analysis was a slope of 1.104 (95% confidence interval [CI], 1.036-1.150) and an intercept of 0.229 (95%CI, 0.144-0.315). Bland-Altman analysis revealed PETINIA overestimates plasma MPA concentration by 26.25% and 95%CI from 21.43 to 31.07%. Conclusion: The measurement of MPA by the PETINIA in Japanese lung transplant patients should evaluate the result with attention to positive bias. PMID- 29619242 TI - Adolescents and health-related behaviour: using a framework to develop interventions to support positive behaviours. AB - Background: Experimentation is a natural part of adolescent maturation. In conjunction with increased exposure to behaviours such as alcohol or substance use, and the potentially intensified influence of peer groups, unhealthy behaviour patterns may develop as part of this experimentation. However, the adolescent years also provide considerable opportunity for behaviour to be shaped in positive ways that may improve immediate and longer term health outcomes. A systematic review carried out by the authors concluded that physiological changes during adolescence need to be considered when designing or implementing interventions, due to their influence on health behaviours. The aim of the study is to demonstrate how the six steps in quality intervention development (6SQuID) framework can be used, in conjunction with research or review findings, to inform the development of pilot or feasibility studies. Using the synthesised findings from our adolescent systematic review, we sought to illustrate how adolescent interventions might be designed to target specific health behaviours and augment positive adolescent health outcomes. Methods: We applied the 6SQuID framework to the findings from a review of adolescent physiological influences on health behaviour. This involved following the process defined within 6SQuID and applying the sequential steps to build a proposed pilot study, based on the pre-defined findings of our systematic review. We used the Social Learning Theory to assist in identifying how and why change can be influenced, with and for adolescents. Results: We devised a pilot study example, targeting teaching assistants, to illustrate how the detailed steps within the 6SQuID framework can assist the development and subsequent implementation of adolescent interventions that are likely to be effective. Conclusions: This paper gives details of how the 6SQuID framework can be used for intervention development, using specific research findings, across a variety of adolescent health behaviours. This example provides details of how to operationalise 6SQuID in practical terms that are transferrable to other populations and situations. In this respect, we anticipate that this illustrative case may be of use in the design, development, and implementation of a wide variety of interventions. PMID- 29619241 TI - Ugly ducklings-the dark side of plastic materials in contact with potable water. AB - Bath toys pose an interesting link between flexible plastic materials, potable water, external microbial and nutrient contamination, and potentially vulnerable end-users. Here, we characterized biofilm communities inside 19 bath toys used under real conditions. In addition, some determinants for biofilm formation were assessed, using six identical bath toys under controlled conditions with either clean water prior to bathing or dirty water after bathing. All examined bath toys revealed notable biofilms on their inner surface, with average total bacterial numbers of 5.5 * 106 cells/cm2 (clean water controls), 9.5 * 106 cells/cm2 (real bath toys), and 7.3 * 107 cells/cm2 (dirty water controls). Bacterial community compositions were diverse, showing many rare taxa in real bath toys and rather distinct communities in control bath toys, with a noticeable difference between clean and dirty water control biofilms. Fungi were identified in 58% of all real bath toys and in all dirty water control toys. Based on the comparison of clean water and dirty water control bath toys, we argue that bath toy biofilms are influenced by (1) the organic carbon leaching from the flexible plastic material, (2) the chemical and biological tap water quality, (3) additional nutrients from care products and human body fluids in the bath water, as well as, (4) additional bacteria from dirt and/or the end-users' microbiome. The present study gives a detailed characterization of bath toy biofilms and a better understanding of determinants for biofilm formation and development in systems comprising plastic materials in contact with potable water. PMID- 29619243 TI - Two-dimensional material-based bionano platforms to control mesenchymal stem cell differentiation. AB - Background: In the past decade, stem cells, with their ability to differentiate into various types of cells, have been proven to be resourceful in regenerative medicine and tissue engineering. Despite the ability to repair damaged parts of organs and tissues, the use of stem cells still entails several limitations, such as low differentiation efficiency and difficulties in guiding differentiation. To address these limitations, nanotechnology approaches have been recently implemented in stem cell research. It has been discovered that stem cells, in combination with carbon-based functional materials, show enhanced regenerative performances in varying biophysical conditions. In particular, several studies have reported solutions to the conventional quandaries in biomedical engineering, using synergetic effects of nanohybrid materials, as well as further development of technologies to recover from diverse health conditions such as bone fracture and strokes. Main text: In this review, we discuss several prior studies regarding the application of various nanomaterials in controlling the behavior of stem cells. We focus on the potential of different types of nanomaterials, such as two-dimensional materials, gold nanoparticles, and three-dimensional nanohybrid composites, to control the differentiation of human mesenchymal stem cells (hMSCs). These materials have been found to affect stem cell functions via the adsorption of growth/differentiation factors on the surfaces of nanomaterials and the activation of signaling pathways that are mostly related to cell adhesion and differentiation (e.g., FAK, Smad, Erk, and Wnt). Conclusion: Controlling stem cell differentiation using biophysical factors, especially the use of nanohybrid materials to functionalize underlying substrates wherein the cells attach and grow, is a promising strategy to achieve cells of interest in a highly efficient manner. We hope that this review will facilitate the use of other types of newly discovered and/or synthesized nanomaterials (e.g., metal transition dichalcogenides, non-toxic quantum dots, and metal oxide frameworks) for stem cell-based regenerative therapies. PMID- 29619244 TI - Antiviral effects of ferric ammonium citrate. AB - Iron is an essential nutrient for cell survival and is crucial for DNA replication, mitochondrial function and erythropoiesis. However, the immunological role of iron in viral infections has not been well defined. Here we found the iron salt ferric ammonium citrate (FAC) inhibited Influenza A virus, HIV virus, Zika virus, and Enterovirus 71 (EV71) infections. Of note, both iron ion and citrate ion were required for the antiviral capability of FAC, as other iron salts and citrates did not exhibit viral inhibition. Mechanistically, FAC inhibited viral infection through inducing viral fusion and blocking endosomal viral release. These were further evidenced by the fact that FAC induced liposome aggregation and intracellular vesicle fusion, which was associated with a unique iron-dependent cell death. Our results demonstrate a novel antiviral function of FAC and suggest a therapeutic potential for iron in the control of viral infections. PMID- 29619246 TI - Enhancing the incorporation of the patient's voice in drug development and evaluation. AB - Plain English summary: People living with a condition are uniquely positioned to inform the understanding of the therapeutic context for drug development and evaluation. In 2012, the U.S. Food and Drug Administration (FDA) established the Patient-Focused Drug Development (PFDD) initiative to more systematically obtain the patient perspective on specific diseases and their currently available treatments. PFDD meetings are unique among FDA public meetings, with a format designed to engage patients and elicit their perspectives on two topic areas: (1) the most significant symptoms of their condition and the impact of the condition on daily life; and, (2) their current approaches to treatment. FDA has conducted 24 disease-specific PFDD meetings to date. The lessons learned from PFDD meetings range from experiences common across rare diseases to more disease specific experiences that matter most to patients. FDA recognizes that FDA-led PFDD meetings alone cannot address the gaps in information on the patient perspective. Patient-focused drug development is an ongoing effort and FDA looks forward to the next steps in advancing the science and the utilization of patient input throughout drug development and evaluation. Abstract: The U.S. Food and Drug Administration (FDA) has multiple mechanisms for its regulators and staff to interact with patients -- but none quite like its novel Patient-Focused Drug Development (PFDD) initiative. FDA established the PFDD initiative to more systematically obtain the patient perspective on specific diseases and their currently available treatments. Since the initiative's inception in 2012, FDA has held 24 PFDD meetings, covering a range of disease areas and hearing directly from thousands of patients and caregivers. FDA's PFDD meetings have also provided key stakeholders, including patient advocates, researchers, drug developers, healthcare providers, and other government officials, an opportunity to hear the patient's voice. The lessons learned include but are not limited to specific experiences that matter most to patients, patient perspectives on meaningful treatment benefits and how patients want to be engaged in the drug development process. FDA recognizes that FDA-led PFDD meetings alone cannot address the gaps in information on the patient perspective. Further enhancing the incorporation of the patient's voice in drug development and evaluation continues to be a priority for FDA. PMID- 29619247 TI - Cardiac arrhythmia and neuroexcitability gene variants in resected brain tissue from patients with sudden unexpected death in epilepsy (SUDEP). AB - Sudden unexpected death in epilepsy (SUDEP) is the leading cause of epilepsy related mortality in young adults. The exact mechanisms are unknown but death often follows a generalized tonic-clonic seizure. Proposed mechanisms include seizure-related respiratory, cardiac, autonomic, and arousal dysfunction. Genetic drivers underlying SUDEP risk are largely unknown. To identify potential SUDEP risk genes, we compared whole-exome sequences (WES) derived from formalin-fixed paraffin embedded surgical brain specimens of eight epilepsy patients who died from SUDEP with seven living controls matched for age at surgery, sex, year of surgery and lobe of resection. We compared identified variants from both groups filtering known polymorphisms from publicly available data as well as scanned for epilepsy and candidate SUDEP genes. In the SUDEP cohort, we identified mutually exclusive variants in genes involved in u-opiod signaling, gamma-aminobutyric acid (GABA) and glutamate-mediated synaptic signaling, including ARRB2, ITPR1, GABRR2, SSTR5, GRIK1, CTNAP2, GRM8, GNAI2 and GRIK5. In SUDEP patients we also identified variants in genes associated with cardiac arrhythmia, including KCNMB1, KCNIP1, DPP6, JUP, F2, and TUBA3D, which were not present in living epilepsy controls. Our data shows that genomic analysis of brain tissue resected for seizure control can identify potential genetic biomarkers of SUDEP risk. PMID- 29619245 TI - Selective deletion of PPARbeta/delta in fibroblasts causes dermal fibrosis by attenuated LRG1 expression. AB - Connective tissue diseases of the skin are characterized by excessive collagen deposition in the skin and internal organs. Fibroblasts play a pivotal role in the clinical presentation of these conditions. Nuclear receptor peroxisome proliferator activated receptors (PPARs) are therapeutic targets for dermal fibrosis, but the contribution of the different PPAR subtypes are poorly understood. Particularly, the role of fibroblast PPARbeta/delta in dermal fibrosis has not been elucidated. Thus, we generated a mouse strain with selective deletion of PPARbeta/delta in the fibroblast (FSPCre-Pparb/d-/-) and interrogated its epidermal and dermal transcriptome profiles. We uncovered a downregulated gene, leucine-rich alpha-2-glycoprotein-1 (Lrg1), of previously unknown function in skin development and architecture. Our findings suggest that the regulation of Lrg1 by PPARbeta/delta in fibroblasts is an important signaling conduit integrating PPARbeta/delta and TGFbeta1-signaling networks in skin health and disease. Thus, the FSPCre-Pparb/d-/- mouse model could serve as a novel tool in the current gunnery of animal models to better understand dermal fibrosis. PMID- 29619248 TI - Retinal and choroidal changes in steroid-associated central serous chorioretinopathy. AB - Background: To evaluate the retinal and choroidal alterations in steroid associated central serous chorioretinopathy (CSC) in comparison to idiopathic CSC. Methods: In this retrospective cohort study, swept source optical coherence tomography scans of eyes with steroid-associated CSC (group A) were compared with the same in idiopathic CSC (group B). The key features included central subfield retinal thickness, subfoveal choroidal thickness, subfoveal large choroidal vessel diameter, subretinal deposits, retinal pigment epithelial irregularities, double layer sign, hyperreflective dots, intraretinal fluid, and choroidal vascularity index (ratio of choroidal luminal area and total choroidal area, measured on a high definition horizontal 9 mm OCT B-scan. Results: There were 20 eyes in group A and 30 in group B. Group A had a higher female proportion (60 vs. 16.67%; P < 0.01) and higher bilaterality (30 vs. 6.67%; P = 0.03). The height of neurosensory detachment was lower in group A (153.1 +/- 175.70 um vs. 312.9 +/- 223.06 um; P < 0.01). There was no significant difference in the prevalence of subretinal deposits, retinal pigment epithelial irregularities, pigment epithelial detachments, double layer sign, outer retinal layer disruption, and intraretinal fluid. Hyperreflective dots (HRDs) were less common in group A (15 vs. 46.67%; P = 0.03). The subfoveal choroidal thickness (P = 0.65) and subfoveal large choroidal vessel diameter (P = 0.78) were comparable. There was a trend towards a higher choroidal vascularity index (CVI) in group A (A: mean, 82%, 95% CI, 66-99%; B: mean, 58%, 95% CI, 57-59%; P = 0.10). Conclusion: Steroid associated CSC has a marginally higher CVI and less common association with HRDs as compared to idiopathic CSC. PMID- 29619249 TI - Participation restriction and assistance needs in people with spinal cord injuries of more than 40 year duration. AB - Study design: Prospective observational. Objectives: Examine changes in participation restriction and assistance needs in a sample of people with long standing spinal cord injuries (SCIs). Setting: Two British spinal centres. Methods: The sample consisted of British ageing with SCI study participants who were seen at baseline (1990 or 1993) and in the final follow-up (2010). Outcome measures were the Craig Handicap Assessment and Reporting Technique-Short Form (CHART-SF) and interview questions about assistance needs. Results: Eighty-five Ageing study participants took part in 2010; their mean age was 67.65 years and the mean time since injury was 46.26 years. The mean CHART-SF physical independence subscore decreased from 97.44 in 1990 to 91.26 in 2010, mobility from 95.58 to 82.10, occupation from 86.82 to 64.49 and social integration from 96.29 to 88.68 (all p < 0.05). Increasing assistance needs were reported by 10.1% of participants in 1990, by 36.6% in 2010 (p < 0.05) and by 62.4% over the entire 20-year study period. Persons requiring more assistance were older and injured longer, had a more severe SCI and lower self-reported quality of life and life satisfaction (p < 0.05). In the multivariate logistic regression, the strongest predictor of needing more assistance was injury severity (p < 0.05). Conclusions: An increase in participation restriction and in assistance needs was reported over the 20 year follow-up in persons injured more than 40 years ago. SCI severity was the main risk factor for needing more assistance. Clinical awareness of how participation changes with age may help provide timely intervention and offset declines. PMID- 29619250 TI - Relationship between autonomic cardiovascular control and obstructive sleep apnoea in persons with spinal cord injury: a retrospective study. AB - Study design: Retrospective study. Objective: To determine if there is an association between obstructive sleep apnoea (OSA) and blood pressure (BP) pattern or heart rate variability (HRV) in people with spinal cord injury (SCI). Setting: A state-based spinal cord service in Victoria, Australia. Methods: We identified 42 subjects who had ambulatory BP monitoring (ABPM) within 6 months of a diagnostic sleep study at Austin Hospital between 2009 and 2014. Markers for autonomic function, including circadian BP pattern and HRV were extracted from the ABPM study database. Apnoea/hypopnoea index (AHI), arousals/hour and oxygen desaturation index were extracted from the sleep study database. Subjects with a nocturnal systolic BP dipping more than 10% of daytime value were defined as dippers, between 10 and 0% were non-dippers and those with a higher night than day systolic BP were reverse dippers. Severity of OSA is classified as non-OSA (AHI < 5), mild (AHI 5-15), moderate (AHI 15-30) and severe (AHI > 30). Results: Subjects (n = 42) were predominantly male (85.7%), aged 44 +/- 15.4 (mean +/- SD), with a BMI of 24.4 +/- 5.7 (mean +/- SD) and mainly tetraplegic (92.9%). There was no difference in AHI, oxygen desaturation index or arousals/hour between dippers, non-dippers and reverse dippers. None of the HRV parameters differed between dippers, non-dippers and reverse dippers. No differences were found in 24 h, night-time, daytime or nocturnal dip in BP between subjects with non-OSA, mild, moderate and severe OSA. Conclusion: We found no relationship between BP pattern or HRV and the severity of OSA in persons with SCI. PMID- 29619251 TI - Spinal subdural hematoma and ankylosing spondylitis: case report and review of literature. AB - Introduction: Spinal subdural hematomas are rare, disabling hemorrhages. Ankylosing spondylitis (AS) is a relatively common inflammatory condition of the spine that can progress to a fragile, unstable fusion vulnerable to fracture. While spinal epidural hematomas have been described, subdural hematomas to date have not been reported in AS. In this report, we describe the unique case of a patient on warfarin with AS who developed a spinal subdural hematoma and fracture in the absence of trauma. We then discuss the pathogenesis, presentation, prognosis, and management strategies for this unique diagnosis. Case presentation: A 60-year-old man with recent AS diagnosis and atrial fibrillation on warfarin presented with 96 h of low back pain and 24 h of leg weakness and urinary retention. CT imaging revealed a bamboo spine and fracture of the posterior elements at L4, while MR revealed a hematoma with thecal sac compression. The warfarin was reversed and the patient taken to the operating room; on laminectomy, however, no hematoma was encountered. The patient then underwent intraoperative ultrasound, durotomy, and evacuation of a thick subdural hematoma, followed by posterior fusion. Discussion: This case represents the first report of an AS patient who developed a subdural hematoma requiring evacuation. Although rare, the clinician should maintain a broad differential and be familiar with this unique pathology, particularly in high-risk patients, such as those with suspected fractures or on warfarin. In patients with back pain and myelopathic symptoms, rapid diagnosis followed by prompt evacuation allows for the best opportunity for neurologic recovery. PMID- 29619252 TI - LepVax, a defined subunit vaccine that provides effective pre-exposure and post exposure prophylaxis of M. leprae infection. AB - Sustained elimination of leprosy as a global health concern likely requires a vaccine. The current standard, BCG, confers only partial protection and precipitates paucibacillary (PB) disease in some instances. When injected into mice with the T helper 1 (Th1)-biasing adjuvant formulation Glucopyranosyl Lipid Adjuvant in stable emulsion (GLA-SE), a cocktail of three prioritized antigens (ML2055, ML2380 and ML2028) reduced M. leprae infection levels. Recognition and protective efficacy of a single chimeric fusion protein incorporating these antigens, LEP-F1, was confirmed in similar experiments. The impact of post exposure immunization was then assessed in nine-banded armadillos that demonstrate a functional recapitulation of leprosy. Armadillos were infected with M. leprae 1 month before the initiation of post-exposure prophylaxis. While BCG precipitated motor nerve conduction abnormalities more rapidly and severely than observed for control infected armadillos, motor nerve injury in armadillos treated three times, at monthly intervals with LepVax was appreciably delayed. Biopsy of cutaneous nerves indicated that epidermal nerve fiber density was not significantly altered in M. leprae-infected animals although Remak Schwann cells of the cutaneous nerves in the distal leg were denser in the infected armadillos. Importantly, LepVax immunization did not exacerbate cutaneous nerve involvement due to M. leprae infection, indicating its safe use. There was no intraneural inflammation but a reduction of intra axonal edema suggested that LepVax treatment might restore some early sensory axonal function. These data indicate that post-exposure prophylaxis with LepVax not only appears safe but, unlike BCG, alleviates and delays the neurologic disruptions caused by M. leprae infection. PMID- 29619253 TI - Long-Term Natural Outcomes of Simple Hemorrhage Associated with Lacquer Crack in High Myopia: A Risk Factor for Myopic CNV? AB - Purpose: To investigate the relationship between simple hemorrhage (SH) associated with lacquer crack (LC) and myopic choroidal neovascularization (CNV) in high myopia. Methods: A cross-sectional evaluation including best-corrected visual acuity (BCVA), axial length, refractive error, color fundus photography, and spectral domain optical coherence tomography (SD-OCT) was performed in patients diagnosed with high myopia and SH. Fundus fluorescein angiography and indocyanine green angiography were performed if the eye was suspected with CNV. Results: Thirty-three eyes of 27 patients with SH were enrolled in the study. None of the eyes developed CNV at final examination following the occurrence of hemorrhage. Recurrent hemorrhage was observed in 36.5% of the eyes. Compared with the initial BCVA, the final BCVA was significantly improved (P < 0.001) and correlated with the integrity of the ellipsoid zone in SD-OCT. There was no significant difference in the final BCVA between group 1 (LC crossed the central fovea) and group 2 (no LC crossed the central fovea) (P = 0.299). Conclusions: SH associated with LC is not a risk factor for the development of myopic CNV in patients with high myopia. LCs have little influence on the final BCVA unless the integrity of the ellipsoid zone in the central fovea is disrupted. PMID- 29619254 TI - Intravitreal Clindamycin and Dexamethasone Combined with Systemic Oral Antitoxoplasma Therapy versus Intravitreal Therapy Alone in the Management of Toxoplasma Retinochoroiditis: A Retrospective Study. AB - Purpose: To compare clinical outcome of IVCD combined with oral therapy with IVCD alone in patients with toxoplasmic retinochoroiditis. Patients and Methods: Thirty eyes were reviewed. Two equal groups were identified (15 eyes each). Clinical outcome measures were resolution of active inflammation, changes in BCVA and CMT, adverse drug reactions, and rate of recurrence. Results: Mean baseline of BCVA 1.08 +/- 0.17 and 1.03 +/- 0.15 improved to 0.64 +/- 0.18 and 0.69 +/- 0.17 at the end of follow-up in group I and II, respectively. No statistically significant difference was observed. CMT was 392.6 +/- 33.16 MUm and 397.3 +/- 14.6 MUm significantly decreased to 314.7 +/- 4.43 MUm and 319.6 +/- 7.8 MUm. Resolution of acute inflammation was achieved in all cases in both groups. There were no recurrent cases in group I, and only one out of 15 (6.7%) in group II. No ocular or systemic adverse events were recorded. Conclusion: IVCD is an effective route of treatment for active toxoplasmic retinochoroiditis that can be used solely without the need to use systemic medications.. PMID- 29619256 TI - Cardiac Aspergilloma: A Rare Case of a Cardiac Mass Involving the Native Tricuspid Valve, Right Atrium, and Right Ventricle in an Immunocompromised Patient. AB - Aspergillus can cause devastating opportunistic infections in immunocompromised patients. Rarely does this fungus invade the heart, and when it does, survival is especially poor despite optimal medical and surgical treatment. We report a case of cardiac aspergilloma with involvement of the tricuspid valve and both the right atrium and ventricle found on a transthoracic echocardiogram in an immunocompromised patient after developing atrial fibrillation with rapid ventricular rate. The findings from this case suggest that early clinical suspicion is critical in early diagnosis and thus early treatment. PMID- 29619255 TI - Dry Eye Post-Laser-Assisted In Situ Keratomileusis: Major Review and Latest Updates. AB - Dry eye is one of the most common complications occurring after laser-assisted in situ keratomileusis (LASIK), with virtually all patients experiencing some degree of postoperative dry eye symptoms. Enhanced understanding of the pathophysiology and mechanism of dry eye development in addition to preoperative screening of patients who are prone to dry eye is essential for better patient satisfaction and for improving short-term visual outcome postoperatively. This article reviews the latest studies published on LASIK-associated dry eye, including epidemiology, pathophysiology, risk factors, preoperative assessment, and management. PMID- 29619257 TI - Spontaneous Regression of Cardiac Rhabdomyoma Presenting as Severe Left Ventricular Inlet Obstruction in a Neonate with Tuberous Sclerosis. AB - Cardiac rhabdomyoma can be subclinical or have a fatal presentation according to the onset age and involved site, size, and degree of invasion. Although most cardiac rhabdomyomas become smaller with time, emergency intervention is indicated when severe obstruction has occurred. In this report, we describe the spontaneous regression of a large cardiac rhabdomyoma (20.5 * 15.6 mm) presenting as severe left ventricular inlet obstruction in a neonate with tuberous sclerosis. Although a cardiac rhabdomyoma can be large enough to induce left ventricular inlet obstruction, conservative treatment without aggressive surgical intervention can be considered if the hemodynamic condition does not deteriorate. PMID- 29619258 TI - Conservative Vertical Groove Technique for Tooth Rehabilitation: 3-Year Follow Up. AB - Reattachment of tooth fragment is a simple, conservative, and noninvasive procedure, and it is the most currently acceptable treatment option. This article presents management of two accidentally damaged maxillary incisors using direct composite resin restoration and fractured tooth fragment. With the advancements in adhesive dentistry, tooth fragment reattachment procedure has become simpler and clinically reliable. The present paper is a report of 3-year follow-up of coronally fractured tooth treated with a very conservative technique of tooth fragment reattachment using vertical groove preparation and reinforcement with fiber post. PMID- 29619259 TI - Primary Effusion Lymphoma without an Effusion: A Rare Case of Solid Extracavitary Variant of Primary Effusion Lymphoma in an HIV-Positive Patient. AB - Primary effusion lymphoma (PEL) is a unique form of non-Hodgkin lymphoma, usually seen in severely immunocompromised, HIV-positive patients. PEL is related to human herpesvirus-8 (HHV-8) infection, and it usually presents as a lymphomatous body cavity effusion in the absence of a solid tumor mass. There have been very few case reports of HIV-positive patients with HHV-8-positive solid tissue lymphomas not associated with an effusion (a solid variant of PEL). In the absence of effusion, establishing an accurate diagnosis can be challenging, and a careful review of morphology, immunophenotype, and presence of HHV-8 is necessary to differentiate from other subtypes of non-Hodgkin lymphoma. Treatment involves intensive chemotherapy, and prognosis is usually poor. We present a rare case of a PEL variant in an HIV-positive patient who presented with extensive lymphadenopathy without any associated effusions. PMID- 29619260 TI - Bilateral Conjunctival Infiltration as an Extramedullary Relapse of AML. AB - Acute myelogenous leukemia (AML) accounts for 1.2% of all cancer deaths. Relapse is the major cause of treatment failure in acute myeloid leukemia (AML) patients. AML rarely presents as ocular manifestation in relapse or at presentation. The M4 subtype of AML is most commonly presented with extramedullary involvement. In this report, we presented a young female with AML who was diagnosed and treated for AML about 40 months ago. She did not transplant because she did not have a full-match donor. About 4 months ago, she visited with a red eye and conjunctival infiltration. She was referred to an ophthalmologist for a biopsy, and the pathology report showed the relapse of AML which was treated with systemic chemotherapy. Red eyes with subconjunctival nodules in patients with a history of previous AML should raise the suspicion for recurrent disease that warrants urgent biopsy and systemic treatment. Eye involvement with leukemia is usually responsive to systemic chemotherapy. PMID- 29619261 TI - Septic Pulmonary Emboli and Renal Abscess Caused by Staphylococcus aureus in an HIV-Infected Patient. AB - Staphylococcus aureus is a common cause of bacteremia in the general population and can lead to serious metastatic infection particularly in immunocompromised persons. However, prompt diagnosis and management can result in favorable outcomes. In the following case report, the clinical course of an HIV-infected man is presented; he developed bloodstream infection (BSI) and associated complications: septic pulmonary embolism, right renal abscess, and ipsilateral renal vein thrombosis. Methicillin-resistant Staphylococcus aureus (MRSA) was identified as the cause of sepsis and successfully treated with surgery and antimicrobials. Intravenous vancomycin was the primary therapy, followed by oral linezolid after resolution of bacteremia. PMID- 29619262 TI - Optical Coherence Tomography Angiography of Combined Central Retinal Artery and Vein Occlusion. AB - Optical coherence tomography angiography (OCTA) is a new, noninvasive technology that enables detailed evaluation of flow in the retinal and choroidal vasculature. The authors believe this to be the first report to describe the optical coherence tomography angiography findings associated with combined central retinal artery occlusion (CRAO) and central retinal vein occlusion (CRVO). PMID- 29619263 TI - A Rare Presentation of Actinic Keratosis Affecting the Tarsal Conjunctiva and Review of the Literature. AB - We report an unusual case of actinic keratosis (AK) of the tarsal conjunctiva in a 63-year-old man. Examination revealed a crusty, leukoplakic lesion prone to bleeding on the tarsal conjunctiva of the right upper eyelid. This was treated by surgical excisional biopsy. At 1-year follow-up, there was no evidence of recurrence and the surgical site was completely healed without conjunctival scarring. Current opinion cites excessive exposure to ultraviolet (UV) radiation, in particular UV-B in sunlight, as the causative agent in developing AK. In the case we present, the tarsal conjunctiva is an unusual place for actinic keratosis due to the lack of direct UV-light exposure. The key learning points are to evert the upper eyelid during examination especially if the lesion involves the eyelid margin and, secondly, to ensure risk factors are addressed during the history. PMID- 29619264 TI - Candida albicans Osteomyelitis Pubis: The Possible Pathogenic Role of Pelvic Irradiation. AB - Radiation to the pelvis, mainly directed against either prostatic or gynecologic cancers, is burdened by a lot of complications. The genitourinary tract is most frequently involved, presenting with bladder irritation, incontinence, and fertility disorders. However, side effects of radiation can also affect the bone, usually causing an osteolytic process which deteriorates the bone structure and leads to fractures, avascular necrosis, and other pathological insults. Here, we describe a case of Candida albicans osteomyelitis of the pubic symphysis as late complication of pelvic radiotherapy performed against prostate cancer. PMID- 29619265 TI - Relapsing Ipsilateral Vestibular Neuritis. AB - In 2013, a 70-year-old male was admitted with an acute episode of vertigo, nausea, and vomiting with duration of one day. The patient's background included prehypertension, vitiligo, left ventricular hypertrophy, and Sjogren's syndrome. He denied any previous episode of vertigo or migraine manifestations. Neither hearing loss nor tinnitus or otorrhea was detected at the time of evaluation. No neurological symptoms were found. There was a left-beating spontaneous nystagmus Grade 3. The patient could stand still and walk on his own with some help without falling. Day 1 vHIT showed a significant reduction in VOR gain and refixation saccades after head impulses were delivered in the planes of the right anterior and horizontal semicircular canals. MRI showed no significant findings. He was treated with steroids. A vHIT performed 14 days later showed recovery of gains and no refixation saccades. In 2015, the patient had a new episode of acute vertigo. The clinical examination was similar, and the vHIT revealed a new drop of right superior and lateral canal gains. Cervical and ocular VEMPs were performed, and no significant asymmetry was detected. Serum PCR for herpes viruses resulted negative. Contrast MRI was performed without relevant brain findings. PMID- 29619266 TI - Intrahepatic Sarcomatous Cholangiocarcinoma: Case Report and Review of the Literature. AB - The authors report a case of a patient with intrahepatic sarcomatous cholangiocarcinoma. A 45-year-old Thai man presented with a 3-month history of right upper abdominal pain. CT scan revealed hepatomegaly with a 6.5 cm hypovascular soft tissue density mass in the right lobe and showed mild delayed enhancement. On exploratory laparotomy, the tumor adherent to right diaphragm was found. We performed right hepatectomy, partial resection of right diaphragm, and cholecystectomy. The immunohistological results suggested "sarcomatous intrahepatic cholangiocarcinoma." The tumor was recurrent in 5 months after operation and unresectable. Therefore, the treatment in this patient was supportive care. He died 11 months after his initial presentation. The literature reviews showed that intrahepatic sarcomatous cholangiocarcinoma is aggressive malignant with poor prognosis. Early detection, radical resection, and careful follow-up would be the treatment for the favorable prognosis. PMID- 29619267 TI - Improving the Classification Accuracy for Near-Infrared Spectroscopy of Chinese Salvia miltiorrhiza Using Local Variable Selection. AB - In order to improve the classification accuracy of Chinese Salvia miltiorrhiza using near-infrared spectroscopy, a novel local variable selection strategy is thus proposed. Combining the strengths of the local algorithm and interval partial least squares, the spectra data have firstly been divided into several pairs of classes in sample direction and equidistant subintervals in variable direction. Then, a local classification model has been built, and the most proper spectral region has been selected based on the new evaluation criterion considering both classification error rate and best predictive ability under the leave-one-out cross validation scheme for each pair of classes. Finally, each observation can be assigned to belong to the class according to the statistical analysis of classification results of the local classification model built on selected variables. The performance of the proposed method was demonstrated through near-infrared spectra of cultivated or wild Salvia miltiorrhiza, which are collected from 8 geographical origins in 5 provinces of China. For comparison, soft independent modelling of class analogy and partial least squares discriminant analysis methods are, respectively, employed as the classification model. Experimental results showed that classification performance of the classification model with local variable selection was obvious better than that without variable selection. PMID- 29619268 TI - Enhancer variants reveal a conserved transcription factor network governed by PU.1 during osteoclast differentiation. AB - Genome-wide association studies (GWASs) have been instrumental in understanding complex phenotypic traits. However, they have rarely been used to understand lineage-specific pathways and functions that contribute to the trait. In this study, by integrating lineage-specific enhancers from mesenchymal and myeloid compartments with bone mineral density loci, we were able to segregate osteoblast and osteoclast (OC)-specific functions. Specifically, in OCs, a PU.1-dependent transcription factor (TF) network was revealed. Deletion of PU.1 in OCs in mice resulted in severe osteopetrosis. Functional genomic analysis indicated PU.1 and MITF orchestrated a TF network essential for OC differentiation. Several of these TFs were regulated by cooperative binding of PU.1 with BRD4 to form superenhancers. Further, PU.1 is essential for conformational changes in the superenhancer region of Nfatc1. In summary, our study demonstrates that combining GWASs with genome-wide binding studies and model organisms could decipher lineage specific pathways contributing to complex disease states. PMID- 29619269 TI - Omentin-1 prevents inflammation-induced osteoporosis by downregulating the pro inflammatory cytokines. AB - Osteoporosis is a frequent complication of chronic inflammatory diseases and increases in the pro-inflammatory cytokines make an important contribution to bone loss by promoting bone resorption and impairing bone formation. Omentin-1 is a newly identified adipocytokine that has anti-inflammatory effects, but little is known about the role of omentin-1 in inflammatory osteoporosis. Here we generated global omentin-1 knockout (omentin-1-/-) mice and demonstrated that depletion of omentin-1 induces inflammatory bone loss-like phenotypes in mice, as defined by abnormally elevated pro-inflammatory cytokines, increased osteoclast formation and bone tissue destruction, as well as impaired osteogenic activities. Using an inflammatory cell model induced by tumor necrosis factor-alpha (TNF alpha), we determined that recombinant omentin-1 reduces the production of pro inflammatory factors in the TNF-alpha-activated macrophages, and suppresses their anti-osteoblastic and pro-osteoclastic abilities. In the magnesium silicate induced inflammatory osteoporosis mouse model, the systemic administration of adenoviral-delivered omentin-1 significantly protects from osteoporotic bone loss and inflammation. Our study suggests that omentin-1 can be used as a promising therapeutic agent for the prevention or treatment of inflammatory bone diseases by downregulating the pro-inflammatory cytokines. PMID- 29619270 TI - CHIP regulates bone mass by targeting multiple TRAF family members in bone marrow stromal cells. AB - Carboxyl terminus of Hsp70-interacting protein (CHIP or STUB1) is an E3 ligase and regulates the stability of several proteins which are involved in different cellular functions. Our previous studies demonstrated that Chip deficient mice display bone loss phenotype due to increased osteoclast formation through enhancing TRAF6 activity in osteoclasts. In this study we provide novel evidence about the function of CHIP. We found that osteoblast differentiation and bone formation were also decreased in Chip KO mice. In bone marrow stromal (BMS) cells derived from Chip-/- mice, expression of a panel of osteoblast marker genes was significantly decreased. ALP activity and mineralized bone matrix formation were also reduced in Chip-deficient BMS cells. We also found that in addition to the regulation of TRAF6, CHIP also inhibits TNFalpha-induced NF-kappaB signaling through promoting TRAF2 and TRAF5 degradation. Specific deletion of Chip in BMS cells downregulated expression of osteoblast marker genes which could be reversed by the addition of NF-kappaB inhibitor. These results demonstrate that the osteopenic phenotype observed in Chip-/- mice was due to the combination of increased osteoclast formation and decreased osteoblast differentiation. Taken together, our findings indicate a significant role of CHIP in bone remodeling. PMID- 29619271 TI - Optical Biosensing of Bacteria and Bacterial Communities. AB - Bacterial sensing is important for understanding the numerous roles bacteria play in nature and in technology, understanding and managing bacterial populations, detecting pathogenic bacterial infections, and preventing the outbreak of illness. Current analytical challenges in bacterial sensing center on the dilemma of rapidly acquiring quantitative information about bacteria with high detection efficiency, sensitivity, and specificity, while operating within a reasonable budget and optimizing the use of ancillary tools, such as multivariate statistics. This review starts from a general description of bacterial sensing methods and challenges, and then focuses on bacterial characterization using optical methods including Raman spectroscopy and imaging, infrared spectroscopy, fluorescence spectroscopy and imaging, and plasmonics, including both extended and localized surface plasmon resonance spectroscopy. The advantages and drawbacks of each method in relation to the others are discussed, as are their applications. A particularly promising direction in bacterial sensing lies in combining multiple approaches to achieve multiplex analysis, and examples where this has been achieved are highlighted. PMID- 29619272 TI - Population health intervention research training: the value of public health internships and mentorship. AB - Background: Better alignment between academia and public health practice and policies are critical to improve public health actions. Training of future researchers to address complex issues and to conduct transdisciplinary and collaborative research will help improve this alignment. In this paper, we describe the role of internship placements and mentorship for trainees' skills development in population health intervention research and the benefits of embedding research trainees within public health organizations. Methods: This qualitative descriptive study assessed the perceptions of the role and benefits of internships and mentorship for population health intervention research training among former doctoral and postdoctoral students, public health mentors, and senior public health managers who participated in the 4P Program, a research training program which bridges academic training and the public health system in Quebec, Canada. Two types of interviews were conducted: telephone semi-structured interviews by an external evaluator and face-to-face trainee "exit" interviews by the Program co-director. Semi-annual evaluation reports from each trainee were also reviewed. Qualitative data were subjected to a thematic analysis. Results: Internships provided trainees with a working knowledge of the public health system and the context in which decisions and public health interventions are implemented. It was an opportunity for trainees to interact with knowledge-user partners and assess the gap between research and practice. Effective mentorship was key to help trainees interpret the public health reality and develop population health intervention research skills. Trainees learned to ask the "how" questions that are critical for in-depth understanding of complex interventions and the conditions under which they can be best implemented. Conditions of success of internships and mentorship for population health intervention research included the alignment of the interests between the trainee, the mentor and the public health organization, quality mentoring, and the acquisition of specific population health intervention skills, especially collaborative research skills. Conclusions: The findings suggest that public health internships and mentorship facilitate trainee engagement in applied public health research. PMID- 29619273 TI - Are Cephalomedullary Nail Guides Accurate? A Case Report of an Unexpected Complication After Nailing an Intertrochanteric Femoral Fracture. AB - Intramedullary nailing is the mainstay of treatment for unstable intertrochanteric hip fractures. Various complications have been described with the use of these nails. We report an unusual complication whereby the lag screw completely missed the nail. We hypothesize that this previously unreported complication may be related to a specific flexible carbon fiber aiming device. Surgeon awareness and thorough intraoperative imaging are crucial to avoiding this complication. PMID- 29619274 TI - Evaluating Postoperative Complications and Outcomes of Orthopedic Fracture Repair in Nonagenarian Patients. AB - Introduction: The United States and the world are currently experiencing a tremendous growth in the elderly population. Moreover, individuals surpassing the ages of 80 and 90 are also continuing to increase. As this unique division of society expands, it is critical that the medical community best understands how to assess, diagnose, and treat this population. The purpose of this study was to analyze morbidity, mortality, and overall outcome of patients aged 90 years and older after orthopedic surgical fracture repair. Such knowledge will guide patients and their families in making decisions when surgery is required among nonagenarians. Methods: The trauma registry of our level I academic medical center was queried to identify potential study participants over the past decade. Two hundred and thirty-three surgical procedures among 227 patients were included and retrospectively assessed. Parameters of specific interest were injury type, mechanism of injury (including high energy vs low energy and height of falls), injury severity score, preoperative comorbidities, postoperative complications, length of hospital stay, discharge destination, and postoperative mortality rate. Results: Overall, 4.3% of the cohort died in the hospital following surgery. Of the patients who survived, 89.7% were discharged to a professionally supervised setting. The nonagenarian population displayed a considerable follow-up rate, as 82.8% of individuals returned for their first postoperative office visit. Discussion: Historically, surgical morbidity and mortality are highly associated with this age group. However, the number of nonagenarians in the United States is increasing, as are these surgical procedures. The epidemiologic and clinical findings of our study support this trend and add further insight into the matter. Conclusion: This investigation demonstrates that orthopedic surgery is an appropriate treatment in this population with an acceptable complication rate. Furthermore, nonagenarians have the potential to demonstrate a substantial follow up rate, but postoperative discharge to a professionally supervised setting may be necessary. PMID- 29619275 TI - Operative Trends in the Treatment of Hip Fractures and the Role of Arthroplasty. AB - Introduction: There is a projected exponential increase in the number of hip fractures in the United States. Trends in patient demographics and the role of total hip arthroplasty (THA) and its associated outcomes following hip fractures surgery have not been well studied. Methods: Patients with proximal femur fractures between 1990 and 2007 were identified in the National Hospital Discharge Survey database. Demographics, comorbidities, perioperative complications, and discharge status for patients undergoing THA, hemiarthroplasty, or internal fixation were examined. Multivariable regression was performed to determine independent risk factors for perioperative complications. Results: Between 1990 and 2007, there was a statistically significant increase in patient age, adverse events, medical comorbidities, surgical complications, medical complications, and nonroutine discharge across all surgical treatment modalities. In the same time period, the utilization of THA for all fracture types decreased significantly. Discussion: Total hip arthroplasty was found to be an independent risk factor for perioperative complications. Orthopedic surgeons should be aware that the hip fracture population continues to get older, with more medical comorbidities and are at higher risk for perioperative complications. Conclusion: Total hip arthroplasty is associated with a higher rate of perioperative complications in the hip fracture population. PMID- 29619276 TI - Use of Anticoagulants Remains a Significant Threat to Timely Hip Fracture Surgery. AB - Introduction: Hip fracture remains the biggest single source of morbidity and mortality in the elderly trauma population, and any intervention focused on quality improvement and system efficiency is beneficial for both patients and clinicians. Two of the variables contributory to improving care and efficiency are time to theater and length of stay, with the overall goal being to improve care as reflected within the achievement of best practice tariff. One of the biggest barriers to optimizing these variables is preinjury anticoagulation. Method: Building on our previous work with warfarin in this population, we utilized a regional hip fracture collaborative network collecting prospective data through the National Hip Fracture Database with custom fields pertaining to all agents, including novel oral anticoagulants. Results: In all, 1965 hip fracture patients median age 83 years (1639 not anticoagulated) were admitted to the 5 centers over 12 months. Median length of stay was 20.71 days; time to theater 23.09 hours, and the populations (anticoagulated vs control) were evenly matched for injury. Anticoagulated patients were delayed to theater (P <= .001), were inpatients for longer (P <= .001) and gained less best practice tariff (P <= .05). All variables per agent were noted and the impact of each assessed. Conclusions: Despite the widespread use of newer anticoagulants, popular due to unmonitored reversal and administration, patients stay longer in hospital and wait longer for surgery than nonanticoagulated patients of the same age and injury. Contemporary perioperative practices impact negatively on the ability to perform timely surgery on hip fracture patients. We propose a guideline specific to the management of anticoagulation in the hip fracture population to aid the optimum preparation of patients for theater, achievement of timely surgery, and potentially reduce length of stay. PMID- 29619277 TI - Deep Learning Nuclei Detection in Digitized Histology Images by Superpixels. AB - Background: Advances in image analysis and computational techniques have facilitated automatic detection of critical features in histopathology images. Detection of nuclei is critical for squamous epithelium cervical intraepithelial neoplasia (CIN) classification into normal, CIN1, CIN2, and CIN3 grades. Methods: In this study, a deep learning (DL)-based nuclei segmentation approach is investigated based on gathering localized information through the generation of superpixels using a simple linear iterative clustering algorithm and training with a convolutional neural network. Results: The proposed approach was evaluated on a dataset of 133 digitized histology images and achieved an overall nuclei detection (object-based) accuracy of 95.97%, with demonstrated improvement over imaging-based and clustering-based benchmark techniques. Conclusions: The proposed DL-based nuclei segmentation Method with superpixel analysis has shown improved segmentation results in comparison to state-of-the-art methods. PMID- 29619279 TI - Computed Tomography-guided Pulmonary Nodule Microcoil Localization Technique, Misplacement Errors, and Complications: A Pictorial Essay. AB - Computed tomography-guided pulmonary nodule microcoil localization is done preoperatively to fluoroscopic-guided video-assisted thoracoscopic surgical resection. This pictorial essay explains and illustrates the microcoil localization technique, various microcoil placement errors, intraoperative fluoroscopy-guided resection, and postmicrocoil localization complications. PMID- 29619278 TI - Digital Imaging and Communications in Medicine Whole Slide Imaging Connectathon at Digital Pathology Association Pathology Visions 2017. AB - As digital pathology systems for clinical diagnostic work applications become mainstream, interoperability between these systems from different vendors becomes critical. For the first time, multiple digital pathology vendors have publicly revealed the use of the digital imaging and communications in medicine (DICOM) standard file format and network protocol to communicate between separate whole slide acquisition, storage, and viewing components. Note the use of DICOM for clinical diagnostic applications is still to be validated in the United States. The successful demonstration shows that the DICOM standard is fundamentally sound, though many lessons were learned. These lessons will be incorporated as incremental improvements in the standard, provide more detailed profiles to constrain variation for specific use cases, and offer educational material for implementers. Future Connectathon events will expand the scope to include more devices and vendors, as well as more ambitious use cases including laboratory information system integration and annotation for image analysis, as well as more geographic diversity. Users should request DICOM features in all purchases and contracts. It is anticipated that the growth of DICOM-compliant manufacturers will likely also ease DICOM for pathology becoming a recognized standard and as such the regulatory pathway for digital pathology products. PMID- 29619280 TI - Radiation Reduction in Low Dose Pulsed Fluoroscopy versus Standard Dose Continuous Fluoroscopy during Fluoroscopically-Guided Lumbar Punctures: A Prospective Controlled Study. AB - Purpose: The purpose of this study was to evaluate radiation dose reduction in fluoroscopically guided lumbar punctures (FGLP) using "pulsed fluoroscopy in a low dose mode" compared with the commonly used "continuous fluoroscopy in a standard dose mode" while maintaining the technical success. Materials and Methods: Thirty-five consecutive patients who underwent FGLP divided randomly to seventeen patients in the control group with standard dose continuous FGLP and eighteen patients in the study group with low-dose low-frame-rate of 3 frames per second (fps) FGLP. Entrance surface dose measurements from a dosimeter device were recorded as well as the dose area product (DAP). Results: A total of 35 patients with average age of 52 years (range: 15-87 [+/-17 standard deviation [SD]]) were evaluated. Average entrance surface dose of the study group was significantly lower (3.81 mGy [range: 0.21-11.14, [+/-2.8 SD]]) compared with the control group (22.45 mGy [range: 1.23-73.44, [+/-19.41 [SD]]). The average DAP of the study group (10 mGy.cm2 [range: 1-41, [+/-9.8 SD]]) was also significantly lower than the control group (65 mGy.cm2 [range: 5-199, [+/-53 SD]]). Success rate was similar between the study and control groups. Conclusion: Low dose pulsed fluoroscopy of 3 fps significantly reduces radiation exposure by about 600% compared with standard dose continuous fluoroscopy in FGLP. Utilizing this radiation saving strategy will allow to dramatically reduce radiation exposure, without impacting the technical success rate. PMID- 29619281 TI - Incremental Value of Magnetic Resonance Imaging in Further Characterizing Hypodense Mediastinal and Paracardiac Lesions Identified on Computed Tomography. AB - Mediastinal and paracardiac lesions are usually first diagnosed on a chest radiograph or echocardiogram. Often, a computed tomography is obtained to further delineate these lesions. CT may be suboptimal for evaluation of enhancement characteristics and direct extension into the adjacent mediastinal structures. With its intrinsic superior soft-tissue characterization, magnetic resonance imaging (MRI) can better delineate these lesions, their internal tissue characteristics, and identify adhesion/invasion into adjacent structures. This pictorial essay provides a brief synopsis of the key MRI sequences and their utility in further characterizing mediastinal and paracardiac lesions. PMID- 29619282 TI - Evaluation of Orthopedic Metal Artifact Reduction Application in Three Dimensional Computed Tomography Reconstruction of Spinal Instrumentation: A Single Saudi Center Experience. AB - Aim of the Study: The aim of the study was to evaluate the commercially available orthopedic metal artifact reduction (OMAR) technique in postoperative three dimensional computed tomography (3DCT) reconstruction studies after spinal instrumentation and to investigate its clinical application. Materials and Methods: One hundred and twenty (120) patients with spinal metallic implants were included in the study. All had 3DCT reconstruction examinations using the OMAR software after obtaining the informed consents and approval of the Institution Ethical Committee. The degree of the artifacts, the related muscular density, the clearness of intermuscular fat planes, and definition of the adjacent vertebrae were qualitatively evaluated. The diagnostic satisfaction and quality of the 3D reconstruction images were thoroughly assessed. Results: The majority (96.7%) of 3DCT reconstruction images performed were considered satisfactory to excellent for diagnosis. Only 3.3% of the reconstructed images had rendered unacceptable diagnostic quality. Conclusion: OMAR can effectively reduce metallic artifacts in patients with spinal instrumentation with highly diagnostic 3DCT reconstruction images. PMID- 29619283 TI - Humanitarian Needs in Government Controlled Areas of Syria. AB - Background: Five years of conflict in Syria have led to 13.5 million people in need of humanitarian assistance and 6.6 million internally displaced people. Humanitarian needs are ever-increasing as an inability to maintain humanitarian corridors and ceasefires continue. In light of the protracted nature of the conflict, immense needs, and dearth of large-scale data, we undertook this assessment to inform humanitarian response. Methods: A survey of accessible areas, which were largely urban and government controlled, was undertaken from April - June 2016 to identify unmet needs and assistance priorities. A cluster design with probability sampling was used to attain a final sample of 2,405 households from ten of fourteen governorates; 31 of 65 (47.7%) districts were included that are home to 38.1% of people in need (PiN). Results: Overall 45% of households received assistance in the preceding month; receipt of aid was lowest in al-Hasakeh (17%). Shelter was a concern, with 48% of households having shelter need(s); the unmet shelter needs were highest in the West Coast, Rif Damascus and al-Hasakeh. Food security was a major concern where 64% had unmet food needs and 65% at least one indicator of concern; food insecurity was most severe in Rif Damascus and the West Coast. Water was also a concern with 36% of households reporting inconsistent access and 48% no access to water for several day periods; water needs were highest in Aleppo. Discussion: This assessment included accessible populations in predominantly urban and government controlled areas, which are likely to have better access to services and fewer needs than populations in rural locations or areas not controlled by the government. The humanitarian situation in inaccessible and non-government controlled areas is likely to be considerably worse, thus findings should not be generalized. An expanded humanitarian response is desperately needed for Syrians to better endure the conflict. PMID- 29619284 TI - Yoga for Young Adults With Noncurative Cancer: A Brief Report. AB - Background: The practice of yoga has been shown to improve disease- and treatment related side effects in the noncurative cancer patient. Objective: This user experience study aimed to examine the feasibility and usefulness of a DVD-based yoga program for young adult cancer patients with a noncurative diagnosis. Methods: Participants were asked to partake in a 7-week DVD-based yoga program and complete measures of program use and usefulness. Results: Nine patients expressed study interest and 5 consented to participate. Four completed the full study protocol. Participants reported being satisfied with the program and described that it provided an opportunity for self-care. Improvements in functional, physical, and spiritual well-being and overall quality of life were found. Barriers included competing time demands and feeling unwell. No adverse events were reported. Conclusion: The program was viewed as an accessible and useful activity option; however, a desire for greater social support from relatable others was highlighted. PMID- 29619285 TI - Marital Dissolution and Major Depression in Midlife: A Propensity Score Analysis. AB - Marital dissolution is commonly assumed to cause increased depression among adults, but causality can be questioned based on directionality and third variable concerns. The present study improves upon past research by using a propensity score matching algorithm to identify a sub-sample of continuously married participants equivalent in divorce risk to participants who actually experienced separation/divorce between two waves of the nationally representative study, Midlife Development in the United States (MIDUS). After correcting for participants' propensity to separate/divorce, increased rates of depression at the second assessment were observed only among participants who were (a) depressed at the initial assessment, and (b) experienced a separation/divorce. Participants who were not depressed at the initial assessment but who experienced a separation/divorce were not at increased risk for a later major depressive disorder (MDE). Thus, both social selection and social causation contribute to the increased risk for a MDE found among separated/divorced adults. PMID- 29619287 TI - Assessment of biomass burning smoke influence on environmental conditions for multi-year tornado outbreaks by combining aerosol-aware microphysics and fire emission constraints. AB - We use the WRF system to study the impacts of biomass burning smoke from Central America on several tornado outbreaks occurring in the US during spring. The model is configured with an aerosol-aware microphysics parameterization capable of resolving aerosol-cloud-radiation interactions in a cost-efficient way for numerical weather prediction (NWP) applications. Primary aerosol emissions are included and smoke emissions are constrained using an inverse modeling technique and satellite-based AOD observations. Simulations turning on and off fire emissions reveal smoke presence in all tornado outbreaks being studied and show an increase in aerosol number concentrations due to smoke. However, the likelihood of occurrence and intensification of tornadoes is higher due to smoke only in cases where cloud droplet number concentration in low level clouds increases considerably in a way that modifies the environmental conditions where the tornadoes are formed (shallower cloud bases and higher low-level wind shear). Smoke absorption and vertical extent also play a role, with smoke absorption at cloud-level tending to burn-off clouds and smoke absorption above clouds resulting in an increased capping inversion. Comparing these and WRF-Chem simulations configured with a more complex representation of aerosol size and composition and different optical properties, microphysics and activation schemes, we find similarities in terms of the simulated aerosol optical depths and aerosol impacts on near-storm environments. This provides reliability on the aerosol-aware microphysics scheme as a less computationally expensive alternative to WRF-Chem for its use in applications such as NWP and cloud-resolving simulations. PMID- 29619288 TI - Tropospheric ozonesonde profiles at long-term U.S. monitoring sites: 1. A climatology based on self-organizing maps. AB - Sonde-based climatologies of tropospheric ozone (O3) are vital for developing satellite retrieval algorithms and evaluating chemical transport model output. Typical O3 climatologies average measurements by latitude or region, and season. Recent analysis using self-organizing maps (SOM) to cluster ozonesondes from two tropical sites found clusters of O3 mixing ratio profiles are an excellent way to capture O3 variability and link meteorological influences to O3 profiles. Clusters correspond to distinct meteorological conditions, e.g. convection, subsidence, cloud cover, and transported pollution. Here, the SOM technique is extended to four long-term U.S. sites (Boulder, CO; Huntsville, AL; Trinidad Head, CA; Wallops Island, VA) with 4530 total profiles. Sensitivity tests on k means algorithm and SOM justify use of 3*3 SOM (nine clusters). At each site, SOM clusters together O3 profiles with similar tropopause height, 500 hPa height/temperature, and amount of tropospheric and total column O3. Cluster means are compared to monthly O3 climatologies. For all four sites, near-tropopause O3 is double (over +100 parts per billion by volume; ppbv) the monthly climatological O3 mixing ratio in three clusters that contain 13 - 16% of profiles, mostly in winter and spring. Large mid-tropospheric deviations from monthly means (-6 ppbv, +7 - 10 ppbv O3 at 6 km) are found in two of the most populated clusters (combined 36 - 39% of profiles). These two clusters contain distinctly polluted (summer) and clean O3 (fall-winter, high tropopause) profiles, respectively. As for tropical profiles previously analyzed with SOM, O3 averages are often poor representations of U.S. O3 profile statistics. PMID- 29619286 TI - Observational constraints on glyoxal production from isoprene oxidation and its contribution to organic aerosol over the Southeast United States. AB - We use a 0-D photochemical box model and a 3-D global chemistry-climate model, combined with observations from the NOAA Southeast Nexus (SENEX) aircraft campaign, to understand the sources and sinks of glyoxal over the Southeast United States. Box model simulations suggest a large difference in glyoxal production among three isoprene oxidation mechanisms (AM3ST, AM3B, and MCM v3.3.1). These mechanisms are then implemented into a 3-D global chemistry climate model. Comparison with field observations shows that the average vertical profile of glyoxal is best reproduced by AM3ST with an effective reactive uptake coefficient gammaglyx of 2 * 10-3, and AM3B without heterogeneous loss of glyoxal. The two mechanisms lead to 0-0.8 MUg m-3 secondary organic aerosol (SOA) from glyoxal in the boundary layer of the Southeast U.S. in summer. We consider this to be the lower limit for the contribution of glyoxal to SOA, as other sources of glyoxal other than isoprene are not included in our model. In addition, we find that AM3B shows better agreement on both formaldehyde and the correlation between glyoxal and formaldehyde (RGF = [GLYX]/[HCHO]), resulting from the suppression of delta-isoprene peroxy radicals (delta-ISOPO2). We also find that MCM v3.3.1 may underestimate glyoxal production from isoprene oxidation, in part due to an underestimated yield from the reaction of IEPOX peroxy radicals (IEPOXOO) with HO2. Our work highlights that the gas-phase production of glyoxal represents a large uncertainty in quantifying its contribution to SOA. PMID- 29619289 TI - Radiative effects of global MODIS cloud regimes. AB - We update previously published MODIS global cloud regimes (CRs) using the latest MODIS cloud retrievals in the Collection 6 dataset. We implement a slightly different derivation method, investigate the composition of the regimes, and then proceed to examine several aspects of CR radiative appearance with the aid of various radiative flux datasets. Our results clearly show the CRs are radiatively distinct in terms of shortwave, longwave and their combined (total) cloud radiative effect. We show that we can clearly distinguish regimes based on whether they radiatively cool or warm the atmosphere, and thanks to radiative heating profiles to discern the vertical distribution of cooling and warming. Terra and Aqua comparisons provide information about the degree to which morning and afternoon occurrences of regimes affect the symmetry of CR radiative contribution. We examine how the radiative discrepancies among multiple irradiance datasets suffering from imperfect spatiotemporal matching depend on CR, and whether they are therefore related to the complexity of cloud structure, its interpretation by different observational systems, and its subsequent representation in radiative transfer calculations. PMID- 29619290 TI - Tropospheric ozonesonde profiles at long-term U.S. monitoring sites: 2. Links between Trinidad Head, CA, profile clusters and inland surface ozone measurements. AB - Much attention has been focused on the transport of ozone (O3) to the Western U.S., particularly given the latest revision of the National Ambient Air Quality Standard (NAAQS) to 70 parts per billion by volume (ppbv) of O3. This makes defining a "background" O3 amount essential so that the effects of stratosphere to-troposphere exchange and pollution transport to this region can be quantified. To evaluate free-tropospheric and surface O3 in the Western U.S., we use self organizing maps to cluster 18 years of ozonesonde profiles (940 samples) from Trinidad Head, CA. Two of nine O3 mixing ratio profile clusters exhibit thin laminae of high O3 above Trinidad Head. A third, consisting of background (~20 - 40 ppbv) O3, occurs in ~10% of profiles. The high O3 layers are located between 1 and 4 km amsl, and reside above a subsidence inversion associated with a northern location of the semi-permanent Pacific subtropical high. Several ancillary data sets are examined to identify the high O3 sources (reanalyses, trajectories, remotely-sensed carbon monoxide), but distinguishing chemical and stratospheric influences of the elevated O3 is difficult. There is marked and long-lasting impact of the elevated tropospheric O3 on high-altitude surface O3 monitors at Lassen Volcanic and Yosemite National Parks, and Truckee, CA. Days corresponding to the high O3 clusters exhibit hourly surface O3 anomalies of +5 - 10 ppbv compared to a climatology; the anomalies can last up to four days. The profile and surface O3 links demonstrate the importance of regular ozonesonde profiling at Trinidad Head. PMID- 29619291 TI - MRSA prevalence among patient transport staff in Hamburg. AB - Introduction: Patient transport employees frequently come into contact with multidrug-resistant organisms (MDROs) and therefore are at a greater risk of infection than the general population. These pathogens pose a significant challenge for employees of patient transport services since they can spread over long distances through patient transfers. To date, little is known about the occupational risk of MRSA infection in patient transport settings. Methods: A cross-sectional study was conducted to investigate the prevalence of MRSA in patient transport personnel, including taxi drivers, as well as the potential risk factors for MRSA colonization. For screening, nasal swabs were taken. When an individual was tested positive, a control swab was taken; if this confirmed a positive result, decolonization measures were offered. A molecular biological examination of the MRSA samples was performed. Results: A total of 222 patient transport employees were screened and 7 employees tested positive, putting the MRSA prevalence at 3.2% (95% CI 1.4-6.5). Significant risk factors among patient transport staff (PTS) for testing positive were the use of antibiotics (OR 11.9; 95% CI 1.8-78.4) and hospital admission (OR 6.9; 95% CI 1.1-45.9). MRSA swabs were also performed on a total of 102 taxi drivers who provide patient transport services. The MRSA prevalence was 0.98 (95% CI <0.01-5.9). Significant group differences between PTS and taxi drivers, with respect to potential risk factors for MRSA colonization, were identified as inpatient treatment (p=0.09), chronic respiratory illnesses (p=0.01), and knowingly transporting patients/passengers with MRSA (p=0.03). Conclusion: This study is the first to make data on the MRSA risk of patient transport employees in Hamburg available. The prevalence data are low in all areas and indicate a somewhat low risk of infection. A good infection control at the facilities is highly recommendable and the employees should acquire in-depth knowledge of infection prevention to improve compliance with personal protective measures. PMID- 29619292 TI - Rate of antibiotic prescriptions in German outpatient care - are the guidelines followed or are they still exceeded? AB - Aim: The consequences of antibiotic overuse are substantial. We combined and analyzed the infection diagnoses and antibiotic prescribing practices of physicians in outpatient settings. Recommendations for targeting policy efforts to focused areas are given. Methods: Antibiotic prescriptions and infections diagnosed were provided by a German statutory health insurance provider over a 12 month period. Antibiotic use was expressed as prescriptions per 100 patients. Results: 2,594,000 patient-physician contacts within twelve months were analyzed. A median of 6.5 antibiotics was prescribed to 100 patients. Antibiotic use in private practice showed large variations between and within medical specialties (the upper quarter of physicians who prescribed above the 75th percentile of all prescriptions, at a rate of approximately 43%), by season (antibiotic prescription was 50% higher in winter than in summer) and a considerable proportion of the antibiotics prescribed did not conform with the recommendations of national guidelines. Fluoroquinolones, predominantly ciprofloxacin, were among the top three antibiotics prescribed by all physicians (except pediatricians), although national guidelines do not recommend these agents for uncomplicated respiratory or urinary tract infections. Respiratory tract infections headed the list for the prescription of antibiotics. Conclusions: Antibiotics were still not prescribed appropriately in respect to indication and selection (often unnecessary and/or too broad). We recommend focusing on I) high/over-prescribers, because improved and appropriate antibiotic prescription by this group would result in an over-proportionally lower antibiotic prescription rate, II) respiratory tract infections, because they represent the vast majority of infections treated in primary care and III) intelligent implementation strategies of guidelines. PMID- 29619293 TI - In Vivo Photoacoustic Imaging of Brain Injury and Rehabilitation by High Efficient Near-Infrared Dye Labeled Mesenchymal Stem Cells with Enhanced Brain Barrier Permeability. AB - Stem cell migration and interaction with pathology are critical to understand the complexity and status of disease recovery progress. However, the dynamic visualization still remains a great challenge due to imaging technical limitation, cell labeling difficulty, or blood-brain barrier (BBB). Herein, fast photoacoustic tomography (PAT) with optical molecular probes is applied to noninvasively monitor traumatic brain injury (TBI) and its rehabilitation. The vascular distribution and TBI hemorrhage are clearly imaged, longitudinally monitored, and quantified. Bone mesenchymal stem cells (BMSCs) labeled with modified Prussian blue particles (PBPs), excellent near-infrared dyes and photoacoustic contrasts, are intravenously injected to the mice for improved observation and efficient therapy. BMSCs are demonstrated to be capable of overcoming BBB with enhanced delivery of PBPs to the brain parenchyma. Notably, the versatile BMSCs are observed by PAT to home to the damage region and repair the ruptured vasculature. Moreover, the wound treated by BMSCs exhibits much faster recovery speed than that without treatment. These findings can potentially provide a new noninvasive and high-resolution approach to image TBI, monitor recovery process, and especially trace BMSCs. This study will stimulate extensive researches on brain diseases and provide promising strategies of dye labeled BMSCs in regenerative medicine. PMID- 29619294 TI - Vertical Hydrodynamic Focusing and Continuous Acoustofluidic Separation of Particles via Upward Migration. AB - A particle suspended in a fluid within a microfluidic channel experiences a direct acoustic radiation force (ARF) when traveling surface acoustic waves (TSAWs) couple with the fluid at the Rayleigh angle, thus producing two components of the ARF. Most SAW-based microfluidic devices rely on the horizontal component of the ARF to migrate prefocused particles laterally across a microchannel width. Although the magnitude of the vertical component of the ARF is more than twice the magnitude of the horizontal component, it is long ignored due to polydimethylsiloxane (PDMS) microchannel fabrication limitations and difficulties in particle focusing along the vertical direction. In the present work, a single-layered PDMS microfluidic chip is devised for hydrodynamically focusing particles in the vertical plane while explicitly taking advantage of the horizontal ARF component to slow down the selected particles and the stronger vertical ARF component to push the particles in the upward direction to realize continuous particle separation. The proposed particle separation device offers high-throughput operation with purity >97% and recovery rate >99%. It is simple in its fabrication and versatile due to the single-layered microchannel design, combined with vertical hydrodynamic focusing and the use of both the horizontal and vertical components of the ARF. PMID- 29619295 TI - Multidrug Resistance in Cancer Circumvented Using a Cytosolic Drug Reservoir. AB - It is discovered that sustained cytosolic drug release at a sufficient concentration is an effective mechanism to circumvent multidrug resistance and consequently enhance antitumor drug efficacy. It is showed that a simple way to enable this mechanism is to reach an intracellular kinetic balance of the drug movement between the drug released from the carrier into the cytosol and the one removed from the cell interior. By adopting nanoparticle (NP) as the drug carrier, a reservoir of drug can be maintained inside the cells upon effective cellular uptake of these NPs via endocytosis. This study shows that gradual release of the drug from the NP carrier provides a feasible scheme for sustained drug release in cells, resulting in relatively stable cytosolic drug concentration level, particularly in the drug resistant case. By implementing an "optical switch" with light irradiation on photosensitizer in the same nanoparticle carrier, cytosolic drug release is further promoted, which increases cytosolic drug concentration with good concentration retention. Enhanced drug efficacy in drug sensitive as well as resistant models is demonstrated both in vitro and in vivo. Such a mechanism is shown to efficiently circumvent multidrug resistance, and at the same time largely reduce the systemic toxicity of the anticancer drug. PMID- 29619296 TI - First-Principle-Based Phonon Transport Properties of Nanoscale Graphene Grain Boundaries. AB - The integrity of phonon transport properties of large graphene (linear and curved) grain boundaries (GBs) is investigated under the influence of structural and dynamical disorder. To do this, density functional tight-binding (DFTB) method is combined with atomistic Green's function technique. The results show that curved GBs have lower thermal conductance than linear GBs. Its magnitude depends on the length of the curvature and out-of-plane structural distortions at the boundary, having stronger influence the latter one. Moreover, it is found that by increasing the defects at the boundary, the transport properties can strongly be reduced in comparison to the effect produced by heating up the boundary region. This is due to the large reduction of the phonon transmission for in-plane and out-of-plane vibrational modes after increasing the structural disorder in the GBs. PMID- 29619298 TI - Design and Construction of Hybrid Microcapsules with Higher-Order Structure and Multiple Functions. AB - The construction of inorganic-protein hybrid microcapsules by using bovine serum albumin, metal ion clusters, and poly (N-isopropylacrylamide) nanoconjugates as building blocks is presented. These microcapsules have robust membranes, which can keep their spherical morphology. They support interfacial catalytic activity by the ion clusters on their surface, and can be used as a platform to immobilize enzyme on the interface of oil/water to increase the diversity and efficiency of catalysis. These microcapsules also act as a container to make materials away from bacteria when existing silver clusters on the membrane. The obtained results highlight the construction of these microcompartments. These novel microcompartments can provide some new opportunities in bottom-up synthetic biology, bioinspired microstorage/ microreactor, and drug/gene delivery in the future. PMID- 29619299 TI - Swimming Back and Forth Using Planar Flagellar Propulsion at Low Reynolds Numbers. AB - Peritrichously flagellated Escherichia coli swim back and forth by wrapping their flagella together in a helical bundle. However, other monotrichous bacteria cannot swim back and forth with a single flagellum and planar wave propagation. Quantifying this observation, a magnetically driven soft two-tailed microrobot capable of reversing its swimming direction without making a U-turn trajectory or actively modifying the direction of wave propagation is designed and developed. The microrobot contains magnetic microparticles within the polymer matrix of its head and consists of two collinear, unequal, and opposite ultrathin tails. It is driven and steered using a uniform magnetic field along the direction of motion with a sinusoidally varying orthogonal component. Distinct reversal frequencies that enable selective and independent excitation of the first or the second tail of the microrobot based on their tail length ratio are found. While the first tail provides a propulsive force below one of the reversal frequencies, the second is almost passive, and the net propulsive force achieves flagellated motion along one direction. On the other hand, the second tail achieves flagellated propulsion along the opposite direction above the reversal frequency. PMID- 29619297 TI - Modularized Extracellular Vesicles: The Dawn of Prospective Personalized and Precision Medicine. AB - Extracellular vesicles (EVs) are ubiquitous nanosized membrane vesicles consisting of a lipid bilayer enclosing proteins and nucleic acids, which are active in intercellular communications. EVs are increasingly seen as a vital component of many biological functions that were once considered to require the direct participation of stem cells. Consequently, transplantation of EVs is gradually becoming considered an alternative to stem cell transplantation due to their significant advantages, including their relatively low probability of neoplastic transformation and abnormal differentiation. However, as research has progressed, it is realized that EVs derived from native-source cells may have various shortcomings, which can be corrected by modification and optimization. To date, attempts are made to modify or improve almost all the components of EVs, including the lipid bilayer, proteins, and nucleic acids, launching a new era of modularized EV therapy through the "modular design" of EV components. One high yield technique, generating EV mimetic nanovesicles, will help to make industrial production of modularized EVs a reality. These modularized EVs have highly customized "modular design" components related to biological function and targeted delivery and are proposed as a promising approach to achieve personalized and precision medicine. PMID- 29619300 TI - Tuning Transpiration by Interfacial Solar Absorber-Leaf Engineering. AB - Plant transpiration, a process of water movement through a plant and its evaporation from aerial parts especially leaves, consumes a large component of the total continental precipitation (~48%) and significantly influences global water distribution and climate. To date, various chemical and/or biological explorations have been made to tune the transpiration but with uncertain environmental risks. In recent years, interfacial solar steam/vapor generation is attracting a lot of attention for achieving high energy transfer efficiency. Various optical and thermal designs at the solar absorber-water interface for potential applications in water purification, seawater desalination, and power generation appear. In this work, the concept of interfacial solar vapor generation is extended to tunable plant transpiration by showing for the first time that the transpiration efficiency can also be enhanced or suppressed through engineering the solar absorber-leaf interface. By tuning the solar absorption of membrane in direct touch with green leaf, surface temperature of green leaf will change accordingly because of photothermal effect, thus the transpiration efficiency as well as temperature and relative humidity in the surrounding environment will be tuned. This tunable transpiration by interfacial absorber leaf engineering can open an alternative avenue to regulate local atmospheric temperature, humidity, and eventually hydrologic cycle. PMID- 29619301 TI - Ultrahigh, Ultrafast, and Self-Powered Visible-Near-Infrared Optical Position Sensitive Detector Based on a CVD-Prepared Vertically Standing Few-Layer MoS2/Si Heterojunction. AB - MoS2, as a typical transition metal dichalcogenide, has attracted great interest because of its distinctive electronic, optical, and catalytic properties. However, its advantages of strong light absorption and fast intralayer mobility cannot be well developed in the usual reported monolayer/few-layer structures, which make the performances of MoS2-based devices undesirable. Here, large-area, high-quality, and vertically oriented few-layer MoS2 (V-MoS2) nanosheets are prepared by chemical vapor deposition and successfully transferred onto an Si substrate to form the V-MoS2/Si heterojunction. Because of the strong light absorption and the fast carrier transport speed of the V-MoS2 nanosheets, as well as the strong built-in electric field at the interface of V-MoS2 and Si, lateral photovoltaic effect (LPE) measurements suggest that the V-MoS2/Si heterojunction is a self-powered, high-performance position sensitive detector (PSD). The PSD demonstrates ultrahigh position sensitivity over a wide spectrum, ranging from 350 to 1100 nm, with position sensitivity up to 401.1 mV mm-1, and shows an ultrafast response speed of 16 ns with excellent stability and reproducibility. Moreover, considering the special carrier transport process in LPE, for the first time, the intralayer and the interlayer transport times in V-MoS2 are obtained experimentally as 5 and 11 ns, respectively. PMID- 29619302 TI - Magnetic Sponge with Neutral-Ionic Phase Transitions. AB - Phase transitions caused by the charge instability between the neutral and ionic phases of compounds, i.e., N-I phase transitions, provide avenues for switching the intrinsic properties of compounds related to electron/spin correlation and dipole generation as well as charge distribution. However, it is extremely difficult to control the transition temperature (Tc) for the N-I phase transition, and only chemical modification based on the original material have been investigated. Here, a design overview of the tuning of N-I phase transition by interstitial guest molecules is presented. This study reports a new chain coordination-polymer [Ru2(3,4-Cl2PhCO2)4TCNQ(EtO)2]?DCE (1-DCE; 3,4-Cl2PhCO2- = 3,4-dichlorobenzoate; TCNQ(EtO)2 2,5-diethoxy-7,7,8,8-tetracyanoquinodimethane; and DCE = 1,2-dichloroethane) that exhibits a one-step N-I transition at 230 K (= Tc) with the N- and I-states possessing a simple paramagnetic state and a ferrimagnetically correlated state for the high- and low-temperature phases, respectively. The Tc continuously decreases depending on the content of DCE, which eventually disappears with the complete evacuation of DCE, affording solvent-free compound 1 with the N-state in the entire temperature range (this behavior is reversible). This is an example of tuning the in situ Tc for the N-I phase transition via the control of the interstitial guest molecules. PMID- 29619303 TI - A Pickering Emulsion Route to Swimming Active Janus Colloids. AB - The field of active colloids is attracting significant interest to both enable applications and allow investigations of new collective colloidal phenomena. One convenient active colloidal system that has been much studied is spherical Janus particles, where a hemispherical coating of platinum decomposes hydrogen peroxide to produce rapid motion. However, at present producing these active colloids relies on a physical vapor deposition (PVD) process, which is difficult to scale and requires access to expensive equipment. In this work, it is demonstrated that Pickering emulsion masking combined with solution phase metallization can produce self-motile catalytic Janus particles. Comparison of the motion and catalytic activity with PVD colloids reveals a higher catalytic activity for a given thickness of platinum due to the particulate nature of the deposited coating. This Pickering emulsion based method will assist in producing active colloids for future applications and aid experimental research into a wide range of active colloid phenomena. PMID- 29619304 TI - Verifying the Rechargeability of Li-CO2 Batteries on Working Cathodes of Ni Nanoparticles Highly Dispersed on N-Doped Graphene. AB - Li-CO2 batteries could skillfully combine the reduction of "greenhouse effect" with energy storage systems. However, Li-CO2 batteries still suffer from unsatisfactory electrochemical performances and their rechargeability is challenged. Here, it is reported that a composite of Ni nanoparticles highly dispersed on N-doped graphene (Ni-NG) with 3D porous structure, exhibits a superior discharge capacity of 17 625 mA h g-1, as the air cathode for Li-CO2 batteries. The batteries with these highly efficient cathodes could sustain 100 cycles at a cutoff capacity of 1000 mA h g-1 with low overpotentials at the current density of 100 mA g-1. Particularly, the Ni-NG cathodes allow to observe the appearance/disappearance of agglomerated Li2CO3 particles and carbon thin films directly upon discharge/charge processes. In addition, the recycle of CO2 is detected through in situ differential electrochemical mass spectrometry. This is a critical step to verify the electrochemical rechargeability of Li-CO2 batteries. Also, first-principles computations further prove that Ni nanoparticles are active sites for the reaction of Li and CO2, which could guide to design more advantageous catalysts for rechargeable Li-CO2 batteries. PMID- 29619305 TI - Graphene-Based MicroRNA Transfection Blocks Preosteoclast Fusion to Increase Bone Formation and Vascularization. AB - The objective of this study is to design a graphene-based miRNA transfection drug delivery system for antiresorptive therapy. An efficient nonviral gene delivery system is developed using polyethylenimine (PEI) functionalized graphene oxide (GO) complex loaded with miR-7b overexpression plasmid. GO-PEI complex exhibits excellent transfection efficiency within the acceptable range of cytotoxicity. The overexpression of miR-7b after GO-PEI-miR-7b transfection significantly abrogates osteoclast (OC) fusion and bone resorption activity by hampering the expression of an essential fusogenic molecule dendritic cell-specific transmembrane protein. However, osteoclastogenesis occurs without cell-cell fusion and preosteoclast (POC) is preserved. Through preservation of POC, GO-PEI miR-7b transfection promotes mesenchymal stem cell osteogenesis and endothelial progenitor cells angiogenesis in the coculture system. Platelet-derived growth factor-BB secreted by POC is increased by GO-PEI-miR-7b both in vitro and in vivo. In treating osteoporotic ovariectomized mice, GO-PEI-miR-7b significantly enhances bone mineral density, bone volume as well as bone vascularization through increasing CD31hiEmcnhi cell number. This study provides a cell-cell fusion targeted miRNA transfection drug delivery strategy in treating bone disorders with excessive osteoclastic bone resorption. PMID- 29619306 TI - Carbon Nanofiber versus Graphene-Based Stretchable Capacitive Touch Sensors for Artificial Electronic Skin. AB - Stretchable capacitive devices are instrumental for new-generation multifunctional haptic technologies particularly suited for soft robotics and electronic skin applications. A majority of elongating soft electronics still rely on silicone for building devices or sensors by multiple-step replication. In this study, fabrication of a reliable elongating parallel-plate capacitive touch sensor, using nitrile rubber gloves as templates, is demonstrated. Spray coating both sides of a rubber piece cut out of a glove with a conductive polymer suspension carrying dispersed carbon nanofibers (CnFs) or graphene nanoplatelets (GnPs) is sufficient for making electrodes with low sheet resistance values (~10 Omega sq-1). The electrodes based on CnFs maintain their conductivity up to 100% elongation whereas the GnPs-based ones form cracks before 60% elongation. However, both electrodes are reliable under elongation levels associated with human joints motility (~20%). Strikingly, structural damages due to repeated elongation/recovery cycles could be healed through annealing. Haptic sensing characteristics of a stretchable capacitive device by wrapping it around the fingertip of a robotic hand (ICub) are demonstrated. Tactile forces as low as 0.03 N and as high as 5 N can be easily sensed by the device under elongation or over curvilinear surfaces. PMID- 29619307 TI - Nanogap-Engineerable Electromechanical System for Ultralow Power Memory. AB - Nanogap engineering of low-dimensional nanomaterials has received considerable interest in a variety of fields, ranging from molecular electronics to memories. Creating nanogaps at a certain position is of vital importance for the repeatable fabrication of the devices. Here, a rational design of nonvolatile memories based on sub-5 nm nanogaped single-walled carbon nanotubes (SWNTs) via the electromechanical motion is reported. The nanogaps are readily realized by electroburning in a partially suspended SWNT device with nanoscale region. The SWNT memory devices are applicable for both metallic and semiconducting SWNTs, resolving the challenge of separation of semiconducting SWNTs from metallic ones. Meanwhile, the memory devices exhibit excellent performance: ultralow writing energy (4.1 * 10-19 J bit-1), ON/OFF ratio of 105, stable switching ON operations, and over 30 h retention time in ambient conditions. PMID- 29619308 TI - Rationally Designed Hierarchically Structured Tungsten Nitride and Nitrogen-Rich Graphene-Like Carbon Nanocomposite as Efficient Hydrogen Evolution Electrocatalyst. AB - Practical application of hydrogen production from water splitting relies strongly on the development of low-cost and high-performance electrocatalysts for hydrogen evolution reaction (HER). The previous researches mainly focused on transition metal nitrides as HER catalysts due to their electrical conductivity and corrosion stability under acidic electrolyte, while tungsten nitrides have reported poorer activity for HER. Here the activity of tungsten nitride is optimized through rational design of a tungsten nitride-carbon composite. More specifically, tungsten nitride (WN x ) coupled with nitrogen-rich porous graphene like carbon is prepared through a low-cost ion-exchange/molten-salt strategy. Benefiting from the nanostructured WN x , the highly porous structure and rich nitrogen dopant (9.5 at%) of the carbon phase with high percentage of pyridinic-N (54.3%), and more importantly, their synergistic effect, the composite catalyst displays remarkably high catalytic activity while maintaining good stability. This work highlights a powerful way to design more efficient metal-carbon composites catalysts for HER. PMID- 29619309 TI - Stimuli-Directed Dynamic Reconfiguration in Self-Organized Helical Superstructures Enabled by Chemical Kinetics of Chiral Molecular Motors. AB - Dynamic controllability of self-organized helical superstructures in spatial dimensions is a key step to promote bottom-up artificial nanoarchitectures and functional devices for diverse applications in a variety of areas. Here, a light driven chiral overcrowded alkene molecular motor with rod-like substituent is designed and synthesized, and its thermal isomerization reaction exhibits an increasing structural entropy effect on chemical kinetic analysis in anisotropic achiral liquid crystal host than that in isotropic organic liquid. Interestingly, the stimuli-directed angular orientation motion of helical axes in the self organized helical superstructures doped with the chiral motors enables the dynamic reconfiguration between the planar (thermostationary) and focal conic (photostationary) states. The reversible micromorphology deformation processes are compatible with the free energy fluctuation of self-organized helical superstructures and the chemical kinetics of chiral motors under different conditions. Furthermore, stimuli-directed reversible nonmechanical beam steering is achieved in dynamic hidden periodic photopatterns with reconfigurable attributes prerecorded with a corresponding photomask and photoinduced polymerization. PMID- 29619310 TI - A One-Structure-Based Multieffects Coupled Nanogenerator for Simultaneously Scavenging Thermal, Solar, and Mechanical Energies. AB - Rapid advances in various energy harvesters impose the challenge on integrating them into one device structure with synergetic effects for full use of the available energies from the environment. Here, a multieffect coupled nanogenerator based on ferroelectric barium titanate is reported. It promotes the ability to simultaneously scavenging thermal, solar, and mechanical energies. By integration of a pyroelectric nanogenerator, a photovoltaic cell, and a triboelectric-piezoelectric nanogenerator in one structure with only two electrodes, multieffects interact with each other to alter the electric output, and a complementary power source with peak current of ~1.5 uA, peak voltage of ~7 V, and platform voltage of ~6 V is successfully achieved. Compared with traditional hybridized nanogenerators with stacked architectures, the one structure-based multieffects coupled nanogenerator is smaller, simpler, and less costly, showing prospective in practical applications and represents a new trend of all-in-one multiple energy scavenging. PMID- 29619312 TI - Impact of Plasma Electron Flux on Plasma Damage-Free Sputtering of Ultrathin Tin Doped Indium Oxide Contact Layer on p-GaN for InGaN/GaN Light-Emitting Diodes. AB - The origin of plasma-induced damage on a p -type wide-bandgap layer during the sputtering of tin-doped indium oxide (ITO) contact layers by using radiofrequency superimposed direct current (DC) sputtering and its effects on the forward voltage and light output power (LOP) of light-emitting diodes (LEDs) with sputtered ITO transparent conductive electrodes (TCE) is systematically studied. Changing the DC power voltage from negative to positive bias reduces the forward voltages and enhances the LOP of the LEDs. The positive DC power drastically decreases the electron flux in the plasma obtained by plasma diagnostics using a cutoff probe and a Langmuir probe, suggesting that the repulsion of plasma electrons from the p -GaN surface can reduce plasma-induced damage to the p -GaN. Furthermore, electron-beam irradiation on p -GaN prior to ITO deposition significantly increases the forward voltages, showing that the plasma electrons play an important role in plasma-induced damage to the p -GaN. The plasma electrons can increase the effective barrier height at the ITO/deep-level defect (DLD) band of p -GaN by compensating DLDs, resulting in the deterioration of the forward voltage and LOP. Finally, the plasma damage-free sputtered-ITO TCE enhances the LOP of the LEDs by 20% with a low forward voltage of 2.9 V at 20 mA compared to LEDs with conventional e-beam-evaporated ITO TCE. PMID- 29619311 TI - Self-Assembled Graphene-Based Architectures and Their Applications. AB - Due to unique planar structures and remarkable thermal, electronic, and mechanical properties, chemically modified graphenes (CMGs) such as graphene oxides, reduced graphene oxides, and the related derivatives are recognized as the attractive building blocks for "bottom-up" nanotechnology, while self assembly of CMGs has emerged as one of the most promising approaches to construct advanced functional materials/systems based on graphene. By virtue of a variety of noncovalent forces like hydrogen bonding, van der Waals interaction, metal-to ligand bonds, electrostatic attraction, hydrophobic-hydrophilic interactions, and pi-pi interactions, the CMGs bearing various functional groups are highly desirable for the assemblies with themselves and a variety of organic and/or inorganic species which can yield various hierarchical nanostructures and macroscopic composites endowed with unique structures, properties, and functions for widespread technological applications such as electronics, optoelectronics, electrocatalysis/photocatalysis, environment, and energy storage and conversion. In this review, significant recent advances concerning the self-assembly of CMGs are summarized, and the broad applications of self-assembled graphene-based materials as well as some future opportunities and challenges in this vibrant area are elucidated. PMID- 29619313 TI - Nickel Hydr(oxy)oxide Nanoparticles on Metallic MoS2 Nanosheets: A Synergistic Electrocatalyst for Hydrogen Evolution Reaction. AB - Molybdenum disulfide (MoS2)-based materials have been recently identified as promising electrocatalysts for hydrogen evolution reaction (HER). However, little work has been done to improve the catalytic performance of MoS2 toward HER in alkaline electrolytes, which is more suitable for water splitting in large-scale applications. Here, it is reported that the hybridization of 0D nickel hydr(oxy)oxide nanoparticles with 2D metallic MoS2 nanosheets can significantly enhance the HER activities in alkaline and neutral electrolytes. Impressively, the optimized hybrid catalyst can drive a cathodic current density of 10 mA cm-2 at an overpotential of ~73 mV for HER in 1 m KOH, about 185 mV smaller than the original MoS2. The improved HER activity is attributed to a bifunctional mechanism adopted in these hybrid catalysts, in which nickel hydr(oxy)oxide promotes the water adsorption and dissociation to supply protons for subsequent reactions occurred on MoS2 to generate H2. PMID- 29619314 TI - Chemotherapeutic Drug Based Metal-Organic Particles for Microvesicle-Mediated Deep Penetration and Programmable pH/NIR/Hypoxia Activated Cancer Photochemotherapy. AB - A novel metal-organic particle (MOP) based nanodrug formed by mild self-assembly of chemotherapeutic drugs, including banoxantrone and doxorubicin, through Cu(II) mediated coordination effects, is reported. In this nanodrug, Cu(II) acts as a bridge to join AQ4N and DOX, and then, self-assembly of [-AQ4N-Cu(II)-(DOX)2 Cu(II)-] n complexes forms nanosized MOPs (referred to as ADMOPs) through multiple interactions including host-metal-guest coordination, hydrophobic interactions, pi-stacking, and van der Waals force. The ADMOPs reported here have several important features over conventional drugs, including tumor microenvironment pH-sensitive drug release that can be tracked by "turning on" the fluorescence of AQ4N or DOX through proton competition with Cu(II) to break the coordination bonds and much deeper penetration into solid tumors via microvesicle-mediated intercellular transfer. Most strikingly, the ADMOPs can serve as stimuli-responsive nanocarriers to efficiently load the photosensitizer phthalocyanine due to their inherent highly porous characteristics. Thus, the ADMOPs significantly enhance the chemotherapeutic efficacy by "on-demand" photodynamic therapy, which further induces a hypoxic environment that enhances the reduction of AQ4N to systematically increase the therapeutic efficiency. Taken together, the designed ADMOPs composed of chemotherapeutic drugs may serve as a potential programmable controlled synergistic agent for cancer therapy. PMID- 29619315 TI - Triboelectrification-Enabled Self-Powered Data Storage. AB - Data storage by any means usually requires an electric driving power for writing or reading. A novel approach for self-powered, triboelectrification-enabled data storage (TEDS) is presented. Data are incorporated into a set of metal-based surface patterns. As a probe slides across the patterned surface, triboelectrification between the scanning probe and the patterns produces alternatively varying voltage signal in quasi-square wave. The trough and crest of the quasi-square wave signal are coded as binary bits of "0" and "1," respectively, while the time span of the trough and the crest is associated with the number of bits. The storage of letters and sentences is demonstrated through either square-shaped or disc-shaped surface patterns. Based on experimental data and numerical calculation, the theoretically predicted maximum data storage density could reach as high as 38.2 Gbit in-2. Demonstration of real-time data retrieval is realized with the assistance of software interface. For the TEDS reported in this work, the measured voltage signal is self-generated as a result of triboelectrification without the reliance on an external power source. This feature brings about not only low power consumption but also a much more simplified structure. Therefore, this work paves a new path to a unique approach of high-density data storage that may have widespread applications. PMID- 29619316 TI - Pulmonary cryptococcal infection presenting with multiple lung nodules. AB - Pulmonary infections from the environmental fungus Cryptococcus gattii (C. gattii) are notable for cryptococcomas, which are usually solitary and can be very large. As with infections with Cryptococcus neoformans (C. neoformans) patients can have concomitant cryptococcal meningitis; however, unlike for C. neoformans, infections with C. gattii often occur in immunocompetent patients. The highest published incidence of C. gattii infection has been in the Indigenous Australian population of Arnhem Land in the tropical north of the country. More recently C. gattii has been responsible for outbreaks of cryptococcosis in the Pacific Northwest of Canada and the United States of America (USA). A previously healthy Indigenous male from Arnhem Land presented with pulmonary cryptococcosis with chest imaging showing >50 bilateral lung nodules. This unusual occurrence was attributed to probable inhalation of fungal elements from prior use of a high pressure leaf blower to clear eucalyptus and other debris in a remote bush camp. PMID- 29619317 TI - Influence of inter-stimulus interval of spinal cord stimulation in patients with disorders of consciousness: A preliminary functional near-infrared spectroscopy study. AB - Spinal cord stimulation (SCS) is a promising treatment for disorders of consciousness (DOC), but the underlying mechanism and most effective procedures remain uncertain. To optimize the protocol, previous studies evaluated the frequency-specific effects of SCS on neurophysiological activities. However, whether and how the inter-stimulus interval (ISI) parameter affects the SCS neuromodulation in DOC remains unknown. We enrolled nine DOC patients who had implanted SCS devices and conducted three different durations of ISIs. Using functional near-infrared spectroscopy (fNIRS), we monitored the blood volume fluctuations in the prefrontal and occipital cortices during the SCS. The results showed that short stimuli (30 s) induced significant cerebral blood volume changes, especially in the prefrontal cortex, an important area in the consciousness system. By comparing the mean value of the responses from the first and the last block in each session, a shorter ISI was found to improve the blood volume in the prefrontal cortex. This phenomenon was more significant for the subgroup of patients with a favorable prognosis. These preliminary results imply that the ISI may be an important factor for SCS. The research paradigm proposed here also provides insights for further quantitative evaluations of the therapeutic effects of neuromodulation. PMID- 29619319 TI - First reported case of vertebral osteomyelitis due to Erysipelothrix rhusiopathiae. AB - We describe a case of acute vertebral osteomyelitis with associated prevertebral abscess due to Erysipelothrix rhusiopathiae in an immunocompetent adult with recent known traumatic inoculation from the barb of a fish. PMID- 29619318 TI - The behavioural patterns and neural correlates of concrete and abstract verb processing in aphasia: A novel verb semantic battery. AB - Typically, processing is more accurate and efficient for concrete than abstract concepts in both healthy adults and individuals with aphasia. While, concreteness effects have been thoroughly documented with respect to noun processing, other words classes have received little attention despite tending to be less concrete than nouns. The aim of the current study was to explore concrete-abstract differences in verbs and identify their neural correlates in post-stroke aphasia. Given the dearth of comprehension tests for verbs, a battery of neuropsychological tests was developed in this study to assess the comprehension of concrete and abstract verbs. Specifically, a sensitive verb synonym judgment test was generated that varied both the items' imageability and frequency, and a picture-to-word matching test with numerous concrete verbs. Normative data were then collected and the tests were administered to a cohort of 48 individuals with chronic post-stroke aphasia to explore the behavioural patterns and neural correlates of verb processing. The results revealed significantly better comprehension of concrete than abstract verbs, aligning with the existing aphasiological literature on noun processing. In addition, the patients performed better during verb comprehension than verb production. Lesion-symptom correlational analyses revealed common areas that support processing of concrete and abstract verbs, including the left anterior temporal lobe, posterior supramarginal gyrus and superior lateral occipital cortex. A direct contrast between them revealed additional regions with graded differences. Specifically, the left frontal regions were associated with processing abstract verbs; whereas, the left posterior temporal and occipital regions were associated with processing concrete verbs. Moreover, overlapping and distinct neural correlates were identified in association with the comprehension and production of concrete verbs. These patient findings align with data from functional neuroimaging and neuro-stimulation, and existing models of language organisation. PMID- 29619320 TI - Corynebacterium jeikeium endocarditis: A case report and comprehensive review of an underestimated infection. AB - Diphtheroids are gram-positive pleomorphic bacilli in the family of Coryneform bacteria. These organisms are present as part of the human flora. Past practice habits had been to consider them as contaminants when isolated from clinical samples. Corynebacterium jeikeium is one of the most clinically important nondiphtherial Corynebacteria that can cause different forms of infections specifically in patients with underlying risk factors and co-morbidities including immunocompromised subjects. Through this article, we present a 67-year old gentleman with extensive co-morbidities including heart failure with reduced ejection fraction and ESRD on hemodialysis through a femoral catheter who presented with chest pain and fatigue. Further investigation confirmed diagnosis of C. jeikeium endocarditis. We go on to review previously reported cases of C. jeikeium endocarditis and we will discuss different aspects of C. jeikeium infection with a focus on microbiology, pathophysiology, and treatment. PMID- 29619321 TI - Rapid pulmonary cavity formation caused by Mycobacterium avium complex in a chemotherapy patient. PMID- 29619322 TI - Burkholderia multivorans: A rare yet emerging cause of bacterial meningitis. AB - Burkholderia multivorans is a member of the Burkholderia cepacia complex. Although it is usually associated with infections in patients with cystic fibrosis, chronic granulomatous disease, and immunosuppression, central nervous infections are not commonly reported. Moreover, management of these infections is difficult due to multiple mechanisms of bacterial resistance to antimicrobial agents. We report a 55-year-old-man who developed Burkholderia multivorans meningitis after two episodes of central line-associated bloodstream infections. The patient was successfully treated with intravenous trimethoprim/sulfamethoxazole. Burkholderia multivorans is an emerging cause of meningitis with limited antibacterial treatment options. However, trimethoprim/sulfamethoxazole remains an effective agent with excellent penetration into the central nervous system. To our knowledge, this is the first case reported of Burkholderia cepacia complex meningitis identified to the species level as Burkholderia multivorans. PMID- 29619323 TI - Bacteremia caused by cellulosimicrobium in a bone marrow transplant patient: A case report and literature review. AB - Background: Cellulosimicrobium sp. is a ubiquitous gram-positive bacillus that was formerly known as Oerskovia. This bacterium is found in soil and decaying plant material and is rarely associated with infections in humans. Case report: We report the case of a 44 year-old woman with history of bone marrow transplant that developed Cellulosimicrobium sp. bacteremia secondary to a central line infection. She was admitted with presumed sepsis. Blood cultures from central line and periphery revealed the growth of gram-positive rods that were further identified as Cellulosimicrobium sp. by MALDI-TOF. She was treated with vancomycin and line removal. Microbiologic cure was achieved; however, she developed hospital-acquired pneumonia, which led to a fatal outcome. Conclusion: To our knowledge, there are only 15 documented cases of Cellulosimicrobium sp. bacteremia. Our case illustrates the potential pathogenicity of this bacterium and the importance of appropriate antimicrobial therapy and removal of infected central catheters. It is essential to know that gram-positive bacilli should not be disregarded as contaminants when recovered from multiple blood cultures. In this situation, a full microbiologic identification must be attempted. PMID- 29619324 TI - Novel case of penicillin resistant E. rhusiopathiae septicemia: Case report with review of the literature. PMID- 29619325 TI - Doxycycline desensitization in chronic Q fever-A critical tool for the clinician. AB - We present the case of a 45 year old woman with acute Q fever pneumonia who progressed to the chronic phase of the disease despite azithromycin therapy. A trial of doxycycline was halted because of severe allergy and she was put on clarithromycin and later moxifloxacin. Failure of both drugs required desensitization to doxycycline with escalating doses. After two-year treatment with doxycycline-hydroxychloroquine combination, complete recovery was declared. Our case highlights the option of doxycycline desensitization when an acute allergic reaction poses an obstacle to optimal treatment. PMID- 29619326 TI - Rare but not forgotten: A case of meningitis due to ceftriaxone-resistant Streptococcus pneumoniae. AB - Despite the dramatic decrease in invasive pneumococcal disease since the widespread use of the first pneumococcal vaccine, invasive and resistant disease still occurs. We present a case of ceftriaxone-resistant pneumococcal meningitis suggesting that continued vigilance is warranted for empiric treatment of meningitis when Streptococcus pneumoniae is a concern. PMID- 29619327 TI - Brucella vertebral osteomyelitis misidentified as an Ochrobactrum anthropi infection. AB - Ochrobactrum anthropi is a Gram-negative bacillus widely distributed in nature. It is a low virulence and low pathogenic microorganism and human infection by this agent is considered rare. This microorganism can cause bacteremia and in some cases can lead to osteomyelitis and endocarditis. Included in Brucellaceae family, this bacterium is phenotypically and genetically closely related to the Brucella genus and may be misidentified by rapid identification systems. The authors describe a patient admitted to the Infectious Diseases Department with vertebral osteomyelitis initially identified as Ochrobactrum anthropi. Despite appropriate antimicrobial therapy, the blood cultures remained positive and there were no signs of clinical improvement. This raised suspicion of a possible misidentification. It was decided to initiate antimicrobial therapy to include the Brucella genus, with slow but progressive clinical improvement. Samples were sent to Instituto Nacional de Saude Doutor Ricardo Jorge (INSA) for genotyping, confirming the initial suspicion of misidentification and identifying Brucella melitensis as the causal agent. Timely diagnosis of brucellosis is essential for the correct management and prevention of its consequences for the patient and for safe handling of the laboratory samples, preventing laboratory-acquired infection. PMID- 29619328 TI - Ciprofloxacin for the treatment of Cardiobacterium hominis prosthetic valve endocarditis. AB - Prosthetic valve endocarditis due to Cardiobacterium hominis is rare and recommended therapy includes a third generation cephalosporin. We report a case of Cardiobacterium hominis endocarditis post transcatheter aortic valve replacement in a patient with significant beta-lactam antimicrobial sensitivities who was successfully treated with ciprofloxacin monotherapy in conjunction with surgery. PMID- 29619329 TI - Botulism-like symptoms in an immunocompetent patient with Clostridium subterminale bacteremia. AB - Clostridium subterminale is a low virulence species of Clostridium that is an infrequent cause of human infections. We report a case of C. subterminale bacteremia in an immunocompetent patient who developed botulism-like symptoms. PMID- 29619330 TI - Effect of the Lippia alba (Mill.) N.E. Brown essential oil and its main constituents, citral and limonene, on the tracheal smooth muscle of rats. AB - The Lippia alba (Mill.) N.E. Brown (Verbenaceae) species, has effects sedative, analgesic and spasmolytic properties. This study had as its main objective to evaluate the essential oil of L. alba (EOLa) effect and that of its main constituents, citral and limonene, over tracheal smooth muscle from Wistar rats. EOLa, citral and limonene promoted relaxation of tracheal smooth muscle in contractions induced by potassium (60 mM K+), presenting an EC50 of 148 +/- 7 MUg/mL for the EOLa, 136 +/- 7 MUg/mL for citral and 581 +/- 7 MUg/mL for limonene. In contractions induced by Acetylcholine (Ach; 10 MUM) the EC50 for the EOLa and citral were of 731 +/- 5 MUg/mL and 795 +/- 9 MUg/mL, respectively. In preparations pre-incubated with 1000 MUg/mL of the EOLa and citral, both agents were found to block the influx of BaCl2 by VOCCs. This study demonstrated that the EOLa and its main component citral present antispasmodic effect over tracheal smooth muscle of rats. PMID- 29619331 TI - Phytochemical analysis and In-vitro Biochemical Characterization of aqueous and methanolic extract of Triphala, a conventional herbal remedy. AB - Triphala, an Indian ayurvedic triherbal formulation, is an equiproportional mixture of fruits of three herbs, amalaki (Emblica officinalis), haritaki (Terminalia chebula) and bibhitaki (Terminalia bellerica). The present study focused on phytocompounds detection and comparative analysis of various biochemical activities in the aqueous and methanolic extracts of triphala and its constituting herbs. Antioxidant activity was determined by 1, 1-diphenyl-2 picrylhydrazyl (DPPH), ferric reducing antioxidant power (FRAP), super oxide dismutase (SOD), catalase assay. Antibacterial potential was determined by broth dilution and agar well diffusion assays. Results revealed the presence of valuable bioactive compounds such as flavonoids, alkaloids, phenols, etc which might be responsible for biochemical activities. Extracts exhibited satisfactory radical-scavenging activity comparable with ascorbic acid. Methanolic extracts demonstrated higher antioxidant activity compared to aqueous extract. Extracts showed promising antibacterial potential against tested strain comparable to ampicillin. Hence, it can be concluded that triphala may be a promising candidate in pharmaceuticals and future medicine. PMID- 29619332 TI - What's New in Critical Illness and Injury Science? The Quest for Effective and Safe Co-induction Agents in Spontaneously Breathing Patients Undergoing General Anesthesia. PMID- 29619333 TI - Role of opioids as coinduction agent with propofol and their effect on apnea time, recovery time, and sedation score. AB - Background: Laryngeal mask airway (LMA) is a supraglottic device which requires lesser depth of anaesthesia, evokes lesser hemodynamic response and causes lesser stimulation of airway as compared to traditional definitive airway device endotracheal tube. Its placement is possible without muscle relaxants thereby allowing maintenance of anaesthesia on spontaneous respiration thus preventing apnoea or minimizing apnoea time. Propofol, the commonly used induction agent, causes cardiorespiratory depression at higher induction doses. To attenuate this, co-induction agents combined with propofol has been a regular I/V anaesthetic technique these days. Aim: Comparing apnoea time, recovery time and sedation scores using propofol-fentanyl and propofol-butorphanol combination. Methodology: Hundred patients scheduled for various elective surgical procedures were randomly selected and divided into two groups of 50 each. As coinduction drug Group F received fentanyl and Group B received butorphanol. In both the groups induction was achieved with I/V propofol and LMA was placed. Apnoea time was noted after induction. Recovery time and sedation scores were recorded after anaesthetic agents were turned off. Results: As compared to group F apnoea time was significantly less and recovery time was significantly more in group B (P < 0.05). Statistically postoperative sedation was significantly higher in group B than in group F at 1/2 hr but clinically, majority were responding to verbal commands. At 1 hour no significant difference in sedation was noted between the groups. Conclusion: Considering respiratory and recovery profile propofol butorphanol combination is a safer alternative to propofol-fentanyl combination for LMA insertion. PMID- 29619334 TI - Factors determining outcomes in adult patient undergoing mechanical ventilation: A "real-world" retrospective study in an Indian Intensive Care Unit. AB - Background: Characteristics of patients admitted to intensive care units with respiratory failure (RF) and undergoing mechanical ventilation (MV) have been described for particular indications and diseases, but there are few studies in the general Intensive Care Unit (ICU) population and even lesser from developing countries. Objective: This study aims to study clinical characteristics, outcomes, and factors affecting outcomes in adult patients with RF on MV admitted to ICU. Methods: A retrospective study of medical records of all patients admitted to ICU between January 1, 2015, and March 31, 2016. Patients receiving MV for more than 6 h were included in the study. Patients younger than 12 years were excluded. Data were recorded of all patients receiving MV during this period regarding demographics, indications for MV, type and characteristics of ventilation, concomitant complications and treatment, and outcomes. Data were recorded at the initiation of MV and daily all throughout the course of MV. The main outcome measure was all-cause mortality at the end of ICU stay. Results: Of the 500 patients admitted to the ICU during the period of the study, a total of 122 patients received MV (and were included in study) for mean (standard deviation [SD]) duration of 4 (3.4) days. The mean (SD) stay in ICU and hospital was 4.49 (3.52) and 6.4 (3.6), respectively. Overall mortality for the unselected general ICU patients on MV was 67.21% while that for ARDS patients was 76.1%. The main factors independently associated with increased mortality were (i) pre-MV factors: age, Apache II scores, heart failure (odds ratio [OR], 1.42; 95% confidence interval [CI], 0.54-3.73; P < 0.001); (ii) patient management factors: positive end-expiratory pressure (OR, 2.69; 95% CI, 0.84-8.61; P < 0.001); (iii) Factors occurring over the course of MV: PaO2/FiO2 ratio < 100 (OR, 1.66; 95% CI, 0.67-4.11; P < 0.001) and development of renal failure (OR, 2.33; 95% CI, 2.05 2.42; P < 0.001) and hepatic failure (OR, 2.07; 95% CI, 1.91-2.24; P < 0.001) after initiation of MV. Conclusions: Outcomes of patients undergoing MV are dependent on various factors (including patient demographics, nature of associated morbidity, characteristics of the MV received, and conditions developing over course of MV) and these factors may be present before or develop after initiation of MV. PMID- 29619335 TI - Role of neomycin polymyxin sulfate solution bladder wash for prevention of catheter associated urinary tract infection in traumatic brain injury patient admitted to Intensive Care Unit: A prospective randomized study. AB - Background: Catheter - associated urinary tract infection (CAUTI) remains a critical threat for patients in intensive care unit especially in traumatic brain injury patients with low Glasgow coma score (GCS). Almost all patients in ICU receive antibiotic either prophylactic or therapeutic based on local antibiogram of particular ICU or hospital. For prophylaxis, systemic antibiotics are used. It will be helpful to avoid systemic side effects by introducing antibiotics locally through bladder irrigation. The indwelling urinary catheter is an essential part of modern medical care. Aims and Objectives: The primary objective was to study the effect of Neomycin and Polymyxin sulphate solution for bladder wash on CAUTI in traumatic brain injury patients. The secondary objectives was to study the various organisms causing CAUTI and their antibiotic sensitivity and resistance pattern. Materials and Methods: This was a prospective randomized controlled study performed on 100 patients who met the inclusion criteria at the trauma intensive care unit of Banaras Hindu University between September and February 2016. The patients were randomized into two groups - one was the study group which received Neomycin and Polymyxin Sulphate solution bladder wash, while the other was the control group that received Normal saline bladder wash. Urine samples were collected at certain days and sent for culture and sensitivity. Results: There was significant reduction in the incidence of CAUTI in neomycin/polymyxin test group in comparison to normal saline irrigated control group. Out of 50 patients in test group 8 patients and in control group 26 patients was identified as CAUTI positive and they were statistically significant. In our study pseudomonas aeruginosa (51%) was the commonest isolated pathogen. Conclusions: Neomycin and Polymyxin Sulphate bladder wash was effective in preventing CAUTI. It can thus decrease the antibiotic usage thereby preventing the emergence of antibiotic resistance. PMID- 29619336 TI - Risk of acute kidney injury in critically ill surgical patients with presumed pneumonia is not impacted by choice of methicillin-resistant staphylococcus aureus therapy. AB - Background: Vancomycin and linezolid are standard treatment options for nosocomial methicillin-resistant Staphylococcus aureus (MRSA) pneumonia. While acute kidney injury (AKI) is commonly attributed to vancomycin, existing data has not definitely confirmed vancomycin as an independent risk factor for AKI. Aims: This study aimed to quantify the incidence of AKI in Surgical Intensive Care Unit (ICU) patients receiving empiric vancomycin or linezolid for nosocomial pneumonia and to identify risk factors for AKI with a focus on MRSA antibiotic therapy. Materials and Methods: A retrospective cohort analysis of surgical ICU patients who received at least 48 h of vancomycin or linezolid for pneumonia was performed. Patients who received vancomycin were compared to those who received linezolid with a primary endpoint of AKI as defined by the risk/injury/failure/loss/end-stage renal disease (RIFLE) criteria. A modified RIFLE criteria assessing only changes in serum creatinine was also used. Results: One hundred one patients were evaluated (63 vancomycin and 38 linezolid). AKI occurred in 51 (81.0%) and 32 (84.2%) patients in the vancomycin and linezolid groups (P = 0.79), respectively. Using the modified RIFLE criteria, AKI occurred in 19 (30.2%) and 14 (36.8%) patients in the vancomycin and linezolid groups (P = 0.448). After adjustment for age, diabetes mellitus, Charlson comorbidity index, and concomitant nephrotoxins, there was no difference in risk of AKI between groups (P = 0.773). Conclusions: Patients who received empiric vancomycin or linezolid for nosocomial pneumonia experienced high, but similar rates of AKI. The results suggest MRSA antibacterial therapy in this setting may not be independently indicative of AKI risk, rather the risk is likely multifactorial. PMID- 29619337 TI - Prevalence and prognostic significance of prolonged QTc interval in emergency medical patients: A prospective observational study. AB - Introduction: QTc interval is affected by many factors and prolongation of same may have prognostic significance. A significant number of patients admitted in medical emergency are acutely ill, have multiple comorbidities and are on medications, all of these factors might affect QTc interval and prognosis. Materials and Methods: Single-center, prospective, observational study was carried out on 279 patients of different illnesses recruited from emergency medical services attached to the Department of Internal Medicine at Postgraduate Institute of Medical Education and Research, Chandigarh, India, a tertiary care hospital. Results: Out of 279 patients, 95 were found to have prolonged QTc interval with the prevalence of 34.1%. Fifteen patients (5.4%) had markedly prolonged QTc interval (QTc >500 ms). Of various medical conditions, we found statistically significantly higher number of patients of chronic kidney disease (P = 0.047), chronic liver disease (P < 0.001), hemorrhagic cerebrovascular accident (P = 0.026), and heart failure (P = 0.009) with prolonged QTc interval. Among laboratory abnormalities, patients with low hemoglobin (P = 0.032), with deranged renal functions (P = 0.033), and with hypokalemia (P = 0.026) had a greater share of patients with prolonged QTc interval. There was no difference in duration of hospital stay and frequency of hospital mortality between two groups, although, on subgroup analysis, patients with markedly prolonged QTc interval had significantly higher hospital mortality (P = 0.029). The frequency of ventricular tachycardia was also significantly higher in patients with prolonged QTc interval (P = 0.008). Conclusion: High prevalence of prolonged QTc interval was found in Indian emergency medical patients. There was no difference in hospital mortality though on subgroup analysis, patients with markedly prolonged QTc interval had significantly more episodes of in-hospital ventricular tachycardia and hospital mortality. PMID- 29619338 TI - Three- versus four-factor prothrombin complex concentrate for the reversal of warfarin-induced bleeding. AB - Objective: The objective of this study was to evaluate the effectiveness of 3 factor prothrombin complex concentrate (3F-PCC) compared to 4-factor PCC (4F-PCC) in warfarin-associated bleeding. Methods: This multicenter, retrospective, cohort study analyzed data from patients admitted between May 2011 and October 2014 who received PCC for warfarin-associated bleeding. The primary outcome was the rate of international normalized ratio (INR) normalization, defined as an INR <=1.3, after administration of 3F-PCC compared to 4F-PCC. Other variables of interest included the incidence of additional reversal agents, new thromboembolic events, and mortality. Results: A total of 134 patients were included in the analysis. The average dose of PCC administered was 24.6 +/- 9.3 units/kg versus 36.3 +/- 12.8 units/kg in the 3F-PCC and 4F-PCC groups, respectively, P < 0.001. Baseline INR in the 3F-PCC and 4F-PCC groups was 3.61 +/- 2.3 and 6.87 +/- 2.3, respectively P < 0.001. 4F-PCC had a higher rate of INR normalization at first INR check post-PCC administration compared to 3F-PCC (84.2% vs. 51.9%, P = 0.0001). Thromboembolic events, intensive care unit and hospital length of stay, and mortality were similar among both groups. Conclusion: The use of 4F-PCC leads to a more significant reduction in INR compared to 3F-PCC though no difference in mortality or length of stay was observed. Thromboembolism rates were similar among both groups. PMID- 29619339 TI - Abortion may be associated with elevated risk of future hypothyroidism. AB - Objective: Fetal microchimerism during pregnancy and abortion has been linked with autoimmune hypothyroidism in females. We conducted a case-control study to investigate the odds of "abortion in the past" in the newly diagnosed hypothyroid females compared to their age-matched euthyroid controls. Methods: All consecutive newly diagnosed hypothyroid females, over 1 year, were enrolled as cases. Age-matched euthyroid controls were selected from the same region. The exposure variable tested was "past history of abortion (elective or therapeutic)." Results: Totally, 120 cases and 172 controls were recruited over 1 year with a mean age of 42.2 +/- 9.8 years and 41.1 +/- 12.4 years, respectively. The exposure variable (abortion) was present in 71 (59%) cases and 10 (6%) controls. Odds ratio (OR): 23.5 (12.2-48.9) P < 0.0001. Autoimmunity, based on thyroid peroxidase (TPO) positivity (TPO levels >=30 U/ml), was present in 92 (77%) of the cases; TPO was negative in 28 (33%) of cases. The exposure variable was documented in 62.4% and 50% of TPO positive and negative cases, respectively (P = 0.28). Discussion and Conclusion: The study suggests that abortion (elective or therapeutic) in the past is strongly associated with newly diagnosed hypothyroidism in females aged 42.2 +/- 9.8 years; OR: 23.5 (P < 0.0001). Interestingly, abortion was associated with both, TPO positive and negative hypothyroidism. PMID- 29619340 TI - Takotsubo cardiomyopathy with Basal Hypertrophy and outflow obstruction in a patient with bowel ischemia. AB - Basal septal hypertrophy is a rare and unique anatomical finding associated with hypertrophic cardiomyopathy (HCM). It is also described as a sigmoid hypertrophy and is linked with aging and chronic hypertension. Takotsubo cardiomyopathy is a transient cardiomyopathy that occurs during periods of high physical or emotional stress. Its occurrence with HCM is relatively common; however, this presentation occurs more often with the classic asymmetrical septal hypertrophy or the apical variant. This case demonstrates its coexistence with isolated sigmoid hypertrophy in an elderly, hypertensive female with severe ischemic bowel disease. PMID- 29619341 TI - Right carotid-cutaneous fistula and right carotid pseudoaneurysm formation secondary to a chronically infected polyethylene terephthalate patch. AB - Carotid endarterectomy (CEA) remains the treatment for significant carotid stenosis and stroke prevention. Approximately 100,000 CEAs are performed in the United States every year. Randomized trials have demonstrated an advantage of patch carotid angioplasty over primary closure. Complications from patches include thrombosis, transient ischemic attack, stroke, restenosis, pseudoaneurysm (PA), and infection. PA after CEA is rare, with a reported average of 0.37% of cases. We describe an unusual case of PA after polyethylene terephthalate (PTFE) patching for CEA. An 88-year-old female with Alzheimer's disease living in a nursing facility with a history of skin cancer on her right chest developed a new area of intermittent brisk bleeding on her right neck which was initially believed to be related to her skin cancer. She had a remote history of right CEA with a PTFE patch approximately a decade ago. A computed tomography angiograph head-and-neck with showed a partially thrombosed PA in the region of her right common carotid artery bifurcation with a tract containing gas and fluid extending to the skin surface suspicious for a partially thrombosed, leaking PA. She was taken urgently to the operating room on broad-spectrum antibiotics where we performed a right neck exploration, ligation of a bleeding carotid PA by ligation of the right common, internal, and external carotid arteries, explantation of a chronically infected polyethylene terephthalate patch, and closure with a sternocleidomastoid advanced flap with multilayered closure. She was discharged to her nursing facility with 6 weeks of ceftriaxone intravenous (IV) and metronidazole IV through a peripherally inserted central catheter (PICC) line with no neurological sequelae. PMID- 29619342 TI - Never over until it is over: Carotid-cutaneous fistula. PMID- 29619343 TI - Alterations of the Human Skin N- and O-Glycome in Basal Cell Carcinoma and Squamous Cell Carcinoma. AB - The glycome of one of the largest and most exposed human organs, the skin, as well as glycan changes associated with non-melanoma skin cancers have not been studied in detail to date. Skin cancers such as basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) are among the most frequent types of cancers with rising incidence rates in the aging population. We investigated the healthy human skin N- and O-glycome and its changes associated with BCC and SCC. Matched patient samples were obtained from frozen biopsy and formalin-fixed paraffin embedded tissue samples for glycomics analyses using two complementary glycomics approaches: porous graphitized carbon nano-liquid chromatography electro spray ionization tandem mass spectrometry and capillary gel electrophoresis with laser induced fluorescence detection. The human skin N-glycome is dominated by complex type N-glycans that exhibit almost similar levels of alpha2-3 and alpha2-6 sialylation. Fucose is attached exclusively to the N-glycan core. Core 1 and core 2 type O-glycans carried up to three sialic acid residues. An increase of oligomannose type N-glycans and core 2 type O-glycans was observed in BCC and SCC, while alpha2-3 sialylation levels were decreased in SCC but not in BCC. Furthermore, glycopeptide analyses provided insights into the glycoprotein candidates possibly associated with the observed N-glycan changes, with glycoproteins associated with binding events being the most frequently identified class. PMID- 29619345 TI - Effectiveness and Complications of Improved Liposuction-Curettage Through Mini Incisions for the Treatment of Axillary Osmidrosis. AB - Background: Liposuction-curettage (LC) is a popular and effective surgical method for the treatment of axillary bromhidrosis (AB). However, residual malodour and skin necrosis often appear after this type of surgery. We investigated the efficacy and complications of 4 methods of LC. Methods: A total of 280 patients with AB comprised the study cohort, of which 228 were followed up. We carried out 4 methods of modified tumescent LC through mini-incisions and provided a questionnaire for evaluation of surgical outcome. Evaluations were malodour elimination, scarring, reduced growth of hair, and complications. Mean follow-up was 15 months. Results: The study involved 449 axillae. In patients with LC in the final phase of improvement (programmed and well-organized LC, skin pinching to wrap up the cannula, LC to the skin around 2 surgical incisions, and cotton balls packed in gauze and an elastic set for post-operative management), excellent elimination of malodor was observed in 141 (89.81%) of 157 axillae. Only 4 (2.55%) cases encountered a small area of skin necrosis, and 28 (17.83%) had local damage to the epidermis. Conclusion: These data suggest that LC with a final phase of improvement through mini-incisions is effective for AB treatment. PMID- 29619344 TI - The Predictive Value of Inflammation-Related Peripheral Blood Measurements in Cancer Staging and Prognosis. AB - In this review, we discuss the interaction between cancer and markers of inflammation (such as levels of inflammatory cells and proteins) in the circulation, and the potential benefits of routinely monitoring these markers in peripheral blood measurement assays. Next, we discuss the prognostic value and limitations of using inflammatory markers such as neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios and C-reactive protein measurements. Furthermore, the review discusses the benefits of combining multiple types of measurements and longitudinal tracking to improve staging and prognosis prediction of patients with cancer, and the ability of novel in silico frameworks to leverage this high dimensional data. PMID- 29619346 TI - Factors Influencing the Rate of Post-Mastectomy Breast Reconstruction in a Canadian Teaching Hospital. AB - Background: Post-mastectomy breast reconstruction (PMBR) improves psychosocial well-being, quality of life, and body image. Reconstruction rates vary widely (up to 42% in the United States), but the few Canadian studies available report rates of 3.8% to 7.9%. We sought to evaluate the current state of breast reconstruction in 1 Canadian teaching hospital and factors determining patients' access to reconstruction. Methods: We performed a retrospective chart review of all patients with breast cancer undergoing mastectomy alone or mastectomy and reconstruction at a Canadian hospital between 2010 and 2013. We calculated rates of breast reconstruction and compared patient characteristics between the 2 groups, and then performed a multiple logistic regression to determine factors increasing the odds of receiving breast reconstruction. Results: A total of 152 patients underwent 154 total or modified radical mastectomies. We obtained a rate of PMBR of 21%, 14% immediate reconstruction, and 8% delayed. Statistical analysis showed that compared to patients with mastectomy alone, patients who received PMBR were significantly younger, with a larger percentage having bilateral mastectomies, non-invasive breast cancer, and residing further from the hospital. Patients less than 50 years old and those with bilateral mastectomies had significantly greater odds of having a reconstruction. Conclusions: Our Canadian tertiary care institution has a high volume of breast surgery and an active breast reconstruction team. However, the rate of immediate reconstruction remains low compared to similar centers in the United States. We recommend a united effort to increase awareness regarding PMBR and address common misconceptions hindering patients' access to breast reconstruction. Level of Evidence: Epidemiologic study, Level III. PMID- 29619347 TI - Enhanced Recovery After Surgery (ERAS) Protocol Enables Safe Same-Day Discharge After Alloplastic Breast Reconstruction. AB - Background: To compare enhanced recovery after surgery (ERAS) with traditional recovery after surgery (TRAS) for patients undergoing alloplastic breast reconstruction. Methods: A retrospective chart review of 2 patient groups (ERAS and TRAS) undergoing alloplastic breast reconstruction was performed. Data were collected from 2012 to 2013 (TRAS) and from 2013 to 2016 (ERAS). The ERAS protocol included day surgery, multimodal analgesia, and preoperative anti emetic. The TRAS pathway involved overnight admission, narcotic-based analgesia, and no preoperative anti-emetic. Demographics, operative variables, and complications were compared between groups. Results: Seventy-eight ERAS patients and 78 TRAS patients were included. Length of stay was shorter for ERAS patients (0.38 nights ERAS and 1.45 nights TRAS; P < .001). The ERAS patients underwent significantly more bilateral surgery (80.8% ERAS and 55.1% TRAS; P < .001), immediate reconstruction (98.6% ERAS and 89.3% TRAS; P = .004), and had more implants versus expanders placed (66% [93/141] ERAS and 24.8% TRAS; P < .001). There were no differences in the number of post-operative emergency department visits (8% ERAS and 14% TRAS; P = .2) and readmissions (8% ERAS and 3.8% TRAS; P = .3) between the groups. There was no difference in the rate of hematoma (0.7% ERAS and 0% TRAS; P = .35), infection requiring explantation (1.4% ERAS and 0.8% TRAS; P = .65), infection requiring outpatient IV antibiotics (1.4% ERAS and 2.5% TRAS; P = .53), and infection requiring IV antibiotics and readmission (2.1% ERAS and 1.7% TRAS; P = .78) between the groups. There were no differences in the number of minor complications (22% ERAS and 23% TRAS; P = .82). Conclusion: The ERAS protocol for alloplastic breast reconstruction is safe, without increased readmission or complication rates compared to TRAS, and significantly decreased length of stay. PMID- 29619348 TI - Balancing the Need for Clinical Photography With Patient Privacy Issues: The Search for a Secure SmartPhone Application to Take and Store Clinical Photographs. AB - Background: Physicians are increasingly using smartphones to take clinical photographs. This study evaluates a smartphone application for clinical photography that prioritizes and facilitates patient security. Methods: Ethics approval was obtained to trial a smartphone clinical photography application, PicSafe Medi. Calgary plastic surgeons and residents used the application to obtain informed consent and photograph patients. Surveys gauging the application's usability, consent process, and photograph storage/sharing were then sent to surgeons and patients. Results: Over a 6-month trial period, 15 plastic surgeons and residents used the application to photograph 86 patients. Over half of the patients (57%) completed the survey. The majority of patients (96%) were satisfied with the application's consent process, and all felt their photographs were secure. The majority (93%) of surgeons/residents completed the survey. The application was felt to overcome issues with current photography practices: inadequate consent and storage of photographs (100%), risk to patient confidentiality (92%), and unsecure photograph sharing (93%). Barriers to regular use of the application included need for cellphone service/Internet (54%), sanitary concerns due to the need for patients to sign directly on the phone (46%), inability to obtain proactive/retroactive consent (85%), and difficulty viewing photographs (80%). The majority of surgeons (85%) believe a smartphone application would be suitable for clinical patient photography, but due to its limitations, only 23% would use the trialed application. Conclusions: A smartphone clinical photography application addresses the patient confidentiality risks of current photography methods; however, limitations of the trialed application prevent its broad implementation. PMID- 29619349 TI - How Well Are We Doing at Teaching Critical Appraisal Skills to Our Residents? A Needs Assessment of Plastic Surgery Journal Club. AB - Objective: To perform a needs assessment of journal club in plastic surgery residency programs. Specifically, this study focused on potential gaps in journal club associated with teaching and assessing critical appraisal of the literature, an important component of medical education and practice. Methods: This is a qualitative study that utilized an online survey tool to collect information about the characteristics of journal club in plastic surgery residency programs in both Canada and the United States. Both program directors and residents were surveyed. Results: When presented with a range of objectives, both program director and resident responses identified that teaching critical appraisal skills was often the main goal of journal club in their program (67.1%). Most trainees perceived that journal club was at least somewhat effective in improving their critical appraisal skills. Despite this perception, many residents felt that they had minimal to no experience in critical appraisal of the literature upon entry into their respective residency programs (46.2%), and only 29.2% indicated that they received formal instruction regarding critical appraisal. Three-quarters of residents indicated that there was no tool provided to aid them in their analysis of the literature. Finally, most residents also responded that they were not assessed objectively with regard to their performance. Conclusions: Although residents in our study perceive journal club to at least somewhat improve their critical appraisal skills, evidence in the literature has been controversial. It cannot be assumed that residents are learning the skills they need by simply attending and reading the articles associated with journal club. Future study should focus on the best way to meet these objectives. PMID- 29619350 TI - Linburg-Comstock: Is Overuse an Etiological Factor? AB - Background: Linburg-Comstock anomaly is typically defined as a tenosynovial interconnection between flexor pollicis longus and flexor digitorum profundus tendon of the second finger. There are several studies stating that the current anomaly is congenital or acquired. The aim of this study is to reveal whether overuse, which is mostly reported as an acquired etiologic factor, effective in development of the current anomaly. Methods: Three hundred thirteen medical secretaries who work with computer keyboard at least 6 hours a day were defined as study group. Three hundred twenty-three volunteers without jobs who necessitate continuous and repetitive hand and finger activities were defined as control group. All individuals were examined by an orthopaedic surgeon. Additionally, cases with Linburg-Comstock anomaly were evaluated in respect of forearm pain and subjective findings of carpal tunnel syndrome. Results: Linburg Comstock anomaly was determined in 27.8% cases of medical secretary group and in 32.2% of healthy control group. In medical secretaries with Linburg-Comstock anomaly, 25.3% had forearm pain and 5.7% had findings of carpal tunnel syndrome. In control group with Linburg-Comstock anomaly, 21.2% had forearm pain and 13.5% had findings of carpal tunnel syndrome. No relationship was found between overuse of the hand and Linburg-Comstock anomaly and the symptoms accompanying the anomaly. Conclusions: The current study reveals that overuse is not an etiologic factor in Linburg-Comstock anomaly existence and related symptoms. We think that the current anomaly develops on congenital basis rather than acquired factors. PMID- 29619351 TI - Cases of Early Infectious Flexor Tenosynovitis Treated Non-Surgically With Antibiotics, Immobilization, and Elevation. AB - Background: Early infectious flexor tenosynovitis has been treated with urgent surgery by most surgeons since Bunnell wrote the first textbook of hand surgery in 1945. Some surgeons have good experience with non-surgical management of early presenting disease in some cases. Methods: This retrospective chart review included 12 inpatients with early infectious flexor synovitis who received conservative treatment with antibiotics, immobilization, and elevation without surgical drainage. Results: The mean time to resolution of infective symptoms for the 12 patients was 5 days (range: 2-11 days) for those receiving conservative management. Half of them required hand therapy. Eight of the 12 patients had good documentation of a full return of hand function. Conclusions: In some patients with early infectious flexor synovitis, urgent surgery may not be required. We present a brief synopsis of 12 such cases. PMID- 29619352 TI - Complementary and Alternative Medicines and Patients With Breast Cancer: A Case of Mortality and Systematic Review of Patterns of Use in Patients With Breast Cancer. AB - Background: The use of complementary and alternative medicines (CAMs) is common among women being treated for breast cancer. A recent mortality associated with CAM at our center precipitated a systematic review of the Cochrane, EMBASE, and PubMed databases to identify English manuscripts including "CAM" and "breast cancer." Methods: Papers included for review were selected based on predefined inclusion and exclusion criteria. The primary outcome was the use of CAM by women with breast cancer. Secondary outcomes included timing of use along disease trajectory, attitudes toward CAM by allopathic practitioners, and patient disclosure of CAM use to treating allopathic physicians. Results: Of 701 titles identified by the search strategy, 36 met the inclusion criteria. The weighted average proportion of women with breast cancer who use CAM was 40% (standard deviation: 18%). The diagnosis of breast cancer also prompts the initiation or increase of CAM use. However, up to 84% of patients do not disclose the use of CAM to their allopathic practitioners. Conclusions: Although CAM is often dismissed as a harmless addition to allopathic therapy, significant complications and interactions can occur. Our review and the dramatic case example provided highlight the need for physicians to educate themselves regarding CAM and to engage with their patients regarding its use. PMID- 29619353 TI - An Evaluation of h-Index as a Measure of Research Productivity Among Canadian Academic Plastic Surgeons. AB - Background: Evaluation of research productivity among plastic surgeons can be complex. The Hirsch index (h-index) was recently introduced to evaluate both the quality and quantity of one's research activity. It has been proposed to be valuable in assessing promotions and grant funding within academic medicine, including plastic surgery. Our objective is to evaluate research productivity among Canadian academic plastic surgeons using the h-index. Methods: A list of Canadian academic plastic surgeons was obtained from websites of academic training programs. The h-index was retrieved using the Scopus database. Relevant demographic and academic factors were collected and their effects on the h-index were analyzed using the t test and Wilcoxon Mann-Whitney U test. Nominal and categorical variables were analyzed using chi2 test and 1-way analysis of variance. Univariate and multivariate models were built a priori. All P values were 2 sided, and P < .05 was considered to be significant. Results: Our study on Canadian plastic surgeons involved 175 surgeons with an average h-index of 7.6. Over 80% of the surgeons were male. Both univariable and multivariable analysis showed that graduate degree (P < .0001), academic rank (P = .03), and years in practice (P < .0001) were positively correlated with h-index. Limitations of the study include that the Scopus database and the websites of training programs were not always up-to-date. Conclusion: The h-index is a novel tool for evaluating research productivity in academic medicine, and this study shows that the h-index can also serve as a useful metric for measuring research productivity in the Canadian plastic surgery community. Plastic surgeons would be wise to familiarize themselves with the h-index concept and should consider using it as an adjunct to existing metrics such as total publication number. PMID- 29619354 TI - Canadian Plastic Surgery Resident Work Hour Restrictions: Practices and Perceptions of Residents and Program Directors. AB - Background: The impact of resident work hour restrictions on training and patient care remains a highly controversial topic, and to date, there lacks a formal assessment as it pertains to Canadian plastic surgery residents. Objective: To characterize the work hour profile of Canadian plastic surgery residents and assess the perspectives of residents and program directors regarding work hour restrictions related to surgical competency, resident wellness, and patient safety. Methods: An anonymous online survey developed by the authors was sent to all Canadian plastic surgery residents and program directors. Basic summary statistics were calculated. Results: Eighty (53%) residents and 10 (77%) program directors responded. Residents reported working an average of 73 hours in hospital per week with 8 call shifts per month and sleep 4.7 hours/night while on call. Most residents (88%) reported averaging 0 post-call days off per month and 61% will work post-call without any sleep. The majority want the option of working post-call (63%) and oppose an 80-hour weekly maximum (77%). Surgical and medical errors attributed to post-call fatigue were self-reported by 26% and 49% of residents, respectively. Residents and program directors expressed concern about the ability to master surgical skills without working post-call. Conclusions: The majority of respondents oppose duty hour restrictions. The reason is likely multifactorial, including the desire of residents to meet perceived expectations and to master their surgical skills while supervised. If duty hour restrictions are aggressively implemented, many respondents feel that an increased duration of training may be necessary. PMID- 29619355 TI - Comparison of Outcomes in Immediate Implant-Based Breast Reconstruction Versus Mastectomy Alone. AB - Objectives: Immediate implant-based techniques are common practice in post mastectomy breast reconstruction. Previous studies have shown an increased complication rate in the setting of immediate versus delayed, MD reconstruction. We aimed to quantify any additional risk in complications when implant-based immediate breast reconstruction (IBR) is performed versus mastectomy alone. Materials and Methods: We retrospectively reviewed all IBR cases and all mastectomies without reconstruction from 2007 to 2011. Patient characteristics, operative details, and complication rates were reviewed and analyzed. Results: IBR was performed in 315 consecutive women; mastectomy alone was performed in 401 women. Patients undergoing mastectomy alone were more often older, diabetic, and more frequently underwent neoadjuvant chemotherapy or radiation. Overall complications were higher in the IBR group, most commonly reoperation and delayed wound healing. In a multivariate analysis, IBR, increasing age, body mass index, history of radiation therapy, smoking, and nipple-sparing mastectomy were independently associated with increased risk of complications. However, IBR was only independently associated with increased risk of major complications such as reoperation or readmission for intravenous antibiotics, not minor complications. Conclusion: Patients selected for IBR are inherently different than those undergoing mastectomy alone. After adjusting for these differences, the increased risk of complications seen in IBR is moderately increased over the risk of complications in mastectomy alone. The observed increased risk of major complications after IBR is largely due to the aggressive management of complications in the setting of a prosthetic implant. IBR is a safe reconstructive strategy with only a slightly increased risk over mastectomy alone. PMID- 29619356 TI - Delivering Breast Reconstruction Information to Patients: Women Report on Preferred Information Delivery Styles and Options. AB - Purpose: To discover missed opportunities for providing information to women undergoing breast reconstruction in an effort to decrease regret and improve patient education, teaching modalities, and satisfaction. Method: Thirty- to 45 minute semi-structured interviews were conducted exploring patient experiences with information provision on breast reconstruction. Purposeful sampling was used to include women with a variety of reconstruction types at different time points along their recovery. Using grounded theory methodology, 2 independent reviewers analyzed the transcripts and generated thematic codes based on patient responses. BREAST-Q scores were also collected to compare satisfaction scores with qualitative responses. Results: Patients were interested in a wide variety of topics related to breast reconstruction including the pros and cons of different options, nipple-sparing mastectomies, immediate breast reconstruction, oncological safety/monitoring and the impact of chemotherapy and radiotherapy, secondary procedures (balancing, nipple reconstruction), post-operative recovery, and long-term expectations. Patients valued accessing information from multiple sources, seeing numerous photographs, being guided to reliable information online, and having access to a frequently asked questions file or document. Information delivery via interaction with medical personnel and previously reconstructed patients was most appreciated. Compared with BREAST-Q scores for satisfaction with the plastic surgeon (mean: 95.7, range: 60-100), informational satisfaction scores were lower at 74.7 (50-100), confirming the informational gaps expressed by interviewees. Conclusions: Women having recently undergone breast reconstruction reported key deficiencies in information provided prior to surgery and identified preferred information delivery options. Addressing women's educational needs is important to achieve appropriate expectations and improve satisfaction. PMID- 29619357 TI - Factors Influencing American Plastic Surgery Residents Toward an Academic Career. AB - Background: Plastic surgery residency program directors have an interest in recruiting applicants who show an interest in an academic practice. Medical school achievements (ie, United States Medical Licensing Examination(r) scores, publications, and Alpha Omega Alpha status) are metrics assessed to grade applicants but may not correlate with ultimately choosing an academic career. Objective: This study was designed to investigate factors influencing residents' choices for or against academic careers. Methods: A 25-item online questionnaire was designed to measure baseline interest in academic plastic surgery and factors that influence decisions to continue on or abandon that career path. This questionnaire was disseminated to the integrated/combined plastic surgery residents during the 2013 to 2014 academic year. Results: One hundred twenty-five respondents indicated that they were currently interested in pursuing academic practice (n = 78) or had lost interest in academic practice (n = 47). Among all respondents, 92.8% (n = 116) stated they were interested in academic careers at the time of residency application, but one-third (n = 41) subsequently lost interest. Those residents who retained interest in academic careers indicated resident/medical student educational opportunities (57%) and complexity of patients (52%) as reasons. Those who lost interest cited a lack of autonomy (43%), publishing requirements (32%), and income discrepancy (26%) as reasons. Discussion: Many residents report losing interest in academics during residency. Traditional metrics valued in the recruitment process may not serve as positive predictors of an academic career path. Conclusion: Reasons why residents lose interest are not easily correctable, but mentorship, adequate career counseling, and research opportunities during training remain factors that can be addressed across all residency programs. PMID- 29619358 TI - Forces Required to Pull the Superficial Fascia in Facelifts. AB - Purpose: The aims of this study were to characterize the histology of the sideburn and cheek area and to measure the force required to pull the superficial fascia (SF) of Asians in facelift procedures. Methods: The hemiface of a formalin fixed Korean male adult cadaver (77 years old) was used to study the histology of the sideburn and cheek area. In 42 patients during facelift procedures, the force needed to pull the overlying skin at the midpoint between the sideburn and nasolabial fold 2 mm was measured using a tensiometer. Results: In the cheek, the superficial fatty layer of the superficial fascia (SFS) was found to maintain its thickness throughout the region between the dermis and the membranous layer of the superficial fascia (MSF). The MSF was continuous with the superficial temporal fascia (STF). In the sideburn, the MSF and parotid fascia closely adhered to each other. The force required to move the overlying skin 2 mm when pulling the MSF (10.27 +/- 3.64 N) was more than twice as great (217%) as the force required when pulling the SFS (4.73 +/- 2.15 N; P < .001). The forces required when pulling the MSF and SFS to move the overlying skin 2 mm were significantly greater in the sideburn area (11.56 +/- 3.37 N and 5.52 +/- 2.08 N, respectively) than in the cheek area (8.97 +/- 3.43 N and 5.52 +/- 2.08 N, respectively; P < .001). Conclusion: When lifting the SF at the cheek or sideburn area, lifting the SFS requires less tension than MSF to move the overlying skin. In the cheek area, less tension is needed to move the overlying skin than in the sideburn area. PMID- 29619359 TI - How Competitive Is Plastic Surgery? An Analysis of the Canadian and American Residency Match. AB - Background: Plastic surgery (PS) is considered to be one of the most competitive specialties. As a result, some students are discouraged from applying, reducing the overall number of PS candidates. Still, much of what we know of the match is based in conjecture. Objective: To examine the Canadian PS match data from 1997 to 2016. To our knowledge, this is the first long-term analysis of the Canadian PS residency match. Method: We examined the Canadian Residency Matching Service reports from 1997 to 2016, extracting key match statistics, including available positions, number of applicants, positions filled, positions unfilled, and gender specific match results. To examine competitiveness, the ratio of total applicants per quota per year (CR) and the ratio of applicants who chose PS as their first choice specialty per quota per year were calculated (FC-CR). The National Residency Matching Program data were used to assess the American integrated PS match over the past decade and served as a comparison. Results: The CR of Canadian PS programs declined over the last 20 years (P < .001), indicating fewer applicants applied to the program per available position. Similarly, the FC-CR also declined over the last 20 years (P < .001). The number of females matching to their first-choice discipline of PS increased from 1997 (P < .001). There was no significant change in the number of males matching to their first-choice discipline of PS (P = .15). There was no significant change in the competitiveness (CR) of the American integrated PS match over the last decade (P = 0.087). Conclusion: Encouragingly, today PS has more training positions and more female residents; yet, the overall number of applicants has remained relatively static over the past 20 years. This analysis serves as a valuable reference for PS programs and should assist in developing strategies to encourage the best applicants to apply. PMID- 29619360 TI - How Many Trigger Fingers Resolve Spontaneously Without Any Treatment? AB - Introduction: There is very little information in the literature evaluating the natural history of adult trigger fingers and their rate of spontaneous resolution over time. Methods: A consecutive case series of patients with trigger finger was generated. For each patient, we recorded whether the patient's disease resolved from either no treatment versus active treatment options and over what time period. Results: Three hundred forty-three patients with trigger finger were included in the study. Fifty-two percent of patients resolved without any treatment whatsoever after waiting a mean (and median) of 8 months from initial consultation. The thumb was the most frequent digit to resolve without treatment (72%). Conclusions: We found that just over half of patients with trigger fingers who are referred to our office resolve spontaneously without any intervention. PMID- 29619361 TI - How to Prevent Costal Cartilage Graft Warping in Secondary Correction of Cleft Lip Nasal Deformity. AB - Introduction: Autologous costal cartilage dorsal onlay graft is widely used for dorsum and radix augmentation in secondary cleft lip nasal rhinoplasty. The most common drawback of costal cartilage dorsal onlay graft is warping. The purpose of this article is to describe our chimeric autologous costal cartilage graft technique, which prevents warping significantly. "Chimeric" means the combination of 2 different tissues (bone and cartilage) to make a single dorsal onlay graft. Patients and Methods: From June 2011 to June 2014, 16 cleft lip patients who underwent rhinoplasty and needed dorsal onlay grafts with costal cartilage graft using the chimeric autologous costal graft method were identified. All patients were operated by the corresponding author. Patients' nasal profiles were documented and photographed preoperatively and postoperatively. Result: There were 5 males and 11 females with ages ranging from 20 to 52 years (averaging 29.5 years). There were 14 unilateral and 2 bilateral cleft lips. The average follow up time was 12.1 months. Six patients received revision surgery, including 1 (6%) warping and 5 (30%) revisions. All patients were harvested rib cartilage graft as cartilage donor and there was no complication with the donor site. Conclusion: From the clinical observation of all patients during the follow-up period, this technique is effective for preventing cartilage warping. PMID- 29619362 TI - Oral Exam. PMID- 29619363 TI - Looking for a Tax Break Offshore: A Primer on Tax Havens and Offshore Accounts. PMID- 29619364 TI - Harnessing Big Data for Communicable Tropical and Sub-Tropical Disorders: Implications From a Systematic Review of the Literature. AB - Aim: According to the World Health Organization (WHO), communicable tropical and sub-tropical diseases occur solely, or mainly in the tropics, thriving in hot, and humid conditions. Some of these disorders termed as neglected tropical diseases are particularly overlooked. Communicable tropical/sub-tropical diseases represent a diverse group of communicable disorders occurring in 149 countries, favored by tropical and sub-tropical conditions, affecting more than one billion people and imposing a dramatic societal and economic burden. Methods: A systematic review of the extant scholarly literature was carried out, searching in PubMed/MEDLINE and Scopus. The search string used included proper keywords, like big data, nontraditional data sources, social media, social networks, infodemiology, infoveillance, novel data streams (NDS), digital epidemiology, digital behavior, Google Trends, Twitter, Facebook, YouTube, Instagram, Pinterest, Ebola, Zika, dengue, Chikungunya, Chagas, and the other neglected tropical diseases. Results: 47 original, observational studies were included in the current systematic review: 1 focused on Chikungunya, 6 on dengue, 19 on Ebola, 2 on Malaria, 1 on Mayaro virus, 2 on West Nile virus, and 16 on Zika. Fifteen were dedicated on developing and validating forecasting techniques for real-time monitoring of neglected tropical diseases, while the remaining studies investigated public reaction to infectious outbreaks. Most studies explored a single nontraditional data source, with Twitter being the most exploited tool (25 studies). Conclusion: Even though some studies have shown the feasibility of utilizing NDS as an effective tool for predicting epidemic outbreaks and disseminating accurate, high-quality information concerning neglected tropical diseases, some gaps should be properly underlined. Out of the 47 articles included, only 7 were focusing on neglected tropical diseases, while all the other covered communicable tropical/sub-tropical diseases, and the main determinant of this unbalanced coverage seems to be the media impact and resonance. Furthermore, efforts in integrating diverse NDS should be made. As such, taking into account these limitations, further research in the field is needed. PMID- 29619365 TI - Chemical Reactivity and Spectroscopy Explored From QM/MM Molecular Dynamics Simulations Using the LIO Code. AB - In this work we present the current advances in the development and the applications of LIO, a lab-made code designed for density functional theory calculations in graphical processing units (GPU), that can be coupled with different classical molecular dynamics engines. This code has been thoroughly optimized to perform efficient molecular dynamics simulations at the QM/MM DFT level, allowing for an exhaustive sampling of the configurational space. Selected examples are presented for the description of chemical reactivity in terms of free energy profiles, and also for the computation of optical properties, such as vibrational and electronic spectra in solvent and protein environments. PMID- 29619367 TI - Effects of Cr Substitution on Negative Thermal Expansion and Magnetic Properties of Antiperovskite Ga1-x Cr x N0.83Mn3 Compounds. AB - Negative thermal expansion (NTE) and magnetic properties were investigated for antiperovskite Ga1-x Cr x N0.83Mn3 compounds. As x increases, the temperature span (DeltaT) of NTE related with Gamma5g antiferromagnetic (AFM) order is expanded and shifted to lower temperatures. At x = 0.1, NTE happens between 256 and 318 K (DeltaT = 62 K) with an average linear coefficient of thermal expansion, alpha L = -46 ppm/K. The DeltaT is expanded to 81 K (151-232 K) in x = 0.2 with alpha L = -22.6 ppm/K. Finally, NTE is no longer visible for x >= 0.3. Ferromagnetic order is introduced by Cr doping and continuously strengthened with increasing x, which may impede the AFM ordering and thus account for the broadening of NTE temperature window. Moreover, our specific heat measurement suggests the electronic density of states at the Fermi level is enhanced upon Cr doping, which favors the FM order rather than the AFM one. PMID- 29619366 TI - Targeting Endoplasmic Reticulum and/or Mitochondrial Ca2+ Fluxes as Therapeutic Strategy for HCV Infection. AB - Chronic hepatitis C is characterized by metabolic disorders and by a microenvironment in the liver dominated by oxidative stress, inflammation and regeneration processes that can in the long term lead to liver cirrhosis and hepatocellular carcinoma. Several lines of evidence suggest that mitochondrial dysfunctions play a central role in these processes. However, how these dysfunctions are induced by the virus and whether they play a role in disease progression and neoplastic transformation remains to be determined. Most in vitro studies performed so far have shown that several of the hepatitis C virus (HCV) proteins also localize to mitochondria, but the consequences of these interactions on mitochondrial functions remain contradictory and need to be confirmed in the context of productively replicating virus and physiologically relevant in vitro and in vivo model systems. In the past decade we have been proposing a temporal sequence of events in the HCV-infected cell whereby the primary alteration is localized at the mitochondria-associated ER membranes and causes release of Ca2+ from the ER, followed by uptake into mitochondria. This ensues successive mitochondrial dysfunction leading to the generation of reactive oxygen and nitrogen species and a progressive metabolic adaptive response consisting in decreased oxidative phosphorylation and enhanced aerobic glycolysis and lipogenesis. Here we resume the major results provided by our group in the context of HCV-mediated alterations of the cellular inter-compartmental calcium flux homeostasis and present new evidence suggesting targeting of ER and/or mitochondrial calcium transporters as a novel therapeutic strategy. PMID- 29619368 TI - The Chondro-Osseous Continuum: Is It Possible to Unlock the Potential Assigned Within? AB - Endochondral ossification (EO), by which long bones of the axial skeleton form, is a tightly regulated process involving chondrocyte maturation with successive stages of proliferation, maturation, and hypertrophy, accompanied by cartilage matrix synthesis, calcification, and angiogenesis, followed by osteoblast mediated ossification. This developmental sequence reappears during fracture repair and in osteoarthritic etiopathology. These similarities suggest that EO, and the cells involved, are of great clinical importance for bone regeneration as it could provide novel targeted approaches to increase specific signaling to promote fracture healing, and if regulated appropriately in the treatment of osteoarthritis. The long-held accepted dogma states that hypertrophic chondrocytes are terminally differentiated and will eventually undergo apoptosis. In this mini review, we will explore recent evidence from experiments that revisit the idea that hypertrophic chondrocytes have pluripotent capacity and may instead transdifferentiate into a specific sub-population of osteoblast cells. There are multiple lines of evidence, including our own, showing that local, selective alterations in cartilage extracellular matrix (ECM) remodeling also indelibly alter bone quality. This would be consistent with the hypothesis that osteoblast behavior in long bones is regulated by a combination of their lineage origins and the epigenetic effects of chondrocyte-derived ECM which they encounter during their recruitment. Further exploration of these processes could help to unlock potential novel targets for bone repair and regeneration and in the treatment of osteoarthritis. PMID- 29619370 TI - An Original Approach to Evaluating the Quality of Blood Donor Selection: Checking Donor Questionnaires and Analyzing Donor Deferral Rate. AB - Blood donor selection is a cornerstone for blood transfusion safety, designed to safeguard the health of both donors and recipients. In the Service du Sang, Belgian Red Cross, French and German-speaking part of Belgium (SFS), health professionals (HPs) are allowed to interview donors on their own after formal qualification. This qualification is afterward evaluated by means of two complementary quality indicators: monitoring of donor health questionnaires (DHQs) and analysis of donor deferral rate. The study aims to evaluate the degree to which both quality indicators may be useful and appropriate tools to evaluate the quality of blood donor selection. An analysis performed on 2016 data showed that noncompliance detected by means of DHQ monitoring seems to be more frequent in HPs who conduct a low number of interviews compared to all HPs as a group (5.67 vs. 3.23%; p < 0.001). Deferral rates are also higher in HPs with a lower activity compared to HPs who interview more donors (14.80 vs. 13.00%, p < 0.001). Furthermore, statistically differences are observed between the type of blood donation venue in terms of the global deferral rate (for instance fixed site vs. schools: 11.9 vs. 19.5%; p < 0.001), and specific reasons for deferral (such as sexual risk behavior and travel in at-risk areas, the differences being highly significant between each category of blood donation venue; p < 0.001). Providing the HPs with feedback on these findings was an opportunity to draw their attention to some aspects of the selection process in order to improve it. PMID- 29619371 TI - Inflammatory Bowel Disease: Complexity and Variability Need Integration. PMID- 29619369 TI - Cell Receptor and Cofactor Interactions of the Contact Activation System and Factor XI. AB - The contact activation system (CAS) or contact pathway is central to the crosstalk between coagulation and inflammation and contributes to diverse disorders affecting the cardiovascular system. CAS initiation contributes to thrombosis but is not required for hemostasis and can trigger plasma coagulation via the intrinsic pathway [through factor XI (FXI)] and inflammation via bradykinin release. Activation of factor XII (FXII) is the principal starting point for the cascade of proteolytic cleavages involving FXI, prekallikrein (PK), and cofactor high molecular weight kininogen (HK) but the precise location and cell receptor interactions controlling these reactions remains unclear. FXII, PK, FXI, and HK utilize key protein domains to mediate binding interactions to cognate cell receptors and diverse ligands, which regulates protease activation. The assembly of contact factors has been demonstrated on the cell membranes of a variety of cell types and microorganisms. The cooperation between the contact factors and endothelial cells, platelets, and leukocytes contributes to pathways driving thrombosis yet the basis of these interactions and the relationship with activation of the contact factors remains undefined. This review focuses on cell receptor interactions of contact proteins and FXI to develop a cell-based model for the regulation of contact activation. PMID- 29619372 TI - Irradiated Human Umbilical Vein Endothelial Cells Undergo Endothelial-Mesenchymal Transition via the Snail/miR-199a-5p Axis to Promote the Differentiation of Fibroblasts into Myofibroblasts. AB - Radiation induced pulmonary fibrosis (RIPF) is one of the major side effects of radiotherapy for lung cancer. Previous studies have shown that endothelial cells and activated myofibroblasts play a key role in RIPF. However, the interaction between irradiated endothelial cells and activation of myofibroblasts has not been reported. The aim of the present study was to examine whether irradiated endothelial cells would affect the differentiation of fibroblasts into myofibroblasts in the process of RIPF. In the current study, we used a coculture system that allowed direct contact between human fetal lung fibroblasts (MRC-5) and irradiated human umbilical vein endothelial cells (HUVECs). After 24 or 48 h, cells were sorted by flow cytometry. Radiation induced endothelial-mesenchymal transition (EndMT) by significantly increasing the expression of Snail and vimentin and reducing the expression of CD31 in HUVECs. In addition, irradiation of HUVECs induced the expression of collagen type I and alpha-smooth muscle actin (alpha-SMA) in MRC-5 cells. Further investigation indicated that irradiation of HUVECs induced the differentiation of fibroblasts into myofibroblasts through the Snail/miR-199a-5p axis. We conclude that irradiated endothelial cells undergo EndMT to promote differentiation of fibroblasts into myofibroblasts via the Snail/miR-199a-5p axis. PMID- 29619373 TI - The Difference in Cervical Vertebral Skeletal Maturation between Cleft Lip/Palate and Non-Cleft Lip/Palate Orthodontic Patients. AB - Objective: The aim was to evaluate differences in the cervical vertebral skeletal maturity of unilateral cleft lip and palate (UCLP) and non-cleft lip/palate (non CLP) Saudi male orthodontic patients. Method: This cross-sectional multicenter study took place at the dental school, King Saud University and King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia, between October 2014 and September 2015. The records of Saudi male orthodontic patients with UCLP (n = 69) were collected. Cervical vertebral maturation was assessed using their cephalometric radiographs. The records of 138 age-matched non-CLP Saudi male orthodontic patients served as controls. Results: There was a significant difference in skeletal maturity between the UCLP and non-CLP groups, as evident in the delayed skeletal development among the UCLP participants. Moreover, pubertal growth spurt onset was significantly earlier in the non-cleft participants in comparison with the UCLP participants (p = 0.009). Conclusions: There is delayed skeletal maturity among the UCLP Saudi male population in comparison with their non-CLP age-matched peers. PMID- 29619374 TI - Modulation of Molecular Biomarker Expression in Response to Chemotherapy in Invasive Ductal Carcinoma. AB - Breast cancer (BC) has varied morphological and biological features and is classified based on molecular and morphological examinations. Molecular classification of BC is based on biological gene-expression profiling. In this study, biomarker modulation was assessed during BC treatment in 30 previously untreated patients. Heterogeneity among patients was pathologically diagnosed and classified into luminal and basal-like immunohistochemical profiles based on estrogen, progesterone, and human epidermal growth factor receptor (ER/PR/HER2) status. Marker heterogeneity was compared with mRNA biomarker expression in patients with BC before and after therapy. Reverse transcription-polymerase chain reaction was performed for molecular characterization. Expression and modulation of biological markers, CK19, hMAM, CEA, MUC, Myc, Ki-67, HER2/neu, ErbB2, and ER, were assessed after treatment, where the expression of the biomarkers CK19, Ki 67, Myc, and CEA was noted to be significantly decreased. Marker expression modulation was determined according to different stages and pathological characteristics of patients; coexpression of three markers (CK19, Ki-67, and Myc) was specifically modulated after therapy. In the histopathologically classified basal-like group, two markers (CK19 and Ki-67) were downregulated and could be considered as diagnostic biomarkers. In conclusion, pathological characteristics and marker variation levels can be evaluated to decide a personalized treatment for patients. PMID- 29619375 TI - The Use of Ultrasound Imaging in the External Beam Radiotherapy Workflow of Prostate Cancer Patients. AB - External beam radiotherapy (EBRT) is one of the curative treatment options for prostate cancer patients. The aim of this treatment option is to irradiate tumor tissue, while sparing normal tissue as much as possible. Frequent imaging during the course of the treatment (image guided radiotherapy) allows for determination of the location and shape of the prostate (target) and of the organs at risk. This information is used to increase accuracy in radiation dose delivery resulting in better tumor control and lower toxicity. Ultrasound imaging is harmless for the patient, it is cost-effective, and it allows for real-time volumetric organ tracking. For these reasons, it is an ideal technique for image guidance during EBRT workflows. Review papers have been published in which the use of ultrasound imaging in EBRT workflows for different cancer sites (prostate, breast, etc.) was extensively covered. This new review paper aims at providing the readers with an update on the current status for prostate cancer ultrasound guided EBRT treatments. PMID- 29619376 TI - Susceptibility of Diabetic Mice to Noise Trauma. AB - Diabetes can lead to many end-organ complications. However, the association between diabetes and hearing loss is not well understood. Here, we investigated the effect of noise exposure on diabetic mice compared with wild-type mice. Hearing threshold shifts, histopathologic changes in the cochlea, and inflammatory responses were evaluated over time. After noise exposure, more severe hearing threshold shifts, auditory hair cell loss, and synaptopathies were notable in diabetic mice compared with wild-type mice. Moreover, increased inflammatory responses and reactive oxygen species production were observed in the ears of diabetic mice. The results demonstrated that diabetic mice are more susceptible to noise trauma. PMID- 29619377 TI - Roles of NUCKS1 in Diseases: Susceptibility, Potential Biomarker, and Regulatory Mechanisms. AB - Nuclear casein kinase and cyclin-dependent kinase substrate 1 (NUCKS1) is a 27 kD chromosomal, highly conserved, and vertebrate-specific protein. NUCKS1 gene encodes a nuclear protein and the conserved regions of NUCKS1 contain several consensus phosphorylation sites for casein kinase II (CK2) and cyclin-dependent kinases (Cdk) and a basic DNA-binding domain. NUCKS1 is similar to the high mobility group (HMG) family which dominates chromatin remodeling and regulates gene transcription. Meanwhile, NUCKS1 is a RAD51 associated protein 1 (RAD51AP1) paralog that is significant for homologous recombination (HR) and genome stability and also a transcriptional regulator of the insulin signaling components. NUCKS1 plays an important role in DNA damage response and metabolism, participates in inflammatory immune response, and correlates with microRNA. Although there is still not enough functional information on NUCKS1, evidences suggest that NUCKS1 can be used as the biomarker of several cancers. This review summarizes the latest research on NUCKS1 about its susceptibility in diseases, expression levels, and regulatory mechanisms as well as the possible functions in reference to diseases. PMID- 29619378 TI - Nonsurgical Clinical Management of Periapical Lesions Using Calcium Hydroxide Iodoform-Silicon-Oil Paste. AB - Background: The study aim is to avoid tooth extraction by nonsurgical treatment of periapical lesion. It assesses healing progress in response to calcium hydroxide-iodoform-silicon oil paste (CHISP). Numeric Pain Rating Scale was used to validate the approach. Furthermore, CHISP was used to treat cystic lesions secondary to posttraumatic avulsion of permanent teeth. Materials and Methods: Over 200 patients with radicular cysts were treated with CHISP through the root canal. Radiographs were used to verify lesion size and position, ensure correct delivery to the site, and monitor the progress of bone healing in the lesion area. Ten males and 10 females were randomly selected for statistical assessment. Results: No severe pain, complications, or failure in cyst healing was reported. Complete healing was achieved in an average of 75 days. Furthermore, healing of radicular cyst secondary to posttraumatic tooth avulsion was successful. Conclusion: CHISP indicated an antiseptic effect, which enhanced and shortened healing time of periapical lesions. The less invasive procedure avoids tooth extraction and reduces bone resorption. Cyst management with CHISP can remedy failed root canal treatments. The results show a bone regenerative capacity of CHISP suggested in first rapid phase and a second slow phase. PMID- 29619380 TI - The Early Clinical Outcomes of a Percutaneous Full-Endoscopic Interlaminar Approach via a Surrounding Nerve Root Discectomy Operative Route for the Treatment of Ventral-Type Lumbar Disc Herniation. AB - The objective of this study is to introduce a method using a percutaneous full endoscopic interlaminar approach via a surrounding nerve root discectomy (SNRD) operative route that involves removing the protrusive disc via both the shoulder and the axilla of the corresponding nerve root for the treatment of ventral-type lumbar disc herniation (VLDH) and its early clinical symptoms. Twenty-two patients with VLDH satisfied the inclusion criteria and underwent the full endoscopic interlaminar approach operation via a SNRD successfully during the period from November 2014 to June 2016. All operations were completed without conversion to other surgical techniques. The average operation time was 78.64 +/- 25.97 min (50-145 min). The average removed disc tissue volume was 2.87 +/- 0.48 ml (2-3.6 ml). No nerve root injury, infection, or other complications occurred. The postoperative ODI and VAS values of low back and sciatic pain were significantly decreased at each time point compared to preoperative measurements (P < 0.05). The MacNab scores at the 12-month follow-up included 15 excellent and 7 good scores. In summary, a percutaneous full-endoscopic interlaminar approach through SNRD is a safe and effective treatment option for patients with VLDH. PMID- 29619381 TI - Efficacy and Safety of Insulin Glargine 300 U/mL versus 100 U/mL in Diabetes Mellitus: A Comprehensive Review of the Literature. AB - To achieve good metabolic control in diabetes and maintain it in the long term, a combination of changes in lifestyle and pharmacological treatment is necessary. The need for insulin depends upon the balance between insulin secretion and insulin resistance. Insulin is considered the most effective glucose-lowering therapy available and is required by people with type 1 diabetes mellitus to control their blood glucose levels; yet, many people with type 2 diabetes mellitus will also eventually require insulin therapy, due to the progressive nature of the disease. A variety of long-acting insulins is currently used for basal insulin therapy (such as insulin glargine, degludec, and detemir), each having sufficient pharmacodynamic and pharmacokinetic profiles to afford lower intrapatient variability and an extended duration of action. The new glargine-300 formulation was developed to have a flatter and more extended time-action profile than the original glargine-100, and these characteristics may translate into more stable and sustained glycemic control over a 24 h dosing interval. The objective of this comprehensive review was to summarize the available evidence on the clinical efficacy and safety of glargine-300 versus glargine-100 from the EDITION clinical trial program, in patients with type 1 and type 2 diabetes mellitus. PMID- 29619382 TI - A Transcriptional Sequencing Analysis of Islet Stellate Cell and Pancreatic Stellate Cell. AB - Background: Our previous studies have shown that islet stellate cell (ISC), similar to pancreatic stellate cell (PSC) in phenotype and biological characters, may be responsible for the islet fibrosis in type 2 diabetes. To further identify the differences between PSC and ISC and for better understanding of the physiological function of ISC, we employed genome-wide transcriptional analysis on the PSCs and ISCs of Wistar rats. Method: PSCs and ISCs from each rat were primarily cultured at the same condition. Genome-wide transcriptional sequence of stellate cells was generated. The identified differentially expressed genes were validated using RT-PCR. Results: 32 significant differentially expressed genes between PSCs and ISCs were identified. Moreover, collagen type 11a1 (COL11A1), was found to be expressed 2.91-fold higher in ISCs compared with PSCs, indicating that COL11A1 might be a potential key gene modulating the differences between PSC and ISC. Conclusions: Our study identified and validated the differences between PSC and ISC in genome-wide transcriptional scale, confirming the assumption that ISC and PSC are similar other than identical. Moreover, our data might be instrumental for further investigation of ISC and islet fibrosis, and some differential expressed genes may provide an insight into new therapeutic targets for type 2 diabetes. PMID- 29619383 TI - #FOAMems: Engaging paramedics with free, online open-access education. AB - BACKGROUND AND AIM: Twitter(r) use among paramedics and other prehospital care clinicians is on the rise and is increasingly being used as a platform for continuing education and international collaboration. In 2014, the hashtag #FOAMems was registered. It is used for the sharing of emergency medical services, paramedicine, and prehospital care-related content. It is a component of the 'free open-access meducation' (FOAM) movement. The aim of this study was to characterize and evaluate the content of #FOAMems tweets since registration. MATERIALS AND METHODS: An analytical report for #FOAMems was generated on symplur.com from February 4, 2014, to April 30, 2017. A transcript of all #FOAMems tweets for a randomly selected 1 month period (October 2015) was generated, and quantitative content analysis was performed by two reviewers. Tweets were categorized according to source (original tweet/retweet) and whether referenced. The top 92 tweeters were analyzed for professional identity. RESULTS: During the study period, there were over 99,000 tweets containing #FOAMems, by over 9,200 participants. These resulted in almost 144 million impressions. Of the top 92 tweeters, 50 were paramedics (54%). Tweets were mainly related to cardiac (23%), leadership (19%), and trauma (14%). The 1-month period resulted in 649 original tweets, with 2110 retweets; 1070 of these were referenced. CONCLUSION: Paramedics are engaging with both clinical and nonclinical content on Twitter(r) using #FOAMems. Social media resources are widely shared, which is in line with the FOAM movement's philosophy. However, opportunities exist for paramedics to share further diverse resources supported by referenced material. PMID- 29619384 TI - Trauma-focused cognitive behavioral therapy a clinical trial to increase self efficacy in abused the primary school children. AB - BACKGROUND: Child abuse and violence toward children has become a complex phenomenon in nowadays societies leaving hurt children with numerous complications such as lowered self-efficacy. Hence, this study was conducted to assess the effect of trauma-focused cognitive behavioral therapy (TF-CBT) in physically abused children self-efficacy. MATERIALS AND METHODS: This study was a randomized clinical trial. From this statistical population of all abused children aged 9-12 in Kermanshah in 2016-2017, 40 were divided into intervention and control groups randomly. Tools used in this study were Maurice self-efficacy questionnaire and child abuse questionnaire. Data analysis was done using Chi square test, paired t-test, and independent t-test. RESULTS: It was revealed that the mean difference between two groups was not meaningful before intervention. After TF-CBT in intervention group, self-efficacy mean scores of social (17.95 vs. 24.20) and emotional (15.05 vs. 19.05) domains showed meaningful differences, whereas academic self-efficacy mean score did not change significantly (14.10 vs. 14.65) (P < 0.086). In control group, social (16.20 vs. 15.55), emotional (13.90 vs. 14.35), and academic (13.40 vs. 13.90) mean self-efficacy scores were not of significant difference (P > 0.001). CONCLUSIONS: TF-CBT can be used as an appropriate therapy intervention to improve social and emotional self-efficacy in abused children. PMID- 29619385 TI - The relationship between anthropometric index and primary dysmenorehea in female high school students. AB - INTRODUCTION: Primary dysmenorrhea, painful menstruation without pelvic pathologic complications, is one of the most common problems in women's gynecology and is one of the main causes for women referring to the clinic. Overweight and obesity may play a role in the etiology of primary dysmenorrhea. As a result, this study was conducted to determine the association between primary dysmenorrhea and anthropometric indices in female high school Students. METHODS: This descriptive, cross-sectional study was conducted on 200 high school female students with primary dysmenorrhea in 2017 in Sabzevar. Anthropometric indicators were considered by the students if they had entry criteria. Data analysis was done using SPSS software. RESULTS: The results of data analysis showed that there was a significant difference between the presence of dysmenorrhea and anthropometric indices at height P = 0.05, waist circumference P = 0.03, waist circumference with height P = 0.01, height to waist circumference P = 0.01, thigh circumference to height P = 0.04, height to thigh circumference P = 0.04, waist circumference to hip circumference P = 0.04, hip circumference to hip circumference P = 0.05, and No significant relationship was found between the other indicators. CONCLUSION: Adherence to a balanced diet and proper lifestyle can prevent dysmenorrhea in adolescent girls. PMID- 29619386 TI - Gender preference between traditional and PowerPoint methods of teaching gross anatomy. AB - INTRODUCTION: Teaching and learning process is increasingly metamorphosing from the traditional chalk and talk to the modern dynamism in the information and communication technology. Medical education is no exception to this dynamism more especially in the teaching of gross anatomy, which serves as one of the bases of understanding the human structure. OBJECTIVE: This study was conducted to determine the gender preference of preclinical medical students on the use of traditional (chalk and talk) and PowerPoint presentation in the teaching of gross anatomy. SUBJECTS AND METHODS: This was cross-sectional and prospective study, which was conducted among preclinical medical students in the University of Maiduguri, Nigeria. Using simple random techniques, a questionnaire was circulated among 280 medical students, where 247 students filled the questionnaire appropriately. The data obtained was analyzed using SPSS version 20 (IBM Corporation, Armonk, NY, USA) to find the method preferred by the students among other things. RESULTS: Majority of the preclinical medical students in the University of Maiduguri preferred PowerPoint method in the teaching of gross anatomy over the conventional methods. The Cronbach alpha value of 0.76 was obtained which is an acceptable level of internal consistency. A statistically significant association was found between gender and preferred method of lecture delivery on the clarity of lecture content where females prefer the conventional method of lecture delivery whereas males prefer the PowerPoint method, On the reproducibility of text and diagram, females prefer PowerPoint method of teaching gross anatomy while males prefer the conventional method of teaching gross anatomy. CONCLUSION: There are gender preferences with regard to clarity of lecture contents and reproducibility of text and diagram. It was also revealed from this study that majority of the preclinical medical students in the University of Maiduguri prefer PowerPoint presentation over the traditional chalk and talk method in most of the questions ask. PMID- 29619379 TI - Eosinophils from Physiology to Disease: A Comprehensive Review. AB - Despite being the second least represented granulocyte subpopulation in the circulating blood, eosinophils are receiving a growing interest from the scientific community, due to their complex pathophysiological role in a broad range of local and systemic inflammatory diseases as well as in cancer and thrombosis. Eosinophils are crucial for the control of parasitic infections, but increasing evidence suggests that they are also involved in vital defensive tasks against bacterial and viral pathogens including HIV. On the other side of the coin, eosinophil potential to provide a strong defensive response against invading microbes through the release of a large array of compounds can prove toxic to the host tissues and dysregulate haemostasis. Increasing knowledge of eosinophil biological behaviour is leading to major changes in established paradigms for the classification and diagnosis of several allergic and autoimmune diseases and has paved the way to a "golden age" of eosinophil-targeted agents. In this review, we provide a comprehensive update on the pathophysiological role of eosinophils in host defence, inflammation, and cancer and discuss potential clinical implications in light of recent therapeutic advances. PMID- 29619387 TI - A comparative study on the effect of "black cohosh" and "evening primrose oil" on menopausal hot flashes. AB - INTRODUCTION: Hot flashes are considered to be a common experience for menopausal women and they can compromise the quality of life. The objective of this study is to assess the efficacy of Cimicifuga racemosa in comparison with evening primrose oil (EPO) in postmenopausal women with menopause-related symptoms. MATERIALS AND METHODS: This study was performed on 80 postmenopausal women with hot flashes. The participants were randomly divided into two groups by blocked randomization. The participants of one group received black cohosh and the other group received EPO for 8 weeks. The severity and number of hot flashes and quality of life were measured by four-point scale, and the Menopause-Specific Quality of Life (MENQOL) questionnaire at pre-intervention, 1st, 4th, and 8th weeks after treatment. Data were analyzed in SPSS Version 16 using independent t-test, Chi-square, and Fisher's exact test. RESULTS: Average severity of hot flashes in both groups and number of hot flashes in black cohosh group in 8th week were significantly lower than 1st week (P < 0.001), but number of hot flashes in primrose oil group in 8th week showed no significant differences (P = 0.32). The number of hot flashes and quality of life score in black cohosh arm compared to EPO showed a significant decrease in the 8th week (P < 0.05). All MENQOL scores were significantly improved in two groups (P < 0.05), but the percentage of improvement in black cohosh arm was significantly superior to EPO group. CONCLUSION: Both herbs were effective in reduction of severity of hot flashes and improvement of the quality of life, but it seems that black cohosh is more effective than primrose oil because it was able to reduce the number of hot flashes too. PMID- 29619388 TI - The effect of an eye health promotion program on the health protective behaviors of primary school students. AB - INTRODUCTION: Undiagnosed and uncorrected refractive errors in childhood can negatively affect the development of vision and cause students to have low academic success and even quit school before graduation. This study aims to determine the effects of an eye health promotion program on the health protective behaviors of primary school students. MATERIALS AND METHODS: This experimental study using a pretest-posttest design with a control group was conducted in three public primary schools in Aydin, a city in the Western Anatolia Region of Turkey, between April and November 2014. The eye health promotion program was provided by the researchers to the experimental Group 2 days in 4 weeks. The data were analyzed using the t-test, Chi-square analysis, the Mann-Whitney U-test, the Wilcoxon signed-rank test, and the McNemar test. RESULTS: The average age of the students was identified as 9.0 +/- 3.64 years. The students wearing glasses all in the experimental group and 53.3% in the control group were found to always wear their glasses after the education program was completed (P < 0.05). These students, 97.9% in the experimental group and 58.1% in the control group underwent eye examinations from an ophthalmologist (P < 0.05). The eye health protective behaviors of the experimental group were found to have positively changed in the final follow-up, compared to the control group (P < 0.05). CONCLUSION: The eye health promotion program was found to be effective in improving eye health protective behaviors within the experimental group. PMID- 29619389 TI - The role of perceived barrier in the postpartum women's health promoting lifestyle: A partial mediator between self-efficacy and health promoting lifestyle. AB - INTRODUCTION: In recent decades, the focuses of health studies were mostly in middle-aged women, and few studies have investigated the lifestyle of women after delivery. The aim of this study was to determine the effects of both self efficacy and perceived barriers on Iranian women health-promoting lifestyle (HPL) in the first 1 year after childbirth. MATERIALS AND METHODS: Using a cross sectional design, 310 women at first-year postpartum were surveyed in Zanjan (Iran) in 2016. The proportionate stratified random sampling method was carried out to select a participant. HPL has assessed with HPL profile II questionnaire. Self-efficacy was assessed using self-rated abilities for health practices scale. Perceived barriers were assessed by Barriers to Health-promoting Activities for Disabled Person scale. A meditational model was used to examine whether perceived barriers mediates between perceived self-efficacy and HPL. RESULTS: The participants mean age was 29.82 (5.1) years, 53.9% were primiparous, and most of them were homemakers (82.9%). The mean total score of HPL was 2.50 (0.29). The relationship between HPL and self-efficacy was mediated by perceived barriers partially. DISCUSSION: Self-efficacy, not only promotes women's HPL but also indirectly affect the women's lifestyle by reducing perceived barriers. PMID- 29619390 TI - Opportunities and challenges of resident specialists' attendance plan guidelines (health-care transformation plan) in Isfahan university hospitals in 2015. AB - BACKGROUND: Given new reforms in Iran's health-care system and due to the need for gathering evidence regarding the implementation of this plan, this study aimed to investigate opportunities and challenges created by resident specialist attendance plan guidelines in university hospitals. MATERIALS AND METHODS: This study used the qualitative method. Semi-structured interviews were used for data gathering. The study population included all experts of Isfahan University of Medical Science. Sampling was carried out using purposeful sampling method and continued until data saturation was reached. In total, 16 experts were interviewed. Criteria such as "reliability of information," "trustworthiness," and "verifiability of the information" were considered. Interviewees were assured that their names would keep hidden and that all information is confidential. Subject analysis method was used for data analysis. RESULTS: The findings of this study based on subject analysis led to extracting three themes in regards of challenges in the implementation of resident (specialist or fellowship) plan in hospitals including structural, management, and resource challenges and one theme in the area of opportunities which were improved quality and timely provision of services. CONCLUSION: The findings showed that despite the strengths of this guideline, there are some fundamental challenges in various areas and need better attention by national level policymakers. These results help health-care policymakers to evaluate the problem with a better attitude and improve the necessary plans for implementation of these guidelines. PMID- 29619391 TI - Neck, back, and shoulder pains and ergonomic factors among dental students. AB - BACKGROUND: Dynamic and static activities in dentistry cause musculoskeletal disorders, but dental students do not have sufficient awareness about the effects of ergonomic factors on their health. The aim of this study was to investigate ergonomic factors that cause pain muscle in dental students in Kerman Medical University, Iran. METHODS: This cross-sectional analysis study was carried out on dental students of the 3rd, 4th, 5th, and 6th year, in clinical practice in the School of Dentistry, Kerman University of Medical Sciences. A convenient sample of 199 students who met the inclusion criteria was selected and those willing to participate signed an informed consent form. Data were collected by means of a structured questionnaire for ergonomic factors and the presence of pain. The variables evaluated were pain, affected zones, gender, postures, and work environment. RESULTS: The present research work reveals that over 69% of the dental students complained of pain in at least one part of their body. Most individuals suffered from hand and elbow (23%) and head (19%) pain. The clinical areas where more pain was found were endodontics and pedodontics. Furthermore, it was found that a high percentage of students usually worked with their legs slightly separated, with the sole of the feet resting on the stool when working. The presence of muscular pain was higher in males in this study. Furthermore, there was a statistically significant relationship with the final Rapid Entire Body Assessment score in different body parts and the participants' demographic data (sex, age, weight, height, sports, and smoking). CONCLUSIONS: The results of this study showed that the students' sitting positions and working environments need to be improved and it seems more training is necessary in this field. PMID- 29619392 TI - The effect of progressive muscle relaxation and guided imagery on stress, anxiety, and depression of pregnant women referred to health centers. AB - BACKGROUND: If anxiety and depression do not detect in pregnant women, they may cause complications for the mother, child, and family, including postpartum depression. With regard to the administrative capability of relaxation in health centers, this study was conducted to determine the effect of progressive muscle relaxation and guided imagery on stress, anxiety, and depression in pregnant women. MATERIALS AND METHODS: This randomized clinical trial was conducted on pregnant women in the city of Kashan at 28-36 weeks. At the onset of the study, demographic questionnaire, Edinburgh Depression Scale, and Depression, Anxiety, and Stress Scale-21 (DASS-21) were completed. Providing obtaining score of mild to-moderate in the stress, anxiety, and depression scale and score of 10 or higher in Edinburgh Depression Scale, individuals were divided randomized to the intervention group (n = 33) and control group (n = 33). DASS-21 was again completed in the 4th-7th weeks of beginning of the study by all women. RESULTS: Analysis of variance with repeated measures indicated significant differences in mean of scores of stress, anxiety, and depression at three different times in relaxation group (P < 0.05) whereas found no significant differences in the mean of scores of stress, anxiety, and depression in the control group. CONCLUSIONS: In this study, relaxation could reduce stress, anxiety, and depression in pregnant women during six sessions. Due to the simplicity and low cost of this technique, it can be used to reduce stress and anxiety in pregnant women and improve pregnancy outcomes. PMID- 29619393 TI - A comparative study of maternal-neonate abdominal and kangaroo (skin-to-skin) skin contact immediately after birth on maternal attachment behaviors up to 2 months. AB - BACKGROUND: Early skin-to-skin maternal-neonate contact during the 1st h following birth prepares both mother and baby to establish a two-way, interactive pattern of interaction. There are few studies on the use of kangaroo care method in term infants and maternal postpartum behavior. OBJECTIVE: The present study aimed to compare abdominal and kangaroo skin contact on maternal attachment behaviors. SETTINGS AND DESIGN: This single-blind randomized clinical trial was performed on 68 eligible pregnant women in Torbat Heydariyeh in 2015. MATERIALS AND METHODS: Individuals were randomly divided into experimental groups (kangaroo skin contact) and control group (abdominal skin contact). Maternal attachment behaviors were observed for 15 min during 1 h postpartum. Each minute was divided into two 30 s, during the first and second 30 s of which the maternal behavior was observed and recorded using a checklist of behavior. Attachment behaviors were assessed using an attachment behavior checklist (including three types of emotional, proximity-seeking, and caring behaviors). STATISTICAL ANALYSIS USED: After data coding, the analysis was performed using Kruskal-Wallis test, Chi square test, t-test, and Mann-Whitney test in SPSS ver. 14. P < 0.05 was considered the significant level. RESULTS: Among emotional, proximity-seeking, and caring behaviors 1 h and 2 months' postpartum in the two groups, only proximity-seeking behaviors were significantly different 2 months' postpartum (P = 0.033). The attachment behavior of 1 h (0.134) and 2 months' postpartum (0.051) did not differ significantly between the two groups. CONCLUSIONS: Kangaroo skin contact has an effect, similar to the abdominal skin contact, on the maternal attachment behaviors and has a positive effect on proximity-seeking behaviors and some components of emotional behaviors compared to abdominal skin contact. PMID- 29619394 TI - Psychophysiological effects of yoga on stress in college students. AB - College students are vulnerable to a critical period in developmental maturation, facing rigorous academic work, and learning how to function independently. Physical activities such as running and bicycling have been shown to improve mood and relieve stress. However, college students often have low levels of physical activity. Yoga is an ancient physical and mental activity that affects mood and stress. However, studies examining the psychophysiological effects of yoga are rare in peer-reviewed journals. The aim of this study is to establish preliminary evidence for the psychophysiological effects of yoga on stress in young-adult college students. The present study suggests that yoga has positive effects on a psychophysiological level that leads to decreased levels of stress in college student. Further research is needed to examine the extent to which different types of yogic practices address the needs of different college subpopulations (e.g., overweight, sedentary, and smokers). PMID- 29619395 TI - Sirolimus in Refractory Cronkhite-Canada Syndrome and Focus on Standard Treatment. AB - Cronkhite-Canada syndrome is a rare syndrome consisting of extensive gastrointestinal polyposis and ectodermal changes including cutaneous hyperpigmentation, alopecia, and onychodystrophy. We report the case of a 45-year old Caucasian male patient who failed multiple treatments over 2 years including steroids, azathioprine, adalimumab, and cyclosporine. He had recurrent and prolonged hospitalizations because of diarrhea, abdominal pain, weight loss, and malnutrition. Sirolimus was initiated with a significant clinical and endoscopic benefit apparent within, respectively, 2 and 8 weeks. An ongoing remission was achieved and maintained for over 6 months after prednisone tapering. We review the current evidence on treatment of Cronkhite-Canada syndrome and suggest the incorporation of sirolimus in that algorithm. PMID- 29619396 TI - Anthropometric and Radiologic Measurements of Coracoid Dimensions and Clinical Implications in an Indian Population. AB - Background: Recurrent shoulder dislocation and anterior instability are most commonly attributed to pathology of the capsulolabral complex with the presence of bony loss at the humeral and glenoid surfaces. Unassessed bone loss has been a cause of failure of primary soft tissue procedures or recurrence of symptoms, despite adequate address of soft tissue pathology. Purpose: To study the anthropometric and radiologic dimensions of the coracoid in relation to glenoid bone loss, its adequacy in filling glenoid defects in an Indian population, and whether the choice of surgical technique (congruent arc vs classical) and graft positioning alters the surgical results. This study also intended to establish whether computed tomography measurements correlate with actual anthropometric measurements. Study Design: Cross-sectional study; Level of evidence, 3. Methods: A total of 64 participants with 108 healthy shoulders were included in this study. Additionally, 100 skeletally mature bone specimens of the scapula were measured to assess glenoid diameter as well as coracoid width and length in 2 perpendicular planes with a humeral subtraction 3-dimensional en face glenoid view. Results: Specimen and participant measurements proved that the congruent arc technique was able to fill up to 50% more glenoid bone loss than the classical technique in an Indian population (mean +/- SD, 13.45 +/- 6.97 vs 7.96 +/- 4.89 mm, respectively), with computed tomography being the best and most accurate modality to study it. The mean difference in the bone block length restoration of the glenoid bony arc was 5.41 +/- 2.08 mm. Radii of curvature were congruent in populations of the Indian subcontinent. Conclusion: The congruent arc technique can be performed in an Indian population but with caution and careful presurgical assessment of bone loss. However, adequate coracoid dimension to accommodate the implant for fixation without failure must be ensured, as anthropometry suggests the existence of a subset of the population in whom the graft may have compromised width for accommodating standard implants for fixation. PMID- 29619397 TI - Treatment of Failed Articular Cartilage Reconstructive Procedures of the Knee: A Systematic Review. AB - Background: Symptomatic articular cartilage lesions of the knee are common and are being treated surgically with increasing frequency. While many studies have reported outcomes following a variety of cartilage restoration procedures, few have investigated outcomes of revision surgery after a failed attempt at cartilage repair or reconstruction. Purpose: To investigate outcomes of revision cartilage restoration procedures for symptomatic articular cartilage lesions of the knee following a previously failed cartilage reconstructive procedure. Study Design: Systematic review; Level of evidence, 4. Methods: A literature search was performed by use of the PubMed, EMBASE, and MEDLINE/Ovid databases for relevant articles published between 1975 and 2017 that evaluated patients undergoing revision cartilage restoration procedure(s) and reported outcomes using validated outcome measures. For studies meeting inclusion criteria, relevant information was extracted. Results: Ten studies met the inclusion criteria. Lesions most commonly occurred in the medial femoral condyle (MFC) (52.8%), with marrow stimulation techniques (MST) the index procedure most frequently performed (70.7%). Three studies demonstrated inferior outcomes of autologous chondrocyte implantation (ACI) following a previous failed cartilage procedure compared with primary ACI. One study comparing osteochondral allograft (OCA) transplant following failed microfracture (MFX) with primary OCA transplant demonstrated similar clinical outcomes and graft survival at midterm follow-up. No studies reported outcomes following osteochondral autograft transfer (OAT) or newer techniques. Conclusion: This systematic review of the literature reporting outcomes following revision articular cartilage restoration procedures (most commonly involving the MFC) demonstrated a high proportion of patients who underwent prior MST. Evidence is sufficient to suggest that caution should be taken in performing ACI in the setting of prior MST, likely secondary to subchondral bone compromise. OCA appears to be a good revision treatment option even if the subchondral bone has been violated from prior surgery or fracture. PMID- 29619398 TI - Functional Classification of the Medial Ulnar Collateral Ligament: An In Vivo Kinematic Study With Computer-Aided Design. AB - Background: It has been widely accepted that the anterior and posterior bundles of the medial ulnar collateral ligament (MUCL) tighten at extension and flexion, respectively. However, this belief is based on anatomic data acquired from cadaveric studies. The advancement of 3-dimensional (3D) model technology has made possible the simulation of dynamic movement that includes each ligament bundle fiber to analyze its functional properties. To date, no study has analyzed ligament kinematics at the level of the fibers while also focusing on their functional properties. Purpose: To propose a new classification for functional properties of the MUCL based on its kinematic pattern. Study Design: Descriptive laboratory study. Methods: Five healthy elbow joints were scanned by use of computed tomography, and 3D models were rendered and translated into vertex points for further mathematical analysis. The humeral origin and ulnar insertion of the MUCL fiber groups were registered. Each vertex point on the origin side was randomly connected to the insertion side, with each pair of corresponding points defined as 1 ligament fiber. Lengths of all the fibers were measured at 1 degrees increments of elbow range of motion (ROM). Ligament fibers were grouped according to their patterns. Mean coverage area for each group, expressed as the percentage of ligament fibers per group to the total number of fibers, was calculated. Results: Four major bundle groups were found based on fiber length properties. Kinematic simulation showed that each group had a different kinematic function throughout elbow ROM. Mean coverage area of groups 1, 2, 3, and 4 was 8% +/- 4%, 10% +/- 5%, 42% +/- 6%, and 40% +/- 8%, respectively. Each group acted as a dominant stabilizer in certain arcs of motion. Reciprocal activity was observed between groups 1 and 3 along with groups 2 and 4 to produce synergistic properties of maintaining elbow stability. Conclusion: Detailed analysis of fibers of the MUCL allows for further understanding of its kinematic function. This study provides MUCL group coverage area and kinematic function for each degree of motion arc, allowing selective reconstruction of the MUCL according to mechanism of injury. Clinical Relevance: Understanding the dominant functional fibers of the MUCL will benefit surgeons attempting MUCL reconstruction and will enhance further anatomic study. PMID- 29619399 TI - Celiac Disease and Secondary Amyloidosis: A Possible Causal Association? AB - We report a rare case of secondary renal amyloidosis in a patient with probable celiac disease presenting as nephrotic syndrome. A 30-year-old man with chronic diarrhea presented with progressive anasarca for 2 years. On further evaluation, he had hypoalbuminemia, significant nephrotic-range proteinuria, and elevated levels of anti-tissue transglutaminase. Renal biopsy suggested deposition of amorphous Congo red-positive material in the glomerular mesangium, positive for amyloid A amyloidosis. Endoscopic duodenal biopsy suggested blunting of the villous architecture and chronic inflammation of the lamina propria. The patient subsequently developed massive pulmonary embolism and died due to refractory cardiogenic shock. PMID- 29619400 TI - Unusual Presentation of Duodenal Ulcer Presenting with Duodenal Intussusception. AB - We present a unique case of duodeno-duodenal intussusception from a duodenal bulb ulcer. A 38-year-old man presented with nausea, vomiting, and abdominal pain. Computed tomography showed duodenal intussusception. Esophagogastroduodenoscopy (EGD) showed a linear gastric ulcer and a duodenal bulb ulcer with an overlying blood clot. Helicobacter pylori status was positive. Intussusception resolved spontaneously without intervention. He completed treatment for H. pylori infection, and repeat EGD showed ulcer healing. Duodenal intussusception is rarely reported; intussusception from an edematous duodenal ulcer with an overlying blood clot mimicking a mass lesion acting as lead point has never been reported to our knowledge. PMID- 29619401 TI - Massive Gastrointestinal Hemorrhage Due to an Arterioenteric Fistula From a Hepatic Artery Pseudoaneurysm. AB - Hepatic artery pseudoaneurysms are a rare cause of upper gastrointestinal bleeding with a high mortality rate. We report a case of a 37-year-old woman who presented with massive gastrointestinal hemorrhage and was found to have an arterioenteric fistula from a hepatic artery pseudoaneurysm. Esophagogastroduodenoscopy revealed a 1.5-cm ulcer overlying a large mucosal bulge that compressed the lumen of the duodenal bulb. A vascular stent graft was placed successfully over the pseudoaneurysm neck. We report the first case of the unique intraluminal appearance of an enteric fistula related to a hepatic artery pseudoaneurysm. PMID- 29619402 TI - Rare Metastasis of Primary Pancreatic Adenocarcinoma to the Bladder. AB - Pancreatic cancer commonly metastasizes to the liver, lungs, stomach, bone, and bowel, but rarely does it spread to the bladder. We describe a case of a 66-year old woman with diabetes mellitus who presented with abnormal liver function laboratory tests, abdominal discomfort, unintentional weight loss, and no urinary symptoms. Abdominal CT revealed a pancreatic and bladder mass. Pathology of the bladder mass confirmed metastatic adenocarcinoma of pancreaticobiliary origin. To our knowledge, this is only the third case of metastatic pancreatic cancer spreading to the bladder since 1953. PMID- 29619403 TI - Fecal microbiota transplantation associated with 10 years of stability in a patient with SPMS. PMID- 29619404 TI - Associations of Smoking, Moderate Alcohol Use, and Function: A 20-Year Cohort Study of Older Women. AB - Objective: The objective of this study is to determine whether the health effects of smoking and moderate alcohol use persist with aging. Method: Smoking status, alcohol use, and measures of function and health were obtained from 9,704 women aged >=65 years at baseline and over 10- and 20-year follow-up periods. Adjusted multiple linear and logistic regression and Cox proportional hazard models estimated associations. Results: Current versus never smokers had worse walking speed, self-reported health, difficulty with instrumental activities of daily living (IADLs), and depression at 10 years and higher death rates at 10 and 20 years. Moderate versus never drinkers had better grip strength, walking speed, self-reported health, and less difficulty with IADLs and were less likely to live in nursing homes at 10 years and die at 10 and 20 years. Discussion: Among aging women over 20 years, smoking is associated with worse physical function, including death, while moderate alcohol use is associated with better outcomes. PMID- 29619406 TI - Unique Cytologic Features of Thyroiditis Caused by Immune Checkpoint Inhibitor Therapy for Malignant Melanoma. AB - Blockade of immune checkpoint molecules to reverse cancer-induced immune suppression can improve anti-tumor immune responses in cancer patients. Monoclonal antibodies targeting two such molecules, Programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte associated protein 4 (CTLA-4) have shown clinical benefit in the treatment of advanced malignancies, including metastatic melanoma. Adverse effects of these immune checkpoint inhibitors include immune related adverse events (irAE) and the inducing of new autoimmunity, of which one of the most common is autoimmune thyroiditis. Though thyroiditis is increasingly recognized, there are no reports of the pathological findings that occur in immunotherapy-induced thyroiditis. We present a case of immunotherapy-induced thyroiditis demonstrating its unique cytopathologic features. A 51-year-old woman with metastatic melanoma was found to have a suppressed TSH and elevated free thyroxine concentration 14 days after starting treatment with nivolumab (PD-1 antagonist) plus ipilimumab (CTLA-4 antagonist) therapy. A thyroid biopsy was performed based on ultrasound findings and cytopathology revealed unique features including abundant clusters of necrotic cells, lymphocytes and CD163-positive histiocytes. This case reports cytopathologic features found in immune checkpoint inhibitor related thyroiditis. These appear to be unique findings and may help inform future research regarding the pathophysiology and mechanisms of this condition. PMID- 29619405 TI - Effects of the modern food environment on striatal function, cognition and regulation of ingestive behavior. AB - Emerging evidence from human and animal studies suggest that consumption of palatable foods rich in fat and/or carbohydrates may produce deleterious influences on brain function independently of body weight or metabolic disease. Here we consider two mechanisms by which diet can impact striatal circuits to amplify food cue reactivity and impair inhibitory control. First, we review findings demonstrating that the energetic properties of foods regulate nucleus accumbens food cue reactivity, a demonstrated predictor of weight gain susceptibility, which is then sensitized by chronic consumption of an energy dense diet. Second, we consider evidence for diet-induced adaptations in dorsal striatal dopamine signaling that is associated with impaired inhibitory control and negative outcome learning. PMID- 29619407 TI - Theta Oscillations Organize Spiking Activity in Higher-Order Visual Thalamus during Sustained Attention. AB - Higher-order visual thalamus plays a fundamental but poorly understood role in attention-demanding tasks. To investigate how neuronal dynamics in higher-order visual thalamus are modulated by sustained attention, we performed multichannel electrophysiological recordings in the lateral posterior-pulvinar complex (LP/pulvinar) in the ferret (Mustela putorius furo). We recorded single unit activity and local field potential (LFP) during the performance of the five choice serial reaction time task (5-CSRTT), which is used in both humans and animals as an assay of sustained attention. We found that half of the units exhibited an increasing firing rate during the delay period before stimulus onset (attention-modulated units). In contrast, the non-attention-modulated units responded to the stimulus, but not during the delay period. Spike-field coherence (SFC) of only the attention-modulated neurons significantly increased from the start of the delay period until screen touch, predominantly in the theta frequency band. In addition, theta power and theta/gamma phase amplitude coupling (PAC) were elevated throughout the delay period. Our findings suggest that the theta oscillation plays a central role in orchestrating thalamic signaling during sustained attention. PMID- 29619408 TI - Common Sense in Choice: The Effect of Sensory Modality on Neural Value Representations. AB - Although it is well established that the ventromedial prefrontal cortex (vmPFC) represents value using a common currency across categories of rewards, it is unknown whether the vmPFC represents value irrespective of the sensory modality in which alternatives are presented. In the current study, male and female human subjects completed a decision-making task while their neural activity was recorded using functional magnetic resonance imaging. On each trial, subjects chose between a safe alternative and a lottery, which was presented visually or aurally. A univariate conjunction analysis revealed that the anterior portion of the vmPFC tracks subjective value (SV) irrespective of the sensory modality. Using a novel cross-modality multivariate classifier, we were able to decode auditory value based on visual trials and vice versa. In addition, we found that the visual and auditory sensory cortices, which were identified using functional localizers, are also sensitive to the value of stimuli, albeit in a modality specific manner. Whereas both primary and higher-order auditory cortices represented auditory SV (aSV), only a higher-order visual area represented visual SV (vSV). These findings expand our understanding of the common currency network of the brain and shed a new light on the interplay between sensory and value information processing. PMID- 29619409 TI - Electrophysiological experiments in microgravity: lessons learned and future challenges. AB - Advances in electrophysiological experiments have led to the discovery of mechanosensitive ion channels (MSCs) and the identification of the physiological function of specific MSCs. They are believed to play important roles in mechanosensitive pathways by allowing for cells to sense their mechanical environment. However, the physiological function of many MSCs has not been conclusively identified. Therefore, experiments have been developed that expose cells to various mechanical loads, such as shear flow, membrane indentation, osmotic challenges and hydrostatic pressure. In line with these experiments, mechanical unloading, as experienced in microgravity, represents an interesting alternative condition, since exposure to microgravity leads to a series of physiological adaption processes. As outlined in this review, electrophysiological experiments performed in microgravity have shown an influence of gravity on biological functions depending on ion channels at all hierarchical levels, from the cellular level to organs. In this context, calcium signaling represents an interesting cellular pathway, as it involves the direct action of calcium-permeable ion channels, and specific gravitatic cells have linked graviperception to this pathway. Multiple key proteins in the graviperception pathways have been identified. However, measurements on vertebrae cells have revealed controversial results. In conclusion, electrophysiological experiments in microgravity have shown that ion-channel-dependent physiological processes are altered in mechanically unloaded conditions. Future experiments may provide a better understanding of the underlying mechanisms. PMID- 29619411 TI - Gender disparities in the associations of behavioral factors, serious psychological distress and chronic diseases with type 2 diabetes screening among US adults. AB - Background: The increasing prevalence of undiagnosed and diagnosed type 2 diabetes (T2D) posed a major challenge for public health and thus screening for T2D becomes essentially important. The social-demographical factors associated with the use of T2D screening have been widely studied, however, little is known about the impact of behavioral factors, mental health and chronic diseases on prevalence of screening, especially by gender and age groups. Methods: We investigated the impact of behavioral factors, mental health and chronic diseases across gender and age groups on the usage rate of T2D screening. To analyze the likelihood of the use of T2D screening, we performed weighted binomial logistic regression analyses. Results: Obesity, physical activity and smoking increased the use of T2D screening for females more than for males, and alcohol use increased screenings only for females. Serious psychological distress (SPD) was found to have a positive association with the use of T2D screening for females rather than for males; whereas hypertension and diabetes increased the use of T2D screening for males more than for females. Physical activity was an effective predictor of screening for T2D in the groups of 45-64 years and 65 years or older. Former drinking was positively associated with T2D screening for people aged 65 or older, and smoking was found to increase the odds of screening for T2D for people aged less than 65. Conclusions: Behavioral factors, mental health, and chronic diseases were significantly associated with the use of T2D screening and further demonstrated that gender differences exist in the role of above factors. PMID- 29619410 TI - Sulforaphane Protects against Brain Diseases: Roles of Cytoprotective Enzymes. AB - Sulforaphane (SFN) is a kind of isothiocyanate derived from broccoli and other cruciferous vegetables. Because of its roles of antioxidant, anti-inflammatory, and anti-tumor through multiple targets and various mechanisms, SFN has drawn broad attention of the researchers. One of the most important target of SFN is nuclear factor erythroid 2 related factor 2 (Nrf2), wildly known for its ability to regulate the expression of a series of cytoprotective enzymes with antioxidative, prosurvival, and detoxification effects. Multiple researches have shown that SFN protects against central nervous system diseases through Nrf2pathway. In this article, we list SFN contents in common cruciferous vegetables, and summarize recent advances in the protective effects of SFN against acute brain injuries and neurodegenerative diseases through activating Nrf2 signaling pathway. PMID- 29619412 TI - Immunotoxicity testing using human primary leukocytes: An adjunct approach for the evaluation of human risk. AB - Historically, immunotoxicity testing for chemicals, pesticides and pharmaceuticals has relied heavily on animal models to identify effects on the immune system followed by extrapolation to humans. Substantial progress has been made in the past decade on understanding human immune cell regulation, adaptive and innate immune responses and its modulation. The human immune system is complex and there exists diversity within composition, localization, and activation of different immune cell types between individuals. The inherent variation in human populations owing to genetics and environment can have a significant influence on the response of the immune system to infectious agents, drugs, chemicals and other environmental factors. Several recent reports have highlighted that mouse models of sepsis and inflammation are poorly predictive of human disease physiology and pathology. Rodent and human immune cells differ in the expression of cell surface proteins and phenotypes expressed in disease models, which may significantly influence the mechanism of action of xenobiotics and susceptibility yielding a different profile of activity across animal species. In the light of these differences and recent trends toward precision medicine, personalized therapies and the 3Rs (reduce, replace and refine animal use) approaches, the importance of using 'all human' model systems cannot be overstated. Hence, this opinion piece aims to discuss new models used to assess the effects of environmental contaminants and immune modulators on the immune response in human cells, the advantages and challenges of using human primary cells in immunotoxicology research and the implication for the future of immunotoxicity testing. PMID- 29619413 TI - Mutational Analysis of Neuropeptide Y Reveals Unusual Thermal Stability Linked to Higher-Order Self-Association. AB - Neuropeptide Y (NPY) is a 36-residue peptide, abundant in the central and peripheral nervous system. The peptide interacts with membrane-bound receptors to control processes such as food intake, vasoconstriction, and memory retention. The N-terminal polyproline sequence of NPY folds back onto a C-terminal alpha helix to form a hairpin structure. The hairpin undergoes transient unfolding to allow the monomer to interact with its target membranes and receptors and to form reversible dimers in solution. Using computational, functional, and biophysical approaches, we characterized the role of two conserved tyrosines (Y20 and Y27) located within the hydrophobic core of the hairpin fold. Successive mutation of the tyrosines to more hydrophobic phenylalanines increased the thermal stability of NPY and reduced functional activity, consistent with computational studies predicting a more stable hairpin structure. However, mutant stability was high relative to wild-type: melting temperatures increased by approximately 20 degrees C for the single mutants (Y20F and Y27F) and by 30 degrees C for the double mutant (Y20F + Y27F). These findings suggested that the mutations were not just simply enhancing hairpin structure stability, but might also be driving self association to dimer. Using analytical ultracentrifugation, we determined that the mutations indeed increased self-association, but shifted the equilibrium toward hexamer-like species. Notably, these latter species were not unique to the NPY mutants, but were found to preexist at low levels in the wild-type population. Collectively, the findings indicate that NPY self-association is more complex than previously recognized and that the ensemble of NPY quaternary states is tunable by modulating hairpin hydrophobicity. PMID- 29619414 TI - Hilar cholangiocarcinoma associated with immunoglobulin G4-positive plasma cells and elevated serum immunoglobulin G4 levels. AB - Immunoglobulin G4 (IgG4)-related disease is a fibroinflammatory systemic disorder with multiorgan involvement. Proximal bile duct involvement results in IgG4 related sclerosing cholangitis, which is characterized by a lymphoplasmacytic infiltrate with abundant IgG4-positive plasma cells and fibrosis. Differentiating between cholangiocarcinoma and IgG4-sclerosing cholangitis can present a diagnostic dilemma. We describe an unusual presentation of a hepatic mass meeting multiple criteria for IgG4-sclerosing cholangitis but was ultimately found to be cholangiocarcinoma. Several published case reports describe patients with suspected cholangiocarcinoma who are later found to have IgG4-sclerosing cholangitis, but few reports have demonstrated the reverse. Distinguishing between cholangiocarcinoma and IgG4-sclerosing cholangitis is challenging, and a high clinical suspicion for cholangiocarcinoma must always be maintained. (Hepatology Communications 2018;2:349-353). PMID- 29619415 TI - Daclatasvir and sofosbuvir treatment of decompensated liver disease or post-liver transplant hepatitis C virus recurrence in patients with advanced liver disease/cirrhosis in a real-world cohort. AB - We report the findings of an early access program providing treatment for chronic hepatitis C virus infection (any genotype) with daclatasvir and sofosbuvir with/without ribavirin to patients with Child-Pugh class C cirrhosis or prior liver transplant recipients with recurrent hepatitis C virus infection and advanced fibrosis/cirrhosis. Patients had <12-month life expectancies per the local investigator. Patients received daclatasvir 60 mg and sofosbuvir 400 mg once daily, with/without ribavirin, for 24 weeks. Sustained virologic response (SVR) at posttreatment week 12 (SVR12) was measured. Assessments adhered to local standards. One patient (prior Child-Pugh class C who improved to class B) enrolled by exemption was included in the overall data but not the class C cohort efficacy/safety data. Of the 77 treated patients, including 62 liver transplant recipients (genotype 1, n = 43, 69%; genotype 3, n = 16, 26%) and 14 patients with Child-Pugh class C cirrhosis (genotype 1, n = 4, 29%; genotype 3, n = 10, 71%), 63 (82%) completed treatment. SVR12 rates by modified intention-to-treat analysis (excluding nonvirologic failures lost to follow-up and withdrawal [consent/no reason]) in the overall, liver transplant, and Child-Pugh class C cohorts were 84% (n = 64/76), 90% (n = 56/62), and 62% (n = 8/13), respectively. Rates increased to 96% (n = 64/67), 97% (n = 56/58), and 89% (n = 8/9), respectively, in patients with available virologic data (including early discontinuations); 22/23 patients with genotype 3 (96%) achieved SVR12. Single cases of virologic nonresponse and relapse (both in liver transplant recipients with genotype 1) and viral breakthrough (Child-Pugh class C; genotype 3) occurred. Six patients died, 10 had adverse events leading to discontinuation, and 30 experienced serious adverse events. Conclusion: Daclatasvir plus sofosbuvir, with/without ribavirin, provided high SVR12 rates and was generally well tolerated in patients with life-threatening disease and high unmet needs. (Hepatology Communications 2018;2:354-363). PMID- 29619416 TI - Early and late changes in natural killer cells in response to ledipasvir/sofosbuvir treatment. AB - Chronic hepatitis C virus (HCV) infection is characterized by dysregulated natural killer (NK) cell responses. NKs play a critical role in achieving sustained responses to interferon (IFN)-alpha-based therapy. Rapid sustained HCV RNA clearance is now achieved with direct-acting antivirals (DAAs). Studies of patients receiving first-wave DAAs suggest NK functional restoration. Here, we investigate the effect of mainstream DAA treatment on NKs. We collected a prospective cohort of male HCV genotype 1-infected patients treated with ledipasvir/sofosbuvir (n = 22). Peripheral blood was obtained at treatment start, week 2 (W2), W4, W8, and W12 of treatment and 12 weeks posttreatment. Flow cytometry was used to characterize NK responses to therapy. Mean baseline viral load was 1.75 million IU/mL. All subjects rapidly cleared virus and remained HCV RNA-negative posttreatment. No change was seen in total NK levels; however, the frequency of immature NKs (clusters of differentiation [CD]56bright) decreased by W2 and was maintained throughout the study. Phenotypic changes were evident by W2/W4, coincident with rapid viral clearance. At W2, T-cell immunoglobulin and mucin-domain containing-3 and CD161 were significantly increased, returning to pretreatment levels by W12. Some changes were not evident until late (W12 or posttreatment). Down-regulation of several activation markers, including NKp30 and tumor necrosis factor-related apoptosis-inducing ligand, was observed at W12 and sustained posttreatment. No difference was observed in IFN-gamma production or cytokine-mediated killing of NK-sensitive cell line K562 posttreatment compared to pretreatment. Conclusion: Our phenotype data suggest transient activation followed by dampening of NK cell activity to pretreatment levels. The NK response to ledipasvir/sofosbuvir is not universal in a homogeneous patient cohort. More studies are needed to elucidate the roles of NK cells in IFN-free regimens, which will have implications for protection from re-infection and fibrosis progression. (Hepatology Communications 2018;2:364-375). PMID- 29619417 TI - Nonalcoholic fatty liver disease contributes to subclinical atherosclerosis: A systematic review and meta-analysis. AB - Nonalcoholic fatty liver disease (NAFLD) is associated with an increased risk of atherosclerotic cardiovascular disease. In our meta-analysis, we aimed to assess the correlation of NAFLD and four surrogate markers of subclinical atherosclerosis. PubMed, Embase, and the Cochrane Library were searched up until April 2017. Original studies investigating the association between NAFLD and subclinical atherosclerosis were included. The outcome data were extracted and pooled for the effect estimate by using a random-effects model. We used the Newcastle-Ottawa Quality Assessment Scale to assess the quality of the included studies. Of the 434 initially retrieved studies, 26 studies involving a total of 85,395 participants (including 29,493 patients with NAFLD) were included in this meta-analysis. The Newcastle-Ottawa Quality Assessment Scale scores suggested the included studies were of high quality. The pooled effects estimate showed that subjects with NAFLD exhibited a significant independent association with subclinical atherosclerosis compared to the non-NAFLD group (odds ratio, 1.60; 95% confidence interval, 1.45-1.78). Subgroup analysis suggested that the presence of NAFLD yielded a remarkable higher risk of increased carotid artery intima-media thickness/plaques, arterial stiffness, coronary artery calcification, and endothelial dysfunction with odds ratios (95% confidence interval) of 1.74 (1.47-2.06), 1.56 (1.24-1.96), 1.40 (1.22-1.60), and 3.73 (0.99 14.09), respectively. Conclusion: Our meta-analysis revealed a close link between NAFLD and subclinical atherosclerosis in light of four different indices. Patients with NAFLD might benefit from screening and surveillance of early atherosclerosis, which would facilitate the prediction of potential cardiovascular disease burden, risk stratification, and appropriate intervention in the long term. (Hepatology Communications 2018;2:376-392). PMID- 29619418 TI - The Role of Intestinal C-type Regenerating Islet Derived-3 Lectins for Nonalcoholic Steatohepatitis. AB - C-type regenerating islet derived-3 (Reg3) lectins defend against pathogens and keep commensal bacteria at a distance. Deficiency of Reg3g and Reg3b facilitates alcohol-induced bacterial translocation and alcoholic liver disease. Intestinal Reg3g is down-regulated in animal models of diet-induced obesity, but the functional consequences for nonalcoholic steatohepatitis (NASH) are unknown. The aim of this study was to investigate the role of Reg3 lectins in NASH. NASH was induced by a Western-style fast-food diet in mice deficient for Reg3g or Reg3b and in transgenic mice overexpressing Reg3g in intestinal epithelial cells (Reg3gTg). Glucose tolerance was assessed after 18 weeks and insulin resistance after 19 weeks of feeding. After 20 weeks, mice were assessed for features of the metabolic syndrome. Obesity was not different in genetically modified mice compared with their respective wild-type littermates. Glucose intolerance, liver injury, hepatic inflammation, steatosis, fibrosis, and bacterial translocation to mesenteric lymph nodes and to the liver were not different in Reg3g-deficient mice compared with wild-type littermates. Plasma endotoxin levels were higher in Reg3g-deficient mice. Reg3b deficiency protected against glucose intolerance, but liver disease, bacterial translocation, and plasma endotoxin levels were similar to wild-type littermates. Absence of either REG3G or REG3B protein in the ileum was not compensated for by up-regulation of the respective other REG3 protein. Transgenic Reg3g mice also developed liver injury, steatosis, and fibrosis similar to their wild-type littermates. Conclusion: In contrast to alcoholic liver disease, loss of intestinal Reg3 lectins is not sufficient to aggravate diet-induced obesity and NASH. This supports a multi-hit pathogenesis in NASH. Only glucose metabolism is affected by Reg3b deficiency. (Hepatology Communications 2018;2:393-406). PMID- 29619419 TI - Tumor necrosis factor-alpha-mediated hepatocyte apoptosis stimulates fibrosis in the steatotic liver in mice. AB - Hepatocyte apoptosis has been implicated in the progression of nonalcoholic steatohepatitis. However, it is unclear whether the induction of tumor necrosis factor (TNF)-alpha-mediated hepatocyte apoptosis in the simple fatty liver triggers liver fibrosis. To address this question, high-fat diet-fed mice were repeatedly administered D-galactosamine, which increases the sensitivity of hepatocytes to TNF-alpha-mediated apoptosis. In mice treated with a high-fat diet plus D-galactosamine, hepatocyte apoptosis and liver fibrosis were induced, whereas both apoptosis and fibrosis were inhibited in these mice following gut sterilization with antimicrobials or knockout of TNF-alpha. Furthermore, liver fibrosis was diminished when hepatocyte apoptosis was inhibited by expressing a constitutively active inhibitor of nuclear factor kappaB kinase subunit beta. Thus, hepatocyte apoptosis induced by intestinal dysbiosis or TNF-alpha up regulation in the steatotic liver caused fibrosis. Organ fibrosis, including liver fibrosis, involves the interaction of cyclic adenosine monophosphate response element-binding protein-binding protein (CBP) and beta-catenin. Here, hepatocyte-specific CBP-knockout mice showed reduced liver fibrosis accompanied by hepatocyte apoptosis diminution; notably, liver fibrosis was also decreased in mice in which CBP was specifically knocked out in collagen-producing cells because the activation of these cells was now suppressed. Conclusion: TNF-alpha mediated hepatocyte apoptosis induced fibrosis in the steatotic liver, and inhibition of CBP/beta-catenin signaling attenuated the liver fibrosis due to the reduction of hepatocyte apoptosis and suppression of the activation of collagen producing cells. Thus, targeting CBP/beta-catenin may represent a new therapeutic strategy for treating fibrosis in nonalcoholic steatohepatitis. (Hepatology Communications 2018;2:407-420). PMID- 29619421 TI - Influence of spontaneous splenorenal shunts on clinical outcomes in decompensated cirrhosis and after liver transplantation. AB - Cirrhosis and portal hypertension can lead to the formation of a spontaneous splenorenal shunt (SSRS) that may divert portal blood flow to the systemic circulation and reduce hepatic perfusion. Our aims were to evaluate SSRSs as an independent prognostic marker for mortality in patients with decompensated cirrhosis and the influence of SSRSs on liver transplantation (LT) outcomes. We retrospectively analyzed adult patients with decompensated cirrhosis undergoing LT evaluation from January 2001 to February 2016 at a large U.S. center. All patients underwent liver cross-sectional imaging within 6 months of evaluation, and images were reviewed by two radiologists. Clinical variables were obtained by electronic health record review. The cohort was followed until death or receipt of LT, and the subset receiving LT was followed for death after LT or graft failure. Survival data were analyzed using multivariable competing risk and Cox proportional-hazards regression models. An SSRS was identified in 173 (23%) of 741 included patients. Patients with an SSRS more often had portal vein thrombosis and less often had ascites (P < 0.01). An SSRS was independently associated with a nonsignificant trend for reduced mortality (adjusted subhazard ratio, 0.81; Gray's test P = 0.08) but had no association with receipt of LT (adjusted subhazard ratio, 1.02; Gray's test P = 0.99). Post-LT outcomes did not differ according to SSRS for either death (hazard ratio, 0.85; log-rank P = 0.71) or graft failure (hazard ratio, 0.71; log-rank P = 0.43). Conclusion: Presence of an SSRS does not predict mortality in patients with decompensated cirrhosis or in LT recipients. (Hepatology Communications 2018;2:437-444). PMID- 29619420 TI - Changes in natural killer cells and exhausted memory regulatory T Cells with corticosteroid therapy in acute autoimmune hepatitis. AB - Autoimmune hepatitis (AIH) is an immune-mediated liver disease currently treated by immunosuppressive medications with significant side effects. Thus, novel mechanistic treatments are greatly needed. We performed prospective deep immunophenotyping of blood immune cells in patients with acute AIH before and after corticosteroid therapy. Blood samples from 26 patients with acute AIH (United Kingdom-AIH Consortium) were phenotyped by flow cytometry at baseline and 4 months after starting corticosteroids. Pretreatment liver tissues were stained for forkhead box P3-positive (FOXP3POS) regulatory T cells (Tregs), clusters of differentiation (CD)56POS natural killer (NK) cells, and chemokine (C-X-C motif) ligand 10. Chemokine secretion by cultured primary hepatocyte and biliary epithelial cells was measured by enzyme-linked immunosorbent assay. Functional coculture assays with stimulated NK cells and Tregs were performed. CD161 ligand, lectin-like transcript-1 expression by intrahepatic immune cells was demonstrated with flow cytometry. Frequencies of NKbright cells declined with therapy (P < 0.001) and correlated with levels of alanine aminotransferase (P = 0.023). The Treg:NKbright ratio was lower pretreatment, and Tregs had an activated memory phenotype with high levels of CD39, cytotoxic T lymphocyte antigen 4, and FOXP3 but also high programmed death ligand 1, indicating exhaustion. Coculture experiments suggested the Tregs could not efficiently suppress interferon-gamma secretion by NK cells. Both Tregs and NK cells had high expression of liver infiltration and T helper 17 plasticity-associated marker CD161 (P = 0.04). Pretreatment and CD161pos NK cells expressed high levels of perforin and granzyme B, consistent with an activated effector phenotype (P < 0.05). Lectin-like transcript 1, a ligand for CD161, is expressed on intrahepatic B cells, monocytes, and neutrophils. Conclusion: Activated effector NK cells, which correlate with biochemical measurements of hepatitis, and exhausted memory Tregs are increased in the blood of patients with treatment-naive AIH and decline with corticosteroid therapy. Inadequate regulation of NK cells by exhausted FOXP3pos Tregs may play a role in AIH pathogenesis and contribute to liver injury. (Hepatology Communications 2018;2:421-436). PMID- 29619422 TI - The molecular adsorbent recirculating system in posthepatectomy liver failure: Results from a prospective phase I study. AB - Posthepatectomy liver failure (PHLF) represents the single most important cause of postoperative mortality after major liver resection, yet no effective treatment option is available. Extracorporeal liver support devices might be helpful, but systematic studies are lacking. Accordingly, we aimed to assess the safety and feasibility of the Molecular Adsorbent Recirculating System (MARS) in patients with PHLF. Between December 2012 and May 2015, a total of 206 patients underwent major or extended hepatectomy, and 10 consecutive patients with PHLF (according to the Balzan 50:50 criteria) were enrolled into the study. MARS treatment was initiated on postoperative day 5-7, and five to seven consecutive treatment sessions were completed for each patient. In total, 59 MARS cycles were implemented, and MARS was initiated and completed without major complications in any patient. However, 1 patient developed an immense asymptomatic hyperbilirubinemia (without encephalopathy), 1 had repeated clotting problems in the MARS filter, and 2 patients experienced access problems with the central venous line. Otherwise, no adverse events were observed. In 9 patients, the bilirubin level and international normalized ratio decreased significantly (P < 0.05) during MARS treatment. The 60- and 90-day mortality was 0% and 10%, respectively. Among the 9 survivors, 4 still had liver dysfunction at 90 days postoperatively. Five patients were alive 1 year postoperatively without any signs of liver dysfunction or disease recurrence. Conclusion: The use of MARS in PHLF is feasible and safe and improves liver function in patients with PHLF. In the present study, 60- and 90-day mortality rates were unexpectedly low compared to a historical control group. The impact of MARS treatment on mortality in PHLF should be further evaluated in a randomized controlled clinical trial. (Hepatology Communications 2018;2:445-454). PMID- 29619423 TI - A single blood test adjusted for different liver fibrosis targets improves fibrosis staging and especially cirrhosis diagnosis. AB - Fibrosis blood tests are usually developed using significant fibrosis, which is a unique diagnostic target; however, these tests are employed for other diagnostic targets, such as cirrhosis. We aimed to improve fibrosis staging accuracy by simultaneously targeting biomarkers for several diagnostic targets. A total of 3,809 patients were included, comprising 1,012 individuals with chronic hepatitis C (CHC) into a derivation population and 2,797 individuals into validation populations of different etiologies (CHC, chronic hepatitis B, human immunodeficiency virus/CHC, nonalcoholic fatty liver disease, alcohol) using Metavir fibrosis stages as reference. FibroMeter biomarkers were targeted for different fibrosis-stage combinations into classical scores by logistic regression. Independent scores were combined into a single score reflecting Metavir stages by linear regression and called Multi-FibroMeter Version Second Generation (V2G). The primary objective was to combine the advantages of a test targeted for significant fibrosis (FibroMeterV2G) with those of a test targeted for cirrhosis (CirrhoMeterV2G). In the derivation CHC population, we first compared Multi-FibroMeterV2G to FibroMeterV2G and observed significant increases in the cirrhosis area under the receiver operating characteristic curve (AUROC), Obuchowski index (reflecting all fibrosis-stage AUROCs), and classification metric (six classes expressed as a correctly classified percentage) and a nonsignificant increase in significant fibrosis AUROC. Thereafter, we compared it to CirroMeterV2G and observed a nonsignificant increase in the cirrhosis AUROC. In all 3,809 patients, respective accuracies for Multi-FibroMeterV2G and FibroMeterV2G were the following: cirrhosis AUROC, 0.906 versus 0.878 (P < 0.001; versus CirroMeterV2G, 0.897, P = 0.014); Obuchowski index, 0.795 versus 0.791 (P = 0.059); classification, 86.0% versus 82.1% (P < 0.001); significant fibrosis AUROC, 0.833 versus 0.832 (P = 0.366). Multi-FibroMeterV2G had the highest correlation with the area of portoseptal fibrosis and the highest reproducibility over time. Correct classification rates of Multi-FibroMeter with hyaluronate (V2G, 86.0%) or without (V3G, 86.1%) did not differ (P = 0.938). Conclusion: Multitargeting biomarkers significantly improves fibrosis staging and especially cirrhosis diagnosis compared to classical single-targeted blood tests. (Hepatology Communications 2018;2:455-466). PMID- 29619424 TI - Liver stiffness measurement predicted liver-related events and all-cause mortality: A systematic review and nonlinear dose-response meta-analysis. AB - Numerous studies have investigated the prognosis value of the liver stiffness measurement (LSM) by transient elastography in assessing the risk of liver related events (LREs) and all-cause mortality in patients with chronic liver disease (CLD). However, the shape of the dose-response relationship between them remains unclear. We searched PubMed, Embase, the Cochrane Library, and reference lists of articles for studies published up to July 1, 2017, that assessed the LSM in predicting LREs and all-cause mortality among subjects with CLD. Fifty-four observational cohort studies with 35,249 participants were included. Summary relative risks (RRs) were calculated using a random-effects model, and a restricted cubic spline function was used to model the dose-response association. LREs and all-cause mortality were increased in subjects with a high LSM (LRE: RR, 7.90; 95% confidence interval [CI], 5.65, 11.05; I2 = 71.6%; all-cause mortality: RR, 4.15; 95% CI, 2.56, 6.72; I2 = 68.5%). For each unit increment of liver stiffness, the summary RR was 1.06 (95% CI, 1.06, 1.07; I2 = 74.6%) for LREs and 1.06 (95% CI, 1.04, 1.07; I2 = 55.7%) for all-cause mortality. A positive relationship with a nonlinear trend for LSM with LREs and all-cause mortality was examined by a dose-response meta-analysis (P < 0.001). When stratified by etiology, a nonlinear association was also found in patients infected with hepatitis C virus and those coinfected with hepatitis C virus and human immunodeficiency virus. In contrast, there was no evidence of departure from linearity among patients with hepatitis B virus infection (Pnonlinearity = 0.072). Conclusion: LSM is useful in screening LREs and all-cause mortality in patients with CLD. Further studies are warranted in assessing the application of LSM in monitoring the risk of LREs and all-cause mortality in clinical practice. (Hepatology Communications 2018;2:467-476). PMID- 29619425 TI - IN VITRO STUDIES ON HEME OXYGENASE-1 AND P24 ANTIGEN HIV-1 LEVEL AFTERHYPERBARIC OXYGEN TREATMENTOFHIV-1 INFECTED ON PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS). AB - Background: Heme oxygenase-1 (HO-1) is a protein secreted by immune cells as a part of immune response mechanism.HO-1 can be induced by variety agents that causingoxidative stress, such as exposure to 100% oxygenat2,4 ATA pressure.It plays a vital role in maintaining cellular homeostasis.This study was conducted to identify the effect of hyperbaric oxygen exposure in cultured ofPBMCthat infected by HIV-1. Material and Methods: Primary culture of PBMCs were isolated from 16 healthy volunteers and HIV-1 infected MT4 cell line by co-culture. The PBMCs were aliquoted into two wells as control group and treatment group. The 16 samples of HIV-1 infected PBMCwere exposed to oxygen at 2,4 ATA in animal hyperbaric chamber forthree times in 30 minutes periods with 5 minutes spacing period, that called 1 session.The Treatment done on 5 sessions within 5 days. 16 samples of HIV-1 infected PMBCs that have no hyperbaric treatment became control group.The supernatant were measured the HO-1 production by ELISA andmRNA expression of HO-1 by real time PCR and the number ofantigen p24 HIV-1by ELISA. Results: The result showed that there was no increasing of HO-1 at both mRNA level and protein level, there was a decreasing number of antigen p24 HIV-1 at the treatment group. In addition, hyperbaric exposure could not increase the expression of HO-1, more over the viral replication might be reduced by other mechanism. Conclusions: Hyperbaric oxygen could increases cellular adaptive response of PBMCs infected HIV-1 through increased expression of proteins that can inhibit HIV viralreplication. PMID- 29619426 TI - GENOTYPING OF HUMAN PAPPILOMAVIRUS IN CERVICAL PRECANCEROUS LESION AND SQUAMOUS CELL CARCINOMA AT DR. SOETOMO HOSPITAL, SURABAYA, INDONESIA. AB - Background: Cervical cancer caused by human papilloma virus (HPV), is the second most common cancer for women. This cancer is distributed worldwide, with ~80% of cases are found in the developing countries. In Indonesia, data of HPV genotypes are still limited and do not represent all regions of the country. Thus, here we report genotyping of HPV samples collected from the Dr. Soetomo Hospital Surabaya Indonesia patients, in 2013. Materials and Method: A cross sectional study was performed using 68 paraffin blocks of low-grade squamous intraepithelial lesion (LSIL), high-grade squamous intraepithelial lesion (HSIL), and squamous cell carcinoma (SCC) cervix. Result: This study showed that HPV genotypes found in LSIL samples are HPV 16, 18, 6/33 or 68/72. Furthermore, those in HSIL are HPV 16, 18, 52, 59, 67, 6/18, 6/45, 16/67, 26/61, or 52/67, while in SCC are HPV 16, 18, 45, 52, 56, 16/18 or 16/45. Single-genotype infection, i.e. by HPV 16, 18, 45, 52, 56, 59, or 67, was observed in 86.77% (59/68) of samples, whereas multiple-genotype infections, i.e. by HPV 6/18, 6/33, 6/45, 16/18, 16/45, 16/67, 26/61, 52/67, or 68/72, was found in 13.23% (9/68) of the samples. Conclutions: The mostly HPV genotype identified in this study is HPV 16 (62.68%), then followed by HPV 18 (20.9%), HPV 45 (5.97%), 52 (5.97%), and 67 (4.48%). HPV 16 and 18 have used as vaccine, and HPV 45 has cross reaction with HPV 18, then HPV 52 and 67 should be considered as the second-generation HPV vaccines. PMID- 29619427 TI - DETERMINATION OF ENVIRONMENTAL FACTORS AFFECTING DENGUE INCIDENCE IN SLEMAN DISTRICT, YOGYAKARTA, INDONESIA. AB - Background: Dengue is a disease related to the environment that spreads rapidly. Prevention movement is considered ineffective; therefore, a more efficient early warning system is required. It is required strongly correlated variables to as predictor in early warning system. This study aims to identify the environmental conditions associated with dengue. Materials and methods: This ecological study was conducted on five sub-districts selected based on the trend of the incidence. Data land cover and elevation obtained using GIS. Climate data were obtained from Meteorology and Climatology and Geophysics Agency of Yogyakarta. Results: There were 1.150 dengue cases from 2008-2013 obtained from District Health Office. The spatial pattern is clustered in all sub-districts (Z-score < -2.58). There is a positive correlation between land cover and dengue (p 0.000; r 0.284) and a negative correlation between elevation areas and dengue (p 0.000; r - 0.127). Multiple Regression Test shows the effect of humidity (p 0.000) and rainfall (p 0.002) with a contribution of 13.5% - 27.4% (r2 0.135 - 0.274), while temperature has no effect in all sub-districts (p > 0.05). There is no effect of climate parameters in sporadic dengue areas (p > 0.05). Conclusion: It is concluded that dengue in Sleman is clustered and associated with the environment parameter, even though it does not have close correlation. High elevated and small building area is consistent with the lower dengue cases. Humidity and rainfall affect dengue, but temperature does not affect dengue. PMID- 29619428 TI - ANTIVIRAL ACTIVITY OF Justicia gendarussa Burm.f. LEAVES AGAINST HIV-INFECTED MT 4 CELLS. AB - Backgrounds: Justicia gendarussa Burm.f. has been known to have anti-HIV activity. This study was conducted to evaluate the effect of incubation time on the antiviral activity of the J. gendarussa leaves extract on HIV-infected MT-4 cells in vitro. Molecular docking test was also conducted to determine the interaction of alkaloids and flavonoids on the J. gendarussa leaves against HIV-1 reverse transcriptase receptor. It is expected that this research will provide scientific information on the development of J. gendarussa leaves as an anti-HIV drug. Materials and Methods: In the activity test, the effect of incubation time on the antiviral activity of J. gendarussa leaves on HIV-infected MT-4 cells were evaluated. During the activity test, a parameter of cytolysis effect inhibition on MT-4 cell line was observed after 4 days and 6 days incubation period. The molecular docking test is performed by using Molegro Virtual Docker software to determine the interaction of alkaloid and flavonoid compounds of J. gendarussa leaves with HIV-1 reverse transcriptase receptor. Results: The incubation time influences the CC50 and EC50 value. Fractionated-70% ethanol extract of J. gendarussa leaves showed a higher anti-HIV activity with EC50 = 3.045 x 10-9 MUg/mL, SI = 6.309 x 1012 (4 days of incubation) and EC50 = 6.066 MUg/mL, SI = 58494.845 (6 days of incubation). From molecular docking test, it was found that flavonoid of J. gendarussa leaves could inhibit the activity of HIV reverse transcriptase enzyme. Conclusion: Fractionated-70% ethanol extract of J. gendarussa has potential as an anti-HIV. PMID- 29619429 TI - ACANTHAMOEBA SP.S-11 PHAGOCYTOTIC ACTIVITY ON MYCOBACTERIUM LEPRAE IN DIFFERENT NUTRIENT CONDITIONS. AB - Background: Mycobacterium leprae (M. leprae) is a pathogenic bacterium that causes leprosy. The presence of M. leprae in the environment is supported by microorganisms that act as the new host for M. leprae. Acanthamoeba's potential to be a host of M. leprae in the environment. Acanthamoeba sp. is Free Living Amoeba (FLA) that classified as holozoic, saprophytic, and saprozoic. The existence of nutrients in the environment influence Acanthamoeba ability to phagocytosis or pinocytosis. This study is aimed to determine Acanthamoeba sp.S 11 phagocytic activity to Mycobacterium leprae (M. leprae) which cultured in non nutrient media and riched-nutrient media. Materials and Methods: This research conducted by culturing Acanthamoeba sp.S-11 and M. leprae on different nutrient media conditions. M. leprae intracellular DNA were isolated and amplified by M. leprae specific primers through Real Time PCR (Q-PCR). Result: The results showed that Acanthamoeba co-cultured on non-nutrient media were more active to phagocyte M. leprae than on rich-nutrient media. Conclusion: The use of non-nutrient media is recommended to optimize Acanthamoeba sp. phagocytic activity to M. leprae. PMID- 29619430 TI - CD4+ AND CD8+ T-CELLS EXPRESSING INTERFERON GAMMA IN ACTIVE PULMONARY TUBERCULOSIS PATIENTS. AB - Background: Tuberculosis (TB) is a global health problem. Immune response through CD4+ and CD8+ T cells is needed to produce Interferon gamma (IFN-gamma), a cytokine eliminate Mycobacterium tuberculosis. We aimed to compare the cellular immune response based on the percentage of CD4+ and CD8+ T cells expressing interferon gamma in active pulmonary tuberculosis patients before and after 2 months of tuberculosis treatment. Methods: It is a longitudinal cohort study included 12 patients with new active pulmonary TB of the Pulmonary Hospital, Surabaya. The CD4+ and CD8+ T cells expressing interferon gamma was measured by flow cytometry method. Results: The mean CD4+ interferon gamma percentage of new active pulmonary TB before treatment was higher than 2 months after tuberculosis treatment (4.48% vs. 1.52%) and there was a significantly decreased (p = 0.025). The mean CD8+ interferon gamma percentage of new active pulmonary TB before treatment was higher than 2 months after tuberculosis treatment (3.56% vs. 2.89%) but not significantly decreased (p = 0.186). Conclusions: The mean CD4+ IFN-gamma percentage of new active pulmonary TB before treatment was higher than 2 months after treatment, suggesting that CD4+ T cells expressing IFN-gamma play a role in protection against pulmonary TB infection. PMID- 29619431 TI - THE ROLE OF PSYCHOLOGICAL WELL-BEING IN BOOSTING IMMUNE RESPONSE: AN OPTIMAL EFFORT FOR TACKLING INFECTION. AB - Background: Many attempts have been made to improve human body resistance towards infection. These attempts were exemplified by promotion of hygiene and the use of antiseptic ingredients, pharmaceutical compounds, and vaccines. To prove an aspect which intentionally less explored was attempt to boosting the host immune responses by creating a psychological balance, which was important aspect of psychological well-being. Material and Method: These article reviews searched and compiled using database Google Scholar, from 1995 to latest. Search keywords were: immune response, psychological well-being, psychological ill-being. Results: Based on literature our findings showed that psychological well-being was proven could increase human body immune response. The evidenced were by improvements of several indicators in saliva, blood and plasma. In other way, psychological ill-being was associated with decreased immune responses. Numerous studies compiled and discussed in review also suggested that improving immune response through psychological well-being could increase living comfort. Conclusion: The psychological well-being could improve the human body immune responses, enhance resistance towards diseases (including infectious diseases), and create a spiritually and physically more prosperous life. PMID- 29619432 TI - ANTIBACTERIAL ACTIVITY OF DRACONTOMELON DAO EXTRACTS ON METHICILLIN-RESISTANT S. AUREUS (MRSA) AND E. COLI MULTIPLE DRUG RESISTANCE (MDR). AB - Background: Staphylococcus aureus, methicillin-resistant and Escherichia coli, multidrug-resistant included in the list of antibiotic-resistant priority pathogens from WHO. As multidrug-resistant bacteria problem is increasing, it is necessary to probe new sources for identifying antimicrobial compounds. Medicinal plants represent a rich source of antimicrobial agents. One of the potential plants for further examined as antibacterial is Dracontomelon dao (Blanco) Merr. & Rolfe. The present study designed to find the antibacterial activity of D. dao stem bark extracts on Methicillin-resistant S. aureus (MRSA) and E. coli Multiple Drug Resistance (MDR), followed by determined secondary metabolites with antibacterial activity and determined the value of MIC (minimum inhibitory concentration) and MBC (minimum bactericidal concentration). Materials and Methods: D. dao stem bark extracted using 60% ethanol. Disc diffusion test methods used to find the antibacterial activity, following by microdilution methods to find the value of MIC and MBC. Secondary metabolites with antibacterial activity determined by bioautography using TLC (thin layer chromatography) methods. Results: D. dao stem bark extracts are sensitive to MSSA, MRSA and E.coli MDR bacteria. The inhibition zone is 16.0 mm in MSSA, 11.7 mm in MRSA and 10.7 mm in E. coli MDR. The entire MBC/MIC ratios for MSSA, MRSA and E.coli MDR is lower than 4. The ratio showed bactericidal effects of D. dao stem bark extracts. In TLC results, colorless bands found to be secondary metabolites with antibacterial activity. Conclusion: D. dao stem bark extracts are potential to develop as antibacterial agent especially against MRSA and E. coli MDR strain. PMID- 29619433 TI - INCREASED APOPTOSIS SKULL OF PUPS BORN TO TOXOPLASMA GONDII-INFECTED MICE ASSOCIATED WITH INCREASED EXPRESSION OF INTERFERON GAMMA, BUT NOT TUMOR NECROSIS FACTOR ALFA. AB - Bacground: Toxoplasma gondii is an intracellular obligate protozoan parasite that infects most warm-blooded animals including humans. It can cause congenital infection with clinical symptoms ranging from mild to severe including microcephaly. At the cellular level, infection T. gondii causes apoptosis in some tissues and it is induced by proinflammatory cytokines, such as IFN-gamma and TNF alpha. The purpose of this study is to determine the role of proinflammatory cytokines (TNF-alpha and IFN-gamma) to apoptosis skull of newborn from T. gondii infected mice. Materials and Methods: Twenty pregnant mice were divided into two groups. The first group was the control group which was not infected with T. gondii tachizoites. The second group was the infected mice, which was infected with T. gondii tachizoites on the day 11.5 of gestation. All mice were cared until delivery. Subsequenly, pups of the mice were sacrificed and their skullcap tissues were taken for histological preparation. The tissues were stained by TUNEL Assay and IHC. Observed variables were apoptotic index and the percentage of skull cell expressing TNF-alpha and IFN-gamma. Data were analyzed with t-test and regression. Results: Compared to the control group, the skull of the pups born to T. gondii-infected mice showed that the number of apoptotic index and percentage of expressing TNF-alpha and IFN-gamma cells were higher than the control group. There is no correlation between increasing expression of TNF-alpha and apoptosis skull of pups. However, an increasing expression of IFN-gamma affected the increased apoptosis of skull pups born to T.gondii-infected mice. Conclusion: Congenital toxoplasmosis in mice increased apoptotic index of skull and the apoptosis of skull associated with increasing expression of IFN-gamma, but not associated with increasing expression of TNF-alpha. PMID- 29619434 TI - ADDITION OF ANTI- Toxoplasma gondii MEMBRANE IMMUNOGLOBULIN Y TO REDUCE NECROTIC INDEX IN MICE'S LIVER. AB - Background: The study aimes to determine the effect of administering anti-T. gondii membrane IgY against liver damage (Necrotic index) and the effectiveness of the antibody's delivery time. Materials and Methods: This research was a laboratory experiment with five treatments and five replicantions. Each treatment used female mice (Mus musculus) as animal models. The treatment groups consisted of a P0 group (not infected), P1 group (infected), P2 group (anti- T. gondii membrane IgY given one day before infection), P3 group (anti-T. gondii membrane IgY given together with infection) and P4 group (anti-T. gondii membrane IgY given two days after the infection. A dose of anti- T. gondii membrane IgY as many as 75 ug/head and infectious dose of 10 tachyzoites/head were given. Four days after infection mice were sacrified and examined. Finally, necrotic index in histopathological liver using Hematoxylin Eosin. Results: The percentage of necrotic index liver showed that result treatment of P2 and P3 treatment that lower than another treatment. Conclusion: Thus, it can be concluded that administration of anti-T. gondii membrane IgY can reduce liver cell necrotic index and it was greatest when given before and simultaneously with infection. PMID- 29619435 TI - SEROPREVALENCE AND RISK FACTOR OF TOXOPLASMOSIS IN SCHIZOPHRENIA PATIENTS REFERRED TO GRHASIA PSYCHIATRIC HOSPITAL, YOGYAKARTA, INDONESIA. AB - Background: Toxoplasmosis is an infectious disease caused by protozoan parasite called Toxoplasma gondii. Toxoplasma gondii is an intracellular protozoan parasite belong to phylum Apicomplexa, is an obligate parasite in mammals. The active proliferating trophozoites or tachyzoites are usually seen in the acute stage of infection, while the resting bradyzoites formed tissue cysts are primary found in muscle and brain. Human infection occurs mainly by ingesting food or water contaminated with oocyst or eating an undercook meat containing tissue cyst. Human might be infected via blood transfusion, organ transplantation or transplacenta transmission. Schizophrenia is a complex neuropsychiatric disease of the central nervous system, which contributing to behavioral changes which may resulted in higher risk to T. gondii infection. The purpose of this study were to know difference of seroprevalence and risk factor of toxoplasmosis between schizophrenia group and control group. Materials and Methods: Serum sample were collected 94 among schizophrenia patient at Grhasia Hospital and 64 normal population (control group). Antibody IgG of T. gondii was measured using ELISA method (Enzym Link Immnusorbent Assay) and questionnaires were used to collect risk factor data among the respondent. Results: The seroprevalence antibody IgG of patient with schizophrenia (69.14%) higher than control group (65.625%), but not significantly different (p>0.05). There was an association between some of risk factor with seropositive of toxoplasmosis in both group. In schizophrenia group, risk factor that associated with toxoplasmosis are uncooked meat consumption, contact with uncooked meat and soil, handwashing habit, uncooked water consumption, and water source. In control group, risk factor that associated are having cattles/pet, undercook meat consumption, and water source. Conclusion: This finding have shown seroprevalence of schizophrenia group higher than non-schizophrenia group and risk factor which associated with toxoplasmosis was different between two groups. PMID- 29619436 TI - CONCOMITANT SEXUALLY TRANSMITTED DISEASES IN PATIENTS WITH DIAGNOSED HIV/AIDS: A RETROSPECTIVE STUDY. AB - Background: Human immunodeficiency virus (HIV) is a virus that causes Acquired Immunodeficiency Syndrome (AIDS) which weaken the human immune system and thus increasing the incidence of sexually transmitted infections (STIs) and vice versa. Materials and Methods: A retrospective study of STIs in HIV/AIDS patients in Unit Perawatan Intermediate Penyakit Infeksi (UPIPI) Dr. Soetomo General Hospital Surabaya was conducted from January 1st, 2013 to December 31st, 2014. We examined the number and type of STIs, age distribution, gender, occupation, number of CD4+, and antiretroviral treatment of patients with HIV/AIDS. The data were presented in a descriptive analysis. Results: The percentage of STIs patients was 4.2% (148 of 3.350) of all patients with HIV/AIDS in the UPIPI Outpatient Clinic of Dr. Soetomo General Hospital. Most patients were 25-44 years old (70.9%) including 54.7% were males, 8.0% were housewives, and 1.4% were students. The five highest prevalence of STIs were condylomata acuminate (43.9%), non-specific genital ulcers (11.5%), syphilis (10.7%), genital herpes (10.1%), and scabies (8.1%). The sexual predilections consisted of heterosexual (70.9%), homosexual (12.2%), bisexual (2.0%), and no data (14.9%). Patients with the number of CD4+ <200 mm3 was 52.0% and 79.1% of the patients received ARV therapy. Conclusion: STIs and HIV/AIDS were closely related. HIV/AIDS could increase the incidence of STIs and STIs could elevate HIV/AIDS. PMID- 29619437 TI - RISK FACTORS OF VULVOVAGINAL CANDIDIASIS IN DERMATO-VENEREOLOGY OUTPATIENTS CLINIC OF SOETOMO GENERAL HOSPITAL, SURABAYA, INDONESIA. AB - Background: Vulvovaginal Candidiasis (VVC) is one-third of vaginitis case. About 75% of women will have at least one episode of VVC. Complication of VVC can be unfavorable to impact the patient's quality of life. Knowing its risk factors can prevent someone suffering from pathological VVC and its sequelae. The purpose of this study was to identify risk factors of VVC. Materials and Methods: A descriptive retrospective study was conducted by total sampling to 213 medical records of VVC patients from 869 fluor albus patients in Sexually Transmitted Infection (STI) Division, Dermatology and Venereology Outpatient Clinic in Dr. Soetomo General Hospital, Surabaya, East-Java, Indonesia in 2011 to 2013. Results: In 2011, 69 cases (22.77%) from 303 fluor albus patients, in 2012 69 cases (22.69%) from 304 fluor albus patients, and in 2013 75 cases (28.63%) from 262 fluor albus patients. As many as 180 (84.50%) of the patients were sexually active age group, which was 15-44 years old. Mostly patients were married (69.48%). As many as 167 (78.40%) sexual partners were patient's husband. About 95 (44.13%) patients presented with recurrent VVC. Risk factors are previous STIs 74 (34.74%), vaginal douching (27.70%), pre-martial sexual intercourse (5.63%), other STIs (3.29%), diabetes mellitus (2.34%), gestation (1.88%), other fluor albus infections (0.94%), pantyliner (0.47%), and STIs in sexual partner (0,47%). Conclusion: Avoiding and/or managing risk factors is important to prevent VVC and its complications. PMID- 29619438 TI - COMPARISON OF ANTI BACTERIAL EFFICACY OF PHOTODYNAMIC THERAPY AND DOXYCYCLINE ON AGGREGATIBACTER ACTINOMYCETEMCOMITANS. AB - Background: Aggregatibacter actinomycetemcomitans (A.actinomycetemcomitans) is an anaerobic bacterium has been frequently associated with aggressive periodontitis. Photodynamic therapy (PDT) is a medical treatment to prevent infection progression that utilizes light to activate a photosensitizing agent. Doxycycline is an antibacterial having photosensitivity. This study aimed to evaluate potential doxycycline as an antibacterial and photosensitizer combine PDT against A.actinomycetemcomitans bacteria. Material and methods: Samples were distributed to 4 groups as follow: (1) Groups A treated with a diode laser, (2) Group B treated with doxycycline 0,1% and laser, (3) Group C treated only with Doxycycline 0.1%, and (4) Group D no exposure doxycycline/laser. Data were analyzed by one-way ANOVA and Tukey's HSD test at 5% significance level. Results: In this study, doxycycline 0.1% has the effect of reducing the bacterial viability of (59.60+/-3.26%). Whereas laser exposure 120 s combined with doxycycline produce the effect of bacterial viability reduction (88.50+/-2.83%) is not significantly different from the effect of laser 120 s exposure (88.79+/ 2.60%). In clinical treatment, the application of laser exposure is generally at the duration of the exposure time of 30 s. The results of this study indicate that the duration of laser exposure 30 s shows a reduction in bacterial viability (44.91+/-1.69%) equal to the laser and with a combination of doxycycline and laser exposure (70.70+/-2.43%). So at low doses of laser exposure, doxycycline 0.1% combined with the laser results in the greatest reduction in bacterial viability, significantly different from laser exposure alone. Conclusion: at low doses of laser exposure (30s with energy 3.68 J/cm2), doxycycline 0.1% combined with the laser results in the greatest reduction in bacterial viability, significantly different with laser exposure alone. PMID- 29619439 TI - EVALUATION OF THE ANTIGENICITY AND IMMUNOGENICITY OF Eimeria tenella BY REPRODUCTIVE INDEX AND HISTOPATHOLOGICAL CHANGES OF CECAL COCCIDIOSIS VIRULENT LIVE VACCINE IN BROILER CHICKENS. AB - Background: The development of vaccine to control coccidiosis caused by Eimeria tenella (E. tenella) in chickens is intensifying because of the increasing threat of drug resistance to anticoccidial agents. It is important, therefore, to develop a reliable standard method for the assessment of vaccine afficacy particularly antigenicity and immunogenicity become crucial. Evaluation of E. tenella antigenicity and immunogenicity to some low doses can be reflected by reproductive index and histopathological changes. Materials and Methods: The complete random design of research was used in this study. Sixty of two weeks old broilers were divided into four groups and each group composed 15 replications. The group 1 was chicken group without virulent E. tenella oocyst inoculation. The group 2, 3 and group 4 were chicken group inoculated with virulent E. tenella oocyst at doses of 1.0 x 102, 2.0 x 102, 3.0 x 102, respectively. Then all chicken groups were challenged with E. tenella oocyst at doses of 1.0 x 103. Observation of research that represented antigenicity and immunogenicity was clinical sign, reproductive index, histopathological changes. Results: On virulent E. tenella inoculation step, some clinical signs such as appetite, weakness, and diarrhea were very slight on all chicken groups. While on challenge test step, there were no clinical signs of all chicken groups except the group 1. For the reproductive index of virulent E. tenella inoculation step, there were no significantly differences in all chicken groups except the group 1. As reproductive index, the same result pattern was seen for histopathological changes. Conclusion: The low number virulent E. tenella had low reproductive index and few histopathological changes effect that represents a promising strategy to prevent cecal coccidiosis in chickens. PMID- 29619440 TI - DETERMINATION OF EFFECTIVE DOSE OF ANTIMALARIAL FROM CASSIA SPECTABILIS LEAF ETHANOL EXTRACT IN PLASMODIUM BERGHEI-INFECTED MICE. AB - Background: The preliminary study on antimalarial activity of the ethanol extract of Cassia spectabilis leaves against Plasmodium berghei has been carried out by in vivo experiment. It was demonstrated that ethanol extract of C. spectabilis leaves could inhibit growth of rodent malaria parasite P. berghei by 59.29 % (at a dose of 100 mg/kg bodyweight). However, further investigation is required to determine an effective dose of the administered extract for a higher inhibitory effect and increasing effectiveness of the extract. Material and Methods: To determine the effective dose of ethanol extract of C. spectabilis leaves, a "4 day suppressive test" of Peter was performed with some modifications. The extract was administered orally to P. berghei-infected mice in multiple doses (twice and thrice daily) and single dose (once daily) with dose ranging from 50 - 250 mg/kg body weight. Antimalarial activities were determined by analyzing suppression of parasitaemia of treated mice. Results: The results showed that oral administration of the ethanol extract of C. spectabilis leaves at dose of 150mg/kg bodyweight thrice daily possessed higher inhibition (62.42%) compared to those twice daily (52.58%) and once daily (46.25%). Conclusion: These results suggested that ethanol extract of C. spectabilis is promising candidate for development of antimalarial drugs. The effective dose of the ethanol extract is 150 mg/kg bodyweight with thrice administration daily. PMID- 29619441 TI - A NEW COPPER (II)-IMIDAZOLE DERIVATIVE EFFECTIVELY INHIBITS REPLICATION OF DENV-2 IN VERO CELL. AB - Background: Dengue is a kind of infectious disease that was distributed in the tropical and sub-tropical areas. To date, there is no clinically approved dengue vaccine or antiviral for humans, even though there have been great efforts towards this end. Therefore, finding the effective compound against dengue virus (DENV) replication is very important. Among the complex compounds, copper(II) imidazole derivatives are of interest because of their biological and medicinal benefits. Materials and Methods: In the present study, antiviral activity of [Cu(2,4,5-triphenylimidazole)2]n, was evaluated against different stages of dengue virus type 2 (DENV-2) replication in Vero cell using focus forming unit reduction assay and quantitative ELISA. Results: [Cu(2,4,5-triphenylimidazole)2]n inhibited DENV-2 replication in Vero cells with IC50 = 2.3 MUg/ml and SI= 19.42 when cells were treated 2 days after virus infection, whereas its CC50 for cytotoxicity to Vero cells was 44.174 MUg/ml. Conclusion: The compound has high anti-DENV2 activity, less toxicity, and a high possibility to be considered a drug candidate. PMID- 29619442 TI - COMPARISON OF MULTIPLEX SINGLE ROUND PCR AND MICROSCOPY IN DIAGNOSIS OF AMOEBIASIS. AB - Background: Amoebiasis, the cause of dysentery and extra-intestinal abscesses, now becomes second fatal parasitic disease in the world. As routine microscopic diagnosis cannot differentiate causative Entamoeba histolytica from non pathogenic E. dispar and E. moshkovskii, better diagnosis has to be searched. Materials and Methods: Multiplex single round PCR was tested and compared with results of microscopy of wet preparation on 30 samples of diarrheic stools and extra intestinal lesions from amoebiasis suspected patients. Results: Microscopy examination showed that 21 (70%) of the samples were positive for E. histolytica/E. dispar/E. moshkovskii complex and 18 (86%) of them contained hematophagous trophozoites. Multiplex single round PCR showed 12 positive results, from which seven were positive for E. histolytica, two were positive for E. moshkovskii, and three showed mixed of E. histolytica and E. moshkovskii. No samples were positive for E. dispar. High positive rate of microscopy might be related with highly suspected amoebiasis cases, while lower positive PCR might be caused by low parasite density and time-related trophozoite disintegration. Conclusion: The study showed that multiplex single-round PCR is a valuable diagnostic tool for species differentiation, but cannot replace microscopy in the diagnosis of amoebiasis because of its low sensitivity and impossibility to discriminate the form of E. histolytica and whether it is in the disease-causing stage, while microscopic examination is capable to demonstrate the presence of hematophagous trophozoites that indicates it is invasive and at the disease causing stage of E. histolytica. PMID- 29619443 TI - CLONING AND EXPRESSION OF MCE1A GENE FROM MYCOBACTERIUM TUBERCULOSIS BEIJING AND H37RV STRAIN FOR VACCINE CANDIDATE DEVELOPMENT. AB - Background: Tuberculosis remains the leading cause of death in the world, especially wherever poverty, malnutrition and poor housing prevail. Mycobacterium tuberculosis Beijing strain is the most common strain that causes tuberculosis in Indonesia. The wide spread of tuberculosis has been further aggravated by HIV AIDS and drug resistance. Unfortunately, Bacille Calmette-Guerin (BCG) as the current vaccine has different protection function and efficacy. According to function analysis, mce1A gene was predicted to have a role in host invasion and survival of Mycobacterium tuberculosis in human macrophages. Materials and Methods: We performed cloning and protein expression of Mce1A gene of Mycobacterium tuberculosis Beijing strain as local isolate and standard strain H37Rv as a comparison on the expression system Escherichia coli BL21(DE3). Mce1A gene from the strains were amplified by PCR and inserted into the vector pET28a. Each resulting recombinant plasmid was subsequently transformed into E. coli BL21(DE3) and Mce1A protein was expressed with IPTG induction. Results: E. coli BL21(DE3) was succesfully transformed with a recombinant plasmid that contains the Mce1A gene insert with correct orientation and reading frame. There was no mutation found in the amino acids sequence for B and T cell epitope. Mce1A expression in E. coli BL21(DE3) showed a protein band that was higher than expected. The protein was confirmed with Western blotting using anti-His detector. Conclusion: We assumed that Mce1A recombinant protein that has been expressed in E. coli BL21(DE3) is in their dimeric form or alternatively formed aggregates of different sizes. PMID- 29619444 TI - EFFECT OF VARYING INCUBATION PERIODS ON CYTOTOXICITY AND VIRUCIDAL ACTIVITIES OF Justicia gendarussa Burm.f. LEAF EXTRACT ON HIV-INFECTED MOLT-4 CELLS. AB - Backgrounds: Justicia gendarussa Burm.f. has an anti-HIV activity. This study was conducted to evaluate the effects of incubation periods on the cytotoxicity and virucidal activities of the J. gendarussa leaves extract on MOLT-4 cells. Materials and Methods: The cytotoxicity assay was evaluated by using the WST-1 test with incubation periods of 3 days and 5 days. The virucidal activity test was determined by measuring the inhibitory activities on the syncytium formation. Results: The cytotoxicity assay showed the value of CC50 on MOLT-4 cell culture with the test material of 70% ethanol extract of J. gendarussa leaves as much as 3928.620 ug /mL and 3176.581 ug /mL (incubation day 3 and day 5, respectively); fractionated-70% ethanol extract = 81782.428 ug /mL and 12175.870 ug/mL; and water extract = 16372.689 ug/mL and 2946.117 ug/mL. The test results of the virucidal activities (inhibit >= 90% the formation of syncytium) of 70% ethanol extract of J. gendarussa leaves is at a concentration 250 ug/mL, 500 ug/mL and 1000 ug/mL (3-day incubation) and 250 ug/mL (5-day incubation); and fractionated 70% ethanol extract at a concentration 250 ug /mL, 500 ug/mL and 1000 ug/mL (3 day incubation) and 1000 ug/mL (5-day incubation). Conclusion: 70% ethanol extract, fractionated-70% ethanol extract, and water extract of J. gendarussa leaves were relatively nontoxic toward MOLT-4 cells, and fractionated-70% ethanol extract had better potentials in virucidal activities. PMID- 29619445 TI - IN SILICO SCREENING AND BIOLOGICAL EVALUATION OF THE COMPOUNDS OF Justicia gendarussa LEAVES EXTRACT AS INTERFERON GAMMA INDUCER: A STUDY OF ANTI HUMAN IMMUNODEFICIENCY VIRUS (HIV) DEVELOPMENT. AB - Background: Justicia gendarussa Burm f. (Achanthaceae) has been known as traditional medicine in Indonesia. It contains of flavonoids and alkaloids. This study was conducted to evaluate the effect of J. gendarussa on the profile of IFN gamma on mice (Mus musculus). Molecular docking test was also conducted to determine the interaction of alkaloids and flavonoids on the J. gendarussa leaves against IFN-gamma receptor. It is expected that this research will provide scientific information on the development of J. gendarussa leaves as an anti-HIV drug. Materials and Methods: The molecular docking test was performed by using Molegro Virtual Docker software to predict the interaction of alkaloid and flavonoid compounds of J. gendarussa leaves with IFN-gamma receptor. In the in vivo test, the effects of 70% ethanol extract, fractionated 70% ethanol extract, and water extract of J. gendarussa leaves were evaluated on the profile of IFN gamma stimulation on mice (Mus musculus). The test was performed by administering the three gendarussa extracts into the nine groups of mice for 14 days. Results: Based on the molecular docking test, it was found that flavonoid of J. gendarussa leaves have lower effects on the IFN-gamma receptor than the alkaloids. From the in vivo test on mice, it was found that the fractionated 70% ethanol extract of J. gendarussa leaves did not induce the level of IFN-gamma. On the other hand, both 70% ethanol and water extract of J. gendarussa leaves induced the production of IFN-gamma. Conclusion: Fractionated 70% ethanol extract of J. gendarussa does not induce the production of IFN-gamma, so it can be developed as anti HIV drugs. PMID- 29619446 TI - ISOLATION AND IDENTIFICATION OF BRUCELLA SUIS IN PIGS AS ZOONOTIC DISEASE IN ENDEMIC AREAS OF EAST JAVA, INDONESIA. AB - Background: Brucellosis in pigs at East Java Indonesia has not only cause great economic losses due to a decrease in productivity of livestock but also are zoonotic. Infection on free brucelosis pigs were initially begun with the infected pigs both male and female, or the use of superior male pigs together. The elimination of the disease either on a group or population is considered as the most effective way to prevent the spread of the disease in pigs. Prevention efforts mainly addressed to vaccination, sanitary maintenace and government policy. The purpose of this study was to isolated and identified Brucella suis as the causative agent. Material and Methods: The survey area were the pig farm owned by breeder farmers in the area of East Java Indonesia, at Kediri, Malang, Blitar and Probolinggo district. Blood samples obtained were tested with RBT. Pigs are suspected of being infected with Brucella if the RBT was positive that characterized with agglutination in the test results. If RBT was positive, bacteriological examination will be performed, with samples of visceral foetus organ, ie liver, spleen, placenta and amniotic fluid. Isolation and identification of Brucella suis were used Brucella Broth and Brucella Agar, and if the bacteri growthwill be continued with biochemical test ie H2S, urease, citrate, catalase and oxidase test. The positive results of Brucella suis showed positive urease, catalase andoxidase, but negative for citrate and H2S. Results: RBT and bacteriolgical examination showed that 1 sample was positive Brucella suis, and 19 negative. The positive results showed positive urease, catalase and oxidase, but negative for citrate and H2S. Conclusion: Based on RBT test and bacteriological examination, there was 1 positive sample of brucellla suis, that is sample coming from Kediri district. PMID- 29619447 TI - Solvent-dependent structural dynamics of an azido-platinum complex revealed by linear and nonlinear infrared spectroscopy. AB - The vibrational and anisotropic relaxation dynamics and structural dynamics of a potential anticancer prodrug, trans,trans,trans-[Pt(N3)2(OH)2(py)2], were investigated using time-resolved infrared pump-probe spectroscopy and ultrafast two-dimensional infrared (2D IR) spectroscopy. Herein, two representative bio friendly solvents, H2O and DMSO, were used, in which the local structural and dynamical variations were monitored using the antisymmetric linear combination of the two N3 stretching vibrational modes as an infrared probe. It was found that the vibrational relaxation process of the N3 antisymmetric stretching (as) mode in H2O is two to three times faster than that in DMSO. The anisotropic relaxation process of the anticancer prodrug was observed to be hindered in DMSO; this indicated a tighter solvent environment around the sample molecule in this solvent. The vibrational frequency time correlation of the N3 antisymmetric stretching mode in H2O decays with a time constant of 1.94 ps, in agreement with the hydrogen bond formation and breaking times of water. In DMSO, the frequency time correlation of the N3 as mode decays on a much longer time scale; this further indicates its sensitivity to the out-layer DMSO structural dynamics, which are relatively static in the experimental time window. PMID- 29619448 TI - Magnetization switching through domain wall motion in Pt/Co/Cr racetracks with the assistance of the accompanying Joule heating effect. AB - Heavy metal/ferromagnetic layers with perpendicular magnetic anisotropy (PMA) have potential applications for high-density information storage in racetrack memories and nonvolatile magnetic random access memories. In these devices, deterministic magnetization switching has been achieved via electric current induced spin orbital torques (SOTs) with the assistance of a current directional external in-plane bias field, which causes technological obstacles for the real application of SOT based spintronic devices. Here, we report that reversible field-free magnetization switching could be achieved via current-driven domain wall motion (DWM) in Pt/Co/Cr micro-sized racetracks with PMA owing to the preformation of the homochiral Neel-type domain wall, in which an in-plane inherent Dzyaloshinskii-Moriya interaction field was generated acting as the external in-plane bias field to break the symmetry. A full magnetization switching can be realized in this device based on the enhanced SOTs from a dedicated design of Pt/Co/Cr structures with Pt and Cr showing opposite signs of spin Hall angles. Therefore, the generated spin currents are expected to work in concert to improve the SOTs. We also demonstrated that the simultaneously accompanying Joule heating effect also plays a key role in the field-free magnetization switching process, including the propagation field as well as the domain wall motion velocity. PMID- 29619449 TI - 3D nanofabrication inside rapid prototyped microfluidic channels showcased by wet spinning of single micrometre fibres. AB - Microfluidics is an established multidisciplinary research domain with widespread applications in the fields of medicine, biotechnology and engineering. Conventional production methods of microfluidic chips have been limited to planar structures, preventing the exploitation of truly three-dimensional architectures for applications such as multi-phase droplet preparation or wet-phase fibre spinning. Here the challenge of nanofabrication inside a microfluidic chip is tackled for the showcase of a spider-inspired spinneret. Multiphoton lithography, an additive manufacturing method, was used to produce free-form microfluidic masters, subsequently replicated by soft lithography. Into the resulting microfluidic device, a three-dimensional spider-inspired spinneret was directly fabricated in-chip via multiphoton lithography. Applying this unprecedented fabrication strategy, the to date smallest printed spinneret nozzle is produced. This spinneret resides tightly sealed, connecting it to the macroscopic world. Its functionality is demonstrated by wet-spinning of single-digit micron fibres through a polyacrylonitrile coagulation process induced by a water sheath layer. The methodology developed here demonstrates fabrication strategies to interface complex architectures into classical microfluidic platforms. Using multiphoton lithography for in-chip fabrication adopts a high spatial resolution technology for improving geometry and thus flow control inside microfluidic chips. The showcased fabrication methodology is generic and will be applicable to multiple challenges in fluid control and beyond. PMID- 29619450 TI - Colloidal silica assisted fabrication of N,O,S-tridoped porous carbon nanosheets with excellent oxygen reduction performance. AB - Herein, we demonstrate a new approach for the fabrication of N,O,S-tridoped porous carbon nanosheets with the assistance of colloidal silica. The carbon nanosheets with an optimal content of doped O (~11.6%) present excellent performance toward the oxygen reduction reaction (ORR), with an onset potential (1.02 V) and a half-wave potential (0.86 V) comparable to those (1.04 V, 0.84 V) of commercial Pt/C electrocatalysts. PMID- 29619451 TI - Theory for controlling individual self-propelled micro-swimmers by photon nudging II: confinement. AB - Photon nudging allows the manipulation and confinement of individual self propelled micro-swimmers in 2D and 3D environments using feedback controls. Presented in this second part of a two-part contribution are theoretical models that afford the characterization for the positioning distribution associated with active localization. A derivation for the optimal nudging speed and acceptance angle is given for minimal placement uncertainty. The analytical solutions allow for a discussion on the physical underpinning that underlies controllability and optimality. PMID- 29619452 TI - Microsensor systems for cell metabolism - from 2D culture to organ-on-chip. AB - Microsensor systems for cell metabolism are essential tools for investigation and standardization in cell culture. Electrochemical and optical read-out schemes dominate, which enable the marker-free, continuous, online recording of transient effects and deliver information beyond microscopy and end-point tests. There has been much progress in microfluidics and microsensors, but the translation of both into standard cell culture procedures is still limited. Within this critical review, we discuss different cell culture formats ranging from standard culture vessels to dedicated microfluidic platforms. Key aspects are the appropriate supply of cells, mass transport of metabolites to the sensors and generation of stimuli. Microfluidics enable the transition from static to dynamic conditions in culture and measurement. We illustrate the parameters oxygen (respiration), pH (acidification), glucose and lactate (energy metabolism) as well as short-lived reactive species (ROS/RNS) from the perspective of microsensor integration in 2D and 3D cell culture. We discuss different sensor principles and types, along with their limitations, microfabrication technologies and materials. The state-of-the art of microsensor platforms for cell culture is discussed with respect to sensor performance, the number of parameters and timescale of application. That includes the advances from 2D culture to the increasingly important 3D approaches, with specific requirements for organotypic microtissues, spheroids and solid matrix cultures. We conclude on the current progress, potential, benefits and limitations of cell culture monitoring systems from monolayer culture to organ-on chip systems. PMID- 29619453 TI - Effect of solar ultraviolet radiation exposure on serum 25(OH)D concentration: a pilot randomised controlled trial. AB - Sunlight generates vitamin D, but there are scant human data from randomised trials on which to base health policy advice about how much sun exposure is necessary to change 25(OH)D concentrations. The purpose of the study was to evaluate the feasibility of using solar ultraviolet (UV) radiation exposure to generate a change in 25(OH)D concentration in a randomised controlled trial (RCT). The intervention tested in this RCT was supervised exposure to one standard erythemal dose (SED; 100 J m-2) of solar UV radiation three days per week for three weeks with approximately 35% of the body surface area not covered by clothing. Thirty-six fair-skinned (skin type II and III) indoor workers from Brisbane, Australia were randomised into either the intervention group (n = 16) or the control group (n = 20); the latter did not receive any supervised sun exposure. We asked both groups to use sunscreen and to minimise time outdoors during the study period. We collected blood samples at baseline, once per week during the three week intervention period, and four weeks after the intervention finished. The cumulative UV radiation exposure over the intervention period measured using polysulphone badges was higher in the intervention group than in the control group (median 8 vs. 4 SEDs, p = 0.14). After three weeks, the mean serum 25(OH)D concentration increased from 60 to 65 nmol l-1 in the intervention group and from 55 to 57 nmol l-1 in the control group. After adjustment for baseline 25(OH)D, the mean change per week during the intervention phase was non significantly higher in the intervention than in the control group (0.7 vs. 0.3; p = 0.35). This difference was not sustained during the follow-up period. Large field trials are needed to inform policy about how much natural sun exposure is required to raise 25(OH)D concentrations. This pilot identified key issues that need to be considered in the design of such a trial. PMID- 29619454 TI - Unusual redox behaviour of the magnetite/hematite core-shell structures processed by the laser floating zone method. AB - Magnetite (Fe3O4) offers unique physical and chemical properties, being an important material for many industrial applications. Certain limitations on the application conditions are, however, imposed by the redox stability issue. Fine control of the iron oxidation states represents a challenge for materials engineering. The present work explores relevant redox processes in iron oxides, processed under highly non-equilibrium laser floating zone (LFZ) conditions under atmospheres with different oxygen activities. The as-grown fibres showed a structure composed of the Fe3O4 core and the Fe2O3 shell. This study uncovers unexpectedly lower hematite content and shell thickness for the fibres processed under more oxidizing conditions. Combined structural and microstructural studies, supported by the analysis of the existing literature data, strongly suggest that the redox processes during the LFZ process can be rather determined by kinetics of melt crystallization, nuclei formation and heat transfer than by the oxygen content in the gas phase. The proposed mechanisms are further confirmed by electrical and magnetic studies of the composite fibres. PMID- 29619455 TI - Recent advances in radical-based C-N bond formation via photo-/electrochemistry. AB - The employment of nitrogen sources with free N-H bonds for amination is considered to be most straightforward and desirable, especially when the C-N bonds are prepared from N-H bonds and non-functionalized carbon sources, such as C-H bonds and C-C double/triple bonds, since this obviates the needs for the pre installation of reactive groups in the starting materials and leads to a high atom and step economy. Recently, radical chemistry has been resuscitated owing to its great value in organic synthesis, and notable advances have been made in the direct use of N-H bonds for radical-based C-N bond formation with photo /electrotechniques. Apart from the well-studied N-radical species addition pathway, radical-mediated aminations also proceed through N-atom nucleophilic addition, C-/N-radical cross-coupling, and a hydrogen-atom transfer (HAT) process. This review highlights the recent advances in this area with emphasis on the related reaction mechanisms. PMID- 29619456 TI - Lithium adsorption and migration in group IV-VI compounds and GeS/graphene heterostructures: a comparative study. AB - By means of first-principles calculations, the adsorption and transport properties of lithium (Li) in orthorhombic group IV-VI compounds MX (M = Ge, Sn; X = S, Se) and GeS/graphene heterostructures have been systematically investigated. Strong interactions and distinct charge transfer between Li and compounds MX are observed. The Li diffusion barriers along the zigzag direction are found to be much lower than that along the armchair direction in monolayer and bulk MX, showing distinct anisotropic diffusion features. In particular, monolayer GeS has a lowest barrier of 0.173 eV (zigzag) among them and it will transit from a semiconductor to a metallic state after Li intercalation, indicating fast Li and electron transport properties. As a comparison, the addition of graphene in a GeS/graphene heterostructure could enhance its binding with Li, decrease the Li diffusion barrier and inhibit the volume expansion dramatically, suggesting a potential performance improvement. Our study not only reveals the directional transport properties of Li in MX, but also improves the understanding of the role of graphene in the MX/graphene heterostructure, and shows great potential application in the field of electrode materials. PMID- 29619457 TI - The influence of a hydrophobic carrier, reactant and product during H2O adsorption on Pd surface for the oxidative esterification of methacrolein to methyl methacrylate. AB - Taking the one-step oxidative esterification of methacrolein (MAL) to methyl methacrylate (MMA) as a model reaction and because H2O that was generated easily formed a film of water on the catalyst surface, which restricted the diffusion of the reactants to the active sites, the effects of the hydrophobic carrier styrene divinylbenzene (SDB) copolymer, the reactant CH3OH and the product MMA during the adsorption of H2O on a Pd surface were investigated. For a Pd/SDB catalyst, the interactions between the active component and the carrier were first calculated using Pd4 clusters. The results implied that Pd4 clusters were chemisorbed on the SDB carrier. By comparing the adsorption energy of H2O molecules on Pd4 clusters with or without SDB, it was found that the adsorption energy of the former was reduced by about 50%, indicating that the hydrophobic carrier SDB reduced the adsorption of H2O on Pd4 clusters. This was also confirmed by the results for the partial density of states, differences in charge density and comparative Mulliken charge analysis. The influences of the reactant CH3OH and the product MMA on the adsorption of H2O were investigated using the Pd(111) surface. The results of co adsorption simulations showed that some of the electrons on CH3OH molecules were transferred to H2O molecules that strengthened the electronic interaction between H2O molecules and the Pd surface and led to a change in the adsorption of isolated H2O molecules from physisorption to chemisorption. However, the product MMA when chemisorbed on the Pd surface had little effect on the adsorption of H2O molecules on the Pd(111) surface. PMID- 29619458 TI - Unravelling the influence of carbon dioxide on the adsorptive recovery of butanol from fermentation broth using ITQ-29 and ZIF-8. AB - The vapor phase adsorption of butanol from ABE fermentation at the head space of the fermenter is an interesting route for the efficient recovery of biobutanol. The presence of gases such as carbon dioxide that are produced during the fermentation process causes a stripping of valuable compounds from the aqueous into the vapor phase. This work studies the effect of the presence of carbon dioxide on the adsorption of butanol at a molecular level. With this aim in mind Monte Carlo simulations were employed to study the adsorption of mixtures containing carbon dioxide, butanol and ethanol. Molecular models for butanol and ethanol that reproduce experimental properties of the molecules such as polarity, vapor-liquid coexistence or liquid density have been developed. Pure component isotherms and heats of adsorption have been computed and compared to experimental data to check the accuracy of the interacting parameters. Adsorption of butanol/ethanol mixtures has been studied in absence and presence of CO2 on two representative materials, a pure silica LTA zeolite and a hydrophobic metal organic framework ZIF-8. To get a better understanding of the molecular mechanism that governs the adsorption of the targeted mixture in the selected materials, the distribution of the molecules inside the structures was analyzed. The combination of these features allows obtaining a deeper understanding of the process and to identify the role of carbon dioxide in the butanol purification process. PMID- 29619459 TI - High switchable dielectric phase transition originating from distortion in inorganic-organic hybrid materials (H2dabco-C2H5) [MIICl4] (M = Co, Zn). AB - Two phase transition materials (H2dabco-C2H5)[ZnCl4] and (H2dabco-C2H5)[CoCl4] were synthesized and characterized. Differential scanning calorimetry detected that the two compounds underwent reversible phase transitions at 245 K and 261 K, respectively. The temperature dependence of the dielectric measurements also confirmed the phase transition. Variable-temperature single-crystal X-ray diffraction suggested that the two compounds underwent the same phase transitions from the space group Pnma to P21/c but at different temperatures. Symmetry breaking occurred with an Aizu notation of mmmF2/m. The structural phase transitions of 1 and 2 were ascribed to the distortion of a [H2dabco-C2H5]2+ cation from inorganic-organic hybrid materials (H2dabco-C2H5)[MIICl4] (M = Zn, Co). The strong variations of dielectric anomaly made compounds 1 and 2 applicable for use in promising switchable dielectric materials. PMID- 29619460 TI - Is RuAs2 a candidate for high temperature thermoelectric applications? AB - The mineral inspired material RuAs2 shows promise as a thermoelectric material with its high stability and attractive band structure. In order to validate these expectations phase-pure polycrystalline ruthenium arsenide was synthesized and densified using Spark Plasma Sintering. RuAs2 is an n-type semiconductor with an indirect band gap 0.69 eV as estimated from temperature dependent resistivity data, while the band gap calculated with DFT is 0.64 eV. The thermal conductivity and electrical resistivity are both high with room temperature values of 16 W m-1 K-1 and 170 mOmega cm respectively, leading to modest thermoelectric properties for the intrinsic system. Band structure calculations suggest that chemical modification should preferably be done at the As site to improve the intrinsic properties. Synchrotron powder X-ray diffraction and Rietveld structural refinements show RuAs2 to be a stable line phase up to 1000 K in both in air and in vacuum, and both as a powder and as a dense pellet. No indication of preferential orientation or material gradients are observed. PMID- 29619461 TI - Can 2,2,2-trifluoroethanol be an efficient protein denaturant than methanol and ethanol under thermal stress? AB - Monohydric alcohols, such as methanol (MEH), ethanol (ETH) and 2,2,2 trifluoroethanol (TFE), have significant effects on biological processes including the protein folding-unfolding phenomenon. Among the several monohydric alcohols, TFE, a fluorine-substituted alcohol, is known to induce a helical structure in proteins. In this work, we report the heterogeneous unfolding phenomenon of a small protein Chymotrypsin Inhibitor 2 in various concentrations of methanol, ethanol and TFE solutions by performing atomistic molecular dynamics simulation studies. Our study reveals that the unfolding phenomenon of CI2 under thermal stress majorly depends on the concentration and the nature of the alcohol. The presence of alcohols in general has been noted to accelerate the unfolding process compared to pure water and TFE, among them all, has been found to speed up the unfolding time scale at low concentrations. The molecular contact frequency between protein and alcohol follows the trend, MEH < ETH < TFE at low concentrations, whereas the trend becomes MEH ~ ETH > TFE at more concentrated solutions. The differential water-mediated and self-clustering phenomena of alcohols, diverse protein-alcohol hydrogen bond strengths and the concentration dependent restricted inhomogeneous protein-water as well as protein-alcohol hydrogen bond dynamics suggest that TFE, a well known alpha-helix stabilizer, could be a good competitor among its class of denaturants. PMID- 29619462 TI - Spectrum of hydrodynamic volumes and sizes of macromolecules of linear polyelectrolytes versus their charge density in salt-free aqueous solutions. AB - Molecular characteristics of statistical copolymers based on hydrophilic poly(N methyl-N-vinylacetamide) have been monitored throughout the entire possible range of charge density from 1.5 to 39 mol%. Different trends in the dependence of intrinsic viscosity on the average charge density of polymer chains at minimal ionic strength were revealed. A new parameter, lqq/Abare, describing this behavior was proposed (lqq is the average distance between the neighboring charges along the chain, and Abare is the statistical segment length of a non charged homologue). For polyelectrolyte chains, this parameter allows the regions of charge density values where electrostatic long-range or short-range interactions dominate to be indicated. Two homologous series of copolymers were characterized by methods of molecular hydrodynamics under conditions of suppressed charge effects. Intrinsic viscosity in salt-free solutions characterizing an individual macromolecule was estimated by a method proposed earlier [Pavlov et al., Russ. J. Appl. Chem., 2006, 79, 1407-1412]. PMID- 29619463 TI - Constrained stoichiometric network analysis. AB - Stoichiometric network analysis (SNA) is a method for studying the stability of steady states of stoichiometric systems by decomposing the corresponding network into elementary subnetworks (also known as extreme currents) and identifying those that may cause loss of a network's stability via interplay of positive and negative feedback. Experimentally studied complex (bio)chemical reactions often display dynamical instabilities leading to oscillations or bistable switches. When modelling such systems, a frequently met case is that an assumed detailed mechanism in terms of power law kinetics is available, but some of the rate coefficients are unknown and obtaining them by traditional kinetic methods based on a least-square fit is cumbersome or unfeasible. We propose a method combining the SNA and experimental data at the point of instability, which provides an estimate of the unknown rate coefficients along with unknown steady state concentrations. The core of the method rests in using constrained linear optimization to find a combination of the elementary subnetworks such that the dominant instability-causing subnetwork is just counter-balanced by stabilizing effects of all other subnetworks to obtain the instability threshold, and at the same time, the experimentally available data (inflow constraints, measured steady state concentrations of some species, frequency of emerging oscillations, etc.) are exactly matched. We illustrate this approach by examining two classical chemical oscillators: the Brusselator chosen as the simplest model for illustration of our methods and the Belousov-Zhabotinsky reaction and its mechanism represented by the Oregonator model as a more advanced example. PMID- 29619465 TI - The effect of alkyl chain length on the structure and thermodynamics of protic aprotic ionic liquid mixtures: a molecular dynamics study. AB - Mixtures of alkylammonium based protic ionic liquids and alkylmethylimidazolium based aprotic ionic liquids were studied by means of molecular dynamics simulations. Close to ideal mixing is observed in most studied magnitudes; however, the effect of increasing alkyl chain length in each of the cations is markedly different, with longer protic cations showing larger deviations, especially with regards to mixing enthalpy, which exhibits a strong compound forming tendency. The compound forming nature of these protic ionic liquids is shown to induce sharp changes in their local environment upon mixing. PMID- 29619464 TI - On the molecular origin of the cooperative coil-to-globule transition of poly(N isopropylacrylamide) in water. AB - By means of atomistic molecular dynamics simulations we investigate the behaviour of poly(N-isopropylacrylamide), PNIPAM, in water at temperatures below and above the lower critical solution temperature (LCST), including the undercooled regime. The transition between water soluble and insoluble states at the LCST is described as a cooperative process involving an intramolecular coil-to-globule transition preceding the aggregation of chains and the polymer precipitation. In this work we investigate the molecular origin of such cooperativity and the evolution of the hydration pattern in the undercooled polymer solution. The solution behaviour of an atactic 30-mer at high dilution is studied in the temperature interval from 243 to 323 K with a favourable comparison to available experimental data. In the water soluble states of PNIPAM we detect a correlation between polymer segmental dynamics and diffusion motion of bound water, occurring with the same activation energy. Simulation results show that below the coil-to globule transition temperature PNIPAM is surrounded by a network of hydrogen bonded water molecules and that the cooperativity arises from the structuring of water clusters in proximity to hydrophobic groups. Differently, the perturbation of the hydrogen bond pattern involving water and amide groups occurs above the transition temperature. Altogether these findings reveal that even above the LCST PNIPAM remains largely hydrated and that the coil-to-globule transition is related with a significant rearrangement of the solvent in the proximity of the surface of the polymer. The comparison between the hydrogen bonding of water in the surrounding of PNIPAM isopropyl groups and in the bulk displays a decreased structuring of solvent at the hydrophobic polymer-water interface across the transition temperature, as expected because of the topological extension along the chain of such interface. No evidence of an upper critical solution temperature behaviour, postulated in theoretical and thermodynamics studies of PNIPAM aqueous solution, is observed in the low temperature domain. PMID- 29619466 TI - A theoretical perspective of the enhanced photocatalytic properties achieved by forming tetragonal ZnS/ZnSe hetero-bilayer. AB - An efficient and economical way to tune the properties of two-dimensional (2D) materials is by forming van der Waals (vdW) hetero-layered structures in order to achieve a better performance in energy-related applications. In this theoretical work, we employ first-principles calculations to investigate a novel tetragonal (t-)ZnS/ZnSe hetero-bilayer (BL), as well as bilayers of ZnS and ZnSe only. A significant quantum confinement effect has been observed for all bilayers by state-of-the-art computations based upon the quasiparticle G0W0 approach and the Bethe-Salpeter equation (BSE). Among them, both t-ZnSe and t-ZnS/ZnSe BLs have strong optical absorption in the solar spectrum, rendering them potentially good candidates for solar energy harvesting. Moreover, the t-ZnS/ZnSe BL demonstrates good electron-hole separation by allocation of photo-induced electrons and holes in different layers, making it potentially suitable for applications in photocatalytic systems. PMID- 29619467 TI - Formation of bimetallic metal-organic framework nanosheets and their derived porous nickel-cobalt sulfides for supercapacitors. AB - Metal-organic frameworks (MOFs) show great advantages as new kinds of active materials for energy storage. In this study, bimetallic metal-organic frameworks (Ni/Co-MOFs) with nanosheet-assembled flower-like structures were synthesized by etching Ni-MOF microspheres in a cobalt nitrate solution. It can be clearly observed that the amount of Co(NO3)2 and etching time play crucial roles in the formation of Ni/Co-MOF nanosheets. The Ni/Co-MOFs were used as electrode materials for supercapacitors and the optimized Ni/Co-MOF-5 exhibited the highest capacitances of 1220.2 F g-1 and 986.7 F g-1 at current densities of 1 A g-1 and 10 A g-1, respectively. Ni/Co-MOF-5 was further sulfurized, and the derived Ni-Co S electrode showed a higher specific capacitance of 1377.5 F g-1 at a current density of 1 A g-1 and a retention of 89.4% when the current density was increased to 10 A g-1, indicating superior rate capability. Furthermore, Ni/Co MOF-5 and Ni-Co-S showed excellent cycling stability, i.e. about 87.8% and 93.7% of initial capacitance can be still maintained after 3000 cycles of charge discharge. More interestingly, the Ni/Co-MOF-5//AC ASC shows an energy density of 30.9 W h kg-1 at a power density of 1132.8 W kg-1, and the Ni-Co-S//AC ASC displays a high energy density of 36.9 W h kg-1 at a power density of 1066.42 W kg-1. These results demonstrate that the as-synthesized bimetallic Ni/Co-MOF nanosheets and their derived nickel-cobalt sulfides have promising applications in electrochemical supercapacitors. PMID- 29619468 TI - Opto-acousto-fluidic microscopy for three-dimensional label-free detection of droplets and cells in microchannels. AB - This paper reports a novel method, opto-acousto-fluidic microscopy, for label free detection of droplets and cells in microfluidic networks. Leveraging the optoacoustic effect, the microscopic system possesses capabilities of visualizing flowing droplets, analyzing droplet contents, and detecting cell populations encapsulated in droplets via the sensing of acoustic waves induced by the intrinsic light-absorbance of matter. PMID- 29619469 TI - Electrically controlled mass transport into microfluidic droplets from nanodroplet carriers with application in controlled nanoparticle flow synthesis. AB - Microfluidic droplets have been applied extensively as reaction vessels in a wide variety of chemical and biological applications. Typically, once the droplets are formed in a flow channel, it is a challenge to add new chemicals to the droplets for subsequent reactions in applications involving multiple processing steps. Here, we present a novel and versatile method that employs a high strength alternating electrical field to tunably transfer chemicals into microfluidic droplets using nanodroplets as chemical carriers. We show that the use of both continuous and cyclic burst square wave signals enables extremely sensitive control over the total amount of chemical added and, equally importantly, the rate of addition of the chemical from the nanodroplet carriers to the microfluidic droplets. An a priori theoretical model was developed to model the mass transport process under the convection-controlled scenario and compared with experimental results. We demonstrate an application of this method in the controlled preparation of gold nanoparticles by reducing chloroauric acid pre loaded in microfluidic droplets with l-ascorbic acid supplied from miniemulsion nanodroplets. Under different field strengths, l-ascorbic acid is supplied in controllable quantities and addition rates, rendering the particle size and size distribution tunable. Finally, this method also enables multistep synthesis by the stepwise supply of miniemulsions containing different chemical species. We highlight this with a first report of a three-step Au-Pd core-shell nanoparticle synthesis under continuous flow conditions. PMID- 29619470 TI - A disposable on-chip microvalve and pump for programmable microfluidics. AB - In this work, a low-cost PDMS micro-pump and -valve have been designed and developed to control multiple reagents for enzyme-linked immunosorbent assay (ELISA) on a programmable lab-on-a-chip (LOC) platform. The micro pump and valves were precisely controlled by selectively pressurizing the PDMS channels and chamber to actuate the multiple reagents in a controlled manner. Selective pressurizing of the PDMS structures was initiated by a simple system that maneuvered a single roller bar operated by a programmed microprocessor. The performance of the micro-pump was fully characterized and a minimum fluid volume of 1 MUL was controlled. Also, the on-chip microvalves were programmed to flow the multiple reagents to automatically process the multi-step ELISA procedures. By applying the proposed platform, 19.40 pg ml-1 cardiac troponin T (cTnT) was successfully detected on the LOC device by using multiple programmed valves as multiple steps of the enzyme-linked sandwich immunoassay. As a result, the developed micro-pump and -valve, which were successfully applied to actuate a series of solutions in a controlled manner, can be widely applied to lab-on-a chip based bioassays. PMID- 29619471 TI - Pyrochlore Ce2Zr2O7 decorated over rGO: a photocatalyst that proves to be efficient towards the reduction of 4-nitrophenol and degradation of ciprofloxacin under visible light. AB - In the present study, a series of Ce2Zr2O7@rGO nanocomposites were synthesized using a simple solution combustion method followed by a photoreduction technique. The as-prepared samples were well characterised using various analytical techniques to determine the morphological, optical, structural, electrochemical and compositional properties. The presence of oxygen defects was observed from Raman and photoluminescence spectra. The photoreduction of GO to rGO was determined from Raman and Fourier-transform infrared (FTIR) spectroscopy results. The role of rGO proved to be quite significant for the enhanced photocatalytic activity of the nanocomposites. The synergistic communication between Ce2Zr2O7 and rGO accelerates the photoreduction of 4-nitrophenol along with the degradation of ciprofloxacin under visible light irradiation. Of the rGO nanocomposites, 3 wt% GO loaded Ce2Zr2O7 reduces 99% of 20 ppm of 4-nitrophenol to 4-aminophenol in 120 min and decomposes 10 ppm of ciprofloxacin by up to 89% in 60 min. The significant enhancement in the activity of the Ce2Zr2O7@rGO nanocomposite was ascribed to the effective charge separation of excitons through pi-conjugation of graphene at the interface, which is well supported by the impedance, photoluminescence and photocatalytic results. PMID- 29619472 TI - Temperature-modulated diastereoselective transformations of 2-vinylindoles to tetrahydrocarbazoles and tetrahydrocycloheptadiindoles. AB - Direct and expedient access to densely substituted tetrahydrocarbazoles and tetrahydrocycloheptadiindoles bearing multiple contiguous stereocentres has been achieved via a two-fold divergent diastereoselective (dr up to >99 : 1) transformation of 2-vinylindoles. The high-yielding conversions (yield up to 87%) that are amenable for a wide range of substituted 2-vinylindoles proceed through Lewis acid-catalyzed [4 + 2] and [4 + 3] cyclization-aromatization cascade reactions, respectively, involving a heretofore-unprecedented reversal of the polarity (umpolung) of 2-vinylindoles. The two synthetic routes are effortlessly transposable into each other by merely modulating the temperature to furnish the corresponding products in a selective and exclusive fashion. In addition, another novel synthetic route to tetrahydroindolocarbazoles has been developed that advances via a formal [4 + 2] cyclization of 4-vinylindoles involving sequential C3 Michael addition-dearomatization-aromatization cascade reactions. PMID- 29619473 TI - Nanotrumpets and circularly polarized luminescent nanotwists hierarchically self assembled from an achiral C3-symmetric ester. AB - An achiral C3-symmetric molecule was found to self-assemble into various hierarchical nanostructures such as nanotwists, nanotrumpets and nanobelts, in which the twisted fibers showed supramolecular chirality as well as circularly polarized luminescence although the compound is achiral. PMID- 29619474 TI - A phage display-based strategy for the de novo creation of disulfide-constrained and isomer-free bicyclic peptide affinity reagents. AB - Bicyclic peptides have been attractive scaffolds for developing high affinity reagents for biomacromolecules. Here we report a general phage-screening strategy for the development of bicyclic peptide ligands constrained with isomerically forbidden disulfide bridges without elaborate chemical modifications and recourses to genetic code reprogramming. PMID- 29619475 TI - Ball-free mechanochemistry: in situ real-time monitoring of pharmaceutical co crystal formation by resonant acoustic mixing. AB - Resonant acoustic mixing (RAM) is a new technology designed for intensive mixing of powders that offers the capability to process powders with minimal damage to particles. This feature is particularly important for mixing impact-sensitive materials such as explosives and propellants. While the RAM technique has been extensively employed for the mixing of powders and viscous polymers, comparatively little is known about its use for mechanosynthesis. We present here the first in situ study of RAM-induced co-crystallisation monitored using synchrotron X-ray powder diffraction. The phase profile of the reaction between nicotinamide and carbamazepine in the presence of a small amount of water was monitored at two different relative accelerations of the mixer. In marked contrast to ball-milling techniques, the lack of milling bodies in the RAM experiment does not hinder co-crystallisation of the two starting materials, which occurred readily and was independent of the frequency of oscillation. The reaction could be optimised by enhancing the number of reactive contacts through mixing and comminution. These observations provide new insight into the role of various experimental parameters in conventional mechanochemistry using liquid assisted grinding techniques. PMID- 29619476 TI - Colloidal synthesis of monolayer-thick formamidinium lead bromide perovskite nanosheets with a lateral size of micrometers. AB - This communication describes a facile hot-injection method for the synthesis of novel micrometer-size formamidinium lead bromide perovskite (FAPbBr3) nanosheets of monolayer thickness (around 2.4 nm). Due to the strong quantum confinement effect, the as-synthesized large-sized perovskite nanosheets displayed an unprecedented extremely blue-shifted first sharp excitonic absorption peak at 435 nm and an emission peak at 437 nm, as compared to that of bulk FAPbBr3 crystals at 551 nm. PMID- 29619477 TI - Effect of water/glycerol polymorphism on dynamic nuclear polarization. AB - A paramount feature of robust experimental methods is acquiring consistent data. However, in dynamic nuclear polarization (DNP), it has been observed that the DNP induced NMR signal enhancement of nominally the same sample can vary between different experimental sessions. We investigated the impact of various freezing conditions on the DNP results for a standard sample, a 50/40/10 by volume d8 glycerol/D2O/H2O solution of 40 mM 4-amino TEMPO, and found that annealing the samples 10 K above the glass transition temperature (Tg) causes significant changes to the DNP profiles and enhancements compared to that in rapidly frozen samples. When varying the glycerol composition to yield a solution of 60/30/10 d8 glycerol/D2O/H2O, the DNP performance became markedly more consistent, even for samples prepared under vastly different sample freezing methods, in stark contrast with that of the 50/40/10 solution. The EPR lineshapes, Tm, and glass transition temperature, Tg, were measured under the same sample and experimental conditions as used for the DNP experiments to support the conclusion that different freezing methods change the distribution of 4-amino TEMPO radials in the 50/40/10 solution due to the formation of different polymorphs of the glass, which is mitigated in the 60/30/10 solution and is consistent with the water/glycerol vitrification literature. PMID- 29619478 TI - Aggregation-induced emission and the working mechanism of 1-benzoyl and 1-benzyl pyrene derivatives. AB - Over the past decade, research studies on solid-state luminescent materials featuring aggregation-induced emission (AIE) have achieved great success. It has been proved that lots of planar ACQ (aggregation-caused quenching) chromophores can be converted to AIE luminogens (AIEgens) by combining with an AIE-active unit such as tetraphenylethene (TPE). In this work, we present a new method to create AIE luminogens just by introducing benzoyl or benzyl to a planar chromophore, pyrene. The generated 1-benzoyl and 1-benzyl pyrene derivatives exhibit weak emission when molecularly dissolved in good solvents but strong emission from pyrene dimers when aggregated in poor solvent or the solid state. Their crystal structure analysis and theoretical calculations are performed to depict the working mechanism of these new AIEgens. The results show that the structural rigidification of these 1-benzoyl pyrene derivatives is the major cause for their AIE effect. This new AIE system along with a clear working mechanism will contribute to the development of AIE-related functional materials and theories. PMID- 29619479 TI - An air-stable N-heterocyclic carbene iminoxyl borate radical zwitterion. AB - A remarkably stable radical zwitterion derived from N-heterocyclic carbene nitric oxide and B(C6F5)3 is reported. The presented radical was generated by steric and electronic protection of the nitric oxide moiety using B(C6F5)3, which secured its stability toward air and moisture. An analogous yet less stable radical derived from C(C6H5)3+ is also synthesized and characterized. PMID- 29619481 TI - Surface microstructure engenders unusual hydrophobicity in phyllosilicates. AB - We present a mechanism of intriguing polar hydrophobicity of a series of naturally formed minerals: their surface cavities can effectively trap water molecules, and the water trapping remarkably disrupts the hydrogen bond interaction among interfacial water and leads to considerable hydrophobicity. Diminishing water trapping by decreasing surface roughness can considerably enhance wettability, which illustrates that a Wenzel model is no longer valid for polar materials with atomic-scale roughness. PMID- 29619480 TI - Supramolecular glyco-poly-cyclodextrin functionalized thin-layer manganese dioxide for targeted stimulus-responsive bioimaging. AB - We have developed a supramoleuclar imaging probe based on thin-layer manganese dioxide functionalized with a fluorescent, multivalent glyco-poly-cycolodextrin for the targeted, stimulus-responsive bioimaging of cancer cells. PMID- 29619482 TI - A comprehensive review of the prevalence of beta globin gene variations and the co-inheritance of related gene variants in Saudi Arabians with beta-thalassemia. AB - Beta-thalassemia is a genetic disorder that is caused by variations in the beta hemoglobin (HBB) gene. Saudi Arabia is among the countries most affected bybeta thalassemia, and this is particularly problematic in the Eastern regions. This review article is an attempt to compile all the reported mutations to facilitate further national-level studies to prepare a Saudi repository of HBB gene variations. In Saudi Arabians, IVSI-5 (G greater than C) and Cd 39 (C greater than T) are the most prevalent HBB gene variations out of 42 variations. The coinheritance of HBB gene variations with ATRX, HBA1, HBA2, HBA12, AHSP, and KLF1 gene variations were observed to be common in the Saudi population. National surveys on the molecular nature of hemoglobinopathies should be set up through collaborations between research centers from various regions to create a well documented molecular data bank. This data bank can be used to develop a premarital screening program and lead to the best treatment and prevention strategies for beta-thalassemia. PMID- 29619483 TI - Pediatric brucellosis. An update review for the new millennium. AB - Brucellosis remains the most common bacterial zoonotic infection in many countries worldwide. Despite being long recognized and controllable, the disease still causes substantial morbidity, affecting especially the young population. The aim of this review is to provide insight to the epidemiology, etiology, clinical features, diagnosis, and management of childhood brucellosis. PMID- 29619484 TI - A simple technique to strengthen the initial and mid-term to long-term stability of the cup during total hip arthroplasty in developmental dysplasia of the hip. AB - OBJECTIVES: To assess the effects of a technique of cup blocking screws combined with impaction bone grafting during total hip arthroplasty (THA) for patients with developmental dysplasia of the hip (DDH). METHODS: From August 2011 to July 2015, 53 patients (59 hips) with DDH in our hospital were treated with THA using the technique of cup blocking screws combined with impaction particulate bone grafting. These patients were prospectively followed, and the clinical and imaging results were collected. RESULTS: Harris hip score (HHS) was raised from 41.24 before surgery to 91.49 at the latest follow-up (p less than 0.001). Length discrepancy (LLD) was reduced from 28.97 mm before surgery to 6.08 mm after surgery (p less than 0.001). No loosening of the cup was detected at the last follow-up. The differences were insignificant in cup inclination and rate of cup coverage among the 3 groups of Crowe type II, type III, and type IV DDH (p greater than 0.05). CONCLUSION: The technique of cup blocking screws combined with impaction particulate bone grafting is simple and reliable, and it not only simplifies the attainment of initial stability, but also strengthens the mid-term to long-term stability during THA in DDH. PMID- 29619485 TI - How often do children receive their vaccinations late, and why? AB - OBJECTIVES: To assess vaccination timeliness, risk factors associated with delays and the reasons for delayed vaccinations among children below the age of 3 years in Jeddah, Kingdom of Saudi Arabia. METHODS: This is a cross-sectional study conducted in Jeddah, Saudi Arabia during the period of May 2016 to August 2017. Data were obtained from parents of children under the age of 3 years using a structured questionnaire comprised of questions about sociodemographics, physical well-being of the child and the reasons that are used to justify delayed vaccinations. Vaccinations were considered delayed if they occurred more than 30 days after the time designated on the primary vaccination schedule. Logistic regression was used to assess the risk factors for vaccination delays. RESULTS: The study included 351 children. Delayed vaccinations were observed in 85/351 (24.2%) of the sample. Delays were noted to occur most frequently for Measles, Mumps, Rubella vaccine (MMR), seconddose of meningococcal conjugate quadrivalent vaccine (MCV4), second dose of oral polio vaccine (OPV) and fourth dose of pneumococcal conjugate vaccine (PCV) in 19/125 (15.2%) of the sample. Traveling at the time of vaccination was the most common delay reason and was reported in 31/142 (21.3%) of the sample. CONCLUSION: Adherence to vaccination is fairly common in this part of the country. However, vaccination delays are still present and should be addressed to improve health care. PMID- 29619486 TI - Assessment of the etiologies and renal outcomes of rapidly progressive glomerulonephritis in pediatric patients at King Abdulaziz University Hospital, Jeddah, Saudi Arabia. AB - OBJECTIVES: To investigate the etiologies and outcomes of rapidly progressive glomerulonephritis (RPGN) in pediatric patients at King Abdulaziz University Hospital (KAUH) in Jeddah, Saudi Arabia. METHODS: A retrospective study was conducted in 19 pediatric patients who were diagnosed with RPGN between 2006 and 2016 at the Department of Pediatric Medicine at KAUH. Associations between variables were evaluated using independent t-test, one-way analysis of variance (ANOVA) and Chi-squared tests. RESULTS: Majority of patients were male, (68.4%), with a mean+/-SD age at diagnosis of 8.52+/-3.15 years. The most common underlying etiologies were post-infectious glomerulonephritis (PIGN) (63.2%) and lupus nephritis (21.1%). Thirteen patients exhibited a good clinical prognosis (68.4%), with 6 exhibiting a poor prognosis (31.6%), 4 of whom progressed to end stage renal disease (ESRD), one experiencing a relapse and one developing chronic kidney disease. Post-infectious glomerulonephritis was associated with the best clinical outcome overall. Treatment was implemented early in most patients and continued for 3 months. Among the 19 patients, 2 died and one underwent hemodialysis. CONCLUSION: Post-infectious glomerulonephritis was the most common etiology of RPGN, with these patients achieving a good clinical prognosis overall. Early identification and treatment of RPGN is important to preserve renal function, which is a key factor for achieving a good prognosis. PMID- 29619487 TI - Etiology, ethics, and outcomes of chronic kidney disease in neonates. AB - OBJECTIVES: To report the epidemiology of chronic kidney disease (CKD) in neonates at a single tertiary center and the outcomes of renal replacement therapy (RRT) in these patients and discuss ethical considerations regarding RRT in this population. METHODS: In this retrospective study, we reviewed clinical data from all neonates with evidence of CKD who were followed up at King Abdulaziz University, Jeddah, Kingdom of Saudi Arabia between 2005 and 2015. Follow-up serum creatinine levels were recorded every 6 months. Results: A total of 181 neonates presented with CKD. Their mean age at the time of presentation was 11.1 days (95% confidence interval [CI]: 9.5-12.8) and the mean creatinine level was 106.5 umol/ (95% CI: 91.3-121.7). Congenital anomalies of the kidneys and urinary tract (CAKUT) were the underlying causes of CKD in 84.5% of the neonates. Mortality was high, particularly in the first 6 months (10%), and reached 16% by 4 years of follow-up. At the time of the last follow-up, 42 (41%) neonates had hypertension and 27 (26.5%) had significant proteinuria. Five patients received dialysis in the neonatal period and another 6 were commenced on dialysis later. CONCLUSION: Congenital anomalies of the kidneys and urinary tract is the most common etiology in neonates with CKD. Chronic kidney disease in neonates is associated with high morbidity and mortality rates. PMID- 29619488 TI - Long-term cognitive outcome of very low birth-weight Saudi preterm infants at the corrected age of 24-36 months. AB - OBJECTIVES: To assess infants' cognitive function at the corrected age of 24-36 months, and to identify factors associated with adverse outcome and examine the correlation between Bayley Infants Neurodevelopmental Screener (BINS) score and Gesell Schedule of Child Development (GSCD). Methods: This retrospective study was performed on Saudi very low birth-weight (VLBW) infants born in King Khalid University Hospital, Riyadh, Saudi Arabia between 1997 and 2014 by the use of BINS as screening test and GSCD as definitive test. Results: Of 561 enrolled infants, 367 (65.4%) continued to follow-up. Three-hundred and fifteen infants (85.6%) had a normal cognitive function. In addition to lower birth weight (beta = -0.003) (p less than 0.001), male gender (OR =3.9) (p=0.001)and cerebral palsy (OR =33.9) (p less than 0.001) were the strongest factors associated with poor cognitive outcome. Approximately 75.4% of infants with normal BINS score had normal cognitive function and 7.6% of total infants had sever cognitive impairment. Conclusion: The majority of VLBW infants in our center have normal cognitive function at the corrected age of 24-36 months. Male gender, lower birth weight, and cerebral palsy are major predictors of poor outcome. The BINS scores were correlated with GSCD as a valid predictor for future developmental outcome. PMID- 29619489 TI - Causes and management of urogenital fistulas. A retrospective cohort study from a tertiary referral center in Saudi Arabia. AB - OBJECTIVES: To reviewe the etiology and management of urogenital fistulas at a tertiary care referral center. METHODS: We retrospectively identified all patients with urogenital fistula referred to the King Fahad Medical City, Riyadh, Saudi Arabia, between January 2005 and July 2016 from electronic records. We collected data on age, parity, etiology and type of fistula, radiologic findings, management, and outcome. Results: Of the 32 patients with urogenital fistula identified, 17 (53.1%) had vesicovaginal fistula. The mean parity was 5.9 (0-15). Obstetric surgery was the most common etiology, accounting for 22 fistulas (68.8%). Twenty of these (90.9%) were complications of cesarean delivery, of which 16 (80%) were repeat cesarean delivery. Forty surgical repair procedures were performed: 20 (50%) via an abdominal approach, 11 (27.5%) via a vaginal approach, 7 (17.5) via a robotic approach, and 2 (5%) using cystoscopic fulguration. The primary surgical repair was successful in 23 patients (74%), the second repair in 5 (16.1%), and the third repair in one (3.1%). One fistula was cured after bladder catheterization, and 2 patients are awaiting their third repair. Conclusion: Unlike the etiology of urogenital fistulas in other countries, most fistulas referred to our unit followed repeat cesarean delivery: none were caused by obstructed labor, and only a few occurred after hysterectomy. Most patients were cured after the primary surgical repair. PMID- 29619490 TI - Nurses' perception and attitudes towards oral care practices for mechanically ventilated patients. AB - OBJECTIVES: To explore the perception and attitudes of intensive care unit (ICU) nurses towards oral care practice for mechanically ventilated (MV) patients. METHOD: A descriptive cross-sectional design was used in this study. A convenience sample of 96 ICU nurses completed a questionnaire on their perception and attitudes towards oral care. The study setting was 3 representative Jordanian hospitals in Al-Karak and the capital, Amman, over a 6-month period between February and September 2016. RESULTS: Ninety-six nurses participated in the study. The response rate was 76.8%. The results revealed that 65% only follow a specific oral care protocol. Nurses did not adhere to minimal standards. Although nurses' attitude towards oral care was strongly positive, 68% of them perceived it as an unpleasant task and 29% agreed that they had insufficient training; 78% agreed to learn more about the best way to perform oral care. Standard descriptive statistics were calculated for all baseline information (sociodemographic characteristics). Binary variables were expressed as proportions, and normally distributed continuous variables as means and standard deviations. CONCLUSION: The poor perception and attitudes of ICU nurses regarding oral care for MV patients require the urgent attention of clinical administrators. In-hospital training regarding oral care protocol could improve nurses' perception and attitudes. PMID- 29619491 TI - Diabetes and driving recommendations among healthcare providers in Saudi Arabia. A significant gap that requires action. AB - OBJECTIVES: To assess healthcare providers' knowledge and awareness of the recommendations for drivers with insulin-treated diabetes in Saudi Arabia. Methods: A cross-sectional study was conducted among healthcare providers working at 4 tertiary hospitals in Riyadh, Saudi Arabia between April 2016 and December 2016 using a self-administered questionnaire. Results: A total of 285 healthcare providers completed the survey (response rate 88.5%). Most (70.2%) were aware of the safe driving recommendations for patients with insulin-treated diabetes. However, the need to check blood glucose levels before driving was underestimated by almost one-third (30.2%). Only one-quarter (24.6%) identified the correct level of blood glucose level that is safe for a patient when driving, and 28.4% identified the recommended time for checking blood glucose before driving. Participants who were aware of the recommendations for safe driving had a significantly higher average knowledge score (68.8%) than those who were not aware (58.8%; p less than 0.001). There was a significant difference in the average knowledge score among medical specialties (p=0.002) and job levels (p less than 0.001). Conclusions: Most healthcare providers identified the importance of evaluating their patients for ability to drive safely, but we found some important areas of knowledge deficit. Professional intervention to improve healthcare providers' awareness and knowledge regarding diabetes and driving is the first step in improving detection and reporting high-risk drivers with diabetes to prevent future driving mishaps. PMID- 29619492 TI - Effects of Ramadan fasting on the symptoms of chronic heart failure. AB - OBJECTIVES: To investigate the effect of Ramadan fasting on the symptoms of chronic heart failure with a reduced ejection fraction (HFrEF). Globally, more than one billion Muslims fast during Ramadan. Data regarding the effect of fasting in heart failure patients with a reduced ejection fraction are limited. METHODS: We prospectively studied 249 outpatients with HFrEF who undertook Ramadan fasting at tertiary care cardiac center in Saudi Arabia in 2017. We obtained information regarding the clinical assessment, diagnosis, emergency department visits, and hospitalization during and in the month preceding Ramadan. RESULTS: We enrolled 249 patients, 227 (91%) undertook the fast for the entire month. During Ramadan, 209 (92%) patients remained hemodynamically stable, whereas 18 (8%) developed instability. The mean New York Heart Association (NYHA) functional class was significantly lower in the stable than in the unstable group (1.46+/-0.7 vs. 3.22+/-0.55, p less than 0.0001), although no intergroup differences were observed before Ramadan. Patients from the unstable vs. the stable group showed significantly less adherence to medications (67% vs. 94%, p less than 0.0001) and to diet (39% vs. 79%, p less than 0.0001), and a lower likelihood of demonstrating ischemic cardiomyopathy as an underlying etiology of HFrEF (33% vs. 57%, p=0.046). Dependent t-test analysis including all patients showed that the NYHA classification before Ramadan was significantly higher than during Ramadan (2.19+/-0.9 vs. 1.6+/-0.8, t-value 8.5, p less than 0.0001). CONCLUSION: In most patients with chronic HFrEF, Ramadan fasting is considered safe. Non-adherence to medication and diet are significantly associated with decompensated heart failure during Ramadan. PMID- 29619494 TI - A giant tonsillolith. AB - Tonsillar stones are the products of calcified accumulates of cellular debris and microorganisms, in the crypts of palatine tonsils. Tonsillar stones are common findings and the known cause of bad breath (halitosis). Development of large tonsillar stones, however, is rare with only a few cases reported in the literature. We present the case of a 45-year-old man with a history of recurrent sore throat and tonsillitis for a long period, and snoring with other unremarkable ears, nose and throat findings. A large-sized tonsillar stone detected in the left tonsil measured 3.1 * 2.3 cm. The patient underwent elective stone removal and tonsillectomy. PMID- 29619493 TI - Prevalence and determinants of physical activity in a mixed sample of psychiatric patients in Saudi Arabia. AB - OBJECTIVES: To estimate prevalence of physical activity and its associations with various psychiatric disorders and the use of psychotropic medications. METHODS: A cross-sectional observational study was carried out between July 2012 and June 2014. Patients were enrolled from a number of hospitals located in 5 regions of the Kingdom of Saudi Arabia. RESULTS: A total of 1185 patients were included in current analysis: 796 were outpatients, and 389 were inpatients. Out of 1,185 patients, 153 (12.9%) were physically active. Much higher rates of physical activity were reported among males than females (15.9% versus 9.6%, p less than 0.001). According to the univariate analysis, higher rates of physical activity were positively correlated with primary bipolar disorders, the use of antianxiety medications and, to a lesser extent, use of antipsychotic medications, but they were negatively correlated with primary anxiety disorders, use of antidepressant medications, and use of multiple psychotropic medications. The associations between physical activity and primary bipolar disorders (odds ratio [OR]=2.47, p=0.002), use of antianxiety medications (OR=3.58, p=0.003), and use of multiple psychotropic medications (OR=0.33, p less than 0.001) remained significant after adjusting for demographic and clinical characteristics. CONCLUSION: We report a variable but generally low prevalence of physical activity among a large, mixed sample of psychiatric patients in Saudi Arabia. These findings may highlight the importance of assessing physical activity status of psychiatric patients and the critical need for physical activity promotion programs among this group of disadvantaged patients. PMID- 29619496 TI - Barriers to special care patients with mental illness receiving oral healthcare. A cross sectional study in the Holy City of Makkah, Saudi Arabia. AB - OBJECTIVES: To assess barriers to patients with mental illness receiving oral healthcare in Makkah city, Saudi Arabia. Methods: This was a 3-month cross sectional study from the Department of Psychiatry at Al-Noor, Specialist Hospital in Makkah city, Saudi Arabia, between January 2017 and April 2017. A structured questionnaire with closed-ended questions was considered. A total of 161 psychiatric patients were recruited, made up of 81 male (50.3%) and 80 female (49.7%) participants. Simple descriptive statistics were used to define the characteristics of the study variables, through a form of counts and percentages. The chi-square test was also used to evaluate the distribution of the nominal variables. Results: Of the 161 psychiatric patients, 51 were aged 26-35 years old (31.7%). Most participants (n=73) had psychological development disorders (45.3%). Ninety-one (56.5%) were unemployed, and among them, 25 (15.5%) reported problems with access to oral health and dental care. Participants also suffered from dry mouth (64%) and dental anxiety (23%). Conclusions: This study suggested that dental anxiety is considered the major barrier to dental care, followed by the cost of dental treatments and accessibility. Most belonged to the group of psychological development disorder and reported having the most barriers to oral healthcare. PMID- 29619495 TI - Fournier's gangrene in an obese female in third trimester of pregnancy. AB - Fournier gangrene is a rapidly progressive necrotizing fasciitis of the perianal and genitourinary area. Although typically affects men, we present here a rare disease founding in a pregnant woman. An obese 36-year-old female patient in her third trimester of pregnancy presented with a history of perianal pain and swelling. She was subsequently diagnosed with Fournier gangrene and underwent emergency cesarean section with a surgical debridement. The key to successful outcomes in such a complicated presentation of Fournier gangrene includes a high index of suspicion, fluid resuscitation, rapid administration of broad-spectrum antibiotics, and an early interdisciplinary approach by multiple teams. This helps share decisions and balance the risk-benefit of the emergency caesarian section without delaying the surgical debridement. PMID- 29619498 TI - Impact of body mass index on high blood pressure among obese children in the western region of Saudi Arabia. AB - [No Abstract Available]. PMID- 29619497 TI - Laryngeal carcinoma in a father and son. Possible familial risk? AB - [No Abstract Available]. PMID- 29619499 TI - Wound infiltration with bupivacaine 0.5% with or without adrenaline does not decrease pain after thyroidectomy. A randomized controlled study. AB - [No Abstract Available]. PMID- 29619501 TI - Bendamustine plus rituximab for relapsed or refractory diffuse large B cell lymphoma: a multicenter retrospective analysis. AB - Bendamustine plus rituximab (BR) showed efficacy and safety in indolent lymphomas and mantle cell lymphoma. However, there were limited experiences of real-world practice of BR in diffuse large B cell lymphoma (DLBCL). In this study, we report the Korean experiences with BR in relapsed or refractory DLBCL who are not eligible for intensive chemotherapy and autologous stem cell transplantation. This is an observational, multicenter, retrospective analysis. Between December 2011 and December 2015, a total of 58 patients with relapsed or refractory DLBCL were treated with BR in 11 tertiary hospitals in Korea. Patients received an intravenous (IV) infusion of rituximab at a dose of 375 mg/m2 on day 1. On days 2 and 3, patients received an IV infusion of bendamustine at doses of 120 or 90 mg/m2. Median age was 69 (range 18-86), 74.1% had stage III or IV disease, and 67.2% showed high-intermediate or high International Prognostic Index scores at diagnosis. In an intention-to-treat analysis, 18 patients (31.0%) showed a complete response and 14 (24.1%) showed a partial response, resulting in an overall response rate of 55.1%. The median duration of the response was 3.7 months (range 1.0-47.2 months). The median progression-free survival was 3.9 months (95% confidence interval [CI], 2.4-5.4 months), and the median overall survival was 6.7 months (95% CI, 4.7-8.7 months). The most common grade 3/4 adverse event was neutropenia (n = 40; 68.9%). Febrile neutropenia was observed in 11 patients (18.9%). Grade 3/4 thrombocytopenia was observed in 34 patients (58.6%). Our study confirmed the high efficacy and acceptable toxicity profile of BR in relapsed or refractory DLBCL patients. However, we need to closely observe the higher tendency of grade 3/4 hematological toxicities in Korean patients. PMID- 29619500 TI - Early-stage osteonecrosis of the femoral head: where are we and where are we going in year 2018? AB - Osteonecrosis of the femoral head (ONFH) is a devastating condition affecting relatively young patients whereby the femoral head is necrotic, resulting in significant pain, articular surface collapse, and eventual osteoarthritis. This condition has been highly associated with chronic steroid use, alcoholism, and hip trauma, as well as other less common conditions. Without intervention, this condition has a high likelihood of progressing and developing into end-stage osteoarthritis. Unfortunately, ONFH is difficult to diagnose on plain radiographs in the early stages of the disease, and often requires more advanced imaging modalities such as MRI in order to fully assess for early degeneration. Providers, therefore, must have a high index of suspicion when a younger patient presents with hip pain and negative X-rays. Unfortunately, in patients whose femoral heads have already collapsed, joint-preserving procedures are not effective, and total hip arthroplasty remains the most reliable long-term treatment. Multiple treatments have been pursued to address osteonecrosis in patients whose femoral head have not yet collapsed, but the results of these treatments are mixed. The most promising of these interventions to date is core decompression with the use of concentrated bone marrow aspirate to improve the healing potential of the femoral head. Further studies including randomized clinical trials are necessary in order to assess the effectiveness of this therapy, the best possible source of cells and the best method of implantation in order to further improve results in those with pre-collapse ONFH. PMID- 29619503 TI - On Abandoning Hypothesis Testing in Environmental Standard Compliance Assessment. AB - We use basic characteristics of statistical significance test to argue the abandonment of hypothesis testing in environmental standard (or criterion) compliance assessment. The typical sample size used for environmental assessment is small, and the natural variation of many water quality constituent concentrations is high. These conditions lead to low statistical power of the hypothesis tests used in the assessment process. As a result, using hypothesis testing is often inefficient in detecting noncompliance. When a noncompliance is detected, it is frequently due to sampling or other types of error. We illustrate the problems using two examples, through which we argue that these problems cannot be resolved under the current practice of assessing compliance one water at a time. We recommend that the hypothesis testing framework be replaced by a statistical estimation approach, which can more effectively leverage information from assessments on similar waters using a probabilistic assessment approach. PMID- 29619502 TI - Safe zone for the posterior interosseous nerve with regard to the lateral and posterior approaches to the proximal radius. AB - PURPOSE: The posterior interosseous nerve (PIN) is at risk during the posterior and lateral approaches to the proximal radius. We aimed to define a safe zone for these approaches to avoid injury of the PIN and to evaluate their close and changing relationship to the nerve during forearm rotation. METHODS: The study collective consisted of 50 upper limbs. After performance of the lateral approach, the distance between the tip of the radial head and the PIN's exit point from the supinator (= distance 1) and the shortest interval between the nerve's exit to the radial margin of the ulna (= distance 2) were measured in maximum pronation and supination. Then, the dorsal approach was conducted and again distance 1 and the interval between the distal margin of the anconeus and the nerve's exit point (distance 2) were evaluated (pronation and supination). RESULTS: There were significantly shorter distances during supination in comparison to pronation. Regarding the lateral approach, distance 1 changed from a mean of 60.3 mm (supination) to 62.7 mm in pronation (p < 0.001). For the dorsal approach, distance 1 decreased significantly (p < 0.001) from 62.9 mm (pronation) to 60.2 mm (supination). CONCLUSION: Supination during the lateral and dorsal approaches to the proximal radius needs to be avoided to protect the PIN. Furthermore, the nerve appeared at an interval between 45 and 84.1 mm (lateral approach) and 47.5-93.8 mm (dorsal approach), respectively. Therefore, care must be taken at this height during extension of the approaches in a distal direction. PMID- 29619504 TI - Genetic diversity analysis of Leuconostoc mesenteroides from Korean vegetables and food products by multilocus sequence typing. AB - In the present study, 35 Leuconostoc mesenteroides strains isolated from vegetables and food products from South Korea were studied by multilocus sequence typing (MLST) of seven housekeeping genes (atpA, groEL, gyrB, pheS, pyrG, rpoA, and uvrC). The fragment sizes of the seven amplified housekeeping genes ranged in length from 366 to 1414 bp. Sequence analysis indicated 27 different sequence types (STs) with 25 of them being represented by a single strain indicating high genetic diversity, whereas the remaining 2 were characterized by five strains each. In total, 220 polymorphic nucleotide sites were detected among seven housekeeping genes. The phylogenetic analysis based on the STs of the seven loci indicated that the 35 strains belonged to two major groups, A (28 strains) and B (7 strains). Split decomposition analysis showed that intraspecies recombination played a role in generating diversity among strains. The minimum spanning tree showed that the evolution of the STs was not correlated with food source. This study signifies that the multilocus sequence typing is a valuable tool to access the genetic diversity among L. mesenteroides strains from South Korea and can be used further to monitor the evolutionary changes. PMID- 29619505 TI - Microbial and genomic characterization of Geobacillus thermodenitrificans OS27, a marine thermophile that degrades diverse raw seaweeds. AB - Seaweeds are a nonlignocellulosic biomass, but they are often abundant in unique polysaccharides that common microbes can hardly utilize; therefore, polysaccharide degradation is key for the full utilization of seaweed biomass. Here, we isolated 13 thermophiles from seaweed homogenates that had been incubated at high temperature. All of the isolates were Gram-positive and preferentially grew at 60-70 degrees C. Most formed endospores and were tolerant to seawater salinity. Despite different sources, all isolates were identical regarding 16S rRNA gene sequences and were categorized as Geobacillus thermodenitrificans. Their growth occurred on seaweed polysaccharides with different profiles but required amino acids and/or vitamins, implying that they existed as proliferative cells by utilizing nutrients on seaweed viscous surfaces. Among 13 isolates, strain OS27 was further characterized to show that it can utilize a diverse range of seaweed polysaccharides and hemicelluloses. Notably, strain OS27 degraded raw seaweeds while releasing soluble saccharides. The degradation seemed to depend on enzymes that were extracellularly produced in an inducible manner. The strain could be genetically modified to produce heterologous endoglucanase, providing a transformant that degrades more diverse seaweeds with higher efficiency. The draft sequences of the OS27 genome contained 3766 coding sequences, which included intact genes for 28 glycoside hydrolases and many hypothetical proteins unusual among G. thermodenitrificans. These results suggest that G. thermodenitrificans OS27 serves as a genetic resource for thermostable enzymes to degrade seaweeds and potentially as a microbial platform for high temperature seaweed biorefinery via genetic modification. PMID- 29619506 TI - Ultrasound for diagnosing radiographically occult scaphoid fracture. AB - OBJECTIVE: To systematically review the literature on the performance of ultrasound in diagnosing radiographically occult scaphoid fracture. METHODS: A systematic search was performed in the MEDLINE and Embase databases. Original studies investigating the performance of ultrasound in diagnosing radiographically occult scaphoid fracture in more than 10 patients were eligible for inclusion. Studies that included both radiographically apparent and occult scaphoid fractures (at initial radiography) were only included if independent data on radiographically occult fractures were reported. Methodological quality of the studies included was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. Accuracy data were extracted. Sensitivity and specificity were pooled with a bivariate random-effects model. RESULTS: The inclusion criteria were met by 7 studies; total sample size comprised 314 patients. All studies, except 1, included cortical disruption of the scaphoid in their diagnostic criteria. The sensitivity and specificity of ultrasound in diagnosing radiographically occult scaphoid fracture ranged from 77.8% to 100% and from 71.4% to 100% respectively, with pooled estimates of 85.6% (95% CI: 73.9%, 92.6%) and 83.3% % (95% CI: 72.0%, 90.6%) respectively. Exclusion of two studies with a high risk of bias in any QUADAS-2 domain did not affect the pooled results. CONCLUSION: Ultrasound can diagnose radiographically occult scaphoid fracture with a fairly high degree of accuracy. Because of its relatively low costs and fairly high sensitivity, ultrasound seems more cost-effective than empiric cast immobilization and may be used when CT and MRI are not readily available. PMID- 29619507 TI - Combination chemotherapy with paclitaxel and oxaliplatin as first-line treatment in patients with advanced gastric cancer. AB - PURPOSE: This study is a retrospective analysis evaluating the efficacy and toxicity of combination chemotherapy with Paclitaxel (PTX) and Oxaliplatin (OXA) as first-line treatment for patients with advanced gastric cancer (AGC). METHODS: One hundred and seven patients with locally advanced or metastatic gastric adenocarcinoma received intravenous infusions of PTX at 135 mg/m2 and OXA at 85 mg/m2 on day 1 every 14 days. RESULTS: Among 107 patients enrolled, 9 patients could not be evaluated for a response because of the absence of any measurable lesions. Assessment of the response of 98 patients was made. The overall objective response rate was 42.9% (95% CI 32.9-52.8%), with two complete responses and 40 partial responses. The disease control was 79.6% (95% CI 71.5 87.7%). With 29 months of the median time of follow-up, the median progression free survival was 5.8 months (95% CI 4.30-7.30 months) and the median overall survival was 11.5 months (95% CI 9.08-13.9 months). The 1-year survival rate was 48.0%. The most common grades 3 and 4 toxicities included neutropenia (32.7%), leucopenia (17.8%), fatigue (5.61%), and anemia (4.67%). Peripheral neuropathy occurred in 23.4% patients and grade 2 or higher peripheral neuropathy occurred in 12.1% of the patients. CONCLUSIONS: Combination chemotherapy with PTX and OXA offers a new, effective and safe regimen for patients with advanced gastric cancer. PMID- 29619508 TI - [Preanalytics and biobanking : Influence of preanalytical factors on tissue sample quality]. AB - Access to well-characterized human biosamples is one of the most important prerequisites for modern biomedical research. Biobanks play a decisive role here, as they provide corresponding biosamples for planned analyses. Many interfering factors influencing the quality of biosamples have to be taken into account. In addition to logistical, ethical, and data protection aspects, preanalytical variables in the context of sample acquisition, storage, and processing should be mentioned in particular. In this paper, therefore, the most important preanalytical influencing factors are presented systematically and an overview of current national and international activities for the standardized recording of these factors is provided with the goal of being able to better understand their influence on results and to minimize them in the near future. PMID- 29619509 TI - Interferon-alpha2b-induced STAT3 suppression in myeloid-derived suppressor cells in mycosis fungoides. PMID- 29619510 TI - Variation and repeatability of cutaneous water loss and skin resistance in relation to temperature and diel variation in the lizard Sceloporus consobrinus. AB - Variation in rates of water loss has been proposed to be an important mechanism in the survival of terrestrial organisms, as high rates of water loss in desiccating environments may lead to hydric stress and death. Vapor density deficit, the driving force for evaporative water loss, increases exponentially as temperature increases. Acute temperature changes may be the result of daily behavioral thermoregulation of ectotherms, which may influence the among individual variation rates of water loss. The goals of this study were to determine (1) how rates of cutaneous water loss (CWL) and skin resistance (Rs) are affected by acute temperature acclimation, (2) how rates of CWL and Rs vary throughout the day allowing behavioral thermoregulation and (3) the repeatability of CWL and Rs within and among sampling periods. We measured CWL and calculated skin resistance (Rs) of 30 male Sceloporus consobrinus lizards across three summers. We measured CWL on the dorsal and ventral surface of each lizard at 23 degrees C followed by measurements at 35 degrees C, and three separate times throughout the day. We found a significant increase in Rs and decrease in CWL at increased acclimation temperatures (35 degrees C), a significant difference in CWL and Rs throughout the day allowing behavioral thermoregulation, and support for the repeatability of CWL and Rs. Our results demonstrate variability in CWL and Rs in relation to temperature acclimation and thermoregulation, but mixed evidence for repeatability across treatments. Our results suggest other factors, such as peripheral blood flow, may be influencing the inter-individual variation in CWL and Rs. PMID- 29619511 TI - Results of Magnetic Sphincter Augmentation for Gastroesophageal Reflux Disease. AB - BACKGROUND: Magnetic sphincter augmentation (MSA) is a modern treatment option for gastroesophageal reflux disease (GERD); however, laparoscopic fundoplication remains the gold standard. The aim of the study was to evaluate outcomes of MSA patients at a reflux center. METHODS: A retrospective review was performed of all patients that underwent MSA between March 2012 and November 2017. Out of 110 patients, 68 with a follow-up >3 months were included. Postoperative gastrointestinal symptoms, proton pump inhibitor (PPI) intake, GERD-Health related Quality of Life (GERD-HRQL) and alimentary satisfaction (AS) were assessed. Postoperative esophageal functioning tests were performed in 50% of patients. RESULTS: Sixty-eight patients underwent MSA; hiatal repair was performed in 31 cases. The median OR time was 27 min, and no intraoperative complications occurred. The median follow-up was 13 months (IQR 4.2-45). Endoscopic dilatation was performed in 2 patients (3%) and device removal in another 2 cases. The postoperative GERD-HRQL score was significantly reduced (3 vs. 24; p < 0.001) and the median AS was 8/10. Preoperative experienced heartburn, regurgitations and dysphagia were eliminated in 92, 96 and 100%. Postoperative new-onset difficulties swallowing with solids only were reported to occur occasionally by 16% and rarely by 21% of patients. Satisfaction with heartburn relief was 95%, and the overall outcome was rated excellent/good in 89%. PPI dependency was eliminated in 87%. The median total percentage pH < 4 and number of reflux episodes were significantly reduced. Postoperative pH results were negative or slightly above the norm in 79% and 12%, respectively. CONCLUSION: Sphincter augmentation results in significantly reduced reflux symptoms, increased GERD-specific Quality of Life and excellent alimentary satisfaction with low perioperative morbidity. This procedure should be considered an excellent alternative to fundoplication in the treatment of GERD. PMID- 29619512 TI - A Nationwide Assessment of Pediatric Surgical Capacity in Mongolia. AB - BACKGROUND: Mongolia is a country characterized by its vast distances and extreme climate. An underdeveloped medical transport infrastructure makes patient transfer from outlying regions dangerous. Providing pediatric surgical care locally is crucial to improve the lives of children in the countryside. This is the first structured assessment of nationwide pediatric surgical capacity. METHODS: Operation rates were calculated using data from the Mongolian Center for Health Development and population data from the Mongolian Statistical Information Service. The Pediatric Personnel, Infrastructure, Procedures, Equipment, and Supplies (PediPIPES) survey tool was used to collect data at all survey sites. Descriptive data analyses were completed using Excel. Studies of association were completed using Stata. All reported percentages are of the hospitals outside of the capital (n = 21). RESULTS: All provincial hospitals have general surgeons; seven (33.3%) of them have pediatric surgeon(s). One facility has no anesthesiologist. All facilities perform basic procedures and provide anesthesia. Four (19%) can treat common congenital anomalies. All facilities have basic operating room equipment. Nine hospitals do not have pulse oximetry available. Twelve hospitals do not have pediatric surgical instruments always available. Pediatric supplies are lacking. CONCLUSIONS: Provincial hospitals in Mongolia can perform basic procedures. However, essential pediatric supplies are lacking. Consequently, certain life-saving procedures are not available to children outside of the capital. Only a few improvements would be amendable to low-cost process improvement adjustment, and the majority of needs require resource additions. Procedure, equipment, and supply availability should be further explored to develop a comprehensive nationwide pediatric surgical program. PMID- 29619513 TI - Letter to the Editor: Risk Factors for Mortality and Morbidity in Elderly Patients Presenting with Digestive Surgical Emergencies. PMID- 29619514 TI - Surgical Indication for Advanced Intrahepatic Cholangiocarcinoma According to the Optimal Preoperative Carbohydrate Antigen 19-9 Cutoff Value. AB - BACKGROUND: The indication of surgery in intrahepatic cholangiocarcinoma (ICC) patients with lymph node metastasis (LNM), macroscopic periductal infiltration (PI), and intrahepatic metastasis (IM) remains unclear. METHODS: Patients who underwent resection for mass-forming (MF) dominant ICC and unresected patients caused by LNM, IM, or locally advanced tumors (UR group) were enrolled. The significance of CA19-9 was investigated in advanced ICC. RESULTS: Seventy-three patients who underwent resection and 20 UR patients were analyzed. Using the minimum p value approach based on the overall survival, the optimal CA19-9 cutoff value was 300 U/mL. The OS of the patients with CA19-9 < 37 U/mL (n = 26; MST, 49.6 months) and 37-300 U/mL (n = 28; MST, 45.1 months) was comparable (P = 0.842); however, the OS of the patients with CA19-9 = 37-300 U/mL was significantly better than that with CA19-9 >= 300 U/mL (n = 19; MST, 15.3 months; P < 0.001). CA19-9 > 300 U/mL, MF + PI, and IM were independently associated with OS. The OS of the patients with CA19-9 < 300 U/mL who developed LNM (MST, 34.0 months), MF + PI (MST, 32.9 months), or IM (MST, 35.2 months), or who required major vascular resection (MST, 45.1 months) was better than those with CA19-9 >= 300 U/mL who developed LNM (MST, 8.7 months; P = 0.005), MF + PI (MST, 7.5 months; P = 0.040), or IM (MST, 8.7 months; P = 0.001), or who required major vascular resection (MST, 14.8 months; P = 0.015); their prognosis was similar with the UR group. CONCLUSIONS: Even if patients had ICC developing LNM, PI, or IM, or require major vascular resection, surgical resection can be indicated for patients with CA19-9 < 300 U/mL. However, the indications for either adjuvant therapy or resection should be carefully determined in patients with CA19-9 >= 300 U/mL. PMID- 29619515 TI - OsEXPA10 mediates the balance between growth and resistance to biotic stress in rice. AB - KEY MESSAGE: OsEXPA10 gene coordinates the balance between rice development and biotic resistance. Expansins are proteins that can loosen the cell wall. Previous studies have indicated that expansin-encoding genes were involved in defense against abiotic stress, but little is known about the involvement of expansins in biotic stress. Brown planthopper (BPH) is one of the worst insect pests of rice in the Asia-Pacific planting area, and many efforts have been made to identify and clone BPH-resistance genes for use in breeding resistant cultivars. At the same time, rice blast caused by Magnaporthe grisea is one of the three major diseases that severely affect rice production worldwide. Here, we demonstrated that one rice expansin-encoding gene, OsEXPA10, functions in both rice growth and biotic resistance. Over expression of OsEXPA10 improved rice growth but also increased susceptibility to BPH infestation and blast attack, while knock-down OsEXPA10 gene expression resulted in reduced plant height and grain size, but also increased resistance to BPH and the blast pathogen. These results imply that OsEXPA10 mediates the balance between rice development and biotic resistance. PMID- 29619516 TI - Hippocampal calcification on brain CT: prevalence and risk factors in a cerebrovascular cohort. AB - OBJECTIVES: Recently, hippocampal calcification as observed on brain CT examinations was identified in over 20% of people over 50 years of age and a relation between hippocampal calcification and cognitive decline was shown. We determined the prevalence and investigated the vascular risk factors of hippocampal calcification in patients with cerebrovascular disease. METHODS: Hippocampal calcification was scored bilaterally on presence and severity on CT examinations in a cohort of 1130 patients with (suspected) acute ischaemic stroke. Multivariable logistic regression analysis, adjusting for age and gender as well as adjusting for multiple cardiovascular disease risk factors, was used to determine risk factors for hippocampal calcification. RESULTS: Hippocampal calcification was present in 381 (34%) patients. Prevalence increased with age from 8% below 40 to 45% at 80 years and older. In multivariable logistic regression analysis, age per decile (OR 1.41 [95% CI 1.26-1.57], p < 0.01), hypertension (OR 0.74 [95% CI 0.56-0.99], p = 0.049), diabetes mellitus (OR 1.57 [95% CI 1.10-2.25], p = 0.01) and hyperlipidaemia (OR 1.63 [95% CI 1.20-2.22], p < 0.01) were significantly associated with hippocampal calcification. CONCLUSIONS: Hippocampal calcification was a frequent finding on CT in this cohort of stroke patients and was independently positively associated with hyperlipidaemia and diabetes mellitus, suggesting an atherosclerotic origin. KEY POINTS: * Hippocampal calcification is prevalent in over 30% of cerebrovascular disease patients. * Prevalence increases from 8% below 40 to 45% over 80 years. * Hippocampal calcification is associated with cardiovascular risk factors hyperlipidaemia and diabetes mellitus. PMID- 29619518 TI - Ischemic stroke enhancement using a variational model and the expectation maximization method. AB - OBJECTIVES: In order to enable less experienced physicians to reliably detect early signs of stroke, A novel approach was proposed to enhance the visual perception of ischemic stroke in non-enhanced CT. METHODS: A set of 39 retrospective CT scans were used, divided into 23 cases of acute ischemic stroke and 16 normal patients. Stroke cases were obtained within 4.5 h of symptom onset and with a mean NIHSS of 12.9+/-7.4. After selection of adjunct slices from the CT exam, image averaging was performed to reduce the noise and redundant information. This was followed by a variational decomposition model to keep the relevant component of the image. The expectation maximization method was applied to generate enhanced images. RESULTS: We determined a test to evaluate the performance of observers in a clinical environment with and without the aid of enhanced images. The overall sensitivity of the observer's analysis was 64.5 % and increased to 89.6 % and specificity was 83.3 % and increased to 91.7 %. CONCLUSION: These results show the importance of a computational tool to assist neuroradiology decisions, especially in critical situations such as the diagnosis of ischemic stroke. KEY POINTS: * Diagnosing patients with stroke requires high efficiency to avoid irreversible cerebral damage. * A computational algorithm was proposed to enhance the visual perception of stroke. * Observers' performance was increased with the aid of enhanced images. PMID- 29619517 TI - Perfusion MRI as a diagnostic biomarker for differentiating glioma from brain metastasis: a systematic review and meta-analysis. AB - OBJECTIVES: Differentiation of glioma from brain metastasis is clinically crucial because it affects the clinical outcome of patients and alters patient management. Here, we present a systematic review and meta-analysis of the currently available data on perfusion magnetic resonance imaging (MRI) for differentiating glioma from brain metastasis, assessing MRI protocols and parameters. METHODS: A computerised search of Ovid-MEDLINE and EMBASE databases was performed up to 3 October 2017, to find studies on the diagnostic performance of perfusion MRI for differentiating glioma from brain metastasis. Pooled summary estimates of sensitivity and specificity were obtained using hierarchical logistic regression modelling. We conducted meta-regression and subgroup analyses to explain the effects of the study heterogeneity. RESULTS: Eighteen studies with 900 patients were included. The pooled sensitivity and specificity were 90% (95% CI, 84-94%) and 91% (95% CI, 84-95%), respectively. The area under the hierarchical summary receiver operating characteristic curve was 0.96 (95% CI, 0.94-0.98). The meta-regression showed that the percentage of glioma in the study population and the study design were significant factors affecting study heterogeneity. In a subgroup analysis including patients with glioblastoma only, the pooled sensitivity was 92% (95% CI, 84-97%) and the pooled specificity was 94% (95% CI, 85-98%). CONCLUSIONS: Although various perfusion MRI techniques were used, the current evidence supports the use of perfusion MRI to differentiate glioma from brain metastasis. In particular, perfusion MRI showed excellent diagnostic performance for differentiating glioblastoma from brain metastasis. KEY POINTS: * Perfusion MRI shows high diagnostic performance for differentiating glioma from brain metastasis. * The pooled sensitivity was 90% and pooled specificity was 91%. * Peritumoral rCBV derived from DSC is a relatively well validated. PMID- 29619519 TI - Fluoroscopic subtraction Eustachian tubography: initial feasibility test in a cadaver model. AB - OBJECTIVES: To evaluate the technical feasibility of direct Eustachian tube catheterisation and subtraction Eustachian tubography in a cadaver model. METHODS: A total of 12 separate sessions were performed on both sides of the Eustachian tube (ET) in six human cadavers. Cadavers were positioned for the submentovertical view on a fluoroscopy table. Endoscopy-guided ET selection was used in the first three cadavers, whereas fluoroscopy-guided ET selection was used in the remaining three. Eustachian tubography was performed by injecting 2 ml of contrast media through a 5-Fr catheter. We recorded the success of ET selection, number of attempts, procedure time, and tubography quality using native and subtraction images (range, 0-3). RESULTS: Both endoscopy- and fluoroscopy-guided selections were successfully performed in five of six sessions (83.3%). There were no statistically significant differences between the endoscopy- and fluoroscopy-guided procedures in terms of the number of attempts, procedure time, rate of immediate contrast leak to the middle ear cavity, and quality of tubography (p > 0.05). An excellent quality of tubography was obtained in 83.3% (10 of 12 sessions) of subtraction images and in 33.3% (4 of 12 sessions) of native images. The tubography quality score was significantly higher for the subtraction images than for the native images (p = 0.04). CONCLUSION: Subtraction Eustachian tubography using direct catheterisation seems to be technically feasible. The entire ET can be well visualised; thus, this technique can be used as a simple tool for assessment of ET function and anatomy. KEY POINTS: * Direct catheterisation of the Eustachian tube is technically feasible. * The entire Eustachian tube could be well visualised by direct Eustachian tubography. * Subtraction Eustachian tubography images have better image quality than native images. * Subtraction Eustachian tubography can provide objective assessment of ET function and anatomy. PMID- 29619520 TI - Differentiation between primary CNS lymphoma and glioblastoma: qualitative and quantitative analysis using arterial spin labeling MR imaging. AB - OBJECTIVES: To evaluate the diagnostic performance of arterial spin labelling perfusion weighted images (ASL-PWIs) to differentiate primary CNS lymphoma (PCNSL) from glioblastoma (GBM). METHODS: ASL-PWIs of pathologically confirmed PCNSL (n = 21) or GBM (n = 93) were analysed. For qualitative analysis, tumours were visually scored into five categories based on ASL-CBF maps. For quantitative analysis, normalised CBF values were derived by contralateral grey matter (GM) in intra- and peritumoral areas (nCBFintratumoral and nCBFperitumoral, respectively). Visual scoring scales and quantitative parameters from PCNSL and GBM were compared. In addition, the area under the receiver-operating characteristic (ROC) curve was used to determine the diagnostic accuracy of ASL PWI for differentiating PCNSL from GBM. Weighted kappa or intraclass correlation coefficients (ICCs) were used to assess reliability between two observers. RESULTS: In qualitative analysis, scores 5 (CBFintratumoral>CBFGM, 68.8% [64/93]) and 4 (CBFintratumoral ~ CBFGM, 47.6% [10/21]) were the most frequently reported scores for GBM and PCNSL, respectively. In quantitative analysis, both nCBFintratumoral and nCBFperitumoral in PCNSL were significantly lower than those in the GBM (nCBFintratumoral, 0.89 +/- 0.59 [mean and SD] vs. 2.68 +/- 1.89, p < 0.001; nCBFperitumoral, 0.17 +/- 0.08 vs. 0.45 +/- 0.28, p < 0.001). nCBFperitumoral demonstrated the best diagnostic performance (area under the ROC curve: visual scoring, 0.814; nCBFintratumoral, 0.849; nCBFperitumoral, 0.908; p < 0.001 for all). Interobserver agreements for visual scoring (weighted kappa = 0.869), nCBFintratumoral_GM (ICC = 0.958) and nCBFperitumoral_GM (ICC = 0.947) were all excellent. CONCLUSIONS: ASL-PWI performs well in differentiating PCNSL from GBM in both qualitative and quantitative analyses. KEY POINTS: * ASL-PWI performs well (AUC > 0.8) in differentiating PCNSL from GBM. * The visual scoring template demonstrated good diagnostic performance, similar to quantitative analysis. * nCBFperitumoral demonstrated better diagnostic performance than nCBFintratumoral or visual scoring. PMID- 29619523 TI - "Mushroom cap" sign in deep rectosigmoid endometriosis. PMID- 29619522 TI - Solitary fibrous tumour of the spine: imaging features of a commonly misdiagnosed entity. AB - OBJECTIVE: Solitary fibrous tumours (SFTs) occurring in the spine are rare. Herein, we review the clinical and imaging data of spinal SFT. METHODS: We retrospectively analysed eight cases of pathologically confirmed spinal SFT imaging and clinical data, pathological manifestations, surgical methods, and follow-up results. RESULTS: Five SFTs cases occurred in the cervical spine, two in the thoracic spine, and one in the lumbosacral spine. Five cases showed a dumbbell-shaped or lobulated soft tissue mass that grew across the intervertebral foramen, two cases showed an expansive intraosseous mass formation in the vertebral body and/or posterior element, and one case showed a long-spindle shaped intraspinal canal mass growing along the spinal canal. Seven caused local invasion and destruction of the vertebral body and posterior element. Benign SFTs displayed a good prognosis, whereas malignant SFTs were prone to recurrence and metastasis (3/4). CONCLUSION: Spinal SFTs are difficult to characterise with imaging and required pathological and immunohistochemical investigation. Prolonged follow-up is recommended once a diagnosis of spinal SFTs has been established because of the unclear biology. KEY POINTS: * Spinal solitary fibrous tumours are extremely rare. * SFTs should be showed the differential of masses developing though the foramen. * Combing imaging with pathology and immunochemistry assesses the diagnosis and establish nature. PMID- 29619521 TI - US-guided percutaneous release of the first extensor tendon compartment using a 21-gauge needle in de Quervain's disease: a prospective study of 35 cases. AB - PURPOSE: To evaluate the efficacy of ultrasonography-guided percutaneous treatment of de Quervain tenosynovitis with the combination of a corticosteroid injection and release of the retinaculum of the first extensor compartment tendons with a 21-gauge needle. MATERIALS AND METHODS: The first part of our study consisted of ten procedures on cadaver wrists followed by dissection to analyse the effectiveness of the retinaculum release and detect any collateral damage. The second part was a prospective clinical study of 35 procedures. Outcomes were evaluated through a 6-month clinical follow-up and telephone interview at the end of the study. The following parameters were monitored over time: pain level on a visual analogue scale, the QuickDASH and the PRWE. Patient satisfaction questionnaires were also administered. RESULTS: No complications were found during the cadaver study. However, the release was confirmed as 'partial' in all wrists. In the clinical portion of this study, significant improvement was observed in 91.4 % of cases (32/35) within 1 month and the results were stable until the end of the study; all of these patients avoided surgery. The release procedure failed in three patients who eventually required surgical treatment. CONCLUSION: US-guided partial release and simultaneous corticosteroid injection for treatment of de Quervain's disease using a 21-gauge needle is feasible in current practice, with minimal complications. KEY POINTS: * Ultrasound-guided treatment of de Quervain's disease is feasible with a 21G needle. * There was notable regression of clinical signs in 91.4 % of cases. * The procedure is very safe, no iatrogenic neurovascular or tendinous injuries occurred. * Our procedure requires only one session and 3 days away from work. PMID- 29619524 TI - Impact of formal training on agreement of videofluoroscopic swallowing study interpretation across and within disciplines. AB - PURPOSE: Formal agreement studies on interpretation of the videofluoroscopic swallowing study (VFSS) procedure among speech-language pathologists, radiology house officers, and staff radiologists have not been pursued. Each of these professions participates in the procedure, interprets the examination, and writes separate reports on the findings. The aim of this study was to determine reliability of interpretation between and within the disciplines and to determine if structured training improved reliability. METHODS: Thirteen speech-language pathologists (SLPs), ten diagnostic radiologists (RADs) and twenty-one diagnostic radiology house officers (HOs) participated in this study. Each group viewed 24 VFSS samples and rated the presence or absence of seven aberrant swallowing features as well as the presence of dysphagia and identification of oral dysphagia, pharyngeal dysphagia, or both. During part two, the groups were provided with a training session on normal and abnormal swallowing, using different VFSS samples from those in part one, followed by re-rating of the original 24 VFSS samples. A generalized estimating equations (GEE) approach with a binomial link function was used to examine each question separately. For each cluster of tests, as example, all pairwise comparisons between the three groups in the pretraining period, a Hochberg's correction for multiple testing was used to determine significance. A GEE approach with a binomial link function was used to compare the premeasure to postmeasure for each of the three groups of raters stratified by experience. RESULTS: The primary result revealed that the HO group scored significantly lower than the SLP and RAD group on identification of the presence of dysphagia (p = 0.008; p = 0.001, respectively), identification of oral phase dysphagia (p = 0.003; p = 0.001, respectively), and identification of both oral and pharyngeal phase dysphagia, (p = 0.014, p = 0.001, respectively) pretraining. Post training there was no statistically significant difference between the three groups on identification of dysphagia and identification of combined oral and pharyngeal dysphagia. CONCLUSIONS: Formal training to identify oropharyngeal dysphagia characteristics appears to improve accuracy of interpretation of the VFSS procedure for radiology house officers. Consideration to include formal training in this area for radiology residency training programs is recommended. PMID- 29619525 TI - Principles of three-dimensional printing and clinical applications within the abdomen and pelvis. AB - Improvements in technology and reduction in costs have led to widespread interest in three-dimensional (3D) printing. 3D-printed anatomical models contribute to personalized medicine, surgical planning, and education across medical specialties, and these models are rapidly changing the landscape of clinical practice. A physical object that can be held in one's hands allows for significant advantages over standard two-dimensional (2D) or even 3D computer based virtual models. Radiologists have the potential to play a significant role as consultants and educators across all specialties by providing 3D-printed models that enhance clinical care. This article reviews the basics of 3D printing, including how models are created from imaging data, clinical applications of 3D printing within the abdomen and pelvis, implications for education and training, limitations, and future directions. PMID- 29619526 TI - Imaging of endoscopic cystogastrostomy in pancreatic walled-off necrosis: what the radiologist needs to know. AB - Acute pancreatitis is a frequent entity encountered by radiologists. In 2012, the Atlanta criteria were revised to help radiologists use a common nomenclature when describing acute pancreatitis and its complications. One delayed complication of acute necrotizing pancreatitis in walled-off necrosis, a collection seen at least 4 weeks after an episode of acute pancreatic necrosis and/or acute peripancreatic necrosis. Multiple treatments have been adapted in the setting of walled-off necrosis, including endoscopic cystogastrostomy. The focus of this article is to familiarize the radiologist with the imaging appearance of this procedure as well as, review the outcomes and potential complications of endoscopic cystogastrostomy. PMID- 29619527 TI - Neuroblastic tumors in young adults as a sequela of malignant neuroblastoma: report of two cases. AB - Neuroblastoma, ganglioneuroblastoma, and ganglioneuroma share the same histological spectrum which originates from neural crest cells. We present herein two young adult patients with neuroblastic tumors with lymph node metastases. Both the patients were diagnosed incidentally as having retroperitoneal masses, which showed little or no immature cells despite coexistence of lymph node involvement. The tumors were considered to represent spontaneous regression of malignant neuroblastoma. Radiologists should consider the possibility of spontaneous regression of neuroblastic tumors, when poorly enhanced multi component masses at the retroperitoneum with lymph node involvement are visualized. PMID- 29619528 TI - Grade 2 pancreatic neuroendocrine tumors: overbroad scope of Ki-67 index according to MRI features. AB - PURPOSE: To evaluate the value of MR imaging features in stratifying Grade 2 (G2) pancreatic neuroendocrine tumors (PNETs) using the 5% cut-off value of the Ki-67 index as reference standards. MATERIALS AND METHODS: Between January 2010 and October 2016, 41 G2 PNET patients (One patient had 3 tumors) with preoperative MR imaging were included. Tumor grading was based on the revised 2016 World Health Organization classification of PNETs. MR imaging features included size, shape, consistency, T1-w and T2-w signal intensities, enhancement pattern, apparent diffusion coefficient (ADC) ratios (tumor/normal pancreatic parenchyma). RESULTS: 16 Ki-67 index < 5% tumors (SKIT, 37.2%) and 27 Ki-67 index >= 5% tumors (LKIT, 62.8%) of G2 were evaluated. The LKIT showed solid consistency (85% vs. 50%, P < 0.05), incomplete envelope-like reinforcement in a delayed phase (74% vs. 62%, P < 0.05), and liver or lymph node metastases (67% vs. 31%, P < 0.05) more frequently than did SKIT. However, ADC ratios of LKIT were smaller than SKIT (0.85 +/- 0.23 vs. 1.29 +/- 0.39, P = 0.001). Using binary logistic regression analysis, the ADC ratio was an independent significant differentiator of SKIT from LKIT. The AUROC of ADC ratios was 0.816 +/- 0.07. The optimal cut-off value for the identification of LKIT was 1.25 * 10-3 (sensitivity 96.3%, specificity 62.5%). CONCLUSION: MRI features may identify the overbroad scope of G2 PNETs and help predict Ki-67 values, as a surrogate for tumor aggressiveness, in G2 PNETs. An optimal cut-off value for predicting Ki-67 status (>=/< 5%) was 1.25 * 10-3 of ADC ratio. PMID- 29619529 TI - My paper 20 years later: NIV in immunocompromized patients. PMID- 29619530 TI - Can targeting ANGPTL proteins improve glucose tolerance? AB - Three members of the angiopoietin-like (ANGPTL) family of proteins, ANGPTL3, ANGPTL4 and ANGPTL8, are known regulators of plasma triacylglycerol levels. Recently, these three proteins have garnered considerable interest as potential targets for therapeutically reducing plasma triacylglycerol levels and improving cardiovascular outcomes. In this issue of Diabetologia, Janssen et al ( https://doi.org/10.1007/s00125-018-4583-5 ) and Vatner et al ( https://doi.org/10.1007/s00125-018-4579-1 ) show that reducing levels of ANGPTL4 and ANGPTL8, respectively, could have the added benefit of improving glucose tolerance. Interestingly, the improvements in glucose tolerance observed in both studies, both done in rodents, were coupled with increased fat mass. These findings suggest that funnelling lipids to adipose tissue and away from ectopic sites could be beneficial and strengthen the argument for pursuing the therapeutic targeting of ANGPTL proteins. PMID- 29619532 TI - In memory of Professor Loris Borghi (1949-2018). PMID- 29619531 TI - Autoantibodies to N-terminally truncated GAD improve clinical phenotyping of individuals with adult-onset diabetes: Action LADA 12. AB - AIMS/HYPOTHESIS: Adult-onset type 1 diabetes, in which the 65 kDa isoform of GAD (GAD65) is a major autoantigen, has a broad clinical phenotype encompassing variable need for insulin therapy. This study aimed to evaluate whether autoantibodies against N-terminally truncated GAD65 more closely defined a type 1 diabetes phenotype associated with insulin therapy. METHODS: Of 1114 participants with adult-onset diabetes from the Action LADA (latent autoimmune diabetes in adults) study with sufficient sera, we selected those designated type 1 (n = 511) or type 2 diabetes (n = 603) and retested the samples in radiobinding assays for human full-length GAD65 autoantibodies (f-GADA) and N-terminally truncated (amino acids 96-585) GAD65 autoantibodies (t-GADA). Individuals' clinical phenotypes were analysed according to antibody binding patterns. RESULTS: Overall, 478 individuals were f-GADA-positive, 431 were t-GADA-positive and 628 were negative in both assays. Risk of insulin treatment was augmented in t-GADA-positive individuals (OR 4.69 [95% CI 3.57, 6.17]) compared with f-GADA-positive individuals (OR 3.86 [95% CI 2.95, 5.06]), irrespective of diabetes duration. Of 55 individuals who were f-GADA-positive but t-GADA-negative, i.e. with antibody binding restricted to the N-terminus of GAD65, the phenotype was similar to type 2 diabetes with low risk of progression to insulin treatment. Compared with these individuals with N-terminal GAD65-restricted GADA, t-GADA-positive individuals were younger at diagnosis (p = 0.005), leaner (p < 0.0001) and more often had multiple diabetes-associated autoantibodies (28.3% vs 7.3%; p = 0.0005). CONCLUSIONS/INTERPRETATION: In individuals with adult-onset diabetes, presence of N-terminally truncated GAD65 autoantibodies is associated with the clinical phenotype of autoimmune type 1 diabetes and predicts insulin therapy. PMID- 29619533 TI - The effects of cannabidiol (CBD) on cognition and symptoms in outpatients with chronic schizophrenia a randomized placebo controlled trial. AB - RATIONALE: Preliminary evidence suggests that cannabidiol (CBD) may be effective in the treatment of neurodegenerative disorders; however, CBD has never been evaluated for the treatment of cognitive impairments associated with schizophrenia (CIAS). OBJECTIVE: This study compared the cognitive, symptomatic, and side effects of CBD versus placebo in a clinical trial. METHODS: This study was a 6-week, randomized, placebo-controlled, parallel group, fixed-dose study of oral CBD (600 mg/day) or placebo augmentation in 36 stable antipsychotic-treated patients diagnosed with chronic schizophrenia. All subjects completed the MATRICS Consensus Cognitive Battery (MCCB) at baseline and at end of 6 weeks of treatment. Psychotic symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) at baseline and biweekly. RESULTS: There was no main effect of time or drug on MCCB Composite score, but a significant drug * time effect was observed (p = 0.02). Post hoc analyses revealed that only placebo treated subjects improved over time (p = 0.03). There was a significant decrease in PANSS Total scores over time (p < 0. 0001) but there was no significant drug * time interaction (p = 0.18). Side effects were similar between CBD and placebo, with the one exception being sedation, which was more prevalent in the CBD group. CONCLUSIONS: At the dose studied, CBD augmentation was not associated with an improvement in MCCB or PANSS scores in stable antipsychotic-treated outpatients with schizophrenia. Overall, CBD was well tolerated with no worsening of mood, suicidality, or movement side effects. TRIAL REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT00588731. PMID- 29619534 TI - [Unmet needs of family dementia caregivers of persons with dementia : Primary medical care]. AB - BACKGROUND: Results of current research studies revealed that providing informal care for people with dementia (PwD) is associated with caregivers' burden and a variety of health impairments. In order to provide optimal support for family caregivers of PwD, general practitioners and specialists should be able to identify caregivers' unmet needs in primary care. OBJECTIVES: The present article provides an overview of unmet needs of family caregivers that are relevant for general practitioners as well as specialists in neurology, psychiatry, psychotherapy and psychosomatics. MATERIAL AND METHODS: The present overview is based on current reviews on unmet needs of caregivers of PwD and on results of the general practitioner-based, cluster-randomized controlled intervention trial DelpHi-MV (Life- and person-centred help in Mecklenburg-Western Pomerania, Germany; Identifier: NCT01401582). RESULTS: The article provides an overview of unmet needs of family caregivers for PwD, especially in the domains of social integration, psychological and physical health, legal and financial issues, as well as available and valid measurements. DISCUSSION: The article illustrates the importance and the possibilities for general practitioners and specialists to identify caregivers' unmet needs. The question to what extent unmet needs' assessments for family caregivers of PwD could be implemented and financed in routine care is still under debate. PMID- 29619535 TI - [Operative treatment of the degenerative cervical spine]. AB - BACKGROUND: Degenerative alterations of the cervical spine often entail disc herniations and stenoses of the spinal canal and/or neural foramen. Mediolateral or lateral compression of nerve roots causes cervical radiculopathy, which is an indication for surgery in cases of significant motor deficits or refractory pain. Median canal encroachment may result in compression of the spinal cord and cervical myelopathy. Its natural history is typically characterized by episodic deterioration, so that surgical decompression is indicated in cases of clear myelopathic signs. OBJECTIVE: The aim of the present article is to outline the operative options for patients with cervical radiculopathy and myelopathy. Furthermore, we describe the operative complications and the outcome in these patients. MATERIAL AND METHODS: For this manuscript a systematic PubMed search was carried out, the papers were systematically analyzed for the best evidence and this was combined with the authors' experience. RESULTS AND CONCLUSION: Depending on the cervical pathology, the most prevalent surgical options for radiculopathy include anterior cervical discectomy and fusion (ACDF), cervical arthroplasty or posterior cervical foraminotomy. Cervical myelopathy may be decompressed by ACDF, corpectomy or posterior approaches like laminectomy plus instrumented fusion or laminoplasty. The outcome depends on the cervical pathology and the type of operation. Overall, in long-term follow-up studies the results of all surgical techniques on the cervical spine are generally considered to be very good, although specific patient characteristics are more suited for a particular approach. PMID- 29619536 TI - Penetrating femoral artery injuries: an urban trauma centre experience. AB - AIM: This study reviews a single centre experience with penetrating femoral artery injuries. PATIENTS AND METHODS: The records of all patients with femoral artery injuries admitted to the Trauma Centre at Groote Schuur Hospital from January 2002 to December 2012 were reviewed. These were analysed for demographics, injury mechanism, perioperative, and surgical management. Outcome was categorised by limb salvage. RESULTS: One-hundred and fifty-eight (158) patients with femoral artery injuries were identified. There were 144 (91%) men and 14 women with a mean age of 28 years. Ninety-five percent (N = 150) sustained penetrating injuries. The superficial femoral artery (87%) was most commonly injured. The most common type of arterial injury was a laceration (39%) and transection (37%). Eighty-one (51%) patients had a primary repair, 53 (33%) patients had a vein interposition graft, and 16 patients (10%) had a prosthetic graft. There were 78 (51%) concomitant venous injuries, 11 were repaired, and 1 vein patch repair was performed (15.4%). There were 4 (2.5%) primary amputations and 10 (6.5%) secondary amputations. There were no deaths. Statistically significant risk factors for secondary amputation derived by univariate analysis were: ischaemia (p < 0.0001), neurological deficit due to ischemia (p < 0.001), temporary vascular shunting (p < 0.001), and the absence of a palpable pulse post repair (p < 0.01). CONCLUSION: This study has a primary and secondary amputation rate of 2.5 and 6.5%, respectively. There was greater than 90% limb salvage rate. The outcome of threatened limbs due to femoral artery injury is good, provided that there is no delay to surgery. PMID- 29619537 TI - [Research Today-Future Tomorrow : 89th Annual Meeting of the German Society of Oto-Rhino-Laryngology, Head and Neck Surgery]. PMID- 29619538 TI - [The German Society of Otorhinolaryngology, Head and Neck Surgery award winners 2015 and 2017]. PMID- 29619539 TI - ? PMID- 29619541 TI - Systemic mastocytosis identified in two women developing fragility fractures during lactation. AB - Two women presenting with fragility fractures during lactation had bone mineral density (BMD) reduced more greatly than usually associated with lactation. The first woman was 29 years old with a BMD T-score of - 3.2 SD at the spine and- 2.0 SD at the femoral neck. The second woman was 35 years old with a BMD T-score of - 4.5 SD at the spine and - 2.8 SD at the femoral neck. Both women had increased cortical porosity and reduced trabecular density. Investigation identified an elevated serum tryptase, and marrow biopsy confirmed the diagnosis of mastocytosis. Lactation causes bone loss, but the occurrence of fractures in the setting of severe deficits in BMD and microstructural deterioration signals the need to consider additional causes of bone loss. PMID- 29619540 TI - Understanding osteoporotic pain and its pharmacological treatment. AB - Osteoporosis, a disorder that affects millions of people worldwide, is characterized by decreased bone mass and microstructural alterations giving rise to an increased risk of fractures. Osteoporotic fractures can cause acute and chronic pain that mainly affects elderly patients with multiple comorbidities and commonly on different drug regimens. The aim of this paper is to summarize the pathogenesis and systemic treatment of osteoporotic pain. This narrative review summarizes the main pathogenetic aspects of osteoporotic pain and the cornerstones of its treatment. Osteoporotic fractures induce both acute and chronic nociceptive and neuropathic pain. Central sensitization seems to play a pivotal role in developing and maintaining chronicity of post-fracture pain in osteoporosis. Antiosteoporosis drugs are able to partially control pain, but additional analgesics are always necessary for pain due to bone fractures. Nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors reduce acute pain but with a poor effect on the chronic neuropathic component of pain and with relevant side effects. Opioid drugs can control the whole spectrum of acute and chronic bone pain, but they differ with respect to their efficacy on neuropathic components, their tolerability and safety. Chronic pain after osteoporotic fractures requires a multifaceted approach, which includes a large spectrum of drugs (antiosteoporosis treatment, acetaminophen, NSAIDs, selective COX-2 inhibitors, weak and strong opioids) and non-pharmacological treatment. Based on a better understanding of the pathogenesis of osteoporotic and post fracture pain, a guided stepwise approach to post-fracture osteoporotic pain will also better meet the needs of these patients. PMID- 29619542 TI - Incidence and outcomes of humeral fractures in the older person. AB - : Humeral fractures are not well understood and thus we examined the incidence and outcomes of elderly humeral fractures at a single institution over a 3-year period. We found increasing incidence in humeral fractures with increasing age and negative outcomes comparable to hip fractures. INTRODUCTION: In this study, we report the incidence of humeral fractures in the older patient and their outcomes, including new nursing homes discharges and mortality, residing in the metropolitan referral area of a Sydney tertiary referral hospital. METHODS: All admissions between 2013 and 2016, of patients aged 65 years or more, presenting to hospital with humeral fractures were reviewed. The data was explored primarily for outcomes (mortality and new admissions to residential aged care facility) and secondarily for clinical association with humeral fractures. RESULTS: Two hundred eighty-one episodes of humeral fracture were identified. Incidence peaked in the above 85-year-old group at 670 per 100,000 persons per year. Proximal fractures were accounted for 84.3% of the cohort. 12.8% received operative management. The in-hospital mortality rate was 3.6%. Gender was a significant predictor for mortality (OR = 5.8, 95% CI 1.3-28.5, p value = 0.0032) with males six times more likely to experience in-hospital mortality compared to females. 17.8% of participants were admitted to a new nursing home. Logistical regression demonstrated age (OR = 1.10, 95% CI 1.04-1.17; p value = 0.001) and Charlson comorbidity index (OR = 1.32, 95% CI 1.04-1.66; p value = 0.02) were predictors of admission to a new nursing home. CONCLUSION: Humeral fractures are common in the older population and cause a substantial amount of new nursing home admissions and mortality. Further study is required to ascertain appropriate guidelines for treatment and rehabilitation. PMID- 29619544 TI - Effect of glycation on human serum albumin-zinc interaction: a biophysical study. AB - Zinc deficiency is common in diabetes. However, the cause of this phenomenon is largely unknown. 80% of the absorbed zinc is transported through the blood in association with human serum albumin (HSA). Under persistent hyperglycemia, HSA frequently undergoes non-enzymatic glycation which can affect its structure and metal-binding function. Hence, in this study, we have examined the interaction of zinc with native and glycated HSA. The protein samples were incubated either in the presence or in the absence of physiologically elevated glucose concentration for 21 days. The samples were then analyzed for structural changes and zinc binding ability using various spectrometric and calorimetric approaches. The study reveals changes in the three-dimensional structure of the protein upon glycation that cause local unfolding of the molecule. Most such regions are localized in subdomain IIA of HSA which plays a key role in zinc binding. This affects zinc interaction with HSA and could in part explain the perturbed zinc distribution in patients with hyperglycemia. The varying degree of HSA glycation in blood could explain the observed heterogeneity pertaining to zinc deficiency among people suffering from diabetes. PMID- 29619545 TI - Morphological and molecular characterization of the senile osteoporosis in senescence-accelerated mouse prone 6 (SAMP6). AB - Although the understanding of the complex pathogenesis for osteoporosis is appreciable, the underlying mechanism is not yet fully elucidated. There is a great need to further characterize the available animal models in osteoporosis research. The senescence-accelerated mouse prone 6 (SAMP6) mice have been developed as the spontaneous experimental model for senile osteoporosis. Here, we provide a comprehensive overview of current research regarding the bone morphological and molecular alterations and the possible mechanisms involved in these changes. There were significant decrease in trabecular bone mass at the axial and appendicular skeletal sites, with no marked alterations of cortical bone. Decreased bone formation on the endosteal surface and trabecular bone, and increased bone marrow adiposity were observed in SAMP6 mice. The elevated expression level of proliferator activator gamma (PPARgamma) in the bone marrow suggest that PPARgamma might regulate osteoblastic bone formation negatively in SAMP6 mice. The expression level of secreted frizzled-related protein 4 (Sfrp4) was found to be higher in SAMP6 mice. Sfrp4 is considered to suppress osteoblastic proliferation mediated by inhibition of Wnt signaling pathway. These findings may help us to gain more insight into the potential mechanism of senile osteoporosis. PMID- 29619546 TI - Clinical application of photodynamic medicine technology using light-emitting fluorescence imaging based on a specialized luminous source. AB - The natural amino acid 5-aminolevulinic acid (ALA) is a protoporphyrin IX (PpIX) precursor and a new-generation photosensitive substance that accumulates specifically in cancer cells. When indocyanine green (ICG) is irradiated with near-infrared (NIR) light, it shifts to a higher energy state and emits infrared light with a longer wavelength than the irradiated NIR light. Photodynamic diagnosis (PDD) using ALA and ICG-based NIR fluorescence imaging has emerged as a new diagnostic technique. Specifically, in laparoscopic examinations for serosa invading advanced gastric cancer, peritoneal metastases could be detected by ALA PDD, but not by conventional visible-light imaging. The HyperEye Medical System (HEMS) can visualize ICG fluorescence as color images simultaneously projected with visible light in real time. This ICG fluorescence method is widely applicable, including for intraoperative identification of sentinel lymph nodes, visualization of blood vessels in organ resection, and blood flow evaluation during surgery. Fluorescence navigation by ALA-PDD and NIR using ICG imaging provides good visualization and detection of the target lesions that is not possible with the naked eye. We propose that this technique should be used in fundamental research on the relationship among cellular dynamics, metabolic enzymes, and tumor tissues, and to evaluate clinical efficacy and safety in multicenter cooperative clinical trials. PMID- 29619543 TI - Intrinsic links among sex, emotion, and reproduction. AB - Species survival is dependent on successful reproduction. This begins with a desire to mate, followed by selection of a partner, copulation and in monogamous mammals including humans, requires emotions and behaviours necessary to maintain partner bonds for the benefit of rearing young. Hormones are integral to all of these stages and not only mediate physiological and endocrine processes involved in reproduction, but also act as neuromodulators within limbic brain centres to facilitate the expression of innate emotions and behaviours required for reproduction. A significant body of work is unravelling the roles of several key hormones in the modulation of mood states and sexual behaviours; however, a full understanding of the integration of these intrinsic links among sexual and emotional brain circuits still eludes us. This review summarises the evidence to date and postulates future directions to identify potential psycho-neuroendocrine frameworks linking sexual and emotional brain processes with reproduction. PMID- 29619547 TI - Combined production of fucoxanthin and EPA from two diatom strains Phaeodactylum tricornutum and Cylindrotheca fusiformis cultures. AB - Fucoxanthin and eicosapentaenoic acid (EPA) provide significant health benefits for human population. Diatom is a potential natural livestock for the combined production of EPA and fucoxanthin. In this study, first, the effects of three important parameters including light intensity, nitrogen concentration and salinity were evaluated for the production of EPA and fucoxanthin in two diatom strains Phaeodactylum tricornutum and Cylindrotheca fusiformis. And then, two steps method based on light intensity were applied to produce EPA and fucoxanthin in large scale. Higher light intensity was first adopted for the high growth rate and lipid content of diatom, and after a period of time, light intensity was lowered to enhance the accumulation of fucoxanthin and EPA. In final, the highest EPA yields were 62.55 and 27.32 mg L-1 for P. tricornutum and C. fusiformis, and the fucoxanthin yield reached 8.32 and 6.05 mg L-1, respectively. PMID- 29619548 TI - All-trans retinoic acid in combination with sodium butyrate enhances specific monoclonal antibody productivity in recombinant CHO cell line. AB - The effects of all-trans retinoic acid (RA) and sodium butyrate (NaBu) on growth, viability and antibody production of two types of transfected Chinese hamster ovary cell lines (CHO-K1 and CHO-S) were investigated using a batch mode cell culture. By adding 0.5 mM NaBu in the CHO-K1 cell culture, the cell specific productivity (Qp) and antibody concentration increased by five- and threefold, respectively. The optimal concentration of RA was 100 nM which resulted in twofold increase in antibody production. In a combination model, RA applied at early growth phase of CHO-K1 cells followed by addition of NaBu with lowering culture temperature at the end of stationary phase resulted in two- and threefold increase in Qp and final antibody concentration, respectively. The latter strategy was also applied on suspended CHO-S cells with enhanced Qp and antibody concentration, but to a lesser extent than the CHO-K1 cells. In conclusion, our results demonstrate that the addition of RA and NaBu along with lowering the culture temperature can increase cell culture period as well as Qp and the final concentration of recombinant monoclonal antibody in both CHO-K1 and CHO-S cells without any significant change in binding affinity of the mAb. PMID- 29619551 TI - Zygotic embryo cell wall responses to drying in three gymnosperm species differing in seed desiccation sensitivity. AB - Plant cell walls (CWs) are dynamic in that they can change conformation during ontogeny and in response to various stresses. Though seeds are the main propagatory units of higher plants, little is known of the conformational responses of zygotic embryo CWs to drying. This study employed cryo-scanning electron microscopy to compare the effects of desiccation on zygotic embryo CW morphology across three gymnosperm species that were shown here to differ in seed desiccation sensitivity: Podocarpus henkelii (highly desiccation-sensitive), Podocarpus falcatus (moderately desiccation-sensitive), and Pinus elliottii (desiccation-tolerant). Fresh/imbibed (i.e. fresh Podocarpus at shedding and imbibed Pi. elliottii) embryos showed polyhedral cells with regular walls, typical of turgid cells with an intact plasmalemma. Upon desiccation to c. 0.05 g g-1 (dry mass basis), CWs assumed an undulating conformation, the severity of which appeared to depend on the amount and type of dry matter accumulated. After desiccation, intercellular spaces between cortical cells in all species were comparably enlarged relative to those of fresh/imbibed embryos. After rehydration, meristematic and cotyledonary CWs of P. henkelii and meristematic CWs of P. falcatus remained slightly undulated, suggestive of plasmalemma and/or CW damage, while those of Pi. elliottii returned to their original conformation. Cell areas in dried-rehydrated P. henkelii root meristem and cotyledon were also significantly lower than those from fresh embryos, suggesting incomplete recovery, even though embryo water contents were comparable between the two states. Electrolyte leakage measurements suggest that the two desiccation sensitive species incurred significant plasmalemma damage relative to the tolerant species upon desiccation, in agreement with the CW abnormalities observed in these species after rehydration. Immunocytochemistry studies revealed that of the four CW epitopes common to embryos of all three species, an increase in arabinan (LM6) upon desiccation and rehydration in desiccation-tolerant Pi. elliottii was the only difference, although this was not statistically significant. Seed desiccation sensitivity in species like P. henkelii and P. falcatus may therefore be partly based on the inability of the plasmalemma and consequently CWs of dried embryos to regain their original conformation following rehydration. PMID- 29619550 TI - Perspectives on diagnosis and management of adult idiopathic intracranial hypertension. AB - PURPOSE: The purpose of this review is to shed light into the diagnostic challenges regarding idiopathic intracranial hypertension (IIH), giving more emphasis to the role of optical coherence tomography (OCT) in IIH, while it also presents recent advances in the management of IIH. METHODS: A literature search in PubMed was performed for studies about the diagnosis and management of IIH published before June 30, 2017. Then, a comprehensive review of the eligible studies and the relevant references was performed. RESULTS: Apart from the updated modified criteria, OCT has been found to be important for the diagnosis of IIH, along with assessment of clinical signs and symptoms, brain imaging, and lumbar puncture. On the other hand, there is no current consensus for the management of IIH, but various interventions have been used, such as dietary therapy (weight loss, bariatric surgery, lifestyle modification, low-salt diet), medications, and surgical treatment. CONCLUSIONS: IIH is a challenging and serious disorder, which may lead to permanent visual impairment if there is a delay in its diagnosis. Advances in retinal imaging have led to better understanding of the pathogenesis of the disease and prompt diagnosis even in subtle cases can be done using OCT. Surgical interventions should be minimized and only used in cases refractory to medical treatment and in those with rapid progression. PMID- 29619552 TI - Using dynamic treatment regimes to understand erythropoietin-stimulating agent hyporesponsiveness. AB - BACKGROUND: Erythropoietin-stimulating agent hyporesponsiveness (ESAH) is associated with increased cardiovascular mortality in patients with end-stage renal disease (ESRD) on hemodialysis. Dynamic treatment regimes (DTR), a clinical decision support (CDS) tool that guides the prescription of specific therapies in response to variations in patient states, have been used to guide treatment for chronic illnesses that require frequent monitoring and therapy changes. Our objective is to explore the role of utilizing a DTR to reduce ESAH in pediatric hemodialysis patients. METHODS: Retrospective analysis of ESRD patients on hemodialysis who received ESAs. Dosing was adjusted using a locally developed protocol designed to target a hemoglobin between 10 and 12 g/dl. Analyzing this protocol as a DTR, we assessed adherence to the protocol over time measuring how the hyporesponse index (ESA dose/hemoglobin value) changed due to varying levels of adherence. RESULTS: Eighteen patients met study criteria. Median hemoglobin was 11.4 g/dl (range 6.1-15.4), and median weekly ESA dose (darbepoetin equivalent) was 0.4 mcg/kg/dose (range 0-2.1). Full adherence to the DTR was identified in 266 (71%) of the 4-week periods, with a median average adherence score of 0.80 (range 0.63-0.91). As adherence to the DTR improved, ESAH decreased. During the last 12 weeks, 13 out of 18 patients had lower average ESA/hemoglobin ratio than the first 12 weeks. CONCLUSIONS: A DTR appears to be well-suited to the treatment of anemia in ESRD and reduces ESAH. Our work shows the potential of DTRs to drive the development and evaluation of clinical practice guidelines. PMID- 29619553 TI - Preoperative PCR analysis of synovial fluid has limited value for the diagnosis of periprosthetic joint infections of total knee arthroplasties. AB - Preoperative diagnosis of periprosthetic joint infection (PJI) is important because of the therapeutic consequences. This prospective study was designed to answer the question, if preoperative PCR analysis of the synovial fluid in addition to the culture and the CRP analysis of the blood are helpful for the diagnosis of PJI in knee arthroplasties. Before revision CRP analysis of the blood, cultivation and PCR analysis of synovial fluid of 116 knee endoprostheses were performed. During revision surgery, five tissue samples of the periprosthetic tissue were cultured and five further samples subjected to histological analysis. These analyses of the periprosthetic tissue were used to verify the results of the preoperative diagnostic methods. Twenty-seven prostheses were identified as infected (prevalence 23.3%). The combined analyses of the joint fluid cultivation and the CRP blood level resulted in a sensitivity of 77.8%, a specificity of 95.5%, a positive-predictive value of 84.0%, a negative-predictive value of 93.4% and an accuracy of 91.4%. The PCR analysis of the synovial fluid resulted in a sensitivity of 55.6%, a specificity of 82.0%, a positive-predictive value of 48.4%, a negative-predictive value of 85.9% and an accuracy of 75.9%. The sensitivity for culture of the aspirate and PCR analysis in combination with an elevated CRP level was 85.2%, the specificity 82.0%, the positive-predictive value 58.9%, the negative-predictive value 94.8% and the accuracy 82.7%. The preoperative PCR analysis of synovial fluid has only limited value in addition to the standard culture analysis. PMID- 29619554 TI - Examining variation across treatment clinics in cancer patients' psychological outcomes: results of a cross sectional survey. AB - PURPOSE: The majority of research on psychological outcomes for cancer patients has focussed on the role of individual characteristics, and disease and treatment factors. There has been very little exploration of the potential contribution of the treatment clinic to these outcomes. This study explored whether there is variation among clinics in cancer patients' psychological outcomes. METHODS: Cancer outpatients were recruited from 22 medical oncology and haematology clinics in Australia. Participants completed a pen and paper survey including the Hospital Anxiety and Depression Scale (HADS), as well as sociodemographic, disease and treatment characteristics. RESULTS: Of those eligible to participate, 4233 (82%) consented and 2811 (81% of consenters) returned the completed survey. There was no statistically significant variation in HADS depression scores across clinics. Some difference in anxiety scores derived from the HADS questionnaire between clinics (p = 0.03) was found with the percentage of between-clinic variation estimated to be 1.11%. However, once all demographic, disease and treatment predictors were adjusted for there was no statistical differences between clinics (percent of between-clinic variation = 0.53%; p = 0.1415). CONCLUSIONS: Psychological outcomes were not found to vary between clinics. Other sources of variation including patient characteristics may over-ride between clinic variability, if it exists. PMID- 29619556 TI - Duodenal histological features in suspected non-celiac gluten sensitivity: new insights into a still undefined condition. PMID- 29619555 TI - Prognostic significance of 1p36 locus deletion in adenoid cystic carcinoma of the salivary glands. AB - Adenoid cystic carcinoma (AdCC) of the salivary glands is characterized by MYB NFIB or MYBL1-NFIB fusion, prolonged but relentlessly progressive clinical course with frequent recurrences, and development of distant metastasis resulting in high long-term mortality. Currently, no effective therapy is available for patients with advanced non-resectable and/or metastatic disease. Complicating the clinical management of this patient group is the lack of prognostic markers. The purpose of this study is to investigate the prognostic value of 1p36 loss in patients with AdCC. The presence of 1p36 deletion and gene fusions involving the MYB, NFIB, and MYBL1 genes in a cohort of 93 salivary gland AdCCs was studied using fluorescence in situ hybridization. These results were statistically correlated with clinical data and outcome. Deletion of 1p36 in AdCC was identified in 13 of 85 analyzable cases (15.29%). MYB-NFIB fusion was detected in 57/85 (67.1%), MYBL1-NFIB fusion in 12/85 (14.1%), MYB-X fusion in 4/85 (4.7%), MYBL1-X in 4/85 (4.7%), and NFIB-X in 2/85 (2.4%) of AdCC cases. None of the 1p36 deleted samples showed MYBL1 rearrangement. Statistical analysis demonstrated a significant correlation between 1p36 deletion and advanced tumor stage and solid histology (p = 0.0061 and 0.0007, respectively). Kaplan-Meier survival curves showed statistically significant correlations between 1p36 deletion and decreased overall survival, disease-specific survival, recurrence-free interval, and recurrence-free survival, all of which were maintained in multivariate analysis. We demonstrate that 1p36 deletion can serve as an indicator of unfavorable outcome of patients with salivary gland AdCC. PMID- 29619557 TI - Performance and skill retention of five supraglottic airway devices for the pediatric difficult airway in a manikin. AB - : Supraglottic airway devices (SADs) have been introduced to assist medical professionals in emergency situations with limited experience in securing airways via conventional endotracheal intubation (ETI). Literature on the use of SADs for securing an airway during pediatric critical settings is scarce, and there is a lack of studies comparing different SADs to each other and to conventional ETI. We conducted a study comparing five different SADs to ETI with regard to success rate, time to first ventilation, and personal rating in a pediatric manikin under simulated physiologic and pathologic airway conditions in 41 pediatricians of varying clinical experience and training. Only the AirQ, AuraG, and laryngeal tube (LT) were inserted within 30 s correctly by all participants under physiologic conditions. In tongue edema (TE), AirQ and LT had the highest success rate. In limited mobility of the cervical spine (CS), AirQ, AuraG, and LT again all were inserted within 30 s. In a multivariate analysis, factors influencing the success were experience with the respective device and level of medical education. Under TE conditions, there were significantly longer insertion times for the ETI, laryngeal mask airway (LMA), and EzT. Under CS conditions, there were significantly longer insertion times for the ETI, LMA, LT, and EzT. A multivariate analysis showed experience with the respective device to be the only factor of influence on time to first ventilation. CONCLUSION: LT, AuraG, and AirQ were superior in providing fast and effective ventilation during simulated difficult airway situations in pediatricians. What is Known: * Supraglottic airway devices have been introduced for medical professionals who lack experience for managing difficult airway situations. * A variety of these devices have been developed so far, but not compared to each other yet. What is New: * We compared five different supraglottic airway devices with regard to success rate, time to first ventilation, and personal rating in a pediatric manikin under simulated physiologic and pathologic airway conditions. * Laryngeal tube, AuraG, and AirQ were superior in providing fast and effective ventilation during simulated difficult airway situations in pediatricians with varying clinical experience. PMID- 29619558 TI - Externalizing behavior problems are related to substance use in adolescents across six samples from Nordic countries. AB - The aim of this study is to investigate associations between use of cigarettes, cannabis, and alcohol (CCA) and psychosocial problems among adolescents with different cultural backgrounds living in Nordic countries. Data from six questionnaire-based surveys conducted in Denmark, Norway, and Greenland, with participants from different cultural and religious backgrounds, were compared. A total of 2212 adolescents between 15 and 18 years of age participated in the study. The surveys were carried out nationally and in school settings. All adolescents answered a 12-item questionnaire (YouthMap12) with six questions identifying externalizing behavior problems and six questions identifying internalizing behavior problems, as well as four questions regarding childhood neglect and physical or sexual abuse, and questions about last month use of CCA. Externalizing behavior problems were strongly associated with all types of CCA use, while childhood history of abuse and neglect was associated with cigarette and cannabis use. The associations did not differ by sample. Despite differences between samples in use of CCA, national, cultural, and socioeconomic background, very similar associations were found between psychosocial problems and use of CCA. Our findings highlight the need to pay special attention to adolescents with externalizing behavior problems and experiences of neglect and assault in CCA prevention programs, across different ethnic and socioeconomic backgrounds. PMID- 29619559 TI - Effect of Nasogastric Tube on Aspiration Risk: Results from 147 Patients with Dysphagia and Literature Review. AB - Nasogastric tube (NGT) is a common feeding strategy for patients at risk of endotracheal aspiration with an oral diet. With NGT feeding, however, swallowing of small amounts saliva cannot be avoided. We investigated whether the aspiration rate when swallowing 1 mL of fluid increased in patients using an NGT in different dysphagia severities. One hundred forty-seven patients who had been receiving NGT feeding underwent a videofluoroscopic swallowing study (VFSS). During VFSS, subjects were offered 1 mL of fluid twice: initially, with the tube inserted (NGT-in) and, subsequently, with the tube removed (NGT-out). Aspiration depth was determined using the 8-point Penetration-Aspiration Scale (PAS) (0 points, no aspiration/penetration; 8 points, aspiration passing the vocal cords with no ejection efforts). PAS-diff was computed (PASNGT-in - PASNGT-out), and a positive PAS-diff (PAS-diff > 0) meant increased aspiration depth in the presence of NGT. After VFSS, diet recommendations were made according to dysphagia severity assessment: non-oral feeding (n = 59), diet modification (n = 74), and diet as tolerated (n = 13). Cognitive level (mini-mental state examination, MMSE) and general functional level (Modified Barthel Index, MBI) were compared between the PAS-diff > 0 and PAS-diff <= 0 groups. Aspiration severity did not significantly change after NGT removal (PASNGT-in, 2.45 +/- 2.40; PASNGT-out, 2.57 +/- 2.58; P = .50). Regardless of recommended diet, PAS-diff values were not significantly different (P = .49). MMSE and MBI were not significantly different (P = .23 and .94) between subjects with PAS-diff > 0 (n = 25) and PAS-diff <= 0 (n = 121). In conclusion, the risk of aspirating a small amount of fluid was not significantly different before and after NGT removal, regardless of swallowing function, cognitive level, or general functional level. PMID- 29619560 TI - Dysphagia and Oral Morbidities in Chemoradiation-Treated Head and Neck Cancer Patients. AB - This study prospectively evaluated relationships between oral morbidities and swallowing ability in head/neck cancer patients following chemoradiation therapy (CRT) and at 3 months following CRT. Thirty patients with confirmed head/neck cancer undergoing chemoradiation were assessed with a battery of swallowing measures and measures of oral morbidities related to chemoradiation (xerostomia, mucositis, pain, taste/smell, oral moisture). All measures were completed at baseline (within the first week of CRT), at 6 weeks (end of treatment), and at 3 months following chemoradiation. Descriptive and univariate statistics were used to depict change over time in swallowing and each oral morbidity. Correlation analyses evaluated relationships between swallowing function and oral morbidities at each time point. Most measures demonstrated significant negative change at 6 weeks with incomplete recovery at 3 months. At 6 weeks, mucositis ratings, xerostomia, and retronasal smell intensity demonstrated significant inverse relationships with swallowing function. In addition, oral moisture levels demonstrated significant positive relationships with swallowing function. At 3 months, mucositis ratings maintained a significant, inverse relationship with swallow function. Taste and both orthonasal and retronasal smell intensity ratings demonstrated inverse relationships with measures of swallow function. Swallow functions and oral morbidities deteriorate significantly following CRT with incomplete recovery at 3 months post treatment. Furthermore, different patterns of relationships between swallow function measures and oral morbidities were obtained at the 6-week versus the 3-month assessment point suggesting that different mechanisms may contribute to the development versus the maintenance of dysphagia over the trajectory of treatment in these patients. PMID- 29619561 TI - Type of adjuvant chemotherapy and treatment frequency in survival outcome of patients with colorectal liver metastases who underwent liver metastasectomy: an 8-year cohort study in Taiwan. AB - PURPOSE: The role of adjuvant chemotherapy (ACT) in treating patients who have colorectal liver metastases (CLM) and undergo liver metastasectomy (LMS) is unclear in this patient population. We aimed to compare the mortality of patients receiving different ACT (i.e., oxaliplatin-based, irinotecan-based, and 5 fluorouracil-only (5FU)) and different treatment frequencies. METHODS: We included 2583 patients with CLM who underwent LMS (including synchronous LMS [SLMS] and metachronous LMS [MLMS]) in this retrospective cohort study. We used Cox proportional hazard model to obtain hazard ratios (HRs) for mortality. The reference group was 5FU-only ACT when comparing ACT type and the reference group was treatment for <= 3 times when comparing ACT frequency. RESULTS: In SLMS patients, oxaliplatin-based ACT (HR = 0.78) and receiving ACT for >= 4 times (4-6 times, HR = 0.61; 7-9 times, HR = 0.69; 10-12 times, HR = 0.66) were associated with lower risk of mortality. In MLMS patients, oxaliplatin-based ACT (HR = 0.52), irinotecan-based ACT (HR = 0.64), and receiving ACT for 10-12 times (HR = 0.65) were associated with lower risk of mortality. CONCLUSIONS: In SLMS and MLMS patients, patients who received oxaliplatin-based ACT were more likely to survive than patients who received 5FU-only ACT. In MLMS patients, patients who received irinotecan-based ACT were also more likely to survive than those who received 5FU only ACT. We recommend a course of at least four to six times of ACT after LMS in this patient population. PMID- 29619562 TI - A preliminary study of 3.0-T magnetic resonance diffusion tensor imaging in cervical spondylotic myelopathy. AB - PURPOSE: To compare diffusion tensor imaging (DTI) parameters of the spinal cord between patients with cervical spondylotic myelopathy (CSM) and normal subjects, and investigate their significance in the clinical diagnosis, surgical planning and post-operative evaluation of CSM. METHODS: Routine sequence magnetic resonance imaging (MRI) and DTI scans were performed in 50 normal subjects and 60 cases of CSM with 3.0-T MR. DTI images, apparent diffusion coefficient (ADC) and fractional anisotropy (FA) colormaps corresponding to spinal cord cross-sections were obtained. The spinal cord function of CSM patients was measured using modified Japanese Orthopaedic Association (mJOA) scoring and Nurick grade at different times. The changes in DTI parameters and their correlation with spinal cord function scores were analysed by SPSS 19. RESULTS: There were significant differences in DTI parameters of the spinal cord between normal subjects and patients with CSM (ADC: 1.119 +/- 0.087 vs. 1.395 +/- 0.091, P < 0.01; FA: 0.661 +/- 0.057 vs. 0.420 +/- 0.080, P < 0.01). The FA values at the maximal compression level of the spinal cord in the patients with CSM were significantly associated with the mJOA score pre-operatively, 1 week, and 1, 3 and 6 months post-operatively, with Pearson's correlation coefficients of 0.58 (P < 0.01), 0.53 (P < 0.05), and 0.51 (P < 0.05), 0.54 (P < 0.05) and 0.55 (P < 0.05), respectively. However, the FA values were significantly negatively associated with the Nurick grade, with Pearson's correlation coefficients of - 0.40 (P < 0.05), - 0.39 (P < 0.05), and -0.41 (P < 0.05), - 0.45 (P < 0.05) and - 0.44 (P < 0.05), respectively. CONCLUSIONS: DTI may play a significant role in diagnosing and predicting the development of CSM. These slides can be retrieved under Electronic Supplementary Material. PMID- 29619564 TI - Jozef Polikarp Brudzinski (1874-1917). PMID- 29619563 TI - Post-transplantation diabetes in kidney transplant recipients: an update on management and prevention. AB - Post-transplantation diabetes mellitus (PTDM) may severely impact both short- and long-term outcomes of kidney transplant recipients in terms of graft and patient survival. However, PTDM often goes undiagnosed is underestimated or poorly managed. A diagnosis of PTDM should be delayed until the patient is on stable maintenance doses of immunosuppressive drugs, with stable kidney graft function and in the absence of acute infections. Risk factors for PTDM should be assessed during the pre-transplant evaluation period, in order to reduce the likelihood of developing diabetes. The oral glucose tolerance test is considered as the gold standard for diagnosing PTDM, whereas HbA1c is not reliable during the first months after transplantation. Glycaemic targets should be individualised, and comorbidities such as dyslipidaemia and hypertension should be treated with drugs that have the least possible impact on glucose metabolism, at doses that do not interact with immunosuppressants. While insulin is the preferred agent for treating inpatient hyperglycaemia in the immediate post-transplantation period, little evidence is available to guide therapeutic choices in the management of PTDM. Metformin and incretins may offer some advantage over other glucose lowering agents, particularly with respect to risk of hypoglycaemia and weight gain. Tailoring immunosuppressive regimens may be of help, although maintenance of good kidney function should be prioritised over prevention/treatment of PTDM. The aim of this narrative review is to provide an overview of the available evidence on management and prevention of PTDM, with a focus on the available therapeutic options. PMID- 29619566 TI - Utility of pediatric female fertility preservation discussions following pelvic radiation. AB - INTRODUCTION: While many childhood cancers are curable with therapy, adverse consequences in fertility exist. We sought to assess the number of female patients with pelvic tumors receiving radiation therapy, and the proportion that undergo measures for fertility preservation (FP). METHODS: A total of 53 female patients treated with pelvic tumors from 2000 to 2016 were retrospectively identified. RESULTS: 19 (34%) of these patients underwent pelvic radiation therapy (pXRT). Three of the patients received pXRT for palliative treatment. Of the 19 female patients receiving pXRT, six (31%) were prepubertal and 13 (68%) were postpubertal. Three patients (16%) had documentation of a discussion of FP measures prior to pXRT. One was prepubertal and the others were post-pubertal. Six patients (32%) were evaluated by endocrinology after radiation therapy, diagnosed with ovarian failure, and placed on hormone therapy. Current guidelines recommend discussion of FP in pre-and postpubertal patients with cancer. This 16 year retrospective review of female patients that underwent pXRT for pelvic tumors demonstrated < 17% of patients have documentation of a discussion of FP measures. CONCLUSION: Female pediatric patients who underwent chemotherapy and pXRT suffer a high rate of premature ovarian failure, high morbidity and mortality as well as low rates of documented FP discussions. Based on these findings we have established a multi-disciplinary fertility preservation team available for consultation and a protocol for discussing and documenting the impact of pXRT, along with other treatments, on fertility. LEVEL OF EVIDENCE: III. PMID- 29619565 TI - Quantitative assessment of finger tapping characteristics in mild cognitive impairment, Alzheimer's disease, and Parkinson's disease. AB - BACKGROUND: Fine motor impairments are common in neurodegenerative disorders, yet standardized, quantitative measurements of motor abilities are uncommonly used in neurological practice. Thus, understanding and comparing fine motor abilities across disorders have been limited. OBJECTIVES: The current study compared differences in finger tapping, inter-tap interval, and variability in Alzheimer's disease (AD), Parkinson's disease (PD), mild cognitive impairment (MCI), and healthy older adults (HOA). METHODS: Finger tapping was measured using a highly sensitive light-diode finger tapper. Total number of finger taps, inter-tap interval, and intra-individual variability (IIV) of finger tapping was measured and compared in AD (n = 131), PD (n = 63), MCI (n = 46), and HOA (n = 62), controlling for age and sex. RESULTS: All patient groups had fine motor impairments relative to HOA. AD and MCI groups produced fewer taps with longer inter-tap interval and higher IIV compared to HOA. The PD group, however, produced more taps with shorter inter-tap interval and higher IIV compared to HOA. CONCLUSIONS: Disease-specific changes in fine motor function occur in the most common neurodegenerative diseases. The findings suggest that alterations in finger tapping patterns are common in AD, MCI, and PD. In addition, the present results underscore the importance of motor dysfunction even in neurodegenerative disorders without primary motor symptoms. PMID- 29619568 TI - Global Supply and Demand of Opioids for Pain Management. AB - PURPOSE OF REVIEW: The goal of this review is to evaluate the global supply and demand of opioids used for pain management and discuss how it relates to the utilization of opioids around the world. The purpose of the review is also to determine the factors that contribute to inappropriate pain management. RECENT FINDINGS: The total global production of opium for opioid manufacturing is enough to supply the growing global demands. However, licit opioids are only consumed by 20% of the world population. Most people throughout the world had no access to opioid analgesics for pain relief in case of need. Opioid misuse and abuse is not only a phenomena plague by the USA but globally across many countries. Many countries have a lack of availability of opioids, contributing factors being strict government regulations limiting access, lack of knowledge of the efficacy of opioid analgesics in treating acute and chronic pain and palliative care, and the stigma that opioids are highly addictive. For the countries in which opioids are readily available and prescribed heavily, diversion, misuse, abuse, and the resurgence of heroin have become problems leading to morbidity and mortality. It is pertinent to find a balance between having opioids accessible to patients in need, with ensuring that opioids are regulated along with other illicit drugs to decrease abuse potential. PMID- 29619567 TI - Ecotoxicological evaluation of two anti-dandruff hair shampoos using Lemna minor. AB - Hair shampoos, a mixture of various organic and organic compounds, are commonly used personnel care products. Since shampoos are used in almost every household and beauty shop, their ingredients are common components of domestic and municipal wastewater. However, studies on the effect of shampoos to aquatic plants can hardly be found in literature. Therefore, the present study was conducted to investigate the phytotoxic effects of two commonly used anti dandruff shampoos (named here AD 1 and AD 2) using Lemna minor as a biotest organism. For toxicity assessment, frond number, fresh and dry biomass, and light harvesting pigments (chlorophyll a, b and total carotenoids) of Lemna were used as end points. Five different concentrations (0.001, 0.01, 0.1, 1, and 5%) of each shampoo were tested in comparison to the control. At lower concentrations of shampoos, some minor and non-significant stimulatory effects were observed in some parameters, but at concentrations above 0.01% both the shampoos significantly inhibited almost all parameters in Lemna. The EC50 values obtained for frond number were 0.034 and 0.11% for AD 1 and AD 2, respectively. The fresh biomass gave EC50 values of 0.07 and 0.066% for AD 1 and AD 2, respectively. Based on the preset study, it can be speculated that shampoo contamination at higher concentrations in water bodies can be a threat to aquatic organisms. This study can be used as a baseline to further investigate shampoo toxicity using other species and to explore the mechanism of shampoo toxicity in aquatic plants. PMID- 29619569 TI - America's Opioid Epidemic: a Comprehensive Review and Look into the Rising Crisis. AB - PURPOSE OF REVIEW: In the USA, there has been a sharp increase in heroin, prescription opiate, and illicitly manufactured fentanyl abuse with overdoses tripling since the 1990s. Several states have been deemed as "high-burden" abuse states where there is a greater proportion of synthetic opiate use. During the same period that prescription limitations were initially implemented throughout the country, the fentanyl epidemic started nationwide. RECENT FINDINGS: In the setting of data demonstrating an almost fourfold increase in overdose deaths from 1999 to 2008, states began restricting access to Food and Drug Agency (FDA) approved opioid medications. Another factor further exacerbating the opioid crises is that the cost of all formulations of naloxone has increased significantly over the past several years. In order to combat the opioid epidemic, stricter prescribing practices and prescription-monitoring programs have been instituted. Also, improvements in abuse-deterrent strategies for all opioid preparations can play an important role by increasing the safety of these medications and is a major focus of the FDA. PMID- 29619570 TI - Brain MRI in a newborn with Zellweger syndrome: ADC quantitation in white matter disease. PMID- 29619571 TI - [Cardiovascular outcomes for people using anticoagulation strategies : COMPASS]. PMID- 29619572 TI - [Recognizing rare cardiac diseases by electrocardiogram]. AB - A number of rare cardiac diseases can be recognized by electrocardiogram (ECG). This article illustrates the clinical importance of ECG as a key diagnostic tool to detect Wolff-Parkinson-White syndrome and channelopathies, which are frequently diagnosed late after one or more affected family members have become victims of sudden cardiac death. These channelopathies include long QT syndrome, short QT syndrome, Brugada syndrome, and catecholaminergic polymorphic ventricular tachycardia. In addition, typical ECG findings are frequently present in patients with idiopathic ventricular tachycardia, arrhythmogenic right ventricular dysplasia, digitalis intoxication, hyperkalemia, acute cor pulmonale due to pulmonary embolism, as well as severe left ventricular hypertrophy as in hypertrophic cardiomyopathy. PMID- 29619573 TI - [Idiopathic systemic capillary leak syndrome (Clarkson disease) : A rare cause of recurrent life-threatening edema]. AB - This case report describes the episodic occurrence of severe generalized edema in a young female patient, who developed hypertension with a massive hemoconcentration (hematocrit >0.5, hemoglobin >20g/dl) and hypoalbuminemia during the course of these acute disease phases. After the first two disease exacerbations were overcome, there was a complete regression of symptoms. After a long symptom-free interval, a new exacerbation occurred as a result of which critical organ ischemia occurred due to the severe hypotension and massive edema. Despite all treatment measures a severe compartment syndrome of the lower extemities with subsequent rhabdomyelosis developed. The patient ultimately died as a result of treatment-refractory cardiovascular failure. The idiopathic systemic capillary leak syndrome (SCLS, also known as Clarkson disease) is a rare and potentially life-threatening disease with a high mortality. Since the first description of the disease only approximately 500 cases have been published worldwide. The pathophysiology of this disease remains unclear despite all previous attempts at clarification. Regulation processes of endothelial permeability seem to be essentially disturbed. Affected patients have a monoclonal gammopathy of undetermined signficance conspicuously often; however, the knowledge of the limited treatment options is of fundamental importance for the prognosis and overall survival of patients. PMID- 29619576 TI - Fracture risk prediction using FRAX in patients following hematopoietic stem cell transplantation. AB - : We aimed to study the utility of the FRAX tool in predicting fractures in patient's receiving a hematopoietic stem cell transplantation (HSCT). Our results indicate that the FRAX tool has modest fracture predictive ability in patients greater than 50 years of age at the time of HSCT. PURPOSE: Identifying patients at high risk of osteoporotic fractures following HSCT is challenging. We aimed to evaluate the utility of the FRAX tool at the time of HSCT in predicting fractures following transplant. METHODS: We conducted a retrospective chart review of adults (> 18 years) who underwent HSCT at MD Anderson Cancer Center from January 1, 2001, to December 31, 2010, and were followed until December 31, 2013, to identify osteoporotic fractures. Multivariate Cox regression models were built using FRAX score thresholds of low risk < 10%, medium risk 10 to 20%, and high risk > 20% probability of osteoporotic fracture. RESULTS: We identified 5170 patients who had undergone HSCT, 10% of whom developed an osteoporotic fracture during a median follow-up of 3.2 years. In patients > 65 years of age, those with medium risk (hazard ratio (HR) 2.38, 95% confidence interval (CI) 1.27-4.47) and high risk (HR 3.41, 95% CI 1.73-6.75) had a greater probability of developing an osteoporotic fracture compared to those at low risk. Similar trends were seen in patients 50 to 65 years of age. CONCLUSIONS: In patients greater than 50 years, the FRAX tool has modest predictive ability and could be used to aid in preventive treatment decision-making at the time of transplant. PMID- 29619575 TI - The Evidence for the Role of Nutraceuticals in the Management of Pediatric Migraine: a Review. AB - PURPOSE OF REVIEW: Nutraceuticals are a form of complementary and alternative medicine that is commonly used by children and adolescents with migraine. In this review, observational studies, randomized controlled trials, systematic reviews, and meta-analyses on the efficacy and safety of single compound nutraceuticals for the management of migraine in children and adolescents were identified through a literature search of MEDLINE, Embase, and EBM Reviews-Cochrane Central Register of Controlled Trials. RECENT FINDINGS: Twenty-one studies were reviewed, of which 11 were observational studies, 7 were randomized controlled trials, and 3 were systematic reviews. Six different nutraceuticals were included in the review: vitamin D, riboflavin, coenzyme Q10, magnesium, butterbur, and polyunsaturated fatty acids. All but three of the studies assessed the role of nutraceuticals in migraine prevention, while three studies evaluated the role of intravenous magnesium for acute migraine management. Overall, the quality and size of the studies were limited. Due to low quality evidence and limited studies, no definite conclusions can be drawn on the efficacy of nutraceuticals for the treatment of pediatric migraine. Future studies are warranted in order to establish evidence upon which to define the role of nutraceuticals in this patient population. PMID- 29619574 TI - Molecularly imprinted polymers for the detection of illegal drugs and additives: a review. AB - This review (with 154 refs.) describes the current status of using molecularly imprinted polymers in the extraction and quantitation of illicit drugs and additives. The review starts with an introduction into some synthesis methods (lump MIPs, spherical MIPs, surface imprinting) of MIPs using illicit drugs and additives as templates. The next section covers applications, with subsections on the detection of illegal additives in food, of doping in sports, and of illicit addictive drugs. A particular focus is directed towards current limitations and challenges, on the optimization of methods for preparation of MIPs, their applicability to aqueous samples, the leakage of template molecules, and the identification of the best balance between adsorption capacity and selectivity factor. At last, the need for convincing characterization methods, the lack of uniform parameters for defining selectivity, and the merits and demerits of MIPs prepared using nanomaterials are addressed. Strategies are suggested to solve existing problems, and future developments are discussed with respect to a more widespread use in relevant fields. Graphical abstract This review gives a comprehensive overview of the advances made in molecularly imprinting of polymers for use in the extraction and quantitation of illicit drugs and additives. Methods for syntheses, highlighted applications, limitations and current challenges are specifically addressed. PMID- 29619577 TI - Effects of sodium chloride salinity on ecophysiological and biochemical parameters of oak seedlings (Quercus robur L.) from use of de-icing salts for winter road maintenance. AB - Salt is widely used to melt snow on roads especially in mountain regions. Whether as rock salt or aerosols, spread or sprayed over road surfaces, salt may result in increased salt concentrations in soils, which, in turn, affect natural vegetation, especially tree seedlings already subjected to various other types of abiotic stress. The authors investigated the effects of salt treatment-related stress on seedling growth and certain biochemical parameters in Quercus robur to determine ion concentrations in root tips. Seedlings growing in a quartz sand/vermiculite mixture were subjected to NaCl concentrations of 0, 50, or 100 mM for 5 weeks. The results showed that high NaCl concentrations caused a marked reduction in total leaf biomass 55 and 75% for 50 and 100 mM treatments, respectively, in dry weight of stems (84%) and roots (175%) for 100 mM treatment and modified root architecture, whereas no changes appeared in leaf number. A non significant decrease in relative water content, with changes in ion balance was recorded. Comparison of stressed to control plants show an increase in sodium (3.5-8-fold), potassium (0.6-fold), and chloride (9.5-14-fold) concentrations in the root tips while the K+/Na+ ratio decreased. In taproots, no significant biochemical differences were observed between the salt-treated and the control plants for acid invertase activity, reducing sugars, sucrose, or soluble protein contents. The significance of ion and sugar accumulations in relation to osmotic adjustment and the ability of oak seedlings to cope with salt stress are discussed. PMID- 29619578 TI - Efficiency Improvement in a Busy Radiology Practice: Determination of Musculoskeletal Magnetic Resonance Imaging Protocol Using Deep-Learning Convolutional Neural Networks. AB - The purposes of this study are to evaluate the feasibility of protocol determination with a convolutional neural networks (CNN) classifier based on short-text classification and to evaluate the agreements by comparing protocols determined by CNN with those determined by musculoskeletal radiologists. Following institutional review board approval, the database of a hospital information system (HIS) was queried for lists of MRI examinations, referring department, patient age, and patient gender. These were exported to a local workstation for analyses: 5258 and 1018 consecutive musculoskeletal MRI examinations were used for the training and test datasets, respectively. The subjects for pre-processing were routine or tumor protocols and the contents were word combinations of the referring department, region, contrast media (or not), gender, and age. The CNN Embedded vector classifier was used with Word2Vec Google news vectors. The test set was tested with each classification model and results were output as routine or tumor protocols. The CNN determinations were evaluated using the receiver operating characteristic (ROC) curves. The accuracies were evaluated by a radiologist-confirmed protocol as the reference protocols. The optimal cut-off values for protocol determination between routine protocols and tumor protocols was 0.5067 with a sensitivity of 92.10%, a specificity of 95.76%, and an area under curve (AUC) of 0.977. The overall accuracy was 94.2% for the ConvNet model. All MRI protocols were correct in the pelvic bone, upper arm, wrist, and lower leg MRIs. Deep-learning-based convolutional neural networks were clinically utilized to determine musculoskeletal MRI protocols. CNN-based text learning and applications could be extended to other radiologic tasks besides image interpretations, improving the work performance of the radiologist. PMID- 29619579 TI - Behavioral problem trajectories and self-esteem changes in relation with adolescent depressive symptoms: a longitudinal study. AB - PURPOSE: Prospectively childhood behavioral problems and low self-esteem are associated with depression. However, these mental health changes over time have never been examined. This study assessed the association of childhood behavioral trajectories and self-esteem changes over time with adolescent depressive symptoms. METHODS: Parent-reported Rutter behavioral assessments and self reported Culture-Free Self-Esteem Inventories (SEI) were obtained via record linkage from the Student Health Service, Department of Health (Hong Kong), and the Patient Health Questionnaire-9 (PHQ-9) depressive symptom scores were obtained via active follow-up of the Hong Kong's Children of 1997" Chinese birth cohort. Partitional clustering was used to generate homogenous trajectories between ~ 7 and ~ 11 years for Rutter scores. Changes in low self-esteem between ~ 10 and ~ 12 years were obtained from the SEI. Multiple linear regression was used to estimate their associations with depressive symptom scores at ~ 13 years. RESULTS: Four trajectories/groups (stable low, declining, rising, and stable high) of Rutter score and self-esteem groups were created. The stable low behavioral trajectory was associated with the fewest depressive symptoms while the stable high trajectory had 1.23 more depressive symptoms [95% confidence interval (CI) 0.84 to 1.61] than the stable low trajectory. Consistently low self esteem (stable low) was associated with 2.96 more depressive symptoms (95% CI 2.35-3.57) compared to consistently high self-esteem (stable high). CONCLUSIONS: Sustained or worsening childhood behavioral problems and low self-esteem were precursors of adolescent depressive symptoms, and as such could be an early indicator of the need for intervention. PMID- 29619581 TI - Approach to undifferentiated dyspnea in emergency department: aids in rapid clinical decision-making. AB - BACKGROUND: Diagnosis and management of patients presenting with acute dyspnea is one of the major challenges for physicians in emergency department (ED). A correct diagnosis is frequently delayed and difficult to ascertain, and clinical uncertainty is common, explaining the need for rapid diagnosis and a management plan. The primary aim of our study is to assess a diagnostic strategy using multiorgan point of care ultrasonography (USG) to differentiate patients presenting with acute dyspnea to ED into different diagnostic categories for timely management in a resource-limited setting. METHODS: This is a prospective cohort study which assessed the diagnostic performance of a strategy in evaluating patients presenting with undifferentiated dyspnea as primary predominant complaint to ED. Focused multiorgan USG which includes cardiac USG for left ventricle systolic function, right ventricle enlargement, and pericardial effusion, inferior vena cava (IVC) diameter and collapsibility, lung USG to identify various patterns (acute interstitial syndrome, pneumothorax, pleural effusion, consolidation, etc.) and renal USG to assess kidney size and echotexture was performed. Later, patients were grouped into one of ten clinical syndromes defined in the study based on USG and clinical patterns. Emergency diagnosis was compared with final hospital diagnosis to assess the accuracy of this strategy. RESULTS: Concordance between ED diagnosis of dyspnea using the diagnostic strategy proposed in the study with final hospital diagnosis was high with agreement in 88% of patients (Kappa statistic = .805, p = .000) which is statistically significant. The most common diagnosis was acute decompensated heart failure (ADHF). Sensitivity and specificity of the diagnostic strategy used in this study to identify ADHF was 97.3 and 93.3%, respectively. On multivariate analysis, jugular venous distension, fever and cough, ejection fraction (by eyeball method), dilated IVC, absent to decreased lung sliding showed independent association in predicting cardiac and non-cardiac diagnosis. CONCLUSIONS: The present study concludes that integrating focused multiorgan USG by lung-cardiac IVC and renal ultrasound into routine clinical evaluation of patients with dyspnea has a higher accuracy for differentiating causes of dyspnea in emergency department. This strategy can be adopted even in resource limited setting. PMID- 29619580 TI - Prevalence and predictors of no lifetime utilization of mental health treatment among people with mental disorders in France: findings from the 'Mental Health in General Population' (MHGP) survey. AB - PURPOSE: No lifetime utilization of mental health treatment (NUMT) is an indicator of the treatment gap among people in need of treatment. Until now, the overall prevalence and predictors of NUMT have never been explored in France. METHODS: In a 39,617-respondent survey, participants were assessed for NUMT, i.e., no lifetime psychotherapy, psychopharmacotherapy, or psychiatric hospitalization. Mental disorders were investigated using the Mini International Neuropsychiatric Interview (MINI 5.0.0). MINI diagnoses were grouped into five categories: mood disorders (MDs); anxiety disorders (ADs); alcohol use disorders (AUDs); substance use disorders (SUDs); and psychotic disorders (PDs). Using multivariable logistic regression models, we explored the factors associated with NUMT among the MINI-positive respondents. The odds ratio and 95% confidence interval were calculated for each factor. RESULTS: In total, 12,818 (32.4%) respondents were MINI-positive, 46.5% of them reported NUMT (35.6% for MDs, 39.7% for PDs, 42.8% for ADs, 56.0% for AUDs, and 56.7% for SUDs). NUMT was positively associated with being male [OR 1.75 (1.59-1.91)] and practising religion [OR 1.13 (1.02-1.25)] and negatively associated with ageing [per 10-year increase: OR 0.88 (0.85-0.91)], being single [OR 0.74 (0.66-0.84)], being a French native [OR 0.67 (0.60-0.75)], and experiencing MDs [OR 0.39 (0.36-0.43)], ADs [OR 0.47 (0.43 0.52)], AUDs [OR 0.83 (0.73-0.96)], SUDs [OR 0.77 (0.65-0.91)], or PDs [OR 0.50 (0.43-0.59)]. CONCLUSIONS: In France, NUMT rates were the highest for AUDs and SUDs. Additionally, suffering from MDs or ADs increased the lifetime treatment utilization for people having any other mental disorder. This finding emphasizes the need to better screen AUDs and SUDs among people treated for MDs or ADs. PMID- 29619582 TI - The use of retinoic acid for the treatment of endometriosis. PMID- 29619583 TI - Therapeutic potential of heterocyclic pyrimidine scaffolds. AB - Heterocyclic compounds offer a high degree of structural diversity and have proven to be broadly and economically useful as therapeutic agents. Comprehensive research on diverse therapeutic potentials of heterocycles compounds has confirmed their immense significance in the pathophysiology of diseases. Heterocyclic pyrimidine nucleus, which is an essential base component of the genetic material of deoxyribonucleic acid, demonstrated various biological activities. The present review article aims to review the work reported on therapeutic potentials of pyrimidine scaffolds which are valuable for medical applications during new generation. PMID- 29619584 TI - Using in vivo fluorescence lifetime imaging to detect HER2-positive tumors. AB - BACKGROUND: Assessment of the status of tumor biomarkers in individual patients would facilitate personalizing treatment strategy, and continuous monitoring of those biomarkers and their binding process to the therapeutic drugs would provide a means for early evaluation of the efficacy of therapeutic intervention. Fluorescent probes can accumulate inside the tumor region due to the leakiness of its vascularization and this can make it difficult to distinguish if the measured fluorescence intensity is from probes bound to target receptors or just accumulated unbound probes inside the tumor. In this paper, we have studied the fluorescence lifetime as a means to distinguish bound HER2 specific affibody probes to HER2 receptors. Our imaging system is a time-resolved fluorescence system using a Ti-Sapphire femtosecond pulse laser as source and Time correlated Single photon Counting (TCSPC) system as detector for calculating the lifetime of the contrast agent. HER2-specific Affibody (His6-ZHER2:GS-Cys) (Affibody, Stockholm, Sweden) conjugated with a Dylight750 fluorescent probe (Thermo-Fisher Scientific, Waltham, Massachusetts) was used as contrast agent and six human cancer cell lines, BT-474, SKOV-3, NCI-N87, MDA-MB-361, MCF-7, and MDA-MB-468, known to express different levels of HER2/neu, are used in athymic mice xenografts. RESULTS: By comparing the lifetime of unbound contrast agent (at the contralateral site) to the fluorescence lifetime at the tumor site, our results show that the fluorescence lifetime decreases as HER2 specific Affibody probes bind to the tumor receptors. A decrease of ~15% (100ps) in tumor fluorescence lifetime was observed in tumors with mid to high HER2 expression. Smaller decreases were observed in tumors with low-level of HER2 receptors and no change was observed in the non-HER2-expressing tumors. CONCLUSIONS: Using HER2-specific Affibody conjugated with the Dylight750 fluorescent probe as contrast agent, we demonstrated in live animals that change in fluorescence lifetime of the bound contrast agent can be used to assess the high to mid-level expression of HER2 expressing tumors in-vivo in only one measurement. The rationale is that the fluorescence lifetime of our specific probe is sensitive to affinity to, and specific interaction with, other molecules. PMID- 29619585 TI - Exploring Treatment Needs and Expectations for People Living with HIV in South Africa: A Qualitative Study. AB - The UNAIDS 90-90-90 treatment targets aim to dramatically increase the number of people who initiate antiretroviral therapy (ART) by 2020. Greater understanding of barriers to ART initiation in high prevalence countries like South Africa is critical. Qualitative semi-structured interviews were conducted with 30 participants in Gugulethu Township, South Africa, including 10 healthcare providers and 20 people living with HIV (PLWH) who did not initiate ART. Interviews explored barriers to ART initiation and acceptability of theory-based intervention strategies to optimize ART initiation. An inductive content analytic approach was applied to the data. Consistent with the Theory of Triadic Influence, barriers to ART initiation were identified at the individual, social, and structural levels. Results suggested high acceptability for intervention strategies involving trained HIV-positive peers among South African PLWH and healthcare providers. Research is needed to evaluate their feasibility and efficacy in high HIV prevalence countries. PMID- 29619587 TI - Rheumatic diseases in HIV-infected patients in the post-antiretroviral therapy era: a tertiary care center experience. AB - The aim of the study was to calculate the proportion of rheumatic diseases in HIV patients who were receiving ART and to identify association of the HIV medications with the development of rheumatologic diseases. We conducted a retrospective chart review during the period of 2010 to 2016. We identified 2996 patients as having chronic HIV infection and on ART, and we collected data regarding patient's demographic characteristics, comorbidities, CD 4 count, HIV viral load, and ART. One hundred thirteen out of 2996 HIV patients (3.8%) were found to have a rheumatic condition (mean age of 48.6 years, 83% male). The most frequent musculoskeletal condition was avascular necrosis (AVN) in 39 (1.3%), and the most frequent autoimmune condition was psoriasis in 28 patients (1%). Compared with the 200 HIV patients without any diagnosis of rheumatic disease were the older patients with rheumatic conditions (mean age of 48.9 vs. 42.7 years; p < 0.01), and had a longer duration of HIV infection (mean duration of 15.5 vs. 10.3 years; p < 0.01). The odds of rheumatic conditions were 1.7 times higher in males (relative to females). Those who received integrase inhibitors were more likely (63.3%) to develop rheumatologic manifestations relative to those who never received integrase inhibitors (21.6%; p < 0.01). The proportion of rheumatic diseases in HIV patients appears to be comparable to the prevalence in the US population. Older age, longer duration of HIV infection, and the use of ART regimens containing integrase inhibitors, appear to increase the risk of developing a rheumatic condition. PMID- 29619586 TI - Social Capital, Depressive Symptoms, and HIV Viral Suppression Among Young Black, Gay, Bisexual and Other Men Who Have Sex with Men Living with HIV. AB - Social capital, the sum of an individual's resource-containing social network connections, has been proposed as a facilitator of successful HIV care engagement. We explored relationships between social capital, psychological covariates (depression, stigma and internalized homonegativity), and viral suppression in a sample of young Black gay, bisexual and other men who have sex with men (YB-GBMSM). We recruited 81 HIV-positive YB-GBMSM 18-24 years of age from a clinic setting. Participants completed a cross-sectional survey, and HIV-1 viral load (VL) measurements were extracted from the medical record. Sixty-five percent (65%) were virally suppressed (HIV-1 VL <= 40 copies/ml). Forty-seven percent (47%) had a positive depression screen. Depressive symptoms affected viral suppression differently in YB-GBMSM with lower vs. higher social capital (p = 0.046, test for statistical interaction between depression and social capital). The odds of viral suppression among YB-GBMSM with lower social capital was 93% lower among those with depressive symptoms (OR 0.07, p = 0.002); however, there was no association between depressive symptoms and viral suppression among those with higher social capital. Our results suggest that social capital may buffer the strong negative effects of depressive symptoms on clinical outcomes in YB GBMSM living with HIV. In addition to treating depression, there is a role for interventions to augment social capital among YB-GBMSM living with HIV as a strategy for enhancing care engagement. PMID- 29619588 TI - Autoimmune/inflammatory syndrome induced by mineral oil: a health problem. AB - Autoimmune/inflammatory syndrome induced by adjuvant (ASIA) includes the following conditions: siliconosis, Gulf War syndrome, macrophagic myofasciitis syndrome, and post-vaccination phenomena. Afterward, other syndromes have been recognized, such as in ASIA by mineral oil (ASIA-MO). These conditions are triggered by adjuvants and they are the result of the interplay of genetic and environmental factors. ASIA-MO is defined as the infiltration of oily type modeling substances for cosmetic purposes. It has been reported in many countries and used surreptitiously. Pathogenesis of ASIA-MO is not clear, but is characterized by chronic granulomatous inflammation, like the pristane model in mice, with increase of proinflammatory cytokines: type I interferons (IFNalpha and IFNbeta), systemic lupus erythematosus (SLE), and erosive arthritis. In humans, an increase of interleukin 1 (IL-1) has been found. Clinical spectrum of ASIA-MO is heterogeneous, varying from mild to severe and being local and systemic. The systemic manifestations can be non-specific and specific, meeting criteria for any autoimmune disease (AID), i.e., SLE, rheumatoid arthritis, and systemic sclerosis, among others. The areas of the body where the mineral oil is mostly applied include the following: buttocks (38-72%), breasts (12-16%), lower extremities (18-22%), and face (6-10%). The penis augmentation is also common. Treatment is focused on local and systemic manifestations and requires medical and surgical management representing a challenge for the physician. PMID- 29619589 TI - Involvement of Acidic Polysaccharide Ph-PS-2 and Protein in Initiation of Coccolith Mineralization, as Demonstrated by In Vitro Calcification on the Base Plate. AB - Coccolithophorids, unicellular marine microalgae, have calcified scales with elaborate structures, called coccoliths, on the cell surface. Coccoliths generally comprise a base plate, CaCO3, and a crystal coat consisting of acidic polysaccharides. In this study, the in vitro calcification conditions on the base plate of Pleurochrysis haptonemofera were examined to determine the functions of the base plate and acidic polysaccharides (Ph-PS-1, -2, and -3). When EDTA treated coccoliths (acidic polysaccharide-free base plates) or low pH-treated coccoliths (whole acidic polysaccharide-containing base plates) were used, mineralization was not detected on the base plate. In contrast, in the case of coccoliths which were decalcified by lowering of the pH and then treated with urea (Ph-PS-2-containing base plates), distinct aggregates, probably containing CaCO3, were observed only on the rim of the base plates. Energy dispersive X-ray spectroscopy (EDS) confirmed that the aggregates contained Ca and O, although X ray diffraction analysis did not reveal any evidence of crystalline materials. Also, in vitro mineralization experiments performed on EDTA-treated coccoliths using isolated acidic polysaccharides demonstrated that the Ca-containing aggregates were markedly formed only in the presence of Ph-PS-2. Furthermore, in vitro mineralization experiments conducted on protein-extracted base plates suggested that the coccolith-associated protein(s) are involved in the Ca deposition. These findings suggest that Ph-PS-2 associated with the protein(s) on the base plate rim initiates Ca2+ binding at the beginning of coccolith formation, and some other factors are required for subsequent calcite formation. PMID- 29619590 TI - A Novel High-Resolution Method for the Respiration Rate and Breathing Waveforms Remote Monitoring. AB - A search for robust noninvasive methods permitting to discern the respiration subtle peculiarities in mammals is a topical issue. A novel approach called "sorption-enhanced infrared thermography" (SEIRT), helping to solve this problem, is described. Its benefits spring from the integration of the infrared thermography (IRT) and chemical physics (phase transition heat release/absorption) within a single method. The SEIRT opportunities were verified in the investigation of 42 humans, 49 rats and 4 minipigs whose breathing waveforms were revealed to the last detail. It is shown that the SEIRT-obtained breathing-conditioned temperature response may exceed 10 degrees C (!) even in small animals (rats) and that the SEIRT sensitivity is 4.5-250 times higher than that of the matched IRT-based techniques. The new method is validated by a comparison with that based on thorax breathing movement (TBM). It is shown that the SEIRT-determined breaths have a close correlation with those determined via TBM (r = + 1.000, p ? 0.05); this is also true for breathing intervals (r = + 0.9772, p ? 0.05). SEIRT opens up the way to a high-resolution noncontact quantitative evaluation of respiration rate and breathing waveforms in both humans and animals. It may become a cutting-edge technique in diagnostic medicine and biomedical research. PMID- 29619591 TI - A case of anastomotic stenosis of the small intestine caused by cholesterol crystal embolism. AB - BACKGROUND: Cholesterol crystal embolism (CCE) is caused by small crystals of cholesterol dispersed from atherosclerotic plaques of the aorta. There is an increasing interest in CCE because of the increased use of endovascular treatments. Here, we report a rare case of intestinal stenosis caused by CCE after functional end-to-end anastomosis (FEEA). To our knowledge, this is the first report of CCE causing such an anastomotic stenosis. CASE PRESENTATION: A 77 year-old male patient underwent laparoscopy-assisted low anterior resection and protective ileostomy for rectal carcinoid tumor. He was admitted to our hospital with ileus 1 year after stoma closure. Eosinophils and creatine kinase level were slightly elevated. Computed tomography revealed a stricture with thickened intestinal wall just distal to the anastomosis site of the ileostomy. The wall of the descending aorta appeared shaggy due to thrombosis. The patient underwent laparoscopic small-bowel resection because ileus reoccurred after any oral intake. Histopathological findings of the resected specimen showed fibrotic changes distal to the anastomosis site, and needle-shaped cholesterol embolus was observed in the submucosal layer. Thus, the stenosis was considered to be caused by CCE. CONCLUSION: This appears to be the first published report of stenosis due to CCE at such an anastomotic site. Intestinal CCE is difficult to diagnose preoperatively and is associated with poor prognosis. If eosinophilia is present or shaggy aorta is observed, CCE should be suspected to make correct diagnosis and prevent recurrence of CCE. PMID- 29619592 TI - The predictors and oncological outcomes of repeat surgery for recurrence after hepatectomy for colorectal liver metastases. AB - PURPOSE: Although recurrence after hepatectomy for colorectal liver metastases (CRLM) is common, the optimal treatment strategy remains unclear. The aims of this study were to clarify the impact of repeat surgery and identify the predictive factors for repeat surgery. METHODS: Among the 170 patients who underwent potentially curative surgery for CRLM, 113 developed recurrence. The predictive factors for the performance of repeat surgery were identified and a predictive model was constructed. RESULTS: The patterns of recurrence were as follows; single site [n = 100 (liver, n = 61; lung, n = 22; other, n = 17)], multiple site (n = 13). Repeat surgery was performed in 54 patients (47.8%) including re-hepatectomy (n = 25), radiofrequency ablation (n = 12), and resection of the extrahepatic recurrent disease (n = 17), and their overall survival (OS) was significantly better than that of those who could not (5-year OS 60.7 vs 19.5%, P < 0.0001). A multivariate analysis revealed that a primary N negative status [relative risk (RR) 2.93, P = 0.017], indocyanine retention rate at 15 min <= 10% before hepatectomy (RR 2.49, P = 0.04), and carcinoembryonic antigen <= 5 ng/mL before hepatectomy (RR 2.96, P = 0.017) independently predicted the performance of repeat surgery. For patients who did not present any factors, the probability of repeat surgery was 19.6%. The addition of each subsequent factor increased the probability to 41.9, 67.8, and 84.0% (for 1, 2, and 3 factors, respectively). CONCLUSIONS: Repeat surgery for not only intrahepatic but also extrahepatic recurrence is crucial for prolonging the survival of CRLM patients. The proposed model may help to predict the possibility of repeat surgery and provide optimal individualized treatment. PMID- 29619593 TI - Authors' reply to Medeiros et al.: Make it easier! Evaluation of the 'vagal sympathetic effect' in different conditions with R-R intervals monitoring. PMID- 29619594 TI - Make it easier! Evaluation of the 'vagal-sympathetic effect' in different conditions with R-R intervals monitoring. PMID- 29619595 TI - New Zealand blackcurrant extract enhances fat oxidation during prolonged cycling in endurance-trained females. AB - PURPOSE: New Zealand blackcurrant (NZBC) extract has previously been shown to increase fat oxidation during prolonged exercise, but this observation is limited to males. We examined whether NZBC intake also increases fat oxidation during prolonged exercise in females, and whether this was related to greater concentrations of circulating fatty acids. METHODS: In a randomised, crossover, double-blind design, 16 endurance-trained females (age: 28 +/- 8 years, BMI: 21.3 +/- 2.1 kg.m-2, VO2max: 43.7 +/- 1.1 ml.kg-1.min-1) ingested 600 mg.day-1 NZBC extract (CurraNZTM) or placebo (600 mg.day-1 microcrystalline cellulose) for 7 days. On day 7, participants performed 120 min cycling at 65% VO2max, using online expired air sampling with blood samples collected at baseline and at 15 min intervals throughout exercise for analysis of glucose, NEFA and glycerol. RESULTS: NZBC extract increased mean fat oxidation by 27% during 120 min moderate intensity cycling compared to placebo (P = 0.042), and mean carbohydrate oxidation tended to be lower (P = 0.063). Pre-exercise, plasma NEFA (P = 0.034) and glycerol (P = 0.051) concentrations were greater following NZBC intake, although there was no difference between conditions in the exercise-induced increase in plasma NEFA and glycerol concentrations (P > 0.05). Mean fat oxidation during exercise was moderately associated with pre-exercise plasma NEFA concentrations (r = 0.45, P = 0.016). CONCLUSIONS: Intake of NZBC extract for 7 days elevated resting concentrations of plasma NEFA and glycerol, indicative of higher lipolytic rates, and this may underpin the observed increase in fat oxidation during prolonged cycling in endurance-trained females. PMID- 29619596 TI - Resection of synchronous bilateral multiple lung adenocarcinomas using virtual assisted lung mapping. AB - BACKGROUND: Virtual-assisted lung mapping (VAL-MAP) is a novel marking technique to assist sub-lobar resection of small hardly palpable lung tumors. Here, we present the first case of synchronous bilateral multiple lung adenocarcinomas that were successfully resected with VAL-MAP navigation. CASE PRESENTATION: A 73 year-old female with multiple nodules (1 in the right upper lobe, 2 in the right lower lobe, 1 in the left upper lobe, and 1 in the left lower lobe) was referred. Complete resection was achieved with left lower lobectomy in combination with sub lobar resections (wedge resection for a lesion in the left upper lobe, segmentectomy for a lesion in the right upper lobe, and complex segmentectomy for lesions in the right lower lobe) in which resection lines with securing adequate margins were determined with VAL-MAP navigation. CONCLUSIONS: VAL-MAP is useful in sub-lobar resections including complex segmentectomy for multiple lung adenocarcinomas. PMID- 29619597 TI - The highly selective oxidation of cyclohexane to cyclohexanone and cyclohexanol over VAlPO4 berlinite by oxygen under atmospheric pressure. AB - BACKGROUND: The oxidation of cyclohexane under mild conditions occupies an important position in the chemical industry. A few soluble transition metals were widely used as homogeneous catalysts in the industrial oxidation of cyclohexane. Because heterogeneous catalysts are more manageable than homogeneous catalysts as regards separation and recycling, in our study, we hydrothermally synthesized and used pure berlinite (AlPO4) and vanadium-incorporated berlinite (VAlPO4) as heterogeneous catalysts in the selective oxidation of cyclohexane with molecular oxygen under atmospheric pressure. The catalysts were characterized by means of by XRD, FT-IR, XPS and SEM. Various influencing factors, such as the kind of solvents, reaction temperature, and reaction time were investigated systematically. RESULTS: The XRD characterization identified a berlinite structure associated with both the AlPO4 and VAlPO4 catalysts. The FT-IR result confirmed the incorporation of vanadium into the berlinite framework for VAlPO4. The XPS measurement revealed that the oxygen ions in the VAlPO4 structure possessed a higher binding energy than those in V2O5, and as a result, the lattice oxygen was existed on the surface of the VAlPO4 catalyst. It was found that VAlPO4 catalyzed the selective oxidation of cyclohexane with molecular oxygen under atmospheric pressure, while no activity was detected on using AlPO4. Under optimum reaction conditions (i.e. a 100 mL cyclohexane, 0.1 MPa O2, 353 K, 4 h, 5 mg VAlPO4 and 20 mL acetic acid solvent), a selectivity of KA oil (both cyclohexanol and cyclohexanone) up to 97.2% (with almost 6.8% conversion of cyclohexane) was obtained. Based on these results, a possible mechanism for the selective oxidation of cyclohexane over VAlPO4 was also proposed. CONCLUSIONS: As a heterogeneous catalyst VAlPO4 berlinite is both high active and strong stable for the selective oxidation of cyclohexane with molecular oxygen. We propose that KA oil is formed via a catalytic cycle, which involves activation of the cyclohexane by a key active intermediate species, formed from the nucleophilic addition of the lattice oxygen ion with the carbon in cyclohexane, as well as an oxygen vacancy formed at the VAlPO4 catalyst surface. PMID- 29619598 TI - PCR array profiling of antiviral genes in human embryonic kidney cells expressing human coronavirus OC43 structural and accessory proteins. AB - Human coronavirus OC43 (HCoV-OC43) is a respiratory virus that usually causes a common cold. However, it has the potential to cause severe infection in young children and immunocompromised adults. Both SARS-CoV and MERS-CoV were shown to express proteins with the potential to evade early innate immune responses. However, the ability of HCoV-OC43 to antagonise the intracellular antiviral defences has not yet been investigated. The potential role of the HCoV-OC43 structural (M and N) and accessory proteins (ns2a and ns5a) in the alteration of antiviral gene expression was investigated in this study. HCoV-OC43M, N, ns2a and ns5a proteins were expressed in human embryonic kidney 293 (HEK-293) cells before challenge with Sendai virus. The Human Antiviral Response PCR array was used to profile the antiviral gene expression in HEK-293 cells. Over 30 genes were downregulated in the presence of one of the HCoV-OC43 proteins, e.g. genes representing mitogen-activated protein kinases, toll-like receptors, interferons, interleukins, and signaling transduction proteins. Our findings suggest that similarly to SARS-CoV and MERS-CoV, HCoV-OC43 has the ability to downregulate the transcription of genes critical for the activation of different antiviral signaling pathways. Further studies are needed to confirm the role of HCoV-OC43 structural and accessory proteins in antagonising antiviral gene expression. PMID- 29619599 TI - Inactivated enterovirus 71 with poly-gamma-glutamic acid/Chitosan nano particles (PC NPs) induces high cellular and humoral immune responses in BALB/c mice. AB - Enterovirus 71 (EV71) is the major causative agent of hand-foot-and-mouth disease (HFMD) and many neurological manifestations. Recently, this virus has become a serious concern because of consecutive epidemics in the Asia-Pacific region. However, no effective vaccine for EV71 has been discovered except two EV71 vaccines which are being used in local communities of China. To develop a safe and efficient EV71 vaccine candidate, we generated inactivated EV71 and evaluated its efficacy with gamma-PGA/Chitosan nanoparticles (PC NPs), which are safe, biodegradable and effective as an adjuvant. The subcutaneous administration of inactivated EV71 with PC NPs adjuvant induces higher levels of virus-specific humoral (IgG, IgG1, and IgG2a) and cell-mediated immune responses (IFN-gamma and IL-4). Additionally, inactivated EV71 with PC NPs adjuvant induces significantly higher virus neutralizing antibody responses compared to the virus only group, and resulted in a long lasting immunity without any noticeable side effects. Together, our findings demonstrate that PC NPs are safe and effective immunogenic adjuvants which may be promising candidates in the development of more efficacious EV71 vaccines. PMID- 29619600 TI - Identification and molecular characterization of a novel varicosa-like virus from red clover. AB - During aetiological study of diseased red clover (Trifolium pratense L.) using high throughput sequencing, a novel virus with a 10 kb genome divided into two segments was discovered. The virus, tentatively named red clover associated varicosavirus (RCaVV), is phylogenetically related to classifiable members of the genus Varicosavirus (family Rhabdoviridae, order Mononegavirales). Analysis of mRNA levels from the individual RCaVV genes suggested possible differences in transcription regulation between rhabdoviruses with divided and undivided genomes. PMID- 29619602 TI - Radiological and hydrochemical study of thermal and fresh groundwater samples of northern Euboea and Sperchios areas, Greece: insights into groundwater natural radioactivity and geology. AB - A radiological and hydrochemical study has been conducted on thermal and fresh groundwater samples of northern Euboea Island and eastern central Greece. Both areas are characterized by complex geology and are renowned since antiquity for their hot springs, that are exploited for therapeutic spa purposes until today. The aim of the study was to combine radiological and hydrochemical data in order to achieve a holistic water quality assessment with insights into the geology of the study areas. All samples were characterized with respect to their major and trace ion and element composition, as well as activity concentrations of 222Rn, 226Ra, 228Ra, 228Th, and 40K. The samples demonstrated elevated natural radioactivity and U concentrations, especially in some locations of the Kamena Vourla area, reaching 179 Bq/L 222Rn, 2.2 Bq/L 226Ra, 2.9 Bq/L 228Ra, and 17 MUg/L U. The estimated circulation depth of thermal groundwater ranges between 250 m in central Greece and 1240 m in north Euboea study area, whereas the calculated water residence times range between 27 and 555 years. Our data suggest the possible presence of an unknown until know U-rich plutonic rock formation in Kamena Vourla area and immiscibility of the fresh and thermal groundwaters in the studied areas. PMID- 29619603 TI - Inosine improves cognitive function and decreases aging-induced oxidative stress and neuroinflammation in aged female rats. AB - In the present study, the effect of inosine was evaluated on learning and memory of 18 months old aged female rats. Inosine (50, 100 and 200 mg/kg; i.p.) was administered to separate groups of rats for 15 successive days. Donepezil (1 mg/kg; i.p.), an acetylcholinesterase inhibitor, was used as a standard drug. Behavioral models such as Morris water maze and elevated plus maze were used to evaluate the effect of drugs on learning and memory of rats. After behavioral studies, animals were killed and their brain was isolated and further processed for estimation of various biochemical parameters such as acetylcholinesterase activity, oxidative stress markers, proinflammatory marker and histological examinations. Inosine (100 and 200 mg/kg) significantly improved learning and memory of aged rats. Further, inosine significantly reduced lipid peroxidation and nitrite, and increased the levels of reduced glutathione and superoxide dismutase. However, no significant difference in AChEs activity was observed in inosine-treated rats as compared to aged control rats. TNF-alpha level was found to be ameliorated in aged rats by inosine. Histopathological evaluation showed that inosine-treated aged rats have less number of pyknotic neurons in hippocampal CA1 region as compared to aged control rats. In conclusion, inosine significantly improved learning and memory of aged female rats possibly through its antioxidant as well as anti-inflammatory effect and improvement of neuronal survival in the hippocampal CA1 region. However, additional studies are required to further explore the downstream signaling pathways involved in the neuroprotective effect of inosine in aged animals. PMID- 29619605 TI - Both melatonin and meloxicam improved sleep and pain in females with primary dysmenorrhea-results from a double-blind cross-over intervention pilot study. AB - Up to 25% of ovulating women suffer from primary dysmenorrhea, a condition associated with pain and transient-reduced quality of life, along with greater irritability and impaired sleep. In the present study, we asked whether and if so to what extent melatonin and meloxicam can improve subjective and objective sleep and reduce pain among women with primary dysmenorrhea (PD). To this end, we conducted a double-blind cross-over clinical trial lasting for three menstrual cycles. A total of 14 women (mean age M = 27.5 years) with primary dysmenorrhea took part in the study. At baseline, that is, during the first menstruation, they completed a visual analogue scale to rate pain; sleep continuity was assessed via actigraphs, and overall sleep quality was assessed with the Pittsburgh Sleep Quality Index (PSQI). Next, participants were randomly assigned to one of two conditions, either melatonin during the second, and meloxicam during the third menstruation, or meloxicam during the second, and melatonin during the third menstruation. Neither participants nor investigators were aware of participants' study assignment. During the second and third menstruations, the assessments described above were repeated. At baseline, sleep assessed both objectively and subjectively was impaired, and pain was high. Subjective sleep improved and pain decreased during the second and third menstruations irrespective of whether melatonin or meloxicam was administered first or second. Likewise, objective sleep efficiency increased and objective sleep latency shortened. The efficacy of melatonin was superior to that of meloxicam. The present pattern of results suggests that both melatonin and meloxicam are suitable to treat pain and PD related sleep complaints among women with primary dysmenorrhea. PMID- 29619604 TI - Prevalence and genetic diversity of norovirus genogroup II in children less than 5 years of age with acute gastroenteritis in Tehran, Iran. AB - Viral gastroenteritis is a major public health problem worldwide. In Iran, very limited studies have been performed with regard to the epidemiology of noroviruses. This study aimed to evaluate the prevalence and molecular epidemiology of GII noroviruses in hospitalized children less than 5 years of age with acute gastroenteritis (AGE). A total of 210 stool specimens were collected from Ali Asghar Children's Hospital and Bahrami Children's Hospital in Tehran, from June 2015 to June 2016. The samples were screened by real-time RT-PCR for genogroup II (GII). Positive samples were genotyped by semi-nested PCR followed by Sanger sequencing and phylogenetic analysis. Norovirus was identified in 36 (17.1%) of 210 specimens. Based on genetic analysis of RdRp and capsid sequences, the strains were clustered into eight RdRp-capsid genotypes: GII.P4-GII.4 Sydney_2012 (41.7%), GII.Pe-GII.4 Sydney_2012 (30.6%), GII.P21-GII.3 (13.9%), GII.P16-GII.4 Sydney_2012 (2.8%), GII.P16-GII.12 (2.8%), GII.P2-GII.4 Sydney_2012 (2.8%), GII.P7-GII.7 (2.8%) and GII.P2-GII.2 (2.8%). We determined several different co-circulating norovirus genotypes in children < 5 years of age with AGE in our hospital in Tehran, Iran. Continued molecular surveillance of noroviruses, including typing of both RdRp and capsid genes, is important for monitoring emerging strains in our continued efforts to reduce the overall burden of norovirus disease. PMID- 29619606 TI - The role of reactive oxygen species in pollen germination in Picea pungens (blue spruce). AB - KEY MESSAGE: Endogenous ROS, including those produced by NADPH oxidase, are required for spruce pollen germination and regulate membrane potential in pollen tubes; [Formula: see text] and H 2 O 2 are unevenly distributed along the tube. Recently, the key role of reactive oxygen species (ROS) in plant reproduction has been decisively demonstrated for angiosperms. This paper is dedicated to the involvement of ROS in pollen germination of gymnosperms, which remained largely unknown. We found that ROS are secreted from pollen grains of blue spruce during the early stage of activation. The localization of different ROS in pollen tube initials and pollen tubes demonstrated the accumulation of H2O2 in pollen tube apex. Colocalization with mitochondria-derived [Formula: see text] showed that H2O2 is produced in mitochondria and amyloplasts in addition to its apical gradient in the cytosol. The necessity of intracellular ROS and, particularly, [Formula: see text] for pollen germination was demonstrated using different antioxidants. .OH and extracellular ROS, on the contrary, were found to be not necessary for germination. Exogenous hydrogen peroxide did not affect the germination efficiency but accelerated pollen tube growth in a concentration dependent manner. The optical measurements of membrane potential showed that in spruce pollen tubes there is a gradient which is controlled by H+-ATPase, potassium- and calcium-permeable channels, anion channels and ROS, as demonstrated by inhibitory analysis. An important role of NADPH oxidase in the regulation of ROS balance in particular, and in germination in general, has been demonstrated by inhibiting the enzyme, which leads to the reduction in ROS release, depolarization of pollen tube plasma membrane, and blocking of pollen germination. PMID- 29619607 TI - Pharmacokinetic/Pharmacodynamic Considerations of Beta-Lactam Antibiotics in Adult Critically Ill Patients. AB - PURPOSE OF REVIEW: Beta-lactam antibiotics are commonly prescribed in critically ill patients for a variety of infectious conditions. Our understanding of how critical illness alters beta-lactam pharmacokinetics/pharmacodynamics (PK/PD) is rapidly evolving. RECENT FINDINGS: There is a growing body of literature in adult patients demonstrating that physiological alterations occurring in critically ill patients may limit our ability to optimally dose beta-lactam antibiotics to reach these PK/PD targets. These alterations include changes in volume of distribution and renal clearance with multiple, often overlapping causative pathways, including hypoalbuminemia, renal replacement therapy, and extracorporeal membrane oxygenation. Strategies to overcome these PK alterations include extended infusions and therapeutic drug monitoring. Combined data has demonstrated a possible survival benefit associated with extending beta-lactam infusions in critically ill adult patients. This review highlights research on physiological derangements affecting beta-lactam concentrations and strategies to optimize beta lactam PK/PD in critically ill adults. PMID- 29619608 TI - Interleukin 15 concentrations in follicular fluid and their effect on oocyte maturation in subfertile women undergoing intracytoplasmic sperm injection. AB - PURPOSE: To calculate the concentrations of interleukin 15 (IL-15) in follicular fluid (FF) and evaluate their relation with oocyte maturation, follicle size, and patients' body mass index (BMI) and age. METHODS: Follicular fluid specimens were obtained from 56 subfertile women undergoing intracytoplasmic sperm injection (ICSI) during oocyte retrieval for measurement of IL-15 concentrations with ELISA. Wilcoxon's test and Pearson's correlation coefficient were used to correlate FF concentrations of IL-15 with follicular size and stage of oocyte maturation, along with patients' BMI and age. RESULTS: IL-15 concentrations in FF of follicles with immature oocytes were significantly greater than those from follicles with mature ones (median 5.333 vs. 3.250 pg/ml, respectively, p < 0.001). There was a significant negative correlation between IL-15 concentrations and follicle size (r = - 0.333, p = 0.003). No significant correlation was observed between IL-15 concentrations and patients' BMI and age (p > 0.05). CONCLUSIONS: IL-15 concentrations in FF are adversely related with the size of the follicles and the maturity of the corresponding retrieved oocytes in a cohort of expected normal responders undergoing intracytoplasmic sperm injection (ICSI). Follicular fluid concentrations of IL-15 should be investigated as a possible predictive factor for oocyte maturity. PMID- 29619609 TI - Groundwater Contamination by Mercury from the Aforetime Carroting Practice. AB - In the southernmost Brazilian city of Rio Grande, the chemical treatment of animal fur named carroting was performed between the eighteenth and twentieth century. This type of industry has led to contamination of urban soil with mercury down to the groundwater level. The present study has revealed that the dissolved mercury concentrations in groundwater in the mercury contaminated areas was up to 13 times higher than that found in the reference site. The association between SO42-, Ca2+ and dissolved mercury indicate that urban man-made grounds composed by soil, construction and demolition waste, urban rubbish and mud contaminated by "carroting mercury" serve as a source of this metal to groundwater. Despite the high level of contamination, mercury concentrations found in groundwater were below the permissible level established for potable water. Most of the dissolved mercury was chemically combined, probably with organic matter. PMID- 29619610 TI - Ultrasound thermal monitoring with an external ultrasound source for customized bipolar RF ablation shapes. AB - PURPOSE: Thermotherapy is a clinical procedure which delivers thermal energy to a target, and it has been applied for various medical treatments. Temperature monitoring during thermotherapy is important to achieve precise and reproducible results. Medical ultrasound can be used for thermal monitoring and is an attractive medical imaging modality due to its advantages including non-ionizing radiation, cost-effectiveness and portability. We propose an ultrasound thermal monitoring method using a speed-of-sound tomographic approach coupled with a biophysical heat diffusion model. METHODS: We implement an ultrasound thermometry approach using an external ultrasound source. We reconstruct the speed-of-sound images using time-of-flight information from the external ultrasound source and convert the speed-of-sound information into temperature by using the a priori knowledge brought by a biophysical heat diffusion model. RESULTS: Customized treatment shapes can be created using switching channels of radio frequency bipolar needle electrodes. Simulations of various ablation lesion shapes in the temperature range of 21-59 [Formula: see text]C are performed to study the feasibility of the proposed method. We also evaluated our method with ex vivo porcine liver experiments, in which we generated temperature images between 22 and 45 [Formula: see text]C. CONCLUSION: In this paper, we present a proof of concept showing the feasibility of our ultrasound thermal monitoring method. The proposed method could be applied to various thermotherapy procedures by only adding an ultrasound source. PMID- 29619611 TI - Self-guided training for deep brain stimulation planning using objective assessment. AB - OBJECTIVE: Deep brain stimulation (DBS) is an increasingly common treatment for neurodegenerative diseases. Neurosurgeons must have thorough procedural, anatomical, and functional knowledge to plan electrode trajectories and thus ensure treatment efficacy and patient safety. Developing this knowledge requires extensive training. We propose a training approach with objective assessment of neurosurgeon proficiency in DBS planning. METHODS: To assess proficiency, we propose analyzing both the viability of the planned trajectory and the manner in which the operator arrived at the trajectory. To improve understanding, we suggest a self-guided training course for DBS planning using real-time feedback. To validate the proposed measures of proficiency and training course, two experts and six novices followed the training course, and we monitored their proficiency measures throughout. RESULTS: At baseline, experts planned higher quality trajectories and did so more efficiently. As novices progressed through the training course, their proficiency measures increased significantly, trending toward expert measures. CONCLUSION: We developed and validated measures which reliably discriminate proficiency levels. These measures are integrated into a training course, which quantitatively improves trainee performance. The proposed training course can be used to improve trainees' proficiency, and the quantitative measures allow trainees' progress to be monitored. PMID- 29619612 TI - Red Emitting Monoazo Disperse Dyes with Phenyl(1H-benzoimidazol-5-yl) Methanone as Inbuilt Photostabilizing Unit: Synthesis, Spectroscopic, Dyeing and DFT Studies. AB - Synthesis of three novel phenyl(1H-benzoimidazol-5-yl)methanone based fluorescent monoazo disperse dyes and their characterization by spectroscopic methods (1H NMR, 13C NMR, IR and MS) are presented. Insertion of phenyl(1H-benzoimidazol-5 yl)methanone moiety bring about induced fluorescence properties and enhanced photostability as compared to the previously reported analogues (CI Solvent Yellow 14, 4-diethylamino-2-hydroxy-1-diazobenzene and 7-(diethylamino)-4-hydroxy 3-(phenyldiazenyl)-2H-chromen-2-one). Synthesized phenyl(1H-benzoimidazol-5 yl)methanone based dyes exhibited red-shifted absorption maxima (497-516 nm), high molar extinction coefficients and are emitting in the far-red region (565 627 nm). Moreover, naphthalene-comprising dyes showed negative solvatochromism while N,N-diethylamine comprising dyes showed positive solvatochromism and are in good agreement with solvent polarity graphs and the computed energy levels of highest occupied and lowest unoccupied molecular orbitals. Synthesised dyes have better photostability (light fastness) and sublimation fastness on dyed polyester and nylon compared to reported analogues. DFT calculated energies, electrophilicity index and Frontier Molecular Orbitals (FMO's) enabled to evaluate the stabilities of azo and hydrazone forms of the dyes. PMID- 29619613 TI - Soft tissue sarcomas in the precision medicine era: new advances in clinical practice and future perspectives. AB - Soft tissue sarcomas (STSs) represent a rare and heterogeneous group of solid tumours derived from mesenchymal progenitors and account for 1% of all adult malignancies. Although in the last decade anthracycline-based chemotherapy single agent or in combinations has been able to improve clinical benefits, prognosis is still poor and STSs represent an important unmet medical need. Continuous advances in cancer genetics and genomics have contributed to change management paradigms of STSs as it occurred for other solid tumours. Several treatments have been recently developed with the specific aim of targeting different cell pathways and immune-checkpoints that have been recognized to drive tumour progression. The following attempts to provide a review of literature focusing on the available data concerning novel treatments and future prospective for the management of metastatic STSs. PMID- 29619615 TI - Dysfunctional gamma-Secretase in Familial Alzheimer's Disease. AB - Genetics strongly implicate the amyloid beta-peptide (Abeta) in the pathogenesis of Alzheimer's disease. Dominant missense mutation in the presenilins and the amyloid precursor protein (APP) cause early-onset familial Alzheimer's disease (FAD). As presenilin is the catalytic component of the gamma-secretase protease complex that produces Abeta from APP, mutation of the enzyme or substrate that produce Abeta leads to FAD. However, the mechanism by which presenilin mutations cause FAD has been controversial, with gain of function and loss of function offered as binary choices. This overview will instead present the case that presenilins are dysfunctional in FAD. gamma-Secretase is a multi-functional enzyme that proteolyzes the APP transmembrane domain in a complex and processive manner. Reduction in a specific function-the carboxypeptidase trimming of initially formed long Abeta peptides containing most of the transmembrane domain to shorter secreted forms-is an emerging common feature of FAD-mutant gamma secretase complexes. PMID- 29619614 TI - TNFalpha and IL-1beta but not IL-18 Suppresses Hippocampal Long-Term Potentiation Directly at the Synapse. AB - CNS inflammatory responses are linked to cognitive impairment in humans. Research in animal models supports this connection by showing that inflammatory cytokines suppress long-term potentiation (LTP), the best-known cellular correlate of memory. Cytokine-induced modulation of LTP has been previously studied in vivo or in brain slices, two experimental approaches containing multiple cell populations responsive to cytokines. In their target cells, cytokines commonly increase the expression of multiple cytokines, thus increasing the complexity of brain cytokine networks even after single-cytokine challenges. Whether cytokines suppress LTP by direct effects on neurons or by indirect mechanisms is still an open question. Here, we evaluated the effect of a major set of inflammatory cytokines including tumor necrosis factor-alpha (TNFalpha), interleukin-1beta (IL 1beta) and interleukin-18 (IL-18) on chemically-induced LTP (cLTP) in isolated hippocampal synaptosomes of mice, using fluorescence analysis of single-synapse long-term potentiation (FASS-LTP). We found that TNFalpha and IL-1beta suppress synaptosomal cLTP. In contrast, cLTP was not affected by IL-18, at a concentration previously shown to block LTP in hippocampal slices. We also found that IL-18 does not impair cLTP or brain-derived neurotrophic factor (BDNF) signaling in primary hippocampal neuronal cultures. Thus, using both synaptosomes and neuron cultures, our data suggest that IL-18 impairs LTP by indirect mechanisms, which may depend on non-neuronal cells, such as glia. Notably, our results demonstrate that TNFalpha and IL-1beta directly suppress hippocampal plasticity via neuron-specific mechanisms. A better understanding of the brain's cytokine networks and their final molecular effectors is crucial to identify specific targets for intervention. PMID- 29619616 TI - Association Between Suicide and Environmental Variables in the North of Spain: A 14-Year Analysis. AB - Suicide is a serious public health problem around the world. Since the nineteenth century, the impact of socio-environmental factors on suicide has attracted much public attention, especially in the context of global climate change. We have performed a retrospective correlation study that analyzes the demographic pattern of suicide in Cantabria, a northern coastland region of Spain. Moreover, we have created a multivariable binomial regression model to study the relationship between suicide and environmental factors (atmospheric pollutants and meteorological variables) among January 1, 2000, and December 31, 2013 in the province. During the 14-year study period, there was a suicide annual incidence of 4.9 cases per 100,000 population in Cantabria. The incidence was highest in adults aged 70-74 years old (11.8 per 100,000 population). The most common method group of suicide was hanging, strangulation and suffocation, accounting for 49.3% of all suicide deaths. When correlating suicide and meteorological variables, a statistically significant association was found with the level of cloudiness (p = 0.007). According to our results, an increase of one eighth of sky cloud-cover correlated to a 7% increase in total deaths by suicide and the association was especially strong during spring. PMID- 29619617 TI - Was Aristotle the 'father' of the epigenesis doctrine? AB - Was Aristotle the 'father' and founder of the epigenesis doctrine? Historically, I will argue, this question must be answered with 'no'. Aristotle did not initiate and had no access to a debate that described itself in terms of 'epigenesis' and 'preformation', and thus cannot be considered the 'father' or founder of the epigenesis-preformation controversy in a literal sense. But many ancient accounts of reproduction and embryological development contain analogies to what early modern scientist called 'epigenesis' and 'preformation', and, in this analogous sense, Aristotle can be considered a precursor of the epigenesis preformation controversy. But is Aristotle's position actually epigenetic (in this analogous sense), as most of the traditional interpreters hold, or preformationist, as some of the recent scholars believe? I will argue against the one-sidedness of both readings that Aristotle's account of reproduction and heredity contains mainly epigenetic, but also a few preformationist characteristics. Whereas, for instance, Aristotle's idea of a successive development of the embryo's parts is doubtlessly epigenetic, Aristotle's idea that the development of the embryo is an actualization and enlargement of potential parts, which are simultaneously present in the semen, can be considered a preformationist feature. PMID- 29619618 TI - Hemangioblastoma in Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome: a phenotypic overlap between VHL and HLRCC Syndromes. AB - Hemangioblastomas are rare vascularized central nervous system tumors, which can occur sporadically or be associated with von Hippel Lindau Syndrome. The pathogenesis of hemangioblastomas in von Hippel Lindau Syndrome is proposed to involve a pseudohypoxic intracellular state induced by dysregulation of hypoxia inducible factor alpha due to the absence of von Hippel Lindau protein complex mediated destruction. Dysregulation of fumarate hydratase, a tricarboxylic acid cycle enzyme, occurs in Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome due to germline fumarate hydratase gene mutations, and also results in oncogenesis via hypoxia inducible factor alpha dysregulation. We present a case study of hemangioblastoma occurrence in a Hereditary Leiomyomatosis and Renal Cell Cancer Syndrome patient and propose it as possible evidence of a phenotypic overlap between von Hippel Lindau and Hereditary Leiomyomatosis and Renal Cell Cancer Syndromes due to their overlapping role in the biochemical regulation of hypoxia inducible factor alpha. PMID- 29619619 TI - Comparison of the antioxidant effects of carnosic acid and synthetic antioxidants on tara seed oil. AB - BACKGROUND: In the present study, tara seed oil was obtained by supercritical fluid extraction and used to investigate the antioxidant strength of carnosic acid (CA) compared with conventional synthetic antioxidants. METHODS: The antioxidants were added to the tara seed oil at 0.2 mg of antioxidant per gram of oil. The samples were then submitted to at 60 degrees C 15 days for an accelerated oxidation process, with samples taken regularly for analysis. After oxidation, the samples were analyzed to determine the peroxide value, thiobarbituric acid reactive substances, conjugated diene content, and free fatty acid content. CA was investigated at three purity levels (CA20, CA60, CA99), and compared with three synthetic antioxidants (butylatedhydroxyanisole, butylatedhydroxytoluene, and tert-butylhydroquinone). RESULTS: The oxidation indicators showed that CA was a strong antioxidant compared to the synthetic antioxidants. The antioxidant activities decreased in the order: tert butylhydroquinone > CA99 > CA60 > CA20 > butylatedhydroxyanisole > butylatedhydroxytoluene. These results show that CA could be used to replace synthetic antioxidants in oil products, and should be safer for human consumption and the environment. PMID- 29619620 TI - Evidence-Based Non-Pharmacological Therapies for Fibromyalgia. AB - PURPOSE OF REVIEW: Fibromyalgia (FM) is the second most common rheumatologic pain disorder after osteoarthritis with a multisystem presentation. While the treatment of FM in a clinical setting incorporates both pharmacologic and non pharmacologic modalities, the present investigation reviews evolving literature on cognitive behavioral and complementary medical therapies. The recent medical literature on FM was reviewed between 2012 and 2017 via MEDLINE and the Cochrane Central Registry of Controlled Trials, with an emphasis on randomized controlled trials, meta-analyses, and evidence-based treatment guidelines. RECENT FINDINGS: Cognitive behavioral therapy continues to play a significant role in the non medical therapy of FM. It is especially helpful in high catastrophizing patients as evidenced by recent studies that note changes in the brain on functional magnetic resonance imaging. Mindfulness meditation can be helpful in improving pain symptoms and pain perception. No particular diet is found to have a meaningful impact in FM; however, various diets including low fermentable oligo- di -monosaccharides and polyols diet, gluten free, and hypocaloric may be helpful in ameliorating gastrointestinal distress in select patient populations. Current literature does not support the routine use of acupuncture for improving pain or quality of life in FM; however, given its benign side effect profile, it should not be discouraged. Goals for symptom management and pain control should be set early, and patient engagement remains critical in the management of this complex pain presentation. While low quality evidence exists for most non-pharmacologic treatment modalities for FM, CBT and mindfulness meditation show promise for future investigation. PMID- 29619621 TI - Early occurrence and recurrence of hepatocellular carcinoma in hepatitis C virus infected patients after sustained virological response. PMID- 29619622 TI - Prevention of mother-to-child transmission: the key of hepatitis B virus elimination. PMID- 29619623 TI - 5-Hydroxymethylfurfural (HMF) levels in honey and other food products: effects on bees and human health. AB - An organic compound known as 5-hydroxymethylfurfural (HMF) is formed from reducing sugars in honey and various processed foods in acidic environments when they are heated through the Maillard reaction. In addition to processing, storage conditions affect the formation HMF, and HMF has become a suitable indicator of honey quality. HMF is easily absorbed from food through the gastrointestinal tract and, upon being metabolized into different derivatives, is excreted via urine. In addition to exerting detrimental effects (mutagenic, genotoxic, organotoxic and enzyme inhibitory), HMF, which is converted to a non-excretable, genotoxic compound called 5-sulfoxymethylfurfural, is beneficial to human health by providing antioxidative, anti-allergic, anti-inflammatory, anti-hypoxic, anti sickling, and anti-hyperuricemic effects. Therefore, HMF is a neo-forming contaminant that draws great attention from scientists. This review compiles updated information regarding HMF formation, detection procedures, mitigation strategies and effects of HMF on honey bees and human health. PMID- 29619625 TI - Effects of plasma glycosyltransferase on the ABO(H) blood group antigens of human von Willebrand factor. AB - Von Willebrand factor (VWF) is one of the plasma protein carrying ABO(H) blood group antigens, but the combining process of these antigens is not clear. In the present study, we examined whether plasma glycosyltransferase affects the blood group antigens on VWF. VWF expressing H-antigen (H-VWF) from blood group O and bovine serum albumin conjugated with H-antigen (H-BSA) were incubated with recombinant alpha1-3-N-acetylgalactosaminyltransferase (rA-transferase) and A plasma with or without an additional UDP-GalNAc. Transformed antigens were detected by western blotting and ELISA, using an anti-A antibody. Both H-VWF and H-BSA acquired the A-antigen after incubation with rA-transferase and UDP-GalNAc. Incubation with A-plasma very weakly converted the H-antigen on BSA and VWF to A antigen only in the presence of supplemented UDP-GalNAc. This conversion was enhanced on desialylation of H-VWF. These results indicate that sugar chains of plasma VWF can be modified by the external glycosyltransferase, but that plasma glycosyltransferase has no effect on the blood group antigens of VWF due to its low activity and the lack of donor sugars. Further, sialic acid residues of VWF may exert a protective effect against post-translational glycosylation. Our results clearly exclude the possibility that blood group antigens of VWF are constructed extracellularly in plasma. PMID- 29619624 TI - Chinese guidelines for treatment of adult primary immune thrombocytopenia. AB - Primary immune thrombocytopenia (ITP) is a bleeding disorder commonly encountered in clinical practice. The International Working Group (IWG) on ITP has published several landmark papers on terminology, definitions, outcome criteria, bleeding assessment, diagnosis, and management of ITP. The Chinese consensus reports for diagnosis and management of adult ITP have been updated to the 4th edition. Based on current consensus positions and new emerging clinical evidence, the thrombosis and hemostasis group of the Chinese Society of Hematology issued Chinese guidelines for management of adult ITP, which aim to provide evidence-based recommendations for clinical decision making. PMID- 29619628 TI - Correction to: Recognizing Gynecological Cancer in Primary Care: Risk Factors, Red Flags, and Referrals. AB - The article "Recognizing Gynecological Cancer in Primary Care: Risk Factors, Red Flags, and Referrals", written by Garth Funston, Helena O'Flynn, Neil A. J. Ryan, Willie Hamilton, Emma J. Crosbie was originally published electronically on the publisher's internet portal (currently Springer-Link) on March 07, 2018 without open access. PMID- 29619627 TI - New Advances in Acute Postoperative Pain Management. AB - PURPOSE OF REVIEW: Postoperative pain remains one of the most common challenges following inpatient and outpatient surgeries. With our advances in modern medicine, pain following surgical procedures still remains a challenge, though significant accomplishments have been made over the past few decades. This article highlights some of the promising new advances and approaches in postoperative pain management. RECENT FINDINGS: Over the last decade, Enhanced Recovery after Surgery (ERAS) pathways and protocols are becoming the benchmark standards for enhancing postoperative recovery. Multimodal analgesia (MMA) is an essential component of such care. Further, in the wake of serious and persistent concern on the opioid epidemic in the USA, there has been a recent renewal of interest in non-opioid alternatives or adjuncts in controlling postoperative pain, often in the context of MMA. Intravenous (IV) acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), magnesium, ketamine, dexmedetomidine, liposomal bupivacaine, and newer neuraxial and peripheral regional techniques as well as patient-controlled modalities are gaining importance. Gabapentinoids have become popular but recent meta-analytic reviews have cast doubt on their routine use in perioperative settings. Among opioids, sublingual sufentanil, IV oxycodone, and iontophoretic transdermal fentanyl hold promise. Acupuncture and transcutaneous electrical nerve stimulation may be useful as adjuncts in MMA packages. Genetic testing, derivatives of herbal preparations, and an extended role of acute pain services may emerge as potential areas of importance in the future. There are, however, critical gaps in good quality evidence in many of the practice guideline recommendations. In the era of opioid epidemic, several lines of evidence have emerged to support non-opioid-based drugs and approaches along with a few newer opioid formulations for postoperative pain management, although more research is needed to find the right balance of efficacy and safety. PMID- 29619626 TI - Laparoscopic liver resection in cirrhotic patients with specific reference to a difficulty scoring system. AB - PURPOSE: Laparoscopic liver resection is widely used for liver tumors, but its utility in patients with cirrhosis remains controversial. The aim of this study was to assess the surgical outcomes of laparoscopic liver resection in patients with liver cirrhosis with specific reference to a difficulty scoring system. METHODS: From January 2010 to March 2016, the outcomes of laparoscopic liver resection in 95 patients were retrospectively reviewed. Surgical outcomes were analyzed to identify differences between the liver cirrhosis and non-liver cirrhosis groups; these groups were further stratified to high and low difficulty scores. The surgical outcomes of both groups were compared according to the difficulty scores. RESULTS: Overall, 53/95 (55.8%) patients were diagnosed with liver cirrhosis. There were no significant differences in surgical duration, blood loss, postoperative hospital stay, and morbidity between groups, although liver function was worse in the liver cirrhosis group than in the non-liver cirrhosis group. Multivariate analysis showed that the difficulty score was an independent predictor of increased blood loss. In particular, blood loss in cirrhotic patients was significantly greater with a high difficulty score than with a low difficulty score. CONCLUSIONS: The safety profile of laparoscopic liver resection was the same in patients with and without liver cirrhosis. However, patients with liver cirrhosis and a high difficulty score require extra attention, because of a higher risk for perioperative blood loss. PMID- 29619629 TI - Effect of Kynurenic Acid on Pupae Viability of Drosophila melanogaster cinnabar and cardinal Eye Color Mutants with Altered Tryptophan-Kynurenine Metabolism. AB - Kynurenic acid (KYNA) is one of the metabolites of evolutionary conserved tryptophan (Trp)/kynurenine (Kyn) metabolic pathway. Elevation of KYNA contributes to development of psychosis in schizophrenia but attenuates neurodegeneration in Drosophila model of Huntington's disease. We have reported that KYNA increased lethality of pupae of wild-type flies, but not of vermilion (v) mutants with impaired formation of Kyn from Trp, suggesting that KYNA toxicity depends on its interaction with downstream Kyn metabolites [i.e., 3 hydroxykynurenine (3-HK) and/or xanthurenic acid (XA)]. The present study aimed to further explore the mechanisms of KYNA-induced lethality by the assessment of KYNA effect on pupae of two Drosophila mutants: cinnabar (cn), characterized by higher KYNA and lower 3-HK production, and cardinal (cd), characterized by higher 3-HK and XA levels compared to wild-type flies. Our microarray datamining revealed that the gene expression pattern of enzymes forming Trp/Kyn pathway stands in line with previously reported developmental changes in KYNA, 3-HK, and XA concentrations in wild-type and mutant flies. Administration of KYNA increased pupae lethality in cd, but not in cn mutants. Present data suggest that toxic effect of exogenous KYNA depends on the presence of 3-HK and/or XA. This is further supported by our finding that early stages of Drosophila development are associated with a positive expression pattern of genes encoding sulfotransferases, enzymes that are inhibited by KYNA and are involved in detoxification of XA. Alternatively, the toxic effect of KYNA might depend on anti-proliferative effects of KYNA. PMID- 29619631 TI - Concentration of Minerals in Nectar Honeys from Direct Sale and Retail in Poland. AB - The aim of the study was to compare the content of selected minerals in different nectar honeys (acacia, buckwheat, raspberry, linden, rapeseed, and multifloral) available on the Polish market. The degree to which the demand for eight minerals (K, Na, Mg, Ca, Zn, Fe, Mn, Cu) by adults is met by a portion of 100 g of honey was estimated as well. The material consisted of 34 artisanal honeys from direct sale and 34 samples purchased from retail stores. The artisanal honeys contained significantly more K, Mg, and Mn, but significantly less Na and Fe than the honeys purchased from the retail stores. The raspberry honey contained significantly the most K and Ca (1104.7 and 68.8 mg kg-1), the multifloral honey contained the most Ca and Mg (68.5 and 48.0 mg kg-1), and the buckwheat honey contained the most Zn and Mn (3.97 and 4.96 mg kg-1). The highest content of Na was shown in buckwheat and linden honeys (79.1 and 80.0 mg kg-1). Consumption of 100 g of honey from direct sale satisfied from 2.5 to 4.5% of the recommended intakes for K and from 10.4 to 17.3% for Mn, while the same portion of honey from retail satisfied from 1.6 to 4.8% for Fe, and from 2.3 to 6.1% for Zn and Cu. The buckwheat honey met to the greatest degree the recommended dietary intakes for Mn (16.5-27.6%), followed by raspberry honey (10.0-16.7%) and multifloral honey (6.9 11.6%). PMID- 29619630 TI - Is Migraine Primarily a Metaboloendocrine Disorder? AB - PURPOSE OF THE REVIEW: The goals of this review are to evaluate recent studies regarding comorbidity between migraine and different metabolic and endocrine disorders and to discuss the role of insulin resistance as a common pathogenetic mechanism of these diseases. RECENT FINDINGS: Recently, several studies showed that migraine is associated with insulin resistance, a condition in which a normal amount of insulin induces a suboptimal physiological response. All the clinical studies that used the oral glucose tolerance test to examine insulin sensitivity found that, after glucose load, there is in migraine patients a significant increase of both plasmatic insulin and glucose concentrations in comparison with controls. On the contrary, no association was found between migraine and type 2 diabetes, while type 1 diabetes seems to have a protective effect in the disease. Obesity and hypertension were shown to be risk factors for both episodic and chronic migraine. Metabolic syndrome has been recently associated mainly with migraine with aura and is now considered a risk factor also for medication overuse headache. Finally, a bidirectional association between migraine and hypothyroidism has been recently demonstrated, suggesting that common genetic or autoimmune mechanisms underlie both diseases. Recent studies showed that insulin receptor signaling and the related physiological responses are altered in migraine and may have a relevant pathogenic role in the disease. Further studies are warranted in order to better elucidate mechanisms underlying insulin resistance in migraine in order to develop new therapeutic strategies for this debilitating disease. PMID- 29619633 TI - Primary extramedullary plasmacytoma of the sigmoid colon with perforation: a case report. AB - BACKGROUND: Extramedullary plasmacytomas account for 4% of all plasma cell tumors and occur mainly in the upper respiratory tract; gastrointestinal system involvement is rare. Extramedullary plasmacytoma of the colon with perforation has not been reported. CASE PRESENTATION: A 77-year-old woman with a 1-year history of lower abdominal pain and nausea was admitted to our hospital. An abdominal computed tomography scan revealed a sigmoid tumor with perforation. The patient underwent emergency surgery. Pathological examination led to a diagnosis of plasmacytoma of the colon. The patient did not undergo postoperative adjuvant chemotherapy. She has had no recurrence in 14 months of regular follow-up. CONCLUSIONS: We have herein described a rare case of extramedullary plasmacytoma of the gastrointestinal tract with perforation involving the sigmoid colon. PMID- 29619632 TI - Food Cues and Obesity: Overpowering Hormones and Energy Balance Regulation. AB - PURPOSE OF REVIEW: In the modern obesogenic environment, food cues play a crucial role in the development of obesity by disrupting hormone and energy balance mechanisms. Thus, it is critical to understand the neurobiology of feeding behaviors and obesity in the context of ubiquitous food cues. The current paper reviews the physiology of feeding, hormonal regulation of energy balance, and food cue responses and discusses their contributions to obesity. RECENT FINDINGS: Food cues have strong impact on human physiology. Obese individuals have altered food cue-elicited responses in the brain and periphery, overpowering hormone and energy balance regulation. Disrupted homeostasis during food cue exposure leads to continued food intake, unsuccessful weight management, and poor treatment outcomes, which further contributes to obesity epidemic. Findings from the review emphasize the crucial role of food cues in obesity epidemic, which necessitates multidimensional approaches to the prevention and treatment of obesity, including psychosocial interventions to reduce food cue reactivity, along with conventional treatment. PMID- 29619634 TI - Add-on treatment with N-acetylcysteine for bipolar depression: a 24-week randomized double-blind parallel group placebo-controlled multicentre trial (NACOS-study protocol). AB - BACKGROUND: Oxidative stress and inflammation may be involved in the development and progression of mood disorders, including bipolar disorder. Currently, there is a scarcity of useful treatment options for bipolar depressive episodes, especially compared with the efficacy of treatment for acute mania. N Acetylcysteine (NAC) has been explored for psychiatric disorders for some time given its antioxidant and anti-inflammatory properties. The current trial aims at testing the clinical effects of adjunctive NAC treatment (compared to placebo) for bipolar depression. We will also explore the biological effects of NAC in this context. We hypothesize that adjunctive NAC treatment will reduce symptoms of depression, which will be reflected by changes in selected markers of oxidative stress. METHODS AND ANALYSIS: In the study, we will include adults diagnosed with bipolar disorder, in a currently depressive episode. Participants will undertake a 20-week, adjunctive, randomized, double-blinded, parallel group placebo-controlled trial comparing 3 grams of adjunctive NAC daily with placebo. The primary outcome is the mean change over time from baseline to end of study on the Montgomery-Asberg Depression Rating Scale (MADRS). Among the secondary outcomes are mean changes from baseline to end of study on the Bech-Rafaelsen Melancholia Scale (MES), the Young Mania Rating Scale (YMRS), the WHO-Five Well being Index (WHO-5), the Global Assessment of Functioning scale (GAF-F), the Global Assessment of Symptoms scale (GAF-S) and the Clinical Global Impression Severity scale (CGI-S). The potential effects on oxidative stress by NAC treatment will be measured through urine and blood samples. DNA will be examined for potential polymorphisms related to oxidative defences. TRIAL REGISTRATION: Registered at The European Clinical Trials Database, ClinicalTrials.gov: NCT02294591 and The Danish Data Protection Agency: 2008-58-0035. PMID- 29619635 TI - The role of arterial hypertension in development heart failure with preserved ejection fraction: just a risk factor or something more? AB - Heart failure with preserved ejection fraction (HFpEF) is an entity that still raises many questions. The agreement about definition, pathophysiology, and therapeutic approach is still missing. Arterial hypertension is present in majority of patients with HFpEF, and it is still not clear if it represent a risk factor or "sine qua non" condition for HFpEF development. The underlying mechanisms of hypertension and HFpEF involve the same biohumoral systems: renin angiotensin-aldosterone, sympathetic nervous system, and oxidative stress. However, not all hypertensive patients have HFpEF. The predisposition of some hypertensive patients to develop HFpEF needs to be resolved. Large randomized controlled trials did not prove the usefulness of renin-angiotensin-aldosterone inhibitors, diuretics, calcium channel blockers, and beta-blockers in HFpEF patients. The majority of studies did not succeed to demonstrate the reduction of cardiovascular and all-cause mortality in HFpEF individuals. One of the major limitations in these investigations was the inconsistency of HFpEF definition, which mainly refers to left ventricular ejection fraction (LVEF) cut-off that ranged from 40 to 50% in different studies. This review article provides the available data about pathophysiology and mechanisms that connect hypertension and HFpEF, investigations and therapy used in both conditions. PMID- 29619636 TI - Toxicological evaluation of nail polish waste discarded in the environment. AB - Nail polish has been widely used around the world. However, the hazards of nail polishes discarded in the environment are still poorly investigated. Thus, the toxicogenetic effects of solubilized (SE) and leached (LE) extracts from nail polishes were investigated, simulating their disposal on water and landfill, respectively, and identifying their physicochemical properties and chemical constituents. Organic compounds and metals were detected in both extracts. SE and LE only induced mutagenic effects in TA98 Salmonella strain in the presence and absence of exogenous metabolic activation. Although both extracts did not significantly increase the frequency of micronucleated HepG2 cells, the cell viability was affected by 24-h exposure. No DNA damage was observed in gonad fish cells (RTG-2) exposed to both extracts; however, the highest SE and LE concentrations induced significant lethal and sublethal effects on zebrafish early-life stages during 96-h exposure. Based on our findings, it can be concluded that if nail polishes enter aquatic systems, it may cause negative impacts to the environment. PMID- 29619637 TI - Assessing links between energy consumption, freight transport, and economic growth: evidence from dynamic simultaneous equation models. AB - We investigate this study to examine the relationship between economic growth, freight transport, and energy consumption for 63 developing countries over the period of 1990-2016. In order to make the panel data analysis more homogeneous, we apply the income level of countries to divide the global panel into three sub panels, namely, lower-middle income countries (LMIC), upper-middle income countries (UMIC), and high-income countries (HIC). Using the generalized method of moments (GMM), the results prove evidence of bidirectional causal relationship between economic growth and freight transport for all selected panels and between economic growth and energy consumption for the high- and upper-middle income panels. For the lower-middle income panel, the causality is unidirectional running from energy consumption to economic growth. Also, the results indicate that the relationship between freight transport and energy use is bidirectional for the high-income countries and unidirectional from freight transport to energy consumption for the upper-middle and lower-middle income countries. Empirical evidence demonstrates the importance of energy for economic activity and rejects the neo-classical assumption that energy is neutral for growth. An important policy recommendation is that there is need of advancements in vehicle technology which can reduce energy intensity from transport sector and improve the energy efficiency in transport activity which in turn allows a greater positive role of transport in global economic activity. PMID- 29619638 TI - A novel approach to evaluate potential risk of organic enrichment in marine aquaculture farms: a case study in Sanggou Bay. AB - A novel approach was proposed to evaluate the potential risk of organic enrichment in marine aquaculture farms without obvious environmental degradation. The approach was based on historical environmental records preserved in sediment cores, and potential risk of organic enrichment can be effectively evaluated by comparing burial fluxes of marine organic carbon (OCM) during times before and after large-scale aquaculture. A case study was conducted in Sanggou Bay. The change trends on burial fluxes of organic carbon in sediment over the past 150 years were rebuilt. OCM burial fluxes have greatly increased since the beginning of large-scale aquaculture in 1980s, reaching 16.0~16.5 times higher than that before large-scale aquaculture. The results indicate that aquaculture activities have resulted in obvious accumulation of aquacultural organic matters, although sedimental environment has not degraded seriously. Besides, if the OCM burial fluxes further increase to 3.5~7.0 times higher than that in present, sedimental environment may degrade obviously. Therefore, potential risks of organic enrichment still exist with aquaculture development in Sanggou Bay. PMID- 29619639 TI - Risk assessment, spatial distribution, and source apportionment of heavy metals in Chinese surface soils from a typically tobacco cultivated area. AB - The heavy metals (As, Cd, Cr, Cu, Hg, Ni, Pb, and Zn) in the surface soils of tobacco (Nicotiana tabacum L.) fields in Jiangxi Province were analyzed, and the mean heavy metal concentrations were 3.55, 0.19, 25.89, 14.96, 0.25, 10.89, 27.80, and 44.00 mg/kg, respectively. Spatial distribution analysis showed that the highest concentrations were recorded in the north-western, south-western, and mid-eastern parts of the study area. The index of geo-accumulation and pollution index indicated modest enrichment with Cd and Hg, which were the only two metals posing a potentially high ecological risk to the local agricultural environment. The health risk assessment showed no considerable non-carcinogenic or carcinogenic risks for children and adults from these elements. The principal component analysis (PCA) and cluster analysis (CA) found that the variations in the Cr and Ni concentrations were largely on account of the soil parent rocks, but the As, Cd, Cu, and Hg variations in the soil were largely owing to agricultural practices of years. However, the main factor influencing Pb and Zn was atmospheric deposition. PMID- 29619640 TI - Efficient removal of arsenic(III) from aqueous media using magnetic polyaniline doped strontium-titanium nanocomposite. AB - In this study, a novel nanocomposite adsorbent based on magnetic polyaniline and strontium-titanium (MP-SrTiO3) nanoparticles was synthesized via a simple and low cost polymerization method for efficiently removing of arsenic(III) ions from aqueous samples. The chemical structure, surface properties, and morphology of the prepared adsorbent were studied using Fourier transform infrared spectroscopy (FTIR), energy-dispersive X-ray spectroscopy (EDX), and scanning electron microscopy (SEM). The main effective parameters on the removal efficiency, such as pH, adsorbent dosage, salt, and contact time, were studied and optimized. The validity of the proposed method was checked by adsorption isotherm and kinetics models. Consequently, the adsorption kinetics corresponded to the first order (R2 > 0.99), and the experimental equilibrium fitted the Langmuir model with a maximum monolayer adsorption capacity of 67.11 mg/g (R2 > 0.99) for arsenic(III) ions. Corresponding to thermodynamic Vant's Hof model (DeltaG degrees (kJ/mol), DeltaH degrees (kJ/mol), and DeltaS degrees (kJ/mol K) - 8.19, - 60.61, and - 0.17, respectively), the mechanism and adsorption nature were investigated with that suggested exothermic and physisorption mechanism. PMID- 29619641 TI - Sorption of 17beta-estradiol to the dissolved organic matter from animal wastes: effects of composting and the role of fulvic acid-like aggregates. AB - Steroid estrogens, such as 17beta-estradiol (E2), in animal manure pose a potential threat to the aquatic environment. The transport and estrogenicity of estrogens influence the sorption of estrogens to dissolved organic matter (DOM) in animal manure, and composting treatment alters the structure and composition of the manure. The objectives of the present study were to identify the contribution of the molecular composition of DOM of composted manure to the sorption of E2 and then elucidate the dominant mechanisms involved in the interaction of E2 with manure-derived DOM. The excitation-emission matrix (EEM) spectra and atomic force microscopy (AFM) showed that composting significantly altered the chemical composition and structure of DOM. A decrease in the atomic ratios of oxygen (O)/carbon (C) occurred in conjunction with the formation of DOM aggregates in the composted manure, indicating that the hydrophilicity and polarity of the DOM decreased after composting. Composting increased the sorption coefficients (KDOC-E2) for E2 to DOM, and KDOC-E2 was positively correlated with the proportion of the fulvic acid (FA)-like fraction and molecular weight (MW) fractions of the DOM (range of 1.0 * 103-7.0 * 103 Da and 7.0 * 103-1.4 * 104 Da). Specifically, E2 showed a tendency for sorption to medium-sized FA-like molecules of DOM aggregates in composted manure. Hydrophobic forces and pi-pi binding appeared to be the main mechanisms underlying the aforementioned interaction. PMID- 29619642 TI - Genome sequence and comparative analysis of Bacillus cereus BC04, reveals genetic diversity and alterations for antimicrobial resistance. AB - In this study, we delineated the genome sequence of a Bacillus cereus strain BC04 isolated from a stool sample in India. The draft genome is 5.1 Mb in size and consists of total 109 scaffolds, GC content is 35.2% with 5182 coding genes. The comparative analysis with other completely sequenced genomes highlights the unique presence of genomic islands, hemolysin, capsular synthetic protein, modifying enzymes accC7 and catA15, regulators of antibiotic resistance MarR and LysR with annotated functions related to virulence, stress response, and antimicrobial resistance. Overall, this study not only signifies the genetic diversity in gut isolate BC04 in particular, but also pinpoints the presence of unique genes possessed by B. cereus which can be pertinently exploited to design novel drugs and intervention strategies for the treatment of food borne diseases. PMID- 29619643 TI - Economic Impact of Multisystemic Therapy for Child Abuse and Neglect. AB - This study evaluated the economics of Multisystemic Therapy for Child Abuse and Neglect (MST-CAN) by applying the Washington State Institute for Public Policy (WSIPP) cost-benefit model to data from a randomized effectiveness trial with 86 families (Swenson et al. in JFP 24:497-507, 2010b). The net benefit of MST-CAN, versus enhanced outpatient treatment, was $26,655 per family at 16 months post baseline. Stated differently, every dollar spent on MST-CAN recovered $3.31 in savings to participants, taxpayers, and society at large. Policymakers and public service agencies should consider these findings when making investments into interventions for high-need families involved with child protective services. PMID- 29619644 TI - Road traffic accidents: a pictorial review. AB - Road traffic accidents are still a major cause of morbidity and mortality. With well-established whole-body CT protocols in trauma, radiologists are an integral part of trauma diagnosis and management teams. Five well-recognized traumatic syndromes (seat belt syndrome, handlebar syndrome, scapulothoracic dissociation, dashboard syndrome, and brake pedal injury) with their frequent associated complications should be diagnosed precociously according to the accident mechanism to avoid diagnostic delays and poor prognosis even if the circumstances seem minor. PMID- 29619645 TI - Parent Expectations and Preparatory Activities as Adolescents with ASD Transition to Adulthood. AB - Community stakeholders, researchers, and providers are increasingly focused on individual, family, and systemic factors that contribute to positive outcomes for adults on the autism spectrum. Parent expectations for their youth's future are associated with adult outcomes (e.g., employment, school success, independence), yet the mechanism for this effect remains unclear. This study investigated how expectations were related to parent transition-related activities in a sample of 298 parents of adolescents on the autism spectrum (48% female adolescents), stratified by parent-reported IQ (average or above, borderline, or below 70). Parent expectations for the future predicted engagement in some activities intended to enhance adult outcomes when controlling for IQ, gender, age, and household income. The results have implications for how providers discuss expectations and support families in preparing for adulthood. PMID- 29619646 TI - [Sarcopenia and frailty in older patients with rheumatism]. AB - Sarcopenia is an age-related generalized loss of muscle mass and muscle strength resulting in low physical performance, which can be observed in up to 50% of >80 year-old individuals. The consequences are manifold and sarcopenia is closely linked to frailty. Important risk factors are genetics/epigenetics, immobilization, malnutrition and anorexia, hormone deficiencies, chronic inflammation and raised levels of inhibitory factors of tissue regeneration. Thus, functional assessment of muscle strength and physical performance are central components of diagnosing sarcopenia, beyond the mere quantification of muscle mass. Currently, many interventional strategies are being tested, including exercise regimens, nutrition programs, hormone replacement and pharmacological strategies involving anabolic principles. According to the current data, training programs and medications have a high potential. PMID- 29619647 TI - Assessment of cerebral hemodynamic parameters using pulsatile versus non pulsatile cerebral blood outflow models. AB - BACKGROUND: Prior methods evaluating the changes in cerebral arterial blood volume (?CaBV) assumed that brain blood transport distal to big cerebral arteries can be approximated with a non-pulsatile flow (CFF) model. In this study, a modified ?CaBV calculation that accounts for pulsatile blood flow forward (PFF) from large cerebral arteries to resistive arterioles was investigated. The aim was to assess cerebral hemodynamic indices estimated by both CFF and PFF models while changing arterial blood carbon dioxide concentration (EtCO2) in healthy volunteers. MATERIALS AND METHODS: Continuous recordings of non-invasive arterial blood pressure (ABP), transcranial Doppler blood flow velocity (CBFVa), and EtCO2 were performed in 53 young volunteers at baseline and during both hypo- and hypercapnia. The time constant of the cerebral arterial bed (tau) and critical closing pressure (CrCP) were estimated using mathematical transformations of the pulse waveforms of ABP and CBFVa, and with both pulsatile and non-pulsatile models of ?CaBV estimation. Results are presented as median values +/- interquartile range. RESULTS: Both CrCP and tau gave significantly lower values with the PFF model when compared with the CFF model (p ? 0.001 for both). In comparison to normocapnia, both CrCP and tau determined with the PFF model increased during hypocapnia [CrCPPFF (mm Hg): 5.52 +/- 8.78 vs. 14.36 +/- 14.47, p = 0.00006; tauPFF (ms): 47.4 +/- 53.9 vs. 72.8 +/- 45.7, p = 0.002] and decreased during hypercapnia [CrCPPFF (mm Hg): 5.52 +/- 8.78 vs. 2.36 +/- 7.05, p = 0.0001; tauPFF (ms): 47.4 +/- 53.9 vs. 29.0 +/- 31.3, p = 0.0003]. When the CFF model was applied, no changes were found for CrCP during hypercapnia or in tau during hypocapnia. CONCLUSION: Our results suggest that the pulsatile flow forward model better reflects changes in CrCP and in tau induced by controlled alterations in EtCO2. PMID- 29619649 TI - Multi-center study finds postoperative residual non-enhancing component of glioblastoma as a new determinant of patient outcome. AB - INTRODUCTION: The aim of the present study is to assess whether postoperative residual non-enhancing volume (PRNV) is correlated and predictive of overall survival (OS) in glioblastoma (GBM) patients. METHODS: We retrospectively analyzed a total 134 GBM patients obtained from The University of Texas MD Anderson Cancer Center (training cohort, n = 97) and The Cancer Genome Atlas (validation cohort, n = 37). All patients had undergone postoperative magnetic resonance imaging immediately after surgery. We evaluated the survival outcomes with regard to PRNV. The role of possible prognostic factors that may affect survival after resection, including age, sex, preoperative Karnofsky performance status, postoperative nodular enhancement, surgically induced enhancement, and postoperative necrosis, was investigated using univariate and multivariate Cox proportional hazards regression analyses. Additionally, a recursive partitioning analysis (RPA) was used to identify prognostic groups. RESULTS: Our analyses revealed that a high PRNV (HR 1.051; p-corrected = 0.046) and old age (HR 1.031; p-corrected = 0.006) were independent predictors of overall survival. This trend was also observed in the validation cohort (higher PRNV: HR 1.127, p-corrected = 0.002; older age: HR 1.034, p-corrected = 0.022). RPA analysis identified two prognostic risk groups: low-risk group (PRNV < 70.2 cm3; n = 55) and high-risk group (PRNV >= 70.2 cm3; n = 42). GBM patients with low PRNV had a significant survival benefit (5.6 months; p = 0.0037). CONCLUSION: Our results demonstrate that high PRNV is associated with poor OS. Such results could be of great importance in a clinical setting, particularly in the postoperative management and monitoring of therapy. PMID- 29619650 TI - Endothelial keratoplasty in eyes with a retained angle-supported intraocular lens. AB - PURPOSE: To describe the outcomes of endothelial keratoplasty (EK) for bullous keratopathy in eyes with a retained angle-supported anterior chamber intraocular lens (acIOL). METHODS: Among 263 consecutive EK procedures, 7 DMEK and 11 DSAEK procedures were identified in eyes with an acIOL and included in the present retrospective case series. Pre- and postoperative status including ocular history, anatomical outcome and complications as well as best-corrected visual acuity was evaluated. RESULTS: Ocular history included complicated cataract surgery (n = 11), ocular trauma (n = 4) and primary intracapsular cataract extraction (n = 3). Surgery-related complications included primary graft failure (n = 1), graft detachment (n = 1), endophthalmitis (n = 1) and allograft rejection (n = 1). A clear cornea at the final examination (14 +/- 4 months) was observed in 14/18 (78%), while the visual outcome was limited due to significant ocular comorbidity in 9 out of 14 uncomplicated procedures. CONCLUSION: The presented short-term outcomes suggest that both DMEK and DSAEK are feasible in eyes with an angle-supported acIOL yielding an acceptable graft survival rate in the first postoperative year. PMID- 29619652 TI - Six indicator genes for zinc (Zn) homeostasis in freshwater teleost yellow catfish Pelteobagrus fulvidraco: molecular characterization, mRNA tissue expression and transcriptional changes to Zn exposure. AB - Excessive Zn in the aquatic environment can be toxic and causes dysfunction in Zn homeostasis for fish, which ultimately influences the function of various biological processes. Zn homeostasis is controlled by Zn transporters. This study cloned and characterized the full-length cDNA sequences of six Zn transport relevant genes (ZnT1, ZnT5, ZnT7, ZIP4, ZIP5 and MTF-1) from yellow catfish Pelteobagrus fulvidraco. The six genes share similar domains to their corresponding members of mammals. Their mRNA amounts were widely existent across eight tissues (intestine, liver, brain, heart, gill, muscle, spleen and mesenteric fat), but relatively predominant in the liver and intestine. On day 28, Zn exposure tended to increase transcript levels of ZnT1, ZnT5 and MTF-1, decrease hepatic ZIP5 expression, but did not significantly affect the expression of ZnT7 and ZIP4. On day 56, Zn exposure tended to increase transcript levels of ZnT1 and MTF-1, down-regulate hepatic mRNA amounts of ZIP4 and ZIP5; among three Zn treatments, ZnT5 expression in the 0.5 mg Zn/L group and ZnT7 expression in the 0.25 mg Zn/L group were the highest. The mRNA abundances of these genes showed Zn concentration- and exposure time-dependent manners. For the first time, we characterized the full-length cDNA sequences of six Zn transport-relevant genes in fish, explored their tissue expression profiles and transcriptional responses to Zn exposure. Our study built good basis for further investigating their physiological functions of these genes and provided new insights into the regulatory mechanisms of Zn homeostasis in fish. PMID- 29619648 TI - On the relation between theory of mind and executive functioning: A developmental cognitive neuroscience perspective. AB - Theory of mind (ToM) and executive functioning (EF) show marked interrelatedness across childhood, and developmental psychologists have long been interested in understanding the nature of this association. The present review addresses this issue from a cognitive neuroscience perspective by exploring three hypotheses regarding their functional overlap: (1) ToM relies on EF (EF->ToM); (2) EF relies on ToM (ToM->EF); and (3) ToM and EF are mutually related, owing to shared neural structures or networks (ToM<->EF). Drawing on evidence from normative brain development, neurodevelopmental and neurodegenerative diseases, patient lesion studies, and brain-imaging studies, we suggest that only a strict version of the ToM<->EF proposal of complete neural overlap can be confidently ruled out on the basis of existing evidence. The balance of evidence suggests that separable neurobiological mechanisms likely underlie ToM and EF, with shared mechanisms for domain-general processing that support both abilities. We highlight how future studies may empirically substantiate the nature of the ToM-EF relationship using various biobehavioral approaches. PMID- 29619651 TI - Increasing access to and utilization of cognitive behavioral therapy for insomnia (CBT-I): a narrative review. AB - The American College of Physicians (ACP) recently identified cognitive behavioral therapy for insomnia (CBT-I) as the first-line treatment for insomnia. Although CBT-I improves sleep outcomes and reduces the risks associated with reliance on hypnotics, patients are rarely referred to this treatment, especially in primary care where most insomnia treatment is provided. We reviewed the evidence about barriers to CBT-I referrals and efforts to increase the use of CBT-I services. PubMed, PsycINFO, and Embase were searched on January 11, 2018; additional titles were added based on a review of bibliographies and expert opinion and 51 articles were included in the results of this narrative review. Implementation research testing specific interventions to increase routine and sustained use of CBT-I was lacking. Most research focused on pre-implementation work that revealed the complexity of delivering CBT-I in routine healthcare settings due to three distinct categories of barriers. First, system barriers result in limited access to CBT-I and behavioral sleep medicine (BSM) providers. Second, primary care providers are not adequately screening for sleep issues and referring appropriately due to a lack of knowledge, treatment beliefs, and a lack of motivation to assess and treat insomnia. Finally, patient barriers, including a lack of knowledge, treatment beliefs, and limited access, prevent patients from engaging in CBT-I. These findings are organized using a conceptual model to represent the many challenges inherent in providing guideline-concordant insomnia care. We conclude with an agenda for future implementation research to systematically address these challenges. PMID- 29619653 TI - Quality control of commercial bovine lactoferrin. AB - Herein we review commercial bovine lactoferrin quality issues by describing an example of industrial production, the current status of global quality standardization, and quality-activity concerns for further discussion. Morinaga Milk Industry has been industrially producing bovine lactoferrin in Milei GmbH, Germany, since 1989. We delineate its production and quality as an example of safe and high-quality manufacturing. Currently, global standardization in the quality of bovine lactoferrin is progressing through Novel Food and GRAS in the EU and USA, respectively. Novel Food was applied or notified to seven lactoferrin manufacturers and GRAS was notified to three manufacturers, two of which are for infant use and one is for adult use, by the end of 2017. The specifications of these regulations are relatively high, including more than 95% lactoferrin purity in protein, which means that such companies can supply relatively high-grade lactoferrin. There appear to be several concerns regarding lactoferrin quality affecting activities, including contamination of lipopolysaccharide (LPS) and angiogenin, purity, and degradation of lactoferrin sample. Although LPS is immunologically toxic when invading the body, it is distributed normally in foods and the gut. However, an industrial lactoferrin sample may contain LPS at a maximum LPS/lactoferrin molecule ratio = 1/1724, which means 99.9% of the lactoferrin molecule is LPS-free. It is difficult to speculate that LPS contained in a lactoferrin sample affects its activities. Finally in order to achieve good and reproducible results, we make proposals to researchers a use of high-grade lactoferrin, careful storage, and indication the manufacturers' names and specifications in the paper. PMID- 29619654 TI - In silico characterization of a cyanobacterial plant-type isoaspartyl aminopeptidase/asparaginase. AB - Asparaginases are found in a range of organisms, although those found in cyanobacteria have been little studied, in spite of their great potential for biotechnological application. This study therefore sought to characterize the molecular structure of an L-asparaginase from the cyanobacterium Limnothrix sp. CACIAM 69d, which was isolated from a freshwater Amazonian environment. After homology modeling, model validation was performed using a Ramachandran plot, VERIFY3D, and the RMSD. We also performed molecular docking and dynamics simulations based on binding free-energy analysis. Structural alignment revealed homology with the isoaspartyl peptidase/asparaginase (EcAIII) from Escherichia coli. When compared to the template, our model showed full conservation of the catalytic site. In silico simulations confirmed the interaction of cyanobacterial isoaspartyl peptidase/asparaginase with its substrate, beta-Asp-Leu dipeptide. We also observed that the residues Thr154, Thr187, Gly207, Asp218, and Gly237 were fundamental to protein-ligand complexation. Overall, our results suggest that L asparaginase from Limnothrix sp. CACIAM 669d has similar properties to E. coli EcAIII asparaginase. Our study opens up new perspectives for the biotechnological exploitation of cyanobacterial asparaginases. PMID- 29619655 TI - Expression of genes that encode cellular oxidant/antioxidant systems are affected by heat stress. AB - Heat stress causes critical molecular dysfunction that affects productivity in chickens. Thus, the purpose of this study was to evaluate the effect of heat stress (HS) on the expression of select genes in the oxidation/antioxidation machinery in the liver of chickens. Chickens at 14 days of age were randomly assigned to two treatment groups and kept under either a constant normal temperature (25 degrees C) or high temperature (35 degrees C) in individual cages for 12 days. mRNA expression of Nrf2, oxidants NADPH(NOX): [NOX1, NOX2, NOX3, NOX4, NOX5 and DUOX2], and antioxidants [SOD1, CAT, GR, GPx1, NQO1] in the liver were analyzed at 1 and 12 days post-HS. We show that, HS changes the mRNA expression of oxidants thereby increasing cellular reactive oxygen species (ROS). Additionally, persistent HS up-regulates SOD which converts superoxides to hydrogen peroxide. We further demonstrated the dynamic relationship between catalase, GSH peroxidase (GPx) and NADPH under both acute and chronic heat stress. The pentose phosphate pathway could be important under HS since it generates NADPH which serves as a cofactor for GPx. Also, methionine, a precursor of cysteine has been shown to have reducing properties and thereby makes for an alternative fuel for redox processes. Genes in the ROS and antioxidant generation pathways may provide insight into nutritional intervention strategies, especially the use of methionine and/or cysteine when birds are suffering from heat stress. PMID- 29619656 TI - Complications Associated with Underweight Primary Immunodeficiency Patients: Prevalence and Associations Within the USIDNET Registry. AB - PURPOSE: The point prevalence of underweight status and obesity in primary immunodeficiency disease (PID) is unknown, despite the described associations between PID and weight loss and failure to thrive. The goal of this study is to estimate the prevalence of underweight status and obesity in PID patients and to investigate the associations between abnormal body weight and complications of PID. METHODS: Using the US Immunodeficiency Network (USIDNET), we performed a retrospective analysis of 653 pediatric (age 2 to 20 years) and 514 adult (age > 20) patient records with information on patient body mass index (BMI). Prevalence of underweight and obese status in PID patients was compared to data from the National Health and Nutrition Examination Survey (NHANES). RESULTS: After separating BMI data by year of entry to the database, we demonstrated that both adult and pediatric patients with PID had significantly higher prevalence of underweight patients in multiple years of analysis. Further examination of underweight patients by PID diagnosis revealed that underweight status in adults with CVID was associated with granulomatous disease as well as earlier age of CVID diagnosis. In the pediatric CVID cohort, underweight status was significantly associated with lymphopenia. Examination of obesity in pediatric and adult PID patients compared to NHANES database revealed only a single year when obesity in PID patients was significantly less prevalent. In other 2-year time intervals from 2005 to 2014, the prevalence of obesity was unchanged in children and adults. CONCLUSIONS: These results quantify the prevalence of underweight status in PID in a North American population and demonstrate that whether as a result of weight loss or poor weight gain, underweight status is more prevalent in the PID population than in the general US population. The prevalence of obesity in PID patients was similar to that seen in the general population. This highlights the need for continued education on the association of low weight and PID. CLINICAL TRIAL REGISTRATION: NCT01953016. PMID- 29619657 TI - Hallmarks in prostate cancer imaging with Ga68-PSMA-11-PET/CT with reference to detection limits and quantitative properties. AB - BACKGROUND: Gallium-68-labeled prostate-specific antigen positron emission tomography/computed tomography imaging (Ga68-PSMA-11-PET/CT) has emerged as a potential gold standard for prostate cancer (PCa) diagnosis. However, the imaging limitations of this technique at the early state of PCa recurrence/metastatic spread are still not well characterized. The aim of this study was to determine the quantitative properties and the fundamental imaging limits of Ga68-PSMA-11 PET/CT in localizing small PCa cell deposits. METHODS: The human PCa LNCaP cells (PSMA expressing) were grown and collected as single cell suspension or as 3D spheroids at different cell numbers and incubated with Ga68-PSMA-11. Thereafter, human HCT116 cells (PSMA negative) were added to a total cell number of 2 * 105 cells per tube. The tubes were then pelleted and the supernatant aspirated. A whole-body PET/CT scanner with a clinical routine protocol was used for imaging the pellets inside of a cylindrical water phantom with increasing amounts of background activity. The actual activity bound to the cells was also measured in an automatic gamma counter. Imaging detection limits and activity recovery coefficients as a function of LNCaP cell number were obtained. The effect of Ga68 PSMA-11 mass concentration on cell binding was also investigated in samples of LnCaP cells incubated with increasing concentrations of radioligand. RESULTS: A total of 1 * 104 LNCaP cells mixed in a pellet of 2 * 105 cells were required to reach a 50% detection probability with Ga68-PSMA-11-PET/CT without background. With a background level of 1 kBq/ml, between 4 * 105 and 1 * 106 cells are required. The radioligand equilibrium dissociation constant was 27.05 nM, indicating high binding affinity. Hence, the specific activity of the radioligand has a profound effect on image quantification. CONCLUSIONS: Ga68-PSMA-11-PET detects a small number of LNCaP cells even when they are mixed in a population of non-PSMA expressing cells and in the presence of background. The obtained image detection limits and characteristic quantification properties of Ga68-PSMA-11 PET/CT are essential hallmarks for the individualization of patient management. The use of the standardized uptake value for Ga68-PSMA-11-PET/CT image quantification should be precluded. PMID- 29619658 TI - Conversing as Metaphor of Human Thinking: Is Mind like a Conversation? AB - How can researchers shape their ideas so that they understand the mind better? This theoretical paper discusses the merits of the conversation metaphor as a means of analyzing the human mind. We will develop arguments concerning conversation as i) a situated and distributed activity, ii) a "product" in perpetual construction, and iii) the amount of credence and belief we afford it. Finally, we will advocate for metaphorical tools that promote a more dynamic conceptualization of human thinking. PMID- 29619659 TI - Spontaneous Elevation of Blood Pressure After SAH: An Epiphenomenon of Disease Severity and Demand, But Not a Surrogate for Outcome? AB - BACKGROUND: Spontaneous blood pressure increase is frequently observed after aneurysmal subarachnoid hemorrhage (aSAH). These episodes of spontaneous blood pressure alterations are usually tolerated under the assumption of an endogenous response to maintain cerebral perfusion. The relevance of blood pressure variability and its relationship to disease severity and outcome, however, remain obscure. METHODS: A total of 115 consecutive patients with aSAH were included for this retrospective analysis of a continuously collected data pool. Demographics, initial clinical severity of aSAH (HH degrees , mFS), treatment modality, clinical course, and outcome (development of DCI, cerebral infarction, and GOS after 3 months) were recorded. Hemodynamic information-recorded automatically with a frequency of 1/15 min-was analyzed for spontaneous blood pressure increase (SBI) and endogenous persistent hypertension (EPH) after exclusion of iatrogenic factors and relevant co-medication. Subgroup analysis included stratification for day 0-3, 4-14, and 14-21. RESULTS: SBI and EPH incidence varied from 17 to 84% depending on detection threshold (15-35 mmHg) and time period under scrutiny. Incidence of blood pressure increase correlated with disease severity upon admission (p < 0.05), but the anticipated association with outcome was not observed. SBI and EPH were more likely to occur between day 4 and 14 (p < 0.001), but only early occurrence (day 0-3) was associated with higher incidence of DCI (p < 0.05). Persistent blood pressure elevation between day 4 and 21 was associated with fewer DCI. However, no influence of spontaneous upregulation on clinical outcome after three months was observed. CONCLUSIONS: Spontaneous hemodynamic upregulation is a frequent phenomenon after aSAH. Our data support the hypothesis that spontaneous blood pressure alterations reflect an endogenous, demand-driven response correlating with disease severity. Early alterations may indicate an aggravated clinical course, while later upregulation in particular-if permitted-does not translate into a higher risk of unfavorable outcome. PMID- 29619660 TI - Response to Letter: Mechanisms Leading to Stress Cardiomyopathy Following Neurologic Injury Remain Elusive. PMID- 29619661 TI - Midline Shift is Unrelated to Subjective Pupillary Reactivity Assessment on Admission in Moderate and Severe Traumatic Brain Injury. AB - BACKGROUND: This study aims to determine the relationship between pupillary reactivity, midline shift and basal cistern effacement on brain computed tomography (CT) in moderate-to-severe traumatic brain injury (TBI). All are important diagnostic and prognostic measures, but their relationship is unclear. METHODS: A total of 204 patients with moderate-to-severe TBI, documented pupillary reactivity, and archived neuroimaging were included. Extent of midline shift and basal cistern effacement were extracted from admission brain CT. Mean midline shift was calculated for each ordinal category of pupillary reactivity and basal cistern effacement. Sequential Chi-square analysis was used to calculate a threshold midline shift for pupillary abnormalities and basal cistern effacement. Univariable and multiple logistic regression analyses were performed. RESULTS: Pupils were bilaterally reactive in 163 patients, unilaterally reactive in 24, and bilaterally unreactive in 17, with mean midline shift (mm) of 1.96, 3.75, and 2.56, respectively (p = 0.14). Basal cisterns were normal in 118 patients, compressed in 45, and absent in 41, with mean midline shift (mm) of 0.64, 2.97, and 5.93, respectively (p < 0.001). Sequential Chi-square analysis identified a threshold for abnormal pupils at a midline shift of 7-7.25 mm (p = 0.032), compressed basal cisterns at 2 mm (p < 0.001), and completely effaced basal cisterns at 7.5 mm (p < 0.001). Logistic regression revealed no association between midline shift and pupillary reactivity. With effaced basal cisterns, the odds ratio for normal pupils was 0.22 (95% CI 0.08-0.56; p = 0.0016) and for at least one unreactive pupil was 0.061 (95% CI 0.012-0.24; p < 0.001). Basal cistern effacement strongly predicted midline shift (OR 1.27; 95% CI 1.17-1.40; p < 0.001). CONCLUSIONS: Basal cistern effacement alone is associated with pupillary reactivity and is closely associated with midline shift. It may represent a uniquely useful neuroimaging marker to guide intervention in traumatic brain injury. PMID- 29619662 TI - Knockdown of Sox2 Inhibits OS Cells Invasion and Migration via Modulating Wnt/beta-Catenin Signaling Pathway. AB - Osteosarcoma (OS) was a prevalent malignant bone tumor which threatens people's health worldwide. Wnt/beta catenin signaling pathway had been proved significant in various cancers, indicating its possible function in OS as well. Sox2, a crucial member among SOX family could regulate cells biologically. How Sox2 modulated Wnt/beta catenin signaling pathway in OS remained to be discussed. The study aimed to investigate the effects of Sox2 on the invasion and migration of OS cells and the related molecular mechanisms. Twenty-four human OS and adjacent tissue samples were involved in this study. Human OS cell lines MG63 and HOS were selected for further investigation. The liposome carrier si-Sox2 which could interfere with the expression of Sox2 gene was built to transfect MG63 and HOS cells). QRT-PCR assay and western blot were utilized to analyze the expression of mRNA and proteins of Sox2. Transwell assay and wound healing assay were conducted to test the invasion and migration level of cells. The expression of GSK3, beta catenin, cyclin D1 and c-myc proteins were detected by western blot assay after transfection with si-Sox2. Compared with normal tissues and cells, the expression of Sox2 in OS tissues and cells was significantly higher. The mRNA and protein levels of Sox2 significantly decreased after transfection with si-Sox2. The invasion and migration of OS cells were down-regulated significantly through the inhibition of Sox2 by inactivating Wnt/beta-catenin signaling pathway related proteins. Knockdown of Sox2 could inhibit invasion and migration of OS cells via modulating Wnt/beta-catenin signaling pathway. PMID- 29619663 TI - Global gene regulation in tomato plant (Solanum lycopersicum) responding to vector (Bactericera cockerelli) feeding and pathogen ('Candidatus Liberibacter solanacearum') infection. AB - KEY MESSAGE: Different responses are elicited in tomato plants by Bactericera cockerelli harboring or not the pathogen 'Candidatus Liberibacter solanacearum'. 'Candidatus Liberibacter solanacearum' (Lso) has emerged as a major pathogen of crops worldwide. This bacterial pathogen is transmitted by Bactericera cockerelli, the tomato psyllid, to solanaceous crops. In this study, the transcriptome profiles of tomato (Solanum lycopersicum) exposed to B. cockerelli infestation and Lso infection were evaluated at 1, 2 and 4 weeks following colonization and/or infection. The plant transcriptional responses to Lso negative B. cockerelli were different than plant responses to Lso-positive B. cockerelli. The comparative transcriptome analyses of plant responses to Lso negative B. cockerelli revealed the up-regulation of genes associated with plant defenses regardless of the time-point. In contrast, the general responses to Lso positive B. cockerelli and Lso-infection were temporally different. Infected plants down-regulated defense genes at week one while delayed the up-regulation of the defense genes until weeks two and four, time points in which early signs of disease development were also detected in the transcriptional response. For example, infected plants regulated carbohydrate metabolism genes which could be linked to the disruption of sugar distribution usually associated with Lso infection. Also, infected plants down-regulated photosynthesis-related genes potentially resulting in plant chlorosis, another symptom associated with Lso infection. Overall, this study highlights that tomato plants induce different sets of genes in response to different stages of B. cockerelli infestation and Lso infection. This is the first transcriptome study of tomato responses to B. cockerelli and Lso, a first step in the direction of finding plant defense genes to enhance plant resistance. PMID- 29619664 TI - Constructing critical thinking in health professional education. AB - INTRODUCTION: Calls for enabling 'critical thinking' are ubiquitous in health professional education. However, there is little agreement in the literature or in practice as to what this term means and efforts to generate a universal definition have found limited traction. Moreover, the variability observed might suggest that multiplicity has value that the quest for universal definitions has failed to capture. In this study, we sought to map the multiple conceptions of critical thinking in circulation in health professional education to understand the relationships and tensions between them. METHODS: We used an inductive, qualitative approach to explore conceptions of critical thinking with educators from four health professions: medicine, nursing, pharmacy, and social work. Four participants from each profession participated in two individual in-depth semi structured interviews, the latter of which induced reflection on a visual depiction of results generated from the first set of interviews. RESULTS: Three main conceptions of critical thinking were identified: biomedical, humanist, and social justice-oriented critical thinking. 'Biomedical critical thinking' was the dominant conception. While each conception had distinct features, the particular conceptions of critical thinking espoused by individual participants were not stable within or between interviews. DISCUSSION: Multiple conceptions of critical thinking likely offer educators the ability to express diverse beliefs about what 'good thinking' means in variable contexts. The findings suggest that any single definition of critical thinking in the health professions will be inherently contentious and, we argue, should be. Such debates, when made visible to educators and trainees, can be highly productive. PMID- 29619665 TI - Expression and Purification of the Main Component Contained in Camel Milk and Its Antimicrobial Activities Against Bacterial Plant Pathogens. AB - Lactoferrin is the most dominant protein in milk after casein. This protein plays a crucial role in many biological processes including the regulation of iron metabolism, induction and modulation of the immune system, the primary defense against microorganisms, inhibiting lipid peroxidation and presenting antimicrobial activity against various pathogens such as parasites, fungi, bacteria, and viruses. The major antimicrobial effect of lactoferrin is related to its N-terminal tail where different peptides for instance lactoferricin and lactoferrampin which are important for their antimicrobial abilities are present. The growth rate of bacterial cells in camel milk is lower than that of the cow milk due to having more antimicrobial compounds. In this study, we have fused a codon-optimized partial camel lactoferrcin and lactoferrampin DNA sequences in order to construct a fused peptide via a lysine. This chimeric 42-mer peptide consists of complete and partial amino acid sequence of camel lactoferrampin and lactoferricin, respectively. Human embryonic kidney 293 (HEK-293) cells were used for synthesizing this recombinant peptide. Finally, the antibacterial activities of this constructed peptide were investigated under in vitro condition. The result showed that, all construction, cloning and expression processes were successfully performed in HEK-293. One His-tag tail was added to the chimera in order to optimize the isolation and purification processes and also reduce the cost of production. Additionally, His-tag retained the antimicrobial activity of the chimera. The antimicrobial tests showed that the growth rate in the majority of bacterial plant pathogens, including gram negative and positive bacteria, was inhibited by recombinant chimera as the level of MIC values were evaluated between 0.39 and 25.07 MUg/ml for different bacterial isolates. PMID- 29619666 TI - Effectiveness of different avian influenza (H5) vaccination regimens in layer chickens on the humoral immune response and interferon-alpha signalling immune marker. AB - Avian influenza (AI) vaccines are widely used to control and eliminate the ongoing avian influenza virus epidemic in Egypt. A strict vaccination policy with inactivated AI vaccines has been widely applied, however the virus still circulating, evolving and causing great negative impact to the poultry sector in Egypt. Therefore, an updated poultry vaccination policy using different vaccine technologies might be valuable as an innovative additional control strategy of AIV in Egypt. In the present study, the effectiveness of different avian influenza (AI) vaccination schedules was evaluated in 300 commercial layer chicks (ISA White) using either the oil-emulsion baculovirus-H5-prototype vaccine (baculovirus-H5 prototype) or turkey herpesvirus (HVT) vector vaccine containing the hemagglutinin (HA) gene from H5N1 strain (rHVT-H5), applied alone or in combination and in different settings. Vaccination with either two injections of the baculovirus-H5 prototype, a single injection of rHVT-H5 or priming with rHVT H5 at 1 day old followed by boosting with the baculovirus-H5 prototype induced AI HI protective antibody responses starting as early as 3 to 4 weeks of age and lasting up to the end of the rearing period (16 weeks). A single vaccination with the baculovirus-H5 prototype did not generate a protective antibody titre for the entire rearing period. Furthermore, the present study elucidated that vaccination once or twice with the baculovirus-H5 vaccine prototype activated the chicken interferon-alpha (Ch-IFN-alpha) signalling pathway via transduction of antiviral components, e.g., Mx1 and IRF7. Birds immunized once with rHVT-H5 at 1 day old did not show activation of the Mx1 and IRF7 transcripts; however, following boosting with the baculovirus-H5 prototype vaccine, up-regulation of Mx1 and IRF7 was observed. Based on our findings, it can be concluded that either reinforcement with two injections of the baculovirus-H5 prototype or prime-boost vaccination (rHVT-H5 at 1 day old followed by the baculovirus-H5 prototype vaccine at 8 days old) is a successful strategy to induce both innate and humoral immune responses and could be recommended for the layer production sector over the entire rearing period, especially in AI-endemic areas. PMID- 29619667 TI - Food Sharing across Borders : First Observation of Intercommunity Meat Sharing by Bonobos at LuiKotale, DRC. AB - Evolutionary models consider hunting and food sharing to be milestones that paved the way from primate to human societies. Because fossil evidence is scarce, hominoid primates serve as referential models to assess our common ancestors' capacity in terms of communal use of resources, food sharing, and other forms of cooperation. Whereas chimpanzees form male-male bonds exhibiting resource-defense polygyny with intolerance and aggression toward nonresidents, bonobos form male female and female-female bonds resulting in relaxed relations with neighboring groups. Here we report the first known case of meat sharing between members of two bonobo communities, revealing a new dimension of social tolerance in this species. This observation testifies to the behavioral plasticity that exists in the two Pan species and contributes to scenarios concerning the traits of the last common ancestor of Pan and Homo. It also contributes to the discussion of physiological triggers of in-group/out-group behavior and allows reconsideration of the emergence of social norms in prehuman societies. PMID- 29619668 TI - Performing studies using the UK Clinical Practice Research Datalink: to link or not to link? AB - The Clinical Practice Research Datalink (CPRD) is a repository of electronic medical records collected during routine primary care clinical practice in the UK, and is one of the most widely used sources of real-world data for healthcare research. Although CPRD provides access to comprehensive longitudinal patient records, the data does not fully capture diagnoses or outcomes occurring in secondary care and/or mortality. We provide here an overview of CPRD and the potential bias when using unlinked data in certain situations. Linkage of CPRD to other datasets can help to overcome these limitations. We discuss when to consider linkage to secondary care, disease-specific data sources or the official mortality data when conducting research using CPRD data. PMID- 29619670 TI - Output factor determination based on Monte Carlo simulation for small cone field in 10-MV photon beam. AB - The difficulty of measuring output factor (OPF) in a small field has been frequently discussed in recent publications. This study is aimed to determine the OPF in a small field using 10-MV photon beam and stereotactic conical collimator (cone). The OPF was measured by two diode detectors (SFD, EDGE detector) and one micro-ion chamber (PinPoint 3D chamber) in a water phantom. A Monte Carlo simulation using simplified detector model was performed to obtain the correction factor for the detector measurements. About 12% OPF difference was observed in the measurement at the smallest field (7.5 mm diameter) for EDGE detector and PinPoint 3D chamber. By applying the Monte Carlo-based correction factor to the measurement, the maximum discrepancy among the three detectors was reduced to within 3%. The results indicate that determination of OPF in a small field should be carefully performed. Especially, detector choice and appropriate correction factor application are very important in this regard. PMID- 29619671 TI - Time irreversibility in reversible shell models of turbulence. AB - Turbulent flows governed by the Navier-Stokes equations (NSE) generate an out-of equilibrium time irreversible energy cascade from large to small scales. In the NSE, the energy transfer is due to the nonlinear terms that are formally symmetric under time reversal. As for the dissipative term: first, it explicitly breaks time reversibility; second, it produces a small-scale sink for the energy transfer that remains effective even in the limit of vanishing viscosity. As a result, it is not clear how to disentangle the time irreversibility originating from the non-equilibrium energy cascade from the explicit time-reversal symmetry breaking due to the viscous term. To this aim, in this paper we investigate the properties of the energy transfer in turbulent shell models by using a reversible viscous mechanism, avoiding any explicit breaking of the [Formula: see text] symmetry. We probe time irreversibility by studying the statistics of Lagrangian power, which is found to be asymmetric under time reversal also in the time reversible model. This suggests that the turbulent dynamics converges to a strange attractor where time reversibility is spontaneously broken and whose properties are robust for what concerns purely inertial degrees of freedoms, as verified by the anomalous scaling behavior of the velocity structure functions. PMID- 29619669 TI - Longitudinal associations of lifetime adiposity with leukocyte telomere length and mitochondrial DNA copy number. AB - Adiposity may cause adverse health outcomes by increasing oxidative stress and systemic inflammation, which can be reflected by altered telomere length (TL) and mitochondrial DNA copy number (mtCN) in peripheral blood leukocytes. However, little is known about the influence of lifetime adiposity on TL and mtCN in later life. This study was performed to investigate the associations of lifetime adiposity with leukocyte TL and mtCN in 9613 participants from the Nurses' Health Study. A group-based trajectory modelling approach was used to create trajectories of body shape from age 5 through 60 years, and a genetic risk score (GRS) was created based on 97 known adiposity susceptibility variants. Associations of body shape trajectories and GRS with dichotomized TL and mtCN were assessed by logistic regression models. After adjustment for lifestyle and dietary factors, compared with the lean-stable group, the lean-marked increase group had higher odds of having below-median TL (OR = 1.18, 95% CI 1.04, 1.35; P = 0.01), and the medium-marked increase group had higher odds of having below median mtCN (OR = 1.28, 95% CI 1.00, 1.64; P = 0.047). There was a suggestive trend toward lower mtCN across the GRS quartiles (P for trend = 0.07). In conclusion, telomere attrition may be accelerated by marked weight gain in middle life, whereas mtCN is likely to be reduced persistently by adiposity over the life course. The findings indicate the importance of lifetime weight management to preserve functional telomeres and mitochondria. PMID- 29619672 TI - Resuscitation on the pitch with cardiac massage and on-site AED. PMID- 29619673 TI - Pre-endoscopic retrograde cholangiopancreatography (ERCP) administration of rectal indomethacin in unselected patients to reduce post-ERCP pancreatitis: A systematic review and meta-analysis. AB - INTRODUCTION: Previous studies have reported that peri-procedural administration of rectal indomethacin reduces the risk of pancreatitis in patients undergoing endoscopic retrograde cholangiopancreatography (ERCP). Based on these studies, gastrointestinal (GI) societies recommend prophylactic rectal indomethacin for all patients undergoing ERCP. However, recent studies have reported contradictory results. The aim of this study was to perform a systematic review and meta analysis to estimate the pooled relative risk (RR) of post-ERCP pancreatitis (PEP) in unselected patients who received rectal indomethacin before the ERCP (pre-ERCP) compared to patients who received pre-ERCP rectal placebo. METHODS: We conducted a comprehensive search of multiple electronic databases and conference proceedings (from inception through September 1, 2017) to identify randomized control trials (RCTs) investigating the role of pre-ERCP rectal indomethacin in reducing the risk of PEP in unselected patients undergoing ERCP. The databases included Ovid, Medline, In-Process, and Other Non-Indexed Citations, Ovid MEDLINE, Ovid EMBASE, Ovid Cochrane Central Register of Controlled Trials, Ovid Cochrane Database of Systematic Reviews, Scopus, and Web of Science. We calculated a pooled estimate of the RR of PEP in patients who received pre-ERCP rectal indomethacin compared to patients who received pre-ERCP rectal placebo. The meta-analysis was performed using the random effects model. RESULTS: Six RCTs with a total of 2229 patients were included in the final meta-analysis. There were 1143 patients in the rectal indomethacin group and 1086 patients in the rectal placebo group. There were 71 events of PEP in the rectal indomethacin group and 114 events of PEP in the rectal placebo group. Pre-ERCP administration of rectal indomethacin significantly reduced the risk of PEP compared to pre-ERCP rectal placebo (RR 0.60, 95% CI, 0.45-0.80; p<0.0001). There was no heterogeneity between the studies (I2 = 0). CONCLUSION: The results of this meta-analysis support the routine pre-ERCP administration of rectal indomethacin in unselected patients to prevent PEP. PMID- 29619674 TI - Chemical constituents from Viburnum fordiae Hance and their anti-inflammatory and antioxidant activities. AB - Three new neolignans, fordianoles A-C (1-3), characterized as (7S,8R)-4-hydroxy 3,3',5'-trimethoxy-8',9'-dinor-8,4'-oxyneolignan-7,7',9-triol, (7R,8R)-4-hydroxy 3,3',5'-trimethoxy-8',9'-dinor-8,4'-oxyneolignan-7,7',9-triol, and (7R,8R)-4 hydroxy-3,3',5'-trimethoxy-8,4'-oxyneolignan-7,9,9'-triol-7'-one, together with an unusual gamma-lactone, 3-(3,4-dihydroxyphenyl)-4-pentanolide (4), and twenty five known compounds (5-29) were isolated from the aerial parts of Viburnum fordiae Hance. Their structures including absolute configurations were determined by spectroscopic and chemical methods. Among them, compounds 6, 7, 11-15, 17-28 were isolated from the Viburnum genus for the first time. The anti-inflammatory and antioxidant activities of all compounds were evaluated in vitro. Compounds 15, 19, 20 and 29 showed significant inhibitory activity on NO production in RAW264.7 cells stimulated by LPS with IC50 values ranging from 8.60 to 13.92 MUM. Meanwhile, compounds 1-4, 15, 19, 20, 22, 23, 25, 26 and 29 exhibited varying antioxidant activities through DPPH, ABTS free radical scavenging and FRAP assays. PMID- 29619675 TI - A new terpene coumarin microbial transformed by Mucor polymorphosporus induces apoptosis of human gastric cancer cell line MGC-803. AB - 2'-Z auraptene (1) is a synthesized monoterpene coumarin with anticancer activity against human gastric cancer cells. In order to find new potential anticancer agent, Mucor polymorphosporus was used to transform cis-auraptene. Four new terpene coumarins with notable changes in the skeletal backbone, 2'-Z auraptene A D (2-5), were obtained and evaluated for their antiproliferative effects against human normal gastric epithelium cells and human gastric cancer cells. These new compounds showed selective cytotoxic activity against MGC-803 cells with IC50 values from 0.78 +/- 0.13 to 10.78 +/- 1.83 MUM and the therapeutic index could also be significantly improved (TI = 59.0) compared with that of 1 (TI = 5.5). The structures of these metabolites were elucidated through extensive spectroscopic methods, and the possible biotransformation pathway of 1 by Mucor polymorphosporus was also proposed. Furthermore, the mechanism of the antiproliferative effects against MGC-803 cells of the most potent compound, 2'-Z auraptene A (2), was characterized. Annexin V/PI staining and abnormal expression of apoptosis-related protein suggested that compound 2 induces apoptosis in gastric cancer MGC-803 cells. Therefore, it is possible that compound 2 has the potential to be applied in gastric cancer therapy. PMID- 29619676 TI - Synthesis and in vitro antimicrobial activity screening of new pipemidic acid derivatives. AB - This article describes the synthesis and antimicrobial activity evaluation of new pipemidic acid derivatives. New compounds were obtained on the basis of Mannich reaction of 4,5-disubstituted 1,2,4-triazole-3-thiones with pipemidic acid. Antimicrobial tests revealed high antibacterial activity of obtained derivatives. Gram-negative rods belonging to Enterobacteriaceae family were particularly most sensitive to new pipemidic acid derivatives. Synthesized compounds exhibited very strong activity towards Proteus mirabilis ATCC 12453, Salmonella typhimurium ATCC 14028 and Escherichia coli ATCC 25922. The minimum inhibitory concentrations of new pipemidic acid derivatives which inhibited the growth of these bacteria were 0.98-7.81 ug/ml, 0.98-7.81 ug/ml and 0.98-3.91 ug/ml, respectively. The antibacterial activity of newly synthesized pipemidic acid derivatives in many cases was far better than the activity of substances used as positive controls (nitrofurantoin, cefuroxime, ampicillin and pipemidic acid). PMID- 29619677 TI - Genetic and Environmental Influences on Language Ability in Older Adults: Findings from the Older Australian Twins Study. AB - We used a sub-sample from the Older Australian Twins Study to estimate the heritability of performance on three tests of language ability: Boston Naming Test (BNT), Letter/Phonemic Fluency (FAS) and Category/Semantic Fluency (CFT) Tests. After adjusting for age, sex, education, mood, and global cognition (GC), heritability estimates obtained for the three tests were 0.35, 0.59, and 0.20, respectively. Multivariate analyses showed that the genetic correlation were high for BNT and CFT (0.61), but low for BNT and FAS (0.17), and for FAS and CFT (0.28). Genetic modelling with Cholesky decomposition indicated that the covariation between the three measures could be explained by a common genetic factor. Environmental correlations between the language ability measures were low, and there were considerable specific environmental influences for each measure. Future longitudinal studies with language performance and neuroimaging data can further our understanding of genetic and environmental factors involved in the process of cognitive aging. PMID- 29619678 TI - Facilitatory Effect of IL-6 Deficiency on Long-Term Spatial Memory in Young Adult Mice. AB - The significance of interleukin 6 (IL-6) in long-term reference memory was tested in the Morris water maze (MWM) in 4-month-old C57BL/6J IL-6-deficient (IL-6 KO) and control mice. Three-day learning measured by escape latency time to find the hidden platform was comparable in both genotypes. In a single probe trial performed 7 days later, without the platform, latency to the platform site and path length to the target place were significantly shorter (p < 0.05 and p < 0.02, respectively), and platform-site crossovers more frequent (p < 0.05) in IL 6 KO mice. The swimming speed in IL-6 KO mice was significantly lower during learning (p = 0.0025) but not in the probe trial. Lack of differences between genotypes in a hole-board and in an elevated plus maze indicates that the observed effects were memory specific. The facilitatory effect of IL-6 deficiency on long-term reference memory in MWM indicates that IL-6 plays a role in consolidation process. PMID- 29619679 TI - ? PMID- 29619680 TI - Correction to: Immunomodulatory Effects of CP-25 on Splenic T Cells of Rats with Adjuvant Arthritis. AB - The original version of this article contained mistakes, and the authors would like to correct them. PMID- 29619681 TI - Glucose sensing technology-current practice? PMID- 29619682 TI - A Population Pharmacokinetic and Pharmacodynamic Analysis of RP5063 Phase 2 Study Data in Patients with Schizophrenia or Schizoaffective Disorder. AB - BACKGROUND AND OBJECTIVE: RP5063 is a novel multimodal dopamine (D)-serotonin (5 HT) stabilizer possessing partial agonist activity for D2/3/4 and 5-HT1A/2A, antagonist activity for 5-HT2B/2C/7, and moderate affinity for the serotonin transporter. Phase 2 trial data analysis of RP5063 involving patients with schizophrenia and schizoaffective disorder defined: (1) the pharmacokinetic profile; and (2) the pharmacokinetic/pharmacodynamic relationships. METHODS: Pharmacokinetic sample data (175 patients on RP5063; 28 doses/patient) were analyzed, utilized one- and two-compartment models, and evaluated the impact of covariates. Pharmacodynamic analysis involved development of an Emax model. RESULTS: The pharmacokinetic analysis identified a one-compartment model incorporating body mass index influence on volume as the optimum construct, with fixed-effect parameters: (1) oral clearance (Cl/F), 5.11 +/- 0.11 L/h; (2) volume of distribution (Vc/F), 328.00 +/- 31.40 L; (3) absorption constant (ka) 0.42 +/- 0.17 h-1; (4) lag time (t lag) of 0.41 +/- 0.02 h; and (5) a calculated half-life of 44.5 h. Pharmacokinetics were linear related to dose. An Emax model for total Positive and Negative Syndrome Scale (PANSS) scores as the response factor against cumulative area under the curve (AUC) provided fixed-effect estimates: (1) Eo = 87.3 +/- 0.71 (PANSS Units; pu); (2) Emax = - 31.60 +/- 4.05 (pu); and (3) AUC50 = 89.60 +/- 30.10 (ug.h/mL). The predicted PANSS improvement reflected a clinical dose range of 5-30 mg. CONCLUSIONS: Pharmacokinetics of RP5063 behaved predictably and consistently. Pharmacodynamics were characterized using an Emax model, reflecting total PANSS score as a function of cumulative AUC, that showed high predictability and low variability when correlated with actual observations. PMID- 29619684 TI - ? PMID- 29619683 TI - ? PMID- 29619685 TI - ? PMID- 29619686 TI - ? PMID- 29619687 TI - ? PMID- 29619688 TI - ? PMID- 29619689 TI - [Cardioprotection and diabetes mellitus - which antidiabetic agents seem to do better]. PMID- 29619690 TI - [Homeopathic remedies as an alternative to synthetic medicines?] PMID- 29619691 TI - [Tarsal tunnel syndrome]. PMID- 29619692 TI - [Cervical spine injury]. PMID- 29619693 TI - [The pale patient]. PMID- 29619694 TI - [Nocturnal dyspnea]. PMID- 29619696 TI - ? PMID- 29619697 TI - ? PMID- 29619695 TI - [Dizziness - differential diagnosis and management]. PMID- 29619698 TI - ? PMID- 29619699 TI - ? PMID- 29619700 TI - ? PMID- 29619701 TI - ? PMID- 29619702 TI - ? PMID- 29619703 TI - ? PMID- 29619704 TI - ? PMID- 29619705 TI - ? PMID- 29619706 TI - ? PMID- 29619707 TI - ? PMID- 29619708 TI - ? PMID- 29619709 TI - ? PMID- 29619710 TI - ? PMID- 29619711 TI - ? PMID- 29619712 TI - ? PMID- 29619713 TI - ? PMID- 29619714 TI - ? PMID- 29619716 TI - ? PMID- 29619715 TI - ? PMID- 29619717 TI - ? PMID- 29619718 TI - ? PMID- 29619720 TI - ? PMID- 29619719 TI - ? PMID- 29619721 TI - ? PMID- 29619722 TI - ? PMID- 29619723 TI - ? PMID- 29619724 TI - ? PMID- 29619725 TI - ? PMID- 29619726 TI - ? PMID- 29619728 TI - ? PMID- 29619727 TI - ? PMID- 29619729 TI - ? PMID- 29619730 TI - ? PMID- 29619731 TI - ? PMID- 29619733 TI - ? PMID- 29619734 TI - ? PMID- 29619735 TI - ? PMID- 29619736 TI - ? PMID- 29619737 TI - [Bleeding diathesis in the general practice: diagnostic approach and treatment]. PMID- 29619738 TI - Uphill energy transfer in photosystem I from Chlamydomonas reinhardtii. Time resolved fluorescence measurements at 77 K. AB - Energetic properties of chlorophylls in photosynthetic complexes are strongly modulated by their interaction with the protein matrix and by inter-pigment coupling. This spectral tuning is especially striking in photosystem I (PSI) complexes that contain low-energy chlorophylls emitting above 700 nm. Such low energy chlorophylls have been observed in cyanobacterial PSI, algal and plant PSI LHCI complexes, and individual light-harvesting complex I (LHCI) proteins. However, there has been no direct evidence of their presence in algal PSI core complexes lacking LHCI. In order to determine the lowest-energy states of chlorophylls and their dynamics in algal PSI antenna systems, we performed time resolved fluorescence measurements at 77 K for PSI core and PSI-LHCI complexes isolated from the green alga Chlamydomonas reinhardtii. The pool of low-energy chlorophylls observed in PSI cores is generally smaller and less red-shifted than that observed in PSI-LHCI complexes. Excitation energy equilibration between bulk and low-energy chlorophylls in the PSI-LHCI complexes at 77 K leads to population of excited states that are less red-shifted (by ~ 12 nm) than at room temperature. On the other hand, analysis of the detection wavelength dependence of the effective trapping time of bulk excitations in the PSI core at 77 K provided evidence for an energy threshold at ~ 675 nm, above which trapping slows down. Based on these observations, we postulate that excitation energy transfer from bulk to low-energy chlorophylls and from bulk to reaction center chlorophylls are thermally activated uphill processes that likely occur via higher excitonic states of energy accepting chlorophylls. PMID- 29619739 TI - 7-Deoxy-trans-dihydronarciclasine Reduces beta-Amyloid and Ameliorates Memory Impairment in a Transgenic Model of Alzheimer's Disease. AB - The critical pathological feature of Alzheimer's disease (AD) is the accumulation of beta-amyloid (Abeta), the main constituent of amyloid plaques. beta-amyloid precursor protein (APP) undergoes amyloidogenic cleavage by beta- and gamma secretase generating Abeta at endosomes or non-amyloidogenic processing by alpha secretase precluding the production of Abeta at the plasma membrane. Recently, several natural products have been widely researched on the prevention of Abeta accumulation for AD treatment. We previously reported that Lycoris chejuensis K. Tae et S. Ko (CJ), which originated from Jeju Island in Korea, improved the disrupted memory functions and reduced Abeta production in vivo. Here, we further explored the effect of its active component, 7-deoxy-trans-dihydronarciclasine (coded as E144), on Abeta generation and the underlying mechanism. Our results showed that E144 reduced the level of APP, especially its mature form, in HeLa cells overexpressing human APP with the Swedish mutation. Concomitantly, E144 decreased the levels of Abeta, sAPPbeta, sAPPalpha, and C-terminal fragment. In addition, administration of E144 normalized the behavioral deficits in Tg2576 mice, an APP transgenic mouse model of AD. E144 also decreased the Abeta and APP levels in the cerebral cortex of Tg2576 mice. Thus, we propose that E144 could be a potential drug candidate for an anti-amyloid disease-modifying AD therapy. PMID- 29619740 TI - Nicotine Modulates Mitochondrial Dynamics in Hippocampal Neurons. AB - Mitochondria are widely recognized as fundamental organelles for cellular physiology and constitute the main energy source for different cellular processes. The location, morphology, and interactions of mitochondria with other organelles, such as the endoplasmic reticulum (ER), have emerged as critical events capable of determining cellular fate. Mitochondria-related functions have proven particularly relevant in neurons; mitochondria are necessary for proper neuronal morphogenesis and the highly energy-demanding synaptic transmission process. Mitochondrial health depends on balanced fusion-fission events, termed mitochondrial dynamics, to repair damaged organelles and/or improve the quality of mitochondrial function, ATP production, calcium homeostasis, and apoptosis, which represent some mitochondrial functions closely related to mitochondrial dynamics. Several neurodegenerative disorders, such as Alzheimer's, Parkinson's, and Huntington's diseases, have been correlated with severe mitochondrial dysfunction. In this regard, nicotine, which has been associated with relevant neuroprotective effects mainly through activation of the nicotinic acetylcholine receptor (nAChR), exerts its effects at least in part by acting directly on mitochondrial physiology and morphology. Additionally, a recent description of mitochondrial nAChR localization suggests a nicotine-dependent mitochondrial function. In the present work, we evaluated in cultured hipocampal neurons the effects of nicotine on mitochondrial dynamics by assessing mitochondrial morphology, membrane potential, as well as interactions between mitochondria, cytoskeleton and IP3R, levels of the cofactor PGC-1alpha, and fission-fusion related proteins. Our results suggest that nicotine modulates mitochondrial dynamics and influences mitochondrial association from microtubules, increasing IP3 receptor clustering showing modulation between mitochondria-ER communications, together with the increase of mitochondrial biogenesis. PMID- 29619742 TI - Abstracts from the EACR seed and soil: in vivo models of metastasis conference. PMID- 29619741 TI - Expression of miR-145 and Its Target Proteins Are Regulated by miR-29b in Differentiated Neurons. AB - MicroRNAs (miRNAs) are emerging as the most potential regulator of neuronal development. Recent studies from our lab and elsewhere have demonstrated a direct role of miRNAs in regulating neuronal differentiation and synaptogenesis. MicroRNA-145, a miRNA identified to regulate pluripotency of stem cells, downregulates the protein levels of reprogramming transcription factors (RTFs) like OCT4, SOX2, and KLF4 (cell, 137,647-658,2009). Studies have shown that miR 145 is multifunctional and crucial for fate determination of neurons. In our recently published study, we have identified a set of miRNAs including miR-145 and miR-29b families differentially expressed in SH-SY5Y cells exposed sequentially with retinoic acid + brain-derived neurotrophic factor (RA+BDNF) for differentiation into mature neurons (Mol Neurobiol (2016) doi: https://doi.org/10.1007/s12035-016-0042-9 ). In the present study, we have identified the role of miR-29b in upregulation of miR-145, which is upregulated after exposure of RA+BDNF in a P53-dependent manner. In differentiating SH-SY5Y cells, expression of miR-29b downregulates expression of P85alpha, a P53 inhibitor, which results in upregulation of miR-145 and downregulation of RTF proteins. Ectopic expression of miR-145 and miR-29b in amounts equivalent to their endogenous expression has induced G1 phase cell cycle arrest. In conclusion, our studies have identified miR-29b as an upstream regulator of miR 145 and targets its RTF genes during differentiation of SH-SY5Y cells. PMID- 29619743 TI - Subcellular localization defines modification and production of Delta9 tetrahydrocannabinolic acid synthase in transiently transformed Nicotiana benthamiana. AB - OBJECTIVE: Through heterologous expression of the tetrahydrocannabinolic acid synthase (THCAS) coding sequence from Cannabis sativa L. in Nicotiana benthamiana, we evaluated a transient plant-based expression system for the production of enzymes involved in cannabinoid biosynthesis. RESULTS: Thcas was modularized according to the GoldenBraid grammar and its expression tested upon alternative subcellular localization of the encoded catalyst with and without fusion to a fluorescent protein. THCAS was detected only when ER targeting was used; cytosolic and plastidal localization resulted in no detectable protein. Moreover, THCAS seems to be glycosylated in N. benthamiana, suggesting that this modification might have an influence on the stability of the protein. Activity assays with cannabigerolic acid as a substrate showed that the recombinant enzyme produced not only THCA (123 +/- 12 fkat g FW-1 activity towards THCA production) but also cannabichromenic acid (CBCA; 31 +/- 2.6 fkat g FW-1 activity towards CBCA production). CONCLUSION: Nicotiana benthamiana is a suitable host for the generation of cannabinoid producing enzymes. To attain whole pathway integration, careful analysis of subcellular localization is necessary. PMID- 29619744 TI - Isolation of human mesenchymal stem cells from amnion, chorion, placental decidua and umbilical cord: comparison of four enzymatic protocols. AB - OBJECTIVE: To compare four enzymatic protocols for mesenchymal stem cells (MSCs) isolation from amniotic (A-MSC) and chorionic (C-MSC) membranes, umbilical cord (UC-MSC) and placental decidua (D-MSC) in order to define a robust, practical and low-cost protocol for each tissue. RESULTS: A-MSCs and UC-MSCs could be isolated from all samples using trypsin/collagenase-based protocols; C-MSCs could be isolated from all samples with collagenase- and trypsin/collagenase-based protocols; D-MSCs were isolated from all samples exclusively with a collagenase based protocol. CONCLUSIONS: The trypsin-only protocol was least efficient; the collagenase-only protocol was best for C-MSCs and D-MSCs; the combination of trypsin and collagenase was best for UC-MSCs and none of tested protocols was adequate for A-MSCs isolation. PMID- 29619745 TI - Enhancing nisin yield by engineering a small noncodding RNA anti41 and inhibiting the expression of glnR in Lactococcus lactis F44. AB - OBJECTIVES: To engineer a small nonconding RNA anti41 to enhance nisin yield by inhibiting the expression of glnR in Lactococcus lactis F44. RESULTS: We constructed a screening library to determine appropriate artificial sRNAs and obtained a sRNA anti41 that can produce approximately three fold of the inhibitory effect on GlnR. Moreover, the transcription levels of the direct inhibitory targets of GlnR (glnP, glnQ, amtB, and glnK) were dramatically upregulated in the anti41 overexpression strain (F44-anti41), thereby confirming the inhibitory effect of anti41 on GlnR. In addition, anti41 overexpression improved the survival rate of cells by approximately three fold under acid stress, promoted cell growth, and increased nisin yield by 29.83%. CONCLUSIONS: We were able to provide a novel strategy for the construction of robust high producing industrial strains. PMID- 29619746 TI - TERT enhances the survival rate of human fibroblasts under endoplasmic reticulum, Golgi apparatus, and lysosomal stresses. AB - OBJECTIVE: The exposure of organelles, such as the endoplasmic reticulum (ER), Golgi apparatus (GA), and lysosomes, to stress activates death mechanisms. Recently, telomerase reverse transcriptase (TERT) has been shown to be involved in cell survival. However, the relationship between TERT and the stress responses is still unclear. Here, we aimed to clarify the possible mechanisms of action through which TERT promotes cell survival by studying its effect on the stresses faced by multiple organelles in human fibroblasts. RESULTS: We found that TERT enhanced the survival rate of cells under ER stress, regardless of ER stress inducers such as tunicamycin (protein glycosylation inhibitor), thapsigargin (Ca2+-ATPase inhibitor), brefeldin A (protein transport inhibitor), or dithiothreitol (disulfide bond formation inhibitor). We also found that TERT enhanced the survival rate of cells under GA and lysosomal stresses. CONCLUSION: Collectively, these results suggest that TERT suppresses cell stress and promotes cell survival via different mechanisms. These findings may offer new insights into the implications of TERT in the treatment of stress-induced conditions such as aging, obesity, and neurodegenerative diseases. PMID- 29619747 TI - Shexiang Tongxin Dropping Pill () Protects against Na2S2O4-Induced Hypoxia Reoxygenation Injury in H9c2 Cells. AB - OBJECTIVES: To investigate the protective effects of Shexiang Tongxin Dropping Pill (, STP) on Na2S2O4-induced hypoxia-reoxygenation injury in cardiomyoblast H9c2 cells. METHODS: The cell viability and levels of mRNA and protein expression in H9c2 cells were determined following Na2S2O4-induced hypoxia using Hoechst staining, annexin V/propidium iodide (PI) flow cytometry, real-time polymerase chain reaction and Western blot analysis. RESULTS: STP pretreatment significantly increased the viability and inhibited aberrant morphological changes in H9c2 cardiomyoblast cells induced by Na2S2O4 treatment (P<0.05). In addition, STP pretreatment attenuated Na2S2O4-induced hypoxic damage, down-regulated the expression of pro-apoptotic Bax, and up-regulated the expression of anti apoptotic Bcl-2 in H9c2 cells (P<0.05). CONCLUSIONS: STP was strongly cardioprotective in hypoxia-reoxygenation injury by preventing hypoxic damage and inhibiting cellular apoptosis. These results further support the use of STP as an effective drug for the treatment of ischemic heart disease. PMID- 29619748 TI - Association of Gene Mutations with Response to Arsenic-Containing Compound Qinghuang Powder () in Patients with Myelodysplastic Syndromes. AB - OBJECTIVES: To investigate the relationship between gene mutations and response to Compound Qinghuang Powder (, CQHP) in patients with myelodysplastic syndrome (MDS). METHODS: Forty-three MDS patients were genotyped by ultra-deep targeted sequencing and the clinical data of patients were collected and the relationship between them was analyzed. RESULTS: Up to 41.86% of patients harbored genet mutations, in most cases with more than one mutation. The most common mutations were in SF3B1, U2AF1, ASXL1, and DNMT3A. After treatment with CQHP, about 88.00% of patients no longer required blood transfusion, or needed half of prior transfusions. CONCLUSIONS: CQHP is an effective treatment for patients with MDS, especially those with gene mutations in SF3B1, DNMT3A, U2AF1, and/or ASXL1. PMID- 29619749 TI - Decreased staging of differentiated thyroid cancer in patients with chronic lymphocytic thyroiditis. AB - PURPOSE: The biological association between chronic lymphocytic thyroiditis (CLT) and differentiated thyroid cancer (DTC) has not been elucidated yet. The aim of the study was to assess whether the presence of CLT exerts any influence on clinical or histological presentation of DTC. METHODS: Nine hundred and seven consecutive patients with DTC treated in the years 1998-2016 were divided into two groups according to the presence or absence of concomitant CLT. The statistical differences were analysed. RESULTS: Out of 907 patients included in the study, 331 were diagnosed with DTC and CLT (studied group), while 576 patients with DTC but without CLT constituted a control group. The distribution of papillary and follicular thyroid cancer did not differ. In CLT group, the prevalence of pT1 was greater than for pT2-pT4 DTC (P = 0.0003; OR = 1.69, 95% CI 1.27-2.24) compared to controls (68.3 vs. 56.1%, respectively). The presence of multifocal lesions was similar. The thyroid capsule infiltration without extrathyroidal invasion (P < 0.0001; OR = 0.21, 95% CI 0.14-0.31) was more frequent in the studied group, unlike extracapsular invasion, which was significantly more often present in patients with DTC but without CLT (P = 0.004; OR = 1.66; 95% CI 1.17-2.34) as well as nodal involvement (P = 0.048; OR = 0.65, 95% CI 0.42-0.99). CONCLUSIONS: The collected data indicate a protective role of CLT in preventing the spread of the DTC. The presence of CLT might limit tumour growth to the primary site. PMID- 29619750 TI - Oral Health Practices, Beliefs and Dental Service Utilization of Albanian Immigrants in Milwaukee, Wisconsin: A Pilot Study. AB - There is limited information on the oral health of Albanian immigrant population residing in the U.S. This creates a hinderance to developing and implementing appropriate dental care programs for the population. This study investigated oral health practices, beliefs, dental visits and associated factors of Albanian adults living in Milwaukee, Wisconsin. Purposive and snowball sampling methods were employed. Self-administered questionnaires were used to collect data on oral health practices, beliefs, dental visits and socio-demographic information. Descriptive and multivariable logistics regression were conducted. Overall, 266 adults were recruited, 54% male, 56% have lived 10 or more years in the U.S., 95% rated their oral health as excellent/good and 87% reported having a dental visit in the last year. Age, ability to speak English, having a usual source of dental care, and reporting excellent/good oral health were associated with having a dental visit in the last year. A substantial number of Albanians adult reported a dental visit in the last year and those that did not write or read in English had lower odds of reporting a dental visit. PMID- 29619751 TI - Basal-Bolus Insulin Therapy with Gla-300 During Hospitalization Reduces Nocturnal Hypoglycemia in Patients with Type 2 Diabetes Mellitus: A Randomized Controlled Study. AB - INTRODUCTION: Although reduction in the incidence of nocturnal hypoglycemia, as estimated by symptom or self-monitored plasma glucose, was shown to be more pronounced with 300 units/mL insulin glargine (Gla-300) than with 100 units/mL insulin glargine (Gla-100) in type 2 diabetes patients, the exact frequency of nocturnal hypoglycemia estimated with continuous glucose monitoring (CGM) has not been reported. METHODS: Forty patients with type 2 diabetes who were admitted for glycemic control with basal-bolus insulin therapy (BBT) were randomized into the Gla-100 and Gla-300 groups. Insulin doses were adjusted to maintain blood glucose levels within 100-120 mg/dL at each meal. Plasma glucose and C-peptide profiles were estimated serially after admission and before discharge. Daily CGM was also performed before discharge. RESULTS: In the Gla-100 and Gla-300 groups, the mean duration of hospitalization was 15 +/- 2 and 15 +/- 1 days, respectively, and the mean basal insulin dose before discharge was 13 +/- 7 and 15 +/- 10 units, respectively. The dose of meal-time insulin was not different between the two groups. Compared with the Gla-300 group, the Gla-100 group had significantly lower nocturnal profiles of plasma glucose and C-peptide, but significantly higher frequency of CGM-estimated nocturnal hypoglycemia (10.7% +/- 18.4% versus 1.2% +/- 3.6%, P = 0.033). CONCLUSION: In type 2 diabetic patients, reduction in the incidence of CGM-estimated nocturnal hypoglycemia by BBT under tightly controlled diet therapy was higher with Gla-300 than with Gla-100. TRIAL REGISTRATION: UMIN clinical trials registry (UMIN000023360). PMID- 29619752 TI - Is a Previously or Currently Reduced Testosterone Level in Male Patients with Type 2 Diabetes Mellitus a Risk Factor for the Development of Coronary Artery Disease? A Systematic Review and Meta-analysis. AB - INTRODUCTION: We aimed to systematically investigate the association between testosterone level and cardiovascular risk in male patients with type 2 diabetes mellitus (T2DM) by comparing male T2DM patients with low testosterone levels to male T2DM patients with normal testosterone levels at baseline in terms of the number of cases of coronary artery disease (CAD). METHODS: Online databases were carefully searched for studies relating to testosterone, diabetes mellitus, and cardiovascular risk by using the search terms 'testosterone,' 'diabetes mellitus,' and 'coronary artery/cardiovascular disease.' The only endpoint in this analysis was CAD/atherosclerosis/coronary plaque/major adverse coronary event prior to or following testosterone reduction at baseline. The analytical parameters used in this analysis were the risk ratio (RR) with the 95% confidence interval (CI), as obtained using the RevMan 5.3 software. RESULTS: 3467 male patients with T2DM (1079 patients with a low testosterone level versus 2388 patients with a normal testosterone level) were included. The results of this analysis showed that when a random effects model was used, a higher risk of CAD/cardiovascular disease was observed in diabetic patients with a low testosterone level than in those with a normal testosterone level (RR 1.24, 95% CI 0.94-1.63; P = 0.13). However, the difference in risk was not statistically significant. Similarly, with a fixed effects model, a low testosterone level was associated with a higher CAD/cardiovascular risk of disease (RR 1.12, 95% CI 0.98 1.34; P = 0.08); in this case, the difference in risk between the T2DM patients with low and normal testosterone levels approached statistical significance. CONCLUSION: A previously or currently reduced testosterone level was not found to be statistically significantly associated with a high risk of CAD/cardiovascular disease in male patients with T2DM. However, the difference in risk between the T2DM patients with low and normal testosterone levels was observed to approach statistical significance. PMID- 29619753 TI - Translating Benzodiazepine Utilization Data into Meaningful Population Exposure: Integration of Two Metrics for Improved Reporting. AB - Drug utilization research on benzodiazepines remains important for measuring trends in consumption within and across borders over time for the sake of monitoring prescribing patterns and identifying potential population safety concerns. The defined daily dose (DDD) system by the World Health Organization (WHO) remains the internationally accepted standard for measuring drug consumption; however, beyond consumption, DDD-based results are difficult to interpret when individual agents are compared with one another or are pooled into a total class-based estimate. The diazepam milligram equivalent (DME) system provides approximate conversions between benzodiazepines and Z-drugs (i.e. zopiclone, zolpidem, zaleplon) based on their pharmacologic potency. Despite this, conversion of total dispensed benzodiazepine quantities into DME values retains diazepam milligrams as the total unit of measurement, which is also impractical for population-level interpretation. In this paper, we propose the use of an integrated DME-DDD metric to obviate the limitations encountered when the component metrics are used in isolation. Through a case example, we demonstrate significant change in results between the DDD and DME-DDD method. Unlike the DDD method, the integrated DME-DDD metric offers estimation of population pharmacologic exposure, and enables superior interpretation of drug utilization results, especially for drug class summary reporting. PMID- 29619755 TI - High-Frequency of Computer Tomography and Surgery for Abdominal Pain After Roux en-Y Gastric Bypass. AB - INTRODUCTION: Acute, intermittent, and chronic abdominal pain is a common complaint after Roux-en-Y gastric bypass (RYGB). OBJECTIVES: The aim of the study was to evaluate the use of medical imaging and the need for surgery treating abdominal pain after RYGB in a cohort with long-term follow-up. METHODS: Data from 569 patients who underwent RYGB as the primary bariatric procedure at a public hospital in Norway between April 2004 and June 2011 were prospectively registered in a local quality registry for bariatric surgery. All abdominal imaging and abdominal surgical procedures were registered until August 2017. RESULTS: Mean follow-up was 100 months (61-159). During the observation period, 22% had one CT, 9% had two CTs, 4% had three CTs, and 5% had four or more CTs for abdominal pain. Twenty-two percent underwent abdominal surgery, as 16% had one and 6% had two or more operations and gynecological procedures excluded. The purpose of operation was postoperative complications (1.4%), suspected internal herniation (9.3%), cholecystectomy (9.3%), appendectomy (2.3%), hernias (3.2%), and perforated ulcer in the gastrojejunal anastomosis (0.7%). Mean time interval was 42 +/- 27 months from RYGB to cholecystectomy and 51 +/- 26 months for suspected IH. CONCLUSION: With a mean follow-up period of more than 8 years after RYGB, 40% of the patients suffered from abdominal pain, needing one or more CT scans. The need for surgery treating suspected internal hernia and cholecystectomy was equal, at 9.3% for both procedures, but the mean time from RYGB to operation was shorter for cholecystectomies. PMID- 29619754 TI - The involvement of purinergic signalling in obesity. AB - Obesity is a growing worldwide health problem, with an alarming increasing prevalence in developed countries, caused by a dysregulation of energy balance. Currently, no wholly successful pharmacological treatments are available for obesity and related adverse consequences. In recent years, hints obtained from several experimental animal models support the notion that purinergic signalling, acting through ATP-gated ion channels (P2X), G protein-coupled receptors (P2Y) and adenosine receptors (P1), is involved in obesity, both at peripheral and central levels. This review has drawn together, for the first time, the evidence for a promising, much needed novel therapeutic purinergic signalling approach for the treatment of obesity with a 'proof of concept' that hopefully could lead to further investigations and clinical trials for the management of obesity. PMID- 29619756 TI - Tissue-Specific Phenotype and Activation of iNKT Cells in Morbidly Obese Subjects: Interaction with Adipocytes and Effect of Bariatric Surgery. AB - BACKGROUND: The immune response of visceral adipose tissue (VAT) in obesity, in particular the role of invariant natural killer T (iNKT) cells, has not yet been fully elucidated. OBJECTIVE: To characterize iNKT cells and its activation status in VAT and peripheral blood mononuclear cells (PBMC) in morbidly obese subjects (MO), and to analyze their association with metabolic parameters. SUBJECTS AND METHODS: Twenty non-obese and 20 MO subjects underwent Roux-en-Y gastric bypass (RYGB) and were studied before and 6 months after RYGB. VAT and PBMC were obtained. RESULTS: A decrease in VAT iNKT cells from MO was found, however, not in PBMC. Visceral adipocytes from MO presented increased CD1d expression (p = 0.032). MO presented an increase in early activated CD69+ iNKT cells in PBMC before RYGB (p < 0.001), but not after RYGB nor in VAT, and an increase in later activated CD25+ iNKT in VAT (p = 0.046), without differences in PBMC. The co expression of early and later markers (CD69+CD25+) in iNKT cells was increased in MO in VAT (p = 0.050) and PBMC (p = 0.006), decreasing after RYGB (p = 0.050). CD69+ iNKT and CD69+CD25+ iNKT cells in PBMC after RYGB correlated negatively with glucose, insulin, and insulin resistance levels. CONCLUSIONS: There is a tissue-specific phenotype and activation of iNKT cells in VAT in morbid obesity, which could be involved in VAT immunometabolism dysregulation. Also, the increase in CD1d expression could be to offset the lack of VAT iNKT cells. PMID- 29619757 TI - Platelet membrane-based and tumor-associated platelet-targeted drug delivery systems for cancer therapy. AB - Platelets have long been known to play critical roles in hemostasis by clumping and clotting blood vessel injuries. Recent experimental evidence strongly indicates that platelets can also interact with tumor cells by direct binding or secreting cytokines. For example, platelets have been shown to protect circulating cancer cells in blood circulation and to promote tumor metastasis. In depth understanding of the role of platelets in cancer progression and metastasis provides promising approaches for platelet biomimetic drug delivery systems and functional platelet-targeting strategies for effective cancer treatment. This review highlights recent progresses in platelet membrane-based drug delivery and unique strategies that target tumor-associated platelets for cancer therapy. The paper also discusses future development opportunities and challenges encountered for clinical translation. PMID- 29619758 TI - Assessing residual cancer cells using MRI and US after preoperative chemotherapy in primary breast cancer to omit surgery. AB - BACKGROUND: Enhanced magnetic resonance imaging (MRI) and ultrasonography (US) are used to assess residual lesions after preoperative chemotherapy before surgery. However, residual lesion assessments based on preoperative imaging often differ from postoperative pathologic diagnoses. We retrospectively reviewed the accuracy of preoperative residual lesion assessments, including ductal carcinoma in situ (DCIS) cases to find criteria for cases in which surgery can be omitted. METHODS: We reviewed 201 patients who received preoperative chemotherapy and surgery in our hospital from January 2013 to November 2016. Presurgical evaluations regarding the possible existence of residual lesions, and clinical Complete Response (cCR) or non-cCR, were compared with postoperative pathological diagnoses. RESULTS: Of the 201 patients, 52 were diagnosed with cCR, and 39 with pathological complete response (pCR). Predictions for residual lesions were 86.4% sensitive, 76.9% specific, and 84.6% accurate. When patients were divided into 4 groups by estrogen receptor (ER) and HER2 status, sensitivity in each group was ER+/HER2-: 91.4%; ER-/HER2-: 94.1%; ER+/HER2+: 78.6%; and ER-/HER2+: 78.5%. Of the 22 patients preoperatively assessed with cCR, but diagnosed with non-pCR, the median invasive residual tumor size was 2 mm (range 0-46 mm); 5 patients (22.7%) had only DCIS. CONCLUSIONS: Predicting residual lesions after preoperative chemotherapy by using MRI and US is a reasonable strategy. However, current methods are inadequate for identifying patients who can omit surgery; therefore, a new strategy for detecting small tumors in these patients is needed. PMID- 29619759 TI - Severity of anxiety moderates the association between neural circuits and maternal behaviors in the postpartum period. AB - Neuroimaging research has suggested that activity in the amygdala, center of the socioemotional network, and functional connectivity between the amygdala and cortical regions are associated with caregiving behaviors in postpartum mothers. Anxiety is common in the early postpartum period, with severity ranging from healthy maternal preoccupation to clinical disorder. However, little is known about the influence of anxiety on the neural correlates of early caregiving. We examined these relationships in a community cohort of 75 postpartum women (ages 18-22; predominantly low-SES, minority race) who listened to infant cry sounds while undergoing an fMRI assessment. Maternal self-reported symptoms of anxiety were mostly within the subclinical range. Positive and negative caregiving behaviors during filmed face-to-face mother-infant interactions were coded by independent observers. The results from whole-brain analyses showed that anxiety severity moderated the brain-maternal behavior relationships. Specifically, our results showed that the higher a mother's anxiety, the stronger the association between positive caregiving (i.e., maternal warmth and involvement) and amygdala right posterior superior temporal sulcus (amygdala-RpSTS) functional connectivity. These results remained significant when we controlled for symptoms of depression and contextual variables. These findings suggest that functional connectivity between the amygdala and a social perception region (RpSTS) plays a particularly important role for anxious mothers in facilitating their positive parenting. These findings extend our understanding of the specific neural circuits that support positive maternal caregiving in the context of maternal anxiety, and they may help inform the future design of personalized and effective interventions. PMID- 29619761 TI - Variability in Weight Concern and Physical Activity Engagement Among African American Adolescent Girls. AB - Lower rates of recreational physical activity (PA) among African American (AA) adolescent girls relative to other US age/race/gender groups are assumed to reflect within-race similarity in PA attitudes and practices. However, variability in PA attitudes and practices among AA adolescent girls is not well studied. To address this, a class-diverse sample of 51 AA adolescent girls' responses to survey items querying weight concern (WC) and PA was examined for sub-groupings using cluster analysis. Three clusters were identified [L/H-low WC, high PA; H/L-high WC, low PA; and L/L-low WC and PA]. Survey item response means were examined by cluster. L/L differed visibly, but not significantly, from L/H and H/L on items assessing PA engagement. The same was true for H/L with WC items. Cluster identification and trends in response differences by cluster have potential implications for targeted PA promotion efforts. Further investigation with larger, representative samples is warranted. PMID- 29619762 TI - [Big data-also relevant in rheumatology?] PMID- 29619760 TI - Effect of Statin Intensity on the Risk of Epilepsy After Ischaemic Stroke: Real World Evidence from Population-Based Health Claims. AB - BACKGROUND: Statins possess neuroprotective effects. However, real-world evidence supporting their utility in post-stroke epilepsy (PSE) prevention is limited. OBJECTIVE: The association between statin use, including timing of prescribing (pre-stroke vs post-stroke), type (lipophilicity, intensity of therapy) and dose intensity, and risk of developing PSE were investigated by studying Taiwanese health claims (2003-2013). METHODS: Patients with new-onset ischaemic stroke were identified. The main outcome was a diagnosis of epilepsy after ischaemic stroke. According to pre-stroke statin use, groups of current users, former users, and non-users were compared using ANOVA. An extended Cox regression model was utilized to estimate the hazard ratio (HR) of PSE, with post-stroke statin use and certain comedications as time-dependent variables. Serial sensitivity analyses were performed to ensure study robustness. RESULTS: Of the 20,858 ischaemic stroke patients, 954 (4.6%) developed PSE. Post-stroke statin use (adjusted HR (aHR) 0.55; 95% confidence interval 0.46-0.67, p < 0.001), but not pre-stroke statin use was associated with a significantly reduced risk of developing PSE. A dose-response correlation was also observed between PSE risk reduction and quartiles of the statin cumulative defined daily dose (cDDD) (aHR 0.84, 0.67, 0.53, and 0.50 for the lowest, second, third, and highest quartiles of cDDD, respectively). Risk predictors and protectors against PSE were also characterized. CONCLUSION: The post-stroke use of statins after ischaemic stroke was associated with PSE risk reduction in a cDDD-dependent manner. Further clinical studies on the potential applications of statins for PSE prophylaxis, particularly among at-risk patients, are warranted. PMID- 29619764 TI - ? PMID- 29619766 TI - Kissing spines: an underdiagnosed cause of low back pain. PMID- 29619768 TI - Right-sided hemothorax from leaking saphenous vein right coronary artery bypass graft aneurysm due to incomplete coiling masquerading as right lower lobe pneumonia. PMID- 29619767 TI - On being an internist in emergency medicine: a rare case of epigastric pain. PMID- 29619770 TI - Impact of city effluents on water quality of Indus River: assessment of temporal and spatial variations in the southern region of Khyber Pakhtunkhwa, Pakistan. AB - The impact of city effluents on water quality of Indus River was assessed in the southern region of Khyber Pakhtunkhwa, Pakistan. Water samples were collected in dry (DS) and wet (WS) seasons from seven sampling zones along Indus River and the physical, bacteriological, and chemical parameters determining water quality were quantified. There were marked temporal and spatial variations in the water quality of Indus River. The magnitude of pollution was high in WS compared with DS. The quality of water varied across the sampling zones, and it greatly depended upon the nature of effluents entering the river. Water samples exceeded the WHO permissible limits for pH, EC, TDS, TS, TSS, TH, DO, BOD, COD, total coliforms, Escherichia coli, Ca2+, Mg2+, NO3-, and PO42-. Piper analysis indicated that water across the seven sampling zones along Indus River was alkaline in nature. Correlation analyses indicated that EC, TDS, TS, TH, DO, BOD, and COD may be considered as key physical parameters, while Na+, K+, Ca2+, Mg2+, Cl-, F-, NO3-, PO42-, and SO42- as key chemical parameters determining water quality, because they were strongly correlated (r > 0.70) with most of the parameters studied. Cluster analysis indicated that discharge point at Shami Road is the major source of pollution impairing water quality of Indus River. Wastewater treatment plants must be installed at all discharge points along Indus River for protecting the quality of water of this rich freshwater resource in Pakistan. PMID- 29619771 TI - A Study of Triplet-Primed PCR for Identification of CAG Repeat Expansion in the HTT Gene in a Cohort of 503 Indian Cases with Huntington's Disease Symptoms. AB - BACKGROUND: Huntington's disease (HD) is an autosomal-dominant neurodegenerative disorder with an average age at onset of 40 years. It is a polyglutamine (polyQ) disorder that is caused by an increase in the number of CAG repeats in the huntingtin (HTT) gene. Genetic tests that accurately determine the number of CAG repeats are performed for confirmation of diagnosis, predictive testing of persons at genetic risk for inheriting HD, and prenatal testing. The aim of our study was to evaluate efficacy of triplet-primed polymerase chain reaction (TP PCR) for routine diagnosis of HD in suspected cases from India. METHODS: We evaluated a combination of CAG flanking PCR and triplet-primed PCR for estimation of CAG repeats in 503 cases with clinical suspicion of HD. RESULTS: There were 250 cases (49.7%) that showed the presence of expanded alleles, with 241 (47.9%) being fully penetrant alleles and nine (1.8%) in the reduced penetrance category. There were seven juvenile cases with an age of onset of < 20 years, with the longest allele comprising 106 CAG repeats found in an 8-year-old male patient. The results demonstrated an inverse (R = - 0.67) relationship between CAG length and age at clinical onset. CONCLUSION: Our study on pan-Indian cases is one of the largest studies reported so far in India and focuses on the most accurate and comprehensive molecular diagnostic evaluation of HD. PMID- 29619772 TI - Molecular Med TRI-CON, 11-16 February 2018, San Francisco, USA. PMID- 29619769 TI - Multiple hormonal and metabolic deficiency syndrome in chronic heart failure: rationale, design, and demographic characteristics of the T.O.S.CA. Registry. AB - Recent evidence supports the concept that progression of chronic heart failure (CHF) depends upon an imbalance of catabolic forces over the anabolic drive. In this regard, multiple hormonal deficiency syndrome (MHDS) significantly has impacts upon CHF progression, and is associated with a worse clinical status and increased mortality. The T.O.S.CA. (Trattamento Ormonale nello Scompenso CArdiaco; Hormone Therapy in Heart Failure) Registry (clinicaltrial.gov = NCT02335801) tests the hypothesis that anabolic deficiencies reduce survival in a large population of mild-to-moderate CHF patients. The T.O.S.CA. Registry is a prospective multicenter observational study coordinated by "Federico II" University of Naples, and involves 19 centers situated throughout Italy. Thyroid hormones, insulin-like growth factor-1, total testosterone, dehydroepiandrosterone , and insulin are measured at baseline and every year for a patient-average follow-up of 3 years. Subjects with CHF are divided into two groups: patients with one or no anabolic deficiency, and patients with two or more anabolic deficiencies at baseline. The primary endpoint is the composite of all-cause mortality and cardiovascular hospitalization. Secondary endpoints include the composite of all-cause mortality and hospitalization, the composite of cardiovascular mortality and cardiovascular hospitalization, and change of VO2 peak. Patient enrollment started in April 2013, and was completed in July 2017. Demographics and main clinical characteristics of enrolled patients are provided in this article. Detailed cross-sectional results will be available in late 2018. The T.O.S.CA. Registry represents the most robust prospective observational trial on MHDS in the field of CHF. The study findings will advance our knowledge with regard to the intimate mechanisms of CHF progression and hopefully pave the way for future randomized clinical trials of single or multiple hormonal replacement therapies in CHF. PMID- 29619773 TI - Discovery of PACAP and its receptors in the brain. AB - Pituitary adenylate-cyclase-activating polypeptide (PACAP) is a 27- or 38-amino acid neuropeptide, which belongs to the vasoactive intestinal polypeptide (VIP)/glucagon/secretin family. PACAP shows particularly high homology (~ 68%) to VIP. Because of the high homology of the amino acid sequences of PACAP and VIP, these peptides share three class B-G-protein coupled receptors: the PAC1-Receptor (PAC1-R), the VPAC1-Receptor (VPAC1-R) and VPAC2-Receptor (VPAC2-R). These receptors have high homology to each other, and their high homology is utilized for these discoveries. This review provides mainly an overview of the history of the discovery of PACAP and its three receptors. PMID- 29619775 TI - Current strategies of spinal cord protection during thoracoabdominal aortic surgery. AB - Despite improved survival rates after thoracoabdominal aortic aneurysm repairs, paraplegia remains a devastating complication with high incidence, ranging from 3 to 10%. Ischemic insults to the spinal cord are unavoidable during thoracoabdominal aortic aneurysm repairs. There is no single measure that can prevent paraplegia alone. A multimodality approach is required to minimize the ischemic insults during thoracoabdominal aortic aneurysm repairs and postoperative second hit to the spinal cord. Distal aortic perfusion is important to maintain the collateral network perfusion pressure, while cerebrospinal drainage allows to directly maintain the spinal cord perfusion. Reattachment of segmental arteries T8-T12 is encouraged to lower the incidence of both immediate and delayed paraplegia. Systemic arterial pressure should be maintained above 130 mmHg and cerebrospinal drainage should be continued until the second postoperative day, despite intact neurological status. In this article, we describe our current operative techniques and perioperative management in patients undergoing repairs of thoracoabdominal aortic aneurysm. A review of recent updates on spinal protection strategies is also reported. PMID- 29619776 TI - Mental Status Examination Training for Medical Students: the Development of an Educational Video Library with Authentic Patients. PMID- 29619774 TI - Pyruvate Kinase Isozyme M2 Plays a Critical Role in the Interactions Between Pancreatic Stellate Cells and Cancer Cells. AB - BACKGROUND: The interaction between pancreatic cancer cells and pancreatic stellate cells plays a pivotal role in the progression of pancreatic cancer. Pyruvate kinase isozyme M2 is a key enzyme in glycolysis. Previous studies have shown that pyruvate kinase isozyme M2 is overexpressed in pancreatic cancer and that it regulates the aggressive behaviors of pancreatic cancer cells. AIMS: To clarify the role of pyruvate kinase isozyme M2 in the interactions between pancreatic cancer cells and pancreatic stellate cells. METHODS: Pyruvate kinase isozyme M2-knockdown pancreatic cancer cells (Panc-1 and SUIT-2 cells) and pancreatic stellate cells were generated by the introduction of small interfering RNA-expressing vector against pyruvate kinase isozyme M2. Cell proliferation, migration, and epithelial-mesenchymal transition were examined in vitro. The impact of pyruvate kinase isozyme M2 knockdown on the growth of subcutaneous tumors was examined in nude mice in vivo. RESULTS: Pyruvate kinase isozyme M2 kockdown pancreatic cancer cells and pancreatic stellate cells showed decreased proliferation and migration compared to their respective control cells. Pancreatic stellate cell-induced proliferation, migration, and epithelial mesenchymal transition were inhibited when pyruvate kinase isozyme M2 expression was knocked down in pancreatic cancer cells. In vivo, co-injection of pancreatic stellate cells increased the size of the tumor developed by the control SUIT-2 cells, but the effects were less evident when pyruvate kinase isozyme M2 was knocked down in SUIT-2 cells or pancreatic stellate cells. CONCLUSIONS: Our results suggested a critical role of pyruvate kinase isozyme M2 in the interaction between pancreatic cancer cells and pancreatic stellate cells. PMID- 29619777 TI - The solution structure of monomeric CCL5 in complex with a doubly sulfated N terminal segment of CCR5. AB - : The inflammatory chemokine CCL5, which binds the chemokine receptor CCR5 in a two-step mechanism so as to activate signaling pathways in hematopoetic cells, plays an important role in immune surveillance, inflammation, and development as well as in several immune system pathologies. The recently published crystal structure of CCR5 bound to a high-affinity variant of CCL5 lacks the N-terminal segment of the receptor that is post-translationally sulfated and is known to be important for high-affinity binding. Here, we report the NMR solution structure of monomeric CCL5 bound to a synthetic doubly sulfated peptide corresponding to the missing first 27 residues of CCR5. Our structures show that two sulfated tyrosine residues, sY10 and sY14, as well as the unsulfated Y15 form a network of strong interactions with a groove on a surface of CCL5 that is formed from evolutionarily conserved basic and hydrophobic amino acids. We then use our NMR structures, in combination with available crystal data, to create an atomic model of full-length wild-type CCR5:CCL5. Our findings reveal the structural determinants involved in the recognition of CCL5 by the CCR5 N terminus. These findings, together with existing structural data, provide a complete structural framework with which to understand the specificity of receptor:chemokine interactions. DATABASE: Structural data are available in the PDB under the accession number 6FGP. PMID- 29619778 TI - Daikenchuto for reducing postoperative ileus in patients undergoing elective abdominal surgery. AB - BACKGROUND: Postoperative ileus is a major complication for persons undergoing abdominal surgery. Daikenchuto, a Japanese traditional medicine (Kampo), is a drug that may reduce postoperative ileus. OBJECTIVES: To assess the efficacy and safety of Daikenchuto for reducing prolonged postoperative ileus in persons undergoing elective abdominal surgery. SEARCH METHODS: We searched the following databases on 3 July 2017: CENTRAL, MEDLINE, Embase, ICHUSHI, WHO (World Health Organization) International Clinical Trials Registry Platform (ICTRP), EU Crinical Trials registry (EU-CTR), UMIN Clinical Trials Registry (UMIN-CTR), ClinicalTrials.gov, The Japan Society for Oriental Medicine (JSOM), American Society of Clinical Oncology (ASCO), Society of American Gastrointestinal and Endscopic Surgeons (SAGES). We set no limitations on language or date of publication. SELECTION CRITERIA: We included randomised controlled trials (RCTs) comparing Daikenchuto with any control condition in adults, 18 years of age or older, undergoing elective abdominal surgery. DATA COLLECTION AND ANALYSIS: We applied standard methodological procedures expected by Cochrane. Two review authors independently reviewed the articles identified by literature searches, extracted data, and assessed risk of bias of the included studies using the Cochrane software Review Manager 5. MAIN RESULTS: We included seven RCTs with a total of 1202 participants. Overall, we judged the risk of bias as low in four studies and high in three studies. We are uncertain whether Daikenchuto reduced time to first flatus (mean difference (MD) -11.32 hours, 95% confidence interval (CI) -17.45 to -5.19; two RCTs, 83 participants; very low-quality evidence), or time to first bowel movement (MD -9.44 hours, 95% CI -22.22 to 3.35; four RCTs, 500 participants; very low-quality evidence) following surgery. There was little or no difference in time to resumption of regular solid food following surgery (MD 3.64 hours, 95% CI -24.45 to 31.74; two RCTs, 258 participants; low-quality evidence). There were no adverse events in either arm of the five RCTs that reported on drug-related adverse events (risk difference (RD) 0.00, 95% CI -0.02 to 0.02, 568 participants, low-quality evidence). We are uncertain of the effect of Daikenchuto on patient satisfaction (MD 0.09, 95% CI -0.19 to 0.37; one RCT, 81 participants; very low-quality of evidence). There was little or no difference in the incidence of any re-interventions for postoperative ileus before leaving hospital (risk ratio (RR) 0.99, 95% CI 0.06 to 15.62; one RCT, 207 participants; moderate-quality evidence), or length of hospital stay (MD -0.49 days, 95% CI 1.21 to 0.22; three RCTs, 292 participants; low-quality evidence). AUTHORS' CONCLUSIONS: Evidence from current literature was unclear whether Daikenchuto reduced postoperative ileus in patients undergoing elective abdominal surgery, due to the small number of participants in the meta-analyses. Very low-quality evidence means we are uncertain whether Daikenchuto improved postoperative flatus or bowel movement. Further well-designed and adequately powered studies are needed to assess the efficacy of Daikenchuto. PMID- 29619779 TI - Watch beyond hypotension. PMID- 29619780 TI - Cardiovascular dysfunction and liver transplantation. AB - Cardiovascular complications have emerged as the leading cause of death after liver transplantation, particularly among those with advanced liver cirrhosis. Therefore, a thorough and accurate cardiovascular evaluation with clear comprehension of cirrhotic cardiomyopathy is recommended for optimal anesthetic management. However, cirrhotic patients manifest cardiac dysfunction concomitant with pronounced systemic hemodynamic changes, characterized by hyperdynamic circulation such as increased cardiac output, high heart rate, and decreased systemic vascular resistance. These unique features mask significant manifestations of cardiac dysfunction at rest, which makes it difficult to accurately evaluate cardiovascular status. In this review, we have summarized the current knowledge of heart and liver interactions, focusing on the usefulness and limitations of cardiac evaluation tools for identifying high-risk patients. PMID- 29619782 TI - Introduction to systematic review and meta-analysis. AB - Systematic reviews and meta-analyses present results by combining and analyzing data from different studies conducted on similar research topics. In recent years, systematic reviews and meta-analyses have been actively performed in various fields including anesthesiology. These research methods are powerful tools that can overcome the difficulties in performing large-scale randomized controlled trials. However, the inclusion of studies with any biases or improperly assessed quality of evidence in systematic reviews and meta-analyses could yield misleading results. Therefore, various guidelines have been suggested for conducting systematic reviews and meta-analyses to help standardize them and improve their quality. Nonetheless, accepting the conclusions of many studies without understanding the meta-analysis can be dangerous. Therefore, this article provides an easy introduction to clinicians on performing and understanding meta analyses. PMID- 29619783 TI - Estimation of the effect-site equilibration rate constant using the time-to-peak effect of muscle relaxants measured by train-of-four stimulation during general anesthesia induction. AB - BACKGROUND: The concept of the effect-site concentration of anesthetic agents is important. The effect compartment model can be explained using the concepts of effect-site concentration and effect-site equilibration rate constant (ke0). This study confirms that the time-to-peak effect (tpe ) can be measured easily in clinical practice by applying a priming dose and train-of-four (TOF) during general anesthesia induction, and ke0 can be calculated from the tpe of the four muscle relaxants that are commonly used in general anesthesia. METHODS: Eighty patients who received general anesthesia were divided into the succinylcholine, rocuronium, atracurium, or vecuronium groups. Priming doses of muscle relaxants were administered. The effects of muscle relaxants were quantified by recording the twitch response of the adductor pollicis muscle after stimulating the ulnar nerve. The tpe was measured at the lowest TOF value. ke0 was calculated from the measured tpe . RESULTS: The ke0 values of the succinylcholine, rocuronium, atracurium, and vecuronium groups were 0.076 (0.030)/min, 0.228 (0.122)/min, 0.062 (0.011)/min, and 0.077 (0.019)/min, respectively. CONCLUSIONS: It is possible to estimate ke0 from the tpe of muscle relaxants using a priming dose and TOF during general anesthesia induction. PMID- 29619781 TI - Perioperative implication of the endothelial glycocalyx. AB - The endothelial glycocalyx (EG) is a gel-like layer lining the luminal surface of healthy vascular endothelium. Recently, the EG has gained extensive interest as a crucial regulator of endothelial funtction, including vascular permeability, mechanotransduction, and the interaction between endothelial and circulating blood cells. The EG is degraded by various enzymes and reactive oxygen species upon pro-inflammatory stimulus. Ischemia-reperfusion injury, oxidative stress, hypervolemia, and systemic inflammatory response are responsible for perioperative EG degradation. Perioperative damage of the EG has also been demonstrated, especially in cardiac surgery. However, the protection of the EG and its association with perioperative morbidity needs to be elucidated in future studies. In this review, the present knowledge about EG and its perioperative implication is discussed from an anesthesiologist's perspective. PMID- 29619784 TI - Comparison between lignocaine nebulization and airway nerve block for awake fiberoptic bronchoscopy-guided nasotracheal intubation: a single-blind randomized prospective study. AB - BACKGROUND: The preferred management strategy for difficult airways is awake fiberoptic bronchoscopy-guided intubation, which requires effective airway anesthesia to ensure patient comfort and acceptance. This randomized single-blind prospective study was conducted to compare lignocaine nebulization and airway nerve block for airway anesthesia prior to awake fiberoptic bronchoscopy-guided intubation. METHODS: Sixty adult patients scheduled for surgical procedures under general anesthesia were randomly allocated to two groups. Group N received jet nebulization (10 ml of 4% lignocaine) and Group B received bilateral superior laryngeal and transtracheal recurrent laryngeal nerve blocks (each with 2 ml of 2% lignocaine) followed by fiberoptic bronchoscopy-guided nasotracheal intubation. All patients received procedural sedation with dexmedetomidine. The intubation time, intubating conditions, vocal cord position, cough severity, and degree of patient satisfaction were recorded. Student's t test was used to analyze parametric data, while the Mann-Whitney U test was applied to non parametric data and Fisher's test to categorical data. P values < 0.05 were considered statistically significant. RESULTS: The time taken for intubation was significantly shorter in Group B [115.2 (14.7) s compared with Group N [214.0 (22.2) s] (P = 0.029). The intubating conditions and degree of patient comfort were better in Group B compared with Group N. Although all patients were successfully intubated, patient satisfaction was higher in Group B. CONCLUSIONS: Airway nerve blocks are preferable to lignocaine nebulization as they provide superior-quality airway anesthesia. However, nebulization may be a suitable alternative when a nerve block is not feasible. PMID- 29619785 TI - Compression stockings reduce the incidence of hypotension but not that of cerebral desaturation events in the beach-chair position: a randomized controlled trial. AB - BACKGROUND: The beach-chair position (BCP) results in decreases in venous return, cardiac output, and cerebral perfusion pressure. In this randomized, prospective study, we investigated whether applying thigh-high compression stockings affected the maintenance of regional cerebral tissue oxygen saturation (rSO2) in the BCP. METHODS: Patients undergoing orthopedic surgery in the BCP under general anesthesia were included and assigned randomly to the control or the compression stocking group. Appropriately sized thigh-high compression stockings were applied to the patients in the stockings group. All patients were tilted, up to 45 degrees , throughout the operation. Non-invasive blood pressure, invasive arterial blood pressure zeroed at the external auditory meatus, and rSO2 were recorded. RESULTS: Data were analyzed from 19 patients per group. In the BCP, the values of rSO2 and blood pressure decreased significantly compared with those at baseline, with no significant difference between the groups. The incidences of cerebral desaturation events (CDEs) were similar between the groups; however, that of hypotension was significantly lower in the compression stocking group. During 36 CDEs, the levels of rSO2 and blood pressure decreased significantly compared with those at baseline in both groups. No significant correlation was found between rSO2 and blood pressure. CONCLUSIONS: Thigh-high compression stockings reduced the incidence of hypotension but not that of CDEs. Our results suggest that other factors, beyond hypotension itself, contribute to CDEs and in other words, efforts just to reduce the incidence of hypotension may not mainly contribute to a reduction of CDEs occurrence in the BCP under general anesthesia. PMID- 29619786 TI - Comparative study of levobupivacaine and bupivacaine for bilateral maxillary nerve block during pediatric primary cleft palate surgery: a randomized double blind controlled study. AB - BACKGROUND: Cleft lip and palate are common major congenital anomalies. Cleft palate (CP) repair causes pain and needs large doses of intravenous opioids. The risk of postoperative airway obstruction or respiratory depression is high, requiring continuous and vigilant monitoring. The primary outcome was to evaluate the efficacy of using different local anesthetics during bilateral maxillary nerve block (MNB) with general anesthesia on quality of recovery after primary CP repair. We hypothesized that levobupivacaine would be better than bupivacaine. Also, to investigate the potency of bilateral MNB in improving quality of postoperative analgesia. METHODS: Sixty children undergoing primary CP repair surgery were enrolled in the study. Combined general anesthesia and regional bilateral MNB were used for all patients. Group L (n = 30): children received 0.15 ml/kg of 0.2% levobupivacaine, while in Group B (n = 30): children received 0.15 ml/kg of 0.2% bupivacaine. RESULTS: Face, Legs, Activity, Cry, and Consolability pain score readings were 0 score in 7 cases of the Group L and 10 cases of Group B, 1 score in 14 cases of the Group L and 12 cases of Group B, and 2 score in 9 cases of the Group L and 8 cases of Group B. We found no statistically significant difference between the two study groups as regarding pain score or serious complications. CONCLUSIONS: Levobupivacaine is as effective and safe as bupivacaine to be used for MNB block with a lower incidence of complications. Bilateral suprazygomatic MNB is an effective, easy, and safe method for pain relief in children undergoing primary cleft palate repair surgeries. PMID- 29619787 TI - Effects of bilateral superficial cervical plexus block on sevoflurane consumption during thyroid surgery under entropy-guided general anesthesia: a prospective randomized study. AB - BACKGROUND: Bilateral superficial cervical plexus block (BSCPB) provides good postoperative analgesia, but its effect on anesthetic consumption is unknown. This study evaluated the effects of BSCPB on sevoflurane consumption during thyroid surgery. METHODS: Fifty patients were randomly allocated into groups A and B of 25 each in this prospective double-blind study. Group A received BSCPB with 20 ml 0.25% bupivacaine, whereas group B received 20 ml saline immediately before entropy-guided general anesthesia. Intraoperative hemodynamic parameters, end-tidal sevoflurane concentration, minimum alveolar concentration, and sevoflurane consumption were recorded. Postoperative pain was assessed using a visual analog scale, and the time of the first request for analgesia was noted. All side effects were recorded. RESULTS: Demographics were comparable. Mean sevoflurane consumption [for 30 min: group A = 7.2 (1.1) ml, group B = 8.8 (2.0) ml, P = 0.001; for 60 min: group A = 13.5 (1.7) ml, group B = 16.5 (3.9) ml, P = 0.002] and mean end-tidal sevoflurane concentration [for 30 min: group A = 1.2% (0.2%), group B = 1.4% (0.2%), P = 0.008; for 60 min: group A = 1.2% (0.1%), group B = 1.4% (0.2%), P = 0.010] were significantly lower in group A. Patients in group A had a longer duration of analgesia [361.6 (79.5) min vs. 151.0 (60.2) min, P < 0.001] compared to those in group B. CONCLUSIONS: Preinduction BSCPB during thyroid surgery significantly reduced sevoflurane consumption and increased the duration of postoperative analgesia. PMID- 29619788 TI - Effects of high-frequency, high-intensity transcutaneous electrical nerve stimulation versus intravenous opioids for pain relief after gynecologic laparoscopic surgery: a randomized controlled study. AB - BACKGROUND: The aim of the study was to compare the pain relieving effect and the time spent in the recovery unit after treatment with high frequency, high intensity transcutaneous electrical nerve stimulation (TENS) or intravenous (IV) opioids after gynecologic laparoscopic surgery. METHODS: All patients who postoperatively reported visual analogue scale (VAS) pain score >= 3 were consecutively included in the study. The TENS treatment was given with a stimulus intensity between 40-60 mA during 1 minute, repeated once if insufficient pain relief. In the opioid group, a maximum dose of 10 mg morphine was given IV. If the patient reported insufficient pain relief (VAS >= 3) on the assigned treatment, the patient crossed over to the other treatment group. RESULTS: Ninety three women were randomized to TENS (n = 47) or IV opioids (n = 46). Both groups reported significant pain relief at leave from the recovery unit (TENS group: VAS 5.4 to 1.0, P < 0.001; IV opioid group: VAS 5.2 to 1.1, P < 0.001) with no differences between the groups. When only responders, i.e. patients with VAS < 3 after assigned treatment, were compared the TENS responders spent significantly shorter time in the recovery unit (90 vs. 122 minutes, P = 0.008) compared to the responders in the opioid group. CONCLUSIONS: TENS and IV opioids are both effective treatments for pain relief after gynecologic laparoscopic surgery. TENS seems to be preferable for first choice of treatment as the treatment is associated with shorter time spent in recovery unit if the patient responds to the treatment. PMID- 29619789 TI - Inadvertent thermal injury following knee arthroscopic surgery in a pediatric patient. AB - Inadvertent thermal injury can occur in pediatric patients under general anesthesia during knee arthroscopic surgery. Here, we report the case of a 10 year-old boy who underwent knee arthroscopic surgery under general anesthesia. After the surgery, he complained of pain in the left lower part of his chin and was diagnosed as having a thermal burn. At three-month follow-up, he recovered without any abnormalities except mild hypertrophy of the wound area. Although rare, arthroscopic surgery has the potential to cause thermal injury from the light source. We recommend that the light source should be connected to the arthroscope before switching the power on and disconnected after a considerable time of switching the power off when not in use. PMID- 29619790 TI - Just think about pyogenic spondylodiscitis before performing the epidural steroid injection for low back pain. PMID- 29619791 TI - Sedation in a child with Klippel-Feil syndrome scheduled for magnetic resonance imaging. PMID- 29619792 TI - Degree of vision impairment influence the fight outcomes in the paralympic judo: a 10-year retrospective analysis. AB - INTRODUCTION: In the International Blind Sports Federation (IBSA) judo Sports Classes B1, B2, and B3 compete against each other within weight- and gender specific categories. B1 athletes are totally blind, whereas B2 and B3 are partially sighted. PURPOSE: The aim of this study is to examine the impact of the degree of vision impairment on fight outcomes. METHODS: We analysed 1,936 fights from official competitions and compare win ratio in fights between discordant Sports Classes. RESULTS: B1 won B2 ratio was 34.8%, B1 won B3 ratio was 36.5%, B2 won B3 ratio = 50.6%. The B1 percent of IBSA judo athletes decreased from 25.9% in 2007 to 19.4% in 2016, while the total number of participants increased over this period. CONCLUSIONS: These findings confirm that blind athletes have fewer chances to win a fight in IBSA Judo and become a member of National Team. Loss of vision functions affects movement coordination, balance, and emotional state, which are important for martial arts and may explain why B1 athletes are more likely to lose competitions against either B2 or B3. Creation of the evidence based and sport-specific classification system and/or improvement of the technical rules are necessary for fair IBSA Judo competitions. PMID- 29619793 TI - Effect of post warm-up resting interval on static and dynamic balance, and maximal muscle strength followed by the FIFA 11+ and dynamic warm-up exercises. AB - BACKGROUND: It has been reported that implementation of the FIFA11+ can immediately increase exercise performance. However, the elapsed time of post-warm up (WU) effect of the FIFA 11+ is unclear. METHODS: Twenty-two male university football players were randomly assigned into the FIFA 11+ (n =10) or control group (conventional dynamic WU exercise, n = 11). The participants performed static, drop jump, and maximal voluntary muscle contraction (MVC) tests before and after the WU protocol in four different occasions with 0, 10, 20 or 30 min resting interval. Static balance with 4 sensory conditions (stable surface with eyes open, stable surface with eyes closed, unstable surface with eyes open, and unstable surface with eyes closed), drop jump (30 and 50 cm heights), and MVC of knee extension and flexion were examined. The electromyography (EMG) of rectus femoris, vastus medialis, biceps femoris were recorded during the drop jump and MVC measurements. The percentage of pre-and-post WU changes were used for comparison. RESULTS: The MVC slightly decrease immediate after the FIFA11+ but slightly increase after 10, 20, and 30 min resting interval. However, there was no significant difference in all variables during static and dynamic balance measurements and the EMG measurements. No between-group differences were found in all comparisons. CONCLUSIONS: The benefit of WU effect on neuromuscular performance lasts 30 min after FIFA11+ WU activity. Considerations to implement FIFA11+ or conventional dynamic WU exercises for beneficial strategy is warranted. PMID- 29619794 TI - Fitness mobile apps positively affect attitudes, perceived behavioral control and physical activities. AB - BACKGROUND: Recent studies suggest that about 6 out of 10 users have installed a fitness tracking application on their smartphone. Nevertheless, more than 59% of adults do not engage in sufficient daily physical activity and much remains unknown with regard to the effectiveness of mobile applications. By adopting the Theory of Planned Behavior, we tested whether the use of fitness apps for daily steps tracking could positively influence people's health behavior. METHODS: Participants (N = 78) were randomly assigned to one of two experimental conditions; in one condition, they were asked to adopt a fitness app for two weeks. No information regarding mobile apps was given for participants in the control condition. In order to test the effects of using a fitness app, a series of two-way mixed ANOVAs were conducted. RESULTS: Participants in the experimental condition reported more favorable attitudes in the post- test compared to the pre test, t(43)=4.09, p < .001, d = 0.50. By contrast, in the control condition, the difference on attitudes between pre-test and post-test was not significant (p = 1.00). They also reported higher perceived behavioral control (PBC) scores, t(43) = 4.97, p < .001, d = 0.76, whereas the difference on PBC for the control condition was not significant (p = .27). Participants who used a fitness app reported to have walked more in the post-test compared to the pre-test, t(43) = 2.41, p = .02, d = 0.87, whereas self-reported behavior did not change for participants in the control condition (p = .46). CONCLUSIONS: The present study provides encouraging evidence for the positive effects of using a fitness tracking app in promoting health behavior. PMID- 29619795 TI - Switching between pitch surfaces: practical applications and future perspectives for soccer training. AB - Soccer training and completion is conventionally practiced on natural grass (NG) or artificial turf (AT). Recently, AT pitches for training / competition, and of unstable surfaces for injury prevention training has increased. Therefore, soccer players are frequently exposed to variations in pitch surface during either training or competition. These ground changes may impact physical and physiological responses, adaptations as well as the injury. The aim of this review was to summarize the acute physical and physiological responses, chronic adaptations, and injury risk associated with exercising on different pitch surfaces in soccer. Eligible studies were published in English, had pitch surface as an independent variable, and had physical, physiological or epidemiological information as outcome variables. Specific data extracted from the articles included the training response, training adaptations or injury outcomes according to different pitch surfaces. A total of 224 studies were retrieved from a literature search. Twenty articles met the inclusion criteria: 9 for acute physical and physiological responses, 2 for training adaptations and 9 for injury assessment. The literature lacks consistent evidence regarding the effects of pitch surface on performance and health outcomes in soccer players. However, it seems that occasionally switching training surfaces seems a valuable strategy for focusing on specific musculoskeletal queries and enhancing players' fitness. For instance, sand training may be occasionally proposed as complementary training strategy, given the recruitment of additional musculature probably not involved on firmer surfaces, but the possible training-induced adaptations of non conventional soccer surfaces (e.g., sand) might potentially result into a negative transfer on AT or NG. Since the specific physical demands of soccer can differ between surfaces, coaches should resort to the use of non-traditional surfaces with parsimony, emphasizing the specific surface-related motor tasks, normally observed on natural grass or artificial turf. Further studies are required to better understand the physiological effects induced by systematic surface-specific training, or switching between pitch surfaces. PMID- 29619797 TI - Acute neuromuscular responses to short and long roundhouse kick striking paces in professional Muay Thai fighters. AB - BACKGROUND: Muay Thai fighters strongly rely on the use of the roundhouse kick due to its effectiveness (i.e. power) and implications on the final score. Therefore, different striking tempos at full power are used during training as a method to enhance kicking power. However, the neuromuscular responses are unknown. Thus, the goal of this study was to investigate neuromuscular responses to a single bout of shorter (every second = H1) and longer (every 3s = H3) kick striking time intervals, measured with the countermovement jump (CMJ). METHODS: Nine professional Muay Thai fighters participated in this randomized, cross-over trial. CMJs were measured on force plates before and after (post 0min, post 5min, post 10min, post 20min and post 30min) two striking (1set x 20reps) conditions (H1; H3). RESULTS: Although no difference was observed between H1 and H3 values, neuromuscular fatigue parameters displayed different patterns over time. CMJ height decreased immediately after H3 striking (P<0.05), whereas for H1 condition CMJ height decreased from post20 as compared to baseline (P<0.05). Peak force in H3 condition was significantly lower at post10, post20 and post30 as compared to baseline. For H1, peak force values were lower than baseline only at post30. Peak power was significantly lower than baseline for both middle kick procedures. A slight but significant increase was observed at post5 for H3 condition, but decreased further post10 and remained constant during subsequent tests. In contrast, for H1 condition peak power remained unaffected after post10, whereas it decreased post20 and post30 minutes only when compared to post0. CONCLUSIONS: Results showed that both kick striking modes provoke comparable neuromuscular fatigue but H3 condition showed the potential to induce post activation potentiation. Muay Thai and conditioning coaches should focus on hard striking with both long and slow pacing during specific heavy bag or pad work. PMID- 29619796 TI - Overnight fasting compromises exercise intensity and volume during sprint interval training but improves high-intensity aerobic endurance. AB - BACKGROUND: The combined effects of sprint interval training (SIT) and exercising in the fasted state are unknown. We compared the effects of SIT with exogenous carbohydrate supplementation (SITCHO) and SIT following overnight fast (SITFast) on aerobic capacity (peak oxygen consumption: V O2peak) and high-intensity aerobic endurance (time-to-exhaustion at 85% V O2peak [T85%]). METHODS: Twenty male cyclists were randomized to SITCHO and SITFast. Both groups performed 30 second all-out cycling followed by 4-minute active recovery 3 times per week for 4 weeks, with the number of sprint bouts progressing from 4 to 7. Peak power output (PPO) and total mechanical work were measured for each sprint interval bout. The SITCHO group performed exercise sessions following breakfast and consumed carbohydrate drink during exercise, whereas the SITFast group performed exercise sessions following overnight fast and consumed water during exercise. Before and after training, V O2peak and T85% were assessed. Blood glucose, non esterified fatty acids, insulin and glucagon concentrations were measured during T85%. RESULTS: Overall PPO and mechanical work were lower in SITFast than SITCHO (3664.9 vs. 3871.7 Joules/kg; p=0.021 and 10.6 vs. 9.9 Watts/kg; p=0.010, respectively). Post- training V O2peak did not differ between groups. Baseline adjusted post-training T85% was longer in SITFast compared to SITCHO (19.7 +/- 3.0 vs. 16.6 +/- 3.0 minutes, ANCOVA p=0.038) despite no changes in circulating energy substrates or hormones. CONCLUSIONS: Our results suggest that SITFast compromises exercise intensity and volume but still can have a greater impact on the ability to sustain high-intensity aerobic endurance exercise compared to SITCHO. PMID- 29619798 TI - Seasonal player wellness and its longitudinal association with internal training load: study in elite volleyball. AB - BACKGROUND: Monitoring training load is critical to minimize the risk of overreaching, injury or illness. The purpose of this study was to assess the relationships and variance between perceived internal load and wellness status of elite male volleyball. METHODS: Thirteen elite volleyball players were studied during a full competitive season (nine months, 237 training sessions and 37 official matches). Perceived exertion, muscle soreness, stress, fatigue and sleep quality levels were daily measured using session RPE and the Hopper Questionnaire. RESULTS: Moderate-to-large correlations were found between weekly training load and perceived status of muscle soreness, fatigue and stress. Stronger correlations were found between weekly training loads than daily training load. Significant greater stress levels in match days than in training were found. No correlations between load and wellness were not found in the last month when players perceived higher levels of stress due to the competition. CONCLUSIONS: The analysis of the weekly training load had a higher relationship with players' wellness status in pre-season and middle of the season. In the last part of the season (final matches for the title), despite of a decrease in perceived load of last month of the season, there was an increase stress and fatigue levels. These results suggest the importance of including the impact on the competition when elite athletes are monitored. The results show the monitoring tools used may help in to characterize the training process of teams and the player's acute and chronic responses. PMID- 29619799 TI - Low-carbohydrate, ketogenic diet impairs anaerobic exercise performance in exercise-trained women and men: a randomized-sequence crossover trial. AB - BACKGROUND: Low-carbohydrate, ketogenic diets cause mild, sub-clinical systemic acidosis. Anaerobic exercise performance is limited by acidosis. Therefore, we evaluated the hypothesis that a low-carbohydrate, ketogenic diet impairs anaerobic exercise performance, as compared to a high-carbohydrate diet. METHODS: Sixteen men and women (BMI, 23+/-1 kg/m2, age 23+/-1 yr) participated in a randomized-sequence, counterbalanced crossover study in which they underwent exercise testing after four days of either a low-carbohydrate, ketogenic diet (LC; <50 g/day and <10% of energy from carbohydrates) or a high-carbohydrate diet (HC; 6-10 g/kg/day carbohydrate). Dietary compliance was assessed with nutrient analysis of diet records, and with measures of urine pH and ketones. Anaerobic exercise performance was evaluated with the Wingate anaerobic cycling test and the yo-yo intermittent recovery test. RESULTS: The diets were matched for total energy (LC: 2333+/-158 kcal/d; HC: 2280+/-160 kcal/d; p=0.65) but differed in carbohydrate content (9+/-1 vs. 63+/-2% of energy intake; p<0.001). LC resulted in lower urine pH (5.9+/-0.1 vs. 6.3+/-0.2, p=0.004) and the appearance of urine ketones in every participant. LC resulted in 7% lower peak power (801+/-58 vs. 857+/-61 watts, p=0.008) and 6% lower mean power (564+/-50 vs. 598+/-51 watts, p=0.01) during the Wingate test. Total distance ran in the yo-yo intermittent recovery test was 15% less after LC diet (887+/-139 vs. 1045+/-145 meters, p=0.02). CONCLUSIONS: Short-term low-carbohydrate, ketogenic diets reduce exercise performance in activities that are heavily dependent on anaerobic energy systems. These findings have clear performance implications for athletes, especially for high-intensity, short duration activities and sports. PMID- 29619801 TI - Evaluation of somatotype in artistic gymnastics competitors: a meta-analytical approach. AB - INTRODUCTION: Studies on the anthropometric characteristics of athletes have a long history, but there are no published reviews on the somatotype of artistic gymnasts. Practitioners and professional coaches can gain guidance from improved understanding of the ideal body constitution and the impact of high-intensity training since preadolescence on body build. The present review is designed to provide this information. EVIDENCE ACQUISITION: Academic Search Complete, SPORTDiscus, Medline, Google Scholar, and ResearchGate were searched in January 2017. All studies on the body composition of male artistic gymnasts were included. We identified 19 studies assessing somatotype in male gymnasts. EVIDENCE SYNTHESIS: We found high heterogeneity of somatotype components between younger gymnasts (<= 18 years) and older gymnasts (> 18 years) (1.6+/-0.3 -5.4+/ 0.8 - 3.0+/-0.6 vs. 1.8+/-0.4 -5.9+/-0.6 -2.2+/-0.4). Four different somatotypes resulted from the literature analysis, and ectomorphic mesomorph was the prevalent somatotype in both younger and older athletes. The main result showed a significant difference in ectomorphy (lower in older gymnasts than in younger gymnasts). CONCLUSIONS: Proper interpretation of the literature data may inform future research and enable professional coaches to longitudinally monitor gymnasts' somatotype components during growth and in talent identification. More research is needed to better understand the most suitable somatotype variations related to the different apparatuses used in artistic gymnastics. PMID- 29619800 TI - Not just contact sports: significant numbers of sports-related concussions in cycling. AB - BACKGROUND: Although sports-related concussions (SRCs) / mild traumatic brain injuries (mTBIs) in contact sports have recently received much attention, investigation of SRCs in cycling - a sport yielding some of the highest percentages of SRC - remains strikingly limited. In particular, rates of incidence, cycling-specific causes, and potential long-term effects of SRC have not been examined in this sport. Here, a retrospective online survey was used to investigate the incidence and potential long-term effects of SRCs among cyclists. METHODS: A cycling-specific questionnaire was developed and administered to 2792 cyclists via an online survey. First, participants were asked about their acute symptomatology, and secondly, cycling-specific items and concussion history were addressed. RESULTS: Of the 999 cyclists whom completed the questionnaire, 23.8% had experienced a concussion. Incidence of concussion was significantly higher in cyclists who were club members, who cycled more than 200 kilometers per week, and who wore a helmet. Cyclists with a history of concussion complained significantly more often about headaches, pressure in the head, sensitivity to light, confusion, and irritability. CONCLUSIONS: Concussions in cycling are a serious injury with a high incidence relative to other sports. Although wearing a helmet reduces the risk of severe brain injury, interesting, the present results show a relation between helmet use, participation in cycling clubs, and increased concussion incidence. These data are in line with the growing number of findings showing that athletes with a history of concussion report more symptoms. PMID- 29619802 TI - Improving muscular strength and hypertrophy: are we following the right scientific way? PMID- 29619803 TI - Measuring the validity and reliability of the Apple Watch as a physical activity monitor. AB - BACKGROUND: This study aimed to investigate the validity and reliability of the energy expenditure (EE) estimation of Apple Watch among college students. METHODS: Thirty college students completed two sets of three 10-minute treadmill walking and running trials while wearing three Apple Watches and being connected to indirect calorimetry. The walking trials were at speeds of 54, 80, and 107 m*min-1 while the running trials were at 134, 161, 188m*min-1. Energy expenditure comparisons were made using Two-way ANOVA with repeatedmeasures. Reliability was analyzed by Intraclass Correlation. RESULTS: There was no significant device x speed interactions (F (15, 696) = 1.113, p = 0.341) between the indirect calorimetry (criterion) and Apple Watch. The lowest Inter-Class Correlation (ICC) scores were 0.49 (95%CI) at 54 while the highest were 0.72 (95%CI) at 107 and 134 m*min-1. CONCLUSIONS: Apple Watch demonstrated a low to moderate validity and reliability on measuring EE. PMID- 29619804 TI - Effect of voluntary teeth clenching and sitting posture on maximal static force of limb muscles. AB - BACKGROUND: People clench their teeth to activate facial, neck and abdominal muscles when they need to generate heavy muscle force against large resistance like lifting heavy objects, in order to gain possible ergogenic advantage. These are termed as remote voluntary contractions. Aim of this study was to evaluate the effect of voluntary teeth clenching on maximal voluntary contraction of extensors and flexors of the knee, shoulder and elbow joints of the dominant side during slouch and unsupported upright sitting. METHODS: One hundred healthy young male adults (mean age 23.3 years) participated in this study. Maximal voluntary contraction was measured using a hand held dynamometer. RESULTS: Jaw clenching caused different ergogenic effect during slouch versus unsupported sitting postures. The data revealed that during unsupported upright sitting, the effect of jaw clenching consistently results in larger maximal voluntary contraction of both extensor and flexor muscles of all the three studied joints. However, during slouch sitting, only the maximal voluntary contraction of extensors of elbow and flexors of knee were larger with clenched teeth position. CONCLUSIONS: Jaw clenching can affect the maximal voluntary contraction of limb muscles which is sitting posture dependent. Jaw clenching can consistently facilitate certain muscles of the upper and lower limbs to generate greater force production during upright sitting. PMID- 29619805 TI - Using blood lactate concentration to predict muscle damage and jump performance response to maximal stretch-shortening cycle exercise. AB - BACKGROUND: It is well known that eccentric muscle contractions induce delayed onset muscle soreness (DOMS) and exertional rhabdomyolysis (ERB), both of which are related to high blood levels of muscle damage markers after exercise. Creatine kinase (CK) is, together with some other markers (e.i. myoglobin, alpha actin, skeletal troponin), widely used in determination of muscle damage. Moreover, DOMS after eccentric exercise has been shown to be associated with altered blood lactate concentration after subsequent submaximal or maximal cycling exercise. However, it is unknown whether blood lactate can predict muscle damage levels after maximal SSC (stretch-shortening cycle) exercise, as due to the differences in types of contractions between the eccentric and SSC protocol. Additionally, we determined the association between blood lactate concentration and CMJ performance after such a protocol. METHODS: Forty-three healthy, physically active young men completed a plyometric training session consisting of maximal countermovement jumps (CMJ) to failure. The blood creatine kinase (CK), myoglobin (Mb) and aspartate aminotransferase (AST) samples were taken pre- and 48 h postexercise. Blood lactate concentration was determined directly postexercise. RESULTS: There was a significant correlation between blood lactate concentration (post) and blood CK (p=0.027), Mb (p=0.007) and AST (p=0.024) (48 h post), which means that higher blood lactate concentration is associated with higher muscle damage values after exercise. No correlation was found between blood lactate concentration (post) and performance loss which was expressed by the decrease in maximum CMJ height 5 min postexercise. CONCLUSIONS: Blood lactate concentration could be used as a predictor of muscle damage levels after maximal SSC exercise, which supports the results found in other studies, although after eccentric exercise. However, it cannot predict acute performance loss in jump height. PMID- 29619806 TI - The influence of single-leg landing direction on lower limbs biomechanics. AB - BACKGROUND: The purpose of this study was to investigate whether different directions of single-leg landing tasks would influence lower limbs joints biomechanics. METHODS: Using a controlled and experimental design, thirty physically active male subjects (age: 26.4 +/- 4.4 years; height: 180.5 +/- 3.7 cm; weight: 79.8: +/- 4.4 kg), by dropping down from the top of a wooden box of 31 cm height, performed three one-leg landing tasks featured by different landing directions: frontward (FL), lateral (LL), and rotational (RL). The trunk and lower limbs' joints biomechanical responses were assessed through a laboratory setup consisting in a 6-camera motion capture system synchronized with force plates. A repeated measures one-way Analysis of Variance (ANOVA) was used to investigate the main effects of the landing directions on the lower limbs joints biomechanics during the main phases of interest of the landing tasks. RESULTS: The results indicated two major findings: (1) FL resulted in an advantageous active whole body configuration; (2) The lower limbs' joints adopted different and specific energy absorption strategies between the landing tasks. CONCLUSIONS: This study indicates that the different landing tasks likely generate meaningful changes in in whole body biomechanics and specific lower limbs joints kinetic and kinematic responses. Such outcomes might be used by clinicians towards a practical approach in selecting either assessment modalities or exercise interventions. PMID- 29619808 TI - PCI Strategies in Acute Myocardial Infarction with Cardiogenic Shock. PMID- 29619809 TI - PCI Strategies in Acute Myocardial Infarction with Cardiogenic Shock. PMID- 29619807 TI - [Recommendations for the care of patients with community-acquired pneumonia in the Emergency Department]. AB - The incidence of community-acquired pneumonia (CAP) ranges from 2-15 cases / 1,000 inhabitants / year, being higher in those older than 65 years and in patients with high co-morbidity. Around 75% of all CAP diagnosed are treated in the Emergency Department (ED). The CAP represents the main cause for sepsis and septic shock in ED, and the most frequent cause of death and admission to the Intensive Care Unit (ICU) due to infectious disease. Overall mortality is 10-14% according to age and associated risk factors. Forty to 60% of CAP will require hospital admission, including observation units (with very variable ranges from 22-65% according to centers, seasonal of the year and patients' characteristics). Between the admissions, 2-10% will be in the ICU. All of previously mentioned reflects the importance of the CAP in the ED, as well as the "impact of the emergency care on the patient with CAP", as it is the establishment where the initial, but key decisions, are made and could condition the outcome of the illness. It is known the great variability among physicians in the diagnostic and therapeutic management of CAP, which is one of the reasons that explains the great differences in the admission rates, achievement of the microbiological diagnosis, request for complementary studies, the choice of antimicrobial treatment, or the diversity of applied care. In this sense, the implementation of clinical practice guidelines with the use of the severity scores and the new tools available, such as biomarkers, can improve patient care with CAP in ED. Therefore, a multidisciplinary group of emergency professionals and specialists involved in the care process of CAP has designed a guideline with several recommendations for decisions-making during the key moments in patients with CAP attended in the ED. PMID- 29619810 TI - PCI Strategies in Acute Myocardial Infarction with Cardiogenic Shock. PMID- 29619811 TI - PCI Strategies in Acute Myocardial Infarction with Cardiogenic Shock. PMID- 29619812 TI - PCI Strategies in Acute Myocardial Infarction with Cardiogenic Shock. PMID- 29619813 TI - PCI Strategies in Acute Myocardial Infarction with Cardiogenic Shock. PMID- 29619814 TI - Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer. PMID- 29619815 TI - Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer. PMID- 29619816 TI - Hyperthermic Intraperitoneal Chemotherapy in Ovarian Cancer. PMID- 29619817 TI - More on Ofatumumab for TTP. PMID- 29619818 TI - Asymmetric Cationic Porphyrin as a New G-Quadruplex Probe with Wash-Free Cancer Targeted Imaging Ability Under Acidic Microenvironments. AB - Porphyrins are promising candidates for nucleic acid G-quadruplex-specific optical recognition. We previously demonstrated that G-quadruplex recognition specificity of porphyrins could be improved by introducing bulky side arm substituents, but the enhanced protonation tendency limits their applications in some cases, such as under acidic conditions. Here, we demonstrated that the protonation tendency of porphyrin derivatives could be efficiently overcome by increasing molecular asymmetry. To validate this, an asymmetric, water-soluble, cationic porphyrin FA-TMPipEOPP (5-{4-[2-[[(2 E)-3-[3-methoxy-4-[2-(1-methyl-1 piperidinyl)ethoxy]phenyl]-1-oxo-2-propenyl]oxy]ethoxy]phenyl},10,15,20-tri{4-[2 (1-methyl-1-piperidinyl)ethoxy]-phenyl}porphyrin) was synthesized by introducing a ferulic acid (FA) unit at one side arm, and its structure was well characterized. Unlike its symmetric counterpart TMPipEOPP that has a tendency to protonate under acidic conditions, FA-TMPipEOPP remained in the unprotonated monomeric form under the pH range of 2.0-8.0. Correspondingly, FA-TMPipEOPP showed better G-quadruplex recognition specificity than TMPipEOPP and thus might be used as a specific optical probe for colorimetric and fluorescent recognition of G-quadruplexes under acidic conditions. The feasibility was demonstrated by two proof-of-concept studies: probing structural competition between G quadruplexes and duplexes and label-free and wash-free cancer cell-targeted bioimaging under an acidic tumor microenvironment. As G-quadruplex optical probes, FA-TMPipEOPP works well under acidic conditions, whereas TMPipEOPP works well under neutral conditions. This finding provides useful information for G quadruplex probe research. That is, porphyrin-based G-quadruplex probes suitable for different pH conditions might be obtained by adjusting the molecular symmetry. PMID- 29619819 TI - Selenium Biofortification in Rice ( Oryza sativa L.) Sprouting: Effects on Se Yield and Nutritional Traits with Focus on Phenolic Acid Profile. AB - The contents of total Se and of inorganic and organic Se species, as well as the contents of proteins, chlorophylls, carotenoids, and phenolic acids, were measured in 10-day old sprouts of rice ( Oryza sativa L.) obtained with increasing levels (15, 45, 135, and 405 mg Se L-1) of sodium selenite and sodium selenate and with distilled water as control. Increasing Se levels increased organic and inorganic Se contents of sprouts, as well as the content of phenolic acids, especially in their soluble conjugated forms. Moderate levels of sodium selenite (i.e., not higher that 45 mg L-1) appeared the best compromise to obtain high Se and phenolic acid yields together with high proportion of organic Se while limiting residual Se in the germination substrate waste. Se biofortification of rice sprouts appears a feasible and efficient way to promote Se and phenolic acid intake in human diet, with well-known health benefits. PMID- 29619820 TI - Online Chemical Characterization of Food-Cooking Organic Aerosols: Implications for Source Apportionment. AB - Food-cooking organic aerosols (COA) are one of the primary sources of submicron particulate matter in urban environments. However, there are still many questions surrounding source apportionment related to instrumentation as well as semivolatile partitioning because COA evolve rapidly in the ambient air, making source apportionment more complex. Online measurements of emissions from cooking different types of food were performed in a laboratory to characterize particles and gases. Aerosol mass spectrometer (AMS) measurements showed that the relative ionization efficiency for OA was higher (1.56-3.06) relative to a typical value of 1.4, concluding that AMS is over-estimating COA and suggesting that previous studies likely over-estimated COA concentrations. Food-cooking mass spectra were generated using AMS, and gas and particle food markers were identified with filter inlets for gases and aerosols-chemical ionization mass spectrometer (CIMS) measurements to be used in future food cooking-source apportionment studies. However, there is a considerable variability in both gas and particle markers, and dilution plays an important role in the particle mass budget, showing the importance of using these markers with caution during receptor modeling. These findings can be used to better understand the chemical composition of COA, and they provides useful information to be used in future source-apportionment studies. PMID- 29619821 TI - Selective Killing of Pathogenic Bacteria by Antimicrobial Silver Nanoparticle Cell Wall Binding Domain Conjugates. AB - Broad-spectrum antibiotics indiscriminately kill bacteria, removing nonpathogenic microorganisms and leading to evolution of antibiotic resistant strains. Specific antimicrobials that could selectively kill pathogenic bacteria without targeting other bacteria in the natural microbial community or microbiome may be able to address this concern. In this work, we demonstrate that silver nanoparticles, suitably conjugated to a selective cell wall binding domain (CBD), can efficiently target and selectively kill bacteria. As a relevant example, CBDBA from Bacillus anthracis selectively bound to B. anthracis in a mixture with Bacillus subtilis, as well in a mixture with Staphylococcus aureus. This new biologically-assisted hybrid strategy, therefore, has the potential to provide selective decontamination of pathogenic bacteria with minimal impact on normal microflora. PMID- 29619822 TI - Drosophila melanogaster as a Versatile Model Organism in Food and Nutrition Research. AB - Drosophila melanogaster has been widely used in the biological sciences as a model organism. Drosophila has a relatively short life span of 60-80 days, which makes it attractive for life span studies. Moreover, approximately 60% of the fruit fly genes are orthologs to mammals. Thus, metabolic and signal transduction pathways are highly conserved. Maintenance and reproduction of Drosophila do not require sophisticated equipment and are rather cheap. Furthermore, there are fewer ethical issues involved in experimental Drosophila research compared with studies in laboratory rodents, such as rats and mice. Drosophila is increasingly recognized as a model organism in food and nutrition research. Drosophila is often fed complex solid diets based on yeast, corn, and agar. There are also so called holidic diets available that are defined in terms of their amino acid, fatty acid, carbohydrate, vitamin, mineral, and trace element compositions. Feed intake, body composition, locomotor activity, intestinal barrier function, microbiota, cognition, fertility, aging, and life span can be systematically determined in Drosophila in response to dietary factors. Furthermore, diet induced pathophysiological mechanisms including inflammation and stress responses may be evaluated in the fly under defined experimental conditions. Here, we critically evaluate Drosophila melanogaster as a versatile model organism in experimental food and nutrition research, review the corresponding data in the literature, and make suggestions for future directions of research. PMID- 29619823 TI - Enhanced Photocurrent in BiFeO3 Materials by Coupling Temperature and Thermo Phototronic Effects for Self-Powered Ultraviolet Photodetector System. AB - Ferroelectric materials can be utilized for fabricating photodetectors because of the photovoltaic effect. Enhancing the photovoltaic performance of ferroelectric materials is still a challenge. Here, a self-powered ultraviolet (UV) photodetector is designed based on the ferroelectric BiFeO3 (BFO) material, exhibiting a high current/voltage response to 365 nm light in heating/cooling states. The photovoltaic performance of the BFO-based device can be well modulated by applying different temperature variations, where the output current and voltage can be enhanced by 60 and 75% in heating and cooling states, respectively. The enhancement mechanism of the photocurrent is associated with both temperature effect and thermo-phototronic effect in the photovoltaic process. Moreover, a 4 * 4 matrix photodetector array has been designed for detecting the 365 nm light distribution in the cooling state by utilizing photovoltage signals. This study clarifies the role of the temperature effect and the thermo-phototronic effect in the photovoltaic process of the BFO material and provides a feasible route for pushing forward practical applications of self powered UV photodetectors. PMID- 29619824 TI - High-Density ZnO Nanowires as a Reversible Myogenic-Differentiation Switch. AB - Mesoangioblasts are outstanding candidates for stem-cell therapy and are already being explored in clinical trials. However, a crucial challenge in regenerative medicine is the limited availability of undifferentiated myogenic progenitor cells because growth is typically accompanied by differentiation. Here reversible myogenic-differentiation switching during proliferation is achieved by functionalizing the glass substrate with high-density ZnO nanowires (NWs). Specifically, mesoangioblasts grown on ZnO NWs present a spherical viable undifferentiated cell state without lamellopodia formation during the entire observation time (8 days). Consistently, the myosin heavy chain, typically expressed in skeletal muscle tissue and differentiated myogenic progenitors, is completely absent. Remarkably, NWs do not induce any damage while they reversibly block differentiation, so that the differentiation capabilities are completely recovered upon cell removal from the NW-functionalized substrate and replating on standard culture glass. This is the first evidence of a reversible myogenic differentiation switch that does not affect the viability. These results can be the first step toward for the in vitro growth of a large number of undifferentiated stem/progenitor cells and therefore can represent a breakthrough for cell-based therapy and tissue engineering. PMID- 29619825 TI - Proteogenomics of Malignant Melanoma Cell Lines: The Effect of Stringency of Exome Data Filtering on Variant Peptide Identification in Shotgun Proteomics. AB - The identification of genetically encoded variants at the proteome level is an important problem in cancer proteogenomics. The generation of customized protein databases from DNA or RNA sequencing data is a crucial stage of the identification workflow. Genomic data filtering applied at this stage may significantly modify variant search results, yet its effect is generally left out of the scope of proteogenomic studies. In this work, we focused on this impact using data of exome sequencing and LC-MS/MS analyses of six replicates for eight melanoma cell lines processed by a proteogenomics workflow. The main objectives were identifying variant peptides and revealing the role of the genomic data filtering in the variant identification. A series of six confidence thresholds for single nucleotide polymorphisms and indels from the exome data were applied to generate customized sequence databases of different stringency. In the searches against unfiltered databases, between 100 and 160 variant peptides were identified for each of the cell lines using X!Tandem and MS-GF+ search engines. The recovery rate for variant peptides was ~1%, which is approximately three times lower than that of the wild-type peptides. Using unfiltered genomic databases for variant searches resulted in higher sensitivity and selectivity of the proteogenomic workflow and positively affected the ability to distinguish the cell lines based on variant peptide signatures. PMID- 29619826 TI - Improved Lubricating Performance by Combining Oil-Soluble Hairy Silica Nanoparticles and an Ionic Liquid as an Additive for a Synthetic Base Oil. AB - This article reports on improved lubricating performance by combining oil-soluble poly(lauryl methacrylate) brush-grafted silica nanoparticles (hairy NPs or HNP) and an oil-miscible phosphonium-phosphate ionic liquid (IL) as a friction reducing additive for a polyalphaolefin (PAO) oil. The HNP was synthesized by surface-initiated reversible addition-fragmentation chain transfer polymerization. At a total concentration of 2% and sufficiently high individual concentrations for HNP and IL in PAO, high-contact stress, ball-on-flat reciprocating tribological tests showed that the friction decreased by up to 23% compared with 2% HNP alone in PAO and by up to 35% compared to the PAO mixed with 2% IL. Scanning electron microscopy, energy-dispersive X-ray spectroscopy, and X ray photoelectron spectroscopy (XPS) analysis revealed that the tribofilm formed from the PAO containing 1% HNP + 1% IL was enriched with both Si and P, indicating that both hairy NPs and IL were involved in the tribochemical reactions. In addition, the O 1s and Si 2p peaks in the core-level XPS spectra exhibited significant shifts for the mixture of 1% HNP + 1% IL compared to those for 2% HNP, suggesting the possible formation of new covalent bonds. These results indicated that HNP and IL reacted with each other and also with the metal substrate during the rubbing process, which likely strengthened the tribofilm and its bonding with the substrate and thus further improved the lubrication. PMID- 29619827 TI - Fast-Response Single-Nanowire Photodetector Based on ZnO/WS2 Core/Shell Heterostructures. AB - The surface plays an exceptionally important role in nanoscale materials, exerting a strong influence on their properties. Consequently, even a very thin coating can greatly improve the optoelectronic properties of nanostructures by modifying the light absorption and spatial distribution of charge carriers. To use these advantages, 1D/1D heterostructures of ZnO/WS2 core/shell nanowires with a-few-layers-thick WS2 shell were fabricated. These heterostructures were thoroughly characterized by scanning and transmission electron microscopy, X-ray diffraction, and Raman spectroscopy. Then, a single-nanowire photoresistive device was assembled by mechanically positioning ZnO/WS2 core/shell nanowires onto gold electrodes inside a scanning electron microscope. The results show that a few layers of WS2 significantly enhance the photosensitivity in the short wavelength range and drastically (almost 2 orders of magnitude) improve the photoresponse time of pure ZnO nanowires. The fast response time of ZnO/WS2 core/shell nanowire was explained by electrons and holes sinking from ZnO nanowire into WS2 shell, which serves as a charge carrier channel in the ZnO/WS2 heterostructure. First-principles calculations suggest that the interface layer i WS2, bridging ZnO nanowire surface and WS2 shell, might play a role of energy barrier, preventing the backward diffusion of charge carriers into ZnO nanowire. PMID- 29619828 TI - Watching Three-Dimensional Movements of Single Membrane Proteins in Lipid Bilayers. AB - It is challenging to assess protein-membrane interactions because of the lack of appropriate tools to detect position changes of single proteins in the ~4 nm range of biological membranes. We developed an assay recently, termed surface induced fluorescence attenuation (SIFA). It is able to track both vertical and lateral dynamic motion of singly labeled membrane proteins in supported lipid bilayers. Similar to the FRET (fluorescence resonance energy transfer) principle, SIFA takes advantage of the energy transfer from a fluorophore to a light absorbing surface to determine the distance at 2-8 nm away from the surface. By labeling a protein with a proper fluorophore and using graphene oxide as a two dimensional quencher, we showed that SIFA is capable of monitoring three dimensional movements of the fluorophore-labeled protein not only inside but also above the lipid bilayer atop the graphene oxide. Our data show that SIFA is a well-suited method to study the interplay between proteins and membranes. PMID- 29619829 TI - Native State Organization of Outer Membrane Porins Unraveled by HDx-MS. AB - Hydrogen-deuterium exchange (HDx) associated with mass spectrometry (MS) is emerging as a powerful tool to provide conformational information about membrane proteins. Unfortunately, as for X-ray diffraction and NMR, HDx performed on reconstituted in vitro systems might not always reflect the in vivo environment. Outer-membrane vesicles naturally released by Escherichia coli were used to carry out analysis of native OmpF through HDx-MS. A new protocol compatible with HDx analysis that avoids hindrance from the lipid contents was setup. The extent of deuterium incorporation was in good agreement with the X-ray diffraction data of OmpF as the buried beta-barrels incorporated a low amount of deuterium, whereas the internal loop L3 and the external loops incorporated a higher amount of deuterium. Moreover, the kinetics of incorporation clearly highlights that peptides segregate well in two distinct groups based exclusively on a trimeric organization of OmpF in the membrane: peptides presenting fast kinetics of labeling are facing the complex surrounding environment, whereas those presenting slow kinetics are located in the buried core of the trimer. The data show that HDx-MS applied to a complex biological system is able to reveal solvent accessibility and spatial arrangement of an integral outer-membrane protein complex. PMID- 29619830 TI - Visible-Light-Mediated Umpolung Reactivity of Imines: Ketimine Reductions with Cy2NMe and Water. AB - A novel carbanionic reactivity of imines mediated by photoredox catalysis is demonstrated. The umpolung imine reactivity is exemplified by proton abstraction from water as a key step in the reduction of benzophenone ketimines to amines (up to 98% yield). Deuterium is introduced into amines efficiently using D2O as an inexpensive deuterium source (>=95% D ratio). The mechanism of this unusual transformation is probed. PMID- 29619831 TI - Tuning the Stereoselectivity and Solvation Selectivity at Interfacial and Bulk Environments by Changing Solvent Polarity: Isomerization of Glyoxal in Different Solvent Environments. AB - Conformational isomerism plays a central role in organic synthesis and biological processes; however, effective control of isomerization processes still remains challenging and elusive. Here, we propose a novel paradigm for conformational control of isomerization in the condensed phase, in which the polarity of the solvent determines the relative concentration of conformers at the interfacial and bulk regions. By the use of state-of-the-art molecular dynamics simulations of glyoxal in different solvents, we demonstrate that the isomerization process is dipole driven: the solvent favors conformational changes toward conformers having molecular dipoles that better match its polar character. Thus, the solvent polarity modulates the conformational change, stabilizing and selectively segregating in the bulk vs the interface one conformer with respect to the others. The findings in this paper have broader implications affecting systems involving compounds with conformers of different polarity. This work suggests novel mechanisms for tuning the catalytic activity of surfaces in conformationally controlled (photo)chemical reactions and for designing a new class of molecular switches that are active in different solvent environments. PMID- 29619832 TI - Recombinant Human Lysyl Oxidase-like 2 Secreted from Human Embryonic Kidney Cells Displays Complex and Acidic Glycans at All Three N-Linked Glycosylation Sites. AB - Human lysyl oxidase-like 2 (hLOXL2), a glycoprotein implicated in tumor progression and organ fibrosis, is a molecular target for anticancer and antifibrosis treatment. This glycoprotein contains three predicted N-linked glycosylation sites; one is near the protein's active site, and at least one more is known to facilitate the protein's secretion. Because the glycosylation impacts the protein's biology, we sought to characterize the native, mammalian glycosylation profile and to determine how closely this profile is recapitulated when the protein is expressed in insect cells. All three glycosylation sites on the protein, expressed in human embryonic kidney (HEK) cells, were characterized individually using a mass spectrometry-based glycopeptide analysis workflow. These data were compared to the glycosylation profile of the same protein expressed in insect cells. We found that the producer cell type imparts a substantial influence on the glycosylation of this important protein. The more relevant version, expressed in HEK cells, contains large, acidic glycoforms; these glycans are not generated in insect cells. The glycosylation differences likely have structural and functional consequences, and these data should be considered when generating protein for functional studies or for high-throughput screening campaigns. PMID- 29619833 TI - Magnetism Control by Doping in LaAlO3/SrTiO3 Heterointerfaces. AB - Magnetic two-dimensional electron gases at the oxide interfaces are always one of the key issues in spintronics, giving rise to intriguing magnetotransport properties. However, reports about magnetic two-dimensional electron gases remain elusive. Here, we obtain the magnetic order of LaAlO3/SrTiO3 systems by introducing magnetic dopants at the La site. The transport properties with a characteristic of metallic behavior at the interfaces are investigated. More significantly, magnetic-doped samples exhibit obvious magnetic hysteresis loops and the mobility is enhanced. Meanwhile, the photoresponsive experiments are realized by irradiating all samples with a 360 nm light. Compared to magnetism, the effects of dopants on photoresponsive and relaxation properties are negligible because the behavior originates from SrTiO3 substrates. This work paves a way for revealing and better controlling the magnetic properties of oxide heterointerfaces. PMID- 29619834 TI - Rationally Designed Sensing Selectivity and Sensitivity of an Aerolysin Nanopore via Site-Directed Mutagenesis. AB - Selectivity and sensitivity are two key parameters utilized to describe the performance of a sensor. In order to investigate selectivity and sensitivity of the aerolysin nanosensor, we manipulated its surface charge at different locations via single site-directed mutagenesis. To study the selectivity, we replaced the positively charged R220 at the entrance of the pore with negatively charged glutamic acid, resulting in barely no current blockages for sensing negatively charged oligonucleotides. For the sensitivity, we substituted the positively charged lumen-exposed amino acid K238 located at trans-ward third of the beta-barrel stem with glutamic acid. This leads to a surprisingly longer duration time at +140 mV, which is about 20 times slower in translocation speed for Poly(dA)4 compared to that of wild-type aerolysin, indicating the stronger pore-analyte interactions and enhanced sensitivity. Therefore, it is both feasible and understandable to rationally design confined biological nanosensors for single molecule detection with high selectivity and sensitivity. PMID- 29619835 TI - Augmented Pairwise Additive Interaction Model for Lateral Adsorbate Interactions: The NO-CO Reaction System on Rh(100) and Rh(111). AB - Lateral adsorbate interactions have been acknowledged to play an important role in heterogeneous catalytic kinetics. To quantify such energies efficiently and accurately, a lattice-gas-based augmented pairwise additive interaction model was proposed. The model Hamiltonian is defined as the summation over all isolated binding energies and all pairwise interactions, with the pairwise interaction used for each adsorbate pair consisting of the corresponding isolated pairwise interaction and some needed modification terms if the surroundings meet specific conditions. The parameters used in this augmented pairwise additive interaction model for the NO-CO reaction system on Rh(100) and Rh(111) were collected based on density functional theory (DFT) calculations. The reliability of the model was examined by the reproduction of some DFT-based predictions and experimental observations. Results suggest that the lateral interactions on Rh(100) are relatively short range and greatly susceptible to the lateral displacements of adsorbates, whereas on Rh(111), the lateral interactions are relatively long range and the lateral displacements of adsorbates are more limited. In addition, the Bronsted-Evans-Polanyi relations for adsorbate diffusion were constructed and a modification strategy was proposed for certain diffusion processes. This work opens up the possibility of accurate microkinetic modeling for this reaction system with a faithful account of lateral interactions and motivates the extensions to other complex surface systems. PMID- 29619837 TI - Creating and evaluating an opportunity for medication reconciliation in the adult population of South Africa to improve patient care. AB - OBJECTIVE: Adverse drug events (ADEs) are a major cause of morbidity and mortality, with more than 50% of ADEs being preventable. Adverse Drug Reactions (ADRs) are typically the result of an incomplete medication history, prescribing or dispensing error, as well as over- or under-use of prescribed pharmacotherapy. Medication reconciliation is the process of creating the most accurate list of medications a patient is taking and subsequently comparing the list against the different transitions of care. It is used to reduce medication discrepancies, and thereby ultimately decreasing ADEs. However, little is known about medicine reconciliation activities among public hospitals in South Africa. METHODS: Prospective quantitative, descriptive design among Internal and Surgical wards in a leading public hospital in South Africa. RESULTS: 145 study participants were enrolled. Over 1300 (1329) medicines were reviewed of which there was a significant difference (p = 0.006) when comparing the medications that the patient was taking before or during hospitalisation. A total of 552 (41.53%) interventions were undertaken and the majority of patients had at least 3.96 medication discrepancies. The most common intervention upon admission was transcribing the home medication onto the hospital prescription (65.2%) followed by medication duplication (13.44%). During patient's hospital stay, interventions included patient counselling (32.5%) and stopping the previous treatment (37.5%). CONCLUSION: To ensure continuity of patient care, medication reconciliation should be implemented throughout patients' hospital stay. This involves all key professionals in hospitals. PMID- 29619836 TI - Phenotypic heterogeneity of intellectual disability in patients with congenital insensitivity to pain with anhidrosis: A case report and literature review. AB - Congenital insensitivity to pain with anhidrosis (CIPA) is a rare autosomal recessive heterogeneous disorder mainly caused by mutations in the neurotrophic tyrosine receptor kinase 1 gene ( NTRK1) and characterized by insensitivity to noxious stimuli, anhidrosis, and intellectual disability. We herein report the first north Han Chinese patient with CIPA who exhibited classic phenotypic features and severe intellectual disability caused by a homozygous c.851-33T>A mutation of NTRK1, resulting in aberrant splicing and an open reading frame shift. We reviewed the literature and performed in silico analysis to determine the association between mutations and intellectual disability in patients with CIPA. We found that intellectual disability was correlated with the specific Ntrk1 protein domain that a mutation jeopardized. Mutations located peripheral to the Ntrk1 protein do not influence important functional domains and tend to cause milder symptoms without intellectual disability. Mutations that involve critical amino acids in the protein are prone to cause severe symptoms, including intellectual disability. PMID- 29619838 TI - Relationship between exercise intervention and NO pathway in patients with heart failure with preserved ejection fraction. AB - OBJECTIVE: Elevated levels of arginine derivatives in the NO pathway, such as asymmetric dimethylarginine (ADMA), are related to disease severity and reduced exercise capacity in heart failure (HF). We investigated the influence of exercise intervention on these parameters and on L-arginine (L-Arg) and L homoarginine (L-hArg) in HF with preserved ejection fraction (HFpEF) patients. MATERIAL AND METHODS: Sixty-two patients (65 +/- 6 years) were included in this analysis and randomized to supervised endurance/resistance training (ET) or to usual care (UC). EDTA-plasma was analysed for NO metabolites. RESULTS: There were baseline associations for adjusted values of maximum workload with ADMA (r= 0.322, p = 0.028) and L-Arg/ADMA ratio (r = 0.331, p = 0.015), and for the 6-min walk test (6MWT) with ADMA (r= -0.314, p = 0.024) and L-Arg/ADMA ratio (r = 0.346, p = 0.015). No significant differences between UC and ET changes of NO parameters were observed at 3-month follow-up. Higher L-hArg levels were associated with a greater improvement in peak oxygen uptake (peak [Formula: see text]O2) at follow-up: 3.4 +/- 2.8 vs. 1.1 +/- 2.9 mL/min/kg (p = 0.005). CONCLUSIONS: Exercise intervention did not influence NO parameters in HFpEF patients, but L-hArg was related to change in peak [Formula: see text]O2. PMID- 29619839 TI - Psychometric validation of the Stoma-QOL questionnaire in a Canadian cross sectional sample of colostomy and ileostomy patients. AB - OBJECTIVES: The Stoma-QOL questionnaire is a patient-reported outcome (PRO) used to measure quality of life in patients with ileostomy or colostomy. This study assesses the Stoma-QOL's overall and item-level psychometric characteristics in patients with temporary stomas, and whether stoma-related quality of life differs by demographic characteristics. MATERIALS AND METHODS: Analysis of cross sectional observational PRO data from hospitals in Vancouver, Canada. Patients registered for elective ileostomy or colostomy closure, over the age of 18, and able to read English were eligible for participation. Emergent and cancer-related cases were excluded. One-way analysis of variance was used to test for demographic differences in Stoma-QOL scores. Cronbach's alpha was used for reliability, and Rasch item-response theory was used to assess overall and item characteristics. RESULTS: 120 patients were included. No statistically significant difference in Stoma-QOL scores was found by age, sex, or socioeconomic status. Reliability was 0.93. Mean item responses ranged from 1.77 to 3.55 and item-total correlation ranged from 0.51 to 0.77. The Rasch item response theory model demonstrated significant misfit, likely due to the misfit of item 9, which asks about sexuality, and high residual correlations between item pairs 6 and 8 about fatigue, and items 16 and 17 about social relationships. CONCLUSIONS: The Stoma-QOL questionnaire is a well-designed PRO for measuring stoma-related quality of life. Demographic variables do not appear to have a strong influence on Stoma-QOL scores. Item 9 demonstrated misfit but removal likely does not improve the instrument. Future research should focus on revising items 6, 8, 16, and 17. PMID- 29619840 TI - Outcome of pediatric cataract surgery with intraocular injection of triamcinolone acetonide: Randomized controlled trial. AB - PURPOSE:: To evaluate the use of intraocular injection of triamcinolone acetonide in pediatric cataract surgery with or without intraocular lens implantation as a vitreous dye to ensure a complete anterior vitrectomy and evaluate its effect on postoperative ocular inflammation, infection, posterior capsule opacification, and intraocular pressure. METHODS:: Randomized controlled trial included children diagnosed with bilateral congenital cataract in both eyes. Their eyes were randomly assigned into two groups: group A underwent aspiration, posterior capsulotomy, and anterior vitrectomy with intraocular injection of triamcinolone acetonide, while group B underwent the same surgical procedure without intraocular injection of triamcinolone acetonide. Intraocular pressure, postoperative inflammation, infection, and posterior capsule opacification were followed up till 6 months. RESULTS:: The study comprised 44 eyes of 22 children. The mean age was 2.4 +/- 2.1 years including 10 males and 12 females. The mean postoperative intraocular pressure was within normal range in both groups. No case of infection in both groups. No eyes in group A showed reaction, while in group B, three eyes showed exudate on the first day, which improved at 2 weeks. Posterior synechiae was recorded in four eyes in group A and in five eyes in group B. Posterior capsule opacification was noted in one eye in group A at 3 month, while it was noted in nine eyes in group B. The difference was statistically significant ( p = 0.004). CONCLUSION:: Triamcinolone acetonide was found to be useful in better visualization of vitreous in pediatric cataract surgery and has good effect in decreasing postoperative inflammation and posterior capsule opacification. PMID- 29619841 TI - Preventable statin adverse reactions and therapy discontinuation. What can we learn from the spontaneous reporting system? AB - BACKGROUND: Statin treatment is often associated with poor adherence, which may be due to the onset of adverse drug reactions (ADRs). We investigated on potential risk factors related to preventable cases of statin-induced ADRs and to the discontinuation of statin therapy. METHODS: We performed a study using the database of Italian spontaneous reporting. The target population for the preventability assessment was all patients with suspected statin-induced ADRs deriving from Campania Region (a territory of Southern Italy) between 2012 and 2017. Additionally, a local sentinel surveillance site involving General Practitioners was selected to countercheck in routine clinical practice the role of ADRs for statin discontinuation. RESULTS: In total, 34 of 655 (5.19%) regional cases were preventable and among detected risk factors 90.0% was related to healthcare professionals' practices and 10.0% to patient behaviour. In 81.4% (533/655) of cases, statin therapy was discontinued due to ADRs, mainly classified as not serious and associated with a positive prognosis. These results were also confirmed in the active sentinel site. CONCLUSIONS: Our findings suggest an inappropriate use of statins among the identified preventable cases and a potential inappropriate statin discontinuation due to ADRs. These factors may be useful for targeting interventions to improve statin adherence. PMID- 29619842 TI - High-sensitivity cardiac troponin T for diagnosis of NSTEMI in the elderly emergency department patient: a clinical cohort study. AB - PURPOSE: The aim of this study is to evaluate the impact of age on the diagnostic performance of high-sensitivity troponin T (hsTnT) under routine conditions. MATERIALS AND METHODS: Data of 4118 consecutive emergency department (ED) patients who underwent a routine TnT measurement between 11 October 2012 and 30 November 2013 were analysed. Diagnostic accuracy of hsTnT was compared in four age categories (<50, 50-64, 65-74, >=75 years of age) for different cut-off values. Primary endpoint was a main hospital diagnosis of NSTEMI. RESULTS: The median age of the study population (n = 4118) was 61 years (IQR: 45-75 years). NSTEMI was diagnosed in 3.3% (n = 136) of all patients. There were significant differences in hsTnT concentrations between age-groups (p < 0.001) in all patients, but not in NSTEMI patients (p = 0.297). 72.2% of all patients >=75 years of age (583/808) without NSTEMI had hsTnT concentrations above the 99th percentile of a healthy reference population. Specificity at 14 ng/L was 93.6% (95% CI: 92.12-94.87) in patients below 50 years of age and 27.9% (95% CI: 24.78 31.08) in patients 75 years of age and older. CONCLUSIONS: Patients' age needs to be considered at least one influencing factor on hsTnT concentrations at admission and should be included in the clinical interpretation of hsTnT concentrations for further clinical workup beneath other influencing factors like comorbidities and symptom onset time. The implementation of age-specific cut-off values could be considered for single troponin testing at admission but is associated with an increased risk of underdiagnosis of NSTEMI. PMID- 29619843 TI - Current Concepts Review: Plantar Fibromatosis. PMID- 29619844 TI - Comparison of Screws to Plate-and-Screw Constructs for Midfoot Arthrodesis. AB - BACKGROUND: We performed a prospective comparison of screws versus plate-and screws for midfoot arthrodesis. MATERIALS: Between 2010 and 2015, a total of 50 patients with midfoot arthritis received screws or plate-and-screws for their midfoot arthrodesis. Function and pain were graded with the Foot and Ankle Ability Measures (FAAM) and visual analog scale (VAS), respectively. Data regarding arthrodesis healing and complications were recorded. RESULTS: Twenty five patients received screws for fusion, where 21 achieved full arthrodesis healing by 6 months from surgery. Mean FAAM increased from 46.4 to 82.7 of 100 between initial and final visit. Mean pain decreased from 8.3 to 2.1 of 10 between initial and latest encounter. Twenty-five patients received plate-and screws for their fusion, where 23 achieved full arthrodesis healing by 6 months from surgery. Mean FAAM increased from 48.2 to 86.3 of 100 between initial and final visit. Mean pain decreased from 8.0 to 1.8 of 10 between initial and latest encounter. These postoperative scores were not significantly different from patients with screws ( P > .05). Three and 6 patients with screws versus plate and-screws, respectively, developed wound complications ( P = .03). Four and 2 patients with screws versus plate-and-screws, respectively, developed delayed or nonunion of their arthrodesis ( P = .15). DISCUSSION: A comparison of outcomes of midfoot arthrodesis with screws or plate-and-screws has not been previously reported. Both constructs provide improved function and pain. Using screws might generate less wound complications, but using plate-and-screws might produce higher rates of bony healing. LEVEL OF EVIDENCE: Level I, randomized, prospective, and comparative cohort study. PMID- 29619845 TI - Contribution of Medial Cuneiform Osteotomy to Correction of Longitudinal Arch Collapse in Stage IIb Adult-Acquired Flatfoot Deformity. AB - : Background Residual forefoot supination after correcting the hindfoot in stage IIb adult-acquired flatfoot deformity can be addressed with a dorsal opening wedge medial cuneiform (Cotton) osteotomy. The amount of correction is generally judged clinically, and there currently are no preoperative guides that can predict the size of graft needed. The aim of this study was to evaluate the correlation between patient and operative factors and the correction achieved with the Cotton osteotomy. METHODS: Seventy-nine feet in 74 patients undergoing Cotton osteotomy as part of flatfoot reconstruction were reviewed retrospectively. Preoperative and minimum 40-week postoperative lateral foot weightbearing radiographs were compared to assess correction of longitudinal arch collapse as measured by 13 radiographic parameters, with particular emphasis on the cuneiform articular angle (CAA). Additional demographic and intraoperative variables analyzed for association with radiographic change included age, gender, body mass index, amounts and graft types of Cotton osteotomy and lateral column lengthening, and amount of medializing calcaneal osteotomy. A multivariate linear regression model was developed for each variable found to be significant in univariate analysis. RESULTS: The Cotton osteotomy graft size was significantly associated with changes in the CAA ( P < .001), calcaneal pitch ( P = .03), lateral talonavicular Cobb angle ( P = .03), and lateral naviculomedial cuneiform Cobb angle ( P = .03). The Cotton graft size was the only factor found to significantly predict a change in the CAA in the final linear regression model ( P < .001, R2 = 0.27), with each millimeter of Cotton corresponding to a 2.1 degree decrease of the CAA. CONCLUSION: Correction of longitudinal arch collapse, as measured by the CAA, was primarily influenced by the size of the graft used for the Cotton osteotomy in a linear fashion. The preoperative CAA may help surgeons titrate the proper amount of graft placed intraoperatively. LEVEL OF EVIDENCE: Level IV, Retrospective Case Series. PMID- 29619847 TI - Scanning electron microscopic characteristics of manually loaded and preloaded foldable acrylic intraocular lenses. AB - PURPOSE: To compare surface alterations between preloaded and manually loaded intraocular lens. METHODS: Scanning electron microscope was utilized to evaluate surface alteration and deposits in four different types of intraocular lenses: preloaded hydrophobic acrylic, preloaded hydrophilic acrylic, manually loaded hydrophobic acrylic, and manually loaded hydrophilic acrylic. Six lenses with different powers (+6 D, +22 D, and +29 D) were used from each category, to represent different thickness categories of the intraocular lenses. RESULTS: In total, 30 intraocular lenses have been evaluated in this study: 4 from the control group (2 hydrophobic and 2 hydrophilic lenses) and 12 from the preloaded intraocular lens and manually loaded groups (6 hydrophilic and 6 hydrophobic lenses with different powers). Surface deposits were found in eight hydrophobic intraocular lenses compared to a single intraocular lens with scattered deposits on the optical surface of a hydrophilic intraocular lens. In manually loaded intraocular lens group, five hydrophobic and one hydrophilic intraocular lenses showed identifiable marks on the optical surface. In the preloaded intraocular lens group, three hydrophobic intraocular lenses showed identifiable marks on the optical surface and three hydrophobic intraocular lenses showed surface wrinkling. All hydrophilic intraocular lenses revealed no identifiable marks. CONCLUSION: Surface alterations and deposits are a common finding in both preloaded and manually loaded intraocular lenses. Water content of acrylic intraocular lenses is an important factor predisposing to these changes, and hydrophobic intraocular lenses are more vulnerable than hydrophilic lenses. The impact on the final visual outcome needs further studies. PMID- 29619846 TI - Lactobacillus fermentum HP3-Mediated Fermented Hericium erinaceus Juice as a Health Promoting Food Supplement to Manage Diabetes Mellitus. AB - The current study investigated the antidiabetic property of Lactobacillus fermentum HP3-mediated fermented Hericium erinaceus juice (FHJ) using male Wistar rats with streptozotocin-induced diabetes mellitus (DM). FHJ was prepared using boiled mushroom juice and L. fermentum HP3. Amino acid and gamma-aminobutyric acid (GABA) content of FHJ was analyzed. Streptozotocin-induced DM rats were supplemented with FHJ in a pre- and posttreatment method. The changes in plasma insulin, plasma glucose level, glycated hemoglobin (HbA1c), representative cytokines, and the antioxidant system were assessed in experimental rats using spectrophotometric methods and enzyme-linked immunosorbent assay. The supplementation of FHJ improved the body mass, insulin level, and recovery progress of hyperglycemia. HbA1c level was altered by the FHJ intervention. The inflammatory cytokines level was suppressed in FHJ supplemented group compared with control. Intervention of FHJ and insulin improved the production of interleukin-10 and transforming growth factor--beta1 in DM rat. The study suggested that fermented H erinaceus juice may be used as one of the food-based health-promoting supplement to manage DM along with medication. PMID- 29619848 TI - Biological treatment for psoriasis and the risk of herpes zoster: Results from the Psoriasis Longitudinal Assessment and Registry (PSOLAR). AB - PURPOSE: To describe the risk of herpes zoster (HZ) in patients with psoriasis and its relation to non-biologic systemic therapies or biologic treatment. MATERIALS AND METHODS: Psoriasis Longitudinal Assessment and Registry (PSOLAR) is an international, prospective, registry that follows adult patients with psoriasis eligible to receive non-biologic systemic therapies or biologic therapies. Mutually exclusive therapy cohorts were defined. HZ incident rates were calculated for each therapy cohort and rates between cohorts were compared using hazard ratios (HR) adjusted for potential confounders, in new users and prevalent-exposure patients. RESULTS: A total of 55 HZ events were identified in 10,469 patients in PSOLAR. The adjusted hazard ratio in the overall study population (new user and prevalent-exposed patients) was 2.22 (95% CI: 0.82-5.97; p = 0.116) for tumor necrosis factor-alpha (TNF) inhibitors, 2.73 (0.98-7.58; p = 0.054) for ustekinumab, and 1.04 (0.20-5.41; p = 0.966) for methotrexate vs. reference (combined phototherapy, systemic steroids, topical therapy, and immunomodulators other than methotrexate). CONCLUSIONS: Exposure to ustekinumab, TNF-alpha inhibitors, and methotrexate was not associated with a statistically significant increased risk of HZ. However, HRs were elevated for ustekinumab and TNF-alpha inhibitors; a larger number of herpes zoster events would be needed to assess the presence or absence of risk. PMID- 29619849 TI - Anatomical and radiologic characteristics of isthmus parameters in guiding pedicle screw placement. AB - Objective To study the clinical application of lumbar isthmus parameters in guiding pedicle screw placement. Methods Lumbar isthmus parameters were measured in normal lumbar x-rays and cadaveric specimens from a Chinese Han population. Distance between the medial pedicle border and lateral isthmus border was recorded as a 'D' value and was compared between X-rays and cadavers. Orthopaedic surgeons estimated different distances (2-6 mm) and angles (5-20 degrees ), and bias ratios between estimated and real values were compared. Orthopaedic residents placed pedicle screws on cadaveric specimens before and after application of the 'D' value, and screw placement accuracy was compared. Results Except for L4 vertebrae, significant differences in the 'D' value were found between 25 cadaveric specimens and x-ray films from 120 patients. Distances and angles estimated by 40 surgeons were significantly different from all real values, except 2 mm distance. Accuracy of pedicle screw placement by six orthopaedic residents was significantly improved by applying the 'D' value. Conclusions Surgeon estimates of distance were more accurate than angle estimates. Addition of a 'D' value to conventional parameters may significantly improve pedicle screw placement accuracy in lumbar spine surgery. PMID- 29619850 TI - Salinomycin nanoparticles interfere with tumor cell growth and the tumor microenvironment in an orthotopic model of pancreatic cancer. AB - AIMS: Recently, salinomycin (SAL) has been reported to inhibit proliferation and induce apoptosis in various tumors. The aim of this study was to deliver SAL to orthotopic model of pancreatic cancer by the aid of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs). METHODS: The NPs were physico-chemically characterized and evaluated for cytotoxicity on luciferase-transduced AsPC-1 cells in vitro as well as implanted orthotopically into the pancreas of nude mice. RESULTS: SAL (3.5 mg/kg every other day) blocked tumor growth by 52% compared to the control group after 3 weeks of therapy. Western blotting of tumor protein extracts indicated that SAL treatment leads to up-regulation of E cadherin, beta-catenin, and transforming growth factor beta receptor (TGFbetaR) expressions in AsPC-1 orthotopic tumor. Noteworthy, immunofluorescence staining of adjacent tumor sections showed that treatment with SAL NPs cause significant apoptosis in the tumor cells rather than the stroma. Further investigations also revealed that TGFbetaR2 over-expression was induced in stroma cells after treatment with SAL NPs. CONCLUSION: These results highlight SAL-loaded PLGA NPs as a promising system for pancreatic cancer treatment, while the mechanistic questions need to be subsequently tested. PMID- 29619851 TI - Ramizol(r) encapsulation into extended release PLGA micro- and nanoparticle systems for subcutaneous and intramuscular administration: in vitro and in vivo evaluation. AB - OBJECTIVE: Novel antibiotic Ramizol(r) is advancing to clinical trials for the treatment of gastrointestinal Clostridium difficile associated disease. Despite this, previous studies have shown a rapid plasma clearance upon intravenous administration and low oral bioavailability indicating pure drug is unsuitable for systemic infection treatment following oral dosing. The current study aims to investigate the development of poly-lactic-(co-glycolic) acid (PLGA) particles to overcome this limitation and increase the systemic half-life following subcutaneous and intramuscular dosing. SIGNIFICANCE: The development of new antibiotic treatments will help in combatting the rising incidence of antimicrobial resistance. METHODS: Ramizol(r) was encapsulated into PLGA nano and microparticles using nanoprecipitation and emulsification solvent evaporation techniques. Formulations were analyzed for particle size, loading level and encapsulation efficiency as well as in vitro drug release profiles. Final formulation was advanced to in vivo pharmacokinetic studies in Sprague-Dawley rats. RESULTS: Formulation technique showed major influence on particle size and loading levels with optimal loading of 9.4% and encapsulation efficiency of 92.06%, observed using emulsification solvent evaporation. Differences in formulation technique were also linked with subsequent differences in release profiles. Pharmacokinetic studies in Sprague-Dawley rats confirmed extended absorption and enhanced bioavailability following subcutaneous and intramuscular dosing with up to an 8-fold increase in Tmax and T1/2 when compared to the oral and IV routes. CONCLUSIONS: Subcutaneous and intramuscular dosing of PLGA particles successfully increased systemic half-life and bioavailability of Ramizol(r). This formulation will allow further development of Ramizol(r) for systemic infection eradication. PMID- 29619852 TI - Manganese in toenails is associated with hearing loss at high frequencies in humans. AB - PURPOSE: Elevated hearing thresholds from high frequencies are known to be one of the hallmarks of age-related hearing loss. Our recent study showed accumulation of manganese (Mn) in inner ears resulting in acceleration of age-related hearing loss in mice orally exposed to Mn. However, there is no evidence showing an association between Mn in non-invasive biological samples and hearing loss in humans evaluated by pure tone audiometry (PTA). In this study, we evaluated Mn in non-invasive biological samples as a possible biomarker for hearing loss in humans. MATERIALS AND METHODS: We determined hearing levels by PTA and Mn levels in toenails, hair and urine with an inductively coupled plasma mass spectrometer (ICP-MS) in 145 healthy subjects in Bangladesh. RESULTS: Multivariable analyses showed that Mn levels in toenails, but not in hair and urine samples, were significantly associated with hearing loss at 8 kHz and 12 kHz. Moreover, our experimental study showed a significant correlation between Mn levels in inner ears and nails, but not hair, in mice orally exposed to Mn. CONCLUSIONS: The results provide novel evidence that Mn in toenails is a possible biomarker for hearing loss at high frequencies in humans. PMID- 29619853 TI - Multi-modality molecular imaging characteristics of dementia with Lewy bodies. AB - Objective Dementia with Lewy bodies (DLB) is a common type of neurodegenerative dementia. Molecular neuroimaging using dopamine transporter (DaT), Pittsburgh compound B (PIB), and fluorodeoxyglucose (FDG) positron emission tomography (PET) has advantages in detecting dopaminergic neuron loss, abnormal amyloid beta protein deposition, and glucose metabolism changes in patients with neurodegenerative disorders. However, the multi-modality molecular imaging features of patients with DLB have rarely been reported. Methods Five patients with a probable diagnosis of DLB were enrolled. PET/magnetic resonance imaging was performed with three tracers: 11C-beta-CFT, 11C-PIB, and 18F-FDG. Clinical and imaging characteristics were analyzed. Results All patients with DLB showed reduced uptake in the bilateral putamen on DaT PET, increased uptake throughout the cerebral cortex on PIB PET, and intact metabolism of the posterior cingulate gyrus on FDG PET. Conclusion Multimodal molecular imaging is helpful for early diagnosis of DLB. Studies with larger sample sizes are needed to confirm the molecular imaging differences between DLB and Alzheimer's disease and Parkinson's disease dementia. PMID- 29619854 TI - Tf ligand-receptor-mediated exenatide-Zn2+ complex oral-delivery system for penetration enhancement of exenatide. AB - Safe and effective oral delivery of peptide is a challenge. Here, we used exenatide and zinc ions (Zn2+) to form a complex to explore a meaningful oral targeted drug-delivery system. Polyethylene glycol-poly(lactic acid-co-glycolic acid) (PEG-PLGA) was used to prepare nanoparticles (NPs) to escape the degradation caused by gastrointestinal enzymes. Transferrin (Tf) was used as a targeting group. PEG-PLGA-NPs and Tf-modified exenatide-Zn2+-loaded NPs (Tf-PEG PLGA-NPs) were uniformly sized spheres according to transmission electron microscopy. The results of pharmacodynamic and pharmacokinetic investigations in vivo were consistent with in vitro studies using Caco-2 cells. Tf enhanced NPs transport in cell-uptake and transmembrane-transport experiments. Our results showed that the relative bioavailability of Tf-exenatide-Zn2+-NPs was higher than that of exenatide-Zn2+-NPs. The relative bioavailability of Tf-exenatide-Zn2+-NPs versus subcutaneous injection of exenatide was 6.45%. This was a preliminary exploration of the oral administration of exenatide, that data from which can be used for future investigations. PMID- 29619855 TI - Victor W. Sidel (7 July 1931-30 January 2018). PMID- 29619856 TI - Number needed to treat and costs per responder among biologic treatments for moderate-to-severe psoriasis: a network meta-analysis. AB - BACKGROUND: The clinical benefits of biologic therapies for moderate-to-severe psoriasis are well established, but wide variations exist in patient response. OBJECTIVES: To determine the number needed to treat (NNT) to achieve a 75% and 90% reduction in the Psoriasis Area and Severity Index (PASI-75/90) with FDA approved agents and evaluate the incremental cost per PASI-75 or PASI-90 responder. METHODS: The relative probabilities of achieving PASI-75 and PASI-90, as well as NNTs, were estimated using a network meta-analysis. Costs (2017 USD) included drug acquisition and administration. The incremental cost per PASI-75 or PASI-90 responder for each treatment was estimated for the clinical trial period, and annually. RESULTS: Compared with supportive care, the NNT to achieve PASI-75 was 1.18 for ixekizumab, 1.29 for secukinumab 300 mg, 1.37 for infliximab, 1.48 for adalimumab, 1.53 for secukinumab 150 mg, 1.58 for ustekinumab, 2.25 for etanercept, and 3.71 for apremilast. The one-year incremental cost per PASI-75 responder relative to supportive care was $59,830 for infliximab, $88,775 for secukinumab 300 mg, $91,837 for adalimumab, $95,898 for ixekizumab, $97,363 for ustekinumab, $105,131 for secukinumab 150 mg, $129,665 for apremilast, and $159,328 for etanercept. Results were similar for PASI-90. CONCLUSION: The NNT and incremental cost per responder are meaningful ways to assess comparative effectiveness and cost effectiveness among psoriasis treatments. PMID- 29619857 TI - Nanocrystal-based drug delivery system of risperidone: lyophilization and characterization. AB - OBJECTIVE: In the present work nanocrystal-based formulation of risperidone (RIS) was proposed to overcome solubility issue of RIS, while lyophilization technique was used effectively, for conversion of RIS nanosuspension to solid state. SIGNIFICANCE: RIS nanosuspension was developed and stabilized with a combination of polycaprolactone and Pluronic(r) F-68 as stabilizers. With focus on critical parameters like nature of cryoprotectants and effect of eutectic temperature on properties of nanosuspension, the suitability of lyophilization technique in improving the physical stability of prepared nanosuspension was also evaluated. Additionally, the developed nanocrystals were also assessed for their solid states properties. METHODS: Various process parameters affecting average particle size and polydispersity index (PDI), viz. drug to surfactant ratio, solvent to anti-solvent ratio, stirring speed, type of stabilizer were optimized. Assessment of lyophilization as a suitable solidification technique (for conversion to powder form) was done with selective cryoprotectants (trehalose dihydrate and sorbitol). RESULTS: The formulation was found to be stable at 4 degrees C for 3 months with size, PDI and zeta potential of 214 +/- 3.4 nm, 0.120, and -10.2 +/- 0.90 mV, respectively. Release profile of developed nanosuspension showed cumulative % release of ~90% in initial 10 h whereas the value for the unprocessed drug was ~11% in same time frame. CONCLUSIONS: These findings suggest that developed formulation was able to enhance water solubility of the drug effectively and can be potentially used in the management of psychotic disorders. PMID- 29619858 TI - Influence of serous retinal detachment on the outcome of ranibizumab treatment in diabetic macular oedema. AB - PURPOSE: The purpose of this study was to evaluate the influence of serous retinal detachment (SRD) on the outcome of intravitreal ranibizumab (IVR) therapy in diabetic macular oedema (DME). MATERIALS AND METHODS: Fifty-one eyes with cystoid macular oedema (CME) and SRD (study group) and 57 eyes with only CME (control group) that received pro re nata (PRN) IVR injections during a 6-month period were retrospectively evaluated. The outcome measures included changes in the central macular thickness (CMT) and best corrected visual acuity (BCVA) and injection numbers. RESULTS: The mean initial CMT in the study and control groups was 467 +/- 101 and 440 +/- 89 um, respectively. The mean BCVA in the study and control groups was 0.75 +/- 0.38 and 0.59 +/- 0.36 logarithm of minimal angle of resolution (LogMAR), respectively (p = 0.010). The study group received a mean of 2.2 +/- 0.92 injections, whereas the control group received a mean of 2.54 +/- 0.9 injections. The decrease in CMT was greater, but not significantly greater, in the study group than in the control group. CONCLUSION: The presence of SRD resulted in a less favourable visual acuity (VA) outcome with IVR. Disruption of the ellipsoid zone and abnormality of the foveal avascular zone at the baseline examination were correlated with a lower VA. Both of the pathologies occurred more frequently in the SRD group. PMID- 29619859 TI - A virtual speaker in noisy classroom conditions: supporting or disrupting children's listening comprehension? AB - AIM: Seeing a speaker's face facilitates speech recognition, particularly under noisy conditions. Evidence for how it might affect comprehension of the content of the speech is more sparse. We investigated how children's listening comprehension is affected by multi-talker babble noise, with or without presentation of a digitally animated virtual speaker, and whether successful comprehension is related to performance on a test of executive functioning. MATERIALS AND METHODS: We performed a mixed-design experiment with 55 (34 female) participants (8- to 9-year-olds), recruited from Swedish elementary schools. The children were presented with four different narratives, each in one of four conditions: audio-only presentation in a quiet setting, audio-only presentation in noisy setting, audio-visual presentation in a quiet setting, and audio-visual presentation in a noisy setting. After each narrative, the children answered questions on the content and rated their perceived listening effort. Finally, they performed a test of executive functioning. RESULTS: We found significantly fewer correct answers to explicit content questions after listening in noise. This negative effect was only mitigated to a marginally significant degree by audio-visual presentation. Strong executive function only predicted more correct answers in quiet settings. CONCLUSIONS: Altogether, our results are inconclusive regarding how seeing a virtual speaker affects listening comprehension. We discuss how methodological adjustments, including modifications to our virtual speaker, can be used to discriminate between possible explanations to our results and contribute to understanding the listening conditions children face in a typical classroom. PMID- 29619860 TI - Progerin phosphorylation in interphase is lower and less mechanosensitive than lamin-A,C in iPS-derived mesenchymal stem cells. AB - Interphase phosphorylation of lamin-A,C depends dynamically on a cell's microenvironment, including the stiffness of extracellular matrix. However, phosphorylation dynamics is poorly understood for diseased forms such as progerin, a permanently farnesylated mutant of LMNA that accelerates aging of stiff and mechanically stressed tissues. Here, fine-excision alignment mass spectrometry (FEA-MS) is developed to quantify progerin and its phosphorylation levels in patient iPS cells differentiated to mesenchymal stem cells (MSCs). The stoichiometry of total A-type lamins (including progerin) versus B-type lamins measured for Progeria iPS-MSCs prove similar to that of normal MSCs, with total A type lamins more abundant than B-type lamins. However, progerin behaves more like farnesylated B-type lamins in mechanically-induced segregation from nuclear blebs. Phosphorylation of progerin at multiple sites in iPS-MSCs cultured on rigid plastic is also lower than that of normal lamin-A and C. Reduction of nuclear tension upon i) cell rounding/detachment from plastic, ii) culture on soft gels, and iii) inhibition of actomyosin stress increases phosphorylation and degradation of lamin-C > lamin-A > progerin. Such mechano-sensitivity diminishes, however, with passage as progerin and DNA damage accumulate. Lastly, transcription-regulating retinoids exert equal effects on both diseased and normal A-type lamins, suggesting a differential mechano-responsiveness might best explain the stiff tissue defects in Progeria. PMID- 29619861 TI - Safety and efficacy of the oblique-axis plane in ultrasound-guided internal jugular vein puncture: A meta-analysis. AB - Objective This meta-analysis was performed to evaluate the safety and efficacy of the oblique-axis plane in ultrasound-guided internal jugular vein puncture. Methods We searched Embase, PubMed, the Cochrane Library, Web of Science, and China National Knowledge Infrastructure for relevant randomized clinical trials comparing the oblique axis with the short axis in ultrasound-guided internal jugular vein puncture. Results Five randomized clinical trials were included in this meta-analysis. The pooled meta-analysis showed that the incidence of arterial puncture in the oblique-axis group was significantly lower than that in the short-axis group. No significant difference was found in the first-pass success rate between the oblique-axis group and short-axis group. Additionally, there were no significant differences in the puncture success rate or number of attempts required between the two groups. Conclusion Ultrasound-guided internal jugular vein puncture using the oblique-axis plane reduced the risk of arterial puncture, but no difference was found in the first-pass success rate, puncture success rate, or number of attempts required. PMID- 29619862 TI - Characteristics of patients with coexisting IgA nephropathy and membranous nephropathy. AB - BACKGROUND: Coexistence of IgA nephropathy (IgAN) and membranous nephropathy (MN) in the same patient is rare. Few studies have reported the clinical and pathological features of patients with combined IgAN and MN (IgAN-MN). METHODS: The clinico-pathological features, levels of galactose-deficient IgA1 (Gd-IgA1) and autoantibodies against M-type transmembrane phospholipase A2 receptor (anti PLA2R) in sera were compared among IgAN-MN, IgAN, and MN patients. RESULTS: Twenty-six patients with biopsy-proven IgAN-MN were enrolled. The mean age at biopsy was 43.6 +/- 15.9 years, and 65.4% were male. Proteinuria and estimated glomerular filtration rate (eGFR) levels in patients with IgAN-MN were similar to that of MN patients. Compared with the IgAN patients, IgAN-MN patients showed a higher median proteinuria level (4.3 vs. 1.2 g/day, p < .001), and a higher mean eGFR level (101.8 +/- 25.4 vs. 78.6 +/- 26.9 mL/min/1.73 m2, p < .001). IgAN-MN patients presented with milder pathological lesions than IgAN patients according to the Oxford Classification. IgAN-MN patients had comparable serum levels of Gd IgA1 with those of IgAN patients (353.4 +/- 95.5 vs. 347.0 +/- 109.6 U/mL, p = .801). Percentage of IgAN-MN patients with detectable serum levels of anti-PLA2R was lower than that of MN patients (38.5% vs. 68.6%, p = .011). CONCLUSIONS: IgAN MN patients display similar clinical features to MN patients and milder pathological lesions than IgAN patients. IgAN-MN patients have similar levels of Gd-IgA1 to those of IgAN patients, and a lower proportion of anti-PLA2R than MN patients. PMID- 29619863 TI - An overview of treatment strategies for Hutchinson-Gilford Progeria syndrome. AB - Hutchinson-Gilford progeria syndrome (HGPS) is a sporadic, autosomal dominant disorder characterized by premature and accelerated aging symptoms leading to death at the mean age of 14.6 years usually due to cardiovascular complications. HGPS is caused by a de novo point mutation in the LMNA gene encoding the intermediate filament proteins lamins A and C which are structural components of the nuclear lamina. This mutation leads to the production of a truncated toxic form of lamin A, issued from aberrant splicing and called progerin. Progerin accumulates in HGPS cells' nuclei and is a hallmark of the disease. Small amounts of progerin are also produced during normal aging. HGPS cells and animal preclinical models have provided insights into the molecular and cellular pathways that underlie the disease and have also highlighted possible mechanisms involved in normal aging. This review reports recent medical advances and treatment approaches for patients affected with HGPS. PMID- 29619864 TI - ATRA attenuate proteinuria via downregulation of TRPC6 in glomerulosclerosis rats induced by adriamycin. AB - OBJECTIVE: In this research, we explored the molecular mechanism of proteinuria in glomerulosclerosis rats and the protective effects of ATRA. METHODS: This research set up three groups: SHO group, GS group, and ATRA group (15 mg/(kg d), Sigma, St. Louis, MO). The serum creatinine (Scr), urea nitrogen (BUN), and 24-h proteinuria were detected 12 weeks after administration of ATRA. The pathological and ultrastructure changes were observed under light microscope and transmission electron microscope. The protein expression of TGF-beta1 and Col-IV in glomerulus was detected by immunohitochemistry method. The mRNA and the protein expression of glomerular TRPC6 were detected by RT-PCR and Western blot. RESULTS: In the rat model of GS, the expressions of TRPC6 were significantly elevated compared with the normal rat group; however, the use of ATRA down-regulated the expression of TRPC6 in the glomeruli and attenuated glomerulosclerosis and proteinuria. Scr and BUN were also improved by the treatment of ATRA. CONCLUSIONS: Our results demonstrated that ATRA could ameliorate glomerulosclerosis and proteinuria in GS, which may be related to suppressed expression of TRPC6. PMID- 29619866 TI - Enteral Guanfacine to Treat Severe Anxiety and Agitation Complicating Critical Care After Cardiac Surgery. AB - This article is the first reported case describing the off-label use of enteral immediate-release guanfacine, a long-acting alpha-2 adrenergic agonist most commonly used in the treatment of attention-deficit hyperactivity disorder, for sedation in a patient with severe anxiety and agitation limiting mechanical ventilation weaning several days after cardiac surgery. In this case, after several days of unsuccessful attempts to control his agitation and anxiety with conventional therapies, guanfacine therapy was initiated, and the patient was rapidly weaned from all other sedatives and mechanical ventilation shortly thereafter. The patient was weaned from guanfacine therapy without evidence of bradycardia, hypotension, or rebound syndrome. Enteral guanfacine therapy should be further studied as a potentially useful and cost-effective sedative therapy for patients with severe anxiety and/or agitation in the intensive care unit following cardiac and thoracic surgical procedures. PMID- 29619867 TI - Usefulness of pretransplant aortic arch calcification evaluation for kidney transplant outcome prediction in one year follow-up. AB - Vascular calcification (VC) is linked to post-transplant cardiovascular events and hypercalcemia which may influence kidney graft function in the long term. We aimed to evaluate whether pretransplant aortic arch calcification (AoAC) can predict post-transplant cardiovascular or cerebrovascular events (CVEs), and to assess its association with post-transplant plasma calcium levels and renal function in one-year follow-up. Our single-center observational prospective study enrolled 37 kidney transplant recipients (KTR) without previous history of vascular events. Two radiologists evaluated pretransplant AoAC on chest X-ray as suggested by Ogawa et al. in 2009. Cohen's kappa coefficient was 0.71. The mismatching results were repeatedly reviewed and resulted in consensus. Carotid femoral (cfPWV) and carotid-radial pulse wave velocity (crPWV) was measured using applanation tonometry before and one year after transplantation. Patient clinical, biochemical data, and cardiovascular/CVE rate were monitored within 1 year. We found out that eGFR1year correlated with eGFRdischarge and calcium based on hospital discharge data (beta = 0.563, p = .004 and beta = 51.360, p = .026, respectively). Multivariate linear regression revealed that donor age, donor gender, and recipient eGFRdischarge (R-squared 0.65, p = .002) better predict eGFR1year than AoAC combined with recipient eGFRdischarge (R-squared 0.35, p = .006). During 1-year follow-up, four (10.81%) patients experienced cardiovascular events, which were predicted by PWV ratio (HR 7.549, p = .045), but not related to AoAC score (HR 1.044, p = .158). In conclusion, KTR without previous vascular events have quite low cardiovascular/CVE rate within 1-year follow-up. VC evaluated as AoAC on pretransplant chest X-ray together with recipient eGFRdischarge could be related to kidney function in one-year follow-up. PMID- 29619868 TI - Fibroblast growth factor-23 is a strong predictor of insulin resistance among chronic kidney disease patients. AB - Insulin resistance (IR) is very common among chronic kidney disease (CKD) patients. Disturbance in mineral and bone metabolism (MBD) seems to play a role in the pathogenesis of insulin resistance. Fibroblast growth factor-23 (FGF23) is evolving as the most important link between MBD and many pathologic sequences of CKD. The aim was to evaluate IR in pre-dialysis CKD patients looking for a possible association to mineral metabolism among CKD patients. A total of 100 stage 3-5 CKD patients were selected beside 20 normal control subjects. Homeostatic model assessment of insulin resistance (HOMA-IR) was used to assess IR in selected cases. Both groups were compared for fasting blood glucose (FBG), fasting blood insulin (FBI), HOMA-IR, estimated glomerular filtration rate (eGFR), serum calcium (Ca), phosphorus (P), 25 hydroxy vitamin D (25 OH vit D), parathormone (PTH), and uric acid (UA). Correlation study between HOMA_IR and different studied parameters was performed. HOMA-IR is significantly higher in CKD (8.87 +/- 3.48 vs. 3.97 +/- 0.34 in CKD vs. control, respectively, p < .001). In addition CKD patients have significantly higher FGF23 (235 +/- 22.96 vs. 139 +/- 12.3 pg/mL, p < .001), PTH (76.9 +/- 15.27 vs. 47.9 +/- 2.52 pg/mL, p < .001), P (4.3 +/- 0.67 vs. 3.6 +/- 0.23 mg/dL, p < .001), and UA (5 +/- 1.22 vs. 4.85 +/- 0.48 mg/dL, p < .001) and significantly lower Ca (8.2 +/- 0.3 vs. 8.9 +/ 0.33 mg/dL, p < .001), and 25 (OH) vit D (17 +/- 5.63 vs. 37 +/- 3.43 ng/mL, p < .001). Stepwise linear regression analysis revealed that BMI, GFR, Ca, P, and FGF23 were the only significant predictors of HOMA IR. Increased IR in CKD is a consequence of the uremic status and is intimately associated with disturbed phosphate metabolism and FGF23. Further studies are needed to look for an underlying mechanism. PMID- 29619865 TI - Mechanotransduction, nuclear architecture and epigenetics in Emery Dreifuss Muscular Dystrophy: tous pour un, un pour tous. AB - The alteration of the several roles that Lamin A/C plays in the mammalian cell leads to a broad spectrum of pathologies that - all together - are named laminopathies. Among those, the Emery Dreifuss Muscular Dystrophy (EDMD) is of particular interest as, despite the several known mutations of Lamin A/C, the genotype-phenotype correlation still remains poorly understood; this suggests that the epigenetic background of patients might play an important role during the time course of the disease. Historically, both a mechanical role of Lamin A/C and a regulative one have been suggested as the driving force of laminopathies; however, those two hypotheses are not mutually exclusive. Recent scientific evidence shows that Lamin A/C sustains the correct gene expression at the epigenetic level thanks to the Lamina Associated Domains (LADs) reorganization and the crosstalk with the Polycomb Group of Proteins (PcG). Furthermore, the PcG dependent histone mark H3K27me3 increases under mechanical stress, finally pointing out the link between the mechano-properties of the nuclear lamina and epigenetics. Here, we summarize the emerging mechanisms that could explain the high variability seen in Emery Dreifuss muscular dystrophy. PMID- 29619869 TI - Platelet indices and stroke. PMID- 29619871 TI - Prediction of human pharmacokinetics of typical compounds by a physiologically based method using chimeric mice with humanized liver. AB - In this study, total body clearance (CLt), volume of distribution at steady state (Vss) and plasma concentration-time profiles in humans of model compounds were predicted using chimeric mice with humanized livers. On the basis of assumption that unbound intrinsic clearance (CLUint) per liver weight in chimeric mice was equal to those in humans, CLt were predicted by substituting human liver blood flow and liver weights in well-stirred model. Vss were predicted by Rodgers equation using scaling factors of tissue-plasma concentration ratios (SFKp) in chimeric mice estimated from a difference between the observed and predicted Vss. These physiological approaches showed high prediction accuracy for CLt and Vss values in humans. We compared the predictability of CLt and Vss determined by the physiologically based predictive approach using chimeric mice with those from predictive methods reported by Pharmaceutical Research Manufacturers of America. The physiological approach using chimeric mice indicated the best prediction accuracy in each predictive method. Simulation of human plasma concentration-time profiles were generally successful with physiologically based pharmacokinetic (PBPK) model incorporating CLUint and SFKp obtained from chimeric mice. Combined application of chimeric mice and PBPK modeling is effective for prediction of human PK in various compounds. PMID- 29619870 TI - Effects of uric acid-lowering therapy on the progression of chronic kidney disease: a systematic review and meta-analysis. AB - OBJECTIVES: Whether uric acid levels were associated with the progression of chronic kidney disease (CKD) remained controversial. This meta-analysis was aimed to assess the effect of lowering serum uric acid therapy on the progression of CKD to clarify the role of uric acid in the progression of CKD indirectly. METHODS: Pubmed, Embase, the Cochrane library, CBM were searched for randomized controlled trials (RCTs) that assessed the efficiency of lowering serum uric acid therapy on the progression of CKD without language restriction. Summary estimates of weighted mean differences (WMDs) and relative risk (RR) were obtained by using random-effect or fixed-effect models. Sensitivity analyses were performed to identify the source of heterogeneity. RESULTS: A total of 12 randomized controlled trials with 832 CKD participants were included in the analysis. Pooled estimate for eGFR was in favor of lowering serum uric acid therapy with a mean difference (MD) of 3.88 ml/min/1.73 m2, 95% CI 1.26-6.49 ml/min/1.73 m2, p = .004 and this was consistent with results for serum creatinine. The risk of worsening of kidney function or ESRD or death was significantly decreased in the treatment group compared to the control group (RR 0.39, 95% CI 0.28-0.52, p< .01). CONCLUSIONS: Uric acid-lowering therapy may be effective in retarding the progression of CKD. Further randomized controlled trials should be performed to confirm the effect of lowering serum uric acid therapy on the progression of CKD. PMID- 29619872 TI - Association of short-term blood pressure variability with cardiovascular mortality among incident hemodialysis patients. AB - OBJECTIVE: To investigate the association of short-term blood pressure variability (BPV) with cardiovascular mortality in hemodialysis (HD) patients, using a reliable index called average real variability (ARV), and to assess the factors associated with ARV in incident HD population. METHODS: A total of 103 HD patients were recruited, with 44-h ambulatory blood pressure monitoring performed after the midweek HD session. Systolic BPV was assessed by SD, coefficient of variation (CV), and ARV, respectively. Laboratory data were obtained from blood samples before the midweek HD. All patients were followed up for 24 months. RESULTS: According to the median of BPV indices, the comparisons between patients with the low and high values were conducted. Kaplan-Meier analysis showed the survival curves corresponding to median of SD and CV exhibit similar performance for the low and high groups (p = .647, p = .098, respectively). In contrast, patients with higher ARV had a lower survival rate than those with lower ARV (77.8% vs. 98.0%, p = .002). After adjustment for demographics and clinical factors, ARV (HR: 1.143; 95% CI: 1.022-1.279, p = .019) and high-sensitivity C reactive protein (HR: 1.394; 95% CI: 1.025-1.363, p = .021) were associated with increased risk of cardiovascular mortality in HD patients. Age and interdialytic weight gain (IDWG) were related factors for ARV (beta = 0.065, p = .005; beta = 0.825, p = .003, respectively). CONCLUSIONS: Greater ARV was independently associated with increased risk of cardiovascular mortality in HD patients. Age and IDWG were independent related factors for ARV. PMID- 29619873 TI - Synthesized and characterization of organobentonites for anionic dye removal: application to real textile effluent. AB - Clays have been considered as potential alternative adsorbents due to their high adsorptive property, abundance and non-toxic compounds. Adsorption of cationic dyes by natural clays has been studied and appreciable results have been reported, but few researchers have been interested in anionic dyes. Anionic dyes are widely used by the textile industries, yet they are toxic, non-biodegradable and hardly adsorbable on natural clay; modified clay (e.g. organoclay) has emerged as an alternative adsorbent. In this study, organobentonites were prepared with hexadecyltrimethylammonium bromide at three cation exchange capacity levels and used as adsorbents for the removal of, reactive blue II - an anionic dye used in Tunisian textile industry to dye jeans. Obtained organobentonite-labelled Hi-bent (I = 1, 2 and 3) was characterized by several techniques in order to study the effect of a surfactant on texture and structure of the initial clay. H3-bent and purified bentonite (Na-bent) were then tested as adsorbents. The amount of dye removal by H3-bent (98%) was found to be around five times higher than that of Na-bent (19%). Adsorption process was well described by Freundlich, Dubinin-Radushkevic and Elovich isotherms model. Kinetic data were fitted by both pseudo-second-order and pseudo-first-order models. The use of Na-bent, as adsorbent, for real textile effluent treatment was tested, and significant results related to two other clay minerals were obtained. PMID- 29619874 TI - Regulatory roles of ephrinA5 and its novel signaling pathway in mouse primary granulosa cell apoptosis and proliferation. AB - Recent findings suggest that ephrinA5 (Efna5) has a novel role in female mouse fertility, in addition to its well-defined role as a neurogenesis factor. Nevertheless, its physiological roles in ovarian granulosa cells (GC) have not been determined. In this study, mouse GC were cultured and transfected with ephrin A5 siRNA and negative control to determine the effects of Efna5 on GC apoptosis, proliferation, cell cycle progression, and related signaling pathways. To understand the mode signaling, the mRNA expression levels of Efna5 receptors (Eph receptor A5, Eph receptor A3, Eph receptor A8, and Eph receptor B2) were examined. Both mRNA and protein expressions of apoptosis-related factors (Bax, Bcl-2, Caspase 8, Caspase 3, and Tnfalpha) and a proliferation marker, Pcna, were investigated. Additionally, the role of Efna5 on paracrine oocyte-secreted factors and steroidogenesis hormones were also explored. Efna5 silencing suppressed GC apoptosis by downregulating Bax and upregulating Bcl-2 in a Caspase 8-dependent manner. Efna5 knockdown promoted GC proliferation via p-Akt and p-ERK pathway activation. The inhibition of Efna5 enhanced BMH15 and estradiol expression, but suppressed GDF9, while progesterone level remained unaltered. These results demonstrated that Efna5 is a pro-apoptotic agent in GC and plays important role in folliculogenesis by mediating apoptosis, proliferation, and steroidogenesis in female mouse. Therefore Efna5 might be potential therapeutic target for female fertility disorders. PMID- 29619875 TI - Protective effect of Gelofusine against cRGD-siRNA-induced nephrotoxicity in mice. AB - Based on successful targeting to the alphavbeta3 integrin of cyclic arginine glycine-aspartic acid (cRGD), cRGD-conjugated small interfering RNA (siRNA) exhibits tumor targeting and has become a new treatment strategy for solid tumors. However, the nephrotoxicity caused by its renal retention limits its clinical application. Here, we evaluated the protective effect of Gelofusine against cRGD-conjugated siRNA-induced nephrotoxicity in mice. Male Kunming mice (six per group) were either co-injected with Gelofusine and cRGD-siRNA or injected with cRGD-siRNA alone. After administration of these treatments five times, creatinine and blood urea nitrogen (BUN) levels were determined. Hematoxylin-eosin staining (HE staining) and transferase dUTP nick end labeling (TUNEL) analysis were used to compare the difference in renal damage between the groups. Additionally, fluorescence imaging was used to observe the distribution of cRGD-siRNA in vivo. The group co-injected with Gelofusine and cRGD-siRNA displayed lower creatinine and BUN levels than the cRGD-siRNA-alone group and showed less renal damage upon HE staining and TUNEL analysis. Gelofusine decreased the retention time and accelerated the elimination of cRGD-siRNA from the organs, as observed in the fluorescence images. These data indicate that Gelofusine significantly increased the excretion of cRGD-conjugated siRNA and reduced the associated renal damage. PMID- 29619876 TI - Inhibitory effects of taraxasterol and aqueous extract of Taraxacum officinale on calcium oxalate crystallization: in vitro study. AB - OBJECTIVE: We investigated and compared the effects of taraxasterol, aqueous extract of T. officinale (AET) aerial part, and potassium citrate (PC) on calcium oxalate (CaOx) crystallization in vitro. MATERIALS AND METHODS: CaOx crystallization was induced by adding sodium oxalate to synthetic urine. Taraxasterol (2.5, 5, 7.5 and 12.5 MUg/mL), extract (1, 2, 4 and 8 mg/mL), and PC (100, 150, 200 and 350 mg/mL) were subjected to anti-crystallization activities. The absorbance and %inhibition of nucleation of CaOx crystals were evaluated by spectrophotometer at 2, 4, 6, 8, 10, 20, 30, 40, 50 and 60 min and the number and morphology of crystals were studied by light microscopy after 60 min. RESULTS: Presence of taraxasterol, extract and PC decreased absorbance in experimental samples compared to control, significantly. The nucleation of crystals is inhibited by taraxasterol, extract, and PC (26-64, 55-63 and 60-70%, respectively). The number of CaOx crystals were decreased in presence of taraxasterol (p < .01), extract (p < .001), and PC (p < .001) in a dose-dependent manner. Presence of taraxasterol, extract, and PC decreased the number of CaC2O4 monohydrate, while increased CaC2O4 dihydrate crystals, significantly. Also, the diameter of CaC2O4 dihydrate crystals was decreased in presence of taraxasterol, extract and PC, significantly. CONCLUSIONS: This research indicated that taraxasterol and extract have anti-crystallization activities and effectiveness of the extract is more potent than taraxasterol. It could be because of another constituent in the extract with the synergistic effect. PMID- 29619877 TI - The estrogen-related receptors in metabolism and cancer: newer insights. AB - The eukaryotic nuclear receptors (NRs) super-family of transcriptional factors include the estrogen-related receptors (ERRs) that have diverse roles in control of cellular energy balance, general metabolism, growth and development, immunity etc. Mouse knock-out models of specific ERR isoforms (ERRalpha, ERRbeta and ERRgamma) exhibit defects in several phenotypic traits. Newer findings indicate important roles of ERRs in the regulation of brown adipocyte tissue mitochondrial oxidative functions as well as metabolic control in association with hypoxia inducible factors during cellular hypoxic state. Genes involved in cardiac metabolism is also influenced by ERRalpha and ERRgamma in association with the co activators PGC-1alpha and PGC-1beta. On the other hand, ERRs have crucial involvement at the interface of metabolism and diseases such as cancer. Recent findings have implicated ERRalpha in the progression of tumor and malignancy of the breast, prostate, colon, endometrium etc. In this article, new insights into the regulatory role of ERRs in metabolism and cancer shall be reviewed. PMID- 29619878 TI - Measurement of daily sodium excretion in patients with chronic kidney disease; special reference to the difference between the amount measured from 24 h collected urine sample and the estimated amount from a spot urine. AB - It is important to grasp a patient's daily sodium intake in the management of chronic kidney disease, as sodium intake is widely recommended at 6 g/day or less. There are multiple equations widely known for estimating the daily sodium excretion from a spot urine sample, but these are aimed at healthy people. There are few reports that validate equations in patients with chronic kidney disease. The purpose of this study is to evaluate whether the amount of measured daily sodium excretion from a sample collected for 24-h urine (24HU) is equal to that of using an equation from a spot urine sample (SU) in patients with chronic kidney disease. One hundred sixty-two patients with chronic kidney disease from Kanagawa Prefecture Shiomidai Hospital, Japan and the Jikei University Kashiwa Hospital, Japan participated in the study. Daily sodium excretion was measured from 24HU and compared with it from SU by using the formula according to Tanaka et al. Sodium excretion by 24HU was 2744 mg/day and estimating daily sodium excretion from SU was 3315 mg/day. The coefficient of determination was 0.17 (p < .001) in multivariate regression analysis. The coefficient of determination was extremely low. Thus, there is a considerable difference between the amount of sodium excretion calculated from a 24HU and that from a SU in patients with chronic kidney disease. PMID- 29619879 TI - Cisplatin-induced oxidative stress stimulates renal Fas ligand shedding. AB - Acute kidney injury (AKI), a significant complication of cisplatin chemotherapy is associated with reactive oxygen species (ROS)-dependent renal cell death, but the cellular targets of ROS in cisplatin nephrotoxicity are not fully resolved. Here, we investigated cisplatin-induced oxidative renal damage and tested the hypothesis that ROS-dependent shedding of death activator Fas ligand (FasL) occurs in cisplatin nephropathy. We show that intraperitoneal injection of sulfobutyl ether-beta-cyclodextrin (CaptisolTM)-solubilized cisplatin elevated the level of lipid peroxidation product malondialdehyde in mouse kidneys and urinary concentration of oxidative DNA damage biomarker 8-hydroxy-2' deoxyguanosine. Cisplatin increased mouse kidney-to-body weight ratio and the plasma or urinary levels of predictive biomarkers of AKI, including creatinine, blood urea nitrogen, microalbumin, neutrophil gelatinase-associated lipocalin, and cystatin C. Histological analysis and dUTP nick end labeling of kidney sections indicated tubular injury and renal apoptosis, respectively in cisplatin treated mice. Whereas the plasma concentration of soluble FasL (sFasL) was unaltered, urinary sFasL was increased ~4-fold in cisplatin-treated mice. Real time quantitative live-cell imaging and lactate dehydrogenase assay showed that cisplatin stimulated caspase 3/7 activation and cytotoxicity in a human proximal tubule epithelial cell line which were attenuated by inhibitors of the FasL/Fas system and poly [ADP-ribose] polymerase-1. Moreover, TEMPOL, an intracellular free radical scavenger mitigated cisplatin-induced renal oxidative stress and injury, AKI biomarker and urinary sFasL elevation, and proximal tubule cell death. Our findings indicate that cisplatin-induced oxidative stress triggers the shedding of membrane-bound FasL to sFasL in the kidney. We demonstrate that cisplatin elicits nephrotoxicity by promoting FasL/Fas-dependent oxidative renal tubular cell death. PMID- 29619881 TI - Characteristics of greenhouse gas emissions from an anaerobic wastewater treatment system in a natural rubber processing factory. AB - Greenhouse gas (GHG) emissions from both open-type and closed anaerobic wastewater treatment systems in a natural rubber processing factory in Vietnam were surveyed. In this factory, wastewater was treated by an open-type anaerobic baffled reactor (OABR) that comprised 60 compartments. A part of the wastewater was fed to a pilot-scale up-flow anaerobic sludge blanket (UASB) reactor to enable a comparison of the process performance and GHG emission characteristics with those of the OABR. In the OABR, 94.4% of the total chemical oxygen demand (COD) and 18.1% of ammonia nitrogen was removed. GHGs emitted from the OABR included both methane and nitrous oxide. The total GHGs emitted from the OABR was 0.153 t-CO2eq/m3-wastewater. Nitrous oxide accounted for approximately 65% of the total GHGs emitted from the OABR. By contrast, 99.6% of the methane emission and 99.9% of nitrous oxide emission were reduced by application of the UASB. However, the ammonia removal efficiency of the UASB was only 2.2%. Furthermore, Acinetobacter johnsonii, which is known as a heterotrophic ammonia remover, was detected only in the OABR. These results indicated that high nitrous oxide emissions were caused by denitrification in the OABR and that application of the closed anaerobic system could drastically reduce the emissions of both methane and nitrous oxide. PMID- 29619880 TI - Low-dose IL-2 expands CD4+ regulatory T cells with a suppressive function in vitro via the STAT5-dependent pathway in patients with chronic kidney diseases. AB - BACKGROUND: Patients with chronic kidney disease (CKD) often have CD4+ regulatory T cells (Tregs) dysfunction and chronic inflammation. We aim to investigate the effect, function, and related mechanism of low-dose IL-2 on CD4+ regulatory T cells expansion in vitro from patients with CKD. METHODS: A total of 148 newly diagnosed patients with CKD at Stage III and 35 healthy volunteer subjects were recruited into our studies. The number of peripheral Tregs in peripheral blood mononuclear cells isolated from CKD patients, which were characterized by FACS as CD4+CD25hi and CD4+CD25+FoxP3+. The effect of low-dose IL-2 on expansion of Tregs, and the suppressive function of expanded Tregs were also analyzed by FACS. The levels of FoxP3 mRNA were detected by qRT-PCR. The activation of IL-2 induced Stat5 and blocking experiments were assessed by Western Blotting and FACS. RESULTS: We found that the frequency of peripheral Tregs from CKD patients was significantly lower than that in healthy volunteer subjects. We also showed that IL-2 selectively expanded CD4+CD25hi and CD4+CD25+FoxP3+ regulatory T cells, and also upregulated the expression of FoxP3 mRNA. Our in vitro studies demonstrated that expanded CD4+ regulatory T cells from CKD patients suppressed proinflammatory Th1 and Th17 cell response. Furthermore, STAT5 activation is required for IL-2-induced expansion of regulatory T cells and expression of FoxP3 mRNA from CKD patients. CONCLUSIONS: Our findings support the clinical Treg defects in CKD patients with glomerular diseases, and the rationale of evaluating low-dose IL-2 treatment for selectively modulating CD4+ Tregs. PMID- 29619884 TI - Cardioprotective effect of beta-d-mannuronic acid (M2000) as a novel NSAID on gene expression of oxLDL scavenger receptors in the experimental diabetic model. AB - CONTEXT: The investigations have shown that patients with diabetes have the elevated levels of glucose and oxLDL. These two play an important role in increased expression levels of oxLDL scavenger receptors on the surface of macrophages and endothelial cells that leads to deposition of oxLDL and macrophages in vascular walls. OBJECTIVE: The present study intends to show the effects of beta-d-mannuronic acid (M2000) on the expression profile of ox-LDL scavenger receptors (including SR-A, LOX-1, CD36, and CD68) in an experimental model of diabetes. MATERIALS AND METHODS: Eighteen Sprague-Dawley rats were randomly divided into three 6-member groups of the healthy control, diabetic control, and treated rats by M2000. Diabetes was induced in rats by intraperitoneal (IP) administration of 60 mg/kg streptozotocin. The treated rats were given daily intraperitoneal injections of M2000 with a dose of 25 mg/kg for 28 days and at the end of the 28th day, their aortas were removed. The qRT-PCR technique was then used to evaluate the expression levels of the proposed gene. RESULTS: The gene expression levels of the SR-A, LOX-1, CD36, and CD68 significantly declined in the diabetic group that received M2000 compared with untreated diabetic rats. CONCLUSIONS: The M2000, as a novel NSAID is able to modify by lowering the gene expression levels of SR-A, LOX-1, CD36, and CD68 in treated rats compared to the untreated diabetic group, which may play an important role in preventing the complications that could lead to a cardioprotective efficacy. PMID- 29619882 TI - ELLPMDA: Ensemble learning and link prediction for miRNA-disease association prediction. AB - Recently, accumulating evidences have indicated miRNAs play critical roles in the progression and development of various human complex diseases, which pointed out that identifying miRNA-disease association could enable us to understand diseases at miRNA level. Thus, revealing more and more potential miRNA-disease associations is a vital topic in biomedical domain. However, it will be extremely expensive and time-consuming if we examine all the possible miRNA-disease pairs. Therefore, more accurate and efficient methods are being highly requested to detect potential miRNA-disease associations. In this study, we developed a computational model of Ensemble Learning and Link Prediction for miRNA-Disease Association prediction (ELLPMDA) to achieve this goal. By integrating miRNA functional similarity, disease semantic similarity, miRNA-disease association and Gaussian profile kernel similarity for miRNAs and diseases, we constructed a similarity network and utilized ensemble learning to combine rank results given by three classic similarity-based algorithms. To evaluate the performance of ELLPMDA, we exploited global and local Leave-One-Out Cross Validation (LOOCV), 5 fold Cross Validation (CV) and three kinds of case studies. As a result, the AUCs of ELLPMDA is 0.9181, 0.8181 and 0.9193+/-0.0002 in global LOOCV, local LOOCV and 5-fold CV, respectively, which significantly exceed almost all the previous methods. Moreover, in three distinct kinds of case studies for Kidney Neoplasms, Lymphoma, Prostate Neoplasms, Colon Neoplasms and Esophageal Neoplasms, 88%, 92%, 86%, 98% and 98% out of the top 50 predicted miRNAs has been confirmed, respectively. Besides, ELLPMDA is based on global similarity measure and applicable to new diseases without any known related miRNAs. PMID- 29619883 TI - Clinical outcomes with a diffractive trifocal intraocular lens. AB - PURPOSE: To evaluate clinical and visual outcomes, quality of near vision, and intraocular optical quality of patients bilaterally implanted with a trifocal PanOptix intraocular lens. METHODS: In this prospective consecutive case-series study, 52 eyes of 26 bilateral patients (mean age, 60.2 +/- 7.4 years) were implanted with the AcrySof IQ Panoptix intraocular lens. Visual acuity, defocus curve, contrast sensitivity (Pelli-Robson test), near activity visual questionnaire, and internal aberrations with Osiris were evaluated. A prototype light-distortion analyzer was used to quantify the postoperative light-distortion indices. The follow-up was 6 months after surgery. RESULTS: Uncorrected, corrected distance, and uncorrected near visual acuities improved with the surgery (p <= 0.02). Distance corrected near visual acuity was 0.13 +/- 0.10, 0.13 +/- 0.13, and 0.13 +/- 0.08 at 1, 3, and 6 months after surgery, respectively (p = 0.82). Distance corrected intermediate visual acuities were 0.09 +/- 0.13, 0.13 +/- 0.15, and 0.12 +/- 0.12 at 1, 3, and 6 months, postoperatively. Binocular contrast sensitivity was 1.86 +/- 0.15 Log Units. Defocus curve provided a visual acuity equal or better to 0.30 LogMAR between defocus levels of +0.50 to -3.00 D. The near activity visual questionnaire scores improved significantly with the surgery (p < 0.01). CONCLUSION: The AcrySof IQ Panoptix intraocular lens is able to restore visual function with an acceptable intermediate and near vision after cataract surgery with good contrast sensitivity and an improvement in the near activity visual questionnaire. PMID- 29619885 TI - Outcomes of Surgical Management for Thumb Basilar Arthritis in Patients 55 Years of Age and Younger. AB - BACKGROUND: Trapeziectomy with ligament reconstruction tendon interposition (LRTI) or suspensionplasty is an effective treatment in older patients with end stage thumb basilar arthritis. However, the survivability of this procedure is unknown in younger patients who may impart more stress on their thumbs. METHODS: A retrospective review was performed on all patients who underwent trapeziectomy and LRTI or suspensionplasty at 55 years of age or younger from 1992 to 2008. Objective clinical outcome measures included preoperative to postoperative changes in thumb range of motion, grip and pinch strength, a study-specific thumb function score, and the Buck-Gramcko subjective outcome score. Progressive metacarpal subsidence was evaluated on radiographs. Survivorship free from revision surgery was calculated with a Kaplan-Meier analysis. RESULTS: A total of 57 wrists underwent trapeziectomy and LRTI (n = 18) or suspensionplasty (n = 39). The mean patient age at the time of surgery was 49.6 years (range: 38-55 years). Mean clinical and radiographic follow-up were 10.2 and 6.4 years, respectively. Overall, there were significant improvements in pain and grip strength despite progressive and metacarpal subsidence. Survivorship was 100% and 86% free from revision surgery at 10 and 15 years, respectively (n = 2 failures). CONCLUSIONS: Trapeziectomy and LRTI or suspensionplasty in patients less than or equal to 55 years of age can result in considerable improvements in pain and grip strength with a 10-year survivorship free from revision. PMID- 29619886 TI - Assessment of Conduit-Assisted Primary Nerve Repair Strength With Varying Suture Size, Number, and Location. AB - BACKGROUND: Outcomes following digital nerve repair are suboptimal despite much research and various methods of repair. Increased tensile strength of the repair and decreased suture material at the repair site may be 2 methods of improving biologic and biomechanical outcomes, and conduit-assisted repair can aid in achieving both of these goals. METHODS: Ninety-nine fresh-frozen digital nerves were equally divided into 11 different groups. Each group uses a different combination of number of sutures at the coaptation site and number of sutures at each end of the nerve-conduit junction, as well as 2 calibers of nylon suture. Nerves were transected, repaired with these various suture configurations using an AxoGuard conduit, and loaded to failure. RESULTS: The 2-way analysis of variance (ANOVA) showed that repairs performed with 8-0 suture have significantly higher maximum failure load compared with 9-0 suture repairs ( P < .01). Increasing the number of sutures in the repair significantly increased the maximum failure load in all groups regardless of suture caliber used ( P < .01). Repairs with 9-0 suture at the coaptation site did not jeopardize repair strength when compared with 8-0 suture. CONCLUSIONS: Conduit-assisted primary digital nerve repairs with 8-0 suture increases the maximum load to failure compared with repairs with 9-0 suture, as does increasing the overall number of sutures. Using 9-0 suture at the coaptation site with 8-0 suture at the nerve-conduit junction does not jeopardize tensile strength when compared with similar repairs using all 8-0 suture and may decrease inflammation at the repair site while still achieving sufficient tensile strength. PMID- 29619887 TI - Corrigendum. AB - Akinleye SD, Makani A, Dalinka MK, et al. Unusual proximal carpal row dislocation without fracture: a case report. Hand (N Y). 2012;7:454-456. (Original DOI:10.1007/s11552-012-9449-6) In this article printed in the December 2012 issue of Hand, the title incorrectly omitted the words "carpal row." The corrected title is presented in the reference above. PMID- 29619888 TI - Proximal Interphalangeal Joint Silicone Arthroplasty for Osteoarthritis: Midterm Outcomes. AB - BACKGROUND: Osteoarthritis of the proximal interphalangeal (PIP) joint affects a large percentage of the population and can lead to significant functional disability. The purpose of this study is to evaluate the midterm clinical effectiveness of PIP joint arthroplasty for nonrheumatic arthritis. METHODS: A single-center retrospective cohort study evaluating preoperative and postoperative objective and subjective measures was conducted. Range of motion (ROM), Disabilities of the Arm, Shoulder and Hand scores, key pinch strength, grip strength, and satisfaction with respect to pain, deformity, function, and strength were measured. RESULTS: Forty-five fingers in 25 patients were followed up for a mean period of 42 months. Preoperative and postoperative mean ROM was equivalent at 59.1 degrees and 59.2 degrees , respectively. Postoperative grip and key pinch strength showed significant improvement and near normalization compared with contralateral extremity. Complication rate was 37% with 20% requiring revision surgery. Patients with diabetes mellitus had higher odds of requiring revision surgery. Pain scores improved from 7.4 to 1.9 on a visual analog scale. Overall satisfaction was high at 84%, and 91% of patients would have the surgery performed again. CONCLUSIONS: Silicone arthroplasty for osteoarthritis of the PIP remains a good option for pain relief. Our study presents midterm follow-up data that support significant pain relief, increased grip and key pinch strength, and high satisfaction associated with this implant. PMID- 29619889 TI - Mild focal hypothermia regulates the dynamic polarization of microglia after ischemic stroke in mice. AB - Objectives The protective effects of hypothermia on acute stroke have been demonstrated in many studies. However, its underlying mechanisms have not been thoroughly elucidated. Following an ischemic stroke event, microglia undertakes an early 'healthy' M2 phenotype and gradually transform into a 'sick' M1 phenotype over time. This transformation of polarity of microglia has influence on the degree of damage following a stroke. This study investigated the effects of mild focal hypothermia on microglia polarization following ischemic stroke. Methods Transient cerebral ischemic models were created by intraluminal filament occlusion of right middle cerebral artery (MCAO) in mice for one hour. By placing an ice box under their skull, hypothermia of mice brain was initiated immediately following MCAO for 2 h. Temporal muscle temperature was recorded and maintained between 32 and 34 degrees C. Brain tissue loss was assessed by hematoxylin and eosin (H&E) staining 28 days after MCAO. Quantitative real-time polymerase chain reaction (qPCR) and immunostaining were used to assess phenotype of microglia in different ischemic perfusion time. Results Hypothermia reduced brain tissue loss 28 days after ischemic stroke. Hypothermia also reduced the number of CD16 positive M1 microglia and increased the numbers of CD206-positive M2 microglia following ischemic stroke. Moreover, hypothermia also led to the reduction of the M1 markers at the level of transcription, while it increased the expression of mRNA for M2 markers. Conclusions Hypothermia is protective following ischemic stroke and can reduce brain tissue loss. Moreover, hypothermia shifts the polarization of microglia from the M1 to the M2 phenotype in the ischemic mice brain. This observed biological phenomenon may partially explain the protective effects seen due to hypothermia in acute ischemic stroke. PMID- 29619890 TI - Evolution of upper limb kinematics four years after subacute robot-assisted rehabilitation in stroke patients. AB - PURPOSE: To assess functional status and robot-based kinematic measures four years after subacute robot-assisted rehabilitation in hemiparesis. MATERIALS AND METHODS: Twenty-two patients with stroke-induced hemiparesis underwent a >=3 month upper limb combined program of robot-assisted and occupational therapy from two months post-stroke, and received community-based therapy after discharge. Four years later, 19 (86%) participated in this follow-up study. Assessments 2, 5 and 54 months post-stroke included Fugl-Meyer (FM), Modified Frenchay Scale (MFS, at Month 54) and robot-based kinematic measures of targeting tasks in three directions, north, paretic and non-paretic: distance covered, velocity, accuracy (root mean square (RMS) error from straight line) and smoothness (number of velocity peaks; upward changes in accuracy and smoothness represent worsening). Analysis was stratified by FM score at two months: >=17 (Group 1) or <17 (Group 2). Correlation between impairment (FM) and function (MFS) was explored at 54 months. RESULTS: FM scores were stable from 5 to 54 months (+1[-2;4], median [1st; 3rd quartiles], ns). Kinematic changes (three directions pooled) were: distance -1[-17;2]% (ns); velocity, -8[-32;28]% (ns); accuracy, +6[-13;98]% (ns); smoothness, +44[-6;126]% (p < 0.05). Group 2 showed decline vs. Group 1 (p < 0.001) in FM (Group 1, +3[1;5], p < 0.01; Group 2, -7[-11;-1], ns) and accuracy (Group 1, -3[-27;38]%, ns; Group 2, +29[17;140]%, p < 0.001). At 54 months, FM and MFS were highly correlated (Pearson's rho = 0.89; p < 0.001). CONCLUSIONS: While impairment appeared stable four years after robot-assisted upper limb training during subacute post-stroke phase, movement kinematics deteriorated despite community-based therapy, especially in more severely impaired patients. TRIAL REGISTRATION: EudraCT 2016-005121-36. Registration: 2016-12-20. Date of enrolment of the first participant to the trial: 2009-11-24. PMID- 29619891 TI - Correlation of nerve fibers in corpus callosum and number of neurons in cerebral cortex: an innovative mathematical model. AB - : Purpose/aim: It is estimated that 109 bits/s information are processed in the human brain. The transmission of this huge amount of information requires all connections in the brain to be highly accurate and have order. The current study attempted to present a new aspect of order and proportion in the ultra-structure of the human brain and to calculate the degree of neural interdependence between the two hemispheres. MATERIALS AND METHODS: In this model, intensity of interdependence of the brain to hemispheres is estimated to be equal to the mathematical proportion of number of neurons in cerebral cortex divided by 2 (number of hemispheres), divided by number of nerve fibers in the human corpus callosum. RESULTS: The calculated number is equal to 30-50 and it indicates that for every 30-50 neurons between the two hemispheres, there is a neural interconnecting bridge. CONCLUSIONS: This connection indicates that the brain's function output follows a mathematical relation. PMID- 29619892 TI - In Response to Gonzalez-Durio: "In Response to a Previous Letter to the Editor Titled, 'Accuracy of a Blood Glucose Monitoring System'". PMID- 29619893 TI - Influences of Anemia, Kidney Disease, Thyroid Dysfunction, and Liver Disease on the Ratio of Glycated Albumin to Hemoglobin A1c. PMID- 29619894 TI - Analysis of "Laboratory and Benchtop Performance of a Mealtime Insulin Delivery System". AB - In the current issue of Journal of Diabetes Science and Technology, Dreon et al give a comprehensive overview of the technical performance of a wearable patch for bolus insulin delivery. The test results generated by the manufacturer of the bolus-patch provide the technical prerequisites for clinical application. As the device received FDA clearance already in 2010, positive results from the nonclinical performance testing were to be expected, but present nevertheless interesting insights into the device development. The single-dose accuracy verification results seem especially promising, but tighter accuracy criteria could have been specified and information on outliers is missing from the analysis. The clinical application of the bolus-patch is currently under investigation in a large-scale 44-week intervention trial. PMID- 29619895 TI - Quality Control of Norwegian Pharmacy HbA1c Testing: A Modest Beginning. AB - BACKGROUND: Many pharmacy services involve laboratory testing using point-of-care (POC) instruments. Our aim was to describe the implementation of quality control of the HbA1c POC instruments and investigate the performance in internal quality control (IQC) and external quality control (EQA) for HbA1c POC instruments in Norwegian community pharmacies. METHODS: Two project pharmacists from each of 11 pharmacies participated in a training program covering capillary blood sampling, how to use the POC HbA1c instrument (DCA Vantage) and IQC and EQA. The pharmacies were enrolled in an EQA program for HbA1c, and their performance was compared with that of general practitioners' (GP) offices. RESULTS: Two of 89 (2.2%) IQC measurements were outside the acceptance interval. Seven out of 11 pharmacies sent in results in EQA in all the three surveys during six months. Two pharmacies did not analyze the control material in any of the surveys, one pharmacy analyzed the control material in one of the surveys, and one pharmacy analyzed two of the surveys. Of these pharmacies, 56-100% obtained "very good" evaluation for trueness and 71-100% obtained "very good" evaluation for precision. The corresponding numbers for GP offices were 75-87% for trueness and 84-94% for precision. No pharmacies obtained a "poor" evaluation. CONCLUSIONS: Norwegian community pharmacies can perform IQC and EQA on a HbA1c POC instrument, and the performance is comparable with that of GP offices. The compliance in the EQA surveys was modest, but the duration of the study and participation in the EQA program was probably too short to implement all the new procedures for all pharmacies. PMID- 29619896 TI - Insulin Pump Therapy in Adolescents With Very Poor Glycemic Control During a 12 Month Cohort Trial. PMID- 29619897 TI - Type 1 Diabetes and Combat Sports: Improvement in Glycemic Control With Gained Experience. PMID- 29619898 TI - Importance of a diphosphorylated intermediate for RppH-dependent RNA degradation. AB - Deprotection of the 5' end appears to be a universal mechanism for triggering the degradation of mRNA in bacteria and eukaryotes. In Escherichia coli, for example, converting the 5' triphosphate of primary transcripts to a monophosphate accelerates cleavage at internal sites by the endonuclease RNase E. Previous studies have shown that the RNA pyrophosphohydrolase RppH catalyzes this transformation in vitro and generates monophosphorylated decay intermediates in vivo. Recently, we reported that purified E. coli RppH unexpectedly reacts faster with diphosphorylated than with triphosphorylated substrates. By using a novel assay, it was also determined that diphosphorylated mRNA decay intermediates are abundant in wild-type E. coli and that their fractional level increases to almost 100% for representative mRNAs in mutant cells lacking RppH. These findings indicate that the conversion of triphosphorylated to monophosphorylated RNA in E. coli is a stepwise process involving sequential phosphate removal and the transient formation of a diphosphorylated intermediate. The latter RNA phosphorylation state, which was previously unknown in bacteria, now appears to define the preferred biological substrates of E. coli RppH. The enzyme responsible for generating it remains to be identified. PMID- 29619899 TI - Salvia przewalskii extract of total phenolic acids inhibit TLR4 signaling activation in podocyte injury induced by puromycin aminonucleoside in vitro. AB - BACKGROUND: TLR4 signaling is known to be involved in podocyte injury. We have previously shown that Salvia przewalskii extract of total phenolic acids (SPE) and its active monomer salvianolic acid B (SalB) and rosmarinic acid (RA) protect podocytes from injury induced by PAN. In the present study, we test whether SPE inhibits TLR4 signaling. METHODS: The conditionally immortalized mouse podocytes were treated with SPE, SalB, RA, SalB + RA or tacrolimus for 30 min, followed by PAN (100 MUg/mL) for 24 h. The F-actin staining with phalloidin was used to assess cytoskeletal injury in the podocytes. Western blotting and semi quantitatives RT-PCR were used to assess the changes of the components in the TLR4 signaling pathway. RESULTS: (1) The F-actin stress fibers of podocytes were almost completely disrupted after PAN treatment for 24 h, and the disruption was significantly alleviated by SPE; (2) the PAN-induced elevation of mRNA levels of TLR4, MyD88 and p65 were inhibited except p65 with high-dose SalB; (3) consistently, the protein levels of TLR4, MyD88 and pp65 were significantly elevated by PAN, and SPE, SalB, RA and admixture, respectively, attenuated the elevations of TLR4 and pp65 proteins; (4) SPE and tacrolimus have a similarly strong effect on inhibition of the expression of TLR4 signaling components. CONCLUSIONS: SPE protects podocytes from PAN-induced injury at least partly through inhibiting TLR4 signaling. SPE is as strong as tacrolimus in inhibiting TLR4 signaling in podocytes. PMID- 29619901 TI - Inflammatory biomarkers to guide diagnostic and therapeutic decisions in children presenting with fever without apparent source. AB - A systematic review of literature from 2011 to 2016 was performed, in order to evaluate the diagnostic performance of inflammatory biomarkers in children with fever without apparent source and their usefulness in clinical decision-making. Data source was the Pubmed database. Thirteen studies were included, analysing the following biomarkers: erythrocyte sedimentation rate, white blood count, absolute neutrophil count, C-reactive protein (CRP), procalcitonin (PCT), interleukin-6 (IL-6) and the Lab-score (a combination of CRP, PCT and urine dipstick). Among the available biomarkers, CRP and PCT seem to be the most useful, showing the best performance at a threshold of 20 mg/L for CRP and 0.5 ng/mL for PCT. Lab-score increases diagnostic accuracy and also health-care costs. PCT demonstrated higher specificity levels, particularly in younger children. However, CRP remains the most accessible biomarker and is also available as a validated point-of-care test. PMID- 29619900 TI - The role of mitofilin in left ventricular hypertrophy in hemodialysis patients. AB - Left ventricular hypertrophy (LVH) is a common abnormality in hemodialysis (HD) patients. Mitochondrial dysfunction contributes to the progression of LVH. As an inner mitochondrial membrane structural protein, mitofilin plays a key role in maintaining mitochondrial structure and function. The aim of this study was to investigate the relationship between mitofilin and LVH in HD patients. A total of 98 HD patients and 32 healthy controls were included in the study. Serum N terminal proBNP (NT-proBNP), endothelin-1 (ET-1), and atrial natriuretic peptide (ANP) were examined. The protein level of mitofilin and the mitochondrial DNA (mtDNA) copy number were estimated in peripheral blood mononuclear cells (PBMCs). The left ventricle mass index (LVMI) was evaluated in all participants, and the interaction between these variables and the LVMI was assessed. The LVMI was positively correlated with the NT-proBNP, ET-1, and ANP levels, and it was negatively correlated with mtDNA copy number and mitofilin levels. Multiple regression analysis showed that the NT-proBNP, ET-1, and ANP levels as well as mitofilin levels and mtDNA copy number were associated with the LVMI. Although further research of these associations is needed, this result suggests that LVH may affect the levels of mitofilin in HD patients. PMID- 29619902 TI - Risk factors of overactive bladder syndrome and its relation to sexual function in menopausal women. AB - BACKGROUND: Overactive bladder syndrome is a common and annoying complication worldwide that could negatively affect the quality of life of afflicted individuals. We aimed to determine the prevalence and risk factors of overactive bladder syndrome and its relation to sexual function in healthy menopausal women. METHODS: This cross-sectional study was done on 340 women aged 45-60 years in Tabriz, northwest Iran, during 2015-2016. Data were collected using a demographic data questionnaire, the Overactive Bladder Syndrome Score, and the McCoy Female Sexuality Questionnaire. RESULTS: Fifty-six (16.5%), 63 (18.5%), and 10 (2.9%) of the participating women had mild, moderate, and severe overactive bladder syndrome, respectively. Predictors of overactive bladder included: night sweats, central prolapse, episiotomy, varicose disease, illiteracy or education at the primary level, systolic blood pressure >140 mmHg and lack of physical activity. We found a significant difference between the women with and without overactive bladder with respect to the total score and sub-domain scores related to sex partner (p = 0.029) and sexual interest (p = 0.049). CONCLUSIONS: The prevalence of overactive bladder was quite high in this study. Since sexual dysfunction is not an easy topic to talk about and can affect women's quality of life, physicians should consider talking about these issues besides urinary issues to all middle-aged women. PMID- 29619903 TI - Healing of spongiosus-cutaneous fistula with Hyperbaric Oxygen Therapy (HBOT): a case report. AB - INTRODUCTION: We present a case of a spongiosus-cutaneous fistula in a 39-year old man with recurrent episodes of cutaneous abscess in dorsal middle third penis (5 * 3 cm) treated with Hyperbaric Oxygen Therapy (HBOT). CASE REPORT: After emptying nodular abscess, the patient was noncompliant for further surgery. Therefore, it was suggested the association between HBOT and antibiotic therapy. HBOT is carried out in a hyperbaric room, where the internal pressure is increased (compression phase) by entering compressed air up to 283.71 kPa in about 10 minutes. Every HBOT cycle lasted 24 days in which the patient had been taking Amoxicillin/Clavulanic Acid 875 mg/125 mg 3 tabs/day and Sulfamethoxazole/Trimethoprim 160 mg/800 mg 2 tabs/day for 2 weeks. At the end of the treatment, a penile magnetic resonance imaging and an ultrasonography were executed and they evidenced a complete remission of the lesion. In the subsequent 22 months, there was no recurrence. CONCLUSIONS: Our results suggest that HBOT is an effective treatment for chronic wounds, including a spongiosus-cutaneous fistula of unknown cause, when used in combination with conventional standard therapy or further interventions. At present time, the gold standard remains surgery; nevertheless, our experience with HBOT may stimulate its use in clinical trials. PMID- 29619904 TI - Dynamics of Evans blue clearance from cerebrospinal fluid into meningeal lymphatic vessels and deep cervical lymph nodes. AB - Objectives Recently, it has been confirmed, that excess fluid and waste products from the brain are drained into the cerebrospinal fluid (CSF) and afterwards cleared via the olfactory route and/or lymphatic vessels in the brain dura and corresponding extracranial lymphatic structures. Therefore, the aim of present study was to monitor time-dependent uptake of Evans blue (EB) tracer from subarachnoid space into the meningeal lymphatic vessels and extracranial lymph nodes in rats during 3 hours-12 days. Methods EB was injected into the cisterna magna of anesthetized rats and after required survival, plasma, brain dura matter and corresponding lymph nodes (cervical, thoracic and lumbar) were dissected and processed for lymphatic vessels analyses using immunofluorescence and immunohistochemistry. Furthermore, we have used sensitive ultra-high-performance liquid chromatography (UHPLC) method for the determination of EB concentrations in selected samples. Results Using a combination of imaging methods, we have detected two different types of the vascular structures in the brain dura and in deep cervical lymph nodes. The blood vessels, which were RECA-1 + positive and the lymphatic-like vessels, expressing bright intense red fluorescence of EB tracer. Subsequently, using UHPLC with UV detection, we have quantified the EB concentration in positive structures by 3 hours up to 12 days after tracer delivery. A significant increase of EB concentration was detected in deep cervical lymph nodes already at 3 hours with a peak at 1 day that decreased to about one-tenth of its peak value by 12 days. Similar pattern was detected in brain dura. On the contrary, the brain tissue and plasma were almost negative for EB tracer during all tested time periods. Conclusion Our results demonstrate the dynamic changes of EB in meningeal lymphatic vessels and in deep cervical lymph nodes, thus recapitulating the downstream outflow of intracisternally injected tracer during 3 hours-12 days via dura mater lymphatic vessels towards corresponding extracranial draining system, particularly the deep cervical lymph nodes. PMID- 29619905 TI - Etiological analysis of graft dysfunction following living kidney transplantation: a report of 366 biopsies. AB - AIM: The aim of this study is to investigate the clinical features of graft dysfunction following living kidney transplantation and to assess its causes. METHODS: We retrospectively analyzed a series of 366 living kidney transplantation indication biopsies with a clear etiology and diagnosis from July 2003 to June 2016 at our center. The classifications and diagnoses were performed based on clinical and pathological characteristics. All biopsies were evaluated according to the Banff 2007 schema. RESULTS: Acute rejection (AR) occurred in 85 cases (22.0%), chronic rejection (CR) in 62 cases (16.1%), borderline rejection (BR) in 12 cases (3.1%), calcineurin inhibitor (CNI) toxicity damage in 41 cases (10.6%), BK virus-associated nephropathy (BKVAN) in 43 cases (11.1%), de novo or recurrent renal diseases in 134 cases (34.7%), and other causes in nine cases (2.3%); additionally, 20 cases had two simultaneous causes. The 80 cases with IgA nephropathy (IgAN) had the highest incidence (59.7%) of de novo or recurrent renal diseases. After a mean +/- SD follow up of 3.7 +/- 2.3 years, the 5-year graft cumulative survival rates of AR, CR, CNI toxicity, BKVAN, and de novo or recurrent renal diseases were 60.1%, 31.2%, 66.6%, 66.9%, and 67.1%, respectively. CONCLUSIONS: A biopsy is helpful for the diagnosis of graft dysfunction. De novo or recurrent renal disease, represented by IgAN, is a major cause of graft dysfunction following living kidney transplantation. PMID- 29619906 TI - The HLA-DRB1 and HLA-DQB1 alleles are associated with multiple sclerosis disability progression in Slovak population. AB - OBJECTIVE: The aim of our present study was to analyse the association of HLA DRB1 and -DQB1 alleles and genotypes with Multiple Sclerosis (MS) disability progression in a cohort of Central European Slovak population. METHODS: The allele and genotype variants were analyzed in 282 non-related MS patients. Rate of disease disability progression was evaluated using EDSS score in the 5th, 7th, 10th, and 15th year of disease duration, time to reach EDSS score 3 and 5, and MSSS score. Genotyping was performed by polymerase chain reaction with sequence specific primers. RESULTS: We found that carriers of homozygous genotype for alleles DRB1*15 and DQB1*03 reached EDSS score 3 significantly earlier than non carriers of these alleles (p = 0.0172; p = 0.00183, respectively). Genotype DQB1*03/03 carriage was also associated with significantly reduced time to reach EDSS score 5 (p = 0.00316). Lower EDSS score in the 5th year of disease duration was found in carriers of DRB1*07 allele (p cor = 0.028). When MSSS score was used, genotype DRB1*15/15 was found to be less frequent in slow progressing MS patients, when compared to MS patients with mid-rate and rapid disease disability progression (p cor = 0.0305). DISCUSSION: We showed for the first time that HLA DRB1 and -DQB1 genotypes are genetic markers associated with disability progression in Slovak MS patients. Genotypes DRB1*15/15 and DQB1*03/*03 were identified as short-term clinical negative prognostic factors, while allele DRB1*07 carriage appeared to be a positive prognostic marker of better MS outcome. PMID- 29619907 TI - Severe Atherosclerosis in Donor Liver Vasculature: An Illustrative Case Report and Review of the Literatur. AB - As the scarcity of transplantable organs continues to increase, juxtaposed with an aging donor population, transplant surgeons are increasingly confronted with marginal organ offers. The presence of atherosclerosis in the donor allograft has been shown to compromise the vascular integrity and predispose to vascular complications in the transplanted liver. Here, we present a case of 54-year-old brain-dead donor who was discovered to have a severely diseased aorta during organ recovery. Pathologic evaluation revealed severe atherosclerosis with calcifications. Because there was no evidence of donor graft dysfunction, we elected to proceed with implantation, although thoughtful consideration was given to aborting the procedure. The donor hepatic artery was resected from the bifurcation of the splenic artery and the common hepatic artery until no further gross atheromas were evident; this segment was then anastomosed with the recipient proper hepatic artery. The recipient is doing well 6 months after transplant without any significant adverse postoperative events. The presence of severe atherosclerosis should not discourage the use of an otherwise adequate graft. Novel newer preservation techniques, such as normothermic perfusion, may enable functional graft evaluation and can increase the utilization of marginal grafts. PMID- 29619908 TI - Prevalence of Sexually Transmitted Diseases in Asymptomatic Renal Transplant Recipients. AB - OBJECTIVES: Sexually transmitted diseases, which may be asymptomatic, have the potential to cause serious health problems in renal transplant recipients. The aim of this study was to determine the prevalence of sexually transmitted diseases in sexually active asymptomatic renal transplant patients by using real time multiplex polymerase chain reaction assays. MATERIALS AND METHODS: This prospective controlled study was conducted between November 2016 and January 2017 in our hospital. Our study group included 80 consecutive, sexually active asymptomatic patients (40 men and 40 women) who had undergone renal transplant in our hospital and who presented to our outpatient clinic for routine follow-up. We also included a control group of 80 consecutive, sexually active nontransplant patients (40 men and 40 women). All patient samples were tested for Gardnerella vaginalis and obligate anaerobes (Prevotella bivia, Porphyromonas species), Candida species, Mycoplasma hominis, Mycoplasma genitalium, Ureaplasma species, Trichomonas vaginalis, Neisseria gonorrhoeae, Chlamydia trachomatis, herpes simplex virus 1 and 2, and Cytomegalovirus by real-time multiplex polymerase chain reaction. RESULTS: The prevalences of infection with Gardnerella vaginalis and obligate anaerobes (P = .043), Ureaplasma species (P = .02), and Cytomegalovirus (P = .016) were found to be significantly higher in the study group versus the control group. However, there was no difference between the 2 groups regarding the prevalence of Mycoplasma infection (P = .70). CONCLUSIONS: Sexually transmitted diseases may occur more frequently in sexually active asymptomatic renal transplant recipients than in nontransplanted individuals. Real-time multiplex polymerase chain reaction analysis may be a suitable method for determining these pathogens. PMID- 29619909 TI - Where to Draw the Line in Surgical Obesity for Renal Transplant Recipients: An Outcome Analysis Based on Body Mass Index. AB - OBJECTIVES: Renal transplant is the criterion standard treatment for patients with end-stage renal disease. Because obesity rates are increasing in the global population, international standards on renal transplant in obese patients remain a gray area. The aim of this study was to determine whether renal transplant remains the treatment of choice in an obese patient with end-stage renal disease. MATERIALS AND METHODS: We performed a retrospective analysis on all patients who underwent renal transplant in our transplant unit between January 2008 and December 2013. Patients were divided into 3 cohorts based on body mass index (cohort A was < 25 kg/m2, cohort B was 25-29.99 kg/m2, and cohort C was >= 30 kg/m2). Postoperative complications within 90 days after transplant were assessed using one-way analysis of variance and chi-square distribution. Patient and graft survival rates over 3 years were assessed with Kaplan-Meier analyses. RESULTS: Of 610 total patients, 92 patients (15%) were classified as "obese" (>= 30 kg/m2) in cohort C, with 294 patients in cohort A and 224 patients in cohort B (24 patients were excluded). Regarding short-term complications during the 90-day posttransplant period, obese individuals were at increased risk of a higher number of complications (P = .039 for cohort A vs cohort C). Lymphocele in particular was associated with obesity (P = .004); fortunately, this condition had no direct impact on the graft itself and was relatively easy to monitor and treat. The long-term outlook (3 years) appeared positive, with both graft survival (92% in cohort A, 91% in cohort B, and 94% in cohort C) and patient survival (97% in cohort A, 99% in cohort B, and 97% in cohort C) being independent of patient obesity. CONCLUSIONS: Increased body mass index up to 37.5 kg/m2 was not associated with increased risk of serious postoperative morbidity or mortality after renal transplant. Surgery should be considered as the criterion standard treatment for obese patients with end-stage renal disease if they are otherwise medically fit with few or well-controlled comorbidities. PMID- 29619910 TI - Impact of Sofosbuvir-Based Regimens for the Treatment of Hepatitis C After Liver Transplant on Renal Function: Results of a Canadian National Retrospective Study. AB - OBJECTIVES: We assessed the impact of sofosbuvir-based regimens on renal function in liver transplant recipients with recurrent hepatitis C virus and the role of renal function on the efficacy and safety of these regimens. MATERIALS AND METHODS: In an expanded pan-Canadian cohort, 180 liver transplant recipients were treated with sofosbuvir-based regimens for hepatitis C virus recurrence from January 2014 to May 2015. Mean age was 58 +/- 6.85 years, and 50% had F3/4 fibrosis. Patients were stratified into 4 groups based on baseline estimated glomerular filtration rate (calculated by the Modification of Diet in Renal Disease formula): < 30, 30 to 45, 46 to 60, and > 60 mL/min/173 m2. The primary outcome was posttreatment changes in renal function from baseline. Secondary outcomes included sustained virologic response at 12 weeks posttreatment and anemia-related and serious adverse events. RESULTS: Posttreatment renal function was improved in most patients (58%). Renal function declined in 22% of patients, which was more marked in those with estimated glomerular filtration rate < 30 mL/min/173 m2, advanced cirrhosis (P = .05), and aggressive hepatitis C virus/fibrosing cholestatic hepatitis (P < .05). High rates (80%-88%) of sustained virologic response at 12 weeks posttreatment were seen across all renal function strata. Cirrhotic patients with glomerular filtration rates < 30 mL/min/173 m2 had sustained virologic response rates at 12 weeks posttreatment comparable to the overall patient group. Rates of anemia-related adverse events and transfusion requirements increased across decreasing estimated glomerular filtration rate groups, with notably more occurrences with ribavirin-based regimens. CONCLUSIONS: Sofosbuvir-based regimens improved overall renal function in liver transplant recipients, with sustained virologic response, suggesting an association of subclinical hepatitis C virus-related renal disease. Sustained virologic response rates at 12 weeks posttreatment (80%-88%) were comparable regardless of baseline renal function but lower in cirrhosis. PMID- 29619911 TI - Early Use of Etanercept for Graft-Versus-Host Disease After Liver Transplant: the Importance of Broad Spectrum Infective Prophylaxis. AB - Graft-versus-host-disease after orthotopic liver transplant is a rare and life threatening complication. The diagnosis is challenging and usually confirmed by chimerism and skin biopsies. The most common cause of death is sepsis (60%), and broad-spectrum antibiotics and antifungal prophylaxis are strongly recommended. We present a case of a 61-year-old man with hepatocellular carcinoma and a previous history of metabolic and alcoholic cirrhosis who underwent orthotopic liver transplant. The immunosuppression regimen consisted of corticosteroids, calcineurin inhibitor, and mammalian target of rapamycin complex 1 inhibitor. Nine days after surgery, the patient developed leukopenia and skin rash. After confirmation of graft-versus-host disease by chimerism and skin biopsy, etanercept, a novel anti-tumor necrosis factor-alpha drug used for patients with hematologic and rheumatologic disease, was administrated. Unfortunately, no clinical improvements or bone marrow recovery were noted, and the patient had subsequent fatal sepsis due to Enterococcus faecium, Aspergillus fumigatus, and viral superinfection. There are no US Food and Drug Administration-approved treatments for graft-versus-host disease after orthotopic liver transplant. The main risk factors are recipients > 50 years old, patients with glucose intolerance, patients transplanted due to hepatocellular carcinoma, donor recipient age difference of > 20 years, and any HLA-class I match. In accordance with the literature, we suggest early use of broad-spectrum antibiotics and antifungal drugs during etanercept treatment. In addition, because of substantially higher risk for severe sepsis, we strongly recommend adding an antiviral prophylaxis to prevent Cytomegalovirus reactivation or unexpected superinfection. PMID- 29619912 TI - Is Serum Prostate-Specific Antigen a Reliable Prostate Cancer Marker in Liver Transplant Candidates. AB - OBJECTIVES: In this study, we aimed to determine whether the prostate-specific antigen level is a reliable marker of prostate cancer in patients with hepatic insufficiency, based on evaluation of alterations in serum prostate-specific antigen levels after liver transplant in patients with hepatic insufficiency. MATERIALS AND METHODS: Medical records of all patients who underwent liver transplant at our hospital between January 2003 and June 2017 were retrospectively reviewed. Male patients who were > 40 years old with available pre- and posttransplant serum total prostate-specific antigen levels were included in the study. RESULTS: Our study included 36 male patients with a mean age of 54.6 +/- 5.3 years (range, 45-73 y) at the time of liver transplant. The mean pretransplant serum total prostate-specific antigen level was 0.75 +/- 0.77 ng/mL, which was significantly lower than the mean posttransplant level of 1.29 +/- 1.57 ng/mL (P < .05). The pretransplant serum total prostate-specific antigen level was measured a mean of 4.9 +/- 5.4 months before liver transplant versus a mean 27.6 +/- 16.3 months after transplant. Prostate-specific antigen velocity was 0.2 ng/mL/year. Biochemical tests of liver function, including the mean serum levels of bilirubin, international normalized ratio, and albumin, were normal after liver transplant at 1.37 +/- 2.33 mg/dL, 1.22 +/- 0.36, and 4.16 +/- 0.69 g/dL, respectively. CONCLUSIONS: Serum prostate-specific antigen levels may decrease in patients with hepatic insufficiency/cirrhosis; therefore, a low serum prostate-specific antigen level may not be a reliable marker for excluding prostate cancer in such patients. Transplant surgeons and clinicians must be aware of this so that all male transplant candidates > 40 years old are evaluated via digital rectal examination, regardless of the serum prostate-specific antigen level. PMID- 29619913 TI - Emergency department boarding: a descriptive analysis and measurement of impact on outcomes. AB - CLINICIAN'S CAPSULE What is known about the topic? Bed boarding is one of the major contributors to emergency department overcrowding. What did this study ask? What are the characteristics of patients with prolonged boarding times, and what are the impacts on patient-oriented outcomes? What did this study find? Patients who were older, sicker, and had isolation and telemetry requirements experienced longer boarding times, and longer inpatient length of stay even after correcting for confounders. Why does this study matter to clinicians? Organization-wide interventions to improve efficiency and flow are required to mitigate the burden of bed boarding. PMID- 29619914 TI - Iron deficiency after bariatric surgery: what is the real problem? AB - The growing prevalence of obesity explains the rising interest in bariatric surgery. Compared with non-surgical treatment options, bariatric surgery results in greater and sustained improvements in weight loss, obesity associated complications, all-cause mortality and quality of life. These encouraging metabolic and weight effects come with a downside, namely the risk of nutritional deficiencies. Particularly striking is the risk to develop iron deficiency. Postoperatively, the prevalence of iron deficiency varies between 18 and 53 % after Roux-en-Y gastric bypass and between 1 and 54 % after sleeve gastrectomy. Therefore, preventive strategies and effective treatment options for iron deficiency are crucial to successfully manage the iron status of patients after bariatric surgery. With this review, we discuss the risks and the contributing factors of developing iron deficiency after bariatric surgery. Furthermore, we highlight the discrepancy in the diagnosis of iron deficiency, iron deficiency anaemia and anaemia and highlight the evidence supporting the current nutritional recommendations in the field of bariatric research. In conclusion, we advocate for more nutrition-related research in patient populations in order to provide strong evidence-based guidelines after bariatric surgery. PMID- 29619915 TI - Development of unfamiliar accent comprehension continues through adolescence. AB - School-age children's understanding of unfamiliar accents is not adult-like and the age at which this ability fully matures is unknown. To address this gap, eight- to fifteen-year-old children's (n = 74) understanding of native- and non native-accented sentences in quiet and noise was assessed. Children's performance was adult-like by eleven to twelve years for the native accent in noise and by fourteen to fifteen years for the non-native accent in quiet. However, fourteen- to fifteen-year old's performance was not adult-like for the non-native accent in noise. Thus, adult-like comprehension of unfamiliar accents may require greater exposure to linguistic variability or additional cognitive-linguistic growth. PMID- 29619916 TI - Descriptions of two new cases of Rocky Mountain spotted fever in Panama, and coincident infection with Rickettsia rickettsii in Rhipicephalus sanguineus s.l. in an urban locality of Panama City, Panama. AB - The clinical and pathologic characterisation of two fatal cases of tick-borne rickettsiosis in rural (El Valle) and urban (City of Panama) Panama are described. Clinical and autopsy findings were non-specific, but the molecular analysis was used to identify Rickettsia rickettsii in both cases. No ticks were collected in El Valle, while in the urban case, R. rickettsii was detected in Rhipicephalus sanguineus s.l., representing the first molecular finding in this tick in Panama and Central America. PMID- 29619917 TI - Emergency department ultrasound for the detection of B-lines in the early diagnosis of acute decompensated heart failure: a systematic review and meta analysis. AB - CLINICIAN'S CAPSULE What is known about the topic? Current diagnostic tools for heart failure in the emergency department (ED) have limited accuracy and often lead to delays in management. What did this study ask? What is the accuracy of early bedside lung ultrasound in the diagnosis of acute decompensated heart failure? What did this study find? This meta-analysis found that the sensitivity and specificity of bedside lung US in ADHF is 82.5% and 83.6%, respectively. Why does this study matter to clinicians? The implementation of early bedside lung US in the ED may lead to more accurate and timely diagnoses of ADHF. PMID- 29619918 TI - Meloidogyne daklakensis n. sp. (Nematoda: Meloidogynidae), a new root-knot nematode associated with Robusta coffee (Coffea canephora Pierre ex A. Froehner) in the Western Highlands, Vietnam. AB - The root-knot nematode species Meloidogyne daklakensis n. sp. was discovered on the roots of Robusta coffee (Coffea canephora Pierre ex A. Froehner) in Dak Lak Province, Vietnam. This species is characterized by the females having rounded or oval perineal patterns, smooth, regular, continuous striae, and reduced lateral lines. The dorsal arch is low, rounded and encloses a quite distinct vulva and tail tip. The stylet is normally straight with well-developed and posteriorly sloped knobs. The males have a rounded cap that extends posteriorly into the lip region. The procorpus is outlined distinctly, and is three times longer than the metacorpus. The metacorpus is ovoid, with a strong valve apparatus. The species closely resembles M. marylandi, M. naasi, M. ovalis, M. panyuensis, M. lopezi, M. mali and M. baetica in the perineal pattern of the females, and the morphology of the males and the second-stage juveniles. Nonetheless, it can be differentiated from other species by a combination of morphometric, morphological and molecular characteristics. Phylogenetic analysis was conducted based on the internal transcribed spacer (ITS) and 28S rDNA as well as the region between the cytochrome c oxidase I (COI) and cytochrome c oxidase II (COII) mitochondrial genes. Herein, this nematode is described, illustrated, and designated as a new species, Meloidogyne daklakensis sp. n., based on morphometric, morphological and molecular analyses. PMID- 29619919 TI - Polyamines are required for normal growth in Sinorhizobium meliloti. AB - Polyamines (PAs) are ubiquitous polycations derived from basic l-amino acids whose physiological roles are still being defined. Their biosynthesis and functions in nitrogen-fixing rhizobia such as Sinorhizobium meliloti have not been extensively investigated. Thin layer chromatographic and mass spectrometric analyses showed that S. meliloti Rm8530 produces the PAs, putrescine (Put), spermidine (Spd) and homospermidine (HSpd), in their free forms and norspermidine (NSpd) in a form bound to macromolecules. The S. meliloti genome encodes two putative ornithine decarboxylases (ODC) for Put synthesis. Activity assays with the purified enzymes showed that ODC2 (SMc02983) decarboxylates both ornithine and lysine. ODC1 (SMa0680) decarboxylates only ornithine. An odc1 mutant was similar to the wild-type in ODC activity, PA production and growth. In comparison to the wild-type, an odc2 mutant had 45 % as much ODC activity and its growth rates were reduced by 42, 14 and 44 % under non-stress, salt stress or acid stress conditions, respectively. The odc2 mutant produced only trace levels of Put, Spd and HSpd. Wild-type phenotypes were restored when the mutant was grown in cultures supplemented with 1 mM Put or Spd or when the odc2 gene was introduced in trans. odc2 gene expression was increased under acid stress and reduced under salt stress and with exogenous Put or Spd. An odc1 odc2 double mutant had phenotypes similar to the odc2 mutant. These results indicate that ODC2 is the major enzyme for Put synthesis in S. meliloti and that PAs are required for normal growth in vitro. PMID- 29619920 TI - Erratum: Streptomyces coelicolor strains lacking polyprenol phosphate mannose synthase and protein O-mannosyl transferase are hyper-susceptible to multiple antibiotics. PMID- 29619921 TI - Reemergence of Human Monkeypox in Nigeria, 2017. AB - In Nigeria, before 2017 the most recent case of human monkeypox had been reported in 1978. By mid-November 2017, a large outbreak caused by the West African clade resulted in 146 suspected cases and 42 laboratory-confirmed cases from 14 states. Although the source is unknown, multiple sources are suspected. PMID- 29619922 TI - Westward Spread of Highly Pathogenic Avian Influenza A(H7N9) Virus among Humans, China. AB - We report infection of humans with highly pathogenic avian influenza A(H7N9) virus in Shaanxi, China, in May 2017. We obtained complete genomes for samples from 5 patients and from live poultry markets or farms in 4 cities. Results indicate that H7N9 is spreading westward from southern and eastern China. PMID- 29619923 TI - Clinical presentation, management and prognosis of patients with cardiac sarcoidosis. AB - INTRODUCTION: The course and prognosis of cardiac sarcoidosis (CS) are sparsely described. The purpose of this study was to assess the clinical presentation, treatment response and prognosis for patients with CS. METHODS: This was a single centre retrospective study of patients with CS from 2006 to 2016. A total of 197 patients with a sarcoidosis diagnosis were screened, and 17 patients (mean age 46.9 years, 59% men) were diagnosed with CS based on Japanese Ministry of Health and Welfare criteria; 53% were diagnosed by a positive MRI, 29% by endomyocardial biopsy. Of 17 patients, nine (53%) had a left ventricular ejection fraction (LVEF) < 45% at the time of diagnosis. The median follow-up was four years. In 13 patients, an implantable defibrillator was used and six of these (46%) received first appropriate shock therapy after a mean follow-up of two years. A total of 11 (65%) patients were treated with prednisolone and five (45%) of these 11 patients were also treated with another immunosuppressant. RESULTS: The median LVEF did not change at the last follow-up (p = 0.68), but improved in 30% of patients on combination therapy with prednisolone and proliferation inhibitors, whereas 23% of patients with prednisolone monotherapy experienced further worsening of LVEF. Immunosuppression was not used in 35% of patients. During follow-up, one patient underwent a successful heart transplant, one had a left ventricular assist device implantation and one died from septic shock. CONCLUSION: In CS patients, ventricular arrhythmias and impairment of LVEF were frequently seen, but the medium-term survival was excellent on heart failure therapy and immunosuppression. FUNDING: none. TRIAL REGISTRATION: Danish Data Protection Agency: (File no. RH-2016-301, I-Suite no. 04965). PMID- 29619924 TI - Research integrity among PhD students within clinical research at the University of Southern Denmark. AB - INTRODUCTION: Responsible conduct of research is the basis for the credibility of all research. Research misconduct is defined as the fabrication, falsification or plagiarism committed willfully or grossly negligently in the planning, performing or reporting of research. We undertook a survey of knowledge of the attitudes towards and experiences with research misconduct among PhD students in clinical research. METHODS: A questionnaire previously used in Swedish and Norwegian studies was distributed to PhD students (n = 330) affiliated with the Department of Clinical Research or Department of Regional Health Research, University of Southern Denmark. RESULTS: A total of 165 PhD students completed the questionnaire in full or in part, yielding an overall response rate of 50%. 18 34% reported to have heard (within the past year) about researchers who had plagiarised, falsified or fabricated data, or plagiarised publications. None reported this to occur in their own department. Few stated that they had felt under pressure to either falsify data (1%) or present results in a misleading way (3%). However, 22% stated to have felt an unethical pressure (within the past year) regarding the inclusion or order of authors. CONCLUSIONS: Results indicate that, albeit at a low frequency, research misconduct involving PhD students is taking place. Likewise, a high fraction of respondents reported to have been under pressure regarding authorships, which points to questionable research practices in clinical research. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 29619925 TI - The validity of the diagnosis of heart failure (I50.0-I50.9) in the Danish National Patient Register. AB - INTRODUCTION: National discharge registers are important and cost-effective data sources for administrative and research purposes, but their value depends much on the validity of the registered data. The objective of this study was to assess the validity of heart failure (HF) diagnoses (ICD10: I50.0-I50.9) in the Danish National Patient Register (DNPR). METHODS: We reviewed medical records from a random sample of 500 patients with either a primary or a secondary discharge diagnosis of HF registered in the DNPR from any department in Northern Denmark in 2007. We noted symptoms, objective signs, diagnostic imaging and biomarkers and used the European Society of Cardiology definition of HF to categorise patients into definite, probable or non-?verified HF. RESULTS: We classified 305 patients as having definite HF and 113 patients as having probable HF. The remaining cases were classified as non-verified HF. Thus, the positive predictive value (PPV) for definite and probable HF was 83.6% (95% confidence interval (CI): 80.1 86.7%).?The PPV increased to 88.0% (95% CI: 84.4-91.0%) when we restricted analyses to primary diagnoses and to 95.2% (95% CI: 89.2-98.4%) when we restricted analyses to HF diagnoses established at cardiology units. CONCLUSIONS: The HF diagnoses (I50.0-I50.9) in the DNPR should be used with caution if validation is not possible. However, restricting analyses to patients registered with a primary diagnosis of HF or patients discharged from cardiology units may be a useful alternative in population-based studies. FUNDING: none. TRIAL REGISTRATION: not relevant. PMID- 29619926 TI - Parenteral nutrition and insulin per protocol improve diabetes management after total pancreatectomy. AB - INTRODUCTION: Pancreatogenic diabetes develops in patients undergoing total pancreatectomy and complicates post-surgical management. The aim of this study was to compare parenteral nutrition (PN) with protocolled insulin treatment to intravenous glucose treatment after total pancreatectomy. METHODS: This was a retrospective study of 97 patients undergoing total pancreatectomy between 2009 and 2014. Patients were divided into a PN cohort (n = 57) and a glucose cohort (n = 40). The PN cohort was given PN with one international unit (IU) rapid-acting insulin per 10 g of carbohydrate. The glucose cohort was given a continuous 5% glucose infusion with 2 IU rapid-acting insulin per 10 g of carbohydrate. Both cohorts were given insulin detemir 0.2 IU/kg/day. RESULTS: Within the first 13 post-operative days, plasma glucose values were within the target range (4.0-10.0 mmol/l) in the PN cohort more frequently than in the glucose cohort (46% versus 42%, p = 0.01) without any increase in hypoglycaemia. Non-infectious complications occurred less frequently in the parenteral cohort than in the glucose cohort (23% versus 43%, p = 0.04). Infectious complications occurred in 19% versus 33% of patients, respectively (p = 0.14). The mean length of hospitalisation was 19.8 +/- 12.7 versus 25.0 +/- 21.5 days, p = 0.14. CONCLUSIONS: After total pancreatectomy, PN with insulin treatment per protocol improves glycaemic control compared with glucose infusion and reduces the number of non-infectious post-operative complications without increasing hypoglycaemia. FUNDING: none. TRIAL REGISTRATION: not relevant. PMID- 29619927 TI - Joinpoint regression analysis of suicides in Denmark during 1980-2015. AB - INTRODUCTION: Major advances have been achieved in suicide prevention over the past decades. Effective suicide prevention requires vigilant monitoring of suicide trends. The aim of this study was to assess the change in the Danish suicide rate over time using joinpoint regression analysis and to examine the distribution of suicide methods in the 1980-2015 period. METHODS: Nationwide register data were obtained from the Central Research Register and the Danish Cause of Death Register. Rates were calculated per 100,000 persons by gender and agegroup. Joinpoint regression analysis was used to assess changes over time in the overall suicide rate. RESULTS: The suicide rate declined from 40.4 (95% confidence interval (CI): 38.4-42.3) in 1980 to 11.9 (95% CI: 10.9-12.9) in 2015. A significant reduction ranging between 2 and 6% was observed during 1980-1999 after which the decrease was modest. The rate was higher for men than for women (rate ratio 1.9; 95% CI: 1.7-2.1), and more so by the end of the period (rate ratio = 2.4; 95% CI: 1.9-2.8). The suicide rate was found to increase with increasing age. Hanging, poisoning and shooting were the most frequent methods for men, whereas poisoning followed by hanging and drowning were the most frequent methods for women. CONCLUSIONS: The suicide rate fell sharply between 1980 and 1999 in Denmark, but since then the decrease has been modest, especially since 2007. Further reduction in the suicide rate requires new and effective measures. FUNDING: none. TRIAL REGISTRATION: not relevant. PMID- 29619928 TI - Studies of upper limb pain in occupational medicine, in general practice, and among computer operators?. AB - Diagnostic consensus criteria cannot be applied in a major proportion of patients with upper limb complaints, many of which are regarded as "non-specific". The three empirical studies in this thesis aimed to address this diagnostic challenge by incorporating representative neurological qualities in the physical examination.?Patterns of muscle weakness, sensory abnormalities and nerve trunk allodynia based on the nerves' topography and their motor and cutaneous innervation were defined to reflect peripheral nerve afflictions and their locations. The physical examination was first validated on patients in clinical occupational medicine. Next, the neurological patterns were studied among computer operators in order to contribute to the characterization of their disorder. Finally, self-reported work-exposures for patients in general practice presenting with symptoms and findings consistent with brachial plexopathy were compared with the exposures of matched control patients without upper limb symptoms.?The inter-rater reliability of manual individual muscle testing, and of assessments of sensibility (touch, pinprick and vibration) and mechanosensitivity of nerve trunks was generally moderate to good. Patterns of findings in accordance with neuropathy at ten locations were identified with moderate to good reliability. The identified patterns reflected the presence of symptoms with high positive and negative predictive values. An examination limited to the assessment of strength in six muscles was shown to be sensitive but non-specific.?Computer operators with severe upper limb complaints are characterized by rather uniform physical findings in accordance with an infraclavicular brachial plexopathy in combination with median and posterior interosseous neuropathy at elbow level. In spite of reduced symptoms at follow-up, the prognosis in terms of work-status and persisting pain is serious. A cross-sectional study of computer operators in current work showed that individual and patterns of neurological findings in symptomatic subjects reflected these three locations of focal neuropathy. Pain was common in the studied sample, but of low intensity. Physical abnormalities were frequent and related to summarized pain. Patterns in accordance with brachial plexopathy, and median (elbow) and posterior interosseous neuropathies were identified in a minor proportion of limbs, in particular in the mouse operating limb. A stretching course designed to improve the mobility and available space for the nerves at the three locations reduced the pain level but did not influence physical findings at follow-up. The relation of symptoms to the identified neurological patterns and the effect of stretching provide additional support to the construct validity of the applied neurological examination. This study indicates the role of nerve afflictions in computer-related upper limb disorders.?The most frequent pattern in the first two studies was in accordance with brachial plexopathy. Therefore additional analyses addressed the relation of this condition to me-chanical exposures at work. Whether assessed as the extent during the workday or days per week, many exposures, in particular adverse upper limb postures, repetitive work, work pace, and the use of force, were significant risk indicators for brachial plexopathy with clear dose-response relationships.?The identification of patterns of physical findings that reflect the function of the peripheral nerves appears to be a rewarding diagnostic procedure in subjects with upper limb symptoms. The relation of patterns to symptoms indicates the diagnostic feasibility of the examination and can contribute to explain symptoms in workers such as computer operators. Patterns in accordance with brachial plexopathy are frequent and related to mechanical work exposures. PMID- 29619929 TI - Depression, stroke, and dementia in patients with myocardial infarction. AB - The connection between the heart and mind has been studied since Sir William Harvey observed more than 350 years ago that negative emotions adversely affect the heart. Today, we know that diseases of the mind can affect the heart and, conversely, that heart diseases can cause both physical and mental diseases of the brain. To explore this relation further, we examined how previous depression affects survival in patients with myocardial infarction (MI) (study II), and how the occurrence of MI affects the risk of ischemic and hemorrhagic stroke (study III) and dementia (study IV). These studies were preceded by a validation study including all major cardiovascular diagnoses in the Danish National Patient Registry (study I). Studies II-IV are population-based cohort studies, of which studies III-IV are matched cohort studies. We identified antidepressant use from prescription registries and used nationwide databases to identify study populations and retrieve data on outcomes and comorbidity. ?In study I (2010 2012), we reviewed a total of 2,153 medical records from one university hospital and two regional hospitals in the Central Denmark Region. We randomly sampled up to 100 cases for each cardiovascular diagnosis. Medical record review served as reference standard to compute the positive predictive value for each diagnosis. For first-time MI, the positive predictive value was 97% (95% CI 91%-99%) and exceeded 90% for the most common cardiovascular disease entities. ?In study II (1995-2014), we identified 170,771 patients with first-time MI. Previous depression was identified by either a depression diagnosis or the use of antidepressants. Patients with MI and a previous depression diagnosis had higher 19-year mortality risks (87% vs. 78%). The overall adjusted mortality rate ratio was 1.11 (95% CI 1.07-1.15), increasing to 1.22 (95% CI 1.17-1.27) when including the use of antidepressants in the definition of depression. The association was stronger in patients with recent depression but was not influenced by depression severity or type of MI.?In study III (1980-2009), we identified 258,806 patients with a first-time MI and 1,244,773 sex-, age-, and calendar year-matched individuals from the general population, and followed them for development ischemic or hemorrhagic stroke. During the first 30 days after MI, the adjusted stroke rate ratio was 31.9 (95% CI 28.4-35.8) for ischemic stroke, 21.8 (95% CI 16.6-28.5) for intracerebral hemorrhage (ICH), and 16.6 (95% CI 8.7-32.0) for subarachnoid hemorrhage (SAH) compared with the general population. The adjusted stroke rate ratio remained increased during 31 to 365 days (3-fold for ischemic stroke, 2-fold for ICH, and 1.5-fold for SAH). During the following 1-30 years, the risk remained 1.6-fold increased for ischemic stroke but decreased to near unity for ICH and SAH.?In study IV (1980-2012), we identified 314,911 patients with first-time MI and 1,573,193 sex-, age-, and calendar year-matched individuals from the general population and followed 1-year survivors for development of dementia. Compared with the general population cohort, MI patients were not at increased risk of all-cause dementia (adjusted hazard ratio = 1.01, 95% CI 0.98-1.03). In subgroups of dementia, we observed no substantial association with Alzheimer's disease (adjusted hazard ratio = 0.92, 95% CI 0.88 0.95) or other dementias (adjusted hazard ratio = 0.98, 95% CI 0.95-1.01). However, patients with MI had an increased risk of vascular dementia (adjusted hazard ratio = 1.35, 95% CI 1.28-1.43). ?In conclusion, we found that preceding depression was associated with moderately increased mortality after MI, and that ?was associated with an increased risk of stroke and vascular dementia, but not dementia from other causes. PMID- 29619930 TI - Neurological and psychiatric comorbidity in patients with heart failure: risk and prognosis. AB - Heart failure is a complex clinical syndrome and one of the leading causes of morbidity and mortality with a prevalence of 1%-2% of the adult population. The prognosis is poor with a 5-year mortality rate of 50%, which partly can be attributed to the presence of concomitant comorbidity, including neurological and psychiatric comorbidities. However, the prognostic impact of depression and the role of heart failure as a risk factor for dementia and stroke are not fully understood.? Denmark is well-known for its unique health registries. The DNPR has been widely used in cardiovascular research in the past decades, although the accuracy of several diseases and interventions is largely unknown.? This thesis explored the PPV of a range of cardiovascular diagnoses including heart failure (study I) and cardiac interventions (study II) recorded in the DNPR. In addition, we aimed to provide new insights into the impact of depression on mortality in heart failure patients with reduced and preserved left ventricular ejection fraction (study III). Finally, we studied the association between heart failure and subsequent short-term and long-term risks of dementia (study IV) and ischemic and hemorrhagic stroke (study V).? In studies I-II, we identified 3386 patients with various cardiovascular diagnoses or cardiac interventions during 2010-2012 using the DNPR. Patient medical charts served as the gold standard for diagnosis confirmation and were adjudicated by physicians. We found a high PPV (>=90%) for the majority of the patients while the PPV was somewhat lower for myocarditis, heart failure, and recurrent events. ?In study III, we analyzed 205,719 patients with incident heart failure during 1995-2014. A history of depression was associated with 15%-20% increased mortality rate in patients with LVEF <=35% and when defining depression based on a combination of ?redeemed antidepressant prescription and hospital-based diagnoses, but not when depression was ascertained based solely on diagnoses. ?In study IV, we included 324,418 heart failure patients and a general population comparison cohort comprising 1,622,079 individuals matched for age and sex during 1980-2012. The heart failure cohort had a 21% increased rate of all-cause dementia, mainly driven by increased hazards of vascular dementia and other dementia, whereas heart failure was not associated with Alzheimer's disease. ?In study V, we identified and followed 289,353 patients with heart failure and 1,446,765 individuals from the general population matched for age, sex, and calendar year. Heart failure patients had a five-fold elevated rate of ischemic stroke, two-fold increased rate of ICH, and a four-fold increased rate of SAH within 30 days. These associations receded towards the null but persisted over 30 years. ?In conclusion, the DNPR contains data on several cardiovascular diagnoses and cardiac interventions recorded with high PPVs. Our data also suggest that a history of depression is an adverse prognostic factor for death in patients with heart failure and low LVEF. Finally, heart failure emerged as a risk factor for all-cause dementia as well as for both ischemic and hemorrhagic stroke. PMID- 29619931 TI - Approaches to radiotherapy in metastatic spinal cord compression. AB - Metastatic spinal cord compression is caused by the progression of metastatic lesions within the vicinity of the spinal cord. The consequences are very severe with loss of neurological function and severe pain. The standard treatment is surgical intervention followed by radiotherapy or radiotherapy alone. However, the majority of patients are treated with radiotherapy only due to contraindications to surgery and technical inoperability. Stereotactic body radiotherapy is a technology to deliver higher radiation dose to the radiotherapy target with the use of spatial coordinates. This modality has shown positive results in treating lesions in brain and lungs. Hence, it could prove beneficial in metastatic spinal cord compression. We designed and planned a trial to investigate this method in patients with metastatic spinal cord compression. The method was usable but the trial was stopped prematurely due to low accrual that made comparison with surgery impossible. Low accrual is a known problem for trials evaluating new approaches in radiotherapy. Target definition in radiotherapy of metastatic spinal cord compression is defined by patient history, examination and imaging. Functional imaging could provide information to guide target definition with the sparring of normal tissue e.g. spinal cord and hematopoietic tissue of the bone marrow. In future trials this may be used for dose escalation of spinal metastases. The trial showed that PET/MRI was feasible in this group of patients but did not change the radiotherapy target in the included patients. Neurological outcome is similar irrespective of course length and therefore single fraction radiotherapy is recommended for the majority of patients. In-field recurrence is a risk factor of both short and long fractionation schemes and re-irradiation have the potential risk of radiation induced myelopathy. In a retrospective study of re-irradiation, we investigated the incidence of radiation-induced myelopathy. In our study population, we found a higher number of patients experiencing vertebral fractures than the number of patient developing myelopathy. Patients with diabetes had an increased risk of toxicity compared to the remaining patients. Stereotactic body radiotherapy is effective in treating metastatic spinal cord compression but the efficacy cannot be determined due low accrual. The use of PET/MRI did not spare normal tissue in radiotherapy planning of spinal metastases. The incidence of toxicity after re irradiation of the spine and spinal cord was low. For patients with in-field recurrence, re-irradiation is safe and has a low incidence of toxicity. PMID- 29619932 TI - Mortality and morbidity in patients with osteogenesis imperfecta in Denmark. AB - Ostegenesis imperfecta (OI) is a hereditary disease of the connective tissue caused by mutations to, mainly, the genes that are involved in the biosynthesis of collagen type 1. Patients are grouped according to clinical severity and mode of inheritance according to Sillence's classification (originally 1979, updated 2014). According to our data, the population prevalence of OI in Denmark was 10.3 per 100,000, with 575 patients registered with an OI diagnosis in the National Patient Register and alive at the end of 2012 out of a total population of 5,602,628 persons. Hallmarks of the disease are multiple fractures, blue sclera and varying degrees of bone deformities. Collagen type 1 is the most abundant collagen in the body and is an important part of the structure and function of the heart and lungs, the skeleton and many other organs. We hypothesize that patients with OI will have increased prevalence and risk of fractures throughout life, lower bone mineral density (BMD), impaired bone microstructure and bone geometry and increased risk of cardiovascular diseasesthus increased risk of all cause mortality compared to the general population. ?This thesis is a systematic search and narrative review covering the four main areas of interest of the PhD scholarship (risk and causes of death, fracture rates, bone mineral density, geometry and -microstructure and cardiovascular diseases in OI). In addition to the review the thesis include the following four studies:? 1) Study 1 aimed to investigate the main causes of death and the risk of premature death in patients with OI in Denmark. We used a nationwide, registry-based, cohort study design, and included all patients registered in the National Patient Register with an OI diagnosis and a matched reference population randomly selected from the Danish Civil Service Register (matched 5:1, on gender and month and year of birth for each OI patient). We identified 687 patients with OI (25,615 person years at risk) and a reference population of 3,435 (132,131 person years at risk). One hundred and twelve patients with OI and 257 persons in the reference population died during the observation period from 1977 to 2013. The all-cause mortality hazard ratio between the OI cohort and the reference population was 2.90. The median survival time for men with OI was 72.4 years, compared to 81.9 in the reference population. The median survival time for women with OI was 77.4 years, compared to 84.5 years in the reference population. Patients with OI had a higher risk of death from respiratory diseases, gastrointestinal diseases and trauma.? Conclusion: The all-cause hazard ratio for premature death in OI was 2.9 compared to the reference population. There was an increased risk of death due to respiratory diseases, gastrointestinal diseases and death following trauma. ?2) Study 2 aimed to compare the fracture rates across the lifespan of patients with OI with that of the general population. Using a nationwide, registry-based, cohort study design, we counted all fractures registered from 1995 in the National Patient Register. The study included the same population as in study 1, but patients who died before 1995 were excluded. We identified 644 patients? ?(55.6% females) in the OI cohort through the Danish National Patient Register and 3,361 persons (55.2% females), randomly selected from the Civil Registry System. A total of 416 patients with OI experienced a total of 1,566 fractures during the observation period of median 17.9 years (IQ-range: 12.4-18.0), adding up to 10,137 person years. In comparison, 709 persons in the reference population experienced a total of 1,018 fractures during follow-up. Both male and female patients with OI had an increased fracture rate throughout their life. The fracture rate ratio for participants aged 0-19 years was 10.7, for participants aged 20-54 years 17.2, and for participants aged 55 years and over 4.1 when compared to the reference population. The highest fracture rate was seen in males with OI aged 0-19 years (257 fractures per 1,000 person years). The fractures appear to follow the same pattern as in the general population, with a peak during the toddler and adolescent years (IR (incidence rates) 233.9 per 1,000 person years), fewer fractures during adulthood (IR 84.5 per 1000 person years), and increased fracture rate in older women (IR 111.9 per 1,000 person years).? Conclusion: Patients with OI have increased risk of fractures throughout life compared to the general population. The relative risk of fractures generally declines with age, however, increases in older women. ?3) Study 3 aimed to evaluate the bone mineral density (BMD) and bone geometry and -microarchitecture in patients with OI type I using a cross-sectional study design and evaluating the participants using HRpQCT. The study included 39 patients with OI type I, and 39 healthy age and gender matched non-OI individuals. The patients were shorter than the reference group (159 +/- 10 cm versus 170 +/- 9 cm, p < 0.001), but had similar body weight. In patients with OI, areal bone mineral density (aBMD) was 8% lower at the hip (p < 0.05) and 13% lower at the spine (p < 0.001) compared with the reference group. The trabecular volumetric bone mineral density (vBMD) was 28% lower in radius (p < 0.001) and 38% lower in tibia (p < 0.001) in patients with OI compared with the reference group. At radius, total bone area was 5% lower in OI patients than in controls (p < 0.05). In the tibia, cortical bone area was 18% lower in patients with OI (p < 0.001). In both radius and tibia the number of trabeculae was lower in patients compared to the reference group (35% and 38%, respectively, p < 0.001 at both sites). Furthermore, trabecular spacing was 55% higher in OI patients in both tibia and radius (p < 0.001 at both sites) when compared with reference group.? Conclusion: Patients with type I OI have lower aBMD, vBMD, bone area, and trabecular number when compared with healthy age- and gender-matched individuals. ?4) Study 4 aimed to evaluate the risk of valvulopathies, atrial arrhythmias, heart failure and vascular dissections in patients with OI using a nationwide, registry-based, cohort study design. The study included the same population as in study 1. As patients with OI have increased risk of premature death, the risk of cardiovascular diseases is biased by the competing risk of death. We corrected for this increased risk by using a competing risk regression model. We found that the OI population had increased relative risk of mitral valve regurgitation (sub hazard ratio (SHR) 6.3), aortic valve regurgitation (SHR 4.5), atrial fibrillation/flutters (SHR 1.7) and heart failure (SHR 2.3) compared to the reference population. There was no difference in the risk of arterial aneurisms or arterial dissections.? Conclusion: Patients with OI have increased risk of valvulopathies, atrial arrhythmias and heart failure when compared to the reference population, even after adjusting for risk factors for these car-diovascular diseases - indicating that the quantitative or qualitative defects of collagen type 1 synthesis seen in OI influence the risk of these cardiovascular diseases in patients with OI. PMID- 29619933 TI - Monitoring ovarian cancer patients during chemotherapy and follow-up with the serum tumor marker CA125. AB - Cancer antigen 125 (CA125) is frequently used in the routine monitoring of patients with epithelial ovarian cancer (EOC). The potential benefit is based on the assumption that changes in serial concentrations may provide early and reliable information on tumor growth expediting an early and potentially effective treatment. However, it has remained a challenge to interpret increments in concentrations that correlate with increasing tumor burden in the individual patient. It has been hypothesized that CA125 assessment criteria taking the random variation (analytical and biological) into account may have better accuracy and lead-time potential than criteria based only on an arbitrary percentage of increase.? The aims of the current PhD project were to i) identify different types of assessment criteria intended to interpret CA125 increments, ii) compare their ability to signal tumor growth, and iii) estimate the time interval between marker progression and clinical progression (lead-time). ?Study 1 was a systematic review of the literature identifying 21 relevant original articles reporting on 37 different assessment criteria to interpret serial CA125 concentrations. Study 2 was a preclinical phase I trial investigating the monitoring potential of seven selected criteria in a computer-based simulation model under standardized conditions. Study 3 was a clinical phase II trial comparing the performances of the seven criteria among 189 patients with EOC stage IC-IV during first-line chemotherapy and the subsequent follow-up period.? Study 1 reported that the median sensitivity of the investigated criteria for recurrence was 57% (range 33%-95%) during primary therapy and 85% (range 62%-93%) during follow-up. The calculated false positive (FP) and false negative (FN) rates, respectively, were in median 1% (range 0%-13%) and 44% (range 5%-67%) during primary therapy and 9% (range 0%-33%) and 15% (range 7%-38%) during follow up. Most of the reports were heterogeneous in terms of study design and format of presentation. Study 2 reported that for increments starting from baseline concentrations >=cut-off, the best performing criterion in terms of low number of FP signals was based on a confirmed increment >=2.5 times the nadir concentration. For increments starting from baseline concentrations <=cut-off, the best performing criterion, also in terms of low number of FP signals, was based on a confirmed increment from <=cut-off to >2 times the cut-off. Accordingly, the best performing criteria in terms of low number of FP events were based on an arbitrary required percentage of change without defining the random variation. Study 3 reported that the accuracy of the seven criteria observed during first-line chemotherapy and follow-up among all histological tumor types and serous tumors only was similar with overlapping 95% confidence intervals. The sensitivities for detecting CA125 increments ranged from 30% to 55%. The FP rates ranged from 0% to 17%; however, the FN rates ranged from 45% to 70%. The median lead-times ranged from 26 days to 87 days. The performances of the CA125 assessment criteria showed low sensitivities and low ability to exclude tumor growth. The chance of developing clinical progression following CA125 progression was high (range of positive predictive value 90%-100%); however, the lead-times were short among several patients. Thus, study 3 questioned the clinical utility of CA125 monitoring. ?Overall, the PhD study showed, that the different CA125 assessment criteria basically provided similar results thus rejecting the hypothesis that criteria based on calculating the random variation would outperform criteria based on a simple percentage of change. The simulated data proved useful for a preclinical evaluation of CA125 assessment criteria. The results suggested that regardless of the approach, fine-tuning of the assessment criteria did not seem to improve the monitoring performance of CA125 probably indicating that CA125 used as a tumor marker for monitoring has inherent limitations in terms of accuracy. Supplementary markers and alternative assessment criteria are needed. PMID- 29619934 TI - Assessing synovitis with conventional static and dynamic contrast-enhanced magnetic resonance imaging in knee osteoarthritis. AB - Knee osteoarthritis (KOA) is one of the most common causes of physical disability in the elderly population. With an increasing ageing and obese population, the prevalence of KOA is expected to rise substantially. The needs for a better understanding of the disease and tools that can predict the course of the disease, for example following treatment, are therefore imperative. ??Inflammation has over the last years been recognised as an important factor for both the symptomatology and disease course in KOA. Synovitis, inflammation of the synovium, is the hallmark of intra-articular inflammation and has been associated with pain, symptoms and disease progression. Synovitis can be visualised on conventional static MRI. However, the addition of a dynamic contrast-enhanced (DCE) MRI-sequence enables the assessment of the synovium both in regards of its morphology and perfusion. Studies in both KOA and rheumatoid arthritis have shown that DCE-MRI measures of synovitis are more sensitive than conventional static MRI in regards of microscopic synovitis and patient-reported outcome measures (PROMs).?? The aims of this PhD project were to characterise synovitis in KOA with conventional static and DCE MRI in regards of histology (study I), its association with PROMs (studies II-III) and changes following a symptoms improving intervention (study III). We found that DCE-MRI-measures of synovitis seem to be superior to conventional static MRI in their association with histological synovitis (study I) and pain (study II) in a cross-sectional setting. However, the use of DCE-MRI over conventional static CE-MRI cannot be justified when assessing the long-term changes in synovitis following an intervention with intra-articular corticosteroids/placebo and exercise (study III). ??Evidence is mounting that KOA is constituted of different phenotypes. There is an urgent need to define these in order to improve and individualise treatment and management. It is essential to gain a better understanding of the different pro-cesses taking place in KOA, on an individual level and in the different stages of the disease. DCE-MRI may very well be a useful tool in facing these challenges especially in regards of the role of perfusion and inflammation in KOA and osteoarthri-tis in general. PMID- 29619935 TI - Tourette syndrome in a longitudinal perspective. Clinical course of tics and comorbidities, coexisting psychopathologies, phenotypes and predictors. AB - INTRODUCTION: Tourette syndrome (TS) is a childhood onset neurodevelopmental disorder characterised by motor and vocal tics and frequent associated comorbidities. The developmental trajectory of tic shows tic-onset in the age of 4-6, peak in the age of 10-12 and decline during adolescence, although only few and small longitudinal studies form the basis of this evidence. Recent studies suggest that comorbid obsessive-compulsive disorder (OCD), attention deficit hyperactivity disorder (ADHD) and coexisting psychopathologies tend to persist and become more dominant in adolescence. This large prospective follow-up study want to examine the clinical course of TS: tic and comorbidities during adolescence, the prevalence of coexisting psychopathologies, the tic-related impairment, development in phenotype expression and find predictors for the expected course of TS. ?Method: This study is examining a large clinical cohort recruited at the Danish National Tourette Clinic during the period 2005-2007 and 2011-2013. At baseline, 314 participants aged 5-19 years were included and at follow-up 6 years later 227 participated, aged 11-26. All participants were uniformly clinically examined at basis and follow-up with a clinical interview and validated measurements to assess comorbidities. The Yale Global Tic Severity Scale was used to asses tic severity and tic-related impairment. At follow-up a cross-sectional diagnostic evaluation was made with the Development and Well Being Assessment to assess coexisting psychopathologies.? Results: A significant decline in tic and the most frequent comorbidities OCD and ADHD was found although some variation existed and some subclinical and partial remissions persisted. Tic-related impairment was not reflected in the tic-decline as expected but influenced by several parameters. The phenotype expression was found to be dynamic but overall changed toward TS without comorbidities. Several predictors were found to predict the clinical course of TS in adolescence and early adulthood. Childhood tics, OCD and ADHD severity were the strongest predictors for future symptoms of the respectively diagnoses. Comorbidities and coexisting psychopathologies were found in 63% at follow-up, whereas 37% had pure TS.? Conclusion: The clinical course of TS during adolescence was confirmed, with solid evidence, with decline in tics, OCD and ADHD severity. We provide evidence of considerable coexisting psychopathologies requiring clinical support and partial remissions and subthreshold symptoms requiring monitoring and clinical guidance to assist the young adults in promoting a healthy transition into early adulthood. Furthermore we provide predictors for the clinical course of TS to be used in the preventive efforts, early intervention and allocation of resources improving quality of life for the children and their families. PMID- 29619936 TI - Intravenous iron treatment in the puerperium. AB - Iron deficiency and anaemia in the puerperium are associated with several important clinical consequences, most prominently physical fatigue. Current treatment practice with oral iron supplementation is associated with gastrointestinal side-effects and subsequent poor compliance. Red blood cell transfusion is also widely used to treat severe postpartum anaemia, though accumulating evidence questions its risk-benefit ratio. Intravenous iron has in previous studies been associated with fast improvement of haemoglobin and iron biochemical markers in the treatment of postpartum anaemia, but there is a lack of studies on patient reported outcomes.? The thesis is based on three studies of intravenous iron (Monofer, iron isomaltoside) as an alternative to current treatment practice in postpartum iron deficiency and anaemia.?The first study is a randomised controlled trial comparing a high single-dose iron infusion with oral iron in women after postpartum haemorrhage without severe anaemia. The primary outcome was the aggregated change in physical fatigue within 12 weeks postpartum. We found a difference that was statistically significant, but less than the consensus-based and predefined minimal clinically relevant level. Across visits, particularly in the first weeks postpartum, we found statistically significant differences in fatigue and depression scores, all in favour of intravenous iron. We confirmed previous findings of a fast haematopoietic response and prompt replenishment of iron stores that persisted throughout the 12 weeks of follow-up. ?The second study, a randomised controlled pilot study, tested feasibility and exploratory outcomes of a high single-dose iron infusion compared with red blood cell transfusion for the treatment of severe postpartum anaemia. We found that randomisation could be feasible with some adjustments for a future study design. The difference in biochemical markers was larger than the patient-reported outcomes in the first week. A larger trial is needed to determine whether a high single-dose iron infusion is non-inferior to red blood cell transfusion in severe postpartum anaemia. ?The third study compared iron concentration in breast milk in a randomised sample of women receiving high single-dose iron infusion or oral iron. A high single-dose iron infusion lead to a transient increase in the iron concentration in breast milk, which remained within the normal range. ?In conclusion, iron isomaltoside seems to be associated with improved patient-reported outcomes compared to oral iron treatment, and in severe postpartum anaemia intravenous iron seems promising as an alternative to red blood cell transfusion. PMID- 29619937 TI - The impact of surgery on quality of life, esophageal motility, and tracheal anatomy and airflow in patients with benign nodular goiter. AB - Surgery - is it any good for goiter? In patients with goiter the benefits of thyroid surgery have previously rarely been investigated, as only few alternatives existed. However, the increasing evidence of the advantages with non surgical substitutes with lower costs and preferable risk profiles prompted us to investi-gate the evidence base for thyroid surgery thoroughly. This thesis consists of three published studies investigating the impact of thyroidectomy on: 1) changes in disease-specific quality of life, 2) swallowing symptoms and esophageal motility, and 3) tracheal anatomy and airflow, in a cohort of patients with benign nodular goiter. PMID- 29619938 TI - Sunscreen use at Danish beaches and how to improve coverage. AB - Exposure to ultraviolet radiation (UVR) from the sun is the main risk factor for development of skin cancer. The incidence of skin cancer in Denmark and worldwide is high and increasing. The overall aim was to achieve basic knowledge about sun protection with sunscreen among beachgoers in Denmark. Other aims were to establish a method to investigate sunscreen distribution on the body and to test two approaches to optimize the used amount and body distribution of sunscreen. Furthermore, time and duration of a beach visit and use of protective clothes among beachgoers were determined to investigate the risk the beachgoers expose themselves to. ?Of the counted number of beachgoers 46% were at the beach between noon and 3 p.m. where the UVR is strongest and a mean beach visit lasted 142 minutes. In the middle of the day 90% of the beachgoers wore swimwear and sunscreen application was their only possible sun protection. More beachgoers wore protective clothes in the morning and late afternoon.? Seventy-eight percent of women wearing swimwear reported sunscreen use at the beach and 49% of men reported sunscreen use. They used a sunscreen with a median sun protection factor (SPF) of 20 (interquartile range: 15-30). The effective SPF probably decreases exponentially with decreasing quantity of sunscreen applied. Users at the beach applied a mean quantity of 0.57 mg/cm2 (standard deviation 0.31 mg/cm2) to their sun accessible skin, i.e. skin not covered by swimwear or scalp hair, providing a mean effective SPF of 2.3. Both SPF chosen and quantity applied were independent of sex. ?Two approaches to increase sunscreen use was tested; the rule of thumb: "Fill up a handful of sunscreen and spread it all over your body", and a recommendation to apply sunscreen two consecutive times. Both strategies increased the total amount of sunscreen significantly. The instruction: "Fill up a handful of sunscreen and spread it all over your body" increased the median quantity of sunscreen to 0.87 mg/cm2 whereas double application increased the quantity to 1.10 mg/cm2. Sunscreen with a label SPF of 20 applied in a quantity of 0.87 mg/cm2 provided an effective SPF of 3.7. Applied in a quantity of 1.10 mg/cm2 provided an effective SPF of 5.2. ?A method based on a link between darkness of skin in black light illumination and the quantity of sunscreen applied was established and made it possible to investigate the distribution of sunscreen on the body. Sunscreen was very unevenly applied both after application of a handful and after double application. The face and the front of the trunk were generally well covered whereas the back of the trunk was poorly covered. After a single application, either as at the beach or with the use of a handful of sunscreen, about one fifth of the total accessible skin was left without sunscreen. After double application only about a 9% of the accessible skin was left uncovered. As especially missed areas are at risk of getting sunburned double application seems to be the better of the two tested strategies to improve coverage. PMID- 29619939 TI - Commercial plant extracts may act as antioxidants or pro-oxidants in cosmetic emulsions based on argan oil. AB - Cosmetic emulsions containing plant extracts should be tested in a range of temperatures from 5 degrees C to 40 degrees C to be sure that they will be stable during general use by consumers and that plant extracts used as antioxidants do not accelerate oxidative degradation of their oil base. The oxidative stability of argan oil-in-water emulsions containing 1% and 5% commercial acerola, willow, and rose extracts [or 0.01% butylhydroxytoluene (BHT)], stored at 5 degrees C and 20 degrees C for 6 months and at 40 degrees C for 4 weeks, was monitored by the determination of peroxide content. The antioxidant or pro-oxidant activities of extracts or BHT in emulsions were expressed as the protection factor (PF) and inhibition of peroxide formation (Ip). At the end of storage, 5% willow, 0.01% BHT, 1% willow, and 5% acerola were the most protective for emulsions stored at 5 degrees C. At 20 degrees C, the most effective was 0.01% BHT, 5% rose, and 5% acerola. At 40 degrees C, inhibition of peroxide formation calculated for 1% rose, 5% acerola, and 0.01 % BHT was similar. Altogether, the results show that some plant extracts, depending on storage conditions, may act as pro-oxidants, whereas the others can be applied as natural antioxidants instead of synthetic BHT. PMID- 29619940 TI - A comparative study of the rheological and sensory properties of a petroleum-free and a petroleum-based cosmetic cream. AB - A petroleum-free skin cream was developed using food-grade ingredients. The rheological and sensorial properties of this petroleum-free skin cream were compared to a commercially available petroleum-based skin cream. Specifically, large-amplitude oscillatory shear (LAOS) characterization of the two skin creams was performed. The petroleum-free skin cream showed similar linear and nonlinear viscoelastic rheological properties, comparable skin hydration functions, and consumer acceptance as the commercially available skin cream. A schematic diagram aiming to correlate the physical and sensorial properties of skin cream was also proposed at the end of the work. Results of this work could provide the cosmetic industry necessary information for the development of alternatives for petroleum based skin creams. PMID- 29619941 TI - Model-based analysis of the torsional loss modulus in human hair and of the effects of cosmetic processing. AB - Torsional analysis of single human hairs is especially suited to determine the properties of the cuticle and its changes through cosmetic processing. The two primary parameters, which are obtained by free torsional oscillation using the torsional pendulum method, are storage (G') and loss modulus (G"). Based on previous work on G', the current investigation focuses on G". The results show an increase of G" with a drop of G' and vice versa, as is expected for a viscoelastic material well below its glass transition. The overall power of G" to discriminate between samples is quite low. This is attributed to the systematic decrease of the parameter values with increasing fiber diameter, with a pronounced correlation between G" and G'. Analyzing this effect on the basis of a core/shell model for the cortex/cuticle structure of hair by nonlinear regression leads to estimates for the loss moduli of cortex (G"co) and cuticle (G"cu). Although the values for G"co turn out to be physically not plausible, due to limitations of the applied model, those for G"cu are considered as generally realistic against relevant literature values. Significant differences between the loss moduli of the cuticle for the different samples provide insight into changes of the torsional energy loss due to the cosmetic processes and products, contributing toward a consistent view of torsional energy storage and loss, namely, in the cuticle of hair. PMID- 29619942 TI - Evaluation of molecules or extracts modulating seborrhea and its consequences, using normal human culture of sebocytes and keratinocytes, skin explants models and in vivo methods: a case study. AB - Skin produces sebum through sebocytes. Hyper-seborrhea creates conditions for the development of inflamed cutaneous alterations through bacteria colonization triggering dead cell accumulation and pro-inflammatory mediator release. Study of sebum production, its modulation, and its consequences requires complementary in vitro models in order to evaluate the effect of molecules on cell metabolisms. Clinical studies need to be performed to confirm in vitro results. Effects of phenylpropanoids, obtained by elicitation and purification from plant cell culture of Syringa vulgaris (CCSV), were studied on sebocytes, keratinocytes, and explants, all derived from normal human skins. Normal human sebocytes (NHSs) expressed markers such as cytokeratin-7, cytokeratin-4, and perilipin-2 (PLIN-2) (1); the latter being colocalized with lipid droplets. Lipid droplets clearly appeared and their size increased rapidly when lipogenic agents were used. NHS, normal human keratinocytes (NHK), and explants reacted to presence of bacterial fragments which trigger pre-inflammatory mediator release. CCSV reduced lipid storage and release of pre-inflammatory mediators in NHS, NHK and explants. CCSV also reduced P. acnes growth and triggered beta-defensin-2 and cathelicidin synthesis by NHS, two natural antimicrobial peptides. On volunteers, sebum production, inflamed blemishes, and retentional lesions were significantly reduced after 1 month treatment with CCSV. PMID- 29619943 TI - Dementia in the UK: preparing the NHS for new treatments. PMID- 29619944 TI - Good news for the world's newest nation. PMID- 29619945 TI - Cybersecurity and patient protection. PMID- 29619946 TI - Transparency of retracting and replacing articles. PMID- 29619947 TI - Offline: The Palestinian health predicament worsens. PMID- 29619948 TI - Gairdner Awards 2018 honour GBD studies. PMID- 29619949 TI - What does the GDPR mean for the medical community? PMID- 29619951 TI - Rethinking cures in Jesse Ball's A Cure for Suicide. PMID- 29619950 TI - Jan Egeland: humanitarian who gives a voice to the displaced. PMID- 29619952 TI - Bridging magic and medicine. PMID- 29619953 TI - Quantification of the effect of terrorism on the HIV response in Nigeria. PMID- 29619954 TI - Liver disease mortality trends: a response to the editor. PMID- 29619955 TI - Did Cro-Magnon 1 have neurofibromatosis type 1? PMID- 29619956 TI - Artificial intelligence in health care: enabling informed care. PMID- 29619957 TI - In support of UNRWA appeal for health and dignity of Palestinian refugees. PMID- 29619958 TI - Type 2 diabetes. PMID- 29619959 TI - Type 2 diabetes. PMID- 29619960 TI - Type 2 diabetes - Authors' reply. PMID- 29619961 TI - Genomics Reloaded: Rise of the Expression Profiles. PMID- 29619962 TI - A Prospective 4pi Radiation Therapy Clinical Study in Recurrent High-Grade Glioma Patients. AB - PURPOSE: To evaluate the feasibility, safety, dosimetric benefits, delivery efficiency, and patient comfort in the clinical implementation of 4pi radiation therapy. METHODS AND MATERIALS: Eleven patients with recurrent high-grade glioma were recruited for the trial. 4pi plans integrating beam orientation and fluence map optimization were created using an in-house column-generation algorithm. The collision-free beam solution space throughout the 4pi steradian was determined using a computer-aided-design model of the Varian TrueBeam system and a human subject. Twenty beams were optimized for each case and imported into Eclipse for intensity modulated radiation therapy planning. Beam orientations with neighboring couch kicks were merged for increased delivery efficiency, generating plans with an average of 16 beam orientations. Volumetric modulated arc therapy (VMAT) plans with 3-4 arcs were also generated for each case, and the plan achieving superior dosimetric quality was selected for treatment. Patient comfort was surveyed after every fraction. Multiple 2-dimensional X-ray images were obtained to measure intrafractional motion. RESULTS: Of 11 patients, 9 were treated with 4pi. Mean and maximum organ at risk doses were equal or significantly lower (P < .05) with 4pi than with VMAT. Particularly substantial dose reduction of 2.92 Gy in the average accumulated brainstem maximum dose enabled treatments that would otherwise not satisfy safe dose constraints with VMAT. One patient was not treated because neither plan met the dosimetric criteria. The other was treated with VMAT owing to comparable dosimetry resulting from a planning target volume located in a separate co-plane superior to organs at risk. Treatments were well tolerated, with an average patient comfort score of 8.6/10. Intrafractional motion was <1.5 mm for all delivered fractions, and the average delivery time was 34.1 minutes. CONCLUSIONS: The feasibility, safety, dosimetric benefits, delivery efficiency, and patient comfort of 4pi radiation therapy have been clinically demonstrated with a prospective clinical trial. The results elucidate the potential and challenges of wider clinical implementations. PMID- 29619964 TI - Stereotactic Ablative Radiation Therapy Versus Surgery in Early Lung Cancer: A Meta-analysis of Propensity Score Studies. AB - PURPOSE: As no completed randomized trials of surgery versus stereotactic ablative radiation therapy (SABR) in patients with early-stage non-small cell lung cancer are available, numerous propensity score studies have attempted to mimic the setting of clinical trials using nonrandomized data. We performed a meta-analysis of propensity score studies comparing SABR and surgery. METHODS AND MATERIALS: The MEDLINE and Embase databases were queried up to December 2016. Two authors independently reviewed the records for inclusion and extracted outcome measures. The study was conducted according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) and MOOSE (Meta-analysis of Observational Studies in Epidemiology) guidelines. The primary meta-analysis and secondary analyses were carried out using R (version 3.3.2) at a significance level of .05. RESULTS: Sixteen studies were included in the meta-analysis. Overall survival favored surgery (hazard ratio for SABR vs surgery, 1.48 [95% confidence interval, 1.26-1.72]; I2 = 80.5%). Lung cancer-specific survival was not significantly different between SABR and surgery (hazard ratio, 1.17 [95% confidence interval, 0.92-1.50]; I2 = 18.6%). On stratification, overall survival favored both lobectomy and sublobar resection over SABR, although lung cancer specific survival was again not significantly different. On secondary analysis, the lymph node upstaging rate was 15.6% following surgery, with 11.4% of patients receiving chemotherapy. The propensity score-matching caliper distance and first author specialty were found to be associated with survival endpoints on regression. CONCLUSIONS: For patients with early-stage non-small cell lung cancer who are eligible for either treatment, better overall survival was seen after surgery compared with SABR. However, lung cancer-specific survival was similar for both treatments. Prospective clinical trials are preferred to propensity analyses in evaluating the nature of non-cancer-related death after SABR. PMID- 29619963 TI - National Cancer Institute Workshop on Proton Therapy for Children: Considerations Regarding Brainstem Injury. AB - PURPOSE: Proton therapy can allow for superior avoidance of normal tissues. A widespread consensus has been reached that proton therapy should be used for patients with curable pediatric brain tumor to avoid critical central nervous system structures. Brainstem necrosis is a potentially devastating, but rare, complication of radiation. Recent reports of brainstem necrosis after proton therapy have raised concerns over the potential biological differences among radiation modalities. We have summarized findings from the National Cancer Institute Workshop on Proton Therapy for Children convened in May 2016 to examine brainstem injury. METHODS AND MATERIALS: Twenty-seven physicians, physicists, and researchers from 17 institutions with expertise met to discuss this issue. The definition of brainstem injury, imaging of this entity, clinical experience with photons and photons, and potential biological differences among these radiation modalities were thoroughly discussed and reviewed. The 3 largest US pediatric proton therapy centers collectively summarized the incidence of symptomatic brainstem injury and physics details (planning, dosimetry, delivery) for 671 children with focal posterior fossa tumors treated with protons from 2006 to 2016. RESULTS: The average rate of symptomatic brainstem toxicity from the 3 largest US pediatric proton centers was 2.38%. The actuarial rate of grade >=2 brainstem toxicity was successfully reduced from 12.7% to 0% at 1 center after adopting modified radiation guidelines. Guidelines for treatment planning and current consensus brainstem constraints for proton therapy are presented. The current knowledge regarding linear energy transfer (LET) and its relationship to relative biological effectiveness (RBE) are defined. We review the current state of LET-based planning. CONCLUSIONS: Brainstem injury is a rare complication of radiation therapy for both photons and protons. Substantial dosimetric data have been collected for brainstem injury after proton therapy, and established guidelines to allow for safe delivery of proton radiation have been defined. Increased capability exists to incorporate LET optimization; however, further research is needed to fully explore the capabilities of LET- and RBE-based planning. PMID- 29619967 TI - In Regard to Seibert et al. PMID- 29619966 TI - Long-Term Outcomes and Prognostic Factors After Pencil-Beam Scanning Proton Radiation Therapy for Spinal Chordomas: A Large, Single-Institution Cohort. AB - PURPOSE: To evaluate the efficacy and safety of high-dose pencil-beam scanning proton therapy (PBS-PT) in the adjuvant treatment of spinal chordomas. METHODS AND MATERIALS: Between 1997 and 2015, 100 patients with spinal chordomas (median age, 56 years; range, 25-81 years) were treated with adjuvant PBS-PT at the Paul Scherrer Institute: cervical (n = 46), thoracic (n = 4), lumbar (n = 12), and sacral (n = 38). The majority (88%) received PBS-PT alone rather than combined photon-proton therapy. The median radiation therapy dose prescribed was 74 Gy (relative biological effectiveness [RBE]) (range, 59.4-77 Gy [RBE]). Thirty-nine patients (39%) had undergone surgical stabilization, primarily with titanium hardware, before radiation therapy. RESULTS: With a median follow-up of 65 months (range, 13-175 months), 5-year local control, disease control, and overall survival rates were 63% (95% confidence interval [CI] 57.7-68.7%; median, 103 months), 57% (95% CI 50.9-62.1%; median, 82 months), and 81% (95% CI 76.8-85.6%; median, 157 months), respectively. On univariate and multivariate analyses, the presence of surgical stabilization was highly prognostic for worsened outcomes. Multivariate analysis also revealed the extent of treatment volumes and presence of gross residual disease to be important in predicting outcomes. High-grade (grade >=3) toxicities were rare in both the acute (8%) and late (6%) settings. CONCLUSION: For spinal chordomas, PBS-PT remains a highly effective and safe method for delivery of dose-escalated adjuvant radiation therapy. The presence of metallic surgical stabilization prognosticates for worsened outcomes. Further investigation is warranted to characterize ideal treatment volumes and effect of surgical stabilization on therapy for these challenging tumors. PMID- 29619965 TI - Impact of Human Immunodeficiency Virus Infection on Survival and Acute Toxicities From Chemoradiation Therapy for Cervical Cancer Patients in a Limited-Resource Setting. AB - PURPOSE: To prospectively compare survival between human immunodeficiency virus (HIV)-infected versus HIV-uninfected cervical cancer patients who initiated curative chemoradiation therapy (CRT) in a limited-resource setting. METHODS AND MATERIALS: Women with locally advanced cervical cancer with or without HIV infection initiating radical CRT in Botswana were enrolled in a prospective, observational, cohort study from July 2013 through January 2015. RESULTS: Of 182 women treated for cervical cancer during the study period, 143 women initiating curative CRT were included in the study. Eighty-five percent of the participants (122 of 143) had stage II/III cervical cancer, and 67% (96 of 143) were HIV infected. All HIV-infected patients were receiving antiretroviral therapy (ART) at the time of curative cervical cancer treatment initiation. We found no difference in toxicities between HIV-infected and HIV-uninfected women. The 2 year overall survival (OS) rates were 65% for HIV-infected women (95% confidence interval [CI] 54%-74%) and 66% for HIV-uninfected women (95% CI 49%-79%) (P = .70). Factors associated with better 2-year OS on multivariate analyses included baseline hemoglobin >10 g/dL (hazard ratio [HR] 0.37, 95% CI 0.19-0.72, P = .003), total radiation dose >=75 Gy (HR 0.52, 95% CI 0.27-0.97, P = .04), and age <40 years versus 40-59 years (HR 2.17, 95% CI 1.05-4.47, P = .03). CONCLUSIONS: Human immunodeficiency virus status had no effect on 2-year OS or on acute toxicities in women with well-managed HIV infection who initiated curative CRT in Botswana. In our cohort, we found that baseline hemoglobin levels, total radiation dose, and age were associated with survival, regardless of HIV status. PMID- 29619968 TI - In Reply to Cihan. PMID- 29619969 TI - In Regard to Rao et al. PMID- 29619970 TI - In Reply to Gultekin et al. PMID- 29619972 TI - In Reply to El Majjaoui et al. PMID- 29619971 TI - In Regard to Pasquier et al. PMID- 29619974 TI - Small Cells, Big Problems. PMID- 29619973 TI - In Regard to Churilla et al. PMID- 29619975 TI - Relationship Between Citation-Based Scholarly Activity of United States Radiation Oncology Residents and Subsequent Choice of Academic Versus Private-Practice Career. AB - PURPOSE: To assess h-index data and their association with radiation oncology resident choice of academic versus private-practice career, using a recent resident graduating class. METHODS AND MATERIALS: A list of 2016 radiation oncology resident graduates (163 residents from 76 Accreditation Council for Graduate Medical Education-certified programs) and their postresidency career choice (academic vs private practice) was compiled. The Scopus bibliometric citation database was then searched to collect h-index data for each resident. Demographics included in analyses were gender and PhD degree status. RESULTS: Mean h-index score for all resident graduates was 4.15. Residents with a PhD had significantly higher h-index scores (6.75 vs 3.42; P < .01), whereas there was no statistically significant difference in h-index scores between male and female residents (4.38 vs 3.36; P = .06). With regard to career choice, residents choosing academic careers had higher h-index scores than those choosing private practice (5.41 vs 2.96; P < .01). There was no significant difference in mean h index scores between male and female residents regardless of private-practice (3.15 vs 2.19; P = .25) or academic (5.80 vs 4.30; P = .13) career choice. CONCLUSIONS: The average radiation oncology resident graduate published a minimum of 4 manuscripts cited at least 4 times. Graduates with a PhD are significantly more likely to have higher h-index scores, as are residents who choose academic over private-practice careers. There is no significant difference in h-index score between male and female residents, regardless of career choice. These results offer up-to-date benchmarks for evaluating radiation oncology resident productivity and have potential utility in predicting postresidency career choices. PMID- 29619976 TI - Ablative Hypofractionated Radiation Therapy Enhances Non-Small Cell Lung Cancer Cell Killing via Preferential Stimulation of Necroptosis In Vitro and In Vivo. AB - PURPOSE: To investigate how necroptosis (ie, programmed necrosis) is involved in killing of non-small cell lung cancer (NSCLC) after ablative hypofractionated radiation therapy (HFRT). METHODS AND MATERIALS: Deoxyribonucleic acid damage, DNA repair, and the death form of NSCLC cells were assessed after radiation therapy. The overexpression and silencing of receptor-interacting protein kinases 3 (RIP3, a key protein involved activation of necroptosis)-stable NSCLC cell lines were successfully constructed. The form of cell death, the number and area of colonies, and the regulatory proteins of necroptosis were characterized after radiation therapy in vitro. Finally, NSCLC xenografts and patient specimens were used to examine involvement of necroptosis after ablative HFRT in vivo. RESULTS: Radiation therapy induced expected DNA damage and repair of NSCLC cell lines, but ablative HFRT at >=10 Gy per fraction preferentially stimulated necroptosis in NSCLC cells and xenografts with high RIP3 expression, as characterized by induction and activation of RIP3 and mixed-lineage kinase domain-like protein and release of immune-activating chemokine high-mobility group box 1. In contrast, RNA interference of RIP3 attenuated ablative HFRT-induced necroptosis and activation of its regulatory proteins. Among central early-stage NSCLC patients receiving stereotactic body radiation therapy, high expression of RIP3 was associated with improved local control and progression-free survival (all P < .05). CONCLUSIONS: Ablative HFRT at >=10 Gy per fraction enhances killing of NSCLC with high RIP3 expression via preferential stimulation of necroptosis. RIP3 may serve as a useful biomarker to predict favorable response to stereotactic body radiation therapy. PMID- 29619977 TI - Consolidative Thoracic Radiation and Serial Central Nervous System Imaging. PMID- 29619978 TI - Select Patients With "Limited" Extensive-Stage Small Cell Lung Cancer Should Be Treated Aggressively. PMID- 29619979 TI - A Small Window of Opportunity When Disease Is Limited in Extensive-Stage Small Cell Lung Cancer? PMID- 29619980 TI - Targeting Myeloid-derived Suppressor Cells and Programmed Death Ligand 1 Confers Therapeutic Advantage of Ablative Hypofractionated Radiation Therapy Compared With Conventional Fractionated Radiation Therapy. AB - PURPOSE: Ablative hypofractionated radiation therapy (AHFRT) presents a therapeutic advantage compared with conventional fractionated radiation therapy (CFRT) for primary and oligometastatic cancers. However, the underlying mechanisms remain largely unknown. In the present study, we compared the immune alterations in response to AHFRT versus CFRT and examined the significance of immune regulations contributing to the efficacy of AHFRT. METHODS AND MATERIALS: We established subcutaneous tumors using syngeneic lung cancer and melanoma cells in both immunocompetent and immunocompromised mice and treated them with AHFRT and CFRT under the same biologically equivalent dose. RESULTS: Compared with CFRT, AHFRT significantly inhibited tumor growth in immunocompetent, but not immunocompromised, mice. On the cellular level, AHFRT reduced the recruitment of myeloid-derived suppressor cells (MDSCs) into tumors and decreased the expression of programmed death-ligand 1 (PD-L1) on those cells, which unlashed the cytotoxicity of CD8+ T cells. Through the downregulation of vascular endothelial growth factor (VEGF), AHFRT inhibited VEGF/VEGF receptor signaling, which was essential for MDSC recruitment. When combined with anti-PD-L1 antibody, AHFRT presented with greater efficacy in controlling tumor growth and improving mouse survival. By altering immune regulation, AHFRT, but not CFRT, significantly delayed the growth of secondary tumors implanted outside the irradiation field. CONCLUSIONS: Targeting MDSC recruitment and enhancing antitumor immunity are crucial for the therapeutic efficacy of AHFRT. When combined with anti-PD-L1 immunotherapy, AHFRT was more potent for cancer treatment. PMID- 29619981 TI - Not All Nails Need a Hammer. PMID- 29619982 TI - STING-Dependent Interferon-lambda1 Induction in HT29 Cells, a Human Colorectal Cancer Cell Line, After Gamma-Radiation. AB - PURPOSE: To investigate the induction of type III interferons (IFNs) in human cancer cells by gamma-rays. METHODS AND MATERIALS: Type III IFN expression in human cancer cell lines after gamma-ray irradiation in vitro was assessed by reverse transcription-quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. Signaling pathways mediating type III IFN induction were examined by a variety of means, including immunoblotting, flow cytometry, confocal imaging, and reverse transcription-quantitative polymerase chain reaction. Key mediators in these pathways were further explored and validated using gene CRISPR knockout or short hairpin RNA knockdown. RESULTS: Exposure to gamma-rays directly induced type III IFNs (mainly IFNL1) in human cancer cell lines in dose- and time-dependent fashions. The induction of IFNL1 was primarily mediated by the cytosolic DNA sensors-STING-TBK1-IRF1 signaling axis, with a lesser contribution from the nuclear factor kappa b signaling in HT29 cells. In addition, type III IFN signaling through its receptors serves as a positive feedback loop, further enhancing IFN expression via up-regulation of the kinases in the STING-TBK1 signaling axis. CONCLUSIONS: Our results suggest that IFNL1 can be up-regulated in human cancer cell lines after gamma-ray treatment. In HT29 cells this induction occurs via the STING pathway, adding another layer of complexity to the understanding of radiation-induced antitumor immunity, and may provide novel insights into IFN-based cancer treatment. PMID- 29619983 TI - Acute Thrombogenicity of Fluoropolymer-Coated Versus Biodegradable and Polymer Free Stents. AB - AIMS: Durable-fluoropolymer coated everolimus-eluting stents (FP-EES) have shown lower rates of stent thrombosis (ST) versus bare-metal stents (BMS) and 1st generation bioabsorbable-polymer (BP) DES. However, the specific role of the FP in thromboresistance has not been explored. METHODS AND RESULTS: A total of 57 stents were assessed in 3 separate ex-vivo swine arterio-venous shunt-model experiments [1st-shunt-experiment, custom-made fluoropolymer-coated BMS (FP-only) vs. BMS (n=8 each); 2nd-shunt-experiment, FP-EES vs. abluminally-coated biodegradable-polymer sirolimus-eluting stents (BP-SES) vs. BMS (n=8 each); and 3rd-shunt-experiment, FP-EES vs. polymer-free BiolimusA9-coated stents (PF-BCS) vs. BMS (n=6 each)]. After 1h of circulation, stents were bisected, and each half was dual-immunostained using platelet cocktail and a marker for inflammation. Antibody staining was visualized by confocal microscopy. In addition, stents were evaluated by scanning electron microscopy. FP-only stents showed significantly lower platelet adherence compared with BMS (% fluorescence-positive area: FP only=1.8%, BMS=5.6%, p=0.047) with similar inflammatory cell density. FP-EES also demonstrated the lowest platelet adherence compared with BP-SES (p=0.056), PF-BCS (p=0.013) and BMS (p=0.003) with the significantly lowest inflammatory cell density. CONCLUSIONS: Fluoropolymer coating imparts greater thromboresistance relative to BMS and to polymer-free-DES designs, which reflects an unique phenomenon known as fluoropassivation, representing one proposed mechanism for clinically observed low ST rates in FP-EES. PMID- 29619984 TI - Sun protection in children: a behavioural study. AB - BACKGROUND: Incidence of skin cancer is increasing worldwide and UV exposure at a young age is an important risk factor. OBJECTIVES: To compare sun exposure related knowledge and behaviour among children during school and holiday periods. MATERIAL & METHODS: A cross-sectional study was undertaken at 12 Oporto public primary schools. Educational sessions for educators were head by dermatologists every spring from 2004 to 2012. An educational activity book, Play and Learn with Jo Spots, was distributed to all primary school children and was explained by the educators every year. A questionnaire about sun exposure and behaviour was given to students in 2004 and 2012. RESULTS: In total, 2,114 students answered the questionnaire (1,233 in 2004 and 881 in 2012). Children practiced more outdoor sports in 2012 than in 2004 (86% vs 56%; p<0.001), but spent less time outside when the sun's rays were most dangerous. The use of hats (64% vs 59%; p = 0.028) and sunscreen (35% vs 15%; p<0.001) at school and the application of sunscreen before going to the beach improved over time (51% vs 26% in 2004; p<0.001). However, there was an increase in sunburn rate (43% vs 37%; p = 0.005). CONCLUSION: Sun exposure-related behaviour among primary school students in Oporto is improving but is still far from optimal. School would appear to be an adequate setting for effective and long-lasting sun protection interventions, and the introduction of educational books at schools, such as Play and Learn with Jo Spots, might be effective in bringing about positive behavioural changes. PMID- 29619985 TI - Juvenile-onset psoriatic arthritis: a survey by the Japanese Society for Psoriasis Research. PMID- 29619986 TI - Bilateral metachronous cutaneous apocrine carcinoma with reduced PTEN expression. PMID- 29619988 TI - The Hidradenitis Suppurativa (HS) "Multidisciplinary Unit": a rationale and practical proposal for an organised clinical approach. PMID- 29619987 TI - Comorbidities of bullous pemphigoid in a Finnish cohort. AB - The incidence of bullous pemphigoid (BP) is increasing in Finland. To investigate the clinical presentation, comorbidities, and medications in a cohort of Finnish patients with confirmed BP managed in a university hospital setting. An observational retrospective study of all consecutive patients diagnosed with BP in 2012-2013 at the Department of dermatology, HUCH. The prevalence of the most common comorbidities was compared to that in a sample population aged over 30 years. Seventy patients were included (mean age: 77 years at diagnosis). The most common comorbidities were hypertension (44%), type 2 diabetes (34%), and ischaemic heart disease (26%). Almost half of the cohort had a neurological condition (46%). A statistically significant association was identified between BP and a past history of malignancies (17%; p<0.001), type 2 diabetes (24%; p<0.001), and chronic obstructive lung disorder (COPD) (10%; p=0.004), compared to an age-matched control group. The most common standard drugs were statins, beta-blockers, and diuretics. In total, 83% of the patients with type 2 diabetes took anti-diabetic treatments, mainly metformin (80%) and gliptins (55%). Significant associations were identified between BP and COPD, type 2 diabetes, and a past history of malignancy, compared to the general population. In this study, the specific role of some medications, such as gliptins, may account for the onset of BP in diabetic type 2 patients. PMID- 29619989 TI - Efficacy of etoposide for myelodysplasia cutis. PMID- 29619991 TI - Accelerated repigmentation of vitiligo after an irritant reaction following occlusion dressing with topical tacrolimus. PMID- 29619990 TI - Do cancer registries play a role in determining the incidence of non-melanoma skin cancers? AB - Non-melanoma skin cancers have the highest incidence of all malignancies worldwide. However, cancer registries rarely include data on non-melanoma skin cancers because they tend to be under-reported. To determine incidence rates and changes over time for non-melanoma skin cancers in a mid-sized Brazilian population. We calculated age-standardized rates, adjusted to the world population using the direct method, from 1996-2012 in the Aracaju Cancer Registry and then calculated incidence trends using the Joinpoint Regression Program. We analysed 11,476 cases (5,695 men and 5,781 women) of non-melanoma skin cancer collected during the study period. The histological subtypes in men were 84.5% basal cell carcinoma, 14.5% squamous cell carcinoma, and 1% other histological subtypes, whereas the corresponding percentages in women were 89.1%, 10%, and 0.9%, respectively. Average incidence age-standardized rates were 228.6 (95% CI: 221.6; 235.6) per 100,000 men and 145.4 (95% CI: 141.0; 149.9) per 100,000 women. The incidence mostly increased in the first years for the series and then stabilized. The under-reporting of non-melanoma skin cancers, due to removal of lesions without histopathological confirmation, decisions to keep skin lesions under observation instead of excising them, and deferring medical examination, is a potential pitfall of this study. Age-standardized incidence of non-melanoma skin cancer was high during the study period, but tended to stabilise in the latter years of the study. PMID- 29619992 TI - Bullous pemphigoid accompanied by IgA nephropathy and atypical haemolytic uraemic syndrome. PMID- 29619993 TI - A case of cutaneous angiosarcoma successfully treated with eribulin. PMID- 29619994 TI - Geometric alopecia associated with lupus erythematosus panniculitis of the scalp: a case series of nine Korean patients. PMID- 29619995 TI - Giant congenital melanocytic nevus associated with cerebellar astrocytoma. PMID- 29619996 TI - Orthostatic hypotension revealed by BASCULE syndrome. PMID- 29619997 TI - Necrobiotic xanthogranuloma: a paraneoplastic skin lesion of haematological malignancies? PMID- 29619998 TI - Association of IL36RN mutations with clinical features, therapeutic response to acitretin, and frequency of recurrence in patients with generalized pustular psoriasis. AB - Previous studies have revealed that IL36RN mutations play a pivotal role in the pathogenesis of generalized pustular psoriasis (GPP), however, the clinical relevance is unclear. To investigate the correlation between IL36RN mutations and clinical features, recurrence frequency, and therapeutic response to acitretin in GPP patients with long-term follow-up. This retrospective cohort study, lasting 2 4 years, included 61 GPP and 48 psoriasis vulgaris (PV) patients. Sequence analysis of all five exons of the IL36RN gene revealed two genetic variants (c.115+6 T>C and c.227C>T). The cohort was divided into three subgroups according to the c.115+6 T>C mutation (present in 52.5% of the patients): homozygous mutation group (HOMG), heterozygous mutation group (HEMG), and non-mutation group (NMG). Initially, 21/25 HOMG patients were diagnosed with GPP with provocative factors, but 13 developed erythrodermic psoriasis after the pustular phase. Patients in the HEMG (5/7) and NMG (23/29) maintained PV diagnosis before and after the pustular phase. Most patients exhibited a marked response to acitretin, but patients who were prescribed a maintenance dosage (10-30 mg/d) had mild recurrence (0-2 times/year) during follow-up. IL36RN mutations were strongly linked with early onset and hyponychial pustules, but not with therapeutic efficacy of acitretin or recurrence frequency. Early onset and hyponychial pustules may be specific to IL36RN mutation, however this alone is an insufficient biomarker for acitretin therapy. Other provocative factors play important roles in disease onset, clinical manifestations, and disease outcome. Low-dose maintenance therapy with acitretin might help reduce the recurrence of GPP. PMID- 29619999 TI - A case of anti-laminin gamma1 (p200) pemphigoid with psoriasis vulgaris successfully treated with apremilast. PMID- 29620000 TI - Lymph node dissection for melanoma using tumescence local anaesthesia: an observational study. AB - The possibility that tumescence local anaesthesia (TLA) may lead to dissemination of tumour cells in lymph nodes is presently unclear. To evaluate whether infiltration by TLA influences metastatic spread and survival probability, compared to general anaesthesia (GA), based on lymph node dissection in melanoma patients. In total, 281 patients (GA: 162; TLA: 119) with cutaneous melanoma and clinically or histologically-confirmed metastases in regional lymph nodes were included. All patients underwent complete lymph node dissection. Median follow-up was 70 months. The rate of lymph node recurrence at the dissection site was 25.3% in the GA group and 17.6% in the TLA group (p = 0.082). No significant difference was found concerning 10-year melanoma-specific survival (GA: 56.2%, TLA: 67.4%; p = 0.09), disease-free survival (GA: 72.8 %, TLA: 81.1%; p = 0.095), or lymph node free survival (GA: 72.8%, TLA: 81.1%; p = 0.095). Distant metastases-free survival appeared to be slightly reduced in the TLA group (GA: 49.9%, TLA: 64.0%; p = 0.025). No differences were identified between the GA and TLA groups regarding prognostic outcome for overall survival or disease-free survival. PMID- 29620001 TI - One-step surgical removal of cutaneous melanoma with surgical margins based on preoperative ultrasound measurement of the thickness of the melanoma. AB - BACKGROUND: Surgical margins of melanoma vary from 5 mm to 1 or 2 cm depending on histology thickness (Breslow). This approach usually requires two surgical steps: excisional biopsy and further re-excision according to histology thickness. A previous systematic review showed that measuring melanoma thickness with high resolution ultrasound imaging equipment correlates well with histological measurement of melanoma thickness. Therefore, we routinely determined tumour sonographic thickness in order to perform surgery as a single step. OBJECTIVES: To determine the proportion of patients who receive one-step surgery with adequate margins based on sonographic measurement of melanoma thickness and identify the reasons for differences between these two measurements. MATERIALS AND METHODS: A retrospective series of patients with melanoma, in which thickness was measured by ultrasound (20 MHz) from April 2007 to December 2015 prior to surgery. RESULTS: Ninety-nine melanomas were treated, of which 78 were removed in a single step with surgical margins based on sonometric thickness measurements; 71 of these (91%, 95% CI: 82-96) did not require re-excision, five had excessive margins, and two had insufficient margins. The correlation between the histometric and sonometric measurements was good; r=0.88. Significant absolute difference between sonometric and histometric measurements was associated with thickness, ulceration, and size of tumours, based on bivariate analysis. Thickness remained the only significant factor based on multivariate analysis. CONCLUSION: Measuring the thickness of melanoma with high-resolution ultrasound imaging equipment makes it possible to remove the melanoma in a single step with adequate margins in at least 82% of the cases in routine care. PMID- 29620002 TI - Assessment of dermal uptake of diphenylmethane-4,4'-diisocyanate using tape stripping and biological monitoring. AB - Very little is known about the dermal uptake of isocyanates, and dermal exposure to isocyanates has been discussed as a factor involved in the induction of respiratory diseases. To investigate the dermal uptake of diphenylmethane-4,4' diisocyanate (4,4'-MDI). Four volunteers were dermally exposed to 10, 25, 49 and 50 mg 4,4'-MDI, respectively, for eight hours. The exposed areas were tape stripped. Urine and blood were biologically monitored for 48 hours. Tape strips, plasma, and urine were analysed by liquid chromatography-mass spectrometry. In total, 35-70% of the applied dose of 4,4'-MDI was absorbed by the skin. Very low fractions of applied dose were found in the tape strips. The 4,4'-MDA concentration in plasma and urine was low, but peaked in urine at 10-14 hours and plasma at 8-32 hours after exposure. 4,4'-MDI is readily absorbed by human skin. Only small fractions of 4,4'-MDI remain as such in the superficial skin layers. The amounts found in blood and urine were only small fractions of the total applied doses which indicates that very small amounts of 4,4'-MDI penetrate the skin and reach the blood stream. The dermal uptake and distribution of 4,4'-MDI is much slower compared to that associated with airway uptake. Our data strongly indicate that formation of 4,4'-MDA from 4,4'-MDI upon reacting with water in the skin can only occur to a very limited extent. PMID- 29620003 TI - Use of sunscreen and risk of melanoma and non-melanoma skin cancer: a systematic review and meta-analysis. AB - The use of sunscreen is a key component of public health campaigns for skin cancer prevention, but epidemiological studies have raised doubts on its effectiveness in the general population. This systematic review and meta-analysis aimed to assess the association between risk of skin cancer and sunscreen use. We searched PubMed, BIREME and Google Scholar from inception to May 17, 2017, to identify observational studies and controlled trials. We used a random-effects model for conventional and cumulative meta-analyses. We included 29 studies (25 case-control, two cohort, one cross-sectional, and one controlled trial) involving 313,717 participants (10,670 cases). The overall meta-analysis did not show a significant association between skin cancer and sunscreen use (odds ratio (OR) = 1.08; 95% CI: 0.91-1.28, I2 = 89.4%). Neither melanoma (25 studies; 9,813 cases) nor non-melanoma skin cancer (five studies; 857 cases) were associated with sunscreen use, with a pooled OR (95% CI) of 1.10 (0.92-1.33) and 0.99 (0.62 1.57), respectively. The cumulative evidence before the 1980s showed a relatively strong positive association between melanoma and sunscreen use (cumulative OR: 2.35; 95% CI: 1.66-3.33). The strength of the association between risk of skin cancer and sunscreen use has constantly decreased since the early 1980s, and the association was no longer statistically significant from the early 1990s. While the current evidence suggests no increased risk of skin cancer related to sunscreen use, this systematic review does not confirm the expected protective benefits of sunscreen against skin cancer in the general population. PMID- 29620004 TI - A new dermoscopic algorithm for the differential diagnosis of facial lentigo maligna and pigmented actinic keratosis. AB - The clinical and dermoscopic diagnosis of facial lentigo maligna (LM) and pigmented actinic keratosis (PAK) remains challenging, particularly at the early disease stages. To identify dermoscopic criteria that might be useful to differentiate LM from PAK, and to elaborate and validate an automated diagnostic algorithm for facial LM/PAK. We performed a retrospective multicentre study to evaluate dermoscopic images of histologically-proven LM and PAK, and assess previously described dermoscopic criteria. In the first part of the study, 61 cases of LM and 74 PAK were examined and a parsimonious algorithm was elaborated using stepwise discriminant analysis. The following eight dermoscopic criteria achieved the greatest discriminative power: (1) light brown colour; (2) a structureless zone, varying in colour from brown to brown/tan, to black; (3) in focus, discontinuous brown lines; (4) incomplete brown or grey circles; (5) a structureless brown or black zone, obscuring the hair follicles; (6) a brown (tan), eccentric, structureless zone; (7) a blue structureless zone; and (8) scales. The newly developed algorithm was subsequently validated using an additional series of 110 LM and 75 PAK cases. Diagnostic accuracy was 86.5% (kappa: 0.73, 95% CI: 0.63-0.83). For the diagnosis of LM vs PAK, sensitivity was 82.7% (95% CI: 75.7-89.8%), specificity was 92.0% (95% CI: 85.9-98.1%), positive predictive value was 93.8% (95% CI: 89.0-98.6%), and negative predictive value was 78.4% (95% CI: 68.4-86.5%). This algorithm may represent an additional tool for clinicians to distinguish between facial LM and PAK. PMID- 29620005 TI - Congenital nevus lipomatosus cutaneous superficialis of Hoffman and Zurhelle on the sole. PMID- 29620006 TI - Electroclinical and radiological observation of dysfunctional zones in a patient with neurosyphilis. AB - We report a 33-year-old Japanese man who suffered from repetitive generalized tonic-clonic seizures which were medically intractable. Neurosyphilis was serologically diagnosed in blood and cerebrospinal fluid, and penicillin G (PcG) was consequently effective. The EEG during PcG pre-treatment showed frequent right occipital spikes and right frontocentral slow waves, which disappeared after treatment. During pre-treatment, positron emission tomography with 18 fluorodeoxyglucose and Tc-99m ethyl cysteinate dimer single-photon emission computed tomography revealed occipital hypermetabolism and hyperperfusion ("hot" area) and fronto-temporo-parietal hypometabolism and hypoperfusion ("cool" area) over the right hemisphere. The spike sources of magnetoencephalography during pre treatment were localized to "hot" areas, and the slow activities were distributed to the fronto-temporo-parietal region, corresponding to "cool" areas. The inflammatory seizure focus and reversible dysfunctional zone associated with neurosyphilis were clearly delineated using these techniques. PMID- 29620007 TI - Ictal spitting in non-dominant temporal lobe epilepsy: an anatomo electrophysiological correlation. AB - We report a patient presenting drug-resistant, non-dominant temporal lobe epilepsy with ictal spitting and prosopometamorphopsia, both extremely rare semiologies. Second-phase pre-surgical monitoring was performed using SEEG due to lesion-negative imaging and the rare semiology. The seizure onset zone was delimited to the right anterior hippocampus and the temporobasal cortex, with the propagation zone within the entorhinal cortex. Interestingly, direct electrical stimulation to the entorhinal cortex, which was reproduced in a number of trials, evoked spitting without leading to seizures or post-discharges. After the resection of the epileptogenic zone, the patient remained seizure-free without AEDs for a follow-up period of five years (Engel Class 1a). The neuropathology revealed a focal cortical dysplasia type FCD-Ia. Spectral analysis of intracranial ictal EEG (iEEG) data suggested a possible role of the basal temporal and entorhinal cortex as a necessary node in ictal spitting. [Published with video sequences on www.epilepticdisorders.com]. PMID- 29620008 TI - De novo late-onset absence status epilepticus or late-onset idiopathic generalized epilepsy? A case report and systematic review of the literature. AB - Idiopathic (genetic) generalized epilepsies (IGEs) are age-related epileptic syndromes with typical age onset in childhood or adolescence. We report a patient with de novo late-onset absence status epilepticus (ASE) occurring at the age of 64 years, with clinical and EEG features suggestive of late-onset IGE. We also discuss the relationship between de novo late-onset ASE and late-onset IGE, and provide a comprehensive and critical review of the available literature on late onset (i.e. onset >=60 years) IGE. MEDLINE (1966-2016 [23th April]) was systematically searched in order to identify reports of patients with late-onset IGE. Grey literature was also comprehensively searched. We identified nine patients with electroclinical features suggestive of late-onset IGE. Median age at seizure onset was 71 years (range: 60-80), with a female prevalence (67%). A family history of epilepsy was reported in 67% of cases. All patients had generalized tonic-clonic seizures, and 44% also had myoclonic seizures. Treatment and outcome were reported for six patients; all of whom reached seizure freedom under monotherapy with valproic acid (83%) or lamotrigine (17%) (range of follow up: 3 to 24 months). Late-onset IGE are entities with unknown prevalence and incidence, and should be differentiated on the basis of late-onset reactivation of previous IGE. Late-onset IGEs are probably unrecognized or misdiagnosed, based on a common misconception that all elderly individuals with first-ever seizures have focal symptomatic epilepsy. Late-onset IGE should be actively investigated by accurate history taking aimed at identifying seizures, which may have been unnoticed, and familial antecedents of epilepsy. In elderly patients presenting with de novo late-onset ASE, a diagnosis of late-onset IGE should be considered in the differential diagnosis, particularly in atypical cases (e.g. absence of triggering factors, coexistence of generalized tonic-clonic or myoclonic seizures, and interictal generalized epileptiform discharges). PMID- 29620009 TI - The link between structural connectivity and neurocognition illustrated by focal epilepsy. AB - Increasing attention is being paid to the assessment of white matter properties and its structural connectivity, both in healthy subjects and patients with cerebral lesions. Within this framework, new neurocognitive models based on hodological properties have been developed under a connectomic perspective in order to explain substrates and cognitive mechanisms related to cerebral functions such as language and memory. With regards to focal and drug-resistant epilepsy conceived as a network disorder, new insights in terms of structural connectivity have led to significant advances in epilepsy research, concerning fundamental research (neurocognitive mechanisms of plasticity) and clinical application (optimization of decision making for curative surgery). We believe that such findings in the literature, focused on the role of white matter in cerebral functioning in relation to neurocognition, may be helpful for both researchers and clinicians working in the field of epilepsy. PMID- 29620010 TI - Epilepsy surgery for patients with genetic refractory epilepsy: a systematic review. AB - In recent years, many different DNA mutations underlying the development of refractory epilepsy have been discovered. However, genetic diagnostics are still not routinely performed during presurgical evaluation and reports on epilepsy surgery outcome for patients with genetic refractory epilepsy are limited. We aimed to create an overview of the literature on seizure outcome following epilepsy surgery in patients with different genetic causes of refractory epilepsy. We systematically searched PubMed and Embase prior to January 2017 and included studies describing treatment outcome following epilepsy surgery in patients with genetic causes of epilepsy. We excluded studies in which patients were described with epilepsy due to Tuberous Sclerosis Complex or Sturge-Weber syndrome (since this extensive body of research has recently been described elsewhere) and articles in which surgery was aimed to be palliative. We identified 24 eligible articles, comprising a total of 82 patients who had undergone surgery for (mainly childhood-onset) refractory epilepsy due to 15 different underlying genetic causes. The success rate of surgery varied widely across these different genetic causes. Surgery was almost never effective in patients with epilepsy due to mutations in genes involved in channel function and synaptic transmission, whereas surgery was significantly more successful regarding seizure control in patients with epilepsy due to mutations in the mTOR pathway. Patients with a lesion on MRI tended to have higher seizure freedom rates than those who were MRI-negative. Although the evidence is still scarce, this systematic review suggests that studying genetic variations in patients with refractory epilepsy could help guide the selection of surgical candidates. PMID- 29620011 TI - Ictal laryngospasm monitored by video-EEG and polygraphy: a potential SUDEP mechanism. AB - A 56-year-old man with refractory bitemporal epilepsy was monitored in the Epilepsy Monitoring Unit (EMU). In a video-EEG captured seizure, brief oroalimentary automatisms were followed by increased inspiratory effort, accompanied by prominent, visible tracheal movements and audible inspiratory stridor. The patient's oxygen saturation rapidly declined to 62%; persistent severe hypoxemia ended with spontaneous effective respiration commencing at seizure end. Subsequent seizures necessitated intensive care unit admission for respiratory distress, and ventilator support. This case suggests that ictal laryngospasm, a rare seizure manifestation, may represent another potential mechanism of sudden unexpected death in epilepsy (SUDEP). [Published with video sequence on www.epilepticdisorders.com]. PMID- 29620012 TI - Rapid antiepileptic drug withdrawal may obscure localizing information obtained during presurgical EEG recordings. AB - Withdrawal of antiepileptic drugs (AEDs) is a standard procedure during presurgical epilepsy assessment. Rapid and, at times, even pre-hospital withdrawal of medication is performed in some centres to enhance the yield of recorded seizures during video-EEG monitoring. AED withdrawal, however, affects the propensity and speed of propagation of epileptic activity, may evoke more severe seizures, and may cause pitfalls in EEG interpretation. We report a case which had been recommended to undergo intracranial EEG recordings in order to clarify apparently discordant MRI findings and ictal EEG patterns when monitoring was performed following complete AED withdrawal. Re-evaluation to assess scalp EEG patterns at several drug levels during slow AED tapering showed a loss of localizing information with AED withdrawal due to contralateral and bitemporal spread of frontal epileptic activity. Our report demonstrates that in individual cases, rapid AED withdrawal during presurgical video-EEG monitoring can impair the validity of EEG recordings and lead to unnecessary risks and investigations during workup. PMID- 29620013 TI - The 2017 ILAE classification of seizure types and the epilepsies: what do people with epilepsy and their caregivers need to know? AB - The International League against Epilepsy (ILAE) published in the April 2017 edition of Epilepsia three companion articles on the classification of seizures and the epilepsies. These represent a long-awaited update on the original 1981 and 1989 publications and provide a modern descriptive template. The new classification presents three levels of terminology, involving seizure types, epilepsy types, and syndromes. In this fourth paper, we present an interpretation of these new concepts for people with epilepsy and those who care for them, as well as for young medical doctors not specialized in epilepsy and nurses. Our goal in writing this paper is to ensure that everyone is speaking and understanding the same language, which is fundamental to the optimal management of people with epilepsy. PMID- 29620014 TI - Highly sensitive wearable strain sensor based on silver nanowires and nanoparticles. AB - Here, we propose a highly sensitive and stretchable strain sensor based on silver nanoparticles and nanowires (Ag NPs and NWs), advancing the rapid development of electronic skin. To improve the sensitivity of strain sensors based on silver nanowires (Ag NWs), Ag NPs and NWs were added to polydimethylsiloxane (PDMS) as an aid filler. Silver nanoparticles (Ag NPs) increase the conductive paths for electrons, leading to the low resistance of the resulting sensor (14.9 Omega). The strain sensor based on Ag NPs and NWs showed strong piezoresistivity with a tunable gauge factor (GF) at 3766, and a change in resistance as the strain linearly increased from 0% to 28.1%. The high GF demonstrates the irreplaceable role of Ag NPs in the sensor. Moreover, the applicability of our high-performance strain sensor has been demonstrated by its ability to sense movements caused by human talking, finger bending, wrist raising and walking. PMID- 29620015 TI - Computational logic with square rings of nanomagnets. AB - Nanomagnets are a promising low-power alternative to traditional computing. However, the successful implementation of nanomagnets in logic gates has been hindered so far by a lack of reliability. Here, we present a novel design with dipolar-coupled nanomagnets arranged on a square lattice to (i) support transfer of information and (ii) perform logic operations. We introduce a thermal protocol, using thermally active nanomagnets as a means to perform computation. Within this scheme, the nanomagnets are initialized by a global magnetic field and thermally relax on raising the temperature with a resistive heater. We demonstrate error-free transfer of information in chains of up to 19 square rings and we show a high level of reliability with successful gate operations of ~94% across more than 2000 logic gates. Finally, we present a functionally complete prototype NAND/NOR logic gate that could be implemented for advanced logic operations. Here we support our experiments with simulations of the thermally averaged output and determine the optimal gate parameters. Our approach provides a new pathway to a long standing problem concerning reliability in the use of nanomagnets for computation. PMID- 29620016 TI - Electronic scattering, focusing, and resonance by a spherical barrier in Weyl semimetals. AB - We solve the Weyl electron scattered by a spherical step potential barrier. Tuning the incident energy and the potential radius, one can enter both quasiclassical and quantum regimes. Transport features related to far-field currents and integrated cross sections are studied to reveal the preferred forward scattering. In the quasiclassical regime, a strong focusing effect along the incident spherical axis is found in addition to optical caustic patterns. In the quantum regime, at energies of successive angular momentum resonances, a polar aggregation of electron density is found inside the potential. The findings will be useful in transport studies and electronic lens applications in Weyl systems. PMID- 29620017 TI - Improved luminescence properties of MoS2 monolayers grown via MOCVD: role of pre treatment and growth parameters. AB - Fabrication of transition metal dichalcogenides (TMDCs) via metalorganic chemical vapor deposition (MOCVD) represents one of the most attractive routes to large scale 2D material layers. Although good homogeneity and electrical conductance have been reported recently, the relation between growth parameters and photoluminescence (PL) intensity-one of the most important parameters for optoelectronic applications-has not yet been discussed for MOCVD TMDCs. In this work, MoS2 is grown via MOCVD on sapphire (0001) substrates using molybdenum hexacarbonyl (Mo(CO)6, MCO) and di-tert-butyl sulphide as precursor materials. A prebake step under H2 atmosphere combined with a reduced MCO precursor flow increases the crystal grain size by one order of magnitude and strongly enhances PL intensity with a clear correlation to the grain size. A decrease of the linewidth of both Raman resonances and PL spectra down to full width at half maxima of 3.2 cm-1 for the E 2g Raman mode and 60 meV for the overall PL spectrum indicate a reduced defect density at optimized growth conditions. PMID- 29620018 TI - Conductivity enhancement of silver nanowire networks via simple electrolyte solution treatment and solvent washing. AB - As a promising replacement material for indium tin oxide in flexible electronics, silver nanowires (AgNWs) usually need complicated post-treatment to reduce the high contact resistance across the intersections when used as transparent conductive films. In this work, a widely applicable nano-joining method for improving the overall conductivity of AgNW networks with different kinds of electrolyte solutions is presented. By treatment with an electrolyte solution with appropriate ionic strengths, the insulating surfactant layer (polyvinylpyrrolidone, PVP) on the AgNWs could be desorbed, and the AgNW network could be densified. The sheet resistance of the AgNW film on a glass slide is reduced by 60.9% (from 67.5 to 26.4 Ohm sq-1) with a transmittance of 92.5%. High resolution transmission electron microscopy analysis indicates that atomic diffusion occurs at the intersection of two AgNWs. Thus, metallurgical bonding on the nanometer scale is achieved across the junctions of the AgNWs, leading to a significant enhancement in the conductivity of the AgNW network. PMID- 29620019 TI - A comparison of probabilistic classifiers for sleep stage classification. AB - OBJECTIVE: To compare conditional random fields (CRF), hidden Markov models (HMMs) and Bayesian linear discriminants (LDs) for cardiorespiratory sleep stage classification on a five-class sleep staging task (wake/N1/N2/N3/REM), to explore the benefits of incorporating time information in the classification and to evaluate the feasibility of sleep staging on obstructive sleep apnea (OSA) patients. APPROACH: The classifiers with and without time information were evaluated with 10-fold cross-validation on five-, four- (wake/N1 + N2/N3/REM) and three-class (wake/NREM/REM) classification tasks using a data set comprising 443 night-time polysomnography (PSG) recordings of 231 participants (180 healthy participants, 100 of which had a 'regular' sleep architecture, and 51 participants previously diagnosed with OSA). MAIN RESULTS: CRF with time information (CRFt) outperforms all other classifiers on all tasks, achieving a median accuracy and Cohen's kappa for all participants of 62.8% and 0.44 for five classes, 68.8% and 0.47 for four classes, and 77.6% and 0.55 for three classes. An advantage was found in training classifiers, specifically for 'regular' and 'OSA' participants, achieving an improvement in classification performance for these groups. For 'regular' participants, CRFt achieved a median accuracy and Cohen's kappa of 67.0% and 0.51, 70.8% and 0.53 and 81.3% and 0.62 for five-, four- and three-classes respectively, and for 'OSA' patients, of 59.9% and 0.40, 69.7% and 0.45, and 75.8% and 0.51 for five-, four- and three-classes respectively. SIGNIFICANCE: The results suggest that CRFt is not only better at learning and predicting more complex and irregular sleep architectures, but that it also performs reasonably well in five-class classification-the standard for sleep scoring used in clinical PSG. Additionally, and albeit with a decrease in performance when compared with healthy participants, sleep stage classification in OSA patients using cardiorespiratory features and CRFt seems feasible with reasonable accuracy. PMID- 29620020 TI - Tetrazolium salts-Pluronic F-127 gels for 3D radiotherapy dosimetry. AB - This work is a follow-up study for a recently-proposed 3D radiochromic gel dosimeter that contains a tetrazolium salt and a physical gel matrix made of poly(ethylene oxide)-block-poly(propylene oxide)-block-poly(ethylene oxide) (Pluronic F-127). Several tetrazolium salts were examined in this work, including tetrazolium violet, blue tetrazolium chloride, nitro blue tetrazolium chloride (NBT), tetranitro blue tetrazolium chloride (tNBT) and thiazolyl blue tetrazolium bromide (TBTB). The salt-containing gel dosimeters were compared with the first Pluronic gel composition that contained 2,3,5-triphenyltetrazolium chloride (TTC) as the radiation-sensitive component (dose sensitivity of 0.0023 (Gy cm)-1). The Pluronic gels with NBT and tNBT outperformed the other gels, including the TTC containing gel, with respect to their dose sensitivity and low dose-response. The NBT gels were found to have better stability over time than tNBT gels. Sensitization of the gels to ionizing radiation was examined by addition of tert butyl alcohol and sodium formate. The best composition was 0.0818% NBT (1 mM), 25% Pluronic F-127 and 0.136 * 10-2% sodium formate. This gel dosimeter was insensitive to changes in dose rate for photons of different energies. The mean dose sensitivity amounted to 0.0047 +/- 0.1 * 10-4 (Gy cm)-1. A diversion in the dose-response was observed for the gel irradiated with electrons. Additional characteristics of the NBT gel were a linear-dose range and a dynamic-dose range between <1 and ?150 Gy and a dose threshold of <1 Gy. The dose distribution registered for the NBT-Pluronic gel was stable after irradiation for over 7 d with no visible diffusion of the irradiated part, which is analogous to the original TTC-Pluronic gel. PMID- 29620021 TI - Quantum transport through MoS2 constrictions defined by photodoping. AB - We present a device scheme to explore mesoscopic transport through molybdenum disulfide (MoS2) constrictions using photodoping. The devices are based on van der-Waals heterostructures where few-layer MoS2 flakes are partially encapsulated by hexagonal boron nitride (hBN) and covered by a few-layer graphene flake to fabricate electrical contacts. Since the as-fabricated devices are insulating at low temperatures, we use photo-induced remote doping in the hBN substrate to create free charge carriers in the MoS2 layer. On top of the device, we place additional metal structures, which define the shape of the constriction and act as shadow masks during photodoping of the underlying MoS2/hBN heterostructure. Low temperature two- and four-terminal transport measurements show evidence of quantum confinement effects. PMID- 29620022 TI - Pyridine 1:1 adducts of urea (Z' = 1) and thiourea (Z' = 8). AB - During our studies of urea and thiourea adducts, we noticed that no adducts with unsubstituted pyridine had been structurally investigated. The 1:1 adduct of pyridine and urea, C5H5N.CH4N2O, crystallizes in the P21/c space group with Z = 4. The structure is of a standard type for urea adducts, whereby the urea molecules form a ribbon, parallel to the a axis, consisting of linked R22(8) rings, and the pyridine molecules are attached to the periphery of the ribbon by bifurcated (N-H...)2N hydrogen bonds. The 1:1 adduct of pyridine and thiourea, C5H5N.CH4N2S, crystallizes in the P21/n space group, with Z = 32 (Z' = 8). The structure displays similar ribbons to those of the urea adduct. There are two independent ribbons parallel to the b axis at z ? 0 and 1/2, and three at z ? 1/4 and 3/4; the latter are crosslinked to form a layer structure by additional long N-H...S interactions, which each formally replace one branch of a bifurcated hydrogen-bond system. PMID- 29620023 TI - Synthesis, structure characterization, photoluminescence properties and TD-DFT calculations for two new borates. AB - Due to their rich structural chemistry and wide variety of applications, borate materials have provided a rich area of research. In a continuation of this research, diethylammonium bis(2-oxidobenzoato-kappa2O1,O2)borate, C4H12N+.BO4(C7H4O)2-, (1), and propylammonium bis(2-oxidobenzoato kappa2O1,O2)borate, C3H10N+.BO4(C7H4O)2-, (2), have been synthesized by the reaction of boric acid with salicylic acid under ambient conditions. In both structures, the B atom exhibits a slightly distorted tetrahedral environment formed by the bidentate coordination of two salicylate anions via the O atoms of the central carboxylate and oxide groups. In the crystals of salts (1) and (2), mixed cation-anion layers lying parallel to the (101) plane are formed through N H...O, C-H...O and C-H...pi/N-H...O hydrogen-bonding interactions, resulting, in each case, in a two-dimensional supramolecular architecture in the solid state. The photoluminescence properties of the salts were studied using the as synthesized samples and reveal that salts (1) and (2) both display a strong blue light emission, with maxima at 489 and 491 nm, respectively. In DFT/TD-DFT (time dependent density functional theory) studies, the blue emission appears to be derived from an intramolecular charge transfer (ICT) excited state. In addition, IR and UV-Vis spectroscopies were used to investigate the title salts. PMID- 29620024 TI - A three-dimensional twofold interpenetrated cobalt(II) MOF containing a flexible carboxylate-based ligand: synthesis, structure and magnetic properties. AB - The design and synthesis of coordination polymers (CPs) have attracted much interest due to the intriguing diversity of their architectures and topologies. The functional solid catena-poly[MU2-aqua-triaqua{MU4-5-[4 carboxyphenoxy)methyl]benzene-1,3-dicarboxylato}{MU3-5-[4 carboxyphenoxy)methyl]benzene-1,3-dicarboxylato}dicobalt(II)], [Co2(C16H10O7)2(H2O)4]n or [Co2(HL)2(MU2-H2O)(H2O)3]n, was synthesized successfully by self-assembly of CoII ions with 5-[(4 carboxyphenoxy)methyl]isophthalic acid (H3L). The title compound was obtained under hydrothermal conditions and exhibits a twofold interpenetrated three dimensional skeleton with hms 3,5-conn topology according to the cluster representation for valence-bonded metal-organic frameworks (MOFs). It has been characterized by single-crystal X-ray diffraction, IR spectroscopy, powder X-ray diffraction (PXRD), thermogravimetric analysis and susceptibility measurements. The antiferromagnetic coupling between adjacent CoII centres occurs via superexchange through the ligands. PMID- 29620025 TI - [1-(Pyrazin-2-yl)ethylidene]hydrazine: a new multitopic ligand for the design of hybrid molecular frameworks. AB - Hydrazones and their derivatives are closely related to imine compounds and are potential antimicrobial agents. They have also found application in supramolecular chemistry as multitopic ligands to link multiple metal centres for the design of hybrid molecular frameworks. The molecule of the title compound, C6H8N4, consists of an imine linkage with an N-N bond length of 1.3540 (14) A. This asymmetric compound is nearly planar and adopts an E configuration about the azomethine C=N double bond. In the solid state, there are two intermolecular N H...N interactions that interconnect the molecules into a two-dimensional network. The three-dimensional arrangement of the crystal packing is further stabilized by intermolecular pi-pi interactions interconnecting the centroids of the heterocyclic rings. PMID- 29620026 TI - Involvement of conformational isomerism in the complexity of the crystal network of 1-(4-nitrophenyl)-1H-1,3-benzimidazole derivatives driven by C-H...A (A = NO2, Npy and pi) and orthogonal Npy...NO2 and ONO...Csp2 interactions. AB - A detailed structural analysis of the benzimidazole nitroarenes 1-(4-nitrophenyl) 1H-1,3-benzimidazole, C13H9N3O2, (I), 1-(4-nitrophenyl)-2-phenyl-1H-1,3 benzimidazole, C19H13N3O2, (II), and 2-(3-methylphenyl)-1-(4-nitrophenyl)-1H-1,3 benzimidazole, C20H15N3O2, (III), has been performed. They are nonplanar structures whose crystal arrangement is governed by Csp2-H...A (A = NO2, Npy and pi) hydrogen bonding. The inherent complexity of the supramolecular arrangements of compounds (I) (Z' = 2) and (II) (Z' = 4) into tapes, helices and sheets is the result of the additional participation of pi-piNO2 and n-pi* (n = O and Npy; pi* = Csp2 and NNO2) interactions that contribute to the stabilization of the equi energetic conformations adopted by each of the independent molecules in the asymmetric unit. In contrast, compound (III) (Z' = 1) is self-paired, probably due to the effect of the steric demand of the methyl group on the crystal packing. Theoretical ab initio calculations confirmed that the presence of the arene ring at the benzimidazole 2-position increases the rotational barrier of the nitrobenzene ring and also supports the electrostatic nature of the orthogonal ONO...Csp2 and Npy...NO2 interactions. PMID- 29620027 TI - Two polymorphs of 2,5-dichloro-3,6-bis(dibenzylamino)-p-hydroquinone with flexible dibenzylamino groups. AB - We obtained two conformational polymorphs of 2,5-dichloro-3,6-bis(dibenzylamino) p-hydroquinone, C34H30Cl2N2O2. Both polymorphs have an inversion centre at the centre of the hydroquinone ring (Z' = 1/2), and there are no significant differences between their bond lengths and angles. The most significant structural difference in the molecular conformations was found in the rotation of the phenyl rings of the two crystallographically independent benzyl groups. The crystal structures of the polymorphs were distinguishable with respect to the arrangement of the hydroquinone rings and the packing motif of the phenyl rings that form part of the benzyl groups. The phenyl groups of one polymorph are arranged in a face-to-edge motif between adjacent molecules, with intermolecular C-H...pi interactions, whereas the phenyl rings in the other polymorph form a lamellar stacking pattern with no significant intermolecular interactions. We suggest that this partial conformational difference in the molecular structures leads to the significant structural differences observed in their molecular arrangements. PMID- 29620028 TI - Molecular structures of a series of substituted bis(eta5 cyclopentadienyl)titanium dihalides CpR2TiX2 [X = F, Cl, Br and I; R = CHPh2, CH(p-Tol)2 and adamantyl]. AB - Metallocene dihalides and derivatives thereof are of great interest as precursors for catalysts in polymerization reactions, as antitumor agents and, due to their increased stability, as suitable starting materials in salt metathesis reactions and the generation of metallocene fragments. We report the synthesis and structural characterization of a series of eleven substituted bis(eta5 cyclopentadienyl)titanium dihalides, namely bis[eta5-1 (diphenylmethyl)cyclopentadienyl]difluoridotitanium(IV), [Ti(C18H15)2F2], bis{eta5-1-[bis(4-methylphenyl)methyl]cyclopentadienyl}difluoridotitanium(IV), [Ti(C20H19)2F2], and bis{eta5-1-[bis(adamantan-2 yl)methyl]cyclopentadienyl}difluoridotitanium(IV), [Ti(C15H19)2F2], together with the bromide and iodide analogues, and the chloride analogues of the diphenylmethyl and adamantyl complexes. These eleven complexes were prepared by the reaction of the corresponding bis(eta5:eta1-pentafulvene)titanium complexes with different hydrogen halides (Cl, Br and I). The titanocene fluorides become available via chloride-fluoride exchange reactions. PMID- 29620029 TI - Supramolecular arrangement and photophysical properties of a dinuclear cyanophenylboronic acid ester. AB - Boronic esters are useful building blocks for crystal engineering and the generation of supramolecular architectures, including macrocycles, cages and polymers (one-, two- and three-dimensional), with potential utility in diverse fields such as separation, storage and luminescent materials. The novel dinuclear cyanophenylboronic ester described herein, namely 4,4'-(2,4,8,10-tetraoxa-3,9 diboraspiro[5.5]undecane-3,9-diyl)dibenzonitrile, C19H16B2N2O4, was prepared by condensation of 4-cyanophenylboronic acid and pentaerythritol and fully characterized by elemental analysis, IR and NMR (1H and 11B) spectroscopy, single crystal X-ray diffraction analysis and TG-DSC (thermogravimetry-differential scanning calorimetry) studies. In addition, the photophysical properties were examined in solution and in the solid state by UV-Vis and fluorescence spectroscopies. Density functional theory (DFT) calculations with ethanol as solvent reproduced reasonably well the HOMO (highest occupied molecular orbital) and LUMO (lowest unoccupied molecular orbital) of the title compound. Hirshfeld surface and fingerprint plot analyses are presented to illustrate the supramolecular connectivity in the solid state. PMID- 29620030 TI - The vanadate garnet Ca2NaCd2V3O12: a single-crystal X-ray diffraction study. AB - Single crystals of the vanadate garnet Ca2NaCd2V3O12 (dicalcium sodium dicadmium trivanadate) were synthesized using the floating-zone method and the crystal structure was investigated using single-crystal X-ray diffraction. We considered the effectiveness of substitution of the Y-site cation with reference to previous structural studies of vanadate garnets. The structures of vanadate garnets are subject to geometric constraints similar to those of silicate garnets. These constraints force the tetrahedral-dodecahedral shared edge length in vanadate garnets to become shorter than the unshared dodecahedral edge length, as in ugrandite (uvarovite, grossular and andradite) garnets. However, the vanadate garnet Ca2NaCd2V3O12 exhibits the normal structural feature, similar to pyralspite (pyrope, almandine and spessartine) garnets, namely that the dodecahedral-dodecahedral shared edge length is shorter than the unshared dodecahedral edge length. With increasing ionic radius of the Y-site cation, the atomic coordinates x, y and z of oxygen adopt values which satisfy Pauling's third rule. PMID- 29620031 TI - Prevalent polymorphism in benzophenones. AB - We report here the crystal structures of dimorphs of 4-hydroxybenzophenone, C13H10O2, and 4-(dimethylamino)benzophenone, C15H15NO, as well as trimorphs of 4,4'-dimethylbenzophenone, C15H14O. The polymorphs were isolated from slow evaporation conditions or from cocrystallization attempts. The main differences between the polymorphs involve differences in packing rather than differences in conformation, owing to the limited conformational freedom of the three molecules. 4-Hydroxybenzophenone is the exception, exhibiting almost identical packing arrangements in the two polymorphs, with the only major changes being in the interplanar orientations. The lattice energies of the respective polymorphs of the three compounds reported here are all within 1 kcal mol-1 of each other. The existence of nine further polymorphic benzophenone derivatives in the literature suggests that there is a good deal of polymorphic space in this class of compounds. PMID- 29620032 TI - Salt forms of sulfadiazine with alkali metal and organic cations. AB - The structures of four salt forms of sulfadiazine (SDH) with alkali metal cations are presented. Three contain the deprotonated SD anion (C10H9N4O2S). These are the discrete complex diaqua{4-[(pyrimidin-2-ylazanidyl-kappaN1)sulfonyl kappaO]aniline}lithium(I), [Li(SD)(H2O)2], (I), and the coordination polymers poly[{MU3-4-[(pyrimidin-2-ylazanidyl)sulfonyl]aniline}sodium(I)], [Na(SD)]n, (II), and poly[diaqua{MU3-4-[(pyrimidin-2 ylazanidyl)sulfonyl]aniline}potassium(I)], [K(SD)(H2O)2]n, (III). Na complex (II) is a three-dimensional coordination polymer, whilst K complex (III) has two crystallographically independent [K(SD)(H2O)2] units per asymmetric unit (Z' = 2) and gives a two-dimensional coordination polymer whose layers propagate parallel to the crystallographic ab plane. The different bonding modes of the SD anion in these three complexes is discussed. Structure (IV) contains protonated SDH2 cations {4-[(pyrimidin-2-yl)sulfamoyl]anilinium, C10H11N4O2S} and the Orange G dianion [OG, 7-oxo-8-(phenylhydrazinylidene)naphthalene-1,3-disulfonate, C16H10N2O7S2], namely, 4-[(pyrimidin-2-yl)sulfamoyl]anilinium tetraaqua[7-oxo-8 (phenylhydrazinylidene)naphthalene-1,3-disulfonato]sodium(I) sesquihydrate, (SDH2)[Na(OG)(H2O)4].1.5H2O. The [Na(OG)(H2O)4]2 dimers have antiparallel naphthyl ring structures joined through two Na centres that bond to the hydrazone anions through the O atoms of the ketone and sulfonate substituents. The structures of the salts formed on reaction of SDH with 2-aminopyridine and ethanolamine are also presented as 2-aminopyridinium 4-[(pyrimidin-2 ylazanidyl)sulfonyl]aniline, [C5H7N2][SD], (V), and ethanolaminium 4-[(pyrimidin 2-ylazanidyl)sulfonyl]aniline monohydrate, [HOCH2CH2NH3][SD].H2O, (VI), respectively. Structure (V) features a heterodimeric R22(8) hydrogen-bond motif between the cation and the anion, whilst structure (VI) has a tetrameric core of two cations linked by a central R22(10) hydrogen-bonded motif which supports two anions linked to this core by R33(8) motifs. PMID- 29620033 TI - The [4 + 4] thermocyclization of 9-anthraldehyde: synthesis, crystal structure, experimental and theoretical UV spectra, natural bonding orbital analysis and prediction of third-order nonlinear optical properties. AB - The dimer of 9-anthraldehyde, namely heptacyclo[8.6.6.62,9.03,8.011,16.017,22.023,28]octacosa 3,5,7,11,13,15,17(22),18,20,23(28),24,26-dodecaene-1,9-carbaldehyde, C30H20O2, has been synthesized by refluxing an ethanol solution in the presence of M(ClO4)2 and 1,3-diaminopropan-2-ol (M = Co2+ or Cu2+). Its structure has been determined by single-crystal X-ray diffraction, showing it to be a new polymorph, referred to as polymorph II, in the monoclinic space group P21/n. It is compared with the previously reported triclinic modification [Ehrenberg (1968). Acta Cryst. B24, 1123-1125], which is referred to as polymorph I. The asymmetric unit of polymorph II contains two half molecules located on crystallographic centres, while the asymmetric unit of polymorph I includes one half molecule, also located on a crystallographic centre. Time-dependent density functional theory (TD-DFT) at the RB3LYP level using the 6-31G(d,p) basis set was applied. The predicted electronic absorption spectrum is in good agreement with the experimental one. The analysis of the calculated electronic absorption spectrum of polymorph II was carried out in order to assign the observed electronic transitions and to determine their character. A natural bonding orbital (NBO) analysis was executed at the same level to evaluate charge-transfer, intramolecular hydrogen-bonding interactions and hyperconjugative interactions. The third-order nonlinear optical (NLO) properties of the compound were appraised by the ZINDO/sum-over-states method in both static and dynamic states. The orientationally averaged (isotropic) value of gamma for the compound is greater than the corresponding value of 4-nitroaniline (pNA). PMID- 29620035 TI - Two new CoII coordination polymers with multifunctional 5-amino-2,4,6 tribromoisophthalic acid and flexible isomeric bis(imidazole) ligands: preparation, crystal structure and characterization. AB - Two new CoII coordination polymers (CPs), namely, catena-poly[[[(5-amino-2,4,6 tribromobenzene-1,3-dicarboxylato-kappaO)aquacobalt(II)]-bis[MU-1,3-bis(imidazol 1-ylmethyl)benzene-kappa2N:N']] 4.75-hydrate], {[Co(C8H2Br3NO4)(C14H14N4)2(H2O)].4.75H2O}n, (1), and poly[(MU-5-amino-2,4,6 tribromobenzene-1,3-dicarboxylato-kappa2O1:O3)[MU-1,2-bis(imidazol-1 ylmethyl)benzene-kappa2N:N']cobalt(II)], [Co(C8H2Br3NO4)(C14H14N4)]n, (2), have been synthesized successfully by the assembly of multifunctional 5-amino-2,4,6 tribromoisophthalic acid (H2ATBIP) and CoII ions in the presence of the flexible isomeric bis(imidazole) ligands 1,3-bis(imidazol-1-ylmethyl)benzene (mbix) and 1,2-bis(imidazol-1-ylmethyl)benzene (obix). The isomeric mbix and obix ligands have a big influence on the structures of CPs (1) and (2). CP (1) is composed of chains of nanometre-sized elliptical rings, in which the CoII atom exhibits a distorted octahedral coordination geometry and ATBIP2- acts as a monodentate ligand. Two adjacent chains are interlinked by pi-pi stacking interactions and hydrogen bonds, resulting in a supramolecular double chain. Hydrogen-bonded R86(16) rings extend adjacent supramolecular double chains into a two-dimensional supramolecular layer. Halogen bonding and a hydrogen-bonded R42(8) ring further link the two-dimensional supramolecular layers, leading to the formation of a three-dimensional supramolecular network. The CoII ion in CP (2) is tetracoordinated, exhibiting a distorted tetrahedral configuration. The ATBIP2- ligand exhibits a bis(monodentate) coordination bridging mode, linking adjacent CoII ions into zigzag chains, which are further bridged by the auxiliary bridging obix ligand, resulting in a two-dimensional (4,4) topological network. Interlayer hydrogen and halogen-halogen bonding further extend the two-dimensional layers into a three-dimensional supramolecular network. A detailed analysis of the solid state UV-Vis-NIR diffuse-reflectance spectra of (1) and (2) indicates that a wide optical band gap exists in both (1) and (2). CP (1) exhibits an irreversible dehydration-rehydration behaviour. PMID- 29620034 TI - Supramolecular hydrogen-bonding patterns in salts of the antifolate drugs trimethoprim and pyrimethamine. AB - Nine salts of the antifolate drugs trimethoprim and pyrimethamine, namely, trimethoprimium [or 2,4-diamino-5-(3,4,5-trimethoxybenzyl)pyrimidin-1-ium] 2,5 dichlorothiophene-3-carboxylate monohydrate (TMPDCTPC, 1:1), C14H19N4O3+.C5HCl2O2S-, (I), trimethoprimium 3-bromothiophene-2-carboxylate monohydrate, (TMPBTPC, 1:1:1), C14H19N4O3+.C5H2BrO2S-.H2O, (II), trimethoprimium 3-chlorothiophene-2-carboxylate monohydrate (TMPCTPC, 1:1:1), C14H19N4O3+.C5H2ClO2S-.H2O, (III), trimethoprimium 5-methylthiophene-2 carboxylate monohydrate (TMPMTPC, 1:1:1), C14H19N4O3+.C6H5O2S-.H2O, (IV), trimethoprimium anthracene-9-carboxylate sesquihydrate (TMPAC, 2:2:3), C14H19N4O3+.C15H9O2-.1.5H2O, (V), pyrimethaminium [or 2,4-diamino-5-(4 chlorophenyl)-6-ethylpyrimidin-1-ium] 2,5-dichlorothiophene-3-carboxylate (PMNDCTPC, 1:1), C12H14ClN4+.C5HCl2O2S-, (VI), pyrimethaminium 5-bromothiophene-2 carboxylate (PMNBTPC, 1:1), C12H14ClN4+.C5H2BrO2S-, (VII), pyrimethaminium anthracene-9-carboxylate ethanol monosolvate monohydrate (PMNAC, 1:1:1:1), C12H14ClN4+.C15H9O2-.C2H5OH.H2O, (VIII), and bis(pyrimethaminium) naphthalene-1,5 disulfonate (PMNNSA, 2:1), 2C12H14ClN4+.C10H6O6S22-, (IX), have been prepared and characterized by single-crystal X-ray diffraction. In all the crystal structures, the pyrimidine N1 atom is protonated. In salts (I)-(III) and (VI)-(IX), the 2 aminopyrimidinium cation interacts with the corresponding anion via a pair of N H...O hydrogen bonds, generating the robust R22(8) supramolecular heterosynthon. In salt (IV), instead of forming the R22(8) heterosynthon, the carboxylate group bridges two pyrimidinium cations via N-H...O hydrogen bonds. In salt (V), one of the carboxylate O atoms bridges the N1-H group and a 2-amino H atom of the pyrimidinium cation to form a smaller R21(6) ring instead of the R22(8) ring. In salt (IX), the sulfonate O atoms mimic the role of carboxylate O atoms in forming an R22(8) ring motif. In salts (II)-(IX), the pyrimidinium cation forms base pairs via a pair of N-H...N hydrogen bonds, generating a ring motif [R22(8) homosynthon]. Compounds (II) and (III) are isomorphous. The quadruple DDAA (D = hydrogen-bond donor and A = hydrogen-bond acceptor) array is observed in (I). In salts (II)-(IV) and (VI)-(IX), quadruple DADA arrays are present. In salts (VI) and (VII), both DADA and DDAA arrays co-exist. The crystal structures are further stabilized by pi-pi stacking interactions [in (I), (V) and (VII)-(IX)], C-H...pi interactions [in (IV)-(V) and (VII)-(IX)], C-Br...pi interactions [in (II)] and C Cl...pi interactions [in (I), (III) and (VI)]. Cl...O and Cl...Cl halogen-bond interactions are present in (I) and (VI), with distances and angles of 3.0020 (18) and 3.5159 (16) A, and 165.56 (10) and 154.81 (11) degrees , respectively. PMID- 29620036 TI - The structures of 1,4-diaryl-5-trifluoromethyl-1H-1,2,3-triazoles related to J147, a drug for treating Alzheimer's disease. AB - J147 [N-(2,4-dimethylphenyl)-2,2,2-trifluoro-N'-(3 methoxybenzylidene)acetohydrazide] has recently been reported as a promising new drug for the treatment of Alzheimer's disease. The X-ray structures of seven new 1,4-diaryl-5-trifluoromethyl-1H-1,2,3-triazoles, namely 1-(3,4-dimethylphenyl)-4 phenyl-5-trifluoromethyl-1H-1,2,3-triazole (C17H14F3N3, 1), 1-(3,4 dimethylphenyl)-4-(3-methoxyphenyl)-5-trifluoromethyl-1H-1,2,3-triazole (C18H16F3N3O, 2), 1-(3,4-dimethylphenyl)-4-(4-methoxyphenyl)-5-trifluoromethyl-1H 1,2,3-triazole (C18H16F3N3O, 3), 1-(2,4-dimethylphenyl)-4-(4-methoxyphenyl)-5 trifluoromethyl-1H-1,2,3-triazole (C18H16F3N3O, 4), 1-[2,4 bis(trifluoromethyl)phenyl]-4-(3-methoxyphenyl)-5-trifluoromethyl-1H-1,2,3 triazole (C18H10F9N3O, 5), 1-(3,4-dimethoxyphenyl)-4-(3,4-dimethoxyphenyl)-5 trifluoromethyl-1H-1,2,3-triazole (C19H18F3N3O4, 6) and 3-[4-(3,4 dimethoxyphenyl)-5-(trifluoromethyl)-1H-1,2,3-triazol-1-yl]phenol (C17H14F3N3O3, 7), have been determined and compared to that of J147. B3LYP/6-311++G(d,p) calculations have been performed to determine the potential surface and molecular electrostatic potential (MEP) of J147, and to examine the correlation between hydrazone J147 and the 1,2,3-triazoles, both bearing a CF3 substituent. Using MEPs, it was found that the minimum-energy conformation of 4, which is nearly identical to its X-ray structure, is closely related to one of the J147 seven minima. PMID- 29620037 TI - Association of interleukin 1 receptor antagonist intron 2 variable number of tandem repeats polymorphism with vitiligo susceptibility in Gujarat population. AB - Background: Vitiligo is a multifactorial, polygenic, autoimmune skin disorder caused by selective destruction of melanocytes. Interleukin 1 receptor antagonist intron 2 polymorphism was found to be associated with various autoimmune disorders. Aims: We aimed to investigate the association of interleukin 1 receptor antagonist intron 2 variable number of tandem repeats polymorphism (rs2234663) with vitiligo to assess interleukin 1 receptor antagonist transcript levels and to perform possible genotype-phenotype correlation. Methods: Three hundred and seven vitiligo patients and 316 controls were enrolled in the study, genotyping of interleukin 1 receptor antagonist rs2234663 was performed by polymerase chain reaction, and relative gene expression of interleukin 1 receptor antagonist was carried out in peripheral blood mononuclear cells from patients (n = 36) and controls (n = 36) by real-time-PCR. Results: A significant difference was observed in the frequency of interleukin 1 receptor antagonist *A (1/2) genotype among patients with active and stable vitiligo (P = 0.0172). Interleukin 1 receptor antagonist*A (2/2) genotype and allele frequencies were significantly different between SV patients and controls (P = 0.0246 and P = 0.0046, respectively). Significant difference was also observed for interleukin 1 receptor antagonist*A2 (allele) in active and stable vitiligo patients (P = 0.0060). However, other comparisons did not show any significant difference in genotype and allele frequencies. Moreover, interleukin 1 receptor antagonist*A (3/2) genotype was observed only in patients whereas interleukin 1 receptor antagonist*A (5/2) was observed only in controls. Gene expression analysis showed no significant difference in interleukin 1 receptor antagonist transcript levels in patients compared to controls (P = 0.5962). Interestingly, genotype-phenotype correlation analysis revealed that individuals with IL1RN*A (2/2) exhibited higher interleukin 1 receptor antagonist expression compared to other major genotypes interleukin 1 receptor antagonist*A (1/2) (P = 0.01) and interleukin 1 receptor antagonist*A (1/1) (P = 0.03). Limitations: More case-control studies on interleukin 1 receptor antagonist rs2234663 polymorphism and gene expression from different ethnic populations are required to explore the impact of interleukin 1 receptor antagonist in vitiligo susceptibility. Conclusion: Interleukin 1 receptor antagonist*A2 might be a risk factor for progressive vitiligo. PMID- 29620038 TI - Dermoscopy of lichen planus pigmentosus in Indian patients - Pitfalls to avoid. PMID- 29620040 TI - An observational study on glabellar wrinkle patterns in Indians. AB - BACKGROUND: Botulinum A exotoxin is an established treatment for glabellar frown lines, crow's feet, and horizontal furrows of the forehead. The glabella is probably the most common site for botulinum toxin treatment in Asians. Five glabellar contraction patterns have been classified in earlier studies based on eyebrow approximation, depression, and elevation. Unfortunately, this was found to be confusing by many practitioners. Indians, as all Asians, have smaller muscles compared to the European population, and there is no consensus on the optimal dosage per injection site or concentration of toxin to be used. AIMS: (a) Identification and classification of glabellar wrinkle patterns in Indians. (b) Optimization of the minimal effective dose of toxin per site. MATERIALS AND METHODS: Retrospective photographic analysis of 200 patients who received botulinum toxin for the first time to treat glabellar wrinkles was conducted. The wrinkle patterns were identified and classified by the authors based on the prevalence of perpendicular and transverse glabellar lines, nasal, and forehead wrinkles. RESULTS: Six patterns were identified: (1) 11 (2) U (3) Pi (4) X (5) W (6) I. The relevant muscles were identified and doses optimized for those sites. LIMITATIONS: The doses mentioned in this study are not universal for all patients and toxin units would have to be altered and individualized according to the bulk of the facial muscles and individual needs. CONCLUSION: The investigators classification, injection patterns, and dosage may provide valuable guidance to facial esthetic treatment. PMID- 29620039 TI - Recurrent unilateral angiolymphoid hyperplasia with eosinophilia in pregnancy. PMID- 29620041 TI - Primary mucinous carcinoma of skin with a trichoadenomatous component: A rare case report. AB - Primary mucinous carcinoma of the skin is a rare subtype of eccrine sweat gland tumors. Differentiating it from metastatic adenocarcinomas is important in the management of this condition. We report the case of a 55-year-old female presenting with a painless nodule, which was subsequently diagnosed as primary mucinous carcinoma of skin with a trichoadenomatous component. The possibility of a metastatic adenocarcinoma was ruled out by performing ultrasound abdomen, total body computed tomography, mammogram and colonoscopy. PMID- 29620042 TI - Dome-shaped nodules and scaly, verruciform plaques on the legs and feet. PMID- 29620043 TI - The strawberry tongue: What, how and where? PMID- 29620044 TI - Primary cutaneous histoplasmosis in an immunocompetent patient presenting with severe pruritus. PMID- 29620045 TI - Authors' reply. PMID- 29620046 TI - Clinical profile and virology analysis of hand, foot and mouth disease cases from North Kerala, India in 2015-2016: A tertiary care hospital-based cross-sectional study. PMID- 29620047 TI - In response to "Effectiveness of topical green tea against multidrug-resistant Staphylococcus aureus in cases of primary pyoderma: An open controlled trial". PMID- 29620049 TI - Oncogene-induced senescence: a double edged sword in cancer. AB - Oncogene-induced cellular senescence (OIS) is a complex program that is triggered in response to aberrant activation of oncogenic signaling. Initially, OIS was thought to be a barrier to malignant transformation because of its suppression on cell proliferation. Later studies showed that senescence induced by oncogenes can also promote the initiation and development of cancer. The opposing effects of OIS occur through different combinations of downstream effectors as well as the interplay of senescent cells and the microenvironment, such as senescence associated inflammation. Here, we review the common features and molecular mechanisms underlying OIS and the interaction between senescent cells and the microenvironment. We propose that targeting senescent cells may have a beneficial therapeutic effect during the treatment of cancer. PMID- 29620048 TI - Protective Effects of Sinomenine on CFA-Induced Inflammatory Pain in Rats. AB - BACKGROUND The purpose of this study was to investigate the effects of sinomenine (SIN) on CFA-induced inflammatory pain in rats, and to explore the underlying molecular mechanisms. MATERIAL AND METHODS To determine the potential influences of SIN in the pathogenesis of inflammatory pain, an inflammatory pain (IP) mouse model was established and rats were treated with SIN (30 mg/kg). Behavioral tests were used to assess the MWT and TWL of the rats. ELISA assay was used to detect the level of inflammation cytokines. Western blotting and qRT-PCR were carried out to measure the related protein and mRNA expression level, respectively. RESULTS We found that the MWT and TWL of the CFA-treated rats were markedly lower than that of the control rats, and they were significantly increased by SIN administration. The results suggest that IP rats had higher levels of TNF-alpha, IL-1beta and IL-6 compared with the control rats. SIN administration decreased the levels of TNF-alpha, IL-1beta, and IL-6. In addition, we found that p-p65 and p-p38 expression notably decreased after SIN treatment in IP rats. Moreover, the results showed that SIN inhibited Cox-2 and PGE2 expression in IP rats. CONCLUSIONS The data indicate that SIN had a protective role in inflammatory pain through repressing inflammatory mediators via preventing the p38MAPK-NF-kappaB pathway. PMID- 29620051 TI - Manipulation-free cultures of human iPSC-derived cardiomyocytes offer a novel screening method for cardiotoxicity. AB - Induced pluripotent stem cell (iPSC)-based cardiac regenerative medicine requires the efficient generation, structural soundness and proper functioning of mature cardiomyocytes, derived from the patient's somatic cells. The most important functional property of cardiomyocytes is the ability to contract. Currently available methods routinely used to test and quantify cardiomyocyte function involve techniques that are labor-intensive, invasive, require sophisticated instruments or can adversely affect cell vitality. We recently developed optical flow imaging method analyses and quantified cardiomyocyte contractile kinetics from video microscopic recordings without compromising cell quality. Specifically, our automated particle image velocimetry (PIV) analysis of phase contrast video images captured at a high frame rate yields statistical measures characterizing the beating frequency, amplitude, average waveform and beat-to beat variations. Thus, it can be a powerful assessment tool to monitor cardiomyocyte quality and maturity. Here we demonstrate the ability of our analysis to characterize the chronotropic responses of human iPSC-derived cardiomyocytes to a panel of ion channel modulators and also to doxorubicin, a chemotherapy agent with known cardiotoxic side effects. We conclude that the PIV derived beat patterns can identify the elongation or shortening of specific phases in the contractility cycle, and the obtained chronotropic responses are in accord with known clinical outcomes. Hence, this system can serve as a powerful tool to screen the new and currently available pharmacological compounds for cardiotoxic effects. PMID- 29620050 TI - Pharmacokinetics and disposition of anlotinib, an oral tyrosine kinase inhibitor, in experimental animal species. AB - Anlotinib is a new oral tyrosine kinase inhibitor; this study was designed to characterize its pharmacokinetics and disposition. Anlotinib was evaluated in rats, tumor-bearing mice, and dogs and also assessed in vitro to characterize its pharmacokinetics and disposition and drug interaction potential. Samples were analyzed by liquid chromatography/mass spectrometry. Anlotinib, having good membrane permeability, was rapidly absorbed with oral bioavailability of 28%-58% in rats and 41%-77% in dogs. Terminal half-life of anlotinib in dogs (22.8+/-11.0 h) was longer than that in rats (5.1+/-1.6 h). This difference appeared to be mainly associated with an interspecies difference in total plasma clearance (rats, 5.35+/-1.31 L.h-1.kg-1; dogs, 0.40+/-0.06 L.h-1/kg-1). Cytochrome P450 mediated metabolism was probably the major elimination pathway. Human CYP3A had the greatest metabolic capability with other human P450s playing minor roles. Anlotinib exhibited large apparent volumes of distribution in rats (27.6+/-3.1 L/kg) and dogs (6.6+/-2.5 L/kg) and was highly bound in rat (97%), dog (96%), and human plasma (93%). In human plasma, anlotinib was predominantly bound to albumin and lipoproteins, rather than to alpha1-acid glycoprotein or gamma-globulins. Concentrations of anlotinib in various tissue homogenates of rat and in those of tumor-bearing mouse were significantly higher than the associated plasma concentrations. Anlotinib exhibited limited in vitro potency to inhibit many human P450s, UDP-glucuronosyltransferases, and transporters, except for CYP3A4 and CYP2C9 (in vitro half maximum inhibitory concentrations, <1 MUmol/L). Based on early reported human pharmacokinetics, drug interaction indices were 0.16 for CYP3A4 and 0.02 for CYP2C9, suggesting that anlotinib had a low propensity to precipitate drug interactions on these enzymes. Anlotinib exhibits many pharmacokinetic characteristics similar to other tyrosine kinase inhibitors, except for terminal half-life, interactions with drug metabolizing enzymes and transporters, and plasma protein binding. PMID- 29620052 TI - Inflammation-activated CXCL16 pathway contributes to tubulointerstitial injury in mouse diabetic nephropathy. AB - Inflammation and lipid disorders play crucial roles in synergistically accelerating the progression of diabetic nephropathy (DN). In this study we investigated how inflammation and lipid disorders caused tubulointerstitial injury in DN in vivo and in vitro. Diabetic db/db mice were injected with 10% casein (0.5 mL, sc) every other day for 8 weeks to cause chronic inflammation. Compared with db/db mice, casein-injected db/db mice showed exacerbated tubulointerstitial injury, evidenced by increased secretion of extracellular matrix (ECM) and cholesterol accumulation in tubulointerstitium, which was accompanied by activation of the CXC chemokine ligand 16 (CXCL16) pathway. In the in vitro study, we treated HK-2 cells with IL-1beta (5 ng/mL) and high glucose (30 mmol/L). IL-1beta treatment increased cholesterol accumulation in HK-2 cells, leading to greatly increased ROS production, ECM protein expression levels, which was accompanied by the upregulated expression levels of proteins in the CXCL16 pathway. In contrast, after CXCL16 in HK-2 cells was knocked down by siRNA, the IL-1beta-deteriorated changes were attenuated. In conclusion, inflammation accelerates renal tubulointerstitial lesions in mouse DN via increasing the activity of CXCL16 pathway. PMID- 29620054 TI - Haemochromatosis. AB - Haemochromatosis is defined as systemic iron overload of genetic origin, caused by a reduction in the concentration of the iron regulatory hormone hepcidin, or a reduction in hepcidin-ferroportin binding. Hepcidin regulates the activity of ferroportin, which is the only identified cellular iron exporter. The most common form of haemochromatosis is due to homozygous mutations (specifically, the C282Y mutation) in HFE, which encodes hereditary haemochromatosis protein. Non-HFE forms of haemochromatosis due to mutations in HAMP, HJV or TFR2 are much rarer. Mutations in SLC40A1 (also known as FPN1; encoding ferroportin) that prevent hepcidin-ferroportin binding also cause haemochromatosis. Cellular iron excess in HFE and non-HFE forms of haemochromatosis is caused by increased concentrations of plasma iron, which can lead to the accumulation of iron in parenchymal cells, particularly hepatocytes, pancreatic cells and cardiomyocytes. Diagnosis is noninvasive and includes clinical examination, assessment of plasma iron parameters, imaging and genetic testing. The mainstay therapy is phlebotomy, although iron chelation can be used in some patients. Hepcidin supplementation might be an innovative future approach. PMID- 29620056 TI - Haemochromatosis. PMID- 29620055 TI - Corrigendum: Control of Radiative Exciton Recombination by Charge Transfer Induced Surface Dipoles in MoS2 and WS2 Monolayers. AB - This corrects the article DOI: 10.1038/srep24105. PMID- 29620057 TI - Bladder cancer: Neuroendocrine disease genomics. PMID- 29620053 TI - Proteostasis in Huntington's disease: disease mechanisms and therapeutic opportunities. AB - Many neurodegenerative diseases are characterized by impairment of protein quality control mechanisms in neuronal cells. Ineffective clearance of misfolded proteins by the proteasome, autophagy pathways and exocytosis leads to accumulation of toxic protein oligomers and aggregates in neurons. Toxic protein species affect various cellular functions resulting in the development of a spectrum of different neurodegenerative proteinopathies, including Huntington's disease (HD). Playing an integral role in proteostasis, dysfunction of the ubiquitylation system in HD is progressive and multi-faceted with numerous biochemical pathways affected, in particular, the ubiquitin-proteasome system and autophagy routes for protein aggregate degradation. Unravelling the molecular mechanisms involved in HD pathogenesis of proteostasis provides new insight in disease progression in HD as well as possible therapeutic avenues. Recent developments of potential therapeutics are discussed in this review. PMID- 29620058 TI - Prostate cancer: Validating radiographic progression-free survival. PMID- 29620059 TI - Erectile dysfunction: Neurotrophins to recover erectile function. PMID- 29620060 TI - Kidney cancer: Combining targeted and immunotherapy. PMID- 29620061 TI - Prostate cancer: Quality of life during chemohormonal therapy. PMID- 29620062 TI - Brain and spinal cord infarcts secondary to an atrial-esophageal fistula. PMID- 29620063 TI - Development of a cerebral mycotic aneurysm within 5 days. PMID- 29620064 TI - Preoperative evaluation for epilepsy surgery: Process improvement. PMID- 29620065 TI - Chronic diphenhydramine abuse and withdrawal: A diagnostic challenge. PMID- 29620066 TI - Reduced diffusion in acute cervical cord multiple sclerosis lesions. PMID- 29620068 TI - Case reports: Connecting the clinical dots. PMID- 29620067 TI - Rabies encephalitis presenting with new-onset refractory status epilepticus (NORSE). PMID- 29620069 TI - Anton syndrome as a result of MS exacerbation. PMID- 29620070 TI - Nivolumab-induced posterior reversible encephalopathy syndrome. PMID- 29620071 TI - A case of cervical radiculopathy due to tuberculosis cervical lymphadenitis. PMID- 29620072 TI - Neurobehavioral characterization of adult-onset Alexander disease: A family study. PMID- 29620073 TI - Commentary: Genetic evolution of classical swine fever virus under immune environments conditioned by genotype 1-based modified live virus vaccine. PMID- 29620074 TI - Focal cerebral beta-amyloid angiopathy: A distinct clinicopathologic presentation. PMID- 29620075 TI - Total spinal and brainstem anesthesia as complication of paravertebral ropivacaine administration. PMID- 29620076 TI - The financial contribution of the multiple sclerosis specialist. PMID- 29620077 TI - Granulomatous meningitis secondary to Avitene (microfibrillar collagen). PMID- 29620078 TI - Acute polyneuropathy in a metastatic melanoma patient treated with vemurafenib and cobimetinib. PMID- 29620080 TI - Neuromyelitis optica spectrum disorder in the elderly associated with bronchiolitis obliterans organizing pneumonia. PMID- 29620079 TI - Correction: A novel lens cleaner to prevent water drop adhesions during colonoscopy and esophagogastroduodenoscopy. AB - [This corrects the article DOI: 10.1055/s-0043-120659.]. PMID- 29620081 TI - Relative adrenal insufficiency in adult-onset cerebral X-linked adrenoleukodystrophy. PMID- 29620082 TI - Brain sagging syndrome presenting with chorea. PMID- 29620083 TI - Cerebral toxoplasmosis diagnosed by brain tissue PCR analysis in an immunocompetent patient. PMID- 29620084 TI - PLP1 mutations and central demyelination: Evidence from electrophysiologic phenotyping in female manifesting carriers. PMID- 29620085 TI - Cerebral microemboli detection for monitoring structural cardiac disease. PMID- 29620086 TI - Drop attacks: A clinical manifestation of LGI1 encephalitis. PMID- 29620087 TI - Sensory and autonomic involvement in West Nile virus-associated acute flaccid paralysis. PMID- 29620088 TI - Persistent focal enhancement of the cisternal segment of oculomotor nerve in ophthalmoplegic migraine. PMID- 29620090 TI - Alternating hemiplegia of childhood: Clinical case and video description. PMID- 29620089 TI - Adult case of acute flaccid paralysis with enterovirus D68 detected in the CSF. PMID- 29620091 TI - NMDA receptor antibody encephalitis presenting with enhancing lesion and seizures. PMID- 29620092 TI - Hierarchically porous, ultra-strong reduced graphene oxide-cellulose nanocrystal sponges for exceptional adsorption of water contaminants. AB - Self-assembly of graphene oxide (GO) nanosheets into porous 3D sponges is a promising approach to exploit their capacity to adsorb contaminants while facilitating the recovery of the nanosheets from treated water. Yet, forming mechanically robust sponges with suitable adsorption properties presents a significant challenge. Ultra-strong and highly porous 3D sponges are formed using GO, vitamin C (VC), and cellulose nanocrystals (CNCs) - natural nanorods isolated from wood pulp. CNCs provide a robust scaffold for the partially reduced GO (rGO) nanosheets resulting in an exceptionally stiff nanohybrid. The concentration of VC as a reducing agent plays a critical role in tailoring the pore architecture of the sponges. By using excess amounts of VC, a unique hierarchical pore structure is achieved, where VC grains act as soft templates for forming millimeter-sized pores, the walls of which are also porous and comprised of micron-sized pores. The unique hierarchical pore structure ensures the interconnectivity of pores even at the core of large sponges as evidenced by micro and nano X-ray computed tomography. The unique pore architecture translates into an exceptional specific surface area for adsorption of a wide range of contaminants, such as dyes, heavy metals, pharmaceuticals and cyanotoxin from water. PMID- 29620093 TI - Carbazole-based compounds as photoinitiators for free radical and cationic polymerization upon near visible light illumination. AB - Six new carbazole based compounds (Ca1-Ca6) are synthesized and proposed as high performance photoinitiators with iodonium salt (iod) and/or an amine (EDB) for both the free radical polymerization (FRP) of acrylates and the cationic polymerization (CP) of epoxides upon near UV and visible light exposure using light emitting diodes (LEDs) @385 nm and @405 nm. Excellent polymerization initiating abilities are found and high final reactive function conversions are acquired. A full picture of the involved photochemical mechanisms is given. PMID- 29620094 TI - An integrated experimental and theoretical reaction path search: analyses of the multistage reaction of an ionized diethylether dimer involving isomerization, proton transfer, and dissociation. AB - An ionization-induced multistage reaction of an ionized diethylether (DEE) dimer involving isomerization, proton transfer, and dissociation is investigated by combining infrared (IR) spectroscopy, tandem mass spectrometry, and a theoretical reaction path search. The vertically-ionized DEE dimer isomerizes to a hydrogen bonded cluster of protonated DEE and the [DEE-H] radical through barrierless intermolecular proton transfer from the CH bond of the ionized moiety. This isomerization process is confirmed by IR spectroscopy and the theoretical reaction path search. The multiple dissociation pathways following the isomerization are analyzed by tandem mass spectrometry. The isomerized cluster dissociates stepwise into a [protonated DEE-acetaldehyde (AA)] cluster, protonated DEE, and protonated AA. The structure of the fragment ion is also analyzed by IR spectroscopy. The reaction map of the multistage processes is revealed through a harmony of these experimental and theoretical methods. PMID- 29620095 TI - Polymer micro/nanocarrier-assisted synergistic chemohormonal therapy for prostate cancer. AB - Hormotherapy and chemotherapy are still the most important palliative therapeutic approaches for androgen-sensitive prostate cancer (PCa). Recently, the combination of hormotherapy and chemotherapy, namely, chemohormonal therapy has aroused considerable attention. Although synergistic chemohormonal therapy can improve PCa suppression efficacy and prolong the lives of patients, it also leads to severe adverse effects, that is, hormonal tolerance caused by hormotherapy, and leukemia or neutropenia caused by chemotherapy. Therefore, alleviating the adverse effects and improving anti-PCa efficacy are the focuses of the chemohormonal therapy for future researches. In this study, the commercial androgen-deprivation therapy (ADT), polyester microsphere Enantone (ENT), and polypeptide micelles loaded with a clinical antitumor agent mitoxantrone (MTO) are employed for micro/nanocarrier-assisted chemohormonal therapy. Encouragingly, the combined chemohormonal therapy significantly boosts antitumor efficacy and ameliorates side effects in preclinical assessments. With these benefits, the micro/nanocarrier-assisted chemohormonal therapy can be incorporated as an efficient clinical strategy for PCa patients. PMID- 29620096 TI - Influence of additives on thermoresponsive polymers in aqueous media: a case study of poly(N-isopropylacrylamide). AB - Thermoresponsive polymers (TRPs) in different solvent media have been studied over a long period and are important from both scientific and technical points of view. Despite numerous studies on the behavior of TRPs with various additives, the interactions of additives with TRPs are still poorly understood. Moreover, despite the vast available literature regarding the biomolecular interactions between various TRPs and naturally occurring additives, it is not possible to provide a unifying declaration about the behavior of different additives, in particular at the phase transition temperature of the polymer. However, potential reviews that describe the behavior of additives as stimuli upon the phase transition of TRPs are also absent. A lack of sufficient knowledge regarding the responses of TRPs to additives as stimuli has hindered the expansion of the wide spectrum of applications of these polymers. Therefore, it was proposed to review the responses of TRPs in the presence of various additives in aqueous media. In depth knowledge acquired via a literature survey has drawn our attention towards filling this gap by analyzing the interactions of TRPs with different additives. In this perspective, we have systematically examined the stability, aggregation, and phase transition behaviours of various polymers in the presence of different additives. The perspective on the influence of additives as stimuli on the behavior of TRPs in an aqueous medium will provide new reliable information about intramolecular interactions between interior polymer segments as well as intermolecular interactions between TRPs and additive molecules, which will be helpful for industrialists in the preparation of new polymeric materials for drug delivery systems. PMID- 29620097 TI - Structure-based design of targeted covalent inhibitors. AB - Covalent inhibition is a rapidly growing discipline within drug discovery. Many historical covalent inhibitors were discovered by serendipity, with such a mechanism of action often regarded as undesirable due to potential toxicity issues. Recent progress has seen a major shift in this outlook, as covalent inhibition shows promise for targets where previous efforts to identify non covalent small molecule inhibitors have failed. Targeted covalent inhibitors (TCIs) can offer drug discovery scientists the ability to increase the potency and/or selectivity of small molecule inhibitors, by attachment of reactive functional groups designed to covalently bind to specific sites in a target. In this tutorial review we introduce the broader concept of covalent inhibition, discuss the potential benefits and challenges of such an approach, and provide an overview of the current status of the field. We also describe some strategies and computational tools to enable successful covalent drug discovery. PMID- 29620098 TI - Maintenance of the spheroid organization and properties of glandular progenitor cells by fabricated chitosan based biomaterials. AB - Dysfunctional salivary gland (SG) is an unsolved clinical challenge, which is presented as xerostomia. Cell therapy is a promising treatment for restoring SG function. Salispheres are spheroid cellular organizations derived from SG stem cells. Benefitting from these cellular organizations, SG stem cells can be expanded to regenerate SG. During in vitro culture, the spontaneous reorganization of salispheres may change the features of residing SG stem cells. Therefore, it is imperative to explore ways to maintain the spheroid structure of salispheres during cell expansion in vitro. Herein, we explored biomaterial approaches using chitosan. Chitosan based biomaterials were fabricated in different forms to offer distinct interactive surfaces for cultured salispheres. The number and size of the salispheres increase in the chitosan-containing systems without increasing the incidence of spheroid cavitation. The effect of chitosan increases with high chitosan concentrations, which is optimum when chitosan is fabricated in a soluble form. The chitosan effect contributes to the regulation of the intercellular interactions and polarization within the spheroid structures. By retarding the process of salisphere cavitation, chitosan preserves the features of salivary gland progenitor cells in the cultured salispheres. The results suggest that the chitosan-containing system could effectively maintain the primitive structures and properties of salispheres during in vitro expansion, which demonstrates the potential application of salispheres for cell therapy of dysfunctional SG. PMID- 29620099 TI - High alkaline ion storage capacity of hollow interwoven structured Sb/TiO2 particles: the galvanic replacement formation mechanism and volumetric buffer effect. AB - A new galvanic replacement synthetic strategy using metallic Ti as a template for hollow voids is presented and an intriguing hollow interwoven structured Sb/TiO2 is introduced. The applied Ti can play the triple role of reducing the Sb-ion into Sb, acting as a sacrificial template to generate hollow voids through a structural evolution and behaving as an alternative non-sensitive titanium salt to form TiO2. Interwoven Sb/TiO2 can be readily activated and can also buffer drastic volumetric variations during storage of alkaline ions (e.g. Li+, Na+), thereby demonstrating high capacity and superior cycling ability in rechargeable batteries. PMID- 29620105 TI - Anisotropic vacancy-mediated phonon mode softening in Sm and Gd doped ceria. AB - Ceria doped with Sm and Gd (SDC and GDC) has been suggested as a promising candidate for the electrolyte used in solid oxide fuel cells (SOFCs), since it has relatively high oxygen ion conductivity at intermediate temperature. There have been many previous experimental and computational studies to investigate the properties, structure, and effect of vacancies, etc. for SDC and GDC. However, in these previous studies, it is commonly assumed that the interaction between oxygen vacancies is negligible and many focus only on the mono-vacancy system. In addition, the possibility of anisotropic vibrational motion of the oxygen ions around vacancies is often neglected. In this paper, using both first-principle density-functional theory and classical molecular dynamics calculations, we investigate the structural and vibrational properties of the optimized SDC and GDC structures, such as bonding analysis, phonon density-of-state and mean-square displacement of the oxygen ions. Also, we report the direction-dependent vibrations at the specific frequency of the oxygen ions near the vacancies, activation energies, and diffusion coefficients of SDC and GDC which can extend our understanding of diffusion dynamics in doped ceria-based electrolytes for SOFC applications. PMID- 29620108 TI - Highly efficient white-light emission in a polar two-dimensional hybrid perovskite. AB - Broadband white-light emission was realized in a polar two-dimensional hybrid perovskite, (2meptH2)PbBr4 (2mept = 2-methyl-1,5-diaminopentane). The white-light emission originates from self-trapped excitons owing to the distortion-induced polar structure. Notably, it exhibits a high photoluminescence quantum efficiency of 3.37% and an ultrahigh colour rendering index of 91. PMID- 29620109 TI - Using porphyrin-amino acid pairs to model the electrochemistry of heme proteins: experimental and theoretical investigations. AB - Quasi reversibility in electrochemical cycling between different oxidation states of iron is an often seen characteristic of iron containing heme proteins that bind dioxygen. Surprisingly, the system becomes fully reversible in the bare iron porphyrin complex: hemin. This leads to the speculation that the polypeptide bulk (globin) around the iron-porphyrin active site in these heme proteins is probably responsible for the electrochemical quasi reversibility. To understand the effect of such polypeptide bulk on iron-porphyrin, we study the interaction of specific amino acids with the hemin center in solution. We choose three representative amino acids-histidine (a well-known iron coordinator in bio-inorganic systems), tryptophan (a well-known fluoroprobe for proteins), and cysteine (a redox-active organic molecule). The interactions of these amino acids with hemin are studied using electrochemistry, spectroscopy, and density functional theory. The results indicate that among these three, the interaction of histidine with the iron center is strongest. Further, histidine maintains the electrochemical reversibility of iron. On the other hand, tryptophan and cysteine interact weakly with the iron center but disturb the electrochemical reversibility by contributing their own redox active processes to the system. Put together, this study attempts to understand the molecular interactions that can control electrochemical reversibility in heme proteins. The results obtained here from the three representative amino acids can be scaled up to build a heme-amino acid interaction database that may predict the electrochemical properties of any protein with a defined polypeptide sequence. PMID- 29620110 TI - Carbon-ZnO alternating quantum dot chains: electrostatic adsorption assembly and white light-emitting device application. AB - Aggregation-induced quenching (ACQ) in carbon nanodots (CNDs) impede their applications in solid devices. Herein, the concept of alternating quantum dot (QD) chains was proposed to overcome the common issue of fluorescence quenching in CNDs; in this study, CNDs and ZnO QDs were interlinked to form carbon-ZnO alternating quantum dot chains (CZA-QDCs), which overcame the ACQ of CNDs and hence ensured efficient full-spectrum fluorescence for white light-emitting devices (WLEDs) without excessive blue emission. Under the excitation of 365 nm lines, white emission resulting from the combination of blue emission from the CNDs and yellow emission from the ZnO QDs has been achieved from these powders. The quantum efficiency of the CZA-QDC powders can reach 49% and remain stable for two months. By coating the powders onto an ultraviolet chip as phosphors, WLEDs with a luminous efficiency of 20.1 lm W-1, color coordinate of (0.30, 0.35), correlated color temperature of 5205 K, and a color rendering index of 84 have been fabricated. Due to the relatively high abundance and eco-friendly characteristics of both carbon and ZnO, the results reported herein may provide a promising alternative to fluorescent phosphors that are widely used in WLEDs. PMID- 29620112 TI - Copper-mediated regioselective hydrodifluoroalkylation of alkynes. AB - A highly regioselective copper-mediated hydrodifluoroalkylation of alkynes with ethyl bromodifluoroacetate or bromodifluoroacetamides has been developed. This strategy provides straightforward access to a variety of difluoroalkylated alkenes under mild reaction conditions with low-cost cuprous bromide and metabisulfite as reduction agents. A wide range of alkynes are applicable under these reaction conditions. The excellent functional-group compatibility and good regio- and stereoselectivities are the notable features of this transformation. PMID- 29620113 TI - Zeolitic imidazolate framework-8 film coated stainless steel meshes for highly efficient oil/water separation. AB - Highly compact ZIF-8 film coated stainless steel meshes (ZFCMs) are simply fabricated via the seeding method. The ZFCMs become more hydrophilic in air and close to superoleophobic under water. The prewetting induced underwater oleophobicity of the ZFCMs has been reported here for the first time. Water prewetted ZFCMs possess excellent aqueous stability and can efficiently separate various oil/water mixtures. PMID- 29620114 TI - A luminescent europium-dipicolinic acid nanohybrid for the rapid and selective sensing of pyrophosphate and alkaline phosphatase activity. AB - As a ubiquitous hydrolysis enzyme in phosphate metabolism, alkaline phosphatase (ALP) is a significant biomarker in laboratory research and clinic diagnosis. Herein, we report a highly water-soluble Eu(DPA)3@Lap nanohybrid material for the rapid and selective assay of PPi and ALP through a luminescence off-on recognition process. Eu(DPA)3@Lap was successfully prepared in an aqueous solution, and it exhibited strong luminescence emission, high photostability, and long lifetime. More interestingly, the strong luminescence of Eu(DPA)3@Lap can be remarkably quenched by Cu2+ due to the high impetus of coordination between the DPA ligand and Cu2+ ion. Using Cu2+ as a signal transducer, the luminescence could be recovered upon the addition of PPi ion owing to the formation of a Cu2+ PPi complex; thus, a luminescence turn-on assay for PPi ions was realized. Utilizing the ability of Cu2+ to differentiate between PPi and Pi, a convenient and straightforward luminescence assay for ALP activity was accomplished based on the specific dephosphorylation of PPi to Pi. To the best of our knowledge, this elaborate luminescence sensing system constitutes the first luminescent nanohybrid material based on a europium organic complex for ALP activity assay. Furthermore, the recognition process of PPi and ALP was completed in a convenient and facile mix-and-readout manner, and it revealed significant potential in point of care testing. PMID- 29620115 TI - The plasmonic properties of gold nanoparticle clusters formed via applying an AC electric field. AB - An external electric AC field with a field strength ranging from 10 V mm-1 to 30 V mm-1 and a frequency ranging from 0.1 kHz to 1 MHz was applied to suspensions of gold nanoparticles (Au NPs) to control their plasmonic properties. Apparent differences in the UV-vis spectra of the Au NPs were observed between the spectra with and without the field application. The characteristic red color of the Au NP suspension darkened; this suggested that the application of the AC field caused the aggregation of the Au NPs. In addition, the sizes of the Au NP clusters in suspension formed by the AC field application depended on the frequency of the applied field. The surface-enhanced Raman scattering (SERS) effects of Au NP clusters were examined by comparing the difference in Raman intensities obtained at 30 V mm-1 and in a frequency range of 0.1 kHz to 1 MHz. The application of a low-frequency field at 0.1 kHz caused a rapid aggregation of the Au NPs, resulting in low Raman intensities of the probe molecules. Conversely, high frequency applications between 1 kHz and 1 MHz successfully enhanced the Raman intensities of the molecules in suspension. The strong correlation of the optical/sensing properties with the Au NP clustering states reveals that the application of an AC electric field is a powerful tool for control over the plasmonic properties. PMID- 29620116 TI - One-step synthesis of ultrathin alpha-Co(OH)2 nanomeshes and their high electrocatalytic activity toward the oxygen evolution reaction. AB - Herein, we demonstrate for the first time the one-step synthesis of ultrathin alpha-Co(OH)2 nanomeshes by an imidazole-directed route. The alpha-Co(OH)2 nanomeshes combine the advantages of ultrathin thickness (3 nm), small mesopores (3.7 nm), large specific surface area (181.1 m2 g-1) and high surface oxygen vacancy density, which exhibit excellent electrocatalytic performance for the oxygen evolution reaction. PMID- 29620118 TI - An asymmetric Mannich reaction of alpha-diazocarbonyl compounds and N-sulfonyl cyclic ketimines catalyzed by complexes generated from chiral and achiral phosphines with gold(i). AB - An unprecedented Lewis acidic gold(i)-complex generated from chiral and achiral phosphines has been developed for the Mannich reaction of alpha-diazocarbonyl compounds and N-sulfonyl cyclic ketimines. A series of chiral beta-amino-alpha diazoesters bearing a quaternary stereocenter were obtained in high yields with good enantioselectivities. In addition, the products could be converted to promising bioactive spirosuccinimide. Furthermore, operando IR, NMR and control experiments were carried out to gain insight into the mechanism. PMID- 29620120 TI - Macromolecular diffusion in crowded media beyond the hard-sphere model. AB - The effect of macromolecular crowding on diffusion beyond the hard-core sphere model is studied. A new coarse-grained model is presented, the Chain Entanglement Softened Potential (CESP) model, which takes into account the macromolecular flexibility and chain entanglement. The CESP model uses a shoulder-shaped interaction potential that is implemented in the Brownian Dynamics (BD) computations. The interaction potential contains only one parameter associated with the chain entanglement energetic cost (Ur). The hydrodynamic interactions are included in the BD computations via Tokuyama mean-field equations. The model is used to analyze the diffusion of a streptavidin protein among different sized dextran obstacles. For this system, Ur is obtained by fitting the streptavidin experimental long-time diffusion coefficient Dlongversus the macromolecular concentration for D50 (indicating their molecular weight in kg mol-1) dextran obstacles. The obtained Dlong values show better quantitative agreement with experiments than those obtained with hard-core spheres. Moreover, once parametrized, the CESP model is also able to quantitatively predict Dlong and the anomalous exponent (alpha) for streptavidin diffusion among D10, D400 and D700 dextran obstacles. Dlong, the short-time diffusion coefficient (Dshort) and alpha are obtained from the BD simulations by using a new empirical expression, able to describe the full temporal evolution of the diffusion coefficient. PMID- 29620121 TI - Dewetting of polymer thin films on modified curved surfaces: preparation of polymer nanoparticles with asymmetric shapes by anodic aluminum oxide templates. AB - We study the dewetting behaviors of poly(methyl methacrylate) (PMMA) thin films coated in the cylindrical nanopores of anodic aluminum oxide (AAO) templates by thermal annealing. Self-assembled monolayers (SAMs) of n-octadecyltrichlorosilane (ODTS) are introduced to modify the pore surfaces of the AAO templates to induce the dewetting process. By using scanning electron microscopy (SEM), the dewetting induced morphology transformation from the PMMA thin films to PMMA nanoparticles with asymmetric shapes can be observed. The sizes of the PMMA nanoparticles can be controlled by the original PMMA solution concentrations. The dewetting phenomena on the modified nanopores are explained by taking into account the excess intermolecular interaction free energy (DeltaG). This work opens a new possibility for creating polymer nanoparticles with asymmetric shapes in confined geometries. PMID- 29620122 TI - Improving the productivity of monodisperse polyhedral cages by the rational design of kinetic self-assembly pathways. AB - Hollow polyhedral cages hold great potential for application in nanotechnological and biomedical fields. Understanding the formation mechanism of these self assembled structures could provide guidance for the rational design of the desired polyhedral cages. Here, by constructing kinetic network models from extensive coarse-grained molecular dynamics simulations, we elucidated the formation mechanism of the dodecahedral cage, which is formed by the self assembly of patchy particles. We found that the dodecahedral cage is formed through increasing the aggregate size followed by structure rearrangement. Based on this mechanistic understanding, we improved the productivity of the dodecahedral cage through the rational design of the patch arrangement of patchy particles, which promotes the structural rearrangement process. Our results demonstrate that it should be a feasible strategy to achieve the rational design of the desired nanostructures via the kinetic analysis. We anticipate that this methodology could be extended to other self-assembly systems for the fabrication of functional nanomaterials. PMID- 29620123 TI - Ultrafast action chemistry in slow motion: atomistic description of the excitation and fluorescence processes in an archetypal fluorescent protein. AB - We report quantum mechanical/molecular mechanical non-adiabatic molecular dynamics simulations on the electronically excited state of green fluorescent protein mutant S65T/H148D. We examine the driving force of the ultrafast (tau < 50 fs) excited-state proton transfer unleashed by absorption in the A band at 415 nm and propose an atomistic description of the two dynamical regimes experimentally observed [Stoner Ma et al., J. Am. Chem. Soc., 2008, 130, 1227]. These regimes are explained in terms of two sets of successive dynamical events: first the proton transfers quickly from the chromophore to the acceptor Asp148. Thereafter, on a slower time scale, there are geometrical changes in the cavity of the chromophore that involve the distance between the chromophore and Asp148, the planarity of the excited-state chromophore, and the distance between the chromophore and Tyr145. We find two different non-radiative relaxation channels that are operative for structures in the reactant region and that can explain the mismatch between the decay of the emission of A* and the rise of the emission of I*, as well as the temperature dependence of the non-radiative decay rate. PMID- 29620125 TI - Novel layered iron vanadate cathode for high-capacity aqueous rechargeable zinc batteries. AB - A layered iron vanadate Fe5V15O39(OH)9.9H2O nanosheet is first introduced to an aqueous zinc battery system as a cathode material, which delivers a high capacity of 385 mA h g-1 at 0.1 A g-1 and remarkable cycling performance at high current density (over 80% capacity retention after 300 cycles at 5 A g-1). PMID- 29620124 TI - Precise targeting of cancer metastasis using multi-ligand nanoparticles incorporating four different ligands. AB - Metastasis displays a highly heterogeneous cellular population with cancer cells continuously evolving. As a result, a single-ligand nanoparticle cannot account for the continuously changing expression of targetable biomarkers over time and space. To effectively direct nanoparticles to metastasis, we developed a multi ligand nanoparticle by using four different types of ligands on the same nanoparticle that target biomarkers on the endothelium associated with metastatic disease. These vascular targets included alphavbeta3 integrin, P-selectin, EGFR and fibronectin. Using terminal and in vivo imaging studies, the targeting performance of the multi-ligand nanoparticles was compared to the single-ligand nanoparticle variants. All four single-ligand nanoparticle variants achieved significant targeting of lung metastasis in the 4T1 mouse model of breast cancer metastasis with about 2.5% of the injected dose being deposited into metastasis. A dual-ligand nanoparticle resulted in a nearly 2-fold higher deposition into lung metastases than its single-ligand counterparts. The multi-ligand nanoparticle significantly outperformed its targeting nanoparticle counterparts achieving a deposition of ~7% of its injected nanoparticles into lung metastases. Using the high sensitivity of radionuclide imaging, PET imaging showed that a multi-ligand nanoparticle labeled with [18F]fluoride was able to precisely target metastatic disease at its very early stage of development in three different animal models of metastatic breast cancer. PMID- 29620126 TI - A titanium dioxide nanoparticle sandwiched separator for Na-O2 batteries with suppressed dendrites and extended cycle life. AB - Na-O2 batteries are highly valued batteries with high energy density and low over potentials, but limited by the threat of sodium dendrites. In this paper, a new trilayer separator with TiO2 nanoparticles as the middle layer is proposed, which can effectively inhibit the growth of sodium dendrites. The TiO2 sandwiched separator was used in a Na-O2 battery, and increased its cycle life. This work provides a new approach to extend the cycle life of sodium-based rechargeable batteries with a sandwiched separator. PMID- 29620127 TI - Radiolytic formation of the carbon dioxide radical anion in acetonitrile revealed by transient IR spectroscopy. AB - The solvated electron in CH3CN is scavenged by CO2 with a rate constant of 3.2 * 1010 M-1 s-1 to produce the carbon dioxide radical anion (CO2-), a strong and versatile reductant. Using pulse radiolysis with time-resolved IR detection, this radical is unambiguously identified by its absorption band at 1650 cm-1 corresponding to the antisymmetric CO2- stretch. This assignment is confirmed by 13C isotopic labelling experiments and DFT calculations. In neat CH3CN, CO2- decays on a ~10 MUs time scale via recombination with solvent-derived radicals (R) and solvated protons. Upon addition of formate (HCO2-), the radiation yield of CO2- is substantially increased due to H-atom abstraction by R from HCO2- (R + HCO2- -> RH + CO2-), which occurs in two kinetically separated steps. The rapid step involves the stronger H-abstracting CN, CH3, and possibly, H primary radicals, while the slower step is due to the less reactive, but more abundant radical, CH2CN. The removal of solvent radicals by HCO2- also results in over a hundredfold increase in the CO2- lifetime. CO2- scavenging experiments suggest that at 50 mM HCO2-, about 60% of the solvent-derived radicals are engaged in CO2 generation. Even under CO2 saturation, no formation of the radical adduct, (CO2)2-, could be detected on the microsecond time scale. PMID- 29620128 TI - Molecular dynamics study of mesophase transitions upon annealing of imidazolium based ionic liquids with long-alkyl chains. AB - Molecular dynamics simulations are performed on a 1-dodecyl-3-methylimidazolium hexafluorophosphate ([C12mim][PF6]) ionic liquid using a united-atom model. The ionic liquid exhibits second step relaxation at temperatures below a crossover point, where the diffusion coefficient shows an Arrhenius to non-Arrhenius transition. Annealing below this crossover temperature makes an isotropic to mesophase transition, where the smectic A (SmA) phase or crystal-like smectic B (SmB) phase forms. Hundreds of nanoseconds are required for completing these transitions. A normal diffusion process is found for anions along the layer normal and -lateral directions in the SmA phase, but only in the lateral directions in the SmB phase. We find a preserved orientational order for the imidazolium-ring rotational and the alkyl-chain reorientational dynamics in both of the smectic phases. PMID- 29620129 TI - A reactive molecular dynamics study of graphene oxide sheets in different saturated states: structure, reactivity and mechanical properties. AB - For GO related nanocomposite design, it is of great importance to understand the behavior of water molecules ultra-confined in the interlayer region of graphene oxide (GO) sheets. In this research, to gain molecular insights into the influence of water on the properties of GO sheets, reactive force field molecular dynamics was employed to model a GO sheet with a water content of 1.3 wt%, 11.5 wt%, 18 wt% and 23.5 wt%. The epoxy and hydroxyl groups in the GO sheet exhibit high reactivity: the proton transferred from hydroxyl to dissociated epoxy contributes to carbonyl formation, which enhances the polarity of the GO sheet and strengthens the H-bond network between the functional groups. The epoxy, hydroxyl and newly formed carbonyl groups contribute to the structural hydrogen bonding with high stability. With increasing water content, the interlayer structural H-bonds between functional groups are gradually substituted by those contributed by water molecules, which weakens the interlayer stiffness and cohesive strength for GO sheets. Furthermore, the reactive force field allows coupling between the mechanical response and chemical reactions during uniaxial tensile deformation in the intra-layer direction. On the one hand, the relative epoxy bond is stretched until it is broken and transformed into a carbonyl group to resist tensile loading. On the other hand, interlayer water molecules, attacking the deformed GO sheets, are dissociated into carboxyl groups in the broken region. PMID- 29620130 TI - Effects of dopants on the adhesion and electronic structure of a SnO2/Cu interface: a first-principles study. AB - Doping has been adopted as a versatile approach for tuning the adhesion of metal oxide/metal interfaces. Understanding the mechanism of doping at the interface adhesion on the atomic and electronic scale is crucial for the rational design and optimization of metal oxide/metal composites. In this work, we have investigated the effects of dopants on the adhesion of SnO2/Cu interfaces through first-principles calculations. Firstly, O-terminated a SnO2(110)/Cu(111) interface (denoted as I) was considered and the work of separation values of the interfaces with various dopants (Mo, Sb, Ti, Zn and Cu) were calculated to evaluate the interface adhesion strength. It was demonstrated that low-valence dopants (Zn2+ and Cu2+) enhance the adhesion strength of interface I, while high valence dopants (Mo6+ and Sb5+) play the opposite role. Secondly, the strengthening effects of low-valence dopants were further verified in four candidate interfacial models with different atomic structures (denoted as II-V). The work of separation values indicated that the adhesion of all of the interfaces involved could be enhanced by low-valence doping. The electronic structure of the interface was demonstrated through density of states, charge density and charge density difference analyses. The results revealed that upon low-valence doping, the holes facilitate charge transfer between Cu and SnO2, which generates strong covalent bonds across the interface and thus significantly enhances the interface adhesion. This work not only provides insight into rational doping to enhance the adhesion of SnO2/Cu composites but can also be expanded upon for the design of other metal oxide/metal composites with strong interface adhesion. PMID- 29620131 TI - Probing the dynamics of photogenerated holes in doped hematite photoanodes for solar water splitting using transient absorption spectroscopy. AB - Hematite (alpha-Fe2O3) has been extensively studied as a promising candidate for photoelectrochemical water splitting; however its overall efficiency is still relatively low. Doping is believed to be efficient in enhancing the photoactivity, while direct evidence for the promoted charge carrier dynamics is very limited. Herein, transient absorption spectroscopy was used to directly investigate the yield and decay dynamics of the photogenerated holes in Sn and/or Ti doped alpha-Fe2O3. Sn or Ti doping was observed to have different origins to the enhanced water oxidation photocurrent: Sn doping retarded the electron-hole recombination, while Ti doping mainly increased the photogenerated charge carrier density. Our results also demonstrated that co-doping may combine both advantages to enhance the overall photoactivity of alpha-Fe2O3. PMID- 29620132 TI - MRI relaxivity enhancement of gadolinium oxide nanoshells with a controllable shell thickness. AB - Gadolinium oxide-based core-shelled nanoparticles have recently emerged as novel magnetic resonance imaging contrast agents for high relaxivity and tumor targeting. However, their relaxivity enhancement mechanism has not yet been clearly understood. We prepared highly dispersible and uniform core-shell structured nanoparticles by encapsulating silica spheres (90 nm in diameter) with gadolinium oxide shells of different thicknesses (from 1.5 nm to 20 nm), and proved experimentally that the shell thickness has an inverse effect on relaxivity. The core-shelled nanoparticles are of a larger relaxivity than the commercial contrast agent Gd-DTPA, with an enhancement from 1.8 to 7.3 times. Based on the Solomon-Bloembergen-Morgan theory which is usually adopted for interpreting the relaxation changes of water protons in Gd3+ chelates, we introduced a shielding ansatz of nanoshells and derived a concise formula specifically to correlate the relaxivity of this sort of core-shelled nanoparticles with the shell thickness directly. The formula calculation is well consistent with the experimental results, and the formula can be generally applied to evaluate the relaxation enhancement underlying the high relaxivity of any core-shelled nanoparticle. Furthermore, the core-shelled nanoparticles possess a negligible nanotoxicity according to the in vitro cytotoxicity and in vivo histopathology and hematology assays. The enhanced signals of in vivo tumor targeted magnetic resonance imaging indicate that the ultrathin gadolinium oxide nanoshells may function as a potential candidate for advanced positive contrast agents in further clinical applications. PMID- 29620133 TI - Light induced charge and energy transport in nucleic acids and proteins: general discussion. PMID- 29620134 TI - Correction: Origin of the temperature dependence of the energy gap in Cr-doped Bi2Se3. AB - Correction for 'Origin of the temperature dependence of the energy gap in Cr doped Bi2Se3' by Turgut Yilmaz et al., Phys. Chem. Chem. Phys., 2018, DOI: 10.1039/c7cp08049b. PMID- 29620135 TI - How nature covers its bases. AB - The response of DNA and RNA bases to ultraviolet (UV) radiation has been receiving increasing attention for a number of important reasons: (i) the selection of the building blocks of life on an early earth may have been mediated by UV photochemistry, (ii) radiative damage of DNA depends critically on its photochemical properties, and (iii) the processes involved are quite general and play a role in more biomolecules as well as in other compounds. A growing number of groups worldwide have been studying the photochemistry of nucleobases and their derivatives. Here we focus on gas phase studies, which (i) reveal intrinsic properties distinct from effects from the molecular environment, (ii) allow for the most detailed comparison with the highest levels of computational theory, and (iii) provide isomeric selectivity. From the work so far a picture is emerging of rapid decay pathways following UV excitation. The main understanding, which is now well established, is that canonical nucleobases, when absorbing UV radiation, tend to eliminate the resulting electronic excitation by internal conversion (IC) to the electronic ground state in picoseconds or less. The availability of this rapid "safe" de-excitation pathway turns out to depend exquisitely on molecular structure. The canonical DNA and RNA bases are generally short-lived in the excited state, and thus UV protected. Many closely related compounds are longer lived, and thus more prone to other, potentially harmful, photochemical processes. It is this structure dependence that suggests a mechanism for the chemical selection of the building blocks of life on an early earth. However, the picture is far from complete and many new questions now arise. PMID- 29620136 TI - Traumatic brain injury: Patient experience and satisfaction with discharge from trauma hospital. AB - OBJECTIVES: To describe the discharge process for patients with traumatic brain injury from a trauma hospital, and patient experience and satisfaction with care transition. Furthermore, to evaluate associations between discharge process and patient satisfaction and quality of care transition. DESIGN: Prospective retrospective observational study. SUBJECTS/PATIENTS: Seventy-four patients admitted to ward or intensive care unit at a trauma referral hospital within 24 h of traumatic brain injury. METHODS: Baseline characteristics and discharge process variables were extracted from medical records. Patients were interviewed 6-months post-injury about their experience and satisfaction with care transition, using a visual analogue scale (VAS) and the Care Transition Measurement (CTM-3(r)) as outcome measures. Regression analyses were performed to investigate associations between discharge process and outcome. RESULTS: One third of patients were not involved in the discharge process, and information in discharge summaries was often inadequate. Patients' involvement in care transition and co-ordination of care were significantly associated with overall satisfaction (VAS, p = 0.002 and p = 0.001, respectively) and quality of care transition (CTM-3(r), p = 0.003 and p = 0.007, respectively). Patients with more severe injuries reported lower satisfaction and quality of care transition. CONCLUSION: Patient's involvement in healthcare decision-making and co-ordination of care is important for self-reported satisfaction with transition and quality of care transition. PMID- 29620137 TI - Effectiveness of Wii-based rehabilitation in stroke: A randomized controlled study. AB - OBJECTIVE: To investigate the efficacy of Nintendo Wii Fit(r)-based balance rehabilitation as an adjunc-tive therapy to conventional rehabilitation in stroke patients. METHODS: During the study period, 70 stroke patients were evaluated. Of these, 23 who met the study criteria were randomly assigned to either the experimental group (n = 12) or the control group (n = 11) by block randomization. Primary outcome measures were Berg Balance Scale, Functional Reach Test, Postural Assessment Scale for Stroke Patients, Timed Up and Go Test and Static Balance Index. Secondary outcome measures were postural sway, as assessed with Emed-X, Functional Independence Measure Transfer and Ambulation Scores. An evaluator who was blinded to the groups made assessments immediately before (baseline), immediately after (post-treatment), and 4 weeks after completion of the study (follow-up). RESULTS: Group-time interaction was significant in the Berg Balance Scale, Functional Reach Test, anteroposterior and mediolateral centre of pressure displacement with eyes open, anteroposterior centre of pressure displacement with eyes closed, centre of pressure displacement during weight shifting to affected side, to unaffected side and total centre of pressure displacement during weight shifting. Demonstrating significant group-time interaction in those parameters suggests that, while both groups exhibited significant improvement, the experimental group showed greater improvement than the control group. CONCLUSION: Virtual reality exercises with the Nintendo Wii system could represent a useful adjunctive therapy to traditional treatment to improve static and dynamic balance in stroke patients. PMID- 29620139 TI - Antiproliferative effects of imatinib mesylate on ZR-75-1 and MDA-MB-231 cell lines via PDGFR-beta, PDGF-BB, c-Kit and SCF expression. AB - Imatinib mesylate is an anti-neoplastic targeted chemotherapeutic agent, which can inhibit tyrosine kinase receptors, including BCR-ABL, platelet-derived growth factor receptors (PDGFRs) and c-Kit. Cellular processes, including differentiation, proliferation and survival are regulated by these receptors. The present study aimed to evaluate the antiproliferative effects of imatinib mesylate, and its effects on apoptotic induction and cell cycle arrest in breast cancer cell lines. In addition, the study aimed to determine whether the effects of this drug were associated with the mRNA and protein expression levels of PDGFR beta, c-Kit, and their corresponding ligands PDGF-BB and stem cell factor (SCF), which may potentially modulate cell survival and proliferation. To assess the antiproliferative effects of imatinib mesylate, an MTS assay was conducted following treatment of cells with 2-10 uM imatinib mesylate for 96, 120 and 144 h; accordingly the half maximal inhibitory concentration of imatinib mesylate was calculated for each cell line. In addition, the proapoptotic effects and cytostatic activity of imatinib mesylate were investigated. To evaluate the expression of imatinib-targeted genes, PDGFR-beta, c-Kit, PDGF-BB and SCF, under imatinib mesylate treatment, mRNA expression was detected using semi-quantitative polymerase chain reaction and protein expression was detected by western blot analysis in ZR-75-1 and MDA-MB-231 breast carcinoma cell lines. Treatment with imatinib mesylate suppressed cell proliferation, which was accompanied by apoptotic induction and cell cycle arrest in the investigated cell lines. In addition, PDGFR-beta, PDGF-BB, c-Kit and SCF were expressed in both breast carcinoma cell lines; PDGFR-beta and c-Kit, as imatinib targets, were downregulated in response to imatinib mesylate treatment. The present results revealed that at least two potential targets of imatinib mesylate were expressed in the two breast carcinoma cell lines studied. In conclusion, the antiproliferative, cytostatic and proapoptotic effects of imatinib mesylate may be the result of a reduction in the expression of c-Kit and PDGFR tyrosine kinase receptors, thus resulting in suppression of the corresponding ligand PDGF-BB. Therefore, imatinib mesylate may be considered a promising target therapy for the future treatment of breast cancer. PMID- 29620138 TI - PFK15, a PFKFB3 antagonist, inhibits autophagy and proliferation in rhabdomyosarcoma cells. AB - Due to the high-level of metastatic and relapsed rates, rhabdomyosarcoma (RD) patients have a poor prognosis, and novel treatment strategies are required. Thereby, the present study evaluated the efficacy of PFK15, a PFKFB3 inhibitor, in RD cells to explore its potential underlying mechanism on the regulation of autophagy and proliferation in these cells. The effects of PFK15 on cell viability loss and cell death in different treatment groups, were evaluated by MTS assay, colony growth assay and immunoblotting, respectively. In addition, the autophagy levels were detected by electron microscopy, fluorescence microscopy and immunoblotting following PFK15 treatment, and the autophagic flux was analyzed with the addition of chloroquine diphosphate salt or by monitoring the level of p62. PFK15 was observed to evidently decrease the viability of RD cells, inhibit the colony growth and cause abnormal nuclear morphology. Furthermore, PFK15 inhibited the autophagic flux and cell proliferation, as well as induced apoptotic cell death in RD cells through downregulation of the adenosine monophosphate-activated protein kinase (AMPK) signaling pathway. An AMPK agonist rescued the inhibited cell proliferation and autophagy induced by PFK15. In conclusion, PFK15 inhibits autophagy and cell proliferation via downregulating the AMPK signaling pathway in RD cells. PMID- 29620140 TI - Diagnostic and prognostic values of contrast-enhanced ultrasound combined with diffusion-weighted magnetic resonance imaging in different subtypes of breast cancer. AB - The present study aimed to investigate the diagnostic and prognostic values of contrast-enhanced ultrasound (CEUS) combined with diffusion-weighted magnetic resonance imaging (DW-MRI) in different subtypes of breast cancer (BC). CEUS and DW-MRI were conducted in 232 patients with BC prior to surgical treatment. Patients were categorized as having the luminal A subtype, the luminal B subtype, triple-negative subtype or the human epidermal growth factor receptor 2 (Her-2) positive subtype according to their expression of the estrogen receptor (ER), progesterone receptor (PR) and Her-2, as detected by immunohistochemistry. The CEUS and DW-MRI parameters of patients with different subtypes of BC were obtained and analyzed. The risk factors for the prognosis of patients with different subtypes of BC were analyzed using Kaplan-Meier and COX regression analyses. The diagnostic accuracy rate of CEUS combined with DW-MRI (93.10%) was higher than that of CEUS (88.79%) or DW-MRI (82.33%) alone. The local recurrence rate and distant metastasis rate of the Her-2-positive subtype were the highest among all the subtypes. Furthermore, patients with Her-2-positive BC exhibited a higher proportion of lesions with indistinct margins and histological grade III. Lymph node metastasis and BC subtype were independent risk factors for the prognosis of BC. The overall survival and disease-free survival of patients with the luminal A subtype were higher than those of patients with the Her-2-positive subtype. The results of the current study therefore indicate that CEUS combined with DW-MRI is more effective at diagnosing the different subtypes of BC than either CEUS or DW-MRI alone. PMID- 29620141 TI - JMJD6 exerts function in neuropathic pain by regulating NF-kappaB following peripheral nerve injury in rats. AB - Treatment of neuropathic pain (NPP) continues to be a major challenge, and the underlying mechanisms remain to be elucidated. Previous studies have demonstrated that histone methylation is important in synaptic plasticity of the nervous system and may affect nuclear factor-kappaB (NF-kappaB) signaling through epigenetic mechanisms. The present study aimed to investigate the role of Jumonji C domain 6 (JMJD6), a histone demethylase, in a chronic constriction injury (CCI) model of NPP. On the third day post-CCI surgery, a JMJD6 overexpressing lentiviral vector (LV-JMJD6) was intrathecally injected in the rats. Mechanical withdrawal threshold and thermal withdrawal latency were assessed prior surgery and on days 3, 7, 10 and 14 post-CCI. The results showed that intrathecal injection with the LV-JMJD6 attenuated CCI-induced pain facilitation. The expression of JMJD6 was lower following CCI surgery, and its expression was significantly increased following intrathecal injection with LV-JMJD6, compared with levels in normal saline (NS)- and negative control lentiviral vector (NC) treated rats. The expression of spinal NF-kappaB phosphorylated (p-)p65 subunit and its downstream pain-associated effectors, including interleukin 1beta (IL 1beta), tumor necrosis factor-alpha (TNF-alpha) and vascular endothelial growth factor (VEGF), were increased following CCI surgery. Intrathecal injection with LV-JMJD6 suppressed activation of the p-p65 subunit in CCI rats. In addition, expression levels of its downstream effectors IL-1beta, TNF-alpha and VEGF were attenuated by intrathecal treatment with LV-JMJD6, compared with those in the NS- and NC-treated CCI rats. Furthermore, the JMJD6- and p65-immunoreactive cells overlapped in the spinal dorsal horn, however, co-immunoprecipitation showed that JMJD6 and the NF-kappaB p65 subunit did not directly interact, indicating other functional connections may exist between these factors following CCI surgery. Collectively, these findings indicated an important mechanism underlying the pathogenesis of NPP. JMJD6 may exert its therapeutic function in NPP by regulating NF-kappaB following CCI. PMID- 29620142 TI - MicroRNA-497 attenuates cerebral infarction in patients via the TLR4 and CREB signaling pathways. AB - The aim of the present study was to investigate the function and mechanism of microRNA-497 (miRNA/miR-149) in the regulation of cerebral infarction. In patients with cerebral infarction, the serum of microRNA-497 expression was upregulated compared with that in healthy controls. In N2A cells, overexpression of miR-497 induced cell proliferation, decreased apoptosis and caspase-3 and caspase-9 activities, and suppressed Bax protein expression compared with that in the negative control group. Overexpression of miR-497 reduced inflammation factors, and suppressed the Toll-like receptor 4 (TLR4), myeloid differentiation primary response protein MyD88 (MyD88) and nuclear factor-kappaB (NF-kappaB) protein expression of the N2A cells. Next, miR-497 overexpression suppressed the protein expression of interleukin-1 receptor associated kinase (IRAK1) and phosphorylated cyclic AMP response element binding protein (p-CREB) in the N2A cells. Following miR-497 overexpression, TLR4 inhibitor was found to suppress the inflammation factors, suppress the TLR4, MyD88 and NF-kappaB protein expression, and reduce the IRAK1 and p-CREB protein expression of the N2A cells. Lastly, CREB inhibitor also suppressed p-CREB protein expression, induced cell proliferation, decreased apoptosis and caspase-3 and caspase-9 activities, and suppressed Bax protein expression in the N2A cells following miR-497 overexpression. Taken together, these data demonstrated that miR-497 attenuated cerebral infarction in patients by regulating the TLR4 and CREB signaling pathways. PMID- 29620143 TI - Exploring the molecular mechanisms of osteosarcoma by the integrated analysis of mRNAs and miRNA microarrays. AB - Osteosarcoma (OS) is the most frequently occurring primary bone malignancy with a rapid progression and poor survival. In the present study, in order to examine the molecular mechanisms of OS, we analyzed the microarray of GSE28425. GSE28425 was downloaded from Gene Expression Omnibus, which also included the miRNA expression profile, GSE28423, and the mRNA expression profile, GSE28424. Each of the expression profiles included 19 OS cell lines and 4 normal bones. The differentially expressed genes (DEGs) and differentially expressed miRNAs (DE miRNAs) were screened using the limma package in Bioconductor. The DEGs associated with tumors were screened and annotated. Subsequently, the potential functions of the DEGs were analyzed by Gene Ontology (GO) and pathway enrichment analyses. Furthermore, the protein-protein interaction (PPI) network was constructed using the STRING database and Cytoscape software. Furthermore, modules of the PPI network were screened using the ClusterOne plugin in Cytoscape. Additionally, the transcription factor (TF)-DEG regulatory network, DE miRNA-DEG regulatory network and miRNA-function collaborative network were separately constructed to obtain key DEGs and DE-miRNAs. In total, 1,609 DEGs and 149 DE-miRNAs were screened. Upregulated FOS-like antigen 1 (FOSL1) also had the function of an oncogene. MAD2 mitotic arrest deficient-like 1 (MAD2L1; degree, 65) and aurora kinase A (AURKA; degree, 64) had higher degrees in the PPI network of the DEGs. In the TF-DEG regulatory network, the TF, signal transducer and activator of transcription 3 (STAT3) targeted the most DEGs. Moreover, in the DE miRNA-DEG regulatory network, downregulated miR-1 targeted many DEGs and estrogen receptor 1 (ESR1) was targeted by several highly expressed miRNAs. Moreover, in the miRNA-function collaborative networks of upregulated miRNAs, miR-128 targeted myeloid dendritic associated functions. On the whole, our data indicate that MAD2L1, AURKA, STAT3, ESR1, FOSL1, miR-1 and miR-128 may play a role in the development and/or progressio of OS. PMID- 29620144 TI - Adenovirus-mediated knockdown of activin A receptor type 2A attenuates immune induced hepatic fibrosis in mice and inhibits interleukin-17-induced activation of primary hepatic stellate cells. AB - Fibrosis induces a progressive loss of liver function, thus leading to organ failure. Activins are secreted proteins that belong to the transforming growth factor (TGF)-beta superfamily, which initiate signaling by binding to their two type II receptors: Activin A receptor type 2A (ACVR2A) and activin A receptor type 2B. Previous studies that have explored the mechanisms underlying immune induced hepatic fibrosis have mainly focused on TGF-beta signaling, not activin signaling. To investigate the role of the activin pathway in this disease, adenovirus particles containing short hairpin (sh)RNA targeting ACVR2A mRNA (Ad ACVR2A shRNA) were administered to mice, which were chronically treated with concanavalin A (Con A). The pathological changes in the liver were evaluated with hematoxylin/eosin staining, Masson trichrome staining and immunohistochemical assay. The results detected an increase in serum activin A and liver ACVR2A in Con A-treated animals. Conversely, liver function was partially restored and fibrotic injury was attenuated when activin signaling was blocked. In addition, the activation of hepatic stellate cells (HSCs) in response to Con A was suppressed by Ad-ACVR2A shRNA, as evidenced by decreased alpha-smooth muscle actin, and type I and IV collagen expression. Furthermore, primary mouse HSCs (mHSCs) were activated when exposed to interleukin (IL)-17A or IL-17F, which are two major cytokines produced by cluster of differentiation 4+ T helper 17 cells. The levels of activin A, type I and IV collagen were determined with ELISA kits and the expression of fibrotic molecules was determined with western blot analysis. Conversely, blocking activin/ACVR2A impaired the potency of HSCs to produce collagens in response to IL-17s. In addition, C terminus phosphorylation of Smad2 on Ser465 and Ser467, induced by either Con A in the liver or by IL-17s in mHSCs, was partly inhibited when activin A/ACVR2A signaling was suppressed. Collectively, the present study demonstrated an involvement of activated activin A/ACVR2A/Smad2 signaling in immune-induced hepatic fibrosis. PMID- 29620145 TI - Leukemia inhibitory factor regulates marmoset induced pluripotent stem cell proliferation via a PI3K/?Akt-dependent Tbx-3 activation pathway. AB - Leukemia inhibitory factor (LIF) is the most pleiotropic cytokine of the interleukin-6 family, and is widely used to establish and maintain pluripotent stem cells, particularly mouse pluripotent stem cells. However, no reports have fully elucidated the application of LIF in marmoset induced pluripotent stem cell (iPSC) culture, particularly the underlying mechanisms. To demonstrate the feasibility of the application of LIF to marmoset iPSCs, the present study assessed these cells in the presence of LIF. Cell proliferation was measured using MTT assay, cell apoptosis was determined by flow cytometric analysis of fluorescein isothiocyanate Annexin V staining and the differentially expressed genes were analysed using Digital Gene Expression (DGE) analysis. The altered expression of pluripotency-associated genes was confirmed by reverse transcription-quantitative polymerase chain reaction and western blot analysis. Furthermore, following treatment with LY294002, cell proliferation was measured by MTT assay and protein levels were confirmed by western blot analysis. The results showed that LIF significantly promoted the number of proliferating cells, but had no effect on apoptosis. Digital Gene Expression analysis was used to examine the differentially expressed genes of marmoset iPSCs in the presence of LIF. The results showed that the pluripotency-associated transcription factor encoding gene T-box 3 (Tbx-3) was activated by LIF. Notably, LIF increased the levels of phosphorylated (p-)AKT and Tbx-3 in the marmoset iPSCs. Furthermore, pretreatment with LY294002, an inhibitor of phosphoinositide 3-kinase (PI3K), significantly impaired the LIF-induced upregulation of p-AKT and Tbx-3 in the marmoset iPSCs, suggesting that the PI3K/Akt signaling pathway is involved in this regulation. Taken together, the results suggested that LIF is effective in maintaining marmoset iPSCs in cultures, which is associated with the activation of Tbx-3 through regulation of the PI3K/Akt signaling pathway. PMID- 29620147 TI - lncRNA PVT1 promotes the angiogenesis of vascular endothelial cell by targeting miR-26b to activate CTGF/ANGPT2. AB - Angiogenesis is essential for various biological processes, including tumor blood supply delivery, cancer cell growth, invasion and metastasis. Plasmacytoma variant translocation 1 (PVT1) long noncoding RNA (lncRNA) has been previously reported to affect angiogenesis of glioma microvascular endothelial cells by regulating microRNA (miR)-186 expression level. However, the specific underlying molecular mechanism of PVT1 regulation of angiogenesis in vascular endothelial cells remains to be elucidated. The present study investigated the role of PVT1 in cell proliferation, migration and vascular tube formation of human umbilical vein endothelial cells (HUVECs) using MTT assay, Transwell migration assay and in vitro vascular tube formation assay, respectively. In order to determine the effect of miR-26b on cell proliferation, migration and vascular tube formation of HUVECs, miR-26 mimic or miR-26b inhibitor were transfected into HUVECs. Reverse transcription-quantitative polymerase chain reaction and western blotting were conducted to quantify the mRNA and protein expression levels of target genes. The present study confirmed that miR-26b bound 3'-untranslated region (3'-UTR) and subsequently influenced gene expression level using dual luciferase reporter assay. The current study observed that PVT1 affected cell proliferation, migration and in vitro vascular tube formation of HUVECs. In addition, it was determined that PVT1 was able to bind and degrade miR-26b to promote connective tissue growth factor (CTGF) and angiopoietin 2 (ANGPT2) expression. miR-26b was also identified to have a suppressive role in cell proliferation, migration and in vitro vascular tube formation of HUVECs via binding 3'-UTR regions and downregulating CTGF and ANGPT2 expression levels. The current findings may improve the understanding of the underlying mechanism of PVT1 contributing to angiogenesis of vascular endothelial cells and offer rationale for targeting PVT1 to treat angiogenesis dysfunction-associated diseases, including cancer metastasis. PMID- 29620146 TI - A study of the key genes and inflammatory signaling pathways involved in HLA-B27 associated acute anterior uveitis families. AB - The present study was conducted to investigate the key genes and the inflammatory signaling pathways involved in HLA-B27-associated acute anterior uveitis (AAU) families. Four families with HLA-B27-positive aau patients and their HLA-B27 positive blood relatives were included in the study. peripheral blood monocytes were isolated from the subjects and stimulated by lipopolysaccharides (LPS). Gene expression microarrays were used to identify the differentially expressed genes (DEGs), and the DEGs were analyzed by a range of bioinformatics-based techniques, including Gene Ontology (GO), Pathway analysis, Signal-Net analysis and Gene Relation Network (Gene-Rel-Net). Finally, ELISA was used to quantify cytokines in the supernatant. The gene expression microarrays identified 801 DEGs, including 349 upregulated and 452 downregulated genes. The GO analysis revealed several important functions, including metabolic, immune and inflammatory responses. The pathway analysis highlighted the enhanced activity of Staphylococcus aureus infection, chemokine and metabolic signaling pathways, as well as cytokine-to cytokine receptor interactions. A total of 18 DEGs that were found to play critical roles by Signal-Net and Gene-Rel-Net and verified by quantitative polymerase chain reaction analysis were identified as key genes. In conclusion, monocytes from the AUU patients were more sensitive and exhibited a more prominent inflammatory response to stimulation by LPS compared with monocytes from healthy HLA-B27-positive blood relatives. These characterized DEGs may provide new evidence for the pathogenesis of AAU and help identify new therapeutic targets. PMID- 29620148 TI - Carnosic acid protects mice from high-fat diet-induced NAFLD by regulating MARCKS. AB - Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of liver damage characterized by abnormal hepatic fat accumulation and inflammatory response. Although the molecular mechanisms responsible for the disease are not yet fully understood, the pathogenesis of NAFLD likely involves multiple signals. The identification of effective therapeutic strategies to target these signals is of utmost importance. Carnosic acid (CA), as a phenolic diterpene with anticancer, anti-bacterial, anti-diabetic and neuroprotective properties, is produced by many species of the Lamiaceae family. Myristoylated alanine-rich C-kinase substrate (MARCKS) is a major protein kinase C (PKC) substrate in many different cell types. In the present study, wild-type C57BL/6 and MARCKS-deficient mice were randomly divided into the normal chow- or high-fat (HF) diet-fed groups. The HF diet increased the fasting glucose and insulin levels, and promoted glucose intolerance in the wild-type mice. MARCKS deficiency further upregulated intolerance, fasting glucose and insulin. The HF diet also promoted hepatic steatosis, serum alanine transaminase (ALT) and aspartate transaminase (AST) activity, inflammation and lipid accumulation in the wild-type mice. These responses were accelerated in the MARCKS-deficient mice. Importantly, increased inflammation and lipid accumulation were associated with phosphoinositide 3 kinase (PI3K)/AKT, NLR family pyrin domain containing 3 (NLRP3)/nuclear factor kappaB (NF-kappaB) and sterol regulatory element binding protein-1c (SREBP-1c) signaling pathway activation. The mice treated with CA exhibited a significantly improved glucose and insulin tolerance. The production of pro-inflammatory cytokines and lipid accumulation were suppressed by CA. Significantly, MARCKS was reduced in mice fed the HF diet. CA treatment upregulated MARCKS expression compared to the HF group. Furthermore, the activation of the PI3K/AKT, NLRP3/NF kappaB and SREBP-1c signaling pathways was inhibited by CA. Taken together, our data suggest that CA suppresses inflammation and lipogenesis in mice fed a HF diet through MARCKS regulation. Thus, CA may be prove to be a useful anti-NAFLD agent. PMID- 29620149 TI - Thromboxane A2 receptor antagonist SQ29548 attenuates SH-SY5Y neuroblastoma cell impairments induced by oxidative stress. AB - Thromboxane A2 receptor (TXA2R) serves a vital role in numerous neurological disorders. Our previous study indicated that SQ29548, an antagonist of TXA2R, attenuated the induced neuron damage in cerebral infarction animals; however, the underlying mechanism remains unknown. Certain studies revealed a new role of TXA2R in the regulation of oxidative stress, which is one of the basic pathological processes in neurological disorders. Thus, the present study attempted to examine whether the inhibition of TXA2R with SQ29548 helped to protect the nerve cells against oxidative stress. SQ29548 was utilized as a TXA2R antagonist, and relevant assays were performed to detect the cell viability, cellular reactive oxygen species (ROS) level, cell apoptosis, expression levels of superoxide dismutase-2 (SOD2), catalase and caspases, and activation of mitogen-activated protein kinase (MAPK) pathways. It was observed that hydrogen peroxide (H2O2) dose-dependently reduced the viability of SH-SY5Y cells. In addition, H2O2 raised the level of ROS in cells, inhibited the expression levels of SOD2 and catalase, and potentially enhanced cell apoptosis and the expression of caspases via activating the MAPK pathways. Pretreatment with SQ29548 not only rescued the viability of SH-SY5Y cells, but also ameliorated the intracellular ROS level and the expression levels of SOD2 and catalase. Furthermore, it decreased the cell apoptosis and the expression of caspases, possibly via the inhibition of MAPK pathways. In conclusion, SQ29548, an antagonist of TXA2R, improved the antioxidant capacities of SH-SY5Y cells and reduced the cell apoptosis through the inhibition of MAPK pathways. PMID- 29620150 TI - Lack of endogenous parathyroid hormone delays fracture healing by inhibiting vascular endothelial growth factor-mediated angiogenesis. AB - Intermittent low-dose injections of parathyroid hormone (PTH) have been reported to exert bone anabolic effects and to promote fracture healing. As an important proangiogenic cytokine, vascular endothelial growth factor (VEGF) is secreted by bone marrow mesenchymal stem cells (BMSCs) and osteoblasts, and serves a crucial regulatory role in the process of vascular development and regeneration. To investigate whether lack of endogenous PTH causes reduced angiogenic capacity and thereby delays the process of fracture healing by downregulating the VEGF signaling pathway, a PTH knockout (PTHKO) mouse fracture model was generated. Fracture healing was observed using X-ray and micro-computerized tomography. Bone anabolic and angiogenic markers were analyzed by immunohistochemistry and western blot analysis. The expression levels of VEGF and associated signaling pathways in murine BMSC-derived osteoblasts were measured by quantitative polymerase chain reaction and western blot analysis. The expression levels of protein kinase A (PKA), phosphorylated-serine/threonine protein kinase (pAKT), hypoxia-inducible factor-1alpha (HIF1alpha) and VEGF were significantly decreased in BMSC-derived osteoblasts from PTHKO mice. In addition, positive platelet endothelial cell adhesion molecule staining was reduced in PTHKO mice, as determined by immunohistochemistry. The expression levels of HIF1alpha, VEGF, runt-related transcription factor 2, osteocalcin and alkaline phosphatase were also decreased in PTHKO mice, and fracture healing was delayed. In conclusion, lack of endogenous PTH may reduce VEGF expression in BMSC-derived osteoblasts by downregulating the activity of the PKA/pAKT/HIF1alpha/VEGF pathway, thus affecting endochondral bone formation by causing a reduction in angiogenesis and osteogenesis, ultimately leading to delayed fracture healing. PMID- 29620152 TI - Effect of hydroxyl group position in flavonoids on inducing single-stranded DNA damage mediated by cupric ions. AB - Quercetin has been demonstrated to produce DNA damage in the presence of metal ions. In the present study, 7 natural and 5 semi-synthetic glycosylated flavonoids were utilized to investigate the cupric ion (Cu2+)-dependent DNA damage in vitro. The reaction mixture, containing single-stranded DNA, different concentrations of flavonoids and cupric ion in the buffer, was incubated at three different temperatures. DNA damage was then assessed by gel electrophoresis followed by densitometric analysis. The reaction mixture with quercetin at 4, 20 and 54C induced DNA damage in a concentration- and temperature-dependent manner. Furthermore, only the reaction at 54C resulted in DNA damage in flavonoids with glucosyl substitution of the hydroxyl group at the 3-position on the C ring in quercetin. By contrast, loss of the hydroxyl group at the 3-position on the C ring, or at the 3'- or 4'-position on the B ring of quercetin, did not portray DNA damage formation at the investigated experimental temperatures. In addition, the experimental results suggested that the hydroxyl group at the 3-position on the C ring produced the strongest capability to induce DNA damage in the presence of cupric ions. Furthermore, hydroxyl groups at the 3'- or 4'-position on the B ring were only able to induce DNA damage at higher temperatures, and were less efficient in comparison with the hydroxyl group at the 3-position on the C ring. Cupric ion chelating capacity was also assessed with spectroscopic analysis, and quercetin presented the largest chelating capacity among the tested flavonoids. Hydroxyl radical formation was assessed with a luminol reaction, and quercetin presented faster consumption of luminol. These results suggest that the 3 position hydroxyl group of the C ring is required to induce DNA damage at low temperatures. Furthermore, the results of the present study also indicated that the presence of cupric ions will decrease the activity of the glycosylated quercetins, in terms of their ability to induce DNA damage. PMID- 29620153 TI - Histone deacetylase inhibitors alter the expression of molecular markers in breast cancer cells via microRNAs. AB - Histone deacetylase inhibitors (HDACis) are able to suppress breast cancer cells in vitro and in vivo by altering the expression of estrogen receptor (ER), progesterone receptor (PR) or human epidermal growth factor receptor 2 (Her2/neu). Since HDACis can alter the expression of various microRNAs (miRNAs/miRs), the present study aimed to examine the role of miRNAs in the effects of HDACis on breast cancer cells. We first examined the mRNA expression of ER, PR, and Her2/neu using RT-PCR and the protein levels of ER, PR, and Her2/neu using western blot analysis in MDA-MB-231 and BT474 cells, after trichostatin A (TSA) or vorinostat (SAHA) treatment. We then conducted miRNA expression profiling using microarrays after BT474 cells were treated with TSA or SAHA. Finally, we examined the effects of synthetic miR-762 and miR-642a-3p inhibitors on SAHA-induced downregulation of Her2/neu and SAHA-induced apoptosis and PARP cleavage in BT474 cells. The results indicated that TSA and SAHA dose dependently enhanced the mRNA and protein expression levels of ER and PR in MDA MB-231 and BT474 cells. In addition, the mRNA expression levels of Her2/neu were reduced in MDA-MB-231 cells, and the mRNA and protein expression levels of Her2/neu were reduced in BT474 cells in response to SAHA and TSA. Furthermore, treatment with TSA (0.2 uM) or SAHA (5.0 uM) induced a marked alteration in the expression of various miRNAs in BT474 cells. Notably, when cells were cotransfected with miR-762 and miR-642a-3p inhibitors, SAHA-induced downregulation of Her2/neu was inhibited, and SAHA-induced apoptosis and poly (ADP-ribose) polymerase cleavage were significantly reduced in BT474 cells. These results indicated that numerous HDACi-induced miRNAs are required to downregulate Her2/neu levels and promote apoptosis of Her2-overexpressing breast cancer cells. PMID- 29620151 TI - Low-intensity pulsed ultrasound promotes periodontal ligament stem cell migration through TWIST1-mediated SDF-1 expression. AB - Low-intensity pulsed ultrasound (LIPUS) is a non-invasive therapeutic treatment for accelerating fracture healing. A previous study from our group demonstrated that LIPUS has the potential to promote periodontal tissue regeneration. However, the underlying molecular mechanism by which LIPUS promotes periodontal tissue regeneration remains unknown. In the present study, periodontal ligament stem cells (PDLSCs) were isolated from premolars. Flow cytometry and differentiation assays were used to characterize the isolated PDLSCs. LIPUS treatment was administered to PDLSCs, and stromal cell-derived factor-1 (SDF-1) expression levels were examined by reverse transcription-quantitative polymerase chain reaction with or without blocking the SDF-1/C-X-C motif chemokine receptor 4 (CXCR4) pathway with AMD3100. ELISA was used to evaluate SDF-1 secretion in PDLSCs. Wound healing and transwell assays were conducted to assess the migration promoting effect of LIPUS. A potential upstream gene of SDF-1, twist family bHLH transcription factor 1 (TWIST1), was silenced by small interfering (si) RNA transfection. The results demonstrated that LIPUS treatment promoted the expression of TWIST1 and SDF-1 at both the mRNA and protein levels. In addition, LIPUS treatment enhanced the cell migration of PDLSCs. Knockdown of TWIST1 impaired the expression of SDF-1 and the cell migration ability of PDLSCs. TWIST1 may be an upstream regulator of SDF-1 in PDLSCs. Taken together, these findings indicate that the SDF1/CXCR4 signaling pathway is involved in LIPUS-promoted PDLSC migration, which might be one of the mechanisms for LIPUS-mediated periodontal regeneration. TWIST1 might be a mechanical stress sensor during mechanotransduction. PMID- 29620154 TI - [Corrigendum] Inhibition of RANKL-induced osteoclastogenesis through the suppression of the ERK signaling pathway by astragaloside IV and attenuation of titanium-particle-induced osteolysis. AB - Following the publication of the article, the authors noticed an error in the published version of Fig. 3. In brief, certain of the images were misplaced, errors which occurred during the preparation and assembly of the figure owing to oversights in labeling of the image data. The corrected version of Fig. 3 is included below. The authors regret that this error occurred, and apologize for the inconvenience caused by the error. They thank the Editor for allowing them the opportunity to publish this Corrigendum. [the original article was published in the International Journal of Molecular Medicine 36: 1335-1344, 2015; DOI: 10.3892/ijmm.2015.2330]. PMID- 29620155 TI - Differential expression of Oct3/4 in human breast cancer and normal tissues. AB - Oct3/4, a transcription factor specifically expressed in mammalian totipotent embryonic stem and germ cells, has a critical role in the regulation and maintenance of pluripotency and self-renewal. However, reactivation of Oct3/4 expression is observed in several human breast cancer cell lines, but not in non malignant cells. To examine Oct3/4 expression in human primary breast carcinomas and normal breast tissues, we obtained breast tumor tissues from 28 patients and normal breast tissues from 9 women. According to quantitative polymerase chain reaction, all of the tumor tissues, irrespective of tumor type or clinicopathological status, expressed Oct3/4 mRNA at 10- to 100- fold higher levels than that in the normal breast tissues. Expression of the Oct3/4 protein in tumors was confirmed by western blot analysis and immunofluorescent staining. Additionally, rapid amplification of cDNA ends and DNA sequencing revealed expression of multiple Oct4 gene transcripts from chromosome 6 (POU5F1) in normal breast tissues and the non-malignant breast epithelial cell line MCF-10A; by contrast, the breast tumors and malignant breast cancer cell line MCF-7 predominantly expressed transcripts of an Oct4-like gene (POU5F1B) from chromosome 8, which was termed Oct3 in the current study. The deduced amino acid sequences of full-length Oct3 and Oct4 are 96% identical. The findings of the current study indicated that Oct3, rather than Oct4, may serve as a novel clinical marker and a potential target for gene-specific therapy of breast cancer. PMID- 29620156 TI - Expression and clinical significance of PD-1 in hepatocellular carcinoma tissues detected by a novel mouse anti-human PD-1 monoclonal antibody. AB - Hepatocellular carcinoma (HCC) is one of the most common malignancies and causes of death worldwide. Research investigating novel therapeutic strategies for the treatment of HCC is urgently required. Monoclonal antibodies (mAbs) that target the programmed cell death-1 (PD-1/PDCD1)/programmed death-ligand 1 (PD-L1) immune checkpoint have demonstrated substantial clinical benefit for a variety of solid tumors; however, these mAbs have not been well studied in HCC. In the present study, Sp2/0-Ag14 myeloma cells and spleen cells derived from BALB/c mice immunized with the recombinant human PD-1/PDCD1 protein were fused for the production of novel antibodies. The 9E11 mAb, which exhibited the highest specificity for PD-1 in HCC tissues in western blot and immunohistochemical staining analyses, was used to investigate the clinical significance of PD-1 expression in HCC tissues from 77 cases, which were collected and examined histologically. Overexpression of PD-1 was identified in peritumoral tissues, primarily in the liver portal region. Importantly, by analyzing the clinical data from 77 HCC patients, the expression of PD-1 was observed to be significantly correlated with larger tumor size (>5 cm) and poorly differentiated tumors. In addition, PD-1 expression was moderately correlated with venous thrombosis, but not correlated with patient sex or age, liver cirrhosis, hepatitis B, tumor, node and metastasis (TNM) stage or tumor location. The results of the present study suggest that high-level PD-1 expression may be an important factor associated with the immune checkpoint pathway in HCC. The results suggest that PD-1 serves an important role in tumor immune evasion and may be a valuable immunodiagnostic marker. In addition, PD-1 may serve as a therapeutic target for patients presenting with poorly differentiated HCC, thus indicating the potential application of a PD-1 inhibitor for the treatment of HCC patients. PMID- 29620157 TI - Glucocorticoid receptor overexpression slightly shifts microRNA expression patterns in triple-negative breast cancer. AB - Triple-negative breast cancer (TNBC) is a particularly aggressive subtype of breast cancer with limited options for clinical intervention. As with many solid tumors, TNBC is known to promote invasiveness and metastasis by secreting extracellular vesicles (EVs) capable of modulating the behaviour of recipient cells. Recent investigations have demonstrated that high expression levels of glucocorticoid receptor (GR) in TNBC are linked to therapy resistance, higher recurrence rates and increased mortality. In addition to activating protein coding genes, GR is also involved in the expression of short non-coding RNAs including microRNAs (miRNAs or miRs). The molecular mechanisms responsible for the oncogenic effects of GR on TNBC have yet to be fully elucidated; however, emerging evidence suggests that miRNAs may play a pivotal role in tumorigenesis and metastasis. Thus, the aim of this study was to identify GR-regulated cellular and vesicular miRNAs that might contribute to the particularly oncogenic phenotype of TNBC with a high GR expression. We analyzed miRNA profiles of three TNBC cell lines using an in vitro model of GR overexpression. Next-generation sequencing revealed minor, cell line-specific changes in cellular miRNA expression, whereas vesicular miRNAs were not significantly regulated by GR. Additionally, the analysis of predicted miRNA targets failed to establish a causal link between GR-induced miRNA expression and oncogenic signaling. On the whole, given that GR influences miRNA profiles to only a small degree, other mechanisms are more likely to be responsible for the increased mortality of patients with TNBC with a high GR expression. PMID- 29620158 TI - LTBP2 promotes the migration and invasion of gastric cancer cells and predicts poor outcome of patients with gastric cancer. AB - Latent transforming growth factor-beta-binding protein (LTBP)2 is a member of the fibrillin/LTBP superfamily of extracellular matrix proteins, and has been demonstrated to exhibit tumor-promoting and tumor-suppressive functions in different types of cancer. However, the function of LTBP2 in gastric cancer (GC) remains unknown. The aim of the present study was to investigate the expression and molecular function of LTBP2 in GC, and to evaluate its prognostic value for patients with GC. The results revealed that the expression of LTBP2 was upregulated in GC tissues and cell lines. Increased LTBP2 expression was associated with poor overall survival in patients with early-stage [tumor-node metastasis (TNM) I/II] and late-stage (TNM III/IV) GC. Furthermore, silencing of LTBP2 effectively suppressed the proliferation, migration, invasion and epithelial-mesenchymal transition in GC cells. These results suggested that LTBP2 may be considered as a potential therapeutic target and a promising prognostic biomarker for human GC. PMID- 29620160 TI - Metabolome analysis of esophageal cancer tissues using capillary electrophoresis time-of-flight mass spectrometry. AB - Reports of the metabolomic characteristics of esophageal cancer are limited. In the present study, we thus conducted metabolome analysis of paired tumor tissues (Ts) and non-tumor esophageal tissues (NTs) using capillary electrophoresis time of-flight mass spectrometry (CE-TOFMS). The Ts and surrounding NTs were surgically excised pair-wise from 35 patients with esophageal cancer. Following tissue homogenization and metabolite extraction, a total of 110 compounds were absolutely quantified by CE-TOFMS. We compared the concentrations of the metabolites between Ts and NTs, between pT1 or pT2 (pT1-2) and pT3 or pT4 (pT3-4) stage, and between node-negative (pN-) and node-positive (pN+) samples. Principal component analysis and hierarchical clustering analysis revealed clear metabolomic differences between Ts and NTs. Lactate and citrate levels in Ts were significantly higher (P=0.001) and lower (P<0.001), respectively, than those in NTs, which corroborated with the Warburg effect in Ts. The concentrations of most amino acids apart from glutamine were higher in Ts than in NTs, presumably due to hyperactive glutaminolysis in Ts. The concentrations of malic acid (P=0.015) and citric acid (P=0.008) were significantly lower in pT3-4 than in pT1-2, suggesting the downregulation of tricarboxylic acid (TCA) cycle activity in pT3-4. On the whole, in this study, we demonstrate significantly different metabolomic characteristics between tumor and non-tumor tissues and identified a novel set of metabolites that were strongly associated with the degree of tumor progression. A further understanding of cancer metabolomics may enable the selection of more appropriate treatment strategies, thereby contributing to individualized medicine. PMID- 29620161 TI - Biotinylation enhances the anticancer effects of 15d-PGJ2 against breast cancer cells. AB - 15-Deoxy-?12,14-prostaglandin J2 (15d-PGJ2) is a natural agonist of peroxisome proliferator-activated receptor gamma (PPARgamma) that displays anticancer activity. Various studies have indicated that the effects of 15d-PGJ2 are due to both PPARgamma-dependent and -independent mechanisms. In the present study, we examined the effects of a biotinylated form of 15d-PGJ2 (b-15d-PGJ2) on hormone dependent MCF-7 and triple-negative MDA-MB-231 breast cancer cell lines. b-15d PGJ2 inhibited cell proliferation more efficiently than 15d-PGJ2 or the synthetic PPARgamma agonist, efatutazone. b-15d-PGJ2 was also more potent than its non biotinylated counterpart in inducing apoptosis. We then analyzed the mechanisms underlying this improved efficiency. It was found not to be the result of biotin receptor-mediated increased incorporation, since free biotin in the culture medium did not decrease the anti-proliferative activity of b-15d-PGJ2 in competition assays. Of note, b-15d-PGJ2 displayed an improved PPARgamma agonist activity, as measured by transactivation experiments. Molecular docking analyses revealed a similar insertion of b-15d-PGJ2 and 15d-PGJ2 into the ligand binding domain of PPARgamma via a covalent bond with Cys285. Finally, PPARgamma silencing markedly decreased the cleavage of the apoptotic markers, poly(ADP-ribose) polymerase 1 (PARP-1) and caspase-7, that usually occurs following b-15d-PGJ2 treatment. Taken together, our data indicate that biotinylation enhances the anti proliferative and pro-apoptotic activity of 15d-PGJ2, and that this effect is partly mediated via a PPARgamma-dependent pathway. These results may aid in the development of novel therapeutic strategies for breast cancer treatment. PMID- 29620162 TI - Chaperonin-containing T-complex protein 1 subunit 8 promotes cell migration and invasion in human esophageal squamous cell carcinoma by regulating alpha-actin and beta-tubulin expression. AB - The chaperonin-containing T-complex protein 1 (CCT) has eight subunits, CCT 1-8, which are dysregulated in several types of cancer. To determine how subunit 8 (CCT8) influences the development of esophageal squamous cell carcinoma (ESCC), immunohistochemistry and western blot analysis were performed on 128 ESCC samples in the present study to measure the expression of CCT8. The prognostic value of CCT8 was analyzed using univariate and multivariate survival analyses. CCT8 knockdown in ESCC cells was performed and subsequently, the migration and invasion of ESCC cells was assessed. The results of immunohistochemistry and western blot analysis of ESCC tissue indicated that the expression of CCT8 in tumor tissues from patients with lymph node metastasis (LNM) was high whereas its expression in tissues from those without LNM was low. In addition, the overall survival rate of patients with high CCT8 expression was poor. It was demonstrated that CCT8 influenced the migration and invasion of ESCC cells by regulating alpha actin and beta-tubulin. Following CCT8 knockdown, cells were treated with cisplatin; it was demonstrated that alpha-actin and beta-tubulin were downregulated and that cell apoptosis was enhanced. These data confirm that alpha actin and beta-tubulin are regulated by CCT8, and that increased CCT8 expression is associated with poor patient prognosis and cisplatin resistance in ESCC. PMID- 29620159 TI - FOXP3 expression is modulated by TGF-beta1/NOTCH1 pathway in human melanoma. AB - Forkhead box protein 3 (FOXP3) transcription factor is expressed by immune cells and several human cancers and is associated with tumor aggressiveness and unfavorable clinical outcomes. NOTCH and transforming growth factor-beta (TGF beta) protumorigenic effects are mediated by FOXP3 expression in several cancer models; however, their interaction and role in melanoma is unknown. We investigated TGF-beta-induced FOXP3 gene expression during NOTCH1 signaling inactivation. Primary (WM35) and metastatic melanoma (A375 and A2058) cell lines and normal melanocytes (NHEM) were used. FOXP3 subcellular distribution was evaluated by immuno-cytochemical analysis. Gene expression levels were assessed by reverse transcription-quantitative polymerase chain reaction. Protein levels were assessed by western blot analysis. The gamma-secretase inhibitor (GSI) was used for NOTCH1 inhibition and recombinant human (rh)TGF-beta was used for melanoma cell stimulation. Cell proliferation and viability were respectively assessed by MTT and Trypan blue dye assays. FOXP3 mRNA and protein levels were progressively higher in WM35, A375 and A2058 cell lines compared to NHEM and their levels were further increased after stimulation with rh-TGF-beta. TGF-beta mediated FOXP3 expression was mediated by NOTCH1 signaling. Inhibition of NOTCH1 with concomitant rh-TGF-beta stimulation determined the reduction in gene expression and protein level of FOXP3. Finally, melanoma cell line proliferation and viability were reduced by NOTCH1 inhibition. The results show that nn increase in FOXP3 expression in metastatic melanoma cell lines is a potential marker of tumor aggressiveness and metastasis. NOTCH1 is a central mediator of TGF-beta-mediated FOXP3 expression and NOTCH1 inhibition produces a significant reduction of melanoma cell proliferation and viability. PMID- 29620163 TI - Mutational burden of resectable pancreatic cancer, as determined by whole transcriptome and whole exome sequencing, predicts a poor prognosis. AB - Despite the genomic characterization of pancreatic cancer (PC), marked advances in the development of prognosis classification and novel therapeutic strategies have yet to come. The present study aimed to better understand the genomic alterations associated with the invasive phenotype of PC, in order to improve patient selection for treatment options. A total of 30 PC samples were analysed by either whole transcriptome (9 samples) or exome sequencing (21 samples) on an Illumina platform (75X2 or 100X2 bp), and the results were matched with normal DNA to identify somatic events. Single nucleotide variants and insertions and deletions were annotated using public databases, and the pathogenicity of the identified variants was defined according to prior knowledge and mutation prediction tools. A total of 43 recurrently altered genes were identified, which were involved in numerous pathways, including chromatin remodelling and DNA damage repair. In addition, an analysis limited to a subgroup of early stage patients (50% of samples) demonstrated that poor prognosis was significantly associated with a higher number of known PC mutations (P=0.047). Samples from patients with a better overall survival (>25 months) harboured an average of 24 events, whereas samples from patients with an overall survival of <25 months presented an average of 40 mutations. These findings indicated that a complex genetic profile in the early stage of disease may be associated with increased aggressiveness, thus suggesting an urgent requirement for an innovative approach to classify this disease. PMID- 29620164 TI - Rapid point-of-care testing for epidermal growth factor receptor gene mutations in patients with lung cancer using cell-free DNA from cytology specimen supernatants. AB - Epidermal growth factor receptor (EGFR) mutations are associated with responses to EGFR tyrosine kinase inhibitors (EGFR-TKIs) in non-small-cell lung cancer (NSCLC). Our previous study revealed a rapid point-of-care system for detecting EGFR mutations. This system analyzes cell pellets from cytology specimens using droplet-polymerase chain reaction (d-PCR), and has a reaction time of 10 min. The present study aimed to validate the performance of the EGFR d-PCR assay using cell-free DNA (cfDNA) from supernatants obtained from cytology specimens. Assay results from cfDNA supernatant analyses were compared with those from cell pellets for 90 patients who were clinically diagnosed with, or suspected of having, lung cancer (80 bronchial lavage fluid samples, nine pleural effusion samples and one spinal fluid sample). EGFR mutations were identified in 12 and 15 cases using cfDNA supernatants and cell pellets, respectively. The concordance rates between cfDNA-supernatant and cell-pellet assay results were 96.7% [kappa coefficient (K)=0.87], 98.9% (K=0.94), 98.9% (K=0.79) and 98.9% (K=0.79) for total EGFR mutations, L858R, E746_A750del and T790M, respectively. All 15 patients with EGFR mutation-positive results, as determined by EGFR d-PCR assay using cfDNA supernatants or cell pellets, also displayed positive results by conventional EGFR assays using tumor tissue or cytology specimens. Notably, EGFR mutations were even detected in five cfDNA supernatants for which the cytological diagnoses of the corresponding cell pellets were 'suspicious for malignancy', 'atypical' or 'negative for malignancy.' In conclusion, this rapid point-of-care system may be considered a promising novel screening method that may enable patients with NSCLC to receive EGFR-TKI therapy more rapidly, whilst also reserving cell pellets for additional morphological and molecular analyses. PMID- 29620165 TI - FOXD1 is targeted by miR-30a-5p and miR-200a-5p and suppresses the proliferation of human ovarian carcinoma cells by promoting p21 expression in a p53-independent manner. AB - High-grade serous ovarian carcinoma (HGSOC) accounts for the highest number of deaths among patients with epithelial ovarian cancer. However, the molecular mechanisms underlying HGSOC tumorigenesis are currently unclear. In the present study, a lentiviral expression system was employed to manipulate forkhead box D1 (FOXD1) expression in ovarian cancer cells. Immunohistochemical staining was used to examine the expression of FOXD1 in tissue samples. Clonogenic and MTT assays were employed to evaluate cell proliferation, and flow cytometry was applied for cell cycle analysis. Dual-luciferase reporter and chromatin immunoprecipitation assays were used to determine the role of FOXD1 in regulating p21 expression. The results demonstrated that FOXD1 expression was downregulated in HGSOC, and high expression levels of FOXD1 were found to be a predictor of good prognosis. FOXD1 significantly inhibited the proliferation of human ovarian cancer cells and induced cell cycle arrest at G1 phase in vitro. In addition, exogenous FOXD1 expression inhibited ovarian cancer cell growth in vivo. Furthermore, microRNA (miR)-30a-5p and miR-200a-5p were observed to be upregulated in HGSOC, and function as direct negative regulators of FOXD1 by targeting its 3'-untranslated region. The present study also revealed that FOXD1 promotes p21 expression in a p53-independent manner. In conclusion, the results of the present study indicate a direct association between FOXD1 and p21 that may be mediated by miR-30a-5p and miR-200a-5p. The authors hypothesize that FOXD1 may serve as a biomarker or therapeutic target in HGSOC. PMID- 29620166 TI - Antitumour effects and mechanisms of action of the panHER inhibitor, dacomitinib, alone and in combination with the STAT3 inhibitor, S3I-201, in human sarcoma cell lines. AB - The 5-year survival rate for metastatic sarcoma is 16%. Although the phosphorylated human epidermal growth factor receptor (pEGFR/HER1) has been shown to be an independent predictor of overall survival in patients with sarcoma, we have previously demonstrated that sarcoma cell lines exhibit resistance, despite gefitinib blocking p-EGFR and signal transducers in EGFR downstream pathways. Gefitinib failed to decrease the ratio of phosphorylated (p-)signal transducer and activator of transcription (STAT3)/p-STAT1, suggesting that relative STAT3 abundance and activation may be involved in drug resistance. In this study, we used the panHER inhibitor, dacomitinib, to further block HER2-dependent activation, applying multiple methods, such as proliferation assay, clonogenic survival assay, anti-anoikis assay and western blot analysis. Although dacomitinib inhibited EGFR, HER2, AKT and Erk activation more effectively than gefitinib, it still only exerted minimal anti-proliferative effects on sarcoma cell lines due to the STAT3 escape pathway. However, the addition of the STAT3 inhibitor, S3I-201, to dacomitinib achieved a significant enhancement in growth inhibition, by perturbing p-STAT3/p-STAT1. Using a panel of sarcoma cell lines with different histological types, we identified that the addition of the STAT3 inhibitor enhanced the growth inhibitory effects of the panHER inhibitor, dacomitinib, on sarcoma cells. Our findings may have clinical implications on overcoming the resistance caused by the STAT3 escape pathway and optimising EGFR/panHER-targeted therapy in sarcoma. PMID- 29620167 TI - Decreased expression of SFRP2 promotes development of the pituitary corticotroph adenoma by upregulating Wnt signaling. AB - Cushing's disease is primarily caused by pituitary adrenocorticotropin-secreting adenoma. However, its pathogenesis has remained obscure. In the present study, whole transcriptome analysis was performed by RNA sequencing (RNA-Seq) and expression of secreted frizzled-related protein 2 (SFRP2) was decreased in corticotroph tumors compared with normal pituitary glands. Furthermore, the RNA Seq results were validated and the expression of SFRP2 in tumor tissues was analyzed by comparing another cohort of 23 patients with Cushing's disease and 3 normal human pituitary samples using reverse transcription-quantitative polymerase chain reaction, western blot and immunohistochemistry staining. Clinically, there was an association between lower SFRP2 expression and aggressive adenoma characteristics, including larger size and invasiveness. Conversely, SFRP2 overexpression reduced the ability of AtT20 cells to proliferate and migrate, and reduced production of the adrenocorticotrophic hormone in vitro. Mechanistically, overexpressed SFRP2 reduced the level of beta catenin in the cytoplasm and nucleus, and decreased Wnt signaling activity in AtT20 cells. Therefore, SFRP2 appears to act as a tumor suppressor in Cushing's disease by regulating the activity of the Wnt signaling pathway. PMID- 29620168 TI - S-phase kinase-associated protein 2 is involved in epithelial-mesenchymal transition in methotrexate-resistant osteosarcoma cells. AB - Osteosarcoma (OS), a common worldwide primary aggressive bone malignancy, arises from primitive transformed cells of mesenchymal origin and usually attacks adolescents and young adults. Methotrexate (MTX) is the anti-folate drug used as a pivotal chemotherapeutic agent in the treatment of OS. However, patients with OS often develop drug resistance, leading to poor treatment outcomes. In the present study, in order to explore the underlying mechanisms responsible for MTX resistance, we established MTX-resistant OS cells using the U2OS and MG63 cell lines and examined whether MTX-resistant OS cells underwent epithelial mesenchymal transition (EMT) by Transwell assay, wound healing assay, MTT assay, RT-PCR and western blot analysis. We found that the viability of the MTX resistant cells remained relatively unaltered following further treatment with MTX compared to the parental cells. The resistant cells appeared to possess a mesenchymal phenotype, with an elongated and more spindle-like shape, and acquired enhanced invasive, migratory and attachment abilities. The measurement of EMT markers also supported EMT transition in the MTX-resistant OS cells. Our result further demonstrated that the overexpression of S-phase kinase-associated protein 2 (Skp2) was closely involved in the resistance of OS cells to MTX and in the acquirement of EMT properties. Thus, the pharmacological inhibition of Skp2 may prove to be a novel therapeutic strategy with which to overcome drug resistance in OS. PMID- 29620169 TI - Lutein inhibits proliferation, invasion and migration of hypoxic breast cancer cells via downregulation of HES1. AB - An intratumoral hypoxic microenvironment is frequently observed in solid tumors, including breast cancer. Lutein, a plant-derived compound and non-vitamin A carotenoid, has been demonstrated to possess multiple protective properties including anti-inflammation, anti-oxidative stress and antitumor effects. The main objective of the present research was to elucidate the involvement of lutein in the production of reactive oxygen species (ROS) under hypoxia, the activation of hairy and enhancer of split 1 (HES1), and the proliferation, invasion and migration of breast cancer cells. The human breast cancer cell lines MDA-MB-157 and MCF-7 were exposed to hypoxic conditions and various concentrations of lutein. An MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] assay was performed to examine cell proliferation, and Annexin V-fluorescein isothiocyanate/propidium iodide staining was performed to analyze the apoptosis ratio. The levels of hypoxia inducible factor-1alpha (HIF-1alpha), NOTCH signaling molecules, HES1 and epithelial-mesenchymal transition (EMT)-associated factors were examined by reverse transcription-quantitative polymerase chain reaction and western blot analysis. Wound healing and Transwell invasion assays were used to detect the invasion and migration of breast cancer cells. Intracellular ROS levels were examined using 2,7-dichlorodihydrofluorescein diacetate and flow cytometry. The results revealed that cell proliferation was inhibited by lutein in a dose-dependent manner, and the apoptosis ratio gradually increased with lutein treatment under hypoxia as evident from flow cytometry based analysis. Exposure to lutein inhibited hypoxia-mediated activation of HIF 1alpha, NOTCH signaling and HES1 expression, and suppressed the hypoxia-induced expression of EMT-associated factors. Lutein markedly inhibited the invasion and migration of breast cancer cells under hypoxia. Hypoxia-induced production of ROS was also decreased by lutein. Furthermore, the ROS scavenger N-acetylcysteine also suppressed hypoxia inducible factor 1alpha and HES1 expression in breast cancer cells during hypoxia, but hydrogen peroxide (H2O2) levels were increased. Taken together, the results of the present study suggested that lutein may be a novel candidate for the chemoprevention of breast cancer. Furthermore, HES1 may be crucial in mediating the involvement of lutein in the suppression of hypoxia driven ROS-induced breast cancer progression. PMID- 29620170 TI - Increased level of cell-derived microparticles in the cyst fluids of odontogenic keratocysts. AB - The aim of this study was to examine the level and basic characteristics of cell derived microparticles (MPs) in the cyst fluids of odontogenic keratocysts (OKCs). For this purpose, MPs from the cyst fluids (CFMPs) of OKCs were purified by a classic differential centrifugation method and characterized by a transmission electron microscope and fluorescence microscope. Flow cytometric analysis was used to determine the size, concentration and cellular origins of the CFMPs. Moreover, the expression level of receptor activator for nuclear factor-kappaB ligand in the OKCs was evaluated by immunohistochemical staining and then analyzed for its correlation with the concentration of CFMPs by Spearman's rank correlation test. In addition, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and tartaric-resistant acid phosphatase (TRAP) staining were performed to examine the osteoclastogenesis of mouse bone marrow-derived macrophages (BMMs) in response to CFMPs. The results revealed that the levels of total CFMPs were significantly elevated in OKCs compared with dentigerous cysts (DCs) and radicular cysts (RCs). In addition, in vitro experiments further revealed that CFMPs derived from the OKCs of patients could be taken up by BMMs, leading to a significant increase in the mRNA expression levels of nuclear factor of activated T-cells 1 (NFATc1) and TRAP. Moreover, TRAP positive multinucleated osteoclasts were successfully cultured in the presence of macrophage colony-stimulating factor (M-CSF) and CFMPs with BMMs. On the whole, our findings indicate that patients with OKCs have higher levels of CFMPs compared with patients with DCs and RCs, which may be associated with the bone resorption of OKCs. PMID- 29620171 TI - Tripterygium glycoside protects against puromycin amino nucleoside-induced podocyte injury by upregulating autophagy. AB - Tripterygium glycoside (TG), an active ingredient of the widely used Chinese herb Tripterygium wilfordii Hook F, has immunosuppressive and anti-inflammatory effects. Previous studies have indicated that TG is a potentially effective therapeutic option to treat nephrotic syndrome. The mechanism underlying the therapeutic effect of TG, including its effect on autophagy and apoptosis in podocyte injury, remains to be fully elucidated. The present study aimed to assess the protective effect of TG on podocytes via its potential role in the activation of autophagic and phosphatidylinositol 3-kinase (PI3K) pathways. Using flow cytometry, western blot analysis, cell counting kit-8 assays and transmission electron microscopy analysis, the effects of TG on puromycin aminonucleoside (PAN)-induced podocyte injury were investigated. Chloroquine (CQ), an inhibitor of autophagy, was used to assess the importance of autophagy in the protective effect of TG. In addition, LY294002, an inhibitor of class III PI3K, was used to identify which signaling pathways TG is involved in. PAN caused marked apoptosis of podocytes, which was significantly antagonized by TG. The expression of microtubule-associated protein 1A/1B-light chain 3 and the appearance of autophagosomes increased significantly following TG treatment, whereas the expression levels of p62 and cleaved caspase-3 were markedly decreased. Podocyte apoptosis decreased significantly when the podocytes were treated with TG compared with the levels of apoptosis in the PAN- and PAN+CQ treated groups. The expression of phosphorylated AKT was increased significantly in the TG-treated groups, and the effects of TG on the podocytes were significantly inhibited by LY294002. In conclusion, TG protected podocytes from PAN-induced injury, and the effects were attributable to the activation of autophagy, mainly via a PI3K-dependent pathway. PMID- 29620172 TI - Long noncoding RNA LINC01296 promotes tumor growth and progression by sponging miR-5095 in human cholangiocarcinoma. AB - The aim of the present study was to elucidate whether, and how, long intergenic non-protein coding RNA 1296 (LINC01296) is involved in the modulation of human cholangiocarcinoma (CCA) development and progression. Microarray data analysis and reverse transcription-quantitative polymerase chain reaction analysis demonstrated that LINC01296 was significantly upregulated in human CCA compared with nontumor tissues. Furthermore, the expression of LINC01296 in human CCA was positively associated with tumor severity and clinical stage. Knockdown of LINC01296 dramatically suppressed the viability, migration and invasion of RBE and CCLP1 cells, and promoted cell apoptosis in vitro. Furthermore, LINC01296 knockdown inhibited tumor growth in a xenograft model. Mechanistically, LINC01296 was demonstrated to sponge microRNA-5095 (miR-5095), which targets MYCN proto oncogene bHLH transcription factor (MYCN) mRNA in human CCA. By inhibition of miR 5095, LINC01296 overexpression upregulated the expression of MYCN and promoted cell viability, migration and invasion in CCA cells. The results reveal that the axis of LINC01296/miR-5095/MYCN may be a mechanism to regulate CCA development and progression. PMID- 29620173 TI - Deregulation of microRNA-31a-5p is involved in the development of primary hypertension by suppressing apoptosis of pulmonary artery smooth muscle cells via targeting TP53. AB - The present study aimed to identify the association between microRNA (miRNA/miR) 31a-5p and the development of hypertension, and its potential molecular mechanism. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analyses were performed to validate the candidate miRNA and genes involved in hypertension, following which an online miRNA database search, luciferase assay, and RT-qPCR and western blot analyses were performed to confirm the interaction between miR-31a-5p and TP53. A MTT assay and flow cytometric analysis were utilized to determine the effect of miR-31a-5p on cell growth and apoptosis. The results revealed that miR-31a-5p and TP53 were the candidate miRNA and gene regulating hypertension, and that TP53 was the virtual target gene of miR-31a-5p with a binding site located in the TP53 3' untranslated region (3'UTR). It was confirmed by luciferase activity that miR-31a-5p markedly reduced the luciferase activity of the Luc-wild-type-TP53-3'UTR, whereas the mutated putative miR-31a-5p binding located on the TP53-3'UTR was found to eliminate such an inhibitory effect. miR-31a-5p had no effect on specificity protein 1, E2F transcription factor 2 or forkhead box P3 luciferase activity. Smooth muscle cells collected from spontaneously hypertensive rats treated with gold nano particles containing anti-rno-miR-31a-5p exhibited a lower growth rate and a higher apoptotic rate. The results of the RT-qPCR and western blot analyses showed that miR-31a-5p negatively regulated the expression of TP53, and transfection with the hsa-miR-31a-5p mimic significantly promoted cell growth and inhibited cell apoptosis, whereas transfection with the anti-hsa-miR-31a-5p mimic significantly suppressed cell growth and induced cell apoptosis. Taken together, these findings indicated that miR-31a-5p is involved in hypertension via the accelerated proliferation of arterial smooth muscle cells and inhibition of apoptosis through targeting TP53. PMID- 29620174 TI - Novel NADPH oxidase inhibitor VAS2870 suppresses TGF-beta-dependent epithelial-to mesenchymal transition in retinal pigment epithelial cells. AB - NADPH oxidases (NOXs) are important in the pathophysiology of fibrotic diseases. The expression and activity of NOXs are regulated by growth factors, including transforming growth factor (TGF-beta). The proliferation of retinal pigment epithelial (RPE) cells following epithelial- to-mesenchymal transition (EMT) is a major pathological change involved in proliferative vitreoretinopathy (PVR). The aim of the present study was to determine the effects of the novel NOX inhibitor VAS2870 on the TGF-beta-dependent expression of NOX4 and associated cellular events in RPE cells. Cell viability was examined using a Cell Counting Kit-8 assay and cell cycle progression was detected by flow cytometric analysis. Immunofluorescence analysis and western blot analysis were performed to assess EMT. It was found that TGF-beta increased the expression of NOX4 and that pre incubation with VAS2870 eliminated this effect. Additionally, TGF-beta promoted RPE migration and increased EMT. Pre-incubation with VAS2870 significantly prevented TGF-beta2-induced EMT by decreasing the levels of alpha-smooth muscle actin and E-cadherin, and also inhibited the migratory ability of the RPE cells, as demonstrated by scratch assays. Finally, VAS2870 suppressed the proliferation of RPE cells, and led to G1-phase cell cycle arrest and a significant downregulation of the expression of cyclin D1. In conclusion, the pharmacological inhibition of NOX may be a promising tool for the treatment of PVR. PMID- 29620175 TI - EGFR-associated pathways involved in traditional Chinese medicine (TCM)-1-induced cell growth inhibition, autophagy and apoptosis in prostate cancer. AB - Traditional Chinese medicine (TCM) has the synergistic effect of the combination of a single ingredient and a monomer, and systemic and local therapeutic effects in cancer treatment, through which TCM is able to enhance the curative effect and reduce the side effects. The present study analyzed the effect of TCM-1 (an anti cancer TCM) on prostate cancer (PCa) cell lines, and studied in detail the mechanism of cell death induced by TCM-1 in vitro and in vivo. From the present results, it was identified for the first time, to the best of our knowledge, that TCM-1 arrested the cell cycle at the G1 phase, decreased cell viability and increased nuclear rupture in a dose-dependent manner; these effects finally resulted in apoptosis in PCa cells. At the molecular level, the data demonstrated that TCM-1 competitively acted on epidermal growth factor receptor (EGFR) with EGF, and suppressed the auto-phosphorylation and activity of EGFR. Inhibition of EGFR further suppressed the downstream phosphatidylinositol 3-kinase (PI3K)/RAC alpha serine/threonine-protein kinase (AKT) and RAF proto-oncogene serine/threonine-protein kinase/extracellular signal regulated kinase signaling pathways and resulted in a decrease in the phosphorylated-forkhead box protein O1 (at Ser256, Thr24 and Ser319) expression level, and induced cell growth inhibition and apoptosis by regulating the expression of apoptosis-and cell cycle associated genes. In addition, TCM-1 markedly inhibited the PI3K/AKT/serine/threonine-protein kinase mTOR signaling pathway and induced cell autophagy by downregulating the phosphorylation of p70S6K and upregulating the levels of Beclin-1 and microtubule-associated protein light chain-3II. In vivo, the TCM-1-treated group exhibited a significant decrease in tumor volume compared with the negative control group in subcutaneous xenograft nude mice by inhibiting EGFR-associated signaling pathways. Therefore, the bio-functions of Chinese medicine TCM-1 in inducing PCa cell growth inhibition, autophagy and apoptosis suggested that TCM-1 may have clinical potential for the treatment of patients with PCa. PMID- 29620176 TI - beta2-adrenergic receptor functionality and genotype in two different models of chronic inflammatory disease: Liver cirrhosis and osteoarthritis. AB - The present study was designed to investigate the functional status of beta2 adrenoceptors (beta2AR) in two models of chronic inflammatory disease: liver cirrhosis (LC) and osteoarthritis (OA). The beta2AR gene contains three single nucleotide polymorphisms at amino acid positions 16, 27 and 164. The aim of the present study was to investigate the potential influence of lymphocyte beta2AR receptor functionality and genotype in LC and OA patients. Blood samples from cirrhotic patients (n=52, hepatic venous pressure gradient 13+/-4 mmHg, CHILD 7+/ 2 and MELD 11+/-4 scores), OA patients (n=30, 84% Kellgren-Lawrence severity 4 grade, 14% knee replacement joint) and healthy volunteers as control group (n=26) were analyzed. Peripheral blood mononuclear cells (PBMC) were isolated from whole blood and basal and isoproterenol induced adenylate cyclase activity (isoproterenol stimulus from 10-9 to 10-4 mM), and beta2AR allelic variants (rs1042713, rs1042714, rs1800888) were determined. beta2AR functionality was decreased in the two different models of chronic inflammatory disease studied, OA (50% vs. control) and LC (85% vs. control). In these patients, the strength of the beta2AR response to adrenergic stimulation was very limited. Adrenergic modulation of PBMC function through the beta2AR stimulus is decreased in chronic inflammatory processes including LC and OA, suggesting that the adrenergic system may be important in the development of these processes. PMID- 29620177 TI - Gardenoside combined with ozone inhibits the expression of P2X3 and P2X7 purine receptors in rats with sciatic nerve injury. AB - Neuropathic pain is a severe health problem for which there is a lack of effective therapy. Ozone and Gardenia fruits have been used separately in pain relief for many years; however, their underlying mechanisms remain unclear. To investigate the pain-relieving effects of combined ozone and Gardenia, a chronic constriction sciatic nerve injury (CCI) rat model was constructed and treated with ozone and gardenoside (Ozo&Gar), which is a compound found in Gardenia fruits. A total of 70 rats were randomly divided into five groups: Control (Ctrl), Ctrl + Ozo&Gar, Sham, CCI, and CCI + Ozo&Gar. The rats in the Ctrl + Ozo&Gar and CCI + Ozo&Gar groups were administered an intravenous injection of 30 ug/ml ozone and 300 umol/l gardenoside. The rats in the Ctrl, Sham and CCI groups were administered the same volume of saline. Pain behavior, mechanical hyperalgesia, thermal hyperalgesia, and the protein expression levels of P2X3 and P2X7 purine receptors in L4-L5 dorsal root ganglion (DRG) were determined 15 days post-surgery. The results demonstrated that treatment with a combination of ozone and gardenoside increased mechanical withdrawal threshold and thermal withdrawal latency, thus confirming their pain-relieving effects. In addition, a significant increase in the mRNA and protein expression levels of P2X3 and P2X7 was detected in the DRG of rats in the CCI group compared with in the control groups; however, following treatment with a combination of ozone and gardenoside, the mRNA and protein expression levels of P2X3 and P2X7 receptors were significantly reduced compared with in the CCI group. These results indicated that the mechanism underlying the pain-relieving effects of ozone and gardenoside may be mediated by inhibition of P2X3 and P2X7 purine receptors in the DRG. This finding suggested that ozone and gardenoside may be considered potential drug candidates that target P2X3 and P2X7 purine receptors. PMID- 29620178 TI - Impact of epigallocatechin-3-gallate on expression of nuclear factor erythroid 2 related factor 2 and gamma-glutamyl cysteine synthetase genes in oxidative stress induced mouse renal tubular epithelial cells. AB - The aim of the present study was to investigate the antioxidant response mechanism of epigallocatechin-3-gallate (EGCG) in H2O2-induced mouse renal tubular epithelial cells (MRTECs). The cultured MRTECs were divided into normal, H2O2 (control) and EGCG treatment groups. The MTT assay was used to assess cell viability, and reverse transcription-quantitative polymerase chain reaction (RT qPCR), immunocytochemical and western blot analyses were performed to detect the expression of nuclear factor erythroid 2-related factor 2 (Nrf2) and gamma glutamyl cysteine synthetase (gamma-GCS). EGCG was able to mitigate H2O2-mediated cell damage. The RT-qPCR results demonstrated that EGCG was able to upregulate the gene expression of Nrf2 and gamma-GCS in MRTECs in a dose-dependent manner. The immunocytochemistry and western blot analyses demonstrated that EGCG was able to increase the protein expression of Nrf2 and gamma-GCS in MRTECs in a dose dependent manner. Oxidative stress may lead to a decrease in the viability of MRTECs, while EGCG was able to promote the expression of Nrf2 and gamma-GCS in MRTECs, thereby improving the antioxidant capacity of the cells and promoting the repair of oxidative stress injury. PMID- 29620179 TI - Intensity-dependent effect of treadmill running on differentiation of rat bone marrow stromal cells. AB - The effect of running on bone mass depends on its intensity. However, the underlying molecular mechanism that associates running intensity with bone mass is unclear. The current study examined the effects of treadmill running at different intensities on bone mass and osteogenic differentiation of bone marrow stromal cells (BMSCs) in a rat model. A total of 24 male Wistar rats were randomly divided into groups and subjected to no running (Con group), low intensity running (LIR group), moderate-intensity running (MIR group), and high intensity running (HIR group). Histological, immunohistochemistry and micro-CT examinations were performed on the femora harvested after 8 weeks of treadmill running. The study demonstrated that treadmill running affected trabecular bone mass in an intensity-dependent manner. In addition, such an intensity-dependent effect was also demonstrated on the osteogenic and adipogenic differentiation and proliferation of BMSCs. Furthermore, the Wnt/beta-catenin signaling pathway may be involved in the running-induced increase in bone mass in rats in the MIR group. There appears to be a biomechanical 'window', in which running-induced strain signals can increase the number of BMSCs and progenitor cells (specific to the osteoblast lineage) causing upregulation of osteogenesis and downregulation of adipogenesis of BMSCs. This finding may provide insight into the molecular and cellular mechanisms responsible for bone homeostasis. PMID- 29620180 TI - A study on the correlation between STAT-1 and mutant p53 expression in glioma. AB - Glioma is the most common primary brain tumor in adults and the second most common malignant tumor in children. Aberrant expression of signal transducer and activator of transcription 1 (STAT-1) and p53 are known to affect the occurrence and progression of malignant tumors. The aim of the present study was to investigate the expression of STAT-1 and mutant p53 gene, as well as their correlation, in patients with glioma. The present study included 50 patients who underwent glioma resection at the First Affiliated Hospital of Inner Mongolia Medical University between December 2007 and December 2011, and 10 patients with acute cerebral contusion who underwent intracerebral hematoma removal at the same hospital between January 2013 and January 2014. The expression of STAT-1 and mutant p53 protein in patients with different grades of glioma was assessed by immunohistochemistry. Spearman's correlation coefficient was employed to examine the correlation between STAT-1 and the grade of glioma, and mutant p53 expression. The results demonstrated that the mean expression of STAT-1 in glioma was significantly lower compared with normal brain tissue (P<0.05). However, there was no significant difference in the STAT-1 positive expression rate between the two groups (chi2=1.38, P>0.05). The expression score (P<0.05) and positive expression rate (chi2=31.27, P<0.05) of mutant p53 in glioma was significantly higher compared with those in normal brain tissue. Statistical analysis revealed a negative correlation between STAT-1 expression and the grade of glioma (r=-0.767, P<0.05). In addition, mutant p53 expression was negatively correlated with STAT-1 expression in glioma (r=-0.876, P<0.05). The observed negative correlation between STAT-1 and the pathological grade of glioma suggested an association between STAT-1 and the occurrence and development of glioma, thus revealing the potential of STAT-1 as a diagnostic biomarker and therapeutic target for glioma. PMID- 29620181 TI - Identification of Streptococcus mitis321A vaccine antigens based on reverse vaccinology. AB - Streptococcus mitis (S. mitis) may transform into highly pathogenic bacteria. The aim of the present study was to identify potential antigen targets for designing an effective vaccine against the pathogenic S. mitis321A. The genome of S. mitis321A was sequenced using an Illumina Hiseq2000 instrument. Subsequently, Glimmer 3.02 and Tandem Repeat Finder (TRF) 4.04 were used to predict genes and tandem repeats, respectively, with DNA sequence function analysis using the Basic Local Alignment Search Tool (BLAST) in the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Cluster of Orthologous Groups of proteins (COG) databases. Putative gene antigen candidates were screened with BLAST ahead of phylogenetic tree analysis. The DNA sequence assembly size was 2,110,680 bp with 40.12% GC, 6 scaffolds and 9 contig. Consequently, 1,944 genes were predicted, and 119 TRF, 56 microsatellite DNA, 10 minisatellite DNA and 154 transposons were acquired. The predicted genes were associated with various pathways and functions concerning membrane transport and energy metabolism. Multiple putative genes encoding surface proteins, secreted proteins and virulence factors, as well as essential genes were determined. The majority of essential genes belonged to a phylogenetic lineage, while 321AGL000129 and 321AGL000299 were on the same branch. The current study provided useful information regarding the biological function of the S. mitis321A genome and recommends putative antigen candidates for developing a potent vaccine against S. mitis. PMID- 29620182 TI - Response of decorin to different intensity treadmill running. AB - Decorin is widely understood to affect collagen fibrillogenesis. However, little is understood about its response to various mechanical loading conditions. In the present study, 36 Wistar rats were randomly divided into control (CON), moderate treadmill running (MTR) and strenuous treadmill running (STR) groups. Animals in the MTR and STR groups were subjected to a 4- or 8-week treadmill running protocol. Subsequently, all Achilles tendons were harvested to perform histological and biochemical analyses. Decorin expression was markedly increased in the MTR group compared with the CON group at 4 and 8 weeks. Conversely, decorin expression was markedly decreased in the STR group compared with the CON and MTR group at 4 and 8 weeks. Furthermore, between the two time points, decorin expression levels were significantly increased in the MTR group, whereas they were markedly decreased in the STR group. These results suggested that MTR exercise may induce increased decorin expression via a balance of MMP-2 and TIMP 2, improving tendon structure and function. However, STR exercise may result in degradation of decorin due to an imbalance of MMP-2 and TIMP-2, with a bias to MMP-2, resulting in a predisposition to tendinopathy. PMID- 29620183 TI - Puerarin regulates neovascular glaucoma through pigment epithelium-derived growth factor-induced NF-kappaB signaling pathway. AB - Neovascular glaucoma is an ophthalmic disease and a potentially blinding secondary glaucoma caused by the formation of abnormal new blood vessels on the iris, which can prevent the normal drainage of water from the anterior segment of the eye. Evidence from China has suggested that puerarin benefits many diseases including myocardial infarction, stable angina, cerebral ischemia and glaucoma in a clinical setting. In the present study, the aim was to investigate the efficacies of puerarin on neovascular glaucoma in a mouse model. The molecular mechanism of puerarin-mediated treatment for neovascular glaucoma was also investigated both in vitro and in vivo. Inflammatory responses in mice with neovascular glaucoma were analyzed by western blotting. Oxidative stress levels were investigated following treatment with puerarin in a mouse model of neovascular glaucoma. The results indicated that puerarin markedly improved growth of vascular endothelial cells. The present study reported that puerarin treatment markedly decreased interleukin (IL)-1beta, IL-17A and tumor necrosis factor-alpha expression levels in mice with neovascular glaucoma. It was found that puerarin significantly decreased oxidative stress levels by reducing reactive oxygen species, superoxide dismutase and malondialdehyde levels, as well as neuronal nitric oxide synthase (NOS) and inducible NOS expression levels. Results indicated that expression levels of pigment epithelium-derived growth factor were significantly inhibited following treatment with puerarin. Mechanism analysis demonstrated that treatment with puerarin effectively inhibited nuclear factor (NF)-kappaB activity and its target protein levels p65, inhibitor of NF kappaB kinase subunit beta and inhibitor of NF-kappaB kinase subunit alpha in vascular endothelial cells. Increasing endothelial-derived growth factor (EDGF) expression levels could stimulate NF-kappaB activity and abolish the inhibitory effects of puerarin. An animal study reported that puerarin treatment presented therapeutic effects for mice with neovascular glaucoma. Numbers of new vessels in iris were recovered to normal following puerarin treatment. In conclusion, these results indicated that puerarin treatment can inhibit inflammatory responses and oxidative stress, platelet-derived growth factor (PDGF) expression and NF-kappaB activity, suggesting puerarin may be a potential agent for the treatment of neovascular glaucoma through PDGF-induced NF-kappaB signaling pathway. PMID- 29620184 TI - Zearalenone regulates endometrial stromal cell apoptosis and migration via the promotion of mitochondrial fission by activation of the JNK/Drp1 pathway. AB - Increased endometrial stromal cell (ESC) survival and migration is responsible for the development and progression of endometriosis. However, little is known about the mechanisms underlying ESC survival and migration, and limited therapeutic strategies that are able to reverse these abnormalities are available. The present study investigated the effects of zearalenone (ZEA) on ESC survival and migration, particularly focusing on mitochondrial fission and the c Jun N-terminal kinase (JNK)/dynamin-related protein 1 (Drp1) pathway. The results revealed that ZEA induced ESC apoptosis in a dose-dependent manner. Furthermore, ZEA treatment triggered excessive mitochondrial fission resulting in structural and functional mitochondrial damage, leading to the collapse of the mitochondrial membrane potential and subsequent leakage of cytochrome c into the cytoplasm. This triggered the mitochondrial pathway of apoptosis. Additionally, ZEA-induced mitochondrial fission decreased ESC migration through F-actin/G-actin homeostasis dysregulation. ZEA also increased JNK phosphorylation and subsequently Drp1 phosphorylation at the serine 616 position, resulting in Drp1 activation. JNK/Drp1 pathway inhibition abolished the inhibitory effects of ZEA on ESC survival and migration. In summary, the present study demonstrated that ZEA reduced ESC survival and migration through the stimulation of mitochondrial fission by activation of the JNK/Drp1 pathway. PMID- 29620185 TI - Procaine stimulates aquaporin-5 expression in human salivary gland ductal cells via the suppression of DNA methyltransferase-1. AB - The present study aimed to investigate whether procaine may upregulate the expression of aquaporin-5 (AQP5) in human salivary gland ductal cells and the underlying mechanisms of this upregulation. Immortalized normal human salivary gland ductal cells (NS-SV-DC), lacking AQP5 protein expression, were used to measure the glandular secretion rate following treatment with procaine, and the protein expression levels of AQP5 in NS-SV-DC cells were measured by western blotting. In order to investigate the mechanism of procaine action on AQP5 protein expression, the protein expression and activity of DNA methyltransferase (DNMT)1, and the CpG methylation of AQP5, were investigated further. In NS-SV-DC cells treated with procaine, the mRNA and protein levels of AQP5, and the secretion rate of cells, were significantly increased. Although no significant alterations were observed in the protein expression of DNMT1 following procaine treatment, its enzymatic activity was reduced, resulting in CpG island demethylation at Sp1-2 and Sp1-3 sites of the AQP5 gene, which may contribute to the significantly upregulated AQP5 gene expression. The results of the present study indicate that procaine may upregulate the protein expression of AQP5 in human submandibular glands by inhibiting the activity of DNMT1 and promoting liquid secretion. The procaine-mediated expression of AQP5 may provide a novel regimen for the treatment of SS syndrome. PMID- 29620186 TI - The transcription factor 7 like 2-binding protein TIP5 activates beta catenin/transcription factor signaling in hepatocellular carcinoma. AB - Aberrant activation of beta-catenin/transcription factor 7 like 2 (TCF7L2) signaling is frequently observed during the progression of hepatocellular carcinoma (HCC). However, regulation of the nuclear beta-catenin/TCF7L2 complex remains largely unknown. In the present study, immunoprecipitation and glutathione S-transferase pull-down assays identified transcription termination factor-1 interacting protein 5 (TIP5) as a binding partner of TCF7L2. TIP5 activated beta-catenin/TCF7L2 signaling by enhancing the interaction between beta catenin and TCF7L2. The results from quantitative polymerase chain reaction and western blot analysis indicated that TIP5 was upregulated in clinical HCC samples. In addition, TIP5 positively regulated the proliferation of HCC cells in the MTT assay, colony formation in the soft agar assay, migration in the Boyden chamber assay and epithelial-mesenchymal transition of HCC cells by activating beta-catenin/TCF7L2 signaling. Therefore, the results of the present study demonstrate that TIP5 serves an oncogenic role in HCC by activating beta catenin/TCF7L2 signaling, suggesting that TIP5 may be a promising therapeutic target for HCC. PMID- 29620187 TI - Metformin inhibits ovarian cancer via decreasing H3K27 trimethylation. AB - Metformin has been used for the treatment of type II diabetes mellitus for decades. Recently, used of metformin in the therapy of diverse human cancer types has received widespread attention, while the underlying mechanisms have been not fully elucidated. In the current study, 5-ethynyl-20-deoxyuridine assay to detect cell proliferation, flow cytometry to detect apoptosis, scratch wound healing and Transwell migration assay to detect cell migration capacity. The current study reported that metformin inhibited cell proliferation and migration, and promoted apoptosis in ovarian cancer cells, particularly under normoglycemic conditions in vitro. Metformin treatment significantly promoted the phosphorylation of AMP activated protein kinase (AMPK), and reduced histone H3 lysine 27 trimethylation (H3K27me3) and polycomb repressor complex 2 (PRC2) levels. Additionally, overexpression of EZH2 to increase H3K27me3 abrogated the effect of metformin on the cell proliferation, migration and apoptosis in SKOV3 and ES2 cells. Similar to metformin, another AMPK agonist, 2-deoxy-D-glucose, reduced the H3K27me3 level and PRC2 expression. In cells pretreated with Compound C, an AMPK inhibitor, metformin was not able to induce AMPK phosphorylation or reduce H3K27me3. Metformin-mediated AMPK activation and H3K27me3 inhibition were more robust in cells exposed to low glucose (5.5 mM) compared with those exposed to high glucose (25 mM). These findings implicate H3K27me3 repression mediated by AMPK phosphorylation in the antitumor effect of metformin in ovarian cancer, indicating that metformin alters epigenetic modifications by targeting PRC2 and supports the use of metformin in treatment of patients with epithelial ovarian cancer without diabetes. PMID- 29620188 TI - The inhibition of heme oxygenase-1 enhances the chemosensitivity and suppresses the proliferation of pancreatic cancer cells through the SHH signaling pathway. AB - Pancreatic cancer (PC) is a type of cancer associated with a high fatality rate due to a poor prognosis and resistance to treatment. Heme oxygenase-1 (HO-1) is significantly overexpressed in a number of types of cancer and seems to play an important role in cancer progression. In this study, we examined the potential effects of HO-1 on PC cell proliferation and sensivity to gemcitabine (Gem). Furthermore, the role of the sonic hedgehog (SHH) signaling pathway in the regulatory effects of HO-1 on PC progression were examined. For this purpose, the expression of HO-1 was examined in cultured PC cells by real-time PCR, western blot analysis and immunofluorescence. Transfection with small interfering RNA against HO-1 or an overexpression plasmid were used to regulate the expression of HO-1 in the MIA PaCa-2 and PANC-1 cell lines. Cell proliferation was examined by MTT assays in response to the different treatments. The results revealed that HO 1 expression differed significantly in the different PC cells. The overexpression of HO-1 induced PC cell proliferation and the inhibition of HO-1 decreased the cell proliferative ability. Furthermore, HO-1 activated the SHH signaling pathway in the PC cells. In addition, the SHH signaling pathway was found to play a role in HO-1-induced PC cell proliferation. The inhibition of HO-1 enhanced the responsiveness of PC cells to Gem and Gem was found to regulate the expression of HO-1 and the activation of the SHH pathway. On the whole, our findings indicate that HO-1 overexpression in PC cells may be responsible for the increased cell proliferation and the resistance to anticancer therapy. Furthermore, the SHH signaling pathway, the activation of which was initiated by HO-1, may be one of the endogenous mechanisms in this process. Our data shed light into the association between HO-1 and SHH in PC cells, and may aid in the development of novel therapeutic targets for the treatment of patients with PC. PMID- 29620189 TI - Curcumol attenuates epithelial-mesenchymal transition of nasopharyngeal carcinoma cells via TGF-beta1. AB - The current study aimed to identify the effect and primary mechanism of Curcumol on the migration of nasopharyngeal carcinoma (NPC) cells in vitro and in vivo. Curcumol was dissolved in absolute ethyl alcohol and the experiment was performed in NPC 5-8F cells in vitro and in vivo. The effect of different concentrations of Curcumol on cell migration was determined using wound healing and Transwell assays. A cell counting kit-8 (CCK-8) assay was also performed in order to determine cell viability. Flow cytometry was used to detect the effect of Curcumol on apoptosis. The expression of epithelial-mesenchymal transition (EMT) associated proteins and genes was evaluated by western blotting, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and ELISA. In addition, the antitumor activity of Curcumol was investigated in female BALB/C nude mice with orthotopic tumor implants. The results indicated that cell apoptosis was increased and the viability of NPC 5-8F cells was decreased following treatment with Curcumol at doses of 0.1, 0.2 and 0.4 uM/ml. The results of in vivo experiments indicated that tumor growth and weight were decreased following Curcumol administration. Furthermore, the results of western blotting and RT-qPCR demonstrated that Curcumol altered the level of E-cadherin and N cadherin in a dose-dependent manner in vivo. Curcumol also regulated the secretion of protein markers in the serum that were associated with EMT and TGF beta1 in the 5-8F xenograft mouse model. Thus, the results indicated that Curcumol induced TGF-beta1-mediated EMT arrest by regulating E-cadherin and N cadherin, which may prevent further development of NPC. PMID- 29620190 TI - lncRNAPCAT29 inhibits pulmonary fibrosis via the TGF-beta1-regulated RASAL1/ERK1/2 signal pathway. AB - Pulmonary fibrosis is a severe respiratory disease characterized by the aggregation of extracellular matrix components and inflammation-associated injury. Studies have suggested that long non-coding RNAs (lncRNA) may serve a role in the pathophysiological processes of pulmonary fibrosis. However, the potential molecular mechanisms involving the lncRNA, prostate cancer-associated transcript 29 (lncRNAPCAT29) in the progression of pulmonary fibrosis are yet to be determined. In the present study, the role of lncRNAPCAT29 and the potential signaling mechanism in pulmonary fibrosis progression was investigated. Reverse transcription-quantitative polymerase chain reaction and immunohistochemistry revealed that the expression levels of lncRNAPCAT29 were downregulated within interstitial lung cells from mice with silica-induced pulmonary fibrosis. Transfection with lncRNAPCAT29 was associated with upregulated expression of microRNA (miRNA)-221 and downregulated expression of transforming growth factor beta1 (TGF-beta1); reduced inflammation and fibrotic progression was also associated with lncRNAPCAT29 transfection. TGF-beta1 expression levels were inhibited within pulmonary fibroblasts due to lncRNAPCAT29 expression; NEDD4 binding protein 2 and Plexin-A4 expression levels were also suppressed. Analysis of the potential mechanism underlying silica-induced pulmonary fibrosis revealed that the expression levels of RAS protein activator like 1 (RASAL1) and extracellular signal-regulated kinases 1/2 (ERK1/2) were suppressed due to lncRNAPCAT29 expression. The results of the present study demonstrated that lncRNAPCAT29 induced miRNA-221 upregulation and TGF-beta1 downregulation. These observations were associated with reduced inflammation and progression of silica induced pulmonary fibrosis via the TGF-beta1-regulated RASAL1/ERK1/2 signaling pathway, which may serve as a potential target for the treatment of pulmonary fibrosis. PMID- 29620191 TI - Arsenic disulfide-induced apoptosis and its potential mechanism in two- and three dimensionally cultured human breast cancer MCF-7 cells. AB - In China, arsenic disulfide (As2S2) has been used for the treatment of hematological malignancies. The present study aimed to evaluate the effects of As2S2 on the human breast cancer MCF-7 cell line cultured in both two-dimensional (2D) monolayers and three-dimensional (3D) spheroids to explore its therapeutic potential in breast cancer treatment. Cellular viability and the induction of apoptosis were examined with a cell counting kit-8 (CCK-8) assay and flow cytometric analysis, respectively. Alterations in the expression levels of apoptosis-associated proteins, including Bcl-2-associated X protein (Bax), B-cell lymphoma 2 (Bcl-2), p53, and caspase-7, as well as the cell survival-associated proteins, phosphatidylinositol 3-kinase (PI3K), Akt, and mammalian target of rapamycin (mTOR), were assessed by western blotting. Although a dose-dependent reduction in cell viability, which occurred in association with the induction of apoptosis triggered by the addition of 2-24 uM As2S2, was observed in both 2D- and 3D-culture systems, 3D spheroids were less sensitive to the cytotoxic effect of As2S2 compared with the 2D cultured cells. A significant increase in the expression levels of Bax, p53, and caspase-7 was observed in treated 2D-cultured cells, whereas a similar increase in the expression levels of Bax was only confirmed in treated 3D spheroids, although there was a trend towards the increased expression of p53 and caspase-7 in the 3D spheroids. These results suggested that these molecules are closely associated with As2S2-mediated cytotoxicity in the two culture systems, and further suggested that the difference in the sensitivity to As2S2 between 2D monolayers and 3D spheroids may be attributed to the differential alterations in the expression levels of proteins associated with cell mortality. Significant downregulation of the expression levels of Bcl-2, PI3K, Akt and mTOR was observed in the two culture systems. Taken together, the results of the present study demonstrated that As2S2 inhibits cell viability and induces apoptosis in both 2D- and 3D- cultured MCF-7 cells, which may be associated with activation of the pro-apoptotic pathway and the inhibition of pro-survival signaling. These results have provided novel insights into clinical applications of As2S2 in the treatment of patients with breast cancer. PMID- 29620192 TI - Tumor-suppressing effects of microRNA-612 in bladder cancer cells by targeting malic enzyme 1 expression. AB - The present study investigated the possible tumor-suppressing function of microRNA (miR)-612 and the underlying molecular mechanism of its action in bladder cancer in vitro and in vivo. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was carried out to quantify the expression levels of miR-612 in bladder cancer tissues and cell lines. The data demonstrated that the level of miR-612 expression was significantly reduced in bladder cancer tissues and cell lines, as compared with that in non-cancerous tissues and cells. Reduced miR-612 expression was associated with advanced tumor, lymph node and metastasis stages, and with distant metastasis of bladder cancer. A functional study revealed that transfection of cells with an miR-612 mimic suppressed bladder cancer cell growth, colony formation, migration, invasion and epithelial mesenchymal transition. Bioinformatics analysis identified that miR-612 targeted the expression of malic enzyme 1 (ME1), and this was confirmed by western blot and luciferase reporter assay results. Furthermore, the ME1 expression levels were inversely associated with miR-612 expression in bladder cancer tissue specimens. In addition, knockdown of ME1 expression using ME1 siRNA mimicked the effect of ectopic miR-612 overexpression in bladder cancer cells in terms of tumor cell growth, migration and invasion. By contrast, ME1 overexpression weakened the inhibitory effect of the miR-612 mimic in bladder cancer cells. In conclusion, the present study demonstrated that miR-612 may function as a tumor suppressor in bladder cancer by targeting ME1 expression. PMID- 29620193 TI - Influence of the interaction between Ac-SDKP and Ang II on the pathogenesis and development of silicotic fibrosis. AB - N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP) is a natural tetrapeptide that is released from thymosin beta4 by prolyl oligopeptides. It is hydrolyzed by the key enzyme of the renin-angiotensin system, angiotensin-converting enzyme (ACE). The aim of the present study was to investigate the alterations in Ac-SDKP and the ACE/angiotensin II (Ang II)/angiotensin II type 1 (AT1) receptor axis and its impact on the pathogenesis and development of silicotic fibrosis. For in vivo studies, a HOPE MED 8050 exposure control apparatus was used to establish different stages of silicosis in a rat model treated with Ac-SDKP. For in vitro studies, cultured primary lung fibroblasts were induced to differentiate into myofibroblasts by Ang II, and were pretreated with Ac-SDKP and valsartan. The results of the present study revealed that, during silicosis development, ACE/Ang II/AT1 expression in local lung tissues increased, whereas that of Ac-SDKP decreased. Ac-SDKP and the ACE/AT1/Ang II axis were inversely altered in the development of silicotic fibrosis. Ac-SDKP treatment had an anti-fibrotic effect in vivo. Compared with the silicosis group, the expression of alpha-smooth muscle actin (alpha-SMA), Collagen (Col) I, Fibronectin (Fn) and AT1 were significantly downregulated, whereas matrix metalloproteinase-1 (MMP-1) expression and the MMP 1/tissue inhibitor of metalloproteinases-1 (TIMP-1) ratio was increased in the Ac SDKP treatment group. In vitro, pre-treatment with Ac-SDKP or valsartan attenuated the expression of alpha-SMA, Col I, Fn and AT1 in Ang II-induced fibroblasts. In addition, MMP-1 expression and the MMP-1/TIMP-1 ratio were significantly higher in Ac-SDKP and valsartan pre-treatment groups compared with the Ang II group. In conclusion, the results of the present study suggest that an imbalance between Ac-SDKP and ACE/Ang II/AT1 molecules promotes the development of silicosis and that Ac-SDKP protects against silicotic fibrosis by inhibiting Ang II-induced myofibroblast differentiation and extracellular matrix production. PMID- 29620194 TI - Crocin inhibits RANKL-induced osteoclastogenesis by regulating JNK and NF-kappaB signaling pathways. AB - Receptor activator of nuclear factor-kappaB ligand (RANKL), a member of the tumor necrosis factor receptor-ligand family, is a crucial factor involved in osteoclast differentiation. Crocin, a pharmacologically active component of Crocus sativus L., has been reported to attenuate ovariectomy-induced osteoporosis in rats. However, the molecular mechanism underlying the effect of crocin on osteoclast formation remains to be determined. The present study aimed to investigate the effect of crocin on RANKL-induced osteoclastogenesis and its underlying molecular mechanism. Results demonstrated that crocin decreased osteoclastogenesis in bone marrow-derived macrophages (BMMs). In addition, the expression levels of osteoclast marker proteins were downregulated by crocin. Mechanistically, crocin inhibited RANKL-induced activation of nuclear factor kappaB (NF-kappaB) by suppressing inhibitor of kappaBalpha degradation and preventing NF-kappaB p65 subunit nuclear translocation, and by activating c-Jun N terminal kinase (JNK) in BMMs. In summary, the results of the present study suggested that crocin downregulates osteoclast differentiation via inhibition of JNK and NF-kappaB signaling pathways. Thus, crocin may be a potential therapeutic agent for the treatment of osteoclast-associated diseases, including osteoporosis. PMID- 29620195 TI - MicroRNA-671-3p inhibits the development of breast cancer: A study based on in vitro experiments, in-house quantitative polymerase chain reaction and bioinformatics analysis. AB - MicroRNAs (miRNAs or miRs) are highly conserved small noncoding RNA molecules involved in gene regulation. An increasing number of studies have demonstrated that miRNAs act as oncogenes or antioncogenes in various types of cancer, including breast cancer (BC). However, the exact role of miR-671-3p in BC has not yet been reported. In the present study, in vitro experiments were implemented to explore the effects of miR-671-3p on the proliferation and apoptosis of BC cells, and reverse transcription-quantitative polymerase chain reaction was conducted using in-house clinical BC samples to address the expression level and clinical value of miR-671-3p in BC. Simultaneously, miR-671-3p target genes were collected, and subsequent bioinformatics analyses were executed to probe the potential signaling pathway through which miR-671-3p influenced the occurrence and progression of BC. According to the results, the expression level of miR-671 3p was lower in BC tissues compared with that in adjacent non-tumorous tissues (P=0.048), and the area under the curve was 0.697 (95% confidence interval=0.538 0.856), with a sensitivity and specificity of 0.818 and 0.579, respectively. Forced miR-671-3p expression in the BC cell line MDA-MB-231 evidently arrested cell proliferation and induced cell apoptosis. Furthermore, in silico enrichment analyses suggested that miR-671-3p may be involved in the initiation and progression of BC through the targeting of genes associated with the Wnt signaling pathway. In conclusion, the present study findings suggested that miR 671-3p may function as a tumor suppressor in BC by influencing the Wnt signaling cascade, which provides a prospective molecular target for the therapy of BC. PMID- 29620196 TI - Combination of TP53 and AGR3 to distinguish ovarian high-grade serous carcinoma from low-grade serous carcinoma. AB - Ovarian high-grade serous carcinoma (HGSC) and low-grade serous carcinoma (LGSC) are distinct gynecologic neoplasms with diverse pathogenesis and characteristic features. They respond differently to same modalities of treatment protocol and have dissimilar prognosis. Thus, it is essential to obtain accurate differential diagnosis of HGSC and LGSC prior to clinical treatment. In the present study, mRNA expression profiles were generated from 5 HGSC and 6 LGSC specimen using HTSeq, and 699 differentially expressed genes (>2-fold difference) were identified using the DESeq R package. Dendrograms produced by unsupervised hierarchical clustering completely distinguished HGSC from LGSC. Among differentially expressed genes between HGSC and LGSC, anterior gradient homolog 3 (AGR3) was highly upregulated in LGSC compared to HGSC, which was validated by reverse transcription-quantitative polymerase chain reaction and western blotting. Then, anti-tumor protein 53 (TP53) and anti-AGR3 immunohistochemistry were performed on 145 HGSC and 30 LGSC samples. Consistent with previous studies, abnormal expression of TP53 (0 or >=75% positive expression) was observed in 87.6% of HGSC and 13.3% of LGSC samples. Positive staining of AGR3 had a sensitivity of 80.0% and specificity of 89.7% for LGSC. TP53 and AGR3 were both efficient in distinguishing HGSC from LGSC (P<0.001). Receiver operating characteristic analysis revealed a similar area under the curve for AGR3 (0.848) and TP53 (0.871). Through combination of the two markers (TP53 wild-type pattern and AGR3-positive expression), the accuracy of differential diagnosis was up to 93.1%. These findings provide compelling evidence that differential diagnosis of HGSC and LGSC can be improved by combined application of these two markers on the basis of conventional histopathological diagnosis. PMID- 29620197 TI - Identification of key genes in non-alcoholic fatty liver disease progression based on bioinformatics analysis. AB - Due to economic development and lifestyle changes, the incidence of non-alcoholic fatty liver disease (NAFLD) has gradually increased in recent years. However, the pathogenesis of NAFLD is not yet fully understood. To identify candidate genes that contribute to the development and progression of NAFLD, two microarray datasets were downloaded from the Gene Expression Omnibus database. The differentially expressed genes (DEGs) were identified and functional enrichment analyses were performed. A protein-protein interaction network was constructed and modules were extracted using the Search Tool for the Retrieval of Interacting Genes and Cytoscape. The enriched functions and pathways of the DEGs included 'cellular macromolecule biosynthetic process', 'cellular response to chemical stimulus', 'extracellular matrix organization', 'metabolic pathways', 'insulin resistance' and 'forkhead box protein O1 signaling pathway'. The DEGs, including type-1 angiotensin II receptor, formin-binding protein 1-like, RNA-binding protein with serine-rich domain 1, Ras-related C3 botulinum toxin substrate 1 and polyubiquitin-C, were identified using multiple bioinformatics methods and validated in vitro with reverse transcription-quantitative polymerase chain reaction analysis. In conclusion, five hub genes were identified in the present study, and they may aid in understanding of the molecular mechanisms underlying the development and progression of NAFLD. PMID- 29620198 TI - Isoflurane-induced postoperative cognitive dysfunction is mediated by hypoxia inducible factor-1alpha-dependent neuroinflammation in aged rats. AB - Elderly patients are at high risk of developing postoperative cognitive dysfunction (POCD) after prolonged exposure to inhaled anesthetics. However, the pathogenesis of POCD remains unknown. Hypoxia-inducible factor-1alpha (HIF 1alpha) is activated by inhaled anesthetics. The aim of the present study was to determine the role of HIF-1alpha in isoflurane-induced neuroinflammation and the resulting cognitive impairment. Following a 4-h exposure to 1.5% isoflurane in 20 month-old rats, increased expression of HIF-1alpha protein, activation of nuclear factor (NF)-kappaB signaling and increased expression of TNF-1alpha were observed in the hippocampus of isoflurane-exposed rats compared with the control group. Pharmacological inhibition of HIF-1alpha activation by 5-[1-(phenylmethyl)-1H indazol-3-yl]-2-furanmethanol (YC-1) markedly suppressed the enhanced expression of HIF-1alpha, disrupted NF-kappaB signaling pathway activity and inhibited the isoflurane-induced increase of TNF-1alpha expression. YC-1 pretreatment also significantly attenuated isoflurane-induced cognitive deficits according to the results of the Morris water maze task. These results suggest that hippocampal HIF 1alpha appears to be involved in an upstream mechanism of isoflurane-induced cognitive impairment. Further research is warranted to fully clarify the pathogenesis and investigate HIF-1alpha as a potential therapeutic target for POCD. PMID- 29620199 TI - Correlation between autophagy levels in peripheral blood mononuclear cells and clinical parameters in patients with chronic obstructive pulmonary disease. AB - Autophagy serves a role in the pathogenesis of chronic inflammatory diseases. The aim of the present study was to compare the autophagy levels in the peripheral blood mononuclear cells (PBMCs) of patients with chronic obstructive pulmonary disease (COPD) and healthy individuals and to assess the association between autophagy and the clinical parameters of COPD. Samples of peripheral blood from 20 patients with stable COPD and 20 healthy controls were collected. PBMCs were harvested using Ficoll density gradient centrifugation. Levels of the autophagy associated proteins ubiquitin-binding protein p62 (p62), microtubule-associated proteins 1A/1B light chain 3A (LC3I/II) and beclin-1 in PBMCs were detected by western blotting. Enzyme-linked immunosorbent assay kits were used to detect the serum concentrations of interleukin (IL)-6, IL-8 and tumor necrosis factor (TNF) alpha. Associations between the levels of autophagy and forced expiratory volume in 1 sec % predicted (FEV1%) and pro-inflammatory factors were assessed. Western blotting demonstrated that the protein expression of p62 was decreased, but LC3II/I and beclin-1 levels increased in patients with COPD compared with healthy controls. Serum levels of IL-6, IL-8 and TNF-alpha were increased in patients with COPD. The extent of PBMC autophagy was negatively correlated with FEV1% predicted, but positively correlated with levels of pro-inflammatory cytokines. The levels of autophagy in PBMCs in patients with COPD were increased and were negatively correlated with FEV1% predicted and positively correlated with circulating levels of pro-inflammatory cytokines. Autophagy may serve a role as a biomarker of the severity of COPD or as a therapeutic target for treatment of COPD. PMID- 29620200 TI - Identification of key genes and pathways in regulating immune-induced diseases of dendritic cells by bioinformatic analysis. AB - Dendritic cells (DCs) serve crucial roles in the activation of the immune response, and imbalance in the activation or inhibition of DCs has been associated with an increased susceptibility to develop immune-induced diseases. However, the molecular mechanisms of regulating immune-induced diseases of DCs are not well understood. The aim of the present study was to identify the gene signatures and uncover the potential regulatory mechanisms in DCs. A total of 4 gene expression profiles (GSE52894, GSE72893, GSE75938 and GSE77969) were integrated and analyzed in depth. In total, 241 upregulated genes and 365 downregulated genes were detected. Gene ontology and pathway enrichment analysis showed that the differentially expressed genes (DEGs) were significantly enriched in the inflammatory response, the tumor necrosis factor (TNF) signaling pathway, the nuclear factor (NF)-kappaB signaling pathway and antigen processing. The top 10 hub genes were identified from the protein-protein analysis. The most significant 2 modules were filtered from the protein-protein network. The genes in 2 modules were involved in type I interferon signaling, the NF-kappaB signaling pathway and the TNF signaling pathway. Furthermore, the microRNA-mRNA network analysis was performed. The results of the present study revealed that the identified DEGs and pathways may improve our understanding of the mechanisms of the maturation of DCs, and the candidate hub genes that may be therapeutic targets for immune-induced diseases. PMID- 29620201 TI - MicroRNA-92a overexpression promotes the osteogenic differentiation of bone mesenchymal stem cells by impeding Smad6-mediated runt-related transcription factor 2 degradation. AB - Bone mesenchymal stem cells (BMSCs) are an important source of stem cells for tissue repair and regeneration; therefore, understanding the mechanisms that regulate stem cell differentiation in a specific lineage is critical. Runt related transcription factor 2 (Runx2) is a bone-specific transcription factor that serves an important role in promoting osteogenic differentiation. However, Runx2 protein levels are regulated by the ubiquitin-proteasome pathway. Previous research has identified that Smad6 can interact with Runx2 and enhance Smurf1 induced Runx2 degradation in a ubiquitin-proteasome-dependent manner. Bioinformatics analysis demonstrated that miR-92a can target Smad6. To characterize the regulatory effect of miR-92a on osteogenic differentiation of BMSCs and assess the interactive association between Smad6 and miR-92a, BMSCs were obtained from mice and miR-92a or Smad6 overexpression vectors were constructed. Reverse transcription-quantitative polymerase chain reaction (RT qPCR) and western blots were used to analyze the expression of miR-92a and Smad6, and the luciferase reporter assay was used to examine the interaction between miR 92a and Smad6. BMSCs were induced in osteogenic differentiation media for 21 days. The alkaline phosphatase activity was assessed and Alizarin Red histochemical staining was also performed. The results suggested that the expression of miR-92a suppressed Smad6-mediated Runx2 degradation by direct integration with the 3'-UTR of Smad6 mRNA, which was confirmed by a luciferase reporter assay. In addition, the expression of miR-92a promoted the osteogenic differentiation of BMSCs. However, the regulatory effect of miR-92a was inhibited by overexpression of Smad6. Taken together, the results suggest that miR-92a expression inhibits the osteogenic differentiation of BMSCs by targeting Smad6. PMID- 29620202 TI - Identification of the tumor-suppressive function of circular RNA FOXO3 in non small cell lung cancer through sponging miR-155. AB - Circular RNAs (circRNAs) are a class of endo-genous noncoding RNAs that have been demonstrated to be potential regulators in the development and progression of various types of human cancer. However, little is known about their roles in cancer initiation and progression, particular in non-small cell lung cancer (NSCLC). In the present study, the expression level of circRNA-forkhead box O3 class (FOXO3) in NSCLC specimens was determined and its functional role was investigated in NSCLC cells. By performing Taq-man based RT-qPCR, it was identified that circRNA-FOXO3 was downregulated in NSCLC tissues and cell lines. Receiver operating curve analysis indicated that circRNA-FOXO3 had a relatively higher diagnostic accuracy. The functional relevance was further examined by biological assays. circRNA-FOXO3 significantly promoted the ability of cell proliferation, migration and invasion of NSCLC cells. The linear isomer of circRNA-FOXO3, FOXO3 gene, was identified as a downstream target. RNA immunoprecipitation indicated that circRNA-FOXO3 sequestering miR-155, which further promoted linear FOXO3 expression. In addition, gain and loss functional assays indicated that circRNA-FOXO3 served an anti-oncogenic role through sequestering miR-155 and enhancing FOXO3 expression. These results suggest that circRNA-FOXO3 is a tumor-suppressor in NSCLC and may serve as a promising therapeutic target. Therefore, restoration of circRNA-FOXO3 expression could be a future approach to develop a novel treatment strategy. PMID- 29620203 TI - Inhibition of DNA-PK activity sensitizes A549 cells to X-ray irradiation by inducing the ATM-dependent DNA damage response. AB - Non-small cell lung cancer (NSCLC) is radioresistant to X-rays due to powerful cellular DNA damage repair mechanisms. DNA-dependent protein kinase (DNA-PK) is a key enzyme involved in DNA damage repair and the phenomenon and molecular mechanism of NSCLC radionsensitivity were investigated following inhibition of DNA-PK activity. In the present study A549 cells were treated with the DNA-PK inhibitor NU7026 and/or siRNA directed against ataxia telangiectasia mutated (ATM), followed by exposure to 4 Gy X-ray irradiation. Radiosensitivity, DNA damage, apoptosis and protein expression were measured by colony formation assay, gammaH2AX foci immunofluorescence, Annexin V/PI staining and western blotting, respectively. A Balb/c-nu/nu xenograft mouse model was established by subcutaneous injection of A549 cells and was used to examine the effect of administering NU7026 via intraperitoneal injection prior to 4 Gy X-ray exposure. The xenograft tumors were weighed and observed by hematoxylin and eosin staining after irradiation. NU7026 treatment followed by X-ray irradiation significantly decreased the colony formation ratio of A549 cells, and increased gammaH2AX foci and cell apoptosis. Furthermore, the combined treatment of NU7026 and X-rays resulted in growth inhibition and cell apoptosis in A549 xenograft tumors. Consequently, apoptosis regulators full-length transactivating (TA) p73 and an N terminally truncated (DN) p73 were upregulated and downregulated respectively, leading to activation of glucosyltransferases and Rab-like GTPase activators and myotubularins domain-containing 4 (GRAMD4) protein to reduce the Bcl-2/Bax protein ratio. In addition, ATM siRNA efficiently prevented gammaH2AX foci formation, and enhanced NU7026-induced inhibition of survival and promoted apoptosis. In conclusion, inhibition of DNA-PK activity increased the radiosensitivity of A549 cells to X-ray irradiation. NU7026 treatment activated the ATM-dependent DNA damage response and induced p73 apoptosis pathway. DNA-PK inhibitor may be an effective constituent of radiosensitization products. DNA damage repair pathway could be a potential target for radiosensitization. PMID- 29620204 TI - Tenascin-C promotes the migration of bone marrow stem cells via toll-like receptor 4-mediated signaling pathways: MAPK, AKT and Wnt. AB - There are currently limitations in stem cell therapy due to the low rate of homing and proliferation of cells following transplantation. The present study was designed to investigate the effects of Tenascin-C (TN-C) on bone marrow mesenchymal stem cells (BMSCs) and its underlying mechanisms. BMSCs were obtained from C57BL/6 mice. The survival and proliferation of BMSCs was analyzed by Cell Counting Kit-8 assay, migration was evaluated using the Transwell method, and differentiation was assessed by immunocytochemistry and immunofluorescence. In addition, the levels of proteins were detected by western blotting. High concentrations of TN-C promoted the migration of BMSCs. H2O2 at concentrations of 60-90 umol/ml induced cell death in BMSCs, and thus, it was used to simulate oxidative stress in the microenvironment of acute myocardial infarction (AMI). High concentrations of TN-C were able to protect BMSCs from cell death, and promoted the migration of BMSCs (P<0.05). However, TAK-242 [the inhibitor of Toll like receptor 4, (TLR4)] reduced the promoting effect of TN-C (P<0.05). By contrast, TN-C had no effect on the proliferation and differentiation of BMSCs. TN-C reduced the phosphorylation levels of p38 mitogen-activated protein kinase (MAPK), and increased the phosphorylation levels of Ser473 protein kinase B (AKT) and beta-catenin, all of which were inhibited by TAK-242 (P<0.05). In the simulated AMI microenvironment, TN-C promoted the migration of BMSCs via TLR4 mediated signaling pathways, including MAPK, AKT and Wnt. PMID- 29620205 TI - Involvement of dysregulated coding and long non-coding RNAs in the pathogenesis of strabismus. AB - Strabismus is a common ocular disorder in children and may result in exterior abnormalities and impaired visual functions. However, the detailed pathogenesis of strabismus unclear. The present study assessed the comprehensive analyses on the roles of RNAs in the development of strabismus. The public datasets of strabismus and the corresponding control tissues were downloaded from the Gene Expression Omnibus (GEO). Reannotations of the dysregulated coding and long non coding RNAs (lncRNAs) and functional enrichments of the differently expressed genes (DEGs) were conducted. A total of 790 DEGs were screened (648 upregulated and 142 downregulated) in the present study. Among the DEGs, a total of 32 differently expressed lncRNAs were detected (14 upregulated and 18 downregulated). When the Gene Ontology (GO) enrichment was considered, it was identified that a total of 143 GO terms (82 for biological process, 31 for cellular component and 30 for molecular function) were identified. Among all the 57 detected Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, the phagosome pathway, which was labeled as hsa004145, demonstrated the most bioinformatics importance. However, most lncRNAs, except LINC01279 and LOC643733, indicated <3 target mRNAs and were not suitable for advanced bioinformatics analyses. Bioinformatics analyses demonstrated that there was a GO term for each lncRNA (proteinaceous extracellular for LINC01279 and cell surface for LOC643733). In conclusion, a set of coding RNA as well as lncRNAs differentially expressed in strabismus EOM samples were indicated. Notably, the present findings important information for advanced pathogenesis research and biomarkers detection. PMID- 29620206 TI - Genetic analysis of a congenital split-hand/split-foot malformation 4 pedigree. AB - In the present study whole-exome sequencing using the Complete Genomics platform was employed to scan a proband from a split-hand/split-foot malformation (SHFM) 4 family. The missense mutation c.728G>A (p.Arg243Gln) in the TP63 gene was revealed to be associated with SHFM. Sanger sequencing confirmed the sequences of the proband and his father. The father was diagnosed with SHFM and harbored a CGG to-CAG mutation in exon 5, which produced a R243Q substitution in the zinc binding site and dimerization site of TP63. The R243Q mutation was predicted to be pathogenic by PolyPhen-2. The proband, who was diagnosed with four digit SHFM, exhibited a more severe phenotype. X-ray analysis returned the following results: Absence of third phalange bilaterally and third metacarpus of the left hand; absence of the second toes bilaterally and partial third toes; and partial fusion of the second, third and metatarsal bones of the right side with deformity of the second metatarsal of the right side. Osteochondroma was present in the fourth proximal radial metacarpal of the left hand and the basal and proximal parts of the second metatarsal of the right side. The proband's father had five digits in both feet. These results indicate that the R243Q mutation produces a novel phenotype named SHFM4. The present study revealed that the R243Q mutation in the TP63 gene produced a novel phenotype named SHFM4, thereby demonstrating the mutational overlap between ectrodactyly-ectodermal dysplasia-cleft syndrome and SHFM4. PMID- 29620207 TI - Calotropin regulates the apoptosis of non-small cell cancer by regulating the cytotoxic T-lymphocyte associated antigen 4-mediated TGF-beta/ERK signaling pathway. AB - Non-small-cell lung cancer (NSCLC) is one of the most common malignancies that is responsible for a high level of cancer-associated mortalities worldwide. Previous evidence has shown that Calotropin is an upstream activator of protein kinase B, which can further inhibit the growth and promote the apoptosis of NSCLC cells. In the present study, the efficacy of Calotropin on growth, aggressiveness and apoptosis of NSCLC cells was investigated, as well as the potential underlying mechanism. The results demonstrated that Calotropin inhibited H358 cell growth, migration and invasion. Flow cytometry assay showed that Calotropin promoted the apoptosis of H358 cells in vitro. Western blot analysis demonstrated that Calotropin inhibited fibronectin (FN), Vimentin (VIM) and E-cadherin (Eca) protein expression levels in H358 cells in vitro. In addition, Calotropin treatment upregulated pro-apoptosis gene expression, including caspase-3, caspase 8 and apoptotic protease activating factor-1, and downregulated anti-apoptosis gene expression, including P53, B-cell lymphoma (Bcl) 2 and Bcl-2-like protein 2 in H358 cells. The results also revealed that the expression levels of cytotoxic T-lymphocyte associated antigen 4 (CTLA-4) were decreased by Calotropin treatment in H358 cells. Analyses of the underlying mechanism indicated that Calotropin inhibited transforming growth factor-beta (TGF-beta) and extracellular signal regulated kinase (ERK) expression. Overexpression of CTLA-4 inhibited Calotropin mediated downregulation of TGF-beta and ERK expression in H358 cells. In vivo assay revealed that Calotropin administration significantly inhibited tumor growth and prolonged animal survival over the 120-day observation period. Immunohistochemistry demonstrated that the number of apoptotic cells increased and the expression levels of CTLA-4 were decreased in the Calotropin-treated tumor group when compared with control. In addition, the expression levels of TGF beta and ERK were downregulated in the Calotropin-treated tumor group compared with control. In conclusion, the results of the present study indicated that Calotropin administration regulated NSCLC apoptosis by downregulating the CTLA-4 mediated TGF-beta/ERK signaling pathway, suggesting that Calotropin may be a potential anti-cancer agent for the treatment of NSCLC. PMID- 29620208 TI - Dehydrocostus lactone suppresses cell growth and induces apoptosis in recombinant human papilloma virus-18 HaCaT cells via the PI3K/Akt signaling pathway. AB - Dehydrocostus lactone is considered to be the major cholagogic ingredient of the Costus genus of plants. It exhibits strong cholagogic effects, and also exerts antimicrobial and antineoplastic activity. The present study aimed to investigate the effects of dehydrocostus lactone on the cell growth and apoptosis of recombinant human papilloma virus (HPV)-18 HaCaT cells. The HPV-18 genome was transfected into HaCaT cells, which were subsequently used for analysis. The results demonstrated that dehydrocostus lactone reduced the cell proliferation and induced apoptosis of HPV-18 HaCaT cells, as determined by MTT and N-acetyl Asp-Glu-Val-Asp p-nitroanilide assays, respectively. Furthermore, caspase-3/9 activity was determined using a caspase-3/9 activity kit and western blotting was performed to investigate the expression of certain proteins. The results demonstrated that caspase-3/9 activities, and the protein expression of Bcl-2 associated X and p53, in HPV-18 HaCaT cells were significantly increased, while cyclin D1 protein expression was suppressed by dehydrocostus lactone. Additionally, dehydrocostus lactone significantly upregulated the protein expression of phosphatase and tensin homolog and inhibited the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway in HPV-18 HaCaT cells. Therefore, the results of the present study indicate that dehydrocostus lactone may suppress cell growth and induce apoptosis in recombinant HPV-18 HaCaT cells via the PI3K/Akt signaling pathway, and may be a represent a novel potential therapeutic agent for the treatment of condyloma acuminatum. PMID- 29620209 TI - Epigallocatechingallate attenuates myocardial injury in a mouse model of heart failure through TGF-beta1/Smad3 signaling pathway. AB - The present study aimed to assess the protective effect of epigallocatechingallate (EGCG) against myocardial injury in a mouse model of heart failure and to determine the mechanism underlying regulation of the transforming growth factor-beta1/mothers against decapentaplegic homolog 3 (TGF beta1/Smad3) signaling pathway. Mouse models of heart failure were established. Alterations in ejection fraction, left ventricular internal diastolic diameter (LVIDd) and left ventricular internal systolic diameter (LVIDs) were measured by echocardiography. Pathological alterations of myocardial tissue were determined by hematoxylin and eosin, and Masson staining. The levels of serum brain natriuretic peptide (BNP), N-terminal-proBNP, interleukin (IL)-1beta, IL-6, tumor necrosis factor-alpha, malondialdehyde, superoxide dismutase and glutathione peroxidase were detected with ELISA. Expression of collagen I, collagen III were detected by western blotting and reverse transcription quantitative polymerase chain reaction. Transforming growth factor-beta1 (TGF-beta1), Smad3, phosphorylated (p)-Smad3, apoptosis regulator BAX (Bax), caspase-3 and apoptosis regulator Bcl2 in mouse cardiac tissue were measured by western blotting. P-smad3 and TGF-beta1 were measured by immunofluorescence staining. EGCG reversed the alterations in LVIDd and LVIDs induced by establishment of the model of heart failure, increased ejection fraction, inhibited myocardial fibrosis, attenuated the oxidative stress, inflammatory and cardiomyocyte apoptosis and lowered the expression levels of collagen I and collagen III. Following treatment with TGF beta1 inhibitor, the protective effect of EGCG against heart failure was attenuated. The results of the present study demonstrated that EGCG can inhibit the progression and development of heart failure in mice through inhibition of myocardial fibrosis and reduction of ventricular collagen remodeling. This protective effect of EGCG is likely mediated through inhibition of TGF beta1/smad3 signaling pathway. PMID- 29620210 TI - Saikosaponin-d alleviates carbon-tetrachloride induced acute hepatocellular injury by inhibiting oxidative stress and NLRP3 inflammasome activation in the HL 7702 cell line. AB - Saikosaponin-d (SSd) the primary active component of triterpene saponin derived from Bupleurum falcatum L., possesses anti-inflammatory and antioxidant properties. The present study aimed to examine the potential therapeutic effects of SSd on carbon tetrachloride (CCl4)-induced acute hepatocellular injury in the HL-7702 cell line and its underlying mechanisms. HL-7702 cells were treated with SSd at different doses (0.5, 1 or 2 umol/l). Cell viability was determined using an MTT assay. Injury was assessed by the levels of serum alanine aminotransferase (ALT) and aspartate transaminase (AST). Oxidative stress was assessed using malondialdehyde (MDA) content and total-superoxide dismutase (T-SOD) activity. The expression of nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3), apoptosis-associated speck-like protein (ASC), caspase-1 and high mobility group protein B1 (HMGB1) was assessed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis. Interleukin (IL)-1beta and IL-18 were determined by RT-qPCR and ELISA. SSd attenuated the inhibition of cell viability and the high AST and ALT levels induced by CCl4 in HL-7702 cells. Oxidative stress was induced in HL-7702 cells by CCl4, as demonstrated by the increase of MDA and the decrease of T-SOD activity. These changes were reversed by SSd. SSd significantly downregulated the mRNA and protein expression of NLRP3, ASC, caspase-1, IL-1beta, IL-18 and HMGB1 induced by CCl4. In conclusion SSd alleviated CCl4-induced acute hepatocellular injury, possibly by inhibiting oxidative stress and NLRP3 inflammasome activation in the HL-7702 cell line. PMID- 29620211 TI - MORC2, a novel oncogene, is upregulated in liver cancer and contributes to proliferation, metastasis and chemoresistance. AB - Microrchidia 2 (MORC2) is important in DNA damage repair and lipogenesis, however, the clinical and functional role of MORC2 in liver cancer remains to be fully elucidated. The aim the present study was to clarify the role of MORC2 in liver cancer. Expression profile analysis, immunohistochemical staining, reverse transcription-quantitative polymerase chain reaction analysis and western blot analysis were performed to evaluate the levels of MORC2 in liver cancer patient specimens and cell lines; subsequently the expression of MORC2 was suppressed or increased in liver cancer cells and the effects of MORC2 on the cancerous transformation of liver cancer cells were examined in vitro and in vivo. MORC2 was upregulated in liver cancer tissues, and the upregulation was associated with certain clinicopathologic features of patients with liver cancer. MORC2 knockdown caused marked inhibition of liver cancer cell proliferation and clonogenicity, whereas the overexpression of MORC2 substantially promoted liver cancer cell proliferation. In addition, the knockdown of MORC2 inhibited the migratory and invasive ability of liver cancer cells, whereas increased migration and invasion rates were observed in cells with ectopic expression of MORC2. In a model of nude mice, the overexpression of MORC2 promoted tumorigenicity and markedly enhanced pulmonary metastasis of liver cancer. Furthermore, MORC2 regulated apoptosis and its expression level had an effect on the sensitivity of liver cancer cells to doxorubicin, 5-fluorouracil and cisplatin. Mechanically, MORC2 modulated the mitochondrial apoptotic pathway, possibly in a p53-dependent manner, and its dysregulation also resulted in the abnormal activation of the Hippo pathway. For the first time, to the best of our knowledge, the present study confirmed that MORC2 was a novel oncogene in liver cancer. These results provide useful insight into the mechanism underlying the tumorigenesis and progression of liver cancer, and offers clues into potential novel liver cancer therapies. PMID- 29620213 TI - Phosphoinositide 3-kinase/protein kinase B regulates inflammation severity via signaling of Toll-like receptor 4 in severe acute pancreatitis. AB - Phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) has been indicated to serve an important role in the pathogenesis of inflammatory diseases. It was previously demonstrated that the PI3K/Akt inhibitor wortmannin alleviated the severity of inflammation and improved the survival rate in rats with induced severe acute pancreatitis (SAP), which indicates that PI3K/Akt may serve a role in the pathogenesis of acute pancreatitis. To date, the mechanism by which PI3K/Akt regulates inflammation has not been elucidated. In the present study, it was hypothesized that PI3K/Akt may be invovled in SAP inflammation via regulation of the Toll-like receptor 4 (TLR4) signaling pathway. Rats with SAP were treated with the PI3K/Akt agonist insulin-like growth factor (IGF)-1, which alleviated the severity of inflammation in a dose-dependent manner. Furthermore, to better understand the role of PI3K/Akt in inflammation, RAW264.7 murine macrophages were stimulated with IGF-1 and wortmannin alone or together before the induction of inflammation by treatment with lipopolysaccharide (LPS). The results indicated that LPS stimulated overexpression of TLR4, myeloid differentiation primary response gene 88 (MyD88), PI3K, Akt, p38MAPK and NF-kappaBp65 mRNA, and increased the levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 in RAW264.7 cells compared with the control group. The levels of all detected factors were increased by stimulation with IGF-1, whereas these levels were decreased following treatment with wortmannin alone, and the effect of IGF-1 was abolished by wortmannin in RAW264.7 cells. In vivo studies indicated that IGF-1 produced the same anti-inflammatory effect as wortmannin and that expression of TLR4, p38MAPK and NF-kappaBp65 decreased following treatment with IGF-1. These findings indicate that PI3K/Akt may take part in the progression of SAP by regulating the TLR4 signaling pathway and that IGF-1 can inhibit inflammation in SAP rats. PMID- 29620212 TI - LARP7 in papillary thyroid carcinoma induces NIS expression through suppression of the SHH signaling pathway. AB - The incidence of thyroid cancer has increased the past few decades, the most frequent type has been identified to be the papillary thyroid carcinoma (PTC). Following thyroidectomy, radioiodine ablation treatment on PTC is routinely performed. However, many patients do not benefit from radioiodine therapy. Therefore, novel targeted therapies to suppress tumor growth and improve radioiodine uptake are required. La ribonucleoprotein domain family member (LARP)7 is a member of the LARP family and functions as a potential suppressor of the progression of carcinoma. In the present study, the expression status of LARP7 in PTC tissues and cell lines was investigated, and the cell viability, proliferation and apoptotic rate, radioiodine uptake ability of PTC cells with overexpression of LARP7 in vitro was determined. Expression levels of LARP7 were significantly downregulated in PTC tissues and cell lines. Overexpression of LARP7 inhibited the proliferation and increased the radioiodine uptake ability of PTC cells in vitro and inhibited the tumor growth in vivo. Furthermore, LARP7 overexpression inhibited the sonic hedgehog (SHH) signaling pathway and increased sodium/iodide symporter (NIS) expression. However, treatment with recombinant human SHH partially reduced radioiodine uptake ability and NIS expression induced by LARP7. In conclusion, LARP7 may act as a tumor suppressor in PTC by inhibiting the SHH signaling pathway and may be a promising therapeutic target in patients with PTC. PMID- 29620214 TI - Dysregulation of PTEN caused by the underexpression of microRNA-130b is associated with the severity of lupus nephritis. AB - There are several reports in the literature regarding microRNA (miR)-130b. It has been reported that miR-130b is involved in several diseases. The present study aimed to understand the association between the levels of miR-130b and lupus nephritis in patients. A total of 61 blood samples were collected and the expression level of miR-130b was determined. The online miRNA database was then searched using the 'seed sequence' located within the 3'-untranslated region of the target gene. Linear analysis and a luciferase assay were performed to understand the regulatory association between miR-130b and phosphatase and tensin homolog (PTEN). In addition, reverse transcription-polymerase chain reaction and western blot analyses were performed to examine the mRNA and protein expression levels of PTEN among individuals with lupus nephritis (n=28) and those without lupus nephritis (n=31), and in mesangial cells treated with scramble control, miR 130b mimics, PTEN small interfering (si)RNA and miR-130b inhibitors. In addition mesangial cells were treated with scramble control, miR-130b mimics, PTEN siRNA and miR-130b inhibitors to investigate the affect of miR-130b and PTEN on the viability and apoptosis of mesangial cells. The results demonstrated that miR 130b was downregulated in the hormone-resistant group of lupus nephritis patients. PTEN was a virtual target of miR-130b. There was a negative regulatory association between miR-130b and PTEN. The mRNA and protein expression levels of PTEN were increased in the hormone-resistant group. miR-130b decreased the expression of PTEN. miR-130b negatively interfered with the viability of mesangial cells and PTEN positively interfered with the viability of mesangial cells. miR-130b accelerated apoptosis and PTEN inhibited apoptosis. Taken together, the results showed that miR-130b was upregulated in the lupus nephritis group. PTEN was a virtual target of miR-130b, and there was a negative regulatory association between miR-130b and PTEN. miR-130b and PTEN interfered with the viability and apoptosis of the mesangial cells. PMID- 29620216 TI - Doxycycline targets aldehyde dehydrogenase-positive breast cancer stem cells. AB - Targeting cancer stem cells (CSCs) is a key strategy to prevent cancers from developing drug resistance and metastasis. Mitochondria have been reported to be a vulnerability of CSCs by multiple studies. Here, we report that doxycycline, functioning as an inhibitor of mitochondrial biogenesis, can effectively target breast cancer stem cells (BCSCs). Our results revealed that doxycycline significantly decreased the frequency of aldehyde dehydrogenase-positive (ALDH+) BCSCs as well as mammosphere formation efficiency in HER2+ and triple-negative breast cancer (TNBC) subtypes. Doxycycline also ameliorated paclitaxel-induced enrichment of ALDH+ BCSCs in TNBC. Mechanistically, we showed that doxycycline decreased the level of reactive oxygen species and their downstream p38 MAPK pathway. In agreement with the key role for p38 in maintaining BCSCs, a specific inhibitor targeting this MAPK pathway significantly decreased the number of ALDH+ cells. Doxycycline is a FDA-approved drug with minor and limited side-effects. Given doxycycline's low toxicity and strong effect on BCSC inhibition, we report that doxycycline should be safe to be used concomitantly with chemotherapy drugs to eradicate both CSCs and bulk tumor cells. PMID- 29620215 TI - Integrated analysis of the gene expression profile and DNA methylation profile of obese patients with type 2 diabetes. AB - In order to better understand the etiology of obese type 2 diabetes (T2D) at the molecular level, the present study investigated the gene expression and DNA methylation profiles associated with T2D via systemic analysis. Gene expression (GSE64998) and DNA methylation profiles (GSE65057) from liver tissues of healthy controls and obese patients with T2D were downloaded from the Gene Expression Omnibus database. Differentially-expressed genes (DEGs) and differentially methylated genes (DMGs) were identified using the Limma package, and their overlapping genes were additionally determined. Enrichment analysis was performed using the BioCloud platform on the DEGs and the overlapping genes. Using Cytoscape software, protein-protein interaction (PPI), transcription factor target networks and microRNA (miRNA) target networks were then constructed in order to determine associated hub genes. In addition, a further GSE15653 dataset was utilized in order to validate the DEGs identified in the GSE64998 dataset analyses. A total of 251 DEGs, including 124 upregulated and 127 downregulated genes, were detected, and a total of 9,698 genes were demonstrated to be differentially methylated in obese patients with T2D compared with non-obese healthy controls. A total of 103 overlapping genes between the two datasets were revealed, including 47 upregulated genes and 56 downregulated genes. The identified overlapping genes were revealed to be strongly associated with fatty acid and glucose metabolic pathways, in addition to oxidation/reduction. The overlapping genes cyclin D1 (CCND1), PPARG coactivator alpha (PPARGC1A), fatty acid synthase (FASN), glucokinase (GCK), steraroyl-coA desaturase (SCD) and tyrosine aminotransferase (TAT) had higher degrees in the PPI, transcription target networks and miRNA target networks. In addition, among the 251 DEGs, a total of 35 DEGs were validated to be being shared genes between the datasets, which included a number of key genes in the PPI network, including CCND1, FASN and TAT. Abnormal gene expression and DNA methylation patterns that were implicated in fatty acid and glucose metabolic pathways and oxidation/reduction reactions were detected in obese patients with T2D. Furthermore, the CCND1, PPARGC1A, FANS, GCK, SCD and TAT genes may serve a role in the development of obesity-associated T2D. PMID- 29620217 TI - Effect and mechanism of the abeta2-GP I/rhbeta2-GP I complex on JEG-3 cell proliferation, migration and invasion. AB - Antiphospholipid antibody (aPL)-mediated antiphospholipid syndrome (APS) is an autoimmune disease. Upon binding to aPL, the primary antigen of aPL, beta2 glycoprotein I (beta2-GP I), induces abnormal immune function, which further activates downstream signaling pathways in the cell and eventually leads to APS. The present study aimed to determine whether beta2-GP I antigen and anti-beta2 glycoprotein I antibody (abeta2-GP I), which belong to the aPL class of antibodies, may affect human chorionic epithelium cell (JEG-3) proliferation, migration and invasion. Recombinant human (rh)beta2-GP I protein was expressed using a prokaryotic expression system and abeta2-GP I antibody was purified from the blood serum of 10 patients with recurrent pregnancy loss. JEG-3 cells were stimulated with rhbeta2-GP I and abeta2-GP I separately or simultaneously, and serum immunoglobulin G of normal pregnant women was used as negative control. Using cell counting kit-8, cell cycle and transwell assays in addition to EdU staining, it was determined that abeta2-GP I/rhbeta2-GP I complex markedly increased JEG-3 cell proliferation, migration and invasion. The results revealed that mRNA levels of inhibitor of nuclear factor (NF)-kappaB kinase subunit (IKKbeta), myeloid differentiation primary response protein MyD88 (MyD88), NF kappaB and NF-kappaB inhibitor alpha (IkappaBalpha), as well as the protein levels of MyD88, IkappaBalpha and phospho(p)-IkappaBalpha in JEG-3 cells increased following incubation with the abeta2-GP I/rhbeta2-GP I complex. The observed upregulation of p-IkappaBalpha protein suggested that IkappaBalpha mediated inhibition of NF-kappaB was weakened. Furthermore, JEG-3 cells were transfected with PGMLV-NF-kappaB-Lu vector. Luciferase activity in JEG-3-NFkappaB Luc1 and JEG-3-NFkappaB-Luc2 cells was enhanced following treatment with abeta2 GP I/rhbeta2-GP I complex. The present study demonstrated that abeta2-GP I/rhbeta2-GP I complex activates NF-kappaB through MyD88 signal transduction pathway, which further enhances JEG-3 cell proliferation, migration and invasion. PMID- 29620218 TI - Quercetin protects rat cortical neurons against traumatic brain injury. AB - Previous studies have demonstrated that traumatic brain injury (TBI) may cause neurological deficits and neuronal cell apoptosis. Quercetin, one of the most widely distributed flavonoids, possesses anti-inflammatory, anti-blood coagulation, anti-ischemic and anti-cancer activities, and neuroprotective effects in the context of brain injury. The purpose of the present study was to investigate the neuroprotective effects of quercetin in TBI. A total of 75 rats were randomly arranged into 3 groups as follows: Sham group (Sham); TBI group (TBI); and TBI + quercetin group (Que). Brain edema was evaluated by analysis of brain water content. The neurobehavioral status of the rats was evaluated by Neurological Severity Scoring. Immunohistochemical and western blot analyses were used to measure the expression of certain proteins. The results of the present study demonstrated that post-TBI administration of quercetin may attenuate brain edema, in addition to improving motor function in rats. Additionally, quercetin caused a marked inhibition of extracellular signal-regulated kinase 1/2 phosphorylation and activated Akt serine/threonine protein kinase phosphorylation, which may result in attenuation of neuronal apoptosis. The present study provided novel insights into the mechanism through which quercetin may exert its neuroprotective activity in a rat model of TBI. PMID- 29620219 TI - Anthricin-induced caspase-dependent apoptosis through IGF1R/PI3K/AKT pathway inhibition in A549 human non-small lung cancer cells. AB - Anthricin (deoxypodophyllotoxin) is a major lignan in Anthriscus sylvestris and possesses many bioactivities such as antiproliferative, antitumor, anti-platelet aggregation, antiviral and anti-inflammatory actions. However, the anticancer effects of anthricin on A549 human non-small cell lung cancer cells and potential molecular mechanisms remain unknown. Therefore, we investigated the anticancer effect of anthricin and the underlying mechanism in A549 cells. Anthricin (10-200 nM) inhibited the viability of A549 cells in a dose- and time-dependent manner. Moreover, anthricin-induced apoptosis was confirmed by live and dead assay, 4,6 dianmidino-2-phenylindole staining, and flow cytometric analysis. In addition, anthricin induced cell cycle arrest at the G2/M phase through suppression of the expression of cell cycle cascade proteins, Cdc2 and Cdc25C. Furthermore, it induced the expression of caspase-related proteins and significantly suppressed the phosphorylation of insulin-like growth factor 1 receptor (IGF1R), PI3K and Akt. Anthricin significantly inhibited tumor growth without any significant change in the body weight of mice in A549 tumor xenograft BALB/c nude mice. Anthricin induced caspase-dependent apoptosis through the IGF1R/PI3K/Akt signaling pathway in A549 cells. PMID- 29620220 TI - Translational control of the undifferentiated phenotype in ER-positive breast tumor cells: Cytoplasmic localization of ERalpha and impact of IRES inhibition. AB - Using a series of potential biomarkers relevant to mechanisms of protein synthesis, we observed that estrogen receptor (ER)-positive breast tumor cells exist in two distinct yet interconvertible phenotypic states (of roughly equal proportion) which differ in the degree of differentiation and use of IRES mediated translation. Nascently translated IGF1R in the cytoplasm positively correlated with IRES activity and the undifferentiated phenotype, while epitope accessibility of RACK1, an integral component of the 40S ribosomal subunit, aligned with the more differentiated IRES-off state. When deprived of soluble growth factors, the entire tumor cell population shifted to the undifferentiated phenotype in which IRES-mediated translation was active, facilitating survival under these adverse microenvironmental conditions. However, if IRES-mediated translation was inhibited, the cells instead were forced to transition uniformly to the more differentiated state. Notably, cytoplasmic localization of estrogen receptor alpha (ERalpha/ESR1) precisely mirrored the pattern observed with nascent IGF1R, correlating with the undifferentiated IRES-active phenotype. Inhibition of IRES-mediated translation resulted in both a shift in ERalpha to the nucleus (consistent with differentiation) and a marked decrease in ERalpha abundance (consistent with the inhibition of ERalpha synthesis via its IRES). Although breast tumor cells tolerated forced differentiation without extensive loss of their viability, their reproductive capacity was severely compromised. In addition, CDK1 was decreased, connexin 43 eliminated and Myc translation altered as a consequence of IRES inhibition. Isolated or low-density ER-positive breast tumor cells were particularly vulnerable to IRES inhibition, losing the ability to generate viable cohesive colonies, or undergoing massive cell death. Collectively, these results provide further evidence for the integral relationship between IRES-mediated translation and the undifferentiated phenotype and demonstrate how therapeutic manipulation of this specialized mode of protein synthesis may be used to limit the phenotypic plasticity and incapacitate or eliminate these otherwise highly resilient breast tumor cells. PMID- 29620221 TI - CT-1042, a novel anticancer agent, exhibits effects by activating p53 and inhibiting survivin. AB - A novel small molecular compound, 4-ethyl-8-fluoro-hydroxy-9-methoxy-11-methyl 1,12-dihydro-4H-2-oxa-6,12a-diaza-dibenzo[b,h]fluorene-3,13-dione (CT-1042) exhibits potent antitumor activity against many tumor cells in vitro. However, the effects and underlying mechanisms of CT-1042 in non-small cell lung cancer (NSCLC) remain unclear. The present study was designed to determine the anticancer properties and underlying molecular mechanisms of CT-1042 in NCI-H460 NSCLC cells. A thiazolyl blue tetrazolium bromide assay (MTT) was performed to evaluate cell viability and flow cytometry was used to analyze apoptosis, mitochondrial membrane potential (MMP) and cell cycle. Real-time quantitative PCR and western blotting were conducted to determine relative mRNA and protein levels. A tumor xenograft experiment was performed to investigate the effects of CT-1042 on tumor growth in vivo. CT-1042 markedly inhibited the proliferation of twelve cancer cell lines, decreased MMP in subject cells and increased caspase-3 activity. Cell cycle analysis indicated that CT-1042 delayed the cell cycle progression during the G2/M phase in a dose-dependent manner. In addition, CT 1042 induced mitochondrial-mediated apoptosis by activating p53 and Bax, as well as inhibiting Bcl-2 and survivin. Finally, CT-1042 significantly suppressed NCI H460 xenograft tumor growth in vivo, with low systemic toxicity. Collectively, these results revealed that CT-1042 has significant lung anticancer properties. PMID- 29620222 TI - miR-29a suppresses IL-13-induced cell invasion by inhibiting YY1 in the AKT pathway in lung adenocarcinoma A549 cells. AB - IL-13 is a proinflammatory cytokine associated with multiple pathological conditions and the promotion of metastasis in lung cancer. Previous studies have demonstrated that IL-13 and YY1 are associated with PI3K/AKT signaling. In addition, miR-29a has been found to play a critical role in cell invasion in lung cancer. However, the molecular mechanism of miR-29a underlying its involvement in IL-13-induced lung cancer cell invasion remains largely unknown. In the present study, we aimed to investigate the role of miR-29a in cell invasion mediated by IL-13 in lung cancer. By using MTT and wound-scratch assays, we assessed cell proliferation and migration induced by IL-13, and identified activation of the PI3K/AKT/YY1 pathway. Inhibition of PI3K/AKT by LY294002 downregulated IL-13 induced YY1 expression. Furthermore, we found that miR-29a directly targets YY1 and suppressed its expression in lung cancer. By using MTT, flow cytometry and Transwell assays, overexpression of miR-29a restricted both YY1 and N-cadherin expression, and inhibited IL-13-induced invasion of lung cancer A549 cells. Taken together, these findings demonstrate that PI3K/AKT/YY1 is involved in the regulation of lung cancer cell behavior induced by IL-13, and miR-29a represents a promising therapeutic target. PMID- 29620223 TI - Resveratrol decreases Rad51 expression and sensitizes cisplatin-resistant MCF-7 breast cancer cells. AB - Resveratrol (RES), a polyphenol compound with anti-proliferative properties, has been previously evaluated for its beneficial effects against a variety of tumour cells. The current study elucidated the means by which RES enhances the anti proliferative effects of cisplatin (CIS) on MCF-7 cells, focusing on the inhibitory effects on DNA repair of double-strand breaks (DSBs). Chemoresistant MCF-7 cells (MCF-7R) were generated by continuous exposure to low concentrations of CIS (10 uM CIS-IC40) during 5 passages, with the IC50 value increasing ~3 fold. Using an MTT assay, we estimated the changes in IC50 for CIS in MCF-7, T47 D, MDA-MB-231 and MCF-7R cells in the presence of RES. The relative transcript level of Nbs-1, Mre-11 and Rad-50 genes was assessed using RT-qPCR analysis. Rad51 and H2AX [pSer139] protein expression was determined by western blot analysis. RES at 50 and 100 uM significantly enhanced the anti-proliferative effects of CIS in both MCF-7 and MCF-7R cells, decreasing the IC50 values for CIS to one-tenth and one-sixth, respectively. A total of 100 uM RES decreased the relative transcript levels of homologous recombination (HR) initiation complex components and the Rad51 protein level in MCF-7 and MCF-7R cells. After 48 h of CIS DNA damage, the levels of Rad51 protein increased, but this effect was inhibited by 100 uM RES. RES also maintained serine 139 phosphorylation of histone H2AX, suggesting that RES prevents the repair of DSBs. It was observed that RES exerts an antagonistic effect over CIS on the activation of Rad51 and sustained phosphorylation of H2AX. The results suggest that RES in combination with DNA damage-based therapy has potential as a strategy to overcome resistance and provide much safer and more effective treatment for breast cancer. PMID- 29620224 TI - Role of COL6A3 in colorectal cancer. AB - Public transcriptome databases provide a valuable resource for genome-wide co expression network analysis and investigation of the molecular mechanisms that underlie pathogenesis. To discover genes that may affect patient survival, a large-scale analysis of human colorectal cancer (CRC) datasets that were retrieved from the NCBI Gene Expression Omnibus was performed. A gene co expression network was constructed using weighted gene co-expression network analysis (WGCNA). A total of 18 co-expressed gene modules were identified, of which two genes corresponded to cell migration and the cell cycle, two genes were involved in immune responses, two genes corresponded to mitochondrial function, and one gene corresponded to RNA splicing. A total of eight hub genes in the cell migration/extracellular matrix module were associated with poor prognosis in CRC, and the P-value for collagen type VI alpha3 chain (COL6A3) was the lowest. In silico analysis of cell type-specific gene expression and COL6A3 knockout experiments indicated the clinical relevance of COL6A3 in the development of CRC. In summary, the present analysis provides a basis for understanding the molecular characterization of CRC at the transcription level. COL6A3 may be a promising biomarker or target for the prognosis and treatment of CRC. PMID- 29620225 TI - Role of cantharidin in the activation of IKKalpha/IkappaBalpha/NF-kappaB pathway by inhibiting PP2A activity in cholangiocarcinoma cell lines. AB - Cantharidin (CAN), a potent inhibitor of serine/threonine-protein phosphatase 2A (PP2A), is widely used in clinical practice, particularly in the treatment of advanced cancer due to its specific action on these types of cancer. In the present study, the inhibitory effect of CAN was examined in two cholangiocarcinoma cell lines (QBC939 and Hucc-t1). Following treatment with CAN, cell viability was effectively reduced in QBC939 and Hucc-t1 cells and normal human intrahepatic biliary epithelial cells. However, a slight increase in reactive oxygen species levels in QBC939 cells treated with CAN was observed post treatment. CAN significantly inhibited cell migration and invasion in a dose dependent manner. Western blot analysis demonstrated that the nuclear factor kappaB (NF-kappaB) pathway was stimulated by CAN, which was confirmed by the upregulated phosphorylation levels of inhibitor of NF-kappaB kinase subunit alpha (IKKalpha) and NF-kappaB inhibitor alpha (IkappaBalpha) in cells, and an increased NF-kappaB p65 subunit level in the nucleus. The expression levels of 72 kDa type IV collagenase (MMP2) and matrix metalloproteinase 9 (MMP9) were downregulated by CAN. Notably, there was a negative association between MMP2 and MMP9 expression levels, and NF-kappaB p65, although NF-kappaB p65 regulates the expression of MMP2 and MMP9 and has a positive association with these proteins in various types of cancer. Notably, it was observed that CAN exerted specific inhibition on PP2A activity and thereby resulted in the activation of the IKKalpha/IkappaBalpha/NF-kappaB pathway. Therefore, CAN-induced cell inhibition maybe partially dependent on the activation of the IKKalpha/IkappaBalpha/NF kappaB pathway. In conclusion, it was demonstrated that CAN selectively and effectively inhibited cholangiocarcinoma cell migration and invasion. The present study may provide a novel insight into the use of CAN as a therapeutic candidate in the treatment of cholangiocarcinoma. PMID- 29620227 TI - Exogenous regucalcin suppresses the growth of human liver cancer HepG2 cells in vitro. AB - Regucalcin, which its gene is localized on the X chromosome, plays a pivotal role as a suppressor protein in signal transduction in various types of cells and tissues. Regucalcin gene expression has been demonstrated to be suppressed in various tumor tissues of animal and human subjects, suggesting a potential role of regucalcin in carcinogenesis. Regucalcin, which is produced from the tissues including liver, is found to be present in the serum of human subjects and animals. This study was undertaken to determine the effects of exogenous regucalcin on the proliferation in cloned human hepatoma HepG2 cells in vitro. Proliferation of HepG2 cells was suppressed after culture with addition of regucalcin (0.01 – 10 nM) into culture medium. Exogenous regucalcin did not reveal apoptotic cell death in HepG2 cells in vitro. Suppressive effects of regucalcin on cell proliferation were not enhanced in the presence of various signaling inhibitors including tumor necrosis factor-α (TNF-α), Bay K 8644, PD98059, staurosporine, worthomannin, 5,6-dichloro-1-β-D ribofuranosylbenzimidazole (DRB) or gemcitabine, which were found to suppress the proliferation. In addition, exogenous regucalcin suppressed the formation of colonies of cultured hepatoma cells in vitro. These findings demonstrated that exogenous regucalcin exhibits a suppressive effect on the growth of human hepatoma HepG2 cells, proposing a strategy with the gene therapy for cancer treatment. PMID- 29620226 TI - Downregulation of NONO induces apoptosis, suppressing growth and invasion in esophageal squamous cell carcinoma. AB - Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies in China, and is associated with high morbidity and mortality. However, the molecular mechanisms that control ESCC tumorigenicity and metastasis remain unclear. Here, we report that the RNA splicing factor, NONO, is an important regulator of ESCC growth, apoptosis and invasion. NONO protein levels were dramatically upregulated in ESCC when compared with that in adjacent benign esophageal squamous epithelium. Particularly, NONO expression was statistically higher in tumors with greater tumor invasion depth. Using multiple ESCC cell models, we further showed that NONO depletion using siRNA significantly inhibited proliferation, invasion, and promoted apoptosis of ESCC cells. In addition we found that knockdown of NONO could reduce protein levels of phosphorylated Akt and Erk1/2. Our findings suggest that NONO plays a potent role in multiple biological aspects of ESCC through activation of the Akt and Erk1/2 signaling pathways. Taken together, our findings suggest that NONO might play an important role in promoting tumorigenesis of ESCC. It may provide a promising approach to prevent the progress of ESCC. PMID- 29620228 TI - beta-arrestin2 promotes 5-FU-induced apoptosis via the NF-kappaB pathway in colorectal cancer. AB - It has been demonstrated that beta-arrestin2 is involved in the initiation and development of many types of cancers. However, its role in colorectal cancer (CRC) remains poorly understood. The present study investigated the role of beta arrestin2 in CRC using CRC patient tissues as well as the LoVo and HCT116 CRC cell lines. Briefly, significantly higher expression of beta-arrestin2 was observed in CRC tissues compared with normal colon tissues. In addition, the downregulation of beta-arrestin2 reduced 5-FU-induced apoptosis in the LoVo cells, while the overexpression of beta-arrestin2 increased the apoptosis of HCT116 cells in vitro. Furthermore, the downregulation of beta-arrestin2 reduced the expression of the pro-apoptotic proteins cleaved-caspase-3 and Bax, and increased the expression of the anti-apoptotic protein Bcl-2 after 5-FU treatment. In addition, the expression of p-p65 was increased after the beta arrestin2 downregulation and was decreased after the beta-arrestin2 overexpression. However, beta-arrestin2 downregulation had no effect on the proliferation, migration and invasion capacity of the LoVo cells. In conclusion, these results indicated that beta-arrestin2 promoted 5-FU-induced CRC cell apoptosis via the NF-kappaB pathway and may be used as a prognosis marker for CRC. PMID- 29620229 TI - miR-22-3p enhances multi-chemoresistance by targeting NET1 in bladder cancer cells. AB - With the discovery of new chemotherapeutic drugs, chemotherapy becomes increasingly valuable. However, the resistance of tumor cells to chemotherapeutic agents significantly limits the effectiveness and causes chemotherapy failure. MicroRNAs have been shown to regulate drug resistance in many types of cancer. In the present study, we measured the chemosensitivity of five bladder cancer (BCa) cell lines to seven commonly used chemotherapeutic drugs by Vita-Blue assay. We then identified the most sensitive (5637) and most tolerant cell lines (H-bc) and conducted a multi-group test. This test included expression group analyses of coding and non-coding genes (miR-omic and RNA-seq). Based on our analyses, we selected miR-22-3p as a target. We then determined its own target gene [neuroepithelial cell transforming 1 (NET1)] by bioinformatic analysis and confirmed this finding by TaqMan-quantitative reverse transcription polymerase chain reaction (qRT-PCR), western blot analysis and luciferase reporter assay. The effect of miR-22-3p on BCa multi-chemoresistance was also determined by transfecting cells with the miR-22-3p-mimic or miR-22-3p-antagomiR. We assessed the involvement of NET1 in BCa chemoresistance by siRNA-mediated NET1 inhibition or pINDUCER21-enhanced green fluorescent protein-NET1-mediated overexpression. Plate colony formation and apoptosis assays were conducted to observe the effects of miR-22-3p and NET1 on BCa chemoresistance. In conclusion, our results suggest that miR-22-3p promotes BCa chemoresistance by targeting NET1 and may serve as a new prognostic biomarker for BCa patients. PMID- 29620230 TI - Formononetin inhibits colon carcinoma cell growth and invasion by microRNA-149 mediated EphB3 downregulation and inhibition of PI3K/AKT and STAT3 signaling pathways. AB - Formononetin (Form), a phytoestrogen extracted from the roots of Astragalus membranaceus, is one of the fundamental herbs used in traditional Chinese medicine because of its protective effects against certain malignant tumors. However, its role in colon carcinoma cells and the underlying molecular mechanisms have not been completely elucidated. The present study aimed to demonstrate that Form significantly inhibited the proliferation and invasion of the colon carcinoma cell lines SW1116 and HCT116. Mechanistic studies have suggested that Form suppresses colon carcinoma cell growth by downregulating cell cycle-associated protein (cyclin D1) expression and arresting the cell cycle at the G0-G1 checkpoint. Further studies revealed that treatment with Form inhibits matrix metalloproteinase (MMP)2 and MMP9 expression. Aditionally, the results demonstrated that Form significantly increased microRNA (miR)-149 expression. Following miR-149 overexpression in SW1116 and HCT116 cells using an miR-149 mimic, cell viability and Ephrin type-B receptor 3 (EphB3) levels decreased. Furthermore, the inhibitory effects of Form were associated with phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) and signal transducer and activator of transcription 3 (STAT3) signaling pathways. These results indicated the suppressive effect of Form on colon carcinoma cell proliferation and invasion, possibly via miR-149-induced EphB3 downregulation and the inhibition of the PI3K/AKT and STAT3 signaling pathways. Overall, Form may be used as a novel candidate for the clinical treatment of colorectal cancer in the future. PMID- 29620231 TI - Granuloma formation in the liver is relatively delayed, although sustained, in BCG-infected mice co-infected with Plasmodium. AB - The purpose of the present study was to examine the effects of Plasmodium on the process of granuloma formation in Bacille Calmette-Guerin (BCG)-infected mice. Female six-week-old BALB/c mice were co-infected with BCG and Plasmodium. The liver index, pathological alterations and quantity of granulomas in the mice were observed when the mice were co-injected with BCG and Plasmodium. The expression of inducible nitric oxide synthase (iNOS) was assessed by immunohistochemistry and reverse transcription-polymerase chain reaction (RT-PCR) analysis. In addition, the expression of interleukin (IL)-10 in liver tissues was observed by RT-PCR. Following co-infection with BCG and Plasmodium, the swelling of the liver had been slowly restored to normal, and the time required to allow granulomas to subside had prolonged. In addition, the expression of iNOS increased, while the expression of IL-10 gradually decreased in Plasmodium-infected mice. It was concluded that the use of Plasmodium relatively delayed granuloma formation in livers of BCG-infected mice. In addition, iNOS and IL-10 are involved in this pathogenesis. PMID- 29620232 TI - TIPE attenuates the apoptotic effect of radiation and cisplatin and promotes tumor growth via JNK and p38 activation in Raw264.7 and EL4 cells. AB - Tumor necrosis factor alpha-induced protein 8 (TIPE) is highly expressed in many types of malignancies. Apoptosis is the process of programmed cell death which maintains the balance of cell survival and death. TIPE is involved in the carcinogenesis of many tumor types, yet the exact role of TIPE in defective apoptosis-associated carcinogenesis remains uncertain. In the present study, TIPE overexpressing Raw264.7 and EL4 cells and vector control cells were treated with 4 mJ/cm2 ultraviolet radiation or 2 ug/ml cisplatin. Following ultraviolet irradiation, TIPE overexpression decreased the percentage of apoptotic cells as detected by flow cytometric and reversed the cisplatin-mediated decrease in mitochondrial membrane potential by JC-1 assay. Western blot analyses also revealed that TIPE overexpression inhibited cisplatin-induced activation of caspase-3 and -9 and PARP. Secondly, TIPE overexpression increased the levels of phosphorylated JNK, MEK and p38. Moreover, inhibition of JNK and p38, but not MEK, efficiently abolished the cell pro-survival effect of TIPE. Most importantly, an in vivo tumor implantation model revealed that TIPE overexpression augmented the volume and weight of the implanted tumors, indicating that TIPE facilitated tumor formation. We found that TIPE exhibited an anti-apoptotic effect via JNK and p38 activation, which ultimately promoted tumor. Hence, the present study revealed that activation of JNK and p38 kinases contribute to the TIPE-mediated anti-apoptotic effect, indicating that JNK and p38 may be potential therapeutic molecules for TIPE overexpression-associated diseases. PMID- 29620233 TI - A frameshift mutation in the CHM gene causes choroideremia with acute angle closure glaucoma. AB - Choroideremia is an X-linked recessive chorioretinal degenerative disease that is characterized by progressive centripetal loss of the photoreceptor, retinal pigment epithelium (RPE), and choriocapillaris layers. The CHM gene [choroideremia (Rab escort protein 1)] has been identified as the pathogenic gene in choroideremia. The aim of the present study was to describe the clinical and genetic characteristics of a family with choroideremia family. In the present study, a family with choroideremia presenting with serious chorioretinal atrophy and pigment proliferation, shallow anterior chambers, angle closure and high intraocular pressure (IOP) were recruited. The affected family members underwent a complete ophthalmologic examination. DNA samples obtained from the proband II:1 and the patient II:2 were used for targeted exome sequencing of the CHM gene. PCR amplification and Sanger sequencing were used to validate the variations exhibited in family members and controls. A novel frameshift mutation c.280delA (p.Thr94LeufsTer32), in CHM was identified in the male proband, the normal carrier I:2 and the phenotyped carrier II:2, which was absent in the normal individual II:3 as well as in 200 normal controls. Comparing the amino acid sequences of CHM between multiple species through Clustal Omega indicated conserved amino acids in these mutant sites. Additionally, an X-chromosome inactivation (XCI) assay was performed in the female carriers in the family, in which DNA of the abnormal carrier II:2 and normal carrier I:2 showed a random XCI pattern. To conclude, the present findings strongly indicate that the c.280delA mutation is a disease-causing mutation in our choroideremia pedigree with acute angle-closure glaucoma. PMID- 29620234 TI - Crocin prevents platelet-derived growth factor BB-induced vascular smooth muscle cells proliferation and phenotypic switch. AB - The phenotypic switch of vascular smooth muscle cells (VSMCs) is a major initiating factor for atherosclerotic cardiovascular diseases. Platelet-derived growth factor-BB (PDGF-BB) initiates a number of biological processes that contribute to VSMC proliferation and phenotypic switch. Crocin, a component of saffron, has been reported to inhibit atheromatous plaque formation. However, the effects of crocin on PDGF-BB-induced VSMC proliferation and phenotypic switch remain unclear. The aim of the present study was to investigate the role of crocin on PDGF-BB-induced VSMCs proliferation and phenotypic switch and its underlying mechanisms. Cell proliferation and markers of VSMCs phenotypic switch were measured using a Cell Counting Kit-8 assay and western blot analysis, respectively. The signaling pathways involved in the effects of crocin on VSMCs were validated by western blot analysis with or without the use of specific pathway inhibitors. Crocin significantly inhibited PDGF-BB-induced VSMCs proliferation compared with the PDGF-BB only group (P<0.05). In addition, crocin significantly abrogated the PDGF-BB-induced increase in contractile protein alpha smooth muscle actin, calponin and decrease in synthetic proteins osteopontin (OPN) in a concentration dependent manner (P<0.05). In addition, crocin slowed PDGF-BB-induced Janus kinase (JAK)-signal transducer and activator of transcription 3 (STAT3) and extracellular signal-regulated kinase (ERK)/Kruppel like factor 4 (KLF4) signaling activation in VSMCs. By applying the JAK inhibitor (AG490) and ERK1/2 inhibitor (U0126), the results suggested that the crocin inhibited PDGF-BB-induced VSMCs phenotypic switch through the JAK/STAT3 and ERK/KLF4 signaling pathways. These results suggested that crocin may effectively prevent PDGF-BB-induced VSMCs proliferation and phenotypic switch and may be a promising candidate for the therapy of atherosclerotic cardiovascular diseases. PMID- 29620235 TI - Toxicity of plant extracts containing pyrrolizidine alkaloids using alternative invertebrate models. AB - Pyrrolizidine alkaloids (PAs) are a widespread class of hepatotoxic heterocyclic organic compounds found in approximately 3% of world flora. Some PAs have been shown to have genotoxic and carcinogenic effects. The present study focuses on the toxicity effects of four dry extracts obtained from medicinal plants (Senecio vernalis, Symphytum officinale, Petasites hybridus and Tussilago farfara), on two aquatic organisms, Artemia salina and Daphnia magna, and the correlation with their PAs content. A new GC-MS method, using a retention time (TR)-5MS type capillary column was developed. PAs Kovats retention indices, for this type of column were computed for the first time. The lethal dose 50% (LC50) values for the two invertebrate models were correlated (Pearson 's coefficient, >0.9) and the toxicity was PA concentration-dependent, for three of the four extracts. All tested extracts were found to be toxic in both aquatic organism models. The results can be used to develop a GC-MS validated method for the assay of PAs in medicinal plants with a further potential application in the risk assessment study of PAs toxicity in humans. PMID- 29620236 TI - Critical role for non-GAP function of Galphas in RGS1-mediated promotion of melanoma progression through AKT and ERK phosphorylation. AB - Regulator of G-protein signaling 1 (RGS1) has been found to be a critical factor in melanoma and other malignancies. However, the mechanism involved in the RGS1 mediated promotion of melanoma progression is not clear. We based our study on samples collected from pathological specimens of melanoma patients. We found by immunohistochemistry that RGS1 expression was significantly higher in melanoma than that noted in nevus tissue (P<0.05). Kaplan-Meier analysis demonstrated a significant correlation between increased RGS1 expression and reduced disease specific survival (P<0.05). RGS1 expression was also found to be related to the proliferation and migration of melanoma cells. RGS1 was able to bind to the Galphas in immunoprecipitation, but this interaction did not accelerate GTP hydrolysis in our experiment. Furthermore, we found that RGS1 may promote melanoma progression through the downstream effects of Galphas signaling, such as the increased phosphorylation of AKT and ERK by western blotting. Our results demonstrated that RGS1 promotes melanoma progression through regulation of Galphas-mediated inactivation of AKT and ERK. Therefore, RGS1 is a novel therapeutic target for melanoma treatment. PMID- 29620237 TI - A novel missense mutation in the ACTG1 gene in a family with congenital autosomal dominant deafness: A case report. AB - The ACTG1 gene encodes the cytoskeletal protein gamma-actin, which functions in non-muscle cells and is abundant in the auditory hair cells of the cochlea. Autosomal dominant missense mutations in ACTG1 are associated with DFNA20/26, a disorder that is typically characterized by post-lingual progressive hearing loss. To date, 17 missense mutations in ACTG1 have been reported in 20 families with DFNA20/26. The present study described a small family with autosomal dominant nonsyndromic hearing loss. A novel heterozygous missense mutation, c.94C>T (p.Pro32Ser), in ACTG1 was identified using the TruSight One sequencing panel. Notably, congenital hearing loss in our proband was identified by newborn hearing screening at birth. In silico predictions of protein structure and function indicate that the p.Pro32Ser mutation may result in conformational changes in gamma-actin. The present study expands the understanding of the phenotypic effects of heterozygous missense mutations in the ACTG1 gene. In specific, the present results emphasize that mutations in ACTG1 result in a diverse spectrum of onset ages, including congenital in addition to post-lingual onset. PMID- 29620238 TI - miR-328-5p inhibits MDA-MB-231 breast cancer cell proliferation by targeting RAGE. AB - MicroRNAs (miRNAs) are a class of short non-coding RNAs that play an important role in gene regulation and are critically involved in the pathogenesis and progression of human cancer. miR-328-5p has been reported to potentially act as a sensitising agent in breast cancer, but its other cellular functions and mechanisms remain unknown. The primary aim of the present study was to discover additional cellular functions and mechanisms of miR-328-5p in the breast cancer cell line MDA-MB-231. In the present study, miRNA microarray was used to find altered miRNAs. MTT and colony formation were used to test cell proliferation. Flow cytometry and western blotting were used to explore potential mechanisms of miR-328-5p regulating cell proliferation. A luciferase reporter assay was used to confirm target binding. miR-328-5p was revealed to be significantly upregulated after knockdown of the receptor for advanced glycosylation end products (RAGE). We also confirmed that miR-328-5p was frequently decreased in breast cancer tissues. Moreover, miR-328-5p mimics inhibited MDA-MB-231 proliferation, drug resistance and cell cycle progression. We confirmed that RAGE was a direct target of miR-328-5p. Functions of miR-328-5p in MDA-MB-231 cells were elucidated by targeting RAGE. In conclusion, these results revealed that miR-328-5p may be considered as a tumour-suppressor factor, and promoting miR-328-5p expression could be a novel therapeutic strategy for breast cancer. PMID- 29620239 TI - A functional polymorphism at miR-491-5p binding site in the 3'UTR of MMP9 gene confers increased risk for pressure ulcers after hip fracture. AB - The roles of matrix metalloproteinase (MMP)9 in the control of pressure ulcers (PU) after hip fracture as well as how the rs1056629 in MMP9 3'UTR compromises the interaction between MMP9 and miR-491 were explored. Online miRNA database (http://www.bioguo.org) was utilized to explore gene polymorphism in MMP9 3'UTR that might break the interaction between MMP9 and miRNA. Luciferase assay was utilized to confirm the miRNA targeted MMP9. Real-time PCR, western blot analysis and immunohistochemistry were carried out to understand the roles of MMP9 in PU as well as how rs1056629 in MMP9 3'UTR compromises the interaction between MMP9 and miR-491. rs1056629 in MMP9 3'UTR that compromised the interaction between MMP9 and four miRNAs including miR-194-3p, miR-491, miR-1915-3p and miR-941, and only miR-491 among miR-194-3p, miR-491, miR-1915-3p and miR-941 decreased luciferase activity of wild-type MMP9 3'UTR, and luciferase activities of mutant 3 and mutant-4 MMP9 3'UTR in miR-491 overexpressing cells was comparable with scramble control. miR-194-3p, miR-491, miR-1915-3p and miR-941 levels in PU group was comparable with healthy control, and miR-194-3p, miR-491, miR-1915-3p and miR 941 in subjects carrying AA genotype was similar with those in AC and CC groups. MMP9 mRNA and protein, and histology score in subjects with PU were much higher, and were also much higher in AA group. Only miR-491 mimic among miR-194-3p, miR 491, miR-1915-3p and miR-941 mimics downregulated the MMP9 level, and only miR 491 inhibitor among miR-194-3p, miR-491, miR-1915-3p and miR-941 inhibitors upregulated the MMP9 level. Our study indicated that rs1056629 polymorphism could be a novel biomarker for predicting the occurrence of PU after a hip fracture. PMID- 29620240 TI - Upregulation of UHRF1 promotes the progression of melanoma by inducing cell proliferation. AB - Melanoma is the most aggressive cutaneous cancer due to its propensity to metastasise and proliferate. Melanoma accounts for 80-90% of skin-cancer related deaths worldwide. Alhough numerous published studies have attempted to define the markers of diagnosis and prognosis of melanoma, a sensitive and specific biomarker for melanoma remains unknown. Recently, ubiquitin-like with PHD and ring finger domains 1 (UHRF1) has attracted attention due to its role in cell proliferation and it has been deemed as a potential therapeutic target for cancer. The aim of the present study was to investigate the role and the clinical significance of UHRF1 in melanoma. Immunohistochemical analysis was performed with tissue microarray (TMA) to examine the expression of UHRF1 and Ki-67, and the role of UHRF1 in cell proliferation was determined through CCK-8, colony formation and flow cytometry by interfering with the expression of UHRF1. Subsequently, the relationship among the expression of UHRF1 and several major clinical characteristics of melanoma were analysed to evaluate the role of UHRF1 in the progression of melanoma. Finally, the clinical significance of UHRF1 was estimated in 56 melanoma patients. It was observed that the expression of UHRF1 was significantly upregulated in melanoma compared with benign nevi tissues (P<0.05). In addition, the downregulation of the expression of UHRF1 significantly decreased cell proliferation. Furthermore, the level of UHRF1 was positively correlated with the expression of Ki-67 in melanoma cells, as well as in melanoma tissues. Clinically, a high level of UHRF1 was prone to be related to a high TNM classification (P=0.017) and Breslow's thickness (P=0.034) of melanoma. Furthermore, a high level of UHRF1 was positively associated with a shorter overall survival of melanoma patients. Importantly, the Cox regression model analysis demonstrated that the expression of UHRF1 was an independent prognostic factor for the overall survival of melanoma patients. In conclusion, the elevated expression of UHRF1 plays an important role in melanoma cell proliferation and progression, and it can be used as a prognostic biomarker for melanoma. PMID- 29620241 TI - Microarray expression profile analysis of circular RNAs in pancreatic cancer. AB - Pancreatic cancer remains one of the most malignant tumors with a poor prognosis. Despite advances in diagnosis and treatment, no reliable biomarkers are available for clinical practice. Circular RNAs (circRNAs) are a novel class of endogenous non-coding RNA, which are abundant, stable and conserved, and serve crucial roles in disease, particularly in cancer. The purpose of the present study was to investigate the expression profile of circRNAs in 20 pancreatic cancer tissues and corresponding paracancerous tissues using arraystar human circRNA array analysis, high-throughput circRNA microarray, bioinformatic analysis and reverse transcription-quantitative polymerase chain reaction. It was revealed that the circRNAs expression profile was significantly different between pancreatic cancer tissue and paracancerous tissue, which indicates a potential role in pancreatic cancer. It was predicted that circRNAs may act as a micro RNA sponge to modulate gene expression in pancreatic cancer. Additionally, microarray expression analysis data was submitted to the Gene Expression Omnibus under accession no. GSE79634. The present study revealed that circRNAs expression was visibly diverse in pancreatic cancer compared with paracancerous tissue and provides more reliable biomarkers and new insights into the mechanisms of pancreatic cancer. PMID- 29620242 TI - Corosolic acid induces cell cycle arrest and cell apoptosis in human retinoblastoma Y-79 cells via disruption of MELK-FoxM1 signaling. AB - Retinoblastoma (Rb) is the most frequent primary intraocular tumor usually diagnosed in infants and children, and current therapy for such disease is still limited. Corosolic acid (CA), an ursane-type pentacyclic triterpene, has been assessed as a promising anticancer agent with little impact on untransformed cells. In the present study, we investigated the cytotoxic effect and underlying mechanism of CA on human retinoblastoma Y-79 cells. The viability of cells was verified by MTT assay. Cell cycle and apoptosis were evaluated by flow cytometric analysis. The expressions and activities of the related molecules were assessed by western blot analysis and luciferase assay. The results demonstrated that the treatment of CA dose-dependently induced cytotoxicity, cell cycle arrest and cell apoptosis in Y-79 cells. Furthermore, MELK-FoxM1 signaling was estimated to be involved in the cytotoxic effect of CA on Y-79 cells, and CA exerted its activity mainly through inhibition of the expression levels of MELK and FoxM1 as well as through suppression of the transcriptional activity of FoxM1 driven by itself or MELK. Our findings establish MELK-FoxM1 signaling as a promising therapeutic target for human retinoblastoma, and suggest the potential development of CA and its derivatives as novel drug candidates against this disease. PMID- 29620243 TI - Knockdown of peroxiredoxin V increases glutamate-induced apoptosis in HT22 hippocampal neuron cells. AB - High concentrations of glutamate may mediate neuronal cell apoptosis by increasing intracellular reactive oxygen species (ROS) levels. Peroxiredoxin V (Prx V), a member of the Prx family, serves crucial roles in protecting cells from oxidative stress. The present study investigated the regulatory effect of Prx V on glutamate-induced effects on viability and apoptosis in HT22 cells. Western blotting was used for protein expression analysis and Annexin V/PI staining and flow cytometry for determination of apoptosis. The results demonstrated that glutamate may ROS-dependently increase HT22 cell apoptosis and upregulate Prx V protein levels. Furthermore, knockdown of Prx V protein expression with a lentivirus significantly enhanced HT22 cell apoptosis mediated by glutamate, which was reversed by inhibition of ROS with N-acetyl-L-cysteine. Inhibiting the extracellular signal-regulated kinase (ERK) signaling pathway with PD98059, a specific inhibitor for ERK phosphorylation, markedly decreased glutamate-induced HT22 cell apoptosis in Prx V knockdown cells, indicating the potential involvement of ERK signaling in glutamate-induced HT22 cell apoptosis. In addition, an increase in nuclear apoptosis-inducing factor was observed in Prx V knockdown HT22 cells following glutamate treatment, compared with mock cells, whereas no differences in B-cell lymphoma-2 and cleaved-caspase-3 protein expression levels were observed between mock and Prx V knockdown cells. The results of the present study indicated that Prx V may have potential as a therapeutic molecular target for glutamate-induced neuronal cell death and provide novel insight into the role of Prx V in oxidative-stress induced neuronal cell death. PMID- 29620244 TI - EGFR mutations subset in Chinese lung squamous cell carcinoma patients. AB - Research has identified that epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) possess large benefits for adenocarcinoma (ADC), although little benefit for squamous cell carcinoma (SCC). The aim of the present study was to investigate the percentage of patients with SCC with the EGFR mutations subset and the benefits of EGFR TKIs in SCC. In the present study, the EGFR mutations subset was detected with an amplification refractory mutation system in 1,359 clinical SCC tissues. The association of the EGFR mutations subset with clinicopathological parameters was evaluated using the Mann-Whitney U test, and Kruskal-Wallis H. Kaplan-Meier survival analysis was used to estimate the effect of the EGFR mutations subset on SCC patient survival rates. A total of 94 out of 1,359 SCC patients were identified as having EGFR mutations, an EGFR mutation rate of 6.92%. The EGFR mutations subset in the 94 cases was identified as follows: 37.2% (35/94) in exon 19; 39.4% (37/94) in L858R; 5.3% (5/94) in T790M; 4.3% (4/94) in G719X; 2.1% (2/94) in L861Q; and 11.7% (11/94) in other mutations. Kaplan-Meier survival analysis identified that the differentiation, pathological tumor, node, metastasis stage, lymph node metastasis and distant metastases were significantly associated with patients' survival (P>0.05; log rank test), and no significant difference was observed between TKI therapy and chemotherapy in terms of patient survival rates (P>0.05). In addition, the overall discordant rate of the EGFR mutations subset in SCC patients was relatively low. Due to the non-significant difference between TKI therapy and chemotherapy in terms of patient survival and the lower discordance rate of the EGFR mutations subset in SCC patients, EGFR TKIs could be a recommended treatment for SCC. PMID- 29620245 TI - Hippocampal beta2-microglobulin mediates sepsis-induced cognitive impairment. AB - Acute brain dysfunction is a frequent complication in sepsis patients and is associated with long-term neurocognitive consequences and increased mortality, yet the underlying mechanism remains unclear. Emerging evidence has suggested that beta2-microglobulin [a component of major histocompatibility complex (MHC) class I molecules] is involved in cognitive dysfunction in various neurological diseases. Therefore, the present study tested the hypothesis that beta2 microglobulin in the brain also mediates sepsis-induced cognitive impairment. In the present study, wild-type and antigen processing 1 (Tap1)-deficient mice (Tap1 /-) were subjected to cecal ligation and puncture (CLP). Survival rate, cognitive function, and biochemical analysis were performed at the indicated time points. The data revealed that CLP induced anxiety-like behavior and impaired hippocampal dependent contextual memory in wild-type mice, which was accompanied by hippocampal microglial activation, increased level of interleukin-1beta, and decreased concentrations of brain derived neurotrophic factor and postsynaptic density protein 95. Notably, it was demonstrated that Tap1-/- mice with reduced cell surface expression of MHC I protected mice from anxiety-like behavior and impaired hippocampal-dependent contextual memory and reversed most of these biochemical parameters following sepsis development. In summary, the results of the present study suggest that beta2-microglobulin negatively regulates cognitive impairment in an animal model of sepsis induced by CLP. PMID- 29620246 TI - Roseburia intestinalis inhibits interleukin-17 excretion and promotes regulatory T cells differentiation in colitis. AB - Roseburia intestinalis (R. intestinalis) is one of the dominant intestinal bacterial microbiota and is decreased in patients with inflammatory bowel disease (IBD). It helps protect colonic mucosa against the development of inflammation and subsequent IBD, however its underlying mechanisms are unclear. The aim of the present study was to evaluate the anti-inflammatory properties of R. intestinalis in vitro and in an animal model of IBD. The effects of R. intestinalis on disease activity index (DAI) scores, intestinal pathology, the expression of interleukin (IL)-17 and the frequency of CD4+CD25+Foxp3+ regulatory T cells (Treg) were evaluated in vivo in a model of 2,4,6-trinitrobenzenesulfonic acid solution (TNBS)-induced colitis. Compared with the control group, TNBS-treated mice had significantly higher secretion of IL-17, higher DAI scores, a lower ratio of Treg, reduced colon lengths and higher histological scores for colon inflammation. The administration of R. intestinalis significantly downregulated the expression of IL-17, increased the ratio of Treg and ameliorated the high DAI scores and the pathological signs of inflammation in the colon compared with mice treated with TNBS alone. Gene expression profiling was also used to detect the expression of IL-17 in human IBD and healthy control specimens. To extend these findings to an in vitro model of inflammation the human colon epithelial cell line NCM460 was stimulated with lipopolysaccharide (LPS) to induce inflammation and co-cultured with R. intestinalis and changes in IL-17 expression were evaluated. R. intestinalis inhibited the LPS-induced secretion of IL-17 by NCM460 cells. In conclusion, these results demonstrate that R. intestinalis inhibits IL 17 secretion and promotes Treg differentiation in colitis, suggesting that R. intestinalis could be of potential use in the treatment of IBD. PMID- 29620248 TI - Expression and oncogenic properties of membranous Notch1 in oral leukoplakia and oral squamous cell carcinoma. AB - Notch1 signaling is essential for tissue development and tumor progression. This signaling pathway has also been implicated in oral leukoplakia (OL) and oral squamous cell carcinoma (OSCC). However, the role of Notch1 expression in OL and its malignant transformation is unknown. This study aimed to examine the Notch1 expression patterns by immunohistochemistry (IHC) in a cohort of 78 Chinese patients with OL and to analyze the relationship between the patterns and progression of OL to OSCC. Strong Notch1 staining was observed in 10 (13%) of the 78 OL patients, but it was not associated with any of the clinicopathological parameters. However, we observed membranous Notch1 expression in 24 (31%) of the OL samples. Membranous Notch1 expression was significantly associated with the severity of dysplasia (P<0.001) and development of OSCC (P=0.003). By multivariate analysis, membranous Notch1 expression was found to be the only independent factor for OSCC development in the patient population (P=0.019). Among the 24 patients with membranous Notch1 expression, 11 (46%) developed OSCC compared to 8 (15%) of the 54 patients without such expression (P=0.001, determined by log-rank test). Furthermore, we established a 4-nitroquinoline-1 oxide (4NQO)-induced murine OSCC model and studied the Notch1 expression patterns in different stages of carcinogenesis. We observed that the extent of expression of membranous Notch1 increased during carcinogenesis. These data indicated a relationship between membranous Notch1 expression and OSCC risk in patients with OL and suggested that membranous Notch1 served as a biomarker for assessing OSCC risk. PMID- 29620249 TI - Generation of haploid spermatids from chicken embryonal primordial germ cells. AB - In vitro production of functional spermatids has special significance in the research of spermatogenesis and the treatment of male infertility. Primordial germ cells (PGCs) are the precursors of oocyte and sperm, which generate the totipotent cells. Studies have shown that PGCs have the potential ability to develop meiotic spermatids in vitro. Here we have shown that retinoic acid (RA) leads to PGC differentiation, and SCF can improve the efficiency of induction. We indicate an efficient approach to produce haploid spermatids from chicken PGCs in the presence of RA and stem cell factor (SCF). Real-time RT-PCR assays showed that RA and SCF induced a remarkable increase in expression of SYCP1, ACR, BOULE and DCM1 of meiotic germ cells and haploid germ cells, respectively. DNA content assays revealed that RA and SCF induced a remarkable increase of haploid cells. This study provides a theoretical basis and a great animal model for spermatogenesis study. PMID- 29620250 TI - Poligoni Multiflori Radix enhances osteoblast formation and reduces osteoclast differentiation. AB - Poligoni Multiflori Radix (PMR) is a traditional Korean medicinal herb that is known to have various pharmacological effects, including antihyperlipidemic, anticancer, and anti-inflammatory effects. However, the effects of PMR on bone metabolism have not been elucidated to date. The present study aimed to investigate the in vitro and in vivo effect of PMR water extract on the regulation of osteoblast and osteoclast activity. Effects of PMR water extract on receptor activator of nuclear factor-kB ligand (RANKL)-induced osteoclast differentiation and survival of mouse bone marrow macrophages (BMMs) obtained from femurs were investigated by tartrate-acid resistant acid phosphatase (TRAP) positive cells and XTT assay. Expression of osteoclast-related genes was assayed by western blot analysis and reverse transcription-quantitative polymerase chain reaction. Additionally, the effects of PMR water extract on osteoblastic proliferation and differentiation were investigated by alkaline phosphatase (ALP) activity assay, alizarin red staining, and levels of mRNA encoding known osteoblast markers. Furthermore, the effects of PMR water extract on lipopolysaccharide (LPS)-induced bone loss were examined in a mouse model. PMR inhibited RANKL-induced osteoclast differentiation of BMMs in a dose-dependent manner without significant cytotoxicity, and suppressed expression of the main osteoclast differentiation markers Fos proto-oncogene and nuclear factor of activated T-cell. In addition, PMR decreased the mRNA expression levels of NFATc1 target genes, including TRAP, osteoclast-associated receptor, ATPase H+ transporting, lysosomal 38 kDa V0 subunit d2, and Cathepsin K. These inhibitory effects were mediated by the p38 and extracellular signal-regulated kinase/nuclear factor-kappaB pathway. Simultaneously, PMR enhanced the differentiation of primary osteoblasts, and increased the mRNA expression of runt related transcription factor 2, ALP, osterix, and osteocalcin. Notably, PMR improved LPS-induced trabecular bone loss in mice. Collectively, the present findings demonstrated that PMR may regulate bone remodeling by reducing osteoclast differentiation and stimulating osteoblast formation. These results suggest that PMR may be used for the treatment of bone diseases, such as osteoporosis and rheumatoid arthritis. PMID- 29620247 TI - Mechanisms in hypertension and target organ damage: Is the role of the thymus key? (Review). AB - A variety of cells and cytokines have been shown to be involved in the whole process of hypertension. Data from experimental and clinical studies on hypertension have confirmed the key roles of immune cells and inflammation in the process. Dysfunction of the thymus, which modulates the development and maturation of lymphocytes, has been shown to be associated with the severity of hypertension. Furthermore, gradual atrophy, functional decline or loss of the thymus has been revealed to be associated with aging. The restoration or enhancement of thymus function via upregulation in the expression of thymus transcription factors forkhead box N1 or thymus transplantation may provide an option to halt or reverse the pathological process of hypertension. Therefore, the thymus may be key in hypertension and associated target organ damage, and may provide a novel treatment strategy for the clinical management of patients with hypertension in addition to different commercial drugs. The purpose of this review is to summarize and discuss the advances in our understanding of the impact of thymus function on hypertension from data from animal and human studies, and the potential mechanisms. PMID- 29620251 TI - Imaging of immunogold labeling in cells and tissues by helium ion microscopy. AB - Helium ion microscopy (HIM) scans samples with a fine ion beam exploiting the very short de Broglie wavelength of helium ions. Because the radiation induces only a small sample region to emit secondary electrons (SEs), very high resolution is expected. In order to explore the applications of SE-HIM in biology, COS7 kidney fibroblast cells and C2C12 myoblast cells cultured on a silicon (Si) nitride (SiN)/Si bilayer were dried and directly observed in high vacuum, without coating or staining. High contrast, high depth-of-field images were obtained revealing the nucleus, endoplasmic reticulum, cytoskeleton and putative mitochondria above a bright background from the support. Gold-tagged antibodies were employed to aid organelle identification. Signals from the gold tags were most clearly distinguishable by secondary electron (SE)-HIM when cells were grown on thin SiN film, and the minimum gap measured between gold particles showed the resolution to be 2 nm. Wheat germ agglutinin-gold labeling revealed clusters of gold particles ~50-200 nm in diameter on COS7 cells, which might represent assemblies of glycosylated proteins, suggesting the formation of membrane raft structures that include membrane proteins. SE-HIM also delivered high contrast images of unstained, uncoated, thin sections of Epon-embedded mouse kidney tissues mounted on a SiN/Si bilayer, revealing the details of sub-tissues and cell organelles. A charge-coupled mechanism explaining the observed SE-HIM contrast is proposed. Ionoluminescence-HIM was also performed targeting zinc oxide particles on cells. In conclusion, the high depth-of-field, high-resolution imaging achieved using HIM may have applications in various fields, including soft materials. PMID- 29620253 TI - Cotylenin A and tyrosine kinase inhibitors synergistically inhibit the growth of chronic myeloid leukemia cells. AB - The treatment of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKIs) has substantially extended patient survival. However, TKIs do not effectively eliminate CML stem cells. In fact, CML stem cells persist and cause relapse in the majority of patients upon discontinuation of the drug treatment. Transcriptomic and proteomic analyses have revealed that p53 and c-Myc play defining roles in CML stem cell survival, suggesting that the dual targeting of p53 and c-Myc may selectively eliminate stem cells in patients with CML. Since the downregulation of c-Myc and then upregulation of p21 (a target gene of p53) are commonly observed during the differentiation of acute myeloid leukemia cells induced by differentiation inducers, we hypothesized that differentiation inducing agents may be useful in regulating c-Myc and p53 expression in CML cells. In the present study, we demonstrate that some differentiation-inducing agents effectively suppress the self-renewal ability of CML cells, and that the combination of these inducers with TKIs results in significantly greater inhibitory effects on CML cell growth compared to the use of TKIs or the inducer alone. The KU812 cells were treated with various concentrations of the inducers in the presence or absence of 30 nM imatinib for 4 days. Among the differentiation inducers we tested, cotylenin A (CN-A) was the most potent at inhibiting the self-renewal ability of the CML cells. CN-A induced the robust expression of CD38, a marker of committed progenitor and more differentiated myelomonocytic cells, and rapidly suppressed c-Myc expression and upregulated p21 expression in CML cells. Thus, these results suggest that CN-A may have potential to promote the elimination of stem cells in CML. PMID- 29620252 TI - TIM-4 blockade of KCs combined with exogenous TGF-beta injection helps to reverse acute rejection and prolong the survival rate of mice receiving liver allografts. AB - An acute reaction response (AR) following liver transplantation (LT) is caused by immune responses that are primarily mediated by T lymphocytes. Kupffer cells (KCs) are the largest antigen presenting cell (APC) group in vivo and are the primary modulators of the inflammatory or tolerogenic immune response in liver tissues. T cell immunoglobulin-domain and mucin-domain-4 (TIM-4), the only TIM protein not expressed on T cells, is expressed on APCs; suggesting that it mediates the various immune responses. However, to the best of our knowledge, the role of TIM-4 expressed by KCs in LT injury remains unknown. The present study aimed to explore whether and how TIM-4 expressed by KCs is involved in the AR of liver allografts. Orthotopic liver transplantation (OLT) was performed in mice to establish a model of AR and results demonstrated that LT may lead to the augmented expression of TIM-4 in activated KCs. It was also revealed that TIM-4 blockade markedly attenuated AR injury in vivo via the nuclear factor-kappaB (NF kappaB) and p38 mitogen-activated protein kinase (p38 MAPK) signaling pathways. In addition, levels of transforming growth factor-beta (TGF-beta) were increased following TIM-4 blockade. Furthermore, in a KC/cluster of differentiation (CD)4+ T cell co-culture system, blocking TIM-4 inhibited T helper 2 (Th2) differentiation, stimulated the conversion of naive (CD)4+ T cells into CD4+CD25+Forkhead box protein p3+ T regulatory cells and suppressed interleukin 4/signal transducer and activator of transcription 6/transcription factor gata3 signaling. These effects were enhanced following the addition of TGF-beta. It was also demonstrated that LT mouse models treated with TIM-4 blockade in combination with exogenous TGF-beta injections, increased the survival times of mice and enhanced the amelioration of AR in LT. These results indicate that blocking the expression of TIM-4 by KCs via exogenous TGF-beta injection may be an effective therapeutic strategy to inhibit the AR of liver allografts. PMID- 29620254 TI - Juglanin ameliorates UVB-induced skin carcinogenesis via anti-inflammatory and proapoptotic effects in vivo and in vitro. AB - Ultraviolet (UV) radiation induces skin injury, and is associated with the development and formation of melanoma, which is a highly lethal form of skin cancer. Juglanin is a natural product, which is predominantly extracted from Polygonum aviculare, and is considered a functional component among its various compounds. Juglanin has been reported to exert marked protective effects in various diseases via the inhibition of inflammation and tumor cell growth. The present study aimed to explore the effects of juglanin on human skin cancer induced by UV and to reveal the underlying molecular mechanism. In the present study, immunohistochemical analysis, western blot analysis, RT-qPCR analysis and flow cytometry assays were mainly used in vivo and/or in vitro. The results indicated that in mice, UVB exposure increased susceptibility to carcinogens, and accelerated disease pathogenesis. Conversely, juglanin was able to ameliorate this condition via inhibition of inflammation, suppression of cell proliferation and induction of apoptosis via p38/c-Jun N-terminal kinase (JNK) blockage, nuclear factor (NF)-kappaB inactivation and caspase stimulation in vivo. In addition, in vitro, the present study demonstrated that treatment of UVB stimulated B16F10 melanoma cells with juglanin resulted in a dose-dependent decrease in cell viability, as well as increased apoptosis via the upregulation of caspase expression and poly (ADP-ribose) polymerase cleavage. In addition, juglanin markedly attenuated p38/JNK signaling, inactivated the phosphoinositide 3-kinase/protein kinase B pathway and suppressed UVB-induced NF-kappaB activation. Taken together, these results indicated the possibility of applying juglanin in combination with UVB as a potential therapeutic strategy for preventing skin cancer. PMID- 29620255 TI - Different splicing isoforms of ERCC1 affect the expression of its overlapping genes CD3EAP and PPP1R13L, and indicate a potential application in non-small cell lung cancer treatment. AB - Numerous genes are arranged in complex overlapping and interlaced patterns, and such arrangements potentially contribute to the regulation of gene expression. Previous studies have demonstrated that a region in chromosome 19q13.2-3 encompassing the overlapping genes excision repair cross-complementation group 1 (ERCC1), CD3e molecule associated protein (CD3EAP) and protein phosphatase 1 regulatory subunit 13 like (PPP1R13L) was found to be associated with the risk and prognosis of non-small cell lung cancer (NSCLC). The present study confirmed the hypothesis that there are co-expression patterns among these overlapping genes. The suggestive bioinformatic evidence of The Cancer Genome Atlas was verified by quantitative polymerase chain reaction (qPCR) analysis of NSCLC tissue samples. In addition, a cisplatin-induced DNA damage cell model was assessed by microarray analysis, qPCR and 3' rapid amplification of cDNA ends (3'RACE) to verify and quantify the expression levels of co-expressed alternative splicing isoforms in the NSCLC tissues, as well as in cancer A549 and normal 16HBE cells. The expression of CD3EAP exon 1 was demonstrated to be significantly associated with PPP1R13L exon 1, while CD3EAP exon 3 was significantly associated with ERCC1 exon 11 in normal and NSCLC tissues. It was observed that short transcripts of ERCC1, CD3EAP and PPP1R13L are co-expressed in A549 cells and full length transcripts are co-expressed in 16HBE cells. Furthermore, a novel transcriptional regulation pattern was described based on the positional associations of overlapping genes. The region encompassing the overlapping genes ERCC1, CD3EAP and PPP1R13L may be involved in linking the upstream and downstream genes, while the different splicing isoforms of ERCC1 affect the expression of its overlapping genes, suggesting potential application in cisplatin resistance in NSCLC treatment. PMID- 29620256 TI - KIFC1, a novel potential prognostic factor and therapeutic target in hepatocellular carcinoma. AB - Kinesin family member C1 (KIFC1, also known as HSET) is a minus end-directed motor protein, which is critical in centrosome clustering. The present study investigated the expression of KIFC1 in paired hepatocellular carcinoma (HCC) tissues and adjacent non-cancerous tissues from 91 patients by immunohistochemical analysis; clinical data were concomitantly collected. KIFC1 was expressed at high levels in HCC tissues, compared with that in peritumoral tissues (54.9 vs. 14.3%; P<0.01), and its expression correlated with tumor emboli, metastasis, recurrence and time of recurrence. Kaplan-Meier analysis showed that the expression of KIFC1 was significantly associated with tumor-free survival rates. In addition, multivariate analyses revealed that the overexpression of KIFC1was an independent predictive marker in patients with HCC. Consistently, data derived from GEPIA was in agreement with the results. In vitro, KIFC1 knockdown effectively decreased HCC cell viability, and induced apoptosis and cell death. KIFC1 knockdown also significantly suppressed tumor cell migration and invasion in vitro. Mechanistically, the apoptosis-related protein, B-cell lymphoma-2 (Bcl-2), was downregulated in KIFC1 small interfering RNA-treated groups, whereas thee levels of Bcl-2-associated X protein and p53 were upregulated. In addition, the expression levels of phosphorylated phosphoinositide 3-kinase and phosphorylated AKT were decreased significantly when KIFC1 was silenced. The epithelial-mesenchymal transition-related proteins, N-cadherin, matrix metalloproteinase-2 (MMP-2), beta-catenin, Slug, and Zinc finger E-box-binding homeobox 1, were downregulated, whereas the expression of E cadherin was upregulated. The overexpression of KIFC1 was correlated closely with the progression of HCC and poor prognosis, and suggested that the expression levels of KIFC1 are a potential prognostic biomarker and therapeutic target in HCC. PMID- 29620257 TI - Curcumin suppresses MUC5AC production via interfering with the EGFR signaling pathway. AB - Excessive mucin production in the airway may contribute to airway inflammatory diseases. Curcumin has been reported to prevent mucin 5AC (MUC5AC) production in human airway epithelial cells; however, the molecular targets of curcumin involved in regulating MUC5AC expression have remained elusive. The present study aimed to elucidate the molecular mechanisms by which curcumin regulates MUC5AC production, utilizing the NCI-H292 human airway epithelial cell line featuring MUC5AC hypersecretion. Curcumin was able to counteract the endothelial growth factor (EGF)-stimulated mRNA and protein expression of MUC5AC. In addition, curcumin treatment prevented EGF-induced phosphorylation of EGF receptor (EGFR) as well as the downstream AKT and signal transducer and activator of transcription 3 (STAT3), while inhibition of PI3K and STAT3 signaling significantly attenuated the expression of MUC5AC that was induced by EGF. Furthermore, EGF-induced increases in the levels of phosphorylated STAT3 in the nuclear fraction were inhibited by curcumin and PI3K inhibitors. In addition, treatment with curcumin significantly decreased MUC5AC and EGFR expression in a time-dependent manner under basal conditions. These results demonstrated that curcumin inhibited MUC5AC protein expression in NCI-H292 cells under basal conditions as well under EGF stimulation. This inhibition was accompanied by decreased activation of the EGFR/AKT/STAT3 pathway and reduced EGFR expression, which indicated that curcumin may have a dual role in interfering with the EGFR signaling pathway and inhibiting mucin expression in human airway epithelial cells. PMID- 29620258 TI - Autophagy inhibition enhances radiosensitivity of Eca-109 cells via the mitochondrial apoptosis pathway. AB - Autophagy inhibition is crucial for the improvement of the efficacy of radiotherapy in cancer. The aim of the present study was to determine the potential therapeutic value of autophagy and its correlation with mitochondria in human esophageal carcinoma cells following treatment with ionizing radiation (IR). Autophagy in Eca-109 cells was induced under poor nutrient conditions. The formation of autophagic vacuoles was monitored using electron microscopy. In addition, cell apoptosis after IR and mitochondrial membrane potential (MMP) were analyzed by flow cytometry. LC3, beclin-1, cytochrome c and apoptosis-related proteins were assayed by western blotting. A nude mouse xenograft model was also employed to verify the biological effects and mechanisms underlying autophagy in vivo. The formed autophagic vesicles and increased LC3 II/LC3 I ratio indicated marked induction of autophagy by Earle's balanced salt solution (EBSS) in Eca-109 cells. 3-Methyladenine or LY294002 significantly antagonized EBSS-induced autophagy and increased apoptosis of irradiated cells, suggesting that autophagy inhibition conferred radiosensitivity in vitro. Notably, IR induced prominent release of cytochrome c and Bax activation, and decreased Bcl-2 and MMP expression in Eca-109 cells under poor nutrient conditions. Of note, these changes were more prominent following pretreatment with autophagy inhibitors. In vivo, IR treatment mildly delayed tumor growth, but the radiotherapeutic effect was improved significantly by abolishing autophagy. Furthermore, mitochondrial signaling was investigated in the Eca-109 xenograft nude mice model, and the results were consistent with the in vitro study. Therefore, the mitochondrial pathway may be associated with improvement of radiosensitivity in Eca-109 cells. PMID- 29620259 TI - Synergistic anti-hepatoma effect of bufalin combined with sorafenib via mediating the tumor vascular microenvironment by targeting mTOR/VEGF signaling. AB - Sorafenib inhibits tumor growth primarily by inhibiting vessel formation, however, its efficacy requires improvement, therefore, the development of strategies which augment its antiangiogenic effect are of primary concern. Bufalin inhibits tumor cell proliferation and metastasis, and induces apoptosis. In our previous study, it was demonstrated that the antiangiogenic effect of sorafenib was improved by bufalin in human umbilical vein endothelial cells (HUVECs). However, whether bufalin synergizes with sorafenib by affecting the tumor vascular microenvironment remains to be elucidated. In the present study, it was found that hepatocellular carcinoma (HCC) cell proliferation was inhibited by either bufalin or sorafenib following incubation for 24 h, and the inhibition was enhanced upon treatment with a combination of the two. Conditioned medium (CM), comprising supernatant from HCC cells was collected from each of the treatment groups. The migration and tubule formation were suppressed the most in the combination-CM treated HUVECs. The secretion of vascular endothelial growth factor (VEGF) was decreased in HCC cells treated with the combination-CM, as determined by an angiogenesis array, enzyme-linked immunosorbent assay (ELISA) and western blot analysis. The inhibition of tube formation in HUVECs treated with the combination-CM was reversed by incubation with VEGF. The in vivo experiments demonstrated that subcutaneous HCC cell tumors from mice treated with the combination treatment expressed the lowest levels of VEGF, as evidenced by immunohistochemistry and ELISA. Additionally, the level of phosphorylated mechanistic target of rapamycin (mTOR) was reduced in HUVECs pretreated with the phosphoinositide 3-kinase inhibitor PI103. Furthermore, the migration of HCC cells and HUVEC tube formation were attenuated by PI103 pretreatment. In conclusion, the results revealed a synergistic anti-hepatoma effect of bufalin combined with sorafenib via affecting the tumor vascular microenvironment by targeting mTOR/VEGF signaling. PMID- 29620260 TI - MicroRNA-142-5p modulates breast cancer cell proliferation and apoptosis by targeting phosphatase and tensin homolog. AB - A total of 60 breast cancer (BC) tissues and adjacent healthy tissues from patients who underwent surgery in Renmin Hospital of Wuhan University were collected for analysis in the present study. Results from reverse transcription quantitative polymerase chain reaction (RT-qPCR) demonstrated that, compared with the adjacent healthy tissues, the expression levels of microRNA (miR)-142-5p were significantly elevated in BC tissues. Bioinformatics analysis was performed using TargetScan for the prediction of potential target sites that matched the seed region of miR-142-5p; phosphatase and tensin homolog (PTEN) exhibited the highest score and was selected for further analysis. Results of RT-qPCR analysis demonstrated that, compared with the adjacent healthy tissues, the mRNA expression levels of PTEN were significantly decreased in breast cancer tissues. miR-142-5p and PTEN expression levels were positively and negatively associated, respectively, with patient tumor size and metastasis. MDA-MB-231 cells were divided into three groups including the Control group, the miR-NC inhibitor group and the miR-142-5p inhibitor group. As for alterations in cell behavior, including cell viability and cell apoptosis, and protein expression levels, there were no significant differences between Control and miR-NC inhibitor groups. MTT assay results revealed that, compared with Control and miR-NC inhibitor groups, miR-142-5p inhibitor reduced MDA-MB-231 cell proliferation. Flow cytometric analysis demonstrated that, compared with Control and miR-NC inhibitor groups, miR-142-5p inhibitor treatment induced MDA-MB-231 cell apoptosis. Western blotting results demonstrated that, compared with Control and miR-NC inhibitor groups, miR-142-5p inhibitor treatment significantly increased the expression of PTEN, reduced the activation of phosphatidylinositol-4,5-bisphosphate 3 kinase/RACalpha serine/threonine-protein kinase signaling. Finally, PTEN was demonstrated to interact with miR-142-5p from the results of dual-luciferase reporter assay in the present study. The findings of the present study suggested that miR-142-5p may be a potential therapeutic target for the future investigations and insights for breast cancer. PMID- 29620261 TI - Upregulation of E-cadherin expression mediated by a novel dsRNA suppresses the growth and metastasis of bladder cancer cells by inhibiting beta-catenin/TCF target genes. AB - Low expression levels of E-cadherin are correlated with poor prognosis in patients with bladder cancer (BCa). A small activating RNA (saRNA) targeting a specific promoter region can activate gene expression. In the present study, two small double-stranded RNAs (dsRNAs) targeting the promoter region of human E cadherin were designed and synthesized, and the regulatory role of saRNAs in E cadherin expression was investigated. The results of reverse transcription quantitative polymerase chain reaction and western blotting demonstrated that transfection of dsEcad-346 into the BCa cell lines T24 and 5637 significantly activated E-cadherin expression. Furthermore, transfection of dsEcad-346 and miR 373 induced cell cycle arrest in G0/G1 phase, promoted apoptosis and significantly inhibited migration and invasion of BCa cells. Results of immunofluorescence and western blotting indicated that beta-catenin was redistributed from the nucleus to the cell membrane following transfection of dsEcad-346 and miR-373. Additionally, the expression of beta-catenin/T-cell factor complex (TCF) target genes (c-MYC, matrix metallopeptidase 2, cyclin D1) was suppressed following transfection of BCa cells with saRNA. Silencing of E cadherin expression blocked the inhibitory effect of dsEcad-346 and miR-373 on BCa cells. In conclusion, a novel designed dsEcad-346 can activate the expression of E-cadherin in BCa cells. saRNA-mediated activation of E-cadherin expression inhibited the growth and metastasis of BCa cells by promoting the redistribution of beta-catenin from nucleus to cell membrane and inhibiting the beta-catenin/TCF target genes. PMID- 29620262 TI - Dynamic expression and roles of sequestome-1/p62 in LPS-induced acute kidney injury in mice. AB - Acute kidney injury (AKI) is one of the most common complications of sepsis. The roles of autophagy in AKI have been demonstrated in previous studies. Sequestosome-1 (p62) has been demonstrated to serve essential roles in autophagy. The dysregulation of autophagy causes p62 accumulation, which is associated with increased inflammation and tumorigenesis. However, the expression patterns and role of p62 in septic AKI remain unknown. The present study detected the renal autophagy level, and the expression and localization of p62, in a lipopolysaccharide (LPS)-induced AKI mouse model. The results demonstrated that autophagy was induced in the kidneys of LPS-treated mice. The mRNA and protein levels of p62 were decreased in whole renal tissue samples and increased in mice treated with LPS. Immunohistochemistry indicated that p62 protein was predominantly expressed in the cytoplasm of proximal tubules under normal conditions and was significantly decreased following LPS injection into the cortex. In addition, p62 protein was gradually redistributed to the outer and inner medullas following treatment with LPS. In vitro experiments demonstrated that overexpression of p62 significantly decreased the viability and increased the lactate dehydrogenase (LDH) release and apoptosis rate, of renal tubular epithelial cells. By contrast, interference with p62 expression using small interfering RNA increased the cell viability and decreased the LDH release and apoptosis rate. The results of the present study demonstrated that p62 may aggravate LPS-induced acute kidney injury in mice by promoting apoptosis in renal tubular epithelial cells. PMID- 29620264 TI - Pegylated liposomal-paclitaxel induces ovarian cancer cell apoptosis via TNF induced ERK/AKT signaling pathway. AB - Ovarian cancer is one of the most common gynecological types of cancer and is characterized by a relatively high incidence and high mortality rate. Evidence has demonstrated that paclitaxel (PTX) is an effective therapeutic treatment for human ovarian cancer. In the present study, the inhibitory effects of pegylated liposomal (PL)-PTX on the growth of ovarian cancer cells were investigated in vitro; a CAOV-3-bearing mouse model was established to investigate the in vivo effects of PL-PTX on ovarian tumor growth. In the present study, the underlying mechanism of tumor necrosis factor (TNF)-induced inhibition of extracellular signal-regulated kinase (ERK)/protein kinase B (AKT) signaling pathway mediated by PL-PTX was analyzed within ovarian cancer cells. The results of the present study revealed that PL-PTX significantly inhibited the growth and aggressiveness of ovarian cancer cells in vitro and in vivo and apoptotic ability increased upon administration of PL-PTX. The expression levels of caspase-3/9 were significantly upregulated within PL-PTX-treated ovarian cancer cells. The expression and phosphorylation levels of ERK and AKT were markedly increased in response to PL PTX treatment. In addition, the inhibitory effects of PL-PTX on ovarian cancer cells were eliminated by neutralizing antibodies against TNF. The observations of the present study revealed that PL-PTX induced ovarian cell apoptosis via the TNF dependent pathway, which was significantly inhibited with the employment of antibodies against TNF. In vivo analysis demonstrated that PL-PTX treatment significantly inhibited ovarian tumor growth and prolonged the survival of tumor bearing mice. In conclusion, the findings of the present study have provided an insight into the potential mechanism of PL-PTX-induced apoptosis of ovarian cancer cells. As PL-PTX has been reported to induce ovarian tumor cell apoptosis via the TNF-induced ERK/AKT signaling pathway, PL-PTX may serve as an efficient anticancer drug for the treatment of ovarian cancer. PMID- 29620263 TI - TPX2 silencing mediated by joint action of microvesicles and ultrasonic radiation inhibits the migration and invasion of SKOV3 cells. AB - Ovarian cancer, with its high morbidity, has one of the highest mortality rates among gynecological malignant tumors. Overexpression of targeting protein for Xklp2 (TPX2) has been identified in numerous malignant tumors. The present study sought to determine whether TPX2 silencing inhibited the growth and metastasis of ovarian cancer cells, and whether microvesicles- and ultrasonic radiation mediated small interfering (si)RNA-TPX2 transfection may improve the therapeutic effect. The SKOV3 cell line, derived from papillary serous cytadenocarcinoma of the human ovary, was selected as a cell model. Cells were divided into five groups: Control, siRNA-TPX2, siRNA-TPX2 + microvesicle (M), siRNA-TPX2 + ultrasonic irradiation (UI), and siRNA-TPX2 + M + UI. Cell viability was evaluated under the aforementioned conditions via the Cell Counting kit 8 (CCK8) assay. Cell migration and invasion were detected using Transwell assays. The expression levels of associated genes, including epithelial cadherin (E cadherin), metalloproteinase inhibitor 2 (TIMP-2), metastasis associated 1 (MTA1) and matrix metallopeptidase 2 (MMP2), were analyzed using reverse transcription quantitative polymerase chain reaction analysis and western blotting. MMP2 activity was determined using a gelatin zymography assay. The results suggested that TPX2 serves an important role in the development of SKOV3 cells; it is additionally able to inhibit cell migration and invasion by upregulating E cadherin and TIMP2, downregulating MMP2 and MTA1, and inhibiting the phosphorylation of p38 and c-Jun N-terminal kinase. The inhibitory effect of siRNA-TPX2 on SKOV3 cellular metastasis in the presence of microvesicles and ultrasonic radiation was observed to be improved compared with the control. It is proposed that the combination of microvesicles and ultrasonic radiation with TPX2 silencing has the potential to be an effective gene therapy against ovarian cancer. PMID- 29620265 TI - Ashwagandha root extract exerts anti-inflammatory effects in HaCaT cells by inhibiting the MAPK/NF-kappaB pathways and by regulating cytokines. AB - A paste composed of the boiled leaves and roots of the Ashwagandha plant is used to cure ulcer and swelling in Ayurvedic medicine. However, the effects of the hot water extract of Ashwagandha roots (ASH-WEX), which is also used in Ayurveda, on skin have not been fully elucidated. Therefore, the present study investigated the anti-inflammatory activity of ASH-WEX on skin, by using the human keratinocyte cell line HaCaT. The results indicated that ASH-WEX significantly inhibited mRNA expression of inflammatory cytokines, including interleukin (IL) 8, IL-6, tumor necrosis factor (TNF-alpha), IL-1beta and IL-12, and promoted the mRNA expression of the anti-inflammatory cytokine transforming growth factor (TGF)-beta1 in HaCaT cells. In addition, ASH-WEX inhibited the lipopolysaccharide induced phosphorylation of p38 and c-Jun N-terminal kinase, as well as the nuclear translocation of nuclear factor (NF)-kappaB p65. Downregulation of TNF alpha mRNA and upregulation of TGF-beta1 mRNA were also observed in vivo following ASH-WEX treatment of mouse skin. In conclusion, the present study demonstrated that the anti-inflammatory effect of ASH-WEX may be due to its ability to suppress the NF-kappaB and mitogen-activated protein kinase pathways, and to modulate cytokine expression. These results suggest that ASH-WEX can potentially protect against skin inflammation. PMID- 29620266 TI - Phosphatidylserine-exposing cells contribute to the hypercoagulable state in patients with multiple myeloma. AB - Multiple myeloma (MM) is characterized by an increased incidence of thromboembolic events, particularly when treated with immunomodulatory drugs (IMiDs) in combination with dexamethasone. The optimal prophylactic strategy to prevent the hypercoagulable state of patients with MM is still debated. The aim of the current study was to investigate the definitive role of phosphatidylserine (PS) in supporting procoagulant activity (PCA) in patients with MM. Patients with MM (n=20) and healthy subjects (n=15) were recruited for the present study. PS analyses were performed by flow cytometry and confocal microscopy. The PCA was evaluated by clotting time, purified coagulation complex assays and fibrin production assays. The percentage of PS+ blood cells was significantly higher in patients with MM than in healthy subjects. Additionally, the patient serum induced more PS exposure on endothelial cells (ECs) in vitro than serum from healthy subjects. Isolated blood cells from patients with MM and ECs cultured with patient serum in vitro demonstrated significantly shortened coagulation time, greatly intrinsic/extrinsic factor Xa generation and increased thrombin formation. In addition, the levels of PS+ erythrocytes, platelets, leukocytes, and ECs incubated with IMiDs and dexamethasone were higher than with IMiDs alone. The findings support the hypothesis that increased PS exposure on blood cells and ECs participates in the hypercoagulable state in patients with MM. Thus, blocking PS may be a novel therapeutic target for the prevention of thrombosis in these patients. PMID- 29620267 TI - Gastrodin inhibits high glucose-induced human retinal endothelial cell apoptosis by regulating the SIRT1/TLR4/NF-kappaBp65 signaling pathway. AB - Diabetic retinopathy (DR), one of the most common complications of late-phase diabetes, is associated with the ectopic apoptosis of microvascular cells. Gastrodin, a phenolic glucoside derived from Gastrodia elata Blume, has been reported to have antioxidant and anti-inflammation activities. The aim of the present study was to investigate the effects of gastrodin on high glucose (HG) induced human retinal endothelial cell (HREC) injury and its underlying mechanism. The results demonstrated that HG induced cell apoptosis in HRECs, which was accompanied by increased levels of reactive oxygen species production. Gastrodin treatment significantly alleviated HG-induced apoptosis and oxidative stress. Furthermore, HG stimulation decreased the levels of SIRT1, which was accompanied by an increase in Toll-like receptor 4 (TLR4) expression and the levels of phosphorylated nuclear factor (NF)-kappaBp65. However, the administration of gastrodin significantly inhibited the activation of the sirtuin 1 (SIRT1)/TLR4/NF-kappaBp65 signaling pathway in HRECs exposed to HG. Collectively, the present study demonstrated that gastrodin may be effective against HG-induced apoptosis and its action may be exerted through the regulation of the SIRT1/TLR4/NF-kappaBp65 signaling pathway. PMID- 29620268 TI - Induction of Huh-7 cell apoptosis by HCV core proteins via CK1alpha-p53-Bid signaling pathway. AB - Hepatitis C virus (HCV)-infected liver cells sensitize host cells to tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL)-induced cell apoptosis; however, the precise mechanisms are unknown. In the present study, flow cytometry demonstrated that the Annexin V-positive Huh-7 cell number was higher in groups transfected with core proteins when compared with the pcDNA3.1 group. The mRNA and protein expression levels of B-cell lymphoma 2 (Bcl-2) were negatively associated, while Bcl-2-associated X protein (Bax) were positively correlated, with cell apoptotic rate, which, were verified by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blotting. There were no significant differences in the expressions of casein kinase 1 (CK1)-epsilon, CK1gamma or CK1delta; however, the mRNA and protein levels of CK1alpha were markedly higher in groups transfected with the T (those derived from the HCV-J6 strain), NT (those derived from non-tumor tissues) and C191 (those derived from tumor tissues) HCV core proteins than in mock group. When compared with the Mock and Negative Control (control known-down) groups, the mRNA and protein levels of CK1alpha were lower in the CK1alpha known-down group, and there were no marked Huh-7 cell morphological changes among the 3 groups. There was more sensitivity to cell apoptosis in CK1alpha-silenced, however, not in non-CK1alpha-silenced, Huh-7 cells. BH3 interacting-domain death agonist (Bid) protein levels in CK1alpha-silenced Huh-7 cells were higher when compared with non-CK1alpha-silenced Huh-7 cells, and the level of p53 that translocated to the nucleus increased. Chromatin immunoprecipitation-PCR demonstrated that p53 bound to human Bid gene promoter. The level of the Bid promoter in CK1alpha-silenced Huh-7 cells was significantly higher than in the non-CK1alpha-silenced Huh-7 cells. Electron microscopy indicated that p53 knockdown decreased HCV core protein and TRAIL-induced cell apoptosis. Bid/caspase-8 protein levels in CK1alpha-silenced Huh-7 cells that were transfected with p53 siRNA were lower than in the control group. The present study demonstrated that HCV core proteins sensitize host cells to TRAIL-induced cell apoptosis by activating the CK1alpha p53-Bid dependent pathway. PMID- 29620269 TI - Prohibitin and the extracellular matrix are upregulated in murine alveolar epithelial cells with LPS-induced acute injury. AB - Inflammation of epithelial and endothelial cells accelerates the progress of acute lung injury (ALI), and pulmonary fibrosis is the leading cause of mortality in patients with acute respiratory distress syndrome. Interleukin-6 (IL-6) is a pleiotropic cytokine implicated in the pathogenesis of a number of immune mediated disorders, and is involved in pulmonary fibrosis. Prohibitin (PHB) is a highly conserved protein implicated in various cellular functions, including proliferation, apoptosis, tumor suppression, transcription and mitochondrial protein folding. PHB was identified to be associated with a variety of pulmonary diseases, including pulmonary fibrosis. Based on the lipopolysaccharide (LPS) induced cell model of ALI, the present study examined the expression of PHB and the extracellular matrix (ECM) in the process of pulmonary inflammation. MLE-12 cells were divided into 2 groups: The control group was administered sterile PBS; the treatment group was administered 500 ng/ml LPS for 12 h. The mRNA expression of IL-6 in the treatment group was significantly upregulated compared with the control group (P<0.05). The protein expression of IL-6 in the treatment group was markedly increased compared with the control group (P<0.05). ECM components, including collagen-IV and fibronectin, in the treatment group were markedly increased when compared with the control group (P<0.05). The mRNA and protein expression levels of PHB1 and PHB2 were significantly upregulated following treatment with LPS (both P<0.05). The present study identified that PHB and ECM component levels increased in the LPS-induced ALI cell model, and further investigations may be performed to verify the detailed mechanism. PMID- 29620270 TI - Pioglitazone/microRNA-141/FOXA2: A novel axis in pancreatic beta-cells proliferation and insulin secretion. AB - MicroRNAs (miRs) are considered to be effective, post-transcriptional regulators in the pathophysiology of type 2 diabetes (T2D) and promising treatment targets. However, the function of miR-141 remains to be elucidated. In the present study, upregulation of miR-141 was demonstrated in diabetic mice and elderly diabetic patients. Using reverse transcriptase-quantitative polymerase chain reaction, luciferase reporter assays and western blotting, forkhead box A2 (FOXA2) was identified as a direct target gene of miR-141. The potential role of miRNA-141 or FOXA2 was evaluated by overexpressing or silencing miR-141 or FOXA2, respectively. The increased expression of miR-141 resulted in impaired glucose stimulated insulin secretion (GSIS) and INS-1 beta cell proliferation. In addition, miR-141 silencing in MIN6 pseudoislets or INS-1 beta cells led to reduced T2D-associated damage. Furthermore, the expression of miR-141 may be corrected by treatment with pioglitazone, which is widely used for insulin resistance therapy. The present study also demonstrated the mechanism by which miR-141 regulated GSIS and proliferation through FOXA2. Overexpression of FOXA2 in MIN6 pseudoislets increased the effect of the miR-141 inhibitor on GSIS. FOXA2 effectively reversed the effect of miR-141 overexpression on beta cell proliferation. In conclusion, the results of the present study indicate that the pioglitazone/miR-141/FOXA2 axis may represent a promising target mechanism for T2D treatment. PMID- 29620271 TI - miR-152 regulates TGF-beta1-induced epithelial-mesenchymal transition by targeting HPIP in tubular epithelial cells. AB - Renal fibrosis is a common pathological feature of chronic kidney diseases, and their development and progression are influenced by epigenetic modifications including aberrant microRNA (miRNA or miR) expression. miRNAs have been demonstrated to modulate the aggressiveness of various cancers and have emerged as possible therapeutic agents for the management of renal fibrosis. Transforming growth factor beta1 (TGF-beta1)-induced epithelial-mesenchymal transition (EMT) of tubular epithelial cells serves a role in the initiation and progression of renal fibrosis. Furthermore, recent results indicated that the progression of EMT is reversible. The present study aimed to clarify the role of miR-152 in EMT of the tubular epithelial cell line HK-2, stimulated by TGF-beta1, using in vitro transfection with a miR-152 mimic and to further investigate the underlying mechanism of miR-152 activity. In the present study, miR-152 expression was significantly reduced in TGF-beta1-treated HK-2 cells, accompanied by an increased expression of hematopoietic pre-B-cell leukemia transcription factor (PBX)-interacting protein (HPIP). Additionally, miR-152 overexpression inhibited TGF-beta1-induced EMT and suppressed HPIP expression by directly targeting the 3' untranslated region of HPIP in HK-2 cells. Furthermore, upregulation of HPIP reversed miR-152-mediated inhibitory effects on the EMT. Collectively, the results suggest that downregulation of miR-152 initiates the dedifferentiation of renal tubules and progression of renal fibrosis, which may provide important targets for prevention strategies of renal fibrosis. PMID- 29620272 TI - TRPM2 promotes the proliferation and invasion of pancreatic ductal adenocarcinoma. AB - The aim of the present study was to investigate transient receptor potential cation channel subfamily M member 2 (TRPM2), a promising therapeutic target and biomarker for pancreatic ductal adenocarcinoma (PDAC) prognosis, in addition to determining its effects regarding tumor progression and invasion. PDAC is a fatal disease with a poor prognosis, and its associated pathogenic molecular mechanisms remain to be determined. In the present study, combined analysis using genomic and transcriptomic data from two PDAC studies was performed to discover a survival-associated biomarker of PDAC. Survival analysis for genes mutated in >=10 patients was performed using a Kaplan-Meier curve and tested for significance using a log-rank test. Furthermore, gene-expression correlation analysis was performed to determine the genes with the strongest correlations to TRPM2. In addition, a Cell Counting Kit-8 assay, a scratch wound-healing assay and a Transwell assay were performed in the present study to investigate the proliferative, invasive and metastatic ability of PANC-1 cells in TRPM2 overexpressing and downregulated groups. The mutated TRPM2 gene had a strong negative correlation with patient survival probability compared with the normal control group (P=1.06x10-4). Expression of TRPM2 was strongly correlated with expression of probable phospholipid-transporting ATPase IM, gamma-parvin, tudor domain containing 9, Toll-like receptor 7 and Scm-like with four MBT domains protein 2 according to the criterion of a correlation coefficient >0.5. Furthermore, the results of the present study demonstrated that the TRPM2 overexpression in a PDAC cell line (PANC-1) promoted cell proliferation, invasion and metastatic ability. TRPM2 represents a potential therapeutic target and prognostic marker for patients with PDAC. TRPM2 regulates cell proliferation, invasion and migration; however, the underlying mechanism requires further investigation in future studies. PMID- 29620273 TI - p38 inhibitor inhibits the apoptosis of cowanin-treated human colorectal adenocarcinoma cells. AB - Colorectal cancer, which is the third most common type of cancer diagnosed in both men and women, is the leading cause of cancer-related deaths worldwide. Cowanin is a pure compound extracted from Garcinia cowa Roxb., a tree species present in Thailand, Malaysia and Myanmar. The crude extract has been demonstrated to have antitumor activity, inflammation induction, antibacterial activity, anti-inflammatory activity and antimalarial activity. In the present study, the effects of cowanin on apoptosis induction and on the apoptosis-related and mitogen-activated protein kinase (MAPK) pathways were investigated in the LoVo human colorectal cancer cell line. The cytotoxicity of cowanin in LoVo cells was determined by MTT assay. Hoechst 33342 and JC-1 staining were used to determine nuclear morphological changes and mitochondrial membrane potential, respectively. The expression levels of BCL2 apoptosis regulator (Bcl-2) family, MAPK and AKT serine/threonine kinase 1 (Akt) pathway proteins following cowanin treatment were determined by western blot analysis. The results demonstrated that cowanin inhibited cell proliferation and induced cell death via the apoptosis pathway. Cowanin treatment increased BCL2 associated X (Bax) and decreased Bcl-2 expression. In addition, cowanin activated caspase-9, -7 and poly-ADP-ribose polymerase expression. Furthermore, cowanin decreased the levels of phosphorylated extracellular signal-regulated kinase (p-ERK), p-Akt, p-3 phosphoinositide-dependent protein kinase-1, while it increased p-p38 expression, thus resulting in the induction of apoptosis. In conclusion, cowanin inhibited cell proliferation and induced apoptosis of LoVo cells via the MAPK and Akt signaling pathways. Notably, inhibition of p38 by using a p38 inhibitor (SB203580) prevented the cowanin-induced apoptosis in LoVo cells. These results suggested that cowanin may be a potential candidate for the treatment of colorectal cancer and provided important information on the molecular mechanisms underlying its antitumor activity. PMID- 29620274 TI - ERBB4 promotes the proliferation of gastric cancer cells via the PI3K/Akt signaling pathway. AB - ERBB4 is one of the members of the epidermal growth factor receptor (EGFR) family. ERBB4 is a large transmembrane glycoprotein and has tyrosine kinase activity. Once combined with epidermal growth factor (EGF), ERBB4 can activate the related genes in the nucleus, thus promoting cell division and proliferation. In the present study, we investigated the effect of ERBB4 in the proliferation of gastric cancer cells. We found that high ERBB4 levels were closely related to the poor prognosis of gastric cancer patients. Furthermore, ERBB4 was highly expressed in gastric cancer cell lines when compared to the normal stomach cell line, GES. Clinical samples provided the same results. Two gastric cancer cell lines, SGC-7901 and MNK-45 were used to study the underlying mechanism of ERBB4 in the promotion of cell proliferation in gastric cancer cells both in vitro and in vivo. It was observed that after the expression of ERBB4 was suppressed, the proliferation of gastric cancer cells was markedly inhibited both in vitro and in vivo. Moreover, treatment with lentiviral vector siRNA-ERBB4 (Lv-siRNA-ERBB4) or the ERBB4 inhibitor AST-1306, markedly inhibited gastric cancer cell proliferation. Further experiments revealed that inhibition of the expression of ERBB4 could inhibit the activation of the PI3K/Akt signaling pathway. In addition, the use of the PI3K/Akt signaling pathway inhibitor LY294002 demonstrated the aforementioned results. Therefore, we believe that ERBB4 regulates cell proliferation mainly through the PI3K signaling pathway. Finally, nude mice xenografted with gastric cancer cells with low expression of ERBB4 exhibited smaller tumors and longer survival than those engrafted with control gastric cancer cells. These data indicated that ERBB4 promoted cell proliferation and is thus a potential therapeutic target for the treatment of gastric cancer. PMID- 29620275 TI - Effects of endoplasmic reticulum stress on autophagy and apoptosis of human leukemia cells via inhibition of the PI3K/AKT/mTOR signaling pathway. AB - The present study aimed to explore the regulatory effects of endoplasmic reticulum stress (ERS) on the phosphoinositide 3-kinase (PI3K)/AKT serine/threonine kinase 1 (AKT)/mammalian target of rapamycin (mTOR) signaling pathway, and its subsequent effects on autophagy and apoptosis of human leukemia cells. Human leukemia cells were cultured and treated with various concentrations of tunicamycin for 0, 24, 48, 72 and 90 h. Subsequently, human leukemia cells were assigned into the ER activation group, which was treated with 100 ng/ml tunicamycin, the ER activation + TO901317 (PI3K inhibitor) group, and the control group. An MTT assay was conducted to detect cell proliferation. In addition, a monodansylcadaverine (MDC) assay was used to detect the formation of autophagosomes and Annexin V-fluorescein isothiocyanate/propidium iodide double staining was used to examine cell apoptosis. Western blotting was performed to detect the expression levels of 78-kDa glucose-regulated protein (GRP78), phosphorylated (p)-protein kinase R-like endoplasmic reticulum kinase (PERK), p alpha subunit of eukaryotic initiation factor 2 (eIF2alpha), microtubule associated protein 1A/1B-light chain 3 (LC3), caspase-3, CCAAT-enhancer-binding protein homologous protein (CHOP), PI3K, AKT and mTOR. Treatment with 100 ng/ml tunicamycin for 72 h was considered the optimal condition for further experiments. Compared with in cells prior to treatment, human leukemia cells treated with tunicamycin exhibited increased expression of p-PERK, p-eIF2alpha and GRP78 after 72 h (P<0.05). In addition, the expression levels of mTOR, AKT and PI3K were decreased in the ER activation group compared with in the control and ER activation + TO901317 groups (P<0.05). Compared with in the control group, cell proliferation was inhibited and MDC fluorescence intensity was increased in the ER activation group (P<0.05). Furthermore, compared with in the control and ER activation + TO901317 groups, western blotting indicated that the expression levels of LC3-II were increased in the ER activation group (P<0.05). The apoptotic rate was also higher in the ER activation group compared with in the control group (P<0.05), and caspase-3 and CHOP expression was elevated in the ER activation group (P<0.05). These findings indicated that ERS may induce autophagy and apoptosis of human leukemia cells via inhibiting the PI3K/AKT/mTOR signaling pathway. PMID- 29620276 TI - MicroRNA-148a inhibition protects against ovariectomy-induced osteoporosis through PI3K/AKT signaling by estrogen receptor alpha. AB - The present study aimed to investigate the effect of microRNA-148a downregulation on osteoporosis by using an ovariectomized rat model. Reverse transcription quantitative polymerase chain reaction was used to analyze microRNA-148a expression levels, MTT and flow cytometry assays were used to examine cytotoxicity and apoptosis, respectively. The gap-associated proteins were quantified using western blotting. The expression of microRNA-148a was significantly increased in osteoporosis rat following ovariectomy. Overexpression of microRNA-148a significantly promoted apoptosis and inhibited cell growth, whereas downregulation of microRNA-148a significantly reduced apoptosis and increased cell growth. Overexpression of microRNA-148a significantly reduced estrogen receptor a (ERalpha) protein expression and suppressed phosphoinositide 3-kinase regulatory subunit 1 (PI3K) and phosphorylated-protein kinase B (AKT) protein expression in osteoblasts in vitro. The inhibition of ERalpha increased the microRNA-148a effect on apoptosis in osteoblasts in vitro. Subsequently, LY294002, an PI3K inhibitor, significantly increased the effect of microRNA-148a on apoptosis in osteoblasts in vitro. The findings of the present study revealed that anti-microRNA-148a protected cells against ovariectomy-induced osteoporosis through ERalpha by PI3K/AKT signaling. PMID- 29620277 TI - Ubiquitin-like protein FAT10 regulates DNA damage repair via modification of proliferating cell nuclear antigen. AB - In response to DNA damage, proliferating cell nuclear antigen (PCNA) has an important role as a positive regulator and as a scaffold protein associated with DNA damage bypass and repair pathways by serving as a platform for the recruitment of associated components. As demonstrated in the present study, the ubiquitin-like modifier human leukocyte antigen F locus adjacent transcript 10 (FAT10), which binds to PCNA but has not previously been demonstrated to be associated with the DNA damage response (DDR), is induced by ultraviolet/ionizing radiation and VP-16 treatment in HeLa cells. Furthermore, DNA damage enhances FAT10 expression. Immunoprecipitation analysis suggested PCNA is modified by FAT10, and the degradation of FATylated PCNA located in the cytoplasm is regulated by the 26S proteasome, which is also responsible for the upregulation of nuclear foci formation. Furthermore, immunofluorescence experiment suggested FAT10 co-localizes with PCNA in nuclear foci, thus suggesting that FATylation of PCNA may affect DDR via the induction of PCNA degradation in the cytoplasm or nucleus. In addition, immunohistochemistry experiment suggested the expression levels of FAT10 and PCNA are enhanced in HCC tissues compared with healthy liver tissues; however, the expression of FAT10 is suppressed in regenerated liver tissues, which express high levels of PCNA, thus suggesting that the association between FAT10 and PCNA expression is only exhibited in tumor tissues. In conclusion, the results of the present study suggest that FAT10 may be involved in DDR and therefore the progression of tumorigenesis. PMID- 29620278 TI - GPNMB silencing suppresses the proliferation and metastasis of osteosarcoma cells by blocking the PI3K/Akt/mTOR signaling pathway. AB - Glycoprotein non-metastatic melanoma protein B (GPNMB) is a glycoprotein that is highly expressed in various types of cancer, including osteosarcoma. However, its cellular functions and related mechanisms in osteosarcoma remain unclear. In the present study, a higher GPNMB mRNA level was observed in osteosarcoma tissues, than in adjacent non-cancerous tissues. In addition, upregulation of the GPNMB mRNA and protein level was detected in the osteosarcoma cells SaOS2, 143B, MG63 and U2OS using western blot analysis and qPCR. Following transfection with GPNMB siRNA, the proliferation, migration and invasion of MG63 and U2OS cells were assessed using MTT and Transwell assays. The knockdown of GPNMB markedly inhibited the proliferation and metastasis of MG63 and U2OS cells. GPNMB silencing inhibited the activation of PI3K/Akt/mTOR signaling in MG63 and U2OS cells. PI3K/AKT activator insulin-like growth factor-1 (IGF-1) significantly activated the PI3K/Akt/mTOR signaling and reversed the suppressive effects of GPNMB silencing. IGF-1 counteracted the inhibitory effects of GPNMB silencing on the proliferation and metastasis of the MG63 and U2OS cells. In conclusion, we provided evidence that GPNMB silencing regulated the proliferation and metastasis of osteosarcoma cells by suppressing the PI3K/Akt/mTOR signaling pathway. Thus, GPNMB may be a potential therapeutic target for osteosarcoma treatment. PMID- 29620279 TI - Impact of RUNX2 gene silencing on the gemcitabine sensitivity of p53-mutated pancreatic cancer MiaPaCa-2 spheres. AB - Recently, it has been well-recognized that the response toward anticancer drugs differs between two- and three-dimensional (2D and 3D) in vitro cancer cell growth models. In the present study, we have demonstrated that, similar to the conventional 2D monolayer culture systems which often lack in vivo physiological insights, RUNX2 gene silencing increases the gemcitabine (GEM) sensitivity of the 3D spheres generated from p53-mutated pancreatic cancer MiaPaCa-2 cells. According to our results, MiaPaCa-2 cells, but not p53-wild-type pancreatic cancer SW1990 cells efficiently formed sphere structures in serum-free sphere forming medium. Although GEM treatment caused a marked induction of TAp73/TAp63 in MiaPaCa-2 spheres accompanied by the transcriptional activation of p53 family target genes such as p21WAF1 and NOXA, only 20% of cells underwent cell death. Under these experimental conditions, mutant p53 expression level was increased in response to GEM and RUNX2 remained unchanged at the protein level regardless of GEM exposure, which may suppress the pro-apoptotic activity of TAp73/TAp63. Notably, RUNX2 gene silencing markedly augmented GEM-mediated cell death of MiaPaCa-2 spheres compared to that of non-depleted ones. Expression analyses revealed that forced depletion of RUNX2 further stimulated GEM-induced upregulation of TAp63 as well as its downstream target genes such as p21WAF1 and NOXA. In summary, our observations strongly indicated that, similarly to 2D monolayer culture, RUNX2 gene silencing increased GEM sensitivity of MiaPaCa-2 spheres and highlighted the therapeutic potential of RUNX2 in pancreatic cancer with p53 mutation. PMID- 29620282 TI - Anti-oxidative and anti-apoptotic neuroprotective effects of Azadirachta indica in Parkinson-induced functional damage. AB - Azadirachta indica has previously been demonstrated to act as a multi-functional medicinal plant for >2,000 years in India, and its neighboring countries. Currently, it is considered a natural resource with great value used in industrial product development and as a medicine for various types of diseases. The present study investigated the neuroprotective effects of Azadirachta indica which improved functional recovery in the 6-hydroxydopamine induced rat Parkinson's disease (PD) model. Catalase, glutathione-peroxidase, tumor necrosis factor-alpha, interleukin (IL)-1beta, IL-6, nuclear factor (NF)-kappaB p65, inducible nitric oxide synthase (iNOS) and AChE activity levels were analyzed via ELISA. Western blotting was used to analyze B cell lymphoma-2 associated X protein (Bax), cytochrome c and p53 protein expression. Treatment with Azadirachta indica significantly decreased the PD-induced rotational behavior in rats. PD-induced catalase, glutathione-peroxidase, iNOS activity and iNOS protein expression were significantly suppressed by treatment with Azadirachta indica. Inflammatory factors, acetylcholinesterase activity and cyclo-oxygenase-2 protein expression levels were additionally significantly suppressed by treatment with Azadirachta indica. The protein expression levels of Bax, cytochrome c and p53 were decreased and caspase-3 and caspase-9 activities diminished, with treatment with Azadirachta indica. Therefore, Azadirachta indica was demonstrated to exhibit neuroprotective antioxidative and anti-apoptotic effects in Parkinson's disease. PMID- 29620281 TI - Bone marrow-derived mesenchymal stem cell-conditioned medium attenuates tubulointerstitial fibrosis by inhibiting monocyte mobilization in an irreversible model of unilateral ureteral obstruction. AB - Mesenchymal stem cell-conditioned medium (MSC-CM) contains various cytokines (osteopontin and macrophage colony stimulating factor 1) secreted by MSCs and may modulate the immune response in tubulointerstitial fibrosis. The aim of the present study was to investigate whether MSC-CM treatment may affect B cell dependent immune responses, which have previously been reported to facilitate the renal fibrotic processes following unilateral ureteral obstruction (UUO). In the present study, histological analysis, flow cytometry, western blotting and reverse transcription-quantitative polymerase chain reaction were performed. MSC CM treatment was observed to impede renal infiltration of B lymphocytes and the expression of CC chemokine ligand-2. Additionally, UUO suppressed the subsequent recruitment of monocytes/macrophages to the kidney, limited local inflammation and attenuated renal fibrosis. The findings of the present study identified a potential mechanism of MSC-CM in ameliorating the UUO-kidney. PMID- 29620280 TI - Melatonin protects brain against ischemia/reperfusion injury by attenuating endoplasmic reticulum stress. AB - Endoplasmic reticulum (ER) stress plays a vital role in mediating ischemic reperfusion damage in brain. In this study, we evaluated whether melatonin inhibits ER stress in cultured neurons exposed to oxygen and glucose deprivation (OGD) and in rats subjected to transient focal cerebral ischemia. Sprague-Dawley rats were treated with melatonin (5 mg/kg) or control at reperfusion onset after transient occlusion of the right middle cerebral artery (MCA) for 90 min. Brain infarction and hemorrhage within infarcts were measured. The expression of ER stress proteins of phosphorylation of PRKR-like endoplasmic reticulum kinase (p PERK), phosphorylation of eukaryotic translation initiation factor 2alpha (p eIF2alpha), activating transcription factor 4 (ATF4) and C/EBP homologous protein (CHOP) were detected by western blotting and immunohistochemistry analysis. The terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) method, cleaved caspase-3 and cytochrome c were used to investigate cell apoptosis in OGD-induced cultured neurons. Our results demonstrated that animals treated with melatonin had significantly reduced infarction volumes and individual cortical lesion sizes as well as increased numbers of surviving neurons. Melatonin can significantly modulate protein levels by decreasing both p PERK and p-eIF2alpha in the ischemic core and penumbra. Moreover, the expressions of ATF4 and CHOP were restrained in the ischemic core and penumbra, respectively. Furthermore, pretreatment with melatonin at 10-100 uM effectively reduced the levels of p-PERK and p-eIF2alpha in cultured neurons after OGD injury. Melatonin treatment also effectively decreased neuron apoptosis resulting from OGD-induced neuron injury. These results indicate that melatonin effectively attenuated post ischemic ER stress after ischemic stroke. PMID- 29620283 TI - Cytochalasin H isolated from mangrove-derived endophytic fungus induces apoptosis and inhibits migration in lung cancer cells. AB - Cytochalasin H (CyH) has been shown to exhibit promising anticancer activities against various types of cancers; however, the underlying mechanisms remain unknown. In a previous study, we isolated CyH from the mangrove-derived endophytic fungus Phomopsis sp. in Zhanjiang, China. In the present study, we further explored the effect of CyH on apoptosis and migration in the human lung adenocarcinoma cell line A549. Cell Counting kit-8 (CCK-8) assay was used to observe the effects of CyH on the growth of A549 cells. The cell cycle and apoptosis were determined using flow cytometry. The effect of CyH on cell migration was observed by scratch wound healing and chamber migration assays. Western blotting was used to detect the expression of apoptosis- and metastasis associated proteins. Our results showed that CyH exhibited cytotoxicity to A549 cells. The treatment of CyH arrested A549 cells at the G2/M phase. Furthermore, sub-G1 peaks and fragmented DNA ladders were observed, and the mitochondrial transmembrane potential was also decreased in CyH-treated A549 cells. CyH significantly increased Bax, P53, and cleaved caspase-3 (17 kDa) protein expression and decreased Bcl-xL, Bcl-2, and full-length caspase-3 (35 kDa) protein expression, resulting in an increased ratio of the pro-apoptosis/anti apoptosis proteins Bax/Bcl-2. Additionally, CyH treatment inhibited the migration ability of A549 cells in a dose-dependent manner. Taken together, our results suggest that CyH may be a potential chemopreventive drug for the treatment of lung cancer. PMID- 29620284 TI - Enrichment and mutation detection of circulating tumor cells from blood samples. AB - The potential of circulating tumor cells (CTCs) in the diagnosis and prognosis of cancer patients has become increasingly attractive. However, molecular analysis of CTCs is hindered by low sensitivity and a high level of background leukocytes in CTC enrichment technologies. We have developed a novel protocol using a microfluidic device, which enriches and retrieves CTCs from blood samples. The principle of CTC capturing is that tumor cells are larger and less deformable than normal blood cells. To evaluate the potential of utilizing Celsee PREP100 in CTC molecular analysis, we prepared prostate cancer cell lines PC3 and LNCaP, retrieved the captured cells and analyzed them using PCR amplicon sequencing. We were able to recover an average of 79% of 110-1,100 PC3 and 60-1,500 LNCaP cells, and detect the p.K139fs*3 deletion of the p53 gene in PC3 cells and p.T877A mutation of the androgen receptor gene in LNCaP cells. Next, we spiked these two types of cells into normal donor blood samples, captured the cells and analyzed them using PCR amplicon sequencing. The PC3 and LNCaP cells were captured and retrieved with the ratio of captured CTCs to the background leukocytes reaching 1:1.5 for PC3 and 1:2.9 for LNCaP cells. We further revealed that the p.K139fs*3 deletion and p.T877A mutation can be detected in the captured PC3 and LNCaP cells, respectively. We successfully validated this approach using clinical blood samples from patients with metastatic prostate cancer. Our results demonstrated a novel approach for CTC enrichment and illustrated the potential of CTC molecular characterization for diagnosis, prognosis and treatment selection of patients with metastatic malignancy. PMID- 29620285 TI - Effect of HOXA6 on the proliferation, apoptosis, migration and invasion of colorectal cancer cells. AB - Colorectal cancer (CRC) is one of the most common types of tumor worldwide. The morbidity and mortality rates of CRC have increased significantly in adults <50 years of age. In the present study, the effects of homeobox A6 (HOXA6) on the proliferation, apoptosis, migration and invasion of CRC cells were investigated. The results of reverse transcription-quantitative polymerase chain reaction (RT qPCR) analysis demonstrated that the expression of HOXA6 in CRC tumor tissue was higher than that in adjacent normal tissue. Appropriate cell lines and plasmids were selected by RT-PCR and western blot analyses, and recombinant plasmids were transfected into Caco2 or HT-29 cells. The results of RT-qPCR and western blot analyses demonstrated that the expression of HOXA6 was effectively enhanced, or inhibited, following transfection. The rate of cell proliferation was measured with cell counting kit-8, colony formation assay and 5-ethynyl-2'-deoxyuridine assay, apoptosis was detected using terminal deoxynucleotidyl transferase dUTP nick end labeling and flow cytometry assays, and migration and invasion were evaluated using Transwell and wound-healing assays. The results demonstrated that the upregulation of HOXA6 promoted cell proliferation, migration and invasion, but inhibited apoptosis, whereas the downregulated expression of HOXA6 produced the opposite effects. In addition, the expression levels of apoptosis- and epithelial-mesenchymal transition (EMT)-related proteins were examined. The results of the western blot analysis revealed that the upregulated expression of HOXA6 suppressed the expression of B-cell lymphoma-2 (Bcl-2)-associated X protein, caspase-3, poly(ADP-ribose) polymerase and E-cadherin, but promoted the expression of Bcl-2, N-cadherin and Vimentin, whereas the opposite effect was observed in cells with downregulated HOXA6. These results indicated that HOXA6 regulated apoptosis through the Bcl-2 signaling pathway, and regulated migration and invasion through the EMT process. In conclusion, the present study confirmed that HOXA6 was involved in the regulation of CRC, which may inform the development of strategies for the diagnosis and treatment of CRC. PMID- 29620286 TI - Diallyl disulfide inhibits TGF-beta1-induced upregulation of Rac1 and beta catenin in epithelial-mesenchymal transition and tumor growth of gastric cancer. AB - Transforming growth factor-beta1 (TGF-beta1) has been demonstrated to promote epithelial-mesenchymal transition (EMT), invasion and proliferation in tumors via the activation of Rac1 and beta-catenin signaling pathways. The present study investigated the effects of diallyl disulfide (DADS) on TGF-beta1-induced EMT, invasion and growth of gastric cancer cells. TGF-beta1 treatment augmented EMT and invasion, concomitantly with increased expression of TGF-beta1, Rac1 and beta catenin in gastric cancer cells. DADS downregulated the expression levels of TGF beta1, Rac1 and beta-catenin. DADS, TGF-beta1 receptor inhibitor as well as Rac1 inhibitor antagonized the upregulation of the TGF-beta1-induced expression of these genes, abolishing the enhanced effects of TGF-beta1 on EMT and invasion. Blocking the TGF-beta1 receptor through inhibition resulted in the decreased expression of Rac1 and beta-catenin. Rac1 inhibitor reduced the TGF-beta1-induced beta-catenin expression. In addition, DADS and the aforementioned inhibitors attenuated the TGF-beta1-induced tumor growth and the expression changes of E cadherin, vimentin, Ki-67 and CD34 in nude mice. These data indicated that the blockage of TGF-beta1/Rac1 signaling by DADS may be responsible for the suppression of EMT, invasion and tumor growth in gastric cancer. PMID- 29620288 TI - Differentiation of genetically modified canine bone mesenchymal stem cells labeled with superparamagnetic iron oxide into neural-like cells. AB - The use of mesenchymal stem cells (MSCs) has been reported to improve outcomes in various types of nervous system diseases, primarily based on their neural regenerative differentiation ability and paracrine effect on different neuroprotective cytokines. Genetically modified MSCs may enhance the paracrine effect and may further improve the cell-based therapeutic outcome of nervous system diseases. Magnetic resonance imaging has been used to monitor distribution and migration of cells labeled with superparamagnetic iron oxide (SPIO) nanoparticles. However, few studies have described the neural differentiation ability of genetically modified and SPIO-labeled MSCs, which is the foundation for cell tracking and cell therapy in vivo. In this study, canine bone marrow derived MSCs (BMSCs) were initially labeled with SPIO, by culturing with 20 ug/ml SPIO for 24 h, and transfected with the brain-derived neurotrophic factor (BDNF) gene using lentivirus transfection at different multiplicities of infection (MOI) values. The optimized MOI value was demonstrated by cellular viability and enhanced green fluorescent protein (eGFP) rate. Subsequently, the BMSCs were induced to differentiate into neuron-like cells by chemical induction. The results demonstrated that BDNF-overexpressing BMSCs labeled with SPIO can be induced into neuron-like cells with high efficiency and minimal effects on cell viability. Additionally, following neural differentiation, the cells transfected with BDNF and labeled with SPIO expressed significantly higher levels of BDNF and neural markers. The overexpression of BDNF may contribute to neural differentiation of BDNFs, and may have potential benefits for further BMSC-based therapy in vivo. PMID- 29620289 TI - Function of microRNA-141 in human breast cancer through cytotoxic CD4+ T cells regulated by MAP4K4 expression. AB - The present study investigated the anti-cancer effect of microRNA (miRNA)-141 on apoptosis rate of breast cancer cells and the possible underlying mechanism. In patients with breast cancer, the expression of miRNA-141 was downregulated. Overexpression of miRNA-141 reduced breast cancer cell growth, inhibited the expression of cyclooxygenase-2 (COX-2), prostaglandin E2 (PGE2) and tumor necrosis factor (TNF)-alpha, and increased the expression levels of interleukin (IL)-10. However, downregulation of miRNA-141 resulted in upregulation of COX-2, PGE2 and TNF-alpha expression levels, and an inhibition of IL-10. Overexpression of miRNA-141 suppressed mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) protein expression. Downregulation of miRNA-141 markedly upregulated MAP4K4 protein expression in MCF-7 cells. Promotion of MAP4K4 protein expression reduced the effects of miRNA-141 on the toxicity of CD4+ T cells on breast cancer cells. The results of the present study indicated that miRNA-141 may cause anti tumor effects in human breast cancer cells via cytotoxic CD4+ T cells. PMID- 29620287 TI - Protein arginine N-methyltransferase 2 reverses tamoxifen resistance in breast cancer cells through suppression of ER-alpha36. AB - Breast cancer is one of the most common malignancies in females, and 17beta estradiol (E2)/estrogen receptor alpha (ERalpha) signaling plays an important role in the initiation and progression of breast cancer. The role of the ER-alpha subtype and its co-regulator in the initiation of breast cancer and the occurrence of tamoxifen resistance remains to be further elucidated. In our previous studies, protein arginine N-methyltransferase 2 (PRMT2), a co-regulator of estrogen receptor-alpha (ER-alpha), was confirmed to interact with ER-alpha66 and has the ability to inhibit cell proliferation in breast cancer cells. In the present study, we found that tamoxifen treatment induced a decrease in PRMT2 and an increase in ER-alpha36 as well as ER-alpha36-mediated non-genomic effect in MDA-MB-231 cells, which were relatively resistant to tamoxifen by contrast to MCF 7 cells. Moreover, PRMT2 was able to interact with ER-alpha36 directly, suppress ER-alpha36 and downstream PI3K/Akt and MAPK/ERK signaling, reversing the tamoxifen resistance of breast cancer cells. The present study may be meaningful for understanding the role of PRMT2 in breast cancer progression and for developing a new endocrine therapeutic strategy for breast cancer patients with tamoxifen resistance. PMID- 29620290 TI - Significance of Lysyl oxidase-like 2 gene expression on the epithelial mesenchymal status of hepatocellular carcinoma. AB - In the present study, we investigated the role of lysyl oxidase-like 2 (LOXL2), the correlation between LOXL2 and epithelial to mesenchymal transition (EMT) and the effects of using beta-aminopropionitrile (BAPN) to inhibit LOXL2 with the aim of reducing tumor progression in hepatocellular carcinoma (HCC). The expression level of LOXL2 was evaluated in HCC and adjacent non-cancerous tissues using quantitative reverse transcription polymerase chain reaction and clinicopathological analyses. The effects of BAPN on cell proliferation, migration and invasion were investigated in vitro. Additionally, LOXL2 expression was assessed in the culture supernatants of HCC cell lines. Our results revealed that LOXL2 expression was higher in HCC cell lines and tissues. There was a significant correlation between EMT status and LOXL2 levels (P=0.004). BAPN reduced migration and invasion in HCC cells. HCC patients with high levels of LOXL2 expression had relatively shorter disease-free survival (P=0.009) and overall survival (P=0.035). The expression level of LOXL2 was similar between cell supernatants and HCC cell lines. A multivariate analysis demonstrated that portal vein invasion (P=0.015), venous invasion (P=0.026), serum AFP (alpha fetoprotein) levels (P=0.019) and LOXL2 expression (P=0.009) were independent prognostic factors. Our results indicated that a higher level of LOXL2 may contribute to tumor progression, indicating that LOXL2 has clinical value as a therapeutic target in HCC. PMID- 29620291 TI - Integrated analysis of long non-coding RNA competing interactions revealed potential biomarkers in cervical cancer: Based on a public database. AB - Cervical cancer (CC) is a common gynecological malignancy in women worldwide. Using an RNA sequencing profile from The Cancer Genome Atlas (TCGA) and the CC patient information, the aim of the present study was to identify potential long non-coding RNA (lncRNA) biomarkers of CC using bioinformatics analysis and building a competing endogenous RNA (ceRNA) co-expression network. Results indicated several CC-specific lncRNAs, which were associated with CC clinical information and selected some of them for validation and evaluated their diagnostic values. Bioinformatics analysis identified 51 CC-specific lncRNAs (fold-change >2 and P<0.05), and 42 of these were included in ceRNA network consisting of lncRNA-miRNA-mRNA interactions. Further analyses revealed that differential expression levels of 19 lncRNAs were significantly associated with different clinical features (P<0.05). A total of 11 key lncRNAs in the ceRNA network for reverse transcription-quantitative polymerase chain reaction (RT qPCR) analysis to detect their expression levels in 31 pairs of CC clinical samples. The results indicated that 7 lncRNAs were upregulated and 4 lncRNAs were downregulated in CC patients. The fold-changes between the RT-qPCR experiments and the TCGA bioinformatics analyses were the same. Furthermore, the area under the receiver operating characteristic (ROC) curve of four lncRNAs (EMX20S, MEG3, SYS1-DBNDD2 and MIR9-3HG) indicated that their combined use may have a significant diagnostic value in CC (P<0.05). To the best of our knowledge, the present study is the first to have identified CC-specific lncRNAs to construct a ceRNA network and has also provided new insights for further investigation of a lncRNA-associated ceRNA network in CC. In additon, the verification results suggested that the method of bioinformatics analysis and screening of lncRNAs was accurate and reliable. To conclude, the use of multiple lncRNAs may thus improve diagnostic efficacy in CC. In addition, these specific lncRNAs may serve as new candidate biomarkers for clinical diagnosis, classification and prognosis of CC. PMID- 29620293 TI - ? PMID- 29620292 TI - NIK- and IKKbeta-binding protein contributes to gastric cancer chemoresistance by promoting epithelial-mesenchymal transition through the NF-kappaB signaling pathway. AB - Systematic chemotherapy is indispensable for gastric cancer patients with advanced stage disease, but the occurrence of chemoresistance drastically limits treatment effectiveness. There is a tremendous need for identifying the underlying mechanism of chemoresistance. NIK- and IKKbeta-binding protein (NIBP) (also known as TRAPPC9, trafficking protein particle complex 9) is a regulator of the cytokine-induced NF-kappaB signaling pathway which has been proven to play pivotal roles in the progression of various malignancies. Nevertheless, it is still ambiguous whether NIBP is involved in the chemoresistance of gastric cancer. The aim of the present study was to investigate the effect of NIBP on chemotherapy resistance of gastric cancer (GC) and to research the mechanisms of Ginkgo biloba extract 761 (EGb 761(r)) on reversing chemoresistence which has been confirmed in our previous study. In the present study, the results of immumohistochemisty revealed that the positive staining rates of NIBP, NF-kappaB p65 and NF-kappaB p-p65 in gastric cancer tissues were obviously higher than those in normal tissues. Furthermore, a close correlation was found to exist between the expression of NIBP and NF-kappaB p65 (p-p65) in gastric cancer tissues. Moreover, the overexpression of NIBP was closely related to tumor differentiation, depth of invasion, clinical stage and lymphatic metastasis in gastric cancer. Western blot analysis, real-time PCR, MTT assay and flow cytometric analysis were performed and the results demonstrated that compared with the gastric cancer SGC-7901 cells, the expression of NIBP, NF-kappaB p65, NF kappaB p-p65 and mesenchymal marker vimentin were significantly increased in gastric cancer multidrug-resistant SGC-7901/CDDP cells, and the epithelial cell marker ZO-1 was significantly decreased. Meanwhile, it was found that SGC 7901/CDDP cells were accompanied by spindle-like mesenchymal appearance and upregulation of stem cell marker CD133 which has been verified to be an upstream regulatory gene of epithelial-mesenchymal transition (EMT). Further research confirmed that downregulation of NIBP by Ginkgo biloba extract (EGb) 761 EGb 761 suppressed the cis-diamminedichloroplatinum(II) (CDDP)-induced NF-kappaB signaling pathway, EMT and the expression of CD133 in SGC-7901 and SGC-7901/CDDP cells. Altogether, these data indicate that the NIBP-regulated NF-kappaB signaling pathway plays a pivotal role in the chemoresistance of gastric cancer by promoting CD133-induced EMT. PMID- 29620294 TI - [Seasonal allergic rhinitis]. AB - Allergic diseases are currently amongst the most frequent diseases of our time. Of all the allergies in the Western countries, allergic rhinoconjunctivitis is the most common. Its diagnosis is based mainly on the history and the correlation between symptoms and contact with the allergen. A step-by-step approach helps optimize diagnostic resources and minimize costs. PMID- 29620295 TI - [Place of immunotherapy in allergic asthma]. AB - Desensitization for pneumallergens is used in daily practice for the treatment of allergic rhinitis and allergic asthma. However, specific immunotherapy has long been debated in the medical literature as a treatment for allergic asthma until the latest international recommendations for the management of asthma (GINA) reveal specific immunotherapy as a treatment in sensitized patients, poorly controlled by inhaled corticosteroids (FEV 1 > 70%). In this article you will find a current overview of the medical literature on the usefulness of specific desensitization to reduce asthma symptoms and symptomatic treatments, prevent the onset of asthma in patients with allergic rhinitis as well as prevent new sensitizations. PMID- 29620296 TI - [Sublingual immunotherapy for the treatment of allergic rhinoconjonctivitis and asthma : a practical approach]. AB - The prevalence of allergic diseases has been increasing over the past 50 years, leading to social and economic consequences. Immunotherapy is the only disease modifying therapy available for allergic diseases, with durable long-term benefits. Immunotherapy is primarily available in two forms : 1) subcutaneous injections or 2) sublingual tablets/drops. The latter offers the advantage of being managed by the patient himself, requires no injections and has a far lower risk of severe systemic adverse events. In Switzerland, the use of sublingual immunotherapy is still scarce. This article reviews the indications, the administration technics and the contraindications to sublingual immunotherapy. PMID- 29620297 TI - [Mastcell activation syndrome]. AB - Mast cell activation syndrome (MCAS) encompasses a heterogeneous group of pathologies, which are characterized by the existence of clinical symptoms secondary to the systemic effects of mediators released by activated mast cells. MCAS-related symptoms may be mild, moderate, severe, or even life-threatening. Detailed knowledge of the pathogenesis and complexity of MCAS can help in the management and treatment of these patients. PMID- 29620298 TI - [Livedo : physiopathology and diagnosis]. AB - The livedo is a purplish erythema forming more or less regular mesh on the skin. This phenomenon is caused by blood deoxygenation and stasis in the dermal venules. It is important to differentiate between a benign form, usually associated with cold exposure, and a secondary form necessitating further investigations of an underlying disease. The purpose of this article is to discuss the pathophysiology and causes of this phenomenon. Treatment is not covered in this article because of its complex and often multidisciplinary approach. PMID- 29620299 TI - [Complement in diseases]. AB - The complement system is part of the innate immunity. It is a multifunctional system including more than 30 plasma and membrane proteins. These are activated by an enzymatic cascade and proteolytic reactions producing activating fragments. Complement is : 1) among the first line of defense towards a pathogen, 2) increasing efficacy of the acquired immunity, 3) responsible for the elimination of immune complexes apoptotic and or necrotic cells (waste removal function) and many other cellular and tissue functions. The aim of this article is to analyze the consequences of complement dysregulation in the development of various diseases. PMID- 29620300 TI - ? PMID- 29620301 TI - ? PMID- 29620302 TI - ? PMID- 29620303 TI - ? PMID- 29620304 TI - ? PMID- 29620305 TI - ? PMID- 29620307 TI - ? PMID- 29620306 TI - ? PMID- 29620308 TI - [Roles of cytoskeletons and cell adhesions in mechano-sensing]. PMID- 29620309 TI - [Recent advances in NMR methods for determining the structures and dynamics of larger proteins]. PMID- 29620310 TI - [The molecular mechanism of cytokinesis in plant cells]. PMID- 29620311 TI - [Structural studies of Toll-like receptors in innate immunity]. PMID- 29620312 TI - [The role of PNKP in maintenance of genome stability and neural development]. PMID- 29620313 TI - [Dystroglycan glycosylation: structure, synthetic pathway, and in vivo role in the brain development]. PMID- 29620314 TI - [Molecular mechanism of amyloid fibril formation by apolipoproteins]. PMID- 29620315 TI - [Glia-mediated ischemic tolerance]. PMID- 29620316 TI - [Analysis of autism-related gene CAPS2]. PMID- 29620317 TI - [Novel radical SAM enzyme forming intrapeptidyl crosslinks]. PMID- 29620318 TI - [Tumor progression through membrane-bound mucin-mediated signaling]. PMID- 29620319 TI - [Functional roles of ezrin, a cytoskeletal adaptor protein in the regulation of epithelial transport]. PMID- 29620320 TI - [Transcriptional regulation by nuclear body]. PMID- 29620321 TI - [Trends in research for spatio-temporal regulatory mechanism of HIV-Env-mediated membrane fusion & development of a reporter for analysis of the membrane fusion dynamics]. PMID- 29620322 TI - [Diversity of fish skin mucus lectins]. PMID- 29620323 TI - [Recent advances of single particle analysis by cryo-electron microscopy and its application to membrane proteins]. PMID- 29620324 TI - [Conditions of effective correctional treatment for reducing recidivism: Focusing on risk principle]. AB - Research on correctional treatment based on the risk principle (Andrews & Bonta, 2010) has found that the intensity of intervention matched with the risk level of offenders' recidivism is successful to reduce recidivism. However, there is no research dealing with this issue in a non-Western context. The purpose of this study was to examine the validity of the risk principle in rehabilitation for Japanese juvenile delinquents. The sample was 321 Japanese male inmates of the juvenile detention and assessment centers. They were followed for an average of 573 days after discharge to assess recidivism. Among high-risk juvenile delinquents, those who were treated in the juvenile training school showed significantly lower rates of recidivism than those who were placed under community supervision, while among low risk juveniles, there was no significant difference in recidivism between the two treatment conditions. The results indicate that the risk principle is valid for the correctional treatment of Japanese juvenile delinquents, suggesting its cross-cultural universality. Implications for juvenile justice policies and directions for future research are discussed. PMID- 29620325 TI - [Relationships between regulation strategies, emotional and behavioral engagement, and academic achievement]. AB - This study examined relationships among regulation strategies, emotional and behavioral engagement, and academic achievement. Regulation strategies included metacognitive and motivational regulation strategies. Motivational regulation strategies have three subtypes: autonomous regulation strategies, cooperative strategies, and performance strategies. A self-reported survey was administered to 199 undergraduates from four universities, and an examination was conducted three months after the survey. Path analysis showed that use of metacognitive strategies was positively correlated with test scores, mainly through behavioral engagement. Moreover, use of autonomous regulation strategies was positively correlated with emotional engagement. Emotional engagement was positively correlated with test scores via behavioral engagement. On the other hand, use of performance strategies was negatively correlated with emotional engagement. Use of cooperative strategies was not correlated with engagement. These results indicate that each regulation strategy has a different function in learning, and that engagement mediates the relationships between various regulation strategies and academic achievement. PMID- 29620326 TI - [Linkage analysis across different types of crime, by using geographical and temporal proximity]. AB - A number of studies have investigated behavioral case linkage between crimes of a specified type, such as linking one residential burglary with another residential burglary. However, only a few studies have investigated the effectiveness of case linkage across crime types, which have been limited to the UK. This study examined whether linking across crime types using spatio-temporal proximity was possible in samples that were different from the UK in terms of the structure of crime classification. This was accomplished by calculating the discrimination accuracy between linked crime pairs (two offenses committed by the same offender) and unlinked crime pairs (two offenses committed by different offenders) using geographical (inter-crime distance) and temporal proximity (number of days between offenses) across various crimes committed in Japan. Both the geographical proximity and temporal proximity had statistically significant levels of discrimination accuracy across crime types as assessed by Receiver Operating Characteristic (ROC) analysis. This suggests the possibility of identifying a crime series by geographical and temporal proximity across multiple crime types in Japan. PMID- 29620327 TI - [Relationships between ignoring instructions and response bias when completing questionnaires]. AB - Certain participants are insincere, or careless when they respond to questionnaires. To identify such participants, we included three items in a questionnaire that instructed participants to choose a particular response category. Nurses (N = 1,000) responded to this questionnaire in a Web survey. One hundred-twenty participants failed to follow the instructions for at least one item (non-followers). Analyzing their responses indicated the following: (a) non followers were more likely to give identical, or midpoint responses; (b) the correlations between their responses to regular and reversed items were low or positive, and their responses to scales containing reversed items tended to show lower internal consistency; and finally, (c) the mean scores of non-followers were closer to the midpoint of the scale, regardless of whether the scale included reversed items. One reason that including reversed items lead to lower internal consistency could be because participants occasionally missed responding to these items. However, the results suggested that non-followers were not diligent in responding to regular items, and merely deleting reversed items from scales will be insufficient to ensure accurate results. PMID- 29620328 TI - [The influence of positive or negative information from facial expressions on preference judgment: Examination of quantity and ratio]. AB - Our preferences are influenced by the presence of others. However, it is unclear how the simultaneous presence of multiple others influences preference judgment. In this study, we presented multiple happy or disgust face images around a target and examined their influence on target preference. In Experiment 1, we presented only happy or disgust faces in order to examine the influence of quantity. In Experiment 2 and 3, we manipulated the ratio of happy or disgust and neutral faces. Findings revealed that the happy face increased the target preference and its effect varied by the ratio of happy faces. On the other hand, the disgust face decreased the target preference only if there was one such face. These results indicate that although the numeric information of others' facial expressions influences preference judgment, this influence differs with the nature of others' expressions. PMID- 29620329 TI - [Construction of the Time Management Scale and examination of the influence of time management on psychological stress response]. AB - We developed a scale to measure time management and assessed its reliability and validity. We then used this scale to examine the impact of time management on psychological stress response. In Study 1-1, we developed the scale and assessed its internal consistency and criterion-related validity. Findings from a factor analysis revealed three elements of time management, "time estimation," "time utilization," and "taking each moment as it comes." In Study 1-2, we assessed the scale's test-retest reliability. In Study 1-3, we assessed the validity of the constructed scale. The results indicate that the time management scale has good reliability and validity. In Study 2, we performed a covariance structural analysis to verify our model that hypothesized that time management influences perceived control of time and psychological stress response, and perceived control of time influences psychological stress response. The results showed that time estimation increases the perceived control of time, which in turn decreases stress response. However, we also found that taking each moment as it comes reduces perceived control of time, which in turn increases stress response. PMID- 29620330 TI - [Development of the unexpected reality scale for childcare training]. AB - This study aimed to develop a scale for unexpected reality for childcare training (Study 1) and examine the change and influence it exerts on the efficacy of preschool teachers (Study 2). In Study 1, the sample consisted of 571 university and junior college students enrolled in a childcare course. After exploratory factor analysis, four factors were extracted: "actual feelings for childcare as a field of study," "difficulties faced during involvement with children," "negative aspects of the childcare worker," and "severity of work." The study's scale was shown to be internally consistent and valid. In Study 2, the sample consisted of 122 junior college students enrolled in a childcare course. The results showed that the high-scoring groups of each unexpected reality subscales experienced less unexpected reality in the subsequent training session. Moreover, the results of multiple regression showed that preschool teacher efficacy was predicted positively by "actual feelings for childcare as a field of study" and negatively by "difficulties faced during involvement with children." Thus, we suggest that for effective pre- and post-guidance of childcare training, unexpected realities should be considered. PMID- 29620331 TI - Detection of Hepatocellular Carcinoma Biomarker Golgi Protein 73 Based on Magnetic Enzyme-Linked Immunoassay. AB - The magnetic enzyme-linked immunoassay (MEIA) based on magnetic nanoparticles as the solid phase was reported in this work. Magnetic nanoparticles (MNPs) have represented perfectly suitable materials for a variety of biomedical and biotechnological applications. Therefore, we used MEIA based on magnetic nanoparticles to provide a screening method for fast analysis of serum Golgi protein 73 (GP73) in hepatocellular carcinoma (HCC) and healthy subjects and comparison was made with the enzyme-linked immunosorbent assay (ELISA) method. Several relevant conditions, including the concentration of anti-GP73 monoclonal antibody and HRP-anti-human GP73 monoclonal antibody, amount of immunomagnetic beads, and the incubation time, were determined and optimized. Finally, the MEIA was successfully established and validated by 79 HCC and 64 healthy subjects. The results showed this method achieved a detection limit of 0.78 ng/mL, which was more sensitive than ELISA. Furthermore, the sensitivity and specificity of the MEIA were 78.43% and 91.47%, respectively, which were higher than ELISA. The MEIA based on MNPs proved to be simple, sensitive, specific and time-saving, therefore holds great potential for development of a commercial kit in the future. PMID- 29620332 TI - [Development of a Japanese version of the International Personality Item Pool Interpersonal Circumplex]. AB - This study was used to develop a Japanese version of the International Personality Item Pool-Interpersonal Circumplex and examined its reliability and validity. Participants included 625 Japanese university students. They completed the IPIP-IPC-J and one or two other scales: the Japanese version of Ten Item Personality Inventory (Oshio et al., 2012); a short form of the Japanese Big Five Scale (Namikawa et al., 2012); the Japanese Version of Dark Triad Dirty Dozen (Tamura et al., 2015); the Friendship scale (Okada, 1995); or the Assertion Inventory (Murayama et al., 1991). The IPIP-IPC-J was administered again to 65 participants five weeks later to determine test-retest reliability. The results generally supported the reliability and validity of the IPIP-IPC-J. PMID- 29620333 TI - Porous Magnetic Pseudo-Carbon Paste Electrode Electrochemical Biosensor for DNA Detection. AB - A novel and sensitive electrochemical sensor based on magnetic porous pseudo carbon paste electrode (MPPCPE) for DNA detection was described in this study. The MPPCPE was fabricated by mixing polymethyl methacrylate (PMMA) microspheres, as template, graphite powders, as filler, pyrrole, as precursor of polymer and magnetic powder. It was demonstrated that the fabricated MPPCPE had more sensitivity for detecting DNA when compared with magnetic carbon paste electrode (MPCPE). Results from anodic stripping voltammetry (ASV) experiments showed that the Ag peak current versus concentration of complementary DNA at MPPCPE had two linear regions. The first region demonstrated linearity over a concentration range from 0.5 to 20 nM, with correlation coefficient of 0.992, while the second linear region had concentration of complementary DNA at 0.005 to 0.1 nM range, with correlation coefficient of 0.957. The detection limit was as low as 0.005 nM and the electrochemical sensor was easy to preserve for a long time, and had good reusability and stability. PMID- 29620334 TI - Evaluation of In Vitro Function by Subcellular Distribution of Lysosomal and Peroxisomal Protein in Saccharomyces cerevisiae. AB - Lysosomes and peroxisomes, contained in all eukaryote cells, are similar but have completely different function. Lysosomes have three dozen different kinds of hydrolytic enzymes and release lysosomal enzymes to digest intra/extracellular materials. The lysosomal enzymes degrade bacteria cell walls and proteins in cell, exhibiting an antimicrobial and anticancerous effect. Peroxisomes contain oxidative enzymes such as peroxidase, D-amino acid oxidase, and catalase allowing the ability to degrade melanin in hyperpigmentation disorders. Exposure of Saccharomyces cerevisiae and HeLa cells to chemical stress alters lysosomal and peroxisomal enzymes. Chemical stresses such as phenylhydrazine, sodium azide, rolipram, NH4Cl, salicylic acid, H2O2 and 6-hydroxdopamine (6-OHDA) have been suggested to stimulate In Vitro function of lysosome and peroxisome-like organelles (LPO) isolated from S. cerevisiae, and we demonstrate activity of LPO in HeLa cells through chemical analysis. The lysosomes of cells exposed to salicylic acid, 6-OHDA and H2O2 had increased antimicrobial and anticancerous activity, and the peroxisomes of cells exposed to phenylhydrazine and sodium azide had reduced effect of melanin degradation. Therefore, our results suggest that activity of lysosomes and peroxisomes can be regulated by several stimuli, therefore lysosomes may be used as antimicrobial agents, apoptosis-inducing materials, or peroxisomal enzymes to be useful agents for cosmeceutical skin lightening and treatment of hyperpigmentation disorders. PMID- 29620336 TI - [Do dysfunctional attitudes and depressogenic inferential styles predict positive life events?] AB - Although research has indicated that dysfunctional attitudes (DA) and depressogenic inferential styles (DIS) lead to depression when negative life events occur, little is known about how these factors function when negative life events do not occur. This longitudinal study examined the hypotheses that DA and DIS at Time 1 would lead to positive life events at Time 2 (four weeks later) in the absence of, but not in the presence of, negative life events at Time 2. This study also examined whether the effects of DA and DIS on positive life events differ depending on initial levels of depression. Hierarchical regression analyses showed that in the prediction of positive events, interactions of DA and DIS with negative events and depression were not significant. The main effect of DA was significant and positive; the main effect of DIS was significant and negative. The results indicate that the effects of DA and DIS on positive events differ, and the effects do not depend on the frequency of negative events. PMID- 29620335 TI - [Development of the Japanese version of the Thought Control Ability Questionnaire and evaluation of its reliability and validity]. AB - Intrusive thoughts and difficulty in controlling thoughts are common, not only for people with psychological disorders, but also for healthy people. Individual differences in thought control ability may underlie such problems. The Thought Control Ability Questionnaire (TCAQ), which consists of 25 items, was developed by Luciano et al. (2005) in order to measure individual differences in the perceived ability to control unwanted intrusive thoughts. The purpose of the present study was to develop the Japanese version of the TCAQ and evaluate its reliability and validity. We translated the English version of the TCAQ into Japanese. We also conducted confirmatory factor analysis with a one factor solution, similar to the previous study. Based on the analysis, we excluded items whose factor loadings were lower than .30, resulting in 22 items for the Japanese version of the TCAQ. The model exhibited acceptable goodness-of-fit. The Japanese version of the TCAQ also demonstrated good reliability as well as evidence of construct validity. Thus, the development of the Japanese version of the TCAQ was successful. PMID- 29620337 TI - Effect of Polylysine on Blood Clotting, and Red Blood Cell Morphology, Aggregation and Hemolysis. AB - Polylysine has broad biomedical applications, though little is known about its hemocompatibility. Here, we studied the influence of polylysine on human red blood cells (RBCs) and blood clotting. We observed the morphology and aggregation and determined the hemolysis of RBCs incubated with polylysine. Plasma coagulation in the presence of polylysine was evaluated by measuring the activated partial thromboplastin time (APTT) and prothrombin time (PT). Human whole blood coagulation in the presence of polylysine was evaluated with the thromboelastograph (TEG). We found that polylysine at 0.01 mg/mL did not result in RBC aggregation or morphological change, while polylysine at >= 0.1 mg/mL caused RBC aggregation. The RBCs did not lyze in the presence of 0.01-0.5 mg/mL of polylysine. Polylysine at 0.001 mg/mL did not cause a significantly different APTT from the control, while polylysine at >= 0.01 mg/mL caused a significantly higher APTT than the control. Polylysine at <= 0.1 mg/mL did not cause a significantly different PT from the control, while polylysine at 1 mg/mL caused a significantly higher PT than the control. TEG parameters for whole blood coagulation in the presence of 0.01 mg/mL polylysine were within the normal range; while polylysine >= 0.1 mg/mL caused one or more abnormal TEG parameters. From these results, the effect of polylysine on RBC aggregation and blood coagulation was concentration-dependent. The results provide important information for the biomedical applications of polylysine. PMID- 29620338 TI - [Effect of aging on attention to the lateral visual field: The use of a visual statistical learning paradigm]. AB - We investigated characteristics of spatial attentional bias in the elderly with the use of a visual statistical learning paradigm. Triplets consisting of pictures that appeared in the same consecutive order were simultaneously presented to the left (LVF) and right visual-field (RVF) across a center fixation point. In the learning phase, both younger (N = 40) and older (N = 40) adults were instructed to attend to either the LVF or RVF and to perform a 1-back task on the visual-field. The test phase was conducted immediately after the learning phase. Implicit memory for the sequential order of the triplets was tested using a speed detection task. Younger adults showed visual statistical learning for both the attended and unattended triplets. The elderly who directed attention towards the LVF showed visual statistical learning not for the attended triplets presented in the LVF, but rather the unattended triplets presented in the RVF. These findings suggest that the elderly show a stronger visuospatial attention bias to the right visual-field, with a decline in executive function compared to younger adults. PMID- 29620339 TI - Heisenberg's Uncertainty Principle, Intense Electric Field, Heavily Doped Optoelectronic Quantized Structures and the Electron Statistics. AB - In this paper we show that the direct application of Heisenberg's uncertainty principle (HUP) leads to the expression of the electron statistics (ES) under extreme degeneracy and intense electric field in bulk, quantum wells, nano wires and in the presence of quantizing magnetic field in III-V, ternary and quaternary materials on the basis of a newly formulated electron dispersion laws without using the usual density-of-states (DOS) function approach for finding out the ES under different physical lattice matched to InP conditions. It appears taking HD InSb, InAs, Hg1-xCdxTe, In1-xGaxAsyP1-y as examples that the Fermi energy increases with increasing electron concentration and the surface electric field in all the cases. Besides the Fermi energy decreases with increasing alloy composition and film thickness in different manners which depend totally on the values of the energy band constants. The Fermi energy oscillates with inverse quantizing magnetic field due to SdH effect. We have also shown that under certain limiting conditions all our generalized results lead to the well known formulas as given in the literature. PMID- 29620340 TI - RED BLOOD CELL DUFFY ANTIGEN RECEPTOR FOR CHEMOKINES AND SUSCEPTIBILITY TO PLASMODIUM VIVAX INFECTION IN THAIS. AB - Plasmodium vivax is the most prevalent malaria infection in Thailand.P. vivax uses Duffy Antigen Receptor for Chemokines (DARC) or Duffy antigen(Fy) as a receptor for entry into reticulocytes. Polymorphism of DARC exon 2 gene(FYA/FYB) in 40 P. vivax-infected subjects were investigated using nested PCR ofblood samples spotted on filter paper collected during August 2013 to November2013 from various malaria clinics in Thailand. Distribution of DARC genotypeswas FYA 62.5%, FYB 20% and FYAB 17.5%, consistent with that of Hardy-Weinbergequation. Mutation G17A was found in both FYA and FYB alleles, resulting inGyl48 and Asp48 of Fya and Fyb antigen, respectively. Mean parasitemia amongthe three groups is not statistically different. To the best of our knowledge, this isthe first such study in Thailand. PMID- 29620341 TI - Nanocomposites of Recycled Polycarbonate/Nano-Zinc Oxide (rPC/nZno): Effect of Nanofiller and Gamma-Radiation on the Properties and as Barrier Against Ultraviolet Light. AB - In order to promote barrier against ultraviolet radiation and increase of mechanical characteristics performance, nanocomposites of recycled polycarbonate/nano-zinc oxide (rPC/nZnO) with different nZnO content were prepared and submitted to doses of gamma-radiation (10-50 kGy). The nanocomposites were also exposed to Xenon light source in a weather chamber viewing to evaluate the action of nZnO against ultraviolet light. The rPC/nZnO nanocomposites were characterized by thermogravimetry (TGA), differential scanning calorimetry (DSC), wide angle X-ray diffraction (WAXD) and infrared spectrometry (FT-IR). There was a progressive reduction of the glass transition temperature (T g) and degradation temperatures, T onset and T max, as function of gamma-radiation dose and nano-zinc oxide content. The lowering of the thermal properties was attributed to the alcoholysis reaction between hydroxyl groups onto the nZnO surface and carbonate linkages of the rPC during the molten state. WAXD revealed a possible chains arrangement (induction of crystallinity) and/or segregation of chains size (scission of rPC chains generating oligomers) associated to the alcoholysis reaction. The action of gamma-radiation as crosslinking agent was not effective. The degree of swelling is zero on account of the stabilization of rPC radicals by oxygen during gamma-radiation exposure. Before exposure to UV light the carbonyl index (CI) show trend to decrease corroborating the scission of the rPC carbonate bonds. After 100 hours of exposure a recovering of the CI was noticed. The result was associated to the free radicals recombination and esterification reactions. In some extent the combined action of nZnO and gamma-radiation as barrier to UV light was successful. PMID- 29620342 TI - EVALUATION OF A COMMERCIAL STOOL CONCENTRATOR KIT COMPARED TO DIRECT SMEAR AND FORMALIN-ETHYL ACETATE CONCENTRATION METHODS FOR DIAGNOSIS OF PARASITIC INFECTION WITH SPECIAL REFERENCE TO OPISTHORCHIS VIVERRINI SENSU LATO IN THAILAND. AB - Opisthorchiasis and cholangiocarcinoma (CCA) are major public healthproblems in Thailand and countries in the lower Mekong Subregion. Eliminationof opisthorchiasis will be an important step toward the prevention, control andreduction of CCA. In order to achieve this goal, a sensitive and robust diagnosticmethod is required to identify people with current Opisthorchis viverrini sensu latoinfection as the parasite is a group 1 carcinogen believed to be an etiology of CCA.To date, sensitive parasitological methods, such as formalin-ethyl acetate concentrationtechnique (FECT) is preferred, but it is not practical in a remote primarycare setting. In this study, we evaluated the diagnostic accuracy of a commercialstool concentrator kit with that of a direct simple smear method and a modifiedFECT. In diagnosing parasite infection and opisthorchiasis, the commercial kithad greater sensitivity (43.8-58.5%) than direct smear method (12.5-31.7%), butwas less sensitive than FECT (73.2-75%). In a separate sample population, similarresults were obtained when comparing the diagnostic accuracy of the commercialkit and FECT. However, the commercial kit was more effective in a field settingthan FECT, and had better accuracy than direct smear method, which suggeststhat the kit could have potential utility in epidemiological studies and controlprograms of opisthorchiasis, as well as other parasitic infections. The design ofthe self-contained one-tube kit plus its long storage time after sample preparationprovides a considerable advantage over other methods, such as direct or Katothick smear method, under similar field conditions. PMID- 29620343 TI - PREVALENCE AND ASSOCIATED RISK FACTORS OF INTESTINAL PARASITES IN HUMANS AND DOMESTIC ANIMALS ACROSS BORDERS OFTHAILAND AND LAO PDR: FOCUS ON HOOKWORM AND THREADWORM. AB - Hookworm and threadworm infections are major public health problemsin developing countries. A cross sectional study comprising 843 participants (346males and 497 females) was conducted in three populations: i) Thai residents (TR)of Ubon Ratchathani Province, Thailand; ii) Laotian immigrant workers (LI) in thesame province; and iii) Laotian residents (LR) in Champasak Province, Lao PDR.Participants were interviewed based on a structured questionnaire regarding theirhealth status. Stool samples from participants and 300 samples from domesticanimals (277 dogs and 23 cats) living in the participants households were collectedand examined for parasitic infection using a formalin-ether concentration anda Harada-Mori filter paper culture techniques. Approximately one third of TRand LI populations and domestic animals in Thailand were positive for parasiticinfections, while almost half of LR population and domestic animals were positive.We confirmed by PCR and DNA sequencing a case of Ancylostoma ceylanicuminfection in a Thai man. We also observed infections of other parasites, such asTaenia spp and Opisthorchis viverrini. Multivariate analysis indicated that risk factorsfor hookworm infection were population group and walking barefoot. Factorsassociated with threadworm infection were population group, adult male, lackof previous antiparasitic treatment and of knowledge of parasitic infection, andfailure to wash hands after contact with domestic animals. Our results highlightthe high prevalence of both hookworm and threadworm infections especiallyamong LI population and domestic animals in both countries. Our findings emphasizethe need for public health intervention to control the spread of parasiticinfections in Thailand and Lao PDR. PMID- 29620344 TI - Conoscopy as a Failure Analysis Method for Single Crystals. AB - Conoscopy is widely used to evaluate single crystals used as substrates on which epitaxial layers are grown in the LED industry, where the quality of the single crystal affects the reliability of the final product, the LED chip, and the package. However, the application of this method is currently restricted to characterizing birefringence. We performed conoscopy measurements on single crystals with failure modes (e.g., birefringence, lineages, dislocations, polycrystallinity, and amorphousness) and examined whether it was possible to inspect such failures using conoscopy. Sapphire (alpha-Al2O3) and silicon carbide (6H-SiC) single crystals containing failures were investigated. X-ray diffraction and transmission electron microscopy analyses were also performed; their results were compared with the conoscopy results. Conoscopy was shown to inspect birefringence as well as other failure modes. Comparison of the conoscopic patterns obtained via simulation and experiment shows that quantitative evaluation of the failure level is possible. These results show that conoscopy can be used to quickly and easily investigate various failure mechanisms in single crystals. PMID- 29620345 TI - INVESTIGATION OF MOSQUITOES WITH EMPHASIS ON AEDES (FINLAYA) POICILIUS, PUTATIVE VECTOROF BANCROFTIAN FILARIASIS ON PANAY ISLAND, THE PHILIPPINES. AB - Entomological investigations were conducted in four remaining lymphaticfilariasis endemic provinces of Panay Island, The Philippines to determinemosquito species present in these areas and to identify host preference and bitingactivity of Aedes (Finlaya) poicilius Theobald, primary vector of nocturnal periodicWuchereria bancrofti in The Philippines. Sampling techniques targeted nocturnallyactive mosquito species using a carabao-baited trap (CBT) and human landingcollection (HLC), the latter taking place from 06:00 to 12:00 pm. A total of 25,536mosquitoes comprising 42 species and 7 genera were collected from CBT, whilstHLC acquired 6,486 mosquitoes comprising 28 species and 5 genera. Three knownor potential vectors of human filarial were collected, namely, Aedes poicilius, Culexquinquefasciatus and Mansonia uniformis. The peak landing (biting) activity for Ae.poicilius was between 09:00 and 11:00 pm. Comparisons between CBT and HLCyields showed this species to be more zoophilic. Based on observed mosquitobehavior and interviews with residents, vector-host contact was promoted by thelocal practice of staying overnight in makeshift shelters in high risk areas withoutadequate protection against mosquito bites. Results of this survey will augmentinformation for integrating vector control and mass drug administration into anisland-wide lymphatic filariasis elimination program. PMID- 29620347 TI - Electrically Triggered Small Molecule Release from Poly( N-Isopropylacrylamide- co-Acrylic Acid) Microgel-Modified Electrodes. AB - A monolithic layer of poly( N-isopropylacrylamide- co-acrylic acid) microgels was deposited on an Au electrode and used for electrically triggered release of the small molecule crystal violet (CV), which was used as a model drug. CV was loaded into the surface-bound microgels by exposing them to a CV solution at pH 6.5, where the microgels are negatively charged and the CV is positively charged. The electrostatic attraction holds the CV inside of the microgels, while a decrease of the solution pH can neutralize the microgels and allow for CV release. In this investigation, we show that when CV-loaded microgels are deposited on the anode in an electrochemical cell and an appropriate voltage applied, there is a decrease in the solution pH near the anode surface that allows for CV release. We also show that removing the applied potential allows the solution pH near the anode to return to pH 6.5, which halts the release. We show that the release rate from the microgel-modified anodes could be controlled by the magnitude of the applied voltage and by pulsing the applied voltage or applying a continuous voltage. Furthermore, we showed that the microgel-modified anodes can be reloaded with CV and used to release CV to a system many times. Such devices could be used as implantable drug delivery devices, as well as for industrial applications, where small molecules need to be released to systems in response to their chemical status. PMID- 29620346 TI - PREVALENCE AND RISK FACTORS OF HEPATITIS B AND C VIRUS INFECTIONS AMONG HEMODIALYSISPATIENTS FROM PRIVATE HEMODIALYSIS UNITS IN SURABAYA, INDONESIA. AB - The aims of the present study were to profile seroprevalence of hepatitisB virus (HBV) and hepatitis C virus (HCV) infections, and possible risk factorsamong hemodialysis (HD) patients in private hemodialysis units (HDU) in Surabaya,Indonesia. Sera were obtained from 180 HD patients in 4 different privateHDUs and tested for hepatitis B surface antigen (HBsAg) and antibody to HCV(anti-HCV). Patients without HBsAg and anti-HCV at first sampling were followedserologically every 3 months for 9 months, while those with HBsAg or anti HCVpositive sera were subjected continually to PCR to detect HBV DNA and HCVRNA. The prevalence of hepatitis infections varied widely between the HDUs,from 0% to 8.1% of patients positive for HBsAg and 0% to 60.6% of those positivefor anti HCV, respectively. These values were markedly higher than those amongthe general population, but not as high as in governmental HDUs in Indonesia.New incidence of HBV was not detected in any HDU, whereas that of HCV wasfound in two HDUs, HCV-1b in one HDU and HCV-1a in the other. Inappropriatepractices were observed, such as shortage of medical staff and malfunctions ininfection-control committees. Prevalence of HBV and HCV infection among HDpatients in private HDUs were high and varied among the HDUs. Isolation ofboth HBV- and HCV-infected patients and staff education should help to reducethe prevalence of hepatitis infections in HDUs. PMID- 29620348 TI - Synthesis of Ultrathin Graphdiyne Film Using a Surface Template. AB - Graphdiyne is predicted to have a natural band gap and simultaneously possesses superior carrier mobility, which makes it potential for electronic devices. Synthesis of ultrathin graphdiyne film is highly demanded. In this work, we proposed an approach for synthesis of ultrathin graphdiyne film using graphene as a surface template, which can induce confined reaction on substrate. With all carbon, conjugated, atomically flat structure, graphene has a strong interaction with the graphdiyne system, resulting the formation of continuous flat ultrathin graphdiyne film with thickness less than 3 nm. Raman spectra, grazing incidence X ray diffraction, and transmission electron microscopy characterization all confirmed the features of graphdiyne. Furthermore, this strategy was also extended to the hexagonal boron nitride (hBN) surface with resembling structure, serving as a perfect dielectric layer. Field-effect transistor devices based on graphdiyne film grown on hBN were fabricated directly, and electrical transport measurements demonstrate the good conductivity with p-type characteristics of the as-obtained graphdiyne film. PMID- 29620350 TI - Toward the Detection of Poisonous Chemicals and Warfare Agents by Functional Mn3O4 Nanosystems. AB - The detection of poisonous chemicals and warfare agents, such as acetonitrile and dimethyl methylphosphonate, is of utmost importance for environmental/health protection and public security. In this regard, supported Mn3O4 nanosystems were fabricated by vapor deposition on Al2O3 substrates, and their structure/morphology were characterized as a function of the used growth atmosphere (dry vs. wet O2). Thanks to the high surface and peculiar nano organization, the target systems displayed attractive functional properties, unprecedented for similar p-type systems, in the detection of the above chemical species. Their good responses, selectivity, and sensitivity pave the way to the fabrication of low-cost and secure sensors for different harmful analytes. PMID- 29620349 TI - Structure-Based Chemical Design of Abscisic Acid Antagonists That Block PYL-PP2C Receptor Interactions. AB - In Arabidopsis, signaling of the stress hormone abscisic acid (ABA) is mediated by PYR/PYL/RCAR receptors (PYLs), which bind to and inhibit group-A protein phosphatases 2C (PP2Cs), the negative regulators of ABA. X-ray structures of several PYL-ABA and PYL-ABA-PP2C complexes have revealed that a conserved tryptophan in PP2Cs is inserted into a small tunnel adjacent to the C4' of ABA in the PYL-ABA complex and plays a crucial role in the formation and stabilization of the PYL-ABA-PP2C complex. Here, 4'-modified ABA analogues were designed to prevent the insertion of the tryptophan into the tunnel adjacent to the C4' of ABA in these complexes. These analogues were predicted to block PYL-PP2C receptor interactions and thus block ABA signaling. To test this, 4'- O-phenylpropynyl ABA analogues were synthesized as novel PYL antagonists (PANs). Structural, thermodynamic, biochemical, and physiological studies demonstrated that PANs completely abolished ABA-induced PYL-PP2C interactions in vitro and suppressed stress-induced ABA responses in vivo more strongly than did 3'-hexylsulfanyl-ABA (AS6), a PYL antagonist we developed previously. The PANs and AS6 antagonized the effects of ABA to different degrees in different plants, suggesting that these PANs can function as chemical scalpels to dissect the complicated regulatory mechanism of ABA signaling in plants. PMID- 29620351 TI - One-Dimensional Hetero-Nanostructures for Rechargeable Batteries. AB - Rechargeable batteries are regarded as one of the most practical electrochemical energy storage devices that are able to convert and store the electrical energy generated from renewable resources, and they function as the key power sources for electric vehicles and portable electronics. The ultimate goals for electrochemical energy storage devices are high power and energy density, long lifetime, and high safety. To achieve the above goals, researchers have tried to apply various morphologies of nanomaterials as the electrodes to enhance the electrochemical performance. Among them, one-dimensional (1D) materials show unique superiorities, such as cross-linked structures for external stress buffering and large draw ratios for internal stress dispersion. However, a homogeneous single-component electrode material can hardly have the characteristics of high electronic/ionic conductivity and high stability in the electrochemical environment simultaneously. Therefore, designing well-defined functional 1D hetero-nanostructures that combine the advantages and overcome the limitations of different electrochemically active materials is of great significance. This Account summarizes fabrication strategies for 1D hetero nanostructures, including nucleation and growth, deposition, and melt-casting and electrospinning. Besides, the chemical principles for each strategy are discussed. The nucleation and growth strategy is suitable for growing and constructing 1D hetero-nanostructures of partial transition metal compounds, and the experimental conditions for this strategy are relatively accessible. Deposition is a reliable strategy to synthesize 1D hetero-nanostructures by decorating functional layers on 1D substrate materials, on the condition that the preobtained substrate materials must be stable in the following deposition process. The melt-casting strategy, in which 1D hetero-nanostructures are synthesizes via a melting and molding process, is also widely used. Additionally, the main functions of 1D hetero-nanostructures are summarized into four aspects and reviewed in detail. Appropriate surface modification can effectively restrain the structure deterioration and the regeneration of the solid-electrolyte interphase layer caused by the volume change. A porous or semihollow external conducting material coating provides advanced electron/ion bicontinuous transmission. Suitable atomic heterogeneity in the crystal structure is beneficial to the expansion and stabilization of the ion diffusion channels. Multiphase-assisted structural design is also an accessible way for the sulfur electrode material restriction. Moreover, some outlooks about the further industrial production, more effective and cheaper fabrication strategies, and new heterostructures with smaller-scale composition are given in the last part. By providing an overview of fabrication methods and performance-enhancing mechanisms of 1D hetero-nanostructured electrode materials, we hope to pave a new way to facile and efficient construction of 1D hetero-nanostructures with practical utility. PMID- 29620352 TI - Correction to Simple Hydrogen Plasma Doping Process of Amorphous Indium Gallium Zinc Oxide-Based Phototransistors for Visible Light Detection. PMID- 29620353 TI - High-Field Liquid-State Dynamic Nuclear Polarization in Microliter Samples. AB - Nuclear hyperpolarization in the liquid state by dynamic nuclear polarization (DNP) has been of great interest because of its potential use in NMR spectroscopy of small samples of biological and chemical compounds in aqueous media. Liquid state DNP generally requires microwave resonators in order to generate an alternating magnetic field strong enough to saturate electron spins in the solution. As a consequence, the sample size is limited to dimensions of the order of the wavelength, and this restricts the sample volume to less than 100 nL for DNP at 9 T (~260 GHz). We show here a new approach that overcomes this sample size limitation. Large saturation of electron spins was obtained with a high power (~150 W) gyrotron without microwave resonators. Since high power microwaves can cause serious dielectric heating in polar solutions, we designed a planar probe which effectively alleviates dielectric heating. A thin liquid sample of 100 MUm of thickness is placed on a block of high thermal conductivity aluminum nitride, with a gold coating that serves both as a ground plane and as a heat sink. A meander or a coil were used for NMR. We performed 1H DNP at 9.2 T (~260 GHz) and at room temperature with 10 MUL of water, a volume that is more than 100* larger than reported so far. The 1H NMR signal is enhanced by a factor of about -10 with 70 W of microwave power. We also demonstrated the liquid state of 31P DNP in fluorobenzene containing triphenylphosphine and obtained an enhancement of ~200. PMID- 29620354 TI - Highly Efficient and Selective Photooxidation of Sulfur Mustard Simulant by a Triazolobenzothiadiazole-Moiety-Functionalized Metal-Organic Framework in Air. AB - A photoactive triazolobenzothiadiazole (TBTD)-conjugated terphenyldicarboxylate (TPDC) linker was introduced into a porous and robust UiO-68 isoreticular zirconium metal-organic framework (denoted as UiO-68-TBTD) by the de novo synthetic approach of mixed TPDC struts. Under blue-light-emitting-diode irradiation, UiO-68-TBTD can serve as a heterogeneous photocatalyst for the highly efficient and selective oxidation of a sulfur mustard simulant (2 chloroethyl ethyl sulfide) to the corresponding much less toxic sulfoxide product, with a half-life of only 3 min in the open air atmosphere. PMID- 29620355 TI - Controlled Synthesis of CuS/TiO2 Heterostructured Nanocomposites for Enhanced Photocatalytic Hydrogen Generation through Water Splitting. AB - Photocatalytic hydrogen (H2) generation through water splitting has attracted substantial attention as a clean and renewable energy generation process that has enormous potential in converting solar-to-chemical energy using suitable photocatalysts. The major bottleneck in the development of semiconductor-based photocatalysts lies in poor light absorption and fast recombination of photogenerated electron-hole pairs. Herein we report the synthesis of CuS/TiO2 heterostructured nanocomposites with varied TiO2 contents via simple hydrothermal and solution-based process. The morphology, crystal structure, composition, and optical properties of the as-synthesized CuS/TiO2 hybrids are evaluated in detail. Controlling the CuS/TiO2 ratio to an optimum value leads to the highest photocatalytic H2 production rate of 1262 MUmol h-1 g-1, which is 9.7 and 9.3 times higher than that of pristine TiO2 nanospindles and CuS nanoflakes under irradiation, respectively. The enhancement in the H2 evolution rate is attributed to increased light absorption and efficient charge separation with an optimum CuS coverage on TiO2. The photoluminescence and photoelectrochemical measurements further confirm the efficient separation of charge carriers in the CuS/TiO2 hybrid. The mechanism and synergistic role of CuS and TiO2 semiconductors for enhanced photoactivity is further delineated. PMID- 29620356 TI - Benzoquinone-Bridged Heterocyclic Zwitterions as Building Blocks for Molecular Semiconductors and Metals. AB - In pursuit of closed-shell building blocks for single-component organic semiconductors and metals, we have prepared benzoquino-bis-1,2,3-thiaselenazole QS, a heterocyclic selenium-based zwitterion with a small gap (lambdamax = 729 nm) between its highest occupied and lowest unoccupied molecular orbitals. In the solid state, QS exists in two crystalline phases and one nanocrystalline phase. The structures of the crystalline phases (space groups R3 c and P21/ c) have been determined by high-resolution powder X-ray diffraction methods at ambient and elevated pressures (0-15 GPa), and their crystal packing patterns have been compared with that of the related all-sulfur zwitterion benzoquino-bis-1,2,3 dithiazole QT (space group Cmc21). Structural differences between the S- and Se based materials are interpreted in terms of local intermolecular S/Se...N'/O' secondary bonding interactions, the strength of which varies with the nature of the chalcogen (S vs Se). While the perfectly two-dimensional "brick-wall" packing pattern associated with the Cmc21 phase of QT is not found for QS, all three phases of QS are nonetheless small band gap semiconductors, with sigmaRT ranging from 10-5 S cm-1 for the P21/ c phase to 10-3 S cm-1 for the R3 c phase. The bandwidths of the valence and conduction bands increase with applied pressure, leading to an increase in conductivity and a decrease in thermal activation energy Eact. For the R3 c phase, band gap closure to yield an organic molecular metal with a sigmaRT of ~102 S cm-1 occurs at 6 GPa. Band gaps estimated from density functional theory band structure calculations on the ambient- and high pressure crystal structures of QT and QS correlate well with those obtained experimentally. PMID- 29620357 TI - Coupling d6 Ir(III) and d8 Pt(II) Chromophores. AB - Two classes of widely studied luminescent metal complexes are octahedral d6 (i.e., Ir3+) and square planar d8 (i.e., Pt2+) polypyridyl complexes, which have distinctly different photophysics and photoreactivity. In this study we report a series of d6-d8 IrIII-PtII hybrid complexes arising from coordination of metalloligands IrL2(benzene-1-thioether-2-thiolate) or Ir(L)2(benzene-1,2 dithiolate) anion [L = 2-phenylpyridine (ppy), 2-(2,4-difluorophenyl)pyridine (dfppy), or 1-phenylisoquinoline (piq)] to Pt(terpy)2+ (terpy = 2,2':6',2" terpyridine). X-ray crystal structures of the Ir-Pt complexes show the IrL2 and Pt(terpy) chromophores are cofacially oriented with interplanar distances of 3.268-3.442 A. Density functional theory (DFT) calculations show that the highest occupied molecular orbital and the lowest unoccupied molecular orbital are localized in the IrL2 and the Pt(terpy), respectively. All the complexes display a low-energy absorption band (lambdamax = 460-534 nm, epsilonmax = (0.75-2.13) * 103 M-1 cm-1), which is attributed to interchromophore-charge-transfer (ICCT) transition, according to time-dependent DFT calculations. The 3ICCT excited state is emissive, giving long-lived phosphorescence that reaches as low as near infrared (lambdamax = 668-710 nm, tau = 0.17-0.79 MUs). PMID- 29620358 TI - Signal Smoothing with PLS Regression. AB - Smoothing of instrumental signals is an important prerequisite in data processing. Various smoothing methods were suggested through the last decades each having their own benefits and drawbacks. Most of the filtering methods are based on averaging in a certain window (e.g., Savitzky-Golay) or on frequency domain representation (e.g., Fourier filtering). The present study introduces novel approach to signal filtering based on signal variance through PLS (projections on latent structures) regression. The influence of filtering parameters on the smoothed spectrum is explained and real world examples are shown. PMID- 29620359 TI - Evaluation of Ligands Effect on the Photophysical Properties of Copper Iodide Clusters. AB - Luminescent materials based on copper complexes are currently receiving increasing attention because of their rich photophysical properties, opening a wide field of applications. The copper iodide clusters formulated [Cu4I4L4] (L = ligand), are particularly relevant for the development of multifunctional materials based on their luminescence stimuli-responsive properties. In this context, controlling and modulating their photophysical properties is crucial and this can only be achieved by thorough understanding of the origin of the optical properties. We thus report here, the comparative study of a series of cubane copper iodide clusters coordinated by different phosphine ligands, with the goal of analyzing the effect of the ligands nature on the photoluminescence properties. The synthesis, structural, and photophysical characterizations along with theoretical investigations of copper iodide clusters with ligands presenting different electronic properties, are described. A method to simplify the analysis of the 31P solid-state NMR spectra is also reported. While clusters with electron donating groups present classical luminescence properties, the cluster bearing strong electron-withdrawing substituents exhibits original behavior demonstrating a clear influence of the ligands properties. In particular, the electron withdrawing character induces a decrease in energy of the unoccupied molecular orbitals, that consequently impacts the emission properties. The modification of the luminescence thermochromic properties of the clusters are supported by density functional theory (DFT) calculations. This study demonstrates that the control of the luminescence properties of these compounds can be achieved through modification of the coordinated ligands, nevertheless the role of the crystal packing should not be underestimated. PMID- 29620360 TI - Correction to: Eight Kinetically Stable but Thermodynamically Activated Molecules that Power Cell Metabolism. PMID- 29620361 TI - Stepwise ortho Chlorination of Carboxyl Groups for Promoting Structure Variance of Heterometallic Uranyl-Silver Coordination Polymers of Isonicotinate. AB - We report the syntheses and characterization of four new heterometallic uranyl silver compounds from isonicotinic acid derivatives with a stepwise ortho chlorination of carboxyl group, that is, isonicotinic acid (H-PCA), 3 chloroisonicotinic acid (H-3-MCPCA), and 3,5-dichloroisonicotinic acid (H-3,5 DCPCA). Compound 1, (UO2)Ag4(3,5-DCPCA)6(3,5-DCPy)2, from H-3,5-DCPCA displays a heterometallic three-dimensional (3D) framework through the connection of 3,5 DCPCA and in situ-formed 3,5-dichloropyridine (3,5-DCPy) with the aid of multiple argentophilic interactions. Compounds 2 ((UO2)Ag(3-MCPCA)3) and 3 ((UO2)Ag2(3 MCPCA)4), which differ from each other in coordination modes of uranyl center, are both heterometallic 3D reticular frameworks from 3-MCPCA based on highly coordinated silver nodes. All these heterometallic uranyl-silver compounds are different from the hydrothermal products from chlorine-free H-PCA ligand in the presence of uranyl and silver ions, U-Ag-PCA ((UO2Ag(OH)(PCA)2)) and 4 ((UO2)Ag2(OH)(H2O)2(PCA)4) due to highly coordinated silver ions found in 1-3, among which carboxyl groups of isonicotinate expected to coordinate with uranyl are the biggest contributors. Detailed structural analysis reveals that the inclination of the carboxyl group of isonicotinate driven by large steric hindrance from bulky ortho chlorine atoms at its ortho positions enables it to participate in the coordination sphere of silver ion and promote the formation and structure variance of 3D heterometallic uranyl-silver frameworks. PMID- 29620362 TI - Correction to "Self-Consistent Charge Density-Functional Tight-Binding Parameterization for Pt-Ru Alloys". PMID- 29620363 TI - Correction to "Atropisomer Control in Macrocyclic Factor VIIa Inhibitors". PMID- 29620364 TI - (Nd/Pr)2NiO4+delta: Reaction Intermediates and Redox Behavior Explored by in Situ Neutron Powder Diffraction during Electrochemical Oxygen Intercalation. AB - Oxygen intercalation/deintercalation in Pr2NiO4+delta and Nd2NiO4+delta was followed by in situ neutron powder diffraction during electrochemical oxidation/reduction, in a dedicated reaction cell at room temperature. For both systems three phases, all showing the same line width, were identified. The starting phases Pr2NiO4.23 and Nd2NiO4.24, considered with an average orthorhombic Fmmm symmetry, although both show a slight monoclinic distortion, get reduced in a two-phase reaction step to tetragonal intermediate phases with 0.07 <= delta <= 0.10 and P42/ ncm space group, which on further reduction transform, again in a two-phase reaction step, toward the respective stoichiometric (Pr/Nd)2NiO4.0 phases, with Bmab space group. Electrochemical oxidation does, however, not proceed fully reversibly for both cases: while the reoxidation of Nd2NiO4+delta is limited to the tetragonal intermediate phase with delta = 0.10, the homologous Pr2NiO4+delta can be reoxidized up to delta = 0.17, showing orthorhombic symmetry. For the intermediate tetragonal phase, we were able to establish for Pr2NiO4.09 a complex anharmonic displacement behavior of the apical oxygen atoms, as analyzed by single-crystal neutron diffraction and maximum entropy analysis, in agreement with a low- T diffusion pathway for oxygen ions, activated by lattice dynamics. PMID- 29620365 TI - Copper-Catalyzed Multicomponent Reaction of DABCO.(SO2)2, Alcohols, and Aryl Diazoniums for the Synthesis of Sulfonic Esters. AB - A Cu-catalyzed multicomponent cascade reaction of DABCO.(SO2)2 (DABSO), alcohol, and aryl diazonium tetrafluoroborate was developed which afforded sulfonic esters in moderate to good chemical yields. In this reaction, the SO2 surrogate DABSO was used for the first time in the synthesis of sulfonic aliphatic esters. This multicomponent reaction was carried out under mild conditions and tolerated a wide range of substrates, which provides a new and efficient strategy for the synthesis of sulfonic esters. PMID- 29620366 TI - Stabilization of Face-Centered Cubic High-Pressure Phase of REH3 (RE = Y, Gd, Dy) at Ambient Pressure by Alkali or Alkaline-Earth Substitution. AB - Heavy rare-earth trihydrides such as GdH3, DyH3, and yttrium trihydide (YH3) usually show a hexagonal crystal structure under ambient pressure. This structure is known to transform to a face-centered cubic (FCC) one at higher pressures (at the order of GPa), and the FCC one returns to the hexagonal structure when the applied pressure is released. In this study, we investigated the structure of alkaline or alkaline-earth (A)-substituted REH3 (RE = Y, Gd, Dy; A = Li, K, or Mg) using X-ray diffraction, and measured the phase transition pressure. We found that this FCC high-pressure phase can be stabilized by 10-33 mol % A substitution for RE in the REH3. The mechanism of phase stabilization is simply explained by the ionic radius ratio between the cation and anion ( rcat/ rani), as well as the stabilities of other ionic crystals such as perovskite materials. For all considered REH3 samples, the FCC phase becomes stable when rcat/ rani > 0.856, such as in the case of 10 mol % Li-substituted YH3. PMID- 29620367 TI - Structural, Mechanical, Imaging and in Vitro Evaluation of the Combined Effect of Gd3+ and Dy3+ in the ZrO2-SiO2 Binary System. AB - Mechanical strength and biocompatibility are considered the main prerequisites for materials in total hip replacement or joint prosthesis. Noninvasive surgical procedures are necessary to monitor the performance of a medical device in vivo after implantation. To this aim, simultaneous Gd3+ and Dy3+ additions to the ZrO2 SiO2 binary system were investigated. The results demonstrate the effective role of Gd3+ and Dy3+ to maintain the structural and mechanical stability of cubic zirconia ( c-ZrO2) up to 1400 degrees C, through their occupancy of ZrO2 lattice sites. A gradual tetragonal to cubic zirconia ( t-ZrO2 -> c-ZrO2) phase transition is also observed that is dependent on the Gd3+ and Dy3+ content in the ZrO2-SiO2. The crystallization of either ZrSiO4 or SiO2 at elevated temperatures is delayed by the enhanced thermal energy consumed by the excess inclusion of Gd3+ and Dy3+ at c-ZrO2 lattice. The addition of Gd3+ and Dy3+ leads to an increase in the density, elastic modulus, hardness, and toughness above that of unmodified ZrO2-SiO2. The multimodal imaging contrast enhancement of the Gd3+ and Dy3+ combinations were revealed through magnetic resonance imaging and computed tomography contrast imaging tests. Biocompatibility of the Gd3+ and Dy3+ dual doped ZrO2-SiO2 systems was verified through in vitro biological studies. PMID- 29620368 TI - Reduced Efficiency Roll-Off and Enhanced Stability in Perovskite Light-Emitting Diodes with Multiple Quantum Wells. AB - Mixed-formamidinium (FA) and -cesium (Cs) cations were used to fabricate multiple quantum well (MQW) perovskite light-emitting diodes (PeLEDs). The partial substitution of FA with Cs facilitates the formation of wider quantum wells, which can effectively reduce efficiency roll-off by suppressing Auger recombination. The device has a peak external quantum efficiency (EQE) of 7.8% at a current density of 125 mA cm-2, maintaining an EQE of ~6.6% at a high current density of 500 mA cm-2. Due to the improved stability of mixed-cation structure, we achieve a PeLED device with a lifetime of ~31 h under a constant current density of 10 mA cm-2. PMID- 29620369 TI - Structure-Based Exciton Hamiltonian and Dynamics for the Reconstituted Wild-type CP29 Protein Antenna Complex of the Photosystem II. AB - We provide an analysis of the pigment composition of reconstituted wild type CP29 complexes. The obtained stoichiometry of 9 +/- 0.6 Chls a and 3 +/- 0.6 Chls b per complex, with some possible heterogeneity in the carotenoid binding, is in agreement with 9 Chls a and 3.5 Chls b revealed by the modeling of low temperature optical spectra. We find that ~50% of Chl b614 is lost during the reconstitution/purification procedure, whereas Chls a are almost fully retained. The excitonic structure and the nature of the low-energy (low-E) state(s) are addressed via simulations (using Redfield theory) of 5 K absorption and fluorescence/nonresonant hole-burned (NRHB) spectra obtained at different excitation/burning conditions. We show that, depending on laser excitation frequency, reconstituted complexes display two (independent) low-E states (i.e., the A and B traps) with different NRHB and emission spectra. The red-shifted state A near 682.4 nm is assigned to a minor (~10%) subpopulation (sub. II) that most likely originates from an imperfect local folding occurring during protein reconstitution. Its lowest energy state A (localized on Chl a604) is easily burned with lambdaB = 488.0 nm and has a red-shifted fluorescence origin band near 683.7 nm that is not observed in native (isolated) complexes. Prolonged burning by 488.0 nm light reveals a second low-E trap at 680.2 nm (state B) with a fluorescence origin band at ~681 nm, which is also observed when using a direct low-fluence excitation near 650 nm. The latter state is mostly delocalized over the a611, a612, a615 Chl trimer and corresponds to the lowest energy state of the major (~90%) subpopulation (sub. I) that exhibits a lower hole-burning quantum yield. Thus, we suggest that major sub. I correspond to the native folding of CP29, whereas the red shift of the Chl a604 site energy observed in the minor sub. II occurs only in reconstituted complexes. PMID- 29620370 TI - Fourier Transform Infrared Analysis of the S-State Cycle of Water Oxidation in the Microcrystals of Photosystem II. AB - Photosynthetic water oxidation is performed in photosystem II (PSII) through a light-driven cycle of intermediates called S states (S0-S4) at the water oxidizing center. Time-resolved serial femtosecond crystallography (SFX) has recently been applied to the microcrystals of PSII to obtain the structural information on these intermediates. However, it remains unanswered whether the reactions efficiently proceed throughout the S-state cycle retaining the native structures of the intermediates in PSII crystals. We investigated the water oxidation reactions in the PSII microcrystals using flash-induced Fourier transform infrared (FTIR) difference spectroscopy. In comparison with the FTIR spectra in solution, it was shown that all of the metastable intermediates in the microcrystals retained their native structures, and the efficiencies of the S state transitions remained relatively high, although those of the S2 -> S3 and S3 -> S0 transitions were slightly lowered possibly due to some restriction of water movement in the crystals. PMID- 29620371 TI - Triflates-Triggered Intermolecular Cyclization of Carbodiimides Leading to 2 Aminoquinazolinone and 2,4-Diaminoquinazoline Derivatives. AB - A triflate-triggered intermolecular cyclization of carbodiimides to provide 2 amino-4-imino-quinazolines, which could be easily transformed to 2 aminoquinazolinones and 2,4-diaminoquinazolines in high yield, has been reported. A variety of functional groups are tolerated in the 2-amino-4-iminoquinazoline scaffolds. PMID- 29620372 TI - A Kinetically Stable Macrocycle Self-Assembled in Water. AB - A macrocycle through a dynamic covalent approach relying on reversible hydrazone formation in acidic aqueous solutions at elevated temperatures is constructed. By decreasing the acidity of the solution and lowering the temperature, the structure becomes kinetically inert. The macrocycle is capable of hosting hydrophobic aromatic guest molecules in water. PMID- 29620373 TI - Contact Line Instability Caused by Air Rim Formation under Nonsplashing Droplets. AB - Drop impact is fundamental to various natural and industrial processes such as rain-induced soil erosion and spray-coating technologies. The recent discovery of the role of air entrainment between the droplet and the impacting surface has produced numerous works, uncovering the unique physics that correlates the air film dynamics with the drop impact outcomes. In this study, we focus on the post failure air entrainment dynamics for We numbers well below the splash threshold under different ambient pressures and elucidate the interfacial instabilities formed by air entrainment at the wetting front of impacting droplets on perfectly smooth, viscous films of constant thickness. A high-speed total internal reflection microscopy technique accounting for the Fresnel reflection at the drop air interface allows for in situ measurements of an entrained air rim at the wetting front. The presence of an air rim is found to be a prerequisite to the interfacial instability which is formed when the capillary pressure in the vicinity of the contact line can no longer balance the increasing gas pressure near the wetting front. A critical capillary number for the air rim formation is experimentally identified above which the wetting front becomes unstable where this critical capillary number inversely scales with the ambient pressure. The contact line instabilities at relatively low We numbers ( We ~ O(10)) observed in this study provide insight into the conventional understanding of hydrodynamic instabilities under drop impact which usually require We ? 10. PMID- 29620374 TI - Self-Powered All-Inorganic Perovskite Microcrystal Photodetectors with High Detectivity. AB - Organic-inorganic lead halide perovskite microcrystal (MC) films are attractive candidates for fabricating high-performance large-area self-powered photodetectors (PDs) because of their lower trap state density and higher carrier mobility than their polycrystalline counterparts and more suitability of synthesizing large lateral area films than their single-crystal counterparts. Here, we report on the fabrication of self-powered all-inorganic CsPbBr3 perovskite MC PDs with high detectivity, using a modified solution synthesis method. The MCs are up to about 10 MUm in size, and the MC layer is also about 11 MUm in thickness. Under 473 nm laser (100 mW) illumination, the CsPbBr3 MC PDs show responsivity values of up to 0.172 A W-1, detectivity values of up to 4.8 * 1012 Jones, on/off ratios of up to 1.3 * 105, and linear dynamic ranges of up to 113 dB. These performances are significantly better than those of PDs based on polycrystalline perovskite thin films and comparable with those of PDs based on perovskite single crystals. PMID- 29620375 TI - Diastereoselective Copper-Mediated Cross-Couplings between Stereodefined Secondary Alkylcoppers with Bromoalkynes. AB - A copper(I)-mediated cross-coupling of stereodefined secondary alkyllithiums with bromoalkynes provided stereodefined alkynes with high diastereoselectivity (dr up to 98:2). This cross-coupling was extended to various secondary alkyllithiums bearing a remote oxygen functionality, and the alkyne synthesis was also performed with optically enriched alkyl iodides (up to 99% ee) providing, after cross-coupling, alkynes bearing two stereocenters (dr = 93:7; up to 99% ee). PMID- 29620376 TI - Early adolescents' relationships with parents, teachers, and peers and increases in social anxiety symptoms. AB - Previous research on social anxiety has clearly identified interpersonal relationships as important for social anxiety symptoms. Few studies, however, have utilized longitudinal designs and have examined mechanisms that might explain links between negative interpersonal relationships and changes in youths' social anxiety over time. Recent models of social anxiety suggest that negative interpersonal relationships are linked to social anxiety through effects on social skills and behaviors. Using an autoregressive design and a sample of 416 two-parent families (51% female, 91% White), this study examined whether connections among parent-adolescent hostility, teacher support (6th grade), and changes in early adolescent social anxiety symptoms (6th to 8th grades) are mediated by youths' compliance with peers (7th grade). Results indicated that youths who experienced greater parent-adolescent hostility and lower teacher support engaged in greater compliance with peers. In turn, those who engaged in greater compliance with peers experienced increases in social anxiety symptoms. Significant indirect effects were substantiated for only parent-adolescent hostility. Associations were unique to adolescent social anxiety after accounting for depressive symptoms. Associations did not differ for early adolescent girls and boys. The results reveal that nuanced social processes involving social behaviors and relationships with parents and teachers have important and potentially unique implications for changes in early adolescent social anxiety symptoms. (PsycINFO Database Record PMID- 29620378 TI - Predictability and parafoveal preview effects in the developing reader: Evidence from eye movements. AB - The current study utilized the gaze-contingent boundary paradigm (Rayner, 1975) to examine the effects of predictability and parafoveal preview on reading behavior of developing readers. Participants ranging in age from 6- to 12-years old read target words placed in a predictable or neutral context. Target words were manipulated to give either a valid identity preview, a visually similar preview that provided partial letter identity information, or a visually dissimilar preview where all of the letters were substituted. Developing readers fixated for a shorter duration on words in a predictable context. Furthermore, they showed significant preview effects and gained the most preview benefit from a full valid preview of the target word, especially within a predictable context. More skilled readers received more parafoveal information and relied less on context than less skilled readers. Implications for models of eye-movement control are discussed. (PsycINFO Database Record PMID- 29620379 TI - Visual search with varying versus consistent attentional templates: Effects on target template establishment, comparison, and guidance. AB - Attentional templates can be represented in visual working memory (VWM) when the target varies from trial-to-trial and can be represented in long-term memory (LTM) when the target is consistent during trial runs. Given that attentional templates can be represented in either VWM or LTM, are there any differences in how these representations impact visual search when targets are consistent compared with varying? The current study tested the consistent template hypothesis, which predicts faster performance with a consistent target compared with a varying target. Experiment 1 examined whether consistent targets could lead to consistent templates that would improve template establishment, guidance, and/or comparison of the template to search items. Search response time was faster for consistent targets, and consistent targets produced faster comparison processes, but not more efficient guidance. Experiment 2 examined the consistent template restoration hypothesis, which predicts faster template establishment and comparison processes for a previously encountered consistent target. Experiment 2 replicated the consistent template hypothesis and supported the consistent template restoration hypothesis. These studies demonstrate that although attentional guidance is similar with varying and consistent attentional templates, consistent templates improve search performance by speeding template establishment and comparison processes. (PsycINFO Database Record PMID- 29620377 TI - Social integration and age-related decline in lung function. AB - OBJECTIVES: We tested the hypothesis that social integration, measured as number of social roles, is associated with less age-related loss of lung function, an important marker of health and longevity. We also investigated possible psychological factors through which social integration might influence lung health. METHODS: Data were analyzed from the Health and Retirement Study (ages 52 94, n = 4,224). RESULTS AND CONCLUSIONS: Each additional social role reported at baseline was associated with less of a decline in lung function between baseline and the follow-up assessment four years later. The association withstood controls for demographics, weight, and height and was mediated by more positive and less negative affect and lower rates of cigarette smoking and more physical activity. Roles were mostly substitutable, with both high (spouse, parent, friends, relatives) and low (employee, religious service attendee, volunteer, members of other groups) intimacy roles independently contributing to less age-related decline in lung function. (PsycINFO Database Record PMID- 29620380 TI - The cost of believing emotions are uncontrollable: Youths' beliefs about emotion predict emotion regulation and depressive symptoms. AB - As humans, we have a unique capacity to reflect on our experiences, including emotions. Over time, we develop beliefs about the nature of emotions, and these beliefs are consequential, guiding how we respond to emotions and how we feel as a consequence. One fundamental belief concerns the controllability of emotions: Believing emotions are uncontrollable (entity beliefs) should reduce the likelihood of trying to control emotional experiences using effective regulation strategies like reappraisal; this, in turn, could negatively affect core indices of psychological health, including depressive symptoms. This model holds particular relevance during youth, when emotion-related beliefs first develop and stabilize and when maladaptive beliefs could contribute to emerging risk for depression. In the present investigation, a pilot diary study (N = 223, aged 21 60) demonstrated that entity beliefs were associated with using reappraisal less in everyday life, even when controlling for possible confounds (i.e., self efficacy, pessimism, stress exposure, stress reactivity). Then, two studies examined whether entity beliefs and associated impairments in reappraisal may set youths on a maladaptive trajectory: In a cross-sectional study (N = 136, aged 14 18), youths with stronger entity beliefs experienced greater depressive symptoms, and this link was mediated by lower reappraisal. This pattern was replicated and extended in a longitudinal study (N = 227, aged 10-18), wherein youth- and parent reported depressive symptoms were assessed 18 months after assessing beliefs. These results suggest that entity beliefs about emotion constitute a risk factor for depression that acts via reappraisal, adding to the growing literature on emotion beliefs and their consequences for self-regulation and health. (PsycINFO Database Record PMID- 29620381 TI - The cognitive effort expenditure for rewards task (C-EEfRT): A novel measure of willingness to expend cognitive effort. AB - Research in animals suggests that decisions about physical versus cognitive effort have distinct neural bases, but exploration of this question in humans is hampered by lack of parallel measures of physical and cognitive effort for rewards. We developed a novel measure of willingness to exert cognitive effort for rewards, the C-EEfRT, paralleling the validated physical effort expenditure for rewards task (EEfRT). To validate the C-EEfRT we: (a) tested whether EEfRT and C-EEfRT tasks were equivalently difficult; (b) tested whether decisions on the EEfRT and C-EEfRT were equivalently responsive to changes in reward; (c) examined relationships between the C-EEfRT and anhedonia, intelligence, and working memory. Last, we tested the relationship between willingness to exert physical and cognitive effort for rewards in humans. Sixty healthy adults completed the EEfRT, the C-EEfRT, an anhedonia self-report, an intelligence test, and a working memory task. Overall willingness to exert effort was higher on the C-EEfRT than the EEfRT, particularly when reward probability and amount were low. This was despite participants perceiving the cognitive task as more difficult, and having greater difficulty completing it. Differential effects of physical fatigue may have contributed. Anhedonia was not related to effort on either measure. Working memory, but not intelligence, was associated with cognitive effort. There was a moderate relationship between cognitive and physical effort. These findings suggest the importance of measuring cognitive effort as distinct from physical effort in humans. Future studies should consider calibrating task difficulty for each individual, and exploring cognitive effort in clinical populations. (PsycINFO Database Record PMID- 29620382 TI - The roles of age and attention in general emotion regulation, reappraisal, and expressive suppression. AB - Life span emotional development theories propose age differences in emotion regulation tendencies and abilities. Research on age-related positivity has identified age differences in attention to emotional content, which may support emotion regulation in older age. The current research examines the roles of age and attention under various emotion regulation instructions. We measured younger (N = 92) and older (N = 88) adults' fixation to negative emotional content and continuously rated affect during normal viewing and instructions to regulate. Those instructed to regulate first did so generally, then using detached or positive reappraisal and expressive suppression. Older adults (OAs) fixated less than younger adults (YAs) in negative areas regardless of instructions, suggesting broad age-related attentional tendencies. In contrast to some previous research, between-subjects analyses showed no age differences in effects of either form of reappraisal or suppression on affect. Within-subject analyses showed specific regulation instructions predicted less negative affect than general instructions for both age groups. Attention was unrelated to affect for both YAs and OAs across instructions. In sum, this research presents pervasive attentional preferences away from negative material in OAs as well as evidence of successful reappraisal and suppression in both age groups. Looking patterns, however, seemed unrelated to emotion regulation instructions' effects on mood for either age group. Age differences in attentional patterns may therefore not translate into age differences in subsequent emotion regulation success. (PsycINFO Database Record PMID- 29620383 TI - Who are the noisiest neighbors in the hood? Using error analyses to study the acquisition of letter-position processing. AB - This research examines the acquisition of letter-position processing. Study 1 investigated letter-position processing in Grades 1-6 and adult readers, using the occurrence of specific error types as the outcome measure. Between Grades 1 and 2, there was a shift from making more other-word to making more letter position errors. This shift was a function of reading proficiency, not of years of reading instruction. Based on the multiple-route model of reading development (Grainger, Lete, Bertand, Dufau, & Ziegler, 2012), we argue that the fact that children make fewer other-word errors (i.e., mostly letter-identity errors) opens up the opportunity for them to make "the more advanced" letter-position errors. Finally, skilled adult readers still made fewer letter-position errors than typical readers in Grade 6, suggesting that the acquisition process is not finalized by the end of primary school. In Study 2, we directly compared letter position processing with letter-identity processing. Thirty children in Grade 3 and 30 children in Grade 4 read aloud words with and without higher-frequency distractors. Children more often misread a word with a higher-frequency distractor than without such a distractor and this effect was stronger for below average than for above-average readers. Converging with the results of Study 1, we found that a letter-position distractor is more disruptive than a letter identity distractor. These results confirm that the acquisition of letter position processing lags behind of that of letter-identity processing. The results are discussed within the framework of the Lexical Tuning Hypothesis (Castles, Davis, Cavalot, & Forster, 2007), which stresses the importance of feedback between letter (identity and position) coding and (developing) orthographic representations. (PsycINFO Database Record PMID- 29620384 TI - Does counting emotion words on online social networks provide a window into people's subjective experience of emotion? A case study on Facebook. AB - Psychologists have long debated whether it is possible to assess how people subjectively feel without asking them. The recent proliferation of online social networks has recently added a fresh chapter to this discussion, with research now suggesting that it is possible to index people's subjective experience of emotion by simply counting the number of emotion words contained in their online social network posts. Whether the conclusions that emerge from this work are valid, however, rests on a critical assumption: that people's usage of emotion words in their posts accurately reflects how they feel. Although this assumption is widespread in psychological research, here we suggest that there are reasons to challenge it. We corroborate these assertions in 2 ways. First, using data from 4 experience-sampling studies of emotion in young adults, we show that people's reports of how they feel throughout the day neither predict, nor are predicted by, their use of emotion words on Facebook. Second, using simulations we show that although significant relationships emerge between the use of emotion words on Facebook and self-reported affect with increasingly large numbers of observations, the relationship between these variables was in the opposite of the theoretically expected direction 50% of the time (i.e., 3 of 6 models that we performed simulations on). In contrast to counting emotion words, we show that judges' ratings of the emotionality of participants' Facebook posts consistently predicts how people feel across all analyses. These findings shed light on how to draw inferences about emotion using online social network data. (PsycINFO Database Record PMID- 29620385 TI - Identity and the body: Trajectories of body esteem from adolescence to emerging adulthood. AB - Although Erikson (1968) originally conceptualized identity development as a process of becoming at home in one's body, little work has been done linking identity development and research on the body. This study examines how trajectories of the development of body esteem over time are related to young people's sense of identity and psychological functioning in a longitudinal sample from age 10 to 24 (N = 967). Using group-based trajectory modeling, three cubic subgroups were determined for each of the three types of body esteem: appearance, weight, and attribution. These groups demonstrated significant variations in the ways in which body esteem changes over time. These trajectory groups importantly differed in relationship to gender, identity coherence, identity confusion, and psychological functioning. Results are discussed in terms of the need to use a sociocultural perspective to explore the body's relation to identity development and the importance of disaggregating mean-level findings using person-centered approaches to determine high-risk groups. (PsycINFO Database Record PMID- 29620386 TI - A cross-language study of decontextualized vocabulary comprehension in toddlerhood and kindergarten readiness. AB - [Correction Notice: An Erratum for this article was reported in Vol 54(7) of Developmental Psychology (see record 2018-30226-001). In the article, the reference for Legacy, Zesiger, Friend, & Poulin-Dubois (2016) should be Legacy, Zesiger, Friend, & Poulin-Dubois (2018). The correct reference for the article is listed below: Legacy, J., Zesiger, P., Friend, M., & Poulin-Dubois, D. (2018). Vocabulary size and speed of word recognition in very young French-English bilinguals: A longitudinal study. Bilingualism: Language and Cognition, 21, 137 149. https://doi.org/10.1017/S1366728916000833. All versions of this article have been corrected.] Recent studies demonstrate that emerging literacy depends on earlier language achievement. Importantly, most extant work focuses on parent reported production prior to 30 months of age. Of interest is whether and how directly assessed vocabulary comprehension in the 2nd year of life supports vocabulary and kindergarten readiness in the 4th year. We first contrasted orthogonal indices of parent-reported production and directly assessed vocabulary comprehension and found that comprehension was a stronger predictor of child outcomes. We then assessed prediction from vocabulary comprehension controlling for maternal education, preschool attendance, and child sex. In 3 studies early, decontextualized vocabulary comprehension emerged as a significant predictor of 4th year language and kindergarten readiness accounting for unique variance above demographic control variables. Further we found that the effect of early vocabulary on 4th year kindergarten readiness was not mediated by 4th year vocabulary. This pattern of results emerged in English monolingual children (N = 48) and replicated in French monolingual (N = 58) and French-English bilingual children (N = 34). Our findings suggest that early, decontextualized vocabulary may provide a platform for the establishment of a conceptual system that supports both later vocabulary and kindergarten readiness, including the acquisition of a wide range of concepts including print and number. Differences between parent reported and directly assessed vocabulary and the mechanisms by which decontextualized vocabulary may contribute to conceptual development are discussed. (PsycINFO Database Record PMID- 29620387 TI - Young adult gay and bisexual men's stigma experiences and mental health: An 8 year longitudinal study. AB - This study investigated longitudinal trajectories of stigma (i.e., enacted, anticipated, internalized, concealed); stress-sensitive mental health disorder symptoms (i.e., depression, social anxiety); and their associations across 8 annual assessments in a sample of 128 young gay and bisexual U.S. university students. All forms of stigma significantly decreased over time, while depressive symptoms remained stable and social anxiety symptoms significantly increased. Men from higher socioeconomic backgrounds experienced quicker reductions in anticipated stigma, compared to men from lower socioeconomic backgrounds. More self-described feminine men experienced quicker reductions in concealment, compared to more self-described masculine men. Enacted stigma demonstrated contemporaneous associations with depression and social anxiety across 8 years; and anticipated stigma and internalized stigma demonstrated contemporaneous associations with social anxiety across 8 years. Enacted stigma was more strongly associated with depressive symptoms among men who reported greater masculinity compared to those who reported greater femininity. Findings are discussed in terms of common developmental influences across early sexual orientation identity formation, including gay and bisexual young men's resilience to stigma-based stress; the transition from college; and the rapidly changing social climate surrounding sexual minority individuals. Findings suggest the need for future longitudinal examinations of stigma and mental health among sexual minorities that utilize multiple age cohorts to determine the relative contribution of cohort-specific versus common maturational factors influencing the mental health of this population. (PsycINFO Database Record PMID- 29620388 TI - Using linked data to investigate developmental vulnerabilities in children of convicted parents. AB - There is evidence that children of incarcerated parents are at risk of poor developmental and educational outcomes. However, much of this evidence is limited by biased samples, as studies must rely on opt-in recruitment. Administrative data present an opportunity to overcome this challenge, as they capture information on all incarcerated individuals. This study used administrative data on convictions of the parents of 19,071 children aged 5-6 years in Western Australia. Records of parental convictions (starting from 1 year prior to the child's birth) were linked to children's scores on the Australian Early Development Census, which is a teacher-reported measure of children's physical, social, emotional, communicative, and cognitive development. Logistic regression models estimated the odds of children of convicted parents being developmentally vulnerable. Models were adjusted for child, parent, and neighborhood sociodemographic factors. Compared to children in the comparison group, children whose parent had either served a community order or been incarcerated were at risk of poor development across all developmental domains, even after adjusting for sociodemographic factors. Furthermore, children of incarcerated parents had higher odds of developmental vulnerability on multiple domains compared to children of parents who had served community orders only. The results suggest that, although children of convicted parents experience a higher incidence of sociodemographic risk, their parents' criminal activity constitutes an independent risk factor for their development. Intervention to support the early development of children of convicted parents is therefore essential, and should consider the family context. (PsycINFO Database Record PMID- 29620389 TI - Variation in the long-term benefits of child care: The role of classroom quality in elementary school. AB - Data from the National Institute of Child Health and Human Development Study of Early Child Care and Youth Development (N = 1,307) were used to estimate the additive and multiplicative benefits of high-quality child care between birth to 54 months of age and high-quality elementary school education between first and fifth grade. Results indicated that the math and language and literacy benefits of high-quality child care accrued from the end of preschool through age 15 only when coupled with higher quality classroom environments during the elementary school years. In contrast, the benefits of high-quality child care were no longer present when children later attended lower quality classrooms in elementary school. Taken together, these results point to the importance of continued investments in children's education throughout the first decade of life. (PsycINFO Database Record PMID- 29620390 TI - Yoga as an intervention for psychological symptoms following trauma: A systematic review and quantitative synthesis. AB - Despite evidence of the physiologic impact of trauma, treatments are only beginning to focus on the impact of trauma on the body. Yoga may be a promising treatment for trauma sequelae, given research that supports yoga for general distress. The present study aims to systematically assess and quantitatively synthesize the effectiveness of yoga interventions for psychological symptoms (posttraumatic stress disorder [PTSD], depression, anxiety symptoms) following potentially traumatic life events. The following electronic databases were systematically searched: PsycINFO, Ovid Medline/PubMed, Cumulative Index to Nursing and Allied Health Literature, and Embase/Embase Classic. Google Scholar, Mendeley, Open Research and Contributor Identification, and Fig Share were hand searched post hoc. The review focused on studies with a comparison group that measured psychological symptoms before and after intervention. After screening and reviewing, 12 articles (N = 791) were included, with interventions ranging from 2 days to 16 weeks. If a study contained multiple conditions, between-groups differences were only examined between the yoga and inactive control group. Though overall between-groups (yoga vs. comparison) effect sizes ranged from ds = 0.40-1.06, the systematic review and quantitative synthesis did not find strong evidence for the effectiveness of yoga as an intervention for PTSD, depression, and anxiety symptoms following traumatic life experiences due to low quality and high risk of bias of studies. As yoga has promise for managing psychological symptoms among trauma survivors, this review calls for more rigorous design of future studies to allow definitive conclusions regarding the use of yoga in mental health treatment of trauma survivors. (PsycINFO Database Record PMID- 29620391 TI - Timely access to mental health care among women veterans. AB - Using survey data on (N = 419) patients at Department of Veterans Affairs (VA) clinics we analyzed women veterans' reports of timely access to VA mental health care. We evaluated problems that patients might face in obtaining care, and examined subjective ratings of VA care as a function of timely access to mental health care. We found that 59% of participants reported "always" getting an appointment for mental health care as soon as needed. In adjusted analyses, two problems were negatively associated with timely access to mental health care: (a) medical appointments that interfere with other activities, and (b) difficulty getting questions answered between visits. Average subjective ratings of VA ranged from 8.2-8.6 out of 10, and 93% of participants would recommend VA care. Subjective ratings of VA were higher among women who reported timely access to mental health care. Findings suggest that overall experience of care is associated with timely access to mental health care, and that such access may be amenable to improvements related to clinic hours or mechanisms for answering patient questions between visits. (PsycINFO Database Record PMID- 29620392 TI - Randomized controlled trial of a culturally-adapted program for Latinas with binge eating. AB - Binge eating disorder (BED) is the most prevalent eating disorder among Latinas. Furthermore, Latinas report more frequent binge eating and higher levels of associated mental health symptoms as compared with non-Latino White women. Research demonstrates that Latinas' eating problems largely go undetected and untreated and that they face numerous barriers to seeking professional help. Cognitive-behavioral therapy (CBT)-based guided self-help (CBTgsh) for binge eating is a more affordable and disseminable intervention than traditional CBT treatment. In this paper, we present the findings from a randomized controlled trial (RCT) of a culturally adapted CBTgsh program in a sample of overweight and obese Latinas with BED, the first RCT of this type with an ethnic minority population. Study participants (N = 40) diagnosed with BED were randomly assigned to the CBTgsh (n = 21) or waitlist (n = 19) condition. Treatment with the CBTgsh program resulted in significant reductions in frequency of binge eating, depression, and psychological distress and 47.6% of the intention-to-treat CBTgsh group were abstinent from binge eating at follow-up. In contrast, no significant changes were found from pre- to 12-week follow-up assessments for the waitlisted group. Results indicate that CBTgsh can be effective in addressing the needs of Latinas who binge eat and can lead to improvements in symptoms. (PsycINFO Database Record PMID- 29620393 TI - Veteran participation in the integrative health and wellness program: Impact on self-reported mental and physical health outcomes. AB - Complementary and integrative health (CIH) services are being used more widely across the nation, including in both military and veteran hospital settings. Literature suggests that a variety of CIH services show promise in treating a wide range of physical and mental health disorders. Notably, the Department of Veterans Affairs is implementing CIH services within the context of a health care transformation, changing from disease based health care to a personalized, proactive, patient-centered approach where the veteran, not the disease, is at the center of care. This study examines self-reported physical and mental health outcomes associated with participation in the Integrative Health and Wellness Program, a comprehensive CIH program at the Washington DC VA Medical Center and one of the first wellbeing programs of its kind within the VA system. Using a prospective cohort design, veterans enrolled in the Integrative Health and Wellness Program filled out self-report measures of physical and mental health throughout program participation, including at enrollment, 12 weeks, and 6 months. Analyses revealed that veterans reported significant improvements in their most salient symptoms of concern (primarily pain or mental health symptoms), physical quality of life, wellbeing, and ability to participate in valued activities at follow-up assessments. These results illustrate the potential of CIH services, provided within a comprehensive clinic focused on wellbeing not disease, to improve self-reported health, wellbeing, and quality of life in a veteran population. Additionally, data support recent VA initiatives to increase the range of CIH services available and the continued growth of wellbeing programs within VA settings. (PsycINFO Database Record PMID- 29620394 TI - The home-field advantage and the perils of professional judgment: Evaluating the performance of the Static-99R and the MnSOST-3 in predicting sexual recidivism. AB - When sex offenders in Minnesota are assigned risk levels prior to their release from prison, correctional staff frequently exercise professional judgment by overriding the presumptive risk level per an offender's score on the Minnesota Sex Offender Screening Tool-3 (MnSOST-3), a sexual recidivism risk-assessment instrument. These overrides enabled us to evaluate whether the use of professional judgment resulted in better predictive performance than did reliance on "actuarial" judgment (MnSOST-3). Using multiple metrics, we also compared the performance of a home-grown instrument (the MnSOST-3) with a global assessment (the revised version of the Static-99 [Static-99R]) in predicting sexual recidivism for 650 sex offenders released from Minnesota prisons in 2012. The results showed that use of professional judgment led to a significant degradation in predictive performance. Likewise, the MnSOST-3 outperformed the Static-99R for both sexual recidivism measures (rearrest and reconviction) across most of the performance metrics we used. These results imply that actuarial tools and home grown tools are preferred relative to those that include professional judgment and those developed on different populations. (PsycINFO Database Record PMID- 29620395 TI - Juvenile probation officers' evaluation of traumatic event exposures and traumatic stress symptoms as responsivity factors in risk assessment and case planning. AB - Juvenile probation officers (JPOs) are increasingly using risk/needs assessments to evaluate delinquency risk, identify criminogenic needs and specific responsivity factors, and use this information in case planning. Justice-involved youth are exposed to traumatic events and experience traumatic stress symptoms at a high rate; such information warrants attention during the case planning process. The extent to which JPOs identify specific responsivity factors, in general, and trauma history, specifically, when scoring risk/need assessments is understudied. In the current study, 147 JPOs reviewed case vignettes that varied by the adolescents' gender (male vs. female), traumatic event exposure (present vs. absent), and traumatic stress symptoms (present vs. absent), and then scored the YLS/CMI and developed case plans based on that information. JPOs who received a vignette that included trauma information identified a higher number of trauma specific responsivity factors on the YLS/CMI. Despite an overall high needs match ratio (57.2%), few JPOs prioritized trauma as a target on case plans. The findings underscore the importance of incorporating trauma screening into risk/needs assessment and case planning. (PsycINFO Database Record PMID- 29620396 TI - Eyewitness identification performance on showups improves with an additional opportunities instruction: Evidence for present-absent criteria discrepancy. AB - We tested the proposition that when eyewitnesses find it difficult to recognize a suspect (as in a culprit-absent showup), eyewitnesses accept a weaker match to memory for making an identification. We tie this proposition to the basic recognition memory literature, which shows people use lower decision criteria when recognition is made difficult so as to not miss their chance of getting a hit on the target. We randomly assigned participant-witnesses (N = 610) to a condition in which they were told that if they did not believe the suspect was the culprit, they would have additional opportunities to make an identification later (additional-opportunities instruction). We fully crossed this instruction with the standard admonition (i.e., the culprit may or may not be present) and with the presence or absence of the culprit in a showup identification procedure. The standard admonition had no impact on eyewitness decision-making; however, the additional-opportunities instruction reduced innocent-suspect identifications (from 33% to 15%) to a greater extent than culprit identifications (57% to 51%). The additional-opportunities instruction yielded a better tradeoff between culprit and innocent-suspect identifications as indicated by binary logistic regression and receiver operator characteristic (ROC) analyses. (PsycINFO Database Record PMID- 29620397 TI - Real-world use of the risk-need-responsivity model and the level of service/case management inventory with community-supervised offenders. AB - The risk-need-responsivity model (RNR; Bonta & Andrews, 2017) has become a leading approach for effective offender case management, but field tests of this model are still required. The present study first assessed the predictive validity of the RNR-informed Level of Service/Case Management Inventory (LS/CMI; Andrews, Bonta, & Wormith, 2004) with a sample of Atlantic Canadian male and female community-supervised provincial offenders (N = 136). Next, the case management plans prepared from these LS/CMI results were analyzed for adherence to the principles of risk, need, and responsivity. As expected, the LS/CMI was a strong predictor of general recidivism for both males (area under the curve = .75, 95% confidence interval [.66, .85]), and especially females (area under the curve = .94, 95% confidence interval [.84, 1.00]), over an average 3.42-year follow-up period. The LS/CMI was predictive of time to recidivism, with lower risk cases taking longer to reoffend than higher risk cases. Despite the robust predictive validity of the LS/CMI, case management plans developed by probation officers generally reflected poor adherence to the RNR principles. These findings highlight the need for better training on how to transfer risk appraisal information from valid risk tools to case plans to better meet the best-practice principles of risk, need, and responsivity for criminal behavior risk reduction. (PsycINFO Database Record PMID- 29620398 TI - People in more racially diverse neighborhoods are more prosocial. AB - Five studies tested the hypothesis that people living in more diverse neighborhoods would have more inclusive identities, and would thus be more prosocial. Study 1 found that people residing in more racially diverse metropolitan areas were more likely to tweet prosocial concepts in their everyday lives. Study 2 found that following the 2013 Boston Marathon bombings, people in more racially diverse neighborhoods were more likely to spontaneously offer help to individuals stranded by the bombings. Study 3 found that people living in more ethnically diverse countries were more likely to report having helped a stranger in the past month. Providing evidence of the underlying mechanism, Study 4 found that people living in more racially diverse neighborhoods were more likely to identify with all of humanity, which explained their greater likelihood of having helped a stranger in the past month. Finally, providing causal evidence for the relationship between neighborhood diversity and prosociality, Study 5 found that people asked to imagine that they were living in a more racially diverse neighborhood were more willing to help others in need, and this effect was mediated by a broader identity. The studies identify a novel mechanism through which exposure to diversity can influence people, and document a novel consequence of this mechanism. (PsycINFO Database Record PMID- 29620399 TI - Robust effects of affective person learning on evaluation of faces. AB - People form impressions of others from multiple sources of information. Facial appearance is one such source and judgments based on facial appearance are made after minimal exposure to faces. A more reliable source of information is affective person learning based on others' past actions. Here we investigated whether the effects of such appearance-independent learning on face evaluation emerge after rapid face exposure, a response deadline procedure, and a lack of explicit recognition of the faces. In three experiments, participants learned to associate novel faces with negative and positive behaviors, and then evaluated the faces presented on their own, without the behaviors. Even after extremely brief exposures (e.g., 35 ms), participants evaluated faces previously associated with negative behaviors more negatively than those associated with positive behaviors (Experiment 1). The learning effect persisted when participants were asked to evaluate briefly presented faces before a response deadline (Experiment 2), although the effect was diminished. Finally, although this learning effect increased as a function of face recognition (Experiment 3), it was present with only minimal recognition, suggesting that participants do not need to deliberately retrieve behavioral information for it to influence face evaluation. Together, the findings suggest that person learning unrelated to facial appearance is a powerful determinant of face evaluation. (PsycINFO Database Record PMID- 29620400 TI - Collective satiation: How coexperience accelerates a decline in hedonic judgments. AB - Individuals often mutually experience a stimulus with a relationship partner or social group (e.g., snacking with friends). Yet, little is currently understood about how a sense of coexperiencing affects hedonic judgments of experiences that unfold over time. Research on the shared attention state has suggested that hedonic judgments are intensified when individuals coexperience a stimulus (vs. experiencing it alone), and other related work has found that the social environment influences hedonic judgments in shared (vs. solo) experiences. Although this past work has focused on judgments of single instances of a stimulus, the present work examines how coexperience affects hedonic judgments of stimuli over time. This work documents the 'collective satiation effect' wherein satiation-a diminished enjoyment of pleasant stimuli with repeated experience-is accelerated by a sense of coexperiencing the stimulus with others. We propose that this happens because shared attention makes the repetitive nature of the experience more salient, by promoting and incorporating thoughts of others also repeatedly having the same shared experience. Five studies document the collective satiation effect, support the proposed mechanism, and show moderators of the effect. Taken together, this research contributes to an understanding of how the social environment influences the experience of hedonic stimuli, which has broad implications for the value individuals place on the time that they spend with others. (PsycINFO Database Record PMID- 29620401 TI - Perspective mistaking: Accurately understanding the mind of another requires getting perspective, not taking perspective. AB - Taking another person's perspective is widely presumed to increase interpersonal understanding. Very few experiments, however, have actually tested whether perspective taking increases accuracy when predicting another person's thoughts, feelings, attitudes, or other mental states. Those that do yield inconsistent results, or they confound accuracy with egocentrism. Here we report 25 experiments testing whether being instructed to adopt another person's perspective increases interpersonal insight. These experiments include a wide range of accuracy tests that disentangle egocentrism and accuracy, such as predicting another person's emotions from facial expressions and body postures, predicting fake versus genuine smiles, predicting when a person is lying or telling the truth, and predicting a spouse's activity preferences and consumer attitudes. Although a large majority of pretest participants believed that perspective taking would systematically increase accuracy on these tasks, we failed to find any consistent evidence that it actually did so. If anything, perspective taking decreased accuracy overall while occasionally increasing confidence in judgment. Perspective taking reduced egocentric biases, but the information used in its place was not systematically more accurate. A final experiment confirmed that getting another person's perspective directly, through conversation, increased accuracy but that perspective taking did not. Increasing interpersonal accuracy seems to require gaining new information rather than utilizing existing knowledge about another person. Understanding the mind of another person is therefore enabled by getting perspective, not simply taking perspective. (PsycINFO Database Record PMID- 29620402 TI - Personal neglect: A comprehensive theoretical and anatomo-clinical review. AB - : Personal neglect (PN) is the hemi-inattention toward the contralesional bodily space that follows a cerebral lesion, usually to the right hemisphere. OBJECTIVE: To provide a historical, comprehensive review of the different theoretical accounts, of the available diagnostic measures, of the relationship with different body representation disorders, and of recovery-related issues. Moreover, to review the anatomo-functional correlates of PN, focusing on group studies that used modern voxel-based lesion-symptoms mapping. METHOD: PubMed database was searched for all the available studies on PN conducted in the last 30 years. Relevant clinical data for each study were reported in a table, which was used as a reference for developing the discussion on the points of interest. RESULTS: Evaluation tools for PN suffer from limitations and should include both face- and body-related testing as well as require both basic exploration and object use in the same personal space. Dedicated rehabilitative procedures are lacking and advocated, given that recovery of PN and extrapersonal neglect can be dissociated and their degree is not correlated. PN is almost constantly associated with a cohort of body representation disorders that do not reveal themselves unless specifically investigated. PN is significantly correlated to alterations at the level of both the anterior parietal cortex and the underlying fronto-parietal fiber bundles. CONCLUSIONS: The discussed data point to the need for a diagnostic and rehabilitative update. Following the topological and hodological lesional pattern, PN might emerge from the combination of a body representation disorder and a spatial inattention for half of the space. (PsycINFO Database Record PMID- 29620403 TI - Choosing spouses and houses: Impaired congruence between preference and choice following damage to the ventromedial prefrontal cortex. AB - OBJECTIVE: A well-documented effect of focal ventromedial prefrontal cortex (vmPFC) damage is a deficit in real-world decision making. An important aspect of this deficit may be a deficiency in "internal consistency" during social decision making-that is, impaired congruence between expressed preferences versus actual behavioral choices. An example of low internal consistency would be if one expressed the desire to marry someone with impeccable moral character, yet proceeded to marry someone convicted of multiple felonies. Here, we used a neuropsychological approach to investigate neural correlates of internal consistency in complex decision making. METHOD: Sixteen individuals with focal vmPFC lesions, 16 brain damage comparison individuals, and 16 normal comparison individuals completed a 3-option forced-choice preference task in which choices were made using attribute sets. Participants also completed visual-analogue preference ratings to indicate how much they liked each option, and rated the influence of each attribute on their decision making. Options were either social (potential spouses) or nonsocial (potential houses). Internal consistency for a trial was defined as agreement between the choice and the most positively rated option. RESULTS: A mixed design analysis of variance revealed that internal consistency between choices and preferences derived from summed attribute ratings was significantly lower for the vmPFC group relative to comparison participants, but only in the social condition (peta2 = .09), 95% CI [.002, .163]. CONCLUSIONS: Internal consistency during social decisions may be deficient in patients with vmPFC damage, leading to a discrepancy between preferences and choices. The vmPFC may provide an important neural mechanism for aligning behavioral choices with expressed preferences. (PsycINFO Database Record PMID- 29620404 TI - Neural correlates of audiovisual sensory integration. AB - OBJECTIVE: The present study aimed to investigate the neural basis of information matching during sensory integration using a spatial-temporal matching task in healthy individuals. METHOD: A total of 37 healthy participants were recruited to match spatial dots with an auditory tone sequence in a 3T GE Discovery MR750 scanner. In addition, they were examined with the sensory integration subscale of the Cambridge Neurological Inventory. RESULTS: We found that the bilateral occipital-parietal conjunction cortex and the precentral frontal gyrus were activated during the matching condition rather than in the nonmatching condition. Activation of the occipital-parietal conjunction cortex was associated with integration of information across visual and auditory modalities, whereas activation of the precentral frontal gyrus was associated with decision making of movements. In addition, activation of the left superior frontal gyrus was associated with scores on the sensory integration subscale of the Cambridge Neurological Inventory. CONCLUSIONS: These findings suggest that the bilateral occipital-parietal conjunction cortex is responsible for matching information input from multiple modalities during audiovisual sensory integration. (PsycINFO Database Record PMID- 29620406 TI - Visual scanning of the eye region of human faces predicts emotion recognition performance in Huntington's disease. AB - OBJECTIVE: Previous research has consistently shown that the ability to recognize emotions from facial expressions is impaired in Huntington's disease (HD). The aim of this study was to examine whether people with the gene expansion for HD visually scan the most emotionally informative features of human faces less than unaffected individuals, and whether altered visual scanning predicts emotion recognition in HD beyond general disease-related decline. METHOD: We recorded eye movements of 25 participants either in the late premanifest or early stage of HD and 25 age-matched healthy control participants during a face-viewing task. The task involved the viewing of pictures depicting human faces with angry, disgusted, fearful, happy, and neutral expressions, and evaluating each face on a valence rating scale. For data analysis, we defined 2 regions of interest (ROIs) on each picture, including an eye-ROI and a nose/mouth-ROI. Emotion recognition abilities were measured using an established emotion-recognition task and general disease-related decline was measured using the UHDRS motor score. RESULTS: Compared to the control participants, the HD participants spent less time looking at the ROIs relative to the total time spent looking at the pictures (partial eta2 = 0.10), and made fewer fixations on the ROIs (partial eta2 = 0.16). Furthermore, visual scanning of the eye-ROI, but not the nose/mouth-ROI, predicted emotion recognition performance in the HD group, over and beyond general disease-related decline. CONCLUSION: The emotion recognition deficit in HD may partly be explained by general disease-related decline in cognition and motor functioning and partly by a social-emotional deficit, which is reflected in reduced eye-viewing. (PsycINFO Database Record PMID- 29620405 TI - Neurocognitive and behavioral predictors of social problems in ADHD: A Bayesian framework. AB - OBJECTIVE: Social problems are a key area of functional impairment for children with attention deficit hyperactivity disorder (ADHD), and converging evidence points to executive dysfunction as a potential mechanism underlying ADHD-related social dysfunction. The evidence is mixed, however, with regard to which neurocognitive abilities account for these relations. METHOD: A well characterized group of 117 children ages 8-13 (M = 10.45, SD = 1.53; 43 girls; 69.5% Caucasian/Non-Hispanic) with ADHD (n = 77) and without ADHD (n = 40) were administered multiple, counterbalanced tests of neurocognitive functioning and assessed for social skills via multi-informant reports. RESULTS: Bayesian linear regressions revealed strong support for working memory and cross-informant interfering behaviors (inattention, hyperactivity/impulsivity) as predictors of parent- and teacher-reported social problems. Working memory was also implicated in social skills acquisition deficits, performance deficits, and strengths based on parent and/or teacher report; inattention and/or hyperactivity showed strong correspondence with cross-informant social problems in all models. There was no evidence for, and in most models strong evidence against, effects of inhibitory control and processing speed. The ADHD group was impaired relative to the non ADHD group on social skills (d = 0.82-0.88), visuospatial working memory (d = 0.89), and phonological working memory (d = 0.58). In contrast, the Bayesian ANOVAs indicated that the ADHD and non-ADHD groups were equivalent on processing speed, IQ, age, gender, and socioeconomic status (SES). There was no support for or against group differences in inhibition. CONCLUSIONS: These findings confirm that ADHD is associated with impaired social performance, and implicate working memory and core ADHD symptoms in the acquisition and performance of socially skilled behavior. (PsycINFO Database Record PMID- 29620407 TI - Enhancing the current evidence on endoscopist-directed propofol-based sedation. AB - During the last years, there is more and more scientific evidence about the safety and feasibility of non-anesthesiologist administration of propofol (NAAP) in gastrointestinal endoscopy, reducing sedation induction and recovery time as well as increasing patient and endoscopist satisfaction. Furthermore, a similar risk of adverse events compared with traditional agents or anesthesiologist administration of propofol (AAP) has been described. The present special issue of the Spanish Journal of Gastroenterology (Revista Espanola de Enfermedades Digestivas) focusses on NAAP in different settings, including complex endoscopic procedures. PMID- 29620408 TI - Cholangitis secondary to afferent loop syndrome from a gastric stump adenocarcinoma. AB - A clinical case of an 85-year-old patient with cholangitis secondary to afferent loop syndrome from gastric stump adenocarinoma. A brief review of the literature on it is made. PMID- 29620409 TI - Is the education available to anesthetists adequate to provide sedation in endoscopy units? AB - It is a letter that aims to emphasize the type of sedation that is sometimes used by anesthetists to perform a standard endoscopy and the excessive use of the operating room, which increases the cost of endoscopy and reduces the resources of surgical time. PMID- 29620410 TI - Sedation assisted by an endoscopist (SAE) for complex endoscopic procedures. Is it time to change the current guidelines? AB - Currently, sedation in endoscopic procedures is considered a necessary condition and a criterion of quality in digestive endoscopy. The role of SAE in conventional endoscopic procedures is clearly established in clinical guidelines, but this is not so clear in complex endoscopic procedures, such as ERCP. In recent years, numerous studies have been published, with results similar to those noticed in this article, endorsing the safety, efficacy and efficiency of SAE, when performed by properly trained staff. PMID- 29620411 TI - Patients' perspective on sedation during upper gastrointestinal endoscopy. Systematic use of sedation or systematic prior information? AB - Although sedation in endoscopy is increasingly used and contributes to the quality of procedures, its role in upper gastrointestinal endoscopy (UGE) is not as well defined as in other procedures. For this reason, we conducted a prospective pilot study where the patient, once informed of the different options, decided whether or not to undergo sedation for UGE. Remarkably, almost 60% preferred not to undergo sedation, with a high degree of satisfaction and no adverse effects in any of the groups (Ferrer Rosique JA, et al. XXXIX Congreso SEED, Toledo 2017). PMID- 29620412 TI - Me, the intruder: revisited and rethought. AB - I have read Dr. Luzon's article (1) and have shared his opinions for a long time. As I indicated in my letter 13 years ago (2), all of our patients need to receive adequate sedation in endoscopic explorations, including ERCP. It is also our obligation as the person responsible for the procedure, to ensure that this is so. At present and without renouncing any of my beliefs, I think it is necessary to ask ourselves several questions: . PMID- 29620413 TI - Portosystemic venous shunt: portocaval fistula in a patient with biliary cirrhosis secondary to a right hepatectomy for hydatidosis. AB - Major intrahepatic venous shunts are rare conditions where a communication between hepatic veins and intrahepatic portal vessels is established. Potential spontaneous development has been proposed in patients with cirrhosis and portal hypertension (PHT). PMID- 29620415 TI - The third New Zealand Psychiatry of Old Age services and workforce survey. AB - OBJECTIVE: To survey the Psychiatry of Old Age (POA) services and workforce in New Zealand (NZ). METHODS: The NZ branch of Faculty of POA contacted the POA lead clinician and/or service manager of the 20 district health boards (DHBs) and completed a survey based on variables used in two similar previous national surveys. RESULTS: Seventeen services responded. We found acute inpatient beds and clinical staff time are funded differently across DHBs. Although there has been an increase in non-medical clinical staff time in the community teams, most DHBs are not planning to increase their medical staff time in the next 3 years. Specialist services for people with intellectual disabilities and young-onset dementia, and older people with substance use disorder are generally not provided within POA services. CONCLUSIONS: A wider POA and non-POA services mapping is required to determine the level of services for clinical populations that have high and complex clinical needs. DHB funders should review the expected population growth in people aged 65+ and consider increasing the funding for these under-served clinical populations. PMID- 29620414 TI - CD24 and CD49f expressions of E14.5 mouse mammary anlagen cells define putative distribution of earlier embryonic mammary stem cell activities. AB - Stem cell biology offers promise for understanding the origins of the mammary gland. However, the distribution of mammary stem cell (MaSC) activities at earlier embryonic stages has not been fully identified. The markers for sorting adult MaSC, CD24, CD29, and CD49f have been applied to analyze fetal MaSCs. Here we explored mammary anlagen MaSCs by investigating the expression of CD24 and CD49f. According to the comparative analysis between adult mammary gland and fetal mammary anlagen, we found that fetal mouse mammary anlagen may possess a high percentage of potential MaSCs. Flow cytometry analysis revealed 2 distinct mammary anlagen populations: Lin-CD24med and Lin-CD24high. Sphere-forming and mammary repopulating assays confirmed that the stem cell activity of E14.5 mouse mammary anlagen was restricted to the Lin-CD24med cell population. Furthermore, CD24med mammary anlagen cells were separated into Lin-CD24medCD49f+ and Lin CD24medCD49f- populations and identified, respectively. The results proved that the mammary anlagen Lin-CD24medCD49f+ cell population possesses more stem cell activities than the Lin-CD24medCD49f- cell population. However, a limited numbers of stem cells and large numbers of stromal cells were identified in mammary anlagen in the Lin-CD24med cell population. PMID- 29620416 TI - Immunological axis of curcumin-loaded vesicular drug delivery systems. AB - Several vesicular systems loaded with curcumin have found their way in the therapeutic applications of several diseases, primarily acting through their immunological pathways. Such systems use particles at a nanoscale range, bringing about their intended use through a range of complex mechanisms. Apart from delivering drug substances into target tissues, these vesicular systems also effectively overcome problems like insolubility and unequal drug distribution. Several mechanisms are explored lately by different workers, and interest over vesicular curcumin has been renewed in the past decade. This commentary discusses several immunological targets in which curcumin is employed in a vesicular form. PMID- 29620417 TI - Body growth, intestinal morphology and microflora of quail on diets supplemented with micronised wheat fibre. AB - 1. Particle size reductions of fibre-rich materials alter structure, functional and digestive properties. To determine the effects of using fibre as an additive in Japanese quail rations on performance and gut physiology, a trial using micronised wheat fibre (MWF) at levels of 0.0, 5, 10 and 15 g/kg in feed was conducted. 2. Growth rate and feed efficiency were significantly improved when diets contained MWF while feed intake was not affected by levels of the fibre. As MWF content increased, the relative weight of gizzard and gastrointestinal tract (GIT) significantly increased whereas liver relative weight significantly decreased. 3. MWF inclusion significantly increased relative length of gut segments, villi height, villus thickness, the villi height to crypt depth proportion in jejunum and ileum and the number of goblet cells in different parts of intestine. 4. Tibia weight, length and ash content were increased linearly with rising MWF inclusion. Litter moisture was affected by MWF inclusions in a quadratic manner. The colony forming unit (CFU/g) of Streptococci spp. in ileal digesta was decreased with increasing MWF inclusion levels in the diet. 5. In conclusion, MWF can be used as a feed additive in quail diets and its inclusion in feed resulted in better performance, beneficial changes in intestinal microbial counts and improvements in small intestine morphology. PMID- 29620418 TI - Determination of antimicrobial resistance to extended-spectrum cephalosporin, quinolones, and vancomycin in selected human enteric pathogens from Prince Edward Island, Canada. AB - The aim of this study was to determine the frequency of fecal carriage of vancomycin-resistant Enterococcus spp. and Escherichia coli with reduced susceptibilities to extended-spectrum cephalosporins (ESCs) and quinolones in humans on Prince Edward Island, Canada. Convenience fecal samples from individuals on Prince Edward Island were screened phenotypically using selective culture and genotypically using multiplex polymerase chain reactions to detect E. coli and Enterococcus spp. resistant to critically important antimicrobials. Twenty-six (5.3%) of 489 individuals had E. coli with reduced susceptibility to ESCs. Twenty-five (96.2%) of the 26 isolates harbored blaTEM, 18 (69.2%) harbored blaCMY-2, 16 (61.5%) harbored blaCTX-M groups, 2 (7.7%) harbored blaSHV genes. None of the ESC-resistant E. coli was positive for carbapenem resistance. Twenty one (8.3%) of 253 individuals had E. coli isolates with reduced quinolone susceptibility. All 21 isolates were positive for at least 1 qnr gene, with 3 (14.3%) isolates positive for qnrB, 5 (23.8%) positive for qnrS, and 13 (61.9%) positive for both qnrB and qnrS genes. All the enterococci isolates were vancomycin-susceptible. Higher susceptibility to the critically important antimicrobials was found in this study. This study can serve as a baseline for future antimicrobial resistance surveillance within this region. PMID- 29620420 TI - Research progress of selective small molecule bromodomain-containing protein 9 inhibitors. AB - The bromodomain proteins, known as the key targets in epigenetics, are 'readers' of acetylated lysine of histones. As a member of bromodomain proteins, bromodomain-containing protein 9 (BRD9) is a subunit of mammalian SWI/SNF chromatin remodeling complexes. However, the biological functions and the potential application in therapeutics of BRD9 remain ambiguous due to a lack of selective small molecule inhibitors of BRD9. Recently, series of chemical ligands against BRD9 were developed by different research institutes. Here, we reviewed the development and characterization of reported BRD9 inhibitors, which will be the foundation of further chemical design and biological evaluation. PMID- 29620419 TI - Artificial oocyte activation with calcium ionophore for frozen sperm cycles. AB - : Fertilization problems are the major problems that may be faced in 30-55% of the patients during an intracytoplasmic sperm injection (ICSI) cycle. A successful oocyte activation depends on factors related to both sperm and oocyte, and one of the important factors that mediates the process is Ca2+ concentration within the oocyte. Artificial oocyte activation (AOA) is a method used for fertilization problems that commonly involve the usage of Ca2+ ionophores and is usually used in problems such as total fertilization failure (TFF) and globozoospermia. The aim of the present study was to investigate possible effects of AOA for different groups of patients with fertilization failure. Four groups of patients (previous TFF, low oocyte number, severe sperm quality, and frozen sperm (FS) group) that underwent ICSI with AOA were included in the study. All groups had similar control groups with same indications except TFF, where AOA was not performed. Fertilization rates were significantly higher in the TFF group than those observed in other AOA groups. Fertilization rates and quality of embryos observed in the remaining AOA groups were higher than those of the controls, which were statistically insignificant. Prgenancy rates were higher in all AOA groups compared to the controls, although the differences were significant in FS group only. Quality of embryos and pregnancy rates were lower in the TFF group compared to the remaining AOA groups indicating possible concomitant problems. Fertilization rates, quality of embryos and pregnancy rates seemed to be increased in all indication groups suggesting that not only TFF patients but also a wide variety of patients with different indications may benefit from AOA. ABBREVIATIONS: ICSI: Intracytoplasmic sperm injection; ARTs: Assisted reproductive techniques; Ca: Calcium; AOA: Artificial oocyte activation; TFF: Total fertilization failures; OAT: Oligoasthenoteratozoospemia; IVF: In vitro fertilization; SOAT: Severe OAT; LON: Low ooctye number; FS: Frozen sperm; hCG: human chorionic gonadotrophin; PVP: polyvinylpyrrolidone; HSA: human serum albumin. PMID- 29620421 TI - Adding bovine seminal plasma prior to freezing improves post-thaw bull sperm kinematics but decreases mitochondrial activity. AB - : Variations in fertility between bulls with comparable sperm quality could be due to differences in their seminal plasma (SP). The aim of this study was to investigate the effect of adding bovine SP from bulls of known fertility to SP free sperm samples. After removal of SP by Single Layer Centrifugation, resuspended sperm pellets were treated with SP from high or low fertility bulls at 0% (control), 1%, or 5% before freezing. Sperm quality was evaluated after thawing. Data were analyzed using Proc MIXED, SAS(r). Bovine SP at 1% or 5% SP1 and SP5, respectively, decreased average path velocity, curvilinear velocity, and amplitude of lateral head displacement whereas wobble and linearity were increased. In addition, the proportion of spermatozoa with high mitochondrial membrane potential (MMP) was lowest for treatment with SP5 compared to SP1 and control. The proportion of SP did not affect other parameters of sperm quality. Thus, adding 5% bovine SP produced a favorable effect on some sperm velocity parameters but had an unfavorable effect on MMP. There were no differences in effect between SP from high and low fertility bulls. ABBREVIATIONS: AI: artificial insemination; BCF: beat cross frequency; CASA: computer-assisted sperm analysis; IVF: in vitro fertilization; MMP: mitochondrial membrane potential; SLC: single layer centrifugation; SP: seminal plasma. PMID- 29620422 TI - The increase in copeptin levels in mild head trauma does not predict the severity and the outcome of brain damage. AB - AIM: To investigate the copeptin prognostic role in mild head trauma. METHODS: We enrolled 105 adult patients who entered the emergency room because of recent mild head trauma; we evaluated: clinical picture, imaging and laboratory data (including copeptin). RESULTS: Copeptin resulted higher in mild head trauma patients compared with controls: 29.89 pmol/l versus 7.05 pmol/l (p = 0.0008). Copeptin failed in identifying patients with or without brain lesions detected by CT scan, and patients with or without adverse events during the 30 days follow up. CONCLUSION: We confirmed that mild head trauma patients have a significantly higher copeptin plasma levels compared with controls. Nevertheless, we did not observe a significant role for copeptin in traumatic brain injury patients regarding brain damage and outcome. PMID- 29620423 TI - Giant chorangioma presenting with an absent foetus: a mystery! PMID- 29620424 TI - Pemphigoid gestationis: a case series and review of the literature. AB - Pemphigoid gestationis (PG) is a rare autoimmune disease associated with pregnancy. Clinically, it presents with severe pruritus that precedes the appearance of vesiculobullous lesions. It usually begins on the trunk and spread rapidly to other parts of the body. Mucosal lesions and facial involvement are rare. In this article, we are discussing three cases of PG. We will discuss clinical-pathological features and management. PMID- 29620425 TI - Disseminated peritoneal leiomyomatosis (DPL): a case report. PMID- 29620426 TI - High rate of latent tuberculosis treatment completion in immigrants seeking asylum in Sweden. AB - BACKGROUND/AIM: Treatment of latently infected individuals at increased risk of reactivation is a cornerstone in tuberculosis control. Although asylum seekers without residence permit in Sweden are offered screening for both active tuberculosis and latent tuberculosis infection (LTBI), treatment for LTBI is often not initiated due to anticipated low rates of treatment completion. We aimed to compare completion rates for LTBI treatment between asylum seekers and other patients, and between asylum seekers with and without residence permit. METHODS: Data were collected retrospectively from tuberculosis clinic registers and medical records. For comparison of treatment completion rates, relative risks (RR) and confidence intervals (CI) were calculated. Predictors of completion were assessed by logistic regression multivariate analysis. RESULTS: Treatment completion was achieved in 506/606 subjects (83%). RR of non-completion for asylum seekers (n = 297) compared to other subjects (n = 309) was 1.13 (95% CI: 0.79-1.61; p = .51), and 0.91 (95% CI: 0.53-1.56; p = .72) for asylum seekers without residence permit (n = 217) compared to asylum seekers with residence permit (n = 80). Completion rates increased from 53% in 2008 to 92% in 2015-2016. The following factors were associated with completion: scheduled interpreter assisted appointments throughout the course of therapy, shorter treatment duration (6 vs. 9 months), and being treated in connection with immunosuppressive therapy. CONCLUSION: Treatment completion rates were similar between asylum seekers and other subjects, supporting initiation of latent tuberculosis treatment in immigrants with recent arrival to low-endemic countries. PMID- 29620428 TI - Dietary dopamine depletion blunts reward network sensitivity to face trustworthiness. AB - Research demonstrating responsiveness of the neural reward network to face trustworthiness has not assessed whether the effects are mediated by dopaminergic function. We filled this gap in the literature by investigating whether dietary dopamine depletion would blunt the sensitivity of neural activation to faces varying in trustworthiness across reward regions as well as the sensitivity of behavioral responses to those faces. As prolactin release is negatively regulated by dopamine, peripheral prolactin levels confirmed the efficacy of our manipulation. The dopamine depletion manipulation moderated neural activation to face trustworthiness in the amygdala, medial orbital frontal cortex, and ventral medial prefrontal cortex. Control participants ( n=20) showed nonlinear and linear neural activation to face trustworthiness in the amygdala and ventral medial prefrontal cortex, and nonlinear activation in the medial orbital frontal cortex, while depleted participants ( n=20) showed only a linear effect in the amygdala. Controls also showed stronger amygdala activation to high trustworthy faces than depleted participants. In contrast to effects on neural activation, dopamine depletion did not blunt the sensitivity of behavioral ratings. While this is the first study to demonstrate that dopamine depletion blunts the sensitivity of the neural reward system to social stimuli, namely faces varying in trustworthiness, future research should investigate behavioral measures that may be more responsive to dopaminergic effects than face ratings. Such research would shed further light on the possibility that individual differences in dopaminergic function that were simulated by our manipulation influence social interactions with people who vary in facial trustworthiness. PMID- 29620427 TI - Blocking oestradiol synthesis pathways with potent and selective coumarin derivatives. AB - A comprehensive set of 3-phenylcoumarin analogues with polar substituents was synthesised for blocking oestradiol synthesis by 17-beta-hydroxysteroid dehydrogenase 1 (HSD1) in the latter part of the sulphatase pathway. Five analogues produced >=62% HSD1 inhibition at 5 uM and, furthermore, three of them produced >=68% inhibition at 1 uM. A docking-based structure-activity relationship analysis was done to determine the molecular basis of the inhibition and the cross-reactivity of the analogues was tested against oestrogen receptor, aromatase, cytochrome P450 1A2, and monoamine oxidases. Most of the analogues are only modestly active with 17-beta-hydroxysteroid dehydrogenase 2 - a requirement for lowering effective oestradiol levels in vivo. Moreover, the analysis led to the synthesis and discovery of 3-imidazolecoumarin as a potent aromatase inhibitor. In short, coumarin core can be tailored with specific ring and polar moiety substitutions to block either the sulphatase pathway or the aromatase pathway for treating breast cancer and endometriosis. PMID- 29620431 TI - Changes in the retreatment radiation tolerance of the spinal cord with time after the initial treatment. AB - PURPOSE: To estimate, from experimental data, the retreatment radiation 'tolerances' of the spinal cord at different times after initial treatment. MATERIALS AND METHODS: A model was developed to show the relationship between the biological effective doses (BEDs) for two separate courses of treatment with the BED of each course being expressed as a percentage of the designated 'retreatment tolerance' BED value, denoted [Formula: see text] and [Formula: see text]. The primate data of Ang et al. ( 2001 ) were used to determine the fitted parameters. However, based on rodent data, recovery was assumed to commence 70 days after the first course was complete, and with a non-linear relationship to the magnitude of the initial BED (BEDinit). RESULTS: The model, taking into account the above processes, provides estimates of the retreatment tolerance dose after different times. Extrapolations from the experimental data can provide conservative estimates for the clinic, with a lower acceptable myelopathy incidence. Care must be taken to convert the predicted [Formula: see text] value into a formal BED value and then a practical dose fractionation schedule. CONCLUSIONS: Used with caution, the proposed model allows estimations of retreatment doses with elapsed times ranging from 70 days up to three years after the initial course of treatment. PMID- 29620429 TI - Synthesis and biological evaluation of alpha-bromoacryloylamido indolyl pyridinyl propenones as potent apoptotic inducers in human leukaemia cells. AB - The combination of two pharmacophores into a single molecule represents one of the methods that can be adopted for the synthesis of new anticancer molecules. To investigate the influence of the position of the pyridine nitrogen on biological activity, two different series of alpha-bromoacryloylamido indolyl pyridinyl propenones 3a-h and 4a-d were designed and synthesized by a pharmacophore hybridization approach and evaluated for their antiproliferative activity against a panel of six human cancer cell lines. These hybrid molecules were prepared to combine the alpha-bromoacryloyl moiety with two series of indole-inspired chalcone analogues, possessing an indole derivative and a 3- or 4-pyridine ring, respectively, linked on either side of 2-propen-1-one system. The structure activity relationship was also investigated by the insertion of alkyl or benzyl moieties at the N-1 position of the indole nucleus. We found that most of the newly synthesized displayed high antiproliferative activity against U-937, MOLT 3, K-562, and NALM-6 leukaemia cell lines, with one-digit to double-digit nanomolar IC50 values. The antiproliferative activities of 3-pyridinyl derivatives 3f-h revealed that N-benzyl indole analogues generally exhibited lower activity compared to N-H or N-alkyl derivatives 3a-b and 3c-e, respectively. Moreover, cellular mechanism studies elucidated that compound 4a induced apoptosis along with a decrease of mitochondrial membrane potential and activated caspase-3 in a concentration-dependent manner. PMID- 29620430 TI - In vitro rhizobia response and symbiosis process under aluminum stress. AB - Aluminum (Al) toxicity is a major problem affecting soil fertility, microbial diversity, and nutrient uptake of plants. Rhizobia response and legume interaction under Al conditions are still unknown; it is important to understand how to develop and improve legume cultivation under Al stress. In this study, rhizobia response was recorded under different Al concentrations. Al effect on rhizobial cells was characterized by combination with different two pH conditions. Symbiosis process was compared between alpha- and beta-rhizobia inoculated onto soybean varieties. Rhizobial cell numbers was decreased as Al concentration increased. However, induced Al tolerance considerably depended on rhizobia types and their origins. Accordingly, organic acid results were in correlation with growth rate and cell density which suggested that citric acid might be a positive selective force for Al tolerance and plant interaction on rhizobia. Al toxicity delayed and interrupted the plant-rhizobia interaction and the effect was more pronounced under acidic conditions. Burkholderia fungorum VTr35 significantly improved plant growth under acid-Al stress in combination with all soybean varieties. Moreover, plant genotype was an important factor to establish an effective nodulation and nitrogen fixation under Al stress. Additionally, tolerant rhizobia could be applied as an inoculant on stressful agroecosystems. Furthermore, metabolic pathways have still been unknown under Al stress. PMID- 29620432 TI - Identifying Algorithms to Improve the Accuracy of Unverified Diagnosis Codes for Birth Defects. AB - OBJECTIVES: We identified algorithms to improve the accuracy of passive surveillance programs for birth defects that rely on administrative diagnosis codes for case ascertainment and in situations where case confirmation via medical record review is not possible or is resource prohibitive. METHODS: We linked data from the 2009-2011 Florida Birth Defects Registry, a statewide, multisource, passive surveillance program, to an enhanced surveillance database with selected cases confirmed through medical record review. For each of 13 birth defects, we calculated the positive predictive value (PPV) to compare the accuracy of 4 algorithms that varied case definitions based on the number of diagnoses, medical encounters, and data sources in which the birth defect was identified. We also assessed the degree to which accuracy-improving algorithms would affect the Florida Birth Defects Registry's completeness of ascertainment. RESULTS: The PPV generated by using the original Florida Birth Defects Registry case definition (ie, suspected cases confirmed by medical record review) was 94.2%. More restrictive case definition algorithms increased the PPV to between 97.5% (identified by 1 or more codes/encounters in 1 data source) and 99.2% (identified in >1 data source). Although PPVs varied by birth defect, alternative algorithms increased accuracy for all birth defects; however, alternative algorithms also resulted in failing to ascertain 58.3% to 81.9% of cases. CONCLUSIONS: We found that surveillance programs that rely on unverified diagnosis codes can use algorithms to dramatically increase the accuracy of case finding, without having to review medical records. This can be important for etiologic studies. However, the use of increasingly restrictive case definition algorithms led to a decrease in completeness and the disproportionate exclusion of less severe cases, which could limit the widespread use of these approaches. PMID- 29620433 TI - What activates thermogenesis when lipid droplet lipolysis is absent in brown adipocytes? AB - Cold exposure activates the sympathetic nervous system. It is generally thought that this sympathetic activation induces heat production by stimulating lipolysis of cytosolic lipid droplets (LDs) in brown adipocytes. However, this concept was not examined in vivo due to lack of appropriate animal models. Recently, we and others have demonstrated that LD lipolysis in brown adipocytes is not required for cold-induced nonshivering thermogenesis. Our studies uncovered an essential role of white adipose tissue (WAT) lipolysis in fueling thermogenesis during fasting. In addition, we showed that lipolysis deficiency in brown adipose tissue (BAT) induces WAT browning. This commentary further discusses the significance of our findings and how whole body may be heated up without BAT lipolysis. PMID- 29620434 TI - Transient receptor potential polymorphism and haplotype associate with crisis pain in sickle cell disease. AB - AIM: Episodes of acute pain crisis contribute to considerable morbidity and mortality in sickle cell disease (SCD). Incomprehensive understanding of the underlying pain heterogeneity results in inadequate pain management. The transient receptor potential (TRP) family of voltage-gated ion channels acts as sensory transducers of diverse noxious stimuli. We performed an association study of polymorphisms in candidate genes TRPV1 and TRPA1 with pain in SCD patients. METHODS: Utilization rate, in other words, number of emergency department/acute care center admissions over 12 months as a result of pain crisis, served as a marker for acute pain. RESULTS & CONCLUSION: We identified that rs920829 (incident rate ratio = 1.44, p = 0.027 additive; IRR=1.68, p=0.008 recessive models of negative binomial regression) and the CGAGG haplotype of TRPA1 (odds ratio = 0.218, p = 0.009) were significantly associated with utilization rate, suggesting that TRPA1 gene polymorphisms may influence acute pain crisis in SCD. PMID- 29620435 TI - Beyond self-monitored plasma glucose and HbA1c: the role of non-traditional glycaemic markers in gestational diabetes mellitus. AB - Strict glycaemic management is the cornerstone of metabolic control in gestational diabetes mellitus (GDM). Current monitoring standards involve self monitoring plasma glucose (SMBG) and haemoglobin A1c (HbA1c). However, both have important limitations. SMBG only reflects instantaneous blood glucose and the inconvenience of self-collecting blood frequently results in poor compliance. HbA1c provides information on blood glucose levels from the previous 2 to 3 months and it is influenced by iron-deficient states, common during pregnancy. There is an urgent need for new shorter-term glycaemic markers, as glycated albumin, fructosamine or 1,5-anhydroglucitol. Glycated albumin seems especially interesting as it provides information on blood glucose levels over the foregoing 2-3 weeks and it is not influenced by iron deficiency or the dilutional anaemia of pregnancy. Fructosamine has a precise and inexpensive measurement and it is not affected by haemoglobin characteristics. This review further discusses the potential value of these non-traditional indicators of glycaemic control in patients with GDM, outlining their possible future applications. PMID- 29620436 TI - Probabilistic risk model to assess the potential for resistance selection following the use of anti-microbial medicated feed in pigs. AB - The cross-contamination of non-medicated feed with residues of anti-microbials (AM) causes a public and animal health concern associated with the potential for selection and dissemination of resistance. To analyse the associated risks, a probabilistic model was built using @Risk(r) (Palisade Corporation(r)) to show the potential extent of the effect of cross-contaminated pig feed on resistance selection. The results of the model include estimations of the proportion of pigs per production stage with residues of doxycycline, chlortetracycline, sulfadiazine and trimethoprim in their intestinal contents, as a result of exposure to cross-contaminated feed with different carry-over levels, in Belgium. By using a semi-quantitative approach, these estimations were combined with experimental data on AM concentrations associated with potential for resistance selection pressure. Based on this model, it is estimated that 7.76% (min = 1.67; max = 36.94) of sows, 4.23% (min = 1.01%; max = 18.78%) of piglets and 2.8% (min = 0.51%; max = 14.9%) of fatteners in Belgium have residues of doxycycline in their intestinal tract due to consumption of feed with at least 1% carry-over. These values were estimated to be almost triple for sulfadiazine, but substantially lower for chlortetracycline and trimethoprim. Doxycycline concentrations as low as 1 mg/L (corresponding to consumed feed with at least 1% carry-over) can select for resistant porcine commensal Escherichia coli in vitro and in vivo. Conclusions on this risk could not be drawn for other AM at this stage, due to the lack of data on concentrations associated with resistance development. However, since the possibility of resistance mechanisms (e.g. co selection) occurring cannot be excluded, the results of this model highlight that the use of AM medicated feed should be minimised where possible. In case of medicated feed production, good practice should be followed thoroughly at all levels of production, distribution, storage and administration, with a special focus on the feed distributed to piglets and sows. PMID- 29620437 TI - Estimated US infant exposures to 3-MCPD esters and glycidyl esters from consumption of infant formula. AB - A dietary exposure assessment was conducted for 3-monochloropropane-1,2-diol (3 MCPD) esters (3-MCPDE) and glycidyl esters (GE) in infant formulas available for consumption in the United States. 3-MCPDE and GE are food contaminants generated during the deodorisation of refined edible oils, which are used in infant formulas and other foods. 3-MCPDE and GE are of potential toxicological concern because these compounds are metabolised to free 3-MCPD and free glycidol in rodents and may have the same metabolic fate in humans. Free 3-MCPD and free glycidol have been found to cause adverse effects in rodents. Dietary exposures to 3-MCPDE and GE from consumption of infant formulas are of particular interest because formulas are the sole or primary food source for some infants. In this analysis, US Food and Drug Administration data on 3-MCPDE and GE concentrations (as 3-MCPD and glycidol equivalents, respectively) in a small convenience sample of infant formulas were used to estimate exposures from consumption of formula by infants 0-6 months of age. 3-MCPDE and GE exposures based on mean concentrations in all formulas were estimated at 7-10 and 2 ug/kg bw/day, respectively. Estimated mean exposures from consumption of formulas produced by individual manufacturers ranged from 1 to 14 ug/kg bw/day for 3-MCPDE and from 1 to 3 ug/kg for GE. PMID- 29620438 TI - Exploring movement and energy in human P-glycoprotein conformational rearrangement. AB - Human P-glycoprotein (P-gp), a kind of ATP-Binding Cassette transporter, can export a diverse variety of anti-cancer drugs out of the tumor cell. Its overexpression is one of the main reasons for the multidrug resistance (MDR) of tumor cells. It has been confirmed that during the substrate transport process, P gp experiences a large-scale structural rearrangement from the inward- to outward facing states. However, the mechanism of how the nucleotide-binding domains (NBDs) control the transmembrane domains (TMDs) to open towards the periplasm in the outward-facing state has not yet been fully characterized. Herein, targeted molecular dynamics simulations were performed to explore the conformational rearrangement of human P-gp. The results show that the allosteric process proceeds in a coupled way, and first the transition is driven by the NBDs, and then transmitted to the cytoplasmic parts of TMDs, finally to the periplasmic parts. The trajectories show that besides the translational motions, the NBDs undergo a rotation movement, which mainly occurs in xy plane and ensures the formation of the correct ATP-binding pockets. The analyses on the interaction energies between the six structure segments (cICLs) from the TMDs and NBDs reveal that their subtle energy differences play an important role in causing the periplasmic parts of the transmembrane helices to separate from each other in the established directions and in appropriate amplitudes. This conclusion can explain the two experimental phenomena about human P-gp in some extent. These studies have provided a detailed exploration into human P-gp rearrangement process and given an energy insight into the TMD reorientation during P-gp transition. PMID- 29620439 TI - Coffee with co-workers: role of caffeine on evaluations of the self and others in group settings. AB - This research explores the effect of consuming a moderate amount of commercially available caffeinated coffee on an individual's self-evaluated participation in a group activity and subsequent evaluations of the experience. Across two studies, results show that consuming a moderate amount of caffeinated coffee prior to indulging in a group activity enhances an individual's task-relevant participation in the group activity. In addition, subjective evaluations of the participation of other group members and oneself are also positively influenced. Finally, the positive impact of consuming a moderate amount of caffeinated coffee on the evaluation of participation of other group members and oneself is moderated by a sense of an increased level of alertness. PMID- 29620441 TI - Acknowledgment of Reviewers 2017. PMID- 29620440 TI - Study on the binding characteristics of hydroxylated polybrominated diphenyl ethers and thyroid transporters using the multispectral technique and computational simulation. AB - Hydroxylated polybrominated diphenyl ethers (OH-PBDEs) are a class of toxic environmental pollutants that are persistent, bioaccumulative, and difficult to degrade. Their structure is very similar to the thyroid hormone (T4) and uses the body's thyroid transporter (TTR) binding to interfere with the endocrine balance, disrupting the body's normal physiological activity. According to Fourier transform infrared spectroscopy and dynamics simulation of do_dssp module analysis, there are three kinds of OH-PBDEs that can induce TTR secondary structural changes. Fluorescence spectra and UV-Vis spectra show that for the three kinds of OH-PBDEs for TTR, the main methods of quenching are static quenching and non-radiative energy transfer. According to thermodynamic analysis, DeltaG < 0, DeltaH > 0, and DeltaS > 0 combine to show that the hydrophobic interaction is the main driving force of the combination. From the molecular docking analysis, it was found that 4'-hydroxy-2,2',4,5'- tetrabromodiphenyl ether (4'-OH-BDE49) and 4 hydroxy-2,2',3,4',5,6,6'- heptabromodiphenyl ether (4 OH-BDE188) had a cationic-pi interaction with TTR, whereas 4 hydroxy 2,2',3,4,5,5',6- heptabromodiphenyl ether (4-OH-BDE187) was bonded to TTR by hydrogen bonds to form stable complexes. In this paper, we highlight the consistency of spectroscopic experiments and computer simulations so as to provide a reliable analytical method for the toxicological properties of small molecule contaminants. PMID- 29620442 TI - MiR-21/STAT3 Signal Is Involved in Odontoblast Differentiation of Human Dental Pulp Stem Cells Mediated by TNF-alpha. AB - Dental pulp stem cells (DPSCs), as one type of mesenchymal stem cells (MSCs), have the capability of self-renewal and multipotency to differentiate into several cell lineages, including osteogenesis, odontoblasts, chondrogenesis, neurogenesis, and adipogenesis. It has found that tumor necrosis factor-alpha (TNF-alpha) can promote osteogenic differentiation of human DPSCs in our previous studies. Other experimentation revealed that signal transducer and activator of transcription 3 (STAT3) underwent a rapid activation both in osteogenesis and inflammation microenvironment of MSCs in vitro. MicroRNAs (miRNAs or miRs) have been proved in previous studies to regulate MSCs differentiation in vitro. In this study, we identified miR-21 as a key miRNA contributed the functional axis of odontoblast differentiation induced by STAT3. It is observed that the expression of miR-21 and STAT3 increased gradually in low concentration (1-10 ng/mL) of TNF-alpha, while they were suppressed in high concentration (50-100 ng/mL). The upregulation of miR-21 may facilitate the odontoblast differentiation of DPSCs coordinating with STAT3. SiSTAT3 or treated by the inhibitor of STAT3, cucurbitacin I (Cuc I), significantly increased primary miR-21 expression along with decreased mature miR-21 expression. Meanwhile, the inhibition of miR-21 (anti-miR-21) decreased the activation of STAT3 as well as suppressed the marker proteins of odontoblast differentiation. The results revealed a new function of miR-21, suggesting that miR-21/STAT3 signal may act as a modulator within a complex network of factors to regulate odontoblast differentiation of human DPSCs. It may provide a novel therapeutic strategy to regulate the odontoblast differentiation of DPSCs. PMID- 29620443 TI - MiR-2861 Behaves as a Biomarker of Lung Cancer Stem Cells and Regulates the HDAC5 ERK System Genes. AB - Cancer stem cells (CSCs) are responsible for cancer initiating, recurrence, and drug resistance. Discovery of novel biomarkers for CSCs is helpful for early diagnosis and prognosis. Lung cancer stem cells (LCSCs) were closely related to the occurrence and development of lung cancer. In our study, the important role of miR-2861 in maintaining the stemness of LCSCs was investigated. The LCSC differentiation model was established through introducing serum into the medium of H460 spheres. miR-2861 expression was significantly higher in LCSCs no matter compared to the differentiation cells or normal cells. HDAC5 expression was positively correlated with miR-2861 in LCSCs, and knockdown of miR-2861 decreased the expression of HDAC5, which implied that HDAC5 may be involved in the differentiation of LCSCs mediated by miR-2861. The role of HDAC5 in the regulation of LCSC differentiation was further verified by the inhibitory effect of LMK-235 on the phosphorylation of ERK1/2, which was recognized as the regulator of CSC differentiation. Our study provided a better understanding of miR-2861 and HDAC5 axis in maintaining the stemness of LCSCs and laid a foundation for molecular targeted therapy. PMID- 29620444 TI - Cloning of Buffalo, a Highly Valued Livestock Species of South and Southeast Asia: Any Achievements? AB - Buffalo (Bubalus bubalis) is a major source of milk, meat, and draught power in many developing countries in Asia. Animal cloning holds a lot of potential for fast multiplication of elite buffaloes and conservation of their valuable germplasm. Although the progress of buffalo cloning has been slow in comparison to cattle or pig, several breakthroughs were reported in buffalo cloning such as the production of cloned calves from somatic cells isolated from over one-decade old frozen-thawed semen or from urine-derived cells. Since the initiation of buffalo cloning, several approaches have been tried to refine nuclear transfer protocols. This has resulted in increasing the blastocyst production rate and improving their quality leading to an increase in live birth rate. In this review, we discuss current developments in buffalo cloning, its challenges, and the future roadmap. PMID- 29620445 TI - Induction of Human Adipose-Derived Mesenchymal Stem Cells into Germ Lineage Using Retinoic Acid. AB - Accumulating evidence indicates that mesenchymal stem cells (MSCs) have been widely used in tissue engineering and regenerative medicine due to their multilineage differentiation potentials. Recent studies show that germ-like cells can also be derived from stem cells, such as human umbilical cord MSCs and human bone marrow MSCs in vitro. However, whether human adipose-derived MSCs (hAD-MSCs) can be induced into germ-like cells has never been reported. In this study, we isolated hAD-MSCs and confirmed that their characteristics were in accordance with that of MSCs established before. Germ cell lineage differentiation was performed by 10 MUM retinoic acid (RA) treatment for 21 days. RA induction led to slender spindles and tadpole-like changes of cell morphology, and the expression of germ cell-specific markers (Oct4, Piwil2, Itgb1, SSEA-1, and Stra8) presented significant upregulation in the RA treatment group according to the polymerase chain reaction and immunofluorescence results. We first demonstrated that hAD MSCs can differentiate into germ-like cells in vitro, which will provide theoretical and experimental basis for the clinical application of hAD-MSCs in the treatment for infertility. PMID- 29620446 TI - Synthesis of dihydroisorcordoin derivatives and their in vitro anti-oomycete activities. AB - A series of novel dihydrochalcone derivatives 2-7 were synthesized from dihydroisorcordoin 1 which was isolated from the aerial parts of Adesmia balsamica. The structures of all compounds were confirmed by 1H NMR, 13C NMR, and HRMS. Their anti-oomycete activity was evaluated in vitro against Saprolegnia parasitica and Saprolegnia diclina. Some of the newly synthesized compounds exhibited better anti-oomycete activities at low values compared with bronopol and fluconazole as positive controls. Among them, compound 7 exhibited strong activity, with minimum inhibitory concentration and minimum oomyceticidal concentration values of 75 and 100 MUg/mL, respectively. PMID- 29620447 TI - Embelin: a benzoquinone possesses therapeutic potential for the treatment of human cancer. AB - Natural products have been gaining recognition and are becoming a significant part of research in the area of drug development and discovery. Phytochemicals derived from these sources have been comprehensively studied and have displayed a wide range of activities against many fatal diseases including cancer. One such product that has gained recognition from its pharmacological properties and nontoxic nature is embelin, obtained from Embelia ribes. Amid all the vivid pharmacological activities, embelin has gained its prominence in the area of cancer research. Embelin binds to the BIR3 domain of XIAP, preventing the association of XIAP and caspase-9 resulting in the suppression of cell growth, proliferation and migration of various types of cancer cells. Furthermore, embelin modulates anti-apoptotic pathways by suppressing the activity of NF kappaB, PI3-kinase/AKT, JAK/STAT pathway - among others. The present review summarizes the various reported effects of embelin on different types of cancer cells and highlights the cellular mechanisms of action. PMID- 29620448 TI - Analysis of flavonoid glycosides with potential medicinal properties on Bauhinia uruguayensis and Bauhinia forficata subspecies pruinosa. AB - Several Bauhinia species are widely used in Southern South America in the treatment of infections, pain and several diseases including diabetes. Flavonoid compounds based on quercetin and kaempferol glycoside derivatives are believed to be responsible for their therapeutic properties. To investigate this, we have studied two native species from Argentina: B. uruguayensis (BU) and B. forficata subsp. pruinosa (BF). We have analyzed the major polyphenol components in hydro methanolic extracts of leaves, by high performance liquid chromatography tandem mass spectrometry. Chromatographic analysis yielded five main compounds in BF, corresponding to rutinosides and rhamnosides derivatives of kaempferol and quercetin, which are considered chemotaxonomic markers and responsible for antioxidant activity. The presence of kaempferitrin, an antidiabetic agent, has been confirmed. In extracts of BU, four major compounds were identified as rhamnosides and galloyl derivates from quercetin and kaempferol. One of these compounds, quercitrin-3-rhamnoside may confer anti-inflammatory and analgesic properties to BU extracts. PMID- 29620450 TI - Clinical pharmacogenetics: how do we ensure a favorable future for patients? AB - Currently, there is sufficient evidence for the use of pharmacogenetic information to optimize medication prescribing, but why has this information not been integrated into the drug prescribing process to improve patient care? A discussion about the major contributing factors that have limited the use of pharmacogenetic information in the drug prescribing process, the solutions to ensure widespread uptake, and a vision for the future of the pharmacogenetic field will be explored. PMID- 29620449 TI - Low lean tissue mass can be a predictor of one-year survival in hemodialysis patients. AB - PURPOSE: Nutritional status has a significant impact on the outcomes in the dialysis population. The aim of this study was to evaluate the association between body composition and a one-year survival of hemodialysis patients. METHODS: Forty-eight patients with chronic kidney disease stage V treated with hemodialysis for more than three months were included. Body composition was assessed by bioimpedance spectroscopy (Body Composition Monitor, Fresenius Medical Care). Blood samples for serum creatinine, serum albumin, serum prealbumin, high sensitivity C-reactive protein (hsCRP), interleukin 6 (IL-6), insulin-like growth factor 1(IGF-1) concentrations were taken before the midweek dialysis session. RESULTS: Over the course of a one-year observation, seven patients died. We observed a significantly lower lean tissue index (LTI) (p = .013) and higher IL-6 (p = .032) and hsCRP levels (p = .011) among the patients who died. The remaining biochemical markers did not differ between these two groups. Kapplan-Meier analysis revealed a worse survival rate in patients with sarcopenia (lower than the 10th percentile for their age and gender) in comparison with those with normal LTI. However, it was not of statistical significance (p = .055). LTI inversely correlated with age and IL-6 and positively with IGF-1. CONCLUSIONS: Sarcopenia defined as decreased LTI, is a relatively common condition among patients undergoing maintenance hemodialysis, it can also be associated with a lower one-year survival rate. Decreased lean tissue mass can be associated with old age, lower IGF-1 levels and higher IL-6 levels. Body composition assessment may provide prognostic data for hemodialysis patients. PMID- 29620451 TI - Flavonoids from Plinia cauliflora (Mart.) Kausel (Myrtaceae) with antifungal activity. AB - Plinia cauliflora is a plant species with edible fruits but its chemical composition is not totally known yet although former studies showed its potential as antifungal agent. This work aimed the chemical analysis of the leaves, the activity against fungi species and evaluated cytotoxicity. Extract was obtained with 70% ethanol. An ethyl acetate fraction was obtained and glycosylated quercetin and myricetin were isolated. Samples were tested against Candida species, dermatophytes and entomopathogenic fungi. Cytotoxicity was evaluated against fibroblast cells. Extract showed good activity against C. albicans (minimum inhibitory concentration at 156 MUg/mL), C. parapsilosis (78 MUg/mL), C. krusei (19 MUg/mL), Trichophyton rubrum (78 MUg/mL) and Microsporum canis (156 MUg/mL). Isolated compounds were more active against C. krusei and T. rubrum. The extract, which was the more active sample, demonstrated low cytotoxic effect and encourage more studies against rising non-albicans species and dermatophyte T. rubrum. PMID- 29620452 TI - Evaluation of Cytology for Diagnosing Avian Pox in Wild Turkeys ( Meleagris gallopavo). AB - Avian pox virus is a common cause of proliferative skin disease in wild turkeys ( Meleagris gallopavo); however, other etiologies may produce grossly indistinguishable lesions. Common methods for diagnosing avian pox include histopathology, virus isolation, and PCR. While these methods are sufficient in most cases, each has their limitations. Cytology is a cost-effective and rapid approach that may be useful when traditional diagnostics are not feasible. The objective of this study was to evaluate the performance of cytology relative to histopathology and PCR for avian pox diagnosis in wild turkeys. Fifty wild turkeys were submitted for necropsy due to nodular skin lesions on unfeathered skin of the head. Of these, five had similar skin lesions on the unfeathered legs and 26 had plaques on the mucosa of the oropharynx or esophagus. Representative skin, oropharyngeal, and esophageal lesions from all birds were examined with cytology and histopathology. Skin lesions on the head of each bird were also tested for avian pox virus via PCR. Histopathology and PCR were equally sensitive in diagnosing avian pox from skin lesions on the head. There were no significant differences between cytologic and histopathologic diagnosis of avian pox from skin lesions on the head (sensitivity = 97.4%, specificity = 100.0%), legs (sensitivity = 75.0%, specificity = 100.0%), or from lesions in the oropharynx and esophagus (sensitivity of 62.5%). Similarly, there were no significant differences between PCR and cytology for diagnosis of pox viral skin lesions of the head. Relative to PCR detection of avian pox virus, cytology had a sensitivity of 90.0% and a specificity of 90.0%. These results suggest that cytology is a useful tool for diagnosis of avian pox in wild turkeys. PMID- 29620453 TI - Isolation and Characteristics of the Arkansas-Type Infectious Bronchitis Virus in China. AB - Two infectious bronchitis virus (IBV) strains, designated as gammaCoV/ck/China/I0712/11 (I0712/11) and gammaCoV/ck/China/I0108/17 (I0108/17), were isolated from diseased chicken flocks in different provinces in China and genotyped as Arkansas (Ark)-type viruses with three other Chinese Ark field strains, the Jilin vaccine strain, and the American Ark- and Ark DPI-like viruses. Complete genomic sequence analysis and pairwise comparison of nucleotide sequences encoding the S1 subunit of the spike protein and other structural and accessory proteins revealed that Chinese Ark field isolates were genetically closely related to the Jilin vaccine and American ArkDPI11 strains, although extensive nucleotide changes were found across the genomes of Chinese Ark field isolates. This suggests that Chinese Ark-type isolates are derived from the Jilin vaccine, and have diverged and evolved independently by point mutations since introduction into China. It is also possible that the Chinese Ark viruses have arisen as a result of different introductions of American ArkDPI11-like strains from the United States; this hypothesis requires further investigation. Pathogenicity testing showed that Chinese Ark viruses had comparable virulence to that of the Massachusetts-type M41 strain, although they had lower affinity for the kidneys of chickens than the M41 strain had. Although Ark-type viruses are not widespread in China, surveillance and updating the currently applied vaccination strategy for sound protection against IBV disease are important because this type of virus has caused heavy economic losses in the United States. PMID- 29620454 TI - Wildlife Presence and Interactions with Chickens on Australian Commercial Chicken Farms Assessed by Camera Traps. AB - The types of wildlife and the frequency of their visits to commercial chicken farms in Australia were assessed using infrared and motion-sensing camera traps. Cameras were set up on 14 free-range layer farms, three cage layer farms, two barn layer farms, five non-free-range meat chicken farms, and six free-range meat chicken farms in the Sydney basin region and South East Queensland. Wildlife visits were found on every farm type and were most frequent on cage layer farms (73%), followed by free-range layer farms (15%). The common mynah ( Acridotheres tristis) was the most frequent wildlife visitor in the study (23.9%), followed by corvids (22.9%) and Columbiformes (7.5%). Most wildlife visits occurred during the day from 6 am to 6 pm (85%). There were infrequent observations of direct contact between chickens and wildlife, suggesting the indirect route of pathogen transfer may be more significant. The level of biosecurity on the farm is suggested to impact the frequency of wildlife visits more so than the farm type. PMID- 29620455 TI - Pancreatitis Is an Important Feature of Broilers Suffering from Inclusion Body Hepatitis Leading to Dysmetabolic Conditions with Consequences for Zootechnical Performance. AB - The aim of the present study was to further unravel the pathophysiologic mechanisms of inclusion body hepatitis (IBH). In a first trial, the susceptibility of specific-pathogen-free (SPF) broilers to fowl aviadenovirus (FAdV) infections was investigated. Regardless of viral dose, route of infection, and susceptibility to disease on day 1, the 3-week-old SPF broilers showed resistance to IBH, with no mortality being recorded throughout the experiment. In a second trial, SPF broilers were orally infected at 3 weeks of age with a FAdV-E strain, and their digestive and metabolic processes were monitored. The birds' performance decreased from 7 days postinfection (dpi) onward, and hepato- and pancreatomegaly were found at necropsy at 4, 7, and 10 dpi and at 7 dpi, respectively. Clinical chemistry revealed transient hyperlipasemia at 4 dpi and hyperglycemia from 4 dpi onwards, with 25% of infected birds showing glycemia levels suggestive of diabetes mellitus. Histopathology findings included typical adenoviral hepatitis in the liver, while in the pancreas, inflammation characterized by multifocal infiltrations of lymphocytes, together with shrinkage of acinar cells, loss of acinar arrangement, and hyperplasia of islet cells, was noticed. Additionally, the pancreatic tissue had tendentiously lower levels of enzyme activity, and in the ileum, the digestibility of fat was significantly impaired. Hence, our data reinforce the concept of age-related resistance to experimentally induced IBH. Additionally, we demonstrated that FAdV-induced pancreatitis in broilers interferes with the digestive process and evolves into a dysmetabolic condition that resembles diabetes, affecting the health and zootechnical performance of birds, and therefore providing an important component of IBH pathogenesis. PMID- 29620456 TI - Blood Glucose Concentrations in Nicarbazin-Fed Broiler Chickens. AB - Four floor pen studies were carried out to evaluate the effects of nicarbazin (NIC) administration on blood glucose concentrations and the onset of hypoglycemia in broiler chickens. All tests involved continuous NIC feeding at 0, 100, or 125 ppm to 28 days of age. In each study, birds were reared at both standard environmental temperatures and at 3 C below this level. In addition, two studies were conducted in the presence of coccidial infection and two were carried out in noninfected broilers. At 26 days of age in each test, two birds per pen were bled by puncture of the brachial vein, and whole blood glucose concentrations were determined. Results indicated that the administration of NIC to broilers for 26 days had no effect on blood glucose concentrations, although graded levels of NIC tended to increase these values. In addition, no evidence of hypoglycemia was recorded in any of the trials. In a similar fashion, blood glucose was unaffected by environmental temperature and coccidial challenge. These findings support previous work showing that NIC administration does not influence blood glucose levels and indicate that the product is not involved when field diagnoses use reduced blood glucose and hypoglycemia as indicators of production anomalies. PMID- 29620457 TI - Retrospective Study of Histomoniasis (Blackhead) in California Turkey Flocks, 2000-2014. AB - The flagellate parasite Histomonas meleagridis causes a severe disease in turkeys. Since nitarsone, the last antiflagellate feed additive, was withdrawn from the market, H. meleagridis has gained increasing clinical and economic importance, and frequently entire turkey flocks are lost to the disease. Even before the antiflagellate market withdrawal, H. meleagridis has been recognized as a noteworthy disease in commercial turkeys. The aim of this study was to compile and analyze data on histomoniasis outbreaks diagnosed by the California Animal Health and Food Safety System in the years 2000 through 2014 while nitarsone was still available. Sixty-two cases were included in the study. In all cases, the parasite was detected by histopathology. Five cases were from breeder flocks, 44 from commercial meat turkey flocks, and 13 from other flocks such as backyard flocks or pet turkeys. There were between one and eight cases each year with no clear trend over time. Most cases occurred in the warmer months between April and October with a clear peak in August. Turkeys in the flocks with the disease were aged between 2 wk and 15 mo, with a median age of 9 wk. In cases for which mortality was reported, daily mortality ranged between 0.04% and 2% with an average of 0.34% and a median of 0.15%. Five-week mortality in infected houses on three infected ranches was between 1.3% and 68%. In 12 cases, the parasite was observed in organs other than ceca and liver. These included spleen, kidney, bursa of Fabricius, proventriculus, lung, pancreas, and crop. In 58 cases, histomoniasis was considered the most significant and primary diagnosis; in four cases histomoniasis was regarded as an incidental finding. In 14 other outbreaks, detailed information was available. In 11 cases, more than one house on the ranch was affected; in five cases the disease spread to all houses. Total mortality in turkeys from affected flocks ranged between 12% and 65%. In eight flocks, the birds were marketed with a weight that was considered too light. In conclusion, the present study shows that even with nitarsone available as antiflagellate feed, additive histomoniasis was a serious disease of turkeys in the United States with an epidemiology similar to that observed in Europe. PMID- 29620458 TI - Comparative Evaluation of the Pathogenicity of Mycoplasma gallinaceum in Chickens. AB - Mycoplasma gallinaceum is not among the most pathogenic mycoplasmas affecting poultry, but its continuous re-isolation from flocks in South Africa displaying typical signs of mycoplasmosis prompted us to revisit its role in respiratory disease. Specific-pathogen-free white leghorn chickens were co-challenged with either M. gallinaceum (MGC) and QX-like infectious bronchitis virus (IBV), or the more virulent Mycoplasm gallisepticum (MG) and IBV. No clinical signs were observed apart from sneezing in chickens challenged with IBV, MGC + IBV, and MG + IBV. On postmortem examination, one bird each in the MGC + IBV and IBV groups developed peritonitis or airsacculitis, respectively. In the tracheas, the MG + IBV group showed the most severe ciliary damage with a mean ciliostatic score of 32.40 compared to scores of 26.83 and 20.4 for the MGC + IBV and IBV groups, respectively. Corresponding tracheal lesions were recorded. Quantitation of the challenge pathogens by quantitative real-time PCR and real-time reverse transcriptase-PCR determined that MGC was shed in much higher titers from the trachea than MG, when co-infected with IBV. Interestingly, the presence of both MG and MGC appeared to enhance IBV replication in the tracheas of infected chickens, whereas the presence of IBV suppressed MG and MGC proliferation in the trachea. In general, the nonpathogenicity of M. gallinaceum in chickens was confirmed, but it was able to aggravate respiratory disease and pathogen proliferation with virulent QX-like IBV. PMID- 29620461 TI - Genetic and Pathologic Characterization of a Novel Recombinant TC07-2-Type Avian Infectious Bronchitis Virus. AB - Avian infectious bronchitis viruses (IBVs) with the TC07-2 genotype have spread rapidly in East Asia since they were first reported in China in 2007. In 2015, an IBV with the TC07-2 genotype (designated KrD1515) was isolated from layer chickens with severe respiratory symptoms in Korea. In the present study, the full-length open reading frames of the spike (S) and nucleocapsid (N) genes of the virus were sequenced and analyzed. S1 gene phylogenetic analysis revealed that the KrD1515 virus clustered with viruses with the TC07-2 genotype, whereas N gene phylogenetic analysis revealed that the KrD1515 virus clustered with Korean IBVs, but not with Chinese TC07-2 IBV. When 7-day-old specific-pathogen-free chickens were inoculated with the KrD1515 virus, they developed severe respiratory symptoms and tracheal lesions. However, there were no other clinical symptoms or pathologic lesions in other tissues. The virus was shed from the trachea for at least a week and from the cloaca for only a day. Our findings suggest that the KrD1515 virus is a recombinant virus between a Chinese TC07-2 IBV and a non-TC07-2 Korean IBV and engages in respiratory tropism in chickens. PMID- 29620462 TI - Propagation of an Avirulent Turkey Hemorrhagic Enteritis Virus Isolate in Chickens. AB - A series of studies were undertaken to optimize the propagation of hemorrhagic enteritis virus (HEV) in specific-pathogen-free (SPF) chickens. A total of 562 SPF chickens were orally inoculated with an Australian avirulent HEV isolate of turkey origin at 9, 14, 21, or 28 days of age with 5, 6, 7, or 8 log 10 genomic copies (GC), while 102 chickens served as uninfected controls. No clinical signs were observed in infected chickens. There was an inoculum-dose-dependent increase in the relative spleen and liver weight ( P < 0.01). Relative spleen weight 7 days post-HEV inoculation was up to 85% higher in chickens that were inoculated with 6 to 7 GC compared with controls, with no further increase at higher doses. Relative liver weight increased up to 14% in chickens inoculated with 6 GC, with no further increase. Birds inoculated with a 7 GC dose had a higher frequency of HEV DNA-positive birds (77% to 86%) than birds inoculated with lower doses (33% to 59%; P < 0.01). The most efficient dose for live passage propagation was 7 GC inoculated in 9-to-14-day-old birds, yielding an infection rate of 81%. Livers and spleens from infected birds at all doses were processed to produce a putative vaccine with a final GC recovery in the vaccine material of 8.6 GC/bird. In summary, HEV of turkey origin can be readily propagated in SPF chickens, and conditions to maximize viral retrieval were established. PMID- 29620463 TI - Biosecurity Assessment and Seroprevalence of Respiratory Diseases in Backyard Poultry Flocks Located Close to and Far from Commercial Premises. AB - Raising backyard chickens is an ever-growing hobby in the United States. These flocks can be a substrate for respiratory disease amplification and transmission to commercial facilities. Five hundred fifty-four chickens from 41 backyard flocks were sampled in this study. ELISA kits were used to detect antibodies against avian influenza (AI), infectious laryngotracheitis (ILT), Newcastle disease (ND), infectious bronchitis (IB), Ornithobacterium rhinotracheale (ORT), Mycoplasma gallisepticum (MG), and Mycoplasma synoviae (MS). All visited flock owners answered a biosecurity questionnaire that assessed biosecurity measures. The questionnaire revealed that backyard poultry owners lack simple biosecurity measures such as use of dedicated shoes, their chicken sources are unreliable, and few of them benefit from veterinary oversight. Only one flock had a clear vaccination history against ND and IB. ORT, ND, IB, MS, MG, and ILT were the most seroprevalent in backyard poultry flocks with 97% (41/42), 77.5% (31/40), 75% (30/40), 73% (31/42), 69% (29/42), and 45% (19/42), respectively. The vaccinated flock was not considered in these calculations. When examining the distance between backyard flocks and the nearest commercial poultry facility, ND and MG were significantly more likely to be found in backyard flocks close to (<4 miles) whereas ORT was significantly more likely in backyard chickens located far from (>4 miles) commercial poultry. Birds purchased directly from National Poultry Improvement Plan hatcheries showed a reduced ND, MG, and MS antibody prevalence. Wearing dedicated shoes decreased MS antibody-positive birds. Finally, history of wild bird contact had a clear effect on an increased seroprevalence of NDV and MG. Serological results suggest that backyard poultry flocks have the potential to serve as a reservoir or amplifier for poultry respiratory diseases. The information generated in this project should direct extension efforts toward emphasizing the importance of small flock biosecurity and chick acquisition sources. PMID- 29620464 TI - The Effect of the Wooden Breast Myopathy on Sarcomere Structure and Organization. AB - The wooden breast (WB) has been classically identified by the phenotypic presence of a wood-like pectoralis major (p. major) muscle. The WB-affected p. major muscle is characterized by necrotic muscle fibers and the replacement of muscle with connective tissue, water, and fat. The objective of the current study was to determine the effect of the WB myopathy on sarcomere organization by transmission electron microscopy. Sarcomere structure and organization were examined in two broiler lines with a high incidence of WB (Lines A and B) and another broiler line without WB (Line C). Affected muscle had an increase in smaller myofibers with diameters of 20 MUm or less. Sarcomere organization decreased with fiber diameter in both Lines A and B. The structure and organization of sarcomeres in Line C were similar to WB-unaffected muscle in Lines A and B. Taken together, these data demonstrate that the WB myopathy detrimentally affects sarcomere organization in a broiler line-specific manner. Disorganization of sarcomere structure will affect the function of the p. major muscle as well as meat quality. PMID- 29620465 TI - Isolation and Characterization of Campylobacter hepaticus from Layer Chickens with Spotty Liver Disease in the United States. AB - Spotty liver disease (SLD) is characterized by multifocal liver lesions, mortality, and drop in egg production. The disease is emerging in Europe and Australia, particularly in free-range and floor-raised layer flocks. Campylobacter hepaticus has been recently identified as the causative agent of SLD. We report the isolation and characterization of C. hepaticus from livers of laying hens affected with SLD in the United States. Two isolates were characterized and found to be highly similar to those described from SLD cases in the United Kingdom and Australia. Initial isolation of C. hepaticus from liver samples required microaerophilic and thermophilic conditions and incubation for a particularly long duration (approximately 7 days). Morphologic and phenotypic properties of the isolates were typical for Campylobacter spp. Phylogenetic analysis based on 16S ribosomal RNA gene sequences and detection of a glycerol kinase gene confirmed the identity of the isolates as C. hepaticus. To the authors' knowledge, this is the first report of C. hepaticus isolation from layer chickens with SLD in the United States. With the increasing changes in the egg industry from conventional cages to cage-free housing systems, the incidence and economic impact of SLD could become significant. PMID- 29620466 TI - Liposarcoma in a Backyard Silkie and Retrospective Summary of Neoplasms Diagnosed in Backyard Chickens Submitted to the California Animal Health and Food Safety Laboratory System, 2008-2017. AB - Liposarcomas are a malignant neoplasm of adipocytes, and are rarely diagnosed in avian species. This case report describes the evidence supporting a diagnosis of metastatic liposarcoma in a backyard silkie chicken. On September 28, 2017, a dead 3-yr-old backyard silkie chicken, with a history of unknown skin lesions involving the entire body and severe weight loss, was submitted to California Animal Health and Food Safety Laboratory System-Turlock branch for necropsy. At necropsy, raised necrotic lesions involving the majority of the skin and multiple nodules in the liver, spleen, and bone marrow were noticed. Microscopically, stellate, spindle, and myxoid cells containing large vacuoles, which were confirmed as lipid droplets by Oil Red O, were observed infiltrating the dermis and underlying a necrotic epidermis, with metastasis to liver, spleen, bone marrow, and ovary being the most significant findings. PAS, Oil Red O, Ziehl Neelsen, Congo red, Gram, and Von Kossa stains, along with immunohistochemistry for pan cytokeratin, vimentin, S100, CD3, pp38, and Meq were used to classify the lesions. Intensely positive vimentin immunohistochemistry, along with large quantities of Oil Red O-positive lipid droplets within the neoplastic cells, were supportive of our diagnosis of liposarcoma. The incidence of neoplastic diseases diagnosed in backyard flock submissions to CAHFS system wide from 2008 to 2017 was also reviewed. PMID- 29620467 TI - The Effect of Infectious Bursal Disease Virus-Induced Immunosuppression on Vaccination Against Highly Pathogenic Avian Influenza Virus. AB - Poor efficacy of avian influenza virus (AIV) vaccines in chickens has been documented in the field in spite of good results in experimental settings. Although the causes are multifactorial and complex, one contributing factor may be prior infection with immunosuppressive viruses. In an effort to evaluate the role of immunosuppressive agents on AIV pathogenesis and vaccine efficacy, the effect of prior infection with infectious bursal disease virus (IBDV), a ubiquitous immunosuppressive virus of chickens, was evaluated. Specific-pathogen free white Plymouth Rock chickens were exposed to variant E IBDV at 1 day of age and were subsequently vaccinated with an inactivated H7 AIV vaccine 2 wk later. Vaccinated chickens exposed to IBDV had a geometric mean antibody titer to AIV of 1:1.7 by hemagglutination inhibition assay compared to a geometric mean titer of 1:47.5 from chickens that were vaccinated but not exposed to IBDV. Three weeks postvaccination, the chickens were challenged with one of six different doses of highly pathogenic (HP) AIV homologous to the vaccine. Within challenge virus dose groups, vaccinated chickens exposed to IBDV had similar mortality rates to nonvaccinated chickens that were not exposed to IBDV. In contrast, vaccinated chickens that were not exposed to IBDV were protected from mortality. Exposure to IBDV also decreased the mean death time (2.3-3.7 days depending on dose) compared with vaccinated birds not exposed to IBDV (4-7 days depending on dose). Neither vaccination nor IBDV infection had an effect on mean bird infection dose with HPAIV, but the 50% bird lethal dose was reduced from >106 50% egg infective dose (EID50) in the vaccinated, IBDV-nonexposed group to 103.3 EID50 in the vaccinated group exposed to IBDV. These results are consistent with IBDV exposure contributing to poor vaccine efficacy in the field. PMID- 29620468 TI - Detection of Mycoplasma gallisepticum in House Finches ( Haemorhous mexicanus) from Arizona. AB - In 1994, an endemic poultry pathogen, Mycoplasma gallisepticum (MG), was identified as the causative agent of a novel disease in house finches ( Haemorhous mexicanus). After an initial outbreak in Maryland, MG spread rapidly throughout eastern North American populations of house finches. Subsequently, MG spread slowly through the northern interior of North America and then into the Pacific Northwest, finally reaching California in 2006. Until 2009, there were no reports of MG in the southwestern United States east of California. In August 2011, after reports of house finches displaying conjunctivitis characteristic of MG infection in Arizona, we trapped house finches at bird feeders in central Arizona (Tempe) and southern Arizona (Tucson and Green Valley) to assay for MG infection. Upon capture, we noted whether birds exhibited conjunctivitis, and we collected choanal swabs to test for the presence of MG DNA using PCR. We detected MG in finches captured from Green Valley (in ~12% of birds captured), but not in finches from Tucson or Tempe. Based on resampling of house finches at these sites in July 2014, we suggest that central Arizona finches likely remain unexposed to MG. We also suggest that low urban connectivity between arid habitats of southern and central Arizona or a reduction in the prevalence of MG after its initial arrival in Arizona may be limiting the spread of MG from south to north in Arizona. In addition, the observed conjunctivitis-like signs in house finches that were negative for MG by PCR may be caused primarily by avian pox virus. PMID- 29620469 TI - Tetratrichomonas and Trichomonas spp.-Associated Disease in Free-Ranging Common Eiders ( Somateria mollissima) from Wellfleet Bay, MA and Description of ITS1 Region Genotypes. AB - During an outbreak of Wellfleet Bay virus (WFBV) in common eiders ( Somateria mollissima) from the Cape Cod region of Massachusetts, several birds were diagnosed with trichomonosis consisting of multiple trichomonad species. Six birds were examined, with trichomonads found in ceca in four birds and associated typhlitis in three of these four birds. PCR and DNA sequencing utilizing trichomonad-specific primers targeting the ITS1 region of the ribosomal DNA (rDNA) revealed the presence of Tetratrichomonas gallinarum in the gastrointestinal tracts of five birds and Trichomonas spp. in the livers of two birds, one of which had a dual Te. gallinarum-Trichomonas gallinae infection. Sequence analysis revealed no variation between Te. gallinarum sequences whereas the ITS1 sequences obtained from the other Trichomonas spp. demonstrated the presence of multiple genotypes. One sequence had 100% identity to a Trichomonas sp. previously isolated from a Cooper's hawk ( Accipiter cooperii) and the other sequence was 100% identical to a previously described Tr. gallinae isolate obtained from a Pacific Coast band-tailed pigeon ( Patagioenas fasciata monilis). These findings suggest Te. gallinarum and other Trichomonas spp. possibly contributed to morbidity and mortality in this species. Furthermore, to the authors' knowledge, this is the first report of trichomonad-associated disease in a free-ranging sea duck. PMID- 29620470 TI - Study of an Outbreak of Highly Pathogenic Avian Influenza H5N8 in Commercial Pekin Ducks ( Anas platyrhynchos domesticus) in California. AB - A February 2015 outbreak of highly pathogenic avian influenza (HPAI) H5N8 in a flock of commercial Pekin ducks ( Anas platyrhynchos domesticus) in California was investigated in detail. Approximately 17,349 five-wk-old ducks experienced an increased mortality from a normal of eight birds per day to 24, 18, 24, 33, and 61 birds per day, respectively, in the last 5 days prior to flock depopulation. Clinically, there was decreased water and feed consumption, and approximately 1.0% of the affected flock exhibited neurologic signs. Necropsy of five clinically ill ducks revealed pale, patchy areas on the epicardium in two birds, pale foci of necrosis in the liver of one bird, and airsacculitis in three birds. Histopathology revealed multifocal nonsuppurative encephalomyelitis, myocarditis, myositis, pancreatitis, hepatitis, and glossitis. Immunohistochemistry revealed avian influenza virus (AIV) nucleoprotein in the nucleus and cytoplasm of various cells in the aforementioned organs, as well as in the skin and feathers. Eight of the 10 sera samples tested were positive for avian influenza antibodies by agar gel immunodiffusion serology. Oropharyngeal and cloacal swabs taken from 15 birds, as well as from the lungs, livers, pancreas, and spleen, were positive for AIV by real-time reverse transcriptase (rRT) PCR. AIV was isolated and typed as Eurasian lineage HPAI H5N8, clade 2.3.4.4, by the National Veterinary Services Laboratory, Ames, IA. Extensive surveillance of birds for AIV around the 10-km zone did not reveal any additional cases. Ducks on the affected premises were humanely euthanatized by foam and composted in-house, the houses were heated to 57 C for 4 days, and swabs were taken periodically from the compost to ensure negativity for AIV by rRT-PCR. The compost and litter were then removed, and the house was pressure cleaned, disinfected, and repopulated approximately 120 days after euthanatization of the ducks. PMID- 29620471 TI - Recombinant Fiber-2 Protein-Based Indirect ELISA for Antibody Detection of Fowl Adenovirus Serotype 4. AB - Clinical cases of hepatitis-hydropericardium syndrome (HHS) from fowl adenovirus serotype 4 (FAdV-4) have increased in China since 2013. Therefore, the development of a new serologic method for HHS detection is now urgent. Here, the FAdV-4 strain JSJ13 was used to construct a plasmid for prokaryotic expression of the JSJ13 fiber-2 protein. The protein, purified by affinity chromatography, was refolded by gradient dialysis. After coating a 96-well plate with the purified fiber-2 protein (1.5 MUg/ml), standard serum and secondary antibodies (1:200 and 1:6000 dilutions, respectively) were used to develop an indirect ELISA (I-ELISA). Nine field-collected serum samples and JSJ13-positive serum were tested by I ELISA and the results corresponded with those of the serum neutralization test. The I-ELISA was used to test 450 clinical serum samples from different parts of China. Chickens from nonvaccinated flocks had low antibody titers and low virus positivity rates. In contrast, FAdV-4 vaccinated chickens were strongly positive, and the positivity rates of all the flocks exceeded 73.3%. The newly developed I ELISA with the recombinant JSJ13 fiber-2 protein as the antigen detected antibodies to FAdV-4 accurately and sensitively. PMID- 29620472 TI - Evaluation of Two Multiplex PCR-High-Resolution Melt Curve Analysis Methods for Differentiation of Campylobacter jejuni and Campylobacter coli Intraspecies. AB - Campylobacter infection is a common cause of bacterial gastroenteritis in humans and remains a significant global public health issue. The capability of two multiplex PCR (mPCR)-high-resolution melt (HRM) curve analysis methods (i.e., mPCR1-HRM and mPCR2-HRM) to detect and differentiate 24 poultry isolates and three reference strains of Campylobacter jejuni and Campylobacter coli was investigated. Campylobacter jejuni and C. coli were successfully differentiated in both assays, but the differentiation power of mPCR2-HRM targeting the cadF gene was found superior to that of mPCR1-HRM targeting the gpsA gene or a hypothetical protein gene. However, higher intraspecies variation within C. coli and C. jejuni isolates was detected in mPCR1-HRM when compared with mPCR2-HRM. Both assays were rapid and required minimum interpretation skills for discrimination between and within Campylobacter species when using HRM curve analysis software. PMID- 29620473 TI - Selecting and validating reference genes for quantitative real-time PCR in Plutella xylostella (L.). AB - Gene expression analysis provides important clues regarding gene functions, and quantitative real-time PCR (qRT-PCR) is a widely used method in gene expression studies. Reference genes are essential for normalizing and accurately assessing gene expression. In the present study, 16 candidate reference genes (ACTB, CyPA, EF1-alpha, GAPDH, HSP90, NDPk, RPL13a, RPL18, RPL19, RPL32, RPL4, RPL8, RPS13, RPS4, alpha-TUB, and beta-TUB) from Plutella xylostella were selected to evaluate gene expression stability across different experimental conditions using five statistical algorithms (geNorm, NormFinder, Delta Ct, BestKeeper, and RefFinder). The results suggest that different reference genes or combinations of reference genes are suitable for normalization in gene expression studies of P. xylostella according to the different developmental stages, strains, tissues, and insecticide treatments. Based on the given experimental sets, the most stable reference genes were RPS4 across different developmental stages, RPL8 across different strains and tissues, and EF1-alpha across different insecticide treatments. A comprehensive and systematic assessment of potential reference genes for gene expression normalization is essential for post-genomic functional research in P. xylostella, a notorious pest with worldwide distribution and a high capacity to adapt and develop resistance to insecticides. PMID- 29620474 TI - Pharmacokinetic drug evaluation of niraparib for the treatment of ovarian cancer. AB - INTRODUCTION: Ovarian cancer is a disease with a propensity to recur despite dramatic responses to initial treatment, which typically consists of a combination of cytoreductive surgery and platinum-based chemotherapy. A maintenance therapy, which may prevent or delay relapse while not negatively impacting quality of life, is critical to improving outcomes. Areas covered: This review discusses the pharmacologic properties, clinical efficacy, and safety profile of niraparib, a poly(ADP-ribose) polymerase (PARP) inhibitor indicated for the maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in a complete or partial response to platinum-based chemotherapy. Expert opinion: Following presentation of ENGOT-OV16/NOVA at the European Society for Medical Oncology (ESMO) 2016 Congress, niraparib became the first PARP inhibitor to receive full approval by the U.S. Food and Drug Administration (FDA) for the maintenance treatment of recurrent ovarian cancer, regardless of a patient's germline or somatic mutational status. This approval has had a sweeping impact on treatment strategies, moving the indication for a PARP inhibitor earlier in the treatment course and greatly expanding the population of patients who may benefit from this class of drugs. Active clinical trials suggest that new indications and novel treatment combinations are eagerly sought. PMID- 29620475 TI - Vascular injury at laparoscopy: a guide to management. AB - Vascular laparoscopic injuries are rare (0.2/1000), however, they are associated with 6-13% morbidity and mortality. Commonest sites for catastrophic haemorrhage are the right iliac vessels, inferior vena cava and less commonly the abdominal aorta. The injuries commonly occur at entry using a Veress needle or insertion of trocars. These risks are inherent to all laparoscopic surgery. A systematic approach for managing these includes prompt recognition, communication within the operative team, immediate resuscitation and specific operative strategies for the control of vascular haemorrhage based on the location and severity of the injury. Major vascular injuries may require midline laparotomy and vascular surgeons. 1:1:1 resuscitation and adjunct haemostatic agents may help. Major vascular injury is a rare but a potentially fatal complication. We propose a skills and drills approach to improve outcomes. We also propose a practical algorithms for the management of haemorrhage in the acute situation. PMID- 29620476 TI - Association of Pre-Admission Statin Therapy and the Inflammatory Response in ST Elevation Myocardial Infarction patients. AB - PURPOSE: To demonstrate the possible association of statin therapy with C reactive protein (CRP) serial measurements in ST elevation myocardial infarction (STEMI) patients. MATERIALS AND METHODS: STEMI patients between 2008 and 2016 with available CRP data from admission were divided into two groups according to pre-admission statin therapy. A second CRP measurement was noted following primary coronary intervention (within 24 hours from admission). The difference between the two measurements was designated DeltaCRP. RESULTS: The cohort consisted of 1134 patients with a median age of 61 (IQR52-70), 81% males. Patients on statins prior to admission (336/1134, 26%) were more likely to have CRP levels within normal range (<=5mg/l) compared to patients without prior treatment, both at admission (75% vs. 24. %, p = 0.004) and at 24 hours (70% vs. 48%, p = 0.029). The prevalence of patients with pre-admission statin therapy decreased as DeltaCRP increased (p = 0.004; n = 301). The likelihood of DeltaCRP to be above 5 mg/l in patients with pre-admission statin therapy was reduced after age and gender adjustments (OR 0.54, 95% CI 0.32-0.92, p = 0.023) and in multivariate (OR 0.57, 95% CI 0.33-0.99, p = 0.048) analysis. CONCLUSION: Pre admission statin therapy is associated with a less robust inflammatory response in STEMI patients, highlighting statins' pathophysiological importance. PMID- 29620477 TI - Accepted Abstracts. PMID- 29620478 TI - The rise of hospitalists: an opportunity for infectious diseases investigators. AB - INTRODUCTION: Despite the essential role played by infectious diseases specialists in patient care, public health, cost-containment, and biomedical research, the field has a substantially higher percentage of vacant positions than other medicine sub-specialties. While much has been written about what this disturbing trend means for patient care, comparatively little attention has been focused on the dire implications for clinical research and the development of novel anti-infective therapy. Areas covered: We examine the ways that hospitalists and infectious disease specialists might collaborate to study emerging diagnostic platforms, novel antimicrobial agents, and strengthen antimicrobial stewardship programs to improve the delivery of high-quality health care. Through the use of PubMed, the manuscript reviews existing collaborations as well as those that might develop in the years to come. Expert commentary: In this paper, we propose potential strategies to confront this emerging problem, focusing on novel collaborations with the hospitalist - the specialist in inpatient medicine - to bolster the pipeline of funding for clinical infectious diseases investigators. PMID- 29620479 TI - Phylogeny-dominant classification of J-proteins in Arabidopsis thaliana and Brassica oleracea. AB - Hsp40s or DnaJ/J-proteins are evolutionarily conserved in all organisms as co chaperones of molecular chaperone HSP70s that mainly participate in maintaining cellular protein homeostasis, such as protein folding, assembly, stabilization, and translocation under normal conditions as well as refolding and degradation under environmental stresses. It has been reported that Arabidopsis J-proteins are classified into four classes (types A-D) according to domain organization, but their phylogenetic relationships are unknown. Here, we identified 129 J proteins in the world-wide popular vegetable Brassica oleracea, a close relative of the model plant Arabidopsis, and also revised the information of Arabidopsis J proteins based on the latest online bioresources. According to phylogenetic analysis with domain organization and gene structure as references, the J proteins from Arabidopsis and B. oleracea were classified into 15 main clades (I XV) separated by a number of undefined small branches with remote relationship. Based on the number of members, they respectively belong to multigene clades, oligo-gene clades, and mono-gene clades. The J-protein genes from different clades may function together or separately to constitute a complicated regulatory network. This study provides a constructive viewpoint for J-protein classification and an informative platform for further functional dissection and resistant genes discovery related to genetic improvement of crop plants. PMID- 29620480 TI - Improved Health and Insurance Status Among Cigarette Smokers After Medicaid Expansion, 2011-2016. AB - OBJECTIVES: The high concentration of smokers among subgroups targeted by the Affordable Care Act and the historically worse health and lower access to health care among smokers warrants an evaluation of how Medicaid expansion affects smokers. We evaluated the impact of Medicaid expansion on smoking behavior, access to health care, and health of low-income adults, and we compared outcomes of all low-income people with outcomes of low-income current smokers by states' Medicaid expansion status. METHODS: We obtained data from the Behavioral Risk Factor Surveillance System (2011-2016) for low-income adults aged 18-64. We estimated multivariable linear ordinary least squares probability models using a quasi-experimental difference-in-difference approach to compare smoking behavior, access to health care, and health between people in expansion states and nonexpansion states and, specifically, on low-income adults and the subgroup of low-income current smokers. RESULTS: Compared with low-income smokers in nonexpansion states, low-income smokers in expansion states were 7.6 percentage points (95% confidence interval [CI], 5.7-9.6; P < .001) more likely to have health insurance, 3.2 percentage points (95% CI, 1.3-5.2; P = .001) more likely to report good or better health, and 2.0 percentage points (95% CI, -3.9 to -0.1; P = .044) less likely to have cost-related barriers to care. Health and insurance gains among current smokers in expansion states were larger relative to health gains (1.6 percentage points; 95% CI, 0.5-2.7; P = .003) and insurance gains (4.6 percentage points; 95% CI, 3.5-5.8; P < .001) of all low-income adults in these states. CONCLUSIONS: Greater improvements among low-income smokers in Medicaid expansion states compared with nonexpansion states could influence future smoking behaviors and warrant longer-term monitoring. Additionally, health and insurance gains among low-income smokers in expansion states suggest the potential for Medicaid expansion to improve health among smokers compared with nonsmokers. PMID- 29620481 TI - Structural, molecular motions, and free-energy landscape of Leishmania sterol 14alpha-demethylase wild type and drug resistant mutant: a comparative molecular dynamics study. AB - Sterol-14alpha-demethylase (CYP51) is an ergosterol pathway enzyme crucial for the survival of infectious Leishmania parasite. Recent high-throughput metabolomics and whole genome sequencing study revealed amphotericin B resistance in Leishmania is indeed due to mutation in CYP51. The residue of mutation (asparagine 176) is conserved across the kinetoplastidae and not in yeast or humans, portraying its functional significance. In order to understand the possible cause for the resistance, knowledge of structural changes due to mutation is of high importance. To shed light on the structural changes of wild and mutant CYP51, we conducted comparative molecular dynamics simulation study. The active site, substrate biding cavity, substrate channel entrance (SCE), and cavity involving the mutated site were studied based on basic parameters and large concerted molecular motions derived from essential dynamics analyses of 100 ns simulation. Results indicated that mutant CYP51 is stable and less compact than the wild type. Correspondingly, the solvent accessible surface area (SASA) of the mutant was found to be increased, especially in active site and cavities not involving the mutation site. Free-energy landscape analysis disclosed mutant to have a rich conformational diversity than wild type, with various free-energy conformations of mutant having SASA greater than wild type with SCE open. More residues were found to interact with the mutant CYP51 upon docking of substrate to both the wild and mutant CYP51. These results indicate that, relative to wild type, the N176I mutation of CYP51 in Leishmania mexicana could possibly favor increased substrate binding efficiency. PMID- 29620482 TI - Capecitabine as a minor groove binder of DNA: molecular docking, molecular dynamics, and multi-spectroscopic studies. AB - The interaction mechanism and binding mode of capecitabine with ctDNA was extensively investigated using docking and molecular dynamics simulations, fluorescence and circular dichroism (CD) spectroscopy, DNA thermal denaturation studies, and viscosity measurements. The possible binding mode and acting forces on the combination between capecitabine and DNA had been predicted through molecular simulation. Results indicated that capecitabine could relatively locate stably in the G-C base-pairs-rich DNA minor groove by hydrogen bond and several weaker nonbonding forces. Fluorescence spectroscopy and fluorescence lifetime measurements confirmed that the quenching was static caused by ground state complex formation. This phenomenon indicated the formation of a complex between capecitabine and ctDNA. Fluorescence data showed that the binding constants of the complex were approximately 2 * 104 M-1. Calculated thermodynamic parameters suggested that hydrogen bond was the main force during binding, which were consistent with theoretical results. Moreover, CD spectroscopy, DNA melting studies, and viscosity measurements corroborated a groove binding mode of capecitabine with ctDNA. This binding had no effect on B-DNA conformation. PMID- 29620483 TI - DNA repair and cell cycle checkpoint defects in a mouse model of 'BRCAness' are partially rescued by 53BP1 deletion. AB - 'BRCAness' is a term used to describe cancer cells that behave similarly to tumors with BRCA1 or BRCA2 mutations. The BRCAness phenotype is associated with hypersensitivity to chemotherapy agents including PARP inhibitors, which are a promising class of recently-licensed anti-cancer treatments. This hypersensitivity arises because of a deficiency in the homologous recombination (HR) pathway for DNA double-strand break repair. To gain further insight into how genetic modifiers of HR contribute to the BRCAness phenotype, we created a new mouse model of BRCAness by generating mice that are deficient in BLM helicase and the Exo1 exonuclease, which are involved in the early stages of HR. We find that cells lacking BLM and Exo1 exhibit a BRCAness phenotype, with diminished HR, and hypersensitivity to PARP inhibitors. We further tested how 53BP1, an important regulator of HR, affects repair efficiency in our BRCAness model. We find that deletion of 53BP1 can relieve several of the repair deficiencies observed in cells lacking BLM and Exo1, just as it does in cells lacking BRCA1. These results substantiate the importance of BRCAness as a concept for classification of cancer cases, and further clarify the role of 53BP1 in regulation of DNA repair pathway choice in mammalian cells. PMID- 29620485 TI - Occurrence of Toxigenic Fungi and Mycotoxins on Root Herbs from Chinese Markets. AB - Herbs derived from roots, leaves, flowers, or fruits of plants are unavoidably contaminated with fungi and mycotoxins during growth, harvest, and storage, thereby posing a health threat to humans. Especially, root herbs (RHs) are more easily contaminated with fungi and mycotoxins because the roots are in direct contact with the soil. Here, we investigated the occurrence of fungi, aflatoxins (AFs), and ochratoxin A (OTA) in eight RHs that are used as medicines, beverages, dietary supplements, and functional foods in China and other countries. Morphological observation and MultiGeneBlast (beta-tubulin and calmodulin) were used to identify the potentially toxigenic fungi. Of the 48 samples tested, all were contaminated by fungi, and 1,844 isolates belonging to 25 genera were detected. The genera Aspergillus and Penicillium, which contain potentially toxigenic fungal species, represented a frequency of 10 and 25%, respectively. Thirty-three isolates of Aspergillus flavus, Aspergillus parasiticus, Aspergillus niger, and Penicillium polonicum were arbitrarily selected for analysis of their toxigenic potential. Five of 13 isolates of A. flavus and 1 isolate of A. parasiticus produced AFs, whereas OTA production was not detected for any of the isolates of A. niger and P. polonicum. The occurrence of AFs and OTA in the 48 samples of eight RHs was tested by ultraperformance liquid chromatography-tandem mass spectrometry; 37.50% of samples from six RHs were contaminated with AFs and 16.67% of samples from four RHs were contaminated with OTA. Seven (14.58%) and four (8.33%) samples of ginseng, polygala, and liquorice exceeded the permissible limits of aflatoxin B1 and AFs, respectively. Because ginseng, polygala, and liquorice are widely used as herbs, dietary supplements, and functional foods, the high frequency of AF contamination of these herbs indicated by our current study warrant attention to raise public awareness. PMID- 29620486 TI - Validation of a Sequential Hide-On Bob Veal Carcass Antimicrobial Intervention Composed of a Hot Water Wash and Lactic Acid Spray in Combination with Scalding To Control Shiga Toxin-Producing Escherichia coli Surrogates?. AB - Scalding of hide-on bob veal carcasses with or without standard scalding chemical agents typically used for hogs, followed by an 82.2 degrees C hot water wash and lactic acid spray (applied at ambient temperature) before chilling, was evaluated to determine its effectiveness in reducing Shiga toxin-producing Escherichia coli surrogate populations. A five-strain cocktail of rifampin-resistant, nonpathogenic E. coli surrogates was used to inoculate hides of veal carcasses immediately after exsanguination (target inoculation level of 7.0 log CFU/100 cm2). For carcasses receiving no scalding treatments, spraying with 82.2 degrees C water as a final wash resulted in a 4.5-log CFU/100 cm2 surrogate reduction, and an additional 1.2-log CFU/100 cm2 reduction was achieved by spraying with 4.5% lactic acid before chilling. Scalding hide-on carcasses in 60 degrees C water (no chemicals added) for 4 min in a traditional hog scalding tank resulted in a 2.1-log CFU/100 cm2 reduction in surrogate levels, and a subsequent preevisceration 82.2 degrees C water wash provided an additional 2.9-log CFU/100 cm2 reduction. Spraying a 4.5% solution of lactic acid onto scalded, hide-on carcasses (after the 82.2 degrees C water wash) resulted in a minimal additional reduction of 0.4 log CFU/100 cm2. Incorporation of scalding chemicals into the scald water resulted in a 4.1-log CFU/100 cm2 reduction (1.9 log CFU/100 cm2 greater than scalding without chemicals) in the surrogate population, and the first 82.2 degrees C wash provided an additional 2.5-log CFU/100 cm2 reduction. Application of antimicrobial interventions did not affect the carcass temperature decline during chilling, the pH decline, or the color characteristics of the ribeye or the flank of the bob veal carcasses. PMID- 29620487 TI - Presence of Classical Enterotoxin Genes, agr Typing, Antimicrobial Resistance, and Genetic Diversity of Staphylococcus aureus from Milk of Cows with Mastitis in Southern Brazil. AB - Staphylococcus aureus is a common causative agent of bovine mastitis in dairy cows and commonly associated with foodborne disease outbreaks. The aim of this study was to evaluate the presence of enterotoxin genes, agr typing, antimicrobial resistance, and genetic diversity of S. aureus isolated from milk of cows with mastitis in dairy farms from southern Brazil. Results showed that 7 (22.6%) of 31 S. aureus isolates were positive for enterotoxin genes. Specifically, the genes encoding for enterotoxins A ( n = 4), C ( n = 2), and B ( n = 1) were detected. Isolates belonging to the agr group III (10 of 31, 32.2%) and agr group I (7 of 31, 22.5%) were the most common. To our knowledge, this is the first report of both agr I and III in the same S. aureus isolate from milk of cows with bovine mastitis. The antimicrobial resistance test showed that 54% of the isolates were multiresistant to antimicrobial agents. The macrorestriction analysis produced 16 different major SmaI pulsed-field gel electrophoresis patterns, with up to two subpatterns. Moreover, the presence of some S. aureus clones in a distinct area was observed. Although this study characterized a limited number of S. aureus isolates, the presence of classical enterotoxin genes and resistance to multiple antimicrobial agents reinforces the importance of this microorganism to animal and human health. In addition, similar genetic profiles have been identified in distinct geographic areas, suggesting clonal dissemination of S. aureus in dairy herds from southern Brazil. PMID- 29620484 TI - Proton pump inhibitors: from CYP2C19 pharmacogenetics to precision medicine. AB - INTRODUCTION: Proton Pump inhibitors (PPIs) are commonly used for a variety of acid related disorders. Despite the overall effectiveness and safety profile of PPIs, some patients do not respond adequately or develop treatment related adverse events. This variable response among patients is in part due to genotype variability of CYP2C19, the gene encoding the CYP450 (CYP2C19) isoenzyme responsible for PPIs metabolism. Areas covered: This article provides an overview of the pharmacokinetics and mechanism of action of the currently available PPIs, including the magnitude of CYPC19 contribution to their metabolism. Additionally, the role of CYP2C19 genetic variability in the therapeutic effectiveness or outcomes of PPI therapy is highlighted in details, to provide supporting evidence for the potential value of CYP2C19 genotype-guided approaches to PPI drug therapy. Expert opinion: There is a large body of evidence describing the impact of CYP2C19 variability on PPIs and its potential role in individualizing PPI therapy, yet, CYP2C19 pharmacogenetics has not been widely implemented into clinical practice. More data are needed but CYP2C19 genotype-guided dosing of PPIs is likely to become increasingly common and is expected to improve clinical outcomes, and minimize side effects related to PPIs. PMID- 29620488 TI - Behavior of 11 Foodborne Bacteria on Whole and Cut Mangoes var. Ataulfo and Kent and Antibacterial Activities of Hibiscus sabdariffa Extracts and Chemical Sanitizers Directly onto Mangoes Contaminated with Foodborne Bacteria. AB - The behavior of foodborne bacteria on whole and cut mangoes and the antibacterial effect of Hibiscus sabdariffa calyx extracts and chemical sanitizers against foodborne bacteria on contaminated mangoes were investigated. Mangoes var. Ataulfo and Kent were used in the study. Mangoes were inoculated with Listeria monocytogenes, Shigella flexneri, Salmonella Typhimurium, Salmonella Typhi, Salmonella Montevideo, Escherichia coli strains (O157:H7, non-O157:H7 Shiga toxin producing, enteropathogenic, enterotoxigenic, enteroinvasive, and enteroaggregative). The antibacterial effect of five roselle calyx extracts (water, ethanol, methanol, acetone, and ethyl acetate), sodium hypochlorite, colloidal silver, and acetic acid against foodborne bacteria were evaluated on contaminated mangoes. The dry extracts obtained with ethanol, methanol, acetone, and ethyl acetate were analyzed by nuclear magnetic resonance spectroscopy to determine solvent residues. Separately, contaminated whole mangoes were immersed in five hibiscus extracts and in sanitizers for 5 min. All foodborne bacteria attached to mangoes. After 20 days at 25 +/- 2 degrees C, all foodborne bacterial strains on whole Ataulfo mangoes had decreased by approximately 2.5 log, and on Kent mangoes by approximately 2 log; at 3 +/- 2 degrees C, they had decreased to approximately 1.9 and 1.5 log, respectively, on Ataulfo and Kent. All foodborne bacterial strains grew on cut mangoes at 25 +/- 2 degrees C; however, at 3 +/- 2 degrees C, bacterial growth was inhibited. Residual solvents were not detected in any of the dry extracts by nuclear magnetic resonance. Acetonic, ethanolic, and methanolic roselle calyx extracts caused a greater reduction in concentration (2 to 2.6 log CFU/g) of all foodborne bacteria on contaminated whole mangoes than the sodium hypochlorite, colloidal silver, and acetic acid. Dry roselle calyx extracts may be a potentially useful addition to disinfection procedures of mangoes. PMID- 29620490 TI - Comparative study of the interactions between bisphenol-A and its endocrine disrupting analogues with bovine serum albumin using multi-spectroscopic and molecular docking studies. AB - Interaction studies of bisphenol analogues; biphenol-A (BPA), bisphenol-B (BPB), and bisphenol-F (BPF) with bovine serum albumin (BSA) were performed using multi spectroscopic and molecular docking studies at the protein level. The mechanism of binding of bisphenols with BSA was dynamic in nature. SDS refolding experiments demonstrated no stabilization of BSA structure denatured by BPB, however, BSA denatured by BPA and BPF was found to get stabilized. Also, CD spectra and molecular docking studies revealed that BPB bound more strongly and induced more conformational changes in BSA in comparison to BPA. Hence, this study throws light on the replacement of BPA by its analogues and whether the replacement is associated with a possible risk, raising a doubt that perhaps BPB is not a good substitute of BPA. PMID- 29620489 TI - Evaluation of mitochondrial redox status and energy metabolism of X-irradiated HeLa cells by LC/UV, LC/MS/MS and ESR. AB - To evaluate the metabolic responses in tumour cells exposed to ionizing radiation, oxygen consumption rate (OCR), cellular lipid peroxidation, cellular energy status (intracellular nucleotide pool and ATP production), and mitochondrial reactive oxygen species (ROS), semiquinone (SQ), and iron-sulphur (Fe-S) cluster levels were evaluated in human cervical carcinoma HeLa cells at 12 and 24 h after X-irradiation. LC/MS/MS analysis showed that levels of 8-iso PGF2alpha and 5-iPF2alpha-VI, lipid peroxidation products of membrane arachidonic acids, were not altered significantly in X-irradiated cells, although mitochondrial ROS levels and OCR significantly increased in the cells at 24 h after irradiation. LC/UV analysis revealed that intracellular AMP, ADP, and ATP levels increased significantly after X-irradiation, but adenylate energy charge (adenylate energy charge (AEC) = [ATP + 0.5 * ADP]/[ATP + ADP + AMP]) remained unchanged after X-irradiation. In low-temperature electron spin resonance (ESR) spectra of HeLa cells, the presence of mitochondrial SQ at g = 2.004 and Fe-S cluster at g = 1.941 was observed and X-irradiation enhanced the signal intensity of SQ but not of the Fe-S cluster. Furthermore, this radiation-induced increase in SQ signal intensity disappeared on treatment with rotenone, which inhibits electron transfer from Fe-S cluster to SQ in complex I. From these results, it was suggested that an increase in OCR and imbalance in SQ and Fe-S cluster levels, which play a critical role in the mitochondrial electron transport chain (ETC), occur after X-irradiation, resulting in an increase in ATP production and ROS leakage from the activated mitochondrial ETC. PMID- 29620491 TI - Alcanivorax mobilis sp. nov., a new hydrocarbon-degrading bacterium isolated from deep-sea sediment. AB - A taxonomic study was carried out on strain MT13131T, which was isolated from deep-sea sediment of the Indian Ocean during the screening of oil-degrading bacteria. The chain length range of n-alkanes (C8 to C32) oxidized by strain MT13131T was determined in this study. The bacterium was Gram-negative, oxidase- and catalase-positive, single rod shaped, and motile by peritrichous flagella. Growth was observed at salinities of 1-12 % and at temperatures of 10-42 degrees C. The isolate was capable of Tween 20, 40 and 80 hydrolysis, but incapable of gelatin, cellulose or starch hydrolysis. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain MT13131T belonged to the genus Alcanivorax, with highest sequence similarity to Alcanivorax marinus R8-12T (96.92 %), other species of genus Alcanivorax shared 92.96-96.69 % sequence similarity. The principal fatty acids were summed feature 3 (C16 : 1omega6c/omega7c), summed feature 8 (C18 : 1omega7c/omega6c), C16 : 0 and C12 : 0 3OH. The G+C content of the chromosomal DNA was 64.2 mol%. Phosphatidylglycerol, phosphatidylethanolamine, three aminolipids and three phospholipids were present. The combined genotypic and phenotypic data showed that strain MT13131T represents a novel species within the genus Alcanivorax, for which the name Alcanivorax mobilis sp. nov. is proposed, with the type strain MT13131T (=MCCC 1A11581T=KCTC 52985T). PMID- 29620492 TI - Phyllobacterium zundukense sp. nov., a novel species of rhizobia isolated from root nodules of the legume species Oxytropis triphylla (Pall.) Pers. AB - Gram-negative strains Tri-36, Tri-38, Tri-48T and Tri-53 were isolated from root nodules of the relict legume Oxytropis triphylla (Pall.) Pers. originating from Zunduk Cape (Baikal Lake region, Russia). 16S rRNA gene sequencing showed that the novel isolates were phylogenetically closest to the type strains Phyllobacterium sophorae LMG 27899T, Phyllobacterium brassicacearum LMG 22836T, Phyllobacterium endophyticum LMG 26470T and Phyllobacterium bourgognense LMG 22837T while similarity levels between the isolates and the most closely related strain P. endophyticum LMG 26470T were 98.8-99.5 %. The recA and glnII genes of the isolates showed highest sequence similarities with P. sophorae LMG 27899T (95.4 and 89.5 %, respectively) and P. brassicacearum LMG 22836T (91.4 and 85.1 %, respectively). Comparative analysis of phenotypic properties between the novel isolates and the closest reference strains P. sophorae LMG 27899T, P. brassicacearum LMG 22836T and P. endophyticum LMG 26470T was performed using a microassay system. Average nucleotide identities between the whole genome sequences of the isolates Tri-38 and Tri-48T and P. sophorae LMG 27899T, P. brassicacearum LMG 22836T and P. endophyticum LMG 26470T ranged from 79.23 % for P. endophyticum LMG 26470T to 85.74 % for P. sophorae LMG 27899T. The common nodABC genes required for legume nodulation were absent from strains Tri-38 and Tri-48T, although some other symbiotic nod and fix genes were detected. On the basis of genotypic and phenotypic analysis, a novel species, Phyllobacterium zundukense sp. nov. (type strain Tri-48T=LMG 30371T=RCAM 03910T), is proposed. PMID- 29620493 TI - Winogradskyella pocilloporae sp. nov. isolated from healthy tissue of the coral Pocillopora damicornis. AB - A novel Gram-stain-negative, rod-shaped, strictly aerobic, and orange-yellow pigmented bacterium, designated strain AFPH31T, was isolated from internal tissues of the scleractinian coral Pocillopora damicornis, cultured in a marine aquarium system at the Justus Liebig University Giessen, Germany. Phylogenetic analyses based on 16S rRNA gene sequences placed the strain within the monophyletic cluster of the genus Winogradskyella and showed highest sequence similarity to type strains of the species Winogradskyella eximia (96.6 %), Winogradskyella wandonensis (96.4 %), and Winogradskyella damuponensis (96.4 %). The strain grew well at 15-37 degrees C (optimum 25 degrees C), in the presence of 0.5-8.5 % NaCl (optimum 2 %), and at pH 5.5-8.5 (optimum pH 6.0-7.5). The major cellular fatty acids of strain AFPH31T were iso-C15 : 0 (22.0 %), iso-C15 : 1 G (16.9 %), iso-C17 : 0 3-OH (14.9 %), and anteiso-C15 : 0 (11.9 %). The major compound in the polyamine pattern was sym-homospermidine. The quinone system contained predominantly menaquinone MK-6. The polar lipid profile contained predominantly phosphatidylethanolamine, one unidentified aminolipid, and two unidentified lipids lacking a functional group. The genomic DNA G+C content was 36.8 mol%. According to the phylogenetic, chemotaxonomic, and phenotypic analyses we propose a novel species of the genus Winogradskyella named Winogradskyella pocilloporae sp. nov. The type strain is AFPH31T (=CCM 8816T=CIP 111546T). PMID- 29620494 TI - Rhodococcus olei sp. nov., with the ability to degrade petroleum oil, isolated from oil-contaminated soil. AB - A Gram-stain-positive, non-motile, creamy-white and rod-coccus shaped actinobacterium, designated strain Ktm-20T, capable of degrading petroleum oil was isolated from oil-contaminated soil. Strain Ktm-20T was able to grow at 15-37 degrees C, at pH 5.5-10.0 and at 0.0-2.0 % (w/v) NaCl concentration. This strain was taxonomically characterized by a polyphasic approach. The 16S rRNA gene sequence analysis showed that strain Ktm-20T belonged to the genus Rhodococcus and is closely related to Rhodococcus triatomae DSM 44892T, Rhodococcus pedocola UC12T, Rhodococcus wratislaviensis NBRC 100605T, Rhodococcus agglutinans CFH S0262T and Rhodococcus canchipurensis MBRL 353T (98.8, 98.7, 98.5, 98.4 and 98.3 % gene sequence similarity, respectively). The only respiratory quinone was MK 8(H2); the major polar lipids were phosphatidylethanolamine, diphosphatidylglycerol, phosphatidylinositol and phosphatidylinositol mannoside; and the predominant fatty acids were C16 : 0, summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c) and C18 : 1omega9c. The cell-wall peptidoglycan contained meso-diaminopimelic acid; and galactose, glucose, arabinose and ribose were detected as diagnostic sugars from whole-cell hydrolysates. Mycolic acids were detected. The DNA G+C content was 70.9 mol%. The DNA-DNA relatedness values between strain Ktm-20T and closely related species of the genus Rhodococcus were between 38.3-25.3 %, which falls below the threshold value of 70 % for the strain to be considered as novel. The morphological, physiological, chemotaxonomic and phylogenetic analyses clearly distinguished this strain from its closest phylogenetic neighbours. Thus, strain Ktm-20T represents a novel species of the genus Rhodococcus, for which the name Rhodococcus olei sp. nov. is proposed. The type strain is Ktm-20T (=KEMB 9005-695T=KACC 19390T=JCM 32206T). PMID- 29620495 TI - Flavobacterium hankyongi sp. nov., isolated from activated sludge. AB - A Gram-stain-negative, aerobic, non-motile and rod-shaped bacterium, designated strain KTCe-4T, was isolated from activated sludge. Based on 16S rRNA gene sequencing and phylogenetic analysis, the novel isolate was found to belong to the genus Flavobacterium and was most closely related to Flavobacteriumterrae DSM 18829T (97.8 %), Flavobacteriumvireti THG-SM1T (97.8 %), Flavobacteriumbrevivitae TTM-43T (97.4 %) and shared <96.4 % sequence similarity to the other members of the genus. Strain KTCe-4T contained MK-6 as the predominant isoprenoid quinone and iso-C15 : 0, iso-C15 : 0 G, iso-C15 : 0 3-OH, iso-C17 : 0 3-OH and iso-C17 : 1omega9c, as the major fatty acids. The major polar lipids were phosphatidylethanolamine, two unidentified polar lipids and one unknown amino lipid. The DNA-DNA relatedness values of strain KTCe-4T with respect to type strains of recognized species of the genus Flavobacterium were less than 70 %. Based on 16S rRNA gene sequencing, low values of DNA-DNA hybridization and polyphasic taxonomic analysis, strain KTCe-4T represents a novel species within the genus Flavobacterium, for which the name Flavobacterium hankyongi sp. nov. is proposed. The type strain of Flavobacterium hankyongi is strain KTCe-4T (=KACC 16613T=JCM 18198T). PMID- 29620496 TI - Streptacidiphilus monticola sp. nov., a novel actinomycete isolated from soil. AB - A novel actinobacterium, designated strain NEAU-SW11T, was isolated from soil collected from Binxian, Heilongjiang province, north China. The isolate was found to have chemical and morphological properties of the genus Streptacidiphilus, with the highest sequence similarities to Streptacidiphilus anmyonensis JCM 16223T (98.1 %), Streptacidiphilus jiangxiensis JCM 12277T (97.8 %), Streptacidiphilus melanogenes JCM 16224T (97.6 %) and Streptacidiphilus rugosus JCM 16225T (97.4 %) and it phylogenetically clustered with these four strains. The cell wall contained ll-diaminopimelic acid as the major diamino acid and the whole-cell hydrolysates were rhamnose, ribose, glucose and galactose. The major polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylinositol, phosphatidylinositol mannoside and two unidentified phospholipids. The predominant menaquinones were MK-9(H8) and MK-9(H6). The major fatty acids were C16 : 0, anteiso-C17 : 0, C14 : 0 and C15 : 0. The DNA G+C content was 71.0 mol%. However, DNA-DNA hybridization, physiological and biochemical data showed that strain NEAU-SW11T could be distinguished from its closest relatives. Therefore, strain NEAU-SW11T represents a novel species of the genus Streptacidiphilus, for which the name Streptacidiphilus monticola sp. nov. is proposed. The type strain is NEAU-SW11T (=CGMCC 4.7427T=DSM 105744T). PMID- 29620497 TI - Sulfitobacter aestuarii sp. nov., a marine bacterium isolated from a tidal flat of the Yellow Sea. AB - A novel bacterial strain, designated hydD52T, was isolated from a sample of tidal flat sediment of the Yellow Sea in the Republic of Korea. The cells were motile, rod-shaped and Gram-stain-negative. Phylogenetic analysis based on the 16S rRNA gene sequences revealed that strain hydD52T was a member of the genus Sulfitobacter and most closely related to Sulfitobacter dubius DSM 16472T (98.0 %), Sulfitobacter indolifex HEL-45T (97.8 %) and Sulfitobacter delicatus DSM 28223T (97.6 %). The major fatty acids (>5 %) of hydD52T were C18 : 1omega7c/C18 : 1omega6c, C16 : 0, C18 : 1omega7c 11-methyl and C19 : 0omega8c. The respiratory quinone of strain hydD52T was ubiquinone-10. The major polar lipids were diphosphatidylglycerol, phosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine and an unidentified amino lipid. The G+C content of this strain was 64.0 mol%. The DNA-DNA relatedness values of hydD52T with the type strains of S. dubius, S. indolifex and S. delicatus were 18.8, 13.1 and 15.7 %, respectively. Based on the results of morphological, physiological and chemotaxonomic characterization, DNA-DNA hybridization relatedness, and 16S rRNA genes analysis, we concluded that strain hydD52T represents a novel species, for which the name Sulfitobacter aestuarii sp. nov. is proposed. The type strain is hydD52T (=KCTC 32982T=TISTR 2562T). PMID- 29620498 TI - Pseudomonas profundi sp. nov., isolated from deep-sea water. AB - A Gram-stain-negative, aerobic bacterium, strain M5T, was isolated from a seawater sample collected from the western Pacific Ocean at a depth of 1000 m and characterized by using polyphasic taxonomy. Cells of the strain were rod-shaped and motile by a single polar flagellum. Cells grew at 4-40 degrees C (optimum, 25 degrees C), at pH 7-10 (optimum, 9) and with 0-10 % NaCl (optimum, 1-2 %). Phylogenetic trees based on 16S rRNA gene sequences showed that strain M5T was associated with the genus Pseudomonas, and showed highest similarities to Pseudomonas pelagia CL-AP6T (97.8 %) and Pseudomonas salina XCD-X85T (97.5 %) and Pseudomonas sabulinigri J64T (96.4 %). The average nucleotide identity scores for strains CL-AP6T and XCD-X85T were 74.6 % and 73.7 %, the Genome-to-Genome Distance Calculator scores were 15.8-19.5 % and 15.4-19.7 %, and the species identification scores were 92.3 % and 92.4 %. The major isoprenoid quinone of strain M5T was ubiquinone (Q-9) and the major cellular fatty acids were summed feature 8 (C18 : 1omega7c and/or C18 : 1omega6c; 33.2 %), summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c; 22.8 %) and C16 : 0 (13 %). The major polar lipids were diphosphatidylglycerol, phosphatidylethanolamine, phosphatidylglycerol, phospholipid and some unidentified lipids. The phylogenetic analysis and physiological and biochemical data showed that strain M5T should be classified as representing a novel species in the genus Pseudomonas, for which the name Pseudomonas profundi sp. nov. is proposed. The type strain is M5T (=CCTCC AB 2017186T=KCTC 62119T=CICC 24308T). PMID- 29620499 TI - EssC is a specificity determinant for Staphylococcus aureus type VII secretion. AB - The type VII protein secretion system (T7SS) is found in actinobacteria and firmicutes, and plays important roles in virulence and interbacterial competition. A membrane-bound ATPase protein, EssC in Staphylococcus aureus, lies at the heart of the secretion machinery. The EssC protein from S. aureus strains can be grouped into four variants (EssC1-EssC4) that display sequence variability in the C-terminal region. Here we show that the EssC2, EssC3 and EssC4 variants can be produced in a strain deleted for essC1, and that they are able to mediate secretion of EsxA, an essential component of the secretion apparatus. They are, however, unable to support secretion of the substrate protein EsxC, which is only encoded in essC1-specific strains. This finding indicates that EssC is a specificity determinant for T7 protein secretion. Our results support a model in which the C-terminal domain of EssC interacts with substrate proteins, whereas EsxA interacts elsewhere. PMID- 29620500 TI - Kordiimonas pumila sp. nov., isolated from coastal sediment. AB - A novel Gram-stain-negative, translucent-white, aerobic, motile and rod-shaped strain, designated N18T, was isolated from a coastal sediment sample collected in Zhoushan, Zhejiang Province, China. 16S rRNA gene similarity analysis revealed that strain N18T demonstrated highest similarity to the genus Kordiimonas(95.3 97.2 %). Phylogenetic analysis of 16S rRNA gene sequence showed that strain N18T represented a distinct lineage in the clade consisting of the genus Kordiimonas. Strain N18T was found to grow at 10-37 degrees C (optimum 28 degrees C), pH 6.0 8.0 (optimum 7.0) and with 1.0-4.0 % (w/v) NaCl (optimum 2.5 %). The G+C content of the genomic DNA was 55.3 mol%. The major cellular fatty acids were identified as summed feature 3 (comprising iso-C15 : 0 2-OH/C16 : 1omega7c), iso-C17 : 1omega9c and iso-C15 : 0. The polar lipid profile of N18T consisted of phosphatidylglycerol, phosphatidylethanolamine, diphosphatidylglycerol, an unidentified glycolipid, an unidentified aminoglycolipid, an unidentified aminophospholipid and five unidentified lipids. The respiratory quinone was Q-10. Based on chemotaxonomic, morphological and physiological properties, strain N18T could be distinguished from its closest phylogenetic neighbours. Thus, we propose Kordiimonas pumila sp. nov., the type strain is N18T (=MCCC 1K03436T=KCTC 62164T). PMID- 29620501 TI - Are commercial providers a viable option for clinical bacterial sequencing? AB - Bacterial whole-genome sequencing in the clinical setting has the potential to bring major improvements to infection control and clinical practice. Sequencing instruments are not currently available in the majority of routine microbiology laboratories worldwide, but an alternative is to use external sequencing providers. To foster discussion around this we investigated whether send-out services were a viable option. Four providers offering MiSeq sequencing were selected based on cost and evaluated based on the service provided and sequence data quality. DNA was prepared from five methicillin-resistant Staphylococcus aureus (MRSA) isolates, four of which were investigated during a previously published outbreak in the UK together with a reference MRSA isolate (ST22 HO 5096 0412). Cost of sequencing per isolate ranged from L155 to L342 and turnaround times from DNA postage to arrival of sequence data ranged from 12 to 63 days. Comparison of commercially generated genomes against the original sequence data demonstrated very high concordance, with no more than one single nucleotide polymorphism (SNP) difference on core genome mapping between the original sequences and the new sequence for all four providers. Multilocus sequence type could not be assigned based on assembly for the two cheapest sequence providers due to fragmented assemblies probably caused by a lower output of sequence data per isolate. Our results indicate that external providers returned highly accurate genome data, but that improvements are required in turnaround time to make this a viable option for use in clinical practice. PMID- 29620502 TI - Butyricicoccus porcorum sp. nov., a butyrate-producing bacterium from swine intestinal tract. AB - A Gram-stain-positive, non-motile, butyrate-producing coccus was cultured from the distal ileum of swine. This organism was isolated on rumen-fluid medium, consumes acetate, and produces butyrate as its major end product when grown on mono- and di-saccharides. A phylogenetic analysis based on near full-length 16S rRNA gene sequences as well as whole-genome phylogenies suggests that this isolate is most closely related to species in the genus Butyricicoccus, with Butyricicoccus pullicaecorum being the closest named relative (93.5 % 16S similarity). The G+C content of this isolate is 54 mol%, and the major cellular fatty acids are C18 : 0 DMA, C14 : 0, C18 : 1omega9c and C16 : 0. These data indicate that this isolate represents a novel species within the genus Butyricicoccus, for which the name Butyricicoccus porcorum sp. nov. is proposed. The type strain of Butyricicoccus porcorum is BB10T (ATCC TSD-102T, DSM 104997T). PMID- 29620503 TI - Roseicyclus marinus sp. nov., isolated from a Synechococcus culture, and emended description of the genus Roseicyclus. AB - A novel Gram-stain-negative, aerobic, non-flagellated, pink-pigmented and rod shaped strain with gliding motility, designated strain CCMM001T, was isolated from a mixed culture of Synechococcus species PCC7002 and a natural bacterial community from a sample of offshore seawater from Qingdao, China, during September 2014. The strain contained bacteriochlorophyll a with a small peak at 802 nm and a large in vivo absorption band at 870 nm. Strain CCMM001T grew optimally at pH 7.0 and 30 degrees C in the presence of 3 % (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain CCMM001T is most closely related to the genus Roseicyclus and its type and only species Roseicyclus mahoneyensis ML6T with 96.9 % sequence similarity. The polar lipids of strain CCMM001T consisted of phosphatidylethanolamine, phosphatidylcholine, one unidentified aminolipid, and five unidentified lipids. The predominant isoprenoid quinone was Q-10. The major fatty acids included C18 : 1omega7c and C19 : 0cyclo omega8c. The DNA G+C content of strain CCMM001T was 63.5 mol%. These phylogenetic, physiological and chemotaxonomic data indicated that strain CCMM001T represents a novel species of the genus Roseicyclus, for which the name Roseicyclus marinus sp. nov. is proposed. The type strain is CCMM001T (=MCCC 1K03242T=KCTC 52641T). PMID- 29620504 TI - Polaromonas ginsengisoli sp. nov., isolated from ginseng field soil. AB - A Gram-reaction-negative, strictly aerobic, milky-white and rod-shaped bacterium (designated Gsoil 115T) isolated from ginseng field soil was characterized by a polyphasic approach to clarify its taxonomic position. Strain Gsoil 115T grew optimally at 30 degrees C and at pH 7.0 on Reasoner's 2A agar medium. Phylogenetic analysis based on 16S rRNA gene sequences indicated that strain Gsoil 115T belongs to the genus Polaromonas and was most closely related to Polaromonaseurypsychrophila B717-2T (98.6 %), Polaromonasvacuolata 34-PT (98.3 %), Polaromonasjejuensis NBRC 106434T (98.1 %), Polaromonas aquatic CCUG 39402T (97.7 %) and Polaromonascryoconiti Cr4-35T (97.5 %). The DNA G+C content was 60.9 mol%. The DNA-DNA hybridization relatedness between strain Gsoil 115T and P. eurypsychrophila B717-2T, P. vacuolata 34-PT, P. jejuensis NBRC 106434T, P. aquatic CCUG 39402T and P. cryoconiti Cr4-35T were 31.2, 21.6, 16.9, 8.7 and 10.1 %, respectively. The major polar lipids were phosphatidylglycerol (PG), diphosphatidylglycerol (DPG) and phosphatidylethanolamine (PE). The sole respiratory quinone was Q-8. The major fatty acids were C16 : 0 and summed feature 3 (C16 : 1omega7c and/or C16 : 1omega6c), which supported the affiliation of strain Gsoil 115T to the genus Polaromonas. Moreover, the physiological, biochemical and low level of DNA-DNA relatedness value allowed the phenotypic and genotypic differentiation of strain Gsoil 115T from the recognized species of the genus Polaromonas. Therefore, strain Gsoil 115T represents a novel species of the genus Polaromonas, for which the name Polaromonas ginsengisoli sp. nov. is proposed, with the type strain Gsoil 115T (LMG 23393T=KCTC 12577T). PMID- 29620505 TI - Influence of RNase E deficiency on the production of stx2-bearing phages and Shiga toxin in an RNase E-inducible strain of enterohaemorrhagic Escherichia coli (EHEC) O157:H7. AB - PURPOSE: In enterohaemorrhagic Escherichia coli (EHEC), stx1 or stx2 genes encode Shiga toxin (Stx1 or Stx2, respectively) and are carried by prophages. The production and release of both stx phages and toxin occur upon initiation of the phage lytic cycle. Phages can further disseminate stx genes by infecting naive bacteria in the intestine. Here, the effect of RNase E deficiency on these two virulence traits was investigated. METHODOLOGY: Cultures of the EHEC strains TEA028-rne containing low versus normal RNase E levels or the parental strain (TEA028) were treated with mitomycin C (MMC) to induce the phage lytic cycle. Phages and Stx2 titres were quantified by the double-agar assay and the receptor ELISA technique, respectively. RESULTS: RNase E deficiency in MMC-treated cells significantly reduced the yield of infectious stx2 phages. Delayed cell lysis and the appearance of encapsidated phage DNA copies suggest a slow onset of the lytic cycle. However, these observations do not entirely explain the decrease of phage yields. stx1 phages were not detected under normal or deficient RNase E levels. After an initial delay, high levels of toxin were finally produced in MMC-treated cultures. CONCLUSION: RNase E scarcity reduces stx2 phage production but not toxin. Normal concentrations of RNase E are likely required for correct phage morphogenesis. Our future work will address the mechanism of RNase E action on phage morphogenesis. PMID- 29620506 TI - Encystation: the most prevalent and underinvestigated differentiation pathway of eukaryotes. AB - Not long ago, protists were considered one of four eukaryote kingdoms, but recent gene-based phylogenies show that they contribute to all nine eukaryote subdomains. The former kingdoms of animals, plants and fungi are now relegated to lower ranks within subdomains. Most unicellular protists respond to adverse conditions by differentiating into dormant walled cysts. As cysts, they survive long periods of starvation, drought and other environmental threats, only to re emerge when conditions improve. For protists pathogens, the resilience of their cysts can prevent successful treatment or eradication of the disease. In this context, effort has been directed towards understanding the molecular mechanisms that control encystation. We here firstly summarize the prevalence of encystation across protists and next focus on Amoebozoa, where most of the health-related issues occur. We review current data on processes and genes involved in encystation of the obligate parasite Entamoeba histolytica and the opportunistic pathogen Acanthamoeba. We show how the cAMP-mediated signalling pathway that controls spore and stalk cell encapsulation in Dictyostelium fruiting bodies could be retraced to a stress-induced pathway controlling encystation in solitary Amoebozoa. We highlight the conservation and prevalence of cAMP signalling genes in Amoebozoan genomes and the suprisingly large and varied repertoire of proteins for sensing and processing environmental signals in individual species. PMID- 29620508 TI - Increasing antigen presentation on HSV-1-infected cells increases lesion size but does not alter neural infection or latency. AB - CD8+ T cells have a role in the control of acute herpes simplex virus (HSV) infection and may also be important in the maintenance of latency. In this study we have explored the consequences of boosting the efficacy of CD8+ T cells against HSV by increasing the amount of an MHC I-presented epitope on the surface of infected cells. To do this we used HSVs engineered to express an extra copy of the immunodominant CD8+ T cell epitope in C57Bl/6 mice, namely gB498 (SSIEFARL). Despite greater presentation of gB498 on infected cells, CD8+ T cell responses to these viruses in mice were similar to those elicited by a control virus. Further, the expression of extra gB498 did not significantly alter the extent or stability of latency in our mouse model, and virus loads in skin and sensory ganglia of infected mice were not affected. Surprisingly, mice infected with these viruses developed significantly larger skin lesions than those infected with control viruses and notably, this phenotype was dependent on MHC haplotype. Therefore increasing the visibility of HSV-infected cells to CD8+ T cell attack did not impact neural infection or latency, but rather enhanced pathology in the skin. PMID- 29620509 TI - Recombinant Expression and Purification of Mouse Nectin-like 4 Glycoprotein in 293ET Cell Line. AB - Objective To screen the transient and stable cell lines with high production of Nectin-like 4 (Necl-4) protein. Methods First, cDNA sequences encoding the extracellular domain of Necls were cloned into the modified vector pAPtag at the N terminus of alkaline phosphatase (AP) for fusion expression. Next, 293ET cells stably expressed Necls-AP fusion protein and secreted it into the culture medium which were detected by the AP activity assay and Western blot analysis. Then, by adding N-glycosylation processing inhibitor kifunensine into the medium, complex glycan was inhibited to generate. The residual glycan of purified protein was removed by endoglycosidase H. Finally, AP protein was removed by using human rhinovirus protease and size exclusion chromatography. The concentration of purified Necl-4 protein was monitored by measuring the absorbance at 280 nm and analyzed by SDS-PAGE. Result The transient and stable cell lines with high production of Necl-4 protein were screened by the color reaction with the AP-tag in the recombinant vector. The soluble and active form of purified Necl-4 protein was obtained after deglycosylation of native N-glycan protein with an expression level of 4 mg/L culture and purity of 95%. Conclusions By using modified AP mammalian protein expression system, we can easily screen the high productive stable cell lines by using AP activity assay. By adding mannosidase inhibitor kifunensine into the medium and cutting purified protein by using endoglycosidase H, we can obtain deglycosylated Necl-4 protein in milligram quantities. Our method might throw a light on the expression and purification of glycoprotein for structural and functional studies. PMID- 29620507 TI - Genomewide characterisation of the genetic diversity of carotenogenesis in bacteria of the order Sphingomonadales. AB - The order Sphingomonadales is a taxon of bacteria with a variety of physiological features and carotenoid pigments. Some of the coloured strains within this order are known to be aerobic anoxygenic phototrophs that contain characteristic photosynthesis gene clusters (PGCs). Previous work has shown that majority of the ORFs putatively involved in the biosynthesis of C40 carotenoids are located outside the PGCs in these strains. The main purpose of this study was to understand the genetic basis for the various colour/carotenoid phenotypes of the strains of Sphingomonadales. Comparative analyses of the genomes of 41 strains of this order revealed that there were different patterns of clustering of carotenoid biosynthesis (crt) ORFs, with four ORF clusters being the most common. The analyses also revealed that co-occurrence of crtY and crtI is an evolutionarily conserved feature in Sphingomonadales and other carotenogenic bacteria. The comparisons facilitated the categorisation of bacteria of this order into four groups based on the presence of different crt ORFs. Yellow coloured strains most likely accumulate nostoxanthin, and contain six ORFs (group I: crtE, crtB, crtI, crtY, crtZ, crtG). Orange coloured strains may produce adonixanthin, astaxanthin, canthaxanthin and erythroxanthin, and contain seven ORFs (group II: crtE, crtB, crtI, crtY, crtZ, crtG, crtW). Red coloured strains may accumulate astaxanthin, and contain six ORFs (group III: crtE, crtB, crtI, crtY, crtZ, crtW). Non-pigmented strains may contain a smaller subset of crt ORFs, and thus fail to produce any carotenoids (group IV). The functions of many of these ORFs remain to be characterised. PMID- 29620510 TI - Therapy of Rituximab in Idiopathic Membranous Nephropathy with Nephrotic Syndrome: A Systematic Review and Meta-analysis. AB - Objective To investigate the efficacy and safety of rituximab (RTX) in the treatment of idiopathic membranous nephropathy (IMN) with nephrotic syndrome with a systematic review and meta-analysis. Methods PubMed, Embase, Cochrane Library and Clinical Trials (December 2016) were searched to identify researches investigating the treatment of RTX in adult patients with biopsy-proven IMN. Complete remission (CR) or partial remission was regarded as effective therapy, and the cumulated remission rate was calculated. Result Seven studies involved 120 patients (73% were men) were included in our systematic review and meta analysis. All were prospective observation cohort studies or matched-cohort studies, mainly came from two medical centers, and one study was multi-centric (four nephrology units in northern Italy). The creatinine clearance was more than 20 ml/(min.1.73 m2) and persistent proteinuria higher than 3.5 g/d for at least 6 months. All patients received treatment previously [44 (36.7%) had immunosuppressive treatment]. In 12- and 24-month, 56% (95%CI, 0.47-0.65) and 68% (95%CI, 0.41-0.87) patients could reach remission, while 15% (95%CI, 0.09-0.23) and 20% (95%CI, 0.12-0.32) patients could reach CR. The reduction in proteinuria was gradual and obvious, paralleled with upward trend of serum albumin level and decreasing serum cholesterol level. Renal functions were stable. Relapses happened in 24 months were around 8%. RTX related adverse events were mild and were mostly infusion-related reactions. Conclusions RTX treatment in IMN was efficient, well tolerated and safe. More than 60% patients can reach partial remission or CR in 24 months, and relapse is rare. Adverse events of RTX are mostly infusion-related reactions and generally mild. PMID- 29620511 TI - Gray Matter Volume Changes over the Whole Brain in the Bulbar- and Spinal-onset Amyotrophic Lateral Sclerosis: a Voxel-based Morphometry Study. AB - Objective To investigate cerebral structural signatures of the bulbar- and spinal onset amyotrophic lateral sclerosis (ALS) using voxel-based morphometry on magnetic resonance imaging. Methods The MR structural images of the brain were obtained from 65 ALS patients (15 bulbar-onset, 50 spinal-onset) and 65 normal controls (NC) on a 3.0T MRI system. Gray matter (GM) volume changes were investigated by voxel-based morphometry, and the distribution of the brain regions with volume changes was compared between ALS and normal controls, as well as between bulbar-onset and spinal-onset ALS based on Neuromorphometrics atlas. Result On voxel-level the decreased volume of brain regions in ALS patients was located in the right precentral gyrus (rPrcGy) and right middle frontal gyrus compared with that in NC. The bulbar-onset ALS presented extra-motor cortex atrophy (fronto-temporal pattern), including left medial orbital gyrus, left inferior temporal gyrus and right middle temporal gyrus; the spinal-onset ALS suffered from motor cortex atrophy (rPrcGy dominance) and extra-motor cortex atrophy (fronto-temporal and extra-fronto-temporal pattern) compared with NC. The spinal-onset ALS featured by GM volume loss of left postcentral gyrus and bulbar onset ALS featured by GM volume loss of left middle temporal gyrus compared with each other. Conclusions The asymmetric GM atrophy of the motor cortex and extra motor cortex represents the common MRI structural signatures of spinal-onset ALS, and sole extra-motor cortex atrophy represents the structural signatures of bulbar-onset ALS. The present study also demonstrated that the pattern of GM damage is likely to distribute wider in spinal-onset ALS than in bulbar-onset ALS. PMID- 29620512 TI - Astragaloside IV Protects Against Abeta1-42-induced Oxidative Stress, Neuroinflammation and Cognitive Impairment in Rats. AB - Objective To investigate the neuroprotective action of astragaloside IV (AS-IV) on spatial learning and memory impairment induced by amyloid-beta 1-42 (Abeta1 42) in rats and elucidate its underlying molecular mechanisms. Methods Adult-male Sprague-Dawley rats (230-250 g) were divided into six groups randomly: control, Abeta1-42, AS-IV, Abeta1-42 plus 5 mg/kg.d AS-IV, Abeta1-42 plus 25 mg/kg.d AS IV, and Abeta1-42 plus 50 mg/kg.d AS-IV groups. Abeta1-42 were delivered by intracerebroventricular injection under the guidance of a brain stereotaxic apparatus. The Morris water maze test (hidden platform test, probe trials, visible platform test) was performed one week after Abeta1-42 injection to obtain the ability of rat spatial learning and memory. AS-IV (5, 25 and 50 mg/kg.d) was administrated intraperitoneally once per day from the 8th day after Abeta1-42 injection for 5 consecutive days. Average escape latencies, distances for searching for the platform under water and the percentage of total time elapsed and distance swam in the right quadrant after removing platform were determined by behavior software system. The vision and swim speeds of rats were also determined to exclude the effect of these factors on the parameters of learning and memory. After behavioral tests, the rats were sacrificed immediately by decapitation. Hippocampus were collected. The enzyme activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-px) and catalase (CAT) in the hippocampus obtained from different-treated rat brain were measured by following the manufacturer's instructions. The levels of interleukin-1 beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) in tissue lysates were assayed with ELISA. Results The water maze test results indicated that chronic treatments with AS-IV effectively protected the rats from Abeta1-42-induced spatial learning and memory impairment. Furthermore, the activities of SOD, GSH-px and CAT decreased by Abeta1-42 were also restored by AS-IV treatment in the hippocampus of rats. In addition, AS-IV significantly decreased the levels of IL-1beta and TNF-alpha in the hippocampus of Abeta1-42-induced amnesia's rats. Conclusion Our findings suggest that AS-IV might be a useful chemical in improving the spatial memory and relieving the oxidative stress and neuroinflammation in Alzheimer patients. PMID- 29620513 TI - Reliability of Three Dimentional Pseudo-continuous Arterial Spin Labeling: A Volumetric Cerebral Perfusion Imaging with Different Post-labeling Time and Functional State in Health Adults. AB - Objective To evaluate the reliability of three dimensional spiral fast spin echo pseudo-continuous arterial spin labeling (3D pc-ASL) in measuring cerebral blood flow (CBF) with different post-labeling delay time (PLD) in the resting state and the right finger taping state. Methods 3D pc-ASL and three dimensional T1 weighted fast spoiled gradient recalled echo (3D T1-FSPGR) sequence were applied to eight healthy subjects twice at the same time each day for one week interval. ASL data acquisition was performed with post-labeling delay time (PLD) 1.5 seconds and 2.0 seconds in the resting state and the right finger taping state respectively. CBF mapping was calculated and CBF value of both the gray matter (GM) and white matter (WM) was automatically extracted. The reliability was evaluated using the intraclass correlation coefficient (ICC) and Bland and Altman plot. Results ICC of the GM (0.84) and WM (0.92) was lower at PLD 1.5 seconds than that (GM, 0.88; WM, 0.94) at PLD 2.0 seconds in the resting state, and ICC of GM (0.88) was higher in the right finger taping state than that in the resting state at PLD 1.5 seconds. ICC of the GM and WM was 0.71 and 0.78 for PLD 1.5 seconds and PLD 2.0 seconds in the resting state at the first scan, and ICC of the GM and WM was 0.83 and 0.79 at the second scan, respectively. Conclusion This work demonstrated that 3D pc-ASL might be a reliable imaging technique to measure CBF over the whole brain at different PLD in the resting state or controlled state. PMID- 29620514 TI - Gene Expression Profile of Hypertrophic Chondrocytes Treated with H2O2: A Preliminary Investigation. AB - Objective To identify the osteogenesis genes whose expression is altered in hypertrophic chondrocytes treated with H2O2. Methods Murine chondrogenitor cells (ATDC5) were differentiated into hypertrophic chondrocytes by Insulin-Transferrin Selenium (ITS) treatment, and then treated with H2O2. Suitable conditions (concentration, time) were determined by using the MTT assay. After total RNA isolation and cDNA synthesis, the levels of 84 genes were determined using the PCR array, whereas quantitative RT-PCR was carried out to validate the PCR array data. Result We identified 9 up-regulated genes and 12 down-regulated genes, encoding proteins with various functions, such as collagen proteins, transcription factors, proteins involved in skeletal development and bone mineral metabolism, as well as cell adhesion molecules. Quantitative RT-PCR confirmed the altered expression of 5 down-regulated genes (Smad2, Smad4, transforming growth factor $?beta$ receptor 1, transforming growth factor $?beta$ receptor 3, and matrix metalloproteinase 10). Conclusions H2O2 significantly changed the expression of several genes involved in a variety of biological functions. Because of the link between oxidative damage and Kashin-Beck disease, these genes may also be involved in the deep-zone necrosis of the cartilage observed in Kashin-Beck disease. PMID- 29620515 TI - Progress in the Diagnosis and Management of Chorea-acanthocytosis. AB - Chorea-acanthocytosis (ChAc) is the most common subtype of neuroacanthocytosis syndrome, characterized by the presence of acanthocytes and neurological disorders. It is thought to be caused by VPS13A mutations. Characteristic movement disorders in ChAc is choreiform movements affecting both trunk and extremities and prominent orolingual dyskinesia is pathognomonic. Acanthocytosis in peripheral blood smear, elevated serum creatine kinase and atrophy of heads of caudate nuclei and dilation of the anterior horn of the lateral ventricles in magnetic resonance imaging could assist the diagnosis of ChAc. Botulinum toxin injection is a possible treatment for the typical orofacial dystonia. Deep brain stimulation is a novel surgical treatment modality. Most cases chose globus pallidus internus as target. Patients with dystonia as a major manifestation will benefit more from high-frequency stimulation and those with major findings of chorea and dysarthria are suitable for low-frequency stimulation. More evidence of long-term outcomes is warranted. PMID- 29620516 TI - Fibronectin Glomerulopathy Caused by the Y973C Mutation in Fibronectin: A Case Report and Literature Review. AB - Fibronectin glomerulopathy is a rare autosomal dominant inherited glomerular disease associated with massive deposition of fibronectin. We recently diagnosed fibronectin glomerulopathy in a 29-year-old woman presenting nephrotic syndrome. Genetic analysis of fibronectin 1 gene showed heterozygosity for the Y973C mutation. However, this mutation was not found in her parents. She had stable renal function but persistent nephrotic proteinuria after one-year follow-up. PMID- 29620517 TI - Solitary Fibrous Tumor of the Kidney Treated with Laparoscopic Partial Nephrectomy: A Case Report. AB - We herein reported a 27-year-old woman with a right renal mass for two years. She underwent laparoscopic partial nephrectomy. Immunohistochemical examination of the specimen confirmed the diagnosis of solitary fibrous tumor by revealing its positive staining for cluster of differentiation (CD)34, epithelial membrane antigen (EMA), B-cell lymphoma-2 (Bcl-2) and CD99 in the tumor cells. No adjuvant treatment was carried out. The patient was in good health without local recurrence or metastasis during 2 years of follow-up. Laparoscopic partial nephrectomy for renal solitary fibrous tumor is an alternative treatment to radical nephrectomy. It can provide a good outcome. However, further follow-up and more cases of renal solitary fibrous tumor treated with laparoscopic partial nephrectomy are necessary to compare the oncological outcome with radical nephrectomy. PMID- 29620518 TI - Examining cognition across the bipolar/schizophrenia diagnostic spectrum. AB - BACKGROUND: Cognitive impairments are well-established features of schizophrenia, but there is ongoing debate about the nature and degree of cognitive impairment in patients with schizoaffective disorder and bipolar disorder. We hypothesized that there is a spectrum of increasing impairment from bipolar disorder to schizoaffective disorder bipolar type, to schizoaffective disorder depressive type and schizophrenia. METHODS: We compared performance on the Measurement and Treatment Research to Improve Cognition in Schizophrenia (MATRICS) Consensus Cognitive Battery between participants with schizophrenia (n = 558), schizoaffective disorder depressive type (n = 112), schizoaffective disorder type (n = 76), bipolar disorder (n = 78) and healthy participants (n = 103) using analysis of covariance with post hoc comparisons. We conducted an ordinal logistic regression to examine whether cognitive impairments followed the hypothesized spectrum from bipolar disorder (least severe) to schizophrenia (most severe). In addition to categorical diagnoses, we addressed the influence of symptom domains, examining the association between cognition and mania, depression and psychosis. RESULTS: Cognitive impairments increased in severity from bipolar disorder to schizoaffective disorder bipolar type, to schizophrenia and schizoaffective disorder depressive type. Participants with schizophrenia and schizoaffective disorder depressive type showed equivalent performance (d = 0.07, p = 0.90). The results of the ordinal logistic regression were consistent with a spectrum of deficits from bipolar disorder to schizoaffective disorder bipolar type, to schizophrenia/schizoaffective disorder depressive type (odds ratio = 1.98, p < 0.001). In analyses of the associations between symptom dimensions and cognition, higher scores on the psychosis dimension were associated with poorer performance (B = 0.015, standard error = 0.002, p < 0.001). LIMITATIONS: There were fewer participants with schizoaffective disorder and bipolar disorder than schizophrenia. Despite this, our analyses were robust to differences in group sizes, and we were able to detect differences between groups. CONCLUSION: Cognitive impairments represent a symptom dimension that cuts across traditional diagnostic boundaries. PMID- 29620519 TI - Neurocognitive, emotional and neuroendocrine correlates of exposure to sexual assault in women. AB - BACKGROUND: Survivors of sexual assault are vulnerable to long-term negative psychological and physical health outcomes, but few studies have investigated changes in cognition, emotional processing and brain function in the early stages after sexual assault. We used a multimodal approach to identify the cognitive and emotional correlates associated with sexual assault in women. METHODS: Twenty seven female survivors of sexual assault were included within 4 weeks of the traumatic event, and they were compared with 20 age-matched controls. Participants underwent functional MRI while performing cognitive/emotional tasks (n-back, emotional go/no-go, mental imagery). We also measured diurnal salivary cortisol and conducted neuropsychological assessments of attention and memory abilities. RESULTS: Relative to the control group, the survivors group had lower levels of morning cortisol and showed attentional deficits. We observed no between-group differences in brain activation during the n-back or mental imagery tasks. During the emotional go/no-go task, however, the survivors group showed a lack of deactivation in the dorsal anterior cingulate cortex when processing emotional material, relative to neutral material. Exploratory analyses in the survivors group indicated that symptom severity was negatively associated with cerebellar activation when positive emotional (happy) content interfered with response inhibition, and positively associated with cerebellar activation when thinking of positive (happy) memories. LIMITATIONS: The small sample size was the main limitation of this study. CONCLUSION: Dysfunctions in the dorsal anterior cingulate cortex and the cerebellum may represent early functional brain modifications that alter higher cognitive processes when emotional material is involved. PMID- 29620520 TI - Synapse-specific and compartmentalized expression of presynaptic homeostatic potentiation. AB - Postsynaptic compartments can be specifically modulated during various forms of synaptic plasticity, but it is unclear whether this precision is shared at presynaptic terminals. Presynaptic homeostatic plasticity (PHP) stabilizes neurotransmission at the Drosophila neuromuscular junction, where a retrograde enhancement of presynaptic neurotransmitter release compensates for diminished postsynaptic receptor functionality. To test the specificity of PHP induction and expression, we have developed a genetic manipulation to reduce postsynaptic receptor expression at one of the two muscles innervated by a single motor neuron. We find that PHP can be induced and expressed at a subset of synapses, over both acute and chronic time scales, without influencing transmission at adjacent release sites. Further, homeostatic modulations to CaMKII, vesicle pools, and functional release sites are compartmentalized and do not spread to neighboring pre- or post-synaptic structures. Thus, both PHP induction and expression mechanisms are locally transmitted and restricted to specific synaptic compartments. PMID- 29620521 TI - Integrating images from multiple microscopy screens reveals diverse patterns of change in the subcellular localization of proteins. AB - The evaluation of protein localization changes on a systematic level is a powerful tool for understanding how cells respond to environmental, chemical, or genetic perturbations. To date, work in understanding these proteomic responses through high-throughput imaging has catalogued localization changes independently for each perturbation. To distinguish changes that are targeted responses to the specific perturbation or more generalized programs, we developed a scalable approach to visualize the localization behavior of proteins across multiple experiments as a quantitative pattern. By applying this approach to 24 experimental screens consisting of nearly 400,000 images, we differentiated specific responses from more generalized ones, discovered nuance in the localization behavior of stress-responsive proteins, and formed hypotheses by clustering proteins that have similar patterns. Previous approaches aim to capture all localization changes for a single screen as accurately as possible, whereas our work aims to integrate large amounts of imaging data to find unexpected new cell biology. PMID- 29620522 TI - MPDZ promotes DLL4-induced Notch signaling during angiogenesis. AB - Angiogenesis is coordinated by VEGF and Notch signaling. DLL4-induced Notch signaling inhibits tip cell formation and vessel branching. To ensure proper Notch signaling, receptors and ligands are clustered at adherens junctions. However, little is known about factors that control Notch activity by influencing the cellular localization of Notch ligands. Here, we show that the multiple PDZ domain protein (MPDZ) enhances Notch signaling activity. MPDZ physically interacts with the intracellular carboxyterminus of DLL1 and DLL4 and enables their interaction with the adherens junction protein Nectin-2. Inactivation of the MPDZ gene leads to impaired Notch signaling activity and increased blood vessel sprouting in cellular models and the embryonic mouse hindbrain. Tumor angiogenesis was enhanced upon endothelial-specific inactivation of MPDZ leading to an excessively branched and poorly functional vessel network resulting in tumor hypoxia. As such, we identified MPDZ as a novel modulator of Notch signaling by controlling ligand recruitment to adherens junctions. PMID- 29620523 TI - An incoherent feedforward loop facilitates adaptive tuning of gene expression. AB - We studied adaptive evolution of gene expression using long-term experimental evolution of Saccharomyces cerevisiae in ammonium-limited chemostats. We found repeated selection for non-synonymous variation in the DNA binding domain of the transcriptional activator, GAT1, which functions with the repressor, DAL80 in an incoherent type-1 feedforward loop (I1-FFL) to control expression of the high affinity ammonium transporter gene, MEP2. Missense mutations in the DNA binding domain of GAT1 reduce its binding to the GATAA consensus sequence. However, we show experimentally, and using mathematical modeling, that decreases in GAT1 binding result in increased expression of MEP2 as a consequence of properties of I1-FFLs. Our results show that I1-FFLs, one of the most commonly occurring network motifs in transcriptional networks, can facilitate adaptive tuning of gene expression through modulation of transcription factor binding affinities. Our findings highlight the importance of gene regulatory architectures in the evolution of gene expression. PMID- 29620524 TI - Stochastic tuning of gene expression enables cellular adaptation in the absence of pre-existing regulatory circuitry. AB - Cells adapt to familiar changes in their environment by activating predefined regulatory programs that establish adaptive gene expression states. These hard wired pathways, however, may be inadequate for adaptation to environments never encountered before. Here, we reveal evidence for an alternative mode of gene regulation that enables adaptation to adverse conditions without relying on external sensory information or genetically predetermined cis-regulation. Instead, individual genes achieve optimal expression levels through a stochastic search for improved fitness. By focusing on improving the overall health of the cell, the proposed stochastic tuning mechanism discovers global gene expression states that are fundamentally new and yet optimized for novel environments. We provide experimental evidence for stochastic tuning in the adaptation of Saccharomyces cerevisiae to laboratory-engineered environments that are foreign to its native gene-regulatory network. Stochastic tuning operates locally at individual gene promoters, and its efficacy is modulated by perturbations to chromatin modification machinery. PMID- 29620525 TI - Shared rhythmic subcortical GABAergic input to the entorhinal cortex and presubiculum. AB - Rhythmic theta frequency (~5-12 Hz) oscillations coordinate neuronal synchrony and higher frequency oscillations across the cortex. Spatial navigation and context-dependent episodic memories are represented in several interconnected regions including the hippocampal and entorhinal cortices, but the cellular mechanisms for their dynamic coupling remain to be defined. Using monosynaptically-restricted retrograde viral tracing in mice, we identified a subcortical GABAergic input from the medial septum that terminated in the entorhinal cortex, with collaterals innervating the dorsal presubiculum. Extracellularly recording and labeling GABAergic entorhinal-projecting neurons in awake behaving mice show that these subcortical neurons, named orchid cells, fire in long rhythmic bursts during immobility and locomotion. Orchid cells discharge near the peak of hippocampal and entorhinal theta oscillations, couple to entorhinal gamma oscillations, and target subpopulations of extra-hippocampal GABAergic interneurons. Thus, orchid cells are a specialized source of rhythmic subcortical GABAergic modulation of 'upstream' and 'downstream' cortico-cortical circuits involved in mnemonic functions. PMID- 29620528 TI - Correction: Infectious polymorphic toxins delivered by outer membrane exchange discriminate kin in myxobacteria. PMID- 29620526 TI - VEGF-C promotes the development of lymphatics in bone and bone loss. AB - Patients with Gorham-Stout disease (GSD) have lymphatic vessels in their bones and their bones gradually disappear. Here, we report that mice that overexpress VEGF-C in bone exhibit a phenotype that resembles GSD. To drive VEGF-C expression in bone, we generated Osx-tTA;TetO-Vegfc double-transgenic mice. In contrast to Osx-tTA mice, Osx-tTA;TetO-Vegfc mice developed lymphatics in their bones. We found that inhibition of VEGFR3, but not VEGFR2, prevented the formation of bone lymphatics in Osx-tTA;TetO-Vegfc mice. Radiological and histological analysis revealed that bones from Osx-tTA;TetO-Vegfc mice were more porous and had more osteoclasts than bones from Osx-tTA mice. Importantly, we found that bone loss in Osx-tTA;TetO-Vegfc mice could be attenuated by an osteoclast inhibitor. We also discovered that the mutant phenotype of Osx-tTA;TetO-Vegfc mice could be reversed by inhibiting the expression of VEGF-C. Taken together, our results indicate that expression of VEGF-C in bone is sufficient to induce the pathologic hallmarks of GSD in mice. PMID- 29620527 TI - A robust and tunable mitotic oscillator in artificial cells. AB - Single-cell analysis is pivotal to deciphering complex phenomena like heterogeneity, bistability, and asynchronous oscillations, where a population ensemble cannot represent individual behaviors. Bulk cell-free systems, despite having unique advantages of manipulation and characterization of biochemical networks, lack the essential single-cell information to understand a class of out of-steady-state dynamics including cell cycles. Here, by encapsulating Xenopus egg extracts in water-in-oil microemulsions, we developed artificial cells that are adjustable in sizes and periods, sustain mitotic oscillations for over 30 cycles, and function in forms from the simplest cytoplasmic-only to the more complicated ones involving nuclear dynamics, mimicking real cells. Such innate flexibility and robustness make it key to studying clock properties like tunability and stochasticity. Our results also highlight energy as an important regulator of cell cycles. We demonstrate a simple, powerful, and likely generalizable strategy of integrating strengths of single-cell approaches into conventional in vitro systems to study complex clock functions. PMID- 29620529 TI - SiO2 decoration dramatically enhanced the stability of PtRu electrocatalysts with undetectable deterioration in fuel cell performance. AB - Prevention of Ru dissolution is essential for steady CO tolerance of anodic electrocatalysts in direct methanol fuel cells. Here, we demonstrate a facile way to stabilize Ru atoms by decorating commercial CB/PtRu with SiO2, which shows a six-fold higher stability and similar activity toward a methanol oxidation reaction leading to no discernible degradation in fuel cell performance compared to commercial CB/PtRu electrocatalysts. The higher stability and stable CO tolerance of SiO2-decorated electrocatalysts originate from the SiO2 coating, since Ru atoms are partially ionized during SiO2 decorating, resulting in difficulties in dissolution; while, in the case of commercial CB/PtRu, the dissolved Ru offers active sites for Pt coalescences and CO species resulting in the rapid decay of the electrochemical surface area and fuel cell performance. To the best of our knowledge, this is the first study about the stabilization of Ru atoms by SiO2. The highest stability is obtained for a PtRu electrocatalyst with negligible effect on the electrochemical properties. PMID- 29620530 TI - Genetic engineered color silk: fabrication of a photonics material through a bioassisted technology. AB - Silk produced by the silkworm Bombyx mori is an attractive material because of its luster, smooth and soft texture, conspicuous mechanical strength, good biocompatibility, slow biodegradation, and carbon neutral synthesis. Silkworms have been domesticated and bred for production of better quality and quantity of silk, resulting in the development of sericulture and the textile industry. Silk is generally white, so dyeing is required to obtain colored fiber. However, the dyeing process involves harsh conditions and generates a large volume of waste water, which have environmentally and economically negative impacts. Although some strains produce cocoons that contain pigments derived from the mulberry leaves that they eat, the pigments are distributed in the sericin layer and are lost during gumming. In trials for production of colored silk by feeding silkworms on diets containing dyes, only limited species of dye molecules were incorporated into the silk threads. A method for the generation of transgenic silkworm was established in conjunction with the discovery of green fluorescent protein (GFP), and silkworms carrying the GFP gene spun silk threads that formed cocoons that glowed bright green and still retained the original properties of silk. A wide range of color variation of silk threads has been obtained by replacing the GFP gene with the genes of other fluorescent proteins chosen from the fluorescent protein palette. The genetically modified silk with photonic properties can be processed to form various products including linear threads, 2D fabrics, and 3D materials. The transgenic colored silk could be economically advantageous due to addition of a new value to silk and reduction of cost for water waste, and environmentally preferable for saving water. Here, I review the literature regarding the production methods of fluorescent silk from transgenic silkworms and present examples of genetically modified color silk. PMID- 29620531 TI - Nanocomposites: suitable alternatives as antimicrobial agents. AB - The exploration of nanocomposites has gained a strong research following over the last decade. These materials have been heavily exploited in several fields, with applications ranging from biosensors to biomedicine. Among these applications, great advances have been made in the field of microbiology, specifically as antimicrobial agents. This review aims to provide a comprehensive account of various nanocomposites that elucidate promising antimicrobial activity. The composition, physical and chemical properties, as well as the antimicrobial performance of these nanocomposites, are discussed in detail. PMID- 29620532 TI - Dopant radial inhomogeneity in Mg-doped GaN nanowires. AB - Using atom probe tomography, it is demonstrated that Mg doping of GaN nanowires grown by Molecular Beam Epitaxy results in a marked radial inhomogeneity, namely a higher Mg content in the periphery of the nanowires. This spatial inhomogeneity is attributed to a preferential incorporation of Mg through the m-plane sidewalls of nanowires and is related to the formation of a Mg-rich surface which is stabilized by hydrogen. This is further supported by Raman spectroscopy experiments which give evidence of Mg-H complexes in the doped nanowires. A Mg doping mechanism such as this, specific to nanowires, may lead to higher levels of Mg doping than in layers, boosting the potential interest of nanowires for light emitting diode applications. PMID- 29620533 TI - Complex magnetic behaviour and evidence of a superspin glass state in the binary intermetallic compound Er5Pd2. AB - The binary intermetallic compound Er5Pd2 has been investigated using dc and ac magnetic susceptibilities, magnetic memory effect, isothermal magnetization, non linear dc susceptibility, heat capacity and magnetocaloric effect studies. Interestingly, even though the compound does not show geometrical frustration it undergoes glassy magnetic phase transition below 17.2 K. Investigation of dc magnetization and heat capacity data divulged absence of long-ranged magnetic ordering. Through the magnetic memory effect, time dependent magnetization and ac susceptibility studies it was revealed that the compound undergoes glass-like freezing below 17.2 K. Analysis of frequency dependence of this transition temperature through scaling and Arrhenius law; along with the Mydosh parameter indicate, that the dynamics in Er5Pd2 are due to the presence of strongly interacting superspins rather than individual spins. This phase transition was further investigated by non-linear dc susceptibility and was characterized by static critical exponents gamma and delta. Our results indicate that this compound shows the signature of superspin glass at low temperature. Additionally, both conventional and inverse magnetocaloric effect was observed with a large value of magnetic entropy change and relative cooling power. Our results suggest that Er5Pd2 can be classified as a superspin glass system with large magnetocaloric effect. PMID- 29620534 TI - Plasmon-modulated bistable four-wave mixing signals from a metal nanoparticle monolayer MoS2 nanoresonator hybrid system. AB - We present a study for the impact of exciton-phonon and exciton-plasmon interactions on bistable four-wave mixing (FWM) signals in a metal nanoparticle (MNP)-monolayer MoS2 nanoresonator hybrid system. Via tracing the FWM response we predict that, depending on the excitation conditions and the system parameters, such a system exhibits 'U-shaped' bistable FWM signals. We also map out bistability phase diagrams within the system's parameter space. Especially, we show that compared with the exciton-phonon interaction, a strong exciton-plasmon interaction plays a dominant role in the generation of optical bistability, and the bistable region will be greatly broadened by shortening the distance between the MNP and the monolayer MoS2 nanoresonator. In the weak exciton-plasmon coupling regime, the impact of exciton-phonon interaction on optical bistability will become obvious. The scheme proposed may be used for building optical switches and logic-gate devices for optical computing and quantum information processing. PMID- 29620535 TI - VSION as high field MRI T1 contrast agent: evidence of their potential as positive contrast agent for magnetic resonance angiography. AB - Because of their outstanding magnetic properties, iron oxide nanoparticles have already been the subject of numerous studies in the biomedical field, in particular as a negative contrast agent for T2-weighted nuclear magnetic resonance imaging, or as therapeutic agents in hyperthermia experiments. Recent studies have shown that below a given particle size (i.e. 5 nm), iron oxide may be used to provide a significant positive (brightening) effect on T1-weighted MRI. In such an application, not only the size of the crystal, but also the control of the coating process is essential to ensure optimal properties, especially at a very high field (> 3 T). In this work, we focused on the development of very small iron oxide nanoparticles as a potential platform for high field T1 magnetic resonance angiography (MRA) applications. The feasibility has been evaluated in vivo at 9.4 T, demonstrating the usefulness of the developed system for MRA applications. PMID- 29620536 TI - Significantly reduced c-axis thermal diffusivity of graphene-based papers. AB - Owing to their very high thermal conductivity as well as large surface-to-volume ratio, graphene-based films/papers have been proposed as promising candidates of lightweight thermal interface materials and lateral heat spreaders. In this work, we study the cross-plane (c-axis) thermal conductivity (k c ) and diffusivity (alpha c ) of two typical graphene-based papers, which are partially reduced graphene paper (PRGP) and graphene oxide paper (GOP), and compare their thermal properties with highly-reduced graphene paper and graphite. The determined alpha c of PRGP varies from (1.02 +/- 0.09) * 10-7 m2 s-1 at 295 K to (2.31 +/- 0.18) * 10-7 m2 s-1 at 12 K. This low alpha c is mainly attributed to the strong phonon scattering at the grain boundaries and defect centers due to the small grain sizes and high-level defects. For GOP, alpha c varies from (1.52 +/- 0.05) * 10-7 m2 s-1 at 295 K to (2.28 +/- 0.08) * 10-7 m2 s-1 at 12.5 K. The cross-plane thermal transport of GOP is attributed to the high density of functional groups between carbon layers which provide weak thermal transport tunnels across the layers in the absence of direct energy coupling among layers. This work sheds light on the understanding and optimizing of nanostructure of graphene-based paper-like materials for desired thermal performance. PMID- 29620537 TI - Grain wall boundaries in centimeter-scale continuous monolayer WS2 film grown by chemical vapor deposition. AB - Centimeter-scale continuous monolayer WS2 film with large tensile strain has been successfully grown on oxidized silicon substrate by chemical vapor deposition, in which monolayer grains can be more than 200 MUm in size. Monolayer WS2 grains are observed to merge together via not only traditional grain boundaries but also non traditional ones, which are named as grain walls (GWs) due to their nanometer scale widths. The GWs are revealed to consist of two or three layers. Though not a monolayer, the GWs exhibit significantly enhanced fluorescence and photoluminescence. This enhancement may be attributed to abundant structural defects such as stacking faults and partial dislocations in the GWs, which are clearly observable in atomically resolved high resolution transmission electron microscopy and scanning transmission electron microscopy images. Moreover, GW based phototransistor is found to deliver higher photocurrent than that based on monolayer film. These features of GWs provide a clue to microstructure engineering of monolayer WS2 for specific applications in (opto)electronics. PMID- 29620538 TI - Pharmaceutical micelles featured with singlet oxygen-responsive cargo release and mitochondrial targeting for enhanced photodynamic therapy. AB - The efficacy of nanoparticulate photodynamic therapy is often compromised by the short life time and limited diffusion radius of singlet oxygen as well as uncontrolled intracellular distribution of photosensitizer. It was hypothesized that rapid photosensitizer release upon nanoparticle internalization and its preferred accumulation in mitochondria would address the above problems. Hence, the aim of this study was to engineer a multifunctional micellar nanosystem featured with singlet oxygen-responsive cargo release and mitochondria-targeting. An imidazole-bearing amphiphilic copolymer was employed as the micelle building block to encapsulate triphenylphosphonium-pyropheophorbide a (TPP-PPa) conjugate or PPa. Upon laser irradiation, the singlet oxygen produced by TPP-PPa/PPa oxidized the imidazole moiety to produce hydrophilic urea, leading to micelle disassembly and rapid cargo release. The co-localization analysis showed that the TPP moiety significantly enhanced the photosensitizer uptake by mitochondria, improved mitochondria depolarization upon irradiation, and hence boosted the cytotoxicity in 4T1 cells. The targeting strategy also dramatically reduced the intracellular ATP concentration as a consequence of mitochondria injury. The mitochondria damage was accompanied with the activation of the apoptosis signals (caspase 3 and caspase 9), whose level was directly correlated to the apoptosis extent. The current work provides a facile and robust means to enhance the efficacy of photodynamic therapy. PMID- 29620539 TI - Basic modelling of transport in 2D wave-mechanical nanodots and billiards with balanced gain and loss mediated by complex potentials. AB - Non-Hermitian quantum mechanics with parity-time (PT) symmetry is presently gaining great interest, especially within the fields of photonics and optics. Here, we give a brief overview of low-dimensional semiconductor nanodevices using the example of a quantum dot with input and output leads, which are mimicked by imaginary potentials for gain and loss, and how wave functions, particle flow, coalescence of levels and associated breaking of PT symmetry may be analysed within such a framework. Special attention is given to the presence of exceptional points and symmetry breaking. Related features for musical string instruments and 'wolf-notes' are outlined briefly with suggestions for further experiments. PMID- 29620540 TI - Reproductive health profile and circumcision of females in the Hali semi-urban region, Saudi Arabia: A community-based cross-sectional survey. AB - BACKGROUND: Improving the reproductive health of females has be.come the focus of the developmental efforts of many nations. OBJECTIVES: To identify the reproductive health style of married females, and to determine the prevalence and predictors of circumcision among girls aged less than or equal 18 years in Hali semi-urban region. DESIGN: A cross-sectional household survey SETTING: Houses in Hali, Al-Qunfudhah governorate, western Saudi Arabia during 2017. SUBJECTS AND METHODS: A multistage systematic cluster random sampling method was used to select participants. A validated questionnaire was used in interviewing the head of the selected houses. MAIN OUTCOME MEASURES: Reproductive health profile of women, and circumcision of girls. SAMPLE SIZE: 365 households. RESULTS: Reproductive life starts early in the Hali region as 41.4% of women are married at or before 18 years of age. Consanguinity was recorded in 57.0% of houses. The prevalence of grand multiparity (GMP) was 54.7%; it was significantly associated with current maternal age, age at marriage, low educational levels of both parents and husbands with non-professional jobs. Current use of birth control methods was reported by 28.9% of families, and oral contraceptives (OCs) were the commonest method. Contraceptive use was significantly associated with higher educational levels of both parents and with women having professional work. The prevalence of circumcision was 80.3%. Circumcision was most frequent (59.4%) at age 7 years or less, and almost always done by doctors (91.4%). Hemorrhage (2.9%) and fever (2.3%) were the minimal recorded complications. Girls with higher parental education, enough income, no parental consanguinity, and whose mothers married at an older age had slightly lower rates of circumcision, but the difference was without statistical significance. CONCLUSION: The pattern of early female marriage, high consanguinity, GMP, low contraceptive use, and a high frequency of circumcision in girls was apparent in Hali. Public health education and legislative policies are needed. LIMITATIONS: Recall bias may affect the reported frequency of circumcision, and related complications. CONFLICTS OF INTEREST: None. PMID- 29620541 TI - Screening of latent tuberculosis infection among health care workers working in Hajj pilgrimage area in Saudi Arabia, using interferon gamma release assay and tuberculin skin test. AB - BACKGROUND: Interferon gamma release assays (IGRA) is highly specific for Mycobacterium tuberculosis and is the preferred test in BCG-vaccinated individuals. The few studies that have screened health care workers (HCWs) in Saudi Arabia for latent tuberculosis infection (LTBI) using IGRA have varied in agreement with the traditional tuberculin skin test (TST). OBJECTIVE: Assess the prevalence of LTBI among HCWs working in the Hajj pilgrimage using IGRA and TST and measuring their agreement. DESIGN: Cross-sectional prospective. SETTING: Multiple non-tertiary care hospitals. PATIENTS AND METHODS: HCWs who worked during the Hajj pilgrimage in Saudi Arabia in December 2015. Data was collected by standarized questionnaire. Samples were drawn and analyzed by standard methods. MAIN OUTCOME MEASURES: The prevalence of LTBI among HCW and the agreement by kappa statistic between QFT-GIT and TST. SAMPLE SIZE: 520 subjects. RESULTS: Nurses accounted for 30.7% of the sample and physicians, 19.2%. The majority were BCG vaccinated (98.5%). There were a total of 56 positive by QFT GIT and the LTBI rate was 10.8%. In 50 QFT positive/476 TST negative the LTBI rate was 10.5% in discordant tests, and in 6 QFT positive/44 TST positive it was 13.6% in concordant tests. The overall agreement between both tests was poor-83% and kappa was 0.02. LTBI prevalence was associated with longer employment (13.1 [9.2] years). The QFT-GIT positive test was significantly higher in physicians (P=.02) and in HCWs working in chest hospitals 16/76 (21.05%) (P=.001). CONCLUSION: Agreement between the tests was poor. QFT-GIT detected LTBI when TST was negative in HCWs who had a history of close contact with TB patients. LIMITATIONS: A second step TST was not feasible within 2-3 weeks. CONFLICT OF INTEREST: None. PMID- 29620542 TI - Donor-specific HLA-DQ antibodies may contribute to poor graft outcome after heart transplantation. AB - BACKGROUND: HLA-DQ donor-specific antibodies (DSA) are implicated in allograft dysfunction after renal and lung transplantation. Limited data exists on the impact of HLA-DQ antibodies on heart transplant patients. OBJECTIVE: To investigate the impact of DSA formation on allograft function and outcomes in heart transplant patients. DESIGN: Retrospective cohort study. SETTING: Collating post-transplantation patient data from computerized database in a tertiary hospital in Riyadh, Saudi Arabia from January 2006 to October 2014. PATIENTS AND METHODS: We excluded recipients with positive preoperative complement-dependent cytotoxicity crossmatch grafts and those with preformed DSA. Anti-HLA antibodies were identified using Luminex-based assay in sera collected before transplantation with a routine endomyocardial biopsy the first year and then annually. MAIN OUTCOME MEASURES: Primary outcome measures were all-cause mortality, development of antibody mediated rejection, treated acute cellular rejection (ACR) and cardiac allograft vasculopathy (CAV). SAMPLE SIZE: 127 patients. RESULTS: DSA formation occurred in 43/127 (34%), with 33/43 (77%) targeting HLA-DQ antigens alone (n=7) or in combination with -DR, -A or B antibodies (n=26). Most (76%) were male and the mean (SD) age was 36 (14) years. Ten patients developed -A, -B or -DR antibodies without -DQ antibodies also present. Treated ACR (P=.011), reduced left ventricular ejection fraction (P less than .001), CAV development (P=.003), and all-cause mortality (P=.01) were all significantly more prevalent in the DSA-positive cohort. CONCLUSION: HLA-DQ donor specific antibodies were the most common type detected and may play a significant role in poor outcomes post-cardiac transplantation. This emphasizes the importance of HLA-DQ matching and monitoring for DSA formation in order to minimize post-transplantation immunological risk. LIMITATIONS: Retrospective design comes with inherent biases, results from single institute, with a particularly young cohort. CONFLICT OF INTEREST: None. PMID- 29620543 TI - Outcomes of common general surgery procedures for patients discharged over weekends at a tertiary care hospital in Saudi Arabia. AB - BACKGROUND: Hospitals usually reduce staffing levels and services over weekends. This raises the question of whether patients discharged over a weekend may be inadequately prepared and possibly at higher risk of adverse events post discharge. OBJECTIVES: To assess the outcomes of common general surgery procedures for patients discharged over weekends, and to identify the key predictors of early readmission. DESIGN: Retrospective cohort study. SETTING: A tertiary care center. PATIENTS AND METHODS: Patients discharged from general surgery services during the one-year period between January and December 2016 after cholecystectomy, appendectomy, or hernia repairs were included. Patient demographic information, comorbidities, and complications as well as admission and follow-up details were collected from electronic medical records. MAIN OUTCOME MEASURES: Outcomes following weekend discharge, and the predictors of early readmission. SAMPLE SIZE: 743 patients. RESULTS: The operations performed: 361 patients (48.6%) underwent a cholecystectomy, 288 (38.8%) an appendectomy, and 94 (12.6%) hernia repairs. A significantly lower number of patients were discharged over the weekend (n=125) compared to those discharged on weekdays (n=618). Patients discharged during the weekend were younger, less likely to have chronic diseases, and had a significantly shorter average length of stay (LOS) (median 2 days, IQR: 1, 4 vs. median 3 days, IQR: 1, 5, P=.002). Overall, the 30 day readmission rate was 3.2% (n=24), and weekend discharge (OR=2.25, 95% CI 0.52 9.70) or any other variable did not predict readmission in 30 days. However, 14 day post-discharge follow-up visits were significantly lower in the weekend discharge subgroup (83.1% vs. 91.2%, P=.006). CONCLUSION: Weekend discharge was not associated with higher readmission rates. Physicians may consider discharging post-operative patients over a weekend without an increased risk to the patient. Day of discharge, length of stay and increased patient age are not predictors of early readmission. LIMITATIONS: Single-center study and retrospective. CONFLICT OF INTEREST: None. PMID- 29620544 TI - Elevated fasting blood glucose, but not obesity, is associated with coronary artery disease in patients undergoing elective coronary angiography in a referral hospital in Jordan. AB - BACKGROUND: Obesity and its metabolic complications are endemic in the Middle East, but the cardiovascular consequences are not well defined in local studies. OBJECTIVE: To assess the association between fasting blood glucose (FBG), obesity and coronary artery disease (CAD) in Jordan. DESIGN: A cross-sectional, hospital based study. SETTING: A referral hospital in Amman, Jordan. PATIENTS AND METHODS: Patients with complete anthropomorphic data who were referred for elective coronary angiography were included in the analysis. Associations between CAD, FBG and obesity were assessed in multivariate logistic regression models, adjusting for known risk factors. MAIN OUTCOME MEASURE: The presence of CAD. SAMPLE SIZE: 434 subjects. RESULTS: Only those who underwent coronary angiography and had complete anthropometric data were included in the study: 291 (67.1%) had CAD and 143 (32.9%) had a normal coronary angiogram.The mean body mass index, waist circumference and FBG of the study participants was 30.0 kg/m2, 106.0 cm and 8.8 mmol/L, respectively. The mean FBG was significantly higher in patients with CAD compared to those without CAD (9.5 vs. 7.3 mmol/L, P less than .001). Waist circumference was significantly higher in women with CAD compared to women without CAD (111.0 vs. 105.9 cm, P=.036), but no significant difference was observed in men. In a multivariate analysis, FBG was a strong and significant predictor of CAD; however, none of the measures of obesity were significantly associated with CAD. The findings were robust in a sensitivity analysis that excluded patients with known diabetes mellitus. CONCLUSIONS: Elevated FBG, but not obesity, predicted CAD in a Middle Eastern population. Improved prevention, detection and management of type 2 diabetes should be a priority in this setting. LIMITATIONS: The cross-sectional design cannot control for temporal changes in risk factors and/or reverse causation. CONFLICT OF INTEREST: None. PMID- 29620545 TI - Endobronchial biopsy in the final diagnosis of chronic obstructive pulmonary disease and asthma: a clinicopathological study. AB - BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) are chronic conditions with an increasing prevalence in developing countries. The evaluation of endobronchial biopsies has emerged as a tool to differentiate between both conditions via the measurement of the reticular basement membrane (RBM) thickness with various conclusions drawn from different studies. OBJECTIVES: Compare the thickness of the RBM between asthma and COPD and evaluate other histomorphological features in both groups. DESIGN: Prospective, descriptive and analytical. SETTING: University teaching hospital. PATIENTS AND METHODS: The study included patients with COPD and irreversible and reversible asthma with diagnosis based on clinical assessment, pulmonary function tests and high resolution computed tomography scans. Endobronchial biopsies were obtained from all patients and, using a light microscope and a computerized image analyzer, the thickness of the reticular basement membrane was calculated in all patients. We also made a qualitative assessment of other histo-morphological features. MAIN OUTCOME MEASURES: Mean RBM thickness. SAMPLE SIZE: Thirty male patients. RESULTS: The mean RBM thickness in asthmatic patients was 8.9 (2.4) micro m. The mean RBM thickness in COPD patients was 5.3 (1.1) micro m. However, there was no thickening of the RBM in patients with reversible asthma. The RBM was significantly thicker in patients with irreversible asthma than in patients with COPD or reversible asthma. There were no significant differences in epithelial desquamation or metaplasia, mucosal or submucosal inflammation, the presence of eosinophils, submucosal glandular hyperplasia or submucosal smooth muscle hyperplasia between groups. CONCLUSIONS: The thickness of the RBM is the only reproducible histopathological feature to differentiate COPD from irreversible asthma. LIMITATIONS: The study included a limited number of patients. A qualitative approach was used to compare epithelial cell injury, inflammation, submucosal glandular and muscular hyperplasia. CONFLICT OF INTEREST: None. PMID- 29620546 TI - Comparison of cochlear duct length between the Saudi and non-Saudi populations. AB - BACKGROUND: There are no data on cochlear duct lengths (CDL) among Middle East populations. OBJECTIVES: The main aims of this study were to estimate the average CDL in the Saudi population and to compare it with the reported CDL in other regions/ethnic groups outside the Middle East. DESIGN: Retrospective study. SETTING: Tertiary otolaryngology head and neck surgery center. SUBJECTS AND METHODS: Temporal bone CT scans were reviewed to determine CDL. We excluded any CT scan of an ear with a congenital inner ear anomaly or acquired pathology. MAIN OUTCOME MEASURES: CDL. SAMPLE SIZE: 441 temporal bone CT scans. RESULTS: The overall CDL mean was 31.9 mm (range 20.3-37.7 mm). The cochleae of males was significantly longer than of females and cochleae from the left side were significantly longer than of the right side. No significant difference was found between children and adults. Inter-study comparison revealed a significant difference in CDL between the Saudi population in our study and European and Australian studies, but not between the present study and North American studies. CONCLUSIONS: The CDL differed significantly according to side of the cochlea and sex, but not by age. Geographically and ethnically, the mean CDL for Saudis was significantly different from the CDL of subjects of some ethnic backgrounds, but not others. Due to this diversity, we recommend that the CDL be measured before cochlear implant surgery. LIMITATIONS: All the measurements were done by one person, and the subjects' physical measurements, such as height or head circumference, were not included. CONFLICT OF INTEREST: None. PMID- 29620547 TI - Vitamin D deficiency in sickle cell disease patients in the Eastern Province of Saudi Arabia. AB - BACKGROUND: Vitamin D deficiency (VDD) is a major global health problem. In sickle cell disease (SCD), VDD is highly prevalent, reaching up to 96% of populations. VDD may contribute to many of the complications of SCD. OBJECTIVE: Estimate the 25-hydroxyvitamin D [25(OH)D] level and the frequency of VDD and insufficiency among among SCD patients by age group and disease status. DESIGN: Analytical cross-sectional. SETTING: Ministry of Health (MOH) secondary care hospital. PATIENTS AND METHODS: Non-probability purposive sampling was used to select SCD patients, aged 12 years and older, of both sexes, who had visited the hospital during a period of 5 years (2010-2014). Blood samples were processed by electrochemiluminescence technology. MAIN OUTCOME MEASURE(S): 25(OH)D levels by demographic data, and disease activity. SAMPLE SIZE: 640 patients. RESULTS: Of those, 82% (n=523) had suboptimal 25(OH)D (0-<30 ng/ mL), and 67% were deficient (0-<20 ng/mL). Patients with any SCD crisis (20.7%, 144/694) had lower 25(OH)D (median, IQR: 10.1 ng/mL [8.6] ng/mL) compared to patients without crisis (71.0%, 493/694) (15.7 ng/ mL [18.2] ng/mL) (P<.001). Deficiency was more common in the young.er age groups and in sickle cell anemia patients with crisis. CONCLUSIONS: VDD is highly prevalent in this population. Established vitamin D screening is a necessity, so that affected patients can be treated. LIMITATIONS: Presence of residual confounders such as nutritional status, physical activity, lack of sun exposure, medications that alleviate SCD crises (such as hydroxyurea), and comorbid illnesses. The relationship between sickle cell disease genotype and vitamin D level was not analyzed. CONFLICT OF INTEREST: None. PMID- 29620548 TI - Age at presentation of undescended testicles: a single-center study in Saudi Arabia. AB - BACKGROUND: The undescended testis (UDT) is the most common genital anomaly encountered in pediatrics with an estimated incidence of 1% to 4% in full-term and 1% to 45% in preterm newborn boys. Over the years, studies on progressive histological deterioration and cancer risk has led to a change in recommendations for when orchidopexy should be done. OBJECTIVES: Determine age at presentation of patients for UDT to a specialist in Saudi Arabia, age of operation and whether the recommended targeted time frame has been met. DESIGN: Descriptive retrospective medical record review. SETTINGS: University hospital setting in urban location. SUBJECTS AND METHODS: The records of patients presenting to our center with UDT between the years 1996-2015 were reviewed for data on the age at presentation and age of operation. MAIN OUTCOME MEASURES: Age at time of evaluation and at time of surgical intervention compared with the international standard. SAMPLE SIZE: 331 cases. RESULTS: Out of the cases included, 195 met the inclusion criteria. The median age of presentation was 13.7 (range: 0-123.2) months. The median age at time of orchiopexy was 25 (range: 7.5-130.2) months. The median waiting time for elective surgery was 4.8 months ( less than 1 day to 49.4 months). CONCLUSION: Despite the international recommendation of carrying out orchidopexy between the ages of 6-12 months, the targeted recommended time frame is not met in Saudi Arabia. This is mainly related to late referral age and the long waiting time for elective surgery. LIMITATIONS: Small sample size and retrospective design. CONFLICT OF INTEREST: None. PMID- 29620549 TI - Turnover among Filipino nurses in Ministry of Health hospitals in Saudi Arabia: causes and recommendations for improvement. AB - BACKGROUND: Nurse turnover is a critical challenge for healthcare organizations as it results in a decreasing nurse/patient ratio and increasing costs. AIM: Identify factors influencing the termination of Filipino nurses in Ministry of Health (MOH) hospitals and record nurse recommendations to improve retention. DESIGN: Cross-sectional. METHODS: Data was gathered from a convenience sample of Filipino nurses with previous experience in MOH hospitals in Saudi Arabia who attended recruitment interviews at the Saudi employment office in Manila. RESULTS: The sample included 124 nurses. Major turnover factors included low salary (18.3%), low nurse/patient ratio (15%), end of contract (14.5%), discrimination (13.5%), and bad accommodations (9%). Suggested areas of improvement included financial motivations (34%), administration support (25%), quality of life (25%), and work environment (16%). CONCLUSION: Managing nurse turnover can be implemented on the organizational as well as at MOH levels. The recommendations given by the participants provide direct targets to improve retention. LIMITATIONS: With convenience sampling, the sample is probably not representative of the Filipino nursing population. CONFLICT OF INTEREST: None. PMID- 29620551 TI - Practical Applications of Delayed-Immediate Autologous Breast Reconstruction: A Flexible and Safe Operative Strategy. AB - BACKGROUND: Timing is an important consideration in patients undergoing mastectomy for breast cancer. While immediate reconstruction results in superior aesthetic outcomes, the need for postmastectomy radiation can often only be ascertained after review of surgical pathology. Delayed-immediate autologous reconstruction (DIAR) is a reconstructive approach that consists of mastectomy with tissue expander placement in the first stage and flap-based breast reconstruction in the second stage. We describe our institution's experience with DIAR to characterize the reasons in which patients opt for this reconstructive approach and analyze its ultimate outcomes. METHODS: We conducted an institutional review board-approved retrospective chart review of all consecutive patients undergoing DIAR performed by the senior author from 2007 to 2016. Data gathered included demographics, operative techniques, and postoperative outcomes. RESULTS: In our study, 17 patients and 26 breasts underwent DIAR. Seven patients initially planned for and eventually underwent DIAR. Ten patients initially planned for implant-based reconstructions but ultimately underwent DIAR instead. Flap types included deep inferior epigastric perforator (n = 6), superficial inferior epigastric artery (n = 2), and muscle-sparing free transverse rectus abdominis myocutaneous (n = 18). The mean time between mastectomy and reconstruction was 208 days. Complications included tissue expander infection, vascular compromise, abscess formation, hematoma, and skin necrosis. CONCLUSIONS: The delayed-immediate approach allows for breast reconstruction with aesthetic and psychosocial benefits, while enabling postmastectomy radiation in patients with advanced disease. We describe modifications to DIAR, including use of a flap skin paddle and prolonged time between stages, which allow for broader applicability. We show that DIAR accommodates a range of patient preferences with few complications. PMID- 29620550 TI - Cerebrospinal fluid leakage after turbinate submucosal diathermy: an unusual complication. AB - : Submucosal diathermy of the inferior turbinate (SMDIT) is a generally safe procedure to control inferior turbinate hypertrophy. We present a case of a cerebrospinal fluid (CSF) leak at the craniocervical junction after SMDIT done in another institution. A 27-year-old man presented 3 weeks after undergoing SMDIT with signs and symptoms of meningitis and postnasal rhinorrhea. Nasal endoscopy and imaging revealed a nasopharyngeal CSF fistula at the craniocervical junction. Transnasal endoscopic repair and reconstruction was performed with no recurrence on repeat imaging and clinical follow up. We describe the first reported case in the literature of an iatrogenic CSF fistula caused by SMDIT, an unusual and potentially fatal complication, and its surgical management. SIMILAR CASES PUBLISHED: 0 CONFLICT OF INTEREST: None. PMID- 29620552 TI - Periumbilical Perforator-Sparing Abdominoplasty in Patients With Abdominal Scars. AB - Abdominoplasty is one of the most common cosmetic surgical procedures. Patients who undergo abdominoplasties with abdominal scars are at an increased risk for skin necrosis and wound breakdown. To prevent further disruption of vascularity, the dissection and mobilization is often limited resulting in a suboptimal esthetic result. The periumbilical perforator-sparing technique allows for vascular preservation and adequate mobilization to produce excellent esthetic results in patients with abdominal scars. PMID- 29620553 TI - Seventh Dedicated California Society of Plastic Surgeons Annals. PMID- 29620554 TI - Comparative Usefulness of Sepsis-3, Burn Sepsis, and Conventional Sepsis Criteria in Patients With Major Burns. AB - OBJECTIVES: We evaluated the ability of new sepsis (S3) criteria (compared with previous definitions of sepsis [S1] and burn sepsis criteria) to accurately determine the mortality in severe burns patients with sepsis. DESIGN: This was retrospective cohort study. SETTING: The Burn ICU of Burn Center, Hangang Sacred Heart Hospital, Hallym University, Seoul, Korea. PATIENTS: A total of 1,185 adult patients (mean age, 49.1 yr) were admitted between January 2009 and December 2015. INTERVENTIONS: The 1,185 patients enrolled in the present study and were then re-evaluated based on S1, burn sepsis, and S3 criteria, following which 565 patients, 812 patients, and 809 patients were diagnosed with sepsis based on S1, burn sepsis, S3 criteria, respectively. MEASUREMENTS AND MAIN RESULTS: For diagnostic performance, sensitivity, specificity, predictive value, and likelihood ratio were calculated. The area under the curve of the receiver operating characteristic curve was calculated to determine the accuracy of mortality prediction. The optimal cutoff value of Sequential Organ Failure Assessment score was calculated by the decision tree method. Total body surface area burned was 33.4%. Patients were identified with sepsis using S1 (812), S3 (809), and burn sepsis (565) criteria. Overall mortality was 20.3%, highest (82.2%) and lowest (26.5%) occurred with new septic shock (SH3) and S3, respectively. The sensitivity and specificity for burn sepsis (84.6% and 61.8%) and SH3 (63.1% and 96.5%) were reported. Area under the curve values for Sequential Organ Failure Assessment scores were the highest in all sepsis categories. With Sequential Organ Failure Assessment score greater than or equal to 6 (with infection), the accuracy was 0.86 (95% CI, 0.82-0.89). CONCLUSIONS: The S3 criteria failed to show superior prognostic accuracy for mortality in severely burned patients. Sequential Organ Failure Assessment score greater than or equal to 6 may be a better criterion for the diagnosis of sepsis in burns patients. PMID- 29620556 TI - Parent Perspectives of Receiving Early Information About Palliative and End-of Life Care Options From Their Child's Pediatric Providers. AB - BACKGROUND: Parents of children diagnosed with cancer may experience decision regret about cancer treatment decisions and dissatisfaction with the perceived clarity in information received from their child's providers. OBJECTIVE: The aim of this study was to describe parental perspectives about receiving an early palliative care and end-of-life (PC/EOL) communication intervention titled "Communication Plan: Early through End of Life Intervention" (COMPLETE) from an interprofessional team of physician and registered nurse providers. METHODS: Ten parents participated in semistructured interviews after receiving the COMPLETE intervention. The COMPLETE intervention included 3 sessions delivered shortly after diagnosis and at the next 2 cancer treatment evaluations. Sessions of COMPLETE focused on early PC/EOL care discussions at diagnosis and after tumor response evaluations with their child's providers. RESULTS: Results included 2 theme categories: (1) COMPLETE nurtures realistic hope and meaningful dialogue by parents connecting with healthcare providers as a dyad, and (2) benefits of COMPLETE helped parents to make informed decisions. In addition, there were offered suggestions to improve COMPLETE. CONCLUSION: The COMPLETE intervention provided a unique mechanism to foster early discussions about PC/EOL options between parents and an interprofessional team during the first 6 months of the child's cancer treatment. Future study is needed using a randomized clinical control-group design to evaluate COMPLETE with a large sample of parents. IMPLICATIONS FOR PRACTICE: Findings provide promising evidence of parents' preference and receptivity to receive early information about PC/EOL care options for a child with a brain tumor with a poor prognosis. The COMPLETE intervention provided a mechanism to help encourage parental consideration of realistic hoped for goals for their child's condition and care. PMID- 29620555 TI - Increased Heat Generation in Postcardiac Arrest Patients During Targeted Temperature Management Is Associated With Better Outcomes. AB - OBJECTIVES: Assess if amount of heat generated by postcardiac arrest patients to reach target temperature (Ttarget) during targeted temperature management is associated with outcomes by serving as a proxy for thermoregulatory ability, and whether it modifies the relationship between time to Ttarget and outcomes. DESIGN: Retrospective cohort study. SETTING: Urban tertiary-care hospital. PATIENTS: Successfully resuscitated targeted temperature management-treated adult postarrest patients between 2008 and 2015 with serial temperature data and Ttarget less than or equal to 34 degrees C. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Time to Ttarget was defined as time from targeted temperature management initiation to first recorded patient temperature less than or equal to 34 degrees C. Patient heat generation ("heat units") was calculated as inverse of average water temperature * hours between initiation and Ttarget * 100. Primary outcome was neurologic status measured by Cerebral Performance Category score; secondary outcome was survival, both at hospital discharge. Univariate analyses were performed using Wilcoxon rank-sum tests; multivariate analyses used logistic regression. Of 203 patients included, those with Cerebral Performance Category score 3-5 generated less heat before reaching Ttarget (median, 8.1 heat units [interquartile range, 3.6-21.6 heat units] vs median, 20.0 heat units [interquartile range, 9.0-33.5 heat units]; p = 0.001) and reached Ttarget quicker (median, 2.3 hr [interquartile range, 1.5-4.0 hr] vs median, 3.6 hr [interquartile range, 2.0-5.0 hr]; p = 0.01) than patients with Cerebral Performance Category score 1-2. Nonsurvivors generated less heat than survivors (median, 8.1 heat units [interquartile range, 3.6-20.8 heat units] vs median, 19.0 heat units [interquartile range, 6.5-33.5 heat units]; p = 0.001) and reached Ttarget quicker (median, 2.2 hr [interquartile range, 1.5-3.8 hr] vs median, 3.6 hr [interquartile range, 2.0-5.0 hr]; p = 0.01). Controlling for average water temperature between initiation and Ttarget, the relationship between outcomes and time to Ttarget was no longer significant. Controlling for location, witnessed arrest, age, initial rhythm, and neuromuscular blockade use, increased heat generation was associated with better neurologic (adjusted odds ratio, 1.01 [95% CI, 1.00-1.03]; p = 0.039) and survival (adjusted odds ratio, 1.01 [95% CI, 1.00-1.03]; p = 0.045) outcomes. CONCLUSIONS: Increased heat generation during targeted temperature management initiation is associated with better outcomes at hospital discharge and may affect the relationship between time to Ttarget and outcomes. PMID- 29620557 TI - Impact of paclitaxel-coated balloon versus newer-generation drug-eluting stent on periprocedural myocardial infarction in stable angina patients. AB - OBJECTIVES: Periprocedural myocardial infarction (PMI) is reported to be associated with adverse long-term clinical outcomes. This study compared the rates of PMI following treatment of de novo coronary lesions using either a paclitaxel-coated balloon (PCB) or a newer-generation drug-eluting stent (DES). PATIENTS AND METHODS: We compared the incidence of PMI in propensity-matched patients with stable angina pectoris and single-vessel de novo coronary lesions who underwent treatment with a PCB or newer-generation DES. Propensity score matching was performed to adjust for differences in baseline clinical and angiographic characteristics. RESULTS: After propensity matching, the study cohort included 108 patients (PCB: n=54 and DES: n=54). The peak mean values of creatine kinase-myocardial band (13.3+/-26.3 vs. 2.2+/-2.8 ng/ml, P=0.003) and high-sensitive troponin T (0.62+/-1.38 vs. 0.09+/-0.19 ng/ml, P=0.007) were significantly higher in the DES group compared with the PCB group. The incidence of PMI was significantly higher in the DES group [DES: 11 (20.4%) vs. PCB: one (1.9%); P=0.002]. Total occlusion of the side-branch occurred in two patients treated with DES, but no patients treated with PCB. Treatment with a newer generation DES was found to be an independent predictor of PMI on multivariable analyses. CONCLUSION: In patients with stable angina using a PCB, compared with deployment of a newer-generation DES, is associated with a significant reduction in the risk of PMI. PMID- 29620558 TI - Effect of low-intensity versus high-intensity resistance training on the functioning of the institutionalized frail elderly. AB - Frailty has emerged as an important risk factor for disability. Age-related declines in physical and physiological function lead to increased risk of loss of independence and poor quality of life. Recent evidence has shown the effectiveness of physical exercise programmes in preventing or reversing frailty. The aim of this study was to evaluate changes in the functioning of frail elderly individuals after undergoing resistance training for 3 days a week for 8 weeks. The effectiveness of exercise training was investigated in 48 frail elderly individuals who were randomly assigned to the following intervention groups: high intensity (HI; n=16; age: 69-96 years) or low-intensity (LI; n=16; age: 77-93 years) strength training groups or a control group (n=16; age: 76-93 years) with no specific exercise programme. Participants were assessed for muscle strength, physical function, activities of daily living, depression and quality of life. The HI group had significantly better results (P<0.05) on the Short Physical Performance Test than the LI group; however, the LI group did show a significant improvement in those scores, whereas the scores of the control group worsened. Results for the other evaluations were similarly favourable in both exercise groups (P>0.05). The study showed that LI exercise was as effective as HI exercise for most parameters tested. Exercise training is useful for the prevention or treatment of frailty, as it improves functioning by contributing positively to muscle strength, gait, balance and quality of life. PMID- 29620559 TI - Unilateral Lateral Epicondylalgia Shows a Pro-nociceptive Pain Profile: A Case control Observational Study. AB - OBJECTIVE: Lateral epicondylalgia (LE, tennis elbow) is characterized by both local tissue pathology and features indicative of secondary hyperalgesia. The aim of this study was to evaluate endogenous pain modulation characteristics in people with chronic LE, and to investigate the relationship between endogenous pain modulation and clinical characteristics. MATERIALS AND METHODS: This case control observational study included 25 participants with LE of at least 6 weeks' duration and 15 age-matched (+/-5 y) healthy control participants, who were each evaluated in a single session. Pain and disability were assessed using the patient-rated tennis elbow evaluation and pain-free grip strength. Endogenous pain modulation was assessed using pressure pain threshold, cold pain threshold, conditioned pain modulation (CPM), and temporal summation (TS). RESULTS: The LE group exhibited significantly lower pain-free grip and pressure pain threshold bilaterally compared with the control group. Cold pain threshold was significantly reduced on the affected side compared with the matched control side. There was no significant difference between groups for CPM; however, the LE group exhibited significantly increased facilitation as measured by TS (between group difference in change score of 9.6 mm on a 0 to 100 mm pain visual analogue scale; 95% confidence intervals, 3.4-15.8 mm). There was no significant correlation between pain modulation and clinical measures of pain and disability. DISCUSSION: LE is characterized by locally increased facilitation of pain, as measured by TS, but this is not associated with severity of pain or disability. PMID- 29620560 TI - Unique Autonomic Responses to Pain in Yoga Practitioners. AB - OBJECTIVE: Autonomic nervous system activity is associated with neurobehavioral aspects of pain. Yogis use breathing, relaxation, and mindfulness to tolerate pain, which could influence autonomic responses. To evaluate how the link between autonomic responses and pain is altered by other factors, we compared perceptual and autonomic responses to pain between yogis and controls. METHODS: Nineteen yogis and 15 controls rated warm and painfully hot stimuli (1-cm thermode on calf), with visual anticipatory cues indicating certainly painful, certainly nonpainful, or uncertainly either painful or nonpainful. Heart rate, skin conductance, respiration, and blood pressure were measured. RESULTS: At baseline, yogis breathed slower and deeper than did controls, with no differences in other autonomic measures. During the task, perceptual ratings did not differ between groups in either the certain or uncertain conditions. Nevertheless, yogis had higher phasic skin conductance responses in anticipation of and response to all stimuli, but particularly during painful heat in uncertain contexts (uncertain: 0.46 [0.34] MUS; certain: 0.37 [0.28] MUS; t(18) = 3.962, p = .001). Furthermore, controls showed a decrease in heart rate to warm (-2.51 [2.17] beats/min) versus painful stimuli (0.83 [1.63] beats/min; t(13) = 5.212, p < .001) and lower respiratory sinus arrhythmia during pain compared with warm trials, whereas yogis had similar reactions to painful and nonpainful stimuli. CONCLUSIONS: Autonomic responses to pain differed in yogis and healthy volunteers, despite similar pain ratings. Thus, autonomic reactivity to pain may be altered by environmental and psychological factors throughout an individual's life. PMID- 29620562 TI - Treatment of Sclerodermoid Graft-Versus-Host Disease With the Fractionated Nonablative 1,927-nm Thulium Fiber Laser. PMID- 29620561 TI - The Influence of Pain-Related Expectations on Intensity Perception of Nonpainful Somatosensory Stimuli. AB - OBJECTIVE: The extent to which pain-related expectations, known to affect pain perception, also affect perception of nonpainful sensations remains unclear, as well as the potential role of unpredictability in this context. METHODS: In a proprioceptive fear conditioning paradigm, various arm extension movements were associated with predictable and unpredictable electrocutaneous pain or its absence. During a subsequent test phase, nonpainful electrocutaneous stimuli with a high or low intensity were presented during movement execution. We used hierarchical drift diffusion modeling to examine the influence of expecting pain on the perceptual decision-making process underlying intensity perception of nonpainful sensations. In the first experiment (n = 36), the pain stimulus was never presented during the test phase after conditioning. In the second experiment (n = 39), partial reinforcement was adopted to prevent extinction of pain expectations. RESULTS: In both experiments, movements that were associated with (un)predictable pain led to higher pain expectancy, self-reported fear, unpleasantness, and arousal as compared with movements that were never paired with pain (effect sizes eta2 ranging from 0.119 to 0.557; all p values < .05). Only in the second experiment-when the threat of pain remained present-we found that the expectation of pain affected decision making. Compared with the no pain condition, an a priori decision-making bias toward the high-intensity decision threshold was found with the strongest bias during unpredictable pain (effect sizes eta2 ranging from 0.469 to 0.504; all p-values < .001). CONCLUSIONS: Thus, the expectation of pain affects inferential processes not only for subsequent painful but also for nonpainful bodily stimuli, with unpredictability moderating these effects, and only when the threat of pain remains present due to partial reinforcement. PMID- 29620563 TI - Comparison of Ipsilateral and Contralateral Paramedian Forehead Flaps to Reconstruct Lateral Nasal Subunits. PMID- 29620564 TI - Geographic Distribution of U.S. Mohs Micrographic Surgery Workforce. PMID- 29620565 TI - Reply. PMID- 29620566 TI - Variability of Tear Osmolarity Measurements With a Point-of-Care System in Healthy Subjects-Systematic Review. AB - PURPOSE: To assess the variability of osmolarity measured by the point-of-care TearLab system in healthy eyes. METHODS: A systematic review was performed by searching MEDLINE, Scopus, and the Web of Science Databases until November 2016 and checking reference lists of included articles and reviews. The requirements for inclusion were the availability of TearLab results in healthy subjects and a minimum study sample of 20 eyes. Two reviewers assessed articles against the inclusion criteria, extracted relevant data, and examined the methodological quality. We computed the weighted mean osmolarity using the study size as the weighting factor and calculated the rate of subjects with osmolarity values >308 mOsm/L, the Dry Eye Workshop Report 2017 (DEWS) cut-off value for dry eye disease (DED). We repeated the analysis after excluding reports with a possible conflict of interest or missing description of subject selection. RESULTS: Searches retrieved 105 nonduplicate articles, and we included 33 studies investigating 1362 eyes of healthy participants who were asymptomatic and showed no clinical signs of DED. Sixty-three percent were female, and mean age was 37.3 years (range: 21.5-69.0 yr). Weighted mean osmolarity was 298 mOsm/L (95% confidence interval, 282-321 mOsm/L). The result of the subgroup analysis was similar. Overall, 386 of 1362 eyes (28.3%) fulfilled the DEWS's definition of DED (>308 mOsm/L). CONCLUSIONS: There is a high variability of osmolarity measurements with the TearLab system. A substantial number of healthy subjects fulfill the DEWS's definition of DED. We propose interpreting the TearLab osmolarity results cautiously and in the context of other established methods. PMID- 29620567 TI - Reduction of Donor Cornea Exposure to Repeat Warming Cycles and Evaluation Times After Implementation of a Rapid Warming Protocol. AB - PURPOSE: To compare tissue evaluation times and specular image quality before and after the implementation of rapid tissue warming at a single eye bank. METHODS: This retrospective study compares the evaluation of 494 donor corneas. All corneas were stored in Optisol-GS. Group 1 contained 247 corneas evaluated immediately before implementation of a tissue incubator and tissue warming protocol. Group 2 contained 247 corneas evaluated immediately after implementation. Total evaluation times (including specular microscopy, optical coherence tomography for corneal thickness measurements, and 2 slit-lamp examinations) were calculated and compared. Representative specular images of donor corneas were rated and compared using a previously described scale by 2 masked readers. RESULTS: Donor tissue characteristics were not significantly different between both groups (age, P = 0.87; sex, P = 0.93; endothelial cell densities, P = 0.47; and death-to-preservation times, P = 0.18). The mean total evaluation time for group 2 corneas was ~3 hours, with 97% (201/208) of evaluations completed on the same day. In contrast, only 73% (164/225) of corneas from group 1 were completely evaluated in 1 day, and the mean evaluation time for those corneas was ~4.25 hours (P < 0.01). Specular images of corneas from group 2 were rated 1 grade higher, on average, than those from group 1 (n = 247 in each group, P < 0.01). Furthermore, 71% of specular images from group 2 were categorized as "good" or "excellent" quality, whereas only 30% of corneas from group 1 received those ratings. CONCLUSIONS: Rapid tissue warming cuts down on tissue evaluation time and reduces the time donor corneas are out of cold storage. Better specular images were obtained after implementation of the rapid warming protocol. PMID- 29620568 TI - Behind the Mask. PMID- 29620569 TI - Neutrophils: A Therapeutic Target of Local Anesthetics? PMID- 29620571 TI - Induction of Anesthesia for Children: Should We Recommend the Needle or the Mask? PMID- 29620570 TI - Free Fatty Acid Receptor G-protein-coupled Receptor 40 Mediates Lipid Emulsion induced Cardioprotection. AB - BACKGROUND: We have previously shown that intralipid (lipid emulsion) protects the heart against ischemia/reperfusion injury and bupivacaine-induced cardiotoxicity. However, the precise underlying mechanisms are not fully understood. Here we explored the hypothesis that free fatty acid receptor-1 or G protein-coupled receptor 40 is expressed in the heart and that cardioprotective effects of lipid emulsion are mediated through G-protein-coupled receptor 40 in two animal models of ischemia/reperfusion injury and bupivacaine-induced cardiotoxicity. METHODS: Langendorff-perfused male mouse hearts were subjected to ischemia/reperfusion with lipid emulsion alone (1%) or with G-protein-coupled receptor 40 antagonist (GW1100, 10 uM). Additionally, cardiotoxicity was achieved in male rats with bupivacaine bolus (10 mg/kg, IV) followed by lipid emulsion alone (20%, 5 ml/kg bolus, and 0.5 ml . kg . min maintenance, IV) or with GW1100 pretreatment (2.5 mg/kg, IV). RESULTS: G-protein-coupled receptor 40 is expressed in rodent hearts. GW1100 abolished lipid emulsion-induced cardioprotection against ischemia/reperfusion in mice because rate pressure product and left ventricular developed pressure were lower than lipid emulsion alone (rate pressure product: 2,186 +/- 1,783 [n = 7] vs. 11,607 +/- 4,347 [n = 8]; left ventricular developed pressure: 22.6 +/- 10.4 vs. 63.8 +/- 20; P < 0.0001). Lipid emulsion + GW1100 also demonstrated reduced LV dP/dtmax and LV dP/dtmin (dP/dtmax = 749 +/- 386 vs. 2,098 +/- 792, P < 0.001; dP/dtmin = -443 +/- 262 vs. -1,447 +/ 546, P < 0.001). In bupivacaine-induced cardiotoxicity rat model, GW1100 pretreatment had no significant effect on heart rate (HR) and ejection fraction after 30 min (HR: 302 +/- 17 vs. 312 +/- 38; ejection fraction: 69 +/- 3% vs. 73 +/- 4%). GW1100 pretreatment, however, prevented lipid-rescue, with no recovery after 10 min. In the control group, lipid emulsion improved HR (215 +/- 16 at 10 min) and fully rescued left ventricle function at 10 min (ejection fraction = 67 +/- 8%, fractional shortening = 38 +/- 6%). CONCLUSIONS: G-protein-coupled receptor 40 is expressed in the rodent heart and is involved in cardioprotection mediated by lipid emulsion against ischemia/reperfusion injury and bupivacaine induced cardiotoxicity. PMID- 29620572 TI - Energetics and the Root Mechanical Cause for Ventilator-induced Lung Injury. PMID- 29620574 TI - A Second Look at the Second Gas Effect. PMID- 29620573 TI - Should We Stop for Growth Arrest-specific 6 in Acute Respiratory Distress Syndrome? PMID- 29620576 TI - Response: Prescription Opioid Use and the Risk of Disability: Erratum. PMID- 29620575 TI - Sphingosine-1-phosphate Receptor 2 Signaling Promotes Caspase-11-dependent Macrophage Pyroptosis and Worsens Escherichia coli Sepsis Outcome. AB - WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Pyroptosis, a type of proinflammatory programmed cell death, drives cytokine storm. Caspase-11-dependent macrophage pyroptosis contributes to mortality during sepsis. Sphingosine-1-phosphate receptor 2 (S1PR2) signaling can amplify interleukin-1beta secretion in endotoxin-induced inflammation. Here, we hypothesized that S1PR2 signaling increases caspase-11-dependent macrophage pyroptosis and worsens Gram-negative sepsis outcome. METHODS: A Gram-negative sepsis model was induced through intraperitoneal injection of Escherichia coli. Primary peritoneal macrophages isolated from wild-type, S1pr2-deficient (S1pr2), or nucleotide-binding oligomerization domain-like receptor protein-3-deficient mice were treated with E. coli. Caspase-11 activation, macrophage pyroptosis, and Ras homolog gene family, member A-guanosine triphosphate levels were assessed in those cells. Additionally, monocyte caspase-4 (an analog of caspase-11) expression and its correlation with S1PR2 expression were determined in patients with Gram-negative sepsis (n = 11). RESULTS: Genetic deficiency of S1PR2 significantly improved survival rate (2/10 [20%] in wild-type vs. 7/10 [70%] in S1pr2, P = 0.004) and decreased peritoneal macrophage pyroptosis (pyroptosis rate: 35 +/- 3% in wild-type vs. 10 +/- 3% in S1pr2, P < 0.001). Decreased caspase-11 activation in S1PR2 deficiency cells contributed to the reduced macrophage pyroptosis. In addition, RhoA inhibitor abrogated the amplified caspase-11 activation in wild-type or S1PR2-overexpressing cells. In patients with Gram-negative sepsis, caspase-4 increased significantly in monocytes compared to nonseptic controls and was positively correlated with S1PR2 (r = 0.636, P = 0.035). CONCLUSIONS: S1PR2 deficiency decreased macrophage pyroptosis and improved survival in E. coli sepsis. These beneficial effects were attributed to the decreased caspase-11 activation of S1PR2-deficient macrophages. S1PR2 and caspase-11 may be promising new targets for treatment of sepsis. PMID- 29620577 TI - Methods of Identifying Limb Dominance in Adolescent Female Basketball Players: Implications for Clinical and Biomechanical Research. AB - OBJECTIVE: To identify relationships between self-reported limb preferences and performance measures for determining limb dominance in adolescent female basketball players. DESIGN: Cross-sectional cohort study. PARTICIPANTS: Forty adolescent female basketball players. INDEPENDENT VARIABLES AND MAIN OUTCOME MEASURES: Participants provided self-reported preferred kicking and jumping limbs, then completed 3 trials of a single-limb countermovement hop (HOPVER) and unilateral triple hop for distance (HOPHOR) on each limb. Each test was used to independently define limb dominance by the limb that produced the largest maximum vertical height and horizontal distance, respectively. RESULTS: Chi-square tests for independence identified a significant relationship between self-reported preferred kicking and jumping legs (chi = 7.41, P = 0.006). However, no significant relationships were found when comparing self-reported preference to measures of performance during the HOPHOR (chi = 0.33, P = 0.57) or HOPVER (chi = 0.06, P = 0.80). In addition, the 2 performance measures did not consistently produce the same definition of limb dominance among individuals (chi = 1.52, P = 0.22). CONCLUSIONS: Self-selection of the dominant limb is unrelated to performance. Furthermore, limb dominance, as defined by vertical jump height, is unrelated to limb dominance defined by horizontal jump distance. The results of this study call into question the validity of consistently defining limb dominance by self-reported measures in adolescent female basketball players. PMID- 29620578 TI - Facilitators and Barriers to the Implementation of iSPRINT: A Sport Injury Prevention Program in Junior High Schools. AB - OBJECTIVES: Sport injury is the leading cause of hospitalization in Canadian youth and represents a high burden to the health care system. This study aims to describe the facilitators and barriers to implementation of a sport injury prevention program in junior high school physical education (known as iSPRINT), previously shown to reduce the risk of sport-related injury in youth (age, 11-15 years). METHODS: Focus group data were mapped onto constructs from the Consolidated Framework for Implementation Research (CFIR). Four schools that implemented iSPRINT participated in this study. Forty-seven key stakeholders (teachers, students, principals) participated in 9 semistructured focus groups and 4 interviews. The CFIR was used to guide the focus group discussions, data coding, and analysis using a qualitative content analysis approach. RESULTS: Of the 22 applicable CFIR constructs, 16 were identified in the transcripts. The most significant facilitators to successful implementation efforts included evidence strength and quality, adaptability, implementation climate, culture, and having a high level of compatibility facilitated successful implementation efforts. Barriers to implementation included intervention complexity, planning, and readiness for implementation. Constructs that acted as both a facilitator and a barrier, depending on the context, were self-efficacy, execution, and individual identification with the organization. CONCLUSIONS: Participants in this study reported positive attitudes about implementing iSPRINT, citing evidence strength, adaptability, and constructs related to the organizational setting that contributed to successful implementation. Potential improvements include modifying certain program components, decreasing the number of components, and reducing the equipment required. PMID- 29620579 TI - How Useful Is the Flexion-Adduction-Internal Rotation Test for Diagnosing Femoroacetabular Impingement: A Systematic Review. AB - OBJECTIVE: Clinicians use the flexion, adduction, and internal rotation (FADIR) test in the diagnosis of femoroacetabular impingement (FAI). However, the diagnostic utility of this test remains unclear. The purpose of this review was to determine the utility of the FADIR test in diagnosing FAI. DATA SOURCES: MEDLINE, EMBASE, and PubMed were searched using relevant key terms and study screening was performed in duplicate. Patient demographics, diagnostic imaging, and summary measures (eg sensitivity, specificity, etc.) of the FADIR test in patients with FAI were recorded. MAIN RESULTS: Eight studies of levels III (87.5%) and IV (12.5%) evidence were included. Four hundred fifty-two patients (622 hips) with a mean age of 27.0 +/- 9.0 were examined. Alpha (75.1%) and/or center-edge (26.8%) angles were used to diagnose hips with FAI. X-ray (78.9%), magnetic resonance imaging (MRI) (16.2%), and computed tomography (CT) (4.8%) were used to confirm the diagnosis of FAI. The sensitivity when confirmed by x ray, MRI, or CT was 0.08 to 1, 0.33 to 1 and 0.90, respectively. The specificity when confirmed by x-ray and MRI was 0.11 and 1, respectively. CONCLUSIONS: Although the overall utility of the FADIR test in diagnosing FAI remains unclear given its moderate sensitivity and specificity, it may be a useful screening tool for FAI because of its low risk. Clinicians should consider the variability in sensitivity and specificity values reported and the low quality of literature available. Future studies should use large sample sizes and consistent radiographic measurements to better understand the usefulness of this physical examination maneuver in diagnosing FAI. LEVEL OF EVIDENCE: Level IV, Systematic Review of Level III and IV studies. PMID- 29620580 TI - Do Initial Symptom Factor Scores Predict Subsequent Impairment Following Concussion? AB - OBJECTIVE: Symptom factors present during the first week following concussion may predict subsequent concussion outcomes and recovery duration. We hypothesized that a high loading on cognitive-fatigue-migraine and somatic factors would be predictive of neurocognitive impairment following concussion. We also hypothesized that the affective factor would be related to vestibular symptoms and impairment. DESIGN: Prospective repeated measures. SETTING: Concussion specialty clinic. PARTICIPANTS: Athletes aged 13 to 20 years diagnosed with a concussion within the past 7 days. INDEPENDENT VARIABLE: Symptom factors at the initial visit 1 to 7 days after injury. MAIN OUTCOME MEASURE: Symptom factor score, neurocognitive testing, and vestibular/ocular motor assessment at the second visit (2-4 weeks after injury). RESULTS: The somatic symptom factor from the initial visit was significant (P < 0.05) in all vestibular/ocular screening components (P < 0.05) but not neurocognitive test performance (P > 0.05) at the second visit. The cognitive-migraine-fatigue and affective symptom factors predicted symptom burden at the second visit (P < 0.001) but did not predict recovery time (P = 0.200). CONCLUSIONS: The somatic symptom factor during the first week after injury predicted symptom provocation during vestibular/ocular screening at 2 to 4 weeks after injury. Specifically, higher scores on somatic symptom factor at the initial visit predicted worse symptom reporting for all vestibular/ocular screening components at the second visit. Patients with higher scores on the cognitive-migraine-fatigue and affective symptom factors at the initial visit predicted total symptom burden at the second visit. PMID- 29620581 TI - Coexistence of BRAF V600E and TERT Promoter Mutations in Low-grade Serous Carcinoma of Ovary Recurring as Carcinosarcoma in a Lymph Node: Report of a Case. AB - Low-grade serous carcinomas only rarely coexist with or progress to high-grade tumors. We present a case of low-grade serous carcinoma with transformation to carcinosarcoma on recurrence in the lymph node. Identical BRAF V600E and telomerase reverse transcriptase promoter mutations were identified in both the original and recurrent tumor. Given that telomerase reverse transcriptase promotor mutations are thought to play a role in progression of other tumor types, the function of telomerase reverse transcriptase mutations in BRAF mutated low-grade serous carcinoma deserves investigation. PMID- 29620582 TI - Radiation-associated Angiosarcoma Mimicking Fallopian Tube High-grade Serous Carcinoma in a Woman With De Novo Li-Fraumeni Syndrome. AB - We present a case study of a woman with history of rectal adenocarcinoma, and a new diagnosis of radiation-associated angiosarcoma mimicking fallopian tube high grade serous carcinoma who was subsequently found to have de novo Li-Fraumeni syndrome. Our objective is to highlight angiosarcoma as a potential pitfall in the diagnosis of high-grade serous carcinoma. PMID- 29620583 TI - Inflammatory Myofibroblastic Tumor Arising in the Cul-De-Sac, Mimicking Ectopic Decidua. AB - Extra-ovarian neoplasms incidentally discovered during cesarean section are very rare. Here we report a case of inflammatory myofibroblastic tumor found during cesarean section of a 30-year-old, full-term woman, forming a mass in her cul-de sac. Histology revealed an extensively decidualized spindle cell process, positive for anaplastic large cell lymphoma kinase (ALK) through immunohistochemistry and fluorescent in situ hybridization (FISH). To the best of our knowledge, this is the first presentation of inflammatory myofibroblastic tumor in this location without concurrent intrauterine component, that additionally demonstrates this degree of decidualization, mimicking ectopic decidua. PMID- 29620584 TI - Endometrial Carcinoma With an Unusual Morphology in a Patient With Cornelia de Lange Syndrome: A Case Study. AB - Cornelia de Lange syndrome (CdLS) is a cohesinopathy, which is characterized by multiple structural anomalies as well as mental and growth retardation. A 36-yr old nulliparous woman with oligomenorrhea was referred to us due to a mass in the uterine corpus. She had been clinically diagnosed with CdLS during infancy based on her specific facial features as well as growth and intellectual retardation. Imaging examinations and an endometrial biopsy revealed endometrial endometrioid carcinoma and polycystic ovary syndrome (PCOS). She underwent a hysterectomy and bilateral salpingo-oophorectomy. The tumor was mainly located at the uterine isthmus and exhibited diffuse exophytic growth. Microscopically, the grade 1 endometrioid carcinoma consisted of extremely well-differentiated glands and showed myometrial invasion. Both swollen ovaries had a thick fibrous cortex and multiple follicles. To the best of our knowledge, this is the first case report of a gynecologic malignancy in an adult patient with CdLS. Several gene mutations have been reported to be causative of CdLS; however, a potential role of these mutations in the pathogenesis of PCOS and subsequent endometrial cancer remains controversial. In this case, PCOS seemed to underlie the endometrial carcinogenesis and then concurrent loss of PTEN and PAX2 expression, confirmed by immunohistochemistry, can facilitate tumor progression. Our case suggests that adult female patients with CdLS can have PCOS and subsequent endometrial carcinoma. As patients with CdLS often have difficulties recognizing and/or reporting menstrual disorder, their care providers should pay particular attention to menstrual cycle irregularities due to the risk of endometrial cancer. PMID- 29620585 TI - Ovarian Sertoli-Leydig Cell Tumor With Heterologous Hepatocytes and a Hepatocellular Carcinomatous Element. AB - Sertoli-Leydig cell tumors are a group of tumors composed of variable proportions of Sertoli cells, Leydig cells, and sometimes heterologous elements. We describe the case of a 68-yr-old woman who presented with abdominal distention. A computed tomographic scan revealed a large right adnexal mass without evidence of intrahepatic tumors, and a complete cytoreductive surgery was performed. Pathologic examination revealed a moderately differentiated Sertoli-Leydig cell tumor with various heterologous elements, including gastrointestinal-type glands, insular carcinoid, and aggregations of hepatocytes without significant cytologic atypia. Moreover, adjacent to these hepatocytes, extensive overgrowth of highly atypical hepatocyte-like cells, providing a striking morphologic similarity to hepatocellular carcinoma of the liver, was identified. Both the heterologous hepatocytes and hepatocellular carcinomatous tumor cells were immunohistochemically positive for alpha-fetoprotein, hepatocyte paraffin 1, and arginase-1. Some Sertoli cells adjacent to the heterologous hepatocytes were also positive for alpha-fetoprotein and hepatocyte paraffin 1. The present case showed that a tumor morphologically and immunohistochemically analogous to hepatocellular carcinoma of the liver can arise in the ovary, in association with Sertoli-Leydig cell tumors. PMID- 29620586 TI - Predictive Histologic Factors in Carcinosarcomas of the Uterus: A Multiinstitutional Study. AB - Uterine carcinosarcomas are rare aggressive biphasic neoplasms. Because of its rarity, limited data are available on potential prognostic parameters. While several studies support that carcinomatous components predict outcomes, others do not. In this study, we evaluated the clinical and histopathologic features of 196 uterine carcinosarcomas to identify potential prognostic factors. Patients' ages ranged from 34 to 95 yr (median, 68 yr). Seventy-three (38%) patients experienced tumor recurrence during follow-up. Tumors >=5 cm, outer half myometrial invasion, lymphovascular invasion, lymph node metastasis, advanced stage (International Federation of Gynecology and Obstetrics stages III-IV), sarcomatous component on recurrence, sarcoma dominance, and positive cytology were significantly associated with shorter disease-free interval (P<0.05). In addition, serous histology and rhabdomyoblastic differentiation was significantly associated with worse 3-yr overall survival. Our data supports that both carcinomatous and sarcomatous components play a role in tumor progression and survival of uterine carcinosarcoma patients, suggesting their equal importance in guiding management decisions. PMID- 29620587 TI - Mucolipidosis Type II Affecting 1 Fetus and Placental Disk of a Dichorionic Diamnionic Twin Gestation: A Case Report and Review of the Literature. AB - Mucolipidosis type II, also known as I-cell disease, is an autosomal recessive inborn error of metabolism, resulting from loss-of-function mutations in GNPTAB. Affected infants exhibit multiple physical anomalies and developmental delay, and death from disease follows in early childhood. Here we present an instructive case of mucolipidosis type II affecting 1 fetus and placental disk in a dichorionic-diamnionic twin pregnancy delivered at 36-wk gestation. The second twin and placental disk showed no abnormality. On microscopic examination, the affected placenta displayed marked vacuolization of the syncytiotrophoblast and Hofbauer cells, which was confirmed on ultrastructural examination. To our knowledge, this is the first description of placental findings in a twin pregnancy, wherein only 1 twin is affected by an inborn error of metabolism. This provides an opportunity to highlight the placental abnormalities seen in this group of diseases, and to emphasize the role of pathologic examination in early detection of otherwise unsuspected inborn errors of metabolism. PMID- 29620588 TI - Atlas Fractures: Diagnosis, Current Treatment Recommendations, and Implications for Elderly Patients. AB - Fractures of the C1 vertebrae (atlas) are commonly the result of falls and other trauma, which cause hyperextension, or axial compression of the cervical spine. Although historically thought as a benign injury with lower neurological risks, current data suggests that this may not hold true for geriatric patients (aged 65 y and older) who may be predisposed to these fractures even after lower-energy trauma such as ground-level falls. Advancements in orthopedic trauma care has increased our diagnostic abilities to identify and manage patients with C1 fractures and other upper cervical spine trauma. However, there are no universal treatment guidelines based on level I trials. Current treatment ranges from nonoperative to operative management depending on fracture-pattern and integrity of the surrounding ligaments. Furthermore, in the elderly patients these fractures present a unique dilemma due to preexisting comorbidities and contraindications to various treatment modalities. C1 fractures warrant greater recognition to provide optimal treatment to patients and minimize the risk for developing complications. The goal of this review is to highlight the most updated treatment guidelines and to discuss the complications of both operative and nonoperative management of C1 fractures especially among the elderly patient population. PMID- 29620589 TI - Nocardia Infection in an Immunosuppressive Patient With Dermatomyositis. PMID- 29620590 TI - Granulomatosis With Polyangiitis as an Uncommon Cause of Panhypopituitarism. PMID- 29620591 TI - A New Comorbidity in Female Patients With Ankylosing Spondylitis: Pelvic Organ Prolapse. AB - AIM: The aim of this study was to investigate whether increased intra-abdominal pressure caused by pelvic inflammation and frequent use of the Valsalva maneuver increases the incidence of pelvic organ prolapse (POP) among female patients with ankylosing spondylitis (AS). METHODS: Thirty-nine patients diagnosed as having AS through the use of the modified New York criteria, 47 patients with chronic low back pain (CLBP), and 38 healthy controls (HCs) were included in this study. All the patients and the HCs underwent thorough physical and gynecological examinations. Pelvic organ prolapse was graded blindly by a gynecologist. Presence or absence of cystocele (CS), rectocele (RC), and uterine descensus (UD) was noted. RESULTS: The incidences of CS, RC, and UD were significantly higher among the AS patients compared with the HCs (P = 0.001, 0.026, and 0002, respectively). The incidences of CS (P = 0.042) and UD (P = 0.017) were significantly higher among the AS patients compared with the CLBP patients. CONCLUSIONS: The incidence of POP is higher among patients with AS compared with normal population. These patients should be questioned about the symptoms of POP and recommended, if necessary, regular gynecological examinations, as well as specific exercises including those targeting AS. PMID- 29620592 TI - Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography in Amyloid Arthropathy Associated to Multiple Myeloma. PMID- 29620593 TI - Evaluation of Learned Helplessness, Perceived Self-efficacy, and Functional Capacity in Patients With Fibromyalgia and Rheumatoid Arthritis. AB - OBJECTIVES: The aims of this study were to compare learned helplessness (LH) and perceived self-efficacy (SE) in patients with fibromyalgia (FM) and rheumatoid arthritis (RA) and to assess their correlation with functional disability, level of perceived pain, and fatigue. METHODS: This multicenter, cross-sectional study included consecutive patients (aged >=18 years) with RA, according to the 2010 American College of Rheumatology/European League Against Rheumatism criteria, and FM, according to 2010 American College of Rheumatology criteria. Learned helplessness was measured by the Rheumatology Attitude Index, Spanish version; SE with the Arthritis Self-efficacy Scale, Spanish version; functional capacity with the Health Assessment Questionnaire (HAQ), Argentine version; depression with Center for Epidemiological Studies-Depression Scale 7-item version and perceived pain and fatigue by the visual analog scale. Disease activity was measured by the Clinical Disease Activity Index (CDAI) and disease impact with the Fibromyalgia Impact Questionnaire (FIQ). RESULTS: A total of 215 patients, 100 with FM and 115 with RA, were included. Mean age was 59 (SD, 14) years and 58 (SD, 13) years for FM and RA, patients respectively. Whereas LH and depression were significantly higher, SE was significantly lower in FM patients. We found a positive correlation between LH and HAQ, pain, depression, fatigue, FIQ, and CDAI in FM and RA patients. We observed a negative correlation between SE and HAQ, pain, depression, fatigue, FIQ (FM), and CDAI (RA) in both groups. CONCLUSIONS: Both LH and SE correlate significantly with functional capacity, perceived pain, disease activity, and disease impact in RA and FM patients. Learned helplessness was higher in patients with active disease or high disease impact, as opposed to those in remission or with low disease impact, and the reverse was true for SE. Patients with FM had significantly more LH, pain, fatigue, and depression and less SE compared with those with RA. PMID- 29620595 TI - Pulmonary Function Tests Abnormalities in Children With Inflammatory Bowel Disease: Is It Common? AB - OBJECTIVE: The aim of the study was to evaluate the frequency and type of pulmonary dysfunction in newly diagnosed children with inflammatory bowel disease (IBD) and the correlation between pulmonary function tests (PFTs) and IBD activity. METHODS: It is an observational case-control study. One hundred newly diagnosed children with IBD were enrolled as the patient group, which was further subdivided into 52 with Crohn disease (CD) and 48 with ulcerative colitis (UC). Fifty healthy children matched for age, sex, height, and body mass index (BMI) served as the control group. PFTs in the form of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), FEV1/FVC, residual volume (RV), total lung capacity (TLC), mid-forced expiratory flow of 25% to 75% (FEF 25%-75%) and diffusing capacity of the lung for carbon monoxide (DLCO) were evaluated in all studied children. PFTs were measured at diagnosis, every 6 months for a period of 3 years, during remission and at least once during activity in patient group. RESULTS: There was significant progressive deterioration in all PFTs in IBD patients compared with their PFTs at the start of the study (P < 0.05) except for FEV1/FVC, RV, and TLC (P > 0.05). There was significant deterioration during disease activity compared with remission state as regards FEV1, FVC, FEF 25% to 75%, and DLCO (P < 0.05). Significant negative correlation was found between disease activity in both UC and CD groups and FEV1, FVC, FEF 25% to 75%, and DLCO. CONCLUSIONS: Subclinical PFTs abnormalities are common in pediatric IBD even during remission period. So, periodic PFTs evaluation should be considered in the routine follow-up of IBD children. PMID- 29620594 TI - Pediatric Liver Transplant Teams Coping With Patient Death. AB - OBJECTIVES: Coping with patient death among pediatric liver transplant teams has received little attention despite general recognition of the potentially negative emotional consequences associated with such loss. The purpose of this study was to investigate the ways in which members of pediatric liver transplant teams cope with the death of patients on the waitlist and post-transplant and the institutional resources available to facilitate this coping. METHODS: Participants included 120 physicians, nurses, and mental health professionals from multiple transplant centers across the United States. Participants completed an online questionnaire that assessed the availability of formal coping resources at their institutions, informal sources of support used to cope with patient death, and as indices of coping, bereavement, and emotional exhaustion symptoms experienced. RESULTS: Debriefing, the most commonly offered support, was available to about half (55.8%) of the sample; yet, nearly all respondents (98.3%) indicated that debriefing would be useful. On average, bereavement and emotional exhaustion levels were comparable to normative data, but patterns of coping varied based on participants' position within the transplant team. For participants who reported that debriefing was available at their institutions, emotional exhaustion was lower. CONCLUSIONS: Overall, formal supports were inconsistently offered to pediatric transplant team members. Team members expressed high acceptability for debriefing, which has been associated with benefits in other populations, and findings indicated better coping in the transplant setting when it was offered. PMID- 29620596 TI - Celiac Disease 30 Years After Diagnosis: Struggling With Gluten-free Adherence or Gaining Gluten Tolerance? AB - OBJECTIVES: Studies investigating patients with coeliac disease (CD) on very long term follow-up are limited. We aimed to evaluate the characteristics of patients with CD diagnosed more than 30 years ago. METHODS: Clinical, histologic, genetic, and demographic data of patients with CD diagnosis made before 1985 were collected and their standardised mortality ratio calculated. According to the gluten-free diet (GFD) status, CD patients were divided into 3 groups and a specific questionnaire on GFD awareness and gluten-free products was administered to patients and caregivers. RESULTS: A total of 337 CD patients were included in the study. The standardised mortality ratio was 0.37 (confidence interval 0.10 to 0.94) compared with a matched population. A total of 197 patients were grouped according to GFD compliance, with 35 CD patients reporting chronic voluntary gluten ingestion. No significant differences were found between groups regarding family history of CD, symptoms and histology at diagnosis, autoimmune disorders. Follow-up histology was performed in 63 patients. Twenty patients had normal histology on gluten-containing diet (GCD). Questionnaire scores were lower in patients on GCD. Caregivers scores were not correlated with patients' gluten consumption. CONCLUSIONS: Although poor adherence to GFD is the major predictor of persistence of mucosal lesions at follow-up histology, a proportion of patients did not show a relapse of villous atrophy in spite chronic voluntary gluten ingestion, nor increase in mortality. Moreover, GFD knowledge and adherence could be partly lost during the transition between childhood and adulthood. PMID- 29620597 TI - Early Serum Gut Hormone Concentrations Associated With Time to Full Enteral Feedings in Preterm Infants. AB - OBJECTIVES: The primary objective of this study was to evaluate early postnatal serum gut hormone concentrations in preterm infants as predictors of time to full enteral feedings. The secondary objective was to identify infant characteristics and nutritional factors that modulate serum gut hormone concentrations and time to full enteral feedings. METHODS: Sixty-four preterm infants less than 30 weeks of gestation were included in this retrospective cohort study. Serum gut hormone concentrations at postnatal days 0 and 7 were measured using enzyme-linked immunosorbent assays. Linear regression and mediation analyses were performed. RESULTS: Median (interquartile range) serum concentrations of glucose-dependent insulinotropic peptide (GIP) and peptide YY (PYY) on postnatal day 7 were 31.3 pg/mL (18.2, 52.3) and 1181.7 pg/mL (859.0, 1650.2), respectively. GIP and PYY concentrations on day 7 were associated with days to full enteral feedings after adjustment for confounders (beta = -1.1, P = 0.03; and beta = -0.002, P = 0.02, respectively). Nutritional intake was correlated with serum concentrations of GIP and PYY on postnatal day 7 and time to full enteral feedings. Mediation analysis revealed that the effect of serum gut hormone concentrations on time to full enteral feedings was not fully explained by nutritional intake. Intrauterine growth restriction, mechanical ventilation on postnatal day 7, and patent ductus arteriosus treated with indomethacin were associated with longer time to full enteral feedings. CONCLUSIONS: Serum concentrations of GIP and PYY on postnatal 7 are independently associated with time to full enteral feedings. The link between serum gut hormone concentrations and time to full enteral feedings is not fully mediated by nutritional factors, suggesting an independent mechanism underlying the influence of gut hormones on feeding tolerance and time to full enteral feedings. PMID- 29620598 TI - Therapeutic Plasma-albumin Exchange for Hyperlipidemia Induced Acute Pancreatitis. PMID- 29620599 TI - Small-Fiber Neuropathy in a Pediatric Patient Following Anti-Tumor Necrosis Factor-alpha Therapy for Ulcerative Colitis. PMID- 29620600 TI - Environmental Enteropathy, Micronutrient Adequacy, and Length Velocity in Nepalese Children: the MAL-ED Birth Cohort Study. AB - OBJECTIVES: Environmental enteropathy (EE) is likely associated with growth retardation in children, but the association between EE and length velocity z score (LVZ) has not been investigated. The objective of the study was to assess associations between fecal markers for intestinal inflammation and LVZ and whether these associations were influenced by micronutrient adequacy among 9 to 24 months old children in Bhaktapur, Nepal. METHODS: Data were divided into 5 time slots (9-12, 12-15, 15-18, 18-21, and 21-24 months). Anthropometric measurement and dietary assessment (by 24 hour recall) were performed monthly. Mean nutrient density adequacy was calculated based on nutrient density adequacy of 10 micronutrients (thiamin, riboflavin, niacin, vitamin B6, folate, vitamin C, vitamin A, calcium, iron, and zinc). Anti-1-antitrypsin (AAT), myeloperoxidase (MPO), and neopterin (NEO) were measured in stool samples collected at the beginning of each time slot. An EE score was calculated based on all 3 fecal markers. Associations between AAT, MPO, NEO and EE score and LVZ were assessed by multiple linear regression analyses and Generalized Estimating Equations models. RESULTS: Associations between fecal markers and EE score and LVZ were generally weak. EE score and MPO for 3-month and MPO for 6-month growth periods were significantly associated with LVZ from 9 to 24 months. These associations were slightly modified by mean nutrient density adequacy. CONCLUSIONS: EE score and MPO were significantly associated with LVZ in 9 to 24 months old Nepali children. Further studies to establish the usefulness of AAT, MPO, and NEO in assessing EE and growth retardation are warranted. PMID- 29620601 TI - Plasma Exchange in Hypertriglyceridemic Pancreatitis in Children. PMID- 29620602 TI - A New Paradigm in the Treatment of Eosinophilic Esophagitis: Proton Pump Inhibitors Are Safe, Aim for "Deep Remission". PMID- 29620603 TI - Eosinophilic Gastroenteritis and Colitis: Not Yet Ready for the Big Leagues. PMID- 29620605 TI - Captopril Attenuates Cardiovascular and Renal Disease in a Rat Model of Heart Failure With Preserved Ejection Fraction. AB - Heart failure with preserved ejection fraction (HFpEF), a prevalent form of heart failure, is frequently accompanied by the metabolic syndrome and kidney disease. Because current treatment options of HFpEF are limited, evaluation of therapies in experimental models of HFpEF with the metabolic syndrome and kidney disease is needed. In this study, we evaluated the effects of captopril, furosemide, and their combination in aged, obese ZSF1 rats, an animal model of HFpEF with the metabolic syndrome and chronic kidney disease as comorbidities. Captopril (100 mg/kg), furosemide (50 mg/kg), or their combination was administered orally to obese ZSF1 rats aged 20 to 44 weeks. Untreated ZSF1 rats served as controls. After 24 weeks of treatment, captopril significantly lowered systemic blood pressure and attenuated HFpEF as evidenced by significantly reduced left ventricular end diastolic pressures (10.5 +/- 1.4 vs. 4.9 +/- 1.3 mm Hg in Control vs. Captopril, respectively) and significantly lower left ventricular relaxation time constants (28.1 +/- 2.9 vs. 18.3 +/- 3.1 ms in Control vs. Captopril, respectively). The captopril-induced improvement in left ventricular function was associated with reduced cardiac hypertrophy, ischemia, necrosis, and vasculitis. Captopril also increased renal blood flow and glomerular filtration rate, reduced renal vascular resistance and proteinuria, and improved renal histology (ie, reduced renal hypertrophy, glomerulosclerosis, and tubular atrophy/dilation). Furosemide alone provided little benefit; moreover, furosemide did not augment the therapeutic benefits of captopril. This study suggests that chronic administration of captopril, but not furosemide, could be beneficial in patients with HFpEF, particularly in those with comorbidities such as obesity, diabetes, and dyslipidemias. PMID- 29620604 TI - Diffusion-Weighted Imaging With Apparent Diffusion Coefficient Mapping for Breast Cancer Detection as a Stand-Alone Parameter: Comparison With Dynamic Contrast Enhanced and Multiparametric Magnetic Resonance Imaging. AB - PURPOSE: The aims of this study were to compare dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) with diffusion-weighted imaging (DWI) with apparent diffusion coefficient mapping as a stand-alone parameter without any other supportive sequence for breast cancer detection and to assess its combination as multiparametric MRI (mpMRI) of the breast. MATERIALS AND METHODS: In this institutional review board-approved single-center study, prospectively acquired data of 106 patients who underwent breast MRI from 12/2010 to 09/2014 for an imaging abnormality (Breast Imaging Reporting and Data System 0, 4/5) were retrospectively analyzed. Four readers independently assessed DWI and DCE as well as combined as mpMRI. Breast Imaging Reporting and Data System categories, lesion size, and mean apparent diffusion coefficient values were recorded. Histopathology was used as the gold standard. Appropriate statistical tests were used to compare diagnostic values. RESULTS: There were 69 malignant and 41 benign tumors in 106 patients. Four patients presented with bilateral lesions. Dynamic contrast-enhanced MRI was the most sensitive test for breast cancer detection, with an average sensitivity of 100%. Diffusion-weighted imaging alone was less sensitive (82%; P < 0.001) but more specific than DCE-MRI (86.8% vs 76.6%; P = 0.002). Diagnostic accuracy was 83.7% for DWI and 90.6% for DCE-MRI. Multiparametric MRI achieved a sensitivity of 96.8%, not statistically different from DCE-MRI (P = 0.12) and with a similar specificity as DWI (83.8%; P = 0.195), maximizing diagnostic accuracy to 91.9%. There was almost perfect interreader agreement for DWI (kappa = 0.864) and DCE-MRI (kappa = 0.875) for differentiation of benign and malignant lesions. CONCLUSION: Dynamic contrast-enhanced MRI is most sensitive for breast cancer detection and thus still indispensable. Multiparametric MRI using DCE-MRI and DWI maintains a high sensitivity, increases specificity, and maximizes diagnostic accuracy, often preventing unnecessary breast biopsies. Diffusion-weighted imaging should not be used as a stand-alone parameter because it detects significantly fewer cancers in comparison with DCE MRI and mpMRI. PMID- 29620608 TI - Rapport Management: Opening the Door for Effective Debriefing: Erratum. PMID- 29620606 TI - Apelin Reduces Nitric Oxide-Induced Relaxation of Cerebral Arteries by Inhibiting Activation of Large-Conductance, Calcium-Activated K Channels. AB - Activation of the apelin/APJ receptor signaling system causes endothelium dependent and nitric oxide (NO)-dependent relaxation in several peripheral arteries. The effects of apelin in cerebral arteries are unknown; however, apelin inhibits voltage-dependent increases in large-conductance, calcium-activated K channel (BKCa) currents in cerebral artery smooth muscle cells. Because NO induced relaxation of cerebral arteries is mediated, in part, by activation of BKCa channels, the goals of this study were to determine the net effect of apelin in cerebral arteries, as well as test the hypothesis that the actions of apelin in cerebral arteries are secondary to stimulation of APJ receptors. Immunoblot and quantitative reverse transcription polymerase chain reaction analyses detected APJ receptors in cerebral arteries of male Sprague-Dawley rats, and immunofluorescence studies using confocal microscopy confirmed APJ receptor localization in smooth muscle cells. In myograph studies, apelin itself had no direct vasomotor effect but inhibited relaxations to the NO-donor, diethylamine NONOate, and to the endothelium-dependent vasodilator, bradykinin. These effects of apelin were mimicked by the selective BKCa-channel blocker, iberiotoxin, and suppressed by the APJ receptor antagonist, F13A. Apelin also inhibited relaxations evoked by the BKCa-channel openers, NS1619 and BMS 191011, but had no effect on relaxation to levcromakalim, a selective KATP-channel opener. Apelin had no effect on diethylamine NONOate-induced or bradykinin-induced increases in cyclic guanosine monophosphate levels. Patch clamp recordings demonstrated that apelin and iberiotoxin each suppressed the increase in BKCa currents induced by DEA and NS1619 in freshly isolated cerebral artery smooth muscle cells. The results demonstrate that apelin inhibits NO-induced relaxation of cerebral arteries through a mechanism involving activation of APJ receptors and inhibition of BKCa channels in cerebral arterial smooth muscle cells. PMID- 29620609 TI - The Use of Closed Incision Negative-Pressure Wound Therapy in Orthopaedic Surgery. AB - Wound complications and surgical site infections after orthopaedic procedures result in substantial morbidity and costs. Traditional postoperative wound care consists of applying sterile, dry gauze and abdominal pads to the surgical site, with more frequent dressing changes performed in cases in which wound drainage is excessive. Persistent incisional drainage is of particular concern because it increases the risk of deep infection. The use of closed incision negative pressure wound therapy (ciNPWT) to manage delayed wound healing was first reported a decade ago, and the benefits of this treatment modality include wound contraction with diminished tensile forces, stabilization of the wound environment, decreased edema and improved removal of exudate, and increased blood and lymphatic flow. Numerous trauma, plastic surgery, and general surgery studies have demonstrated that ciNPWT improves wound healing. In orthopaedic surgery, ciNPWT has been shown to be clinically effective for incisions at high risk for perioperative complications. However, specific indications for ciNPWT continue to be defined. PMID- 29620611 TI - Bleach for Atopic Dermatitis: Beyond Antimicrobials. AB - Individuals with atopic dermatitis (AD) have used bleach baths to treat superinfections, although their mechanism of action is not well understood. The ClinicalTrials.gov, National Eczema Association, and PubMed databases were searched for studies that investigate the role bleach plays in modulating AD. Fifteen studies were included in this review. Bleach bath improves clinical symptoms of AD and restores surface microbiome by eradicating bacteria, most notably Staphylococcus aureus. Many studies have noted that this antimicrobial effect has reduced the need for topical corticosteroids or topical antibiotics. In addition, bleach seems to have strong anti-inflammatory and antipruritogenic effects. Lastly, bleach baths seem to be safe on human skin, without disrupting epidermal barrier function. Although the effects of bleach are promising, studies that investigate the long-term use of bleach alone, without concomitant AD treatment modalities, are needed. The emergence of new bleach-containing products warrants future investigations to examine their effects on cutaneous microbiome, epidermal barrier function, and immunity. PMID- 29620610 TI - Applications of Implantable Hemodynamic Monitoring in the Setting of Durable Mechanical Circulatory Support. PMID- 29620613 TI - Incidence, Risk Factors, and Outcomes of Clostridium difficile Infections in Kidney Transplant Recipients. AB - BACKGROUND: Kidney transplant recipients (KTR) may be at increased risk for Clostridium difficile infections (CDI) but risk factors and outcomes in this population have not been well studied. METHODS: An observational cohort study was conducted to determine the incidence, risk factors, and outcomes of CDI in KTR. A total of 1816 KTR transplanted between 2000 and 2013 at the Toronto General Hospital were included. Sixty-eight patients developed CDI. Controls were selected at a 4:1 ratio using risk-set sampling, and risk factors were explored using conditional logistic regression models. The impact of CDI on graft outcomes was evaluated using Cox proportional hazards models. RESULTS: The incidence rate of CDI was 0.64 cases/100 person-years. Independent predictors of CDI included antibiotic use (odds ratio [OR], 2.88; 95% confidence interval [CI], 1.35-6.15), increased duration of hospitalization posttransplant (OR, 1.04; 95% CI, 1.02 1.06]), receiving a deceased donor kidney (OR, 2.98; 95% CI, 1.47-6.05), and a history of biopsy-proven acute rejection (OR, 5.82; 95% CI, 2.22-15.26). In the Cox proportional hazards model, CDI was found to be an independent risk factor for the subsequent development of biopsy-proven acute rejection (hazard ratio, 2.18; 95% CI, 1.34-3.55). CONCLUSIONS: Our results confirm that transplant specific factors place KTR at a higher risk for CDI. Clostridium difficile infections may increase the risk of adverse outcomes, such as biopsy-proven acute rejection. These findings emphasize the importance of preventive strategies to reduce the morbidity associated with CDI in KTR. PMID- 29620612 TI - Tofacitinib Halts Progression of Graft Dysfunction in a Rat Model of Mixed Cellular and Humoral Rejection. AB - BACKGROUND: The progression from acute to chronic antibody-mediated rejection in kidney transplant recipients is usually not prevented by current therapeutic options. Here, we investigated whether the use of tofacitinib (TOFA), a Janus kinase 3 inhibitor, was capable of preventing the progression of allograft dysfunction in a Fisher-to-Lewis rat model of kidney transplantation. METHODS: Rats were treated from the third week after transplantation to allow the development of rejection. Treatment was based on cyclosporin A, rapamycin or TOFA. Renal function was assessed at 1, 4, 8, and 12 weeks after transplantation, whereas rat survival, histological lesions, and infiltrating lymphocytes were analyzed at 12 weeks. RESULTS: Tofacitinib prolonged graft survival, preserved tubular and glomerular structures and reduced humoral damage characterized by C4d deposition. Tofacitinib was able to reduce donor-specific antibodies. In addition, T and natural killer cell graft infiltration was reduced in TOFA treated rats. Although rapamycin-treated rats also showed prolonged graft survival, glomerular structures were more affected. Moreover, only TOFA treatment reduced the presence of T, B and natural killer cells in splenic parenchyma. CONCLUSIONS: Tofacitinib is able to reduce the immune response generated in a rat model of kidney graft rejection, providing prolonged graft and recipient survival, better graft function, and less histological lesions. PMID- 29620614 TI - Reduced Access to Liver Transplantation in Women: Role of Height, MELD Exception Scores, and Renal Function Underestimation. AB - BACKGROUND: Sex-based disparities in liver transplantation (LT) are incompletely understood. We assessed the role of height, Model for End-Stage Liver Disease (MELD), MELD-Na, and exception points in the disparate access to LT. METHODS: Adults waitlisted for LT at Organ Procurement and Transplantation Network between 2002 and 2013 were included. Covariates associated with likelihood of LT were analyzed by Cox proportional model. In a separate cohort of waitlisted adults with glomerular filtration rate measurement by iothalamate clearance (n = 611), we determined the number of creatinine-derived MELD points in men versus women, across all ranges of glomerular filtration rate. The impact of correcting the MELD score deficit in women on LT was modeled. RESULTS: Among 90 720 Organ Procurement and Transplantation Network registrants, women had higher mortality than men (4 years after listing: 22% vs 18%, P < 0.0001), and lower likelihood of LT (49% vs 58%, P < 0.0001); women were 20% less likely to be transplanted (hazard ratio, 0.80; 95% confidence interval, 0.78-0.81). Differences in height and MELD exception scores accounted for most of the LT deficit in women (hazard ratio, 0.91; 95% confidence interval, 0.89-0.94). Women received between 1 and 2.4 fewer creatinine-derived MELD points than men with similar renal dysfunction. MELD-Na worsened the gender disparity. Addition of 1 or 2 MELD points to women significantly impacted LT access. CONCLUSIONS: Differences in height and MELD exception points explained most of the sex-based disparity in LT. Additionally, MELD score underestimated disease severity in women by up to 2.4 points and MELD Na exacerbated this disparity. The degree of underestimation based on MELD had significant impact on allocation. PMID- 29620615 TI - Long-term Outcomes of ABO-incompatible Pediatric Living Donor Liver Transplantation. AB - BACKGROUND: ABO-incompatible (ABOi) living donor liver transplantation (LDLT) has been performed to compensate for donor shortage. To date, few studies have reported detailed B-cell desensitization protocols and long-term outcomes of ABOi pediatric LDLT. METHODS: Twenty-nine pediatric ABOi LDLT recipients were retrospectively analyzed. We compared the clinical outcomes between ABOi (n = 29) and non-ABOi (n = 131) pediatric LDLT recipients. Furthermore, we evaluated the safety and efficacy of our rituximab-based regimen for ABOi pediatric LDLT (2 <= age < 18; n = 10). RESULTS: There were no significant differences in the incidence of infection, vascular complications, biliary complications, and acute cellular rejection between ABOi and non-ABOi groups. The cumulative graft survival rate at 1, 3, and 5 years for non-ABOi group were 92.1%, 87.0%, and 86.1%, and those for ABOi group were 82.8%, 82.8%, and 78.2%, respectively. Rituximab-based desensitization protocol could be performed safely, and reduced CD19+ lymphocyte counts effectively. Although rituximab-treated ABOi group showed comparable clinical outcomes and graft survival rate, 2 patients developed antibody-mediated rejection. CONCLUSIONS: ABOi LDLT is a feasible option for pediatric end-stage liver disease patients. However, it should be noted that current desensitization protocol does not completely prevent the onset of antibody-mediated rejection in several cases. PMID- 29620616 TI - Meeting Report of the 13th Congress of the International Society of Vascularized Composite Allotransplantation. AB - The International Society of Vascularized Composite Allotransplantation held its 13th congress "Defining Success" in October 2017 in Salzburg, Austria. A total of 122 delegates from 22 countries representing 5 continents attended the conference. The theme strived to provide pathways to accomplish best possible outcomes in this unique and multifaceted field of transplantation. "Ignite talks," a new feature introduced for the first time at the Salzburg meeting served as key elements for productive discussions on both congress days. The "ignitors" had been selected as experts from Europe, the Americas and Asia in vascularized composite allotransplantation and neighboring disciplines and provided a global perspective of their topic. Posttransplant treatment regimens, including the most burdensome side effects of immunosuppressants in addition to novel and future therapeutic options were discussed in depth. An additional ethics symposium summarized and advanced topics that had been discussed during the first international workshop on bioethical challenges in reconstructive transplantation held earlier in 2017. PMID- 29620617 TI - Pancreas Transplantation From Pediatric Donors: A Single-Center Experience. AB - BACKGROUND: Pancreas allografts from pediatric donors are considered less suitable due to the increased risk of surgical complications and reduced islet cell mass that may compromise function. METHODS: All pancreatic transplants, procured from donors younger than 18 years, between January 2007 and March 2017, were included in the analysis. The grafts were subdivided into 3 groups by donor's weight: less than 30 kg, 30 to 60 kg, greater than 60 kg. Analysis of patient and graft survival was done between the groups, and subsequently between the pediatric cohort and the adult-donor control group. RESULTS: Sixty-three pediatric-donor pancreas transplants were performed. The mean donor age and weight were of 12.10 +/- 4.13 years and 47.8 +/- 21.3 kg. Excellent metabolic control was achieved in 59 (93.65%) patients at the time of discharge and at a mean 5 year follow up, with the average hemoglobin A1c of 5.30 +/- 0.61% and blood glucose level of 102.75 +/- 20.70 mg/dL in those with a functioning graft. Nine graft losses were registered, of which one (1.6%) was due to arterial thrombosis. Eight (12.7%) patients experienced rejection. Overall graft survival and patient survival were of 85.7% and 92.1%, respectively, at a median follow-up of 37.07 months (minimum, 0.19 to maximum, 119.57). No differences among the 3 groups were identified. Long-term patient and allograft survival was comparable to that of the adult-donor pancreatic transplants. CONCLUSIONS: Pediatric-donor pancreas demonstrated excellent short-term outcomes with no surgical complications and promising long-term outcomes despite the smaller islet mass. Pancreata from pediatric donors should not be marginalized and can offset worsening organ shortage. PMID- 29620619 TI - eNews Tool to Prevent Central Line-Associated Bloodstream Infection. PMID- 29620621 TI - Barriers for Hospital-Based Nurse Practitioners Utilizing Clinical Decision Support Systems: A Systematic Review. PMID- 29620622 TI - CC1 Emergent Endovascular Repair of a Ruptured Descending Thoracic Aortic Aneurysm in an Arresting Patient. AB - OBJECTIVE: Our goal was to present a case of emergent endovascular repair of a ruptured descending aortic aneurysm in an actively arresting patient. PATIENT: The patient was a 75-year-old woman with a known history of a 6.5-cm descending thoracic aortic aneurysm with acute onset of back pain and syncope. A computed tomographic angiogram revealed disruption of the descending thoracic aorta and a mediastinal hematoma. The patient was taken emergently to the operating room. During induction, the patient developed pulseless electrical activity arrest, and cardiopulmonary resuscitation was promptly initiated. The bilateral groins were prepped and draped, and an emergent cutdown was made to gain access to the femoral artery. Wire access of the aortic arch was obtained via a 6F micropuncture sheath, over which a 45- * 45- * 20-mm covered endograft was introduced. Using fluoroscopic guidance alone without angiography, the endograft was rapidly deployed proximally to the level of the distal aortic arch using calcification as a landmark (Fig. CC1-1). Immediately after deployment, the patient regained a pulse, and cardiopulmonary resuscitation was discontinued for a total of 30 minutes of continuous compressions. A right thoracotomy was then performed for evacuation of the hemothorax and ligation of the torn intercostal arteries. The patient was cooled to 35 degrees Celsius for 24 hours post-arrest and a lumbar drain was placed postoperatively. The patient thereafter regained all neurological and end-organ function and at the 6-month follow-up has had no progression of her aneurysm (Fig. CC1-1). CONCLUSIONS: Rapid introduction and deployment of a descending thoracic aortic endograft for a ruptured descending aortic aneurysm is safe and effective in an arresting patient. PMID- 29620623 TI - Suicidal hanging donors for lung transplantation: Is this chapter still closed? Midterm experience from a single center in United Kingdom. AB - In the context of limited donor pool in cardiothoracic transplantation, utilization of organs from high risk donors, such as suicidal hanging donors, while ensuring safety, is under consideration. We sought to evaluate the outcomes of lung transplantations (LTx) that use organs from this group.Between January 2011 and December 2015, 265 LTx were performed at our center. Twenty-two recipients received lungs from donors after suicidal hanging (group 1). The remaining 243 transplantations were used as a control (group 2). Analysis of recipient and donor characteristics as well as outcomes was performed.No statistically significant difference was found in the donor characteristics between analyzed groups, except for higher incidence of cardiac arrest, younger age and smoking history of hanging donors (P < .001, P = .022 and P = .0042, respectively). Recipient preoperative and perioperative characteristics were comparable. Postoperatively in group 1 there was a higher incidence of extracorporeal life support (27.3 vs 9.1%, P = .019). There were no significant differences in chronic lung allograft dysfunction-free survival between group 1 and 2: 92.3 vs 94% at 1 year and 65.9 vs 75.5% at 3 years (P = .99). The estimated cumulative survival rate was also similar between groups: 68.2 vs 83.2% at 1 year and 68.2% versus 72% at 3 years (P = .3758).Hanging as a donor cause of death is not associated with poor mid-term survival or chronic lung allograft dysfunction following transplantation. These results encourage assessment of lungs from hanging donors, and their consideration for transplantation. PMID- 29620624 TI - The expression of HtrA2 and its diagnostic value in patients with hepatocellular carcinoma. AB - The purpose of this study was to detect the expression of high-temperature requirement A2 (HtrA2) and its diagnostic value in the patients with hepatocellular carcinoma (HCC).The relative serum HtrA2 expression at mRNA and protein level was severally detected by quantitative real-time polymerase chain reaction and western blot analysis in 198 HCC patients and 48 healthy controls. And its association with clinicopathological features was analyzed by chi-square test. The diagnostic value of HtrA2 expression was estimated by establishing a receiver operating characteristic (ROC) curve.Serum HtrA2 was significantly higher in patients with HCC than that in healthy controls both at mRNA and protein levels (P < .05 for both). In addition, the high HtrA2 expression was associated with large tumor size and advanced clinical stage. Furthermore, the value of the area under the ROC curve was 0.808 corresponding with a sensitivity of 65.2% and a specificity of 89.6%, revealed that HtrA2 might be a diagnostic biomarker in HCC.HtrA2 is upregulated and considered to be a potential biomarker for the diagnosis of patients with HCC. PMID- 29620626 TI - Acupotomy for calcaneodynia: A systematic review protocol. AB - BACKGROUND: Calcaneodynia customarily induces inferior heel pain, specialists believe that the pain is principally caused by acute or chronic injury due to the plantar fascia from accumulative overload pressure. Acupotomy has been widely used to treat calcaneodynia. But its efficiency has not been scientifically and methodically evaluated. The aim of this study is to evaluate the efficacy and safety of the acupotomy treatment in patients with calcaneodynia. METHODS: Relevant randomized controlled trials in 6 databases (PubMed, Embase, and Cochrane Library, Chinese literature databases, Chinese Biomedical Literature Database [CBM], China National Knowledge Infrastructure [CNKI], and Wanfang Database). The randomized controlled trials (RCTs) of the acupotomy for calcaneodynia patients will be searched in the databases from inception to December 2017 by 2 researchers. Visual analog scale (VAS) will be assessed as the primary outcomes. Roles and Maudsley Score (RM) will be assessed as the secondary outcome. The RevMan V.5.3 will be used for meta-analysis. Continuous outcomes will be presented as the mean difference or standard mean difference, while dichotomous data will be expressed as relative risk. RESULTS: This study will provide a high-quality synthesis of VAS and RM to assess the effectiveness and safety of acupotomy for calcaneodynia patients. CONCLUSION: This systematic review will provide evidence to judge whether acupotomy is an effective intervention for patients with Calcaneodynia. PMID- 29620625 TI - Decreased functional connectivity and structural deficit in alertness network with right-sided temporal lobe epilepsy. AB - Patients with temporal lobe epilepsy (TLE) often suffer from alertness alterations. However, specific regions connected with alertness remain controversial, and whether these regions have structural impairment is also elusive. This study aimed to investigate the characteristics and neural mechanisms underlying the functions and structures of alertness network in patients with right-sided temporal lobe epilepsy (rTLE) by performing the attentional network test (ANT), resting-state functional magnetic resonance imaging (R-SfMRI), and diffusion tensor imaging (DTI).A total of 47 patients with rTLE and 34 healthy controls underwent ANT, R-SfMRI, and DTI scan. The seed-based functional connectivity (FC) method and deterministic tractography were used to analyze the data.Patients with rTLE had longer reaction times in the no-cue and double-cue conditions. However, no differences were noted in the alertness effect between the 2 groups. The patient group had lower FC compared with the control group in the right inferior parietal lobe (IPL), amygdala, and insula. Structural deficits were found in the right parahippocampal gyrus, superior temporal pole, insula, and amygdala in the patient group compared with the control group. Also significantly negative correlations were observed between abnormal fractional anisotropy (between the right insula and the superior temporal pole) and illness duration in the patients with rTLE.The findings of this study suggested abnormal intrinsic and phasic alertness, decreased FC, and structural deficits within the alerting network in the rTLE. This study provided new insights into the mechanisms of alertness alterations in rTLE. PMID- 29620627 TI - Small bowel capsule endoscopy: Indications, results, and clinical benefit in a University environment. AB - Capsule endoscopy (CE) opened a new method for visualization of the small intestine. We here further explore its clinical implications.We retrospectively analyzed the clinical benefit of CE in view of medical history, diagnostics, and therapy. Our patient collective consisted of 203 patients. CE was investigated in the context of bleeding, anemia, abdominal pain, diarrhea, Crohn's disease, and suspected tumors.The study collective consisted of 118 male and 85 female patients with a mean age of 58 years (range 8-90 years). Complete bowel transit took place in 82% of the patients. The diagnostic yield in the detection of obscure gastrointestinal bleeding was 80% and for anemia 78%. Mucosal lesions were the most common finding (43%). Unclear abdominal pain had the lowest diagnostic yield (41%). Ensuing therapeutic interventions were mostly medical (66%), and to a minor extent surgical (4.4%) as well as endoscopic (4%).In conclusion, small intestinal CE is a secure method to clarify small intestinal diseases, especially obscure gastrointestinal bleeding, even in pre-operated patients without stenosis symptoms. Our study emphasizes in a collective of patients with extensive prior diagnostics that due to CE therapeutic measures resulted in 73%. PMID- 29620628 TI - The significance of bacterial engulfment in Gram-stained sputum in patients with respiratory infections. AB - In general, physicians believe that the presence of bacterial engulfment in white blood cells (WBCs) on Gram-stained sputum is a hallmark of lower respiratory infection. However, no studies have described the significance or diagnostic accuracy of engulfment in lower respiratory tract infections.We prospectively studied sputum samples by Gram staining (Favor method) for their quality and engulfment score in WBCs obtained from patients with respiratory symptoms at inpatient and outpatient settings at Kyorin University Hospital between December 2012 and April 2015.A total of 163 patients were enrolled. The patients were classified into an infection (n = 93) or non-infection (n = 70) group based on clinical or radiological findings prior to the evaluation of sputum samples. The proportion of engulfment-positive cases was equal in the infection and non infection groups (49.5% vs 35.7%, P = 0.11). In the infection group, the engulfment score (%) for Streptococcus pneumoniae was significantly lower (median 3%, interquartile range [IQR]: 2% to 5%, P = 0.005) than that of the non-S. pneumoniae bacteria (H. influenzae, M. catarrhalis, and methicillin-susceptible Staphylococcus aureus (MSSA))(median 22.5%, IQR: 17% to 35.5%). The engulfment score of S. pneumoniae in the WBC was low in the infection group, and no cases were recognized in the non-infection group. Using a cut-off value of 3%, the diagnostic accuracy for infection was as follows: sensitivity: 50%, specificity: 65.7%, and area under the curve (AUC): 0.579 (95% CI 0.464 to 0.694). For the non S. pneumoniae bacteria (H. influenzae, M. catarrhalis, and MSSA), the engulfment score was significantly higher in the infection group (median 22.5%, IQR 17 to 35.5%) than in the non-infection group (median 6.0%, IQR: 3 to 13%, P = 0.011), and the diagnostic accuracy for infection was as follows: sensitivity: 75%, specificity: 85.7%, and AUC: 0.902 (95% CI 0.75 to 1.00) when the threshold for the engulfment score was defined as 18%.This study provides the first evidence that the engulfment of bacteria in WBCs is not always indicative of infection and that the engulfment score can fluctuate according to the pathogen. PMID- 29620629 TI - Identification of biomarkers of venous thromboembolism by bioinformatics analyses. AB - Venous thromboembolism (VTE) is a common vascular disease and a major cause of mortality. This study intended to explore the biomarkers associated with VTE by bioinformatics analyses.Based on Gene Expression Omnibus (GEO) database, the GSE19151 expression profile data were downloaded. The differentially expressed genes (DEGs) between single VTE (sVTE)/recurrent VTE (rVTE) and control were identified. Then, pathway enrichment analysis of DEGs were performed, followed by protein-protein interaction (PPI) network construction.Total 433 upregulated and 222 downregulated DEGs were obtained between sVTE and control samples. For rVTE versus control, 625 upregulated and 302 downregulated DEGs were identified. The overlap DEGs were mainly enriched in the pathways related to ribosome, cancer, and immune disease. The DEGs specific to rVTE were enriched in several pathways, such as nod-like receptor signaling pathway. In the PPI network, 2 clusters of VTE genes, including ribosomal protein family genes and NADH family-ubiquinol cytochrome genes, were identified, such as ribosomal protein L9 (RPL9), RPL5, RPS20, RPL23, and tumor protein p53 (TP53).The nod-like receptor signaling pathway, ribosomal protein family genes, such as RPL9, RPL5, RPS20, and RPL23, and DEG of TP53 may have the potential to be used as targets for diagnosis and treatment of VTE. PMID- 29620630 TI - Computed tomography-guided percutaneous transthoracic needle biopsy for solitary pulmonary nodules in diameter less than 20 mm. AB - To evaluate the diagnostic value of computed tomography (CT)-guided percutaneous lung biopsy for solitary pulmonary nodules (SPN) < 20 mm.A total of 248 patients who were diagnosed a SPN of < 20 mm underwent CT-guided percutaneous transthoracic needle biopsy were reviewed.Specimens of 248 patients were obtained successfully. Around 174 cases were proved to be malignancies and 74 cases of benign lesions by biopsy. About 178 malignancies (71.8%) and 70 benign lesions were proved by surgery and clinical course. The diagnostic accuracy was 96.8%. The diagnostic accuracy of large nodules group (>10 and < 20 mm) was 99.3%, higher than 93.5% of small nodules group (<=10 mm) with statistical significance. The incidence of phenmothorax and hemorrhage was 16.1% and 6.8%, respectively. No death-related complications happened. The incidence of phenmothorax was related to puncture times (P = .013) and the length of puncture needle in lung tissues (P = .019).CT-guided percutaneous lung biopsy for SPN of < 20 mm is an efficient and safe diagnostic method. PMID- 29620631 TI - Pediatric hyperimmunoglobulin E syndrome: A case series of 4 children in China. AB - Hyperimmunoglobulin E syndromes (HIES) are rare primary immunodeficiency diseases characterized by markedly elevated serum immunoglobulin (Ig) E, recurrent pneumonia, and chronic eczema. To date, information about pediatric HIES is limited. We aimed to evaluate the spectrum of clinical and immunological features in pediatric patients with HIES in China.We retrospectively reviewed the cases of 4 pediatric patients with HIES followed at the Guangzhou Women and Children's Medical Center from May 2013 to September 2017. We analyzed clinical presentation, laboratory data, immunological evaluations, imagenological characteristics, treatment, response to therapy, genetic and bronchoalveolar lavage fluid (BALF) findings, and prognosis.The common clinical features of the patients were recurrent respiratory and mucocutaneous infections and eczematoid skin lesions. In 3 of 4 patients, BALF and transbronchial lung biopsy (TBLB) demonstrated fungal pneumonia with organisms including invasive Aspergillus and Penicillium marneffei. Elevated serum IgG and IgM were detected in 3 and 2 cases, respectively, while CD4+ T and CD19+ B cells were slightly reduced in only 1 patient. Nitroblue tetrazolium tests (NBTs) were normal in all patients, and reduced natural killer cell counts were identified in 3 patients. A novel missense mutation in exon 17 (c.1593A>T, p.K531N) was identified in the signal transducer and activator of transcription 3 (STAT3) gene that has not been reported previously. One patient had 3 homozygous nonsynonymous variations of the complement receptor 2 (CR2) gene distributed in exons 10 (c.1916G>A, p.S639N) and 11 (c.1987T>C, p.S663P and c.2012G>A, p.R671H) with high frequency.This case series suggests that fungi are important respiratory pathogens in children with HIES and should be considered in cases of pneumonia in this population. The NIH scoring system does not allow diagnostic certainty, particularly in infants, because some of the common manifestations of HIES may not develop until the patient matures. Pulmonary complications must be identified in the early stage of the disease to treat them effectively. In addition, we report a mutation in STAT3 that has not been identified previously. PMID- 29620632 TI - Efficacy of escitalopram oxalate for patients with post-stroke depression. AB - This retrospective study investigated the efficacy and safety of escitalopram oxalate (ESO) for the treatment of post-stroke depression (PSD).A total of 115 patients with PSD were included in this study. A total of 65 patients underwent ESO (Intervention group). A total of 50 patients received acupressure (Control group). The outcome measurements included Montgomery-Asberg Depression Rating Scale (MADRS), Hamilton Anxiety Rating Scale (HAM-A), and Sheehan Disability Scale (SDS). In addition, we also recorded the adverse events in this study.At the end of 8-week treatment, ESO showed greater efficacy in depression, measured by MADRS (P < .01); anxiety, measured by HAM-A scale (P < .01); and disability, measured by SDS (P < .01), compared to acupressure. Additionally, there were not significant differences regarding adverse events between two groups (P > .05).The present results indicate that ESO can decrease symptoms of patients with PSD. PMID- 29620633 TI - A meta-analysis of randomized control trials assessing mesh fixation with glue versus suture in Lichtenstein inguinal hernia repair. AB - BACKGROUND: The use of glue to fix mesh instead of sutures in Lichtenstein inguinal hernia repair has been accepted worldwide, with the increasing worries about postoperative chronic groin pain and recurrence. The aim of this meta analysis was to clarify which mesh fixation method was more suitable in Lichtenstein inguinal hernia repair. METHODS: Articles published up to July 2017 were searched using MEDLINE, the Cochrane Library, Embase, and the Web of Science. Randomized controlled trials (RCTs) comparing glue versus suture mesh fixation in Lichtenstein inguinal hernia repair were included in the review. The quality assessment and data extraction of included studies were applied by 2 independent authors. Statistical analysis was performed using RevMan 5.2 software. RESULTS: Thirteen RCTs with 2375 patients were eligible for inclusion. Eight trials compared synthetic glue with suture fixation and 5 compared biological glue with suture fixation. The results showed that there was a lower incidence of early chronic pain (subgroup analysis, biological glue versus sutures, odds ratio (OR) = 0.41; 95% confidence interval (CI), 0.19-0.90; P = .03), and hematoma (subgroup analysis, synthetic glue versus sutures, OR = 0.56; 95% CI, 0.34-0.95; P = .03) in the glue fixation group. Suture mesh fixation method cost more time in operation than glue (mean difference = -4.60, 95% CI 7.60 to -1.60; P = .003). There was no evidence of an increase in chronic pain or recurrence rates with glue fixation method in the long-term follow-up. CONCLUSIONS: Mesh fixation with glue compared with sutures in Lichtenstein repair inguinal hernia is faster and less painful, without an increasing in terms of recurrence rates in the long term. PMID- 29620634 TI - Relationships between patient characteristics and contrast agent dose for successful computed tomography venography with a body-weight-tailored contrast protocol. AB - The aim of this study was to evaluate the effect of patient characteristics on the contrast agent dosage that is required to reach effective enhancement of the inferior vena cava (IVC) on computed tomography venographs (CTV).This retrospective study included 50 patients who underwent CTV at 80 kVp. The contrast injection protocol (iodine 600 mg/kg) was tailored to their body weight. We calculated the required contrast agent volume (CAVmean-IVC) to reach the mean enhancement of IVC. We performed univariate and multivariate linear regression analyses between the sex, age, body weight (BW), lean body weight (LBW), body surface area (BSA), height (HT), estimated glomerular filtration rate (eGFR), and CAVmean-IVC.The univariate linear regression analysis show that HT, BW, LBW, and BSA were significantly correlated with CAVmean-IVC (P < .01 for all). The CAVmean IVC was significantly higher for males than females (P < .01). Multivariate regression analysis showed that BW, LBW, and BSA had a statistically significant effect on CAVmean-IVC. There was no significant correlation of age, HT, or eGFR with CAVmean-IVC.BW, LBW, and BSA each had an independent significant effect on CAVmean-IVC. The conventional BW-tailored contrast injection protocol might be insufficient for CTV. PMID- 29620635 TI - Effects of fixed orthodontic brackets on oral malodor: A systematic review and meta-analysis according to the preferred reporting items for systematic reviews and meta-analyses guidelines. AB - BACKGROUND: This systematic review and meta-analysis aimed to identify whether there is any relationship between fixed orthodontic appliances and malodor, and if self-ligating brackets (SLBs) prevent malodor better than conventional brackets (CBs). METHODS: The electronic databases PubMed, Ovid, EMBASE, and the Cochrane Library were searched from inception to September 2016; a manual search was also performed. Randomized controlled and clinical controlled trials, in which experimental groups received fixed orthodontic therapy and malodor was measured, were included. Patients treated with fixed orthodontic brackets were compared with those without any treatment, and SLB systems were compared with CB systems. Two reviewers independently selected potentially relevant studies, evaluated the risk for bias, extracted essential data, and synthesized findings using Review Manager version 5.3 (Copenhagen: The. Nordic Cochrane Centre, The Cochrane Collaboration, 2014). RESULTS: Four studies, involving a total of 152 participants, met the inclusion criteria. Fixed orthodontic appliances caused malodor from the initial visit to 2 to 3 months, but was only significant after the first week (mean difference 20.24 [95% confidence interval [CI]11.75-28.74]; P < .00001). Plaque index, gingival index, and periodontal pocket depths demonstrated no statistical differences between the SLB and CB groups after the first week. However, SLBs significantly controlled malodor better than CBs after the first week (mean difference 4.32 [95% CI 6.02 to 2.61]; P < .00001). The quality of the included studies was relatively low and relevant research in this field is quite scarce. CONCLUSIONS: Although the evidence base was relatively weak, fixed orthodontic treatment appeared to be a risk factor for malodor, independent of periodontal changes, and SLB systems controlled malodor better than CB systems. PMID- 29620636 TI - Clinical characteristic and risk factors of recurrent sexual abuse and delayed reported sexual abuse in childhood. AB - Child sexual abuse (CSA) is a global problem that affects children of all ages, and the evaluation of these victims by psychologic and gynecologic experts in pediatric emergency departments is an important issue. Few data are available on the characteristics of children admitted to pediatric emergency department with recurrent CSA and delayed reported CSA. The aim of the present study was to describe the clinical features of, and risk factors for, recurrent CSA and delayed reported CSA. The study retrospectively analyzed victims of CSA who were admitted to a pediatric emergency department. Chi-square tests and univariate analyses were performed to assess the risk factors of recurrent or delayed reported CSA. Of the 91 CSA cases, 32 (35.2%) were recurrent assaults. Of the 70 cases recorded the duration of the event, 22 (31.4%) were delayed report cases. Comparisons of the non-recurrent and recurrent CSA assault groups revealed a significant increase in comorbidities (odds ratio [OR]: 4.46, 95% confidence interval [CI]: 1.54-12.93), acute psychiatric problems (OR: 3.18, CI: 1.26-8.06), attempted suicide (OR: 4.23, CI: 1.28-13.99), and the need for treatment with antipsychotic medications (OR: 5.57, CI: 1.37-22.65). Compared with non-delayed reported cases, the delay reported cases of CSA were significantly more likely to have anxiety (P < .05). The CSA victims in the present study exhibited acute medical and/or psychosocial problems, which indicate that pediatric emergency professionals have a responsibility to look for and recognize particular characteristics in these victims. PMID- 29620637 TI - Decreased postural control in people with moderate hearing loss. AB - Balance is a complex process that involves multiple sensory integrations. The auditory, visual, and vestibular systems are the main contributors. Hearing loss or hearing impairment may induce inappropriate postural strategies that could affect balance and therefore increase the risk of falling.The aim of this study was to understand whether hearing loss could influence balance, cervical posture, and muscle activation in the cervical region.Thirteen patients (61 +/- 13 years; 161.8 +/- 11.0 cm; 70.5 +/- 15.9 kg) with moderate hearing loss (Right ear -60 +/ 21 dB; Left ear -61 +/- 24 dB) underwent: an audiometric examination, a postural examination (with open and closed eyes) through a stabilometric platform, a cervical ROM examination through a head accelerometer, and a sternocleidomastoid electromyography (EMG) examination.A linear regression analysis has shown a regression coefficient (R) 0.76 and 0.69 between hearing loss and the posturographic parameters, on the sagittal sway, with open and closed eyes, respectively. The combination of frontal and sagittal sway is able to explain up to 84% of the variance of the audiometric assessment. No differences were found between right and left hemibody between the audiometric, posturographic, cervical ROM parameters, and in EMG amplitude. ROM and EMG parameters have not shown any significant associations with hearing loss, for both right and left head rotation.Hearing loss is associated to increased posturographic measures, especially the sagittal sway, underlining a reduced postural control in people with hearing impairments. No association was found between the heads posture and neck activation with hearing loss. Hearing loss may be associated with an increased risk of falls. PMID- 29620638 TI - Factors associated with HIV infection among Yi minority residents in Liangshan Prefecture, Sichuan Province: A path analysis. AB - We aimed to evaluate HIV prevalence among residents of Liangshan Prefecture through HIV sentinel surveillance (HSS) data over the period from 2010 to 2016, and investigate risk factors for HIV infection in this population and interactions among them.Two sites (Dechang and Ningnan counties) with majority Han populations, and 1 site (Butuo) with a majority-Yi population were selected. We used questionnaires to investigate residents' demographic and behavioral characteristics from 2010 to 2016, and performed HIV testing. Multivariate logistic regression and path analysis were undertaken to investigate the interactions and mediating effects among significant risk factors for HIV infection.A total of 5403 community residents in the Yi area and 10,897 community residents in the Han areas were enrolled. HIV prevalence in the Yi area was consistently high, ranging from 9.46% (63/666, 2011) to 2.88% (23/798, 2012) over the period from 2010 to 2016. HIV prevalence in the Han areas ranged from 0.15% (2/1333, 2010) to 0.44% (7/1604, 2011) over the same period. Multivariate logistic regression showed that unprotected casual sexual behavior, male gender, illiteracy, drug use, and injection drug use were positively associated with HIV infection risk in the Yi area. Path analysis of the risk factors revealed that casual sexual behavior (0.051) and injection drug use (0.161) were directly associated with HIV infection. However, marital status (0.004), ethnicity (0.017), education level (-0.004), HIV/AIDS-related prevention knowledge ( 0.012), and drug use (0.11) had an indirect influence on HIV infection through casual sexual behavior and injection drug use.The prevalence of HIV is high among residents of majority-Yi areas, and injection drug use and casual sexual behavior are risk factors for infection. PMID- 29620640 TI - Acupuncture for anxiety: A protocol for a systematic review of controlled trials. AB - BACKGROUND: Acupuncture has been widely, used in Asian countries since the Yuan Dynasty in China. Moreover, acupuncture has been reported to exhibit anti-allergy effects in many clinical trials. This systematic review will assess the effectiveness, and safety of acupuncture for anxiety treatment. METHODS: Eleven databases, including Asian databases, will be searched for studies conducted through December in the year 2017. We will include randomized controlled trials (RCTs) assessing acupuncture for anxiety. The risk of bias will be evaluated using the Cochrane risk of bias assessment tool, and confidence in the cumulative evidence will be evaluated using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) instrument. ETHICS AND DISSEMINATION: This systematic review will be published in a peer-reviewed journal. It will also be disseminated electronically, and in print. The review will be updated to inform, and guide healthcare practices. REGISTRATION NUMBER: PROSPERO 2018 under number CRD42018080034. PMID- 29620639 TI - The role of leptin in osteoarthritis. AB - BACKGROUND: The pathogenesis of osteoarthritis (OA) is not clear; leptin may be related to its pathogenesis. METHODS: We reviewed articles on leptin in OA, chondrocytes, and in vitro experiments. It is concluded that leptin may lead to OA via some signaling pathways. At the same time, the concentration of leptin in vitro experiments and OA/rheumatoid arthritis (RA) patients was summarized. RESULTS: Leptin levels in serum and synovial fluid of OA/RA patients were higher than normal person. In the condition of infection and immunity, serum leptin levels in the peripheral blood significantly increase. Because of the close relationship between obesity, leptin, and OA, it is crucial to study the effects of weight loss and exercise intervention on serum leptin levels to improve the symptoms of OA patients. CONCLUSION: Treatment for leptin-increased obesity may be a treatment for OA. The role of leptin in OA cannot be ignored and needs to be further studied. PMID- 29620641 TI - Expression and prognostic value of lactate dehydrogenase-A and -D subunits in human uterine myoma and uterine sarcoma. AB - OBJECTIVE: This study aimed to determine the expression of lactate dehydrogenase (LDH)-A and LDH-D in patients with uterine myoma, cellular leiomyoma (CLM), and uterine sarcoma and to evaluate their prognostic significance. METHODS: Protein expression levels of LDH-A and LDH-D were determined in tissue samples from 86 patients (26 uterine myoma, 10 CLM, 50 uterine sarcoma) by immunohistochemistry and their associations with clinicopathologic parameters and outcomes were analyzed in patients with uterine sarcoma. RESULTS: The positivity rates for LDH A and LDH-D were significantly higher in patients with uterine sarcoma compared with those with uterine myoma or CLM (P < .05). Patients with uterine sarcoma were classified as having uterine leiomyosarcoma (LMS), malignant endometrial stromal sarcoma, and malignant mixed Mullerian tumor, with 5-year overall survival rates of 59%, 71%, and 29%, respectively (P < .05). Univariate analysis showed that patients younger than 50 years and with stage I-II had better clinical prognoses. LDH-A-positive LMS patients had a poorer prognosis than LDH-A negative patients (P = .03). The median survival time of LDH-A-positive patients was 35 months. CONCLUSIONS: We demonstrated that LDH-D was expressed in patients with uterine sarcoma. Furthermore, the overexpressions of LDH-A and LDH-D in uterine sarcoma patients may contribute to further understanding of the mechanism of LDH in tumor metabolism in uterine sarcoma. Positive expression of LDH-A in patients with LMS may act as a potential prognostic biomarker in these patients. PMID- 29620642 TI - In-hospital mortality and morbidity of pediatric scoliosis surgery in Japan: Analysis using a national inpatient database. AB - Several previous reports have elucidated the mortality and incidence of complications after pediatric scoliosis surgery using nationwide databases. However, all of these studies were conducted in North America. Hence, this study aimed to identify the incidence and risk factors for in-hospital mortality and morbidity in pediatric scoliosis surgery, utilizing the Diagnosis Procedure Combination database, a national inpatient database in Japan.We retrospectively extracted data for patients aged less than 19 years who were admitted between 01 June 2010 and 31 March 2013 and underwent scoliosis surgery with fusion. The primary outcomes were in-hospital death and postoperative complications, including surgical site infection, ischemic heart disease, acute renal failure, pneumonia, stroke, disseminated intravascular coagulation, pulmonary embolism, and urinary tract infection.We identified 1,703 eligible patients (346 males and 1,357 females) with a mean age of 14.1 years. There were no deaths among the patients. At least one postoperative complication was found in 49 patients (2.9%). The most common complication was surgical site infection (1.4%). The multivariable logistic regression analysis showed that male sex (odds ratio, 2.22; 95% confidence interval, 1.28-3.70), comorbid diabetes (7.00; 1.56-31.51), and use of allogeneic blood transfusion (3.43; 1.86-6.41) were associated with the occurrence of postoperative complications. The present nationwide study elucidated the incidence and risk factors for in-hospital mortality and morbidity following surgery for pediatric scoliosis in an area other than North America. Diabetes was identified for the first time as a risk factor for postoperative complications in pediatric scoliosis surgery. PMID- 29620643 TI - Endovascular stenting of a complicated type B aortic dissection in an 11-year-old patient: Case Report. AB - RATIONALE: Endovascular aortic repair in children in the case of aortic dissection (AD) is currently unavailable. This is the first report of aortic dissection type B in an 11-years old child treated in endovascular way. PATIENT CONCERNS: Complicated AD. Since bowel malperfusion and aortic rupture the surgery was necessary in emergency. DIAGNOSES: Computed angio tomography. INTERVENTION: The modified PETTICOAT technique (Provisional Extension To Induce Complete Attachment) was used. OUTCOME: Full recovery. LESSONS: For the first-time telescope modification were used, to allow aorta to grow with a child. Such a strategy seems to be possible with long overlap and lack of oversizing between implants. PMID- 29620644 TI - Intrathyroidal ectopic thymus in children: A benign lesion. AB - As ultrasound is commonly used these days, more and more lesions are found incidentally, including simple cysts, isoechoic nodules, and hypoechoic nodules, such as ectopic thymus. We here report the prevalence of ectopic thymus and its natural course.We retrospectively reviewed the charts of 690 subjects (342 males, 348 females) who were under 18 years old and had undergone neck or thyroid ultrasound at Hallym University Sacred Heart Hospital from January 2014 to June 2017. Ectopic thymus was defined when the incidental lesion was hypo- to iso echoic compared to adjacent muscles with vascularity and did not have a connection to the thymus in the mediastinum.Of the 690 children, 16 (9 males, 7 females; median and ranges of age at diagnosis, 13 months and 18 days to 10 years) were diagnosed as having ectopic thymus. The most common location of ectopic thymus was in the inferior aspect of the left thyroid lobe. The median and ranges of the longest diameter at the time of initial diagnosis was 22.5 mm and 8 mm to 38 mm, respectively. Four cases underwent follow-up ultrasound, of which 3 cases showed no change in size and 1 case showed decreased size.Ectopic thymus should be kept in mind when a lesion is found in the neck and thyroid incidentally, and physicians should reassure parents about its benign course. PMID- 29620645 TI - A systematic review and meta-analysis of single-incision mini-slings (MiniArc) versus transobturator mid-urethral slings in surgical management of female stress urinary incontinence. AB - BACKGROUND: To assess the current evidence of effectiveness and safety of single incision mini-slings (MiniArc) versus transobturator midurethral slings in the management of female stress urinary incontinence (SUI). METHODS: A systematic search was performed from the electronic databases including PubMed, EMBASE, and Cochrane Library by November 2017. Using RevMan5.3 statistical software, the primary outcomes including subject and objective cure rates at 6 to 24 months follow-up were evaluated. Meanwhile, analysis was also performed for comparing the secondary outcomes such as peri- and postoperative complications, operative data, and quality of life. RESULTS: Six randomized controlled trials (RCTs) and 6 retrospective cohort studies involving 1794 patients with SUI were analyzed based on the inclusion criteria. On the basis of our analysis, MiniArc was proven to have a noninferior clinical efficacy compared with transobturator midurethral slings with respect to the objective cure rate (risk ratio [RR] = 0.98, 95% confidence interval [CI] 0.94-1.03, P = .43) and subjective cure rate (RR = 0.97, 95% CI 0.91-1. 04, P = .38). In addition, pooled analysis showed that MiniArc had significantly lower postoperative pain scores (mean difference [MD] = -1.70, 95% CI -3.17 to -0.23, P = .02) and less postoperative groin pain (RR = 0.42, 95% CI 0.18-0.98, P = .04). Moreover, the MiniArc group also had a significantly shorter operation time (MD = -6.12, 95% CI -8.61 to -3.64, P < .001), less blood loss (MD = -16.67, 95% CI -26.29 to -7.05, P < .001), shorter in-patient stay (MD = 1.30, 95% CI -1.74 to -0.86, P < .001), and less urinary retention risk (RR = 1.15, 95% CI 0.46-2.87, P = .77). However, overall evidence was insufficient to suggest a statistically significant difference in the adverse event profile for MiniArc compared with transobturator slings. CONCLUSIONS: This meta-analysis indicates that MiniArc is an effective method treating SUI. When compared with transobturator slings, it not only has a similar high cure rates, but also is associated with shorter operation time, less blood loss, more favorable recovery time, lower postoperative pain scores, less postoperative groin pain, less urinary retention, and absence of a visible wound. However, the findings of this study should be further confirmed by well-designed prospective RCTs with a larger patient series. PMID- 29620646 TI - Multiple metastases of clear-cell renal cell carcinoma to different region of the nasal cavity and paranasal sinus 3 times successively: A case report and literature review. AB - RATIONALE: Distant metastasis of clear-cell renal cell carcinoma (ccRCC) to the nasal cavity and paranasal sinus is rare. Endoscopic biopsy used to be performed for diagnosis when it is difficult for complete resection due to intense bleeding during surgery. According to previous literature, the outcomes of metastasis after endoscopic surgery remain unclear. PATIENT CONCERNS: A 62-year-old man with a history of epistaxis was referred to our institution. The clinical, computed tomography (CT) and magnetic resonance imaging (MRI) examination indicate metastasis to sinonasal sinuses.Diagnoses: He was histopathologically diagnosed with different anatomical structures of nasal cavity and paranasal sinus metastases 6, 14, and 15 years after the initial nephrectomy for ccRCC. INTERVENTIONS: He underwent endoscopic surgery 3 times, once at the time of each metastasis. OUTCOMES: He survived for 20 years despite of multitransfers and died due to multiple organ failure. LESSONS: Metastasis of ccRCC to the nasal cavity and paranasal sinus is characterized by varied growth rates, metastatic times and spreading patterns; ccRCC metastasis should be considered with the presence of hemorrhagic lesions in the nasal cavity and paranasal sinus. Endoscopic surgery is the first-line treatment. PMID- 29620647 TI - Spontaneous rupture of the branches of left subclavian artery: A case report and review of the literatures. AB - RATIONALE: Spontaneous rupture of the branches of left subclavian artery (LSA) without any obvious risk factors is rare. PATIENT CONCERNS: A 51-year-old female patient without history of trauma and hypertension complained about left chest pain. DIAGNOSES: A chest Computed tomography (CT) scan revealed a large pleural effusion (PE) in the left thorax cavity and hemothorax was confirmed by thoracentesis. INTERVENTIONS: The patient underwent surgery. OUTCOMES: spontaneous rupture of the branches of LSAwas confirmed. LESSONS: The patient recovered well and discharged after timely treatments. The unusual possibility should be paid attention in mind in acute chest pain cases. PMID- 29620648 TI - Epiduroscopic laser neural decompression as a treatment for migrated lumbar disc herniation: Case series. AB - OBJECTIVE: Epiduroscopic laser neural decompression (ELND) is one of the more invasive techniques for managing patients with herniated lumbar disc. However, ELND can be used to treat, and diagnose the epidural pathology; indications for ELND remain controversial, especially, when applied in cases of large disc extrusion and migrated disc. This paper reports cases of patients that were satisfied with the ELND procedure for migrated lumbar disc herniation. METHODS: We reviewed the medical records of patients that received ELND for migrated lumbar disc in an outpatient clinic. The patients complained of low back pain with radicular pain with an intensity over 5 on a numeric rating scale (NRS) that had persisted for over 1 month. The Magnetic resonance imaging (MRIs) showed migrated lumbar disc herniation, and patients opted for ELND because they had previously experienced nerve blocks, and did not want to receive open surgery for their pain, even after the limitations of ELND were explained. RESULTS: Patients reported that their pain was dramatically reduced, and other discomfort symptoms, such as numbness, were also reduced after the procedure. In follow-up, all of the patients were satisfied with the results. CONCLUSION: We applied the ENLD procedure to mechanically, remove disc material that compressed the spinal nerve, and the patients were satisfied, and reported symptom relief. ELND was a sufficient treatment approach for lumbar migrated herniated disc for patients who did not want to undergo open spine surgery. PMID- 29620649 TI - Primary medullary hemorrhage in a patient with coagulopathy due to alcoholic cirrhosis: A case report. AB - RATIONALE: Mild-to-moderate alcoholic cirrhosis of the liver is related to spontaneous intracerebral hemorrhage (ICH). In terms of spontaneous brainstem hemorrhage, pontine is considered as the most common site in contrast to medulla oblongata where the hemorrhage is rarely seen. This rare primary medullary hemorrhage has been attributed so far to vascular malformation (VM), anticoagulants, hypertension, hemorrhagic transformation, and other undetermined factors. PATIENT CONCERNS: Herein, we describe a 53-year-old patient with 35-year history of alcohol abuse was admitted for acute-onset isolated hemianesthesia on the right side. He was normotensive on admission. A neurological examination revealed isolated hemihypoaesthesia on the right side. He had no history of hypertension, and viral hepatitis, and nil use of anticoagulants. DIAGNOSES: Brain computed tomography (CT) image demonstrated hemorrhagic lesion in dorsal and medial medulla oblongata which was ruptured into the fourth ventricle. Brain magnetic resonance imaging (MRI), and magnetic resonance angiography (MRA) demonstrated no evidence of VM. The laboratory tests implied liver dysfunction, thrombocytopenia, and coagulation disorders. Abdominal ultrasound, and CT image showed a small, and nodular liver with splenomegaly, suggestive of moderate alcoholic cirrhosis. INTERVENTIONS: Liver protection therapy and the management of coagulation disorders. OUTCOMES: After 14 days, he was discharged with mild hemianesthesia but with more improved parameters in laboratory tests. At the 6 month follow-up, brain MRI, MRA, and non-contrast MRI showed no significant findings except for a malacic lesion. LESSONS: We conclude that the patient had alcoholic cirrhosis with coagulopathy, and this may have resulted in primary medullary hemorrhage. This is a first case to report alcoholic cirrhosis as etiology of primary medullary hemorrhage. PMID- 29620650 TI - Durable remission in a patient of mixed phenotype acute leukemia with Philadelphia chromosome-positive treated with nilotinib and lenalidomide: A case report. AB - RATIONALE: Philadelphia chromosome-positive mixed phenotype acute leukemia (Ph+ MPAL) is a rare type of leukemia with poor prognosis. Tyrosine kinase inhibitors (TKIs) in combination with chemotherapy have significantly improved its remission rate. However, relapse remains the major obstacle to achieve long survival. Lenalidomide is a second-generation oral immunomodulatory drug that has been broadly applied in the treatment of various hematological malignancies. PATIENT CONCERNS: A 54-year-old Chinese male patient who complained of chest pain and fatigue for 20 days. Bone marrow aspirate examination revealed hypercellularity with 70% blast cells. Flow cytometry analysis revealed that the blast cells exhibit both myeloid and lymphoid lineage antigens. Chromosomal analysis reveals t(9;22)(q34;q11) translocation. Minor BCR-ABL fusion gene was positive. DIAGNOSIS: Philadelphia chromosome-positive mixed phenotype acute leukemia. INTERVENTIONS: After relapsed from routine chemotherapy plus imatinib, the therapy was switched to oral therapy with nilotinib and lenalidomide due to his feeble condition. OUTCOMES: He successfully achieved long survival after oral therapy with nilotinib and lenalidomide. LESSONS: Combination of TKIs with lenalidomide may be an effective maintenance treatment regimen for Ph+ MPAL patients with minimal side effect. PMID- 29620651 TI - Treatment of giant cavernous aneurysm in an elderly patient via extracranial intracranial saphenous vein bypass graft in a hybrid operating room: A case report. AB - RATIONALE: Extracranial-intracranial saphenous vein bypass (EC-IC SVB) remains indispensable for treating giant cavernous aneurysms. We report an unusual case of a giant cavernous aneurysm in an elderly patient treated with EC-IC SVB in a hybrid operating room. Immediately following proximal ligation of the internal carotid artery (ICA), she suffered an acute intraoperative encephalocele. PATIENT CONCERNS: A 71-year-old woman had suffered from severe headache and double vision for 4 months. DIAGNOSES: The woman was diagnosed with a right giant cavernous aneurysm. INTERVENTIONS: She was treated with an EC-IC SVB with therapeutic ICA occlusion in the first biplane hybrid operating room in China. Just after proximal ligation of the ICA, she developed an acute encephalocele, and immediately underwent decompressive craniectomy. During the surgery she underwent 3 angiographic explorations. OUTCOMES: After surgery, the aneurysm disappeared, and the graft was patent. Postoperative computed tomography and computed tomography angiography indicated a cranial defect and graft patency. LESSONS: Although a hybrid operating room could improve the patency of grafts, the timing of ICA ligation for giant cavernous aneurysm via EC-IC bypass deserves further discussion. Second-stage ICA occlusion could offer an alternative for elderly patients requiring such treatment. In addition, cranial flap removal could prevent further neurologic deficits in a case of acute intraoperative encephalocele. PMID- 29620652 TI - Use of low-dose neostigmine intravenously in the treatment of thyroid storm induced severe tachycardia in patient during huge pelvic mass resection: A case report and review of literature. AB - RATIONALE: Thyroid storm is a rare and life-threatening metabolic crisis because of an emergent release of excess thyroid hormone. Sinus tachycardia induced by excess thyroid hormone may result in congestive heart failure due to decreased diastolic filling time. PATIENT CONCERNS: A controlled hyperthyroidism patient with severe sinus tachycardia. DIAGNOSES: A controlled hyperthyroidism patient was induced thyroid storm during huge pelvic mass resection. INTERVENTIONS: Application of low-dose neostigmine and beta-antagonist esmolol to control the heart rate (HR) avoided hemodynamic collapse. OUTCOMES: The patient improved dramatically following application of low-dose neostigmine instead of esmolol to control the HR avoided hemodynamic collapse. LESSONS: Our case suggests that neostigmine, an acetylcholinesterase inhibitor, may warrant further investigation in patients with thyroid storm-induced severe sinus tachycardia. PMID- 29620653 TI - Association between PRKAA1 rs13361707 T>C polymorphism and gastric cancer risk: Evidence based on a meta-analysis. AB - BACKGROUND: Recently, several published studies investigating the relationship between protein kinase catalytic subunit alpha-1 gene (PRKAA1) rs13361707 T>C polymorphism and gastric cancer (GC) susceptibility reported controversial results. The purpose of this meta-analysis was to estimate the strength of the relationship. METHODS: Qualified studies were identified form a comprehensive search conducted in the Embase, Pubmed, Wangfang, and China National Knowledge Infrastructure (CNKI) databases for studies published before February 12, 2018. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) were used to assess the relationship between the PRKAA1 rs13361707 T>C polymorphism and GC risk. RESULTS: Fifteen independent case-control studies, which included 14,615 GC patients and 18,143 control subjects, were included in this present meta analysis. The overall analysis of the 15 studies indicated that the PRKAA1 rs13361707 T>C polymorphism significantly increased susceptibility for GC in all genetic models. When stratified analysis was carried out by country and source of controls, similar results were found in each subgroup, except for the Hispanic Americans. There was no publication bias in our study. Omitting each study 1 at a time in the sensitivity analysis of the PRKAA1 rs13361707 T>C polymorphism and GC risk had no noticeable influence on the pooled OR, which identified the reliability of the meta-analysis. False-positive report probability analysis and trial sequential analysis demonstrated that such relationship was confirmed in the present study. CONCLUSIONS: The meta-analysis reveals that the PRKAA1 rs13361707 T>C polymorphism has a significant relationship with increased GC risk. To confirm the risk identified in the present meta-analysis, well-designed and large-scale case-control studies are warranted to investigate the relationship, especially among non-Asian ethnicity. PMID- 29620654 TI - Successful endoscopic removal of a rare, large impacted pancreatic duct stone using grasping forceps: A case report with video. AB - RATIONALE: As a main complication of chronic pancreatitis (CP), pancreatic duct stones (PDSs) are often associated with ductal obstruction resulting in increasing intraductal and parenchymal pressure and long-lasting pain. There are many methods for removing PDSs. However, for large stones, it is technically difficult to remove them entirely by endoscopic retrograde cholangiopancreatography (ERCP). PATIENT CONCERNS: A 57-year-old man presented with a chief complaint of severe epigastric pain radiating to his back 3 or 4 times annually for 2 years. DIAGNOSIS: The abdominal computed tomography scan revealed dilation of the proximal pancreatic duct with an irregular high-density calcification shadow located at the head of the pancreas. INTERVENTIONS: A pancreatic stent was placed initially by ERCP to relieve epigastric pain and alleviate symptom. Repeated ERCP was subsequently performed 2 months later to extract the impacted large pancreatic stone. OUTCOME: By using grasping forceps, the huge coralloid stone (272 * 0 mm) was successfully extracted in an en bloc manner. Then, a 7-French * 5 cm plastic pancreatic stent was placed for 2 weeks. The patient was free of any pancreatic pain during the 2-year follow-up. LESSONS: Generally, for large or impacted pancreatic stones, endoscopic removal is technically difficult to achieve. Pancreatic stenting can be an effective method of alleviating abdominal pain and facilitating subsequent endoscopic lithoextraction. Extraction of large stones with grasping forceps can be an alternative approach instead of extracorporeal shock wave lithotripsy or surgery when stones are impacted at the papilla's orifice and partially protruding into the duodenal lumen. PMID- 29620655 TI - Clinical characteristics and treatment outcomes in Camurati-Engelmann disease: A case series. AB - BACKGROUND: Camurati-Engelmann disease is an extremely rare disease characterized by hyperostosis of multiple long bones. This condition is caused by heterozygous mutations in the TGFB1 gene. METHODS: We describe the clinical and genetic characteristics of 4 Korean patients with this rare disease diagnosed at Asan Medical Center in Korea between June 2012 and May 2016, to increase awareness about this condition among general physicians and orthopedists. The presenting features, biochemical findings, radiographic and nuclear imaging findings, molecular analysis, and treatment outcomes of 4 patients were reviewed retrospectively. RESULTS: Two patients had sporadic disease, whereas the other 2 were familial cases. The average age at symptom onset was 8.8 +/- 5.5 (4-14) years. Symptoms included waddling gait or leg pain. Bone pain and easy fatigability were documented in all patients. Skeletal deformities such as osteoporosis, genu valgum, and severe scoliosis were observed. Visual and otologic manifestations presenting as exophthalmos, retinal detachment, and vestibulopathy were found in 3 patients. Skeletal survey showed diaphyseal expansion with diffuse cortical thickening of long bones in all patients. Bone scintigraphy images showed increased uptake of radioactive material in the calvarium and diaphysis of long bones. The mean erythrocyte sedimentation rate was 46.5 +/- 22.2 (20-72) mm/h. Sequence analysis of TGFB1 revealed the previously reported mutations p.Arg218His, p.Arg218Cys, and p.Glu169Lys. Corticosteroid was effective in relieving pain, and losartan was used as maintenance therapy. CONCLUSIONS: Our experience suggests that this rare condition can be suspected in patients with characteristic symptoms and skeletal findings. Considering the presence of effective medical treatment, efforts are needed to identify more cases. PMID- 29620656 TI - Reliability of radiographic measurement of lateral capitellohumeral angle in healthy children. AB - This retrospective cohort study was designed to validate the reliability of measurement of the lateral capitellohumeral angle (LCHA), an index of sagittal angulation of the elbow, in healthy children. The results were compared to the Baumann angle (BA), which is a similar concept to LCHA.Sixty-two radiographs of the elbow in healthy children (range, 2-11 years) were reviewed by 6 examiners at 2 sessions. The mean value and reliability of the measurement of LCHA and BA were assessed. Intraobserver reliability and interobserver reliability were calculated using intraclass correlation coefficients (ICCs).The mean LCHA value was 45 degrees (range, 22 degrees to 70 degrees ) and the mean BA was 71 degrees (range, 56 degrees to 86 degrees ). The ICCs for intraobserver reliability of the LCHA measurements were almost perfect for 2 examiners, substantial for 3 examiners, and moderate for 1 examiner with a mean value of 0.77 (range, 0.57 0.95). For BA measurements, the ICCs were almost perfect for 1 examiner and substantial for 5 examiners with a mean value of 0.74 (range, 0.66-0.83). The ICCs for interobserver reliability between the first and second measurements were both moderate for LCHA (0.56 and 0.51) and for BA (0.52 and 0.50).LCHA showed almost the same reliability in measurement as BA, which is the gold standard assessment for coronal alignment of the elbow. LCHA showed moderate-to-good reliability in the evaluation of sagittal plane elbow alignment. PMID- 29620657 TI - Fenofibrate monotherapy-induced rhabdomyolysis in a patient with hypothyroidism: A rare case report and literature review. AB - RATIONALE: Fenofibrate is a fibric acid derivative indicated for use in hypertriglyceridemia and mixed dyslipidemia treatment among adults. Rhabdomyolysis is a syndrome characterized by muscle necrosis and the release of intracellular muscle contents into the systemic circulation, which is the most serious and fatal side effect of fenofibrate. The objective of this paper is to discuss fatal side effect of fenofibrate and keep safe medication. PATIENT CONCERNS: A patient with hypothyroidism who presented with rhabdomyolysis during fenofibrate monotherapy for hypertriglyceridemia was reported. DIAGNOSES: Fenofibrate Monotherapy Induced Rhabdomyolysis. INTERVENTIONS: Fenofibrate was stopped. Adequate fluid resuscitation, mannitol diuresis, myocardium protection, hepatoprotection and urine alkalinization with sodium bicarbonate were performed. OUTCOMES: Blood tests were normal and the patient was good and discharged 2 weeks later. LESSONS: 13 cases associated with fenofibrate monotherapy-induced rhabdomyolysis were reviewed, which had been published in the English literature. The severity of fenofibrate muscle toxicity may be the result of the combination of two rhabdomyolysis enhancers, such as hypothyroidism and female gender. To avoid it, strict clinical and laboratory monitoring should be maintained, particularly hypothyroidism. Patients should be informed of possible potentially irreversible effects after taking fibrates. PMID- 29620658 TI - Scrotal Paragonimiasis in adults: Two case reports and review of literature. AB - RATIONALE: Paragonimiasis is a parasitic disease caused by Paragonimus in the lungs; it can be divided into intrapulmonary type and extrapulmonary type. Adult patients with scrotal paragnonimus are rarely seen clinically and not widely reported in the literature. Here, we report 2 cases of scrotal paragonimiasis in adults and their treatment process. PATIENT CONCERNS: Two young males sought medical advice because of scrotal masses. Both patients had the previous history of eating uncooked river crabs and presented with palpable quasicircular nodules of about 1.5 * 1.0 cm in testicles, which were well-defined, resilient in tenderness. The bilateral inguinal lymph nodes were not enlarged. DIAGNOSIS AND INTERVENTIONS: The 2 patients underwent scrotal mass resection; postoperative pathology examination confirmed scrotum paragonimiasis. Both the patients were administered praziquantel after operation. OUTCOMES: They were followed up for 1 year and 4 years, respectively; both recovered well, free from recurrence. Scrotum color Doppler ultrasound examination found no obvious abnormality. LESSONS: Adult patients with scrotum paragonimiasis are rarely seen clinically. Moreover, its clinical manifestations are not typical that leads to missed diagnosis and misdiagnosis. Diagnosis of the disease needs to combine with disease histories, manifestations, and relevant auxiliary examinations. But the diagnosis can be confirmed only by histopathological examination. The main method for treatment of scrotal paragonimiasis is antiparasitic treatment. However, health education is crucial to prevent this disease and relapse. PMID- 29620659 TI - Individualized pelvic lymphadenectomy should follow neoadjuvant concurrent chemoradiotherapy for locally advanced cervical cancer. AB - To study the outcomes following concurrent chemoradiotherapy (CCRT) and subsequent radical surgery for locally advanced cervical cancer (LACC), analyze the relationship between imaging-diagnosed and postoperative-diagnosed lymph node (LN) involvement, and identify patients who would benefit from individualized pelvic lymphadenectomy.We retrospectively reviewed records of 410 patients who underwent CCRT followed by radical surgery for International Federation of Gynecology and Obstetrics Stage Ib2-IIIb disease. Correlations of LN size on imaging before CCRT with pathological responses after CCRT, overall survival (OS), distant metastasis-free survival (DMFS), and complications were analyzed.During a median follow-up of 51.3 months, the respective 5-year OS and DMFS were 86.7% and 88.6%, respectively. Pathological primary tumor type, LN size on imaging before CCRT, and pathologic response after CCRT were independent prognostic factors for OS. Patients with a LN >=0.8 cm had a significantly higher residual carcinoma rate versus those with LN <0.8 cm (33% vs 22.6%, P = .032). Postoperative pathological positive LN frequencies differed significantly by LN size on imaging (LN <0.8 cm vs LN >=0.8 cm, 3% vs 19.3%, P < .0001). Grade 1-3 lower extremity edema occurred in 23.9% of cases; no grade 3-4 gastrointestinal and genitourinary toxicities were observed.CCRT followed by radical surgery for LACC yielded encouraging outcomes without unacceptable complications. Additionally, patients with a LN <0.8 cm on imaging before CCRT had a very low risk of postoperative pathological positive LN identification. Individualized pelvic lymphadenectomy (e.g., omitting or limiting the extent of LN dissection) might be an alternative option for some patients with a low risk of LN metastasis. PMID- 29620660 TI - Nurses' objective knowledge regarding venous thromboembolism prophylaxis: A national survey study. AB - Venous thromboembolism (VTE) is a common vascular disorder with high mortality and morbidity. Clinical nurses are a pivotal group that can serve as first-line health care providers. Lack of knowledge about VTE is an important barrier to effective nursing performance. This study aimed to determine nurses' knowledge of VTE prophylaxis through a nationwide survey across China, to understand gaps between current knowledge, and guidelines, and to help improve clinical nursing.The survey included 5 topics with 68 items on VTE, including basic knowledge, risk assessment, basic prophylaxis, physical prophylaxis, and pharmacological prophylaxis.The survey was distributed to 106 AAA-grade hospitals throughout China; 5218 valid questionnaires were submitted for analysis. There were 5097 women and 121 men respondents, with average age 30.29 +/- 8.60 years. The average rate of correct responses regarding VTE knowledge was 59.90 +/- 15.63%; 77.81% of subjects answered more than half of the survey items correctly. Better knowledge about thromboprophylaxis was observed among nurses who were more highly educated, more experienced, had received continuing education, intensive care unit (ICU), and lead nurses. Correct response rates were 68.39 +/- 17.03%, 60.35 +/- 21.01%, 75.51 +/- 22.85%, 41.72 +/- 17.47%, and 46.01 +/- 21.22% for basic knowledge, risk assessment, basic prophylaxis, physical prophylaxis, and pharmacological prophylaxis, respectively.Respondents showed satisfactory results regarding basic prophylaxis, basic knowledge, and risk assessment for VTE; respondents had poorer knowledge regarding physical and pharmacological prophylaxis. Better mastery of knowledge about thromboprophylaxis was observed among nurses who were more highly educated, more experienced, had received continuous education, ICU, and lead nurses.This study suggested that nurse trainers should develop comprehensive educational programs that focus on low correct rate aspects. Higher-level continuous education could improve nurses' knowledge of thromboprophylaxis. PMID- 29620661 TI - The combination of cisplatin and topotecan as a second-line treatment for patients with advanced/recurrent uterine cervix cancer. AB - We retrospectively reviewed outcomes of treatments with cisplatin and topotecan in patients with previously-treated uterine cervix cancer.We analyzed the medical records of patients with advanced (stage IVB) or recurrent or persistent squamous or non-squamous cell carcinoma of the cervix, who were treated with cisplatin and topotecan as a second-line chemotherapy between January 2000 and December 2015. The patients were treated with a combination of cisplatin (50 mg/m for 1 day) and topotecan (0.75 mg/m for 3 days) once every 3 weeks. Treatment response, progression-free survival (PFS), and overall survival (OS) were analyzed in all patients and between responder and non-responder groups (responders showed at least a partial response to prior systemic chemotherapy).Thirty-nine patients with a median age of 47 years (range, 32-73 years) were treated with cisplatin and topotecan. The median PFS was 4.6 months (95% confidence interval [CI], 1.2 7.9 months) and the median OS was 14.1 months (95% CI, 10.0-18.2 months). The overall response rate (ORR) was 30.8%, and the disease control rate was 56.4%. The ORR was significantly better in the responder group compared with the non responder group (50.0% vs 10.5%; P = .008). All patients reported some grade of hematological toxicity. The most frequently encountered toxicity was anemia, with a rate of 59.7% for any grade and 13.2% for grade 3 or 4.The combination of cisplatin and topotecan was effective as second-line chemotherapy in patients with advanced/recurrent uterine cervix cancer. PMID- 29620662 TI - Good outcomes after the delayed removal of an epidural hematoma: A case report. AB - RATIONALE: Epidural hematomas can develop following intrathecal puncture, spinal vascular malformation, or spontaneous hemorrhage. Prompt recognition of symptoms and referral to neurosurgical services are crucial for recovery. We report a rare case of delayed removal of an epidural hematoma that resulted in good patient outcomes. PATIENT CONCERNS: A 69-year-old woman weighing 58 kg presented with back pain that had persisted for 12 years. Her medical history was notable for hypertension. Cervical computed tomography angiography indicated a giant abdominal aortic aneurysm measuring 11.58 * 17.34 * 13.00 cm in her abdominal cavity. Stent graft implantation was scheduled by the interventional therapy group to treat her abdominal aortic aneurysm under single-dose spinal anesthesia. Postoperatively, the patient complained of numbness and swelling of her lower extremities, with progressive paralysis developing in both legs accompanied with sensory disturbances. DIAGNOSES: Delayed magnetic resonance imaging detected an epidural hematoma. INTERVENTIONS: Eighty hours after the onset of sensorimotor symptoms, lumbar decompression and removal of the hematoma were performed via laminectomy under general anesthesia. OUTCOMES: The patient was discharged 2 months after the operation with a 3/5 score on the Muscle Strength Grading System. LESSONS: Laminectomy may be effective in achieving a good prognosis despite a considerable delay in diagnosis. PMID- 29620663 TI - Effects of a low salt diet on isolated systolic hypertension: A community-based population study. AB - Evidence has shown that long-term sodium reduction can not only reduce blood pressure, but also provide cardiovascular benefits. To date, there is little evidence related to the effects of salt reduction on isolated systolic hypertension (ISH).A total of 126 hypertensive patients were divided into an ISH group (n = 51) and a non-ISH (NISH) group (n = 75). The members of each group were then randomly assigned to low sodium salt (LSSalt) or normal salt (NSalt) diets for 6 months. Their blood pressure was measured every 2 months. Serum plasma renin-angiotensin activity, blood biochemical assays and urinary measurements were determined at the baseline and at the end of the 6 months.At the end of the study, the mean systolic blood pressure (SBP) of the ISH LSSalt group had significantly decreased by 10.18 mm Hg (95% confidence interval (CI): 3.13 to 17.2, P = .006) compared with that of the ISH NSalt group, while the mean SBP only decreased by 5.10 mm Hg (95% CI: -2.02 to 12.2, P = .158) in the NISH LSSalt group compared with that of the NISH NSalt group. The mean diastolic blood pressure (DBP) had no significant differences in the ISH and NISH groups. No obvious renin angiotensin system activation was found after LSSalt intervention. Regarding the urinary excretion of electrolytes and blood biochemical assays, the LSSalt treatment had the same effects on the ISH group as on the NISH group.The present study showed that the SBP of ISH patients was significantly decreased with the LSSalt intervention, while neither the SBP of the NISH patients nor the DBP of either group were similarly decreased, which indicated that ISH patients were more sensitive to salt restriction. PMID- 29620664 TI - Adult renal neuroblastoma: A case report and literature review. AB - RATIONALE: Adult renal neuroblastoma (NB) is extremely rare, and there have been only a few cases previously described in the literature. We report a case of adult renal NB and summarize the clinical and imaging features of the reported cases. PATIENT CONCERNS: A 41-year-old female was admitted to our hospital with a chief complaint of gross hematuria that had persisted for a month. Nonenhanced computed tomography (CT) revealed a hypodense right renal mass without calcification. Enhanced CT showed an infiltrative, heterogeneously enhancing right renal mass with retrocaval lymphadenopathy and right renal vein thrombus. Magnetic resonance imaging (MRI) revealed that the right renal mass was isointense relative to the renal parenchyma on nonenhanced T1-weighted images; it showed mixed hypointensity and hyperintensity on T2-weighted images, and heterogeneous enhancement with a hyperintense rim on fat-saturated, enhanced T1W images. The initial impression was renal cell carcinoma (RCC). DIAGNOSES: Adult renal neuroblastoma. INTERVENTIONS: Right nephroureterectomy with lymph node dissection was performed. The pathology and immunohistochemistry confirmed the diagnosis of renal NB with retrocaval lymphadenopathy and retroperitoneal metastasis. OUTCOMES: After surgery, the patient received 6 courses of chemotherapy, and no recurrence was observed during a 24-month follow-up period. LESSONS: The clinical picture of adult renal NB is that of a 44-year-old woman, presenting with an abdominal or renal mass about 13cm in size, accompanied by hypertension, hematuria, or pain. In contrast to CT features described in previous literature, no tumor calcification is mentioned in these adult renal NB cases. It is difficult to differentiate renal NB from RCC based on CT or MRI. However, biopsy, urinary catecholamine levels, and metaiodobenzylguanidine (MIBG) scan may aid in presurgical diagnosis. PMID- 29620665 TI - Thera-Band application changes muscle activity and kyphosis and scapular winging during knee push-up plus in subjects with scapular winging: The cross-sectional study. AB - Scapular winging (SW) is defined as increased prominence of the whole medial border of the scapula. Many researchers recently recommended knee push-up plus (KPP) for enhancing serratus anterior (SA) activation. However, during push-up plus, thoracic kyphosis (TK) may usually occur as a compensatory movement. Thus, the purpose of this study was to investigate the effect of Thera-Band application during KPP on rectus abdominis (RA) activity, TK angle (TKA), SA activity, and amount of SW in subjects with SW.Fifteen subjects performed KPP with Thera-Band applied to different posterior body parts (no Thera-Band, in the occiput, and in the thoracic region). Electromyography was used to record the RA and SA activities. Image J software was used to calculate the compensatory TKA during KPP, and a scapulometer was used to measure SW in the quadruped position. One-way repeated-measures analysis of variance was used to test for significance.KPP with Thera-Band in the occiput showed significantly lower RA activity (P = .001) and TKA (P < .001) than KPP with no Thera-Band. SA activity (P = .020, P = .047) and SW (P < .001, P < .001) were significantly lower with Thera-Band applied to the occiput and thoracic regions than in KPP with no Thera-Band.Thera-Band applied to the occiput and thorax can be beneficial as it decreases RA and SA muscle activity and reduces TKA and SW during KPP in subjects with SW. PMID- 29620666 TI - Evaluation of the clinical value of hematological parameters in patients with urothelial carcinoma of the bladder. AB - This study aimed to evaluate the clinical significance of pretreatment red cell distribution width (RDW), monocyte/lymphocyte ratio (MLR), neutrophil/lymphocyte ratio (NLR), and platelet/lymphocyte ratio (PLR) in patients with urothelial carcinoma of the bladder (UCB).Hematological parameters of 127 consecutive patients with UCB and 162 healthy controls were retrospectively analyzed. Receiver operating characteristic curve was plotted to determine the optimal cut off value of RDW, MLR, NLR, and PLR to predict UCB. Whether these parameters could be independent predictors of UCB and had an association with the demographics and clinical characteristics of patients were also assessed.Patients with UCB had higher pretreatment RDW, MLR, NLR, and PLR compared with the healthy controls. With the tumor progression, MLR, NLR, and PLR rose consistently, whereas no significant difference was observed in RDW across tumor stages. NLR and PLR were associated with tumor size and tumor grade, while MLR was correlated with tumor size only. The best threshold of RDW, MLR, NLR, and PLR to predict UCB was 13.50%, 0.26, 2.16, and 128.46, respectively. Multivariate logistic regression model identified NLR >= 2.16 (odds ratio [OR] = 2.914; P < .001) and PLR >= 128.46 (OR = 2.761; P < .001) as independent predictors of UCB. High NLR and PLR were also associated with tumor markers, such as carcinoembryonic antigen and alpha-fetoprotein.Pretreatment NLR and PLR could be significant independent predictors of UCB. These simple and readily available inflammatory markers therefore might be used to manage the disease. PMID- 29620667 TI - Early plasma monocyte chemoattractant protein 1 predicts the development of sepsis in trauma patients: A prospective observational study. AB - Monocyte chemoattractant protein 1 (MCP-1) is an initiating cytokine of the inflammatory cascade. Extracellular MCP-1 exhibits pro-inflammatory characteristic and plays a central pathogenic role in critical illness. The purpose of the study was to identify the association between plasma MCP-1 levels and the development of sepsis after severe trauma.The plasma levels of MCP-1 in severe trauma patients were measured by a quantitative enzyme-linked immune sorbent assay and the dynamic release patterns were recorded at three time points during seven days post-trauma. The related factors of prognosis were compared between sepsis and non-sepsis groups and analyzed using multivariate logistic regression analysis. We also used receiver operating characteristic (ROC) curves to assess the values of different variables in predicting sepsis.A total of 72 patients who met criteria indicative of severe trauma (72.22% of male; mean age, 49.40 +/- 14.29 years) were enrolled. Plasma MCP-1 concentrations significantly increased on post-trauma day 1 and that this increase was significantly correlated with the Injury Severity Score (ISS) and interleukin-6 (IL-6). Multivariate logistic regression analysis showed that early MCP-1, ISS, and IL-6 were independent risk factors for sepsis in severe trauma patients. Incorporation of the early MCP-1 into the ISS can increase the discriminative performance for predicting development of sepsis.Early plasma MCP-1 concentrations can be used to assess the severity of trauma and is correlated with the development of sepsis after severe trauma. The addition of the early MCP-1 levels to the ISS significantly improves its ability to predict development of sepsis. PMID- 29620668 TI - How to treat the combination of coronary artery fistula and occluded coronary artery: A case report. AB - RATIONALE: Coronary artery fistulae (CAF) are uncommon and are reported in 0.25% of patients undergoing routine coronary angiography. The combination of severe coronary artery disease and a CAF was rare. PATIENT CONCERNS: A 76-year-old man presented unstable angina. DIAGNOSES: Coronary angiography showed a subtotal occlusion lesion and a CAF at left anterior descending artery. INTERVENTIONS: The combination of transcatheter coil embolization and a drug-eluting stent was used for this problem. OUTCOMES: The patient was symptom-free and had regularly followed up as an outpatient for three years. LESSONS: The combination of a CAF and atherosclerotic change in the same site of the coronary artery is unique. It is feasible to solve the combination of CAF and severe coronary atherosclerotic lesion by transcatheter coil embolization and stent implantation. A big case series study is necessary to evaluate the safety and efficacy of the technique of transcatheter coil embolization and stent implantation in the patients with severe coronary atherosclerotic lesion and a CAF. PMID- 29620669 TI - Detection and genotyping of human papillomavirus (HPV) in HIV-infected women and its relationship with HPV/HIV co-infection. AB - HPV have been identified as high-risk and low-risk, depending on their association with the development of cancer. HPV infections can be facilitated by co-infection with HIV. Here, we investigated HPV prevalence and genotypes and the risk factors affecting HPV/HIV co-infection. Forty HIV-positive patients had 80 cervical swab samples collected in 2 consecutive years. Polymerase chain reaction and DNA direct sequencing were used to perform HPV genotyping. Statistical analyses were performed regarding risk factors for HPV/HIV co-infection and the occurrence of cervical lesions. HPV DNA was detected in 59 samples (73.75%), and high-risk HPVs were predominant (59.3%). The most prevalent type was HPV56 (17%), followed by HPV16 (15.3%). Patient age did not affect the risk of cervical cancer (P = .84) or HPV prevalence in different years (P = .25/P = .63). CD4 count also did not affect the risk for cervical lesions in the tested samples (P = .15/P = .28). Although the HIV viral load was not correlated with an increase in cervical lesion detection in the first group of analyzed samples (P = .12), it did affect cervical cancer risk in the group of samples analyzed in the following year (P = .045). HIV-infected patients presented a high prevalence of HPV co-infection, and HPV16 and HPV56 were the most prevalent genotypes. Considering this, it is possible that immunodeficiency can contribute to increased susceptibility to HPV56 infection in HIV-infected patients. The association between HIV viral load and the lesions also confirmed the importance of monitoring HIV/HPV co-infected patients with high HIV viral loads. PMID- 29620670 TI - Effectiveness of multiple therapeutic strategies in neovascular glaucoma patients: A PRISMA-compliant network meta-analysis. AB - PURPOSE: Neovascular glaucoma (NVG) is a severe secondary glaucoma with uncontrolled intraocular pressure that leads to serious eye pain and vision loss. Presently, the therapeutic strategies for NVG are diverse, but the therapeutic effects are still not ideal. We performed a network analysis to assess the effect of multiple therapeutic strategies on the treatment of NVG patients. METHODS: We searched public electronic databases through April 2017 using the following keywords "neovascular glaucoma," "iris neovascularization," "hemorrhagic glaucoma," and "random" without language restrictions. The outcome considered in the present analysis was treatment success rate. A network meta-analysis and multilevel mixed-effects logistic regression were used to compare regimens. RESULTS: We included 27 articles assessing a total of 1884 NVG patients in our analysis. According to the network analysis, interferon and mitomycin plus trabeculectomy (94.9%), glaucoma valve implantation (86.9%), and iris photocoagulation plus trabeculectomy (81.9%) were the most likely to improve treatment success rate in NVG patients. The multilevel logistic regression analysis showed that glaucoma valve, bevacizumab, interferon, cyclophotocoagulation, trabeculectomy, iris photocoagulation, ranibizumab, and mitomycin had advantages in terms of improving treatment success rate in NVG patients. However, the application of retinal photocoagulation and vitrectomy reduced patient treatment success rate. CONCLUSION: The regimen including mitomycin, interferon, and trabeculectomy was the most likely to improve the treatment success rate in NVG patients. The application of glaucoma valve and bevacizumab were more beneficial for improving patient treatment success rate as a surgery and as an agent, respectively. PMID- 29620671 TI - Intraplacental choriocarcinoma coexisting with fetomaternal hemorrhage: Case report, chemotherapy management, and literature review. AB - RATIONALE: Near-term intraplacental choriocarcinoma (IC) coexisting with massive fetomaternal hemorrhage (FMH) is rare, and its clinical course is poorly understood. Here, we report a new case from our hospital, with detailed discussion and literature review. PATIENT CONCERNS: A 21-year-old Chinese female at 35 weeks gestation was admitted to our hospital due to reduced fetal movement. Near-term IC coexisting with massive FMH was diagnosed after delivery. INTERVENTION: The mother and infant were followed 3 months after delivery. Beta human chorionic gonadotropin (beta-HCG), pathological examination of the placenta, and computed tomography scans were performed for the mother and beta HCG was performed for the infant. OUTCOMES: The mother's beta-HCG serum level increased from 31,280 IU/L (6 days postdelivery) to 192,070 IU/L (49 days postdelivery), and then steadily fell to 42,468 IU/L (3 months postdelivery) without chemotherapy. The mother died from metastasis and cerebral hemorrhage. The infant survived and his beta-HCG serum level fell to within the normal range without chemotherapy. LESSONS: FMH associated with near-term IC is a rare disease. Measurement of maternal beta-HCG may therefore represent a useful parameter when IC is a possible differential diagnosis. A pathological examination of the placenta should be performed in all cases of FMH to better identify cases of IC. Future research should aim to develop methods of identifying which patients with IC should receive chemotherapy, whether we should use single- or multiagent chemotherapies, and whether there is a positive correlation between chemotherapy regimen and beta-HCG serum levels. PMID- 29620672 TI - Beyond the Lamppost: A Proposal for a Fourth Wave of Education for Collaboration. AB - Interprofessional education (IPE) is an increasingly popular educational model that aims to educate health care students to be better collaborators by enabling them to learn with, from, and about each other. IPE's rising popularity is evident in the increase in scholarship on this topic over the last few decades. In this Perspective, the authors briefly describe three historical "waves" of IPE: managing the health workforce through shared curriculum, maximizing population health through health workforce planning, and fixing individuals to fix health care. Using insights from the social sciences and past practice, they then discuss six reasons why the current third wave of IPE is likely to fall short of meeting its goals, including that (1) IPE is logistically complex and costly, (2) IPE is developmentally inappropriate, (3) the link between IPE and key outcomes is still missing, (4) IPE insufficiently engages with theory, (5) IPE rarely addresses power and conflict, and (6) health care is an inertial system that IPE is unlikely to change. The authors conclude by sharing their vision for a fourth wave of education for collaboration, addressing workplace systems and structures, which would combine undergraduate, uniprofessional education for collaboration with practice-based interventions. PMID- 29620673 TI - National Internal Medicine Milestone Ratings: Validity Evidence From Longitudinal Three-Year Follow-up. AB - PURPOSE: To evaluate validity evidence for internal medicine milestone ratings across programs for three resident cohorts by quantifying "not assessable" ratings; reporting mean longitudinal milestone ratings for individual residents; and correlating medical knowledge ratings across training years with certification examination scores to determine predictive validity of milestone ratings for certification outcomes. METHOD: This retrospective study examined milestone ratings for postgraduate year (PGY) 1-3 residents in U.S. internal medicine residency programs. Data sources included milestone ratings, program characteristics, and certification examination scores. RESULTS: Among 35,217 participants, there was a decreased percentage with "not assessable" ratings across years: 1,566 (22.5%) PGY1s in 2013-2014 versus 1,219 (16.6%) in 2015-2016 (P = .01), and 342 (5.1%) PGY3s in 2013-2014 versus 177 (2.6%) in 2015-2016 (P = .04). For individual residents with three years of ratings, mean milestone ratings increased from around 3 (behaviors of an early learner or advancing resident) in PGY1 (ranging from a mean of 2.73 to 3.19 across subcompetencies) to around 4 (ready for unsupervised practice) in PGY3 (mean of 4.00 to 4.22 across subcompetencies, P < .001 for all subcompetencies). For each increase of 0.5 units in two medical knowledge (MK1, MK2) subcompetency ratings, the difference in examination scores for PGY3s was 19.5 points for MK1 (P < .001) and 19.0 for MK2 (P < .001). CONCLUSIONS: These findings provide evidence of validity of the milestones by showing how training programs have applied them over time and how milestones predict other training outcomes. PMID- 29620674 TI - I Am an African American: Distinguishing Between African American and African Applicants in Medical School Admissions Matters. AB - Ignoring the diverse and rich cultures and histories of Africa and the African diaspora by applying the term African American to anyone of sub-Saharan African ancestry in medical school admissions does a disservice to applicants, medical schools, and the communities they serve. To determine how applicants can contribute to a diverse educational environment, admissions decisions must go beyond racial and ethnic self-reporting and recognize the diversity that applicants bring to their medical school. Using a holistic approach, institutions can fairly evaluate applicants and strategically fill their incoming classes. What each medical school is looking for based on its mission and how each student reflects that mission and enhances the educational environment should be revisited as each application is considered. Medical schools must adopt practices that strategically enroll applicants who help achieve their mission and better the communities they serve. The benefits of diversity are not achieved in a linear fashion but require a critical mass for each diverse group. Different strategies are needed to enhance the educational environment, address underrepresentation in medicine, and eliminate health disparities. If racial justice and health equity are to be realized, diversity policies need to recognize the differences between African and Afro Caribbean immigrants and African Americans.In this Perspective, the author argues for distinguishing between these groups in medical school admissions. He explores the differences in their history, culture, and experiences and demonstrates their uniqueness. He concludes by discussing diversity in medicine and offering suggestions for considering diversity in medical school admissions. PMID- 29620676 TI - Hepatitis-associated Aplastic Anemia Treated Successfully With Antithymocyte Globulin. AB - Hepatitis-associated aplastic anemia (HAAA) is a variant of acquired aplastic anemia in which bone marrow failure follows the development of an acute episode of seronegative hepatitis. HAAA occurs most frequently in male children and is lethal if left untreated. Antilymphocyte globulin, antithymocyte globulin, and allogeneic bone marrow transplantation have been used in the treatment of this disease. In this work, we report the case of a 3-year-old boy with HAAA treated successfully with immunosuppressive therapy. PMID- 29620675 TI - Educational Interventions to Improve Handover in Health Care: An Updated Systematic Review. AB - PURPOSE: Effective handovers (handoffs) are vital to patient safety. Medical educators investigated educational interventions to improve handovers in a 2011 systematic review. The number of publications on handover education has increased since then, so authors undertook this updated review. METHOD: The authors considered studies involving educational interventions to improve handover amongst undergraduate or postgraduate health professionals in acute care settings. In September 2016, two authors independently conducted a standardized search of online databases and completed a data extraction and quality assessment of the articles included. They conducted a content analysis of and extracted key themes from the interventions described. RESULTS: Eighteen reports met the inclusion criteria. All but two were based in the United States. Interventions most commonly involved single-patient exercises based on simulation and role play. Many studies mentioned multiprofessional education or practice, but interventions occurred largely in single-professional contexts. Analysis of interventions revealed three major themes: facilitating information management, reducing the potential for errors, and improving confidence. The majority of studies assessed Kirkpatrick's outcomes of satisfaction and knowledge/skill improvement (Levels 1 and 2). The strength of conclusions was generally weak. CONCLUSIONS: Despite increased interest in and publications on handover, the quality of published research remains poor. Inadequate reporting of interventions, especially as they relate to educational theory, pedagogy, curricula, and resource requirements, continues to impede replication. Weaknesses in methodologies, length of follow-up, and scope of outcomes evaluation (Kirkpatrick levels) persist. Future work to address these issues, and to consider the role of multiprofessional and multiple-patient handovers, is vital. PMID- 29620677 TI - A Case of Ataxia-telangiectasia Presented With Hemophagocytic Syndrome. AB - Ataxia-telangiectasia (A-T) is a multisystem disease caused by a genetic defect located on the long arm of chromosome 11 (11p22-23). The gene defect results in the loss of A-T-mutated protein, subsequently leading to unrepaired DNA fractures and defects in the signal transduction pathway. As a result, characteristic findings arise, including recurrent sinopulmonary infections, hypersensitivity against ionized radiation with the tendency to develop cancer related to progressive cerebellar ataxia, pathognomonic oculocutaneous telangiectasias, varying degrees of humoral and cellular immunodeficiency, and infertility. This case report presents a 3-year-old male patient with A-T who developed hemophagocytic syndrome. To the best of our knowledge, no such case has been previously reported. PMID- 29620678 TI - Quantitative Ultrasound of Proximal Phalanxes in Childhood Acute Lymphoblastic Leukemia Survivors. AB - Reduced bone mineral density (BMD) is a well-known complication in childhood acute lymphoblastic leukemia (ALL) survivors; the optimal method to assess BMD is still debated. We studied BMD by quantitative ultrasound (QUS) in 72 ALL survivors, and evaluated any correlation with cumulative doses of steroids and cytotoxic agents. Mean age at diagnosis was 61+/-45 months, while mean age at QUS was 318.3+/-129.6 months; mean period of follow-up was 41.2+/-37.8 months. Mean amplitude-dependent speed of sound z-score was -1.22+/-1.19. Ten survivors (13.8%) presented a z-score below -2 SD. A negative correlation was found between amplitude-dependent speed of sound z-score and age at diagnosis (P=0.01). A positive correlation was observed with length of follow-up (P=0.01). No correlation was found with cytotoxic drugs. This study represents the largest cohort of childhood ALL survivors studied by QUS. Our results suggest that QUS for its characteristics of being radiation free may be an effective option to assess BMD in pediatric age. In addition, our data outline the importance to improve the awareness about the specific expression of this complication in the pediatric age, concerning the major determinants of bone impairment, which are the disease itself and the phase of bone growth when the disease occurs. PMID- 29620679 TI - Diagnostic Accuracy of 18F-FDG PET/CT in the Staging and Assessment of Response to Chemotherapy in Children With Ewing Sarcoma. AB - INTRODUCTION: The purpose of this study was to evaluate the potential role of fluorine-18 fluorodeoxyglucose (18F-FDG) positron-emission tomography/computed tomography (PET-CT) in the staging and assessment of chemotherapy response in Ewing sarcoma. MATERIALS AND METHODS: For 13 patients with Ewing sarcoma, whole body FDG PET-CT was assessed for site of primary disease, disease extent, and response to therapy. Chest CT, localized magnetic resonance imaging or CT of primary site, and bone scintigrams were evaluated for imaging features of the primary lesion and presence or absence of metastatic disease. Response to therapy was also assessed. Descriptive statistics are reported. RESULTS: Nine patients (69%) presented metastatic disease. All metastatic lung lesions were detected by spiral CT, but some failed to be detected using FDG PET-CT. As regards bone lesions, both FDG PET-CT and bone scans were able to identify bone metastasis, but FDG PET-CT identified more lesions than bone scans. All PET-CT scans at the end of the neoadjuvant chemotherapy showed a decreased FDG uptake. CONCLUSIONS: FDG PET-CT seems to be superior to bone scan in the detection of bone metastasis in all districts except skull bones. For pulmonary metastasis smaller than 7 mm, FDG PET-CT is less sensitive than CT. FDG PET-CT may have an important role in initial staging of Ewing sarcoma and subsequent evaluation of response to therapy. PMID- 29620680 TI - Triptorelin for Fertility Preservation in Adolescents Treated With Chemotherapy for Cancer. AB - BACKGROUND: Triptorelin, a gonadotropin releasing hormone analogue, can be administered to postpubertal female individuals with cancer who receive chemotherapy to obtain menstrual suppression and decrease the risk of hemorrhage caused by thrombocytopenia. Our goal was to assess whether triptorelin also has a protective role against the gonadotoxicity of chemotherapy. PATIENTS AND METHODS: This retrospective observational study includes all postmenarchal female patients who presented to our Unit from 2000 to 2015 and received chemotherapy for cancer. They were administered depot triptorelin. We evaluated long-term ovarian function in order to detect clinical signs of ovarian damage, miscarriages, and pregnancies. Laboratory follow-up consisted in dosing serum follicle stimulating hormone, luteinizing hormone, prolactin, estradiol, and progesterone. Ultrasound of the ovaries was performed as well. RESULTS: Of 36 evaluable patients, 9 received hematopoietic stem cell transplantation (HSCT). The remaining 27 patients maintained normal ovarian function at clinical, laboratory, and ultrasound assessment. Five of them achieved spontaneous physiological pregnancy. Four of the 9 patients who underwent HSCT developed premature ovarian failure. CONCLUSION: Our study suggests that gonadotropin releasing hormone-a administered during chemotherapy can prevent premature ovarian failure in patients treated without HSCT and that it is not enough to preserve the ovarian function during HSCT. Hence, a prospective randomized trial with a larger population would be recommended. PMID- 29620681 TI - "Immune" Thrombocytopenia as Key Feature of a Novel ADA2 Deficiency Variant: Implication on Differential Diagnostics of ITP in Children. AB - Thrombocytopenia presenting during early childhood is most commonly diagnosed as immune/idiopathic thrombocytopenic purpura (ITP), where the antibody-mediated destruction of thrombocytes is often transient. If treatment is indicated, the majority of patients respond to immune-modulation by intravenous immunoglobulin G infusion or systemic corticosteroids. Differential diagnoses to childhood ITP includes thrombocytopenia due to infections, drugs, rheumatologic conditions, immune dysregulation, and inherited bone marrow failures, for example, congenital amegakaryocytic thrombocytopenia. Isolated thrombocytopenia in an otherwise healthy appearing child that recurs after therapy and/or persists suggest a differential diagnosis rather than ITP. We present a case of symptomatic thrombocytopenia in a 2-year-old girl associated with adenosine deaminase deficiency. PMID- 29620682 TI - GATA2 Deficiency Due to de Novo Complete Monoallelic Deletion in an Adolescent With Myelodysplasia. AB - GATA2 deficiency is an inherited bone marrow failure syndrome that can manifest with myelodysplasia (myelodysplastic syndrome) with chromosomal aberrations and high risk of evolution to leukemia (particularly, acute myeloid leukemia); immunodeficiency with opportunistic infections; and/or lymphedema. It can be transmitted in families in autosomal-dominant fashion, or present de novo as sporadic disease in adults or children. The authors report a case of an adolescent male with features of GATA2 deficiency resulting from a complete monoallelic deletion, review chromosomal anomalies associated with this disorder, and discuss the management implications. PMID- 29620683 TI - X-Linked Severe Combined Immunodeficiency and Hepatoblastoma: A Case Report and Review of Literature. AB - Severe combined immunodeficiency is an inherited disease with profoundly defective T cells, B cells, and natural killer cells. X-linked severe combined immunodeficiency is the most common form. In this report, we describe a 4-month old male infant who was admitted to our hospital with progressive breathlessness and abdominal mass. He was diagnosed with hepatoblastoma and presented a pneumocystis jirovecii pneumonia at the beginning of chemotherapy. Definitive diagnosis of X-linked severe combined immunodeficiency was established by DNA analysis of the interleukin 2 receptor gamma chain gene. This case is the first report which describes an X-linked severe combined immunodeficiency patient with hepatoblastoma. PMID- 29620684 TI - Neutropenia and Increased Mean Corpuscular Volume (MCV) With Abnormal Neurological Findings: A Case of Cobalamin D Deficiency. AB - BACKGROUND: Disorders of intracellular cobalamin (Cbl) metabolism are classified from A to J according to biochemical phenotype, and genetic and complementation analyses. CblD-deficient patients present with developmental, hematologic, neurologic, and metabolic findings. CLINICAL OBSERVATION: An 11-year-old boy presented with neutropenia, increased mean corpuscular volume, psychomotor retardation, and seizures. His plasma total homocysteine and urinary methylmalonic acid levels were elevated, and a homozygous nonsense mutation [p. R250X (c.748C>T] leading to premature termination of translation was identified in the MMADHC gene, which was compatible with CblD defect. CONCLUSION: In the presence of increased mean corpuscular volume and other hematologic manifestations, such as leukopenia, thrombocytopenia, and megaloblastic anemia, with severe nonspecific or mild neurological symptoms, Cbl synthesis defects should be considered. PMID- 29620685 TI - EBV-PTLD, Adenovirus, and CMV in Pediatric Allogeneic Transplants With Alemtuzumab as Part of Pretransplant Conditioning: A Retrospective Single Center Study. AB - The risk of viral infections and reactivation occurring in the setting of pediatric allogeneic hematopoietic stem cell transplantation is a concern in the pediatric patient, especially with the use of Alemtuzumab (Campath) as a conditioning agent. The purpose of this study was to determine the incidence of Epstein-Barr virus posttransplant lymphoproliferative disorder (EBV-PTLD), cytomegalovirus (CMV), and adenovirus among pediatric recipients of alemtuzumab at our institution. We found that EBV-PTLD occurred in 2.1% of transplants (1 matched unrelated donor [MUD] recipient), CMV reactivation occurred in 12.5% of transplants (4 MUD and 2 matched related donor [MRD] recipients) with disseminated CMV in 2.1% of cases (1 MRD recipient), and adenovirus infection occurred in 8.3% of the total transplants (2 MUD and 2 MRD recipients). Alemtuzumab continues to be used as a method of graft-versus-host disease and graft failure prevention among pediatric recipients of hematopoietic stem cell transplantation and seems to be safer than previously reported. At our institution, alemtuzumab has not increased the risk for EBV-PTLD, CMV infection, or adenovirus. PMID- 29620687 TI - Size as an Important Determinant of Chest Blow-induced Commotio Cordis. AB - PURPOSE: Commotio cordis is sudden cardiac death caused by a relatively innocent blow to the left chest wall. Adolescents account for the majority of the cases; whether this is due to the higher frequency of adolescents playing ball sports or whether there is some maturational reduction of risk is not known. METHODS: In a swine model of commotio cordis, the effect of body weight/size (directly related to age) to the susceptibility of chest impact-induced ventricular fibrillation (VF) is examined. METHODS: Ball impacts were delivered at escalating velocities from 48.3 to 96.9 km.h (30-60 mph) to 128 swine ranging in weight from 5 to 54 kg. RESULTS: VF occurred in 29% of impacts to the smallest animals compared with 34% in the 14- to 239-kg group, 27% in the 24- to 33.9-kg group, 30% in 34- to 43 kg group, and 15% in the 44- to 54-kg animals. The highest-weight group was associated with a significantly lower incidence of VF compared with other weights (P = 0.002). In a multivariate logistic regression analysis, controlling for repeated measures, four variables predicted VF: body weight (P = 0.0008), velocity (P < 0.0001), distance from the center of the heart, (P < 0.0001), and peak left ventricular pressure induced by the blow (P = 0.0007). CONCLUSIONS: In this experimental model, animals weighing <44 kg seem to have a similar susceptibility to commotio cordis, whereas animals weighing >=44 kg have a lower susceptibility. An increase in size of the individual, rather than reduced play of ball sports, is the likely reason for the decreased commotio cordis incidence in older individuals. PMID- 29620686 TI - Physiological and Functional Alterations after Spaceflight and Bed Rest. AB - INTRODUCTION: Exposure to microgravity causes alterations in multiple physiological systems, potentially impacting the ability of astronauts to perform critical mission tasks. The goal of this study was to determine the effects of spaceflight on functional task performance and to identify the key physiological factors contributing to their deficits. METHODS: A test battery comprised of seven functional tests and 15 physiological measures was used to investigate the sensorimotor, cardiovascular, and neuromuscular adaptations to spaceflight. Astronauts were tested before and after 6-month spaceflights. Subjects were also tested before and after 70 d of 6 degrees head-down bed rest, a spaceflight analog, to examine the role of axial body unloading on the spaceflight results. These subjects included control and exercise groups to examine the effects of exercise during bed rest. RESULTS: Spaceflight subjects showed the greatest decrement in performance during functional tasks that required the greatest demand for dynamic control of postural equilibrium which was paralleled by similar decrements in sensorimotor tests that assessed postural and dynamic gait control. Other changes included reduced lower limb muscle performance and increased HR to maintain blood pressure. Exercise performed during bed rest prevented detrimental change in neuromuscular and cardiovascular function; however, both bed rest groups experienced functional and balance deficits similar to spaceflight subjects. CONCLUSION: Bed rest data indicate that body support unloading experienced during spaceflight contributes to postflight postural control dysfunction. Further, the bed rest results in the exercise group of subjects confirm that resistance and aerobic exercises performed during spaceflight can play an integral role in maintaining neuromuscular and cardiovascular functions, which can help in reducing decrements in functional performance. These results indicate that a countermeasure to mitigate postflight postural control dysfunction is required to maintain functional performance. PMID- 29620690 TI - Angioedema Caused by Rivastigmine Patch: A Rare Case. PMID- 29620688 TI - Effects of Branched-Chain Amino Acid Supplementation on Spontaneous Seizures and Neuronal Viability in a Model of Mesial Temporal Lobe Epilepsy. AB - BACKGROUND: The essential branched-chain amino acids (BCAAs) leucine, isoleucine, and valine have recently emerged as a potential novel treatment for medically refractory epilepsy. Blood-derived BCAAs can readily enter the brain, where they contribute to glutamate biosynthesis and may either suppress or trigger acute seizures. However, the effects of BCAAs on chronic (ie, spontaneous recurrent) seizures and epilepsy-associated neuron loss are incompletely understood. MATERIALS AND METHODS: Sixteen rats with mesial temporal lobe epilepsy were randomized into 2 groups that could drink, ad libitum, either a 4% solution of BCAAs in water (n=8) or pure water (n=8). The frequency and relative percent of convulsive and nonconvulsive spontaneous seizures were monitored for a period of 21 days, and the brains were then harvested for immunohistochemical analysis. RESULTS: Although the frequency of convulsive and nonconvulsive spontaneous recurrent seizures over a 3-week drinking/monitoring period were not different between the groups, there were differences in the relative percent of convulsive seizures in the first and third week of treatment. Moreover, the BCAA-treated rats had over 25% fewer neurons in the dentate hilus of the hippocampus compared with water-treated controls. CONCLUSIONS: Acute BCAA supplementation reduces seizure propagation, whereas chronic oral supplementation with BCAAs worsens seizure propagation and causes neuron loss in rodents with mesial temporal lobe epilepsy. These findings raise the question of whether such supplementation has a similar effect in humans. PMID- 29620691 TI - Do Antipsychotics "Thin" the Brain?: It Is a Rather Gray Matter. PMID- 29620692 TI - Efficacy and Safety of Agomelatine vs Paroxetine Hydrochloride in Chinese Han Patients with Major Depressive Disorder: A Multicentre, Double-Blind, Noninferiority, Randomized Controlled Trial. AB - PURPOSE: The purpose of this study is to investigate the efficacy, safety, and tolerability of agomelatine and paroxetine in Chinese Han patients with major depressive disorder (MDD). METHODS: A 8-week, double-blind, randomized, parallel study was conducted in 14 medical centers in mainland China from December 2011 to September 2012. A total of 264 subjects with a primary Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition diagnosis of MDD were randomly assigned to receive agomelatine 25-50 mg/d (n = 132) or paroxetine 20-40 mg/d (n = 132). The primary efficacy was evaluated by the decrease of Hamilton Depression Rating Scale (HAM-D17) scores. The secondary measurements of efficacy included Hamilton Anxiety Rating Scale, Montgomery-Asberg Depression Rating Scale, Sheehan Disability Scale, Clinical Global Impressions-Severity, and Clinical Global Impressions-Improvement. The laboratory test abnormity, and observed and self reported adverse events were all assessed as the measurements of safety and tolerability. RESULTS: Both the agomelatine and paroxetine groups showed significant improvement from baseline to the end point (P < 0.05) without between group differences (P > 0.05). The mean decrease of HAM-D17 of agomelatine group was not inferior to the paroxetine group over the 8-week treatment (agomelatine 15.26 +/- 6.44 vs paroxetine 14.87 +/- 5.89, delta = 2.0; MUA-MUB 95% confidence interval, -1.13 to 1.91). The percentage of responders at the last postbaseline assessment was similar in the 2 groups on both HAM-D17 (agomelatine 66.15% vs paroxetine 63.49%) and Clinical Global Impressions-Improvement (agomelatine 79.09% vs paroxetine 80.36%). The anxiety (Hamilton Anxiety Rating Scale) and sleep symptoms (sleep items of HAM-D17) of the patients were improved significantly in the 2 groups at week 8 without between-group differences (P > 0.05). The incidence of overall adverse events was similar in the 2 groups (agomelatine 49.62% vs paroxetine 56.15%, P > 0.05). The incidence of adverse events in skin and subcutaneous tissue was higher in the paroxetine group than in the agomelatine group (none in agomelatine and 4.62% in paroxetine, P = 0.0144). CONCLUSIONS: Agomelatine showed equivalent antidepressant efficacy to paroxetine in treating MDD patients after 8 weeks of treatment with an acceptable safety. PMID- 29620693 TI - Longer-Term Effectiveness and Tolerability of Adjunctive Open Lurasidone in Patients With Bipolar Disorder. AB - PURPOSE: To retrospectively assess lurasidone effectiveness/efficacy/tolerability in bipolar disorder (BD) patients. METHODS: Outpatients assessed with Systematic Treatment Enhancement Program for BD Affective Disorders Evaluation received naturalistically administered (primarily adjunctive) open lurasidone while monitored at visits with the Systematic Treatment Enhancement Program for BD Clinical Monitoring Form. RESULTS: Sixty-one patients (32 type I, 26 type II, 3 type not otherwise specified; mean +/- SD age, 45.1 +/- 14.0 years; 63.9% were female) received lurasidone with 3.1 +/- 1.4 (>=2 in 88.5%, monotherapy in only 3.3%) other nonanxiolytic/hypnotic prescription psychotropics, started during syndromal depression in 57.4%, subsyndromal depression in 23.0%, and euthymia in 19.7%. Lurasidone was taken for median 126 days, with final dose 55.6 +/- 30.8 mg/d. By final visit taking lurasidone, syndromal depression rate decreased by nearly one-half to 31.1%, and euthymia rate more than doubled to 42.6%, whereas subsyndromal depression rate was unchanged at 23.0%. Clinical Global Impressions BD-Overall Severity improved significantly only in patients with baseline syndromal depression. Seventy-seven percent of patients discontinued lurasidone after median 103 days, because of adverse events in 54.1% (most often akathisia, sedation/somnolence, nausea, and weight gain), inefficacy in 16.4%, and other reasons in 6.6%; 12.1% had equal to or greater than 7% weight gain, and 3.3% developed hypomania. Limitations to this study were the open design and demographically homogeneous (relatively affluent, predominantly white female) small sample taking complex pharmacotherapy. CONCLUSIONS: In American specialty clinic BD outpatients, adjunctive longer-term lurasidone commonly relieved syndromal depression and maintained euthymia, suggesting possible effectiveness/efficacy. However, lurasidone was discontinued in 54.1% because of adverse events, suggesting tolerability limitations in these challenging patients, nearly 90% of whom were already taking at least 2 other nonanxiolytic/hypnotic prescription psychotropics. PMID- 29620694 TI - Genetic Polymorphisms Associated With Constipation and Anticholinergic Symptoms in Patients Receiving Clozapine. AB - BACKGROUND: Clozapine impairs gastrointestinal motility owing to its anticholinergic and antiserotonergic properties. This commonly leads to constipation and potentially to more severe complications such as bowel obstruction and ischemia. The aim of this study was to determine whether genetic variations in the genes encoding muscarinic and serotonergic receptors (CHRM2, CHRM3, HTR2, HTR3, HTR4, and HTR7) explain the variations in incidence of constipation and anticholinergic symptoms during clozapine treatment. Genes associated with opiate-induced constipation were also included in this analysis (TPH1, OPRM1, ABCB1, and COMT). PROCEDURES: Blood samples from 176 clozapine treated, Finnish, white patients with schizophrenia were genotyped. Constipation and anticholinergic symptoms were rated using the Liverpool University Neuroleptic Side Effect Rating Scale self-report questionnaire. In total, 192 single-nucleotide polymorphisms (SNPs) were detected and grouped to formulate a weighted genetic-risk score (GRS). RESULTS: No significant associations between individual SNPs or GRSs and constipation or laxative use were observed. A GRS of 19 SNPs in CHRM2, CHRM3, HTR3C, HTR7, ABCB1, OPRM1, and TPH1 was associated with anticholinergic symptoms in a generalized linear univariate model, with body mass index, clozapine monotherapy, and GRS as explaining variables (permuted P = 0.014). Generalized linear univariate model analysis performed on the opiate induced constipation-associated SNPs and a single CHRM3 SNP revealed an association between anticholinergic symptoms and a score of 8 SNPs (adjusted P = 0.038, permuted P = 0.002). CONCLUSIONS: Two GRSs are able to predict the risk of anticholinergic symptoms in patients receiving clozapine and possibly an increased risk of gastrointestinal hypomotility. PMID- 29620696 TI - Mephenesin: Is There a Progression in Cases of Substance Use Related Disorders in France? PMID- 29620695 TI - Misuse of Trihexyphenidyl (Artane) on Reunion Island. AB - BACKGROUND: Trihexyphenidyl (THP) is an anticholinergic drug misused to procure hallucination, sedation, and anxiolysis. The aim of this cohort was to show and describe, within a public health risk management policy, the risks of a long standing but relatively unknown addiction: THP addiction. METHODS: On Reunion island, a cohort with systematic data collection has been set up by addictologists working in the Centres for Addiction Prevention and Treatment, in the university hospital, and in general practices who have active lists of patients misusing THP. Data collection included socioeconomic data and clinical data concerning addiction. RESULTS: This cohort included 69 patients during November 2016. The average age of the patients was 36 years; 97% were men; 93% had living accommodation but only 32 % were employed. In this cohort drug administration was exclusively oral. The most common reasons for use were anxiolytic (46%), stimulation (26%), and sedation (10%), the main effects described were dyskinesia and behavioral disorders. Over half (61%) of the patients reported a coaddiction, mainly to benzodiazepines, cannabis, tobacco, alcohol, and buprenorphine. CONCLUSIONS: This cohort describing the clinical characteristics of 69 patients is the largest cohort studied for THP addiction. Patients from the Centres for Addiction Prevention and Treatment were the youngest and most recently addicted, whereas general practice patients had been addicted for longer and were more socially integrated. This clinical description of THP addiction therefore enables us to identify the patients who are the most at risk, to set up an adapted care protocol. PMID- 29620697 TI - Iatrogenic Engorgement of the Clitoris Due to Antidepressants: Report of a Case. PMID- 29620698 TI - Complex Polypharmacy in Patients With Schizophrenia-Spectrum Disorders Before a Psychiatric Hospitalization: Prescribing Patterns and Associated Clinical Features. AB - BACKGROUND: Current evidence-based guidelines provide unclear support for many common polypharmacy practices in schizophrenia. Excessive or complex polypharmacy (>=4 psychotropics) has been studied in patients with bipolar disorder, but not in schizophrenia to date. METHODS: We conducted a digital medical record data extraction of 829 patients consecutively admitted to a psychiatric hospital and diagnosed as having schizophrenia-spectrum disorders. RESULTS: In those prescribed psychiatric medication preadmission, 28.1% (n = 169) met the criteria for complex polypharmacy. Complex polypharmacy patients were older, female, white, and disabled, and had more comorbidities compared with those without complex polypharmacy. In multivariable analysis, complex polypharmacy was specifically associated with being white and disabled, and having a comorbid anxiety disorder, tobacco use disorder, metabolic condition, and neurological condition compared with noncomplex polypharmacy patients. CONCLUSIONS: Although there is little evidence to support complex polypharmacy in schizophrenia, rates were relatively high in patients requiring hospitalization, especially when they are also diagnosed as having comorbid psychiatric and medical conditions. Future research is needed to study the risk-benefit profile for these patients, especially considering their higher medical burden and related health risks. PMID- 29620699 TI - Comedication of Valproic Acid Is Associated With Increased Metabolism of Clozapine. AB - OBJECTIVES: Valproic acid and clozapine are drugs commonly used in the treatment of schizophrenic and schizoaffective disorders. Pharmacokinetic interactions of valproic acid with several drugs are well known, yet results concerning the interaction with clozapine are inconsistent. METHODS: Steady-state dose-corrected serum concentrations of clozapine and its main metabolite norclozapine were retrospectively analyzed in 45 patients receiving both clozapine and valproic acid. Controls were matched for sex, age, smoking, comedication, and inflammatory response. RESULTS: The group receiving comedication with valproic acid showed significantly lower median dose-corrected serum concentrations of norclozapine (0.44 [0.27-0.58] (ng/mL)/(mg/d) vs 0.78 [0.60-1.07] (ng/mL)/(mg/d)) as well as metabolite to parent compound ratios (0.40 [0.36-0.47] vs 0.71 [0.58-0.84]) by approximately 44%. Dose-corrected serum concentrations of clozapine were not significantly lower. The effect of valproic acid was independent of sex and smoking. CONCLUSIONS: Comedication with valproic acid accelerated metabolism of clozapine with predominant effects on the degradation of norclozapine. Therapeutic drug monitoring should be applied to guide individual patient responses upon initiation of comedication. PMID- 29620700 TI - Doxepin: Misuse and Abuse. PMID- 29620701 TI - Pharmacokinetics of Sustained-Release Oral Dexamphetamine Sulfate in Cocaine and Heroin-Dependent Patients. AB - INTRODUCTION: Research has shown that sustained-release (SR) dexamphetamine is a promising agonist treatment for cocaine dependence. However, little is known about the pharmacokinetics (PKs) of SR oral dexamphetamine. This study examined the PKs of a new SR dexamphetamine formulation in cocaine plus heroin-dependent patients currently in heroin-assisted treatment. METHODS: The study was designed as an open-label PK study in 2 cohorts: n = 5 with once daily 60 mg and n = 7 with once daily 30 mg SR oral dexamphetamine. Five days of blood plasma dexamphetamine concentrations measured with liquid chromatography-mass spectrometry with PK parameter estimates using noncompartmental analysis. RESULTS: Twelve cocaine-dependent plus heroin-dependent patients in heroin assisted treatment were included. The initial cohort 1 dose of 60 mg once daily was adjusted to 30 mg after mild to moderate adverse events. After oral administration, tmax values (coefficient of variation %) were 6.0 (17.0%) and 6.3 (16.3%) hours and t1/2 were 11 (24.6%) and 12 (25.4%) hours for 60 mg and 30 mg SR dexamphetamine, respectively. At steady state, CSSmax values were reached at 100 (27.5%) ng/mL and 58.4 (14.4%) ng/mL, whereas CSSmin values were 39.5 (38.9%) ng/mL and 21.8 (19.8%) ng/mL for 60 mg and 30 mg, respectively. CONCLUSIONS: The investigated SR formulation of dexamphetamine showed favorable slow-release characteristics in cocaine and heroin-dependent patients. A dose-proportional steady-state concentration was achieved within 3 days. These findings support the suitability of the SR formulation in the treatment of cocaine dependence. PMID- 29620702 TI - Electronic Health Records in Simulation Education: Literature Review and Synthesis. AB - STATEMENT: During the last decade, the use of electronic health records (EHRs) in clinical settings has risen sharply. Many clinical education programs have not incorporated the use of electronic documentation into their curriculum. It is important to incorporate technologies that will be used in real-world settings into educational clinical simulations to better prepare students for clinical practice and promote patient safety. Electronic documentation can be harder to teach to students because it requires a more in-depth orientation on how to use the electronic documentation system and because health care organizations often give students limited or no access to the documentation system. This review will include a discussion on the benefits and disadvantages of using educational EHRs, barriers and facilitators to implementing educational EHRs, and best practices for incorporating educational EHRs into current educational curriculums. PMID- 29620703 TI - A Multicenter Collaboration for Simulation-Based Assessment of ACGME Milestones in Emergency Medicine. AB - STATEMENT: In 2014, the six allopathic emergency medicine (EM) residency programs in Chicago established an annual, citywide, simulation-based assessment of all postgraduate year 2 EM residents. The cases and corresponding assessment tools were designed by the simulation directors from each of the participating sites. All assessment tools include critical actions that map directly to numerous EM milestones in 11 different subcompetencies. The 2-hour assessments provide opportunities for residents to lead resuscitations of critically ill patients and demonstrate procedural skills, using mannequins and task trainers respectively. More than 80 residents participate annually and their assessment experiences are essentially identical across testing sites. The assessments are completed electronically and comparative performance data are immediately available to program directors. PMID- 29620704 TI - Learners' Perceptions During Simulation-Based Training: An Interview Study Comparing Remote Versus Locally Facilitated Simulation-Based Training. AB - INTRODUCTION: Remotely facilitated simulation-based training (RF-SBT) is less positively appraised than face-to-face, locally facilitated simulation-based training (LF-SBT), despite being considered as an acceptable alternative. This study compared the perceptions of learners after RF-SBT and LF-SBT to explain differences between the two and identify relevant theories that would guide future practice. METHODS: Telephone interviews were conducted with 21 newly graduated doctors and nurses who completed a standardized simulation course delivered in both RF-SBT and LF-SBT formats. RESULTS: Participants reported that both SBT formats to be highly beneficial, however, were less positive about RF SBT. They described a range of psychosocial and cognitive responses that explained their positive and negative attitudes to different aspects of the training. These perceptions, occurring across both formats, included a sense of the following: belonging to instructor and group, surveillance, responsibility, realism, contextual understanding, conscious mental effort, control of attention, and engagement with task. Participants associated these perceptions and ensuing attitudes to SBT with factors arising during, and/or existing before, the SBT as if in an input-output process model. The former 'enabling' factors related to human interaction, technology, and instructional design, whereas the latter 'precursor' factors reflected pre-existing attributes of the participants and instructors. These findings are supported by several theoretical models of which the technology acceptance model is arguably the best fit. CONCLUSIONS: Locally facilitated simulation-based training is easier to use and experience than RF SBT; however, the latter's negative impact may be concealed by SBT's overarching very high perceived value. The technology acceptance model is an appropriate conceptual model to explain these processes. PMID- 29620705 TI - Building Ultrasound Phantoms With Modified Polyvinyl Chloride: A Comparison of Needle Insertion Forces and Sonographic Appearance With Commercial and Traditional Simulation Materials. AB - INTRODUCTION: Training using ultrasound phantoms allows for safe introduction to clinical skills and is associated with improved in-hospital performance. Many materials have been used to simulate human tissue in phantoms including commercial manikins, agar, gelatin, and Ballistics Gel; however, phantom tissues could be improved to provide higher-fidelity ultrasound images or tactile sensation. This article describes a novel phantom tissue mixture of a modified polyvinyl chloride (PVC) polymer, mineral oil, and chalk powder and evaluates needle cutting and ultrasonic properties of the modified PVC polymer mixture compared with a variety of phantom tissues. METHODS: The first experiment measured axial needle forces of a needle insertion into nine phantom materials, including three formulations of modified PVC. The second experiment used a pairwise comparison survey of ultrasound images to determine the perceived realism of phantom ultrasound images. RESULTS: It was found that the materials of Ballistics Gel and one of the PVC mixtures provide stiff force feedback similar to cadaver tissue. Other phantom materials including agar and gelatin provide very weak unrealistic force feedback. The survey results showed the PVC mixtures being viewed as the most realistic by the survey participants, whereas agar and Ballistics Gel were seen as the least realistic. CONCLUSIONS: The realism in cutting force and ultrasound visualization was determined for a variety of phantom materials. Novel modified PVC polymer has great potential for use in ultrasound phantoms because of its realistic ultrasound imaging and modifiable stiffness. This customizability allows for easy creation of multilayer tissue phantoms. PMID- 29620706 TI - Furosemide Response Predicts Acute Kidney Injury After Cardiac Surgery in Infants and Neonates. AB - OBJECTIVE: Cardiac surgery-induced acute kidney injury occurs frequently in neonates and infants and is associated with postoperative morbidity/mortality; early identification of cardiac surgery-induced acute kidney injury may be crucial to mitigate postoperative morbidity. We sought to determine if hourly or 6-hour cumulative urine output after furosemide in the first 24 hours after cardiopulmonary bypass could predict development of cardiac surgery-induced acute kidney injury and other deleterious outcomes. DESIGN: Retrospective chart review. SETTING: Pediatric cardiac ICU. PATIENTS: All infants younger than 90 days old admitted to the cardiac ICU from October 2012 to December 2015 who received at least one dose of furosemide in the first 24 hours after cardiopulmonary bypass surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Ninety-nine patients met inclusion and exclusion criteria. In total, 45.5% developed cardiac surgery induced acute kidney injury. Median time between cardiopulmonary bypass and furosemide was 7.7 hours (interquartile range, 4.4-9.5). Six-hour cumulative urine output was 33% lower (p = 0.031) in patients with cardiac surgery-induced acute kidney injury. Area under the curve for prediction of cardiac surgery induced acute kidney injury was 0.69 (p = 0.002). Other models demonstrated urine output response to furosemide had significant area under the curves for prediction of peak fluid over load greater than 15% (0.68; p = 0.047), prolonged peritoneal dialysis (area under the curve, 0.79; p = 0.007), prolonged mechanical ventilation (area under the curve, 0.79; p < 0.001), prolonged hospitalization (area under the curve, 0.62; p = 0.069) and mortality (area under the curve, 0.72; p = 0.05). CONCLUSIONS: Urine output response to furosemide within 24 hours of cardiopulmonary bypass predicts cardiac surgery-induced acute kidney injury development and other important morbidity in children younger than 90 days old; prospective validation is warranted. PMID- 29620707 TI - Risks-Benefits of Mini-Bolus Epinephrine for Hypotension. PMID- 29620708 TI - Dexmedetomidine During Noninvasive Ventilation: Different Acuity, Different Risks? PMID- 29620709 TI - PICS-p: It Is About Time (and Family)! But How Did Adult Medicine Beat Pediatrics to a Holistic View of the Patient? PMID- 29620710 TI - Capnography and Outcomes in Congenital Cardiac Surgery...Ready for Prime Time? PMID- 29620711 TI - Pediatric Neurocritical Care and Neuromonitoring in 2018-Maybe We Need to Go Back to the Basics? PMID- 29620712 TI - Timing Matters But Is Not Everything: Gauging the Influence of Technology on Nurse and Orderly Work. PMID- 29620713 TI - First Get the Data, Then Do the Science! PMID- 29620715 TI - Utilizing a Collaborative Learning Model to Promote Early Extubation Following Infant Heart Surgery: Erratum. PMID- 29620714 TI - Austere Surgical Care in the Era of Specialization. PMID- 29620717 TI - The microbial metabolite trimethylamine-N-oxide in association with inflammation and microbial dysregulation in three HIV cohorts at various disease stages. AB - OBJECTIVE: HIV-1-infection infers an increased cardiovascular risk where gut dysbiosis and microbial translocation may contribute. We assessed TMAO, a microbial metabolite with atherosclerotic properties, in plasma of HIV-1-infected individuals at different clinical stages in relation to inflammatory markers, cardiovascular events and gut microbiota. METHODS: Primary HIV-1-infected (n = 17) and chronic HIV-1-infected individuals (n = 22) were sampled before and after ART-initiation. In the chronic HIV-1-cohort, repeated faecal samples were analysed by 16SrRNA gene sequencing. HIV-1-infected individuals on longstanding ART (n = 101) and healthy HIV-1-negative individuals (n = 60), served as controls. TMAO and markers of immune activation were analysed by LC/MS/MS and immune assays, respectively. RESULTS: TMAO levels were lower in untreated HIV-1 infected individuals, increased significantly after ART-initiation (P = 0.040 and P < 0.001) but remained similar to healthy controls. TMAO levels were not affected by ART, immune status or degree of systemic inflammation. Higher TMAO in HIV-1-infected individuals on longstanding ART was not significantly associated with cardiovascular risk (P = 0.38). Additionally, TMAO levels correlated inversely with Bacteroidetes (Rho: -0.62, P = 0.002), and positively with Firmicutes (Rho: 0.65, P = 0.001) but held no correlation to TMA-producing genera. Notably gut dysbiosis at follow-up was more pronounced in patients without increase in TMAO levels after ART characterized by loss of Bacteroidetes (P = 0.023) and significantly elevated LPS levels (P = 0.01). CONCLUSION: Our data does not support that TMAO is a significant link between gut dysbiosis and inflammation in HIV-1-infection. We propose that HIV-1, microbial composition and ART disparately confound TMAO levels, thus limiting its role as a cardiovascular risk marker in HIV-1-infected individuals. PMID- 29620716 TI - Viral control in chronic HIV-1 subtype C infection is associated with enrichment of p24 IgG1 with Fc effector activity. AB - OBJECTIVE: Postinfection HIV viral control and immune correlates analysis of the RV144 vaccine trial indicate a potentially critical role for Fc receptor-mediated antibody functions. However, the influence of functional antibodies in clade C infection is largely unknown. DESIGN: Plasma samples from 361 chronic subtype C infected, antiretroviral therapy-naive participants were tested for their HIV specific isotype and subclass distributions, along with their Fc receptor mediated functional potential. METHOD: Total IgG, IgG subclasses and IgA binding to p24 clade B/C and gp120 consensus C proteins were assayed by multiplex. Antibody-dependent uptake of antigen-coated beads and Fc receptor-mediated natural killer cell degranulation were evaluated as surrogates for antibody dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC), respectively. RESULTS: p24 IgG1 was the only subclass associated with viral control (P = 0.01), with higher p24-specific ADCP and ADCC responses detected in individuals with high p24 IgG1. Although p24 IgG1 levels were enriched in patients with elevated Gag-specific T-cell responses, these levels remained an independent predictor of low-viral loads (P = 0.04) and high CD4 cell counts (P = 0.004) after adjusting for Gag-specific T-cell responses and for protective HLA class I alleles. CONCLUSION: p24 IgG1 levels independently predict viral control in HIV-1 clade C infection. Whether these responses contribute to direct antiviral control via the recruited killing of infected cells via the innate immune system or simply mark a qualitatively superior immune response to HIV, is uncertain, but highlights the role of p24-specific antibodies in control of clade C HIV-1 infection. PMID- 29620718 TI - Kingella kingae as the Main Cause of Septic Arthritis: Importance of Molecular Diagnosis. AB - BACKGROUND: Kingella kingae is an emergent pathogen causing septic arthritis (SA) in children.The objective of this study was to analyze the etiology of SA in children before and after the implementation of universal 16S rRNA gene polymerase chain reaction and sequencing (16SPCR) in synovial fluid. METHODS: Children <=14 years with acute SA from a Madrid cohort (2002-2013) were reviewed. Differences in etiology were analyzed before (period 1) and after (period 2) the implementation of bacterial 16SPCR in 2009. A comparison in epidemiology, clinical syndromes, therapy and outcome between infections caused by K. kingae and other bacteria was performed. RESULTS: Bacteria were detected from 40/81 (49.4%) children, with a higher proportion of diagnosis after 16SPCR establishment (period 2, 63% vs. period 1, 31.4%; P = 0.005). The main etiologies were Staphylococcus aureus (37.5%) and K. kingae (35%), although K. kingae was the most common microorganism in P2 (48.3%). Children with K. kingae SA were less likely to be younger than 3 months (0 vs. 42.3%; P < 0.001), had less anemia (21.4 vs. 50%; P = 0.010), lower C-reactive protein (3.8 vs. 8.9 mg/dL; P = 0.039), less associated osteomyelitis (0 vs. 26.9%; P = 0.033), shorter intravenous therapy (6 vs. 15 days; P < 0.001), and had a nonsignificant lower rate of sequelae (0 vs. 30%; P = 0.15) than children with SA caused by other bacteria. However, they tended to have higher rate of fever (86 vs. 57%; P = 0.083). CONCLUSIONS: K. kingae was frequently recovered in children with SA after the implementation of bacterial 16SPCR, producing a milder clinical syndrome and better outcome. Therefore, the use of molecular techniques may be important for the management of these children. PMID- 29620719 TI - Preoperative Illnesses in Children Do Not Increase the Risk of Complications After Hypospadias Repair. AB - BACKGROUND: Preoperative illnesses might induce immunosuppression and subsequently increase morbidity after surgery. Several studies have tried to identify risk factors for complications after hypospadias correction, but effects of illnesses in the weeks just before surgery are unknown. We aimed to determine the associations between preoperative illnesses not severe enough to postpone surgery and short-term complications after hypospadias repair in children. METHODS: In this retrospective cohort study, data were collected from 681 children with anterior or middle type hypospadias that had initial one-stage repair in the period 1983-2012 in the Radboudumc, The Netherlands. The associations between common illnesses, such as common cold, fever, and ear infection, within 2 weeks before repair, and postoperative complications, such as urethrocutaneous fistula, wound dehiscence, and stenosis, within 2 months and one year after surgery were analyzed using multivariable logistic regression analyses. RESULTS: Of the 681 boys, 22% had preoperative illnesses, most often common cold, and 14% had postoperative complications. Children with preoperative illnesses had fewer postoperative complications within two months (n=13, 9%) than children without preoperative illnesses (n=79, 16%), resulting in a 50% risk reduction (OR 0.49, 95%CI 0.26-0.93). Preoperative infections (common cold, fever, ear infection) in particular reduced the risk of postoperative infections (wound and urinary tract infections) (OR 0.37, 95%CI 0.14-0.98). Results were similar for complications within one year. CONCLUSIONS: Common preoperative illnesses not severe enough to postpone surgery did not increase the postoperative complication risk and even seemed to have a protective effect, especially for postoperative infections. Consequently there is no reason to alter preoperative screening. PMID- 29620720 TI - Brodie's Abscess in Children: A Ten-Year Single Institution Retrospective Review. AB - Brodie's abscess is a subacute hematogenous osteomyelitis characterized by intraosseous abscess formation. Treatment recommendations and clinical outcomes for this unusual infection are not well-established. We report fifteen cases of Brodie's abscess in a ten-year retrospective review of pediatric patients at Texas Children's Hospital and describe their clinical presentation and outcomes. PMID- 29620721 TI - Pediatric Coccidioidomycosis: Case Series from a California Pediatric Infectious Diseases Clinic. AB - BACKGROUND: Coccidioidomycosis is not as well described in the pediatric population as it is in the adult population. We describe clinical findings, diagnosis, and management of coccidioidomycosis in 108 pediatric patients seen in an outpatient clinic in the California Central Valley, an area endemic for coccidioidomycosis. METHODS: We reviewed medical records of a convenience sample of pediatric patients (<=17 years of age) diagnosed with coccidioidomycosis who visited an infectious diseases clinic in Madera, CA during January 1-October 1, 2012. We described demographic characteristics, symptoms, diagnostic testing, extent of infection (acute/pulmonary or disseminated), treatment, and management. RESULTS: Of 108 patients, 90 (83%) had acute/pulmonary coccidioidomycosis and 18 (17%) had disseminated disease. The median age at diagnosis was 9 years (range, 5 months-17 years). Only 3 (3%) patients were immunocompromised. Before coccidioidomycosis diagnosis, 72 (82%) patients received antibiotics, and 31 (29%) had at least one negative coccidioidomycosis serology at the time of or before diagnosis. Coccidioidomycosis was diagnosed significantly later after symptom onset among patients with disseminated (median 57 days) than with acute/pulmonary (median 16 days) disease (p<0.01). A total of 104 (96%) patients received antifungal therapy, 51 (47%) visited an emergency room, and 59 (55%) were hospitalized with a median stay of 44 days (range, 1-272 days). DISCUSSION: Substantial acute/pulmonary and disseminated coccidioidomycosis was seen among pediatric patients at this infectious disease clinic in California. In endemic areas, increased coccidioidomycosis awareness and vigilance among families and providers is necessary to facilitate early diagnosis and appropriate management. PMID- 29620722 TI - Immunogenicity and Reactogenicity of DTPa-HBV-IPV/Hib and PHiD-CV When Coadministered With MenACWY-TT in Infants: Results of an Open, Randomized Trial. AB - BACKGROUND: This study evaluated the immunogenicity and reactogenicity of a combined diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated poliovirus virus-Haemophilus influenzae type b vaccine (DTPa-HBV-IPV/Hib) and a 10-valent pneumococcal conjugate vaccine (PHiD-CV) coadministered with a quadrivalent meningococcal conjugate vaccine (MenACWY-TT) in infants/toddlers. METHODS: In this open, controlled, phase III study (NCT01144663), 2095 healthy infants were randomized (1:1:1:1) into 4 groups to receive MenACWY-TT at 2, 3, 4 and 12 months of age or MenACWY-TT, MenC-CRM197, or MenC-TT at 2, 4 and 12 months of age. All participants received PHiD-CV and DTPa-HBV-IPV/Hib at 2, 3, 4 and 12 months of age. Immunogenicity of DTPa-HBV-IPV/Hib was evaluated in exclusive randomized subsets of 25% of participants from each group postprimary, prebooster and postbooster vaccination, whereas immunogenicity of PHiD-CV was evaluated at all time points. Reactogenicity was evaluated on the total vaccinated cohorts during 8 days after each vaccination. RESULTS: For each DTPa-HBV-IPV/Hib antigen, >=97.2%, >=76.5% and >=97.9% of participants had seropositive/seroprotective levels 1 month postprimary vaccination, before the booster dose and 1 month postbooster, respectively. For each vaccine pneumococcal serotype, >=74.0% of infants had antibody concentrations >=0.35 MUg/mL at 1 month postprimary vaccination, and robust increases in antibody geometric mean concentrations were observed from prebooster to postbooster. Redness was the most frequent solicited local symptom at the DTPa-HBV-IPV/Hib and PHiD-CV injection sites, reported after up to 47.7% and 57.0% of doses postprimary and postbooster vaccination, respectively. CONCLUSIONS: Primary and booster vaccinations of infants/toddlers with DTPa-HBV-IPV/Hib and PHiD-CV coadministered with MenACWY-TT were immunogenic with clinically acceptable reactogenicity profiles. These results support the coadministration of MenACWY-TT with routine childhood vaccines. PMID- 29620723 TI - Perinatal Risk Factors Associated with Gastroenteritis Hospitalizations in Aboriginal and Non-Aboriginal Children in Western Australia (2000-2012): A Record Linkage Cohort Study. AB - BACKGROUND: Gastroenteritis is a leading cause of childhood morbidity worldwide. We aimed to assess the maternal and infant characteristics and population attributable fractions (PAFs) associated with childhood gastroenteritis-related hospitalizations. METHODS: We conducted a whole-of-population retrospective birth cohort study of 367,476 children live-born in Western Australia (WA) 2000-2012. We identified hospital admissions up to age <15 years pertaining to these children, with a principal diagnosis code for infectious gastroenteritis. Cox regression was used to obtain the adjusted hazard ratios with 95% confidence intervals (CIs) and the PAFs associated with each risk factor in Aboriginal and non-Aboriginal children for their first gastroenteritis hospital admission. RESULTS: There were a total of 15,888 gastroenteritis-related hospital admissions (25.7% occurring among Aboriginal children). The overall gastroenteritis hospitalization rate for children aged <15 years was 4.6/1000 child-years for non Aboriginal children and 21.5/1000 child-years for Aboriginal children. Male gender, maternal age <20 years, pre-term birth, low birth weight, residence in remote regions of WA and birth in the pre-rotavirus vaccine era were significant independent risk factors for gastroenteritis hospitalization in both Aboriginal and non-Aboriginal children. Additionally, birth by caesarean section and low socio-economic status were identified as being associated with gastroenteritis hospitalization in non-Aboriginal children. PAFs suggest that 39% of all gastroenteritis hospitalizations in non-Aboriginal children (38% in Aboriginal children) could be averted if all children receive the rotavirus vaccine. CONCLUSION: Given the beneficial effect of infant rotavirus vaccination in preventing all-cause gastroenteritis hospitalization, efforts should be taken to optimize rotavirus vaccine coverage in those at highest risk. PMID- 29620725 TI - Erratum: Evolutionary history resolves global organization of root functional traits. AB - This corrects the article DOI: 10.1038/nature25783. PMID- 29620726 TI - Investigating non-Joulian magnetostriction. PMID- 29620724 TI - Expanding the phenome and variome of skeletal dysplasia. AB - PurposeTo describe our experience with a large cohort (411 patients from 288 families) of various forms of skeletal dysplasia who were molecularly characterized.MethodsDetailed phenotyping and next-generation sequencing (panel and exome).ResultsOur analysis revealed 224 pathogenic/likely pathogenic variants (54 (24%) of which are novel) in 123 genes with established or tentative links to skeletal dysplasia. In addition, we propose 5 genes as candidate disease genes with suggestive biological links (WNT3A, SUCO, RIN1, DIP2C, and PAN2). Phenotypically, we note that our cohort spans 36 established phenotypic categories by the International Skeletal Dysplasia Nosology, as well as 18 novel skeletal dysplasia phenotypes that could not be classified under these categories, e.g., the novel C3orf17-related skeletal dysplasia. We also describe novel phenotypic aspects of well-known disease genes, e.g., PGAP3-related Toriello-Carey syndrome-like phenotype. We note a strong founder effect for many genes in our cohort, which allowed us to calculate a minimum disease burden for the autosomal recessive forms of skeletal dysplasia in our population (7.16E-04), which is much higher than the global average.ConclusionBy expanding the phenotypic, allelic, and locus heterogeneity of skeletal dysplasia in humans, we hope our study will improve the diagnostic rate of patients with these conditions.GENETICS in MEDICINE advance online publication, 5 April 2018; doi:10.1038/gim.2018.50. PMID- 29620727 TI - Corrigendum: Commensal bacteria make GPCR ligands that mimic human signalling molecules. AB - This corrects the article DOI: 10.1038/nature23874. PMID- 29620728 TI - Improving outcomes in congenital cataract. PMID- 29620729 TI - Lens regeneration in children. PMID- 29620731 TI - Liu et al. reply. PMID- 29620730 TI - Molecular nucleation mechanisms and control strategies for crystal polymorph selection. AB - The formation of condensed (compacted) protein phases is associated with a wide range of human disorders, such as eye cataracts, amyotrophic lateral sclerosis, sickle cell anaemia and Alzheimer's disease. However, condensed protein phases have their uses: as crystals, they are harnessed by structural biologists to elucidate protein structures, or are used as delivery vehicles for pharmaceutical applications. The physiochemical properties of crystals can vary substantially between different forms or structures ('polymorphs') of the same macromolecule, and dictate their usability in a scientific or industrial context. To gain control over an emerging polymorph, one needs a molecular-level understanding of the pathways that lead to the various macroscopic states and of the mechanisms that govern pathway selection. However, it is still not clear how the embryonic seeds of a macromolecular phase are formed, or how these nuclei affect polymorph selection. Here we use time-resolved cryo-transmission electron microscopy to image the nucleation of crystals of the protein glucose isomerase, and to uncover at molecular resolution the nucleation pathways that lead to two crystalline states and one gelled state. We show that polymorph selection takes place at the earliest stages of structure formation and is based on specific building blocks for each space group. Moreover, we demonstrate control over the system by selectively forming desired polymorphs through site-directed mutagenesis, specifically tuning intermolecular bonding or gel seeding. Our results differ from the present picture of protein nucleation, in that we do not identify a metastable dense liquid as the precursor to the crystalline state. Rather, we observe nucleation events that are driven by oriented attachments between subcritical clusters that already exhibit a degree of crystallinity. These insights suggest ways of controlling macromolecular phase transitions, aiding the development of protein-based drug-delivery systems and macromolecular crystallography. PMID- 29620732 TI - Erratum: Asparagine bioavailability governs metastasis in a model of breast cancer. AB - This corrects the article DOI: 10.1038/nature25465. PMID- 29620733 TI - A density cusp of quiescent X-ray binaries in the central parsec of the Galaxy. AB - The existence of a 'density cusp'-a localized increase in number-of stellar-mass black holes near a supermassive black hole is a fundamental prediction of galactic stellar dynamics. The best place to detect such a cusp is in the Galactic Centre, where the nearest supermassive black hole, Sagittarius A*, resides. As many as 20,000 black holes are predicted to settle into the central parsec of the Galaxy as a result of dynamical friction; however, so far no density cusp of black holes has been detected. Low-mass X-ray binary systems that contain a stellar-mass black hole are natural tracers of isolated black holes. Here we report observations of a dozen quiescent X-ray binaries in a density cusp within one parsec of Sagittarius A*. The lower-energy emission spectra that we observed in these binaries is distinct from the higher-energy spectra associated with the population of accreting white dwarfs that dominates the central eight parsecs of the Galaxy. The properties of these X-ray binaries, in particular their spatial distribution and luminosity function, suggest the existence of hundreds of binary systems in the central parsec of the Galaxy and many more isolated black holes. We cannot rule out a contribution to the observed emission from a population (of up to about one-half the number of X-ray binaries) of rotationally powered, millisecond pulsars. The spatial distribution of the binary systems is a relic of their formation history, either in the stellar disk around Sagittarius A* (ref. 7) or through in-fall from globular clusters, and constrains the number density of sources in the modelling of gravitational waves from massive stellar remnants, such as neutron stars and black holes. PMID- 29620735 TI - Female leadership falls at top universities. PMID- 29620734 TI - Climatic control of Mississippi River flood hazard amplified by river engineering. AB - Over the past century, many of the world's major rivers have been modified for the purposes of flood mitigation, power generation and commercial navigation. Engineering modifications to the Mississippi River system have altered the river's sediment levels and channel morphology, but the influence of these modifications on flood hazard is debated. Detecting and attributing changes in river discharge is challenging because instrumental streamflow records are often too short to evaluate the range of natural hydrological variability before the establishment of flood mitigation infrastructure. Here we show that multi-decadal trends of flood hazard on the lower Mississippi River are strongly modulated by dynamical modes of climate variability, particularly the El Nino-Southern Oscillation and the Atlantic Multidecadal Oscillation, but that the artificial channelization (confinement to a straightened channel) has greatly amplified flood magnitudes over the past century. Our results, based on a multi-proxy reconstruction of flood frequency and magnitude spanning the past 500 years, reveal that the magnitude of the 100-year flood (a flood with a 1 per cent chance of being exceeded in any year) has increased by 20 per cent over those five centuries, with about 75 per cent of this increase attributed to river engineering. We conclude that the interaction of human alterations to the Mississippi River system with dynamical modes of climate variability has elevated the current flood hazard to levels that are unprecedented within the past five centuries. PMID- 29620736 TI - Uphold Hawking's and Sulston's support for European science. PMID- 29620737 TI - Nature: the truth. PMID- 29620738 TI - Beguiling dark-matter signal persists 20 years on. PMID- 29620740 TI - NASA reveals major delay for $8-billion Hubble successor. PMID- 29620739 TI - How researchers are ensuring that their work has an impact. PMID- 29620741 TI - Forests in flux as climate varies. PMID- 29620743 TI - Sciences unite in Spain to promote research for advancing society. PMID- 29620744 TI - Bacterial persister cells tackled. PMID- 29620745 TI - Developing countries must lead on solar geoengineering research. PMID- 29620748 TI - Rogue space station, CRISPR crops and French AI pledge. PMID- 29620747 TI - Cancer researchers push to relax rules for clinical trials. PMID- 29620750 TI - Observations of the birth of crystals. PMID- 29620751 TI - Novel electronic states seen in graphene. PMID- 29620753 TI - Reward food companies for improving nutrition. PMID- 29620754 TI - Uptick in US female members of International Astronomical Union. PMID- 29620755 TI - Ecology's remote-sensing revolution. PMID- 29620756 TI - Mississippi rising. PMID- 29620757 TI - Canada gains popularity with prospective students. PMID- 29620758 TI - Alfred Nobel's 1895 will is strictly upheld to this day. PMID- 29620759 TI - Use our personal data for the common good. PMID- 29620760 TI - Two-pore channels open up. PMID- 29620761 TI - EU copyright reforms draw fire from scientists. PMID- 29620763 TI - Time to talk about why so many postgrads have poor mental health. PMID- 29620764 TI - Gunter Blobel (1936- 2018). PMID- 29620766 TI - How philosophy was squeezed out of the PhD. PMID- 29620765 TI - Squeaky clean mice could be ruining research. PMID- 29620767 TI - Enthalpic interactions in aqueous strong electrolytes upon addition of ionic liquids. AB - The present study deals with the inter-ionic interactions between strong electrolytes and ionic liquids based on the thermodynamic properties such as excess partial molar enthalpy, HEIL, relative apparent molar enthalpy, phiL, and the enthalpic interaction parameters. The thermodynamic properties of the systems are the key indicators to understand the interionic interactions. We have conducted a systematic investigation of the enthalpic behavior of aqueous solution of salts and ionic liquids and their mixtures. The present study also emphasizes how the HEIL values for the mixture of aqueous solution of ionic liquids and salts deviate from linearity as compared to those of the constituent aqueous ionic liquid or salt. This deviation from linearity for the HEIL values has been discussed here. PMID- 29620768 TI - A unified model of Grignard reagent formation. AB - Grignard reagents are among the most fundamental reagents in organic synthesis, yet studies have hitherto failed to fully explain the selectivity and kinetics of Grignard reagent formation (GRF). The present study provides new insights into the intermediates and pathways of GRF using density functional theory (DFT) calculations. Potential energy surfaces of RX dissociation along different directions reveal the origin of configuration retention of alkenyl and aromatic halides. Radical intermediates participate solely in the dissociation stage, and depend on the geometry of the reactant halide. Dissociation of organic halides yields stabilized surface anions, and the rest of the reaction is ionic in nature. MgX+/RMg+ were proposed as the key intermediates of Mg leaving from the surface in the self-activation of GRF, which explains the accelerated kinetics upon addition of RMgX or MgX2. The intermediacy of the cations was supported by a simple electrochemical experiment. To the best of our knowledge, this is the first unified ionic model (I-model) developed for resolving the controversial issues of GRF. PMID- 29620770 TI - Bromine adatom promoted C-H bond activation in terminal alkynes at room temperature on Ag(111). AB - The activation of C-H bonds in terminal alkynyl groups at room temperature was achieved in the reaction of 2,5-diethynyl-1,4-bis(4-bromophenylethynyl)benzene on Ag(111). Scanning tunneling microscopy studies showed the formation of organometallic species, whose stabilization was confirmed by density functional theory calculations, at room temperature as the product of C-H bond activation. The partial conversion of organometallic structures into covalent products of the homocoupling between the terminal alkynes was achieved by further annealing the sample at 420 K. Detached Br adatoms were suggested to play a key role in promoting the C-H bond activation. This proposal was supported by the theoretical study based on a simplified model of the system, showing the weakening of the C-H bond in the alkynyl group by an approaching Br atom. The results provide a new strategy for on-surface C-H bond activation under mild conditions, which register great potential applications in on-surface synthesis and bottom-up preparation of functional nanomaterials. PMID- 29620771 TI - An early investigative serum Raman spectroscopy study of meningioma. AB - Meningiomas represent one of the most frequently reported non-glial, primary brain and central nervous system (CNS) tumors. Meningiomas often display a spectrum of anomalous locations and morphological attributes, deterring their timely diagnosis. Majority of them are sporadic in nature and thus the present day screening strategies, including radiological investigations, often result in misdiagnosis due to their aberrant and equivocal radiological facets. Therefore, it is pertinent to explore less invasive and patient-friendly biofluids such as serum for their screening and diagnostics. The utility of serum Raman spectroscopy in diagnosis and therapeutic monitoring of cancers has been reported in the literature. In the present study, for the first time, to the best of our knowledge, we have explored Raman spectroscopy to classify the sera of meningioma and control subjects. For this exploration, 35 samples each of meningioma and control subjects were accrued and the spectra revealed variance in the levels of DNA, proteins, lipids, amino acids and beta-carotene, i.e., a relatively higher protein, DNA and lipid content in meningioma. Subsequent Principal Component Analysis (PCA) and Principal Component-Linear Discriminant Analysis (PC-LDA) followed by Leave-One-Out Cross-Validation (LOOCV) and limited independent test data, in a patient-wise approach, yielded a classification efficiency of 92% and 80% for healthy and meningioma, respectively. Additionally, in the analogous analysis between healthy and different grades of meningioma, similar results were obtained. These results indicate the potential of Raman spectroscopy in differentiating meningioma. As present methods suffer from known limitations, with the prospective validation on a larger cohort, serum Raman spectroscopy could be an adjuvant/alternative approach in the clinical management of meningioma. PMID- 29620772 TI - From isodesmic to highly cooperative: reverting the supramolecular polymerization mechanism in water by fine monomer design. AB - Two structurally-similar discotic molecules able to self-assemble in water, forming supramolecular fibers, are reported. While both self-assembled polymers are indistinguishable from a morphological point-of-view, a dramatic change in their polymerization mechanism is observed (i.e., one self-assemble via an isodesmic mechanism, while the other shows one of the highest cooperativity values). PMID- 29620773 TI - Impact of primer dimers and self-amplifying hairpins on reverse transcription loop-mediated isothermal amplification detection of viral RNA. AB - Loop-mediated isothermal amplification (LAMP), coupled with reverse transcription (RT), has become a popular technique for detection of viral RNA due to several desirable characteristics for use in point-of-care or low-resource settings. The large number of primers in LAMP (six per target) leads to an increased likelihood of primer dimer interactions, and the inner primers in particular are prone to formation of stable hairpin structures due to their length (typically 40-45 bases). Although primer dimers and hairpin structures are known features to avoid in nucleic acid amplification techniques, there is little quantitative information in literature regarding the impact of these structures on LAMP or RT LAMP assays. In this study, we examine the impact of primer dimers and hairpins on previously published primer sets for dengue virus and yellow fever virus. We demonstrate that minor changes to the primers to eliminate amplifiable primer dimers and hairpins improves the performance of the assays when monitored in real time with intercalating dyes, and when monitoring a fluorescent endpoint using the QUASR technique. We also discuss the thermodynamic implications of these minor changes on the overall stability of amplifiable secondary structures, and we present a single thermodynamic parameter that can be correlated to the probability of non-specific amplification associated with LAMP primers. PMID- 29620775 TI - Numerical insights into the early stages of nanoscale electrodeposition: nanocluster surface diffusion and aggregative growth. AB - Fundamental understanding of the early stages of electrodeposition at the nanoscale is key to address the challenges in a wide range of applications. Despite having been studied for decades, a comprehensive understanding of the whole process is still out of reach. In this work, we introduce a novel modelling approach that couples a finite element method (FEM) with a random walk algorithm, to study the early stages of nanocluster formation, aggregation and growth, during electrochemical deposition. This approach takes into account not only electrochemical kinetics and transport of active species, but also the surface diffusion and aggregation of adatoms and small nanoclusters. The simulation results reveal that the relative surface mobility of the nanoclusters compared to that of the adatoms plays a crucial role in the early growth stages. The number of clusters, their size and their size dispersion are influenced more significantly by nanocluster mobility than by the applied overpotential itself. Increasing the overpotential results in shorter induction times and leads to aggregation prevalence at shorter times. A higher mobility results in longer induction times, a delayed transition from nucleation to aggregation prevalence, and as a consequence, a larger surface coverage of smaller clusters with a smaller size dispersion. As a consequence, it is shown that a classical first order nucleation kinetics equation cannot describe the evolution of the number of clusters with time, N(t), in potentiostatic electrodeposition. Instead, a more accurate representation of N(t) is provided. We show that an evaluation of N(t), which neglects the effect of nanocluster mobility and aggregation, can induce errors of several orders of magnitude in the determination of nucleation rate constants. These findings are extremely important towards evaluating the elementary electrodeposition processes, considering not only adatoms, but also nanoclusters as building blocks. PMID- 29620776 TI - Highly infrared sensitive VO2 nanowires for a nano-optical device. AB - Recent studies on the electronic, magnetic and optical properties of VO2 (vanadium dioxide) materials have motivated the exploration of one dimensional VO2 nanowires. First principles calculations were performed to investigate the structural, electronic, magnetic and optical properties of the monoclinic (M) and rutile (R) phases of VO2 nanowires. The monoclinic phase shows semiconducting behaviour with a band gap of 1.17 eV, whereas the rutile phase of VO2 nanowires behaves as a spin gapless semiconducting material, as band lines cross the Fermi level due only to up spin contribution. The monoclinic structure of VO2 nanowires is found to be paramagnetic and the rutile structure shows ferromagnetic half metal behavior. The conductivity calculation for VO2 nanowires shows the metal insulator transition (MIT) temperature to be 250 K. The possible mechanism of VO2 nanowires to be used as smart windows has been discussed, as the nanowires are highly sensitive in the infrared (IR) region. Interestingly, at low temperature, the VO2 monoclinic structure allows infrared light to be transmitted, while VO2 with the rutile phase blocks light in the IR region. Furthermore, we adsorbed CO2, N2 and SO2 gas molecules on 1D VO2 monoclinic nanowire to investigate their interaction behaviour. It was observed that the absorption and transmission properties of VO2 dramatically change upon the adsorption of CO2 and SO2 gas molecules, which is likely to open up its application as an optical gas sensor. PMID- 29620779 TI - Design and properties of functional zwitterions derived from ionic liquids. AB - A zwitterion, an ion pair where cation and anion are covalently tethered, is known to be a type of salt. These ions have not been recognised as interesting, but they are physicochemically unique and fascinating ions. In the present review, some functional zwitterions derived from ionic liquids are mentioned to emphasise the usefulness of the tethering of the component cations and anions of ionic liquids. Basic properties, advantages and disadvantages after the functional design of zwitterions, and some applications are summarised. PMID- 29620778 TI - Characterization of the mechanical properties of cancer cells in 3D matrices in response to collagen concentration and cytoskeletal inhibitors. AB - Cellular processes, such as cell migration, adhesion, and proliferation depend on the interaction between the intracellular environment and the extracellular matrix (ECM). While many studies have explored the role of the microenvironment on cell behavior, the influence of 3D matrix mechanics on intracellular activity is not completely understood. To characterize the relationship between the mechanical components of the microenvironment and intracellular behavior, we use particle-tracking microrheology of metastatic breast cancer cells embedded in 3D collagen gels to quantify the intracellular activity from which the molecular motor activity and stiffness can be determined. Our results show that increasing collagen concentration of the 3D environments leads to an increase in intracellular stiffness and motor activity. Furthermore, our studies demonstrate that intracellular fluctuations depend on collagen concentration, even in the presence of a number of frontline chemotherapeutic and anti-MMP drugs, indicating that ECM concentration is an important and indispensable parameter to consider in drug screening. PMID- 29620781 TI - Comment on "Isomerization of the methoxy radical revisited: the impact of water dimers" by B. Bandyopadhyay et al., Phys. Chem. Chem. Phys., 2016, 18, 27728 and "Isomerization of methoxy radical in the troposphere: competition between acidic, neutral and basic catalysts" by P. Kumar, B. Bandyopadhyay et al., Phys. Chem. Chem. Phys., 2017, 19, 278. AB - In two recent papers Bandyopadhyay and co-workers studied how atmospheric trace gases catalyze the isomerization of methoxy radical (CH3O) to hydroxymethyl radical (CH2OH). Their second paper extensively discussed the altitude dependence of this catalyzed isomerization. Unfortunately, they did not compare their computed isomerization rates with the abundant kinetic data on the long established fate of CH3O: reaction with O2. This Comment shows that the fastest rate they compute for catalyzed isomerization is over one million times slower than the O2 reaction at all altitudes considered in those papers. Furthermore, we argue that, even if the reaction CH3O -> CH2OH were to occur, it would not have any atmospheric consequence. This is because the near-exclusive atmospheric fate of both CH2OH and CH3O is reaction with O2 to produce CH2[double bond, length as m-dash]O + HOO. PMID- 29620782 TI - Covalent attachment of [Ni(alkynyl-cyclam)]2+ catalysts to glassy carbon electrodes. AB - Surface modification of glassy carbon electrodes (GCEs) with molecular electrocatalysts is an important step towards developing more efficient heterogeneous CO2 reduction materials. Here, we report direct anodic electrografting of [Ni(alkynyl-cyclam)]2+ catalysts to the surface of GCEs in one simple step using inexpensive earth-abundant chemicals. When modified, these electrodes show reversible electrochemistry in organic solvents with zero peak-to peak separations (DeltaE = 0) and non-diffusive I (V) profiles that are typical for heterogeneous redox materials. CPE of these electrodes showed enhanced formation of H2 gas relative to CO compared to homogeneous catalysts. PMID- 29620783 TI - Oxidative removal of quinclorac by permanganate through a rate-limiting [3 + 2] cycloaddition reaction. AB - Quinclorac, a widely used herbicide in agriculture, has been recognized as an emerging environmental pollutant owing to its long persistence and potential risk to humans. However, no related information is available on the degradation of quinclorac by employing oxidants. Herein, the reactivity of quinclorac with permanganate was systematically investigated in water by combining experimental and computational approaches. The reaction followed overall second-order kinetics pointing to a bimolecular rate-limiting step. The second-order rate constant was found to be 3.47 * 10-3 M-1 s-1 at 25 degrees C, which was independent of pH over the range from 5 to 9 and was dependent on temperature over the range from 19 to 35 degrees C. The initial product was identified by UPLC-Q-TOF-MS to be mono-hydroxylated quinclorac, which was more susceptible to further oxidation. The result could be supported by the complete simulation of the reaction process in DFT calculations, indicating the [3 + 2] cycloaddition oxidation of the benzene ring in the rate-limiting step. The plausible mechanism was then proposed, accompanied by the analysis of the HOMO indicating the hydroxylation position and of the ESP suggesting a more electron-rich moiety. Considering the high effectiveness and low toxicity, permanganate oxidation was considered to be a very promising technique for removing quinclorac from aquatic environments. PMID- 29620784 TI - Prebiotic effects of resistant starch from purple yam (Dioscorea alata L.) on the tolerance and proliferation ability of Bifidobacterium adolescentis in vitro. AB - The in vitro prebiotic effects of resistant starch (RS), prepared by different treatments from purple yam, on Bifidobacterium adolescentis (bifidobacteria for short), were investigated. Tolerance tests indicated that bifidobacteria in PDS (prepared by debranching combined with autoclaving) and PDS.H (PDS further treated by double enzyme hydrolysis) media adapted better to simulated upper gastrointestinal conditions (at pH 1.5-3.0 and 0.3% and 1.0% bile acid) than those in GLU (glucose) and DAS (prepared by autoclaving) media. PDS.H, which had the highest digestion resistibility, exhibited significant effects on the OD600 nm value (1.544) and the pH value (4.21) when the carbohydrate concentration was 20 g L-1. Additionally, the exponential growth phase of bifidobacteria was 2 h in the PDS or PDS.H media, whereas it was 4 h in the GLU or DAS media. A higher content of short-chain fatty acids (SCFAs) was obtained in the PDS.H medium. Analysis of the structural features of RS and fermented RS indicated that PDS, especially PDS.H, had a rougher surface and higher crystallinity than DAS. Fermented RS in a simulated large bowel environment showed an eroded surface and decreased crystallinity. All of these findings suggest that RS with a rough surface and perfect crystalline structure could protect bifidobacteria from gastrointestinal conditions and enhance the proliferation of bifidobacteria. PMID- 29620786 TI - Parallelized biocatalytic scanning probe lithography for the additive fabrication of conjugated polymer structures. AB - Scanning probe lithography (SPL) offers a more accessible alternative to conventional photolithography as a route to surface nanofabrication. In principle, the synthetic scope of SPL could be greatly enhanced by combining the precision of scanning probe systems with the chemoselectivity offered by biocatalysis. This report describes the development of multiplexed SPL employing probes functionalized with horseradish peroxidase, and its subsequent use for the constructive fabrication of polyaniline features on both silicon oxide and gold substrates. This polymer is of particular interest due to its potential applications in organic electronics, but its use is hindered by its poor processability, which could be circumvented by the direct in situ synthesis at the desired locations. Using parallelized arrays of probes, the lithography of polymer features over 1 cm2 areas was achieved with individual feature widths as small as 162 +/- 24 nm. The nature of the deposited materials was confirmed by Raman spectroscopy, and it was further shown that the features could be chemically derivatized postlithographically by Huisgen [2 + 3] "click" chemistry, when 2-propargyloxyaniline was used as the monomer in the initial lithography step. PMID- 29620787 TI - Distribution of genital Mollicutes in the vaginal ecosystem of women with different clinical conditions. AB - Ureaplasma urealyticum (UU), Ureaplasma parvum (UP), Mycoplasma hominis (MH) and Mycoplasma genitalium (MG) are the most common Mollicutes of the female genital tract. Although many studies have addressed their possible role in the vaginal ecosystem, many aspects remain to be elucidated. The aim of this study was to evaluate the vaginal presence of ureaplasmas/mycoplasmas in women with different clinical conditions. By means of quantitative PCR assays, the prevalence and load of each Mollicute were assessed in different groups of pre-menopausal women: 'healthy' (n=29), women with bacterial vaginosis (BV) (n=21), patients with Chlamydia trachomatis (CT) infection (n=25) and subjects with vulvo-vaginal candidiasis (VVC) (n=23). Globally, UP was the most prevalent Mollicutes in the vagina (67.3%), followed by MH (14.3%), UU (9.2%) and MG (3.1%). The presence of UU and UP was almost never associated. MH showed a significantly higher prevalence and higher bacterial loads in BV-positive women (P<0.05), whereas patients with CT and VVC were characterized by a Mollicutes pattern similar to healthy women. Mollicutes can be frequently found in the vaginal ecosystem, even in asymptomatic 'healthy' women. Although its presence is not a strict requirement, MH displays a significant role in the pathogenesis of BV. PMID- 29620788 TI - Susceptibility of clinical isolates of Campylobacter jejuni and Campylobacter coli to colistin. AB - Campylobacter spp. are one of the most frequent causes of bacterial diarrhea worldwide. Although severe diarrhea is not highly prevalent, the risk of a fatal outcome is increased when infection is caused by strains resistant to macrolides, fluoroquinolones, and/or tetracyclines. It is therefore necessary to test the susceptibility of these bacteria to other antibiotics such as colistin, which may serve as an alternative therapeutic option in these situations. The E-test was used to investigate the activity of erythromycin and colistin against 30 clinical isolates of Campylobacter spp. The MIC values obtained (range: 0.38-8 mg/liter) were sufficiently low, given the elevated concentrations that colistin sulfate can reach in the intestinal lumen, for this antibiotic to be considered useful to treat severe diarrhea caused by Campylobacter spp. resistant to first-line antibiotics. PMID- 29620789 TI - Infectious meningitis/encephalitis: evaluation of a rapid and fully automated multiplex PCR in the microbiological diagnostic workup. AB - Infectious diseases of the central nervous system (CNS) such as meningitis/encephalitis (ME) require rapid identification of causative pathogens for effective treatment. This study evaluated the analytical performance and clinical utility of a fully automated multiplex PCR test to improve the microbiological diagnostic workup of ME. Seventy-seven cerebrospinal fluid (CSF) samples from 77 patients with suspected ME were studied. The samples were tested by FilmArrayTM (FA) ME Panel test and the results were compared with those obtained using conventional microbiological procedures (CMP). Furthermore, the assay's validity was evaluated testing 5 pooled CSF samples positive for different pathogens. The data showed a good concordance (90.9%) between the FA ME panel test and CMP results. Discrepant results were observed in CSF samples with low viral load (5/77) and in samples of patients (2/77) undergoing antimicrobial therapy for fungal infection. The ability of the FA ME panel test to correctly detect the target pathogens was confirmed. Faster microbiological diagnosis was obtained by the FA ME test in comparison to CMP for both bacterial and viral analytes (P<0.001). Implementation of microbiological diagnostic workup with FA ME panel test may improve the management of patients with suspected CNS infection. PMID- 29620790 TI - John Cunningham virus: an overview on biology and disease of the etiological agent of the progressive multifocal leukoencephalopathy. AB - John Cunningham virus (JCV), the etiological agent of progressive multifocal leukoencephalopathy (PML), is the first human polyomavirus described. After asymptomatic primary infection which occurs in childhood, the virus spreads by the hematogenous route from the primary site of infection to secondary sites including kidneys, lymphoid tissues, peripheral blood leukocytes, and brain to establish latent infection. During immunosuppression the virus undergoes molecular rearrangements that allow it to replicate in glial tissues causing PML. PML occurs in people with underlying immunodeficiency or in individuals being treated with potent immunomodulatory therapies. Although the hypothesis that immune deficiency is a predisposing factor for PML, there are many unsolved issues including the pathogenic mechanisms related to the interaction of JCV infection/reactivation with the host. This is due to the difficulty of propagating the virus in human cell cultures and the absence of an animal model. This review updates current understanding in the context of JCV and human disease. PMID- 29620791 TI - Feasibility of all-oral anti-HCV treatment during DHAP chemotherapy and autologous stem cell transplantation for T-cell lymphoma. AB - The role of anti-HCV direct-acting agents (DAAs) is well described in HCV-related lymphoproliferative disorders, whereas few data are available on their use in other malignancies, such as aggressive T-cell lymphomas requiring autologous stem cell transplantation (ASCT). We describe two oncologic cirrhotic patients treated with DAAs who underwent ASCT achieving cure for both diseases. Co-administration of sofosbuvir with cisplatin led an unexpected severe kidney impairment that did not resolve 30 weeks after drug exposure. The optimal timing of DAA administration in the ASCT setting has yet to be defined: our experience shows that co-administration is feasible, but requires close monitoring for adverse events. PMID- 29620792 TI - Risk-reducing mastectomy for the prevention of primary breast cancer. AB - BACKGROUND: Recent progress in understanding the genetic basis of breast cancer and widely publicized reports of celebrities undergoing risk-reducing mastectomy (RRM) have increased interest in RRM as a method of preventing breast cancer. This is an update of a Cochrane Review first published in 2004 and previously updated in 2006 and 2010. OBJECTIVES: (i) To determine whether risk-reducing mastectomy reduces death rates from any cause in women who have never had breast cancer and in women who have a history of breast cancer in one breast, and (ii) to examine the effect of risk-reducing mastectomy on other endpoints, including breast cancer incidence, breast cancer mortality, disease-free survival, physical morbidity, and psychosocial outcomes. SEARCH METHODS: For this Review update, we searched Cochrane Breast Cancer's Specialized Register, MEDLINE, Embase and the WHO International Clinical Trials Registry Platform (ICTRP) on 9 July 2016. We included studies in English. SELECTION CRITERIA: Participants included women at risk for breast cancer in at least one breast. Interventions included all types of mastectomy performed for the purpose of preventing breast cancer. DATA COLLECTION AND ANALYSIS: At least two review authors independently abstracted data from each report. We summarized data descriptively; quantitative meta analysis was not feasible due to heterogeneity of study designs and insufficient reporting. We analyzed data separately for bilateral risk-reducing mastectomy (BRRM) and contralateral risk-reducing mastectomy (CRRM). Four review authors assessed the methodological quality to determine whether or not the methods used sufficiently minimized selection bias, performance bias, detection bias, and attrition bias. MAIN RESULTS: All 61 included studies were observational studies with some methodological limitations; randomized trials were absent. The studies presented data on 15,077 women with a wide range of risk factors for breast cancer, who underwent RRM.Twenty-one BRRM studies looking at the incidence of breast cancer or disease-specific mortality, or both, reported reductions after BRRM, particularly for those women with BRCA1/2 mutations. Twenty-six CRRM studies consistently reported reductions in incidence of contralateral breast cancer but were inconsistent about improvements in disease-specific survival. Seven studies attempted to control for multiple differences between intervention groups and showed no overall survival advantage for CRRM. Another study showed significantly improved survival following CRRM, but after adjusting for bilateral risk-reducing salpingo-oophorectomy (BRRSO), the CRRM effect on all-cause mortality was no longer significant.Twenty studies assessed psychosocial measures; most reported high levels of satisfaction with the decision to have RRM but greater variation in satisfaction with cosmetic results. Worry over breast cancer was significantly reduced after BRRM when compared both to baseline worry levels and to the groups who opted for surveillance rather than BRRM, but there was diminished satisfaction with body image and sexual feelings.Seventeen case series reporting on adverse events from RRM with or without reconstruction reported rates of unanticipated reoperations from 4% in those without reconstruction to 64% in participants with reconstruction.In women who have had cancer in one breast, removing the other breast may reduce the incidence of cancer in that other breast, but there is insufficient evidence that this improves survival because of the continuing risk of recurrence or metastases from the original cancer. Additionally, thought should be given to other options to reduce breast cancer risk, such as BRRSO and chemoprevention, when considering RRM. AUTHORS' CONCLUSIONS: While published observational studies demonstrated that BRRM was effective in reducing both the incidence of, and death from, breast cancer, more rigorous prospective studies are suggested. BRRM should be considered only among those at high risk of disease, for example, BRCA1/2 carriers. CRRM was shown to reduce the incidence of contralateral breast cancer, but there is insufficient evidence that CRRM improves survival, and studies that control for multiple confounding variables are recommended. It is possible that selection bias in terms of healthier, younger women being recommended for or choosing CRRM produces better overall survival numbers for CRRM. Given the number of women who may be over-treated with BRRM/CRRM, it is critical that women and clinicians understand the true risk for each individual woman before considering surgery. Additionally, thought should be given to other options to reduce breast cancer risk, such as BRRSO and chemoprevention when considering RRM. PMID- 29620793 TI - Antidepressants versus placebo for panic disorder in adults. AB - BACKGROUND: Panic disorder is characterised by repeated, unexpected panic attacks, which represent a discrete period of fear or anxiety that has a rapid onset, reaches a peak within 10 minutes, and in which at least four of 13 characteristic symptoms are experienced, including racing heart, chest pain, sweating, shaking, dizziness, flushing, stomach churning, faintness and breathlessness. It is common in the general population with a lifetime prevalence of 1% to 4%. The treatment of panic disorder includes psychological and pharmacological interventions. Amongst pharmacological agents, the National Institute for Health and Care Excellence (NICE) and the British Association for Psychopharmacology consider antidepressants, mainly selective serotonin reuptake inhibitors (SSRIs), as the first-line treatment for panic disorder, due to their more favourable adverse effect profile over monoamine oxidase inhibitors (MAOIs) and tricyclic antidepressants (TCAs). Several classes of antidepressants have been studied and compared, but it is still unclear which antidepressants have a more or less favourable profile in terms of effectiveness and acceptability in the treatment of this condition. OBJECTIVES: To assess the effects of antidepressants for panic disorder in adults, specifically:1. to determine the efficacy of antidepressants in alleviating symptoms of panic disorder, with or without agoraphobia, in comparison to placebo;2. to review the acceptability of antidepressants in panic disorder, with or without agoraphobia, in comparison with placebo; and3. to investigate the adverse effects of antidepressants in panic disorder, with or without agoraphobia, including the general prevalence of adverse effects, compared to placebo. SEARCH METHODS: We searched the Cochrane Common Mental Disorders' (CCMD) Specialised Register, and CENTRAL, MEDLINE, EMBASE and PsycINFO up to May 2017. We handsearched reference lists of relevant papers and previous systematic reviews. SELECTION CRITERIA: All double-blind, randomised, controlled trials (RCTs) allocating adults with panic disorder to antidepressants or placebo. DATA COLLECTION AND ANALYSIS: Two review authors independently checked eligibility and extracted data using a standard form. We entered data into Review Manager 5 using a double-check procedure. Information extracted included study characteristics, participant characteristics, intervention details and settings. Primary outcomes included failure to respond, measured by a range of response scales, and treatment acceptability, measured by total number of dropouts for any reason. Secondary outcomes included failure to remit, panic symptom scales, frequency of panic attacks, agoraphobia, general anxiety, depression, social functioning, quality of life and patient satisfaction, measured by various scales as defined in individual studies. We used GRADE to assess the quality of the evidence for each outcome MAIN RESULTS: Forty-one unique RCTs including 9377 participants overall, of whom we included 8252 in the 49 placebo-controlled arms of interest (antidepressant as monotherapy and placebo alone) in this review. The majority of studies were of moderate to low quality due to inconsistency, imprecision and unclear risk of selection and performance bias.We found low-quality evidence that revealed a benefit for antidepressants as a group in comparison with placebo in terms of efficacy measured as failure to respond (risk ratio (RR) 0.72, 95% confidence interval (CI) 0.66 to 0.79; participants = 6500; studies = 30). The magnitude of effect corresponds to a number needed to treat for an additional beneficial outcome (NNTB) of 7 (95% CI 6 to 9): that means seven people would need to be treated with antidepressants in order for one to benefit. We observed the same finding when classes of antidepressants were compared with placebo.Moderate-quality evidence suggested a benefit for antidepressants compared to placebo when looking at number of dropouts due to any cause (RR 0.88, 95% CI 0.81 to 0.97; participants = 7850; studies = 30). The magnitude of effect corresponds to a NNTB of 27 (95% CI 17 to 105); treating 27 people will result in one person fewer dropping out. Considering antidepressant classes, TCAs showed a benefit over placebo, while for SSRIs and serotonin-norepinephrine reuptake inhibitor (SNRIs) we observed no difference.When looking at dropouts due to adverse effects, which can be considered as a measure of tolerability, we found moderate-quality evidence showing that antidepressants as a whole are less well tolerated than placebo. In particular, TCAs and SSRIs produced more dropouts due to adverse effects in comparison with placebo, while the confidence interval for SNRI, noradrenergic reuptake inhibitors (NRI) and other antidepressants were wide and included the possibility of no difference. AUTHORS' CONCLUSIONS: The identified studies comprehensively address the objectives of the present review.Based on these results, antidepressants may be more effective than placebo in treating panic disorder. Efficacy can be quantified as a NNTB of 7, implying that seven people need to be treated with antidepressants in order for one to benefit. Antidepressants may also have benefit in comparison with placebo in terms of number of dropouts, but a less favourable profile in terms of dropout due to adverse effects. However, the tolerability profile varied between different classes of antidepressants.The choice of whether antidepressants should be prescribed in clinical practice cannot be made on the basis of this review.Limitations in results include funding of some studies by pharmaceutical companies, and only assessing short-term outcomes.Data from the present review will be included in a network meta-analysis of psychopharmacological treatment in panic disorder, which will hopefully provide further useful information on this issue. PMID- 29620794 TI - Systematic review with meta-analysis: association between acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs) and risk of Crohn's disease and ulcerative colitis exacerbation. AB - BACKGROUND: Unlike acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs) have generally been thought to be associated with increased risk of IBD exacerbation. AIM: To carry out a systematic review and meta-analysis of previous studies examining the association between acetaminophen and NSAIDs including cyclooxygenase (COX-2) inhibitors use, and risk of Crohn's disease (CD) and ulcerative colitis (UC) exacerbation. METHODS: We identified published manuscripts and abstracts through 1 March 2017 by systematic search of Medline, Embase, Cochrane and other trial registries. Quality assessment was done using Newcastle-Ottawa scale and random-effect meta-analysis using pooled relative risks (RRs) and 95% CIs were calculated. RESULTS: Eighteen publications between years 1983 and 2016 were identified. For the meta-analysis, pooled RRs of disease exacerbation with NSAIDs use were (1.42, 95% CI, 0.65-3.09), I2 = 60.3% for CD, and (1.52, 95% CI, 0.87-2.63), I2 = 56.1% for UC. The corresponding values for acetaminophen use were (1.40, 95% CI, 0.96-2.04), I2 = 45.6% for UC, and (1.56, 95% CI, 1.22-1.99), I2 = 0.0% for IBD. Sensitivity analyses limited to studies with low risk of bias showed a significantly increased risk of CD exacerbation (1.53, 95% CI, 1.08-2.16) but not UC (0.94, 95% CI, 0.36-2.42) with NSAIDs use. CONCLUSIONS: Contrary to generally accepted belief, we did not find a consistent association between NSAIDs use and risk of CD and UC exacerbation. There was also no consistent evidence for association with acetaminophen although further studies are needed. PMID- 29620795 TI - Alpha-blockers as medical expulsive therapy for ureteral stones. AB - BACKGROUND: Ureteral colic is a common reason for patients to seek medical care. Alpha-blockers are commonly used to improve stone passage through so-called medical expulsive therapy (MET), but their effectiveness remains controversial. This is an update of a 2014 Cochrane review; since that time, several large randomised controlled trials (RCTs) have been reported, making this update relevant. OBJECTIVES: To assess effects of alpha-blockers compared with standard therapy for ureteral stones 1 cm or smaller confirmed by imaging in adult patients presenting with symptoms of ureteral stone disease. SEARCH METHODS: On 18 November 2017, we searched CENTRAL, MEDLINE Ovid, and Embase. We also searched ClinicalTrials.gov and the WHO Portal/ICTRP to identify all published/unpublished and ongoing trials. We checked all references of included and review articles and conference proceedings for articles relevant to this review. We sent letters to investigators to request information about unpublished or incomplete studies. SELECTION CRITERIA: We included RCTs of ureteral stone passage in adult patients that compared alpha-blockers versus standard therapy. DATA COLLECTION AND ANALYSIS: Two review authors screened studies for inclusion and extracted data using standard methodological procedures. We performed meta-analysis using a random-effects model. Primary outcomes were stone clearance and major adverse events; secondary outcomes were stone expulsion time, number of pain episodes, use of diclofenac, hospitalisation, and surgical intervention. We assessed the quality of evidence on a per-outcome basis using the GRADE approach. MAIN RESULTS: We included 67 studies with 10,509 participants overall. Of these, 15 studies with 5787 participants used a placebo.Stone clearance: Based on the overall analysis, treatment with an alpha-blocker may result in a large increase in stone clearance (risk ratio (RR) 1.45, 95% confidence interval (CI) 1.36 to 1.55; low-quality evidence). A subset of higher-quality, placebo-controlled trials suggest that the likely effect is probably smaller (RR 1.16, 95% CI 1.07 to 1.25; moderate-quality evidence), corresponding to 116 more (95% CI 51 more to 182 more) stone clearances per 1000 participants.Major adverse events: Based on the overall analysis, treatment with an alpha-blocker may have little effect on major adverse events (RR 1.25, 95% CI 0.80 to 1.96; low-quality evidence). A subset of higher-quality, placebo-controlled trials suggest that alpha-blockers likely increase the risk of major adverse events slightly (RR 2.09, 95% CI 1.13 to 3.86), corresponding to 29 more (95% CI 3 more to 75 more) major adverse events per 1000 participants.Patients treated with alpha-blockers may experience shorter stone expulsion times (mean difference (MD) -3.40 days, 95% CI -4.17 to 2.63; low-quality evidence), may use less diclofenac (MD -82.41, 95% CI -122.51 to -42.31; low-quality evidence), and likely require fewer hospitalisations (RR 0.51, 95% CI 0.34 to 0.77; moderate-quality evidence), corresponding to 69 fewer hospitalisations (95% CI 93 fewer to 32 fewer) per 1000 participants. Meanwhile, the need for surgical intervention appears similar (RR 0.74, 95% CI 0.53 to 1.02; low-quality evidence), corresponding to 28 fewer surgical interventions (95% CI 51 fewer to 2 more) per 1000 participants.A predefined subgroup analysis (test for subgroup differences; P = 0.002) suggests that effects of alpha-blockers may vary with stone size, with RR of 1.06 (95% CI 0.98 to 1.15; P = 0.16; I2 = 62%) for stones 5 mm or smaller versus 1.45 (95% CI 1.22 to 1.72; P < 0.0001; I2 = 59%) for stones larger than 5 mm. We found no evidence suggesting possible subgroup effects based on stone location or alpha-blocker type. AUTHORS' CONCLUSIONS: For patients with ureteral stones, alpha-blockers likely increase stone clearance but probably also slightly increase the risk of major adverse events. Subgroup analyses suggest that alpha-blockers may be less effective for smaller (5 mm or smaller) than for larger stones (greater than 5 mm). PMID- 29620796 TI - Recent alcohol use prolongs hospital length of stay following lung transplant. AB - Little is known about the alcohol habits of people with advanced lung disease. Following lung transplantation, patients are asked to abstain from or minimize alcohol use. The aim of this investigation was to assess alcohol use in a cohort of patients with advanced lung disease undergoing evaluation for lung transplant. This is a prospective observational investigation comparing patient self-report of alcohol use with their responses on the Alcohol Use Disorders Identification Test (AUDIT), and alcohol biomarkers collected at the time of transplant. There were 86 included in the cohort, 34% currently using alcohol, 13% had AUDIT scores >3, and 10% had positive results for alcohol biomarkers at the time of transplantation. Patients with evidence of recent alcohol use prior to lung transplant surgery had a 1.5-fold increase in hospital length of stay following lung transplant (P = .028), spent 3 times as long on mechanical ventilation after transplant, and required intensive care unit monitoring nearly 3 times longer than those without recent alcohol use (P = .008). There were no differences in primary graft dysfunction, although several patients with recent alcohol use had post-transplant atrial arrhythmias, acute kidney injury, and acute cellular rejection. Abstaining from alcohol use may optimize outcomes following lung transplant. PMID- 29620797 TI - KNOWLEDGE AND ATTITUDE OF HEALTH CARE WORKERS TOWARD PATIENTS WITH HEPATITIS C INFECTION. AB - This study aimed to evaluate the level of knowledge of healthcare workersin Kutahya (a western province of Turkey) about HCV infection and their attitudestoward patients with hepatitis C infection. A total of 335 healthcare workersworking in Kutahya Evliya Celebi Research and Training Hospital were includedin the study. A questionnaire evaluating demographic characteristics, level ofknowledge and attitudes of healthcare workers toward patients with hepatitis Cinfection was administered to the participants. Thirty-six point four percent ofthe participants were males. According to the occupations, distributions of theparticipants were as followings: 54.6% nurse, 25.1% physician, 11.6% trainee nurse,4.5% intern and 4.2% anesthesia technician. The mean age of healthcare professionalswas 30.32+/-8.10 years. Fifty-eight point eight percent of them experiencedpercutaneous injury. The mean knowledge score was 18.05+/-3.01 (from a total of25). There was a statistically significant relationship between knowledge scoreand age, working year, occupational group (p<0.001). There was also a significantrelationship between total attitude score and gender (p=0.006), age (p=0.002),working year (p=0.021) and occupational group (p<0.001). It was determinedthat as total knowledge score of the participants increased they exhibited a morepositive attitude toward patients with hepatitis C infection (p<0.001). A positiverelationship was determined between the level of knowledge of healthcare workersand positive attitudes toward patients with hepatitis C infection. Therefore,increasing the level of knowledge is necessary for more positive attitudes. PMID- 29620798 TI - A Parametric Study on the Influence of Synthesis and Transfer Conditions on the Quality of Graphene. AB - In this paper, a systematic and comprehensive study has been carried out to observe the effect of synthesis and transfer conditions on the quality and uniformity of graphene deposition in an atmospheric pressure chemical vapour deposition set up. It was observed that the quality of graphene was highly affected by the synthesis conditions, such as, synthesis temperature, synthesis duration, methane and hydrogen flow rate ratio and total flow rate during deposition and cooling cycles. The quality of graphene was observed to be significantly improved upon increasing the synthesis temperature while increase in methane and hydrogen flow rates beyond a particular limit resulted into degradation in the quality of graphene. From the comparison of scanning electron microscopy images of graphene grown at different times, it was found that the nucleation and growth of graphene domains strongly depend on the growth time. The process of transfer of monolayer graphene was significantly improved by controlling the PMMA concentration using a modified three step technique. Raman spectroscopy and the high mobility (~8153 cm2V-1s-1) of graphene after transferred onto a SiO2/Si substrate confirm the high quality of monolayer graphene obtained by the optimizations of synthesis and transfer conditions in this study. PMID- 29620799 TI - HENOCH-SCHONLEIN PURPURA NEPHRITIS FOLLOWING INFLUENZA VACCINATION: A CASE REPORT AND REVIEW OF THE LITERATURE AB - We reported a 16-year-old boy who developed Henoch-Schonleinpurpura (HSP) 15 days after receiving a seasonal influenza vaccine. His symptomsimproved temporally with treatment but he developed HSP nephritis(HSPN) that relapsed multiple times over the following three years. This caseof Henoch-Schonlein purpura may have been due to the seasonal influenzavaccine. The mechanism for this association is unclear. Practitioners shouldbe aware of this possible complication. PMID- 29620800 TI - DETECTION OF BURKHOLDERIA PSEUDOMALLEI FROM POST-FLOOD SOIL SAMPLES IN KELANTAN, MALAYSIA. AB - Burkholderia pseudomallei is an important causative organism of fatalcommunity bacteremia especially in Southeast Asia and northern Australia.Outbreaks of melioidosis have been reported post-floods and -typhoons. A crosssectional study was conducted in January 2015, following a major flood in Kelantan,Malaysia to detect presence of B. pseudomallei from soil. A total of 89 soilsamples were cultured for B. pseudomallei on Ashdown agar. Putative coloniesunderwent further staining and biochemical testing prior to confirmation byPCR. Rate of detection was 1%, although low, it nevertheless indicated a risk formelioidosis among flood victims in Kelantan. Flood affected individuals shouldbe made aware of symptoms of melioidosis and healthcare providers must havea high index of suspicion of patients presenting with fever. Such subjects shouldbe screened for the possibility of melioidosis and given prompt treatment to avoidpreventable death. PMID- 29620801 TI - SXT ELEMENT, CLASS 1 INTEGRON AND MULTIDRUG-RESISTANCE GENES OF VIBRIO CHOLERAEISOLATED FROM CLINICAL AND ENVIRONMENTAL SOURCES IN NORTHEAST THAILAND. AB - Emergence of multiple drug resistance in Vibrio cholerae has beenincreasing around the world including Northeast Thailand. In this study, 92isolates of V. cholerae (50 O1 and 42 non-O1/non-O139 isolates) from clinicaland environmental sources in Northeast Thailand were randomly selectedand investigated for the presence of SXT element, class 1 integron and antimicrobialresistance genes. Genotypic-phenotypic concordance of antimicrobialresistance was also determined. Using PCR-based assays, 79% of V. choleraeisolates were positive for SXT element, whereas only 1% was positive forclass 1 integron. SXT element harbored antimicrobial resistance genes, dfrA1or dfr18, floR, strB, sul2, and tetA. Overall phenotypic-genotypic concordanceof antimicrobial resistance was 78%, with highest and lowest value being fortrimethoprim (83%) and chloramphenicol (70%), respectively. Ninety-twopercent of V. cholerae O1 strains isolated from clinical sources harbored bothdfrA1 (O1-specific trimethoprim resistance gene) and dfr18 (non-O1-specific trimethoprimresistance gene), whereas only 5% of V. cholerae non O1/non-O139strains harbored both genes. All V. cholerae O1 isolated from environmentalsource harbored dfr18 but 48% of V. cholerae non-O1/non-O139 harbored dfrA1.This study indicates that SXT element was the main contributor to the circulationof multiple-drug resistance determinants in V. cholerae strains in NortheastThailand and that genetic exchange of SXT element can occur in both V. choleraeO1 and non-O1/non-O139 strains from clinical and environmental sources. PMID- 29620802 TI - A CAT-BITE WOUND INFECTED WITH VIBRIO ALGINOLYTICUS FOLLOWING USE OF SEA CUCUMBER OIL. AB - Vibrio alginolyticus is a halophilic gram-negative marine pathogen. Themodes of transmission are mainly via direct contact with seawater and indirectcontact through marine creatures. We report here a 28-year-old accountant diagnosedwith right leg abscess after being bitten and scratched by a stray cat. Vibrioalginolyticus was isolated from the pus sample. The patient gave no history ofcontact with ocean water immediately before or after the cat scratch episode. Thepatient did apply commercial sea cucumber oil to the wound; we presume thisis the cause of the Vibrio alginolyticus wound infection. To the best of our knowledge,this is the first reported case of Vibrio alginolyticus wound infection causedby commercially available sea cucumber oil. PMID- 29620803 TI - RISK OF SALMONELLA IN A SUBURBAN REGION OF VIENTIANE, LAO PEOPLE'S DEMOCRATIC REPUBLIC. AB - The study examined non-typhoid Salmonella infection incidence in asuburban region of Vientiane, Lao People's Democratic Republic (PDR), an areathat has undergone rapid economic development in recent years. The researchwas conducted in two rural villages located in the suburb of Vientiane duringthe period 2005 - 2013. Two new methods of non-typhoid Salmonella detection,namely, MY Phenomenon/MIDO Ring and enhanced visibility of color change inmedia, were used to monitor the changes in non-typhoid Salmonella-positivityrate over the 9-year period. Both methods were effective in detecting non-typhoidSalmonella. Non-typhoid Salmonella infection rate in one village decreased duringthe study period. However, further research regarding non-typhoid Salmonella inLao PDR is necessary from an economical point of view. PMID- 29620804 TI - CLINICAL CHARACTERISTICS AND ANTIBIOTIC RESISTANCE PATTERN OF PATHOGENS IN PEDIATRIC URINARY TRACT INFECTION. AB - Medical records of children less than 15-years of age admitted to hospitalfor urinary tract infection (UTI) from January 2010 to December 2014 werereviewed. Among 100 children (59% males and 41% females) with upper UTI,the most common pathogen (88%) was Escherichia coli, of which 69% were nonextendedspectrum beta lactamase (ESBL) and 19 % ESBL producers. Resistance toampicillin and trimethoprim/sulfamethoxazole was 90% and 60%, respectively. AllESBL-producing E. coli were resistant to ampicillin and third generation cephalosporins(cefotaxime and ceftriaxone), while 87% and 1.5% of non ESBL-producingE. coli were resistant to ampicillin and the two third generation cephalosporins,respectively. These data highlight the high prevalence of ESBL-producing E. coliin pediatric UTI and the potential problem in treating such infections. PMID- 29620805 TI - ANTIBIOTIC RESISTANCE AND MORTALITY IN CHILDREN WITH NOSOCOMIAL BLOODSTREAM INFECTION IN A TEACHING HOSPITAL ININDONESIA. AB - Nosocomial infection is a major problem in hospitals worldwide. Understandingpatterns of bacterial etiology and antibiotic susceptibility are importantfactors to combating nosocomial infection. Among children with nosocomialbloodstream infection (BSI), we identified pathogens and determined antibioticsresistance patterns and mortality rates for antibiotic-susceptible and multidrugresistant(MDR) infection in patients with nosocomial BSI in pediatric wardsand PICU at Dr Sardjito Hospital, Indonesia during December 2010 to February2013. Of 174 isolates from 170 patients, 168 pathogens were bacteria, of which148 were gram-negative. Pseudomonas aeruginosa, Klebsiella spp, Enterobacteriaceae,Acinetobacter baumanii, and Escherichia coli was found in 55%, 6%, 4%, 1%,and <1%, respectively of the isolates. Imipenem, amikacin, ciprofloxacin, andceftazadime had the highest sensitivity to nosocomial pathogens at 86%, 84%,84%, and 75%, respectively. Eleven patients had MDR-infections, 7 of whom died.Among 153 patients infected with bacteria resistant to <3 classes of antibiotics(non-MDR), mortality was 40%, and among 4 patients with fully drug susceptiblesepsis only one died. Thus, substantial mortality was observed in children withnosocomial-BSI, particularly with MDR pathogens. Given the further high riskof resistance with wider use of carbapenems, third generation cephalosporinsand flouroquinolones, prevention should be given highest priority in combatinghospital-acquired infection. PMID- 29620806 TI - PREVALENCE AND PREDICTORS OF BACTEREMIA AMONG CHILDREN HOSPITALIZED WITH PNEUMONIA. AB - National guidelines from many countries recommend obtaining bloodculture from children with pneumonia upon hospitalization if the case is moderateto severe. However, etiological, microbes, and health systems vary by countryand factors associated with bacteremia may also vary. We aimed to determinethe prevalence and identify factors associated with bacteremia among childrenhospitalized with community-acquired pneumonia (CAP) in Thailand. We conducteda prospective descriptive study. The study population was children aged60 days to 15 years hospitalized with CAP at King Chulalongkorn MemorialHospital, Bangkok, Thailand from June 2014 to April 2015. We compared subjectwith positive and negative blood cultures. One hundred fifty-two children withCAP were recruited. Thirteen cases (8.6%) had a positive blood culture; 7 cases(4.6%) with a positive blood culture were considered contamination, leaving 6(3.9%) true positive cases. The isolated organisms were Streptococcus pneumoniae,Escherichia coli, and Salmonella group B. Five factors were found to be associatedwith bacteremia: 1) body temperature >38.5 degrees C [odds ratio (OR) = 9], 2) severesepsis status (OR = 27), 3) severe respiratory distress requiring mechanical ventilation(OR = 145), 4) leukocytosis >17,000/MUl (OR = 6), and 5) patchy infiltration(OR=13). Children hospitalized with community acquired pneumonia have a lowrate of bacteremia. The prevalence of subjects in our study with bacteremia was3.9% and there were 3 clinical and 2 laboratory factors significantly associatedwith bacteremia. This study shows that hemoculture do not need to be routinelyperformed in all children hospitalized with CAP. PMID- 29620807 TI - EMERGENCE OF CO-CARBAPENEMASE GENES, BLA(OXA23), BLA(VIM) AND BLA(NDM) IN CARBAPENEMRESISTANT ACINETOBACTER BAUMANNII CLINICAL ISOLATES. AB - This study investigated presence of carbapenemase genes amongcarbapenem-resistant Acinetobacter baumannii (CRAB) clinical isolates and theirclonal relationships. Fifty-six CRAB isolates were collected from patients admittedto Hua Hin Hospital, Prachuap Khiri Khan, Thailand. PCR amplification andDNA sequencing were used to identify blaOXA23, blaOXA40, blaOXA58, blaVIM, blaSIM andblaNDM. Clonal relationship was explored using repetitive element palindromic(REP)-PCR. Plasmid profiling was obtained from EcoRI-digested fragments. TheCRAB isolates were classified by REP-PCR into 12 groups, with 71% belongingto group I, which was associated with the presence of blaOXA23. Co-existence ofblaOXA23 + blaVIM2 (n = 20), blaOXA23 + blaNDM1 (n = 2), blaVIM2 + blaNDM1 (n = 1), andblaOXA23 + blaVIM2 + blaNDM1 (n = 1) were discovered. The emergence of CRAB carryingmultiple types of carbapenemase genes (the first such report in Thailand)is a worrying phenomenon and public health measures should be put in placeto prevent any serious nosocomial infection and to contain the spread of suchCRAB genotypes. PMID- 29620809 TI - NOCARDIA BEIJINGENSIS BRAIN ABSCESS IN AN HIV INFECTED PATIENT: A FIRST CASE REPORT AND LITERATURE REVIEW. AB - We report here brain abscesses caused by Nocardia beijingensis in a59-year-old Thai male with human immunodeficiency virus (HIV) infectionpresenting with progressive right sided hemiparesis. A computed tomographyscan of the brain showed multiple brain abscesses. A stereotactic brain biopsyand 16S rRNA sequencing showed Nocardia beijingensis. The patient was treatedwith trimethoprim sulfamethoxazole and recovered completely. As far as we areaware, this is the first reported case of a brain abscess in an HIV infected patientdue to Nocardia beijingensis. PMID- 29620808 TI - HIGH LEVEL OF SHIGA TOXIN-PRODUCING ESCHERICHIA COLI AND OCCURRENCE OF STX NEGATIVE E. COLI O157 FROM RAW MEATS:CHARACTERIZATION OF VIRULENCE PROFILE AND GENETIC RELATEDNESS. AB - Raw meats, especially beef, are particularly prone to Shiga toxinproducingEscherichia coli (STEC)/enterohemorrhagic E. coli (EHEC) contamination.However, data regarding their quantity in raw meats are seldom reportedin Thailand. Among four common meat types, beef possessed highest value ofstx1-producing E. coli (STEC1) contamination in February 2015 [> 1,100 most probablenumber (MPN)/g] and stx2-producing E. coli (STEC2) highest MPN/g (460) inMarch of the same year. STEC2 was found, for the first time, in shrimp samples inMarch and April, 2015 with MPN/g value of 6.6 and 9.3, respectively. EHEC at 3MPN/g was detected in only one (2%) beef sample. Even though stx-negative E.coli O157 from beef has rarely been reported in Thailand, isolation of E. coli O157using immunomagnetic separation method revealed that four strains (PSVX 1,PSVX-2, PSVX-3, and PSVX-4) from three (8%) beef samples were shown to bestx negative E. coli O157. These strains were members of phylogenetic group A andwere multi-drug resistant. Genetic relatedness as determined by polytrinucleotide(GTG)5-PCR and BOX-PCR showed identical DNA profiles of PSVX-2 andPSVX-4, which by BOX-PCR were 90% to a clinical isolate, O157 strain PSU120,from Hat-Yai Hospital in 2014. The presence of these environment stx negativeE. coli O157 strains with the ability to acquire additional virulence properties couldpose a potential public health problem particularly in this region of Thailand. PMID- 29620810 TI - A CLADOPHIALOPHORA BRAIN ABSCESS IN A RENAL TRANSPLANT RECIPIENT. AB - Cladophialophora bantiana is a dematiceous fungus with neurotrophicpropensity for which therapy is not standardized and mortality is high. We reporthere a 49 year old non-diabetic renal transplant patient on triple immunosuppressanttherapy who presented with a history of falls, weakness and headaches. Acomputed tomography scan of the brain revealed a 30 mm diameter abscess inthe brain which was removed surgically and diagnosed on culture as C. bantiana.The patient was successfully treated medically post-operatively with chronicposaconazole. We review the literature regarding central nervous system infectionsdue to C. bantiana. PMID- 29620812 TI - Rising out-of-pocket costs threaten an already vulnerable population: an introduction to the PAN Foundation and AJMC collaborative supplement. AB - This supplement showcases the winning papers from the PAN Challenge, which aimed to foster conversations about how to rein in out-of-pocket costs to eliminate barriers between patients and their critical medical treatments. PMID- 29620811 TI - PREVALENCE OF HYPERTENSION, ANEMIA, ASYMPTOMATIC URINARY TRACT INFECTION, SYPHILIS, HIV AND HEPATITIS B VIRUS INFECTIONAMONG PREGNANT WOMEN ATTENDING AN ANTENATAL CLINIC AT A RURAL HOSPITAL IN SOUTHERN ETHIOPIA. AB - Antenatal care (ANC) is provided to prevent, diagnose early and treatpregnant women for a variety of diseases. The objective of this study was to determinethe seroprevalences of syphilis, human immunodeficiency virus (HIV)and hepatitis B virus (HVB) and asymptomatic urinary tract infections and theprevalence of hypertension and anemia among pregnant women attending theantenatal clinic at Gambo Rural Hospital in southern Ethiopia. The following testswere conducted among study subjects: hemoglobin (Hgb) level, rapid plasma reagin(RPR) for syphilis, anti-HIV antibodies, hepatitis B surface antigen (HBsAg)and urine analysis. A total of 574 pregnant women were included in this study.The mean age of the participants was 25.7 (SD: 4.8) years old; 88.2% were livingin urban areas and 11.8% in rural areas. Sixty-seven point two percent of participantsbegan their attended care during the second trimester of their pregnancy.Overall, anemia (Hgb < 11 mg/dl) was present in 8.9% (95% CI: 6.9-11.6): severeanemia (Hgb < 7 mg/dl), moderate anemia (Hgb 7-8.9 mg/dl) and mild anemia(Hgb 9-10.9 mg/dl) were found in 0.5% (95% CI: 0.2-1.5), 0.2% (95% CI: 0.03-0.9)and 8.2% (95% CI: 6.2-10.8). The overall prevalence of hypertension was 1.2% (95%CI: 0.06-2.6). This was significantly higher (p=0.01) in the third trimester (3.2%)than in the second (0.5%) and first (0%) trimesters. The prevalence of preeclampsia,defined by have hypertension and proteinuria, was 0.7% (95% CI: 0.3-1.8).Asymptomatic urinary tract infection (having >=10 white blood cells /high powerfield in the urine) was present in 12.7% of participants (95% CI: 10.0-15.5). TheRPR test was positive in two patients (0.3%; 95% CI: 0.1-1.3). The prevalences ofpositive test for HBsAg and HIV-1 were 2.3% (95% CI: 1.3-3.8) and 0.2% (95% CI:0.03-0.9), respectively. No HIV-2 cases were detected. Our data show relativelylow prevalences of anemia, hypertension, urinary tract infection, syphilis, HIV,and hepatitis B virus infections among study subjects at a rural antenatal clinicin southern Ethiopia. PMID- 29620813 TI - Ensuring access to prescription medications in the post-ACA healthcare access landscape: the essential role of FQHCs in the safety net for the underinsured. AB - OBJECTIVES: Federally qualified health centers (FQHCs) are essential to underinsured populations in the safety net by offering them several means of access to reduced cost medications. This study employed a 2-pronged approach to evaluate FQHCs' role, estimating both the need for patient assistance and the impact of the safety net. STUDY DESIGN: A multiyear panel data study for post Affordable Care Act (ACA) years 2012 to 2016 and a 2016 cross-sectional analysis design were utilized to analyze FQHCs, their patient populations, and prescription assistance programs. METHODS: Publicly available Health Resources and Services Administration (HRSA) Uniform Data System data were merged with HRSA Office of Pharmacy Affairs Information System data on 340B programs. Descriptive statistics were produced to evaluate the need for patient assistance, costs, and conditions treated at FQHCs. RESULTS: There were 1337 FQHCs serving more than 2.5 million patients, nearly 29% of whom were uninsured. FQHCs utilized 2 programs to provide affordable, reduced-cost prescriptions for patients without insurance: 1) the HRSA 340B Drug Pricing Program and 2) prescription assistance programs, which rely on pharmaceutical manufacturer donations of reduced-cost medications or coupons. Although these programs were effective at providing affordable prescriptions, program accessibility varied widely by state and FQHC resources. CONCLUSIONS: Despite changes in the healthcare access landscape due to the ACA, underinsured populations remain prevalent and the need for financial assistance with medications persists. FQHCs are uniquely situated to provide access to these essential services. Further policy and funding efforts, such as expansion of 340B programs, could assist FQHCs in fulfilling the role of prescription safety-net providers. PMID- 29620814 TI - Impact of trained oncology financial navigators on patient out-of-pocket spending. AB - OBJECTIVES: Patients with cancer often face financial hardships, including loss of productivity, high out-of-pocket (OOP) costs, depletion of savings, and bankruptcy. By providing financial guidance and assistance through specially trained navigators, hospitals and cancer care clinics may be able mitigate the financial burdens to patients and also minimize financial losses for the treating institutions. STUDY DESIGN: Financial navigators at 4 hospitals were trained through The NaVectis Group, an organization that provides training to healthcare staff to increase patient access to care and assist with OOP expenses. Data regarding financial assistance and hospital revenue were collected after instituting these programs. METHODS: Amount and type of assistance (free medication, new insurance enrollment, premium/co-pay assistance) were determined annually for all qualifying patients at the participating hospitals. RESULTS: Of 11,186 new patients with cancer seen across the 4 participating hospitals between 2012 and 2016, 3572 (32%) qualified for financial assistance. They obtained $39 million in total financial assistance, averaging $3.5 million per year in the 11 years under observation. Patients saved an average of $33,265 annually on medication, $12,256 through enrollment in insurance plans, $35,294 with premium assistance, and $3076 with co-pay assistance. The 4 hospitals were able to avoid write-offs and save on charity care by an average of $2.1 million per year. CONCLUSIONS: Providing financial navigation training to staff at hospitals and cancer centers can significantly benefit patients through decreased OOP expenditures and also mitigate financial losses for healthcare institutions. PMID- 29620815 TI - A descriptive study of patients receiving foundational financial assistance through local specialty pharmacies. AB - OBJECTIVES: To describe the population of patients who received financial assistance from the Good Days Foundation (GDF) as facilitated by Walgreens local specialty pharmacies (LSPs). STUDY DESIGN: This was a retrospective descriptive study. METHODS: This study used a joint foundational and pharmacy claim database between January 1, 2014, and December 31, 2016. RESULTS: Among 1572 eligible patients who received GDF financial assistance as facilitated by Walgreens LSPs, 1524 had disease state information and 14 of these patients receveived financial assistance for 2 disease states (patient count denominator, 1538). The top 3 disease states by patient count were oncology (1403; 91.2%), multiple sclerosis (49; 3.2%), and hepatitis C (39; 2.5%). Of the 777 patients who had complete data and disease state information, 2 received finanical assistance for 2 disease states (denominator, 779); oncology remained the disease with the highest patient count (724; 92.9%). The mean annual financial assistance per patient was highest for hepatitis C ($4156), followed by oncology ($3603) and miscellaneous/rare disease ($1829), which covered 98.8%, 99.3%, and 99.6% of these patients' total co-pay requirements, respectively. In addition to prescription co-pay assistance, 21 patients received travel assistance of $554 per year per patient from GDF. The mean persistence of oncology patients was 170.7 days without a 30-day gap over 1 year of observation time. CONCLUSIONS: The facilitation of treatment by GDF and Walgreens LSPs may be the key to many patients receiving their treatment and maintaining medication persistence. GDF co-pay assistance helped cover most out of-pocket costs associated with medications and aided with travel expenses for patients, especially in the area of oncology. For many patients, this meant reducing the significant financial barriers to accessing care and facilitating the necessary treatment for their chronic or life-altering disease. Without this assistance, many patients would simply not have been able to meet the expected medication persistence and thus would have received suboptimal treatment. PMID- 29620816 TI - Introduction to basal insulin therapy: clinical management of diabetes. AB - Diabetes is a series of metabolic conditions associated with many serious comorbidities, such as heart disease and stroke, peripheral arterial disease and lower-extremity amputations, retinopathy, nephropathy, and peripheral neuropathy. The American Diabetes Association, the American Association of Clinical Endocrinologists, and the International Diabetes Federation recommend that individuals with diabetes be as near to normoglycemic as possible. There are many glycemic management barriers among patients, such as cost, patient perceptions, and clinical inertia. Advancements in the treatment of diabetes with novel pharmacotherapeutic products have changed the therapeutic landscape of diabetes. Newer longer-acting insulin products that closely resemble endogenous insulin secretion patterns are demonstrating some improvements in clinical outcomes. PMID- 29620817 TI - Evaluating the managed care implications of longer-acting basal insulin analog therapies. AB - Diabetes, particularly type 2 diabetes (T2D), has become an epidemic in the United States, with a significant portion of patients unable to meet recommended glycemic targets. All individuals with type 1 diabetes (T1D) and a significant majority of those with T2D will ultimately require insulin therapy. However, there are several barriers to its use. The introduction of the new, ultra-long acting basal insulins degludec and glargine U-300, and the single-injection combinations of insulin degludec/liraglutide and insulin glargine U 100/lixisenatide, offer options that may overcome several of those barriers, including the high risk of hypoglycemia, glycemic variability, and relatively short duration of action. This article spotlights the outcomes of the phase 3 clinical trials for these newer formulations, as well as more recent meta analyses and real-world studies. It also highlights the implications for managed care plans as they move to add these insulins to their formularies. PMID- 29620818 TI - PILOT SCREENING PROGRAM FOR THALASSEMIA IN A COUNTRY WITH LIMITED RESOURCES: A COLLABORATION MODEL BETWEEN CLOSENEIGHBORING COUNTRIES. AB - Screening for thalassemia carriers should not only be conducted inmiddle-income countries but also can be possible in low-middle income countries,through cooperation of experienced professionals from middle income countries.We describe a collaborating model between two close neighboring countries inestablishing such a screening program for thalassemia. After training and settingup of facilities, a total of 152 out of 187 hospital staff were screened as a pilotactivity to encourage community participation. Referring system for sendingblood samples to a reference center in Thailand was also established. Among 152health staff, 12.5% alpha0-thal, 2% beta-thal and 13% Hb E carriers were found. Applyingthalassemia screening to 411 pregnant women and 71 spouses, 5 couples at risk ofbearing a child of thalassemia disease were identified. The thalassemia screeningprogram has a sensitivity of 99.5%, specificity of 77%, positive predictive value of73%, and negative predictive value of 99.5%. Thus, it is possible to operate a thalassemiascreening program with acceptable performance in a low-middle incomecountry (Lao People's Democratic Republic) with the cooperation of a referralcenter located within close proximity in a middle income country (Thailand). PMID- 29620819 TI - FIRST IDENTIFICATION OF HEMOGLOBIN LANSINGRAMATHIBODI [alpha87(F8)His -> Gln; CAC>CAG (HBA1: c.264C>G)] IN A THAI FAMILY WITHSPURIOUS HYPOXEMIA. AB - We report, for the first time, hemoglobin (Hb) Lansing-Ramathibodi[alpha87(F8)His -> Gln; CAC>CAG (HBA1: c.264C>G)] in four members of a Thaifamily presented with low measured oxygen saturation by pulse oximetry (SpO2),with discrepancy between low SpO2 and normal calculated oxygen saturation byarterial blood gas analysis, and no cyanosis or methemoglobinemia. The causativemutation is located in HBA1 whereas in previous reports of Hb Lansingthe mutation is on HBA2, including that in a Japanese individual. The indexand a male sibling also co-inherited Hb Pakse, a non-deletional alpha-thalassemia 2,resulting in mild reticulocytosis. Correct Hb identification is crucial for geneticcounselling and, thereby, avoiding unnecessary investigation and treatment forspurious hypoxemia. PMID- 29620820 TI - COMPARISON OF MEDICAL COSTS AND CARE OF APPENDECTOMY PATIENTS BETWEEN FEE-FOR SERVICE AND SET FEE FOR DIAGNOSIS-RELATED GROUP SYSTEMS IN 20 CHINESE HOSPITALS. AB - The objective of this study was to compare the fee-for-service and setfee for diagnosis-related group systems with regard to quality of medical careand cost to appendectomy patients. We conducted a retrospective study of 208inpatients (from 20 hospitals) who undergone appendectomy in Changsha, Chinaduring 2013. Data were obtained from databases of medical insurance informationsystems directly connected to the hospital information systems. We collectedand compared patient ages, length of study, and total medical costs for impatientappendectomies between patients using fee-for-service and set fee for diagnosisrelatedgroup systems. One hundred thirty-three patients used the fee for servicesystem and 75 used the set fee diagnosis related group system. For those usingthe diagnosis related group system, the mean length of hospitalization (6.2 days)and mean number of prescribed antimicrobials (2.4) per patient were significantlylower than those of the patients who used the fee-for-service system (7.3 daysand 3.0, respectively; p = 0.018; p < 0.05) and were accompanied by lower medicalcosts and cost of antimicrobials (RMB 2,518 versus RMB 4,484 and RMB476 versusRMB1,108, respectively; p = 0.000, p = 0.000). There were no significant differencesin post surgical complications between the two systems. The diagnosis-relatedgroup system had significantly medical costs for appendectomy compared to thefee-for-service system, without sacrificing quality of medical care. PMID- 29620822 TI - PREVALENCE AND FACTORS INFLUENCING BETEL NUT CHEWING AMONG ADULTS IN WEST INSEIN TOWNSHIP, YANGON, MYANMAR. AB - Betel nut chewing can cause precancerous oral lesions and is commonin Myanmar. We conducted a cross sectional study aimed to estimate prevalenceand factors influencing betel nut chewing among 420 subjects aged >=18 years inWest Insein Township, Yangon, Myanmar in order to inform preventive healthprograms. The mean age of the study subjects was 45(+/-15) years. The overallprevalence of current betel nut chewing among study subjects was 55.2%. Themean age starting betel nut chewing was 29(+/-13) years, and the mean durationof chewing was 15(+/-13) years. The reasons given by study subjects for chewingbetel nut included the addictive effect to betel nut, to release tension, to get ridof boredom and to stop smoking. Sixty-two point three percent of current betelnut chewers also chewed tobacco and 24.2% also smoked cigarettes. Factors significantlyassociated with betel nut chewing were male gender, current alcoholconsumer, having no education or finishing primary or secondary school, havinga low score regarding their attitude about the health effects of betel nut chewing,and having high score on interpersonal factors by family and peer pressure. Ourresults show a need to better educate the public about the health effects of betelnut chewing among the study population. PMID- 29620821 TI - EFFECT OF INSTITUTION-BASED MANAGEMENT FOR ELDERLY HEALTH PROMOTION PROGRAM IN NORTHEASTERN THAILAND. AB - The increasingly aging population raises a major challenge for healthcare in Thailand and worldwide. Health promotion has been considered a strategyfor improving elderly quality of life. There are a small number of elderly peopleliving in government elderly services in Thailand, and little is known about theirhealth promotion behaviors and how these behaviors have been shaped in aninstitution-based setting. This study aimed to examine the current situation andeffectiveness of the Institution-based Management for Elderly Health Promotion(IBM-EHP) program in enhancing the health and health promotion behaviors ofthe elderly living in two out of five government elderly home service institutes(GEHSI) in northeastern Thailand. The elderly participants in one GEHSI wereassigned into the management group and received the IBM-EHP program (n=60),and those in another GEHSI were in the control group and received the usual careprovided by the institution (n=55). Before and after (six months) the programimplementation, assessments of knowledge, self-efficacy, received social support,health promotion behaviors, and health status depicted by fasting plasma glucoselevel and lipid profile of the participants in both groups were performed. Datacollection used an interview guide, and clinical and diagnostic measurementmethods. Data analysis used frequency, mean, standard deviation, paired simplet-test, independent t-test, and multiple regression. Results indicated that the managementgroup, compared to the control group, demonstrated improvements inperceived self-efficacy, received social support, health promotion behaviors, andHDL-C level (p<0.05). Perceived self-efficacy and received social support werepredictive factors, which contributed to explain 50.6% of the health promotionbehaviors of the institutionalized elderly participants in the management group.Modification solutions for suitable health promotion behaviors of the institutionalizedelderly persons should emphasize on enhancing their self efficacy and socialsupport from the elderly home service institute and their peers. PMID- 29620823 TI - A 3-MONTH STUDY OF FLUORIDE RELEASE FROM DIFFERENT CALCIUM PHOSPHATE FLUORIDE VARNISHES ON PRIMARY TEETH. AB - A range of dental varnishes containing several calcium and phosphatecompounds in addition to fluoride to promote remineralization have recently beencommercialized. However, the fluoride varnish in the presence of calcium andphosphate can react to form relative poorly soluble phases and its bioavailability.Most of previous studies have focused on fluoride release over a short period. Thepurpose of this in vitro study was to evaluate the fluoride release from differentfluoride varnishes on primary teeth during 3 months. Twenty five sound primaryincisors were randomly divided into five groups: Group A control group (notreatment), Group B - 5% sodium fluoride varnish (5%NaF)(Duraphat(r)), GroupC-5% sodium fluoride plus tricalcium phosphate varnish (5%NaF+TCP)(ClinproTMWhite), Group D- 5% sodium fluoride plus amorphous calcium phosphate varnish(5%NaF+ACP)(Enamel Pro(r)), and Group E-5% sodium fluoride plus tricalciumphosphate varnish (5%NaF+TCP)(Mahidol). The samples were then immersedin artificial saliva at room temperature until used. The concentration of fluoridereleased was measured with F-ion-specific electrode at 2, 4, 8, 12, 24, and 48 hoursand then weekly for three months. To analyze the results, we used the one-wayANOVA and Tukey's multiple comparison tests at a 95% level of confidence. GroupE had the greatest initial fluoride release within the first 24 hours and Group B hadthe lowest initial release fluoride of the treatment groups. Group B had a slowerrate of decline in fluoride release over time than the other treatment groups. By3 months, the varnishes with the highest to the lowest release of fluoride wereGroup B=C>E>D>A. All the treatment samples released more fluoride than thecontrol group. Duraphat(r)(5%NaF) and Clinprotm(5%NaF+TCP) had the highestrelease of fluoride at 3-month evaluation. The TCP fluoride varnish released morefluoride than the ACP fluoride varnish by 3 months. PMID- 29620824 TI - PREVALENCE, SEVERITY AND FACTORS ASSOCIATED WITH DENTAL FLUOROSIS AMONG CHILDREN AGED 8-10 YEARS IN BANGKOK, THAILAND. AB - This study aimed to evaluate the prevalence and factors associated withdental fluorosis in permanent incisors among children aged 8-10 years in Bangkok,Thailand. We studied 707 children selected by stratified randomization andexamined each of them to determine their Dean's fluorosis index. Parents of thestudied children were asked to fill out a questionnaire. The study was conductedfrom July to October 2014. Chi-square test and multiple logistic regression analysiswere used to study the association between various factors and fluorosis amongstudy subjects. Dental fluorosis was found in 18.4% of subjects. Sixteen point onepercent and 2.3% of 707 subjects had very mild fluorosis and mild fluorosis, respectively.Factors significantly associated with dental fluorosis were family income(aOR=1.77; 95% CI: 1.10-2.86, p=0.02) and history of taking fluoride supplements(aOR=1.66; 95% CI: 1.07-2.61, p=0.03). This study indicated that the prevalence offluorosis had increased in Bangkok, but the majority was very mild level. PMID- 29620825 TI - FLUORIDE CONTENT OF COMMERCIALLY AVAILABLE BOTTLED DRINKING WATER IN BANGKOK, THAILAND. AB - The use of bottled drinking water may be a source of fluoride and couldbe a risk factor for fluorosis among infants and young children. The aim of thisstudy was to evaluate the fluoride content of commercially available bottled drinkingwater in Bangkok, Thailand. Forty-five water samples (15 samples of plainwater and 30 samples of mineral water) were purchased from several supermarketsin Bangkok, Thailand. Three bottles of each water sample were purchased,and the fluoride content of each sample was measured twice using a combinationfluoride-ion selective electrode. The average reading for each sample was thencalculated. Data were analyzed by descriptive statistics. Differences betweenmineral and plain water samples were determined by Student's t-test. The mean(+/-SD) fluoride content for all the water samples was 0.17 (+/-0.17) mg F/l (range:0.01-0.89 mg F/l). Six brands (13%) tested stated the fluoride content on the label.The actual fluoride content in each of their brands varied little from the label.Eight samples (18%) had a fluoride content >0.3 mg F/l and two samples (4%)had a fluoride content >0.6 mg F/l. The mean mineral water fluoride concentrationwas significantly higher than the mean fluoride concentration of plain water(p=0.001). We found commercially sold bottled drinking water in Bangkok, Thailandcontained varying concentrations of fluoride; some with high concentrationsof fluoride. Health professions need to be aware this varying fluoride content ofbottled drinking water and educate the parents of infants and small children aboutthis when prescribing fluoride supplements. Consideration should be made tohave fluoride content put on the label of bottled water especially among brandswith a content >0.3 mg F/l. PMID- 29620826 TI - Annealing Temperature Dependent Structural and Optical Properties of RF Sputtered ZnO Thin Films. AB - This work investigates the effect of annealing temperature on structural and optical properties of ZnO thin films grown over Si 100 and glass substrates using RF sputtering technique. Annealing temperature has been varied from 300 degrees C to 600 degrees C in steps of 100, and different microstructural parameters such as grain size, dislocation density, lattice constant, stress and strain have been evaluated. The structural and surface morphological characterization has been done using X-ray Diffraction (XRD) and Scanning Electron Microscope (SEM). XRD analysis reveals that the peak intensity of 002 crystallographic orientation increases with increased annealing temperature. Optical characterization of deposited films have been done using UV-Vis-NIR spectroscopy and photoluminescence spectrometer. An increase in optical bandgap of deposited ZnO thin films with increasing annealing temperature has been observed. The average optical transmittance was found to be more than 85% for all deposited films. Photoluminiscense spectra (PL) suggest that the crystalline quality of deposited film has increased at higher annealing temperature. PMID- 29620827 TI - Functionalization of Nanodiamond with Four Kinds of Expoxies. AB - In this work, a simple and effective method for the covalent functionalization of nanodiamond (ND) with four epoxies has been developed. After homogenization by mixed acids and thionyl chlorides, the surface of ND was modified with triethylenetetramine (TETA) to possess amine groups, which were used as active points to react with epoxy by ring opening reaction. Four different epoxies used are bifunctional diglycidyl ether of bisphenol-A (DGEBA), trifunctional triglycidyl p-amino phenol (TGAP), tetrafunctional tetraglycidyldiamino diphenylmethane (TGDDM) and bisphenol-A novolac epoxy resin (BAEPN). FT-IR spectra revealed that the epoxy was covalently attached to the ND (ND-g-epoxy). In addition, functionalized ND particles were characterized with WAXD and UV-Vis spectra to confirm the result. The weight gains as a result of the epoxy functionalized ND were determined by TGA analysis. The ND-g-epoxy particles were better dispersed in common organic solvents and the average diameters were characterized. The better dispersion and of the modified ND were identified from the SEM images. PMID- 29620828 TI - Photocatalytic Reduction of Carbon Dioxide by Using Bare and Copper Oxide Impregnated Nano Titania Catalysts. AB - Synthesis of nano TiO2 has been done by sol-gel method. Various weight percentages (1%, 3%, 5%, 7% and 10% w/w) of CuO were impregnated over titania. Physicochemical and instrumental characterization of all the catalysts confirmed the crystallinity, structure and morphology of titania and CuO supported titania. The bandgap value of TiO2 decreased from 3.22 eV to 2.82 eV with increase in the impregnation of CuO. Synthesized catalysts and TiO2 (Degussa P25) were evaluated towards the photocatalytic reduction of carbon dioxide under UV irradiation (lambda = 254 nm and 6 W). The reduction ability of the most active catalyst was also tested under visible irradiation and compared with that of bare titania. Photocatalytic reduction of carbon dioxide yielded the products such as methanol, formic acid, formaldehyde and among them methanol was found to be the predominant product. Among the catalysts 3%CuO/TiO2 yielded the highest amount of methanol both at 8 hours and 20 hours of UV irradiation (1814 MUmol/g cat and 4120 MUmol/g cat respectively). Three times recycling the best catalyst (3%CuO/TiO2) yielded 3080 MUmol of methanol per gram of the catalyst. The slight loss in catalytic activity is attributed to difficulty in recovering the catalyst. 3%CuO/TiO2 also yielded 408 MUmol/g cat of methanol at under visible irradiation. This catalyst on complete reduction and partial oxidation yielded 3%Cu/TiO2 and 3%Cu2O/TiO2. Both reduced and partially oxidized catalysts showed less reduction ability of CO2 than 3%CuO/TiO2. PMID- 29620829 TI - Spongy Nanostructures. AB - Spongy structures are hollow-containing materials, encountered in natural or synthesized zeolites, spongy carbon, etc. The design and topological study of some hypothetical spongy nanostructures is presented in terms of map operations and genus calculation of their associated graphs, respectively. Among the discussed structures one remarks some novel spongy polyhedra that can evolve with 1-periodicity or radially, to provide multi-shell cages. Filling the space inside such complex nanostructures can be achieved by small fullerenes that self-arrange in aggregates with a well-defined geometry, of which energy trends to a minimal value. The way of space filling varies function of the dimension and shape of composing small fullerenes. An attempt of building and stability evaluating of several fullerene aggregates was made. The calculations were made at the HF, DFT and DFTB level of theory. The design of nanostructures was performed by our original software packages CVNET and Nano Studio. PMID- 29620831 TI - Synthesize Large-Diameter and Porous Carbon Nanotubes with Nickel Nanowires as the Template. AB - We report a method to synthesize Large-diameter and porous carbon nanotubes (LPCNTs) by carbon segregation with nickel nanowires (Ni-NWs) as the template. Unlike carbon nanotubes synthesized via conventional routes, the wall thickness is determined by the carburization time and the tube diameter and length are followed the template. The surface and structure of the LPCNTs were characterized by scanning and transmission electron microscopy (SEM and TEM), the LPCNTs retained their original tube shape, the thickness of the wall of the tube could be controlled, and a great amount of pores formed in the tube wall, the capacitance of the LPCNTs with the unique porous structure tube were increased compared with the Large-diameter CNTs (LCNTs), and the capacitance of the LPCNTs and LCNTs were 61 F/g and 78 F/g, respectively. We also performed further heat treatment at high temperature to improve the quality of the tube, resulting in a substantial changed of its morphology, the tubes exhibit relatively straight, smooth of its morphology, and the larger diameter was substantially shrink. PMID- 29620832 TI - Effects of MgO Nanocrystal Powder on Long-Term Sustain and Address Discharge Characteristics in ac-Plasma Display Panel. AB - We investigated the characteristics of MgO surface with MgO nanocrystal powders due to the longterm (500 hours) ion bombardment comparing with the conventional MgO surface in this study. When the MgO nanocrystal powders were coated on the conventional MgO surface, it was observed that the sputtered Mg particles from MgO surface were re-deposited on the MgO nanocrystal powders, which was able to significantly suppress the re-crystallization on the phosphor layers. We confirm that the MgO nanocrystal powders play a significant role in suppressing the degradation of the MgO surface and phosphor layer after long-term severe ion bombardments. Accordingly, when the MgO nanocrystal powers were applied to the conventional MgO surface, the variations of discharge characteristics, such as address discharge delay time, firing voltage of sustain and address discharge, and luminance, were significantly reduced comparing with the conventional MgO surface. PMID- 29620833 TI - LifePo4 Coated Homogeneously with 3D Carbon Nanotube Conductive Networks for Enhanced Electrochemical Performance. AB - LiFePO4 (LFP) microparticles coated homogeneously with three-dimensional (3D) carbon nanotube (CNT) conductive networks were successfully prepared via a simple and effective ball milling method by controlling Polyvinylidene fluoride (PVDF) content in cathode electrode slurry. Scanning electron microscopy (SEM) demonstrated that the electrical bridge between the LFP could be well modulated by varying the amount of the CNTs and PVDF. The LFP/CNTs composite with 3 wt% CNTs and 5 wt% PVDF, in which CNTs are embedded in the microspheres homogeneously, possesses the best 3D CNT conductive networks and exhibits the best electrochemical property with high capacity retention of 95.72% at 0.25 C after 50 cycles. Essentially, in comparison with those samples without CNT networks, this CNT network structure can greatly enhance the electrical conductivity, thus markedly improving the electrochemical performance. (LFP) microparticles coated homogeneously with three-dimensional (3D) carbon nanotube (CNT) conductive networks were successfully prepared via a simple and effective ball milling method by controlling Polyvinylidene fluoride (PVDF) content in cathode electrode slurry. Scanning electron microscopy (SEM) demonstrated that the electrical bridge between the LFP could be well modulated by varying the amount of the CNTs and PVDF. The LFP/CNTs composite with 3 wt% CNTs and 5 wt% PVDF, in which CNTs are embedded in the microspheres homogeneously, possesses the best 3D CNT conductive networks and exhibits the best electrochemical property with high capacity retention of 95.72% at 0.25 C after 50 cycles. Essentially, in comparison with those samples without CNT networks, this CNT network structure can greatly enhance the electrical conductivity, thus markedly improving the electrochemical performance. PMID- 29620834 TI - Sol-Gel Derived Al-Ga Co-Doped ZnO Thin Films Embedded with Microrods. AB - Aluminium-gallium (Al-Ga) co-doped ZnO (AGZO) thin films with different Al-Ga at.% were spin coated on glass substrates using sol-gel spin coating technique. Morphological images by atomic force microscopy (AFM) and field emission scanning electron microscopy (FESEM) reveal that the granular structures of co-doped films are embedded with microrods, which has never been reported before. The density of the microrods increases with higher co-doping at.%. The Hall Transport measurements reveal that the electrical properties of the co-doped films are comparable with single Ga doped ZnO films, which implies that the co-doping method can be a way forward to reduce the fabrication cost of the doped ZnO films involving expensive raw material. Also, the unique features of the AGZO films embedded with microrods may create new opportunity for these films to be implemented in emerging optoelectronic devices such as solar cells and organic light emitting diodes. PMID- 29620835 TI - Enhancement of Power Conversion Efficiency of TiO2-Based Dye-Sensitized Solar Cells on Various Acid Treatment. AB - The surface modification of the TiO2 photoelectrode film is one of the promising ways to improve the photovoltaic performance of dye-sensitized solar cell (DSSC). In this work for the acid treatment of TiO2 powder, fluorine containing compounds such as trifluoroacetic acid was carried out to enhance the properties of photoanode. In order to investigate the effect of trifluoroacetyl group, the TiO2 nanopowders were also treated with different acids such as acetic acid, nitric acid, hydrochloric acid, and sulfuric acid and their properties were compared. The TiO2 powders treated with both acetic acid and TFA have possessed smooth surface morphologies as well as enhanced particle dispersions with reduced particle sizes. Photoelectrodes prepared for these two kinds of TiO2 powders accommodated high amounts of dye loading and exhibited excellent light transmittance (wavelength region of 400-600 nm). Electrochemical impedance spectroscopy analysis showed the smallest radius of the semicircle which indicates the enhanced rate of electron transport for the cell based photoelectrode with trifluoroacetic acid treated TiO2 powder. The solar cell from the untreated TiO2 film showed the power conversion efficiency of 8.86% and the highest efficiency of 9.51% was achieved by the cell fabricated from trifluoroacetic acid treated TiO2 film. PMID- 29620836 TI - Fabrication of In(0.75)Zn(1.5)Sn(1.0) (IZTO) Thin-Film Transistors Using Solution Processable Materials and PZT Inkjet-Printing. AB - Recently, Thin Film Transistors (TFTs) have been studied widely because of potential applications in low cost, low-temperature process and flexible displays. They can be fabricated by easy processes based on solution methods. But the mobility of organic TFTs is lower and the threshold voltage is higher than amorphous Si TFTs. In order to enhance the channel mobility and satisfy with the requirement of low-cost fabrication, we prepare a low-cost, mask-free, reduced material wastage, deposited technology using transparent, directly printable, air stable semiconductor slurries and dielectric solutions. In our investigations, we attempt to obtain a high performance and low-cost TFT via preparing materials, designing device structure, and using PZT inkjet-printing technology. A stable and non-precipitated metal oxide ink with appropriate doping was prepared for the fabrication of an InxZn1.5Sn1.0 (IZTO) by PZT inkjet-printing. The soluble direct printing process is a powerful tool for material research and implies that the printable materials and the printing technology enable the use of all-printed low cost flexible displays and other transparent electronic applications. Transparent materials including dielectric PVP, conductive carbon nanotube (CNT) and active IZTO were employed into the fabrication of our PZT inkjet-printing process. After annealed at 180 degrees C, The experimental all-printed TFT exhibit the carrier mobility of 0.194 cm2/Vs, sub-threshold slope of 20 V/decade, and the threshold voltage of 5 V, initially. All-inkjet-printed films have great transparency, potentially in transparent electronics and the transmittance pattern in visible part of the spectrum (400-700 nm) is over 80%. PMID- 29620837 TI - Surface Modification of Fe(3)O(4)@SiO(2) Magnetic Nanoparticles for Immobilization of Lipase. AB - Magnetic Fe(3)O(4) nanoparticles were prepared through hydrothermal method and coated with silica on the surface to obtain Fe3O4@SiO2 core-shell nanoparticles. After modification with different functional groups including aldehyde, amine and diimide, the nanoparticles were used as carrier for covalent immobilization of lipase. The nanoparticles with aldehyde groups showed highest immobilization yield (52.8%) and efficiency (86.5%). And the immobilization conditions including pH, temperature and the concentration of enzyme were optimized. After immobilization, the K m of lipase was altered from 2.3 to 3.2 mM. The thermal stability and pH stability were enhanced by immobilization at the investigated conditions: pH 5.0-8.0 and temperature 30-70 degrees C. After 10 batches conversion of 4-Nitrophenyl palmitate into p-Nitrophenol, the immobilized lipase retained over 75% of the original activity. Compared with the commercial lipase Novozym435, the immobilized lipase showed better stability and higher catalytic efficiency. These results demonstrate that the immobilized lipase on the modified Fe3O4@SiO2 magnetic nanoparticles has enhanced stability and reusability, which make lipase of potential interest in a number of industrial applications. PMID- 29620838 TI - Enhanced Circular Dichroism of Gold Bilayered Slit Arrays Embedded with Rectangular Holes. AB - Gold bilayered slit arrays with rectangular holes embedded into the metal surface are designed to enhance the circular dichroism (CD) effect of gold bilayered slit arrays. The rectangular holes in these arrays block electric currents and generate localized surface plasmons around these holes, thereby strengthening the CD effect. The CD enhancement factor depends strongly on the rotational angle and the structural parameters of the rectangular holes; this factor can be enhanced further by drilling two additional rectangular holes into the metal surfaces of the arrays. These results help facilitate the design of chiral structures to produce a strong CD effect and large electric fields. PMID- 29620839 TI - Synergistic Effect Between Tea Polyphenols and Aluminum Flake on the Reduction of Graphene Oxide. AB - Chemical reduction of graphene oxide (GO) using nontoxic reductants is a promising and green approach to produce graphene with versatile functionalities in large scale. However, the relatively low reduction extent of the reduced graphene oxide (RGO) is the main hindrance for many applications. In the present work, significantly enhanced reduction of aqueous RGO suspension is achieved by the chemical reduction with combination of tea polyphenols (TPs) and aluminum flake. In comparison with the RGO reduced by TPs only, the defect of the RGO achieved by the combination of TPs and aluminum flake decrease by 6.70%. The sp 2 structure fraction in the RGO increases by 9.67% due to the synergistic effect between TPs and aluminum flake. In addition, a possible mechanism for the synergistic effect between TPs and aluminum flake on the enhanced reduction of RGO is proposed. This approach provides new significant insights on the efficient and environmentally friendly preparation of RGO with much improved quality. PMID- 29620840 TI - Direct Synthesis of Carbon Sheathed Tungsten Oxide Nanoparticles via Self Assembly Route for High Performance Electrochemical Charge Storage Electrode. AB - Using a stabilizing agent-assisted co-assembly method, a novel nanocomposite of mesoporous carbon embedded with uniform tungsten oxide nanorods is obtained, which is converted into carbon-sheathed tungsten oxide nanoparticles by delicate calcination and further reduction. Through optimization of tungsten content, it is found that highly crystalline tungsten oxide nanoparticles are uniformly coated with an ultra-thin carbon layer. When applied into electrochemical charge storage electrodes for supercapacitor and lithium-ion battery, an excellent average capacitance (129 F g-1, above 400 F cm-3), higher rate performance and significantly advanced cycle stability are observed. These improved charge storage properties are attributed to improved electrical conductivity and enhanced structural stability, which is induced by uniform carbon coating on partially reduced tungsten oxide nanoparticles. PMID- 29620841 TI - In-Situ Growth of CoS Nanoparticles Onto Electrospun Graphitized Carbon Nanofibers as an Efficient Counter Electrode for Dye-Sensitized Solar Cells. AB - One-dimensional graphitized carbon nanofibers (G-CNFs) were prepared by employing facile electrospinning technique using 10 wt% of polyacrylonitrile (PAN) solution in N,N-dimethyl formamide (DMF) as precursor followed by successive stabilization, carbonization and purification processes. Cobalt sulfide (CoS) nanoparticles were grown onto G-CNFs by hydrothermal method using cobalt chloride and L-cysteine as precursors. The results of X-ray diffraction (XRD) and Raman spectroscopy confirmed the phase formation and degree of graphitization, respectively. Field-emission scanning electron microscope (FE-SEM) and transmission electron microscope (TEM) images confirmed the morphology, growth and distribution of CoS nanoparticles over G-CNFs (CoS/G-CNFs). The electrochemical studies such as cyclic voltammetry (CV), electrochemical impedance and Tafel polarization revealed that CoS/G-CNFs have lower overpotential, low charge transfer resistance and higher exchange current density for triiodide (I- 3 reduction reaction. The superior electrocat- alytic activity of CoS/G-CNFs than std. Pt is due to combined contribution of interconnected pore structure with high surface area of G-CNFs and excellent electrocatalytic activity of CoS. In addition, the dye sensitized solar cell (DSSC) based on platinum-free CoS/G-CNFs has exhibited higher photo-conversion efficiency (PCE) under a simulated solar light irradiation of 100 mW cm-2 when compared to standard platinum (std. Pt) which is attributed to the synergistic effect of CoS with G-CNFs. PMID- 29620842 TI - Spontaneous and Selective Nanowelding of Silver Nanowires by Electrochemical Ostwald Ripening and High Electrostatic Potential at the Junctions for High Performance Stretchable Transparent Electrodes. AB - Metal nanowires have been gaining increasing attention as the most promising stretchable transparent electrodes for emerging field of stretchable optoelectronic devices. Nanowelding technology is a major challenge in the fabrication of metal nanowire networks because the optoelectronic performances of metal nanowire networks are mostly limited by the high junction resistance between nanowires. We demonstrate the spontaneous and selective welding of Ag nanowires (AgNWs) by Ag solders via an electrochemical Ostwald ripening process and high electrostatic potential at the junctions of AgNWs. The AgNWs were welded by depositing Ag nanoparticles (AgNPs) on the conducting substrate and then exposing them to water at room temperature. The AgNPs were spontaneously dissolved in water to form Ag+ ions, which were then reduced to single-crystal Ag solders selectively at the junctions of the AgNWs. Hence, the welded AgNWs showed higher optoelectronic and stretchable performance compared to that of as-formed AgNWs. These results indicate that electrochemical Ostwald ripening-based welding can be used as a promising method for high-performance metal nanowire electrodes in various next-generation devices such as stretchable solar cells, stretchable displays, organic light-emitting diodes, and skin sensors. PMID- 29620844 TI - Facile Sol-Gel-Derived Craterlike Dual-Functioning TiO2 Electron Transport Layer for High-Efficiency Perovskite Solar Cells. AB - Organic-inorganic hybrid perovskite solar cells (PSCs) are considered promising materials for low-cost solar energy harvesting technology. An electron transport layer (ETL), which facilitates the extraction of photogenerated electrons and their transport to the electrodes, is a key component in planar PSCs. In this study, a new strategy to concurrently manipulate the electrical and optical properties of ETLs to improve the performance of PSCs is demonstrated. A careful control over the Ti alkoxide-based sol-gel chemistry leads to a craterlike porous/blocking bilayer TiO2 ETL with relatively uniform surface pores of 220 nm diameter. Additionally, the phase separation promoter added to the precursor solution enables nitrogen doping in the TiO2 lattice, thus generating oxygen vacancies. The craterlike surface morphology allows for better light transmission because of reduced reflection, and the electrically conductive craterlike bilayer ETL enhances charge extraction and transport. Through these synergetic improvements in both optical and electrical properties, the power conversion efficiency of craterlike bilayer TiO2 ETL-based PSCs could be increased from 13.7 to 16.0% as compared to conventional dense TiO2-based PSCs. PMID- 29620843 TI - Biofunctionalized 3D Nanopillar Arrays Fostering Cell Guidance and Promoting Synapse Stability and Neuronal Activity in Networks. AB - A controlled geometry of in vitro neuronal networks allows investigation of the cellular mechanisms that underlie neuron-to-neuron and neuron-extracellular matrix interactions, which are essential to biomedical research. Herein, we report a selective guidance of primary hippocampal neurons by using arrays of three-dimensional vertical nanopillars (NPs) functionalized with a specific adhesion-promoting molecule-poly-dl-ornithine (PDLO). We show that 90% of neuronal cells are guided exclusively on the combinatorial PDLO/NP substrate. Moreover, we demonstrate the influence of the interplay between nanostructures and neurons on synapse formation and maturation, resulting in increased expression of postsynaptic density-95 protein and enhanced network cellular activity conferred by the endogenous c-fos expression. Successful guidance to foster synapse stability and cellular activity on multilevel cues of surface topography and chemical functionalization suggests the potential to devise technologies to control neuronal growth on nanostructures for tissue engineering, neuroprostheses, and drug development. PMID- 29620845 TI - Thermomchromic Reaction-Induced Reversible Upconversion Emission Modulation for Switching Devices and Tunable Upconversion Emission Based on Defect Engineering of WO3:Yb3+,Er3+ Phosphor. AB - Reversible luminescence modulation of upconversion phosphors has the potential applications as photoswitches and optical memory and data storage devices. Previously, the photochromic reaction was extensively used for the realization of reversible luminescence modulation. It is very necessary to develop other approaches such as thermomchromic reaction to obtain the reversible upconversion luminescence modulation. In this work, the WO3:Yb3+,Er3+ phosphors with various colors were prepared at various temperatures, exhibiting tunable upconversion luminescence attributed to the formation of oxygen vacancies in the host. Upon heat treatment in the reducing atmosphere or air, the WO3:Yb3+,Er3+ phosphors show a reversible thermomchromic property. The reversible upconversion luminescence modulation of WO3:Yb3+,Er3+ phosphors was observed based on thermomchromic reaction. Additionally, the upconversion luminescence modulation is maintained after several cycles, indicating its excellent stability. The WO3:Yb3+,Er3+ phosphors with reversible upconversion luminescence and excellent reproducibility have potential applications as the photoswitches and optical memory and data storage devices. PMID- 29620846 TI - Dielectric Properties of Bio-Based Diphenolate Ester Epoxies. AB - Thermoset bio-based diglycidyl ether of diphenolate esters (DGEDP) exhibit comparable mechanical properties as petroleum-derived diglycidyl ether of bisphenol A (DGEBA), whereas DGEDP is derived from levulinic acid, a safe and readily renewable feedstock. To determine the potential replacement of DGEBA as dielectric materials, a series of DGEDP-esters (i.e., methyl, ethyl, propyl, and butyl esters) were synthesized and studied. Broadband dielectric spectroscopy revealed that DGEDP-propyl has the highest dielectric constant in the series, comparable to DGEBA. Differences in the dielectric properties of DGEDP-esters is attributed to the interplay of segmental, small local, and side-chain motions on one hand and free volume and steric hindrance on the other. PMID- 29620847 TI - Trace Detection of Organophosphorus Chemical Warfare Agents in Wastewater and Plants by Luminescent UIO-67(Hf) and Evaluating the Bioaccumulation of Organophosphorus Chemical Warfare Agents. AB - Organophosphorus chemical warfare agents (OPCWAs) are a group of organic pollutants characterized by high toxicity and chemical stability, and they are very difficult to be degraded. The trace quality of OPCWAs in water and food will cause great harm to the human body. Therefore, the detection of OPCWAs is a difficult challenge, which has become the research hotspot over the world. In this work, a Hf-based luminescent metal-organic framework (Eu@1) is prepared, and the reactivity of Hf12 results in a methanephosphonic acid (MPA)-induced luminescence quenching and the charge transfer from MPA to Hf(IV) and generated exciplexes which are responsible for this quenching effect. The excellent performance of Eu@1 in the detection of MPA, with its finer selectivity, high sensitivity (LOD = 0.4 ppm), and large linear range (10-7 to 10-3 M), is encouraging for application in wastewater detection. Importantly, MPA is a pollutant that can be absorbed by plants and causes the bioaccumulation effect, and thus, the detection of MPA in real plant samples is a purposeful topic. Eu@1 also achieved satisfactory results in actual plant sample testing, and the bioaccumulation of MPA in onions, turnips, and cabbages is determined via our sensor. This fabricated detector provides a feasible path for the detection of ppm-level OPCWAs in a complex environment, which will help humans to avoid OPCWA contaminated foods. PMID- 29620848 TI - Integrated Interface Strategy toward Room Temperature Solid-State Lithium Batteries. AB - Solid-state lithium batteries have drawn wide attention to address the safety issues of power batteries. However, the development of solid-state lithium batteries is substantially limited by the poor electrochemical performances originating from the rigid interface between solid electrodes and solid-state electrolytes. In this work, a composite of poly(vinyl carbonate) and Li10SnP2S12 solid-state electrolyte is fabricated successfully via in situ polymerization to improve the rigid interface issues. The composite electrolyte presents a considerable room temperature conductivity of 0.2 mS cm-1, an electrochemical window exceeding 4.5 V, and a Li+ transport number of 0.6. It is demonstrated that solid-state lithium metal battery of LiFe0.2Mn0.8PO4 (LFMP)/composite electrolyte/Li can deliver a high capacity of 130 mA h g-1 with considerable capacity retention of 88% and Coulombic efficiency of exceeding 99% after 140 cycles at the rate of 0.5 C at room temperature. The superior electrochemical performance can be ascribed to the good compatibility of the composite electrolyte with Li metal and the integrated compatible interface between solid electrodes and the composite electrolyte engineered by in situ polymerization, which leads to a significant interfacial impedance decrease from 1292 to 213 Omega cm2 in solid-state Li-Li symmetrical cells. This work provides vital reference for improving the interface compatibility for room temperature solid state lithium batteries. PMID- 29620849 TI - Folic Acid Targeting for Efficient Isolation and Detection of Ovarian Cancer CTCs from Human Whole Blood Based on Two-Step Binding Strategy. AB - Studies regarding circulating tumor cells (CTCs) have great significance for cancer prognosis, treatment monitoring, and metastasis diagnosis. However, due to their extremely low concentration in peripheral blood, isolation and enrichment of CTCs are the key steps for early detection. To this end, targeting the folic acid receptors (FRs) on the CTC surface for capture with folic acid (FA) using bovine serum albumin (BSA)-tether for multibiotin enhancement in combination with streptavidin-coated magnetic nanoparticles (MNPs-SA) was developed for ovarian cancer CTC isolation. The streptavidin-biotin-system-mediated two-step binding strategy was shown to capture CTCs from whole blood efficiently without the need for a pretreatment process. The optimized parameters for this system exhibited an average capture efficiency of 80%, which was 25% higher than that of FA-decorated magnetic nanoparticles based on the one-step CTC separation method. Moreover, the isolated cells remained highly viable and were cultured directly without detachment from the MNPs-SA-biotin-CTC complex. Furthermore, when the system was applied for the isolation and detection of CTCs in ovarian cancer patients' peripheral blood samples, it exhibited an 80% correlation with clinical diagnostic criteria. The results indicated that FA targeting, in combination with BSA-based multibiotin enhancement magnetic nanoparticle separation, is a promising tool for CTC enrichment and detection of early-stage ovarian cancer. PMID- 29620850 TI - Enhancement in Proton Conductivity and Thermal Stability in Nafion Membranes Induced by Incorporation of Sulfonated Carbon Nanotubes. AB - Proton exchange membrane fuel cell (PEMFC) is one of the most promising green power sources, in which perfluorinated sulfonic acid ionomer-based membranes (e.g., Nafion) are widely used. However, the widespread application of PEMFCs is greatly limited by the sharp degradation in electrochemical properties of the proton exchange membranes under high temperature and low humidity conditions. In this work, the high-performance sulfonated carbon nanotubes/Nafion composite membranes (Su-CNTs/Nafion) for the PEMFCs were prepared and the mechanism of the microstructures on the macroscopic properties of membranes was intensively studied. Microstructure evolution in Nafion membranes during water uptake was investigated by positron annihilation lifetime spectroscopy, and results strongly showed that the Su-CNTs or CNTs in Nafion composite membranes significantly reinforced Nafion matrices, which influenced the development of ionic-water clusters in them. Proton conductivities in Su-CNTs/Nafion composite membranes were remarkably enhanced due to the mass formation of proton-conducting pathways (water channels) along the Su-CNTs. In particular, these pathways along Su-CNTs in Su-CNTs/Nafion membranes interconnected the isolated ionic-water clusters at low humidity and resulted in less tortuosity of the water channel network for proton transportation at high humidity. At a high temperature of 135 degrees C, Su-CNTs/Nafion membranes maintained high proton conductivity because the reinforcement of Su-CNTs on Nafion matrices reduced the evaporation of water molecules from membranes as well as the hydrophilic Su-CNTs were helpful for binding water molecules. PMID- 29620851 TI - Antimicrobial Amino-Functionalized Nitrogen-Doped Graphene Quantum Dots for Eliminating Multidrug-Resistant Species in Dual-Modality Photodynamic Therapy and Bioimaging under Two-Photon Excitation. AB - Developing a nanomaterial, for use in highly efficient dual-modality two-photon photodynamic therapy (PDT) involving reactive oxygen species (ROS) generation and for use as a two-photon imaging contrast probe, is currently desirable. Here, graphene quantum dots (GQDs) doped with nitrogen and functionalized with an amino group (amino-N-GQDs) serving as a photosensitizer in PDT had the superior ability to generate ROS as compared to unmodified GQDs. Multidrug-resistant (MDR) species were completely eliminated at an ultralow energy (239.36 nJ pixel-1) through only 12 s two-photon excitation (TPE) in the near-infrared region (800 nm). Furthermore, the amino-N-GQDs had an absorption wavelength of approximately 800 nm, quantum yield of 0.33, strong luminescence, an absolute cross section of approximately 54 356 Goeppert-Mayer units, a lifetime of 1.09 ns, a ratio of the radiative to nonradiative decay rates of approximately 0.49, and high two-photon stability under TPE. These favorable properties enabled the amino-N-GQDs to act as a two-photon contrast probe for tracking and localizing analytes through in depth two-photon imaging in a three-dimensional biological environment and concurrently easily eliminating MDR species through PDT. PMID- 29620852 TI - Three MOF-Templated Carbon Nanocomposites for Potential Platforms of Enzyme Immobilization with Improved Electrochemical Performance. AB - An efficient and facile metal-organic framework (MOF)-template strategy for preparing carbon nanocomposites has been developed. First of all, a series of metal ions, including Fe3+, Zr4+, and La3+, were respectively connected with 2 aminoterephthalate (H2ATA) to form three metal-organic frameworks (MOFs) and then three novel MOF-derived materials were obtained by annealing them at 550 degrees C under N2 atmosphere. The morphologies and microstructure results showed that they still retained the original structure of MOFs and formed carbon-supported metal oxide hybrid nanomaterials. Interestingly, it was found that La-MOF-NH2 and its derived materials were first reported, which had wool-ball-like structure formed by many streaky-shaped particles intertwining each other. Furthermore, these MOF-derived materials were all successfully used as effective immobilization matrixes of acetylcholinesterase (AChE) to construct biosensors for the detection of methyl parathion. Especially, [La-MOF-NH2]N2 with wool-ball like structure not only provided more active sites of multicontents to increase AChE immobilization amount but also facilitated the accessibility of electron transfer and shorten their diffusion length on the surface of electrode. Under optimal conditions, the biosensor based on [La-MOF-NH2]N2 displayed the widest linear range of 1.0 * 10-13-5.0 * 10-9 g mL-1 and the lowest detection limit of 5.8 * 10-14 g mL-1 in three biosensors. This study illustrates the feasibility and the potential of a series of MOF-derived materials for biosensors with improved electrochemical performance. PMID- 29620853 TI - Anomalous Photovoltaic Response of Graphene-on-GaN Schottky Photodiodes. AB - Graphene has attracted great attention as an alternative to conventional metallic or transparent conducting electrodes. Despite its similarities with conventional electrodes, recent studies have shown that a single-atom layer of graphene possesses unique characteristics, such as a tunable work function and transparencies for electric potential, reactivity, and wetting. Nevertheless, a systematic analysis of graphene and semiconductor junction characteristics has not yet been carried out. Here, we report the photoresponse characteristics of graphene-on-GaN Schottky junction photodiodes (Gr-GaN SJPDs), showing a typical rectifying behavior and distinct photovoltaic and photoelectric responses. Following the initial abrupt response to UV illumination, the Gr-GaN SJPDs exhibited a distinct difference in photocarrier dynamics depending on the applied bias voltage, which is characterized by either a negative or positive change in photocurrent with time. We propose underlying mechanisms for the anomalous photocarrier dynamics based on the interplay between electrostatic molecular interactions over the one-atom-thick graphene and GaN junction and trapped photocarriers at the defect states in the GaN thin film. PMID- 29620854 TI - Existence of Solid Electrolyte Interphase in Mg Batteries: Mg/S Chemistry as an Example. AB - Magnesium redox chemistry is a very appealing "beyond Li ion chemistry" for realizing high energy density batteries due to the high capacity, low reduction potential, and most importantly, highly reversible and dendrite-free Mg metal anode. However, the progress of rechargeable Mg batteries has been greatly hindered by shortage of electrolytes with wide stability window, high ionic conductivity, and good compatibility with cathode materials. Unlike solid electrolyte interphase on Li metal anode, surface film formed by electrolyte decomposition in Mg batteries was considered to block Mg ion transport and passivate Mg electrode. For this reason, the attention of the community has been mainly focusing on surface layer free electrolytes, while reductively unstable salts/solvents are barely considered, despite many of them possessing all the necessary properties for good electrolytes. Here, for the first time, we demonstrate that the surface film formed by electrolyte decomposition can function as a solid electrolyte interphase (SEI). Using Mg/S chemistry as a model system, the SEI formation mechanism on Mg metal anode was thoroughly examined using electrochemical methods and surface chemistry characterization techniques such as EDX and XPS. On the basis of these results, a comprehensive view of the Mg/electrolyte interface that unifies both the SEI mechanism and the passivation layer mechanism is proposed. This new picture of surface layer on Mg metal anode in Mg batteries not only revolutionizes current understanding of Mg/electrolyte interface but also opens new avenues for electrolyte development by uncovering the potential of those reductively unstable candidates through interface design. PMID- 29620855 TI - Charge Properties of TiO2 Nanotubes in NaNO3 Aqueous Solution. AB - Charging of material surfaces in aqueous electrolyte solutions is one of the most important processes in the interactions between biomaterials and surrounding tissue. Other than a biomaterial, titania nanotubes (TiO2 NTs) represent a versatile material for numerous applications such as heavy metal adsorption or photocatalysis. In this article, the surface charge properties of titania NTs in NaNO3 solution were investigated through electrophoretic mobility and polyelectrolyte colloid titration measuring techniques. In addition, we used high resolution transmission electron microscopy imaging to determine the morphology of TiO2 NTs. A theoretical model based on the classical density functional theory coupled with the charge regulation method in terms of mass action law was developed to understand the experimental data and to provide insights into charge properties at different physical conditions, namely, pH and NaNO3 concentration. Two intrinsic protonation constants and surface site density have been obtained. The electrostatic properties of the system in terms of electrostatic potentials and ion distributions were calculated and discussed for various pH values. The model can quantitatively describe the titration curve as a function of pH for higher bulk salt concentrations and the difference in the equilibrium amount of charges between the inner and outer surfaces of TiO2 NTs. Calculated counterion (NO3-) distributions show a pronounced decrease of NO3- ions for high bulk pH (both inside and outside TiO2 NT) because of the strong electric field. With the decrease of bulk pH or the increase of the salt concentration, NO3- is able to accumulate near the TiO2 NTs surfaces. PMID- 29620856 TI - A Bottle-around-a-Ship Method To Generate Hollow Thin-Shelled Particles Containing Encapsulated Iron Species with Application to the Environmental Decontamination of Chlorinated Compounds. AB - Thin-shelled hollow silica particles are synthesized using an aerosol-based process where the concentration of a silica precursor tetraethyl orthosilicate (TEOS) determines the shell thickness. The synthesis involves a novel concept of the salt bridging of an iron salt, FeCl3, to a cationic surfactant, cetyltrimethylammonium bromide (CTAB), which modulates the templating effect of the surfactant on silica porosity. The salt bridging leads to a sequestration of the surfactant in the interior of the droplet with the formation of a dense silica shell around the organic material. Subsequent calcination consistently results in hollow particles with encapsulated iron oxides. Control of the TEOS levels leads to the generation of ultrathin-shelled (~10 nm) particles which become susceptible to rupture upon exposure to ultrasound. The dense silica shell that is formed is impervious to entry of chemical species. Mesoporosity is restored to the shell through desilication and reassembly, again using CTAB as a template. The mesoporous-shelled hollow particles show good reactivity toward the reductive dichlorination of trichloroethylene (TCE), indicating access of TCE to the particle interior. The ordered mesoporous thin-shelled particles containing active iron species are viable systems for chemical reaction and catalysis. PMID- 29620857 TI - Synthesis of Sub-10 nm Two-Dimensional Covalent Organic Thin Film with Sharp Molecular Sieving Nanofiltration. AB - We demonstrated here a novel and facile synthesis of two-dimensional (2D) covalent organic thin film with pore size around 1.5 nm using a planar, amphiphilic and substituted heptacyclic truxene based triamine and a simple dialdehyde as building blocks by dynamic imine bond formation at the air/water interface using Langmuir-Blodgett (LB) method. Optical microscopy (OM), scanning electron microscopy (SEM), transmission electron microscopy (TEM), and atomic force microscopy (AFM), all unanimously showed the formation of large, molecularly thin and free-standing membrane that can be easily transferred on different substrate surfaces. The 2D membrane supported on a porous polysulfone showed a rejection rate of 64 and 71% for NaCl and MgSO4, respectively, and a clear molecular sieving at molecular size around 1.3 nm, which demonstrated a great potential in the application of pretreatment of seawater desalination and separation of organic molecules. PMID- 29620858 TI - Multifunctional Wearable Electronic Textiles Using Cotton Fibers with Polypyrrole and Carbon Nanotubes. AB - Multifunctional wearable electronic textiles based on interfacial polymerization of polypyrrole on carbon nanotubes/cotton fibers offer advantages of simple and low-cost materials that incorporate bactericidal, good electrochemical performance, and electrical heating properties. The high conductivity of doped polypyrrole/CNT composite provides textiles that reaches temperature on order of 70 degrees C with field of 5 V/cm, superior electrochemical performance applied as electrodes of supercapacitor prototypes, reaching capacitance in order of 30 F g-1 and strong bactericidal activity against Staphylococcus aureus. The combination of these properties can be explored in smart devices for heat and microbial treatment on different parts of body, with incorporated storage of energy on textiles. PMID- 29620859 TI - Insight Investigation of Active Palladium Surface Sites in Palladium-Ceria Catalysts for NO + CO Reaction. AB - The palladium species in ceria-based catalysts have a significant influence on their catalytic performance. In this work, the structure evolution of palladium species induced by various calcination rate was investigated and then these calcined catalysts were applied to NO + CO catalytic reaction. Systematic investigations by various measurements demonstrate that the calcination rate and catalytic process play crucial roles on the formation ways of palladium species and identify the forms of active palladium surface sites for NO + CO reaction. Results indicate that the calcination process resulted in the formation of three types of palladium components: PdO interacted with ceria supports (PdO x/Pd-O-Ce cluster), PdO nanoparticles on the surface, and Pd2+ ions incorporated into the subsurface lattice (Pd-O-Ce solid solution). It is also proven that the state and distribution of palladium components are dependent on the calcination rate: rapid calcination rate is beneficial for the generation of PdO species (PdO x/Pd-O-Ce and PdO), while slow calcination rate makes contribution to the formation of Pd-O Ce. Furthermore, the subsequent catalytic process could induce the decomposition of PdO x/Pd-O-Ce and formation of more fractions of active Pd species in PdO oxide phase. On the basis of the catalytic performances, we found the superior catalytic properties are detected for catalysts containing 0.5% Pd (0.5% is corresponding to the palladium content in molar ratio) with fast calcination rate. This is due to the synergistic effect of active Pd in PdO decomposed form PdO x/Pd-O-Ce in the catalytic process and the palladium ions in Pd-O-Ce solid solution. PMID- 29620860 TI - Acid-Promoted One-Pot Synthesis of Substituted Furan and 6-Methylpyrazin-2(1 H) one Derivatives via Allene Intermediate Formed in Situ. AB - Under the acidic conditions, substituted furans were constructed from gamma alkynyl ketones through corresponding allene intermediates in one-pot. The methodology was also tailored to a series of the Ugi reaction products for the synthesis of 6-methylpyrazin-2(1 H)-one derivatives. The current method offered significant advantages for the combinatorial applications of these chemical scaffolds. PMID- 29620861 TI - Enhancing Photovoltaic Performance of Inverted Planar Perovskite Solar Cells by Cobalt-Doped Nickel Oxide Hole Transport Layer. AB - Electron and hole transport layers have critical impacts on the overall performance of perovskite solar cells (PSCs). Herein, for the first time, a solution-processed cobalt (Co)-doped NiO X film was fabricated as the hole transport layer in inverted planar PSCs, and the solar cells exhibit 18.6% power conversion efficiency. It has been found that an appropriate Co-doping can significantly adjust the work function and enhance electrical conductivity of the NiO X film. Capacitance-voltage ( C- V) spectra and time-resolved photoluminescence spectra indicate clearly that the charge accumulation becomes more pronounced in the Co-doped NiO X-based photovoltaic devices; it, as a consequence, prevents the nonradiative recombination at the interface between the Co-doped NiO X and the photoactive perovskite layers. Moreover, field-dependent photoluminescence measurements indicate that Co-doped NiO X-based devices can also effectively inhibit the radiative recombination process in the perovskite layer and finally facilitate the generation of photocurrent. Our work indicates that Co-doped NiO X film is an excellent candidate for high-performance inverted planar PSCs. PMID- 29620862 TI - Gelatin-Based Photocurable Hydrogels for Corneal Wound Repair. AB - In this study, an injectable, photocurable gelatin system, consisting of acrylated gelatin and thiolated gelatin, with tunable mechanical, biodegradation, and biological properties was used as a potential cell-supportive scaffold for the repair of focal corneal wounds. The mechanical property of hydrogels can be readily modified (postcure shear modulus of between 0.3 and 22 kPa) by varying the ratio of acrylate to thiol groups, photointensity, and solid content, and the biodegradation times also varied with the change of solid content. More importantly, the generated hydrogels exhibited excellent cell viability in both cell seeding and cell encapsulation experiments. Furthermore, the hydrogels were found to be biocompatible with rabbit cornea and aided the regeneration of a new tissue under a focal corneal wound (exhibiting epithelial wound coverage in <3d), and ultraviolet irradiation did not have any obvious harmful effect on the cornea and posterior eye segment tissues. Along with their injectability and tunable mechanical properties, the photocurable thiol-acrylate hydrogels showed promise as corneal substitutes or substrates to construct a new corneal tissue. PMID- 29620863 TI - Soft and Flexible Bilayer Thermoplastic Polyurethane Foam for Development of Bioinspired Artificial Skin. AB - Inspired by the epidermis-dermis composition of human skin, here we have simply developed a lightweight, robust, flexible, and biocompatible single-electrode triboelectric nanogenerator (S-TENG)-based prototype of bilayer artificial skin, by attaching one induction electrode with unfoamed skin layer of microcellular thermoplastic polyurethane (TPU) foam, which shows high-performance object manipulation [by responding differently toward different objects, viz., aluminum foil, balloon, cotton glove, human finger, glass, rubber glove, artificial leather, polyimide, poly(tetrafluoroethylene) (PTFE), paper, and wood], due to electrification and electrostatic induction during contact with the objects having different chemical functionalities. Comparative foaming behavior of ecofriendly supercritical fluids, viz., CO2 over N2 under variable temperatures (e.g., 130 and 150 degrees C) and constant pressure (15 MPa), have been examined here to pursue the soft and flexible triboelectric TPU foam. The foam derived by CO2 foaming at 150 degrees C has been prioritized for development of S-TENG. Foam derived by CO2 foaming at 130 degrees C did not respond as well due to the smaller cell size, higher hardness, and thicker skin. Inflexible N2-derived foam was not considered for S-TENG fabrication. Object manipulation performance has been visualized by principal component analysis (PCA), which shows good discrimination among responses to different objects. PMID- 29620864 TI - Interfacial Kinetics and Ionic Diffusivity of the Electrodeposited MoS2 Film. AB - The transition-metal disulfide (MoS2) is a fantastic material used in diverse fields of applications. Ionic diffusivity and interfacial exchange current density are model parameters that play a crucial role for the optimization of device performances, which are not clearly known for this material. The additive free dense film of MoS2 has been deposited by a facile electrodeposition approach and characterized by structural, morphological, and compositional analyses. This report provides the characterization of interfacial charge-transfer kinetics and diffusion of lithium ion in the MoS2 films as a function of lithium concentration at 25 degrees C temperature. The interfacial exchange current density is observed to be varied barely, ~0.069-0.066 mA/cm2, with the change of lithium content, from x = 0.01-0.25, in Li xMoS2. The ionic diffusivity of the film is found to be in the range of ~3 * 10-11-10-11 cm2 s-1 and does not vary much with the measured lithium concentration window. The electrochemical performances of the material are limited by the transport of lithium ion and interfacial kinetics over the measured state of lithium content. A submicron-size particle with high surface area is needed to be used as an electrode of the material for practical C rates. PMID- 29620865 TI - Utilizing van der Waals Slippery Interfaces to Enhance the Electrochemical Stability of Silicon Film Anodes in Lithium-Ion Batteries. AB - High specific capacity anode materials such as silicon (Si) are increasingly being explored for next-generation, high performance lithium (Li)-ion batteries. In this context, Si films are advantageous compared to Si nanoparticle based anodes since in films the free volume between nanoparticles is eliminated, resulting in very high volumetric energy density. However, Si undergoes volume expansion (contraction) under lithiation (delithiation) of up to 300%. This large volume expansion leads to stress build-up at the interface between the Si film and the current collector, leading to delamination of Si from the surface of the current collector. To prevent this, adhesion promotors (such as chromium interlayers) are often used to strengthen the interface between the Si and the current collector. Here, we show that such approaches are in fact counter productive and that far better electrochemical stability can be obtained by engineering a van der Waals "slippery" interface between the Si film and the current collector. This can be accomplished by simply coating the current collector surface with graphene sheets. For such an interface, the Si film slips with respect to the current collector under lithiation/delithiation, while retaining electrical contact with the current collector. Molecular dynamics simulations indicate (i) less stress build-up and (ii) less stress "cycling" on a van der Waals slippery substrate as opposed to a fixed interface. Electrochemical testing confirms more stable performance and much higher Coulombic efficiency for Si films deposited on graphene-coated nickel (i.e., slippery interface) as compared to conventional nickel current collectors. PMID- 29620866 TI - MIDAS: A Modular DNA Assembly System for Synthetic Biology. AB - A modular and hierarchical DNA assembly platform for synthetic biology based on Golden Gate (Type IIS restriction enzyme) cloning is described. This enabling technology, termed MIDAS (for Modular Idempotent DNA Assembly System), can be used to precisely assemble multiple DNA fragments in a single reaction using a standardized assembly design. It can be used to build genes from libraries of sequence-verified, reusable parts and to assemble multiple genes in a single vector, with full user control over gene order and orientation, as well as control of the direction of growth (polarity) of the multigene assembly, a feature that allows genes to be nested between other genes or genetic elements. We describe the detailed design and use of MIDAS, exemplified by the reconstruction, in the filamentous fungus Penicillium paxilli, of the metabolic pathway for production of paspaline and paxilline, key intermediates in the biosynthesis of a range of indole diterpenes-a class of secondary metabolites produced by several species of filamentous fungi. MIDAS was used to efficiently assemble a 25.2 kb plasmid from 21 different modules (seven genes, each composed of three basic parts). By using a parts library-based system for construction of complex assemblies, and a unique set of vectors, MIDAS can provide a flexible route to assembling tailored combinations of genes and other genetic elements, thereby supporting synthetic biology applications in a wide range of expression hosts. PMID- 29620867 TI - pytc: Open-Source Python Software for Global Analyses of Isothermal Titration Calorimetry Data. AB - Here we describe pytc, an open-source Python package for global fits of thermodynamic models to multiple isothermal titration calorimetry experiments. Key features include simplicity, the ability to implement new thermodynamic models, a robust maximum likelihood fitter, a fast Bayesian Markov-Chain Monte Carlo sampler, rigorous implementation, extensive documentation, and full cross platform compatibility. pytc fitting can be done using an application program interface or via a graphical user interface. It is available for download at https://github.com/harmslab/pytc . PMID- 29620869 TI - Mechanisms of Persistence of the Ammonia-Oxidizing Bacteria Nitrosomonas to the Biocide Free Nitrous Acid. AB - Free nitrous acid (FNA) exerts a broad range of antimicrobial effects on bacteria, although susceptibility varies considerably among microorganisms. Among nitrifiers found in activated sludge of wastewater treatment processes (WWTPs), nitrite-oxidizing bacteria (NOB) are more susceptible to FNA compared to ammonia oxidizing bacteria (AOB). This selective inhibition of NOB over AOB in WWTPs bypasses nitrate production and improves the efficiency and costs of the nitrogen removal process in both the activated sludge and anaerobic ammonium oxidation (Anammox) system. However, the molecular mechanisms governing this atypical tolerance of AOB to FNA have yet to be understood. Herein we investigate the varying effects of the antimicrobial FNA on activated sludge containing AOB and NOB using an integrated metagenomics and label-free quantitative sequential windowed acquisition of all theoretical fragment ion mass spectra (SWATH-MS) metaproteomic approach. The Nitrosomonas genus of AOB, on exposure to FNA, maintains internal homeostasis by upregulating a number of known oxidative stress enzymes, such as pteridine reductase and dihydrolipoyl dehydrogenase. Denitrifying enzymes were upregulated on exposure to FNA, suggesting the detoxification of nitrite to nitric oxide. Interestingly, proteins involved in stress response mechanisms, such as DNA and protein repair enzymes, phage prevention proteins, and iron transport proteins, were upregulated on exposure to FNA. In addition enzymes involved in energy generation were also upregulated on exposure to FNA. The total proteins specifically derived from the NOB genus Nitrobacter was low and, as such, did not allow for the elucidation of the response mechanism to FNA exposure. These findings give us an understanding of the adaptive mechanisms of tolerance within the AOB Nitrosomonas to the biocidal agent FNA. PMID- 29620868 TI - Deep Top-Down Proteomics Using Capillary Zone Electrophoresis-Tandem Mass Spectrometry: Identification of 5700 Proteoforms from the Escherichia coli Proteome. AB - Capillary zone electrophoresis (CZE)-tandem mass spectrometry (MS/MS) has been recognized as a useful tool for top-down proteomics. However, its performance for deep top-down proteomics is still dramatically lower than widely used reversed phase liquid chromatography (RPLC)-MS/MS. We present an orthogonal multidimensional separation platform that couples size exclusion chromatography (SEC) and RPLC based protein prefractionation to CZE-MS/MS for deep top-down proteomics of Escherichia coli. The platform generated high peak capacity (~4000) for separation of intact proteins, leading to the identification of 5700 proteoforms from the Escherichia coli proteome. The data represents a 10-fold improvement in the number of proteoform identifications compared with previous CZE-MS/MS studies and represents the largest bacterial top-down proteomics data set reported to date. The performance of the CZE-MS/MS based platform is comparable to the state-of-the-art RPLC-MS/MS based systems in terms of the number of proteoform identifications and the instrument time. PMID- 29620870 TI - Synthesis and Electronic Structure Diversity of Pyridine(diimine)iron Tetrazene Complexes. AB - A series of pyridine(diimine)iron tetrazene compounds, (iPrPDI)Fe[(NR)NN(NR)] [iPrPDI = 2,6-(ArN = CMe)2C5H3N; Ar = 2,6-iPr2C6H3] has been prepared either by the addition of 2 equiv of an organic azide, RN3, to the corresponding iron bis(dinitrogen) compound, (iPrPDI)Fe(N2)2 or by the addition of azide to the iron imide derivatives, (iPrPDI)FeNR. The electronic structures of these compounds were determined using a combination of metrical parameters from X-ray diffraction, solution and solid-state magnetic measurements, zero-field 57Fe Mossbauer and 1H NMR spectroscopies, and density functional theory calculations. The overall electronic structure of the iron tetrazene compounds is sensitive to the nature of the tetrazene nitrogen substituent with three distinct classes of compounds identified: (i) overall diamagnetic ( S = 0) compounds arising from intermediate-spin iron(II) centers ( SFe = 1) engaged in antiferromagnetic coupling with both pyridine(diimine) and tetrazene radical anions ( SPDI = -1/2 and Stetrazene = -1/2; R = 2-adamantyl, cyclooctyl, benzyl); (ii) overall S = 1 compounds best described as intermediate-spin iron(III) ( SFe = 3/2) derivatives engaged in antiferromagnetic coupling with a pyridine(diimine) radical anion ( SPDI = -1/2; R = 3,5-Me2C6H3, 4-MeC6H4); (iii) overall S = 2 compounds best described as high-spin iron(III) centers ( SFe = 5/2) engaged in antiferromagnetic coupling to a pyridine(diimine) radical anion ( SPDI = -1/2; R = 1-adamantyl). For both the intermediate- and high-spin ferric cases, the tetrazene ligand adopts the closed-shell, dianionic form, [N4R2]2-. For the case where R = SiMe3, spin-crossover behavior is observed, arising from a spin-state change from intermediate- to high-spin iron(III). PMID- 29620871 TI - Skin-Inspired Hierarchical Polymer Architectures with Gradient Stiffness for Spacer-Free, Ultrathin, and Highly Sensitive Triboelectric Sensors. AB - The gradient stiffness between stiff epidermis and soft dermis with interlocked microridge structures in human skin induces effective stress transmission to underlying mechanoreceptors for enhanced tactile sensing. Inspired by skin structure and function, we fabricate hierarchical nanoporous and interlocked microridge structured polymers with gradient stiffness for spacer-free, ultrathin, and highly sensitive triboelectric sensors (TESs). The skin-inspired hierarchical polymers with gradient elastic modulus enhance the compressibility and contact areal differences due to effective transmission of the external stress from stiff to soft layers, resulting in highly sensitive TESs capable of detecting human vital signs and voice. In addition, the microridges in the interlocked polymers provide an effective variation of gap distance between interlocked layers without using the bulk spacer and thus facilitate the ultrathin and flexible design of TESs that could be worn on the body and detect a variety of pressing, bending, and twisting motions even in humid and underwater environments. Our TESs exhibit the highest power density (46.7 MUW/cm2), pressure (0.55 V/kPa), and bending (~0.1 V/ degrees ) sensitivities ever reported on flexible TESs. The proposed design of hierarchical polymer architectures for the flexible and wearable TESs can find numerous applications in next-generation wearable electronics. PMID- 29620872 TI - Second-Shell Hydrogen Bond Impacts Transition-State Structure in Bacillus subtilis Oxalate Decarboxylase. AB - There is considerable interest in how "second-shell" interactions between protein side chains and metal ligands might modulate Mn(II) ion redox properties and reactivity in metalloenzymes. One such Mn-dependent enzyme is oxalate decarboxylase (OxDC), which catalyzes the disproportionation of oxalate monoanion into formate and CO2. Electron paramagnetic resonance (EPR) studies have shown that a mononuclear Mn(III) ion is formed in OxDC during catalytic turnover and that the removal of a hydrogen bond between one of the metal ligands (Glu101) and a conserved, second-shell tryptophan residue (Trp132) gives rise to altered zero field splitting parameters for the catalytically important Mn(II) ion. We now report heavy-atom kinetic isotope effect measurements on the W132F OxDC variant, which test the hypothesis that the Glu101/Trp132 hydrogen bond modulates the stability of the Mn(III) ion during catalytic turnover. Our results suggest that removing the Glu101/Trp132 hydrogen bond increases the energy of the oxalate radical intermediate from which decarboxylation takes place. This finding is consistent with a model in which the Glu101/Trp132 hydrogen bond in WT OxDC modulates the redox properties of the Mn(II) ion. PMID- 29620873 TI - Batch Fabrication of Ultrasensitive Carbon Nanotube Hydrogen Sensors with Sub-ppm Detection Limit. AB - Carbon nanotube (CNT) has been considered as an ideal channel material for building highly sensitive gas sensors. However, the reported H2 sensors based on CNT always suffered from the low sensitivity or low production. We developed the technology to massively fabricate ultra-highly sensitive H2 sensors based on solution derived CNT network through comprehensive optimization of the CNT material, device structure, and fabrication process. In the H2 sensors, high semiconducting purity solution-derived CNT film sorted by poly[9-(1-octylonoyl)-9 H-carbazole-2,7-diyl](PCz) is used as the main channel, which is decorated with Pd nanoparticles as functionalization for capturing H2. Meanwhile, Ti contacts are used to form a Schottky barrier for enhancing transferred charge-induced resistance change, and then a response of resistance change by 3 orders of magnitude is achieved at room temperature under the concentration of ~311 ppm with a very fast response time of approximately 7 s and a detection limit of 890 ppb, which is the highest response to date for CNT H2 sensors and the very first time to show the sub-ppm detection for H2 at room temperature. Furthermore, the detection limit concentration can be improved to 89 ppb at 100 degrees C. The batch fabrication of CNT film H2 sensors with ultra-high sensitivity and high uniformity is ready to promote CNT devices to application for the first time in some specialized field. PMID- 29620874 TI - Through-Space Paramagnetic NMR Effects in Host-Guest Complexes: Potential Ruthenium(III) Metallodrugs with Macrocyclic Carriers. AB - The potential of paramagnetic ruthenium(III) compounds for use as anticancer metallodrugs has been investigated extensively during the past several decades. However, the means by which these ruthenium compounds are transported and distributed in living bodies remain relatively unexplored. In this work, we prepared several novel ruthenium(III) compounds with the general structure Na+[ trans-RuIIICl4(DMSO)(L)]- (DMSO = dimethyl sulfoxide), where L stands for pyridine or imidazole linked with adamantane, a hydrophobic chemophore. The supramolecular interactions of these compounds with macrocyclic carriers of the cyclodextrin (CD) and cucurbit[ n]uril (CB) families were investigated by NMR spectroscopy, X-ray diffraction analysis, isothermal titration calorimetry, and relativistic DFT methods. The long-range hyperfine NMR effects of the paramagnetic guest on the host macrocycle are related to the distance between them and their relative orientation in the host-guest complex. The CD and CB macrocyclic carriers being studied in this account can be attached to a vector that attracts the drug-carrier system to a specific biological target and our investigation thus introduces a new possibility in the field of targeted delivery of anticancer metallodrugs based on ruthenium(III) compounds. PMID- 29620875 TI - Highly Adaptive Solid-Liquid Interfacing Triboelectric Nanogenerator for Harvesting Diverse Water Wave Energy. AB - Harvesting water wave energy presents a significantly practical route to energy supply for self-powered wireless sensing networks. Here we report a networked integrated triboelectric nanogenerator (NI-TENG) as a highly adaptive means of harvesting energy from interfacing interactions with various types of water waves. Having an arrayed networking structure, the NI-TENG can accommodate diverse water wave motions and generate stable electric output regardless of how random the water wave is. Nanoscaled surface morphology consisting of dense nanowire arrays is the key for obtaining high electric output. A NI-TENG having an area of 100 * 70 mm2 can produce a stable short-circuit current of 13.5 MUA and corresponding electric power of 1.03 mW at a water wave height of 12 cm. This merit promises practical applications of the NI-TENG in real circumstances, where water waves are highly variable and unpredictable. After energy storage, the generated electric energy can drive wireless sensing by autonomously transmitting data at a period less than 1 min. This work proposes a viable solution for powering individual standalone nodes in a wireless sensor network. Potential applications include but are not limited to long-term environment monitoring, marine surveillance, and off-shore navigation. PMID- 29620876 TI - Electron-Rich, Diiron Bis(monothiolato) Carbonyls: C-S Bond Homolysis in a Mixed Valence Diiron Dithiolate. AB - The synthesis and redox properties are presented for the electron-rich bis(monothiolate)s Fe2(SR)2(CO)2(dppv)2 for R = Me ([1]0), Ph ([2]0), CH2Ph ([3]0). Whereas related derivatives adopt C2-symmetric Fe2(CO)2P4 cores, [1]0 [3]0 have Cs symmetry resulting from the unsymmetrical steric properties of the axial vs equatorial R groups. Complexes [1]0-[3]0 undergo 1e- oxidation upon treatment with ferrocenium salts to give the mixed valence cations [Fe2(SR)2(CO)2(dppv)2]+. As established crystallographically, [3]+ adopts a rotated structure, characteristic of related mixed valence diiron complexes. Unlike [1]+ and [2]+ and many other [Fe2(SR)2L6]+ derivatives, [3]+ undergoes C-S bond homolysis, affording the diferrous sulfido-thiolate [Fe2(SCH2Ph)(S)(CO)2(dppv)2]+ ([4]+). According to X-ray crystallography, the first coordination spheres of [3]+ and [4]+ are similar, but the Fe-sulfido bonds are short in [4]+. The conversion of [3]+ to [4]+ follows first-order kinetics, with k = 2.3 * 10-6 s-1 (30 degrees C). When the conversion is conducted in THF, the organic products are toluene and dibenzyl. In the presence of TEMPO, the conversion of [3]+ to [4]+ is accelerated about 10*, the main organic product being TEMPO-CH2Ph. DFT calculations predict that the homolysis of a C-S bond is exergonic for [Fe2(SCH2Ph)2(CO)2(PR3)4]+ but endergonic for the neutral complex as well as less substituted cations. The unsaturated character of [4]+ is indicated by its double carbonylation to give [Fe2(SCH2Ph)(S)(CO)4(dppv)2]+ ([5]+), which adopts a bioctahedral structure. PMID- 29620878 TI - Ion Microbeam Analyses of Dust Particles and Codeposits from JET with the ITER Like Wall. AB - Generation of metal dust in the JET tokamak with the ITER-like wall (ILW) is a topic of vital interest to next-step fusion devices because of safety issues with plasma operation. Simultaneous Nuclear Reaction Analysis (NRA) and Particle Induced X-ray Emission (PIXE) with a focused four MeV 3He microbeam was used to determine the composition of dust particles related to the JET operation with the ILW. The focus was on "Be-rich particles" collected from the deposition zone on the inner divertor tile. The particles found are composed of a mix of codeposited species up to 120 MUm in size with a thickness of 30-40 MUm. The main constituents are D from the fusion fuel, Be and W from the main plasma-facing components, and Ni and Cr from the Inconel grills of the antennas for auxiliary plasma heating. Elemental concentrations were estimated by iterative NRA-PIXE analysis. Two types of dust particles were found: (i) larger Be-rich particles with Be concentrations above 90 at% with a deuterium presence of up to 3.4 at% and containing Ni (1-3 at%), Cr (0.4-0.8 at%), W (0.2-0.9 at%), Fe (0.3-0.6 at%), and Cu and Ti in lower concentrations and (ii) small particles rich in Al and/or Si that were in some cases accompanied by other elements, such as Fe, Cu, or Ti or W and Mo. PMID- 29620877 TI - A Family of Rhodium Complexes with Selective Toxicity toward Mismatch Repair Deficient Cancers. AB - Rhodium metalloinsertors are a unique set of metal complexes that bind specifically to DNA base pair mismatches in vitro and kill mismatch repair (MMR) deficient cells at lower concentrations than their MMR-proficient counterparts. A family of metalloinsertors containing rhodium-oxygen ligand coordination, termed "Rh-O" metalloinsertors, has been prepared and shown to have a significant increase in both overall potency and selectivity toward MMR-deficient cells regardless of structural changes in the ancillary ligands. Here we describe DNA binding and cellular studies with the second generation of Rh-O metalloinsertors in which an ancillary ligand is varied in both steric bulk and lipophilicity. These complexes, of the form [Rh(L)(chrysi)(PPO)]2+, all include the O-containing PPO ligand (PPO = 2-(pyridine-2-yl)propan-2-ol) and the aromatic inserting ligand chrysi (5,6-chrysene quinone diimine) but differ in the identity of their ancillary ligand L, where L is a phenanthroline or bipyridyl derivative. The Rh-O metalloinsertors in this family all show micromolar binding affinities for a 29 mer DNA hairpin containing a single CC mismatch. The complexes display comparable lipophilic tendencies and p Ka values of 8.1-9.1 for dissociation of an imine proton on the chrysi ligand. In cellular proliferation and cytotoxicity assays with MMR-deficient cells (HCT116O) and MMR-proficient cells (HCT116N), the complexes containing the phenanthroline-derived ligands show highly selective cytotoxic preference for the MMR-deficient cells at nanomolar concentrations. Using mass spectral analyses, it is shown that the complexes are taken into cells through a passive mechanism and exhibit low accumulation in mitochondria, an off target organelle that, when targeted by parent metalloinsertors, can lead to nonselective cytotoxicity. Overall, these Rh-O metalloinsertors have distinct and improved behavior compared to previous generations of parent metalloinsertors, making them ideal candidates for further therapeutic assessment. PMID- 29620879 TI - Correction to "Total Synthesis of (-)-Sarain A". PMID- 29620880 TI - Reinforcement Effects from Nanodiamond in Cellulose Nanofibril Films. AB - Although research on nanopaper structures from cellulose nanofibrils (CNFs) is well established, the mechanical behavior is not well understood, especially not when CNF is combined with hard nanoparticles. Cationic CNF (Q-CNF) was prepared and successfully decorated by anionic nanodiamond (ND) nanoparticles in hydrocolloidal form. The Q-CNF/ND nanocomposites were filtered from a hydrocolloid and dried. Unlike many other carbon nanocomposites, the Q-CNF/ND nanocomposites were optically transparent. Reinforcement effects from the nanodiamond were remarkable, such as Young's modulus (9.8 -> 16.6 GPa) and tensile strength (209.5 -> 277.5 MPa) at a content of only 1.9% v/v of ND, and the reinforcement mechanisms are discussed. Strong effects on CNF network deformation mechanisms were revealed by loading-unloading experiments. Scratch hardness also increased strongly with increased addition of ND. PMID- 29620881 TI - Microplastics Affect Energy Balance and Gametogenesis in the Pearl Oyster Pinctada margaritifera. AB - Plastic pollution in the environment is increasing at global scale. Microplastics (MP) are derived from degradation of larger plastic items or directly produced in microparticles form (< 5 mm). Plastics, widely used in structures and equipment of pearl farming, are a source of pollution to the detriment of the lagoon ecosystem. To evaluate the impact of MP on the physiology of Pinctada margaritifera, a species of ecological and commercial interests, adult oysters were exposed to polystyrene microbeads (micro-PS of 6 and 10 MUm) for 2 months. Three concentrations, 0.25, 2.5, and 25 MUg L-1, and a control were tested. Ingestion and respiration rate and assimilation efficiency were monitored on a metabolic measurement system to determine the individual energy balance (Scope For Growth, SFG). Effects on reproduction were also assessed. The assimilation efficiency decreased significantly according to micro-PS concentration. The SFG was significantly impacted by a dose-dependent decrease from 0.25 MUg L-1 ( p < 0.0001), and a negative SFG was measured in oysters exposed to 25 MUg L-1. Gonads may have provided the missing energy to maintain animals' metabolism through the production of metabolites derived from germ cells phagocytosis. This study shows that micro-PS significantly impact the assimilation efficiency and more broadly the energy balance of P. margaritifera, with negative repercussions on reproduction. PMID- 29620882 TI - Selective Synergism Created by Interactive Nacre Framework-Associated Proteins Possessing EGF and vWA Motifs: Implications for Mollusk Shell Formation. AB - In the nacre layer of the Pinctada fucata oyster shell there exists a multimember proteome, known as the framework family, which regulates the formation of the aragonite mesoscale tablets and participates in the creation of an organic coating around each tablet. Several approaches have been developed to understand protein-associated mechanisms of nacre formation, yet we still lack insight into how protein ensembles or proteomes manage nucleation and crystal growth. To provide additional insights we have created a proportionally defined combinatorial model consisting of two recombinant framework proteins, r-Pif97 (containing a von Willebrand Factor Type A domain (vWA)) and r-n16.3 (containing an EGF-like domain), whose individual in vitro mineralization functionalities are distinct from one another. We find that at 1:1 molar ratios r-Pif97 and r-n16.3 exhibit little or no synergistic activity regarding modifying existing calcite crystals. However, during the early stages of nucleation in solution, we note synergistic effects on nucleation kinetics and ACC formation/stability (via dehydration) that are not observed for the individual proteins. This selective synergism is generated by Ca2+-mediated protein-protein interactions (~4 molecules of r-n16.3 per 1 molecule of r-Pif97) which lead to the formation of nucleation-responsive hybrid hydrogel particles in solution. Interestingly, in the absence of Ca2+ there are no significant interactions occurring between the two proteins. This unique behavior of the framework-associated n16.3 and Pif97 proteins suggests that the Asp/Glu-containing regions of the vWA and EGF-like domains may play a role in both nacre matrix formation and mineralization. PMID- 29620883 TI - An Oxetane-Based Polyketide Surrogate To Probe Substrate Binding in a Polyketide Synthase. AB - Polyketides are a large class of bioactive natural products with a wide range of structures and functions. Polyketides are biosynthesized by large, multidomain enzyme complexes termed polyketide synthases (PKSs). One of the primary challenges when studying PKSs is the high reactivity of their poly-beta-ketone substrates. This has hampered structural and mechanistic characterization of PKS polyketide complexes, and, as a result, little is known about how PKSs position the unstable substrates for proper catalysis while displaying high levels of regio- and stereospecificity. As a first step toward a general plan to use oxetanes as carbonyl isosteres to broadly interrogate PKS chemistry, we describe the development and application of an oxetane-based PKS substrate mimic. This enabled the first structural determination of the acyl-enzyme intermediate of a ketosynthase (KS) in complex with an inert extender unit mimic. The crystal structure, in combination with molecular dynamics simulations, led to a proposed mechanism for the unique activity of DpsC, the priming ketosynthase for daunorubicin biosynthesis. The successful application of an oxetane-based polyketide mimic suggests that this novel class of probes could have wide-ranging applications to the greater biosynthetic community interested in the mechanistic enzymology of iterative PKSs. PMID- 29620884 TI - Cyclopentadienyl-Ru(II)-Pyridylamine Complexes: Synthesis, X-ray Structure, and Application in Catalytic Transformation of Bio-Derived Furans to Levulinic Acid and Diketones in Water. AB - A series of cationic half-sandwich cyclopentadienyl-ruthenium(II)-pyridylamine complexes, [(eta5-C5H5)Ru(kappa2-L)(PPh3)]+ (L = Namine-substituted pyridylamine ligands) ([Ru]-1-[Ru]-6), along with the analogous cyclopentadienyl-ruthenium(II) N-isopropylpyridylimine complex [(eta5-C5H5)Ru(kappa2-L)(PPh3)]+ (L = N isopropylpyridylimine) ([Ru]-7), have been synthesized in good yields. Structural identities of all the complexes have been authenticated by 1H, 13C, and 31P NMR, mass spectrometry, and X-ray crystallography. The synthesized complexes exhibited high catalytic activity for the transformation of the bio-derived furans, 2 furfural (furfural), 5-methyl-2-furfural (5-MF), and 5-hydroxymethyl-2-furfural (5-HMF) to levulinic acid (LA) and the diketones, 3-hydroxyhexane-2,5-dione (3 HHD), 1-hydroxyhexane-2,5-dione (1-HHD), and hexane-2,5-dione (HD) in water. Efficient transformation of furfural to LA over a range of eta5-Cp-Ru pyridylamine complexes is substantially affected by the Namine-substituents, where a eta5-Cp-Ru- N-propylpyridylamine complex ([Ru]-2) exhibited higher catalytic activity in comparison to other eta5-Cp-Ru-pyridylamine and eta5-Cp-Ru pyridylimine complexes. The relative catalytic activity of the studied complexes demonstrated a substantial structure-activity relationship which is governed by the basicity of Namine, steric hindrance at Namine, and the hemilabile nature of the coordinated pyridylamine ligands. PMID- 29620885 TI - Deformation Mechanisms of Vertically Stacked WS2 /MoS2 Heterostructures: The Role of Interfaces. AB - The mechanical and optical properties generated due to the stacking of different atomically thin materials have made it possible to tune and engineer these materials for next-generation electronics. The understanding of the interlayer interactions in such stacked structures is of fundamental interest for structure and property correlation. Here, a combined approach of in situ Raman spectroscopy and mechanical straining along with molecular dynamics (MD) simulations has been used to probe one such interface, namely, the WS2/MoS2 heterostructure. Vertical heterostructures on poly(methyl methacrylate), when flexed, showed signs of decoupling at 1.2% strain. Theoretical calculations showed strain-induced stacking changes at 1.75% strain. The sliding characteristics of layers were also investigated using scanning probe microscopy based nanoscratch testing, and the results are further supported by MD simulations. The present study could be used to design future optoelectronic devices based on WS2/MoS2 heterostructures. PMID- 29620887 TI - Accurate Explicit-Correlation-MRCI-Based DMBE Potential-Energy Surface for Ground State CNO. AB - We report a new global double many-body expansion potential energy surface for the ground state of the CNO(2A') manifold, calculated by the explicit correlation multireference configuration interaction method. The functional form was accurately fitted to 3701 ab initio points with a root mean squared deviation of 0.99 kcal mol-1. All stationary points reported in previous forms are systematically described and improved, in addition to three new ones and a characterization of an isomerization transition state between the CNO and NCO minima. The novel proposed form gives a realistic description of both short-range and long-range interactions and hence is commended for dynamics studies. PMID- 29620886 TI - Role of Molecular Interactions and Protein Rearrangement in the Dissociation Kinetics of p38alpha MAP Kinase Type-I/II/III Inhibitors. AB - Understanding the governing factors of fast or slow inhibitor binding/unbinding assists in developing drugs with preferred kinetic properties. For inhibitors with the same binding affinity targeting different binding sites of the same protein, the kinetic behavior can profoundly differ. In this study, we investigated unbinding kinetics and mechanisms of fast (type-I) and slow (type II/III) binders of p38alpha mitogen-activated protein kinase, where the crystal structures showed that type-I and type-II/III inhibitors bind to pockets with different conformations of the Asp-Phe-Gly (DFG) motif. The work used methods that combine conventional molecular dynamics (MD), accelerated molecular dynamics (AMD) simulations, and the newly developed pathway search guided by internal motions (PSIM) method to find dissociation pathways. The study focuses on revealing key interactions and molecular rearrangements that hinder ligand dissociation by using umbrella sampling and post-MD processing to examine changes in free energy during ligand unbinding. As anticipated, the initial dissociation steps all require breaking interactions that appeared in crystal structures of the bound complexes. Interestingly, for type-I inhibitors such as SB2, p38alpha keeps barrier-free conformational fluctuation in the ligand-bound complex and during ligand dissociation. In contrast, with a type-II/III inhibitor such as BIRB796, with the rearrangements of p38alpha in its bound state, ligand unbinding features energetically unfavorable protein-ligand concerted movement. Our results also show that the type-II/III inhibitors preferred dissociation pathways through the allosteric channel, which is consistent with an existing publication. The study suggests that the level of required protein rearrangement is one major determining factor of drug binding kinetics in p38alpha systems, providing useful information for development of inhibitors. PMID- 29620888 TI - Bis(amino)cyclopropenium Trifluoroborates: Synthesis, Hydrolytic Stability Studies, and DFT Insights. AB - A simple and direct two-step synthesis of bis(amino)cyclopropenium trifluoroborate (BAC-BF3) derivatives from readily available reagents is reported. Hydrolysis studies revealed these BAC-BF3 derivatives were remarkably stable toward defluorination. Notably, this first study of BAC-BF3 adduct hydrolytic stability establishes the compounds reported herein possess half-lives ( t1/2) exceeding 0.23 * 106 min (~160 days). Density functional theory (DFT) and quantum theory of atoms in molecules (QTAIM) calculations exploring the basis of this high stability are described. PMID- 29620889 TI - Synthetic Approaches to New Drugs Approved During 2016. AB - New drugs introduced to the market every year represent privileged structures for particular biological targets. These new chemical entities provide insight into molecular recognition while serving as leads for designing future new drugs. This annual review describes the most likely process-scale synthetic approaches to 19 new chemical entities that were approved for the first time in 2016. PMID- 29620890 TI - Mapping the Efficiency and Physicochemical Trajectories of Successful Optimizations. AB - The practices and tactics employed in successful optimizations are examined, judged from the trajectories of ligand efficiency and property evolution. A wide range of targets is analyzed, encompassing a variety of hit finding methods (HTS, fragments, encoded library technology) and types of molecules, including those beyond the rule of five. The wider employment of efficiency metrics and lipophilicity control is evident in contemporary practice and the impact on quality demonstrable. What is clear is that while targets are different, successful molecules are almost invariably among the most efficient for their target, even at the extremes. Trajectory mapping, based on principles rather than rules, is useful in assessing quality and progress in optimizations while benchmarking against competitors and assessing property-dependent risks. PMID- 29620891 TI - The Anomeric Effect: It's Complicated. AB - The origin of the anomeric effect has been reexamined in a coordinated experimental and computational investigation. The results of these studies implicate a number of different, but correlated, interactions that in the aggregate are responsible for the anomeric effect. No single factor is uniquely responsible for the axial preference of a substituent that is the hallmark of the anomeric effect. A CH...G nonbonded attraction between a polar axial substituent (G) and the syn-axial hydrogen(s) in the heterocycle has been demonstrated experimentally. The hyperconjugation model involving electron transfer from a ring heteroatom to an excited state of an axial C-G bond was shown to be, at most, a minor contributor because of the very small changes in charge density at the ring heteroatom(s): the main charge transfer is from hydrogen to G in the H-C G unit. This appears to result from lengthening the C-G bond to minimize repulsion with the ring atom lone pair(s) and the advantage of having a more positive hydrogen that leads to a stabilizing Coulombic interaction with the ring heteroatom(s). In short, the anomeric effect arises mainly from two separate CH...G nonbonded Coulombic attractions. PMID- 29620892 TI - Hydroxamic Acids Constitute a Novel Class of Autotaxin Inhibitors that Exhibit in Vivo Efficacy in a Pulmonary Fibrosis Model. AB - Autotaxin (ATX) catalyzes the hydrolysis of lysophosphatidylcholine (LPC) generating the lipid mediator lysophosphatidic acid (LPA). Both ATX and LPA are involved in various pathological inflammatory conditions, including fibrosis and cancer, and have attracted great interest as medicinal targets over the past decade. Thus, the development of novel potent ATX inhibitors is of great importance. We have developed a novel class of ATX inhibitors containing the zinc binding functionality of hydroxamic acid. Such novel hydroxamic acids that incorporate a non-natural delta-amino acid residue exhibit high in vitro inhibitory potency over ATX (IC50 values 50-60 nM). Inhibitor 32, based on delta norleucine, was tested for its efficacy in a mouse model of pulmonary inflammation and fibrosis induced by bleomycin and exhibited promising efficacy. The novel hydroxamic ATX inhibitors provide excellent tools for the study of the role of the enzyme and could contribute to the development of novel therapeutic agents for the treatment of fibrosis and other chronic inflammatory diseases. PMID- 29620893 TI - Esterification of Aryl and Alkyl Amides Enabled by Tailor-Made and Proposed Nickel Catalyst: Insights from Theoretical Investigation. AB - DFT calculations are used to address the mechanism of Ni-catalyzed esterification of aryl and alkyl amides. The insight of the tailor-made catalysts in the chemo selectivity is addressed in this work. The reaction steps for esterification of aryl and alkyl amides catalyzed by both Ni(SIPr)2 and Ni(terpyridine)2 include: oxidative addition, metathesis, and reductive elimination processes. Ni(SIPr)2 can catalyze the esterification of aryl amides rather than Ni(terpyridine)2 due to high reaction barrier in oxidative addition process, while Ni(terpyridine)2 can catalyze the esterification of alkyl amides rather than Ni(SIPr)2 due to high reaction barrier in metathesis process. It is found that the charge distribution on Ni is different in these two complexes. An amino-substituted terpyridine Ni complex is designed to catalyze both aryl and alkyl amides through low transition state energies because of the electron-donating ability of three amino substitutes. The results reveal that the chemo-selectivity is mainly controlled by the electron-donating ability of ligands. PMID- 29620894 TI - Kinetics of the Gas-Phase O(1D) + CO2 and C(1D) + CO2 Reactions over the 50-296 K Range. AB - The kinetics of the reactions of CO2 with atomic oxygen and atomic carbon in their first excited singlet states have been studied at room temperature and below using the Laval nozzle reactor method. O(1D) and C(1D) atoms were created in situ by the 266 nm pulsed laser photolysis of O3 and CBr4 precursor molecules, respectively. While O(1D) atoms were detected directly by vacuum ultraviolet laser-induced fluorescence at 115 nm, C(1D) atoms were followed indirectly through a chemical tracer method. The measured rate constants for the O(1D) + CO2 reaction are found to be in excellent agreement with earlier work and extend the available kinetic data for this process down to 50 K. The present work represents the first kinetics study of the C(1D) + CO2 reaction below room temperature. Both reactions display rate constants that increase as the temperature falls, with a more substantial rate increase observed for the O(1D) + CO2 reaction. This finding could be due to the increasing lifetimes of the intermediate species involved at lower temperatures. PMID- 29620895 TI - Thermal Decomposition Mechanism of CL-20 at Different Temperatures by ReaxFF Reactive Molecular Dynamics Simulations. AB - Hexanitrohexaazaisowurtzitane (CL-20) has a high detonation velocity and pressure, but its sensitivity is also high, which somewhat limits its applications. Therefore, it is important to understand the mechanism and characteristics of thermal decomposition of CL-20. In this study, a epsilon-CL-20 supercell was constructed and ReaxFF-lg reactive molecular dynamics simulations were performed to investigate thermal decomposition of epsilon-CL-20 at various temperatures (2000, 2500, 2750, 3000, 3250, and 3500 K). The mechanism of thermal decomposition of CL-20 was analyzed from the aspects of potential energy evolution, the primary reactions, and the intermediate and final product species. The effect of temperature on thermal decomposition of CL-20 is also discussed. The initial reaction path of thermal decomposition of CL-20 is N-NO2 cleavage to form NO2, followed by C-N cleavage, leading to the destruction of the cage structure. A small number of clusters appear in the early reactions and disappear at the end of the reactions. The initial reaction path of CL-20 decomposition is the same at different temperatures. However, as the temperature increases, the decomposition rate of CL-20 increases and the cage structure is destroyed earlier. The temperature greatly affects the rate constants of H2O and N2, but it has little effect on the rate constants of CO2 and H2. PMID- 29620897 TI - Design, Synthesis, and Characterization of 4-Undecylpiperidine-2-carboxamides as Positive Allosteric Modulators of the Serotonin (5-HT) 5-HT2C Receptor. AB - An impaired signaling capacity of the serotonin (5-HT) 5-HT2C receptor (5-HT2CR) has been implicated in the neurobehavioral processes that promote relapse vulnerability in cocaine use disorder (CUD). Restoration of the diminished 5 HT2CR signaling through positive allosteric modulation presents a novel therapeutic approach. Several new molecules with the 4-alkylpiperidine-2 carboxamide scaffold were designed, synthesized, and pharmacologically evaluated, leading to the discovery of selective 5-HT2CR positive allosteric modulators (PAMs). Compound 16 (CYD-1-79) potentiated 5-HT-evoked intracellular calcium release in cells stably expressing the human 5-HT2CR but not the 5-HT2AR cells. A topographically distinct allosteric site was identified based on the newly solved 5-HT2CR structure. Compound 16 modulated 5-HT2CR-mediated spontaneous ambulation, partially substituted for the training dose of the 5-HT2CR agonist WAY163909, synergized with a low dose of WAY163909 to substitute fully for the stimulus effects of WAY163909, and attenuated relapse vulnerability as assessed in a rodent self-administration model, indicating its therapeutic promise for CUD. PMID- 29620896 TI - Nanoporous Copper-Silver Alloys by Additive-Controlled Electrodeposition for the Selective Electroreduction of CO2 to Ethylene and Ethanol. AB - Electrodeposition of CuAg alloy films from plating baths containing 3,5-diamino 1,2,4-triazole (DAT) as an inhibitor yields high surface area catalysts for the active and selective electroreduction of CO2 to multicarbon hydrocarbons and oxygenates. EXAFS shows the co-deposited alloy film to be homogeneously mixed. The alloy film containing 6% Ag exhibits the best CO2 electroreduction performance, with the Faradaic efficiency for C2H4 and C2H5OH production reaching nearly 60 and 25%, respectively, at a cathode potential of just -0.7 V vs RHE and a total current density of ~ - 300 mA/cm2. Such high levels of selectivity at high activity and low applied potential are the highest reported to date. In situ Raman and electroanalysis studies suggest the origin of the high selectivity toward C2 products to be a combined effect of the enhanced stabilization of the Cu2O overlayer and the optimal availability of the CO intermediate due to the Ag incorporated in the alloy. PMID- 29620898 TI - Analysis of Advanced Glycation Endproducts in Rat Tail Collagen and Correlation to Tendon Stiffening. AB - Methylglyoxal is a major 1,2-dicarbonyl compound in vivo and leads to nonenzymatic protein modifications, known as advanced glycation endproducts. Especially long-lived proteins like collagen are prone to changes of the mechanical or biological function, respectively, by accumulation of Maillard derived modifications. Specifically, the resulting nonenzymatic cross-link structures in parallel to the natural maturation process of collagen fibrils lead to complications with age or during disease. A novel lysine-lysine amide cross link derived from methylglyoxal, 2,15-diamino-8-methyl-9-oxo-7,10-diaza-1,16 hexadecanedioic acid, named MOLA, was synthesized and identified in vitro and in vivo. Tail tendons of young, adult, and old rats (3, 12, and 22 months) were enzymatically digested prior to analysis of acid-labile glycation products via liquid chromatography-tandem mass spectrometry (LC-MS/MS). As a result, nine monovalent amino acid modifications, mostly originating from methylglyoxal (36 MUmol/mol leucine-equivalents in total), and four glycation cross-links (0.72 MUmol/mol glucosepane, 0.24 MUmol/mol DODIC (3-deoxyglucosone-derived imidazoline cross-link), 0.04 MUmol/mol MODIC (methylglyoxal-derived imidazoline cross-link), 0.34 MUmol/mol MOLA) were quantitated in senescent tendon collagen. The results correlated with increased tail tendon breaking time from 10 to 190 min and indicate that methylglyoxal is a major player in the aging process of connective tissue. PMID- 29620899 TI - Absorption and Emission of Light in Optoelectronic Nanomaterials: The Role of the Local Optical Environment. AB - Tailoring the interaction of electromagnetic radiation with matter is central to the development of optoelectronic devices. This becomes particularly relevant for a new generation of devices offering the possibility of solution processing with competitive efficiencies as well as new functionalities. These devices, containing novel materials such as inorganic colloidal quantum dots or hybrid organic-inorganic lead halide perovskites, commonly demand thin (tens of nanometers) active layers in order to perform optimally and thus maximizing the way electromagnetic radiation interacts with these layers is essential. In this Perspective, we discuss the relevance of tailoring the optical environment of the active layer in an optoelectronic device and illustrate it with two real-world systems comprising photovoltaic cells and light emitting devices. PMID- 29620900 TI - Unipolar n-Type Black Phosphorus Transistors with Low Work Function Contacts. AB - Black phosphorus (BP) is a promising two-dimensional (2D) material for nanoscale transistors, due to its expected higher mobility than other 2D semiconductors. While most studies have reported ambipolar BP with a stronger p-type transport, it is important to fabricate both unipolar p- and n-type transistors for low power digital circuits. Here, we report unipolar n-type BP transistors with low work function Sc and Er contacts, demonstrating a record high n-type current of 200 MUA/MUm in 6.5 nm thick BP. Intriguingly, the electrical transport of the as fabricated, capped devices changes from ambipolar to n-type unipolar behavior after a month at room temperature. Transmission electron microscopy analysis of the contact cross-section reveals an intermixing layer consisting of partly oxidized metal at the interface. This intermixing layer results in a low n-type Schottky barrier between Sc and BP, leading to the unipolar behavior of the BP transistor. This unipolar transport with a suppressed p-type current is favorable for digital logic circuits to ensure a lower off-power consumption. PMID- 29620901 TI - One-Step Synthesis of Aliphatic Potassium Acyltrifluoroborates (KATs) from Organocuprates. AB - A one-step synthesis of aliphatic KATs from organocuprates is reported. Organolithium and organomagnesium reagents were readily transmetalated onto Cu(I) and coupled with a KAT-forming reagent to yield the respective aliphatic KAT. The protocol is suitable for primary, secondary and-for the first time-tertiary alkyl substrates. These protocols considerably expand the range of KATs that can be readily accessed in one step from commercially available starting materials. PMID- 29620902 TI - Why Is Gyroid More Difficult to Nucleate from Disordered Liquids than Lamellar and Hexagonal Mesophases? AB - Block copolymers, surfactants, and biomolecules form lamellar, hexagonal, and gyroid mesophases. Across these systems, the nucleation of lamellar from the disordered liquid is the easiest and the nucleation of gyroid the most challenging. This poses the question of what are the factors that determine the rates of nucleation of the mesophases and whether they are controlled by the complexity of the structures or the thermodynamics of nucleation. Here, we use molecular simulations to investigate the nucleation and thermodynamics of lamellar, hexagonal, and gyroid in a binary mixture of particles that produces the same mesophases as those of surfactants and block copolymers. We demonstrate that a combination of averaged bond-order parameters q2 and q8 identifies and distinguishes the three mesophases. We use these parameters to track the microscopic process of nucleation of each mesophase and investigate the existence of heterogeneous nucleation (cross-nucleation) between mesophases. We estimate the surface tensions of the liquid/mesophase interfaces from nucleation rates using classical nucleation theory and find that they are comparable for the three mesophases with values that are about a third of those expected for liquid crystal interfaces. The driving forces for nucleation, on the other hand, are quite different and increase in the order gyroid < hexagonal < lamellar at any temperature. We find that the nucleation rates of the mesophases follow the order of their driving forces. We conclude that the difficulty to nucleate the gyroid originates in its lower temperature of melting and extremely low entropy of melting compared to those of the hexagonal and lamellar mesophases. PMID- 29620903 TI - Palladium-Metalated Porous Organic Polymers as Recyclable Catalysts for the Chemioselective Synthesis of Thiazoles from Thiobenzamides and Isonitriles. AB - Two types of thiazole derivatives are synthesized through a multistep cascade sequence with Pd-metalated phosphorus-doped porous organic polymers (POPs) as heterogeneous catalysts. The POPs could be used as both ligands and catalyst supports. No obvious aggregation and loss of any catalytic activity of the catalysts were observed after 10 runs of the reaction. More importantly, imidazo[4,5- d]thiazoles, which are a new class of thiazole derivatives, could be obtained through K2CO3-promoted intramolecular cyclization of the synthesized polysubstituted thiazoles. Furthermore, the in vitro anticancer activity of these new compounds were tested with MTT assay, and compound 4b exhibited good antitumor activity toward T-24 and A549 cells with IC50 values of 10.3 +/- 0.8 and 11.8 +/- 0.5 MUM, respectively. In addition, the action mechanism of 4b on tumor cells was determined. PMID- 29620904 TI - Contorted Naphtho- and Fluorenocoronenes: Syntheses and Properties of Polycyclic Aromatics beyond Benzo- and Thiophenocoronenes. AB - Selective oxidative cyclodehydrogenation reactions on olefins carrying larger aromatic units are described to offer modular access to contorted polyaromatics of naphtho- and fluorenocoronenes, which are more extended frameworks than the known benzocoronenes. The annulation proceeded regioselectively when more than one mode was possible, based either on electronic or steric effect. The single crystal field-effect transistor based on one of the derivatives, dinaphtho[ a, d]coronene, gave a p-carrier mobility of 0.04 cm2/(V s) and on/off current ratio of 102-103. PMID- 29620905 TI - Structure and Dynamics of Solvated Polymers near a Silica Surface: On the Different Roles Played by Solvent. AB - Whereas it is experimentally known that the inclusion of nanoparticles in hydrogels can lead to a mechanical reinforcement, a detailed molecular understanding of the adhesion mechanism is still lacking. Here we use coarse grained molecular dynamics simulations to investigate the nature of the interface between silica surfaces and solvated polymers. We show how differences in the nature of the polymer and the polymer-solvent interactions can lead to drastically different behavior of the polymer-surface adhesion. Comparing explicit and implicit solvent models, we conclude that this effect cannot be fully described in an implicit solvent. We highlight the crucial role of polymer solvation for the adsorption of the polymer chain on the silica surface, the significant dynamics of polymer chains on the surface, and details of the modifications in the structure solvated polymer close to the interface. PMID- 29620906 TI - Catalyst-Directed Chemoselective Double Amination of Bromo-chloro(hetero)arenes: A Synthetic Route toward Advanced Amino-aniline Intermediates. AB - A chemoselective sequential one-pot coupling protocol was developed for preparing several amino-anilines in high yield as building blocks for active pharmaceutical ingredients (APIs). Site (Cl vs Br on electrophile) and nucleophile (amine vs imine) selectivity is dictated by the catalyst employed. A Pd-crotyl (t-BuXPhos) precatalyst selectively coupled the Ar-Br of the polyhaloarene with benzophenone imine, even in the presence of a secondary amine, while Pd-based RuPhos or (BINAP)Pd(allyl)Cl coupled the Ar-Cl site with secondary amines. PMID- 29620907 TI - Asymmetric alpha-Allylation of Aldehydes with Alkynes by Integrating Chiral Hydridopalladium and Enamine Catalysis. AB - A palladium-catalyzed asymmetric alpha-allylation of aldehydes with alkynes has been established by integrating the catalysis of enamine and chiral hydridopalladium complex that is reversibly formed from the oxidative addition of Pd(0) to chiral phosphoric acid. The ternary catalyst system, consisting of an achiral palladium complex, a primary amine, and a chiral phosphoric acid allows the reaction to tolerate a wide scope of alpha,alpha-disubstituted aldehydes and alkynes, affording the corresponding allylation products in high yields and with excellent levels of enantioselectivity. PMID- 29620908 TI - Molecular Understanding and Implication of Structural Integrity in the Deformation Behavior of Binary Drug-Drug Eutectic Systems. AB - In eutectic, a lamellar microstructure offers better tableting than that of the nonreacted physical mixture. However, bulk deformation remains elusive in two binary eutectics. We hypothesized that the binary eutectic of a drug with different components, having different H-bonding dimensionalities and crystal structure, shall allow the understanding of the structural integrity in the bulk deformation behavior. The shearing molecular solid (FXT Q) shared a common composition with the viscoelastic crystal (ASP I) and brittle (PCM I), forming EM 1 (phi1 = 41.27:58.73% w/w) and EM-2 (phi2 = 41.10:58.90% w/w), respectively. The excess thermodynamic functions were contributed by high energy microstructures (nonbonding interactions) along incoherent phase boundaries (visualized under CLSM). The energy dispersive analysis enabled the recognition of the relative distribution of higher atoms over the heterogeneous surface. EM-1 (FXT Q-ASP I) demonstrated higher compressibility, tensile strength, and compactibility (CTC profile) compared to those of EM-2 (FXT Q-PCM I) over a range of applied compaction pressures. The lower true yield strength (sigma0(EM-1) = 138.66 MPa) of EM-1 as compared to that of EM-2 (sigma0(EM-2) = 166.66 MPa) suggested a better deformation performance and incipient plasticity quantified from the "out of-die" Heckel analysis. From Ryshkewitch analysis, the tensile strength at zero porosity (tau01 = 3.83 MPa) was predicted to be higher for EM-1 than EM-2 (tau02 = 2.54 MPa). The higher bonding strength of EM-1 was contributed to the additional influence of true density and isotropic van der Waals interactions of ASP I (0D). In contrast, EM-2 demonstrated lower compressibility and compactibility, having herringbone molecular packing of PCM I (1D) with a common shearing component (FXT Q (1D)). This study confirmed that the intrinsic deformational and chemical nature of the second component defined the compressibility and compactibility tendency to a greater extent in the tableting performance of conglomerates of crystalline solid solution. PMID- 29620909 TI - Plasmonic Glasses and Films Based on Alternative Inexpensive Materials for Blocking Infrared Radiation. AB - The need for energy-saving materials is pressing. This Letter reports on the design of energy-saving glasses and films based on plasmonic nanocrystals that efficiently block infrared radiation. Designing such plasmonic composite glasses is nontrivial and requires taking full advantage of both material and geometrical properties of the nanoparticles. We compute the performance of solar plasmonic glasses incorporating a transparent matrix and specially shaped nanocrystals. This performance depends on the shape and material of such nanocrystals. Glasses designed with plasmonic nanoshells are shown to exhibit overall better performances as compared to nanorods and nanocups. Simultaneously, scalable synthesis of plasmonic nanoshells and nanocups is technologically feasible using gas-phase fabrication methods. The computational simulations were performed for noble metals (gold and silver) as well as for alternative plasmonic materials (aluminum, copper, and titanium nitride). Inexpensive plasmonic materials (silver, copper, aluminum, and titanium nitride) show an overall good performance in terms of the commonly used figures of merit of industrial glass windows. Together with numerical data for specific materials, this study includes a set of general rules for designing efficient plasmonic IR-blocking media. The plasmonic glasses proposed herein are good candidates for the creation of cheap optical media, to be used in energy-saving windows in warm climates' housing or temperature-sensitive infrastructure. PMID- 29620910 TI - Origin and Manipulation of Stable Vortex Ground States in Permalloy Nanotubes. AB - We present a detailed study on the static magnetic properties of individual permalloy nanotubes (NTs) with hexagonal cross-sections. Anisotropic magnetoresistance (AMR) measurements and scanning transmission X-ray microscopy (STXM) are used to investigate their magnetic ground states and its stability. We find that the magnetization in zero applied magnetic field is in a very stable vortex state. Its origin is attributed to a strong growth-induced anisotropy with easy axis perpendicular to the long axis of the tubes. AMR measurements of individual NTs in combination with micromagnetic simulations allow the determination of the magnitude of the growth-induced anisotropy for different types of NT coatings. We show that the strength of the anisotropy can be controlled by introducing a buffer layer underneath the magnetic layer. The magnetic ground states depend on the external magnetic field history and are directly imaged using STXM. Stable vortex domains can be introduced by external magnetic fields and can be erased by radio-frequency magnetic fields applied at the center of the tubes via a strip line antenna. PMID- 29620911 TI - Association Between History of Multiple Concussions and Health Outcomes Among Former College Football Players: 15-Year Follow-up From the NCAA Concussion Study (1999-2001). AB - BACKGROUND: Previous research has examined associations between concussion history and adverse health outcomes among former professional football players. Less is known about the potential effects of concussion among former college football players without additional exposure at the professional level. PURPOSE: To examine the association between concussion and adverse health outcomes in a cohort of former college football players without exposure to professional football, 15 years after their playing careers ended. STUDY DESIGN: Cross sectional study; Level of evidence, 3. METHODS: A sample of 204 former collegiate football players (23.4% of eligible athletes with available contact information) all of whom played at least 1 season of football from 1999 to 2001 in the National Collegiate Athletic Association (NCAA) and had no professional football exposure-completed a general health survey that assessed lifetime concussion history and included the following: the Veterans RAND 36 Item Health Survey, containing a physical composite score (PCS) and mental composite score (MCS); the depression module of the Patient Health Questionnaire; and the 4-item CAGE alcohol dependence questionnaire (for "cutting down, annoyance by criticism, guilty feeling, and eye-openers"). Multivariable binomial regression models estimated adjusted prevalence ratios (PRs) with 95% CIs while controlling for demographics and playing history covariates through forward selection model building. RESULTS: Most participants reported a concussion history (84.3%). Overall, 22.1% and 39.2% of participants reported a PCS and an MCS <50, respectively (indicating worse health than the US national average); 19.1% reported Patient Health Questionnaire scores >=10 (indicating moderate/severe depression); and 24.8% reported CAGE scores >=2 (indicating alcohol dependence). The prevalence of having an MCS <50 was higher among those reporting >=3 versus 0 concussions (PR, 2.5; 95% CI, 1.3-4.9). Controlling for body mass index (BMI), the prevalence of moderate/severe depression was higher among those reporting >=3 versus 0 concussions (PR, 4.2; 95% CI, 1.0-16.3). Controlling for BMI, the prevalence of having a PCS <50 was higher among those reporting >=3 versus 1 or 2 concussions (PR, 2.6; 95% CI, 1.3-5.0) but not 0 concussions (PR, 1.5; 95% CI, 0.6-3.6). No associations were found for alcohol dependence. CONCLUSION: Associations between a history of multiple concussions and adverse health outcomes were found among former collegiate football players without professional football exposure but were limited to those reporting >=3 prior concussions. Because only 23.4% of eligible athletes responded to the survey, the possibility of ascertainment bias exists, and our findings should thus be interpreted with some caution. Continued examination within nonprofessional football populations is needed, but findings highlight the need for prevention efforts to reduce concussion incidence. PMID- 29620912 TI - Duration of Home Oxygen Therapy in Young Children Enrolled in an Accountable Care Organization. PMID- 29620913 TI - Into-Tunnel Repair Versus Onto-Surface Repair for Rotator Cuff Tears in a Rabbit Model. AB - BACKGROUND: Clinically, onto-surface repair is commonly used for rotator cuff tears. The retear rate after rotator cuff repair (RCR) is relatively high, with failure occurring mostly at the tendon-bone connection site. For anterior cruciate ligament (ACL) reconstruction, into-tunnel reconstruction is commonly employed. The retear rate after ACL reconstruction is relatively low, with retears seldom occurring at the tendon-bone interface. No study on into-tunnel RCR has been conducted. HYPOTHESIS: Into-tunnel RCR could promote fibrocartilage regeneration at the tendon-bone interface and has biomechanical advantage over onto-surface repair in a rabbit rotator cuff tear model. STUDY DESIGN: Controlled laboratory study. METHODS: Thirty-six New Zealand White rabbits were used in this study. The supraspinatus tendons were cut from the footprint to create a rotator cuff tear on both shoulders. On one side, the supraspinatus was cut longitudinally into 2 halves, sutured, and pulled into 2 tunnels through the greater tuberosity (into-tunnel repair). On the other side, the tendon was reattached to the surface of the footprint with transosseous sutures (onto surface repair). Twelve animals were sacrificed, of which 6 were used for a histological examination and the other 6 for biomechanical testing, at 4, 8, and 12 weeks, respectively. RESULTS: The tendon-bone interface in the into-tunnel group showed a different healing pattern from that in the onto-surface group. In the former, most of the tendon tissue in the tunnel was replaced with newly generated fibrocartilage; the rest of the tendon fibers appeared in large bundles with direct connection to the bone. In the latter, fibrocartilage regeneration was seldom found at the tendon-bone interface; the tendon near the bone surface appeared as small fibrils. The biomechanical evaluation revealed a higher ultimate load ( P < .001) and stiffness ( P < .001) at the tendon-bone junction in the into-tunnel group than those in the onto-surface group at 12 weeks. CONCLUSION: In a rabbit rotator cuff tear model, into-tunnel RCR could result in a different tendon-bone healing pattern, with obvious fibrocartilage regeneration at the interface and higher tendon-bone healing strength than that in onto surface repair. CLINICAL RELEVANCE: New RCR patterns may be developed to improve the tendon-bone healing pattern and obtain better tendon-bone healing strength. PMID- 29620914 TI - Effects of Metformin on Spatial and Verbal Memory in Children with ASD and Overweight Associated with Atypical Antipsychotic Use. AB - OBJECTIVES: Studies in humans and rodents suggest that metformin, a medicine typically used to treat type 2 diabetes, may have beneficial effects on memory. We sought to determine whether metformin improved spatial or verbal memory in children with autism spectrum disorder (ASD) and overweight associated with atypical antipsychotic use. METHODS: We studied the effects of metformin (Riomet(r)) concentrate on spatial and verbal memory in 51 youth with ASD, ages 6 through 17 years, who were taking atypical antipsychotic medications, had gained significant weight, and were enrolled in a trial of metformin for weight management. Phase 1 was a 16-week, randomized, double-blind, placebo-controlled, parallel-group comparison of metformin (500-850 mg given twice a day) versus placebo. During Phase 2, all participants took open-label metformin from week 17 through week 32. We assessed spatial and verbal memory using the Neuropsychological Assessment 2nd Edition (NEPSY-II) and a modified children's verbal learning task. RESULTS: No measures differed between participants randomized to metformin versus placebo, at either 16 or 32 weeks, after adjustment for multiple comparisons. Sixteen-week change in memory for spatial location on the NEPSY-II was nominally better among participants randomized to placebo. However, patterns of treatment response across all measures revealed no systematic differences in performance, suggesting that metformin had no effect on spatial or verbal memory in these children. CONCLUSIONS: Although further study is needed to support these null effects, the overall impression is that metformin does not affect memory in overweight youth with ASD who were taking atypical antipsychotic medications. PMID- 29620915 TI - Kneading Acceptance: Experiential Massage Therapy Education Fosters Nursing Acceptance of Massage Therapy for Pediatric Patients. PMID- 29620916 TI - Adult-Specific Life Outcomes of Cleft Lip and Palate in a Western Australian Cohort. AB - BACKGROUND: People with a cleft of the lip and/or palate (CL/P) differ from their peers due to their facial appearance, hearing and speech difficulties, and the significant time spent attending appointments and recovering from surgical interventions. These differences may impact life outcomes including occupation, income, education, relationships, psychosocial health issues, and lifestyle choices. METHODOLOGY: A self-administered questionnaire was posted to 338 former and current patients of the Cleft Lip and Palate Unit of Princess Margaret Hospital (PMH), Perth, Western Australia. RESULTS: Completed questionnaires were returned by 158 former and current patients. In comparison to the Australian Bureau of Statistics, study participants attained equivalent highest education levels, full-time annual income levels, occupational categories, employment rates, and home ownership levels. They did not marry later and demonstrated positive health-related lifestyle behaviors. However independent living was significantly delayed, and the number of romantic relationships, marriages, and children was lower, with separation/divorce rates also being lower. A key finding was that 78% of participants self-reported that they experienced at least 1 psychosocial health issue and more than half experienced anxiety and/or depression. CONCLUSION: When comparing the sociological outcomes for the study participants, the psychosocial outcomes were the areas of most concern. Further investigation is required to determine the causes for the high self-reported rates of anxiety and/or depression found in this study. PMID- 29620917 TI - Speech Production Skills in Children With Cleft Palate Who Were Internationally Adopted. AB - OBJECTIVE: The objective of this study was to investigate the impact of international adoption (IA), age at palatoplasty (PR age), and velopharyngeal sufficiency (VPS) on articulation outcomes. DESIGN: This was a cross-sectional, prospective, observational study. SETTING: Outpatient hospital clinic. PARTICIPANTS: Fifty-one IA and 65 not-adopted (NA) children between the ages of 3 and 9 with nonsyndromic cleft palate with or without cleft lip. MAIN OUTCOME MEASURE(S): The Goldman-Fristoe Test of Articulation-2nd Edition (GFTA-2) standard score and cleft-related articulation errors (CREs). RESULTS: Articulation impairment was observed for 40% to 76% of NA children and 71% to 92% IA children, depending on age. PR age mean IA = 2.07 (0.86) years; NA = 1.23 (0.71) years. Children who were IA had poorer performance on the GFTA-2 ( B = 13.82, P = .015). Children who were IA were not significantly more likely to make CRE; rather, age at the time of assessment ( B = -.10, P = .002) and VPS ( B = .24, P = .021) were associated with CRE. CONCLUSIONS: Children who were IA demonstrated poorer articulation skills. Although primary palatoplasty was accomplished later among children who were IA, age at assessment and VP status (not PR age) were significantly correlated with articulation outcomes. Implications for timing of surgical intervention are discussed. PMID- 29620918 TI - Web Support for Weight-Loss Interventions: PREDIRCAM2 Clinical Trial Baseline Characteristics and Preliminary Results. AB - An ongoing clinical trial is testing the efficacy of web telematic support in a structured program for obesity treatment and diabetes prevention. Participants were recruited from two tertiary-care hospitals and randomized to receive either a telematic intervention (TI) supported by PREDIRCAM2 web platform or a non telematic intervention (NTI). All receive 1-year follow-up. Both interventions consist of tailored dietary and exercise prescriptions, based on a Mediterranean dietary pattern and general WHO exercise recommendations for adults. At 6 months, both groups have received 7 contacts, 3 exclusively telematic for the TI group. This is a preliminary result intention-to-treat analysis. One hundred eighty three participants were recruited, with a mean body mass index of 34.75 +/- 2.75 kg/m2. General dropout rate at 6 months was 26.8%. Weight changes were statistically significant at months 3 and 6 compared to baseline, -2.915 +/- 0.24 kg, -3.29 +/- 0.36 kg, respectively (P < 0.001), but not statistically significant between the 3- and 6-month time points -0.37 +/- 0.21 kg (P = 0.24). Mean group differences showed that the TI group lost 1.61 +/- 1.88 kg more than the NTI group (P = 0.39). Waist, waist/hip ratio, resting heart rate, blood pressure, HbA1c, and low-density lipoprotein cholesterol also showed statistically significant changes at 6 months, with no significant differences between groups. Weight loss in the TI group shows similar results as the usual care NTI group for weight loss and control of obesity comorbidities. At completion of the clinical trial, these results will be reevaluated to assess the potential role of web support in weight-loss maintenance and its cost effectiveness. PMID- 29620920 TI - AllSome Sequence Bloom Trees. AB - The ubiquity of next-generation sequencing has transformed the size and nature of many databases, pushing the boundaries of current indexing and searching methods. One particular example is a database of 2652 human RNA-seq experiments uploaded to the Sequence Read Archive (SRA). Recently, Solomon and Kingsford proposed the Sequence Bloom Tree data structure and demonstrated how it can be used to accurately identify SRA samples that have a transcript of interest potentially expressed. In this article, we propose an improvement called the AllSome Sequence Bloom Tree. Results show that our new data structure significantly improves performance, reducing the tree construction time by 52.7% and query time by 39% 85%, with a price of upto 3 * memory consumption during queries. Notably, it can query a batch of 198,074 queries in <8 hours (compared with around 2 days previously) and a whole set of k-mers from a sequencing experiment (about 27 million k-mers) in <11 minutes. PMID- 29620919 TI - Trends in the Prevalence of Overweight and Obesity among Chinese School-Age Children and Adolescents from 2010 to 2015. AB - BACKGROUND: In China, recent rapid economic growth has been associated with increasing prevalence of childhood obesity. This study aimed to provide the most updated prevalence and trends in overweight and obesity among school-age children and adolescents in Shanghai, China, in 2010-2015. METHODS: Annual physical examination data were collected from 66,410, 43,812, 104,887, 113,667, 119,401, and 109,068 school children and adolescents aged 6-17 in Minhang District, Shanghai, in 2010-2015. The outcome of interest was the prevalence of overweight and obesity based on the body mass index (BMI) criteria from the International Obesity Task Force. RESULTS: In 2010-2015, the age-adjusted prevalence of overweight and obesity among boys increased from 21.2% to 31.7% and from 10.6% to 16.9% among girls. In 2015, the prevalence of obesity among boys was 9.3% higher than among girls (3.5%). The prevalence for boys was consistently higher than that for girls at each age and across years. The prevalence of overweight and obesity was highest at 11 years: 37.3% for boys and 19.8% for girls. CONCLUSIONS: The prevalence of overweight and obesity among Chinese urban children and adolescents is comparable to that in developed countries and was still increasing in 2010-2015. The prevalence among boys was alarmingly high. The findings highlight the need to develop public intervention strategies targeting urban children to stop the increasing trend in childhood obesity in China. PMID- 29620921 TI - Vast Differences in Psychotropic Prescription Rates, But Not Outcomes, for Obese Adolescents in Immersion Treatment across Geographical Regions. AB - BACKGROUND: Pediatric obesity is recognized as a worldwide epidemic. Treatment of this problem has proven difficult, but many promising interventions exist, including immersion treatment. The purpose of this study is to examine the potential influence of psychotropic medications on immersion treatment outcomes in a real-world treatment setting. METHODS: This study examines the prescription rates of psychotropic medications and treatment process and outcomes of 642 adolescents in ten different cognitive behavioral therapeutic immersion weight loss camps in the United States and in the United Kingdom. RESULTS: The US participants received psychotropic medications at drastically varying rates by geographical location and overall at almost ten times the rate of UK participants. Those taking psychotropic medications engaged in treatment and decreased percentage overweight at similar rates as their nonmedicated peers. The medication group reported higher initial and final rates of distress, but both groups improved their moods during camp and exhibited smaller differences in mood ratings by the end of camp. CONCLUSIONS: Significantly higher prescription rates of psychotropic medication, especially evident comparing the United States to the United Kingdom, were unrelated to immersion obesity treatment process and outcomes for youth. Immersion treatment for obese adolescents appears effective regardless of psychotropic medication status of the participant. This finding supports the use of cognitive behavioral immersion treatments for adolescent obesity and leads to several possible conclusions and directions for future study. PMID- 29620922 TI - Immediate Symptom Relief After a First Session of Massage Therapy or Reiki in Hospitalized Patients: A 5-Year Clinical Experience from a Rural Academic Medical Center. AB - OBJECTIVES: There is an increasing demand for and use of alternative and complementary therapies, such as reiki and massage therapy, in hospital-based settings. Most controlled studies and practice-based reports include oncology and surgical patient populations; thus the effect in a more heterogeneous hospitalized patient population is hard to estimate. We examined the immediate symptom relief from a single reiki or massage session in a hospitalized population at a rural academic medical center. DESIGN: Retrospective analysis of prospectively collected data on demographic, clinical, process, and quality of life for hospitalized patients receiving massage therapy or reiki. SETTINGS/LOCATION: A 396-bed rural academic and tertiary medical center in the United States. SUBJECTS: Hospitalized patients requesting or referred to the healing arts team who received either a massage or reiki session and completed both a pre- and post-therapy symptom questionnaire. INTERVENTIONS: First session of routine reiki or massage therapy during a hospital stay. OUTCOME MEASURES: Differences between pre- and postsession patient-reported scores in pain, nausea, fatigue, anxiety, depression, and overall well-being using an 11-point Likert scale. RESULTS: Patients reported symptom relief with both reiki and massage therapy. Analysis of the reported data showed reiki improved fatigue (-2.06 vs. 1.55 p < 0.0001) and anxiety (-2.21 vs. -1.84 p < 0.001) statistically more than massage. Pain, nausea, depression, and well being changes were not statistically different between reiki and massage encounters. Immediate symptom relief was similar for cancer and noncancer patients for both reiki and massage therapy and did not vary based on age, gender, length of session, and baseline symptoms. CONCLUSIONS: Reiki and massage clinically provide similar improvements in pain, nausea, fatigue, anxiety, depression, and overall well-being while reiki improved fatigue and anxiety more than massage therapy in a heterogeneous hospitalized patient population. Controlled trials should be considered to validate the data. PMID- 29620923 TI - Compatibility of Amino Acids in Ice Ih: Implications for the Origin of Life. AB - Icy environments may have been common on early Earth due to the faint young sun. Previous studies have proposed that the formation of large icy bodies in the early ocean could concentrate the building blocks of life in eutectic fluids and, therefore, facilitate the polymerization of monomers. This hypothesis is based on the untested assumption that organic molecules are virtually incompatible in ice Ih (hexagonal ice). In this study, we conducted freezing experiments to explore the partitioning behavior of selected amino acids (AAs; glycine, l-alanine, l proline, and l-phenylalanine) between ice Ih and aqueous solutions analogous to seawater. We allowed ice crystals to grow slowly from a few seeds in equilibrium with the solution and used Raman spectroscopy to analyze in situ the relative concentrations of AAs in the ice and aqueous solution. During freezing, there was no precipitation of AA crystals, indicating that the concentrations in solution never reached their solubility limit, even when the droplet was mostly frozen. Analyses of the Raman spectra of the ice and eutectic solution suggested that considerable amounts of AAs existed in the ice phase with partition coefficients varying between 0.2 and 0.5. These observations imply little incompatibility of AAs in ice Ih during the freezing of the solutions, rendering the concentration hypothesis in a eutectic system unwarranted. However, incorporation into ice Ih could protect AAs from decomposition or racemization and significantly improve the efficiency of extraterrestrial transport of small organics. Therefore, this study supports the hypothesis of extraterrestrial delivery of organic molecules in icy comets and asteroids to the primitive Earth as suggested by an increasing number of independent observations. Key Words: Ice Ih-Partition coefficient-Amino acids-Polymerization-Extraterrestrial transport of organics. Astrobiology 18, 381 392. PMID- 29620924 TI - Desvenlafaxine Versus Placebo in a Fluoxetine-Referenced Study of Children and Adolescents with Major Depressive Disorder: Design, Definitions, and Ongoing Challenges for Child and Adolescent Psychopharmacology Research. PMID- 29620925 TI - Sexualized Drug Use (Chemsex) Is Associated with High-Risk Sexual Behaviors and Sexually Transmitted Infections in HIV-Positive Men Who Have Sex with Men: Data from the U-SEX GESIDA 9416 Study. AB - The magnitude of sexualized drug use (SDU), also known as chemsex, and its association with sexually transmitted infections (STI) has not been systematically explored in HIV-positive patients. This study aimed to calculate the prevalence of SDU and associated factors in a sample of HIV-positive men who have sex with men (MSM) in Spain. We calculated the frequency of SDU in a sample of HIV-positive MSM who responded to an anonymous online survey on sexual behavior and recreational drug use. We also analyzed differences between those who responded and those who did not (data taken from the physician's registry). The association between SDU, sexual risk behaviors, and STI was evaluated using a univariate and a multivariate analysis. Data were collected and managed using Research Electronic Data Capture (REDCap). The survey was completed by 742 HIV positive MSM, of whom 60% had had unprotected anal intercourse (UAI), 62% had been diagnosed with a STI, and 216 (29.1%) reported recent SDU (slamsex in 16% of cases). In the multivariate analysis, patients who engaged in SDU were more likely to have had high-risk sexual behaviors and a diagnosis of STI than participants who did not engage in SDU. A diagnosis of hepatitis C was independently associated with slamsex (5.2 [95% confidence interval (CI), 2.06 13.13]; p < 0.001), chemsex (2.51 [95% CI, 1.28-4.91]; p = 0.007), and UAI (1.82 [95% CI, 0.90-3.70]; p = 0.094). The magnitude of SDU or chemsex in our sample is relatively high. We found a clear association between SDU, high-risk sexual behaviors, and STI including hepatitis C. PMID- 29620926 TI - Patient and Facility Correlates of Racial Differences in Viral Control for Black and White Veterans with HIV Infection in the Veterans Administration. AB - Black persons with HIV are less likely than white persons to experience viral control even while in treatment. We sought to understand whether patient characteristics and site of care explain these differences using a cross sectional analysis of medical records. Our cohort included 8779 black and 7836 white patients in the Veterans Administration (VA) health system with HIV who received antiretroviral medication during 2013. Our primary outcome, viral control, was defined as HIV serum RNA <200 copies/mL. We examined the degree to which racial differences in viral control are related to site of care, patient characteristics (demographics, HIV treatment history, comorbid conditions, time in care, and medication adherence), retention in care, and combination antiretroviral therapy (cART) adherence, using multi-variable logistic regression models. Compared to whites, blacks were younger and had lower CD4 counts, more comorbidities, lower retention in care, and poorer medication adherence. The odds of uncontrolled viral load were 2.02 (p < 0.001) for black relative to white patients without risk adjustment (15% vs. 8% uncontrolled viral load, respectively). The odds decreased to 1.83 (p < 0.001), 1.65 (p < 0.001), 1.62 (p < 0.001), and 1.24 (p = 0.01) in models that sequentially controlled for site of care, age and clinical characteristics, care retention, and cART adherence, respectively. Overall, 51% of the viral control difference between blacks and whites was accounted for by adherence; 26% by site of care. We conclude that differences in the site of HIV care and cART adherence account for most of the difference in viral control between black and white persons receiving HIV care, although the exact pathway by which this relationship occurs is unknown. Targeting poorer performing sites for quality improvement and focusing on improving antiretroviral adherence in black patients may help alleviate disparities in viral control. PMID- 29620929 TI - Short Communication: Long Noncoding RNA GAS5 Inhibits HIV-1 Replication Through Interaction with miR-873. AB - HIV is the causative pathogen of AIDS, which has generated worldwide concern. Long noncoding RNAs (lncRNAs) are a rising star in virus-host cross-talk pathways; they are differentially expressed during many viral infections and are involved in multiple biological processes. Currently, lncRNA growth arrest specific transcript 5 (GAS5) is known to be downregulated during HIV-1 infection. However, the functions and mechanisms of GAS5 in HIV-1 infection remain largely unknown. In this report, it was found for the first time that GAS5 could inhibit HIV-1 replication. Interestingly, using bioinformatics analyses (with Genomica and starBase.v2.0), GAS5 was found to potentially interact with miR-873. It was further verified that GAS5 could suppress miR-873. Moreover, miR-873 could promote HIV-1 replication. Together, these results not only suggest that GAS5 may inhibit HIV-1 replication through interaction with miR-873 but the results may also provide novel biomarkers for antiviral drugs or potential targets for future therapeutics for HIV/AIDS. PMID- 29620927 TI - Development and Piloting of a Home-Based Couples Intervention During Pregnancy and Postpartum in Southwestern Kenya. AB - Engaging both partners of a pregnant couple can enhance prevention of mother-to child transmission of HIV and promote family health. We developed and piloted an intervention to promote couple collaboration in health during pregnancy and postpartum in southwestern Kenya. We utilized formative data and stakeholder input to inform development of a home-based couples intervention. Next, we randomized pregnant women to intervention (n = 64) or standard care (n = 63) arms, subsequently contacting their male partners for enrollment. In the intervention arm, lay health workers conducted couple home visits, including health education, couple relationship and communication skills, and offers of couple HIV testing and counseling (CHTC) services. Follow-up questionnaires were conducted 3 months postpartum (n = 114 women, 86 men). Baseline characteristics and health behaviors were examined by study arm using t-tests, chi-square tests, and regression analyses. Of the 127 women randomized, 96 of their partners participated in the study. Of 52 enrolled couples in the intervention arm, 94% completed at least one couple home visit. Over 93% of participants receiving couple home visits were satisfied and no adverse social consequences were reported. At follow-up, intervention couples had a 2.78 relative risk of having participated in CHTC during the study period compared with standard care couples (95% confidence interval: 1.63-4.75), and significant associations were observed in other key perinatal health behaviors. This pilot study revealed that a home based couples intervention for pregnant women and male partners is acceptable, feasible, and has the potential to enhance CHTC and perinatal health behaviors, leading to improved health outcomes. PMID- 29620930 TI - Antiviral Activity of Tenofovir Alafenamide Against HIV-1 Subtypes and Emergence of K65R. AB - Differences in emergence of HIV resistance between subtypes B and C in vitro and potential implications on tenofovir alafenamide efficacy in vivo were evaluated. Dose escalation resistance selections showed K65R emerging earlier for subtype C viruses in vitro, as previously reported. Viral breakthrough experiments at therapeutic drug concentrations, however, showed no difference in time to breakthrough between these subtypes. Finally, clinical trial data found no evidence of greater K65R emergence in patients harboring subtype C HIV. PMID- 29620931 TI - Prevalence of Drug Resistance Mutations in Protease, Reverse Transcriptase, and Integrase Genes of North Central Mexico HIV Isolates. AB - This study set out to determine the frequency of antiretroviral drug resistance mutations in treatment-naive subjects of the north central Mexican state of San Luis Potosi. Mexican studies of antiretroviral drug resistance mutations have focused mainly on large metropolitan areas and border towns subjected to intense international migrations. This study set forth to describe the frequency of these mutations in a Mexican region less subjected to such migratory influences and more representative of smaller Mexican cities. Thirty-eight full-length pol sequences spanning the protease, reverse-transcriptase, and integrase-encoding regions were obtained from 42 treatment-naive human immunodeficiency virus (HIV) infected subjects. Most exhibited subtype B homology, but CRF02_AG was also detected. Evidence of APOBEC3 hypermutation was seen in two samples. Calibrated population analysis revealed a surveillance drug resistance mutation prevalence of 4.9% for protease inhibitors, of 2.7% for nucleoside reverse transcriptase inhibitors, of 8.1% for non-nucleoside reverse transcriptase inhibitors, and an overall prevalence of 9.5%. This corresponds to an intermediate level of transmitted drug resistance according to the World Health Organization. The identification of integrase mutations suggests that transmitted drug mutations are being imported, as inhibitors targeting integrase have not been widely used in Mexico. Our results provide a greater understanding of HIV diversity in Mexico and highlight the way internal migrations allow HIV mutations and genetic features to permeate regions less subjected to international migrations. The implications of these findings will become more evident as Mexico hosts increased repatriations of migrants in the coming years. PMID- 29620935 TI - Bonnie Mathieson (1945-2018). PMID- 29620932 TI - Clinical Benefits and Cost-Effectiveness of Laboratory Monitoring Strategies to Guide Antiretroviral Treatment Switching in India. AB - Current Indian guidelines recommend twice-annual CD4 testing to monitor first line antiretroviral therapy (ART), with a plasma HIV RNA test to confirm failure if CD4 declines, which would prompt a switch to second-line ART. We used a mathematical model to assess the clinical benefits and cost-effectiveness of alternative laboratory monitoring strategies in India. We simulated a cohort of HIV-infected patients initiating first-line ART and compared 11 strategies with combinations of CD4 and HIV RNA testing at varying frequencies. We included adaptive strategies that reduce the frequency of tests after 1 year from 6 to 12 months for virologically suppressed patients. We projected life expectancy, time on failed first-line ART, cumulative 10-year HIV transmissions, lifetime cost (2014 US dollars), and incremental cost-effectiveness ratios (ICERs). We defined strategies as cost-effective if their ICER was <1 * the Indian per capita gross domestic product (GDP, $1,600). We found that the current Indian guidelines resulted in a per person life expectancy (from mean age 37) of 150.2 months and a per person cost of $2,680. Adding annual HIV RNA testing increased survival by ~8 months; adaptive strategies were less expensive than similar nonadaptive strategies with similar life expectancy. The most effective strategy with an ICER <1 * GDP was the adaptive HIV RNA strategy (ICER $840/year). Cumulative 10-year transmissions decreased from 27.2/1,000 person-years with standard-of-care to 20.9/1,000 person-years with adaptive HIV RNA testing. In India, routine HIV RNA monitoring of patients on first-line ART would increase life expectancy, decrease transmissions, be cost-effective, and should be implemented. PMID- 29620933 TI - Dynamics of Lymphocyte Reconstitution After Hematopoietic Transplantation During Chronic Lymphocytic Choriomeningitis Virus Infection. AB - Bone marrow transplantation is a treatment for various cancers and genetic diseases, and the only case of a cured HIV infection involved the use of this clinical procedure, highlighting the potential use of this therapy for curing many chronic diseases. However, little is known about how chronic viral infection influences lymphocyte reconstitution after bone marrow transplantation. To address this, we infected mice with chronic lymphocytic choriomeningitis virus, and performed bone marrow transplantation to assess lymphocyte reconstitution. Interestingly, we observed that adoptively transferred marrow cells exhibited preferential B cell differentiation in chronically infected mice. Moreover, donor marrow cells that were adoptively transferred into chronically infected mice differentiated into virus-specific CD8 T cells that were able to expand after PD L1 blockade. Taken together, our data show that chronic viral infection induces a biased differentiation of bone marrow stem cells into B cells, and that exhausted virus-specific CD8 T cells generated de novo in this setting are rescuable by PD 1 blockade. These data contribute to the understanding of how chronic viral infection impacts lymphocyte reconstitution, and may provide valuable information to improve current hematopoietic transplantation regimens in chronically infected hosts. PMID- 29620934 TI - Factors Associated with Lower Respiratory Tract Infections in HIV-Exposed Uninfected Infants. AB - To identify factors that predispose human immunodeficiency virus (HIV)-exposed uninfected infants (HEUs) to higher incidence of severe infections, hospitalization, and death in the first 6-24 months of life compared with HEUs with and without lower respiratory tract infection (LRTI) in the first 6 months of life. Nested case-control study of 107 LRTI+ infants enrolled in the International Site Development Initiative (NISDI) Perinatal and Longitudinal Study in Latin American Countries (LILAC) studies with and 140 LRTI- in the first 6 months, matched by date and place of birth. Infants and mothers had plasma antibodies measured against respiratory syncytial virus (RSV), parainfluenza (PIV) 1, 2, 3, influenza, and pneumococcus 1, 5, 6B, and 14. Compared with LRTI-, mothers of LRTI+ HEUs had lower years of education, lower CD4+ cells, and higher HIV plasma viral load at delivery, but similar use of antiretrovirals and cotrimoxazole and other sociodemographic characteristics. LRTI+ and LRTI- HEUs had similar demographic and hematological characteristics and antibody concentrations against respiratory pathogens at birth. At 6 months, the rates of seroconversions to respiratory pathogens and antibody responses to tetanus vaccine were also similar. However, antibody concentrations to RSV were significantly higher in LRTI+ compared with LRTI- HEUs and marginally higher to PIV1. Maternal factors associated with advanced HIV disease, but unrelated to the use of antiretrovirals, cotrimoxazole, or the level of maternal antibodies against respiratory pathogens, contribute to the increased risk of LRTI in HEUs. In HEUs, antiretroviral and cotrimoxazole use, exposure to respiratory pathogens and humoral immune responses were not associated with the incidence of LRTI. PMID- 29620936 TI - The Impact of Preterm Infants' Continuous Exposure to Breast Milk Odor on Stress Parameters: A Pilot Study. AB - OBJECTIVE: This pilot study aimed to assess the effect of continuous exposure to the odor of own mothers' breast milk (BM) on the stress parameters of preterm infants. MATERIALS AND METHODS: Fifteen healthy preterm infants were included. Mean heart rate and salivary cortisol were measured over three consecutive time periods, each lasting 2 days: (1) preintervention (odor free); (2) intervention, during which a cotton pad soaked with 1.5 mL of BM was placed near the infant's head with the aim of providing continuous exposure to its odor; (3) postintervention period (odor free). RESULTS: Saliva cortisol levels differed significantly between the three exposure periods (pre-, during, and post-BM odor exposure): 11.38 +/- 5.03, 9.51 +/- 4.38, and 4.99 +/- 3.42 nmol/L, respectively. A repeated univariate analysis of the cortisol measure showed a significant difference (F = 9.34; df = 2.28, p < 0.001). There was no difference in mean heart rate over the three study periods. CONCLUSIONS: Preterm infants exposed to BM odor from their own mothers demonstrate a persistent decrease in saliva cortisol levels, which continues after termination of the intervention. This finding may suggest that exposure to own mothers' BM odor has a soothing effect on preterm infants. Further randomized controlled studies are needed to evaluate this simple, safe, and inexpensive intervention. PMID- 29620938 TI - Breastfeeding Medicine's New Standards for Submission of Articles; the CONSORT and PRISMA Guidelines. PMID- 29620937 TI - Defining Tip-Frenulum Length for Ankyloglossia and Its Impact on Breastfeeding: A Prospective Cohort Study. AB - OBJECTIVE: The purpose of this study was to investigate the normal lingual frenulum anatomy in newborns and to evaluate tip-frenulum distance as an objective diagnostic tool for identifying newborns at risk for anterior and posterior tongue tie and breastfeeding difficulty. MATERIALS AND METHODS: The distance from the tongue tip to the insertion of the lingual frenulum was measured in a group of 100 healthy newborns to establish normative data. The presence of a visible or palpable cord was noted. Inter-rater reliability was assessed. Breastfeeding surveys including a maternal pain scale and Infant Breastfeeding Assessment Tool (IBFAT) were administered on days of life 2 and 14 to determine whether these findings predict breastfeeding difficulty. RESULTS: Mean tip-frenulum length was 9.07 mm. Intraclass correlation coefficient between observers for tip-frenulum length was 0.82. A visible cord was identified in 21 subjects (21%). A palpable cord was identified in 59 subjects (59%). Unweighted kappa coefficients for inter-rater reliability of visible and palpable cords were 0.91 and 0.47, respectively. Visible cord and shorter tip-frenulum distance were independently predictive of higher maternal pain scores. A positive correlation was identified between tip-frenulum length and IBFAT scores for mothers with two or more previous breastfed children. CONCLUSIONS: Tongue tip-frenulum length correlated with maternal nipple pain, and was useful as an objective tool for identifying newborns at risk for ankyloglossia. Maternal breastfeeding experience appears to be an important factor in the link between tongue anatomy and breastfeeding difficulty. The presence of a palpable cord was variable across examiners, and should be interpreted with caution when evaluating newborns for posterior tongue tie. PMID- 29620939 TI - Mommy, What's That Baby Doing? PMID- 29620940 TI - Validation and Generalizability of Preoperative PROMIS Scores to Predict Postoperative Success in Foot and Ankle Patients. AB - BACKGROUND: A recent publication reported preoperative Patient-Reported Outcomes Measurement Instrumentation System (PROMIS) scores to be highly predictive in identifying patients who would and would not benefit from foot and ankle surgery. Their applicability to other patient populations is unknown. The aim of this study was to assess the validation and generalizability of previously published preoperative PROMIS physical function (PF) and pain interference (PI) threshold t scores as predictors of postoperative clinically meaningful improvement in foot and ankle patients from a geographically unique patient population. METHODS: Prospective PROMIS PF and PI scores of consecutive patient visits to a tertiary foot and ankle clinic were obtained between January 2014 and November 2016. Patients undergoing elective foot and ankle surgery were identified and PROMIS values obtained at initial and follow-up visits (average, 7.9 months). Analysis of variance was used to assess differences in PROMIS scores before and after surgery. The distributive method was used to estimate a minimal clinically important difference (MCID). Receiver operating characteristic curve analysis was used to determine thresholds for achieving and failing to achieve MCID. To assess the validity and generalizability of these threshold values, they were compared with previously published threshold values for accuracy using likelihood ratios and pre- and posttest probabilities, and the percentages of patients identified as achieving and failing to achieve MCID were evaluated using chi2 analysis. RESULTS: There were significant improvements in PF ( P < .001) and PI ( P < .001) after surgery. The area under the curve for PF (0.77) was significant ( P < .01), and the thresholds for achieving MCID and not achieving MCID were similar to those in the prior study. A significant proportion of patients (88.9%) identified as not likely to achieve MCID failed to achieve MCID ( P = .03). A significant proportion of patients (84.2%) identified as likely to achieve MCID did achieve MCID ( P < .01). The area under the curve for PROMIS PI was not significant. CONCLUSIONS: PROMIS PF threshold scores from published data were successful in classifying patients from a different patient and geographic population who would improve with surgery. If functional improvement is the goal, these thresholds could be used to help identify patients who will benefit from surgery and, most important, those who will not, adding value to foot and ankle health care. LEVEL OF EVIDENCE: Level II, Prospective Comparative Study. PMID- 29620941 TI - Cerebrovascular beta-amyloid deposition and associated microhemorrhages in a Tg2576 Alzheimer mouse model are reduced with a DHA-enriched diet. AB - Cerebral amyloid angiopathy (CAA) is a major contributor to Alzheimer's disease (AD) pathogenesis. Like AD, CAA is often accompanied by marked inflammation, aggravating associated vasculopathies. No evidence-based prevention or treatment strategies are available. Here, we evaluate the possible beneficial effect of a diet enriched with docosahexaenoic acid (DHA), which is known to attenuate inflammation in CAA. Tg2576 mice, a transgenic model of AD/CAA, were fed a DHA enriched diet starting at 2 mo of age and ending at 10, 14, or 18 mo of age. beta Amyloid (Abeta)-peptide deposition and bleeding were visualized by immunohistochemistry or histochemistry on coronal sections of the brain. DHA, arachidonic acid, and eicosanoid levels were measured by liquid chromatography/mass spectrometry or GC-MS. DHA-enriched diet throughout aging limits the accumulation of vascular Abeta peptide deposits as well as the likelihood of microhemorrhages. There is a strong correlation between systemic 12 hydroxyeicosatetraenoic acid (HETE) levels and the size of the area affected by both vascular amyloid deposits and hemorrhages. The lowest levels of 12-HETE, a lipid-derived proinflammatory product of 12-lipoxygenase (LOX), were found in DHA fed mice. In vitro experiments performed on amyloid vascular smooth muscle cells showed that a 12-LOX inhibitor almost completely blocked the Abeta1-40 peptide induced apoptosis of these cells. This study yet again highlights the important role of inflammation in CAA pathogenesis and identifies potential new targets for preventive care.-Hur, J., Mateo, V., Amalric, N., Babiak, M., Bereziat, G., Kanony-Truc, C., Clerc, T., Blaise, R., Limon, I. Cerebrovascular beta-amyloid deposition and associated microhemorrhages in a Tg2576 Alzheimer mouse model are reduced with a DHA-enriched diet. PMID- 29620942 TI - Food withdrawal alters the gut microbiota and metabolome in mice. AB - Food withdrawal as a health-enhancing measure has beneficial effects on aging, disease prevention, and treatment. However, the cellular and molecular mechanisms involving gut microbial changes and metabolic consequences resulting from food withdrawal have yet to be elucidated. In this study, we subjected lean and obese mice to a dietary intervention that consisted of a 4-d complete food withdrawal and an 8-d 50% food withdrawal, and we studied changes in cecal microbiome and host serum metabolome. The abundance of potentially pathogenic Proteobacteria was decreased and Akkermansia muciniphila was elevated by food withdrawal in mice fed a high-fat diet (HFD). Meanwhile, food withdrawal decreased the abundance of metabolites in branched chain amino acid, lipid, and free fatty acid metabolisms in host serum, more so in HFD mice than in normal mice. Microbial predicted function also showed that food withdrawal decreased the abundance of microbes associated with predicted diseases in the HFD group but not in the normal chow group. Correlation between the microbiome data and metabolomics data revealed a strong association between gut microbial and host metabolic changes in response to food withdrawal. In summary, our results showed that food withdrawal was safer and more metabolically beneficial to HFD-induced obese mice than to normal lean mice, and the beneficial effects were primarily derived from the changes in gut microbiota, which were closely associated with the host metabolome.-Zheng, X., Zhou, K., Zhang, Y., Han, X., Zhao, A., Liu, J., Qu, C., Ge, K., Huang, F., Hernandez, B., Yu, H., Panee, J., Chen, T., Jia, W., Jia, W. Food withdrawal alters the gut microbiota and metabolome in mice. PMID- 29620943 TI - Epigenome-wide analysis reveals specific DNA hypermethylation of T cells during human hematopoietic differentiation. AB - AIM: Epigenetic regulation plays an important role in cellular development and differentiation. A detailed map of the DNA methylation dynamics that occur during cell differentiation would contribute to decipher the molecular networks governing cell fate commitment. METHODS: Illumina MethylationEPIC BeadChip platform was used to describe the genome-wide DNA methylation changes observed throughout hematopoietic maturation by analyzing multiple myeloid and lymphoid hematopoietic cell types. RESULTS: We identified a plethora of DNA methylation changes that occur during human hematopoietic differentiation. We observed that T lymphocytes display substantial enhancement of de novo CpG hypermethylation as compared with other hematopoietic cell populations. T-cell-specific hypermethylated regions were strongly associated with open chromatin marks and enhancer elements, as well as binding sites of specific key transcription factors involved in hematopoietic differentiation, such as PU.1 and TAL1. CONCLUSION: These results provide novel insights into the role of DNA methylation at enhancer elements in T-cell development. PMID- 29620944 TI - p53 Plays a Key Role in the Apoptosis of Human Ovarian Cancer Cells Induced by Adenovirus-Mediated CRM197. AB - Cross-reacting material 197 (CRM197) is a mutant form of the diphtheria toxin. Recent studies have found that CRM197 exerts an experimental antitumor effect on several types of tumors. This study applied a novel treatment of adenovirus mediated CRM197 (AdCRM197) to human ovarian cancer cells. Interestingly, it was found that A2780 cells were sensitive to AdCRM197, but SKOV3 cells were resistant to it. Since SKOV3 cells are p53 deletion cells, while A2780 cells are p53 wild type cells, it was postulated that p53 might play a key role in AdCRM197-induced apoptosis. This presumption was demonstrated by means of knockdown of p53 of the A2780 cells through lentivirus-mediated RNA interference. This knockdown resulted in the A2780 cells becoming resistant to AdCRM197. To verify this presumption further, the wild-type p53 gene in the SKOV3 cells was replaced with adenovirus mediated p53 (Adp53). As expected, AdCRM197 plus Adp53 resulted in apoptosis of the SKOV3 cells. The combined treatment of AdCRM197 plus Adp53 also showed a good antitumor effect in the in vivo experiment on nude mice with xenograft tumors. Taking these results together, it is concluded that AdCRM197 induces apoptosis of human ovarian cancer cells via the p53 pathway. Moreover, it was found that Adp53 can reverse the resistance of p53-deletion human ovarian cancer cells to AdCRM197. The combination of AdCRM197 and Adp53 may be a potentially effective method for overcoming the resistance of p53-deficient human ovarian cancer to AdCRM197. PMID- 29620945 TI - Influence of Depressive Symptoms on Hallux Valgus Surgical Outcomes. AB - BACKGROUND: The relationship between depressive symptoms and patient outcomes after hallux valgus surgery has not been well-studied. We hypothesized that patients with depressive symptoms would have greater subjective dysfunction preoperatively and less functional improvement and satisfaction after surgery when compared with patients without depressive symptoms. METHODS: A total of 239 adult patients who had surgical hallux valgus correction over a 2-year period were retrospectively enrolled. A telephone survey was administered prospectively at least 11 months postoperatively inquiring about overall satisfaction level with surgery and satisfaction with postoperative pain level. A scale of 0 to 6 was used, with 0 indicating complete dissatisfaction and 6 indicating complete satisfaction. Patients were divided into 2 groups based on depressive symptoms; a Short Form-12 mental component score (SF-12 MCS) of less than 45.6 points was considered indicative of active depressive symptoms based on literature correlating SF-12 scores with Patient Health Questionnaire-9 for depression. Given the great variability of depressive symptoms in patients with or without self-reported depression and medicated or unmedicated status, we elected to use the MCS classification of depressive symptoms for our analysis. Data from 239 patients were available for analysis, with an average age of 51.6 years and 207 women (87%). Two hundred eighteen patients (91%) completed preoperative functional scores, 160 patients (67%) completed the satisfaction survey at an average of 23 months postoperatively (range 11 to 43 months), and 154 patients (64%) completed postoperative functional scores an average of 21 months postoperatively (range, 11-44 months). Results Thirty-six of 239 patients (15%) with baseline functional scores exhibited depressive symptoms. There was no significant difference in baseline functional scores and pain levels between groups with the exception of the SF-12 MCS ( P < .001). Most outcomes improved significantly over time, including the SF-12 physical component score ( P = .013), Foot and Ankle Ability Measure (FAAM; P = .013), and FAAM Activities of Daily Living ( P = .046). The patients with depressive symptoms generally had lower scores at baseline and final follow-up in all functional scores, with the exception of visual analog scale (VAS). VAS pain scores started higher in the group of patients with depressive symptoms and ended lower. Satisfaction with postoperative pain was lower in the group with depressive symptoms when compared with patients without depressive symptoms (3.6 vs 4.5, P = .042). There was no significant difference in satisfaction after surgery between groups ( P = .251). CONCLUSION: Patients with depressive symptoms had greater pain at baseline and less pain postoperatively when compared with patients without depressive symptoms; however, satisfaction levels with postoperative pain were lower in these patients. Furthermore, most functional scores were lower in patients with depressive symptoms, with the exception of the MCS. Reported history of depression was not associated with any significant difference in functional outcome scores or satisfaction. Further study is warranted to determine why patients with depressive symptoms fare worse after surgical hallux valgus correction by most subjective measures. LEVEL OF EVIDENCE: Level III, comparative study. PMID- 29620946 TI - Multi-Institution Case Series of Pediatric Patients with Laparoscopic Repair of Morgagni Hernia. AB - INTRODUCTION: Morgagni Larray hernia (MLH) is a very rare disease, which accounts for less than 5% of all congenital diaphragmatic hernias. Laparoscopic repair has been widely used and accepted as a treatment option for patients with this disease. The purpose of our study is to analyze the outcomes of patients with MLH who underwent laparoscopic repair, and to evaluate their postoperative course for outcome, morbidity, and mortality. MATERIALS AND METHODS: A retrospective chart review was performed of patients who were diagnosed with MLH and treated laparoscopically by 10 board-certified pediatric surgeons. RESULTS: Fourteen patients were included in the study. One patient died 1 month postoperatively due to respiratory complications unrelated to the surgery. Thirteen patients were followed for a median of 1.75 years (interquartile 0.3-6.95). There was a single recurrence, which resulted in a partial resection of the hernia sac and repaired without a mesh. We had a success rate of 92.86%. CONCLUSION: MLH is a rare congenital diaphragmatic hernia that is usually diagnosed incidentally. Laparoscopic repair has high success rates and is a viable option for patients with this pathology. PMID- 29620947 TI - Outcomes of Transhiatal and Intercostal Pleural Drain After Ivor Lewis Esophagectomy: Comparative Analysis of Two Consecutive Patient Cohorts. AB - BACKGROUND: In a previous proof of concept study, transhiatal pleural drain has been shown to be safe and effective after hybrid Ivor Lewis esophagectomy. Aim of this study was to compare the short-term outcomes of transhiatal and intercostal pleural drainage. PATIENTS AND METHODS: This is an observational retrospective cohort study. Two methods of pleural drainage were compared in patients undergoing hybrid Ivor Lewis esophagectomy. Patients treated with a transhiatal drain connected to a vacuum bag were compared to a historical cohort of patients treated with the conventional intercostal drain connected to underwater seal and suction. Postoperative morbidity, total and daily drainage output, serum albumin levels, and total dose of paracetamol and ketorolac administered on demand were recorded. RESULTS: Between January 2014 and December 2016, 50 patients with transhiatal drain and 50 with intercostal drains met the criteria for inclusion in the study. Demographic and clinicopathological variables were similar in the two groups. There was no statistically significant difference in the rate of postoperative complications. The total volume of drain output and the serum albumin levels were similar in the two groups. The total dose of ketorolac was significantly reduced in patients with transhiatal drain (P < .001). CONCLUSIONS: Transhiatal pleural drainage connected to a portable vacuum system could safely replace the intercostal drain after hybrid Ivor Lewis esophagectomy. It has the potential to reduce postoperative pain and use of nonsteroidal anti-inflammatory drugs, and to enhance recovery from surgery. PMID- 29620948 TI - Impact of Vancomycin Treatment on Human Mesenchymal Stromal Cells During Osteogenic Differentiation. AB - BACKGROUND: Vancomycin is frequently applied locally to the operative site during foot and ankle procedures to help prevent infection. Although the efficacy of locally applied vancomycin has been demonstrated in spine surgery, there is no consensus on dosing and indication within foot and ankle surgery. Osteogenic differentiation of human mesenchymal stromal cells (hMSCs) is key to healing of both fractures and arthrodesis. The purpose of this research was to determine the impact of vancomycin on human hMSCs during the process of osteogenic differentiation. METHODS: hMSCs were cultured in osteogenic differentiation media to promote osteogenic differentiation. Cells were treated with vancomycin at differing concentrations of 0, 50, 500, and 5000 ug/mL. Viability and cell growth were assessed via LIVE/DEAD viability/cytotoxicity kit (Invitrogen, Waltham, MA) after 1, 3, and 7 days of vancomycin treatment. Differentiation and mineralization was assessed via alizarin red staining after 21 days of treatment. Mean cell viability, cell number, and mineralization were compared between treatment groups using 1-way analysis of variance and the Tukey-Kramer method for post hoc pairwise comparisons. RESULTS: At the highest concentrations of vancomycin, there was a significant reduction in cell viability and proliferation after 3 days compared with all other treatment groups. Mineralization was also significantly decreased with higher doses of vancomycin. CONCLUSION: At high concentrations, vancomycin may impair hMSC viability and osteogenic differentiation. CLINICAL RELEVANCE: Surgeons should exercise caution and consider the limited soft tissue envelope when applying vancomycin locally during foot and ankle surgery, especially during arthrodesis procedures. PMID- 29620949 TI - Associations between Race and Dementia Status and the Quality of End-of-Life Care. AB - BACKGROUND: Non-Hispanic black and dementia patients receive more invasive and futile treatment at end of life (EOL) relative to others. Little is known about the relationship between race/ethnicity, dementia, and EOL care quality. OBJECTIVE: Identify the relationship between race/ethnicity, dementia, and proxy reporters' evaluation of EOL care quality in older adults. DESIGN: Latent class analysis (LCA) of national survey data. SETTING: 1588 deceased Medicare beneficiaries age 65 and older from the National Health and Aging Trends Study (2011-2016). MEASUREMENTS: LCA identified three types of quality EOL care using nine measures of symptom management, quality of healthcare encounters, and dignified treatment. Race and dementia were primary predictors of EOL care quality type. Adjusted models controlled for decedent education, sex, marital status, age, number of illnesses, number of hospitalizations, self-rated health, place of death, hospice involvement, and proxy relationship to decedent and familiarity with care. RESULTS: Over 20% of proxies report that dying individuals experienced suboptimal EOL care quality, characterized by pain, sadness, poor communication, and inattention to personal care needs. In adjusted analyses, proxies for non-Hispanic black decedents were less likely to provide negative care assessments than proxies for non-Hispanic white decedents (adjusted odds ratio [AOR]: 0.58; 95% confidence interval [CI]: 0.40-0.86). Proxies for decedents with dementia were less likely to provide negative assessments than proxies for decedents without dementia (AOR: 0.70; 95% CI: 0.51-0.97). IMPLICATIONS: Efforts to improve EOL care quality are needed. More positive EOL care quality assessments for non-Hispanic Black and dementia decedents appear counterintuitive given research demonstrating that these groups of individuals are likely to have received suboptimal EOL care. Because caregiver expectations for care may differ by decedent race and dementia status, research is needed to explore the role of caregiver expectations for EOL care to explain these paradoxical findings. PMID- 29620950 TI - A Systematic Review and Meta-Analysis Reveals Altered Drug Pharmacokinetics in Humans During Acute Exposure to Terrestrial High Altitude-Clinical Justification for Dose Adjustment? AB - : Bailey, Damian Miles, Benjamin S. Stacey, and Mark Gumbleton. A systematic review and meta-analysis reveals altered drug pharmacokinetics in humans during acute exposure to terrestrial high altitude-clinical justification for dose adjustment? High Alt Med Biol. 19:141-148, 2018. OBJECTIVE: While physiological responses during acute ascent to terrestrial high altitude (HA) have the potential to alter the pharmacokinetics (PKs) that define absorption and disposition of medicinal drugs, there have been no systematic reviews and meta analyses performed to date. METHODS: We conducted a systematic literature search in June 2017 using NCBI PubMed, EMBASE, Web of Science, and Ovid MEDLINE databases to identify relevant observational studies. Studies were deemed eligible based on the following criteria: (1) participants: healthy, nonacclimatized male or female lowlanders (born and bred at sea level) and (2) environment: exposure to low altitude (LA, <=600 m), followed by terrestrial high altitude (HA, <=24 hours to >=2500 m), the time course specifically selected to avoid interpretive complications associated with erythrocytosis. All PK parameters were standardized to be in the same units and the weighted standardized mean difference (SMD) calculated using a combination of fixed and random effects models with heterogeneity evaluated using chi2 and I2 statistics. RESULTS: Of 20,840 studies reviewed, 6 prospective cohort studies (n = 75) qualified for inclusion, with participants exposed to a mean altitude of 4025 (mean) +/- 380 (SD) m. We observed increases for absorption half-life (SMD: 0.40, 95% CI: 0.01-0.80, p = 0.04], elimination half-life (SMD: 0.89, 95% CI: 0.30 1.48, p = 0.003), and erythrocyte binding (SMD: 0.52, 95% CI: 0.16-0.88, p = 0.004) and reduction in clearance (SMD: -0.56, 95% CI: -1.13 to 0.00, p = 0.05). CONCLUSIONS: Collectively, these findings reveal impairments in both oral absorption and corresponding clearance of the, although limited, sample of drugs at HA that may potentially require closer patient monitoring and dose adjustments to maintain therapeutic efficacy and avoid incidental toxicity. PMID- 29620951 TI - CAR T Cells in Trials: Recent Achievements and Challenges that Remain in the Production of Modified T Cells for Clinical Applications. AB - The adoptive transfer of chimeric antigen receptor (CAR)-modified T cells is attracting growing interest for the treatment of malignant diseases. Early trials with anti-CD19 CAR T cells have achieved spectacular remissions in B-cell leukemia and lymphoma, so far refractory, very recently resulting in the Food and Drug Administration approval of CD19 CAR T cells for therapy. With further applications and increasing numbers of patients, the reproducible manufacture of high-quality clinical-grade CAR T cells is becoming an ever greater challenge. New processing techniques, quality-control mechanisms, and logistic developments are required to meet both medical needs and regulatory restrictions. This paper summarizes the state-of-the-art in manufacturing CAR T cells and the current challenges that need to be overcome to implement this type of cell therapy in the treatment of a variety of malignant diseases and in a greater number of patients. PMID- 29620952 TI - Anti-Inflammatory Activity of Epimedium brevicornu Maxim Ethanol Extract. AB - Epimedium brevicornu Maxim has been used as a traditional herbal drug in China. In this study, the anti-inflammatory effects of E. brevicornu Maxim ethanol extract (EBME) were investigated in RAW264.7 macrophages and mice challenged with lipopolysaccharide (LPS). Results showed that EBME attenuated inflammation by decreasing the production of several proinflammatory mediators, such as nitric oxide (NO), prostaglandin (PG) E2, inducible nitric oxide synthase, and cyclooxygenase-2, in LPS-stimulated RAW264.7 macrophages. EBME increased the expression of heme oxygenase-1 (HO-1) and promoted the nuclear translocation of nuclear factor erythroid 2-related factor 2. The inhibitory effects of EBME on LPS-stimulated NO and PGE2 expression were partially reversed by HO-1 inhibitor. EBME also elicited an anti-inflammatory effect by inhibiting the production of tumor necrosis factor-alpha, interleukin (IL)-1beta, and IL-6 in LPS-induced peritonitis. Therefore, EBME exhibited anti-inflammatory effects in vitro and in vivo. PMID- 29620953 TI - The Impact of Women's Health Residency Tracks on Career Outcomes. AB - BACKGROUND: Women's health residency tracks within several internal medicine residencies provide gender-specific education to residents. The impact of these programs has not been evaluated. The objective of this study was to determine the impact that women's health residency tracks have on career outcomes. MATERIALS AND METHODS: The participants in the study were women's health track (WHT) graduates from three different programs. To account for the impact of gender, we also surveyed female graduates who did not participate in WHT from the same programs, paired by year of graduation (non-WHT). Participants completed an online survey and provided a copy of their updated curriculum vitae (CV). Survey responses and CV data were analyzed separately. RESULTS: Of the 218 eligible graduates, 133 completed the survey and 86 provided a CV for a response rate of 63.8%. Regarding clinical care, 31.8% of WHT graduates focused on women's health in practice compared with only 16.1% of non-WHT graduates (Cohen's h 0.43). WHT graduates were more likely to have presented nationally on women's health topics (53.3% vs. 16.7%, p-value 0.030) and teach women's health topics (51.4% vs. 26.7%%, Cohen's h 0.51). WHT graduates were more likely to have assumed a women's health leadership role (34.5% vs. 0.0%, p-value 0.018). CONCLUSION: Graduates of women's health residency tracks remain involved in women's health in clinical practice, scholarship, teaching, and leadership. While all internal medicine residents should receive comprehensive women's health education, WHTs are an effective way of promoting women's healthcare and scholarship. PMID- 29620954 TI - Association Between Household Food Environment and Excessive Gestational Weight Gain. AB - BACKGROUND: Understanding the role of home food environment on gestational weight gain (GWG) may provide a useful weight management strategy to help reduce excessive GWG. MATERIALS AND METHODS: Pregnant women recruited between 2011 and 2014 (N = 165; normal weight N = 65, overweight N = 62, obese N = 38) in Arkansas completed measures of high-fat food availability, low-fat food availability, and food storage practices at baseline (4-10 weeks) and 30 weeks gestation. GWG was calculated as the difference between weight at the first (4-10 weeks) and final (36 weeks) prenatal visit, and based on each participant's baseline body mass index (BMI) category, GWG was classified as being above or within the 2009 Institute of Medicine's GWG guidelines. Multivariable models were adjusted for mother's age, race, marital status, and household income. RESULTS: There were no significant relationships between gaining above the guidelines and the home food environment variables. At baseline, after adjusting for covariates, overweight and obese pregnant women stored significantly more foods visibly in their home compared to normal weight women (overweight: beta: 0.30, standard error [SE]: 0.13, p = 0.01; obese: beta: 0.28, SE: 0.14, p = 0.04). At 30 weeks, obese pregnant women had significantly fewer low-fat foods in the home (beta: -0.17; SE: 0.08, p = 0.04), although after adjusting for covariates, this relationship became a nonsignificant trend (p = 0.08). There were no significant relationships between BMI category and number of high-fat foods in the home. CONCLUSIONS: These findings are consistent with other studies in nonpregnant populations that demonstrate that home food environment may influence weight status of overweight and obese pregnant women, although we did not find a significant relationship between the home food environment and GWG. PMID- 29620955 TI - The Anatomy Features and Variations of the Point Where Right Gastroepiploic Vein Flows into Superior Mesenteric Vein/Portal Vein: Anatomical Study of Catheterization of Portal Vein Infusion Chemotherapy. AB - INTRODUCTION: To study the anatomical features and classification of the angle between the right gastroepiploic vein (RGEV) and superior mesenteric vein/portal vein (SMV/PV) and to guide the catheterization of intraportal infusion chemotherapy through RGEV and reduce surgical complications. PATIENTS AND METHODS: A retrospective three-dimensional (3D) computed tomography study was undertaken on 200 consecutive subjects with or without hepatic malignant tumors with a dedicated workstation 3D-MIA (the improved MI-3DVS workstation) developed by ourselves to determine the prevalence of surgically significant angle between RGEV and SMV/PV anatomic variations and its classification. RESULTS: The mean value of the angles between the end of RGEV and SMV/PV (AERS/P) (200 cases) was 84.2 degrees +/- 23.8 (31.4 degrees -151.5 degrees ): 40.6 degrees +/- 92.3 ( 177.9 degrees to 178.0 degrees ) (sagittal angle), 81.7 degrees +/- 29.8 (-79.3 degrees to 160.7 degrees ) (coronal angle), and 10.5 degrees +/- 94.3 (-178.7 degrees to 175.8 degrees ) (horizontal angle). The mean value of the angles between the right bend of RGEV and SMV/PV (ARRS/P) (168 cases) was 104.8 degrees +/- 26.1 (20.5 degrees -159.7 degrees ):49.3 degrees +/- 117.8 (-175.3 degrees to 179.5 degrees ) (sagittal angle), 103.5 degrees +/- 37.7 (-178.8 degrees to 168.9 degrees ) (coronal angle), and 12.6 degrees +/- 102.8 (-179.9 degrees to 179.2 degrees ) (horizontal angle). The AERS/P were classified into large angle group (32 cases, 16%), middle angle group (113 cases, 56.5%), and small angle group (55 cases, 27.5%) based on angle variations and risks of catheterization. CONCLUSIONS: Precognition of the variations of AERS/P and ARRS/P before surgery is useful during chemotherapy pump catheterizing through RGEV in reduction of surgical complications by modulating the angle and direction of RGEV running into SMV/PV properly. PMID- 29620957 TI - Corn-Based Distillers' Grains in Diets for Feedlot Cattle Are Associated with the Burden of Escherichia coli O157 in Feces. AB - Inclusion of distillers' grains (DGs) has been associated with increased prevalence of Escherichia coli O157:H7 in cattle housed in research settings. Our objective was to quantify the relationship between inclusion of DGs in commercial feedlot rations and the burden of E. coli O157. A convenience sample of 10 feedlots was enrolled based on DG use in finishing diets; 1 cohort included 5 feedlots in which DGs were greater than 15% of the dietary dry matter and the other cohort consisted of 5 feedlots at a concentration less than 8%. Sampling occurred at each feedlot on four occasions at ~6-week intervals. At each feedlot visit, 4 pens of cattle within 3 weeks of slaughter were selected and 24 freshly voided fecal pats were sampled. Ten-gram samples were enriched in 90 mL of modified tryptic soy broth with novobiocin (20 mg/L) for 14 h at 42 degrees C. Enrichments were subjected to immunomagnetic separation, plating onto chromogenic agar with novobiocin (5 mg/L) and potassium tellurite (2.5 mg/L), incubation for 18 h at 37 degrees C, and latex agglutination of morphologically typical colonies. E. coli O157 was recovered from 16.7% of 3840 samples. Adjusted prevalence was 14.3% after controlling for within-feedlot and within-pen clustering. Prevalence during each sampling period was 19.9% (round 1), 21.0% (round 2), 14.1% (round 3), and 11.7% (round 4). Prevalence varied between cohorts, but this difference varied over time (p = 0.06). Among those with greater than 15% of the diet as DGs, prevalence was greater than those with less than 8% inclusion for all rounds of sampling (p < 0.01). Averaged across time, prevalence was 23.9% and 9.4% for those with greater than 15% and those with less than 8% of DGs, respectively. While observational, these data provide real-world support of reports of increased E. coli O157:H7 burden associated with DG use in cattle diets. PMID- 29620956 TI - Clinical, Hormonal, and Metabolic Parameters in Women with Subclinical Hypothyroidism and Polycystic Ovary Syndrome: A Cross-Sectional Study. AB - BACKGROUND: Polycystic ovary syndrome (PCOS) is the most common endocrinopathy in reproductive age women, yet its clinical presentation shares similarities with several other endocrine disorders such as thyroid disease. Hence, the objective of this study was to further evaluate this association by investigating the clinical, hormonal, and metabolic parameters between subclinical hypothyroidism (SCH) and PCOS. METHODS: This is a cross-sectional study conducted in a tertiary care clinic at Cleveland, Ohio, USA. A total of 137 women diagnosed with PCOS by Rotterdam criteria were examined. SCH was defined as thyroid-stimulating hormone >2.5 mIU/L in the absence of symptoms of overt hypothyroidism. The mean age, body mass index (BMI), fasting plasma glucose (FPG), glucose tolerance test, hemoglobin A1c, fasting insulin, a 2 hours insulin level after 75 g glucose load, cholesterol, LDL, HDL, and homeostatic model assessment (HOMA) were compared between women with and without SCH. Logistic regression was used to adjust for age and BMI. RESULTS: Among 137 women with PCOS, 21.9% had SCH. Comparison groups were similar in both age and BMI and there was no difference in the mean values of all endocrine and metabolic parameters tested. However, abnormal FPG levels (OR 3.01; CI: 1.12-8.07. p = 0.03) and abnormal HOMA (OR 3.7; CI: 1.14-12.00. p = 0.03) were more likely in women who had SCH than in women without SCH independent of age and BMI. CONCLUSIONS: Women with PCOS and SCH are more likely to have impaired FPG values and impaired insulin sensitivity even after adjusting for age and BMI. Hence, close monitoring of PCOS patients for SCH may be beneficial. PMID- 29620959 TI - Journal of Endourology and Videourology Our 2017 Reviewers. PMID- 29620958 TI - Sequence Analysis of IncA/C and IncI1 Plasmids Isolated from Multidrug-Resistant Salmonella Newport Using Single-Molecule Real-Time Sequencing. AB - Multidrug-resistant (MDR) plasmids play an important role in disseminating antimicrobial resistance genes. To elucidate the antimicrobial resistance gene compositions in A/C incompatibility complex (IncA/C) plasmids carried by animal derived MDR Salmonella Newport, and to investigate the spread mechanism of IncA/C plasmids, this study characterizes the complete nucleotide sequences of IncA/C plasmids by comparative analysis. Complete nucleotide sequencing of plasmids and chromosomes of six MDR Salmonella Newport strains was performed using PacBio RSII. Open reading frames were assigned using prokaryotic genome annotation pipeline (PGAP). To understand genomic diversity and evolutionary relationships among Salmonella Newport IncA/C plasmids, we included three complete IncA/C plasmid sequences with similar backbones from Salmonella Newport and Escherichia coli: pSN254, pAM04528, and peH4H, and additional 200 draft chromosomes. With the exception of canine isolate CVM22462, which contained an additional IncI1 plasmid, each of the six MDR Salmonella Newport strains contained only the IncA/C plasmid. These IncA/C plasmids (including references) ranged in size from 80.1 (pCVM21538) to 176.5 kb (pSN254) and carried various resistance genes. Resistance genes floR, tetA, tetR, strA, strB, sul, and mer were identified in all IncA/C plasmids. Additionally, blaCMY-2 and sugE were present in all IncA/C plasmids, excepting pCVM21538. Plasmid pCVM22462 was capable of being transferred by conjugation. The IncI1 plasmid pCVM22462b in CVM22462 carried blaCMY-2 and sugE. Our data showed that MDR Salmonella Newport strains carrying similar IncA/C plasmids clustered together in the phylogenetic tree using chromosome sequences and the IncA/C plasmids from animal-derived Salmonella Newport contained diverse resistance genes. In the current study, we analyzed genomic diversities and phylogenetic relationships among MDR Salmonella Newport using complete plasmids and chromosome sequences and provided possible spread mechanism of IncA/C plasmids in Salmonella Newport Lineage II. PMID- 29620960 TI - Rates and Predictors of Conversion to Open Surgery During Minimally Invasive Radical Cystectomy. AB - OBJECTIVE: To assess the frequency of minimally invasive radical cystectomy (MIRC) conversion to open surgery, what factors influence conversion, whether or not the benefits of MIRC vs open radical cystectomy (ORC) persist after conversion, and compare ORC and MIRC outcomes. MATERIALS AND METHODS: We performed a retrospective cohort study from the National Cancer Data Base (2010 to 2013) analyzing patients who underwent completed MIRC (n = 5750), converted MIRC (n = 245), and ORC (n = 12,053) without prior radiotherapy. Multivariable logistic and linear regression analyses were used to assess the association between covariates, open conversion as well as surgical approach, and secondary outcomes such as positive surgical margins (PSMs), use of lymphadenectomy, lymph node yield, hospital length of stay (LOS), and 30-day readmission. RESULTS: Rates of conversion were independent of patient factors such as race, sex, use of neoadjuvant chemotherapy, and clinical stage. Conversion occurred in 245 of 5750 MIRCs (4.3%) and declined over time (5.8% in 2010 vs 3.2% in 2013, odds ratio [OR] 0.50, 95% confidence interval [CI] 0.34-0.75, p = 0.001). MIRC was associated with fewer positive margins, higher lymph node yield, shorter LOS, and fewer readmissions compared with ORC, however, patients requiring open conversion had longer median hospital stays (8 days vs 7 days, p = 0.013), lower median lymph node yields (14 vs 17, p = 0.007), more PSMs (17% vs 11%, p = 0.006), and more 30-day readmissions (14% vs 9%, p = 0.008) compared to nonconverted. Converted MIRC had similar hospital LOS and 30-day readmission rates compared to ORC. CONCLUSION: Open conversion during MIRC is uncommon and has decreased in recent years despite the rising use of MIRC. MIRC had better short-term outcomes compared with ORC. These benefits were negated with open conversion; however, outcomes were similar compared to planned ORC. PMID- 29620961 TI - Building a Medicaid Ambulatory Complex Care Program Within an Urban Medical Home. AB - Five percent of Medicaid patients account for 50% of total costs. Preventable costs are often incurred by patients with complex medical, behavioral, and social needs who disproportionately utilize acute care services. Evidence for design, implementation, and evaluation of complex care programs in the urban Medicaid population is lacking. The article provides a description of a complex care program (CCP), challenges, and early outcomes based on a pre-post evaluation. The CCP was located within an existing urban medical home. Patients were eligible if they lived within 10 miles of the clinic and had at least 2 inpatient visits and/or 3 emergency room visits within the prior 6 months. Ambulatory Care Groups(r) were used to predict estimated total costs of patients, who were included if potential cost savings exceeded $5000. Patient experience and quality of care were assessed using validated measures and costs. Return on investment was calculated based on investment and cost savings. Costs include visits (clinic, specialty, and emergency room), hospital admissions, medications, tests and services, as well as salary and benefits of clinical staff. Eighty-six of 211 eligible patients (41%) were enrolled during the first 18 months of the pilot program. There were positive trends in quality metrics and patient satisfaction. The pre-post evaluation demonstrated a reduction in emergency room visits and hospitalizations (67% and 65%, respectively), which resulted in a 2.2:1 return on investment. This article offers lessons learned to colleagues considering population health approaches in the care of high-risk Medicaid patients. PMID- 29620962 TI - Addressing Social Determinants of Health: Case Studies from Epic's Population Health Steering Board. PMID- 29620963 TI - Minimal Invasive Linea Alba Reconstruction for the Treatment of Umbilical and Epigastric Hernias with Coexisting Rectus Abdominis Diastasis. AB - INTRODUCTION: Patients with umbilical or epigastric hernias benefit from mesh- based repairs, and even more so if a concomitant rectus diastasis (RD) is present. The ideal technique is, however, still under debate. In this study we introduce the minimal invasive linea alba reconstruction (MILAR) with the supraaponeurotic placement of a fully absorbable synthetic mesh. MATERIALS AND METHODS: Midline reconstruction with anterior rectus sheath repair and mesh augmentation by an open approach is a well-known surgical technique for ventral hernia repair. Between December 1, 2016, and November 30, 2017, 20 patients with symptomatic umbilical and/or epigastric hernias, and coexisting RD underwent a minimally invasive complete reconstruction of the midline through a small access route. The inner part of both incised and medialized anterior rectus sheaths was replaced by a fully absorbable synthetic mesh placed in a supraaponeurotic position. RESULTS: Patients were hospitalized for an average of 4 days and the mean operating time was 79 minutes. The mean hernia defect size was 1.5 cm in diameter and the mean mesh size was recorded as 15.8 cm in length and 5.2 cm in width. Two patients sustained surgical postoperative complications in terms of symptomatic seroma occurrences with successful interventional treatment.The early results (mean follow-up period of 5 months) showed no recurrences and only 1 patient reported occasional pain following exertion without rest. DISCUSSION: MILAR is a modification of the recently published endoscopic linea alba reconstruction restoring the normal anatomy of the abdominal wall. A new linea alba is formed with augmentation of autologous tissue consisting of the plicated anterior rectus sheaths. Supraaponeurotic placement of a fully absorbable synthetic mesh eliminates potential long-term mesh-associated complications. Regarding MILAR, there is no need for endoscopic equipment due to the uniquely designed flexible lighted retractors, meaning one assistant less is required. PMID- 29620964 TI - Prognostic Implication of N1b Classification in the Eighth Edition of the Tumor Node-Metastasis Staging System of Differentiated Thyroid Cancer. AB - BACKGROUND: Regional lymph node metastases (LNM) have prognostic significance in differentiated thyroid cancer (DTC). However, there was no distinction between N1a and N1b in the final staging classification in the eighth edition of the tumor-node-metastasis (TNM) staging system. This study aimed to evaluate the prognostic implication of N1b classification for predicting disease-specific survival (DSS) in DTC patients with stage I/II disease. METHODS: A total of 3089 patients with stage I/II DTC who underwent thyroid surgery between 1996 and 2005 were included. DSS was evaluated according to N classification and number of LNM. A modification of the TNM was assessed that classified N1b cases in patients aged >=55 years as stage IIB and the remaining cases as stage IIA. RESULTS: The mean patient age was 45.6 years, and the median follow-up period was 10.0 years. In patients aged >=55 years, patients with N1b had significantly poorer DSS compared to those with N0 (hazard ratio [HR] = 11.0; p < 0.001) and N1a (HR = 4.2; p = 0.013). The large-volume LNM group had significantly poorer DSS compared to the N0 (HR = 10.1; p < 0.001) and small-volume LNM (HR = 3.9; p = 0.019) groups. When patients were reclassified using the modified TNM staging system, DSS was significantly poorer in stage IIB patients than in stage IIA patients (HR = 2.9; p = 0.030). CONCLUSIONS: N1b classification has a significant prognostic implication in patients with stage I/II DTC, especially in older patients. Modified TNM staging employing N1b classification could be more useful for the prediction of DSS. PMID- 29620965 TI - Nonlinear Parametric Excitation Effect Induces Stability Transitions in Swimming Direction of Flexible Superparamagnetic Microswimmers. AB - Microscopic artificial swimmers have recently become highly attractive due to their promising potential for biomedical microrobotic applications. Previous pioneering work has demonstrated the motion of a robotic microswimmer with a flexible chain of superparamagnetic beads, which is actuated by applying an oscillating external magnetic field. Interestingly, they have shown that the microswimmer's orientation undergoes a 90 degrees -transition when the magnetic field's oscillation amplitude is increased above a critical value. This unexpected transition can cause severe problems in steering and manipulation of flexible magnetic microrobotic swimmers. Thus, theoretical understanding and analysis of the physical origins of this effect are of crucial importance. In this work, we investigate this transition both theoretically and experimentally by using numerical simulations and presenting a novel flexible microswimmer with an anisotropic superparamagnetic head. We prove that this effect depends on both frequency and amplitude of the oscillating magnetic field, and demonstrate existence of an optimal amplitude achieving maximal swimming speed. Asymptotic analysis of a minimal two-link model reveals that the changes in the swimmer's direction represent stability transitions, which are induced by a nonlinear parametric excitation. PMID- 29620966 TI - The influence of training load, exposure to match play and sleep duration on daily wellbeing measures in youth athletes. AB - This study assessed the influence of training load, exposure to match play and sleep duration on two daily wellbeing measures in youth athletes. Forty-eight youth athletes (age 17.3 +/- 0.5 years) completed a daily wellbeing questionnaire (DWB), the Perceived Recovery Status scale (PRS), and provided details on the previous day's training loads (TL) and self-reported sleep duration (sleep) every day for 13 weeks (n = 2727). Linear mixed models assessed the effect of TL, exposure to match play and sleep on DWB and PRS. An increase in TL had a most likely small effect on muscle soreness (d = -0.43;+/- 0.10) and PRS (d = -0.37;+/ 0.09). Match play had a likely small additive effect on muscle soreness (d = 0.26;+/- 0.09) and PRS (d = -0.25;+/- 0.08). An increase in sleep had a most likely moderate effect on sleep quality (d = 0.80;+/- 0.14); a most likely small effect on DWB (d = 0.45;+/- 0.09) and fatigue (d = 0.42;+/- 0.11); and a likely small effect on PRS (d = 0.25;+/- 0.09). All other effects were trivial or did not reach the pre-determined threshold for practical significance. The influence of sleep on multiple DWB subscales and the PRS suggests that practitioners should consider the recovery of an athlete alongside the training stress imposed when considering deviations in wellbeing measures. PMID- 29620968 TI - Association Between Thyroid Function and Development of Different Obesity Phenotypes in Euthyroid Adults: A Nine-Year Follow-Up. AB - BACKGROUND: Considering inconsistent and conflicting data on associations of thyroid function, within the reference range, with anthropometric measures and metabolic syndrome, this study aimed to investigate the relationship between thyroid function and different obesity phenotypes over nine years of follow-up. METHODS: This study was conducted on 1938 individuals from an ongoing population based cohort study, the Tehran Thyroid Study. Participants were categorized into four obesity phenotypes based on body mass index and metabolic status. To investigate the associations of thyrotropin and free thyroxine (fT4) with incidence of different obesity phenotypes across the study period, a multivariate approach based on a generalized estimating equation method was used. RESULTS: At baseline, individuals with the metabolically healthy normal weight (MHNW) phenotype had higher serum fT4 levels (1.2 +/- 0.16 ng/dL vs. 1.14 +/- 0.14 ng/dL, 1.16 +/- 0.14 ng/dL, and 1.17 +/- 0.15 ng/dL in metabolically healthy obese [MHO], metabolically unhealthy normal weight, and metabolically unhealthy obese individuals, respectively). The results of the generalized estimating equation analysis after multivariate adjustment for age, sex, smoking, physical activity, education level, thyroid peroxidase antibody status, and homeostasis model assessment-insulin resistance showed that each 1 ng/dL increment in fT4 levels within the reference range was accompanied with a 1.65-fold [confidence interval (CI) 1.09-2.5] increase of developing the MHNW phenotype during 9.2 years of follow-up. Moreover, each 1.0 ng/dL increment in fT4 within the reference range was associated with a 50% decreased risk of developing the MHO phenotype (odds ratio = 0.50 [CI 0.32-0.76]). Meanwhile, a significant positive association was found between serum thyrotropin levels and development of the metabolically unhealthy normal weight phenotype (odds ratio = 1.22 [CI 1.01 1.48]). CONCLUSIONS: Serum fT4 concentrations within the reference range are associated with the development of some obesity phenotypes, including the MHNW and MHO phenotypes, after consideration of potential confounders. PMID- 29620969 TI - Clinical Analysis of Endoscopic Submucosal Dissection for the Synchronous Multiple Primary Early Cancers in Esophagus and Stomach: 12 Cases Report. AB - OBJECTIVE: With the improvement of endoscopic diagnosis, the discovery rate of the synchronous multiple primary early cancers in esophagus and stomach is gradually increased, while the traditional surgery bringing serious damages. Endoscopic submucosal dissection (ESD) has become the first treatment option of early cancer in the digestive tract partly. This study intends to explore the feasibility, safety, and effectiveness of ESD in the treatment of the synchronous multiple early gastric cancer or precancerous lesions in the esophagus and stomach. METHODS: From January 2008 to December 2016, data of 12 patients with early esophageal cancer and early gastric cancer treated by ESD in the Endoscopy Center of Zhongshan Hospital, Fudan University were reviewed. We analyzed the patient's history, the size of esophageal and gastric lesions, pathological results, the results of complete or curative resection, and so on. RESULTS: Among the 12 patients described in this study, all were diagnosed with synchronous multiple primary early cancers in the esophagus and stomach. Lesions were removed by ESD in 10 cases at the same time and were removed by stage in 2 cases. The complete resection rate was 100% (24/24), and the curative resection rate was 100% (24/24). Postoperative esophageal stricture occurred in 2 cases, which improved after dilation. Median follow-up time was 30 (8-115) months, when 9 patients survived and 3 patients died. However, the cause of death was not associated with treatment of this disease. CONCLUSION: ESD is a minimally invasive endoscopic surgery, which can be used as a method of treating synchronous multiple primary early cancers in the esophagus and stomach. PMID- 29620970 TI - Wear compliance, sedentary behaviour and activity in free-living children from hip-and wrist-mounted ActiGraph GT3X+ accelerometers. AB - The GT3X+ worn at the wrist promotes greater compliance than at the hip. Minutes in SB and PA calculated from raw accelerations at the hip and wrist provide contrasting estimates and cannot be directly compared. Wear-time for the wrist (15.6 to 17.4 h.d-1) was greater than the hip (15.2 to 16.8 h.d-1) across several wear-time criteria (all P < 0.05). Moderate-strong associations were found between time spent in SB (r = 0.39), LPA (r = 0.33), MPA (r = 0.99), VPA (r = 0.82) and MVPA (r = 0.81) between the two device placements (All P < 0.001). The wrist device detected more minutes in LPA, MPA, VPA and MVPA whereas the hip detected more SB (all P = 0.001). Estimates of time in SB and all activity outcomes from the wrist and hip lacked equivalence. One hundred and eighty-eight 9-12-year-old children wore a wrist- and hip-mounted accelerometer for 7 days. Data were available for 160 (hip) and 161 (wrist) participants. Time spent in SB and PA was calculated using GGIR. This study examined the compliance of children wearing wrist- and hip-mounted ActiGraph GT3X+ accelerometers and compared estimates of sedentary behaviour (SB) and physical activity (PA) between devices. PMID- 29620971 TI - Benefits and Barriers to Telehealth Credentialing by Proxy. AB - BACKGROUND: Medical staff credentialing is the time-intensive process of verifying a provider's qualifications before granting privileges within a hospital. This process creates a large administrative barrier for telehealth services, as a large number of providers must be credentialed at each participating originating site within a telehealth network. INTRODUCTION: Despite the availability of a streamlined telehealth credentialing method called Credentialing by Proxy (CBP), a significant number of hospitals still opt for traditional credentialing. This project seeks to better understand the barriers and benefits to CBP. MATERIALS AND METHODS: This study utilized stratified sampling to recruit nine participants who manage telehealth credentialing. Researchers conducted qualitative interviews using a semistructured interview guide and analysis through the constant comparative method. Length of the credentialing time for providers was also tracked over an 18-month period for 20 originating sites. RESULTS: The majority of participants experienced uncertainty due to a loss of control over the process with CBP but also acknowledged the benefits of this method. Hospitals utilizing CBP had a significantly shortened credentialing period of 36 days, compared with 103 days with traditional credentialing. DISCUSSION: A lack of clarity and a fear of ultimate responsibility or liability were the largest contributors to uncertainty. Factors that decreased uncertainty among originating site hospitals included awareness of regulatory standards for CBP, continuing to check certain credentialing requirements themselves, and adopting a "wait-and-see approach." CONCLUSIONS: This study provided valuable insights into the barriers and benefits of CBP and can be utilized to better address these barriers and increase efficiency within telehealth networks. PMID- 29620972 TI - An Online Survey of Hypothyroid Patients Demonstrates Prominent Dissatisfaction. AB - BACKGROUND: Approximately 15% more patients taking levothyroxine (LT4) report impaired quality of life compared to controls. This could be explained by additional diagnoses independently affecting quality of life and complicating assignment of causation. This study sought to investigate the underpinnings of reduced quality of life in hypothyroid patients and to provide data for discussion at a symposium addressing hypothyroidism. METHODS: An online survey for hypothyroid patients was posted on the American Thyroid Association Web site and forwarded to multiple groups. Respondents were asked to rank satisfaction with their treatment for hypothyroidism and their treating physician. They also ranked their perception regarding physician knowledge about hypothyroidism treatments, need for new treatments, and life impact of hypothyroidism on a scale of 1-10. Respondents reported the therapy they were taking, categorized as LT4, LT4 and liothyronine (LT4 + LT3), or desiccated thyroid extract (DTE). They also reported sex, age, cause of hypothyroidism, duration of treatment, additional diagnoses, and prevalence of symptoms. RESULTS: A total of 12,146 individuals completed the survey. The overall degree of satisfaction was 5 (interquartile range [IQR] = 3-8). Among respondents without self-reported depression, stressors, or medical conditions (n = 3670), individuals taking DTE reported a higher median treatment satisfaction of 7 (IQR = 5-9) compared to other treatments. At the same time, the LT4 treatment group exhibited the lowest satisfaction of 5 (IQR = 3-7), and for the LT4 + LT3 treatment group, satisfaction was 6 (IQR = 3-8). Respondents taking DTE were also less likely to report problems with weight management, fatigue/energy levels, mood, and memory compared to those taking LT4 or LT4 + LT3. CONCLUSIONS: A subset of patients with hypothyroidism are not satisfied with their current therapy or their physicians. Higher satisfaction with both treatment and physicians is reported by those patients on DTE. While the study design does not provide a mechanistic explanation for this observation, future studies should investigate whether preference for DTE is related to triiodothyronine levels or other unidentified causes. PMID- 29620973 TI - A Role for Satb1 in Thyroid Autoimmunity? PMID- 29620974 TI - Lisfranc injuries: assessment, diagnosis and management. PMID- 29620975 TI - Occult fractures around the hip. PMID- 29620976 TI - Osteoarthritis and arthroplasty of the hip and knee. PMID- 29620977 TI - Reflections from participants in the chief registrar scheme. PMID- 29620979 TI - The future of internal medicine: a new curriculum for 2019. AB - A new 3-year curriculum for training in internal medicine was approved by the General Medical Council in December 2017. This will replace core medical training in August 2019. It mandates specific experiences and introduces a novel assessment strategy that hopefully will lessen the perceived 'burden of assessment' on trainees (and trainers). It is hoped that it will improve the experience of and enthusiasm for training in internal medicine. PMID- 29620980 TI - Management of lower limb amputations. AB - The most common reason for lower limb amputations in the UK is peripheral arterial disease. A thoughtful approach to surgery, with consideration of optimal amputation level and residual limb shape, can improve prosthetic use and functional outcomes. Prosthesis socket design and fit, as well as use of appropriate components, must be considered in accordance with the patient's activity level and potential. Major developments in prosthetics over the past 20 years, particularly in the area of joint design, including microprocessor knees, have increased options to improve ambulation. This is particularly significant among those with more proximal amputations, for whom energy expenditure on walking is even greater. Management of post-amputation pain syndromes including phantom limb pain can prove challenging, although there are novel options for pain control. Long-term care of both the residual and contralateral limbs is paramount to reduce risk of further amputation surgery, and optimize longer term function and quality of life. PMID- 29620981 TI - Cardiopulmonary exercise testing. PMID- 29620982 TI - Captain Thomas Coram: philanthropist who established the Foundling Hospital. PMID- 29620983 TI - Are multidisciplinary teams a legal shield or just a clinical comfort blanket? AB - Discussion about and management of patients through multidisciplinary team meetings has become the standard of care in medical and surgical specialties, but does the team nature of these provide a legal shield for clinicians? This article discusses the legal implications of decision making within a multidisciplinary team. PMID- 29620985 TI - Tracheal intubation in critically ill adults: failing to plan is planning to fail. PMID- 29620984 TI - Controlled ovarian stimulation for in-vitro fertilization. AB - Controlled ovarian stimulation with gonadotrophins is an essential part of in vitro fertilization treatment. The aim is to produce an optimum number of oocytes to maximize success in the safest possible way. Pituitary downregulation with a gonadotrophin-releasing hormone agonist and stimulation with recombinant follicle stimulating hormone is used widely. However, there are many different protocols in use with little evidence to determine the optimum regimen. Markers of ovarian reserve and patient characteristics are used in an attempt to individualize treatment. However, these do not necessarily reflect the quality of the oocytes and resultant embryos. Inadequate doses of gonadotrophins can lead to a poor response resulting in treatment failure. However, higher doses can lead to a hyper response, resulting in ovarian hyperstimulation syndrome which is potentially life-threatening. Both poor and hyper response are associated with reduced pregnancy rates. Various strategies, such as electively freezing all the embryos, are being introduced to optimize outcomes while ensuring patient safety. PMID- 29620986 TI - Pulmonary nodules with a rash. PMID- 29620987 TI - Oocyte freezing: reproductive panacea or false hope of family? AB - Advanced technology now allows young women to freeze and store oocytes with a realistic chance of future pregnancy. Vitrification has revolutionized oocyte preservation, with comparable pregnancy rates to fresh oocyte use. Traditionally used for women who were about to undergo sterilizing oncology treatment, now the opportunity has been extended for 'social freezing'. A steady rise in all women accessing freezing continues. Despite this, there is a lack of understanding of natural fertility and the impact of age on pregnancy outcomes. The optimum time for freezing is before a woman reaches her late 30s, which unfortunately is not reflected in those accessing egg freezing. The underlying message prevails that planning for fertility is best done early, whether that be by physical completion of family size or storing oocytes before the passage of time and age prevents it. PMID- 29620988 TI - A simple guide to regional anaesthesia. AB - Regional anaesthesia is widely used in modern anaesthetic practice for perioperative and postoperative analgesia. In the operating theatre, regional anaesthesia is used both on its own and in combination with other techniques (general anaesthesia and sedation). Regional anaesthesia is now a core skill set in anaesthetic training. This article provides a basic outline of regional anaesthesia for surgeons and other non-anaesthetic staff working with anaesthetists, reviewing preparation, consent, basic and specialist equipment, central neuraxial blocks (spinal, epidural and caudal), trunk blocks, upper limb blocks (interscalene, supraclavicular, infraclavicular and axillary) and lower limb blocks (femoral, fascia iliaca, sciatic, popliteal and ankle). It also discusses the pharmacology of the agents used and common complications. PMID- 29620989 TI - Giant liver cyst causing haemodynamic instability. PMID- 29620990 TI - Don't forget about syphilis: the great pretender. PMID- 29620991 TI - Improving the quality and speed of access to operation notes. AB - INTRODUCTION: Operation notes are often poorly completed, potentially compromising patient care. This project was undertaken to improve the quantity, quality and clarity of information included in operation notes, and make them easier to locate within a set of patient notes. METHODS: Operation notes were audited against standards laid out in national guidelines. The time taken for staff to locate an operation note, and information within it, was then measured. The layout was re-designed, followed by a re-audit. RESULTS: The number of operation notes with all measured domains completed rose from 4% to 34% (P<0.001). The mean time to locate the operation note fell from 30 to 4 seconds, and the mean time to locate all requested pieces of information within the operation note fell from 35 to 20 seconds. CONCLUSIONS: The interventions have improved quality and speed of access of operation notes, but there is still room for improvement. PMID- 29620993 TI - Clinical News. PMID- 29620992 TI - Torrential aortic regurgitation: a first presentation of an old disease. PMID- 29620994 TI - FOLFOX or CAPOX in Stage II to III Colon Cancer: Efficacy Results of the Italian Three or Six Colon Adjuvant Trial. AB - Purpose Given the cumulative neurotoxicity associated with oxaliplatin, a shorter duration of adjuvant therapy, if equally efficacious, would be advantageous for patients and health-care systems. Methods The Three or Six Colon Adjuvant trial is an open-label, phase III, multicenter, noninferiority trial randomizing patients with high-risk stage II or stage III colon cancer to receive 3 months or 6 months of FOLFOX (fluorouracil, leucovorin, and oxaliplatin) or CAPOX (capecitabine plus oxaliplatin). Primary end-point is relapse-free survival. Results 3,759 patients were accrued from 130 Italian sites, 64% receiving FOLFOX and 36% CAPOX. Two-thirds were stage III. The median time of follow up was 62 months and 772 relapses or deaths have been observed. The hazard ratio (HR) of the 3 months versus 6 months for relapse/death was 1.14 (95% CI, 0.99 to 1.32; P [for noninferiority] = .514) and the CI crossed the noninferiority limit of 1.20. However, the absolute difference in 3-year RFS was 1.9% (95% CI, -0.7% to 4.4%). Counter-intuitively, while the RFS curves were similar for stage III (HR, 1.07; 95% CI, 0.91 to 1.26) and for CAPOX treated patients (HR, 0.98; 95% CI, 0.77 to 1.26), they were not for stage II and for FOLFOX treated patients, with HR of 1.41 (95% CI, 1.05 to 1.89) and 1.23 (95% CI, 1.03 to 1.46), respectively, favoring the 6 months of treatment. Conclusion The Three or Six Colon Adjuvant trial failed to formally show noninferiority of 3 versus 6 months of treatment to the predefined margin of 20% relative increase. The results depended on the adjuvant regimen and risk. For CAPOX, 3 months were as good as 6 months; for FOLFOX, 6 months added extra benefit. Counter-intuitively, the low-risk patients benefitted more than the high-risk population from the 6-month duration. The choice of regimen and duration should depend on patient characteristics and be balanced against the extra toxicity of longer therapy. PMID- 29620996 TI - Advances in Adjuvant Therapy for Colon Cancer: P value or Practical Value. PMID- 29620995 TI - Three Versus 6 Months of Oxaliplatin-Based Adjuvant Chemotherapy for Patients With Stage III Colon Cancer: Disease-Free Survival Results From a Randomized, Open-Label, International Duration Evaluation of Adjuvant (IDEA) France, Phase III Trial. AB - Purpose Reduction of adjuvant treatment duration may decrease toxicities without loss of efficacy in stage III colon cancer. This could offer clear advantages to patients and health care providers. Methods In International Duration Evaluation of Adjuvant Chemotherapy (IDEA) France, as part of the IDEA international collaboration, patient with colon cancer patients were randomly assigned to 3 and 6 months of modified FOLFOX6 (mFOLFOX6: infusional fluorouracil, leucovorin, and oxaliplatin) or capecitabine plus oxaliplatin (CAPOX) by physician choice. The primary end point was disease-free survival (DFS), and analyses were descriptive. Results A total of 2,010 eligible patients received either 3 or 6 months of chemotherapy (modified intention-to-treat population); 2,000 (99%) had stage III colon cancer (N1: 75%, N2: 25%); 1,809 (90%) received mFOLFOX6, and 201 (10%) received CAPOX. The median age was 64 years, and the median follow-up time was 4.3 years. Overall, 94% (3 months) and 78% (6 months) of patients completed treatment (fluoropyrimidines +/- oxaliplatin). Maximal grade 2 and 3 neuropathy rates were 28% and 8% in the 3-month arm and 41% and 25% in the 6-month arm ( P < .001). Final rates of residual neuropathy greater than grade 1 were 3% in the 3 month arm and 7% in the 6-month arm ( P < .001). There were 578 DFS events: 314 and 264 in the 3- and 6-month arms, respectively. The 3-year DFS rates were 72% and 76% in the 3- and 6-month arms, respectively (hazard ratio [HR], 1.24; 95% CI, 1.05 to 1.46; P = .0112). In the 3 and 6-month arms, respectively, for patients who received mFOLFOX6, the 3-year DFS rates were 72% and 76% (HR, 1.27; 95% CI, 1.07 to 1.51); for the T4 and/or N2 population, they were 58% and 66% (HR, 1.44; 95% CI, 1.14 to 1.82); and for the T1-3N1 population, they were 81% and 83% (HR, 1.15; 95% CI, 0.89 to 1.49). Conclusion IDEA France, in which 90% of patients received mFOLFOX6, shows superiority of 6 months of adjuvant chemotherapy compared with 3 months, especially in the T4 and/or N2 subgroups. These results should be considered alongside the international IDEA collaboration data. PMID- 29620997 TI - Fertility Preservation in Patients With Cancer: ASCO Clinical Practice Guideline Update. AB - Purpose To provide current recommendations about fertility preservation for adults and children with cancer. Methods A systematic review of the literature published from January 2013 to March 2017 was completed using PubMed and the Cochrane Library. An Update Panel reviewed the identified publications. Results There were 61 publications identified and reviewed. None of these publications prompted a significant change in the 2013 recommendations. Recommendations Health care providers should initiate the discussion on the possibility of infertility with patients with cancer treated during their reproductive years or with parents/guardians of children as early as possible. Providers should be prepared to discuss fertility preservation options and/or to refer all potential patients to appropriate reproductive specialists. Although patients may be focused initially on their cancer diagnosis, providers should advise patients regarding potential threats to fertility as early as possible in the treatment process so as to allow for the widest array of options for fertility preservation. The discussion should be documented. Sperm, oocyte, and embryo cryopreservation are considered standard practice and are widely available. There is conflicting evidence to recommend gonadotrophin-releasing hormone agonists (GnRHa) and other means of ovarian suppression for fertility preservation. The Panel recognizes that, when proven fertility preservation methods are not feasible, and in the setting of young women with breast cancer, GnRHa may be offered to patients in the hope of reducing the likelihood of chemotherapy-induced ovarian insufficiency. GnRHa should not be used in place of proven fertility preservation methods. The panel notes that the field of ovarian tissue cryopreservation is advancing quickly and may evolve to become standard therapy in the future. Additional information is available at www.asco.org/survivorship-guidelines . PMID- 29620999 TI - Dose-Dependent Lowering of Mutant Huntingtin Using Antisense Oligonucleotides in Huntington Disease Patients. AB - On December 11 of 2017, Ionis Pharmaceuticals published a press release announcing dose-dependent reductions of mutant huntingtin protein in their HTTRx Phase 1/2a study in Huntington disease (HD) patients. The results from this Ionis trial have gained much attention from the patient community and the oligonucleotide therapeutics field, since it is the first trial targeting the cause of HD, namely the mutant huntingtin protein, using antisense oligonucleotides (ASOs). The press release also states that the primary endpoints of the study (safety and tolerability) were met, but does not contain data. This news follows the approval of another therapeutic ASO nusinersen (trade name Spinraza) for a neurological disease, spinal muscular atrophy, by the U.S. Food and Drug Administration and European Medicines Agency, in 2016 and 2017, respectively. Combined, this offers hope for the development of the HTTRx therapy for HD patients. PMID- 29621000 TI - Concept Test of a Smoking Cessation Smart Case. AB - BACKGROUND: Wearable/portable devices that unobtrusively detect smoking and contextual data offer the potential to provide Just-In-Time Adaptive Intervention (JITAI) support for mobile cessation programs. Little has been reported on the development of these technologies. INTRODUCTION: To address this gap, we offer a case report of users' experiences with a prototype "smart" cigarette case that automatically tracks time and location of smoking. Small-scale user-experience studies are typical of iterative product design and are especially helpful when proposing novel ideas. The purpose of the study was to assess concept acceptability and potential for further development. MATERIALS AND METHODS: We tested the prototype case with a small sample of potential users (n = 7). Participants used the hardware/software for 2 weeks and reconvened for a 90-min focus group to discuss experiences and provide feedback. RESULTS: Participants liked the smart case in principle but found the prototype too bulky for easy portability. The potential for the case to convey positive messages about self also emerged as a finding. Participants indicated willingness to pay for improved technology (USD $15-$60 on a one-time basis). DISCUSSION: The smart case is a viable concept, but design detail is critical to user acceptance. Future research should examine designs that maximize convenience and that explore the device's ability to cue intentions and other cognitions that would support cessation. CONCLUSIONS: This study is the first to our knowledge to report formative research on the smart case concept. This initial exploration provides insights that may be helpful to other developers of JITAI-support technology. PMID- 29620998 TI - Breast Cancer Family History and Contralateral Breast Cancer Risk in Young Women: An Update From the Women's Environmental Cancer and Radiation Epidemiology Study. AB - Purpose The Women's Environmental Cancer and Radiation Epidemiology (WECARE) study demonstrated the importance of breast cancer family history on contralateral breast cancer (CBC) risk, even for noncarriers of deleterious BRCA1/2 mutations. With the completion of WECARE II, updated risk estimates are reported. Additional analyses that exclude women negative for deleterious mutations in ATM, CHEK2*1100delC, and PALB2 were performed. Patients and Methods The WECARE Study is a population-based case-control study that compared 1,521 CBC cases with 2,212 individually matched unilateral breast cancer (UBC) controls. Participants were younger than age 55 years when diagnosed with a first invasive breast cancer between 1985 and 2008. Women were interviewed about breast cancer risk factors, including family history. A subset of women was screened for deleterious mutations in BRCA1/2, ATM, CHEK2*1100delC, and PALB2. Rate ratios (RRs) were estimated using multivariable conditional logistic regression. Cumulative absolute risks (ARs) were estimated by combining RRs from the WECARE Study and population-based SEER*Stat cancer incidence data. Results Women with any first-degree relative with breast cancer had a 10-year AR of 8.1% for CBC (95% CI, 6.7% to 9.8%). Risks also were increased if the relative was diagnosed at an age younger than 40 years (10-year AR, 13.5%; 95% CI, 8.8% to 20.8%) or with CBC (10-year AR, 14.1%; 95% CI, 9.5% to 20.7%). These risks are comparable with those seen in BRCA1/2 deleterious mutation carriers (10-year AR, 18.4%; 95% CI, 16.0% to 21.3%). In the subset of women who tested negative for deleterious mutations in BRCA1/2, ATM, CHEK2*1100delC, and PALB2, estimates were unchanged. Adjustment for known breast cancer single-nucleotide polymorphisms did not affect estimates. Conclusion Breast cancer family history confers a high CBC risk, even after excluding women with deleterious mutations. Clinicians are urged to use detailed family histories to guide treatment and future screening decisions for young women with breast cancer. PMID- 29621001 TI - Antibiotic Use and Antimicrobial Resistance of Surgical Patients with Peritonitis at a Tertiary Referral Hospital in Rwanda. AB - BACKGROUND: There is growing recognition of the worsening problem of antibiotic resistance and the need for antibiotic stewardship in low-resource settings. The aim of this study was to describe antibiotic use and antimicrobial resistance in patients undergoing surgery for peritonitis at a Rwandan referral hospital. PATIENTS AND METHODS: All surgical patients with peritonitis at a Rwandan referral hospital were enrolled. Prospective data were collected on epidemiology, clinical features, interventions, and outcomes. Antibiotic agents were prescribed and cultures were collected according to surgeon discretion. High risk for antibiotic treatment failure or death was defined as patients with severe sepsis, older than 70 years of age, tumor, or operating room delay more than 24 hours from hospital admission. Logistic regression was used to determine factors associated with high risk of antibiotic treatment failure or death. RESULTS: Over a six-month period, 280 patients underwent operation for peritonitis; 79 patients were excluded because no infectious etiology was identified at operation. Data on antibiotic usage were available for 165 patients. The most common diagnoses were intestinal obstruction (n = 43) and appendicitis (n = 36). Most patients received antibiotic agents, the most of of which being third-generation cephalosporins (n = 149; 90%) and metronidazole (n = 140; 85%). The mean duration of antibiotics was 5.1 days (range: 0-14). Overall, 80 (54%) patients were high-risk for antibiotic treatment failure or death. Risk for antibiotic treatment failure or death was associated with localized peritonitis (p = 0.001) and high American Society of Anesthesiologist score (p = 0.003). Cultures were collected from 33 patients and seven patients had an organism isolated. Escherichia coli was identified in in five surgical specimens and two 2 urine cultures. All Escherichia coli specimens showed resistance to cephalosporins. CONCLUSIONS: Broad antibiotic coverage with third-generation cephalosporins and metronidazole is common in Rwandan surgical patients with peritonitis. Areas for improvement should focus on choice and duration of antibiotic agents, tailored to underlying diagnosis and risk factors for antibiotic treatment failure or death. More data are needed on antibiotic resistance patterns to guide antimicrobial therapy. PMID- 29621003 TI - Design and Performance of a 1 mm3 Resolution Clinical PET System Comprising 3-D Position Sensitive Scintillation Detectors. AB - We are developing a 1-mm3 resolution, high-sensitivity positron emission tomography (PET) system for loco-regional cancer imaging. The completed system will comprise two cm detector panels and contain 4 608 position sensitive avalanche photodiodes (PSAPDs) coupled to arrays of mm3 LYSO crystal elements for a total of 294 912 crystal elements. For the first time, this paper summarizes the design and reports the performance of a significant portion of the final clinical PET system, comprising 1 536 PSAPDs, 98 304 crystal elements, and an active field-of-view (FOV) of cm. The sub-system performance parameters, such as energy, time, and spatial resolutions are predictive of the performance of the final system due to the modular design. Analysis of the multiplexed crystal flood histograms shows 84% of the crystal elements have>99% crystal identification accuracy. The 511 keV photopeak energy resolution was 11.34+/-0.06% full-width half maximum (FWHM), and coincidence timing resolution was 13.92 +/- 0.01 ns FWHM at 511 keV. The spatial resolution was measured using maximum likelihood expectation maximization reconstruction of a grid of point sources suspended in warm background. The averaged resolution over the central 6 cm of the FOV is 1.01 +/- 0.13 mm in the X-direction, 1.84 +/- 0.20 mm in the Y-direction, and 0.84 +/- 0.11 mm in the Z-direction. Quantitative analysis of acquired micro-Derenzo phantom images shows better than 1.2 mm resolution at the center of the FOV, with subsequent resolution degradation in the y-direction toward the edge of the FOV caused by limited angle tomography effects. PMID- 29621002 TI - Penalized-Likelihood Reconstruction With High-Fidelity Measurement Models for High-Resolution Cone-Beam Imaging. AB - We present a novel reconstruction algorithm based on a general cone-beam CT forward model, which is capable of incorporating the blur and noise correlations that are exhibited in flat-panel CBCT measurement data. Specifically, the proposed model may include scintillator blur, focal-spot blur, and noise correlations due to light spread in the scintillator. The proposed algorithm (GPL BC) uses a Gaussian Penalized-Likelihood objective function, which incorporates models of blur and correlated noise. In a simulation study, GPL-BC was able to achieve lower bias as compared with deblurring followed by FDK as well as a model based reconstruction method without integration of measurement blur. In the same study, GPL-BC was able to achieve better line-pair reconstructions (in terms of segmented-image accuracy) as compared with deblurring followed by FDK, a model based method without blur, and a model-based method with blur but not noise correlations. A prototype extremities quantitative cone-beam CT test-bench was used to image a physical sample of human trabecular bone. These data were used to compare reconstructions using the proposed method and model-based methods without blur and/or correlation to a registered CT image of the same bone sample. The GPL BC reconstructions resulted in more accurate trabecular bone segmentation. Multiple trabecular bone metrics, including trabecular thickness (Tb.Th.) were computed for each reconstruction approach as well as the CT volume. The GPL-BC reconstruction provided the most accurate Tb.Th. measurement, 0.255 mm, as compared with the CT derived value of 0.193 mm, followed by the GPL-B reconstruction, the GPL-I reconstruction, and then the FDK reconstruction (0.271 mm, 0.309 mm, and 0.335 mm, respectively). PMID- 29621004 TI - A Probabilistic Model of Social Working Memory for Information Retrieval in Social Interactions. AB - Social working memory (SWM) plays an important role in navigating social interactions. Inspired by studies in psychology, neuroscience, cognitive science, and machine learning, we propose a probabilistic model of SWM to mimic human social intelligence for personal information retrieval (IR) in social interactions. First, we establish a semantic hierarchy as social long-term memory to encode personal information. Next, we propose a semantic Bayesian network as the SWM, which integrates the cognitive functions of accessibility and self regulation. One subgraphical model implements the accessibility function to learn the social consensus about IR-based on social information concept, clustering, social context, and similarity between persons. Beyond accessibility, one more layer is added to simulate the function of self-regulation to perform the personal adaptation to the consensus based on human personality. Two learning algorithms are proposed to train the probabilistic SWM model on a raw dataset of high uncertainty and incompleteness. One is an efficient learning algorithm of Newton's method, and the other is a genetic algorithm. Systematic evaluations show that the proposed SWM model is able to learn human social intelligence effectively and outperforms the baseline Bayesian cognitive model. Toward real world applications, we implement our model on Google Glass as a wearable assistant for social interaction. PMID- 29621005 TI - Hierarchical Type Stability Criteria for Delayed Neural Networks via Canonical Bessel-Legendre Inequalities. AB - This paper is concerned with global asymptotic stability of delayed neural networks. Notice that a Bessel-Legendre inequality plays a key role in deriving less conservative stability criteria for delayed neural networks. However, this inequality is in the form of Legendre polynomials and the integral interval is fixed on . As a result, the application scope of the Bessel-Legendre inequality is limited. This paper aims to develop the Bessel-Legendre inequality method so that less conservative stability criteria are expected. First, by introducing a canonical orthogonal polynomial sequel, a canonical Bessel-Legendre inequality and its affine version are established, which are not explicitly in the form of Legendre polynomials. Moreover, the integral interval is shifted to a general one . Second, by introducing a proper augmented Lyapunov-Krasovskii functional, which is tailored for the canonical Bessel-Legendre inequality, some sufficient conditions on global asymptotic stability are formulated for neural networks with constant delays and neural networks with time-varying delays, respectively. These conditions are proven to have a hierarchical feature: the higher level of hierarchy, the less conservatism of the stability criterion. Finally, three numerical examples are given to illustrate the efficiency of the proposed stability criteria. PMID- 29621006 TI - A Bayesian Framework for Estimating the Concordance Correlation Coefficient Using Skew-elliptical Distributions. AB - The concordance correlation coefficient (CCC) is a widely used scaled index in the study of agreement. In this article, we propose estimating the CCC by a unified Bayesian framework that can (1) accommodate symmetric or asymmetric and light- or heavy-tailed data; (2) select model from several candidates; and (3) address other issues frequently encountered in practice such as confounding covariates and missing data. The performance of the proposal was studied and demonstrated using simulated as well as real-life biomarker data from a clinical study of an insomnia drug. The implementation of the proposal is accessible through a package in the Comprehensive R Archive Network. PMID- 29621007 TI - Disseminated intravascular coagulation: is it fact or fancy? AB - : 'Disseminated intravascular coagulation (DIC)' occurs commonly in critical illnesses such as sepsis, trauma, cancer, and complications of surgery and pregnancy. Mortality is very high. The pathogenesis has been ascribed to tissue factor-initiated coagulation disorder, resulting in disseminated microblood clots that are made of platelets, plasma factors, fibrins, and blood cells. True DIC depletes coagulation factors and consumes platelets, and activates fibrinolysis. 'DIC' is assumed to orchestrate thrombocytopenia, microangiopathic hemolytic anemia and hypoxic multiorgan dysfunction syndrome, and causes hemorrhagic disorder due to depleted coagulation factors. In contrast, disseminated intravascular microthrombosis (DIT) occurs in thrombotic thrombocytopenic purpura (TTP) and TTP-like syndrome due to ADAMTS13 deficiency or insufficiency. The pathogenesis is due to formation of intravascular 'microthrombi' composed of complexes of platelets and unusually large von Willebrand factor multimers. Interestingly, DIT also occurs in the same critically ill patients as 'DIC' does. Following activation of complement system, the terminal complex C5b-9 causes endotheliopathy via channel formation to the endothelial cell membrane. Endotheliopathy activates microthrombotic pathway and initiates microthrombogenesis, leading to endotheliopathy-associated DIT. DIT results in TTP-like syndrome with hematologic phenotype of consumptive thrombocytopenia, microangiopathic hemolytic anemia, and multiorgan dysfunction syndrome. In reinterpretation of 'DIC', the true lesion is 'microthrombi' but not microblood clots. Thus, 'DIC' is endotheliopathy-associated DIT. This concept reconciles all the clinical features of 'DIC', and dramatically changes our understanding of pathophysiological mechanism in hemostasis and thrombosis. This new paradigm should assist the physician with correct diagnostic evaluation and treatment intervention. PMID- 29621008 TI - Incidence and clinical significance of hyperfibrinolysis during living donor liver transplantation. AB - : We evaluated the incidence and clinical significance of hyperfibrinolysis during living donor liver transplantation (LDLT) using viscoelastic coagulation tests. We retrospectively reviewed adult LDLT recipients from February 2010 to February 2015. Hyperfibrinolysis was defined when clot lysis index [LY60 = (MA - A60)/MA * 100, %] was less than 85, where A60 is the clot amplitude at 60 min after maximum amplitude (MA) occurred. Viscoelastic coagulation tests were performed six times (T1: immediately after anesthetic induction, T2: end of preanhepatic phase, T3: 1 h after anhepatic phase, T4: 5 min after reperfusion, T5: 1 h after reperfusion, and T6: 3 h after reperfusion). One hundred-ten recipients were included in final analysis. Hyperfibrinolysis was uncommon in preanhepatic phase (0% at T1 and 4.5% at T2) and aggravated during anhepatic phase and peaked immediately after reperfusion, 18% at T3 and 71% at T4. However, hyperfibrinolysis nearly disappeared 1 h after reperfusion and did not recur; 0.9% at T5 and 0% at T6. Hyperfibrinolysis was not predicted from preoperative demographics and coagulation profiles. However, the degree of coagulation profile derangements and intraoperative blood loss was greater in the hyperfibrinolysis group. During LDLT, hyperfibrionlysis frequently occurred at anhepatic phase and immediately after reperfusion, but it was resolved during postreperfusion phase. PMID- 29621009 TI - Percutaneous coronary intervention for treating de-novo lesions in small coronary vessels: initial experience with the Essential paclitaxel-coated balloon. AB - BACKGROUND: Paclitaxel-coated balloon (PCB) coronary angioplasty is an alternative treatment for de-novo coronary lesions in small vessels. This study with the new Essential PCB aimed to evaluate early and mid-term clinical outcomes following angioplasty with the Essential PCB in the treatment of de-novo lesions in small vessels. PATIENTS AND METHODS: We included all patients who underwent PCB angioplasty for treating de-novo coronary lesions in small vessels (reference diameter <2.5 mm) between October 2015 and June 2016 in 2 centres. The primary endpoint was the 12-month target lesion failure (TLF) rate: a composite of cardiac death, target vessel-related myocardial infarction, and target lesion revascularization. The secondary endpoints were rates of target vessel failure and global major adverse cardiac events (MACE). RESULTS: A total of 71 patients (comprising 71 lesions) were included, with a mean age of 66+/-11 years. A 56% were diabetic and 70% had an acute coronary syndrome as an indication for coronary revascularization. The mean vessel diameter and lesion length were 2.21+/-0.41 and 20.7+/-9.2 mm, respectively. Predilatation was performed in 85.9% of patients. The median diameter, length, and inflation pressure of the Essential balloon were 2.0 [interquartile range (IQR): 2.0-2.5] mm, 20 (IQR: 15-30) mm, and 12+/-2 atmospheres, respectively. Angiographic success was achieved in 97.2% of cases, and bail-out stenting was required in nine (12.7%) cases. The incidence of TLF at the 12-month follow-up was 4.2%, with a target lesion revascularization rate of 4.2%. Target vessel failure and global MACE rates were 4.2 and 9.9%, respectively. CONCLUSION: Use of the Essential PCB for treating de-novo coronary lesions in small vessels was safe, with low TLF and MACE rates at the 12-month follow-up. PMID- 29621011 TI - Central Sleep Apnea Post Vagal Nerve Manipulation and Stimulation During Neck Tumor Resection: A Case Report. AB - We describe a pediatric patient who underwent neck dissection for removal of a tumor and had unexpected transient central sleep apnea in the recovery room. To the best of our knowledge, this is the first report in the existing literature of central sleep apnea after surgical manipulation of the vagal nerve under anesthesia. PMID- 29621012 TI - Spinal Cord Neuromodulation Therapy for Levofloxacin-Reinduced Complex Regional Pain Syndrome and Neurotoxicity: A Case Report. AB - Fluoroquinolones are a class of popular outpatient antimicrobial agents with a wide spectrum of therapeutic indications for respiratory and genitourinary infections. Though the most common side effects are gastrointestinal, fluoroquinolones have been increasingly associated with neurotoxicity including peripheral neuropathy and seizures. We present here a case of a 43-year-old woman with previously resolved type I complex regional pain syndrome (CRPS) who presented with symptoms of CRPS and neurotoxicity in the setting of levofloxacin administration. Our aim is to advocate for increased caution in prescribing to patients with a history of neuropathology including CRPS. PMID- 29621010 TI - Periprocedural Management of Direct Oral Anticoagulants Surrounding Cardioversion and Invasive Electrophysiological Procedures. AB - As direct oral anticoagulants (DOACs) have demonstrated favorable efficacy and safety outcomes compared with vitamin K antagonists for the treatment and prevention of venous thromboembolism and the prevention of stroke and systemic embolism in patients with nonvalvular atrial fibrillation, their role in the management of anticoagulation during electrophysiological procedures continues to evolve. At present, guidelines are limited regarding specific recommendations for the use of DOACs in these clinical settings. Here, we review available data regarding the risks and benefits associated with various periprocedural anticoagulation management approaches when patients receiving DOACs undergo electrophysiologic procedures including cardioversion, ablation, and device implantation. This discussion is intended to provide clinicians with an overview of available evidence and best practices to minimize the risk of both thromboembolic and bleeding events in the periprocedural setting. PMID- 29621013 TI - Allergic Acute Coronary Syndrome (Kounis Syndrome) in a Young Woman During Spinal Anesthesia: A Case Report. AB - Kounis syndrome represents the concurrence of acute coronary syndromes or anginal pain with allergic, hypersensitivity, and anaphylactoid reactions that are increasingly found in clinical practice. We present a case of a young woman who experienced attacks of dyspnea, hypoxemia, and hypotension during and after spinal anesthesia. Based on the pattern of clinical symptoms and laboratory findings, she was retrospectively diagnosed with Kounis syndrome, even though no apparent trigger of hypersensitivity was found. PMID- 29621014 TI - Laryngoscopy and Bronchoscopy in an Infant With a Congenital Laryngeal Web Complicated by Bilateral Pneumothoraces: A Case Report. AB - Neonates with laryngeal webs pose unique challenges to the anesthesiologist. We present a 2-day-old neonate with aphonia and stridor who underwent microdirect laryngoscopy. Intraoperatively, a Cohen type 4 laryngeal web was diagnosed not immediately amenable to resection. Therefore, the decision was made for endotracheal intubation and subsequent tracheostomy. After endotracheal intubation, there was acute respiratory compromise and oxygen desaturation that improved moderately after urgent tracheostomy. A chest radiograph revealed a large pneumothorax. Our experience suggests that in the presence of high-grade laryngeal webs, the possibility of intraoperative development of pneumothorax should be considered if respiratory difficulties are encountered. PMID- 29621015 TI - Hamstring Muscle Injury Prediction by Isokinetic Ratios Depends on the Method Used. AB - OBJECTIVES: Hamstring muscle injury prediction by isokinetic strength ratios is low but could result from the method-depending either on the use of the limbs or of the sportsmen as references. We aimed to establish a predictive model including unilateral and bilateral ratios calculated from the dominant, nondominant, right, and left limb in injured and uninjured professional soccer players. DESIGN: Cohort study. SETTING: Soccer team of the French Professional Premier League. PATIENTS: Ninety-one professional soccer players. INTERVENTIONS: Isokinetic muscle strength was prospectively measured at the beginning of 5 consecutive seasons (2009-2014). MAIN OUTCOME MEASURES: Several bilateral, conventional, and functional ratios were calculated from isokinetic measurements at different angular speeds (60 and 240 degrees/s in concentric mode and 30 degrees/s in eccentric mode). Thirty-one soccer players had a hamstring injury during the seasons and were compared with 60 uninjured players. Four models were tested to predict the occurrence of hamstring injury from isokinetic ratios calculated in accordance with the dominant, nondominant, right, and left limb. RESULTS: No predictive model was found when ratios were calculated from the dominant or the right limb. Two models of prediction were found when ratios were calculated from the nondominant or the left limb. In these 2 models, only the bilateral concentric hamstring-to-hamstring ratio at 60 degrees/s was predictive. The best prediction was found with the left limb. CONCLUSIONS: We identified 2 low predictive models for hamstring muscle injuries depending on the limbs studied. Because of a low prediction, the consensual method used to predict hamstring muscle injury must be defined in future studies. PMID- 29621016 TI - ImPACT Normative Data of Ethnically Diverse Adolescent Athletes. AB - OBJECTIVE: The aim of this research was to develop preliminary norms for the Immediate Post-Concussion Assessment and Cognitive Testing (ImPACT) administered to a large sample of adolescent athletes from diverse ethnic backgrounds. DESIGN: A retrospective records review. SETTING: Middle and high school athletic departments. PARTICIPANTS: A total of 5741 male and female adolescent athletes in Hawaii, aged 13 to 18 years, in grades 9 to 12 were included in the study. INDEPENDENT VARIABLES: Age, sex, ethnicity, and sport. MAIN OUTCOME MEASURES: ImPACT Composite scores (Verbal Memory, Visual Memory, Visual Motor Speed, Reaction Time, and Impulse Control) and Total Symptom score from baseline testing. RESULTS: The results indicated statistically significant differences between age and sex groups, as well as between ethnic and sport groups. CONCLUSIONS: The findings support the continued use of stratified norms for age and sex for ethnically diverse adolescent athletes. Comparisons of ethnic and sport groups deserve further investigation. When baseline scores are not available for postconcussion comparison, present observations tentatively support the cautious use of standard ImPACT norms with ethnically diverse athletes. PMID- 29621017 TI - Exertional Medial Compartment Syndrome of the Foot: Referred Pain and Sequelae of Delayed Diagnosis-A Case Report. AB - In a 31-year-old man, the diagnosis of medial compartment syndrome of foot was delayed for 8 days. In contrast to previously reported cases, the patient presented with mainly bilateral lateral thigh-referred pain rather than foot pain. Although delayed decompression of the medial compartment provided dramatic relief of the referred pain, the patient complained of sensory deficit at the medial side of the foot and flexion deformity of the great toe at the final follow-up visit. Medial compartment syndrome of the foot can cause referred pain, and delayed or missed diagnosis can cause irreversible damage. Therefore, prompt diagnosis of compartment syndrome is crucial, and clinicians must consider the possibility of referred pain when the origin of pain is uncertain. PMID- 29621018 TI - Management of anaphylaxis in Spain: pediatric emergency care providers' knowledge. AB - BACKGROUND: Acute care providers must diagnose and treat patients with anaphylaxis. The objective was to analyze Spanish pediatric emergency departments' (ED) providers' knowledge of the international recommendations for the management of anaphylaxis. METHODS: A web-based survey including providers (both attending and residents) from seven Spanish pediatric EDs was conducted. To analyze the knowledge of the identification of anaphylaxis, we used the diagnostic criteria given by the National Institute of Allergy and Infectious Disease and Food Allergy and the Food Allergy and Anaphylaxis Network (2005). To analyze the management, we used the practical recommendations on the management of anaphylaxis published by the Joint Task Force on Practice Parameters (2014). RESULTS: A total of 425 physicians received the link and 337 (79.2%) completed the survey (138 attending, 76.6%; 199 residents, 81.2%, P<0.05). More than 90% of the providers correctly identified the anaphylaxis, except for not diagnosing it when reduced blood pressure is detected after exposure to a known allergen (69.7%) and misdiagnosis of anaphylaxis in patients with progressive urticaria with significant angioedema (65.9%). Nearly 100% identified epinephrine as the first-line treatment. Main failures of treatment were related to the position of the patient, the effect of medications in preventing a biphasic reaction, the recommended time to observe patients, and those related to the follow-up. No significant differences were found between attendings and residents. CONCLUSION: Even though the Spanish pediatric ED providers' knowledge of the management of anaphylaxis is good, certain improvement areas are identified in both the identification and the management of these patients. PMID- 29621019 TI - Show Me the Shape of your Face and I Will Tell You What Crime You Have Committed. PMID- 29621020 TI - Moulages: Art and History of Medicine. AB - The aim of this article is to introduce the museum we have at the Pathology Department, School of Medicine of the National University of Rosario, Argentina. The origin dates from to 1922 when Dermatology Professor Dr. Enrique P. Fidanza bought moulages at L'Hopital Saint-Louis in Paris for the purpose of teaching. The collection included around 100 moulages and was worth approximately 1000 dollars. These pieces were exhibited at the Dermatology Department for many years and later moved to the Pathology Department where some pieces started being repaired, whereas others have deteriorated. The collection is composed of 100 moulages done by a French craftsman by the name of Niclet and 258 made by Argentine craftsmen including Alba Ramirez and G. Rouzaut, among others. The pieces are classified according to different dermatological diseases such as: the different stages of syphilis, lupus, benign and malignant neoplasm, infectious diseases, etc. PMID- 29621021 TI - Subconjunctival Herniation of Fat Does Not Demonstrate Loss of RB Gene Expression. PMID- 29621022 TI - Locatelli Piera, Not Pietro! PMID- 29621023 TI - Papanicolaou Cytology as a Suitable Technique for a Diagnostic Approach to an Adverse Reaction to Polyalkylamide Gel Filler. PMID- 29621024 TI - Spindle Cell-Predominant Trichodiscoma With a Palisaded Arrangement of Stromal Cells. PMID- 29621025 TI - Sexual Problems of Patients With Breast Cancer After Treatment: A Systematic Review. AB - BACKGROUND: Sexual health is a crucial part of quality of life in breast cancer survivors, regardless of their relationship status. However, previous studies have rarely used qualitative methods to explore the postoperative experiences and feelings of patients with breast cancer. OBJECTIVE: The aim of this study was to explore the reasons underlying postoperative sexual relationship changes, sexual inactivity, and adaptation to sexual life in patients with breast cancer, as well as interventions provided by medical staff. INTERVENTIONS/STUDY METHODS: A survey was performed by using electronic databases and electronic journals accessed through the Internet. The following keywords were used: "breast cancer," "sexual problem," "sexual dysfunction," and "qualitative." RESULTS: Seven articles were included in the literature review. Three main domains were explored, namely, reasons for sexual relationship changes, including age and treatment; the way patients used to adapt to sexual life after the diagnosis of breast cancer, including support systems, communication with partner, and religious beliefs; and intervention by healthcare workers, including intimacy enhancement measures and patient-provider communication. CONCLUSIONS: The results of this study can facilitate and encourage health professionals to identify, examine, and solve most of the patient's sexual problems by using the functional and medical framework of the healthcare system. IMPLICATIONS FOR PRACTICE: One practical recommendation of this study is the incorporation of sexual counseling units into the national healthcare system. Counselors in these units can aid patients with breast cancer in resolving their sexual issues and promoting sexual satisfaction in the husbands (or partners) of the patients. PMID- 29621026 TI - Fluid status assessment in hemodialysis patients and the association with outcome: review of recent literature. AB - PURPOSE OF REVIEW: In this review, we will discuss the most recent literature regarding fluids status assessment in hemodialysis patients, and the associations with outcome. RECENT FINDINGS: Research toward technique-assisted assessment of fluid status in hemodialysis patients has been going on for many years. However, there is no absolute agreement between techniques, such as bioimpedance, lung ultrasound, biochemical markers or vena caval diameter, likely because they reflect different fluid compartments with potentially altered distribution in hemodialysis patients. Recent studies, mostly based on bioimpedance, have shown not only an association of severe, but also of moderate predialysis fluid overload with overall survival. Also predialysis fluid depletion has been found to associate with and increased mortality risk. Interventional studies with fluid guided management are scarce and outline the difficulties of achieving dry weight is the dialysis population. SUMMARY: Optimal estimation of predialysis fluid status remains challenging and may require a combination of clinical and technical derived parameters. There appears to be a narrow window of optimal predialysis fluid status. Further clinical studies are necessary to identify strategies to improve survival in hemodialysis patients with abnormalities in fluid status. PMID- 29621027 TI - Cardiac output monitoring: how to choose the optimal method for the individual patient. AB - PURPOSE OF REVIEW: To review the different methods available for the assessment of cardiac output (CO) and describe their specific indications in intensive care and perioperative medicine. RECENT FINDINGS: In critically ill patients, persistent circulatory shock after initial resuscitation is an indication for the assessment of CO to monitor the response to fluids and vasoactive agents. In patients with circulatory shock associated with right ventricular dysfunction, pulmonary artery hypertension, or acute respiratory distress syndrome, invasive CO monitoring using indicator dilution methods is indicated. Calibrated and uncalibrated pulse wave analysis enable absolute or relative CO changes to be monitored in real-time during the assessment of fluid responsiveness. In patients undergoing open-heart and thoracic aortic surgery, transesophageal echocardiography is recommended. In selected cardiac surgery patients, advanced hemodynamic monitoring using thermodilution methods can be considered. In high risk noncardiac surgical patients, invasive pulse wave analysis or esophageal Doppler should be used for perioperative hemodynamic management. SUMMARY: Various invasive, minimally invasive, and noninvasive methods to assess CO are available. A profound understanding of the different CO monitoring methods is key to define indications for CO monitoring in the individual critically ill or surgical patient. PMID- 29621028 TI - Risk of Perforation Is High During Corrective Reaming of Retroverted Glenoids: A Computer Simulation Study. AB - BACKGROUND: Corrective anterior reaming is an accepted method for addressing retroversion in a biconcave retroverted (Walch classification, type B2) glenoid in anatomic total shoulder arthroplasty. However, concern still exists regarding early glenoid component failure in the setting of severe retroversion, which may be related to loss of component containment and/or violation of subchondral bone resulting from reaming. The goal of this study was to determine what characteristics of B2 glenoids are less amenable to corrective reaming by virtually implanting anatomic glenoid components. QUESTIONS/PURPOSES: (1) How much medial reaming is required to correct the version of a B2 glenoid to an acceptable position? (2) Are glenoids with more severe retroversion (> 25 degrees ) at higher risk of component perforation than less retroverted glenoids? (3) Is correcting to 10 degrees of retroversion associated with greater risk as compared with reaming to 15 degrees ? (4) How does corrective reaming affect the underlying bone density on the glenoid face of B2 glenoids? METHODS: A series of 71 patients with B2 glenoids (posterior subluxation of the humeral head with posterior bone loss) with CT scans who were indicated for shoulder arthroplasty were reviewed. Forty-four of 71 glenoids (62.5%) had < 25 degrees of native retroversion. Anatomic glenoid implants were then virtually implanted using three dimensional CT software that allows for preoperative shoulder arthroplasty planning to correct native retroversion to 15 degrees or 10 degrees of retroversion using both a central peg with an inverted triangle peg configuration or a keel. The amount of reaming of the anterior glenoid required to correct retroversion, perforation of peripheral pegs, or keel was compared. Additionally, assessment of the surface area of the glenoid that had poor bone density (defined as cancellous bone under the subchondral plate) was analyzed by the software after correction. RESULTS: Correction to 15 degrees of retroversion required 5 +/- 3 mm of reaming, and correction to 10 degrees of retroversion required 8 +/- 3 mm of reaming to obtain at least 80% seating. Peripheral peg perforation with correction to 15 degrees occurred in 15 of 27 (56%) glenoids with > 25 degrees of retroversion compared with 10 of 44 (23%) of glenoids with < 25 degrees of retroversion (relative risk [RR], 2.4; 95% confidence interval [CI], 1.3-4.6; p = 0.006). There was no difference in perforation with keeled components. Increased correction to 10 degrees did not increase the risk of component perforation. When correction to 15 degrees , glenoids with higher native version (> 25 degrees ) had a greater risk of poor bone quality support (10 of 27 [37%]) when compared with glenoids with less version (four of 44 [9%]; RR, 4.1; 95% CI, 1.5-12.8; p = 0.006). Increased correction resulted in 13 of 27 (48%) glenoids with version > 25 degrees having poor bone density versus 10 of 44 (23%) with <= 25 degrees of version (RR, 2.1; 95% CI, 1.1-4.1; p = 0.028). CONCLUSIONS: There is a high risk of vault perforation after corrective reaming. Glenoid retroversions > 25 degrees are at a higher risk of having poor bone quality supporting the component. CLINICAL RELEVANCE: When contemplating options for patients with severe retroversion, surgeons should consider alternatives other than corrective reaming if achieving normal glenoid version is desired. PMID- 29621029 TI - Trimethoprim-sulfamethoxazole and antineutrophil cytoplasmic antibodies associated vasculitis. AB - PURPOSE OF REVIEW: In antineutrophil cytoplasmic antibodies-associated vasculitis (AAV), the treatment of choice is either Rituximab or cyclophosphamide in combination with steroids. In less extended forms of AAV, however, less toxic regimens are being used.In the current review, we will focus on the role of one of these less toxic regimens, that is trimethoprim-sulfamethoxazole monotherapy as induction treatment or as maintenance therapy in AAV. RECENT FINDINGS: A substantial portion of patients with active granulomatosis with polyangiitis (GPA) limited to the upper airways can be initially controlled with trimethoprim sulfamethoxazole (2 * 960 mg/day) monotherapy. In patients with initially a complete response, long-term control of the disease seems possible. In addition, trimethoprim-sulfamethoxazole (2 * 960 mg/day) maintenance therapy is an option for patients with GPA that have been proven to be frequent relapsers. The mechanism by which trimethoprim-sulfamethoxazole works in GPA is at present unknown. Suppression of Staphylococcus aureus carriage and/or anti-inflammatory mechanisms has been postulated. SUMMARY: Trimethoprim-sulfamethoxazole may be considered as a safe initial treatment in GPA patients with disease localized to the ear, nose, and throat region. Furthermore, trimethoprim-sulfamethoxazole in a dose of 2 * 960 mg/day may be used to prevent relapses in GPA. PMID- 29621030 TI - Long-term treatment strategies for postmenopausal osteoporosis. AB - PURPOSE OF REVIEW: Osteoporosis guidelines do not usually provide specific recommendations regarding what medication is most appropriate for individual patients. Generic oral bisphosphonates are often considered first-line treatment for osteoporosis, but treatment duration is limited, based on potential long-term safety concerns, and there is no consensus about what to do after 5 years. There are no recommendations concerning long-term management of osteoporosis over 30 or more years of postmenopausal life. RECENT FINDINGS: This review attempts to specify medication choices and provide the best clinical management strategies for women at different stages of life and with different underlying disease severity. Because there is no evidence that considers the entire postmenopausal lifespan, much of the discussion here will be based on expert opinion. The review considers a role for estrogens and selective estrogen receptor modulators, oral and intravenous bisphosphonates, denosumab and the anabolic agents, teriparatide and abaloparatide. SUMMARY: Optimal sequential monotherapy, over an average of 30 postmenopausal years, should be able to minimize exposure to pharmacology while maximizing benefits on bone strength and minimizing imminent and long-term risk of fracture. PMID- 29621032 TI - Electrical Impedance Tomography for Confirmation of Lung Isolation during One lung Ventilation: Erratum. PMID- 29621033 TI - Relationship of Ethical Knowledge to Action in Senior Baccalaureate Nursing Students. AB - It is not known if nursing graduates have skills to manage ethical clinical situations. This study examined the relationship between knowledge of ethics to choices of action in baccalaureate nursing students. It explored individual student characteristics to determine what impact these have on the relationship between knowledge and action. A significant correlation between knowledge of ethics and action was found. College courses on ethics, previous experience in making health care decisions, or general health care experience did not significantly impact this relationship, but the data trended toward significance with previous experience in making decisions and supported a need for further research. PMID- 29621034 TI - Role of Emergency Laparoscopic Colectomy for Colorectal Cancer: A Population Based Study in England. AB - OBJECTIVE: To evaluate factors associated with the use of laparoscopic surgery and the associated postoperative outcomes for urgent or emergency resection of colorectal cancer in the English National Health Service. SUMMARY OF BACKGROUND DATA: Laparoscopy is increasingly used for elective colorectal cancer surgery, but uptake has been limited in the emergency setting. METHODS: Patients recorded in the National Bowel Cancer Audit who underwent urgent or emergency colorectal cancer resection between April 2010 and March 2016 were included. A multivariable multilevel logistic regression model was used to estimate odds ratios (ORs) of undergoing laparoscopic resection and postoperative outcome according to approach. RESULTS: There were 15,516 patients included. Laparoscopy use doubled from 15.1% in 2010 to 30.2% in 2016. Laparoscopy was less common in patients with poorer physical status [American Society of Anaesthesiologists (ASA) 4/5 vs 1, OR 0.29 (95% confidence interval, 95% CI 0.23-0.37), P < 0.001] and more advanced T stage [T4 vs T0-T2, OR 0.28 (0.23-0.34), P < 0.001] and M-stage [M1 vs M0, OR 0.85 (0.75-0.96), P < 0.001]. Age, socioeconomic deprivation, nodal stage, hospital volume, and a dedicated colorectal emergency service were not associated with laparoscopy. Laparoscopic patients had a shorter length of stay [median 8 days (interquartile range (IQR) 5 to 15) vs 12 (IQR 8 to 21), adjusted mean difference -3.67 (-4.60 to 2.74), P < 0.001], and lower 90-day mortality [8.1% vs 13.0%; adjusted OR 0.78 (0.66-0.91), P = 0.004] than patients undergoing open resection. There was no significant difference in rates of readmission or reoperation by approach. CONCLUSION: The use of laparoscopic approach in the emergency resection of colorectal cancer is linked to a shorter length of hospital stay and reduced postoperative mortality. PMID- 29621035 TI - Lessons Learned From the TRIAD Research Opportunities to Improve Patient Safety in Emergency Care Near End of Life. PMID- 29621036 TI - Comparative Evaluation of Gemcabene and Peroxisome Proliferator-Activated Receptor Ligands in Transcriptional Assays of Peroxisome Proliferator-Activated Receptors: Implication for the Treatment of Hyperlipidemia and Cardiovascular Disease. AB - Gemcabene, a late-stage clinical candidate, has shown efficacy for LDL-C, non-HDL cholesterol, apoB, triglycerides, and hsCRP reduction, all risk factors for cardiovascular disease. In rodents, gemcabene showed changes in targets, including apoC-III, apoA-I, peroxisomal enzymes, considered regulated through peroxisome proliferator-activated receptor (PPAR) gene activation, suggesting a PPAR-mediated mechanism of action for the observed hypolipidemic effects observed in rodents and humans. In the current study, the gemcabene agonist activity against PPAR subtypes of human, rat, and mouse were compared with known lipid lowering PPAR activators. Surprisingly, gemcabene showed no or little PPAR-alpha transactivation compared with reference agonists, which showed concentration dependent transactivation against human PPAR-alpha of 2.4- to 30-fold (fenofibric acid), 17-fold (GW590735), and 2.3- to 25-fold (WY-14643). These agents also showed robust transactivation of mouse and rat PPAR-alpha in a concentration dependent manner. The known PPAR-delta agonists, GW1516, L165041, and GW0742, showed potent agonist activity against human, mouse, and rat receptors (ranging from 165- to 396-fold). By contrast, gemcabene at the highest concentration tested (300 MUM) showed no response in mouse and rat and a marginal response against human PPAR-delta receptors (3.2-fold). For PPAR-gamma, gemcabene showed no agonist activity against all 3 species at 100 MUM and marginal activity (3.6- to 5-fold) at 300 MUM. By contrast, the known agonists, rosiglitazone, indomethacin, and muraglitazar showed strong activation against the mouse, rat, and human PPAR-gamma receptors. No clear antagonist activity was observed with gemcabene against any PPAR subtypes for all 3 species over a wide range of concentrations. In summary, the transactivation studies rule out gemcabene as a direct agonist or antagonist of PPAR-alpha, PPAR-gamma, and PPAR-delta receptors of these 3 species. These data suggest that the peroxisomal effects observed in rodents and the lipid regulating effects observed in rodents and humans are not related to a direct activation of PPAR receptors by gemcabene. PMID- 29621037 TI - "No-Go Considerations" for In Situ Simulation Safety. AB - STATEMENT: In situ simulation is the practice of simulation in the actual clinical environment and has demonstrated utility in the assessment of system processes, identification of latent safety threats, and improvement in teamwork and communication. Nonetheless, performing simulated events in a real patient care setting poses potential risks to patient and staff safety. One integral aspect of a comprehensive approach to ensure the safety of in situ simulation includes the identification and establishment of "no-go considerations," that is, key decision-making considerations under which in situ simulations should be canceled, postponed, moved to another area, or rescheduled. These considerations should be modified and adjusted to specific clinical units. This article provides a framework of key essentials in developing no-go considerations. PMID- 29621038 TI - A new improved graphical and quantitative method for detecting bias in meta analysis. AB - Detection of publication and related biases remains suboptimal and threatens the validity and interpretation of meta-analytical findings. When bias is present, it usually differentially affects small and large studies manifesting as an association between precision and effect size and therefore visual asymmetry of conventional funnel plots. This asymmetry can be quantified and Egger's regression is, by far, the most widely used statistical measure for quantifying funnel plot asymmetry. However, concerns have been raised about both the visual appearance of funnel plots and the sensitivity of Egger's regression to detect such asymmetry, particularly when the number of studies is small. In this article, we propose a new graphical method, the Doi plot, to visualize asymmetry and also a new measure, the LFK index, to detect and quantify asymmetry of study effects in Doi plots. We demonstrate that the visual representation of asymmetry was better for the Doi plot when compared with the funnel plot. We also show that the diagnostic accuracy of the LFK index in discriminating between asymmetry due to simulated publication bias versus chance or no asymmetry was also better with the LFK index which had areas under the receiver operating characteristic curve of 0.74-0.88 with simulations of meta-analyses with five, 10, 15, and 20 studies. The Egger's regression result had lower areas under the receiver operating characteristic curve values of 0.58-0.75 across the same simulations. The LFK index also had a higher sensitivity (71.3-72.1%) than the Egger's regression result (18.5-43.0%). We conclude that the methods proposed in this article can markedly improve the ability of researchers to detect bias in meta-analysis. PMID- 29621039 TI - A generalized pairwise modelling framework for network meta-analysis. AB - Indirect comparison methods are used to measure the effect of two treatments that were each compared against a similar control group in a meta-analysis. The network meta-analysis method extends this to multiple treatments which are assessed simultaneously. Currently, there exist Bayesian and multivariate modelling approaches to these analyses, but these are computationally intensive and rely on assumptions that may not be valid in practice. Here we introduce a generalized pairwise modelling (GPM) framework for network meta-analysis, so named as it is based on the repeated application of adjusted indirect comparisons, also known as the Bucher method. The validity of this method hinges on the sufficient similarity of the common control node (transitivity), and for the application in the GPM framework this requirement extends to all common nodes used to make an indirect comparison estimate. Apart from the assumption of sufficient similarity, the GPM framework assumes only standard arithmetic and statistical rules making it more robust when compared with existing methods for network meta-analysis. A software program (MetaXL; www.epigear.com) is available to run this framework, so it is easily accessible to researchers. PMID- 29621031 TI - Neurocognitive Function after Cardiac Surgery: From Phenotypes to Mechanisms. AB - For half a century, it has been known that some patients experience neurocognitive dysfunction after cardiac surgery; however, defining its incidence, course, and causes remains challenging and controversial. Various terms have been used to describe neurocognitive dysfunction at different times after cardiac surgery, ranging from "postoperative delirium" to "postoperative cognitive dysfunction or decline." Delirium is a clinical diagnosis included in the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Postoperative cognitive dysfunction is not included in the DSM-5 and has been heterogeneously defined, though a recent international nomenclature effort has proposed standardized definitions for it. Here, the authors discuss pathophysiologic mechanisms that may underlie these complications, review the literature on methods to prevent them, and discuss novel approaches to understand their etiology that may lead to novel treatment strategies. Future studies should measure both delirium and postoperative cognitive dysfunction to help clarify the relationship between these important postoperative complications. PMID- 29621040 TI - Concomitant Repair of Pelvic Floor Disorders in Women Undergoing Surgery for Gynecologic Malignancies. AB - OBJECTIVE: The aims of this study were to determine the rate and describe 30-day postoperative complications of concomitant pelvic organ prolapse and/or urinary incontinence (POPUI) procedures in women undergoing surgery for a gynecologic malignancy. METHODS: Women who underwent surgical intervention for a gynecologic malignancy between 2010 and 2014 were identified using postoperative International Classification of Diseases, Ninth Revision codes 179.0 to 184.9 in the American College of Surgeons National Surgical Quality Improvement Program database. Women who underwent POPUI procedures were identified using Current Procedural Terminology codes between 51840 and 58294. Infectious, pulmonary, cardiac, and venous thromboembolism complication rates were calculated. Patient demographics and postoperative complication rates were analyzed using Student t, chi, and Fisher exact tests and compared between women with a gynecologic malignancy who did and did not undergo concomitant POPUI procedures. RESULTS: We identified 23,501 women with a diagnosis of a gynecologic malignancy. The most common included uterine (63%), ovarian (25%), and cervical cancer (8%). Only a small proportion of the women undergoing gynecologic cancer surgery (n = 556 [2.4%]) had concomitant POPUI procedures. The most commonly performed POPUI procedures included anterior and/or posterior colporrhaphy (n = 205 [32%]), laparoscopic colpopexy (n = 181 [28.2%]), and midurethral sling (n = 70 [10.9%]). There were no differences in 30-day reoperation; infectious, pulmonary, and cardiac complications; or venous thromboembolic events between women who did and did not have concomitant POPUI surgery. CONCLUSIONS: Using a large national surgical database, only 2.4% of women undergoing gynecologic cancer surgery had a concomitant POPUI procedure. Our data suggest that postoperative complications may not increase when concomitant surgery for POPUI is done at the time of gynecologic cancer surgery. PMID- 29621041 TI - Transvaginal Trigger Point Injections Improve Pain Scores in Women with Pelvic Floor Hypertonicity and Pelvic Pain Conditions. AB - OBJECTIVES: Chronic pelvic pain in women often requires multimodal treatment regimens. We describe our method of transvaginal trigger point injections (TPIs) and report outcomes using change in pain scores. METHODS: This was a retrospective review of women treated with in-office pelvic floor muscle injections from January 2012 to August 2015. Lidocaine 1% and 2%, bupivacaine 0.5%, or ropivacaine 0.5% with or without the addition of triamcinolone 40 mg was used for the injections. Pain was reported on a 0- to 10-point numerical rating scale before and after injection. Differences in pretreatment and posttreatment pain scores were analyzed after the first injection and after subsequent injections. Repeated-measures analysis was used to determine if any variable affected treatment response. RESULTS: One hundred one women with a mean age of 44 years had a total of 257 separate visits for pelvic floor muscle injections. Triamcinolone was used at 90.2% (230/255) of the TPI visits. After the initial TPI visit, there was significant decrease in total levator numerical rating scale score (maximum score, 20; mean, -6.21 +/- 4.7; P < 0.0001), and 77% (70/91) of patients had improved. These significant improvements were noted at all visits 1 through 4 and whether bilateral or unilateral injections were done. Only the total amount of local anesthestic used had a significant effect on the change in total levator pain scores (P = 0.002). Minor adverse effects including leg numbness, dizziness, nausea, bleeding, and headache occurred at 10% of visits. CONCLUSIONS: Pelvic floor muscle injections decrease pain levels in women with pelvic floor dysfunction. PMID- 29621042 TI - EXPERIENCE WITH OCRIPLASMIN IN PATIENTS WITH VITREOMACULAR TRACTION SYNDROME: A RETROSPECTIVE STUDY OF 10 PATIENTS. AB - PURPOSE: To assess the efficacy of ocriplasmin in patients with vitreomacular traction (VMT) syndrome <1,500 MUm with or without a full-thickness macular holes of <400 MUm. METHODS: In this study, a retrospective analysis of 10 eyes of 10 patients with VMT who were treated with ocriplasmin between December 2014 and January 2016 was performed. Ocriplasmin 0.125 mg was injected only once in all cases. Outcome measures included the detachment of VMT, best-corrected visual acuity, the evaluation of optical coherence tomography, including the closure of full-thickness macular holes, and the reduction of macular edema (if present) and the decrease of metamorphopsia if present. RESULTS: Ten patients (7 women and 3 men) with an average age of 75.1 years (range, 63-84 years) were treated with ocriplasmin with a follow-up period of 8 weeks. All patients were treated for VMT syndrome, and 5 patients (50.0%) showed an additional macular hole. An absolute detachment of VMT was seen in 3 patients (30.0%) and partially in 4 patients (40.0%). In three of the five patients, a complete closure of the full-thickness macular holes was seen. The two other patients needed an additional pars plana vitrectomy as a result of the persistent macular hole. An improvement of visual acuity was seen in 6 out of 10 patients (60.0%), a reduction of macular edema in 8 out of 9 patients (88.9%), and a decrease of metamorphopsia in 6 out of 7 patients (85.7%). CONCLUSION: In this retrospective analysis, the treatment with ocriplasmin showed a resolution of VMT in 7 of 10 patients (70.0%) after a follow up period of 8 weeks. PMID- 29621043 TI - Erratum. PMID- 29621046 TI - Persistent Physical Symptoms as Perceptual Dysregulation: A Neuropsychobehavioral Model and Its Clinical Implications. AB - OBJECTIVE: The mechanisms underlying the perception and experience of persistent physical symptoms are not well understood, and in the models, the specific relevance of peripheral input versus central processing, or of neurobiological versus psychosocial factors in general, is not clear. In this article, we proposed a model for this clinical phenomenon that is designed to be coherent with an underlying, relatively new model of the normal brain functions involved in the experience of bodily signals. METHODS: Based on a review of recent literature, we describe central elements of this model and its clinical implications. RESULTS: In the model, the brain is seen as an active predictive processing or inferential device rather than one that is passively waiting for sensory input. A central aspect of the model is the attempt of the brain to minimize prediction errors that result from constant comparisons of predictions and sensory input. Two possibilities exist: adaptation of the generative model underlying the predictions or alteration of the sensory input via autonomic nervous activation (in the case of interoception). Following this model, persistent physical symptoms can be described as "failures of inference" and clinically well-known factors such as expectation are assigned a role, not only in the later amplification of bodily signals but also in the very basis of symptom perception. CONCLUSIONS: We discuss therapeutic implications of such a model including new interpretations for established treatments as well as new options such as virtual reality techniques combining exteroceptive and interoceptive information. PMID- 29621047 TI - Fluoroscopically Guided Lumbar Transforaminal Epidural Steroid Injection: Procedural Technique. AB - Fluoroscopically guided lumbar transforaminal epidural steroid injections are indicated for the treatment of lumbar radicular pain that has failed more conservative options. This article details proper equipment and medications, patient positioning and set-up, step-by-step instructions for multiplanar fluoroscopic visualization, needle advancement and medication instillation, and postoperative management. Pearls and pitfalls are also discussed. In addition, an instructional procedure video accompanies this paper. PMID- 29621045 TI - Prospective Analyses of Cytokine Mediation of Sleep and Survival in the Context of Advanced Cancer. AB - OBJECTIVE: The aims of this study were to examine the potential association between sleep problems, symptom burden, and survival in patients with advanced cancer. METHODS: A prospective study of 294 patients with gastrointestinal cancer administered questionnaires assessing sleep, depression, anxiety, stress, pain, fatigue, and health-related quality of life. Serum levels of cytokines including interleukin (IL)-1alpha, IL-1beta, tumor necrosis factor alpha, IL-10, IL-2, and interferon-gamma were measured to assess biological mediation between sleep and survival. Survival was measured as time from diagnosis to death. RESULTS: Fifty nine percent of patients reported poor sleep quality, 53% reported poor sleep efficiency, 39% reported sleep latency greater than 30 minutes, and 45% reported sleeping less than 6 hours or greater than 10 hours. We found a significant association between sleep duration and symptom burden. Shorter sleep duration was significantly associated with higher levels of fatigue (r = -0.169, p = .01), pain (r = -0.302, p = .01), anxiety (r = -0.182, p = .01), depression (r = 0.172, p = .003), and lower levels of quality of life (r = 0.240, p = .01). After adjustment for demographic, psychological, and disease-specific factors, short sleep duration was associated with reduced survival (hazard ratio [HR] linear = 0.485, 95% confidence interval = 0.275-0.857) and there was also evidence for a quadratic pattern (HR quadrati = 1.064, 95% confidence interval = 1.015-1.115) suggesting a curvilinear relationship between sleep duration and survival. Interleukin 2 was the only cytokine significantly related to survival (HR = 1.01, p = .003) and sleep duration (beta = -30.11, p = .027). When of IL-2 was added to the multivariable model, short and long sleep (beta = -0.557, p = .097; beta = 0.046, p = .114) were no longer significantly related to survival, suggesting mediation by IL-2. CONCLUSION: Sleep duration was associated with symptom burden and poorer survival and IL-2 was found to mediate the association between sleep and survival. Screening and treatment of sleep problems in patients diagnosed with cancer are warranted. PMID- 29621044 TI - Impact of Oxygen on Pancreatic Islet Survival. AB - Pancreatic islet transplantation is a promising treatment option for individuals with type 1 diabetes; however, maintaining islet function after transplantation remains a large challenge. Multiple factors, including hypoxia associated events, trigger pretransplant and posttransplant loss of islet function. In fact, islets are easily damaged in hypoxic conditions before transplantation including the preparation steps of pancreas procurement, islet isolation, and culture. Furthermore, after transplantation, islets are also exposed to the hypoxic environment of the transplant site until they are vascularized and engrafted. Because islets are exposed to such drastic environmental changes, protective measures are important to maintain islet viability and function. Many studies have demonstrated that the prevention of hypoxia contributes to maintaining islet quality. In this review, we summarize the latest oxygen-related islet physiology, including computational simulation. Furthermore, we review recent advances in oxygen-associated treatment options used as part of the transplant process, including up-to-date oxygen generating biomaterials as well as a classical oxygen inhalation therapy. PMID- 29621048 TI - The effects of tongue pressure strength and accuracy training on tongue pressure strength, swallowing function, and quality of life in subacute stroke patients with dysphagia: a preliminary randomized clinical trial. AB - Tongue pressure strength and accuracy training (TPSAT) has been proposed as an intervention to improve dysphagia. However, the effects of TPSAT on dysphagia in subacute stroke patients remain unclear. The aim of this study was to investigate the effects of TPSAT on tongue pressure strength, swallowing function, and quality of life in subacute stroke patients with dysphagia. Sixteen subacute stroke patients were assigned randomly to two groups: the TPSAT group (n=8) or the control group (n=8). In the former, both TPSAT and traditional dysphagia therapies were performed for 30 min each per day; in the latter, only traditional dysphagia therapy was performed for 30 min twice a day. Both groups performed each daily intervention five times per week for 8 weeks. To assess the tongue pressure strength, maximum isometric tongue pressures (MIPs) of the anterior and posterior tongue using the Iowa Oral Performance Instrument were measured before and after the intervention. Mann Assessment of Swallowing Ability (MASA) and Swallowing-Quality of Life (SWAL-QOL) were also used to assess the swallowing function and quality of life, respectively. TPSAT with traditional dysphagia therapy significantly improved MASA, SWAL-QOL, and MIPs both anteriorly and posteriorly, and traditional dysphagia therapy significantly increased MASA, SWAL QOL, and MIPs anteriorly (P<0.05). The TPSAT group showed a significant improvement in anterior and posterior MIPs and tongue movement score in MASA compared with the control group (P<0.05). Our findings suggest that TPSAT may significantly improve dysphagia management in subacute stroke patients. PMID- 29621049 TI - Hepatitis B virus reactivation in patients with resolved hepatitis B virus infection receiving chemotherapy or immunosuppressive therapy. AB - BACKGROUND: The role of antiviral prophylaxis before chemotherapy or immunosuppressive therapy to prevent hepatitis B virus (HBV) reactivation in patients with resolved HBV infection [hepatitis B surface antigen (HBsAg) negative, hepatitis B core antibody (anti-HBc) positive] is unclear. This study aimed to evaluate the efficacy of prophylactic antiviral therapy and outcomes of HBsAg-negative, anti-HBc-positive patients who received chemotherapy or immunosuppressive therapy. PATIENTS AND METHODS: We retrospectively evaluated the medical records of HBsAg-negative, anti-HBc-positive patients who underwent chemotherapy or immunosuppressive therapy from January 2013 through November 2016 at a single institute in southern Taiwan. RESULTS: Among 1000 included HBsAg negative, anti-HBc-positive patients, the rate of hepatitis B surface antibody (anti-HBs) seropositivity before chemotherapy or immunosuppressive therapy was 76.6%. Twenty-six patients received a prophylactic oral antiviral agent (one telbuvudine, two lamivudine, 22 entecavir, and one tenofovir). Seven (0.7%) patients were diagnosed with HBV reactivation during or after chemotherapy courses. In multivariate Cox regression analysis, an rituximab-based regimen (hazard ratio: 11.74; 95% confidence interval: 1.62-84.94; P=0.02) and baseline anti-HBs-positive status (hazard ratio: 0.17; 95% confidence interval: 0.04-0.8; P=0.03) were significant predictive factors for HBV reactivation. Among anti-HBs negative recipients of rituximab-based chemotherapy, HBV reactivation was observed in zero of nine patients who received prophylactic antiviral therapy and three (33.3%) of nine patients who did not. CONCLUSION: Negative anti-HBs status and rituximab-containing regimens are both important factors for predicting chemotherapy or immunosuppressive therapy-related HBV reactivation in patients with resolved HBV infection. Therefore, antiviral prophylaxis should be considered in this patient population. PMID- 29621050 TI - Sudden Cardiac Death in Hypertrophic Cardiomyopathy. AB - Hypertrophic cardiomyopathy (HCM) is a heart disease characterized by hypertrophy of the left ventricular myocardium and is most often caused by mutations in sarcomere genes. The structural and functional abnormalities are not explained by flow-limiting coronary artery disease or loading conditions. The disease affects at least 0.2% of the population worldwide and is the most common cause of sudden cardiac death in young people and competitive athletes because of fatal ventricular arrhythmia. In some patients, however, HCM has a benign course. Therefore, it is of utmost importance to properly evaluate patients and single out those who would benefit from an implanted cardioverter defibrillator. In this article, we review and summarize the sudden cardiac death risk stratification algorithms, methods of preventing death due to HCM, and novel factors that may improve the existing prediction models. PMID- 29621051 TI - Clinical Applications of Ultrasonography in the Shoulder and Elbow. AB - In the past 30 years, the use of ultrasonography in the field of orthopaedics has evolved. As ultrasonography has been refined, smaller machines with higher fidelity and better transducers have become available at a lower cost. Diagnostic and therapeutic applications of ultrasonography in the shoulder and elbow have expanded imaging options and provided alternatives to surgical management. Ultrasonography is a dynamic tool that affords immediate diagnostic assessment for clinical correlation and can be used for serial examinations and image guidance during therapeutic procedures. This imaging modality is highly reliable and accurate and may limit the need for costly imaging referrals, particularly in geographic areas where advanced imaging is not readily available. However, clinical expertise is paramount for ultrasonography, which is an operator dependent modality. Ultrasonography is an effective educational resource; therefore, the curriculum in orthopaedic residency training programs should include education on this modality as the use of ultrasonography increases among orthopaedic surgeons. PMID- 29621052 TI - AAOS Appropriate Use Criteria: Surgical Management of Osteoarthritis of the Knee. PMID- 29621053 TI - Making Sense of Hypertension Guidelines. AB - Hypertension is a leading risk factor for heart disease, stroke, kidney failure, and diabetes and is a predisposing risk factor for most cardiovascular chronic illnesses. The risk for major cardiovascular events drops significantly when guideline-based blood pressure targets are achieved. Several different societies and organizations have released guidelines during the past 6 years, and significant clinical trial data have been recently released. Here, we summarize existing guidelines and recent pertinent clinical trial data to assist practitioners in identifying optimal treatment strategies for the successful management of hypertension. PMID- 29621054 TI - The Importance of Heart Rate in Heart Failure and Reduced Ejection Fraction. AB - BACKGROUND: Heart failure with reduced ejection fraction (HFrEF) is a progressive, chronic, and burdensome cardiovascular condition. It is associated with limiting symptoms, such as dyspnea and fatigue; a decline in functional capacity; and premature mortality and hospitalization. In heart failure (HF) management, heart rate is commonly assessed yet frequently overlooked as a modifiable risk factor and a predictor of mortality. An elevated heart rate increases myocardial demand and decreases diastolic filling time. Hospitalized patients with HFrEF who have a heart rate greater than 70 beats per minute at discharge were found to have lower survival rates. PURPOSE: The aims of this study were to review the association between heart rate and clinical outcome in patients with HF and discuss the contribution of heart rate to HFrEF pathophysiology. Medications currently used to modulate heart rate in patients with HF are also reviewed. CONCLUSIONS: In patients with HFrEF, an elevated heart rate contributes to HF progression, and it is both a prognostic and modifiable risk factor. Medications such as an evidence-based beta-blockers, digoxin, and ivabradine are recommended for modulation of heart rate in patients with HFrEF. CLINICAL IMPLICATIONS: Nurses play a pivotal role in managing HFrEF and must understand current evidence of the pathophysiology of elevated heart rate, risks, and management strategies. Early recognition of elevated heart rate and application of guideline-directed pharmacologic treatment for patients with HFrEF and an elevated heart rate remains key to improving patient outcomes. PMID- 29621055 TI - LINC00673 silencing inhibits cell migration and invasion by suppressing PI3K/AKT signaling in glioma. AB - LINC00673 is an oncogene that plays a key role in various cancer types. However, the role of LINC00673 in glioma remains unclear. In this study, we examined its expression in glioma cells by quantitative real-time PCR and found higher expression of LINC00673 in glioma cells compared with that in normal human astrocytes. Furthermore, LINC00673 silencing inhibited the migration and invasion of U87MG and U118MG cells, phosphoinositide 3-kinase (PI3K) expression, and AKT phosphorylation. Moreover, activation of the PI3K/AKT signaling pathway by insulin-like Growth factor-1 abolished the inhibitory effect of LINC00673 silencing on the migration and invasion of U87MG and U118MG cells. In conclusion, LINC00673 silencing inhibits glioma cell migration and invasion by suppressing the PI3K/AKT signaling pathway, and it is a potential therapeutic target for the treatment of metastatic glioma. PMID- 29621056 TI - Associations Between Ambient Nitrogen Dioxide and Daily Cause-specific Mortality: Evidence from 272 Chinese Cities. AB - BACKGROUND: There has been a long history of debate regarding whether ambient nitrogen dioxide (NO2) directly affects human health. METHODS: We conducted a nationwide time-series analysis in 272 major Chinese cities (2013-2015) to evaluate the associations between short-term exposure to NO2 and cause-specific mortality. We used the overdispersed generalized linear model together with the Bayesian hierarchical model to estimate the associations between NO2 and mortality at the national and regional levels. We examined two-pollutant models with adjustment of fine particles, sulfur dioxide, carbon monoxide, and ozone to evaluate robustness for the effects of NO2. RESULTS: At the national-average level, we observed linear and positive associations between NO2 and mortality from all causes and main cardiorespiratory diseases. A 10 MUg/m increase in 2-day average concentrations of NO2 would lead to increments of 0.9% (95% posterial interval [PI], 0.7%, 1.1%) in mortality from total nonaccidental causes, 0.9% (95% PI, 0.7%, 1.2%) from total cardiovascular disease, 1.4% (95% PI, 0.8%, 2.0%) from hypertension, 0.9% (95% PI, 0.6%, 1.2%) from coronary heart disease, 0.9% (95% PI, 0.5%, 1.2%) from stroke, 1.2% (95% PI, 0.9%, 1.5%) from total respiratory diseases, and 1.6% (95% PI, 1.1%, 2.0%) from chronic obstructive pulmonary disease. There were no appreciable differences in estimates from single pollutant and two-pollutant models. The associations were stronger in the south of China, in the elderly, and in females. CONCLUSIONS: The present study provided robust epidemiologic evidence of associations between day-to-day NO2 and mortality from total natural causes and main cardiorespiratory diseases that might be independent of other criteria air pollutants. PMID- 29621058 TI - Can Survival Bias Explain the Age Attenuation of Racial Inequalities in Stroke Incidence?: A Simulation Study. AB - BACKGROUND: In middle age, stroke incidence is higher among black than white Americans. For unknown reasons, this inequality decreases and reverses with age. We conducted simulations to evaluate whether selective survival could account for observed age patterning of black-white stroke inequalities. METHODS: We simulated birth cohorts of 20,000 blacks and 20,000 whites with survival distributions based on US life tables for the 1919-1921 birth cohort. We generated stroke incidence rates for ages 45-94 years using Reasons for Geographic and Racial Disparities in Stroke (REGARDS) study rates for whites and setting the effect of black race on stroke to incidence rate difference (IRD) = 20/10,000 person-years at all ages, the inequality observed at younger ages in REGARDS. We compared observed age-specific stroke incidence across scenarios, varying effects of U, representing unobserved factors influencing mortality and stroke risk. RESULTS: Despite a constant adverse effect of black race on stroke risk, the observed black-white inequality in stroke incidence attenuated at older age. When the hazard ratio for U on stroke was 1.5 for both blacks and whites, but U only directly influenced mortality for blacks (hazard ratio for U on mortality =1.5 for blacks; 1.0 for whites), stroke incidence rates in late life were lower among blacks (average observed IRD = -43/10,000 person-years at ages 85-94 years versus causal IRD = 20/10,000 person-years) and mirrored patterns observed in REGARDS. CONCLUSIONS: A relatively moderate unmeasured common cause of stroke and survival could fully account for observed age attenuation of racial inequalities in stroke. PMID- 29621059 TI - Presence of Hepatitis B Surface Antibody in Addition to Hepatitis B Core Antibody Confers Protection Against Hepatitis B Virus Infection in Hepatitis B Surface Antigen-negative Patients Undergoing Kidney Transplantation. AB - BACKGROUND: The American Gastroenterological Association and European Association for the Study of the Liver recommend that hepatitis B surface antigen (HBsAg) negative and hepatitis B core antibody (anti-HBc)-positive patients who receive immunosuppression should be monitored for hepatitis B virus (HBV) infection regardless of hepatitis B surface antibody (anti-HBs) status. However, anti-HBs may provide protection against infection. To investigate whether the presence of anti-HBs in addition to anti-HBc confers protection, we classified HBsAg(-) kidney transplantation (KT) patients into 4 groups according to anti-HBc and anti HBs status, and compared the HBV infection rate between the anti-HBc(+)anti HBs(+) group and the other 3 groups. METHODS: In this single-center retrospective study, we classified 1959 patients into 4 groups: anti-HBc(-)anti-HBs(-) (n = 356), anti-HBc(-)anti-HBs(+) (n = 652), anti-HBc(+)anti-HBs(-) (n = 142), and anti-HBc(+)anti-HBs(+) (n = 809). RESULTS: Hepatitis B virus infection was noted in 31 (1.6%) patients after KT. There was a significant difference in HBV infection rate between anti-HBc(+)anti-HBs(+) (1.2%) and anti-HBc(+)anti-HBs(-) (5.6%) (P < 0.001), but not between anti-HBc(+)anti-HBs(+) and anti-HBc(-)anti HBs(-) (1.1%) or anti-HBc(-)anti-HBs(+) (1.4%). There was a significant difference in HBV infection rate according to anti-HBs titer, but no difference according to the donor viral profile. Hepatic failure occurred in 1 anti HBc(+)anti-HBs(-) patient and 1 anti-HBc(+)anti-HBs(+) patient, both of whom died. Hepatocellular carcinoma was noted in 4 anti-HBc(-) patients, but not in anti-HBc(+) patients. CONCLUSIONS: The presence of anti-HBs confers protection against HBV infection. We recommend monitoring for HBV infection after KT in HBsAg(-) anti-HBc(+) anti-HBs(-) patients, but not in HBsAg(-) anti-HBc(+) anti HBs(+) patients. PMID- 29621057 TI - Controlling for Frailty in Pharmacoepidemiologic Studies of Older Adults: Validation of an Existing Medicare Claims-based Algorithm. AB - BACKGROUND: Frailty is a geriatric syndrome characterized by weakness and weight loss and is associated with adverse health outcomes. It is often an unmeasured confounder in pharmacoepidemiologic and comparative effectiveness studies using administrative claims data. METHODS: Among the Atherosclerosis Risk in Communities (ARIC) Study Visit 5 participants (2011-2013; n = 3,146), we conducted a validation study to compare a Medicare claims-based algorithm of dependency in activities of daily living (or dependency) developed as a proxy for frailty with a reference standard measure of phenotypic frailty. We applied the algorithm to the ARIC participants' claims data to generate a predicted probability of dependency. Using the claims-based algorithm, we estimated the C statistic for predicting phenotypic frailty. We further categorized participants by their predicted probability of dependency (<5%, 5% to <20%, and >=20%) and estimated associations with difficulties in physical abilities, falls, and mortality. RESULTS: The claims-based algorithm showed good discrimination of phenotypic frailty (C-statistic = 0.71; 95% confidence interval [CI] = 0.67, 0.74). Participants classified with a high predicted probability of dependency (>=20%) had higher prevalence of falls and difficulty in physical ability, and a greater risk of 1-year all-cause mortality (hazard ratio = 5.7 [95% CI = 2.5, 13]) than participants classified with a low predicted probability (<5%). Sensitivity and specificity varied across predicted probability of dependency thresholds. CONCLUSIONS: The Medicare claims-based algorithm showed good discrimination of phenotypic frailty and high predictive ability with adverse health outcomes. This algorithm can be used in future Medicare claims analyses to reduce confounding by frailty and improve study validity. PMID- 29621061 TI - Spontaneous Regression of Diffuse Periosteal Melanotic Neuroectodermal Tumor of Infancy in the Tibia, With 13-Year Follow-up. AB - Melanotic neuroectodermal tumor of infancy (MNTI) is a rare entity primarily affecting the craniofacial bones during the first year of life, with only 5 reported cases involving peripheral long bones. We herein present a case of MNTI in the tibia of an infant, with a somewhat atypical presentation, and a noteworthy clinical course characterized by progressive spontaneous resolution without therapy, thus sparing the child the trauma of amputation. There is no evidence of active residual or recurrent disease with 13-year follow-up. To the best of our knowledge, essentially all reported cases of MNTI have received empirical treatment, some at the price of mutilating surgery or fatal chemotherapy. We propose that the necessity of aggressive treatment be evaluated on a case-by-case basis, especially in patients with diffuse periosteal involvement, as in this patient. A trial of watchful waiting can be considered when treatment would involve substantial morbidity or risk of complications. PMID- 29621060 TI - Prediction of the Development of Persistent Massive Ascites After Living Donor Liver Transplantation Using a Perioperative Risk Score. AB - BACKGROUND: Persistent massive ascites (PMAS) longer than 14 days after living donor liver transplantation is not uncommon and associated with worse outcome. A predictive risk scoring system was constructed after analysis of recipient, graft, and surgery-related factors. METHODS: We retrospectively reviewed adult living donor liver transplantation recipients from 2005 to 2011 after excluding cases that experienced any intervention for perioperative vascular-related events. Two groups were identified, PMAS and non-PMAS. The score was constructed from significant factors using weighted odds ratios (OR). RESULTS: The study population included 439 recipients. Persistent massive ascites was evident in 74 cases (17%). Five significant risk predictors were identified in multivariate analysis: pretransplant serum creatinine greater than 1.5 mg/dL (OR, 5.693; weighted OR, 2), recipient spleen to graft volume ratio greater than 1.3 (OR, 4.466; weighted OR, 2), left lobe graft (OR, 3.196; weighted OR, 1), more than 1000 mL ascites at laparotomy (OR, 2.541; weighted OR, 1), and graft recipient weight ratio less than 0.8 (OR, 2.419; weighted OR, 1). The clinical scoring system was constructed and ranged from 0 to 7. Receiver operating characteristic analysis showed an area under the curve (0.778, P < 0.001). Internal validation of the score showed an area under the curve of 0.783. The 5- and 10-year survival rates for the non-PMAS versus the PMAS groups were 89% and 84% versus 81% and 48%, respectively (P = 0.001). CONCLUSIONS: The PMAS score is a predictive pretransplant clinical tool. A Clinical cutoff score of 4 might be decision changing. Pretransplant correction of renal functions, deciding to harvest a large graft and/or consideration of splenic artery embolization could reduce the risk of PMAS. PMID- 29621062 TI - Radiation-induced Cataracts in Children With Brain Tumors Receiving Craniospinal Irradiation. AB - Radiation is a well-known cause of the development of cataracts. For children with brain tumors, craniospinal irradiation (CSI) would be expected to result in a significant risk of cataract development. We reviewed the incidence of cataracts in children with brain tumors who received CSI at our institution. Of 45 children who received CSI and had ophthalmologic examinations, 13 developed cataracts. The median time to develop cataracts was 27.6 months. Seven children underwent surgery for cataract. Given this high incidence of cataracts, we suggest routine eye examinations for all children receiving CSI. PMID- 29621063 TI - Posttransplant Cyclophosphamide for HLA-haploidentical Transplantation in Patients With Mucopolysaccharidosis. AB - We successfully used a haploidentical transplantation protocol with posttransplant cyclophosphamide (CY) (50 mg/kg/d on days +3 and +4) for in vivo T cell depletion in patients with mucopolysaccharidosis using reduced-intensive conditioning regimens, followed by a busulfan-based conditioning regimen, which included busulfan (12 to 16 mg/kg) and fludarabine(150 to 200 mg/m)+rabbit antihuman thymocyte globulin (7.5 to 10 mg/kg) as a conditioning regimen. Cyclosporine or tacrolimus, methotrexate, mycophenolate mofetil, and methylprednisolone were administered to prevent graft-versus-host disease (GVHD). After follow-up for a median period of 1.5 years, all 8 patients without preexisting severe comorbidities and early transplant referrals are alive, with 100% donor chimerism and excellent performance status. Only 1 patient developed chronic GVHD(II). We conclude that posttransplant CY is effective in vivo for T cell depletion to promote full donor engraftment in patients with mucopolysaccharidosis. In addition, with posttransplant CY, the procedure reduced the rate of GVHD and the cost of transplant and improved the patients' quality of life. PMID- 29621065 TI - A Rare Case of Pediatric Bone Precursor B-Cell Lymphoma Presenting With Multiple Fractures. PMID- 29621064 TI - Muscle Strength, Power, and Torque Deficits in Children With Type SS Sickle Cell Disease. AB - In African-American children aged 5 to 17 years with and without type SS sickle cell disease (SCD-SS), dominant hand maximal handgrip strength, peak power, and plantar flexion isometric maximal voluntary contraction (MVC) torque were compared with adjustments for body size and composition. Children with SCD-SS (n=21; age, 11+/-1 y) compared with healthy control children (n=23; 10+/-1 y) did not differ by age, sex, or maturation stage, but had significantly lower Z scores for height, weight, body mass index, arm circumference, upper arm muscle area, and lean mass-for-height. Children with SCD-SS had significantly lower unadjusted handgrip strength (16+/-2 vs. 23+/-2 kg, P<0.01), peak power (1054+/-107 vs. 1488+/-169 W, P<0.04) and MVC torques at 2 angles (10 degrees: 27+/-3 vs. 42+/-5 Nm; 20 degrees: 21+/-3 vs. 34+/-4 Nm; all P<0.05). Performance decrements persisted when handgrip strength was adjusted for lean body mass and fat mass explaining 66% of the variance; peak power adjusted for age, lean body mass, fat mass, and height explaining 91% of the variance; and the highest MVC torque (10 degree angle) adjusted for left leg length, lean mass-for-height, and fat mass for-height Z scores explaining 65% of the variance. This suggests additional factors contribute to the attenuated anaerobic performance. PMID- 29621066 TI - Electrical stimulation-based renal nerve mapping exacerbates ventricular arrhythmias during acute myocardial ischaemia. AB - OBJECTIVE: Blood pressure elevation in response to transient renal nerve stimulation (RNS) has been used to determine the ablation target and endpoint of renal denervation. This study aimed to evaluate the safety of transient RNS in canines with normal or ischaemic hearts. METHODS: In ten normal (Group 1) and six healed myocardial infarction (HMI) (Group 2) canines, a large-tip catheter was inserted into the left or right renal artery to perform transient RNS. The left stellate ganglion neural activity (LSGNA) and ventricular electrophysiological parameters were measured at baseline and during transient RNS. In another 20 acute myocardial infarction (AMI) canines, RNS (Group 3, n = 10) or sham RNS (Group 4, n = 10) was intermittently (1 min ON and 4 min OFF) performed for 1 h following AMI induction. The LSGNA and AMI-induced ventricular arrhythmias were analysed. RESULTS: In normal and HMI canines, although transient RNS significantly increased the LSGNA and facilitated the action potential duration (APD) alternans, it did not induce any ventricular arrhythmias and did not change the ventricular effective refractory period, APD or maximum slope of the APD restitution curve. In AMI canines, transient RNS significantly exacerbated LSG activation and promoted the incidence of ventricular arrhythmias. CONCLUSION: Transient RNS did not increase the risk of ventricular arrhythmias in normal or HMI hearts, but it significantly promoted the occurrence of ventricular arrhythmias in AMI hearts. Therefore, electrical stimulation-based renal nerve mapping may be unsafe in AMI patients and in patients with a high risk for malignant ventricular arrhythmias. PMID- 29621067 TI - Prevalence, awareness, treatment and control of hypertension in Nepal: data from nationally representative population-based cross-sectional study. AB - BACKGROUND: Previous studies in Nepal noted an alarming increase in prevalence of hypertension. However, these studies were geographically sparse and coverage of population, mostly limited to single site. The current study fills this gap by examining the current status of prevalence, awareness, treatment and control of hypertension, using recently collected population-based data. METHODS: We used the Nepal Demographic Health Survey 2016 data. Sample selection was based on stratified two-stage cluster sampling in rural areas and three stages in urban areas. Blood pressure was measured in all women and men aged 15 and above. RESULTS: A total of 13 598 participants: 5593 men and 8005 women aged 15-69 had their blood pressures measured. Overall, 18% (95% CI 16.7-19.2) of the participants aged 15-69 years were hypertensive. Prevalence of hypertension was more among men (22%; 95% CI 21.1-23.5), aged 45-69 years (34%), with no formal education (22%), richest quintile (25%), formerly/ever married (32%), urban dwellers (19%), residents of Province 4 (24%), residents of hills (21%), and obese (41.6%). Among the total hypertensive individuals, only 38% were aware of their hypertensive status and 18% were taking antihypertensive medication. Only half of the hypertensive participants on treatment (52%) had their blood pressure under control. CONCLUSION: This nationally representative survey data showed that the prevalence of hypertension is high in Nepal, whereas its awareness, treatment and control rates are low at entire population level. PMID- 29621068 TI - Late life socioeconomic status and hypertension in an aging cohort: the Atherosclerosis Risk in Communities Study. AB - OBJECTIVE: To investigate the association between individual and area-level socioeconomic status and hypertension risk among individuals later in life. METHODS: We used Cox proportional hazards models to examine the association of socioeconomic status with incident hypertension using race-specific neighborhood socioeconomic status, median household income, and education among 3372 participants (mean age, 61 years) from the Atherosclerosis Risk in Communities Study at Visit 4 (1996-1998). Incident hypertension was defined as self-reported diagnosis or reported use of antihypertensive medications. RESULTS: Over a median follow-up time of 9.4 years, there were 1874 new cases of hypertension (62.1 per 1000 person-years). Overall, being in high as compared with low socioeconomic status categories was associated with a lower risk of developing hypertension in late life, with hazard ratios (95% confidence intervals) of 0.87 (0.77-0.98) for high neighborhood socioeconomic status tertile, 0.79 (0.69-0.90) for high individual income, and 0.75 (0.63-0.89) for college education after adjustment for traditional risk factors. These findings were consistent and robust whenever accounting for competing risks of all-cause mortality. No significant interactions by race and age (dichotomized at age 65) were observed. CONCLUSION: Among participants free of hypertension in midlife, high neighborhood and individual socioeconomic status are associated with a decreased risk of incident hypertension. Our findings support population-level interventions, such as blood pressure screening at senior centers and faith-based organizations, that are tailored to shift the distribution of blood pressure and reduce hypertension health inequalities among older adults. PMID- 29621069 TI - Highlights of the issue. PMID- 29621070 TI - Blood pressure in acute ischemic stroke: challenges in trial interpretation and clinical management: position of the ESH Working Group on Hypertension and the Brain. AB - : Altered blood pressure (BP) is a common phenomenon in acute ischemic stroke (AIS), with high BP being the most frequent scenario. The pathophysiology of BP changes in AIS is complex and only partially understood. The available evidence indicates that extremely high BP during AIS is associated with a poor outcome. Importantly, the observed relationship between BP and stroke outcome may or may not be causally related. Higher baseline BPs in focal cerebral ischemia may indicate preexisting hypertension, but may also be an effect of both nonspecific and stroke-related factors. Although antihypertensive therapy effectively reduces BP in AIS, studies on early BP lowering in AIS produce conflicting results in terms of functional outcome and mortality. Systematic reviews on BP management in AIS did not result in clinically applicable conclusions in general. However, the investigation on the effect of BP and its alterations in AIS are hampered by various important methodological issues. This position statement was prepared by a group of experts from the European Society of Hypertension and invited neurologists to discuss the main reasons for the discrepancies in the current evidence on the prognosis and treatment of altered BP in AIS which should be taken into account in future studies. PMID- 29621072 TI - A Comprehensive Onboarding and Orientation Plan for Neurocritical Care Advanced Practice Providers. AB - BACKGROUND: As the role of advanced practice providers (APPs) expands to include increasingly complex patient care within the intensive care unit, the educational needs of these providers must also be expanded. An onboarding process was designed for APPs in the neurocritical care service line. METHODS: Onboarding for new APPs revolved around 5 specific areas: candidate selection, proctor assignment, 3-phased orientation process, remediation, and mentorship. To ensure effective training for APPs, using the most time-conscious approach, the backbone of the process is a structured curriculum. This was developed and integrated within the standard orientation and onboarding process. The curriculum design incorporated measurable learning goals, objective assessments of phased goal achievements, and opportunities for remediation. RESULTS: The neurocritical care service implemented an onboarding process in 2014. Four APPs (3 nurse practitioners and 1 physician assistant) were employed by the department before the implementation of the orientation program. The length of employment ranged from 1 to 4 years. Lack of clinical knowledge and/or sufficient training was cited as reasons for departure from the position in 2 of the 4 APPs, as either self-expression or peer evaluation. Since implementation of this program, 12 APPs have completed the program, of which 10 remain within the division, creating an 83% retention rate. DISCUSSION: The onboarding process, including a 3-phased, structured orientation plan for neurocritical care, has increased APP retention since its implementation. The educational model, along with proctoring and mentorship, has improved clinical knowledge and increased nurse practitioner retention. A larger-scale study would help to support the validity of this onboarding process. PMID- 29621071 TI - Back to Basics: Adherence With Guidelines for Glucose and Temperature Control in an American Comprehensive Stroke Center Sample. AB - BACKGROUND: Variance from guideline-directed care for glucose and temperature control remains unknown in the United States at a time when priorities have shifted to ensure rapid diagnosis and treatment of acute stroke patients. However, protocol-driven nursing surveillance for control of hyperglycemia and hyperthermia has been shown to improve patient outcomes. METHODS: We conducted an observational pilot study to assess compliance with American guidelines for glucose and temperature control and association with discharge outcomes in consecutive acute stroke patients admitted to 5 US comprehensive stroke centers. Data for the first 5 days of stroke admission were collected from electronic medical records and entered and analyzed in SPSS using descriptive statistics, Mann-Whitney U test, Student t tests, and logistic regression. RESULTS: A total of 1669 consecutive glucose and 3782 consecutive temperature measurements were taken from a sample of 235 acute stroke patients; the sample was 87% ischemic and 13% intracerebral hemorrhage. Poor glucose control was found in 33% of patients, and the most frequent control method ordered (35%) was regular insulin sliding scale without basal dosing. Poor temperature control was noted in 10%, and 39% did not have temperature recorded in the emergency department. Lower admission National Institutes of Health Stroke Scale score and well-controlled glucose were independent predictors of favorable outcome (discharge modified Rankin Scale score, 0-2) in reperfusion patients. CONCLUSION: Glucose and temperature control may be overlooked in this era of rapid stroke diagnosis and treatment. Acute stroke nurses are well positioned to assume leadership of glucose and temperature monitoring and treatment. PMID- 29621074 TI - Short Implants: Analysis of 69 Implants Loaded in Mandible Compared With Longer Implants. AB - OBJECTIVES: In the last decade, several studies have reported that short implants achieve excellent results with a 2-stage technique. According to the literature, short dental implants have often been used for the replacement of teeth. METHODS AND MATERIALS: A total of 69 short implants (Bone System) were inserted in the posterior mandibular area (41 in males, 28 in females, with a median age of 55 years and an age ranging from 41 to 70 years). RESULTS: Mean loss of bone levels at 1 year was 0.20 +/- 0.03 mm, mean changes in bone levels for periods longer than 1 year was 0.07 mm. Survival rate (SRR) of short implants was 98.5%. CONCLUSION: This study showed no complications in short implants and they could represent predictable solutions for the rehabilitation of atrophic posterior mandible to avoid complementary surgical procedures. PMID- 29621073 TI - Normalization of Speech Processing After Whole-Vault Cranioplasty in Sagittal Synostosis. AB - BACKGROUND: Neurocognitive studies have found impairments in language-related abilities in nonsyndromic craniosynostosis, highlighting clinical importance of early language processing. In this study, neural response to speech sounds in infants with nonsyndromic sagittal craniosynostosis (NSC) is compared, preoperatively and postoperatively, using event-related potentials (ERPs) to objectively characterize development in language processing. METHODS: Electroencephalogram was recorded while 39 infants (12 NSC and 27 controls; ages 73-283 days) listened to the Hindi dental /(Equation is included in full-text article.)a/ and retroflex /da/ phonemes (non-native phonemic discrimination task). The mismatch negativity (MMN) ERP was extracted as the peak amplitude of the largest negative deflection in the difference wave over 80 to 300 milliseconds poststimulus. Differences in MMN were analyzed using repeated measures analysis of variance. RESULTS: The MMN amplitude was attenuated in the infants with NSC preoperatively compared with controls (P = 0.047). A significant region by group interaction (P = 0.045) was observed, and infants with NSC displayed attenuated MMN in the frontal electrodes compared with controls (P = 0.010). Comparing the preoperative and postoperative MMN, a time by group interaction trend (P = 0.070) was observed. Pair-wise comparisons showed a trend for increase in MMN amplitude from preoperatively to postoperatively in the infants with NSC (P = 0.059). At the postoperative time point, infants with NSC showed no significant difference in MMN from controls (P = 0.344). CONCLUSION: Infants with NSC demonstrated atypical neural response to language preoperatively. After undergoing surgery, infants with NSC showed increased MMN amplitude which was not significantly different from controls. These findings support the idea that whole vault cranioplasty may improve neurocognitive outcomes in sagittal craniosynostosis. PMID- 29621075 TI - Comparison of Incidence and Severity of Chronic Postsurgical Pain Following Ear Surgery. AB - OBJECTIVES: Literature review shows a limited number of studies investigating chronic pain following ear surgeries. The effect of mastoidectomy on chronic postsurgical pain, however, has never been investigated. The present study investigates not only the incidence and severity of chronic pain following ear surgeries with and without mastoidectomy, but also predisposing diseases for pain. PATIENTS AND METHODS: The study was performed in a total of 150 patients who underwent tympanoplasty or tympanomastoidectomy through a retroauricular incision in a single tertiary health care center. During the routine postoperative 3rd-month examination, the patients were questioned for the presence and severity of chronic pain, as well as the diseases that might predispose the pain. RESULTS: The difference between the visual analog scale scores of the groups was not statistically significant. Comparison of pain character revealed that neuropathic pain is more prevalent in both the groups. Evaluating the relationship between concomitant diseases and chronic pain, it was observed that migraine, cervical pathology, and acute postsurgical pain were closely associated with chronic pain. CONCLUSION: It was demonstrated that mastoidectomy does not pose an additional risk for chronic postsurgical pain. However, patients with migraine, cervical pathology, and acute postsurgical pain are at risk for chronic postsurgical pain. PMID- 29621076 TI - Multiple Intracranial Cavernous Angiomas With a Trigonal Cavernous Angioma Mimicking Glioma. AB - Intracranial cavernous angiomas (CAs) are hamartomatous vascular malformations consisting of thin-walled vascular channels located within the brain, but typically lacking intervening neural parenchyma, large feeding arteries, or draining veins. The CAs occurring in the ventricular system are rare, with an incidence of 2.5% to 10.3% of the intracranial CAs, and those arising from the trigone of the lateral ventricle are even rarer. Till now, there are <20 patients with trigonal CAs have been reported in the English literature. In this study, the authors describe an extremely rare case of multiple intracranial CAs with a trigonal CA mimicking glioma. Furthermore, they also discuss the characteristic aspects of symptoms, radiologic findings, diagnosis, and treatment of this benign lesion. PMID- 29621077 TI - Modified Rotational Anterior Segmental Osteotomy for Prevention of Common Complication (Aged Appearance). AB - Although anterior segmental osteotomy (ASO) is powerful procedures in treating the patient who has bimaxillary dentoalveolar protrusion, there is significant change in all soft and hard tissue parameters. Soft tissue changes in response to ASO can have a deleterious effect of an aged appearance. To prevent this aged appearance, the authors tried to rotate the maxillary anterior segment rather than simply posteriorly translating the segments. The application of a clockwise pivot rotation method during ASO can prevent overcorrection by controlling the degree of setback of the piriform aperture, and it can also affect convexity of the facial profile. PMID- 29621078 TI - A Patient With Severe Lower Face Degloving Injury. AB - Avulsions of mandible are among the most devastating lesions observed in cranio maxillofacial traumas. They present an important health problem because of the high risk of morbidity related to deformities that cause functional limitations and esthetic changes. The avulsions commonly result from high-energy effects, which cause complete or partial separation of the mandibular bone of the face. As a result of the intense aggression, the skin and subcutaneous tissues of the bone are usually removed, affecting muscles, fascia, blood vessels, and the surrounding nerves. This article aimed to present a case of partial avulsion of mandible caused by car accident. Here, we emphasize the importance of correctly performing patient stabilization and maintenance of the airways, damage control, and facial reconstruction. Finally, we proceeded with a literature review to discuss standard protocols and controversies in the treatment of these lesions. PMID- 29621080 TI - Robbing Peter to Pay Paul. PMID- 29621079 TI - A Step-By-Step Technique for the Piezosurgical Removal of Fractured Implants. AB - With the increasing popularity of dental implants, the removal of fractured implants has become a major challenge for clinicians. Several tools can be used for the removal of osseointegrated implants; however, few of these have the characteristics of easy control, selective cutting, and rapid healing. In this study, the authors describe a step-by-step technique for the removal of osseointegrated fractured implants via multiple peri-implant osteotomies performed using a piezoelectric device and appropriate inserts. All patients ended with primary wound closure without any soft tissue dehiscence and no healing problems during the postoperative period. As the use of ultrasonic inserts enables precise and selective cuts, piezosurgical implant removal is an attractive alternative to trephine burs or rotary drills. PMID- 29621081 TI - Odontogenic Keratocysts as First Manifestation of Nevoid Basal Cell Carcinoma Syndrome: Surgical Management and Immunohistochemical Analysis. AB - Nevoid Basal Cell Carcinoma Syndrome (NBCCS), also known as Gorlin syndrome, is a rare autosomal dominant disorder, with no gender predilection. Individuals with NBCCS are commonly diagnosed between 17 and 35 years old and can present multiple basal cell carcinomas scattered throughout the body, presence of recurrent and early-onset odontogenic keratocysts (OKCs) and skeletal abnormalities. This article describes a case of a 13-year-old white boy who referred complaining of facial asymmetry. Extraoral examination revealed volumetric increase displacing the nasal ala from the right side and extended to the zygomatic bone. The intraoral evaluation showed mixed dentition with moderate degree of malocclusion. In addition, bilateral vestibular fornix swelling was observed in the upper canine region. An increase in volume was also detected on the hard palate on the right side. Computed tomography revealed multiple hypodense lesions with cystic appearance. The aspiration was positive, with a yellowish aspirate of serous consistency of all lesions. Given the numerous lesions, it was decided to decompress them for posterior enucleation procedures. In addition to other manifestations, the patient was diagnosed with NBCCS. Although common, the occurrence of OKCs in pediatric patients, especially in multiple lesions, is highly indicative of NBCCS, and its investigation should be considered, even in the absence of other signs of this syndrome. Synchronous decompression was satisfactory and can be used in similar cases of multiple cystic lesions. PMID- 29621082 TI - Thornwaldt Cyst. AB - Thornwaldt cyst (Tc) is a benign mass, usually localized in the median plan of the nasopharynx. It is generate from permanent notochord remainings. The pharyngeal bursa-being an embryological residual-occurs in 3% of healthy adults. Closing of the orifice of a nasopharyngeal bursa results in the occurrence of Tc. When the Tc become infected or inflamed, causing to signs. The general indications for radiologic study in patients are nasopharyngeal symptoms, headache, seizures, and dizziness. Computed tomography is less effective than magnetic resonance imaging in the detection and characterization of Tc. On histopathologic study, the walls of Tc are seen to be infiltrated vaguely by lymphocytes and absent lymph follicles. Asymptomatic patients do not necessitate surgery, whereas symptomatic cysts need surgical treatment by a transnasal or transoral access. Marsupialization is the method of option to avoid recurrence. This review provides fundamental knowledge on Tc from an objective perspective. PMID- 29621083 TI - Factors Associated With the Complexity of Facial Trauma. AB - INTRODUCTION: Facial fractures have their incidence, etiology, clinical presentation, and features influenced by variables such as economic, cultural, and demographic factors. A large number of these fractures require simple or more complex approaches, and it becomes important to understand their clinical and epidemiological profile and factors associated with the fracture event and surgical indication. OBJECTIVE: The objective of this research is to analyze the clinical and epidemiological profile of surgical fractures and their associations with causal factors such as alcohol consumption, day of the incident, and nonuse of helmet for motorcycle accidents. METHOD: A retrospective study was conducted with collection of data from medical records of patients operated for facial fractures at the Hospital Regional of Cariri, state of Ceara, the Northeast of Brazil. Records from 2012 to 2014 were acquired highlighting sex, age, occupation, etiology, anatomical sites of fractures, and surgeries of varying complexities for single or multiple fractures. The day of the event, report or signs of alcohol consumption, and the use of helmets in motorcycle accidents were named associated factors. RESULTS: As a result the authors had a total of 624 cases of surgical facial fractures. Out of these, 546 (87.5%) were male and the majority of them presented between 20 and 30 years of age (40.5%). It was also observed that as an etiological factor motorcycle accidents led to more cases of surgical facial fractures, with 357 cases (62.1%), followed by physical aggression with 72 cases (12.5%). CONCLUSIONS: It can be concluded that there is a high prevalence of surgical facial fractures in male patients between 20 and 30 years of age, caused by motorcycle accidents, and that there was a strong association between the consumption of alcohol, failure to wear a helmet, and the presence of surgical facial multiple fractures. PMID- 29621084 TI - An Honorable Scar on the Face: A Scar Worthy of Satisfaction. PMID- 29621085 TI - Primary and Secondary Stability of Single Short Implants. AB - PURPOSE: This prospective cohort study assessed the effect of bone quality on the primary and secondary stability of single short implants placed in the posterior region. MATERIALS AND METHODS: A total of 39 short implants (4.1 * 6-mm long) were placed in the posterior region of the maxilla or mandible in 18 patients. Bone quality was classified into type I, II, III, or IV as assessed intrasurgically. Primary implant stability was measured with insertion torque, damping capacity (PTV values), and resonance frequency analysis (ISQ values). Secondary stability was measured by ISQ and PTV at abutment installation. Data were analyzed by using repeated-measures ANOVA and Tukey's test, Kruskall-Wallis test, and Spearman correlation tests. RESULTS: Implants placed in bone type IV had significant lower insertion torque and ISQ values as well as higher PTV values than in bone types I to II (P < 0.05). The mean ISQ values were higher at abutment installation than at implant placement (P < 0.05), regardless the bone type. The assessment methods of implant stability showed a moderate correlation. CONCLUSIONS: Bone quality influences both the primary and secondary stability of single short implants in the posterior region. PMID- 29621086 TI - Primary Alveolar Echinococcosis Presenting with Simultaneous Cerebral and Craniofacial Involvement. AB - Alveolar echinococcosis (AE) is an important parasitic infestation caused by the larval stage of the Echinococcus multilocularis. Turkey is one of the countries occurred endemic of the disease. The disease primarily affects the liver. Cerebral and craniofacial involvements are very rare. Here the authors report a 46-year-old woman with simultaneous cerebral and craniofacial involvement of E. multilocularis. Although primary AE lesions with simultaneous cerebral and craniofacial involvement are exceedingly rare, radiologist must suspect from other unusual involvement such as craniofacial and muscular location in patients with cerebral AE. PMID- 29621087 TI - Comparison of Osseointegration of Five Different Surfaced Titanium Implants. AB - The topography, chemical features, surface charge, and hydrophilic nature of titanium implant surfaces are crucial factors for successful osseointegration. This study aimed to investigate the bone implant contact (BIC) ratio of titanium dental implants with different surface modification techniques using the rat femoral bone model. Sandblasted and acid washed (SL-AW), sandblasted (SL), resorbable blast material (RBM), microarc (MA), and sandblasted and microarc (SL MA) surfaces were compared in this study. Forty male Sprague-Dawley rats were used in this study. The rats were divided into 5 equal groups (n = 8), and totally 40 implants were integrated into the right femoral bones of the rats. The rats were sacrificed 12 weeks after the surgical integration of the implants. The implant surface-bone tissue interaction was directly observed by a light microscope, and BIC ratios were measured after the nondecalcified histological procedures. Bone implant contact ratios were determined as follows: SL-AW: 59.26 +/- 14.36%, SL: 66.01 +/- 9.63%, RBM: 63.53 +/- 11.23%, MA: 65.51 +/- 10.3%, and SL-MA: 68.62 +/- 6.6%. No statistically significant differences were found among the 5 different surfaced titanium implant groups (P > 0.05). Our results show that various implant surface modification techniques can provide favorable bone responses to the BIC of dental implants. PMID- 29621088 TI - Treatment of Facial Infantile Hemangioma: Comparative Study Between Propranolol and Ethanolamine Oleate. AB - BACKGROUND: Infantile hemangiomas (IH) are the most common benign vascular tumors in childhood. Approximately 10% to 15% of these tumors require drug or surgical intervention. There are many options for IH treatment, of which propranolol is currently considered the gold standard. This study aims to compare the therapeutic results of 2 distinct drugs (ethanolamine oleate and propranolol), in order to increase the available therapeutic arsenal for the treatment of IH, thereby benefiting a larger group of patients. METHODS: A retrospective observational study was conducted to assess 16 patients with facial IH, allocated into 2 groups (n = 8). All patients met the same inclusion and exclusion criteria. The resulting evolution assessment was based on photographic documentation produced in a professional setting, and was performed before, during, and after treatment. Two measurement scales, photographic-based assessment of infantile hemangioma characteristics, and outcomes were used for comparison between the 2 therapeutic methods. RESULTS: Both assessment methods did not present any significant statistical difference (P > 0.05) at 1 year of follow-up. CONCLUSION: Both therapeutic modalities are able to offer the patient similar and satisfactory final esthetic results. PMID- 29621089 TI - Intense, Instantaneous, and Shooting Pain During Local Anesthesia for Implant Surgery. AB - Administration of local anesthetics is daily routine for most dental practitioners. Normally, the effect is achieved, and no adverse effects are seen. In this article, the authors describe the complications of immediate, intense and shooting pain, numbness, and marked pallor of the cheek, which occurred during infiltration of a local anesthetic in buccal vestibule infiltration. The patients moved suddenly because of pain and marked pallor of the cheek near the root of the nose and lower eyelid pallor was observed. The pain was very short and the injection was performed again after a few minutes. Two patients also reported an alteration of vision or paralysis of the extra-ocular muscles and drooping eyelid due to paralysis of the levator palpebrae superioris muscle and signs of numbness in the infraorbital area on the same side as the anesthesia. While 3 patients were also apprehensive and started to scare with heart palpitations, as they did not understand what was happening. Probably the anesthetic solutions were injected into an intravascular artery and passed from the extraosseous branch of posterior superior alveolar artery through to the infraorbital artery, which could produce the clinical signs observed in the present study. At the same time, the inoculation of anesthetic in the artery could be grounds for legal disputes for the dentist. In fact, in the absence of vascular disease, anomalies documented by the dentist, they would, however, respond to professional liability and be liable for damages caused to the patient. In conclusion, despite the fact that this condition requires no treatment, it could lead to the recognition of clinical signs in patient with injection of local anesthesia into the artery. At the same time, the inoculation of anesthetic in the artery could be grounds for legal disputes for the dentist. PMID- 29621090 TI - Superficial Fascia in the Cheek and the Superficial Musculoaponeurotic System. AB - The origins and validity of the term "superficial musculoaponeurotic system" (SMAS) is reviewed. Gray stated the superficial fascia connects the skin with the deep or aponeurotic fascia and consists of fibro-areolar tissue. Hollinshead wrote superficial fascia exists throughout the body and contains a variable amount of fat. In the head and neck, it encloses voluntary muscles in its deep portion. Skoog found superficial fascia was fixed to the dense, deep fascia by fibrous adhesions in the temporal, preauricular, and parotid area. Mitz stated "There is a 'superficial muscular and aponeurotic system' (SMAS) in the parotid and cheek areas." SMAS has an intimate relationship with the entire superficial fascia of the head and neck and divides the subcutaneous fat into 2 layers. Wassef found a continuous fibromuscular layer at the deep limit of the "subcutis," which corresponded to the "superficial fascia." Nakajima reported the subcutaneous adipofascial tissue was made up of 2 adipofascial layers. Macchi found 2 different fibroadipose connective layers bounded to the laminar connective tissue layer (SMAS). In the cheek, Hwang found horizontal fibrous connective tissues (membranous layer of superficial fascia) divided the superficial fascia into the superficial fatty layer and the deep fatty layer. Recently, Mitz explained the reason for the term SMAS. The "musculo+aponeurotic" component is based on histology of muscle cells, including the risorius, in the same structure to be surgically consistent. The aponeurotic cells belong to the same surgical layer. SMAS is not sufficient to replace the old term "superficial fascia" of the cheek area. PMID- 29621091 TI - Severe Cognitive Impairment Associated With a High Free But Therapeutic Total Concentration of Valproic Acid Due to Hypoalbuminemia in an Older Patient With Bipolar Disorder. PMID- 29621092 TI - A Case of Drug Dependence Syndrome to Baclofen Following High-Dose Therapy. PMID- 29621093 TI - Discriminant Ability, Concurrent Validity, and Responsiveness of PROMIS Health Domains Among Patients With Lumbar Degenerative Disease Undergoing Decompression With or Without Arthrodesis. AB - STUDY DESIGN: A prospective cohort study. OBJECTIVE: The aim of this study was to investigate the ability of Patient-Reported Outcomes Measurement Information System (PROMIS) health domains to discriminate between levels of disease severity and to determine the concurrent validity and responsiveness of PROMIS relative to "legacy" measures. SUMMARY OF BACKGROUND DATA: PROMIS may measure recovery after lumbar spine surgery. Concurrent validity and responsiveness have not been compared with legacy measures in this population. METHODS: We included 231 adults undergoing surgery for lumbar degenerative disease. Discriminant ability of PROMIS was estimated for adjacent categories of disease severity using the Oswestry Disability Index (ODI). Concurrent validity was determined through correlation between preoperative legacy measures and PROMIS. Responsiveness was estimated using distribution-based and anchor-based criteria (change from preoperatively to within 3 months postoperatively) anchored to treatment expectations (North American Spine Society Patient Satisfaction Index) to determine minimal important differences (MIDs). Significance was accepted at P < 0.05. RESULTS: PROMIS discriminated between disease severity levels, with mean differences between adjacent categories of 3 to 8 points. There were strong to very strong correlations between Patient Health Questionnaire-8, Generalized Anxiety Disorder-7, and PROMIS anxiety, depression, fatigue, and sleep disturbance; between ODI and PROMIS fatigue, pain, and physical function; between the 12-Item Short-Form Health Survey physical component and PROMIS pain and physical function; and between the Brief Pain Inventory (BPI) pain interference and PROMIS depression and pain. BPI back pain and leg pain intensity showed weak or no correlation with PROMIS. Distribution-based MIDs ranged from 3.0 to 3.5 points. After incorporating longitudinal anchor-based estimates, final PROMIS MID estimates were anxiety, -4.4; depression, -6.0; fatigue, -5.3; pain, -5.4; physical function, 5.2; satisfaction with participation in social roles, 6.0; and sleep disturbance, -6.5. CONCLUSION: PROMIS discriminated between disease severity levels, demonstrated good concurrent validity, and was responsive to changes after lumbar spine surgery. LEVEL OF EVIDENCE: 2. PMID- 29621094 TI - Is Short Same-Segment Fixation Really Better than Short-Segment Posterior Fixation in the Treatment of Thoracolumbar Fractures? AB - STUDY DESIGN: A retrospective study. OBJECTIVE: This retrospective study assessed whether short same-segment fixation (SSSF) is better than short-segment posterior fixation (SSPF) for reducing thoracolumbar fractures, improving the kyphosis angle, maintaining vertebral height, or reducing the incidence of broken screws. SUMMARY OF BACKGROUND DATA: In clinical practice, single-segment thoracolumbar fractures were then more likely to be treated with SSPF that included pedicle fixation at the level of the fracture (short same-segment fixation, or SSSF). Whether SSSF could really achieve vertebral height recovery, improve the kyphosis, reduce postoperative kyphosis loss, and reduce the incidence of internal fixation failure better than SSPF. METHODS: Patients treated with SSPF or SSSF at our institution during 2006 to 2014 were reviewed. Effects of thoracolumbar fracture reduction, improved kyphosis angle, and maintaining vertebral height were compared between groups. Logistic regression analysis was used to identify factors related to instrumentation breakage and correlation analysis to assess possible relations between loss of correction of the kyphosis angle (LAWAC) and other factors. RESULTS: Altogether, 130 patients were enrolled (53 SSPF, 77 SSSF). SSPF (22F, 31M) group's mean (range) age was 37.7 (16-60) years, and the follow-up was 26.2 (9-120) months. SSSF (27F, 50M) group's mean (range) age was 39.3 (17-61) years, and the follow-up was 23.2 (9-60) months. All patients underwent either internal fixation or screw repair. Immediately postoperatively, restoration after middle vertebral fractures was better in SSSF patients than in SSPF patients (P = 0.003), with no differences in other fracture related factors (P > 0.05). Only LAWAC was significantly associated with instrumentation breakage (P < 0.05). Also, immediately postoperatively, the anterior/posterior vertebral heights ratio was negatively related to LAWAC. CONCLUSION: Pedicle fixation of the fracture did not obtain better recovery of anterior or posterior vertebral heights nor did it improve AWA restoration. There was no significant difference in LAWAC between groups or in the incidence of broken screws. LAWAC may increase the incidence of broken screws. LEVEL OF EVIDENCE: 4. PMID- 29621095 TI - NordiQC Assessments of PAX8 Immunoassays. AB - This paper is number 3 in a series developed through a partnership between ISIMM and NordiQC for the purpose of reporting research assessing the performance characteristics of immunoassays in an external proficiency testing program. PMID- 29621096 TI - PTEN Expression in Mucinous Prostatic Adenocarcinoma, Prostatic Adenocarcinoma With Mucinous Features, and Adjacent Conventional Prostatic Adenocarcinoma: A Multi-institutional Study of 92 Cases. AB - Recent studies have demonstrated that most patients with mucinous prostatic adenocarcinoma may have a better prognosis than those with conventional prostatic adenocarcinoma; however, the mechanism remains unclear. Loss of phosphatase and tensin homolog (PTEN) expression is known to occur in aggressive high-grade prostatic adenocarcinoma, but expression in mucinous prostatic adenocarcinoma has not been well characterized. In this study, we sought to analyze PTEN expression in mucinous prostatic adenocarcinoma, prostatic adenocarcinoma with mucinous features, and the adjacent conventional prostatic adenocarcinoma. Cases were obtained from the Urologic Pathology files of 3 major academic institutions. Ninety-two cases were identified. PTEN expression was positive in the mucinous component of 79/92 (86%) cases. Concordant positive expression of PTEN between mucinous prostatic adenocarcinoma, prostatic adenocarcinoma with mucinous features, and the adjacent conventional prostatic adenocarcinoma was present in 60/79 (76%) cases. The fact that 86% of cases of mucinous prostatic adenocarcinoma and prostatic adenocarcinoma with mucinous features were positive for PTEN despite relatively high Gleason scores is in keeping with the fact that these tumors may be less aggressive than conventional prostatic adenocarcinoma without associated extraluminal mucinous components. In 76% of cases, the expression profiles (PTEN positive or negative) of mucinous prostatic adenocarcinoma and prostatic adenocarcinoma with mucinous features were similar to those of the adjacent conventional prostatic adenocarcinoma, implying that they may likely be clonal from a molecular standpoint. In addition, it is highly conceivable that the subset of PTEN-negative mucinous tumors may still have a relatively good prognosis due to a different/PTEN-independent protective pathway or mechanism. PMID- 29621097 TI - Applying DDX3X Biomarker to Discriminate Atypical from Benign Meningiomas in Tissue Microarray. AB - Patients with atypical meningiomas have a higher recurrence rate and poorer prognosis than patients with benign meningeal tumors. However, differentiating atypical from benign meningiomas based on fragmented specimens from brain tumor biopsy is complicated. We tested the association of DDX3X cytoplasmic expression and World Health Organization grading system in various subtypes of meningiomas. In our study, DDX3X expression was evaluated immunohistochemically in 10 non neoplastic brain tissues and 71 meningiomas. The immunostaining scores were calculated as the product of cytoplasmic DDX3X intensity and the percentage of positively stained cells. Our results revealed most of the non-neoplastic brain tissues were immunonegative for DDX3X. The average DDX3X immunostaining score was significantly higher in meningiomas than non-neoplastic brain tissues and significantly higher in atypical meningiomas than in various subtypes of benign meningiomas. In conclusion, DDX3X immunohistochemistry combined with hematoxylin and eosin staining may help differentiate atypical meningiomas from benign meningeal tumors. PMID- 29621098 TI - Comparison of the Efficacy and Efficiency of the Use of Virtual Reality Simulation With High-Fidelity Mannequins for Simulation-Based Training of Fiberoptic Bronchoscope Manipulation. AB - INTRODUCTION: This study compared the efficacy and efficiency of virtual reality simulation (VRS) with high-fidelity mannequin in the simulation-based training of fiberoptic bronchoscope manipulation in novices. METHODS: Forty-six anesthesia residents with no experience in fiberoptic intubation were divided into two groups: VRS (group VRS) and mannequin (group M). After a standard didactic teaching session, group VRS trained 25 times on VRS, whereas group M performed the same process on a mannequin. After training, participants' performance was assessed on a mannequin five consecutive times. Procedure times during training were recorded as pooled data to construct learning curves. Procedure time and global rating scale scores of manipulation ability were compared between groups, as well as changes in participants' confidence after training. RESULTS: Plateaus in the learning curves were achieved after 19 (95% confidence interval = 15-26) practice sessions in group VRS and 24 (95% confidence interval = 20-32) in group M. There was no significant difference in procedure time [13.7 (6.6) vs. 11.9 (4.1) seconds, t' = 1.101, P = 0.278] or global rating scale [3.9 (0.4) vs. 3.8 (0.4), t = 0.791, P = 0.433] between groups. Participants' confidence increased after training [group VRS: 1.8 (0.7) vs. 3.9 (0.8), t = 8.321, P < 0.001; group M = 2.0 (0.7) vs. 4.0 (0.6), t = 13.948, P < 0.001] but did not differ significantly between groups. CONCLUSIONS: Virtual reality simulation is more efficient than mannequin in simulation-based training of flexible fiberoptic manipulation in novices, but similar effects can be achieved in both modalities after adequate training. PMID- 29621099 TI - Interpersonal Skills Among Fourth- and Fifth-Year Medical Students: Validation of an Assessment Tool. AB - OBJECTIVE: The aim of this study was to validate a French version of the standardized patient satisfaction questionnaire (SPSQ), an interpersonal skills assessment form, originally published in English, destined to be completed by SPs and used as a validated tool for the evaluation of communication skills of French medical students, during ambulatory care consultations. METHODS: During the academic year, fourth- and fifth-year medical students participated in mock ambulatory care consultations. The French SPSQ was completed by 16 SPs who performed scenarios written by professors of medicine. Validity evidence for test content, response process, internal structure, and relation to other variables was determined by calculating the Cronbach alpha coefficient, the Loevinger H index (response coherence), intraclass coefficients, the differences between fourth- and fifth-year students and by using item correlations as well as the correlation with an independent validated assessment form. G theory was used to identify the sources of variations in the mean of SPSQ. RESULTS: Four hundred thirty-three students were evaluated for a period of 2 months and participated in a total of 1703 mock consultations. The Cronbach alpha coefficient (0.94) was superior to that of the English SPSQ. The Loevinger H index was good ranging from 0.65 to 0.70. The reproducibility among external observers (intraclass correlation coefficient = 0.67) and between external observers and the SPs (intraclass correlation coefficient = 0.79 and 0.78, respectively) was satisfactory. Results of the French SPSQ were positively and significantly correlated to the scores obtained via an independent, validated, questionnaire (R = 0.72) and showed a significant difference between fourth- and fifth-year students' scores (P < 0.0001). G coefficients were estimated at 0.64 and 0.52 for year 4 and year 5, respectively. CONCLUSIONS: Validity evidence supports the use of French-version SPSQ scores to screen for students experiencing difficulty with communication. PMID- 29621100 TI - Clinical Macrosystem Simulation Translates Between Organizations. AB - INTRODUCTION: Simulation has become an integral tool in healthcare facility redesign. Immersing clinical experts into their future environment has demonstrated benefits for transition planning. This study evaluates translation of a proven macrosystems testing protocol, TESTPILOT, to an organization with limited simulation experience. METHODS: An experienced TESTPILOT team guided Woman's Hospital Baton Rouge's simulation preparation for their new neonatal intensive care unit. Metrics included participant evaluations, latent safety threats (LST), and clinician surveys. Latent safety threats recorded during debriefings were addressed by workflow committees. Clinicians were surveyed at four time points for readiness and preparedness on 24 key processes. RESULTS: The local team invested nearly 750 hours into learning and implementing seven simulations that participants rated positively. Most of the 305 LST were minor issues. Surveys at baseline (42% of staff), postsim (18%), pretransition (26%), and postmove (29%) demonstrated strong internal consistency. System readiness lagged behind staff preparedness (P < 0.007); both were higher after simulations (P <= 0.001) but at no other interval. Critical laboratory notification, rounding structure, team coverage, and feedback were still evolving as of move day (P < 0.02). DISCUSSION: Macrosystems testing using simulation identifies LST, improves process, and prepares staff. The methodology is implementable in organizations with limited prior exposure. Woman's Hospital Baton Rouge accrued essential skills to model and orchestrate an immersive neonatal intensive care unit and then drive effective multidisciplinary debriefings. Staff immersed in the new environment began to articulate their jobs before moving in. The trajectory of system readiness improvement corroborated LST correction. Future research is needed to determine the extent of simulation required for different organizational structures. PMID- 29621101 TI - NACNS Newsletter: President's Message. PMID- 29621102 TI - Widening Our Lens for a More Global Perspective. PMID- 29621103 TI - Work Life Quality, Healthy Work Environments, and Nurse Retention. PMID- 29621104 TI - Pseudouridimycin: Light in the Darkness of Antimicrobial Resistance. PMID- 29621105 TI - Breastfeeding for Procedural Pain in Infants Beyond the Neonatal Period. PMID- 29621106 TI - Optimizing Data Generation and Application in Healthcare: The Integral Role of Nurses. PMID- 29621107 TI - The Role of the Clinical Nurse Specialist From the Perspective of Parents of Children Born With Cleft Lip and/or Palate in the United Kingdom: A Qualitative Study. AB - PURPOSE/AIM: This qualitative study explores parents' perspectives of the clinical nurse specialist (CNS) after diagnosis of cleft lip and/or palate and while preparing for/after lip or palate closure and other events on the cleft treatment pathway in the United Kingdom. DESIGN: Parents with children on the "cleft treatment pathway" were recruited from multiple regions across the United Kingdom. In-depth interviews were conducted with 24 parents of children born with cleft lip and/or palate. METHODS: Thematic analysis identified 4 key themes: relationship with CNS, information provision, preoperative care and multidisciplinary team (MDT), and postoperative support. RESULTS: Clinical nurse specialists are a highly valued point of contact and act as a trusted mediator between parents and other professionals in the MDT. Clinical nurse specialists are important gatekeepers in providing support and information and developing trust after diagnosis and birth and throughout the cleft treatment pathway. CONCLUSION: The present findings affirm the emotional, social, and informational support that the CNS can offer parents whose children are on a cleft treatment pathway. The CNS is a vital member of the cleft service MDT. PMID- 29621108 TI - A Qualitative Investigation of the Self-Perceived Health Behavior Changes in Seniors After Their Transitions Into a Retirement Home. AB - PURPOSE/AIMS: It is important for seniors to engage in positive health behaviors to reduce the incidence of health-related consequences associated with aging. The purpose of this research study was to examine self-perceived changes in physical activity, nutrition, and alcohol consumption behaviors of seniors living in a retirement home through consideration of previous behaviors and self-perceptions of behavior changes. DESIGN: A qualitative research design was used for this study. METHODS: Semistructured one-on-one interviews were conducted with 9 Canadian women living in a retirement home. RESULTS: Two key themes, each with 3 subthemes, highlighted the various factors that influenced changes in health behaviors. The 2 themes consisted of (a) aging and adapting and (b) the transition: give a little to gain a lot. CONCLUSIONS: Participants' insights revealed the importance of maintaining a positive attitude, the influence of the social environment on health behaviors, and the nutritional sacrifices of retirement living. Future research should investigate ways in which nurses can assist seniors in enhancing health behaviors throughout transitions into retirement homes. PMID- 29621109 TI - Distinguishing the Clinical Nurse Specialist From Other Graduate Nursing Roles. AB - PURPOSE: Today's healthcare environment poses diverse and complex patient care challenges and requires a highly qualified and experienced nursing workforce. To mitigate these challenges are graduate nursing roles, each with a different set of competencies and expertise. With the availability of many different graduate nursing roles, both patients and healthcare professionals can be confused in understanding the benefit of each role. To gain the maximum benefit from each role, it is important that healthcare providers and administrators are able to distinguish the uniqueness of each role to best use the role and develop strategies for effective collaboration and interprofessional interaction. The purpose of this article was to define the role, educational preparation, role differences, and practice competencies for the clinical nurse specialist (CNS), nurse practitioner, clinical nurse leader, and nurse educator/staff development educator roles. A second purpose was to provide role clarity and demonstrate the unique value the CNS brings to the healthcare environment. DESCRIPTION: Using evidence and reviewing role competencies established by varying organizations, each role is presented with similarities and differences among the roles discussed. In addition, collaboration among the identified roles was reviewed, and recommendations were provided for the new and practicing CNSs. OUTCOMES: Although there are some similarities among the graduate nursing roles such as in educational, licensing, and certification requirements, each role must be understood to gain the full role scope and benefit and glean the anticipated outcomes. CONCLUSIONS: Healthcare providers must be aware of the differences in graduate nursing roles, especially in comparing the CNS with other roles to avoid confusion that may lead to roles being underused with a limited job scope. The CNS provides a unique set of services at all system outcome levels and is an essential part of the healthcare team especially in the acute care setting. PMID- 29621110 TI - Steps to Enhance Early Recovery After Hematopoietic Stem Cell Transplantation: Lessons Learned From a Physical Activity Feasibility Study. AB - AIMS: This pilot study tested and refined a free-living physical activity intervention. The investigators evaluated the acceptability and feasibility of the intervention after hematopoietic stem cell transplantation and determined preliminary effects on physical activity, fatigue, muscle strength, functional ability, and quality of life. DESIGN: This pilot study used a 1-group, pretest posttest design. METHODS: The free-living physical activity intervention consisted of an education component and 6 weeks of gradually increasing physical activity after discharge from the hospital. The intervention was designed to increase steps by 10% weekly. Subjects were assessed before transplantation and during the seventh week after discharge from the hospital after completing the intervention. Pretest-posttest scores were analyzed with paired t tests. RESULTS: Subject wore the physical activity tracker for an average of 38 of 42 days and met their physical activity goals 57% of the time. Subjects reported significantly less physical fatigue after the free-living physical activity intervention compared with baseline (P = .05). Improvements in quality of life approached significance (P = .06). CONCLUSION: The findings demonstrate that the free-living physical activity intervention implemented during the very early recovery period after transplantation is feasible and acceptable. The intervention potentially reduces fatigue and improves quality of life. The positive results must be interpreted cautiously given the pilot nature of the study. The evidence supports continued investigation. PMID- 29621111 TI - Facing the Unfaceable. PMID- 29621113 TI - A Repeated Power Training Enhances Fatigue Resistance While Reducing Intraset Fluctuations. AB - Oliver, GS, Julio, TF, Moras, G, Jose Luis, AS, and Alberto, MV. A repeated power training enhances fatigue resistance while reducing intraset fluctuations. J Strength Cond Res XX(X): 000-000, 2018-The present study analyzed the effects of adding an upper-body repeated power ability (RPA) training to habitual strength training sessions. Twenty young elite male basketball players were randomly allocated into a control group (CON, n = 10) or repeated power group (RPG, n = 10) and evaluated by 1 repetition maximum (1RM), incremental load, and RPA tests in the bench press exercise before and after a 7-week period and a 4-week cessation period. Repeated power group performed 1-3 blocks of 5 sets of 5 repetitions using the load that maximized power output with 30 seconds and 3 minute of passive recovery between sets and blocks, respectively. Between-group analysis showed substantial greater improvements in RPG compared with CON in: best set (APB), last set (APL), mean power over 5 sets (APM), percentage of decrement, fluctuation decrease during APL and RPA index (APLpost/APBpre) during the RPA test (effect size [ES] = 0.64-1.86), and 1RM (ES = 0.48) and average power at 80% of 1RM (ES = 1.11) in the incremental load test. The improvements of APB and APM were almost perfectly correlated. In conclusion, RPA training represents an effective method to mainly improve fatigue resistance together with the novel finding of a better consistency in performance (measured as reduced intraset power fluctuations) at the end of a dynamic repeated effort. PMID- 29621114 TI - Allometric Grip Strength Norms for American Children. AB - Kocher, MH, Oba, Y, Kimura, IF, Stickley, CD, Morgan, CF, and Hetzler, RK. Allometric grip strength norms for American children. J Strength Cond Res XX(X): 000-000, 2018-To develop normative data from a large cohort of American school children (ages 6-18) for unscaled and allometrically scaled handgrip strength data that are uninfluenced by body size (body mass [BM] and stature [Ht]). Data (age, handgrip strength, BM, and Ht) were collected from the 2011-2012 and 2013 2014 National Health and Nutrition Examination Survey databases, resulting in 4,665 cases (2,384 boys and 2,281 girls). Multiple log-linear regressions were used to determine allometric exponents for BM and Ht separately for each age and sex to satisfy the common exponent and group difference principles described by Vanderburgh. Appropriateness of the allometric model was assessed through regression diagnostics, including normality and homoscedasticity of residuals. Allometrically scaled, ratio-scaled, and unscaled grip strength were then correlated with BM and Ht to examine the effectiveness of the procedure in controlling for body size. The data did not allow for development of a common exponent across age and sex that did not violate the common exponent and group difference principles. Correlations between allometrically scaled handgrip strength with BM and Ht were not significant (p <= 0.479) and approached zero, unlike correlations of unscaled handgrip strength with BM and Ht (p < 0.001 for all), indicating that allometric scaling was successful in removing the influence of body size. Allometric scaling handgrip strength by age and sex effectively controls for body size (Ht and BM) and perhaps maturation (Ht). The allometric exponents and normative values developed can be used to compare handgrip strength within age and sex while controlling for body size. PMID- 29621115 TI - Acute Effect of Foam Rolling and Dynamic Stretching on Flexibility and Jump Height. AB - Smith, JC, Pridgeon, B, and Hall, MC. Acute effect of foam rolling and dynamic stretching on flexibility and jump height. J Strength Cond Res 32(8): 2209-2215, 2018-Dynamic stretching (DS) can acutely improve vertical jump (VJ) performance but its effect lasts no more than 5 minutes. Foam rolling (FR), a form of self myofascial release, can acutely increase range of motion (ROM) with this effect lasting less than 10 minutes. Therefore, the purpose of this study was to evaluate the time course of these effects, separately and combined, on VJ height and ROM. Twenty-nine university students completed 4 different sessions (control, FR, DS, and combo) in a randomized order. After a warm-up and baseline assessments of VJ height and sit-and-reach, participants rested (control) and performed FR, DS, and the combination of FR and DS (combo). Vertical jump height and ROM were assessed every 5 minutes for 20 minutes after treatment. Mean scores at each time point were expressed as a percent change from baseline scores. Immediately after FR, sit-and-reach was significantly greater than control (p = 0.003). Vertical jump height immediately after treatment for DS and combo was significantly greater than the control and FR counterparts (p <= 0.002). Vertical jump height for DS and combo was also significantly greater than the control counterpart at 5 minutes after treatment (p < 0.001). At 15 minutes after treatment, the percent change in VJ height for the combo was significantly greater than the control counterpart (p = 0.002). Although FR has no effect on VJ performance, it can acutely increase ROM, but its effect was quickly dissipated. Foam rolling does not seem to enhance VJ height either alone or in combination with DS. PMID- 29621116 TI - Reliability and Validity of the 6-Minute Step Test for Clinical Assessment of Cardiorespiratory Fitness in People at Risk of Cardiovascular Disease. AB - Giacomantonio, N, Morrison, P, Rasmussen, R, and MacKay-Lyons, MJ. Reliability and validity of the 6-minute step test for clinical assessment of cardiorespiratory fitness in people at risk of cardiovascular disease. J Strength Cond Res XX(X): 000-000, 2018-The purpose of this study was to determine the test retest reliability and validity of the 6-minute step test (6MST) as a potential assessment of cardiorespiratory fitness (CRF) of people at risk of cardiovascular disease (CVD). A prospective, cross-sectional, correlational study design was used. A single cohort of 30 adults with 2 or more risk factors for CVD was recruited. Exercise tests were scheduled on 2 days, separated by 1 week. Validity was determined by comparing 6MST results with those obtained in a symptom-limited treadmill test and the 6-minute walk test (6MWT). Main outcome variables were peak heart rate (HRpeak) and peak oxygen consumption (V[Combining Dot Above]O2peak) measured during the 6MST, treadmill test, and 6MWT. Test-retest reliability of HRpeak and V[Combining Dot Above]O2peak during the 6MST was very strong (intraclass correlation coefficient [ICC], 0.92; 95% confidence interval [CI], 0.83-0.97 and ICC, 0.93; 95% CI, 0.84-0.97, respectively). Correlations were also very strong between 6MST and treadmill test HRpeak (r = 0.81) and between 6MST and treadmill test V[Combining Dot Above]O2peak (r = 0.88). Correlations were moderate between 6MST HRpeak and 6MWT steady-state HR (r = 0.57) and strong between 6MST V[Combining Dot Above]O2peak and 6MWT steady-state V[Combining Dot Above]O2 (r = 0.70). The 6MST seems to be a reliable, valid option for assessing CRF of people at risk of CVD in a broad range of clinical settings. Providing practical, accessible tests will help facilitate the goal of establishing CRF as a clinical vital sign. The next step in the development of the 6MST should be to identify the most appropriate 6MST predictor variables to estimate V[Combining Dot Above]O2max. PMID- 29621117 TI - Cerebral Multimodal Monitoring in Sepsis: An Experimental Study. AB - Acute brain dysfunction is a complication of sepsis and its pathophysiology remains poorly understood. We studied the brain metabolism in a resuscitated animal model of sepsis. Twelve anesthetized, mechanically ventilated and invasively monitored pigs were allocated to a sham procedure (N = 5) or sepsis (N = 7). Sepsis was induced through fecal inoculation in the peritoneum. Fluid resuscitation was maintained during the entire study period. Animals were observed until spontaneous death or for a maximum of 24 hours. In addition to global hemodynamic and laboratory assessment, intracranial pressure and cerebral microdialysis (MD) were evaluated at baseline, 6, 12, 18 and 24 hours after sepsis induction. After euthanasia, the brain was rapidly removed and a fragment from the frontal cortex was analyzed for markers of neuroinflammation, metabolism and neurotransmission. Septic animals developed a hyperdynamic state associated with increased arterial lactate. Cerebral microdialysis showed unchanged levels of lactate/pyruvate ratios and brain glucose between the groups. Brain/serum glucose ratios were increased in the septic animals during the study period despite a progressive decrease in serum glucose. Moreover, extracellular glutamine levels were elevated starting at 6 hours after sepsis. Tissue analysis showed elevated glutamate, glutamine and glutamine synthetase in the sepsis group. However, C-Fos, a marker of neuronal activity, was unchanged between groups. In this animal model of resuscitated sepsis, we found increased oxidative stress and alterations in neuroenergetics characterized by exacerbated activity of the glutamate/glutamine cycle and increased glucose utilization by the brain, however without any evidence of decompensated energy metabolism. PMID- 29621118 TI - Bone Marrow Cells Transplant in Septic Mice Modulates Systemic Inflammatory Response Via Cell-Cell Contact. AB - Sepsis is a dynamic disease, displaying an inflammatory profile that varies over time and for each organ. Controlling the inflammatory response based in targeting a single molecule has been proved useless. We hypothesized that treatment with bone marrow derived mononuclear cells (BMDMC) may be more efficient to modulate the systemic inflammatory response to infection. Adult male Balb/c mice were subjected to cecal ligation and puncture (CLP) or endotoxemia model of experimental sepsis. BMDMC were separated under Ficoll gradient and injected intravenously 1 hour after the procedures. Cytokines concentration were quantified in plasma, lungs, heart and gut. Spleens, lymph nodes and thymus were used for lymphocytes isolation and cell death assessment. All measurements were performed 2 hours after BMDMC injection. RAW264.7 macrophages and BMDMC were co cultivated in vitro to investigate the mechanisms involved. Our data showed that an early single intravenous injection of BMDMC in animals submitted to the murine model of endotoxemia led to: (1) improvement of survival rate; (2) BMDMC persistency in lung, liver and spleen after 24 hours; (3) decreased necrosis and apoptosis of mononuclear cells; (4) lower TNF-alpha, but increased IL-10 concentration in plasma and (5) tissue specific cytokine profile. In vitro experiments demonstrated that IL-6, IL-10 and nitric oxide production depends on direct contact of BMDMC to macrophages and that TNF-alpha production is negatively regulated by PGE2. BMDMC are efficient in protecting animals from endotoxemia and sepsis, reducing systemic inflammation as well as specifically modulating tissue inflammation, producing the necessary immune regulation to re equilibrate the inflammatory response. PMID- 29621119 TI - Clinical Importance of a Cytokine Network in Major Burns. AB - Major burns elicit an acute inflammatory response including various inflammatory cytokines. Cytokines play mutual interacting roles in inflammatory diseases. There is little evidence of the clinical significance of the cytokine network in patients with major burns. This study aimed to investigate the clinical significance of the cytokine network in patients with major burn. This prospective observational study comprising 38 patients with major burns (total body surface area (%TBSA) >= 20%) and 12 healthy controls was conducted from April 2014 to December 2016. Blood samples were collected from patients at six points: day 1, day 2, days 3-5, 1 week, 2 weeks and 1 month after the burn injury. Inflammatory cytokines (IFN-alpha, IFN-gamma, IL-1beta, IL-6, IL-8, IL 12/IL-23p40, IL-17A, MCP-1, TNF-alpha) and anti-inflammatory cytokines (IL-4, IL 10) were measured. Twenty-eight-day mortality, %TBSA, prognostic burn index (PBI) and SOFA and APACHE II scores were evaluated. Hierarchical clustering analysis and network visualization showed one cluster and network, respectively. Both were formed by four cytokines including IL-6, IL-8, IL-10 and MCP-1 on days 1 and 2, suggesting the presence of a cytokine network in the early hospital phase. Each cytokine showed significant associations with the SOFA score within 5 days and 1 month after burn injury. Cox regression analysis highlighting days 1 and 2 showed significant correlation of IL-6, IL-8 and IL-10 with 28-day mortality. We showed a cytokine network and its relation with prognosis and injury severity on days 1 and 2 and suggest that this cytokine network may play a role in major burns. PMID- 29621121 TI - A Longitudinal Study of the Effect of Organized Physical Activity on Free Active Play. AB - PURPOSE: The relationship between organized sport participation and positive youth development is well established. However, overinvolvement in sport and organized physical activity has been identified as having a potentially negative effect. Overscheduling and its impact on free play is one concern, given the importance of free play to overall health and development. Currently, it is not known if greater participation in organized sport has a positive or negative effect on discretionary free play in children and youth. METHODS: The Physical Health and Activity Study Team study was a 5-yr, longitudinal cohort study that followed 2278 fourth grade children (ages 9-10 yr). Organized sport and free play was assessed in the fall of each school year from fifth to eighth grades using self-report questionnaires. RESULTS: Using mixed-effects modeling, we found that higher participation in organized sport was associated with increased participation in free play over time (coefficient = 0.20, P < 0.001). Although this effect was independent of age and socioeconomic status, we did find that boys with high levels of organized participation reported the highest levels of free play overall. CONCLUSIONS: Possible explanations for this association are related to the role sport might play in supporting physical literacy and the development of fundamental movement skills, allowing children to participate in more active free play pursuits. It might also be the case that active children simply seek out both organized and unorganized physical activity opportunities during this developmental period. Limitations and implications for further research and policy are discussed. PMID- 29621120 TI - Absences of Endothelial Microvesicle Changes in the Presence of the Endotheliopathy of Trauma. AB - INTRODUCTION: Severe trauma is accompanied by endothelial glycocalyx disruption, which drives coagulopathy, increasing transfusion requirements and death. This syndrome has been termed traumatic endotheliopathy (EOT). Some have suggested EOT results from endothelial cellular damage and apoptosis. Endothelial microvesicles (EMVs) represent cellular damage. We hypothesized that EOT is associated with endothelial damage and apoptosis resulting in an increase in circulating EMVs. METHODS: Prospective, observational study enrolling severely injured patients. Twelve patients with EOT, based on elevated syndecan-1 levels, were matched with 12 patients with lower levels, based on injury severity score (ISS), abbreviated injury scale profile, and age. Thrombelastography and plasma levels of biomarkers indicative of cellular damage were measured from blood samples collected on admission. EMVs were determined by flow cytometry using varied monoclonal antibodies associated with endothelial cells. Significance was set at p < 0.05. RESULTS: Admission physiology and ISS (29 vs.28) were similar between groups. Patients with EOT had higher Syndecan-1, 230 (158, 293) vs. 19 (14, 25) ng/ml, epinephrine and soluble thrombomodulin levels. Based on thrombelastography, EOT had reductions in clot initiation, amplification, propagation and strength, and a greater frequency of transfusion, 92% vs 33%. There were no differences in EMVs irrespective of the antibody used. Plasma norepinephrine, sE-selectin, sVE cadherin and histone-complexed DNA fragments levels were similar. CONCLUSION: In trauma patients presenting with EOT, endothelial cellular damage or apoptosis does not appear to occur based on the absence of an increase in EMVs and other biomarkers. Thus, this suggests endothelial glycocalyx disruption is the underlying primary cause of EOT. PMID- 29621122 TI - Survival Time to Biopsy-Proven Acute Rejection and Tacrolimus Adverse Drug Reactions in Pediatric Liver Transplantation. AB - BACKGROUND: Despite advances in surgical procedures and the optimization of immunosuppressive therapies in pediatric liver transplantation, acute rejection (AR) and serious adverse drug reaction (ADR) to tacrolimus still contribute to morbidity and mortality. Identifying risk factors of safety and efficacy parameters may help in optimizing individual immunosuppressive therapies. This study aimed to identify peritransplant predictors of AR and factors related to the risk of ADR to tacrolimus in a large Latin American cohort of pediatric liver transplant patients. METHODS: We performed a retrospective cohort study in a pediatric liver transplant population (n = 72). Peritransplant variables were collected retrospectively including demographic, clinical, laboratory parameters, genomic (CYP3A5 donor and recipients polymorphism), and tacrolimus trough concentrations (C0) over a 2-year follow-up period. Variability in tacrolimus C0 was calculated using percent coefficient of variation and tortuosity. ADR- and AR free survival rates were calculated using the Kaplan-Meier method, and risk factors were identified by multivariate Cox regression models. RESULTS: Cox proportional hazard models identified that high tortuosity in tacrolimus C0 was associated with an 80% increased risk of AR [hazard ratio (HR), 1.80; 95% confidence interval (CI), 1.01-3.22; P < 0.05], whereas steroid in maintenance doses decreased this risk (HR, 0.56; 95% CI, 0.31-0.99; P < 0.05). Forty-six patients experienced at least one ADR including hypomagnesemia, nephrotoxicity, hypertension, malignancies, and tremor as a first event. Multivariate analysis showed that C0 values 10 days before the event (HR, 1.25; 95% CI, 1.21-1.39; P < 0.0001) and CYP3A5 expresser recipients (HR, 2.05; 95% CI, 1.03-4.06; P < 0.05) were independent predictors of ADR. CONCLUSIONS: Tacrolimus C0 values, its variability, and CYP3A5 polymorphisms were identified as risk factors of AR and tacrolimus ADR. This knowledge may help to control and reduce their incidence in pediatric liver transplant patients. Prospective studies are important to validate these results. PMID- 29621124 TI - Therapeutic Drug Monitoring of methotrexate in plasma using U-HPLC-MS/MS: necessary after administration of glucarpidase in methotrexate intoxications. AB - High-dose methotrexate (HD-MTX) is used to treat a variety of cancers. In all patients receiving HD-MTX, plasma MTX levels are monitored mainly to anticipate rescue therapy to prevent adverse events. We present two children treated with HD MTX and afterward treated with glucarpidase at different time-points after their HD-MTX infusions. After the administration of glucarpidase, a non-toxic metabolite of MTX cross-reacts with MTX in the standard immunoassay (Abbott Diagnostics, Hoofddorp, The Netherlands) resulting in an artificially elevated MTX level. An artificially elevated MTX level results in unnecessarily long folinic acid administration, which decreases the effectivity of MTX. This grand round highlights the importance of measuring plasma MTX levels after the administration of glucarpidase with a U-HPLC-MS/MS method instead of with an immunoassay. PMID- 29621125 TI - Small Cell Carcinoma of the Ovary: A Rare Tumor With a Poor Prognosis. AB - OBJECTIVE: The aim of this study was to investigate the demographic and clinicopathological characteristics and prognosis of women diagnosed with small cell carcinoma of the ovary. METHODS: The National Cancer Data Base was accessed, and women diagnosed with small cell carcinoma of the ovary, between 2004 and 2014 were identified. Median and 3- and 5-year overall survival (OS) rates were calculated following generation of Kaplan-Meir curves and compared with the log rank test. A Cox multivariate model was constructed to identify variables associated with mortality. RESULTS: A total 469 women were identified with a median age of 39 years; 81.7% of tumors were unilateral, whereas median size was 13 cm. Only 20.1% of patients had stage I disease. Women who underwent cancer directed surgery had a 5-year OS rate of 24.1%. Five-year OS rates were 48.6%, 30.7%, 18%, and 12.3% for those with stages I, II, III, and IV disease, respectively, P < 0.001. Younger age (P = 0.013) and the combination of surgery with chemotherapy (CT) (P < 0.001) were associated with superior OS. By multivariate analysis, earlier disease stage and use of CT, but not patient age or performance of lymphadenectomy, were associated with lower mortality. CONCLUSIONS: Small cell carcinomas of the ovary are unilateral tumors primarily arising in premenopausal women. Multimodal treatment with cancer-directed surgery and CT results in a modest increase of a generally poor survival. PMID- 29621126 TI - Examining Survival Outcomes of 852 Women With Advanced Ovarian Cancer: A Multi institutional Cohort Study. AB - INTRODUCTION: This study examines patterns of clinical practice in the management of women with advanced high-grade serous ovarian carcinoma (HGSC). METHODS: A total of 852 patients with advanced HGSC were included in this retrospective cohort analysis. Patients underwent primary cytoreductive surgery (PCS) or neoadjuvant chemotherapy (NACT). Wilcoxon rank-sum test and chi test were applied. Univariate- and multivariate-analyses were performed, and survival outcomes were measured using Kaplan-Meier curves. RESULTS: A total of 449 (53%) of 852 patients underwent PCS, and 403(47%) of 852 patients underwent NACT. The median 5-year overall survival (OS) was 3.89 in PCS and 2.48 in NACT. Patients with 0 mm residual had OS of 4.66, compared with 1- to 9-mm residual (OS = 2.80) and 10-mm residual or longer (OS = 2.50). The survival advantage harbored by the extent of surgical cytoreduction was more pronounced in PCS compared with NACT (P < 0.001). Patients who had PCS with 1- to 9-mm residual had similar OS to NACT patients with 0-mm residual (P = 0.17) and superior OS to NACT with 1- to 9-mm residual (P < 0.001). CONCLUSIONS: In this multicenter study, 53% of women with advanced HGSC seen by a gynecologic oncologist were selected for PCS. Survival was longer in patients who underwent PCS than patients who underwent NACT. Within each group, survival was highest in those who had complete cytoreduction to 0-mm residual disease. We believe all patients with advanced HGSC should be assessed by a gynecologic oncologist for the feasibility of surgical resection. Primary cytoreductive surgery should be the favorable treatment modality with the goal of complete resection to 0 mm residual disease. Importantly, if 0 mm residual is not feasible, PCS to a residual of 1 to 9 mm should be attempted given the survival advantage in this group over patients who were treated with NACT. PMID- 29621127 TI - Prognostic Factors of Uterine Serous Carcinoma-A Multicenter Study. AB - BACKGROUND: The prognostic factors of uterine serous carcinoma (USC) vary among studies, and there is no report of Chinese USC patients. OBJECTIVE: The aim of this study was to investigate the clinicopathological characteristics and prognostic factors in Chinese patients with USC. METHODS: Patients with USC from 13 authoritative university hospitals in China and treated between 2004 and 2014 were retrospectively reviewed. Three-year disease-free survival rate (DFSR), cumulative recurrence, and cumulative mortality were estimated by Kaplan-Meier analyses and log-rank tests. Multivariate Cox regression analysis was used to model the association of potential prognostic factors with clinical outcomes. RESULTS: Data of a total of 241 patients were reviewed. The median follow-up was 26 months (range, 1-128 months). Median age was 60 years (range, 39-84 years), and 58.0% had stages I-II disease. The 3-year DFSR and cumulative recurrence were 46.8% and 27.7%. Advanced stage (III and IV) (P = 0.004), myometrial invasion (P = 0.001), adnexal involvement (P < 0.001), lymph node metastasis (P = 0.025), and positive peritoneal cytology (P = 0.007) were independently associated with 3 year DFSR. Advanced stage (P = 0.017), myometrial invasion (P = 0.008), adnexal involvement (odds ratio, 2.987; P = 0.001), lymph node metastasis (P = 0.031), and positive peritoneal cytology (P = 0.001) were independently associated with the cumulative recurrence. Myometrial invasion (P = 0.004) and positive peritoneal cytology (P = 0.025) were independently associated with 3-year cumulative mortality. CONCLUSIONS: Peritoneal cytology and myometrial invasion could be independent prognostic factors for 3-year DFSR, cumulative recurrence, and cumulative mortality of patients with USC. Prospective studies are needed to confirm these results. PMID- 29621128 TI - Can Teamwork and High-Volume Experience Overcome Challenges of Lymphadenectomy in Morbidly Obese Patients (Body Mass Index of 40 kg/m2 or Greater) with Endometrial Cancer?: A Cohort Study of Robotics and Laparotomy and Review of Literature. AB - OBJECTIVE: This study aimed to compare surgical outcomes and the adequacy of surgical staging in morbidly obese women with a body mass index (BMI) of 40 kg/m or greater who underwent robotic surgery or laparotomy for the staging of endometrioid-type endometrial cancer. METHODS: This is a retrospective cohort study of patients who underwent surgical staging between May 2011 and June 2014. Patients' demographics, surgical outcomes, intraoperative and postoperative complications, and pathological outcomes were compared. RESULTS: Seventy-six morbidly obese patients underwent robotic surgery, and 35 underwent laparotomy for surgical staging. Robotic surgery was associated with more lymph nodes collected with increasing BMI (P < 0.001) and decreased chances for postoperative respiratory failure and intensive care unit admissions (P = 0.03). Despite a desire to comprehensively stage all patients, we performed successful pelvic and paraaortic lymphadenectomy in 96% versus 89% (P = 0.2) and 75% versus 60% (P = 0.12) of robotic versus laparotomy patients, respectively. In the robotic group, with median BMI of 47 kg/m, no conversions to laparotomy occurred. The robotic group experienced less blood loss and a shorter length of hospital stay than the laparotomy group; however, the surgeries were longer. CONCLUSIONS: In a high volume center, a high rate of comprehensive surgical staging can be achieved in patients with BMI of 40 kg/m or greater either by laparotomy or robotic approach. In our experience, robotic surgery in morbidly obese patients is associated with better quality staging of endometrial cancer. With a comprehensive approach, a professional bedside assistant, use of a monopolar cautery hook, and our protocol of treating morbidly obese patients, robotic surgeries can be safely performed in the vast majority of patients with a BMI of 40 kg/m or greater, with lymph node counts being similar to nonobese patients, and with conversions to laparotomy reduced to a minimum. PMID- 29621129 TI - Plants and Surgery: The Protective Effects of Thymoquinone on Hepatic Injury-A Systematic Review of In Vivo Studies. AB - Multimodal treatment concepts including liver transplantation for hepatocellular carcinoma (HCC), extended resection methods and neoadjuvant chemotherapy for colorectal liver metastasis significantly improve patients’ outcome. However, surgery-induced hepatic ischemia-reperfusion injury (IRI) and chemotherapy-associated hepatotoxicity result in hepatocellular damage and compromised liver function. Activation of common key pathways in ischemic liver and hepatotoxic injury results in oxidative stress, inflammatory responses and apoptosis causing organ damage. Controlling liver damage before and during surgery is essential for the postoperative outcome. Nigella sativa has a long tradition as a natural remedy. In the essential oil, Thymoquinone (TQ) was identified as the main component and responsible for most of the therapeutic effects. Therefore, this systematic review aimed to summarize the hepatoprotective effects of TQ and its potential suitability to improve surgical outcome by reducing surgical ischemic injury and hepatotoxicity of neoadjuvant chemotherapy. The key findings can be summarized as TQ having strong antioxidant, anti-inflammatory, antifibrotic, anti-/proapoptotic and anticarcinogenic effects. Almost no side effects were reported irrespective of a large dose range, suggesting a wide therapeutic window. These results give rise to the expectation that TQ could evolve to a novel powerful drug to reduce hepatic injury. PMID- 29621130 TI - Astaxanthin Promotes Nrf2/ARE Signaling to Inhibit HG-Induced Renal Fibrosis in GMCs. AB - Oxidative stress is the main cause of diabetic nephropathy (DN) progression. Nuclear factor-erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling is a crucial cellular defense system to cope with oxidative stress. Astaxanthin (AST) is a fat-soluble xanthophyll carotenoid with remarkable antioxidative capacity. AST exerted renal protective in diabetic rats. This study aimed to determine whether AST could alleviate the pathological progress of DN by activating Nrf2/ARE signaling and diminishing the excessive oxidative stress and fibronectin (FN) accumulation in glomerular mesangial cells (GMCs) challenged with high glucose (HG). In the current study, we found that AST treatment alleviated the metabolic parameters, renal morphology and extracellular matrix (ECM) accumulation in streptozotocin-induced diabetic rats. Additionally, HG induced the adaptively activated Nrf2/ARE signaling and increased the expression of FN, intercellular adhesion molecule-1 (ICAM-1) and transforming growth factor β1 (TGF-β1), as well as the intracellular reactive oxygen species (ROS) generation in GMCs. However, AST treatment strongly promoted the nuclear translocation and transcriptional activity of Nrf2 as well as upregulated the expression of superoxide dismutase (SOD1), NAD(P)H: quinone oxidoreductase (NQO1) and heme oxygenase-1 (HO-1), ultimately quenching the higher level of ROS and inhibiting the FN, ICAM-1 and TGF-β1 expression induced by HG. Collectively, our data suggest that the renoprotective effect of AST on DN depends on Nrf2/ARE signaling activation, which could be a potentially therapeutic strategy in the treatment of DN. PMID- 29621131 TI - A Weighted Deep Representation Learning Model for Imbalanced Fault Diagnosis in Cyber-Physical Systems. AB - Predictive maintenance plays an important role in modern Cyber-Physical Systems (CPSs) and data-driven methods have been a worthwhile direction for Prognostics Health Management (PHM). However, two main challenges have significant influences on the traditional fault diagnostic models: one is that extracting hand-crafted features from multi-dimensional sensors with internal dependencies depends too much on expertise knowledge; the other is that imbalance pervasively exists among faulty and normal samples. As deep learning models have proved to be good methods for automatic feature extraction, the objective of this paper is to study an optimized deep learning model for imbalanced fault diagnosis for CPSs. Thus, this paper proposes a weighted Long Recurrent Convolutional LSTM model with sampling policy (wLRCL-D) to deal with these challenges. The model consists of 2-layer CNNs, 2-layer inner LSTMs and 2-Layer outer LSTMs, with under-sampling policy and weighted cost-sensitive loss function. Experiments are conducted on PHM 2015 challenge datasets, and the results show that wLRCL-D outperforms other baseline methods. PMID- 29621133 TI - QuantifyMe: An Open-Source Automated Single-Case Experimental Design Platform. AB - Smartphones and wearable sensors have enabled unprecedented data collection, with many products now providing feedback to users about recommended step counts or sleep durations. However, these recommendations do not provide personalized insights that have been shown to be best suited for a specific individual. A scientific way to find individualized recommendations and causal links is to conduct experiments using single-case experimental design; however, properly designed single-case experiments are not easy to conduct on oneself. We designed, developed, and evaluated a novel platform, QuantifyMe, for novice self experimenters to conduct proper-methodology single-case self-experiments in an automated and scientific manner using their smartphones. We provide software for the platform that we used (available for free on GitHub), which provides the methodological elements to run many kinds of customized studies. In this work, we evaluate its use with four different kinds of personalized investigations, examining how variables such as sleep duration and regularity, activity, and leisure time affect personal happiness, stress, productivity, and sleep efficiency. We conducted a six-week pilot study (N = 13) to evaluate QuantifyMe. We describe the lessons learned developing the platform and recommendations for its improvement, as well as its potential for enabling personalized insights to be scientifically evaluated in many individuals, reducing the high administrative cost for advancing human health and wellbeing. PMID- 29621132 TI - Anti-Cancer Potential of Homemade Fresh Garlic Extract Is Related to Increased Endoplasmic Reticulum Stress. AB - The use of garlic and garlic-based extracts has been linked to decreased incidence of cancer in epidemiological studies. Here we examine the molecular and cellular activities of a simple homemade ethanol-based garlic extract (GE). We show that GE inhibits growth of several different cancer cells in vitro, as well as cancer growth in vivo in a syngeneic orthotopic breast cancer model. Multiple myeloma cells were found to be especially sensitive to GE. The GE was fractionated using solid-phase extractions, and we identified allicin in one GE fraction; however, growth inhibitory activities were found in several additional fractions. These activities were lost during freeze or vacuum drying, suggesting that the main anti-cancer compounds in GE are volatile. The anti-cancer activity was stable for more than six months in −20 °C. We found that GE enhanced the activities of chemotherapeutics, as well as MAPK and PI3K inhibitors. Furthermore, GE affected hundreds of proteins involved in cellular signalling, including changes in vital cell signalling cascades regulating proliferation, apoptosis, and the cellular redox balance. Our data indicate that the reduced proliferation of the cancer cells treated by GE is at least partly mediated by increased endoplasmic reticulum (ER) stress. PMID- 29621134 TI - Dosimetric Implications of Computerised Tomography-Only versus Magnetic Resonance Fusion Contouring in Stereotactic Body Radiotherapy for Prostate Cancer. AB - Background: Magnetic resonance (MR)-fusion contouring is the standard of care in prostate stereotactic body radiotherapy (SBRT) for target volume localisation. However, the planning computerised tomography (CT) scan continues to be used for dose calculation and treatment planning and verification. Discrepancies between the planning MR and CT scans may negate the benefits of MR-fusion contouring and it adds a significant resource burden. We aimed to determine whether CT-only contouring resulted in a dosimetric detriment compared with MR-fusion contouring in prostate SBRT planning. Methods: We retrospectively compared target volumes and SBRT plans for 20 patients treated clinically with MR-fusion contouring (standard of care) with those produced by re-contouring using CT data only. Dose was 36.25 Gy in 5 fractions. CT-only contouring was done on two occasions blind to MR data and reviewed by a separate observer. Primary outcome was the difference in rectal volume receiving 36 Gy or above. Results: Absolute target volumes were similar: 63.5 cc (SD ± 27.9) versus 63.2 (SD ± 26.5), Dice coefficient 0.86 (SD ± 0.04). Mean difference in apex superior inferior position was 1.1 (SD ± 3.5; CI: −0.4–2.6). Small dosimetric differences in favour of CT-only contours were seen, with the mean rectal V36 Gy 0.3 cc (95% CI: 0.1–0.5) lower for CT-only contouring. Conclusions: Prostate SBRT can be successfully planned without MR-fusion contouring. Consideration can be given to omitting MR-fusion from the prostate SBRT workflow, provided reference to diagnostic MR imaging is available. Development of MR-only work flow is a key research priority to gain access to the anatomical fidelity of MR imaging. PMID- 29621135 TI - Applying Fourier Transform Mid Infrared Spectroscopy to Detect the Adulteration of Salmo salar with Oncorhynchus mykiss. AB - The aim of this study was to evaluate the potential of Fourier transform infrared (FTIR) spectroscopy coupled with chemometric methods to detect fish adulteration. Muscles of Atlantic salmon (Salmo salar) (SS) and Salmon trout (Onconrhynchus mykiss) (OM) muscles were mixed in different percentages and transformed into mini-burgers. These were stored at 3 °C, then examined at 0, 72, 160, and 240 h for deteriorative microorganisms. Mini-burgers was submitted to Soxhlet extraction, following which lipid extracts were analyzed by FTIR. The principal component analysis (PCA) described the studied adulteration using four principal components with an explained variance of 95.60%. PCA showed that the absorbance in the spectral region from 721, 1097, 1370, 1464, 1655, 2805, to 2935, 3009 cm−1 may be attributed to biochemical fingerprints related to differences between SS and OM. The partial least squares regression (PLS-R) predicted the presence/absence of adulteration in fish samples of an external set with high accuracy. The proposed methods have the advantage of allowing quick measurements, despite the storage time of the adulterated fish. FTIR combined with chemometrics showed that a methodology to identify the adulteration of SS with OM can be established, even when stored for different periods of time. PMID- 29621136 TI - Complex Regulatory Networks Governing Production of the Glycopeptide A40926. AB - Glycopeptides (GPAs) are an important class of antibiotics, with vancomycin and teicoplanin being used in the last 40 years as drugs of last resort to treat infections caused by Gram-positive pathogens, including methicillin-resistant Staphylococcus aureus. A few new GPAs have since reached the market. One of them is dalbavancin, a derivative of A40926 produced by the actinomycete Nonomuraea sp. ATCC 39727, recently classified as N. gerenzanensis. This review summarizes what we currently know on the multilevel regulatory processes governing production of the glycopeptide A40926 and the different approaches used to increase antibiotic yields. Some nutrients, e.g., valine, l-glutamine and maltodextrin, and some endogenous proteins, e.g., Dbv3, Dbv4 and RpoBR, have a positive role on A40926 biosynthesis, while other factors, e.g., phosphate, ammonium and Dbv23, have a negative effect. Overall, the results available so far point to a complex regulatory network controlling A40926 in the native producing strain. PMID- 29621137 TI - TRAP1 Regulation of Cancer Metabolism: Dual Role as Oncogene or Tumor Suppressor. AB - Metabolic reprogramming is an important issue in tumor biology. An unexpected inter- and intra-tumor metabolic heterogeneity has been strictly correlated to tumor outcome. Tumor Necrosis Factor Receptor-Associated Protein 1 (TRAP1) is a molecular chaperone involved in the regulation of energetic metabolism in cancer cells. This protein is highly expressed in several cancers, such as glioblastoma, colon, breast, prostate and lung cancers and is often associated with drug resistance. However, TRAP1 is also downregulated in specific tumors, such as ovarian, bladder and renal cancers, where its lower expression is correlated with the worst prognoses and chemoresistance. TRAP1 is the only mitochondrial member of the Heat Shock Protein 90 (HSP90) family that directly interacts with respiratory complexes, contributing to their stability and activity but it is still unclear if such interactions lead to reduced or increased respiratory capacity. The role of TRAP1 is to enhance or suppress oxidative phosphorylation; the effects of such regulation on tumor development and progression are controversial. These observations encourage the study of the mechanisms responsible for the dualist role of TRAP1 as an oncogene or oncosuppressor in specific tumor types. In this review, TRAP1 puzzling functions were recapitulated with a special focus on the correlation between metabolic reprogramming and tumor outcome. We wanted to investigate whether metabolism-targeting drugs can efficiently interfere with tumor progression and whether they might be combined with chemotherapeutics or molecular-targeted agents to counteract drug resistance and reduce therapeutic failure. PMID- 29621138 TI - Is Dyslexia a Brain Disorder? AB - Specific word reading difficulty, commonly termed ‘developmental dyslexia’, refers to the low end of the word reading skill distribution but is frequently considered to be a neurodevelopmental disorder. This term implies that brain development is thought to be disrupted, resulting in an abnormal and dysfunctional brain. We take issue with this view, pointing out that there is no evidence of any obvious neurological abnormality in the vast majority of cases of word reading difficulty cases. The available relevant evidence from neuroimaging studies consists almost entirely of correlational and group-differences studies. However, differences in brains are certain to exist whenever differences in behavior exist, including differences in ability and performance. Therefore, findings of brain differences do not constitute evidence for abnormality; rather, they simply document the neural substrate of the behavioral differences. We suggest that dyslexia is best viewed as one of many expressions of ordinary ubiquitous individual differences in normal developmental outcomes. Thus, terms such as “dysfunctional” or “abnormal” are not justified when referring to the brains of persons with dyslexia. PMID- 29621139 TI - Dynamically Rough Boundary Scattering Effect on a Propagating Continuous Acoustical Wave in a Circular Pipe with Flow. AB - The pattern of the free surface of the turbulent flow in a partially filled circular pipe contains information on the underlying hydraulic processes. However, the roughness of the free surface of flow and its temporal variation in a pipe is a dynamic and non-stationary process that is difficult to measure directly. This work examines a new acoustic method that is used to study the characteristics of the free surface roughness under controlled laboratory conditions. The acoustic method makes use of a continuous sine wave that is transmitted through the air above the turbulent flow of water over a section of the pipe instrumented with an array of wave probes and microphones. The results obtained for a representative range of flow regimes and variety of pipe bed conditions illustrate that it is possible to unambiguously relate variations in the recorded acoustic field to the standard deviation in the free surface roughness and mean flow depth. These variations are clearly linked to the hydraulic friction factor of the pipe, which is shown to be related to airborne acoustic data obtained non-invasively. PMID- 29621140 TI - Naturalness and Animal Welfare. AB - Naturalness is considered important for animals, and is one criterion for assessing how we care for them. However, it is a vague and ambiguous term, which needs definition and assessments suitable for scientific and ethical questions. This paper makes a start on that aim. This paper differentiates the term from other related concepts, such as species-typical behaviour and wellbeing. It identifies contingent ways in which naturalness might be used, as: (i) prompts for further welfare assessment; (ii) a plausible hypothesis for what safeguards wellbeing; (iii) a threshold for what is acceptable; (iv) constraints on what improvements are unacceptable; and (v) demarcating what is not morally wrong, because of a lack of human agency. It then suggests an approach to evaluating animals' behaviour that is quantitative, is based on reality, and which assesses naturalness by degrees. It proposes classing unaffected wild populations as natural by definition. Where animals might have been affected by humans, they should be compared to the closest population(s) of unaffected animals. This approach could allow us both to assess naturalness scientifically, and to make practical decisions about the behaviour of domestic animals. PMID- 29621142 TI - A Vehicular Mobile Standard Instrument for Field Verification of Traffic Speed Meters Based on Dual-Antenna Doppler Radar Sensor. AB - Traffic speed meters are important legal measuring instruments specially used for traffic speed enforcement and must be tested and verified in the field every year using a vehicular mobile standard speed-measuring instrument to ensure speed measuring performances. The non-contact optical speed sensor and the GPS speed sensor are the two most common types of standard speed-measuring instruments. The non-contact optical speed sensor requires extremely high installation accuracy, and its speed-measuring error is nonlinear and uncorrectable. The speed-measuring accuracy of the GPS speed sensor is rapidly reduced if the amount of received satellites is insufficient enough, which often occurs in urban high-rise regions, tunnels, and mountainous regions. In this paper, a new standard speed-measuring instrument using a dual-antenna Doppler radar sensor is proposed based on a tradeoff between the installation accuracy requirement and the usage region limitation, which has no specified requirements for its mounting distance and no limitation on usage regions and can automatically compensate for the effect of an inclined installation angle on its speed-measuring accuracy. Theoretical model analysis, simulated speed measurement results, and field experimental results compared with a GPS speed sensor with high accuracy showed that the dual-antenna Doppler radar sensor is effective and reliable as a new standard speed-measuring instrument. PMID- 29621141 TI - Correcting Calcium Dysregulation in Chronic Heart Failure Using SERCA2a Gene Therapy. AB - Chronic heart failure (CHF) is a major contributor to cardiovascular disease and is the leading cause of hospitalization for those over the age of 65, which is estimated to account for close to seventy billion dollars in healthcare costs by 2030 in the US alone. The successful therapies for preventing and reversing CHF progression are urgently required. One strategy under active investigation is to restore dysregulated myocardial calcium (Ca2+), a hallmark of CHF. It is well established that intracellular Ca2+ concentrations are tightly regulated to control efficient myocardial systolic contraction and diastolic relaxation. Among the many cell surface proteins and intracellular organelles that act as the warp and woof of the regulatory network controlling intracellular Ca2+ signals in cardiomyocytes, sarco/endoplasmic reticulum Ca2+ ATPase type 2a (SERCA2a) undoubtedly plays a central role. SERCA2a is responsible for sequestrating cytosolic Ca2+ back into the sarcoplasmic reticulum during diastole, allowing for efficient uncoupling of actin-myosin and subsequent ventricular relaxation. Accumulating evidence has demonstrated that the expression of SERCA2a is downregulated in CHF, which subsequently contributes to severe systolic and diastolic dysfunction. Therefore, restoring SERCA2a expression and improving cardiomyocyte Ca2+ handling provides an excellent alternative to currently used transplantation and mechanical assist devices in the treatment of CHF. Indeed, advancements in safe and effective gene delivery techniques have led to the emergence of SERCA2a gene therapy as a potential therapeutic choice for CHF patients. This mini-review will succinctly detail the progression of SERCA2a gene therapy from its inception in plasmid and animal models, to its clinical trials in CHF patients, highlighting potential avenues for future work along the way. PMID- 29621143 TI - Introduction to the Special Issue: Application of Essential Oils in Food Systems. AB - Essential oils have received increasing attention as natural additives for the shelf-life extension of food products due to the risk in using synthetic preservatives. Synthetic additives can reduce food spoilage, but the present generation is very health conscious and believes in natural products rather than synthetic ones due to their potential toxicity and other concerns. Therefore, one of the major emerging technologies is the extraction of essential oils from several plant organs and their application to foods. Essential oils are a good source of several bioactive compounds, which possess antioxidative and antimicrobial properties, so their use can be very useful to extend shelf-life in food products. Although essential oils have been shown to be promising alternative to chemical preservatives, they present special limitations that must be solved before their application in food systems. Low water solubility, high volatility, and strong odor are the main properties that make it difficult for food applications. Recent advances that refer to new forms of application to avoid these problems are currently under study. Their application into packaging materials and coated films but also directly into the food matrix as emulsions, nanoemulsions, and coating are some of their new applications among others. PMID- 29621144 TI - Association between Vegetable Consumption and Blood Pressure, Stratified by BMI, among Chinese Adolescents Aged 13-17 Years: A National Cross-Sectional Study. AB - The association between vegetable intake and blood pressure (BP) in adolescents is still inconsistent, and the description of the recommended daily vegetable consumption is abstract and nonfigurative. Here we aimed to investigate the association between vegetable consumption and BP and further look for a simple way to describe a satisfactory level of daily vegetable consumption for adolescents. We recruited 18,757 adolescents, aged 13-17 years, from seven provinces in China in 2013. A standard physical examination, including height, weight and BP was conducted. Information regarding vegetable intake was collected by questionnaire, and one serving of vegetables was defined as the size of an adult's fist. Multivariable linear and logistic regression models were used for analysis after adjusting for covariates. Approximately 12.2%, 38.0%, 28.7%, and 21.1% of the adolescents reported daily vegetable consumption of <1, 1~2, 2~3, and >=3 servings, respectively. Adolescents whose daily vegetable consumption was >=3 servings showed a lower risk of high blood pressure (HBP) (OR = 0.74, 95%CI: 0.58~0.94, p = 0.013) compared to those with daily vegetable consumptions of < 1 serving. When stratified by body mass index (BMI), in overweight adolescents, participants with 2~3 or >=3 servings/day had an OR of 0.66 (95%CI: 0.45~0.97) or 0.63 (95%CI: 0.42~0.95) compared with the reference group. Daily vegetable intake of at least three servings (three adult's fists) is associated with a lower HBP risk in adolescents, which leads to a simple message: "consuming at least three fists of vegetables every day will improve your blood pressure profile". PMID- 29621146 TI - Effects of Prolonged Silver Nanoparticle Exposure on the Contextual Cognition and Behavior of Mammals. AB - Silver nanoparticles have been widely used in the lighting and food industries, in medicine, and in pharmaceutics as an antiseptic agent. Recent research demonstrates that, after prolonged oral administration, silver nanoparticles may cross the blood-brain barrier and accumulate in the brain in rather high amounts. In ex vivo experiments, it has also been shown that silver nanoparticles demonstrate neurotoxicity. The objective of this work was to answer the questions whether silver nanoparticles change cognitive and behavioral functions of mammals after prolonged administration if silver nanoparticles have accumulated in the brain. C57Bl/6 male mice were orally exposed to PVP-coated silver nanoparticles daily for 30, 60, 120 and 180 days. Control mice were exposed to distilled water. After that they were tested in the Open Field, Elevated Plus Maze, Light-Dark Box and contextual fear conditioning task. The data have shown that the experimental mice went through three periods of switching in the behavior caused by adaptation to the toxic silver nanoparticles: anxiety, appearance of research instinct and impairment of long-term memory. This provides evidence of the hazardous effect of silver nanoparticles, which appears after long periods of silver nanoparticle oral administration. PMID- 29621147 TI - The Effect of the MEMS Measurement Platform Design on the Seebeck Coefficient Measurement of a Single Nanowire. AB - In order to study the thermoelectric properties of individual nanowires, a thermoelectric nanowire characterization platform (TNCP) has been previously developed and used in our chair. Here, we report on a redesigned platform aiming to optimize performance, mechanical stability and usability. We compare both platforms for electrical conductivity and the Seebeck coefficient for an individual Ag nanowire of the previously-used batch and for comparable measurement conditions. By this, the measurement performance of both designs can be investigated. As a result, whereas the electrical conductivity is comparable, the Seebeck coefficient shows a 50% deviation with respect to the previous studies. We discuss the possible effects of the platform design on the thermoelectric measurements. One reason for the deviation of the Seebeck coefficient is the design of the platform leading to temperature gradients along the bond pads. We further analyze the effect of bonding materials Au and Pt, as well as the effect of temperature distributions along the bond pads used for the thermovoltage acquisition. Another major reason for the variation of the measurement results is the non-homogeneous temperature distribution along the thermometer. We conclude that for the measurement of small Seebeck coefficients, an isothermal positioning of voltage-probing bond pads, as well as a constant temperature profile at the measurement zone are essential. PMID- 29621145 TI - Zebrafish as a Model System for Investigating the Compensatory Regulation of Ionic Balance during Metabolic Acidosis. AB - Zebrafish (Danio rerio) have become an important model for integrative physiological research. Zebrafish inhabit a hypo-osmotic environment; to maintain ionic and acid-base homeostasis, they must actively take up ions and secrete acid to the water. The gills in the adult and the skin at larval stage are the primary sites of ionic regulation in zebrafish. The uptake of ions in zebrafish is mediated by specific ion transporting cells termed ionocytes. Similarly, in mammals, ion reabsorption and acid excretion occur in specific cell types in the terminal region of the renal tubules (distal convoluted tubule and collecting duct). Previous studies have suggested that functional regulation of several ion transporters/channels in the zebrafish ionocytes resembles that in the mammalian renal cells. Additionally, several mechanisms involved in regulating the epithelial ion transport during metabolic acidosis are found to be similar between zebrafish and mammals. In this article, we systemically review the similarities and differences in ionic regulation between zebrafish and mammals during metabolic acidosis. We summarize the available information on the regulation of epithelial ion transporters during acidosis, with a focus on epithelial Na+, Cl- and Ca2+ transporters in zebrafish ionocytes and mammalian renal cells. We also discuss the neuroendocrine responses to acid exposure, and their potential role in ionic compensation. Finally, we identify several knowledge gaps that would benefit from further study. PMID- 29621148 TI - Fungal Metabolite Antagonists of Plant Pests and Human Pathogens: Structure Activity Relationship Studies. AB - Fungi are able to produce many bioactive secondary metabolites that belong to different classes of natural compounds. Some of these compounds have been selected for their antagonism against pests and human pathogens and structure activity relationship (SAR) studies have been performed to better understand which structural features are essential for the biological activity. In some cases, these studies allowed for the obtaining of hemisynthetic derivatives with increased selectivity and stability in respect to the natural products as well as reduced toxicity in view of their potential practical applications. This review deals with the SAR studies performed on fungal metabolites with potential fungicidal, bactericidal, insecticidal, and herbicidal activities from 1990 to the present (beginning of 2018). PMID- 29621149 TI - Criteria for Selecting Suitable Infectious Diseases for Phage Therapy. AB - One of the main issues with phage therapy from its earliest days has been the selection of appropriate disease targets. In early work, when the nature of bacteriophages was unknown, many inappropriate targets were selected, including some now known to have no bacterial involvement whatsoever. More recently, with greatly increased understanding of the highly specific nature of bacteriophages and of their mechanisms of action, it has been possible to select indications with an increased chance of a successful therapeutic outcome. The factors to be considered include the characteristics of the infection to be treated, the characteristics of the bacteria involved, and the characteristics of the bacteriophages themselves. At a later stage all of this information then informs trial design and regulatory considerations. Where the work is undertaken towards the development of a commercial product it is also necessary to consider the planned market, protection of intellectual property, and the sourcing of funding to support the work. It is clear that bacteriophages are not a "magic bullet". However, with careful and appropriate selection of a limited set of initial targets, it should be possible to obtain proof of concept for the many elements required for the success of phage therapy. In time, success with these initial targets could then support more widespread use. PMID- 29621150 TI - Arsenic, Cadmium and Lead Exposure and Immunologic Function in Workers in Taiwan. AB - There has been growing concern over the impact of environmental exposure to heavy metals and other trace elements on immunologic functions. This study investigated men's arsenic (As), cadmium (Cd) and lead (Pb) contents in hair samples and their associations with immunological indicators, including white blood cell (WBC), lymphocyte and monocyte counts, and the immunoglobulin (Ig) levels including IgA, IgG and IgE. We recruited 133 men from one antimony trioxide manufacturing plant, two glass manufacturing plants and two plastics manufacturing plants. The mean concentration of Cd [0.16 (SD = 0.03) ug/g] was lower than means of As [0.86 (SD = 0.16) ug/g] and Pb [0.91 (SD = 0.22) ug/g] in hair samples, exerting no relationship with immunologic functions for Cd. The Spearman's correlation analysis showed a positive relationship between monocyte counts and hair Pb levels, but negative relations between As and IgG and between As and IgE. In conclusion, findings from these industry workers suggest that As levels in hair may have a stronger relation with immunologic function than Cd and PB have. Further research is needed to confirm the negative relationship. PMID- 29621151 TI - Immunohistochemistry for Diagnosis of Metastatic Carcinomas of Unknown Primary Site. AB - Immunohistochemistry has become an essential ancillary examination for the identification and classification of carcinomas of unknown primary site (CUPs). Over the last decade, the diagnostic accuracy of organ- or tumour-specific immunomarkers and the clinical validation of effective immunohistochemical panels has improved significantly. When dealing with small sample sizes, diagnostic accuracy is crucial, particularly in the current era of targeted molecular and immune-based therapies. Effective systematic use of appropriate immunohistochemical panels enables accurate classification of most of the undifferentiated carcinomas as well as careful preservation of tissues for potential molecular or other ancillary tests. This review discusses the algorithmic approach to the diagnosis of CUPs using CK7 and CK20 staining patterns. It outlines the most frequently used tissue-specific antibodies, provides some pitfalls essential in avoiding potential diagnostic errors and discusses the complementary tools, such as molecular tumour profiling and mutation-specific antibodies, for the improvement of diagnosis and prediction of the treatment response. PMID- 29621152 TI - Taurine Administration Recovers Motor and Learning Deficits in an Angelman Syndrome Mouse Model. AB - Angelman syndrome (AS, MIM 105830) is a rare neurodevelopmental disorder affecting 1:10-20,000 children. Patients show moderate to severe intellectual disability, ataxia and absence of speech. Studies on both post-mortem AS human brains and mouse models revealed dysfunctions in the extra synaptic gamma aminobutyric acid (GABA) receptors implicated in the pathogenesis. Taurine is a free intracellular sulfur-containing amino acid, abundant in brain, considered an inhibiting neurotransmitter with neuroprotective properties. As taurine acts as an agonist of GABA-A receptors, we aimed at investigating whether it might ameliorate AS symptoms. Since mice weaning, we orally administered 1 g/kg/day taurine in water to Ube3a-deficient mice. To test the improvement of motor and cognitive skills, Rotarod, Novel Object Recognition and Open Field tests were assayed at 7, 14, 21 and 30 weeks, while biochemical tests and amino acid dosages were carried out, respectively, by Western-blot and high-performance liquid chromatography (HPLC) on frozen whole brains. Treatment of Ube3am-/p+ mice with taurine significantly improved motor and learning skills and restored the levels of the post-synaptic PSD-95 and pERK1/2-ERK1/2 ratio to wild type values. No side effects of taurine were observed. Our study indicates taurine administration as a potential therapy to ameliorate motor deficits and learning difficulties in AS. PMID- 29621154 TI - Drain Current Stress-Induced Instability in Amorphous InGaZnO Thin-Film Transistors with Different Active Layer Thicknesses. AB - In this study, the initial electrical properties, positive gate bias stress (PBS), and drain current stress (DCS)-induced instabilities of amorphous indium gallium zinc oxide (a-IGZO) thin-film transistors (TFTs) with various active layer thicknesses (TIGZO) are investigated. As the TIGZO increased, the turn-on voltage (Von) decreased, while the subthreshold swing slightly increased. Furthermore, the mobility of over 13 cm2·V−1·s−1 and the negligible hysteresis of ~0.5 V are obtained in all of the a-IGZO TFTs, regardless of the TIGZO. The PBS results exhibit that the Von shift is aggravated as the TIGZO decreases. In addition, the DCS-induced instability in the a-IGZO TFTs with various TIGZO values is revealed using current–voltage and capacitance–voltage (C–V) measurements. An anomalous hump phenomenon is only observed in the off state of the gate-to-source (Cgs) curve for all of the a-IGZO TFTs. This is due to the impact ionization that occurs near the drain side of the channel and the generated holes that flow towards the source side along the back-channel interface under the lateral electric field, which cause a lowered potential barrier near the source side. As the TIGZO value increased, the hump in the off state of the Cgs curve was gradually weakened. PMID- 29621155 TI - Dual-Polarization Ku-Band Compact Spaceborne Antenna Based on Dual-Reflectarray Optics. AB - This article demonstrated an accurate analysis technique for dual-reflectarray antennas that take into account the angle of incidence of the impinging electric field on the main reflectarray cells. The reflected field on the sub and the main reflectarray surfaces is computed using Method of Moments in the spectral domain and assuming local periodicity. The sub-reflectarray is divided into groups of elements and the field radiated by each group is used to compute the incident and reflected field on the main reflectarray cells. A 50-cm demonstrator in Ku-band that provides European coverage has been designed, manufactured and tested to validate the analysis technique. The measured radiation patterns match the simulations and they fulfill the coverage requirements, achieving a cross-polar discrimination better than 25 dB in the frequency range: 12.975-14.25 GHz. PMID- 29621156 TI - Real-Life/Real-Time Elderly Fall Detection with a Triaxial Accelerometer. AB - The consequences of a fall on an elderly person can be reduced if the accident is attended by medical personnel within the first hour. Independent elderly people often stay alone for long periods of time, being in more risk if they suffer a fall. The literature offers several approaches for detecting falls with embedded devices or smartphones using a triaxial accelerometer. Most of these approaches have not been tested with the target population or cannot be feasibly implemented in real-life conditions. In this work, we propose a fall detection methodology based on a non-linear classification feature and a Kalman filter with a periodicity detector to reduce the false positive rate. This methodology requires a sampling rate of only 25 Hz; it does not require large computations or memory and it is robust among devices. We tested our approach with the SisFall dataset achieving 99.4% of accuracy. We then validated it with a new round of simulated activities with young adults and an elderly person. Finally, we give the devices to three elderly persons for full-day validations. They continued with their normal life and the devices behaved as expected. PMID- 29621157 TI - Motor Subtypes of Parkinson's Disease Can Be Identified by Frequency Component of Postural Stability. AB - Parkinson's disease (PD) can be divided into two subtypes based on clinical features-namely tremor dominant (TD) and postural instability and gait difficulty (PIGD). This categorization is important at the early stage of PD, since identifying the subtypes can help to predict the clinical progression of the disease. Accordingly, correctly diagnosing subtypes is critical in initiating appropriate early interventions and tracking the progression of the disease. However, as the disease progresses, it becomes increasingly difficult to further distinguish those attributes that are relevant to the subtypes. In this study, we investigated whether a method using the standing center of pressure (COP) time series data can separate two subtypes of PD by looking at the frequency component of COP (i.e., COP position and speed). Thirty-six participants diagnosed with PD were evaluated, with their bare feet on the force platform, and were instructed to stand upright with their arms by their sides for 20 s (with their eyes open and closed), which is consistent with the traditional COP measures. Fast Fourier transform (FFT) and wavelet transform (WT) were performed to distinguish between the motor subtypes using the COP measures. The TD group exhibited larger amplitudes at the frequency range of 3-7 Hz when compared to the PIGD group. Both the FFT and WT methods were able to differentiate the subtypes. COP time series information can be used to differentiate between the two motor subtypes of PD, using the frequency component of postural stability. PMID- 29621153 TI - Linkage of Infection to Adverse Systemic Complications: Periodontal Disease, Toll Like Receptors, and Other Pattern Recognition Systems. AB - Toll-like receptors (TLRs) are a group of pattern recognition receptors (PRRs) that provide innate immune sensing of conserved pathogen-associated molecular patterns (PAMPs) to engage early immune recognition of bacteria, viruses, and protozoa. Furthermore, TLRs provide a conduit for initiation of non-infectious inflammation following the sensing of danger-associated molecular patterns (DAMPs) generated as a consequence of cellular injury. Due to their essential role as DAMP and PAMP sensors, TLR signaling also contributes importantly to several systemic diseases including cardiovascular disease, diabetes, and others. The overlapping participation of TLRs in the control of infection, and pathogenesis of systemic diseases, has served as a starting point for research delving into the poorly defined area of infection leading to increased risk of various systemic diseases. Although conflicting studies exist, cardiovascular disease, diabetes, cancer, rheumatoid arthritis, and obesity/metabolic dysfunction have been associated with differing degrees of strength to infectious diseases. Here we will discuss elements of these connections focusing on the contributions of TLR signaling as a consequence of bacterial exposure in the context of the oral infections leading to periodontal disease, and associations with metabolic diseases including atherosclerosis and type 2 diabetes. PMID- 29621158 TI - The Cramer-Rao Bounds and Sensor Selection for Nonlinear Systems with Uncertain Observations. AB - This paper considers the problems of the posterior Cramer-Rao bound and sensor selection for multi-sensor nonlinear systems with uncertain observations. In order to effectively overcome the difficulties caused by uncertainty, we investigate two methods to derive the posterior Cramer-Rao bound. The first method is based on the recursive formula of the Cramer-Rao bound and the Gaussian mixture model. Nevertheless, it needs to compute a complex integral based on the joint probability density function of the sensor measurements and the target state. The computation burden of this method is relatively high, especially in large sensor networks. Inspired by the idea of the expectation maximization algorithm, the second method is to introduce some 0-1 latent variables to deal with the Gaussian mixture model. Since the regular condition of the posterior Cramer-Rao bound is unsatisfied for the discrete uncertain system, we use some continuous variables to approximate the discrete latent variables. Then, a new Cramer-Rao bound can be achieved by a limiting process of the Cramer-Rao bound of the continuous system. It avoids the complex integral, which can reduce the computation burden. Based on the new posterior Cramer-Rao bound, the optimal solution of the sensor selection problem can be derived analytically. Thus, it can be used to deal with the sensor selection of a large-scale sensor networks. Two typical numerical examples verify the effectiveness of the proposed methods. PMID- 29621159 TI - Bioactive Compounds Isolated from Neglected Predatory Marine Gastropods. AB - A diverse range of predatory marine gastropods produce toxins, yet most of these molecules remain uncharacterized. Conus species have received the most attention from researchers, leading to several conopeptides reaching clinical trials. This review aims to summarize what is known about bioactive compounds isolated from species of neglected marine gastropods, especially in the Turridae, Terebridae, Babyloniidae, Muricidae, Buccinidae, Colubrariidae, Nassariidae, Cassidae, and Ranellidae families. Multiple species have been reported to contain bioactive compounds with potential toxic activity, but most of these compounds have not been characterized or even clearly identified. The bioactive properties and potential applications of echotoxins and related porins from the Ranellidae family are discussed in more detail. Finally, the review concludes with a call for research on understudied species. PMID- 29621160 TI - Therapeutic Potential and Recent Advances of Curcumin in the Treatment of Aging Associated Diseases. AB - Curcumin, a low molecular weight, lipophilic, major yellow natural polyphenolic, and the most well-known plant-derived compound, is extracted from the rhizomes of the turmeric (Curcuma longa) plant. Curcumin has been demonstrated as an effective therapeutic agent in traditional medicine for the treatment and prevention of different diseases. It has also shown a wide range of biological and pharmacological effects in drug delivery, and has actively been used for the treatment of aging-associated diseases, including cardiovascular diseases, atherosclerosis, neurodegenerative diseases, cancer, rheumatoid arthritis, ocular diseases, osteoporosis, diabetes, hypertension, chronic kidney diseases, chronic inflammation and infection. The functional application and therapeutic potential of curcumin in the treatment of aging-associated diseases is well documented in the literature. This review article focuses mainly on the potential role of plant derived natural compounds such as curcumin, their mechanism of action and recent advances in the treatment of aging-associated diseases. Moreover, the review briefly recaps on the recent progress made in the preparation of nanocurcumins and their therapeutic potential in clinical research for the treatment of aging associated diseases. PMID- 29621161 TI - Oral and Intravenous Fumonisin Exposure in Pigs-A Single-Dose Treatment Experiment Evaluating Toxicokinetics and Detoxification. AB - We examined the toxicokinetics of fumonisin B1 (FB1) and its main metabolites after single dose application intravenously (iv) of 139 nmol FB1 or hydrolyzed FB1 (HFB1)/kg bodyweight (BW) in barrows (BW: 34.4 kg +/- 2.7 kg), as well as the toxicokinetics of FB1, FB2, FB3 and FB1 bioavailability from oral exposure (3425 nmol FB1/kg BW, on top of ration). Additionally, detoxification efficacy of FumD (240 U/kg feed; 3321 nmol FB1/kg BW), a fumonisin esterase, was examined for oral fumonisin application. Urine and feces were collected quantitatively and serum samples were taken over a period of 120 h. Serum toxicokinetics of FB1iv showed a short distribution half-life of 6 min followed by a longer elimination half-life of 36 min. After HFB1iv administration, serum clearance was three times higher compared to FB1iv group (5.6 and 1.8 L/kg/h respectively) which together with a 5 times higher volume of distribution indicates that HFB1 is more rapidly cleared from systemic circulation but distributed more extensively into the extravasal space than FB1. The bioavailability of FB1 in orally exposed pigs was 5.2% (incl. metabolites). Moreover, we found a significant reduction of FB1 bioavailability by 90% caused by the action of fumonisin esterase in the gastrointestinal tract, clearly demonstrating the efficacy of FumD. PMID- 29621163 TI - Development, Implementation and Evaluation of an Educational Intervention to Prevent Low Speed Vehicle Run-Over Events: Lessons Learned. AB - There is a growing body of literature regarding low speed vehicle runover (LSVRO) events among children. To date, no literature exists on evaluation of interventions to address this serious childhood injury. Knowledge, attitudes, and behaviour regarding LSVROs were assessed via survey at a shopping centre (pre intervention), then five months later (post-intervention), to investigate the effect of a population level educational intervention in Queensland, Australia. Participants' knowledge regarding frequency of LSVRO events was poor. No participant demonstrated 'adequate behaviour' in relation to four safe driveway behaviours pre-intervention; this increased at post-intervention (p < 0.05). Most of the sample perceived other's driveway behaviour as inadequate, and this reduced significantly (<0.05). Perceived effectiveness of LSVRO prevention strategies increased from pre- to post-intervention, but not significantly. TV was the greatest source of knowledge regarding LSVROs pre- and post-intervention. This study provides some evidence that the educational campaign and opportunistic media engagement were successful in increasing awareness and improving behaviour regarding LSVROs. While there are several limitations to this study, our experience reflects the 'real-world' challenges associated with implementing prevention strategies. We suggest a multi-faceted approach involving media (including social media), legislative changes, subsidies (for reversing cameras), and education to prevent LSVROs. PMID- 29621164 TI - Source Apportionment and Influencing Factor Analysis of Residential Indoor PM2.5 in Beijing. AB - In order to identify the sources of indoor PM2.5 and to check which factors influence the concentration of indoor PM2.5 and chemical elements, indoor concentrations of PM2.5 and its related elements in residential houses in Beijing were explored. Indoor and outdoor PM2.5 samples that were monitored continuously for one week were collected. Indoor and outdoor concentrations of PM2.5 and 15 elements (Al, As, Ca, Cd, Cu, Fe, K, Mg, Mn, Na, Pb, Se, Tl, V, Zn) were calculated and compared. The median indoor concentration of PM2.5 was 57.64 MUg/m3. For elements in indoor PM2.5, Cd and As may be sensitive to indoor smoking, Zn, Ca and Al may be related to indoor sources other than smoking, Pb, V and Se may mainly come from outdoor. Five factors were extracted for indoor PM2.5 by factor analysis, explained 76.8% of total variance, outdoor sources contributed more than indoor sources. Multiple linear regression analysis for indoor PM2.5, Cd and Pb was performed. Indoor PM2.5 was influenced by factors including outdoor PM2.5, smoking during sampling, outdoor temperature and time of air conditioner use. Indoor Cd was affected by factors including smoking during sampling, outdoor Cd and building age. Indoor Pb concentration was associated with factors including outdoor Pb and time of window open per day, building age and RH. In conclusion, indoor PM2.5 mainly comes from outdoor sources, and the contributions of indoor sources also cannot be ignored. Factors associated indoor and outdoor air exchange can influence the concentrations of indoor PM2.5 and its constituents. PMID- 29621162 TI - Toxic Effects of Bisphenol A, Propyl Paraben, and Triclosan on Caenorhabditis elegans. AB - Bisphenol A (BPA) is a ubiquitous plasticizer which is absorbed by ingestion and dermal contact; propyl paraben (PPB) inhibits the microbiome and extends the shelf life of many personal care products, whereas triclosan (TCS) is commonly found in antiseptics, disinfectants, or additives. In this work, Caenorhabditis elegans was used as a biological model to assess the toxic effects of BPA, PPB, and TCS. The wild type strain, Bristol N2, was used in bioassays with the endpoints of lethality, growth, and reproduction; green fluorescent protein (GFP) transgenic strains with the hsp-3, hsp-4, hsp-16.2, hsp-70, sod-1, sod-4, cyp 35A4, cyp-29A2, and skn-1 genes were evaluated for their mRNA expression through fluorescence measurement; and quick Oil Red O (q ORO) was utilized to stain lipid deposits. Lethality was concentration-dependent, while TCS and PPB showed more toxicity than BPA. BPA augmented worm length, while PPB reduced it. All toxicants moderately increased the width and the width-length ratio. BPA and PPB promoted reproduction, in contrast to TCS, which diminished it. All toxicants affected the mRNA expression of genes related to cellular stress, control of reactive oxygen species, and nuclear receptor activation. Lipid accumulation occurred in exposed worms. In conclusion, BPA, PPB, and TCS alter the physiology of growth, lipid accumulation, and reproduction in C. elegans, most likely through oxidative stress mechanisms. PMID- 29621165 TI - Keeping Antibiotics at Home Promotes Self-Medication with Antibiotics among Chinese University Students. AB - BACKGROUND: Inappropriate use of antibiotics has caused antimicrobial resistance, presenting a major health challenge to the world population. Self-medication with antibiotics (SMA) is currently at an alarming level in China. OBJECTIVES: To determine the sources of antibiotics leftover at home, the risk factors of keeping antibiotics at home, and the associations between keeping antibiotics at home and SMA among Chinese university students. METHODS: Six provinces were purposely selected from six regions of China, and one multi-disciplinary university was selected from each chosen province. A total of 11,192 university students were selected using cluster random sampling from the selected universities. Logistic regression was conducted to examine the relationship between keeping antibiotics at home and SMA. RESULTS: Out of the 11,192 students surveyed, 7057 (63.1%) reported keeping antibiotics at home at the time they were surveyed. Of those who kept antibiotics in their home, 1965 (27.8%) reported that these antibiotics were left over from a previous prescription by a doctor and 4893 (69.3%), purchased antibiotics over the counter. Additionally, 29.6% (507/1711) of students self-medicated with antibiotics when ill during the month before the survey. Students keeping antibiotics at home were five times (95% CI 3.53, 7.05) more likely to engage in SMA when ill and 2.6 times (95% CI 2.34, 2.89) more likely to self-medicating with antibiotics for prophylaxis than the other students. Female students, those with a family background of higher education, and those who had a parent working in the medical field had a significantly higher chance of keeping antibiotics at home. CONCLUSIONS: The high prevalence of keeping antibiotics at home and SMA among young adults is a serious concern. Professional regulations and population-tailored health education are needed. PMID- 29621166 TI - Subclinical Enteric Parasitic Infections and Growth Faltering in Infants in Sao Tome, Africa: A Birth Cohort Study. AB - The associations between enteric pathogenic parasites and growth in infants in Sao Tome were explored using a refined anthropometric approach to recognize early growth faltering. A birth cohort study was conducted with follow-up to 24 months of age. Microscopic examination for protozoa and soil-transmitted helminths was performed. Anthropometric assessments included: z-scores for weight-for-length (WLZ), length-for-age (LAZ), weight (WAVZ) and length velocities (LAVZ), length for-age difference (LAD), and wasting and stunting risk (<=-1 SD). Generalized additive mixed effects regression models were used to explore the associations between anthropometric parameters and enteric parasitic infections and cofactors. A total of 475 infants were enrolled, and 282 completed the study. The great majority of infants were asymptomatic. Giardia lamblia was detected in 35.1% of infants in at least one stool sample, helminths in 30.4%, and Cryptosporidium spp. in 14.7%. Giardia lamblia and helminth infections were significantly associated with mean decreases of 0.10 in LAZ and 0.32 in LAD, and of 0.16 in LAZ and 0.48 in LAD, respectively. Cryptosporidium spp. infection was significantly associated with a mean decrease of 0.43 in WAVZ and 0.55 in LAVZ. The underestimated association between subclinical parasitic enteric infections and mild growth faltering in infants should be addressed in public health policies. PMID- 29621167 TI - Underestimation of Self-Reported Smoking Prevalence in Korean Adolescents: Evidence from Gold Standard by Combined Method. AB - The objective of this study was to evaluate the validity of self-reported smoking prevalence in Korean adolescents by using an improved gold standard by a combined method. Using a stratified sampling method, we selected 13 schools from among 397 high schools that participated in the 2015 Korean Youth Health Risk Behavior Web Based Survey (KYRBS). A second survey (repeated self-reporting questionnaire and urinary cotinine test) was conducted on 1058 students who completed the KYRBS. The gold standard of current smoker was defined as those either self-reporting as a smoker in the second survey or having a urinary cotinine concentration >=50 ng/mL. The current smoking prevalence in the first survey (KYRBS) was 7.9% (boys 16.5% and girls 1.8%), which was lower than the results based on gold standard (11.3% total, boys 21.9% and girls 3.7%). The sensitivity and specificity of self reported smoking status was 62.5% and 99.0%, respectively. In particular, the sensitivity of girls (43.5%) was lower than that of boys (67.0%). The self reported smoking prevalence in Korean adolescents was underestimated, particularly among girls. Careful attention should be paid to interpreting adolescents' smoking prevalence, and supplementary surveys or periodic validity tests need to be considered in Asian countries. PMID- 29621168 TI - A Lightweight Continuous Authentication Protocol for the Internet of Things. AB - Modern societies are moving toward an information-oriented environment. To gather and utilize information around people's modern life, tiny devices with all kinds of sensing devices and various sizes of gateways need to be deployed and connected with each other through the Internet or proxy-based wireless sensor networks (WSNs). Within this kind of Internet of Things (IoT) environment, how to authenticate each other between two communicating devices is a fundamental security issue. As a lot of IoT devices are powered by batteries and they need to transmit sensed data periodically, it is necessary for IoT devices to adopt a lightweight authentication protocol to reduce their energy consumption when a device wants to authenticate and transmit data to its targeted peer. In this paper, a lightweight continuous authentication protocol for sensing devices and gateway devices in general IoT environments is introduced. The concept of valid authentication time period is proposed to enhance robustness of authentication between IoT devices. To construct the proposed lightweight continuous authentication protocol, token technique and dynamic features of IoT devices are adopted in order to reach the design goals: the reduction of time consumption for consecutive authentications and energy saving for authenticating devices through by reducing the computation complexity during session establishment of continuous authentication. Security analysis is conducted to evaluate security strength of the proposed protocol. In addition, performance analysis has shown the proposed protocol is a strong competitor among existing protocols for device-to-device authentication in IoT environments. PMID- 29621169 TI - Adaptive LINE-P: An Adaptive Linear Energy Prediction Model for Wireless Sensor Network Nodes. AB - In the context of wireless sensor networks, energy prediction models are increasingly useful tools that can facilitate the power management of the wireless sensor network (WSN) nodes. However, most of the existing models suffer from the so-called fixed weighting parameter, which limits their applicability when it comes to, e.g., solar energy harvesters with varying characteristics. Thus, in this article we propose the Adaptive LINE-P (all cases) model that calculates adaptive weighting parameters based on the stored energy profiles. Furthermore, we also present a profile compression method to reduce the memory requirements. To determine the performance of our proposed model, we have used real data for the solar and wind energy profiles. The simulation results show that our model achieves 90-94% accuracy and that the compressed method reduces memory overheads by 50% as compared to state-of-the-art models. PMID- 29621170 TI - A Two-Stage Reconstruction Processor for Human Detection in Compressive Sensing CMOS Radar. AB - Complementary metal-oxide-semiconductor (CMOS) radar has recently gained much research attraction because small and low-power CMOS devices are very suitable for deploying sensing nodes in a low-power wireless sensing system. This study focuses on the signal processing of a wireless CMOS impulse radar system that can detect humans and objects in the home-care internet-of-things sensing system. The challenges of low-power CMOS radar systems are the weakness of human signals and the high computational complexity of the target detection algorithm. The compressive sensing-based detection algorithm can relax the computational costs by avoiding the utilization of matched filters and reducing the analog-to-digital converter bandwidth requirement. The orthogonal matching pursuit (OMP) is one of the popular signal reconstruction algorithms for compressive sensing radar; however, the complexity is still very high because the high resolution of human respiration leads to high-dimension signal reconstruction. Thus, this paper proposes a two-stage reconstruction algorithm for compressive sensing radar. The proposed algorithm not only has lower complexity than the OMP algorithm by 75% but also achieves better positioning performance than the OMP algorithm especially in noisy environments. This study also designed and implemented the algorithm by using Vertex-7 FPGA chip (Xilinx, San Jose, CA, USA). The proposed reconstruction processor can support the 256 * 13 real-time radar image display with a throughput of 28.2 frames per second. PMID- 29621171 TI - A Temperature-Hardened Sensor Interface with a 12-Bit Digital Output Using a Novel Pulse Width Modulation Technique. AB - A fully integrated sensor interface for a wide operational temperature range is presented. It translates the sensor signal into a pulse width modulated (PWM) signal that is then converted into a 12-bit digital output. The sensor interface is based on a pair of injection locked oscillators used to implement a differential time-domain architecture with low sensitivity to temperature variations. A prototype has been fabricated using a 180 nm partially depleted silicon-on-insulator (SOI) technology. Experimental results demonstrate a thermal stability as low as 65 ppm/ degrees C over a large temperature range from -20 degrees C up to 220 degrees C. PMID- 29621172 TI - Cu(OH)2 and CuO Nanorod Synthesis on Piezoresistive Cantilevers for the Selective Detection of Nitrogen Dioxide. AB - Self-controlled active oscillating microcantilevers with a piezoresistive readout are very promising sensitive sensors, despite their small surface. In order to increase this surface and consequently their sensitivity, we nanostructured them with copper hydroxide (Cu(OH)2) or with copper oxide (CuO) nanorods. The Cu(OH)2 rods were grown, on a homogeneous copper layer previously evaporated on the top of the cantilever. The CuO nanorods were further obtained by the annealing of the copper hydroxide nanostructures. Then, these copper based nanorods were used to detect several molecules vapors. The results showed no chemical affinity (no formation of a chemical bond) between the CuO cantilevers and the tested molecules. The cantilever with Cu(OH)2 nanorods is selective to nitrogen dioxide (NO2) in presence of humidity. Indeed, among all the tested analytes, copper hydroxide has only an affinity with NO2. Despite the absence of affinity, the cantilevers could even so condensate explosives (1,3,5-trinitro-1,3,5-triazinane (RDX) and pentaerythritol tetranitrate (PETN) on their surface when the cantilever temperature was lower than the explosives source, allowing their detection. We proved that in condensation conditions, the cantilever surface material has no importance and that the nanostructuration is useless because a raw silicon cantilever detects as well as the nanostructured ones. PMID- 29621173 TI - Statistical Analysis of SSMIS Sea Ice Concentration Threshold at the Arctic Sea Ice Edge during Summer Based on MODIS and Ship-Based Observational Data. AB - The threshold of sea ice concentration (SIC) is the basis for accurately calculating sea ice extent based on passive microwave (PM) remote sensing data. However, the PM SIC threshold at the sea ice edge used in previous studies and released sea ice products has not always been consistent. To explore the representable value of the PM SIC threshold corresponding on average to the position of the Arctic sea ice edge during summer in recent years, we extracted sea ice edge boundaries from the Moderate-resolution Imaging Spectroradiometer (MODIS) sea ice product (MOD29 with a spatial resolution of 1 km), MODIS images (250 m), and sea ice ship-based observation points (1 km) during the fifth (CHINARE-2012) and sixth (CHINARE-2014) Chinese National Arctic Research Expeditions, and made an overlay and comparison analysis with PM SIC derived from Special Sensor Microwave Imager Sounder (SSMIS, with a spatial resolution of 25 km) in the summer of 2012 and 2014. Results showed that the average SSMIS SIC threshold at the Arctic sea ice edge based on ice-water boundary lines extracted from MOD29 was 33%, which was higher than that of the commonly used 15% discriminant threshold. The average SIC threshold at sea ice edge based on ice water boundary lines extracted by visual interpretation from four scenes of the MODIS image was 35% when compared to the average value of 36% from the MOD29 extracted ice edge pixels for the same days. The average SIC of 31% at the sea ice edge points extracted from ship-based observations also confirmed that choosing around 30% as the SIC threshold during summer is recommended for sea ice extent calculations based on SSMIS PM data. These results can provide a reference for further studying the variation of sea ice under the rapidly changing Arctic. PMID- 29621174 TI - Recognition of Broken Wire Rope Based on Remanence using EEMD and Wavelet Methods. AB - The magnetic flux leakage method is widely used for non-destructive testing in wire rope applications. A non-destructive testing device for wire rope based on remanence was designed to solve the problems of large volume, low accuracy, and complex operations seen in traditional devices. A wavelet denoising method based on ensemble empirical mode decomposition was proposed to reduce the system noise in broken wire rope testing. After extracting the defects image, the wavelet super-resolution reconstruction technique was adopted to improve the resolution of defect grayscale. A back propagation neural network was designed to classify defects by the feature vectors of area, rectangle, stretch length, and seven invariant moments. The experimental results show that the device was not only highly precise and sensitive, but also easy to operate; noise is effectively suppressed by the proposed filtering algorithm, and broken wires are classified by the network. PMID- 29621175 TI - Evaluation for Bearing Wear States Based on Online Oil Multi-Parameters Monitoring. AB - As bearings are critical components of a mechanical system, it is important to characterize their wear states and evaluate health conditions. In this paper, a novel approach for analyzing the relationship between online oil multi-parameter monitoring samples and bearing wear states has been proposed based on an improved gray k-means clustering model (G-KCM). First, an online monitoring system with multiple sensors for bearings is established, obtaining oil multi-parameter data and vibration signals for bearings through the whole lifetime. Secondly, a gray correlation degree distance matrix is generated using a gray correlation model (GCM) to express the relationship of oil monitoring samples at different times and then a KCM is applied to cluster the matrix. Analysis and experimental results show that there is an obvious correspondence that state changing coincides basically in time between the lubricants' multi-parameters and the bearings' wear states. It also has shown that online oil samples with multi parameters have early wear failure prediction ability for bearings superior to vibration signals. It is expected to realize online oil monitoring and evaluation for bearing health condition and to provide a novel approach for early identification of bearing-related failure modes. PMID- 29621177 TI - The Role of Title IX Coordinators on College and University Campuses. AB - The purpose of this study was to better understand the role of Title IX coordinators and their policies across four-year universities and two-year community colleges in the United States (U.S.). There is little information regarding Title IX coordinators' training, background, and policies on how they handle Title IX investigations regarding sexual violence. The data come from an online survey that included 692 Title IX coordinators across four-year (private and public) and two-year campuses and represented 42 different states in the US. The current study found that most Title IX coordinators were in part-time positions with less than three years of experience. Most of the coordinators and their investigators were trained in Title IX policies. Most coordinators provide Title IX training for their students and faculty, and most have completed a campus climate survey; however, 15% had not completed a survey. The findings suggest that the majority of campuses are continuing to increase their Title IX visibility; however, there are several recommendations for campuses to improve their policies. The current study was able to shed light on how Title IX coordinators do their jobs and the role they play in helping with the challenging issues surrounding sexual violence at institutions across the nation. PMID- 29621176 TI - Functionalized Thick Film Impedance Sensors for Use in In Vitro Cell Culture. AB - : Multi-electrode arrays find application in electrophysiological recordings. The quality of the captured signals depends on the interfacial contact between electrogenic cells and the electronic system. Therefore, it requires reliable low impedance electrodes. Low-temperature cofired ceramic technology offers a suitable platform for rapid prototyping of biological reactors and can provide both stable fluid supply and integrated bio-hardware interfaces for recordings in electrogenic cell cultures. The 3D assembly of thick film gold electrodes in in vitro bio-reactors has been demonstrated for neuronal recordings. However, especially when dimensions become small, their performance varies strongly. This work investigates the influence of different coatings on thick film gold electrodes with regard to their influence on impedance behavior. PEDOT: PSS layer, titanium oxynitride and laminin coatings are deposited on LTCC gold electrodes using different 2D and 3D MEA chip designs. Their impedance characteristics are compared and discussed. Titanium oxynitride layers emerged as suitable functionalization. Small 86-um-electrodes have a serial resistance Rs of 32 kOhm and serial capacitance Cs of 4.1 pF at 1 kHz. Thick film gold electrodes with such coatings are thus qualified for signal recording in 3-dimensional in vitro cell cultures. PMID- 29621178 TI - Assessment of the Pro12Ala Polymorphism in the PPAR-gamma2 Gene among Type 2 Diabetes Patients in a Nigerian Population. AB - The association between the Pro12Ala polymorphism of the PPARgamma2 gene, type 2 diabetes (T2D), and obesity in certain ethnic populations has been reported. However, this relationship has not yet been described among diabetes patients in Nigeria. This study investigated the relationship between the Pro12Ala polymorphism in the PPARgamma2 gene, obesity, and lipid abnormalities characterizing T2D among patients in Nigeria. This case-control study recruited 73 T2D and 75 non-diabetic (ND) patients. Demographic and clinical data were collected and blood glucose levels together with serum lipid profile for patients were measured. Pro12Ala polymorphism in the PPARgamma2 gene was genotyped by restriction fragment length-Polymerase Chain Reaction (RFLP-PCR). The PPAR-gamma2 gene (amplicon size = 270 base pair) was successfully amplified for all samples. Following restriction enzyme digestion and analysis by agarose gel electrophoresis, amplicons from samples showed a band of size 270 bp and were of the wild homozygous Pro/Pro genotype. Ala12 variant was totally absent from the study population. Obesity, estimated using Body Mass Index (BMI) and waist circumference (WC), was significantly higher (p < 0.05) in T2D patients compared to the non-diabetic patients. More so, the prevalence of lipid abnormalities; hypercholesterolaemia (TC > 200 mg/dL), hypertriglyceridaemia (TG > 150 mg/dL), high HDL (>100 mg/dL), and low HDL (<50 mg/dL) was significantly greater (p < 0.001) in T2D patients compared to non-diabetic patients. Results obtained further indicated lack of significant association between PPAR-gamma2 gene polymorphism, T2D, and obesity. However, obesity and dyslipidaemia were strongly associated in T2D patients. PMID- 29621179 TI - The Validity of Functional Near-Infrared Spectroscopy Recordings of Visuospatial Working Memory Processes in Humans. AB - Functional near infrared spectroscopy (fNIRS) is increasingly used for investigating cognitive processes. To provide converging evidence for the validity of fNIRS recordings in cognitive neuroscience, we investigated functional activation in the frontal cortex in 43 participants during the processing of a visuospatial working memory (WM) task and a sensory duration discrimination (DD) task functionally unrelated to WM. To distinguish WM-related processes from a general effect of increased task demand, we applied an adaptive approach, which ensured that subjective task demand was virtually identical for all individuals and across both tasks. Our specified region of interest covered Brodmann Area 8 of the left hemisphere, known for its important role in the execution of WM processes. Functional activation, as indicated by an increase of oxygenated and a decrease of deoxygenated hemoglobin, was shown for the WM task, but not in the DD task. The overall pattern of results indicated that hemodynamic responses recorded by fNIRS are sensitive to specific visuospatial WM capacity related processes and do not reflect a general effect of increased task demand. In addition, the finding that no such functional activation could be shown for participants with far above-average mental ability suggested different cognitive processes adopted by this latter group. PMID- 29621181 TI - Dabrafenib Treatment in a Patient with an Epithelioid Glioblastoma and BRAF V600E Mutation. AB - Novel therapeutic targets in malignant glioma patients are urgently needed. Point mutations of the v-Raf murine sarcoma viral oncogene homolog B (BRAF) gene occur predominantly in melanoma patients, but may also occur in gliomas. Thus, this is a target of great interest for this group of patients. In a nine-year-old male patient, an anaplastic astrocytoma in the left temporoparietal region was diagnosed histologically. After first- and second-line treatment, a malignant progression to a secondary glioblastoma was observed ten years after the initial diagnosis. Within the following seven years, all other conventional treatment options were exhausted. At this time point, recurrent tumor histology revealed an epithelioid glioblastoma, without a mutation in the isocitrate dehydrogenase gene (IDH wild-type). In order to identify a potential target for an experimental salvage therapy, mutational tumor analysis showed a BRAF V600E mutation. Consecutively, dabrafenib treatment was initiated. The patient remained clinically stable, and follow-up magnetic resonance images (MRI) were consistent with "Stable Disease" according to the Response Assessment in Neuro-Oncology Working Group (RANO) criteria for the following ten months until tumor progression was detected. The patient died 16 months after dabrafenib treatment initiation. Particularly in younger glioma patients as well as in patients with an epithelioid glioblastoma, screening for a V600E BRAF mutation is promising since, in these cases, targeted therapy with BRAF inhibitors seems to be a useful salvage treatment option. PMID- 29621180 TI - Applications of CRISPR/Cas System to Bacterial Metabolic Engineering. AB - The clustered regularly interspaced short palindromic repeats/CRISPR-associated (CRISPR/Cas) adaptive immune system has been extensively used for gene editing, including gene deletion, insertion, and replacement in bacterial and eukaryotic cells owing to its simple, rapid, and efficient activities in unprecedented resolution. Furthermore, the CRISPR interference (CRISPRi) system including deactivated Cas9 (dCas9) with inactivated endonuclease activity has been further investigated for regulation of the target gene transiently or constitutively, avoiding cell death by disruption of genome. This review discusses the applications of CRISPR/Cas for genome editing in various bacterial systems and their applications. In particular, CRISPR technology has been used for the production of metabolites of high industrial significance, including biochemical, biofuel, and pharmaceutical products/precursors in bacteria. Here, we focus on methods to increase the productivity and yield/titer scan by controlling metabolic flux through individual or combinatorial use of CRISPR/Cas and CRISPRi systems with introduction of synthetic pathway in industrially common bacteria including Escherichia coli. Further, we discuss additional useful applications of the CRISPR/Cas system, including its use in functional genomics. PMID- 29621182 TI - Emerging Roles of Estrogen-Related Receptors in the Brain: Potential Interactions with Estrogen Signaling. AB - In addition to their well-known role in the female reproductive system, estrogens can act in the brain to regulate a wide range of behaviors and physiological functions in both sexes. Over the past few decades, genetically modified animal models have greatly increased our knowledge about the roles of estrogen receptor (ER) signaling in the brain in behavioral and physiological regulations. However, less attention has been paid to the estrogen-related receptors (ERRs), the members of orphan nuclear receptors whose sequences are homologous to ERs but lack estrogen-binding ability. While endogenous ligands of ERRs remain to be determined, they seemingly share transcriptional targets with ERs and their expression can be directly regulated by ERs through the estrogen-response element embedded within the regulatory region of the genes encoding ERRs. Despite the broad expression of ERRs in the brain, we have just begun to understand the fundamental roles they play at molecular, cellular, and circuit levels. Here, we review recent research advancement in understanding the roles of ERs and ERRs in the brain, with particular emphasis on ERRs, and discuss possible cross-talk between ERs and ERRs in behavioral and physiological regulations. PMID- 29621184 TI - The Flavonoid Isoquercitrin Precludes Initiation of Zika Virus Infection in Human Cells. AB - The medical importance of Zika virus (ZIKV) was fully highlighted during the recent epidemics in South Pacific islands and Americas due to ZIKV association with severe damage to fetal brain development and neurological complications in adult patients. A worldwide research effort has been undertaken to identify effective compounds to prevent or treat ZIKV infection. Fruits and vegetables may be sources of compounds with medicinal properties. Flavonoids are one class of plant compounds that emerge as promising antiviral molecules against ZIKV. In the present study, we demonstrated that flavonoid isoquercitrin exerts antiviral activity against African historical and Asian epidemic strains of ZIKV in human hepatoma, epithelial, and neuroblastoma cell lines. Time-of-drug addition assays showed that isoquercitrin acts on ZIKV entry by preventing the internalisation of virus particles into the host cell. Our data also suggest that the glycosylated moiety of isoquercitrin might play a role in the antiviral effect of the flavonoid against ZIKV. Our results highlight the importance of isoquercitrin as a promising natural antiviral compound to prevent ZIKV infection. PMID- 29621185 TI - Illumination on "Reserving Phloem and Discarding Xylem" and Quality Evaluation of Radix polygalae by Determining Oligosaccharide Esters, Saponins, and Xanthones. AB - The root of Polygala tenuifolia Willd. or Polygala sibirica L. exhibits protective effects on the central nervous system and is frequently used to treat insomnia, amnesia, and other cognitive dysfunction. In our study, we studied nine bioactive compounds spanning oligosaccharide esters, saponins, and xanthones by using a sensitive, efficient, and validated method established on ultra performance liquid chromatography coupled with triple quadrupole mass spectrometry. The quantified result of interesting compounds proved that accumulation of those compounds were found in phloem rather than in xylem. By taking the standardized result of nine compound contents into account, the "Spider-web" analytical result of xylem and phloem from Radix polygalae (RP) unveiled the rationality of RP's classical use in clinic including discarding the xylem and reserving the phloem. Moreover, the remarkable variation was also revealed from the quantitative result of 45 samples with different diameters from the different origins, which did not significantly correlate with the variation of RP's diameter. Our study could shed the light on the quality assessment of RP for further research and illustrate the scientific connotation of the processing method of "discarding the xylem and reserving the phloem". PMID- 29621186 TI - Using a Counting Process Method to Impute Censored Follow-Up Time Data. AB - Censoring occurs when complete follow-up time information is unavailable for patients enrolled in a clinical study. The process is considered to be informative (non-ignorable) if the likelihood function for the model cannot be partitioned into a set of response parameters that are independent of the censoring parameters. In such cases, estimated survival time probabilities may be biased, prompting the need for special statistical methods to remedy the situation. The problem is especially salient when censoring occurs early in a study. In this paper, we describe a method to impute censored follow-up times using a counting process method. PMID- 29621183 TI - Tau-Induced Pathology in Epilepsy and Dementia: Notions from Patients and Animal Models. AB - Patients with dementia present epilepsy more frequently than the general population. Seizures are more common in patients with Alzheimer's disease (AD), dementia with Lewy bodies (LBD), frontotemporal dementia (FTD) and progressive supranuclear palsy (PSP) than in other dementias. Missense mutations in the microtubule associated protein tau (MAPT) gene have been found to cause familial FTD and PSP, while the P301S mutation in MAPT has been associated with early onset fast progressive dementia and the presence of seizures. Brains of patients with AD, LBD, FTD and PSP show hyperphosphorylated tau aggregates, amyloid-beta plaques and neuropil threads. Increasing evidence suggests the existence of overlapping mechanisms related to the generation of network hyperexcitability and cognitive decline. Neuronal overexpression of tau with various mutations found in FTD with parkinsonism-linked to chromosome 17 (FTDP-17) in mice produces epileptic activity. On the other hand, the use of certain antiepileptic drugs in animal models with AD prevents cognitive impairment. Further efforts should be made to search for plausible common targets for both conditions. Moreover, attempts should also be made to evaluate the use of drugs targeting tau and amyloid-beta as suitable pharmacological interventions in epileptic disorders. The diagnosis of dementia and epilepsy in early stages of those diseases may be helpful for the initiation of treatments that could prevent the generation of epileptic activity and cognitive deterioration. PMID- 29621188 TI - Chloride Ion Adsorption Capacity of Anion Exchange Resin in Cement Mortar. AB - This paper presents the effect of anion exchange resin (AER) on the adsorption of chloride ions in cement mortar. The kinetic and equilibrium behaviors of AER were investigated in distilled water and Ca(OH)2 saturated solutions, and then the adsorption of chloride ions by the AER in the mortar specimen was determined. The AER was used as a partial replacement for sand in the mortar specimen. The mortar specimen was coated with epoxy, except for an exposed surface, and then immersed in a NaCl solution for 140 days. The chloride content in the mortar specimen was characterized by energy dispersive X-ray fluorescence analysis and electron probe microanalysis. The results showed that the AER could adsorb the chloride ions from the solution rapidly but had a relatively low performance when the pH of its surrounding environment increased. When the AER was mixed in the cement mortar, its chloride content was higher than that of the cement matrix around it, which confirms the chloride ion adsorption capacity of the AER. PMID- 29621187 TI - Identification of a WNT5A-Responsive Degradation Domain in the Kinesin Superfamily Protein KIF26B. AB - Noncanonical WNT pathways function independently of the beta-catenin transcriptional co-activator to regulate diverse morphogenetic and pathogenic processes. Recent studies showed that noncanonical WNTs, such as WNT5A, can signal the degradation of several downstream effectors, thereby modulating these effectors' cellular activities. The protein domain(s) that mediates the WNT5A dependent degradation response, however, has not been identified. By coupling protein mutagenesis experiments with a flow cytometry-based degradation reporter assay, we have defined a protein domain in the kinesin superfamily protein KIF26B that is essential for WNT5A-dependent degradation. We found that a human disease causing KIF26B mutation located at a conserved amino acid within this domain compromises the ability of WNT5A to induce KIF26B degradation. Using pharmacological perturbation, we further uncovered a role of glycogen synthase kinase 3 (GSK3) in WNT5A regulation of KIF26B degradation. Lastly, based on the identification of the WNT5A-responsive domain, we developed a new reporter system that allows for efficient profiling of WNT5A-KIF26B signaling activity in both somatic and stem cells. In conclusion, our study identifies a new protein domain that mediates WNT5A-dependent degradation of KIF26B and provides a new tool for functional characterization of noncanonical WNT5A signaling in cells. PMID- 29621189 TI - Nanoscale Origins of the Size Effect in the Compression Response of Single Crystal Ni-Base Superalloy Micro-Pillars. AB - Nickel superalloys play a pivotal role in enabling power-generation devices on land, sea, and in the air. They derive their strength from coherent cuboidal precipitates of the ordered gamma' phase that is different from the gamma matrix in composition, structure and properties. In order to reveal the correlation between elemental distribution, dislocation glide and the plastic deformation of micro- and nano-sized volumes of a nickel superalloy, a combined in situ nanoindentation compression study was carried out with a scanning electron microscope (SEM) on micro- and nano-pillars fabricated by focused ion beam (FIB) milling of Ni-base superalloy CMSX4. The observed mechanical response (hardening followed by softening) was correlated with the progression of crystal slip that was revealed using FIB nano-tomography and energy-dispersive spectroscopy (EDS) elemental mapping. A hypothesis was put forward that the dependence of material strength on the size of the sample (micropillar diameter) is correlated with the characteristic dimension of the structural units (gamma' precipitates). By proposing two new dislocation-based models, the results were found to be described well by a new parameter-free Hall-Petch equation. PMID- 29621191 TI - Syringomyelia in an Adult American Paint Horse. AB - Syringomyelia is a form of myelodysplasia defined by the formation of one or more fluid-filled cavities within the spinal cord that do not communicate with the central canal. The defect may be congenital or acquired. Clinical signs correlate to the segment of spinal cord affected and include pain, paresis, proprioceptive deficits, alterations in sensation, scoliosis, and autonomic dysfunction. This report describes the clinical and pathologic changes in a case of acquired syringomyelia in a 10-year-old American Paint Horse mare. The horse had a six week history of progressive proprioceptive deficits in all four limbs, bilateral pelvic limb ataxia, and muscle fasciculations that were unresponsive to treatment with stall rest, phenylbutazone, and dexamethasone. Syringomyelia was diagnosed postmortem within cervical, thoracic, and lumbar spinal cord segments. Acquired syringomyelia should be considered among differential diagnoses in adult horses displaying progressive neurologic deficits. PMID- 29621190 TI - Chlamydomonas angulosa (Green Alga) and Nostoc commune (Blue-Green Alga) Microalgae-Cellulose Composite Aerogel Beads: Manufacture, Physicochemical Characterization, and Cd (II) Adsorption. AB - This study presents composite aerogel beads prepared by mixing dissolved cellulose with Chlamydomonas angulosa and Nostoc commune cells, respectively, at 0.1, 0.3, and 0.5% (w/w). The manufactured composites (termed regenerated cellulose (RC)), with C. angulosa (RCCA-(1, 3, and 5)), and with N. commune (RCNC (1, 3, and 5)) were analyzed. Both RCCA-5 and RCNC-5 showed the high specific surface area to be about 261.3 and 332.8 m2.g-1. In the microstructure analysis, network structures were observed in the cross-sections of RC, RCCA-5, and RCNC-5. The pyrolysis temperature of the RCCA-5 and RCNC-5 composite aerogel beads was rapidly increased about 250 degrees C during the mixing of cellulose with C. angulosa and N. commune. The chemical analysis of RC, RCCA-5, and RCNC-5 showed peaks corresponding to various functional groups, such as amide, carboxyl, and hydroxyl groups from protein, lipid, and carbohydrate. RCNC-5 at pH 6 demonstrated highest Cd2+ removal rate about 90.3%, 82.1%, and 63.1% at 10, 25, and 50 ppm Cd2+, respectively. At pH 6, Cd2+ adsorption rates per unit weight of the RCNC-5 were about 0.9025, 2.0514, and 3.1547 mg/g at 10, 25, and 50 ppm, respectively. The peaks assigned to the amide, carboxyl, and hydroxyl groups in RCCA-5, RCNC-5, and RC were shifted or disappeared immediately after adsorption of Cd2+. The specific surface area, total pore volume, and mean pore diameter of composites was decreased due to adsorption of Cd2+ on the developed materials. As can be seen in the X-ray powder diffraction (XRD) spectrum, significant changes in the molecular structure of the composite aerogel beads were not observed even after adsorption of Cd2+. PMID- 29621192 TI - Testing the Predictive Validity of the Healthy Eating Index-2015 in the Multiethnic Cohort: Is the Score Associated with a Reduced Risk of All-Cause and Cause-Specific Mortality? AB - The Healthy Eating Index-2015 (HEI-2015) was created to assess conformance of dietary intake with the Dietary Guidelines for Americans (DGA) 2015-2020. We assessed the association between the HEI-2015 and mortality from all-cause, cardiovascular disease (CVD), and cancer in the Multiethnic Cohort (MEC). White, African American, Native Hawaiian, Japanese American, and Latino adults (n > 215,000) from Hawaii and California completed a quantitative food-frequency questionnaire at study enrollment. HEI-2015 scores were divided into quintiles for men and women. Radar graphs were used to demonstrate how dietary components contributed to HEI-2015 scores. Mortality was documented over 17-22 years of follow-up. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed using Cox proportional hazards models. High HEI-2015 scores were inversely associated with risk of mortality from all-cause, CVD, and cancer for men and women (p-trend <0.0001 for all models). For men, the HRs (CIs) for all-cause, CVD, and cancer comparing the highest to the lowest quintile were 0.79 (0.76, 0.82), 0.76 (0.71, 0.82), and 0.80 (0.75, 0.87), respectively. For women, the HRs were 0.79 (0.76, 0.82), 0.75 (0.70, 0.81), and 0.84 (0.78, 0.91), respectively. These results, in a multiethnic population, demonstrate that following a diet aligned with the DGAs 2015-2020 recommendations is associated with lower risk of mortality from all-cause, CVD, and cancer. PMID- 29621193 TI - 3D-Subspace-Based Auto-Paired Azimuth Angle, Elevation Angle, and Range Estimation for 24G FMCW Radar with an L-Shaped Array. AB - In this paper, a three-dimensional (3D)-subspace-based azimuth angle, elevation angle, and range estimation method with auto-pairing is proposed for frequency modulated continuous waveform (FMCW) radar with an L-shaped array. The proposed method is designed to exploit the 3D shift-invariant structure of the stacked Hankel snapshot matrix for auto-paired azimuth angle, elevation angle, and range estimation. The effectiveness of the proposed method is verified through a variety of experiments conducted in a chamber. For the realization of the proposed method, K-band FMCW radar is implemented with an L-shaped antenna. PMID- 29621194 TI - Vibration and Noise in Magnetic Resonance Imaging of the Vocal Tract: Differences between Whole-Body and Open-Air Devices. AB - This article compares open-air and whole-body magnetic resonance imaging (MRI) equipment working with a weak magnetic field as regards the methods of its generation, spectral properties of mechanical vibration and acoustic noise produced by gradient coils during the scanning process, and the measured noise intensity. These devices are used for non-invasive MRI reconstruction of the human vocal tract during phonation with simultaneous speech recording. In this case, the vibration and noise have negative influence on quality of speech signal. Two basic measurement experiments were performed within the paper: mapping sound pressure levels in the MRI device vicinity and picking up vibration and noise signals in the MRI scanning area. Spectral characteristics of these signals are then analyzed statistically and compared visually and numerically. PMID- 29621195 TI - Indium-Catalyzed Annulation of o-Acylanilines with Alkoxyheteroarenes: Synthesis of Heteroaryl[b]quinolines and Subsequent Transformation to Cryptolepine Derivatives. AB - We disclose herein the first synthetic method that is capable of offering heteroaryl[b]quinolines (HA[b]Qs) with structural diversity, which include tricyclic and tetracyclic structures with (benzo)thienyl, (benzo)furanyl, and indolyl rings. The target HA[b]Q is addressed by the annulation of o-acylanilines and MeO-heteroarenes with the aid of an indium Lewis acid that effectively works to make two different types of the N-C and C-C bonds in one batch. A series of indolo[3,2-b]quinolines prepared here can be subsequently transformed to structurally unprecedented cryptolepine derivatives. Mechanistic studies showed that the N-C bond formation is followed by the C-C bond formation. The indium catalyzed annulation reaction thus starts with the nucleophilic attack of the NH2 group of o-acylanilines to the MeO-connected carbon atom of the heteroaryl ring in an SNAr fashion, and thereby the N-C bond is formed. The resulting intermediate then cyclizes to make the C-C bond through the nucleophilic attack of the heteroaryl-ring-based carbon atom to the carbonyl carbon atom, providing the HA[b]Q after aromatizing dehydration. PMID- 29621196 TI - Tannins from Acacia mearnsii De Wild. Bark: Tannin Determination and Biological Activities. AB - The bark of Acacia mearnsii De Wild. (black wattle) contains significant amounts of water-soluble components acalled "wattle tannin". Following the discovery of its strong antioxidant activity, a wattle tannin dietary supplement has been developed and as part of developing new dietary supplements, a literature search was conducted using the SciFinder data base for "Acacia species and their biological activities". An analysis of the references found indicated that the name of Acacia nilotica had been changed to Vachellia nilotica, even though the name of the genus Acacia originated from its original name. This review briefly describes why and how the name of A. nilotica changed. Tannin has been analyzed using the Stiasny method when the tannin is used to make adhesives and the hide powder method is used when the tannin is to be used for leather tanning. A simple UV method is also able to be used to estimate the values for both adhesives and leather tanning applications. The tannin content in bark can also be estimated using NIR and NMR. Tannin content estimations using pyrolysis/GC, electrospray mass spectrometry and quantitative 31P-NMR analyses have also been described. Tannins consists mostly of polyflavanoids and all the compounds isolated have been updated. Antioxidant activities of the tannin relating to anti-tumor properties, the viability of human neuroblastoma SH-SY5Y cells and also anti hypertensive effects have been studied. The antioxidant activity of proanthocyanidins was found to be higher than that of flavan-3-ol monomers. A total of fourteen papers and two patents reported the antimicrobial activities of wattle tannin. Bacteria were more susceptible to the tannins than the fungal strains tested. Several bacteria were inhibited by the extract from A. mearnsii bark. The growth inhibition mechanisms of E. coli were investigated. An interaction between extracts from A. mearnsii bark and antibiotics has also been studied. The extracts from A. mearnsii bark inhibit the growth of cyanobacteria. Wattle tannin has the ability to inactivate alpha-amylase, lipase and glucosidase. In vivo experiments on anti-obesity and anti-diabetes were also reported. Several patents relating to these enzymes for anti-diabetes and anti obesity are in the literature. In addition, studies on Acacia bark extract regarding its antitermite activities, inhibition of itching in atopic dermatitis and anti-inflammatory effects have also been reported. The growth of bacteria was inhibited by the extract from A. mearnsii bark, and typical intestinal bacteria such as E. coli, K. pneumoniae, P. vulgaris and S. marcescenes was also inhibited in vitro by extracts. Based on these results, the Acacia bark extract may inhibit not only the growth of these typical intestinal bacteria but also the growth of other types of intestinal bacteria such as Clostridium and Bacteroides, a so called "bad bacteria". If the tannin extract from A. mearnsii bark inhibits growth of these "bad bacteria" in vivo evaluation, the extracts might be usable as a new dietary supplement, which could control the human intestinal microbiome to keep the body healthy. PMID- 29621197 TI - Suicide Precipitants Differ Across the Lifespan but Are Not Significant in Predicting Medically Severe Attempts. AB - An important risk factor for suicide assessment is the suicide precipitant. This study explores suicide attempt precipitants across the lifespan. Three years of medical records related to suicide attempters who were admitted to the emergency department of a large teaching hospital in Singapore were subjected to analysis. These cases were divided into three age groups: Adolescence, Early Adulthood, and Middle Adulthood. A total of 540 cases were examined (70.9% females; 63.7% Chinese, 13.7% Malays, 15.9% Indians), whose ages ranged from 12 to 62. There were eight cases above the age of 65 years which were excluded from the analysis. Significant differences were found in precipitants for suicide attempts across the lifespan. Middle adults had relatively fewer relationship problems, and adolescents had comparatively fewer financial and medical problems. The models to predict medically severe attempts across the age groups using suicide precipitants were not significant. The findings were discussed in regards to implications in suicide assessment and primary prevention in Singapore, as well as limitations and recommendations for future research. PMID- 29621198 TI - CuGaS2 and CuGaS2-ZnS Porous Layers from Solution-Processed Nanocrystals. AB - The manufacturing of semiconducting films using solution-based approaches is considered a low cost alternative to vacuum-based thin film deposition strategies. An additional advantage of solution processing methods is the possibility to control the layer nano/microstructure. Here, we detail the production of mesoporous CuGaS2 (CGS) and ZnS layers from spin-coating and subsequent cross-linking through chalcogen-chalcogen bonds of properly functionalized nanocrystals (NCs). We further produce NC-based porous CGS/ZnS bilayers and NC-based CGS-ZnS composite layers using the same strategy. Photoelectrochemical measurements are used to demonstrate the efficacy of porous layers, and particularly the CGS/ZnS bilayers, for improved current densities and photoresponses relative to denser films deposited from as-produced NCs. PMID- 29621200 TI - Complementation Studies of Bacteriophage lambda O Amber Mutants by Allelic Forms of O Expressed from Plasmid, and O-P Interaction Phenotypes. AB - lambda genes O and P are required for replication initiation from the bacteriophage lambda origin site, orilambda, located within gene O. Questions have persisted for years about whether O-defects can indeed be complemented in trans. We show the effect of original null mutations in O and the influence of four origin mutations (three are in-frame deletions and one is a point mutation) on complementation. This is the first demonstration that O proteins with internal deletions can complement for O activity, and that expression of the N-terminal portion of gene P can completely prevent O complementation. We show that O-P co expression can limit the lethal effect of P on cell growth. We explore the influence of the contiguous small RNA OOP on O complementation and P-lethality. PMID- 29621199 TI - Expert Opinion on Three Phage Therapy Related Topics: Bacterial Phage Resistance, Phage Training and Prophages in Bacterial Production Strains. AB - Phage therapy is increasingly put forward as a "new" potential tool in the fight against antibiotic resistant infections. During the "Centennial Celebration of Bacteriophage Research" conference in Tbilisi, Georgia on 26-29 June 2017, an international group of phage researchers committed to elaborate an expert opinion on three contentious phage therapy related issues that are hampering clinical progress in the field of phage therapy. This paper explores and discusses bacterial phage resistance, phage training and the presence of prophages in bacterial production strains while reviewing relevant research findings and experiences. Our purpose is to inform phage therapy stakeholders such as policy makers, officials of the competent authorities for medicines, phage researchers and phage producers, and members of the pharmaceutical industry. This brief also points out potential avenues for future phage therapy research and development as it specifically addresses those overarching questions that currently call for attention whenever phages go into purification processes for application. PMID- 29621203 TI - Notes from the Field: Pharmacy Needs After a Natural Disaster - Puerto Rico, September-October 2017. PMID- 29621202 TI - Thoracic Inlet Parameters for Degenerative Cervical Spondylolisthesis Imaging Measurement. AB - BACKGROUND The aim of this study was to explore the diagnostic value of sagittal measurement of thoracic inlet parameters for degenerative cervical spondylolisthesis (DCS). MATERIAL AND METHODS We initially included 65 patients with DCS and the same number of health people as the control group by using cervical radiograph evaluations. We analyzed the x-ray and computer tomographic (CT) data in prone and standing position at the same time. Measurement of cervical sagittal parameters was carried out in a standardized supine position. Multivariate logistic regression analysis was performed to evaluate these parameters as a diagnostic index for DCS. RESULTS There were 60 cases enrolled in the DCS group, and 62 cases included in the control group. The T1 slope and thoracic inlet angle (TIA) were significantly greater for the DCS group compared to the control group (24.33+/-2.85o versus 19.59+/-2.04o, p=0.00; 76.11+/-9.82o versus 72.86+/-7.31o, p=0.03, respectively). We observed no significant difference for the results of the neck tilt (NT), C2-C7 angle in the control and the DSC group (p>0.05). Logistic regression analysis and receiver operating characteristic (ROC) curve revealed that preoperative T1 slope of more than 22.0o showed significantly diagnostic value for the DCS group (p<0.05). CONCLUSIONS Patients with preoperative sagittal imbalance of thoracic inlet have a statistically significant increased risk of DCS. T1 slope of more than 22.0o showed significantly diagnostic value for the incidence of DCS. PMID- 29621201 TI - Remote Ischemic Preconditioning Does Not Affect the Release of Humoral Factors in Propofol-Anesthetized Cardiac Surgery Patients: A Secondary Analysis of the RIPHeart Study. AB - In contrast to several smaller studies, which demonstrate that remote ischemic preconditioning (RIPC) reduces myocardial injury in patients that undergo cardiovascular surgery, the RIPHeart study failed to demonstrate beneficial effects of troponin release and clinical outcome in propofol-anesthetized cardiac surgery patients. Therefore, we addressed the potential biochemical mechanisms triggered by RIPC. This is a predefined prospective sub-analysis of the randomized and controlled RIPHeart study in cardiac surgery patients (n = 40) that was recently published. Blood samples were drawn from patients prior to surgery, after RIPC of four cycles of 5 min arm ischemia/5 min reperfusion (n = 19) and the sham (n = 21) procedure, after connection to cardiopulmonary bypass (CPB), at the end of surgery, 24 h postoperatively, and 48 h postoperatively for the measurement of troponin T, macrophage migration inhibitory factor (MIF), stromal cell-derived factor 1 (CXCL12), IL-6, CXCL8, and IL-10. After RIPC, right atrial tissue samples were taken for the measurement of extracellular-signal regulated kinase (ERK1/2), protein kinase B (AKT), Glycogen synthase kinase 3 (GSK-3beta), protein kinase C (PKCepsilon), and MIF content. RIPC did not significantly reduce the troponin release when compared with the sham procedure. MIF serum levels intraoperatively increased, peaking at intensive care unit (ICU) admission (with an increase of 48.04%, p = 0.164 in RIPC; and 69.64%, p = 0.023 over the baseline in the sham procedure), and decreased back to the baseline 24 h after surgery, with no differences between the groups. In the right atrial tissue, MIF content decreased after RIPC (1.040 +/- 1.032 Arbitrary units [au] in RIPC vs. 2.028 +/- 1.631 [au] in the sham procedure, p < 0.05). CXCL12 serum levels increased significantly over the baseline at the end of surgery, with no differences between the groups. ERK1/2, AKT, GSK-3beta, and PKCE phosphorylation in the right atrial samples were no different between the groups. No difference was found in IL-6, CXCL8, and IL10 serum levels between the groups. In this cohort of cardiac surgery patients that received propofol anesthesia, we could not show a release of potential mediators of signaling, nor an effect on the inflammatory response, nor an activation of well-established protein kinases after RIPC. Based on these data, we cannot exclude that confounding factors, such as propofol, may have interfered with RIPC. PMID- 29621205 TI - State Medicaid Coverage for Tobacco Cessation Treatments and Barriers to Accessing Treatments - United States, 2015-2017. AB - Cigarette smoking prevalence among Medicaid enrollees (25.3%) is approximately twice that of privately insured Americans (11.8%), placing Medicaid enrollees at increased risk for smoking-related disease and death (1). Medicaid spends approximately $39 billion annually on treating smoking-related diseases (2). Individual, group, and telephone counseling and seven Food and Drug Administration (FDA)-approved medications* are effective in helping tobacco users quit (3). Although state Medicaid coverage of tobacco cessation treatments improved during 2014-2015, coverage was still limited in most states (4). To monitor recent changes in state Medicaid cessation coverage for traditional (i.e., nonexpansion) Medicaid enrollees, the American Lung Association collected data on coverage of a total of nine cessation treatments: individual counseling, group counseling, and seven FDA-approved cessation medications? in state Medicaid programs during July 1, 2015-June 30, 2017. The American Lung Association also collected data on seven barriers to accessing covered treatments, such as copayments and prior authorization. As of June 30, 2017, 10 states covered all nine of these treatments for all enrollees, up from nine states as of June 30, 2015; of these 10 states, Missouri was the only state to have removed all seven barriers to accessing these cessation treatments. State Medicaid programs that cover all evidence-based cessation treatments, remove barriers to accessing these treatments, and promote covered treatments to Medicaid enrollees and health care providers would be expected to reduce smoking, smoking-related disease, and smoking-attributable federal and state health care expenditures (5-7). PMID- 29621204 TI - Prevalence of Asthma, Asthma Attacks, and Emergency Department Visits for Asthma Among Working Adults - National Health Interview Survey, 2011-2016. AB - In 2010, an estimated 8.2% of U.S. adults had current asthma, and among these persons, 49.1% had had an asthma attack during the past year (1). Workplace exposures can cause asthma in a previously healthy worker or can trigger asthma exacerbations in workers with current asthma* (2). To assess the industry- and occupation-specific prevalence of current asthma, asthma attacks, and asthma related emergency department (ED) visits among working adults, CDC analyzed 2011 2016 National Health Interview Survey (NHIS) data for participants aged >=18 years who, at the time of the survey, were employed at some time during the 12 months preceding the interview. During 2011-2016, 6.8% of adults (11 million) employed at any time in the past 12 months had current asthma; among those, 44.7% experienced an asthma attack, and 9.9% had an asthma-related ED visit in the previous year. Current asthma prevalence was highest among workers in the health care and social assistance industry (8.8%) and in health care support occupations (8.8%). The increased prevalence of current asthma, asthma attacks, and asthma related ED visits in certain industries and occupations might indicate increased risks for these health outcomes associated with workplace exposures. These findings might assist health care and public health professionals in identifying workers in industries and occupations with a high prevalence of current asthma, asthma attacks, and asthma-related ED visits who should be evaluated for possible work-related asthma. Guidelines intended to promote effective management of work related asthma are available (2,3). PMID- 29621206 TI - Phosphine Exposure Among Emergency Responders - Amarillo, Texas, January 2017. AB - Phosphine is a highly toxic gas that forms when aluminum phosphide, a restricted use pesticide* typically used in agricultural settings, reacts with water. Acute exposure can lead to a wide range of respiratory, cardiovascular, and gastrointestinal symptoms, and can be fatal (1). On January 2, 2017, the Texas Department of State Health Services (DSHS) was notified by the Texas Panhandle Poison Center of an acute phosphine exposure incident in Amarillo, Texas. DSHS investigated potential occupational phosphine exposures among the 51 on-scene emergency responders; 40 (78.4%) did not use respiratory protection during response operations. Fifteen (37.5%) of these 40 responders received medical care for symptoms or as a precaution after the incident, and seven (17.5%) reported new or worsening symptoms consistent with phosphine exposure within 24 hours of the incident. Emergency response organizations should ensure that appropriate personal protective equipment (PPE) is used during all incidents when an unknown hazardous substance is suspected. Additional evaluation is needed to identify targeted interventions that increase emergency responder PPE use during this type of incident. PMID- 29621208 TI - Erratum: Vol. 67, No. 7. PMID- 29621207 TI - QuickStats: Age-Adjusted Percentage* of Adults Aged >=25 Years Who Were Told in the Past 12 Months by a Doctor or Other Health Professional That They Had a Liver Condition,? by Education Level - National Health Interview Survey,S 2016. AB - In 2016, 2.0% of adults aged >=25 years who were surveyed had been told by a doctor or other health professional in the past 12 months that they had a liver condition. The prevalence of liver condition declined as education level increased. Adults who had completed a bachelor's degree or higher were the least likely to have been diagnosed with any liver condition (1.3%), whereas those without a high school diploma were the most likely (3.3%). PMID- 29621210 TI - Gender differences in obtaining and maintaining patent rights. PMID- 29621209 TI - Vital Signs: Containment of Novel Multidrug-Resistant Organisms and Resistance Mechanisms - United States, 2006-2017. AB - BACKGROUND: Approaches to controlling emerging antibiotic resistance in health care settings have evolved over time. When resistance to broad-spectrum antimicrobials mediated by extended-spectrum beta-lactamases (ESBLs) arose in the 1980s, targeted interventions to slow spread were not widely promoted. However, when Enterobacteriaceae with carbapenemases that confer resistance to carbapenem antibiotics emerged, directed control efforts were recommended. These distinct approaches could have resulted in differences in spread of these two pathogens. CDC evaluated these possible changes along with initial findings of an enhanced antibiotic resistance detection and control strategy that builds on interventions developed to control carbapenem resistance. METHODS: Infection data from the National Healthcare Safety Network from 2006-2015 were analyzed to calculate changes in the annual proportion of selected pathogens that were nonsusceptible to extended-spectrum cephalosporins (ESBL phenotype) or resistant to carbapenems (carbapenem-resistant Enterobacteriaceae [CRE]). Testing results for CRE and carbapenem-resistant Pseudomonas aeruginosa (CRPA) are also reported. RESULTS: The percentage of ESBL phenotype Enterobacteriaceae decreased by 2% per year (risk ratio [RR] = 0.98, p<0.001); by comparison, the CRE percentage decreased by 15% per year (RR = 0.85, p<0.01). From January to September 2017, carbapenemase testing was performed for 4,442 CRE and 1,334 CRPA isolates; 32% and 1.9%, respectively, were carbapenemase producers. In response, 1,489 screening tests were performed to identify asymptomatic carriers; 171 (11%) were positive. CONCLUSIONS: The proportion of Enterobacteriaceae infections that were CRE remained lower and decreased more over time than the proportion that were ESBL phenotype. This difference might be explained by the more directed control efforts implemented to slow transmission of CRE than those applied for ESBL producing strains. Increased detection and aggressive early response to emerging antibiotic resistance threats have the potential to slow further spread. PMID- 29621213 TI - Recent patents in tumor detection and treatment. PMID- 29621212 TI - The long view on sequencing. PMID- 29621214 TI - Epigenome editing to the rescue. PMID- 29621215 TI - Rollout of high-priced cell and gene therapies forces payer rethink. PMID- 29621216 TI - Low-molecular-weight albumin drug touted for severe osteoarthritis. PMID- 29621217 TI - Nature Biotechnology's academic spinouts of 2017. PMID- 29621218 TI - Portable gene expression guaranteed. PMID- 29621221 TI - New drug for multidrug-resistant HIV. PMID- 29621220 TI - Patching the retina with stem cells. PMID- 29621223 TI - Around the world in a month. PMID- 29621224 TI - Critics say 'right to try' wrong for patients. PMID- 29621222 TI - Metabolomics activity screening for identifying metabolites that modulate phenotype. AB - Metabolomics, in which small-molecule metabolites (the metabolome) are identified and quantified, is broadly acknowledged to be the omics discipline that is closest to the phenotype. Although appreciated for its role in biomarker discovery programs, metabolomics can also be used to identify metabolites that could alter a cell's or an organism's phenotype. Metabolomics activity screening (MAS) as described here integrates metabolomics data with metabolic pathways and systems biology information, including proteomics and transcriptomics data, to produce a set of endogenous metabolites that can be tested for functionality in altering phenotypes. A growing literature reports the use of metabolites to modulate diverse processes, such as stem cell differentiation, oligodendrocyte maturation, insulin signaling, T-cell survival and macrophage immune responses. This opens up the possibility of identifying and applying metabolites to affect phenotypes. Unlike genes or proteins, metabolites are often readily available, which means that MAS is broadly amenable to high-throughput screening of virtually any biological system. PMID- 29621226 TI - FDA approves stroke-detecting AI software. PMID- 29621225 TI - Roche pays $1.9 billion for Flatiron's army of electronic health record curators. PMID- 29621227 TI - Involving undergraduates in genomics research to narrow the education-research gap. PMID- 29621228 TI - Preclinical efficacy studies in investigator brochures: Do they enable risk benefit assessment? AB - Human protection policies require favorable risk-benefit judgments prior to launch of clinical trials. For phase I and II trials, evidence for such judgment often stems from preclinical efficacy studies (PCESs). We undertook a systematic investigation of application materials (investigator brochures [IBs]) presented for ethics review for phase I and II trials to assess the content and properties of PCESs contained in them. Using a sample of 109 IBs most recently approved at 3 institutional review boards based at German Medical Faculties between the years 2010-2016, we identified 708 unique PCESs. We then rated all identified PCESs for their reporting on study elements that help to address validity threats, whether they referenced published reports, and the direction of their results. Altogether, the 109 IBs reported on 708 PCESs. Less than 5% of all PCESs described elements essential for reducing validity threats such as randomization, sample size calculation, and blinded outcome assessment. For most PCESs (89%), no reference to a published report was provided. Only 6% of all PCESs reported an outcome demonstrating no effect. For the majority of IBs (82%), all PCESs were described as reporting positive findings. Our results show that most IBs for phase I/II studies did not allow evaluators to systematically appraise the strength of the supporting preclinical findings. The very rare reporting of PCESs that demonstrated no effect raises concerns about potential design or reporting biases. Poor PCES design and reporting thwart risk-benefit evaluation during ethical review of phase I/II studies. PMID- 29621229 TI - Ten quick tips for teaching programming. PMID- 29621231 TI - House dust mites use a plant-like siRNA pathway to silence transposable elements. PMID- 29621230 TI - Conditional mouse models support the role of SLC39A14 (ZIP14) in Hyperostosis Cranialis Interna and in bone homeostasis. AB - Hyperostosis Cranialis Interna (HCI) is a rare bone disorder characterized by progressive intracranial bone overgrowth at the skull. Here we identified by whole-exome sequencing a dominant mutation (L441R) in SLC39A14 (ZIP14). We show that L441R ZIP14 is no longer trafficked towards the plasma membrane and excessively accumulates intracellular zinc, resulting in hyper-activation of cAMP CREB and NFAT signaling. Conditional knock-in mice overexpressing L438R Zip14 in osteoblasts have a severe skeletal phenotype marked by a drastic increase in cortical thickness due to an enhanced endosteal bone formation, resembling the underlying pathology in HCI patients. Remarkably, L438R Zip14 also generates an osteoporotic trabecular bone phenotype. The effects of osteoblastic overexpression of L438R Zip14 therefore mimic the disparate actions of estrogen on cortical and trabecular bone through osteoblasts. Collectively, we reveal ZIP14 as a novel regulator of bone homeostasis, and that manipulating ZIP14 might be a therapeutic strategy for bone diseases. PMID- 29621233 TI - Degenerate time-dependent network dynamics anticipate seizures in human epileptic brain. AB - Epileptic seizures are known to follow specific changes in brain dynamics. While some algorithms can nowadays robustly detect these changes, a clear understanding of the mechanism by which these alterations occur and generate seizures is still lacking. Here, we provide crossvalidated evidence that such changes are initiated by an alteration of physiological network state dynamics. Specifically, our analysis of long intracranial electroencephalography (iEEG) recordings from a group of 10 patients identifies a critical phase of a few hours in which time dependent network states become less variable ("degenerate"), and this phase is followed by a global functional connectivity reduction before seizure onset. This critical phase is characterized by an abnormal occurrence of highly correlated network instances and is shown to be particularly associated with the activity of the resected regions in patients with validated postsurgical outcome. Our approach characterizes preseizure network dynamics as a cascade of 2 sequential events providing new insights into seizure prediction and control. PMID- 29621232 TI - Identification and functional analysis of glycemic trait loci in the China Health and Nutrition Survey. AB - To identify genetic contributions to type 2 diabetes (T2D) and related glycemic traits (fasting glucose, fasting insulin, and HbA1c), we conducted genome-wide association analyses (GWAS) in up to 7,178 Chinese subjects from nine provinces in the China Health and Nutrition Survey (CHNS). We examined patterns of population structure within CHNS and found that allele frequencies differed across provinces, consistent with genetic drift and population substructure. We further validated 32 previously described T2D- and glycemic trait-loci, including G6PC2 and SIX3-SIX2 associated with fasting glucose. At G6PC2, we replicated a known fasting glucose-associated variant (rs34177044) and identified a second signal (rs2232326), a low-frequency (4%), probably damaging missense variant (S324P). A variant within the lead fasting glucose-associated signal at SIX3-SIX2 co-localized with pancreatic islet expression quantitative trait loci (eQTL) for SIX3, SIX2, and three noncoding transcripts. To identify variants functionally responsible for the fasting glucose association at SIX3-SIX2, we tested five candidate variants for allelic differences in regulatory function. The rs12712928 C allele, associated with higher fasting glucose and lower transcript expression level, showed lower transcriptional activity in reporter assays and increased binding to GABP compared to the rs12712928-G, suggesting that rs12712928-C contributes to elevated fasting glucose levels by disrupting an islet enhancer, resulting in reduced gene expression. Taken together, these analyses identified multiple loci associated with glycemic traits across China, and suggest a regulatory mechanism at the SIX3-SIX2 fasting glucose GWAS locus. PMID- 29621234 TI - Clinical Cysticercosis epidemiology in Spain based on the hospital discharge database: What's new? AB - BACKGROUND: Cysticercosis (CC) is a tissue infection caused by the larval cysts of the pork tapeworm Taenia solium. It is usually acquired by eating contaminated food or drinking water. CC Cysts can develop in the muscles, the eyes, the brain, and/or the spinal cord. T. solium is found worldwide, but its prevalence has decreased in developed countries due to stricter meat inspection and better hygiene and sanitation. Nevertheless, CC is still a leading cause of seizures and epilepsy. In Spain, The disease is not nationally reportable and data on CC infected animals are also missing, despite the European Directive 2003/99/EC. METHODOLOGY/PRINCIPAL FINDINGS: We performed a retrospective descriptive study using the Spanish Hospitalization Minimum Data Set (CMBD). Data with ICD-9 CM cysticercosis code ("123.1") placed in first or second diagnostic position from 1997 to 2014 were analyzed. Hospitalization rates were calculated and clinical characteristics were described. Spatial distribution of cases and their temporal behavior were also assessed. A total of 1,912 hospital discharges with clinical cysticercosis were identified. From 1998 to 2008, an increasing trend in the number of CC hospitalizations was observed, decreasing afterwards, in parallel with a decrease in the external migration rate. The Murcia region had the highest median hospitalization rate (13.37 hospitalizations/100,000 population), followed by Navarra and Madrid. The 16-44 age group was the most represented (63.6%). The three most frequent associated diagnoses were epilepsy and convulsions (49.5%), hydrocephalus (11.8%) and encephalitis/myelitis/meningitis (11.6%). CONCLUSIONS/SIGNIFICANCE: There is a need for a common strategy on data collection, monitoring and reporting, which would facilitate a more accurate picture on the CC epidemiological scenario. Even if most cases might be imported, improving the human and animal CC surveillance will result useful both in gaining extended disease knowledge and reducing morbidity and related-costs. PMID- 29621235 TI - Survival after PICU admission: The impact of multiple admissions and complex chronic conditions. AB - OBJECTIVE: Factors predicting survival over time after pediatric intensive care unit (PICU) admissions are not fully understood. The primary aim of the current study was to investigate whether multiple admissions (MADM) compared to single PICU admissions (SADM) were associated with poor survival over time after being admitted to PICU facilities. Our secondary aim was to investigate if the presence of a complex chronic condition (CCC) would further impair prognosis. DESIGN: A closed cohort of all children up to 16 years of age admitted to the three PICUs in Sweden between 2008 and 2010 was prospectively collected and followed until 2012, providing survival data for at least one but up to four years of follow-up. SETTING: Three Swedish tertiary referral centers for pediatric intensive care and extracorporeal membrane oxygenation (ECMO) care were used. PATIENTS: In total, 3,688 Swedish children with 5,019 PICU admissions were included. INTERVENTIONS: No interventions were conducted. MEASUREMENTS: An extensive data set was recorded, including up to four-year survival information following first PICU admission. The patients were assigned to seven admission diagnostic groups, which were then divided into SADM or MADM groups. The difference in survival over time and mortality rates (MR) and mortality rate ratios (MRR) were calculated. SADM and MADM groups with and without an existing CCC were formed. The difference in survival over time between groups was calculated. MAIN RESULTS: A highly significant difference in survival over time was noted between SADM and MADM patients (p<0.0001), which was intensified by the presence of a CCC. MADM patients with a CCC had the worst outcome, while SADM patients without a CCC had the best outcome. MADM patients with no CCC demonstrated decreased survival over time compared to SADM patients with a CCC. Survival over time was statistically worsened for patients with MADM compared to SADM for the following admission diagnostic groups: Cardiovascular, Gastrointestinal/Renal, Respiratory, Neurological, and Miscellaneous. The mortality rate (deaths/patient year of follow-up) during the time of follow-up was 0.023 for SADM and 0.062 for MADM patients. The mortality rate ratio (MRR) between these groups was 2.69. CONCLUSION: Compared to single admissions, multiple admissions to PICU were associated with a significant decrease in survival over time in some but not all diagnostic groups. Regarding our secondary aim, we found that when the presence of a CCC is factored into the survival analysis, survival over time is further impaired. PMID- 29621236 TI - Automated plant species identification-Trends and future directions. AB - Current rates of species loss triggered numerous attempts to protect and conserve biodiversity. Species conservation, however, requires species identification skills, a competence obtained through intensive training and experience. Field researchers, land managers, educators, civil servants, and the interested public would greatly benefit from accessible, up-to-date tools automating the process of species identification. Currently, relevant technologies, such as digital cameras, mobile devices, and remote access to databases, are ubiquitously available, accompanied by significant advances in image processing and pattern recognition. The idea of automated species identification is approaching reality. We review the technical status quo on computer vision approaches for plant species identification, highlight the main research challenges to overcome in providing applicable tools, and conclude with a discussion of open and future research thrusts. PMID- 29621237 TI - Amino acid starvation sensing dampens IL-1beta production by activating riboclustering and autophagy. AB - Activation of the amino acid starvation response (AAR) increases lifespan and acute stress resistance as well as regulates inflammation. However, the underlying mechanisms remain unclear. Here, we show that activation of AAR pharmacologically by Halofuginone (HF) significantly inhibits production of the proinflammatory cytokine interleukin 1beta (IL-1beta) and provides protection from intestinal inflammation in mice. HF inhibits IL-1beta through general control nonderepressible 2 kinase (GCN2)-dependent activation of the cytoprotective integrated stress response (ISR) pathway, resulting in rerouting of IL-1beta mRNA from translationally active polysomes to inactive ribocluster complexes-such as stress granules (SGs)-via recruitment of RNA-binding proteins (RBPs) T cell-restricted intracellular antigen-1(TIA-1)/TIA-1-related (TIAR), which are further cleared through induction of autophagy. GCN2 ablation resulted in reduced autophagy and SG formation, which is inversely correlated with IL 1beta production. Furthermore, HF diminishes inflammasome activation through suppression of reactive oxygen species (ROS) production. Our study unveils a novel mechanism by which IL-1beta is regulated by AAR and further suggests that administration of HF might offer an effective therapeutic intervention against inflammatory diseases. PMID- 29621238 TI - Genome-wide detection of conservative site-specific recombination in bacteria. AB - The ability of clonal bacterial populations to generate genomic and phenotypic heterogeneity is thought to be of great importance for many commensal and pathogenic bacteria. One common mechanism contributing to diversity formation relies on the inversion of small genomic DNA segments in a process commonly referred to as conservative site-specific recombination. This phenomenon is known to occur in several bacterial lineages, however it remains notoriously difficult to identify due to the lack of conserved features. Here, we report an easy-to implement method based on high-throughput paired-end sequencing for genome-wide detection of conservative site-specific recombination on a single-nucleotide level. We demonstrate the effectiveness of the method by successfully detecting several novel inversion sites in an epidemic isolate of the enteric pathogen Clostridium difficile. Using an experimental approach, we validate the inversion potential of all detected sites in C. difficile and quantify their prevalence during exponential and stationary growth in vitro. In addition, we demonstrate that the master recombinase RecV is responsible for the inversion of some but not all invertible sites. Using a fluorescent gene-reporter system, we show that at least one gene from a two-component system located next to an invertible site is expressed in an on-off mode reminiscent of phase variation. We further demonstrate the applicability of our method by mining 209 publicly available sequencing datasets and show that conservative site-specific recombination is common in the bacterial realm but appears to be absent in some lineages. Finally, we show that the gene content associated with the inversion sites is diverse and goes beyond traditionally described surface components. Overall, our method provides a robust platform for detection of conservative site-specific recombination in bacteria and opens a new avenue for global exploration of this important phenomenon. PMID- 29621239 TI - Distinct interactions of Sox5 and Sox10 in fate specification of pigment cells in medaka and zebrafish. AB - Mechanisms generating diverse cell types from multipotent progenitors are fundamental for normal development. Pigment cells are derived from multipotent neural crest cells and their diversity in teleosts provides an excellent model for studying mechanisms controlling fate specification of distinct cell types. Zebrafish have three types of pigment cells (melanocytes, iridophores and xanthophores) while medaka have four (three shared with zebrafish, plus leucophores), raising questions about how conserved mechanisms of fate specification of each pigment cell type are in these fish. We have previously shown that the Sry-related transcription factor Sox10 is crucial for fate specification of pigment cells in zebrafish, and that Sox5 promotes xanthophores and represses leucophores in a shared xanthophore/leucophore progenitor in medaka. Employing TILLING, TALEN and CRISPR/Cas9 technologies, we generated medaka and zebrafish sox5 and sox10 mutants and conducted comparative analyses of their compound mutant phenotypes. We show that specification of all pigment cells, except leucophores, is dependent on Sox10. Loss of Sox5 in Sox10-defective fish partially rescued the formation of all pigment cells in zebrafish, and melanocytes and iridophores in medaka, suggesting that Sox5 represses Sox10 dependent formation of these pigment cells, similar to their interaction in mammalian melanocyte specification. In contrast, in medaka, loss of Sox10 acts cooperatively with Sox5, enhancing both xanthophore reduction and leucophore increase in sox5 mutants. Misexpression of Sox5 in the xanthophore/leucophore progenitors increased xanthophores and reduced leucophores in medaka. Thus, the mode of Sox5 function in xanthophore specification differs between medaka (promoting) and zebrafish (repressing), which is also the case in adult fish. Our findings reveal surprising diversity in even the mode of the interactions between Sox5 and Sox10 governing specification of pigment cell types in medaka and zebrafish, and suggest that this is related to the evolution of a fourth pigment cell type. PMID- 29621241 TI - Spreading dynamic of acute and carrier hepatitis B with nonlinear incidence. AB - Hepatitis B infection caused by the hepatitis B virus. It is one of the serious viral infection and a global health problem. In the transmission of hepatitis B infection different phases, i.e., acute and chronic carrier stages play an important role. The chronic carries individuals do not exhibit any symptoms and are able to transmit the infection. Here we assessed the transmissibility associated with different infection stages of hepatitis B and generated an epidemic model with nonlinear incidence rate. In order to do this, first we formulate the model by splitting the infectious class into two subclasses, namely acutely infected and chronic carries with both horizontal and vertical transmission. The basic properties of the proposed model are presented. The basic reproductive number is obtained by using the next generation matrix approach. Biological sense of the threshold condition is investigated and discussed in detail. We also find the conditions to investigate all possible equilibria of the model in terms of the basic reproduction number. Finally, we perform numerical simulations to support our analytical work. PMID- 29621240 TI - A genomic overview of the population structure of Salmonella. AB - For many decades, Salmonella enterica has been subdivided by serological properties into serovars or further subdivided for epidemiological tracing by a variety of diagnostic tests with higher resolution. Recently, it has been proposed that so-called eBurst groups (eBGs) based on the alleles of seven housekeeping genes (legacy multilocus sequence typing [MLST]) corresponded to natural populations and could replace serotyping. However, this approach lacks the resolution needed for epidemiological tracing and the existence of natural populations had not been independently validated by independent criteria. Here, we describe EnteroBase, a web-based platform that assembles draft genomes from Illumina short reads in the public domain or that are uploaded by users. EnteroBase implements legacy MLST as well as ribosomal gene MLST (rMLST), core genome MLST (cgMLST), and whole genome MLST (wgMLST) and currently contains over 100,000 assembled genomes from Salmonella. It also provides graphical tools for visual interrogation of these genotypes and those based on core single nucleotide polymorphisms (SNPs). eBGs based on legacy MLST are largely consistent with eBGs based on rMLST, thus demonstrating that these correspond to natural populations. rMLST also facilitated the selection of representative genotypes for SNP analyses of the entire breadth of diversity within Salmonella. In contrast, cgMLST provides the resolution needed for epidemiological investigations. These observations show that genomic genotyping, with the assistance of EnteroBase, can be applied at all levels of diversity within the Salmonella genus. PMID- 29621243 TI - Clinical diagnostic model for sciatica developed in primary care patients with low back-related leg pain. AB - BACKGROUND: Identification of sciatica may assist timely management but can be challenging in clinical practice. Diagnostic models to identify sciatica have mainly been developed in secondary care settings with conflicting reference standard selection. This study explores the challenges of reference standard selection and aims to ascertain which combination of clinical assessment items best identify sciatica in people seeking primary healthcare. METHODS: Data on 394 low back-related leg pain consulters were analysed. Potential sciatica indicators were seven clinical assessment items. Two reference standards were used: (i) high confidence sciatica clinical diagnosis; (ii) high confidence sciatica clinical diagnosis with confirmatory magnetic resonance imaging findings. Multivariable logistic regression models were produced for both reference standards. A tool predicting sciatica diagnosis in low back-related leg pain was derived. Latent class modelling explored the validity of the reference standard. RESULTS: Model (i) retained five items; model (ii) retained six items. Four items remained in both models: below knee pain, leg pain worse than back pain, positive neural tension tests and neurological deficit. Model (i) was well calibrated (p = 0.18), discrimination was area under the receiver operating characteristic curve (AUC) 0.95 (95% CI 0.93, 0.98). Model (ii) showed good discrimination (AUC 0.82; 0.78, 0.86) but poor calibration (p = 0.004). Bootstrapping revealed minimal overfitting in both models. Agreement between the two latent classes and clinical diagnosis groups defined by model (i) was substantial, and fair for model (ii). CONCLUSION: Four clinical assessment items were common in both reference standard definitions of sciatica. A simple scoring tool for identifying sciatica was developed. These criteria could be used clinically and in research to improve accuracy of identification of this subgroup of back pain patients. PMID- 29621242 TI - Comparison of phasing strategies for whole human genomes. AB - Humans are a diploid species that inherit one set of chromosomes paternally and one homologous set of chromosomes maternally. Unfortunately, most human sequencing initiatives ignore this fact in that they do not directly delineate the nucleotide content of the maternal and paternal copies of the 23 chromosomes individuals possess (i.e., they do not 'phase' the genome) often because of the costs and complexities of doing so. We compared 11 different widely-used approaches to phasing human genomes using the publicly available 'Genome-In-A Bottle' (GIAB) phased version of the NA12878 genome as a gold standard. The phasing strategies we compared included laboratory-based assays that prepare DNA in unique ways to facilitate phasing as well as purely computational approaches that seek to reconstruct phase information from general sequencing reads and constructs or population-level haplotype frequency information obtained through a reference panel of haplotypes. To assess the performance of the 11 approaches, we used metrics that included, among others, switch error rates, haplotype block lengths, the proportion of fully phase-resolved genes, phasing accuracy and yield between pairs of SNVs. Our comparisons suggest that a hybrid or combined approach that leverages: 1. population-based phasing using the SHAPEIT software suite, 2. either genome-wide sequencing read data or parental genotypes, and 3. a large reference panel of variant and haplotype frequencies, provides a fast and efficient way to produce highly accurate phase-resolved individual human genomes. We found that for population-based approaches, phasing performance is enhanced with the addition of genome-wide read data; e.g., whole genome shotgun and/or RNA sequencing reads. Further, we found that the inclusion of parental genotype data within a population-based phasing strategy can provide as much as a ten-fold reduction in phasing errors. We also considered a majority voting scheme for the construction of a consensus haplotype combining multiple predictions for enhanced performance and site coverage. Finally, we also identified DNA sequence signatures associated with the genomic regions harboring phasing switch errors, which included regions of low polymorphism or SNV density. PMID- 29621244 TI - The cost-saving effect of centralized histological reviews with soft tissue and visceral sarcomas, GIST, and desmoid tumors: The experiences of the pathologists of the French Sarcoma Group. AB - OBJECTIVE: This study examined the types of discordance occurring in the diagnosis of soft tissue and visceral sarcomas, gastrointestinal stromal tumors (GIST), and desmoid tumors, as well as the economic impact of diagnostic discrepancies. METHODS: We carried out a retrospective, multicenter analysis using prospectively implemented databases performed on a cohort of patients within the French RRePS network in 2010. Diagnoses were deemed to be discordant based on the 2013 World Health Organization (WHO) classification. Predictive factors of discordant diagnoses were explored. A decision tree was used to assess the expected costs of two strategies of disease management: one based on revised diagnoses after centralized histological review (option 1), the other on diagnoses without centralized review (option 2). Both were defined based on the patient and the disease characteristics, according to national or international guidelines. The time horizon was 12 months and the perspective of the French National Health Insurance (NHI) was retained. Costs were expressed in Euros for 2013. Sensitivity analyses were performed using low and high scenarios that included +/- 20% estimates for cost. RESULTS: A total of 2,425 patients were included. Three hundred forty-one patients (14%) had received discordant diagnoses. These discordances were determined to mainly be benign tumors diagnosed as sarcomas (n = 124), or non-sarcoma malignant tumors diagnosed as sarcomas (n = 77). The probability of discordance was higher for a final diagnosis of desmoid tumors when compared to liposarcomas (odds ratio = 5.1; 95%CI [2.6-10.4]). The expected costs per patient for the base-case analysis (low and high-case scenarios) amounted to ?8,791 (?7,033 and ?10,549, respectively) for option 1 and ?8,904 (?7,057 and ?10,750, respectively) for option 2. CONCLUSIONS: Our findings highlight misdiagnoses of sarcomas, which were found to most often be confused with benign tumors. Centralized histological reviews are likely to provide cost-savings for the French NHI. PMID- 29621245 TI - Study on essential drug use status and its influencing factors among cerebral infarction inpatients in county level hospitals of Anhui Province, China. AB - BACKGROUND AND PURPOSE: Drug costs is one of the main components of hospitalization expenditure for cerebral infarction inpatients. In China, the National Essential Medicine System (NEMS) was created to relieve the heavy drug cost burden for patients. The objective of this study was to investigate essential drug-use status and its influencing factors among cerebral infarction inpatients in county-level hospitals of Anhui province, China. METHODS: Three county-level hospitals were selected through a multi-stage cluster random sampling method. The hospitalization cost data of cerebral infarction inpatients in the three hospitals were extracted from the Anhui provincial information platform of the New Rural Cooperative Insurance System (NCMS), and whether the proportion of essential drug cost in the total drug cost reached the median value of 33.05% which was set as the evaluation index for essential drug-use status. Questionnaires for hospitals and physicians were designed and given to them to assess influencing factors. RESULTS: We retrieved the cost data of 2,189 inpatients from the NCMS platform and investigated 51 corresponding physicians in total. The drug costs accounted for 52.6% of the total hospitalization cost, and essential drug costs alone accounted for 37.0% of the total drug costs. The essential drug-cost proportion was high among physicians with a higher recognition degree on NEMS, older age, lower final academic degree, longer work experience and lower professional title. Married physicians and those with tight organizational affiliation also prescribed more essential drugs. CONCLUSIONS: Increasing the proportion of essential drugs was an effective way to reduce the disease burden for cerebral infarction patients. Perfecting the NEMS, increasing government investment, reinforcing education and propaganda, and formulating relevant incentive and restrictive mechanisms were all effective ways to promote and increase the number of essential drug prescriptions written by physicians. PMID- 29621246 TI - p53 is required for brain growth but is dispensable for resistance to nutrient restriction during Drosophila larval development. AB - BACKGROUND: Animal growth is influenced by the genetic background and the environmental circumstances. How genes promote growth and coordinate adaptation to nutrient availability is still an open question. p53 is a transcription factor that commands the cellular response to different types of stresses. In adult Drosophila melanogaster, p53 regulates the metabolic adaptation to nutrient restriction that supports fly viability. Furthermore, the larval brain is protected from nutrient restriction in a phenomenon called 'brain sparing'. Therefore, we hypothesised that p53 may regulate brain growth and show a protective role over brain development under nutrient restriction. RESULTS: Here, we studied the function of p53 during brain growth in normal conditions and in animals subjected to developmental nutrient restriction. We showed that p53 loss of function reduced animal growth and larval brain size. Endogenous p53 was expressed in larval neural stem cells, but its levels and activity were not affected by nutritional stress. Interestingly, p53 knockdown only in neural stem cells was sufficient to decrease larval brain growth. Finally, we showed that in p53 mutant larvae under nutrient restriction, the energy storage levels were not altered, and these larvae generated adults with brains of similar size than wild type animals. CONCLUSIONS: Using genetic approaches, we demonstrate that p53 is required for proper growth of the larval brain. This developmental role of p53 does not have an impact on animal resistance to nutritional stress since brain growth in p53 mutants under nutrient restriction is similar to control animals. PMID- 29621247 TI - Dynamic changes in microbial communities during the bioremediation of herbicide (chlorimuron-ethyl and atrazine) contaminated soils by combined degrading bacteria. AB - Chlorimuron-ethyl and atrazine are two herbicides with long half-lives in soil; their long-term and excessive application has led to a series of environmental problems. In this study, the strains Chenggangzhangella methanolivorans CHL1 and Arthrobacter sp. ART1 were combined and used for the remediation of chlorimuron ethyl, atrazine and combined contaminated soils in a microcosm experiment. Changes in chlorimuron-ethyl and atrazine concentrations in soils were monitored, and variations in the soil microbial community were studied by phospholipid fatty acid (PLFA) analysis. The two inoculated degrading strains accelerated the degradation of chlorimuron-ethyl and atrazine in soil, especially in the combined contaminated soil. Addition of the two herbicides and their combination generally decreased the concentrations of total PLFAs, total bacterial PLFAs, Gram-negative and Gram-positive bacterial PLFAs and Shannon-Wiener indices, and changed microbial community composition, whilst stimulating fungal PLFA concentrations. In addition, the combined herbicide treatment had more impact on microbial biomass than the single herbicide treatments. Inoculation treatments significantly relieved the effects of herbicides on soil microbial biomass, diversity and community structure. This study demonstrated that strains CHL1 and ATR1 have the potential to remediate chlorimuron-ethyl, atrazine and combined contaminated soils, and provided valuable information for remediation of chlorimuron-ethyl, atrazine and combined contaminated soils in situ. PMID- 29621248 TI - Adherence to rivaroxaban versus apixaban among patients with non-valvular atrial fibrillation: Analysis of overall population and subgroups of prior oral anticoagulant users. AB - BACKGROUND: Medication non-adherence can result in poor health outcomes. Understanding differences in adherence rates to non-vitamin K oral anticoagulants (NOACs) could guide treatment decisions and improve clinical outcomes among patients with non-valvular atrial fibrillation (NVAF). OBJECTIVE: To compare adherence to rivaroxaban and apixaban among the overall NVAF population and subgroups of prior oral anticoagulant (OAC) users (e.g., multiple comorbidities, non-adherence risk factors). METHODS: Using healthcare claims from the Truven Health Analytics MarketScan (7/2012-7/2015), adult patients with >=2 dispensings of rivaroxaban or apixaban >= 180 days apart with > 60 days of supply, >= 6 months of pre- and post-index eligibility, >= 1 atrial fibrillation diagnosis pre or on the index date, and without valvular involvement were identified. Propensity-score methods adjusting for potential baseline confounders were used to create matched cohorts of rivaroxaban and apixaban patients. Adherence was assessed during the implementation phase using the percentage of patients with proportion of days covered (PDC) >=0.8 at 6 months. Subgroups of patients with prior OAC use were evaluated; additional subgroups were identified and evaluated by Quan-Charlson Comorbidity index >=2 and presence of non-adherence risk factors (i.e., mental disorders, stress, isolation, and rheumatoid arthritis). RESULTS: A total of 13,890 NVAF subjects were included in each of the 2 matched cohorts. All baseline characteristics were balanced between cohorts. At 6 months, significantly more rivaroxaban users were adherent to treatment compared to apixaban users (81.8% vs. 78.0%; absolute difference of 3.8%; p<.001). Rivaroxaban users had significantly higher adherence rates in all subgroups examined. CONCLUSION: Rivaroxaban users had consistently higher adherence rates than apixaban users overall and among all NVAF subgroups examined. PMID- 29621249 TI - Understanding the mechanisms behind the sexualized-body inversion hypothesis: The role of asymmetry and attention biases. AB - A controversial hypothesis, named the Sexualized Body Inversion Hypothesis (SBIH), claims similar visual processing of sexually objectified women (i.e., with a focus on the sexual body parts) and inanimate objects as indicated by an absence of the inversion effect for both type of stimuli. The current study aims at shedding light into the mechanisms behind the SBIH in a series of 4 experiments. Using a modified version of Bernard et al.'s (2012) visual-matching task, first we tested the core assumption of the SBIH, namely that a similar processing style occurs for sexualized human bodies and objects. In Experiments 1 and 2 a non-sexualized (personalized) condition plus two object-control conditions (mannequins, and houses) were included in the experimental design. Results showed an inversion effect for images of personalized women and mannequins, but not for sexualized women and houses. Second, we explored whether this effect was driven by differences in stimulus asymmetry, by testing the mediating and moderating role of this visual feature. In Experiment 3, we provided the first evidence that not only the sexual attributes of the images but also additional perceptual features of the stimuli, such as their asymmetry, played a moderating role in shaping the inversion effect. Lastly, we investigated the strategy adopted in the visual-matching task by tracking eye movements of the participants. Results of Experiment 4 suggest an association between a specific pattern of visual exploration of the images and the presence of the inversion effect. Findings are discussed with respect to the literature on sexual objectification. PMID- 29621250 TI - RNA secondary structure prediction with pseudoknots: Contribution of algorithm versus energy model. AB - MOTIVATION: RNA is a biopolymer with various applications inside the cell and in biotechnology. Structure of an RNA molecule mainly determines its function and is essential to guide nanostructure design. Since experimental structure determination is time-consuming and expensive, accurate computational prediction of RNA structure is of great importance. Prediction of RNA secondary structure is relatively simpler than its tertiary structure and provides information about its tertiary structure, therefore, RNA secondary structure prediction has received attention in the past decades. Numerous methods with different folding approaches have been developed for RNA secondary structure prediction. While methods for prediction of RNA pseudoknot-free structure (structures with no crossing base pairs) have greatly improved in terms of their accuracy, methods for prediction of RNA pseudoknotted secondary structure (structures with crossing base pairs) still have room for improvement. A long-standing question for improving the prediction accuracy of RNA pseudoknotted secondary structure is whether to focus on the prediction algorithm or the underlying energy model, as there is a trade off on computational cost of the prediction algorithm versus the generality of the method. RESULTS: The aim of this work is to argue when comparing different methods for RNA pseudoknotted structure prediction, the combination of algorithm and energy model should be considered and a method should not be considered superior or inferior to others if they do not use the same scoring model. We demonstrate that while the folding approach is important in structure prediction, it is not the only important factor in prediction accuracy of a given method as the underlying energy model is also as of great value. Therefore we encourage researchers to pay particular attention in comparing methods with different energy models. PMID- 29621251 TI - Ultrastructural localisation of protein interactions using conditionally stable nanobodies. AB - We describe the development and application of a suite of modular tools for high resolution detection of proteins and intracellular protein complexes by electron microscopy (EM). Conditionally stable GFP- and mCherry-binding nanobodies (termed csGBP and csChBP, respectively) are characterized using a cell-free expression and analysis system and subsequently fused to an ascorbate peroxidase (APEX) enzyme. Expression of these cassettes alongside fluorescently labelled proteins results in recruitment and stabilisation of APEX, whereas unbound APEX nanobodies are efficiently degraded by the proteasome. This greatly simplifies correlative analyses, enables detection of less-abundant proteins, and eliminates the need to balance expression levels between fluorescently labelled and APEX nanobody proteins. Furthermore, we demonstrate the application of this system to bimolecular complementation ('EM split-fluorescent protein'), for localisation of protein-protein interactions at the ultrastructural level. PMID- 29621252 TI - Xome-Blender: A novel cancer genome simulator. AB - The adoption of next generation sequencing based methods in cancer research allowed for the investigation of the complex genetic structure of tumor samples. In the last few years, considerable importance was given to the research of somatic variants and several computational approaches were developed for this purpose. Despite continuous improvements to these programs, the validation of their results it's a hard challenge due to multiple sources of error. To overcome this drawback different simulation approaches are used to generate synthetic samples but they are often based on the addition of artificial mutations that mimic the complexity of genomic variations. For these reasons, we developed a novel software, Xome-Blender, that generates synthetic cancer genomes with user defined features such as the number of subclones, the number of somatic variants and the presence of copy number alterations (CNAs), without the addition of any synthetic element. The singularity of our method is the "morphological approach" used to generate mutation events. To demonstrate the power of our tool we used it to address the hard challenge of evaluating the performance of nine state-of-the art somatic variant calling methods for small and large variants (VarScan2, MuTect, Shimmer, BCFtools, Strelka, EXCAVATOR2, Control-FREEC and CopywriteR). Through these analyses we observed that by using Xome-Blender data it is possible to appraise small differences between their performance and we have designated VarScan2 and EXCAVATOR2 as best tool for this kind of applications. Xome-Blender is unix-based, licensed under the GPLv3 and freely available at https://github.com/rsemeraro/XomeBlender. PMID- 29621253 TI - A correlation comparison between Altmetric Attention Scores and citations for six PLOS journals. AB - This study considered all articles published in six Public Library of Science (PLOS) journals in 2012 and Web of Science citations for these articles as of May 2015. A total of 2,406 articles were analyzed to examine the relationships between Altmetric Attention Scores (AAS) and Web of Science citations. The AAS for an article, provided by Altmetric aggregates activities surrounding research outputs in social media (news outlet mentions, tweets, blogs, Wikipedia, etc.). Spearman correlation testing was done on all articles and articles with AAS. Further analysis compared the stratified datasets based on percentile ranks of AAS: top 50%, top 25%, top 10%, and top 1%. Comparisons across the six journals provided additional insights. The results show significant positive correlations between AAS and citations with varied strength for all articles and articles with AAS (or social media mentions), as well as for normalized AAS in the top 50%, top 25%, top 10%, and top 1% datasets. Four of the six PLOS journals, Genetics, Pathogens, Computational Biology, and Neglected Tropical Diseases, show significant positive correlations across all datasets. However, for the two journals with high impact factors, PLOS Biology and Medicine, the results are unexpected: the Medicine articles showed no significant correlations but the Biology articles tested positive for correlations with the whole dataset and the set with AAS. Both journals published substantially fewer articles than the other four journals. Further research to validate the AAS algorithm, adjust the weighting scheme, and include appropriate social media sources is needed to understand the potential uses and meaning of AAS in different contexts and its relationship to other metrics. PMID- 29621254 TI - IL-13 receptors as possible therapeutic targets in diffuse intrinsic pontine glioma. AB - Diffuse intrinsic pontine glioma (DIPG) is a universally fatal childhood cancer of the brain. Despite the introduction of conventional chemotherapy and radiotherapy, improvements in survival have been marginal and long-term survivorship is uncommon. Thus, new targets for therapeutics are critically needed. Early phase clinical trials exploring molecularly-targeted therapies against the epidermal growth factor receptor (EGFR) and novel immunotherapies targeting interleukin receptor-13alpha2 (IL-13Ralpha2) have demonstrated activity in this disease. To identify additional therapeutic markers for cell surface receptors, we performed exome sequencing (16 new samples, 22 previously published samples, total 38 with 26 matched normal DNA samples), RNA deep sequencing (17 new samples, 11 previously published samples, total 28 with 18 matched normal RNA samples), and immunohistochemistry (17 DIPG tissue samples) to examine the expression of the interleukin-4 (IL-4) signaling axis components (IL-4, interleukin 13 (IL-13), and their respective receptors IL-4Ralpha, IL-13Ralpha1, and IL-13Ralpha2). In addition, we correlated cytokine and receptor expression with expression of the oncogenes EGFR and c-MET. In DIPG tissues, transcript level analysis found significant expression of IL-4, IL-13, and IL-13Ralpha1/2, with strong differential expression of IL-13Ralpha1/2 in tumor versus normal brain. At the protein level, immunohistochemical studies revealed high content of IL-4 and IL-13Ralpha1/2 but notably low expression of IL-13. Additionally, a strong positive correlation was observed between c-Met and IL-4Ralpha. The genomic and transcriptional landscape across all samples was also summarized. These data create a foundation for the design of potential new immunotherapies targeting IL-13 cell surface receptors in DIPG. PMID- 29621255 TI - Empirical estimation of life expectancy from a linked health database of adults who entered care for HIV. AB - BACKGROUND: While combination antiretroviral therapy (cART) has significantly improved survival times for persons diagnosed with HIV, estimation of life expectancy (LE) for this cohort remains a challenge, as mortality rates are a function of both time since diagnosis and age, and mortality rates for the oldest age groups may not be available. METHODS: A validated case-finding algorithm for HIV was used to update the cohort of HIV-positive adults who had entered care in Ontario, Canada as of 2012. The Chiang II abridged life table algorithm was modified to use mortality rates stratified by time since entering the cohort and to include various methods for extrapolation of the excess HIV mortality rates to older age groups. RESULTS: As of 2012, there were approximately 15,000 adults in care for HIV in Ontario. The crude all-cause mortality rate declined from 2.6% (95%CI 2.3, 2.9) per year in 2000 to 1.3% (1.2, 1.5) in 2012. Mortality rates were elevated for the first year of care compared to subsequent years (rate ratio of 2.6 (95% CI 2.3, 3.1)). LE for a 20-year old living in Ontario was 62 years (expected age at death is 82), while LE for a 20-year old with HIV was estimated to be reduced to 47 years, for a loss of 15 years of life. Ignoring the higher mortality rates among new cases introduced a modest bias of 1.5 additional years of life lost. In comparison, using 55+ as the open-ended age group was a major source of bias, adding 11 years to the calculated LE. CONCLUSIONS: Use of age limits less than the expected age at death for the open-ended age group significantly overstates the estimated LE and is not recommended. The Chiang II method easily accommodated input of stratified mortality rates and extrapolation of excess mortality rates. PMID- 29621256 TI - New computational approaches to understanding molecular protein function. PMID- 29621257 TI - Safeguarding against Ebola: Vaccines and therapeutics to be stockpiled for future outbreaks. PMID- 29621258 TI - DIVA metabolomics: Differentiating vaccination status following viral challenge using metabolomic profiles. AB - Bovine Respiratory Disease (BRD) is a major source of economic loss within the agricultural industry. Vaccination against BRD-associated viruses does not offer complete immune protection and vaccine failure animals present potential routes for disease spread. Serological differentiation of infected from vaccinated animals (DIVA) is possible using antigen-deleted vaccines, but during virus outbreaks DIVA responses are masked by wild-type virus preventing accurate serodiagnosis. Previous work by the authors has established the potential for metabolomic profiling to reveal metabolites associated with systemic immune responses to vaccination. The current study builds on this work by demonstrating for the first time the potential to use plasma metabolite profiling to differentiate between vaccinated and non-vaccinated animals following infection challenge. Male Holstein Friesian calves were intranasally vaccinated (Pfizer RISPOVAL(r)PI3+RSV) and subsequently challenged with Bovine Parainfluenza Virus type-3 (BPI3V) via nasal inoculation. Metabolomic plasma profiling revealed that viral challenge led to a shift in acquired plasma metabolite profiles from day 2 to 20 p.i., with 26 metabolites identified whose peak intensities were significantly different following viral challenge depending on vaccination status. Elevated levels of biliverdin and bilirubin and decreased 3 indolepropionic acid in non-vaccinated animals at day 6 p.i. may be associated with increased oxidative stress and reactive oxygen scavenging at periods of peak virus titre. During latter stages of infection, increased levels of N [(3alpha,5beta,12alpha)-3,12-dihydroxy-7,24-dioxocholan-24-yl]glycine and lysophosphatidycholine and decreased enterolactone in non-vaccinated animals may reflect suppression of innate immune response mechanisms and progression to adaptive immune responses. Levels of hexahydrohippurate were also shown to be significantly elevated in non-vaccinated animals from days 6 to 20 p.i. These findings demonstrate the potential of metabolomic profiling to identify plasma markers that can be employed in disease diagnostic applications to both differentially identify infected non-vaccinated animals during disease outbreaks and provide greater information on the health status of infected animals. PMID- 29621259 TI - Copy number of pancreatic polypeptide receptor gene NPY4R correlates with body mass index and waist circumference. AB - Multiple genetic studies have linked copy number variation (CNV) in different genes to body mass index (BMI) and obesity. A CNV on chromosome 10q11.22 has been associated with body weight. This CNV region spans NPY4R, the gene encoding the pancreatic polypeptide receptor Y4, which has been described as a satiety stimulating receptor. We have investigated CNV of the NPY4R gene and analysed its relationship to BMI, waist circumference and self-reported dietary intake from 558 individuals (216 men and 342 women) representing a wide BMI range. The copy number for NPY4R ranged from 2 to 8 copies (average 4.6+/-0.8). Rather than the expected negative correlation, we observed a positive correlation between NPY4R copy number and BMI as well as waist circumference (r = 0.267, p = 2.65*10-7 and r = 0.256, p = 8*10-7, respectively). Each additional copy of NPY4R correlated with 2.6 kg/m2 increase in BMI and 5.67 cm increase in waist circumference (p = 3.3*10-7 and p = 1*10-6, respectively) for women. For men, there was no statistically significant correlation between CNV and BMI. Our results suggest that NPY4R genetic variation influences body weight in women, but the exact role of this receptor appears to be more complex than previously proposed. PMID- 29621260 TI - Reassembling haplotypes in a mixture of pooled amplicons when the relative concentrations are known: A proof-of-concept study on the efficient design of next-generation sequencing strategies. AB - Next-generation sequencing can be costly and labour intensive. Usually, the sequencing cost per sample is reduced by pooling amplified DNA = amplicons) derived from different individuals on the same sequencing lane. Barcodes unique to each amplicon permit short-read sequences to be assigned appropriately. However, the cost of the library preparation increases with the number of barcodes used. We propose an alternative to barcoding: by using different known proportions of individually-derived amplicons in a pooled sample, each is characterised a priori by an expected depth of coverage. We have developed a Hidden Markov Model that uses these expected proportions to reconstruct the input sequences. We apply this method to pools of mitochondrial DNA amplicons extracted from kangaroo meat, genus Macropus. Our experiments indicate that the sequence coverage can be efficiently used to index the short-reads and that we can reassemble the input haplotypes when secondary factors impacting the coverage are controlled. We therefore demonstrate that, by combining our approach with standard barcoding, the cost of the library preparation is reduced to a third. PMID- 29621261 TI - A multicenter, randomized controlled trial of individualized occupational therapy for patients with schizophrenia in Japan. AB - The individualized occupational therapy (IOT) program is a psychosocial program that we developed to facilitate proactive participation in treatment and improve cognitive functioning and other outcomes for inpatients with acute schizophrenia. The program consists of motivational interviewing, self-monitoring, individualized visits, handicraft activities, individualized psychoeducation, and discharge planning. This multicenter, open-labeled, blinded-endpoint, randomized controlled trial evaluated the impact of adding IOT to a group OT (GOT) program as usual for outcomes in recently hospitalized patients with schizophrenia in Japanese psychiatric hospitals setting compared with GOT alone. Patients with schizophrenia were randomly assigned to the GOT+IOT group or the GOT alone group. Among 136 randomized patients, 129 were included in the intent-to-treat population: 66 in the GOT+IOT and 63 in the GOT alone groups. Outcomes were administered at baseline and discharge or 3 months following hospitalization including the Brief Assessment of Cognition in Schizophrenia Japanese version (BACS-J), the Schizophrenia Cognition Rating Scale Japanese version, the Social Functioning Scale Japanese version, the Global Assessment of Functioning scale, the Intrinsic Motivation Inventory Japanese version (IMI-J), the Morisky Medication Adherence Scale-8 (MMAS-8), the Positive and Negative Syndrome Scale (PANSS), and the Japanese version of Client Satisfaction Questionnaire-8 (CSQ 8J). Results of linear mixed effects models indicated that the IOT+GOT showed significant improvements in verbal memory (p <0.01), working memory (p = 0.02), verbal fluency (p < 0.01), attention (p < 0.01), and composite score (p < 0.01) on the BACS-J; interest/enjoyment (p < 0.01), value/usefulness (p < 0.01), perceived choice (p < 0.01), and IMI-J total (p < 0.01) on the IMI-J; MMAS-8 score (p < 0.01) compared with the GOT alone. Patients in the GOT+IOT demonstrated significant improvements on the CSQ-8J compared with the GOT alone (p < 0.01). The present findings provide support for the feasibility in implementing an IOT program and its effectiveness for improving cognitive impairment and other outcomes in patients with schizophrenia. PMID- 29621262 TI - Rescue of hyperexcitability in hippocampal CA1 neurons from Mecp2 (-/y) mouse through surface potential neutralization. AB - Hyperventilation is a known feature of Rett syndrome (RTT). However, how hyperventilation is related to other RTT symptoms such as hyperexcitability is unknown. Intense breathing during hyperventilation induces hypocapnia and culminates in respiratory alkalosis. Alkalinization of extracellular milieu can trigger epilepsy in patients who already have neuronal hyperexcitability. By combining patch-clamp electrophysiology and quantitative glutamate imaging, we compared excitability of CA1 neurons of WT and Mecp2 (-/y) mice, and analyzed the biophysical properties of subthreshold membrane channels. The results show that Mecp2 (-/y) CA1 neurons are hyperexcitable in normal pH (7.4) and are increasingly vulnerable to alkaline extracellular pH (8.4), during which their excitability increased further. Under normal pH conditions, an abnormal negative shift in the voltage-dependencies of HCN (hyperpolarization-activated cyclic nucleotide-gated) and calcium channels in the CA1 neurons of Mecp2 (-/y) mice was observed. Alkaline pH also enhanced excitability in wild-type (WT) CA1 neurons through modulation of the voltage dependencies of HCN- and calcium channels. Additionally alkaline pH augmented spontaneous glutamate release and burst firing in WT CA1 neurons. Conversely, acidic pH (6.4) and 8 mM Mg2+ exerted the opposite effect, and diminished hyperexcitability in Mecp2 (-/y) CA1 neurons. We propose that the observed effects of pH and Mg2+ are mediated by changes in the neuronal membrane surface potential, which consecutively modulates the gating of HCN and calcium channels. The results provide insight to pivotal cellular mechanisms that can regulate neuronal excitability and help to devise treatment strategies for hyperexcitability induced symptoms of Rett syndrome. PMID- 29621263 TI - Wide scan imaging with swept-source optical coherent tomography for glaucoma diagnosis. AB - PURPOSE: To determine glaucoma-discriminating abilities of macular and circumpapillary retinal nerve fiber layer (cpRNFL) thickness measurements of wide scan (12X9mm) using swept-source optical coherence tomography (SS-OCT) compared to measurements of standard macula and disc scans (6 X 6 mm). METHODS: This retrospective chart review study included 60 glaucomatous and 62 healthy eyes of total 122 subjects who visited a glaucoma clinic and were examined with wide, standard macula, and standard disc scans of SS-OCT (DRI-OCT-1 Atlantis; Topcon Inc., Tokyo, Japan) on the same day. Thickness measurements of the ganglion cell layer plus inner plexiform layer (mGCIPL), mGCIPL plus nerve fiber layer (mGCC), and total retinal layer (TRL) were assessed in wide and standard macula scans. Thickness measurements of cpRNFL were assessed in wide and standard disc scans. The repeatability and agreement of measurements taken in each scan were evaluated using intraclass correlation coefficients (ICCs). The abilities of parameters to discriminate between glaucoma and normal groups were assessed using areas under receiver operating characteristic curves (AUCs). RESULTS: The repeatability and agreement of all parameters showed high ICC values (all >= 0.800). AUCs for mGCIPL thickness were 0.710-0.847 and 0.701-0.836 in standard macula and wide scans, respectively. AUCs for cpRNFL thickness were 0.749-0.902 and 0.726-0.897 in standard disc and wide scans, respectively. There were no significant differences in AUCs between wide and standard scans. CONCLUSIONS: The agreement between SS-OCT wide and standard scans for mGCIPL, mGCC and cpRNFL measurements were excellent. As the glaucoma-discriminating ability of wide scans was comparable to that of standard macula/disc scans, a single wide scan can replace separate standard macula/disc scans for evaluating glaucoma. PMID- 29621264 TI - Improving the understanding of sleep apnea characterization using Recurrence Quantification Analysis by defining overall acceptable values for the dimensionality of the system, the delay, and the distance threshold. AB - Our contribution focuses on the characterization of sleep apnea from a cardiac rate point of view, using Recurrence Quantification Analysis (RQA), based on a Heart Rate Variability (HRV) feature selection process. Three parameters are crucial in RQA: those related to the embedding process (dimension and delay) and the threshold distance. There are no overall accepted parameters for the study of HRV using RQA in sleep apnea. We focus on finding an overall acceptable combination, sweeping a range of values for each of them simultaneously. Together with the commonly used RQA measures, we include features related to recurrence times, and features originating in the complex network theory. To the best of our knowledge, no author has used them all for sleep apnea previously. The best performing feature subset is entered into a Linear Discriminant classifier. The best results in the "Apnea-ECG Physionet database" and the "HuGCDN2014 database" are, according to the area under the receiver operating characteristic curve, 0.93 (Accuracy: 86.33%) and 0.86 (Accuracy: 84.18%), respectively. Our system outperforms, using a relatively small set of features, previously existing studies in the context of sleep apnea. We conclude that working with dimensions around 7-8 and delays about 4-5, and using for the threshold distance the Fixed Amount of Nearest Neighbours (FAN) method with 5% of neighbours, yield the best results. Therefore, we would recommend these reference values for future work when applying RQA to the analysis of HRV in sleep apnea. We also conclude that, together with the commonly used vertical and diagonal RQA measures, there are newly used features that contribute valuable information for apnea minutes discrimination. Therefore, they are especially interesting for characterization purposes. Using two different databases supports that the conclusions reached are potentially generalizable, and are not limited by database variability. PMID- 29621265 TI - Optimum strata boundaries and sample sizes in health surveys using auxiliary variables. AB - Using convenient stratification criteria such as geographical regions or other natural conditions like age, gender, etc., is not beneficial in order to maximize the precision of the estimates of variables of interest. Thus, one has to look for an efficient stratification design to divide the whole population into homogeneous strata that achieves higher precision in the estimation. In this paper, a procedure for determining Optimum Stratum Boundaries (OSB) and Optimum Sample Sizes (OSS) for each stratum of a variable of interest in health surveys is developed. The determination of OSB and OSS based on the study variable is not feasible in practice since the study variable is not available prior to the survey. Since many variables in health surveys are generally skewed, the proposed technique considers the readily-available auxiliary variables to determine the OSB and OSS. This stratification problem is formulated into a Mathematical Programming Problem (MPP) that seeks minimization of the variance of the estimated population parameter under Neyman allocation. It is then solved for the OSB by using a dynamic programming (DP) technique. A numerical example with a real data set of a population, aiming to estimate the Haemoglobin content in women in a national Iron Deficiency Anaemia survey, is presented to illustrate the procedure developed in this paper. Upon comparisons with other methods available in literature, results reveal that the proposed approach yields a substantial gain in efficiency over the other methods. A simulation study also reveals similar results. PMID- 29621266 TI - Intrinsic and extrinsic motivators of attachment under active inference. AB - This paper addresses the formation of infant attachment types within the context of active inference: a holistic account of action, perception and learning in the brain. We show how the organised forms of attachment (secure, avoidant and ambivalent) might arise in (Bayesian) infants. Specifically, we show that these distinct forms of attachment emerge from a minimisation of free energy-over interoceptive states relating to internal stress levels-when seeking proximity to caregivers who have a varying impact on these interoceptive states. In line with empirical findings in disrupted patterns of affective communication, we then demonstrate how exteroceptive cues (in the form of caregiver-mediated AMBIANCE affective communication errors, ACE) can result in disorganised forms of attachment in infants of caregivers who consistently increase stress when the infant seeks proximity, but can have an organising (towards ambivalence) effect in infants of inconsistent caregivers. In particular, we differentiate disorganised attachment from avoidance in terms of the high epistemic value of proximity seeking behaviours (resulting from the caregiver's misleading exteroceptive cues) that preclude the emergence of coherent and organised behavioural policies. Our work, the first to formulate infant attachment in terms of active inference, makes a new testable prediction with regards to the types of affective communication errors that engender ambivalent attachment. PMID- 29621267 TI - Food hygiene practices and its associated factors among model and non model households in Abobo district, southwestern Ethiopia: Comparative cross-sectional study. AB - BACKGROUND: In developing country most of human infectious diseases are caused by eating contaminated food. Estimated nine out ten of the diarrheal disease is attributable to the environment and associated with risk factors of poor food hygiene practice. Understanding the risk of eating unsafe food is the major concern to prevent and control food borne diseases. The main goal of this study was to assessing food hygiene practices and its associated factors among model and non model households at Abobo district. METHODS: This study was conducted from 18 October 2013 to 13 June 2014. A community-based comparative cross sectional study design was used. Pretested structured questionnaire was used to collect data. A total of 1247 households (417 model and 830 non model households) were included in the study from Abobo district. Bivariate and multivariate logistic regression analysis was used to identify factors associated with outcome variable. RESULTS: The study revealed that good food hygiene practice was 51%, of which 79% were model and 36.70% were non model households. Type of household [AOR: 2.07, 95% CI: (1.32-3.39)], sex of household head [AOR: 1.63, 95% CI: (1.06 2.48)], Availability of liquid wastes disposal pit [AOR: 2.23, 95% CI: (1.39,3.63)], Knowledge of liquid waste to cause diseases [AOR: 1.95, 95% (1.23,3.08)], and availability of functional hand washing facility [AOR: 3.61, 95% CI: (1.86-7.02)] were the factors associated with food handling practices. CONCLUSION: This study revealed that good food handling practice is low among model and non model households. While type of household (model versus non model households), sex, knowledge of solid waste to cause diseases, availability of functional hand washing facility, and availability of liquid wastes disposal pit were the factors associated with outcome variable. Health extension workers should play a great role in educating households regarding food hygiene practices to improve their knowledge and practices of the food hygiene. PMID- 29621268 TI - Vertically distinct microbial communities in the Mariana and Kermadec trenches. AB - Hadal trenches, oceanic locations deeper than 6,000 m, are thought to have distinct microbial communities compared to those at shallower depths due to high hydrostatic pressures, topographical funneling of organic matter, and biogeographical isolation. Here we evaluate the hypothesis that hadal trenches contain unique microbial biodiversity through analyses of the communities present in the bottom waters of the Kermadec and Mariana trenches. Estimates of microbial protein production indicate active populations under in situ hydrostatic pressures and increasing adaptation to pressure with depth. Depth, trench of collection, and size fraction are important drivers of microbial community structure. Many putative hadal bathytypes, such as members related to the Marinimicrobia, Rhodobacteraceae, Rhodospirilliceae, and Aquibacter, are similar to members identified in other trenches. Most of the differences between the two trench microbiomes consists of taxa belonging to the Gammaproteobacteria whose distributions extend throughout the water column. Growth and survival estimates of representative isolates of these taxa under deep-sea conditions suggest that some members may descend from shallower depths and exist as a potentially inactive fraction of the hadal zone. We conclude that the distinct pelagic communities residing in these two trenches, and perhaps by extension other trenches, reflect both cosmopolitan hadal bathytypes and ubiquitous genera found throughout the water column. PMID- 29621269 TI - Artificial neural network model for predicting the bioavailability of tacrolimus in patients with renal transplantation. AB - The objective of the current study was to explore the role of ABCB1 and CYP3A5 genetic polymorphisms in predicting the bioavailability of tacrolimus and the risk for post-transplant diabetes. Artificial neural network (ANN) and logistic regression (LR) models were used to predict the bioavailability of tacrolimus and risk for post-transplant diabetes, respectively. The five-fold cross-validation of ANN model showed good correlation with the experimental data of bioavailability (r2 = 0.93-0.96). Younger age, male gender, optimal body mass index were shown to exhibit lower bioavailability of tacrolimus. ABCB1 1236 C>T and 2677G>T/A showed inverse association while CYP3A5*3 showed a positive association with the bioavailability of tacrolimus. Gender bias was observed in the association with ABCB1 3435 C>T polymorphism. CYP3A5*3 was shown to interact synergistically in increasing the bioavailability in combination with ABCB1 1236 TT or 2677GG genotypes. LR model showed an independent association of ABCB1 2677 G>T/A with post transplant diabetes (OR: 4.83, 95% CI: 1.22-19.03). Multifactor dimensionality reduction analysis (MDR) revealed that synergistic interactions between CYP3A5*3 and ABCB1 2677 G>T/A as the determinants of risk for post transplant diabetes. To conclude, the ANN and MDR models explore both individual and synergistic effects of variables in modulating the bioavailability of tacrolimus and risk for post-transplant diabetes. PMID- 29621270 TI - Measurement of shear wave speed dispersion in the placenta by transient elastography: A preliminary ex vivo study. AB - BACKGROUND: Placental elasticity may be modified in women with placental insufficiency. Shear wave elastography (SWE) can measure this, using acoustic radiation force, but the safety of its use in pregnant women has not yet been demonstrated. Transient elastography (TE) is a safer alternative, but has not yet been applied to the placenta. Moreover, the dispersion of shear wave speed (SWS) as a function of frequency has received relatively little study for placental tissue, although it might improve the accuracy of biomechanical assessment. OBJECTIVE: To explore the feasibility and reproducibility of TE for placental analysis, to compare the values of SWS and Young's modulus (YM) from TE and SWE, and to analyze SWS dispersion as a function of frequency ex vivo in normal placentas. MATERIALS AND METHODS: Ten normal placentas were analyzed ex vivo by an Aixplorer ultrasound system as shear waves were generated by a vibrating plate and by using an Aixplorer system. The frequency analysis provided the value of the exponent n from a fractional rheological model applied to the TE method. We calculated intra- and interobserver agreement for SWS and YM with 95% prediction intervals, created Bland-Altman plots with 95% limits of agreement, and estimated the intraclass correlation coefficient (ICC). MAIN RESULTS: The mean SWS was 1.80 m/s +/- 0.28 (standard deviation) with the TE method at 50 Hz and 1.82 m/s +/ 0.13 with SWE (P = 0.912). No differences were observed between the central and peripheral regions of placentas with either TE or SWE. With TE, the intraobserver ICC for SWS was 0.68 (0.50-0.82), and the interobserver ICC for SWS 0.65 (0.37 0.85). The mean parameter n obtained from the fractional rheological model was 1.21 +/- 0.12, with variable values of n for any given SWS. CONCLUSIONS: TE is feasible and reproducible on placentas ex vivo. The frequency analysis of SWS provides additional information about placental elasticity and appears to be able to distinguish differences between placental structures. PMID- 29621271 TI - Comprehensive haematological indices reference intervals for a healthy Omani population: First comprehensive study in Gulf Cooperation Council (GCC) and Middle Eastern countries based on age, gender and ABO blood group comparison. AB - BACKGROUND: Reference intervals for venous blood parameters differs with age, gender, geographic region, and ethnic groups. Hence local laboratory reference intervals are important to improve the diagnostic accuracy of health assessments and diseases. However, there have been no comprehensive published reference intervals established in Oman, the Gulf Cooperation Council or Middle Eastern countries. Hence, the aim of this study was to establish reference intervals for full blood count in healthy Omani adults. METHODS: Venous blood specimens were collected from 2202 healthy individuals aged 18 to 69 years from January 2012 to April 2017, and analysed by Sysmex XS-1000i and Cell-Dyn Sapphire automated haematology analysers. Results were statistically analysed and compared by gender, age, and ABO blood group. The lower and upper reference limits of the haematology reference intervals were established at the 2.5th and 97.5th percentiles respectively. RESULTS: Reference intervals were calculated for 17 haematology parameters which included red blood cell, white blood cell, and platelet parameters. Red blood cell (RBC), haemoglobin (HGB), haematocrit (HCT), platelet and platelet haematocrit counts of the healthy donors were significantly different between males and females at all ages (p < 0.05), with males having higher mean values of RBC, HGB and HCT than females. Other complete blood count parameters showed no significant differences between genders, age groups, instruments, or blood groups. Our study showed a lower haemoglobin limit for the normal reference interval in males and females than the currently used in Oman. CONCLUSIONS: Data from this study established specific reference intervals which could be considered for general use in Oman. The differences in haematology reference intervals highlights the necessity to establish reference intervals for venous blood parameters among the healthy population in each country or at least in each region. PMID- 29621272 TI - Mortality in a cohort of remote-living Aboriginal Australians and associated factors. AB - OBJECTIVES: We aimed to describe mortality in a cohort of remote-living Aboriginal Australians using electronic record linkage. METHODS: Between 2004 and 2006, 363 Aboriginal people living in remote Western Australia (WA) completed a questionnaire assessing medical history and behavioural risk factors. We obtained mortality records for the cohort from the WA Data Linkage System and compared them to data for the general population. We used Cox proportional hazards regression to identify predictors of mortality over a 9-year follow-up period. RESULTS: The leading causes of mortality were diabetes, renal failure, and ischaemic heart disease. Diabetes and renal failure accounted for 28% of all deaths. This differed from both the Australian population as a whole, and the general Indigenous Australian population. The presence of chronic disease did not predict mortality, nor did behaviours such as smoking. Only age, male sex, poor mobility, and cognitive impairment were risk factors. CONCLUSIONS: To reduce premature mortality, public health practitioners should prioritise the prevention and treatment of diabetes and renal disease in Aboriginal people in remote WA. This will require a sustained and holistic approach. PMID- 29621273 TI - Ultrafiltered recombinant AAV8 vector can be safely administered in vivo and efficiently transduces liver. AB - Viral vectors are extensively purified for use in biomedical research, in order to separate biologically active virus particles and to eliminate production related impurities that are assumed to be detrimental to the host. For recombinant adeno-associated virus (rAAV) vectors this is typically accomplished using density gradient-based methods, which are tedious and require specialized ultracentrifugation equipment. In order to streamline the preparation of rAAV vectors for pilot and small animal studies, we recently devised a simple ultrafiltration approach that permits rapid virus concentration and partial removal of production-related impurities. Here we show that systemic administration of such rapidly prepared (RP) rAAV8 vectors in mice is safe and efficiently transduces the liver. Across a range of doses, delivery of RP rAAV8 CMV-eGFP vector induced enhanced green fluorescent protein (eGFP) expression in liver that was comparable to that obtained from a conventional iodixanol gradient purified (IP) vector. Surprisingly, no liver inflammation or systemic cytokine induction was detected in RP rAAV injected animals, revealing that residual impurities in the viral vector preparation are not deleterious to the host. Together, these data demonstrate that partially purified rAAV vector can be safely and effectively administered in vivo. The speed and versatility of the RP method and lack of need for cumbersome density gradients or expensive ultracentrifuge equipment will enable more widespread use of RP prepared rAAV vectors, such as for pilot liver gene transfer studies. PMID- 29621274 TI - Phenotype and biochemical heterogeneity in late onset Fabry disease defined by N215S mutation. AB - BACKGROUND: Fabry disease (FD) results from X-linked inheritance of a mutation in the GLA gene, encoding for alpha galactosidase A, and is characterized by heterogeneous clinical manifestations. Two phenotypes have been described "Classic" and "late onset" which cannot be predicted exclusively by genotype. The latter has been considered an attenuated form of the disease often affecting a single organ system commonly the heart. Recent studies have demonstrated that cardiac outcomes are similar in patients with classic and late onset mutations. In this study we investigate the relationship between clinical heterogeneity and plasma lyso-Gb3 in a large single centre cohort of N215S patients and compare this to patients with other mutations. METHODS: In this single-centre, retrospective, cross-sectional study we analysed a cohort of 251 FD patients: 84 N215S mutation (37 males) and 167 non-N215S mutations (58 males). The Mainz severity score index (MSSI) was used as an index of overall disease severity. Cardiac function and morphology were assessed by electrocardiogram and echocardiogram. Left ventricular mass was calculated using the Devereux formula and the left ventricular mass index (LVMI) calculated to adjust for height (g/m2.7). The presence of white matter lesions was assessed by cerebral MRI or computed tomography (CT). GFR was measured by radio-isotope (chromium-EDTA) method and adjusted for patient height (ml/min/m2.7), and urinary protein quantification was undertaken by 24 hour urine collection. Plasma globotriaosylsphingosine (lyso-Gb3) was analysed prior to ERT in 84 patients. RESULTS: N215S patients showed later symptom onset (males: p< 0.0001, females: p<0.03), later development of left ventricular hypertrophy (LVH) (median survival without LVH: 41 (non-N215S) vs. 64 (N215S) years, p< 0.0001), later development of proteinuria (median survival without proteinuria 43 (non-N215S) vs 71 years (N215S), p< 0.0001), later occurrence of cerebrovascular events (stroke/ Transient Ischaemic Attacks (TIA); median survival without stroke: 74 years (non N215S) vs. not reached (N215S), p< 0.02), later decline in renal function to GFR <60 ml/min/1.73m2 (median survival: 56 (non-N215S) vs. 72 (N215S) years, p< 0.01), and greater overall survival (median survival 81 (N215S) vs. 66 (non N215S) years, p< 0.0006). Lyso-Gb3 was found to be less elevated in N215S compared to non-N215S male and female patients. However, the N215S population eventually reached an overall severity measured by MSSI comparable to the non N215S without equivalent elevation of lyso-Gb3 (means: 6.7 vs. 74.3 nmol/L, p < 0.001). In addition, N215S patients showed strong correlations between lyso-Gb3 levels and LVMI, GFR, and MSSI. These associations became stronger when we investigated individuals' life time exposure to lyso-Gb3 (calculated as [lyso Gb3]*age): MSSI (r2 = 0.88, p< 0.0001), LVMI (r2 = 0.59, p< 0.005), and GFR (r2 = 0.75, p = 0.0001). CONCLUSION: These results demonstrate that the N215S mutation results in a late onset phenotype involving the heart and other organs. Correlations between clinical manifestations and plasma lyso-Gb3 variations in this group suggest a Fabry-relevant disease mechanism for the heterogeneity observed in this group. PMID- 29621275 TI - A threshold-free model of numerosity comparisons. AB - A dominant mechanism in the Judgment and Decision Making literature states that information is accumulated about each choice option until a decision threshold is met. Only after that threshold does a subject start to execute a motor response to indicate their choice. However, recent research has revealed spatial gradients in motor responses as a function of comparison difficulty as well as changes-of mind in the middle of an action, both suggesting continued accumulation and processing of decision-related signals after the decision boundary. Here we present a formal model and supporting data from a number comparison task that a continuous motor planner, combined with a simple statistical inference scheme, can model detailed behavioral effects without assuming a threshold. This threshold-free model reproduces subjects' sensitivity to numerical distance in reaching, accuracy, reaction time, and changes of mind. We argue that the motor system positions the effectors using an optimal biomechanical feedback controller, and continuous statistical inference on outputs from cognitive processes. PMID- 29621276 TI - Rotavirus intestinal infection induces an oral mucosa cytokine response. AB - INTRODUCTION: Salivary glands are known immune effector sites and considered to be part of the whole mucosal immune system. The aim of the present study was to assess the salivary immune response to rotavirus (RV) infection through the analysis of the cytokine immune profile in saliva. MATERIAL AND METHODS: A prospective comparative study of serial saliva samples from 27 RV-infected patients (sampled upon admission to the hospital during acute phase and at convalescence-i.e. at least three months after recovery) and 36 healthy controls was performed. Concentrations of 11 salivary cytokines (IFN-gamma, IFN-alpha2, IL 1beta, IL-6, IL-8, IL-10, IL-15, IL12p70, TNF-alpha, IFN-lambda1, IL-22) were determined. Cytokine levels were compared between healthy controls acute infection and convalescence. The correlation between clinical data and salivary cytokine profile in infected children was assessed. RESULTS: The salivary cytokine profile changes significantly in response to acute RV infection. In RV infected patients, IL-22 levels were increased in the acute phase with respect to convalescence (P-value < 0.001). Comparisons between infected and control group showed significant differences in salivary IFN-alpha2, IL-1beta, IL-6, IL-8, IL 10 and IL-22. Although acute-phase levels of IL-12, IL-10, IL-6 and IFN-gamma showed nominal association with Vesikari's severity, this trend did not reach statistical significance after multiple test adjustment. CONCLUSIONS: RV infection induces a host salivary immune response, indicating that immune mucosal response to RV infection is not confined to the intestinal mucosa. Our data point to a whole mucosal implication in the RV infection as a result of the integrative mucosal immune response, and suggest the salivary gland as effector site for RV infection. PMID- 29621277 TI - Horizontal gene transfer of Chlamydia: Novel insights from tree reconciliation. AB - Recent comparative genomics studies have suggested that horizontal gene transfer (HGT) is one of the major processes in bacterial evolution. In this study, HGT events of 64 Chlamydia strains were investigated based on the pipeline employed in HGTree database constructed in our recent study. Tree reconciliation method was applied in order to calculate feasible HGT events. Following initial detection and an evaluation procedure, evidence of the HGT was identified in 548 gene families including 42 gene families transferred from outside of Chlamydiae phylum with high reliability. The donor species of inter-phylum HGT consists of 12 different bacterial and archaeal phyla, suggesting that Chlamydia might have even more various host range than in previous reports. In addition, each species of Chlamydia showed varying preference towards HGT, and genes engaged in HGT within Chlamydia and between other species showed different functional distribution. Also, examination of individual gene flows of niche-specific genes suggested that many of such genes are transferred mainly within Chlamydia genus. Our results uncovered novel features of HGT acting on Chlamydia genome evolution, and it would be also strong evidence that HGT is an ongoing process for intracellular pathogens. We expect that the results provide more insight into lineage- and niche-specific adaptations regarding their infectivity and pathogenicity. PMID- 29621278 TI - Heart rate variability can clarify students' level of stress during nursing simulation. AB - Simulation is regarded as an effective educational method for the delivery of clinical scenarios. However, exposure to unfamiliar environments during simulation can cause excessive stress among students, possibly leading to unnatural speech/behavior and poor skill learning (Yerkes-Dodson's law). Thus, assessing students' stress in a simulation can provide educators with a better understanding of their mental state. This study sought to clarify stress changes throughout the progression of the simulation by measuring heart rate variability and students' subjective reactions in 74 nursing students. Heart rate variability was calculated in terms of its high-frequency (HF) and low-frequency/high frequency (LF/HF) components during 4 phases-the break, patient care, reporting, and debriefing. Students were interviewed about stress experienced during the simulation. The results showed that HF decreased significantly from the break to the patient care and reporting phases. Furthermore, LF/HF increased significantly from the break to the reporting phases. Approximately 55 students felt stressed during the simulation, 24 of whom felt most stressed during the reporting phase. Therefore, the reporting phase involved high objective and subjective stress. It may be possible that the educator's evaluative attitude increased students' stress. Therefore, a stress intervention during the reporting phase might further improve students' performance during that phase. The debriefing phase did not significantly differ from the break phase for objective stress, and students did not report feeling stressed. Thus, in this phase, they were released from the stress of the reporting phase and the unfamiliar environment. During this phase, they might be able to learn what they could not understand owing to high stress in the patient care and reporting phases. This study provides objective and subjective evidence of students' stress during simulation, and indicates the necessity of providing support during the reporting phase and the importance of debriefing when using clinical scenarios for teaching clinical skills. PMID- 29621279 TI - Assessing worst case scenarios in movement demands derived from global positioning systems during international rugby union matches: Rolling averages versus fixed length epochs. AB - The assessment of competitive movement demands in team sports has traditionally relied upon global positioning system (GPS) analyses presented as fixed-time epochs (e.g., 5-40 min). More recently, presenting game data as a rolling average has become prevalent due to concerns over a loss of sampling resolution associated with the windowing of data over fixed periods. Accordingly, this study compared rolling average (ROLL) and fixed-time (FIXED) epochs for quantifying the peak movement demands of international rugby union match-play as a function of playing position. Elite players from three different squads (n = 119) were monitored using 10 Hz GPS during 36 matches played in the 2014-2017 seasons. Players categorised broadly as forwards and backs, and then by positional sub group (FR: front row, SR: second row, BR: back row, HB: half back, MF: midfield, B3: back three) were monitored during match-play for peak values of high-speed running (>5 m.s-1; HSR) and relative distance covered (m.min-1) over 60-300 s using two types of sample-epoch (ROLL, FIXED). Irrespective of the method used, as the epoch length increased, values for the intensity of running actions decreased (e.g., For the backs using the ROLL method, distance covered decreased from 177.4 +/- 20.6 m.min-1 in the 60 s epoch to 107.5 +/- 13.3 m.min-1 for the 300 s epoch). For the team as a whole, and irrespective of position, estimates of fixed effects indicated significant between-method differences across all time points for both relative distance covered and HSR. Movement demands were underestimated consistently by FIXED versus ROLL with differences being most pronounced using 60 s epochs (95% CI HSR: -6.05 to -4.70 m.min-1, 95% CI distance: -18.45 to -16.43 m.min-1). For all HSR time epochs except one, all backs groups increased more (p < 0.01) from FIXED to ROLL than the forward groups. Linear mixed modelling of ROLL data highlighted that for HSR (except 60 s epoch), SR was the only group not significantly different to FR. For relative distance covered all other position groups were greater than the FR (p < 0.05). The FIXED method underestimated both relative distance (~11%) and HSR values (up to ~20%) compared to the ROLL method. These differences were exaggerated for the HSR variable in the backs position who covered the greatest HSR distance; highlighting important consideration for those implementing the FIXED method of analysis. The data provides coaches with a worst-case scenario reference on the running demands required for periods of 60-300 s in length. This information offers novel insight into game demands and can be used to inform the design of training games to increase specificity of preparation for the most demanding phases of matches. PMID- 29621280 TI - Assessing the validity of a data driven segmentation approach: A 4 year longitudinal study of healthcare utilization and mortality. AB - BACKGROUND: Segmentation of heterogeneous patient populations into parsimonious and relatively homogenous groups with similar healthcare needs can facilitate healthcare resource planning and development of effective integrated healthcare interventions for each segment. We aimed to apply a data-driven, healthcare utilization-based clustering analysis to segment a regional health system patient population and validate its discriminative ability on 4-year longitudinal healthcare utilization and mortality data. METHODS: We extracted data from the Singapore Health Services Electronic Health Intelligence System, an electronic medical record database that included healthcare utilization (inpatient admissions, specialist outpatient clinic visits, emergency department visits, and primary care clinic visits), mortality, diseases, and demographics for all adult Singapore residents who resided in and had a healthcare encounter with our regional health system in 2012. Hierarchical clustering analysis (Ward's linkage) and K-means cluster analysis using age and healthcare utilization data in 2012 were applied to segment the selected population. These segments were compared using their demographics (other than age) and morbidities in 2012, and longitudinal healthcare utilization and mortality from 2013-2016. RESULTS: Among 146,999 subjects, five distinct patient segments "Young, healthy"; "Middle age, healthy"; "Stable, chronic disease"; "Complicated chronic disease" and "Frequent admitters" were identified. Healthcare utilization patterns in 2012, morbidity patterns and demographics differed significantly across all segments. The "Frequent admitters" segment had the smallest number of patients (1.79% of the population) but consumed 69% of inpatient admissions, 77% of specialist outpatient visits, 54% of emergency department visits, and 23% of primary care clinic visits in 2012. 11.5% and 31.2% of this segment has end stage renal failure and malignancy respectively. The validity of cluster-analysis derived segments is supported by discriminative ability for longitudinal healthcare utilization and mortality from 2013-2016. Incident rate ratios for healthcare utilization and Cox hazards ratio for mortality increased as patient segments increased in complexity. Patients in the "Frequent admitters" segment accounted for a disproportionate healthcare utilization and 8.16 times higher mortality rate. CONCLUSION: Our data-driven clustering analysis on a general patient population in Singapore identified five patient segments with distinct longitudinal healthcare utilization patterns and mortality risk to provide an evidence-based segmentation of a regional health system's healthcare needs. PMID- 29621281 TI - Evidence of functional cell-mediated immune responses to nontypeable Haemophilus influenzae in otitis-prone children. AB - Otitis media (OM) remains a common paediatric disease, despite advances in vaccinology. Susceptibility to recurrent acute OM (rAOM) has been postulated to involve defective cell-mediated immune responses to common otopathogenic bacteria. We compared the composition of peripheral blood mononuclear cells (PBMC) from 20 children with a history of rAOM (otitis-prone) and 20 healthy non otitis-prone controls, and assessed innate and cell-mediated immune responses to the major otopathogen nontypeable Haemophilus influenzae (NTHi). NTHi was a potent stimulator of inflammatory cytokine secretion from PBMC within 4 hours, with no difference in cytokine levels produced between PBMC from cases or controls. In the absence of antigen stimulation, otitis-prone children had more circulating Natural Killer (NK) cells (p<0.01), particularly NKdim (CD56lo) cells (p<0.01), but fewer CD4+ T cells (p<0.01) than healthy controls. NTHi challenge significantly increased the proportion of activated (CD107a+) NK cells in otitis prone and non-otitis-prone children (p<0.01), suggesting that NK cells from otitis-prone children are functional and respond to NTHi. CD8+ T cells and NK cells from both cases and controls produced IFNgamma in response to polyclonal stimulus (Staphylococcal enterotoxin B; SEB), with more IFNgamma+ CD8+ T cells present in cases than controls (p<0.05) but similar proportions of IFNgamma+ NK cells. Otitis-prone children had more circulating IFNgamma-producing NK cells (p<0.05) and more IFNgamma-producing CD4+ (p<0.01) or CD8+ T-cells (p<0.05) than healthy controls. In response to SEB, more CD107a-expressing CD8+ T cells were present in cases than controls (p<0.01). Despite differences in PBMC composition, PBMC from otitis-prone children mounted innate and T cell-mediated responses to NTHi challenge that were comparable to healthy children. These data provide evidence that otitis-prone children do not have impaired functional cell mediated immunity. PMID- 29621282 TI - Predictive value of the preoperative neutrophil-to-lymphocyte ratio for the development of hepatocellular carcinoma in HBV-associated cirrhotic patients after splenectomy. AB - The neutrophil to lymphocyte ratio (NLR), a simple marker of inflammation, has recently been showed to predict tumor recurrence in hepatocellular carcinoma (HCC) patients after hepatic resection or liver transplantation. However, whether it can be used to predict HCC development in cirrhotic patients remained unknown. The aim of this study was to evaluate the predictive value of the preoperative NLR for the development of HCC in cirrhotic patients who underwent splenectomy. A total of 230 HBV-associated cirrhotic patients who underwent splenectomy in our hospital from January 2000 to December 2012 were included in this study. Detailed clinical data included patients' general characteristics, laboratory tests and imaging studies, surgical procedures and complications. Information on patients' follow-up data was also obtained. We found that 38 (16.52%) patients developed HCC after splenectomy during the follow-up period. An elevated preoperative NLR was associated with increased risk of developing HCC in cirrhotic patients after splenectomy. The optimal cutoff value of NLR for HCC development was 2.27. In patients who developed HCC during the follow-up period, NLR scores showed no predictive value in overall survival after splenectomy. However, NLR scores appeared to have a much better predictive value in overall survival in patients who did not develop HCC. In conclusion, cirrhotic patients who underwent splenectomy remain at a relatively high risk of developing HCC, and an elevated preoperative NLR is associated with HCC development in cirrhotic patients who underwent splenectomy for hypersplenism. PMID- 29621283 TI - Exploratory analysis of the ecological variables associated with sexual health profiles in high-risk, sexually-active female learners in rural KwaZulu-Natal. AB - PURPOSE: Young women are at high risk for negative sexual health outcomes. Despite their high risk, many sexually-active women never experience negative sexual health outcomes. This study explored the ecological risk factors associated with the risk profiles of sexually-active female high school-learners in rural KwaZulu-Natal, South Africa. METHODS: Using baseline data from N = 596 sexually-active school-going women, we explored the ecological factors associated with being sexually-active and managing risk successfully [SARS] or unsuccessfully [SARU]. Generalised estimated equations (GEE) were applied to data collected at multiple levels while adjusting for school and other included variables. GEE were used to calculate probability of being SARU. RESULTS: Amongst SARU learners, 21.9% had HIV, 38.6% had HSV-2, 12.5% were pregnant, 28.7% self reported STI symptoms and 51.9% reported a previous pregnancy. Individual-level factors had the greatest impact on being SARU. Univariate and multivariate analysis highlighted several important partner factors associated with SARU. Age was significantly associated with the risk profiles (p<0.0001), a greater proportion of SARU learners were 18 or older compared to the SARS learners. The odds of being SARU decreased when >=18 years (aOR = 0.2577, 95% CI 0.1462-0.4542) or if not falling pregnant was important (aOR = 0.6343, 95% CI 0.4218-0.9538). Having >1 HIV test (aOR = 2.2161, 95% CI 1.3964-3.5169) increased the odds a SARU profile. CONCLUSION: Individual and partner level factors are important for the sexual health profile of an adolescent female. While the exploratory findings require further research; managing multiple sexual health outcomes, tailoring responses around a risk profile and including partners is essential for successful interventions. PMID- 29621284 TI - Illness management and recovery: Clinical outcomes of a randomized clinical trial in community mental health centers. AB - OBJECTIVE: Illness Management and Recovery (IMR) is a psychosocial intervention with a recovery-oriented approach. The program has been evaluated in different settings; however evidence for the effects of IMR is still deficient. The aim of this trial was to investigate the benefits and harms of the IMR program compared with treatment as usual in Danish patients with schizophrenia or bipolar disorder. METHOD: The trial was designed as a randomized, assessor-blinded, multi center, clinical trial investigating the IMR program compared with usual treatment. 198 people diagnosed with schizophrenia or bipolar disorder participated. The primary outcome was the Global Assessment of Functioning (GAF F) at the end of intervention and the secondary and explorative outcomes included severity of symptoms and service utilization. RESULTS: IMR had no significant effect on functioning, symptoms, substance use or service utilization. CONCLUSION: This randomized trial contributes to the evidence base of IMR by providing a methodological solid base for its conclusions; however the trial has some important limitations. More research is needed to get a firm answer on the effectiveness of the IMR. PMID- 29621286 TI - Expert-guided optimization for 3D printing of soft and liquid materials. AB - Additive manufacturing (AM) has rapidly emerged as a disruptive technology to build mechanical parts, enabling increased design complexity, low-cost customization and an ever-increasing range of materials. Yet these capabilities have also created an immense challenge in optimizing the large number of process parameters in order achieve a high-performance part. This is especially true for AM of soft, deformable materials and for liquid-like resins that require experimental printing methods. Here, we developed an expert-guided optimization (EGO) strategy to provide structure in exploring and improving the 3D printing of liquid polydimethylsiloxane (PDMS) elastomer resin. EGO uses three steps, starting first with expert screening to select the parameter space, factors, and factor levels. Second is a hill-climbing algorithm to search the parameter space defined by the expert for the best set of parameters. Third is expert decision making to try new factors or a new parameter space to improve on the best current solution. We applied the algorithm to two calibration objects, a hollow cylinder and a five-sided hollow cube that were evaluated based on a multi-factor scoring system. The optimum print settings were then used to print complex PDMS and epoxy 3D objects, including a twisted vase, water drop, toe, and ear, at a level of detail and fidelity previously not obtained. PMID- 29621285 TI - Serious hemorrhages after ischemic stroke or TIA - Incidence, mortality, and predictors. AB - BACKGROUND: Data are lacking on the risk and impact of a serious hemorrhage on the prognosis after ischemic stroke (IS) or transient ischemic attack (TIA). We aimed to estimate the incidence of serious hemorrhage, analyze the impact on mortality, and identify predictors of hemorrhage after discharge from IS or TIA. METHODS AND FINDINGS: All patients admitted to Ostersund Hospital for an IS or TIA in 2010-2013 were included (n = 1528, mean age: 75.1 years). Serious hemorrhages were identified until 31st December 2015. Incidence rates were calculated. The impact on mortality (stratified by functional level) was determined with Kaplan-Meier analysis. Non-parametric estimation under the assumption of competing risk was performed to assess the cumulative incidence and predictors of serious hemorrhages. The incidence rates of serious (n = 113) and intracranial hemorrhages (n = 45) after discharge from IS and TIA were 2.48% and 0.96% per year at risk, respectively. Patients with modified Rankin Scale (mRS) scores of 3-5 exhibited 58.9% mortality during follow-up and those with mRS scores of 0-2 exhibited 18.4% mortality. A serious hemorrhage did not affect mortality in patients with impaired functional status, but it increased the risk of death in patients with mRS scores of 0-2. Hypertension was associated with increased risk of serious hemorrhage. CONCLUSIONS: We found that, after discharge from an IS or TIA, serious hemorrhages were fairly common. Impairments in function were associated with high mortality, but serious hemorrhages only increased the risk of mortality in patients with no or slight disability. Improved hypertension treatment may decrease the risk of serious hemorrhage, but in patients with low functional status, poor survival makes secondary prevention challenging. PMID- 29621287 TI - Weather and landscape factors affect white-tailed deer neonate survival at ecologically important life stages in the Northern Great Plains. AB - Offspring survival is generally more variable than adult survival and may limit population growth. Although white-tailed deer neonate survival has been intensively investigated, recent work has emphasized how specific cover types influence neonate survival at local scales (single study area). These localized investigations have often led to inconsistences within the literature. Developing specific hypotheses describing the relationships among environmental, habitat, and landscape factors influencing white-tailed deer neonate survival at regional scales may allow for detection of generalized patterns. Therefore, we developed 11 hypotheses representing the various effects of environmental (e.g., winter and spring weather), habitat (e.g., hiding and escape cover types), and landscape factors (e.g., landscape configuration regardless of specific cover type available) on white-tailed deer neonate survival up to one-month and from one- to three-months of age. At one-month, surviving fawns experienced a warmer lowest recorded June temperature and more June precipitation than those that perished. At three-months, patch connectance (percent of patches of the corresponding patch type that are connected within a predefined distance) positively influenced survival. Our results are consistent with white-tailed deer neonate ecology: increased spring temperature and precipitation are likely associated with a flush of nutritional resources available to the mother, promoting increased lactation efficiency and neonate growth early in life. In contrast, reduced spring temperature with increased precipitation place neonates at risk to hypothermia. Increased patch connectance likely reflects increased escape cover available within a neonate's home range after they are able to flee from predators. If suitable escape cover is available on the landscape, then managers could focus efforts towards manipulating landscape configuration (patch connectance) to promote increased neonate survival while monitoring spring weather to assess potential influences on current year survival. PMID- 29621289 TI - Unsafe disposal of feces of children <3 years among households with latrine access in rural Bangladesh: Association with household characteristics, fly presence and child diarrhea. AB - BACKGROUND: Young children frequently defecate in the living environment in low income countries. Unsafe child feces disposal has been associated with risk of diarrhea. Additionally, reported practices can underestimate socially undesirable unhygienic behaviors. This analysis aimed to assess (1) the sensitivity of reported child feces disposal practices as an indicator for observed presence of human feces in the domestic environment, (2) household characteristics associated with reported unsafe feces disposal and (3) whether unsafe feces disposal is associated with fly presence and diarrhea among children <3 years. METHODS: We recorded caregiver-reported feces disposal practices for children <3 years; unsafe disposal was defined as feces put/rinsed into a drain, ditch, bush or garbage heap or left on the ground and safe disposal as feces put/rinsed into latrine or specific pit or buried. We conducted spot checks for human feces, counted flies in the compound and recorded caregiver-reported child diarrhea prevalence among 803 rural Bangladeshi households. We assessed associations using generalized estimating equations (GEE) and generalized linear models (GLM) with robust standard errors. RESULTS: Unsafe disposal of child feces was reported by 80% of households. Reported disposal practices had high sensitivity (91%) but low positive predictive value (15%) as an indicator of observed feces in the compound. Unsafe disposal was more common among households that reported daily adult open defecation (PR: 1.13, 1.02-1.24) and had children defecating in a nappy or on the ground versus in a potty (PR: 2.92, 1.98-4.32), and less common in households where adults reported always defecating in latrines (PR: 0.91, 0.84 0.98). The presence of observed human feces was similarly associated with these household characteristics. Reported unsafe feces disposal or observed human feces were not associated with fly detection or child diarrhea. CONCLUSION: Despite access to on-site sanitation, unsafe child feces disposal was reported by the majority of households. However, this practices was not associated with diarrhea; suggesting that child feces may not be the most important fecal exposure. Before resources are invested to improve child feces management practices, studies should explore whether these contribute meaningfully to risk of enteric disease. PMID- 29621288 TI - Low power laser irradiation and human adipose-derived stem cell treatments promote bone regeneration in critical-sized calvarial defects in rats. AB - Both stem cell therapy and physical treatments have been shown to be beneficial in accelerating bone healing. However, the efficacy of combined treatment with stem cells and physical stimuli for large bone defects remains uncertain. The aim of this study was to evaluate the bone regeneration effects of low-power laser irradiation (LPLI) and human adipose-derived stem cell (ADSC) treatments during fracture repair using a comparative rat calvarial defect model. We evaluated the viability of human ADSCs, which were cultured on a porous PLGA scaffold using an MTS assay. The critical-sized calvarial bone defect rats were divided into 4 groups: control group, LPLI group, ADSC group, and ADSC+LPLI group. Bone formation was evaluated using micro-CT. New bone formation areas and osteogenic factor expression levels were then examined by histomorphological analysis and immunohistochemical staining. Our data showed that PLGA had no cytotoxic effect on human ADSCs. Micro-CT analyses revealed that both the LPLI and ADSC groups showed improved calvarial bone defect healing compared to the control group. In addition, the ADSC+LPLI group showed significantly increased bone volume at 16 weeks after surgery. The area of new bone formation ranked as follows: control group < LPLI group < ADSC group < ADSC+LPLI group. There were significant differences between the groups. In addition, both ADSC and ADSC+LPLI groups showed strong signals of vWF expression. ADSC and LPLI treatments improved fracture repair in critical-sized calvarial defects in rats. Importantly, the combined treatment of ADSCs and LPLI further enhances the bone healing process. PMID- 29621290 TI - Early-life conditions and health at older ages: The mediating role of educational attainment, family and employment trajectories. AB - OBJECTIVES: We examine to what extent the effect of early-life conditions (health and socioeconomic status) on health in later life is mediated by educational attainment and life-course trajectories (fertility, partnership, employment). METHODS: Using data from the Survey of Health, Ageing and Retirement in Europe (N = 12,034), we apply, separately by gender, multichannel sequence analysis and cluster analysis to obtain groups of similar family and employment histories. The KHB method is used to disentangle direct and indirect effects of early-life conditions on health. RESULTS: Early-life-conditions indirectly impact on health in later life as result of their influence on education and family and employment trajectories. For example, between 22% and 42% of the effect of low parental socio-economic status at childhood on the three considered health outcomes at older age is explained by educational attainment for women. Even higher percentages are found for men (35% - 57%). On the contrary, the positive effect of poor health at childhood on poor health at older ages is not significantly mediated by education and life-course trajectories. Education captures most of the mediating effect of parental socio-economic status. More specifically, between 66% and 75% of the indirect effect of low parental socio-economic status at childhood on the three considered health outcomes at older age is explained by educational attainment for women. Again, higher percentages are found for men (86% - 93%). Early-life conditions, especially socioeconomic status, influence family and employment trajectories indirectly through their impact on education. We also find a persistent direct impact of early-life conditions on health at older ages. CONCLUSIONS: Our findings demonstrate that early-life experiences influence education and life-course trajectories and health in later life, suggesting that public investments in children are expected to produce long lasting effects on people's lives throughout the different phases of their life course. PMID- 29621291 TI - Fungal community profiles in agricultural soils of a long-term field trial under different tillage, fertilization and crop rotation conditions analyzed by high throughput ITS-amplicon sequencing. AB - Fungal communities in agricultural soils are assumed to be affected by soil and crop management. Our intention was to investigate the impact of different tillage and fertilization practices on fungal communities in a long-term crop rotation field trial established in 1992 in Central Germany. Two winter wheat fields in replicated strip-tillage design, comprising conventional vs. conservation tillage, intensive vs. extensive fertilization and different pre-crops (maize vs. rapeseed) were analyzed by a metabarcoding approach applying Illumina paired-end sequencing of amplicons generated by two recently developed primer pairs targeting the two fungal Internal Transcribed Spacer regions (ITS1, ITS2). Analysis of 5.1 million high-quality sequence reads uncovered a diverse fungal community in the two fields, composed of 296 fungal genera including 3,398 Operational Taxonomic Units (OTUs) at the 97% sequence similarity threshold. Both primer pairs detected the same fungal phyla (Basidio-, Asco-, Zygo-, Glomero- and Chytridiomycota), but in different relative abundances. OTU richness was higher in the ITS1 dataset, while ITS2 data were more diverse and of higher evenness. Effects of farming practice on fungal community structures were revealed. Almost two-thirds of the fungal genera were represented in all different soil treatments, whereas the remaining genera clearly responded to farming practice. Principal Component Analysis revealed four distinct clusters according to tillage practice and pre-crop. Analysis of Variance (ANOVA) substantiated the results and proved significant influences of tillage and pre-crop, while fertilization had the smallest and non-significant effect. In-depth analysis of putative phytopathogenic and plant beneficial fungal groups indicated distinct responses; for example Fusarium was significantly enriched in the intensively fertilized conservation tillage variants with the pre-crop maize, while Phoma displayed significant association with conventional tillage and pre-crop rapeseed. Many putative plant beneficial fungi also reacted differentially to farming practice with the most distinct responders identified among the Glomeromycota (arbuscular mycorrhizal fungi, AMF). PMID- 29621292 TI - Strategic predictors of performance in a divided attention task. AB - In this study we investigate the strategies of subjects in a complex divided attention task. We conducted a series of experiments with ten participants and evaluated their performance. After an extensive analysis, we identified four strategic measures that justify the achievement of the participants, by highlighting the individual differences and predicting performance in a regression analysis using generalized estimating equations. Selecting the more urgent task and user action between multiple simultaneous possibilities form two of the strategic decisions, respectively. The third one refers to choosing a response within the same task when the opportunity is present. The fourth and most important measure of strategy involves thinking ahead and executing an action before a situation would become critical. This latter one has the effect of reducing later cognitive load or timing constraints and it is shown to explain almost as much variance in performance as the other three, more straightforward predictors together. In addition to determining these strategic predictors, we also show how manipulating task difficulty induces a shift in strategy, thus impairing human performance in the rehearsed task. The results of this study indicate that considerable differences in the divided attention ability of normal subjects can be identified early and with simple measurements. The importance of describing and analyzing strategies is also emphasized, which can substantially influence performance in complex tasks and may serve training needs. PMID- 29621293 TI - The effects of a dopamine agonist (apomorphine) on experimental and spontaneous pain in patients with chronic radicular pain: A randomized, double-blind, placebo controlled, cross-over study. AB - BACKGROUND: Although evidence suggests that dopaminergic systems are involved in pain processing, the effects of dopaminergic interventions on pain remains questionable. This randomized, double blinded, placebo-controlled, cross-over study was aimed at exploring the effect of the dopamine agonist apomorphine on experimental pain evoked by cold stimulation and on spontaneous pain in patients with lumbar radicular (neuropathic) pain. METHODS: Data was collected from 35 patients with chronic lumbar radiculopathy (18 men, mean age 56.2+/-13 years). The following parameters were evaluated before (baseline) and 30, 75 and 120 minutes subsequent to a subcutaneous injection of 1.5 mg apomorphine or placebo: cold pain threshold and tolerance in the painful site (ice pack, affected leg) and in a remote non-painful site (12 degrees C water bath, hand), and spontaneous (affected leg) pain intensity (NPS, 0-100). RESULTS: One-hundred and twenty minutes following apomorphine (but not placebo) injection, cold pain threshold and tolerance in the hand increased significantly compared to baseline (from a median of 8.0 seconds (IQR = 5.0) to 10 seconds (IQR = 9.0), p = 0.001 and from a median of 19.5 seconds (IQR = 30.2) to 27.0 seconds (IQR = 37.5), p<0.001, respectively). In addition, apomorphine prolonged cold pain tolerance but not threshold in the painful site (from a median of 43.0 seconds (IQR = 63.0) at baseline to 51.0 seconds (IQR = 78.0) at 120 min, p = 0.02). Apomorphine demonstrated no superiority over placebo in reducing spontaneous pain intensity. CONCLUSION: These findings are in line with previous results in healthy subjects, showing that apomorphine increases the ability to tolerate cold pain and therefore suggesting that dopaminergic interventions can have potential clinical relevance. PMID- 29621294 TI - The redox-sensing protein Rex modulates ethanol production in Thermoanaerobacterium saccharolyticum. AB - Thermoanaerobacterium saccharolyticum is a thermophilic anaerobe that has been engineered to produce high amounts of ethanol, reaching ~90% theoretical yield at a titer of 70 g/L. Here we report the physiological changes that occur upon deleting the redox-sensing transcriptional regulator Rex in wild type T. saccharolyticum: a single deletion of rex resulted in a two-fold increase in ethanol yield (from 40% to 91% theoretical yield), but the resulting strains grew only about a third as fast as the wild type strain. Deletion of the rex gene also had the effect of increasing expression of alcohol dehydrogenase genes, adhE and adhA. After several serial transfers, the ethanol yield decreased from an average of 91% to 55%, and the growth rates had increased. We performed whole-genome resequencing to identify secondary mutations in the Deltarex strains adapted for faster growth. In several cases, secondary mutations had appeared in the adhE gene. Furthermore, in these strains the NADH-linked alcohol dehydrogenase activity was greatly reduced. Complementation studies were done to reintroduce rex into the Deltarex strains: reintroducing rex decreased ethanol yield to below wild type levels in the Deltarex strain without adhE mutations, but did not change the ethanol yield in the Deltarex strain where an adhE mutation occurred. PMID- 29621295 TI - Experimental analysis of multiple factors on hydraulic fracturing in coalbed methane reservoirs. AB - Hydraulic fracturing can improve the permeability of coalbed methane (CBM) reservoirs effectively, which is of great significance to the commercial production of CBM. However, the efficiency of hydraulic fracturing is affected by multiple factors. The mechanism of fracture initiation, morphology and propagation in CBM reservoirs is not clear and need to be further explored. Hydraulic fracturing experiment is an accurate tool to explore these mechanisms. The quantity of experimental coal rock is large and processing method is complex, so specimen made of similar materials was applied to replace coal rock. The true triaxial hydraulic fracturing experimental apparatus, 3D scanning device for coal rock section were applied to carry out hydraulic fracturing experiment. The results show that the initiation pressure is inversely proportional to the horizontal stress difference (Deltasigma) and positively related to fracturing fluid injection rate. When vertical stress (sigmav) is constant, the initiation pressure and fracture width decrease with the increasing of Deltasigma. Natural fractures can be connected by main fracture when propagates perpendicular to the direction of minimum horizontal stress (sigmah), then secondary fractures and fracture network form in CBM reservoirs. When two stresses of crustal stress are close and far different from the third one, the fracture morphology and propagation become complex. Influenced by perforations and filtration of fracturing fluid in specimen, fracturing fluid flows to downward easily after comparing horizontal well fracturing with vertical well fracturing. Fracture width increases with the decreasing of elastic modulus, the intensity of fracture is positively related with the elastic modulus of coal rock. The research results can provide theoretical basis and technical support for the efficient development of CBM. PMID- 29621296 TI - Inhibition of biofilm formation on the surface of water storage containers using biosand zeolite silver-impregnated clay granular and silver impregnated porous pot filtration systems. AB - Development of biofilms occurring on the inner surface of storage vessels offers a suitable medium for the growth of microorganisms and consequently contributes to the deterioration of treated drinking water quality in homes. The aim of this study was to determine whether the two point-of-use technologies (biosand zeolite silver-impregnated clay granular (BSZ-SICG) filter and silver-impregnated porous pot (SIPP) filter) deployed in a rural community of South Africa could inhibit the formation of biofilm on the surface of plastic-based containers generally used by rural households for the storage of their drinking water. Culture-based methods and molecular techniques were used to detect the indicator bacteria (Total coliforms, faecal coliform, E. coli) and pathogenic bacteria (Salmonella spp., Shigella spp. and Vibrio cholerae) in intake water and on the surface of storage vessels containing treated water. Scanning electron microscopy was also used to visualize the development of biofilm. Results revealed that the surface water source used by the Makwane community was heavily contaminated and harboured unacceptably high counts of bacteria (heterotrophic plate count: 4.4-4.3 Log10 CFU/100mL, total coliforms: 2.2 Log10 CFU/100 mL-2.1 Log10 CFU/100 mL, faecal coliforms: 1.9 Log10 CFU/100 mL-1.8 Log10 CFU/100 mL, E. coli: 1.7 Log10 CFU/100 mL-1.6 Log10 CFU/100 mL, Salmonella spp.: 3 Log10 CFU/100 mL -8 CFU/100 mL; Shigella spp. and Vibrio cholerae had 1.0 Log10 CFU/100 mL and 0.8 Log10 CFU/100 mL respectively). Biofilm formation was apparent on the surface of the storage containers with untreated water within 24 h. The silver nanoparticles embedded in the clay of the filtration systems provided an effective barrier for the inhibition of biofilm formation on the surface of household water storage containers. Biofilm formation occurred on the surface of storage plastic vessels containing drinking water treated with the SIPP filter between 14 and 21 days, and on those containing drinking water treated with the BSZ-SICG filter between 3 and 14 days. The attachment of target bacteria on the surface of the coupons inoculated in storage containers ranged from (0.07 CFU/cm2-227.8 CFU/cm2). To effectively prevent the development of biofilms on the surface of container stored water, which can lead to the recontamination of treated water, plastic storage containers should be washed within 14 days for water treated with the SIPP filter and within 3 days for water treated with the BSZ-SICG filter. PMID- 29621297 TI - iCopyDAV: Integrated platform for copy number variations-Detection, annotation and visualization. AB - Discovery of copy number variations (CNVs), a major category of structural variations, have dramatically changed our understanding of differences between individuals and provide an alternate paradigm for the genetic basis of human diseases. CNVs include both copy gain and copy loss events and their detection genome-wide is now possible using high-throughput, low-cost next generation sequencing (NGS) methods. However, accurate detection of CNVs from NGS data is not straightforward due to non-uniform coverage of reads resulting from various systemic biases. We have developed an integrated platform, iCopyDAV, to handle some of these issues in CNV detection in whole genome NGS data. It has a modular framework comprising five major modules: data pre-treatment, segmentation, variant calling, annotation and visualization. An important feature of iCopyDAV is the functional annotation module that enables the user to identify and prioritize CNVs encompassing various functional elements, genomic features and disease-associations. Parallelization of the segmentation algorithms makes the iCopyDAV platform even accessible on a desktop. Here we show the effect of sequencing coverage, read length, bin size, data pre-treatment and segmentation approaches on accurate detection of the complete spectrum of CNVs. Performance of iCopyDAV is evaluated on both simulated data and real data for different sequencing depths. It is an open-source integrated pipeline available at https://github.com/vogetihrsh/icopydav and as Docker's image at http://bioinf.iiit.ac.in/icopydav/. PMID- 29621298 TI - Natural locomotion based on a reduced set of inertial sensors: Decoupling body and head directions indoors. AB - Inertial sensors offer the potential for integration into wireless virtual reality systems that allow the users to walk freely through virtual environments. However, owing to drift errors, inertial sensors cannot accurately estimate head and body orientations in the long run, and when walking indoors, this error cannot be corrected by magnetometers, due to the magnetic field distortion created by ferromagnetic materials present in buildings. This paper proposes a technique, called EHBD (Equalization of Head and Body Directions), to address this problem using two head- and shoulder-located magnetometers. Due to their proximity, their distortions are assumed to be similar and the magnetometer measurements are used to detect when the user is looking straight forward. Then, the system corrects the discrepancies between the estimated directions of the head and the shoulder, which are provided by gyroscopes and consequently are affected by drift errors. An experiment is conducted to evaluate the performance of this technique in two tasks (navigation and navigation plus exploration) and using two different locomotion techniques: (1) gaze-directed mode (GD) in which the walking direction is forced to be the same as the head direction, and (2) decoupled direction mode (DD) in which the walking direction can be different from the viewing direction. The obtained results show that both locomotion modes show similar matching of the target path during the navigation task, while DD's path matches the target path more closely than GD in the navigation plus exploration task. These results validate the EHBD technique especially when allowing different walking and viewing directions in the navigation plus exploration tasks, as expected. While the proposed method does not reach the accuracy of optical tracking (ideal case), it is an acceptable and satisfactory solution for users and is much more compact, portable and economical. PMID- 29621299 TI - Influence of seating styles on head and pelvic vertical movement symmetry in horses ridden at trot. AB - Detailed knowledge of how a rider's seating style and riding on a circle influences the movement symmetry of the horse's head and pelvis may aid rider and trainer in an early recognition of low grade lameness. Such knowledge is also important during both subjective and objective lameness evaluations in the ridden horse in a clinical setting. In this study, inertial sensors were used to assess how different rider seating styles may influence head and pelvic movement symmetry in horses trotting in a straight line and on the circle in both directions. A total of 26 horses were subjected to 15 different conditions at trot: three unridden conditions and 12 ridden conditions where the rider performed three different seating styles (rising trot, sitting trot and two point seat). Rising trot induced systematic changes in movement symmetry of the horses. The most prominent effect was decreased pelvic rise that occurred as the rider was actively rising up in the stirrups, thus creating a downward momentum counteracting the horses push off. This mimics a push off lameness in the hindlimb that is in stance when the rider sits down in the saddle during the rising trot. On the circle, the asymmetries induced by rising trot on the correct diagonal counteracted the circle induced asymmetries, rendering the horse more symmetrical. This finding offers an explanation to the equestrian tradition of rising on the 'correct diagonal.' In horses with small pre-existing movement asymmetries, the asymmetry induced by rising trot, as well as the circular track, attenuated or reduced the horse's baseline asymmetry, depending on the sitting diagonal and direction on the circle. A push off hindlimb lameness would be expected to increase when the rider sits during the lame hindlimb stance whereas an impact hindlimb lameness would be expected to decrease. These findings suggest that the rising trot may be useful for identifying the type of lameness during subjective lameness assessment of hindlimb lameness. This theory needs to be studied further in clinically lame horses. PMID- 29621300 TI - Characteristics of non-cardia gastric cancer with a high serum anti-Helicobacter pylori IgG titer and its association with diffuse-type histology. AB - BACKGROUND: Data on implications of a high positive titer of serum anti Helicobacter pylori antibody on gastric cancer (GC) is limited. This study aimed to investigate the characteristics of GC with a high serum anti-H. pylori IgG (Hp IgG) titer, and its association with diffuse-type GC. METHODS: We analyzed clinical and histological characteristics of 917 non-cardia GC patients who underwent gastrectomy. H. pylori infection was determined serologically by measuring Hp-IgG titer with immunoassay. Seropositive patients were divided into three groups (low-positive, mid-positive, and high-positive) according to the Hp IgG titer value. Tumors were classified according to the Lauren criteria as diffuse or intestinal types. RESULTS: The median age of the patients was 59.0 years, and 33.8% were female. The patents were grouped as follows: seronegative, 188 (20.5%); low-positive, 288 (31.4%); mid-positive, 290 (31.6%); and high positive 151 (16.5%). The high-positive group was significantly younger (median age, 55.0 years), with a higher proportion of female (45.0%) and non-smokers (58.9%). The proportion of diffuse-type GC increased in the order low-, mid-, and high-positive groups (p<0.001). In univariate analysis, the factors associated with diffuse-type GC were younger age, female sex, non-smokers, and a high positive Hp-IgG titer. Younger age, female sex, and non-smokers remained significant on multivariate analysis whereas the high-positive Hp-IgG titer showed only a tendency toward the association (p = 0.078). CONCLUSIONS: Non cardia GC patients with a high Hp-IgG titer have distinct clinicopathologic characteristics. A high-positive Hp-IgG titer should be interpreted together with patients' age, sex, and smoking status. PMID- 29621301 TI - Human-centric predictive model of task difficulty for human-in-the-loop control tasks. AB - Quantitatively measuring the difficulty of a manipulation task in human-in-the loop control systems is ill-defined. Currently, systems are typically evaluated through task-specific performance measures and post-experiment user surveys; however, these methods do not capture the real-time experience of human users. In this study, we propose to analyze and predict the difficulty of a bivariate pointing task, with a haptic device interface, using human-centric measurement data in terms of cognition, physical effort, and motion kinematics. Noninvasive sensors were used to record the multimodal response of human user for 14 subjects performing the task. A data-driven approach for predicting task difficulty was implemented based on several task-independent metrics. We compare four possible models for predicting task difficulty to evaluated the roles of the various types of metrics, including: (I) a movement time model, (II) a fusion model using both physiological and kinematic metrics, (III) a model only with kinematic metrics, and (IV) a model only with physiological metrics. The results show significant correlation between task difficulty and the user sensorimotor response. The fusion model, integrating user physiology and motion kinematics, provided the best estimate of task difficulty (R2 = 0.927), followed by a model using only kinematic metrics (R2 = 0.921). Both models were better predictors of task difficulty than the movement time model (R2 = 0.847), derived from Fitt's law, a well studied difficulty model for human psychomotor control. PMID- 29621302 TI - Factors associated with death and loss to follow-up in children on antiretroviral care in Mingalardon Specialist Hospital, Myanmar, 2006-2016. AB - BACKGROUND: Myanmar National AIDS programme's priority is to improve the survival of all people living with HIV by providing anti-retroviral therapy (ART) care. More than 7200 children (aged <15 years) have been enrolled into ART care from 2005 to 2016. A previous study showed that ~11% children on ART care had either died or were lost to follow-up by 60 months. Factors associated with death and lost-to follow-up (adverse outcomes) have not been previously studied. OBJECTIVES: To describe the association between demographic and clinical characteristics at enrollment into ART care with adverse outcomes. METHODS: Cohort study using records of children enrolled for ART care at Mingalardon Specialist Hospital (main Paediatric ART center in Myanmar) from 2006-2016. We used multivariable Cox proportional hazards regression models for analysis. RESULTS: 1,159 children were enrolled for ART care and they contributed a total of 1.45 million person-days of follow-up period. 112 (10%) had an adverse outcome during the follow-up time period (55 deaths, 57 lost to follow-up). Enrollment into the ART care through in-patient care department of the hospital, CD4 Cell count <50/mm3, enrollment during changing ART guidelines (different ART eligibility criteria and preferred ART regimen) were independently associated with higher hazards of adverse outcome. Receiving protease inhibitor-based ART regimen at enrollment was independently associated with lower hazards of adverse outcome. Age, sex, residing in urban or rural areas, WHO clinical stage, having TB at the time of enrollment, receiving cotrimoxazole prophylaxis were not statistically associated with adverse outcomes. CONCLUSION: Our analysis reconfirms good survival of children on ART care (including those with TB). The characteristics associated with adverse outcomes (other than CD4 cell count<50) are surrogates of some unmeasured underlying health system/ patient related factors that needs further exploration to improve the survival of children on ART care. PMID- 29621303 TI - Time-dependent regulation of morphological changes and cartilage differentiation markers in the mouse pubic symphysis during pregnancy and postpartum recovery. AB - Animal models commonly serve as a bridge between in vitro experiments and clinical applications; however, few physiological processes in adult animals are sufficient to serve as proof-of-concept models for cartilage regeneration. Intriguingly, some rodents, such as young adult mice, undergo physiological connective tissue modifications to birth canal elements such as the pubic symphysis during pregnancy; therefore, we investigated whether the differential expression of cartilage differentiation markers is associated with cartilaginous tissue morphological modifications during these changes. Our results showed that osteochondral progenitor cells expressing Runx2, Sox9, Col2a1 and Dcx at the non pregnant pubic symphysis proliferated and differentiated throughout pregnancy, giving rise to a complex osteoligamentous junction that attached the interpubic ligament to the pubic bones until labour occurred. After delivery, the recovery of pubic symphysis cartilaginous tissues was improved by the time-dependent expression of these chondrocytic lineage markers at the osteoligamentous junction. This process potentially recapitulates embryologic chondrocytic differentiation to successfully recover hyaline cartilaginous pads at 10 days postpartum. Therefore, we propose that this physiological phenomenon represents a proof-of-concept model for investigating the mechanisms involved in cartilage restoration in adult animals. PMID- 29621304 TI - Trends in congenital anomalies in Europe from 1980 to 2012. AB - BACKGROUND: Surveillance of congenital anomalies is important to identify potential teratogens. METHODS: This study analysed the prevalence of 61 congenital anomaly subgroups (excluding chromosomal) in 25 population-based EUROCAT registries (1980-2012). Live births, fetal deaths and terminations of pregnancy for fetal anomaly were analysed with multilevel random-effects Poisson regression models. RESULTS: Seventeen anomaly subgroups had statistically significant trends from 2003-2012; 12 increasing and 5 decreasing. CONCLUSIONS: The annual increasing prevalence of severe congenital heart defects, single ventricle, atrioventricular septal defects and tetralogy of Fallot of 1.4% (95% CI: 0.7% to 2.0%), 4.6% (1.0% to 8.2%), 3.4% (1.3% to 5.5%) and 4.1% (2.4% to 5.7%) respectively may reflect increases in maternal obesity and diabetes (known risk factors). The increased prevalence of cystic adenomatous malformation of the lung [6.5% (3.5% to 9.4%)] and decreased prevalence of limb reduction defects [ 2.8% (-4.2% to -1.5%)] are unexplained. For renal dysplasia and maternal infections, increasing trends may be explained by increased screening, and deceases in patent ductus arteriosus at term and increases in craniosynostosis, by improved follow up period after birth and improved diagnosis. For oesophageal atresia, duodenal atresia/stenosis and ano-rectal atresia/stenosis recent changes in prevalence appeared incidental when compared with larger long term fluctuations. For microcephaly and congenital hydronephrosis trends could not be interpreted due to discrepancies in diagnostic criteria. The trends for club foot and syndactyly disappeared once registries with disparate results were excluded. No decrease in neural tube defects was detected, despite efforts at prevention through folic acid supplementation. PMID- 29621305 TI - Biomarkers associated with low, moderate, and high vastus lateralis muscle hypertrophy following 12 weeks of resistance training. AB - We sought to identify biomarkers which delineated individual hypertrophic responses to resistance training. Untrained, college-aged males engaged in full body resistance training (3 d/wk) for 12 weeks. Body composition via dual x-ray absorptiometry (DXA), vastus lateralis (VL) thickness via ultrasound, blood, VL muscle biopsies, and three-repetition maximum (3-RM) squat strength were obtained prior to (PRE) and following (POST) 12 weeks of training. K-means cluster analysis based on VL thickness changes identified LOW [n = 17; change (mean+/-SD) = +0.11+/-0.14 cm], modest (MOD; n = 29, +0.40+/-0.06 cm), and high (HI; n = 21, +0.69+/-0.14 cm) responders. Biomarkers related to histology, ribosome biogenesis, proteolysis, inflammation, and androgen signaling were analyzed between clusters. There were main effects of time (POST>PRE, p<0.05) but no cluster*time interactions for increases in DXA lean body mass, type I and II muscle fiber cross sectional area and myonuclear number, satellite cell number, and macronutrients consumed. Interestingly, PRE VL thickness was ~12% greater in LOW versus HI (p = 0.021), despite POST values being ~12% greater in HI versus LOW (p = 0.006). However there was only a weak correlation between PRE VL thickness scores and change in VL thickness (r2 = 0.114, p = 0.005). Forced post hoc analysis indicated that muscle total RNA levels (i.e., ribosome density) did not significantly increase in the LOW cluster (351+/-70 ng/mg to 380+/-62, p = 0.253), but increased in the MOD (369+/-115 to 429+/-92, p = 0.009) and HI clusters (356+/-77 to 470+/-134, p<0.001; POST HI>POST LOW, p = 0.013). Nonetheless, there was only a weak association between change in muscle total RNA and VL thickness (r2 = 0.079, p = 0.026). IL-1beta mRNA levels decreased in the MOD and HI clusters following training (p<0.05), although associations between this marker and VL thickness changes were not significant (r2 = 0.0002, p = 0.919). In conclusion, individuals with lower pre-training VL thickness values and greater increases muscle total RNA levels following 12 weeks of resistance training experienced greater VL muscle growth, although these biomarkers individually explained only ~8-11% of the variance in hypertrophy. PMID- 29621306 TI - Conventional and transepithelial corneal cross-linking for patients with keratoconus. AB - Previous studies investigating the effectiveness of conventional corneal collagen cross-linking (CXL) and transepithelial CXL in keratoconus treatment have reported conflicting outcomes. Therefore, we conducted a meta-analysis to compare the effectiveness of these treatments. We searched MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials for prospective randomized controlled trials (RCTs) with no restrictions. We included visual acuity (corrected distance visual acuity, uncorrected distance visual acuity) and corneal keratometry (K) as primary outcome parameters, and spherical equivalent, central corneal thickness (CCT), and endothelial cell density, as secondary parameters. We finally included seven reports (including six RCTs involving 305 participants and 344 eyes). Our analysis revealed significant postoperative differences in average K and CCT values between conventional and transepithelial CXL-treated patients [K: weighted mean difference (WMD) = 0.79, 95% confidence interval (CI) = 0.04-1.53, p = 0.04; CCT: WMD = 4.53, 95% CI = 0.42-8.64, p = 0.03]. In contrast, we did not find any significant differences in visual acuity, flattest K value, steepest K value, cylinder K value, apex K value, spherical equivalent, or endothelial cell density between groups. In conclusion, transepithelial CXL has a more protective influence on corneal thickness than conventional CXL, and results in lesser postoperative corneal flattening. Further investigation of the clinical outcomes of transepithelial CXL is required. PMID- 29621307 TI - Is empathy one of the Big Three? Identifying its role in a dual-process model of ideology and blatant and subtle prejudice. AB - In the field of the social psychology of prejudice, John Duckitt's Dual-Process Cognitive-Motivational Model of Ideology and Prejudice has gained a firm grounding over the past decade and a half, while empathy has become one of the most powerful predictors of prejudice, alongside right-wing authoritarianism and social dominance orientation. This study integrates empathy into the dual-process model, exploring the effects of this variable, along with the impact of personality and ideological attitudes, on prejudice in both its blatant and subtle forms. A cross-sectional research design was used to collect data from 260 university students by self-report measures. Despite its cross-sectional nature, a pattern of causal relationships was hypothesized according to experimental and longitudinal findings from previous studies. The path analysis results show that in the model fitted to the data, empathy does not have any direct impact on prejudice, although it plays a significant role in the prediction of prejudice towards a particular immigrant group. On the other hand, the dual-process model is confirmed in the explanation of blatant prejudice and, in a weaker and indirect way, of subtle prejudice; sustaining the distinctive nature of these constructs on some differential predictors and paths. In the discussion, this study proposes that when ideological and personality-based variables are both included in the model, general empathy is not so robust in the explanation of prejudice, since some of the empathetic components might become diluted among other covariates. But even so, its indirect effectiveness through personality and ideological attitudes remains relevant. PMID- 29621308 TI - Acceptability and performance of a directly assisted oral HIV self-testing intervention in adolescents in rural Mozambique. AB - INTRODUCTION: Whereas progress in HIV testing and treatment has been made globally, the UNAIDS goal of "90 90 90" is still out of sight in rural northern Mozambique. New strategies that promote testing in hard to reach groups will aid Mozambique's response to the HIV epidemic. HIV self-testing (HIVST) is recommended by the WHO as an additional approach to augment the HIV testing services available to adolescents. This study evaluates acceptability and performance of a directly assisted oral HIVST intervention for adolescents in rural Mozambique. METHODS: Adolescents aged 16-20 years were included at schools and invited to attend the local hospital's youth friendly service for directly assisted oral HIVST. Baseline and post-test questionnaires were obtained. OraQuick Rapid HIV-1/2 Anti body test(r) was used. Results were read by the participant and by a nurse. Results were confirmed by finger prick HIV test (Determine(r) HIV 1/2 Alere and UnigoldTM HIV Trinity Biotech) according to the Mozambican national standard. RESULTS: Between September and November 2016, 496 adolescents were included, of which 299 performed an oral HIV self-test. 70% were first time testers. The positivity rate was 1.7%. The inter-rater agreement between adolescent and nurse was 99.6% (kappa 0.93); there were no false negative or false positive results of the oral HIV self-test. Five tests were invalid. 7.1% found the test difficult to use. Over 80% preferred directly assisted HIVST compared to the standard finger prick testing. While 20% thought it would be good to do HIVST at home, 76% preferred to do HIVST at the health centre, for reasons including increased security, privacy, and the presence of a counsellor. CONCLUSIONS: Directly assisted oral HIVST is a feasible intervention for adolescents in rural Mozambique and showed encouraging results for first time HIV testers. PMID- 29621309 TI - Diabetic retinopathy screening in incident diabetes mellitus type 2 in Germany between 2004 and 2013 - A prospective cohort study based on health claims data. AB - OBJECTIVE: To assess factors associated with diabetic retinopathy (DR) screening uptake following a diagnosis of type 2 diabetes mellitus (type 2 diabetes) in Germany. MATERIALS AND METHODS: A nationally representative prospective sample of individual-level health claims data for 250,000 members from Germany's largest public insurance provider in 2004-2013 was assessed. In the sample, 26,560 persons with incident type 2 diabetes were identified. Factors associated with subsequent DR screening were assessed using descriptive statistics, Kaplan-Meier estimator, and Cox regression analysis. RESULTS: On average 27.6 visits to an ophthalmologist per 100 person-years in persons with incident type 2 diabetes occurred. Half of all incident cases (Kaplan-Meier estimator) had not seen an ophthalmologist after more than two years (2.25 years) following their diabetes diagnosis. In the multivariate analysis, an older age (from hazard ratio HR(70 74) = 0.93 [95%-CI: 0.89-0.97] to HR(90+) = 0.50 [95%-CI: 0.42-0.60] compared to persons aged 50-69 years) and a higher disability level (i.e. HR(disability level 3) = 0.30 [95%-CI: 0.25-0.36]) were associated with a lower likelihood, while female sex (HR = 1.12 [95%-CI: 1.08-1.15]), six or more comorbidities (HR = 1.26 [95%-CI: 1.15-1.37]), moderate (HR = 1.51 [95%-CI: 1.46-1.56]) or severe type 2 diabetes (HR = 1.53 [95%-CI: 1.45-1.61]) as well as being enrolled in a type 2 diabetes disease management program (HR = 1.78 [95%-CI: 1.69-1.87]) were associated with a higher likelihood of DR screening. CONCLUSIONS: A high proportion of newly diagnosed persons with type 2 diabetes did not follow current German recommendations for DR screening, impeding timely detection and management of potential complications. This was more apparent among persons who were men, older or had a disability. The uptake of screening was considerably greater among those enrolled in a diseases management program. These factors need to be considered when planning DR screening services and/or referrals. PMID- 29621310 TI - Mutations in Neisseria gonorrhoeae grown in sub-lethal concentrations of monocaprin do not confer resistance. AB - Neisseria gonorrhoeae, due to its short lipooligosaccharide structure, is generally more sensitive to the antimicrobial effects of some fatty acids than most other Gram negative bacteria. This supports recent development of a fatty acid-based potential treatment for gonococcal infections, particularly ophthalmia neonatorum. The N. gonorrhoeae genome contains genes for fatty acid resistance. In this study, the potential for genomic mutations that could lead to resistance to this potential new treatment were investigated. N. gonorrhoeae strain NCCP11945 was repeatedly passaged on growth media containing a sub-lethal concentration of fatty acid myristic acid and monoglyceride monocaprin. Cultures were re-sequenced and assessed for changes in minimum inhibitory concentration. Of note, monocaprin grown cultures developed a mutation in transcription factor gene dksA, which suppresses molecular chaperone DnaK and may be involved in the stress response. The minimum inhibitory concentration after exposure to monocaprin showed a modest two-fold change. The results of this study suggest that N. gonorrhoeae cannot readily evolve resistance that will impact treatment of ophthalmia neonatorum with monocaprin. PMID- 29621311 TI - Global trends of local ecological knowledge and future implications. AB - Local and indigenous knowledge is being transformed globally, particularly being eroded when pertaining to ecology. In many parts of the world, rural and indigenous communities are facing tremendous cultural, economic and environmental changes, which contribute to weaken their local knowledge base. In the face of profound and ongoing environmental changes, both cultural and biological diversity are likely to be severely impacted as well as local resilience capacities from this loss. In this global literature review, we analyse the drivers of various types of local and indigenous ecological knowledge transformation and assess the directionality of the reported change. Results of this analysis show a global impoverishment of local and indigenous knowledge with 77% of papers reporting the loss of knowledge driven by globalization, modernization, and market integration. The recording of this loss, however, is not symmetrical, with losses being recorded more strongly in medicinal and ethnobotanical knowledge. Persistence of knowledge (15% of the studies) occurred in studies where traditional practices were being maintained consiously and where hybrid knowledge was being produced as a resut of certain types of incentives created by economic development. This review provides some insights into local and indigenous ecological knowledge change, its causes and implications, and recommends venues for the development of replicable and comparative research. The larger implication of these results is that because of the interconnection between cultural and biological diversity, the loss of local and indigenous knowledge is likely to critically threaten effective conservation of biodiversity, particularly in community-based conservation local efforts. PMID- 29621313 TI - Relative solidarity: Conceptualising communal participation in genomic research among potential research participants in a developing Sub-Saharan African setting. AB - OBJECTIVE: As genomic research gathers momentum in sub-Saharan Africa, it has become increasingly important to understand the reasons why individuals wish to participate in this kind of medical research. Against the background of communitarianism conceived as typical of African communities, it is often suggested that individuals consent to participate on the grounds of solidarity and to further the common good. In this paper, we seek to explore this contention by presenting data from focus groups with potential research participants about what would influence their decisions to participate in genomic research. METHODS AND RESULTS: These focus groups were conducted as part of a larger qualitative study with a purposively selected group of participants from a community situated in south west Nigeria. We conducted fifteen focus group sessions comprising 50 participants organized by age and sex, namely: 1) adult (>30 years) males, 2) adult females, 3) youth (18-30 years) males, and 4) youth females. A mixed age group was conducted to probe different views between the age groups. There was discordance and clear division between the adults and youths regarding the decision to participate in genomic research based on commitment to communal values. Adults based their decision to participate on altruism and furthering the common good while youths based their decisions on personal benefits and preferences and also took into account the views and welfare of family members and neighbours. CONCLUSIONS: This discordance suggests a 'generational shift' and we advance a model of 'relative solidarity' among the youths, which is different from the communal solidarity model typical of African communitarianism. Our findings suggest the need for a closer look at strategies for implementation of community engagement and informed consent in genomic research in this region, and we recommend further studies to explore this emerging trend. PMID- 29621312 TI - Reactive oxygen species and nitric oxide signaling in bystander cells. AB - It is now well accepted that radiation induced bystander effects can occur in cells exposed to media from irradiated cells. The aim of this study was to follow the bystander cells in real time following addition of media from irradiated cells and to determine the effect of inhibiting these signals. A human keratinocyte cell line, HaCaT cells, was irradiated (0.005, 0.05 and 0.5 Gy) with gamma irradiation, conditioned medium was harvested after one hour and added to recipient bystander cells. Reactive oxygen species, nitric oxide, Glutathione levels, caspase activation, cytotoxicity and cell viability was measured after the addition of irradiated cell conditioned media to bystander cells. Reactive oxygen species and nitric oxide levels in bystander cells treated with 0.5Gy ICCM were analysed in real time using time lapse fluorescence microscopy. The levels of reactive oxygen species were also measured in real time after the addition of extracellular signal-regulated kinase and c-Jun amino-terminal kinase pathway inhibitors. ROS and glutathione levels were observed to increase after the addition of irradiated cell conditioned media (0.005, 0.05 and 0.5 Gy ICCM). Caspase activation was found to increase 4 hours after irradiated cell conditioned media treatment (0.005, 0.05 and 0.5 Gy ICCM) and this increase was observed up to 8 hours and there after a reduction in caspase activation was observed. A decrease in cell viability was observed but no major change in cytotoxicity was found in HaCaT cells after treatment with irradiated cell conditioned media (0.005, 0.05 and 0.5 Gy ICCM). This study involved the identification of key signaling molecules such as reactive oxygen species, nitric oxide, glutathione and caspases generated in bystander cells. These results suggest a clear connection between reactive oxygen species and cell survival pathways with persistent production of reactive oxygen species and nitric oxide in bystander cells following exposure to irradiated cell conditioned media. PMID- 29621314 TI - Sildenafil ameliorates right ventricular early molecular derangement during left ventricular pressure overload. AB - Right ventricular (RV) dysfunction following left ventricular (LV) failure is associated with poor prognosis. RV remodeling is thought initiated by the increase in the afterload of RV due to secondary pulmonary hypertension (PH) to impaired LV function; however, RV molecular changes might occur in earlier stages of the disease. cGMP (cyclic guanosine monophosphate)-phosphodiesterase 5 (PDE5) inhibitors, widely used to treat PH through their pulmonary vasorelaxation properties, have shown direct cardiac benefits, but their impacts on the RV in LV diseases are not fully determined. Here we show that RV molecular alterations occur early in the absence of RV hemodynamic changes during LV pressure-overload and are ameliorated by PDE5 inhibition. Two-day moderate LV pressure-overload (transverse aortic constriction) neither altered RV pressure/ function nor RV weight in mice, while it induced only mild LV hypertrophy. Importantly, pathological molecular features were already induced in the RV free wall myocardium, including up-regulation of gene markers for hypertrophy and inflammation, and activation of extracellular signal-regulated kinase (ERK) and calcineurin. Concomitant PDE5 inhibition (sildenafil) prevented induction of such pathological genes and activation of ERK and calcineurin in the RV as well as in the LV. Importantly, dexamethasone also prevented these RV molecular changes, similarly to sildenafil treatment. These results suggest the contributory role of inflammation to the early pathological interventricular interaction between RV and LV. The current study provides the first evidence for the novel early molecular cross-talk between RV and LV, preceding RV hemodynamic changes in LV disease, and supports the therapeutic strategy of enhancing cGMP signaling pathway to treat heart diseases. PMID- 29621315 TI - Molecular evolution of DNMT1 in vertebrates: Duplications in marsupials followed by positive selection. AB - DNA methylation is mediated by a conserved family of DNA methyltransferases (Dnmts). The human genome encodes three active Dnmts (Dnmt1, Dnmt3a and Dnmt3b), the tRNA methyltransferase Dnmt2, and the regulatory protein Dnmt3L. Despite their high degree of conservation among different species, genes encoding Dnmts have been duplicated and/or lost in multiple lineages throughout evolution, indicating that the DNA methylation machinery has some potential to undergo evolutionary change. However, little is known about the extent to which this machinery, or the methylome, varies among vertebrates. Here, we study the molecular evolution of Dnmt1, the enzyme responsible for maintenance of DNA methylation patterns after replication, in 79 vertebrate species. Our analyses show that all studied species exhibit a single copy of the DNMT1 gene, with the exception of tilapia and marsupials (tammar wallaby, koala, Tasmanian devil and opossum), each of which displays two apparently functional DNMT1 copies. Our phylogenetic analyses indicate that DNMT1 duplicated before the radiation of major marsupial groups (i.e., at least ~75 million years ago), thus giving rise to two DNMT1 copies in marsupials (copy 1 and copy 2). In the opossum lineage, copy 2 was lost, and copy 1 recently duplicated again, generating three DNMT1 copies: two putatively functional genes (copy 1a and 1b) and one pseudogene (copy 1psi). Both marsupial copies (DNMT1 copies 1 and 2) are under purifying selection, and copy 2 exhibits elevated rates of evolution and signatures of positive selection, suggesting a scenario of neofunctionalization. This gene duplication might have resulted in modifications in marsupial methylomes and their dynamics. PMID- 29621316 TI - Fair ranking of researchers and research teams. AB - The main drawback of ranking of researchers by the number of papers, citations or by the Hirsch index is ignoring the problem of distributing authorship among authors in multi-author publications. So far, the single-author or multi-author publications contribute to the publication record of a researcher equally. This full counting scheme is apparently unfair and causes unjust disproportions, in particular, if ranked researchers have distinctly different collaboration profiles. These disproportions are removed by less common fractional or authorship-weighted counting schemes, which can distribute the authorship credit more properly and suppress a tendency to unjustified inflation of co-authors. The urgent need of widely adopting a fair ranking scheme in practise is exemplified by analysing citation profiles of several highly-cited astronomers and astrophysicists. While the full counting scheme often leads to completely incorrect and misleading ranking, the fractional or authorship-weighted schemes are more accurate and applicable to ranking of researchers as well as research teams. In addition, they suppress differences in ranking among scientific disciplines. These more appropriate schemes should urgently be adopted by scientific publication databases as the Web of Science (Thomson Reuters) or the Scopus (Elsevier). PMID- 29621317 TI - Muscular and metabolic responses to different Nordic walking techniques, when style matters. AB - Due to poling action and upper body engagement, Nordic walking (NW) has additional health benefits with respect to conventional walking. The aim of this study was to evaluate the differences in muscle activation and metabolic responses between NW, performed with the technique suggested by NW instructors, and with some modifications in the way to move upper limb and poles. Ten NW instructors volunteered to walk on a treadmill at 5.5 km*h-1 in five conditions: walking (W), Nordic walking (NW), NW with a weak poling action (NWweak), with straight-upper limbs moving the shoulders (NWshoulder) and with elbow flexion extension pattern and shoulder freezed (NWelbow). Poling forces, body segments and poles movement, upper and lower body muscle activation, as well as metabolic parameters were measured.All modified NW techniques elicited lower muscular activation and metabolic responses with respect to the suggested NW technique (P < 0.05). All NW techniques elicited higher muscular activation and metabolic responses than W. All parameters observed with the NWweak were lower than NW. A decreased activation of shoulder extensor muscles and increased activation of anterior deltoid muscle were the main features of NWshoulder. Lower triceps brachii muscle activation and reduced propulsive poling action with respect to NW were seen for NWelbow, resulting also in shorter steps.Nordic walking instructors, sport technicians and practitioners should be aware that any deviation from the technique usually suggested might lead to lower benefits. However it is worth to note that any walking technique with poles elicits higher metabolic responses and muscular activation than walking. PMID- 29621318 TI - Co-morbid mental disability among Chinese elderly with motor disability: Based on a nationwide survey. AB - This study aimed to investigate the prevalence rate and associated factors of co morbid mental disability among the elderly with motor disability. Data was obtained from the second China National Sample Survey on Disability (CNSSD). 250,752 older adults aged 65 years and above were sampled from 5964 sites, 2980 towns, 734 counties in 31 provinces in China. Descriptive statistics were used for population-weighted numbers and prevalence of co-morbid mental disability by different characteristics. Univariate logistic regression and multivariate logistic regression were used to calculate the association between mental disability, and the factors of co-morbid mental disability among physical disability. Among the elderly with motor disability, 275,607 persons (2.28%, 99% CI: 1.97-2.59) had co-morbid mental disability at the survey time, which was significantly higher than those without motor disability (OR: 2.11, 99% CI: 1.83 2.43). The factors associated with a higher risk of co-morbid mental disability included urban areas (OR: 1.38; 99% CI: 1.04-1.84), east (2.60, 1.76-3.83) or west (1.65, 1.06-2.55) regions, having other co-morbid disabilities (5.93, 4.48 7.85), and having more severe motor disability (Moderate: 1.81, 1.28-2.57; Severe: 2.90, 2.08-4.04; Extremely severe: 4.22, 2.96-6.01). The elderly with motor disability have a high risk of co-morbid mental disability, especially for higher socioeconomic groups. These findings highlight the need of and will be beneficial for implementing more comprehensive prevention and rehabilitation strategies, to prevent and control the emergence and development of multiple disabilities and promote the physical and mental health of the elderly. PMID- 29621319 TI - Dosimetric impact of intra-fraction prostate motion under a tumour-tracking system in hypofractionated robotic radiosurgery. AB - For CyberKnife-mediated prostate cancer treatment, a tumour-tracking approach is applied to correct the target location by acquiring X-ray images of implanted fiducial markers intermittently. This study investigated the dosimetric impact of intra-fraction prostate motion during CyberKnife treatment. We retrospectively analyzed 16 patients treated using the CyberKnife (35 Gy delivered in five fractions). Using log files of recorded prostate motion, the intra-fraction prostate motion was simulated. We defined the worst-case intra-fraction prostate motion as the difference between pre- and post-deviation on log files and shifted structure sets according to the corresponding offsets for each beam. The dose volume indices were calculated and compared with the original plan in terms of clinical target volume (CTV), planning target volume (CTV plus a 2-mm margin), rectum, bladder, and urethra. Prostate motions of >3, >5, and >10 mm were observed for 31.3, 9.1, and 0.5% of the 1929 timestamps, respectively. Relative differences between the simulated and original plans were mostly less than 1%. Although significant decreases were observed in D50% and D98% of the target, absolute dose differences were <0.1 Gy compared with the planned dose. The dosimetric impact of intra-fraction prostate motion may be small even with longer treatment durations, indicating that the tumour tracking using the CyberKnife could be a robust system for examining prostate motion. PMID- 29621321 TI - Differential responses of avian and mammalian predators to phenotypic variation in Australian Brood Frogs. AB - Anti-predator signaling is highly variable with numerous examples of species employing cryptic coloration to avoid detection or conspicuous coloration (often coupled with a secondary defense) to ensure detection and recollection. While the ends of this spectrum are clear in their function, how species use intermediate signals is less clear. Australian Brood Frogs (Pseudophryne) display conspicuous coloration on both their dorsum and venter. Coupled with the alkaloid toxins these frogs possess, this coloration may be aposematic, providing a protective warning signal to predators. We assessed predation rates of known and novel color patterns and found no difference for avian or mammalian predators. However, when Pseudophryne dorsal phenotypes were collectively compared to the high-contrast ventral phenotype of this genus, we found birds, but not mammals, attacked dorsal phenotypes significantly less frequently than the ventral phenotype. This study, importantly, shows a differential predator response to ventral coloration in this genus which has implications for the evolution of conspicuous signaling in Pseudophryne. PMID- 29621320 TI - Medication and trial duration influence postural and pointing parameters during a standing repetitive pointing task in individuals with Parkinson's disease. AB - We aimed to determine the effects of levodopa medication on the performance of a repetitive pointing task while standing, and to investigate the optimal trial duration in individuals with Parkinson's disease, and older adults. Seventeen individuals with Parkinson's disease (5 freezers) and 9 older adults stood on force platforms for 30 s and 120 s while performing a bilateral repetitive pointing task, tracked by motion capture. Participants with Parkinson's disease were assessed on and off medication and older adults were also assessed on separate days. The main findings were that: 1) on medication, participants with Parkinson's exhibited greater center of pressure root mean square in the medial lateral direction, greater velocity in the medial-lateral and anterior-posterior directions, and greater range in the medial-lateral direction than off medication; 2) longer trial durations resulted in greater center of pressure range in the medial-lateral and anterior-posterior directions and greater coefficient of variation in finger pointing on the least affected side; 3) Parkinson's participants exhibited larger range in the medial-lateral direction compared to older adults; 4) off medication, freezers presented with less range and root mean square in the anterior-posterior direction than non-freezers; and 5) a correlation emerged between the freezing of gait questionnaire and pointing asymmetry and the coefficient of variation of pointing on the most affected side. Therefore, Parkinson's medication may increase instability during a repetitive pointing task. Longer trials may provide a better depiction of sway by discriminating between those with and without neurological impairment. Individuals with Parkinson's were less stable than older adults, supporting that they are at a greater risk for falls. The greater restrictive postural strategy in freezers compared to non-freezers is likely a factor that augments fall-risk. Lastly, the link between freezing of gait and upper-limb movement indicates that freezing may manifest first in the lower-limbs. PMID- 29621322 TI - Sexual dimorphism in the association between gestational diabetes mellitus and overweight in offspring at 5-7 years: The OBEGEST cohort study. AB - Evidence from literature is mixed regarding a possible association of maternal gestational diabetes mellitus (GDM) and overweight in the offspring. Sexual dimorphism, or sex disparities in the pathogenesis linking GDM exposure to overweight, could be at play. The objective of this study was to investigate the association between GDM and child overweight at 5-7 years. Six hundred pairs (1:1) of Reunionese liveborn singletons selected from a hospital-based birth registry, matched for sex, gestational age, and birth period, underwent a prospective in-home follow-up and were analyzed with respect to their exposure to GDM. The primary outcome was child overweight at 5-7 years, as defined by the International Obesity Task Force. The association between GDM exposure and child overweight was estimated by the odds ratio (OR) using conditional logistic regression models. For the subset of children exposed to GDM with available maternal glycemic data, we analyzed the relationship between maternal glycemic levels during pregnancy and child body mass index (BMI) at 5-7 years with a linear regression model. In light of the significant interaction between sex and GDM, all statistical analyses were then stratified by sex. After controlling for pre-pregnancy BMI and maternal sociodemographic characteristics, the risk of overweight increased with exposure to GDM for boys (adjusted OR: 2.34; 95% confidence interval = 1.26-4.34, P = 0.007) but not for girls (adjusted OR: 0.56; 95%CI = 0.28-1.10, P = 0.093). Consistent with this, the linear increase of boys' BMI at 5-7 years with maternal blood glucose levels during pregnancy, in the exposed group, displayed a dose-response relationship. Our findings indicate that exposure to GDM is a risk factor for childhood overweight in boys but not in girls, which adds to the growing body of evidence suggesting greater sensitivity of male offspring to intrauterine hyperglycemia. PMID- 29621323 TI - Performance comparison of three DNA extraction kits on human whole-exome data from formalin-fixed paraffin-embedded normal and tumor samples. AB - Next-generation sequencing (NGS) studies are becoming routinely used for the detection of novel and clinically actionable DNA variants at a pangenomic scale. Such analyses are now used in the clinical practice to enable precision medicine. Formalin-fixed paraffin-embedded (FFPE) tissues are still one of the most abundant source of cancer clinical specimen, unfortunately this method of preparation is known to degrade DNA and therefore compromise subsequent analysis. Some studies have reported that variant detection can be performed on FFPE samples sequenced with NGS techniques, but few or none have done an in-depth coverage analysis and compared the influence of different state-of-the-art FFPE DNA extraction kits on the quality of the variant calling. Here, we generated 42 human whole-exome sequencing data sets from fresh-frozen (FF) and FFPE samples. These samples include normal and tumor tissues from two different organs (liver and colon), that we extracted with three different FFPE extraction kits (QIAamp DNA FFPE Tissue kit and GeneRead DNA FFPE kit from Qiagen, MaxwellTM RSC DNA FFPE Kit from Promega). We determined the rate of concordance of called variants between matched FF and FFPE samples on all common variants (representing at least 86% of the total number of variants for SNVs). The concordance rate is very high between all matched FF / FFPE pairs, with equivalent values for the three kits we analyzed. On the other hand, when looking at the difference between the total number of variants in FF and FFPE, we find a significant variation for the three different FFPE DNA extraction kits. Coverage analysis shows that FFPE samples have less good indicators than FF samples, yet the coverage quality remains above accepted thresholds. We detect limited but statistically significant variations in coverage indicator values between the three FFPE extraction kits. Globally, the GeneRead and QIAamp kits have better variant calling and coverage indicators than the Maxwell kit on the samples used in this study, although this kit performs better on some indicators and has advantages in terms of practical usage. Taken together, our results confirm the potential of FFPE samples analysis for clinical genomic studies, but also indicate that the choice of a FFPE DNA extraction kit should be done with careful testing and analysis beforehand in order to maximize the accuracy of the results. PMID- 29621324 TI - Self-reported musculoskeletal complaints and injuries and exposure of physical workload in Swedish soldiers serving in Afghanistan. AB - BACKGROUND: Musculoskeletal complaints and injuries (MSCI) are common in military populations. However, only a limited number of studies have followed soldiers during international deployments and investigated the prevalence of MSCI during and at the end of their deployment. The aim was to describe the prevalence of MSCI in different military occupational specialties and categorise their most common tasks in terms of exposures to physical workloads during a six-month long international deployment in Afghanistan. METHODS: Cross-sectional survey, including 325 soldiers (300 men), aged 20-62 participating in an international deployment in Afghanistan during the spring of 2012. Soldiers were clustered into different military occupational specialties: Infantry, Administration, Logistics, Logistics/Camp, Medical and Other. Data were collected through the use of the Musculoskeletal Screening Protocol at the end of the international mission. RESULTS: Forty-seven percent reported MSCI during deployment, with 28% at the end. The most common locations of MSCI during the mission were lower back, knee, shoulders, upper back, neck and foot, while the knee and lower back prevailed at the end of the mission. Almost half of the soldiers who had MSCI reported affected work ability. The most common duties during the mission were vehicle patrolling, staff duties, guard/security duties, foot patrols and transportation. Soldiers reported that vehicle patrolling, staff duties and transportation were demanding with respect to endurance strength, guard/security duties challenged both maximum and endurance strength while foot patrolling challenged maximum and endurance strength, aerobic and anaerobic endurance and speed. CONCLUSIONS: MSCI during international deployment are common among Swedish soldiers. The results indicate the need to further develop strategies focusing on matching the soldiers' capacity to the job requirements, with relevant and fair physical selection-tests during the recruitment process and proactive interventions targeting MSCI before and during deployment, in order to enhance soldiers' readiness and promote operational readiness. PMID- 29621325 TI - Stochastic satisficing account of confidence in uncertain value-based decisions. AB - Every day we make choices under uncertainty; choosing what route to work or which queue in a supermarket to take, for example. It is unclear how outcome variance, e.g. uncertainty about waiting time in a queue, affects decisions and confidence when outcome is stochastic and continuous. How does one evaluate and choose between an option with unreliable but high expected reward, and an option with more certain but lower expected reward? Here we used an experimental design where two choices' payoffs took continuous values, to examine the effect of outcome variance on decision and confidence. We found that our participants' probability of choosing the good (high expected reward) option decreased when the good or the bad options' payoffs were more variable. Their confidence ratings were affected by outcome variability, but only when choosing the good option. Unlike perceptual detection tasks, confidence ratings correlated only weakly with decisions' time, but correlated with the consistency of trial-by-trial choices. Inspired by the satisficing heuristic, we propose a "stochastic satisficing" (SSAT) model for evaluating options with continuous uncertain outcomes. In this model, options are evaluated by their probability of exceeding an acceptability threshold, and confidence reports scale with the chosen option's thus-defined satisficing probability. Participants' decisions were best explained by an expected reward model, while the SSAT model provided the best prediction of decision confidence. We further tested and verified the predictions of this model in a second experiment. Our model and experimental results generalize the models of metacognition from perceptual detection tasks to continuous-value based decisions. Finally, we discuss how the stochastic satisficing account of decision confidence serves psychological and social purposes associated with the evaluation, communication and justification of decision-making. PMID- 29621326 TI - Genetic identification of eggs from four species of Ophichthidae and Congridae (Anguilliformes) in the northern East China Sea. AB - We report the first genetic identification of eggs of four species of Anguilliformes caught in the northern East China Sea during August 2016, where leptocephali and adults have been collected. The species were Ophisurus macrorhynchos and Echelus uropterus belonging to the Ophichthidae, and Ariosoma majus and Gnathophis heterognathos belonging to the Congridae. The eggs were identified using three molecular genetic markers (mitochondrial 12S rRNA, 16S rRNA, and cytochrome c oxidase subunit 1), sequences obtained from local adult specimens, and geographical distribution data. All eggs were in the early or middle developmental stages. For all species except A. majus, the eggs were found near the range of small leptocephali in the East China Sea and the southern Korean Peninsula, which indicates these species had spawned along the continental near these areas during the summer. PMID- 29621327 TI - Effects of feed allowance and indispensable amino acid reduction on feed intake, growth performance and carcass characteristics of growing pigs. AB - The hypothesis that pigs placed on diets with reduced indispensable amino acid (AA) content attempts to offset the reduction in the nutrient density with increased feed intake was tested. In the experiment, feeds with a high or a low AA content were administrated to pigs fed ad-libitum or restrictively according to a 2 * 2 factorial design. Ninety-six barrows were housed in 8 pens (12 pigs/pen) equipped with automatic feeders. Within pen, and from 47 body weight (BW) onwards, 6 pigs were fed ad libitum. The others pigs were allowed to consume, as a maximum, the feed amounts indicated by the breeding company feeding plane to optimize the feed efficiency. In early (86-118 kg BW) and late (118-145 kg BW) finishing, the pigs of 4 pens received feeds with high indispensable AA contents (8.1 and 7.5 g lysine/kg in the two periods, respectively). The other pigs received feeds with reduced indispensable AA contents (lysine, methionine, threonine and tryptophan) by 9 and 18% in early and late finishing, respectively. Body lipid and protein (Pr) retentions were estimated from BW and back-fat depth measures recorded at the beginning and the end of each period. Nitrogen excretion was estimated as actual intake minus estimated N-retention (Pr/6.25). Pigs were slaughtered at 144 kg BW. Restricted feeding decreased feed intake (-7%), daily gain (-5%), carcass weight (-2.6%) and back-fat depth (-8.0%) but increased gain:feed ratio (+2%). The AA restriction increased feed intake (+5.9%), carcass weight (+4.9%) and intramuscular fat (+17.6%), and reduced carcass weight variation (-36%), with no effects on the feed efficiency and the estimated Pr (142 g/d). N excreted was reduced by feed (-9%) and dietary AA (-15%) restrictions. Irrespectively of the feeding level, the pigs responded to a reduction of the dietary essential AA content by increasing their feed intake. PMID- 29621328 TI - Differences in prevalence of hypertension and associated risk factors in urban and rural residents of the northeastern region of the People's Republic of China: A cross-sectional study. AB - BACKGROUND: Hypertension is a significant global public health problem and recognized as an important risk factor for cardiovascular diseases. This study was designed to assess the current prevalence of hypertension and to explore risk factors associated with hypertension by urban and rural status to guide the prevention and control of hypertension in Jilin province. METHODS: A multi-stage stratified random cluster sampling method was used to obtain data on hypertension, which was investigated by physical examination and face-to-face questionnaire in July 2014-December 2015. Sample data were analyzed by complex weighted statistical analysis to estimate blood pressure levels and prevalence of hypertension in the province. Multivariable logistic regression analysis was used to identify factors influencing hypertension rates. RESULTS: The prevalence of hypertension was significantly higher in rural areas than urban areas (25.93% versus 22.73%, respectively). The rates of hypertension known (46.7% versus 38.1%, respectively), control (13.7% versus 5.0%, respectively), and controlled among treated subjects (38.3% versus 17.5%, respectively) were higher in urban areas than in rural areas (all p < 0.001), while the treatment rate was not statistically significantly different between urban and rural areas (35.9% versus 28.4%, respectively). After adjusting for demographic covariates, hypertension prevalence in rural areas was still significantly greater than in urban areas (adjusted OR = 1.22; 95%CI: 1.10, 1.36; p < 0.001). Common risk factors for hypertension among urban and rural residents included older age; male; married; employed; less education; overweight/obese; greater abdominal waist circumference; family history of hypertension, stroke, or coronary heart disease; current smoker; alcohol consumption; higher visceral adiposity index; and higher body fat percentage. CONCLUSIONS: This study identified an increased risk for hypertension in rural regions of Jilin province, suggesting that rural hypertension screening and treatment guidelines should receive greater attention. PMID- 29621329 TI - Patient-important outcomes in systematic reviews: Poor quality of evidence. AB - BACKGROUND: Cochrane reviewers are strongly encouraged to evaluate the quality of evidence for the most important outcomes by using the GRADE approach and to report these results in a Summary of Findings (SoF) table. We aimed to assess whether outcomes reported in the SoF table of Cochrane reviews could be considered patient-important outcomes (PIOs) and the quality of the available evidence for these outcomes. METHODS: We performed a methodological review of Cochrane reviews published between March 2011 and September 2014. For a random sample of Cochrane reviews reporting a SoF table, we extracted all outcomes reported in this table and evaluated whether they could be considered PIOs (i.e., mortality, other clinical events, adverse events, function, pain, quality of life and therapeutic decisions). Then, we collected the quality of evidence for every outcome in these SoF tables. RESULTS: We included 290 reviews issued by 47 of the 53 Cochrane Review Groups. Every SoF table included a median of 5 outcomes, for a total of 1414 outcomes; 1089 (77%) could be considered PIOs. Almost all reviews (n = 278, 96%) included at least one PIO in their SoF table. The quality of evidence for the outcomes was high for 12% (n = 168), moderate for 28% (n = 402) and low or very low for 45% (n = 640). Less than one quarter of reviews (n = 63) included at least one PIO with high-quality evidence that favoured a benefit of the experimental intervention evaluated in half of them (n = 34 reviews). CONCLUSIONS: Many outcomes reported in the SoF table of recent Cochrane reviews can be considered PIOs. However, the quality of available evidence remains limited for these outcomes. PMID- 29621330 TI - Conservation planning under uncertainty in urban development and vegetation dynamics. AB - Systematic conservation planning is a framework for optimally locating and prioritizing areas for conservation. An often-noted shortcoming of most conservation planning studies is that they do not address future uncertainty. The selection of protected areas that are intended to ensure the long-term persistence of biodiversity is often based on a snapshot of the current situation, ignoring processes such as climate change. Scenarios, in the sense of being accounts of plausible futures, can be utilized to identify conservation area portfolios that are robust to future uncertainty. We compared three approaches for utilizing scenarios in conservation area selection: considering a full set of scenarios (all-scenarios portfolio), assuming the realization of specific scenarios, and a reference strategy based on the current situation (current distributions portfolio). Our objective was to compare the robustness of these approaches in terms of their relative performance across future scenarios. We focused on breeding bird species in Israel's Mediterranean region. We simulated urban development and vegetation dynamics scenarios 60 years into the future using DINAMICA-EGO, a cellular-automata simulation model. For each scenario, we mapped the target species' available habitat distribution, identified conservation priority areas using the site-selection software MARXAN, and constructed conservation area portfolios using the three aforementioned strategies. We then assessed portfolio performance based on the number of species for which representation targets were met in each scenario. The all-scenarios portfolio consistently outperformed the other portfolios, and was more robust to 'errors' (e.g., when an assumed specific scenario did not occur). On average, the all-scenarios portfolio achieved representation targets for five additional species compared with the current distributions portfolio (approximately 33 versus 28 species). Our findings highlight the importance of considering a broad and meaningful set of scenarios, rather than relying on the current situation, the expected occurrence of specific scenarios, or the worst-case scenario. PMID- 29621331 TI - A Gossypium hirsutum GDSL lipase/hydrolase gene (GhGLIP) appears to be involved in promoting seed growth in Arabidopsis. AB - GDSL lipase (GLIP) plays a pivotal role in plant cell growth as a multifunctional hydrolytic enzyme. Herein, a cotton (Gossypium hirsutum L. cv Xuzhou 142) GDSL lipase gene (GhGLIP) was obtained from developing ovules and fibers. The GhGLIP cDNA contained an open reading frame (ORF) of 1,143 base pairs (bp) and encodes a putative polypeptide of 380 amino acid residues. Sequence alignment indicated that GhGLIP includes four enzyme catalytic amino acid residue sites of Ser (S), Gly (G), Asn (N) and His (H), located in four conserved blocks. Phylogenetic tree analysis showed that GhGLIP belongs to the typical class IV lipase family with potential functions in plant secondary metabolism. Subcellular distribution analysis demonstrated that GhGLIP localized to the nucleus, cytoplasm and plasma membrane. GhGLIP was expressed predominantly at 5-15 day post anthesis (dpa) in developing ovules and elongating fibers, measured as mRNA levels and enzyme activity. Ectopic overexpression of GhGLIP in Arabidopsis plants resulted in enhanced seed development, including length and fresh weight. Meanwhile, there was increased soluble sugar and protein storage in transgenic Arabidopsis plants, coupled with the promotion of lipase activity. Moreover, the expression of cotton GhGLIP is induced by ethylene (ETH) treatment in vitro. A 1,954-bp GhGLIP promoter was isolated and expressed high activity in driving green fluorescence protein (GFP) expression in tobacco leaves. Cis-acting element analysis of the GhGLIP promoter (pGhGLIP) indicated the presence of an ethylene-responsive element (ERE), and transgenic tobacco leaves with ectopic expression of pGhGLIP::GFP-GUS showed increased GUS activity after ETH treatment. In summary, these results suggest that GhGLIP is a functional enzyme involved in ovule and fiber development and performs significant roles in seed development. PMID- 29621332 TI - Prediction of response to medical therapy by serum soluble (pro)renin receptor levels in Graves' disease. AB - Antithyroid drugs are generally selected as the first-line treatment for Graves' Disease (GD); however, the existence of patients showing resistance or severe side effects to these drugs is an important issue to be solved. The (pro)renin receptor [(P)RR] is a multi-functional protein that activates the tissue renin angiotensin system and is an essential constituent of vacuolar H+-ATPase, necessary for the autophagy-lysosome pathway. (P)RR is cleaved to soluble (s)(P)RR, which reflects the status of (P)RR expression. In this retrospective study, we aimed to investigate whether serum s(P)RR concentration can be used as a biomarker to predict the outcome of antithyroid drug treatment in GD patients. Serum s(P)RR levels were measured in 54 untreated GD patients and 47 control participants. Effects of medical treatment with antithyroid drugs on these levels were investigated in GD patients. Serum s(P)RR levels were significantly higher in patients with Graves' disease than in control subjects (P<0.005) and were significantly reduced after medical treatment for Graves' disease. High serum s(P)RR levels were associated with resistance to antithyroid drug treatment, suggesting that serum s(P)RR concentration can be used as a useful biomarker to predict the outcome of antithyroid drug treatment in these patients. Patients with Graves' disease with low body mass index showed higher levels of serum soluble (pro)renin receptor levels than those with high body mass index. In addition, in patients with Graves' disease, serum triglyceride levels were negatively correlated with serum soluble (pro)renin receptor levels. All these data indicated an association between low nutrient condition due to hyperthyroidism and increased (pro)renin receptor expression in these patients, suggesting that (pro)renin receptor expression could be increased in the process of stimulating intracellular energy production via activating autophagy function to compensate energy loss. PMID- 29621333 TI - Influenza A virus recovery, diversity, and intercontinental exchange: A multi year assessment of wild bird sampling at Izembek National Wildlife Refuge, Alaska. AB - Western Alaska is a potential point-of-entry for foreign-origin influenza A viruses (IAVs) into North America via migratory birds. We sampled waterfowl and gulls for IAVs at Izembek National Wildlife Refuge (NWR) in western Alaska, USA, during late summer and autumn months of 2011-2015, to evaluate the abundance and diversity of viruses at this site. We collected 4842 samples across five years from 25 species of wild birds resulting in the recovery, isolation, and sequencing of 172 IAVs. With the intent of optimizing sampling efficiencies, we used information derived from this multi-year effort to: 1) evaluate from which species we consistently recover viruses, 2) describe viral subtypes of isolates by host species and year, 3) characterize viral gene segment sequence diversity with respect to host species, and assess potential differences in the viral lineages among the host groups, and 4) examine how evidence of intercontinental exchange of IAVs relates to host species. We consistently recovered viruses from dabbling ducks (Anas spp.), emperor geese (Chen canagica) and glaucous-winged gulls (Larus glaucescens). There was little evidence for differences in viral subtypes and diversity from different waterfowl hosts, however subtypes and viral diversity varied between waterfowl host groups and glaucous-winged gulls. Furthermore, higher proportions of viral sequences from northern pintails (Anas acuta), emperor geese and glaucous-winged gulls were grouped in phylogenetic clades that included IAV sequences originating from wild birds sampled in Asia as compared to non-pintail dabbling ducks, a difference that may be related to intercontinental migratory tendencies of host species. Our summary of research and surveillance efforts at Izembek NWR will assist in future prioritization of which hosts to sample and swab types to collect in Alaska and elsewhere in order to maximize isolate recovery, subtype and sequence diversity for resultant viruses, and detection of evidence for intercontinental viral exchange. PMID- 29621334 TI - How cyclophosphamide at environmentally relevant concentration influences Daphnia magna life history and its proteome. AB - The waste of commonly used medicines is known to contaminate freshwater ecosystems. Pharmaceuticals can be toxic, mutagenic, or modifying to freshwater organisms even at low concentrations if consider their permanent presence in the environment. Chemotherapeutics used to treat cancer, and in particular alkylating agents, contribute significantly to this form of pollution, the latter introducing cytotoxic and/or mutagenic lesions to the DNA and RNA of organisms which can be disruptive to their cells. The aim of the present study was to investigate the influence of the alkylating anticancer agent cyclophosphamide (CP) on Daphnia magna clones. We evaluated the life history parameters and protein profiles of this crustacean following exposure to environmentally relevant CP concentration of 10 ng L-1. Even at this low concentration, the alkylating agent caused modification of the life history parameters and proteome profile of the Daphnia. These changes were clone-specific and involved growth rate, age at first reproduction, neonate number, and proteins related to cell cycle and redox state regulation. The disturbance caused by pharmaceuticals contaminating freshwater ecosystem is probably weaker and unlikely to be cytotoxic in character due to the high dilution of these substances in the water. However, our results indicate that prolonged exposure of organisms to these toxins may lead to modifications on the organismal and molecular levels with unpredictable significance for the entire ecosystem. PMID- 29621335 TI - Impacts of human recreation on carnivores in protected areas. AB - Mammalian carnivores can be particularly sensitive to human disturbance, even within protected areas (PAs). Our objective was to understand how human disturbance affects carnivore communities in southern Arizona, USA by studying habitat occupancy based on data collected using non-invasive methods in three PAs with different levels of human disturbance. Carnivore occupancy varied based on human disturbance variables (i.e., roads, trails, etc.). Common carnivore species (coyotes, gray foxes, and bobcats) had high occupancy probability in highly disturbed sites, while all other carnivore species had a higher probability of occupancy in low disturbance protected areas. Additionally, overall carnivore diversity was higher in PAs with low human disturbance. Edges of PAs appeared to negatively impact occupancy of nearly all carnivore species. We also found the presence of roads and trails, and not necessarily how much they are used, had a significant negative impact on the occupancy of most carnivore species. Furthermore, the overall level of disturbance within a PA influenced how sensitive carnivores were to human disturbance variables. Carnivores were more sensitive in PAs with higher levels of disturbance and were relatively unaffected by disturbance variables in a PA with low base levels of disturbance. Increased visitation to PAs, expected with the region's high level of population growth, is likely to cause shifts in the carnivore communities favoring species that are less sensitive to disturbance. PMID- 29621336 TI - Polyvalent vaccines: High-maintenance heroes. PMID- 29621337 TI - Serial evaluation of SOFA and APACHE II scores to predict neurologic outcomes of out-of-hospital cardiac arrest survivors with targeted temperature management. AB - OBJECTIVE: This study was aimed at a serial evaluation and comparison of the prognostic values of Sequential Organ Failure Assessment (SOFA) and Acute Physiology and Chronic Health Evaluation (APACHE) II scores for neurologic outcomes in comatose, out-of-hospital cardiac arrest (OHCA) survivors, treated with targeted temperature management (TTM). METHODS: We analysed a prospective cohort of comatose OHCA patients, with TTM, admitted to an emergency intensive care unit (ICU), between January 2010 and December 2015. SOFA and APACHE II scores were calculated initially, and then at day 1, 2, 3, 5, and 7 after ICU admission. Primary and secondary outcomes were the 28-day neurologic outcome and the 28-day mortality, respectively. Prognostic value of the SOFA and APACHE II scores was analysed using the receiver operating characteristic curve. RESULTS: Of the 143 selected patients, 62 survived and 34 had good neurologic outcomes at day 28. There was no significant difference in the SOFA and extracerebral SOFA scores between the good and poor neurologic outcome groups. However, the APACHE II scores were significantly higher in the good outcome group; they displayed good discriminatory power in predicting poor outcomes, unlike the SOFA scores. The APACHE II score at day 3 had the highest prognostic value for predicting poor neurologic outcomes with an area under the cure of 0.793, and with a cut-off value of 20, the APACHE II score predicted poor neurologic outcomes with a sensitivity of 43.75%, a specificity of 94.12%, a positive predictive value of 94.59%, and a negative predictive value of 41.56%. CONCLUSIONS: Identifying APACHE II score might assist as one piece of multimodal prognostic approach for the assessment of neurologic outcomes in OHCA survivors treated with TTM. PMID- 29621338 TI - Auditory sensitivity to spectral modulation phase reversal as a function of modulation depth. AB - The present study evaluated auditory sensitivity to spectral modulation by determining the modulation depth required to detect modulation phase reversal. This approach may be preferable to spectral modulation detection with a spectrally flat standard, since listeners appear unable to perform the task based on the detection of temporal modulation. While phase reversal thresholds are often evaluated by holding modulation depth constant and adjusting modulation rate, holding rate constant and adjusting modulation depth supports rate-specific assessment of modulation processing. Stimuli were pink noise samples, filtered into seven octave-wide bands (0.125-8 kHz) and spectrally modulated in dB. Experiment 1 measured performance as a function of modulation depth to determine appropriate units for adaptive threshold estimation. Experiment 2 compared thresholds in dB for modulation detection with a flat standard and modulation phase reversal; results supported the idea that temporal cues were available at high rates for the former but not the latter. Experiment 3 evaluated spectral modulation phase reversal thresholds for modulation that was restricted to either one or two neighboring bands. Flanking bands of unmodulated noise had a larger detrimental effect on one-band than two-band targets. Thresholds for high-rate modulation improved with increasing carrier frequency up to 2 kHz, whereas low rate modulation appeared more consistent across frequency, particularly in the two-band condition. Experiment 4 measured spectral weights for spectral modulation phase reversal detection and found higher weights for bands in the spectral center of the stimulus than for the lowest (0.125 kHz) or highest (8 kHz) band. Experiment 5 compared performance for highly practiced and relatively naive listeners, and found weak evidence of a larger practice effect at high than low spectral modulation rates. These results provide preliminary data for a task that may provide a better estimate of sensitivity to spectral modulation than spectral modulation detection with a flat standard. PMID- 29621340 TI - Chinook salmon (Oncorhynchus tshawytscha) genome and transcriptome. AB - When unifying genomic resources among studies and comparing data between species, there is often no better resource than a genome sequence. Having a reference genome for the Chinook salmon (Oncorhynchus tshawytscha) will enable the extensive genomic resources available for Pacific salmon, Atlantic salmon, and rainbow trout to be leveraged when asking questions related to the Chinook salmon. The Chinook salmon's wide distribution, long cultural impact, evolutionary history, substantial hatchery production, and recent wild-population decline make it an important research species. In this study, we sequenced and assembled the genome of a Chilliwack River Hatchery female Chinook salmon (gynogenetic and homozygous at all loci). With a reference genome sequence, new questions can be asked about the nature of this species, and its role in a rapidly changing world. PMID- 29621341 TI - Second course of stereotactic radiosurgery for locally recurrent brain metastases: Safety and efficacy. AB - In the present study, we have evaluated the efficacy and toxicity of repeated brain metastases (BM) stereotactic radiosurgery (SRS2) following local failure of a prior radiosurgical procedure (SRS1). Between December 1996 and August 2015, 30 patients with 36 BM underwent SRS2 with a median dose of 18Gy. All BM were located outside critical structures. Following SRS2, local control at 6 months and one year were respectively 82.9% (IC 95%: 67.6-91.9) and 67.8% (IC 95%: 51 81). On multivariate analysis, planning target volume (PTV) < 3cc (HR: 0.19 (0.1 0.52)) and whole brain radiotherapy (WBRT) prior to SRS2 (HR: 0.25 (0.1-0.64)) were significantly associated with a better local control. One- and two-year overall survival rates after SRS2 were respectively 65.5% (IC 95%: 47.3-80%) and 27.6% (IC 95%: 14.7-45.7). Median overall survival following SRS2 was 14.2 months (range 1-106). Nineteen (63%) patients died from progressive systemic disease. Three (10%) patients died from out-field progressive brain disease and 8 (27%) in field. Concerning toxicities, edema, radionecrosis, and hemorrhages were identified in 5 (12.8%), 4 (10.2%), and 5 (12.8%) patients respectively. No toxicity resulted in a neurological deficit. On univariate analysis, toxicities were significantly associated with PTV > 7cc (p = 0.02) and all patients had a WBRT before SRS2. A second course of SRS for locally recurrent brain metastases showed encouraging rates of local control. This treatment led to acceptable toxicities, especially for brain metastases smaller than 7cc, in our selected cohort of patients with BM located outside critical structures. Further studies are needed. PMID- 29621339 TI - Clarithromycin expands CD11b+Gr-1+ cells via the STAT3/Bv8 axis to ameliorate lethal endotoxic shock and post-influenza bacterial pneumonia. AB - Macrolides are used to treat various inflammatory diseases owing to their immunomodulatory properties; however, little is known about their precise mechanism of action. In this study, we investigated the functional significance of the expansion of myeloid-derived suppressor cell (MDSC)-like CD11b+Gr-1+ cells in response to the macrolide antibiotic clarithromycin (CAM) in mouse models of shock and post-influenza pneumococcal pneumonia as well as in humans. Intraperitoneal administration of CAM markedly expanded splenic and lung CD11b+Gr 1+ cell populations in naive mice. Notably, CAM pretreatment enhanced survival in a mouse model of lipopolysaccharide (LPS)-induced shock. In addition, adoptive transfer of CAM-treated CD11b+Gr-1+ cells protected mice against LPS-induced lethality via increased IL-10 expression. CAM also improved survival in post influenza, CAM-resistant pneumococcal pneumonia, with improved lung pathology as well as decreased interferon (IFN)-gamma and increased IL-10 levels. Adoptive transfer of CAM-treated CD11b+Gr-1+ cells protected mice from post-influenza pneumococcal pneumonia. Further analysis revealed that the CAM-induced CD11b+Gr 1+ cell expansion was dependent on STAT3-mediated Bv8 production and may be facilitated by the presence of gut commensal microbiota. Lastly, an analysis of peripheral blood obtained from healthy volunteers following oral CAM administration showed a trend toward the expansion of human MDSC-like cells (Lineage-HLA-DR-CD11b+CD33+) with increased arginase 1 mRNA expression. Thus, CAM promoted the expansion of a unique population of immunosuppressive CD11b+Gr-1+ cells essential for the immunomodulatory properties of macrolides. PMID- 29621342 TI - A staphylococcal anti-sigma factor possesses a single-domain, carries different denaturant-sensitive regions and unfolds via two intermediates. AB - RsbW, an anti-sigma factor possessing kinase activity, is expressed by many Gram positive bacteria including Staphylococcus aureus. To obtain clues about the domain structure and the folding-unfolding mechanism of RsbW, we have elaborately studied rRsbW, a recombinant S. aureus RsbW. Sequence analysis of the protein fragments, generated by the limited proteolysis of rRsbW, has proposed it to be a single-domain protein. The unfolding of rRsbW in the presence of GdnCl or urea was completely reversible in nature and occurred through the formation of at least two intermediates. The structure, shape, and the surface hydrophobicity of no intermediate completely matches with those of other intermediates or the native rRsbW. Interestingly, one of the intermediates, formed in the presence of less GdnCl concentrations, has a molten globule-like structure. Conversely, all of the intermediates, like native rRsbW, exist as dimers in aqueous solution. The putative molten globule and the urea-generated intermediates also have retained some kinase activity. Additionally, the putative ATP binding site/catalytic site of rRsbW shows higher denaturant sensitivity than the tentative dimerization region of this enzyme. PMID- 29621343 TI - Differential accumulation of proteins in oil palms affected by fatal yellowing disease. AB - There is still no consensus on the true origin of fatal yellowing, one of the most important diseases affecting oil palm (Elaeis guineensis Jacq.) plantations. This study involved two-dimensional liquid chromatography coupled with tandem mass spectrometry (2D-UPLC-MSE) analyses to identify changes in protein profiles of oil palms affected by FY disease. Oil palm roots were sampled from two growing areas. Differential accumulation of proteins was assessed by comparing plants with and without symptoms and between plants at different stages of FY development. Most of the proteins identified with differential accumulation were those related to stress response and energy metabolism. The latter proteins include the enzymes alcohol dehydrogenase and aldehyde dehydrogenase, related to alcohol fermentation, which were identified in plants with and without symptoms. The presence of these enzymes suggests an anaerobic condition before or during FY. Transketolase, isoflavone reductase, cinnamyl alcohol dehydrogenase, caffeic acid 3-O-methyltransferase, S-adenosylmethionine synthase, aldehyde dehydrogenase and ferritin, among others, were identified as potential marker proteins and could be used to guide selection of FY-tolerant oil palm genotypes or to understand the source of this anomaly. When comparing different stages of FY, we observed high accumulation of alcohol dehydrogenase and other abiotic stress related-proteins at all disease stages. On the other hand, biological stress related proteins were more accumulated at later stages of the disease. These results suggest that changes in abiotic factors can trigger FY development, creating conditions for the establishment of opportunistic pathogens. PMID- 29621344 TI - Hemodynamic forces in the left and right ventricles of the human heart using 4D flow magnetic resonance imaging: Phantom validation, reproducibility, sensitivity to respiratory gating and free analysis software. AB - PURPOSE: To investigate the accuracy, reproducibility and sensitivity to respiratory gating, field strength and ventricle segmentation of hemodynamic force quantification in the left and right ventricles of the heart (LV and RV) using 4D-flow magnetic resonance imaging (MRI), and to provide free hemodynamic force analysis software. MATERIALS AND METHODS: A pulsatile flow phantom was imaged using 4D flow MRI and laser-based particle image velocimetry (PIV). Cardiac 4D flow MRI was performed in healthy volunteers at 1.5T (n = 23). Reproducibility was investigated using MR scanners from two different vendors on the same day (n = 8). Subsets of volunteers were also imaged without respiratory gating (n = 17), at 3T on the same day (n = 6), and 1-12 days later on the same scanner (n = 9, median 6 days). Agreement was measured using the intraclass correlation coefficient (ICC). RESULTS: Phantom validation showed good accuracy for both scanners (Scanner 1: bias -14+/-9%, y = 0.82x+0.08, R2 = 0.96, Scanner 2: bias -12+/-8%, y = 0.99x-0.08, R2 = 1.00). Force reproducibility was strong in the LV (0.09+/-0.07 vs 0.09+/-0.07 N, bias 0.00+/-0.04 N, ICC = 0.87) and RV (0.09+/-0.06 vs 0.09+/-0.05 N, bias 0.00+/-0.03, ICC = 0.83). Strong to very strong agreement was found for scans with and without respiratory gating (LV/RV: ICC = 0.94/0.95), scans on different days (ICC = 0.92/0.87), and 1.5T and 3T scans (ICC = 0.93/0.94). CONCLUSION: Software for quantification of hemodynamic forces in 4D-flow MRI was developed, and results show high accuracy and strong to very strong reproducibility for both the LV and RV, supporting its use for research and clinical investigations. The software including source code is released freely for research. PMID- 29621345 TI - Unlocking preservation bias in the amber insect fossil record through experimental decay. AB - Fossils entombed in amber are a unique resource for reconstructing forest ecosystems, and resolving relationships of modern taxa. Such fossils are famous for their perfect, life-like appearance. However, preservation quality is vast with many sites showing only cuticular preservation, or no fossils. The taphonomic processes that control this range are largely unknown; as such, we know little about potential bias in this important record. Here we employ actualistic experiments, using, fruit flies and modern tree resin to determine whether resin type, gut microbiota, and dehydration prior to entombment affects decay. We used solid phase microextraction gas chromatography-mass spectrometry (SPME GC-MS) to confirm distinct tree resin chemistry; gut microbiota of flies was modified using antibiotics and categorized though sequencing. Decay was assessed using phase contrast synchrotron tomography. Resin type demonstrates a significant control on decay rate. The composition of the gut microbiota was also influential, with minor changes in composition affecting decay rate. Dehydration prior to entombment, contrary to expectations, enhanced decay. Our analyses show that there is potential significant bias in the amber fossil record, especially between sites with different resin types where ecological completeness and preservational fidelity are likely affected. PMID- 29621348 TI - Religion and perceptions of community-based conservation in Ghana, West Africa. AB - Adapting community-based protected areas to local context and evaluating their success across a range of possible socio-economic and ecological outcomes depends, in part, on understanding the perceptions of local actors. This article presents results from a mixed methods study that focuses on how and why religious identity, a prominent aspect of Ghanaian culture, is related to perceptions of the performance of several Community Resource Management Areas (CREMAs). CREMAs are a form of Ghanaian protected area that emphasizes community participation and a range of socio-economic and ecological objectives. Using importance satisfaction analysis, large-scale survey results show that respondents that identify as Christians consistently assign greater importance to CREMA outcomes than do those that identify with Traditional religions. Education and whether respondents were native to an area (both of which were correlated with religious identity) were also systematically related to perceptions of CREMA importance, with those that are educated and non-native to an area tending to assign higher importance to CREMA outcomes. Follow up focus group participants from the Avu Lagoon CREMA suggest that the patterns result from differing 'openness' to new ideas, relative dependence on natural resources, acceptance of Traditional practices associated with conservation, and a sense, for some, that ecological conditions are divinely ordained. Christianity, education and non-nativity are associated with much larger performance gaps, particularly with respect to socio economic impacts. The article concludes with a discussion of the implications for conservation interventions and the use of perceptions in assessing protected area performance. PMID- 29621346 TI - Accuracy of rapid diagnosis of Talaromyces marneffei: A systematic review and meta-analysis. AB - BACKGROUND: To examine the accuracy of Rapid Diagnosis of Talaromyces marneffei (RDTM) in order to improve diagnosis and treatment for clinical measures and reduce the mortality due to associated infections. METHODS: In this systematic review and meta-analysis, we screened PubMed, Ovid (Cochrane library) and Web of Science, Chinese database CNKI and Wanfang for articles published between 1956 and December, 2017. Data were taken from cross-sectional studies as well as from baseline measurements in longitudinal studies with clinical follow-up. Articles were excluded if they did not contain a cohort with T. marneffei and a control cohort or a cohort with standard fungus culture. Data were extracted by two authors and checked by three for accuracy. For quality assessment, modified QUADAS-2 criteria were used. RESULTS: The 26 included diagnostic studies enrolled 5,594 objectives in 632 patients with T. marneffei infections and 2,612 negative controls between 1996 and 2017 in Thailand, Vietnam and China. The total combined sensitivity and specificity of rapid diagnosis of T. marneffei was 0.82 (95% CI: 0.68-0.90) and 0.99 (95% CI: 0.98-1.00). According to the experimental method, the included studies can be divided into three subgroups, including PCR-based, ELISA-based and others. The results showed these three subgroups had a highly pooled specificity of 1.00 (95% CI: 0.99-1.00), 0.99 (0.98-1.00) and 0.97 (95% CI: 0.91-1.00), respectively, while combined sensitivity was 0.84 (95% CI: 0.37 0.98), 0.82 (95% CI: 0.64-0.92) and 0.77 (95% CI: 0.54-0.91), respectively. CONCLUSIONS: Although serological methods with a high specificity is essential for potential rapid diagnostic, false-negative results can be obtained in the serum samples, there is no suitable rapid serological test to refer to as is the case with TM infection. PMID- 29621347 TI - Investigation of multiple mortality events in eastern box turtles (Terrapene carolina carolina). AB - Wildlife mortality investigations are important for conservation, food safety, and public health; but they are infrequently reported for cryptic chelonian species. Eastern box turtles (Terrapene carolina carolina) are declining due to anthropogenic factors and disease, and while mortality investigations have been reported for captive and translocated individuals, few descriptions exist for free-living populations. We report the results of four natural mortality event investigations conducted during routine health surveillance of three Illinois box turtle populations in 2011, 2013, 2014, and 2015. In April 2011, over 50 box turtles were found dead and a polymicrobial necrotizing bacterial infection was diagnosed in five survivors using histopathology and aerobic/anaerobic culture. This represents the first reported occurrence of necrotizing bacterial infection in box turtles. In August 2013, paired histopathology and qPCR ranavirus detection in nine turtles was significantly associated with occupation of moist microhabitats, identification of oral plaques and nasal discharge on physical exam, and increases in the heterophil count and heterophil to lymphocyte ratio (p < 0.05). In July 2014 and 2015, ranavirus outbreaks reoccurred within a 0.2km radius of highly-disturbed habitat containing ephemeral ponds used by amphibians for breeding. qPCR ranavirus detection in five individuals each year was significantly associated with use of moist microhabitats (p < 0.05). Detection of single and co-pathogens (Terrapene herpesvirus 1, adenovirus, and Mycoplasma sp.) was common before, during, and after mortality events, but improved sample size would be necessary to determine the impacts of these pathogens on the occurrence and outcome of mortality events. This study provides novel information about the causes and predictors of natural box turtle mortality events. Continued investigation of health, disease, and death in free-living box turtles will improve baseline knowledge of morbidity and mortality, identify threats to survival, and promote the formation of effective conservation strategies. PMID- 29621349 TI - Signature pathway expression of xylose utilization in the genetically engineered industrial yeast Saccharomyces cerevisiae. AB - Haploid laboratory strains of Saccharomyces cerevisiae are commonly used for genetic engineering to enable their xylose utilization but little is known about the industrial yeast which is often recognized as diploid and as well as haploid and tetraploid. Here we report three unique signature pathway expression patterns and gene interactions in the centre metabolic pathways that signify xylose utilization of genetically engineered industrial yeast S. cerevisiae NRRL Y 50463, a diploid yeast. Quantitative expression analysis revealed outstanding high levels of constitutive expression of YXI, a synthesized yeast codon optimized xylose isomerase gene integrated into chromosome XV of strain Y-50463. Comparative expression analysis indicated that the YXI was necessary to initiate the xylose metabolic pathway along with a set of heterologous xylose transporter and utilization facilitating genes including XUT4, XUT6, XKS1 and XYL2. The highly activated transketolase and transaldolase genes TKL1, TKL2, TAL1 and NQM1 as well as their complex interactions in the non-oxidative pentose phosphate pathway branch were critical for the serial of sugar transformation to drive the metabolic flow into glycolysis for increased ethanol production. The significantly increased expression of the entire PRS gene family facilitates functions of the life cycle and biosynthesis superpathway for the yeast. The outstanding higher levels of constitutive expression of YXI and the first insight into the signature pathway expression and the gene interactions in the closely related centre metabolic pathways from the industrial yeast aid continued efforts for development of the next-generation biocatalyst. Our results further suggest the industrial yeast is a desirable delivery vehicle for new strain development for efficient lignocellulose-to-advanced biofuels production. PMID- 29621350 TI - Infection history of the blood-meal host dictates pathogenic potential of the Lyme disease spirochete within the feeding tick vector. AB - Lyme disease in humans is caused by several genospecies of the Borrelia burgdorferi sensu lato (s.l.) complex of spirochetal bacteria, including B. burgdorferi, B. afzelii and B. garinii. These bacteria exist in nature as obligate parasites in an enzootic cycle between small vertebrate hosts and Ixodid tick vectors, with humans representing incidental hosts. During the natural enzootic cycle, infected ticks in endemic areas feed not only upon naive hosts, but also upon seropositive infected hosts. In the current study, we considered this environmental parameter and assessed the impact of the immune status of the blood-meal host on the phenotype of the Lyme disease spirochete within the tick vector. We found that blood from a seropositive host profoundly attenuates the infectivity (>104 fold) of homologous spirochetes within the tick vector without killing them. This dramatic neutralization of vector-borne spirochetes was not observed, however, when ticks and blood-meal hosts carried heterologous B. burgdorferi s.l. strains, or when mice lacking humoral immunity replaced wild type mice as blood-meal hosts in similar experiments. Mechanistically, serum mediated neutralization does not block induction of host-adapted OspC+ spirochetes during tick feeding, nor require tick midgut components. Significantly, this study demonstrates that strain-specific antibodies elicited by B. burgdorferi s.l. infection neutralize homologous bacteria within feeding ticks, before the Lyme disease spirochetes enter a host. The blood meal ingested from an infected host thereby prevents super-infection by homologous spirochetes, while facilitating transmission of heterologous B. burgdorferi s.l. strains. This finding suggests that Lyme disease spirochete diversity is stably maintained within endemic populations in local geographic regions through frequency dependent selection of rare alleles of dominant polymorphic surface antigens. PMID- 29621351 TI - Spatial distribution of 12 class B notifiable infectious diseases in China: A retrospective study. AB - BACKGROUND: China is the largest developing country with a relatively developed public health system. To further prevent and eliminate the spread of infectious diseases, China has listed 39 notifiable infectious diseases characterized by wide prevalence or great harm, and classified them into classes A, B, and C, with severity decreasing across classes. Class A diseases have been almost eradicated in China, thus making class B diseases a priority in infectious disease prevention and control. In this retrospective study, we analyze the spatial distribution patterns of 12 class B notifiable infectious diseases that remain active all over China. METHODS: Global and local Moran's I and corresponding graphic tools are adopted to explore and visualize the global and local spatial distribution of the incidence of the selected epidemics, respectively. Inter correlations of clustering patterns of each pair of diseases and a cumulative summary of the high/low cluster frequency of the provincial units are also provided by means of figures and maps. RESULTS: Of the 12 most commonly notifiable class B infectious diseases, viral hepatitis and tuberculosis show high incidence rates and account for more than half of the reported cases. Almost all the diseases, except pertussis, exhibit positive spatial autocorrelation at the provincial level. All diseases feature varying spatial concentrations. Nevertheless, associations exist between spatial distribution patterns, with some provincial units displaying the same type of cluster features for two or more infectious diseases. Overall, high-low (unit with high incidence surrounded by units with high incidence, the same below) and high-high spatial cluster areas tend to be prevalent in the provincial units located in western and southwest China, whereas low-low and low-high spatial cluster areas abound in provincial units in north and east China. CONCLUSION: Despite the various distribution patterns of 12 class B notifiable infectious diseases, certain similarities between their spatial distributions are present. Substantial evidence is available to support disease-specific, location-specific, and disease-combined interventions. Regarding provinces that show high-high/high-low patterns of multiple diseases, comprehensive interventions targeting different diseases should be established. As to the adjacent provincial units revealing similar patterns, coordinated actions need to be taken across borders. PMID- 29621352 TI - Hypocomplementemia is associated with worse renal survival in ANCA-positive granulomatosis with polyangiitis and microscopic polyangiitis. AB - Recent data suggest the existence of a complement alternative pathway activation in the pathogenesis of antineutrophilic cytoplasmic antibody (ANCA)-associated vasculitis (AAV), a condition that remains poorly understood. This study aims to assess the clinical characteristics and outcomes of granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) patients with regard to their plasma complement levels at diagnosis. A retrospective monocentric study carried out at Caen University Hospital led to the identification of proteinase-3 or myeloperoxidase-ANCA-positive GPA and MPA patients from January 2000 to June 2016 and from September 2011 to June 2016, respectively. All patients with available C3 and C4 levels at diagnosis were included. Patients were categorized in the hypocomplementemia group if their C3 and/or C4 levels at diagnosis were below the lower limit of the normal range. Among the 76 AAV patients (43 GPA, 33 MPA), 4 (5%) had hypocomplementemia, and the 72 remaining patients exhibited normal plasma complement levels. All 4 hypocomplementemia patients had renal involvement. Hypocomplementemia was followed in 1 patient whose post-treatment complement level normalized within 1 month. Among all clinical and ANCA specificity, including relapse-free survival (p = 0.093), only overall and renal survival rates were significantly lower in the hypocomplementemia group (p = 0.0011 and p<0.001, respectively). Hypocomplementemia with low C3 and/or C4 levels at GPA or MPA diagnosis may be responsible for worse survival and renal prognosis. These results argue for larger and prospective studies to better determine the epidemiology of the disease and to assess complement-targeting therapy in these patients. PMID- 29621353 TI - Mid-life psychosocial work environment as a predictor of work exit by age 50. AB - OBJECTIVES: To examine whether psychosocial work characteristics at age 45 years predict exit from the labour market by the age of 50 years in data from the 1958 British Birth Cohort. METHODS: Psychosocial work characteristics (decision latitude, job demands, job strain and work social support at 45 years and job insecurity at 42 years) measured by questionnaire were linked to employment outcomes (unemployment, retirement, permanent sickness, homemaking) at 50 years in 6510 male and female participants. RESULTS: Low decision latitude (RR = 2.01, 95%CI 1.06,3.79), low work social support (RR = 1.96, 95%CI 1.12,3.44), and high job insecurity (RR = 2.27, 95%CI 1.41, 3.67) predicted unemployment at 50, adjusting for sex, housing tenure, socioeconomic status, marital status, and education. High demands were associated with lower risk of unemployment (RR = 0.50, 95%CI 0.29,0.88) but higher risk of permanent sickness (RR = 2.14, 95%CI 1.09,4.21). CONCLUSIONS: Keeping people in the workforce beyond 50 years may contribute to both personal and national prosperity. Employers may wish to improve working conditions for older workers, in particular, increase control over work, increase support and reduce demands to retain older employees in the workforce. PMID- 29621354 TI - Identifying high-risk individuals for lung cancer screening: Going beyond NLST criteria. AB - BACKGROUND: There are two main types of strategies to identify target population for lung cancer screening: 1) strategies based on age and cumulative smoking criteria, 2) risk prediction models allowing the calculation of an individual risk. The objective of this study was to compare different strategies to identify the proportion of the Spanish population at high risk of developing lung cancer, susceptible to be included in a lung cancer screening programme. METHODS: Cross sectional study. We used the data of the Spanish National Interview Health Survey (ENSE) of 2011-2012 (21,006 individuals) to estimate the proportion of participants at high risk of developing lung cancer. This estimation was performed using the U.S. national lung screening trial (NLST) criteria and a 6 year prediction model (PLCOm2012), both independently and in combination. RESULTS: The prevalence of individuals at high risk of developing lung cancer according to the NLST criteria was 4.9% (7.9% for men, 2.4% for women). Among the 1,034 subjects who met the NLST criteria, 533 (427 men and 106 women) had a 6 year lung cancer risk >=2.0%. The combination of these two selection strategies showed that 2.5% of the Spanish population had a high risk of developing lung cancer. However, this selection process did not take into account different groups of subjects <75 years old having an individual risk of lung cancer >=2%, such as heavy smokers <55 years old who were long-time former smokers, and ever smokers having smoked <30 pack-years with other risk factors. CONCLUSIONS: Further research is needed to determine which selection strategy achieves a higher benefit/harm ratio and to assess other prevention strategies for individuals with elevated risk for lung cancer but who do not meet the screening eligibility criteria. PMID- 29621355 TI - Participation of pregnant women in a community-based nutrition program in Mumbai's informal settlements: Effect on exclusive breastfeeding practices. AB - BACKGROUND: In urban Maharashtra, India, approximately half of mothers exclusively breastfeed. For children residing in informal settlements of Mumbai, this study examines factors associated with exclusive breastfeeding, and whether exclusive breastfeeding, in a community-based nutrition program to prevent and treat wasting among children under age three, is associated with enrolment during the mother's pregnancy. METHODS: The nutrition program conducted a cross sectional endline survey (October-December 2015) of caregivers in intervention areas. Factors associated with exclusive breastfeeding for infants under six months of age were explored using multi-level logistic regressions. Additionally, program surveillance data collected during home-based counselling visits documented breastfeeding practices for children under six months of age. Using the surveillance data (January 2014-March 2016), exclusive breastfeeding status was regressed adjusting for child, maternal and socioeconomic characteristics, and whether the child was enrolled in the program in utero or after birth. RESULTS: The community-based endline survey included 888 mothers of infants. Mothers who received the nutrition program home visits or attended group counselling sessions were more likely to exclusively breastfeed (adjusted odds ratio 1.67, 95% CI 1.16, 2.41). Having a normal weight-for-height z-score (adjusted odds ratio 1.57, 95% CI 1.00, 2.45) was associated positively with exclusive breastfeeding. As expected, being an older infant aged three to five months (adjusted odds ratio 0.34, 95% CI 0.25, 0.48) and receiving a prelacteal feed after birth (adjusted odds ratio 0.57, 95% CI 0.41, 0.80) were associated with lower odds of exclusively breastfeeding. Surveillance data (N = 3420) indicate that infants enrolled in utero have significantly higher odds of being exclusively breastfed (adjusted odds ratio 1.55, 95% CI 1.30, 1.84) than infants enrolled after birth. CONCLUSIONS: Prenatal enrolment in community-based programs working on child nutrition in urban informal settlements of India can improve exclusive breastfeeding practices. PMID- 29621356 TI - Quantifying the three-dimensional facial morphology of the laboratory rat with a focus on the vibrissae. AB - The morphology of an animal's face will have large effects on the sensory information it can acquire. Here we quantify the arrangement of cranial sensory structures of the rat, with special emphasis on the mystacial vibrissae (whiskers). Nearly all mammals have vibrissae, which are generally arranged in rows and columns across the face. The vibrissae serve a wide variety of important behavioral functions, including navigation, climbing, wake following, anemotaxis, and social interactions. To date, however, there are few studies that compare the morphology of vibrissal arrays across species, or that describe the arrangement of the vibrissae relative to other facial sensory structures. The few studies that do exist have exploited the whiskers' grid-like arrangement to quantify array morphology in terms of row and column identity. However, relying on whisker identity poses a challenge for comparative research because different species have different numbers and arrangements of whiskers. The present work introduces an approach to quantify vibrissal array morphology regardless of the number of rows and columns, and to quantify the array's location relative to other sensory structures. We use the three-dimensional locations of the whisker basepoints as fundamental parameters to generate equations describing the length, curvature, and orientation of each whisker. Results show that in the rat, whisker length varies exponentially across the array, and that a hard limit on intrinsic curvature constrains the whisker height-to-length ratio. Whiskers are oriented to "fan out" approximately equally in dorsal-ventral and rostral-caudal directions. Quantifying positions of the other sensory structures relative to the whisker basepoints shows remarkable alignment to the somatosensory cortical homunculus, an alignment that would not occur for other choices of coordinate systems (e.g., centered on the midpoint of the eyes). We anticipate that the quantification of facial sensory structures, including the vibrissae, will ultimately enable cross species comparisons of multi-modal sensing volumes. PMID- 29621357 TI - Oncolytic effect of wild-type Newcastle disease virus isolates in cancer cell lines in vitro and in vivo on xenograft model. AB - Oncolyic virotherapy is one of the modern experimental techniques to treat human cancers. Here we studied the antitumor activity of wild-type Newcastle disease virus (NDV) isolates from Russian migratory birds. We showed that NDV could selectively kill malignant cells without affecting healthy cells. We evaluated the oncolytic effect of 44 NDV isolates in 4 histogenetically different human cell lines (HCT116, HeLa, A549, MCF7). The safety of the isolates was also tested in normal peripheral blood mononuclear (PBMC) cells. The viability of tumor cell lines after incubation with NDV isolates was evaluated by MTT. All cell lines, except for normal PBMC primary cells, had different degrees of susceptibility to NDV infection. Seven NDV strains had the highest oncolytic activity, and some NDV strains demonstrated oncolytic selectivity for different cell lines. In vivo, we described the intratumoral activity of NDV/Altai/pigeon/770/2011 against subcutaneous non-small cell lung carcinoma using xenograft SCID mice model. All animals were responsive to therapy. Histology confirmed therapy-induced destructive changes and growing necrotic bulk density in tumor tissue. Our findings indicate that wild-type NDV strains selectively kill tumor cells with no effect on healthy PBMC cells, and intratumoral virotherapy with NDV suppresses the subcutaneous tumor growth in SCID mice. PMID- 29621358 TI - Metabolomics: Eavesdropping on silent conversations between hosts and their unwelcome guests. PMID- 29621359 TI - Applying chlorogenic acid in an alginate scaffold of chondrocytes can improve the repair of damaged articular cartilage. AB - Damaged cartilage has very low regenerative potential which has led to the search for novel tissue-engineering approaches to help treat cartilage defects. While various approaches have been reported, there is no perfect treatment currently. In this study we evaluated the effects of a plant extract, chlorogenic acid (CGA), as part of chondrocyte transplantation on a model of knee joint injury in chicks. First, primary cultured chondrocytes used to evaluate the effects of CGA on chondrogenesis. Then using an articular cartilage injury model of chick knee we assessed the functional recovery after transplantation of the complexes containing chondrocytes and CGA in an alginate scaffold. Histological analysis, PCR, and western blot were further used to understand the underlying mechanisms. We showed that 60 MUM CGA in alginate exhibited notable effects on stimulating chondrogenesis in vitro. Secondly, it was shown that the application of these complexes accelerated the recovery of injury-induced dysfunction by gait analysis when followed for 21 days. Histochemical analysis demonstrated that there was less abnormal vasculature formation, more chondrocyte proliferation and cartilage matrix synthesis in the presence of the complexes containing CGA. We discovered CGA treated transplantation up-regulated the expressions of Sox9 and Col2a1 which were responsible for the stimulation of chondrogenesis. Furthermore, the application of these complexes could suppress the abnormal angiogenesis and fibrosis at the injury site. Lastly, the elevated levels of inflammatory cytokines IL-1beta, TNF-alpha, p-p65, and MMPs expression were decreased in the presence of CGA. This may be caused through adjusting cellular redox homeostasis associated with Nrf2. This study suggests that combining chondrocytes and CGA on an alginate scaffold can improve the recovery of damaged articular cartilage. PMID- 29621360 TI - The combination of Cassia obtusifolia L. and Foeniculum vulgare M. exhibits a laxative effect on loperamide-induced constipation of rats. AB - Chronic constipation is a functional gastrointestinal disease that is detrimental to the quality of patient life. Cassia obtusifolia L. (CO) and Foeniculum vulgare M. (FV) are commonly used as medicinal foods in many countries. We aimed to examine the laxative effect and their underlying mechanism of CO and FV mixture on loperamide (lop)-induced constipated rats. To determine the laxative effects of these compounds, Sprague-Dawley rats were divided into six groups: the control, lop-induced constipated (2mg/kg), and three doses (100, 300, and 500mg/kg) of CO and FV mixture-, and Bisacodyl (bis, 3.3mg/kg)-treated groups. The mixture of CO and FV and bis were orally administered once a day for 4 weeks. For induction of constipation, the lop were treated with a dose of 2 mg/kg twice a day on the 3rd week after treatments of CO and FV extracts and bis. The results were revealed that the CO and FV mixture has the laxative effects more than those in CO and FV-alone treatments on constipated rats by determining the stool parameters, including stool number and weight. Indeed, stool parameters, such as, stool number, weight, and water contents and colonic peristalsis from the intestinal transit length and ratio were dramatically improved by CO and FV mixture treatment. Histological study also revealed that CO and FV mixture enhanced the thicknesses of mucosa and muscular layers of the colon in constipated rats. For their underlying mechanism, the mRNAs and proteins expression of muscarinic acetylcholine receptors (mAchR) M2 and M3 and their downstream signaling were preserved by CO and FV mixture treatment in constipated rats. Therefore, this study suggests that treatment with CO and FV mixture has beneficial effects against constipation. We further suggest that CO and FV mixture may be utilized as an alternative therapeutic strategy for constipation. PMID- 29621363 TI - Ultra-Widefield Angiography With Oral Fluorescein in Pediatric Patients With Retinal Disease. PMID- 29621361 TI - Optimal linguistic expression in negotiations depends on visual appearance. AB - We investigate the influence of the visual appearance of a negotiator on persuasiveness within the context of negotiations. Psychological experiments were conducted to quantitatively analyze the relationship between visual appearance and the use of language. Male and female participants were shown three female and male photographs, respectively. They were asked to report how they felt about each photograph using a seven-point semantic differential (SD) scale for six affective factors (positive impression, extraversion, intelligence, conscientiousness, emotional stability, and agreeableness). Participants then answered how they felt about each negotiation scenario (they were presented with pictures and a situation combined with negotiation sentences) using a seven-point SD scale for seven affective factors (positive impression, extraversion, intelligence, conscientiousness, emotional stability, agreeableness, and degree of persuasion). Two experiments were conducted using different participant groups depending on the negotiation situations. Photographs with good or bad appearances were found to show high or low degrees of persuasion, respectively. A multiple regression equation was obtained, indicating the importance of the three language factors (euphemistic, honorific, and sympathy expressions) to impressions made during negotiation. The result shows that there are optimal negotiation sentences based on various negotiation factors, such as visual appearance and use of language. For example, persons with good appearance might worsen their impression during negotiations by using certain language, although their initial impression was positive, and persons with bad appearance could effectively improve their impressions in negotiations through their use of language, although the final impressions of their negotiation counterpart might still be more negative than those for persons with good appearance. In contrast, the impressions made by persons of normal appearance were not easily affected by their use of language. The results of the present study have significant implications for future studies of effective negotiation strategies considering visual appearance as well as gender. PMID- 29621362 TI - Long-term Accuracy of Breast Cancer Risk Assessment Combining Classic Risk Factors and Breast Density. AB - Importance: Accurate long-term breast cancer risk assessment for women attending routine screening could help reduce the disease burden and intervention associated harms by personalizing screening recommendations and preventive interventions. Objective: To report the accuracy of risk assessment for breast cancer during a period of 19 years. Design, Setting, and Participants: This cohort study of the Kaiser Permanente Washington breast imaging registry included women without previous breast cancer, aged 40 to 73 years, who attended screening from January 1, 1996, through December 31, 2013. Follow-up was completed on December 31, 2014, and data were analyzed from March 2, 2016, through November 13, 2017. Exposures: Risk factors from a questionnaire and breast density from the Breast Imaging and Reporting Data System at entry; primary risk was assessed using the Tyrer-Cuzick model. Main Outcomes and Measures: Incidence of invasive breast cancer was estimated with and without breast density. Follow-up began 6 months after the entry mammogram and extended to the earliest diagnosis of invasive breast cancer, censoring at 75 years of age, 2014, diagnosis of ductal carcinoma in situ, death, or health plan disenrollment. Observed divided by expected (O/E) numbers of cancer cases were compared using exact Poisson 95% CIs. Hazard ratios for the top decile of 10-year risk relative to the middle 80% of the study population were estimated. Constancy of relative risk calibration during follow-up was tested using a time-dependent proportional hazards effect. Results: In this cohort study of 132 139 women (median age at entry, 50 years; interquartile range, 44-58 years), 2699 invasive breast cancers were subsequently diagnosed after a median 5.2 years of follow-up (interquartile range, 2.4-11.1 years; maximum follow-up, 19 years; annual incidence rate [IR] per 1000 women, 2.9). Observed number of cancer diagnoses was close to the expected number (O/E for the Tyrer-Cuzick model, 1.02 [95% CI, 0.98-1.06]; O/E for the Tyrer-Cuzick model with density, 0.98 [95% CI, 0.94-1.02]). The Tyrer-Cuzick model estimated 2554 women (1.9%) to be at high risk (10-year risk of >=8%), of whom 147 subsequently developed invasive breast cancer (O/E, 0.79; 95% CI, 0.67-0.93; IR per 1000 women, 8.7). The Tyrer-Cuzick model with density estimated more women to be at high risk (4645 [3.5%]; 273 cancers [10.1%]; O/E, 0.78; 95% CI, 0.69-0.88; IR per 1000 women, 9.2). The hazard ratio for the highest risk decile compared with the middle 80% was 2.22 (95% CI, 2.02-2.45) for the Tyrer-Cuzick model and 2.55 (95% CI, 2.33-2.80) for the Tyrer-Cuzick model with density. Little evidence was found for a decrease in relative risk calibration throughout follow-up for the Tyrer-Cuzick model (age-adjusted slope, -0.003; 95% CI, -0.018 to 0.012) or the Tyrer-Cuzick model with density (age-adjusted slope, -0.008; 95% CI, -0.020 to 0.004). Conclusions and Relevance: Breast cancer risk assessment combining classic risk factors with mammographic density may provide useful data for 10 years or more and could be used to guide long-term, systematic, risk-adapted screening and prevention strategies. PMID- 29621364 TI - A Child's Complaint of "Throat Freeze"-Not Brain Freeze-and Experiences With Zenker Diverticulum. PMID- 29621366 TI - Avoid Compromises in the Current Opioid Crisis, Using Cautious but Confident Patient Care. PMID- 29621365 TI - Association of Hypovitaminosis D With Increased Risk of Uveitis in a Large Health Care Claims Database. AB - Importance: Understanding the role of vitamin D-which regulates inflammatory responses-in noninfectious uveitis (an inflammatory disease) may provide insight into treatment and prevention of this disease. Objective: To investigate whether there is an association between hypovitaminosis D and incident noninfectious uveitis. Design, Setting, and Participants: In a retrospective case-control study, data from a health care claims database containing deidentified medical claims from a large private insurer were used to identify 558 adults enrolled from January 1, 2000, to December 31, 2016, who received a diagnosis of noninfectious uveitis from an eye care clinician (with receipt of a confirmatory diagnosis within 120 days of the initial diagnosis) and who had a vitamin D level measured within 1 year before the first diagnosis. Exclusion criteria included having systemic disease or receiving medication known to lower vitamin D levels, having undergone intraocular surgery, and having infectious uveitis. Each case patient was matched with 5 controls on the basis of age, sex, race/ethnicity, and index date (2790 controls). The controls had vitamin D level determined either within 1 year before or within 6 months after receiving an eye examination with normal findings. Multiple logistic regression models were used to examine the association between hypovitaminosis D and noninfectious uveitis. Main Outcomes and Measures: The primary, prespecified analysis assessed the association of noninfectious uveitis with hypovitaminosis D (vitamin D level <=20 ng/mL). Results: The 558 cases and 2790 controls were matched on age, and each group had a mean (SD) age of 58.9 (14.7) years. Among the cohort of 3348 patients, 2526 (75.4%) were female, and the racial/ethnic distribution in the matched samples was 2022 (60.4%) white, 552 (16.5%) black, 402 (12.0%) Hispanic, 162 (4.8%) Asian, and 210 (6.3%) unknown. Patients with normal vitamin D levels had 21% lower odds of having noninfectious uveitis than patients with low vitamin D levels (odds ratio [OR], 0.79; 95% CI, 0.62-0.99; P = .04). In a race-stratified analysis, an association between vitamin D and uveitis was found in black patients (OR, 0.49; 95% CI, 0.30-0.80; P = .004) and was qualitatively similar but nonsignificant in white patients (OR, 0.87; 95% CI, 0.62-1.21; P = .40) and Hispanic patients (OR, 0.60; 95% CI, 0.33-1.10; P = .10). Conclusions and Relevance: This and other reports have found an association between hypovitaminosis D and noninfectious uveitis. However, these studies cannot establish a causal relationship. Prospective studies are warranted to evaluate whether hypovitaminosis D causes increased risk of uveitis and the role of vitamin D supplementation in prevention and treatment of uveitis. PMID- 29621367 TI - Uveal Mass, Uveitis, and Diffuse Rash in a Woman in Her 50s. PMID- 29621368 TI - Survival Outcomes for Patients With T3N0M0 Squamous Cell Carcinoma of the Glottic Larynx. PMID- 29621369 TI - Visual Disturbance in a Middle-aged Woman With Non-Small Cell Lung Cancer. PMID- 29621370 TI - Avoid Compromises in the Current Opioid Crisis, Using Cautious but Confident Patient Care-Reply. PMID- 29621371 TI - Auricular Swelling After Mild Trauma. PMID- 29621373 TI - Ophthalmoscopy and Telemedicine in Retinopathy of Prematurity. PMID- 29621372 TI - Outcomes From Lateral Eyelid Coupling for Facial Paralysis Using the Modified Tarsoconjunctival Flap. AB - Importance: In the setting of facial paralysis, inadequate eyelid closure and lower eyelid ectropion can lead to corneal exposure and impaired quality of life. Repair of paralytic ectropion is challenging, and an ideal surgical approach for all cases has not been identified. Objective: To assess the patient-reported outcomes and eyelid position improvement in patients with flaccid facial paralysis undergoing lateral eyelid coupling with a tarsal strip canthoplasty and modified tarsoconjunctival flap to correct eyelid malposition. Design, Setting, and Participants: Review of medical records of adults with flaccid facial paralysis who underwent a single-stage tarsal strip canthoplasty and modified tarsoconjunctival flap at a tertiary academic center. Inclusion criteria included a minimum of 3 months of follow-up. Intervention: The lateral upper and lower eyelid are coupled with the hybrid tarsoconjunctival flap. Main Outcomes and Measures: Patient-reported outcome measures and objective photograph analysis. Preoperative and postoperative Facial Clinimetric Evaluation (FaCE) scores and Moe Ectropion Grading Scale scores were compared. The relationship between radiation therapy (RT) and outcomes was analyzed. Results: Sixteen patients (8 [50%] female; mean [SD] age at surgery, 71.5 [9.6] years) were identified between January 2014 and August 2017. Twelve (75%) had paralysis from facial nerve sacrifice during cancer ablation. The mean time between paralysis and referral for surgical repair of ectropion was 23 months (range, 0-151 months) and mean follow-up after surgery was 9.8 months (range, 3-39 months). The most common symptom was epiphora, which was significantly reduced after surgery (75% vs 25%; P = .01). Median Moe Ectropion Grading Scale score improved from 3 (interquartile range, 2-3) to 0 (interquartile range, 0-1; P < .001). Quality of life measured using the FaCE scale demonstrated a significant improvement in mean eye comfort (from 18.8 [95% CI, 2.3-35.2] to 47.9 [95% CI, 31.9-63.9]; P = .01) and lacrimal control scores (from 12.5 [95% CI, 0-29.2] to 45.8 [95% CI, 29.3-62.3]; P = .03) in the 6 patients in the RT group, but no difference in the 4 patients in the non RT group. Conclusions and Relevance: Ocular symptoms, eyelid appearance, and quality of life were improved after lateral eyelid coupling among patients with flaccid facial paralysis and paralytic ectropion. The tarsoconjunctival flap does limit peripheral vision, but is reversible if dynamic eyelid closure is returned with nerve grafting. Level of Evidence: 4. PMID- 29621374 TI - Novel Use of a Volumizing Hyaluronic Acid Filler for Treatment of Infraorbital Hollows. AB - Importance: Hyaluronic acid filler can be safely used as a soft-tissue filler for correction of infraorbital hollowing. It has a high overall patient satisfaction profile among patients. Objective: To report safety and patient satisfaction outcomes of Juvederm Voluma XC for correction of infraorbital hollows. Design, Setting, and Patients: This was a retrospective observational study performed at a private ambulatory facial plastic and reconstructive surgery practice. Participants were all patients 21 to 85 years old who presented to our practice and underwent Juvederm Voluma XC treatment for correction of infraorbital hollows as a singular intervention from February 2016 to March 2017. Interventions: Injection of Juvederm Voluma XC to the tear trough, nasojugal fold, and/or palpebromalar groove. Main Outcomes and Measures: Primary outcome measures include the number of recorded short- and long-term adverse events, need for additional treatment, and patient questionnaire FACE-Q scores. Results: A total of 202 eyes were treated in 101 patients with a mean follow-up of 12 months. Patients were principally female (90 [89%]) with an average age of 54 years (range, 21-85 years). Most patients (99) had Fitzpatrick grade 1 to 4 skin type (98%) and had an infraorbital hollows score of 2 to 4 (89 [88%]). The average initial treatment volume was 1 mL with 18 patients (18%) requiring additional treatment within 3 months. The average time until additional treatment was 35.7 days. Adverse effects include bruising (in 10 [10%], contour irregularities (2 [2%]), swelling (3 [3%]), and Tyndall effect (1 [1%]). Hyaluronidase was required in 3 patients (3%). Forty-one patients completed the FACE-Q Satisfaction With Eyes survey, and 42 patients completed the FACE-Q Satisfaction With Decision survey (41% and 42%). Overall mean (SD) patient satisfaction (based on FACE-Q scores) was 71.1% (27.3) and 65.6% (31.3), respectively. Conclusions and Relevance: Juvederm Voluma XC has a high patient satisfaction profile and an acceptable safety profile for the correction of infraorbital hollowing. Level of Evidence: 4. PMID- 29621375 TI - Findings Linking Mismatch Repair Mutation With Age at Endometrial and Ovarian Cancer Onset in Lynch Syndrome-Reply. PMID- 29621376 TI - Management of Metastatic Melanoma in 2018. PMID- 29621377 TI - Thyroidosis Mistaken for Thyroid Cancer. PMID- 29621378 TI - Oral Ketamine vs Placebo in Patients With Cancer-Related Neuropathic Pain: A Randomized Clinical Trial. PMID- 29621379 TI - Fluorescein Angiographic Characteristics of Macular Edema During Infancy. AB - Importance: Macular edema during infancy, a subclinical feature identified in premature infants by handheld spectral-domain optical coherence tomography (SD OCT), has been associated with poorer visual acuity and neurodevelopmental outcomes. Features of macular edema on fluorescein angiography (FA) are needed to understand its pathophysiology, but to date have not been reported previously. Objective: To investigate the FA features of macular edema during infancy. Design, Setting, and Participants: A retrospective review was conducted of 8 infants at Duke Eye Center who received simultaneous SD-OCT and FA imaging from July 1, 2011, to June 30, 2017. Research and clinical care images were obtained during examination of the infants under anesthesia or at the bedside in the neonatal intensive care unit. Main Outcomes and Measures: Side-to-side comparison of research handheld SD-OCT images and clinically indicated FA. Results: Imaging was conducted at a mean (SD) of 42.8 (4.2) weeks' postmenstruation age in the 8 infants (1 [13%] female; 2 [25%] African American; 6 [75%] white). Examination of the FA and SD-OCT images found (1) no macular fluorescein leakage in 3 eyes of 2 infants with retinopathy of prematurity without macular edema and 1 eye with a single cyst, (2) equivocal fluorescein leakage in 2 eyes of 1 infant with mild macular edema, (3) late macular fluorescein leakage in 4 eyes of 2 infants with moderate to severe macular edema, and (4) macular fluorescein leakage from posterior preretinal neovascularization in the macula in 4 eyes of 3 infants with retinopathy of prematurity without macular edema. Conclusions and Relevance: This observation of fluorescein leakage in 4 infant eyes with macular edema provides new insights into the possible mechanisms of this subclinical finding. Macular fluorescein leakage could indicate a breakdown or delayed maturation of the blood retinal barrier or dysfunction of the retinal pigment epithelium. Furthermore, the cross-sectional OCT view aids in identifying preretinal neovascularization, which can also cause focal macular leakage in these infants. This new perspective may improve our understanding and potentially guide future treatments of premature infants with subnormal vision. PMID- 29621381 TI - Clinical Trials in Medical Center Advertising. PMID- 29621380 TI - Association of Muscle and Adiposity Measured by Computed Tomography With Survival in Patients With Nonmetastatic Breast Cancer. AB - Importance: Sarcopenia (low muscle mass), poor muscle quality (low muscle radiodensity), and excess adiposity derived from computed tomography (CT) has been related to higher mortality in patients with metastatic breast cancer, but the association with prognosis in patients with nonmetastatic breast cancer is unknown. Objective: To evaluate associations of all 3 body composition measures, derived from clinically acquired CT at diagnosis, with overall mortality in nonmetastatic breast cancer. Design, Setting, and Participants: This observational study included 3241 women from Kaiser Permanente of Northern California and Dana Farber Cancer Institute diagnosed from January 2000 to December 2013 with stages II or III breast cancer. We calculated hazard ratios (HRs) to evaluate the associations of all-cause mortality with sarcopenia, low muscle radiodensity, and total adipose tissue (TAT). Models were adjusted for sociodemographics, tumor characteristics, treatment, body mass index (BMI; calculated as weight in kilograms divided by height in meters squared), and other body composition measures. We also evaluated the cross-classification of categories of sarcopenia (yes/no) and tertiles of TAT, with outcomes. Main Outcomes and Measures: Overall survival time and all-cause mortality. Results: Median (range) age of 3241 women included in this study was 54 (18-80) years, and median follow-up was 6.0 years; 1086 patients (34%) presented with sarcopenia, and 1199 patients (37%) had low muscle radiodensity. Among patients with nonmetastatic breast cancer, those with sarcopenia showed higher overall mortality (HR, 1.41; 95% CI, 1.18-1.69) compared with those without sarcopenia. Patients in the highest tertile of TAT also showed higher overall mortality (HR, 1.35; 95% CI, 1.08-1.69) compared with those in the lowest tertile. Low radiodensity was not associated with survival. In analyses of sarcopenia and TAT, highest mortality was seen in patients with sarcopenia and high TAT (HR, 1.89; 95% CI, 1.30-2.73); BMI alone was not significantly related to overall mortality and did not appropriately identify patients at risk of death owing to their body composition. Conclusions and Relevance: Sarcopenia is underrecognized in nonmetastatic breast cancer and occurs in over one-third of newly diagnosed patients. Measures of both sarcopenia and adiposity from clinically acquired CT scans in nonmetastatic patients provide significant prognostic information that outperform BMI and will help to guide interventions to optimize survival outcomes. PMID- 29621382 TI - Survival Outcomes for Patients With T3N0M0 Squamous Cell Carcinoma of the Glottic Larynx-Reply. PMID- 29621383 TI - Obesity, Body Composition, and Breast Cancer: An Evolving Science. PMID- 29621385 TI - The effects of red surrounds on visual magnocellular and parvocellular cortical processing and perception. AB - More than 50 years ago, Hubel and Wiesel identified a subpopulation of geniculate magnocellular (M) neurons that are suppressed by diffuse red light. Since then, many human psychophysical studies have used red and green backgrounds to study the effects of M suppression on visual task performance, as a means to better understand neurodevelopmental disorders such as dyslexia and schizophrenia. Few of these studies have explicitly assessed the relative effects of red backgrounds on the M and P (parvocellular) pathways. Here we compared the effects of red and green diffuse background illumination on well-accepted cortical M and P signatures, both physiologically through nonlinear analysis of visual evoked potentials (VEPs; N = 15), and psychophysically through pulsed and steady pedestal perceptual thresholds (N = 9 with gray pedestals and N = 8 with colored pedestals). Red surrounds reduced P-generated temporal nonlinearity in the VEPs, but they did not influence M-generated VEP signatures. The steady and pulsed pedestal results suggest that red surrounds can have different effects on M and P contrast sensitivities, depending on whether the target is colored gray or red, presented centrally or peripherally, or whether it is brighter or dimmer than the surround. Our results highlight difficulties in interpreting the effects of red backgrounds on human VEPs or perception in terms of M specific suppression. PMID- 29621386 TI - Trans-saccadic integration of orientation information. AB - Does visual processing start anew after each eye movement, or is information integrated across saccades? Here we test a strong prediction of the integration hypothesis: that information acquired after a saccade interferes with the perception of images acquired before the saccade. We investigate perception of a basic visual feature, grating orientation, and we take advantage of a delayed interference phenomenon-in human participants, the reported orientation of a target grating, briefly presented at an eccentric location, is strongly biased toward the orientation of flanker gratings that are flashed shortly after the target. Crucially, we find that the effect is the same whether or not a saccade is made during the delay interval even though the eye movement produces a large retinotopic separation between target and flankers. However, the trans-saccadic effect nearly vanishes when flankers are displaced to a different screen location even when this location matches the retinotopic coordinates of the target. We conclude that information about grating orientation is integrated across saccades within a spatial region that is defined in external coordinates and thereby is stable in spite of the movement of the eyes. PMID- 29621384 TI - Binocular summation for reflexive eye movements. AB - Psychophysical studies and our own subjective experience suggest that, in natural viewing conditions (i.e., at medium to high contrasts), monocularly and binocularly viewed scenes appear very similar, with the exception of the improved depth perception provided by stereopsis. This phenomenon is usually described as a lack of binocular summation. We show here that there is an exception to this rule: Ocular following eye movements induced by the sudden motion of a large stimulus, which we recorded from three human subjects, are much larger when both eyes see the moving stimulus, than when only one eye does. We further discovered that this binocular advantage is a function of the interocular correlation between the two monocular images: It is maximal when they are identical, and reduced when the two eyes are presented with different images. This is possible only if the neurons that underlie ocular following are sensitive to binocular disparity. PMID- 29621388 TI - Findings Linking Mismatch Repair Mutation With Age at Endometrial and Ovarian Cancer Onset in Lynch Syndrome. PMID- 29621387 TI - Diagnostic Accuracy of Ophthalmoscopy vs Telemedicine in Examinations for Retinopathy of Prematurity. AB - Importance: Examinations for retinopathy of prematurity (ROP) are typically performed using binocular indirect ophthalmoscopy. Telemedicine studies have traditionally assessed the accuracy of telemedicine compared with ophthalmoscopy as a criterion standard. However, it is not known whether ophthalmoscopy is truly more accurate than telemedicine. Objective: To directly compare the accuracy and sensitivity of ophthalmoscopy vs telemedicine in diagnosing ROP using a consensus reference standard. Design, Setting, and Participants: This multicenter prospective study conducted between July 1, 2011, and November 30, 2014, at 7 neonatal intensive care units and academic ophthalmology departments in the United States and Mexico included 281 premature infants who met the screening criteria for ROP. Exposures: Each examination consisted of 1 eye undergoing binocular indirect ophthalmoscopy by an experienced clinician followed by remote image review of wide-angle fundus photographs by 3 independent telemedicine graders. Main Outcomes and Measures: Results of both examination methods were combined into a consensus reference standard diagnosis. The agreement of both ophthalmoscopy and telemedicine was compared with this standard, using percentage agreement and weighted kappa statistics. Results: Among the 281 infants in the study (127 girls and 154 boys; mean [SD] gestational age, 27.1 [2.4] weeks), a total of 1553 eye examinations were classified using both ophthalmoscopy and telemedicine. Ophthalmoscopy and telemedicine each had similar sensitivity for zone I disease (78% [95% CI, 71%-84%] vs 78% [95% CI, 73%-83%]; P > .99 [n = 165]), plus disease (74% [95% CI, 61%-87%] vs 79% [95% CI, 72%-86%]; P = .41 [n = 50]), and type 2 ROP (stage 3, zone I, or plus disease: 86% [95% CI, 80%-92%] vs 79% [95% CI, 75%-83%]; P = .10 [n = 251]), but ophthalmoscopy was slightly more sensitive in identifying stage 3 disease (85% [95% CI, 79%-91%] vs 73% [95% CI, 67%-78%]; P = .004 [n = 136]). Conclusions and Relevance: No difference was found in overall accuracy between ophthalmoscopy and telemedicine for the detection of clinically significant ROP, although, on average, ophthalmoscopy had slightly higher accuracy for the diagnosis of zone III and stage 3 ROP. With the caveat that there was variable accuracy between examiners using both modalities, these results support the use of telemedicine for the diagnosis of clinically significant ROP. PMID- 29621389 TI - Increasing Naloxone Awareness and Use: The Role of Health Care Practitioners. PMID- 29621390 TI - Association of Myopia With Peripapillary Perfused Capillary Density in Patients With Glaucoma: An Optical Coherence Tomography Angiography Study. AB - Importance: This study used optical coherence tomographic angiography to assess for impaired blood flow in myopic eyes with or without open-angle glaucoma. Objective: To compare the peripapillary perfused capillary density (PCD) between eyes with and without glaucoma. Design, Setting, and Participants: In this cross sectional study at a tertiary glaucoma referral practice, we recruited patients with myopic eyes of spherical equivalent of more than -3.0 diopters with and without open-angle glaucoma, patients with nonmyopic eyes with glaucoma, and patients with no disease from February 2016 to October 2016. We obtained 4.5 * 4.5-mm optical coherence tomographic angiography images of the optic nerve head and calculated PCD as the ratio of pixels associated with capillaries to the number of pixels in the region of interest after large blood vessel removal. Both eyes of each patient were used in the analysis. Continuous variables were assessed by analysis of variance and Tukey tests. A marginal model of generalized estimating equations was performed to adjust for confounding factors and intraclass correlations. Main Outcomes and Measures: Mean PCD. Results: We matched 87 patients with myopic eyes with glaucoma (of whom 39 [45%] were women), 17 with myopic eyes without glaucoma (of whom 10 [59%] were women), and 93 with non-myopic eyes with glaucoma (of whom 55 [59%] were women) for visual field defects and included 51 control participants (or whom 38 [75%] were women). Mean (SD) ages were 67.5 (12.0) years for patients with myopia and glaucoma, 48.2 (19.0) years for those with myopia without glaucoma, 67.3 (11.0) years for those with glaucoma without myopia, and 64.7 (8.9) years in control participants. Global PCD demonstrated a progressive decrease from the control group (mean [SD], 41.0 [4.2]) to those with myopia without glaucoma (38.4 [5.8]) to those with glaucoma without myopia (31.9 [7.5]) to those with both (28.2 [6.0]; all P < .001). The mean difference in global PCD between the 3 groups and control group, adjusted for age and axial length, was greatest in those with myopia and glaucoma (-11.1; 95% CI, -14.0 to -8.1; P < .001), followed by those with glaucoma without myopia (-8.6; 95% CI, -10.9 to -6.3; P < .001) and those with myopia without glaucoma (-2.8; 95% CI, -6.9 to 1.2; P = .17). No interaction was found between glaucoma and myopia. Conclusions and Relevance: These findings demonstrate peripapillary microvascular attenuation to a greater extent in open-angle glaucoma than myopia. The cross-sectional design means we cannot determine if this association is a cause and/or is associated with other confounding factors. PMID- 29621391 TI - Findings Linking Mismatch Repair Mutation With Age at Endometrial and Ovarian Cancer Onset in Lynch Syndrome. PMID- 29621392 TI - Life Experience of Patients With Unilateral Vocal Fold Paralysis. AB - Importance: Clinicians and patients benefit when they have a clear understanding of how medical conditions influence patients' life experiences. Patients' perspectives on life with unilateral vocal fold paralysis have not been well described. Objective: To promote patient-centered care by characterizing the patient experiences of living with unilateral vocal fold paralysis. Design, Setting, and Participants: This study used mixed methods: surveys using the voice and dysphagia handicap indexes (VHI and DHI) and semistructured interviews with adults with unilateral vocal cord paralysis recruited from a tertiary voice center. Recorded interviews were transcribed, coded using a hierarchical coding system, and analyzed using an iterative inductive-deductive approach. Main Outcomes and Measures: Symptom domains of the patient experience. Results: In 36 patients (26 [72%] were female, and the median age and interquartile range [IQR] were 63 years [48-68 years]; median interview duration, 42 minutes), median VHI and DHI scores were 96 (IQR, 77-108) and 55.5 (IQR, 35-89) at the time of interviews, respectively. Frustration, isolation, fear, and altered self-identity were primary themes permeating patients' experiences. Frustrations related to limitations in communication, employment, and the medical system. Sources of fear included a loss of control, fear of further dysfunction or permanent disability, concern for health consequences (eg, aspiration pneumonia), and/or an inability to call for help in emergency situations. These experiences were modified by the following factors: resilience, self-efficacy, perceived sense of control, and social support systems. Conclusions and Relevance: Effects of unilateral vocal fold paralysis extend beyond impaired voice and other somatic symptoms. Awareness of the extent to which these patients experience frustration, isolation, fear, and altered self-identity is important. A patient-centered approach to optimizing unilateral vocal fold paralysis treatment is enhanced by an understanding of both the physical dimension of this condition and how patients cope with the considerable emotional and social consequences. Recognizing the psychosocial dimensions of disease allows clinicians to communicate more effectively, be more empathetic, and to better personalize treatment plans, which may lead to improved patient care and patient satisfaction. PMID- 29621393 TI - The 'PhenoBox', a flexible, automated, open-source plant phenotyping solution. AB - There is a need for flexible and affordable plant phenotyping solutions for basic research and plant breeding. We demonstrate our open source plant imaging and processing solution ('PhenoBox'/'PhenoPipe') and provide construction plans, source code and documentation to rebuild the system. Use of the PhenoBox is exemplified by studying infection of the model grass Brachypodium distachyon by the head smut fungus Ustilago bromivora, comparing phenotypic responses of maize to infection with a solopathogenic Ustilago maydis (corn smut) strain and effector deletion strains, and studying salt stress response in Nicotiana benthamiana. In U. bromivora-infected grass, phenotypic differences between infected and uninfected plants were detectable weeks before qualitative head smut symptoms. Based on this, we could predict the infection outcome for individual plants with high accuracy. Using a PhenoPipe module for calculation of multi dimensional distances from phenotyping data, we observe a time after infection dependent impact of U. maydis effector deletion strains on phenotypic response in maize. The PhenoBox/PhenoPipe system is able to detect established salt stress responses in N. benthamiana. We have developed an affordable, automated, open source imaging and data processing solution that can be adapted to various phenotyping applications in plant biology and beyond. PMID- 29621394 TI - Stability and Antimicrobial Activity of Nisin-Loaded Mesoporous Silica Nanoparticles: A Game-Changer in the War against Maleficent Microbes. AB - Antimicrobial agents, such as nisin, are used extensively in the food industry. Here, we investigated various approaches to load nisin onto mesoporous silica nanoparticles (MSNs, 92 +/- 10 nm in diameter), to enhance its stability and sustained release. The morphology, size, and surface charge of the as-prepared nanoparticles were analyzed using scanning transmission electron microscopy, dynamic light scattering, and zeta potential measurement. Nisin was either physically adsorbed or covalently attached to the variously functionalized MSNs, with high loading capacities (>600 mg of nisin g-1 of nanoparticles). The results of antibacterial activity analysis of nisin against Staphylococcus aureus showed that, despite the very low antibacterial activity of nisin covalently conjugated onto MSNs, the physical adsorption of nisin onto the unfunctionalized nanoparticles enhances its antimicrobial activities under various conditions, with no significant cytotoxicity effects on mouse fibroblast L929 cells. In conclusion, MSNs can be recommended as suitable carriers for nisin under various conditions. PMID- 29621395 TI - New Insight into Uracil Stacking in Water from ab Initio Molecular Dynamics. AB - Nucleobases spontaneously aggregate in water by forming stacked dimers and multimers. It is assumed that the main contributions to the aggregation stem from hydrophobic and base-base dispersion interactions. By studying the uracil monomer and dimer in bulk water with the first principle molecular dynamics, we discuss dimer structure and provide evidence that stacking increases the uracil-water hydrogen bonding strength and alters the hydration structure of uracil. These changes have a significant influence on the intensity and shift of the carbonyl stretching band as revealed by simulated infrared absorption spectra of the monomer and dimer and available experimental spectra. The contributions of dipole dipole, dispersion, and water mediated forces to the stacking are discussed. The reported findings are valuable for understanding the microscopic mechanism of heteroaromatic association in water which is relevant to a large range of chemical and biological systems. PMID- 29621396 TI - Reversal of Ovarian Cancer Multidrug Resistance by a Combination of LAH4-L1 siMDR1 Nanocomplexes with Chemotherapeutics. AB - The mortality of ovarian cancer stably ranks first in gynecological malignancies due to the lack of specific symptoms and diagnostic methods at an early stage. For most patients, the cancer cells had metastasized before they were diagnosed. As a result, 90% of them died of multidrug resistance (MDR) to chemotherapeutics. In our study, RNAi technology was introduced and applied to overcome this big problem. LAH4-L1, an amphipathic cationic polypeptide, was reported to have high transfection efficiency and was first selected by us to deliver siMDR1 for overcoming ovarian cancer cells MDR. In this research, LAH4-L1-siRNA nanocomplexes (LSCs) delivery system was designed via electrostatic interactions. The nanocomplexes could realize 87.3% MDR1 gene silence and 85% P-gp down regulation on SKOV-3 cells. What's more, with the combination of chemotherapeutics, SKOV-3 cells growth inhibition can reach to 82.9%. We have also found that there was about 50% reduction on cells migration when MDR1 gene was down-regulated. Besides what have been mentioned above, physicochemical characteristics, cytotoxicity, pH responsivity, cells cycle, cellular uptake, and endosomal escape abilities were also studied in this research. In conclusion, lower cytotoxicity, higher down-regulation of targeted gene, and great cell inhibition, when combined with chemotherapeutics, all show the great potential of LSCs for the reversal of multidrug resistance on SKOV-3 cells in the future. PMID- 29621397 TI - Volatile Organic Compound Gas-Sensing Properties of Bimodal Porous alpha-Fe2O3 with Ultrahigh Sensitivity and Fast Response. AB - Porous solid with multimodal pore size distribution provides plenty of advantages including large specific surface area and superior mass transportation to achieve high gas-sensing performances. In this study, alpha-Fe2O3 nanoparticles with bimodal porous structures were prepared successfully through a nanocasting pathway, adopting the bicontinuous 3D cubic symmetry mesoporous silica KIT-6 as the hard template. Its structure and morphology were characterized by X-ray diffraction, nitrogen adsorption-desorption, transmission electron microscopy, and so on. Furthermore, the gas sensor fabricated from this material exhibited excellent gas-sensing performance to several volatile organic compounds (acetone, ethyl acetate, isopropyl alcohol, n-butanol, ethanol, and methanol), such as ultrahigh sensitivity, rapid response speed (less than 10 s) and recovery time, good reproducibility, as well as stability. These would be associated with the desirable pore structure of the material, facilitating the molecules diffusion toward the entire sensing surface, and providing more active sensing sites for analytical gas. PMID- 29621398 TI - Green Synthesis of Cyclodextrin-Based Metal-Organic Frameworks through the Seed Mediated Method for the Encapsulation of Hydrophobic Molecules. AB - Metal-organic frameworks (MOFs) are attracting considerable attention as a result of their unique structural properties, such as a high surface area, highly porous topology, and tunable size and shape, which enable them to have potential applications as a new class of carriers for functional agent or drug delivery. However, most of the MOFs and the polymers used are not pharmaceutically acceptable. For the first time, this study successfully conducted the rapid synthesis of cyclodextrin metal-organic frameworks (CD-MOFs) through a facile and green seed-mediated method. The size control, crystal structure, and thermal properties of CD-MOFs with and without seeds were investigated. When 1 mg/mL seed was added, the size of gamma-CD-MOF crystals decreased from 6.2 +/- 0.8 to 1.8 +/ 0.4 MUm. The CD-MOFs synthesized though the seed-mediated method had higher crystallinity and thermal stability than those that were not. Furthermore, the CD MOFs could encapsulate hydrophobic molecules, such as Nile red (NR), which was chosen as a model, and the interaction mechanism between gamma-CD-MOFs and NR was investigated. Results showed the formation of a 1:1 complex between NR and CD MOFs, demonstrating the potential of these polymers as carriers for hydrophobic drug delivery applications. PMID- 29621399 TI - A Concise Approach to Anthraquinone-Xanthone Heterodimers. AB - A synthetic approach to anthraquinone-xanthone heterodimers is described. The route to the pentacyclic core features an efficient assembly of a benzocycloheptenone via a new intramolecular oxidative arylation of an enol ether and a Hauser-Kraus annulation-aldol reaction sequence to access the characteristic bicyclo[3.2.2]nonene motif. Acremoxanthone A is synthesized in 10 steps from commercially available material to demonstrate the application of this approach. PMID- 29621400 TI - Maillard-Reaction-Functionalized Egg Ovalbumin Stabilizes Oil Nanoemulsions. AB - Egg white proteins are an excellent source of nutrition, with high biological and technological values. However, their limited functional properties prevent their widespread industrial applications. In this study, the ovalbumin functionality was improved via glycation by Maillard reaction with d-lactose. The free amino groups and sodium dodecyl sulfate-polyacrylamide gel electrophoresis profile were determined, confirming that glycation occurred between ovalbumin and lactose. The emulsification of the conjugate was 2.69-fold higher than that of ovalbumin at pH 7.0 after glycation. The thermal stability also improved remarkably. The glycated protein products were used to form an oil-water nanoemulsion for polymethoxyflavone-rich aged orange peel oil. The resulting nanoemulsion showed good pH, thermal, and storage stabilities. PMID- 29621401 TI - Broadband Anisotropic Photoresponse of the "Hydrogen Atom" Version Type-II Weyl Semimetal Candidate TaIrTe4. AB - The layered ternary compound TaIrTe4 is an important candidate to host the recently predicted type-II Weyl Fermions that break Lorentz invariance. Photodetectors based on Weyl semimetal promise extreme performance in terms of highly sensitive, broadband, and self-powered operation owing to its topologically protected band structures. In this work, we report the realization of a broadband self-powered photodetector based on TaIrTe4. The photocurrent generation mechanisms are investigated with power- and temperature-dependent photoresponse measurements. The prototype metal-TaIrTe4-metal photodetector exhibits a responsivity of 20 MUA W-1 or a specific detectivity of 1.8 * 106 Jones with 27 MUs response time at 10.6 MUm. Broadband responses from 532 nm to 10.6 MUm are experimentally tested with potential detection range extendable to far-infrared and terahertz. Furthermore, anisotropic response of the TaIrTe4 photodetector is identified using polarization-angle-dependent measurement with linearly polarized light. The anisotropy is found to be wavelength dependent, and the degree of anisotropy increases as the excitation wavelength gets closer to the Weyl nodes. Our results suggest this emerging class of materials can be harnessed for broadband, polarization angle-sensitive, self-powered photodetection with reasonable responsivities. PMID- 29621402 TI - Bacterial spore inactivation induced by cold plasma. AB - Cold plasma has emerged as a non-thermal technology for microbial inactivation in the food industry over the last decade. Spore-forming microorganisms pose challenges for microbiological safety and for the prevention of food spoilage. Inactivation of spores induced by cold plasma has been reported by several studies. However, the exact mechanism of spore deactivation by cold plasma is poorly understood; therefore, it is difficult to control this process and to optimize cold plasma processing for efficient spore inactivation. In this review, we summarize the factors that affect the resistance of spores to cold plasma, including processing parameters, environmental elements, and spore properties. We then describe possible inactivation targets in spore cells (e.g., outer structure, DNA, and metabolic proteins) that associated with inactivation by cold plasma according to previous studies. Kinetic models of the sporicidal activity of cold plasma have also been described here. A better understanding of the interaction between spores and cold plasma is essential for the development and optimization of cold plasma technology in food the industry. PMID- 29621403 TI - Amelioration of Diabetes-Induced Diabetic Nephropathy by Aloe vera: Implication of Oxidative Stress and Hyperlipidemia. AB - This study investigated the effect of Aloe vera in diabetes-induced nephropathy in rats. As diabetes-associated hyperlipidemia and oxidative stress have been implicated in the pathogenesis of diabetic nephropathy, we evaluated the protective effect of whole leaf extract of Aloe vera on the basis of its hypolipidemic and antioxidative property. Aloe vera (300 mg/kg orally) has been noted to possess renoprotective effect in experimental diabetic nephropathy. However, its mechanism is not fully understood. Rats were administered streptozotocin (STZ) (55 mg/kg intraperitoneally once) to induce experimental diabetes mellitus. The development of diabetic nephropathy was assessed biochemically and histologically. In addition, the diabetes-induced lipid profile and renal oxidative stress were assessed. The single administration of STZ produced diabetes, which induced renal oxidative stress, altered the lipid profile, and subsequently produced nephropathy in eight weeks by increasing serum creatinine, blood urea nitrogen, proteinuria, and glomerular damage. Treatment with Aloe vera (300 mg/kg/day orally) was noted to be more effective against the diabetes-induced nephropathy and renal oxidative stress as compared to lisinopril (1 mg/kg/day orally), a reference agent. It may be concluded that diabetes induced oxidative stress and lipid alterations may be accountable for the induction of nephropathy in diabetic rats. The treatment with Aloe vera (300 mg/kg/day orally) may have prevented the development of diabetes-induced nephropathy by reducing lipid alteration, decreasing renal oxidative stress, and providing direct renoprotective action. PMID- 29621404 TI - Inorganic Nanomaterials for Soft Tissue Repair and Regeneration. AB - Inorganic nanomaterials have witnessed significant advances in areas of medicine including cancer therapy, imaging, and drug delivery, but their use in soft tissue repair and regeneration is in its infancy. Metallic, ceramic, and carbon allotrope nanoparticles have shown promise in facilitating tissue repair and regeneration. Inorganic nanomaterials have been employed to improve stem cell engraftment in cellular therapy, material mechanical stability in tissue repair, electrical conductivity in nerve and cardiac regeneration, adhesion strength in tissue approximation, and antibacterial capacity in wound dressings. These nanomaterials have also been used to improve or replace common surgical materials and restore functionality to damaged tissue. We provide a comprehensive overview of inorganic nanomaterials in tissue repair and regeneration, and discuss their promise and limitations for eventual translation to the clinic. PMID- 29621405 TI - Searching for effective components of cognitive rehabilitation for children and adolescents with acquired brain injury: A systematic review. AB - AIM: Cognitive rehabilitation is of interest after paediatric acquired brain injury (ABI). The present systematic review examined studies investigating cognitive rehabilitation interventions for children with ABI, while focusing on identifying effective components. Components were categorized as (1) metacognition and/or strategy use, (2) (computerized) drill-based exercises, and (3) external aids. METHODS: The databases PubMed (including MEDLINE), PsycInfo, and CINAHL were searched until 22nd June 2017. Additionally, studies were identified through cross-referencing and by consulting experts in the field. RESULTS: A total of 20 articles describing 19 studies were included. Metacognition/strategy use trainings (five studies) mainly improved psychosocial functioning. Drill-based interventions (six studies) improved performance on tasks similar to training tasks. Interventions combining these two components (six studies) benefited cognitive and psychosocial functioning. External aids (two studies) improved everyday memory. No studies combined external aids with drill-based interventions or all three components. CONCLUSION: Available evidence suggests that multi-component rehabilitation, e.g. combining metacognition/strategy use and drill-based training is most promising, as it can lead to improvements in both cognitive and psychosocial functioning of children with ABI. Intervention setting and duration may play a role. Conclusions remain tentative due to small sample sizes of included studies heterogeneity regarding outcome measures, intervention and therapist variables, and patient characteristics. PMID- 29621406 TI - Is a vegetarian diet safe to follow during pregnancy? A systematic review and meta-analysis of observational studies. AB - BACKGROUND: Whether a vegetarian diet is appropriate for pregnancy remains unclear. OBJECTIVE: This study aimed to determine the association between vegetarian diet during pregnancy and various maternal-fetal outcomes. METHOD: PubMed-Medline, EMBASE, and Cochrane Library databases were searched for relevant articles published by August 30, 2017. Quantitative data were analyzed by a random-effects model with pooled odds ratios or weighted mean difference (WMD) and 95% confidence interval as aggregate estimations. RESULTS: A total of 19 observational studies were identified for each of meta-analysis and narrative review. The overall estimated relation between vegetarian pregnancy and low birth weight (LBW) was marginally significant (1.27 (0.98, 1.65), P = 0.07, I2 = 0%). Asian (India/Nepal) vegetarian mothers exhibited increased risks to deliver a baby with LBW (1.33 (1.01, 1.76), P = 0.04, I2 = 0%). However, the WMD of neonatal birth weight in five studies suggested no difference between vegetarians and omnivores. Given the high heterogeneity of the included studies, lack of high quality evidence, and limited studies included for each category, we failed to reach conclusive results regarding the risks of hypospadias, intrauterine growth retardation, maternal anemia, and gestational diabetes mellitus. CONCLUSION: Asian vegetarian mothers presented increased risks to deliver babies with LBW than those of omnivores. Large-scale prospective studies focusing on pre- and/or early gestational nutrition will help clarify the correlation between vegetarian diet and various pregnancy outcomes. PMID- 29621407 TI - Critical Review on the Analytical Methods for the Estimation of Clofazimine in Bulk, Biological Fluids and Pharmaceutical Formulations. AB - Clofazimine (CFZ), a riminophenazine derivative and a crucial drug in the treatment of lepromatous leprosy, has been reintroduced clinically to treat multidrug-resistant tuberculosis. CFZ holds both antimycobacterial and anti inflammatory properties. But, due to its highly hydrophobic, polar and photosensitive nature, it is challenging to extract and quantify the drug from different biological fluids and its pharmaceutical formulations. This has also hampered the pharmacokinetic evaluation of the CFZ. This article accentuates various analytical methods viz. Identification methods, titrimetric methods, spectrometric methods such as colorimetric, fluorometric, mass spectroscopy and UV/Vis spectroscopy, Chromatographic methods like paper chromatography, thin layer chromatography, high-performance thin layer chromatography, high performance liquid chromatography, liquid chromatography tandem mass spectrometry for the estimation of CFZ in bulk, biological fluids and its pharmaceutical formulations. PMID- 29621408 TI - Review of Sample Preparation Techniques for the Analysis of Selected Classes of Pesticides in Plant Matrices. AB - The aim of this article is to present the trends in extraction techniques applied for the isolation of pesticides from plant matrix. To fully compare the effectiveness of different extraction techniques, it was required to analyze compounds with possibly wide spectrum of physicochemical properties. Hence, compounds representing neonicotinoids, pyrethroids, sulfonylureas and phenylamides were selected. Based on literature studies, it may be concluded that there are three main approaches to make the analytical procedures for pesticides determination more effective: (i) the optimization of extraction conditions, however, according to ANOVA conducted on the collected literature data, not all parameters influence the extraction process equally; chemometric studies based on literature reports may lead to the conclusion that the most favorable conditions (criterion: analyte recovery, repeatability) for neonicotinoid, pyrethroid and sulfonylurea herbicide extraction from plant tissues are provided by QuEChERS - extraction with acetonitrile, while the mixtures of PSA and GCB (for neonicotinoids), and PSA, GCB, C18 (for pyrethroids) should be used in d-SPE step. For sulfonylurea compounds and metalaxyl it was impossible to identify a sorbent(s) that cleans up the extract more effectively than the others; (ii) to develop a new generation of sorbents; however, the range of their applicability is limited, mainly due to difficulties in their synthesis; (iii) to develop the new extraction techniques with as few "trouble spots" as possible. PMID- 29621410 TI - Exploring the effect of chronotype on hippocampal volume and shape: A combined approach. AB - Current evidence suggests that acute depression is associated with reduced total hippocampal volume and regional atrophy. Here, using structural magnetic resonance imaging, we assayed linear effects of chronotype on total hippocampal volume and morphology. Later chronotype was associated with localised atrophy in the subiculum region of the right hippocampus in the absence of changes in total volume. The hippocampus forms a key node in a network of brain regions implicated in emotional regulation and alterations in the structure of this region may underpin, in part, the increased vulnerability for depression in late chronotype individuals. PMID- 29621409 TI - Dstac is required for normal circadian activity rhythms in Drosophila. AB - The genetic, molecular and neuronal mechanism underlying circadian activity rhythms is well characterized in the brain of Drosophila. The small ventrolateral neurons (s-LNVs) and pigment dispersing factor (PDF) expressed by them are especially important for regulating circadian locomotion. Here we describe a novel gene, Dstac, which is similar to the stac genes found in vertebrates that encode adaptor proteins, which bind and regulate L-type voltage-gated Ca2+ channels (CaChs). We show that Dstac is coexpressed with PDF by the s-LNVs and regulates circadian activity. Furthermore, the L-type CaCh, Dmca1D, appears to be expressed by the s-LNVs. Since vertebrate Stac3 regulates an L-type CaCh we hypothesize that Dstac regulates Dmca1D in s-LNVs and circadian activity. PMID- 29621411 TI - The Southern Sweden Adolescent Allergy-Cohort: Prevalence of allergic diseases and cross-sectional associations with individual and social factors. AB - OBJECTIVES: Asthma and allergic diseases are the most frequent chronic diseases in childhood worldwide, and considered a burden for the affected children and their families. The diseases impose an economic burden on society if not diagnosed and treated properly and management of and these diseases are challenging for healthcare professionals. The aim of the present investigation was to assess the prevalence of allergic diseases in an unselected cohort of adolescents in southern Sweden. Additionally, associations with sociodemographic factors were investigated, as well as impact on daily life. METHODS: This cross sectional study was based on a cohort of n = 1 530 school children, aged 13 to 14, from 13 municipalities in southern Sweden. Data were collected through web based questionnaires. RESULTS: Of all children 32% reported at least one allergic disease. 67% reported one allergic disease and 33% reported more than one. No allergy-related disease were reported by 68%. Current asthma was reported by 9.8% and current rhino-conjunctivitis was reported by 13%. The prevalence of food hypersensitivity was 12% and the prevalence of eczema was 11%. One to three wheezing attacks were reported from 55% and 40% reported more than four attacks of wheezing in the preceding year. The self-reported allergic diseases were diagnosed by a doctor in; 36% (food hypersensitivity) to 69% (rhinoconjunctivitis) of the cases. CONCLUSIONS: A high number of affected children were identified. Some children being undiagnosed and some not receiving satisfactory treatment. These results suggest that additional studies to evaluate treatment procedures in order to improve healthcare for allergic children are warranted. PMID- 29621412 TI - Association of the melatonin circadian rhythms with clock 3111T/C gene polymorphism in Caucasian and Asian menopausal women with insomnia. AB - A comparative analysis of melatonin circadian rhythms in Caucasian (incoming population) and Asian (indigenous population) menopausal women with/without sleep disorders depending on the genotype of Clock 3111T/C gene polymorphism was realized.The melatonin level in the saliva was determined four times a day (6:00 7:00, 12:00-13:00, 18:00-19:00, 23:00-00:00 h). The Caucasian women-carriers of the TT-genotype with insomnia as compared to control group-had a higher morning melatonin level and a lower night melatonin level. The Asian women with TT genotype and insomnia had a lower levels of melatonin as compared to control at daytime, evening and night. A significantly higher melatonin level in the early morning hours was detected in the Caucasian women-carriers of the TT-genotype with insomnia as compared to group womencarriers of the minor 3111C-allele. There were no statistically significant differences in the circadian rhythms of melatonin in the Asian women depending on the genotype of the Clock 3111T/C polymorphism. An assumption with respect to the protective role of the minor allele 3111C in the development of insomnia associated with the displacement of melatonin circadian rhythms in the representatives of the incoming population was made. PMID- 29621413 TI - Alpha-Tocopherol Supplementation Restricts Aluminium- and Ethanol-Induced Oxidative Damage in Rat Brain but Fails to Protect Against Neurobehavioral Damage. AB - The concurrent presence of oxidative stress (OS) and aluminium exposure is an inducer of neurodegenerative changes. Aluminium can augment OS in a pro-oxidant dominant condition. Antioxidative property of alpha-tocopherol may be useful in restricting these degenerative changes in the brain. OS parameters are tested in frontal cortex (FC), hippocampus (HC), and cerebellum (CL) of alpha-tocopherol supplemented (5 IU/day) male Wistar rats exposed to aluminium (10 mg Al/Kg/day; "Al"), ethanol (0.6 g ethanol/Kg/day; "Et"), and both ("Al-Et") and vehicle treated control ("C") for 4 weeks. The alpha-tocopherol supplementation restricted regional alterations of reduced glutathione, superoxide dismutase, catalase, and glutathione peroxidase. Accordingly, the regional superoxide and peroxide handling capacities (SPHC) also remain unaltered. Al-Et group demonstrated significant elevation in the lipid peroxidation level in FC and CL regions compared to the group C; similar elevations in lipid peroxidation were noted in all the tested brain regions of Al group. Likewise, declines in glutathione reductase activity were noted in HC (versus Et group) and CL (versus Al and Et groups) of Al-Et group. Interestingly, changes in behavioral patterns of all the treatment groups are comparable while differing from that of the control group. Significant difference with group C is observed during first through fourth weeks, third to fourth weeks, and second to third weeks in terms of spontaneous motor activity, Rota Rod performance, and Hebb-Williams maze performance, respectively. Hence, the current dose and duration of alpha tocopherol supplementation failed to provide full protection against the aluminium-induced neurodegeneration; nevertheless, it could provide only partial protection toward aluminium-induced augmentation of OS in specific brain regions. PMID- 29621414 TI - Magnetic field direction differentially impacts the growth of different cell types. AB - Magnetic resonance imaging (MRI) machines have horizontal or upright static magnetic field (SMF) of 0.1-3 T (Tesla) at sites of patients and operators, but the biological effects of these SMFs still remain elusive. We examined 12 different cell lines, including 5 human solid tumor cell lines, 2 human leukemia cell lines and 4 human non-cancer cell lines, as well as the Chinese hamster ovary cell line. Permanent magnets were used to provide 0.2-1 T SMFs with different magnetic field directions. We found that an upward magnetic field of 0.2-1 T could effectively reduce the cell numbers of all human solid tumor cell lines we tested, but a downward magnetic field mostly had no statistically significant effect. However, the leukemia cells in suspension, which do not have shape-induced anisotropy, were inhibited by both upward and downward magnetic fields. In contrast, the cell numbers of most non-cancer cells were not affected by magnetic fields of all directions. Moreover, the upward magnetic field inhibited GIST-T1 tumor growth in nude mice by 19.3% (p < 0.05) while the downward magnetic field did not produce significant effect. In conclusion, although still lack of mechanistical insights, our results show that different magnetic field directions produce divergent effects on cancer cell numbers as well as tumor growth in mice. This not only verified the safety of SMF exposure related to current MRI machines but also revealed the possible antitumor potential of magnetic field with an upward direction. PMID- 29621415 TI - Mutual regulation between miR-21 and the TGFbeta/Smad signaling pathway in human bronchial fibroblasts promotes airway remodeling. AB - OBJECTIVE: Airway remodeling is an important pathological feature of asthma. Excessive deposition of extracellular matrix (e.g., collagen) secreted from fibroblasts is a major factor contributing to airway remodeling. Currently, the mechanism by which collagen continues to be oversynthesized in the airway remains unclear. In this study, we investigated the role of the microRNA-21 (miR-21) and TGFbeta/Smad signaling pathway in human bronchial fibroblasts (HBFs), and explored the regulatory mechanism of airway remodeling. METHODS: HBFs were cultured in vitro and treated with the transforming growth factor beta (TGFbeta), receptor inhibitor (SB431542), and TGFbeta1. miR-21 and Smad7 overexpressing lentiviruses, as well as an miR-21 interfering lentivirus were constructed and transfected into HBFs. Western blotting was used to determine the expression of airway remodeling-related proteins and proteins in the TGFbeta/Smad signaling pathway. miR-21 expression was measured by quantitative real-time PCR. RESULTS: The high expression of miR-21 induced by TGFbeta1 was reduced following the treatment with the SB431542 in HBFs. Smad7 overexpression inhibited the elevated expression of the COL I protein induced by miR-21 overexpression in HBFs. Inhibiting miR-21 expression upregulated the level of Smad7 protein, thus reducing the expression of airway remodeling-related proteins induced by TGFbeta1 stimulation in HBFs. CONCLUSIONS: TGFbeta1 can induce miR-21 expression in HBFs through the TGFbeta/Smad signaling pathway to promote airway remodeling. miR-21 downregulates Smad7, activates the TGFbeta/Smad signaling pathway, and promotes airway remodeling. Mutual regulation between miR-21 and the TGFbeta/Smad signaling pathway in HBFs promotes airway remodeling. PMID- 29621416 TI - C-MET inhibitors for advanced non-small cell lung cancer. AB - INTRODUCTION: The role of the c-mesenchymal-epithelial transition factor (c-MET) signaling pathway in tumor progression and invasion has been extensively studied. C-MET inhibitors have shown anti-tumor activity in NSCLC both in preclinical and in clinical trials. However, given the molecular heterogeneity of NSCLC, it is likely that only a specific subset of NSCLC patients will benefit from c-MET inhibitors. Emerging data also suggest that MET inhibitors in combination with EGFR-TKIs (epidermal growth factor receptor tyrosine kinase inhibitors) may have a role in therapy for both EGFR-TKI resistant and EGFR-TKI naive patients. The challenges ahead are in the identification of the molecular subtypes that benefit most. Areas covered: This review summarizes the current understanding of c-MET biology in relation to studies evaluating c-MET inhibitors in the treatment of NSCLC. Expert opinion: MET inhibitors have the potential to benefit subsets of NSCLC patients with specific genetic alterations. Exon-14 skipping mutations appear so far to be the most promising molecular subset that is sensitive to MET inhibitors, whereas overexpression, amplification and point mutations of MET seem more challenging subgroups to target. Combination with other target agents, such as EGFR inhibitors, may represent a promising therapeutic strategy in specific areas (e.g. EGFR-TKI resistance). PMID- 29621418 TI - Highlighting the results of a trial by using appropriate inferential statistics. PMID- 29621417 TI - Risk of cancer after primary total hip replacement: The influence of bearings, cementation and the material of the stem. PMID- 29621419 TI - Sponsored page. PMID- 29621421 TI - Role of bulk and Nanosized SiO2 to overcome salt stress during Fenugreek germination (Trigonella foenum- graceum L.). AB - The effects of bulk and Nanosized SiO2 on seed germination and seedling growth indices of fenugreek under salinity stress were studied in the College of Agriculture, Ferdowsi University of Mashhad, Iran, in 2013. The experimental treatments included 4 levels of salinity stress (0, 50, 100 and 150 mM), 2 concentrations of bulk (50 and 100 ppm), 2 concentrations of nanosized SiO2 (50 and 100 ppm), and control (without any SiO2 types). Seedling growth attributes significantly improved when bulk and nanosized SiO2 concentrations applied singly or with different levels of salt stress. However, they significantly declined with salt application. The adverse effects of salt on shoot, root and seedling lengths were alleviated by application of 50 ppm nanosized SiO2 treatment. Under salt stress condition, addition of 50 and 100 ppm nanosized SiO2 to fenugreek seeds increased shoot, root and seedling dry weights as compared to bulk SiO2 concentrations and control treatments, though 50 ppm nanosized SiO2 was more effective than 100 ppm nanosized SiO2 application. It was concluded that nanosized SiO2 improves growth attributes of fenugreek and mitigate adverse effects of salt stress. PMID- 29621420 TI - Regulation of eosinophil recruitment and allergic airway inflammation by heparan sulfate proteoglycan (HSPG) modifying enzymes. AB - BACKGROUND: HSPGs are glycoproteins containing covalently attached heparan sulfate (HS) chains which bind to growth factors, chemokines, etc., and regulate various aspects of inflammation including cell recruitment. We previously showed that deletion of endothelial N-acetylglucosamine N-deacetylase-N-sulfotransferase 1 (Ndst1), an enzyme responsible for N-sulfation during HS biosynthesis, reduces allergic airway inflammation (AAI). Here, we investigated the importance of O sulfation mediated by uronyl 2-O-sulfotransferase (Hs2st) in development of AAI relative to N-sulfation. METHODS: Mice deficient in endothelial and leukocyte Hs2st (Hs2stf/fTie2Cre+) or Ndst1 (Ndst1f/fTie2Cre+) and WT mice were challenged with Alternaria alternata and evaluated for airway inflammation. Trafficking of murine eosinophils on lung endothelial cells was examined in vitro under conditions of flow. RESULTS: Exposure to Alternaria decreased expression level of Hs2st in WT mice while level of Ndst1 remained unchanged. Compared to WT mice, Alternaria-challenged Hs2stf/fTie2Cre+ mice exhibited significantly increased eosinophils in the bone marrow, bronchoalveolar lavage fluid [BALF] and lung tissue associated with persistent airway hyperresponsiveness, airway mucus hypersecretion and elevated Th2 cytokines. In contrast, Alternaria-challenged Ndst1f/fTie2Cre+ mice exhibited a marked reduction in airway eosinophilia, mucus secretion and smooth muscle mass compared to WT counterparts. While BALF eotaxins were lower in Alternaria-challenged Hs2stf/fTie2Cre+ relative to WT mice, they were not reduced to background levels as in allergen-challenged Ndst1f/fTie2Cre+ mice. Trafficking of murine eosinophils under conditions of flow in vitro was similar on Hs2st-deficient and WT endothelial cells. Expression of ZO-1 in Hs2st deficient lung blood vessels in control and allergen-challenged mice was significantly lower than in WT counterparts. CONCLUSIONS: Our study demonstrates that allergen exposure reduces expression of Hs2st; loss of uronyl 2-O-sulfation in endothelial and leukocyte HSPG amplifies recruitment of eosinophils likely due to a compromised vascular endothelium resulting in persistent inflammation whereas loss of N-sulfation limits eosinophilia and attenuates inflammation underscoring the importance of site-specific sulfation in HSPG to their role in AAI. PMID- 29621422 TI - Fire service instructors' working practices: A UK survey. AB - Analysis of Fire Service Instructors (FSI) working practices and health is needed to minimise health risks related to heat illness, cardiovascular events and immunological stress. Online surveys were distributed to UK FSI and Firefighters (FF). One hundred and thirty FSI (age: 43 +/- 7yrs) and 232 FF (age: 41 +/- 8yrs) responded. FSI experienced 2-10 live fires per week, with 45% of FSI reporting management does not set a limit on the number of exposures. Few FSI followed hydration guidelines, or cooling methods. New symptoms of ill health were reported by 41% of FSI and 21% of FF. FSI with >=11 Breathing Apparatus exposures per month were 4.5 times (95% CI 1.33-15.09) more likely to experience new symptoms. A large proportion of FSI are experiencing new symptoms of illness after starting their career, and guidelines on exposure and hydration are not universally in place to reduce the risk of future health problems. PMID- 29621423 TI - Particle bombardment - mediated gene transfer and GFP transient expression in Seteria viridis. AB - Setaria viridis is one of the most important model grasses in studying monocot plant biology. Transient gene expression study is a very important tool in plant biotechnology, functional genomics, and CRISPR-Cas9 genome editing technology via particle bombardment. In this study, a particle bombardment-mediated protocol was developed to introduce DNA into Setaria viridis in vitro leaf explants. In addition, physical and biological parameters, such as helium pressure, distance from stopping screen to the target tissues, DNA concentration, and number of bombardments, were tested and optimized. Optimum concentration of transient GFP expression was achieved using 1.5 ug plasmid DNA with 0.6 mm gold particles and 6 cm bombardment distance, using 1,100 psi. Doubling the bombardment instances provides the maximum number of foci of transient GFP expression. This simple protocol will be helpful for genomics studies in the S. viridis monocot model. PMID- 29621425 TI - Age-related Changes in Postural Sway During Sit-to-stand in Typical Children and Children with Cerebral Palsy. AB - OBJECTIVE: To assess age-related changes in postural sway during sit-to-stand (STS) in typical children (TC) and children with mild cerebral palsy (CP). METHODS: Thirty-five TC and 23 children with mild CP were allocated in four different age groups: 5-6, 7-9, 10-12, and 13-15 years; they all performed STS movements over a force plate. Anterior-posterior and medial-lateral amplitude of center of pressure (CoP) displacement, area and velocity of CoP sway were analyzed and compared between the age groups for TC and children with CP. RESULTS: TC at 5 to 6 years of age showed higher values of anterior-posterior CoP displacement and Area of CoP sway than at 10-12 years, during the stabilization phase. There were no age-related changes for CP. CONCLUSION: TC change their postural sway during the last STS phase over the years, reducing their body sway. Children with CP did not show age-related changes in sway during STS, reflecting a distinct rhythm of postural control development in this population. PMID- 29621427 TI - Is inclusion a valid control for ostracism? AB - Considerable knowledge about ostracism's impact comes from research using Cyberball, an online ball-tossing game. In Cyberball, the inclusion condition is the control condition, to which ostracism is compared. The assumption is that Cyberball-inclusion is not affirming and represents an expected level of inclusion. However, without a no-inclusion control condition, it is unclear whether inclusion elevates need satisfaction, whether ostracism depresses need satisfaction, or both. We introduce Cybertree-a control condition designed to provide a similar experience to Cyberball without inclusion. Individuals playing Cybertree did not differ from included individuals in terms of feeling ostracized, level of need satisfaction, and mood. Both Cyberball inclusion and Cybertree differed significantly from ostracized individuals. We conclude that Cyberball inclusion is a reasonable control group for Cyberball ostracism but discuss research questions that may benefit from the use of Cybertree. PMID- 29621424 TI - Oxidative and genotoxic damages in plants in response to heavy metal stress and maintenance of genome stability. AB - Plants, being sessile in nature, are constantly exposed to various environmental stresses, such as solar UV radiations, soil salinity, drought and desiccation, rehydration, low and high temperatures and other vast array of air and soil borne chemicals, industrial waste products, metals and metalloids. These agents, either directly or indirectly via the induction of oxidative stress and overproduction of reactive oxygen species (ROS), frequently perturb the chemical or physical structures of DNA and induce both cytotoxic or genotoxic stresses. Such condition, in turn, leads to genome instability and thus eventually severely affecting plant health and crop yield. With the growing industrialization process and non-judicious use of chemical fertilizers, the heavy metal mediated chemical toxicity has become one of the major environmental threats for the plants around the globe. The heavy metal ions cause damage to the structural, enzymatic and non enzymatic components of plant cell, often resulting in loss of cell viability, thus negatively impacting plant growth and development. Plants have also evolved with an extensive and highly efficient mechanism to respond and adapt under such heavy metal toxicity mediated stress conditions. In addition to morpho anatomical, hormonal and biochemical responses, at the molecular level, plants respond to heavy metal stress induced oxidative and genotoxic damage via the rapid change in the expression of the responsive genes at the transcriptional level. Various families of transcription factors play crucial role in triggering such responses. Apart from transcriptional response, epigenetic modifications have also been found to be essential for maintenance of plant genome stability under genotoxic stress. This review represents a comprehensive survey of recent advances in our understanding of plant responses to heavy metal mediated toxicity in general with particular emphasis on the transcriptional and epigenetic responses and highlights the importance of understanding the potential targets in the associated pathways for improved stress tolerance in crops. PMID- 29621426 TI - Tumor-infiltrating Treg, MDSC, and IDO expression associated with outcomes of neoadjuvant chemotherapy of breast cancer. AB - BACKGROUND: Regulatory T cells(Tregs) and myeloid-derived suppressor cells(MDSCs) represent two immunosuppressive cell populations that are important in the establishment and maintenance of cancer immune tolerance. MDSCs can express IDO and promote immune tolerance via expansion of Treg cell. METHOD: We use needle biopsy breast cancer tissues prior to neoadjuvant chemotherapy(NCT) staining for CD33, Foxp3 and IDO by immunohistochemistry to evaluate whether they were correlated with subsequent treatment responses in breast cancer. RESULTS: Expressions of IDO, CD33+MDSCs and Foxp3+Tregs were correlated with each other. Immunohistochemical double staining revealed that IDO expression in CD33+MDSCs was positively correlated with Foxp3+Tregs (P < 0.05). CD33+MDSCs, Foxp3+Tregs, and IDO expression in tumor tissues were associated with advanced clinical stage prior to NCT (P < 0.05). CD33+MDSCs, Foxp3+Tregs, IDO expression, IDO expression in CD33+MDSCs and clinical T3-T4 stage prior to NCT, pathological T3-T4 stage, ER(+), luminal type were correlated with clinical responses of PD+SD (P < 0.05). Multivariate analysis showed that CD33+MDSCs, IDO expression, IDO expression in CD33+MDSCs, and advanced pathological T stage were risk factors for PD+SD. Focusing on the pCR of NCT, only CD33+MDSCs, clinical T3-T4, and N1-N3 stage prior to NCT were associated with no-pCR (P < 0.05). The multivariate analysis showed that advanced clinical T stage and N stage were risk factors for no-pCR. Clinical stage prior to NCT were significantly correlated with progression free survival (P = 0.021), while Foxp3+Tregs and clinical T stage were significantly correlated with overall survival (P = 0.022 and P = 0.001, respectively). Foxp3+Treg was significant risk factor for overall survival after adjusting covariates by COX regression. CONCLUSION: Tumor-infiltrating MDSCs, Tregs, IDO expression and IDO expression in MDSCs were correlated with clinicopathological features, NCT response, and prognosis of breast cancer patients, suggesting that they might be potential markers for clinical outcomes of NCT and help clinical decision-making for improved therapies for breast cancer. PMID- 29621429 TI - A Psychometric Investigation of the Painful and Provocative Events Scale: Moving Forward. AB - Acquired capability for suicide is posited to develop through repeated exposure to physically painful and psychologically provocative events; however, there is limited research evaluating the assessment of painful and provocative events. The current study examined the factor structure, validity, and reliability of the Painful and Provocative Events Scale (PPES). Categorical exploratory and confirmatory factor analyses were conducted in a sample of undergraduate students (N = 732). A 15-item PPES with a 3-factor solution best fits the data; however, both the subscales derived from factor analyses yielded inconsistent validity and reliability. Despite addressing limitations of previous psychometric investigations of the PPES, the inconsistent findings of the current study suggest the theoretical reconceptualization of painful and provocative events and the subsequent development of a valid and reliable assessment of painful and provocative events is needed to take the place of current versions of the PPES. PMID- 29621431 TI - Arriving old: A qualitative study of elder refugee women's self-perceptions of the first year of resettlement. AB - This qualitative study examines eight elder women's experiences of resettling with their family and the protective factors that enhanced their resiliency. The implications for social work include the need to assess elder refugees' strengths, resilience, pre-resettlement functioning instead of services that might encourage integration into the dominant culture and community, and that the refugee experience is a lifelong experience that shapes and informs various stages of life. PMID- 29621428 TI - Hematopoietic cells as site of first-pass catabolism after subcutaneous dosing and contributors to systemic clearance of a monoclonal antibody in mice. AB - The neonatal Fc receptor (FcRn) has been demonstrated to contribute to a high bioavailability of monoclonal antibodies (mAbs). In this study, we explored the cellular sites of FcRn-mediated protection after subcutaneous (SC) and intravenous (IV) administration. SC absorption and IV disposition kinetics of a mAb were studied in hFcRn transgenic (Tg) bone marrow chimeric mice in which hFcRn was restricted to radioresistant cells or hematopoietic cells. SC bioavailabilities close to 90% were observed in hFcRn Tg mice and chimeric mice with hFcRn expression in hematopoietic cells, whereas SC bioavailabilities were markedly lower when FcRn was missing in hematopoietic cells. Our study demonstrates: 1) FcRn in radiosensitive hematopoietic cells is required for high SC bioavailability, indicating first-pass catabolism after SC administration by hematopoietic cells; 2) FcRn-mediated transcytosis or recycling by radioresistent cells is not required for high SC bioavailability; and 3) after IV administration hematopoietic and radioresistent cells contribute about equally to clearance of the mAb. A pharmacokinetic model was devised to describe a mixed elimination via radioresistent and hematopoietic cells from vascular and extravascular compartments, respectively. Overall, the study indicates a relevant role of hematopoietic cells for first-pass clearance of mAbs after SC administration and confirms their role in the overall clearance of mAbs. PMID- 29621430 TI - 17beta-estradiol Induces MMP-9 and MMP-13 in TMJ Fibrochondrocytes via Estrogen Receptor alpha. AB - Temporomandibular joint (TMJ) disorders, including degenerative TMJ disease, occur primarily in women of reproductive age. Previous studies showed elevated estrogen levels in subjects with TMJ disorders relative to controls and the presence of estrogen receptors alpha and beta (ERalpha and ERbeta) in TMJ fibrocartilage. Additionally, estrogen-induced overexpression of specific matrix metalloproteinases (MMPs), including MMP-9 and MMP-13, in TMJ fibrocartilage is accompanied by loss of extracellular matrices. However, the contribution of ERalpha and ERbeta in estrogen-mediated induction of MMP-9 and MMP-13 and the signaling cascade leading to the upregulation of these MMPs have not been elucidated. Here, we show that specific siRNAs and selective ER antagonists effectively block ERalpha or ERbeta expression in primary mouse TMJ fibrochondrocytes, but that only blockage of ERalpha suppresses MMP-9 and MMP-13 levels induced by 17beta-estradiol (E2). Overexpression of ERalpha but not ERbeta enhances E2-induced MMP-9. Using the same loss-of-function and gain-of-function approaches, we demonstrate that E2 stimulates ERK activation through ERalpha and that inhibition of ERK phosphorylation reduces E2-induced MMP-9. Furthermore, we reveal that E2 promotes NF-kappaB and ELK-1 activation through ERalpha/ERK signaling and that knockdown of either one decreases the respective activity of these signaling mediators and MMP-9 expression induced by E2, indicating that both contribute to E2/ERalpha/ERK-mediated MMP-9 upregulation. This is supported by findings in which mutated binding sites of either NF-kappaB or ELK-1 in the MMP-9 promoter lead to a significant reduction of E2-stimulated promoter activity. Our findings provide novel molecular mechanisms for the understanding of E2-mediated upregulation of MMPs, having implications to pathophysiologic TMJ cartilage matrix turnover that may yield therapeutic intervention targets for TMJ disorders. PMID- 29621432 TI - "It's Changed Everything": Voices of Veterans in the Veteran-Directed Home and Community Based Services Program. AB - The purpose of this study was to understand the value and impact of the Veteran Directed Home and Community Based Services program (VD-HCBS) on Veterans' lives in their own voices. Focus groups and individual interviews by telephone were conducted to elicit participant perspectives on what was most meaningful, and what difference VD-HCBS made in their lives. Transcripts were analyzed using content analysis. The sample included 21 Veterans, with a mean age of 66+/-14, enrolled in VD-HCBS an average of 20.8 months. All were at risk of institutional placement based on their level of disability. Five major categories captured the information provided by participants: What a Difference Choice Makes; I'm a Person!; It's a Home-Saver; Coming Back to Life; and Keeping Me Healthy & Safe. Participants described the program as life changing. This study is the first time that Veterans themselves have identified the ways in which VD-HCBS impacted their lives, uncovering the mechanisms underlying positive outcomes. These categories revealed new ways of understanding VD-HCBS as an innovative approach to meeting the person-centered needs of Veterans wishing to remain at home, while experiencing quality care and leading meaningful lives, areas identified as priorities for improving long term services and supports. PMID- 29621433 TI - Mediterranean Diet and Cognitive Status in Free-Living Elderly: A Cross-Sectional Study in Northern Italy. AB - OBJECTIVE: Few data are available on the Italian elderly population with regard to adherence to the Mediterranean diet (MD) and cognitive impairment. Our aim was to investigate adherence to the MD and its association with cognitive function in an Italian urban sample. METHODS: A cross-sectional study of 279 participants aged >= 65 years (80 men, 199 women) was carried out at a nutritional center. Adherence to the MD was evaluated using a 14-item questionnaire. Cognitive function was assessed with the Mini-Mental State Examination (MMSE). RESULTS: The clinical and nutritional assessments performed revealed 30.1% to have a dietary pattern in accordance with the MD; 13.6% had suspected or mild cognitive impairment (MMSE score <= 23). The MD pattern was associated with a lower risk of cognitive impairment (odds ratio [OR] = 0.39; 95% confidence interval [CI], 0.15 0.99; p = 0.045), as was the consumption of wine (OR = 0.37; 95% CI, 0.16-0.84; p = 0.018) and nuts (OR = 0.30; 95% CI, 0.13-0.69, p = 0.005). No association was found with other food groups. CONCLUSION: A closer adherence to the MD was associated with a better cognitive status. Further cohort studies and randomized controlled trials are warranted. PMID- 29621434 TI - Isocyanates in Australia: Current exposure to an old hazard. AB - Exposure to isocyanates has consistently been reported as the most common cause of occupational asthma. The objectives of this study were to assess how many Australian workers are currently exposed to isocyanates, identify the occupations with highest proportion of exposed workers and identify the main circumstances of exposures. Data comes from the Australian Workplace Exposure Study-Asthma, a national telephone survey which explored the prevalence of current occupational exposure to 227 asthmagens, grouped into 27 groups, among current Australian workers aged 18-65 years. A web-based tool, OccIDEAS, was used to collect job task information and to assign exposure to asthmagens, including isocyanates. Of the 4,878 eligible participants, 2.5% of them were deemed to be probably exposed to isocyanates at work in their current job (extrapolated to 3.0% of the Australian working population). The majority of those exposed were males (90.8%). The most common tasks undertaken that led to these exposures were using expanding foam fillers/sprays and isocyanate and/or polyurethane paints. Exposure occurred mainly among construction workers, wood workers, and painters or printers. This study investigating occupational exposure to isocyanates in a national working population provides information that can be used to inform the direction of occupational interventions and policies to decrease occupational asthma. PMID- 29621435 TI - Special Issue on Vietnamese women's health issues. PMID- 29621436 TI - Women's health and health care in Vietnam. PMID- 29621437 TI - Inspired Translation: Synthesizing Qualitative Research and Boot Camp Translation to Achieve Meaningful Community Engagement. PMID- 29621438 TI - Diversity Beyond Race and Ethnicity: Enhancing Inclusion With an Expanded Definition of Diversity. PMID- 29621439 TI - When Research Regulations and Ethics Conflict. PMID- 29621440 TI - Fairness in Manufacturing Cellular Therapies. PMID- 29621441 TI - Best to Exclude but Pay. PMID- 29621442 TI - Learning Is Not Enough: Earning Institutional Trustworthiness Through Knowledge Translation. PMID- 29621443 TI - The Role of the Health Care Provider in Building Trust Between Patients and Precision Medicine Research Programs. PMID- 29621445 TI - Perspectives on Achieving Institutional Trust in Personalized Medicine. PMID- 29621444 TI - Trust, Precision Medicine Research, and Equitable Participation of Underserved Populations. PMID- 29621446 TI - Grudging Trust and the Limits of Trustworthy Biorepository Curation. PMID- 29621447 TI - Mutual Obligations in Research and Withholding Payment From Deceptive Participants. PMID- 29621448 TI - Conflicts Between Regulations and Ethical Principles: Resolving Ambiguity in Favor of the Ethically Preferable Outcome. PMID- 29621449 TI - Response to Open Peer Commentaries on "The Default Position: Optimizing Pediatric Participation in Medical Decision Making". PMID- 29621451 TI - What's in a Name? The Politics of 'Precision Medicine'. PMID- 29621450 TI - Enhance Diversity Among Researchers to Promote Participant Trust in Precision Medicine Research. PMID- 29621452 TI - To Pay or Not to Pay? Withholding Payment From Research Participants. PMID- 29621453 TI - What's Trust Got To Do With It? Ensuring Meaningful Community Engagement. PMID- 29621454 TI - When to Avoid Giving Advice on the Ethical Conduct of Research. PMID- 29621455 TI - Deconstructing Trust and Recognizing Vulnerability in Research With Diverse Populations. PMID- 29621456 TI - Review of Ronald W. Dworkin, Medical Catastrophe: Confessions of an Anesthesiologist1. PMID- 29621458 TI - Ethical Ruminations of a Rheumatologist: Autoimmunity Is an Important Consideration for Immunotherapy Trials. PMID- 29621459 TI - Perverse Effects: How Insufficient Guidance to IPFs Can Undermine Both Research and Health Outcomes of Clinical Trials. PMID- 29621457 TI - Beyond Consent: Building Trusting Relationships With Diverse Populations in Precision Medicine Research. AB - With the growth of precision medicine research on health data and biospecimens, research institutions will need to build and maintain long-term, trusting relationships with patient-participants. While trust is important for all research relationships, the longitudinal nature of precision medicine research raises particular challenges for facilitating trust when the specifics of future studies are unknown. Based on focus groups with racially and ethnically diverse patients, we describe several factors that influence patient trust and potential institutional approaches to building trustworthiness. Drawing on these findings, we suggest several considerations for research institutions seeking to cultivate long-term, trusting relationships with patients: (1) Address the role of history and experience on trust, (2) engage concerns about potential group harm, (3) address cultural values and communication barriers, and (4) integrate patient values and expectations into oversight and governance structures. PMID- 29621460 TI - Prioritizing Facts and Values in Immunotherapy Trial Selection: Some Further Guidance. PMID- 29621461 TI - Disease Prevalence and the Magnitude of Research Benefits. PMID- 29621462 TI - Building a Trustworthy Precision Health Research Enterprise. PMID- 29621463 TI - Geometry of Trust: Why We Need to Distinguish Between Horizontal and Vertical Trust. PMID- 29621464 TI - Patients' Trust as Fundament for Research Ethics Boards. PMID- 29621465 TI - Response to Open Peer Commentaries on "From 'Longshot' to 'Fantasy': Obligations to Pediatric Patients and Families When Last-Ditch Medical Efforts Fail". PMID- 29621467 TI - Involving Pregnant Women in Research: What Should We Recommend When the Regulations Seem Ethically Problematic? PMID- 29621468 TI - Including Everyone but Engaging No One? Partnership as a Prerequisite for Trustworthiness. PMID- 29621466 TI - Unjust Outcomes and Unfair Process? PMID- 29621469 TI - Misplaced Trust: Building Research Relationships in the Age of Biorepository Networks. PMID- 29621470 TI - On Scarcity and the Value of Clinical Trials. PMID- 29621471 TI - Fairness and Desert: A Critique of the Random Selection Criterion in Clinical Trials. PMID- 29621472 TI - Is It Ethically Appropriate to Refuse to Compensate Participants Who Are Believed to Have Intentionally Concealed Medical Conditions? PMID- 29621473 TI - Ethical Guidance for Selecting Clinical Trials to Receive Limited Space in an Immunotherapy Production Facility. AB - Our aims are to (1) set forth a multiprinciple system for selecting among clinical trials competing for limited space in an immunotherapy production facility that supplies products under investigation by scientific investigators; (2) defend this system by appealing to justice principles; and (3) illustrate our proposal by showing how it might be implemented. Our overarching aim is to assist manufacturers of immunotherapeutic products and other potentially breakthrough experimental therapies with the ethical task of prioritizing requests from scientific investigators when production capacity is limited. PMID- 29621474 TI - Invisible Elephants. PMID- 29621475 TI - Management of Opioid-Induced Constipation in Patients with Malignancy. PMID- 29621476 TI - Honoring a Patient: From Suspicion to Diagnosis. PMID- 29621477 TI - Stromal vascular fraction promotes fibroblast migration and cellular viability in a hyperglycemic microenvironment through up-regulation of wound healing cytokines. AB - Diabetic wounds have impaired healing and a propensity for further morbidity, which may result in amputations. Stromal vascular fraction (SVF) is an autologous source of heterogeneous cell population obtained from adipose tissue, which is rich in stem cells and presents little immunogenicity to the host. In this study, we hypothesized that murine fibroblasts subjected to hyperglycemic conditions co treated with SVF exhibit greater functional activity through the colorimetric MTT assay and a cell-monolayer in-vitro scratch assay. We sought to establish the underlying mechanism of action via the utility of an ELISA chemiluminescence array on the supernatant medium of the cells. Our results demonstrate that the mean percentage gap closure at 24 h in the hyperglycemia + SVF group was significantly greater at 41.1% +/- 1.6% compared to the hyperglycemia alone group 16.6% +/- 1.5% (post-hoc Bonferroni test p < 0.001, n = 3) although there was no difference between the SVF and normoglycemia group. Further, this SVF group exhibited a significantly greater 2.4 fold increase in fibroblastic cell viability as compared to the hyperglycemia alone group (p = 0.001, n = 3). The supernatant medium of the cells upon testing with ELISA indicated that early phase wound healing cytokines including platelet-derived growth factor (p = 0.012, n = 3), interleukin-1 (p = 0.003, n = 3), basic fibroblast growth factor (p = 0.003, n = 3) and interleukin-10 (p = 0.009, n = 3) were expressed in significantly greater relative luminescent units in SVF as compared to hyperglycemia alone groups (Student t-test). Taken together and for the first time, our study shows that SVF is a promising therapeutic agent for up-regulating fibroblastic activity in a hyperglycemic microenvironment, and this result can be explained in part by the stimulation of wound-healing cytokines. PMID- 29621478 TI - Hyperglycemia-induced Bcl-2/Bax-mediated apoptosis of Schwann cells via mTORC1/S6K1 inhibition in diabetic peripheral neuropathy. AB - Schwann cell apoptosis is one of the characteristics of diabetic peripheral neuropathy (DPN). The mammalian target of rapamycin (mTOR) is a multifunctional signaling pathway that regulates cell apoptosis in various types of tissues and cells. To investigate whether the mTOR pathway is involved in cell apoptosis in the Schwann cells of DPN, diabetic mice and rat Schwann cells (RSC96) were chosen to detect phospho-mTOR (Ser 2448), phospho-S6K1 (Thr 389), phospho-4EBP1 (Thr 37/46), Bcl-2, Bax and cleaved caspase-3 by diverse pathological and biological techniques. The results showed that phospho-mTOR (Ser 2448) was decreased in the sciatic nerves of diabetic mice, concomitant with decreased Bcl-2, increased Bax, cleaved caspase-3 and cell apoptosis. In addition, high glucose treatment for 72 h caused a 35.95% decrease in the phospho-mTOR (Ser 2448)/mTOR ratio, a 65.50% decrease in the phospho-S6K1 (Thr 389)/S6K1 ratio, a 3.67-fold increase in the Bax/Bcl-2 ratio and a 1.47-fold increase in the cleaved caspase-3/caspase-3 ratio. Furthermore, mTORC1 inhibition, rather than mTORC2 inhibition, resulted in mitochondrial controlled apoptosis in RSC96 cells by silencing RAPTOR or RICTOR. Again, suppression of the mTORC1 pathway by a chemical inhibitor led to mitochondrial controlled apoptosis in cultured RSC96 cells in vitro. By contrast, activation of the mTORC1 pathway with MHY1485 prevented decreased phospho-S6K1 (Thr 389) levels caused by high glucose and cell apoptosis. Additionally, constitutive activation of S6K1 avoided high glucose-induced cell apoptosis in RSC96 cells. In summary, our findings suggest that activating mTORC1/S6K1 signaling in Schwann cells may be a promising strategy for the prevention and treatment of DPN. PMID- 29621479 TI - Taste of glucose elicits cephalic-phase insulin release in mice. AB - We reported previously that when C57BL/6 (B6) mice ingest glucose, plasma insulin levels rise above baseline before blood glucose levels do so. This observation led us to speculate that the taste of glucose elicits cephalic-phase insulin release (CPIR) in mice. Here, we examined the specific contributions of taste and glucose to CPIR. In Experiment 1, we bypassed the mouth and delivered glucose directly to the stomach. We found that plasma insulin levels did not rise above baseline until after blood glucose levels did so. This revealed that taste stimulation is necessary for rapid insulin release (i.e., CPIR) in mice. In Experiment 2, we examined the observation that sucrose, maltose and Polycose (a maltodextrin) all elicit CPIR. We proposed in a prior study that these carbohydrates did not directly elicit CPIR; instead, they were digested by oral amylases and alpha-glucosidases, and that it was the enzymatically liberated glucose that elicited CPIR. In support of this possibility, we reported that acarbose (an alpha-glucosidase inhibitor) prevented sucrose, maltose and Polycose from eliciting CPIR. Here, we sought to confirm that glucose alone could elicit CPIR in the presence of acarbose. Indeed, we found that glucose alone and glucose+acarbose each elicited equally robust CPIR. Taken together, these results provide further support for the hypothesis that mice possess a glucose-specific taste transduction pathway that triggers rapid insulin release. PMID- 29621480 TI - Identifying dementia cases with routinely collected health data: A systematic review. AB - INTRODUCTION: Prospective, population-based studies can be rich resources for dementia research. Follow-up in many such studies is through linkage to routinely collected, coded health-care data sets. We evaluated the accuracy of these data sets for dementia case identification. METHODS: We systematically reviewed the literature for studies comparing dementia coding in routinely collected data sets to any expert-led reference standard. We recorded study characteristics and two accuracy measures-positive predictive value (PPV) and sensitivity. RESULTS: We identified 27 eligible studies with 25 estimating PPV and eight estimating sensitivity. Study settings and methods varied widely. For all-cause dementia, PPVs ranged from 33%-100%, but 16/27 were >75%. Sensitivities ranged from 21% to 86%. PPVs for Alzheimer's disease (range 57%-100%) were generally higher than those for vascular dementia (range 19%-91%). DISCUSSION: Linkage to routine health-care data can achieve a high PPV and reasonable sensitivity in certain settings. Given the heterogeneity in accuracy estimates, cohorts should ideally conduct their own setting-specific validation. PMID- 29621482 TI - Large-Scale CRISPR-Mediated Somatic Mutagenesis Identifies a Signaling Pathway that Guides Retinal Development. AB - As the mammalian outer retina develops, rod and cone photoreceptors synapse with their respective bipolar cells. Sarin et al. (2018) develop a somatic CRISPR technique to determine how genes differentially expressed among the four cell types mediate outer retina development. PMID- 29621481 TI - In Inflamed Intestinal Tissues and Epithelial Cells, Interleukin 22 Signaling Increases Expression of H19 Long Noncoding RNA, Which Promotes Mucosal Regeneration. AB - BACKGROUND & AIMS: Inflammation affects regeneration of the intestinal epithelia; long noncoding RNAs (lncRNAs) regulate cell functions, such as proliferation, differentiation, and migration. We investigated the mechanisms by which the lncRNA H19, imprinted maternally expressed transcript (H19) regulates regeneration of intestinal epithelium using cell cultures and mouse models of inflammation. METHODS: We performed RNA-sequencing transcriptome analyses of intestinal tissues from mice with lipopolysaccharide (LPS)-induced sepsis to identify lncRNAs associated with inflammation; findings were confirmed by quantitative real-time polymerase chain reaction and in situ hybridization analyses of intestinal tissues from mice with sepsis or dextran sulfate sodium (DSS)-induced mucosal wound healing and patients with ulcerative colitis compared to healthy individuals (controls). We screened cytokines for their ability to induce expression of H19 in HT-29 cells and intestinal epithelial cells (IECs), and confirmed findings in crypt epithelial organoids derived from mouse small intestine. IECs were incubated with different signal transduction inhibitors and effects on H19 lncRNA levels were measured. We assessed intestinal epithelial proliferation or regeneration in H19DeltaEx1/+ mice given LPS or DSS vs wild-type littermates (control mice). H19 was overexpressed in IECs using lentiviral vectors and cell proliferation was measured. We performed RNA antisense purification, RNA immunoprecipitation, and luciferase reporter assays to study functions of H19 in IECs. RESULTS: In RNA-sequencing transcriptome analysis of lncRNA expression in intestinal tissues from mice, we found that levels of H19 lncRNA changed significantly with LPS exposure. Levels of H19 lncRNA increased in intestinal tissues of patients with ulcerative colitis, mice with LPS-induced and polymicrobial sepsis, or mice with DSS-induced colitis, compared with controls. Increased H19 lncRNA localized to epithelial cells in the intestine, regardless of Lgr5 messenger RNA expression. Exposure of IECs to interleukin 22 (IL22) increased levels of H19 lncRNA with time and dose, which required STAT3 and protein kinase A activity. IL22 induced expression of H19 in mouse intestinal epithelial organoids within 6 hours. Exposure to IL22 increased growth of intestinal epithelial organoids derived from control mice, but not H19DeltaEx1/+ mice. Overexpression of H19 in HT-29 cells increased their proliferation. Intestinal mucosa healed more slowly after withdrawal of DSS from H19DeltaEx1/+ mice vs control mice. Crypt epithelial cells from H19DeltaEx1/+ mice proliferated more slowly than those from control mice after exposure to LPS. H19 lncRNA bound to p53 and microRNAs that inhibit cell proliferation, including microRNA 34a and let-7; H19 lncRNA binding blocked their function, leading to increased expression of genes that promote regeneration of the epithelium. CONCLUSIONS: The level of lncRNA H19 is increased in inflamed intestinal tissues from mice and patients. The inflammatory cytokine IL22 induces expression of H19 in IECs, which is required for intestinal epithelial proliferation and mucosal healing. H19 lncRNA appears to inhibit p53 protein and microRNA 34a and let-7 to promote proliferation of IECs and epithelial regeneration. PMID- 29621483 TI - Neuroscience: Past and Future. AB - Reflecting on when Neuron was launched and what the next 30 years may bring, neuroscientists share their excitement and visions for the future of the field. PMID- 29621484 TI - Rbfox1 Regulates Synaptic Transmission through the Inhibitory Neuron-Specific vSNARE Vamp1. AB - Dysfunction of the neuronal RNA binding protein RBFOX1 has been linked to epilepsy and autism spectrum disorders. Rbfox1 loss in mice leads to neuronal hyper-excitability and seizures, but the physiological basis for this is unknown. We identify the vSNARE protein Vamp1 as a major Rbfox1 target. Vamp1 is strongly downregulated in Rbfox1 Nes-cKO mice due to loss of 3' UTR binding by RBFOX1. Cytoplasmic Rbfox1 stimulates Vamp1 expression in part by blocking microRNA-9. We find that Vamp1 is specifically expressed in inhibitory neurons, and that both Vamp1 knockdown and Rbfox1 loss lead to decreased inhibitory synaptic transmission and E/I imbalance. Re-expression of Vamp1 selectively within interneurons rescues the electrophysiological changes in the Rbfox1 cKO, indicating that Vamp1 loss is a major contributor to the Rbfox1 Nes-cKO phenotype. The regulation of interneuron-specific Vamp1 by Rbfox1 provides a paradigm for broadly expressed RNA-binding proteins performing specialized functions in defined neuronal subtypes. PMID- 29621485 TI - Complementary Tuning of Na+ and K+ Channel Gating Underlies Fast and Energy Efficient Action Potentials in GABAergic Interneuron Axons. AB - Fast-spiking, parvalbumin-expressing GABAergic interneurons (PV+-BCs) express a complex machinery of rapid signaling mechanisms, including specialized voltage gated ion channels to generate brief action potentials (APs). However, short APs are associated with overlapping Na+ and K+ fluxes and are therefore energetically expensive. How the potentially vicious combination of high AP frequency and inefficient spike generation can be reconciled with limited energy supply is presently unclear. To address this question, we performed direct recordings from the PV+-BC axon, the subcellular structure where active conductances for AP initiation and propagation are located. Surprisingly, the energy required for the AP was, on average, only ~1.6 times the theoretical minimum. High energy efficiency emerged from the combination of fast inactivation of Na+ channels and delayed activation of Kv3-type K+ channels, which minimized ion flux overlap during APs. Thus, the complementary tuning of axonal Na+ and K+ channel gating optimizes both fast signaling properties and metabolic efficiency. PMID- 29621488 TI - Protected by a Fox. AB - Cell-specific regulation of gene expression is important for maintaining cortical excitatory/inhibitory balance. In this issue of Neuron, Vuong et al. (2018) reveal an unlikely role for a broadly expressed RNA binding protein, Rbfox1, in protecting inhibitory transmission in the hippocampus. PMID- 29621486 TI - Neural Circuit Mechanisms of Social Behavior. AB - We live in a world that is largely socially constructed, and we are constantly involved in and fundamentally influenced by a broad array of complex social interactions. Social behaviors among conspecifics, either conflictive or cooperative, are exhibited by all sexually reproducing animal species and are essential for the health, survival, and reproduction of animals. Conversely, impairment in social function is a prominent feature of several neuropsychiatric disorders, such as autism spectrum disorders and schizophrenia. Despite the importance of social behaviors, many fundamental questions remain unanswered. How is social sensory information processed and integrated in the nervous system? How are different social behavioral decisions selected and modulated in brain circuits? Here we discuss conceptual issues and recent advances in our understanding of brain regions and neural circuit mechanisms underlying the regulation of social behaviors. PMID- 29621487 TI - A Hypothalamic Midbrain Pathway Essential for Driving Maternal Behaviors. AB - Maternal behaviors are essential for the survival of the young. Previous studies implicated the medial preoptic area (MPOA) as an important region for maternal behaviors, but details of the maternal circuit remain incompletely understood. Here we identify estrogen receptor alpha (Esr1)-expressing cells in the MPOA as key mediators of pup approach and retrieval. Reversible inactivation of MPOAEsr1+ cells impairs those behaviors, whereas optogenetic activation induces immediate pup retrieval. In vivo recordings demonstrate preferential activation of MPOAEsr1+ cells during maternal behaviors and changes in MPOA cell responses across reproductive states. Furthermore, channelrhodopsin-assisted circuit mapping reveals a strong inhibitory projection from MPOAEsr1+ cells to ventral tegmental area (VTA) non-dopaminergic cells. Pathway-specific manipulations reveal that this projection is essential for driving pup approach and retrieval and that VTA dopaminergic cells are reliably activated during those behaviors. Altogether, this study provides new insight into the neural circuit that generates maternal behaviors. PMID- 29621491 TI - A Neural Circuit Driving Maternal Behaviors. AB - In this issue of Neuron, Fang et al. (2018) identified a neural circuit that connects the medial preoptic area to the ventral tegmental area as a critical pathway for pup retrieval in female mice. PMID- 29621492 TI - Cortical Signal Propagation: Balance, Amplify, Transmit. AB - The neural code of cortical processing remains uncracked; however, it must necessarily rely on faithful signal propagation between cortical areas. In this issue of Neuron, Joglekar et al. (2018) show that strong inter-areal excitation balanced by local inhibition can enable reliable signal propagation in data constrained network models of macaque cortex. PMID- 29621490 TI - An Optical Neuron-Astrocyte Proximity Assay at Synaptic Distance Scales. AB - Astrocytes are complex bushy cells that serve important functions through close contacts between their processes and synapses. However, the spatial interactions and dynamics of astrocyte processes relative to synapses have proven problematic to study in adult living brain tissue. Here, we report a genetically targeted neuron-astrocyte proximity assay (NAPA) to measure astrocyte-synapse spatial interactions within intact brain preparations and at synaptic distance scales. The method exploits resonance energy transfer between extracellularly displayed fluorescent proteins targeted to synapses and astrocyte processes. We validated the method in the striatal microcircuitry following in vivo expression. We determined the proximity of striatal astrocyte processes to distinct neuronal input pathways, to D1 and D2 medium spiny neuron synapses, and we evaluated how astrocyte-to-excitatory synapse proximity changed following cortical afferent stimulation, during ischemia and in a model of Huntington's disease. NAPA provides a simple approach to measure astrocyte-synapse spatial interactions in a variety of experimental scenarios. VIDEO ABSTRACT. PMID- 29621489 TI - Regulation of Body Temperature by the Nervous System. AB - The regulation of body temperature is one of the most critical functions of the nervous system. Here we review our current understanding of thermoregulation in mammals. We outline the molecules and cells that measure body temperature in the periphery, the neural pathways that communicate this information to the brain, and the central circuits that coordinate the homeostatic response. We also discuss some of the key unresolved issues in this field, including the following: the role of temperature sensing in the brain, the molecular identity of the warm sensor, the central representation of the labeled line for cold, and the neural substrates of thermoregulatory behavior. We suggest that approaches for molecularly defined circuit analysis will provide new insight into these topics in the near future. PMID- 29621493 TI - Temporal properties of amodal completion: Influences of knowledge. AB - We studied the influence of knowledge in the interpretation of partly occluded objects. In the past decades, amodal completion has often been studied by using abstract, meaningless outlines of rather stylistic, geometric shapes. It has been recognized that smooth continuation of partly occluded contours behind an occluding surface is a strong completion tendency. In the current study we contrast this structurally driven completion tendency with knowledge driven tendencies. We used a set of partly occluded well-known objects for which structure-based completions and knowledge-based completions resulted in either the same or different interpretations. We adopted the behavioural primed matching paradigm to measure differential priming effects due to these completion tendencies. Our results implied differential temporal properties for structure based and knowledge-based effects during perception of partly occluded objects. Interestingly, knowledge has an influence as early as 150 ms after the onset of the prime. PMID- 29621494 TI - Pirfenidone inhibits cryoablation induced local macrophage infiltration along with its associated TGFb1 expression and serum cytokine level in a mouse model. AB - PURPOSE: To investigate the effects of pirfenidone (PFD) on post-cryoablation inflammation in a mouse model. MATERIALS AND METHODS: In this IACUC-approved study, eighty Balb/c mice were randomly divided into four groups (20/group): sham + vehicle, sham + PFD, cryoablation + vehicle, and cryoablation + PFD. For cryoablation groups, a 20% freeze rate cryoablation (20 s to less than -100 degrees C) was used to ablate normal muscle in the right flank. For sham groups, the cryoprobe was advanced into the flank and maintained for 20 s without ablation. PFD or vehicle solution was intraperitoneally injected (5 mg/kg) at days 0, 1, 2, 3, and then every other day until day 13 after cryoablation. Mice were euthanized at days 1, 3, 7, and 14. Blood samples were used for serum IL-6, IL-10, and TGFbeta1 analysis using electrochemiluminescence and ELISA assays, respectively. Immunohistochemistry-stained ablated tissues were used to analyze macrophage infiltration and local TGFbeta1 expression in the border region surrounding the cryoablation-induced coagulation zone. RESULTS: Cryoablation induced macrophage infiltration and increased TGFbeta1 expression in the border of the necrotic zone, and high levels of serum IL-6, peaking at days 7 (70.5 +/- 8.46/HPF), 14 (228 +/- 18.36/HPF), and 7 (298.67 +/- 92.63), respectively. Animals receiving PFD showed reduced macrophage infiltration (35.5 +/- 16.93/HPF at day 7, p < 0.01) and cytokine levels (60.2 +/- 7.6/HPF at day 14, p < 0.01). PFD also significantly reduced serum IL-6 levels (p < 0.001 vs. all non-PFD groups). CONCLUSIONS: PFD mitigates cryoablation induced muscle tissue macrophage infiltration, increased IL-6 levels, and local TGFbeta1 expression in a small animal model. PMID- 29621495 TI - Vesicles mimicking normal and cancer cell membranes exhibit differential responses to the cell-penetrating peptide Pep-1. AB - The cell-penetrating peptide (CPP) Pep-1 presents a great potential in drug delivery due to its intrinsic property to cross plasma membrane. However, its mechanism of entry into the cell remains unresolved. In this study, we compare the selectivity of Pep-1 towards vesicles mimicking normal and cancer cell membranes. The interaction was performed in a wide range of peptide-to-lipid molar ratios using infrared (IR), fluorescence, scanning electron microscopy (SEM), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC) techniques. At low peptide concentration, fluorescence experiments show that lipid-phosphatidylserine (PS) seems to enable Pep-1 translocation into cancer cell membrane as evidenced by the blue shift of its maximal emission wavelength. DSC data show that Pep-1 induces segregation of lipids. At high peptide concentration, IR data indicate that the interaction of Pep-1 is relatively stronger with normal cell membrane than with cancer cell membrane through the phosphate groups, while the interaction is weaker with normal cell membrane than with cancer cell membrane through the carbonyl groups. TGA and DSC data reveal that vesicles of normal cell membrane are thermally more stable than vesicles of cancer cell membrane. This suggests that the additional lipid PS included in cancer cell membrane has a destabilizing effect on the membrane structure. SEM images reveal that Pep-1 form superstructures including spherical particles and fibrils in the presence of both model membranes. PS seems to enhance peptide transport across cellular membranes. The biophysical techniques in this study provide valuable insights into the properties of CPPs in drug delivery systems. PMID- 29621498 TI - Urinary Ascites Secondary to Bilateral Mid-ureteral Stenosis in a Neonate. AB - Urinary ascites is most commonly seen in fetuses and newborns with obstructive uropathy. The majority of cases are associated with lower urinary tract obstruction, such as posterior urethral valves. In this report, we present a unique case of neonatal urinary ascites caused by congenital supravesical obstruction. To date, neonatal urinary ascites secondary to bilateral mid ureteral stenosis without a history of antenatal diagnosis has not been reported. PMID- 29621496 TI - Hydrophobic interactions modulate antimicrobial peptoid selectivity towards anionic lipid membranes. AB - Hydrophobic interactions govern specificity for natural antimicrobial peptides. No such relationship has been established for synthetic peptoids that mimic antimicrobial peptides. Peptoid macrocycles synthesized with five different aromatic groups are investigated by minimum inhibitory and hemolytic concentration assays, epifluorescence microscopy, atomic force microscopy, and X ray reflectivity. Peptoid hydrophobicity is determined using high performance liquid chromatography. Disruption of bacterial but not eukaryotic lipid membranes is demonstrated on the solid supported lipid bilayers and Langmuir monolayers. X ray reflectivity studies demonstrate that intercalation of peptoids with zwitterionic or negatively charged lipid membranes is found to be regulated by hydrophobicity. Critical levels of peptoid selectivity are demonstrated and found to be modulated by their hydrophobic groups. It is suggested that peptoids may follow different optimization schemes as compared to their natural analogues. PMID- 29621497 TI - Arsenic-gene interactions and beta-cell function in the Strong Heart Family Study. AB - We explored arsenic-gene interactions influencing pancreatic beta-cell activity in the Strong Heart Family Study (SHFS). We considered 42 variants selected for associations with either beta-cell function (31 variants) or arsenic metabolism (11 variants) in the SHFS. Beta-cell function was calculated as homeostatic model - beta corrected for insulin resistance (cHOMA-B) by regressing homeostatic model - insulin resistance (HOMA-IR) on HOMA-B and adding mean HOMA-B. Arsenic exposure was dichotomized at the median of the sum of creatinine-corrected inorganic and organic arsenic species measured by high performance liquid chromatography inductively coupled plasma mass spectrometry (HPLC-ICPMS). Additive GxE models for cHOMA-B were adjusted for age and ancestry, and accounted for family relationships. Models were stratified by center (Arizona, Oklahoma, North Dakota and South Dakota) and meta-analyzed. The two interactions between higher vs. lower arsenic and SNPs for cHOMA-B that were nominally significant at P < 0.05 were with rs10738708 (SNP overall effect -3.91, P = 0.56; interaction effect with arsenic -31.14, P = 0.02) and rs4607517 (SNP overall effect +16.61, P = 0.03; interaction effect with arsenic +27.02, P = 0.03). The corresponding genes GCK and TUSC1 suggest oxidative stress and apoptosis as possible mechanisms for arsenic impacts on beta-cell function. No interactions were Bonferroni significant (1.16 * 10-3). Our findings are suggestive of oligogenic moderation of arsenic impacts on pancreatic beta-cell endocrine function, but were not Bonferroni-significant. PMID- 29621499 TI - New insight into the allosteric effect of L-tyrosine on mushroom tyrosinase during L-dopa production. AB - Kinetics studies of L-tyrosine (LTy) ortho-hydroxylation by mushroom tyrosinase (MT) confirmed that MT was severely, but not completely, inhibited at higher concentrations of LTy. Despite the availability of the crystal structure reports, no allosteric site has been identified on MT. To examine the assumption that a non-specific binding site works as a regulatory site, docking simulations were run for the second molecule of L-tyrosine (LTy2) on the complexes of the first L tyrosine molecule (LTy1) with the heavy chain (H) of MT (LTy1/HMT) and its dimer with the light chain (Ty1/LHMT). In both, LTy2 occupied a non-specific binding site (MTPc). MD simulations revealed LTy2/HMT/LTy1 and LTy2/LHMT/LTy1 were stable. Binding free-energy analysis supported the formation of LTy2/HMT/LTy1 and LTy2/LHMT/LTy1 at higher concentrations of LTy and disclosed the importance of DeltaEelec and DeltaGpolar during binding of LTy2 to MTPc. Upon LTy2 binding to MTPc, the Cu-Cu distance remained unchanged while the spatial position of LTy1 in the active site (MTPa) changed so that it would not be able to participate in ortho-hydroxylation. This study suggests a tuning role for L chain during binding of the ligands to MTPa and MTPc. Given these results, a plausible mechanism was proposed for the MT substrate inhibition. PMID- 29621500 TI - Intra-fibrillar citric acid crosslinking of marine collagen electrospun nanofibres. AB - The physical strength of the collagen fibre network in the extracellular matrix is due to the covalent crosslinks between the molecules within the fibres (intra fibrillar crosslinks). Citric acid was investigated as an agent to introduce crosslinks within marine collagen electrospun fibres. We used collagen films to understand the ideal conditions for citric acid crosslinking. This information was used to develop an optimised method for intra-fibrillar crosslinking in electrospun marine collagen fibres, which increased the stability of these fibres in aqueous environments. The optimised method included a spinning solution containing collagen and citric acid at pH3.5 at high concentrations (260:1 citric acid:collagen molar ratio) coupled with high temperature annealing (165 degrees C), which resulted in the highest intra-fibrillar crosslinking density in electrospun fibres. PMID- 29621501 TI - An innovative immunosensor for ultrasensitive detection of breast cancer specific carbohydrate (CA 15-3) in unprocessed human plasma and MCF-7 breast cancer cell lysates using gold nanospear electrochemically assembled onto thiolated graphene quantum dots. AB - The accurate quantification of the level of breast cancer specific protein CA 15 3 in serum is crucial for cancer prognosis. This work, a novel and sensitive label-free immunoassay based on gold nanospear (Au NSs) electrochemically assembled onto thiolated graphene quantum dots (CysA/GQDs) for the detection of CA 15-3 antibodies. The CysA/Au NSs/GQDs hybrid interface provides a large surface area for the effective immobilization of CA 15-3 antigens, as well as it ascertains the bioactivity and stability of immobilized CA 15-3 antigens. Field emission scanning electron microscope (FE-SEM), and EDS photoelectron spectroscopies were used to monitor the sensor fabrication. Also, cyclic voltammetry was used to quantify the extent of Au NSs' surface coverage by CA 15 3 antigens. Square wave voltammetry (SWV) was employed to investigate the immunosensor fabrication and to monitor the binding events between CA 15-3 antigens-antibodies. Under optimized experimental conditions, the immunosensor displayed good sensitivity and specificity. The CA 15-3 were detected in a concentration as low as 0.11U/mL with a linear range from 0.16-125U/mL. The high sensitivity of the immunosensor may derive from the high loading of CA 15-3 antibodies on CysA/Au NSs/GQDs hybrid interface which increases the number of binding events. The method was successfully applied assay of the CA 15-3 in unprocessed human plasma samples. Also, proposed immunosensor was applied to the assay of CA 15-3 malignant cell line lysates (human breast adenocarcinoma cell line-MCF-7). PMID- 29621502 TI - Binding efficacy of tRNA with folic acid-PAMAM nanoparticles. AB - tRNA binding efficacy to folic acid-PAMAM nanoparticles was determined, using multiple spectroscopic methods, thermodynamic analysis and transmission electron microscopy (TEM). The structural analysis showed tRNA binds folic acid-PAMAM through H-bonding, hydrophobic and van der Waals contacts. As PAMAM size increases the binding efficacy and the stability of tRNA conjugates are enhanced. TEM analysis showed major tRNA morphological changes, upon folic acid-PAMAM complexation. Folic acid-PAMAM nanoparticles can transport tRNA in vitro. PMID- 29621503 TI - A comparative study of single-needle and coaxial electrospun amyloid-like protein nanofibers to investigate hydrophilic drug release behavior. AB - In this study, nanofibers containing an amyloid-like bovine serum albumin (AL BSA) carrier and a model drug (ampicillin) were produced by electrospinning. The release behavior of ampicillin was compared from electrospun nanofibers prepared as either coaxial or single-needle types. SEM images showed that the membranes had a uniform and smooth structure and the core/shell fibers were found to be thicker than the core fibers. Core/shell production was proved by transmission electron microscopy images. Fourier transform infrared spectroscopy indicated the existence of compatibility between ampicillin and the AL-BSA matrix. The in vitro antimicrobial properties of ampicillin were studied through the comparison of bacterial inhibition zones and ampicillin was found to be more effective against Gram-positive Staphylococcus aureus than Gram-negative Escherichia coli. Moreover, in vitro drug release tests were conducted to explore the relationship between the shell thickness and the drug release rate. A burst release was observed for all membranes owing to the small fiber diameters and thus short diffusion lengths. For core membranes, the drug release mechanism followed Fickian transport, which was close to zero-order kinetic. A typical biphasic release mechanism was observed for the core/shell nanofibers. Overall, we present the first evidence of AL-BSA as a potential core/shell drug mediator. PMID- 29621504 TI - Interleukin10-1082 A/G polymorphism: Allele frequency, correlation with disease markers, messenger RNA and serum levels in North Indian rheumatoid arthritis patients. AB - BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune inflammatory disorder of unknown etiology. IL-10 stimulates B cell survival and is involved in antibody isotype switching. The serum IL-10 levels are increased in RA patients. Ethnicity influences polymorphisms in cytokine genes. Therefore, this study was designed to explore possible association, if any, between polymorphism of IL10-1082 A/G, serum cytokine levels, inflammatory markers and gene expression in RA patients of North India. METHODOLOGY: A total of 187 RA patients classified according to American college of rheumatology 2010 criteria and 214 controls were included in the study. Levels of serum IL-10 and inflammatory markers were estimated by ELISA. PCR-RFLP was used to analyze IL10-1082 A/G polymorphism. Quantitative real time PCR was used to measure the mRNA expression of IL-10 gene. RESULTS: The serum inflammatory markers were significantly higher in RA patients. Circulating IL-10 levels were positively and significantly correlated with RF (r = 0.28), anti-CCP (r = 0.26), CRP (r = 0.17) and mRNA expression levels (r = 0.59) among RA patients. Homozygous mutant variant (GG) and heterozygous mutant variant (AG) were associated with patients of RA (OR = 2.87 and 1.55, p < 0.05) as compared to controls. The association still persisted when the heterozygous and homozygous mutants (AG + GG) were clubbed together (OR = 1.67, p < 0.05). The mRNA expression of IL-10 was found to be 3.63 folds higher (housekeeping gene, beta actin) and 2.42 folds higher (housekeeping gene, 18S rRNA) in RA patients as compared to controls. CONCLUSION: The results indicate that IL10-1082 A/G polymorphism is associated with genetic susceptibility/predisposition to RA in North Indian population. PMID- 29621506 TI - Parents' Knowledge and Education of Retinopathy of Prematurity in Four California Neonatal Intensive Care Units. AB - PURPOSE: Retinopathy of prematurity (ROP) may cause visual impairment in infants with very low birth weight. Lack of parent knowledge may contribute to gaps in screening and treatment. We studied parents' knowledge and education of ROP. DESIGN: Cross-sectional study. METHODS: Setting: Four high-acuity neonatal intensive care units in California (40-84 beds). PARTICIPANTS: Total of 194 English- and Spanish-speaking parents of very low birth weight (<1500 grams) infants recruited from September 2013 to April 2015. MAIN OUTCOME MEASURES: We asked parents what they knew about ROP, how they were educated about ROP, and their experiences obtaining outpatient eye care. We used multivariate analysis to assess whether parent knowledge was associated with level of English proficiency and literacy, education modality (verbal, written, online, video), and hospital transfer status. RESULTS: Of the 194 participants, 131 (68%) completed surveys: 18% had both limited English proficiency and low literacy while overall 26% had limited English proficiency and 37% had low literacy; 17% did not know that ROP is an eye disease, and 38% did not know that very low birth weight and prematurity are both risk factors for ROP. Parents reported receiving verbal (62%) or written (56%) information; few used online resources (12%) or videos (3%). Half reported receiving information about infants' retinopathy status at discharge. No education modality was associated with higher knowledge. Limited English proficiency and low literacy were associated with lower knowledge (vs English-proficient, literate). CONCLUSIONS: Parents of infants with very low birth weight, particularly those with limited English proficiency and low health literacy, lack knowledge about ROP. PMID- 29621505 TI - Structure of the NDH-2 - HQNO inhibited complex provides molecular insight into quinone-binding site inhibitors. AB - Type II NADH:quinone oxidoreductase (NDH-2) is a proposed drug-target of major pathogenic microorganisms such as Mycobacterium tuberculosis and Plasmodium falciparum. Many NDH-2 inhibitors have been identified, but rational drug development is impeded by the lack of information regarding their mode of action and associated inhibitor-bound NDH-2 structure. We have determined the crystal structure of NDH-2 complexed with a quinolone inhibitor 2-heptyl-4 hydroxyquinoline-N-oxide (HQNO). HQNO is nested into the slot-shaped tunnel of the Q-site, in which the quinone-head group is clamped by Q317 and I379 residues, and hydrogen-bonds to FAD. The interaction of HQNO with bacterial NDH-2 is very similar to the native substrate ubiquinone (UQ1) interactions in the yeast Ndi1 UQ1 complex structure, suggesting a conserved mechanism for quinone binding. Further, the structural analysis provided insight how modifications of quinolone scaffolds improve potency (e.g. quinolinyl pyrimidine derivatives) and suggests unexplored target space for the rational design of new NDH-2 inhibitors. PMID- 29621507 TI - Internal Limiting Membrane Peeling in Macula-off Retinal Detachment Complicated by Grade B Proliferative Vitreoretinopathy. AB - PURPOSE: To investigate the clinical benefit of internal limiting membrane (ILM) peeling as a surgical adjunct in the repair of primary retinal detachment (RD) complicated by grade B proliferative vitreoretinopathy (PVR). DESIGN: Retrospective, interventional, comparative case series. METHODS: Setting, study population, observationalprocedures and Main outcome measures. SETTING: Institutional. STUDY POPULATION: Seventy-five consecutive patients who underwent vitrectomy for primary macula-off RD complicated by grade B PVR. OBSERVATIONAL PROCEDURES: Patients were divided into an ILM peeling (Group P) and a no ILM peeling group (Group NP). MAIN OUTCOME MEASURES: Anatomic success rate, best corrected visual acuity, and spectral-domain optical coherence tomography (SD OCT) characteristics were collected at 1 and 6 months. RESULTS: In all, 37 eyes with ILM peeling were included in Group P and 38 eyes without ILM peeling were included in Group NP. The anatomic success rate after single surgery was higher in Group P (89%) than in Group NP (66%, P = .03). Mean final visual acuity was 0.41 +/- 0.40 logMAR in Group P vs 0.43 +/- 0.22 logMAR in Group NP (P = .82). We found no epiretinal membrane (ERM) formation in Group P, whereas 5 cases of ERM (20%) were detected in Group NP (P = .012). The 2 groups did not differ in terms of cystoid macular edema occurrence, macular thickness, or photoreceptor damage. CONCLUSIONS: ILM peeling during vitrectomy in macula-off RD complicated by grade B PVR reduces the need for a second surgery for redetachment or macular pucker. PMID- 29621508 TI - Angiopoietin-like 3 Is a Potential Biomarker for Retinopathy in Type 2 Diabetic Patients. AB - PURPOSE: To investigate whether angiopoietin-like 3 (ANGPTL3) and angiopoietin like 4 (ANGPTL4) are differentially associated with the severity of retinopathy in patients with type 2 diabetes mellitus (T2DM). DESIGN: Cross-sectional study. METHODS: Serum levels of ANGPTL3, ANGPTL4, high-sensitivity C-reactive protein (CRP), vascular adhesion molecule-1 (VCAM-1), intracellular adhesion molecule-1 (ICAM-1), and vascular endothelial growth factor (VEGF) were quantified by ELISA. Retinal images were recorded to assess the grade of diabetic retinopathy (DR). Multivariable-adjusted logistic analysis was performed to estimate the association of each biomarker and DR stage. RESULTS: Among 1192 T2DM patients, 426 (35.7%) had nonproliferative diabetic retinopathy (NPDR) and 56 (4.5%) had proliferative diabetic retinopathy (PDR). After adjusting for covariables, the odds ratios expressing the risk of having DR vs no DR (n = 710 vs 482) were 1.23 (95% confidence interval [CI], 1.08-1.40, P = .002) for ANGPTL3; 0.90 (95% CI, 0.79-1.02; P = .095) for ANGPTL4; and 1.14 (95% CI, 1.00-1.29; P = .044) for VEGF. The risk of having no DR vs NPDR (n = 710 vs 426) was 1.16 (95% CI, 1.01 1.32; P = .036) for ANGPTL3; 0.90 (95% CI, 0.79-1.04; P = .15) for ANGPTL4; and 1.14 (95% CI, 1.00-1.31; P = .045) for VEGF. The odds ratios of having NPDR vs PDR (n = 426 vs 56) was 1.47 (95% CI, 1.03-2.10; P = .035) for serum ANGPTL3; 0.96 (95% CI, 0.69-1.35; P = .83) for ANGPTL4; and 1.05 (95% CI, 0.77-1.45; P = .74) for VEGF. CONCLUSIONS: ANGPTL3 is independently and strongly associated with DR progression in all stages. Blockade of ANGPTL3 signal in retina might postpone the onset and development of DR in T2DM patients. PMID- 29621509 TI - Long-term Choroidal Thickness Changes in Eyes With Drusenoid Pigment Epithelium Detachment. AB - PURPOSE: To analyze the changes in visual acuity and subfoveal choroidal thickness in patients with non-neovascular age-related macular degeneration (AMD) and drusenoid pigment epithelium detachments (PED). DESIGN: Consecutive observational case series. METHODS: Observational retrospective review of eyes diagnosed with drusenoid PED in a single clinical setting. Demographic and clinical data included age, sex, laterality, best-corrected visual acuity (BCVA), and subfoveal choroidal thickness measured at baseline. before and after the collapse of the PED, and at the last available follow-up. The presence of geographic atrophy (GA) was also assessed. RESULTS: Thirty-seven eyes of 25 patients (18 female) were included in the analysis. Mean age at baseline was 71 +/- 8.4 years. During a mean follow-up period of 4.9 +/-1.9 years, PED collapse was observed in 25 eyes (68%). Mean BCVA, mean maximum PED height, and mean subfoveal choroidal thickness significantly decreased from baseline to the last available follow-up (P < .001) in patients showing PED collapse. Choroidal thinning was faster during the PED collapse (speed rate of 35.9 MUm/year). From those, 23 eyes (92%) developed GA. A significant correlation between the area of GA and the decrease in choroidal thickness was found (P = .010). CONCLUSIONS: Choroidal thickness significantly decreased in eyes showing drusenoid PED collapse, but not in eyes in which the PED persisted. A significant correlation with resultant GA area following PED collapse and the magnitude of choroidal thinning was found. Further studies are warranted to better understand the mechanisms involved in the occurrence of choroidal changes during the life cycle of drusenoid PEDs. PMID- 29621510 TI - Peripheral Changes Associated With Delayed Dark Adaptation in Age-related Macular Degeneration. AB - PURPOSE: To study the association between peripheral changes in age-related macular degeneration (AMD) and dark adaptation (DA). DESIGN: Prospective, cross sectional study. METHODS: We recruited patients with AMD and a control group (>50 years) without any vitreoretinal disease. Ultra-widefield (UWF) pseudocolor and fundus autofluorescence (FAF) were obtained, and were assessed by 2 graders for the presence of several peripheral changes in perimacular, midperipheral, and far peripheral zones. All participants were also imaged with 7-field color fundus photographs used for AMD staging (Age-Related Eye Disease Study classification system). Both eyes of study participants were tested with a dark adaptation (DA) extended protocol (20 minutes). Multilevel mixed-effect models (accounting for correlated outcomes between 2 eyes) were used for analyses. RESULTS: We included 128 eyes (n = 72 patients), 75% with AMD and the remainder controls. The presence of reticular pigmentary changes in the midperipheral (beta = 4.3, P = .012) and far-peripheral zones (beta = 8.4, P < .001) was associated with delayed rod intercept times (RITs), even after adjusting for confounding factors. The presence, number, and extent of peripheral classic drusen did not show a similar association (P >= .148). The presence of a mottled decreased FAF pattern in the midperipheral zone was also associated with prolonged RITs (beta = 4.4, P = .031). CONCLUSION: Our results suggest an association between DA and the presence of peripheral reticular pigmentary changes, as well as the presence of a peripheral mottled decreased FAF pattern. This provides new insights on the clinical significance of peripheral changes in AMD, and their contribution to impairments on DA. PMID- 29621511 TI - Spectral-domain Optical Coherence Tomography in Limbal Stem Cell Deficiency. A Case-Control Study. AB - PURPOSE: To evaluate the efficacy of optical coherence tomography (OCT) as a noncontact method for imaging the ocular surface in limbal stem cell deficiency (LSCD) and normal eyes. DESIGN: Retrospective case-control study. METHODS: Setting: Institutional. STUDY POPULATION: Twenty-two eyes with LSCD (study group, 22 patients) and 10 normal eyes (control group, 10 patients). OBSERVATION PROCEDURES: Spectral-domain (SD)-OCT and confocal microscopy in both the limbal and central corneal zones. MAIN OUTCOME MEASURES: Pachymetry data from the central cornea, presence of the palisades of Vogt, limbal crypts, and clear transition between the hyporeflective corneal epithelium and the hyperreflective conjunctival epithelium assessed on cross sections parallel and perpendicular to the limbus and en face sections of the limbal region. Parallel, perpendicular, and en face limbal scores were calculated by adding results of the 4 limbal quadrants. RESULTS: Both the difference between the minimal and the maximal epithelial thicknesses and the epithelial thickness standard deviation were significantly higher in the study group (mean, 47 MUm/10 MUm) compared with the control group (mean, 8 MUm/2 MUm). The parallel, perpendicular, and en face limbal scores were significantly lower in the study group (0.1/0.6/0.2) compared with the control group (7.4/4.8/3.5). Poorer visual acuity was significantly associated with higher standard deviation and difference between minimal and maximal corneal epithelial thicknesses (rs, +0.81/+0.77) and lower parallel, perpendicular, and en face limbal scores (-0.82/-0.73/-0.82). CONCLUSIONS: SD-OCT of both the central cornea and limbus with various section orientations is a valuable imaging modality allowing noninvasive and rapid overall precise assessment of both normal and LSCD eyes. PMID- 29621512 TI - Evolution of Consecutive Descemet Membrane Endothelial Keratoplasty Outcomes Throughout a 5-Year Period Performed by Two Experienced Surgeons. AB - PURPOSE: To assess the evolution of clinical outcomes of more than 1300 Descemet membrane endothelial keratoplasties (DMEKs) alone or in combination with cataract surgery (triple DMEK) throughout a 5-year period at a single center, performed by 2 already experienced DMEK surgeons. DESIGN: Retrospective trend study. METHODS: Review of charts between July 2011 and July 2016 at the Department of Ophthalmology, University of Cologne, Germany. RESULTS: A total of 1340 out of 1340 eyes with sufficient information were included. Six-month and 12-month best spectacle-corrected visual acuity (logMAR) had already reached high levels for the surgeries performed in 2011 (0.10 +/- 0.06 and 0.09 +/- 0.07, respectively) and did not further improve in later years (P = .272). Likewise, endothelial cell loss (ECL) and central corneal thickness (CCT) reached comparable levels independently of the year of surgery (average 12-month ECL was 38% +/- 15% and average 6-month CCT decrease was 19% +/- 11%). However, there was a decrease in the rebubbling rate, from 68% in 2011, 67% in 2012, and 70% in 2013 to 53% in 2014, 29% in 2015, and 16% in 2016, which was associated with the introduction of 20% sulfur hexafluoride (SF6) instead of room air for anterior chamber tamponade in 2015 (n = 986; P < .001). The percentage of severe complications after DMEK surgery also decreased significantly with surgeons' growing experience (P < .001; 95% confidence interval [0.09; 0.12]) over the years. CONCLUSIONS: After an initial learning curve in DMEK surgery, results of visual acuity and ECL do not seem to further improve. However, the complication rate continuously declines, at least over the subsequent 5-year period analyzed herein. PMID- 29621513 TI - Altered Tryptophan Levels in Patients With Inflammatory Bowel Disease Owing to Colonic Leakage, Metabolism, or Malabsorption? PMID- 29621514 TI - Pretreatment Lesions on Magnetic Resonance Imaging in Patients With Hepatitis C Virus Infection Diagnosed With Hepatocellular Carcinoma After Initiating Direct Acting Antiviral Therapy. PMID- 29621515 TI - The Multiple Modulation of miR-122 in the Attenuation of Alcoholic Liver Disease. PMID- 29621516 TI - Methylated MicroRNA Biomarkers for Identifying Ulcerative Colitis-Associated Colorectal Cancers. PMID- 29621517 TI - Predicting Outcomes of Patients Undergoing Liver Transplantation for Hepatocellular Carcinoma. PMID- 29621518 TI - Chronic Pancreatitis Prognosis Score System Is Not Ready Yet. PMID- 29621519 TI - Individual State Hepatitis C Data Supports Expanding Screening Beyond Baby Boomers to All Adults. PMID- 29621520 TI - Reply. PMID- 29621521 TI - Histone acetyltransferase 1 up regulates Bcl2L12 expression in nasopharyngeal cancer cells. AB - The deregulation of Bcl2L12 expression in cancer has been recognized, but the causative factors are unknown. Histone acetyltransferases (HAT) play critical roles in the regulation gene transcription. This study tests a hypothesis that the aberrant activities of HAT induce deregulation of Bcl2L12 in nasopharyngeal cancer (NPC). In this study, human NPC tissues were collected from the clinic. The expression of Bcl2L12 and HATs in NPC cells was analyzed by real time RT-PCR and Western blotting. NPC cell apoptosis was analyzed by flow cytometry. The results showed that by screening the subtypes of HAT, the levels of HAT1 were uniquely higher in NPC as compared with non-cancer nasopharyngeal tissue. The levels of Bcl2L12 in NPC cells were positively correlated with HAT1. HAT1 involved in the STAT5 binding to the Bcl2L12 promoter. HAT1 increased the expression of Bcl2L12. Bcl2L12 mediated the effects of HAT1 on suppressing NPC cell apoptosis. Absorption of the HAT1 shRNA plasmid-carrying liposomes induced NPC cell apoptosis. In conclusion, inhibition of HAT1 can induce NPC cell apoptosis via increasing Bcl2L12 expression, which can be a potential therapy for NPC treatment. PMID- 29621522 TI - Metabolic changes in urine and serum during progression of diabetic kidney disease in a mouse model. AB - Diabetic kidney disease (DKD) involves various pathogenic processes during progression to end stage renal disease, and activated metabolic pathways might be changing based on major pathophysiologic mechanisms as DKD progresses. In this study, nuclear magnetic resonance spectroscopy (NMR)-based metabolic profiling was performed in db/db mice to suggest potential biomarkers for early detection and its progression. We compared concentrations of serum and urinary metabolites between db/m and db/db mice at 8 or 20 weeks of age and investigated whether changes between 8 and 20 weeks in each group were significant. The metabolic profiles demonstrated significantly increased urine levels of glucose and tricarboxylic acid cycle intermediates at both 8 and 20 weeks of age in db/db mice. These intermediates also exhibited strong positive associations with urinary albumin excretion, suggesting that they may be potential biomarkers for early diagnosis. On the contrary, branched chain amino acid and homocysteine methionine metabolism were activated early in the disease, whereas ketone and fatty acid metabolism were significantly changed in the late phase of the disease. We demonstrated phase-specific alterations in metabolites during progression of DKD. This study provides insights into perturbed mechanisms during evolution of the disease and identifies potential novel biomarkers for DKD. PMID- 29621523 TI - Effects of quercetin on heart nitric oxide metabolism in l-NAME treated rats. AB - This study investigated the effects of a quercetin-supplemented diet on the biochemical changes installed in the heart of NO-deficient rats in terms of oxidants production and NO bioavailability determinants. Sprague-Dawley rats were subjected to Nomega-nitro-l-arginine methyl ester (l-NAME) treatment (360 mg/L l NAME in the drinking water, 4 d) with or without supplementation with quercetin (4 g/kg diet). l-NAME administration led to increased blood pressure (BP) (30%), decreased nitric oxide synthase (NOS) activity (50%), and increases in NADPH oxidase (NOX)-dependent superoxide anion production (60%) and p47phox protein level (65%). The co-administration of quercetin prevented the increase in BP and the activation of NOX but did not modify the decrease in NOS activity caused by l NAME. In addition, quercetin affected oxidative stress parameters as glutathione oxidation, and the activities of oxidant detoxifying enzymes superoxide dismutase, glutathione peroxidase, and catalase. Thus, quercetin administration counteracts l-NAME effects on NO bioavailability determinants in vivo, essentially through controlling NOX-mediated superoxide anion production. PMID- 29621524 TI - Snakebites in French Guiana: Conclusions of an international symposium. AB - A workshop on epidemiology and management of snakebites in French Guiana was performed at Cayenne, French Guiana from September 15 to September 16, 2017, under the auspices of the French Regional Health Agency (ARS) and the Pan American Health Organization (PAHO). The activity was attended by experts from France (Angers, Martinique, French Guiana, Guadeloupe, and Paris), Costa Rica, Brazil, Saint Lucia, and Surinam. The epidemiology, clinical manifestations, clinical grading and the management of snakebite in French Guiana were discussed. The conclusions of this symposium illustrated the urgent need to ensure accessibility of effective and safe polyvalent viperid antivenom in French Guiana. Finally, the results of this symposium have forged ties based on mutual goals and objectives. PMID- 29621525 TI - Simultaneous degradation of aflatoxin B1 and zearalenone by a microbial consortium. AB - Mycotoxins are toxic secondary metabolites mainly produced by filamentous fungal species that commonly contaminate staple foods and feeds. They cause significant economic losses and greatly harm food security. Simultaneous contamination of multiple mycotoxins and the accompanying additive and synergistic effects may cause even more serious harm. To develop a microbial consortium with the ability to degrade multiple mycotoxins, a previously identified consortium with aflatoxin B1 (AFB1) degradation ability, TADC7, was domesticated by co-culturing with 500 MUg l-1 AFB1 and 500 MUg l-1 zearalenone (ZEA), yielding the derived microbial consortium TMDC. After 168 h of co-culture with TMDC, 2000 MUg l-1AFB1 and 2000 MUg l-1 ZEA were degraded by 98.9% and 88.5%, respectively. The proteins or enzymes in the TADC7 cell-free supernatant played a major role in mycotoxins degradation. The degradation ratios of 5000 MUg l-1 AFB1 and 5000 MUg l-1 ZEA by 48 h TMDC cell-free supernatant were 93.8% and 90.3% at 72 h, respectively. Based on 16S rRNA sequencing, Geobacillus and Tepidimicrobium might play important roles in mycotoxin degradation by TMDC, and the TMDC community composition was stable, irrespective of mycotoxin. This study established the biodegradation of different categories of mycotoxins, and will facilitate the practical application of microbial consortia in mycotoxin degradation. PMID- 29621526 TI - Comparative studies on the cytotoxic effects induced by nodularin in primary carp leukocytes and the cells of the fish CLC line. AB - Nodularin, one of the toxins produced by cyanobacteria commonly occurring in brackish waters, is a cyclic pentapeptide, that may exert adverse effects on animal and human health. The aim of the present study was to evaluate the cytotoxicity of nodularin on different fish cellular models. The leukocytes isolated from carp head kidney and common carp (Cyprinus carpio L.) leukocyte cell line (CLC) were incubated with the cyanotoxin at the concentrations of 0.001, 0.01, 0.05 or 0.1 MUg/mL. Treatment of cells with the higher concentrations of the toxin resulted in a dramatic decrease in cell viability. Simultaneously, we observed an increase in the percentage of necrotic cells. Nodularin also induced apoptosis as demonstrated by increased caspase-3/7 activity, and DNA fragmentation. We found, that primary cell cultures were more sensitive to the toxin than CLC cells. Our study also demonstrated significant increases in intracellular ROS production and decreases in GSH levels, observed in both primary leukocytes and CLC cells exposed to nodularin at 0.01-0.1 MUg/mL. These cells exhibited similar GSH/GSSG ratios and similar level of oxidized glutathione. PMID- 29621527 TI - Transmammary transfer of toxicity to nursing kids from Isocoma pluriflora (rayless goldenrod) dosed to lactating goats. AB - Rayless goldenrod (RG; Isocoma pluriflora) poisons livestock in the southwestern U.S., west Texas, and northern Mexico. The putative toxin(s) have historically been thought to be benzofuran ketones. Goats have been used successfully as a model of RG poisoning. The transmammary transfer of toxicity to offspring from lactating goats has not been studied, thus the objective of this study was to determine if nursing kids would become poisoned via mother's milk when the dams were dosed with RG. Twelve lactating goats (6 controls and 6 treated; all with twin kids) were dosed via oral gavage with alfalfa or rayless goldenrod at 2% of BW per day for 14 days. Two kids showed overt clinical signs near the end of the study; however, no dams showed clinical signs, and none developed exercise intolerance or muscle weakness. After day 11 of treatment, the RG kids showed increased (P < 0.05) serum aspartate aminotransferase (AST), alanine aminotransferase (ALT), and creatinine kinase (CK) activities until exposure to the plant via mothers' milk ended. Serum CK activity of kids declined rapidly over 7 days after transmammary exposure ended. Histopathology revealed that one kid had extensive myonecrosis that involved both myocardium and skeletal muscles. The other kids from RG-treated does had minimal myocyte degeneration and necrosis characterized by individual myofiber swelling, hypereosinophilia and loss of striation. Benzofuran ketones were not detected in the milk of lactating goats; further, dosing with RG did not alter milk composition. In summary, milk ingestion from does dosed with >300 mg/kg BW of benzofuran ketones from RG over 14 days increased mean CK concentrations in treated kids compared to controls; however kids rapidly recovered when exposure ended. Additional work is needed to better define benzofuran ketone metabolism, toxicity, and animal susceptibility. PMID- 29621528 TI - What can be learned in the snake antivenom field from the developments in human plasma derived products? AB - Human plasma-derived medicinal products and snake antivenom immunoglobulins are unique and complex therapeutic protein products. Human plasma products are obtained by fractionating large pools of plasma collected from blood plasma donors. They comprise a wide range of protein products, including polyvalent and hyperimmune immunoglobulins, coagulation factors, albumin, and various protease inhibitors that are transfused to patients affected by congenital or acquired protein deficiencies, immunological disorders, or metabolic diseases. Snake antivenoms are manufactured from pools of plasma collected from animals, typically horses, which have been immunized against snake venoms. Transfusing antivenoms is the cornerstone therapy to treat patients affected by snakebite envenoming. Over the last thirty years, much technical and regulatory evolution has been implemented to ensure that this class of biologicals meets modern quality requirements. The purpose of this review is to compare the main developments that took place in plasma production, protein fractionation, pathogen safety, quality control, preclinical and clinical studies, and regulations of these products. We also analyze whether both fields have been influencing and cross-fertilizing each other technically and in regulatory aspects to reach modern safety and efficacy standards at global levels, and how experience in the human plasma fractionation industry can further impact the manufacture of snake antivenom and that of other animal-derived antisera. PMID- 29621529 TI - Severe snakebite envenomation in French Guiana: When antivenom is not available. AB - In French Guiana, Bothrops atrox, Bothrops brazili, Bothrops bilineatus, Lachesis muta and Micrurus sp are responsible for most cases of snakebite envenomation. The clinical features in patients suffering from envenomations by viperid snakes involve local tissue damage and systemic manifestations, such as hemorrhage, coagulopathies and hemodynamic instability. We report a severe case of envenomation in a patient bitten by a large unidentified pit viper in French Guiana. Due to lack of antivenom, the patient only received symptomatic management. Severe manifestations of local and systemic envenomation developed, and the patient needed multiple debridement procedures and ultimately required a transfemoral amputation. In addition, Aeromonas hydrophila was cultivated from the affected tissue, suggesting that infection contributed to necrotizing fasciitis. This case highlights the clinical features of a severe viperid snakebite envenomation, and illustrates the urgent need to ensure accessibility of effective and safe polyvalent viperid antivenom in French Guiana. PMID- 29621530 TI - Molecular cloning and expression study on Toll-like receptor 5M in turbot, Scophthalmus maximus. AB - Toll-like receptor 5 (TLR5) is responsible for the recognition of bacterial flagellin in mammals and play an important role in innate immunity. In the present study, a TLR5M gene was cloned from turbot, Scophthalmus maximus, and its immune responsive expression was subsequently studied in vivo. The Scophthalmus maximus (Sm)TLR5M gene is 4268 bp in length, consists of four exons and three introns and encodes a peptide of 892 amino acids (aa). The deduced protein possesses a signal peptide sequence, a leucine-rich repeat (LRR) domain composed of 23 LRR motifs, a transmembrane (TM) domain and a Toll/interleukin-1 receptor (TIR) domain. Phylogenetic analysis grouped SmTLR5M with other teleost TLR5Ms. A number of binding sites for transcription factors involved in immune response regulation were predicted in the 5'-flanking region of SmTLR5M. Quantitative real time PCR (qPCR) analysis demonstrated that SmTLR5M mRNA was expressed ubiquitously with higher levels in head kidney and spleen. Its expression following stimulation with flagellin and lipopolysaccharide (LPS) was further tested in gills, spleen, head kidney and muscle. The maximum increases of SmTLR5M transcript levels ranged from 1.3 to 6.8-fold and appeared at 3 h to 5 day post injection depending on different organs and stimuli. These findings suggest that SmTLR5M may play an important role in immune responses to infections with bacterial pathogens. PMID- 29621531 TI - Honeybee (Apis cerana) vitellogenin acts as an antimicrobial and antioxidant agent in the body and venom. AB - Honeybee (Apis mellifera) egg-yolk protein vitellogenin (Vg) plays roles in immunity, antioxidation, and life span beyond reproduction, but it also acts as an allergen Api m 12 in venom. Here we established antimicrobial and antioxidant roles of honeybee Vg in the body and venom. Using the cDNA encoding Vg identified from Asiatic honeybee (A. cerana) workers, recombinant A. cerana Vg (AcVg) protein of approximately 180 kDa was produced in baculovirus-infected insect cells. In A. cerana worker bees, AcVg was expressed in the fat body and venom gland and was present in the secreted venom. AcVg induced structural damage in microbial cell walls via binding to microbial surfaces and exhibited antimicrobial activity against bacteria and fungi. AcVg protected mammalian and insect cells against oxidative damage through direct shielding of cell membranes. Interestingly, AcVg exhibited DNA protection activity against reactive oxygen species (ROS). Furthermore, the transcript level of AcVg was upregulated in the fat body, but not in the venom gland, of worker bees with antimicrobial peptides and antioxidant enzymes in response to microbial infection and oxidative stress. Our data indicate that AcVg is involved in innate immunity upon infection and in a defense system against ROS, supporting a crucial role of honeybee Vg as an antimicrobial and antioxidant agent in the body and venom. PMID- 29621532 TI - The D5 region of the intelectin domain is a new type of carbohydrate recognition domain in the intelectin gene family. AB - Intelectin is a recently characterized soluble galactofuranose-binding lectin that exists in species ranging from amphioxus to human. Interestingly, intelectin does not contain a canonical carbohydrate-recognition domain (CRD). Therefore, we designed serial deletions of intelectin in the Chinese amphioxus (Branchiostoma belcheri tsingtauense, AmphiITLN71469) in order to identify functional regions required for carbohydrate binding. Our results revealed that Domain 5 (aa 203 302) was able to bind lipopolysaccarides (LPS) or peptidoglycan (PGN) and agglutinate bacteria as efficiently as the full-length protein. Three dimensional (3D) atomic models of Domain 5 were generated by ab initio based program QUARK and by Iterative Threading Assembly Refinement (I-TASSER) programs, in which four amino acids mediating calcium-binding (G54-G55-G56-E91) were identified by hemagglutination assay. Furthermore, a striking functional conservation of Domain 5 was detected in zebrafish intelectin 1. Taken together, our findings identified for the first time a new CRD domain in intelectin, thereby providing new knowledge leading to a better understanding of pathogen-host interactions. PMID- 29621533 TI - Distribution of black flies (Diptera: Simuliidae) along an elevational gradient in the Andes Mountains of Colombia during the El Nino Southern Oscillation. AB - Vector ecology is a key factor in understanding the transmission of disease agents, with each species having an optimal range of environmental requirements. Scarce data, however, are available for how interactions of local and broad-scale climate phenomena, such as seasonality and the El Nino Southern Oscillation (ENSO), affect simuliids. We, therefore, conducted an exploratory study to examine distribution patterns of species of Simuliidae along an elevational gradient of the Otun River in the Colombian Andes, encompassing four ecoregions. Larval and pupal simuliids were sampled at 52 sites ranging from 1800 to 4750 m above sea level in dry and wet seasons and during the La Nina phase (2011-2012) and the El Nino phase (2015-2016) of the ENSO; physicochemical measurements were taken during the El Nino phase. Twenty-seven species in two genera (Gigantodax and Simulium) were collected. Species richness and occurrence in each ecoregion were influenced by elevation, seasonality, and primarily the warm El Nino and cool La Nina phases of the ENSO. The degree of change differed among ecoregions and was related to physicochemical factors, mainly with stream discharge. Some putative simuliid vectors of Leucocytozoon, such as G. misitu and S. muiscorum, markedly changed in distribution and occurrence, potentially influencing parasite transmission. PMID- 29621534 TI - Diversity of dengue virus-3 genotype III in Jeddah, Saudi Arabia. AB - BACKGROUND: Dengue is the most important arboviral disease in tropical and subtropical countries. Dispersal of the vector and an increase in migratory flow between countries have led to large epidemics and severe clinical outcomes. Over the past 20 years, dengue epidemics have become more wide-spread and frequent. Previous studies have shown that dengue is endemic in Jeddah, Makkah and Al Madinah in western Saudi Arabia as well as in Jazan region in the southern part of the country. The four serotypes of dengue virus (DENV) have been reported from western Saudi Arabia. It has been suggested that pilgrims could play a significant and unique role in DENV-1 and DENV-2 introduction into Saudi Arabia, especially in the cities of Jeddah, Makkah and Al-Madinah during Hajj and Umrah seasons. However, only limited data on DENV-3 in Saudi Arabia are available. METHODS: All available DENV-3 sequences published and unpublished from Saudi Arabia and other countries were retrieved from Genbank and gene sequence repository and phylogenetically analyzed to examine the diversity of DENV-3 into the city of Jeddah. RESULTS: Based on the analysis of the envelope gene and non structural 1 (E/NS1) junction sequences, we show that there were at least four independent introductions of DENV-3, all from genotype III into Jeddah. The first introduction was most probably before 1997 as Saudi virus isolates from 1997 formed a cluster without any close relationship to other globally circulating isolates, suggesting their local circulation from previous introduction events. Two introductions were most probably in 2004 with isolates closely-related to isolates from Africa and India (Asia), in addition to another introduction in 2014 with isolates clustering with those from Singapore (Asia). CONCLUSIONS: Our data shows that only genotype III isolates of DENV-3 are circulating in Jeddah and highlights the potential role of pilgrims in DENV-3 importation into western Saudi Arabia and subsequent exportation to their home countries during Hajj and Umrah seasons. Therefore, it is highly recommended to establish DENV sentinel surveillance programs targeting clinical cases and the mosquito vector in the country to implement effective control measures and to minimize the burden of the disease in the kingdom. PMID- 29621535 TI - Coxiella burnetii in dairy goats with a history of reproductive disorders in Brazil. AB - Coxiella burnetii, an intracellular bacterium, is the agent of Q fever/coxiellosis, a worldwide zoonosis. Dairy animals are the primary reservoirs of C. burnetii, and although the disease is usually asymptomatic or subclinical, abortion is a serious clinical outcome among small ruminants. This study was conducted to investigate C. burnetii seroprevalence and infection In a flock of dairy goats in Brazil. Serum samples from 312 goats collected from a dairy goat flock with a history of reproductive failure were tested by a commercial ELISA (LSIVet Ruminant Q Fever - Serum/Milk; Thermo Fisher Scientific, Lissieu, France) for anti-C. burnetii IgG antibodies. Samples of cotyledons from 23 placentas were analyzed by nested PCR for the presence of the bacterial DNA. ELISA seroreactivity was found in 55.1% (172/312; 95% CI = 49.4%-60.7%) of the serum samples analyzed. C. burnetii DNA was detected in 8.7% (2/23) of the placental samples tested, where both animals were also seropositive. This study reports the first description of C. burnetii infection in an abortion outbreak in goats in Brazil. The results point out to the importance of including this disease in animal and public health surveillance programs as well as into the list of abortive diseases in goats in Brazil. PMID- 29621536 TI - Emergence of a genotype I variant of avian infectious bronchitis virus from Northern part of India. AB - Infectious bronchitis virus (IBV) is one of the foremost causes of a persistent economic burden to poultry industries worldwide. IBV belongs to the genus Gammacoronavirus within the family Coronaviridae. The IBV infection leads to respiratory and nephrogenic symptoms in broiler chickens. In addition, its infection leads to reduced fertility and hatchability in layer birds. We determined the first complete genome sequence of a variant IBV from an outbreak in Haryana state of the Northern part of India using next generation sequencing. On phylogenetic analysis of the IBV isolate, it clustered with genotype I lineage 1 (GI-1). The deduced amino acid sequence of S gene of IBV isolates showed a high level of identity with strains isolated from Tamil Nadu and the reference vaccine strains. Our result suggests that the IBV virus isolated from unvaccinated chicken flocks in North India might be a revertant strain originally evolved from the live attenuated vaccine strains used in the region. Determination of the complete genome sequence of additional IBV isolates from India is necessary to understand the epidemiology of IBV in India. PMID- 29621537 TI - A fine scale eco-epidemiological study on endemic visceral leishmaniasis in north ethiopian villages. AB - Visceral Leishmaniasis (VL) is a disseminated protozoan infection caused by Leishmania donovani that affects almost half a million people annually. In Northern Ethiopia, VL is common in migrant agricultural laborers returning from the lowland sesame fields of Metema and Humera. Recent VL foci have emerged in resident rural populations near the town. In the current study, we evaluate multilevel entomological, epidemiological and ecological factors associated with infection and disease through fine-scale eco-epidemiological analyses in three villages. Satellite images showed that villages constructed in or close to vertisols, were likely to become endemic for VL. Vertisols or black-cotton soil, are characterized by high contents of smectitic clay minerals, which swell when hydrated and shrink upon desiccation, causing extensive deep cracking during the dry season. The population densities of Phlebotomus orientalis, the vector, were negatively correlated with distance from vertisols and persons living close to vertisols were more likely to be bitten by sand flies, as evidenced by sero positivity to Ph. orientalis saliva. Apparent (albeit non-significant) clustering of VL cases and abundant asymptomatic infections close to vertisols, suggest anthroponotic transmission around houses located close to vertisols. Comparable rates of male and female volunteers, mostly under 15 years of age, were infected with L. donovani but a significantly higher proportion of males succumbed to VL indicating a physiological gender-linked male susceptibility. Our data suggest that the abundant infected persons with high parasitemias who remain asymptomatic, may serve as reservoir hosts for anthroponotic transmission inside villages. Only limited insights on the transmission dynamics of L. donovani were gained by the study of environmental factors such as presence of animals, house structure and vegetation cover. PMID- 29621538 TI - Ketamine and ketamine metabolites as novel estrogen receptor ligands: Induction of cytochrome P450 and AMPA glutamate receptor gene expression. AB - Major depressive disorder (MDD) is the most common psychiatric illness worldwide, and it displays a striking sex-dependent difference in incidence, with two thirds of MDD patients being women. Ketamine treatment can produce rapid antidepressant effects in MDD patients, effects that are mediated-at least partially-through glutamatergic neurotransmission. Two active metabolites of ketamine, (2R,6R) hydroxynorketamine (HNK) and (2S,6S)-HNK, also appear to play a key role in ketamine's rapid antidepressant effects through the activation of alpha-amino-3 hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) glutamate receptors. In the present study, we demonstrated that estrogen plus ketamine or estrogen plus active ketamine metabolites displayed additive effects on the induction of the expression of AMPA receptor subunits. In parallel, the expression of estrogen receptor alpha (ERalpha) was also significantly upregulated. Even more striking, radioligand binding assays demonstrated that [3H]-ketamine can directly bind to ERalpha (KD: 344.5 +/- 13 nM). Furthermore, ketamine and its (2R,6R)-HNK and (2S,6S)-HNK metabolites displayed similar affinity for ERalpha (IC50: 2.31 +/- 0.1, 3.40 +/- 0.2, and 3.53 +/- 0.2 uM, respectively) as determined by [3H] ketamine displacement assays. Finally, induction of AMPA receptors by either estrogens or ketamine and its metabolites was lost when ERalpha was knocked down or silenced pharmacologically. These results suggest a positive feedback loop by which estrogens can augment the effects of ketamine and its (2R,6R)-HNK and (2S,6S)-HNK metabolites on the ERalpha-induced transcription of CYP2A6 and CYP2B6, estrogen inducible enzymes that catalyze ketamine's biotransformation to form the two active metabolites. These observations provide novel insight into ketamine's molecular mechanism(s) of action and have potential implications for the treatment of MDD. PMID- 29621539 TI - Molecular determinants of Kv7.1/KCNE1 channel inhibition by amitriptyline. AB - Amitriptyline (AMIT) is a compound widely prescribed for psychiatric and non psychiatric conditions including depression, migraine, chronic pain, and anorexia. However, AMIT has been associated with risks of cardiac arrhythmia and sudden death since it can induce prolongation of the QT interval on the surface electrocardiogram and torsade de pointes ventricular arrhythmia. These complications have been attributed to the inhibition of the rapid delayed rectifier potassium current (IKr). The slow delayed rectifier potassium current (IKs) is the main repolarizing cardiac current when IKr is compromised and it has an important role in cardiac repolarization at fast heart rates induced by an elevated sympathetic tone. Therefore, we sought to characterize the effects of AMIT on Kv7.1/KCNE1 and homomeric Kv7.1 channels expressed in HEK-293H cells. Homomeric Kv7.1 and Kv7.1/KCNE1 channels were inhibited by AMIT in a concentration-dependent manner with IC50 values of 8.8 +/- 2.1 MUM and 2.5 +/- 0.8 MUM, respectively. This effect was voltage-independent for both homomeric Kv7.1 and Kv7.1/KCNE1 channels. Moreover, mutation of residues located on the P loop and S6 domain along with molecular docking, suggest that T312, I337 and F340 are the most important molecular determinants for AMIT-Kv7.1 channel interaction. Our experimental findings and modeling suggest that AMIT preferentially blocks the open state of Kv7.1/KCNE1 channels by interacting with specific residues that were previously reported to be important for binding of other compounds, such as chromanol 293B and the benzodiazepine L7. PMID- 29621540 TI - TGF beta inhibits expression of SP-A, SP-B, SP-C, but not SP-D in human alveolar type II cells. AB - TGF beta is a multifunctional cytokine that regulates alveolar epithelial cells as well as immune cells and fibroblasts. TGF beta inhibits surfactant protein A, B and C expression in fetal human lung and can inhibit type II cell proliferation induced by FGF7 (KGF). However, little is known about direct effects of TGF beta on adult human type II cells. We cultured alveolar type II cells under air/liquid interface conditions to maintain their state of differentiation with or without TGF beta. TGF beta markedly decreased expression of SP-A, SP-B, SP-C, fatty acid synthase, and the phospholipid transporter ABCA3. However, TGF beta increased protein levels of SP-D with little change in mRNA levels, indicating that it is regulated independently from other components of surfactant. TGF beta is a negative regulator of both the protein and the phospholipid components of surfactant. TGF beta did not induce EMT changes in highly differentiated human type II cells. SP-D is an important host defense molecule and regulated independently from the other surfactant proteins. Taken together these data are the first report of the effect of TGF beta on highly differentiated adult human type II cells. The effects on the surfactant system are likely important in the development of fibrotic lung diseases. PMID- 29621541 TI - Kruppel-like factor 9 suppressed tumorigenicity of the pancreatic ductal adenocarcinoma by negatively regulating frizzled-5. AB - Kruppel-like factor 9 (KLF9) has been implicated in mediating a diverse range of biological processes. However, the expression pattern and biological functions of KLF9 in pancreatic ductal adenocarcinoma (PDAC) are still unknown. Here, we evaluated the role of KLF9 in pancreatic ductal adenocarcinoma (PDAC). Overexpression of KLF9 significantly inhibited proliferation and clone formation in PDAC cells, while silencing KLF9 expression dramatically promoted this effect in vitro. Knocking down the expression of KLF9 also promoted the tumorigenesis in the PDAC mouse xneograft model. In in vitro mechanism study, KLF9 negatively regulated the activity of wnt/beta-catenin pathway in Top/Fop reporter assay. Frizzled-5, a key component involving in this pathway, was sharp inhibited by KLF9 both in mRNA and protein level. Furthermore, a KLF9-binding site (BTE) was identified in the promoter region of Frizzled-5. Mutation or deletion of this BTE strongly disrupted the KLF9's regulatory effect on Frizzled-5. More importantly, the expression level of KLF9 was significantly lower in clinical PDAC tissue compared to matched normal tissues and inversely associated with survival of the patients. Together, our findings indicated that KLF9 suppressed tumorigenicity of the pancreatic ductal adenocarcinoma by negatively regulating frizzled-5. PMID- 29621542 TI - Glycolytic inhibitor 2-Deoxy-d-Glucose activates migration and invasion in glioblastoma cells through modulation of the miR-7-5p/TFF3 signaling pathway. AB - Glioblastomas (GBMs) are characterized by the metabolic shift towards aerobic glycolysis, rapid proliferation and acquisition of the migratory and invasive phenotype aiding tumor angiogenesis. The glycolytic inhibitor 2-Deoxy-d-glucose (2-DG) used for targeting glycolysis in GBMs is ineffective in inhibiting migration and invasion. In the present study we report that 2-DG treatment downregulates the tumor suppressive miR-7-5p in GBM cell lines in vitro. Overexpression of miR-7-5p significantly reduced migration and invasion in GBM cell lines. The 2-DG induced suppression of miR-7-5p in turn activated the PI3K/Akt signaling activator Trefoil Factor 3 (TFF3) in GBM cell lines. TFF3 was found to be upregulated in cell lines and clinical samples and its genomic inhibition significantly decreased migration and invasion in GBM cell lines either alone or in combination with 2-DG. Collectively, our results provide the molecular basis for the limited efficacy of 2-DG monotherapy and underscores the significance of the miR-7-5p/TFF3 signaling pathway in the regulation of migration and invasion in 2-DG treated GBM cell lines. PMID- 29621543 TI - Cardiac-specific delivery by cardiac tissue-targeting peptide-expressing exosomes. AB - Naturally occurring RNA carriers such as exosomes might be an untapped source of effective delivery vehicles. However, if exosomes are to be exploited for therapeutic applications, they must target specific tissues or cell types to avoid off-target effects. This study evaluated whether genetic modification of exosomes could enhance exosome delivery to heart cells and heart tissue without toxicity. Exosomes expressing cardiac-targeting peptide (CTP)-Lamp2b on the exosomal membrane (CTP-Exo) were generated by introducing vectors encoding CTP Lamp2b into HEK 293 cells. The expression of CTP-Lamp2b peptide on exosomes was stabilized by attaching glycosylation sequences. Exosomes expressing only Lamp2b on exosomal membranes (CTL-Exo) were generated as a control. The in vitro and in vivo uptake of CTL-Exo and CTP-Exo was evaluated in cell lines and mice. Both exosomes were delivered to HEK 293 and H9C2 cells. The delivery of the exosome was not different between CTP-Exo and CTL-Exo in HEK 293 cells, whereas the delivery of CTP-Exo was 16% greater than that of CTL-Exo in H9C2 cells (P = 0.047). Cell viability was maintained at almost 100% with different dosages of both CTL-Exo and CTP-Exo. Moreover, compared with CTL-Exo, the in vivo delivery of exosomes to the hearts of mice was increased by 15% with CTP-Exo (P = 0.035). The delivery to livers and spleens was not different between the two exosomes. Genetic modification of exosomes by expressing CTP-Lamp2b on the exosomal membrane enhanced exosome delivery to heart cells and the heart tissue. These results suggested that CTP-Exo might be used as a therapeutic tool for heart disease. PMID- 29621544 TI - Prevalence of NS5A resistance associated variants in NS5A inhibitor treatment failures and an effective treatment for NS5A-P32 deleted hepatitis C virus in humanized mice. AB - Patients with chronic hepatitis C virus (HCV) infection who have failed to respond to direct-acting antiviral (DAA) treatment often acquire drug resistance associated variants (RAVs). The NS5A-P32 deletion (P32del) RAV confers potent resistance to NS5A inhibitors; therefore, patients who acquire this deletion are likely to fail to respond to DAA re-treatment. We investigated the prevalence of N55A-P32del in patients who failed to respond to prior NS5A inhibitor treatment using direct sequencing and analyzed the efficacy of DAA combination treatment in the presence of NS5A-P32del RAVs using human hepatocyte transplanted mice. NS5A P32del was detected in one of 23 (4.3%) patients who had failed to respond to prior NS5A inhibitor treatment. Although four weeks of NS3/4A protease inhibitor glecaprevir plus NS5A inhibitor pibrentasvir treatment effectively suppressed HCV replication in wild-type HCV-infected mice, serum HCV RNA never became negative in P32del HCV-infected mice. When P32del HCV-infected mice were treated with four weeks of glecaprevir plus pibrentasvir combined with the NS5B polymerase inhibitor sofosbuvir, serum HCV RNA became negative, and the virus was eliminated from the liver in three out of four mice. We conclude that the combination of sofosbuvir and glecaprevir plus pibrentasvir may be an effective new treatment option for patients with NS5A-P32del. PMID- 29621545 TI - Caspase-2 associates with FAN through direct interaction and overlapping functionality. AB - Caspase-2 has been implicated in diverse cellular processes, and the identification of factors with which it interacts has steadily increased. In the present study, we report a direct interaction between caspase-2 and factor associated with neutral sphingomyelinase activation (FAN) using yeast two-hybrid screening and co-immunoprecipitation. Further, stable suppression of caspase-2 expression in HEK293T and HeLa cells enabled a systematic investigation of putative novel enzyme functionalities, especially with respect to ceramide production, cell migration, IL-6 production and vesicular homeostasis, all of which have been previously reported to be associated with FAN. Lipidomics excluded the involvement of caspase-2 in the generation of ceramide species, but caspase-2-dependent deregulation of IL-6 release, vesicular size and delayed cell relocation supported an association between caspase-2 and FAN. Collectively, these data identify a novel caspase-2-interacting factor, FAN, and expand the role for the enzyme in seemingly non-apoptotic cellular mechanisms. PMID- 29621546 TI - Aberrant upregulation of KLK10 promotes metastasis via enhancement of EMT and FAK/SRC/ERK axis in PDAC. AB - Pancreatic Ductal Adenocarcinoma (PADC) metastasis is the leading cause of morality of this severe malignant tumor. Proteases are key players in the degradation of extracellular matrix which promotes the cascade of tumor metastasis. As a kind of serine proteases, the kallikrein family performs vital function on the cancer proteolysis scene, which have been proved in diverse malignant tumors. However, the specific member of kallikrein family and its function in PDAC remain unexplored. In this study, by data mining of GEO datasets, we have identified KLK10 is upregulated gene in PDAC. We found that KLK10 was significantly overexpressed in tissues of pancreatic intraepithelial neoplasia (PanIN) and PDAC from Pdx1-Cre; LSL-KrasG12D/+ mice (KC) and Pdx1-Cre; LSL-KrasG12D/+; LSL-Trp53R172H/+ mice (KPC) by immunohistochemical analysis. Moreover, KLK10 is extremely elevated in the PDAC tissues, especially that from the PDAC patients with lymphatic and distant metastasis. Aberrant KLK10 expression is significantly correlated with poor prognosis and shorter survival by univariable and multivariable analysis. Functionally, knockdown of KLK10 observably inhibits invasion and metastatic phenotype of PDAC cells in vitro and metastasis in vivo. In addition, blockade of KLK10 attenuates epithelial mesenchymal transition and activation of FAK-SRC-ERK signaling, which explains the mechanism of KLK10 in promoting metastasis. Collectively, KLK10 should be considered as a promising biomarker for diagnosis and potential target for therapy in PDAC. PMID- 29621547 TI - Down-regulation of cancer-associated gene CDC73 contributes to cellular senescence. AB - Dysregulated gene expression is another important contributor in explaining cancer-related phenotypes in addition to mutations. Cellular senescence is a mechanism for the prevention of cancer and thus it is important to understand the regulation of gene expression in senescence due to its potential in anti-cancer therapy. Here, we found that CDC73, which encodes the cell division cycle 73 and acts as a tumor suppressor, was unexpectedly up-regulated in several cancer types but down-regulated in a variety of senescent cells. Importantly, depletion of CDC73 could induce senescence-associated phenotypes in both normal and cancer cells, with an increase in p21 expression. In terms of molecular mechanism, alternative polyadenylation (APA)-mediated 3' untranslated region (3' UTR) lengthening explained, at least in part, the decreased CDC73 expression in senescent cells because longer 3' UTR had a higher rate of RNA degradation compared to the shorter one. Our work discovered that post-transcriptional down regulation of CDC73 contributed to cellular senescence. PMID- 29621549 TI - Osh6p, a homologue of the oxysterol-binding protein, is involved in production of functional cytochrome P450 belonging to CYP52 family in n-alkane-assimilating yeast Yarrowia lipolytica. AB - In this study, we investigated the role of OSH6, which encodes a homolog of the oxysterol-binding protein, in the assimilation of n-alkanes in the yeast Yarrowia lipolytica. The deletion mutant of OSH6 showed growth defects on n-alkanes of 10 16 carbons. In the deletion mutant, production of the functional cytochrome P450 was not observed. However, transcription of ALK1, encoding a major P450 belonging to the CYP52 family that plays a critical role in n-alkane hydroxylation, and further translation of its transcript were noted in the deletion mutant as well as in the wild-type strain. The phospholipid composition was altered and, the ratio of phosphatidylserine (PS) was reduced by the deletion of OSH6. Residues involved in the transport of PS and phosphatidylinositol-4-phosphate in Osh6 of Saccharomyces cerevisiae are conserved in Y. lipolytica Osh6p and substitutions of these residues resulted in a defect in the n-alkane assimilation by Y. lipolytica. From these results, we propose a hypothesis that Osh6p provides an ideal endoplasmic reticulum membrane environment for Alk proteins to have a functional conformation via lipid transport activity in Y. lipolytica. PMID- 29621548 TI - TREM2 modulates microglia phenotypes in the neuroinflammation of Parkinson's disease. AB - Neuroinflammation and overactivated microglia underlies the pathogenesis of Parkinson's disease (PD). Furthermore, microglia could polarize into classic inflammatory M1 and immunosuppressive M2 phenotype. Thus, inhibiting the overactivated inflammatory M1 microglia by promoting the transformation of microglia to the protective M2 phenotype provides potential therapy for PD, but the mechanism that modulates microglia polarization remains unknown. Triggering receptor expressed on myeloid cells-2 (TREM2) is a recently identified immune receptor expressed by the microglia in the brain. Emerging evidence indicates that TREM2 enhances the phagocytosis function of microglia and suppress inflammation. Based on these evidence, we hypothesized that TREM2 might play a protective role through regulating microglia polarization. Here, we employ a lentiviral strategy to overexpress or suppress TREM2 on microglia and found that TREM2 was essential for M2 microglia polarization. Knockdown of TREM2 in BV2 microglia inhibited M2 polarization and lead to exaggeration of M1 microglial inflammatory responses, whereas overexpression of TREM2 promoted M2 polarization and alleviated microglial inflammation. We also observed that the TREM2 level was higher in the midbrain of PD mice, which was accompanied by an elevated level of Arginase-1 and increased proinflammatory cytokines, suggesting that TREM2 is an important factor in switching the microglia phenotypes. Taken together, these findings indicate that TREM2 plays a crucial role in altering the proinflammatory M1 microglia to M2 phenotype and has beneficial effects in the immune pathogenesis of PD. PMID- 29621550 TI - Anti-angiogenic effect of Interleukin-26 in oxygen-induced retinopathy mice via inhibiting NFATc1-VEGF pathway. AB - Retinal neovascularization (RNV) is a devastating pathological feature of numerous ocular diseases and is a major cause of blindness. In this study, we examined the effect and potential mechanism of interleukin-26 (IL-26) in the pathogenesis of RNV in an oxygen-induced retinopathy (OIR) model. OIR model was induced by exposure of hypoxia (75% oxygen) to C57BL/6J mice from postnatal day 7 (P7) to P12 and then returned to room air. A significant up-regulation of IL-26 was detected in the retina at P17 after OIR, and the expression of IL-26 was observed to be localized mainly in the retinal endothelial cells (RECs). Furthermore, recombinant (r) IL-26 could effectively prevented RNV by reduction the areas of RNV, and IL-26 deficiency markedly increased RNV formation. In addition, the increased expressions of nuclear factor of activated T-cell (NFATc) 1 and vascular endothelial growth factor (VEGF) in the retina at P17 after OIR were increased in IL-26 -/- mice, and were down-regulated following rIL-26 treatment. Collectively, these data suggested a possibility that IL-26 suppressed RNV via NFATc1-VEGF pathway. PMID- 29621551 TI - Quantitation of HBV cccDNA in anti-HBc-positive liver donors by droplet digital PCR: A new tool to detect occult infection. AB - BACKGROUND & AIMS: The accurate diagnosis of occult hepatitis B virus (HBV) infection (OBI) requires the demonstration of HBV DNA in liver biopsies of hepatitis B surface antigen-negative individuals. However, in clinical practice a latent OBI is deduced by the finding of the antibody to the hepatitis B core antigen (anti-HBc). We investigated the true prevalence of OBI and the molecular features of intrahepatic HBV in anti-HBc-positive individuals. METHODS: The livers of 100 transplant donors (median age 68.2 years; 64 males, 36 females) positive for anti-HBc at standard serologic testing, were examined for total HBV DNA by nested-PCR and for the HBV covalently closed circular DNA (HBV cccDNA) with an in-house droplet digital PCR assay (ddPCR) (Linearity: R2 = 0.9998; lower limit of quantitation and detection of 2.4 and 0.8 copies/105 cells, respectively). RESULTS: A total of 52% (52/100) of the individuals studied were found to have OBI. cccDNA was found in 52% (27/52) of the OBI-positive, with a median 13 copies/105 cells (95% CI 5-25). Using an assay specific for anti-HBc of IgG class, the median antibody level was significantly higher in HBV cccDNA positive than negative donors (17.0 [7.0-39.2] vs. 5.7 [3.6-9.7] cut-off index [COI], respectively, p = 0.007). By multivariate analysis, an anti-HBc IgG value above 4.4 COI was associated with the finding of intrahepatic HBV cccDNA (odds ratio 8.516, p = 0.009); a lower value ruled out its presence with a negative predictive value of 94.6%. CONCLUSIONS: With a new in-house ddPCR-based method, intrahepatic HBV cccDNA was detectable in quantifiable levels in about half of the OBI cases examined. The titer of anti-HBc IgG may be a useful surrogate to predict the risk of OBI reactivation in immunosuppressed patients. LAY SUMMARY: The covalently closed circular DNA (cccDNA) form of the hepatitis B virus (HBV) sustains the persistence of the virus even decades after resolution of the symptomatic infection (occult HBV infection). In the present study we developed a highly sensitive method based on droplet digital PCR technology for the detection and quantitation of HBV cccDNA in the liver of individuals with occult HBV infection. We observed that the amount of HBV cccDNA may be inferred from the titer in serum of the IgG class antibody to the hepatitis B core antigen. The quantitation of this antibody may represent a surrogate to determine which patients are at the highest risk of HBV reactivation following immunosuppressive therapies. PMID- 29621552 TI - A mechanistic study on tablet ejection force and its sensitivity to lubrication for pharmaceutical powders. AB - Pharmaceutical powders can exhibit markedly different tablet ejection forces. The purpose of this study is to understand the factors leading to the variability of the tablet ejection force and its sensitivity to lubrication. The study showed that the tablet ejection force is mainly governed by 1) tablet diameter and thickness, 2) compact-die wall friction coefficient, and 3) residual die wall stress upon ejection; the latter was further controlled by the maximum compression pressure, as well as the degree of non-elastic deformation during compression. Brittle powders, such as lactose or dicalcium phosphate, often exhibit exceeding ejection force because of their significant contribution from the non-elastic deformation during loading. These conclusions were verified through compaction experiments of five pharmaceutical powders with diverse compaction properties. Additionally, we found that boundary lubrication was highly effective in reducing tablet ejection force, achievable through decreasing the compact-die wall friction coefficient, but not through altering the intrinsic consolidation behavior of powders. High ejection force is indicative of the sub optimal stress condition of the tablet post-unloading. Therefore learnings from this study are beneficial for practitioners to harness the ejection force as an effective metric to identify and mitigate risks of tablet defects. PMID- 29621553 TI - Enhanced polymalic acid production from the glyoxylate shunt pathway under exogenous alcohol stress. AB - Polymalic acid (PMA) is a water-soluble biopolymer produced by the yeast-like fungus Aureobasidium pullulans. In this study, the physiological response of A. pullulans against exogenous alcohols stress was investigated. Interestingly, ethanol stress was an effective inducer of enhanced PMA yield, although cell growth was slightly inhibited. The stress-responsive gene malate synthase (mls), which is involved in the glyoxylate shunt, was identified and was found to be regulated by exogenous ethanol stress. Therefore, an engineered strain, YJ-MLS, was constructed by overexpressing the endogenous mls gene, which increased the PMA titer by 16.2% compared with the wild-type strain. Following addition of 1% (v/v) of ethanol, a high PMA titer of 40.0 +/- 0.38 g/L was obtained using batch fermentation with the mutant YJ-MLS in a 5-L fermentor, with a strongest PMA productivity of 0.56 g/L h. This study was the interesting report to show strengthening of the carbon metabolic flow from the glyoxylate shunt for PMA synthesis, and also provided a new sight for re-recognizing the regulatory behavior of alcohol stress in eukaryotic microbes. PMID- 29621554 TI - Principles behind variance misallocation in temporal exploratory factor analysis for ERP data: Insights from an inter-factor covariance decomposition. AB - Temporal exploratory factor analysis (EFA) is commonly applied to ERP data sets to reduce their dimensionality and the ambiguity with respect to the underlying components. However, the risk of variance misallocation (i.e., the incorrect allocation of condition effects) has raised concerns with regard to EFA usage. Here, we show that variance misallocation occurs because of biased factor covariance estimates and the temporal overlap between the underlying components. We also highlight the consequences of our findings for the analysis of ERP data with EFA. For example, a direct consequence of our expositions is that researchers should use oblique rather than orthogonal rotations, especially when the factors have a substantial topographic overlap. A Monte Carlo simulation confirms our results by showing, for instance, that characteristic biases occur only for orthogonal Varimax rotation but not for oblique rotation methods such as Geomin or Promax. We discuss the practical implications of our results and outline some questions for future research. PMID- 29621555 TI - Cutis laxa associated with monoclonal gammopathy: 14 new cases and review of the literature. PMID- 29621556 TI - From Fear to Confidence: Changing Providers' Attitudes About Pediatric Palliative and Hospice Care. AB - CONTEXT: Children have limited access to hospice care: few existing hospice programs have dedicated pediatric teams, and adult hospice providers feel inadequately trained to care for children. OBJECTIVES: The aim of this study was to increase access to pediatric hospice care by empowering adult hospice providers to care for children through a comprehensive education program. Education empowers providers by changing their attitudes from inadequacy to confidence. METHODS: The authors developed a two-day education program to train interdisciplinary teams of adult hospice providers in pediatric care. The curriculum consists of 13 modules to improve participants' knowledge, skills, and attitudes. Ninety-three providers across the U.S. learned via multiple teaching methods including lectures, role plays by professional actors, interviews of bereaved parents, and self-reflections. Learning was evaluated with assessments before, immediately after, and six months after the program. Responses were compared using a one-sided analysis of variation with a significance level of alpha <0.05. RESULTS: Participants improved their knowledge in 12 of 13 modules. Self-reported confidence levels with pediatric care improved significantly in all 13 modules (P < 0.05). After this program, 79% of providers reported feeling better prepared to care for pediatric hospice patients. Qualitative data reinforced that learners felt more prepared to care for pediatric patients. CONCLUSION: A two-day, high-intensity low-cost community-based education program can improve adult providers' knowledge of and skill level with pediatric care, leading to a change in attitude from fear to confidence. This model has the potential to increase access to pediatric hospice care as it uses existing adult hospice infrastructure. PMID- 29621557 TI - CRISPR-Cas9; an efficient tool for precise plant genome editing. AB - Efficient plant genome editing is dependent upon induction of double stranded DNA breaks (DSBs) through site specified nucleases. These DSBs initiate the process of DNA repair which can either base upon homologous recombination (HR) or non homologous end jointing (NHEJ). Recently, CRISPR-Cas9 mechanism got highlighted as revolutionizing genetic tool due to its simpler frame work along with the broad range of adaptability and applications. So, in this review, I have tried to sum up the application of this biotechnological tool in plant genome editing. Furthermore, I have tried to explain successful adaptation of CRISPR in various plant species where it is used for the successful generation of stable mutations in a steadily growing number of species through NHEJ. The review also sheds light upon other biotechnological approaches relying upon single DNA lesion induction such as genomic deletion or pair wise nickases for evasion of offsite effects. PMID- 29621558 TI - Changes in gene expression in lungs of mice exposed to traffic-related air pollution. AB - Long-term exposure to traffic-related pollutants can lead to a variety of respiratory diseases, including inflammation, asthma, and lung cancer; however, the underlying biological mechanisms are not fully understood. We focused on the effects of exposure to different air pollutants on the expression of genes associated with inflammatory immune responses, allergic reactions and asthma, and lung cancer. In order to understand the cellular responses induced by exposure to different traffic-related pollutants, we performed PCR array to evaluate the mRNA expression of genes associated with inflammatory immune responses, allergic reactions and asthma, and lung cancer in the lungs of mice exposed to three different environments, including the laboratory (clean air), and polluted parking garages in Foshan and Guangzhou for four weeks. Cytokines (IFN-gamma, IL 4, and IL-17A) were analyzed by Flow cytometry; the morphological structures were detected by Haematoxylin and eosin (H&E) staining. Our results revealed that the main pollutant in Guangzhou was PM2.5, the main pollutants in Foshan were gaseous pollutants including CO, NOx and SO2. IFN-gamma was significantly lower, and IL 4, and IL-17A were significantly higher in mice in the Guangzhou and Foshan groups compared with laboratory group. The morphological structures were damaged in Guangzhou and Foshan groups. In addition, we found that exposure to traffic related pollutants triggered the expression of inflammatory genes (Cxcl11 and Tnfs4), allergy and asthma genes (Clca3 and Prg2), and lung cancer genes (Agr2, Col11a1, and Sostdc1). As such, our results demonstrate that persistent exposure to traffic-related pollutants may elevate the incidence of immune disorders and asthma, and may be as a risk factor for lung cancer. PMID- 29621559 TI - Neurotrophins and cholinergic enzyme regulated by calpain-2: New insights into neuronal apoptosis induced by polybrominated diphenyl ether-153. AB - Polybrominated diphenyl ether-153 (BDE-153) has been demonstrated to induce neuronal apoptosis in rat cerebral cortex and primary neurons. Neurotrophins and cholinergic enzymes play critical roles in the neuronal survival, maintenance, synaptic plasticity and learning memory, however, their roles in neuronal apoptosis following the BDE-153 treatment remain unclear. In this study, we firstly explored the possible predominant pathway underlying the neuronal apoptotic induced by the BDE-153 treatment in rat cerebral cortex, by measuring expression levels (mRNA and protein) of p53, caspase-3, 8, 9, calpain-1, and calpain-2, detected the levels (protein contents and mRNA) of neurotrophins including brain-derived neurotrophic factor (BDNF), glial-derived neurotrophic factor (GDNF), nerve growth factor (NGF), neurotrophin-3 (NT-3), and neurotrophin 4 (NT-4), and measured acetylcholinesterase (AchE) and choline acetyltransferase (ChaT) activities in rat cerebral cortex and primary neurons following BDE-153 treatment with or without pretreatment with inhibitors. Results showed that the neuronal apoptosis induced by BDE-153 was dependent on p53, and dependent on more calpain-2 than caspase-3 in the cerebral cortex of rats. Following the BDE-153 treatment, the protein contents and mRNA levels of BDNF, GDNF, NGF, NT-3, and NT 4, as well as the AchE and ChaT activities were significantly decreased in the cerebral cortex and primary neurons when compared to the untreated group. When pretreated primary neurons with calpain inhibitor PD150606 or cyclin-dependent kinase (cdk5, the downstream complex of calpain) inhibitor Roscovitine, the neurotrophins contents and activities of ChaT and AchE were reverted, along with the improvement of neuron survival compared with BDE-153 treatment alone. We conclude that neurotrophins and cholinergic enzymes were regulated by the calpain 2 activation and its downstream cdk5 pathway, and which was involved in the neuronal apoptosis induced by the BDE-153 treatment. PMID- 29621560 TI - In vitro comparative cytotoxicity study of a novel biocidal iodo-thiocyanate complex. AB - Novel biocides, which avoid the induction of cross-resistance to antibiotics, are an urgent societal requirement. Here, we compared the cytotoxic and bactericidal effects of a new antimicrobial agent, the iodo-thiocyanate complex (ITC), with those of the common antiseptics, hydrogen peroxide (H2O2), povidone iodine (PVP I) and Lugol's iodine (Lugol). The antimicrobials were co-incubated for 10 min with HeLa and Escherichia coli cells in the presence and absence of organic matter (Dulbecco's modified Eagle's medium, supplemented with 10% fetal bovine serum). The cytotoxic concentrations of ITC were equivalent to its bactericidal concentrations (7.8 MUg ml-1). By contrast, cytotoxic effects of H2O2, PVP-I and Lugol were apparent at concentrations lower than their bactericidal concentrations (250, 250 and 125 MUg ml-1, respectively). The cellular effects of ITC were not quenched by organic matter, unlike the other antiseptics. ITC, PVP-I and Lugol had hemolytic effect on horse erythrocytes at high concentrations, while H2O2 showed no hemolysis. ITC, at 30 or 300 MUg ml-1, did not cause DNA breakage in HeLa cells as assessed by an in vitro comet assay in the absence of S9 metabolic activation, whereas H2O2 caused extensive single-strand DNA breaks. The pronounced antimicrobial potency of ITC and its favorable cytotoxicity profile suggests that ITC should be considered for antiseptic applications. PMID- 29621561 TI - Different inhibitory effects of azole-containing drugs and pesticides on CYP2C9 polymorphic forms: An in vitro study. AB - CYP2C9 plays a major role in drug metabolism. It is highly polymorphic and among the variants, CYP2C9*2 and CYP2C9*3 have been known to encode the protein with moderately to markedly reduced catalytic activity. Azole antifungals are among the most frequently used drugs in human pharmacotherapy and represent a widely used class of pesticides to which humans are inevitably exposed. Due to the similarities in CYP organization throughout species, azoles can interact not only with the target fungal CYP51 substrate-binding site but can also modulate the catalytic activity of human cytochrome P450s, including CYP2C9, causing severe adverse effects. In the present study the potency of azole-containing drugs and pesticides to inhibit recombinant wild-type CYP2C9*1 and the allelic variants CYP2C9*2 and CYP2C9*3 was evaluated. Significant differences were found in their affinity to CYP2C9*1, CYP2C9*2, and CYP2C9*3 as well as in the catalytic activity of CYP2C9 allelic variants. Moreover, addition of cytochrome b5 resulted in a decrease of CYP2C9*3 activity to diclofenac in a concentration-dependent manner. Increasing the knowledge of how azoles influence polymorphic variants of CYP2C9 could help individualize drug treatment, leading to optimization of the selection of drugs and doses for individuals based on genetic information. PMID- 29621562 TI - Development and validation of a scoring system for prediction of insulin requirement for optimal control of blood glucose during glucocorticoid treatments. AB - AIMS: We have developed and validated a novel scoring system to predict insulin requirement for optimal control of blood glucose during glucocorticoid (GC) treatments, by retrospective analyses of clinical parameters before GC treatment. METHODS: Three hundred-three adults (the Developing set) undergoing their first treatment of prednisolone (PSL) were divided into two groups, depending on treatment with or without insulin. Independent risk factors for insulin requirement were identified by a stepwise logistic regression analysis after univariate analyses between the two groups. We constructed a point-addition scoring system consisting of several categories and their coefficients in each risk factor derived from another logistic regression analysis. We validated it to two validation sets, A and B. RESULTS: Male, higher levels of fasting plasma glucose (FPG), HbA1c, and serum creatinine (CRE) and a higher initial dose of PSL were identified as the risk factors. The sensitivity, specificity, and accuracy were 90.0%, 88.1%, and 88.4%; 87.5%, 66.7%, and 70.5%; 83.3%, 76.1%, and 76.6% in the Developing set, Validation set A, and Validation set B, respectively, when the scoring system was applied. CONCLUSIONS: The scoring system is a valid and reliable tool to predict insulin requirements in advance during GC treatment. PMID- 29621563 TI - Should the IADPSG criteria be applied when diagnosing early-onset gestational diabetes? AB - AIMS: To investigate whether the broad interpretation of the International Association of Diabetes and Pregnancy Study Groups (IADPSG) criteria with application to the early pregnancy, which is adopted as the standard in Japan, is appropriate. METHODS: We conducted this investigation by comparing diabetes related adverse pregnancy outcomes among women treated for gestational diabetes mellitus (GDM) following an early-pregnancy diagnosis (early-onset GDM, n = 528) and those treated for GDM following a mid-pregnancy diagnosis, which is the international standard (Mid-term-onset GDM, n = 147). RESULTS: Gestational weight gain was significantly lower in the early-onset GDM group (7.5 kg) than in the mid-term-onset GDM group (8.4 kg). The frequency of hypertensive disorders of pregnancy tended to be lower in the early-onset GDM group (5.6% vs. 8.8%, p = 0.085), but infant birth weight did not differ significantly between the groups. No between-group difference was observed in macrosomia, large-for-gestational-age (LGA), small-for-gestational age (SGA), low Apgar score, shoulder dystocia, cesarean delivery, NICU admission, hyperbilirubinemia, neonatal hypoglycemia, or respiratory distress syndrome. The frequency of LGA showed a significant association with pre-pregnancy body mass index, but did not differ according to the timing of therapy initiation. CONCLUSIONS: We could not find the effectiveness of therapeutic interventions initiated after GDM diagnosis in the early pregnancy based on the IADPSG criteria, compared with therapeutic interventions after a mid-pregnancy GDM diagnosis. It was suggested that the IADPSG criteria for diagnosing GDM at 24-28 weeks' gestation should not be applied to Japanese women in the early pregnancy by a broader interpretation. PMID- 29621564 TI - Past, present and future of hepatitis E virus infection: Zoonotic perspectives. AB - The origin of hepatitis E virus (HEV) is not fully understood, but it is considered an emerging zoonotic pathogen. To date, HEV has been isolated from many animal species. The family Hepeviridae consists of two genera. The genus Orthohepevirus includes four distinct species (A, B, C, and D), each with distinct genotypes. Within the Orthohepevirus A species, HEV-1 and HEV-2 host ranges are restricted to humans, whereas genotypes 3 and 4 primarily infect a wide range of diverse animal species, in addition to being zoonotic to humans. Swine and wild boar species were previously thought to be the primary natural HEV reservoir, but recently rabbits have also been identified as major carriers. Moreover, increasing the number of HEV infections within the food supply chain underscore the important role of farming and food processing practices in limiting virus transmission. Notably, a Chinese commercial vaccine has the potential to protect humans and possibly animal reservoirs from HEV infection. This review summarizes the status of HEV infection worldwide in different animal species and outlines various modes of zoonotic transmission, with reference to cross-species transmission and recent vaccine developments. PMID- 29621565 TI - P. aeruginosa blood stream infection isolates: A "full house" of virulence genes in isolates associated with rapid patient death and patient survival. AB - We have recently characterised the epidemiology of P. aeruginosa blood stream infection (BSI) in a large retrospective multicentre cohort study [1]. Utilising corresponding patient BSI isolates we aimed to characterise the genotypic virulence profile of the P. aeruginosa isolates that were associated with rapid death in the non-neutropenic host. Five P. aeruginosa BSI episodes were identified from a larger cohort of P. aeruginosa BSI episodes previously described by McCarthy et al. [1]. The genotypic profile of another 5 isolates from this cohort in whom the non-neutropenic host had survived one year post the BSI was also analysed for comparison. These isolates underwent Illumina whole genome sequencing, de novo assembly and annotation. A comprehensive suite of virulence genes was collated from the Pseudomonas Genome Database (http://www.pseudomonas.com/) and were searched by BLAST based analysis in assemblies of all BSI isolates [2]. There was extensive conservation of virulence genes across all of the BSI isolates studied. The exoU gene was found in two isolates from patients who died rapidly and in one isolate from a patient that survived one year post BSI. The higA and higB genes were detected in all isolates. The exlA gene was not detected in any of the isolates studied. These findings suggest that to cause a BSI that it is only the virulent P. aeruginosa isolate that succeeds. The virulence gene profile seen was independent of patient outcome. Further phenotypic correlation is required to determine if there is any difference in genotypic expression by the BSI isolates that were associated with rapid death of the host and those BSI isolates associated with host survival at one year. PMID- 29621566 TI - William Hunter and lymphatics. AB - William Hunter along with his brother, John, and their colleagues William Hewson, William Cruikshank and John Sheldon made a large contribution to understanding of lymphatic vessels. Hewson, Cruikshank and Sheldon all carried out mercury injections and made much progress in mapping the distribution of lymphatics in the human body. William Hunter appreciated that lymphatics absorbed fluid from the tissues of the body and that lacteals of the intestine and lymphatics are similar structures. John Hunter carried out an elegant series of experiments that proved that lacteals absorb products of digestion. The Hunters, however, were wrong in dismissing absorption by blood vessels and missed the importance of blood capillaries. William Hewson showed that lymphatics were not confined to mammals but that they are present in reptiles, birds and fish. Hewson also demonstrated that tracheobronchial glands are lymph nodes and not mucus-secreting glands as previously thought. Although William Hunter appreciated that tuberculosis and venereal diseases might involve the regional lymph nodes, he does not seem to have fully grasped that malignant disease might involve the local nodes or the concept that knowledge of lymph drainage could be used to define the likely site of a primary malignancy. PMID- 29621567 TI - Salivary biomarkers of inflammation in systemic lupus erythematosus. AB - Saliva is currently used as a reliable diagnostic fluid in a wide range of local and systemic diseases. However, the link between salivary diagnosis and the inflammatory process in autoimmune diseases has not yet been explored. The aim of our study is to assess possible correlations between salivary inflammatory markers and systemic lupus erythematosus (SLE). Patients fulfilling the Systemic Lupus International Collaborating Clinics (SLICC) diagnosis criteria were included. Salivary and serum levels of interleukin-6 (IL-6), leptin, monocyte chemoattractant protein-1 (MCP-1) and plasminogen activator inhibitor-1 (PAI-1) were determined using stochastic sensors. Serum leptin and IL-6 had significantly higher levels in SLE patients compared to non-SLE. Also, salivary IL-6 levels highly correlated with the serum IL-6 levels. A positive correlation was found between salivary and serum levels of IL-6, signaling salivary IL-6 as a reliable marker for assessing the inflammation process in SLE. PMID- 29621568 TI - Effect of an experimental mouth rinse containing NaF and TiF4 on tooth erosion and abrasion in situ. AB - OBJECTIVE: This study compared the effect of an experimental NaF/TiF4 mouth rinse with a commercial tin/F mouth rinse on the prevention of tooth wear in situ. METHODS: Fifteen subjects took part in this crossover and double-blind study, in which they wore a palatal appliance with 8 bovine teeth samples (4 enamel and 4 root dentine) in each of 3 phases (5 days each). Half of the samples were subjected to erosive challenges, and the other half to erosive plus abrasive challenges. The phases corresponded to the use of 1) Experimental solution containing NaF/TiF4 (189 ppm Ti+4, 500 ppm F-, pH 4.4); 2) commercial solution containing SnCl2/NaF/AmF (800 ppm Sn+2, 500 ppm F-, pH 4.5, Elmex(r)/GABA, positive control); 3) distilled water (negative control). Erosive challenges were performed using 0.1% citric acid (pH 2.5) for 90 s 4 times per day. The abrasion was done using a toothbrush and slurry of fluoride toothpaste, for 15 s 2 times per day. Thereafter, the subjects rinsed with the tested mouth rinse for 60s. Tooth wear was measured using contact profilometry (MUm) and submitted to a two way RM ANOVA/Bonferroni test (p < 0.05). RESULTS: No significant differences were detected between the experimental and the commercial mouth rinses, regardless of the challenge. Both fluoride mouth rinses were able to significantly reduce tooth wear compared to the negative control (p < 0.0001). No significant differences were detected with respect to tooth wear between the challenges (erosion and erosion plus abrasion). CONCLUSION: The experimental NaF/TiF4 mouth rinse has a similar protective effect to the commercial one against tooth wear in situ. CLINICAL SIGNIFICANCE: The experimental NaF/TiF4 solution protected against tooth wear in situ, regardless of the challenge (erosion or erosion plus abrasion), for both enamel and dentine, similarly to a commercial solution (tin/F-Elmex(r)) applied for this proposal. This result supports the conduction of clinical trials and a possible application of this solution in the future. PMID- 29621569 TI - Alignment-based and alignment-free methods converge with experimental data on amino acids coded by stop codons at split between nuclear and mitochondrial genetic codes. AB - Genetic codes mainly evolve by reassigning punctuation codons, starts and stops. Previous analyses assuming that undefined amino acids translate stops showed greater divergence between nuclear and mitochondrial genetic codes. Here, three independent methods converge on which amino acids translated stops at split between nuclear and mitochondrial genetic codes: (a) alignment-free genetic code comparisons inserting different amino acids at stops; (b) alignment-based blast analyses of hypothetical peptides translated from non-coding mitochondrial sequences, inserting different amino acids at stops; (c) biases in amino acid insertions at stops in proteomic data. Hence short-term protein evolution models reconstruct long-term genetic code evolution. Mitochondria reassign stops to amino acids otherwise inserted at stops by codon-anticodon mismatches (near cognate tRNAs). Hence dual function (translation termination and translation by codon-anticodon mismatch) precedes mitochondrial reassignments of stops to amino acids. Stop ambiguity increases coded information, compensates endocellular mitogenome reduction. Mitochondrial codon reassignments might prevent viral infections. PMID- 29621571 TI - ECG changes during resuscitation of patients with initial pulseless electrical activity are associated with return of spontaneous circulation. AB - BACKGROUND: Pulseless electrical activity (PEA) is a frequent initial rhythm in cardiac arrest, and ECG characteristics have been linked to prognosis. The aim of this study was to examine the development of ECG characteristics during advanced life support (ALS) and cardiopulmonary resuscitation (CPR) in cardiac arrest with initial PEA, and to assess any association with survival. METHODS: Patients with in-hospital cardiac arrest with initial PEA at St. Olav Hospital (Trondheim, Norway) over a three-year period were included. A total of 2187 combined observations of QRS complex rate (heart rate) and QRS complex width for the duration of ALS were determined from defibrillator recordings from 74 episodes of cardiac arrest. RESULTS: Increasing heart rate and decreasing QRS complex width during ALS was significantly more prevalent in patients who obtained return of spontaneous circulation compared to patients who were declared dead. CONCLUSION: Changes in ECG characteristics during ALS in cardiac arrest presenting as PEA are related to prognosis. An increase in heart rate was observed in the last 3-6 min before ROSC was obtained. PMID- 29621570 TI - MNE Scan: Software for real-time processing of electrophysiological data. AB - BACKGROUND: Magnetoencephalography (MEG) and Electroencephalography (EEG) are noninvasive techniques to study the electrophysiological activity of the human brain. Thus, they are well suited for real-time monitoring and analysis of neuronal activity. Real-time MEG/EEG data processing allows adjustment of the stimuli to the subject's responses for optimizing the acquired information especially by providing dynamically changing displays to enable neurofeedback. NEW METHOD: We introduce MNE Scan, an acquisition and real-time analysis software based on the multipurpose software library MNE-CPP. MNE Scan allows the development and application of acquisition and novel real-time processing methods in both research and clinical studies. The MNE Scan development follows a strict software engineering process to enable approvals required for clinical software. RESULTS: We tested the performance of MNE Scan in several device-independent use cases, including, a clinical epilepsy study, real-time source estimation, and Brain Computer Interface (BCI) application. COMPARISON WITH EXISTING METHOD(S): Compared to existing tools we propose a modular software considering clinical software requirements expected by certification authorities. At the same time the software is extendable and freely accessible. CONCLUSION: We conclude that MNE Scan is the first step in creating a device-independent open-source software to facilitate the transition from basic neuroscience research to both applied sciences and clinical applications. PMID- 29621572 TI - Identification of a unique loss-of-function mutation in IGF1R and a crosstalk between IGF1R and Wnt/beta-catenin signaling pathways. AB - IGF1R is a ubiquitous receptor tyrosine kinase that plays critical roles in cell proliferation, growth and survival. Clinical studies have demonstrated upregulation of IGF1R mediated signaling in a number of malignancies including colon, breast, and lung cancers. Overexpression of the IGF1R in these malignancies is associated with a poor prognosis and overall survival. IGF1R specific kinase inhibitors have failed in multiple clinical trials partly because of the complex nature of IGF1R signaling. Thus identifying new binding partners and allosteric sites on IGF1R are emerging areas of research. More recently, IGF1R has been shown to translocate into the nucleus and perform many functions. In this study, we generated a library of IGF1R deletion and point mutants to examine IGF1R subcellular localization and activation of downstream signaling pathways. We show that the nuclear localization of IGF1R is primarily defined by its cytoplasmic domain. We identified a cross-talk between IGF1R and Wnt/beta catenin signaling pathways and showed, for the first time, that IGF1R is associated with upregulation of TCF-mediated beta-catenin transcriptional activity. Using loss-of-function mutants, deletion analysis and IGF1R specific inhibitor(s), we show that cytoplasmic and nuclear activities are two independent functions of IGF1R. Furthermore, we identified a unique loss-of-function mutation in IGF1R. This unique loss-of-function mutant retains only nuclear functions and sits in a pocket, outside ATP and substrate binding region, that is suited for designing allosteric inhibitors of IGF1R. PMID- 29621573 TI - Genomic, molecular evolution, and expression analysis of NOX genes in soybean (Glycine max). AB - Reactive oxygen species (ROS) are versatile signaling molecules in sensing stresses and play critical roles in signaling and development. Plasma membrane NADPH oxidases (NOXs) are key producers of ROS, and play important roles in the regulation of plant-pathogen interactions. Here, we performed a comprehensive analysis of the NOX gene family in the soybean genome (Glycine max) and 17 NOX (GmNOX) genes were identified. Structural analysis revealed that the GmNOX proteins in soybean were as conserved as those in other plants. 8 duplicated gene pairs were formed by a Glycine-specific whole-genome duplication (WGD) event approximately 13 million years ago (Mya). The Ka/Ks ratios of GmNOX genes ranged from 0.04 to 0.28, suggesting that the GmNOX family had undergone purifying selection in soybean. Gene expression patterns showed different expression of these duplicate genes, suggesting that the GmNOXs were retained by substantial subfunctionalization during the soybean evolutionary processes. Subsequently, the expression of GmNOXs in response to drought and phytohormones were characterized via qPCR. Importantly, four GmNOXs showed strong expression in nodules, pointing to their probable involvement in nodulation. Thus, our results shed light on the evolutionary history of this family in soybean and contribute to the functional characterization of GmNOX genes in soybean. PMID- 29621574 TI - Catalytically important flavin linked through a phosphoester bond in a eukaryotic fumarate reductase. AB - One of the three domains of kinetoplastid NADH:fumarate oxidoreductase (FRD) is homologous to bacterial flavin transferase that catalyzes transfer of FMN residue from FAD to threonine in flavoproteins. Leptomonas pyrrhocoris FRD produced in yeast cells, which lack flavin transferase gene in their proteome, reduces fumarate in the presence of NADH and contains an FMN residue covalently linked to a Ser9 residue. The conserved flavinylation motif of FRD, D3(g/s)x(s/t)(s/g)AS9, is similar to the Dxx(s/t)gAT motif recognized by flavin transferase in prokaryotic proteins. Ser9 replacement abolished the flavinylation and fumarate reductase activity of FRD. These findings suggest that the flavinylation is important for the activity of FRD and that this post-translational modification is carried out by the own flavin transferase domain. PMID- 29621575 TI - Introduction: Current trends in research and regulation of microbial-based cleaning products. PMID- 29621576 TI - A comparative study of the disinfection efficacy of H2O2/ferrate and UV/H2O2/ferrate processes on inactivation of Bacillus subtilis spores by response surface methodology for modeling and optimization. AB - Although chlorination can inactivate most of the microorganisms in water but protozoan parasites like C. parvum oocysts and Giardia cysts can resist against it. Therefore, many researches have been conducted to find a novel method for water disinfection. Present study evaluated the synergistic effect of H2O2 and ferrate followed by UV radiation to inactivate Bacillus subtilis spores as surrogate microorganisms. Response surface methodology(RSM) was employed for the optimization for UV/H2O2/ferrate and H2O2/ferrate processes. By using central composite design(CCD), the effect of three main parameters including time, hydrogen peroxide, and ferrate concentrations was examined on process performance. The results showed that the combination of UV, H2O2 and ferrate was the most effective disinfection process in compare with when H2O2 and ferrate were used. This study indicated that by UV/H2O2/ferrate, about 5.2 log reductions of B. subtilis spores was inactivated at 9299 mg/l of H2O2 and 0.4 mg/l of ferrate concentrations after 57 min of contact time which was the optimum condition, but H2O2/ferrate can inactivate B. subtilis spores about 4.7 logs compare to the other process. Therefore, the results of this research demonstrated that UV/H2O2 /ferrate process is a promising process for spore inactivation and water disinfection. PMID- 29621577 TI - Six months exposure to a real life mixture of 13 chemicals' below individual NOAELs induced non monotonic sex-dependent biochemical and redox status changes in rats. AB - This study assessed the potential adverse health effects of long-term low-dose exposure to chemical mixtures simulating complex real-life human exposures. Four groups of Sprague Dawley rats were administered mixtures containing carbaryl, dimethoate, glyphosate, methomyl, methyl parathion, triadimefon, aspartame, sodium benzoate, calcium disodium ethylene diamine tetra-acetate, ethylparaben, butylparaben, bisphenol A, and acacia gum at doses of 0, 0.25, 1 or 5 times the respective Toxicological Reference Values (TRV): acceptable daily intake (ADI) or tolerable daily intake (TDI) in a 24 weeks toxicity study. Body weight gain, feed and water consumption were evaluated weekly. At 24 weeks blood was collected and biochemistry parameters and redox status markers were assessed. Adverse effects were observed on body weight gain and in hepatotoxic parameters such as the total bilirubin, alanine aminotransferase (ALT) and alkaline phosphatase (ALP), especially in low dose and affecting mainly male rats. The low dose group showed increased catalase activity both in females and males, whereas the high dose group exhibited decreased protein carbonyl and total antioxidant capacity (TAC) levels in both sex groups. Non-monotonic effects and adaptive responses on liver function tests and redox status, leading to non-linear dose-responses curves, are probably produced by modulation of different mechanisms. PMID- 29621578 TI - Determination of heavy metal content of processed fruit products from Tehran's market using ICP- OES: A risk assessment study. AB - In this study, the levels of Cd, Hg, Sn, Al, Pb and As of 72 samples (36 samples for fruits juices and 36 samples for fruits canned) of three different brands including of Peach, Orange, Cherry, and Pineapple (18 samples of each fruits) marketed in Tehran, Iran (2015) were evaluated using Inductively Coupled Plasma Optical Emission Spectrometry (ICP-OES) technique. Also, Probabilistic risk assessment (non-carcinogenic and carcinogenic risks) was estimated by models include target hazard quotient (THQ) and cancer risk (CR) in the Monte Carlo Simulation (MCS) model. However, all samples were contaminated with the heavy metals investigated, most of them not surpassed established standards. The range of concentration for Al, Sn, As, Cd, Hg, and Pb as average in fruit juices were reported as 340.62 (65.17-1039.2), 72.33 (49.76-119.4), 3.76 (1.137-18.36), 2.12 (0.89-3.44), 0.351 and 40.86 (27.87-66.1) MUg/kg, respectively. The level of heavy metals measured in different kinds of fruit juices was ranked as Al > Sn > Pb > As > Cd > Hg, and for fruits canned this rank was Pb > Al > Sn > As > Cd > Hg. The range of concentration for Al, Sn, As, Cd, Hg, and Pb in fruits canned were reported as 361.23 (43.15-1121.2), 101.42 (71.45-141.61), 3.92 (1.279 19.50), 2.78 (1.09-5.56), 0.35 and 690.54 (470.56-910.14) MUg/kg, respectively. The lead (Pb) concentration in 97.22% (35 out of 36 samples) of fruit juices samples surpassed Codex limit (0.05 mg/kg) and in all samples of FC was lower than the legal limit of Codex limit (1 mg/kg). All of the samples had Tin (Sn) lower than the legal limit of Codex (fruit juices 100 mg/kg and FC 250 mg/kg). The MCS indicated that the rank order of heavy metals in both adults and children based on THQ was Al > Sn > As > Pb > Cd > Hg. The THQ of Al and Sn in the FJ and FC, for both adults, and children, was considerably higher than 1 value. Also, CR of As in both adults and children were higher than 1E-6 value. Although the mean concentration of heavy metal in the FJ and FC was lower than the standard limit, the MCS indicated that adults and children are at considerable non-carcinogenic and carcinogenic risks. PMID- 29621579 TI - Diet composition and serum levels of selenium species: A cross-sectional study. AB - Selenium is a trace element of both nutritional and toxicological interest, depending on its dose and chemical form. Diet is the primary source of exposure for most individuals. We sought to investigate the influence of food intake on serum levels of selenium species. Among fifty subjects randomly selected from a Northern Italian population, we assessed dietary habits using a validated semi quantitative food frequency questionnaire. We also measured circulating levels of selenium species in serum using high pressure liquid chromatography associated with inductively-coupled plasma dynamic reaction cell mass spectrometer. Circulating levels of inorganic selenium, the most toxic selenium species, were positively associated with intake of fish, legumes and dry fruits, and inversely associated with intake of dairy products and mushrooms. Concerning the organic selenium species, selenoproteinP-bound selenium was inversely associated with intake of fish, fresh fruits, vegetables, and legumes, while selenocysteine-bound selenium positively associated with intake of fresh fruit, potato, legume and mushroom. In the present study, intakes of different foods were correlated with different types of selenium species. These results have important public health implications when assessing the nutritional and toxicological potential of diet composition with reference to selenium exposure. PMID- 29621580 TI - Use of nutritional supplements contaminated with banned doping substances by recreational adolescent athletes in Athens, Greece. AB - Although the use of nutritional supplements by adult athletes has been extensively studied, information on supplements consumption by adolescent athletes is still limited. The present study reports on the use of nutritional supplements contaminated with banned doping substances among 170 recreational adolescent athletes from eleven, randomly selected, gym centres, in Athens, Greece. Nutritional supplements consumption was reported by almost 60% of the study population, with proteins/amino acids and vitamins being the most popular. Nine per cent of the users were found to consume nutritional supplements contaminated with anabolic steroids, prohormones, selective androgen receptor modulators (SARMs) and aromatase inhibitors, all pharmacological substances with endocrine modulating properties not stated on the label. None of these individuals had previously consulted a physician or a nutritionist. A representative sample (ca 15%) of the protein/aminoacids and creatine preparations used by the study population were also tested and found free from doping substances. The majority (63%) of adolescents purchased products from the internet. In conclusion, exercising adolescents can have easy access to contaminated nutritional supplements and "black market" products, which could constitute a risk for public health. Low level of awareness and low involvement of medical care professionals among recreational adolescent athletes is also observed. PMID- 29621581 TI - A multiplex real-time PCR assay, based on invA and pagC genes, for the detection and quantification of Salmonella enterica from cattle lymph nodes. AB - Cattle lymph nodes can harbor Salmonella and potentially contaminate beef products. We have developed and validated a new real-time PCR (qPCR) assay for the detection and quantification of Salmonella enterica in cattle lymph nodes. The assay targets both the invA and pagC genes, the most conserved molecular targets in Salmonella enterica. An 18S rRNA gene assay that amplifies from cattle and other animal species was also included as an internal control. Available DNA sequences for invA, pagC and 18S rRNA genes were used for primer and probe selections. Three Salmonella serotypes, S. Typhimurium, S. Anatum, and S. Montevideo, were used to assess the assay's analytical sensitivity. Correlation coefficients of standard curves generated for each target and for all three serotypes were >99% and qPCR amplification efficiencies were between 93% and 110%. Assay sensitivity was also determined using standard curve data generated from Salmonella-negative cattle lymph nodes spiked with 10-fold dilutions of the three Salmonella serotypes. Assay specificity was determined using Salmonella culture method, and qPCR testing on 36 Salmonella strains representing 33 serotypes, 38 Salmonella strains of unknown serotypes, 252 E. coli strains representing 40 serogroups, and 31 other bacterial strains representing 18 different species. A collection of 647 cattle lymph node samples from steers procured from the Midwest region of the US were tested by the qPCR, and compared to culture-method of detection. Salmonella prevalence by qPCR for pre-enriched and enriched lymph nodes was 19.8% (128/647) and 94.9% (614/647), respectively. A majority of qPCR positive pre-enriched samples (105/128) were at concentrations between 104 and 105 CFU/mL. Culture method detected Salmonella in 7.7% (50/647) and 80.7% (522/647) of pre- and post-enriched samples, respectively; 96.0% (48/50) of pre-enriched and 99.4% (519/522) of post-enriched culture-positive samples were also positive by qPCR. More samples tested positive by qPCR than by culture method, indicating that the real-time PCR assay was more sensitive. Our data indicate that this triplex qPCR can be used to accurately detect and quantify Salmonella enterica strains from cattle lymph node samples. The assay may serve as a useful tool to monitor the prevalence of Salmonella in beef production systems. PMID- 29621582 TI - Fast and easy detection of CMY-2 in Escherichia coli by direct MALDI-TOF mass spectrometry. AB - Fast typing methods for third generation cephalosporin resistance mechanisms are needed to guide appropriate treatment and prevent potential dissemination events. In this study we used a novel short and fast methodology for the identification of CMY-2 in 50 well characterized clinical isolates of E. coli by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry- MALDI-TOF MS. Samples were prepared using the double layer sinapinic acid technique for detection of intact proteins Comparison among mass spectral profile of different strains between m/z 35,000-45,000 Da showed that two groups of isolates could be differentiated after peak analysis. A single distinctive peak with different intensities, at approximately m/z 39,800 Da was found in all CMY-2 producing strains (transconjugant, transformant and wild type) and consistently absent in the control groups (ESBL producers and susceptible strains). Statistical results showed 100% values for sensitivity and specificity, indicating a perfect test and a high discriminative power. In this study, we demonstrated that MALDI-TOF MS has the potential to detect directly the most clinically relevant acquired AmpC beta lactamase, the CMY-2-enzyme, in E. coli with a less time-consuming process as compared to conventional methods. Our results may constitute the basis for further research to detect other beta-lactamases, or even other resistance markers. PMID- 29621583 TI - A review of the traditional use of southern African medicinal plants for the treatment of selected parasite infections affecting humans. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Worldwide, more than three billion cases of parasitic disease are reported yearly and it is likely that this figure is substantially under-estimated. Approximately one in six people globally are estimated to be infected with at least one parasite species annually. In South Africa, the prevalence of Schistosoma haematobium (bilharzia) and intestinal worms and helminths are particularly high, especially in children and in crowded or poorer rural communities with inadequate sanitation and nutrition. Despite alarmingly high estimates, medical research into parasitic diseases remains neglected and only malaria receives significant attention and funding. Traditional medicines have been used for centuries in Africa by multiple ethnic groups and many people rely on these healing systems as their primary healthcare modality. The traditional use of South African medicinal plants to treat parasite infestations is relatively well documented, and it is important to link these traditional uses to scientific evidence validating efficacy. AIM OF THE STUDY: To document the medicinal plants used for parasitic infections and critically review the literature on the anti-parasitic properties of South African plants against some neglected parasitic diseases. MATERIALS AND METHODS: A review of the literature (ethnobotanical books and publications documenting traditional plant use) was undertaken related to specific medicinal use for parasitic infections in Southern Africa. Inclusion criteria focused on human use. Exclusion criteria included veterinary use and malaria due to the extensive nature of these subject matters. An in-depth analysis of previous studies was undertaken and future prospectives are considered. RESULTS: In particular, bilharzia, gastrointestinal worms and helminths, ectoparasites, trichomoniasis, leishmaniasis and trypanosomiasis are reviewed with special emphasis on the gaps in research. CONCLUSIONS: Despite the availability of relatively extensive ethnobotanical records on the anti-parasitic properties of southern African medicinal plants, the antiparasitic properties of many plants have been poorly examined. There was in many instances a lack of evidence to support traditional use of many species towards some parasites and research is urgently needed in this area. PMID- 29621584 TI - Amaranthus caudatus extract inhibits the invasion of E. coli into uroepithelial cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Amaranthus caudatus is traditionally used to treat infections. Based on its traditional usage, we investigated the effect of A. caudatus on the bladder epithelial cells in the protection of E. coli infection. MATERIALS AND METHODS: The direct antimicrobial effects of A. caudatus on uropathogenic bacteria were investigated using minimum inhibitory concentration (MIC) assay. Bladder epithelial cell lines T24 and 5637 and uropathogenic E. coli strain #12 were used to investigate the effect of A. caudatus. Bacterial adhesion and invasion into bladder cells treated with A. caudatus was analyzed. Expression of uroplakin-1a (UPK1A), beta1 integrin (ITGB1), caveolin-1 (CAV1) and the antimicrobial peptides human beta defensin-2 (DEFB4A) and LL-37 (CAMP) was evaluated using RT-PCR. RESULTS: No direct antibacterial effect on E. coli or any of the tested uropathogenic strains was observed by A. caudatus. However, we demonstrated reduced mRNA expression of uroplakin-1a and caveolin-1, but not beta1 integrin after treatment of uroepithelial cells, mirrored by the decreased adhesion and invasion of E. coli. A. caudatus treatment did not induce increased gene expression of the antimicrobial peptides, LL-37 and human beta-defensin-2. CONCLUSIONS: Our results showed that A. caudatus has a protective role on bladder epithelial cells against uropathogenic E. coli infection by decreasing the bacterial adhesion and invasion, thereby preventing infection. PMID- 29621585 TI - Cloning, identification, and functional analysis of bone marrow stromal cell antigen-2 from sika deer (Cervus nippon). AB - BST-2(tetherin/CD317/HM1.24) has been identified as a cellular antiviral factor that inhibits the release of a wide range of enveloped viruses from infected cells. Orthologs of BST-2 have been identified in several species including humans, monkeys, cows, sheep, pigs, and mice. In this study, we cloned the gene and characterized the protein of the BST-2 homolog from sika deer (Cervus nippon). cnBST-2 shares 37.8% and 74.2% identity with the BST-2 homologs from Homo sapiens and Ovis aries, respectively. The extracellular domain of cnBST-2 has two putative N-linked glycosylation sites and three potential dimerization sites. cnBST-2 was shown to be expressed on the cell surface, like human BST-2. Exogenous expression of cnBST-2 resulted in potent inhibition of HIV-1 particle release in 293T cells; however, this activity resisted antagonism by HIV-1 Vpu. Moreover, cnBST-2 was not able to activate nuclear factor-kappaB, in contrast to human BST-2. This study is the first report of the isolation and characterization of BST-2 from C. nippon. PMID- 29621586 TI - Long non-coding RNA DILC suppresses cell proliferation and metastasis in colorectal cancer. AB - Colorectal cancer (CRC) is one of the most common malignant tumors and one of the leading causes of cancer-related death in both men and women. The prognosis of CRC remains poor due to the advanced stage and cancer metastasis at the time of diagnosis. However, the exact mechanism of tumorigenesis in CRC remains unclear. Long non-coding RNAs (lncRNAs), which refer to transcripts longer than 200 nucleotides that are not translated into protein, are known to play important roles in multiple human cancers. Lnc-DILC is reported to be an important tumor suppressor gene and its inactivation is closely associated with liver cancer stem cells. However, the role of lnc-DILC in CRC remains to be elucidated. In the present study, we observed that lnc-DILC overexpression inhibited the growth and metastasis of CRC cells. Consistently, lnc-DILC knockdown facilitated the proliferation and metastasis of CRC cells. Mechanically, lnc-DILC suppressed CRC cell progression via IL-6/STAT3 signaling inactivation. More importantly, the specific STAT3 inhibitor S3I-201 and IL-6R inhibitor tocilizumab abolished the discrepancy of growth and metastasis capacity between lnc-DILC-interference CRC cells and control cells, which further confirmed that IL-6/STAT3 signaling was required in lnc-DILC-disrupted CRC cell growth and metastasis. Taken together, our results suggest that lnc-DILC is a novel CRC suppressor and may prove to be an inhibitor of CRC progression by inactivating IL-6/STAT3 signaling. PMID- 29621587 TI - bta-miR-378 promote the differentiation of bovine skeletal muscle-derived satellite cells. AB - The mechanism by which bta-miR-378 regulates bovine skeletal muscle-derived satellite cell (bMDSC) myogenesis remains unknown. In this study, stem-loop RT PCR was used to assess bta-miR-378 expression during the proliferation and differentiation of bMDSCs. The results showed that bta-miR-378 expression did not obviously change during bMDSC proliferation but increased significantly when bMDSCs began to differentiate. Then, a bta-miR-378 mimic (bta-miR-378-M) and bta miR-378 inhibitor (bta-miR-378-I) were transfected into bMDSCs to explore the effect of bta-miR-378 on bMDSC differentiation. Cell differentiation was detected using myosin heavy chain 3 immunofluorescence, myotube formation, and desmin and myogenin western blotting analyses. As expected, bta-miR-378-M enhanced bMDSC differentiation, whereas bta-miR-378-I had the opposite effect. Moreover, luciferase reporter and western blotting assays showed that bta-miR-378 directly targeted the 3'-untranslated regions of DNA polymerase alpha subunit B (POLA2) to regulate its protein expression. In summary, these data indicate that bta-miR-378 targets POLA2 to promote the differentiation of bMDSCs, which provides further insight into the biological functions of bta-miR-378 in bovines. PMID- 29621588 TI - The rs2609255 polymorphism in the FAM13A gene is reproducibly associated with silicosis susceptibility in a Chinese population. AB - BACKGROUND: Two recent genome-wide association studies (GWASs) reported that the FAM13A gene at the 4q22 locus associated with pulmonary fibrosis (defined by rs2609255) overlapping with COPD (defined by rs6837671). We hypothesized that single-nucleotide polymorphisms (SNPs) related to lung disease (especially pulmonary fibrosis) identified in this region are also associated with the risk of silicosis. METHODS: To test this hypothesis, we genotyped these two SNPs (rs2609255 and rs6837671) in a case-control study including 177 silicosis cases and 204 controls with silica dust exposure years similar to the levels for cases in a Chinese population. RESULTS: We found that rs2609255 was significantly associated with increased silicosis risk (dominant model: OR = 1.71; 95% CI = 1.01-2.92; P = 0.047). Additionally, eQTL analysis based on the GTEx database indicated that the rs2609255 polymorphism may alter the expression level of FAM13A in lung tissues (P = 1.8 * 10-4). Furthermore, interaction analyses showed that rs2609255 interacts multiplicatively with years of silica dust exposure to contribute to silicosis risk (interaction P = 0.040). CONCLUSIONS: These results indicate that rs2609255 may modify silicosis susceptibility in the Chinese population. PMID- 29621589 TI - Identification of rare heterozygous missense mutations in FANCA in esophageal atresia patients using next-generation sequencing. AB - Esophageal atresia and tracheoesophageal fistula (EA/TEF) are relatively common malformations in newborns, but the etiology of EA/TEF remains unknown. Fanconi anemia (FA) complementation group A (FANCA) is a key component of the FA core complex and is essential for the activation of the DNA repair pathway. The middle region (amino acids 674-1208) of FANCA is required for its interaction with FAAP20. We performed targeted sequencing of this binding region of FANCA (exons 23-36) in 40 EA/TEF patients. We also investigated the effect of the p.A958V mutation on the protein-protein interaction between FANCA and FAAP20 using an in vitro binding assay and co-immunoprecipitation. Immunolocalization analysis was performed to investigate the subcellular localization of FANCA, and tissue sections and immunohistochemistry were used to explore the expression of FANCA. We identified four rare missense variants in the FANCA binding region. FANCA mutations were significantly overrepresented in EA/TEF patients compared with 4300 control subjects from the NHLBI-ESP project (Fisher's exact p = 2.17 * 10-5, odds ratio = 31.75). p.A958V, a novel de novo mutation in the FANCA gene, was identified in one patient with EA/TEF. We provide further evidence that the p.A958V mutation reduces the binding affinity of FANCA for FAAP20. Interestingly, the p.A958V mutation impaired the nuclear localization of the FANCA protein expressed in HeLa cells. We found that FANCA was more highly expressed in stratified squamous epithelium than in smooth muscle. In conclusion, mutations in the FANCA gene are associated with EA/TEF in humans. PMID- 29621590 TI - Vancomycin resistance in Enterococcus faecium isolated from Danish chicken meat is located on a pVEF4-like plasmid persisting in poultry for 18 years. AB - The occurrence of vancomycin-resistant Enterococcus faecium (VREfm) in food is relevant to public health as foodborne VREfm may colonize the gut of consumers and transfer vancomycin resistance genes to the indigenous gut microbiota. Therefore, we determined occurrence and elucidated genetic traits of VREfm in Danish retail chicken meat. Three out of 40 samples (7.5%) from two slaughterhouses yielded VREfm (vancomycin MIC > 32 mg/L). This is the first report of VREfm in Danish retail poultry meat since 2010 (DANMAP). All three VREfm belonged to the sequence type ST32, cluster type CT1068. Using whole genome sequencing, we detected transposon Tn1546 harbouring the vanA operon encoding vancomycin resistance. The vanA operon was located on a 43.4 kb plasmid highly similar (99.9% identity across 97.5% of the sequence) to pVEF4, which was observed in VREfm in Norwegian poultry in 1998 and in Danish poultry in 2010. The remarkable persistence of a pVEF4-like plasmid in enterococcal populations may be explained by the presence of two independent plasmid stability systems, the omega/epsilon/zeta toxin-antitoxin system and the prgOPN gene cluster. Filter mating experiments showed that the pVEF4-like plasmid could transfer between E. faecium strains in vitro and that transfer occurred concomitantly with a larger, co-residing plasmid. The data presented here indicate that poultry meat constitutes a reservoir of VREfm and further investigations are needed to assess the risk of foodborne transmission to humans. PMID- 29621591 TI - Bacteraemia due to extensively drug-resistant Pseudomonas aeruginosa sequence type 235 high-risk clone: Facing the perfect storm. AB - Predictors of mortality and the impact of multidrug resistance and virulence on patients with Pseudomonas aeruginosa (PA) bacteraemia were evaluated. Patients with PA bacteraemia in a 12-month period were retrospectively analysed. Carbapenemase production, molecular typing and identification of virulence factor ExoU were carried out. The activity of ceftolozane-tazobactam and ceftazidime avibactam was also investigated. The primary endpoint was 30-day crude mortality. Of 64 patients with bacteraemia, 24 (37.5%) were caused by extensively drug resistant PA (XDR-PA): 10 (41.7%) cases involved the VIM-2 carbapenemase producing ST175 clone, 11 (45.8%) the GES-5 carbapenemase-producing ST235 clone, and 3 (12.5%) were non-carbapenemase producers. The exoU genotype was detected in all ST235 strains and in 6 (15%) of the non-XDR isolates. Ceftazidime-avibactam (58.3%) showed greater activity than ceftolozane-tazobactam (12.5%) against XDR PA isolates, particularly in GES-5 producers (100%). The 30-day crude mortality rate in patients with XDR-PA bacteraemia was higher than in cases caused by susceptible strains (62.5% vs. 30%; P=0.02). Multivariate analysis showed that independent risk factors associated with 30-day crude mortality were Pitt score >=2 (OR, 42.31; 95% CI, 4.88-366.7; P=0.001) and respiratory source of bacteraemia (OR, 49.13; 95% CI 3.89-620.5; P=0.003). Stratified analysis adjusting for respiratory source revealed a non-significant trend towards higher mortality in patients with bacteraemia caused by the ST235 clone and exoU producing isolates. These data support the notion that the XDR phenotype associated with the GES-5 carbapenemase-producing ST235 clone and the exoU positive genotype adversely affects the outcome of patients with PA bacteraemia, particularly those with respiratory tract infections and a severe clinical presentation. PMID- 29621592 TI - Role of association of OmpK35 and OmpK36 alteration and blaESBL and/or blaAmpC in conferring carbapenem resistance among non-producing carbapenemase-Klebsiella pneumoniae. AB - In K. pneumoniae, the loss of the two major outer membrane porins (OMPs) OmpK35 and OmpK36 confers resistance to carbapenem in strains producing extended spectrum beta-lactamases or plasmid-mediated AmpC-type beta-lactamases. At Charles Nicolle hospital of Tunis, all carbapenem-resistant Enterobacteriaceae (CRE) were collected over a 6-year period. The aim of this work was to investigate the mechanisms responsible for carbapenem resistance in non carbapenemase-producing K. pneumoniae (NCPK) strains. Among the 334 CRE collected strains between 2010 and 2015, 44 (13.8%) were NCPK. MICs ranges of ertapenem, imipenem and meropenem were 1->32 mg/L, 0.125-8 mg/L and 0.125-32mg/L, respectively. All strains showed multidrug resistant phenotype and were negative for carbapenemase activity. None of the carbapenemase genes searched was found. ESBL production was confirmed in all isolates, but one [CTX-M-15 (n=39), SHV-5 (n=4)]. Three isolates produce DHA-1 (associated to CTX-M-15 in 2 strains). Molecular fingerprints grouped the 44 isolates into 7 clusters. In 7 representative strains of these clusters, the SDS-PAGE results showed that four isolates lacked the OmpK35 porin, one isolate lacked the OmpK36, and two isolates lacked both OmpK35 and OmpK36. Sequencing of the corresponding porin genes showed amino acid insertions and deletions leading to the early termination of translation, point mutations in the promoter region, or insertion sequences disrupting the gene coding sequence. Loss or deficiency of OMPs, coupled with ESBL and/or AmpC production, plays an important role in conferring carbapenem resistance in K. pneumoniae. Dissemination of these multidrug resistant bacteria in our hospital may create serious therapeutic problems in the future. PMID- 29621594 TI - ROCK inhibition in models of neurodegeneration and its potential for clinical translation. AB - Neurodegenerative disorders like Parkinson's disease, Alzheimer's disease, or amyotrophic lateral sclerosis are affecting a rapidly increasing population worldwide. While common pathomechanisms such as protein aggregation, axonal degeneration, dysfunction of protein clearing and an altered immune response have been characterized, no disease-modifying therapies have been developed so far. Interestingly, a significant involvement of the Rho kinase (ROCK) signaling pathway has been described in all of these mechanisms making it a promising target for new therapeutic approaches. In this article, we first review current knowledge of the involvement of ROCK in neurodegenerative disorders and the utility of its inhibition as a disease-modifying therapy in different neurodegenerative disorders. After a detailed description of the biochemical characteristics of ROCK and its molecular interactors, differences of ROCK expression under physiological and pathological conditions are compared. Next, different pharmacological and molecular-genetic strategies to inhibit ROCK function are discussed, focusing on pharmacological ROCK-inhibitors. The role of the ROCK-pathway in cellular processes that are central in neurodegenerative disorders pathology like axonal degeneration, autophagy, synaptic and glial function is explained in detail. Finally, all available data on ROCK-inhibition in different animal models of neurodegenerative disorders is reviewed and first approaches for translation into human patients are discussed. Taken together, there is now extensive evidence from preclinical studies in several neurodegenerative disorders that characterize ROCK as a promising drug target for further translational research in neurodegenerative disorders. PMID- 29621593 TI - Double-barreled gun: Combination of PARP inhibitor with conventional chemotherapy. AB - DNA repair pathways are evolutionarily conserved molecular mechanisms that maintain the integrity of genomic DNA. In cancer therapies, the integrity and activity of DNA repair pathways predict therapy resistance and disease outcome. Members of the poly (ADP-ribose) polymerase (PARP) family initiate and organize the biologic process of DNA repair, which counteracts many types of chemotherapies. Since the first development in approximately 3 decades ago, PARP inhibitors have greatly changed the concept of cancer therapy, leading to encouraging improvements in tumor suppression and disease outcomes. Here we summaries both pre-clinical and clinical findings of PARP inhibitors applications, particularly for combination therapies. PMID- 29621596 TI - A novel action of lacosamide on GABAA currents sets the ground for a synergic interaction with levetiracetam in treatment of epilepsy. AB - Epilepsy is one of the most common chronic neurological diseases, and its pharmacological treatment holds great importance for both physicians and national authorities, especially considering the high proportion of drug-resistant patients (about 30%). Lacosamide (LCM) is an effective and well-tolerated new generation antiepileptic drug (AED), currently licensed as add-on therapy for partial-onset seizures. However, LCM mechanism of action is still a matter of debate, although its effect on the voltage sensitive sodium channels is by far the most recognized. This study aimed to retrospectively analyze a cohort of 157 drug-resistant patients treated with LCM to describe the most common and effective therapeutic combinations and to investigate if the LCM can affect also GABAA-mediated neurotransmission as previously shown for levetiracetam (LEV). In our cohort, LEV resulted the compound most frequently associated with LCM in the responder subgroup. We therefore translated this clinical observation into the laboratory bench by taking advantage of the technique of "membrane micro transplantation" in Xenopus oocytes and electrophysiological approaches to study human GABAA-evoked currents. In cortical brain tissues from refractory epileptic patients, we found that LCM reduces the use-dependent GABA impairment (i.e., "rundown") that it is considered one of the specific hallmarks of drug-resistant epilepsies. Notably, in line with our clinical observations, we found that the co treatment with subthreshold concentrations of LCM and LEV, which had no effect on GABAA currents on their own, reduced GABA impairment in drug-resistant epileptic patients, and this effect was blocked by PKC inhibitors. Our findings demonstrate, for the first time, that LCM targets GABAA receptors and that it can act synergistically with LEV, improving the GABAergic function. This novel mechanism might contribute to explain the clinical efficacy of LCM-LEV combination in several refractory epileptic patients. PMID- 29621597 TI - Mesenchymal stem cells encapsulated into biomimetic hydrogel scaffold gradually release CCL2 chemokine in situ preserving cytoarchitecture and promoting functional recovery in spinal cord injury. AB - Spinal cord injury (SCI) is an acute neurodegenerative disorder caused by traumatic damage of the spinal cord. The neuropathological evolution of the primary trauma involves multifactorial processes that exacerbate the pathology, worsening the neurodegeneration and limiting neuroregeneration. This complexity suggests that multi-therapeutic approaches, rather than any single treatment, might be more effective. Encouraging preclinical results indicate that stem cell based treatments may improve the disease outcome due to their multi-therapeutic ability. Mesenchymal Stem Cells (MSCs) are currently considered one of the most promising approaches. Significant improvement in the behavioral outcome after MSC treatment sustained by hydrogel has been demonstrated. However, it is still not known how hydrogel contribute to the delivery of factors secreted from MSCs and what factors are released in situ. Among different mediators secreted by MSCs after seeding into hydrogel, we have found CCL2 chemokine, which could account for the neuroprotective mechanisms of these cells. CCL2 secreted from human MSCs is delivered efficaciously in the lesioned spinal cord acting not only on recruitment of macrophages, but driving also their conversion to an M2 neuroprotective phenotype. Surprisingly, human CCL2 delivered also plays a key role in preventing motor neuron degeneration in vitro and after spinal cord trauma in vivo, with a significant improvement of the motor performance of the rodent SCI models. PMID- 29621595 TI - Extracellular vesicles as potential biomarkers for alcohol- and drug-induced liver injury and their therapeutic applications. AB - Extracellular vesicles (EVs) are small membranous vesicles originating from various cells and tissues, including the liver parenchymal hepatocytes and nonparenchymal cells such as Kupffer and stellate cells. Recently, the pathophysiological role of EVs, such as exosomes and microvesicles, has been increasingly recognized based on their properties of intercellular communications. These EVs travel through the circulating blood and interact with specific cells and then deliver their cargos such as nucleic acids and proteins into recipient cells. In addition, based on their stabilities, circulating EVs from body fluids such as blood, cerebrospinal fluid, urine, saliva, semen, breast milk and amniotic fluids are being studied as a valuable source of potential biomarkers for providing information about the physiological status of original cells or tissues. In addition, EVs are considered potential therapeutic agents due to their ability for intercellular communications between different cell types within the liver and between various organs through transfer of their cargos. In this review, we have briefly described recent advances in the characteristics and pathophysiological roles of EVs in alcoholic liver disease (ALD) or drug-induced liver injury (DILI) and discuss their advantages in the discovery of potential biomarkers and therapeutic agents. PMID- 29621598 TI - New isocoumarins, naphthoquinones, and a cleistanthane-type diterpene from Nectria pseudotrichia 120-1NP. AB - Four new compounds, namely, nectriapyrones A (2) and B (3), nectriaquinone B (5), and zythiostromic acid C (8), were isolated from the brown rice culture of Nectria pseudotrichia 120-1NP together with four known compounds (1, 4, 6, and 7). To the best of our knowledge, this is the first report of 4 from a natural source. Their structures were determined on the basis of 1D/2D-NMR spectroscopy and HRESITOFMS data. In addition, the absolute configuration of secondary alcohols in 8 were determined using modified Mosher's ester method. All isolated compounds were evaluated for their antimicrobials activity, phytotoxicity, and cytotoxicity. PMID- 29621599 TI - Caroguaianolide A-E, five new cytotoxic sesquiterpene lactones from Carpesium abrotanoides L. AB - Five new guaiane-type sesquiterpene lactones, caroguaianolide A-E (1-5), along with nine known sesquiterpene lactones (6-14) were isolated from the whole plant of Carpesium abrotanoides L. Their structures were elucidated on the basis of spectroscopic date, HRESIMS analysis, and comparison of experimental and calculated ECD data. All isolated compounds (1-14) were tested in vitro for their cytotoxic activities against the MDA-MB-231, HGC-27 cancer cell lines, of which compounds 1-3, 6, 7, 11 and 12 showed significant cytotoxic activities with IC50 values ranging from 2.67 to 12.34 MUM. PMID- 29621600 TI - Nosocomial transmission of carbapenem-resistant Klebsiella pneumoniae in an Italian university hospital: a molecular epidemiological study. AB - AIM: To describe the phenotypic and genotypic profiles of Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-Kp) strains isolated from patients with invasive infections at an Italian university hospital in order to assess the epidemiological trend. METHODS: An observational prospective study was undertaken at the University Hospital of Sassari, Italy to detect KPC-Kp strains in patients with invasive bacteraemia. Isolates were identified phenotypically; carbapenemase production was assessed using phenotypic and genotypic methods. Sequencing of blaKPC genes, pulsed-field gel electrophoresis and multi-locus sequence typing were performed. RESULTS: During the period 2015-2017, 46 cases of invasive infection with K. pneumoniae were recorded. Two-thirds (67.4%) of the patients were male, and the mean age was 69.4 years. Most patients had at least one comorbidity (56.5%) and/or had been hospitalized previously (70.5%), 81.8% had current or recent medical device use, and 85.4% had recent antibiotic exposure. The mortality rate was 52.3%. A multi-drug-resistant pattern (including carbapenems, fluoroquinolones, third-/fourth-generation cephalosporins) was shown for all K. pneumoniae isolates. KPC-3 and -2 were produced by all strains. The most common sequence types were 512 (91.3%) and 101 (8.7%), grouped into three clusters (A, A1 and B). CONCLUSIONS: A high incidence of KPC-Kp in patients with invasive infections was recorded at an Italian university hospital compared with the incidence measured before 2015. This study confirmed the importance of the KPC-3 carbapenemase variant, as reported by other Italian studies. High mortality and comorbidity rates appear to be associated with KPC-Kp infection. PMID- 29621601 TI - Results from the third Scottish National Prevalence Survey: is a population health approach now needed to prevent healthcare-associated infections? AB - BACKGROUND: Healthcare-associated infections (HCAIs) are a major public health concern and a significant cause of morbidity and mortality. A robust and current evidence base that is specific to local, national and Europe-wide settings is necessary to inform the development of strategies to reduce HCAI and contain antimicrobial resistance. AIM: To measure the prevalence of HCAI and antimicrobial prescribing and identify key priority areas for interventions to reduce the burden of infection. METHODS: A national rolling point-prevalence survey (PPS) in National Health Service (NHS) acute, NHS non-acute, NHS paediatric, and independent hospitals was carried out between September and November 2016 using the European Centre for Disease Prevention and Control protocol designed for the European PPS. FINDINGS: The prevalence of HCAI was 4.6%, 2.7%, and 3.2% in acute adults, paediatric and non-acute patient groups, respectively. The most frequent HCAI types reported in adult patients were urinary tract infection and pneumonia. The prevalence of antimicrobial prescribing was 35.7%, 29.3%, and 13.8% in acute adults, paediatric, and non acute patient groups, respectively. Respiratory, skin and soft tissue, gastrointestinal, and urinary tract infections were the most common infections being treated at the time of survey. CONCLUSION: HCAI continues to be a public health concern in Scotland. Urinary tract infection and pneumonia continue to place a significant burden on patients and on healthcare delivery, including those that develop in the community and require hospital admission. A broader population health approach which focuses on reducing the risk of infection upstream would reduce these infections in both community and hospital settings. PMID- 29621602 TI - Neutrophil extracellular traps possess anti-human respiratory syncytial virus activity: Possible interaction with the viral F protein. AB - Human respiratory syncytial virus (hRSV) is one of the main etiological agents of diseases of the lower respiratory tract, and is often responsible for the hospitalization of children and the elderly. To date, treatments are only palliative and there is no vaccine available. The airways of patients infected with hRSV exhibit intense neutrophil infiltration, which is responsible for the release of neutrophil extracellular traps (NETs). These are extracellular structures consisting of DNA associated with intracellular proteins, and are efficient in capturing and eliminating various microorganisms, including some viruses. hRSV induces the release of NETs into the lung tissue of infected individuals; however, the pathophysiological consequences of this event have not been elucidated. The objective of this study was to utilize in vitro and in silico assays to investigate the impact of NETs on hRSV infection. NETs, generated by neutrophils stimulated with phorbol myristate acetate (PMA), displayed long fragments of DNA and an electrophoretic profile suggestive of the presence of proteins that are classically associated with these structures (elastase, cathepsin G, myeloperoxidase, and histones). The presence of NETs (>2 MUg/ml) in HEp-2 cell culture medium resulted in cellular cytotoxicity of less than 50%. Pre-incubation (1 h) of viral particles (multiplicity of infection (MOI) values of 0.1, 0.5, and 1.0) with NETs (2-32 MUg/ml) resulted in cellular protection from virus-induced death of HEp-2 cells. Concurrently, there was a reduction in the formation of syncytia, which is related to decreased viral spread in infected tissue. Results from western blotting and molecular docking, suggest interactions between F protein of the hRSV viral envelope and BPI (bactericidal permeability-increasing protein), a microbicidal member of NETs. Interactions occurred at sites important for the neutralization and coordination of the hRSV infection/replication process. Our results showed that the presence of NETs decreases hRSV-induced cellular damage, possibly by directly affecting viral particle capture and/or interfering with the fusion activity of the F protein. These findings broaden the understanding of the role of NETs during hRSV infection. PMID- 29621603 TI - Type C botulism in domestic chickens, dogs and black-pencilled marmoset (Callithrix penicillata) in Minas Gerais, Brazil. AB - Botulism is a well-known intoxication that affects humans and animals. The disease is endemic in cattle in Brazil and recently emerged as an important disease in commercial laying hens and broiler chickens in Europe. Dogs and other animal species can also be affected. Although antitoxins are commonly administered to humans diagnosed with botulism, in animals this is rarely the case and the treatment of botulism is still based only on support therapy. In the present work, we report an outbreak of type C botulism in Brazil that simultaneously affected domestic chickens, dogs and a black-pencilled marmoset (Callithrix penicillata). The successful use of Clostridium botulinum types C and D antitoxin for the treatment of an affected dog is also described. PMID- 29621604 TI - Clostridioides difficile infection in dogs with chronic-recurring diarrhea responsive to dietary changes. AB - Five dogs with chronic-recurring diarrhea were positive for Clostridioides difficile infection (CDI), but were unresponsive to treatment with metronidazole. One of these animals was subjected to a colonoscopy, which revealed eosinophilic infiltration of the colon. All five animals completely recovered after dietary changes. The present work suggests that CDI might occur in dogs with other intestinal alterations. In addition, this report suggests that dysbiosis should be considered in animals that have chronic-recurring diarrhea and test positive for C. difficile. PMID- 29621605 TI - Hip joint moments during walking in people with hip osteoarthritis: a systematic review and meta-analysis. AB - OBJECTIVE: This systematic review and meta-analysis investigated surrogate measures of hip joint loading during walking in people with hip osteoarthritis (OA). METHODS: Five databases were searched up to January 14th, 2018. Studies that measured hip joint moments in the frontal or sagittal plane during walking in people with hip OA and used either a healthy control group or the unaffected leg to compare hip joint moments were included. Standardised mean differences (SMD) in sagittal and frontal plane moments were pooled as appropriate, using a random effect approach. Methodological quality was assessed using the Downs and Black checklist. RESULTS: Thirteen studies with 1,141 participants were eligible and suitable for meta-analyses. Overall, people with hip OA had lower sagittal (SMD -0.55 (95% confidence interval (CI) -1.00 to -0.10) and frontal plane moments (SMD -0.63 (95% CI -0.92, -0.34) compared to controls. However, substantial heterogeneity was observed (I2 <= 89%). Results by disease stage suggest that people with end-stage hip OA have lower sagittal (SMD -0.96; -1.30, 0.61; I2 = 69%) and frontal (SMD -1.17; 95% CI -1.71, -0.64; I2 = 85%) plane moments compared to controls. People with less severe hip OA than end-stage disease have comparable sagittal (SMD 0.37; 95% CI -0.17, 0.90; I2 = 69%) and frontal (SMD -0.24; 95% CI -0.76, 0.27; I2 = 51%) plane moments compared to controls. CONCLUSION: Hip joint loading may be dependent on disease stage. People with end-stage hip OA under-loaded compared to controls, while those who were not awaiting hip joint replacement had comparable hip joint loads to controls. PMID- 29621606 TI - Rhodamine binds to silk fibroin and inhibits its self-aggregation. AB - Amyloid structures are universal structures, widely diffuse in nature. Silk, capable of forming some of the strongest tensile materials on earth represents an important example of formation of functional amyloid fibrils, a process reminiscent of the oligomerization of peptides involved in neurodegenerative diseases. The stability of silk fibroin solutions in different conditions and its transition from alpha-helix/random coil to beta-sheet structures, at the basis of gelation processes and fibril formation, have been here investigated and monitored employing different biophysical approaches. Silk fibroin aggregation state as a function of concentration, pH and aging has been characterized employing NMR ordered diffusion spectroscopy. The change of silk fibroin diffusion coefficient over time, which reflects the progress of oligomerization, has been monitored for silk fibroin alone and in the presence of a polycondensed aromatic dye, namely rhodamine 6G. NMR, UV and DLS measurements indicated that rhodamine specifically binds to silk fibroin with a micromolar KD. The reported data reveal, for the first time, that RHD is capable of inhibiting fibroin self association, thus controlling beta-conformational transition at the basis of fibril formation. The described approach could be extended to further protein systems, allowing better control of the oligomerisation process. PMID- 29621607 TI - Counseling Patients with a Glioblastoma Amenable Only for Subtotal Resection: Results of a Multicenter Retrospective Assessment of Survival and Neurologic Outcome. AB - BACKGROUND: Patients with a glioblastoma (GB) amenable only for subtotal resection (STR) represent a challenge in patient counseling. Our objective was to assess impact of extent of resection (EoR) on survival and clinical outcome of these patients. METHODS: We performed a retrospective multicenter assessment. Patients receiving an intended STR in 3 centers with unilocular, primary, highly eloquent GB who received the same adjuvant treatment were included. We assessed EoR, neurologic outcome, and rate of complications. Progression-free survival (PFS) and overall survival (OS) were calculated with Kaplan-Meier estimations. We used 1% EoR and 1-cm3 steps to detect a threshold for a minimal EoR and residual tumor volume (RV) to be beneficial for survival and performed multivariate Cox regression models to assess its influence on PFS and OS. RESULTS: In total, 67 patients were included. EoR and RV were not significantly associated with PFS in multivariate Cox regression. Multivariate Cox regression model for OS revealed that volumetric EoR is a significant predictor for OS (P = 0.002, OR 0.982), same as RV (P = 0.007, OR 1.03), controlling for age, preoperative tumor volume, sex, and recurrent surgery. We found a significant benefit for OS if an EoR >60% or a RV <8 cm3 was reached. In the aforementioned multivariate Cox regression models, an EoR <=60% and a RV >=8 cm3 independently showed a significantly negative association with OS (P = 0.044, OR 1.96/P = 0.024, OR 2.07). CONCLUSIONS: In highly eloquent GB, EoR significantly matters for patients' OS. Also, potential RV should be considered when treating these patients. In cases with an expected RV above or an EoR below the aforementioned thresholds, open surgery should be carefully considered. PMID- 29621608 TI - Impact of an External Ventricular Drain Placement and Handling Protocol on Infection Rates: A Meta-Analysis and Single Institution Experience. AB - BACKGROUND: Numerous studies have examined the impact of initiating an external ventricular drain (EVD) placement and handling protocol on the infection rate dating back to the early 2000s. METHODS: We report a quantitative systematic review of the published literature, described our own protocol (including a mandatory checklist), and present our single institution experience. Search terms "external ventricular drain protocol" or "external ventricular drain placement protocol" or "preventing infections in external ventricular drains" or "external ventricular drain infections" were entered into standard search engines in a systematic fashion. Articles were reviewed and graded independently for class of evidence. There were 10 relevant class IV articles and no discrepancies among article ratings (i.e., kappa = 1). The published evidence was reviewed and evaluated using the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) criteria. RESULTS: Our meta-analysis revealed a statistically significant drop in rates of EVD infection after initiation of the protocol, although the overall quality of the body of evidence according to the GRADE criteria was "very poor". Preimplementation and postimplementation infection rates were collected and analyzed in combination with the results from our literature review. The EVD infection rate in our institution was 12% in the 8 months before protocol initiation (January 2015 to August 2015), and dropped to 0% in the 7 months after initiation. CONCLUSIONS: Although the quality of the literature supporting EVD placement protocols is poor, all published studies show a consistent and substantial benefit, and this effect was recapitulated in our own meta-analysis-based prospective EVD protocol experience. PMID- 29621609 TI - Diversity of symbiotic microbiota in Deltocephalinae leafhoppers (Insecta, Hemiptera, Cicadellidae). AB - Symbiotic microorganisms associated with thirteen species of the subfamily Deltocephalinae were examined using microscopic and molecular techniques. Athysanus argentarius, Euscelis incisus, Doratura stylata, Arthaldeus pascuellus, Errastunus ocellaris, Jassargus flori, Jassargus pseudocellaris, Psammotettix alienus, Psammotettix confinis, Turrutus socialis and Verdanus abdominalis harbor two types of ancient bacteriome-associated microorganisms: bacteria Sulcia (phylum Bacteroidetes) and bacteria Nasuia (phylum Proteobacteria, class Betaproteobacteria). In Balclutha calamagrostis and Balclutha punctata, the bacterium Nasuia has not been detected. In the bacteriomes of both species of Balclutha examined, only bacteria Sulcia occur, whereas Sodalis-like symbionts (phylum Proteobacteria, class Gammaproteobacteria) are localized in the fat body cells, in close vicinity of the bacteriomes. To our knowledge, this is the first report of the co-existence in Deltocephalinae leafhoppers of the ancient symbiont Sulcia and the more recently acquired Sodalis-like bacterium. The obtained results provide further evidence indicating that Deltocephalinae leafhoppers are characterized by a large diversity of symbiotic systems, which results from symbiont acquisition and replacement. The obtained results are additionally discussed in phylogenetic context. PMID- 29621610 TI - Hyperapolytic species of Acanthobothrium (Cestoda: Onchoproteocephalidea) from batoids off Argentina. AB - Two hyperapolytic species of Acanthobothrium Blanchard, 1848 have been collected from Discopyge tschudii Heckel, 1846 and Zapteryx brevirostris (Muller et Henle) along the coast of Argentina. Acanthobothrium stefaniae sp. n. from D. tschudii is a category one species (i.e., it is less than 15 mm in total length, possesses fewer than 50 proglottids, fewer than 80 testes and essentially symmetrical ovary), and differs from all congeners by the following combination of features: proglottid hyperapolysis, hook morphology, size and shape of the cirrus sac, and by having spinitriches in the distal bothridial surface. This is the first record of Acanthobothrium in Discopyge Heckel, 1846. The specimens from Z. brevirostris conform to the morphology of Acanthobothrium zapterycum Ostrowski de Nunez, 1971. A redescription of this species is presented, which expands most ranges of measurements originally given, and provides details omitted in the original description, including the microthrix pattern. This study allowed us to observe the intraspecific variation in ovarian symmetry in A. zapterycum, which shed some doubt on the validity of this as a diagnostic feature. The reproductive strategy (apolysis) of several species of Acanthobothrium was reviewed and summarized. PMID- 29621611 TI - Hypanocotyle bullardi n. gen. n. sp. (Monogenea: Hexabothriidae) from gill of the diamond stingray Hypanus dipterurus (Jordan et Gilbert) (Myliobatiformes: Dasyatidae) in the Southeastern Pacific Ocean off Peru. AB - A new genus and species of monogenean belonging to Hexabothriidae, Hypanocotyle bullardi n. gen. n. sp., is described based on specimens collected from the gill filaments of the diamond stingray, Hypanus dipterurus (Jordan et Gilbert) (Myliobatiformes: Dasyatidae), a demersal chondrichthyan collected off the coast of Callao, Peru. Hypanocotyle n. gen. has the following combination of diagnostic features that differentiate it from other hexabothriid genera: haptor symmetrical; vasa efferentia having proximal (narrow, with thin glandular wall) and distal (expanded, interlaced, with thick glandular wall) portions, joining medially to form vas deferens; vas deferens having proximal (expanded, sinuous, with thick glandular wall) and distal (narrow, strongly sinuous, with thin glandular wall) portions; male copulatory organ unarmed, proximal portion slightly sinuous and tube-like, distal portion funnel-shaped; prostatic glands present, distributed around of the MCO; seminal receptacle present; ootype lacking longitudinal rows of large cells (no ootype cotele); vaginae parallel, with well-differentiated proximal (glandular, narrow, tube-like, slightly sinuous) and distal (musculoglandular, convoluted) portions; gland cells surrounding the vaginal duct along the entire length of distal portion, densely clustered in middle portion; uterine eggs with 2 elongate filaments. Phylogenetic reconstructions by maximum-likelihood method, based on newly obtained partial 18S and 28S sequences, shows that H. bullardi n. gen. is included within the family Hexabothriidae, order Diclybothriidea. This is the second hexabothriid genus recorded from a diamond stingray (Dasyatidae), and the fourth hexabothriid species recorded from Peru. A key to hexabothriid genera is provided. PMID- 29621612 TI - Laparoscopic Anterior Pelvic Exenteration with Super Radical Parametrectomy for a Recurrent Low-Grade Endometrial Sarcoma That is Resistant to Hormone Therapy and Chemotherapy. AB - STUDY OBJECTIVE: To show total laparoscopic complete resection of a recurrent low grade endometrial sarcoma. DESIGN: Step-by-step demonstration of the technique of laparoscopic anterior pelvic exenteration with super radical parametrectomy, including the explanation of detailed pelvic anatomy (Canadian Task Force classification III). SETTING: Low-grade endometrial stromal sarcoma (LGESS) is a rare malignancy that makes up around 0.2% of all uterine malignancies [1]. Total abdominal hysterectomy and bilateral salpingo-oophorectomy is a standard treatment; however, the recurrence risk is quite high [2]. For a recurrent LGESS that is resistant to hormone therapy and chemotherapy, complete resection with negative surgical margins (R0 resection) can be the most promising method [3]. PATIENT: The patient had undergone total abdominal hysterectomy and bilateral salpingo-oophorectomy because of a LGESS. Almost 20 years later, a recurrent LGESS was detected at the vaginal stump, and the patient underwent several rounds of chemotherapy and hormonal therapy. These treatments were inefficacious, and the recurrent tumor progressed. An abdominal computed tomographic scan revealed that the recurrent tumor occupied the vaginal stump, involved the bladder and the left ureter, and extended to the left pelvic sidewall. INTERVENTIONS: Anterior pelvic exenteration with super radical parametrectomy was performed laparoscopically with no blood transfusion. R0 resection could be achieved without any intraoperative and postoperative complications. Without any adjuvant treatment, there has been no sign of recurrence during the 12 months that have passed since the surgery. This video obtained institutional review board approval through our local ethics committee in the Cancer Institutional Hospital (institutional review board number 2016-1007). CONCLUSION: The good visualization and meticulous dissection provided during laparoscopic surgery can make the approach advantageous and may contribute to R0 achievement. PMID- 29621613 TI - Cytokine targeting in rheumatoid arthritis. PMID- 29621616 TI - Contaminants in blood cultures: importance, implications, interpretation and prevention. AB - BACKGROUND: Despite the development of new microbiologic technologies, blood cultures (BCs) remain the first-line tool for the diagnosis of bloodstream infections. Their diagnostic value may be affected when a microorganism of questionable evidence is isolated-for example, coagulase-negative staphylococci, Bacillus spp., viridans group streptococci, Corynebacterium spp., Propionibacterium spp. and Micrococcus spp. Finally, making a correct diagnosis of pathogenicity (vs. contamination) is challenging. AIMS: To review the current ways of dealing with the problem of BC contaminants (BCCs) and to provide practical suggestions to decrease BCC rates. SOURCES: PubMed electronic databases and existing reviews were searched up to December 2017 to retrieve relevant publications related to the topic. CONTENTS: This review describes the burden of BCC and analyses the main current issues and controversies in interpreting the occurrence of potential BC contaminants. It focuses on the best-described approaches to decide whether BCC is present and discusses the different strategies of prevention in adults. IMPLICATIONS: Each institution should have an efficient policy to prevent BCC, emphasizing the importance of following guidelines for prescribing and collecting BCs. Training healthcare workers should focus on detrimental influence on patient care and highlight the work and costs due to contaminants. The accurate differentiation of a contaminant from a true pathogen relies on a multidisciplinary approach and the clinical judgement of experienced practitioners. PMID- 29621617 TI - Genetic characterization and pathogenicity of Japanese porcine deltacoronavirus. AB - Porcine deltacoronavirus (PDCoV) have recently emerged in several swine producing countries. Our survey found that in addition to porcine epidemic diarrhoea virus (PEDV), PDCoV has also been a causative enteric pathogen of diarrhoeic outbreaks occurring at swine farms around Japan since late 2013. Phylogenetic analysis using the complete genomes of PDCoVs detected in Japan in 2014 demonstrated that the PDCoVs from Japan may be closely related to the PDCoVs from the U.S. and Korea during 2013 to 2014 but not the PDCoVs from China and Hong Kong during 2004 to 2016 and from Thailand, Vietnam and Laos during 2015 to 2016. To investigate the pathogenicity of a representative Japanese PDCoV, we performed an experimental infection using hysterectomy-produced colostrum-deprived piglets. The PDCoV-inoculated piglets showed acute, watery diarrhoea, but all recovered and survived. In addition, all piglets inoculated with the Japanese PDCoV exhibited virus shedding at high level in faeces and viremia corresponding to their clinical symptoms. In the PDCoV-inoculated group, viruses were mainly detected from jejunums to colons by a quantitative PDCoV-specific PCR and microscopic observation. These findings would provide useful information for establishing a diagnostic methodology for distinguishing diarrhoea caused by PDCoV from that caused by other enteric pathogens, such as PEDV. PMID- 29621615 TI - Statistical power comparisons at 3T and 7T with a GO / NOGO task. AB - The field of cognitive neuroscience is weighing evidence about whether to move from standard field strength to ultra-high field (UHF). The present study contributes to the evidence by comparing a cognitive neuroscience paradigm at 3 Tesla (3T) and 7 Tesla (7T). The goal was to test and demonstrate the practical effects of field strength on a standard GO/NOGO task using accessible preprocessing and analysis tools. Two independent matched healthy samples (N = 31 each) were analyzed at 3T and 7T. Results show gains at 7T in statistical strength, the detection of smaller effects and group-level power. With an increased availability of UHF scanners, these gains may be exploited by cognitive neuroscientists and other neuroimaging researchers to develop more efficient or comprehensive experimental designs and, given the same sample size, achieve greater statistical power at 7T. PMID- 29621614 TI - Ras and Rap1: A tale of two GTPases. AB - Ras oncoproteins play pivotal roles in both the development and maintenance of many tumor types. Unfortunately, these proteins are difficult to directly target using traditional pharmacological strategies, in part due to their lack of obvious binding pockets or allosteric sites. This obstacle has driven a considerable amount of research into pursuing alternative ways to effectively inhibit Ras, examples of which include inducing mislocalization to prevent Ras maturation and inactivating downstream proteins in Ras-driven signaling pathways. Ras proteins are archetypes of a superfamily of small GTPases that play specific roles in the regulation of many cellular processes, including vesicle trafficking, nuclear transport, cytoskeletal rearrangement, and cell cycle progression. Several other superfamily members have also been linked to the control of normal and cancer cell growth and survival. For example, Rap1 has high sequence similarity to Ras, has overlapping binding partners, and has been demonstrated to both oppose and mimic Ras-driven cancer phenotypes. Rap1 plays an important role in cell adhesion and integrin function in a variety of cell types. Mechanistically, Ras and Rap1 cooperate to initiate and sustain ERK signaling, which is activated in many malignancies and is the target of successful therapeutics. Here we review the role activated Rap1 in ERK signaling and other downstream pathways to promote invasion and cell migration and metastasis in various cancer types. PMID- 29621618 TI - Stereoscopic digital mammogram: Usefulness in daily practice. AB - OBJECTIVES: To assess the benefit of stereoscopic digital mammography in daily practice. METHODS: Stereoscopic digital (SD) mammography allows a fused 3D view of mammogram. A 4-degree cranio-caudal (CC) angle view matched with a regular CC view allows generating a stereoscopic view. Three breast radiologists reviewed retrospectively 1110 stereoscopic digital mammograms (1075 women) performed between November 2011 and February 2013 with the following sequence: each evaluated firstly conventional mammogram alone, and then integrated SD mammograms. The benefit was quoted in 3-grade scale: 0 for no benefit, 1 moderate and 2 excellent. The concordance between radiologists was evaluated by the W Randall coefficient. Subgroup analysis according to the BI-RADS classification, breast density and type of abnormalities were performed by calculating odds ratio. RESULTS: The readers had the same opinion regarding the value of stereoscopic digital mammograms in 87% of cases (962/1110). Benefit was null, moderate and excellent in 8, 52 and 26% respectively. The concordance of radiologists was excellent with a W coefficient above 0.89. CONCLUSIONS: SD mammogram improved interpretation of abnormal mammograms. This potentially interesting and promising complementary tool might be beneficial in daily breast imaging practice. PMID- 29621620 TI - Benign hereditary chorea and deletions outside NKX2-1: What's the role of MBIP? AB - Heterozygous point mutations or deletions of the NKX2-1 gene cause benign hereditary chorea (BHC) or a various combinations of primary hypothyroidism, respiratory distress and neurological disorders. Deletions proximal to, but not encompassing, NKX2-1 have been described in few subjects with brain-lung-thyroid syndrome. We report on a three-generation Italian family, with 6 subjects presenting BHC and harboring a genomic deletion adjacent to NKX2-1 and including the gene MBIP, recently proposed to be relevant for the pathogenesis of brain lung-thyroid syndrome. We observed a clear reduction of NKX2-1 transcript levels in fibroblasts from our patients compared to controls; this finding suggests that MBIP deletion affects NKX2-1 expression, mimicking haploinsufficiency caused by classical NKX2-1 related mutations. PMID- 29621619 TI - Adventures with RNA graphs. AB - The structure of RNA has been a natural subject for mathematical modeling, inviting many innovative computational frameworks. This single-stranded polynucleotide chain can fold upon itself in numerous ways to form hydrogen bonded segments, imperfect with single-stranded loops. Illustrating these paired and non-paired interaction networks, known as RNA's secondary (2D) structure, using mathematical graph objects has been illuminating for RNA structure analysis. Building upon such seminal work from the 1970s and 1980s, graph models are now used to study not only RNA structure but also describe RNA's recurring modular units, sample the conformational space accessible to RNAs, predict RNA's three-dimensional folds, and apply the combined aspects to novel RNA design. In this article, we outline the development of the RNA-As-Graphs (or RAG) approach and highlight current applications to RNA structure prediction and design. PMID- 29621621 TI - Phenotypic consequences of gene disruption by a balanced de novo translocation involving SLC6A1 and NAA15. AB - Mapping of de novo balanced chromosomal translocations (BCTs) in patients with sporadic poorly characterized disease(s) is an unbiased method of finding candidate gene(s) responsible for the observed symptoms. We present a paediatric patient suffering from epilepsy, developmental delay (DD) and atrial septal defect IIo (ASD) requiring surgery. Karyotyping indicated an apparently balanced de novo reciprocal translocation 46,XX,t(3;4)(p25.3;q31.1), whereas aCGH did not reveal any copy number changes. Using shallow mate-pair whole genome sequencing and direct Sanger sequencing of breakpoint regions we found that translocation disrupted SLC6A1 and NAA15 genes. Our results confirm two previous reports indicating that loss of function of a single allele of SLC6A1 causes epilepsy. In addition, we extend existing evidence that disruption of NAA15 is associated with DD and with congenital heart defects. PMID- 29621622 TI - Outcomes of the Arterial Switch Operation in <=2.5-kg Neonates. AB - Although low birth weight is a known risk factor for mortality in congenital heart lesions and may consequently delay surgical repair, outcomes in low-weight neonates undergoing the arterial switch operation (ASO) have not been well described. Our objective was to assess the safety of this procedure in infants weighing <=2.5 kg at the time of surgery. We retrospectively analyzed outcomes for all neonates undergoing the ASO at our institution from 2005 to 2015. Our primary outcome of interest was major morbidity or operative mortality, assessed as a composite outcome. From 2005 to 2015, 217 neonates underwent the ASO, with 31 (14%) weighing <=2.5 kg at the date of surgery, and 8 weighing <2.0 kg. Neonates weighing <=2.5 kg were more likely to be premature than those weighing >2.5 kg, but there was no difference in the age at operation between these groups. Overall, 32 infants experienced a major morbidity or mortality, including 37.5% (n = 3) weighing <2.0 kg, 8.7% (n = 2) weighing 2.0-2.5 kg, and 14.5% (n = 7) weighing >2.5 kg (P = 0.141). One infant weighing <2.0 kg (1.1 kg) and 4 infants weighing >2.5 kg died. In multivariable models, odds of major morbidity or mortality were significantly higher for infants weighing <2 kg compared with infants weighing >2.5 kg (odds ratio 3.93, 95% confidence interval 1.04-14.85, P = 0.044), but there was no difference between infants weighing 2.0-2.5 kg and those weighing >2.5 kg (P = 0.225). The ASO can be performed safely in 2.0- to 2.5-kg neonates and yields results comparable with higher weight infants. Imposed delays for corrective surgery may not be necessary for these low-weight infants with transposition of the great arteries. PMID- 29621623 TI - Maritime varicella illness and death reporting, U.S., 2010-2015. AB - BACKGROUND: Ships destined for, or departing from, U.S. ports of entry must report certain signs and symptoms of potentially communicable diseases of public health interest among travelers to the Division of Global Migration and Quarantine (DGMQ) at the Centers for Disease Control and Prevention. METHODS: We reviewed ships' varicella case and outbreak reports from January 2010 through December 2015. RESULTS: DGMQ received 967 reports of varicella and 13 reports of herpes zoster. Most varicella case-patients were 20-49 years of age (84.7%, 472/557) and were cruise ship crew members (78.4%, 758/967). Most often, cruise ship crew member case-patients were born in or held passports from Indonesia (21.7%, 80/369), Philippines (17.6%, 65/369), or India (17.3%, 64/369). Ninety nine varicella outbreaks were reported, including 439 varicella cases and one herpes zoster case; 97 (98.0%) outbreaks occurred on cruise ships, and 90.2% of associated cases were among crew members (397/440). Most varicella cases were in crew members, who are adults often from tropical regions where varicella immunity is acquired later in childhood or young adulthood or without varicella vaccination programs. CONCLUSION: Varicella vaccination as appropriate for susceptible travelers, particularly crew members, before maritime travel may decrease risk of varicella infection and prevent outbreaks on ships. PMID- 29621624 TI - Astilbin ameliorates pulmonary fibrosis via blockade of Hedgehog signaling pathway. AB - BACKGROUND AND OBJECTIVE: The nature of pulmonary fibrosis involves inadequate repair of the epithelial cell barrier accompanied by impaired regulation of the fibroblast. Moreover, pulmonary fibrosis currently lacks an effective therapeutic drug. This study targets the protection of the epithelial cell and fibroblast to identify a novel, potentially therapeutic drug (i.e., astilbin). METHODS: In this study, the cytotoxicity of astilbin was firstly detected using CCK-8. A real-time proliferation/migration analysis system was used to test the inhibitory proliferation and migration of astilbin in vitro. The expression of mesenchymal markers and the loss of epithelial cell markers were analyzed to evaluate the antifibrotic activity of astilbin on TGF-beta1-treated AEC-II and L929 cells and bleomycin-treated mice. Then, in fibrosis-associated signaling pathways, the regulation of astilbin was tested using RNA sequencing and Cignal Finder 45 Pathway system. Rescue and other experiments were used to confirm this pathway regulation further. RESULTS: The data showed that astilbin inhibited proliferation and migration of cell samples. Its treatment resulted in the reduction of pathological score and collagen deposition, with a decrease in alpha SMA and Snail and an increase in E-cadherin and SP-C in vivo and in vitro. The fibrosis-associated aberrant genes are some of the most notable components of the Hedgehog signaling pathway. CONCLUSIONS: Astilbin ameliorates pulmonary fibrosis via blockade of Hedgehog signaling pathway and has potential therapeutic value for lung fibrosis treatment. PMID- 29621625 TI - Ciprofloxacin Dry Powder for Inhalation (ciprofloxacin DPI): Technical design and features of an efficient drug-device combination. AB - Bronchiectasis is a chronic respiratory disease with heterogeneous etiology, characterized by a cycle of bacterial infection and inflammation, resulting in increasing airway damage. Exacerbations are an important cause of morbidity and are strongly associated with disease progression. Many patients with bronchiectasis suffer from two or more exacerbations per year. However, there are no approved therapies to reduce or delay exacerbations in this patient population. Ciprofloxacin DPI is in development as a long-term, intermittent therapy to reduce exacerbations in patients with non-cystic fibrosis (CF) bronchiectasis and evidence of respiratory pathogens. Ciprofloxacin DPI combines drug substance, dry powder manufacturing technology, and an efficient, pocket sized, dry powder inhaler to deliver an effective antibiotic directly to the site of infection, with minimal systemic exposure and treatment burden. Here we review the drug substance and particle engineering (PulmoSphereTM) technology used, and key physical properties of Ciprofloxacin Inhalation Powder, including deposition, delivered dose uniformity, consistency, and stability. Design features of the T 326 Inhaler are described in relation to lung targeting, safety and tolerability of inhalation powders, as well as treatment burden and adherence. If approved, Ciprofloxacin DPI may provide a valuable treatment option for those with frequent exacerbations and respiratory pathogens. PMID- 29621626 TI - The plasma membrane protein Rch1 and the Golgi/ER calcium pump Pmr1 have an additive effect on filamentation in Candida albicans. AB - Pmr1 is the Golgi/ER calcium pump, while Rch1 is a newly identified negative regulator of calcium influx in the plasma membrane of yeast cells. We show here that CaRch1 plays a dominant role over CaPmr1 in response of Candida albicans to SDS and tunicamycin stresses, while CaPmr1 has a major role in cell wall stress. Deletion of CaRCH1 increases the calcium/calcineurin signaling level in cells lacking CaPMR1. Calcineurin function is required for the role of CaRch1 in SDS stresses, while it is required for the function of CaPmr1 under all conditions examined. Disruption of CaRCH1 alone does not reduce the cell wall chitin, mannan or beta-glucan content, but lack of CaRCH1 slightly decreases the chitin content of cells lacking CaPMR1. Furthermore, CaRch1 and CaPmr1 have an additive effect on filamentation of C. albicans cells in vitro. Cells lacking both CaRCH1 and CaPMR1 and cells lacking CaPMR1 alone show a similar degree of virulence attenuation, being much more attenuated than cells lacking CaRCH1 alone. Therefore, CaRch1 genetically interacts with CaPmr1 in the regulation of in vitro filamentation in C. albicans. PMID- 29621627 TI - Extended-spectrum beta-lactamase (ESBL)-producing Serratia marcescens causing healthcare-associated infections in Assiut University Hospitals, Egypt. PMID- 29621628 TI - A Japanese trial to monitor methicillin-resistant Staphylococcus aureus (MRSA) in imported swine during the quarantine period. AB - OBJECTIVES: This study aimed to determine the prevalence of methicillin-resistant Staphylococcus aureus (MRSA) in imported swine during the quarantine period in Japan. METHODS: Nasal swabs from a total of 125 swine belonging to 15 lots (unit of import) from five countries were investigated for MRSA from July 2016 to February 2017. Two isolates per positive lot were chosen for multilocus sequence typing (MLST). PCR was performed to determine the presence of the czrC gene, and antimicrobial susceptibility testing was performed by the broth dilution method. RESULTS: MRSA isolates were obtained from six lots (41 heads; 32.8%) from two countries. All 12 isolates that underwent MLST (two per positive lot) were classified as ST398, harboured the czrC gene and were resistant to ampicillin and tetracycline; some isolates showed additional resistance to erythromycin or streptomycin, but resistance to ciprofloxacin, gentamicin or chloramphenicol was not observed. CONCLUSIONS: MRSA ST398 isolates were obtained from imported swine in this first trial to monitor MRSA during the quarantine period in Japan. For the 'One Health' approach against antimicrobial resistance, monitoring imported animals and generating feedback data would be important. PMID- 29621629 TI - Genetic characterisation of Staphylococcus aureus isolated from milk and nasal samples of healthy cows in Tunisia: First report of ST97-t267-agrI-SCCmecV MRSA of bovine origin in Tunisia. AB - OBJECTIVES: This study aimed to screen for and characterise methicillin susceptible Staphylococcus aureus (MSSA) and methicillin-resistant S. aureus (MRSA) in nasal swabs and milk from healthy cows from different regions in Tunisia. METHODS: A total of 141 Staphylococcus spp. isolates were recovered from milk and nasal samples of cows. S. aureus isolates were further characterised by determining their antimicrobial susceptibilities, genes encoding antimicrobial resistance and virulence factors, biofilm production, agr type and PFGE. spa and SCCmec typing and MLST were also performed for the MRSA isolate. RESULTS: Twenty seven isolates (19.1%) were identified as S. aureus, of which 26 were MSSA and 1 was MRSA. The MSSA isolates were resistant to penicillin (73.1%), fusidic acid (61.5%), clindamycin (34.6%) and erythromycin (34.6%). The MRSA isolate, from a milk sample, was resistant to cefoxitin, penicillin, fusidic acid, amikacin and clindamycin. Twenty-five isolates (92.6%) had at least one enterotoxin gene. Only four isolates (14.8%) were positive for the tsst-1 gene. Genes encoding the exfoliative toxins D and A were detected in 9 (33.3%) and 6 (22.2%) isolates, respectively. The single MRSA isolate and 22 MSSA isolates were biofilm-producers on Congo red agar plates. Twelve pulsotypes were identified amongst 25 MSSA isolates revealing the clonal diversity of these isolates; however, one MSSA isolate was identified as CC398. The MRSA isolate was PVL-negative and was typed as ST97-t267-agrI-SCCmecV. CONCLUSION: Contamination of milk with S. aureus, especially enterotoxin- and TSST-1-positive strains, poses a potential public health threat. This is the first report of MRSA of bovine origin in Tunisia. PMID- 29621630 TI - Conformational properties of intrinsically disordered proteins bound to the surface of silica nanoparticles. AB - BACKGROUND: Protein-nanoparticle (NP) interactions dictate properties of nanoconjugates relevant to bionanotechnology. Non-covalent adsorption generates a protein corona (PC) formed by an inner and an outer layer, the hard and soft corona (HC, SC). Intrinsically disordered proteins (IDPs) exist in solution as conformational ensembles, whose response to the presence of NPs is not known. METHODS: Three IDPs (alpha-casein, Sic1 and alpha-synuclein) and lysozyme are compared, describing conformational properties inside HC on silica NPs by circular dichroism (CD) and Fourier-transform infrared (FTIR) spectroscopy. RESULTS: IDPs inside HC are largely unstructured, but display small, protein specific conformational changes. A minor increase in helical content is observed for alpha-casein and alpha-synuclein, reminiscent of membrane effects on alpha synuclein. Frozen in their largely disordered conformation, bound proteins do not undergo folding induced by dehydration, as they do in their free forms. While HC thickness approaches the hydrodynamic diameter of the protein in solution for lysozyme, it is much below the respective values for IDPs. NPs boost alpha synuclein aggregation kinetics in a dose-dependent manner. CONCLUSIONS: IDPs maintain structural disorder inside HC, experiencing minor, protein-specific, induced folding and stabilization against further conformational transitions, such as formation of intermolecular beta-sheets upon dehydration. The HC is formed by a single layer of protein molecules. SC likely plays a key role stabilizing amyloidogenic alpha-synuclein conformers. GENERAL SIGNIFICANCE: Protein-NP interactions can mimic those with macromolecular partners, allowing dissection of contributing factors by rational design of NP surfaces. Application of NPs in vivo should be carefully tested for amyloidogenic potential. PMID- 29621631 TI - Spontaneous intracranial hypotension is diagnosed by a combination of lipocalin type prostaglandin D synthase and brain-type transferrin in cerebrospinal fluid. AB - BACKGROUND: Spontaneous intracranial hypotension (SIH) is caused by cerebrospinal fluid (CSF) leakage. Definitive diagnosis can be difficult by clinical examinations and imaging studies. METHODS: SIH was diagnosed with the following criteria: (i) evidence of CSF leakage by cranial magnetic resonance imaging (MRI) findings of intracranial hypotension and/or low CSF opening pressure; (ii) no recent history of dural puncture. We quantified CSF proteins by ELISA or Western blotting. RESULTS: Comparing with non-SIH patients, SIH patients showed significant increase of brain-derived CSF glycoproteins such as lipocalin-type prostaglandin D synthase (L-PGDS), soluble protein fragments generated from amyloid precursor protein (sAPP) and "brain-type" transferrin (Tf). Serum-derived proteins such as albumin, immunoglobulin G, and serum Tf were also increased. A combination of L-PGDS and brain-type Tf differentiated SIH from non-SIH with sensitivity 94.7% and specificity 72.6%. CONCLUSION: L-PGDS and brain-type Tf can be biomarkers for diagnosing SIH. GENERAL SIGNIFICANCE: L-PGDS and brain-type Tf biosynthesized in the brain appears to be markers for abnormal metabolism of CSF. PMID- 29621632 TI - CRISPR/Cas9-mediated deletion of EcMIH shortens metamorphosis time from mysis larva to postlarva of Exopalaemon carinicauda. AB - The recently emerged CRISPR/Cas9 technology is the most flexible means to produce targeted mutations at the genomic loci in a variety of organisms. In Crustaceans, molt-inhibiting hormone (MIH) is an important negative-regulatory factor and plays a key role in suppressing the molting process. However, whether precise disruption of MIH in crustacean can be achieved and successfully used to improve the development and growth has not been proved. In this research, the complementary DNA (cDNA) and genomic DNA, including flanking regions of the MIH gene (EcMIH) of ridgetail white prawn Exopalaemon carinicauda, were cloned and sequenced. Sequence analysis revealed that EcMIH was composed of three exons and two introns. Analysis by RT-PCR showed that EcMIH mainly expressed in eyestalks. During different development periods, EcMIH was highest in juvenile stage and extremely low in others but adult prawns eyestalks. In addition, we applied CRISPR/Cas9 technology to generate EcMIH knock-out (KO) prawns and then analyzed the changes in their phenotypes. We efficiently generated 12 EcMIH-KO prawns out of 250 injected one-cell stage embryos and the mutant rate reached 4.8% after embryo injection with one sgRNA targeting the second exon of EcMIH. The EcMIH-KO prawns exhibited increased the body length and shortened the metamorphosis time of larvae from mysis larva to postlarva. Meanwhile, EcMIH-KO did not cause the health problems such as early stage death or deformity. In conclusion, we successfully obtained EcMIH gene and generated EcMIH-KO prawns using CRISPR/Cas9 technology. This study will certainly lead to a wide application prospect of MIH gene in prawns breeding. PMID- 29621633 TI - Molecular characterization of kappa class glutathione S-transferase from the disk abalone (Haliotis discus discus) and changes in expression following immune and stress challenges. AB - Glutathione S-transferase (GST; EC 2.5.1.18) isoenzymes represent a complex group of proteins that are involved in phase II detoxification in several organisms. In this study, GST kappa (GSTkappa) from the disk abalone (Haliotis discus discus; AbGSTkappa) was characterized at both the transcriptional and functional levels to determine its potential capacity to perform as a detoxification agent under conditions of different stress. The predicted AbGSTkappa protein consists of 227 amino acids, with a predicted molecular weight of 25.6 kDa and a theoretical isoelectric point (pI) of 7.78. In silico analysis reveals that AbGSTkappa is a disulfide bond formation protein A (DsbA), consisting of a thioredoxin domain, GSH binding sites (G-sites), and a catalytic residue. In contrast, no hydrophobic ligand binding site (H-site), or signal peptides, were detected. AbGSTkappa showed the highest sequence identity with the orthologue from pufferfish (Takifugu obscurus) (60.0%). In a phylogenetic tree, AbGSTkappa clustered closely together with other fish GSTkappas, and was evolutionarily distanced from other cytosolic GSTs. The predicted three-dimensional structure clearly demonstrates that the dimer adopts a butterfly-like shape. A tissue distribution analysis revealed that GSTkappa was highly expressed in the digestive tract, suggesting it has detoxification ability. Depending on the tissue and time, AbGSTkappa showed different expression patterns, and levels of expression, following challenge of the abalone with immune stimulants. Enzyme kinetics of the purified recombinant proteins demonstrated its conjugating ability using 1-Chloro-2,4-dinitrobenzene (CDNB) and glutathione (GSH) as substrates, and suggested it has a low affinity for both substrates. The optimum temperature and pH for the rAbGSTkappa GSH: CDNB conjugating activity were found to be 35 degrees C and pH 8, respectively indicating that the abalone is well adapted to a wide range of environmental conditions. Cibacron blue (100 MUM) was capable of completely inhibiting rAbGSTkappa (100%) with an IC50 (half maximal inhibitory concentration) of 0.05 MUM. A disk diffusion assay revealed that rAbGSTkappa could significantly protect cells from H2O2, CdCl2, and ZnCl2. Altogether, this current study suggests that AbGSTkappa is involved in detoxification and immunological host defense mechanisms and allows abalones to overcome stresses in order for them to have an increased chance of survival. PMID- 29621634 TI - Novel L-type lectin from fresh water prawn, Macrobrachium rosenbergii participates in antibacterial and antiviral immune responses. AB - L-type lectins (LTLs) play important roles in the secretory pathway of animals, including selective protein trafficking, sorting, and targeting. They have a leguminous lectin domain and can bind to high-mannose-type oligosaccharides. In this study, a novel LTL, designated as MrVIP36, was identified from Macrobrachium rosenbergii. The full-length cDNA of MrVIP36 was 1687 bp with a 972 bp open reading frame encoding a putative protein of 323 deduced amino acids. The deduced MrVIP36 protein contained an LTL-like domain (LTLD) and a transmembrane domain. Phylogenetic tree analysis indicated that MrVIP36 was a member of invertebrate LTLs. It has a closer evolutionary distance with invertebrate LTLs than vertebrate LTLs. Quantitative real time polymerase chain reaction showed that MrVIP36 is expressed widely in all tested tissues, especially in the hepatopancreas and intestine. MrVIP36 was significantly up-regulated in hemocytes of prawns at different time points after Staphylococcus aureus, Vibrio parahaemolyticus, and White spot syndrome virus (WSSV) infections. The recombinant protein MrLTLD (rMrLTLD) could bind and agglutinate all tested bacteria. Sugar binding assay revealed that rMrLTLD could also bind to the glycoconjugates of the bacterial surface, such as lipopolysaccharide and peptidoglycan. Moreover, rMrLTLD could inhibit the growth activities of microorganisms in vitro and accelerate the bacterial clearance in vivo. rMrLTLD could also inhibit WSSV replication in vivo. Survival rate analysis showed that rMrLTLD could protect prawns against WSSV infection. Taken together, our results suggested that MrVIP36 functioned as a pattern recognition receptor involved in the antibacterial and antiviral immune responses of M. rosenbergii. PMID- 29621636 TI - Correlates of protective immunity for fish vaccines. AB - Vaccination is one of the most effective disease control strategies that has contributed to the significant reduction of disease outbreaks and antibiotics usage in salmonid aquaculture. To date, licensing of fish vaccines is to a limited extent based on in vitro correlates of protection, as done for many mammalian vaccines. This is because the immunological mechanisms of vaccine protection have not been clearly elucidated for most fish vaccines. Herein, we provide an overview of the different steps required to establish correlates of protective immunity required to serve as benchmarks in optimizing vaccine production in aquaculture. We highlight the importance of optimizing challenge models needed to generate consistent results used during vaccine development as a basis for establishing immune correlates of protection. Data generated this far shows that antibodies are potentially the most reliable correlates of protective immunity for fish vaccines. Our findings also show that antigen dose can be optimized to serve as a correlate of protection for fish vaccines. Further, there is need to establish signatures of T-cell protective immunity when antibodies fail to serve as proxies of immune protection, particularly for vaccines against intracellular pathogens. We can anticipate that documentation of efficacy for future vaccines in aquaculture, particularly batch testing will be based on in vitro correlates of protective immunity. PMID- 29621635 TI - Protective effects of chicken egg yolk immunoglobulins (IgY) against experimental Aeromonas hydrophila infection in blunt snout bream (Megalobrama amblycephala). AB - The emergence of multi antibiotic resistance by the pathogens and toxic impacts on host metabolism has opened new perspectives to rational novel vaccine techniques. Outbreaks of Aeromonas hydrophila in aquaculture caused high mortality throughout the world and resulted in the extensive economic loss in the aquaculture industry. In this study, we report the efficacy of anti-A. hydrophila IgY antibodies by passive vaccination and its prophylactic or therapeutic effects against A. hydrophila in blunt snout bream. Inactivated A. hydrophila immunized hens produced effective IgY antibodies that were stable at temperatures less than 60 degrees C or the pH value was >4. The specific IgY can be bound directly to A. hydrophila that efficiently agglutinated and inhibited the bacterial growth in a dose-dependent manner. The specific IgY had significantly enhanced the phagocytosis activity of macrophages and resulted in rapid bacterial clearance. Anti-A. hydrophila IgY antibodies significantly increased macrophage mediated respiratory burst, including nitric oxide and superoxide anion production and subsequently killed the pathogen. Histopathological studies of intestine and spleen from vaccinated blunt-snout bream challenged with A. hydrophila showed the structural integrity of the organs was maintained intact from the bacterial injury. In addition, the prophylactic and therapeutic immunization, protected the blunt snout bream and the survival is approximately about 60% and 50%, respectively. These data suggest that specific IgY has the potential for protecting blunt snout bream against A. hydrophila infection and show promise for the future development of harmless vaccines. PMID- 29621637 TI - Exploiting natural polysaccharides to enhance in vitro bio-constructs of primary neurons and progenitor cells. AB - : Current strategies in Central Nervous System (CNS) repair focus on the engineering of artificial scaffolds for guiding and promoting neuronal tissue regrowth. Ideally, one should combine such synthetic structures with stem cell therapies, encapsulating progenitor cells and instructing their differentiation and growth. We used developments in the design, synthesis, and characterization of polysaccharide-based bioactive polymeric materials for testing the ideal composite supporting neuronal network growth, synapse formation and stem cell differentiation into neurons and motor neurons. Moreover, we investigated the feasibility of combining these approaches with engineered mesenchymal stem cells able to release neurotrophic factors. We show here that composite bio-constructs made of Chitlac, a Chitosan derivative, favor hippocampal neuronal growth, synapse formation and the differentiation of progenitors into the proper neuronal lineage, that can be improved by local and continuous delivery of neurotrophins. STATEMENT OF SIGNIFICANCE: In our work, we characterized polysaccharide-based bioactive platforms as biocompatible materials for nerve tissue engineering. We show that Chitlac-thick substrates are able to promote neuronal growth, differentiation, maturation and formation of active synapses. These observations support this new material as a promising candidate for the development of complex bio-constructs promoting central nervous system regeneration. Our novel findings sustain the exploitation of polysaccharide-based scaffolds able to favour neuronal network reconstruction. Our study shows that Chitlac-thick may be an ideal candidate for the design of biomaterial scaffolds enriched with stem cell therapies as an innovative approach for central nervous system repair. PMID- 29621638 TI - Proving cortical death after vascular coma: Evoked potentials, EEG and neuroimaging. AB - OBJECTIVES: Several studies have shown that bilateral abolition of somatosensory evoked potentials after a nontraumatic coma has 100% specificity for nonawakening with ethical consequences for active care withdrawal. We propose to evaluate the prognostic value of bilateral abolished cortical components of SEPs in severe vascular coma. METHODS: A total of 144 comatose patients after subarachnoid haemorrhage were evaluated by multimodal evoked potentials (EPs); 7 patients presented a bilateral abolition of somatosensory and auditory EPs. Their prognosis value was interpreted with respect to brainstem auditory EPs, EEG, and structural imaging. RESULTS: One patient emerged from vegetative state during follow-up; 6 patients did not return to consciousness. The main neurophysiological difference was a cortical reactivity to pain preserved in the patient who returned to consciousness. This patient had focal sub-cortical lesions, which could explain the abolition of primary cortical components by a bilateral deafferentation of somatosensory and auditory pathways. CONCLUSIONS: This is the first report of a favourable outcome after a multimodal abolition of primary cortex EPs in vascular coma. For the 3 cases of vascular coma with preserved brainstem function, EEG reactivity and cortical EPs were abolished by a diffuse ischaemia close to cerebral anoxia. SIGNIFICANCE: The complementarity of EPs, EEG, and imaging must be emphasised if therapeutic limitations are considered to avoid over-interpretation of the prognosis value of EPs. PMID- 29621640 TI - Synthesis and characterization of new inhibitors of cholinesterases based on N phenylcarbamates: In vitro study of inhibitory effect, type of inhibition, lipophilicity and molecular docking. AB - Based on current treatment of Alzheimer's disease, where the carbamate inhibitor Rivastigmine is used, two series of carbamate derivatives were prepared: (i) N phenylcarbamates with additional carbamate group (1-12) and (ii) N phenylcarbamates with monosaccharide moiety (13-24). All compounds were tested for the inhibitory effect on both of the cholinesterases, electric eel acetylcholinesterase (eeAChE) and butyrylcholinesterase from equine serum (eqBChE) and the inhibitory activity (expressed as IC50 values) was compared with that of the established drugs Galanthamine and Rivastigmine. The compounds with two carbamate groups 1-12 revealed higher inhibitory efficiency on both cholinesterases in compared with monosaccharide derived carbamates 13-24 and with Rivastigmine. The significant decrease of inhibitory efficiency on eqBChE (also for eeAChE but in less manner) was observed after deacetalization of monosaccharide. Moreover, the type of inhibitory mechanism of five chosen compounds was studied. It was found, that compounds with two carbamate groups act presumably via a mixed inhibitory mechanism and the compounds with monosaccharide moiety act as non-competitive inhibitors. The lipophilicity of tested compounds was determined using partition coefficient. Specific positions of the inhibitors in the binding sites of cholinesterases were determined using molecular modeling and the results indicate the importance of phenylcarbamate orientation in the catalytic gorges of both enzymes. PMID- 29621641 TI - Anticancer effects of new dibenzenesulfonamides by inducing apoptosis and autophagy pathways and their carbonic anhydrase inhibitory effects on hCA I, hCA II, hCA IX, hCA XII isoenzymes. AB - In this study, new dibenzensulfonamides, 7-9, having the chemical structure 4,4' (5'-chloro-3'-methyl-5-aryl-3,4-dihydro-1'H,H-[3,4'-bipyrazole]-1',2 diyl)dibenzenesulfonamide were synthesized in five steps to develop new anticancer drug candidates. Their chemical structures were confirmed by 1H NMR, 13C NMR and HRMS spectra. Cytotoxicities of the dibenzensulfonamides were investigated towards HCC1937, MCF7, HeLa, A549 as tumor cell lines and towards MRC5 and Vero as non-tumor cells. Carbonic anhydrase (CAs, EC 4.2.1.1) inhibitory effects of the dibenzensulfonamides 7-9 were also evaluated on the cytosolic human (h) hCA I and II and the tumor-associated hCA IX and XII isoenzymes. Results indicate that both 7 and 8 induced cleavage of poly (ADP ribose) polymerase (PARP), activation of caspases -3, -7 and -9 which are the hallmarks of apoptosis. Meanwhile both compounds induced autophagy in HCC1937 cells which is shown by enhanced expression of LC3 and decreased level of p62 protein. The compounds tested were also effectively inhibited tumor-associated hCA IX and hCA XII isoenzymes in the range of 20.7-28.1 nM and 4.5-9.3 nM, respectively. PMID- 29621639 TI - Distinct and complementary roles of CD4 T cells in protective immunity to influenza virus. AB - CD4 T cells play a multiplicity of roles in protective immunity to influenza. Included in these functions are help for high affinity antibody production, enhancement of CD8 T cell expansion, function and memory, acceleration of the early innate response to infection and direct cytotoxicity. The influenza specific CD4 T cell repertoire in humans established through exposures to infection and vaccination has been found to be highly variable in abundance, specificity and functionality. Deficits in particular subsets of CD4 T cells recruited into the response result in diminished antibody responses and protection from infection. Therefore, improved strategies for vaccination should include better methods to identify deficiencies in the circulating CD4 T cell repertoire, and vaccine constructs that increase the representation of CD4 T cells of the correct specificity and functionality. PMID- 29621642 TI - Adipose-derived stem cells improve full-thickness skin grafts in a rat model. AB - To investigate the effects of heterologous adipose-derived stem cells (ADSCs) on autologous full-thickness skin grafts, we designed a first-intention healing model using Wistar rats. We harvested and sutured two full-thickness skin grafts in the dorsal recipient beds of 15 rats, randomized into three groups. In the treatment group, 1 * 106 ADSCs resuspended in saline solution (200 MUL) were administered subcutaneously to the skin graft. The control group received only saline solution subcutaneously, whereas the negative control group did not receive any treatment. Compressive dressings were maintained until postoperative day 5. The grafts were assessed by two observers, who checked for the presence of epidermolysis on day 14. Planimetry showed the relative areas of normal skin, redness, ulceration, and contraction. Graft samples were obtained on day 14 and stained with hematoxylin and eosin and Masson's trichrome. Epidermal analysis evaluated thickening, keratosis, acanthosis, hydropic degeneration, and inflammatory infiltrate. Dermal evaluation investigated the absence of hair follicles, granulation tissue formation, presence of inflammatory infiltrate, and collagen deposition. Immunohistochemistry was performed for dermal anti-VEGF and epidermal anti-Ki-67 staining. The ADSC group presented better macroscopic aspects, lower incidence of epidermolysis, and less loss of hair follicles. In addition, the ADSC group presented the lowest frequency of histopathological changes in the dermis and epidermis, as well as the largest subcutaneous and granulation tissue VEGF averages and the weakest Ki-67 staining of the epidermal basal layer. Subcutaneous administration of ADSCs may improve the integration of skin grafts, reducing the deleterious effects of ischemia and reperfusion injury. PMID- 29621643 TI - Potential-induced reversible uptake/release of perchlorate from wastewater by polypyrrole@CoNi-layered double hydroxide modified electrode with proton-ligand effect. AB - In this study, CoNi-layered double hydroxide (CoNi-LDH) nanosheets coated conducting polypyrrole (PPy) nanowire was controllably fabricated on Pt plate or carbon cloth by using unipolar pulse electrodeposition (UPED) method and served as a novel electrochemically switched ion exchange (ESIX) hybrid film with proton ligand effect for the removal of perchlorate anions (ClO4-). It is expected that the space among CoNi-LDH nanosheets of the shell could act as the reservoir for the anions while the PPy core serve as the potential-induced element for proton ligand. The effects of pulse potential during film deposition and initial pH of the wastewater on the ClO4- removal performance of this core-shell hybrid film were investigated. It is found that ClO4- adsorption onto PPy@CoNi-LDH followed pseudo-second-order model, and the film fabricated with -1.5 V pulse potential showed an excellent performance for the rapid removal of ClO4- with a high selectivity, and the ClO4- adsorption quantity reached as high as 302 mg g-1. In a wide pH range (3-10), the hybrid film removed ClO4- efficiently. The proton ligand effect in PPy@CoNi-LDH was proved by using XPS analysis and density functional theory. Such a PPy@CoNi-LDH hybrid core-shell film should be a potential electroactive material for the separation of ClO4- and other anions from wastewater. PMID- 29621644 TI - New phenophospholipids equipped with multi-functionalities: Regiospecific synthesis and characterization. AB - HYPOTHESIS: In multi-phase systems, many complex reactions take place at the interface where a molecule equipped with manifold functionalities is demanded. By taking advantage of the surface-active property of phosphatidylcholine (PC) scaffold and antioxidant properties of phenolic acids, new multifunctional molecules are generated, which are expected to confer physical and oxidative stability to sensitive bioactive ingredients in delivery systems. EXPERIMENTS: This work reports a successful synthesis of two new arrays of phenophospholipids sn-1-acyl(C12-C18)-sn-2-caffeoyl and sn-1-caffeoyl-sn-2-acyl phosphatidylcholines via mild scalable regiospecific pathways; as structurally verified by MS, 1H/13C NMR analyses, and characterized by critical micelle concentrations (CMC), FTIR, and DSC analysis. Synthesized phenophospholipids are subjected to stabilizing o/w emulsion, and antioxidation tests as demonstrated by TBARS (Thiobarbituric Acid Reactive Substances) and DPPH (2,2-diphenyl-1-picrylhydrazyl) assays. FINDINGS: This study has demonstrated that; (1) phenophospholipids with a broad spectrum of CMC are created, affording superior emulsion stability than soybean PC; (2) all phenophospholipids present improved oxidation inhibition and sn-2-caffeoyl phenophospholipids display superior performance to sn-1-caffeoyl phenophospholipids, soybean PC or admixture of caffeic acid and soybean PC; (3) incorporation of caffeoyl in PC scaffold does not sacrifice radical scavenging ability of caffeic acid, whilst the ion chelating capacity of sn-1-myristoyl(C14) sn-2-caffeoyl PC enhance by 4.5 times compared to soy PC. Fluorescence Microscopy imaging verified the location of phenophospholipids in the interface as desired. Among synthetic phenophospholipids, sn-1-myristoyl(C14)-sn-2-caffeoyl PC commits the cut-off effect in most desired functionalities, which might be of great potential for multi-purpose applications. PMID- 29621645 TI - Self-assembled and pH-sensitive mixed micelles as an intracellular doxorubicin delivery system. AB - Nanocarrier-based drug delivery systems have been explored extensively in cancer therapy. Among the vast number of different nanocarrier systems applied to deliver chemotherapeutics to cancer tumor, intelligent systems which deliver drug to various sites in the body have attracted considerable attentions. Finding a specific stimulant that triggers the carrier to release its payload in the target tissue is a key parameter for efficacy of delivery systems. Acidic pH of cancer tumor helps a pH-sensitive carrier to release drug at the tumor site. In this study, a pH-sensitive mixed micellar system was developed using Dextran-Stearic Acid (Dex-SA) and Dextran-Histidine (Dex-His) conjugated polymers to deliver doxorubicin (DOX) to cancer cells. Drug release from this micellar system showed higher release rate at acidic pH than that of in neutral environment, where the release was 56 and 76% at pH 7.4 and acidic pH, respectively. Finally, the in vitro cytotoxicity and cell uptake of DOX-loaded micelles and free DOX on U87 MG cell line showed that micellar systems had more anti-proliferation effect and uptake compared to free drug. PMID- 29621646 TI - Electrochemical synthesis of nitrogen-doped carbon quantum dots decorated copper oxide for the sensitive and selective detection of non-steroidal anti inflammatory drug in berries. AB - We report a sensitive non-steroidal anti-inflammatory drug aspirin (ASA) sensor studies using the nitrogen-doped carbon quantum dots (N-CQD) decorated copper oxide (Cu2O). A simplistic approach of electrochemical deposition method has been used to prepare the N-CQD incorporated with copper oxide (N-CQD/Cu2O) and the resulting composite has characterized by analytical techniques. Modified glassy carbon electrode of N-CQD/Cu2O/GCE is developed and is used for the sensor studies of aspirin. The modified N-CQD/Cu2O/GCE has exhibited a higher current (Ipa) response to the oxidation process when compared to N-CQD/GCE, Cu2O/GCE and bare GCE. Furthermore, it has shown a good linear range of 1-907 uM with a limit of detection (LOD) ~0.002 uM and sensitivity ~21.87 uA uM-1 cm-2. The developed sensor has displayed outstanding repeatability, stability and accumulation time along with better electro-catalytic response in berries for real-life application. PMID- 29621647 TI - Molecular mechanisms underlying intraspecific variation in snake venom. AB - : Elucidating the molecular mechanisms underlying snake venom variability provides important clues for understanding how the biological functions of this powerful toxic arsenal evolve. We analyzed in detail individual transcripts and venom protein isoforms produced by five specimens of a venomous snake (Bothrops atrox) from two nearby but genetically distinct populations from the Brazilian Amazon rainforest which show functional similarities in venom properties. Individual variation was observed among the venoms of these specimens, but the overall abundance of each general toxin family was conserved both in transcript and in venom protein levels. However, when expression of independent paralogues was analyzed, remarkable differences were observed within and among each toxin group, both between individuals and between populations. Transcripts for functionally essential venom proteins ("core function" proteins) were highly expressed in all specimens and showed similar transcription/translation rates. In contrast, other paralogues ("adaptive" proteins) showed lower expression levels and the toxins they coded for varied among different individuals. These results provide support for the inferences that (a) expression and translational differences play a greater role in defining adaptive variation in venom phenotypes than does sequence variation in protein coding genes and (b) convergent adaptive venom phenotypes can be generated through different molecular mechanisms. SIGNIFICANCE: Analysis of individual transcripts and venom protein isoforms produced by specimens of a venomous snake (Bothrops atrox), from the Brazilian Amazon rainforest, revealed that transcriptional and translational mechanisms contribute to venom phenotypic variation. Our finding of evidence for high expression of toxin proteins with conserved function supports the hypothesis that the venom phenotype consists of two kinds of proteins: conserved "core function" proteins that provide essential functional activities with broader relevance and less conserved "adaptive" proteins that vary in expression and may permit customization of protein function. These observations allowed us to suggest that genetic mechanisms controlling venom variability are not restricted to selection of gene copies or mutations in structural genes but also to selection of the mechanisms controlling gene expression, contributing to the plasticity of this important phenotype for venomous snakes. PMID- 29621648 TI - Integrating phosphoproteomics into kinase-targeted cancer therapies in precision medicine. AB - : Protein phosphorylation is a post-translational modification that is involved in the regulation of all major biological processes in cells. As a rapid and reversible means to modulate protein activity and transduce signals, aberrant protein phosphorylation is implicated in the onset and progression of most cancer types. Therefore, pharmacological inhibitors against protein kinases are highly pursued therapeutic approaches for treating cancer. Phosphoproteomics has become an important approach for investigating protein phosphorylation, and it is a technique that provides measurements of kinase pathway activation and the circuitry of signalling networks with both spatial and temporal resolution. Combined with the recent advances in mass spectrometry and development in biochemical procedures for phosphopeptide enrichment and computational approaches, high-throughput phosphoproteomics enables the investigation of kinase signalling networks with unprecedented depth. Here, we review the recent progresses in phosphoproteomics methodology and how phosphoproteomics profiling could be implemented in translational research to aid cancer therapies, facilitate novel drug target discovery and overcome the therapeutic obstacles caused by drug resistance. SIGNIFICANCE: In this review, we summarized the recent progress in mass spectrometry-based phosphoproteomics and discussed how phosphoproteomics profiling can be implemented in translational research to aid cancer therapies, facilitate novel drug target discovery and overcome the therapeutic obstacles caused by drug resistance due to the rapid remodelling of signalling networks in response to kinase inhibitor treatment. In addition, we addressed the insights and challenges of applying MS phosphoproteomics in clinical routine practice in precision medicine. This review will help readers become more familiar with the recent advancements and applications of phosphoproteomics, especially in the field of kinase-targeted cancer therapy. PMID- 29621649 TI - The STAT3 Target Gene TNFRSF1A Modulates the NF-kappaB Pathway in Breast Cancer Cells. AB - The transcription factor STAT3 is activated inappropriately in 70% of breast cancers, most commonly in triple negative breast cancer (TNBC). Although the transcriptional function of STAT3 is essential for tumorigenesis, the key target genes regulated by STAT3 in driving tumor pathogenesis have remained unclear. To identify critical STAT3 target genes, we treated TNBC cell lines with two different compounds that block STAT3 transcriptional function, pyrimethamine and PMPTP. We then performed gene expression analysis to identify genes whose expression is strongly down-regulated by both STAT3 inhibitors. Foremost among the down-regulated genes was TNFRSF1A, which encodes a transmembrane receptor for TNFalpha. We showed that STAT3 binds directly to a regulatory region within the TNFRSF1A gene, and that TNFRSF1A levels are dependent on STAT3 function in both constitutive and cytokine-induced models of STAT3 activation. Furthermore, TNFRSF1A is a major mediator of both basal and TNFalpha-induced NF-kappaB activity in breast cancer cells. We extended these findings to primary human breast cancers, in which we found that high TNFRSF1A transcript levels correlated with STAT3 activation. In addition, and consistent with a causal role, increased TNFRSF1A expression was associated with an NF-kappaB gene expression in signature in breast cancers. Thus, TNFRSF1A is a STAT3 target gene that regulates the NF kappaB pathway. These findings reveal a novel functional crosstalk between STAT3 and NF-kappaB signaling in breast cancer. Furthermore, elevated TNFRSF1A levels may predict a subset of breast tumors that are sensitive to STAT3 transcriptional inhibitors, and may be a biomarker for response to inhibition of this pathway. PMID- 29621650 TI - What matters more? Common or specific factors in cognitive behavioral therapy for OCD: Therapeutic alliance and expectations as predictors of treatment outcome. AB - CBT for obsessive-compulsive disorder (OCD) is a strong challenge to the contention that common factors explain most of the variance in outcomes in all therapies and all disorders, given that the treatment is focused and placebo response is low. In this study, the relative contributions of expectancy and therapeutic alliance as predictors of outcome in the treatment of OCD are examined and compared to the contribution of specific treatment effects. One hundred and eight patients with OCD were randomly assigned to two forms of CBT: exposure and response prevention (EX/RP) or stress management training (SMT). Measures of OCD symptoms, quality of life, therapist and patient expectancy and alliance were collected at several timepoints. Treatment type was a substantially stronger predictor of symptom reduction compared to alliance and expectancy. However, neither specific nor common factors predicted improvement in quality of life very well. Only in EX/RP, symptom change was associated with subsequent changes in alliance. Finally, therapist effects were estimated using Bayesian methods and were negligible. In the context of CBT for OCD, the data support the specific factor model, and suggest that the relative contribution of common vs. specific factors likely varies by disorder and by treatment type. PMID- 29621651 TI - Effects of warming and nutrients on the microbial food web in shallow lake mesocosms. AB - We analysed changes in the abundance, biomass and cell size of the microbial food web community (bacteria, heterotrophic nanoflagellates, ciliates) at contrasting nutrient concentrations and temperatures during a simulated heat wave. We used 24 mesocosms mimicking shallow lakes in which two nutrient levels (unenriched and enriched by adding nitrogen and phosphorus) and three different temperature scenarios (ambient, IPCC A2 scenario and A2+%50) are simulated (4 replicates of each). Experiments using the mesocosms have been running un-interrupted since 2003. A 1-month heat wave was imitated by an extra 5 degrees C increase in the previously heated mesocosms (from 1st July to 1st August 2014). Changes in water temperature induced within a few days a strong effect on the microbial food web functioning, demonstrating a quick response of microbial communities to the changes in environment, due to their short generation times. Warming and nutrients showed synergistic effects. Microbial assemblages of heterotrophic nanoflagellates and ciliates responded positively to the heating, the increase being largest in the enriched mesocosms. The results indicate that warming and nutrients in combination can set off complex interactions in the microbial food web functioning. PMID- 29621652 TI - Response of testate amoebae to a late Holocene ecosystem shift in an Amazonian peatland. AB - To date there have only been two studies using testate amoebae as palaeoecological indicators in tropical peatlands. Here we present a new ~500 year testate amoeba record from San Jorge, a domed peatland in Peruvian Amazonia, which has a well-constrained vegetation history based on pollen analysis. We observe a major shift from Hyalosphenia subflava to Cryptodifflugia oviformis dominated communities at ~50 cm depth (c. AD 1760), which suggests a change to drier conditions in the peatland. The application of a statistical transfer function also suggests a deepening of the water table at this time. The transition in the microbial assemblage occurs at a time when pollen and geochemical data indicate drier conditions (reduced influence of river flooding), leading to an ecosystem switch to more ombrotrophic-like conditions in the peatland. Our work illustrates the potential of testate amoebae as important tools in tropical peatland palaeoecology, and the power of multiproxy approaches for understanding the long-term development of tropical peatlands. PMID- 29621653 TI - New contribution to the species-rich genus Euplotes: Morphology, ontogeny and systematic position of two species (Ciliophora; Euplotia). AB - The morphology, ontogeny and phylogeny of two Euplotes species, E. estuarinus sp. nov. and a population of E. platystoma Dragesco and Dragesco-Kerneis, 1986, both collected from tropical brackish waters in south China, were investigated based on living morphology, ciliary pattern and molecular data. Euplotes estuarinus sp. nov. is small (about 60 * 40 MUm in vivo), has a dargyrome of the double eurystomus type, and the transverse cirri are arranged in two groups, with two left and three right ones. The original description of the poorly known species, E. platystoma, is brief, and the species was never investigated using live observation and molecular methods Hence, we provided a detailed redescription. Some stages of their morphogenesis were observed which proceed in the same pattern as in their congeners. The new species E. estuarinus sp. nov. clusters with E. curdsi, differing only by 1 bp in their SSU rRNA gene sequences, which is likely due to the recent speciation event and the limited resolution of the SSU rRNA gene at species level in this group as the two species are clearly morphologically distinct. PMID- 29621654 TI - Posttranslational mechanisms controlling centromere function and assembly. AB - Accurate chromosome segregation is critical to ensure the faithful inheritance of the genome during cell division. Human chromosomes distinguish the location of the centromere from general chromatin by the selective assembly of CENP-A containing nucleosomes at the active centromere. The location of centromeres in most higher eukaryotes is determined epigenetically, independent of DNA sequence. CENP-A containing centromeric chromatin provides the foundation for assembly of the kinetochore that mediates chromosome attachment to the microtubule spindle and controls cell cycle progression in mitosis. Here we review recent work demonstrating the role of posttranslational modifications on centromere function and CENP-A inheritance via the direct modification of the CENP-A nucleosome and pre-nucleosomal complexes, the modification of the CENP-A deposition machinery and the modification of histones within existing centromeres. PMID- 29621655 TI - Methodological aspects of biologically active compounds quantification in the genus Hypericum. AB - Accumulation of selected secondary metabolites in two Hypericum species (H. perforatum and H. annulatum) was compared in their vegetative parts (stems and leaves) and in terms of the extraction solvent (80% aq. methanol or 60% aq. ethanol). The presence of chlorogenic acid and quercitrin was not detected in stem of both species. Almost all metabolites were more accumulated in the leaves than in the stems (rutin, hyperoside, quercetin and hypericin) but epicatechin showed the opposite in both species and hyperforin in H. annulatum. Extraction solvents showed rather species-specific differences with EtOH being more suitable for the extraction of hypericin, quercetin, quercitrin, and hyperoside (on average, for both the leaves and stems, extraction increased by approximately 130, 30, 25, and 15%, respectively) while MeOH for the extraction of epicatechin, rutin, and hyperforin (increased extraction by approximately 50, 40, and 35%, respectively). On the other hand, content of total soluble phenols did not differ in relation to solvent in any organ or species. Various ages of H. annulatum plants did not show dramatic impact on the amount of metabolites. Subsequently, the usefulness of capillary electrophoresis (CE) as an alternative to HPLC for the quantification of metabolites in H. perforatum was tested and results showed non-significant differences between CE and HPLC with the methods we developed (the difference did not exceed 10%). PMID- 29621656 TI - Surgical and oncological long term outcomes of gastrointestinal stromal tumors (GIST) resection- retrospective cohort study. AB - PURPOSE: Surgery remains the mainstay of gastrointestinal stromal tumors (GISTs) treatment. The aim of our study was to compare postoperative outcomes and long term oncologic results of GISTs resection. An analysis of laparoscopic versus open surgery for GISTs and a subgroup analysis of lesions larger than 5 cm were realized. MATERIALS AND METHODS: Between January 2005 and December 2014, 143 patients with primary GISTs were treated with radical resection in two tertiary centers. Eight patients with metastatic disease were excluded. The remaining patients were assigned to 2 groups: laparoscopy and open surgery. A separate analysis of tumors larger than 5 cm was realized for the laparoscopy group. Long term follow-up was used to analyze the oncologic and surgical results. Relevant clinical variables were evaluated using univariate and multivariate analyses. RESULTS: With similar oncological outcomes(p = 0.09) and morbidity(p = 0.56), laparoscopy compared to open surgery significantly reduced length of hospitalization (p = 0.01). For lesions >5 cm laparoscopic resection is associated with similar short-term outcomes with resection for small tumors without compromising oncological outcomes (p = 0.89). For all patients, the probability of remaining disease free at 3 years, and 5 years was 97, 6% and 95%, respectively. CONCLUSION: Laparoscopic resection is a technically and oncologically safe and feasible approach for GISTs compared with open resection. Resection of lesions superior of 5 cm by laparoscopy has efficacy and recurrence rates similar to open surgical controls. Large tumor resection should only be attempted by surgeons with a large experience with minimally invasive surgery in order to avoid operative complications and unfavorable long term outcome. PMID- 29621657 TI - The 100 most-cited papers in general thoracic surgery: A bibliography analysis. AB - BACKGROUND: The status of citations can reflect the impact of a paper and its contribution to surgical practice. The aim of our study was to identify and review the 100 most-cited papers in general thoracic surgery. MATERIALS AND METHODS: Relevant papers on general thoracic surgery were searched through Thomson Reuters Web of Science in the last week of November 2017. Results were returned in descending order of total citations. Their titles and abstracts were reviewed to identify whether they met our inclusion criteria by two thoracic surgeons independently. Characteristics of the first 100 papers, including title, journal name, country, first author, year of publication, total citations, citations in latest 5 years and average citation per year (ACY) were extracted and analyzed. RESULTS: Of the 100 papers, the mean number of citations was 322 with a range from 184 to 921. 19 journals published the papers from 1956 to 2012. Annals of Surgery had the largest number (29), followed by Journal of Thoracic and Cardiovascular Surgery (22) and Annals of Thoracic Surgery (21). The majority of the papers were published in 2000s (48) and originated from United States of America (62). There were 65 retrospective studies, 13 RCTs and 11 prospective studies. Orringer MB and Grillo HC contributed 4 first-author articles respectively. There were 53 papers on esophagus, 36 on lung, 6 on pleura and 5 on trachea. CONCLUSIONS: Our study identified the most-cited papers in the past several decades and offered insights into the development and advances of general thoracic surgery. It can help us understand the evidential basis of clinical decision-making today in the area. PMID- 29621658 TI - The incidence of occult malignancy following uterine morcellation: A ten-year single institution experience retrospective cohort study. AB - INTRODUCTION: When the Food and Drug Administration (FDA) initially reported on the parlous incidence (0.28%) of occult malignancy identified following uterine power morcellation, investigations thereafter documented their particular experience with this surgical procedure. Nevertheless, the precise risk of identifying a sarcoma following uterine morcellation remains indeterminate, primarily due to varying study patient risk factors, diagnostic criteria and operative approach. METHOD: We retrospectively evaluated subjects who underwent an endoscopic hysterectomy and uterine power morcellation for the treatment of a presumptive, benign indication from January 2006 until December 2015. The primary outcome was the incidence of an occult malignancy. Secondarily, we were interested in characterizing the patients' specific clinical (age, menopausal status, body mass index (BMI)) risk factors within the context of a confirmed malignant or pre-malignant pathology. RESULTS: We identified 281 patients who underwent endoscopic surgery that incorporated uterine morcellation. During the study period, one subject was ultimately diagnosed with a uterine leiomyosarcoma; the overall incidence of occult malignancy was 0.36%. There were also 3 cases of uterine premalignant disease on final pathology (2 patients had complex hyperplasia with or without atypia and 1 subject was diagnosed with a smooth muscle tumor of uncertain malignant potential (an incidence of 1.1%)). We were unable to establish any relationship between patient age, uterine weight, menopausal status or BMI and the incidence of a malignant or pre-malignant pathology (P > 0.05). CONCLUSION: The rate of occult malignancy in the present investigation was similar to previously documented studies and that which has been reported by the FDA. Additional study of methods in which to enhance preoperative work-up and mitigate the surgical risk for tumor cell dissemination is warranted. PMID- 29621659 TI - Suicide deaths by intentional self-poisoning in people with cardiovascular disease. AB - OBJECTIVE: We aimed to characterize self-poisoning deaths in people with cardiovascular disease (CVD) and compare to other suicide decedent groups. METHODS: Suicide deaths by self-poisoning in people with CVD (n = 151) were compared to suicide deaths by other methods in people with CVD (n = 260) and suicide deaths by self-poisoning in people without CVD (n = 509). Sub-analysis of the CVD self-poisoning group compared people with depression and without depression. Toxicology reports were compared between intentional self-poisoning groups. RESULTS: A higher proportion of suicide deaths were due to self-poisoning in the CVD group compared to the non-CVD group. People with CVD were less likely to have any identified stressor (excluding medical stressor) prior to dying from self-poisoning compared to those without CVD. Female sex, past suicide attempts, living circumstances, and comorbid substance abuse were each significantly associated with self-poisoning as the method of suicide in people with CVD. Opioid, any antidepressants, benzodiazepines, and tricyclic antidepressants (TCAs) were commonly identified as lethal in people with CVD. Compared to people in the CVD self-poisoning without depression group, people in the CVD self poisoning with depression group were more likely to have lethal levels of TCAs. CONCLUSIONS: Our findings characterize suicide deaths in people with CVD, and identified notable differences based on method of death and presence of depression. PMID- 29621660 TI - The effects of plantar perception training on balance and falls efficacy of the elderly with a history of falls: A single-blind, randomized controlled trial. AB - PURPOSE: The purpose of this study was to identify the effects of plantar perception training using a hardness discrimination task on balance and falls efficacy of the elderly who have experienced a fall. MATERIALS AND METHODS: Sixty two elderly persons 65 years of age or older were randomly allocated to the experimental group (n = 31) or the control group (n = 31). The experimental group performed a hardness discrimination task using five different levels of hardness of sponge mats, while the control group performed the same task except that they were not asked to discriminate hardness levels of sponge mats. All subjects performed 10 sessions for two weeks. Outcome measures were conducted using center of pressure (CoP) sway in the standing position, the Timed Up and Go (TUG) test, and falls efficacy scale (FES) to measure balance and falls efficacy. RESULTS: There were no significant differences in general characteristics between both groups (p > .05). After 10 sessions, plantar perception was significantly improved in the experimental group (F = 101.18, p < .001). Additionally, changes in CoP sway with eye closed and TUG test were significantly different (p < .05) between the experimental group (CoP sway with eye closed, -208.32 +/- 74.89; TUG test, -1.91 +/- 0.72) and the control group (CoP sway with eye closed, -14.55 +/- 35.44; TUG test, -1.31 +/- 0.75). CONCLUSIONS: These results showed that plantar perception training might be beneficial to improve falls efficacy as well as balance of the elderly. PMID- 29621661 TI - Gene therapy for repair and regeneration of bone and cartilage. AB - Gene therapy refers to the use of viral and non-viral vectors to deliver nucleic acids to tissues of interest using direct (in vivo) or transduced cell-mediated (ex vivo) approaches. Over the past few decades, strategies have been adopted to express therapeutic transgenes at sites of injury to promote or facilitate repair of bone and cartilage. Targets of interest have typically included secreted proteins such as growth factors and anti-inflammatory mediators; however, work has also begun to focus intracellularly on signaling components, transcription factors and small, regulatory nucleic acids such as microRNAs (miRNAs). In recent years, a number of single therapeutic gene approaches (termed 'monotherapies') have proven effective in preclinical models of disease, and several are being evaluated in clinical trials. In particular, an ex vivo TGF-beta1 gene therapy was approved in Korea in 2017 for treatment of moderate-to-severe osteoarthritis (OA). The ability to utilize viral vectors for context-specific and combinatorial gene therapy is also being investigated, and these strategies are likely to be important in more robustly addressing the complexities of tissue repair and regeneration in skeletal disease. In this review, we provide an overview of viral gene therapies being developed for treatment of bone and cartilage pathologies, with an emphasis on emerging combinatorial strategies as well as those targeting intracellular mediators such as miRNAs. PMID- 29621662 TI - Plasma membrane depolarization and permeabilization due to electric pulses in cell lines of different excitability. AB - In electroporation-based medical treatments, excitable tissues are treated, either intentionally (irreversible electroporation of brain cancer, gene electrotransfer or ablation of the heart muscle, gene electrotransfer of skeletal muscles), or unintentionally (excitable tissues near the target area). We investigated how excitable and non-excitable cells respond to electric pulses, and if electroporation could be an effective treatment of the tumours of the central nervous system. For three non-excitable and one excitable cell line, we determined a strength-duration curve for a single pulse of 10ns-10ms. The threshold for depolarization decreased with longer pulses and was higher for excitable cells. We modelled the response with the Lapicque curve and the Hodgkin Huxley model. At 1MUs a plateau of excitability was reached which could explain why high-frequency irreversible electroporation (H-FIRE) electroporates but does not excite cells. We exposed cells to standard electrochemotherapy parameters (8*100MUs pulses, 1Hz, different voltages). Cells behaved similarly which indicates that electroporation most probably occurs at the level of lipid bilayer, independently of the voltage-gated channels. These results could be used for optimization of electric pulses to achieve maximal permeabilization and minimal excitation/pain sensation. In the future, it should be established whether the in vitro depolarization correlates to nerve/muscle stimulation and pain sensation in vivo. PMID- 29621663 TI - Up-Regulation of PI 3-Kinases and the Activation of PI3K-Akt Signaling Pathway in Cancer Stem-Like Cells Through DNA Hypomethylation Mediated by the Cancer Microenvironment. AB - Previously, we have succeeded in converting induced pluripotent stem cells (iPSCs) into cancer stem cells (CSCs) by treating the iPSCs with conditioned medium of Lewis lung carcinoma (LLC) cells. The converted CSCs, named miPS-LLCcm cells, exhibited the self-renewal, differentiation potential, and potential to form malignant tumors with metastasis. In this study, we further characterized miPS-LLCcm cells both in vivo and in vitro. The tumors formed by subcutaneous injection showed the structures with pathophysiological features consisting of undifferentiated and malignant phenotypes generally found in adenocarcinoma. Metastasis in the lung was also observed as nodule structures. Excising from the tumors, primary cultured cells from the tumor and the nodule showed self-renewal, differentiation potential as well as tumor forming ability, which are the essential characters of CSCs. We then characterized the epigenetic regulation occurring in the CSCs. By comparing the DNA methylation level of CG rich regions, the differentially methylated regions (DMRs) were evaluated in all stages of CSCs when compared with the parental iPSCs. In DMRs, hypomethylation was found superior to hypermethylation in the miPS-LLCcm cells and its derivatives. The hypo- and hypermethylated genes were used to nominate KEGG pathways related with CSC. As a result, several categories were defined in the KEGG pathways from which most related with cancers, significant and high expression of components was PI3K AKT signaling pathway. Simultaneously, the AKT activation was also confirmed in the CSCs. The PI3K-Akt signaling pathway should be an important pathway for the CSCs established by the treatment with conditioned medium of LLC cells. PMID- 29621664 TI - Chemotherapy and Radiofrequency-Induced Mild Hyperthermia Combined Treatment of Orthotopic Pancreatic Ductal Adenocarcinoma Xenografts. AB - Patients with pancreatic ductal adenocarcinomas (PDAC) have one of the poorest survival rates of all cancers. The main reason for this is related to the unique tumor stroma and poor vascularization of PDAC. As a consequence, chemotherapeutic drugs, such as nab-paclitaxel and gemcitabine, cannot efficiently penetrate into the tumor tissue. Non-invasive radiofrequency (RF) mild hyperthermia treatment was proposed as a synergistic therapy to enhance drug uptake into the tumor by increasing tumor vascular inflow and perfusion, thus, increasing the effect of chemotherapy. RF-induced hyperthermia is a safer and non-invasive technique of tumor heating compared to conventional contact heating procedures. In this study, we investigated the short- and long-term effects (~20 days and 65 days, respectively) of combination chemotherapy and RF hyperthermia in an orthotopic PDAC model in mice. The benefit of nab-paclitaxel and gemcitabine treatment was confirmed in mice; however, the effect of treatment was statistically insignificant in comparison to saline treated mice during long-term observation. The benefit of RF was minimal in the short-term and completely insignificant during long-term observation. PMID- 29621665 TI - Effect of sex and RYR1 gene mutation on the muscle proteomic profile and main physiological biomarkers in pigs at slaughter. AB - Gender and RYR1 gene mutation might have an effect on the muscle metabolic characteristics and on the animal's stress at slaughter, which could influence the process of muscle-to-meat conversion. Forty-eight pigs were distributed in a design including two factors: sex (male/female) and RYR1 genotype (NN/Nn). At slaughter, physiological blood biomarkers and muscle proteome were analyzed and carcass and meat quality traits were registered. Females had higher serum levels of glucose, urea, C-reactive protein "CRP", Pig-MAP and glutation-peroxidase "GPx" and lower levels of lactate, showed faster muscle pH decline and higher meat exudation. RYR1 mutation increased serum creatinine, creatine kinase and CRP and decreased GPx. The proteomic study highlighted significant effects of gender and RYR1 genotype on proteins related to fibre composition, antioxidant defense and post mortem glycolytic pathway, which correlate to differences of meat quality. This study provides interesting information on muscle biomarkers of the ultimate meat quality that are modulated by the animal's individual susceptibility to stress at slaughter. PMID- 29621666 TI - Super-resolution microscopy to decipher multi-molecular assemblies. AB - Super-resolution fluorescence microscopy (SRM) is increasingly being applied as a complementary method to resolve the organization of large biomolecular assemblies. One of its main advantages is that it provides information on protein organization and identity simultaneously, within the native cellular milieu. It also extends the accessible range of structures up to the micrometer scale, offering complementary information relative to classical structural biology methods. Furthermore, SRM is capable of resolving the organization of some biomolecular assemblies not accessible to other methods. We highlight these advantages within the context of deciphering the structure of the centrosome and chromatin, and discuss how computational data post-processing has been adapted for SRM data. We also outline current limitations and potential approaches to overcome them. PMID- 29621667 TI - A comprehensive analysis of human dental pulp cell spheroids in a three dimensional pellet culture system. AB - OBJECTIVE: Three-dimensional (3D) cell culture methods are of high importance to studies of biological processes. This is particularly the case with spheroid cultures, which create 3D cell aggregates without the use of exogenous materials. Compared to conventional monolayer cultures, cellular spheroid cultures have been demonstrated to improve multilineage potential and extracellular matrix production. To address this issue in depth, we present a more comprehensive analysis of 3D human dental pulp cell (hDPC) spheroids. DESIGN: hDPC spheroids were fabricated by the pellet culture method and were cultured without adding any reagent to induce differentiation. The gene-expression profiles of the 3D and two dimensional (2D) cultured hDPCs were compared by complementary DNA microarray analysis. Odontoblastic and osteoblastic differentiation marker gene expression was evaluated by quantitative real-time PCR (RT-qPCR). Hematoxylin-eosin (HE) staining and transmission electron microscopy (TEM) were applied to examine the morphology of hDPC spheroids and extracellular matrix components. RESULTS: Compared with 2D monolayer culture, microarray analysis identified 405 genes and 279 genes with twofold or greater differential expression after 3 days and 28 days of 3D culture, respectively. In 3D hDPC spheroids, gene ontology analysis revealed upregulation of extracellular matrix-related genes and downregulation of cell growth-related genes. RT-qPCR analysis showed higher expression levels of osteocalcin, dentin sialophosphoprotein, and alkaline phosphatase. TEM revealed the morphological characteristics of the fibrillar collagen-rich matrix and cell cell interactions. CONCLUSIONS: The present findings provide clues to understanding the mechanisms of pellet-cultured hDPCs and contribute to future research in the comparative studies of different 3D culture methods. PMID- 29621668 TI - Exendin-4 relieves the inhibitory effects of high glucose on the proliferation and osteoblastic differentiation of periodontal ligament stem cells. AB - BACKGROUND: With the impaired regenerative potential in patients with diabetes mellitus (DM), Periodontal ligament stem cells (PDLSCs) are regarded as an attractive source of stem cells for periodontal cytotherapy. Recent studies have shown that Exendin-4 (Ex-4) exerts cell-protective effects and bone remodeling ability on many types of cells. The aim of this study was to investigate whether Ex-4 alleviates the inhibition of high glucose on the proliferation and osteogenic differentiation of PDLSCs. METHODS: PDLSCs were incubated in medium supplemented with 5.5 mM d-glucose (NG), 30 mM d-glucose (HG), NG plus Ex-4, and HG plus different concentration (1, 10, 20, 100 nM) of Ex-4 respectively. Cell proliferation was detected by CCK-8 assay and cell cycle analysis. Osteogenesis was assessed by Alizarin Red S staining and evaluation of the mRNA expression of Runx2, ALP and Osx at day 7, 14 and 21. Intracellular level of reactive oxygen species (ROS) was detected using 5-(and-6)-chloromethyl-2',7'-dichlorodihydro fluorescein diacetate (CMH2DCF-DA). RESULTS: The proliferation ability, mineralized nodules forming capacity and the mRNA expression of Runx2, ALP and Osx of PDLSCs in HG group were decreased, the ROS level was increased compared to NG group. With the treatment of Ex-4, the HG-inhibited proliferation ability and osteogenic differentiation ability of PDLSCs were significantly reversed, the HG increased ROS level could be down-regulated. Moreover, Ex-4 enhanced the osteogenic differentiation of normal PDLSCs. CONCLUSIONS: Ex-4 alleviates the inhibitory effect of HG on the proliferation and osteoblastic differentiation of PDLSCs, and has a significant enhance in the osteoblastic differentiation of normal PDLSCs, giving new insights into the possible therapeutic method of diabetic periodontitis. PMID- 29621669 TI - Omega-3 fatty acids in obesity and metabolic syndrome: a mechanistic update. AB - Strategies to reduce obesity have become public health priorities as the prevalence of obesity has risen in the United States and around the world. While the anti-inflammatory and hypotriglyceridemic properties of long-chain omega-3 polyunsaturated fatty acids (n-3 PUFAs) are well known, their antiobesity effects and efficacy against metabolic syndrome, especially in humans, are still under debate. In animal models, evidence consistently suggests a role for n-3 PUFAs in reducing fat mass, particularly in the retroperitoneal and epididymal regions. In humans, however, published research suggests that though n-3 PUFAs may not aid weight loss, they may attenuate further weight gain and could be useful in the diet or as a supplement to help maintain weight loss. Proposed mechanisms by which n-3 PUFAs may work to improve body composition and counteract obesity related metabolic changes include modulating lipid metabolism; regulating adipokines, such as adiponectin and leptin; alleviating adipose tissue inflammation; promoting adipogenesis and altering epigenetic mechanisms. PMID- 29621670 TI - Characterization and comparison of transcriptional activities of the retinoid X receptors by various organotin compounds in three prosobranch gastropods; Thais clavigera, Nucella lapillus and Babylonia japonica. AB - Two cDNAs of RXR were isolated, for the first time, from the ivory shell, Babylonia japonica, and the transcriptional activities were tested in vitro to compare with other gastropod (Thais clavigera and Nucella lapillus) RXR isoforms. The transcriptional activities of all of these RXR isoforms were significantly induced by mammalian RXR agonist, 9-cis retinoic acid (9cRA). The transcriptional activity of T. clavigera RXR-1 was also examined by using 9cRA and 16 organotin compounds, and significant ligand-dependent transactivations were observed by 9cRA and 5 organotins (tributyltin (TBT), tetrabutyltin (TeBT), tripropyltin (TPrT), tricyclohexyltin (TcHT) and triphenyltin (TPhT)). These 5 organotins also induced significant transcriptional activities in N. lapillus and B. japonica RXR isoforms. These 4 organotins, except for TeBT, have been reported to promote the development of imposex after a month of a single injection each, using female T. clavigera. To investigate the function of gastropod RXR isoforms, the effects of mammalian specific pan-agonist, PA024, and pan-antagonist, HX531, were examined, and significant induction of transcriptional activity by PA024 was demonstrated in these gastropod RXR isoforms. The additions of HX531 significantly suppressed the transcriptional activities of these gastropod RXR isoforms by 9cRA and 5 organotins. Using the mammalian two retinoic acid response elements, the transcriptional activities by 2 agonists, 9cRA and PA024, were different among the RXR isoforms of each gastropod species. With retinoid X response element (RXRE), transcriptional activities of TcRXR-1, BjRXR-1, and NlRXRa were significantly higher than those of TcRXR-2, BjRXR-2, and NlRXRb. Transcriptional activities of TcRXR-2, BjRXR-2, and NlRXRb, however, were significantly higher than those of TcRXR-1, BjRXR-1, and NlRXRa with thyroid hormone response element, TREpal. Thus, induction of imposex in prosobranch gastropods is strongly suggested to be triggered by 9cRA and certain organotins, such as TBT and TPhT through the activation of RXRs. These gastropod RXRs might control the different gene transcription by forming homo- or heterodimer complex with their own isoforms. These findings will contribute to our understanding of the fundamentals of the endocrine system in molluscs, particularly on RXR signaling pathway. PMID- 29621671 TI - Microcystin-leucine arginine mediates apoptosis and engulfment of Leydig cell by testicular macrophages resulting in reduced serum testosterone levels. AB - Microcystin-leucine arginine (MC-LR) causes decline of serum testosterone levels resulting in impaired spermatogenesis; however, the underlying molecular mechanisms are not fully understood. In this study, we aimed to investigate the effects of MC-LR exposure on the number of Leydig cells (LCs) in testis. Following chronic low dose exposure to MC-LR, the number of LCs was markedly decreased while macrophages were significantly increased. Then, we established a co-culture system to study the interaction between macrophages and LCs in the presence of MC-LR. No significant apoptosis of LCs cultured alone was observed after MC-LR (< 5 000 nM) treatment; however, apoptosis was robustly increased when LCs were co-cultured with macrophages in the presence of MC-LR. Further studies identified that MC-LR could stimulate macrophage to produce TNF-alpha, and secreted TNF-alpha induced LC apoptosis by binding to the tumor necrosis factor receptor 1 (TNFR1) on the LCs and thus activating reactive oxygen species (ROS)-p38MAPK signaling pathway. Furthermore, we also examined increased expression of Axl receptor and growth arrest-specific 6 (Gas6) in macrophages after MC-LR treatment. GAS6 mediates phagocytosis of apoptotic LCs by binding to the Axl receptor on macrophages and phosphatidylserine (PtdSer) on apoptotic LCs. Together, these results suggested that reduced serum testosterone levels may be associated with decrease of LCs as a result of LC apoptosis and phagocytosis by immune cells in MC-LR-treated mice. PMID- 29621672 TI - Oyster transcriptome response to Alexandrium exposure is related to saxitoxin load and characterized by disrupted digestion, energy balance, and calcium and sodium signaling. AB - Harmful Algal Blooms are worldwide occurrences that can cause poisoning in human seafood consumers as well as mortality and sublethal effets in wildlife, propagating economic losses. One of the most widespread toxigenic microalgal taxa is the dinoflagellate Genus Alexandrium, that includes species producing neurotoxins referred to as PST (Paralytic Shellfish Toxins). Blooms cause shellfish harvest restrictions to protect human consumers from accumulated toxins. Large inter-individual variability in toxin load within an exposed bivalve population complicates monitoring of shellfish toxicity for ecology and human health regulation. To decipher the physiological pathways involved in the bivalve response to PST, we explored the whole transcriptome of the digestive gland of the Pacific oyster Crassostrea gigas fed experimentally with a toxic Alexandrium minutum culture. The largest differences in transcript abundance were between oysters with contrasting toxin loads (1098 transcripts), rather than between exposed and non-exposed oysters (16 transcripts), emphasizing the importance of toxin load in oyster response to toxic dinoflagellates. Additionally, penalized regressions, innovative in this field, modeled accurately toxin load based upon only 70 transcripts. Transcriptomic differences between oysters with contrasting PST burdens revealed a limited suite of metabolic pathways affected, including ion channels, neuromuscular communication, and digestion, all of which are interconnected and linked to sodium and calcium exchanges. Carbohydrate metabolism, unconsidered previously in studies of harmful algal effects on shellfish, was also highlighted, suggesting energy challenge in oysters with high toxin loads. Associations between toxin load, genotype, and mRNA levels were revealed that open new doors for genetic studies identifying genetically-based low toxin accumulation. PMID- 29621673 TI - Part B: Morphometric and transcriptomic responses to sub-chronic exposure to the polycyclic aromatic hydrocarbon phenanthrene in the fathead minnow (Pimephales promelas). AB - Phenanthrene is a tricyclic polycyclic aromatic hydrocarbon and environmental contaminant found in high concentrations around urban catchments and in the vicinity of oil extraction activities. Fish exposed to phenanthrene can exhibit altered reproductive hormone profiles and/or differences within gonadosomatic index and altered gamete proportions, but the mechanisms underlying these changes are not fully understood. In this study, we conducted a sub-chronic bioassay and measured transcriptional responses in the liver, the major tissue involved in generating lipids for oocyte growth. Adult male and female fathead minnow (Pimephales promelas) were exposed to an average measured concentration of 202 MUg phenanthrene/L for a 7 week period. Condition factor was reduced in both males and females, while female fish also showed decreased gonadosomatic index relative to control females. In females exposed to phenanthrene, perinucleolar proportions were increased ~1.9-fold relative to the control group whereas the proportions of vitellogenic oocytes decreased ~8.8 fold. In males exposed to phenanthrene, spermatogonia proportions were increased ~2.3 fold in testicular tissues compared to control fish. Thus, gametes were at an earlier stage of maturation in phenanthrene-treated fish compared to controls. However, no differences were detected in the production of 17beta-estradiol or testosterone from the gonad in either sex. Catalase activity was also assessed in the liver as a measure of oxidative stress and this biomarker did not change in activity in either sex. In addition to endpoints in the ovary, the female hepatic transcriptome was measured, as this tissue produces lipids for oocyte maturation. Transcriptomic responses to phenanthrene exposure suggested a reduction in vitellogenin mRNA, and lipid metabolism and immune system pathways. Comparisons of hepatic transcriptome responses with Part A (72 h phenanthrene exposure) showed that energy homeostasis pathways were consistently altered following phenanthrene exposure over multiple durations and concentrations. We suggest that altered energy homeostasis may be adversely affecting reproductive efforts, as impaired reproduction has been observed in other studies investigating polycyclic aromatic hydrocarbons. PMID- 29621674 TI - Part A: Temporal and dose-dependent transcriptional responses in the liver of fathead minnows following short term exposure to the polycyclic aromatic hydrocarbon phenanthrene. AB - Phenanthrene is a low molecular weight polycyclic aromatic hydrocarbon (PAH) that is composed of three fused benzene rings. PAHs are formed naturally through incomplete combustion of organic materials, and are environmental contaminants due to anthropogenic activities (e.g. oil extraction and refining, industrial and municipal effluents, fossil fuel burning). Fish exposed to PAHs such as phenanthrene have been reported to exhibit altered reproductive axis endpoints, however the mechanisms that underlie these responses are not fully characterized. To better understand effects at the mechanistic level, we applied transcriptomics to identify molecular pathways altered after acute exposure to phenanthrene on both a dose and temporal scale. Female fathead minnow (Pimephales promelas) were exposed to an average measured concentration of either 0, 29.8, 389 or 943 MUg phenanthrene/L for 24, 48, and 72 h in a static-renewal bioassay. Ovaries were assessed for oocyte distribution as well as in vitro 17beta-estradiol production and gene expression for transcripts related to steroidogenesis and estrogen signalling. In addition, the liver transcriptome was measured as this tissue is the primary source of the egg yolk precursor protein vitellogenin. Exposure to 29.8 MUg phenanthrene/L increased proportions of the cortical alveolar stage in the ovaries after 48 h while the proportion of cortical alveolar oocyte were decreased in fish exposed to 943 MUg phenanthrene/L for 48 h. Phenanthrene did not affect 17beta-estradiol production at any time or dose, and did not affect transcripts associated with hormone synthesis nor signalling pathways. In the liver, the transcriptome showed fewer genes in common across time when compared to those transcripts affected by concentration at a single time point. Cholesterol metabolism was the only pathway perturbed in the liver following all comparisons in both the dose and time course experiments. Our data suggest that transcriptome networks associated with hepatic lipid metabolism are rapidly affected by phenanthrene, and this may indirectly reduce resources available for reproductive efforts. PMID- 29621675 TI - The problem of overcontrol: Perfectionism, emotional inhibition, and personality disorders. AB - BACKGROUND AND AIMS: Some individuals with Personality Disorders (PD), particularly of a non-Borderline type, present with difficulties relating to over control of cognitions, emotion and behavior, perfectionistic traits, and impaired social interactions. The current study sought to evaluate the strength of association, and interactions of both emotional inhibition and perfectionism in PD's, after controlling for symptoms and interpersonal problems. METHOD: We recruited a sample of 578 treatment seeking outpatients. Diagnosis of PD was made with the SCID-II. Individual's completed measures of perfectionism (Frost-MPS), Emotional Inhibition (EIS), Depression (BDI-II), Anxiety (STAI-Y), Global symptoms (SCL-90-R), and interpersonal problems (IIP-32). RESULTS: Perfectionism was related to interpersonal problems, to the majority of PD symptomatology and to PD severity via number of SCID-II criteria met. Emotional inhibition was linked to symptoms and interpersonal problems as well as with avoidant, dependent, depressive and paranoid PDs; and with overall PD Severity. Inhibition and perfectionism were correlated with each other. Both variables predicted PD above and beyond other variables assessed. Mediation modeling demonstrated that the effect of emotional inhibition on PD severity was fully mediated by perfectionism and interpersonal problems. CONCLUSIONS: Psychological mechanisms of overcontrol are a maintaining factor in many PDs. Both perfectionism and emotional inhibition impact on a broad range of PDs and there is an urgent need for research into these processes, and to adapt psychological interventions to consider these factors. PMID- 29621676 TI - Oral bioaccessibility of semi-volatile organic compounds (SVOCs) in settled dust: A review of measurement methods, data and influencing factors. AB - Many semi-volatile organic compounds (SVOCs), suspected of reprotoxic, neurotoxic or carcinogenic effects, were measured in indoor settled dust. Dust ingestion is a non-negligible pathway of exposure to some of these SVOCs, and an accurate knowledge of the real exposure is necessary for a better evaluation of health risks. To this end, the bioaccessibility of SVOCs in dust needs to be considered. In the present work, bioaccessibility measurement methods, SVOCs' oral bioaccessibility data and influencing factors were reviewed. SVOC bioaccessibilities (%) ranged from 11 to 94, 8 to 100, 3 to 92, 1 to 81, 6 to 52, and 2 to 17, for brominated flame retardants, organophosphorus flame retardants, polychlorobiphenyls, phthalates, pesticides and polycyclic aromatic hydrocarbons, respectively. Measurements method produced varying results depending on the inclusion of food and/or sink in the model. Characteristics of dust, e.g., organic matter content and particle size, also influenced bioaccessibility data. Last, results were influenced by SVOC properties, such as octanol/water partition coefficient and migration pathway into dust. Factors related to dust and SVOCs could be used in prediction models. To this end, more bioaccessibility studies covering more substances should be performed, using methods that are harmonized and validated by comparison to in-vivo studies. PMID- 29621677 TI - Svalbard reindeer as an indicator of ecosystem changes in the Arctic terrestrial ecosystem. AB - Over the years, noticeable effort has been directed towards contaminant determination in multiple biotic samples collected from the inhabitants of the Arctic. Little consideration has been given to polar herbivores, however, especially those from the European parts of the Arctic. To provide a broader perspective, we aimed to decipher trace element concentration in hairs of the key species in the Arctic, namely the Svalbard reindeer (Rangifer tarandus platyrhynchus), and to recognise whether diet variations could correspond with forward exposure. The effect of habitat and diet was investigated using the ratios of stable isotopes of carbon (delta13C) and nitrogen (delta15N), and previous literature studies on vegetation from the areas of interest. Analysis was performed for eighteen elements in total, both toxic and essential. Metals were present in a decreasing order Fe > Zn > Ba > Cu > Pb > Cr > Ni > V > Ga =La > Rb > As > Li > Co > Hg > Cd > Cs > Be. Similarity in trends in the studied subpopulations was observed for many metals. A significant log-linear correlation was observed for most of the elements, excluding nitrogen and carbon isotopes signature. Extremely high iron levels were determined in some of the samples, suggesting past iron overload. Zinc, in contrast to the remaining metals, did not correlate well with any other element. Mercury was determined at very low levels, in accordance with previous literature regarding its concentrations in moss and lichen species in Svalbard. The analysis of stable isotopes showed a high variation in nitrogen isotopes signatures. Further research is required to properly evaluate the potential health risks and ecological implications of elevated exposure. PMID- 29621678 TI - Concentration/time-dependent dissipation, partitioning and plant accumulation of hazardous current-used pesticides and 2-hydroxyatrazine in sand and soil. AB - The dissipation, partitioning dynamics and biouptake was measured for selected hazardous current-used pesticides (conazole fungicides: epoxiconazole, flusilazole, tebuconazole; prochloraz, chlorpyrifos, pendimethalin) and for a transformation product (2-hydroxyatrazine) in agricultural soil and quartz sand as representatives of a real and a worst-case scenario. Dissipation, uptake to Lactuca sativa and the freely dissolved concentration along with the organic carbon-normalized sorption coefficients (Koc) were determined on days 12, 40, and 90 following the application of compounds at three fortification levels (0.1-1.0 10 mg/kg). Conazole fungicides showed similar dissipation patterns and were more persistent in soil than prochloraz, chlorpyrifos and pendimethalin. 2 Hydroxyatrazine showed a concentration-depended decrease in persistency in soil. Lettuce roots were shown to accumulate higher amounts than shoots where the extent of root uptake was driven by compound partitioning. This was evidenced by the ability of freely dissolved concentration (Cfree) to reliably (r2 = 0.94) predict root uptake. Concentration in leaves did not exceed the maximum residue levels (MRLs) for lettuce, which was likely given by the low root-to-shoot translocation factors (TFs) of the tested compounds varying between 0.007 and 0.14. Koc values were in the range of literature values. Sorption to soil was higher than to sand for all compounds, yet following the Koc dynamics compounds did not appear to be sequestered in soil with increasing residence time. From these results, it follows that the tested compounds may persist in soil but since they did not accumulate in lettuce above MRLs, contamination of the food web is unlikely. PMID- 29621679 TI - Biochar, wood ash and humic substances mitigating trace elements stress in contaminated sandy loam soil: Evidence from an integrative approach. AB - We conducted a pot experiment with biochar (BC), wood ash (WA), and humic substances (HS) to investigate their effect on As, Zn, Cu, Cd and Pb mobility in soil, as well as enzyme activities involved in C-, N-, and P-cycles, and Eisenia foetida toxicity in multi-contaminated soils. Amendments were dosed to increase eru soil pH from initial 6.0 to ~6.5 and ~7.0. Applying amendments has revealed, that WA significantly immobilized Cu, Zn and Pb, BC - Cu and Zn, and HS decreased solely Cu mobility in soil. The partition indices of Zn, Cu, and Pb, quantitatively describing the bioavailable species of elements in soil, were the lowest for WA. Changes in the water-soluble species of metals were more pronounced than in the exchangeable ones for all amendments. An opposite effect was observed on enzyme activity and earthworm toxicity for the WA and carbonaceous amendments. The BC and HS provided favourable soil conditions to dehydrogenase, beta-glucosidase, urease activity and fluorescein diacetate hydrolysis, while WA significantly decreased the activity of all the mentioned enzymes in soil. The results are supported by an enzymes-based weighted mean index, being the highest for BC and HS and the lowest for WA (lower than in the control sample). At the same time, WA was suitable to eliminate the trace elements' stress to earthworms (biomass endpoints and cocoons production). Our data revealed that each amendment has its own advantages and disadvantages. The choice of the most suitable amendment therefore should always be made within an integral approach and based on the purpose of remediation. PMID- 29621681 TI - Parents' drinking motives and problem drinking predict their children's drinking motives, alcohol use and substance misuse. AB - The aim of the current study was to test the direct and indirect influence of parents' drinking motives and problem drinking on their children's drinking motives, alcohol use and substance misuse. Cross-sectional analysis of parent and child drinking patterns and motives, derived from the nationally representative Drinkaware Monitor panel survey. The sample comprised a total of 148 couples of parents and child. Path analysis revealed that children's alcohol use and substance misuse were influenced by their own drinking motives and parents' problem drinking. Parents' conformity motives were linked to their children's conformity motives. Finally, parental drinking problems mediated the effect of their coping motives on their childrens' alcohol use and substance misuse. In conclusion, parental drinking styles relate to their children's alcohol use and substance misuse through problem drinking and drinking motives. PMID- 29621680 TI - National surveillance of 2,3,7,8-substituted polychlorinated dibenzo-p dioxins/furans in soil in Taiwan. AB - In this study, the polychlorinated dibenzo-p-dioxin/furan (PCDD/F) levels in 381 soil samples coming from different background areas (n = 238) and contaminated areas (n = 143) in Taiwan were investigated from 2011 to 2015 using high resolution gas chromatograph/high resolution mass spectrometry (HRGC/HRMS). The contaminated areas showed higher PCDD/F contamination as compared to the background areas (1230 vs 749 pg/g dry weight (dw)); 14.0 vs 6.25 pg WHO2005 TEQ/g dw). The lowest levels were recorded in the outlying islands (1.28 pg WHO2005-TEQ/g dw). PCDD/F congener distribution profiles in the background and contaminated areas as well as on the islands varied. OCDD was the dominant congener in almost all locations, including the northern background (87.7%) and central contaminated (74.2%) areas. Other dominant species included OCDF and 1,2,3,4,6,7,8-HpCDD. Levels of PCDD/F-TEQs in Taiwanese soils, including the background areas, were higher than in some developing countries and regions with global background levels due to high industrialization except for the contaminated areas. Geographic differences in dioxin-contaminated soils were also shown in this study. Higher soil dioxin-TEQs were observed in locations with high populations and population densities. Despite the limitations, the economic status of Taiwan represented by the annual averaged family income (AAFI) was positively correlated to soil dioxin-TEQs. PMID- 29621682 TI - Transfer of a learned coordination function: Specific, individual and generalizable. AB - It is generally held that transfer of practice is a function of the similarity between the originally learned task and the subsequent transfer task. In the present paper, we examine the proposition that individuals learn a coordination function that is specific to the task, individual and yet generalizable, depending on the characteristics of the learned coordination function. Seventeen individuals performed for 5 days the task of learning to throw for accuracy to a target and then performed two transfer tests that differed in terms of the axis of variation that individuals could vary in task outcome. The results showed individual differences in terms of the acquired movement pattern even when a similar performance was achieved. Additionally, the coordination function characterized by principal component analysis and its projection into the landing plane predicted performance in the transfer tests. These results support the proposition that individuals learn a coordination function that is specific, individual and generalizable. PMID- 29621683 TI - The inter-observer reliability and agreement of lateral balance recovery responses in older and younger adults. AB - The purpose of this study was to evaluate the inter-observer reliability and agreement of balance recovery responses, step and multiple-steps thresholds, and kinematic parameters of stepping responses. Older and younger adults were exposed to 36 progressively challenging right and left unannounced surface translations during quiet standing. Subjects were instructed to "react naturally". Step threshold and multiple-step threshold were defined as the minimum disturbance magnitude that consistently elicited one and more than one recovery step, respectively. Fall threshold is defined as the minimum disturbance magnitude from which a fall resulted (i.e., fall into harness system or grasped one of the anchor straps of the harness, or grasped the research assistant to maintain balance). The inter-observer reliability of balance recovery responses for older adults were excellent, especially for step and multiple-step thresholds (ICC2,1 = 0.978 and ICC2,1 = 0.971, respectively; p < 0.001). Also kinematic parameters of stepping responses such as step recovery duration and step length were excellent (ICC2,1 > 0.975 and ICC2,1 = 0.978, respectively; p < 0.001), substantial reliability was found for swing phase duration (ICC2,1 = 0.693, p < 0.001). Younger adults showed similar ICCs. The Bland-Altman plots demonstrated excellent limits of agreement (LOA > 90%) for most kinematic step parameters and stepping thresholds. These results suggest that balance recovery responses and kinematic parameters of stepping including step threshold and multiple-step threshold are extremely reliable parameters. The measure of balance recovery responses from unexpected loss of balance is feasible and can be used in clinical setting and research-related assessments of fall risk. PMID- 29621684 TI - Identification of novel enzymes to enhance the ruminal digestion of barley straw. AB - Crude enzyme extracts typically contain a broad spectrum of enzyme activities, most of which are redundant to those naturally produced by the rumen microbiome. Identification of enzyme activities that are synergistic to those produced by the rumen microbiome could enable formulation of enzyme cocktails that improve fiber digestion in ruminants. Compared to untreated barley straw, Viscozyme(r) increased gas production, dry matter digestion (P < 0.01) and volatile fatty acid production (P < 0.001) in ruminal batch cultures. Fractionation of Viscozyme(r) by Blue Native PAGE and analyses using a microassay and mass-spectrometry revealed a GH74 endoglucanase, GH71 alpha-1,3-glucanase, GH5 mannanase, GH7 cellobiohydrolase, GH28 pectinase, and esterases from Viscozyme(r) contributed to enhanced saccharification of barley straw by rumen mix enzymes. Grouping of these identified activities with their carbohydrate active enzymes (CAZy) counterparts enabled selection of similar CAZymes for downstream production and screening. Mining of these specific activities from other biological systems could lead to high value enzyme formulations for ruminants. PMID- 29621685 TI - Responses of microbial capacity and community on the performance of mesophilic co digestion of food waste and waste activated sludge in a high-frequency feeding CSTR. AB - To understand the relationship between microbes and digester performance of high frequency feeding CSTR, which could achieve stable CH4 production at high OLR by easing instantaneous feeding shock, attentions were paid on the variations of methanogenic capacity (MC) and microbial community with OLR increasing. Results showed that the MC for feedstock degradation could satisfy the need of effective conversion from feedstock to CH4 when the OLR remained below 16.4 g-TS/L/d. Furthermore, the MC for acetate, propionate and butyrate degradation increased by 73.8%, 303%, and 164%, respectively, with OLR increasing from 3.03 g-TS/L/d 12.6 g-TS/L/d. The evolution of both bacterial and archaeal communities provided additional information on the adaptation of functional microbes to environmental factors. The significant increase of abundance of Methanoculleus and Methanomassiliicoccus likely promoted the utilization of H2, thus facilitating syntrophic methanogenesis, and consequently ensuring efficient CH4 production in stable stage. PMID- 29621686 TI - Examination of sustainability indicators for fall prevention strategies in three states. AB - With 1-in-4 older adults suffering a fall each year, fall prevention efforts have emerged as a public health priority. Multi-level, evidence-based fall prevention programs have been promoted by the CDC and other government agencies. To ensure participants and communities receive programs' intended benefits, organizations must repeatedly deliver the programs over time and plan for program sustainability as part of 'scaling up' the initiative. The State Falls Prevention Project (SFPP) began in 2011 when the CDC provided 5 years of funding to State Departments of Health in Colorado, New York, and Oregon to simultaneously implement four fall prevention strategies: 1) Tai Chi: Moving for Better Balance; 2) Stepping On; 3) Otago Exercise Program; and 4) STEADI (STopping Elderly Accidents, Deaths, and Injuries) toolkit. Surveys were performed to examine systems change and perceptions about sustainability across states. The purposes of this study were to: 1) examine how funding influenced the capacity for program implementation and sustainability within the SFPP; and 2) assess reported Program Sustainability Assessment Tool (PSAT) scores to learn about how best to sustain fall preventing efforts after funding ends. Data showed that more organizations offered evidence-based fall prevention programs in participants' service areas with funding, and the importance of programming implementation, evaluation, and reporting efforts were likely to diminish once funding concluded. Participants' reported PSAT scores about perceived sustainability capacity did not directly align with previously reported perceptions about PSAT domain importance or modifiability. Findings suggest the importance of grantees to identify potential barriers and enablers influencing program sustainability during the planning phase of the programs. PMID- 29621687 TI - Viscoelastic finite element analysis of residual stresses in porcelain-veneered zirconia dental crowns. AB - The main problem of porcelain-veneered zirconia (PVZ) dental restorations is chipping and delamination of veneering porcelain owing to the development of deleterious residual stresses during the cooling phase of veneer firing. The aim of this study is to elucidate the effects of cooling rate, thermal contraction coefficient and elastic modulus on residual stresses developed in PVZ dental crowns using viscoelastic finite element methods (VFEM). A three-dimensional VFEM model has been developed to predict residual stresses in PVZ structures using ABAQUS finite element software and user subroutines. First, the newly established model was validated with experimentally measured residual stress profiles using Vickers indentation on flat PVZ specimens. An excellent agreement between the model prediction and experimental data was found. Then, the model was used to predict residual stresses in more complex anatomically-correct crown systems. Two PVZ crown systems with different thermal contraction coefficients and porcelain moduli were studied: VM9/Y-TZP and LAVA/Y-TZP. A sequential dual-step finite element analysis was performed: heat transfer analysis and viscoelastic stress analysis. Controlled and bench convection cooling rates were simulated by applying different convective heat transfer coefficients 1.7E-5 W/mm2 degrees C (controlled cooling) and 0.6E-4 W/mm2 degrees C (bench cooling) on the crown surfaces exposed to the air. Rigorous viscoelastic finite element analysis revealed that controlled cooling results in lower maximum stresses in both veneer and core layers for the two PVZ systems relative to bench cooling. Better compatibility of thermal contraction coefficients between porcelain and zirconia and a lower porcelain modulus reduce residual stresses in both layers. PMID- 29621688 TI - Influence of strain rate on indentation response of porcine brain. AB - Knowledge of brain tissue mechanical properties may be critical for formulating hypotheses about some specific diseases mechanisms and its accurate simulations such as traumatic brain injury (TBI) and tumor growth. Compared to traditional tests (e.g. tensile and compression), indentation shows superiority by virtue of its pinpoint and nondestructive/quasi-nondestructive. As a viscoelastic material, the properties of brain tissue depend on the strain rate by definition. However most efforts focus on the aspect of velocity in the field of brain indentation, rather than strain rate. The influence of strain rate on indentation response of brain tissue is taken little attention. Further, by comparing different results from literatures, it is also obvious that strain rate rather than velocity is more appropriate to characterize mechanical properties of brain. In this paper, to systematically characterize the influence of strain rate, a series of indentation-relaxation tests n = 210) are performed on the cortex of porcine brain using a custom-designed indentation device. The mechanical response that correlates with indenter diameters, depths of indentation and velocities, is revealed for the indentation portion, and elastic behavior of brain tissue is analyzed as the function of strain rate. Similarly, a linear viscoelastic model with a Prony series is employed for the indentation-relaxation portion, wherein the brain tissue shows more viscous and responds more quickly with increasing strain rate. Understanding the effect of strain rate on mechanical properties of brain indentation may be far-reaching for brain injury biomechanics and accurate simulations, but be important for bridging between indentation results of different literatures. PMID- 29621689 TI - Analyzing nature's protective design: The glyptodont body armor. AB - Many animal species evolved some form of body armor, such as scales of fish and bony plates or osteoderms of reptiles. Although a protective function is often taken for granted, recent studies show that body armor might comprise multiple functionalities and is shaped by trade-offs among these functionalities. Hence, despite the fact that natural body armor might serve as bio-inspiration for the development of artificial protective materials, focussing on model systems in which body armor serves a solely protective function might be pivotal. In this study, we investigate the osteoderms of Glyptotherium arizonae, an extinct armadillo-like mammal in which body armor evolved as protection against predators and/or tail club blows of conspecifics. By using a combination of micro-computed tomography, reverse-engineering, stress simulations and mechanical testing of 3D printed models, we show that the combination of dense compact layers and porous lattice core might provide an optimized combination of strength and high energy absorption. PMID- 29621690 TI - Albizia chevalier based Ag nanoparticles: Anti-proliferation, bactericidal and pollutants degradation performance. AB - The eco-friendly biosynthesis of silver nanoparticles (AgNps) from bark extract of Albizia chevalier are reported here for their anti-proliferative, antibacterial and pollutant degradation potentials. The synthesized AgNps were characterized by FTIR spectroscopy, transmission electron microscopy (TEM), field emission scanning electron microscopy (FESEM), energy dispersive X-rays spectrometry (EDS) and X-ray diffraction studies. The TEM and FESEM images show a monodispersed spherical shaped particles of approximately 30 nm. Crystalline peaks were obtained for the synthesized AgNps in XRD spectrum. The AgNps were investigated for in vitro anticancer and antibacterial activities and its potential to degrade 4-nitrophenol (4-NP) and congo red dye (CR). The MTT results shows a significant dose-dependent antiproliferation effect of the AgNps on the cell lines HepG2, MDA-MB-231 and MFC7. The effect was found more pronounced in MDA-MB-231 as compared to MFC-7 cell lines. The antibacterial results indicated 99 and 95% killing of Escherichia coli (E. coli) and Staphylococcus aureus (S. aureus) respectively, after 24 h of incubation with the AgNps. The AgNps were found to speed up the reductive degradation of 4-NP and CR dye, which give an alternative route for the removal of toxic organic pollutants from the wastewater. The synthesized AgNps were not only used as a bactericidal and anticancer agent, but also effectively used for the reductive degradation of carcinogenic compounds which are listed as the priority pollutants. Therefore, AgNps have the potential for the treatment of various cancers, bacterial infections and for industrial detoxification of wastewater. PMID- 29621691 TI - Stem cells and regenerative medicine for neural repair. AB - Clinical trials of cell-based therapies that use pluripotent stem cells (PSC) have already started for several neurological diseases including spinal cord injury and age-related macular degeneration. Regarding future PSC-based clinical trials for other neurological diseases, these trials have been instrumental at recognizing first, the difference between research cell lines and clinical cell lines of a stem cell product, second, the selection of an appropriate animal model for pre-clinical study, third, criteria and the quality control of donor cells, and fourth, the mode of action of the grafts. PMID- 29621692 TI - Attachment across the lifespan: insights from adoptive families. AB - Research with adoptive families offers novel insights into longstanding questions about the significance of attachment across the lifespan. We illustrate this by reviewing adoption research addressing two of attachment theory's central ideas. First, studies of children who were adopted after experiencing severe adversity offer powerful tests of the unique consequences of experiences in early attachment relationships. Although children who experience early maltreatment or institutionalization show remarkable recovery in the quality of their attachments after being placed with their adoptive families, experiencing pre-adoptive adversity also has long-lasting repercussions for these individuals' later attachment representations. Second, adoptive families allow for genetically informed examinations of the intergenerational transmission process. Indeed, despite the lack of genetic relatedness, adoptive parents' attachment representations are associated with their children's attachment behaviors and representations across childhood and adolescence. PMID- 29621693 TI - Attachment security priming: a systematic review. AB - Attachment security priming has been used to shed light on the cognitive processes related to attachment internal working models as well as the cognitive substrates of people's attachment-related affect and behavior. Security primes activate a sense of attachment security by making mental representations in one's memory more accessible and salient. In the current paper, we report on a qualitative synthesis of 20 studies published in the last two years to determine the effects of security priming. We found that supraliminally administered security priming (especially via guided imagery or visualization) is associated with beneficial effects across a diverse set of domains. The effects were especially strong among anxiously attached individuals. PMID- 29621694 TI - Changes in the prevalence of child maltreatment in Vietnam over 10 years. AB - OBJECTIVES: In the context of the shortage of studies on child maltreatment changes over time in limited resource settings, this paper explored the changes in the prevalence of multiple types of child maltreatment over a period of 10 years in Vietnam and tested the moderating role of some demographic characteristics in these changes. METHODS: We used data from two prevalence studies conducted in 2004 and in 2014 using similar methodologies. Both studies used self-report questionnaires which were completed by randomly selected students aged 12-17 years from different provinces in Vietnam. We also compared Hanoi subgroups to examine the trend using the most equivalent samples. RESULTS: While the prevalence estimates of sexual abuse and neglect were unchanged over 10 years, the prevalence of physical abuse and emotional abuse declined. The decrease in the prevalence of physical abuse was larger for younger adolescents and boys than for their counterparts. For sexual abuse, older adolescents reported an increase in the prevalence of sexual abuse. In the Hanoi sample comparison, only the prevalence of emotional abuse declined and this reduction was smaller for younger adolescents than for the older group. CONCLUSION: Despite the reduction of emotional and physical abuse in the whole sample and emotional abuse in the Hanoi sample, all types of child maltreatment were still highly prevalent in Vietnam. We argue that interventions on all types of child maltreatment should be further implemented. Similar studies could be conducted to evaluate the effect of child protection policies on the prevalence of child maltreatment. PMID- 29621695 TI - Incidence of isolated local breast cancer recurrence and contralateral breast cancer: A systematic review. AB - An increasing number of women is surviving breast cancer and due to that at risk of developing an isolated ipsilateral breast tumor recurrence (IBTR) or a contralateral breast cancer (CBC). Patients' main concern is cancer recurrence. Patient counseling on breast cancer recurrence is challenging. In order to provide healthcare professionals and patients more guidance, a systematic literature review of the incidence of isolated IBTR and CBC in women diagnosed with early invasive breast cancer was performed. Medline, EMBASE and the Cochrane Library were searched from 2000 until October 2015. Multicenter studies reporting an IBTR or CBC rate in curatively treated adult females diagnosed with invasive breast cancer were included. The initial search yielded 6998 potentially relevant articles. Twenty were eligible for inclusion, representing 25 recurrence incidence rates. Both isolated IBTR and CBC incidence rates steadily increased with the length of follow-up, indicating that IBTR and CBC occur even more than 15 years after diagnosis. The annual incidence rate of isolated IBTR and CBC in women diagnosed with an early invasive breast cancer was 0.6% (range: 0.4-1.1%) and 0.5% (range: 0.2-0.7%), respectively. Analyzed data were lacking information about important risk factors and given treatment with regard to the incidence of recurrence, which hampers the prediction of patient tailored recurrence risks. The presented rates are therefore the best available estimates of isolated IBTR and CBC annual incidence rates based on the current literature. Healthcare professionals could use these rates in their communication with patients diagnosed with early invasive breast cancer. PMID- 29621696 TI - Forensic medical aspects of femicide in Jordan. AB - : This study aims to highlight three types of femicide in Jordan - so-called 'honour killings', fatal intimate partner violence (IPV), and domestic violence committed by male family members other than the husband (DV) - and to compare them with the killing of women in non-gender related situations such as during a robbery. The autopsy reports of 100 adult female homicide victims dealt with at Jordan University Hospital in Amman during a 10-year period from 2006 to 2015 were reviewed. Based on information contained in the police reports they were assigned to one of four categories. Of the 100 deaths, 52% were classed as honour killings, 33% as fatal IPV and 5% as DV crimes, with non-gender related murders making up the remaining 10%. The majority (76%) occurred in the woman's home. The commonest cause of death was gunshot injuries, the severity of violence as judged by the largest number of major injuries was greatest in the honour killings, and 14 victims had defence wounds, again the majority in the honour cases. The hymen was found to be intact in 38% of the honour victims, while 33% in this category were pregnant at the time of death, compared to only 3% of fatal IPV victims. CONCLUSIONS: Most female murders in Jordan are committed by an assailant who is either a partner or a family member, the home becoming the most dangerous place to be for a threatened woman. With extra-marital pregnancy being one of the strongest motivators for honour killings, and old injuries a potential sign of ongoing intimate partner violence, forensic doctors can assist in recognizing these risk factors and thereby help potential victims. It is thus important to highlight some of the characteristic features of femicide. PMID- 29621698 TI - Plasma methionine and risk of acute myocardial infarction: Effect modification by established risk factors. AB - BACKGROUND AND AIMS: Methionine (Met) is an essential amino acid involved in methylation reactions and lipid metabolism. A Met-deficient diet may cause hepatic lipid accumulation, which is considered an independent risk factor for atherosclerosis. However, the prospective relationship between circulating Met and incident acute myocardial infarction (AMI) is unknown. METHODS: We studied the associations of plasma Met and incident AMI in 4156 patients (77% men; median age 62 years) with stable angina pectoris, among whom the majority received lipid lowering therapy with statins. Risk associations were estimated using Cox regression analyses. RESULTS: Plasma Met was negatively related to age, serum levels of total cholesterol, low-density lipoprotein cholesterol (LDL-C) and apolipoprotein (apo) B at baseline (all p<=0.05). During a median follow-up of 7.5 years, 534 (12.8%) patients experienced an AMI. There was no overall association between plasma Met and incident AMI; however, plasma Met was inversely associated with risk among patients with high as compared to low levels of serum LDL-C or apo B 100 (multivariate adjusted HRs per SD [95% CI] 0.84 [0.73 0.96] and 0.83[0.73-0.95], respectively; p-interaction <=0.02). Trends towards an inverse risk relationship were also observed among those younger than 62 years and patients without diabetes or hypertension. CONCLUSIONS: Low plasma Met was associated with increased risk of AMI in patients with high circulating levels of atherogenic lipids, but also in subgroups with presumably lower cardiovascular risk. The determinants of Met status and their relation with residual cardiovascular risk in patients with coronary heart disease should be further investigated. PMID- 29621699 TI - Photodegradation of methylene blue with PVA/PVP blend under UV light irradiation. AB - Homogenous films of PVA/PVP blend (1:1) doped with different levels of methylene blue dye (MB) were prepared using the casting technique. The absorption spectra of doped PVA/PVP blend showed two absorption peaks due to the chromophor groups of MB while the pure PVA/PVP blend does not. The UV irradiation causes photodegradation of MB dye. The recovery of photodegraded MB is observed after keeping the sample 3h in atmospheric air. The value of the optical energy gap (Eg) decreases with increasing the doping levels with MB. The spectral distribution of absorption index (k) and refractive index (n) are determined from the reflection and transmission spectra in the spectral range 200-2500nm. The dependence of both n and k on wavelength of the incident light and the wt% content of MB in PVA/PVP blend is discussed. A normal dispersion observed at wavelength lambda>370nm for pure PVA/PVP blend and lambda>800nm for MB doped samples. The obtained results suggest the possible use of the studied system in many applications. PMID- 29621697 TI - Transcriptional programming of tissue-resident memory CD8+ T cells. AB - Tissue-resident memory CD8+ T cells (TRM) are localized in non-lymphoid tissues throughout the body where they mediate long-lived protective immunity at common sites of pathogen exposure. As the signals controlling TRM differentiation are uncovered, it is becoming apparent that the dynamic activities of numerous transcription factors are intricately involved in TRM formation. Here, we highlight known transcriptional regulators of TRM differentiation and discuss how understanding the transcriptional programming of CD8+ T cell residency in non lymphoid tissues can be leveraged to prevent or treat disease. PMID- 29621701 TI - Hydrological model using ground- and satellite-based data for river flow simulation towards supporting water resource management in the Red River Basin, Vietnam. AB - The Red River basin (RRB) exhibits substantial variation of water resource seasonally and annually. Sustainable water resource management in the RRB has been challenging due to the lack of in situ hydrological measurement data over the basin-wide scale. To address this issue, this study aimed to perform the setting up, calibration, and validation of the variable infiltration capacity (VIC) hydrological model forced with ground- and satellite-based datasets at a high spatial resolution of 0.1 degrees for simulating the daily river flow of the Red River system in the RRB during the period of 2005-2014. By using the finely resolved land cover characterization with 15 types of land cover and leaf area index - the most important feature of vegetation that significantly influences the simulation of hydrological variables provided by the spatially distributed satellite remote sensing data, this study would not only address the poor data availability over the RRB but also enhance the accuracy of model simulation. The simulation results generally indicated that the calibrated VIC model could satisfactorily capture the river flow dynamics of the Red River system in the RRB. The VIC model's underestimated river flow compared to the observed data during the dry season for the downstream stations was likely due to the operation of the large man-made reservoirs and dams in the upstream catchments of the RRB that not represented by the VIC model. The findings also suggested that for further improving the VIC model performance, the use of more spatially representative meteorological data provided by satellite remote sensing should be considered in future studies. PMID- 29621700 TI - Removal of ciprofloxacin from seawater by reverse osmosis. AB - Much of the deterioration of water resources is anthropogenically caused as a consequence of the incessant production of chemical compounds to obtain the quality of life that society demands today. This constant presence and harmful accumulation of these pollutants in different ecosystems have seen them emerge as a major concern both for human health and for environmental safety. Scientific advances have succeeded in legislating against, reducing and even eliminating priority pollutants, while new technologies are being constantly developed to identify and treat newly emerging pollutants. The objective of this work is the evaluation of the seawater reverse osmosis membrane as a method for the removal of an antibiotic present in seawater. The novelty of the study is that the tests were undertaken using water of high ionic strength. A critical selection of the antibiotic to be used in the study was carried out. The experiments were performed under constant pressure conditions, employing synthetic seawater in a pilot-scale unit with a commercial spiral-wound reverse osmosis membrane. Results are shown in terms of selectivity of the reverse osmosis process for antibiotic removal. The RO membrane element successfully reject most of the ciprofloxacin (removal rate >90%), with maximum rejection value of 99.96%. PMID- 29621702 TI - Biodegradation of bilge water: Batch test under anaerobic and aerobic conditions and performance of three pilot aerobic Moving Bed Biofilm Reactors (MBBRs) at different filling fractions. AB - The bilge water that is stored at the bottom of the ships is saline and greasy wastewater with a high Chemical Oxygen Demand (COD) fluctuations (2-12 g COD L 1). The aim of this study was to examine at a laboratory scale the biodegradation of bilge water using first anaerobic granular sludge followed by aerobic microbial consortium (consisted of 5 strains) and vice versa and then based on this to implement a pilot scale study. Batch results showed that granular sludge and aerobic consortium can remove up to 28% of COD in 13 days and 65% of COD removal in 4 days, respectively. The post treatment of anaerobic and aerobic effluent with aerobic consortium and granular sludge resulted in further 35% and 5% COD removal, respectively. The addition of glycine betaine or nitrates to the aerobic consortium did not enhance significantly its ability to remove COD from bilge water. The aerobic microbial consortium was inoculated in 3 pilot (200 L) Moving Bed Biofilm Reactors (MBBRs) under filling fractions of 10%, 20% and 40% and treated real bilge water for 165 days under 36 h HRT. The MBBR with a filling fraction of 40% resulted in the highest COD decrease (60%) compared to the operation of the MBBRs with a filling fraction of 10% and 20%. GC-MS analysis on 165 day pointed out the main organic compounds presence in the influent and in the MBBR (10% filling fraction) effluent. PMID- 29621703 TI - Shielding design of a target station and radiation dose level investigation of proton linac for a compact accelerator-driven neutron source applied at industrial sites. AB - The shielding design for a compact accelerator-driven neutron source (CANS) that is applied in industries was studied using both theoretical simulations and experimental measurements. Neutron shielding material composition for CANS was optimized by coupling the genetic algorithm with the Monte Carlo code. A multi layer shielding structure was developed and successfully applied to a CANS target station. The high radiation dose of CANS proton linac was investigated in detail on the basis of experimental measurements, and the radiation dose was significantly reduced by replacing the material of its bellow pipes. PMID- 29621704 TI - PAHs would alter cyanobacterial blooms by affecting the microcystin production and physiological characteristics of Microcystis aeruginosa. AB - The wide presence of polycyclic aromatic hydrocarbons (PAHs) in lakes necessitates a better understanding of cyanobacteria metabolites under the contamination of PAHs. The M. aeruginosa strain PCC7806 was selected to investigate the effects of naphthalene and pyrene on the physiological and biochemical reactions of cyanobacteria, including antioxidant defense system (superoxide dismutase, catalase), intracellular microcystin (MC) content, phycobiliprotein (phycocyanin, allophycocyanin) contents, and specific growth rate. Naphthalene and pyrene altered the growth of the M. aeruginosa strain, reduced the contents of phycocyanin and allophycocyanin, and stimulated the activities of antioxidant enzymes without lipid peroxidation. Remarkably, the intracellular MC content was significantly increased by 68.1% upon exposure of M. aeruginosa to 0.45 mg L-1 naphthalene, and increased by 51.5% and 77.9% upon exposure of M. aeruginosa to 0.45 mg L-1 pyrene and 1.35 mg L-1 pyrene, respectively (P<0.05). Moreover, significant correlations were observed between these physiological reactions, referring that a series of physiological and biochemical reactions in M. aeruginosa worked together against the PAH contamination. Considering that MCs are the most studied cyanobacterial toxins, our results clarified that the promoting MC production by PAH contamination cannot be neglected when making related risk assessments of eutrophic waters. PMID- 29621705 TI - Off-site transport of fungicides with runoff: A comparison of flutolanil and pentachloronitrobeneze applied to creeping bentgrass managed as a golf course fairway. AB - Flutolanil and pentachloronitrobenzene (PCNB) are fungicides used to control or suppress foliar and soil borne diseases in turf and ornamental crops. On golf courses, sports fields, sod farms and commercial lawns these fungicides are used as preventive treatments to combat snow mold, brown patch and fairy ring. Depending on the aquatic organism, flultolanil and PCNB are considered to be moderately to highly toxic. Therefore runoff or drift from treated areas may be hazardous to organisms in adjacent aquatic sites. This research compared the transport of flutolanil and PCNB with runoff from turfgrass managed as a golf course fairway. The quantity of fungicide transported with runoff and observations reported with the chemographs followed trends in agreement with the chemical properties of the compounds. Overall, we observed the rate of transport for flutolanil was greater than PCNB, which contributed to the more than 12 times larger load (ug/m2) of flutolanil transported off-site at the conclusion of the simulated storm runoff. A better understanding of the off-site transport of pesticides with runoff is needed to make informed decisions on management practices to reduce potential adverse effects on non-target organisms, as well as maintain control of targeted pests in the area of application. In addition, data obtained with this research can be used in model simulations to predict nonpoint source pollution potentials beyond experimental conditions. PMID- 29621706 TI - Antibiotics in surface water and sediments from Hanjiang River, Central China: Occurrence, behavior and risk assessment. AB - Thirteen antibiotics including sulfonamides (SAs), tetracyclines (TETs) and fluoroquinolones (FQs) were measured in Hanjiang River (HR) during two periods. The total concentrations of 13 antibiotics in surface water and sediments ranged from 3.1 to 109 ng/l and from 10 to 45 ng/g dry weight, respectively. SAs were dominant in water while the concentrations of TETs were the highest in sediments in two seasons. For their spatial distribution, total concentrations of 13 antibiotics in both matrices were significantly higher in the lower section of HR (p < 0.02, F > 5.15) due to wastewater release, agricultural activities and water transfer project. Obvious seasonal variations of sulfadiazine, sulfameter, trimethoprim and oxytetracycline in water were observed (p < 0.05, F > 4.62). Phase partition of antibiotics between water and sediments suggested a greater affinity of TETs and FQs to sediments. In addition, significantly positive relationships were found between SAs (sulfameter, sulfamethoxazole and trimethoprim) and sediment TOC (p < 0.05). Risk assessment indicated that the hazard quotients of antibiotics were higher in the sediment than those in the water. Moreover, antibiotic mixtures posed higher ecological risks to aquatic organisms. PMID- 29621707 TI - Identification of Cd-responsive RNA helicase genes and expression of a putative BnRH 24 mediated by miR158 in canola (Brassica napus). AB - RNA helicases play crucial roles in RNA splicing, transport, editing and degradation, protein translation initiation and siRNA-mediated gene silencing. However, knowledge about their functionality in rapeseed (Brassica napus) is rare. In the study, we identified and annotated 271 RNA helicase genes from B. napus using bioinformatics and high-throughput RNA-sequencing (RNA-seq). Three subfamilies DEAD-box, DEAH-box, or DExD/H-box have been identified. One hundred and ninety-five RNA helicases were confirmed by RNA-seq and 49 were identified to differentially respond to cadmium (Cd) stress (> 1.5 fold change, p < 0.05). As an example, we functionally specified BnaA04g26450D encoding a BnRH24 under Cd exposure. BnRH24 is a constitutive gene expressing throughout the life span. Using our previously generated degradome datasets, we found that BnRH24 can be cleaved by miR158, suggesting that BnRH24 is a target of miR158 in B. napus. The mature miR158 was induced, while BnRH24 was repressed in B. napus under Cd stress. The contrasting expression pattern of B. napus miR158 and BnRH24 under the normal and Cd would support the post-transcriptional regulation of BnRH24 by miR158. Ectopic expression of BnRH24 in Arabidopsis revealed that the transgenic lines showed more sensitivity to Cd toxicity by reducing root elongation, fresh mass production, chlorophyll accumulation and increasing oxidative products such as O2-., H2O2 and thiobarbituric acid reactive substances (TBARS), indicating that the controlling the level of BnRH24 by miR158 may be required for Cd tolerance in plants. PMID- 29621708 TI - Abundances and profiles of antibiotic resistance genes as well as co-occurrences with human bacterial pathogens in ship ballast tank sediments from a shipyard in Jiangsu Province, China. AB - Ship ballasting operations may transfer harmful aquatic organisms across global ocean. This study aims to reveal the occurrences and abundances of antibiotic resistance genes (ARGs) and human bacterial pathogens (HBPs) in ballast tank sediments. Nine samples were collected and respectively analyzed by real-time quantitative PCR and high-throughput sequencing technologies. Ten ARGs (aadA1, blaCTX-M, blaTEM, ermB, mefA, strB, sul1, sul2, tetM, and tetQ) and the Class-I integron gene (intI1) were highly prevalent (105-109 gene copies/g) in ballast tank sediments. The sul1 was the most abundant ARG with the concentration of 108 109 copies/g and intI1 was much more abundant than the ARGs in ballast tank sediments. The strong positive correlations between intI1 and ARGs (blaCTX-M, sul1, sul2 and tetM) indicated the potential spread of ARGs via horizontal gene transfer. In ballast tank sediments, 44 bacterial species were identified as HBPs and accounted for 0.13-21.46% of the total bacterial population although the three indicator pathogenic microbes (Vibrio cholerae, Escherichia coli, and Enterococci) proposed by the International Maritime Organization were not detected. Pseudomonas pseudoalcaligenes, Enterococcus hirae, Shigella sonnei and Bacillus anthracis were the dominant pathogens in ballast tank sediments. Zn and P in sediments had positive effects on the ARGs. Network analysis results indicated that sul1 and sul2 genes existed in several bacterial pathogens. Ballast tank sediments could be regarded as a carrier for the migration of ARGs. It is important to manage ballast tank sediments reasonably in order to prevent the dissemination of ARGs and bacterial pathogens. PMID- 29621709 TI - Detection of arsenic-binding siderophores in arsenic-tolerating Actinobacteria by a modified CAS assay. AB - The metalloid arsenic is highly toxic to all forms of life, and in many countries decontamination of water and soil is still required. Some bacteria have mechanisms to detoxify arsenic and can live in its presence. Actinobacteria are well known for their ability to produce a myriad of biologically-active compounds. In the present study, we isolated arsenic-tolerant Actinobacteria from contaminated water in Saxony, Germany, and determined their ability to produce siderophores able to bind arsenic. The binding capacity of different siderophore like compounds was determined by a modified chrome azurol S (As-mCAS) assay with As(III) at high pH and using CAS decolorization as a readout. Arsenic-tolerant isolates from three actinobacterial genera were identified by 16 S rRNA gene sequence analysis: Rhodococcus, Arthrobacter and Kocuria. The isolated Actinobacteria showed a high As(III)-binding activity by siderophore-like compounds, resulting in 82-100% CAS decolorization, as compared to the results with EDTA. The interaction between As(III) and siderophore-like compounds was also detected at neutral pH. In summary, our results suggest that the isolated arsenic-tolerant Actinobacteria produce siderophores that bind arsenic, and open new perspectives on potential candidates for decontaminating environments with arsenic and for other biotechnological applications. PMID- 29621710 TI - Major and trace elements in Boletus aereus and Clitopilus prunulus growing on volcanic and sedimentary soils of Sicily (Italy). AB - The aim of this study was to determine and compare the content of 28 elements (Ag, Al, As, Ba, Be, Bi, Ca, Cd, Co, Cr, Cu, Fe, K, Li, Mg, Mn, Mo, Na, Ni, Pb, Rb, Sb, Se, Sr, Tl, U, V and Zn) in fruiting bodies of Boletus aereus Bull. and Clitopilus prunulus P. Kumm collected from eleven unpolluted sites of Sicily (Italy) and, also to relate the abundance of chemical elements in soil with their concentration in mushrooms. Median concentrations of the most abundant elements in Boletus aereus ranged from 31,290 MUg/g (K) to 107 MUg/g (Zn) in caps and from 24,009 MUg/g (K) to 57 MUg/g (Zn) in stalks with the following abundance order: K > Na > Ca > Mg > Fe > Al > Rb > Zn. The same elements, in the whole fruiting body of Clitopilus prunulus samples, varied in the range 54,073-92 MUg/g following the abundance order: K > Na > Mg > Ca > Fe > Al > Rb > Zn. Metal contents in Boletus aereus and in the whole fruiting body of Clitopilus prunulus, collected from the same sampling sites, showed statistically significant differences for most elements. In particular, Clitopilus prunulus contained around two to four times more Co, Cr, Fe, Mg, Mo, Pb, U and V than caps and stalks of Boletus aereus species which, in turn, was from two to four times more enriched in Cu, Se and Tl. Thus, the elemental content of Boletus aereus and Clitopilus prunulus appeared to be species-dependent. The distribution of chemical elements in Boletus aereus was not uniform throughout the whole fruiting body as most elements were significantly bioconcentrated in caps. Furthermore, the fruit bodies of Boletus aereus from the volcanic soil differed both in major and minor elements concentrations from those collected from sedimentary soils. Cadmium and lead concentrations were below the threshold limits for wild mushrooms proposed by EU Directives (2008 and 2015). The elemental content was not significantly influenced by soil pH. PMID- 29621711 TI - Combined effects of four pesticides and heavy metal chromium (VI) on the earthworm using avoidance behavior as an endpoint. AB - In natural ecosystems, organisms are commonly exposed to chemical mixtures rather than individual compounds. However, environmental risk is traditionally assessed based on data of individual compounds. In the present study, we aimed to investigate the individual and combined effects of four pesticides [fenobucarb (FEN), chlorpyrifos (CPF), clothianidin (CLO), acetochlor (ACE)] and one heavy metal chromium [Cr(VI)] on the earthworm (Eisenia fetida) using avoidance behavior as an endpoint. Our results indicated that CLO had the highest toxicity to E. fetida, followed by Cr(VI), while FEN showed the least toxicity. Two mixtures of CPF+CLO and Cr(VI)+CPF+CLO+ACE exhibited synergistic effects on the earthworms. The other two quaternary mixtures of CLO+FEN+ACE+Cr(VI) and Cr(VI)+FEN+CPF+ACE at low concentrations also displayed synergistic effects on the earthworms. In contrast, the mixture of Cr(VI)+FEN had the strongest antagonistic effects on E. fetida. Besides, the quinquenary mixture of Cr(VI)+FEN+CPF+CLO+ACE also exerted antagonistic effects. These findings highlighted the importance to evaluate chemical mixtures. Moreover, our data strongly pointed out that the avoidance tests could be used to assess the effects of combined effects. PMID- 29621712 TI - Degradation and metabolite formation of 17beta-estradiol-3-glucuronide and 17beta estradiol-3-sulphate in river water and sediment. AB - Laboratory degradation tests with two model estrogen conjugates, 17beta-estradiol 3-glucuronide (E2-3G) and 17beta-estradiol-3-sulphate (E2-3S), using river water and sediment as inoculum under aerobic conditions were investigated. Throughout the 14-day incubation, degradation of E2-3G in river water, at environmentally relevant level (25 ng/L), obeyed first-order kinetics with the formation of 17 beta estradiol and estrone; in contrast, E2-3S was slowly converted to estrone-3 sulphate stoichiometrically. Degradation of the two conjugates across the spiking concentrations (0.01-1 MUg/g) was much faster in sediment than in river water where 25 ng/L of conjugate standards were spiked, possibly due to relatively high population densities of microorganisms in sediment. De-conjugation of the thio ester bond at C-3 position and oxidation at C-17 position were the predominant degradation mechanisms for E2-3G and E2-3S, respectively, with negligible presence of metabolites estrone-3-glucuronide for E2-3G and 17beta-estradiol for E2-3S. In addition, delta-9(11)-dehydroestrone and 6-ketoestrone were determined as new metabolites of the two conjugates. Also, a lactone compound, hydroxylated estrone and a few sulfate conjugates were tentatively identified. With the observation of new metabolites, biodegradation pathways of E2-3G and E2-3S were proposed. The formation of new metabolites may pose unknown risks to aquatic biota. PMID- 29621713 TI - Analysis of endocrine activity in drinking water, surface water and treated wastewater from six countries. AB - The aquatic environment can contain numerous micropollutants and there are concerns about endocrine activity in environmental waters and the potential impacts on human and ecosystem health. In this study a complementary chemical analysis and in vitro bioassay approach was applied to evaluate endocrine activity in treated wastewater, surface water and drinking water samples from six countries (Germany, Australia, France, South Africa, the Netherlands and Spain). The bioassay test battery included assays indicative of seven endocrine pathways, while 58 different chemicals, including pesticides, pharmaceuticals and industrial compounds, were analysed by targeted chemical analysis. Endocrine activity was below the limit of quantification for most water samples, with only two of six treated wastewater samples and two of six surface water samples exhibiting estrogenic, glucocorticoid, progestagenic and/or anti mineralocorticoid activity above the limit of quantification. Based on available effect-based trigger values (EBT) for estrogenic and glucocorticoid activity, some of the wastewater and surface water samples were found to exceed the EBT, suggesting these environmental waters may pose a potential risk to ecosystem health. In contrast, the lack of bioassay activity and low detected chemical concentrations in the drinking water samples do not suggest a risk to human endocrine health, with all samples below the relevant EBTs. PMID- 29621714 TI - Removal of pharmaceuticals in urban wastewater: High rate algae pond (HRAP) based technologies as an alternative to activated sludge based processes. AB - Microalgae biotechnology is a promising tool for many applications, including the elimination of nutrients and other contaminants from wastewater. In this work, we measured the removal efficiency of two wastewater treatment processes: an activated-sludge based conventional process and another based on microalgae biotechnology using high-rate algae ponds (HRAPs). The latter was tested using two different configurations. In the first one, HRAPs were placed after an UASB reactor and used as a tertiary treatment to remove nutrients. In the second, the UASB reactor was disconnected so the HRAPs were directly fed with pretreated wastewater. Additional treatment was performed using dissolved air flotation (DAF). The performances of both configurations (UASB-HRAP and HRAP-DAF) were compared to that of the conventional line including primary and secondary biological treatments and operating in parallel within the same wastewater treatment plant (WWTP). Sixty-four out of 81 target PhACs were detected in the influent of the WWTP, at an average concentration of 223 MUg L-1, whereas 55 and 54 were measured in the conventional (14 MUg L-1) and non-conventional (17 MUg L 1) effluents. Average removal efficiencies were similar (94 vs. 92%) for both treatment lines when comparing total PhACs concentrations. The compositional patterns of the resulting effluents, however, were not, suggesting the occurrence of differential removal mechanisms depending on the chemicals and wastewater treatments considered. Highly consumed compounds such as ibuprofen and acetaminophen were predominant in the non-conventional effluent (>1 MUg L-1), denoting lower removal than in the conventional line. On the other hand, elimination of diclofenac and some specific antibiotics and diuretics (e.g., hydrochlorothiazide) was between 15 and 50% higher using HRAPs. Overall, the efficiency of the microalgae technology removing PhACs was found to be comparable to that used in conventional WWTPs. This, combined with a higher efficiency removing nutrients, shows the potential of HRAP technology for wastewater treatment as an alternative (or addition as tertiary treatment) to more conventional approaches based on activated sludge. PMID- 29621715 TI - Comparison of phosphodiesterase type V inhibitors use in eight European cities through analysis of urban wastewater. AB - In this work a step forward in investigating the use of prescription drugs, namely erectile dysfunction products, at European level was taken by applying the wastewater-based epidemiology approach. 24-h composite samples of untreated wastewater were collected at the entrance of eight wastewater treatment plants serving the catchment within the cities of Bristol, Brussels, Castellon, Copenhagen, Milan, Oslo, Utrecht and Zurich. A validated analytical procedure with direct injection of filtered aliquots by liquid chromatography-tandem mass spectrometry was applied. The target list included the three active pharmaceutical ingredients (sildenafil, tadalafil and vardenafil) together with (bio)transformation products and other analogues. Only sildenafil and its two human urinary metabolites desmethyl- and desethylsildenafil were detected in the samples with concentrations reaching 60 ng L-1. The concentrations were transformed into normalized measured loads and the estimated actual consumption of sildenafil was back-calculated from these loads. In addition, national prescription data from five countries was gathered in the form of the number of prescribed daily doses and transformed into predicted loads for comparison. This comparison resulted in the evidence of a different spatial trend across Europe. In Utrecht and Brussels, prescription data could only partly explain the total amount found in wastewater; whereas in Bristol, the comparison was in agreement; and in Milan and Oslo a lower amount was found in wastewater than expected from the prescription data. This study illustrates the potential of wastewater-based epidemiology to investigate the use of counterfeit medication and rogue online pharmacy sales. PMID- 29621716 TI - Assessment of dermal exposure to halogenated flame retardants: Comparison using direct measurements from hand wipes with an indirect estimation from settled dust concentrations. AB - There are few studies estimating dermal exposure to halogenated flame retardants in adults. To fill this gap, sixty-one hand wipe samples were collected from a Norwegian adult cohort using gauze pads immersed in isopropanol. BDE-47, BDE-209, bis(2-ethyl-hexyl)-3,4,5,6-tetrabromophthalate (BEH-TEBP) and decabromodiphenylethane (DBDPE) were the most frequently detected chemicals. The highest median mass in hand wipes was that of sumEHFR (570 ng), followed by sumHBCDD (180 ng) and sumPBDE (2.9 ng). The high EHFR level was mainly driven by tetrabromobisphenol A (TBBPA) which accounted for 77% of the total mass. Positive and significant correlations were observed between FR levels in hand wipes and settled dust (0.26 < r < 0.56, p < 0.05), as well as between FR levels in hand wipes and the number of electronic consumer products at home (0.27 < r < 0.40, p < 0.05). Significant bivariate associations with number of laptops/tablets and phones/mobiles were further confirmed by multivariate linear regression analyses. Dermal exposure was estimated using the levels measured in handwipes. The estimated median dermal exposure was 2600, 840 and 6.2 pg/kg bw/d for sumEHFR, sumHBCDD and sumPBDE, respectively. Further, we compared these results with the dermal exposure as estimated indirectly by utilizing previously reported FR levels in settled dust collected from the residences of the same studied cohort. With the indirect approach, higher dermal exposures to sumPBDE but lower exposures to sumEHFR and sumHBCDD were observed compared to the direct dermal exposure estimated via hand wipes. Comparable exposure estimates between hand wipes and the indirect method were obtained for alpha-, beta tetrabromoethylcyclohexane (DBE-DBCH), DBDPE, BDE-28, -35, -49, -99, -153, 154, and -183. For other individual HFRs, the exposure estimates obtained from the two approaches were significantly different (Mann-Whitney U test, p < 0.05). Both methods gave similar dermal exposure estimates for many individual FRs. However, it is important to be aware of the value and limitations of each method when using them to estimate human exposure. PMID- 29621717 TI - Circulating levels of perfluoroalkyl substances and left ventricular geometry of the heart in the elderly. AB - AIMS: Some persistent organic pollutants (POPs) such as hexachlorobenzene (HCB) and some polychlorinated biphenyls (PCBs) have been shown to interfere with myocardial function and geometry. We therefore investigated if also another group of POPs: per- and polyfluoroalkyl substances (PFASs) were associated with alterations in left ventricular geometry. METHODS: 801 subjects aged 70 years were investigated in a cross-sectional study within the scope of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Eight PFASs were detected in >75% of participants' plasma by ultra-performance liquid chromatograph/tandem mass spectrometry. Left ventricular geometry was determined by echocardiography. Multivariable linear regression was used to investigate the associations between PFASs and left ventricular geometry of the heart after exclusion of subjects with previous myocardial infarction (n = 72). RESULTS: When adjusting for multiple comparisons, none of the eight PFASs evaluated were significantly related to left ventricular mass. However, perfluorononanoic acid (PFNA), perfluorodecanoic acid (PFDA), and perfluoroundecanoic acid (PFUnDA) were related to relative wall thickness (RWT) in a negative fashion (p < 0.0021). Besides being inversely related to RWT, PFNA was also positively related to left ventricular end-diastolic volume (LVEDD) (p < 0.0021). These analyses were adjusted for traditional cardiovascular risk factors. CONCLUSION: In this cross sectional study, several of the PFASs evaluated, especially PFNA, were related to myocardial geometry: a reduction in relative wall thickness and an increase in left ventricular diameter following adjustment for traditional cardiovascular risk factors, suggesting a role for PFASs in cardiac remodeling. PMID- 29621718 TI - A cell viability assessment method based on area-normalized impedance spectrum (ANIS). AB - Impedance measurement of cells using electric cell-substrate impedance sensing (ECIS) is widely accepted as an effective method to assess cell status. However, the sensitive frequency drifts over time with the changes of culture condition according to the built circuit model and experimental results. The area normalized impedance spectrum (ANIS) method, which uses normalized area of impedance spectrum in a certain interval to assess cell viability, was proposed in this paper to solve the problem. The certain interval is calculated due to the threshold Zth, which is determined by 2% decline of the maximum impedance. Stabilities of two methods were analyzed by normalizing the area and impedance, showing that the normalized impedance fluctuated like a wave, while the normalized area was smoother. In addition, Cell Count Kit-8 (CCK-8) assay was carried out proving that the correlation index of ANIS method increases by 2.4% compared with impedance sensing method, and the maximum error of ANIS method decreases by 4%. Comparison analysis of two methods with random measurement noise was also discussed in this paper, and the results showed that the ANIS method was less affected by measurement noise than impedance sensing method. It demonstrated that the ANIS method is a more stable and accurate method to assess cell viability. PMID- 29621719 TI - Effect of combined waterlogging and salinity stresses on euhalophyte Suaeda glauca. AB - Salinity and waterlogging are abiotic stresses that have a significant impact on agricultural production and ecosystem conservation. The response of euhalophyte Suaeda glauca to waterlogging and salinity stresses was investigated. The results revealed that waterlogging markedly decreased seedling emergence. Compared to drained conditions, waterlogging inhibited the shoot dry weight, net photosynthetic rate, stomatal conductance, maximal efficiency of PSII photochemistry and chlorophyll content at salinity. Salinity decreased these values in both waterlogged and drained conditions, while the opposite trend was found in intercellular CO2 concentrations. Waterlogging increased Na+, Cl-, O2-, H2O2 and MDA content in the leaves compared with those in drained conditions, but this was not the case for K+ content and SOD and APX activity. Salinity increased these values except that salinity decreased K+ content in both waterlogged and drained conditions. In conclusion, S. glauca is not tolerant to combined waterlogging and salinity stresses during both seedling emergence and seedling growth stages, and this trait may limit the distribution of the species in lowland saline areas. PMID- 29621720 TI - Elevated nitrogen metabolism and nitric oxide production are involved in Arabidopsis resistance to acid rain. AB - Acid rain (AR) can induce great damages to plants and could be classified into different types according to the different SO42-/NO3- ratio. However, the mechanism of plants' responding to different types of AR has not been elucidated clearly. Here, we found that nitric-rich simulated AR (N-SiAR) induced less leaves injury as lower necrosis percentage, better physiological parameters and reduced oxidative damage in the leaves of N-SiAR treated Arabidopsis thaliana compared with sulfate and nitrate mixed (SN-SiAR) or sulfuric-rich (S-SiAR) simulated AR treated ones. Of these three types of SiAR, N-SiAR treated Arabidopsis maintained the highest of nitrogen (N) content, nitrate reductase (NR) and nitrite reductase (NiR) activity as well as N metabolism related genes expression level. Nitric oxide (NO) content showed that N-SiAR treated seedlings had a higher NO level compared to SN-SiAR or S-SiAR treated ones. A series of NO production and elimination related reagents and three NO production-related mutants were used to further confirm the role of NO in regulating acid rain resistance in N-SiAR treated Arabidopsis seedlings. Taken together, we concluded that an elevated N metabolism and enhanced NO production are involved in the tolerance to different types of AR in Arabidopsis. PMID- 29621722 TI - PTSD and depressive symptoms are linked to DHEAS via personality. AB - BACKGROUND: Research results on dehydroepiandrosterone sulfate ester (DHEAS) in post-traumatic stress disorder (PTSD) are inconsistent. We hypothesized that personality traits could be the confounders of DHEAS levels and disease symptoms, which could in part explain the discrepancy in findings. METHOD: This study was a part of a broader project in which simultaneous psychological and biological investigations were carried out in hospital conditions. 380 male subjects were categorized in four groups: A) current PTSD (n = 132), B) lifetime PTSD (n = 66), C) trauma controls (n = 101), and D) healthy controls (n = 81), matched by age. RESULTS: The level of DHEAS is significantly lower in the current PTSD group than in trauma controls. All groups significantly differ in personality traits Disintegration and Neuroticism (current PTSD group having the highest scores). DHEAS is related to both PTSD and depressive symptoms; however, Structural Equation Model (SEM) shows that the relations are indirect, realized via their confounder - personality trait Disintegration. CONCLUSIONS: According to our project results, DHEAS is the second putative biomarker for trauma-related disorders that fails to fulfil this expectation. It appears to be more directly related to personality than to the disease symptoms (the first one being basal cortisol). Our data promote personality as a biologically based construct with seemingly important role in understanding the mental health status. PMID- 29621721 TI - Interventions and controls to prevent emergency service vehicle incidents: A mixed methods review. AB - BACKGROUND: Emergency service vehicle incidents (ESVI), including crashes, rollovers, and roadside struck-by-incidents, are a leading cause of occupational fatality and injury among firefighters and other emergency responders. Though there are numerous strategies and interventions to prevent ESVIs, the evidence base for these strategies is limited and dispersed. The goal of this study was to gather and present a review of evidence-based ESVI interventions. METHODS: We searched five academic databases for articles published within the last decade featuring interventions to reduce or prevent ESVIs. We interviewed key informants from fire departments serving major metropolitan areas for additional interventions. Interventions from both sources were summarized and data on intervention effectiveness were reported when available. RESULTS: Sixty-five articles were included in the final review and 17 key informant interviews were completed. Most articles focused on vehicle engineering interventions (38%), followed by policy and administration interventions (26%), environmental engineering interventions (19%) and education or training (17%). Most key informants reported policy (49%) and training interventions (29%). Enhanced drivers' training and risk management programs were associated with 19-50% and 19 58% reductions in ESVIs, respectively. CONCLUSIONS: Only a limited number of interventions to address ESVIs had adequate outcome data. Based on the available data, training and risk management approaches may be particularly effective approaches to reducing ESVIs. PMID- 29621724 TI - Development of hypertension after long-term exposure to static magnetic fields among workers from a magnetic resonance imaging device manufacturing facility. AB - OBJECTIVE: To assess the association between long-term exposure to static magnetic fields (SMF) in a magnetic resonance imaging (MRI)-manufacturing environment and hypertension. METHODS: In an occupational cohort of male workers (n = 538) of an MRI-manufacturing facility, the first and last available blood pressure measurements from the facility's medical surveillance scheme were associated with modeled cumulative exposure to SMF. Exposure modeling was based on linkage of individual job histories from the facility's personnel records with a facility specific historical job exposure matrix. Hypertension was defined as a systolic pressure of above 140 mm Hg and/or a diastolic blood pressure above 90 mm Hg. Logistic regression models were used to associate cumulative SMF exposure to hypertension while adjusting for age, body mass index and blood pressure at time of first blood pressure measurement. Stratified analysis by exposure duration was performed similarly. RESULTS: High cumulative exposure to SMF (>= 7.4 K Tesla minutes) was positively associated with development of hypertension (Odds Ratio [OR] 2.32, 95% confidence interval [CI] 1.27 - 4.25, P = 0.006). Stratified analysis showed a stronger association for those with high cumulative SMF exposure within a period up to 10 years (OR 3.96, 95% CI 1.62 - 9.69, P = 0.003), but no significant association was found for (high) cumulative exposure accumulated in a period of 10 or more years. Our findings suggest SMF exposure intensity to be more important than exposure duration for the risk of developing hypertension. CONCLUSIONS: Our data revealed that exposure to high levels of MRI related SMF during MRI-manufacturing might be associated with developing hypertension. PMID- 29621723 TI - Persistent organic pollutants as predictors of increased FSH:LH ratio in naturally cycling, reproductive age women. AB - Although several recent studies suggest endocrine disrupting compounds, such as polychlorinated biphenyls (PCBs), dichlorodiphenyldichloroethylene (p,p', DDE), and hexachlorobenzene (HCB), target different organs and systems in the body, their impact on female reproductive function in humans is not well characterized. We seek to determine the relationship between several known endocrine disrupting compounds and a marker of ovarian responsivity, the FSH:LH ratio (higher ratio indicates less ovarian responsivity). For this analysis, 169 naturally cycling women between 21 and 38 years of age completed interviews and had their blood drawn on day 3 of their menstrual cycle for analyses of toxicants, gonadal sex hormones (E2 and P4), and gonadotropins (FSH and LH). PCB congeners were classified into five groups based on their environmental persistence, distribution in human tissue, and toxicological action, reflecting the structure, mechanism, and known biological activity of individual PCB congeners. For every unit (ppb) increase in the level of the estrogenic PCB group, there was a 5-fold greater risk of a FSH:LH ratio >= 2, controlling for individual differences in age, percent body fat, cycle day 3 estradiol levels, parity, alcohol use and cigarette smoking in the past year (exp[beta] = 5; p = <=0.01). PCB congeners identified as estrogenic were analyzed individually, and, of the 19 potentially estrogenic congeners, five were significantly, and positively related to an increased FSH:LH ratio. Four of these congeners are non-persistent, easily volatilize in the environment, and are easily metabolized, and hence, are indicative of very recent or current exposure. p,p'-DDE and HCB were not associated with FSH:LH ratio. We find a clinical indicator of ovarian responsivity, FSH:LH ratio, is associated with a specific group of estrogenic PCBs. These congeners may become airborne when they volatilize from dredged PCB contaminated soil or from indoor PCB-containing window caulk and sealants in older buildings leading to inhalation exposure. PCB exposure, particularly to non persistent, estrogenic congeners, may pose an unrecognized threat to female fecundity within the general population. PMID- 29621725 TI - Multi-analytical strategy for unassigned peaks using physical/mathematical separation, fragmental rules and retention index prediction: An example of sesquiterpene metabolites characterization in Cyperus rotundus. AB - Comprehensive two-dimensional gas chromatography- mass spectrometry (GC * GC-qMS) can provide powerful physical separation, signal enhancement, and spectral identification for analytes in complex samples. Unassigned peaks are commonly presented in the untargeted profile after a single run with EI-MS spectral matching and retention index (RI) confirmation. The procedure proposed in this work can be applied as a general method for suggesting or narrowing down the candidates of unassigned GC * GC-qMS peaks. To begin, peak purity detection and chemometric resolution are employed to acquire pure mass spectra. In addition, the fragmental rules and in-silico spectra from structures are available for annotating certain unassigned peaks with reference spectra that are not observed in commercial databases. Furthermore, the procedure proposed in this work allows for in silico RI calculation by means of random forest (RF) analysis based on the retention data under the same chromatographic conditions. The calculated RIs can aid in analysis when the RI information of peaks of interest is not available in retention data libraries. Using the proposed strategy, certain unassigned peaks can be attributed to sesquiterpene metabolites in an in-house database for Cyperus rotundus. PMID- 29621726 TI - Effects of ozone (O3) and ethylenediurea (EDU) on the ecological stoichiometry of a willow grown in a free-air exposure system. AB - Ground-level ozone (O3) concentrations have been elevating in the last century. While there has been a notable progress in understanding O3 effects on vegetation, O3 effects on ecological stoichiometry remain unclear, especially early in the oxidative stress. Ethyelenediurea (EDU) is a chemical compound widely applied in research projects as protectant of plants against O3 injury, however its mode of action remains unclear. To investigate O3 and EDU effects early in the stress, we sprayed willow (Salix sachalinensis) plants with 0, 200 or 400 mg EDU L-1, and exposed them to either low ambient O3 (AOZ) or elevated O3 (EOZ) levels during the daytime, for about one month, in a free air O3 controlled exposure (FACE); EDU treatment was repeated every nine days. We collected samples for analyses from basal, top, and shed leaves, before leaves develop visible O3 symptoms. We found that O3 altered the ecological stoichiometry, including impacts in nutrient resorption efficiency, early in the stress. The relation between P content and Fe content seemed to have a critical role in maintaining homeostasis in an effort to prevent O3-induced damage. Photosynthetic pigments and P content appeared to play an important role in EDU mode of action. This study provides novel insights on the stress biology which are of ecological and toxicological importance. PMID- 29621727 TI - Importance of accurate trophic level determination by nitrogen isotope of amino acids for trophic magnification studies: A review. AB - During the last several decades, persistent organic pollutants and metals cause great concern for their toxicity in organisms as well as for their bioaccumulation and/or trophic transfer through the food chains in ecosystems. A large number of studies therefore have focused on the trophic levels of organisms to illustrate food web structure, as a critical component in the study of pollutant dynamics and biomagnification. The trends in biomagnification of pollutants in food webs indeed provide fundamental information about the properties and fates of pollutants in ecosystems. The trophic magnification supports the establishment of a reliable trophic structure, which can further aid the understanding of the transport and exposure routes of contaminants in accumulation and risk assessments. Recently, efforts to interpret the food web structure using carbon and nitrogen stable isotope ratios have contributed to better understanding of the fate of pollutants in the ecosystem. However, it is known that this isotope analysis of bulk ones has many weaknesses, particularly for uncertainties on the estimate of trophic levels and therefore of magnification factors for studied organisms, enough to support a regulatory interpretation. In this review, we collate studies that investigated biomagnification characteristics of pollutants in aquatic ecosystems, along with calculated trophic magnification factors. Moreover, we introduce a novel approach, compound-specific stable isotope analysis of nitrogen in amino acids, to establish reliable food web structures and accurate trophic levels for biomagnification studies. This method promises to provide sound results for interpreting the influence of the pollutant in organisms, along with their bioaccumulation and magnification characteristics, as well as that in ecosystem. PMID- 29621728 TI - Modeling of residential indoor PM2.5 exposure in 37 counties in China. AB - It is critical to estimate the exposure to indoor air pollution of residents spending most of their time in such microenvironments. However, the understanding regarding PM2.5 exposure in residential indoor environments is very limited. In this study, we collected participants' basic information and time-activity patterns, as well as details of other factors related to indoor air pollution exposure, through questionnaires presented to a large population in 37 counties of China. Continuous monitoring of ambient PM2.5 concentrations was performed using an environmental fixed-site monitoring network. Residential indoor PM2.5 concentrations were predicted using a mass balance model based on the data obtained. Evaluation of continuous daily average residential indoor PM2.5 exposure doses for large populations during winter revealed concentrations ranged from 67 to 195 MUg/m3. Finally, differences in residential indoor PM2.5 exposure between northern and southern China were investigated. The results suggested that residential indoor PM2.5 concentrations in northern China, associated with heating, were higher than in the south. The established model could be important for improved understanding of human exposure to indoor PM2.5 air pollution. PMID- 29621729 TI - Maternal dietary intake of polyunsaturated fatty acids modifies association between prenatal DDT exposure and child neurodevelopment: A cohort study. AB - BACKGROUND: Maternal 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) serum levels during pregnancy have been negatively linked to child neurodevelopment in contrast to intake of omega-3 and -6 (omega-3 and omega-6) fatty acids. OBJECTIVES: To assess whether maternal dietary intake of omega-3 and omega-6 during pregnancy modifies the association between exposure to DDE and child neurodevelopment from age 42-60 months. METHODS: Prospective cohort study with 142 mother-child pairs performed in Mexico. DDE serum levels were determined by electron capture gas chromatography. Dietary omega-3 and omega-6 intake was estimated by questionnaire. Child neurodevelopment was assessed by McCarthy Scales. RESULTS: Docosahexaenoic (DHA) fatty acid intake significantly modified the association between DDE and motor component: increased maternal DDE was associated with lower motor development in children whose mothers had lower DHA intake (betalog2DDE = -1.25; 95% CI: -2.62, 0.12), in contrast to the non significant increase among children whose mothers had higher DHA intake (betalog2DDE-motor = 0.50; 95% CI: 0.55, 1.56). Likewise, arachidonic fatty acid (ARA) intake modified the association between DDE and memory component: increased maternal DDE was associated with a significantly larger reduction in the memory component in children whose mothers had lower ARA intake (betalog2DDE = -1.31; 95% CI: -2.29, -0.32) than children whose mothers had higher ARA intake (betalog2DDE-memory = 0.17; 95% CI: -0.78, 1.11). CONCLUSIONS: Dietary intake of DHA and ARA during pregnancy may protect against child neurodevelopment damage associated with prenatal maternal DDE levels. PMID- 29621730 TI - Field biomonitoring using the zebra mussel Dreissena polymorpha and the quagga mussel Dreissena bugensis following immunotoxic reponses. Is there a need to separate the two species? AB - The zebra mussel, Dreissena polymorpha constitutes an extensively used sentinel species for biomonitoring in European and North American freshwater systems. However, this invasive species is gradually replaced in freshwater ecosystem by Dreissena bugensis, a closely related dreissenid species that shares common morphological characteristics but possess some physiological differences. However, few are known about differences on more integrated physiological processes that are generally used as biomarkers in biological monitoring studies. Declining of zebra mussel populations raises the question of the sustainability of using one or both species indifferently to maintain the quality of environmental pollution monitoring data. In our study, we performed a field comparative study measuring immune-related markers and bioaccumulation of PCBs, PAHs and PBDEs in sympatrically occurring mussel populations from three sites of the St. Lawrence River. For tested organisms, species were identified using RFLP analysis. Measurement of bioaccumulated organic compounds indicated a higher accumulation of PCBs and PBDEs in D. bugensis soft tissues compared to D. polymorpha while no differences were noticed for PAHs. Results of hemocytic parameters highlighted that differences of hemocyte distributions were associated to modulations of phagocytic activities. Moreover, marked differences occurred in measurement of hemocytic oxidative activity, indicating divergences between the two species for ROS regulation strategies. This physiological characteristic may deeply influence species responses facing environmental or pollution related stress and induce bias if the two species are not differentiated in further biomarker or bioaccumulation measurement-based studies. PMID- 29621731 TI - Relationship between maternal exposure to bisphenol S and pregnancy duration. AB - Bisphenol S (BPS) has been progressively used due to the potential safety problems of bisphenol A (BPA). Thus Human studies are needed to investigate the developmental effects of BPS. In this study, the impact of maternal BPS exposure on birth outcomes was evaluated with linear and logistic regression models. BPS was analyzed in spot urine samples collected from 985 pregnant women at admission to labor. It was found in 93.7% of the urine samples with the specific gravity adjusted geometric mean concentration of 0.17 MUg/L. One ln-unit increase in urinary BPS was associated with a 0.72-day increase in pregnancy duration (95% CI: 0.34, 1.09). When stratified by fetal sex, each ln-unit increase in maternal urinary BPS was significantly correlated with increased gestational age [adjusted beta = 1.02, 95% confidence intervals (CI): 0.47, 1.57] and increased odds of late term birth [adjusted odds ratio = 1.29, 95% CI: 1.00, 1.67] for girls, but not significantly for boys. Including maternal urinary BPA and BPS in one model did not change the results. Associations of BPS with birth weight or length were not observed. This is the first report about BPS exposure for pregnant women from China. Higher maternal urinary BPS concentrations were associated with increased gestational age, suggesting maternal BPS exposure may interfere with pregnancy duration. The findings require replication but reveal the probable risks posed by the developmental BPS exposure. PMID- 29621732 TI - C5a receptor1 inhibition alleviates influenza virus-induced acute lung injury. AB - Influenza A virus is an important human pathogen that causes 3 to 5 million severe cases of influenza worldwide each year. An aberrant innate immune response, particularly hypercytokinemia, is thought to play an important role in the disease, although the pathogenesis of severe influenza virus infection remains unclear and no specific and efficacious immunotherapy is available. This study reports dysregulated complement activation in mice after infection with A/Puerto Rico/8/34 (PR8). C5aR1-deficient mice and mice treated with an anti C5aR1 antibody were used as models to study the C5a-C5aR1 axis during acute lung injury (ALI) induced by influenza virus infection. The results showed that blocking the C5a-C5aR1 axis alleviated ALI by inhibiting endothelial cell activation and dampening the host immune response (i.e., reduced TNF-alpha, IL 1beta, IL-6, IP-10, MCP-1, IL-12p70, and IFN-gamma concentrations in plasma), particularly CTL-mediated immunopathology. Furthermore, blockade of the C5a-C5aR1 axis inhibited viral replication in lung tissue. Taken together, the results indicate that the C5a-C5aR1 axis plays an important role in the outcome of ALI induced by influenza virus infection and that regulation of complement activation, particularly the C5aR1 inhibition, is a promising intervention and adjunctive treatment. PMID- 29621733 TI - 20(R)-ginsenoside Rg3, a rare saponin from red ginseng, ameliorates acetaminophen induced hepatotoxicity by suppressing PI3K/AKT pathway-mediated inflammation and apoptosis. AB - Although ginsenoside Rg3 was isolated as a major component of Korea red ginseng and confirmed to exert potential hepatoprotective effect on acetaminophen (APAP) induced liver injury via induction of glutathione S-transferase (GST) in vitro, thein vivo hepatoprotective effect of Rg3 and the underlying molecular mechanism of action remain unclear. The current study was aimed to explore whether 20(R) Ginsenoside Rg3 (20(R)-Rg3) could alleviate acetaminophen-induced liver injury in mice and to determine the involvement of PI3K/AKT signaling pathway. Our findings demonstrated that a single injection of APAP (250 mg/kg) increased the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta); such increases were attenuated by pretreatment of mice with 20(R)-Rg3 for seven days. The depletion of glutathione (GSH), generation of malondialdehyde (MDA) and the over expression of cytochrome P450 E1 (CYP2E1) and 4-hydroxynonenal (4-HNE) caused by APAP exposure were also inhibited by 20(R)-Rg3 pretreatment. Moreover, 20(R)-Rg3 pretreatment significantly alleviated APAP-induced apoptosis, necrosis, and inflammatory infiltration in liver tissues. Importantly, 20(R)-Rg3 effectively attenuated APAP-induced liver injury in part via activating PI3K/AKT signaling pathway. In summary, 20(R)-Rg3 exerted liver protection against APAP-caused hepatotoxicity evidenced by inhibition of oxidative stress and inflammatory response, alleviation of hepatocellular necrosis and apoptosis via activation of PI3K/AKT signaling pathway, showing potential as a novel therapeutic agent to prevent liver damage. PMID- 29621734 TI - Protective effect of pristimerin against LPS-induced acute lung injury in mice. AB - Pristimerin (Pris) is a triterpenoid derivative obtained from Celastraceae and Hippocrateaceae families. This compound has been extensively tested for its potent anti-cancer activity against different types of tumors. However, its effects against acute lung injury (ALI) remain to be investigated. This study explored the efficacy of Pris to protect against lipopolysaccharide (LPS)-induced ALI and its possible pathways. Results have shown that Pris possesses potent protective activity against LPS-induced acute lung damage. It significantly decreased pulmonary edema as presented by significant decrease in lung W/D ratio and in protein content. Pris attenuated LPS-induced inflammatory cell infiltration into the lung tissue and suppressed the activity of myeloperoxidase in lung. LPS-induced histopathological lesions were significantly improved via Pris pretreatment. Pris exhibited not only inhibition of LPS-induced oxidative stress, but also enhancement of the suppressed antioxidant capacity of the lung tissue. The anti-inflammatory activity of Pris against LPS-induced ALI was clearly evident via attenuation of the levels of pro-inflammatory cytokines namely, tumor necrosis factor-alpha and interleukin-6. Similarly, Pris inhibited LPS-induced elevation of pro-apoptotic protein, Bax, and caspase-3. Pris also increased the diminished level of Bcl2 induced by LPS. Collectively, Pris exerted protective activity against LPS-induced ALI via anti-oxidant, anti-inflammatory and anti-apoptotic pathways. PMID- 29621735 TI - JMJD3 is involved in neutrophil membrane proteinase 3 overexpression during the hyperinflammatory response in early sepsis. AB - Excessive production of pro-inflammatory cytokines in early sepsis causes high early mortality rates. Membrane proteinase 3 (mPR3) expression on neutrophils plays a critical role in pro-inflammatory cytokine production. However, the mechanism underlying mPR3 overexpression in early sepsis is unknown. Here, we explored mPR3 expression in early sepsis and its regulatory mechanism. Thirty-two patients with sepsis and 20 healthy controls were prospectively enrolled. On day 1 after the onset of sepsis, mPR3 and jumonji domain-containing protein D3 (JMJD3) expression levels were measured in peripheral blood neutrophils. Lipopolysaccharide (LPS) was employed to induce JMJD3 expression in vitro, and GSK-J4 was used to inhibit JMJD3. Neutrophils were divided into four groups, control, LPS, LPS + GSK-J4, and GSK-J4, and cultured with THP-1 cells respectively. Plasma and culture supernatant cytokine levels were measured by enzyme-linked immunosorbent assays. Neutrophil mPR3 levels were significantly higher in patients with early sepsis than in healthy controls. Plasma cytokine (IL-1beta and TNF-alpha) levels were increased in patients with sepsis exhibiting high mPR3 expression. Additionally, JMJD3 expression levels in neutrophils were increased in early sepsis. In vitro, both mPR3 on neutrophils and IL-1beta in culture supernatants increased in response to LPS stimulation. Neutrophil mPR3 expression and IL-1beta levels were significantly reduced by GSK-J4 in cells treated with LPS. IL-1beta level was significantly higher in LPS-stimulated co culture supernatants than in the corresponding individual cultured cells. Thus, our results suggest that JMJD3 contributes to the high expression of neutrophil mPR3, which promotes the production of proinflammatory IL-1beta in early sepsis. PMID- 29621736 TI - Antiviral activity of porcine interferon delta 8 against foot-and-mouth disease virus in vitro. AB - Foot-and-mouth disease (FMD) is one of the most devastating diseases affecting livestock. Since vaccines fail to provide protection until seven days post vaccination, the application of anti-viral molecules is imperative for suppressing the spread of FMDV prior to development of an adaptive immune response. Interferons (IFNs) are effective for the host to fight FMDV infections; however, a novel type I IFNs, interferon delta (IFN-delta), has not been investigated for their antiviral effects against this virus. Thus, this study investigated FMDV infection, upon pre- and post-treatment with PoIFN-delta8. Real time quantitative PCR was used to quantify the expression levels of IFN stimulated genes (ISGs), including ISG15, OAS1, PKR, and Mx1. Results showed the PoIFN-delta8 lacking its signal sequence was efficiently expressed in Escherichia coli, and the purified recombinant PoIFN-delta8 exerted a significantly protective effect against two different serotypes of FMDV in IBRS-2 cells. In addition, PoIFN-delta8 induced the expression of IFN-stimulated genes. These findings highlight the significance of PoIFN-delta might serve as an antiviral agent for the prevention of FMDV in pigs and will stimulate the study of exploiting the potential biological functions of IFN-delta in the future. PMID- 29621737 TI - Time for food: The impact of diet on gut microbiota and human health. AB - There is growing recognition of the role of diet on modulating the composition and metabolic activity of the human gut microbiota, which in turn influence health. Dietary ingredients and food additives have a substantial impact on the gut microbiota and hence affect human health. Updates on current understanding of the gut microbiota in diseases and metabolic disorders are addressed in this review, providing insights into how this can be transferred from bench to bench side as gut microbes are integrated with food. The potency of microbiota-targeted biomarkers as a state-of-art tool for diagnosis of diseases was also discussed, and it would instruct individuals with healthy dietary consumption. Herein, recent advances in understanding the effect of diet on gut microbiota from an ecological perspective, and how these insights might promote health by guiding development of prebiotic and probiotic strategies and functional foods, were explored. PMID- 29621738 TI - Application of a phage in decontaminating Vibrio parahaemolyticus in oysters. AB - Vibrio parahaemolyticus is a major pathogen that is mainly associated with seafood and is a global concern of food safety. With high prevalence of contamination in food, efficient strategy is needed to decontaminate those contaminated foods and control the emergence of vibriosis. In the present study, a V. parahaemolyticus-specific phage vB_VpaS_OMN (designated as phage OMN) was isolated from oyster. Phage OMN had good pH (5-9) and temperature tolerance (<50 degrees C). Phage OMN exhibited broad host range against isolates of V. parahaemolyticus (20/31). After treatment with phage OMN in the liquid condition for 7 h, the number of V. parahaemolyticus was reduced significantly compared to control treatment. When phage OMN was applied to oyster samples for 48 and 72 h, 90% and 99%, respectively, of V. parahaemolyticus was inactivated on Oyster meat surface. Sequence analysis showed that phage OMN had a 42.202 bp genome and revealed about 59.04% homology with Cronobacter phage vB_CsaP_Ss1. Only 10 CDSs can be predicted based on the GenBank database, while 42% of the CDSs were unique to OMN and had no known function, indicating that phage OMN is a new lytic phage. Fully understanding of the function for the phage genes and the properties of the phage is important for the development of strategies to control V. parahaemolyticus contamination in oysters and disease in aquaculture. PMID- 29621739 TI - Incidence of hypersensitivity and anaphylaxis with sugammadex. AB - STUDY OBJECTIVE: To evaluate the incidence of hypersensitivity and anaphylaxis after administration of sugammadex. DESIGN: Retrospective analysis. SETTING: Sugammadex clinical development program and post-marketing experience. PATIENTS: Surgical patients and healthy volunteers who received sugammadex or placebo/comparator with anesthesia and/or neuromuscular blockade (NMB). INTERVENTIONS: Sugammadex administered as 2.0 mg/kg at reappearance of the second twitch, 4.0 mg/kg at 1-2 post-tetanic count, or 16.0 mg/kg at 3 min after rocuronium 1.2 mg/kg. MEASUREMENTS: Three analytical methods were used: 1) automated MedDRA queries; 2) searches of adverse events (AEs) consistent with treatment-related hypersensitivity reactions as diagnosed by the investigator; and 3) a retrospective adjudication of AEs suggestive of hypersensitivity by a blinded, independent adjudication committee (AC). In addition, a search of all post-marketing reports of events of hypersensitivity was performed, and events were retrospectively adjudicated by an independent AC. Anaphylaxis was determined according to Sampson Criterion 1. MAIN RESULTS: The pooled dataset included 3519 unique subjects who received sugammadex and 544 who received placebo. The automated MedDRA query method showed no apparent increase in hypersensitivity or anaphylaxis with sugammadex as compared to placebo or neostigmine. Similarly, there was a low overall incidence of AEs of treatment-related hypersensitivity (<1%), with no differences between sugammadex and placebo or neostigmine. Finally, the retrospective adjudication of AEs suggestive of hypersensitivity showed a low incidence of hypersensitivity (0.56% and 0.21% for sugammadex 2 mg/kg and 4 mg/kg, respectively), with an incidence similar to subjects who received placebo (0.55%). There were no confirmed cases of anaphylaxis in the pooled studies. During post-marketing use, spontaneous reports of anaphylaxis occurred with approximately 0.01% of sugammadex doses. CONCLUSIONS: Subjects who received sugammadex with general anesthesia and/or NMB had a low overall incidence of hypersensitivity, with no apparent increase in hypersensitivity or anaphylaxis with sugammadex as compared to placebo or neostigmine. PMID- 29621740 TI - Glucose-lowering treatment in cardiovascular and peripheral artery disease. AB - Diabetes-induced hyperglycemia is a causal factor for cardiovascular disease (CVD) and, specifically, peripheral artery disease (PAD). Metformin is the cornerstone drug therapy for glucose-lowering that exerts beneficial effects beyond glycemic control. New glucose-lowering drugs have recently been shown cardiovascular benefits and their impact on CVD risk is of increasing importance. Current guidelines recommend these novel therapies as second-line options for patients with diabetes and established CVD. Given the prevalence of CVD in this population, a complete understanding of the cardiovascular safety/efficacy of glucose-lowering drugs is needed. The present review provides an update overview of the anti-diabetic drugs and their impact on PAD and cardiovascular outcomes, summarizing key recent trial findings highlights their risk and benefits. PMID- 29621741 TI - Harm from others' drinking-related aggression, violence and misconduct in five Asian countries and the implications. AB - BACKGROUND: Harm from alcohol-attributable aggression and violence is linked to diminished personal safety and reduced physical and mental health and wellbeing in many countries. But there has been limited evidence on these harms in low- and middle-income countries (LMICs). This study measured harm from others' drinking related aggression, violence and misconduct in five Asian LMICs (Thailand, Sri Lanka, India, Vietnam, and Lao PDR), aiming to compare the magnitude and pattern of harm across countries by gender, age group, educational level, rurality, and country-level indicators. METHODS: Data from 9832 respondents from the WHO/Thai Health International Collaborative Research Project on the Harm from Others' Drinking undertaken between 2012 and 2014 were analysed. FINDINGS: 50-73% of respondents from five countries reported being harmed at least once in the past year. Public disorder and feeling unsafe due to someone else's drinking was frequently reported, followed by harassment, assaults and threats, traffic harm, and property damage. In most countries, men were more likely than women to report traffic harms, property harm, and assaults, whereas women were more likely to report feeling unsafe in public. Being young, less educated, living in urban areas, and one's own drinking were significant predictors of more harm from others' drinking for both genders. CONCLUSIONS: This study revealed a consistently high prevalence of alcohol-related aggression and violence in the five Asian countries. Patterns of harm within countries and populations at most risk for different forms of harms were identified. Alongside services for those affected, efforts to strengthen alcohol policies are needed in each society. PMID- 29621742 TI - Offline constraints in online drug marketplaces: An exploratory analysis of a cryptomarket trade network. AB - BACKGROUND: Cryptomarkets, or illegal anonymizing online platforms that facilitate drug trade, have been analyzed in a rapidly growing body of research. Previous research has found that, despite increased risks, cryptomarket sellers are often willing to ship illegal drugs internationally. There is little to no information, however, about the extent to which uncertainty and risk related to geographic constraints shapes buyers' behavior and, in turn, the structure of the global online drug trade network. In this paper, we analyze the structure of a complete cryptomarket trade network with a focus on the role of geographic clustering of buyers and sellers. METHODS: We use publicly available crawls of the cryptomarket Abraxas, encompassing market transactions between 463 sellers and 3542 buyers of drugs in 2015. We use descriptive social network analysis and Exponential Random Graph Models (ERGM) to analyze the structure of the trade network. RESULTS: The structure of the online drug trade network is primarily shaped by geographical boundaries. Buyers are more likely to buy from multiple sellers within a single country, and avoid buying from sellers in different countries, which leads to strong geographic clustering. The effect is especially strong between continents and weaker for countries within Europe. A small fraction of buyers (10%) account for more than a half of all drug purchases, while most buyers only buy once. CONCLUSION: Online drug trade networks might still be heavily shaped by offline (geographic) constraints, despite their ability to provide access for end-users to large international supply. Cryptomarkets might be more "localized" and less international than thought before. We discuss potential explanations for such geographical clustering and implications of the findings. PMID- 29621743 TI - B cell depleting therapy for multiple sclerosis overlapping with neuromyelitis optica spectrum disorder. AB - Multiple sclerosis and neuromyelitis optica spectrum disorder are currently thought to be independent entities. Some patients display intermediate manifestations that fit the criteria for both diseases without positive relevant serobiomarkers. An overall standard and consensus for the diagnosis and treatment of these overlapping patients have not been reached. We describe a patient with frequently relapsing demyelinating episodes and repeatedly adjusted treatment regimens due to diagnostic difficulties. This case did not respond adequately to glucocorticoid plus azathioprine or to interferon. Benefits were finally obtained by using rituximab, an anti-CD20 specific monoclonal antibody targeting B cells. Treatments targeting B cell mediated humoral immunity such as rituximab, may be a safe and appropriate choice for these challenging demyelinating cases, especially in Asian population. PMID- 29621744 TI - Undergraduate peer assisted learning tutors' performance in summative anatomy examinations: a pilot study. AB - Objectives: To compare summative anatomy examination results of Peer Assisted Learning (PAL) tutors and learners in the same undergraduate classroom. Methods: Comparative study of Year-1 medical students who did/did not serve as PAL tutors. PAL tutors gave six hours of teaching in lower limb anatomy. Percent marks for written and spotting examinations were compared between PAL tutors and PAL learners. Results: The 12 self-selected PAL tutors were not significantly different from their peers (n=191) in terms of age or nationality, but 20% were female compared to 51% of PAL learners. Except for upper limb anatomy, PAL tutors performed at the same level as their tutees in all basic science examinations taken before PAL was introduced. PAL tutors performed better (M=89.0, SD=8.2) in the lower limb examinations than PAL learners (M=79.7, SD=13.0), but these differences were only statistically significantly bigger in the subject they had taught (t(184) = 2.40, p=0.002). Overall PAL tutors performed better in all anatomy spotting exams in both pre-clinical years (Year-1: M=80.4, SD=7.4; Year 2: M=74.8, SD=3.4) compared to PAL learners (Year-1: M=75.1, SD=6.6; Year-2: M=67.2, SD=3.0; (t(1) = 4.2, p=0.07). Conclusions: Undergraduate PAL tutors performed better than PAL learners in the subject they taught and continued to do so in all anatomy spotting exams, even after the PAL experience had ended, suggesting that actively involving anatomy students as PAL tutors should be encouraged especially among undergraduate medical students. PMID- 29621745 TI - Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy in the Treatment of Colorectal Liver Metastases: Current Scenario. AB - Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS) has expanded the surgical armamentarium for patients with advanced and bilateral colorectal liver metastases. However, the enthusiasm that the medical fraternity had about ALPPS was hampered by a high mortality rate and early and frequent tumor recurrence. While surgical safety has improved, mainly due to technical refinements and a better patient selection, the oncological value in the face of early tumor recurrence remains unclear. The only randomized controlled trial on ALPPS versus two-stage hepatectomy (TSH) so far confirmed that ALPPS led to higher resectability with comparable perioperative complication rate, but oncological outcome was not measured. Robust data regarding long-term outcome are still missing. TSH and ALPPS might be complementary strategies for the resection of colorectal liver metatsases (CRLM) with ALPPS being reserved for patients with no other surgical option, that is, after failed portal vein embolization or those with an extremely small future liver remnant. In other words, ALPPS can be considered a supplementary tool and a last resort in the liver surgeon's hand to offer resectability in otherwise nonresectable CRLM. In these individual cases, and always embedded into a multimodal treatment setting, ALPPS may offer a chance of complete tumor removal and prolonged survival and even a chance for cure. PMID- 29621748 TI - Is High-Flow Nasal Cannula Useful as Primary Respiratory Support in Preterm Infants? PMID- 29621746 TI - Crocin Improves the Endothelial Function Regulated by Kca3.1 Through ERK and Akt Signaling Pathways. AB - BACKGROUND/AIMS: Based on the protective effect of crocin against cardiovascular diseases, we hypothesize that crocin could improve endothelial function through activating the eNOS(endothelial nitric oxide synthase) /NO pathway and/or the intermediate-conductance Ca2+-activated K+ channels (KCa3.1). METHODS: In this study, rat aortic rings were used to assess the regulatory effect of crocin on vascular tone and nitric oxide, prostacyclin, and KCa3.1, all endothelial vasodilators, were analyzed for effects by crocin. The expression profiles of p eNOS, total-eNOS, p-ERK, total-ERK, p-Akt, total-Akt, KCa3.1, CD31, thrombomodulin, ICAM-1 and VCAM-1 were tested by western blotting. KCa3.1 was also analyzed by qPCR and immunofluorescence staining. Fluorescence and confocal microscopy were used to determine NO generation and intracellular Ca2+. Both EdU and MTT assays were used to evaluate cell viability. Cellular migration was assessed using transwell assay. RESULTS: Crocin relaxed pre-contracted artery rings through either NO or KCa3.1, but not PGI, in an endothelium-dependent manner. Furthermore, crocin increased p-eNOS, total-eNOS expression and NO production as well as intracellular Ca2+ in both HUVECs and HUAECs (Human Umbilical Artery Endothelial cells). Crocin also stimulated the expression of CD31, thrombomodulin and vascular cell adhesion molecule 1 (VCAM-1), as well as increased cellular proliferation and migration in vitro. Interestingly, we determined for the first time that by blocking or silencing KCa3.1 there was inhibition of crocin induced upregulation of p-eNOS and total-eNOS. Correspondingly, the KCa3.1 inhibitor TRAM-34 also reduced the expression of CD31, thrombomodulin and VCAM-1, as well as diminished intracellular Ca2+, cellular proliferation and migration. Finally, crocin stimulated the expression of p-ERK, total-ERK, p-Akt and total-Akt, however suppression of MEK and Akt inhibited this expression profile in endothelial cells. CONCLUSION: In the present study, these data strongly support the hypothesis that crocin could improve endothelial function through stimulation of the eNOS/NO pathway and other endothelial markers. This functional improvement is regulated by KCa3.1 via the MEK/ERK and PI3K/Akt signaling pathway. PMID- 29621747 TI - Changes in Biomarker Profile and Left Ventricular Hypertrophy Regression: Results from the Frequent Hemodialysis Network Trials. AB - BACKGROUND: Regression of left ventricular hypertrophy (LVH) is feasible with more frequent hemodialysis (HD). We aimed to ascertain pathways associated with regression of left ventricular mass (LVM) in patients enrolled in the Frequent HD Network (FHN) trials. METHODS: This was a post hoc observational cohort study. We hypothesized LVH regression with frequent HD was associated with a different cardiovascular biomarker profile. Regressors were defined as patients who achieved a reduction of more than 10% in LVM at 12 months. Progressors were defined as patients who had a minimum of 10% increase in LVM at 12 months. RESULTS: Among 332 randomized patients, 243 had biomarker data available. Of these, 121 patients did not progress or regress, 77 were regressors, and 45 were progressors. Mean LVM change differed between regressors and progressors by -65.6 (-74.0 to -57.2) g, p < 0.001. Regressors had a median (interquartile range) increase in dialysis frequency (from 3.0 [3.0-3.0] to 4.9 [3-5.7] per week, p = 0.001) and reductions in pre-dialysis systolic (from 149.0 [136.0-162.0] to 136.0 [123.0-152.0] mm Hg, p < 0.001) and diastolic (from 83.0 [71.0-91.0] to 76.0 [68.0-84.0] mm Hg, p < 0.001) blood pressures. Klotho levels increased in regressors versus progressors (76.9 [10.5-143.3] pg/mL, p = 0.024). Tissue inhibitors of metalloproteinase (TIMP)-2 levels fell in regressors compared to progressors (-7,853 [-14,653 to -1,052] pg/mL, p = 0.024). TIMP-1 and log (brain natriuretic -peptide [BNP]) levels also tended to fall in regressors. Changes in LVM correlated inversely with changes in klotho (r = -0.24, p = 0.014). Conclusions: Markers of collagen turnover and changes in klotho levels are potential novel pathways associated with regression of LVH in the dialysis population, which will require further prospective validation. PMID- 29621750 TI - Enhanced Vascular Biocompatibility and Remodeling of Decellularized and Secured Xenogeneic/Allogeneic Matrices in a Porcine Model. AB - BACKGROUND/PURPOSE: Calcifications and absence of growth potential are the major drawbacks of glutaraldehyde-treated prosthesis. Decellularized and secured xeno /allogeneic matrices were assessed in a preclinical porcine model for biocompatibility and vascular remodeling in comparison to glutaraldehyde-fixed bovine pericardium (GBP; control). METHODS: Native human (fascia lata, pericardium) and porcine tissues (peritoneum) were used and treated. In vitro, biopsies were performed before and after treatment to assess decellularization (hematoxylin and eosin/DAPI). In vivo, each decellularized and control tissue sample was implanted subcutaneously in 4 mini-pigs. In addition, 9 mini-pigs received a patch or a tubularized prosthesis interposition on the carotid artery or abdominal aorta of decellularized (D) human fascia lata (DHFL; n = 4), human pericardium (DHP; n = 9), porcine peritoneum (DPPt; n = 7), and control tissue (GBP: n = 3). Arteries were harvested after 1 month and subcutaneous samples after 15-30 days. Tissues were processed for hematoxylin and eosin/von Kossa staining and immunohistochemistry for CD31, alpha-smooth muscle actin, CD3, and CD68. Histomorphometry was achieved by point counting. RESULTS: A 95% decellularization was confirmed for DHP and DPPt, and to a lower degree for DHFL. In the subcutaneous protocol, CD3 infiltration was significantly higher at day 30 in GBP and DHFL, and CD68 infiltration was significantly higher for GBP (p < 0.05). In intravascular study, no deaths, aneurysms, or pseudoaneurysms were observed. Inflammatory reaction was significantly higher for DHFL and GBP (p < 0.05), while it was lower and comparable for DHP/DPPt. DHP and DPPt showed deeper recellularization, and a new arterial wall was characterized. CONCLUSIONS: In a preclinical model, DPPt and DHP offered better results than conventional commercialized GBP for biocompatibility and vascular remodeling. PMID- 29621749 TI - The Endocannabinoid System Affects Myocardial Glucose Metabolism in the DOCA-Salt Model of Hypertension. AB - BACKGROUND/AIMS: Recent interest in the use of cannabinoids as therapeutic agents has revealed the involvement of the endogenous cannabinoid system (ECS) in the regulation of the cardiovascular system in hypertension. Abnormalities in glucose metabolism and insulin action are commonly detected in hypertensive animals. Thus, potential antihypertensive drugs should be investigated with respect to modulation of glucose homeostasis. Therefore, the aim of the present study was to evaluate the effects of the ECS activation after chronic fatty acid amide hydrolase inhibitor (URB597) administration on plasma glucose and insulin concentrations as well as parameters of myocardial glucose metabolism in the deoxycorticosterone acetate (DOCA)-salt hypertensive rats, an animal model of secondary hypertension. METHODS: Hypertension was induced by DOCA (25mg/kg) injections and addition of 1% NaCl in the drinking water for six weeks. Chronic activation of the ECS was performed by URB597 (1mg/kg) injections for two weeks. We examined fasting plasma levels of insulin (ELISA), glucose and intramyocardial glycogen (colorimetric method). Expressions of glucose transporters (GLUT1, 4) and selected proteins engaged in GLUT translocation as well as glucose metabolism were determined using Western blotting. RESULTS: Hypertension induced hypoinsulinemia with concomitant lack of significant changes in glycemia, reduced intramyocardial glycogen content and increased pyruvate dehydrogenase (PDH) expression in the cardiac muscle. Importantly, chronic URB597 administration in the hypertensive rats increased insulin concentration, elevated plasmalemmal GLUT1 and GLUT4 expression and concomitantly improved myocardial glycogen storage. CONCLUSION: Chronic administration of fatty acid amide hydrolase (FAAH) inhibitor has potential protective properties on myocardial glucose metabolism in hypertension. PMID- 29621751 TI - Skin Barrier Restoration and Moisturization Using Horse Oil-Loaded Dissolving Microneedle Patches. AB - BACKGROUND: Horse oil (HO) has skin barrier restoration and skin-moisturizing effects. Although cream formulations have been used widely and safely, their limited penetration through the stratum corneum is a major obstacle to maximizing the cosmetic efficacy of HO. Therefore, we aimed to encapsulate HO in a cosmetic dissolving microneedle (DMN) for efficient transdermal delivery. METHODS: To overcome these limitations of skin permeation, HO-loaded DMN (HO-DMN) patches were developed and evaluated for their efficacy and safety using in vitro and clinical studies. RESULTS: Despite the lipophilic nature of HO, the HO-DMN patches had a sharp shape and uniform array, with an average length and tip diameter of 388.36 +/- 16.73 and 38.54 +/- 5.29 um, respectively. The mechanical strength of the HO-DMN patches was sufficient (fracture force of 0.29 +/- 0.01 N), and they could successfully penetrate pig skin. During the 4-week clinical evaluation, HO-DMN patches caused significant improvements in skin and dermal density, skin elasticity, and moisturization. Additionally, a brief safety assessment showed that the HO-DMN patches induced negligible adverse events. CONCLUSION: The HO-DMNs are efficient, safe, and convenient for wide use in cosmetic applications for skin barrier restoration and moisturization. PMID- 29621752 TI - Fibroblast Growth Factor 23: A Biomarker of Kidney Function Decline. AB - BACKGROUND: Fibroblast growth factor 23 (FGF-23) is a hormone that regulates phosphorus levels and vitamin D metabolism. Previous studies have shown FGF-23 to be a risk factor for incident end-stage renal disease; however, there are less data on the association of FGF-23 with earlier kidney-related outcomes. METHODS: Serum FGF-23 was assayed using an intact ELISA assay in 2,496 participants of the Healthy Aging and Body Composition Study, a cohort of well-functioning older adults. Kidney function was estimated by assaying cystatin C at baseline and years 3 and 10. The associations between FGF-23 and decline in kidney function (defined by estimated glomerular filtration rate (eGFR) decline >=30% or >=3 mL/min/year) and incident chronic kidney disease (CKD; incident eGFR <60 mL/min/1.73 m2 and >=1 mL/min/year decline) were evaluated. Models were adjusted for demographics, baseline eGFR, urine albumin/creatinine ratio, comorbidity, and serum calcium, phosphorus, 25(OH) vitamin D and parathyroid hormone. RESULTS: The mean (SD) age was 75 (3) years, with 52% female and 38% black. There were 405 persons with 30% decline, 702 with >3 mL/min/year decline, and 536 with incident CKD. In fully adjusted continuous models, doubling of FGF-23 concentrations was not associated with kidney function decline (OR [95% CI] = 0.98 [0.82-1.19] for >=30% decline and OR 1.17 [95% CI 1.00-1.37] for >=3 mL/min/year decline), or incident CKD (incident rate ratio [IRR] 1.05 [95% CI 0.91-1.22]). In adjusted quartile analysis, the highest quartile of FGF-23 was significantly associated with incident CKD (IRR 1.27 [95% CI 1.02-1.58] for highest vs. lowest quartile). CONCLUSION: Higher FGF-23 concentrations were not consistently associated with decline in kidney function or incident CKD in community-dwelling older adults. PMID- 29621753 TI - Necroptosis Contributes to Urban Particulate Matter-Induced Airway Epithelial Injury. AB - BACKGROUND/AIMS: Necroptosis, a form of programmed necrosis, is involved in the pathologic process of several kinds of pulmonary diseases. However, the role of necroptosis in particulate matter (PM)-induced pulmonary injury remains unclear. The objective of this study is to investigate the involvement of necroptosis in the pathogenesis of PM-induced toxic effects in pulmonary inflammation and mucus hyperproduction, both in vitro and in vivo. METHODS: PM was administered into human bronchial epithelial (HBE) cells or mouse airways, and the inflammatory response and mucus production were assessed. The mRNA expressions of IL6, IL8 and MUC5AC in HBE cells and Cxcl1, Cxcl2, and Gm-csf in the lung tissues were detected by quantitative real-time RT-PCR. The secreted protein levels of IL6 and IL8 in culture supernatants and Cxcl1, Cxcl2, and Gm-csf in bronchoalveolar lavage fluid (BALF) were detected by enzyme-linked immunosorbent assay (ELISA). We used Western blot to measure the protein expressions of necroptosis-related proteins (RIPK1, RIPK3, and Phospho-MLKL), NF-kappaB (P65 and PP65), AP-1 (P-c Jun and P-c-Fos) and MUC5AC. Cell necrosis and mitochondrial ROS were detected using flow cytometry. In addition, pathological changes and scoring of lung tissue samples were monitored using hemoxylin and eosin (H&E), periodic acid schiff (PAS) and immunohistochemistry staining. RESULTS: Our study showed that PM exposure induced RIP and MLKL-dependent necroptosis in HBE cells and in mouse lungs. Managing the necroptosis inhibitor Necrostatin-1 (Nec-1) and GSK'872, specific molecule inhibitors of necroptosis, markedly reduced PM-induced inflammatory cytokines, e.g., IL6 and IL8, and MUC5AC in HBE cells. Similarly, administering Nec-1 significantly reduced airway inflammation and mucus hyperproduction in PM-exposed mice. Mechanistically, we found PM-induced necroptosis was mediated by mitochondrial reactive oxygen species-dependent early growth response gene 1, which ultimately promoted inflammation and mucin expression through nuclear factor kappaB and activator protein-1 pathways, respectively. CONCLUSIONS: Our results demonstrate that necroptosis is involved in the pathogenesis of PM-induced pulmonary inflammation and mucus hyperproduction, and suggests that it may be a novel target for treatment of airway disorders or disease exacerbations with airborne particulate pollution. PMID- 29621754 TI - Male-Male Mounting Behaviour in Free-Ranging Golden Snub-Nosed Monkeys (Rhinopithecus roxellana). AB - An all-male band of golden snub-nosed monkeys (Rhinopithecus roxellana) was observed for 3 months in the Qinling Mountains of China, in order to collect data on the frequencies and contextual significance of male-male mounting behaviour. Mounts occurred in a variety of affiliative, dominance-related and sexual contexts, which differed depending upon the ages of the males involved. Mounting behaviour in this group was mainly initiated by adults. Juveniles mounted each other in affiliative contexts (during play and prior to grooming). Adult males mounted subadult and juvenile partners in a greater variety of sociosexual contexts (dominance/rank-related interactions; reconciliation following agonistic encounters, and sometimes as a prelude to receiving grooming). However, subadults and juveniles were never observed to mount adults. In one dyad, involving an adult male and a subadult partner, mounting was more frequent and prolonged, and included bouts of deep pelvic thrusting. Two mounts resulted in anal intromissions and, in 1 case, the subadult partner exhibited seminal emission. Given that the study took place during the annual mating peak period of R. roxellana, it is possible that this unusual male-male sexual activity was related to the absence of mating opportunities for those adults that were excluded from 1 male units. PMID- 29621755 TI - Reply to the Letter to the Editor: "Is High-Flow Nasal Cannula Useful as Primary Respiratory Support in Preterm Infants?" PMID- 29621756 TI - Experience with Transcordal Silicone Stents in Adult Laryngotracheal Stenosis: A Bicentric Retrospective Study. AB - BACKGROUND: Benign stenosis involving laryngeal and upper tracheal structures represents a therapeutic challenge. Open surgery and endoscopic management have to be discussed by a multidisciplinary board in order to evaluate the risk and benefit for each patient. OBJECTIVE: The objective of this retrospective study was to report the experience of two French centers with transcordal silicone stents (TSS) in the endoscopic management of benign laryngotracheal stenosis (BLTS) in adults, with focus on efficacy, safety, and tolerability. METHODS: We performed a retrospective chart review of all cases of BLTS treated with TSS between January 2001 and June 2017 at two tertiary centers in France: the Centre Hospitalier Regional Universitaire de Strasbourg and the Hopital Nord de Marseille. RESULTS: A total of 17 patients were included. Eleven had a tracheostomy at initial management which consisted of 8 T-tubes and 9 strictly endoluminal stents placements. The main complications were minor aspirations in 5 patients (29%), granulation in 3 patients (18%), migration in 2 patients (12%), and severe dysphonia in 3 patients (18%). After a mean duration of 18.3 months, 11 patients (65%) had had their TSS definitely removed, 13 patients were tracheostomy free (76%), and a TSS remained in place in 4 patients (24%). CONCLUSIONS: Adult BLTS treatment with TSS placement is associated with low morbidity and excellent clinical outcomes, with a large proportion of patients free of airway instrumentation on long-term follow-up. PMID- 29621757 TI - Secondary Caries in situ Models: A Systematic Review. AB - : In situ caries research serves as a bridge between clinical research and laboratory studies. In this kind of research, volunteers wear a removable intraoral splint or prosthesis containing research samples. Many different in situ models exist to investigate secondary caries. This systematic review compared currently existing secondary caries models and their lesion progression per day values. MATERIALS AND METHODS: Three databases (Medline, Embase, and Cochrane) were searched for relevant literature. Bias risk was assessed and model parameters and caries-related outcomes were extracted by 2 independent researchers. Where possible, caries-related outcomes were normalized by estimating lesion progression per day by dividing lesion depth extracted from microradiographic or microhardness data by the number of days the study lasted. RESULTS: The literature search identified 335 articles. After eliminating duplicates and selection, 31 articles were included. The models differed greatly on factors such as sample location, presence of fluoride in the model, and analysis methods. Three main groups could be identified by sample placement; 68% of models placed samples palatally in the upper jaw, and the lower jaw model could be divided into the buccal (26%) and approximal (6%) areas. Average lesion progression in enamel next to composite was 4.3 +/- 2.8 um (range1.1-8.8 um/day). DISCUSSION: Studies conducted with palatal models showed caries progression rates 2-5 times higher than the estimated clinical progression rates. Lesion progression per day could be a useful tool for future comparison of models and establishing a standardized model. PMID- 29621758 TI - Targeting mTOR by CZ415 Inhibits Head and Neck Squamous Cell Carcinoma Cells. AB - BACKGROUND/AIMS: mTOR is an important therapeutic target for human head and neck squamous cell carcinoma (HNSCC). The current study tested the anti-HNSCC cell activity by a mTOR kinase inhibitor CZ415. METHODS: HNSCC cells were treated with CZ415. Cell death was tested by lactate dehydrogenase (LDH) assay and MTT assay. Cell proliferation was tested by BrdU ELISA assay and [H3] thymidine incorporation assay, with apoptosis assayed by the TUNEL staining. A Western blotting assay was applied to test autophagy-associated proteins, mTOR and signalings. The nude mice xenograft model was established to study CZ415-mediated anti-tumor activity. RESULTS: In established (SCC-9, SQ20B and A253 lines) and primary human HNSCC cells, CZ415 efficiently inhibited cell survival and proliferation. CZ415 blocked mTORC1/2 activation and inhibited ERK in HNSCC cells. CZ415 provoked feedback autophagy activation. Conversely, autophagy inhibitors (3-methyladenine and chloroquine) or Beclin-1 shRNA sensitized CZ415 induced HNSCC cell death. In vivo, CZ415 gavage inhibited SCC-9 tumor growth in nude mice, showing higher efficiency against Beclin-1-silenced tumors. CONCLUSION: CZ415 inhibits HNSCC cell growth in vitro and in vivo. Inhibition of autophagy can further sensitize CZ415 against HNSCC cells. PMID- 29621760 TI - Age, Loss Minimization, and the Role of Probability for Decision-Making. AB - BACKGROUND: Older adults are stereotypically considered to be risk averse compared to younger age groups, although meta-analyses on age and the influence of gain/loss framing on risky choices have not found empirical evidence for age differences in risk-taking. OBJECTIVE: The current study extends the investigation of age differences in risk preference by including analyses on the effect of the probability of a risky option on choices in gain versus loss situations. METHODS: Participants (n = 130 adults aged 19-80 years) chose between a certain option and a risky option of varying probability in gain- and loss framed gambles with actual monetary outcomes. RESULTS: Only younger adults displayed an overall framing effect. Younger and older adults responded differently to probability fluctuations depending on the framing condition. Older adults were more likely to choose the risky option as the likelihood of avoiding a larger loss increased and as the likelihood of a larger gain decreased. Younger adults responded with the opposite pattern: they were more likely to choose the risky option as the likelihood of a larger gain increased and as the likelihood of avoiding a (slightly) larger loss decreased. CONCLUSION: Results suggest that older adults are more willing to select a risky option when it increases the likelihood that larger losses be avoided, whereas younger adults are more willing to select a risky option when it allows for slightly larger gains. This finding supports expectations based on theoretical accounts of goal orientation shifting away from securing gains in younger adulthood towards maintenance and avoiding losses in older adulthood. Findings are also discussed in respect to the affective enhancement perspective and socioemotional selectivity theory. PMID- 29621759 TI - Peripheral Retinal Imaging Biomarkers for Alzheimer's Disease: A Pilot Study. AB - PURPOSE: To examine whether ultra-widefield (UWF) retinal imaging can identify biomarkers for Alzheimer's disease (AD) and its progression. METHODS: Images were taken using a UWF scanning laser ophthalmoscope (Optos P200C AF) to determine phenotypic variations in 59 patients with AD and 48 healthy controls at baseline (BL). All living participants were invited for a follow-up (FU) after 2 years and imaged again (if still able to participate). All participants had blood taken for genotyping at BL. Images were graded for the prevalence of age-related macular degeneration-like pathologies and retinal vascular parameters. Comparison between AD patients and controls was made using the Student t test and the chi2 test. RESULTS: Analysis at BL revealed a significantly higher prevalence of a hard drusen phenotype in the periphery of AD patients (14/55; 25.4%) compared to controls (2/48; 4.2%) [chi2 = 9.9, df = 4, p = 0.04]. A markedly increased drusen number was observed at the 2-year FU in patients with AD compared to controls. There was a significant increase in venular width gradient at BL (zone C: 8.425 * 10-3 +/- 2.865 * 10-3 vs. 6.375 * 10-3 +/- 1.532 * 10-3, p = 0.008; entire image: 8.235 * 10-3 +/- 2.839 * 10-3 vs. 6.050 * 10-3 +/- 1.414 * 10-3, p = 0.004) and a significant decrease in arterial fractal dimension in AD at BL (entire image: 1.250 +/- 0.086 vs. 1.304 +/- 0.089, p = 0.049) with a trend for both at FU. CONCLUSIONS: UWF retinal imaging revealed a significant association between AD and peripheral hard drusen formation and changes to the vasculature beyond the posterior pole, at BL and after clinical progression over 2 years, suggesting that monitoring pathological changes in the peripheral retina might become a valuable tool in AD monitoring. PMID- 29621761 TI - Transient Receptor Potential Channel, Vanilloid 5, Induces Chondrocyte Apoptosis in a Rat Osteoarthritis Model Through the Mediation of Ca2+ Influx. AB - BACKGROUND/AIMS: Chondrocyte apoptosis is the most common pathological feature in cartilage in osteoarthritis (OA). Transient receptor potential channel vanilloid 5 (TRPV5) is important in regulating calcium ion (Ca2+) influx. Accumulating evidences suggest that Ca2+ is a major intracellular second messenger that can trigger cell apoptosis. Therefore, we investigate the potential role of TRPV5 in mediating Ca2+ influx to promote chondrocyte apoptosis in OA. METHODS: The monoiodoacetic acid (MIA)-induced rat OA model was assessed by macroscopic and radiographic analyses. Calmodulin protein immunolocalization was detected by immunohistochemistry. The mRNA and protein level of TRPV5, calmodulin and cleaved caspase-8 in articular cartilage were assessed by real time polymerase chain reaction and western blotting. Primary chondrocytes were isolated and cultured in vitro. TRPV5 small interfering RNA was used to silence TRPV5 in chondrocytes. Then, calmodulin and cleaved caspase-8 were immunolocalized by immunofluorescence in chondrocyte. Fluo-4AM staining was used to assess intracellular Ca2+ to reflect TRPV5 function of mediation Ca2+ influx. Annexin V-fluorescein isothiocyanatepropidium iodide flow cytometric analysis was performed to determine chondrocytes apoptosis. Western blotting techniques were used to measure the apoptosis-related proteins in chondrocyte level. RESULTS: Here, we reported TRPV5 was up-regulated in MIA-induced OA articular cartilage. Ruthenium red (a TRPV5 inhibitor) can relieve progression of joint destruction in vivo which promoted us to demonstrate the effect of TRPV5 in OA. We found that TRPV5 had a specific role in mediating extracellular Ca2+ influx leading to chondrocytes apoptosis in vitro. The apoptotic effect was inhibited even reversed by silencing TRPV5. Furthermore, we found that the increase Ca2+ influx triggered apoptosis by up-regulating the protein of death-associated protein, FAS associated death domain, cleaved caspase-8, cleaved caspase-3, cleaved caspase-6, and cleaved caspase-7, and the up-regulated proteins were abolished by silencing TRPV5 or 1, 2-bis-(o-Aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid, tetraacetoxymethyl ester (a Ca2+ chelating agent). CONCLUSION: The up-regulated TRPV5 could used be as an initiating factor that induces extrinsic chondrocyte apoptosis via the mediation of Ca2+ influx. These findings suggested TRPV5 could be an intriguing mediator for drug target in OA. PMID- 29621762 TI - Mifepristone Inhibits the Migration of Cervical Cancer Cells by Inhibiting Exocrine Secretion. AB - Cervical cancer (CC) is one of the most common gynecological malignancies, and metastasis limits the use of surgical resection. Metapristone (MIF) was reported to suppress the proliferation and migration of several cancer cells. Exosomes play a variety of roles in cellular biological processes. The relation of exosomes and CC is less studied. Cell viability, apoptosis assay and migration assay was conducted in HeLa cells treated by MIF by CCK-8 kit, staining by Annexin V-fluorescein isothiocyanate and propidium iodide, and wound test respectively. ISG15 expression level was examined in MIF-treated HeLa cells by Western blot. The migration of HeLa cells treated by MIF/GW4869 was measured by wound test. MIF suppressed the growth and migration, as well as induced apoptosis of CC cells. MIF inhibited the exocrine secretion of CC cells by upregulating ISG15, while treating CC cells by ISG15 stimulus, IFN, inhibited the secretion of exosomes. The inhibition of exocrine secretion by GW4869 enhanced the migration inhibition of MIF on CC cells. This study demonstrates that MIF suppresses the CC cell migration by inhibiting exocrine secretion through upregulating ISG1. PMID- 29621763 TI - Predictive Value of Four-Dimensional Strain Echocardiography for Adverse Cardiovascular Outcomes in ST-Elevation Myocardial Infarction Patients Treated with Primary Percutaneous Coronary Intervention. AB - OBJECTIVES: To investigate the predictive value of four-dimensional (4D) strain echocardiography for major adverse cardiovascular events (MACE) in ST-elevation acute myocardial infarction (STEMI) patients. METHODS: Consecutive STEMI patients who underwent successful primary coronary interven tion (PCI) were enrolled and followed, with 2D and 4D strain echocardiography performed within 1 week after PCI. RESULTS: Twenty-six first MACE were recorded in 81 patients who finished a ~3.0 year follow-up. Compared with those without MACE, subjects with MACE were more likely to have anterior MI (73.08 vs. 38.18%, p = 0.003), significantly decreased 2D left ventricular ejection fraction (2DLVEF) and 4DLVEF (all p < 0.05), as well as an overtly compromised 4D strain parameters. The prediction models incorporating infarct location with either 2DLVEF or 4D strain parameters were then developed. Model comparisons revealed that the global area strain (GAS) based model had the highest discriminative capacity (c statistics = 0.774) and was well calibrated for MACE. Additionally, the clinical utility of the GAS-based prediction model was verified by decision curve analysis showing a consistent positive and larger net benefit compared to the 2DLVEF-based model. CONCLUSIONS: Our data support a superiority of 4D strain echocardiography over conventional 2D echocardiography, especially GAS, for risk stratification in STEMI patients after successful primary PCI. PMID- 29621764 TI - Right Ventricular Functions in Pulmonary Thromboembolism. PMID- 29621766 TI - Preliminaries. PMID- 29621765 TI - Nrf2 Activation Induced by Sirt1 Ameliorates Acute Lung Injury After Intestinal Ischemia/Reperfusion Through NOX4-Mediated Gene Regulation. AB - BACKGROUND/AIMS: Nuclear erythroid 2-related factor-2 (Nrf2) is a major stress response transcription factor that has been implicated in regulating ischemic angiogenesis. We investigated the effects of Nrf2 in regulating revascularization and modulating acute lung injury. METHODS: The expression of Nrf2 and sirtuin1 (Sirt1) was assessed in lung tissue by western blotting and immunofluorescence staining after intestinal ischemia/reperfusion (IIR) in Nrf2-/- and wild-type (WT) mice. The involvement of Nrf2 in angiogenesis, cell viability, and migration was investigated in human pulmonary microvascular endothelial cells (PMVECs). Additionally, the influence of Nrf2 expression on NOX pathway activation was measured in PMVECs after oxygen-glucose deprivation/reoxygenation. RESULTS: We found activation and nuclear accumulation of Nrf2 in lung tissue after IIR. Compared to IIR in WT mice, IIR in Nrf2-/- mice significantly enhanced leukocyte infiltration and collagen deposit, and inhibited endothelial cell marker CD31 expression. Nrf2 upregulation and translocation into the nucleus stimulated by Sirt1 overexpression exhibited remission of histopathologic changes and enhanced CD31 expression. Nrf2 knockdown repressed non-phagocytic cell oxidase 4 (NOX4), hypoxia-inducible factor (HIF-1alpha) and vascular endothelial growth factor (VEGF) expression after IIR. Nrf2 upregulation by Sirt1 enhances NOX4, HIF-1alpha and VEGF expression after IIR in WT mice. Furthermore, Nrf2 knockdown suppressed cell viability, capillary tube formation and cell migration in PMVECs after oxygen-glucose deprivation/reoxygenation and also inhibited NOX4, HIF-1 and VEGF expression. Moreover, NOX4 knockdown in PMVECs decreased the levels of VEGF, HIF 1alpha and angiogenesis. CONCLUSION: Nrf2 stimulation by Sirt1 plays an important role in sustaining angiogenic potential through NOX4-mediated gene regulation. PMID- 29621767 TI - Understanding Iron Deficiency and Exercise: Looking Beyond Ferritin. PMID- 29621768 TI - Protective Role of the Hepatic Vagus Nerve against Liver Metastasis in Mice. AB - OBJECTIVE(S): Although accumulating evidence has shown that the autonomic nervous system is involved in liver pathology, its role in regulating cancer development remains unclear. The purpose of this study was to elucidate its detailed mechanisms. METHODS: A mouse model of liver metastasis of colorectal cancer was used. To elucidate the potential mechanisms involved, we examined the effect of selective hepatic vagotomy on the survival rate and liver-to-body weight. We further evaluated the possible involvement of the hepatic sympathetic nerve fibers in this model. RESULTS: The mortality rate and the liver-to-body weight ratio after cancer inoculation were significantly higher in the vagotomized mice than in the sham-operated mice. The vagotomized mice exhibited a transient decrease in hepatic norepinephrine levels following cancer inoculation. Interestingly, the vagotomy-induced exacerbation of liver metastasis was attenuated by supplementary norepinephrine or phenylephrine, a selective alpha1 adrenoceptor agonist, but not by clonidine, a selective alpha2-adrenoceptor agonist. CONCLUSION: Collectively, these results suggest that the hepatic vagus nerve may play a protective role against liver metastasis. Hepatic sympathetic nerves may also be involved as a protective efferent loop, possibly acting through the alpha1-adrenoceptor. PMID- 29621769 TI - Checkpoint Kinase 1 Is Overexpressed during HPV16-Induced Cervical Carcinogenesis. AB - PURPOSE: Cervical cancer is one of the leading causes of cancer death among women worldwide. Checkpoint kinase 1 (Chk1) has a critical role in DNA damage response and cell cycle checkpoint control. Emerging evidence suggests that Chk1 promotes tumor growth. However, whether Chk1 is important for development of cervical cancer is largely unknown. METHODS: The levels of Chk1 mRNA expression were determined using quantitative real-time polymerase chain reaction in a panel of 90 cervical specimens, including 30 cervical cancer tissues, 30 CIN II-III, and 30 normal cervical tissues. We investigated the correlation between Chk1 and HPV16 E6/E7 at the mRNA level using another 30 CIN II-III and 32 cervical cancer tissues with HPV16 infection. MTT and cell cycle assays were conducted to show the function role of Chk1 in cervical cancer SiHa cells. RESULTS: Chk1 was gradually increased during cervical lesion progression and positively correlated with HPV16 E6/E7 expression. Inhibition of Chk1 resulted in suppressed cell proliferation concomitant with the blocking of cell cycle at S-phase in cervical cancer SiHa cells. CONCLUSIONS: These results indicate that maintained Chk1 expression by HPV16 E6/E7 in cervical cancer cells promotes cell growth by blocking the cell cycle progression, and may point to novel strategies for targeting Chk1 in cancer therapy. PMID- 29621770 TI - Identifying Risk Factors Shared by Bronchopulmonary Dysplasia, Severe Retinopathy, and Cystic Periventricular Leukomalacia in Very Preterm Infants for Targeted Intervention. AB - BACKGROUND: Bronchopulmonary dysplasia (BPD), severe retinopathy of prematurity (sROP), and cystic periventricular leukomalacia (cPVL) are 3 major morbidities with long-term neurodevelopmental impairments in preterm infants. OBJECTIVE: To investigate the strength of associations and identify key risk factors shared by BPD, sROP, and cPVL for targeted intervention. METHODS: We studied the Taiwanese very-preterm-infant registry data on 3,507 infants admitted to neonatal intensive care units and discharged at postmenstrual age >=36 weeks between 2008 and 2013. RESULTS: Of 3,507 infants, 1,497 presented with at least 1 morbidity (26 [1.7%], 386 [25.8%], and 1,085 [72.5%] exhibited 3, 2, and 1 morbidities, respectively). BPD was strongly associated with sROP (odds ratio 5.93; 95% confidence interval 5.02-7.03), followed by cPVL (2.08; 1.63-2.64), but sROP and cPVL were weakly associated (1.59; 1.17-2.13). Most risk factors contributed to BPD, which shared risk factors with sROP and cPVL. A birth weight of < 1,000 g, male sex, and prolonged mechanical ventilation (MV) were shared by BPD and sROP, and chorioamnionitis, severe respiratory distress syndrome, and prolonged MV specifically contributed to BPD and cPVL. Prolonged MV was the single risk factor common to BPD, sROP, and cPVL. Avoiding prolonged MV reduced the risk of having at least 1 of the 3 morbidities by 37%. CONCLUSIONS: BPD and sROP were most strongly associated. Most risk factors contributed to BPD, with differentially shared effects on sROP and cPVL. Prolonged MV was the only risk factor shared by all 3 morbidities, and avoiding it potentially reduced the risk of having at least 1 of them. PMID- 29621771 TI - Low Necroptosis Process Predicts Poor Treatment Outcome of Human Papillomavirus Positive Cervical Cancers by Decreasing Tumor-Associated Macrophages M1 Polarization. AB - BACKGROUND/AIM: The aim of this study was to assess the functions of the necroptosis process on the prognosis of high-risk human papillomavirus (HR-HPV) related cervical cancer. METHODS: PCR and western blotting were used to demonstrate the expression of the necroptosis marker, mixed lineage kinase domain like protein (MLKL), in whole blood and peripheral blood mononuclears (PBMCs) of 89 cervical cancer patients and 15 healthy volunteers. Necroptosis levels and M1 polarization were determined in tumor co-cultured macrophages. RESULTS: We found that MLKL expressions were significantly increased in cervical cancer patients in both whole blood and PBMC samples compared to the expressions in the healthy controls. Low MLKL expression was significantly associated with decreased survival rate in overall survival and disease-free survival. Co-culture cervical cancer cells decrease the necroptosis process of macrophage, together with the proinflammatory factors (M1 markers) downregulation, and this negative regulation was exacerbated in HPV-positive cases. Necroptosis enhancer RIPK3 overexpression showed reversed regulation of these M1 markers, suggesting that co-culture cervical cancer cells decrease the macrophage M1 polarization partly through necroptosis downregulation. CONCLUSION: Our study revealed that necroptosis process could be a relevant marker for the determination of the prognosis in cervical cancer patients, which might be because of its role in regulating macrophage polarization. PMID- 29621772 TI - A Complete Pathological Response to Pembrolizumab following ex vivo Liver Resection in a Patient with Colorectal Liver Metastases. AB - Advances in the systemic treatment of stage IV colorectal cancer with liver metastases has offered improved survival rates for patients who otherwise face a dismal prognosis. However, a pathologically complete response (PCR) to chemotherapy for colorectal liver metastases is still rare, and its significance is not fully understood. In this case report, we describe a patient who achieved PCR after neoadjuvant immunotherapy with pembrolizumab and a left hepatectomy using an ex vivo resection technique. PMID- 29621773 TI - MicroRNA-214-5p Inhibits the Invasion and Migration of Hepatocellular Carcinoma Cells by Targeting Wiskott-Aldrich Syndrome Like. AB - BACKGROUND/AIMS: This study aims to explore the effects of microRNA-214-5p (miR 214-5p) on the invasion and migration of Hepatocellular Carcinoma cells (HCC). METHODS: Hepatocellular Carcinoma tissues and adjacent normal tissues from 44 hepatocellular carcinoma patients were prepared for this study. The HepG2 and BEL 7402 cells were transfected with miR-214-5p mimic and inhibitor. qRT-PCR was performed to detect the expressions of miR-214-5p. Transwell assays were used to detect the invasion and migration assays in HepG2 and BEL-7402 cells. A dual luciferase reporter assay was conducted to examine the effect of miR-214-5p on Wiskott-Aldrich Syndrome Like (WASL/ N-WASP). Western blot and qRT-PCR were used to measure the expressions of the E-cadherin, N-cadherin and Vimentin proteins. Transwell chamber assays were performed to detect cell invasion and migration. RESULTS: Compared with normal tissues, HCC tissues demonstrated significantly lower expression of miR-214-5p. Overexpression of miR-214-5p significantly inhibited the migration and invasion of HCC cells and inhibition of miR-214-5p promoted the migration and invasion. Additionally, miR-214-5p suppressed the epithelial-mesenchymal transition (EMT). Further study showed WASL was a putative target gene of miR-214-5p. Up-regulating the expression of WASL could reverse the inhibition effect of miR-214-5p on invasion and migration. CONCLUSION: Our data suggested that miR-214-5p inhibited the invasion and migration of HepG2 and BEL 7402 by targeting WASL in Hepatocellular carcinoma. PMID- 29621774 TI - Role of Alpha-Smooth Muscle Actin and Fibroblast Activation Protein Alpha in Ovarian Neoplasms. AB - BACKGROUND/AIMS: Studies show that tumor growth is not just determined by the presence of malignant cells, since interactions between cancer cells and stromal microenvironment have important impacts on the cancer growth and progression. Cancer-associated fibroblasts play a prominent role in this process. The aims of the study were to investigate 2 cancer-associated fibroblasts markers, alpha smooth muscle actin (alpha-SMA), and fibroblast activation protein alpha (FAP) in the stromal microenvironment of benign and malignant ovarian epithelial neoplasms, and to relate their tissue expression with prognostic factors in ovarian cancer. METHODS: alpha-SMA and FAP were evaluated by immunohistochemistry in malignant (n = 28) and benign (n = 28) ovarian neoplasms. Fisher's exact test was used with a significance level lower than 0.05. RESULTS: FAP immunostaining was stronger in ovarian cancer when compared to benign neoplasms (p = 0.0366). There was no significant difference in relation to alpha-SMA expression between malignant and benign ovarian neoplasms as well as prognostic factors. In ovarian cancer, FAP stainings 2/3 was significantly related to histological grades 2 and 3 (p = 0.0183). CONCLUSION: FAP immunostaining is more intense in malignant neoplasms than in benign ovarian neoplasms, as well as in moderately differentiated and undifferentiated ovarian carcinomas compared to well differentiated neoplasms, thus indicating that it can be used as a marker of worse prognosis. PMID- 29621776 TI - Carnosine Catalyzes the Formation of the Oligo/Polymeric Products of Methylglyoxal. AB - BACKGROUND/AIMS: Reactive dicarbonyl compounds, such as methylglyoxal (MG), contribute to diabetic complications. MG-scavenging capacities of carnosine and anserine, which have been shown to mitigate diabetic nephropathy, were evaluated in vitro and in vivo. METHODS: MG-induced cell toxicity was characterized by MTT and MG-H1-formation, scavenging abilities by Western Blot and NMR spectroscopies, cellular carnosine transport by qPCR and microplate luminescence and carnosine concentration by HPLC. RESULTS: In vitro, carnosine and anserine dose-dependently reduced N-carboxyethyl lysine (CEL) and advanced glycation end products (AGEs) formation. NMR studies revealed the formation of oligo/polymeric products of MG catalyzed by carnosine or anserine. MG toxicity (0.3-1 mM) was dose-dependent for podocytes, tubular and mesangial cells whereas low MG levels (0.2 mM) resulted in increased cell viability in podocytes (143+/-13%, p<0.001) and tubular cells (129+/-3%, p<0.001). Incubation with carnosine/anserine did not reduce MG-induced toxicity, independent of incubation times and across large ranges of MG to carnosine/anserine ratios. Cellular carnosine uptake was low (<0.1% in 20 hours) and cellular carnosine concentrations remained unaffected. The putative carnosine transporter PHT1 along with the taurine transporter (TauT) was expressed in all cell types while PEPT1, PEPT2 and PHT2, also belonging to the proton-coupled oligopeptide transporter (POT) family, were only expressed in tubular cells. CONCLUSION: While carnosine and anserine catalyze the formation of MG oligo/polymers, the molar ratios required for protection from MG-induced cellular toxicity are not achievable in renal cells. The effect of carnosine in vivo, to mitigate diabetic nephropathy may therefore be independent upon its ability to scavenge MG and/or carnosine is mainly acting extracellularly. PMID- 29621775 TI - Association of Polymorphisms of Serotonin Transporter (5HTTLPR) and 5-HT2C Receptor Genes with Criminal Behavior in Russian Criminal Offenders. AB - BACKGROUND: Human aggression is a heterogeneous behavior with biological, psychological, and social backgrounds. As the biological mechanisms that regulate aggression are components of both reward-seeking and adversity-fleeing behavior, these phenomena are difficult to disentangle into separate neurochemical processes. Nevertheless, evidence exists linking some forms of aggression to aberrant serotonergic neurotransmission. We determined possible associations between 6 serotonergic neurotransmission-related gene variants and severe criminal offenses. METHODS: Male Russian prisoners who were convicted for murder (n = 117) or theft (n = 77) were genotyped for variants of the serotonin transporter (5HTTLPR), tryptophan hydroxylase, tryptophan-2,3-dioxygenase, or type 2C (5-HT2C) receptor genes and compared with general-population male controls (n = 161). Prisoners were psychologically phenotyped using the Buss Durkee Hostility Inventory and the Beck Depression Inventory. RESULTS: No differences were found between murderers and thieves either concerning genotypes or concerning psychological measures. Comparison of polymorphism distribution between groups of prisoners and controls revealed highly significant associations of 5HTTLPR and 5-HTR2C (rs6318) gene polymorphisms with being convicted for criminal behavior. CONCLUSIONS: The lack of biological differences between the 2 groups of prisoners indicates that the studied 5HT-related genes do not differentiate between the types of crimes committed. PMID- 29621778 TI - Dermal Filler Injections Mimic Tumor Activity during Immune Checkpoint Inhibition. PMID- 29621777 TI - Loading MiR-210 in Endothelial Progenitor Cells Derived Exosomes Boosts Their Beneficial Effects on Hypoxia/Reoxygeneation-Injured Human Endothelial Cells via Protecting Mitochondrial Function. AB - BACKGROUND/AIMS: Stem cell-derived exosomes (EXs) offer protective effects on various cells via their carried microRNAs (miRs). Meanwhile, miR-210 has been shown to reduce mitochondrial reactive oxygen species (ROS) overproduction. In this study, we determined the potential effects of endothelial progenitor cell derived EXs (EPC-EXs) on hypoxia/ reoxygenation (H/R) injured endothelial cells (ECs) and investigated whether these effects could be boosted by miR-210 loading. METHODS: Human EPCs were used to generate EPC-EXs, or transfected with scrambler control or miR-210 mimics to generate EPC-EXssc and EPC-EXsmiR-210. H/R-injured human ECs were used as a model for functional analysis of EXs on apoptosis, viability, ROS production and angiogenic ability (migration and tube formation) by flow cytometry, MTT, dihydroethidium and angiogenesis assay kits, respectively. For mechanism analysis, the mitochondrion morphology, membrane potential (MMP), ATP level and the expression of fission/fusion proteins (dynamin related protein 1: drp1 and mitofusin-2: mfn2) were assessed by using JC-1 staining, ELISA and western blot, respectively. RESULTS: 1) Transfection of miR 210 mimics into EPCs induced increase of miR-210 in EPC-EXsmiR-210 without change of average size; 2) EPC-EXsmiR-210, but not EPC-EXs or EPC-EXssc, significantly elevated miR-210 level in ECs; 3) EPC-EXsmiR-210 were more effective than EPC-EXs and EPC-EXssc in reducing H/R-induced EC apoptosis, ROS overproduction and angiogenic dysfunction; 4) EPC-EXs decreased mitochondrial fragmentation, elevated MMP and ATP level, as well as improved mitochondrial mfn2 and drp1 dysregulation, which were more effective in EPC-EXsmiR-210. CONCLUSION: Our results suggest that EPC-EXs protect ECs against H/R injury via improving mitochondrial function and miR-210 enrichment could boost their effects. PMID- 29621779 TI - Vessel Morphologies of the Brain in Cytological Squash Preparations Are Useful for Intraoperative Diagnosis of High-Grade Astrocytomas. AB - OBJECTIVE: The aim of this study was to determine whether intraoperative cytological evaluation of squash preparations is of benefit for differentiating high-grade from low-grade astrocytomas. METHODS: Squash preparations of 42 astrocytomas were classified histologically according to the World Health Organization (WHO) 2007 classification system as grade II (n = 12), grade III (n = 11), and grade IV (n = 19) and were divided into 2 groups, namely a low-grade group (grade II) and a high-grade group (grades III and IV). The focus was on morphological cell and vessel characteristics, namely nuclear atypia, chromatin pattern, nuclear enlargement, variation in nuclear size, the presence of nucleoli, mitosis, tumor necrosis, cell density, multibranched vessels, and vascular dilatation, and these characteristics were compared between the low- and high-grade groups. RESULTS: Nuclear atypia, the presence of coarse chromatin, variations in nuclear size, and cell density >=200 per high-power field were significantly more prevalent in high- than in low-grade astrocytomas (p = 0.0407, p < 0.01, p < 0.01, and p < 0.01, respectively). Vessels with > 3 branches and a mean vessel diameter >=20 MUm were more prevalent in high- than in low-grade astrocytomas (p < 0.01). CONCLUSION: Squash preparation cytology provides added benefit for the intraoperative identification of high-grade astrocytoma. PMID- 29621781 TI - The Burden of Untreated Hepatitis C Virus Infection in Renal Patients in the United Kingdom. PMID- 29621780 TI - Short-Term Results of Intravitreal Triamcinolone Acetonide Combined with Cataract Surgery for Diabetic Macular Edema in Japan: In the Era of Anti-Vascular Endothelial Growth Factor Therapy. AB - PURPOSE: To evaluate the effectiveness of an intravitreal triamcinolone acetonide injection (IVTA) combined with cataract surgery for diabetic macular edema (DME) resistant to anti-vascular endothelial growth factor (anti-VEGF) therapy. PROCEDURE: IVTA combined with cataract surgery was performed on 29 eyes of patients with DME (aged 70.5 +/- 6.2 years) who were refractive to anti-VEGF treatments. The visual acuity, central retinal thickness (CRT), and the central retinal sensitivity were assessed at 1, 4, 12, and 24 weeks after the treatment. RESULTS: The visual acuity improved significantly from 0.49 +/- 0.30 logMAR units to 0.35 +/- 0.33 logMAR units at 24 weeks after the treatment (p < 0.05; repeated ANOVA). The CRT decreased significantly from 435.1 +/- 112.3 MUm to 350.8 +/- 123.3 MUm at 12 weeks after the treatment (p < 0.05). The retinal sensitivity threshold also improved significantly from 18.2 +/- 4.3 dB to 20.4 +/- 3.8 dB at 4 weeks after the treatment (p < 0.05). CONCLUSIONS: IVTA combined with cataract surgery is effective for successful treatment of eyes with DME refractive to anti VEGF therapy. PMID- 29621782 TI - Enhanced Pro-Inflammatory Response of Macrophages to Interleukin-33 in an Allergic Environment. AB - BACKGROUND: Allergic asthma is common in childhood and is associated with a T helper type 2 (Th2)-biased immunological response. Exacerbations of asthma are characterised by increased inflammation of the airways, which appears to be driven by interleukin (IL)-33 that can activate pulmonary macrophages. The Th2 cytokine environment of allergic asthma may contribute to exaggerated airway inflammation. OBJECTIVES: To test this, we assessed whether production of pro inflammatory cytokines by IL-33-stimulated macrophages was enhanced in cells pre treated with the key Th2 cytokines IL-4 and IL-13. We also investigated whether this was associated with altered expression of regulatory microRNAs (miRNAs). METHODS: RAW264.7 cells cultured with IL-4 and IL-13 for 48 h were stimulated with IL-33 for 4 h. Pro-inflammatory mediators were assessed using quantitative real-time PCR (RT-PCR). Expression of miRNAs was assessed using microarrays and RT-PCR. In further experiments, we examined whether resolvin E1 (RvE1), which promotes the resolution of experimental asthmatic inflammation in vivo, could suppress the enhanced response by treating cells with RvE1 concurrently with IL 33 stimulation. RESULTS: In cells pre-treated with IL-4 and IL-13, expression of mRNA for Ccl3, Ccl5, Ccl17, Ccl24, and Il1b in response to IL-33 stimulation was significantly increased. This was paralleled by up-regulated expression of miR 155-5p, a miRNA that is predicted to regulate several aspects of allergic inflammation. RvE1 suppressed the enhanced production of Ccl3, Ccl5, Ccl24, and Il1b. CONCLUSIONS: We conclude that IL-33-activated macrophages may contribute to the exaggerated airway inflammation in exacerbations of allergic asthma, and that RvE1 has potential as a therapeutic agent that targets macrophages. PMID- 29621783 TI - Prevalence and Genotype Distribution of Hepatitis C Virus Infection among Patients with Type 2 Diabetes Mellitus. AB - OBJECTIVE: This study was conducted to determine the prevalence and genotype distribution of hepatitis C virus (HCV) infection among patients with type 2 diabetes mellitus (DM). SUBJECTS AND METHODS: We included 556 consecutive patients with confirmed type 2 DM attending the Diabetic Clinic of the Bushehr University of Medical Sciences and 733 nondiabetic subjects as controls. Serum levels of fasting blood sugar (FBS), alanine transaminase (ALT), aspartate transaminase (AST), total cholesterol (TCH), and triglycerides (TG) were measured by enzymatic colorimetric methods, and the presence of anti-HCV antibodies was determined by enzyme-linked immunosorbent assay. Semi-nested reverse transcriptase-polymerase chain reaction (RT-PCR) followed by sequencing was performed on all anti-HCV-seropositive samples. Data were analyzed using the Statistical Package for the Social Sciences 17, and descriptive statistics, chi2 test, Fisher exact test, and the Student t test were used for analysis. RESULTS: The seroprevalence of HCV in the diabetic patients was 1.98% (11/556), which was higher than HCV prevalence among the nondiabetic controls (4/733, 0.54%) (p = 0.032). No significant differences in ALT, AST, FBS, TG, and TCH levels were found between the HCV-seropositive and HCV-seronegative diabetic patients, although HCV-seropositive diabetic patients tended to have higher ALT, AST, and TCH levels, but lower TG and FBS levels than HCV-seronegative patients. In logistic regression analysis, only AST levels were significantly associated with HCV seropositivity among diabetic patients. The AST level of 41-80 IU/L was the only significant predictive variable for HCV seropositivity in the diabetic patients (odds ratio, 4.89; 95% CI: 1.06-22.49; p = 0.041). Of the 11 HCV seropositive diabetic patients, 10 (91%) had HCV viremia with genotype 3a. CONCLUSION: Patients with type 2 DM had a higher prevalence of HCV infection than controls, and HCV seropositivity was independent of biochemical parameters. PMID- 29621784 TI - Exosomes Derived from Dendritic Cells Attenuate Liver Injury by Modulating the Balance of Treg and Th17 Cells After Ischemia Reperfusion. AB - BACKGROUND/AIMS: The present study aimed to evaluate the effects as well as the underlying mechanisms of bone marrow-derived dendritic cells (BMDCs) and exosomes produced by BMDCs (DEXs) on hepatic ischemia-reperfusion (I/R) injury (IRI). METHODS: Primary hepatocytes were isolated and used to mimic the liver IR microenvironment. BMDCs were induced and characterized both biochemically with a flow cytometer (FCM) and biophysically with a microscope. Then, we exposed BMDCs to the supernatants from primary hepatocytes and evaluated the maturation of BMDCs by FCM. BMDCs were systemically injected into mice before liver IR via the tail vein, and the therapeutic effects were evaluated. The serum levels of transaminases (aspartate aminotransferase (AST) and alanine aminotransferase (ALT), inflammatory cytokines, and histological changes were respectively examined by ELISA, RT-qPCR and microscopy. Furthermore, we isolated DEXs by ultracentrifugation, characterized DEXs by transmission electron microscopy (TEM) and nanosight tracking analysis (NTA) and western blotting (WB), and then we co cultured BMDCs/DEXs and naive T cells and performed FCM, ELISA and confocal imaging. Moreover, we injected DEXs into mice prior to liver IR via the tail vein and examined its therapeutic effects by microscopy and ELISA. Finally, inhibitors of HSP70 (cmHSP70.1), PI3K (BKM120) and mTOR (Rapamycin) were used to investigate the role of HSP70 and the PI3K/mTOR axis in the effects of DEXs on naive T cells by WB and FCM. RESULTS: Bone marrow cells were efficiently induced into dendritic cells (DCs) with typical DC characteristics. The supernatants from primary hepatocytes exposed to H/R upregulated DC maturation markers. After DC administration, liver IR injury was improved with histopathological scores and serum transaminases. Additionally, we found that the anti-inflammatory cytokines TGF-beta, Foxp3 and interleukin (IL)-10 were upregulated and that IL-17 was downregulated. Furthermore, confocal imaging revealed that the uptake of H/R-DEXs by naive T cells was greater than that of DEXs derived from the control or negative group of BMDCs, and this increase was correlated with a significantly greater degree of differentiation of Tregs and Th17 cells. Moreover, H/R-DEXs administration improved liver function in mice after IR. Finally, the inhibition of HSP70, PI3K and mTOR completely abolished the effect of DEXs on naive T cells. CONCLUSION: These results demonstrated that BMDCs and DEXs could alleviate hepatic I/R injury via modulating the balance between Tregs and Th17 cells. DEXs transported HSP70 into naive T cells and stimulated the PI3K/mTOR axis to modulate the balance between Tregs and Th17 cells and protect the liver from IR injury. PMID- 29621787 TI - VegMed: "VegMed - Scientific Congress for Plant-based Nutrition and Medicine", April, 20-22, 2018, Berlin: Abstracts. PMID- 29621785 TI - Perioperative Changes and Progress in Photoselective Vaporization of the Prostate with GreenLight XPS 180 W System: A Single Center Experience. AB - PURPOSE: The study aimed to evaluate progression of GreenLight-XPS 180 W photoselective vaporization of the prostate (GL-XPS) with respect to effectiveness, efficacy, and safety over time at a tertiary referral high volume center. METHODS: The retrospective study included 375 men who underwent GL-XPS for symptomatic benign prostate obstruction (BPO) between June 2010 and February 2015. Primary outcome measurements were operation time (OT; min) and effective laser time (LT; min of OT) analyzed with regard to prostatic volume (PV; mL) (group 1 <40 mL up to 4 >80 mL in 20 mL steps) and the year of surgery (2010 2015). RESULTS: The median age was 72 years (range 64-79), the median PV was 58 mL (range 33-98) and the median PV increased from 42 mL in 2012 to 80 mL in 2015. The OT and LT clearly correlated with the PV, being doubled for glands of median 95 mL compared to median 30 mL while the applied laser energy per LT likewise steadily increased. Overall, both OT and LT could be significantly reduced each year by 37% (OT; p < 0.05) and 36% (LT; p < 0.05) within 5 years. The hospital stay (days) and catheterization time (days) remained constant, without any changes over time. The overall complication rate (Clavien-Dindo >2) ranged from 36 to 15% between 2010 and 2015. The pre (median 22 + 4) and postoperative International Prostate Symptom Score-Quality of Life (median 5 + 1) showed a sufficient reduction in symptomatic BPO. CONCLUSION: GL-XPS is a safe and effective surgical method for symptomatic BPO. Our single center experience showed a significant improvement of both OT and effective LT within 5 years whilst maintaining stable low complication rate and high patient satisfaction. PMID- 29621786 TI - Relationship between the von Willebrand Factor Plasma Concentration and Ultrasonographic Doppler Findings in Pregnancies Complicated by Hypertensive Disorders: A Pilot Study. AB - BACKGROUND/AIMS: Recent evidence suggests that impaired cytotrophoblast proliferation and migration are major factors responsible for the development of hypertension in pregnancy. Studies report that von Willebrand factor (vWf) is a specific endothelial damage plasma marker. The aim of this study was to evaluate the relationship between vWf maternal plasma concentration and maternal and fetal Doppler flow measurements in pregnancies complicated by hypertension. It may provide additional insight into the pathophysiology of pregnancy-related hypertension and show the potential method for disease prevention and therapy. METHODS: We created 3 study groups: pregnant women with chronic hypertension (n = 10), gestational hypertension (n = 18), preeclampsia (n = 21), and control (22 healthy pregnant women). Every woman underwent ultrasound Doppler flow measurements performed simultaneously with venous blood collection. The vWf plasma concentrations were assessed using the commercially available enzyme linked immunosorbent assay kit. RESULTS: The preeclampsia group had significantly higher vWf plasma concentrations in those patients with ultrasonographic features of placental insufficiency than in those without these characteristics (638 +/- 208 vs. 377 +/- 74 ng/mL; p < 0.017). CONCLUSION: Our results may confirm the arrangement and severity of endothelial damage in preeclamptic patients and may have identified those patients with a significantly higher risk of developing cardiovascular disease. PMID- 29621788 TI - Characteristics of Early Oropharyngeal Dysphagia in Patients with Multiple System Atrophy. AB - BACKGROUND/AIMS: Dysphagia, a symptom of multiple system atrophy (MSA), is a major clinical concern. In this study, we investigate the characteristics of early oropharyngeal dysphagia (OD) in patients with MSA, and the differences between MSA subtypes. METHODS: Patients enrolled in the study had previously been diagnosed with MSA at the clinic of the Department of Neurology, and had been referred for a videofluoroscopic swallowing study (VFSS), between 2005 and 2014, to check for dysphagia. The clinical characteristics and VFSS findings were analyzed and compared between the MSA subtypes. RESULTS: This study enrolled 59 patients with MSA (24 men; 31 with MSA-P, 21 with MSA-C, and 7 with MSA-PC). Dysphagia symptoms were mostly limited to aspiration symptoms (90.48%) in patients with MSA-C, while difficulty in swallowing, increased mealtime, and drooling were frequent in those with MSA-P. The most common VFSS finding amongst patients was vallecular residue (n = 53, 89.8%), followed by penetration/aspiration (n = 40, 67.8%), and coating of the pharyngeal wall (n = 39, 66.1%). Comparison analysis between subtypes showed that apraxia and vallecular residue were more frequent and severe in MSA-P than in MSA-C (p = 0.033 and p = 0.010, respectively). CONCLUSION: Understanding early OD characteristics in patients with MSA and the differences between MSA subtypes could be helpful in managing dysphagia in patients with MSA. Several dysphagia symptoms similar to those of Parkinson disease were frequently observed in MSA-P, but not in MSA-C. A follow-up study is needed to elucidate the natural course of OD in MSA patients and the difference between MSA subtypes. PMID- 29621794 TI - Introduction to the Clinical Forum: Exploring Curriculum-Based Language Assessment and Interventions. AB - Purpose: The purpose of this article is to introduce the Clinical Forum: Exploring Curriculum-Based Language Assessment and Interventions, which investigates the current evidence supporting curriculum-based language intervention and assessment. Method: This introduction highlights the need for speech-language pathologists to approach intervention with knowledge of the best evidence available and highlights the 6 articles presented in this clinical forum. Conclusion: The articles in this clinical forum shed light on the current state of the evidence for curriculum-based language intervention and assessment across the educational continuum. Authors provide readers with access to techniques available to all school-based speech-language pathologists to advocate for, assess, and implement interventions within the classroom curriculum. This forum also establishes the need for more data to support current school-based models of assessment and intervention. PMID- 29621789 TI - Temporal Trends of Stroke Epidemiology in Southern Sweden: A Population-Based Study on Stroke Incidence and Early Case-Fatality. AB - BACKGROUND: Up-to-date epidemiological stroke studies are important for healthcare planning and evaluating prevention strategies. This population-based study investigates temporal trends in stroke incidence and case-fatality in southern Sweden. METHODS: First-ever stroke cases in the local catchment area of Skane University Hospital in Lund, Sweden, between March, 2015 and February, 2016, were included from several sources, including 2 prospective hospital-based registers, retrospective screening of primary care visits, and autopsy registers. Stroke incidence and 28-day case-fatality rates were compared with data from this area obtained through similar methodology between March, 2001 and February, 2002. RESULTS: Altogether, 456 and 413 first-ever stroke patients were identified during the earlier and later time periods respectively. The age- and sex standardized stroke incidence rates decreased from 246 (95% CI 224-270) to 165 (95% CI 149-182) per 100,000 people. However, incidence remained unaltered among those <65 years. Early case-fatality decreased from 14 to 11% (p = 0.165). Conclusion: First-ever stroke incidence in southern Sweden has decreased with 33% since the beginning of this millenni-um. Incidence rates have decreased among the elderly but remain unchanged among younger age groups. Our findings warrant further studies on trends in risk factor profiles and effects of prevention strategies, and heightened focus on stroke in the young. PMID- 29621795 TI - Unique Contributors to the Curriculum: From Research to Practice for Speech Language Pathologists in Schools. AB - Purpose: This lead article of the Clinical Forum focuses on the research that supports why speech-language pathologists (SLPs) are an integral part of the overarching curriculum for all students in schools. Method: Focus on education has shifted to student performance in our global world, specifically in college and career readiness standards. This article reviews recommendations on best practice from the American Speech-Language-Hearing Association on SLPs' roles in schools, as well as data on school-based services. Implementation of these practices as it is applicable to school initiatives will be explored. Methods of interventions available in schools, from general education to special education, will be discussed based on national guidelines for a Response to Intervention and Multi-Tiered System of Support. Research regarding teacher knowledge of the linguistic principles of reading instruction will be explored, as well as correlation between teacher knowledge and student performance. Results: The implications for how SLPs as the linguistic experts offer unique roles in curriculum and the evidence available to support this role will be explored. Implications for future research needs will be discussed. Conclusion: The demands of a highly rigorous curriculum allow SLPs a unique opportunity to apply their knowledge in linguistic principles to increase student performance and achievement. With the increased focus on student achievement, growth outcome measures, and value-added incentives, it is critical that SLPs become contributors to the curriculum for all students and that data to support this role are gathered through focused research initiatives. PMID- 29621796 TI - Laying a Firm Foundation: Embedding Evidence-Based Emergent Literacy Practices Into Early Intervention and Preschool Environments. AB - Purpose: As part of this clinical forum on curriculum-based intervention, the goal of this tutorial is to share research about the importance of language and literacy foundations in natural environments during emergent literacy skill development, from infancy through preschool. Following an overview of intervention models in schools by Powell (2018), best practices at home, in child care, and in preschool settings are discussed. Speech-language pathologists in these settings will be provided a toolbox of best emergent literacy practices. Method: A review of published literature in speech-language pathology, early intervention, early childhood education, and literacy was completed. Subsequently, an overview of the impact of early home and preschool literacy experiences are described. Research-based implementation of best practice is supported with examples of shared book reading and child-led literacy embedded in play within the coaching model of early intervention. Finally, various aspects of emergent literacy skill development in the preschool years are discussed. These include phonemic awareness, print/alphabet awareness, oral language skills, and embedded/explicit literacy. Results: Research indicates that rich home literacy environments and exposure to rich oral language provide an important foundation for the more structured literacy environments of school. Furthermore, there is a wealth of evidence to support a variety of direct and indirect intervention practices in the home, child care, and preschool contexts to support and enhance all aspects of oral and written literacy. Conclusions: Application of this "toolbox" of strategies should enable speech-language pathologists to address the prevention and intervention of literacy deficits within multiple environments during book and play activities. Additionally, clinicians will have techniques to share with parents, child care providers, and preschool teachers for evidence based literacy instruction within all settings during typical daily activities. PMID- 29621797 TI - Curriculum-Based Language Interventions: What, Who, Why, Where, and How? AB - Purpose: School-based speech-language pathologists (SLPs) have been asked to be contributors to the educational curriculum (American Speech-Language-Hearing Association, 2010). The aim of this tutorial is to provide elementary school based SLPs with a guide to explore curriculum-based language interventions (CBLIs) in their practices. Method: In this tutorial, the authors (a) describe CBLI, (b) review the existing literature available to guide this type of practice in elementary school, (c) provide examples of how we have explored CBLIs, and (d) discuss the existing barriers for implementing CBLIs in schools. Conclusion: SLPs have language and literacy expertise qualifying us to be well-suited for playing an important role in supporting CBLI. The information presented in this article provides school-based SLPs with support to implement CBLIs in early elementary school and illustrates the need for additional evidence to support CBLIs. PMID- 29621798 TI - Facilitating Postsecondary Transition and Promoting Academic Success Through Language/Literacy-Based Self-Determination Strategies. AB - Purpose: As noted by Powell (2018), speech-language pathologists (SLPs) are an integral part of the overarching curriculum for all students in schools, and this holds true for adolescents who require transition planning. The purpose of this tutorial is to focus on transition planning for secondary school students with a language-based learning disability (LLD) and provide a case illustration for how SLPs may use self-determination strategies to facilitate postsecondary transition while promoting academic success. Method: As students with LLD enter secondary school, they are expected to write and think at more complex levels than ever before to meet post-graduation workforce demands, yet the provision of needed language-literacy intervention services drastically declines. Teaching students with LLD self-determination skills, such as awareness of their own strengths and limitations, self-advocacy strategies, and self-regulation, is found to be related to positive post-school outcomes and can be readily integrated into transition planning by the SLP. Conclusion: SLPs may ideally support secondary school student language-literacy needs in transition planning by using self determination strategies to help access the curriculum and experience postsecondary success. PMID- 29621799 TI - Curriculum-Based Language Assessment With Culturally and Linguistically Diverse Students in the Context of Mathematics. AB - Purpose: The purpose of this tutorial is to discuss the use of curriculum-based language assessment (CBLA) with students who are English language learners and students who speak nonmainstream varieties of English, such as African American English. Method: The article begins with a discussion of the discourse of mathematics and the role of the speech-language pathologist (SLP), followed by a review of studies that includes those that examined the performance of English language learner and nonmainstream dialect-speaking students on word-based math items. Results: The literature review highlights the linguistic and content biases associated with word-based math problems. Useful strategies that SLPs and educators can incorporate in culturally and linguistically appropriate assessments are discussed. The tutorial ends with a discussion of CBLA as a viable assessment approach to use with culturally and linguistically diverse students. Conclusions: Tests used at national, state, and school levels to assess students' math abilities have associated linguistic bias and content bias often leading to an inaccurate depiction of culturally and linguistically diverse students' math skills. CBLA as an assessment method can be used by school-based SLPs to gather valid and useful information about culturally and linguistically diverse students' language for learning math. By using CBLA, SLPs can help modify curricular tasks in broader contexts in an effort to make math, including high level math, "accessible and achievable for all" students (American Speech Language-Hearing Association, 2017). PMID- 29621800 TI - Improving Narrative Production in Children With Language Disorders: An Early Stage Efficacy Study of a Narrative Intervention Program. AB - Purpose: As noted in this forum, more research is needed to support the work of school-based speech-language pathologists who are designing and implementing interventions for students with language disorders. This article presents the findings of a multiple-baseline, single-subject study that was conducted to assess the outcomes of an intervention designed to improve narrative discourse proficiency for children with language disorders. Method: Four school-age children with language disorders that included deficits in narration received an experimental version of a 3-phase narrative language intervention program called Supporting Knowledge in Language and Literacy (Gillam, Gillam, & Laing, 2014). Two additional children remained in baseline throughout the study and served as controls for history, testing, and maturation effects. Measures of story productivity (number of different words) and overall story complexity (Monitoring Indicators of Scholarly Language; Gillam, Gillam, Fargo, Olszewski, & Segura, 2016) were used to assess the children's self-generated narratives. Results: After the onset of treatment, all 4 children who received the narrative intervention made moderate-to-large improvements in narrative productivity (number of different words). Three of the 4 children also made moderate-to-large improvements in narrative complexity (Monitoring Indicators of Scholarly Language). The narrative abilities of the 2 children who did not receive intervention did not change over the course of the study. Conclusion: This study provides evidence for the feasibility of the Supporting Knowledge in Language and Literacy narrative instruction program for improving self-generated narratives by children with language disorders. Future research is needed to determine how gains in oral narration transfer to written narrative skills. PMID- 29621801 TI - Prologue: Toward Accurate Identification of Developmental Language Disorder Within Linguistically Diverse Schools. AB - Purpose: Although the 5 studies presented within this clinical forum include children who differ widely in locality, language learning profile, and age, all were motivated by a desire to improve the accuracy at which developmental language disorder is identified within linguistically diverse schools. The purpose of this prologue is to introduce the readers to a conceptual framework that unites the studies while also highlighting the approaches and methods each research team is pursuing to improve assessment outcomes within their respective linguistically diverse community. Method: A disorder within diversity framework is presented to replace previous difference vs. disorder approaches. Then, the 5 studies within the forum are reviewed by clinical question, type of tool(s), and analytical approach. Conclusion: Across studies of different linguistically diverse groups, research teams are seeking answers to similar questions about child language screening and diagnostic practices, using similar analytical approaches to answer their questions, and finding promising results with tools focused on morphosyntax. More studies that are modeled after or designed to extend those in this forum are needed to improve the accuracy at which developmental language disorder is identified. PMID- 29621802 TI - Classification Accuracy of Teacher Ratings When Screening Nonmainstream English Speaking Kindergartners for Language Impairment in the Rural South. AB - Purpose: We compared teacher ratings as measured by the Teacher Rating of Oral Language and Literacy (TROLL; Dickinson, McCabe, & Sprague, 2001, 2003) and Children's Communication Checklist-Second Edition (CCC-2; Bishop, 2006) to 2 established screeners, the Part II of the Diagnostic Evaluation of Language Variation-Screening Test (DELV-ST-II; Seymour, Roeper, & de Villiers, 2003) and Dynamic Indicators of Basic Early Literacy Skills-Next (DIBELS; Good, Gruba, & Kaminski, 2009), and then examined whether teacher ratings alone or when combined with the DELV-ST-II or DIBELS accurately classify nonmainstream English-speaking kindergartners by their clinical status. Method: Data came from 98 children who lived in the rural South; 47 spoke African American English, and 51 spoke Southern White English. Using the syntax subtest of the Diagnostic Evaluation of Language Variation-Norm Referenced (Seymour, Roeper, & de Villiers, 2005) as the reference standard, 43 were language impaired and 55 were typically developing. Analyses included analysis of variance, correlations, and discriminant function with sensitivity and specificity indices. Results: The TROLL, CCC-2, DELV-ST-II, and DIBELS showed clinical status but not dialect effects, and they correlated with each other, the Diagnostic Evaluation of Language Variation-Norm Referenced, and other language measures. Classification accuracies of all 4 tools were too low for screening purposes; however, empirically derived cut scores improved the results, and a discriminant function selected the TROLL and DELV-ST-II as optimal for determining who should be referred for an evaluation, with the TROLL yielding the highest level of sensitivity (77%). Conclusion: Findings support teacher ratings as measured by the TROLL when screening nonmainstream English-speaking kindergartners for language impairment in the rural South, while also calling for additional development and study of teacher rating tools and other screening instruments. Supplemental Material: https://doi.org/10.23641/asha.6007712. PMID- 29621803 TI - The Impact of Dialect Density on the Growth of Language and Reading in African American Children. AB - Purpose: The goal of the current study was to examine the impact of dialect density on the growth of oral language and reading skills in a sample of African American English (AAE)-speaking children reared in urban communities. Method: Eight hundred thirty-five African American children in first through fifth grades participated. Using an accelerated cohort design, univariate and bivariate growth models were employed to examine dialect density, oral language and reading, and the relationships between these variables. Results: For the univariate models, results indicated that (a) dialect density decreased over time by approximately 5% per year beyond first grade, (b) language skills improved approximately 0.5 SD per year, and (c) reading comprehension increased significantly from first to second grade and slowed 23% per year in second through fifth grades. Results from the bivariate models revealed that (a) dialect density and language ability are negatively associated, although dialect density did not affect change in language over time, and (b) higher dialect density is related to slower growth in reading. Conclusions: Findings from this investigation provide converging evidence for accounts in the extant literature particularly supporting a negative relationship between dialect density and oral language and between dialect density and reading while also contributing novel longitudinal evidence that suggests that changes in dialect use over time may be driven by oral language skills and that reading and dialect have a reciprocal relationship. PMID- 29621804 TI - A Multiyear Population-Based Study of Kindergarten Language Screening Failure Rates Using the Rice Wexler Test of Early Grammatical Impairment. AB - Purpose: The purpose of this study was to evaluate, over 2 separate school years, the school-district-wide failure rate of kindergartners on a screener of grammatical tense marking-the Rice Wexler Test of Early Grammatical Impairment (TEGI) Screening Test (Rice & Wexler, 2001)-composed of past tense (PT) and third person singular (3S) probes. Method: In the fall of 2 consecutive school years, consented and eligible kindergartners (n = 148 in Year 1, n = 126 in Year 2) in a rural southern school district were administered the TEGI Screening Test. Children who failed the screening test or either of the individual probes (PT or 3S) were administered the Primary Test of Nonverbal Intelligence. All children also completed the Test of Articulation Performance-Screen (Bryant & Bryant, 1983) and, in Year 2, the Get Ready to Read! emergent literacy screener (Whitehurst & Lonigan, 2001). Results: The screening tool outcome most closely and consistently aligned with the recommended failure rate of approximately 30% (Oetting, Gregory, & Riviere, 2016; based on Tomblin et al., 1997) was the TEGI PT probe. TEGI Screening Test and 3S probe failure rates fell below the recommended level. Most children who failed the PT probe demonstrated nonverbal intelligence skills within the average range. In addition, most children who failed the PT probe would not have been readily identified on the basis of only the results of their articulation or emergent literacy screenings. Conclusions: The TEGI PT probe is an efficient and reliable screener that identifies children for monitoring or additional language assessment. Children with language vulnerabilities are not necessarily identified by articulation or emergent literacy screenings at entry to kindergarten. To identify children at risk for language impairment, it is therefore necessary to directly screen oral language. PMID- 29621805 TI - Evaluating English Morpheme Accuracy, Diversity, and Productivity Measures in Language Samples of Developing Bilinguals. AB - Purpose: This work explores the clinical relevance of three measures of morpheme use for preschool-age Spanish-English bilingual children with varying language skills. The 3 measures reflect accuracy, diversity (the tense marker total), and productivity (the tense and agreement productivity score [TAP score]) of the English tense and agreement system. Method: Measures were generated from language samples collected at the beginning and end of the participants' preschool year. Participants included 74 typically developing Spanish-English bilinguals and 19 peers with low language skills. The morpheme measures were evaluated with regard to their relationships with other language sample measures, their ability to reflect group differences, and their potential for capturing morphological development at group and individual levels. Results: Across both groups, the tense marker total and TAP scores were associated with other language measures and demonstrated both group differences and growth over time. The accuracy measure met few of these benchmarks. Conclusion: The tense marker total and TAP score, which were designed to capture emerging morphological abilities, contribute valuable information to a comprehensive language assessment of young bilinguals developing English. Case examples are provided to illustrate the clinical significance of including these measures in assessment. PMID- 29621808 TI - In Vitro Human Dihydroorotate Dehydrogenase Inhibitory, Anti-inflammatory and Cytotoxic Activities of Alkaloids from the Seeds of Nigella glandulifera. AB - Four new dolabellane-type diterpene alkaloids, glandulamines A - D (1: - 4: ), together with twelve known compounds (5: - 16: ), were isolated from the seeds of Nigella glandulifera using repeated column chromatography and semipreparative HPLC. The structures of 1: - 16: were elucidated based on NMR data analysis, HRMS experiments and other spectroscopic interpretations. The absolute configuration of 5: was determined by single-crystal X-ray diffraction data for the first time. Compounds 10: and 12: showed human dihydroorotate dehydrogenase inhibitory activity with IC50 values of 61.1 +/- 5.3 and 45.9 +/- 3.0 uM, respectively. Molecular docking of the active compound 12: and positive control teriflunomide on the inhibitor-binding site of human dihydroorotate dehydrogenase was subsequently performed to visualize the interaction pattern. In addition, compounds 8: and 10: exhibited inhibitory effects against lipopolysaccharide induced nitric oxide production with inhibition rates of 61 and 41%, respectively, at the concentration of 10 uM. Compounds 9: and 12: showed cytotoxic activities with cell viability varying from 29 ~ 57% at 100 uM against T98G, U87, U251, and GL261 glioma cancer cell lines. These data provide new insights on the pharmacologically active compounds of this plant widely used in folk medicine. PMID- 29621806 TI - Understanding Disorder Within Variation: Production of English Grammatical Forms by English Language Learners. AB - Purpose: This study examines English performance on a set of 11 grammatical forms in Spanish-English bilingual, school-age children in order to understand how item difficulty of grammatical constructions helps correctly classify language impairment (LI) from expected variability in second language acquisition when taking into account linguistic experience and exposure. Method: Three hundred seventy-eight children's scores on the Bilingual English-Spanish Assessment Middle Extension (Pena, Bedore, Gutierrez-Clellen, Iglesias, & Goldstein, 2008) morphosyntax cloze task were analyzed by bilingual experience groups (high Spanish experience, balanced English-Spanish experience, high English experience, ability (typically developing [TD] vs. LI), and grammatical form. Classification accuracy was calculated for the forms that best differentiated TD and LI groups. Results: Children with LI scored lower than TD children across all bilingual experience groups. There were differences by grammatical form across bilingual experience and ability groups. Children from high English experience and balanced English-Spanish experience groups could be accurately classified on the basis of all the English grammatical forms tested except for prepositions. For bilinguals with high Spanish experience, it was possible to rule out LI on the basis of grammatical production but not rule in LI. Conclusions: It is possible to accurately identify LI in English language learners once they use English 40% of the time or more. However, for children with high Spanish experience, more information about development and patterns of impairment is needed to positively identify LI. PMID- 29621809 TI - ? PMID- 29621810 TI - [Secondary Full Title: Effects of high intensity interval training in plain and uphill regarding physical performance]. AB - BACKGROUND: As the number of HIITs is increasing in competitive and non competitive sports, the risk of injuries and overload is increasing. There are no scientific data to support specific recommendations in regard to intensity, duration, number of intervals and gradient for HIIT that result in improved muscular parameters in athletes. Therefore the aim of this study was to compare HIIT in plain and uphill exercise, with respect to exercise tolerance and improvements in performance (VO2max and 800 m running time in the plain and uphill). VOLUNTEERS AND METHODS: 17 well-trained sport students (10 females, 7 males; O VO2max: 53.7 ml/min/kg) were randomly assigned to the plain group (plain; GE) (n = 8) or the uphill group (hill, GB) (n = 9). In the four weeks of training, all subjects completed 14 HIIT sessions. Each session consisted of 8 * 2 min running at 90 - 95 % of the maximal heart rate (HRmax), separated by 2 min recovery periods (work/rest ratio: 1:1). Before the intervention phase, subjects performed treadmill spirometry, a 800 m field test in the plain, as well as an 800 m uphill field test to determine baseline performance. One week after the intervention period, all subjects completed a retest of all measurements and tests. After the intervention, all subjects completed a questionnaire by giving their level of perceived exertion during training, using the BORG scale. RESULTS: In GE, three subjects dropped out of the study because of overtraining. In GB, two subjects did not complete the study because of time constraints. The evaluation of the perceived exertion of the training in flat terrain showed a trend (p = 0.08; t = - 1.96) towards being perceived as more exhausting then in hilly terrain. A four week HIIT showed significant improvements in VO2max by 5.2 % (p = 0.02; t = - 2.76), and a reduction in the running time in the plain by 4.6 % (p = 0.01; t = 3.48) and uphill by 6.3 % (p = 0.02; t = 2.77). No significant group effect was detected. DISCUSSION AND CONCLUSION: In this study, the application of HIIT leads to significant improvements in the performance of well trained athletes. There is no evidence that the mode of training influenced the running improvements. However, uphill training tends to be better tolerated by the athletes. PMID- 29621811 TI - The Effects of Injected Vitamin D on Prognosis of Patients with Urosepsis. AB - The aim of this study was to evaluate the effect of prescribing vitamin D on improving the symptoms of patients diagnosed with urosepsis. The participants were randomly divided into two equal groups (each consisting of 50 patients). The patients in the first group received standard treatment with 300 000 units of injected vitamin with a volume of 1 cc. As for the patients in the second group, they received standard treatment along with 1 cc normal saline injected to them as placebo. Vital signs of the patients were checked every 6 h, while their CBC, EXR, CRP, creatinine, urea, and uric acid were checked 0, 24, 48, and 72 h following the interventions. Calcium, phosphorus, and vitamin D levels were measured 72 h following injection of the medicine. A significant difference was observed between the two groups in terms of the number of WBC's in 24th, 48th, and 72nd hours. A similarly significant difference was reported between the case and control group in terms of the average BUN within 24th, 48th, and 72nd hours. The difference observed between the two groups in terms of average Cr within the 0th, 24th, 48th, and 72nd hours and in terms of days of hospitalization was also significant. Considering these results and keeping in mind the fact that no particular side effects were reported as a result of utilizing muscular injections of vitamin D and the easy and cheap use of this medicine, it can be used in auxiliary treatment of patients with urosepsis. PMID- 29621812 TI - Systematic Review of Plant-Based Homeopathic Basic Research: An Update. AB - BACKGROUND: Plant-based test systems have been described as a useful tool for investigating possible effects of homeopathic preparations. The last reviews of this research field were published in 2009/2011. Due to recent developments in the field, an update is warranted. Publications on plant-based test systems were analysed with regard to publication quality, reproducibility and potential for further research. METHODS: A literature search was conducted in online databases and specific journals, including publications from 2008 to 2017 dealing with plant-based test systems in homeopathic basic research. To be included, they had to contain statistical analysis and fulfil quality criteria according to a pre defined manuscript information score (MIS). Publications scoring at least 5 points (maximum 10 points) were assumed to be adequate. They were analysed for the use of adequate controls, outcome and reproducibility. RESULTS: Seventy-four publications on plant-based test systems were found. Thirty-nine publications were either abstracts or proceedings of conferences and were excluded. From the remaining 35 publications, 26 reached a score of 5 or higher in the MIS. Adequate controls were used in 13 of these publications. All of them described specific effects of homeopathic preparations. The publication quality still varied: a substantial number of publications (23%) did not adequately document the methods used. Four reported on replication trials. One replication trial found effects of homeopathic preparations comparable to the original study. Three replication trials failed to confirm the original study but identified possible external influencing factors. Five publications described novel plant-based test systems. Eight trials used systematic negative control experiments to document test system stability. CONCLUSIONS: Regarding research design, future trials should implement adequate controls to identify specific effects of homeopathic preparations and include systematic negative control experiments. Further external and internal replication trials, and control of influencing factors, are needed to verify results. Standardised test systems should be developed. PMID- 29621813 TI - Cushing's Syndrome: A Historic Review of the Treatment Strategies and Corresponding Outcomes in a Single Tertiary Center over the Past Half-Century. AB - Cushing's syndrome (CS) is associated with serious comorbidities and an increased mortality rate that could be reduced only if strict biochemical control is achieved. The aim of this study was to show the 50-year experience of a single tertiary center in the management of CS patients - the different treatment modalities used over the years and the corresponding outcomes. It was a retrospective study of a large cohort of patients from the Bulgarian CS database: 613 patients (374 with ACTH-dependent and 239 with ACTH-independent CS). Pituitary surgery was applied to 242 patients with Cushing's disease (CD) with initial remission rate of 74% of which 10% relapsed. Approximately 36% manifested with active disease during the long-term follow-up (26% with persistent disease, 10% relapses) most of which were subjected to a secondary treatment (13.6% to pituitary resurgery, 14% to pituitary radiotherapy, and 5.4% to bilateral adrenalectomy). A total of 294 CD patients received medical therapy with overall remission rates for the most commonly used drugs: dopamine agonists 20%, pasireotide 30%, and ketoconazole 63%. Significant improvement of results was achieved by combining drugs with different mechanisms of action. Regardless of the progress in the neurosurgery and radiotherapy techniques and new drugs discovery, the management of patients with CS remains a real challenge for physicians. Not only patients with adrenal carcinoma but also significant percentage of subjects with persistent and recurrent Cushing's disease often require a polymodal approach and the efforts of a multidisciplinary highly qualified, experienced, and motivated team in order to achieve a long-term remission. PMID- 29621814 TI - A Meta-Analysis of the Associations Between the ATP-Binding Cassette Transporter ABCA1 R219K (rs2230806) Polymorphism and the Risk of Type 2 Diabetes in Asians. AB - Asians have relatively low insulin secretion capacity and readily develop type 2 diabetes mellitus (T2DM) when insulin resistant. For that reason, insufficient insulin secretion is critical factor for Asians at the early stage of T2DM. ATP binding cassette transporter1 (ABCA1) is a membrane protein responsible for cholesterol efflux and its function is also important for secreting insulin in pancreatic beta-cells. Given the importance of its role, different polymorphisms of ABCA1 gene might contribute differently to the development of T2DM. Here, we analyzed the association between a variant form of ABCA1 gene called ABCA1 rs2230806 and the prevalence of T2DM in a large sample size by pooling all of the case-control studies published. Relevant case-control studies were identified by searching PubMed, EMBASE, Cochrane Library, Korean scientific database, Chinese medical databases, and the Indian medical database. The association was evaluated using five genetic models such as the allelic (AG), recessive (RG), dominant (DG), homozygous (HMG), and heterozygous (HTG) genetic models. Heterogeneity of each genetic model was determined by the I2 test. A total of eight studies (7 published studies and one data set from the Korean Genetic Epidemiology Study) were eligible, satisfying Hardy-Weinberg equilibrium and included 2755 T2DM patients (case) and 16 635 nondiabetic subjects (control). All subjects in the studies were Asians. Each genetic model exhibited heterogeneity. In all genetic models, ABCA1 rs2230806 had a significant association with prevalence of T2DM: AG (OR=0.78, 95% CI: 0.61-0.98), RG (OR=0.72, 95% CI: 0.51-1.03), DG (OR=0.73, 95% CI: 0.55-0.97), HMG (OR=0.62, 95% CI: 0.41-0.96), and HTG (OR=0.78, 95% CI: 0.61 0.99). There was no single study that changed the overall effects in allelic genetic model with random effects. No publication bias existed in any models except the RG model. In conclusion, middle-aged and elderly adults with the minor allele of ABCA1 rs2230806 will have a lower risk of T2DM. This is the first meta analysis to evaluate the association in Asians. PMID- 29621816 TI - [Beginning of a new series: psychiatry and neurology based issues]. PMID- 29621815 TI - Influence of Stem Cell Therapy on Thyroid Function and Reactive Oxygen Species Production in Diabetic Rats. AB - Cell therapy with mesenchymal stem cells (MSC) has been proposed for the treatment of diabetes mellitus (DM). It is known that the prevalence of thyroid disease is higher among diabetic patients than in general population. Therefore, our aim was to investigate the effect of the treatment with MSC on thyroid function and ROS generation in an experimental model of type 1 DM. Adult male Wistar rats were divided into the following groups: control, DM (80 mg/kg BW streptozotocin, iv.) and DM+MSC. MSC treatment occurred 4 weeks after DM induction and the animals were euthanized 4 weeks after MSC administration. We also evaluated the effect of co-culture with MSC or extracellular vesicles (EV) obtained from these cells on the rat thyroid cell line PCCL3 exposed to high glucose. Thyroid H2O2 generation was increased in DM, which was reversed by MSC treatment. These changes paralled a significant DuOx1 mRNA increase. The incubation of PCCL3 with high glucose increased extracellular H2O2 generation, which was reversed by both the co-culture with MSC and EV. Even though MSC treatment normalized thyroid ROS generation, serum thyroid hormone (TH) concentration remained low, along with increased serum TSH concentrations. Thyroperoxidase (TPO) activity, was reduced in DM, and MSC treatment did not normalize TPO. Therefore, we conclude that the treatment with MSC was able to reverse the increased thyroid H2O2 generation in diabetic animals and in PCCL3 cells exposed to high glucose, an effect probably mediated by EV produced by these cells, acting in a paracrine fashion. PMID- 29621817 TI - [ICD-11: Current state of revision and further development]. PMID- 29621818 TI - [A new approach to classifying Personality Disorders]. AB - Starting from the still valid ICD-10 classification of personality disorders, this text presents the process initiated and led by the WHO that aims at a fundamental change of conceptualizing personality disorders in ICD-11. The categorical classification of differential types based on polythetic criteria list will be replaced by a widely dimensional classification; in case the general criteria of a personality disorder are given, three severity levels and five trait domains are differentiated. In the original draft of the ICD-11 group, the trait qualifiers were meant only to be used in the expert setting and the severity levels described psychosocial impacts only. Meanwhile a revised draft has been prepared by the International societies for the study of personality disorders which operationalize the severity levels in a more systematized way by describing functional impairments of the self as well as of interpersonal relationships, presenting symptoms concerning emotions, cognitions and behaviors and evaluating the psychosocial impacts. PMID- 29621819 TI - [ICD-11: Neurocognitive Disorders]. AB - The section 06 (Mental, Behavioural or Neurodevelopmental Disorders) of the current version Beta Draft (Mortality and Morbidity Statistics, 16.12.2017) of the ICD 11 (International Statistical Classification of Diseases and Related Health Problems) replaces the F0-section of the ICD-10. Several changes, particularly with regard to the classification of neurodegenerative disorders have been introduced. It can be considered a progress that the concept of "organic" syndromes has been dropped and that the section focusses on acquired conditions with cognition as the main area of symptoms. Regarding dementia, the 06 section still uses a syndromal approach of for example dementia due to Alzheimer disease (AD). The development of biomarkers and the molecular concept of AD is not incorporated, yet. In section 08 (Diseases of the Nervous System) Alzheimer disease without reference to symptoms can be classified, however, this section also misses reference to biomarkers, which leaves uncertainty of how the diagnosis should be made.In section 06 the condition of minor neurocognitive disorder was originally only defined as a syndrome without reference to a disease. This has been modified and it is now possible to classify the condition in association with a disease (e. g. AD), however, also without reference to biomarkers.The syndromal approach of section 06 is of value, since in many parts of the world, there is no access to AD biomarkers and all current therapies are tested and in some cases approved for Alzheimer dementia rather than AD as a molecular condition. The lack of any reference to AD biomarkers within ICD-11 so far, however, is a highly relevant limitation with the development of treatments, which target specific components of pathology (e. g. anti-amyloid treatment). PMID- 29621820 TI - [Mental disorders specifically associated with stress in the upcoming ICD-11: An overview]. AB - The release of upcoming ICD-11 results in important changes to the classification of stress-related mental disorders. With the aim to improve clinical utility there is a new organizational structure for the different disorders as they are now categorized by the response to specific types of stressors. These range from reactions based on the experience of psychosocial strains (adjustment disorder), to grief reactions with a need for treatment (prolonged grief disorder) and reactions after exposure to traumatic events (posttraumatic stress disorder), also with more complex clinical picture (complex posttraumatic stress disorder). This article gives an overview of the major changes in the shift in disorder categorization from ICD-10 to ICD-11. This includes prevalence rates, if available, as well as suggestions of measurement instruments for the purpose of clinical diagnostics. Furthermore, ongoing discussions among the research community will be considered. PMID- 29621821 TI - [Schizophrenia and other primary psychotic disorders in ICD-11]. AB - In the development of the International Classsification of Disorders (ICD-11), the World Health Organisation (WHO) has used a systematic approach with a focus on the utility of the revised classification criteria. For all major groups of mental and behavioural disorders working groups were set up, and these reviewed the scientific evidence and developed suggestions for revised classification criteria. These initial proposals, then submitted to public consultation and review, resulted in updated proposals. The chapter title for the primary psychotic disorders will be "Schizophrenia and other primary psychotic disorders". The clinical subtypes of schizophrenia will be substituted by symptom specifiers, which are applicable to all primary psychotic disorders. The role of Schneider's first-rank symptoms will be deemphasized. Course specifiers will be introduced and will be compatible with the U.S.-American classification system for mental disorders (Diagnostic and Statistical Manual, 5th revision, DSM-5). The group of Acute and Transient Psychotic Disorders will be more clearly differentiated from schizophrenia. Currently, field trials are under way both in clinical and internet-based settings to test the utility of the revised classification criteria. In early 2018, the final classification criteria of ICD 11 should be available. PMID- 29621823 TI - ? PMID- 29621822 TI - [Web-based field studies on diagnostic classification and code assignment of mental disorders: comparison of ICD-11 and ICD-10]. AB - The German Society for Psychiatry, Psychosomatics and Psychotherapy (DGPPN,) conducted a comprehensive field study (principal investigator WG) funded by the German Federal Ministry of Health in cooperation with 4 other German medical societies in the field of mental health (DGPM, DGPPR, DeGFS, DGfS) * to support WHO's development of the ICD-11 (Chapters 6 and 17). The objective of the web based field study was to compare ICD-10 and ICD-11 (beta draft) for selected mental disorders, regarding consistency, accuracy and assessment of utility. The first study (TP1) focused on the diagnostic classification and the second (TP2) on assignment of diagnostic codes.In TP1, clinicians used either the ICD-10 Clinical Descriptions and Diagnostic Guidelines (CDDG) version or a draft version of the ICD-11 CDDG to evaluate 10 case vignettes in a randomized study implemented through the WHO GCPN **. As hypothesized, consistency was in favor of the ICD-11 (p = .02; n = 319 expert participants) though there was some variability across the different diagnostic categories. In addition, time for diagnosis was shorter (p = .01) and clinicians' judgment of utility (ease of use; goodness of fit) was better for ICD-11 (p = .047 and p < .001 respectively).TP2 focused on consistency of diagnostic code assignment for 25 short case descriptions (including explicit diagnosis and additional clinical information) using both ICD-10 and ICD-11 in a randomized web-based field study which was run on the WHO ICD-FiT *** platform. Based on 531 code assignments by120 expert clinicians, consistency for ICD-11 was significantly lower compared to ICD-10 (71 % vs. 82 %, p < .001) contrary to study hypothesis, and time required was significantly higher for ICD-11 (p < .001). Nevertheless, utility assessments were in favor of ICD-11 (p < .005).In summary, in TP1, given vignettes with more complex clinical descriptions more similar to clinical cases, ICD-11 showed advantages in the consistency of correct diagnoses among clinicians, time required to reach a diagnosis, and clinicians' ratings of clinical utility. These results provide evidence for quality improvement of the diagnostic process due to the revision of the more complete diagnostic guidelines for ICD-11. In the coding task of TP2, coding by clinicians using the ICD-10 was more consistent and faster than coding using the ICD-11. This may be a result of the greater complexity for coding use of the ICD-11 (e. g., due to 'post-coordination'), as well as greater familiarity with the ICD-10 system (which German clinicians currently use) and lack of practice with the new ICD-11 codes and tools. In spite of this, users assessed the ICD-11 system as more useful than the ICD-10, in part also because of ICD-11's more systematic and comprehensive coding tools. In addition, time needed for coding improved with practice, indicating need for intense education and training initiatives when ICD-11 is adopted and implemented into clinical practice. PMID- 29621824 TI - True or false umbilical cord knot? Differentiation via 3D/4D color Doppler ultrasound. PMID- 29621826 TI - Cognitive Functions of the Fetus. AB - The human brain is intricately designed to execute cognitive functions, such as perception, attention, action, memory and learning. The complete nervous system is active during prenatal development and the aim of this review is to present data on fetal cognitive functions. The fetus processes sensory stimuli at a cortical level, including painful stimulus, from about 25 weeks of gestation onwards. At gestational week 34, the fetus is able not only to perceive complex acoustic external sounds but also to discriminate between different sounds. Fetal action planning is established by 22 weeks and investigations using four dimensional ultrasound reveal that complexity of fetal motor action and behavior increases as pregnancy progresses. The capacity of the fetus to learn and memory are prodigious. At term, subcortical structures of the brain are well developed. There is high activity in primary cortical areas and low activity in association areas. Clinically relevant data on cognitive functions of the fetus could be important for the management of fetal pain and treatment of preterm infants as well as for improved neurodevelopmental outcome of fetuses from high-risk pregnancies. Finally, the brain's developmental journey, including development of cognitive functions, continues with the same intensity in the postnatal period. PMID- 29621827 TI - Validation Of The Automated Electronic Microemboli Detection System. PMID- 29621828 TI - Response to letter to the editor: Microembolic Detection System. PMID- 29621830 TI - Validating UMLS Semantic Type Assignments Using SNOMED CT Semantic Tags. AB - BACKGROUND: The UMLS assigns semantic types to all its integrated concepts. The semantic types are widely used in various natural language processing tasks in the biomedical domain, such as named entity recognition, semantic disambiguation, and semantic annotation. Due to the size of the UMLS, erroneous semantic type assignments are hard to detect. It is imperative to devise automated techniques to identify errors and inconsistencies in semantic type assignments. OBJECTIVES: Designing a methodology to perform programmatic checks to detect semantic type assignment errors for UMLS concepts with one or more SNOMED CT terms and evaluating concepts in a selected set of SNOMED CT hierarchies to verify our hypothesis that UMLS semantic type assignment errors may exist in concepts residing in semantically inconsistent groups. METHODS: Our methodology is a four stage process. 1) partitioning concepts in a SNOMED CT hierarchy into semantically uniform groups based on their assigned semantic tags; 2) partitioning concepts in each group from 1) into the disjoint sub-groups based on their semantic type assignments; 3) mapping all SNOMED CT semantic tags into one or more semantic types in the UMLS; 4) identifying semantically inconsistent groups that have inconsistent assignments between semantic tags and semantic types according to the mapping from 3) and providing concepts in such groups to the domain experts for reviewing. RESULTS: We applied our method on the UMLS 2013AA release. Concepts of the semantically inconsistent groups in the PHYSICAL FORCE and RECORD ARTIFACT hierarchies have error rates 33% and 62.5% respectively, which are greatly larger than error rates 0.6% and 1% in semantically consistent groups of the two hierarchies. CONCLUSION: Concepts in semantically in - consistent groups are more likely to contain semantic type assignment errors. Our methodology can make auditing more efficient by limiting auditing resources on concepts of semantically inconsistent groups. PMID- 29621831 TI - SSDOnt: An Ontology for Representing Single-Subject Design Studies. AB - BACKGROUND: Single-Subject Design is used in several areas such as education and biomedicine. However, no suited formal vocabulary exists for annotating the detailed configuration and the results of this type of research studies with the appropriate granularity for looking for information about them. Therefore, the search for those study designs relies heavily on a syntactical search on the abstract, keywords or full text of the publications about the study, which entails some limitations. OBJECTIVE: To present SSDOnt, a specific purpose ontology for describing and annotating single-subject design studies, so that complex questions can be asked about them afterwards. METHODS: The ontology was developed following the NeOn methodology. Once the requirements of the ontology were defined, a formal model was described in a Description Logic and later implemented in the ontology language OWL 2 DL. RESULTS: We show how the ontology provides a reference model with a suitable terminology for the annotation and searching of single-subject design studies and their main components, such as the phases, the intervention types, the outcomes and the results. Some mappings with terms of related ontologies have been established. We show as proof-of-concept that classes in the ontology can be easily extended to annotate more precise information about specific interventions and outcomes such as those related to autism. Moreover, we provide examples of some types of queries that can be posed to the ontology. CONCLUSIONS: SSDOnt has achieved the purpose of covering the descriptions of the domain of single-subject research studies. PMID- 29621832 TI - Identifying Associations between Somatic Mutations and Clinicopathologic Findings in Lung Cancer Pathology Reports. AB - OBJECTIVE: We aim to build an informatics methodology capable of identifying statistically significant associations between the clinical findings of non-small cell lung cancer (NSCLC) recorded in patient pathology reports and the various clinically actionable genetic mutations identified from next-generation sequencing (NGS) of patient tumor samples. METHODS: We built an information extraction and analysis pipeline to identify the associations between clinical findings in the pathology reports of patients and corresponding genetic mutations. Our pipeline leverages natural language processing (NLP) techniques, large biomedical terminologies, semantic similarity measures, and clustering methods to extract clinical concepts in freetext from patient pathology reports and group them as salient findings. RESULTS: In this study, we developed and applied our methodology to lobectomy surgical pathology reports of 142 NSCLC patients who underwent NGS testing and who had mutations in 4 oncogenes with clinical ramifications for NSCLC treatment (EGFR, KRAS, BRAF, and PIK3CA). Our approach identified 732 distinct positive clinical concepts in these reports and highlighted multiple findings with strong associations (P-value <= 0.05) to mutations in specific genes. Our assessment showed that these associations are consistent with the published literature. CONCLUSIONS: This study provides an automatic pipeline to find statistically significant associations between clinical findings in unstructured text of patient pathology reports and genetic mutations. This approach is generalizable to other types of pathology and clinical reports in various disorders and can provide the first steps toward understanding the role of genetic mutations in the development and treatment of different types of cancer. PMID- 29621833 TI - An Image Processing and Genetic Algorithm-based Approach for the Detection of Melanoma in Patients. AB - Melanoma skin cancer is the most aggressive type of skin cancer. It is most commonly caused by excessive exposure to Ultraviolet radiation which triggers uncontrollable proliferation of melanocytes. Early detection makes melanoma relatively easily curable. Diagnosis is usually done using traditional methods such as dermoscopy which consists of a manual examination performed by the physician. However, these methods are not always well founded because they depend heavily on the physician's experience. Hence, there is a great need for a new automated approach in order to make diagnosis more reliable. In this paper, we present a twophase technique to classify images of lesions into benign or malignant. The first phase consists of an image processing-based method that extracts the Asymmetry, Border Irregularity, Color Variation and Diameter of a given mole. The second phase classifies lesions using a Genetic Algorithm. Our technique shows a significant improvement over other well-known algorithms and proves to be more stable on both training and testing data. PMID- 29621834 TI - Application of Accelerated Time Models to Compare Performance of Two Comorbidity adjusting Methods with APACHE II in Predicting Short-term Mortality Among the Critically Ill. AB - OBJECTIVE: This study aimed to determine how the abilities of the Charlson Index and Elixhauser comorbidities compared with the chronic health components of the Acute Physiology and Chronic Health Evaluation (APACHE II) to predict in-hospital 30 day mortality among adult critically ill patients treated inside and outside of Intensive Care Unit (ICU). METHODS: A total of 701 critically ill patients, identified in a prevalence study design on four randomly selected days in five acute care hospitals, were followed up from the date of becoming critically ill for 30 days or until death, whichever occurred first. Multiple data sources including administrative, clinical, pathology, microbiology and laboratory patient records captured the presence of acute and chronic illnesses. The exponential, Gompertz, Weibull, and log-logistic distributions were assessed as candidate parametric distributions available for the modelling of survival data. Of these, the log-logistic distribution provided the best fit and was used to construct a series of parametric survival models. RESULTS: Of the 701 patients identified in the initial prevalence study, 637 (90.9%) had complete data for all fields used to calculate APACHE II score. Controlling for age, sex and Acute Physiology Score (APS), the chronic health components of the APACHE II score, as a group, were better predictors of survival than Elixhauser comorbidities and Charlson Index. Of the APACHE II chronic health components, only the relatively uncommon conditions of liver failure (3.4%) and immunodeficiency (9.6%) were statistically associated with inferior patient survival with acceleration factors of 0.35 (95% CI 0.17, 0.72) for liver failure, and 0.42 (95% CI 0.26, 0.72) for immunodeficiency. Sensitivity analyses on an imputed dataset that also included the 64 individuals with imputed APACHE II score showed identical results. CONCLUSION: Our study suggests that, in acute critical illness, most co-existing comorbidities are not major determinants of shortterm survival, indicating that observed variations in ICU patient 30-day mortality may not be confounded by lack of adjustment to pre-existing comorbidities. PMID- 29621835 TI - Causal Analysis of Self-tracked Time Series Data Using a Counterfactual Framework for N-of-1 Trials. AB - Many of an individual's historically recorded personal measurements vary over time, thereby forming a time series (e.g., wearable-device data, self-tracked fitness or nutrition measurements, regularly monitored clinical events or chronic conditions). Statistical analyses of such n-of-1 (i.e., single-subject) observational studies (N1OSs) can be used to discover possible cause-effect relationships to then self-test in an n-of-1 randomized trial (N1RT). However, a principled way of determining how and when to interpret an N1OS association as a causal effect (e.g., as if randomization had occurred) is needed.Our goal in this paper is to help bridge the methodological gap between risk-factor discovery and N1RT testing by introducing a basic counterfactual framework for N1OS design and personalized causal analysis.We introduce and characterize what we call the average period treatment effect (APTE), i.e., the estimand of interest in an N1RT, and build an analytical framework around it that can accommodate autocorrelation and time trends in the outcome, effect carryover from previous treatment periods, and slow onset or decay of the effect. The APTE is loosely defined as a contrast (e.g., difference, ratio) of averages of potential outcomes the individual can theoretically experience under different treatment levels during a given treatment period. To illustrate the utility of our framework for APTE discovery and estimation, two common causal inference methods are specified within the N1OS context. We then apply the framework and methods to search for estimable and interpretable APTEs using six years of the author's self-tracked weight and exercise data, and report both the preliminary findings and the challenges we faced in conducting N1OS causal discovery.Causal analysis of an individual's time series data can be facilitated by an N1RT counterfactual framework. However, for inference to be valid, the veracity of certain key assumptions must be assessed critically, and the hypothesized causal models must be interpretable and meaningful. PMID- 29621836 TI - A Systematic Review of Coding Systems Used in Pharmacoepidemiology and Database Research. AB - BACKGROUND: Clinical coding systems have been developed to translate real-world healthcare information such as prescriptions, diagnoses and procedures into standardized codes appropriate for use in large healthcare datasets. Due to the lack of information on coding system characteristics and insufficient uniformity in coding practices, there is a growing need for better understanding of coding systems and their use in pharmacoepidemiology and observational real world data research. OBJECTIVES: To determine: 1) the number of available coding systems and their characteristics, 2) which pharmacoepidemiology databases are they adopted in, 3) what outcomes and exposures can be identified from each coding system, and 4) how robust they are with respect to consistency and validity in pharmacoepidemiology and observational database studies. METHODS: Electronic literature database and unpublished literature searches, as well as hand searching of relevant journals were conducted to identify eligible articles discussing characteristics and applications of coding systems in use and published in the English language between 1986 and 2016. Characteristics considered included type of information captured by codes, clinical setting(s) of use, adoption by a pharmacoepidemiology database, region, and available mappings. Applications articles describing the use and validity of specific codes, code lists, or algorithms were also included. Data extraction was performed independently by two reviewers and a narrative synthesis was performed. RESULTS: A total of 897 unique articles and 57 coding systems were identified, 17% of which included country-specific modifications or multiple versions. Procedures (55%), diagnoses (36%), drugs (38%), and site of disease (39%) were most commonly and directly captured by these coding systems. The systems were used to capture information from the following clinical settings: inpatient (63%), ambulatory (55%), emergency department (ED, 34%), and pharmacy (13%). More than half of all coding systems were used in Europe (59%) and North America (57%). 34% of the reviewed coding systems were utilized in at least 1 of the 16 pharmacoepidemiology databases of interest evaluated. 21% of coding systems had studies evaluating the validity and consistency of their use in research within pharmacoepidemiology databases of interest. The most prevalent validation method was comparison with a review of patient charts, case notes or medical records (64% of reviewed validation studies). The reported performance measures in the reviewed studies varied across a large range of values (PPV 0-100%, NPV 6-100%, sensitivity 0-100%, specificity 23-100% and accuracy 16-100%) and were dependent on many factors including coding system(s), therapeutic area, pharmacoepidemiology database, and outcome. CONCLUSIONS: Coding systems vary by type of information captured, clinical setting, and pharmacoepidemiology database and region of use. Of the 57 reviewed coding systems, few are routinely and widely applied in pharmacoepidemiology database research. Indication and outcome dependent heterogeneity in coding system performance suggest that accurate definitions and algorithms for capturing specific exposures and outcomes within large healthcare datasets should be developed on a case-by-case basis and in consultation with clinical experts. PMID- 29621837 TI - Leptospirosis. AB - BACKGROUND: Leptospirosis is one of the most common zoonotic diseases worldwide. Infection occurs through contact with infected animals, or soil or water that has been contaminated by the urine of infected animals. Risk factors include occupational and recreational exposures, contact with floodwaters, and travel to areas with a high risk of leptospirosis, particularly tropical, developing countries. With climate change, flood-related outbreaks are becoming more common. OBJECTIVE: This article aims to improve awareness of leptospirosis, and provide an update for general practitioners on its epidemiology, risk factors, clinical presentation, laboratory diagnosis, management and prevention. DISCUSSION: Leptospirosis is sometimes misdiagnosed because clinical presentation can be non specific and overlap with many other causes of acute febrile illnesses. In patients with risk factors for leptospirosis, a high index of clinical suspicion is important to ensure early diagnosis and treatment. Delays in treatment could increase the risk of severe complications, including pulmonary haemorrhage, acute renal failure and acute liver failure. PMID- 29621838 TI - An atypical case of typical pneumonia PMID- 29621839 TI - Q fever: A rural disease with potential urban consequences AB - BACKGROUND: Q fever often presents as an undifferentiated febrile illness. Cases occur throughout Australia, with higher rates occurring in northern New South Wales and southern Queensland. OBJECTIVE: This article aims to provide clinicians with an overview of Q fever, and covers epidemiology, clinical features, laboratory diagnosis, sequelae, management and prevention. DISCUSSION: In Australia, Q fever is the most commonly reported zoonotic disease. Presentation includes fever, rigors, chills, headache, extreme fatigue, drenching sweats, weight loss, arthralgia and myalgia, often in conjunction with abnormal liver function tests. These features make it indistinguishable from many other febrile illnesses. Exposure occurs through contact with livestock and other animals. Coxiella bacteria can survive in dust, where infection may result from inhalation. Laboratory diagnosis is made by serology or polymerase chain reaction. An effective vaccine is available for adults (aged >15 years), but can only be administered after a rigorous pre-vaccination assessment to exclude prior exposure to Coxiella burnetii, requiring a detailed medical history, skin test and serology. PMID- 29621840 TI - Pigs, pooches and pasteurisation: The changing face of brucellosis in Australia AB - BACKGROUND: Brucellosis, also known as undulant, Mediterranean or Malta fever, is a systemic infection that causes fever, sweats, arthralgias and myalgias. A globally important disease, brucellosis is re-emerging in Australia in association with feral pig hunting activities. OBJECTIVE: This article aims to provide clinicians with an overview of brucellosis, covering epidemiology, clinical features, diagnosis, management and prevention. DISCUSSION: Brucellosis should be suspected in all patients with non-specific, flu-like illness who fall into one of the major risk groups (feral pig hunters, overseas travellers and migrants). Depression is common and often severe, relative to other symptoms. Early diagnosis and treatment are important for preventing complications, which include osteoarticular, genitourinary or, more rarely, neurological or cardiovascular diseases. Diagnosing acute infections is based on serology and blood cultures; imaging and biopsy may be required for diagnosis of focal infections. Dual therapy with doxycycline and gentamicin is the recommended treatment. Relapse occurs in up to 10% of patients. Prevention is achieved through the use of protective gear during hunting and avoidance of unpasteurised dairy products in countries where occur in animals. PMID- 29621841 TI - Australian bat lyssavirus AB - BACKGROUND: Australian bat lyssavirus (ABLV) causes human illness that is indistinguishable from classical rabies. All Australian bats have the potential to carry and transmit ABLV, and potentially risky human exposures to bats are common. ABLV infection has resulted in three human deaths in Australia since 1996. OBJECTIVE: The aim of this article is to equip general practitioners (GPs) to assist in the prevention and management of potential ABLV exposures in Australia, including complex clinical scenarios that are not fully addressed in current national guidelines. DISCUSSION: Potential ABLV exposures are frequently encountered in general practice. GPs play a critical role in risk mitigation for groups such as veterinarians and wildlife carers, and in triggering urgent multidisciplinary responses to potential exposures. Timely notification of the public health unit following a potential exposure is crucial to ensure appropriate assessment and access to correct treatment. Complex exposure scenarios require careful consideration. PMID- 29621842 TI - Repetitive transcranial magnetic stimulation in the treatment of depression AB - BACKGROUND: Transcranial magnetic stimulation (TMS)is a treatment for major depressive disorder that is otherwise resistant to treatment. Although world leading research in TMS has been conducted in Australia, where it has had some availability for two decades, there is limited familiarity with the treatment in the general medical community. Availability, however, is increasing. OBJECTIVE: The aim of this article is to inform general practitioners of some scientific and practical aspects of TMS treatment. DISCUSSION: In TMS, an electromagnetic apparatus is used to generate small electric currents in targeted regions of the cortex. Anaesthesia is not required, patients remain conscious and there are no seizure or memory problems. TMS is a first-line treatment for treatment-resistant depression. Current evidence indicates that TMS-induced remission is associated with normalisation of connectivity in cortical-subcortical networks. PMID- 29621843 TI - Case report of rapid onset cognitive and functional decline Diagnosis of sporadic Creutzfeldt-Jakob disease PMID- 29621844 TI - Multiple tender, deep nodules on the legs of a seven-year-old boy PMID- 29621845 TI - Ins and outs of urinary catheters AB - BACKGROUND: Inserting an indwelling catheter (IDC) is a common medical procedure that is often performed poorly and inappropriately, and can lead to significant morbidity. Although most catheterisations are performed by nursing staff, medical personnel need to be aware of the procedure, products and common IDC complications. OBJECTIVE: Current guidelines and literature were reviewed to outline catheterisation indications, catheter types and provide a general understanding of complications associated with IDCs for the general practitioner (GP). DISCUSSION: There is evidence that IDCs are often used when not indicated and improperly managed when inserted. IDCs can cause significant morbidity, prolong hospital stay and increase healthcare costs. Infection and traumatic insertion are common complications; advances in catheter design have helped to limit these complications. Most complications are avoidable, do not require specialist input and can be managed by community nurses or GPs. Reviewing indications, adopting proper technique for insertion and defining management strategies can limit complications. PMID- 29621846 TI - The CRISP-Q study: Communicating the risks and benefits of colorectal cancer screening AB - Background and objectives: Many Australians at average risk of colorectal cancer (CRC) are undergoing unnecessary colonoscopic screening, while many at increased risk are getting inadequate screening. The aim of this study was to test different ways of communicating the risks and benefits of CRC screening, as part of the development of a CRC risk prediction (CRISP) tool. Method: General practice patients were shown five different risk presentations for hypothetical 'average' and 'increased' risk cases and were asked to choose the screening method they would undergo. Associations were explored between risk presentation type and 'risk-appropriate screening' choice. Results: All risk formats were associated with improved risk-appropriate screening by participants (n = 204); however, there was a statistical trend favouring absolute risk with a government recommendation and an 'expected frequency tree'. The icon array was most weakly associated with appropriate screening. Discussion: This research will inform approaches to communicating risk in CRISP and may be of wider relevance to supporting informed decisions about cancer screening. PMID- 29621847 TI - How do general practitioners conceptualise self-harm in their older patients? A qualitative study AB - Background and objectives: Little is known about how general practitioners (GPs) conceptualise self-harm in older people. The aim of this study was to explore GPs' understanding of the reasons for recent self-harm in an older patient. Method: Short questionnaires were sent to the GPs of patients aged 80 years or older who had recently self-harmed and were participants in a qualitative study about self-harm. Questions evaluated GPs' understanding of the self-harm. Thematic analysis was used to identify and analyse themes. Results: Thirteen GP responses were analysed. GPs could identify multiple factors contributing to self harm in their patients but did not see a role for themselves in addressing these issues. They feared repetition of self-harm if these underlying contributory factors, including depression, did not change. Discussion: Targeted education and practical options for GPs regarding management of the issues underlying self-harm in older people are needed. Families and carers may be underused allies in management. These strategies may serve to counter therapeutic nihilism and clinician isolation. PMID- 29621849 TI - March clinical challenge. PMID- 29621848 TI - Building a bridge from the swamp to the ivory tower: Conducting randomised controlled trials in general practice AB - BACKGROUND: Primary care research is underfunded. Few randomised controlled trials (RCTs) are conducted in a primary care setting. However, it is important that clinical practice be informed by adequate primary care evidence so general practitioners (GPs) have tools and guidelines applicable to the patients they see. OBJECTIVE: The aim of this article is to describe and reflect on the experience of conducting five RCTs between 2003 and 2017 in a general practice setting with minimal funding, in North Queensland. DISCUSSION: Enabling factors include using grassroots research questions and engaging practice nurses. Barriers include ethics applications and insufficient funding. Recommendations to reduce study costs include compensating practice nurses rather than GP time. The findings are designed to encourage grassroots GPs to consider participating in pragmatic, feasible projects. The success of the projects was underpinned by the fact that they were established by a group of GPs who had interesting questions that were relevant to their clinical practice and not answered by current evidence. PMID- 29621850 TI - March correspondence PMID- 29621851 TI - Editorial: Unravelling zoonotic diseases in Australia PMID- 29621852 TI - Editorial. PMID- 29621853 TI - Editorial: What brings you here today? PMID- 29621854 TI - Increasing multimorbidity in an Australian street health service: A 10-year retrospective cohort study AB - Background and objectives: Street-based clinics provide general practice services to marginalised and homeless persons. The objective of this study was to examine prevalence, patterns and severity of multimorbidity in patients attending one such service. Method: A retrospective cohort study (2006-15), comprising medical record review of patients (n = 4285), was undertaken. A Cumulative Illness Rating Scale (CIRS) was used to assess multimorbidity. Results: Average age of patients was 38.2 +/- 17.9 years. Of 31.5% Aboriginal patients, 50.8% were female (37.6% in non Aboriginal patients). Of all patients, 53% had multimorbidity. Aboriginal patients had higher rates of multimorbidity than non-Aboriginal patients (58.0% vs 50.6%, P <0.001). Psychiatric, musculoskeletal (especially skin) and respiratory conditions were most common. Disease severity was mild to moderate, with 26.8% having at least one severe or extremely severe condition. Multimorbidity and disease severity increased between 2006-11 and 2012-15. Aboriginality was the strongest predictor of multimorbidity (odds ratio [OR] = 2.1; 95% confidence interval [CI]: 1.8-2.4; P <0.001). Discussion: Street-based general practice services are critical to facilitate easy access to primary and secondary management of chronic multimorbid conditions in marginalised (especially Aboriginal) patients. PMID- 29621855 TI - e-Therapy in primary care mental health AB - BACKGROUND: The Australian Government's Fifth National Mental Health and Suicide Prevention Plan recommends a stepped care model of mental healthcare that focuses on matching the intensity of care to the severity of illness. General practitioners (GPs) need to learn more about low-intensity online interventions to better meet the needs of patients of lower severity. OBJECTIVE: This article provides GPs with information about low-intensity, evidence-based online resources developed in Australia and available for integration into the care of patients with mild-to-moderate mental health conditions. This article has an emphasis on new developments since 2015. DISCUSSION: The internet provides an opportunity to deliver effective mental health treatment to people who would otherwise not seek, or be able to reach, skilled help for their mental health conditions. High-quality, evidence-based cognitive behavioural therapy treatment programs are available to all Australians, at no or low cost. These options can be integrated into a stepped care model of mental healthcare, and provide GPs with an opportunity to help patients access treatment that suits their needs. PMID- 29621856 TI - Minimally disruptive medicine for patients with complex multimorbidity AB - BACKGROUND: Patients with complex multimorbidity often experience a substantial burden because of the treatments they receive as well as the burden of their chronic health problems. There has been increasing recognition of this issue, particularly in the UK and US. OBJECTIVE: This article summarises the evolution of the concept ‘minimally disruptive medicine’ for patients with complex multimorbidity. It outlines some of the factors that should be considered in assessing both the burden of treatment and a patient’s capacity to cope with this workload. The potential role of shared decision-making and discussion aids such as the Instrument for Patient Capacity Assessment (ICAN) tool are highlighted. DISCUSSION: Australian general practice is at the forefront of care for patients with complex multimorbidity. The explicit inclusion of assessment of treatment burden and capacity would encourage healthcare that is kind, empathic andfeasible. PMID- 29621857 TI - Ten tips for becoming a Time Lord AB - BACKGROUND: There is evidence that extended waiting is the most important cause of patient dissatisfaction with a visit to their general practice. While waiting is sometimes unavoidable in primary care, sometimes its causes are systemic and modifiable. Our experience is that some doctors rarely run late and yet seem to meet their patients' needs. We call these colleagues 'Time Lords'. OBJECTIVE: The aim of this article is to revise and share tips to help others become Time Lords. DISCUSSION: We describe four tips that depend on good preparation. A further six involve maximising the value of consulting time. Waiting is sometimes unavoidable in general practice. Our patients accept this and so must we. However, we can do much to improve our patients' satisfaction by taking waiting as seriously as they do and minimising it. PMID- 29621858 TI - Common neonatal presentations to the primary care physician AB - BACKGROUND: Newborn babies are very vulnerable in their first weeks of life. Timely and appropriate management of neonatal conditions is paramount for health and developmental outcomes. OBJECTIVE: The aim of this article is to provide an overview of common neonatal presentations to general practice, and highlight significant conditions that may require referral to the emergency department and/or other specialist. DISCUSSION: Clinical history and examination are the most important tools in neonatal assessment. Babies often present with non specific symptoms, but a thorough clinical assessment can identify the ‘unwell baby’ who requires immediate transfer to hospital. This includes babies with sepsis, moderate-to-severe dehydration or who are in acute cardiorespiratory compromise. A comprehensive neonatal assessment will also help to differentiate babies with significant conditions that may warrant further specialist input from those with normal neonatal development where parental support and reassurance may be sufficient. PMID- 29621859 TI - Infants of emotionally dysregulated or borderline personality disordered mothers: Issues and management in primary care AB - BACKGROUND: Knowledge has increased regarding the developmental needs and capabilities of infants, and parental behaviours that support optimum infant development. Despite a better understanding of the emotional dysregulation in borderline personality disorder (BPD) and its effects on infants, general practitioners have had few guidelines for how to recognise and help emotionally dysregulated mother-infant dyads. OBJECTIVE: This article focuses on the behaviours and needs of infants whose mothers have BPD, including knowledge and skills for primary care practitioners to help these troubled families. DISCUSSION: Understanding the adequacy of parenting and troubling infant signs, such as hypervigilance, can potentially lead to either more intervention in primary care, including support, reassurance, guidance regarding development and interaction, and enhanced family support or else specialist referral for enhanced infant care. Infants’ needs are urgent, and timely intervention can begin a better life trajectory for infant and mother. PMID- 29621860 TI - A review of tinnitus AB - BACKGROUND: Tinnitus is one of the most common otological symptoms. In recent times our understanding of tinnitus has significantly progressed. Tinnitus may be defined as conscious awareness of a sound in the absence of an external auditory stimulus. People with tinnitus almost always seek the attention of their general practitioner, who is best placed to assess, investigate and provide appropriate counselling. OBJECTIVE: The aim of this article is to define and provide guidelines on causes, assessment, appropriate investigation and management of tinnitus. DISCUSSION: Tinnitus may be categorised as subjective, objective, primary or secondary. The assessment of tinnitus begins by determining which of these types with the patient presents with. All patients with tinnitus warrant formal audiometric assessment, and a proportion will warrant further imaging. Management requires treatment of reversible causes. Those with subjective, bothersome chronic tinnitus require tinnitus-specific therapies. PMID- 29621861 TI - Unilateral cataract: A potentially fatal prognosis PMID- 29621862 TI - Temporomandibular dysfunction AB - BACKGROUND: Orofacial pain is a common presentation in the primary healthcare setting and temporomandibular dysfunction represents one of the major causes. Its aetiology is multifactorial, caused by both masticatory muscle dysfunction and derangement within the temporomandibular joint. OBJECTIVE: The aim of this article is to provide an overview of temporomandibular dysfunction, its management and referral considerations for general practioners. DISCUSSION: Temporomandibular joint dysfunction affects a large number of adults. Conservative management involving non-pharmacological and pharmacological therapies is effective in the majority of cases. PMID- 29621863 TI - Improving diagnostic accuracy of skin biopsies AB - BACKGROUND: The skin biopsy is a simple but essential clinical skill of the general practitioner. Performed properly, it can be quick and comfortable for the patient, and yield a very high level of diagnostic information. Performed incorrectly, it can lead to delays in diagnosis and treatment for the patient. OBJECTIVE: This article reviews some simple but effective steps the clinician can take to ensure proper technique and maximise the diagnostic accuracy of their skin biopsies. DISCUSSION: Diagnostic accuracy can be improved through optimal selection of biopsy site, correct biopsy technique, requesting ancillary tests where appropriate, proper handling of specimens, and providing detailed clinical information for the dermatopathologist. PMID- 29621864 TI - Sodium-glucose co-transporter 2 inhibitors: Think twice about diabetic ketoacidosis PMID- 29621865 TI - Polycystic ovary syndrome in Central Australia: Diagnosis and screening of cardiometabolic risk and emotional wellbeing AB - Background and objectives: Polycystic ovary syndrome (PCOS) is a common condition that affects fertility, body image and emotional wellbeing in women, as well as significantly increasing a woman's likelihood of developing type 2 diabetes mellitus (T2DM) and other cardiovascular disease risk factors. The objective of this study was to assess how management of PCOS in an Aboriginal primary care setting aligns with national standards for diagnosis and screening of cardiometabolic risk and emotional wellbeing. Method: We conducted a retrospective clinical audit of 63 women who had PCOS listed as a diagnosis in their clinical record. Results: Most women (95%) were correctly diagnosed, the most common trigger being menstrual irregularity (83%). Screening for cardiometabolic complications and emotional wellbeing as recommended by the national guideline was applied inconsistently, including 38% of eligible women not being screened for T2DM in the previous 12 months, and no woman being formally screened for emotional wellbeing. Discussion of lifestyle management was nearly universal; most women (75%) were referred to a dietician, although a third did not attend their appointment. Discussion: Some components of recommended PCOS care were provided at high levels, including correct application of diagnostic criteria. However, PCOS management and screening for complications are being applied inconsistently in a population with high levels of cardiometabolic and emotional wellbeing risk. PMID- 29621867 TI - April clinical challenge. PMID- 29621866 TI - Elder abuse: The role of general practitioners in community-based screening and multidisciplinary action AB - BACKGROUND: There are growing calls for elder abuse screening to be conducted by a range of community-based service providers, including general practitioners (GPs), practice nurses, home care workers and lawyers. Improved screening may be a valuable first step towards improving elder abuse detection and response; however, practitioners need evidence-based strategies for screening and follow up. OBJECTIVE: This article summarises several brief screening tools for various forms of elder abuse. Screening tool properties and evidence gaps are noted. As elder abuse often requires multidisciplinary responses, initiatives to connect health, legal and other service providers are highlighted. DISCUSSION: GPs are trusted professionals who are well placed to identify older patients at risk of, or experiencing, various forms of abuse. They should be aware of available screening tools and consider how best to incorporate them into their own practice. They also play an important role in multidisciplinary action to address elder abuse.
. PMID- 29621868 TI - What brings you here today? PMID- 29621869 TI - Intensity-modulated radiation therapy: a review with a physics perspective. AB - Intensity-modulated radiation therapy (IMRT) has been considered the most successful development in radiation oncology since the introduction of computed tomography into treatment planning that enabled three-dimensional conformal radiotherapy in 1980s. More than three decades have passed since the concept of inverse planning was first introduced in 1982, and IMRT has become the most important and common modality in radiation therapy. This review will present developments in inverse IMRT treatment planning and IMRT delivery using multileaf collimators, along with the associated key concepts. Other relevant issues and future perspectives are also presented. PMID- 29621870 TI - Preoperative short course radiotherapy with concurrent and consolidation chemotherapies followed by delayed surgery in locally advanced rectal cancer: preliminary results. AB - PURPOSE: This study aimed to assess complications and outcomes of a new approach, that is, combining short course radiotherapy (SRT), concurrent and consolidative chemotherapies, and delayed surgery. MATERIALS AND METHODS: In this single arm phase II prospective clinical trial, patients with T3-4 or N+ M0 rectal adenocarcinoma were enrolled. Patients who received induction chemotherapy or previous pelvic radiotherapy were excluded. Study protocol consisted of three dimensional conformal SRT (25 Gy in 5 fractions in 1 week) with concurrent and consolidation chemotherapies including capecitabine and oxaliplatin. Total mesorectal excision was done at least 8 weeks after the last fraction of radiotherapy. Primary outcome was complete pathologic response and secondary outcomes were treatment related complications. RESULTS: Thirty-three patients completed the planned preoperative chemoradiation and 26 of them underwent surgery (24 low anterior resection and 2 abdominoperineal resection). Acute proctitis grades 2 and 3 were seen in 11 (33.3%) and 7 (21.2%) patients, respectively. There were no grades 3 and 4 subacute hematologic and non hematologic (genitourinary and peripheral neuropathy) toxicities and perioperative morbidities such as anastomose leakage. Grade 2 or higher late toxicities were observed among 29.6% of the patients. Complete pathologic response was achieved in 8 (30.8%) patients who underwent surgery. The 3-year overall survival and local control rates were 65% and 94%, respectively. CONCLUSION: This study showed that SRT combined with concurrent and consolidation chemotherapies followed by delayed surgery is not only feasible and tolerable without significant toxicity but also, associated with promising complete pathologic response rates. PMID- 29621871 TI - Impact of radiation dose on concurrent chemoradiotherapy for limited-stage small cell lung cancer. AB - PURPOSE: To evaluate clinical outcomes according to radiation dose in patients with limited-stage small-cell lung cancer (LS-SCLC) treated with concurrent chemoradiotherapy (CCRT). MATERIALS AND METHODS: From January 2006 to December 2015, 38 patients with LS-SCLC were treated with CCRT with etoposide and cisplatin. Total radiation doses ranged from 45 Gy to 66 Gy (1.8-2 Gy/fraction) and were classified into three groups: 45-54 Gy, 60-63 Gy, and 66 Gy. The impact of radiation dose on survival outcomes were evaluated. Toxicities were evaluated according to the Common Terminology Criteria for Adverse Events version 4.03. RESULTS: The median follow-up period was 21 months. The 2-year overall survival (OS) and local failure-free survival (LFFS) rates were 45.8% and 67.5%, respectively. The 2-year LFFS rates were 33.3% for 45-54 Gy group, 68.6% for 60 63 Gy group, and 87.1% for 66 Gy group (p = 0.014). In multivariate analysis, radiation dose was a significant factor for LFFS (p = 0.015). Although radiation dose was not a significant factor for OS and disease-free survival (DFS) in multivariate analysis, both OS and DFS of 66 Gy group tended to be better than that of 45-63 Gy group in univariate analysis. However, there were no differences in severe toxicities among three groups. CONCLUSION: Higher radiation dose achieved better local control in patients with LS-SCLC treated with CCRT. In addition, a total dose of 66 Gy tended to improve OS and DFS. PMID- 29621872 TI - Dosimetric comparison of IMRT versus 3DCRT for post-mastectomy chest wall irradiation. AB - PURPOSE: To compare the dose distribution of three-dimensional conformal radiation therapy (3DCRT) with intensity-modulated radiation therapy (IMRT) for post-mastectomy radiotherapy (PMRT) to left chest wall. MATERIALS AND METHODS: One hundred and seven patients were randomised for PMRT in 3DCRT group (n = 64) and IMRT group (n = 43). All patients received 50 Gy in 25 fractions. Planning target volume (PTV) parameters-Dnear-max (D2), Dnear-min (D98), Dmean, V95, and V107-homogeneity index (HI), and conformity index (CI) were compared. The mean doses of lung and heart, percentage volume of ipsilateral lung receiving 5 Gy (V5), 20 Gy (V20), and 55 Gy (V55) and that of heart receiving 5 Gy (V5), 25 Gy (V25), and 45 Gy (V45) were extracted from dose-volume histograms and compared. RESULTS: PTV parameters were comparable between the two groups. CI was significantly improved with IMRT (1.127 vs. 1.254, p < 0.001) but HI was similar (0.094 vs. 0.096, p = 0.83) compared to 3DCRT. IMRT in comparison to 3DCRT significantly reduced the high-dose volumes of lung (V20, 22.09% vs. 30.16%; V55, 5.16% vs. 10.27%; p < 0.001) and heart (V25, 4.59% vs. 9.19%; V45, 1.85% vs. 7.09%; p < 0.001); mean dose of lung and heart (11.39 vs. 14.22 Gy and 4.57 vs. 8.96 Gy, respectively; p < 0.001) but not the low-dose volume (V5 lung, 61.48% vs. 51.05%; V5 heart, 31.02% vs. 23.27%; p < 0.001). CONCLUSIONS: For left sided breast cancer, IMRT significantly improves the conformity of plan and reduce the mean dose and high-dose volumes of ipsilateral lung and heart compared to 3DCRT, but 3DCRT is superior in terms of low-dose volume. PMID- 29621874 TI - Psychosocial Health of Disease-Free Breast Cancer Survivors Compared with Matched Non-cancer Controls. AB - Purpose: The present study investigated the psychosocial health of disease-free breast cancer survivors who receive health examinations compared to matched non cancer controls in a community setting. Materials and Methods: We used baseline data from the Health Examinee cohort, which is composed of subjects participating in health. The disease-free breast cancer survivors were defined as those who were >=2 years from initial diagnosis of breast cancer who had completed treatment. Females without a history of cancer were randomly selected at 1:4 ratio by 5-year age groups, education, and household income as a comparison group. We analyzed results from the Psychosocial Well-being Index-Short Form (PWI SF) as a psychosocial health measurement. Results: A total of 347 survivors of breast cancer and 1,388 matched controls were included. Total scores on the PWI SF were lower in breast cancer survivors than matched non-cancer controls (p=0.006), suggesting a lower level of psychosocial stress in breast cancer survivors. In comparison to the control group, prevalence of drinking, smoking and obesity were lower, while exercising for >=150 min/wk was higher in breast cancer survivors (p < 0.05). These findings suggest that breast cancer survivors have better health behaviors than their non-cancer controls. After adjusting for other sociodemographic variables, breast cancer survivors were 36% less likely to be included in the stress group (odds ratio, 0.64; 95% confidence interval, 0.42 to 0.98). Conclusion: The disease-free breast cancer survivors resuming daily life demonstrated better psychosocial health status compared to matched non cancer controls. PMID- 29621873 TI - Set-up errors in head and neck cancer treated with IMRT technique assessed by cone-beam computed tomography: a feasible protocol. AB - PURPOSE: To investigate set-up errors, suggest the adequate planning target volume (PTV) margin and image-guided radiotherapy frequency in head and neck (H&N) cancer treated with intensity-modulated radiotherapy (IMRT) assessed by kV cone-beam computed tomography (CBCT). METHODS: We analyzed 360 CBCTs in 60 patients with H&N cancer treated with IMRT. The target delineation was contoured according to ICRU62. PTVs were generated by adding a 3-5 mm margin in all directions to the respective clinical target volumes. The kV CBCT images were obtained at first three days of irradiation and weekly thereafter. The overall mean displacement, range, systematic (?) and random (sigma) errors were calculated. Adequate PTV margins were calculated according to the van Herk formula (2.5? + 0.7r). RESULTS: The mean of set-up errors was less than 2 mm in any direction. The overall frequency of set-up displacements greater than 3 mm was 3.9% in medial-lateral (ML) direction, 8% in superior-inferior (SI) direction, and 15.5% in anterior-posterior (AP) direction. The range of translations shifts was 0-9 mm in ML direction, 0-5 mm in SI direction and 0-10 mm in AP direction, respectively. After systematic set-up errors correction, the adequate margin to overcome the problem of set-up errors was found to be less than 3 mm. CONCLUSION: Image-guided kV CBCT was effective for the evaluation of set-up accuracy in H&N cancer. The kV CBCT at first three fractions and followed by weekly appears adequate for reducing significantly set-up errors in H&N cancer treated with IMRT technique. Finally, 3-5 mm PTV margins appear adequate and safe to overcome the problem of set-up errors. PMID- 29621875 TI - The Risk of Herpes Zoster in Patients with Non-small Cell Lung Cancer according to Chemotherapy Regimens: Tyrosine Kinase Inhibitors versus Cytotoxic Chemotherapy. AB - Purpose: Despite the successful use of tyrosine kinase inhibitors (TKIs) in cancer patients, their effect on herpes zoster development has not been studied. The aim of this study was to evaluate and compare the effects of epidermal growth factor receptor (EGFR) TKI and cytotoxic chemotherapy on the risk of herpes zoster development in non-small cell lung cancer (NSCLC) patients. Materials and Methods: We conducted a medical review of all eligible NSCLC patients in Seoul National University hospital between 2002 and 2015. We classified patients based on whether they previously underwent EGFR TKI therapy into either the TKI group or the cytotoxic group. We compared the incidence rates of herpes zoster during TKI therapy and cytotoxic chemotherapy. Additionally, the longitudinal risk of herpes zoster from TKIs was analyzed using the incidence rate ratio (IRR) of the TKI group to the cytotoxic group and the log-rank test of the Kaplan-Meier method. Results: Of the 2,981 NSCLC patients, 54 patients (1.54%) developed herpes zoster. In the TKI group (2,002 patients), the IRR of herpes zoster during TKI therapy compared to that during cytotoxic chemotherapy was 1.05 (95% confidence interval [CI], 0.53 to 2.09). The IRR of the TKI group compared to the cytotoxic group was 1.33 (95% CI, 0.64 to 2.76). The Kaplan-Meier cumulative risk of both groups was not significantly different. Conclusion: Our results show that the incidence rate of herpes zoster in the TKI group was not statistically different from the incidence in the cytotoxic group during and after chemotherapy in NSCLC patients. PMID- 29621876 TI - Impact of Pulmonary Tuberculosis on the EGFR Mutational Status and Clinical Outcome in Patients with Lung Adenocarcinoma. AB - Purpose: Although it has been suggested that pulmonary tuberculosis (TB) is associated with increased risk of lung cancer, the exact mechanism is not clearly identified. We investigated the effect of pulmonary TB on the epidermal growth factor receptor (EGFR) mutational status and clinical outcome in patients with pulmonary adenocarcinoma. Materials and Methods: We reviewed data of patients diagnosed with pulmonary adenocarcinoma harboring EGFR mutations and treated at our institution from 2008 to 2015. We divided our population into two groups: patients with pre-existing TB lesions on chest computed tomography scan (TB group) and those without the lesions (non-TB group). We compared the differences in EGFR mutational status, response to tyrosine kinase inhibitors (TKIs) and survival between the two groups. Results: A total of 477 patients with pulmonary adenocarcinoma were analyzed. 183 (39%) patients had EGFR-mutated tumors and 100 (21%) patients had pre-existing TB lesions. The frequency of EGFR mutation was significantly higher in the TB group compared with the non-TB group (56% vs. 34%, p=0.038). Pre-existing TB lesions were independently associated with more frequent EGFR mutations in multivariate analysis (odds ratio, 1.43). In addition, both the progression-free survival (9.1 months vs. 11.6 months, p=0.020) and the overall survival (19.4 months vs. 24.5 months, p=0.014) after first-line EGFR TKIs were significantly shorter in the TB group than in the non-TB group. Conclusion: Previous pulmonary TB may be associated with more frequent EGFR mutations and poorer treatment response to EGFR-TKIs in patients with pulmonary adenocarcinoma. PMID- 29621877 TI - The Prognostic Role of Circulating Epstein-Barr Virus DNA Copy Number in Angioimmunoblastic T-Cell Lymphoma Treated with Dose-Adjusted EPOCH. AB - Purpose: Determine the frequency and prognostic value of circulating Epstein-Barr virus (EBV) DNA copy number in angioimmunoblastic T-cell lymphoma (AITL) patients who were treated with dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide and doxorubicin (DA-EPOCH) regimens. Materials and Methods: Sixty newly-diagnosed AITL patients were retrospectively enrolled in the present study. All patients were treated with DA-EPOCH regimen. Results: Twenty-two subjects (36.7%) had a EBV-DNA-positive test at diagnosis. EBV DNA-positive patients were associated with lower lymphocyte-monocyte ratio (p=0.024). Median follow-up was 40 months (range, 14 to 100 months). The overall response rate for all the 60 AITL patents were 71.7% (95% confidence interval [CI], 58.6% to 82.5%) with 3-year progressive-free survival (PFS) rate of 30.9%+/-6.1% and overall survival (OS) rate of 60.1%+/-6.6%. Not only did PFS estimation differ between the EBV DNA-positive and EBV DNA-negative group (hazard ratio [HR], 2.24; 95% CI, 1.15 to 4.35; p=0.006), but also worse OS was observed in the pretreatment EBV DNA-positive group than in the EBV DNA-negative group (HR, 2.74; 95% CI, 1.22 to 6.19; p=0.006). EBV DNA test positivity was independent prognostic marker for both PFS (HR, 2.17; 95% CI, 1.17 to 4.00; p=0.014) and OS (HR, 3.24; 95% CI, 1.48 to 7.11; p=0.004) after adjusting International Prognostic Index and prognostic index for AITL score. Reduction in EBV copies was significantly associated with therapy-response. Conclusion: Circulating EBV DNA level was an important prognostic and monitoring marker for AITL patients who treated with DA-EPOCH regimens which cannot improve outcomes for AITL patients. PMID- 29621878 TI - Characteristics of Synchronous and Metachronous Multiple Gastric Tumors after Endoscopic Submucosal Dissection of Early Gastric Neoplasm. AB - Background/Aims: Endoscopic submucosal dissection (ESD) has been widely accepted as a method of treatment of early gastric tumor. This study aimed to identify the incidence and characteristics of multiple gastric tumors after ESD. METHODS: Patients with early gastric tumors who were treated by ESD from January 2004 to June 2012 and followed up with endoscopic examination periodically for at least 1 year were enrolled. All multiple gastric lesions were subsequently treated with ESD and the medical records of the patients were retrospectively reviewed. RESULTS: In total, 643 patients were included. The mean duration of endoscopic follow-up was 45.27+/-27.59 (range, 12-148) months. Overall, 144 patients (22.4%) showed multiple gastric tumors during the follow-up period (44 synchronous [6.8%] and 100 metachronous [15.5%]). The cumulative incidence rate steadily increased during the follow-up period. More than 50% of the tumors that developed at the same longitudinal location of the stomach were of the same macroscopic and histological type as the primary lesions. Conclusions: Because synchronous and/or metachronous gastric tumors are common, considerable attention should be paid to detect multiple gastric lesions after ESD of early gastric neoplasm. PMID- 29621879 TI - Recurrent Indeterminate Dendritic Cell Tumor of the Skin. AB - Indeterminate dendritic cell tumor (IDCT) is a dendritic cell tumor that displays histologic features similar to those of Langerhans cells. The origin of the indeterminate cells may represent precursors of Langerhans cells or skin dendritic cells. IDCT is extremely rare, and tumor progression and predictive factors are not well known. Here, we report a case of a 61-year-old man who presented with a papule on his back and was finally diagnosed with IDCT based on histology and immunohistochemistry. The tumor recurred three months after surgical excision. PMID- 29621880 TI - Let Archived Paraffin Blocks Be Utilized for Research with Waiver of Informed Consent. AB - Advances in biomedical and genetic research have contributed to more effective public health improvement via bench-to-bed research and the emergence of personalized medicine. This has certainly showcased the importance of archived human tissues, especially paraffin-embedded blocks in pathology. Currently in Korea, undue legislative regulations of the Bioethics and Safety Act suspend and at times discourage studies from taking place. In this paper, the authors underline the value of paraffin blocks in the era of personalized and translational medicine. We discuss detailed clauses regarding the applicability of paraffin blocks from a legal perspective and compare Korea's regulations with those of other countries. The necessity for allowing waived consent and Institutional Review Board (IRB) approval will be argued throughout. The authors suggest that researchers declare the following to obtain IRB approval and waiver of informed consents: research could not be practically carried out without a waiver of consent; the proposed research presents no more than minimal risk of harm to subjects, and the waiver of consent will not adversely affect the rights and welfare of subjects; and research will not utilize a tissue block if only 1 is available for each subject, to allow future clinical use such as re-evaluation or further studies. PMID- 29621881 TI - Disentangling Ligand Effects on Metathesis Catalyst Activity: Experimental and Computational Studies of Ruthenium-Aminophosphine Complexes. AB - Second-generation ruthenium olefin metathesis catalysts bearing aminophosphine ligands were investigated with systematic variation of the ligand structure. The rates of phosphine dissociation ( k1; initiation rate) and relative phosphine reassociation ( k-1) were determined for two series of catalysts bearing cyclohexyl(morpholino)phosphine and cyclohexyl(piperidino)phosphine ligands. In both cases, incorporating P-N bonds into the architecture of the dissociating phosphine accelerates catalyst initiation relative to the parent [Ru]-PCy3 complex; however, this effect is muted for the tris(amino)phosphine-ligated complexes, which exhibit higher ligand binding constants in comparison to those with phosphines containing one or two cyclohexyl substituents. These results, along with X-ray crystallographic data and DFT calculations, were used to understand the influence of ligand structure on catalyst activity. Especially noteworthy is the application of phosphines containing incongruent substituents (PR1R'2); detailed analyses of factors affecting ligand dissociation, including steric effects, inductive effects, and ligand conformation, are presented. Computational studies of the reaction coordinate for ligand dissociation reveal that ligand conformational changes contribute to the rapid dissociation for the fastest-initiating catalyst of these series, which bears a cyclohexyl bis(morpholino)phosphine ligand. Furthermore, the effect of amine incorporation was examined in the context of ring-opening metathesis polymerization, and reaction rates were found to correlate well with catalyst initiation rates. The combined experimental and computational studies presented in this report reveal important considerations for designing efficient ruthenium olefin metathesis catalysts. PMID- 29621882 TI - Hydrogen Evolution Reaction at Anion Vacancy of Two-Dimensional Transition-Metal Dichalcogenides: Ab Initio Computational Screening. AB - The catalytic activity for the hydrogen evolution reaction (HER) at the anion vacancy of 40 2D transition-metal dichalcogenides (TMDs) is investigated using the hydrogen adsorption free energy (Delta GH) as the activity descriptor. While vacancy-free basal planes are mostly inactive, anion vacancy makes the hydrogen bonding stronger than clean basal planes, promoting the HER performance of many TMDs. We find that ZrSe2 and ZrTe2 have similar Delta GH as Pt, the best HER catalyst, at low vacancy density. Delta GH depends significantly on the vacancy density, which could be exploited as a tuning parameter. At proper vacancy densities, MoS2, MoSe2, MoTe2, ReSe2, ReTe2, WSe2, IrTe2, and HfTe2 are expected to show the optimal HER activity. The detailed analysis of electronic structure and the multiple linear regression results identifies the vacancy formation energy and band-edge positions as key parameters correlating with Delta GH at anion vacancy of TMDs. PMID- 29621883 TI - Sentinel Wraps: Real-Time Monitoring of Food Contamination by Printing DNAzyme Probes on Food Packaging. AB - Here, we report the development of a transparent, durable, and flexible sensing surface that generates a fluorescence signal in the presence of a specific target bacterium. This material can be used in packaging, and it is capable of monitoring microbial contamination in various types of food products in real time without having to remove the sample or the sensor from the package. The sensor was fabricated by covalently attaching picoliter-sized microarrays of an E. coli specific RNA-cleaving fluorogenic DNAzyme probe (RFD-EC1) to a thin, flexible, and transparent cyclo-olefin polymer (COP) film. Our experimental results demonstrate that the developed (RFD-EC1)-COP surface is specific, stable for at least 14 days under various pH conditions (pH 3-9), and can detect E. coli in meat and apple juice at concentrations as low as 103 CFU/mL. Furthermore, we demonstrate that our sensor is capable of detecting bacteria while still attached to the food package, which eliminates the need to manipulate the sample. The developed biosensors are stable for at least the shelf life of perishable packaged food products and provide a packaging solution for real-time monitoring of pathogens. These sensors hold the potential to make a significant contribution to the ongoing efforts to mitigate the negative public-health-related impacts of food-borne illnesses. PMID- 29621884 TI - Plasma polymer film designs through the eyes of ToF-SIMS. AB - Time-of-flight secondary ion mass spectrometry (ToF-SIMS) is increasingly used for the detailed chemical characterization of complex organic materials. Of particular interest in biointerface materials, it provides the accurate molecular information on their surface, a prerequisite for the understanding of subsequent interaction with biomaterials. Plasma polymer films are promising biointerface materials, as tuning the deposition parameters allows the control over film stability and density of surface functional groups. However, the optimization of these film properties not only requires a detailed characterization of the film chemistry, but also that of the deposition mechanisms. Here, ToF-SIMS is used within its different operation modes to investigate those on several plasma polymer film designs. The detailed information on surface molecular chemistry, interface conformation, vertical and lateral chemical and cross-linking gradients is gathered and linked to the underlying deposition mechanisms. In combination with other techniques, the interpretation and understanding of the final functional property of the films in terms of protein adsorption and site-specific binding is achieved. PMID- 29621885 TI - Improvement in exercise capacity and delayed anaerobic metabolism induced by far infrared-emitting garments in active healthy subjects: A pilot study. AB - Background Far-infrared-emitting garments have several biological properties including the capability to increase blood perfusion in irradiated tissues. Design The aim of the study was to evaluate whether far-infrared radiation increases exercise capacity and delays anaerobic metabolism in healthy subjects. Methods With a double-blind, crossover protocol, a maximal cardiopulmonary exercise test was performed in 20 volunteers, wearing far-infrared or common sport clothes, identical in texture and colour. Results Comparing far-infrared with placebo garments, higher oxygen uptake at peak of exercise and longer endurance time were observed (peak oxygen uptake 38.0 +/- 8.9 vs. 36.2 +/- 8.5 ml/kg/min, endurance time 592 +/- 85 vs. 570 +/- 71 seconds; P < 0.01); the anaerobic threshold was significantly delayed (anaerobic threshold time 461 +/- 93 vs. 417 +/- 103 seconds) and anaerobic threshold oxygen uptake and anaerobic threshold oxygen pulse were significantly higher (25.3 +/- 6.4 vs. 20.9 +/- 5.4 ml/kg/min and 13.3 +/- 3.8 vs. 12.4 +/- 3.3 ml/beat, respectively). In 10 subjects the blood lactate concentration was measured every 2 minutes during exercise and at peak; lower values were observed with far-infrared fabrics compared to placebo from the eighth minute of exercise, reaching a significant difference at 10 minutes (3.6 +/- 0.83 vs. 4.4 +/- 0.96 mmol/l; P = 0.02). Conclusions In healthy subjects, exercising with a far-infrared outfit is associated with an improvement in exercise performance and a delay in anaerobic metabolism. In consideration of the acknowledged non-thermic properties of functionalised clothes, these effects could be mediated by an increase in oxygen peripheral delivery secondary to muscular vasodilation. These data suggest the need for testing far-infrared-emitting garments in patients with exercise limitation or in chronic cardiovascular and respiratory patients engaged in rehabilitation programmes. PMID- 29621886 TI - Plain Language to Communicate Physical Activity Information: A Website Content Analysis. AB - Plain language techniques are health literacy universal precautions intended to enhance health care system navigation and health outcomes. Physical activity (PA) is a popular topic on the Internet, yet it is unknown if information is communicated in plain language. This study examined how plain language techniques are included in PA websites, and if the use of plain language techniques varies according to search procedures (keyword, search engine) and website host source (government, commercial, educational/organizational). Three keywords ("physical activity," "fitness," and "exercise") were independently entered into three search engines (Google, Bing, and Yahoo) to locate a nonprobability sample of websites ( N = 61). Fourteen plain language techniques were coded within each website to examine content formatting, clarity and conciseness, and multimedia use. Approximately half ( M = 6.59; SD = 1.68) of the plain language techniques were included in each website. Keyword physical activity resulted in websites with fewer clear and concise plain language techniques ( p < .05), whereas fitness resulted in websites with more clear and concise techniques ( p < .01). Plain language techniques did not vary by search engine or the website host source. Accessing PA information that is easy to understand and behaviorally oriented may remain a challenge for users. Transdisciplinary collaborations are needed to optimize plain language techniques while communicating online PA information. PMID- 29621887 TI - Recombinant human hair keratin proteins for halting bleeding. AB - Keratins derived from human hair have been widely used for tissue engineering. However, some drawbacks relative to the traditional keratins extracts have been found: (a): difficultly controlling the amino acid composition; (b): batch to batch inconsistent quality; and (c): producing complex keratin and keratin associated proteins (KAPs), which problems have made some studies concerning human hair keratins stagnant, especially in the mechanism studies related to hemostasis of keratins. Herein, a type-I human hair keratin of K37 and a type-II human hair keratin of K81 were heterologously expressed and firstly used for haemostatic application. SDS-PAGE analysis shows that the recombinant keratins had higher purity compared to the extracted keratins. The circular dichroism (CD) spectra of K37 and K81 suggested that the secondary structures were rich in alpha helix. In addition, the recombinant keratin proteins could enhance fibrin colt formation at the site of injury and decrease the bleeding time and blood loss in liver puncture and femoral artery injury rat models. This study provides a new strategy for future works involving design and mechanism studies of keratin biomaterials. PMID- 29621888 TI - Asthma knowledge, care, and outcome during pregnancy: The QAKCOP study. AB - Asthma is the most common chronic medical condition affecting pregnancy. Optimizing asthma management in pregnancy is paramount for the well-being of both the mother and the baby. The primary objectives of this study were to assess patient's knowledge about asthma, the level of asthma care, and fetal and maternal outcomes among pregnant asthmatic women in this wealthy country with tremendous improvement in maternal and fetal health care. The secondary objective was to identify barriers to asthma control. This was a cross-sectional, face-to face, prospective study of 80 pregnant women with physician-diagnosed asthma. About 56% of patients reported worsening of their asthma control during pregnancy, of which 52.3% felt this worsening in the third trimester. About 65% of patients had uncontrolled asthma during their pregnancy, and inhaler technique was incorrect in 64.4%. Only 38% of patients knew the difference between controller and reliever asthma medications, 12.7% of patients had received written asthma action plan, 17% had a spirometry done in the previous 5 years, and 3.8% had peak expiratory flow meter at home. The main reasons for uncontrolled asthma were lack of knowledge about right asthma medications in 30% and fear of side effects of inhaled corticosteroids in 19% of patients. No financial reason was reported. Significant associations between total number of pregnancies, poor perception of asthma medications, asthma exacerbation during delivery and poor asthma control were observed. Preeclampsia and congenital anomalies occurred at higher rates than previously reported among general population in this country. The tremendous improvements in maternal health care and socioeconomic status do not seem to be a barrier to the globally recognized poor asthma care in pregnancy. Important strategies are much needed. PMID- 29621889 TI - Impacts of natural history and exhibit factors on carnivore welfare. AB - To improve the welfare of nonhuman animals under professional care, zoological institutions are continuously utilizing new methods to identify factors that lead to optimal welfare. Comparative methods have historically been used in the field of evolutionary biology but are increasingly being applied in the field of animal welfare. In the current study, data were obtained from direct behavioral observation and institutional records representing 80 individual animals from 34 different species of the order Carnivora. Data were examined to determine if a variety of natural history and animal management factors impacted the welfare of animals in zoological institutions. Output variables indicating welfare status included behavioral diversity, pacing, offspring production, and infant mortality. Results suggested that generalist species have higher behavioral diversity and offspring production in zoos compared with their specialist counterparts. In addition, increased minimum distance from the public decreased pacing and increased offspring production, while increased maximum distance from the public and large enclosure size decreased infant mortality. These results have implications for future exhibit design or renovation, as well as management practices and priorities for future research. PMID- 29621890 TI - Biomechanical analysis of likelihood of optic canal damage in peri-orbital fracture. AB - PURPOSE: Detection of optic canal fractures is often difficult because of the subtleness of the fracture. If we could clarify impact on which region around the orbit is likely to accompany the fracture of the optic canal, the knowledge should be useful to make early diagnosis of optic canal fractures. The present study was conducted to elucidate this issue. METHODS: Ten finite element models were produced simulating the skulls of ten humans (8 males and 2 females; 43.8 +/ 10.2 y/o). The peri-orbital area of each of the ten models was divided into eight regions in a clockwise fashion per 45 degrees. These regions were defined as Superior-Medial (0-45 degrees), Medial-Superior (45-90 degrees), Medial Inferior (90 to 135 degrees), Inferior-Medial (135 to 180 degrees), Inferior Lateral (180-225 degrees), Lateral-Inferior (225 to 270 degrees), Lateral Superior (270-315 degrees), and Superior-Lateral regions (315-360 degrees), respectively. Dynamic simulation of applying traumatic energy on each of these regions was conducted. Resultant fracture patterns were evaluated using finite element analyses. Thereafter, frequencies of fracture involvement of the optic canal were evaluated for each of the eight regions. RESULTS: The involvement of the optic canal was most frequent for the Superior-Medial region (7/10), followed by the Medial-Superior region (5/10). CONCLUSION: Optic canal fracture is likely to occur when the area between the supra-orbital notch and the medial canthus are strongly impacted. When evident fracture or serious damage of soft tissue is observed in this area, occurrence of optic canal fracture should be suspected. PMID- 29621891 TI - Critically Ill Patient Leaving Against Medical Advice. PMID- 29621892 TI - Competence Enhancement Program of Expressive Arts in End-of-Life Care for Health and Social Care Professionals: A Mixed-Method Evaluation. AB - In the recent decades, expressive arts (EXA) has been used in end-of-life care (EOLC) for facilitating the quality of life of the patients and the caregivers. However, it may not be practical for every EOLC service to dispense EXA activities solely by extensively trained art therapy specialists. There is currently a lack of brief training for nonart therapists, which may have stifled the application of the techniques in clinical settings. The current study therefore described and evaluated the effectiveness of a 2-day EXA training workshop in enhancing practice, knowledge, and self-competence among health and social care professionals working in EOLC using a mixed-method approach. The quantitative findings show significant improvement in perceived competence of providing services per holistic and person-centered EOLC objectives, nonpharmaceutical management of symptoms, and evidence-based psychosocial care as well as self-competence in death work (SCDW) after the workshop. The qualitative findings corroborated the quantitative results by suggesting that the improvement in competence could be associated with enhanced communication, meaning reconstruction, and therapeutic relationship with the clients as well as the improvement in mood, socialization, and self-esteem among the clients through the learned EXA activities. Our findings support the efficacy of a brief training of EXA activities for nonart therapists in enhancing multifaceted intervention competence. Further research on brief training will be needed to promote the use of EXA activities in the EOLC context. PMID- 29621893 TI - Facilitating Home Hospice Transitions of Care in Oncology: Evaluation of Clinical Pharmacists' Interventions, Hospice Program Satisfaction, and Patient Representation Rates. AB - BACKGROUND: The importance of medication reconciliation and the pharmacist's role within the interdisciplinary team at the point of transition to home hospice is understudied. A transitions of care pilot initiative was developed to streamline the transition for patients at end of life from inpatient cancer center care to home hospice. The initiative consisted of using a hospice discharge checklist, pharmacist-led discharge medication reconciliation in consultation with the primary team responsible for inpatient care, review of discharge prescriptions, and facilitation of bedside delivery of discharge medications. METHODS: This was a single-center, prospective, pilot initiative. The objectives of this study were to characterize pharmacist interventions at the time of transition, to assess changes in hospice organizations' perceptions of discharge readiness, and to evaluate differences in representation rates with the implementation of the pilot discharge process. RESULTS: Fifteen patients in the preimplementation period and 12 patients in the postimplementation period were included. One hundred eleven pharmacist interventions were captured, an average of 9.3 interventions per patient, with an acceptance rate of 82.9% by providers. There was a statistically significant ( P = .035) improvement in hospice organizations' perceptions of discharge readiness. There was no difference in 30-day representation rates postdischarge ( P = 1). CONCLUSION: This well-received pilot initiative demonstrated an improvement in local hospice's perception of patient readiness for discharge and a high percentage of accepted pharmacist interventions during discharge medication reconciliation. A larger sample size of patients and longer follow-up period may be needed to demonstrate statistically significant improvements in representation rates postintervention. PMID- 29621894 TI - An investigation into the relationship between parent satisfaction and child fluency in the Lidcombe Program: Clinic versus telehealth delivery. AB - PURPOSE: Parents have a vital role in the delivery of the Lidcombe Program when treating stuttering in young children. Research into parent experiences and perceptions throughout the Lidcombe Program is currently limited. Qualitative literature indicates that parent experiences and child progress are closely linked with program duration. This preliminary quantitative study examined parent satisfaction with child fluency at three time points. Data from clinic and telehealth delivery of the Lidcombe Program were used to further explore between group non-inferiority. METHOD: The data were drawn from a parallel, non inferiority, randomised controlled trial. Forty-nine children were randomised to the clinic or telehealth group. Parent satisfaction ratings with child fluency, the percentage of syllables stuttered and parent reported severity ratings were measured pre-treatment, 9 months and 18 months post-commencement of treatment. RESULT: An increase in parent satisfaction paralleled a decrease in stuttering severity across the three time points universally, however, the relationship between parent satisfaction and stuttering severity was not found at every time point. CONCLUSION: Though a general increase in parent satisfaction was seen as severity decreased, a global assumption on satisfaction cannot be made based on stuttering severity when measured using an ordinal scale. PMID- 29621895 TI - From Tobacco to Obesity Prevention Policies: A Framework for Implementing Community-Driven Policy Change. AB - Efforts to reverse the obesity epidemic require policy, systems, and environmental (PSE) change strategies. Despite the availability of evidence-based and other promising PSE interventions, limited evidence exists on the "how-to" of transitioning them into practice. For the past 13 years, the Los Angeles County Department of Public Health has been building capacity among community residents and other stakeholders to create effective community coalitions and to implement well-designed policy strategy campaigns using an evidence-based approach to policy change, the policy adoption model (PAM). Implementing a phase-based approach to policy change, the PAM was initially used to support the passage of over 140 tobacco control and prevention policies in Los Angeles County. Following these successes, Los Angeles County Department of Public Health applied the PAM to obesity prevention, operationalizing the policy process by training community residents and other stakeholders on the use of the model. The PAM has shown to be helpful in promoting PSE change in tobacco control and obesity prevention, suggesting a local-level model potentially applicable to other fields of public health seeking sustainable, community-driven policy change. PMID- 29621896 TI - Stigma modifies the association between social support and mental health among sexual violence survivors in the Democratic Republic of Congo: implications for practice. AB - BACKGROUND AND OBJECTIVES: The aim of this study was to further understanding of the relationship between social support, internalized and perceived stigma, and mental health among women who experienced sexual violence in the eastern Democratic Republic of Congo (DRC). METHODS: Drawing from baseline survey data collected in eastern DRC, researchers conducted a secondary cross-sectional analysis using data from 744 participants. Regression and moderation analyses were conducted to examine associations between social support variables, felt stigma, and depression, anxiety and posttraumatic stress disorder (PTSD). RESULTS: Emotional support seeking and felt stigma were positively associated with increased symptom severity across all three mental health variables. Stigma modified associations between emotional support seeking and depression (t = 2.49, p = .013), anxiety (t = -3.08, p = .002), and PTSD (t = -2.94, p = .003). Increased frequency of emotional support seeking was associated with higher mental health symptoms of anxiety and PTSD among women experiencing all levels of stigma. CONCLUSIONS: Enhancing understanding of social support and stigma may inform research and intervention among Congolese forced migrant populations across circumstances and geographic locations. Implications for practice and research are discussed. PMID- 29621897 TI - Current and potential targets for drug design in the androgen receptor pathway for prostate cancer. AB - INTRODUCTION: Modulating the androgen axis by different agents has been one of the most successful therapeutic interventions in the field of prostate cancer therapy. Newer agents such as abiraterone and enzalutamide have been widely adapted and have contributed to an increase in the overall survival of prostate cancer patients. However, most of these patients will develop resistance to these agents and will need chemotherapy. Areas covered: In this review, this author discusses current agents which modulate the androgen axis, the mechanisms of resistance to these agents and investigative agents which are designed to bypass these mechanisms of resistance. Potential targets in the androgen axis and related biochemical pathways are, furthermore, identified. Expert opinion: Understanding the mechanism of resistance to these agents is crucial in developing third generation anti-androgen agents which can potentially contribute to the longevity of prostate cancer patients to a greater extent. Besides developing more potent agents, it is also important to formulate new strategies to resensitize patients to current anti-androgen agents by carefully sequencing chemotherapy regimens and abrogating genetic changes which are known to cause resistance to anti-androgens. Combinatorial approach with immunotherapy offers prospects which may yield better results and need to be thoroughly explored. PMID- 29621899 TI - Introduction to the Special Issue: Interventions to Reduce Challenging Behavior Among Individuals With Autism Spectrum Disorder. AB - The prevalence of autism spectrum disorder (ASD) is on the rise. In addition to the social communication skill deficits and restrictive repetitive behaviors and interests, many individuals with ASD engage in challenging behavior. Challenging behavior is associated with a multitude of negative outcomes. Challenging behavior may cause harm to the individual with ASD as well as limit opportunities for educational, vocational, and social participation and development. In addition, caregivers experience high stress and low quality of mental health. As a result, challenging behavior warrants intervention that is specifically tailored to the unique characteristics of individuals with ASD. The purpose of this Special Issue is to showcase recent research in the treatment of challenging behavior for individuals with ASD. This two-part Special Issue contains 12 studies that range from systematic and quality reviews of the intervention literature, to innovative treatment approaches, to studies that develop and evaluate treatments for restrictive and repetitive behaviors and interests. PMID- 29621898 TI - Curcumin and its synthetic analogue dimethoxycurcumin differentially modulates antioxidant status of normal human peripheral blood mononuclear cells. AB - Curcumin is a polyphenol derived from the herb Curcuma longa, which has been extensively studied in terms of its antitumour, antioxidant, and chemopreventive activity as well as various other effects. In the present work we compared curcumin with its synthetic analogue dimethoxycurcumin (dimc) in terms of its antioxidant enzyme-modulating effects in human peripheral blood mononuclear cells (PBMC). We found that these compounds modulate antioxidant enzymes differentially. Both curcumin and dimethoxycurcumin effected a decrease in lipid peroxidation status in PBMC, however, curcumin had better activity in this regard. An increase in the activity of catalase was seen in the case of curcumin treated PBMC, whereas dimc increased catalase activity significantly to almost twofold level. Real time-polymerase chain reaction (RT-PCR) analysis revealed significant up-regulation of catalase at mRNA level post treatment with curcumin as well as dimc, however, dimc had better activity in this regard. Glutathione reductase (GR) activity and reduced glutathione levels increased in the case of peripheral blood mononuclear cells (PBMC) treated with curcumin, however, the trend was reversed with dimethoxycurcumin where, both glutathione reductase activity and reduced glutathione levels were significantly reduced. RT-PCR analysis of glutathione reductase mRNA levels showed decrease in mRNA levels post treatment with dimethoxycurcumin (dimc) further corroborating GR enzyme assay results, however, we could not obtain significant result post curcumin treatment. NFkB reporter assay and western blot analysis of nuclear as well as cytosolic fractions of NFkB revealed that curcumin inhibits NFkB activation whereas inhibition was much less with dimc. It has been reported that curcumin and dimc exerts differential cytotoxicity in normal and tumour cells and the reason for this had been attributed to the differential uptake of these compounds by normal cells and tumour cells. Based on our results we propose that differential modulation of antioxidant enzymes via NFkB pathway could be the reason behind differential cytotoxicity of dimc as well as curcumin in normal cells and tumour cells in addition to differential uptake of these compounds as reported previously. PMID- 29621900 TI - 20-Year Nationwide Follow-Up Study on Discontinuation of Antipsychotic Treatment in First-Episode Schizophrenia. AB - OBJECTIVE: It is generally believed that after the first episode of schizophrenia, the risk of relapse decreases with time in patients who are stabilized. Many treatment guidelines recommend that after stabilization, antipsychotic treatment should be continued for 1-5 years, and longer exposure should be avoided if possible. However, there is no published evidence to substantiate this view. The authors used nationwide databases to investigate this issue. METHOD: Prospectively gathered nationwide register data were used to study the risk of treatment failure (psychiatric rehospitalization or death) after discontinuation of antipsychotic treatment. Multivariate Cox regression was used to assess outcomes among all patients hospitalized for the first time with a schizophrenia diagnosis in Finland during the period of 1996-2014 (N=8,719). RESULTS: The lowest risk of rehospitalization or death was observed for patients who received antipsychotic treatment continuously (adjusted hazard ratio=1.00), followed by patients who discontinued antipsychotic use immediately after discharge from the first hospital treatment (hazard ratio=1.63, 95% CI=1.52 1.75), within 1 year (hazard ratio=1.88, 95% CI=1.57-2.24), within 1-2 years (hazard ratio=2.12, 95% CI=1.43-3.14), within 2-5 years (hazard ratio=3.26, 95% CI=2.07-5.13), and after 5 years (a median of 7.9 years) (hazard ratio=7.28, 95% CI=2.78-19.05). Risk of death was 174%-214% higher among nonusers and patients with early discontinuation of antipsychotics compared with patients who received antipsychotic treatment continuously for up to 16.4 years. CONCLUSIONS: Whatever the underlying mechanisms, these results provide evidence that, contrary to general belief, the risk of treatment failure or relapse after discontinuation of antipsychotic use does not decrease as a function of time during the first 8 years of illness, and that long-term antipsychotic treatment is associated with increased survival. PMID- 29621901 TI - The Clinical Effectiveness and Cost-Effectiveness of Lamotrigine in Borderline Personality Disorder: A Randomized Placebo-Controlled Trial. AB - OBJECTIVE: The authors examined whether lamotrigine is a clinically effective and cost-effective treatment for people with borderline personality disorder. METHOD: This was a multicenter, double-blind, placebo-controlled randomized trial. Between July 2013 and November 2016, the authors recruited 276 people age 18 or over who met diagnostic criteria for borderline personality disorder. Individuals with coexisting bipolar affective disorder or psychosis, those already taking a mood stabilizer, and women at risk of pregnancy were excluded. A web-based randomization service was used to allocate participants randomly in a 1:1 ratio to receive either an inert placebo or up to 400 mg/day of lamotrigine. The primary outcome measure was score on the Zanarini Rating Scale for Borderline Personality Disorder (ZAN-BPD) at 52 weeks. Secondary outcome measures included depressive symptoms, deliberate self-harm, social functioning, health-related quality of life, resource use and costs, side effects of treatment, and adverse events. RESULTS: A total of 195 (70.6%) participants were followed up at 52 weeks, at which point 49 (36%) of those in the lamotrigine group and 58 (42%) of those in the placebo group were taking study medication. The mean ZAN-BPD score was 11.3 (SD=6.6) among those in the lamotrigine group and 11.5 (SD=7.7) among those in the placebo group (adjusted difference in means=0.1, 95% CI=-1.8, 2.0). There was no evidence of any differences in secondary outcomes. Costs of direct care were similar in the two groups. CONCLUSIONS: The results suggest that treating people with borderline personality disorder with lamotrigine is not a clinically effective or cost-effective use of resources. PMID- 29621904 TI - The birth canal: correlation between the pubic arch angle, the interspinous diameter, and the obstetrical conjugate: a computed tomography biometric study in reproductive age women. AB - BACKGROUND: Assessment of pelvic configuration is an important factor in the prediction of a successful vaginal birth. However, manual evaluation of the pelvis is practically a vanishing art, and imaging techniques are not available as a real-time bed-side tool. Unlike the obstetrical conjugate diameter (OC) and inter spinous diameter (ISD), the pubic arch angle (PAA) can be easily measured by transperineal ultrasound. OBJECTIVES: Three-dimensional computed tomography bone reconstructions were used to measure the three main birth canal diameters, evaluate the correlation between them, and establish the normal reference range for the inlet, mid-, and pelvic outlet. STUDY DESIGN: Measurements of the PAA, obstetric conjugate (OC), and ISD were performed offline using three-dimensional post processing reconstruction in bone algorithm application of the pelvis on examinations performed for suspected renal colic in nonpregnant reproductive age woman. The mean of two measurements was used for statistical analysis which included reproducibility of measurements, regression curve estimation between PAA, OC, and ISD, and calculation of the respective reference range centiles for each PAA degree. RESULTS: Two hundred ninety-eight women comprised the study group. The mean +/- SD of the PAA, ISD, and OC were 104.9 degrees (+/-7.4), 103.8 mm (+/-7.3), and 129.9 mm (+/-8.3), respectively. The intra- and interobserver agreement defined by the intraclass correlation coefficient (ICC) was excellent for all parameters (range 0.905-0.993). A significant positive correlation was found between PAA and ISD and between PAA and OCD (Pearson's correlation = 0.373 (p < .001), and 0.163 (p = .022), respectively). The best regression formula was found with quadratic regression for inter spinous diameter (ISD): 34.122778 + (0.962182*PAA - 0.002830*PAA2), and linear regression for obstetric conjugate (OC): 110.638397 + 0.183156*PAA. Modeled mean, SD, and reference centiles of the ISD and OCD were calculated using the above regression models as function of the PAA. CONCLUSIONS: We report significant correlation between the three pelvic landmarks with greatest impact on the prediction of a successful vaginal delivery: the PAA which is easily measured sonographically and the ISD and OC which are not measurable by ultrasound. This correlation may serve as a basis for future studies to assess its utility and prognostic value for a safe vaginal delivery. PMID- 29621903 TI - Impact of Nrf2 on tumour growth and drug sensitivity in oncogenic K-ras transformed cells in vitro and in vivo. AB - K-ras is one of the most common oncogenes in human cancers, and its aberrant activation may lead to malignant transformation associated with oxidative stress and activation of the transcription factor Nrf2 that regulates multiple detoxification enzymes. The purpose of this research was to use gene editing technology to evaluate the role of Nrf2 in affecting tumour growth and drug sensitivity of K-rasG12V-transformed cells. We showed that induction of K-rasG12V caused a significant activation of Nrf2 associated with increased expression of its target genes NAD(P)H:quinone oxidoreductase 1 (NQO1) and haem oxygenase-1 (HO 1). Interestingly, knock-out of Nrf2 by CRISPR/Cas9 in K-rasG12V-expressing cells only impacted the expression of NQO1 but not HO-1. We also found that Nrf2 knock out caused high reactive oxygen species (ROS) stress, suppression of cell proliferation, increased apoptosis in vitro, and a decrease of tumour growth in vivo. Furthermore, abrogation of Nrf2 significantly increased the sensitivity of K-rasG12V cells to multiple anticancer agents including phenethyl isothiocyanate (PEITC), doxorubicin, etoposide, and cisplatin. These results show that genetic abrogation of Nrf2 impairs the malignant phenotype of K-RasG12V-transformed cells in vitro and in vivo, and demonstrates the critical role of Nrf2 in promoting cell survival and drug resistance in cells harbouring oncogenic K-ras. As such, inhibition of Nrf2 would be an attractive strategy to increase the therapeutic effect and overcome drug resistance in cancer with oncogenic K-ras activation. PMID- 29621902 TI - All for One and One for All: Mental Disorders in One Dimension. AB - In both child and adult psychiatry, empirical evidence has now accrued to suggest that a single dimension is able to measure a person's liability to mental disorder, comorbidity among disorders, persistence of disorders over time, and severity of symptoms. This single dimension of general psychopathology has been termed "p," because it conceptually parallels a dimension already familiar to behavioral scientists and clinicians: the "g" factor of general intelligence. As the g dimension reflects low to high mental ability, the p dimension represents low to high psychopathology severity, with thought disorder at the extreme. The dimension of p unites all disorders. It influences present/absent status on hundreds of psychiatric symptoms, which modern nosological systems typically aggregate into dozens of distinct diagnoses, which in turn aggregate into three overarching domains, namely, the externalizing, internalizing, and psychotic experience domains, which finally aggregate into one dimension of psychopathology from low to high: p. Studies show that the higher a person scores on p, the worse that person fares on measures of family history of psychiatric illness, brain function, childhood developmental history, and adult life impairment. A dimension of p may help account for ubiquitous nonspecificity in psychiatry: multiple disorders share the same risk factors and biomarkers and often respond to the same therapies. Here, the authors summarize the history of the unidimensional idea, review modern research into p, demystify statistical models, articulate some implications of p for prevention and clinical practice, and outline a transdiagnostic research agenda. [AJP AT 175: Remembering Our Past As We Envision Our Future October 1910: A Study of Association in Insanity Grace Helen Kent and A.J. Rosanoff: "No sharp distinction can be drawn between mental health and mental disease; a large collection of material shows a gradual and not an abrupt transition from the normal state to pathological states."(Am J Psychiatry 1910; 67(2):317-390 )]. PMID- 29621906 TI - FHR patterns that become significant in connection with ST waveform changes and metabolic acidosis at birth. AB - INTRODUCTION: Recent developments have produced new CTG classification systems and the question is to what extent these may affect the model of FHR + ST interpretation? The two new systems (FIGO2015 and SSOG2017) classify FHR + ST events differently from the current CTG classification system used in the STAN interpretation algorithm (STAN2007). AIM: Identify the predominant FHR patterns in connection with ST events in cases of cord artery metabolic acidosis missed by the different CTG classification systems. Indicate to what extent STAN clinical guidelines could be modified enhancing the sensitivity. Provide a pathophysiological rationale. MATERIAL AND METHODS: Forty-four cases with umbilical cord artery metabolic acidosis were retrieved from a European multicenter database. Significant FHR + ST events were evaluated post hoc in consensus by an expert panel. RESULTS: Eighteen cases were not identified as in need of intervention and regarded as negative in the sensitivity analysis. In 12 cases, ST changes occurred but the CTG was regarded as reassuring. Visual analysis of the FHR + ST tracings revealed specific FHR patterns: Conclusion: These findings indicate FHR + ST analysis may be undertaken regardless of CTG classification system provided there is a more physiologically oriented approach to FHR assessment in connection with an ST event. PMID- 29621905 TI - Pharmacodynamic and pharmacokinetic evaluation of buprenorphine + samidorphan for the treatment of major depressive disorder. AB - INTRODUCTION: Treatment resistant depression (TRD) represents approximately 20% of all individuals receiving care for major depressive disorder. The opioidergic system is identified as a novel target which hitherto has not been sufficiently investigated in adults with TRD. The combination product buprenorphine + samidorphan is an opioid modulatory agent which has demonstrated replicated evidence of efficacy in TRD without abuse liability. Areas covered: Databases Pubmed, Google Scholar and clinicaltrials.gov were searched from inception through December 2017 for clinical trial information, pharmacokinetics, and pharmacodynamics of buprenorphine + samidorphan. Herein we provide a summary of the available information. Eight clinical trials were identified for inclusion, of the eight trials, five trials had available results and are included in detail in our review. Expert opinion: Buprenorphine + samidorphan has demonstrated efficacy in TRD. Extant evidence surrounding the safety and tolerability profile of buprenorphine + samidorphan does not identify any significant safety concerns. Additional studies are needed in order to assess the long-term safety and efficacy of this product. PMID- 29621907 TI - Does high-dose benzodiazepine abuse really produce liver toxicity? Results from a series of 201 benzodiazepine monoabusers. AB - BACKGROUND: Several side-effects related to prolonged benzodiazepines (BZD) use have been reported. Given the primary role of liver in BZD metabolism, toxicity related to prolonged high-dose BZD use could be conceivable. No data are available on the long-term impact of high-dose BZD use on liver. RESEARCH DESIGN AND METHODS: A total of 201 BZD mono-abusers admitted to an Addiction Unit for detoxification were evaluated. Liver enzymes were evaluated at admission, before starting any treatment. An elevation of more than five times the upper limit of normal range (ULN) in serum ALT or conjugated bilirubin, or a combined elevation of AST, alkaline phosphatase and total bilirubin, one of which exceeding >2 the ULN, was considered diagnostic for drug-induced liver injury. RESULTS: None of the evaluated subjects showed significant alterations of liver enzymes. Those with the highest transaminase levels were showing high body mass index. Twenty patients (10%) showed elevated gamma-glutamyl-transferase. No alteration of alkaline phosphatase, nor bilirubin was found in any patient. The average dosage of BZD was 307 mg of diazepam-equivalents for 7 years. CONCLUSIONS: Present data suggest that prolonged use of high-dose BZD, although very dangerous for several reasons, does not seem to produce a significant drug-induced liver injury. PMID- 29621908 TI - Cost-utility analysis on telemonitoring of users with pacemakers: The PONIENTE study. AB - Introduction Few studies have confirmed the cost-saving of telemonitoring of users with pacemakers (PMs). The purpose of this controlled, non-randomised, non masked clinical trial was to perform an economic assessment of telemonitoring (TM) of users with PMs and check whether TM offers a cost-utility alternative to conventional follow-up in hospital. Methods Eighty-two patients implanted with an internet-based transmission PM were selected to receive either conventional follow-up in hospital ( n = 52) or TM ( n = 30) from their homes. The data were collected during 12 months while patients were being monitored. The economic assessment of the PONIENTE study was performed as per the perspectives of National Health Service (NHS) and patients. A cost-utility analysis was conducted to measure whether the TM of patients with PMs is cost-effective in terms of costs per gained quality-adjusted life years (QALYs). Results There was a significant cost-saving for participants in the TM group in comparison with the participants in the conventional follow-up group. From the NHS's perspective, the patients in the TM group gained 0.09 QALYs more than the patients in the conventional follow-up group over 12 months, with a cost saving of 57.64% (?46.51 versus ?109.79, respectively; p < 0.001) per participant per year. In-office visits were reduced by 52.49% in the TM group. The costs related to the patient perspective were lower in the TM group than in the conventional follow-up group (?31.82 versus ?73.48, respectively; p < 0.005). The costs per QALY were 61.68% higher in the in-office monitoring group. Discussion The cost-utility analysis performed in the PONIENTE study showed that the TM of users with PMs appears to be a significant cost-effective alternative to conventional follow-up in hospital. PMID- 29621909 TI - On intellectual and developmental disabilities in the United States: A historical perspective. AB - The history of intellectual and developmental disabilities (IDD) in the United States is, in many ways, a triumphant story reflecting an increasingly progressive attitude acknowledging the equality of all persons. The law now recognizes people with IDD as citizens, possessing an equal right to education, health care, and employment-each of which represents milestone victories. However, this progression was not a linear development but rather a product of periods of growth and decline, backsliding, and hard-won battles across political, cultural, and legal domains. This article explores the vacillating historical trajectory for people with IDD in the United States from the colonial period to the present. Particular attention is paid to the conceptual understanding of disability itself across time periods as that which informs particular developments in treatment, law, and social status. The capabilities approach, as outlined by Martha Nussbaum, is then brought to bear as a heuristic framework, consonant with current developments in disability studies, and which may guide future social and legislative action. PMID- 29621910 TI - "No! You can't have it": Problematizing choice in institutionalized adults with intellectual disabilities. AB - Institutionalized adults with profound intellectual disabilities (ID) face significant challenges to having their choice-making cultivated and supported. Based on observational and interview data from an institutional ethnographic study, this article explores how choice-making during mealtimes is acknowledged and problematized by staff. First, we suggest that Foucauldian problematization offers a lens through which to better understand how mealtime intervention plans passed down over time become embodied restrictive practices. Second, we provide examples and analyses of mealtime negotiations between staff and residents. Analyses revealed staff infantilize and misrepresent residents' choice-making during meals as manipulation; additionally, analyses suggest that past experiences of staff with residents and historical meal plans color how they acknowledge and interpret residents' choices. Our argument is an attempt to move forward discussions concerning the implementation of quality habilitation services by highlighting the ways contemporary institutional systems perpetuate misrepresentations of nonverbal behaviors in adults with profound ID. PMID- 29621911 TI - Incidence and natural history of preeclampsia/eclampsia at the university maternity of Antananarivo, Madagascar: high prevalence of the early-onset condition. AB - OBJECTIVES: To investigate the incidence of early - (delivery <34 weeks) (EOP) versus late-onset (delivery >=34 weeks) (LOP) in Madagascar. STUDY DESIGN: Eight months observational study of all preeclamptic/eclamptic women delivering at the maternity of the University Hospital of Befelatanana, Antananarivo, Madagascar. Sociodemographical and obstetrical risk factors are analyzed. RESULTS: Over the study period, we found 142 combined preeclampsia/eclampsia among 4316 births (incidence 3.3% for singleton pregnancies), of which 65 eclampsia (1.5% of all deliveries). The rate of delivery <34 weeks of gestation in preeclamptic women was 37.3% and 38.5% in eclamptic ones. The overall rate of fetal and neonatal mortality was of 50% (71/142). In EO forms the infant death rate was 83% (44/53), of which approximately 33% were due to intrauterine fetal death. In LO forms, the infant death rate was 20% in preeclampsia (15% of fetal deaths), while in case of maternal eclamptic seizures the infant mortality rate was doubled (40%). There were seven maternal deaths (of which four were eclamptic women). CONCLUSIONS: We have in Madagascar a high rate of early-onset preeclampsia/eclampsia EOP (37% versus approximately 10% in international literature) and a consequent worrying rate of maternal-fetal mortality. We could find other high incidence of EOP in nine other geographical locations: Guadeloupe (31%), Reunion (31%), Mauritius (34%), Cameroon (37.4%), China (38%), Zimbabwe (58%), Thailand (34%), Turkey (29%), and India (26%). Emerging and tropical countries may belong to the "high rate of EOP standard." There is an urgent need to have additional data from these areas to confirm the hypothesis. PMID- 29621912 TI - Effective suppression of tumour cells by oligoclonal HER2-targeted delivery of liposomal doxorubicin. AB - Synergistic effect of combined antibodies targeting distinct epitopes of a particular tumour antigen has encouraged some clinical trial studies and is now considered as an effective platform for cancer therapy. Providing several advantages over conventional antibodies, variable domain of heavy chain of heavy chain antibodies (VHH) is now major tools in diagnostic and therapeutic applications. Active targeting of liposomal drugs is a promising strategy, resulting in enhanced binding and improved cytotoxicity of tumour cells. In the present study, we produced four anti-HER2 recombinant VHHs and purified them via native and refolding method. ELISA and flow cytometry analysis confirmed almost identical function of VHHs in refolded and native states. Using a mixture of four purified VHHs, PEGylated liposomal doxorubicin was targeted against HER2 overexpressing cells. The drug release was analyzed at pH 7.4, 6.4 and 5.5 and dynamic light-scattering detector and TEM micrograph was applied to characterize the produced nanoparticles. The binding efficiency of these nanoparticles to BT474 and SKBR3 as HER2-positive and MCF10A as HER2-negative cell line was examined by flow cytometry. Our results indicated effective encapsulation of about 94% of the total drug in immunoliposomes. Flow cytometry results verified receptor-specific binding of targeted liposomes to SKBR3 and BT474 cell lines and more efficient binding was observed for liposomes conjugated with oligoclonal VHHs mixture compared with monoclonal VHH-targeted liposomes. Oligoclonal nanoparticles also showed more cytotoxicity compared with non-targeted liposomes against HER2-positive tumour cells. Oligoclonal targeting of liposomes was represented as a promising strategy for the treatment of HER2-overexpressing breast cancers. PMID- 29621914 TI - Transitions of Care Pilot Programs-We Have Your Missing Positive Results. PMID- 29621915 TI - Purchasing Suggestions for Hyperinflation Drugs. PMID- 29621917 TI - The inferior vena cava diameter is a useful ultrasound finding for predicting postpartum blood loss. AB - PURPOSE: To assess whether the ultrasonographic measurement of the inferior vena cava (IVC) diameter in postpartum women is a useful parameter in evaluating the actual blood loss during delivery due to massive postpartum hemorrhage. MATERIALS AND METHODS: In postpartum women with blood loss >=500 g, abdominal ultrasonography was performed 1 hour after delivery. The IVC diameter was measured during inspiration (IVCi) and expiration (IVCe). The maternal heart rate, blood pressure, and shock index (heart rate/systolic blood pressure) were also measured. The predictive value of these parameters for severe anemia (hemoglobin <7.0 g/dL) a day after delivery was evaluated via receiver operating characteristic (ROC) analyses. RESULTS: Seven patients with severe anemia and 77 controls were included in the analysis. The area under the curve (AUC) for IVCi (0.905) and IVCe (0.926) was higher than that for the shock index (0.890), heart rate (0.874), or systolic blood pressure (0.752). Among the examined parameters, the best sensitivity was achieved by IVCe and systolic blood pressure (71.4%). CONCLUSIONS: The ultrasonographic measurement of the IVC diameter was found to be the most useful parameter in evaluating the actual maternal blood loss after delivery. PMID- 29621916 TI - Is gain in health-related quality of life after a total hip arthroplasty depended on the comorbidity burden? AB - Background and purpose - Using patient-reported health-related quality of life (HRQoL), approximately 10% of patients report some degree of dissatisfaction after a total hip arthroplasty (THA). The preoperative comorbidity burden may play a role in predicting which patients may have limited benefit from a THA. Therefore, we examined whether gain in HRQoL measured with the EuroQol-5D (EQ-5D) at 3 and 12 months of follow-up depended on the comorbidity burden in THA patients Patients and methods - 1,582 THA patients treated at the Regional Hospital West Jutland from 2008 to 2013 were included. The comorbidity burden was collected from an administrative database and assessed with the Charlson Comorbidity Index (CCI). The CCI was divided into 3 levels: no comorbidity burden, low, and high comorbidity burden. HRQoL was measured using the EQ-5D preoperatively and at 3 and 12 months' follow-up. Association between low and high comorbidity burden compared with no comorbidity burden and gain in HRQoL was analyzed with multiple linear regression. Results - All patients, regardless of comorbidity burden, gained significantly in HRQoL. A positive association between comorbidity burden and gain in HRQoL was found at 3-month follow-up for THA patients with a high comorbidity burden (coeff: 0.09 (95% CI 0.02 - 0.16)) compared with patients with no comorbidity burden. Interpretation - A comorbidity burden prior to THA does not preclude a gain in HRQoL up to 1 year after THA. PMID- 29621918 TI - Analyzing research trends on drug safety using topic modeling. AB - INTRODUCTION: Published drug safety data has evolved in the past decade due to scientific and technological advances in the relevant research fields. Considering that a vast amount of scientific literature has been published in this area, it is not easy to identify the key information. Topic modeling has emerged as a powerful tool to extract meaningful information from a large volume of unstructured texts. Areas covered: We analyzed the titles and abstracts of 4347 articles in four journals dedicated to drug safety from 2007 to 2016. We applied Latent Dirichlet allocation (LDA) model to extract 50 main topics, and conducted trend analysis to explore the temporal popularity of these topics over years. Expert Opinion/Commentary: We found that 'benefit-risk assessment and communication', 'diabetes' and 'biologic therapy for autoimmune diseases' are the top 3 most published topics. The topics relevant to the use of electronic health records/observational data for safety surveillance are becoming increasingly popular over time. Meanwhile, there is a slight decrease in research on signal detection based on spontaneous reporting, although spontaneous reporting still plays an important role in benefit-risk assessment. The topics related to medical conditions and treatment showed highly dynamic patterns over time. PMID- 29621919 TI - Lung transplantation in idiopathic pulmonary fibrosis. AB - INTRODUCTION: Idiopathic Pulmonary Fibrosis (IPF) is a unique type of interstitial pneumonia in which progressive fibrosis can ultimately result in respiratory failure and death. The median survival of IPF remains dismal despite newer anti-fibrotic therapies. Lung transplantation is the only modality currently known to enhance survival for patients with IPF. Areas covered: Since IPF is predominantly a disorder of the elderly, determination of the impact of co morbidities is crucial for risk stratification of the individual patient. We review the potential effect of anti-fibrotic therapy in the pre and post transplant period; and also discuss the factors that need to be considered in deciding between single lung and bilateral lung transplantation. Expert commentary: Early referral to a transplant center is recommended for patients with IPF due to the high waiting list mortality. Evaluation of the transplant candidate should also be directed specifically at identifying co-morbidities that portend higher risk. While there has been a universal trend favoring bilateral lung transplantation over single lung transplantation for IPF, there are inherent pros and cons for both strategies and decisions should be individualized. Further studies are required to deduce the efficacy and safety of anti-fibrotic drugs in the immediate pre-and post-lung transplantation period. PMID- 29621920 TI - Medically indicated late preterm delivery and its impact on perinatal morbidity and mortality: a retrospective population-based cohort study. AB - OBJECTIVE: In the last few decades, attention has been focused on morbidity and mortality associated with late preterm delivery (34-36 + 6/7 weeks), accounting for 60-70% of all preterm births. This study is aimed to determine (1) the prevalence of late preterm deliveries (spontaneous and medically indicated) in our population; and (2) the rate of neonatal morbidity and mortality as well as maternal complications associated with the different phenotypes of late preterm deliveries. STUDY DESIGN: This retrospective population-based cohort study, included 96,176 women who had 257,182 deliveries, occurred between 1988 and 2011, allocated into three groups: term (n = 242,286), spontaneous (n = 10,063), and medically indicated (n = 4833) late preterm deliveries. RESULTS: (1) Medically indicated late preterm deliveries were associated with increased maternal morbidity, as well as neonatal morbidity and mortality, in comparison with other study groups (p < .01 for all comparisons); (2) medically indicated late preterm delivery was an independent risk factor for composite neonatal morbidity (low Apgar score at 5', seizures, asphyxia, acidosis) after adjustment for confounding factors (maternal age and ethnicity and neonatal gender) and stratification according to gestational age at delivery; and (3) the proportion of medically indicated late preterm deliveries affected the neonatal mortality rate. Below 35% of all late preterm deliveries, indicated late preterm birth were associated with a reduction in neonatal mortality; however, above this threshold medically indicated late preterm deliveries were associated with an increased risk for neonatal death. CONCLUSIONS: (1) Medically indicated late preterm deliveries were independently associated with adverse composite neonatal outcome; and (2) to benefit in term of neonatal outcome from the tool of medically indicated late preterm birth, their proportion should be kept below 35% of all late preterm deliveries, while exceeding this threshold increases the risk of neonatal mortality. PMID- 29621921 TI - Temporal and quantitative associations of electronic fetal heart rate monitoring patterns and neonatal outcomes?. AB - OBJECTIVE: The objective of this study is to evaluate the associations of electronic fetal heart rate monitoring (EFM) patterns and adverse neonatal outcomes Study design: From 2013 to 2016; 12,067 term, singleton deliveries in labor >=2 h with abnormal EFM defined as absent accelerations, variable, late or prolonged decelerations, tachycardia, bradycardia, or minimal variability were analyzed as any documentation during labor, in first hour and last hour of labor. Outcomes were composite neonatal adverse outcomes, neonatal intensive care unit (NICU) admission, neonatal hypoxia, neonatal hypoglycemia, umbilical artery pH, and base excess. Independent associations were ascertained using regression analysis. RESULTS: Significant independent associations occurred between any abnormal EFM during the last hour and five adverse neonatal outcomes; between abnormal EFM at any time and one adverse neonatal outcome while there was none with the first hour of labor. In the last hour, accelerations had significant negative associations with three adverse neonatal outcomes, while prolonged decelerations, late decelerations, tachycardia, and bradycardia had significant positive associations with three adverse neonatal outcomes. Throughout labor, increasing accelerations events were significantly negatively correlated with all adverse neonatal outcomes, while increasing frequency of late, variable, and prolonged decelerations were positively associated with five adverse neonatal outcomes. Hierarchical analysis showed that bradycardia/tachycardia contributed only 0.8%, while all EFM periodic changes contributed 1%; the addition of the frequencies of abnormal EFM events contributed 0.6% to the variance in umbilical artery pH and base excess. CONCLUSIONS: Terminal EFM patterns are independently associated with neonatal outcomes. Accelerations are protective of adverse neonatal outcomes. Increasing frequency of EFM patterns overtime contributes to neonatal outcome. PMID- 29621922 TI - Understanding the role played by parents, culture and the school curriculum in socializing young women on sexual health issues in rural South African communities. AB - BACKGROUND: the decline in South Africa's HIV infection rates especially among young women is encouraging. However, studies show that the 15-24-year-old cohort remains vulnerable. As they still report early sexual debut, being involved in sexual partnerships with older men as well as having unprotected sex. These risky sexual behaviors may be linked to factors such as the parent-child sexual health communication and the timing of the first talk. The quality of sexual health information received in school may also be important for enhancing healthier sexual behaviors. AIMS AND OBJECTIVES: to investigate the what, when and how sexual health communication occurs in rural South African families and to determine whether such communication patterns have changed over time. We also wanted to get an in-depth understanding of the roles played by culture, sexual health education and peers in the socialization of young women on sexual matters. METHODS: a purposive sample of (n = 55) women who were 18-35 years old was selected and interviewed in focus group discussions (FGDs). RESULTS: the FGD findings show that parent-child communication on sexual matters in rural communities is limited to messages that warn against pregnancy. It is also laden with cultural idioms that are not well explained. The school sexual health curriculum also fails to adequately equip adolescents to make informed decisions regarding sexual matters. All this seems to leave room for reception of misguided information from peers. CONCLUSIONS: findings highlight a need for designing interventions that can create awareness for parents on the current developmental needs and sexual behavior of adolescents. For adolescents programs would need to focus on providing skills on personal responsibility, and how to change behavior to enhance sexual health. PMID- 29621923 TI - Laparoscopic hysterectomy for endometrial cancer: impact of age on clinical outcomes. AB - INTRODUCTION: Improvement in preoperative care for the ageing population has resulted in an increasing number of elderly patients to be considered for surgery. With an increased incidence of endometrial cancer, it is inevitable that a significant number of elderly patients are referred for surgery, despite the concerns over co-morbid conditions and diminished cardiopulmonary reserves. AIM: To evaluate the clinical outcomes of laparoscopic hysterectomy for elderly women operated on for endometrial cancer with comparison to younger patients. METHODS: A retrospective study of women who had undergone total laparoscopic hysterectomy for endometrial cancer at Ninewells Hospital between January 2015 and January 2017 was conducted. Patients were identified from the gynaecology oncology multidisciplinary team e-case database and were categorised into younger and older group according to their age. Both groups were compared and analysed for demographics details, pre-existing comorbidity, METS score, perioperative and postoperative data. RESULTS: There were 100 women meeting the study criteria. Of these, 79 patients were aged <=75 (Group A) and 21 patients were aged >75 (Group B). The mean age was 62.9 (age range 37-75) and 80.6 (age range 76-90) in Group A and Group B, respectively. Group A presented with higher mean BMI ( = 33.8) compared to Group B ( = 28.8). With the increase in patient's age, reduced METS score was observed. No difference was found between the groups in the incidence of estimated blood loss and postoperative hospital stay. Fisher's exact test was used to evaluate the postoperative complication in both groups. The two-tailed p value (p = .1108) had illustrated that the observation was statistically insignificant between both groups. One patient in Group A (n = 79) was found to have pelvic haematoma after the procedure; while two patients in Group B (n = 21) developed port site haematoma. Otherwise, no other patients from both groups developed postoperative complication regardless of their pre-existing medical conditions. Only one patient in Group A (n = 79) required conversion to open surgery due to difficult access and large uterine fibroid. CONCLUSIONS: Total laparoscopic hysterectomy appears to be feasible and safe in elderly women with no significant difference between groups. Minimally invasive surgery has shown to extend considerable benefits to patient safety regardless of their age. PMID- 29621924 TI - Using the device-oriented subjective outcome (DOSO) scale to measure outcomes of different hearing aids. AB - OBJECTIVE: The device-oriented subjective outcome (DOSO) is a device-oriented questionnaire, intended to minimise the influence of personality on self-reported measures. The aim of this study was to provide normative data with 2015-era hearing aid technologies. DESIGN: This retrospective study evaluated data from records of three clinical trials. The DOSO was administered for the participants' own devices as a part of the intake and after using research devices in the field. STUDY SAMPLE: The DOSO data were collected from 132 experienced bilateral hearing aid wearers who participated in the clinical trials. RESULTS: The DOSO data collected with the participants' own devices were compared to the interim normative data collected between 2004 and 2005. The DOSO subscale scores from the participants' own devices were significantly higher than those from the interim norms, except Listening Effort subscale. To demonstrate the utility of the new norms, a separate set of DOSO data collected from the same participants after using research hearing aids were contrasted to the new normative data. After accounting for possible placebo effects, the DOSO data with research devices revealed additional self-reported benefit of technological advancements. CONCLUSIONS: Norms for the DOSO are recommended for evaluating hearing aids with more recent technologies. PMID- 29621925 TI - Transport kinetics of chromium in perfused human placental lobule in late gestation: in vitro study. AB - OBJECTIVE: Reports relating to maternal-fetal transport kinetics of chromium, an essential trace element in the human pregnancies are scanty. Hence, we thought it interesting to investigate the transport kinetics of this trace element in the human placenta in late gestation in vitro. METHODS: Human placentae were collected immediately after delivery from normal uncomplicated pregnancies. Chromium chloride solution (GFS Chem Inc, Ohio, USA) at 10 times the physiological concentrations and antipyrine (Sigma Chem Co., St. Louis, USA) as internal reference marker was injected as a single bolus (100 ul) into the maternal arterial circulation of perfused placental lobules and perfusate samples were collected from maternal and fetal circulations over a study period of 5 minutes. National culture and Tissue collection medium, diluted with Earle's buffered salt solution was used as the perfusate. Serial perfusate samples were collected from fetal venous perfusate for a period of 30 minutes. Chromium concentration in perfusate samples was determined using atomic absorption spectrophotometry and the concentration of reference marker, antipyrine was measured by spectrophotometry. Transport kinetics and transport parameters of study and reference markers were assessed using well-established parameters. RESULTS: Differential transport rates of chromium and antipyrine in 10 perfusions differed significantly for 10 and 50% efflux fractions (ANOVA test, p < .05) while those of 25, 75, and 90% efflux fractions were not significantly different between the study and reference substances. Chromium transport fraction (TF) averaged 54.9% of bolus dose in 10 perfusions while that of antipyrine averaged 89% of bolus dose, representing 61.80% of reference marker TF. The difference observed in TF values of chromium and antipyrine was statistically significant (Student's t-test, p < .05). Pharmacokinetic parameters such as area under the curve, clearance, absorption rate, elimination rate of chromium compared to reference marker was significantly different (ANOVA test, p < .05) between the study and reference substances. CONCLUSIONS: Our studies report for the first time maternal-fetal transport kinetics of chromium in human placenta in vitro. Considering the restricted transfer of this essential trace element from maternal to fetal circulation despite its small molecular weight, we hypothesize an active transport of chromium across the human placental membrane. Further studies relating to placental transport kinetics of this trace element in various pregnancy-related disease states are in progress. PMID- 29621926 TI - Social Perception in Mesial Temporal Lobe Epilepsy: Interpreting Social Information From Moving Shapes and Biological Motion. AB - Dysfunction in the understanding of social signals has been reported in persons with epilepsy, which may partially explain lower levels of life satisfaction in this patient population. Extensive assessment is necessary, particularly when the mesial temporal lobe, responsible for emotion processing, is affected. The authors examined multiple levels of social perception in patients with mesial temporal lobe epilepsy (MTLE), including judgments of point-light motion displays of human communicative interactions (Communicative Interactions Database-5 Alternative Forced Choice format) and theory-of-mind processes evaluated using geometric shapes (Frith-Happe animations [FHA]). This case-control study included MTLE patients with anterior temporal lobectomies (ATL+) (N=19), MTLE patients without lobectomies (ATL-) (N=21), and healthy controls (HCs) (N=20). Both groups of MTLE patients were less efficient in recognizing goal-directed and mentalizing interactions of FHA compared with HC subjects. The ATL+ group attributed emotions to FHA less accurately than HC subjects. Both the ATL- and ATL+ groups classified individual point-light animations more often as communicative than the HC group. ATL+ patients were also less efficient in interpreting point-light animations in terms of individual actions than the HC group. The number of years of epilepsy duration was inversely correlated with recognition of FHA interactions. The mean number of seizures was inversely correlated with the interaction identification in point-light stimuli. Patients with MTLE, irrespective of surgical treatment, present impaired social perception in domains assessed with abstract moving shapes or nonabstract biological motion. This impairment may be the basis of problems faced by patients reporting difficulties in understanding the intentions and feelings of other individuals. PMID- 29621928 TI - Biomimetic porous high-density polyethylene/polyethylene- grafted-maleic anhydride scaffold with improved in vitro cytocompatibility. AB - A major challenge for tissue engineering is to design and to develop a porous biocompatible scaffold, which can mimic the properties of natural tissue. As a first step towards this endeavour, we here demonstrate a distinct methodology in biomimetically synthesized porous high-density polyethylene scaffolds. Co extrusion approach was adopted, whereby high-density polyethylene was melt mixed with polyethylene oxide to form an immiscible binary blend. Selective dissolution of polyethylene oxide from the biphasic system revealed droplet-matrix-type morphology. An attempt to stabilize such morphology against thermal and shear effects was made by the addition of polyethylene- grafted-maleic anhydride as a compatibilizer. A maximum ultimate tensile strength of 7 MPa and elastic modulus of 370 MPa were displayed by the high-density polyethylene/polyethylene oxide binary blend with 5% maleated polyethylene during uniaxial tensile loading. The cell culture experiments with murine myoblast C2C12 cell line indicated that compared to neat high-density polyethylene and high-density polyethylene/polyethylene oxide, the high-density polyethylene/polyethylene oxide with 5% polyethylene- grafted-maleic anhydride scaffold significantly increased muscle cell attachment and proliferation with distinct elongated threadlike appearance and highly stained nuclei, in vitro. This has been partly attributed to the change in surface wettability property with a reduced contact angle (~72 degrees ) for 5% PE- g-MA blends. These findings suggest that the high-density polyethylene/polyethylene oxide with 5% polyethylene- grafted-maleic anhydride can be treated as a cell growth substrate in bioengineering applications. PMID- 29621927 TI - Skin Conduction Levels Differentiate Frontotemporal Dementia From Alzheimer's Disease. AB - Patients with behavioral variant frontotemporal dementia (bvFTD) and Alzheimer's disease (AD) differ in basic emotional tone. Skin conduction levels (SCLs), a measure of sympathetic tone, may be a sensitive test for discriminating these two dementias early in their course. Previous research has shown differences in resting SCLs between patients with bvFTD and AD, but no study has evaluated the discriminability of SCLs during different environmental conditions. The authors compared bvFTD patients (N=8), AD patients (N=10), and healthy control subjects (N=9) on SCL measures pertaining to real-life vignettes or scenarios differing in valence and emotional intensity. The SCLs among the bvFTD patients were decreased across all conditions, whereas the SCLs among the AD patients were increased compared with control participants. On analysis, the SCLs in response to emotional stimuli differentiated bvFTD from AD with an area under the receiver operator characteristic curve of 95.3%. At a cutoff <=0.77 MUS, emotional vignettes distinguished bvFTD from AD with a sensitivity of 86% and a specificity of 96%. These preliminary results indicate the potential utility of SCLs for differentiating bvFTD from AD early in their course, regardless of environmental condition. PMID- 29621929 TI - Laser-synthesized nanocrystalline, ferroelectric, bioactive BaTiO3/Pt/FS for bone implants. AB - The goal of our study is to design BaTiO3 ferroelectric layers that will cover metal implants and provide improved osseointegration. We synthesized ferroelectric BaTiO3 layers on Pt/fused silica substrates, and we studied their physical and bio-properties. BaTiO3 and Pt layers were prepared using KrF excimer laser ablation at substrate temperature Ts in the range from 200 degrees C to 750 degrees C in vacuum or under oxygen pressure of 10 Pa, 15 Pa, and 20 Pa. The BaTiO3/Pt and Pt layers adhered well to the substrates. BaTiO3 films of crystallite size 60-140 nm were fabricated. Ferroelectric loops were measured and ferroelectricity was also confirmed using Raman scattering measurements. Results of atomic force microscopy topology and the X-ray diffraction structure of the BaTiO3/Pt/fused silica multilayers are presented. The adhesion, viability, growth, and osteogenic differentiation of human osteoblast-like Saos-2 cells were also studied. On days 1, 3, and 7 after seeding, the lowest cell numbers were found on non-ferroelectric BaTiO3, while the values on ferroelectric BaTiO3, on non-annealed and annealed Pt interlayers, and on the control tissue culture polystyrene dishes and microscopic glass slides were similar, and were usually significantly higher than on non-ferroelectric BaTiO3. A similar trend was observed for the intensity of the fluorescence of alkaline phosphatase, a medium term marker of osteogenic differentiation, and of osteocalcin, a late marker of osteogenic differentiation. At the same time, the cell viability, tested on day 1 after seeding, was very high on all tested samples, reaching 93-99%. Ferroelectric BaTiO3 films deposited on metallic bone implants through a Pt interlayer can therefore markedly improve the osseointegration of these implants in comparison with non-ferroelectric BaTiO3 films. PMID- 29621930 TI - Violence in Rural, Suburban, and Urban Schools in Pennsylvania. AB - School violence is a public health issue with direct and collateral consequences that has academic and social impacts for youth. School violence is often considered a uniquely urban problem, yet more research is needed to understand how violence in rural and suburban schools may be similar or different from urban counterparts. Using school violence data from a state with urban, suburban, and rural counties, we explored the landscape of school violence in Pennsylvania (PA) through mapping, descriptive statistics, and factor analysis. Results show school violence is not solely an urban problem. Schools in all county types and across grade levels deal with violence to varying degrees, and the majority of schools across county types experience low levels of violence. Types of violence experienced by PA schools loaded onto three factors, suggesting that targeted interventions may be better suited to addressing school violence. PMID- 29621931 TI - Contrasting co-inheritance of alpha and beta mutations in delta beta thalassemia and hereditary persistence of fetal hemoglobin: a study from India. AB - BACKGROUND AND OBJECTIVES: Coinheritance of deltabeta thalassemia and HPFH with inherited factors is sparsely documented and may affect treatment modalities. So, we screened the presence of alpha deletion and beta mutations in deltabeta thalassemia and HPFH disorders in 52 cases with high Hb F concentration. MATERIAL AND METHODS: Fifty-two individuals with raised HbF levels were study subjects. CZE was done for quantitative assessment of hemoglobin variants. Asian Indian inversion deletion break point type A, B and HPFH-3 were done by GAP-PCR. RESULTS: 18/52 cases of deltabeta Ggamma (Agammadeltabeta)0 thalassemia and 28/52 cases of HPFH-3 deletion were characterized. 6/52 patients with raised HbF levels were negative for deltabeta Ggamma (Agammadeltabeta)0 and HPFH-3 deletion. 9/18 (50%) were heterozygous for Ggamma(Agammadeltabeta)0 break point type A, 6/18 (33%) were heterozygous for break point type B and 3/18 (17%) were homozygous. Of the nine patients heterozygous for Ggamma(Agammadeltabeta)0 break point type A, three (33%) patients were double heterozygous with alpha 3.7 kb deletion and two (22%) patients showed compound heterozygosity with IVS 1-5(G-C) mutation. 4/9 (45%) patients were Ggamma(Agammadeltabeta)0 heterozygous. DISCUSSION AND CONCLUSION: We found 5/18(27.beta) deltabeta-thalassemia cases with co-inherited alpha 3.7 deletion and 3/18 (16beta) cases with IVS 1-5(G-C) mutation. Patients showed features of thalassemia intermedia phenotype among which those with co inherited IVS 1-5(G-C) mutation showed severe phenotype as compared to those with co-inherited alpha 3.7 deletion. So, we highlight importance of genotyping of patients with deltabeta thalassemia or HPFH and coinheritance with inherited factors which plays crucial role in clinicopathological profile and setting up prenatal diagnostic protocol. PMID- 29621932 TI - Financial security and public health: How basic income & cash transfers can promote health. AB - Inadequate financial resources are a major driver for poor health. Financial insecurity contributes to health inequities in mutually reinforcing ways, with some effects lasting years. Fostering financial security to reduce the likelihood or magnitude of such pressures would have significant present and future health benefits. We review several models for bolstering financial security to determine which have the most significant health contributions based on current evidence and their theoretical potential. We hypothesise that basic income guarantees might have the greatest positive health impact for beneficiaries, though this is heavily contingent on programme design and how financing affects other social welfare programmes. Cash transfer programmes also contribute to financial security and promote health, with particularly strong evidence for the health benefits of conditional cash transfers, and may be more feasible programmes in some contexts. PMID- 29621933 TI - Challenges in day-to-day midwifery practice; a qualitative study from a regional referral hospital in Dar es Salaam, Tanzania. AB - BACKGROUND: Maternal and infant mortality rates in Tanzania have decreased over the past decades, but remain high. One of the challenges the country faces, is the lack of skilled health care workers. High fertility rates make midwives and their patients particularly susceptible to stress as a result of understaffing. OBJECTIVE: This paper explores the challenges midwives face in their day-to-day practice at a regional referral hospital in Tanzania, and investigates which measures the midwives themselves find necessary to implement to improve their situation. METHODS: A qualitative study design with focus group discussions (FGDs) was employed to explore which challenges the midwives experienced. Each focus group consisted of five to six midwives. A FGD topic guide covering challenges, consequences, motivation, ideal situation and possible solutions was used. These data were analyzed using Systematic Text Condensation. RESULTS: A total of 28 Midwives, six men and 22 women, participated in five FGDs. Four categories emerged from the collected material: Feelings of demoralization, shortage of resources, societal challenges and personal struggles. A feeling of demoralization was especially prevalent and was caused by a lack of support from the leaders and little appreciation from the patients. Shortage of resources, and shortage of personnel in particular, was also highlighted as it led to an excessive workload resulting in difficulties with providing adequate care. These difficulties were intensified by lack of equipment, facilities and a non-optimal organization of the healthcare system. CONCLUSION: The challenges revealed during the FGDs prevent the midwives from providing sufficient midwifery care. To improve the situation, measures such as supportive leadership, reduction of workload, increasing availability of equipment and increasing knowledge of reproductive health in society, should be taken. PMID- 29621934 TI - Processing speed in children treated for brain tumors: effects of radiation therapy and age. AB - The current study examined processing speed in children two years post-treatment for brain tumors (BT) with radiation therapy (RT) compared to those treated with without RT. Participants included 59 children (4-17 years) with BT assessed as part of the Brain Radiation Investigative Study Consortium (BRISC). Processing speed was assessed at two time points: Time1 (3-9 months post-surgery) for 26 children who received whole brain or focal RT (RT group) and 33 treated without RT (no-RT group), and again two years later (Time2) for 42 participants (17 RT, 25 no-RT). Linear mixed effects (LME) regression analyses examined differences in cognitive and motor speed between groups and across visits, with age at Time1 (age1) treated as a moderating variable, and sex and primary tumor size as covariates. No effects for treatment group or visit were found for motor speed (Pegboard) or mean reaction time (Attention Network Task). On the Wechsler Processing Speed Index (PSI), the no-RT group performed better than the RT group, with a group-by-age interaction such that across visits, the difference between the no-RT and RT groups was larger among children who were older at initial treatment (>=10 years) than among those who were younger (<10 years). Cumulative brain injury earlier in life (tumor, surgery, plus RT) may result in greater impact on more complex tasks of cognitive efficiency. Children receiving RT showed reduced processing speed over time, with a larger group difference among those who were over 10 years at treatment. PMID- 29621935 TI - Negative affect varying in motivational intensity influences scope of memory. AB - Emotions influence cognitive processes involved in memory. While some research has suggested that cognitive scope is determined by affective valence, recent models of emotion-cognition interactions suggest that motivational intensity, rather than valence, influences these processes. The present research was designed to clarify how negative affects differing in motivational intensity impact memory for centrally or peripherally presented information. Experiments 1 & 2 found that, relative to a neutral condition, high intensity negative affect (anger) enhances memory for centrally presented information. Experiment 3 replicated this effect using another high intensity negative affect (threat). Experiment 4 extended this by finding that, relative to a neutral condition, low intensity negative affect (sadness) enhanced memory for peripherally presented information. Finally, in Experiment 5, the effects of sadness and threat on scope of memory were directly compared, finding that threat narrowed scope of memory, while sadness broadened scope of memory. Together, these results provide additional support for the motivational dimensional model of cognitive scope, in that high intensity emotions narrow cognitive scope, while low intensity emotions broaden cognitive scope. PMID- 29621936 TI - Colonoscopic diagnosis and reduction of recurrent intussusception owing to Henoch Schonlein purpura without purpura. AB - About 50-75% of patients with Henoch-Schonlein purpura (HSP) develop gastro intestinal symptoms with surgical complications such as intussusception occurring in 0.7-13.6%. In 10-40% of patients, however, gastro-intestinal manifestations may precede the onset of purpura. In patients with gastro-intestinal tract involvement without purpura, confirming the diagnosis of HSP and determining the appropriate treatment remains difficult. A seven-year-old boy presented with recurrent intussusception owing to HSP without purpura. It was confirmed pathologically and treated via colonoscopy. Early colonoscopic intervention can contribute to the early diagnosis of HSP and its subsequent management by avoiding unnecessary surgical invasion. PMID- 29621937 TI - Identification of EGFR in pearl oyster (Pinctada fucata martensii) and correlation analysis of its expression and growth traits. AB - Marine pearl production is directly influenced by the growth speed of Pinctada fucata martensii. However, the slow growth rate of this organism remains the main challenge in aquaculture production. Epidermal growth factor receptor (EGFR), an important receptor of tyrosine kinases in animals, plays versatile functions in development, growth and tissue regeneration. In this study, we described the characteristic and function of an EGFR gene identified from P. f. martensii (PmEGFR). PmEGFR possesses a typical EGFR structure and is expressed in all studied tissues, with the highest expression level in adductor muscle. PmEGFR expression level is significantly higher in the fast-growing group than that in the slow-growing one. Correlation analysis represents that shell height and shell weight show positive correlation with PmEGFR expression (p < 0.05), and total weight and tissue weight exhibit positive correlation with it (p < 0.01). This study indicates that PmEGFR is a valuable functional gene associated with growth traits. PMID- 29621938 TI - Does strategy instruction on the Rey-Osterrieth Complex Figure task lead to transferred performance improvement on the Modified Taylor Complex Figure task? A randomized controlled trial in school-aged children. AB - OBJECTIVE: Providing children with organizational strategy instruction on the Rey Osterrieth Complex Figure (ROCF) has previously been found to improve organizational and accuracy performance on this task. It is unknown whether strategy instruction on the ROCF would also transfer to performance improvement on copying and the recall of another complex figure. METHODS: Participants were 98 typically developing children (aged 9.5-12.6 years, M = 10.6). Children completed the ROCF (copy and recall) as a pretest. Approximately a month later, they were randomized to complete the ROCF with strategy instruction in the form of a stepwise administration of the ROCF or again in the standard format. All children then copied and recalled the Modified Taylor Complex Figure (MTCF). All productions were assessed in terms of organization, accuracy and completion time. RESULTS: Organization scores for the MTCF did not differ for the two groups for the copy production, but did differ for the recall production, indicating transfer. Accuracy and completion times did not differ between groups. Performance on all measures, except copy accuracy, improved between pretest ROCF and posttest MTCF production for both groups, suggesting practice effects. CONCLUSION: Findings indicate that transfer of strategy instruction from one complex figure to another is only present for organization of recalled information. The increase in RCF-OSS scores did not lead to a higher accuracy or a faster copy or recall. PMID- 29621939 TI - Unique GH18 chitinase from Euglena gracilis: full-length cDNA cloning and characterization of its catalytic domain. AB - A cDNA of putative chitinase from Euglena gracilis, designated EgChiA, encoded 960 amino acid residues, which is arranged from N-terminus in the order of signal peptide, glycoside hydrolase family 18 (GH18) domain, carbohydrate binding module family 18 (CBM18) domain, GH18 domain, CBM18 domain, and transmembrane helix. It is likely that EgChiA is anchored on the cell surface. The recombinant second GH18 domain of EgChiA, designated as CatD2, displayed optimal catalytic activity at pH 3.0 and 50 degrees C. The lower the polymerization degree of the chitin oligosaccharides [(GlcNAc)4-6] used as the substrates, the higher was the rate of degradation by CatD2. CatD2 degraded chitin nanofibers as an insoluble substrate, and it produced only (GlcNAc)2 and GlcNAc. Therefore, we speculated that EgChiA localizes to the cell surface of E. gracilis and is involved in degradation of chitin polymers into (GlcNAc)2 or GlcNAc, which are easily taken up by the cells. PMID- 29621940 TI - Joint Relationship Between Physical Activity, Weight Status, and Motor Skills in Children Aged 3 to 10 Years. AB - While the relationships between physical activity (PA), obesity, and motor skills have been independently examined by previous research, this study explored both independent and combined relationships between children's PA, weight status, and motor skills within a multiple regression analysis. We measured height and weight and calculated body mass index (BMI) z scores for 96 children (3-10 years of age). We measured motor skills using the Movement Assessment Battery for Children 2nd edition (MABC-2), and we measured PA levels through accelerometry. Children with more time in moderate and moderate-to-vigorous PA had higher Total motor skill scores on the MABC-2. Further, children with higher moderate PA levels had higher Balance scores and those with moderate-to-vigorous PA demonstrated higher Aiming and Catching scores. Among children with healthier BMIs, more time spent in PA, regardless of intensity, was related to higher Aiming and Catching scores. Among children with BMI scores suggestive of overweight/obesity, both moderate and moderate-to-vigorous PA were positively related to Balance scores. In conclusion, while BMI z scores were not directly related to motor skills, PA levels were positively related to motor skills, and weight status mediated the relationship between PA and specific components of motor skills. PMID- 29621941 TI - Anti-melanogenic effects of resorcinol are mediated by suppression of cAMP signaling and activation of p38 MAPK signaling. AB - In this study, we investigated the inhibitory mechanisms of resorcinol in B16F10 mouse melanoma cells. We found that resorcinol reduced both the melanin content and tyrosinase activity in these cells. In addition, resorcinol suppressed the expression of melanogenic gene microphthalmia-associated transcriptional factor (MITF) and its downstream target genes tyrosinase, tyrosinase-related protein (TRP)-1, and TRP-2. In addition, we found that resorcinol reduced intracellular cAMP levels and protein kinase A (PKA) activity, and increased phosphorylation of the p38 mitogen-activated protein kinase (MAPK). Resorcinol was also found to directly inhibit tyrosinase activity. However, resorcinol-induced decrease in melanin content, tyrosinase activity, and tyrosinase protein levels were attenuated by SB203580, a p38 MAPK inhibitor. Taken together, these data indicate that anti-melanogenic activity of resorcinol is be mediated through the inhibition of cAMP signaling and activation of p38 MAPK, indicating that resorcinol may be a possible ameliorating agent in the treatment of hyperpigmentation skin disorders. PMID- 29621942 TI - Intestinal lesions in dogs with acute hemorrhagic diarrhea syndrome associated with netF-positive Clostridium perfringens type A. AB - Acute hemorrhagic diarrhea syndrome (AHDS), formerly named canine hemorrhagic gastroenteritis, is one of the most common causes of acute hemorrhagic diarrhea in dogs, and is characterized by acute onset of diarrhea, vomiting, and hemoconcentration. To date, histologic examinations have been limited to postmortem specimens of only a few dogs with AHDS. Thus, the aim of our study was to describe in detail the distribution, character, and grade of microscopic lesions, and to investigate the etiology of AHDS. Our study comprised 10 dogs with AHDS and 9 control dogs of various breeds, age, and sex. Endoscopic biopsies of the gastrointestinal tract were taken and examined histologically (H&E, Giemsa), immunohistochemically ( Clostridium spp., parvovirus), and bacteriologically. The main findings were acute necrotizing and neutrophilic enterocolitis (9 of 10) with histologic detection of clostridia-like, gram positive bacteria on the necrotic mucosal surface (9 of 10). Clostridium perfringens isolated from the duodenum was identified as type A (5 of 5) by multiplex PCR (5 of 5). In addition, each of the 5 genotyped isolates encoded the pore-forming toxin netF. Clostridium spp. (not C. perfringens) were cultured from duodenal biopsies in 2 of 9 control dogs. These findings suggest that the pore forming netF toxin is responsible for the necrotizing lesions in the intestines of a significant proportion of dogs with AHDS. Given that the stomach was not involved in the process, the term "acute hemorrhagic diarrhea syndrome" seems more appropriate than the frequently used term "hemorrhagic gastroenteritis." PMID- 29621944 TI - Elections Have Consequences for Student Mental Health: An Accidental Daily Diary Study. AB - Polling suggested that the 2016 United States presidential election affected citizens' mood and stress levels. Yet, polling often fails to employ repeated measurement designs that can capture pre- and post-levels of change within the same person. In this study, undergraduate students ( N = 85) completed a 14-day daily diary where mood, stress, and mental health outcomes were assessed before and after the election. Multilevel modeling revealed an immediate upsurge in anxiety, stress, and poor sleep quality the day after the election, followed by a recovery period indicating these effects were short-lived. Other reactions (anger, fear, marginalization, and experiencing discrimination) evidenced a significant upsurge without a significant recovery. We consider how daily diary research designs like this one could be integrated into college settings to inform counseling center resource allocation, and we also comment on the promise of the daily diary methodology for political research. PMID- 29621943 TI - High copy number of ovine gammaherpesvirus 2 DNA associated with malignant catarrhal fever-like syndrome in a lamb. AB - Domestic and wild sheep are the natural reservoirs for ovine gammaherpesvirus 2 (OvHV-2), the causative agent of sheep-associated malignant catarrhal fever (SA MCF). Virtually all adult sheep are infected with OvHV-2 under natural flock conditions, and infection is normally subclinical. MCF-like clinical signs and typical histologic lesions in sheep have been linked during case investigations at veterinary diagnostic laboratories; however, the confirmation of naturally occurring MCF in sheep is problematic. To date, the assays for detection of OvHV 2-specific antibodies or DNA are usually positive in sheep, regardless of health status, so mere detection of antibodies or the agent is of minimal diagnostic significance in this species. We document herein a naturally occurring MCF case in a 4-mo-old domestic lamb and demonstrate that the affected animal had 100 1,000 times more OvHV-2 copy numbers in tissues than in healthy adult and age matched sheep. These results indicate that high copy numbers of viral DNA in tissues associated with characteristic lesions can be used to confirm the diagnosis of MCF in sheep. PMID- 29621945 TI - Empathy Intervention to Reduce Implicit Bias in Pre-Service Teachers. AB - There have been long-term concerns regarding discriminatory discipline practices used with culturally and linguistically diverse students, with little research on the impact teacher-centered empathy interventions may have on this population. This randomized pretest-posttest control group design investigates the ability of a brief empathy-inducing intervention to improve the implicit bias of pre-service teachers, as measured by the Implicit Association Test. We found the empathy intervention statistically significant at decreasing the implicit bias of White female pre-service teachers toward Black individuals ( F = 7.55, eta2 = 0.22, p = 0.01). Implications and future research are discussed, including extended intervention periods. PMID- 29621946 TI - Congenital pulmonary airway malformation mimicking as pulmonary tuberculosis in five paediatric patients: a diagnostic dilemma. AB - A series of five children with delayed presentation of congenital pulmonary airway malformation (CPAM), all initially misdiagnosed as pulmonary tuberculosis, is described. All five children presented with recurrent respiratory infections and failure to thrive, having shown poor response to multiple antibiotics course, including anti-tubercular therapy for variable periods. Successful surgical intervention was belatedly instigated. PMID- 29621948 TI - Sinecatechins 10% ointment for genital warts: Case report of a beneficial reaction in an HIV-positive woman. AB - Patients with HIV infection are more likely to develop anogenital warts compared to HIV-negative people and are susceptible to treatment failures and recurrences. We report a case of extensive vulvar warts in an HIV-positive woman successfully treated with sinecatechins ointment. After the failure of a combination of cryotherapy and imiquimod 5% cream, we started therapy with sinecatechins 10% ointment. The patient developed an intense local inflammatory reaction after three weeks that induced the discontinuation of the therapy. After two weeks, we observed a complete regression of inflammation and a reduction of genital warts. The lesions completely regressed within a few weeks, with no relapse after eight months. Sinecatechins is a standardized extract of green tea leaves, effective in the treatment of external genital and perianal warts in immunocompetent patients, but their role has not been yet studied for immunocompromised people. Our case may represent a starting point for further studies, in order to evaluate the relation between treatment dosage, side effects, and drug response in immunocompromised patients. PMID- 29621949 TI - A case of secondary syphilis with pulmonary involvement and review of the literature. AB - Syphilis is a sexually transmitted systemic infection caused by Treponema pallidum. We report a case of a heterosexual, HIV-positive man who presented with secondary syphilis and a lung abscess. A bacterial lung abscess was suspected and a computed tomography-guided percutaneous needle aspiration of the lung abscess was performed. Direct pulmonary involvement by T. pallidum was suggested by a positive PCR result on the aspirated fluid specimen. The clinical signs of secondary syphilis improved, and the lung abscess was resolved after treatment with benzathine penicillin G and amoxicillin-clavulanate. The final diagnosis was secondary pulmonary syphilis. Few reports of secondary syphilis with pulmonary involvement have been reported to date. PMID- 29621950 TI - Translation of clinical trial data to changes in clinical practice: rapid transition from tenofovir disoproxil fumarate to tenofovir alafenamide-based therapies in a Sydney HIV clinic. AB - The transition of clinical trial data to changes in routine clinical practice is often a slow process. We describe a rapid transition of patients from one form of antiviral therapy to a modified and potentially safer version that can occur quickly when there are no financial or organisational restrictions on the prescribers. PMID- 29621947 TI - Comparison of Two Music Training Approaches on Music and Speech Perception in Cochlear Implant Users. AB - In normal-hearing (NH) adults, long-term music training may benefit music and speech perception, even when listening to spectro-temporally degraded signals as experienced by cochlear implant (CI) users. In this study, we compared two different music training approaches in CI users and their effects on speech and music perception, as it remains unclear which approach to music training might be best. The approaches differed in terms of music exercises and social interaction. For the pitch/timbre group, melodic contour identification (MCI) training was performed using computer software. For the music therapy group, training involved face-to-face group exercises (rhythm perception, musical speech perception, music perception, singing, vocal emotion identification, and music improvisation). For the control group, training involved group nonmusic activities (e.g., writing, cooking, and woodworking). Training consisted of weekly 2-hr sessions over a 6 week period. Speech intelligibility in quiet and noise, vocal emotion identification, MCI, and quality of life (QoL) were measured before and after training. The different training approaches appeared to offer different benefits for music and speech perception. Training effects were observed within-domain (better MCI performance for the pitch/timbre group), with little cross-domain transfer of music training (emotion identification significantly improved for the music therapy group). While training had no significant effect on QoL, the music therapy group reported better perceptual skills across training sessions. These results suggest that more extensive and intensive training approaches that combine pitch training with the social aspects of music therapy may further benefit CI users. PMID- 29621951 TI - Patient-level outcomes and virologic suppression rates in HIV-infected patients receiving antiretroviral therapy in Rwanda. AB - The Rwanda national HIV program has been successful at scaling up antiretroviral therapy (ART) to achieve universal access. The AIDSRelief Model of Care focuses on four key principles: (1) earlier initiation of ART; (2) use of durable, highly potent, and sequence-friendly first-line ART regimens; (3) early detection of treatment failure; and (4) provision of community-based care and support to ensure optimal adherence and follow up/engagement in care. We conducted a retrospective cohort study of randomly-selected HIV-infected patients at AIDSRelief-supported sites using a stratified, random sample of 583 adults (>15 years) who initiated ART from 30 June 2008 to 1 February 2010. At ART initiation, the median patient age was 38 years, and 67% were female. The baseline median CD4+ cell count was 309 cells/mm3. Overall virologic suppression was 91%. Married/ever married status (adjusted prevalence odds ratio [aPOR] 3.75, 95% confidence interval [CI] 1.30-10.78) and self-reported adherence >=95% in the past month (aPOR 2.76, 95% CI 1.00-7.62) were significantly associated with viral suppression in the multivariable model. Excellent virologic outcomes were achieved in Rwandan AIDSRelief sites utilizing the AIDSRelief Model of Care during the scale-up of ART in the country. PMID- 29621952 TI - Dolutegravir as a trigger for DRESS syndrome? AB - Dolutegravir is an increasingly-used second-generation human immunodeficiency virus integrase strand transfer inhibitor. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome has been described in several patients treated with raltegravir but to our knowledge, there is no previous report of DRESS syndrome associated with dolutegravir. PMID- 29621953 TI - Changes in Metabolism, Mitochondrial Function, and Oxidative Stress Between Female Rats Under Nonreproductive and 3 Reproductive Conditions. AB - Women who do not lactate display increased incidence of obesity, type II diabetes, and cancer. Stuebe and Rich-Edwards proposed that these effects occur because physiological changes that ensue during pregnancy are not reversed without lactation. To empirically test this hypothesis, we compared markers of metabolism, mitochondrial function, and oxidative stress between 4 groups of Sprague-Dawley rats: (1) nonreproductive (NR) rats, (2) rats killed at day 20 of gestation, (3) rats that gave birth but were not allowed to suckle their pups (nonlactating), and (4) rats that suckled their young for 14 days. Nonlactating females displayed higher body fat compared to all other groups. Peroxisome proliferator-activated receptor delta (PPARdelta) in skeletal muscle and white adipose tissue of nonlactating rats was lower than the other groups. The PPARdelta is associated with lipid metabolism suggesting that the higher fat mass in nonlactating females was not associated with the retention of a physiological state that was set during pregnancy but instead an independent drop in PPARdelta. Relative mitochondrial respiratory function and complex activity in the liver and skeletal muscle of nonlactating mice were not predictive of higher body mass, and measures of oxidative stress displayed minimal variation between groups. PMID- 29621954 TI - LPAR2 and LPAR4 are the Main Receptors Responsible for LPA Actions in Ovarian Endometriotic Cysts. AB - Endometriosis has been considered as an estrogen (E2)-dependent and progesterone (P4)-resistant disease. On the other hand, lysophosphatidic acid (LPA) has been suggested as a significant modulator of ovarian pathology, acting via both LPA levels and LPA receptor (LPAR) upregulation. Therefore, the objective of the present study was to evaluate LPA concentration as well as LPARs, autotaxin (ATX), and phospholipase A2 (PLA2) expression in ovarian endometriotic cysts and normal endometrium with correlation of the expression of E2 and P4 receptors in endometriotic cysts. The analyses were carried out using the tissues derived from 37 patients with ovarian endometriosis and 20 endometrial samples collected from women without endometriosis were used as a control. We found that ovarian endometriotic cysts are a site of LPA synthesis due to the presence of enzymes involved in LPA synthesis in the tissue. Additionally, when we compared endometriotic cysts versus normal endometrium, we were able to show overexpression of 3 from 6 examined LPARs and both enzymes responsible for LPA synthesis in endometriotic cysts. Finally, we found the correlations between LPARs, ATX, and PLA2 and the expression of E2 and P4 receptors in endometriotic cysts. Owing to the high LPAR2 and LPAR4 transcript and protein expression in endometriotic ovarian cysts and positive correlations of both these receptors with the PR-B and ERbeta, respectively, those receptors seem to be the most promising predictors of the endometriotic cysts as well as the main receptors responsible for LPA action in the ovarian endometriosis. PMID- 29621955 TI - The Hyaluronic Acid System is Intact in Menstrual Endometrial Cells in Women With and Without Endometriosis. AB - OBJECTIVE: To characterize the production and degradation of hyaluronic acid (HA) in menstrual endometrial epithelial cells (EECs) and endometrial stromal cells (ESCs) in women with and without endometriosis. To identify the presence of CD44, the primary receptor of HA, in menstrual EECs and ESCs in women with and without endometriosis. DESIGN: In vitro study. SETTING: Academic center. PATIENT(S): Deidentified patient samples from women with and without endometriosis. INTERVENTIONS: EECs and ESCs were isolated from menstrual endometrial biopsies performed on women with (N = 9) and without (N = 11) endometriosis confirmed by laparoscopy. MAIN OUTCOME MEASURE: Real-time polymerase chain reaction, Western blot, and immunohistochemistry were used to assess hyaluronic acid synthase (HAS) isoforms 1, 2, and 3; hyaluronidase (HYAL) isoforms 1 and 2; and standard CD44. Student t test was used to analyze the results. RESULTS: There was no significant difference in messenger RNA (mRNA) or protein expression of HAS2, HAS3, HYAL1, or HYAL2 in EECs or ESCs from women with or without endometriosis. HAS1 mRNA was variably detected, whereas HAS1 protein was similarly expressed in EECs and ESCs from women with and without endometriosis. Standard CD44 was expressed in both cell types, and expression did not differ in cells from women with or without endometriosis. CONCLUSIONS: The HA system is expressed in eutopic menstrual ESCs and EECs from women with and without endometriosis. There are no differences in expression in HA production or degradation enzymes in EECs or ESCs from women with and without endometriosis. Standard CD44 expression does not differ in eutopic menstrual endometrial cells from women with and without endometriosis. PMID- 29621956 TI - Ovarian Hyperstimulation Reduces Vascular Endothelial Growth Factor-A During Uterine Receptivity. AB - The angiogenic factor vascular endothelial growth factor-A (VEGFA) plays a critical role during early pregnancy in many species including the rat, and any alterations in VEGFA levels can severely impact blastocyst implantation rates. The rat ovarian hyperstimulation (OH) model is useful in studying how the induction of superovulation affects VEGFA levels and endometrial receptivity to blastocyst implantation. The present study shows that the major isoform in the rat uterus, Vegf188, is reduced at the time of receptivity in OH compared to normal pregnancy, whereas there is no change in Vegf164 and Vegf120 messenger RNA (mRNA). The VEGFA receptor 2 (VEGFR2) protein levels are also reduced at the time of receptivity in OH. Our ovariectomy studies show that Vegf164, Vegf188, and Vegf120 are significantly decreased by estrogen, and, to a lesser extent progesterone, when compared to control animals. Although no change in the percentage of endometrial blood vessels was seen across all stages of pregnancy, at the time of receptivity in OH pregnancies, blood vessels were typically larger compared to other stages. The altered progesterone-estrogen ratio seen in OH, taken together with our ovariectomy studies, explains the changes to Vegfa mRNA in OH at the time of receptivity. Since VEGFA is important during implantation, the changes to Vegfa and VEGFR2 levels in the endometrium may help explain the observed lower endometrial receptivity following OH. This study aimed to analyse how ovarian hyperstimulation alters the levels of vascular endothleial growth factor and its major receptor, VEGFR2 in the uterus in a rat model. PMID- 29621957 TI - Climate change: a brief overview of the science and health impacts for Australia. AB - The scientific relationship between atmospheric CO2 and global temperatures has been understood for over a century. Atmospheric concentrations of CO2 due to burning of fossil fuels have contributed to 75% of the observed 1 degrees C rise in global temperatures since the start of the industrial era (about 1750). Global warming is associated with intensifying climatic extremes and disruption to human society and human health. Mitigation is vital for human health as continued current emission rates are likely to lead to 4 degrees C of warming by 2100. Further escalation of Australia's hot and erratic climate will lead to more extreme climate-related disasters of heatwaves, droughts, fires and storms, as well as shifts in disease burdens. PMID- 29621958 TI - Whole genome sequencing provides better diagnostic yield and future value than whole exome sequencing. PMID- 29621959 TI - Disease-modifying approaches for Parkinson disease. PMID- 29621960 TI - Experimental Uterus Transplant in Various Models: Review of Surgical Techniques. AB - Uterus transplantation may become the surgical therapeutic modality of choice for uterine factor infertility. However, this procedure still faces technical, therapeutic, and immunologic challenges that limit its success and clinical application. Experimental studies are therefore still needed to address various challenges in the field of uterus transplantation. Among various laboratory animals, small animals are ideal models for the purpose of experimental uterus transplant. However, clinical success in small animal models is not generalizable to clinical application and treatment for uterine factor infertility in humans. Large animal models are necessary because their uterine anatomy and reproductive physiology closely resemble those of humans. In the literature, in general with small or large animal models, the same striking characteristic has been previous regular menstruation. Anesthesia was usually induced through inhalation and/or intraperitoneal injection in small models and intravenous injection in large models. Systemic heparinization was usually performed after preparation of uterus and vessels and before crossclamping of the vessels. Flushing of the graft was performed through the interior iliac artery or aorta. A grafted segment was frequently selected only from one horn of the uterus. The uterine artery, internal iliac artery, and aorta have been frequently used for arterial revascularization into the recipient's external iliac artery or abdominal aorta. The uterine vein, internal iliac vein, and inferior vena cava have been used for venous drainage into the recipient's inferior vena cava, external iliac vein, or uteroovarian vein. In most models, the native uterus was resected to reconstruct the grafted uterus continuity. Other models have left the native uterus in the recipient's abdomen, and stomas have been used for end of the grafted uterus. PMID- 29621961 TI - Antegrade Balloon Dilatation as a Treatment Option for Posttransplant Ureteral Strictures: Case Series of 50 Patients. AB - OBJECTIVES: The aim of this study was to investigate the effects of antegrade balloon dilatation on ureteral strictures that developed after kidney transplant. MATERIALS AND METHODS: The hospital databases of the Erasmus Medical Center (Rotterdam, The Netherlands) and the Academic Medical Center (Amsterdam, The Netherlands) were retrospectively screened for patients who underwent balloon dilatation after kidney transplant. Balloon dilatation was technically successful whenever it was able to pass the strictured segment with the guidewire followed by balloon inflation; the procedure was clinically successful if no further interventions (for example, surgical revision of the ureteroneocystostomy or prolonged double J placement) were necessary. RESULTS: Fifty patients (2.4%) of 2075 kidney transplant recipients underwent antegrade balloon dilatation because of urinary outflow obstruction. Median time between transplant and balloon dilatation was 3 months (range, 0-139 mo). In 43 patients (86%), balloon dilatation was technically successful. In the remaining 7 patients (14%), it was impossible to pass the strictured segment with the guidewire. In 20 of 43 patients (47%) having a technically successful procedure, the procedure was also clinically successful, with median follow-up after balloon dilatation of 35.5 months (range, 0-102 mo). We did not identify any patient or stricture characteristic that influenced the outcome of treatment. CONCLUSIONS: Balloon dilatation is a good option for ureter stricture treatment after kidney transplant as it is minimal invasive and can prevent surgical exploration in almost 50% of cases. PMID- 29621962 TI - Maternal Hair and Neonatal Meconium to Assess Gestational Consumption and Prenatal Exposure to Drugs of Abuse and Psychoactive Drugs. AB - BACKGROUND: In the last two decades, the consumption of drugs of abuse among women of childbearing age has experienced a significant increase and results from analyses of surveys concerning maternal intake of psychoactive prescription drugs during pregnancy indicate that the rates of intake are increasing each year. Analyses of biological matrices such as maternal hair and neonatal meconium have recently been used for assessment of gestational consumption and consequent prenatal exposure to drugs of abuse in high-risk groups of women. METHODS: Maternal hair and neonatal meconium were analyzed by validated chromatographic mass spectrometric methodologies to disclose the gestational use of drugs of abuse and psychoactive prescription drugs and consequent prenatal exposure in a cohort of 513 mother-newborn dyads at the Sant Joan de Deu Barcelona Hospital, Spain, during 2012-2013. RESULTS: A total of 3.9% women reported drugs of abuse or prescription psychoactive drug consumption at any time during pregnancy. The prevalence of gestational consumption and the consequent prenatal exposure to drugs of abuse (e.g. cannabis, cocaine and MDMA) was 1.2% in maternal hair and 0.4% in meconium; and of psychoactive prescription drugs (e.g. venlafaxine, citalopram, fluoxetine, clomipramine), was 1.7% in maternal hair and 1.2% in meconium. The prevalence of drugs of abuse and prescription psychoactive drug consumption was lower in our specific cohort of Spanish pregnant women than in other cohorts such as those from U.S. or Denmark. CONCLUSION: Analysis of materno fetal matrices provides a viable alternative to study prenatal exposure to these substances and develop specific social and health intervention recommendations. PMID- 29621963 TI - Detecting Autologous Blood Transfusion in Doping Control: Biomarkers of Blood Aging and Storage Measured by Flow Cytofluorimetry. AB - BACKGROUND: Blood transfusions are banned by the World Anti-Doping Agency as a form of "blood doping". A method of detection of homologous blood transfusion (HBT) has been implemented by the accredited anti-doping laboratories worldwide; however, no internationally recognized method has been finalized so far for the direct detection of autologous blood transfusions, which can at present be revealed only by targeted longitudinal profiling of key blood parameters. METHODS: The present article reports the results of an investigation aimed to pre select potential biomarkers of blood aging and storage that can be measured to identify the presence in the sample of reinfused blood. Microparticles from platelets and erythrocytes, erythrocytes size and density, annexin V (as a marker of phosphatidylserine externalization), and the membrane surface antigens CD 55 and CD 59, were specifically considered as potential biomarkers and measured by flow cytofluorimetric techniques. RESULTS AND CONCLUSION: Our results indicate that the parameters more strongly affected by the ex vivo storage of whole blood are erythrocytes size and density, annexin V and microparticles. Although the real diagnostic value of the proposed biomarkers shall obviously be confirmed by further studies carried out on blood samples collected after an actual autologous blood transfusion, these results appear very encouraging towards the development of a direct method for detecting autologous blood transfusion in sport doping. PMID- 29621964 TI - Ethyl Glucuronide in Hair (hEtG) after Exposure to Alcohol-based Perfumes. AB - BACKGROUND: Ethyl Glucuronide in hair (hEtG) is a commonly used biomarker in the diagnosis of chronic excessive alcohol consumption. Despite high diagnostic specificity, some cosmetic treatments may influence the hEtG concentration, leading to false positive results. AIM: The aim of this study was to evaluate three cases of alleged false positive hair samples due to the exposure to perfumes. METHODS: Three subjects were monitored for up to 3 years; at least one sample collection was performed each year; all three men declared to have exposed hair to alcohol-based perfumes during the entire period, except for the last three months before last sample collection. A volunteer treated the right side of his scalp every day during a month period with alcohol-based perfumes. Collection of hair was done at both sides before the first sample treatment and at the end of the month. Hair were processed following the method routinely used in the laboratory for the determination of hEtG (double washing with methanol/dichloromethane, pulverization, overnight incubation in water, and LC MS/MS analysis, LLOQ: 3pg/mg). RESULTS: EtG levels in hair collected from the three men during the declared exposition period ranged from < 3.0 pg/mg to 1130 pg/mg. hEtG concentrations, at the end of the three-month period without any use of perfumes, were < 3.0 pg/mg for the two men declaring an abstinence from alcoholic beverages and 26.3 pg/mg for the subject declaring an average drinking habit of about 35 g/day ethyl alcohol. Non-treated hair of the volunteer provided negative results, while hEtG levels in treated hair were 14.6 and 24.7 pg/mg. CONCLUSION: Prolonged exposition of hair to alcohol-based perfumes may increase hEtG levels, resulting in false positive results. PMID- 29621965 TI - Analytical Approaches in Fatal Intoxication Cases Involving New Synthetic Opioids. AB - BACKGROUND: Synthetic opioids are compounds that were created to act on the opioid receptors. Novel synthetic opioids include various analogs of fentanyl (e.g., acetylfentanyl, acryloylfentanyl, carfentanil, furanylfentanyl, 4 fluorobutyrylfentanyl or ocfentanil) and newly emerging non-fentanyl compounds with different chemical structures, such as AH-7921, MT-45, and U-47700. In the last years, these drugs have rapidly emerged on the recreational drug market, and their abuse has been increasing worldwide. Due to the high potency and the low dose required to produce desired effects, the risk of overdose for these compounds including severe health implications, is quite high. Several fatal intoxication cases related to the abuse of synthetic opioids have recently been reported in the literature. CONCLUSION: As a consequence, the detection of these compounds in biological samples is crucial in order to get a better understanding of their concentration and distribution in body fluids. We overviewed the analytical approaches for the investigation of synthetic opioids in postmortem samples reported in the literature, with special emphasis given to cases of lethal intoxication. PMID- 29621967 TI - Current Updates on Role of Lipids in Hematopoiesis. AB - Hematopoiesis is the process which generates all the mature blood cells from the rare pool of Hematopoietic stem cells (HSCs). Asymmetric cell division of HSCs provide it dual capacity for self-renewal and multi-potent differentiation. Hematopoiesis is a steady state process in which mature blood cells are produced at the same rate at which they are lost, establishing a homeostasis. HSCs are regulated through their environmental niche, cytokine signalling, and the orchestrated activities of various transcription factors. However, there is very little information available about the signal transduction events that regulate HSC function; in particular, the effects of bioactive lipids and lipid mediators are not well understood. Recent studies have added an important aspect of this process, introducing the role of lipids in cell fate decisions during hematopoiesis. The mechanisms of bioactive lipids and their derivatives have been studied extensively in signal transduction and various other cellular processes. This review focuses on various categories of lipids and their regulatory mechanisms in HSCs and their comment into different blood cells. Moreover, we also discuss the role of lipid signalling specifically in megakaryocyte and platelets. PMID- 29621966 TI - Epidemiology of Urinary Tract Infections in HIV Positive Patients at a Tertiary Care University Hospital in Central Europe (2011 - 2016). AB - OBJECTIVES: There is limited published data concerning the recent epidemiology of urinary tract infections (UTI) in HIV-patients, thus we analysed independent risk factors for UTI in HIV positive individuals and antimicrobial resistance rates of E. coli to antimicrobial agents commonly used in UTI. To determine the prevalence of symptomatic urinary tract infections (UTI) in HIV-patients, we performed a retrospective case-control study. METHODS: We included 313 HIV-patients, 101 with UTI and 212 age and gendermatched controls, attending the HIV outpatient clinic at the Vienna University Hospital (VUH) over a period from January 2011 to September 2016. The patients' specific data was gathered from the electronic database of the VUH. The statistical analysis was performed using SPSS Software Version 20.0. RESULTS: HIV infected individuals with CD4 count >200 cells/mm3 were less likely than HIV infected individuals with CD4 count <200 cells/mm3 to experience UTI (OR 0.811, 95% CI 0.712-0.923 vs. OR 2.555, 95% CI 1.553 - 4.205, respectively). The in vitro resistance rate of E. coli to antimicrobial agents was as follows: ciprofloxacin (41%), mecillinam (20.5%), trimethoprim (61%), ampicillin (67%), ampicillin/ clavulanic acid (23%), cefuroxime (17%), nitrofurantoin (2%), amikacin (0%) and gentamicin (9.5%). CONCLUSION: Immunological status (CD4 count) is an important parameter for risk assessment of UTIs in HIV-patients. The increased resistance rate of E. coli to commonly used antimicrobial agents needs to be considered when it comes to the management of UTI, additionally, surveillance strategies should be implemented in HIV-patients. PMID- 29621968 TI - Effects of Micro RNAs and their Targets in Periodontal Diseases. AB - RNA interference (RNAi) or Post-Transcriptional Gene Silencing is a strong mechanism of gene silencing which is moderated by MicroRNAs (miRNAs), underlying many fields of eukaryotic biology. The miRNAs are small noncoding RNAs and a gene regulation expression system which showing a tissue-specific expression pattern, and inhibits protein synthesis. For the first time, miRNA has been seen in Caenorhabditis elegans. They play an important role in signaling pathways of various diseases especially periodontal disease during periodontal inflammation and oral cancers. The most important miRNAs in periodontal diseases and oral squamous cell carcinoma are miR-142-3p, miR-146a, miR-155, miR-203, and miR- 223. One of the most important diseases in association with gingival infectious is periodontal diseases which if left untreated, would lead to tooth loss. Hence, the aim of the present study is to focus the effects of miRNAs and their targets in diseases which are mentioned above. PMID- 29621969 TI - Baseline Widal Titer Among Healthy Adult Males from the Greater Mymensingh Division of Bangladesh. AB - BACKGROUND: Widal test is the most widely used laboratory investigation for diagnosis of typhoid. However, the test interpretation remains controversial in the context of endemic regions such as Bangladesh, as agglutination occurs at varied titrations among a large percentage of healthy population. Paired Widal tests are often not feasible; hence single unpaired test has to be used for screening, diagnosis and treatment. OBJECTIVE: We aimed to assess the normal range of baseline titre for Anti TO, TH, AO, AH, BO agglutinins among healthy population in an endemic country with a view to guide the researchers and the clinicians, facilitating further investigation on updating cut off points of single Widal test for screening and diagnosis of typhoid fever in the context of Bangladesh. METHODS: A cross-sectional study was carried out in Mymensingh Medical College, Bangladesh on 2925 male immigration applicants. A single blood sample was collected for Widal test and interpreted using standard guidelines. RESULTS: The highest baseline titer for Anti TO, TH, AO, AH, BO agglutinins among 95% of the healthy participants was found to be 1:80 for each respectively. A titre of 1: 40 was observed for BH antigen. CONCLUSION: In case of singular Widal test, baseline values for the normal range was found to be 1:20 - 1:80 for all the antigens (TO, TH, AO, AH, BO, BH), except BH, for which it was 1:20-1:40. Further studies, inclusive of other sociodemographic groups and positive controls are required to determine the updated cut off values. PMID- 29621970 TI - The interplay of BDNF-TrkB with NMDA receptor in propofol-induced cognition dysfunction : Mechanism for the effects of propofol on cognitive function. AB - BACKGROUND: The aim of the present study was to verify whether propofol impaired learning and memory through the interplay of N-methyl-D-aspartate (NMDA) receptor with brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB) signaling pathway. METHODS: 120 Sprague-Dawley (SD) rats were randomly assigned into eight groups. Experimental drugs including saline, intralipid, propofol, N-methyl-D aspartate (NMDA), 7,8-dihydroxyflavone (7,8-DHF), K252a and MK-801. Spatial learning and memory of rats were tested by the Morris water maze (MWM) test. The mRNA and protein expression were determined by immunohistochemistry, RT-PCR and western blot. Finally, hippocampus cells proliferation and apoptosis were examined by PCNA immunohistochemistry and TUNEL respectively. RESULTS: The memory and learning was diminished in the propofol exposure group, however, the impaired memory and learning of rats were improved with the addition of NMDA and 7,8-DHF, while the improvement of memory and learning of rats were reversed with the addition of K252a and MK-801. In addition, the mRNA and protein expression levels and hippocampus cells proliferation were the same trend with the results of the MWM test, while apoptosis in hippocampus was reversed. CONCLUSION: The propofol can impair memory and learning of rats and induce cognition dysfunction through the interplay of NMDA receptor and BDNF-TrkB-CREB signaling pathway. PMID- 29621971 TI - Linear MALDI-ToF simultaneous spectrum deconvolution and baseline removal. AB - BACKGROUND: Thanks to a reasonable cost and simple sample preparation procedure, linear MALDI-ToF spectrometry is a growing technology for clinical microbiology. With appropriate spectrum databases, this technology can be used for early identification of pathogens in body fluids. However, due to the low resolution of linear MALDI-ToF instruments, robust and accurate peak picking remains a challenging task. In this context we propose a new peak extraction algorithm from raw spectrum. With this method the spectrum baseline and spectrum peaks are processed jointly. The approach relies on an additive model constituted by a smooth baseline part plus a sparse peak list convolved with a known peak shape. The model is then fitted under a Gaussian noise model. The proposed method is well suited to process low resolution spectra with important baseline and unresolved peaks. RESULTS: We developed a new peak deconvolution procedure. The paper describes the method derivation and discusses some of its interpretations. The algorithm is then described in a pseudo-code form where the required optimization procedure is detailed. For synthetic data the method is compared to a more conventional approach. The new method reduces artifacts caused by the usual two-steps procedure, baseline removal then peak extraction. Finally some results on real linear MALDI-ToF spectra are provided. CONCLUSIONS: We introduced a new method for peak picking, where peak deconvolution and baseline computation are performed jointly. On simulated data we showed that this global approach performs better than a classical one where baseline and peaks are processed sequentially. A dedicated experiment has been conducted on real spectra. In this study a collection of spectra of spiked proteins were acquired and then analyzed. Better performances of the proposed method, in term of accuracy and reproductibility, have been observed and validated by an extended statistical analysis. PMID- 29621972 TI - TrawlerWeb: an online de novo motif discovery tool for next-generation sequencing datasets. AB - BACKGROUND: A strong focus of the post-genomic era is mining of the non-coding regulatory genome in order to unravel the function of regulatory elements that coordinate gene expression (Nat 489:57-74, 2012; Nat 507:462-70, 2014; Nat 507:455-61, 2014; Nat 518:317-30, 2015). Whole-genome approaches based on next generation sequencing (NGS) have provided insight into the genomic location of regulatory elements throughout different cell types, organs and organisms. These technologies are now widespread and commonly used in laboratories from various fields of research. This highlights the need for fast and user-friendly software tools dedicated to extracting cis-regulatory information contained in these regulatory regions; for instance transcription factor binding site (TFBS) composition. Ideally, such tools should not require prior programming knowledge to ensure they are accessible for all users. RESULTS: We present TrawlerWeb, a web-based version of the Trawler_standalone tool (Nat Methods 4:563-5, 2007; Nat Protoc 5:323-34, 2010), to allow for the identification of enriched motifs in DNA sequences obtained from next-generation sequencing experiments in order to predict their TFBS composition. TrawlerWeb is designed for online queries with standard options common to web-based motif discovery tools. In addition, TrawlerWeb provides three unique new features: 1) TrawlerWeb allows the input of BED files directly generated from NGS experiments, 2) it automatically generates an input-matched biologically relevant background, and 3) it displays resulting conservation scores for each instance of the motif found in the input sequences, which assists the researcher in prioritising the motifs to validate experimentally. Finally, to date, this web-based version of Trawler_standalone remains the fastest online de novo motif discovery tool compared to other popular web-based software, while generating predictions with high accuracy. CONCLUSIONS: TrawlerWeb provides users with a fast, simple and easy-to-use web interface for de novo motif discovery. This will assist in rapidly analysing NGS datasets that are now being routinely generated. TrawlerWeb is freely available and accessible at: http://trawler.erc.monash.edu.au . PMID- 29621973 TI - Comparison of ventral organ development across Pycnogonida (Arthropoda, Chelicerata) provides evidence for a plesiomorphic mode of late neurogenesis in sea spiders and myriapods. AB - BACKGROUND: Comparative studies of neuroanatomy and neurodevelopment provide valuable information for phylogenetic inference. Beyond that, they reveal transformations of neuroanatomical structures during animal evolution and modifications in the developmental processes that have shaped these structures. In the extremely diverse Arthropoda, such comparative studies contribute with ever-increasing structural resolution and taxon coverage to our understanding of nervous system evolution. However, at the neurodevelopmental level, in-depth data remain still largely confined to comparably few laboratory model organisms. Therefore, we studied postembryonic neurogenesis in six species of the bizarre Pycnogonida (sea spiders), which - as the likely sister group of all remaining chelicerates - promise to illuminate neurodevelopmental changes in the chelicerate lineage. RESULTS: We performed in vivo cell proliferation experiments with the thymidine analogs 5-bromo-2'-deoxyuridine and 5-ethynl-2'-deoxyuridine coupled to fluorescent histochemical staining and immunolabeling, in order to compare ventral nerve cord anatomy and to localize and characterize centers of postembryonic neurogenesis. We report interspecific differences in the architecture of the subesophageal ganglion (SEG) and show the presence of segmental "ventral organs" (VOs) that act as centers of neural cell production during gangliogenesis. These VOs are either incorporated into the ganglionic soma cortex or found on the external ganglion surface. Despite this difference, several shared features support homology of the two VO types, including (1) a specific arrangement of the cells around a small central cavity, (2) the presence of asymmetrically dividing neural stem cell-like precursors, (3) the migration of newborn cells along corresponding pathways into the cortex, and (4) the same VO origin and formation earlier in development. CONCLUSIONS: Evaluation of our findings relative to current hypotheses on pycnogonid phylogeny resolves a bipartite SEG and internal VOs as plesiomorphic conditions in pycnogonids. Although chelicerate taxa other than Pycnogonida lack comparable VOs, they are a characteristic feature of myriapod gangliogenesis. Accordingly, we propose internal VOs with neurogenic function to be part of the ground pattern of Arthropoda. Further, our findings illustrate the importance of dense sampling in old arthropod lineages - even if as gross-anatomically uniform as Pycnogonida - in order to reliably differentiate plesiomorphic from apomorphic neurodevelopmental characteristics prior to outgroup comparison. PMID- 29621974 TI - Characteristics of a newly diagnosed Polish cohort of patients with neurological manifestations of Wilson disease evaluated with the Unified Wilson's Disease Rating Scale. AB - BACKGROUND: Wilson disease is a rare genetic disorder in which impaired copper excretion results in toxic copper levels and tissue damage. Manifestations are primarily hepatic and/or neuropsychiatric, with a variety of neurological phenotypes. The aim of this study was to characterize neurological signs of Wilson disease in newly diagnosed patients and to determine whether they correlated with disability, liver function, and copper metabolism. METHODS: Fifty three treatment-naive patients recently diagnosed with Wilson disease who exhibited neurological symptoms were included. Neurological manifestations were characterized by examination in terms of symptom type and degree of neurological impairment (Unified Wilson's Disease Rating Scale [UWDRS] Part III) and correlated with degree of disability (UWDRS Part II), abnormalities in copper parameters and hepatic status. RESULTS: Most patients (62.3%) exhibited tremor and ataxia, whereas 15.1% were dystonic, and 11.3% had parkinsonism. Discrete or unclassified signs only were observed in 11.3% of patients. A good correlation between disability (UWDRS Part II) and neurological impairment (UWDRS Part III) was observed (Pearson r = 0.84). However, there was a lack of correlation when either disability or neurological impairment were analyzed with copper parameters or liver impairment. CONCLUSIONS: The predominant neurological manifestations in this cohort of newly diagnosed Wilson disease patients were ataxia and tremor. Neurological impairment measured was highly correlated with the level of disability. However, hepatic manifestations of Wilson disease and copper levels did not appear to be correlated with neurological status and disability. These results highlight the challenges faced when assessing Wilson disease with its highly variable symptomatology. PMID- 29621975 TI - A new fast method for inferring multiple consensus trees using k-medoids. AB - BACKGROUND: Gene trees carry important information about specific evolutionary patterns which characterize the evolution of the corresponding gene families. However, a reliable species consensus tree cannot be inferred from a multiple sequence alignment of a single gene family or from the concatenation of alignments corresponding to gene families having different evolutionary histories. These evolutionary histories can be quite different due to horizontal transfer events or to ancient gene duplications which cause the emergence of paralogs within a genome. Many methods have been proposed to infer a single consensus tree from a collection of gene trees. Still, the application of these tree merging methods can lead to the loss of specific evolutionary patterns which characterize some gene families or some groups of gene families. Thus, the problem of inferring multiple consensus trees from a given set of gene trees becomes relevant. RESULTS: We describe a new fast method for inferring multiple consensus trees from a given set of phylogenetic trees (i.e. additive trees or X trees) defined on the same set of species (i.e. objects or taxa). The traditional consensus approach yields a single consensus tree. We use the popular k-medoids partitioning algorithm to divide a given set of trees into several clusters of trees. We propose novel versions of the well-known Silhouette and Calinski Harabasz cluster validity indices that are adapted for tree clustering with k medoids. The efficiency of the new method was assessed using both synthetic and real data, such as a well-known phylogenetic dataset consisting of 47 gene trees inferred for 14 archaeal organisms. CONCLUSIONS: The method described here allows inference of multiple consensus trees from a given set of gene trees. It can be used to identify groups of gene trees having similar intragroup and different intergroup evolutionary histories. The main advantage of our method is that it is much faster than the existing tree clustering approaches, while providing similar or better clustering results in most cases. This makes it particularly well suited for the analysis of large genomic and phylogenetic datasets. PMID- 29621976 TI - A simple method for exploring adverse drug events in patients with different primary diseases using spontaneous reporting system. AB - BACKGROUND: Patient background (e.g. age, sex, and primary disease) is an important factor to consider when monitoring adverse drug events (ADEs) for the purpose of pharmacovigilance. However, in disproportionality methods, when additional factors are considered, the number of combinations that have to be computed increases, and it becomes very difficult to explore the whole spontaneous reporting system (SRS). Since the signals need to be detected quickly in pharmacovigilance, a simple exploration method is required. Although association rule mining (AR) is commonly used for the analysis of large data, its application to pharmacovigilance is rare and there are almost no studies comparing AR with conventional signal detection methods. METHODS: In this study, in order to establish a simple method to explore ADEs in patients with kidney or liver injury as a background disease, the AR and proportional reporting ratio (PRR) signal detection methods were compared. We used oral medicine SRS data from the Japanese Adverse Drug Event Report database (JADER), and used AR as the proposed search method and PRR as the conventional method for comparison. "Rule count >= 3", "min lift value > 1", and "min conviction value > 1" were used as the AR detection criteria, and the PRR detection criteria were "Rule count >=3", "PRR >= 2", and "chi2 >= 4". RESULTS: In patients with kidney injury, the AR method had a sensitivity of 99.58%, specificity of 94.99%, and Youden's index of 0.946, while in patients with liver injury, the sensitivity, specificity, and Youden's index were 99.57%, 94.87%, and 0.944, respectively. Additionally, the lift value and the strength of the signal were positively correlated. CONCLUSIONS: It was suggested that computation using AR might be simple with the detection power equivalent to that of the conventional signal detection method as PRR. In addition, AR can theoretically be applicable to SRS other than JADER. Therefore, complicated conditions (patient's background etc.) that must take factors other than the ADE into consideration can be easily explored by selecting the AR as the first screening for ADE exploration in pharmacovigilance using SRS. PMID- 29621977 TI - Occupational exposure to petroleum-based and oxygenated solvents and hypopharyngeal and laryngeal cancer in France: the ICARE study. AB - BACKGROUND: To examine associations between occupational exposure to petroleum based and oxygenated solvents and the risk of hypopharyngeal and laryngeal cancer. METHODS: ICARE is a large, frequency-matched population-based case control study conducted in France. Lifetime occupational history, tobacco smoking and alcohol consumption were collected. Analyses were restricted to men and included 383 cases of hypopharyngeal cancer, 454 cases of laryngeal cancer, and 2780 controls. Job-exposure matrices were used to assess exposure to five petroleum-based solvents (benzene; gasoline; white spirits; diesel, fuels and kerosene; special petroleum products) and to five oxygenated solvents (alcohols; ketones and esters; ethylene glycol; diethyl ether; tetrahydrofuran). Odds ratios (ORs) adjusted for smoking, alcohol drinking and other potential confounders and 95% confidence intervals (CI) were estimated with unconditional logistic models. RESULTS: No significant association was found between hypopharyngeal or laryngeal cancer risk and exposure to the solvents under study. Non-significantly elevated risks of hypopharyngeal cancer were found in men exposed to high cumulative levels of white spirits (OR = 1.46; 95% CI: 0.88-2.43) and tetrahydrofuran (OR = 2.63; 95CI%: 0.55-12.65), with some indication of a dose-response relationship (p for trend: 0.09 and 0.07 respectively). CONCLUSION: This study provides weak evidence for an association between hypopharyngeal cancer and exposure to white spirits and tetrahydrofuran, and overall does not suggest a substantial role of exposure to petroleum-based or oxygenated solvents in hypopharyngeal or laryngeal cancer risk. PMID- 29621978 TI - High frequency of the TARDBP p.M337 V mutation among south-eastern Chinese patients with familial amyotrophic lateral sclerosis. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating motor neuron disease characterized by substantial clinical and genetic heterogeneity. Thus far, only a few TARDBP-ALS families have been reported in China, and no mutation analysis has been reported in south-eastern China. METHODS: Seven index cases from ALS families negative for SOD1 and FUS mutations were screened by Sanger sequencing for TARDBP gene exons 2-6. TARDBP exon 6 was analysed in 215 sporadic ALS patients. RESULTS: Two TARDBP mutations in exon 6 (p.M337 V and p.G348C) were identified in 5 unrelated families. Four of these 5 families carried the same p.M337 V mutation (family 1II3, family 2II6, family 3II4, and family 4II4), and the p.G348C mutation was identified in family 5 (II5). Among the 215 sporadic patients, only a single nucleotide polymorphism (p.A366A) was detected in 5 patients, and no responsible mutation was identified. Among the TARDBP-linked familial ALS patients, the average age of onset was 57.0 +/- 4.7 years, and a trend towards higher rates of bulbar (50.0%, 6/12) onset and upper limb (41.7%, 5/12) onset than lower rates of limb onset (8.3%, 1/12) was observed. Furthermore, ALS patients with TARDBP mutations showed a benign disease course, and the average survival was 106.5 +/- 41.8 months (n = 8). CONCLUSIONS: We found a high frequency of the TARDBP p.M337 V mutation in familial ALS in south-eastern China. The TARDBP-linked ALS patients showed a benign disease course and prolonged survival. PMID- 29621979 TI - Nordic Innovative Trial to Evaluate OsteoPorotic Fractures (NITEP-group): non operative treatment versus surgery with volar locking plate in the treatment of distal radius fracture in patients aged 65 and over - a study protocol for a prospective, randomized controlled trial. AB - BACKGROUND: In the literature, there are numerous studies that compare different surgical procedures in the treatment of distal radius fractures (DRF). It is, however, unknown whether operative treatment and better restoration of anatomy with volar locking plate yields a better functional outcome in the elderly population when compared with non-operative treatment. METHODS AND DESIGN: This study is a prospective, randomized, controlled, multi-center trial. The purpose will be to compare the non-operative and operative treatment of initially or early malaligned distal radius fractures in patients aged 65 and older. The primary outcome in this study will be the patient rated wrist evaluation (PRWE) score measured after 1 and 2 years. DISCUSSION: We expect that initial operative treatment of a DRF with volar locking plate will not yield superior results when compared with non-operative treatment with cast immobilization in terms of functional outcome, pain, disability, quality of life, grip strength, and number of complications. TRIAL REGISTRATION: This trial is registered on clinicaltrials.gov , identifier NCT02879656 , registration date 08/17/2016. PMID- 29621981 TI - The home electronic media environment and parental safety concerns: relationships with outdoor time after school and over the weekend among 9-11 year old children. AB - BACKGROUND: Time spent outdoors is associated with higher physical activity levels among children, yet it may be threatened by parental safety concerns and the attraction of indoor sedentary pursuits. The purpose of this study was to explore the relationships between these factors and outdoor time during children's discretionary periods (i.e., after school and over the weekend). METHODS: Data from 462 children aged 9-11 years old were analysed using generalised linear mixed models. The odds of spending > 1 h outdoors after school, and > 2 h outdoors on a weekend were computed, according to demographic variables, screen-based behaviours, media access, and parental safety concerns. Interactions with sex and socioeconomic status (SES) were explored. RESULTS: Boys, low SES participants, and children who played on their computer for < 2 h on a school day had higher odds of spending > 1 h outside after school than girls, high SES children and those playing on a computer for >=2 h, respectively. Counterintuitive results were found for access to media devices and crime-related safety concerns as both of these were positively associated with time spent outdoors after school. A significant interaction for traffic-related concerns*sex was found; higher road safety concerns were associated with lower odds of outdoor time after school in boys only. Age was associated with weekend outdoor time, which interacted with sex and SES; older children were more likely to spend > 2 h outside on weekends but this was only significant among girls and high SES participants. CONCLUSIONS: Our results suggest that specific groups of children are less likely to spend their free time outside, and it would seem that only prolonged recreational computer use has a negative association with children's outdoor time after school. Further research is needed to explore potential underlying mechanisms, and parental safety concerns in more detail. PMID- 29621980 TI - Modulations in the offspring gut microbiome are refractory to postnatal synbiotic supplementation among juvenile primates. AB - BACKGROUND: We and others have previously shown that alterations in the mammalian gut microbiome are associated with diet, notably early life exposure to a maternal high fat diet (HFD). Here, we aimed to further these studies by examining alterations in the gut microbiome of juvenile Japanese macaques (Macaca fuscata) that were exposed to a maternal HFD, weaned onto a control diet, and later supplemented with a synbiotic comprised of psyllium seed and Enterococcus and Lactobacillus species. RESULTS: Eighteen month old offspring (n = 7) of 36% HFD fed dams were fed a control (14% fat) diet post weaning, then were synbiotic supplemented for 75 days and longitudinal stool and serum samples were obtained. All stool samples were subjected to 16S rRNA metagenomic sequencing, and microbiome profiles and serum lipids and triglycerides were compared to untreated, healthy age matched and diet matched controls (n = 7). Overall, 16S based metagenomic analysis revealed that supplementation exerted minimal alterations to the gut microbiome including transient increased abundance of Lactobacillus species and decreased abundance of few bacterial genera, including Faecalibacterium and Anaerovibrio. However, serum lipid analysis revealed significant decreases in triglycerides, cholesterol, and LDL (p < 0.05). Nevertheless, supplemented juveniles challenged 4 months later were not protected from HFD-induced gut dysbiosis. CONCLUSIONS: Synbiotic supplementation is temporally associated with alterations in the gut microbiome and host lipid profiles of juvenile Japanese macaques that were previously exposed to a maternal HFD. Despite these presumptive temporal benefits, a protective effect against later HFD-challenge gut dysbiosis was not observed. PMID- 29621982 TI - Using a nomogram based on preoperative serum fibrinogen levels to predict recurrence of papillary thyroid carcinoma. AB - BACKGROUND: Hyperfibrinogenemia is increasingly being recognized as an important risk factor related to cancer stage, development and outcomes. We evaluated whether preoperative serum fibrinogen levels predict recurrence of papillary thyroid carcinoma (PTC). METHODS: We retrospectively collected data for 1023 PTC patients who underwent surgery at our institution from Aug 2014 to Aug 2016. In total, 414 patients (from Aug 2014 to Dec 2015) were used as the training set to build the model, and 609 patients (from Jan 2016 to Aug 2016) were used as the testing set to validate the model. RESULTS: In the training set, PTC cases with high serum fibrinogen levels were more likely to have multiple PTCs (P = 0.001) and to exhibit surrounding tissue or organ invasion (both P < 0.01). Moreover, PTC patients with higher serum fibrinogen levels were also more likely to have an advanced tumor stage (T, P = 0.001) and distance metastasis (P < 0.001), and these patients had a significantly higher rate of postoperative PTC recurrence (P = 0.002). All of these findings were validated in the testing set. The results of univariate and multivariate analyses indicated that hyperfibrinogenemia was a risk factor for PTC recurrence. The identified risk factors were incorporated into a nomogram and validated using the testing set (C-index = 0.811, 95% CI: 0.762-0.871). CONCLUSION: PTC cases with hyperfibrinogenemia are more likely to have an advanced TNM stage and have a higher rate of PTC recurrence. Our nomogram could be used to objectively and accurately predict PTC recurrence in a clinical setting. PMID- 29621983 TI - Single and dual antiplatelet therapy in elderly patients of medically managed myocardial infarction. AB - BACKGROUNDS: To examine the comparative effectiveness between dual and single antiplatelet therapies in real-world, medically managed elderly patients with acute myocardial infarction (AMI). METHODS: This retrospective study identified very elderly (> 85 years) patients, who were medically managed, with their first AMI from the Taiwan National Health Insurance claims database from 2007 to 2010. Patients were classified as dual antiplatelet therapy (DAPT) group, aspirin only group and clopidogrel only group. Study outcomes included all-cause death, cardiovascular death and gastrointestinal bleeding. Treating DAPT group as the reference, we employed a multivariable Cox regression model to compare the relative risks of outcomes between 3 groups using pairwise comparison approach. RESULTS: Among 1469 patients with incident ST-elevation myocardial infarction (STEMI, 14%) or non-STEMI (86%), 390 patients were prescribed DAPT, 549 aspirin only, and 530 clopidogrel only. After 9 months of follow-up, aspirin only group had similar risks of all-cause death (adjusted HR 1.21, 95% CI 0.77-1.89, p = 0.41), cardiovascular death (adjusted HR 1.16, 95% CI 0.66-2.04, p = 0.60) and gastrointestinal bleeding (adjusted HR 1.66, 95% CI 0.77-3.57, p = 0.20) in comparison with DAPT group. Clopidogrel users had a higher risk of all-cause death (adjusted HR 1.50, 95% CI 1.00-2.25, p = 0.049) but similar risks of cardiovascular death and gastrointestinal bleeding when compared with DAPT. CONCLUSIONS: Among very elderly patients who were medically managed after AMI, single antiplatelet therapy had comparable protective effect as DAPT. But clopidogrel only strategy was associated with a higher risk of all-cause death. PMID- 29621984 TI - Management of isolated coronal shear fractures of the humeral capitellum with Herbert screw fixation through anterolateral approach. AB - BACKGROUND: Due to the intraarticular and complex nature of the coronal shear fracture of the humeral capitellum and its rarity, it has been difficult to formulate a universally accepted method of surgical management. The purpose of this study is to retrospectively evaluate the clinical outcomes of 15 patients with isolated coronal shear fractures of the capitellum treated by Herbert screw fixation through anterolateral approach, and to address the safety and tips for this surgical procedure. METHODS: This retrospective study included 15 isolated coronal shear fractures of the capitellum without posterior involvement, which were classified according to the Dubberley classification as 11 type 1A fractures and 4 type 3A fractures. All fractures were treated with Herbert screws fixation via the anterolateral approach. Clinical and radiographic evaluation was performed regularly, with a mean follow-up of 29 months. RESULTS: The mean operative time was 81 min. There were no wound healing problems or infection. One incomplete posterior interosseous nerve injury occurred, which recovered soon without residual compromise. All fractures healed well. At the final follow-up, the average range of motion was 134 degrees in flexion-extension and 172 degrees in supination-pronation. There was no significant difference between the affected and the unaffected elbows with regard to motion in flexion-extension or flexion extension. The average Mayo Elbow Performance Index Score was 93 with 11 excellent and 4 good. No evidence of avascular necrosis, posttraumatic osteoarthritis, or heterotrophic ossification was found. CONCLUSION: Open reduction and internal fixation using Herbert screws through a anterolateral approach is a reliable and effective treatment for coronal shear fractures of capitellum, and able to achieve stable fixation and restoration of a functional range of motion. PMID- 29621985 TI - Implementation of a multidisciplinary psychoeducational intervention for Parkinson's disease patients and carers in the community: study protocol. AB - BACKGROUND: Parkinson's disease progressively limits patients at different levels and as a result family members play a key role in their care. However, studies show lack of an integrative approach in Primary Care to respond to the difficulties and psychosocial changes experienced by them. The aim of this study is to evaluate the effects of a multidisciplinary psychoeducational intervention focusing on improving coping skills, the psychosocial adjustment to Parkinson's disease and the quality of life in patients and family carers in a Primary Care setting. METHODS: This quasi-experimental study with control group and mixed methods was designed to evaluate a multidisciplinary psychoeducational intervention. Based on the study power calculations, 100 people with Parkinson's disease and 100 family carers will be recruited and assigned to two groups. The intervention group will receive the ReNACE psychoeducational intervention. The control group will be given a general educational programme. The study will be carried out in six community-based health centres. The results obtained from the two groups will be collected for evaluation at three time points: at baseline, immediately after the intervention and at 6 months post-intervention. The results will be measured with these instruments: the Quality of Life Scale PDQ-39 for patients and the Scale of Quality of Life of Care-givers SQLC for family carers, and for all participants the Psychosocial Adjustment to Illness scale and the Brief COPE Inventory. Focus groups will be organised with some patients and family carers who will have received the ReNACE psychoeducational intervention and also with the healthcare professionals involved in its development. DISCUSSION: An important gap exists in the knowledge and application of interventions with a psychosocial approach for people with PD and family carers as a whole. This study will promote this comprehensive approach in Primary Care, which will clearly contribute in the existing knowledge and could reduce the burden of PD for patients and family carers, and also in other long-term conditions. TRIAL REGISTRATION: NCT03129425 (ClinicalTrials.gov). Retrospectively registered on April 26, 2017. PMID- 29621986 TI - The roles of health culture and physical environment in workplace health promotion: a two-year prospective intervention study in China. AB - BACKGROUND: To understand the potential influencing factors on the effectiveness of workplace health promotion interventions and examine whether workplace health culture and physical environment can mediate the relationship between workplace health promotion and intervention effectiveness. METHODS: A total of 719 participants from 10 Chinese government agencies were recruited for a prospective self-controlled trial. Questionnaires, qualitative interviews, and direct observation were used for the baseline evaluation, process evaluation, and effectiveness evaluation. Based on the results of the need assessment and risk assessment at each workplace, a two-year comprehensive health intervention was conducted by each workplace. Health outcomes including self-rated health (SRH) and mental health were measured at baseline and 24 months. Health culture was measured at 24 months. Physical environment and intervention implementation were measured at 12 months and 24 months. RESULTS: Compared with the baseline, the means of SRH and mental health increased significantly by 0.302 and 2.698, respectively. The SRH scores were different before and after intervention; furthermore, the differences varied by workplace. Health culture mediated the relationship between intervention implementation and intervention effectiveness, including SRH and mental health improvement, but physical environment did not. Physical environment quality was significantly negatively correlated with SRH improvement and mental health improvement. Under the relatively high-quality interventions with scores higher than 4.047 or 4.151 (out of 5), better health culture may led to greater SRH and mental health improvements. CONCLUSIONS: Health culture may mediate the relationship between intervention implementation and intervention effectiveness, whereas physical environment does not seem to mediate this relationship. Under relatively high-quality interventions, a better health culture may lead to more positive improvements in SRH and mental health. Future studies will need to examine the physical environment as a moderating effect rather than mediating effect. TRIAL REGISTRATION: This study was retrospectively registered in Chinese Clinical Trial Registry. TRIAL REGISTRATION NUMBER: ChiCTR-OOC-16010059 . Date of registration: Dec 1, 2016. PMID- 29621987 TI - Distribution of ossified spinal lesions in patients with severe ossification of the posterior longitudinal ligament and prediction of ossification at each segment based on the cervical OP index classification: a multicenter study (JOSL CT study). AB - BACKGROUND: In patients with ossification of the posterior longitudinal ligament (OPLL) in the cervical spine, it is well known that the thoracic ossified lesions often coexist with the cervical lesions and can cause severe myelopathy. However, the prevalence of OPLL at each level of the thoracic and lumbar spinal segments is unknown. The aims of this study were to investigate how often OPLL occurs at each level in the thoracolumbar spine in patients with a radiological diagnosis of cervical OPLL and to identify the spinal levels most likely to develop ossification. METHODS: Data were collected from 20 institutions in Japan. Three hundred and twenty-two patients with a diagnosis of cervical OPLL were included. The OPLL index (OP index), defined as the sum of the vertebral body and intervertebral disc levels where OPLL is present, was used to determine disease severity. An OP index >=20 was defined as severe OPLL. The prevalence of OPLL at each level of the thoracic and lumbar spinal segments was calculated. RESULTS: Women were more likely to have ossified lesions in the thoracolumbar spine than men. Severe OPLL was significantly more common in women than in men (20% vs. 4.5%). For thoracic vertebral OPLL, the most frequently affected was the T1 segment in both men and women, followed by the T1/2 and T3/4 intervertebral levels in men and women, respectively. Ossified lesions were frequently seen at the intervertebral and vertebral levels around the cervicothoracic and thoracolumbar junctions in men with severe OPLL, whereas OPLL was more diffusely distributed in the thoracic spine in women with severe OPLL. CONCLUSION: Thoracolumbar OPLL occurred most often at T1 in men and at T3/4 in women. In severe OPLL cases, although ossified lesions were frequently seen at the intervertebral and vertebral levels around the cervicothoracic and thoracolumbar junctions in men, OPLL could be observed more diffusely in the thoracic spine in women. PMID- 29621988 TI - Sorafenib versus Transarterial chemoembolization for advanced-stage hepatocellular carcinoma: a cost-effectiveness analysis. AB - BACKGROUND: Sorafenib and transarterial chemoembolization (TACE) might both provide survival benefit for advanced hepatocellular carcinoma (HCC). Adopting either as a first-line therapy carries major cost and resource implications. We aimed to estimate the cost-effectiveness of sorafenib and TACE in advanced HCC. METHODS: A Markov model was constructed in a hypothetical cohort of patients aged 60 years with advanced HCC and Child-Pugh A/B cirrhosis over a 2-year time frame. Three strategies (full or dose-adjusted sorafenib and TACE) were compared in two cost settings: China and the USA. Transition probabilities, utility and costs were extracted from systematic review of 27 articles. Sensitivity analysis and Monte Carlo analysis were conducted. RESULTS: Full and dose-adjusted sorafenib respectively produced 0.435 and 0.482 quality-adjusted life years (QALYs) while TACE produced 0.375 QALYs. The incremental cost-effectiveness ratio (ICER) of full-dose sorafenib versus TACE was $101,028.83/QALY in China whereas full-dose sorafenib is a dominant strategy (ICER of -$1,014,507.20/ QALY) compared with TACE in the USA. Compared to full-dose sorafenib, dose-adjusted sorafenib was the dominant strategy with the negative ICERs in both China (-$132,238.94/QALY) and the USA (-$230,058.09/QALY). However, dose-adjusted sorafenib is not available currently, so full-dose sorafenib should be compared with TACE. As the acceptability curves shown, full-dose sorafenib was the optimal strategy at the accepted thresholds of WTP in these two countries. Specifically, full-dose sorafenib was the cost-effective treatment compared with TACE if a WTP was set above $21,670 in the USA, whereas in China, TACE could be more favorable than full-dose sorafenib if a WTP was set below $10,473. CONCLUSIONS: Dose-adjusted sorafenib may be cost-effective compared to full-dose sorafenib or TACE for advanced HCC patients. However, when confining the comparisons between full-dose sorafenib and TACE, full-dose sorafenib was cost-effective for these patients, under the accepted thresholds of WTP. PMID- 29621989 TI - Examining neighborhood and interpersonal norms and social support on fruit and vegetable intake in low-income communities. AB - BACKGROUND: We examined whether neighborhood-, friend-, and family- norms and social support for consumption and purchase of fruits and vegetables (F&V) were associated with F&V intake among low-income residents in subsidized housing communities. We examined baseline data from a study ancillary to the Live Well/Viva Bien intervention. Participants included 290 residents in four low income subsidized housing sites who were >= 18 years of age, English and/or Spanish speaking, and without medical conditions that prevented consumption of F&V. METHODS: Linear regression models examined associations of norms and social support with F&V intake after adjustments for sociodemographic characteristics. RESULTS: In the analysis, neighborhood social support for F&V was associated with a 0.31 cup increase in F&V intake (95% CI = 0.05, 0.57). The family norm for eating F&V and family social support for eating F&V were associated with a 0.32 cup (95% CI = 0.13, 0.52) and 0.42 cup (95% CI = 0.19, 0.64) increase in F&V intake, respectively. CONCLUSIONS: To our knowledge, no other studies have examined neighborhood, family, and peer norms and social support simultaneously and in relation to F&V intake. These findings may inform neighborhood interventions and community-level policies to reduce neighborhood disparities in F&V consumption. PMID- 29621990 TI - Risk factors for long-term mortality in patients admitted with severe infection. AB - BACKGROUND: Severe infection is a main cause of mortality. We aim to describe risk factors for long-term mortality among inpatients with severe infection. METHODS: Prospective cohort study in a 600-bed university hospital in Portugal including all patients with severe infection admitted into intensive care, medical, surgical, hematology and nephrology wards over one-year period. The outcome of interest was 5-year mortality following infection. Variables of patient background and infectious episode were studied in association with the main outcome through multiple logistic regression. There were 1013 patients included in the study. Hospital and 5-year mortality rates were 14 and 37%, respectively. RESULTS: Two different models were developed (with and without acute-illness severity scores) and factors independently associated with 5-year mortality were [adjusted odds ratio (95% confidence interval)]: age = 1.03 per year (1.02-1.04), cancer = 4.36 (1.65-11.53), no comorbidities = 0.4 (0.26-0.62), Karnovsky Index < 70 = 2.25 (1.48-3.40), SAPS (Simplified Acute Physiology Score) II = 1.05 per point (1.03-1.07), positive blood cultures = 1.57 (1.01-2.44) and infection by an ESKAPE pathogen (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeroginosa and Enterobacter species) = 1.61 (1.00- 2.60); and in the second model [without SAPS II and SOFA (Sequential Organ Failure Assessment) scores]: age = 1.04 per year (1.03-1.05), cancer = 5.93 (2.26-15.51), chronic haematologic disease = 2.37 (1.14-4.93), no comorbidities = 0.45 (0.29-0.69), Karnovsky Index< 70 = 2.32 (1.54- 3.50), septic shock [reference is infection without SIRS (Systemic Inflammatory Response Syndrome)] = 3.77 (1.80-7.89) and infection by an ESKAPE pathogen = 1.61 (1.00-2.60). Both models presented a good discrimination power with an AU-ROC curve (95% CI) of 0.81 (0.77-0.84) for model 1 and 0.80 (0.76 0.83) for model 2. If only patients that survived hospital admission are included in the model, variables retained are: age = 1.03 per year (1.02-1.05), cancer = 4.69 (1.71-12.83), chronic respiratory disease = 2.27 (1.09-4.69), diabetes mellitus = 1.65 (1.06-2.56), Karnovsky Index < 70 = 2.50 (1.63-3.83) and positive blood cultures = 1.66 (1.04-2.64) with an AU-ROC curve of 0.77 (0.73-0.81). CONCLUSIONS: Age, previous comorbidities, and functional status and infection by an ESKAPE pathogen were consistently associated with long-term prognosis. This information may help in the discussion of individual prognosis and clinical decision-making. PMID- 29621992 TI - Analytical typology of multiprofessional primary care models. AB - BACKGROUND: There is only limited evidence to support care redefinition and role optimization processes needed for scaling up of a stronger primary care capacity. METHODS: Data collection was based on a keyword search in MEDLINE, EMBASE and CINAHL databases. Three thousand, two hundred and twenty-nine documents were identified, 1851 met our inclusion criteria, 71 were retained for full-text assessment and 52 included in the final selection. The analysis process was done in four steps. In the end, the elements that were identified as particularly central to the process of transforming primary care provision were used as the basis of two typologies. RESULTS: The first typology is based on two structural dimensions that characterize promising multiprofessional primary care teams. The first is the degree to which the division of tasks in the team was formalized. The second dimension is the centrality and autonomy of nurses in the care model. The second typology offers a refined definition of comprehensiveness of care and its relationship with the optimization of professional roles. CONCLUSIONS: The literature we analyzed suggests there are several plausible avenues for coherently articulating the relationships between patients, professionals, and care pathways. The expertise, preferences, and numbers of available human resources will determine the plausibility that a model will be a coherent response that is appropriate to the needs and environmental constraints (funding models, insurance, etc.). The typologies developed can help assess existing care models analytically or evaluatively and to propose, prospectively, some optimal operational parameters for primary care provision. PMID- 29621991 TI - Adjuvant trastuzumab duration trials in HER2 positive breast cancer - what results would be practice-changing? Persephone investigator questionnaire prior to primary endpoint results. AB - BACKGROUND: Twelve months treatment is the current standard of care for adjuvant trastuzumab in patients with HER2 positive early breast cancer however the optimal duration is not known. Persephone is a non-inferiority randomised controlled trial comparing 6- to 12-months of trastuzumab. In this trial there will be a trade-off between a possible small decrease in disease-free survival (DFS) with 6-months and reduced cardiotoxicity and cost. METHODS: A structured questionnaire asked clinicians who had recruited patients into the Persephone trial about their prior beliefs with regards to the clinical effectiveness of trastuzumab and cardiotoxicity profile, in the comparison of 6- and 12-month durations. RESULTS: Fifty-one clinicians from 40 of the 152 Persephone sites completed the questionnaire. 30/50 responders (60%) believed that 6-months trastuzumab would give the same 4-year DFS rate as 12-months trastuzumab, with 21/50 (42%) holding this belief across all breast cancer subsets. In addition, 46/49 responders (94%) reported expecting to change their clinical practice to 6 months, with their prior beliefs (most commonly 85% 4-year DFS rate with 6 months) being greater than their lowest acceptable rate (most commonly 83% 4-year DFS rate with 6-months). Low levels of cardiotoxicity were expected with both 6 and 12-months trastuzumab, with the majority expecting lower levels with 6 months. With increasing hypothesised differences of cardiotoxicity rates between the two durations, significantly lower levels of 4-year DFS with 6-months trastuzumab were deemed acceptable (p < 0.0001). CONCLUSION: Most responders believe that 6-months trastuzumab is adequate, both overall and within each subset of breast cancer, and plan to change their clinical practice if the Persephone results support their prior belief. An individual patient meta analysis of the duration trials would give greater precision to estimates of the differences in efficacy and toxicity, and adequate statistical power to establish a 2% level of non-inferiority for 6-months adjuvant trastuzumab. PMID- 29621993 TI - Cholinergic receptor nicotinic alpha 5 subunit polymorphisms are associated with smoking cessation success in women. AB - BACKGROUND: The identification of variants in the nicotinic acetylcholine receptor (nAChR) subunit genes associated with smoking phenotypes are increasingly important for prevention and treatment of nicotine dependence. In the context of personalized medicine, the aims of this study were to evaluate whether cholinergic receptor nicotinic alpha 2 (CHRNA2), cholinergic receptor nicotinic alpha 3 (CHRNA3), cholinergic receptor nicotinic alpha 5 (CHRNA5) and cholinergic receptor nicotinic beta 3 (CHRNB3) polymorphisms were associated with nicotine dependence severity, and to investigate possible pharmacogenetics markers of smoking cessation treatment. METHODS: This study cohort enrolled 1049 smoking patients who received pharmacological treatment (varenicline, varenicline plus bupropion, bupropion plus/or nicotine replacement therapy). Smoking cessation success was considered for patients who completed 6 months of continuous abstinence. Fagerstrom test for nicotine dependence (FTND) and Issa situational smoking scores (Issa score) were analyzed for nicotine dependence. CHRNA2 (rs2472553), CHRNA3 (rs1051730), CHRNA5 (rs16969968 and rs2036527) and CHRNB3 (rs6474413) polymorphisms were genotyped by high resolution melting analysis. RESULTS: Females with GA and AA genotypes for CHRNA5 rs16969968 and rs2036527 polymorphisms had higher success rate in smoking cessation treatment: 44.0% and 56.3% (rs16969968), 41.5% and 56.5% (rs2036527), respectively, compared with carriers of the GG genotypes: 35.7% (rs16969968), 34.8% (rs2036527), (P = 0.03, n = 389; P = 0.01, n = 391). The GA or AA genotypes for the rs16969968 and rs2036527 were associated with higher odds ratio for success in women (OR = 1.63; 95% CI = 1.04 to 2.54; P = 0.03 and OR = 1.59, 95% CI = 1.02 to 2.48; P = 0.04; respectively). We did not find association of these polymorphisms with nicotine dependence related scores. Polymorphisms in the CHRNA2, CHRNA3 and CHRNB3 genes were not associated with the phenotypes studied. CONCLUSION: CHRNA5 rs16969968 and rs2036527 were associated with higher success rate in the smoking cessation treatment in women. These findings might contribute to advances in personalized medicine. PMID- 29621994 TI - The PiGeOn project: protocol for a longitudinal study examining psychosocial, behavioural and ethical issues and outcomes in cancer tumour genomic profiling. AB - BACKGROUND: Genomic sequencing in cancer (both tumour and germline), and development of therapies targeted to tumour genetic status, hold great promise for improvement of patient outcomes. However, the imminent introduction of genomics into clinical practice calls for better understanding of how patients value, experience, and cope with this novel technology and its often complex results. Here we describe a protocol for a novel mixed-methods, prospective study (PiGeOn) that aims to examine patients' psychosocial, cognitive, affective and behavioural responses to tumour genomic profiling and to integrate a parallel critical ethical analysis of returning results. METHODS: This is a cohort sub study of a parent tumour genomic profiling programme enrolling patients with advanced cancer. One thousand patients will be recruited for the parent study in Sydney, Australia from 2016 to 2019. They will be asked to complete surveys at baseline, three, and five months. Primary outcomes are: knowledge, preferences, attitudes and values. A purposively sampled subset of patients will be asked to participate in three semi-structured interviews (at each time point) to provide deeper data interpretation. Relevant ethical themes will be critically analysed to iteratively develop or refine normative ethical concepts or frameworks currently used in the return of genetic information. DISCUSSION: This will be the first Australian study to collect longitudinal data on cancer patients' experience of tumour genomic profiling. Findings will be used to inform ongoing ethical debates on issues such as how to effectively obtain informed consent for genomic profiling return results, distinguish between research and clinical practice and manage patient expectations. The combination of quantitative and qualitative methods will provide comprehensive and critical data on how patients cope with 'actionable' and 'non-actionable' results. This information is needed to ensure that when tumour genomic profiling becomes part of routine clinical care, ethical considerations are embedded, and patients are adequately prepared and supported during and after receiving results. TRIAL REGISTRATION: Not required for this sub-study, parent trial registration ACTRN12616000908437 . PMID- 29621995 TI - Labour force participation and the cost of lost productivity due to cancer in Australia. AB - BACKGROUND: In Australia, 40% of people diagnosed with cancer will be of working age (25-64 years). A cancer diagnosis may lead to temporary or permanent changes in a person's labour force participation, which has an economic impact on both the individual and the economy. However, little is known about this economic impact of cancer due to lost productivity in Australia. This paper aims to determine the labour force participation characteristics of people with cancer, to estimate the indirect cost due to lost productivity, and to identify any inequality in the distribution of labour force absence in Australia. METHODS: This study used national cross-sectional data from the 2015 Survey of Disability, Ageing and Carers, conducted by the Australian Bureau of Statistics (ABS). The ABS weighted each component of the survey to ensure the sample represented the population distribution of Australia. The analysis was limited to people aged 25 64 years. Participants were assigned to one of three health condition groups: 'no health condition', 'cancer', and 'any other long-term health condition'. A series of logistic regression models were constructed to determine the association between health condition and labour force participation. RESULTS: A total of 34,393 participants surveyed were aged 25-64 years, representing approximately 12,387,800 Australians. Almost half (46%) of people with cancer were not in the labour force, resulting in a reduction of $1.7 billion to the Australian gross domestic product (GDP). Amongst those in the labour force, people with no health condition were 3.00 times more likely to be employed full-time compared to people with cancer (95% CI 1.96-4.57), after adjusting for age, sex, educational attainment and rurality. Amongst those with cancer, people without a tertiary qualification were 3.73 times more likely to be out of the labour force (95% CI 1.97-7.07). CONCLUSIONS: This paper is the first in Australia to estimate the national labour force participation rates of people with cancer. People with cancer were less likely to be in the labour force, resulting in a reduction in Australia's GDP. Cancer survivors, especially those without a tertiary qualification may benefit from support to return to work after a diagnosis. PMID- 29621996 TI - Magnitude and factors associated with adherence to Iron-folic acid supplementation among pregnant women in Eritrean refugee camps, northern Ethiopia. AB - BACKGROUND: Globally, anemia is a public health problem affecting the life of more than two billion people. Pregnant women are at high risk of iron deficiency anemia due to increased nutrient requirement during pregnancy. Iron-folic acid supplementation is the main strategy for prevention and control of iron deficiency anemia and its effectiveness depends on adherence to Iron-Folic Acid tablets. In the refugee camps of Ethiopia, despite the efforts made to reduce iron deficiency anemia during pregnancy, information about adherence to iron folic acid supplementation and its associated factors are lacking. The objective of this study was to assess magnitude and factors associated with adherence to iron-folic acid supplementation, among pregnant women, in Shire refugee camps. METHODS: Institution based cross-sectional study with mixed design (quantitative and qualitative) was carried out among pregnant women in Shire refugee camps from September to November 2015. For quantitative data, a sample of 320 pregnant women was systematically selected and data were collected via interview administered structured questionnaire. Quantitative data were coded and entered into Epi-info version 3.5.1 and exported into a statistical package for social sciences (SPSS) Version 19.0 software for analysis. Bivariable and multivariable logistic regressions were employed to identify the predictors at p-value < 0.2 and 0.05 respectively. For the qualitative part, six focus group discussions and three key informant interviews were conducted on purposely-selected individuals. Open-Code version 3.6.2.0 was used for analysis. Identified themes were arranged into coherent groupings and triangulated with quantitative findings. RESULTS: The adherence rate was found to be 64.7% [95% CI (59.7%, 70.0%)]. Women who were having lower knowledge about anemia [AOR; 0.23 95% CI (0.14, 0.38)] and not receiving information about importance of iron-folic acid supplementation [AOR; 0.43 95% CI (0.25, 0.74)] were negatively associated with adherence to iron and folic acid., Having four or more antenatal care visits [AOR; 2.83 95% CI (1.46, 5.48)] were positively significantly associated with adherence to iron-folic acid supplementation. CONCLUSIONS: Adherence rate of iron-folic acid supplementation during pregnancy in the study area is relatively low. Proper counseling and health promotion about Iron-Folic Acid tablet intake, promoting the benefits of early and frequent ANC visit, health promotion on anemia prevention and health benefits of the importance of iron-folic acid supplements are recommended to increase adherence with iron-folic acid supplementation. PMID- 29621998 TI - A factor XIa-activatable hirudin-albumin fusion protein reduces thrombosis in mice without promoting blood loss. AB - BACKGROUND: Hirudin is a potent thrombin inhibitor but its antithrombotic properties are offset by bleeding side-effects. Because hirudin's N-terminus must engage thrombin's active site for effective inhibition, fusing a cleavable peptide at this site may improve hirudin's risk/benefit ratio as a therapeutic agent. Previously we engineered a plasmin cleavage site (C) between human serum albumin (HSA) and hirudin variant 3 (HV3) in fusion protein HSACHV3. Because coagulation factor XI (FXI) is more involved in thrombosis than hemostasis, we hypothesized that making HV3 activity FXIa-dependent would also improve HV3's potential therapeutic profile. We combined albumin fusion for half-life extension of hirudin with positioning of an FXIa cleavage site N-terminal to HV3, and assessed in vitro and in vivo properties of this novel protein. RESULTS: FXIa cleavage site EPR was employed. Fusion protein EPR-HV3HSA but not HSAEPR-HV3 was activated by FXIa in vitro. FVIIa, FXa, FXIIa, or plasmin failed to activate EPR HV3HSA. FXIa-cleavable EPR-HV3HSA reduced the time to occlusion of ferric chloride-treated murine arteries and reduced fibrin deposition in murine endotoxemia; noncleavable mycHV3HSA was without effect. EPR-HV3HSA elicited less blood loss than constitutively active HV3HSA in murine liver laceration or tail transection but extended bleeding time to the same extent. EPR-HV3HSA was partially activated in citrated human or murine plasma to a greater extent than HSACHV3. CONCLUSIONS: Releasing the N-terminal block to HV3 activity using FXIa was an effective way to limit hirudin's bleeding side-effects, but plasma instability of the exposed EPR blocking peptide rendered it less useful than previously described plasmin-activatable HSACHV3. PMID- 29621997 TI - Decreased photosynthetic rate under high temperature in wheat is due to lipid desaturation, oxidation, acylation, and damage of organelles. AB - BACKGROUND: High temperature is a major abiotic stress that limits wheat (Triticum aestivum L.) productivity. Variation in levels of a wide range of lipids, including stress-related molecular species, oxidative damage, cellular organization and ultrastructural changes were analyzed to provide an integrated view of the factors that underlie decreased photosynthetic rate under high temperature stress. Wheat plants of cultivar Chinese Spring were grown at optimum temperatures (25/15 degrees C, maximum/minimum) until the onset of the booting stage. Thereafter, plants were exposed to high temperature (35/25 degrees C) for 16 d. RESULTS: Compared with optimum temperature, a lower photosynthetic rate was observed at high temperature which is an interplay between thylakoid membrane damage, thylakoid membrane lipid composition, oxidative damage of cell organelle, and stomatal and non-stomatal limitations. Triacylglycerol levels were higher under high temperature stress. Polar lipid fatty acyl unsaturation was lower at high temperature, while triacylglycerol unsaturation was the same at high temperature and optimum temperature. The changes in lipid species indicates increases in activities of desaturating, oxidizing, glycosylating and acylating enzymes under high temperature stress. Cumulative effect of high temperature stress led to generation of reactive oxygen species, cell organelle and membrane damage, and reduced antioxidant enzyme activity, and imbalance between reactive oxygen species and antioxidant defense system. CONCLUSIONS: Taken together with recent findings demonstrating that reactive oxygen species are formed from and are removed by thylakoid lipids, the data suggest that reactive oxygen species production, reactive oxygen species removal, and changes in lipid metabolism contribute to decreased photosynthetic rate under high temperature stress. PMID- 29621999 TI - Histo-epidemiological profile of breast cancers among women in the Central African Republic: about 174 cases. AB - BACKGROUND: Breast cancer (BC) is the most common cancer in women worldwide and leading cause of cancer deaths indeveloping countries. There is very limited data on BC in the Central African Republic. The purpose of this study was to describe the epidemiological and histopathological characteristics of BC in Bangui. METHODS: This retrospective study reviewed cancer data registries and medical records from the Pathology Unit of the National Laboratory in Bangui and the General Surgery and Gyneacology service from 2003 to 2015. A questionnaire was designed to collect information and data was analysed using descriptive and inferential statistical methods. RESULTS: In total, 174 cases of BC were recorded, with an average annual frequency of13.4 cases per year. The age of the women at diagnosis varied from 16 to 90 years with a median of 45.5 years and InterQuartile range (IQR) 18 years. The age group of 45-54 years represented the majority of the study population (n = 51, 29.3%).About 25.9%ofthe patients were non-educated and 85.6% lived in cities. Over 48 % of the women were housewives with a moderate economic status (n = 99, 56.9%). Sixty nine percent of the specimens received at the pathology unit were pieces of breast tumour. Invasive ductal carcinoma (n = 113, 64.9%) was the main histological form and most of the tumours were of Grade III (n = 14, 46.7%). The only imaging assessment was ultrasound performed in (n = 53, 30.4%) women. Surgery was performed in (n = 166, 95.4%) patients, while (n = 159, 91.4%) received complementary chemotherapy. At the end of the study, 84.5%of the cases had died, 12.1% were alive and 3.4% were considered "lost to follow-up". CONCLUSION: BC is an important public health problem and affected most of the younger Central African women. Epidemiological and histological characteristics are more or less common to those described other developing countries. It is imperative to improve the awareness of health care institutions and women on the burden of BC, to carry out early screening of BC, and to strengthen the capacity of women's health care system. PMID- 29622000 TI - Consequences of early extraction of compromised first permanent molar: a systematic review. AB - BACKGROUND: The aim of this study was to systematically review the literature to determine the sequelae of early extraction of compromised first permanent molars (FPMs) with regard to the skeletal and dental development of 5- to 15-year-old children. Meta-analysis was conducted when applicable. METHODS: Our research protocol included a search strategy, inclusion/exclusion criteria, and a data extraction plan. The search engines used were PubMed, Scopus, and Science Direct. Study selection was performed independently by three reviewers. Articles published from 1960 to 2017 were reviewed based on inclusion and exclusion criteria. Meta-analysis was performed to compare space closure between upper and lower arches. RESULTS: Eleven studies fulfilled the inclusion criteria. The consequences were decrease in post extraction space, accelerated development and eruption of second permanents molars (SPMs) and third molars, a decrease in caries and/or fillings on the proximal surfaces of adjacent teeth, lingual tipping and retrusion of incisors, and counter clockwise rotation of the occlusal plane. CONCLUSION: There were several consequences of early extraction of FPMs, which were related to skeletal and dental development. Our systematic review suggests that comprehensive evaluation of the compromised FPMs should be performed before planning an extraction. The ideal time for FPM extraction is when the SPM is at the early bifurcation stage in order to achieve complete closure of the extraction space by the SPM. Benefits should be weighed over the risks to decrease the risk of unfavorable outcomes as much as possible. However, due to the limited evidence on the outcomes and variables that influence them, high-quality prospective studies are needed. PMID- 29622001 TI - Clinical and molecular genetic risk determinants in adult long QT syndrome type 1 and 2 patients : Koponen et al. Follow-up of adult LQTS patients. AB - BACKGROUND: Long QT syndrome (LQTS) is an inherited cardiac disorder predisposing to sudden cardiac death (SCD). We studied factors affecting the clinical course of genetically confirmed patients, in particular those not receiving beta-blocker treatment. In addition, an attempt was made to associate risk of events to specific types of KCNQ1 and KCNH2 mutations. METHODS: A follow-up study covering a mean of 18.6 +/- 6.1 years was conducted in 867 genetically confirmed LQT1 and LQT2 patients and 654 non-carrier relatives aged 18-40 years. Cox regression models were used to evaluate the contribution of clinical and genetic risk factors to cardiac events. RESULTS: In mutation carriers, risk factors for cardiac events before initiation of beta-blocker included LQT2 genotype (hazard ratio [HR] = 2.1, p = 0.002), female gender (HR = 3.2, p < 0.001), a cardiac event before the age of 18 years (HR = 5.9, p < 0.001), and QTc >=500 ms (vs < 470 ms, HR = 2.7, p = 0.001). LQT1 patients carrying the KCNQ1 D317N mutation were at higher risk (HR = 3.0-3.9, p < 0.001-0.03) compared to G589D, c.1129-2A > G and other KCNQ1 mutation carriers after adjusting for gender, QTc duration, and cardiac events before age 18. KCNH2 c.453delC, L552S and R176W mutations associated with lower risk (HR = 0.11-0.23, p < 0.001) than other KCNH2 mutations. CONCLUSIONS: LQT2 (compared to LQT1), female gender, a cardiac event before age 18, and long QT interval increased the risk of cardiac events in LQTS patients aged 18 to 40 years. The nature of the underlying mutation may be associated with risk variation in both LQT1 and LQT2. The identification of high risk and low-risk mutations may enhance risk stratification. PMID- 29622003 TI - Scaling-up strategic purchasing: analysis of health system governance imperatives for strategic purchasing in a free maternal and child healthcare programme in Enugu State, Nigeria. AB - BACKGROUND: Significant knowledge gaps exist in the functioning of institutional designs and organisational practices in purchasing within free healthcare schemes in low resource countries. The study provides evidence of the governance requirements to scale up strategic purchasing in free healthcare policies in Nigeria and other low-resource settings facing similar approaches. METHODS: The study was conducted at the Ministry of Health and in two health districts in Enugu State, Nigeria, using a qualitative case study design. Semi-structured interviews were conducted with 44 key health system actors (16 policymakers, 16 providers and 12 health facility committee leaders) purposively selected from the Ministry of Health and the two health districts. Data collection and analysis were guided by Siddiqi and colleagues' health system governance framework. Data were analysed using a framework approach. RESULTS: The key findings show that supportive governance practices in purchasing included systems to verify questionable provider claims, pay providers directly for services, compel providers to procure drugs centrally and track transfer of funds to providers. However, strategic vision was undermined by institutional conflicts, absence of purchaser-provider split and lack of selective contracting of providers. Benefit design was not based on stakeholder involvement. Rule of law was limited by delays in provider payment. Benefits and obligations to users were not transparent. The criteria and procedure for resource allocation were unclear. Some target beneficiaries seemed excluded from the scheme. Effectiveness and efficiency was constrained by poor adherence to purchasing rules. Accountability of purchasers and providers to users was weak. Intelligence and information is constrained by paper-based system. Rationing of free services by providers and users' non-adherence to primary gate-keeping role hindered ethics. CONCLUSION: Weak governance of purchasing function limits potential of FMCHP to contribute towards universal health coverage. Appropriate governance model for strengthening strategic purchasing in the FMCHP and possibly free healthcare interventions in other low-resource countries must pay attention to the creation of an autonomous purchasing agency, clear framework for selective contracting, stakeholder involvement, transparent benefit design, need-based resource allocation, efficient provider payment methods, stronger roles for citizens, enforcement of gatekeeping rules and use of data for decision-making. PMID- 29622002 TI - Does specialist physician supply affect pediatric asthma health outcomes? AB - BACKGROUND: Pediatrician and pediatric subspecialist density varies substantially among the various Canadian provinces, as well as among various states in the US. It is unknown whether this variability impacts health outcomes. To study this knowledge gap, we evaluated pediatric asthma admission rates within the 2 Canadian provinces of Manitoba and Saskatchewan, which have similarly sized pediatric populations and substantially different physician densities. METHODS: This was a retrospective cross-sectional cohort study. Health regions defined by the provincial governments, have, in turn, been classified into "peer groups" by Statistics Canada, on the basis of common socio-economic characteristics and socio-demographic determinants of health. To study the relationship between the distribution of the pediatric workforce and health outcomes in Canadian children, asthma admission rates within comparable peer group regions in both provinces were examined by combining multiple national and provincial health databases. We generated physician density maps for general practitioners, and general pediatricians practicing in Manitoba and Saskatchewan in 2011. RESULTS: At the provincial level, Manitoba had 48.6 pediatricians/100,000 child population, compared to 23.5/100,000 in Saskatchewan. There were 3.1 pediatric asthma specialists/100,000 child population in Manitoba and 1.4/100,000 in Saskatchewan. Among peer-group A, the differences were even more striking. A significantly higher number of patients were admitted in Saskatchewan (590.3/100,000 children) compared to Manitoba (309.3/100,000, p < 0.0001). CONCLUSIONS: Saskatchewan, which has a lower pediatrician and pediatric asthma specialist supply, had a higher asthma admission rate than Manitoba. Our data suggest that there is an inverse relationship between asthma admissions and pediatrician and asthma specialist supply. PMID- 29622004 TI - Redefining diagnosis-related groups (DRGs) for palliative care - a cross sectional study in two German centres. AB - BACKGROUND: Hospital costs and cost drivers in palliative care are poorly analysed. It remains unknown whether current German Diagnosis-Related Groups, mainly relying on main diagnosis or procedure, reproduce costs adequately. The aim of this study was therefore to analyse costs and reimbursement for inpatient palliative care and to identify relevant cost drivers. METHODS: Two-center, standardised micro-costing approach with patient-level cost calculations and analysis of the reimbursement situation for patients receiving palliative care at two German hospitals (7/2012-12/2013). Data were analysed for the total group receiving hospital care covering, but not exclusively, palliative care (group A) and the subgroup receiving palliative care only (group B). Patient and care characteristics predictive of inpatient costs of palliative care were derived by generalised linear models and investigated by classification and regression tree analysis. RESULTS: Between 7/2012 and 12/2013, 2151 patients received care in the two hospitals including, but not exclusively, on the PCUs (group A). In 2013, 784 patients received care on the two PCUs only (group B). Mean total costs per case were ? 7392 (SD 7897) (group A) and ? 5763 (SD 3664) (group B), mean total reimbursement per case ? 5155 (SD 6347) (group A) and ? 4278 (SD 2194) (group B). For group A/B on the ward, 58%/67% of the overall costs and 48%/53%, 65%/82% and 64%/72% of costs for nursing, physicians and infrastructure were reimbursed, respectively. Main diagnosis did not significantly influence costs. However, duration of palliative care and total length of stay were (related to the cost calculation method) identified as significant cost drivers. CONCLUSIONS: Related to the cost calculation method, total length of stay and duration of palliative care were identified as significant cost drivers. In contrast, main diagnosis did not reflect costs. In addition, results show that reimbursement within the German Diagnosis-Related Groups system does not reproduce the costs adequately, but causes a financing gap for inpatient palliative care. PMID- 29622005 TI - Changing hearts and minds: examining student nurses' experiences and perceptions of a general practice placement through a 'community of practice' lens. AB - BACKGROUND: The recent UK Government paper 'Five year forward view' describes the need to move much patient management from secondary to primary care, and this will require a significant increase in the numbers of General Practice Nurses (GPNs). Until recently, there has been no clear recruitment strategy to address this. There have however been a number of proposed solutions to address the impending GPN recruitment crisis and to increase the numbers of new GPNs in post. General Practitioners (GPs) working in the Advanced Training Practice Scheme (ATPS) have been commissioned by Health Education England to provide placements for student nurses. This paper reports upon the findings of a study evaluating the South Yorkshire ATPS network in relation to nursing students' perceptions of general practice as a placement and a potential career option post-graduation. METHODS: Data were collected using semi-structured interviews with 18 nursing students. Qualitative data analysis used a framework approach and themes were cross-checked within the team. The research had ethical approval and anonymity and confidentiality were maintained throughout. RESULTS: Using the Communities of Practice (CoP) framework as a theoretical lens, two main themes emerged from the data: 'Myths and misunderstandings' outlined some of the misconceptions that abounded in the absence of an established CoP in general practice. These included perceptions of what constitutes a 'good' placement, an apparent lack of relevant content in the curriculum, and the widespread use of social media by students as a means of information gathering. 'Changing hearts and minds' referred to the need to positively influence the culture within general practice by addressing some of the longstanding myths. Through the fledgling CoP, the students' perceptions of the GPN role in particular were positively revised, as was the prospect of a career in general practice upon graduation. CONCLUSIONS: The CoP that is emerging through the ATPS placements appear to be gradually changing the socio-cultural landscape within general practice by enabling student nurses to experience the reality of life in general practice nursing, and to view the GPN role as a viable career option upon graduation. PMID- 29622006 TI - A before-after study of hospital use in two frail populations receiving different home-based services over the same time in Vancouver, Canada. AB - BACKGROUND: As individuals age, they are more likely to experience increasing frailty and more frequent use of hospital services. First, we explored whether initiating home-based primary care in a frail homebound cohort, influenced hospital use. Second, we explored whether initiating regular home care support for personal care with usual primary care, in a second somewhat less frail cohort, influenced hospital use. METHODS: This was a before-after retrospective cohort study of two frail populations in Vancouver, Canada using administrative data to assess the influence of two different services started in two different cohorts over the same time period. The participants were 246 recipients of integrated home-based primary care and 492 recipients of home care followed between July 1st, 2008 and June 30th, 2013 before and after starting their respective services. Individuals in each group were linked to their hospital emergency department visit and discharge abstract records. The main outcome measures were mean emergency department visit and hospital admission rates per 1000 patient days for 21 months before versus the period after receipt of services, and the adjusted incidence rate ratios (IRRs) on these outcomes post receipt of service. RESULTS: Before versus after starting integrated home-based primary care, emergency department visit rates per 1000 patient days (95% confidence intervals) were 4.1 (3.8, 4.4) versus 3.7 (3.3, 4.1), and hospital admissions rates were 2.3 (2.1, 2.5) versus 2.2 (1.9, 2.5). Before versus after starting home care, emergency department visit rates per 1000 patient days (95% confidence intervals) were 3.0 (2.8, 3.2) versus 4.0 (3.7, 4.3) visits and hospital admissions rates were 1.3 (1.2, 1.4) versus 1.9 (1.7, 2.1). Home-based primary care IRRs were 0.91 (0.72, 1.15) and 0.99 (0.76, 1.27) and home care IRRs were 1.34 (1.15, 1.56) and 1.46 (1.22, 1.74) for emergency department visits and hospital admissions respectively. CONCLUSIONS: After enrollment in integrated home-based primary care, emergency department visit and hospital admission rates stabilized. After starting home care with usual primary care, emergency department visit and hospital admission rates continued to rise. PMID- 29622007 TI - Synergistic effect of phytochemicals on cholesterol metabolism and lipid accumulation in HepG2 cells. AB - BACKGROUND: Crocin (CRO), chlorogenic acid (CGA), geniposide (GEN), and quercetin (QUE) are all natural compounds with anti-obesity properties, in particular, hypolipidemic effects, which have been widely used for the treatment of obesity related metabolic diseases. However, it is not yet known whether these compounds interact synergistically. Here, we investigated the effects and molecular mechanisms of CRO, CGA, GEN, QUE, and a combination of all four compounds (CCGQ), on lipid accumulation in human hepatoma (HepG2 cells). METHODS: The optimal concentration of CRO, CGA, GEN, QUE to stimulate HepG2 cells proliferation was determined using MTT assay. HepG2 cells were pretreated with 10 MUmol/L simvastatin, 1 MUmol/L CRO, 30 MUmol/L CGA, 10 MUmol/L GEN, 10 MUmol/L QUE, and CCGQ (a combination of 1 MUmol/L CRO, 30 MUmol/L CGA, 10 MUmol/L GEN, and 10 MUmol/L QUE) for 24 or 48 h. Oil red O staining and extracellular TC and TG levels were detected. The RT-PCR was used to observe on cholesterol metabolism related gene expression. Immunocytochemistry and western-blot assayed the 3 hydroxy-3-methylglutaryl-coenzyme (HMGCR) protein expression in HepG2 cells. RESULTS: Compared to those of control, we demonstrated that treating HepG2 cells for 48 h with CCGQ resulted in a strong synergistic effect, causing a marked decrease in lipid deposition in comparison to individual treatments, in both triglyceride and total cholesterol (CRO, 5.74- and 1.49-folds; CGA, 3.38- and 1.12-folds; GEN, 4.04- and 1.44-folds; QUE, 3.36- and 1.24-folds; simvastatin, 5.49- and 1.83-folds; and CCGQ, 7.75- and 2.20-folds), and Oil red O staining assays. In addition, CCGQ treatment increased ATP-binding cassette transporter (ABCA1), cholesterol 7alpha-hydroxylase (CYP7A1), and AMP-activated protein kinase 2alpha (AMPKalpha2) mRNA expression, while decreasing sterol regulatory element binding protein 2 (SREBP2), and liver X receptor alpha (LXRalpha) mRNA expression. Notably, CCGQ was more effective in decreasing HMGCR expression than the individual treatments. CONCLUSION: The CCGQ combination has potential, both as a complementary therapy for hyperlipemia, and in preventing further obesity related complications. PMID- 29622008 TI - Factors associated with internal medicine physician job attitudes in the Veterans Health Administration. AB - BACKGROUND: US healthcare organizations increasingly use physician satisfaction and attitudes as a key performance indicator. Further, many health care organizations also have an academically oriented mission. Physician involvement in research and teaching may lead to more positive workplace attitudes, with subsequent decreases in turnover and beneficial impact on patient care. This article aimed to understand the influence of time spent on academic activities and perceived quality of care in relation to job attitudes among internal medicine physicians in the Veterans Health Administration (VHA). METHODS: A cross sectional survey was conducted with inpatient attending physicians from 36 Veterans Affairs Medical Centers. Participants were surveyed regarding demographics, practice settings, workplace staffing, perceived quality of care, and job attitudes. Job attitudes consisted of three measures: overall job satisfaction, intent to leave the organization, and burnout. Analysis used a two level hierarchical model to account for the nesting of physicians within medical centers. The regression models included organizational-level characteristics: inpatient bed size, urban or rural location, hospital teaching affiliation, and performance-based compensation. RESULTS: A total of 373 physicians provided useable survey responses. The majority (72%) of respondents reported some level of teaching involvement. Almost half (46%) of the sample reported some level of research involvement. Degree of research involvement was a significant predictor of favorable ratings on physician job satisfaction and intent to leave. Teaching involvement did not have a significant impact on outcomes. Perceived quality of care was the strongest predictor of physician job satisfaction and intent to leave. Perceived levels of adequate physician staffing was a significant contributor to all three job attitude measures. CONCLUSIONS: Expanding opportunities for physician involvement with research may lead to more positive work experiences, which could potentially reduce turnover and improve system performance. PMID- 29622009 TI - Health service utilisation during the last year of life: a prospective, longitudinal study of the pathways of patients with chronic kidney disease stages 3-5. AB - BACKGROUND: Chronic kidney disease (CKD) is a growing global problem affecting around 10% of many countries' populations. Providing appropriate palliative care services (PCS) to those with advanced kidney disease is becoming paramount. Palliative/supportive care alongside usual CKD clinical treatment is gaining acceptance in nephrology services although the collaboration with and use of PCS is not consistent. METHODS: The goal of this study was to track and quantify the health service utilisation of people with CKD stages 3-5 over the last 12 months of life. Patients were recruited from a kidney health service (Queensland, Australia) for this prospective, longitudinal study. Data were collected for 12 months (or until death, whichever was sooner) during 2015-17 from administrative health sources. Emergency department presentations (EDP) and inpatient admissions (IPA) (collectively referred to as critical events) were reviewed by two Nephrologists to gauge if the events were avoidable. RESULTS: Participants (n = 19) with a median age of 78 years (range 42-90), were mostly male (63%), 79% had CKD stage 5, and were heavy users of health services during the study period. Fifteen patients (79%) collectively recorded 44 EDP; 61% occurred after-hours, 91% were triaged as imminently and potentially life-threatening and 73% were admitted. Seventy-four IPA were collectively recorded across 16 patients (84%); 14% occurred on weekends or public holidays. Median length of stay was 3 days (range 1-29). The median number of EDP and IPA per patient was 1 and 2 (range 0 12 and 0-20) respectively. The most common trigger to both EDP (30%) and IPA (15%) was respiratory distress. By study end 37% of patients died, 63% were known to PCS and 11% rejected a referral to a PCS. All critical events were deemed unavoidable. CONCLUSIONS: Few patients avoided using acute health care services in a 12 month period, highlighting the high service needs of this cohort throughout the long, slow decline of CKD. Proactive end-of-life care earlier in the disease trajectory through integrating renal and palliative care teams may avoid acute presentations to hospital through better symptom management and planned care pathways. PMID- 29622010 TI - Mechanical barriers and transforming growth factor beta inhibitor on epidural fibrosis in a rabbit laminectomy model. AB - BACKGROUND: TGF-beta has been described as a mediator of fibrosis and scarring. Several studies achieved reduction in experimental scarring through the inhibition of TGF-beta. Fibroblasts have been defined as the cell population originating fibrosis, blocking fibroblast invasion may impair epidural fibrosis appearance. For this purpose, biocompatible materials used as mechanical barriers and a TGF-beta inhibitor peptide were evaluated in the reduction of epidural fibrosis. METHODS: A L6 laminectomy was performed in 40 New Zealand white rabbits. Divided into four groups, each rabbit was assigned to receive either collagen sponge scaffold (CS group), gelatin-based gel (GCP group), P144(r) (iTGFbeta group), or left untreated (control group). Four weeks after surgery, cell density, collagen content, and new bone formation of the scar area were determined by histomorphometry. Two experienced pathologists scored dura mater adhesion, scar density, and inflammatory infiltrate in a blinded manner. RESULTS: In all groups, laminectomy site was filled with fibrous tissue and the dura mater presented adhesions. Only GCP group presented a significant reduction in collagen content and scar density. CONCLUSION: GCP treatment reduces epidural fibrosis although did not prevent dura mater adhesion completely. PMID- 29622011 TI - Informal caregiving burden and perceived social support in an acute stroke care facility. AB - BACKGROUND: Providing informal caregiving in the acute in-patient and post hospital discharge phases places enormous burden on the caregivers who often require some form of social support. However, it appears there are few published studies about informal caregiving in the acute in-patient phase of individuals with stroke particularly in poor-resource countries. This study was designed to evaluate the prevalence of caregiving burden and its association with patient and caregiver-related variables and also level of perceived social support in a sample of informal caregivers of stroke survivors at an acute stroke-care facility in Nigeria. METHODS: Ethical approval was sought and obtained. Fifty-six (21 males, 35 females) consecutively recruited informal caregivers of stroke survivors at the medical ward of a tertiary health facility in South-Southern Nigeria participated in this cross-sectional survey. Participants' level of care giving strain/burden and perceived social support were assessed using the Caregiver Strain Index and the Multidimensional Scale of Perceived Social Support respectively. Caregivers' and stroke survivors' socio-demographics were also obtained. Data was analysed using frequency count and percentages, independent t test, analysis of variance (ANOVA) and partial correlation at alpha =0.05. RESULTS: The prevalence of care-giving burden among caregivers is 96.7% with a high level of strain while 17.9% perceived social support as low. No significant association was found between caregiver burden and any of the caregiver- or survivor-related socio-demographics aside primary level education. Only the family domain of the Multidimensional Scale of Perceived Social Support was significantly correlated with burden (r = - 0.295). CONCLUSION: Informal care giving burden was highly prevalent in this acute stroke caregiver sample and about one in every five of these caregivers rated social support low. This is a single center study. Healthcare managers and professionals in acute care facilities should device strategies to minimize caregiver burden and these may include family education and involvement. PMID- 29622012 TI - If you can't measure it- you can't change it - a longitudinal study on improving quality of care in hospitals and health centers in rural Kenya. AB - BACKGROUND: The Kenyan Ministry of Health- Department of Standards and Regulations sought to operationalize the Kenya Quality Assurance Model for Health. To this end an integrated quality management system based on validated indicators derived from the Kenya Quality Model for Health (KQMH) was developed and adapted to the area of Reproductive and Maternal and Neonatal Health, implemented and analysed. METHODS: An integrated quality management (QM) approach was developed based on European Practice Assessment (EPA) modified to the Kenyan context. It relies on a multi-perspective, multifaceted and repeated indicator based assessment, covering the 6 World Health Organization (WHO) building blocks. The adaptation process made use of a ten step modified RAND/UCLA appropriateness Method. To measure the 303 structure, process, outcome indicators five data collection tools were developed: surveys for patients and staff, a self assessment, facilitator assessment, a manager interview guide. The assessment process was supported by a specially developed software (VISOTOOL(r)) that allows detailed feedback to facility staff, benchmarking and facilitates improvement plans. A longitudinal study design was used with 10 facilities (6 hospitals; 4 Health centers) selected out of 36 applications. Data was summarized using means and standard deviations (SDs). Categorical data was presented as frequency counts and percentages. RESULTS: A baseline assessment (T1) was carried out, a reassessment (T2) after 1.5 years. Results from the first and second assessment after a relatively short period of 1.5 years of improvement activities are striking, in particular in the domain 'Quality and Safety' (20.02%; p < 0.0001) with the dimensions: use of clinical guidelines (34,18%; p < 0.0336); Infection control (23,61%; p < 0.0001). Marked improvements were found in the domains 'Clinical Care' (10.08%; p = 0.0108), 'Management' (13.10%: p < 0.0001), 'Interface In/out-patients' (13.87%; p = 0.0246), and in total (14.64%; p < 0.0001). Exemplarily drilling down the domain 'clinical care' significant improvements were observed in the dimensions 'Antenatal care' (26.84%; p = 0.0059) and 'Survivors of gender-based violence' (11.20%; p = 0.0092). The least marked changes or even a -not significant- decline of some was found in the dimensions 'delivery' and 'postnatal care'. CONCLUSIONS: This comprehensive quality improvement approach breathes life into the process of collecting data for indicators and creates ownership among users and providers of health services. It offers a reflection on the relevance of evidence-based quality improvement for health system strengthening and has the potential to lay a solid ground for further certification and accreditation. PMID- 29622013 TI - A cross-sectional study of the availability and pharmacist's knowledge of nano pharmaceutical drugs in Palestinian hospitals. AB - BACKGROUND: Nanomedicine is the medical application of nanomaterials that may have an infinite size with the range less than 100 nm. This science has provided solutions to many of the current limitations in the diagnosis and treatment of diseases. Therefore, the pharmacist's knowledge and awareness of nano pharmaceutical drugs will increase their availability in the market, and will improve the patient's compliance to their drug therapy. This study aimed to determine the availability of nano-pharmaceutical drugs in Palestinian hospitals and evaluate the extent of pharmacist's knowledge about them. METHODS: A cross sectional study design questionnaire was used to determine the availability of nano-pharmaceutical drugs based on the database of the ministry of health in the Palestinian hospitals (governmental, private and non- governmental organizations). Moreover, the knowledge of these nano-pharmaceutical drugs among pharmacists working in Palestinian hospitals was assessed based on developed questionnaire from the literature of the pharmaceutical formulations and nano formulations. The variables were analyzed using Statistical Package for Social Sciences (SPSS 22). RESULT: Fifty six pharmacists from 27 hospitals in the West bank completed the survey. The results regarding the availability of nano pharmaceutical drugs indicated only eight available in hospitals with a frequency range 0-39.3%. Moreover, pharmacist's knowledge in the pharmaceutical formulations was better than that in nano-formulations. CONCLUSIONS: The availability of nano-pharmaceutical drugs in Palestinian hospitals was not adequate due to the lack of various nano-pharmaceutical drugs. The knowledge among pharmacists regarding nano-pharmaceutical drugs should be improved by providing courses in nanomedicine during the undergraduate pharmacy programs. PMID- 29622015 TI - Empathy is proprioceptive: the bodily fundament of empathy - a philosophical contribution to medical education. AB - BACKGROUND: The current philosophical debate on empathy entails accounts of theory of mind and simulation as well as a phenomenological opposition. The first focuses on a detached observation of others from a 3rd person perspective and formulates the common claim that there is no direct access to the mental and emotional life of others, only simulation or analogy can grant access to the emotions and behaviour of others. The philosophical respectively phenomenological account of Fuchs instead opposes by focusing personal interaction within a 1st or 2nd person perspective claiming that the emotions of others are experienceable through bodily expression and bodily resonance. Fuchs offers an account of embodied affectivity that emphasizes the role of the (subjective) body for emotion and empathy. By experiencing the bodily expressed emotions of a vis-a-vis with and through the own body empathy and social understanding are bodily grounded. Following this core thesis Fuchs differentiates a primary, bodily empathy and an extended empathy that focuses on putting myself in the shoes of others (perspective taking). DISCUSSION: By comparison of different forms of social understanding as discussed in the phenomenological tradition - like contagion, sharing and empathy - it can be shown that extended empathy has an egocentric character. By putting myself in the shoes of others I miss a person's otherness that transcends my capacity of imagination respectively the personal frame of my experience. Further Fuchs' disregards that a bodily based empathy is co-structured by higher level form of understanding like contextual biographic knowledge. CONCLUSION: The philosophical discussion offers fertile impulses for Medical Education (ME) and the training of empathic communication skills. The account of Fuchs highlights the role of bodily perception (proprioception) as a resource of understanding others. Thus proprioceptive skills of a physician can support the empathic understanding of the physician. The objection against the egocentric trait of perspective taking admonishes not to generalize the own perspective as decisive for empathy and to adopt an attitude that remains open to the otherness of a patient and its experiences. PMID- 29622014 TI - Consumption of meat in relation to physical functioning in the Seniors-ENRICA cohort. AB - BACKGROUND: Meat is an important source of high-quality protein and vitamin B but also has a relatively high content of saturated and trans fatty acids. Although protein and vitamin B intake seems to protect people from functional limitations, little is known about the effect of habitual meat consumption on physical function. The objective of this study was to examine the prospective association between the intake of meat (processed meat, red meat, and poultry) and physical function impairment in older adults. METHODS: Data were collected for 2982 participants in the Seniors-ENRICA cohort, who were aged >=60 years and free of physical function impairment. In 2008-2010, their habitual diet was assessed through a validated computer-assisted face-to-face diet history. Study participants were followed up through 2015 to assess self-reported incident impairment in agility, mobility, and performance-based lower-extremity function. RESULTS: Over a median follow-up of 5.2 years, we identified 625 participants with impaired agility, 455 with impaired mobility, and 446 with impaired lower extremity function. After adjustment for potential confounders, processed meat intake was associated with a higher risk of impaired agility (hazard ratio [HR] for highest vs. lowest tertile: 1.33; 95% confidence interval [CI]: 1.08-1.64; p trend = 0.01) and of impaired lower-extremity function (HR for highest vs. lowest tertile: 1.31; 95% CI: 1.02-1.68; p trend = 0.04). No significant associations were found for red meat and poultry. Replacing one serving per day of processed meat with one serving per day of red meat, poultry, or with other important protein sources (fish, legumes, dairy, and nuts) was associated with lower risk of impaired agility and lower-extremity function. CONCLUSIONS: A higher consumption of processed meat was associated with a higher risk of impairment in agility and lower-extremity function. Replacing processed meat by other protein sources may slow the decline in physical functioning in older adults. PMID- 29622016 TI - Detection of calcium pyrophosphate dihydrate crystals in knee meniscus by dual energy computed tomography. AB - BACKGROUND: Calcium pyrophosphate dihydrate (CPPD) crystals are commonly observed in osteoarthritic joints. The aim of our study was to investigate the efficacy of a dual-energy computed tomography (DECT) for detecting CPPD crystals in knee meniscus. METHODS: Twenty-six patients undergoing primary total knee arthroplasty were included in the study. Radiographs of knee joint and synovial fluid specimens were analyzed for the presence of CPPD crystals. Meniscus extracted during surgery was scanned using DECT. Sensitivity and specificity of DECT and radiograph for detecting CPPD crystals were calculated against a reference standard (polarizing light microscopy of synovial fluid aspirate). Meniscus in which CPPD crystals were suspected with DECT was further examined to confirm the crystals using a polarized microscopy. RESULTS: CPPD crystals in synovial fluid were observed in 9 (36%) patients. The sensitivity and specificity of DECT in the detection of CPPD crystals, against microscopic identification, were 77.8 and 93.8%, respectively. The sensitivity and specificity of conventional radiography in the detection of CPPD crystals were 44.4 and 100%, respectively. DECT was able to detect the area where CPPD crystals were deposited in the meniscus. CONCLUSION: DECT provides good diagnostic sensitivity and specificity for detection of CPPD crystals in knee meniscus as well as spatial information about CPPD crystals. DECT is currently a research tool, but we believe that DECT can be a useful instrument to diagnose CPPD deposition disease, especially for the regions where aspiration is difficult to be performed such as pubic symphysis, atlantoaxial joint, interphalangeal joint. PMID- 29622017 TI - Correction to: Type 2 diabetes-associated carotid plaque burden is increased in patients with retinopathy compared to those without retinopathy. AB - The author found errors in Table 1 after publication of the original article [1]. PMID- 29622018 TI - From problem people to addictive products: a qualitative study on rethinking gambling policy from the perspective of lived experience. AB - BACKGROUND: Previous research has shown that government and industry discussions of gambling may focus on personal responsibility for gambling harm. In Australia, these discussions have largely excluded people with lived experience of problem gambling, including those involved in peer support and advocacy. METHODS: We conducted 26 in-depth interviews with people with current or previous problem gambling on electronic gaming machines (EGMs) involved in peer support and advocacy activities, using an approach informed by Interpretive Policy Analysis and Constructivist Grounded Theory. RESULTS: Participants perceived that government and industry discussed gambling as safe and entertaining with a focus on personal responsibility for problem gambling. This focus on personal responsibility was perceived to increase stigma associated with problem gambling. In contrast, they described gambling as risky, addictive and harmful, with problem gambling resulting from the design of EGMs. As a result of their different perspectives, participants proposed different interventions to reduce gambling harm, including reducing accessibility and making products safer. CONCLUSIONS: Challenging the discourses used by governments and industry to describe gambling, using the lived experience of people with experience of gambling harm, may result in reduced stigma associated with problem gambling, and more effective public policy approaches to reducing harm. PMID- 29622019 TI - In vitro antioxidant and cholinesterase inhibitory activities of Elatostema papillosum leaves and correlation with their phytochemical profiles: a study relevant to the treatment of Alzheimer's disease. AB - BACKGROUND: Alzheimer's disease (AD), one of the major causes of dementia, is an overwhelming neurodegenerative disease that particularly affects the brain, leading to memory loss and impairment of language and judgment capacity. The aim of the present study was to investigate the antioxidant and anticholinesterase properties of the leaves of Elatostema papillosum (EPL) and correlate with their phytochemical profiles, which are relevant to the treatment of AD. METHODS: The dried coarse powder of EPL was extracted with 80% methanol (EPL-M80) by cold extraction method. The resultant EPL-M80 was assessed for acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) inhibitory activity by the Ellman method. The antioxidant activity was determined by DPPH (1, 1-diphenyl-2-picrylhydrazyl) and hydroxyl radical scavenging assays. Quantitative phytochemical (phenolic and flavonoid contents) analysis of endogenous substances in EPL-M80 was performed by standard spectrophotometric methods. RESULTS: EPL-M80 significantly (p < 0.05) inhibited AChE and BChE activity with IC50 of 165.40 +/- 4.01 and 213.81 +/- 3.57 MUg/mL, respectively in a dose-dependent manner. Additionally, EPL-M80 exhibited strong radical scavenging activity against DPPH (IC50 = 32.35 +/- 0.68 MUg/mL) and hydroxyl radical (IC50 = 19.67 +/- 1.42 MUg/mL) when compared to that of standards. EPL-M80 was found to be rich in phenolic (23.74 mg gallic acid equivalent/g of dry extract) and flavonoid (31.18 mg quercetin equivalent/g of dry extract) content. Furthermore, a positive correlation (p < 0.001) was observed between the total phenolics and antioxidant as well as the anticholinesterase potential. CONCLUSIONS: The marked inhibition of AChE and BChE, and potent antioxidant activity of the leaves of Elatostema papillosum highlight its potential to provide an effective treatment for AD. PMID- 29622021 TI - Substance use and associated factors among Debre Berhan University students, Central Ethiopia. AB - BACKGROUND: Being a global burden of youths, substances use is unhealthy behavior that exposes youths to health and social problems. Knowledge of the prevalence and predictors of substance use behavior among university students is important for designing periodic and locally appropriate interventions. This study is conducted to assess the prevalence and predicators of substances among Debre Berhan University students. METHODS: Cross-sectional quantitative study was employed in May 2016. Stratified two-stage sampling technique was applied to choose 695 students. Substance use behaviors were assessed using tools derived from World Health Organization Model Students' Substance Use Core Questionnaire. RESULT: The lifetime utilization of alcohol, khat and cigarette among students was found to be 36.3%, 10.9% and 7.4% respectively. The lifetime utilization of shisha and cannabis was 4.2% and 4.5% respectively. About 17%, 5.7%, and 3.1% of students are currently using alcohol, Khat and Cigarette respectively. Using multivariate binary logistic regression, being male, feeding out of the university cafe, being from private preparatory school, having higher monthly income, having substance user families and friends were found to be variables significantly associated with students' substance use behaviors. CONCLUSIONS: The current prevalence of substances use among Debre Berhan University students is low comparing to other Ethiopian and African universities. Youth are starting substance use at lower grades especially at preparatory schools. Substance use behaviors are affected by complex factors at individual, family, school, social, and environmental factors. Therefore, strategies to alleviate youth substance use problems should focus on changing individual perception, knowledge, and intention towards substances. There is a need for further research with more powerful sample size and weighted estimates using complex analysis. Reasons for lower prevalence of substance use from other Ethiopian universities shall be further explored using qualitative study. PMID- 29622020 TI - Benefits, barriers and opinions on multidisciplinary team meetings: a survey in Swedish cancer care. AB - BACKGROUND: Case review and discussion at multidisciplinary team meetings (MDTMs) have evolved into standard practice in cancer care with the aim to provide evidence-based treatment recommendations. As a basis for work to optimize the MDTMs, we investigated participants' views on the meeting function, including perceived benefits and barriers. METHODS: In a cross-sectional study design, 244 health professionals from south Sweden rated MDTM meeting structure and function, benefits from these meetings and barriers to reach a treatment recommendation. RESULTS: The top-ranked advantages from MDTMs were support for patient management and competence development. Low ratings applied to monitoring patients for clinical trial inclusion and structured work to improve the MDTM. Nurses and cancer care coordinators did less often than physicians report involvement in the case discussions. Major benefits from MDTM were reported to be more accurate treatment recommendations, multidisciplinary evaluation and adherence to clinical guidelines. Major barriers to a joint treatment recommendation were reported to be need for supplementary investigations and insufficient pathology reports. CONCLUSIONS: Health professionals' report multiple benefits from MDTMs, but also define areas for improvement, e.g. access to complete information and clarified roles for the different health professions. The emerging picture suggests that structures for regular MDTM evaluations and increased focus on patient-related perspectives should be developed and implemented. PMID- 29622022 TI - IL-6 blockade in systemic juvenile idiopathic arthritis - achievement of inactive disease and remission (data from the German AID-registry). AB - BACKGROUND: Systemic juvenile idiopathic arthritis (sJIA) is a complex disease with an autoinflammatory component of unknown etiology related to the innate immune system. A major role in the pathogenesis has been ascribed to proinflammatory cytokines like interleukin-6 (IL-6), and effective drugs inhibiting their signaling are being developed. This study evaluates sJIA patients treated with the IL-6 inhibitor tocilizumab (TCZ) concerning clinical response rate, disease course and adverse effects in a real-life clinical setting. METHODS: In 2009 a clinical and research consortium was established, including an online registry for autoinflammatory diseases (AID) ( https://aid register.de ). Data for this retrospective TCZ study were documented by 13 centers. RESULTS: From 7/2009 to 4/2014, 200 patients with sJIA were recorded in the AID-registry. Out of these, 46 (19 m, 27 f, age 1-18 years) received therapy with TCZ. Long term treatment (median 23 months) has been documented in 24/46 patients who were evaluated according to Wallace criteria (active disease 6/24, inactive disease 5/24, remission 13/24 cases). Under observation co-medication were used in 40/46 cases. Adverse events were reported in 11/46 patients. The clinical response rate (no clinical manifestation, no increased inflammation parameters) within the first 12 weeks of treatment was calculated to be 35%. CONCLUSION: Out of 200 sJIA children reported in the German AID-registry, 46 were treated with TCZ, showing a clinical response rate of 35% during the first 12 weeks, and inactive disease and/or remission under medication in 75% after one year. Adverse events were seen in 24% and severe adverse events in 4%. TRIAL REGISTRATION: The AID-Registry is funded by the BMBF (01GM08104, 01GM1112D, 01GM1512D). PMID- 29622023 TI - Role of cathepsin S In periodontal wound healing-an in vitro study on human PDL cells. AB - BACKGROUND: Cathepsin S is a cysteine protease, which is expressed in human periodontal ligament (PDL) cells under inflammatory and infectious conditions. This in vitro study was established to investigate the effect of cathepsin S on PDL cell wound closure. METHODS: An in vitro wound healing assay was used to monitor wound closure in wounded PDL cell monolayers for 72 h in the presence and absence of cathepsin S. In addition, the effects of cathepsin S on specific markers for apoptosis and proliferation were studied at transcriptional level. Changes in the proliferation rate due to cathepsin S stimulation were analyzed by an XTT assay, and the actions of cathepsin S on cell migration were investigated via live cell tracking. Additionally, PDL cell monolayers were treated with a toll-like receptor 2 agonist in the presence and absence of a cathepsin inhibitor to examine if periodontal bacteria can alter wound closure via cathepsins. RESULTS: Cathepsin S enhanced significantly the in vitro wound healing rate by inducing proliferation and by increasing the speed of cell migration, but had no effect on apoptosis. Moreover, the toll-like receptor 2 agonist enhanced significantly the wound closure and this stimulatory effect was dependent on cathepsins. CONCLUSIONS: Our findings provide original evidence that cathepsin S stimulates PDL cell proliferation and migration and, thereby, wound closure, suggesting that this cysteine protease might play a critical role in periodontal remodeling and healing. In addition, cathepsins might be exploited by periodontal bacteria to regulate critical PDL cell functions. PMID- 29622025 TI - Health workers' experiences of coping with the Ebola epidemic in Sierra Leone's health system: a qualitative study. AB - BACKGROUND: The 2014 Ebola Virus Disease epidemic evolved in alarming ways in Sierra Leone spreading to all districts. The country struggled to control it against a backdrop of a health system that was already over-burdened. Health workers play an important role during epidemics but there is limited research on how they cope during health epidemics in fragile states. This paper explores the challenges faced by health workers and their coping strategies during the Ebola outbreak in four districts - Bonthe, Kenema, Koinadugu and Western Area - of Sierra Leone. METHODS: We used a qualitative study design: key informant interviews (n = 19) with members of the District Health Management Teams and local councils, health facility managers and international partners; and in depth interviews with health workers (n = 25) working in public health facilities and international health workers involved with the treatment of Ebola patients. RESULTS: There were several important coping strategies including those that drew upon existing mechanisms: being sustained by religion, a sense of serving their country and community, and peer and family support. Externally derived strategies included: training which built health worker confidence in providing care; provision of equipment to do their job safely; a social media platform which helped health workers deal with challenges; workshops that provided ways to deal with the stigma associated with being a health worker; and the risk allowance, which motivated staff to work in facilities and provided an additional income source. CONCLUSIONS: Supportive supervision, peer support networks and better use of communication technology should be pursued, alongside a programme for rebuilding trusting relations with community structures. The challenge is building these mechanisms into routine systems, pre-empting shocks, rather than waiting to respond belatedly to crises. PMID- 29622024 TI - Longitudinal associations of long-term exposure to ultrafine particles with blood pressure and systemic inflammation in Puerto Rican adults. AB - BACKGROUND: Few longitudinal studies have examined the association between ultrafine particulate matter (UFP, particles < 0.1 MUm aerodynamic diameter) exposure and cardiovascular disease (CVD) risk factors. We used data from 791 adults participating in the longitudinal Boston Puerto Rican Health Study (Massachusetts, USA) between 2004 and 2015 to assess whether UFP exposure was associated with blood pressure and high sensitivity C-reactive protein (hsCRP, a biomarker of systemic inflammation). METHODS: Residential annual average UFP exposure (measured as particle number concentration, PNC) was assigned using a model accounting for spatial and temporal trends. We also adjusted PNC values for participants' inhalation rate to obtain the particle inhalation rate (PIR) as a secondary exposure measure. Multilevel linear models with a random intercept for each participant were used to examine the association of UFP with blood pressure and hsCRP. RESULTS: Overall, in adjusted models, an inter-quartile range increase in PNC was associated with increased hsCRP (beta = 6.8; 95% CI = - 0.3, 14.0%) but not with increased systolic blood pressure (beta = 0.96; 95% CI = - 0.33, 2.25 mmHg), pulse pressure (beta = 0.70; 95% CI = - 0.27, 1.67 mmHg), or diastolic blood pressure (beta = 0.55; 95% CI = - 0.20, 1.30 mmHg). There were generally stronger positive associations among women and never smokers. Among men, there were inverse associations of PNC with systolic blood pressure and pulse pressure. In contrast to the primary findings, an inter-quartile range increase in the PIR was positively associated with systolic blood pressure (beta = 1.03; 95% CI = 0.00, 2.06 mmHg) and diastolic blood pressure (beta = 1.01; 95% CI = 0.36, 1.66 mmHg), but not with pulse pressure or hsCRP. CONCLUSIONS: We observed that exposure to PNC was associated with increases in measures of CVD risk markers, especially among certain sub-populations. The exploratory PIR exposure metric should be further developed. PMID- 29622026 TI - Evidence of the factors that influence the utilisation of Kangaroo Mother Care by parents with low-birth-weight infants in low- and middle-income countries (LMICs): a scoping review protocol. AB - BACKGROUND: The Sustainable Development Goal (SDG) 3 emphasises on reducing neonatal deaths caused by low birth weight (LBW) complications by the implementation and utilisation of Kangaroo Mother Care (KMC) in low- and middle income countries (LMICs). Despite the empirical evidence of KMC optimising low birth-weight infants' (LBWIs') survival, its advantages and the LMICs implementing the service, studies have shown that LBW infant deaths occurring in LMICs are largely contributing to global child mortality. The aim of this scoping review is to map out the literature on barriers, challenges and facilitators of KMC utilisation by parents with LBWIs. METHODS AND ANALYSIS: This scoping review will use Endnote X7 reference management software to manage articles. The review search strategy will use SCIELO and LILACS databases. Other databases will be used via EBSCOHost search engine and these are Academic search complete, CINAHL with full text, Education source, Health source: Nursing/Academic Edition, Medline with full text and Medline. We will also use Google Scholar, JSTOR, Open grey search engines and reference lists. A two-phase search mapping out process will be done. In phase 1, one reviewer will perform the title screening and removal of duplicates. Two reviewers will do a parallel abstract screening according to eligibility criteria. Phase 2 will involve the reading of full articles and exclusion of articles, in accordance with the eligibility criteria. Data extraction from the articles will be done by two reviewers independently and parallel to the data extraction form. The data quality assessment of the eligible studies will be done using the Mixed Method Appraisal Tool (MMAT). The extraction of the synthesised results and thematic content analysis of the studies will be done by NVIVO version 10. DISCUSSION: We expect to find studies on barriers, challenges and facilitating factors of KMC utilisation by parents with LBWIs in LMICs. The review outcomes will guide future research and practice and inform policy. The findings will be disseminated in print, electronic and conference presentations related to maternal child and neonatal health. PMID- 29622027 TI - Correction to: Role of protein kinases CK1alpha and CK2 in multiple myeloma: regulation of pivotal survival and stress-managing pathways. AB - The original article [1] contains an inadvertent error in the following sentence in the Abstract regarding the erroneous description of Ser/Thr kinases as 'phylogenetically related'. PMID- 29622028 TI - Association of parental methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism in couples with unexplained recurrent pregnancy loss. AB - OBJECTIVE: The aim of this study was to identify the association of parental MTHFR C677T gene polymorphism in couples with and without RPL history. RESULTS: During the study, 21.4% (15/70) of Ala222Val polymorphism was observed among RPL couples while no polymorphism was seen among normal, healthy couples. Our study did not find any association between MTHFR C677T polymorphism and gender (p > 0.05), gestational period (p > 0.05), geographical region (p > 0.05) and menstrual history (p > 0.05). However, significant association was seen between MTHFR C677T polymorphism and number of losses (p < 0.05), concluding that the risk of the polymorphism increased with the increase in number of losses. Significant variation in the MTHFR C677T genotype with number of losses among RPL couples were seen but not with other study variables. PMID- 29622029 TI - Admission rates in a general practitioner-based versus a hospital specialist based, hospital-at-home model: ACCESS, an open-labelled randomised clinical trial of effectiveness. AB - BACKGROUND: Hospital at home (HaH) is an alternative to acute admission for elderly patients. It is unclear if should be cared for a primarily by a hospital intern specialist or by the patient's own general practitioner (GP). The study assessed whether a GP based model was more effective than a hospital specialist based model at reducing number of hospital admissions without affecting the patient's recovery or number of deaths. METHODS: Pragmatic, randomised, open labelled multicentre parallel group trial with two arms in four municipalities, four emergency departments and 150 GPs in Southern Denmark, including + 65 years old patients with an acute medical condition that required acute hospital in patient care. The patients were randomly assigned to hospital specialist based model or GP model of HaH care. Five physical and cognitive performance tests were performed at inclusion and after 7 days. Primary outcome was number of hospital admissions within 7 days. Secondary outcomes were number of admissions within 14, 21 and 30 days, deaths within 30 and 90 days and changes in performance tests. RESULTS: Sixty seven patients were enrolled in the GP model and 64 in the hospital specialist model. 45% in the hospital specialist arm versus 24% in the GP arm were admitted within 7 days (effect size 2.7, 95% CI 1.3-5.8; p = 0.01) and this remained significant within 30 days. No differences were found in death or changes in performance tests from day 0-7 days between the two groups. CONCLUSIONS: The GP based HaH model was more effective than the hospital specialist model in avoiding hospital admissions within 7 days among elderly patients with an acute medical condition with no differences in mental or physical recovery rates or deaths between the two models. REGISTRATION: No. NCT02422849 Registered 27 March 2015. Retrospectively registered. PMID- 29622031 TI - Prevalence of drug-drug interactions in geriatric patients at an ambulatory care pharmacy in a tertiary care teaching hospital. AB - OBJECTIVE: A cross-sectional study was performed from February to May 2015, to estimate the prevalence of drug-drug interactions in geriatric patients at the ambulatory care pharmacy at King Abdul-Aziz Medical City in Jeddah, Saudi Arabia. RESULTS: A total of 310 patients were included, with a mean age (+/- SD) of 73.78 +/- 6.96, and 48.70% were female. The overall prevalence of DDIs of all categories was 90.64%. Category B DDIs was 55.80%, category C DDIs 87.74%, category D DDIs 51.93%, and category X DDIs 16.45%. Atorvastatine plus omeprazole was identified as the most common interacting pair, with a prevalence of 25.26%. Multivariate logistic regression analysis showed that category D or X DDIs are more likely to occur in the female patient (OR = 1.79; 95% CI 1.07, 2.97), the patient taking more than three medications (OR = 22.62; 95% CI 2.93, 174.83), and the patient with more than two conditions (OR = 3.09; 95% CI 1.81, 5.27). PMID- 29622030 TI - Mapping human pluripotent stem cell differentiation pathways using high throughput single-cell RNA-sequencing. AB - BACKGROUND: Human pluripotent stem cells (hPSCs) provide powerful models for studying cellular differentiations and unlimited sources of cells for regenerative medicine. However, a comprehensive single-cell level differentiation roadmap for hPSCs has not been achieved. RESULTS: We use high throughput single cell RNA-sequencing (scRNA-seq), based on optimized microfluidic circuits, to profile early differentiation lineages in the human embryoid body system. We present a cellular-state landscape for hPSC early differentiation that covers multiple cellular lineages, including neural, muscle, endothelial, stromal, liver, and epithelial cells. Through pseudotime analysis, we construct the developmental trajectories of these progenitor cells and reveal the gene expression dynamics in the process of cell differentiation. We further reprogram primed H9 cells into naive-like H9 cells to study the cellular-state transition process. We find that genes related to hemogenic endothelium development are enriched in naive-like H9. Functionally, naive-like H9 show higher potency for differentiation into hematopoietic lineages than primed cells. CONCLUSIONS: Our single-cell analysis reveals the cellular-state landscape of hPSC early differentiation, offering new insights that can be harnessed for optimization of differentiation protocols. PMID- 29622032 TI - Change in the profile of traumatic spinal cord injury over 15 years in Spain. AB - BACKGROUND: Traumatic spinal cord injury remains a serious public health and social problem. Although incidence rates are decreasing in our environment, it is a high cost condition that is associated with great disability. The objective of this study was to describe the epidemiological and demographic characteristics of traumatic spinal cord injury and to analyse its epidemiological changes. METHODS: This study was an observational study with prospective monitoring of all traumatic spinal cord injury patients in the Canary Islands, Spain (2.1 million inhabitants) between 2001 and 2015. RESULTS: Over the specified period of the study, 282 patients suffered a traumatic spinal cord injury. The crude incidence rate was 9.3 cases per million people/year. The patients' mean age increased from 38 years (2001-2005) to 48 years (2011-2015) (p < 0.05). Overall, 80.1% of patients were males. The trauma mechanisms of spinal cord injury were falls in 44%, traffic accidents in 36.5%, diving accidents in 8.9% and others in 10.7%. While traffic accidents decreased, falls increased, particularly in the elderly (p < 0.05). The most frequently affected level was the cervical spine (50.9%), and incomplete tetraplegia was the most prevalent group (29.8%). A total of 76.6% of all patients suffered a vertebral fracture, and 91.6% of these required surgery. Among 282 patients, 12.5% were transferred to residences. The patients transferred increased from 8.5% in the first period to 20.0% (p < 0.05) in the last period. Such cases were related to age, cervical level injuries and injuries associated with poor functionality (p < 0.05). CONCLUSIONS: The rise in the number of falls among the older population, as well as the reduction in traffic accidents, decreased the incidence of traumatic spinal cord injury in our environment. This change in the profile of new traumatic spinal cord injuries led us to reformulate the functional objectives planned for these patients upon admission to specialized units, to plan destination-upon-discharge in advance and to promote campaigns to prevent spinal cord injury in older adults. PMID- 29622033 TI - Phlebotomine mortality effect of systemic insecticides administered to dogs. AB - BACKGROUND: Zoonotic visceral leishmaniasis (ZVL) caused by Leishmania (Leishmania) infantum is an important disease in humans and dogs. Different mammal species are reservoirs but dogs are considered to be the main one. Phlebotomine sand flies are the proven vector. Four systemic insecticides approved for their use in dogs were previously selected based on their potential to be used in endemic countries as part of the control programs of ZVL. These insecticides are proved to be safe and effective against the on-label insects and parasites, but there is no information about their activity against phlebotomine sand flies. METHODS: The phlebotomine mortality of four systemic insecticides in dogs was evaluated using two randomized clinical trials. For the first trial, thirty dogs were randomly allocated into five groups: four treatments and one control, of equal size. The treatments evaluated were: Guardian(r)SR, Elanco (moxidectin); Comfortis(r), Elanco (spinosad); Bravecto(r), Merck Animal Health (fluralaner); and NexGard(r), Merial (afoxolaner). Blood from dogs was taken at days 2, 4, 21 and 31 post-treatment (trial 1). The compound that showed the highest efficacy was selected for a second trial (trial 2) with 20 dogs sampled at days 0, 2, 4, 7, 14, 18, 32, 39, 51 and 84 post-treatment. Membrane feeding bioassays with Phlebotomus papatasi were used to evaluate the phlebotomine mortality efficacy of the different treatments. Phlebotomine mortality was observed every 24 h following the membrane feeding during 5 days. A mixed model for a negative binomial logistic regression, and a Cox proportional hazard mixed model were used to estimate phlebotomine mortality due to different treatments. RESULTS: Fluralaner was the only compound that showed significant phlebotomine mortality. Fluralaner maintained the phlebotomine mortality between 60-80% for 30 days after treatment. In trial 1 we found that fluralaner increased the risk of death by 1.9 times (95% CI: 1.02-3.6) and 1.7 times (95% CI: 1.09-2.6) at days 2 and 4 after treatment. The Cox model resulted in an increase of 1.47 (95% CI: 1.1 1.96) times in hazard risk at day 2 and 1.89 (95% CI: 1.35-2.45) at day 4 after treatment. In trial 2 we found that fluralaner increased the risk of death by 1.64 times (95% CI: 1.16-2.54) and 1.97 times (95% CI: 1.23-3.17) at days 14 and 32. The hazard risk was also increased by 1.92 (95% CI: 1.4-2.64) times at day 14 after treatment. Phlebotomine survival including all experimental days was significantly lower in the fluralaner group in both trials. CONCLUSIONS: A single oral treatment of fluralaner in dogs induces phlebotomine mortality. Systemic insecticides in dogs should be considered as a potential preventive measure of ZVL. PMID- 29622034 TI - The impact of group activities and their content on persons with dementia attending them. AB - BACKGROUND: Individuals suffering from dementia and residing in nursing homes often feel lonely and bored. This study examined the engagement and mood of people with dementia in group activities, and how personal characteristics, such as cognitive function, may impact on an individual's responses to group activities. METHODS: The study included 102 participants, who took part in group activities while their mood and engagement levels were observed. Participants were invited to attend 10 different types of group activities, each of which was offered twice. RESULTS: Results found improved engagement and mood during group activities as compared to control no-group times. Significant relationships between the type of activity and ratings of engagement and mood were also found. Although participants with higher levels of cognitive functioning manifested greater responsiveness to groups, the pattern of response to different contents did not differ by cognitive function. CONCLUSIONS: This study shows the potential utility of group activities for improving quality of life of persons with dementia and demonstrates a methodology that can be used for quality improvement to optimize group contents. Future research should expand the range of contents of group activities in order to enhance the options for improving mood and engagement of individuals with dementia. PMID- 29622035 TI - CCL17 blockade as a therapy for osteoarthritis pain and disease. AB - BACKGROUND: Granulocyte macrophage-colony stimulating factor (GM-CSF) has been implicated in the pathogenesis of a number of inflammatory diseases and in osteoarthritis (OA). We identified previously a new GM-CSF->Jmjd3->interferon regulatory factor 4 (IRF4)->chemokine (c-c motif) ligand 17 (CCL17) pathway, which is important for the development of inflammatory arthritis pain and disease. Tumour necrosis factor (TNF) can also be linked with this pathway. Here we investigated the involvement of the pathway in OA pain and disease development using the GM-CSF-dependent collagenase-induced OA (CiOA) model. METHODS: CiOA was induced in C57BL/6 wild-type (WT), Irf4 -/- , Ccl17 E/E , Ccr4 -/- , Tnf -/- and GM-CSF -/- mice. Additionally, therapeutic targeting of CCL17, Jmjd3 and cyclooxygenase 2 (COX-2) was evaluated. Development of pain (assessment of weight distribution) and OA disease (histologic scoring of synovitis, cartilage destruction and osteophyte size) were assessed. Synovial joint cells, including neutrophils, macrophages, fibroblasts and endothelial cells, were isolated (cell sorting) and gene expression analyzed (quantitative PCR). RESULTS: Studies in the gene-deficient mice indicated that IRF4, CCL17 and the CCL17 receptor, CCR4, but not TNF, were required for CiOA pain and optimal cartilage destruction and osteophyte size. Therapeutic neutralization of CCL17 and Jmjd3 ameliorated both pain and disease, whereas the COX-2 inhibitor only ameliorated pain. In the synovium Ccl17 mRNA was expressed only in the macrophages in a GM-CSF-dependent and IRF4-dependent manner. CONCLUSIONS: The GM-CSF->Jmjd3->IRF4->CCL17 pathway is important for the development of CiOA, with CCL17 thus being a potential therapeutic target for the treatment of both OA pain and disease. PMID- 29622036 TI - The mosquito adulticidal Chromobacterium sp. Panama causes transgenerational impacts on fitness parameters and elicits xenobiotic gene responses. AB - BACKGROUND: Vector control is critical in reducing the disease burden caused by mosquitoes, and insecticides are an effective tool to control vector populations. Resistance to common insecticides is now widespread, and novel classes of insecticides are needed. In previous work, we described the mosquitocidal activity of Chromobacterium sp. Panama (C.sp_P), a bacterium found in association with mosquitoes in natural populations. In the current work, we further explored the effects of exposure to the bacterium on mosquito fitness and mosquito physiology. RESULTS: We found that C.sp_P has mosquitocidal activity against a broad range of mosquito taxa. When exposed to C.sp_P as adults, female An. gambiae suffered reduced longevity, but experienced no change in fecundity. The offspring of these females, however, had higher mortality as larvae and were slower to develop compared to offspring of control females. We also found that the mosquitocidal activity of C.sp_P was retained after removal of live cells from biofilm culture media, suggesting the bacteria secrete mosquitocidal compound(s) into the media during growth. Exposure to this cell-free C.sp_P conditioned media caused female midgut transcriptional changes comprising detoxification, xenobiotic response, and stress response genes, suggesting the physiological response to C.sp_P is similar to that of insecticide exposure. Finally, we found that multiple members of the Chromobacterium genus had mosquitocidal activity, but this activity was highest in mosquitoes treated with C.sp_P. CONCLUSIONS: Our findings suggest that C.sp_P produces factor(s) with strong effects on mosquito longevity and fitness, which may be of interest for mosquitocide development. More generally, they indicate that further exploration of mosquito-associated and environmental microbes for novel insecticidal compounds or biocontrol agents is warranted. PMID- 29622037 TI - A Phase 2 clinical trial of PF-05212377 (SAM-760) in subjects with mild to moderate Alzheimer's disease with existing neuropsychiatric symptoms on a stable daily dose of donepezil. AB - BACKGROUND: Symptomatic benefits have been reported for 5-HT6 receptor antagonists in Alzheimer's disease (AD) trials. SAM-760 is a potent and selective 5-HT6 receptor antagonist that has demonstrated central 5-HT6 receptor saturation in humans at a dose of 30 mg. METHODS: This was a randomized, double-blind, placebo-controlled, parallel-group, multicenter trial evaluating the efficacy and safety of SAM-760 30 mg once daily (QD) for 12 weeks in subjects with AD on a stable regimen of donepezil 5 to 10 mg QD. The study included an interim analysis with stopping rules for futility or efficacy after 180 subjects completed the week 12 visit. Up to 342 subjects with AD (Mini-Mental State Examination (MMSE) score 10-24) and neuropsychiatric symptoms (Neuropsychiatric Inventory (NPI) total score >= 10) were to be enrolled if the study continued after the interim analysis. After a 4-week, single-blind, placebo run-in period, subjects entered the 12-week double-blind period and were randomized to either SAM-760 or placebo. The primary and key secondary efficacy endpoints were the change from baseline in Alzheimer's Disease Assessment Scale-cognitive subscale (ADAS-cog13) and NPI total scores. Mixed models for repeated measures were used to analyze the data. RESULTS: At the interim analysis, when 186 subjects had been randomized and 163 had completed the week 12 visit, the study met futility criteria and was stopped. The mean week 12 treatment difference was 0.70 points (P = 0.43) for ADAS-cog13 and 2.19 points (P = 0.20) for NPI score, both of which were numerically in favor of placebo. Other secondary endpoints did not demonstrate any significant benefit for SAM-760. In total, 46.2% of SAM-760 subjects reported adverse events (AE) versus 44.7% for placebo, and there were 5 (5.5%) serious AEs in the SAM-760 group versus 3 (3.2%) for placebo. There were two deaths, one prior to randomization and one in the SAM-760 group (due to a traffic accident during washout of active treatment). CONCLUSIONS: SAM-760 was safe and well tolerated, but there was no benefit of SAM-760 on measures of cognition, neuropsychiatric symptoms, or daily function. Differences in trial design, study population, region, or pharmacological profile may explain differences in outcome compared with other 5-HT6 receptor antagonists. TRIAL REGISTRATION: Clinicaltrials.gov, NCT01712074 . Registered 19 October 2012. PMID- 29622038 TI - The phenotype control kernel of a biomolecular regulatory network. AB - BACKGROUND: Controlling complex molecular regulatory networks is getting a growing attention as it can provide a systematic way of driving any cellular state to a desired cell phenotypic state. A number of recent studies suggested various control methods, but there is still deficiency in finding out practically useful control targets that ensure convergence of any initial network state to one of attractor states corresponding to a desired cell phenotype. RESULTS: To find out practically useful control targets, we introduce a new concept of phenotype control kernel (PCK) for a Boolean network, defined as the collection of all minimal sets of control nodes having their fixed state values that can generate all possible control sets which eventually drive any initial state to one of attractor states corresponding to a particular cell phenotype of interest. We also present a detailed method with which we can identify PCK in a systematic way based on the layered network and converging tree of a given network. We identify all candidates for control nodes from the layered network and then hierarchically search for all possible minimal sets by using the converging tree. We show the usefulness of PCK by applying it to cell proliferation and apoptosis signaling networks and comparing the results with other control methods. PCK is the unique control method for Boolean network models that can be used to identify all possible minimal sets of control nodes. Interestingly, many of the minimal sets have only one or two control nodes. CONCLUSIONS: Based on the new concept of PCK, we can identify all possible minimal sets of control nodes that can drive any molecular network state to one of multiple attractor states representing a same desired cell phenotype. PMID- 29622039 TI - Genome-scale portrait and evolutionary significance of human-specific core promoter tri- and tetranucleotide short tandem repeats. AB - BACKGROUND: While there is an ongoing trend to identify single nucleotide substitutions (SNSs) that are linked to inter/intra-species differences and disease phenotypes, short tandem repeats (STRs)/microsatellites may be of equal (if not more) importance in the above processes. Genes that contain STRs in their promoters have higher expression divergence compared to genes with fixed or no STRs in the gene promoters. In line with the above, recent reports indicate a role of repetitive sequences in the rise of young transcription start sites (TSSs) in human evolution. RESULTS: Following a comparative genomics study of all human protein-coding genes annotated in the GeneCards database, here we provide a genome-scale portrait of human-specific short- and medium-size (>= 3-repeats) tri and tetranucleotide STRs and STR motifs in the critical core promoter region between - 120 and + 1 to the TSS and evidence of skewing of this compartment in reference to the STRs that are not human-specific (Levene's test p < 0.001). Twenty-five percent and 26% enrichment of human-specific transcripts was detected in the tri and tetra human-specific compartments (mid-p < 0.00002 and mid-p < 0.002, respectively). CONCLUSION: Our findings provide the first evidence of genome-scale skewing of STRs at a specific region of the human genome and a link between a number of these STRs and TSS selection/transcript specificity. The STRs and genes listed here may have a role in the evolution and development of characteristics and phenotypes that are unique to the human species. PMID- 29622040 TI - Measuring DNA hybridization using fluorescent DNA-stabilized silver clusters to investigate mismatch effects on therapeutic oligonucleotides. AB - BACKGROUND: Short nucleic acid oligomers have found a wide range of applications in experimental physics, biology and medicine, and show potential for the treatment of acquired and genetic diseases. These applications rely heavily on the predictability of hybridization through Watson-Crick base pairing to allow positioning on a nanometer scale, as well as binding to the target transcripts, but also off-target binding to transcripts with partial homology. These effects are of particular importance in the development of therapeutic oligonucleotides, where off-target effects caused by the binding of mismatched sequences need to be avoided. RESULTS: We employ a novel method of probing DNA hybridization using optically active DNA-stabilized silver clusters (Ag-DNA) to measure binding efficiencies through a change in fluorescence intensity. In this way we can determine their location-specific sensitivity to individual mismatches in the sequence. The results reveal a strong dependence of the hybridization on the location of the mismatch, whereby mismatches close to the edges and center show a relatively minor impact. In parallel, we propose a simple model for calculating the annealing ratios of mismatched DNA sequences, which supports our experimental results. CONCLUSION: The primary result shown in this work is a demonstration of a novel technique to measure DNA hybridization using fluorescent Ag-DNA. With this technique, we investigated the effect of mismatches on the hybridization efficiency, and found a significant dependence on the location of individual mismatches. These effects are strongly influenced by the length of the used oligonucleotides. The novel probe method based on fluorescent Ag-DNA functions as a reliable tool in measuring this behavior. As a secondary result, we formulated a simple model that is consistent with the experimental data. PMID- 29622041 TI - Predictors of fitness to practise declarations in UK medical undergraduates. AB - BACKGROUND: Misconduct during medical school predicts subsequent fitness to practise (FtP) events in doctors, but relatively little is known about which factors are associated with such issues during undergraduate education. This study exploits the newly created UK medical education database (UKMED), with the aim of identifying predictors of conduct or health-related issues that could potentially impair FtP. The findings would have implications for policies related to both the selection and support of medical students. METHODS: Data were available for 14,379 students obtaining provisional registration with the General Medical Council who started medical school in 2007 and 2008. FtP declarations made by students were available, as were various educational and demographic predictor variables, including self-report 'personality measures' for students who participated in UK Clinical Aptitude Test (UKCAT) pilot studies. Univariable and multivariable logistic regression models were developed to evaluate the predictors of FtP declarations. RESULTS: Significant univariable predictors (p < 0.05) for conduct-related declarations included male gender, white ethnicity and a non-professional parental background. Male gender (OR 3.07) and higher 'self esteem' (OR 1.45) were independently associated with an increased risk of a conduct issue. Female gender, a non-professional background, and lower self reported 'confidence' were, among others, associated with increased odds of a health-related declaration. Only 'confidence' was a significant independent predictor of a health declaration (OR 0.69). Female gender, higher UKCAT score, a non-professional background and lower 'confidence' scores were significant predictors of reported depression, and the latter two variables were independent predictors of declared depression. CONCLUSIONS: White ethnicity and UK nationality were associated with increased odds of both conduct and health related declarations, as were certain personality traits. Students from non professional backgrounds may be at increased risk of depression and therefore could benefit from targeted support. The small effect sizes observed for the 'personality measures' suggest they would offer little potential benefit for selection, over and above those measures already in use. PMID- 29622042 TI - Engineering CRISPR interference system in Klebsiella pneumoniae for attenuating lactic acid synthesis. AB - BACKGROUND: Klebsiella pneumoniae is a promising industrial species for bioproduction of bulk chemicals such as 1,3-propanediol, 2,3-butanediol and 3 hydroxypropionic acid (3-HP). However, lactic acid is a troublesome by-product when optimizing for 3-HP production. Therefore, it is highly desirable to minimize lactic acid. RESULTS: Here, we show that lactic acid synthesis can be largely blocked by an engineered CRISPR interference (CRISPRi) system in K. pneumoniae. EGFP was recruited as a reporter of this CRISPRi system. Fluorescence assay of this CRISPRi system showed that enhanced green fluorescent protein (EGFP) expression level was repressed by 85-90%. To further test this CRISPRi system, guide RNAs were designed to individually or simultaneously target four lactate-producing enzyme genes. Results showed that all lactate-producing enzyme genes were significantly repressed. Notably, D-lactate dehydrogenase (ldhA) was shown to be the most influential enzyme for lactic acid formation in micro aerobic conditions, as inhibiting ldhA alone led to lactic acid level similar to simultaneously repressing four genes. In shake flask cultivation, the strain coexpressing puuC (an aldehyde dehydrogenase catalyzing 3-hydroxypropionaldehyde to 3-HP) and dCas9-sgRNA inhibiting ldhA produced 1.37-fold 3-HP relative to the reference strain. Furthermore, in bioreactor cultivation, this CRISPRi strain inhibiting ldhA produced 36.7 g/L 3-HP, but only generated 1 g/L lactic acid. Clearly, this engineered CRISPRi system largely simplified downstream separation of 3-HP from its isomer lactic acid, an extreme challenge for 3-HP bioprocess. CONCLUSIONS: This study offers a deep understanding of lactic acid metabolism in diverse species, and we believe that this CRISPRi system will facilitate biomanufacturing and functional genome studies of K. pneumoniae or beyond. PMID- 29622043 TI - Aripiprazole-induced sleep-related eating disorder: a case report. AB - BACKGROUND: Sleep-related eating disorder is characterized by parasomnia with recurrent episodes of nocturnal eating or drinking during the main sleep period. Several drugs, including atypical antipsychotics, induce sleep-related eating disorder. However, aripiprazole has not previously been associated with sleep related eating disorder. CASE PRESENTATION: A 41-year-old Japanese man visited our clinic complaining of depression. The patient was treated with sertraline, which was titrated up to 100 mg for 4 weeks. A sleep inducer and an anxiolytic were coadministered. His depressive mood slightly improved, but it continued for an additional 4 months. Subsequently, aripiprazole (3 mg) was added as an adjunctive therapy. After 3 weeks, the patient's mother found that the patient woke up and ate food at night. The next morning, the patient was amnesic for this event, felt full, and wondered why the bags of food were empty. This episode lasted for 2 days. The patient gained 5 kg during these 3 weeks. After the aripiprazole dose was reduced to 1.5 mg, the patient's nocturnal eating episodes rapidly and completely disappeared. CONCLUSIONS: To the best of our knowledge, this is first report of sleep-related eating disorder induced by aripiprazole, and it indicates that this disorder should be considered a possible side effect of aripiprazole. Although aripiprazole is used mainly in patients with schizophrenia, its recently documented use as an adjunctive therapy in patients with depression might induce hitherto unknown side effects. PMID- 29622044 TI - Ultrasound shear wave elastography of breast lesions: correlation of anisotropy with clinical and histopathological findings. AB - BACKGROUND: Ultrasound shear-wave elastography (SWE) may increase specificity of breast lesion assessment with ultrasound, but elasticity measurements may change with transducer orientation, defined as anisotropy. In this study, we aimed to observe the anisotropy of SWE of breast lesions, and its correlation with clinical and histopathological findings. METHODS: This retrospective study was approved by institutional review board. From June 2014 to June 2015, a total of 276 women (mean age, 48.75 +/- 12.12 years) with 276 breast lesions (174 malignant, 102 benign) were enrolled for conventional ultrasound and SWE before surgical excision. Elasticity modulus in the longest diameter and orthogonal diameter were recorded, including maximum elasticity (Emax), mean elasticity (Emean), standard deviation (Esd) and ratio between mean elasticity of lesion and normal fatty tissue (Eratio). Anisotropy coefficients including anisotropic difference (AD) and anisotropy factors (AF) were calculated, and correlations with malignancy, tumor size, palpability, movability, lesion location and histopathology were analyzed. RESULTS: The average Emax, Emean, Esd and Eratio of the longest diameter were significantly higher than orthogonal diameter (P < 0.05). AUCs of ADs and AFs were inferior to quantitative parameters (P < 0.001), with AUCs of AFs superior to ADs (P < 0.001). ADs showed no significant correlation with malignancy, palpability, movability, distance from nipple and skin, and histopathological patterns. ADmean was significantly higher in inner half than outer half of the breast (P = 0.034). Higher AFs were significantly correlated with larger lesion size (P = 0.042), palpability (P < 0.05), shorter distance from nipple and skin (P < 0.05) and higher suspicion for malignancy (P < 0.001). AFs were significantly higher in IDC than DCIS (P < 0.05), higher in Grade II/III than Grade I IDC (P < 0.001), and correlated with ER/PR(+) (P < 0.05). CONCLUSIONS: AF of SWE was an indicator for malignancy and more aggressive breast cancer. PMID- 29622045 TI - A couple-based HIV prevention intervention for Latino men who have sex with men: study protocol for a randomized controlled trial. AB - BACKGROUND: Latino men who have sex with men (MSM) experienced a 13% increase in HIV diagnoses from 2010 to 2014, more than any other racial/ethnic subgroup of MSM in the United States. If current HIV diagnoses rates persist, about one in four Latino MSM in the United States will be diagnosed with HIV during their lifetime. Although some efficacious HIV prevention interventions for Latino MSM exist, none have focused on couples. This paper describes the protocol of a randomized controlled trial (RCT) to test the preliminary efficacy of a couple based HIV prevention intervention that is culturally tailored for Latino men and their same-sex partners. METHODS: The RCT will determine the preliminary efficacy of Connecting Latinos en Pareja (CLP) to increase the proportion of anal sex acts that are HIV protected (i.e., anal sex acts in which condoms, pre-exposure prophylaxis (PrEP), treatment as prevention (TasP), or a combination thereof, are used to reduce risk of HIV transmission). CLP builds upon previous couple-based interventions with white and black MSM by incorporating biomedical prevention techniques, such as PrEP and TasP, implementing a framework responsive to the couple's serostatus, and addressing the socio-cultural factors that influence HIV risk among Latino MSM. We also include input from community stakeholders, members of the target population, and a community advisory board as part of intervention development. Assessments will be conducted at baseline, and 3- and 6-months post intervention to examine the intervention effects on outcomes (HIV-protected sex acts), and factors potentially mediating or moderating intervention effects. DISCUSSION: This paper describes an innovative RCT that incorporates multiple HIV prevention techniques for Latino MSM in couples, regardless of serostatus. The ongoing involvement of community stakeholders, members of the target population, and a community advisory board is emphasized, and plans for widespread dissemination and application of findings into practice are discussed. TRIAL REGISTRATION: Trial registration: NCT03048838 . Registered on 3 February 2017. PMID- 29622046 TI - Complete intracranial response to talimogene laherparepvec (T-Vec), pembrolizumab and whole brain radiotherapy in a patient with melanoma brain metastases refractory to dual checkpoint-inhibition. AB - BACKGROUND: Immunotherapy, in particular checkpoint blockade, has changed the clinical landscape of metastatic melanoma. Nonetheless, the majority of patients will either be primary refractory or progress over follow up. Management of patients progressing on first-line immunotherapy remains challenging. Expanded treatment options with combination immunotherapy has demonstrated efficacy in patients previously unresponsive to single agent or alternative combination therapy. CASE PRESENTATION: We describe the case of a patient with diffusely metastatic melanoma, including brain metastases, who, despite being treated with stereotactic radiosurgery and dual CTLA-4/PD-1 blockade (ipilimumab/nivolumab), developed systemic disease progression and innumerable brain metastases. This patient achieved a complete CNS response and partial systemic response with standard whole brain radiation therapy (WBRT) combined with Talimogene laherparepvec (T-Vec) and pembrolizumab. CONCLUSION: Patients who do not respond to one immunotherapy combination may respond during treatment with an alternate combination, even in the presence of multiple brain metastases. Biomarkers are needed to assist clinicians in evidence based clinical decision making after progression on first line immunotherapy to determine whether response can be achieved with second line immunotherapy. PMID- 29622048 TI - Systemic inflammation and intelligence in early adulthood and subsequent risk of schizophrenia and other non-affective psychoses: a longitudinal cohort and co relative study. AB - BACKGROUND: Schizophrenia is associated with impaired neurodevelopment as indexed by lower premorbid IQ. We examined associations between erythrocyte sedimentation rate (ESR), a marker of low-grade systemic inflammation, IQ, and subsequent schizophrenia and other non-affective psychoses (ONAP) to elucidate the role of neurodevelopment and inflammation in the pathogenesis of psychosis. METHODS: Population-based data on ESR and IQ from 638 213 Swedish men assessed during military conscription between 1969 and 1983 were linked to National Hospital Discharge Register for hospitalisation with schizophrenia and ONAP. The associations of ESR with IQ (cross-sectional) and psychoses (longitudinal) were investigated using linear and Cox-regression. The co-relative analysis was used to examine effects of shared familial confounding. We examined mediation and moderation of effect between ESR and IQ on psychosis risk. RESULTS: Baseline IQ was associated with subsequent risk of schizophrenia (adjusted HR per 1-point increase in IQ = 0.961; 95% confidence interval (CI) 0.960-0.963) and ONAP (adjusted HR = 0.973; 95% CI 0.971-0.975). Higher ESR was associated with lower IQ in a dose-response fashion. High ESR was associated with increased risk for schizophrenia (adjusted HR = 1.14; 95% CI 1.01-1.28) and decreased risk for ONAP (adjusted HR = 0.85; 95% CI 0.74-0.96), although these effects were specific to one ESR band (7-10 mm/hr). Familial confounding explained ESR-IQ but not ESR psychoses associations. IQ partly mediated the ESR-psychosis relationships. CONCLUSIONS: Lower IQ is associated with low-grade systemic inflammation and with an increased risk of schizophrenia and ONAP in adulthood. Low-grade inflammation may influence schizophrenia risk by affecting neurodevelopment. Future studies should explore the differential effects of inflammation on different types of psychosis. PMID- 29622047 TI - A randomised active-controlled trial to examine the effects of an online mindfulness intervention on executive control, critical thinking and key thinking dispositions in a university student sample. AB - BACKGROUND: Arguments for including mindfulness instruction in higher education have included claims about the benefits of mindfulness practice for critical thinking. While there is theoretical support for this claim, empirical support is limited. The aim of this study was to test this claim by investigating the effects of an online mindfulness intervention on executive function, critical thinking skills and associated thinking dispositions. METHOD: Participants recruited from a university were randomly allocated, following screening, to either a mindfulness meditation group or a sham meditation group. Both the researchers and the participants were blind to group allocation. The intervention content for both groups was delivered through the Headspace online application, an application which provides guided meditations to users. Both groups were requested to complete 30 guided mindfulness meditation sessions across a 6 week period. Primary outcome measures assessed mindfulness, executive functioning, critical thinking, actively open-minded thinking and need for cognition. Secondary outcome measures assessed wellbeing, positive and negative affect, and real-world outcomes. RESULTS: In a series of full-information maximum likelihood analyses, significant increases in mindfulness dispositions and critical thinking scores were observed in both the mindfulness meditation and sham meditation groups. However, no significant effects of group allocation were observed for either primary or secondary measures. Furthermore, mediation analyses testing the indirect effect of group allocation through executive functioning performance did not reveal a significant result and moderation analyses showed that the effect of the intervention did not depend on baseline levels of the key thinking dispositions, actively open-minded thinking and need for cognition. CONCLUSION: No evidence was found to suggest that engaging in guided mindfulness practice for 6 weeks using the online intervention method applied in this study improves critical thinking performance. While further research is warranted, claims regarding the benefits of mindfulness practice for critical thinking should be tempered in the meantime. TRIAL REGISTRATION: The study was initially registered in the AEA Social Science Registry before the recruitment was initiated (RCT ID: AEARCTR-0000756; 14/11/2015) and retrospectively registered in the ISRCTN registry ( RCT ID: ISRCTN16588423 ) in line with requirements for publishing the study protocol. PMID- 29622049 TI - Socio-Cultural Challenges of Family Planning Initiatives for Displaced Populations in Conflict Situations and Humanitarian Settings. AB - Provision of family planning services for refugee populations in conflict and humanitarian settings has been improving. Availability of services, however, does not translate into acceptability and uptake; understanding socio-cultural settings and barriers is critical to ensure utilization of services. Misconceptions and apprehensions surrounding family planning services are common. Populations may see limiting pregnancies as counterproductive in light of high child mortality or suspicious in the context of ethnic violence; larger family size has the perceived advantage of additional security for the community or ethnic group, assistance with family duties in a subsistence structure, and a social service investment for parents as they age; and there may be religious and moral objections to contraception. Any service planning and implementation must take into account community perceptions and address socio-cultural contextual subtleties. Ongoing community education via local initiatives from within the refugee community, region-wide structural strategies for service implementation and sustainability, and efforts to reconcile reproductive rights and family planning services within the religious and social context are crucial. (Disaster Med Public Health Preparedness. 2018;page 1 of 5). PMID- 29622050 TI - Amygdala-prefrontal connectivity during appraisal of symptom-related stimuli in obsessive-compulsive disorder. AB - BACKGROUND: Cognitive models of obsessive-compulsive disorder (OCD) posit dysfunctional appraisal of disorder-relevant stimuli in patients, suggesting disturbances in the processes relying on amygdala-prefrontal connectivity. Recent neuroanatomical models add to the traditional view of dysfunction in corticostriatal circuits by proposing alterations in an affective circuit including amygdala-prefrontal connections. However, abnormalities in amygdala prefrontal coupling during symptom provocation, and particularly during conditions that require stimulus appraisal, remain to be demonstrated directly. METHODS: Amygdala-prefrontal connectivity was examined in unmedicated OCD patients during appraisal (v. distraction) of symptom-provoking stimuli compared with an emotional control condition. Subsequent analyses tested whether hypothesized connectivity alterations could be also identified during passive viewing and the resting state in two independent samples. RESULTS: During symptom provocation, reductions in positive coupling between amygdala and orbitofrontal cortex were observed in OCD patients relative to healthy control participants during appraisal and passive viewing of OCD-relevant stimuli, whereas abnormally high amygdala-ventromedial prefrontal cortex coupling was found when appraisal was distracted by a secondary task. In contrast, there were no group differences in amygdala connectivity at rest. CONCLUSIONS: Our finding of abnormal amygdala prefrontal connectivity during appraisal of symptom-related (relative to generally aversive) stimuli is consistent with the involvement of affective circuits in the functional neuroanatomy of OCD. Aberrant connectivity can be assumed to impact stimulus appraisal and emotion regulation, but might also relate to fear extinction deficits, which have recently been described in OCD. Taken together, we propose to integrate abnormalities in amygdala-prefrontal coupling in affective models of OCD. PMID- 29622051 TI - Infectious Complications of Cryoablation and Microwave Ablation in Metastatic Solid Tumors. AB - Cryoablation and microwave ablation are commonly used techniques to reduce tumor burden in unresectable neoplasms. This retrospective study demonstrated low risk for infectious complications (1.4%) following these invasive procedures. Abscess formation was the most common infection around the ablation sites. All infections were successfully treated with imaging-guided drainage and antibiotics.Infect Control Hosp Epidemiol 2018;39:723-726. PMID- 29622052 TI - Ketamine as the anaesthetic for electroconvulsive therapy: the KANECT randomised controlled trial - CORRIGENDUM. AB - SummaryThis notice describes a correction to the above mentioned paper. PMID- 29622053 TI - Risks, Health Consequences, and Response Challenges for Small-Island-Based Populations: Observations From the 2017 Atlantic Hurricane Season. AB - ABSTRACTThe intensely active 2017 Atlantic basin hurricane season provided an opportunity to examine how climate drivers, including warming oceans and rising seas, exacerbated tropical cyclone hazards. The season also highlighted the unique vulnerabilities of populations residing on Small Island Developing States (SIDS) to the catastrophic potential of these storms. During 2017, 22 of the 29 Caribbean SIDS were affected by at least one named storm, and multiple SIDS experienced extreme damage. This paper aims to review the multiplicity of storm impacts on Caribbean SIDS throughout the 2017 season, to explicate the influences of climate drivers on storm formation and intensity, to explore the propensity of SIDS to sustain severe damage and prolonged disruption of essential services, to document the spectrum of public health consequences, and to delineate the daunting hurdles that challenged emergency response and recovery operations for island-based, disaster-affected populations. (Disaster Med Public Health Preparedness. 2018;page 1 of 13). PMID- 29622054 TI - Do children go for the nice guys? The influence of speaker benevolence and certainty on selective word learning. AB - This study investigated how speaker certainty (a rational cue) and speaker benevolence (an emotional cue) influence children's willingness to learn words in a selective learning paradigm. In two experiments four- to six-year-olds learnt novel labels from two speakers and, after a week, their memory for these labels was reassessed. Results demonstrated that children retained the label-object pairings for at least a week. Furthermore, children preferred to learn from certain over uncertain speakers, but they had no significant preference for nice over nasty speakers. When the cues were combined, children followed certain speakers, even if they were nasty. However, children did prefer to learn from nice and certain speakers over nasty and certain speakers. These results suggest that rational cues regarding a speaker's linguistic competence trump emotional cues regarding a speaker's affective status in word learning. However, emotional cues were found to have a subtle influence on this process. PMID- 29622055 TI - A comparison of work stressors in higher and lower resourced emergency medicine health settings. AB - CLINICIAN'S CAPSULE What is known about the topic? Emergency physicians and trainees have high rates of stress and burnout. What did this study ask? How do reported stressors for emergency physicians and trainees differ between high and low resource settings? What did this study find? Trainees in the low resource setting reported higher stressors. Trainees reported higher levels of stressors than specialists in general. Why does this study matter to clinicians? High levels of reported stressors among trainees, and in low resource settings should be acknowledged and mitigated where possible. PMID- 29622056 TI - Psychosocial and health-related risk factors for depressive symptom trajectories among midlife women over 15 years: Study of Women's Health Across the Nation (SWAN). AB - BACKGROUND: Psychosocial and health-related risk factors for depressive symptoms are known. It is unclear if these are associated with depressive symptom patterns over time. We identified trajectories of depressive symptoms and their risk factors among midlife women followed over 15 years. METHODS: Participants were 3300 multiracial/ethnic women enrolled in a multisite longitudinal menopause and aging study, Study of Women's Health Across the Nation. Biological, psychosocial, and depressive symptom data were collected approximately annually. Group-based trajectory modeling identified women with similar longitudinal patterns of depressive symptoms. Trajectory groups were compared on time-invariant and varying characteristics using multivariable multinomial analyses and pairwise comparisons. RESULTS: Five symptom trajectories were compared (50% very low; 29% low; 5% increasing; 11% decreasing; 5% high). Relative to whites, blacks were less likely to be in the increasing trajectory and more likely to be in the decreasing symptom trajectory and Hispanics were more likely to have a high symptom trajectory than an increasing trajectory. Psychosocial/health factors varied between groups. A rise in sleep problems was associated with higher odds of having an increasing trajectory and a rise in social support was associated with lower odds. Women with low role functioning for 50% or more visits had three times the odds of being in the increasing symptom group. CONCLUSIONS: Changes in psychosocial and health characteristics were related to changing depressive symptom trajectories. Health care providers need to evaluate women's sleep quality, social support, life events, and role functioning repeatedly during midlife to monitor changes in these and depressive symptoms. PMID- 29622057 TI - A longitudinal study on psychosocial causes and consequences of Internet gaming disorder in adolescence. AB - BACKGROUND: In 2013, Internet gaming disorder (IGD) was incorporated in the current version of the DSM-5. IGD refers to a problematic use of video games. Longitudinal studies on the etiology of IGD are lacking. Furthermore, it is currently unclear to which extent associated psychopathological problems are causes or consequences of IGD. In the present survey, longitudinal associations between IGD and adolescent and parental mental health were investigated for the first time, as well as the temporal stability of IGD. METHODS: In a cross-lagged panel design study, family dyads (adolescent with a parent each) were examined in 2016 (t1) and again 1 year later (2017, t2). Overall, 1095 family dyads were assessed at t1 and 985 dyads were re-assessed at t2 with standardized measures of IGD and several aspects of adolescent and parental mental health. Data were analyzed with structural equation modeling (SEM). RESULTS: Male gender, a higher level of hyperactivity/inattention, self-esteem problems and IGD at t1 were predictors of IGD at t2. IGD at t1 was a predictor for adolescent emotional distress at t2. Overall, 357 out of the 985 adolescents received a diagnosis of IGD at t1 or t2: 142 (14.4%) at t1 and t2, 100 (10.2%) only at t1, and 115 (11.7%) only at t2. CONCLUSIONS: Hyperactivity/inattention and self-esteem problems seem to be important for the development of IGD. We found first empirical evidence that IGD could prospectively contribute to a deterioration of adolescent mental health. Only a subgroup of affected adolescents showed IGD consistently over 1 year. PMID- 29622058 TI - Association of health literacy with type 2 diabetes mellitus self-management and clinical outcomes within the primary care setting of Iran. AB - This study explores the potential association of health literacy with type 2 diabetes mellitus (T2DM) self-management and clinical outcomes in the primary care setting of Iran. A total of 347 T2DM patients, mostly female (52.4%), 50 years old or younger (63.1%), unemployed (53.6%) and rural residents (55.6%) participated in this study. Most of the respondents had type 2 diabetes mellitus (T2DM) for 2-5 years (63.1%) and did not receive any T2DM education (52.2%). Approximately 19.0% were hospitalised due to uncontrolled T2DM. Participants mainly found managing T2DM self-management behaviours difficult. Approximately half of the participants had poor fasting blood sugar (FBS) (47.0%) and haemoglobin A1c (HbA1c) (59.4%) control and were overweight or obese (77.6%). The level of health literacy was poor and most of the participants had difficulties reading hospital materials (66.0%), understanding medical materials (62.5%) and engaging in medical conversations (63.7%). Health literacy could predict 22.5% variance in difficulty of T2DM self-management and 3.8-23.3% variance in T2DM clinical outcomes after controlling for sociodemographic factors. Participants with higher health literacy were more likely to find managing T2DM less challenging and their clinical outcomes were within the normal range. This implies that interventions targeting patient's health literacy can be a promising tool for addressing the burden of T2DM. PMID- 29622059 TI - Combined oral contraceptives promote androgen receptor and oestrogen receptor alpha upregulation in the female prostate (Skene. AB - The aim of this study was to evaluate the effects of cyproterone acetate (CPA) and ethinyloestradiol (EE) alone or in combination on the female prostate of adult gerbils. Adult females were exposed for 21 days to daily oral doses of CPA (1mgkg-1), EE (10ugkg-1) or a combination of CPA and EE. Female prostatic complexes were removed, weighed and subjected to morphological, stereological, immunohistochemical and ultrastructural analyses. CPA treatment caused epithelial atrophy and decreased prostate secretory activity. The EE treatment group showed glandular hyperplasia, a high cell-proliferation index and an increase in androgen and oestrogen receptor alpha (AR and ERalpha) immunoreactivity. Combined treatment (CPA+EE) caused adverse effects, such as an increase in cell proliferation, higher AR and ERalpha immunoreactivity, prostatic intraepithelial neoplasia, cell degeneration and aging. In conclusion, the CPA-only treatment promoted antiandrogenic effects on the female gerbil prostate, whereas EE-only had a potent oestrogenic activity. However, when combined, EE overlapped the effects of CPA, changing the pattern of glandular hormonal regulation and stimulating the development of prostatic lesions in female gerbils. PMID- 29622060 TI - Partners in Recovery: paving the way for the National Disability Insurance Scheme. AB - Australians experiencing severe and persistent mental illness and who require services from multiple agencies, experience a fragmented service delivery system. In 2014, the Commonwealth Government introduced the Partners in Recovery (PIR) service, which provides service coordination and flexible funding to improve outcomes for this group of people. This study presents qualitative findings from a research project that aimed to understand the experiences of PIR participants, including aspects of the planning process and the effectiveness of the PIR program in meeting their needs from the perspective of the participant, their carer or family member and other support people within their lives. Semi structured interviews were conducted with 31 stakeholders involved in the PIR program, of which 14 were participants, 17 were members of the participant's support network and three were members of a consumer and carer advisory group. Overall participation in the PIR program had a positive effect on the participant's lives. Relationships with the support facilitators were seen as an important element of the process, along with a focus on recovery-oriented goals and advocacy and linking to other agencies. These findings are important for informing the roll-out of the National Disability Insurance Scheme in Australia, which will replace PIR. PMID- 29622062 TI - ? PMID- 29622061 TI - Supporting primary care nurses to work at an advanced level through changing practices' organisational governance. AB - General practice nurses wishing to develop their careers in general practice are often unsupported, relying on the culture of individual practices. Given the structural diversity of Australian general practice, we qualitatively explored staff experiences of organisational governance, what supports are in place and can be used to assist nurses to advance. Semi-structured interviews with 28 staff (including nurses, GPs, receptions and practice managers) were undertaken across three practices, as part of a case-study approach. It was found that general practice staff know little of organisational governance and how it may be harnessed. Practical and flexible organisational governance were the most important factors in supporting general practice nurses to develop and utilise nursing skills, but advocacy from medical colleagues was necessary to support advancement. Barriers include funding structures, non-supportive cultures and inflexible organisational governance structures. Organisation governance has the potential to assist nurses to work at an advanced level, but significant financial, structural and cultural barriers may be too difficult for organisational governance resources alone to overcome. In addition to utilising resources, it may be useful for general practices to undertake a review of how they function as a team and reflect upon their practice culture. PMID- 29622063 TI - ? PMID- 29622064 TI - [Diagnosis of seizures in the neonatal period]. AB - Seizures in the neonatal period are practically always a symptom of an underlying illness. Quick diagnosis and treatment can be crucial to the outcome. A few aetiological factors account for most of the seizures. However, a significant number is caused by rare conditions such as metabolic or genetic disorders, and arriving at the right diagnosis can be challenging. Previous studies indicate, that a standardized algorithm clearly improves the diagnostic success. This article presents an overview of aetiological factors and an algorithm for a standardized work-up. PMID- 29622065 TI - [Endoscopic ultrasonography in tumour staging of colonic cancer]. AB - Tumour staging of colonic cancer has become increasingly important due to advancements in minimally invasive surgical techniques and potential benefits of neoadjuvant treatments for advanced but operable tumours. Selection of patients for the latter is based on CT-scans although the staging quality of this image modality is widely debated. Endoscopic ultrasonography (EUS) has not routinely been used for staging colonic cancer. This article presents the current knowledge of EUS for T-staging of colonic cancers and discusses the rationale for its supplement to routine CT-scans in selected patients. PMID- 29622066 TI - [Preimplantation genetic diagnosis]. AB - In Denmark, preimplantation genetic diagnosis (PGD) is offered within the public healthcare to families with a known risk of an inherited disease in a child - as an alternative to prenatal diagnosis. It is a well-established technique with rather well-described perinatal- and neonatal outcomes, being comparable to what is seen following in vitro fertilization/intracytoplasmic sperm injection (IVF/ICSI). The most common strategy is now to perform trophectoderm biopsy and then vitrify, while the diagnostic test is performed. Until 2013, 134 children have been born following PGD. Today, the clinical pregnancy rates are comparable to those following IVF/ICSI. PMID- 29622067 TI - [Lipschutz ulcus as a differential diagnosis of vulvar ulcus]. AB - Lipschutz ulcus (LU) is a rare and probably underdiagnosed non-venereal disease, which usually presents in young women. It is characterised by an acute onset of influenza-like symptoms with painful, necrotic ulcerations on the vulva or lower vagina, and the aetiology and pathogenesis is unknown. The diagnosis is clinical after exclusion of other causes of vulvar ulcers. LU heals spontaneously within 4 6 weeks, and treatment is mainly symptomatic. PMID- 29622068 TI - [Renal venous thrombosis as a complication of nephrotic syndrome]. AB - Venous thromboembolism is a very common complication of nephrotic syndrome (NS). This case report concerns a 19-year-old male, who had known NS and was admitted two times in a short period, first presenting with recurrent symptoms of NS and later with an acute abdomen, which was diagnosed as renal venous thrombosis (RVT) and pulmonary thromboembolism. The patient was treated with prednisolone and therapeutic doses of dalteparin and warfarin. Venous thrombosis, particularly RVT and pulmonary thromboembolism, should be considered in patients with NS. PMID- 29622069 TI - [Neurogenic autonomic dysfunction in primary amyliodosis]. AB - Neurogenic autonomic dysfunction (NAD) and polyneuropathy occur in common conditions like diabetes and alcoholism. However, it can also be seen in rare diseases like in this case report of amyloid light-chain amyloidosis: primary amyloidosis. A 56-year-old man presented with polyneuropathy, a sympathetic dysfunction causing orthostatic intolerance, syncope, parasympathetic dysfunction and involvement of the enteric nervous system. The report illustrates, that routine screening can be insufficient in diagnosing amyloidosis. NAD and polyneuropathy without clear aetiology may require a multidisciplinary elucidation of more rare diseases. PMID- 29622070 TI - Management of Incidental Lung Nodules: Current Strategy and Rationale. AB - Incidentally detected lung nodules are increasingly common in routine diagnostic computed tomography (CT) imaging. Formal management recommendations for incidental nodules, such as those outlined by the Fleischner Society, must therefore reflect a balance of malignancy risk and the clinical context in which nodules are discovered. Nodule size, attenuation, morphology, and location all influence the likelihood of malignancy and, thus, the necessity and timing of follow-up according to current Fleischner recommendations. As technological advancements in CT imaging continue, there may be greater reliance on advanced computerized analysis of lung nodule features to help determine the risk of clinically significant disease. PMID- 29622071 TI - Pulmonary Nodule Management in Lung Cancer Screening: A Pictorial Review of Lung RADS Version 1.0. AB - The number of screening-detected lung nodules is expected to increase as low-dose computed tomography screening is implemented nationally. Standardized guidelines for image acquisition, interpretation, and screen-detected nodule workup are essential to ensure a high standard of medical care and that lung cancer screening is implemented safely and cost effectively. In this article, we review the current guidelines for pulmonary nodule management in the lung cancer screening setting. PMID- 29622072 TI - Missed Lung Cancer. AB - The chest radiograph is one of the most commonly used imaging studies and is the modality of choice for initial evaluation of many common clinical scenarios. Over the last two decades, chest computed tomography has been increasingly used for a wide variety of indications, including respiratory illnesses, trauma, oncologic staging, and more recently lung cancer screening. Diagnostic radiologists should be familiar with the common causes of missed lung cancers on imaging studies in order to avoid detection and interpretation errors. Failure to detect these lesions can potentially have serious implications for both patients as well as the interpreting radiologist. PMID- 29622073 TI - Lung Cancer Biopsies. AB - Image-guided percutaneous transthoracic needle biopsy (PTNB) is a well established and minimally invasive technique for evaluating pulmonary nodules. Implementation of a national lung screening program and increased use of chest computed tomography have contributed to the frequent identification of indeterminate pulmonary nodules that may require tissue sampling. The advent of biomarker-driven lung cancer therapy has led to increased use of repeat PTNB after diagnosis. Percutaneous insertion of markers for preoperative localization of small nodules can aid in minimally invasive surgery and radiation treatment planning. This article discusses PTNB, patient selection, and biopsy technique, including minimizing and managing complications. PMID- 29622074 TI - Tumor Staging of Lung Cancer: Essential Concepts for the Radiologist. AB - Several important modifications have been proposed for the tumor (T) descriptor for lung cancers. New size cutoffs have been determined and there are new T descriptors for adenocarcinoma in situ, minimally invasive adenocarcinoma, and part-solid adenocarcinomas with a solid component > 0.5 cm to 3 cm (T1a, T1b, T1c). There are also recommendations for multifocal adenocarcinoma, which are classified by the lesion with the highest level T descriptor, and the number of lesions is indicated. Knowledge of these changes is important in the appropriate clinical staging of patients with lung cancer. PMID- 29622075 TI - Staging Lung Cancer: Regional Lymph Node Classification. AB - This article reviews regional lymph node assessment in lung cancer. In the absence of a distant metastasis, the absence or location of lung cancer spread to a regional mediastinal lymph node affects treatment options and prognosis. Regional lymph node maps have been created to standardize assessment of the N descriptor. The International Association for the Study of Lung Cancer lymph node map is used for the standardization of N descriptor assessment. CT, PET/CT with fluorodeoxyglucose, endobronchial ultrasound-guided and/or esophageal ultrasound guided biopsy, and mediastinoscopy are common modalities used to determine the N descriptor. PMID- 29622076 TI - Staging Lung Cancer: Metastasis. AB - The updated eighth edition of the tumor, node, metastasis (TNM) classification for lung cancer includes revisions to T and M descriptors. In terms of the M descriptor, the classification of intrathoracic metastatic disease as M1a is unchanged from TNM-7. Extrathoracic metastatic disease, which was classified as M1b in TNM-7, is now subdivided into M1b (single metastasis, single organ) and M1c (multiple metastases in one or multiple organs) descriptors. In this article, the rationale for changes in the M descriptors, the utility of preoperative staging with PET/computed tomography, and the treatment options available for patients with oligometastatic disease are discussed. PMID- 29622077 TI - Dilemmas in Lung Cancer Staging. AB - The advent of the 8th edition of the lung cancer staging system reflects a further meticulous evidence-based advance in the stratification of the survival of patients with lung cancer. Although addressing many limitations of earlier staging systems, several limitations in staging remain. This article reviews from a radiological perspective the limitations of the current staging system, highlighting the process of TNM restructuring, the residual issues with regards to the assignment of T, N, M descriptors, and their associated stage groupings and how these dilemmas impact guidance of multidisciplinary teams taking care of patients with lung cancer. PMID- 29622078 TI - Update of MR Imaging for Evaluation of Lung Cancer. AB - Since MR imaging was introduced for the assessment of thoracic and lung diseases, various limitations have hindered its widespread adoption in clinical practice. Since 2000, various techniques have been developed that have demonstrated the usefulness of MR imaging for lung cancer evaluation, and it is now reimbursed by health insurance companies in many countries. This article reviews recent advances in lung MR imaging, focusing on its use for lung cancer evaluation, especially with regard to pulmonary nodule detection, pulmonary nodule and mass assessment, lung cancer staging and detection of recurrence, postoperative lung function prediction, and therapeutic response evaluation and prediction. PMID- 29622079 TI - Lung Cancer: Posttreatment Imaging: Radiation Therapy and Imaging Findings. AB - In this review, we discuss the different radiation delivery techniques available to treat non-small cell lung cancer, typical radiologic manifestations of conventional radiotherapy, and different patterns of lung injury and temporal evolution of the newer radiotherapy techniques. More sophisticated techniques include intensity-modulated radiotherapy, stereotactic body radiotherapy, proton therapy, and respiration-correlated computed tomography or 4-dimensional computed tomography for radiotherapy planning. Knowledge of the radiation treatment plan and technique, the completion date of radiotherapy, and the temporal evolution of radiation-induced lung injury is important to identify expected manifestations of radiation-induced lung injury and differentiate them from tumor recurrence or infection. PMID- 29622080 TI - Targeted Therapy and Immunotherapy in the Treatment of Non-Small Cell Lung Cancer. AB - The treatment strategy in advanced non-small cell lung cancer (NSCLC) has evolved from empirical chemotherapy to a personalized approach based on histology and molecular markers of primary tumors. Targeted therapies are directed at the products of oncogenic driver mutations. Immunotherapy facilitates the recognition of cancer as foreign by the host immune system, stimulates the immune system, and alleviates the inhibition that allows the growth and spread of cancer cells. The authors describes the role of targeted therapy and immunotherapy in the treatment of NSCLC, patterns of disease present on imaging studies, and immune-related adverse events encountered with immunotherapy. PMID- 29622081 TI - Imaging of Lung Cancer: Update on Screening, Staging, and Therapy. PMID- 29622082 TI - Retinal organotypic culture - A candidate for research on retinas. AB - Reliable disease models are essential for investigations on mechanisms and therapies. The Retinal organotypic culture can maintain the architecture and cellular connections within the tissue in vitro. The system is a refined retinal experiment platform. It narrows the gap between cell line studies and in vivo models and is flexible enough for sophisticated experimental procedures. It greatly reduces the consumption of time or resources. Retinas of many species in various development stages have been used for diverse explorations based on their morphologies and physical characteristics. But the culture time course and the viability of the cultured tissue restrict the utility of the system. Recently, researchers have made increasing attempts to improve the culture conditions and applications of this systems for retina experiments in vitro. Accordingly, there is a great need for a comprehensive summary of these systems for researchers seeking proper in vitro models. In this review, we clarify several key points for the culture procedure and summarize its utility in retinal research. PMID- 29622084 TI - Morphologic variations in the pineal gland of the albino rat after a chronic alcoholisation process. AB - We studied the effect of alcohol on the pineal gland of 48 male Wistar rats. Animals were divided into control and experimental groups. The experimental group underwent a previous progressive alcoholisation period with ethanol diluted in water at a concentration of 40%. Animals were sacrificed at 3, 6, 9 and 12 months, and the ultrastructure, karyometric indices, and number of synaptic bodies in the pineal gland were analysed. The results showed progressive morphologic alterations in the ethanol-treated animals, which culminated in fatty degeneration of the pineal parenchyma after 6 months. The karyometric indices decreased in both the central and peripheral areas compared with the control group. Moreover, the seasonal rhythmicity observed in the controls disappeared in the experimental groups, whose number of different populations of synaptic bodies (synaptic ribbons and synaptic spherules) considerably lowered with inversion of their normal seasonal rhythm. These results support that chronic alcoholisation leads to fatty degeneration of the pineal parenchyma, and a considerable alteration in nuclear functional rhythms and synaptic bodies. PMID- 29622083 TI - Role of drug transporters and heat shock proteins during ethanol exposure to human neural precursor cells and its lineages. AB - INTRODUCTION: Ethanol exposure to developing brain may alter the growth and differentiation of neurological cells resulting in unfavorable pathologies. Earlier studies have provided very limited mechanistic insights of cellular and molecular mechanisms which do not mimic with human situation due to varying cell types and poses potential challenges for investigation. Therefore, the present study was undertaken to evaluate the role of ABC transporters and heat shock proteins mediated response in human neural precursor cells (NPCs) and its lineages during proliferation and lineage differentiation against ethanol exposure. METHODS: Effect of ethanol exposure was examined for neuronal cell survival and variation in cellular phenotype during neurospheres development and lineage differentiation. Generation of reactive oxygen species, and variation in cell cycle was identified along with transcriptional profiling for pluripotent markers (Nestin, NCAM, Sox-2, and Notch-2), drug transporters (ABCB1 and ABCG2) and stress protein (HSP70) during ethanol exposure. RESULTS: ABC transporters as well as HSP70 mRNA expression was higher during proliferation as compared to differentiation with chronic ethanol (1 M) exposure (p < 0.01). Ethanol exposure resulted in higher variability in size and shape of developing neurospheres and decreased ability to form new neurosphere colonies. Significant changes were observed in dendrite development due to late ethanol exposure (p < 0.0001). CONCLUSION: The present study demonstrated significant role of ABC transporters and HSP70 proteins in providing defense against ethanol-induced damage in human neurological cells. However, the over-expression of ABC transporter and HSP-70 proteins during such pathological conditions do not provide complete defense and additional strategies are required to repair the damage. PMID- 29622085 TI - L. inermis-loaded nanofibrous scaffolds for wound dressing applications. AB - Since ancient times, some herbal medicines have been extensively used for burn and wound treatments, showing preference to the common synthetic medications by virtue of having less side effects and faster healing rate. In this study, hybrid nanofibrous scaffolds of poly-l-lactic-acid (PLLA) and gelatin incorporated L. inermis were fabricated via electrospinning technique. Morphology and characteristics of the scaffolds were studied by scanning electron microscopy (SEM) and Fourier transform infrared (FTIR), respectively. The release profile of the L. inermis from the nanofibers was also assessed in vitro. Moreover, the structural stability of the released L. inermis from the nanofibers was evaluated using high-performance liquid chromatography (HPLC). The nanofibers showed a gradual release of L. inermis up to two days while the intact structure was preserved. Furthermore, antibacterial assay demonstrated that L. inermis-loaded nanofibrous scaffolds could effectively kill E. coli and S. aureus within 2 h. Finally, biocompatibility of the nanofibers was proven on 3T3 fibroblasts. Therefore, the L. inermis loaded PLLA-Gelatin nanofibers showed a potential application as a wound dressing in order to control wound infections. PMID- 29622086 TI - High Kpnbeta1 expression promotes non-small cell lung cancer proliferation and chemoresistance via the PI3-kinase/AKT pathway. AB - Karyopherin beta1 (Kpnbeta1), also known as importin-beta, is part of the karyopherin superfamily of nuclear transport proteins. Kpnbeta1 is an oncogene that is overexpressed in various human cancers. Recent studies have showed that Kpnbeta1 is one of the leading causes of cancer-related deaths in the world. However, the role of Kpnbeta1 in non-small cell lung cancer (NSCLC) remains uncertain. In this study, we used western blotting to show that Kpnbeta1 expression is higher in lung-cancer tissues and cells, and immunohistochemistry analysis revealed that Kpnbeta1 was significantly associated with the clinicopathological features of NSCLC. Kaplan-Meier analysis showed that elevated Kpnbeta1 expression correlated with a poor prognosis in NSCLC patients. Serum starvation-refeeding experiments and Kpnbeta1-shRNA transfection assays revealed that elevated Kpnbeta1 expression promoted cell proliferation and reduced sensitivity to cis-diamminedichloroplatinum. Immunoprecipitation assays showed that Kpnbeta1 interacts with PI3 K to activate the PI3-kinase/AKT pathway, leading to enhanced cell survival and drug resistance in NSCLC cells. Collectively, our findings suggest that Kpnbeta1 plays a significant role in NSCLC progression and chemoresistance. Our study provides new insights for targeted therapy to treat NSCLC. PMID- 29622087 TI - Generation of Venus fluorochrome expressing transgenic handmade cloned buffalo embryos using Sleeping Beauty transposon. AB - The objective of this study was to optimise the electroporation conditions for efficient integration of Venus construct in buffalo fetal fibroblasts using Sleeping Beauty (SB) based transposition and to produce Venus expressing transgenic cloned embryos through handmade cloning (HMC) approach. Primary culture of buffalo fetal fibroblast cells was established and subsequently cultured cells were co-transfected with Venus and helper plasmid at different combinations of electroporation condition. In different combinations of voltage, time and plasmid dose, we observed that 300 V, single pulse for 10 ms in 2 mm cuvette and 1.5-2.0 MUg transposons with 200-300 ng transposase dose was optimum for expressing Venus fluorescence in cells via electroporation. After electroporation, the cells were cultured for 2-3 days and then Venus expressing cells were picked with the help of a Pasteur pipette under the fluorescence microscope to enrich them through single cell culture method before using as donor cells for HMC. In vitro matured oocytes were reconstructed with either transfected or non-transfected buffalo somatic cells by electric fusion followed by activation. The reconstructed, activated embryos were cultured in 400 MUL of Research Vitro Cleave medium supplemented with 1% fatty acid-free BSA in 4-well dish, covered with mineral oil and incubated in an incubator (5% CO2 in air) at 38.5 degrees C for 8 days and the developmental competence was observed. The percentage of cleaved, 4-8 and 8-16 cells stage embryos generated through Venus expressing cells were comparable with control, whereas, the morula (21.0 vs 53.0%) and blastocysts (10.5 vs 30.6%) produced through Venus expressing cells was found low as compared to control. These results indicate that fetal fibroblasts transfected with Venus could be used as donor cells for buffalo cloning and that Venus gene can be safely used as a marker of foreign gene in buffalo transgenesis. PMID- 29622088 TI - Re-description of the sperm morphology of Dalbulus maidis (Hemiptera: Cicadellidae: Deltocephalinae). AB - The corn leafhopper, Dalbulus maidis, which is one of the most important vectors of maize diseases, had the morphology of its spermatozoa described more than 40 years ago. However, the description is imprecise, requiring certain rectifications. Hence, we re-describe the sperm morphology of this species using light microscopy and transmission electron microscopy. Their spermatozoa measured from 118.1 to 128.5 MUm in length, this value being about three times smaller than what was previously described. The head region is formed by a small acrosome and the nucleus. The acrosome is paracrystalline and has the bifurcated base that is docked in two cavities on one side of the anterior region of the nucleus. The nucleus, which is linear and thin, measured from 19.3 to 22.9 MUm in length, and exhibited homogeneously compact chromatin. In cross-section, it has a thumbtack shape, except in the anterior and posterior regions, where it is oval. The flagellum consists of an axoneme with 9 + 9 + 2 microtubules, two similar mitochondrial derivatives, two accessory bodies each associated with a small sub ellipsoidal structure, and a 'center-flagellar material'. In all the spermatozoa observed, the final portion of the flagellum was branched into four filaments. Some of these morphological features are now being re-described, while others have been observed for the first time in the Cicadellidae family, as the center flagellar material. PMID- 29622089 TI - Gross anatomy and ultrastructure of Moorish Gecko, Tarentola mauritanica skin. AB - The epidermis of Tarentola mauritanica in the skin regions of back, flank and belly has been described using light and electron microscopy. This animal model was useful to give an insight of the functional pattern involved in pigmentation, cryptism and photosensitivity. Skin from back and flanks, in electron microscopy, shows a high concentration of chromatophores, among those melanophores, xanthophores and iridophores have been reported. Interestingly, in the flank-back transition region electron microscopy reveals the presence of nerve endings. Our contribution adds new knowledge about the skin of this species, and it could be useful to study in deep the mechanism of cryptic colour change in reptiles. PMID- 29622090 TI - The effect of 1,25 dihydroxyvitamin D3 on HCl/Ethanol-induced gastric injury in rats. AB - This study evaluated ulceroprotective and antioxidant effect of 1,25 dihydroxyvitamin D3 against gastric damage in rats. Rats were treated intraperitoneally with either 1,25 dihydroxyvitamin D3 (0.25 MUg/kg) or saline for 14 days. On day-15, the non-selective cyclooxygenase inhibitor indomethacin (10 mg/kg; subcutaneously), the inhibitor of sulfhydryl groups N-ethylmaleimide (10 mg/kg; intraperitoneally) or ATP-sensitive K+ channel blocker glibenclamide (10 mg/kg; orally) was given prior to 1,25 dihydroxyvitamin D3. Animals were euthanized at 60 min post ulcerogenic challenge (0.3 M HCl and 60% ethanol (0.2 mL; orally). Stomach and blood were collected for biochemical and histological evaluations. HCl/Ethanol group revealed severely damaged mucous and glandular epithelium with diffuse hemorrhage and inflammatory cell infiltration (microscopic score: 10.67 +/- 0.67 and ulcer index: 33.13 +/- 5.09). 1,25 dihydroxyvitamin D3 decreased the extent of damage (microscopic score: 6.80 +/- 0.02 and ulcer index: 19.00 +/- 4.34; p < 0.05), and the elevations in gastric malondialdehyde level (p < 0.001), myeloperoxidase activity (p < 0.001), nuclear factor-kappaB expression (p < 0.05), and apoptotic index (p < 0.05) following HCl/Ethanol challenge. Decreased gastric glutathione following HCl/Ethanol administration was restored by 1,25 dihydroxyvitamin D3 (p < 0.01). These findings demonstrated protection of the gastric mucosa against HCl/Ethanol induced injury by 1,25 dihydroxyvitamin D3 via attenuation of inflammatory reaction, oxidative stress and apoptosis. PMID- 29622091 TI - Detection of cell proliferation in adults of the water bear Hypsibius dujardini (Tardigrada) via incorporation of a thymidine analog. AB - The taxon Tardigrada, commonly called "water bears", consists of microscopic, eight-legged invertebrates that are well known for their ability to tolerate extreme environmental conditions. Their miniscule body size means that tardigrades possess a small total number of cells, the number and arrangement of which may be highly conserved in some organs. Although mitoses have been observed in several organs, the rate and pattern of cell divisions in adult tardigrades has never been characterized. In this study, we incubated live tardigrades over a period of several days with a thymidine analog in order to visualize all cells that had divided during this time. We focus on the midgut, the largest part of the digestive system. Our results show that new cells in the midgut arise from the anterior and posterior ends of this organ and either migrate or divide toward its middle. These cells divide at a constant rate and all cells of the midgut epithelium are replaced in approximately one week. On the other hand, we found no cell divisions in the nervous system or any other major organs, suggesting that the cell turnover of these organs may be extremely slow or dependent on changing environmental conditions. PMID- 29622092 TI - Hematology and serum biochemistry parameters of captive Chinese alligators (Alligator sinensis) during the active and hibernating periods. AB - The Chinese alligator Alligator sinensis is an endangered freshwater crocodilian species endemic to China. Hematology and serum biochemistry reference range are useful in the assessment and management of animal health condition. In this study, a total of 74 Chinese Alligators (30 males and 44 females) were examined to establish reference range values of hematology and serum biochemistry parameters during the active and hibernating periods. We measured and analyzed 9 hematology and 21 serum biochemistry parameters including 4 serum electrolyte parameters, and described the morphology of different types of blood cells. No statistical differences between the sexes were found for hematology parameter, while significant differences were noted for some serum biochemistry parameters, with males having greater alkaline phosphatase activity level and lower globulin concentration value than females. There were some significant differences between the two different periods with alligators during the active period possessing lower values for mean corpuscular volume, mean corpuscular hemoglobin, total bilirubin and creatine kinase, but higher values for red blood cell and white blood cell counts, monocyte percentage, aspartate aminotransferase, a-amylase, blood urea nitrogen, creatinine, triglycerides, and cholesterol. These baseline data were essential for health condition evaluation and disease diagnosis of this endangered species. PMID- 29622094 TI - Correlation of Online Physician Reviews and Overall Patient Satisfaction. PMID- 29622093 TI - Glycoconjugates pattern and chemosensory cells in the camel respiratory mucosa: Lectin and immunohistochemical studies. AB - The glycoconjugates pattern of acidic secretions and distribution of chemosensory cells (SCCs) in the respiratory mucosa of dromedary camels were analyzed so as to identify their functional role. Secretions of the goblet cells and mucous glandular cells were analyzed to evaluate the variety of sugar chains, focusing on the acidic glycoconjugates. Using lectin histochemistry, WGA, STL, DBA, SBA, VVA and RCA-120 intensely bound to the goblet cells. PNA and ECL labeled the goblet cells with moderate intensity. While, s-WGA, UEA-I faintly bound to them. Lectins bound to the glycocalyx: WGA, LEL, STL, DSL, DBA, SBA, VVA, RCA-120, ECL and PHA-L (tetra- and tri-antennary N-glycans). The mucous secretory cells reacted with: WGA, s-WGA, STL, DBA, SBA, ECL and Con A. Glycoconjugates secreted by the camel respiratory mucosa are rich in sialomucins, glucosaminy-lated residuals with some galactosyl/galactosaminylated residues; few L-fucose and mannosylated sugar residues are also included. For identification of SCCs, the camel respiratory mucosa was immunostained with phospholipase C-beta2 (PLC beta2), a taste signaling marker. Several PLC-beta2 immunoreactive cells were detected in camel respiratory epithelium. Finally, prevalence of sialomucins and SCCs which can respond to noxious chemicals may suggest a vital role in optimizing physiological and pathological reactions in camel respiratory mucosa. PMID- 29622095 TI - Online Physician Reviews Do Not Reflect Patient Satisfaction Survey Responses. AB - Online physician reviews have become increasingly prevalent and are a common means by which patients explore medical options online. Currently, there are no data comparing physicians with negative online reviews and those without negative reviews. We sought to compare industry-vetted patient satisfaction surveys (PSSs), such as Press Ganey (PG) PSSs, between those physicians with negative online reviews and those without negative reviews. Overall, there were 113 unique individuals with negative online reviews from September 1, 2014, to December 31, 2014, with 8 being nonphysicians. We matched 113 physicians in similar departments/divisions. We obtained PG PSS scores of both groups and compared the mean scores of the 2 groups. Press Ganey PSS scores were available for 98 physicians with negative online reviews compared with 82 matched physicians without negative online reviews. The mean raw PG PSS scores were not different between the 2 groups (4.05; 95% CI, 3.99-4.11 vs 4.04; 95% CI, 3.97-4.11; P=.92). We also noted no difference in mean scores on questions related to physician patient communication and interaction skills between those with poor online reviews and those without (4.38; 95% CI, 4.32-4.43 vs 4.41; 95% CI, 4.35-4.47; P=.42). However, there was a significantly lower non-physician-specific mean in those with negative online reviews (3.91; 95% CI, 3.84-3.97) vs those without negative online reviews (4.01; 95% CI, 3.95-4.09) (P=.02). Here, we provide data indicating that online physician reviews do not correlate to formal institutional PG PSS. Furthermore, physicians with negative online reviews have lower scores on non-physician-specific variables included in the PG PSSs, emphasizing that these discrepancies can negatively affect overall patient experience, online physician reviews, and physician reputation. It is prudent that an improved mechanism for online ratings be implemented to better inform patients about a physician's online reputation. PMID- 29622096 TI - Management of Patients With Aortic Valve Stenosis. AB - With increased life expectancy and aging of the population, aortic stenosis is now one of the most common valvular heart diseases. Early recognition and management of aortic stenosis are of paramount importance because untreated symptomatic severe disease is universally fatal. The advent of transcather aortic valve replacement technologies provides exciting avenues of care to patients with this disease in whom traditional surgical procedures could not be performed or were associated with high risk. This review for clinicians offers an overview of aortic stenosis and updated information on the current status of various treatment strategies. An electronic literature search of PubMed, MEDLINE, EMBASE, and Scopus was performed from conception July 1, 2016, through November 30, 2017, using the terms aortic stenosis, aortic valve replacement, transcatheter aortic valve replacement (TAVR), transcatheter aortic valve insertion (TAVI), surgical aortic valve replacement, aortic stenosis flow-gradient patterns, low-flow aortic valve stenosis, natural history, stress testing, pathophysiology, bicuspid aortic valve, and congenital aortic valve disease. PMID- 29622097 TI - Not All That Flattens Villi Is Celiac Disease: A Review of Enteropathies. AB - Enteropathies can be overwhelming for clinicians. There is a wide spectrum of diseases involved; their effect on patients can be severe; and their underlying cause can be obscure. In this article, we outline a practical approach to enteropathies that are most common and not to be missed and is applicable to general and specialist physicians. PMID- 29622098 TI - Diagnosis and Management of Acute Ischemic Stroke. AB - Acute ischemic stroke (AIS) is among the leading causes of death and long-term disability. Intravenous tissue plasminogen activator has been the mainstay of acute therapy. Recently, several prospective randomized trials documented the value of endovascular revascularization in selected patients with large-vessel occlusion within the anterior circulation. This finding has led to a paradigm shift in the management of AIS, including wide adoption of noninvasive neuroimaging to assess vessel patency and tissue viability, with the supplemental and independent use of intravenous tissue plasminogen activator to improve clinical outcomes. In this article, we review the landmark studies on management of AIS and the current position on the diagnosis and management of AIS. The review also highlights the importance of early stabilization and prompt initiation of therapeutic interventions before, during, and after the diagnosis of AIS within and outside of the hospital. PMID- 29622099 TI - Transaxillary Intra-aortic Balloon Pump Placement: A New Approach With Great Potential. PMID- 29622100 TI - Multiple Cranial Neuropathies From Nivolumab in a Patient With Metastatic Hepatocellular Carcinoma. PMID- 29622101 TI - Statin Use Associated With a Decreased Risk of Community-Acquired Staphylococcus aureus Bacteremia. PMID- 29622102 TI - Daratumumab for POEMS Syndrome. PMID- 29622103 TI - In Reply-Statin Use Associated With a Decreased Risk of Community-Acquired Staphylococcus aureus Bacteremia. PMID- 29622104 TI - Physician Burnout: A Leading Indicator of Health Performance and "Head-Down" Mentality in Medical Education-II. PMID- 29622105 TI - Physician Burnout: A Leading Indicator of Health Performance and "Head-Down" Mentality in Medical Education-I. PMID- 29622106 TI - In Reply-Physician Burnout: A Leading Indicator of Health Performance and "Head Down" Mentality in Medical Education-I and II. PMID- 29622107 TI - Inferior Vena Cava: Chronic Total Occlusion. PMID- 29622108 TI - Desmoid Tumor. PMID- 29622109 TI - The Tree by the Lake by Alejos Lorenzo Vergara. AB - Recognizing the contribution art has had in the Mayo Clinic environment since the original Mayo Clinic Building was finished in 1914, Mayo Clinic Proceedings features some of the numerous works of art displayed throughout the buildings and grounds on Mayo Clinic campuses as interpreted by the author. PMID- 29622110 TI - Cross-Sectional Imaging Techniques and Normal Anatomy of the Salivary Glands. AB - The salivary glands play an important role in digestion and oral hygiene, and give rise to a variety of benign and malignant pathologies. In suspected pathology, the goal of imaging is to confirm a lesion as being of salivary gland origin, narrow the list of differential considerations, define the extent of disease, and guide further management decisions. This review outlines the function, embryologic development, anatomy, and normal imaging features of the major salivary glands. The article also discusses imaging indications, the general approach to imaging the salivary glands, and the commonly used cross sectional techniques used for evaluating the salivary gland. PMID- 29622111 TI - Imaging of Benign Neoplastic and Nonneoplastic Salivary Gland Tumors. AB - This article reviews the multimodality diagnostic imaging features of benign neoplastic and nonneoplastic tumors associated with the major salivary glands. Examples of neoplastic conditions that are depicted and discussed include pleomorphic adenoma, Warthin tumor, oncocytoma, peripheral nerve sheath tumors, lipoma, and hemangiomas or hemangioendotheliomas. Examples of nonneoplastic conditions that are depicted and discussed include ranulas, benign lymphoepithelial lesions, Kimura disease, and vascular malformations. Specific imaging and clinical features of these conditions are emphasized in this article. PMID- 29622112 TI - A Review of Salivary Gland Malignancies: Common Histologic Types, Anatomic Considerations, and Imaging Strategies. AB - Major and minor salivary gland malignancies come in various shapes and sizes. They can present as palpable masses or can be detected incidentally when imaging patients for other indications. A complete evaluation of salivary gland malignancies requires knowledge of the anatomy and various routes of spread of neoplasias. Computed tomography (CT) and MR imaging are complementary tools in this respect and offer useful information to the proceduralist. Advanced imaging (diffusion-weighted imaging and PET-CT) and other modalities (eg, ultrasound) help with characterization, although biopsy or excision is often needed for definitive tissue diagnosis. PMID- 29622113 TI - Imaging of Sjogren Syndrome and Immunoglobulin G4-Related Disease of the Salivary Glands. AB - The salivary glands are commonly affected in systemic autoimmune disease and diseases of unknown pathogenesis. Sjogren syndrome (SjS) can be affected by other systemic diseases. Immunoglobulin G4-related disease (IgG4-RD) commonly affects salivary glands. Imaging findings are usually nonspecific; however, radiologists should be familiar with the manifestations to avoid diagnostic delay. Findings of early-stage SjS are difficult to identify on routine computed tomography or MR imaging. Chronic SjS can be diagnosed from MR imaging and sialographic findings. Multiglandular and localized involvement of IgG4-RD is difficult to differentiate from malignant lymphoma for multiglandular disease and salivary gland carcinoma for localized disease. PMID- 29622114 TI - Imaging of Posttreatment Salivary Gland Tumors. AB - The aim of this study is to review the imaging appearance of posttreatment salivary gland tumors. The authors discuss the imaging appearance of parotidectomy and reconstructive surgery of parotid defects. Imaging is important to diagnose tumor recurrence and also assess for complications related to surgery, such as a sialocele, fluid collection, hematoma, pseudoaneurysm, and graft stenosis. The article also provides a current-state assessment of the applications of advanced imaging techniques. PMID- 29622115 TI - Imaging of Pediatric Salivary Glands. AB - Salivary gland diseases in children are uncommon, and the relative incidence of pathologies is different than in adults. This article presents a comprehensive review of congenital and acquired disorders that affect the major salivary glands in the pediatric population, highlighting the imaging findings that are important in defining the appropriate diagnosis or narrowing of the differential diagnosis. PMID- 29622116 TI - Imaging of Submandibular and Sublingual Salivary Glands. AB - The submandibular and sublingual salivary glands are major salivary glands with a wide spectrum of pathologic conditions. The corresponding spaces along the floor of mouth have complex anatomy, best evaluated with cross-sectional imaging. The spectrum of diseases in these regions varies from simple infection to advanced malignancy, not just from the gland itself but also from the surrounding structures. The most common abnormalities in these spaces are inflammatory and infectious, and computed tomography is currently the most common imaging modality used. The anatomy of these spaces is much better depicted with MR; however, all the modalities have their unique roles. PMID- 29622117 TI - Routine and Advanced Diffusion Imaging Modules of the Salivary Glands. AB - This article reviews the role of routine and advanced diffusion imaging modules of the salivary glands. Routine and advanced diffusion imaging modules have a role in differentiation of malignant from benign salivary gland tumors, characterization of some benign salivary gland tumors, and staging of salivary gland cancer. The role of advanced diffusion modules in patients with salivary gland cancer after surgery, radiation therapy, or radioiodine therapy is discussed. Advanced diffusion imaging modules can help in diagnosis and staging of Sjogren syndrome. PMID- 29622118 TI - Imaging of Inflammatory Disorders of Salivary Glands. AB - Sialadenitis is among the most common conditions that affect the salivary glands. Inflammation of the salivary glands occurs as the end result of a variety of pathologic conditions, including infectious, autoimmune, and idiopathic causes. Clinically, inflammation of the salivary gland causes pain and localized swelling. The presentation may be acute or chronic, and can be recurrent. Because there is significant overlap of underlying disease mechanisms and clinical presentations, radiologic evaluation often plays a significant role in evaluation. This article is a brief review of sialadenitis, including disease mechanisms, causes, and the practical imaging of the salivary glands. PMID- 29622119 TI - Routine and Advanced Ultrasound of Major Salivary Glands. AB - Ultrasound is the preferred initial imaging modality in Europe and Asia for assessing the major salivary glands. In experienced hands, it is sensitive for a range of salivary pathologies, often diagnostic, and also a safe, cost-effective gatekeeper for further investigations as well as image-guided diagnostic biopsies and aspirations. This article reviews the scanning technique and normal sonographic anatomy of major salivary glands and overviews typical sonographic appearances of salivary pathologies, including infective and inflammatory conditions, sialolithiasis, and neoplasms. Limitations of ultrasound and the current evidence for advanced techniques, including contrast-enhanced ultrasound and ultrasound elastography, are also discussed. PMID- 29622120 TI - Imaging of Minor Salivary Glands. AB - Neoplastic and non-neoplastic lesions may involve the minor salivary glands. Tumors of minor salivary glands are commonly seen in the oral cavity. Malignant tumors are more common than benign minor salivary gland tumors. The most common malignant tumors are adenoid cystic carcinoma and mucoepidermoid carcinoma, and the most common benign tumor is pleomorphic adenoma. Non-neoplastic lesions may involve minor salivary glands such as Sjogrene disease, immunoglobulin G4-related disease, necrotizing sialometaplasia, and subacute necrotizing sialadenitis. Contrast MR imaging and computed tomography are adequate for localization and extension of neoplastic and non-neoplastic lesions of minor salivary glands. PMID- 29622121 TI - State-of-the-Art Imaging of Salivary Gland Tumors. AB - MR imaging is the modality of choice in evaluation of salivary gland tumors. Postcontrast MR imaging is adequate for exact localization and extension of salivary gland tumors and multiparametric of diffusion-weighted and dynamic contrast-enhanced MR imaging helps in characterization of benign and malignant salivary gland tumors. Imaging is important for preoperative localization, characterization of salivary gland tumors and locoregional extension, perineural spread, and nodal and distant staging of malignant salivary gland tumors. Imaging has a role in detection of tumor recurrence, monitoring patients after therapy, prediction of malignant transformation of benign tumors, and differentiation of salivary gland tumors from simulating inflammatory and autoimmune disorders. PMID- 29622122 TI - Imaging of Salivary Glands. PMID- 29622123 TI - State-of-the-Art Imaging of Salivary Glands Disorders. PMID- 29622124 TI - Breast MR Imaging: Atlas of Anatomy, Physiology, Pathophysiology, and Breast Imaging Reporting and Data Systems Lexicon. AB - The latest edition of the Breast Imaging Reporting and Data Systems lexicon, copyrighted in 2013, contains several changes to the breast MR imaging section. Most changes were implemented to standardize descriptors across breast imaging modalities. New sections on special topics and implant evaluation are included. We review basic MR imaging breast anatomy and a detailed pictorial review of the Breast Imaging Reporting and Data Systems lexicon, including these new sections. In each section we discuss which descriptors are more concerning for malignancy and information radiologists can use to better categorize findings as lower risk or benign. PMID- 29622125 TI - Role of MR Imaging for the Locoregional Staging of Breast Cancer. AB - Breast MR imaging has been shown to identify unsuspected sites of cancer in the ipsilateral breast in 16% of women with newly diagnosed breast cancer. Breast MR imaging identifies occult cancer in the contralateral breast in 3% to 5% of women. Early evidence suggests that the added value of MR imaging for staging may be attenuated in women who also undergo tomosynthesis, particularly those with nondense breasts. Breast MR imaging is complementary to ultrasound imaging in evaluating regional nodal basins. Ongoing prospective randomized clinical trials should clarify the impact of preoperative breast MR imaging on clinical outcomes. PMID- 29622126 TI - Role of MR Imaging in Neoadjuvant Therapy Monitoring. AB - Neoadjuvant chemotherapy (NAC) has become an important treatment approach for stage II/III breast cancers to downsize tumor and enable breast-conserving surgery for patients that may otherwise undergo mastectomy. MR imaging has the potential to identify early response or disease progression, enabling potential modification to NAC regimens. Detection of size and morphologic changes is better appreciated with MR imaging than other modalities and is different between molecular subtypes of breast cancer. The combination of DCE-MR imaging and DWI provides the highest sensitivity and specificity. Other new modalities such as FDG PET/MR imaging and molecular breast imaging are still undergoing research. PMID- 29622127 TI - Problem-Solving MR Imaging for Equivocal Imaging Findings and Indeterminate Clinical Symptoms of the Breast. AB - Breast MR imaging is commonly used for high-risk screening and for assessing the extent of disease in patients with newly diagnosed breast cancer, but its utility for assessing suspicious symptoms and equivocal imaging findings is less widely accepted. The authors review current literature and guidelines regarding the use of breast MR imaging for these indications. Overall, problem-solving breast MR imaging is best reserved for pathologic nipple discharge and sonographically occult architectural distortion with limited biopsy options. Further study is necessary to define the role of problem-solving MR imaging for calcifications, mammographic asymmetries, and surgical scarring. PMID- 29622128 TI - MR Imaging-Guided Breast Interventions: Indications, Key Principles, and Imaging Pathology Correlation. AB - MR imaging is now routinely performed for breast cancer screening and staging. For suspicious MR imaging-detected lesions that are mammographically and sonographically occult, MR imaging-guided breast interventions, including biopsy, clip placement, and preoperative needle localization, have been developed to permit accurate tissue diagnosis and aid in surgical planning. These procedures are safe, accurate, and effective when performed according to key principles, including proper patient selection, use of appropriate technique, adequate preprocedure preparation and postprocedure patient care, and postprocedure imaging-pathology correlation. Imaging-pathology correlation after MR imaging guided biopsy is essential to confirm accurate sampling and guide development of a comprehensive management plan. PMID- 29622129 TI - Developments in Breast Imaging: Update on New and Evolving MR Imaging and Molecular Imaging Techniques. AB - This article reviews new developments in breast imaging. There is growing interest in creating a shorter, less expensive MR protocol with broader applicability. There is an increasing focus on and consideration for the additive impact that functional analysis of breast pathology have on identifying and characterizing lesions. These developments apply to MR imaging and molecular imaging. This article reviews evolving breast imaging techniques with attention to strengths, weaknesses, and applications of these approaches. We aim to give the reader familiarity with the state of current developments in the field and to increase awareness of what to expect in breast imaging. PMID- 29622130 TI - Comparison of Contrast-Enhanced Mammography and Contrast-Enhanced Breast MR Imaging. AB - Contrast-enhanced mammography (CEM) is a contrast-enhanced modality for breast cancer detection that utilizes iodinated contrast and dual-energy imaging performed on a digital mammography unit with only slight modifications. It is approved by the US Food and Drug Administration, commercially available, and in routine clinical use at centers around the world. It has similar sensitivity and specificity to MR Imaging and has advantages in terms of cost, patient acceptability, and examination time. MR Imaging has some advantages compared with CEM, especially in its ability to image the complete axilla and the chest wall. PMID- 29622132 TI - Comparison of Breast MR Imaging with Molecular Breast Imaging in Breast Cancer Screening, Diagnosis, Staging, and Treatment Response Evaluation. AB - Breast MR imaging and molecular breast imaging (MBI) are functional imaging modalities that can be used to noninvasively evaluate the pathophysiology and biology of breast cancer. In the era of personalized medicine, these imaging techniques give clinicians insight into cancer pathobiology and allows them to individualize treatment regimens. Breast MR imaging has gained acceptance for breast cancer evaluation; work is ongoing on validation of MBI for breast cancer evaluation. This article discusses clinical applications of breast MR imaging and MBI, and compares the performance of these techniques in breast cancer screening, diagnosis, staging, and treatment response evaluation. PMID- 29622131 TI - Use of Breast-Specific PET Scanners and Comparison with MR Imaging. AB - The goals of this article are to discuss the role of breast-specific PET imaging of women with breast cancer, compare the clinical performance of positron emission mammography (PEM) and MR imaging for current indications, and provide recommendations for when women should undergo PEM instead of breast MR imaging. PMID- 29622133 TI - How Does MR Imaging Help Care for My Breast Cancer Patient? Perspective of a Surgical Oncologist. AB - MR imaging is now readily available for surgeons to incorporate into their practice, thus, begging the question, is this new modality clinically useful? Current literature and expert opinion are reviewed concerning the implementation of breast MR imaging to clinical management of breast cancer. Although breast MR imaging is acknowledged to be highly sensitive in detection of breast cancer, its routine application to surgical practice remains controversial because these gains in sensitivity have not been demonstrated to translate into improved long term patient outcomes. Current clinical trials and the future of breast MR imaging are also discussed. PMID- 29622134 TI - How Does MR Imaging Help Care for the Breast Cancer Patient? Perspective of a Medical Oncologist. AB - Although traditional assessment with clinical examination, mammogram, and ultrasound is generally accepted for detection and staging of breast cancer, MR imaging is commonly used to detect occult cancers in the breast and regional nodes in the early stage and to determine the extent of disease in patients with metastatic disease. Several studies have shown a variety of uses for MR imaging in the staging of breast cancer and assessment of treatment response in the neoadjuvant (preoperative) setting. This article reviews the impact of MR imaging in different settings on medical oncology decision-making in patients with breast cancer. PMID- 29622135 TI - How Does MR Imaging Help Care for My Breast Cancer Patient? Perspective of a Radiation Oncologist. AB - Radiation therapy is used in many cases of both early and late breast cancer. The authors examine the role of MR imaging as it pertains to radiotherapy planning and treatment approaches for patients with breast cancer. MR imaging can assist the radiation oncologist in determining the best radiation approach and in creating treatment planning volumes. MR imaging may be useful in the setting of accelerated partial breast irradiation. Radiation oncologists should attend to MR breast images, when obtained, to ensure that these imaging findings are taken into consideration when developing a radiation therapy plan. PMID- 29622137 TI - Breast MR Imaging. PMID- 29622138 TI - Breast MR Imaging in Era of Value-Based Medicine. PMID- 29622136 TI - American College of Radiology Accreditation, Performance Metrics, Reimbursement, and Economic Considerations in Breast MR Imaging. AB - Accreditation through the American College of Radiology (ACR) Breast Magnetic Resonance Imaging Accreditation Program is necessary to qualify for reimbursement from Medicare and many private insurers and provides facilities with peer review on image acquisition and clinical quality. Adherence to ACR quality control and technical practice parameter guidelines for breast MR imaging and performance of a medical outcomes audit program will maintain high-quality imaging and facilitate accreditation. Economic factors likely to influence the practice of breast MR imaging include cost-effectiveness, competition with lower-cost breast imaging modalities, and price transparency, all of which may lower the cost of MR imaging and allow for greater utilization. PMID- 29622139 TI - Major depressive disorder: An organic disorder! PMID- 29622140 TI - [Stent-grafts for aortic aneurysms, 25 years later!] PMID- 29622141 TI - Clinical, Angiographic, and Procedural Correlates of Very Late Absorb Scaffold Thrombosis: Multistudy Registry Results. AB - OBJECTIVES: The aim of this study was to identify independent correlates of very late scaffold thrombosis (VLST) from an analysis of consecutively treated patients from 15 multicenter studies. BACKGROUND: Recent analyses suggest an increased risk for VLST with the Absorb Bioresorbable Vascular Scaffold compared with drug-eluting stents, but insights as to correlates of risk are limited. METHODS: A total of 55 patients were identified with scaffold thrombosis. They were matched 2:1 with control subjects selected randomly from patients without thrombosis from the same study. Quantitative coronary angiography was available for 96.4% of patients. Multiple logistic and Cox regression analysis were used to identify significant independent outcome correlates from 6 pre-specified characteristics. RESULTS: Patients had scaffold thrombosis at a median of 20 months (interquartile range: 17 to 27 months). Control subjects were followed for 36 months (interquartile range: 24 to 38 months). For the combined groups, reference vessel diameter (RVD) was 2.84 +/- 0.50 mm, scaffold length was 26 +/- 16 mm, and post-dilatation was performed in 56%. Univariate correlates of thrombosis were smaller nominal scaffold/RVD ratio (linear p = 0.001; ratio <1.18:1; odds ratio: 7.5; p = 0.002) and larger RVD (linear p = 0.001; >2.72 mm; odds ratio: 3.4; p = 0.001). Post-dilatation at >=16 atm, post-dilatation balloon/scaffold ratio, final percentage stenosis, and dual antiplatelet therapy were not correlated with VLST. Only scaffold/RVD ratio remained a significant independent correlate of VLST (p = 0.001), as smaller ratio was correlated with RVD (p < 0.001). Post hoc analysis of 8 other potential covariates revealed no other correlates of outcome. CONCLUSIONS: In the present analysis, the largest to date of its type, relative scaffold undersizing was the strongest determinant of VLST. Given current understanding of "scaffold dismantling," this finding likely has ramifications for all bioresorbable scaffolds. PMID- 29622142 TI - Bioresorbable Vascular Scaffolds: Back to the Drawing Board. PMID- 29622143 TI - Bioresorbable Scaffold for Treatment of Coronary Artery Lesions: Intravascular Ultrasound Results From the ABSORB Japan Trial. AB - OBJECTIVES: The aim of this study was to characterize post-procedural intravascular ultrasound (IVUS) findings in the ABSORB Japan trial, specifically stratified by the size of target coronary arteries. BACKGROUND: Despite overall noninferiority confirmed in recent randomized trials comparing bioresorbable vascular scaffolds (BVS) (Absorb BVS) and cobalt-chromium everolimus-eluting metallic stents (CoCr-EES), higher event rates of Absorb BVS have been reported with suboptimal deployment, especially in small coronary arteries. METHODS: In the ABSORB Japan trial, 150 patients (2:1 randomization) were scheduled in the IVUS cohort. Small vessel was defined as mean reference lumen diameter <2.75 mm. Tapered-vessel lesions were defined as tapering index (proximal/distal reference lumen diameter) >=1.2. RESULTS: Overall, IVUS revealed that the Absorb BVS arm had smaller device expansion than the CoCr-EES arm did, which was particularly prominent in small- and tapered-vessel lesions. Higher tapering index was also associated with higher rates of incomplete strut apposition in Absorb BVS, but not in CoCr-EES. With respect to procedural techniques, small-vessel lesions were treated more frequently with noncompliant balloons at post-dilatation but using significantly lower pressure in the Absorb BVS arm. In contrast, tapered-vessel lesions were post-dilated at equivalent pressure but with significantly smaller balloon catheters in the Absorb BVS arm, compared with the CoCr-EES arm. CONCLUSIONS: The significantly smaller device expansion especially in small vessels may account for the poorer outcomes of Absorb BVS in this lesion type. Appropriate optimization strategy, possibly different between polymeric and metallic devices, needs to be established for bioresorbable scaffold technology. (AVJ-301 Clinical Trial: A Clinical Evaluation of AVJ-301 AbsorbTM BVS) in Japanese Population [ABSORB JAPAN]; NCT01844284). PMID- 29622144 TI - Why Do We Still Tolerate "Suboptimal Deployment"? PMID- 29622146 TI - Percutaneous Coronary Intervention Readmissions: Where Are the Solutions? PMID- 29622145 TI - Burden of 30-Day Readmissions After Percutaneous Coronary Intervention in 833,344 Patients in the United States: Predictors, Causes, and Cost: Insights From the Nationwide Readmission Database. AB - OBJECTIVES: This study aimed to examine the 30-day unplanned readmissions rate, predictors of readmission, causes of readmissions, and clinical impact of readmissions after percutaneous coronary intervention (PCI). BACKGROUND: Unplanned rehospitalizations following PCI carry significant burden to both patients and the local health care economy and are increasingly considered as an indicator of quality of care. METHODS: Patients undergoing PCI between 2013 and 2014 in the U.S. Nationwide Readmission Database were included. Incidence, predictors, causes, and cost of 30-day unplanned readmissions were determined. RESULTS: A total of 833,344 patients with PCI were included, of whom 77,982 (9.3%) had an unplanned readmission within 30 days. Length of stay for the index PCI was greater (4.7 vs. 3.9 days) and mean total hospital cost ($23,211 vs. $37,524) was higher for patients who were readmitted compared with those not readmitted. The factors strongly independently associated with readmissions were index hospitalization discharge against medical advice (odds ratio [OR]: 1.91; 95% confidence interval [CI]: 1.65 to 2.22), transfer to short-term hospital for inpatient care (OR: 1.62; 95% CI: 1.38 to 1.90), discharge to care home (OR: 1.57; 95% CI: 1.51 to 1.64), and chronic kidney disease (OR: 1.50; 95% CI: 1.44 to 1.55). Charlson Comorbidity Index score (OR: 1.28; 95% CI: 1.27 to 1.29) and number of comorbidities (OR: 1.18; 95% CI: 1.17 to 1.18) were independently associated with unplanned readmission. The majority of readmissions were due to noncardiac causes (56.1%). CONCLUSIONS: Thirty-day readmissions after PCI are relatively common and relate to baseline comorbidities and place of discharge. More than one-half of the readmissions were due to noncardiac causes. PMID- 29622147 TI - Transcatheter Laceration of Aortic Leaflets to Prevent Coronary Obstruction During Transcatheter Aortic Valve Replacement: Concept to First-in-Human. AB - OBJECTIVES: This study sought to develop a novel technique called bioprosthetic or native aortic scallop intentional laceration to prevent coronary artery obstruction (BASILICA). BACKGROUND: Coronary artery obstruction is a rare but fatal complication of transcatheter aortic valve replacement (TAVR). METHODS: We lacerated pericardial leaflets in vitro using catheter electrosurgery, and tested leaflet splaying after benchtop TAVR. The procedure was tested in swine. BASILICA was then offered to patients at high risk of coronary obstruction from TAVR and ineligible for surgical aortic valve replacement. BASILICA used marketed devices. Catheters directed an electrified guidewire to traverse and lacerate the aortic leaflet down the center line. TAVR was performed as usual. RESULTS: TAVR splayed lacerated bovine pericardial leaflets. BASILICA was successful in pigs, both to left and right cusps. Necropsy revealed full length lacerations with no collateral thermal injury. Seven patients underwent BASILICA on a compassionate basis. Six had failed bioprosthetic valves, both stented and stent-less. Two had severe aortic stenosis, including 1 patient with native disease, 3 had severe aortic regurgitation, and 2 had mixed aortic valve disease. One patient required laceration of both left and right coronary cusps. There was no hemodynamic compromise in any patient following BASILICA. All patients had successful TAVR, with no coronary obstruction, stroke, or any major complications. All patients survived to 30 days. CONCLUSIONS: BASILICA may durably prevent coronary obstruction from TAVR. The procedure was successful across a range of presentations, and requires further evaluation in a prospective trial. Its role in treatment of degenerated TAVR devices remains untested. PMID- 29622148 TI - Tearing Down the Risk for Coronary Obstruction With Transcatheter Aortic Valve Replacement. PMID- 29622149 TI - Prevalence and Outcomes of Mitral Stenosis in Patients Undergoing Transcatheter Aortic Valve Replacement: Findings From the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapies Registry. AB - OBJECTIVES: This study sought to examine the prevalence of mitral stenosis (MS) and its impact on in-hospital and 1-year clinical outcomes among patients undergoing transcatheter aortic valve replacement (TAVR). BACKGROUND: Patients with coexisting severe aortic stenosis and MS are increasingly being considered for TAVR. METHODS: The study cohort included 44,755 patients (age >=18 years) who underwent TAVR during November 1, 2011, to September 30, 2015, and were registered in Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapies (TVT) Registry. One-year outcomes were assessed by linking TVT registry data of this cohort to patient-specific Centers for Medicare & Medicaid Services administrative claims data (n = 31,453). The primary outcome was the composite of death, stroke, heart failure-related hospitalization, and mitral valve intervention at 1 year. RESULTS: MS was present in 11.6% of cohort (mean age, 82 years; 52% males), being severe in 2.7%. Severe MS was associated with higher in-hospital mortality rates (5.6% vs. 3.9% for nonsevere MS and 4.1% for no MS; p = 0.02). In contrast to those without MS, severe MS group had significantly higher risk for the primary outcome, mortality (1 year), and heart failure-related hospitalization (1 year) (adjusted hazard ratio: 1.2 [95% confidence interval (CI): 1.1 to 1.4], 1.2 [95% CI: 1.0 to 1.4], and 1.3 [95% CI: 1.1 to 1.5], respectively; p < 0.05 for all). CONCLUSIONS: Approximately one tenth of patients undergoing TAVR have concomitant MS. Severe MS is an independent predictor of 1-year adverse clinical outcomes following TAVR. The higher risk for long-term adverse events must be considered when evaluating patients with combined aortic stenosis and MS for TAVR. PMID- 29622150 TI - Combined Severe Aortic and Mitral Stenoses: An Expanding Potential for Transcatheter Therapies? PMID- 29622151 TI - The Presence of a CTO in a Non-Infarct-Related Artery During a STEMI Treated With Contemporary Primary PCI Is Associated With Increased Rates of Early and Late Cardiovascular Morbidity and Mortality: The CTO-TOTAL Substudy. PMID- 29622152 TI - Morphological Patterns of In-Stent Chronic Total Occlusions: An Intravascular Ultrasound Study. PMID- 29622153 TI - Is There Light at the End of the Thin-Strut Tunnel?: In Vitro Insights on Strut Thickness Impact on Thrombogenicity in Bioresorbable Stents or Scaffolds. PMID- 29622154 TI - Publication bias and the chase for statistical significance. PMID- 29622155 TI - Lack of Association Between Heart Failure and Incident Cancer. AB - BACKGROUND: Several recent studies have suggested an increased cancer risk among patients with heart failure (HF). However, these studies are constrained by limited size and follow-up, lack of comprehensive data on other health attributes, and adjudicated cancer outcomes. OBJECTIVES: This study sought to determine whether HF is associated with cancer incidence and cancer-specific mortality. METHODS: The study assembled a cohort from the Physicians' Health Studies I and II, 2 randomized controlled trials of aspirin and vitamin supplements conducted from 1982 to 1995 and from 1997 to 2011, respectively, that included annual health evaluations and determination of cancer and HF diagnoses. In the primary analysis, the study excluded participants with cancer or HF at baseline and performed multivariable-adjusted Cox models to determine the relationship between HF and cancer, modeling HF as a time-varying exposure. In a complementary analysis, the study used the landmark method and identified cancer free participants at 70 years of age, distinguishing between those with and without HF, and likewise performed Cox regression. Sensitivity analyses were performed at 65, 75, and 80 years of age. RESULTS: Among 28,341 Physicians' Health Study participants, 1,420 developed HF. A total of 7,363 cancers developed during a median follow-up time of 19.9 years (25th to 75th percentile: 11.0 to 26.8 years). HF was not associated with cancer incidence in crude (hazard ratio: 0.92; 95% confidence interval: 0.80 to 1.08) or multivariable-adjusted analysis (hazard ratio: 1.05; 95% confidence interval: 0.86 to 1.29). No association was found between HF and site-specific cancer incidence or cancer-specific mortality after multivariable adjustment. Results were similar when using the landmark method at all landmark ages. CONCLUSIONS: HF is not associated with an increased risk of cancer among male physicians. PMID- 29622156 TI - Impact of Heart Failure on Cancer Incidence: A Complicated Question. PMID- 29622158 TI - Delayed Coronary Obstruction After TAVR: A Call for Vigilance. PMID- 29622157 TI - Delayed Coronary Obstruction After Transcatheter Aortic Valve Replacement. AB - BACKGROUND: Delayed coronary obstruction (DCO) is an uncommon and barely reported complication following transcatheter aortic valve replacement (TAVR). OBJECTIVES: The aim of this study was to describe the incidence and pathophysiological features of DCO after TAVR, obtained from a large international multicenter registry. METHODS: Data were retrospectively collected from an international multicenter registry consisting of 18 centers between November 2005 and December 2016. RESULTS: During the study period, 38 DCO (incidence 0.22%) cases were identified from a total of 17,092 TAVR procedures. DCO occurred more commonly after valve-in-valve procedures (0.89% vs. 0.18%; p < 0.001) and if self expandable valves were used during the index procedure (0.36% vs. 0.11% balloon expandable; p < 0.01). DCO was most likely to occur <=24 h after the TAVR procedure (47.4%; n = 18); 6 (15.8%) cases occurred between 24 h and <=7 days, with the remaining 14 (36.8%) at >=60 days. The most frequent presentation was cardiac arrest (31.6%; n = 12), followed by ST-segment elevation myocardial infarction (23.7%; n = 9). The left coronary artery was obstructed in most cases (92.1%; n = 35). Percutaneous coronary intervention was attempted in the majority of cases (74.3% left main; 60% right coronary), and stent implantation was successful in 68.8%. The overall in-hospital death rate was 50% (n = 19), and was higher if DCO occurred <=7 days from the index procedure (62.5% vs. 28.6%; p = 0.09). CONCLUSIONS: DCO following TAVR is a rare phenomenon that is associated with a high in-hospital mortality rate. Clinicians should be aware that coronary obstruction can occur after the original TAVR procedure and have a low threshold for performing coronary angiography when clinically suspected. PMID- 29622159 TI - Device-Related Thrombosis After Percutaneous Left Atrial Appendage Occlusion for Atrial Fibrillation. AB - BACKGROUND: Transcatheter left atrial appendage (LAA) occlusion is an alternative strategy for stroke prevention in patients with atrial fibrillation (AF). OBJECTIVES: This study sought to determine the incidence, predictors, and prognosis of thrombus formation on devices in patients with AF who were treated with LAA closure. METHODS: The study retrospectively analyzed data from patients treated with 2 LAA closure devices seen in 8 centers in France from February 2012 to January 2017. RESULTS: A total of 469 consecutive patients with AF underwent LAA closure (272 Watchman devices [Atritech, Boston Scientific, Natick, Massachusetts] and 197 Amplatzer devices [St. Jude Medical, Minneapolis, Minnesota]). Mean follow-up was 13 +/- 13 months, during which 339 (72.3%) patients underwent LAA imaging at least once. There were 98 major adverse events (26 thrombi on devices, 19 ischemic strokes, 2 transient ischemic attacks, 18 major hemorrhages, 33 deaths) recorded in 89 patients. The incidence of device related thrombus in patients with LAA imaging was 7.2% per year. Older age (hazard ratio [HR]: 1.07 per 1-year increase; 95% confidence interval [CI]: 1.01 to 1.14; p = 0.02) and history of stroke (HR: 3.68; 95% CI: 1.17 to 11.62; p = 0.03) were predictors of thrombus formation on the devices, whereas dual antiplatelet therapy (HR: 0.10; 95% CI: 0.01 to 0.76; p = 0.03) and oral anticoagulation at discharge (HR: 0.26; 95% CI: 0.09 to 0.77; p = 0.02) were protective factors. Thrombus on the device (HR: 4.39; 95% CI: 1.05 to 18.43; p = 0.04) and vascular disease (HR: 5.03; 95% CI: 1.39 to 18.23; p = 0.01) were independent predictors of ischemic strokes and transient ischemic attacks during follow-up. CONCLUSIONS: Thrombus formation on the device is not uncommon in patients with AF who are treated by LAA closure. Such events are strongly associated with a higher risk of ischemic stroke during follow-up. (REgistry on Real-Life EXperience With Left Atrial Appendage Occlusion [RELEXAO]; NCT03279406). PMID- 29622160 TI - Left Atrial Appendage Occlusion Device-Related Thrombus: Certainties and Uncertainties. PMID- 29622162 TI - Science Moves Slowly. PMID- 29622161 TI - Elevated Cardiac Troponin T in Patients With Skeletal Myopathies. AB - BACKGROUND: Cardiac troponins are often elevated in patients with skeletal muscle disease who have no evidence of cardiac disease. OBJECTIVES: The goal of this study was to characterize cardiac troponin concentrations in patients with myopathies and derive insights regarding the source of elevated troponin T measurements. METHODS: Cardiac troponin T (cTnT) and cardiac troponin I (cTnI) concentrations were determined by using high sensitivity assays in 74 patients with hereditary and acquired skeletal myopathies. Patients underwent comprehensive cardiac evaluation, including 12-lead electrocardiogram, 24-h electrocardiogram, cardiac magnetic resonance imaging, and coronary artery computed tomography. cTnT and cTnI protein expression was determined in skeletal muscle samples of 9 patients and in control tissues derived from autopsy using antibodies that are used in commercial assays. Relevant Western blot bands were subjected to liquid chromatography tandem mass spectrometry for protein identification. RESULTS: Levels of cTnT (median: 24 ng/l; interquartile range: 11 to 54 ng/l) were elevated (>14 ng/l) in 68.9% of patients; cTnI was elevated (>26 ng/l) in 4.1% of patients. Serum cTnT levels significantly correlated with creatine kinase and myoglobin (r = 0.679 and 0.786, respectively; both p < 0.001). Based on cTnT serial testing, 30.1% would have fulfilled current rule-in criteria for myocardial infarction. Noncoronary cardiac disease was present in 23%. Using cTnT antibodies, positive bands were found in both diseased and healthy skeletal muscle at molecular weights approximately 5 kDa below cTnT. Liquid chromatography tandem mass spectrometry identified the presence of skeletal troponin T isoforms in these bands. CONCLUSIONS: Measured cTnT concentrations were chronically elevated in the majority of patients with skeletal myopathies, whereas cTnI elevation was rare. Our data indicate that cross-reaction of the cTnT immunoassay with skeletal muscle troponin isoforms was the likely cause. PMID- 29622164 TI - TLR4 in Atherogenesis: Paying the Toll for Antimicrobial Defense. PMID- 29622165 TI - Respiratory Syncytial Virus and Associations With Cardiovascular Disease in Adults. AB - Respiratory syncytial virus (RSV) is historically known for causing respiratory illness in young children, but the appreciation of its impact on older adults is growing. Studies have shown that hospitalization for respiratory illness due to RSV is complicated by cardiovascular events in 14% to 22% of adult patients, including worsening congestive heart failure, acute coronary syndrome, and arrhythmias. Additionally, underlying cardiovascular disease is associated with hospitalization in 45% to 63% of adults with confirmed RSV. In summary, patients with cardiopulmonary disease have higher rates of health care utilization for RSV related illness and worse outcomes. Patients with cardiovascular disease likely represent an important target population for the rapidly developing field of RSV vaccines. PMID- 29622163 TI - Chlamydia and Lipids Engage a Common Signaling Pathway That Promotes Atherogenesis. AB - BACKGROUND: Recent studies indicate that Toll-like receptor 4 (TLR4) and myeloid differentiation factor 88 (MyD88) signaling promote the development of high fat diet-induced atherosclerosis in hypercholesterolemic mice. OBJECTIVES: The authors investigated the role of TLR4/MyD88 signaling in hematopoietic and stromal cells in the development and infection-mediated acceleration of atherosclerosis. METHODS: The authors generated bone marrow chimeras between wild type and Tlr4-/- mice, as well as wild-type and Myd88-/- mice. All mice were on the Apoe-/- background and fed high fat diet. The authors infected the chimeric mice with C. pneumoniae (CP) and fed them high fat diet. RESULTS: Aortic sinus plaques and lipid content were significantly reduced in Apoe-/- mice that received Tlr4-/-or Myd88-/- bone marrow compared with control animals despite similar cholesterol levels. Similarly, Tlr4 or Myd88 deficiency in stromal cells also led to a reduction in the lesion area and lipid in aortic sinus plaques. MyD88 expression only in CD11c+ dendritic cells (myeloid cells) in cells was sufficient in otherwise MyD88-deficient mice to induce CP infection-mediated acceleration of atherosclerosis, underlining the key role of MyD88 in CD11c+ dendritic cells (myeloid cells). Whereas CP infection markedly accelerated atherosclerosis in TLR4- or MyD88-positive chimeras, CP infection had a minimal effect on atherosclerosis in TLR4- or MyD88-deficient mice (either in the hematopoietic or stromal cell compartments). CONCLUSIONS: The authors show that both CP infection and metabolic stress associated with dyslipidemia use the same innate immune response pathway, utilizing TLR4/MyD88 signaling, with similar relative contributions in bone marrow-derived hematopoietic cells and in stromal cells. Further studies are required to understand this intricate and complex cross talk among innate and adaptive immune systems in various conditions to more effectively design dendritic cell-mediated atheroprotective vaccines and other therapeutic strategies. PMID- 29622166 TI - A Changing Landscape in Cardiovascular Research Publication Output: Bridging the Translational Gap. AB - The concern about predominance of basic discovery research and lack of translation into clinical medicine, and segregation between these research communities, led the authors to study these research communities through mapping networks of publications and cross-references. Cardiovascular research from 1993 to 2013 was published in 565 journals, including 104 new journals. Only 50% were published in core cardiovascular journals, such as the Journal of the American College of Cardiology, whereas one-half of cardiovascular publications were found in broader biomedical/multidisciplinary journals. The growth of the clinical journal community and merging into one broad journal community suggests a decreasing dichotomy between basic/preclinical and clinical research, potentially contributing to bridging the translational gap. PMID- 29622167 TI - The Challenge of Identifying and Addressing Psychological Comorbidities. PMID- 29622168 TI - Effect of Low-Dose Versus Standard-Dose Ticagrelor and Clopidogrel on Platelet Inhibition in Acute Coronary Syndromes. PMID- 29622169 TI - Admissions for Infective Endocarditis in Intravenous Drug Users. PMID- 29622170 TI - The Role of Salt Reduction in the Management of Hypertension. PMID- 29622171 TI - Reply: The Role of Salt Reduction in the Management of Hypertension. PMID- 29622172 TI - True Story. PMID- 29622173 TI - Impact of the California Breast Density Law on Screening Breast MR Utilization, Provider Ordering Practices, and Patient Demographics. AB - PURPOSE: To assess the impact of California's Breast Density Law (BDL) on MRI utilization and clinician ordering practices. MATERIALS AND METHODS: Our institutional review board approved this study that retrospectively compared the ordering pattern for screening breast MRI examinations in the 30-month period before and after the BDL was enacted. Examinations were subcategorized into those with breast density mentioned as an examination indication. Patients were classified into (1) high risk; (2) above average risk, defined but not quantified; and (3) undefined or average risk. chi2 test or Fisher's exact test was used to compare MRI utilization, use of breast density as an indication, patient demographics, and provider characteristics. RESULTS: Screening MRI examinations with breast density as the indication increased from 8.5% (32 of 376) to 21.1% (136 of 646, P < .0001) after BDL. When high-risk patients were excluded, the increase was from 8% to 17.2% (P < .0001). Patient demographics before and after BDL were, by race: white 71.8% versus 71.2%; Asian 6.4% versus 10.5%; black 3.7% versus 3.1%; American Indian 0.3% versus 1.4%; Native Hawaiian or Pacific Islander 1.6% versus 1.7%; by ethnicity: Hispanic or Latino 10.6% versus 7.9%. Before and after BDL, predominantly female providers (81.4% and 77.4%, P = not significant [NS]) and specialists (62.5% and 63.5%, P = NS) ordered the majority of breast MRI examinations compared with males (18.6% and 22.6%, P = NS). CONCLUSION: Screening breast MRI utilization for non-high-risk women more than doubled after the California BDL went into effect. BDL has had an impact on MRI utilization, and its clinical value for changing outcomes deserves further study. PMID- 29622174 TI - Point: Losing the Zero-Sum Game: It's Time to Eliminate Required Research in Radiology Residency. PMID- 29622175 TI - Counterpoint: Research by Radiology Residents Is Meaningful and Important. PMID- 29622176 TI - Paging Dr Sisyphus. PMID- 29622177 TI - Standardization of Administered Activities in Pediatric Nuclear Medicine. PMID- 29622178 TI - Ephemeral Effusive Constrictive Pathophysiology. PMID- 29622179 TI - Arrhythmogenic Potential of Border Zone After Myocardial Infarction: Scar Is More Than Just a Healed Wound.... PMID- 29622180 TI - Roles of Transesophageal Echocardiography and Cardiac Computed Tomography for Evaluation of Left Atrial Thrombus and Associated Pathology: A Review and Critical Analysis. AB - Evaluation of the left atrium and left atrial appendage for the presence of thrombus prior to cardioversion and pulmonary vein isolation, and of the entire heart for embolic sources in the setting of cryptogenic stroke, has long been standard medical care. Guidelines have uniformly recommended transesophageal echocardiography (TEE) to accomplish these goals. In recent years, computed tomographic angiography has demonstrated diagnostic accuracy similar to that of TEE for the detection of thrombus. Analysis of the pertinent data and relative merits of the 2 technologies leads to the conclusions that: 1) both modalities have some unique, nonoverlapping capabilities that may dictate their use in specific situations; 2) computed tomographic angiography is a reasonable alternative to TEE when the primary aim is to exclude left atrial and left atrial appendage thrombus and in patients in whom the risks associated with TEE outweigh the benefits; and 3) both options should be discussed with the patient in the setting of shared decision making. PMID- 29622181 TI - Mitral Valve Regurgitation in the Contemporary Era: Insights Into Diagnosis, Management, and Future Directions. AB - Mitral valve regurgitation (MR) is the most common valvular heart disease. Primary MR is a disease of the mitral valve apparatus, whereas secondary MR is a disease of the left ventricle. Diagnosing and managing MR is often challenging and requires a structured approach, integrating findings on history, physical examination, and imaging. Decisions regarding treatment depend on knowledge of the etiology, natural history, and outcome of interventions for these patients with mitral valve disease. The optimal timing of intervention requires a comprehensive 2-dimensional and Doppler echocardiogram in each patient to determine the cause of the mitral valve disease, the severity of the regurgitation, and the effect of the volume overload on the left ventricle, as well as determining if a durable valve repair can be performed. Advances in both surgical and catheter-based therapies have resulted in recommendations for lower thresholds for operation and extension of interventional treatments to the older, sicker population of patients with MR. The current review discusses the pathophysiological rationale for current diagnostic and management strategies in MR. PMID- 29622182 TI - JACC: Cardiovascular Imaging 2.0: The Next Decade in Digital. PMID- 29622183 TI - Corrigendum to "Carbendazim exposure induces developmental, biochemical and behavioural disturbance in zebrafish embryos" [Aquat. Toxicol. 170 (2016) 390 399]. PMID- 29622184 TI - Determination of patulin in apple juice by single-drop liquid-liquid-liquid microextraction coupled with liquid chromatography-mass spectrometry. AB - Quick and simple analytical methodology has been developed for the measurement of patulin in apple juice by combining single-drop liquid-liquid-liquid microextraction with isotope dilution ultra-high performance liquid chromatography-mass spectrometry. After systematic parameters optimization, the whole sample pretreatment only consisted of single extraction that consumed 1.5 mL ethyl acetate. While, other methods usually needed complicated pretreatment, including extraction, purification, evaporation and redissolution. This sample pretreatment method could greatly lower the interferences from sugar-rich matrix, and the limit of detection was 0.5 MUg/L and limit of quantification was 2 MUg/L in apple juice. Moreover, linear range covered three orders of magnitude from 2 to 2000 MUg/L. The proposed method is promising for patulin extraction and detection in apple juice, which will opens a new perspective in the enrichment of trace contaminations in high sugar complex matrix. PMID- 29622185 TI - Physicochemical characterization of mineral (iron/zinc) bound caseinate and their mineral uptake in Caco-2 cells. AB - Milk proteins (especially caseins) are widely accepted as good vehicle for the delivery of various bioactive compounds including minerals. Succinylation is one of the most acceptable chemical modification techniques to enhance the mineral binding ability of caseins. Addition of minerals to succinylated proteins may alter their physicochemical and biochemical properties. Physicochemical characteristics of succinylated sodium caseinate (S.NaCN)-mineral (iron/zinc) complexes were elucidated. Chromatographic behaviour and fluorescence intensity confirmed the structural modification of S.NaCN upon binding with minerals. The bound mineral from protein complexes showed significantly higher (P < 0.05) in vitro bioavailability (mineral uptake) than mineral salts in Caco-2 cells. Also, iron bound S.NaCN showed higher cellular ferritin formation than iron in its free form. These mineral bound protein complexes with improved bioavailability could safely replace inorganic fortificants in various functional food formulations. PMID- 29622186 TI - Non-targeted detection of paprika adulteration using mid-infrared spectroscopy and one-class classification - Is it data preprocessing that makes the performance? AB - A method for the non-targeted detection of paprika adulteration was developed using Fourier transform mid-infrared (FT-MIR) spectroscopy and one-class soft independent modelling of class analogy (OCSIMCA). One-class models based on commercially available paprika powders were developed and optimised to provide >80% sensitivity by external validation. The performances of the established models for adulteration detection were tested by predicting spiked paprika samples with various types of fraudulent material and levels of adulterations including 1% (w/w) Sudan I, 1% (w/w) Sudan IV, 3% (w/w) lead chromate, 3% (w/w) lead oxide, 5% (w/w) silicon dioxide, 10% (w/w) polyvinyl chloride, and 10% (w/w) gum arabic. Further, the influence of data preprocessing on the model performance was investigated. Relationship between classification results and data preprocessing was identified and specificity >80% was achieved for all adulterants by applying different preprocessing methods including standard normal variate (SNV), first and second derivatives, smoothing, and combinations thereof. PMID- 29622187 TI - Assessment of oxidation compounds in oaked Chardonnay wines: A GC-MS and 1H NMR metabolomics approach. AB - The oxidation of oaked Chardonnay wine during long-term storage was studied by headspace solid-phase microextraction coupled to gas chromatography-mass spectrometry (HS-SPME-GC/MS) and proton (1H) nuclear magnetic resonance (NMR) spectroscopy. Three distinct groups of wine were defined based on the browning index: control, least oxidized (OX1) and most oxidized (OX2). HS-SPME-GC/MS and 1H NMR spectroscopy enabled the profiling of a total of 155 compounds in all wine samples including aldehydes, ketones, esters, polyphenols, among other classes. Acetaldehyde, 3-methylbutanal, 2-phenylacetaldehyde, methional, 3-penten-2-one, beta-damascenone and four unknown carbonyl compounds showed the highest percentage of variation with oxidation. Novel oxidation markers found in this work include pentanal, 3-methyl-2-butanone, 3-penten-2-one, 2 methyltetrahydrofuran-3-one, beta-damascenone, ethyl 2-methylbutanoate and vinyl decanoate. In addition, several correlations between polyphenols, aroma compounds and absorbance at 420 nm (A420) were observed, suggesting the occurrence of chemical reactions with a possible impact in wine browning. PMID- 29622188 TI - Inhibitory activity of minor phlorotannins from Ecklonia cava on alpha glucosidase. AB - alpha-Glucosidase is an enzyme that plays a key role in raising blood sugar level and is considered a good target for developing drugs to treat type 2 diabetes. This study was performed to evaluate the inhibition of the catalytic reaction of alpha-glucosidase by minor phlorotannin derivatives (1-5) from Ecklonia cava. These derivatives demonstrated inhibitory activity, with IC50 values ranging from 2.3 +/- 0.1 to 59.8 +/- 0.8 MUM. Among the phlorotannins identified, compounds 2 and 3-5 were revealed to be non-competitive and competitive inhibitors, respectively. Furthermore, a fluorescence-quenching study of receptor-ligand binding was performed to calculate the kinetic parameters (Ksv, Kq, and K). These signal data indicated a 1:1 ratio of ligand-receptor binding. The binding conformations of the phlorotannin ligands were visually solved through molecular simulation. In conclusion, these minor phlorotannins may serve as alpha glucosidase inhibitors targeted for the treatment of type 2 diabetes. PMID- 29622189 TI - Physicochemical and functional properties of coconut (Cocos nucifera L) cake dietary fibres: Effects of cellulase hydrolysis, acid treatment and particle size distribution. AB - Effects of cellulase hydrolysis, acid treatment and particle size distribution on the structure, physicochemical and functional properties of coconut cake dietary fiber (DCCDF) were studied. Results showed that both the cellulase hydrolysis and acid treatment contributed to the structural modification of DCCDF as evident from XRD, FT-IR and SEM analysis. Moreover, the cellulase hydrolysis enhanced soluble carbohydrate content, water holding capacity (WHC) and swelling capacity (WSC), alpha-amylase inhibition activity (alpha-AAIR), glucose dialysis retardation index (GDRI) and cation-exchange capacity (CEC) of DCCDF; but it had undesirable effects on colour, oil holding capacity (OHC) and emulsifying capacity (EC). On other hand, acid treatment decreased the WHC, WSC and GDRI, but improved the colour, CEC, OHC and emulsion stability of DCCDF. Furthermore, the WHC, WSC and EC of DCCDF increased as the particle size reduced from 250 to 167 MUm, while the GDRI, OHC, alpha-AAIR and emulsion stability decreased with decreasing particle size. PMID- 29622190 TI - Structural characterization of blackberry wine polysaccharides and immunomodulatory effects on LPS-activated RAW 264.7 macrophages. AB - Three polysaccharide fractions were isolated from blackberry wine. The crude extract BWPs was obtained with ethanol precipitation and freeze-thawing process, it was then submitted to Fehling treatment, giving soluble BWPFs and insoluble BWPFp fractions. These fractions were characterized by Gas Chromatography-Mass Spectrometry (GC-MS) and Nuclear Magnetic Resonance (NMR). Major polysaccharides were identified for each fraction: mannan, type II arabinogalactan and type I rhamnogalacturonan for BWPs, a mannan formed by a major chain of alpha-Manp(1 -> 6)-linked units, O-2 substituted with alpha-d-Manp(1 -> 2)-linked side chains for BWPFp and a AG II formed by a major chain of beta-d-Galp(1 -> 3)-linked, substituted at O-6 by side chains of the beta-d-Galp(1 -> 6)-linked, which then are substituted at O-3 by non-reducing units of alpha-l-Araf and a RG I, formed by [->4)-alpha-d-GalpA-(1 -> 2)-alpha-l-Rhap-(1->]n for BWPFs. Anti-inflammatory effects of polysaccharide fractions were evaluated in RAW 264.7 cells. Fractions markedly reduced nitric oxide (NO) and pro-inflammatory cytokine production (TNF alpha and IL-1beta) in LPS-treated cells. PMID- 29622191 TI - Lipase immobilized on ionic liquid-functionalized magnetic silica composites as a magnetic biocatalyst for production of trans-free plastic fats. AB - The main objective of this study is to develop an efficient and environmentally gentle process for production of trans-free plastic fats. To acheive this, the core-shell structured magnetic composites were prepared, and then imidazole-based ionic liquids (ILs) were covalently grafted on the magnetic composites. Thereafter, Candida rugosa lipase was immobilized on the magnetic IL functionalized composites. The immobilized lipase could be facilely separated using an external magnetic filed. With the magnetic biocatalyst, enzymatic interesterifications of solid palm stearin and liquid rice bran oil blends were performed at 45 degrees C. It was shown that the total fatty acid (FA) compositions of the binary blends were almost unchanged after the interesterifications, whereas the FA positional distribution and triacylglycerol species were significantly varied. As compared with the physical blends, the interesterified products had a lower slip melting point, and the interesterification could result in an obvious change in the microstructure of the final products. PMID- 29622192 TI - Highly selective and rapidly responsive fluorescent probe for hydrogen sulfide detection in wine. AB - A new fluorescent probe 6-(2, 4-dinitrophenoxy)-2-naphthonitrile (probe 1) was designed and synthesized for the selective detection of hydrogen sulfide (H2S). The addition of H2S to a solution of probe 1 resulted in a marked fluorescence turn-on alongside a visual color change from colorless to light yellow. Importantly, this distinct color response indicated that probe 1 could be used as a visual sensor for H2S. Moreover, probe 1 was successfully used as a signal tool to determine the H2S levels in beer and red wine. PMID- 29622194 TI - Structural characteristics of low bitter and high umami protein hydrolysates prepared from bovine muscle and porcine plasma. AB - The aim of this study was to use different enzyme mixtures to investigate the influence of peptide characteristics and taste of protein hydrolysates from bovine muscle and porcine plasma. Minced beef and porcine plasma were hydrolysed using 10 food-grade enzymes, including Protease A, Protease P, ProteAX, Flavourzyme, Alcalase, Papain, Bromelain, Protamex, Neutrase and Sumizyme BNP-L. The relationship between degree of hydrolysis (DH), molecular weight (MW) distribution, enzyme specificity, and sensory characteristics of hydrolysates were investigated. The results demonstrated that Protease A, a mixture of endo- and exo-peptidases, was the optimal protease to generate hydrolysates with low bitterness. Endopeptidases (Papain and Bromelain) elicited bitter taste of protein hydrolysates. A positive correlation was suggested between umami taste and MW distribution (<0.5 kDa), while bitterness was positively correlated with MW distribution (0.5-1 kDa). Overall, hydrolysis with enzyme preparations containing endo- and exo-peptidases was effective to reduce bitterness of hydrolysates. PMID- 29622193 TI - A hybrid monolithic column based on layered double hydroxide-alginate hydrogel for selective solid phase extraction of lead ions in food and water samples. AB - In order to develop an accurate and precise determination method based on solid phase extraction of Pb(II) in food and water samples, a hybrid monolithic column based on layered double hydroxides (LDHs) nanosheets-alginate hydrogel has been synthesized. Combining the advantages of porous 3D framework of hydrogel with selective adsorption of LDHs toward Pb(II), the hydrogel-based hybrid monolithic column shows enhanced enrichment selectivity and efficiency for target ions. Effects of hydrogel composition, pH, concentration and type of eluent, sample volume, and interfering ions on the recoveries of the analytes were also investigated. Under the optimal experiment conditions of method, the limit of detection, preconcentration factor and precision as RSD% are found to be 0.39 MUg L-1, 53.7 and 2.65%, respectively. Trace Pb(II) can be quantitatively preconcentrated at pH 6.0 with recoveries >97%. Finally, the method was successfully verified by analyzing spiked Pb2+ in water and drinking samples. PMID- 29622195 TI - Selecting odorant compounds to enhance sweet flavor perception by gas chromatography/olfactometry-associated taste (GC/O-AT). AB - Gas chromatography/olfactometry-associated taste (GC/O-AT) analysis combined with mass spectrometry allowed identification of odorant compounds associated with taste attributes (sweet, salty, bitter and sour) in a multi-fruit juice. Nine compounds were selected for their odor-associated sweetness enhancement in a multi-fruit juice odor context using Olfactoscan and for their odor-induced sweet taste enhancement in sucrose solution and sugar-reduced fruit juice through sensory tests. Sweetness of the fruit juice odor was significantly enhanced by methyl 2-methylbutanoate, ethyl butanoate, ethyl 2-methylbutanoate and linalool; sweet perception was significantly enhanced in 7% sucrose solution by ethyl 2 methylbutanoate, furaneol and gamma-decalactone, and in 32% sugar-reduced fruit juice by ethyl 2-methylbutanoate. GC/O-AT analysis is a novel, efficient approach to select odorants associated with a given taste. The further screening of taste associated odorants by Olfactoscan helps to identify the most efficient odorants to enhance a target taste perception and may be used to find new ways to modulate taste perception in foods and beverages. PMID- 29622196 TI - Simultaneous determination of carotenoids, tocopherols, retinol and cholesterol in ovine lyophilised samples of milk, meat, and liver and in unprocessed/raw samples of fat. AB - An accurate, fast, economic and simple method to determine carotenoids, tocopherols, retinol and cholesterol in lyophilised samples of ovine milk, muscle and liver and raw samples of fat, which are difficult to lyophilise, is sought. Those analytes have been studied in animal tissues to trace forage feeding and unhealthy contents. The sample treatment consisted of mild overnight saponification, liquid-liquid extraction, evaporation with vacuum evaporator and redissolution. The quantification of the different analytes was performed by the use of ultra-high performance liquid chromatography with diode-array detector for carotenoids, retinol and cholesterol and fluorescence detector for tocopherols. The retention times of the analytes were short and the resolution between analytes was very high. The limits of detection and quantification were very low. This method is suitable for all the matrices and analytes and could be adapted to other animal species with minor changes. PMID- 29622197 TI - Pre-concentration of Zn(II) ions from aqueous solutions using meso-porous pyridine-enrobed magnetite nanostructures. AB - A simple, cheap and efficient method for pre-concentrating and separating Zn(II) ions from aqueous solutions and real samples has been designed. The method was implemented in a prototype featuring interchangeable chromatography-column-like cartridges, filled with meso-porous silica nanostructures, allowing easy exchange of the type and quantity of the sorbent. The adsorbents inside the column are held in place by means of porous polymer nano-fibre membranes. The effects of various parameters on the adsorption of Zn(II) ions from aqueous solutions were investigated. Maximal adsorption (~99%) was found for Zn(II) ions amongst a mixture of Cu(II), Co(II), Ni(II), Ag(I), Au(III), Pd(II) and Pb(II) in aqueous solution. The procedure was tested for pre-concentrating and determining traces of zinc in real samples of meat, fish and hen marketed in Tehran. A desorption process using 0.5 mol L-1 HCl as eluent, showed ~97% recovery of the Zn(II) ions adsorbed on the MSMPP sorbent. PMID- 29622198 TI - Preparation of aqueous nanodispersions with annatto (Bixa orellana L.) extract using an organic solvent-free and low energy method. AB - The seeds of Bixa orellana L. is widely used in food industry as a natural colorant. A major technological challenge for its utilization on aqueous food products is the low water solubility. Therefore, the present study aimed to obtain aqueous nanodispersions using this natural raw material by using a simple organic solvent-free and low energy method. Bixin and geranylgeraniol were found on the extract. The nanodispersions were prepared by addition of water on a mixture of extract and surfactant (s). The effect of the surfactants and dilution on the nanodispersions were also evaluated. Best results were achieved using polysorbate 80/sorbitan monooleate (HLB 13) (diluted in water, 1:10). The results shows the potential of this ecofriendly approach, in contrast to common methods that make use of potentially toxic organic solvents and high input of energy, which elevate the costs for further industrialization. PMID- 29622199 TI - Phenolic profile and effect of growing area on Pistacia lentiscus seed oil. AB - In this investigation, we aimed to study, for the first time, the phenolic composition of Pistacia lentiscus seed oils from different growing areas. Extraction of the phenolic fraction from oils was done by methanol/water. Phenolic profiles were determined using chromatographic analysis by High Performance Liquid Chromatography (HPLC-DAD/MSD) and its quantification was done using an internal standard which is unidentified in the studied oil (syringic acid). Forty phenolic compounds were quantified and only eighteen of them were identified. The eight studied oils showed different phenolic profiles. The total phenols amount varied from 538.03 mg/kg oil in Jbel Masour oils to 4260.57 mg/kg oil in oils from Kef Erraai. The highest amount of secoiridoids was reached by Bouchoucha oil containing 366.71 mg/kg oil of Oleuropein aglycon. Oils from Kef Erraai locality contained the highest concentrations in flavonols (377.44 mg/kg oil) and in phenolic acids (2762.67 mg/kg oil). PMID- 29622200 TI - Safety assessment of sodium acetate, sodium diacetate and potassium sorbate food additives. AB - Cytotoxicity and genotoxicity of sodium acetate (SA), sodium diacetate (SDA), and potassium sorbate (PS) was tested on Human Umbilical Vein Endothelial Cells (HUVEC). Cytotoxicity was investigated by MTT assay and flow cytometry analysis, while genotoxicity was evaluated using DNA fragmentation and DAPI staining assays. The growth of treated HUVECs with various concentrations of SA, SDA and PS decreased in a dose-and time-dependent manner. The IC50 of 487.71, 485.82 and 659.96 uM after 24 h and IC50 of 232.05, 190.19 and 123.95 uM after 48 h of treatment were attained for SA, SDA and PS, respectively. Flow cytometry analysis showed that early and late apoptosis percentage in treated cells was not considerable. Also neither considerable DNA fragmentation nor DNA smear was observed using DAPI staining and DNA ladder assays. Overall, it can be concluded that the aforementioned food additives can be used as safe additives at low concentration in food industry. PMID- 29622201 TI - Short-term frozen storage enhances cross-linking that was induced by transglutaminase in surimi gels from silver carp (Hypophthalmichthys molitrix). AB - To enhance the application of transglutaminase (TGase) in processing and preserving of frozen surimi, the mechanism that enhances surimi gelation induced by TGase after short-term freezing was investigated. Gel properties and cross linking extent of surimi gels increased when surimi was frozen at -18 degrees C for 5-7 days. However when storage time exceeded 10 days, textural properties and water-holding capacity decreased significantly. Moreover, the difference of breaking force and hardness between surimi gels with and without TGase reached the maximum after 3-5 days of frozen storage. Free amino content of myosin increased during the first 7 days, and TGase activity increased significantly during the first 3 days. Short-term frozen storage unfolded myosin structure, decreased alpha-helix content, and exposed hydrophobic patches, which promoted cross-linking reactions and intermolecular hydrophobic interactions. This study provides some new ideas for the processing, storage and transport of frozen surimi and manufacture of frozen surimi-based products. PMID- 29622202 TI - Simultaneous extraction of hydrophobic and hydrophilic bioactive compounds from ginger (Zingiber officinale Roscoe). AB - Ginger is a commonly used spice around the world. Its bioactive compounds contain hydrophobic gingerols and hydrophilic polysaccharides. Huge physiochemical differences between these compounds and the thermal instability of gingerols impede fast and effective extraction of them using conventional methods. In this research, ionic liquid-based ultrasonic-assisted extraction (ILUAE) was applied to simultaneously extract gingerols and polysaccharides from ginger. Parameters influencing the recovery of gingerols were ionic liquid type, ionic liquid concentration, solid/liquid ratio, ultrasonic power, extraction temperature and extraction time. Compared with traditional methods, LUAE significantly increased the yield of total gingerols and shortened the extraction time. Meanwhile, ginger polysaccharides recovery reached up to 92.82% with ILUAE. Our results indicated that ILUAE has a remarkable capacity to extract gingerols and ginger polysaccharides in one step. Therefore, ILUAE represents a promising technology for simultaneous extraction of hydrophilic and hydrophobic bioactive compounds from plant materials. PMID- 29622203 TI - Parboiling reduced the crystallinity and in vitro digestibility of non-waxy short grain rice. AB - The impact of parboiling on starch digestibility of cooked rice was examined through an in vitro digestion model. Results indicated that the equilibrium starch hydrolysis of polished rice was the highest (86.55%), followed by that of parboiled-polished (83.94%), brown (80.59%) and parboiled rice (76.95%). X-ray diffraction analysis indicated that A-type crystals were predominant in brown rice and polished rice, while A-, B- and V-type crystalline structures coexisted in parboiled rice and parboiled-polished rice. Thin and compact layers were observed on the surfaces of parboiled rice and were considered to be physical barriers that reduce the starch digestibility. The study demonstrates that parboiling could change the crystallinity and reduce the starch digestion of rice significantly. PMID- 29622204 TI - Realistic risk assessment of arsenic in rice. AB - Over 3 billion people share a diet consisting mainly of rice, which may contain significant amounts of arsenic. Because the toxicity of arsenic is dependent on its chemical form and that it may be in a form that is not bio-accessible (i.e. dissolved in the gastrointestinal tract) and can thus not become bio-available (i.e. end up in the blood stream, where it may exert its toxic effect), the bio accessibility of arsenic was determined in thirteen different types of rice. The effects of washing and cooking were also studied. The total concentration of arsenic ranged from 93 to 989 ug kg-1 and its bio-accessibility ranged from 16 to 93%. Cooking only changed arsenic speciation in a few cases. However, simply washing rice with arsenic-free water before cooking removed 3-43% of the arsenic, resulting in all the rice tested except the most contaminated one being safe to consume by adults. PMID- 29622205 TI - Assessing the influence of temperature on NIRS prediction models for the determination of sodium content in dry-cured ham slices. AB - Temperature fluctuations are a key factor in the development of prediction models using near infrared spectroscopy (NIRS). In the present study, this influence has been investigated and a methodology has been proposed to reduce the effect of sample temperature on NIRS model prediction of the sodium content in dry-cured ham slices. Spectra were taken directly from the slices using a remote measurement probe (for non-contact analysis) at three different temperature ranges: -12 degrees C to -5 degrees C, -5 degrees C to 10 degrees C and 10 degrees C to 20 degrees C. Local and global temperature compensation methods were established. Partial-least squares (PLS) regression was used as a chemometrics tool to perform the calibrations. The results showed that local models were sensitive to changes in temperature, while a global temperature model using sample spectra over the entire temperature range showed good prediction ability, reducing the error caused by temperature fluctuations to acceptable levels for practical applications. PMID- 29622206 TI - Water-in-oil-in-water double emulsion for the delivery of starter cultures in reduced-salt moromi fermentation of soy sauce. AB - This study investigated the application of water-oil-water (W1/O/W2) double emulsions (DE) for yeast encapsulation and sequential inoculation of Zygosaccharomyces rouxii and Tetragenococcus halophilus in moromi stage of soy sauce fermentation with reduced NaCl and/or substitution with KCl. Z. rouxii and T. halophilus were incorporated in the internal W1 and external W2 phase of DE, respectively. NaCl reduction and substitution promoted T. halophilus growth to 8.88 log CFU/mL, accompanied with faster sugar depletion and enhanced lactic acid production. Reducing NaCl without substitution increased the final pH (5.49) and decreased alcohols, acids, esters, furan and phenol content. However, the application of DE resulted in moromi with similar microbiological and physicochemical characteristics to that of high-salt. Principal component analysis of GC-MS data demonstrated that the reduced-salt moromi had identical aroma profile to that obtained in the standard one, indicating the feasibility of producing low-salt soy sauce without compromising its quality. PMID- 29622207 TI - Enhancing storage stability of guava with tannic acid-crosslinked zein coatings. AB - The quality of zein (Z)- and zein-tannic acid (ZTA)-coated guavas was monitored throughout 12 days of storage. Coated fruit showed lower changes in terms of visual appearance, chlorophyll contents and color. Weight loss, softening, and changes in soluble solids were also decreased by the coatings. The respiration peak as well as H2O2 and superoxide dismutase activity peaks were delayed by the coatings, and the ethylene production was reduced. So, the results were consistent with a slowed down ripening of guavas by the coatings, which was probably related to lowered oxygen permeability of guava skin. ZTA coating was more effective than Z to reduce weight loss, softening, color changes, ethylene production, and oxidative stress. The higher efficiency of ZTA coating was ascribed to zein crosslinking, which probably resulted in decreased gas permeability, promoting lower respiration rates and lower ROS production, slowing down the ripening process, and extending guava stability. PMID- 29622208 TI - Multiclass analysis of 25 veterinary drugs in milk by ultra-high performance liquid chromatography-tandem mass spectrometry. AB - The aim of this work was to develop a simple and rapid analytical method for the simultaneous determination of a wide range of drug residues in milk by UHPLC MS/MS. A total of 25 typical veterinary drugs investigated belong to six families including beta-lactams, quinolones, beta-agonists, phenicols, glucocorticoids and nitrofurans. The samples were extracted by acetonitrile and defatted with n hexane twice. Electrospray ionization and positive/negative polarity switching were utilized for the analysis of 25 veterinary drugs in a single chromatographic run. The linearity, recovery, precision and matrix effects of the method were fully validated. The intra- and inter-precision were in the range of 1.7-11.1% and 2.5-10.4%, respectively. The average recoveries ranged from 65.9% to 123.5% with RSD less than 10.8% at three concentration levels. The proposed method was demonstrated to be simple, economical and reliable for the fast monitoring of these drug residues in milk samples. PMID- 29622209 TI - Physicochemical and biochemical traits of sweet pepper hybrids as a function of harvest times. AB - The current study aims to evaluate in commercial hybrids the influence of harvest period about physicochemical and biochemical characterization of different genotypes at the unripe fruit stages. Therefore, 16 hybrids were assessed within 4 harvest times, making up to 64 treatments. Physicochemical and biochemical characterization of sweet pepper at unripe fruit stages were influenced by harvest times and genotypes. Results indicated a decrease in pigment contents in all hybrids when harvested at 130 days after sowing (DAS). Additionally, Eppo, Magali, Dahra and Anabell decreased in ascorbic acid contents at 175 DAS; while Melina, Anabell, Don Santino, Balico and Lucigno increased in reducing sugar contents at same harvest time. PMID- 29622210 TI - Comparison of physicochemical properties and cooking edibility of waxy and non waxy proso millet (Panicum miliaceum L.). AB - The quality characteristics of waxy and non-waxy proso millet (Panicum miliaceum L.) are different because of their varying amylose content. Physical appearance, pasting properties, cooking and edibility were investigated in five waxy and five non-waxy proso millet varieties. The results showed that the amylose content of proso millet flour was positively correlated with peak viscosity, trough viscosity, breakdown viscosity, final viscosity, setback viscosity, peak time, and pasting temperature. The porridge made with non-waxy proso millet was thicker as compared with that of made with waxy proso millet. Cooked non-waxy proso millet was hard whereas waxy proso millet was sticky. The non-waxy proso millet contained higher resistant starch and lower rapidly digestible starch than waxy proso millet. From this study, we can conclude that quality characteristics of waxy and non-waxy proso millet are different, and this may provide an insight in food processing and commercial production of proso millet. PMID- 29622211 TI - Characterization and comparison of the structure and antioxidant activity of glycosylated whey peptides from two pathways. AB - Glycosylated whey peptides (WPP-Gal A and WPP-Gal B) were formed from two pathways. WPP-Gal A showed higher browning intensity and fluorescence intensity than WPP-Gal B. Loss of amino groups and reducing sugar was heavier for WPP-Gal A than WPP-Gal B. Size exclusion chromatography revealed that WPP-Gal A and B had similar curves, but the molecular weight distribution of WPP-Gal B was more extensive than that of WPP-Gal A. Particle size was larger for WPP-Gal B than WPP Gal A. Furthermore, WPP-Gal A showed greater antioxidant activity than WPP-Gal B. FT-IR analysis indicated that vibrations of several chemical bonds in amide I, II and III bands of WPP-Gal A were more obvious than those of WPP-Gal B. WPP-Gal A showed greater Caco-2 cell proliferation than WPP-Gal B. Therefore, WPP-Gal A showed more significant structural and characteristic changes, higher antioxidant activity and better proliferative activity than WPP-Gal B. PMID- 29622212 TI - Development of an upconversion fluorescence DNA probe for the detection of acetamiprid by magnetic nanoparticles separation. AB - An upconversion fluorescence DNA probe which consists of aptamer-conjugated magnet nanoparticles (apt-MNPs) and complementary DNA-conjugated upconversion nanoparticles (cDNA-UCNPs) was developed to detect acetamiprid. Acetamiprid can specifically conjugate with the apt-MNPs to dissociate the cDNA-UCNPs from the apt-MNPs and resulted in reduced fluorescence intensity through an external magnet. The change of fluorescence intensity (?I) is positively related to the concentration of acetamiprid, which can be applied for the quantification of acetamiprid. Under optimal conditions, a linear detection range and detection limit are 0.89-114.18 MUg/L and 0.65 MUg/L, respectively. The probe was successfully used to detect acetamiprid in spiked paddy water, soil, pear, apple, wheat and cucumber. Average recoveries are 78.2%-103.5% with intra-day relative standard deviations (RSDs) of 2.6%-10.9% and inter-day RSDs of 4.3%-10.2%. The amounts of acetamiprid in the authentic paddy water and pear samples detected by the DNA probe are significantly correlated with that detected by high-performance liquid chromatography (HPLC). PMID- 29622213 TI - Efficient transformation of sucrose into high pullulan concentrations by Aureobasidium melanogenum TN1-2 isolated from a natural honey. AB - A very high pullulan producing yeast-like fungus, Aureobasidium melanogenum TN1-2 isolated from a natural honey was found to be able to produce 97.0 g/L of pullulan from 140.0 g/L sucrose at a flask level while it could yield 114.0 g/L of pullulan within 134 h during a 10-liter fermentation, the yield was 0.81 g/g and the productivity was 0.86 g/L/h. The high ability to biosynthesize pullulan by this yeast-like fungal strain TN1-2 was related to high glucosyltransferase activity, high phosphofructo-2-kinase activity, high content of its cellular glycerol and low glucose repressor. The Mw of the produced pullulan was 1.42 * 105 g/mol. The low Mw may be due to the high alpha-amylase, glucoamylase and isopullulanase activities. The intracellular level of trehalose had no influence on high pullulan production by the yeast-like fungal strain TN1-2. PMID- 29622214 TI - Nutritional analysis of Spirulina dietary supplements: Optimization procedure of ultrasound-assisted digestion for multielemental determination. AB - Arthrospira platensis and Arthrospira maxima are a type of blue-green microalga used as a dietary supplement (Spirulina). A low time-consuming ultrasound assisted digestion (UAD) of Spirulina supplements for multielemental determination by microwave induced plasma atomic emission spectrometry (MPAES) was performed. Several parameters such as acid concentration (AC), thermostated water bath (TWB), digestion time (DT) and UAD - probe or bath - affecting the digestion process were evaluated through a full factorial design. Under the optimal conditions -100 degrees C for TWB, 5% for AC and 10 min for DT- and selecting the bath as the proper UAD system, the concentrations of 15 analytes (Al, Ba, Ca, Cd, Cr, Cu, Fe, K, Mg, Mn, Na, Ni, P, V, Zn) were reported. The values are in accordance with the recommendation established by Food and Drug Administration (FDA) excepting for Cd. The knowledge of Spirulina multielemental composition contributes to an outstanding nutritional and toxicological report for human health. PMID- 29622215 TI - Use of fish trypsin immobilized onto magnetic-chitosan composite as a new tool to detect antinutrients in aquafeeds. AB - The unplanned inclusion of antinutrients in fish food affects many biological processes, such as digestibility of amino acids and diet conversion, resulting in undesirable effects on body growth. Thus, the objective of this research was to propose the use of immobilized fish proteases in the detection of protease inhibitors, one of the most important antinutrients. In order to evaluate the detection of antinutritional factors through the immobilized trypsin, the enzyme was incubated with eight diets developed for commercial fish, and residual activity was measured. Comparatively, the tilapia trypsin showed an inhibition of antinutrients (protease inhibitors), present in the eight studied diets, up to 48% greater than the porcine trypsin immobilized in magnetic chitosan. Thus, it is possible to suggest the use of immobilized derivatives containing specific proteases of the target organism in the detection of antinutritional factors that reduce animal's digestive capacity and negatively influence their growth during husbandry. PMID- 29622216 TI - Cold low pressure O2 plasma treatment of Crocus sativus: An efficient way to eliminate toxicogenic fungi with minor effect on molecular and cellular properties of saffron. AB - In this study cold low pressure radiofrequency oxygen plasma was used for the first time to inactivate toxicogenic fungi proliferation on saffron. Varieties of plasma produced reactive oxygen species which were investigated by optical emission spectroscopy. The data were indicative of the absence of UV radiation. Effects of plasma treatment on antioxidant activity, metabolic content, colour, odour and flavour parameters and physical impact on saffron were investigated. A range of plasma powers and exposure times were assayed in suppression of fungal growth. Amongst which power of 60 W for 15 min was used to eradicate Aspergillus and other microorganisms. The ferric reducing antioxidant power was changed from 1778.21 to 1674.25 mM/g dry weight following plasma treatment. Moreover, crocin ester, picrocrocin and safranal metabolites reduced insignificantly. Additionally, plasma had no significant impact on colour, odour and flavour of saffron. PMID- 29622217 TI - Maximizing carotenoid extraction from microalgae used as food additives and determined by liquid chromatography (HPLC). AB - Microalgae are an interesting source of natural pigments that have valuable applications. However, further research is necessary to develop processes that allow us to achieve high levels of carotenoid recovery while avoiding degradation. This work presents a comprehensive study on the recovery of carotenoids from several microalgae genera, optimizing carotenoid extraction using alkaline saponification at various temperatures and KOH concentrations. Results show that I. galbana requires a temperature of 60 degrees C and <10% KOH, N. gaditana and K. veneficum require 60 degrees C and no saponification, P. reticulatum requires 40 degrees C and 10% KOH, T. suecica and H. pluvialis require 25 degrees C and 40% KOH while C. sp. and S. almeriensis require 80 degrees C and 40% KOH. The influence of the solvent on carotenoid recovery was also studied. In general terms, an ethanol:hexane:water (77:17:6 v/v/v) mixture results in good yields. PMID- 29622218 TI - Quality assessment of saffron (Crocus sativus L.) extracts via UHPLC-DAD-MS analysis and detection of adulteration using gardenia fruit extract (Gardenia jasminoides Ellis). AB - A new UHPLC-DAD-MS method based on a Core-Shell particles column was developed to realize the rapid separation of saffron stigma metabolites (Crocus sativus L.). A single separation of 35 compounds included cis and trans-crocetin esters (crocins), cis-crocetin, trans-crocetin, kaempferol derivatives, safranal, and picrocrocin from pure saffron stigmas. This method permitted the detection of 11 picrocrocin derivatives as the typical group of compounds from saffron as well as the detection of gardenia-specific compounds as typical adulterant markers. The metabolite concentration in a Standardized Saffron Extract (SSE) was determined using the method described herein and by comparison to the ISO3632 conventional method. The safranal content was 5-150 times lower than the value of 2% that was expected via ISO3632 analyses. Using the same Core-Shell separation, geniposide detection appeared to be a relevant approach for detecting the adulteration of saffron by using gardenia. PMID- 29622219 TI - Modification of carrot (Daucus carota Linn. var. Sativa Hoffm.) pomace insoluble dietary fiber with complex enzyme method, ultrafine comminution, and high hydrostatic pressure. AB - Insoluble dietary fiber (DF) extracted from carrot pomace was modified by complex enzyme method, ultrafine comminution and high hydrostatic pressure and their structural, physicochemical, and functional properties were evaluated. Results showed that complex enzyme method increased the content of soluble DF to 15.07%, and the cholesterol adsorption capacity peaked; ultrafine comminution greatly improved the total antioxidant activities, DPPH radical scavenging capacity and antioxidant abilities in linoleic acid system of DF; high hydrostatic pressure led to a significant increase in capacities of water retention (7.14 g/g, 600 MPa), water swelling (10.02 mL/g, 500 MPa), oil retention (2.35 g/g, 500 MPa), cation exchange (2.29 mmol/g, 600 MPa), and glucose adsorption (2.634 mmol/g, 400 MPa). Furthermore, SEM showed that surface structures of all modified DF were loose. Overall, three kinds of modification methods have shown their respective advantages. Modified DF from carrot pomace can be applied as a functional ingredient in diverse food products. PMID- 29622220 TI - Individual contributions of Savinase and Lactobacillus plantarum to lentil functionalization during alkaline pH-controlled fermentation. AB - Legumes offer the possibility to develop multifunctional foods with benefits for metabolic syndrome. Our objective was to study the effect of alkaline fermentation by Lactobacillus plantarum and Savinase (FLPS) as well the individual effects of both processes on peptides, phenolics and bioactivity of lentil. FLPS increased peptides and some flavonoids and enhanced antioxidant activity, inhibition of angiotensin I-converting enzyme (ACE) and intestinal maltase activities of lentil soluble fraction. Savinase contributed to peptide release, ACE inhibitory and antioxidant activities of lentil soluble fraction. L. plantarum affected to phenolic composition, alpha-glucosidase and lipase inhibitory activities. Mass spectrometry analysis of the most active fermented lentil subfraction allowed the identification of the main bioactive compounds. Gastrointestinal digestion of fermented lentil increased bioaccessibility of peptides and phenolics as well as antioxidant activity. FLPS enhanced the overall healthy potential of lentil offering the possibility of its use as strategy for lentil functionalization. PMID- 29622222 TI - Screening of critical factors influencing the efficient hydrolysis of zeaxanthin dipalmitate in an adapted in vitro- digestion model. AB - As hydrolysis of carotenoid esters is believed to be highly efficient in vivo, their insufficient hydrolysis in in vitro-digestion models, particularly, regarding zeaxanthin diesters, is a current issue. Therefore, in this study, several factors related to the enzymatic hydrolysis were investigated in an adapted version of the standardized INFOGEST in vitro-digestion model, using zeaxanthin dipalmitate (ZDP) as a substrate. The results showed that pancreatic lipase was able to hydrolyze ZDP, whereas carboxyl ester lipase (CEL) substantially contributed to ZDP cleavage. Replacement of commonly used porcine with bovine bile extracts and the substitution of coffee creamer for soybean oil at identical fat contents both significantly improved hydrolysis efficiency and bioaccessibility of total zeaxanthin to better mimic in vivo conditions. Thus, bile and lipids selection for in vitro digestion of carotenoid esters was crucial. The combined use of coffee creamer, pancreatin, CEL, and bovine bile led to the highest hydrolysis efficiency of 29.5%. PMID- 29622221 TI - Volatile profile of white wines fermented with sequential inoculation of Starmerella bacillaris and Saccharomyces cerevisiae. AB - Mixed fermentations with Starmerella bacillaris and Saccharomyces cerevisiae affect the chemical composition of wines, by modulating various metabolites of oenological interest. The current study was carried out to elucidate the effect of sequential inoculation of the above mentioned species on the production of white wines, especially on the chemical and aromatic characteristics of Chardonnay, Muscat, Riesling and Sauvignon blanc wines. Titratable acidity and glycerol content exhibited evident differences among the wines after fermentation. For volatile compounds, mixed fermentations led to a reduction of the total esters, including ethyl acetate, which is a compound responsible for wine deterioration. However, Sauvignon blanc wines fermented by mixed cultures contained significantly higher levels of esters and thiols, both associated with positive sensory attributes. These findings suggest that sequential inoculations possess great potential in affecting and modulating the chemical and aromatic profile of white wines, especially those produced from Sauvignon blanc grapes. PMID- 29622223 TI - Characterisation of beta-carotene partitioning in protein emulsions: Effects of pre-treatments, solid fat content and emulsifier type. AB - Understanding the bioactive partitioning between the phases of an emulsion system underpins strategies for improving the efficiency of bioactive protection against degradation. We analysed partitioning of beta-carotene in emulsions with various formulations in-situ using confocal Raman microscopy (CRM). The partitioning of beta-carotene into the aqueous phase of emulsions increased when whey protein isolate (WPI) was heat or high pressure-treated prior to emulsion formation. However, increasing the concentration of high pressure-treated WPI reduced the beta-carotene partitioning into the aqueous phase. Increasing the solid fat content in the carrier oil favoured the migration of beta-carotene into the aqueous phase. The use of WPI as the emulsifier resulted in a greater partitioning of beta-carotene into the aqueous phase compared to when Tween 40 was the emulsifier. This study demonstrates that partitioning of beta-carotene between the aqueous and oil phase is dependent on the characteristics of the oil phase, emulsifier type and processing. PMID- 29622224 TI - Genetic diversity of potato genotypes estimated by starch physicochemical properties and microsatellite markers. AB - Genetic diversity of 29 potato genotypes was estimated by their starch physicochemical properties and microsatellite markers. The apparent amylose content (AAC) of potato starches averaged 25.3%, ranging from 18.9 to 29.4%. Significance differences were observed in pasting and gel texture properties among potato accessions. Wide genetic diversity was also found in the gelatinization temperatures (To, Tp, Tc), enthalpies of gelatinization, enthalpies of retrogradation and retrogradation percentage, which had ranges of 62.2-67.6 degrees C, 66.1-71.1 degrees C, 73.5-77.4 degrees C, 17.5-21.0 J/g, 1.95-4.41 J/g, and 10.6-21.4%, respectively. AAC had significant correlation with pasting viscosities and gel hardness, but had no correlation with thermal and retrogradation properties. The grouping of the potato genotypes using 30 microsatellite markers did not correspond to that drawn using the starch physicochemical properties. Molecular analysis revealed that genotypes with interesting starch properties were distributed among three clusters. Potato starches exhibited interesting physiochemical properties could be applied in food and industrial applications. PMID- 29622225 TI - Bioactive compounds and quality parameters of avocado oil obtained by different processes. AB - The objective of this study was to evaluate the quality of avocado oil whose pulp was processed through different drying and oil extraction methods. The physicochemical characteristics of avocados cv. Breda were determined after drying the pulp in an oven under ventilation (40 degrees C and 60 degrees C) and vacuum oven (60 degrees C), followed by the oil extracted by mechanical pressing or the Soxhlet method. From the approximately 72% pulp found in the avocado fruit, the 16% fraction is lipids. The quality indices evaluated in avocado oil showed better results when the pulp was dried at 60 degrees C under vacuum and oil extraction was done by the Soxhlet method with petroleum ether, whereas the bioactive compounds were better preserved when the avocado pulp was dried at 60 degrees C under ventilation and mechanical pressing was used for the oil extraction. Among the fatty acids found, oleic acid was the main. PMID- 29622226 TI - Specific colorimetric ELISA method based on DNA hybridization reaction and non crosslinking gold nanoparticles aggregation for the detection of amantadine. AB - Amantadine (AMD), a banned antiviral veterinary drug, is still being abused. This study developed a novel enzyme linked immunosorbent assay for the colorimetric detection of AMD involving DNA hybridization reaction and non-crosslinking gold nanoparticles (AuNPs) aggregation. Accordingly, the Primer 1-AuNPs-anti-AMD monoclonal antibody (mAb) could be captured by AMD artificial antigen on ELISA wells. Primer 2, which was complementary paired to Primer 1, was eventually added into the ELISA wells. After the hybridization reaction, the free Primer 2 in the supernatant was mixed with AuNPs and NaCl and induced a rapid color change of AuNPs. The lack of AMD in the sample resulted in capturing a substantial Primer 1 AuNPs-mAb complex and limited free Primer 2 in the supernatant. After adding NaCl, the color of AuNPs turned blue with limited Primer 2. This simple and visualized novel method had good sensitivity (0.033 MUM) and exhibited a potential application for AMD screening on site. PMID- 29622227 TI - The terroir of Port wine: Two hundred and sixty years of history. AB - Port wine is an internationally acclaimed fortified wine produced in Douro Demarcated Region (DDR) in Portugal, and recognized with protected designation of origin. This review represents a compilation of the known chromatic and aromatic descriptors of Port wine. A comprehensive review of literature is performed regarding the influence of geography, climate, soil, grapevine cultivars, and vitivinicultural practices on the unique Port wine attributes. This manuscript provides an extensive insight regarding the different aspects that influence the quality and uniqueness of Port wine, especially its main sensory attributes: colour, aroma, and flavour. Its main goal is to assess the importance of the DDR as a unique and defined terroir that ensures quality and confers authenticity. PMID- 29622228 TI - The relative antioxidant activity and steric structure of green tea catechins - A kinetic approach. AB - There are eight most abundant green tea catechins (GTCs) existing in four pairs of eipimers, and carbon-3 configuration represents the only steric difference within each pair. This study aimed to use a new kinetic approach to elucidate the effect of stereochemical changes on the antioxidant activity. A mixture of eight GTCs was treated by 2,2-diphenyl-1-picrylhydrazyl (DPPH) prepared in a series of concentrations, their relative reaction rates towards scavenging DPPH were revealed by the recently introduced parameter, i.e. Dm. The 3-R configuration in (-)-epicatechin, (-)-epigallocatechin and (-)-epigallocatechin gallate gave lower Dm values demonstrating faster kinetics as opposed to their 3-S counterparts, with the only exception of the pair of (-)-catechin gallate and (-)-epicatechin gallate in which 3-S configuration was faster. These results suggested that the kinetic approach adopted in this study could reflect the different antioxidant activity of GTCs attributed by minor steric changes. PMID- 29622229 TI - Gas chromatography-mass spectrometry determination of polycyclic aromatic hydrocarbons in baby food using QuEChERS combined with low-density solvent dispersive liquid-liquid microextraction. AB - A sensitive GC-MS method is reported for the determination of twelve polycyclic aromatic hydrocarbons (PAHs) in baby food. The sample preparation involves QuEChERS extraction combined with low-density solvent dispersive liquid-liquid microextraction (LDS-DLLME) and ultra-low temperature (-80 degrees C). Plackett Burman screening design was employed to identify the main sample preparation variables that affect the extraction efficiency, such as the volume of toluene used in LDS-DLLME. The suitability of proposed method was verified by analytical selectivity, linearity in solvent and matrix-matched calibration curves and adequate recoveries (72-112%) and precision (RSD values <=11%), under repeatability and within-laboratory reproducibility conditions. High analytical sensitivity was achieved for the monitoring of PAHs at the strict limit of 1 ug kg-1 fixed by the European Commission for baby foods. The validated method was applied to thirty-two commercial baby food samples, and the investigated PAHs were not detected in any sample. PMID- 29622230 TI - Hydrophilic interaction chromatography in food matrices analysis: An updated review. AB - This review focuses on the most recent papers (from 2011 to submission date in 2017) dealing with the analysis of different organic components in foods (i.e. nucleobases, nucleosides, nucleotides, uric acid, and creatinine, amino acids and related compounds, choline-related compounds and phospholipids, carbohydrates, artificial sweeteners and polyphenolic compounds), using hydrophilic interaction liquid chromatography (HILIC) combined with different detection techniques. For each compound class, the investigated food matrices are grouped per: foods of animal origin, vegetables, fruits and related products, baby food, and other matrices such as drinks and mushrooms/fungi. Furthermore, the main advantages of HILIC chromatography respect to the other commonly used techniques are discussed. PMID- 29622231 TI - Development of loop-mediated isothermal amplification (LAMP) assays for the rapid detection of allergic peanut in processed food. AB - Peanut is a widely and common used in many cuisines around the world. However, peanut is also one of the most important food allergen for causing anaphylactic reaction. To prevent allergic reaction, the best way is to avoid the food allergen or food containing allergic ingredient such as peanut before food consuming. Thus, to efficient and precisely detect the allergic ingredient, peanut or related product, is essential and required for maintain consumer's health or their interest. In this study, a loop-mediated isothermal amplification (LAMP) assay was developed for the detection of allergic peanut using specifically designed primer sets. Two sets of the specific LAMP primers respectively targeted the internal transcribed sequence 1 (ITS1) of nuclear ribosomal DNA sequence regions and the ara h1 gene sequence of Arachia hypogeae (peanut) were used to address the application of LAMP for detecting peanut in processed food or diet. The results demonstrated that the identification of peanut using the newly designed primers for ITS 1 sequence is more sensitive rather than primers for sequence of Ara h1 gene when performing LAMP assay. Besides, the sensitivity of LAMP for detecting peanut is also higher than the traditional PCR method. These LAMP primers sets showed high specificity for the identification of the peanut and had no cross-reaction to other species of nut including walnut, hazelnut, almonds, cashew and macadamia nut. Moreover, when minimal 0.1% peanuts were mixed with other nuts ingredients at different ratios, no any cross-reactivity was evident during performing LAMP. Finally, genomic DNAs extracted from boiled and steamed peanut were used as templates; the detection of peanut by LAMP was not affected and reproducible. As to this established LAMP herein, not only can peanut ingredients be detected but commercial foods containing peanut can also be identified. This assay will be useful and potential for the rapid detection of peanut in practical food markets. PMID- 29622232 TI - Modulating analytical characteristics of thermovinified Carignan musts and the volatile composition of the resulting wines through the heating temperature. AB - The impact of two temperature levels (50 degrees C and 75 degrees C) and heating times (30 min and 3 h) on the composition of thermovinified musts and wines from Carignan was investigated at the laboratory scale in 2014 and 2015. The heating temperature had a significant impact on the extraction of amino acids and a probable thermal degradation of anthocyanins was noted at 75 degrees C. In 2014, musts from grapes that underwent a heat treatment at 50 degrees C for 3 h had a similar level of phenolic compounds as those treated at 75 degrees C for 30 min. This indicates that the reduction of the heating temperature in some vintages can be compensated for through an extension of the heating period. Several grape-derived molecules were impacted by the rise in temperature and wines made from grapes treated at 50 degrees C in most cases contained larger concentrations of geraniol, beta-citronellol, beta-damascenone and 3 mercaptohexanol. PMID- 29622233 TI - Comparison of structural and functional properties of starches from five fruit kernels. AB - Starch was isolated from the kernels of jackfruit, longan, loquat, litchi, and mango fruits, which contained approximately 56, 59, 71, 53, and 64% starch, respectively, indicating that these fruit kernels are good starch sources. The structural and functional properties of these isolated starches were investigated and compared. The starches had irregular, truncated, spherical, and elliptical shapes with central hila and exhibited different sizes, with mango starch being the largest and jackfruit and longan starches being the smallest. The five starches had similar amylose contents but exhibited significantly different crystalline properties including crystalline type, relative crystallinity, short range ordered structure, and lamellar intensity. Among the five starches, the jackfruit and loquat starches had the highest and lowest gelatinization temperature and enthalpy, respectively, and the litchi and mango starches had the highest and lowest pasting viscosity, respectively. The longan and loquat starches were more susceptible to enzyme hydrolysis than the other starches. PMID- 29622234 TI - Exploring reserve lots of Cymbopogon citratus, Aloysia citrodora and Thymus * citriodorus as improved sources of phenolic compounds. AB - Given the increasing consumers demand for novelty, tea companies have been presenting new added value products such as reserve lots of aromatic plants. Herein, infusions from different lots of three aromatic plants were assessed in terms of phenolic composition (HPLC-DAD-ESI/MS) and antioxidant properties (reducing power, free radical scavenging and lipid peroxidation inhibition capacity). Cymbopogon citratus (C. citratus; main compound 5-O-caffeoylquinic acid) and Aloysia citrodora (A. citrodora; prevalence of verbascoside) reserve lots revealed higher phenolic compounds concentration than the respective standard lots. Thymus * citriodorus (T. citriodorus; main compound rosmarinic acid) standard lot presented higher amounts of phenolic acids than the reserve lot, nonetheless, total flavonoids and phenolic compounds were not significantly different. The differences between both lots antioxidant activity were more noticeable in C. citratus, with the reserve lot presenting the highest activity. This study provides evidence of the differences between these plants chemical composition and bioactivity depending on the harvesting conditions. PMID- 29622236 TI - My Kind of Town (Chicago Is): Content Collections Optimize Learning Related to the 2018 AANA Annual Meeting. AB - The 2018 Arthroscopy Association of North America Annual Meeting represents an opportunity to deepen one's understanding of a wide variety of topics. Arthroscopy journal readers have diverse practices and interests, and the meeting is designed to accommodate individual needs. The constructivist learning theory provides that scholars learn in many different ways. Thus, to enrich your learning experience, selected recently published Arthroscopy articles are suggested to supplement material presented at the meeting. The articles are collated on our web site in Content Collections, to allow meeting participants to prepare and to allow those unable to attend to remain engaged. We offer suggestions and encourage readers to customize their own learning experience. PMID- 29622237 TI - Regarding "Development and Efficacy Testing of a 'Hollow Awl' That Leads to Patent Bone Marrow Channels and Greater Mesenchymal Stem Cell Mobilization During Bone Marrow Stimulation Cartilage Repair Surgery". PMID- 29622235 TI - Metabolic profiling of four South African herbal teas using high resolution liquid chromatography-mass spectrometry and nuclear magnetic resonance. AB - Increased preference to herbal drinks has led to global interest in the use and production of different plant species for the preparation of various drink formulations. Medicinal properties derived from bioactive compounds remain the main driver of choice for herbal teas. This study determined the chemical variation in honeybush, rooibos, special and bush tea, profiled compounds responsible for such differences and compared their peak areas. Nuclear magnetic resonance and high resolution liquid chromatography-mass spectrometry were used to determine compound variation and profiling. Principal component analysis and partial-least square multivariate statistical analysis showed distinct differences (P < 0.05) between the different types of herbal teas. Detected compounds included flavonoids, phenolics, lignans, megastigmane glycoside, most of which possess health benefits. The findings showed that South African herbal teas could play a vital role as health promoting drinks, and that bush tea and special tea are phytochemically comparable with other commercialized herbal teas. PMID- 29622238 TI - Regarding "Revision Arthroscopic Repair Versus Latarjet Procedure in Patients With Recurrent Instability After Initial Repair Attempt: A Cost-Effectiveness Model". PMID- 29622239 TI - Author Reply to "Regarding 'Revision Arthroscopic Repair Versus Latarjet Procedure in Patients With Recurrent Instability After Initial Repair Attempt: A Cost-Effectiveness Model'". PMID- 29622240 TI - Spouse Reply to "Research Pearls: The Significance of Statistics and Perils of Pooling". PMID- 29622241 TI - Author Reply: Research Pearls: The Significance of Statistics and Perils of Pooling-"Know Your Audience". PMID- 29622242 TI - Editorial Commentary: The Anterolateral Ligament: The Emperor's New Clothes? AB - In the following editorial commentary, the lateral soft tissues responsible for resisting the pivot shift phenomenon with the anterior cruciate ligament (ACL) are considered. The recent history of the anterolateral ligament (ALL) has led to rapid adoption of surgical techniques that have often not been investigated with scientific due process. A step-by-step approach starts with biomechanical testing to establish the anatomy and biomechanical characteristics of soft tissue structures and questions the importance of the ALL and proposes a more important role for the iliotibial band (ITB) passing between attachments to the distal lateral femur and tibia. Subsequent laboratory testing of various operative options shows superiority of lateral extra-articular tenodeses (LETs) as compared with ALL reconstruction. PMID- 29622243 TI - Editorial Commentary: Standing the Test of Time and Sport: Fulkerson Tibial Tubercle Osteotomy of the Knee. AB - A biplanar osteotomy aiming to anteromedialize the anterior tibial tuberosity to realign the patellofemoral joint described by Prof. Fulkerson is one of the classical operations to address many pathologies of the patellofemoral joint. The procedure is evidence-based and effective for the management of patellofemoral pain and osteoarthritis, confirming that the original ideas and concepts are still valid, and still stand strong. In high-demand patients, the Fulkerson osteotomy offers good opportunities of success in terms of return to sport. With the right indications, patients will gain several years of pain-free sports participation. PMID- 29622244 TI - Editorial Commentary: To Treat or Not to Treat? Are We Any Closer to Knowing What to Do With Cartilage Lesions of the Tibia? AB - The increasing interest and use of cartilage repair procedures in the knee has led to a better understanding of when and how chondral lesions should be treated. Nonetheless, there are still key areas where we lack understanding and need better data to guide clinical decision making. One of these areas is how to manage lesions of the tibia, particularly when they occur in conjunction with the more commonplace lesions of the femoral condyle. In this setting, a tibial chondral lesion may reflect a bigger clinical problem-a "bipolar defect" or more advanced joint disease-"established osteoarthritis." My preferred treatment for these tibial lesions is to ignore the lesion (or perform a chondroplasty at most), except in cases of osteochondritis dissecans, focal defects in association with cysts, or tibial plateau fracture malunion. PMID- 29622245 TI - Editorial Commentary: We Know We Need to Fix Knee Meniscal Radial Root Tears-But How Best to Perform the Repairs? AB - The present work further contributes to building the base of the research pyramid by noting the importance of repairing knee meniscal radial root tears. Because of the extensive biomechanical studies that have now been published on the restoration of joint mechanics and with what I believe results in a higher likelihood of an improved healing environment with securing the meniscus root tear down to bone, I would strongly recommend that when one does see a meniscus root tear that the transtibial pullout root repair technique be considered over a side-to-side repair. The biggest challenge going forward is to validate and improve the healing potential of knee meniscal radial root repairs. PMID- 29622246 TI - Editorial Commentary: Knee Medial Patellofemoral Ligament Reconstruction Does Not Always Result in the "Bee's Knees". AB - Reconstruction of the medial patellofemoral ligament has gained in popularity as a surgical technique to reconcile recurrent lateral patellar instability. This technique has shown success in a variety of settings including with concomitant osseous abnormalities. Despite the general good to excellent results with medial patellofemoral ligament reconstruction, a number of technical errors are still commonly made and may result in decreased range of motion, pain, chondrosis, and arthrofibrosis. In a recent study, the importance of knee flexion angle during final fixation of the graft is emphasized. Even with appropriate tunnel placement, and minimal tension on the graft, graft fixation performed at less than or greater than 60 degrees of knee flexion results in medial patellar overload with risk of the aforementioned complications. PMID- 29622247 TI - Editorial Commentary: Using Computer Simulations to Predict Functional Outcome After Surgery. AB - Computer simulations of surgical procedures can be used to predict functional outcome after surgery. To impact clinical decision making, the simulations must be an accurate representation of the in vivo condition. PMID- 29622248 TI - Editorial Commentary: We PROMIS...One More Patient-Reported Outcome Questionnaire! AB - The Patient-Reported Outcomes Measurement Information System (PROMIS) is a set of powerful computer adaptive patient-reported outcome tools that have the ability to evaluate physical, mental, and social health measures in adults and children. It has recently been implemented for a variety of musculoskeletal conditions, but the psychometric properties of the scores in the setting of orthopaedic sports medicine and arthroscopy are incompletely explored. Determining normative data and responsiveness in cohorts of interest is vital if these measures are to be used to track patient-reported outcomes postoperatively. PMID- 29622249 TI - Editorial Commentary: Put Down Your Saw and Pick Up Your Scope! Or, Why Burn Down the Bridge When the Road Ahead Is Full of Potholes? Reverse Total Shoulder Replacement Versus Arthroscopic Rotator Cuff Repair. AB - Are we doing too many reverse total shoulder replacements and not fixing enough repairable rotator cuff tears? A convincing argument can be made for attempting to repair most, not all, very large rotator cuff tears in patients who do not have a significant arthritic change in the shoulder. My experience over more than 25 years of arthroscopic rotator cuff repair (ARCR) is that the only good way to know if it is repairable is to try. But some patients really do not pass my "eyeball test" as to whether they can rehabilitate and heal enough to make an ARCR reasonable. Magnetic resonance imaging scans are useful, mostly to help me with tear pattern recognition, how much time and skill I might need for the repair, and to help me council my patients as to their ultimate functional recovery. I have had surprises both ways: some ARCRs that I thought would be easy turned out to be very challenging and others that I thought would be "mission impossible" turned out to be "mission accomplished"! The rationale for jumping ahead primarily to reverse total shoulder replacements reminds me of certain tax cut plans I have heard talk of lately. Sounds great now (well, maybe the complication rate is a little high) but there might be a price to pay down the road. PMID- 29622250 TI - Editorial Commentary: Don't Throw Away the Retractors: Complications of Open Versus Arthroscopic Rotator Cuff Repair Could Be Influenced by Indications. AB - Shoulder surgeons must carefully interpret literature that compares outcomes and complications of open and arthroscopic rotator cuff repair techniques. It is important for shoulder surgeons to be facile with both techniques. PMID- 29622251 TI - Editorial Commentary: An Alternative to Opioids? Adhesive Drapes and Chlorhexidine Skin Preparation May Reduce Propionibacterium acnes-Related Pain After Shoulder Surgery. AB - Propionibacterium acnes has long been known to play a detrimental role in shoulder surgery. This thoughtful and revealing study found significant evidence of lower rates of P. acnes cultured during arthroscopic rotator cuff repair with the use of an adhesive drape and chlorhexidine skin preparation. PMID- 29622252 TI - Editorial Commentary: Complications of Shoulder Rotator Cuff Repair Are Relevant in Modern Health Care. AB - Understanding the type and rate of complications after shoulder rotator cuff repair could help surgeons to focus their quality improvement efforts. This is of great current relevance because value in health care is defined as the ratio of outcomes over cost, and complications increase cost significantly. A particular focus could be on lowering the rate of complications associated with "riskier" patients and "riskier" surgical techniques. PMID- 29622253 TI - Editorial Commentary: "Popeye" Deformity After Spontaneous Proximal Biceps Tendon Rupture: Image, Treat, or Ignore? AB - We have long been accustomed to treat proximal biceps tendon ruptures with reassurance unless the patient cannot accept the resulting "Popeye" deformity. A recent study hypothesizes that these patients deserve a magnetic resonance imaging scan to identify associated rotator cuff pathology, specifically supraspinatus and subscapularis tendon tears. The authors of this study ask an important question and provide a compelling, if incomplete, answer. PMID- 29622254 TI - Editorial Commentary: A Model for Shoulder Rotator Cuff Repair and for Basic Science Investigations. AB - "Breaking the fourth wall" is a theater convention where the narrator or character speaks directly to the audience. As an Assistant Editor-in-Chief, as I comment on a recent basic science study investigating rotator cuff repair, I break the fourth wall and articulate areas of basic science research excellence that align with the vision that we hold for our journal. Inclusion of a powerful video strengthens the submission. We prefer to publish clinical videos in our companion journal, Arthroscopy Techniques, and encourage basic science video submissions to Arthroscopy. Basic science research requires step-by-tedious-step analogous to climbing a mountain. Establishment of a murine rotator cuff repair model was rigorous and research intensive, biomechanically, radiographically, histologically, and genetically documented, a huge step toward the bone-to-tendon healing research summit. This research results in a model for both rotator cuff repair and the pinnacle of quality, basic science research. PMID- 29622255 TI - Editorial Commentary: Distal Mononeuropathy in Conjunction With Rotator Cuff Repair: Don't Forget the Preoperative Assessment. AB - Distal mononeuropathy can be a pre-existing condition in patients undergoing arthroscopic rotator cuff repair. It can also develop after the surgical procedure. PMID- 29622256 TI - Editorial Commentary: Treatment of Partial Thickness Undersurface Abductor Tears of the Hip: Like Backwards a Bike Riding. AB - Partial thickness undersurface abductor tears can be effectively treated with a transtendinous gluteus medius and minimus repair, with decreased pain and improvement in abductor strength. The surgical treatment of this condition runs counter to traditional treatment for "greater trochanteric bursitis," and adoption may be more difficult as a result. PMID- 29622257 TI - Editorial Commentary: What Irks a Hip Arthroscopist? Intraoperative Anchor Failure. AB - Intraoperative suture anchor failure is a seemingly unavoidable event during hip arthroscopy and it can happen to the best of us. To date, biomechanical cadaveric studies saturate hip anchor failure literature with only one known, published in vivo investigation. We now know that intraoperative anchor failure is an uncommon occurrence that does not significantly vary between basic population demographics. However, we have only been provided with foundational knowledge, and our community must continue to expand upon the basics. PMID- 29622258 TI - Editorial Commentary: Be on the Lookout for White Chalk! Hip Labrum Calcification. AB - Amorphous calcification of the hip labrum is a little known and relatively rare condition. Although patients with amorphous calcification have favorable post arthroscopic surgery self-reported outcome, it is unclear how much of their improvement can be attributed to the debridement of the calcific lesion itself. PMID- 29622259 TI - Editorial Commentary: Hip Labral Revision Reconstruction in a Fellowship Training Center: A Report From the Mountains. AB - Hip labral reconstruction has proven to be a successful technique in restoring normal labrum function. However, sometimes revision surgery is required. A recent, well-designed prospective study provides significant support for revision labral reconstruction, showing how it leads to improved hip mechanics and reduction in pain. The success of the study design and this report is a testament to an educational institution dedicated to fellowship training. PMID- 29622260 TI - Editorial Commentary: Is Endoscopy Really Helpful During Repair of Acute Rupture of the Achilles Tendon? AB - Endoscopically assisted Achilles tendon repair is an attractive minimally invasive approach to reduce the risk of sural nerve injury. However, I do not believe that endoscopy is necessary for all types of minimally invasive Achilles tendon repair. Endoscopy is only helpful to make suture passage through the proximal lateral portal safe. It cannot help to reduce the risk of sural nerve injury if the tendon is repaired with percutaneous locking sutures. Abandonment of the proximal lateral portal and development of "all-inside" endoscopic repair of the Achilles tendon with locking sutures should be the future goal. PMID- 29622261 TI - Editorial Commentary: Is Vitamin D the New Wheaties? Preventing Muscle Fatigue Could Keep Athletes in the Game. AB - Vitamin D deficiency is an oft overlooked and underevaluated condition that is widespread in patient-athletes, including the elite and professional. Although the symptomatology of this deficiency is well known in the general population (osteoporosis and increased risk of fracture), the symptom of muscle fatigue is not. It is only recently that the association between vitamin D deficiency and muscle fatigue in professional athletes has been placed in the spotlight. However, vitamin D deficiency should be of increasing concern for orthopaedists in regard to all athletes. In the elite collegiate/professional ranks, this condition may lead to detrimental injuries with career-altering effects. Although this condition may not affect career and financial well-being for most patients, modifications in athletic performance and lifestyle are still of utmost value to any athlete. Although I do not condone ordering vitamin D levels as a screening tool, nor broadly prescribing supplements to all patient-athletes, I do believe that it is warranted if certain "high-risk" criteria are met. PMID- 29622262 TI - Editorial Commentary: Shoulder Instability Outcome Reporting Requires Standardization. AB - A recent review highlights outcomes reported after arthroscopic anterior shoulder instability repair in adolescents and shows great variability in the reporting of outcome in terms of patient-reported outcome measures (PROMs), recurrence, return to sport, satisfaction, pain, and physical examination findings. These findings highlight the importance of more standardized outcome reporting including using consistent measures between studies, using validated PROMs, and using age appropriate PROMs. PMID- 29622263 TI - Editorial Commentary: Is the Biceps Tendon a Valid Option for Augmentation in Rotator Cuff Repair? Future Perspectives on Superior Capsule Reconstruction. AB - Biceps autograft can be a viable option for biological augmentation of massive rotator cuff repair, albeit results of this procedure might depend on the surgical technique. In the present qualitative systematic review, 8 case series were analyzed, in which biceps autograft was used as a scaffold or tissue bridge. Indeed, leaving the proximal portion intact and fixing it onto the greater tuberosity can simulate a superior capsule reconstruction, with potentially high biologic and mechanical advantages. PMID- 29622264 TI - Editorial Commentary: A Hip Scope Scoping Review on Surgical Outcome Reporting-If You Want to Know the Answer, You Have to Ask the Question. AB - The existing literature on subjects with femoroacetabular impingement syndrome undergoing arthroscopic or open hip preservation surgery reveals that outcome reporting is heterogeneous. There is significant inconsistency in patient reported outcome scores collected, symptoms and complaints assessed, clinical signs evaluated, and pre- and postoperative imaging metrics measured. PMID- 29622265 TI - Editorial Commentary: Medial Patellofemoral Ligament Reconstruction Alone Works Well When the Patient Has Normal Alignment, But Don't Forget to Move the Tibial Tubercle When Necessary! AB - Medial patellofemoral ligament reconstruction works very well, regardless of graft choice, for controlling lateral patella instability when performed correctly in patients with normal alignment, even in the face of trochlea dysplasia. However, sometimes a tibial tubercle transfer is necessary in patella instability surgery. PMID- 29622266 TI - Editorial Commentary: Not All Bone Marrow Aspirate Concentrates Are the Same: The Necessity of Detailed Reporting and Other Lessons Learned From Cell-based Treatments in Orthopaedics. AB - Bone marrow aspirate concentrates have become a popular therapeutic approach for several musculoskeletal conditions. A plethora of different preparations exist that make difficult to evaluate their clinical outcome and, thus, to make safe conclusions for their effectiveness. The first step for this assessment is comprehensive and reliable reporting of all the important variables that would allow characterization of their content and properties. This is critical for the understanding of their mechanism of action and the identification of the proper indications based on patient and disorder characteristics that could potentially lead to their effective application in clinical scenarios. PMID- 29622267 TI - Predicting performance and safety based on driver fatigue. AB - Fatigue causes decrements in vigilant attention and reaction time and is a major safety hazard in the trucking industry. There is a need to quantify the relationship between driver fatigue and safety in terms of operationally relevant measures. Hard-braking events are a suitable measure for this purpose as they are relatively easily observed and are correlated with collisions and near-crashes. We developed an analytic approach that predicts driver fatigue based on a biomathematical model and then estimates hard-braking events as a function of predicted fatigue, controlling for time of day to account for systematic variations in exposure (traffic density). The analysis used de-identified data from a previously published, naturalistic field study of 106 U.S. commercial motor vehicle (CMV) drivers. Data analyzed included drivers' official duty logs, sleep patterns measured around the clock using wrist actigraphy, and continuous recording of vehicle data to capture hard-braking events. The curve relating predicted fatigue to hard-braking events showed that the frequency of hard braking events increased as predicted fatigue levels worsened. For each increment on the fatigue scale, the frequency of hard-braking events increased by 7.8%. The results provide proof of concept for a novel approach that predicts fatigue based on drivers' sleep patterns and estimates driving performance in terms of an operational metric related to safety. The approach can be translated to practice by CMV operators to achieve a fatigue risk profile specific to their own settings, in order to support data-driven decisions about fatigue countermeasures that cost-effectively deliver quantifiable operational benefits. PMID- 29622270 TI - Emulsions in porous media: From single droplet behavior to applications for oil recovery. AB - Emulsions are suspensions of droplets ubiquitous in oil recovery from underground reservoirs. Oil is typically trapped in geological porous media where emulsions are either formed in situ or injected to elicit oil mobilization and thus enhance the amount of oil recovered. Here, we briefly review basic concepts on geometrical and wetting features of porous media, including thin film stability and fluids penetration modes, which are more relevant for oil recovery and oil contaminated aquifers. Then, we focus on the description of emulsion flow in porous media spanning from the behaviour of single droplets to the collective flow of a suspension of droplets, including the effect of bulk and interfacial rheology, hydrodynamic and physico-chemical interactions. Finally, we describe the particular case of emulsions used in underground porous media for enhanced oil recovery, thereby discussing some perspectives of future work. Although focused on oil recovery related topics, most of the insights we provide are useful towards remediation of oil-contaminated aquifers and for a basic understanding of emulsion flow in any kind of porous media, such as biological tissues. PMID- 29622269 TI - Bromelain-loaded nanoparticles: A comprehensive review of the state of the art. AB - Stem bromelain is a common available cysteine protease derived from pineapple (Ananas comosus L.). Bromelain finds widespread applications in several areas, such as medicine, health, food, and cosmetics, and its strong proteolytic activity supports its future application in many additional fields. However, most proteins and/or enzymes are fragile, leading to important considerations about increase storage and operational stability to enable their practical application. In this scenario, the use of nanoparticles to deliver proteins is increasing exponentially, given that these systems are capable of enhance active's stability, solubility and permeability, and decrease toxicity. In the pharmaceutical nanotechnology field, bromelain has played different roles and thus this paper aims to review the available literature for the use of nanoparticles and bromelain. PMID- 29622271 TI - Discussion of "Retro-peritoneal cooling for kidney preservation from multi-organ cadaver donors". PMID- 29622268 TI - Withdrawal From Cocaine Self-administration Alters the Regulation of Protein Translation in the Nucleus Accumbens. AB - BACKGROUND: Cue-induced cocaine craving incubates during abstinence from cocaine self-administration. Expression of incubation ultimately depends on elevation of homomeric GluA1 alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors in the nucleus accumbens (NAc). This adaptation requires ongoing protein translation for its maintenance. Aberrant translation is implicated in central nervous system diseases, but nothing is known about glutamatergic regulation of translation in the drug-naive NAc or after incubation. METHODS: NAc tissue was obtained from drug-naive rats and from rats after 1 or >40 days of abstinence from extended-access cocaine or saline self-administration. Newly translated proteins were labeled using 35S-Met/Cys or puromycin. We compared basal overall translation and its regulation by metabotropic glutamate receptor 1 (mGlu1), mGlu5, and N-methyl-D-aspartate receptors (NMDARs) in drug-naive, saline control, and cocaine rats, and we compared GluA1 and GluA2 translation by immunoprecipitating puromycin-labeled proteins. RESULTS: In all groups, overall translation was unaltered by mGlu1 blockade (LY367385) but increased by mGlu5 blockade (MTEP). NMDAR blockade (AVP) increased overall translation in drug-naive and saline control rats but not in cocaine/late withdrawal rats. Cocaine/late withdrawal rats exhibited greater translation of GluA1 (but not GluA2), which was not further affected by NMDAR blockade. CONCLUSIONS: Our results suggest that increased GluA1 translation contributes to the elevated homomeric GluA1 alpha amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptor levels in the NAc that mediate incubation. Additional contributions to incubation-related plasticity may result from loss of the braking influence on translation normally exerted by NMDARs. Apart from elucidating incubation-related adaptations, we found a suppressive effect of mGlu5 on NAc translation regardless of drug exposure, which is opposite to results obtained in the hippocampus and points to heterogeneity of translational regulation between brain regions. PMID- 29622272 TI - Discussion of: "Pre-surgical chemotherapy for breast cancer may be associated with improved outcomes". PMID- 29622273 TI - FR- Risk of Nonmelanoma Skin Cancer in Patients on Hemodialysis. PMID- 29622274 TI - Solitary Lesion on the Lateral Aspect of the Index Finger. PMID- 29622275 TI - Longitudinal cross-lagged relationships between mindfulness, posttraumatic stress symptoms, and posttraumatic growth in adolescents following the Yancheng tornado in China. AB - Treatment of posttraumatic stress symptoms and facilitation of posttraumatic growth are two encouraging areas of research, yet little is understood about the relationships between trait mindfulness, posttraumatic stress symptoms, and posttraumatic growth. Previous work suggests the linkages among these variables, but most studies have been conducted in adult samples. The aim of this study was to examine longitudinal cross-lagged relationships between mindfulness, posttraumatic stress symptoms, and posttraumatic growth among adolescent survivors of the 2016 Jiangsu tornado in China. Data was collected at two secondary schools located in Yancheng city, where the severe catastrophic damage occurred during the tornado. The sample included 247 adolescent survivors (59.5% girls) aged 12-14 years who were directly affected by the tornado. Participants self-reported their trait mindfulness, posttraumatic stress symptoms, and posttraumatic growth at two time points: 6-month (T1) and 9-month post-tornado (T2; attrition rate 17.4%). Cross-lagged structural equation modelling analyses were conducted. Results showed that posttraumatic stress symptoms at T1 significantly predicted reduced trait mindfulness at T2 but not posttraumatic growth; trait mindfulness at T1 did not significantly predict posttraumatic stress symptoms nor posttraumatic growth at T2; and posttraumatic growth at T1 did not predict trait mindfulness nor posttraumatic stress symptoms at T2. These findings suggested that posttraumatic stress symptoms may negatively influence the development of trait mindfulness in disaster-affected adolescents in China, and that posttraumatic growth may have unique implications for this young population which was not associated with posttraumatic stress symptoms or trait mindfulness. PMID- 29622277 TI - The role of extracorporeal membrane oxygenation in severe pulmonary coccidioidomycosis. AB - BACKGROUND: Severe coccidioidal pneumonia with acute respiratory distress syndrome (ARDS) is associated with high mortality. Extracorporeal membrane oxygenation (ECMO) has been applied successfully to other severe fungal pneumonia associated with ARDS. We review our experience with the use of ECMO in severe coccidioidal ARDS. OBJECTIVES: To review indications and outcome of ECMO in severe pulmonary coccidioidomycosis. METHODS: Three cases of severe ARDS caused by coccidioidomycosis are presented. All were managed with ECMO. Clinical course, complications, antifungal therapy and outcome are reviewed. RESULTS: Three cases of severe coccidioidal ARDS survived after treatment with ECMO. Common complications included bacterial pneumonia, encephalopathy and critical illness myopathy. They received liposomal amphotericin during ECMO, and transitioned to azole therapy. All required prolonged hospitalization and rehabilitation. CONCLUSIONS: ECMO was life-saving in cases of coccidioidal ARDS. Common complications included pneumonia, encephalopathy and critical illness myopathy. All cases were successfully managed with liposomal amphotericin followed by azole therapy. They required prolonged hospitalization and rehabilitation. PMID- 29622276 TI - Prospective assessment of patient-reported outcomes in gynecologic cancer patients before and after pelvic exenteration. AB - OBJECTIVE: Pelvic exenteration (PE) is a surgical procedure associated with significant morbidity offered to select women with locally advanced or recurrent gynecologic cancers. This ongoing study examines an array of patient-reported outcomes and satisfaction with PE. METHODS: Since February 2009, prospectively enrolled participants completed questionnaires evaluating body image (BIS), depression (CESD), social support (DUFSS), symptoms (MDASI), sexual function (SAQ), functional status (SF-12), quality of life (The Stoma-QOL), satisfaction with decision (SWD) and an investigator-designed survey at baseline, 6, and 12months after PE. Mann-Whitney and Wilcoxon signed-rank tests were used to evaluate the data. RESULTS: Fifty-four women enrolled. Median age was 56years (31, 85). Median BMI was 30.7kg/m2 (16.8, 54.4). The majority of patients (78%) were white. Cancer diagnoses included 41% cervix, 22% uterus, 19% vagina, 17% vulva and 2% ovary. Most surgeries were total PEs (76%). Patients were satisfied with their decision to undergo PE at 6 and 12months. One year after exenteration, 79% of women stated they would have a PE again. Sexual pleasure decreased from baseline to 12months after PE (p=0.02), while sexual discomfort remained unchanged (p=0.42). Body image worsened over time (p=0.003). Physical functioning (SF-12) declined (p=0.001), while mental functioning remained stable (p=0.46). There were no significant changes in stoma-related QOL, social support, or depression scores. CONCLUSIONS: Despite a decrease in physical functioning, persistent low body image and sexual pleasure, most women were satisfied with their decision and would undergo pelvic exenteration again. This study identifies survivorship issues that should be addressed after PE. PMID- 29622278 TI - Oxidative stress in placental pathology. AB - The most important function of the placenta is the exchange of nutrients and oxygen between a mother and her fetus. To establish a healthy functioning placenta, placentation needs to occur with adequate remodelling of spiral arteries by extravillous trophoblasts. When this process is impaired, the resulting suboptimal and inadequate placenta function results in the manifestation of pregnancy complications. Impaired placenta function can cause preeclampsia and leads to fetal growth restriction due to hypoxia. Presence of hypoxia leads to oxidative stress due to an imbalance between reactive oxygen species and antioxidants, thereby causing damage to proteins, lipids and DNA. In the placenta, signs of morphological adaptation in response to hypoxia can be found. Different placental lesions like maternal or fetal vascular malperfusion or chronic villitis lead to a decreased exchange of oxygen between the mother and the fetus. Clinically, several biomarkers indicative for oxidative stress, e.g. malondialdehyde and reduced levels of free thiols are found. This review aims to give an overview of the causes and (potential) role of placental oxidative stress in the development of placental parenchymal pathology and its clinical consequences. Also, therapeutic options aiming at prevention or treatment of hypoxia of the placenta and fetus are described. PMID- 29622279 TI - Corrigendum to "Rapid induction of expression by LPS is accompanied by favorable chromatin and rapid binding of c-Jun" [Mol. Immunol. 95 (2018) 99-106]. PMID- 29622280 TI - Effectiveness of total corpus callosotomy for diffuse bilateral polymicrogyria: Report of three pediatric cases. AB - PURPOSE: Polymicrogyria, a malformation of the cerebral cortex, frequently causes epilepsy. Diffuse bilateral polymicrogyria (DBP) is related to poor epilepsy prognosis, but most patients with DBP are not good candidates for resective epilepsy surgery and effectiveness of corpus callosotomy (CC), a palliative surgery, for patients without resective epileptogenic cortices, has not been established in DBP. Because CC might be effective against DBP-related epilepsy, we conducted total CC in three pediatric DBP cases. METHODS: Case 1. A girl developed epilepsy at 3 months of age, with focal versive seizures and epileptic spasms. The electroencephalogram (EEG) showed a suppression-burst pattern. Total CC was performed at 6 months of age. Case 2. A female infant developed epilepsy on the day of birth, exhibiting epileptic spasms, generalized tonic-clonic seizures, and eye-deviating seizures. She had a history of clusters of tonic seizures. Total CC was performed at 1 year and 2 months of age. After CC, the epileptic focus of the tonic seizures was identified; a secondary resective surgery was conducted. Case 3. A girl developed multiple types of seizures at 3 years of age. Frequent atypical absence status was refractory to antiepileptic drugs. Total CC was conducted at 8 years of age. RESULTS: Case 1: Frequencies of both seizure types decreased. The background EEG changed to continuous high voltage slow waves. Case 2: Clusters of tonic seizures were well-controlled. Case 3: Atypical absence seizures completely disappeared. CONCLUSION: CC could be effective for patients with DBP, whose habitual seizures include epileptic spasms and absence seizures. PMID- 29622281 TI - The effect of diabetes self-management education on psychological status and blood glucose in newly diagnosed patients with diabetes type 2. AB - OBJECTIVE: The purpose of this study was to evaluate the efficacy of self management education on psychological outcomes and glycemic control in type 2 diabetes mellitus. METHODS: Patients were randomly assigned to education group and control group. Education group received professional education and control group received routine outpatient education. RESULTS: A total of 118 patients were randomly assigned to two groups (education group, n = 63; control group, n = 55). Compared with control group, the anxiety score (36.00 vs. 42.50, P < 0.05) and depression score (35.50 vs. 44.00, P < 0.05) significantly decreased at the sixth month in education group, respectively. Compared with control group, fasting blood glucose (6.78 mmol/L vs. 7.70 mmol/L, P < 0.00), postprandial blood glucose (7.90 mmol/L vs. 10.58 mmol/L, P < 0.00) and glycosylated haemoglobin A1C level [6.20 (5.80, 6.60)% vs. 6.70 (6.40, 7.30)%, P < 0.01] significantly decreased after the sixth month in education group. CONCLUSION: The psychological status and blood glucose of patients with diabetes receiving self-management education were significantly improved. PRACTICE IMPLICATIONS: Type 2 diabetes mellitus has been usually linked to increased prevalence and risk of depression and anxiety, which can affect blood glucose levels. Through education, the mood of newly diagnosed patients with diabetes improved, resulting in better blood glucose control. PMID- 29622282 TI - "The more you know, the more you realise it is really challenging to do": Tensions and uncertainties in person-centred support for people with long-term conditions. AB - OBJECTIVE: To identify and examine tensions and uncertainties in person-centred approaches to self-management support - approaches that take patients seriously as moral agents and orient support to enable them to live (and die) well on their own terms. METHODS: Interviews with 26 UK clinicians about working with people with diabetes or Parkinson's disease, conducted within a broader interdisciplinary project on self-management support. The analysis reported here was informed by philosophical reasoning and discussions with stakeholders. RESULTS: Person-centred approaches require clinicians to balance tensions between the many things that can matter in life, and their own and each patient's perspectives on these. Clinicians must ensure that their supportive efforts do not inadvertently disempower people. When attending to someone's particular circumstances and perspectives, they sometimes face intractable uncertainties, including about what is most important to the person and what, realistically, the person can or could do and achieve. The kinds of professional judgement that person-centred working necessitates are not always acknowledged and supported. CONCLUSION: Practical and ethical tensions are inherent in person-centred support and need to be better understood and addressed. PRACTICE IMPLICATIONS: Professional development and service improvement initiatives should recognise these tensions and uncertainties and support clinicians to navigate them well. PMID- 29622283 TI - A comparison of cochlear distribution and glucocorticoid receptor activation in local and systemic dexamethasone drug delivery regimes. AB - Local and systemically delivered glucocorticoids are commonly administered to protect the cochlea against damage associated with a variety of insults. There is reason to believe that dexamethasone administered by these routes may arrive at cochlear target sites via different pathways. Clinically, there is a lack of clarity as to which route is more effective in any specific circumstance. This study explores dexamethasone distribution within the guinea pig cochlea following local and systemic delivery methods. A combination of mass spectroscopy and immunohistochemistry were employed to compare both perilymph distribution, tissue uptake and receptor activation. Local administration of dexamethasone to the round window membrane resulted in greater perilymph concentrations, with a basal to apical gradient that favours the cochlear base. Tissue immunofluorescence was intimately related to perilymph concentration following local administration. Systemic administration resulted in much lower perilymph concentrations, with an inverse basal to apical gradient favouring the cochlear apex. Lower perilymph concentrations following systemic administration were associated with minimal tissue immunofluorescence. Despite this, GR activation of the SGNs was equivalent in both administration regimes. These results bring into question the efficacy of measuring perilymph concentrations alone as a surrogacy for dexamethasone distribution and activity in the cochlea, suggesting that the steroid ligand may arrive at its target receptor via alternative pathways. Our results suggest an equivalence in efficacy between local and systemic administration routes early after drug delivery, when the ultimate outcome of GR activation is the goal. PMID- 29622284 TI - In vitro combination of voriconazole with micafungin against azole-resistant clinical isolates of Aspergillus fumigatus from different geographical regions. AB - In vitro interaction of voriconazole with micafungin was evaluated against 33 clinical Aspergillus fumigatus isolates, including azole-resistant (n=31) and susceptible (n=2) isolates. Interaction was synergistic for only 1 resistant isolate carrying the TR34/L98H mutation. No antagonistic effects were observed for 96.8% of azole-resistant isolates. PMID- 29622285 TI - Blurred Lines: Disentangling the Concept of Fetal Viability from Abortion Law. PMID- 29622286 TI - The German emergency and disaster medicine and management system-history and present. AB - As well for optimized emergency management in individual cases as for optimized mass medicine in disaster management, the principle of the medical doctors approaching the patient directly and timely, even close to the site of the incident, is a long-standing marker for quality of care and patient survival in Germany. Professional rescue and emergency forces, including medical services, are the "Golden Standard" of emergency management systems. Regulative laws, proper organization of resources, equipment, training and adequate delivery of medical measures are key factors in systematic approaches to manage emergencies and disasters alike and thus save lives. During disasters command, communication, coordination and cooperation are essential to cope with extreme situations, even more so in a globalized world. In this article, we describe the major historical milestones, the current state of the German system in emergency and disaster management and its integration into the broader European approach. PMID- 29622287 TI - Financial Implications and Impact of Pre-existing Atrial Fibrillation on In Hospital Outcomes in Patients Who Underwent Transcatheter Aortic Valve Implantation (from the National Inpatient Database). AB - The objective of this study was to evaluate the financial implications and the impact of pre-existing atrial fibrillation (AF) on in-hospital outcomes in patients who underwent transcatheter aortic valve implantation (TAVI) using the Nationwide Inpatient Sample (NIS) database. We identified patients who underwent TAVI from 2011 to 2014. The primary end point was the effect of pre-existing AF on in-hospital mortality. Secondary end points included periprocedural cardiac complications, stroke, and hemorrhage requiring transfusion. We also assessed length of stay (LOS) and cost of hospitalization. A mixed-effect logistic model was used for clinical end points, and a linear mixed model was used for cost and LOS. In 6,778 patients who underwent TAVI (46.1% women and 81.4 +/- 8.5 years old), the incidence of AF was 43.3%. After adjusting for patient- and hospital level characteristics, pre-existing AF was not found to influence in-hospital mortality (odds ratio 1.05, 95% confidence interval 0.80 to 1.36). AF was associated with an increased risk of periprocedural cardiac complications (odds ratio 1.46, 95% confidence interval 1.22 to 1.75), longer LOS (p <0.001) and an increased cost of hospitalization (US$51,852 vs US$49,599). In conclusion, pre existing AF did not impact in-hospital mortality in TAVI patients but was associated with increased cardiac complications, a longer hospital LOS, and a higher cost of hospitalization. PMID- 29622288 TI - Comparison of Prognostic Usefulness of Serum Insulin-Like Growth Factor-Binding Protein 7 in Patients With Heart Failure and Preserved Versus Reduced Left Ventricular Ejection Fraction. AB - We aimed to characterize of the role of insulin-like growth factor-binding protein 7 (IGFBP-7) in heart failure (HF) pathophysiology. IGFBP-7 has been associated with cardiac hypertrophy and diastolic dysfunction in HF. In 86 patients with HF with a preserved ejection fraction (HFpEF) (ejection fraction [EF] >=45%) and 79 with HF with a reduced ejection fraction (HFrEF), we assessed concentrations of serum IGFBP-7, correlations between serum IGFBP-7 and clinical data, diastolic function, and associations with outcome. IGFBP-7 was lower in HFpEF than HFrEF (102 vs 152 ug/L, p <0.001) and correlated with New York Heart Association class (HFpEF: r = 0.25, p = 0.020; HFrEF: r = 0.26, p = 0.022), N terminal pro-brain natriuretic peptide (NT-proBNP) (HFpEF: r = 0.53, p <0.001; HFrEF: r = 0.50, p <0.001), and estimated glomerular filtration rate (eGFR) (HFpEF: r = -0.47, p <0.001; HFrEF: r = -0.45, p <0.001). In HFpEF, IGFBP-7 correlated with E/e' (r = 0.31, p = 0.012) and E/A ratio (r = 0.31, p = 0.011). In HFrEF, but not HFpEF, IGFBP-7 correlated with age (r = 0.29, p = 0.009) and atrial fibrillation (r = 0.34, p = 0.002). IGFBP-7 predicted the outcome in HFpEF (hazard ratio 4.19 [1.01 to 17.35], p = 0.048]) but not in HFrEF (0.72 [0.24 to 2.14], p = 0.554). In conclusion in HFrEF, IGFBP-7 was elevated and associated with HF severity but not prognostic, suggesting a marker of risk. In HFpEF, IGFBP 7 was less elevated but associated with markers of diastolic dysfunction, HF severity, and prognosis. IGFBP-7 may contribute to the progression of HFpEF possibly through inflammation and oxidative stress. PMID- 29622289 TI - Continuity defects of the mandible: Comparison of three techniques for osseous reconstruction and their impact on implant loading. AB - Computer-aided design/manufacturing (CAD/CAM) is now widely used, but whether it can help to overcome complications in mandibular reconstruction and accelerate dental implantation is still a matter for debate. Therefore, we aimed to evaluate the benefits of this technique using vascularized iliac crest or fibula flaps in mandibular reconstruction, with respect to the time between reconstruction and implantation, and the ratio of planned to inserted implants. We reviewed retrospectively the records of 54 patients who underwent mandibular reconstructions between 2012 and 2016, and included in our study the last 10 cases representing each of the following groups: iliac crest flap with CAD/CAM (Group 1); fibula flap with CAD/CAM (Group 2); and fibula flap without CAD/CAM (Group 3). Groups 1 (p = 0.045) and 2 (p = 0.034) showed significantly shorter delays when compared with Group 3. Significant differences in average counts of implants placed were also found between Group 1 and Groups 2 (p = 0.04) and 3 (p = 0.019). The ratio of planned to placed implants was highest in Group 1. The observed differences between Group 1 and Groups 2 (p = 0.04) and 3 (p = 0.019) were significant. Our results indicate an accelerating effect of CAD/CAM on graft consolidation and dental rehabilitation. PMID- 29622290 TI - Minimal Clinically Important Difference: A Review of Outcome Measure Score Interpretation. AB - Clinicians, researchers, and outcome stakeholders have the crucial, albeit difficult, task of quantifying when a person or group experiences important change or difference on any given outcome measure, often in response to a specific intervention. The minimal clinically important difference (MCID) provides this quantified value of change/difference for a measure. There are many methods for MCID derivation, which can result in multiple values for the same measure. Thus, it is important for potential users of MCID values to be aware of the nuances of MCID development and cautions for interpreting values. This review outlines MCID-related definitions, methods, and guidelines. PMID- 29622291 TI - Alternative Design and Analytical Techniques for Longitudinal Rheumatology Studies: Improved Understanding of Outcomes. AB - Longitudinal cohort designs (with three or more measurement occasions) are invaluable to investigate between- and within-individual variation in outcomes. However, traditional longitudinal designs require a lengthy implementation and data collection period and impose a substantial burden on participants and investigators. We discuss alternative longitudinal designs, including planned missing data designs and retrospective cohort studies with secondary data, which require a shorter period for data accrual and reduce participant burden while maintaining statistical power. We also discuss analysis strategies to maximize data use and produce unbiased estimates of treatment effectiveness, including models for recurrent or multistate events and time-varying covariates. PMID- 29622292 TI - Propensity Score Methods for Bias Reduction in Observational Studies of Treatment Effect. AB - A challenge to the use of observational data to study treatment effects is the issue of confounding. Noncomparability of exposed and nonexposed subjects can lead to biased estimation of the treatment effect. The propensity score is a balancing score that can be used to form matched groups, or pairs, that are not systematically different and enable nonbiased comparisons between groups. This article reviews propensity score methods with an illustrative example of the application of propensity score matching in an observational study of an uncommon disease (systemic sclerosis). PMID- 29622293 TI - US National Health and Nutrition Examination Survey Arthritis Initiatives, Methodologies and Data. AB - The US National Health and Nutrition Examination Survey (NHANES) has collected population-based, nationally representative examination, laboratory, and radiographic data for arthritis and musculoskeletal diseases for more than 50 years. The resulting body of data and publications are substantial, yet much data remain unpublished. This review provides a basic understanding of the design and capabilities of the NHANES survey, reviewing the major accomplishments in the area of arthritis and musculoskeletal diseases. Currently available US National Health and Nutrition Examination Survey arthritis-related datasets are identified. Guidelines for using these data, and opportunities for data analysis and designing future studies are presented. PMID- 29622294 TI - Qualitative Methods to Advance Care, Diagnosis, and Therapy in Rheumatic Diseases. AB - This article provides an overview of the basis, usefulness, and validity of qualitative methods in research. It is aimed to enhance the understanding of a broad spectrum of readers, ranging from those mystified by such approaches, to those wanting a better critical knowledge to apply to literature review, and for health care providers considering developing an interest in the field. Qualitative research is crucial in augmentation of disease knowledge as well as the development of incremental care strategies and operational aspects of care that improves health outcomes. PMID- 29622295 TI - Similarity Network Fusion: A Novel Application to Making Clinical Diagnoses. AB - Similarity Network Fusion (SNF) is a novel methodological tool that integrates multiple different types of data to identify homogeneous subsets of patients in whom disease classification may be otherwise unclear or challenging. In this review article, the authors hope to provide insight into how SNF can be used in clinical decision making where the aim is to have little influence on the data prior to obtaining the results of the analysis. PMID- 29622296 TI - Randomized Trials, Meta-Analyses, and Systematic Reviews: Using Examples from Rheumatology. AB - This article introduces contemporary ideas and standards for clinical research in rheumatology for randomized trials, systematic reviews, and meta-analyses. Examples of different randomized trials in rheumatic diseases are provided to understand the methods for trials and the rationale for outcomes within trials. Insights from meta-analyses and systematic literature reviews, including network meta-analyses within rheumatology treatment, are provided. Ethical considerations, sample size calculations, and types of randomized controlled trials are discussed. PMID- 29622297 TI - "Big Data" in Rheumatology: Intelligent Data Modeling Improves the Quality of Imaging Data. AB - Analysis of imaging data in rheumatology is a challenge. Reliability of scores is an issue for several reasons. Signal-to-noise ratio of most imaging techniques is rather unfavorable (too little signal in relation to too much noise). Optimal use of all available data may help to increase credibility of imaging data, but knowledge of complicated statistical methodology and the help of skilled statisticians are required. Clinicians should appreciate the merits of sophisticated data modeling and liaise with statisticians to increase the quality of imaging results, as proper imaging studies in rheumatology imply more than a supersensitive imaging technique alone. PMID- 29622298 TI - Strategies for Dealing with Missing Accelerometer Data. AB - Missing data is a universal research problem that can affect studies examining the relationship between physical activity measured with accelerometers and health outcomes. Statistical techniques are available to deal with missing data; however, available techniques have not been synthesized. A scoping review was conducted to summarize the advantages and disadvantages of identified methods of dealing with missing data from accelerometers. Missing data poses a threat to the validity and interpretation of trials using physical activity data from accelerometry. Imputation using multiple imputation techniques is recommended to deal with missing data and improve the validity and interpretation of studies using accelerometry. PMID- 29622299 TI - Use of Administrative Databases to Assess Reproductive Health Issues in Rheumatic Diseases. AB - Administrative databases, registers, and other sources of big data can be interesting sources to address important research questions on reproduction in women with rheumatic diseases. There are many different types of administrative datasets worldwide, and it is important to understand the type of data present and unavailable in each dataset, validity and potential misclassification of data, and the ability to link maternal data with infant data. This article discusses the advantages and methodologic issues associated with administrative database use for the conduct of observational studies on reproductive issues in women with rheumatic diseases. PMID- 29622300 TI - Measuring Patient Preferences: An Overview of Methods with a Focus on Discrete Choice Experiments. AB - There is increasing recognition of the importance of patient preferences and methodologies to measure them. In this article, methods to quantify patient preferences are reviewed, with a focus on discrete choice experiments. In a discrete choice experiment, patients are asked to choose between 2 or more treatments. The results can be used to quantify the relative importance of treatment outcomes and/or other considerations relevant to medical decision making. Conducting and interpreting a discrete choice experiment requires multiple steps and an understanding of the potential biases that can arise, which we review in this article with examples in rheumatic diseases. PMID- 29622301 TI - Cluster and Multiple Correspondence Analyses in Rheumatology: Paths to Uncovering Relationships in a Sea of Data. AB - Rheumatic diseases encompass a wide range of conditions caused by inflammation and dysregulation of the immune system resulting in organ damage. Research in these heterogeneous diseases benefits from multivariate methods. The aim of this review was to describe and evaluate current literature in rheumatology regarding cluster analysis and correspondence analysis. A systematic review showed an increase in studies making use of these 2 methods. However, standardization in how these methods are applied and reported is needed. Researcher expertise was determined to be the main barrier to considering these approaches, whereas education and collaborating with a biostatistician were suggested ways forward. PMID- 29622303 TI - The Brave New World of Rheumatic Disease Research Today. PMID- 29622302 TI - Applied Bayesian Methods in the Rheumatic Diseases. AB - The use of applied Bayesian methods is increasing in rheumatology. Using the Bayes theorem, past evidence is updated with new data. Preexisting data are expressed as a prior probability distribution or prior. New observations are expressed as a likelihood. Through explicit incorporation of preexisting data and new data, this process informs how this new information should change the way we think. In this article, the authors highlight the use of applied Bayesian methods in the study of rheumatic diseases. PMID- 29622304 TI - Advanced Epidemiologic Methods for the Study of Rheumatic and Musculoskeletal Diseases. PMID- 29622305 TI - Corrigendum to 'Djhsp90s are crucial regulators during planarian regeneration and tissue homeostasis' Biochem and Biophy Res Commun Volume 498, Pages 723-728. PMID- 29622306 TI - Are You Ready for Emergency Medical Services in Your Oral and Maxillofacial Surgery Office? AB - Efficient responses to emergencies in the oral and maxillofacial surgery office require preparation, communication, and thorough documentation of the event and response. The concept of team anesthesia is showcased with these efforts. Emergency medical services training and response times vary greatly. The oral and maxillofacial surgery office should be prepared to manage the patient for at least 15 minutes after making the call to 911. Patient outcomes are optimized when providers work together to manage and transport the patient. Oral and maxillofacial surgery offices should develop and rehearse emergency plans and coordinate these protocols with local Emergency medical services teams. PMID- 29622307 TI - Preoperative Evaluation and Patient Selection for Office-Based Oral Surgery Anesthesia. AB - Provision of an outpatient anesthetic requires careful review of the patient's medical history along with salient aspects of the physical examination. The oral and maxillofacial surgeon may need to consult with the patient's medical providers to gain an understanding of the patient's potential risks for an adverse event. This article reviews key aspects of the patient evaluation so that an informed determination of suitability for an office anesthetic can be made. PMID- 29622308 TI - Oral and Maxillofacial Surgery Team Anesthesia Model and Anesthesia Assistant Training. AB - The model for oral and maxillofacial surgery (OMFS) delivery of office-based, open airway anesthesia has morphed from the operator-anesthetist to the delivery of team anesthesia, supporting a widespread focus on organizational aspects of the delivery of care. The training, continuing education, and coordination of a diverse anesthesia team provides a system to improve the safety and efficacy of anesthesia delivery. The hallmarks of this system include communication, checks and balances, monitoring, team dynamics, protocols, emergency scenario preparation and rehearsal, and crisis resource management during an emergent situation. This system contributes to and continually supports a culture of safety in the OMFS office. PMID- 29622309 TI - Anesthetic Agents Commonly Used by Oral and Maxillofacial Surgeons. AB - Oral and maxillofacial surgeons have a variety of anesthetic agents that can be used to provide anesthesia safely and efficiently in the office-based environment. However, it is critical to have a thorough understanding of the particulars for each agent. Commonly used anesthetic agents, administered either individually or in combination, include diazepam, midazolam, propofol, ketamine, opioid agonists such as fentanyl or remifentanil, dexmedetomidine, and inhalational agents, including nitrous oxide and sevoflurane. These agents help provide extreme flexibility for those creating an individualized anesthetic plan that also balances the patient's history and the anticipated surgical plan to maximize success. PMID- 29622310 TI - The Failed Sedation: Solutions for the Oral and Maxillofacial Surgeon. AB - Due to wide variation in patient responses, both intended and adverse, it is impossible to successfully sedate all patients. Choosing the right drug and dose regimen can be challenging, especially in patients who are naive to anesthesia. Underdosing can lead to pain perception, patient movement and combativeness, awareness with recall, and the sympathetic neuroendocrine stress response. Overdosing can lead to unintended loss of upper airway tone, hypoventilation/apnea, adverse cardiovascular changes, and prolonged sedation (with its attendant problems). PMID- 29622311 TI - Anesthesia for the Pediatric Oral and Maxillofacial Surgery Patient. AB - Pediatric patients present to the oral and maxillofacial surgeon for surgical services that can be performed safely and efficiently. Children and parents tend to be anxious; achieving cooperation is paramount for successful procedures. Several techniques can be used to alleviate anxiety and provide analgesia and anesthesia. This article outlines the anatomy and physiology of children and the preoperative anesthetic preparation and techniques unique to pediatric anesthesia. It discusses standards in training in pediatric anesthesia and current recommendations for monitoring. Management of children with autism spectrum disorders and attention deficit hyperactivity disorders highlights special considerations in the management of these children. PMID- 29622312 TI - Oral Surgery Patient Safety Concepts in Anesthesia. AB - An effective office emergency preparedness plan for the oral and maxillofacial surgery office can be developed through the use of well-designed checklists, cognitive aids, and regularly scheduled in situ simulations with debriefings. In order to achieve this goal, the hierarchal culture of medicine and dentistry must be overcome, and an inclusive team concept embraced by all members of the staff. Technologic advancements in office automation now make it possible to create interactive cognitive aids. These enhance office emergency training and provide a means for more rapid retrieval of essential information and guidance during both simulations and a real crisis. PMID- 29622313 TI - The American Association of Oral and Maxillofacial Surgeons Simulation Program. AB - Patient safety in dental anesthesia has been called into question in recent years. Simulation training has been proposed and developed as one possibility for increasing preparedness and training in cases of adverse events in dental anesthesia. This article presents an overview of the challenges of patient safety in dental anesthesia and how to address them with simulation training. The American Association of Oral and Maxillofacial Surgeons simulation program is unique in its potential to become a standardized, validated competency course with objective grading criteria, mastery-based cooperative learning model, and low facilitator-to-participant ratio, leading to a practical delivery cost structure. PMID- 29622314 TI - Airway Management for the Oral Surgery Patient. AB - This article discusses anesthesia assessment concepts related to airway evaluation and airway maintenance for safe and reliable selection of either open system (entrainment of room air) or closed system (no entrainment of room air) airway devices, which can be used during office-based oral surgical procedures, depending on the needs of a patient. Dental facial and oral structures are integral to an anesthetist's preoperative patient evaluation prior to surgery. The preoperative medical history and physical examination as well as the nature of the oral surgical procedure affect the selection of a proper and safe airway device. PMID- 29622315 TI - Anesthetic Pump Techniques Versus the Intermittent Bolus: What the Oral Surgeon Needs to Know. AB - The most popular agents in use for office-based anesthesia are propofol, ketamine, and remifentanil, which have the desirable properties of rapid onset and short duration of action. A useful parameter in assessing these agents is the context-sensitive half-time. These anesthetic agents demonstrate relatively low, flat plots compared with older agents. For delivery of intravenous anesthetics, oral and maxillofacial surgeons have relied small incremental boluses with great success. However, relatively simple syringe infusion pumps can provide an even "smoother" anesthetic. This article familiarizes oral and maxillofacial surgeons with the advantages of infusion pumps and provides examples of their use. PMID- 29622317 TI - ? PMID- 29622318 TI - Editorial introduction to the special issue: Insect innate immunity in China. PMID- 29622319 TI - Epidural and transforaminal corticosteroid injections: Towards reduced risks of neurological complications. PMID- 29622320 TI - Laryngomalacia, Tracheomalacia and Bronchomalacia. AB - Airway malacia can occur in the larynx (larygomalacia), trachea (tracheomalacia), or bronchi (bronchomalacia). As a group these are the most common congenital abnormalities of the pediatric airway and are characterized by increased airway compliance, resulting in excessive dynamic collapse during the respiratory cycle. While a diagnosis can be suspected based on clinical history and physical examination, definitive evaluation is based of nasopharyngolaryngoscopy and/or bronchoscopy. Observation and conservative management are typically all that are required. However, surgical intervention can be necessary in the most severe cases, and can result in significant improvement in symptoms. PMID- 29622321 TI - Evaluation and Management of Dehydration in Children. AB - The article discusses the evaluation of dehydration in children and reviews the literature on physical findings of dehydration. Pediatric dehydration is a common problem in emergency departments and wide practice variation in treatment exists. Dehydration can be treated with oral, nasogastric, subcutaneous, or intravenous fluids. Although oral rehydration is underutilized in the United States, most children with dehydration can be successfully rehydrated via the oral route. Selection of oral rehydration solution and techniques for successful oral rehydration are presented. Appropriate selection and rate of administration of intravenous fluids are also discussed for isonatremic, hyponatremic, and hypernatremic dehydration. PMID- 29622322 TI - Bronchiolitis: From Practice Guideline to Clinical Practice. AB - The American Academy of Pediatrics' clinical practice guideline in bronchiolitis was last updated in 2014 with recommendations to improve care for pediatric patients with bronchiolitis. As most treatments of bronchiolitis are supportive, the guideline minimizes the breadth of treatments previously used and cautions the use of tests and therapies that have a limited evidence base. Emergency physicians must be familiar with the guidelines in order to apply best practices appropriately. PMID- 29622323 TI - Pediatric Minor Head Injury 2.0: Moving from Injury Exclusion to Risk Stratification. AB - Visits for pediatric minor blunt head trauma continue to increase. Variability exists in clinician evaluation and management of this generally low-risk population. Clinical decision rules identify very low-risk children who can forgo neuroimaging. Observation before imaging decreases neuroimaging rates. Outcome data can be used to risk stratify children into more discrete categories. Decision aids improves knowledge and accuracy of risk perception and facilitates identification of caregiver preferences, allowing for shared decision making. For children in whom imaging is performed and is normal or shows isolated linear skull fractures, deterioration and neurosurgical intervention are rare and hospital admission can be avoided. PMID- 29622324 TI - Pediatric Syncope: High-Risk Conditions and Reasonable Approach. AB - Syncope is a common presentation to the emergency room. Unlike in the adult population, most pediatric syncope has non-life-threatening causes, and minimal evaluation in the emergency department is appropriate with parental reassurance. Despite this benign prognosis, care must be made to find uncommon and potentially fatal causes. The primary purpose of evaluation of the patient with syncope is to determine whether the patient is at increased risk for death and needs either admission to the hospital or an expedited outpatient evaluation. This article reviews some of the most dangerous causes of syncope in the pediatric patient. PMID- 29622325 TI - Pediatric Pain Management. AB - Nearly 20 years ago, standards were established for hospitals to assess and treat pain in all patients. Research continues to demonstrate evolving trends in the measurement and effective treatment of pain in children. Behavioral research demonstrating long-lasting effects of inadequate pain control during childhood supports the concepts of early and adequate pain control for children suffering from painful conditions in the acute care setting. The authors discuss pain concepts, highlighting factors specific to the emergency department, and include a review of evidence for pharmacologic and nonpharmacologic treatments. PMID- 29622326 TI - What to Do when Babies Turn Blue: Beyond the Basic Brief Resolved Unexplained Event. AB - The term "brief resolved unexplained event" was created to replace "apparent life threatening event," narrowing the definition and providing evidence-based guidelines for management. The emphasis is placed on using clinical clues to classify patients as low risk or exclude them from the categorization altogether. Infants who meet low-risk classification can be briefly observed in the emergency department and be discharged home. Infants who demonstrate elements suggestive of a specific etiology should be evaluated and treated accordingly. Patients who demonstrate no specific findings yet who are high risk should be evaluated for the most common etiologies of apneic events and be admitted. PMID- 29622327 TI - Imaging Gently. AB - Advances in medical imaging are invaluable in the care of pediatric patients in the emergent setting. The diagnostic accuracy offered by studies using ionizing radiation, such as plain radiography, computed tomography, and fluoroscopy, are not without inherent risks. This article reviews the evidence supporting the risk of ionizing radiation from medical imaging as well as discusses clinical scenarios in which clinicians play an important role in supporting the judicious use of imaging studies. PMID- 29622328 TI - Inborn Errors of Metabolism in the Emergency Department (Undiagnosed and Management of the Known). AB - An inborn error of metabolism should be considered in any neonate who presents to the emergency department in extremis and in any young child who presents with altered mental status and vomiting. In children with unknown diagnoses, it is crucial to draw the appropriate laboratory studies before the institution of therapy, although treatment needs rapid institution to mitigate neurologic damage and avoid worsening metabolic crisis. Although there are hundreds of individual genetic disorders, they are roughly placed into groups that present similarly. This article reviews the approach to the patient with unknown metabolic diagnosis and up-to-date management pearls for children with known disorders. PMID- 29622329 TI - Pediatric Emergency Noninvasive Ventilation. AB - Noninvasive ventilation (NIV) has emerged as a powerful tool for the pediatric emergency management of acute respiratory failure (ARF). This therapy is safe and well tolerated and seems to frequently prevent both the need for invasive mechanical ventilation and the associated risks/complications. Although NIV can be the primary treatment of ARF resulting from multiple respiratory disease states, it must be meticulously monitored and, when unsuccessful, may aid in preoxygenation for prompt endotracheal intubation and invasive mechanical ventilation. The following article reviews the physiologic effects of NIV and its role in common respiratory diseases encountered in pediatric emergency medicine. PMID- 29622330 TI - Pediatric Ventilator Management in the Emergency Department. AB - Pediatric mechanical ventilation is first initiated by emergency physicians when performing active airway management in a critically ill or injured child. When initiating and adjusting mechanical ventilation, the child has unique anatomy and physiology to consider. The EP is the first to respond to ventilator alarm triggers, and the initial medical provider to resuscitate the ventilated pediatric patient who is deteriorating while in the emergency department. This article uses cases to provide a framework to initiate and troubleshoot mechanical ventilation of pediatric patients in the emergency department. PMID- 29622331 TI - Postoperative Tonsillectomy Hemorrhage. AB - Post-tonsillectomy hemorrhage represents a potentially life-threatening condition that occurs in up to 5% of pediatric patients. Minor bleeding often precedes severe hemorrhage. Patients with minor or self-resolving bleeding should be observed in the emergency department or admitted for monitoring. Patients with severe bleeding should be immediately assessed for airway and hemodynamic stability. Management of severe bleeding includes immediate surgical consultation or initiation of the transfer process to a center with surgical capabilities, direct pressure to the site of hemorrhage with or without the additional of a hemostatic agent, possible rapid sequence intubation, and management of hemodynamic instability with volume resuscitation. PMID- 29622332 TI - Emergency Department Management of Pediatric Shock. AB - Shock, a state of inadequate oxygen delivery to tissues resulting in anaerobic metabolism, lactate accumulation, and end-organ dysfunction, is common in children in emergency department. Shock can be divided into 4 categories: hypovolemic, distributive, cardiogenic, and obstructive. Early recognition of shock can be made with close attention to historical clues, physical examination and vital sign abnormalities. Early and aggressive treatment can prevent or reverse organ dysfunction and improve morbidity and mortality. PMID- 29622333 TI - Emergency Care of Pediatric Burns. AB - Although the overall incidence of and mortality rate associated with burn injury have decreased in recent decades, burns remain a significant source of morbidity and mortality in children. Children with major burns require emergent resuscitation. Resuscitation is similar to that for adults, including pain control, airway management, and administration of intravenous fluid. However, in pediatrics, fluid resuscitation is needed for burns greater than or equal to 15% of total body surface area (TBSA) compared with burns greater than or equal to 20% TBSA for adults. Unique to pediatrics is the additional assessment for non accidental injury and accurate calculation of the percentage of total burned surface area (TBSA) in children with changing body proportions are crucial to determine resuscitation parameters, prognosis, and disposition. PMID- 29622334 TI - Pediatric Major Head Injury: Not a Minor Problem. AB - Traumatic brain injury is a highly prevalent and devastating cause of morbidity and mortality in children. A rapid, stepwise approach to the traumatized child should proceed, addressing life-threatening problems first. Management focuses on preventing secondary injury from physiologic extremes such as hypoxemia, hypotension, prolonged hyperventilation, temperature extremes, and rapid changes in cerebral blood flow. Initial Glasgow Coma Score, hyperglycemia, and imaging are often prognostic of outcome. Surgically amenable lesions should be evacuated promptly. Reduction of intracranial pressure through hyperosmolar therapy, decompressive craniotomy, and seizure prophylaxis may be considered after stabilization. Nonaccidental trauma should be considered when evaluating pediatric trauma patients. PMID- 29622335 TI - Pediatric Thoracic Trauma: Recognition and Management. AB - Thoracic injuries account for less than one-tenth of all pediatric trauma-related injuries but comprise 14% of pediatric trauma-related deaths. Thoracic trauma includes injuries to the lungs, heart, aorta and great vessels, esophagus, tracheobronchial tree, and structures of the chest wall. Children have unique anatomic features that change the patterns of observed injury compared with adults. This review article outlines the clinical presentation, diagnostic testing, and management principles required to successfully manage injured children with thoracic trauma. PMID- 29622336 TI - Pediatric Emergencies. PMID- 29622337 TI - Pediatric Emergencies: The Common and the Critical. PMID- 29622338 TI - Pathologic intimal thickening in human atherosclerosis is formed by extracellular accumulation of plasma-derived lipids and dispersion of intimal smooth muscle cells. AB - BACKGROUND AND AIMS: Pathologic intimal thickening (PIT) is an important stage of atherosclerosis that leads to atheroma. The present study aimed to clarify the pathogenesis of PIT in humans. METHODS: Coronary arteries were obtained from 43 autopsy subjects aged 15-49 years. Non-atherosclerotic intima and atherosclerotic intimal lesions were classified into four groups, i.e. diffuse intimal thickening, fatty infiltration, fatty streak, and PIT, and the number and density of macrophages and smooth muscle cells (SMCs) were determined. Components of the lesions and proliferative and apoptotic activities of macrophages and SMCs were investigated by immunohistochemistry and TUNEL assay. RESULTS: Extracellular lipids accumulated mildly in the fatty infiltration and fatty streak, and abundantly in the PIT to form the lipid pool. The extracellular lipids co localized with apolipoprotein B and fibrinogen. Macrophage foam cells accumulated in the fatty streak and PIT, but no TUNEL-positive macrophages were detected in any lesion. No significant difference in the number of SMCs was found between the four groups, but the density of SMCs decreased in the fatty streak and PIT. The decrease correlated with an increase in the number of macrophages, and the accumulation of extracellular lipids in the lipid pool. Neither Ki-67-positive nor TUNEL-positive SMCs were detected in any lesion. CONCLUSIONS: In PIT in human atherosclerosis, the lipid pool is formed by infiltration and deposition of plasma-derived lipids. Intimal SMCs are dispersed in association with macrophage infiltration and lipid pool formation without undergoing significant proliferation or death. PMID- 29622339 TI - Optimizing Cancer Treatment for Older Adults. PMID- 29622340 TI - Frequency of Poison Center Exposures for Pediatric Accidental Unsupervised Ingestions of Acetaminophen after the Introduction of Flow Restrictors. AB - OBJECTIVE: To assess the temporal association of flow restrictor introduction and the rate of accidental unsupervised ingestions (AUIs) of liquid acetaminophen products. STUDY DESIGN: The National Poison Data System was used to identify AUIs of single ingredient acetaminophen in patients aged <12 years reported between 2007 and 2015. Six regional poison centers obtained additional information using a structured telephone survey. RESULTS: Pediatric AUIs involving acetaminophen averaged 30 000 exposures per year between 2007 and 2012. From 2012 to 2015, after flow restrictor introduction, exposures steadily decreased at a rate of 2400 fewer exposures annually, reaching 21 877 exposures in 2015. Normalized to sales volume, exposures involving liquid acetaminophen products decreased by 40% from 2010 to 2015. Exposures involving products with flow restrictors tended to have a lower estimated ingestion per exposure, fewer exposures exceeding a 150 mg/kg acetaminophen threshold, and were associated with lower rates of hospital admissions when compared with products without restrictors. Caregivers reported improper storage and child confusion of the medicine with treats as common contributing factors to exposures. CONCLUSIONS: The introduction of flow restrictors was associated with a decrease in pediatric AUIs of liquid acetaminophen products. Decreases in the dose ingested and risk of hospital admission per exposure may also have resulted. Efforts to optimize flow restrictors and increase their use with medicines associated with high pediatric overdose risk should be encouraged. PMID- 29622341 TI - Characteristics of Infant Deaths during Sleep While Under Nonparental Supervision. AB - OBJECTIVE: To compare risk factors for infant sleep-related deaths under the supervision of parents and nonparents. STUDY DESIGN: We conducted a secondary analysis of sleep-related infant deaths from 2004 to 2014 in the National Center for Fatality Review and Prevention Child Death Review Case Reporting System. The main exposure was supervisor at time of death. Primary outcomes included sleep position, location, and objects in the environment. Risk factors for parental vs nonparental supervisor were compared using chi2 and multivariable logistic regression models. Risk factors associated with different nonparental supervisors were analyzed using chi2. RESULTS: Of the 10 490 deaths, 1375 (13.1%) occurred under nonparental supervision. Infants who died under nonparental supervision had higher adjusted odds of dying outside the home (OR 12.87, 95% CI 11.31-14.65), being placed prone (OR 1.61, 95% CI 1.39-1.86) or on their side (OR 1.35, 95% CI 1.12-1.62), or being found prone (OR 1.74, 95% CI 1.50-2.02). Among infants who died under nonparental supervision, those supervised by relatives or friends were more often placed on an adult bed or couch for sleep and bed sharing (P < .0001), and to have objects in the sleep environment (P = .01). CONCLUSIONS: Infants who died of sleep-related causes under nonparental supervision were more likely to have been placed nonsupine. Among nonparental supervisors, relatives and friends were more likely to use unsafe sleep environments, such as locations other than a crib or bassinet and bed sharing. Pediatricians should educate parents that all caregivers must always follow safe sleep practices. PMID- 29622342 TI - Twitter(r) use and its implications in Spanish Association of Surgeons meetings and congresses. AB - INTRODUCTION: The use of web 2.0 tools and especially Twitter is in full expansion. Twitter has jumped from the personal field to the professional with great success, joining as a means of regular dissemination in scientific congresses. MATERIAL AND METHODS: The use of Twitter from 2013 to 2016 was monitored at the congresses of the Spanish Association of Surgeons (AEC). To do this, the hashtags (# rnc13, # cnc14, # rnc15, # cncirugia16) were analyzed through various websites for analysis of hashtags. RESULTS: The use of Twitter among the members of the Spanish Association of Surgeons has increased clearly, surpassing other American societies. It has increased in number of tweets, in number of tweeters and in the ratio of the same with respect to those attending congresses. While at the beginning the majority of tweets (65%) were the responsibility of a group of influencers, in recent years, due to the increase in tweets, the maximum influencers are only responsible for 35% of tweets. The number of institutional accounts in the top 10 has also been reduced. CONCLUSION: n the AEC the use of twitter has grown clearly and almost exponentially in recent years. Although initially the tweeted community was small and a few were responsible for a majority of tweets, the progressive growth and penetration of twitter has made that in recent congresses, these influencers and institutional accounts are no longer the main driver of the use of twitter in the congresses. Given the global trend and the Spanish Association of Surgeons, it is expected that tools such as Twitter play an increasingly important role in the management and transmission of knowledge, as well as in the creation of collaborative networks between professionals. PMID- 29622343 TI - Efficacy of curcumin and Boswellia for knee osteoarthritis: Systematic review and meta-analysis. AB - PURPOSE: The unfavorable safety profiles of commonly prescribed knee osteoarthritis (OA) treatments have led clinicians and patients to seek safer alternatives. Research has suggested that curcuminoid and boswellia formulations could moderate key inflammatory pathways that are associated with worsening symptoms and disease progression. We conducted a systematic review and meta analysis to assess the efficacy and safety of these treatments vs. placebo or NSAIDs for knee OA. METHODS: We searched Medline, EMBASE, Google Scholar, Web of Science and the Cochrane database from inception to February 21, 2018. We also hand searched reference lists and reviewed conference proceedings. We included randomized clinical trials (RCTs) comparing curcuminoid or boswellia formulations with placebo or NSAIDs for knee OA. We calculated standardized mean differences (SMD) or risk ratios (RR) for all relevant outcomes. Meta-analyses were conducted using random effects models. Heterogeneity was assessed using the I2 statistic. RESULTS: Eleven RCTs (N = 1009) were eligible for analysis. Study quality was low overall, and most included RCTs were conducted on fewer than 100 participants. Both curcuminoid and boswellia formulations were statistically significantly more effective than placebo for pain relief and functional improvement. There were no significant differences between curcuminoids or boswellia and placebo in safety outcomes. Curcuminoids showed no statistically significant differences in efficacy outcomes compared to NSAIDs; patients receiving curcuminoids were significantly less likely to experience gastrointestinal adverse events. No RCTs compared boswellia against approved NSAIDs. CONCLUSIONS: The results of our study suggest that curcuminoid and boswellia formulations could be a valuable addition to the knee OA treatment regimens by relieving symptoms while reducing safety risks. The current body of evidence is not adequate in size or quality to make any meaningful clinical practice recommendations. Further research through large, high quality RCTs probably investigating the synergistic effect of these products with other OA treatments is warranted. PMID- 29622344 TI - Re: 'Access to treatment with controlled medicines: rationale and recommendations for neutral, precise, and respectful language'. PMID- 29622345 TI - Early islets and mesenchyme from an injured adult pancreas improve syngeneic engraftments and islet graft function in diabetic rats. AB - A decrease in mass of isografts and a decline in islet function are major challenges in islet transplantations. Despite this, transplantation of 84 h harvested pancreatic duct ligation (PDL) tissues have been shown to have the same functional ability to foetal pancreata, but there was only 40% success in reverting hyperglycaemia. We tested the potential of early islets with mesenchymal stromal cells (MSCs) to promote isogeneic grafts survival and to restore normoglycemia in diabetic rats, in comparison with late islets. Islets were isolated from injured adult pancreata of donor rats at 24 h post ligation either with MSCs (24 h islet/MSC+) or without MSCs (24 h islet/MSC-), and at 84 h without MSCs (84 h islet/MSC-). These cells were transplanted under the renal capsule of syngeneic STZ-diabetic recipient rats. The islet grafts were monitored using the BGLs of recipients and the immunohistomorphology of the grafts were analysed using anti-insulin and anti-Ki67 antibodies. The mean BGL in 24 h islet/MSC+ recipients was reduced over time toward the control value. The curves of the mean BGLs in the control islet/MSC- and the 24 h islet/MSC- recipients dropped significantly below the control normal glucose group's levels to reach their nadirs on weeks 4 and 6, respectively. Both curves had a peak overshoot on week 9, with no statistical significant difference between them. Engrafted islets were evident in these recipients, lasted for 5 and 6 weeks and correspondingly survived failure. However, insulin+ cells were present in the isografts of all recipients; but, only isografts in the 24 h islet/MSC+ presented with a homogenous subcapsular beta cell mass. In addition, the tendency of 24 h islet/MSC- to restore normoglycaemia with its survival capacity was statistically highly significant compared to the 84 islet/MSC- recipients (80%; 20%; p = 0.001). Transplantation of early islets with MSCs from injured adult pancreata prolongs islet graft survival and improves isograft function in diabetic rats. This novel observation requires much further exploration for its clinical application, but this model already provides hope for new sources of donor islets for transplantation. PMID- 29622346 TI - A response to Marquis et al. (2017) What is the error margin of your signature analysis? PMID- 29622347 TI - Optical imaging with a high-resolution microendoscope to identify sinonasal pathology. AB - OBJECTIVES: High-resolution microendoscopy (HRME) is an optical imaging modality that allows real time imaging of epithelial tissue and structural changes within. We hypothesize that HRME, using proflavine, a contrast agent that preferentially stains cell nuclei and allows detection of cellular morphologic changes, can distinguish sinonasal pathology from uninvolved mucosa, potentially enabling real time surgical margin differentiation. STUDY DESIGN: Ex vivo imaging of histopathologically confirmed samples of sinonasal pathology and uninvolved, normal sinus epithelium. SETTING: Single tertiary-level institution. SUBJECTS AND METHODS: Five inverted papillomas, one oncocytic papilloma, two uninvolved sinus epithelia specimens, and three inflammatory polyps were imaged ex vivo with HRME after surface staining with proflavine. Following imaging, the specimens were submitted for hematoxylin and eosin staining to allow histopathological correlation. RESULTS: Results show that sinonasal pathology and normal sinus epithelia have distinct HRME imaging characteristics. Schneiderian papilloma specimens show increased nuclear-to-cytoplasmic ratio, nuclear crowding, and small internuclear separation, whereas normal sinus epithelia specimens show small, bright nuclei with dark cytoplasm and relatively large internuclear separation. Inflammatory polyps, however, have varying imaging characteristics, that resemble both Schneiderian papilloma and normal sinus epithelia. CONCLUSIONS: This study demonstrates the feasibility of HRME imaging to discriminate sinonasal pathology from normal sinus epithelia. While the system performed well in the absence of inflammation, discrimination of inflamed tissue was inconsistent, creating a significant limitation for this application. Novel imaging systems such as HRME with alternative contrast agents may assist with real-time surgical margin differentiation, enabling complete surgical resection of inverted papilloma and reducing recurrence rates. PMID- 29622348 TI - Effects of orexins on 17beta-estradiol synthesis and P450 aromatase modulation in the testis of alpaca (Vicugna pacos). AB - The steroidogenic enzyme P450 aromatase (ARO) has a key role in the conversion of testosterone (T) into estrogens (E), expressed as 17beta-estradiol. The presence and localization of this key enzyme have not been described before in the South American camelid alpaca (Vicugna pacos). In our previous studies of the expression and biological effects of orexin A (OxA) and OxB on the alpaca testis demonstrated that OxA, via its specific receptor 1 (OX1R), stimulated T synthesis. In order to extend these findings, we presently explored the presence and localization of ARO in the alpaca male gonad, and the possible correlation between ARO and the orexinergic complex. Western blotting and immunohistochemistry demonstrated the presence of ARO in tissue homogenates and its localization in the tubular and interstitial compartments of the alpaca testis, respectively. The addition of OxA to fresh testicular slices decreased the 17beta-estradiol E levels. This effect was annulled by the sequential addition of the selective OX1R antagonist, SB-408124. OxB incubation did not have any effect on the biosynthesis of E. Furthermore, the OxA-mediated down regulation of E secretion could be ascribed to ARO inhibition by exogenous OxA, as indicated by measurement of ARO activity in tissue slices incubated with OxA. Overall, our findings suggest that locally secreted OxA interacting with OX1R could indirectly inhibit ARO activity, disabling the conversion of T to E, and consequently lowering E biosynthesis and increasing the production of T in mammalian testis. PMID- 29622349 TI - Impaired insulin signaling pathways affect ovarian steroidogenesis in cows with COD. AB - Cystic ovarian disease (COD) represents an important cause of infertility in dairy cattle and is associated with multiple physiological disorders. Steroidogenesis, which is necessary to ensure normal ovarian functions, involves multiple enzymatic pathways coordinated by insulin and other proteins. We have previously shown that cows with COD have an altered insulin response. Therefore, in the present study, we evaluated further alterations in intermediates downstream of the PI3K pathway and pathways mediated by ERK as critical signals for the expression of steroidogenic enzymes in the ovaries of control cows and cows with spontaneous COD. To this end, we evaluated the gene and protein expression of pan-AKT, mTOR, ERK1/2, and steroidogenic enzymes by real-time PCR and immunohistochemistry. Steroid hormone concentrations were assessed at systemic and intrafollicular level. Results showed altered expression of intermediate molecules of the insulin signaling pathway, whose action might modify the synthetic pathway of steroidogenic hormones. Similarly, the expression of steroidogenic enzymes and the concentration of progesterone in serum and follicular fluid were altered. These alterations support the hypothesis that systemic factors contribute to the development and/or maintenance of COD, and that metabolic hormones within follicles such as insulin exert determinant effects on ovarian functionality in cows with COD. PMID- 29622350 TI - Effect of vibration emissions during shipping of artificial insemination doses on boar semen quality. AB - The shipping of semen doses to sow farms can impair boar semen quality. Unfortunately, there is currently no practice-oriented information available regarding general shipping conditions of boar semen. For this reason, a special mobile sensing app (TransportLog 1.0), utilizing the built-in sensors of smartphones, has been programmed to capture vibration emissions during shipping of semen doses (QuickTip Flexitubes(r), Minitub). Data were analyzed, transformed and used as standards for simulating vibration emissions from an orbital shaker IKA MTS 4 (Laborgerate Munchen) in a spermatological reference laboratory. Twenty ejaculates were collected randomly and diluted using a one-step isothermal process in a split-sample procedure in Beltsville Thawing Solution (BTS, Minitub). The sperm concentration was adjusted to 24 * 106 sperm/mL. The dose filling volume was 85 +/- 1 mL. Samples were stored for seven days at 17 degrees C. The results showed that circular horizontal vibration emissions with frequencies of 300 rpm for a duration of 6 h led to a significant alkalization of the BTS-extended semen. Semen motility, mitochondrial activity, acrosome and plasma membrane integrity as well as thermo-resistance all demonstrated a frequency-dependent negative response to vibration emissions during long-term storage. This study leads to new insights and recommendations for the shipping of boar semen in the artificial insemination industry. Furthermore, a new monitoring tool for boar semen shipping was established using mobile sensing. PMID- 29622351 TI - Proteomics: A valuable approach to elucidate spermatozoa post -testicular maturation in the endangered Acipenseridae family. AB - Proteomics techniques, such as two-dimensional polyacrylamide gel electrophoresis, mass spectrometry, and differential gel electrophoresis, have been extensively used to describe the protein composition of male gametes in different animals, mainly mammals. They have also provided a deeper understanding of protein functions involved in sperm processes, as in processes that in humans lead to male infertility. However, few studies focus on fish sperm proteomics and even fewer have tried to explore the proteomic profile of Sturgeon spermatozoa. Sturgeon is an endangered, ancient group of fish species exploited mostly for caviar. In this fish group, a part of the process that leads to final functional maturation of spermatozoa so as to have the capability to activate eggs during the fertilization process. This process has a broad similarity to post-testicular maturation in mammals; where spermatozoa leaving the testes must be mixed with seminal fluid along the transit through the Wolffian ducts to modify its surface membrane protein composition, leading to axonemal and acrosomal competence. The aim of this study was to review the current literature on various proteomic techniques, their usefulness in separating, identifying and studying the proteome composition of the fish spermatozoon, as well as their potential applications in studying the post-testicular maturation process in Sturgeon. Such understanding could lead to development of more sophisticated aquaculture techniques, favorable for sturgeon reproduction. PMID- 29622352 TI - Simultaneous evaluation of superoxide content and mitochondrial membrane potential in stallion semen samples provides additional information about sperm quality. AB - An improved fertility prediction for stallions is of importance for equine breeding. Here, we investigate the potential of a combined staining of stallion spermatozoa for superoxide and mitochondrial membrane potential (MMP) for this purpose. Semen samples were analysed immediately after arrival at the laboratory, as well as after 24 h. Superoxide was measured by MitoSOXRed, while MMP was measured with JC-1. Menadione was used to stimulate superoxide production. In addition, other parameters of sperm quality, namely motility, membrane integrity, chromatin integrity, sperm kinematics and Hoechst 33258 exclusion were measured and correlated to superoxide production and MMP. Both bivariate correlations between measured parameters as well as multivariate analysis were performed. Measured values in the superoxide/MMP assay did not correlate with other parameters. However, there was a strong negative correlation (r = 0.96 after 0 h, r = 0.95 after 24 h) between membrane integrity and chromatin integrity. Moderate positive correlations were found between motility parameters and membrane integrity, as well as moderate negative correlations between motility parameters and chromatin integrity. The multivariate analysis revealed that membrane integrity, chromatin integrity and motility contributed to the first principal component, while the second was influenced by superoxide/MMP parameters as well as sperm kinematics. Storage of samples for 24 h decreased motility, chromatin integrity and membrane integrity. In conclusion, combined measurement of superoxide and MMP provides additional information not obtained by other assays of sperm quality. PMID- 29622353 TI - Discussion. PMID- 29622354 TI - Perioperative risk factors for hospital readmission after elective endovascular aortic aneurysm repair. AB - BACKGROUND: Elective endovascular aneurysm repair (EVAR) is generally well tolerated. However, the incidence of hospital readmission after EVAR and the risk factors and reasons for it are not well studied. This study sought to determine the incidence, to characterize the indications, and to identify perioperative patient-centered risk factors for hospital readmission within 30 days after elective EVAR. METHODS: All patients who underwent EVAR electively in 2012 to 2013 were identified from the American College of Surgeons National Surgical Quality Improvement Program Targeted Vascular database (n = 3886). Preoperative demographics, operation-specific variables, and postoperative outcomes were compared between those who were readmitted within 30 days of the index operation and those who were not. Multivariate logistic regression was then used to determine independent predictors of hospital readmission. RESULTS: The unadjusted 30-day readmission rate after EVAR was 8.2%. Of all readmissions, 55% were for reasons related to the procedure. Median time to readmission was 12 days. Significant preoperative risk factors associated with readmission were female sex, preoperative steroid use, congestive heart failure, and dialysis dependence (P < .05). Multiple postoperative medical complications were independently predictive of readmission, including myocardial infarction and deep venous thrombosis (P < .05). Surgical complications that were independently predictive of readmission were surgical site infection (odds ratio, 10.24; 95% confidence interval, 5.31-19.75; P < .01) and need for unplanned reoperation (odds ratio, 17.50; 95% confidence interval, 10.43-29.37; P < .01). Readmitted patients ultimately had significantly higher rates of 30-day mortality (3.5% vs 0.3%; P < .01). CONCLUSIONS: Hospital readmissions remain a costly problem after vascular surgery and are associated with 30-day mortality after elective EVAR. Whereas female sex and certain irreversible medical comorbidities are nonmodifiable, focusing on medical optimization and identifying those perioperative variables that can affect the need for post-EVAR interventions will be an important step in decreasing hospital readmission. PMID- 29622355 TI - A prospective randomized study of stent graft placement after balloon angioplasty versus balloon angioplasty alone for the treatment of hemodialysis patients with prosthetic graft outflow stenosis. AB - BACKGROUND: Hemodialysis graft outflow stenosis is a significant complication occurring in hemodialysis patients with prosthetic grafts for vascular access. Balloon angioplasty remains the first-line endovascular treatment of this complication, although covered stent graft implantation after balloon angioplasty also appears to be an effective and promising treatment. The aim of this study was to evaluate the efficacy and durability of stent graft placement after balloon angioplasty in comparison to balloon angioplasty alone for the treatment of graft outflow stenosis in hemodialysis patients. METHODS: We conducted a prospective randomized study of 98 patients with clinically significant dialysis graft outflow stenosis treated in the vascular surgery section of a tertiary medical center. The patients were randomized into two groups; 49 patients were treated with stent graft placement after balloon angioplasty, and 49 patients were treated with balloon angioplasty alone. All patients underwent angiography of the graft site at 3 and 6 months after intervention, and restenosis rates were compared between the two groups. In addition, the duration of postintervention primary patency in the two groups was recorded and analyzed. RESULTS: The postintervention restenosis rate of the stent graft placement group was superior to that seen in the balloon angioplasty alone group (9% vs 69% at 3 months [P < .0001] and 29% vs 72% at 6 months [P < .0001]). The mean postintervention primary patency duration was 380.22 +/- 28.54 days for the stent graft placement group and 151.08 +/- 16.79 days for the balloon angioplasty alone group (P < .0001). CONCLUSIONS: The use of stent grafts in hemodialysis patients with graft outflow stenosis yielded superior results compared with the results seen in hemodialysis patients treated with balloon angioplasty alone. Patients treated with stent grafts after balloon angioplasty had a lower restenosis rate and a longer duration of postintervention primary patency. The placement of a stent graft after balloon angioplasty appears to be an optimal therapeutic approach for the treatment of hemodialysis patients with graft outflow stenosis. PMID- 29622356 TI - Risk and outcome profile of carotid endarterectomy with proximal intervention is concerning in multi-institutional assessment. AB - OBJECTIVE: Approaching tandem bifurcation and brachiocephalic disease using carotid endarterectomy (CEA) with ipsilateral proximal endovascular intervention (IPE) has been promulgated as safe and durable. There have been recent concerns about neurologic risk with this technique. The goal of this study was to define stroke and perioperative risk with this uncommon procedure across multiple centers. METHODS: Between August 2002 and July 2016, patients who underwent CEA + IPE were identified by operative records at three institutions. Primary end points were perioperative stroke and death, restenosis, freedom from neurologic event, and need for reintervention. Factors related to these end points were analyzed. RESULTS: There were 62 patients who underwent CEA + IPE. The average age was 69 +/- 9 years. Most were female 34 (55%); 56 (90%) were taking a statin and at least one antiplatelet agent. Bilateral internal carotid stenosis (>50%) was present in 32 (52%); 26 (42%) patients were symptomatic and 12 (19%) had undergone prior ipsilateral CEA. Bifurcation operations included longitudinal CEA/patch (38 [61%]), eversion CEA (20 [32%]), bypass graft (3 [5%]), and CEA/primary repair (1 [2%]). CEA was performed first in 53 (85%). All IPEs included stenting, with a single stent used in 58 (94%). Balloon-expandable stents were placed in the majority of patients (51 [82%]). Proximal arteries treated included the innominate (20 [32%]), left common carotid (32 [52%]), right common carotid (8 [13%]) and both innominate and right common carotid (2 [3%]). IPE was protected by carotid cross-clamp in 48 (77%). Shunting occurred in 14 (23%). There were four (6.5%) perioperative ipsilateral strokes and two hyperperfusion events. There were three (4.8%) operative deaths, one from stroke and two cardiovascular. Combined stroke and death rate was 11.3% and was not different between centers. Mean clinical follow-up was 6 +/- 4 years. Mean imaging follow-up was 3 +/- 4 years. Restenosis >=50% at either intervention occurred in 20 (34%). Reintervention was performed for five proximal and three bifurcation failures (14%). Symptomatic status, redo operation, carotid clamp protection, multiple stents, and procedural order were not associated with operative stroke. Carotid clamp protection was associated with less restenosis (P = .003). Redo operation (P = .04) and hyperlipidemia (P = .05) were associated with reintervention. The 5-year actuarial survival was 81%, whereas freedom from stroke and reintervention were 94% and 81%, respectively. CONCLUSIONS: Perioperative stroke and death with CEA + IPE are substantial and consistent across centers. It is strikingly different from isolated CEA or CEA added to open brachiocephalic reconstruction. Restenosis is frequent, and reintervention at either the proximal stent or bifurcation is common. This technical strategy should be used cautiously and selectively reserved for those who are symptomatic with hemodynamically relevant tandem lesions and unfit for open revascularization. PMID- 29622357 TI - The Society for Vascular Surgery Wound, Ischemia, and foot Infection (WIfI) classification independently predicts wound healing in diabetic foot ulcers. AB - OBJECTIVE: Previous studies have reported correlation between the Wound, Ischemia, and foot Infection (WIfI) classification system and wound healing time on unadjusted analyses. However, in the only multivariable analysis to date, WIfI stage was not predictive of wound healing. Our aim was to examine the association between WIfI classification and wound healing after risk adjustment in patients with diabetic foot ulcers (DFUs) treated in a multidisciplinary setting. METHODS: All patients presenting to our multidisciplinary DFU clinic from June 2012 to July 2017 were enrolled in a prospective database. A Cox proportional hazards model accounting for patients' sociodemographics, comorbidities, medication profiles, and wound characteristics was used to assess the association between WIfI classification and likelihood of wound healing at 1 year. RESULTS: There were 310 DFU patients enrolled (mean age, 59.0 +/- 0.7 years; 60.3% male; 60.0% black) with 709 wounds, including 32.4% WIfI stage 1, 19.9% stage 2, 25.2% stage 3, and 22.4% stage 4. Mean wound healing time increased with increasing WIfI stage (stage 1, 96.9 +/- 8.3 days; stage 4, 195.1 +/- 10.6 days; P < .001). Likelihood of wound healing at 1 year was 94.1% +/- 2.0% for stage 1 wounds vs 67.4% +/- 4.4% for stage 4 (P < .001). After risk adjustment, increasing WIfI stage was independently associated with poor wound healing (stage 4 vs stage 1: hazard ratio, [HR] 0.44; 95% confidence interval, 0.33-0.59). Peripheral artery disease (HR, 0.73), increasing wound area (HR, 0.99 per square centimeter), and longer time from wound onset to first assessment (HR, 0.97 per month) also decreased the likelihood of wound healing, whereas use of clopidogrel was protective (HR, 1.39; all, P <= .04). The top three predictors of poor wound healing were WIfI stage 4 (z score, -5.40), increasing wound area (z score, 3.14), and WIfI stage 3 (z score, -3.11), respectively. CONCLUSIONS: Among patients with DFU, the WIfI classification system predicts wound healing at 1 year in both crude and risk-adjusted analyses. This is the first study to validate the WIfI score as an independent predictor of wound healing using multivariable analysis. PMID- 29622358 TI - Arterial reconstructions for pediatric splanchnic artery occlusive disease. AB - OBJECTIVE: Pediatric splanchnic arterial occlusive disease is uncommon and a rare cause of clinically relevant intestinal ischemia. This study was undertaken to better define the clinical manifestations and appropriate treatment of celiac artery (CA) and superior mesenteric artery (SMA) occlusive disease in children. METHODS: Clinical courses of 30 consecutive children undergoing operations for splanchnic arterial occlusive disease at the University of Michigan from 1992 to 2017 were retrospectively analyzed. RESULTS: Vascular reconstructions were performed for splanchnic arterial disease in 18 boys and 12 girls, 1.5 to 16 years of age (mean, 7.5 +/- 4.1 years). Isolated splanchnic arterial disease was uncommon (2 children), being more often associated with abdominal aortic coarctations (19 children) or ostial renal artery stenoses (25 children). Primary splanchnic arterial reconstructions (30) included aortic reimplantation of SMAs (15) or celiacomesenteric arteries (2), aortoceliac and aortomesenteric bypasses (7), reimplantation of the CA as a patch over the stenotic SMA orifice (3), and patch angioplasty of the CA (2) or SMA (1). There was no perioperative mortality. Two groups (I and II) were identified for study. Group I children (14) experienced symptomatic intestinal ischemia, manifested by various combinations of chronic postprandial abdominal discomfort (14), ischemia-related intestinal bleeding (2), or failure to thrive (4). Four children in group I became symptomatic after known CA and SMA occlusive disease was left untreated at the time they underwent earlier interventions for renovascular hypertension. Seven secondary redo interventions were undertaken for recurrent symptoms in six group I children. Only one major periprocedural complication occurred: segmental colon infarction. The assisted patency rate of reconstructed arteries in group I children was 93%, and intestinal ischemic symptoms resolved in every child. Group I follow-up from the most recent splanchnic arterial reconstruction averaged 4.3 years. Group II children (16) without manifestations of intestinal ischemia underwent prophylactic splanchnic arterial reconstructions in concert with combined aortic and renal artery procedures (11), isolated abdominal aortic reconstructions (3), or renal artery reconstructions alone (2). Group II children experienced no major perioperative morbidity and remained asymptomatic postoperatively, and none required secondary splanchnic artery interventions. Group II follow-up averaged 7.4 years. CONCLUSIONS: Pediatric splanchnic artery occlusive lesions are often associated with developmental aortic and renal artery occlusive disease. Carefully conducted therapeutic and prophylactic reconstructive procedures are appropriate in children having splanchnic arterial occlusive disease. PMID- 29622359 TI - First case of sepsis by Ignatzschineria in Spain associated with myiasis. Description of a case and review of the literature. PMID- 29622360 TI - Microplastic does not magnify the acute effect of PAH pyrene on predatory performance of a tropical fish (Lates calcarifer). AB - Microplastic (MP) leads to widespread pollution in the marine ecosystem. In addition to the physical hazard posed by ingestion of microplastic particles, concern is also on their potential as vector for transport of hydrophobic contaminants. We experimentally studied the single and interactive effects of microplastic and pyrene, a polycyclic aromatic hydrocarbon, on the swimming behaviour and predatory performance of juvenile barramundi (Lates calcarifer). Juveniles (18+ days post hatch) were exposed to MPs, or pyrene (100 nM), or combination of both, and feeding rate and foraging activity (swimming) were analysed. Exposure to MPs alone did not significantly influence feeding performance of the juveniles, while a dose-effect series of pyrene showed strong effect on fish behaviour when concentrations were above 100 nM. In the test of combined MP and pyrene exposure, we observed no effect on feeding while swimming speed decreased significantly. Thus, our results confirm that short-time exposure to pyrene impacts the performance of fish juveniles, while additional exposure to microplastic at the given conditions influenced their activity only and not their feeding rate. Further studies of the combined effects of microplastics and pollutants on tropical fish behaviour are encouraged. PMID- 29622361 TI - Perception of radiology reporting efficacy by neurologists in general and university hospitals. AB - AIM: To investigate how neurologists perceive the value of the radiology report and to analyse the relation with the neurologists own expertise in radiology and the level of subspecialisation of radiologists. MATERIALS AND METHODS: A web based survey was distributed to neurologists. The level of subspecialisation was assessed by the percentage of fellowship-trained radiologists and the percentage of radiologists that were members of the Dutch Society of Neuroradiology. RESULTS: Most neurologists interpret all computed tomography (CT) and magnetic resonance imaging (MRI) studies themselves, and their self-confidence in making correct interpretations is high. Residents gave higher scores than neurologists for "Radiologist report answers the question" (p=0.039) and for "Radiologist reports give helpful advice" (p=0.001). Neurologists from university hospitals stated more frequently that the report answered their questions than neurologists from general hospitals (p=0.008). The general appreciation for radiology reports was higher for neurologists from university hospitals than from general hospitals (8.2 versus 7.2; p=0.003). Radiologists at university hospitals have a higher level of subspecialisation than those at general hospitals. CONCLUSION: Subspecialisation of radiologists leads to higher quality of radiology reporting as perceived by neurologists. Because of their expertise in radiology, neurologists are valuable sources of feedback for radiologists. Paying attention to the clinical questions and giving advice tailored to the needs of the referring physicians are opportunities to improve radiology reporting. PMID- 29622362 TI - Clinical outcomes of 23 patients who had repeat pelvic arterial embolisation for uncontrolled post-partum haemorrhage at a single centre. AB - AIM: To evaluate the safety and efficacy of repeated pelvic arterial embolisation (PAE) for uncontrolled postpartum haemorrhage (PPH) after a single session of PAE and to compare angiographic findings between the two sessions of PAE. MATERIALS AND METHODS: A total of 23 consecutive patients (age range, 23-44 years) who underwent repeated PAE for uncontrolled PPH between March 2001 and January 2016 in Severance Hospital were reviewed. The interval times between the two sessions of PAE, the angiographic findings, embolic materials, arteries embolised during PAE, and the clinical outcomes were reviewed retrospectively. RESULTS: Overall clinical success was achieved after repeated PAE in 21 of 23 patients (91.3%). There were no procedure-related, major complications. On angiography, active bleeding from the uterine collateral arteries was more frequently observed in the second session of PAE (p>0.05), and embolisation of the anterior division of the internal iliac artery was significantly higher during the second session of PAE. Use of permanent embolic materials was significantly higher during the second session of PAE. Recanalisation of a previously embolised artery was identified in 14 patients (60.9%) during the second session. CONCLUSION: Repeated PAE is safe and effective for managing recurrent bleeding after a single session of PAE. Repeated PAE is related to a higher chance of embolisation of the anterior division of the internal iliac artery, with the use of permanent embolic materials. Recanalisation of a previously embolised artery seems to be a principal source of rebleeding during a repeated session of PAE. PMID- 29622364 TI - Lung Siliconoma, a Rare Complication of Breast Prosthesis Rupture. PMID- 29622363 TI - Overlap between functional abdominal pain disorders and organic diseases in children. AB - Functional abdominal pain disorders are highly prevalent in children. These disorders can be present in isolation or combined with organic diseases, such as celiac disease and inflammatory bowel diseases. Intestinal inflammation (infectious and non-infectious) predisposes children to the development of visceral hypersensitivity that can manifest as functional abdominal pain disorders, including irritable bowel syndrome. The new onset of irritable bowel syndrome symptoms in a patient with an underlying organic disease, such as inflammatory bowel disease, is clinically challenging, given that the same symptomatology may represent a flare-up of the inflammatory bowel disease or an overlapping functional abdominal pain disorder. Similarly, irritable bowel syndrome symptoms in a child previously diagnosed with celiac disease may occur due to poorly controlled celiac disease or the overlap with a functional abdominal pain disorder. There is little research on the overlap of functional abdominal disorders with organic diseases in children. Studies suggest that the overlap between functional abdominal pain disorders and inflammatory bowel disease is more common in adults than in children. The causes for these differences in prevalence are unknown. Only a handful of studies have been published on the overlap between celiac disease and functional abdominal pain disorders in children. The present article provides a review of the literature on the overlap between celiac disease, inflammatory bowel disease, and functional abdominal pain disorders in children and establish comparisons with studies conducted on adults. PMID- 29622365 TI - Lung cryobiopsy and the KISS principle. PMID- 29622366 TI - Theory of mind, empathy and emotion perception in cortical and subcortical neurodegenerative diseases. AB - Although the impact of neurodegenerative diseases on everyday interactions is well known in the literature, their impact on social cognitive processes remains unclear. The concept of social cognition refers to a set of skills, all of which are essential for living in a community. It involves social knowledge, perception and processing of social cues, and representation of mental states. This report is a review of recent findings on the impact of cortical and subcortical neurodegenerative diseases on three social cognitive processes, namely, the theory of mind, empathy and processing emotions. The focus here is on a conceptual approach to each of these skills and their cerebral underpinnings. PMID- 29622367 TI - How many leads? PMID- 29622368 TI - Substernal goiter presenting as acute respiratory failure. PMID- 29622369 TI - Anticoagulation control in hospitalised patients with nonvalvular atrial fibrillation undergoing long-term oral anticoagulant therapy. PMID- 29622370 TI - Minimal-invasive, ablative surgery - Potential and limitations for a curative treatment approach in epilepsy. PMID- 29622371 TI - A Reanalysis of Predictors for the Risk of Hemorrhage in Brain Arteriovenous Malformation. AB - BACKGROUND: Brain arteriovenous malformation (BAVM) is a congenital cerebral vascular disease that characterized with intracranial hemorrhage and epilepsy. It has some risk in current treatments including microsurgery, endovascular, and radiation therapy. Some patients with bAVMs may keep unruptured in their whole life. Whether it should be treated depends on the evaluation of the hemorrhage risk of bAVM. Although previous studies gave many significant predictors, we tried to find some new and more significant predictors in 173 patients with bAVMS by retrospective analysis. METHODS: Except for previous predictors reported such as age, gender, epilepsy, location, aneurysm related with bAVM, volume of nidus, types of venous drainage, and the number of draining veins, we also collected time to peak (TTP) and sum of cross-sectional area of the feeding arteries and sum of cross-sectional area of the draining veins (?SA/?SV) data to proceed univariate and multivariate statistical analysis in 173 patients with bAVM. RESULTS: The results of the statistical analysis show that gender, the location of bAVM nidus, and TTP are significant predictors of hemorrhage risk, but age, size, the number of draining veins, and types of venous drainage do not appear so significant. The value of predictors of bleeding risk including TTP was assessed by receiver operating characteristic curve and area under curve to be stronger. CONCLUSIONS: When TTP and ?SA/?SV data were added, some previous important indicators such as age, size, the number of draining veins, and types of venous drainage appear less significant in predicting the hemorrhage risk of bAVM in statistics, but TTP, gender, and the location of bAVM nidus are significant; moreover, TTP is a predictor that needs to be emphasized. PMID- 29622372 TI - Treatment of Unruptured Cerebral Aneurysms with the Mineralocorticoid Receptor Blocker Eplerenone-Pilot Study. AB - BACKGROUND: Currently there are no pharmacological therapies for patients with unruptured cerebral aneurysms. Elsewhere we showed that the mineralocorticoid receptor antagonist eplerenone prevented the formation of cerebral aneurysms in our ovariectomized hypertensive aneurysm rat model. The current pilot study evaluated whether it can be used to prevent the growth and rupture of cerebral aneurysms in hypertensive patients. METHODS: Between August 2011 and May 2014, we enrolled 82 patients with 90 aneurysms in an open-label uncontrolled clinical trial. All provided prior informed consent for inclusion in this study, and all were treated with eplerenone (25-100 mg/d). The primary end points of our study were the rupture and enlargement of the cerebral aneurysms. RESULTS: Of the 82 patients, 80 (88 unruptured aneurysms) were followed for a mean of 21.3 months (153.4 aneurysm-years); 12 patients (15.0%) permanently discontinued taking the drug. One month after the start of eplerenone administration and throughout the follow-up period, eplerenone kept the blood pressure within the normal range. Most notably, no aneurysms smaller than 9 mm ruptured or enlarged. However, of 2 large thrombosed aneurysms, 1 enlarged and the other ruptured. The overall annual rupture rate was .65%; it was 13.16% for aneurysms larger than 10 mm; the overall annual rate for reaching the primary end points was 1.30%. CONCLUSION: Our observations suggest that eplerenone may help to prevent the growth and rupture of unruptured cerebral aneurysms smaller than 9 mm. To assess its potential long term clinical benefits, large clinical trials are needed. PMID- 29622374 TI - Renal dysfunction predicts mortality in type 2 diabetic patients suffering from an acute ischemic stroke. PMID- 29622373 TI - Antidepressants appear safe in patients with carcinoid tumor: Results of a retrospective review. AB - INTRODUCTION: Patients living with neuroendocrine tumors have high rates of depression, often necessitating antidepressants, including selective serotonin reuptake inhibitors (SSRI). Neuroendocrine tumors (NETs) secrete vasoactive substances, including serotonin, which contribute to the cluster of symptoms known as carcinoid syndrome (flushing and diarrhea). Controversy exists over whether or not antidepressants are safe in NET. We aimed to study the safety of antidepressant use in NET patients. METHODS: We conducted a retrospective chart review of patients with well differentiated NET who were also prescribed antidepressants from January 2008 through April 2015. The study took place at Memorial Sloan Kettering Cancer Center and was approved by the hospital's institutional review board. RESULTS: Ninety-two patients were included. There were 16 (17.4%) patients with carcinoid syndrome (10 ileum, 1 duodenum, 1 jejunum and 4 unknown primary); and 76 (82.6%) patients without (41 lung, 9 pancreas, 8 ileal, 5 duodenum, 5 appendix, 2 unknown primary, 1 jejunum and 5 other). Median duration of antidepressant prescription was 11.6 months (range, 0-121) among those with carcinoid syndrome (N = 16) and 14.3 months (range, 0-172) among those without carcinoid syndrome (n = 76). Antidepressants were stopped in 31 cases (33.7%), though the reason was not specified in the majority of cases (n = 18; 58%). None of the patients developed carcinoid syndrome while being prescribed antidepressants. No patients developed carcinoid crisis. CONCLUSION: Our findings do not support previous authors' recommendations that SSRIs must be avoided in NET patients. Several classes of antidepressants appeared safe in NET patients with and without carcinoid syndrome. PMID- 29622375 TI - An increase in diagnostic JAK2 V617F mutation testing: Is masked polycythaemia vera the explanantion? PMID- 29622376 TI - Mahaim fiber-mediated tachycardia. AB - We present the case of a previously healthy 42-year-old man who attended the emergency department due to a sudden onset of rapid and regular palpitations. The ECG showed 190 bpm, wide QRS with left bundle branch block tachycardia. He was started on amiodarone with progression to 230 bpm, wide QRS tachycardia with multiple morphologies, followed by spontaneous conversion to sinus rhythm, normal PR interval and rS pattern in LIII. The echocardiogram was negative for structural heart disease. The electrophysiological study demonstrated the presence of an accessory pathway with anterograde decremental conduction and no retrograde conduction. Both episodes of clinical tachycardia were induced. A diagnosis of Mahaim fiber-mediated antidromic atrioventricular reentrant tachycardia and pre-excited atrial fibrillation was made. Mapping was performed with detection of an M potential (His-like) at the lateral region of the tricuspid ring followed by radiofrequency ablation with immediate success criteria. Post-ablation there was a change to a qR pattern in LIII. At 12-months follow-up there was no recurrence of the tachycardia. PMID- 29622377 TI - Physico-chemical properties of excavated plastic from landfill mining and current recycling routes. AB - In Europe over 5.25 billion tonnes of waste has been landfilled between 1995 and 2015. Among this large amount of waste, plastic represents typically 5-25 wt% which is significant and has the potential to be recycled and reintroduced into the circular economy. To date there is still however little information available of the opportunities and challenges in recovering plastics from landfill sites. In this review, the impacts of landfill chemistry on the degradation and/or contamination of excavated plastic waste are analysed. The feasibility of using excavated plastic waste as feedstock for upcycling to valuable chemicals or liquid fuels through thermochemical conversion is also critically discussed. The limited degradation that is experienced by many plastics in landfills (>20 years) which guarantee that large amount is still available is largely due to thermooxidative degradation and the anaerobic conditions. However, excavated plastic waste cannot be conventionally recycled due to high level of ash, impurities and heavy metals. Recent studies demonstrated that pyrolysis offers a cost effective alternative option to conventional recycling. The produced pyrolysis oil is expected to have similar characteristics to petroleum diesel oil. The production of valuable product from excavated plastic waste will also increase the feasibility of enhanced landfill mining projects. However, further studies are needed to investigate the uncertainties about the contamination level and degradation of excavated plastic waste and address their viability for being processed through pyrolysis. PMID- 29622378 TI - Cost-effectiveness of nutrition therapy. PMID- 29622379 TI - Vaccination against the human cytomegalovirus. AB - The human cytomegalovirus (HCMV) is the most important infectious cause of congenital abnormalities and also of infectious complications of transplantation. The biology of the infection is complex and acquired immunity does not always prevent reinfection. Nevertheless, vaccine development is far advanced, with numerous candidate vaccines being tested, both live and inactivated. This article summarizes the status of the candidate vaccines. PMID- 29622380 TI - A randomized, placebo-controlled, single ascending-dose study to assess the safety, tolerability, pharmacokinetics, and immunogenicity of subcutaneous tralokinumab in Japanese healthy volunteers. AB - Tralokinumab is a human monoclonal antibody in clinical development for asthma and atopic dermatitis that specifically neutralizes interleukin-13. This phase I, single-blind, randomized, placebo-controlled, single ascending-dose study assessed the safety, tolerability, pharmacokinetics (PK), and immunogenicity of subcutaneous tralokinumab (150, 300, or 600 mg) in thirty healthy Japanese adults. The most frequent treatment-emergent adverse event (TEAE) in all treatment groups was injection-site pain. The frequency and severity of TEAEs was similar across tralokinumab doses. Cmax, AUC(0-t), and AUC(0-inf) increased in a dose-proportional manner, and mean t1/2 ranged from 20 to 25 days. No anti-drug antibodies were detected. A post-hoc pooled population PK modeling analysis, incorporating PK data from this study, demonstrated that Japanese individuals had greater systemic exposure to tralokinumab than non-Japanese individuals. This difference was not clinically relevant and was primarily due to differences in body weight, with lower body weight associated with greater PK exposure. Japanese ethnicity was not a significant predictor of tralokinumab PK. This study indicates that single-dose subcutaneous administration of tralokinumab 150-600 mg was well tolerated in Japanese healthy volunteers, and supports the 300 mg dose selection for Japanese patients with asthma in ongoing clinical trials. PMID- 29622381 TI - Harnessing the private health sector by using prices as a policy instrument: Lessons learned from South Africa. AB - Governments frequently draw upon the private health care sector to promote sustainability, optimal use of resources, and increased choice. In doing so, policy-makers face the challenge of harnessing resources while grappling with the market failures and equity concerns associated with private financing of health care. The growth of the private health sector in South Africa has fundamentally changed the structure of health care delivery. A mutually reinforcing ecosystem of private health insurers, private hospitals and specialists has grown to account for almost half of the country's spending on health care, despite only serving 16% of the population with the capacity to pay. Following years of consolidation among private hospital groups and insurance schemes, and after successive failures at establishing credible price benchmarks, South Africa's private hospitals charge prices comparable with countries that are considerably richer. This compromises the affordability of a broad-based expansion in health care for the population. The South African example demonstrates that prices can be part of a structure that perpetuates inequalities in access to health care resources. The lesson for other countries is the importance of norms and institutions that uphold price schedules in high-income countries. Efforts to compromise or liberalize price setting should be undertaken with a healthy degree of caution. PMID- 29622382 TI - Prospective Study of Breast Radiation Dermatitis. AB - BACKGROUND: Despite clear benefits of radiotherapy (RT) for breast cancer, there are numerous side effects. Radiation dermatitis has a significant impact on quality of life and can result in treatment interruptions or cessation. The purpose of this study was to prospectively follow breast radiation dermatitis and determine trends including peak toxicity. PATIENTS AND METHODS: Upon initiation of RT treatment, to assess skin reaction, each patient was seen weekly by the healthcare team, or contacted via telephone to assess patient-reported symptoms. Weekly progression of radiation dermatitis was assessed using the Common Terminology Criteria for Adverse Events (CTCAE), version 4.03. Patients were stratified for analysis of radiation dermatitis based on RT technique and dosage. RESULTS: A total of 148 patients with 2 or more skin assessments were analyzed. The majority of patients received 2-field tangential RT (64.2%) with a dose of 5000 cGy in 25 fractions. Overall, patients experienced the most Grade 2 CTCAE toxicity (61.9%) 2 weeks after completion of RT; Grade 3 toxicity also peaked at this time (8.3%). Regardless of stratification by RT technique or by dosage of RT, Grade 2 and 3 toxicities consistently peaked at 1 or 2 weeks after RT. CONCLUSIONS: Breast radiation dermatitis appears to peak approximately 2 weeks after RT. Treatment factors such as technique or dosing regimen do not appear to have a substantial effect on radiation dermatitis, but our study was limited by small sample size. This study provides additional evidence that radiation dermatitis should continue to be followed closely, especially in the 2 weeks following RT. PMID- 29622383 TI - Invasive Breast Carcinoma Tumor Size on Core Needle Biopsy: Analysis of Practice Patterns and Effect on Final Pathologic Tumor Stage. AB - INTRODUCTION: In the absence of nodal metastasis, pathologic tumor (pT) size remains one of the most important factors in adjuvant treatment decisions and patient prognosis in breast cancer. The aim of this study was to evaluate the effect of core needle biopsy (CNB) tumor size on final pT stage. MATERIALS AND METHODS: Our information system was searched to identify all patients who underwent excisional procedures for invasive breast carcinoma from January 1, 2014 to December 31, 2015. The tumor size on CNB and final excision, the number of cases in which the CNB size was larger, and the percentage of cases in which using the CNB tumor size changed the final pT stage were recorded. RESULTS: From 1380 primary breast excisions/mastectomies, a total of 870 cases were included. In 82 (9.4%) the CNB tumor size was larger (63 of 82 cases) or no residual tumor was identified on excision (19 of 82 cases). From these 82 cases, 40 (48.7%) were properly staged on the basis of CNB tumor size, 16 (19.5%) were not staged, and 26 (31.7%) were staged using the final excision tumor size. Change in stage occurred in 7 of these 26 patients. CONCLUSION: Our study revealed that in most cases, the largest tumor size is found in the excision/mastectomy specimen. However, in 9.4% (82 of 870), the CNB contains the most accurate tumor size for pT staging. On the basis of our results, including the largest linear tumor extent on the CNB report is recommended. PMID- 29622384 TI - Chemotherapy Dose Intensity and Overall Survival Among Patients With Advanced Breast or Ovarian Cancer. AB - BACKGROUND: The effects of chemotherapy dose intensity on patient outcomes in advanced cancer are not well understood. We studied the association between chemotherapy relative dose intensity (RDI) and overall survival (OS) among patients with advanced breast or ovarian cancer. PATIENTS AND METHODS: This retrospective cohort study included adults with advanced breast or ovarian cancer who received first-line myelosuppressive chemotherapy (January 2007 to December 2010) in US Oncology Network community practices. Dose delays >= 7 days, dose reductions >= 15%, and RDI relative to standard regimens were described. OS was measured by the Kaplan-Meier method and Cox proportional hazards models. RESULTS: Among 874 patients with advanced breast cancer, 33.2% experienced dose delays >= 7 days, 48.7% experienced dose reductions >= 15%, and 38.9% had RDI < 85%. In the multivariable Cox proportional hazards model, Eastern Cooperative Oncology Group performance status 1/2 versus 0 (hazard ratio [HR] = 1.45; 95% confidence interval [CI], 1.15-1.82) and triple-negative status (HR = 3.14; 95% CI, 1.15 8.62) were significantly associated with mortality. Among 170 patients with advanced ovarian cancer, 43.5% experienced dose delays >= 7 days, 48.2% experienced dose reductions >= 15%, and 46.5% had RDI < 85%. In the multivariable Cox proportional hazards model, dose reductions >= 15% (HR = 1.94; 95% CI, 1.09 3.46) and other tumor histology (vs. nonserous adenocarcinoma; HR = 3.55; 95% CI, 1.38-9.09) were significantly associated with mortality. CONCLUSION: Dose delays, dose reductions, and reduced RDI were common. In advanced breast cancer, health status and triple-negative disease were significantly associated with mortality. In advanced ovarian cancer, dose reductions and tumor histology were significantly associated with mortality. These results can help identify potential risk factors and characterize the effect of chemotherapy dose modification strategies on mortality. PMID- 29622385 TI - Necrolytic acral erythema leading to diagnosis of chronic hepatitis C. PMID- 29622386 TI - Long-term outcome of transjugular intrahepatic portosystemic shunt for portal hypertension in autosomal recessive polycystic kidney disease. AB - BACKGROUND: Autosomal recessive polycystic kidney disease (ARPKD) with congenital hepatic fibrosis (CHF) causes portal hypertension and its complications. A transjugular intrahepatic portosystemic shunt (TIPSS) could serve as a symptomatic treatment for portal hypertension-related symptoms in these children. AIMS: To study the effect of TIPSS on portal hypertension, liver and kidney function and the long term complications. MATERIALS AND METHODS: We report on 5 children with CHF treated with a TIPSS to manage severe portal hypertension related symptoms. RESULTS: Mean follow-up time was 7 years and 2 months. At the end of follow-up there was a reduction of spleen size (p = 0.715) and hypersplenism with a rise in platelet count (p = 0.465). Esophageal varices and ascites disappeared in all patients. Liver and kidney function remained stable. In two patients endotipsitis was suspected and two patients developed an in-stent stenosis. There was no sign of encephalopathy in our patients. CONCLUSION: TIPSS using ePTFE-covered stent is a feasible and effective alternative for surgical portosystemic shunting in children with CHF, also on the long term. It can postpone the need of a liver transplantation but close monitoring remains important for early diagnosis of endotipsitis or stent dysfunction related to stenosis. PMID- 29622387 TI - Hepatic resection vs. transarterial chemoembolization for hepatocellular carcinoma beyond the Milan criteria with portal hypertension. AB - OBJECTIVE: To assess the value of hepatic resection by comparing it with transarterial chemoembolization for hepatocellular carcinoma beyond the Milan criteria with clinically relevant portal hypertension. METHODS: A total of 363 patients and 193 propensity score-matched patients who had hepatocellular carcinoma beyond the Milan criteria with clinically relevant portal hypertension and underwent hepatic resection or transarterial chemoembolization were retrospectively analyzed. The short-term and long-term results were compared. RESULTS: Postoperative complications and 30-day mortality were similar between the two groups. The hepatic resection provided a survival benefit over TACE at 1, 2, 3, and 5 years. Similar results were observed in the propensity score analysis. Five variables were identified as independent prognostic factors: treatment, AFP, Child-Pugh classification, tumor number and extension of disease in a multivariate analysis of the whole study population. In addition, only the tumor number was identified as an independent risk factor after propensity matching. The subgroup analysis demonstrated that the survival benefit of the hepatic resection can only be derived in a subset of patients with a single tumor. CONCLUSIONS: In a properly selected group of patients with hepatocellular carcinoma beyond the Milan criteria with clinically relevant portal hypertension, hepatic resection appears to be as safe as TACE and provides a significant survival benefit. PMID- 29622388 TI - Towards a RAS mutation status in a single day for patients with advanced colorectal cancers. PMID- 29622389 TI - Dying in hospital: Qualitative study among caregivers of terminally ill patients who are transferred to the emergency department. AB - INTRODUCTION: Most people in France die in the hospital, even though a majority would like to die at home. These end-of-life hospital admissions sometimes occur in the emergency setting, in the hours preceding death. OBJECTIVE: To understand the motives that incite main natural caregivers to transfer terminally ill patients at the end of life to the emergency department. METHODS: A qualitative study was performed among caregivers of terminally ill patients receiving palliative care and living at home, and who died within 72hours of being admitted to the emergency department of the University Hospital of Besancon, France. RESULTS: Eight interviews were performed; average duration 48minutes. The caregivers described the difficult conditions of daily life, characterised by marked anguish about what the future might hold. Although they were aware that the patient was approaching the end of life, the caregivers did not imagine the death at all. The transfer to the emergency department was considered as a logical event, occurring in the continuity of the home care, and was not in any way criticised, even long after death had occurred. Overall, the caregivers had a positive opinion of how the end-of-life accompaniment went. DISCUSSION: Difficulty in imagining death at home is underpinned by its unpredictable nature, and by the accumulation of suffering and anguish in the caregiver. Hospital admission and medicalisation of death help to channel the caregiver's anguish. In order to improve end-of-life accompaniment, it is mandatory to make home management more reassuring for the patient and their family. PMID- 29622390 TI - [Therapeutic advances in the management of biliary tract carcinoma]. AB - Cancers of the bile ducts or cholangiocarcinomas are a rare entity whose incidence is increasing in France. Surgical resection of cholangiocarcinoma remains the only curative therapy. Adjuvant therapy with capecitabine at a fixed dose of 1250mg/m2 twice daily from day 1 to day 14 (21-day cycle) for a 6 months period is now the standard of care after curative surgery. At a metastatic stage, the reference treatment consists of the combination of a platinum salt in addition to gemcitabine. No biomarker has been identified to predict the response to chemotherapy. DNA sequencing of the tumor can identify specific tumor mutations in bile duct cancers that are the focus of targeted studies. PMID- 29622391 TI - The authors reply to the optimal dose and volume of local anesthetic for erector spinae plane blockade for posterior rib fractures. PMID- 29622392 TI - Comparison of drug administration logistics between prothrombin complex concentrates and plasma in the emergency department. AB - BACKGROUND: Prothrombin complex concentrate (PCC) is used as an alternative to fresh frozen plasma (FFP) for emergency bleeding. The primary objective of this study was to compare the time from order to start of administration between 3 factor PCC (PCC3), 4-factor (PCC4), and FFP in the emergency department (ED). The secondary objective was to evaluate the effect of an ED pharmacist on time to administration of PCCs. METHODS: This was a single center three-arm retrospective cohort study. Adult patients in the ED with bleeding were included. The primary outcome measure was the time from order to administration, which was compared between PCC3, PCC4, and FFP. The time from order to administration was also compared when the ED pharmacist was involved versus not involved in the care of patients receiving PCC. RESULTS: There were 90 patients included in the study cohort (30 in each group). The median age was 69years (IQR 57-82years), and 57% (n=52) were male. The median time from order to administration was 36min (IQR 20 58min) for PCC3, 34min (IQR 18-48min) for PCC4, and 92min (IQR 63-133) for FFP (PCC3 versus PCC4, p=0.429; PCC3 versus FFP, p<0.001; PCC4 versus FFP, p<0.001). The median time from order to administration was significantly decreased when the ED pharmacist was involved (24min [IQR 15-35min] versus 42min [IQR 32-59min], p<0.001). CONCLUSIONS: Time from order to administration is faster with PCC than FFP. ED pharmacist involvement decreases the time from order to administration of PCC. PMID- 29622393 TI - Heart failure education in the emergency department markedly reduces readmissions in un- and under-insured patients. AB - BACKGROUND: Heart failure (HF) readmissions are a longstanding national healthcare issue for both hospitals and patients. Our purpose was to evaluate the efficacy of a structured, educational intervention targeted towards un- and under insured emergency department (ED) HF patients. METHODS: HF patients presenting to the ED for care were enrolled between July and December 2015 as part of an open label, interventional study, using a parallel observational control group. Eligible patients provided informed consent, had an established HF diagnosis, and were hemodynamically stable. Intervention patients received a standardized educational intervention in the ED waiting room before seeing the emergency physician, and a 30-day telephone follow-up. Primary and secondary endpoints were 30- and 90-day ED and hospital readmission rates, as well as days alive and out of hospital (DAOH) respectively. RESULTS: Of the 94 patients enrolled, median age was 58.4 years; 40.4% were female, and 54.3% were African American. Intervention patients (n = 45) experienced a 47.8% and 45.3% decrease in ED revisits (P = 0.02 &P < 0.001), and 60.0% and 47.4% decrease in hospital readmissions (P = 0.049 &P = 0.007) in the 30 and 90 days pre- versus post-intervention respectively. Control patients (n = 49) had no change in hospital readmissions or 30-day ED revisits, but experienced a 36.6% increase in 90-day ED revisits (P = 0.03). Intervention patients also saw a 59.2% improvement in DAOH versus control patients (P = 0.03). CONCLUSION: An ED educational intervention markedly decreases ED and hospital readmissions in un- and under-insured HF patients. PMID- 29622394 TI - Factors associated with absent microhematuria in symptomatic urinary stone patients. AB - INTRODUCTION: The aim of this study was to identify factors associated with absent hematuria in patients with symptomatic urinary stones. METHODS: This retrospective study analyzed the clinical and imaging findings of emergency department patients who underwent computed tomography (CT) for suspected ureteral colic over the past 2years. All patients also underwent a microscopic urinalysis, and the presence of 4 or more red blood cells/high-power field was defined as microhematuria. RESULTS: A total of 798 patients were included in this study. Of these patients, 750 (94.0%) presented with hematuria, while 48 (6.0%) urine samples did not have evidence of hematuria. The group with an absence of hematuria was more likely to have a lower stone location (located in an area from the distal ureter to the bladder) and perinephric stranding on CT than the hematuria group (75.0% vs. 54.3%, p=0.005; 47.9% vs. 30.5%, p=0.012, respectively). The degree of hematuria at each stone location was significantly different (p=0.001). In multivariate analysis, perinephric stranding (odds ratios (OR) 1.87 [95% confidence interval (CI) 1.01-3.46], p=0.047), a lower stone location (OR 2.72 [95% CI 1.37-5.36], p=0.004), and elevated serum blood urea nitrogen (BUN) levels (OR 1.06 [95% CI 1.01-1.12], p=0.026) were associated with absent hematuria. CONCLUSIONS: In this large cohort of patients with renal colic, 6% had no microhematuria. Although some CT findings and elevated BUN were independently associated with hematuria absence, there was no difference in the demographics, time of presentation and degree and location of pain between the groups. PMID- 29622395 TI - From Petri Dishes to Model Ecosystems. AB - Model ecosystems could provide significant insight into the evolution and behavior of real ecosystems. We discuss the advantages and limitations of common approaches like mesocosms. In this context, we highlight recent breakthroughs that allow for the creation of networks of organisms with independently controlled environments and rates of chemical exchange. PMID- 29622396 TI - The Distended Fetal Hypopharynx: A Sensitive and Novel Sign for the Prenatal Diagnosis of Esophageal Atresia. AB - BACKGROUND/PURPOSE: Although advances have been made in the prenatal diagnosis of esophageal atresia (EA), most neonates are not identified until after birth. The distended hypopharynx (DHP) has been suggested as a novel prenatal sign for EA. We assess its diagnostic accuracy and predictive value on ultrasound (US) and magnetic resonance imaging (MRI), both alone and in combination with the esophageal pouch (EP) and secondary signs of EA (polyhydramnios and a small or absent fetal stomach). METHODS: We retrospectively reviewed fetal US and MRI reports and medical records of 88 pregnant women evaluated for possible EA from 2000 to 2016. Seventy-five had postnatal follow-up that confirmed or disproved the diagnosis of EA and were included in our analysis. RESULTS: Seventy-five women had 107 study visits (range 1-4). DHP and/or EP were seen on US and/or MRI in 36% of patients, and 78% of those patients had EA. DHP was 24% more sensitive for EA than EP, while EP was 30% more specific. After 28weeks of gestation, DHP had a predictive accuracy for EA of 0.929 (P=0.001). CONCLUSIONS: DHP is a sensitive additional prenatal sign of EA. More accurate diagnosis of EA allows for improved counseling regarding delivery, postnatal evaluation, and surgical correction. TYPE OF STUDY: Diagnostic. LEVEL OF EVIDENCE: Level II. PMID- 29622397 TI - The route and timing of hydrogen sulfide therapy critically impacts intestinal recovery following ischemia and reperfusion injury. AB - PURPOSE: Hydrogen sulfide (H2S) has many beneficial properties and may serve as a novel treatment in patients suffering from intestinal ischemia-reperfusion injury (I/R). The purpose of this study was to examine the method of delivery and timing of administration of H2S for intestinal therapy during ischemic injury. We hypothesized that 1) route of administration of hydrogen sulfide would impact intestinal recovery following acute mesenteric ischemia and 2) preischemic H2S conditioning using the optimal mode of administration as determined above would provide superior protection compared to postischemic application. METHODS: Male C57BL/6J mice underwent intestinal ischemia by temporary occlusion of the superior mesenteric artery. Following ischemia, animals were treated according to one of the following (N=6 per group): intraperitoneal or intravenous injection of GYY4137 (H2S-releasing donor, 50mg/kg in PBS), vehicle, inhalation of oxygen only, inhalation of 80ppm hydrogen sulfide gas. Following 24-h recovery, perfusion was assessed via laser Doppler imaging, and animals were euthanized. Perfusion and histology data were assessed, and terminal ileum samples were analyzed for cytokine production following ischemia. Once the optimal route of administration was determined, preischemic conditioning with H2S was undertaken using that route of administration. All data were analyzed using Mann-Whitney. P values <0.05 were significant. RESULTS: Mesenteric perfusion following intestinal I/R was superior in mice treated with intraperitoneal (IP) GYY4137 (IP vehicle: 25.6+/-6.0 vs. IP GYY4137: 79.7+/-15.1; p=0.02) or intravenous (IV) GYY4137 (IV vehicle: 36.3+/-5.9 vs. IV GYY4137: 100.7+/-34.0; p=0.03). This benefit was not observed with inhaled H2S gas (O2 vehicle: 66.6+/-11.4 vs. H2S gas: 81.8+/-6.0; p=0.31). However, histological architecture was only preserved with intraperitoneal administration of GYY4127 (IP vehicle: 3.4+/-0.4 vs. IP GYY4137: 2+/-0.3; p=0.02). Additionally, IP GYY4137 allowed for significant attenuation of inflammatory chemokine production of IL-6, IP-10 and MIP-2. We then analyzed whether there was a difference between pre- and postischemic administration of IP GYY4137. We found that preconditioning of animals with intraperitoneal GYY4137 only added minor improvements in outcomes compared to postischemic application. CONCLUSION: Therapeutic benefits of H2S are superior with intraperitoneal application of an H2S donor compared to other administration routes. Additionally, while intraperitoneal treatment in both the pre- and postischemic period is beneficial, preischemic application of an H2S donor was found to be slightly better. Further studies are needed to examine long term outcomes and further mechanisms of action prior to widespread clinical application. TYPE OF STUDY: Basic science. LEVEL OF EVIDENCE: N/A. PMID- 29622398 TI - Time to reintroduction of feeding in infants with nonsurgical necrotizing enterocolitis. AB - BACKGROUND: For infants with necrotizing enterocolitis (NEC) treated nonoperatively, no consensus exists on the optimal fasting period prior to reintroducing feeds after NEC. We report our experience with early (<7days) and late (>=7days) refeeding in this population. METHODS: A chart review of infants with NEC born between 2006 and 2016 was performed. Data elements include demographics, comorbidities, day of diagnosis, Bell's stage, recurrence, strictures, length of stay and mortality, and were grouped into early and late refeeding. T-tests were used for means and chi-squared tests for distribution of proportions. Linear and logistic regressions were used to further evaluate the association of length of stay, stricture, recurrence, and death with time to refeeding. RESULTS: Of 228 NEC patients, 149(65%) were treated nonoperatively (Bell Stages I, IIA, IIB, IIIA). Eleven patients were excluded owing to never restarting feeds, largely secondary to early death. The early (n=40) and late refeeding (n=98) groups were not significantly different with regard to mean gestational age at birth, race, birth weight, day of life at NEC diagnosis, or cardiac disease. NEC Stage was significantly different (p<0.001). The late group had significantly more Stage IIB patients (p=.02), and the early group had more stage I patients (p=<0.01). After adjusting for Bell's stage, the odds of NEC recurrence, death, and the composite outcome of recurrence or stricture or death were not significantly different between early and late groups. CONCLUSIONS: No standardized guidelines exist for restarting enteral nutrition following medical NEC. In patients managed nonoperatively, early reintroduction of feeding was not significantly associated with increased NEC recurrence, mortality, or stricture. LEVEL OF EVIDENCE: Treatment Study - Level III. PMID- 29622400 TI - Patient-specific and hospital resource-specific considerations in operative versus nonoperative management of acute appendicitis. PMID- 29622401 TI - The academic tweet: Twitter as a tool to advance academic surgery. AB - Social media, Twitter in particular, has emerged as an essential tool for surgeons. In the realm of academic surgery, it enables surgeons to advance the core values of academic surgery, as outlined by the Association for Academic Surgery: inclusion, leadership, innovation, scholarship, and mentorship. This article details the ways in which surgeons are using Twitter to embody these values and how the Twitter account for the Association of Academic Surgeons accomplishes its goal of inspiring and developing young academic surgeons. PMID- 29622399 TI - Can a gastric cancer risk survey identify high-risk patients for endoscopic screening? A pilot study. AB - BACKGROUND: A questionnaire that distinguishes how variability in gastric cancer prevalence is associated with ethnicity/birth country/immigration/cultural diet along with known risk factors may improve targeting populations for gastric cancer screening in the United States. METHODS: Existing literature was used to identify the item pool. Cluster analysis, focus groups, and cognitive interviewing were used to reduce collinear items and refine the questionnaire. Logistic regression analysis was used to determine which items distinguished gastric cancer cases from the primary care and community controls. RESULTS: The results of analysis of data from 40 cases and 100 controls (primary care = 47; community = 53) were used to reduce the 227 item pool to 12 items. After ranking these variables using model bootstrapping, a logistic regression model using the highest ranked eight variables was chosen as the final model. Older age, foreign nativity, daily consumption of cultural food at ages 15-18, less than high-school education, and greater acculturation were significantly associated with being a gastric cancer case compared with the controls. CONCLUSIONS: An eight-item survey that addresses gastric cancer risk factors, ethnicity, cultural habits, and immigration patterns has potential to identify high-risk persons from multicultural areas within the US, who might benefit from endoscopic screening for gastric cancer. PMID- 29622402 TI - Vascular invasion and survival after liver transplantation for hepatocellular carcinoma: a study from the European Liver Transplant Registry. AB - BACKGROUND: Studies suggest that vascular invasion may be a superior prognostic marker compared with traditional selection criteria, e.g. Milan criteria. This study aimed to investigate the prognostic value of micro and macrovascular invasion in a large database material. METHODS: Patients liver transplanted for HCC and cirrhosis registered in the European Liver Transplant Registry (ELTR) database were included. The association between the Milan criteria, Up-to-seven criteria and vascular invasion with overall survival and HCC specific survival was investigated with univariate and multivariate Cox regression analyses. RESULTS: Of 23,124 patients transplanted for HCC, 9324 had cirrhosis and data on explant pathology. Patients without microvascular invasion, regardless of number and size of HCC nodules, had a five-year overall survival of 73.2%, which was comparable with patients inside both Milan and Up-to-seven criteria. Patients without macrovascular invasion had an only marginally reduced survival of 70.7% after five years. Patients outside both Milan and Up-to-seven criteria without micro or macrovascular invasion still had a five-year overall survival of 65.8%. CONCLUSION: Vascular invasion as a prognostic indicator remains superior to criteria based on size and number of nodules. With continuously improving imaging studies, microvascular invasion may be used for selecting patients for transplantation in the future. PMID- 29622403 TI - Cryostorage duration does not affect pregnancy and neonatal outcomes: a retrospective single-centre cohort study of vitrified-warmed blastocysts. AB - A retrospective cohort study of 8736 autologous single vitrified-warmed blastocyst transfer cycles was conducted in a single centre to investigate the effect of cryostorage on clinical and neonatal outcomes. Cryostorage duration was classified into three groups: (A) 0-2 months (n = 4702); (B) 2-13 months (n = 2853) and (C) 13-97 months (n = 1181). Blastocysts were vitrified using the Cryotop method. No significant differences were observed in live birth rates: (A) 37.3%; (B) 34.9%; (C) (35.2%). Gestational period was significantly shorter in group C: (A) 38.7 +/- 1.8; (B) 38.6 +/- 1.6; (C) 38.1 +/- 1.7; P < 0.05. This was clinically unimportant as the average gestational age was more than 38 weeks. No significant differences between groups were observed in birth weight: (A) 3060 +/ 455 g; (B) 3052 +/- 449 g; (C) 2992 +/- 445 g, or congenital malformation rates: (A) 2.2%; (B) 1.9%; (C) 1.8%. The limitation of this study was that maximum storage duration was 8 years; most blastocysts were in cryostorage for much shorter periods. Long-term storage of blastocysts that are vitrified using an open device vitrification system has no negative effect on pregnancy and neonatal outcomes. PMID- 29622404 TI - Depression and state anxiety scores during assisted reproductive treatment are associated with outcome: a meta-analysis. AB - This meta-analysis investigated whether state anxiety and depression scores during assisted reproductive technology (ART) treatment and changes in state anxiety and depression scores between baseline and during ART treatment are associated with treatment outcome. PubMed, PsycInfo, Embase, ScienceDirect, Web of Science and Scopus were searched and meta-analytic data analysed using random effects models to estimate standardized mean differences. Eleven studies (2202 patients) were included. Women who achieved pregnancy had significantly lower depression scores during treatment than women who did not become pregnant ( 0.302; 95% CI: -0.551 to -0.054, z = -2.387, P = 0.017; I2 = 77.142%, P = 0.001). State anxiety scores were also lower in women who became pregnant (-0.335; 95% CI: -0.582 to -0.087, z = -2.649, P = 0.008; I2 = 81.339%, P = 0.001). However, changes in state anxiety (d = -0.056; 95% CI: -0.195 to 0.082, z = -0.794; I2 = 0.00%) and depression scores (d = -0.106; 95% CI: -0.296 to 0.085, z = -1.088; I2 = 0.00%) from baseline to treatment were not associated with ART outcome. Clinics should aim to promote better psychosocial care to help patients manage the psychological and physical demands of ART treatment, giving realistic expectations. PMID- 29622405 TI - Can we refine the management of blunt liver trauma? AB - AIM: To describe the management of blunt liver injury and to study the potential relation between delayed complications, type of trauma mechanisms and liver lesions. PATIENTS AND METHODS: This is a retrospective single center study including 116 consecutive patients admitted with blunt liver injury between 2007 and 2015. RESULTS: Initial CT-scan identified an active bleeding in 33 (28%) patients. AAST (American Association for the Surgery of Trauma) grade was 1 to 3 in 82 (71%) patients and equal to 5 in 15 (13%) patients. Eighty (69%) patients had NOM, with a success rate of 96%. Other abdominal organ lesions were associated to invasive initial management. A follow-up CT-scan was useful to detect hepatic and extra-hepatic complications (46 complications in 80 patients), even without clinical or biological abnormalities. Subsequent hepatic complications such as bleeding, pseudo aneurysms, biloma and biliary peritonitis developed in 15 patients and were associated with the severity of blunt liver injury according to AAST classification (3.7+/-1.0 vs. 3.0+/-1.1, P=0.010). Total biliary complications occurred in 13 patients and were significantly more frequently observed in patients with injury of central segments 1, 4 and 9 (69% vs. 36%, P=0.033). CONCLUSIONS: Non-operative management is possible in most blunt liver injury with a success rate of 96%. A systematic CT-scan should be advocated during follow-up, especially when AAST grade is equal or superior to 3. Biliary complications should be suspected when lesions involve segments 1, 4 and 9. PMID- 29622406 TI - In the wake of the 2017 ASCO meetings, the surgical strategy for ovarian cancer remains on track. PMID- 29622407 TI - [Satisfaction survey on the use of autologous oocyte vitrification in Assisted Reproductive Technologies]. AB - OBJECTIVES: We organized a survey for in-vitro fertilization couples who beneficiated on self-preservation of part of the oocyte cohort. The main objective was to measure couples' satisfaction. Secondary objectives were; to identify how patients had been informed; to verify that the use of the ART technique met their expectations, and how they felt about oocyte or embryo freezing. METHODS: The data were collected by a questionnaire sent electronically to couples who had undergone partial vitrification of the oocyte cohort and at least one warming cycle. The questionnaire consisted of 2 components; one for the women and another one for their husband. RESULTS: Eighty-eight women and 62 men responded to the survey respectively, representing 50.86% and 35.84% of the targeted patients. They were satisfied with a 90% rate, men and women combined. The information we give in the center is heard by couples and is part of the trust in the medical staff. Men are more worried than women about the risks of stimulation or ovarian pick-up and are not displeased to be called upon for sperm recovery for every attempt at oocyte warming. The ambiguity of the answers on the representation of the embryo confirms what is already described, but is independent of the acceptance of freezing whether it is oocyte or embryo. CONCLUSION: In the same way as evaluating the results, the evaluation of patient satisfaction is useful for the implementation of therapeutic strategies and care pathways. PMID- 29622408 TI - The Use of a Magnetic Port Finder in the Retrieval of Air Rifle BBs to the Upper Extremity. AB - Air-powered rifles shoot ball bearings with enough kinetic energy to penetrate skin and fracture underlying bones. In addition, there are reports of these ball bearings embolizing within the vascular network, causing serious injuries such as ischemic stroke with resultant blindness. The severity of these complications warrants occasional removal of these foreign bodies; however, they can be difficult to localize. In this case report, we describe the use of a magnetic port finder, a sterilizable tool used in breast reconstruction, to localize the foreign body in situ. We believe that this tool is effective at locating ferrous foreign bodies precisely, allowing for surgical retrieval while minimizing damage to surrounding tissue. PMID- 29622409 TI - Optimal Measurement Level and Ulnar Nerve Cross-Sectional Area Cutoff Threshold for Identifying Ulnar Neuropathy at the Elbow by MRI and Ultrasonography. AB - PURPOSE: Imaging criteria for diagnosing compressive ulnar neuropathy at the elbow (UNE) have recently been established as the maximum ulnar nerve cross sectional area (UNCSA) upon magnetic resonance imaging (MRI) and/or ultrasonography (US). However, the levels of maximum UNCSA and diagnostic cutoff values have not yet been established. We therefore analyzed UNCSA by MRI and US in patients with UNE and in controls. METHODS: We measured UNCSA at 7 levels in 30 patients with UNE and 28 controls by MRI and at 15 levels in 12 patients with UNE and 24 controls by US. We compared UNCSA as determined by MRI or US and determined optimal diagnostic cutoff values based on receiver operating characteristic curve analysis. RESULTS: The UNCSA was significantly larger in the UNE group than in controls at 3, 2, 1, and 0 cm proximal and 1, 2, and 3 cm distal to the medial epicondyle for both modalities. The UNCSA was maximal at 1 cm proximal to the medial epicondyle for MRI (16.1 +/- 3.5 mm2) as well as for US (17 +/- 7 mm2). A cutoff value of 11.0 mm2 for MRI and US was found to be optimal for differentiating between patients with UNE and controls, with an area under the receiver operating characteristic curve of 0.95 for MRI and 0.96 for US. The UNCSA measured by MRI was not significantly different from that by US. Intra rater and interrater reliabilities for UNCSA were all greater than 0.77. The UNCSA in the severe nerve dysfunction group of 18 patients was significantly larger than that in the mild nerve dysfunction group of 12 patients. CONCLUSIONS: By measuring UNCSA with MRI or US at 1 cm proximal to the ME, patients with and without UNE could be discriminated at a cutoff threshold of 11.0 mm2 with high sensitivity, specificity, and reliability. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic III. PMID- 29622410 TI - Soft Tissue Atrophy Related to Corticosteroid Injection: Review of the Literature and Implications for Hand Surgeons. AB - Corticosteroid injections (CIs) are frequently used by hand surgeons to treat a wide range of pathology including de Quervain tenosynovitis and lateral epicondylitis. Although generally viewed as a benign modality, and a way to potentially avoid or postpone surgical intervention, common complications from CI should be considered and discussed with patients before the procedure. One such complication is local soft tissue atrophy and hypopigmentation after injection. We discuss the incidence of soft tissue-related adverse effects from CI, the pathophysiology and influence of different steroid preparations on soft tissues, and potential treatment options once atrophy has occurred. PMID- 29622411 TI - Hydrophobic structure of hairpin ten-ring pyrrole-imidazole polyamides enhances tumor tissue accumulation/retention in vivo. AB - To examine the hydrophobic structure of PI polyamides on tumor accumulation in vivo, PI polyamide-fluorescein conjugates 1-5 with the distinct number of N methylimidazole (Im) units were synthesized. There existed an inverse relationship between the Im unit number of the compounds and their hydrophobicity. Compound 1 with one Im unit and 3 with three Im units accumulated and retained preferentially in tumor tissues compared to 5 with five Im units. These results suggest the importance of a PI polyamide's primary structure, which partly contributes to its hydrophobic property, on its accumulation and/or retention in tumor tissues in vivo. PMID- 29622412 TI - Synthesis and evaluation of aminobenzothiazoles as blockers of N- and T-type calcium channels. AB - Both N- and T-type calcium ion channels have been implicated in pain transmission and the N-type channel is a well-validated target for the treatment of neuropathic pain. An SAR investigation of a series of substituted aminobenzothiazoles identified a subset of five compounds with comparable activity to the positive control Z160 in a FLIPR-based intracellular calcium response assay measuring potency at both CaV2.2 and CaV3.2 channels. These compounds may form the basis for the development of drug leads and tool compounds for assessing in vivo effects of variable modulation of CaV2.2 and CaV3.2 channels. PMID- 29622413 TI - Use of genitofemoral and ilioinguinal and iliohypogastric nerve block during orchiectomy in a post-lung transplant patient. A case report. AB - The case is presented of a post-lung transplant patient, ASA III, proposed for orchiectomy due to testicular cancer. A combination of iliohypogastric (ILH), ilioinguinal (ILI) and genitofemoral (GF) nerve block together with sedation was used as anaesthetic technique. The inguinal area received sensory innervation mainly from ILI, ILH and GF nerves. The genital branch of the GF nerve supplies innervation to skin of the anterosuperior portion of the scrotum. When performing the echo-guided block of GF nerve, it is necessary to identify the spermatic cord, and administer the local anaesthetic on the inside and periphery of the cord. Peripheral nerve blocks are a valid option for complex patients. Its main advantage is the anaesthesia and analgesia level that it provides without the haemodynamic instability associated with general or neuraxial anaesthesia. GF nerve block provides hemi-scrotal anaesthesia, allowing manipulation and intervention in the inguinal-scrotal area, complementing the anaesthesia provided by ILI and ILH nerve blocks. PMID- 29622414 TI - [Impact of screening and treatment of low systemic blood flow in the prevention of severe intraventricular haemorrhage and/or death in pre-term infants]. AB - OBJECTIVE: To assess the effect of a protocolised intervention for low systemic blood flow (SBF) in the occurrence of severe intraventricular haemorrhage (IVH) or death in pre-term infants. METHODS: A study with a quasi-experimental design with retrospective controls was conducted on pre-term infants of less than 30weeks of gestational age, born between January 2016 and July 2017, who were consecutively included in the intervention period. The control cohort included pre-term infants (born between January 2013 and December 2015) matched by gestational age, birth weight, and gender (two controls for each case). The cases of low SBF diagnosed according to functional echocardiography during the study period received dobutamine (5-10MUg/kg/min) for 48hours. RESULTS: The study included 29 cases (intervention period) and 54 controls (pre-intervention period). Ten out of 29 (34.5%) infants received dobutamine for low SBF during the intervention period, with 3/29 (10.3%) cases of severe IVH and/or death compared to 17/54 (31.5%) in the control cohort (p=.032). There was an independent association between the intervention and a decreased occurrence of severe IVH/death after adjusting for confounding factors both in the logistic regression model [OR 0.11 (95%CI: 0.01-0.65), p=.015], as well as in the sensitivity analysis using inverse probability of treatment weighting [OR 0.23 (95%CI: 0.09 0.56); p=.001]. CONCLUSIONS: In this study with retrospective controls, a protocolised screening, and treatment for low SBF was associated with a decreased occurrence of severe IVH or death in preterm infants. Large, adequately powered trials, are needed in order to determine whether postnatal interventions directed at low SBF can improve neurological outcomes. PMID- 29622415 TI - [Conflicts of interests of the editors]. PMID- 29622416 TI - Routine screening for sleep apnea in patients with atrial fibrillation: Ready for primetime? PMID- 29622417 TI - Can we "ScREEN" response to cardiac resynchronization therapy by a simple score? PMID- 29622418 TI - Permanent his bundle pacing: A physiological alternative to conventional right ventricular pacing or just a futile artifice? PMID- 29622419 TI - Should we isolate superior vena cava and to ablate cavo-tricuspid isthmus in all patients with atrial fibrillation during pulmonary vein isolation? PMID- 29622420 TI - Reply to "Should we isolate superior vena cava and to ablate cavo-tricuspid isthmus in all patients with atrial fibrillation during pulmtonary vein isolation?" PMID- 29622421 TI - Low prevalence of inter-atrial block in the general population from China: A possible reason for its low rates of atrial fibrillation. PMID- 29622422 TI - Authors' reply: Low prevalence of inter-atrial block in the general population from China: A possible reason for its low rates of atrial fibrillation. PMID- 29622423 TI - Optimization of heart rate lowering therapy in hospitalized patients with heart failure: Insights from the Optimize Heart Failure Care Program. AB - BACKGROUND: Hospitalization is an opportunity to optimize heart failure (HF) therapy. As optimal treatment for hospitalized HF patients in sinus rhythm with heart rate>=70bpm is unclear, we investigated the impact of combined beta-blocker (BB) and ivabradine versus BBs alone on short and longer term mortality and rehospitalization. METHODS AND RESULTS: A retrospective analysis was performed on 370 hospitalized HF patients with heart rate>=70bpm (150 BB+ivabradine, 220 BB alone) in the Optimize Heart Failure Care Program in Armenia, Azerbaijan, Belarus, Georgia, Kazakhstan, Russia, Ukraine, and Uzbekistan, from October 2015 to April 2016. RESULTS: At 1month, 3months, 6months and 12months, there were fewer deaths, HF hospitalizations and overall hospitalizations in patients on BB+ivabradine vs BBs alone. At 12months, all-cause mortality or HF hospitalization was significantly lower with BB+ivabradine than BBs (adjusted hazard ratio [HR] 0.45 (95% confidence interval [CI] 0.32-0.64, P<0.0001). Significantly greater improvement was seen in quality of life (QOL) from admission to 12months with BB+ivabradine vs BBs alone (P=0.0001). With BB+ivabradine, significantly more patients achieved >=50% target doses of BBs at 12months than on admission (82.0% vs 66.6%, P=0.0001), but the effect was non significant with BBs alone. CONCLUSIONS: Heart rate lowering therapy with BB+ivabradine started in hospitalized HF patients (heart rate>=70bpm) is associated with reduced overall mortality and re-hospitalization over the subsequent 12months. A prospective randomized trial is needed to confirm the advantages of this strategy. PMID- 29622424 TI - Two-dimensional global longitudinal strain is superior to left ventricular ejection fraction in prediction of outcome in patients with left-sided infective endocarditis. AB - BACKGROUND: Impaired cardiac function is the main predictor of poor outcome in infective endocarditis (IE). Global longitudinal strain (GLS) derived from two dimensional strain echocardiography has proven superior in prediction of long term outcome as compared to left ventricular ejection fraction (LVEF) in valvular disease and heart failure in general. Whether measurements of cardiac deformation can predict survival in patients with IE has not previously been investigated. METHODS: The study included consecutive patients with Duke definite IE who underwent transthoracic and transesophageal echocardiography within 7 days. Clinical and echocardiographic markers associated with 1-year survival were identified using a Cox-proportional hazards model that included propensity adjustment for surgery. Reclassification statistics including receiver operating characteristic curves and net reclassification improvement were applied to LVEF and GLS, respectively. RESULTS: A cohort of 190 patients met eligibility criteria. LVEF and GLS were both prognostic markers of mortality. Independent markers of 1-year mortality were S. aureus IE (HR:2.02; 95%CI 1.11-5.72, p = .022), diabetes (HR:2.05; 95%CI 1.12-3.75, p = .020), embolic stroke (HR:3.95; 95%CI 1.93-8.10, p < .001) and LVEF<45% (HR: 3.02; 95% CI 1.70-5.38, p < .001), GLS> -15.4% (HR:2.95; 95%CI 1.52-5.72, p < .001). Adding LVEF<45% to a model with known risk factors of IE did not significantly improve risk classification, whereas addition of GLS to the model resulted in significant increase (AUC = 0.763, p < .001). CONCLUSIONS: When treatment was taken into account, LVEF<45% and GLS > -15.4% were both associated with adverse long-term outcome in left sided IE. GLS >-15.4 % was significantly associated with 1-year mortality in the multivariate analysis. Further, GLS was superior to LVEF in risk prediction and risk discrimination of long-term outcome in patients with left-sided IE. PMID- 29622426 TI - Heart rate as a target: Ready for pole position? PMID- 29622425 TI - Myocardial regeneration therapy in heart failure: Current status and future therapeutic implications in clinical practice. AB - Despite multiple treatment regimens the morbidity and mortality of patients with advanced heart failure (HF) have reached pandemic proportions. In an effort to address the root cause of the problem, curative strategies are increasingly being considered. A case in point is the evolution of regenerative medicine technologies aiming to halt or even reverse progressive organ deterioration in the HF setting. The prevailing unmet clinical needs in HF therapy have provided a major incentive for the development of cell-based treatment strategies, which have shown encouraging results in experimental studies. In turn, this has led to a significant international effort in cell-based clinical trials. In order to translate the promise of biotherapies into clinical benefit many more questions need to be addressed. In this review we analyze current clinical experience regarding cell therapy in the setting of ischemic/nonischemic HF and address key issues that could be a guide for future successful cell-based therapeutic application in HF patients in clinical practice. PMID- 29622427 TI - Prognostic value of global longitudinal strain versus ejection fraction: Time to pass on the torch? PMID- 29622428 TI - Stem cell therapy in heart failure: Is the best yet to come? PMID- 29622429 TI - Right ventricular pacing in Chagas heart disease. PMID- 29622430 TI - Cardiovascular morbidity and mortality in patients with aortic valve sclerosis: A systematic review and meta-analysis. AB - AIMS: The association between aortic valve sclerosis (AVSc) and cardiovascular (CV) events is not consistent among different studies. We have performed a meta analysis evaluating the association between AVSc and fatal and/or non-fatal CV and cerebrovascular events. METHODS AND RESULTS: A systematic search was performed in the electronic databases (PubMed, Web of Science, Scopus, EMBASE). Studies evaluating coronary artery disease (CAD), stroke and CV mortality in AVSc patients and controls were included. Differences among cases and controls were expressed as Odds Ratio (OR) with pertinent 95% Confidence Intervals (CI). Thirty one studies on 10,537 AVSc patients and 25,005 controls were included in the final analysis. The absolute risk of CAD was 45.8% (95% CI: 32.9-59.3) in AVSc patients and 29.4% (95% CI: 21.8-38.5) in controls with an OR of 2.02 (95% CI: 1.67-2.44) and an attributable risk of 35.8%. Moreover, stroke was reported in 11.8% (95% CI: 4.4-27.7) of AVSc patients and 7.9% (95% CI: 2.5-22.7) of controls (OR: 1.41, 95% CI: 1.16-1.71) with an attributable risk of 33.0%. CV mortality was 6.2% (95% CI: 2.7-13.5) in AVSc patients and 2.0% (95% CI: 0.5-7.9) in controls (OR: 2.70, 95% CI: 1.45-5.01), with an attributable risk of 67.7%. Results were confirmed when pooling together ORs for CAD, stroke and CV mortality obtained by means of multivariate analysis. CONCLUSIONS: AVSc is associated with CAD, stroke and CV mortality. Taken together, these data suggest that patients with AVSc may benefit from a stricter CV risk monitoring and that AVSc screening may be included in the frame of CV risk stratification protocols. PMID- 29622431 TI - Ultrasound cardiac calcification as a marker of subclinical atherosclerosis and future cardiovascular events in clinical practice: Is there enough evidence? PMID- 29622432 TI - Sirtuin 5 as a novel target to blunt blood-brain barrier damage induced by cerebral ischemia/reperfusion injury. AB - BACKGROUND: In acute ischemic stroke (AIS) patients, impaired blood-brain barrier (BBB) integrity is associated with hemorrhagic transformation and worsened outcome. Yet, the mechanisms underlying these relationships are poorly understood and consequently therapeutic strategies are lacking. This study sought to determine whether SIRT5 contributes to BBB damage following I/R brain injury. METHODS AND RESULTS: SIRT5 knockout (SIRT5-/-) and wild type (WT) mice underwent transient middle cerebral artery (MCA) occlusion (tMCAO) followed by 48h of reperfusion. Genetic deletion of SIRT5 decreased infarct size, improved neurological function and blunted systemic inflammation following stroke. Similar effects were also achieved by in vivo SIRT5 silencing. Immunohistochemical analysis revealed decreased BBB leakage and degradation of the tight junction protein occludin in SIRT5-/- mice exposed to tMCAO as compared to WT. In primary human brain microvascular endothelial cells (HBMVECs) exposed to hypoxia/reoxygenation (H/R), SIRT5 silencing decreased endothelial permeability and upregulated occludin and claudin-5; this effect was prevented by the PI3K inhibitor wortmannin. Lastly, SIRT5 gene expression was increased in peripheral blood monocytes (PBMCs) of AIS patients at 6h after onset of stroke compared to sex- and age-matched healthy controls. CONCLUSION: SIRT5 is upregulated in PBMCs of AIS patients and in the MCA of WT mice exposed to tMCAO; SIRT5 mediates I/R induced brain damage by increasing BBB permeability through degradation of occludin. This effect was reproduced in HBMVECs exposed to H/R, mediated by the PI3K/Akt pathway. Our findings shed new light on the mechanisms of I/R-dependent brain damage and suggest SIRT5 as a novel therapeutic target. PMID- 29622433 TI - Cocaine and acute coronary syndromes: Novel management insights for this clinical conundrum. PMID- 29622434 TI - The effects of tastes on cardiac function. PMID- 29622435 TI - Reactive hyperemia-peripheral arterial tonometry is useful for assessment of not only endothelial function but also stenosis of the digital artery. AB - BACKGROUND: Although reactive hyperemia-peripheral arterial tonometry (RH-PAT) is widely used for assessment of endothelial function, RH index (RHI) cannot be measured in some cases when pulse wave amplitude (PWA) is very low. Decrease in PWA is mainly caused by proper palmar digital artery (PPDA) stenosis. The purpose of this study was to evaluate the relationship between PWA measured by RH-PAT and stenosis of the PPDA measured by digital subtraction angiography and to evaluate the limitation of assessment of endothelial function measured by RHI in patients with PPDA stenosis. METHODS: We measured baseline PWA in 51 fingers including the first to third fingers of both hands in 10 patients who had PPDA stenosis and in 66 fingers that were the first fingers of both hands in 33 subjects who had no PPDA stenosis. Severe stenosis was defined as over 75% by lower percent diameter stenosis between two PPDAs in a finger. RESULTS: PWA was significantly correlated with stenosis of the digital artery (r=-0.55; P<0.0001). A PWV value of 300mV was the optimal cut-off value for severe stenosis (sensitivity, 84.0%; specificity, 88.5%). Log RHI was significantly lower in patients with PPDA stenosis than in subjects without PPDA stenosis (0.33+/-0.27 versus 0.73+/-0.27, P=0.007). CONCLUSIONS: RH-PAT may be useful for assessment of not only endothelial function but also PPDA stenosis. RHI may be underestimated in patients with PPDA stenosis. We should pay attention to low baseline PWA when measuring RHI. CLINICAL TRIAL REGISTRATION INFORMATION: URL for clinical trial: http://UMIN; registration number for clinical trial: UMIN000003409. PMID- 29622436 TI - The role of CD27-CD70-mediated T cell co-stimulation in vasculogenesis, arteriogenesis and angiogenesis. AB - BACKGROUND: T cells have a distinctive role in neovascularization, which consists of arteriogenesis and angiogenesis under pathological conditions and vasculogenesis under physiological conditions. However, the role of co stimulation in T cell activation in neovascularization has yet to be established. The aim of this study was to investigate the role T cell co-stimulation and inhibition in angiogenesis, arteriogenesis and vasculogenesis. METHODS AND RESULTS: Hind limb ischemia was induced by double ligation of the left femoral artery in mice and blood flow recovery was measured with Laser Doppler Perfusion Imaging in control, CD70-/-, CD80/86-/-, CD70/80/86-/- and CTLA4+/- mice. Blood flow recovery was significantly impaired in mice lacking CD70 compared to control mice, but was similar in CD80/86-/-, CTLA4+/- and control mice. Mice lacking CD70 showed impaired vasculogenesis, since the number of pre-existing collaterals was reduced as observed in the pia mater compared to control mice. In vitro an impaired capability of vascular smooth muscle cells (VSMC) to activate T cells was observed in VSMC lacking CD70. Furthermore, CD70-/-, CD80/86-/- and CD70/80/86-/- mice showed reduced angiogenesis in the soleus muscle 10 days after ligation. Arteriogenesis was also decreased in CD70-/- compared to control mice 10 and 28 days after surgery. CONCLUSIONS: The present study is the first to describe an important role for T cell activation via co-stimulation in angiogenesis, arteriogenesis and vasculogenesis, where the CD27-CD70 T cell co stimulation pathway appears to be the most important co-stimulation pathway in pre-existing collateral formation and post-ischemic blood flow recovery, by arteriogenesis and angiogenesis. PMID- 29622437 TI - Clinical outcome according to spasm type of single coronary artery provoked by intracoronary ergonovine tests in patients without significant organic stenosis: Methodological and statistical issues. PMID- 29622438 TI - Function over form: Is it time to use endothelial function to diagnose vascular diseases? PMID- 29622439 TI - Janus revisited: The intricate role of the immune system in neovascularization. PMID- 29622440 TI - Effects of tastes and taste receptors. PMID- 29622441 TI - Prevalence of dyslipidemia and achievement of low-density lipoprotein cholesterol targets in Chinese adults: A nationally representative survey of 163,641 adults. AB - BACKGROUND: Elevated serum total cholesterol and low-density lipoprotein cholesterol (LDL-C) levels are established risk factors for cardiovascular diseases, a leading cause of death in China. We sought to assess the latest levels of serum lipids, prevalence of dyslipidemia and achievement of LDL-C lowering targets among Chinese adults. METHODS: Data was obtained from a national representative survey recruited 163,641 adults aged >18years in mainland China between 2013 and 2014. Fasting serum total cholesterol (TC), LDL-C, high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) were measured by standard methods. Multiple logistic regression was preformed to estimate potential risk factors for dyslipidemias. Proportion of residents not achieve the therapeutic goals for LDL-C by atherosclerotic cardiovascular diseases (ASCVD) risk stratification were evaluated. RESULTS: Nationally, the population-weighted means of TC, HDL-C, and LDL-C, and median of TG were 4.70, 1.35, 2.88, and 1.49mmol/L, respectively. The prevalence of high TC, high LDL-C, low HDL-C and high TG was 6.9%, 8.1%, 20.4% and 13.8%. Among individuals with high ASCVD risk, 74.5% had uncontrolled LDL-C levels (<2.6mmol/L) and 5.5% of them were treated. For very high-risk individuals, 93.2% didn't achieve their LDL-lowering goals (<1.8mmol/L) and 14.5% of them were treated. CONCLUSIONS: Chinese adults currently experienced a high prevalence of abnormal serum lipid levels, more common in urban adults or those with obesity or central obesity. A significant proportion of people with high or very high ASCVD risk didn't meet LDL-C targets. Improvements in achievement of lipid-level targets and of LDL-lowering therapy rates based on ASCVD risk stratification were necessary. PMID- 29622442 TI - Right ventricular pacing in Chagas heart disease. PMID- 29622443 TI - Pericardial and visceral, but not total body fat, are related to global coronary and extra-coronary atherosclerotic plaque burden. AB - BACKGROUND: To explore the relationship between coronary and extra-coronary atherosclerotic plaque burden with total and regional fat depots among patients undergoing ECG-gated aortic computed tomography angiography (CTA). METHODS: The subjects of this study comprised a cohort of consecutive patients who underwent ECG-gated thoracoabdominal CTA. We assessed the number of coronary segments with plaques (segment-involvement score, SIS); and the extra-coronary atherosclerotic plaque burden, comprising the aorta and supra-aortic trunks, iliofemoral arteries, and visceral arteries (extra-coronary SS). Total and regional fat volume (FV) were calculated. RESULTS: A total of 2700 vascular segments were evaluated in 90 patients. Obese patients (n = 31, 34%) showed similar coronary SIS (p = 0.41) and extra-coronary SS (p = 0.22) than non-obese patients. General body fat measurements were not related to atherosclerotic plaque burden scores, without associations between coronary or extra-coronary plaque burden and BMI (p = 0.68, and p = 0.91), abdominal circumference (p = 0.13, p = 0.89), total body FV (p = 0.50, p = 0.98), or abdominal FV (p = 0.51, p = 0.99). Pericardial FV was related to coronary SIS (p < 0.0001) and extra-coronary SS (p = 0.008), and visceral FV was related to the coronary SIS (p = 0.006) and extra-coronary SS (p = 0.056). Abdominal subcutaneous fat was inversely related to coronary SIS (p = 0.038) and extra-coronary SS (p = 0.010). Pericardial FV was identified as the only independent predictor of extensive coronary [OR 1.020 (95% CI 1.001-1.039), p = 0.036] and extra-coronary [OR 1.018 (95% CI 1.001-1.036), p = 0.035] plaque burden. CONCLUSIONS: In the present study, pericardial and visceral fat were associated with an increased atherosclerotic burden, whereas we identified an inverse relationship between subcutaneous abdominal fat and plaque burden. PMID- 29622444 TI - Reply letter to Dr. Xu et al. on role of circulating endothelial progenitor cells in the reparative mechanisms of stable ischemic myocardium. PMID- 29622445 TI - Pericardial fat as a new independent biomarker of vascular aging. PMID- 29622446 TI - Reply to: Is serum uric acid a pretty accurate prognostic predictor of ST elevated acute coronary syndrome? Author: Alexander E. Berezin. PMID- 29622447 TI - Carotid artery stenosis at the time of coronary artery bypass grafting is a risk factor but not a cause for peri-operative stroke. PMID- 29622448 TI - Long-term prognostic value of invasive and non-invasive measures early after heart transplantation. AB - BACKGROUND: Invasively assessed coronary microvascular resistance early after heart transplantation predicts worse long-term outcome; however, little is known about the relationship between microvascular resistance, left ventricular function and outcomes in this setting. METHODS: A total of 100 cardiac transplant recipients had fractional flow reserve (FFR) and the index of microcirculatory resistance (IMR) measured in the left anterior descending artery and echocardiographic assessment of left ventricular ejection fraction (LVEF) and global longitudinal strain (GLS) at 1 year after heart transplantation. The primary endpoint was the composite of death and retransplantation occurring beyond the first post-operative year. RESULTS: The mean FFR, IMR, LVEF, and GLS values at 1 year were 0.87 +/- 0.06, 21.3 +/- 17.3, 60.4 +/- 5.4%, and 14.2 +/- 2.4%, respectively. FFR and IMR had no significant correlation with LVEF and GLS. During a mean follow-up of 6.7 +/- 4.2 years, the primary endpoint occurred in 24 patients (24.0%). By ROC curve analysis, IMR = 19.3 and GLS = 13.3% were the best cutoff values for predicting death or retransplantation. Cumulative event-free survival was significantly lower in patients with higher IMR (log-rank p = 0.02) and lower GLS (log-rank p < 0.001). Cumulative event-free survival can be further stratified by the combination of IMR and GLS (long-rank p < 0.001). By multivariable Cox proportional hazards model, higher IMR and lower GLS were independently associated with long-term death or retransplantation (elevated IMR, hazard ratio = 2.50, p = 0.04 and reduced GLS, hazard ratio = 3.79, p = 0.003, respectively). CONCLUSION: Invasively assessed IMR does not correlate with GLS at 1 year after heart transplantation. IMR and GLS determined at 1 year may be used as independent predictors of late death or retransplantation. PMID- 29622450 TI - Invasive and non-invasive prognostic markers - What to trust and how to optimize surveillance after heart transplantation. PMID- 29622449 TI - One-year clinical outcome of biodegradable polymer sirolimus-eluting stent in all comers population. Insight from the ULISSE registry (ULtimaster Italian multicenter all comerS Stent rEgistry). AB - BACKGROUND: This study was designed to confirm in a large population of unselected patients the promising results of Ultimaster(r) biodegradable polymer sirolimus-eluting stent (BP-SES) already shown in previous trial. METHODS: ULISSE is an observational, multicenter, national registry evaluating all patients undergoing PCI with the Ultimaster(r) BP-SES. Incidence of 1-year TLF (cardiac death or target vessel MI or clinically indicated TLR) was the primary endpoint. Pre-specified subgroup analysis was performed for diabetic patients and for those with lesion longer than 25 mm, bifurcation and CTO lesions. RESULTS: 1660 patients were enrolled in 9 Italian cardiology centers, 82% were males, mean age of 68 +/- 10 years, and 29% were diabetics. Overall 2422 lesions were treated, 65% type B2/C lesions, 7% CTOs, 17% bifurcations and 38% long lesions. The incidence of 1-year TLF was 5%, with 3.2% of clinically indicated TLR. TLF occurred in 8% of the patients with diabetes mellitus, and 7% in bifurcation, 6.7% in CTO and 6.2% in long lesions. Definite overall ST was 0.9%, and 1.2% in patients treated for type B2/C lesions. Multivariate logistic regression analysis identified stenting on unprotected LMT (OR = 4.80), stenting on ISR lesion (OR = 3.19) and need for rotational atherectomy (OR = 6.24) as the strongest independent predictors of TLF. CONCLUSIONS: The results of this national all comers registry show that the Ultimaster(r) BP-SES real-world performance was comparable with that observed in the clinical trial, with low rate of primary endpoint and TLR. Long term follow-up will be necessary to prove the theoretical advantage of the BP-SES over time. PMID- 29622451 TI - Performance of drug-eluting stents in real-world clinical practice. PMID- 29622452 TI - Perioperative levosimendan therapy is not associated with lower mortality in patients undergoing cardiac surgery. PMID- 29622453 TI - Looking beyond luminal stenosis in carotid artery disease. PMID- 29622454 TI - Perioperative levosimendan in cardiac surgery: Positive, neutral, or detrimental effects? PMID- 29622455 TI - "How long will I continue to be normal?" Adults with a Fontan circulation's greatest concerns. AB - BACKGROUND: Little is known about adults living with a Fontan circulation's concerns outside the scope of their clinical outcomes. We examined adults with a Fontan circulations' greatest concerns, as well as their concerns around anti coagulation, pregnancy and finances. METHODS: Adults with a Fontan circulation in the Australian and New Zealand Fontan Registry were invited to complete an anonymous online survey, of which 57 participated. A qualitative method approach using thematic analyses was used. RESULTS: The greatest concerns for adults living with a Fontan circulation were fear of death/uncertainty around life expectancy which for many individuals colored their concerns around physical health, pregnancy and having children, quality of life and finances. Improving information about outcomes to patients with a Fontan circulation might alleviate uncertainties about their future. CONCLUSIONS: Fear of death is the primary concern of adults with a Fontan circulation. It may require improved communication and targeted psychological interventions. Physical exercise incorporated as part of their lifestyle should be encouraged to alleviate physical concerns and also improve psychological well-being. PMID- 29622456 TI - beta-Blocker treatment and prognosis in acute coronary syndrome associated with cocaine consumption: The RUTI-Cocaine Study. AB - BACKGROUND: The use of beta-blocker therapy in the setting of acute coronary syndrome (ACS) associated with cocaine consumption (ACS-ACC) is discouraged due to the risk of coronary vasoconstriction. We examined the prognostic value of beta-blocker therapy in a contemporary ACS cohort. METHODS AND RESULTS: Prospective, single-center study conducted between January 2001 and December 2014 that examined cocaine use among young (<=50-year-old) consecutive patients admitted with an ACS. During the study period, 1002 patients were admitted; of these, 57 (5.7%) had a positive cocaine urine test We collected data on clinical characteristics and major adverse cardiovascular events (MACE) during follow-up. Among ACS-ACC patients, 33 (57.9%) received beta-blocker therapy during hospital admission and after discharge. During a median follow-up of 4.0 (IQR: 2.4-6.5) years after the index event, 2 (6.1%) patients treated with beta-blocker therapy died and 6 (18.2%) experienced hospital re-admission for myocardial infarction (MI); in contrast, there were 5 (20.8%) deaths and 5 (20.8%) readmissions due to MI in patients without beta-blocker therapy. Lower rates of MACE were observed in patients treated with beta-blocker therapy (30.3%) than those without beta blocker therapy (41.7%). The 90-day survival was higher in patients treated with beta-blocker therapy (87.5% vs. 100%; Log rank test p = 0.035). CONCLUSIONS: In patients with ACS-ACC, beta-blocker treatment was associated with a significantly better clinical outcome, with lower rates of death and MI. Our findings support the evidence for long-term beta-blocker administration in high-risk patients and highlight the need for large prospective multicenter studies of beta-blocker treatment in ACS-ACC. PMID- 29622457 TI - Bridging the psychological issues of living with the Fontan circulation. PMID- 29622458 TI - Usefulness of a clinical risk score to predict the response to cardiac resynchronization therapy. AB - BACKGROUND: Almost 1/3 of heart failure patients fail to respond to cardiac resynchronization therapy (CRT). A simple clinical score to predict who these patients are at the moment of referral or at time of implant may be of importance for early optimization of their management. METHODS: Observational study. A risk score was derived from factors associated to CRT response. The derivation cohort was composed of 1301 patients implanted with a CRT defibrillator in a multi center French cohort-study. External validation of this score and assessment of its association with CRT response and all-cause mortality and/or heart transplant was performed in 1959 CRT patients implanted in 4 high-volume European centers. RESULTS: Independent predictors of CRT response in the derivation cohort were: female gender (OR = 2.08, 95% CI 1.26-3.45), NYHA class <= III (OR = 2.71, 95% CI 1.63-4.52), left ventricular ejection fraction >= 25% (OR = 1.75, 95% CI 1.27 2.41), QRS duration >= 150 ms (OR = 1.70, 95% CI 1.25-2.30) and estimated glomerular filtration rate >= 60 mL/min (OR = 2.01, 95% CI 1.48-2.72). Each was assigned 1 point. External validation showed good calibration (Hosmer-Lemeshow test-P = 0.95), accuracy (Brier score = 0.19) and discrimination (c-statistic = 0.67), with CRT response increasing progressively from 37.5% in patients with a score of 0 to 91.9% among those with score of 5 (Gamma for trend = 0.44, P < 0.001). Similar results were observed regarding all-cause mortality or heart transplant. CONCLUSION: The ScREEN score (Sex category, Renal function, ECG/QRS width, Ejection fraction and NYHA class) is composed of widely validated, easy to obtain predictors of CRT response, and predicts CRT response and overall mortality. It should be helpful in facilitating early consideration of alternative therapies for predicted non-responders to CRT therapy. PMID- 29622459 TI - Upgrade to his bundle pacing in pacing-dependent patients referred for pulse generator change: Feasibility and intermediate term follow up. AB - BACKGROUND: Right ventricular pacing (RVP) is associated with an increased incidence of heart failure and may impair cardiac function. Permanent His bundle pacing (HBP) has the potential to physiologically preserve and prevent cardiac dysfunction. This study was to evaluate the feasibility and intermediate follow up results of upgrade to HBP implantation in patients referred for pulse generator change with long term RVP. METHODS: Twelve of 14 pacing dependent patients who were referred for pulse generator exchange underwent upgrade into HBP successfully in our center. QRS duration, New York Heart Association (NYHA) functional class, echocardiography, use of diuretics and lead parameters were measured at baseline and during the follow-up. RESULTS: Among the 12 patients attempted (mean age, 70.8 +/- 8.9 years, 75% males) successfully, the average ejection fraction (EF) was 52.2 +/- 11.2%. Nine of 12 patients underwent upgrade to HBP, and three patients with EF < 40% underwent HBP and biventricular pacing (BVP) as well. A significant reduction in mean QRS duration was observed compared with pre-implantation, from 157.8 +/- 13.3 ms to 109.3 +/- 16.9 ms (p < 0.001). After 6 months follow-up period, median NYHA functional class was improved from 2.7 +/- 0.6 to 1.8 +/- 0.6 (p = 0.007) and left ventricular internal diastolic diameter (LVIDd) was reduced from 5.5 +/- 0.4 cm to 5.3 +/- 0.3 cm (p = 0.03). CONCLUSIONS: HBP improves heart failure symptoms with preserved EF by long term RVP. Permanent HBP is feasible and safe for upgrade in patients with long term RVP irrespective of LVEF. PMID- 29622460 TI - Prevalence and clinical characteristics of obstructive- and central-dominant sleep apnea in candidates of catheter ablation for atrial fibrillation in Japan. AB - INTRODUCTION: We aimed to study the prevalence and types of sleep apnea (SA) as well as their clinical characteristics in atrial fibrillation (AF) ablation candidates in Japan. METHODS: Before catheter ablation, 197 consecutive AF patients (age: 60 +/- 9 years, body mass index; 25.0 +/- 3.0) were evaluated with portable polygraphy. We compared the clinical characteristics, according to the severity of SA as well as its types, as defined by the presence of obstruction and the mixed vs. central apnea indices. RESULTS: The mean apnea-hypopnea index (AHI) was 17.7 +/- 11.9, with 135 AF patients having an AHI >=10 (68.5%). Patients with an AHI >=10 had a significantly higher body mass index, plasma brain natriuretic peptide (BNP) level, prevalence of hypertension, and larger left atrial size. Among patients with an AHI >=10, the incidence of obstructive dominant SA was 60.9% and that of central-dominant SA was 7.6%. The prevalence of hypertension was significantly higher in obstructive-dominant SA patients (obstructive vs. central: 48.3% vs. 20.0%, P = 0.038). The obstructive apnea index correlated with plasma BNP level and age, but the central and mixed apnea indices did not. CONCLUSIONS: The prevalence of SA was common in AF ablation candidates, even without an obesity epidemic, and the SA type was predominantly obstructive. Portable polygraphy was useful for detecting undiagnosed SA patients in AF ablation candidates. PMID- 29622461 TI - Return to sport following arthroscopic Bankart repair: a systematic review. AB - HYPOTHESIS AND BACKGROUND: The purpose of this systematic review was to determine the return-to-sport rate following arthroscopic Bankart repair, and it was hypothesized that patients would experience a high rate of return to sport. METHODS: The MEDLINE, Embase, and PubMed databases were searched by 2 reviewers, and the titles, abstracts, and full texts were screened independently. The inclusion criteria were English-language studies investigating arthroscopic Bankart repair in patients of all ages participating in sports at all levels with reported return-to-sport outcomes. A meta-analysis of proportions was used to combine the rate of return to sport using a random-effects model. RESULTS: Overall, 34 studies met the inclusion criteria, with a mean follow-up time of 46 months (range, 3-138 months). The pooled rate of return to participation in any sport was 81% (95% confidence interval [CI], 74%-87%). In addition, the pooled rate of return to the preinjury level was 66% (95% CI, 57%-74%) (n = 1441). Moreover, the pooled rate of return to a competitive level of sport was 82% (95% CI, 79%-88%) (n = 273), while the pooled rate of return to the preinjury level of competitive sports was 88% (95% CI, 66%-99%). CONCLUSION: Arthroscopic Bankart repair yields a high rate of return to sport, in addition to significant alleviation of pain and improved functional outcomes in the majority of patients. However, approximately one-third of athletes do not return to their preinjury level of sports. PMID- 29622462 TI - Organ donor management: Common recommendations that deserve evidence. PMID- 29622467 TI - Introduction to symposium: a century after the 1918 influenza pandemic. PMID- 29622468 TI - Correlates of long-acting reversible contraception versus sterilization use in advanced maternal age. AB - PURPOSE: To identify correlates associated with choosing long-acting reversible contraception (LARC) over female sterilization (FS) from a subsample of women aged 35 to 44 years in a nationally representative survey. METHODS: We analyzed data from women aged 35 to 44 years from the 2011-2013 National Survey of Family Growth Female Respondent File (n = 1532). Data were analyzed using SAS 9.3 software. All analyses accounted for the complex survey sample design. Multinomial logistic regression was used to identify factors associated with choosing LARC versus FS. A domain analysis was performed focusing on women aged 35 to 44 years. RESULTS: Approximately 90% of the surveyed women had not received counseling or information about birth control in the past 12 months. Factors associated with using an LARC method versus FS were higher level of education, birth outside of the United States, and higher number of lifetime male sexual partners. Factors associated with using FS versus an LARC method were non Hispanic black race and women who had not had a checkup related to using a birth control method in the last 12 months. CONCLUSIONS: The results of our study suggest that a large proportion of women of advanced maternal age in the United States have not received contraceptive counseling in the past 12 months. Providers should focus on providing comprehensive contraceptive and sterilization counseling to women aged 35 to 44 years, especially those using unreliable, reversible contraception. PMID- 29622469 TI - [Microcystic adnexal carcinoma: A case report]. AB - We report a case of microcystic adnexal carcinoma in a 80-year-old woman. This is a rare malignant adnexal cutaneous tumor with glandular and follicular differentiation, rare, often asymptomatic, with late diagnosis and slow growth, locally aggressive and rarely metastatic. The distinction with other benign and malignant skin tumors is difficult. PMID- 29622470 TI - Clinician tasking in ambulance control improves the identification of major trauma patients and pre-hospital critical care team tasking. AB - INTRODUCTION: Trauma remains the fourth leading cause of death in western countries and is the leading cause of death in the first four decades of life. NICE guidance in 2016 advocated the attendance of pre-hospital critical care trauma team (PHCCT) in the pre-hospital stage of the care of patients with major trauma. Previous publications support dispatch by clinicians who are also actively involved in the delivery of the PHCCT service; however there is a lack of objective outcome measures across the current reviewed evidence base. In this study, we aimed to assess the accuracy of PHCCT clinician led dispatch, when measured by Injury Severity Score (ISS). METHODS: A retrospective cohort study over a 2 year period pre and post implementation of a PHCCT clinician led dispatch of PHCCT for potential major trauma patients, using national ambulance data combined with national trauma registry data. RESULTS: A total of 99,702 trauma related calls were made to SAS including 495 major trauma patients with an ISS >15, and a total of 454 dispatches of a PHCCT. Following the introduction of a PHCCT clinician staffed trauma desk, the sensitivity for major trauma was increased from 11.3% to 25.9%. The difference in sensitivity between the pre and post trauma desk group was significant at 14.6% (95% CI 7.4%-21.4%, p < .001). DISCUSSION: The results from the study support the results from other studies recommending that a PHCCT clinician should be located in ambulance control to identify major trauma patients as early as possible and co-ordinate the response. PMID- 29622471 TI - HbA1C, finding the right target in 2018. PMID- 29622473 TI - Impact of bone marrow-derived signals on NK cell development and functional maturation. AB - Natural killer (NK) cells are cytotoxic members of type I innate lymphocytes (ILC1) with a prominent role in anti-tumor and anti-viral immune responses. Despite the increasing insight into NK cell biology, the steps and stages leading to mature circulating NK cells require further investigation. Natural killer cell development and functional maturation are complex and multi-stage processes that occur predominantly in the bone marrow (BM) and originate from haematopoietic stem cells CD34+ (HSC). Within the BM, NK cell precursor (NKP) and NK cell development intermediates reside in specialized niches that are characterized by particular cellular components that provide signals required for their maturation. These signals consist of soluble factors or direct cellular-contact interactions mediated by cytokines and growth factors with complementary, as well as overlapping roles in distinct developmental steps. Emerging evidence highlights the plasticity of the early phase of NK cell development, and the capacity of different signal combinations to redirect precursor lineage commitment through other innate cell populations. Here, we summarize the role of signals known to guide NK cell differentiation with a particular focus on the cytokines and the receptor/ligand pairs playing a critical role in these processes. A comprehensive understanding of the mechanisms underlying NK cell development will elucidate their roles in pathological conditions and will improve protocols for NK cell therapeutic application. PMID- 29622472 TI - Sleep disorders in a sample of students in Taif University, Saudi Arabia: The role of obesity, insulin resistance, anemia and high altitude. AB - AIM: The aim of this study was to assess the incidence of sleep disorders and excessive daytime sleepiness (EDS) among Taif University students and to explore the precipitating factors of these disorders. METHODS: This study was carried out on 1066 students in Taif University of both sexes aging from 18 to 25 years. All included individuals were subjected to full history taking and thorough clinical examination, with special concern on anthropometric measurements (weight, height, waist-to-hip ratio and body mass index). Also, fasting blood glucose, fasting serum insulin, homeostatic model assessment (HOMA) index and blood hemoglobin levels were measured. Sleep disorders were assessed using sleep disturbances scale and the Epworth sleepiness scale. RESULTS: The overall incidence of sleep disorders and EDS was 31.33% and 15.29% respectively with statistically significant prevalence in females than males. There was significant positive correlation between sleep disturbances scale and Epworth sleepiness scale on one hand and body weight, body mass index, waist-to-hip ratio, the height of the residence place above the sea level, fasting and post-prandial blood glucose, fasting serum insulin and HOMA index on the other hand. Also, there was significant negative correlation between sleep disturbances scale and Epworth sleepiness scale on one hand and blood hemoglobin levels on the other hand. CONCLUSION: Sleep disorders and EDS in Taif University students were precipitated by high altitude, anemia, obesity and glucose intolerance. Control of these factors may have a positive impact on the incidence of sleep disorders and EDS in this age group. PMID- 29622476 TI - Total penile reconstruction: A systematic review. AB - BACKGROUND: Phalloplasty poses a unique challenge to the plastic and reconstructive surgeon. The development of advanced microsurgical techniques has greatly augmented the range of surgical approaches available. METHODS: A systematic review of the MEDLINE and Cochrane databases was performed to identify clinical studies of total penile reconstruction published within the last 10 years using the search algorithm: "(phallus or penis or penile) and (reconstruction or phalloplasty or transplant)". RESULTS: The primary literature search retrieved 1400 articles. After applying inclusion and exclusion criteria, 30 studies were selected for review. The radial forearm free flap is the preferred technique for total phalloplasty; however, other techniques including the fibular osteocutaneous flap, anterolateral thigh flap, latissimus dorsi flap, scapular free flap, and abdominal flap are described. Background, indications, and preoperative and postoperative care are also discussed. CONCLUSIONS: Total penile reconstruction can provide functional, aesthetic, and psychosocial benefits to the patient. Use of the radial forearm free flap has been proposed as the gold standard; however, the wide range of potential complications associated with phalloplasty warrants an individualized approach to each patient. PMID- 29622474 TI - The burden of not-weighted factors - Nursing workload in a medical Intensive Care Unit. AB - OBJECTIVES: Body weight and infection status affect nursing workload and are not accounted for in the Therapeutic Intervention Scoring System 28 (TISS-28) and Nine Equivalents of Nursing Manpower Use Score (NEMS). The objective of this study was to analyse the correlation between weight and infection status with TISS 28 and NEMS in a cohort of medical Intensive Care Unit patients. RESEARCH METHODOLOGY: A retrospective observational trial was conducted on the nursing records of 26 randomly selected patients over a 12-month period. TISS-28 and NEMS were calculated for each day of ICU stay. Infectious status was determined based on positive cultures to multi-resistant organisms while overweight and obesity were based on Body Mass Index. RESULTS: A total of 809 nursing shifts' activity records were analysed. There were 12 infected patients that required isolation, 14 overweight patients and 3 obese: 9 patients presented both conditions. Only the presence of both conditions was statistically associated with an increase in workload (TISS-28p-value = 0.041 and NEMS p-value = 0.011). CONCLUSIONS: Although TISS-28 and NEMS do not specifically consider body weight and infection status, their integration into nursing workload scores may improve the accuracy as management tools, increasing the quality of the cares provided. PMID- 29622477 TI - Zinc oxide nanoparticles induce HIF-1alpha protein stabilization through increased reactive oxygen species generation from electron transfer chain complex III of mitochondria. PMID- 29622478 TI - Bicycle helmets are protective against facial injuries, including facial fractures: a meta-analysis. AB - Cycling is a popular activity. However there are risks associated with cycling, including facial injury. Helmets are often worn to prevent head injury. Evidence for their protection against facial injury is limited. This meta-analysis investigated the effect of bicycle helmets on the incidence of facial injury. The PubMed/MEDLINE, Google Scholar, and Cochrane Library databases were searched. Studies included were observational and involved adult participants. Paediatric studies, studies on helmet legislation, and those combining facial injuries with other injury types were excluded. The studies were evaluated by two reviewers. Risk of bias was assessed using the RevMan bias assessment tool. Odds ratios (OR) were extracted for facial injuries and facial fractures. Two meta-analyses were performed using these categories. Nine of the 102 studies identified were included. Helmets were protective against facial injury (OR 0.69, 95% confidence interval 0.63-0.75, P<0.0001). Five studies reported facial fracture rates; helmets were protective against these also (OR 0.79 95% confidence interval 0.70 0.90, P=0.0003). There are no randomized controlled trials on this topic and the number of studies available is small. Bicycle helmets offer protection against facial injuries and this should be considered by cyclists when deciding whether or not to use one. PMID- 29622479 TI - Clefts of the lip and palate: is the Internet a trustworthy source of information for patients? AB - Great numbers of patients use the Internet to obtain information and familiarize themselves with medical conditions. However, the quality of Internet-based information on clefts of the lip and palate has not yet been examined. The goal of this study was to assess the quality of Internet-based patient information on orofacial clefts. Websites were evaluated based on the modified Ensuring Quality Information for Patients (EQIP) instrument (36 items). Three hundred websites were identified using the most popular search engines. Of these, 146 were assessed after the exclusion of duplicates, irrelevant sites, and web pages in languages other than English. Thirty-four (23.2%) web pages, designed mostly by academic centres and hospitals, covered more than 22 items and were classified as high-score websites. The EQIP score achieved by websites ranged between 4 and 30, out of a total possible 36 points; the median score was 19 points. The top five high-scoring web pages are highlighted. The overall quality of Internet-based patient information on orofacial clefts is low. Also, the majority of web pages created by medical practitioners have a marketing perspective and in order to attract more patients/customers avoid mentioning the risks of the reconstructive procedures needed. PMID- 29622475 TI - Myeloid Conditioning with c-kit-Targeted CAR-T Cells Enables Donor Stem Cell Engraftment. AB - We report a novel approach to bone marrow (BM) conditioning using c-kit-targeted chimeric antigen receptor T (c-kit CAR-T) cells in mice. Previous reports using anti-c-kit or anti-CD45 antibody linked to a toxin such as saporin have been promising. We developed a distinctly different approach using c-kit CAR-T cells. Initial studies demonstrated in vitro killing of hematopoietic stem cells by c kit CAR-T cells but poor expansion in vivo and poor migration of CAR-T cells into BM. Pre-treatment of recipient mice with low-dose cyclophosphamide (125 mg/kg) together with CXCR4 transduction in the CAR-T cells enhanced trafficking to and expansion in BM (<1%-13.1%). This resulted in significant depletion of the BM c kit+ population (9.0%-0.1%). Because congenic Thy1.1 CAR-T cells were used in the Thy1.2-recipient mice, anti-Thy1.1 antibody could be used to deplete CAR-T cells in vivo before donor BM transplant. This achieved 20%-40% multilineage engraftment. We applied this conditioning to achieve an average of 28% correction of chronic granulomatous disease mice by wild-type BM transplant. Our findings provide a proof of concept that c-kit CAR-T cells can achieve effective BM conditioning without chemo-/radiotherapy. Our work also demonstrates that co expression of a trafficking receptor can enhance targeting of CAR-T cells to a designated tissue. PMID- 29622480 TI - Relative contributions of microbial and infrastructure heat at a crude oil contaminated site. AB - Biodegradation of contaminants can increase the temperature in the subsurface due to heat generated from exothermic reactions, making temperature observations a potentially low-cost approach for determining microbial activity. For this technique to gain more widespread acceptance, it is necessary to better understand all the factors affecting the measured temperatures. Biodegradation has been occurring at a crude oil-contaminated site near Bemidji, Minnesota for 39 years, creating a quasi-steady-state plume of contaminants and degradation products. A model of subsurface heat generation and transport helps elucidate the contribution of microbial and infrastructure heating to observed temperature increases at this site. We created a steady-state, two-dimensional, heat transport model using previous-published parameter values for physical, chemical and biodegradation properties. Simulated temperature distributions closely match the observed average annual temperatures measured in the contaminated area at the site within less than 0.2 degrees C in the unsaturated zone and 0.4 degrees C in the saturated zone. The model results confirm that the observed subsurface heat from microbial activity is due primarily to methane oxidation in the unsaturated zone resulting in a 3.6 degrees C increase in average annual temperature. Another important source of subsurface heat is from the active, crude-oil pipelines crossing the site. The pipelines impact temperatures for a distance of 200 m and contribute half the heat. Model results show that not accounting for the heat from the pipelines leads to overestimating the degradation rates by a factor of 1.7, demonstrating the importance of identifying and quantifying all heat sources. The model results also highlighted a zone where previously unknown microbial activity is occurring at the site. PMID- 29622481 TI - Pre-clinical assessment of total knee replacement anterior-posterior constraint. AB - Pre-clinical, bench-top assessment of Total Knee Replacements (TKR) can provide information about the inherent constraint provided by a TKR, which does not depend on the condition of the patient undergoing the arthroplasty. However little guidance is given by the ASTM standard on test configurations such as medial-lateral (M:L) loading distribution, flexion angle or restriction of secondary motions. Using a purpose built rig for a materials testing machine, four TKRs currently in widespread clinical use, including medial-pivot and symmetrical condyle types, were tested for anterior-posterior translational constraint. Compressive joint loads from 710 to 2000 N, and a range of medial lateral (M:L) load distributions, from 70:30% to 30:70% M:L, were applied at different flexion angles with secondary motions unconstrained. It was found that TKA constraint was significantly less at 60 and 90 degrees flexion than at 0 degrees , whilst increasing the compressive joint load increased the force required to translate the tibia to limits of AP constraint at all flexion angles tested. Additionally when M:L load distribution was shifted medially, a coupled internal rotation was observed with anterior translation and external rotation with posterior translation. This paper includes some recommendations for future development of pre-clinical testing methods. PMID- 29622482 TI - Understanding the relationship between cell death and tissue shrinkage via a stochastic agent-based model. AB - Cell death, a process which can occur both naturally and in response to insult, is both a complex and diverse phenomenon. Under some circumstances, dying cells actively contract and cause their neighbors to rearrange and maintain tissue integrity. Under other circumstances, dying cells leave behind gaps, which results in tissue separation. A better understanding of how the cellular scale features of cell death manifest on the population scale has implications ranging from morphogenesis to tumor response to treatment. However, the mechanistic relationship between cell death and population scale shrinkage is not well understood, and computational methods for studying these relationships are not well established. Here we propose a mechanically robust agent-based cell model designed to capture the implications of cell death on the population scale. In our agent-based model, algorithmic rules applied on the cellular level emerge on the population scale where their effects are quantified. To better quantify model uncertainty and parameter interactions, we implement a recently developed technique for conducting a variance-based sensitivity analysis on the stochastic model. From this analysis and subsequent investigation, we find that cellular scale shrinkage has the largest influence of all model parameters tested, and that by adjusting cellular scale shrinkage population shrinkage varies widely even across simulations which contain the same fraction of dying cells. We anticipate that the methods and results presented here are a starting point for significant future investigation toward quantifying the implications of different mechanisms of cell death on population and tissue scale behavior. PMID- 29622483 TI - Mesenchymal stromal cell exosome-enhanced regulatory T-cell production through an antigen-presenting cell-mediated pathway. AB - BACKGROUND AIMS: The immunomodulatory property of mesenchymal stromal cell (MSC) exosomes is well documented. On the basis of our previous report that MSC exosomes increased regulatory T-cell (Treg) production in mice with allogenic skin graft but not in ungrafted mice, we hypothesize that an activated immune system is key to exosome-mediated Treg production. METHODS: To test our hypothesis, MSC exosomes were incubated with mouse spleen CD4+ T cells that were activated with either anti-CD3/CD28 mAbs or allogenic antigen-presenting cell (APC)-enriched spleen CD11c+ cells to determine whether production of mouse CD4+CD25+ T cells or CD4+CD25+Foxp3+ Tregs could be induced. MSC exosomes were also administered to the lethal chimeric human-SCID mouse model of graft-versus host disease (GVHD) in which human peripheral blood mononuclear cells were infused into irradiated NSG mice to induce GVHD. RESULTS: We report here that MSC exosome-induced production of CD4+CD25+ T cells or CD4+CD25+Foxp3+ Tregs from CD4+ T cells activated by allogeneic APC-enriched CD11C+ cells but not those activated by anti-CD3/CD28 mAbs. This induction was exosome- and APC dose dependent. In the mouse GVHD model in which GVHD was induced by transplanted human APC-stimulated human anti-mouse CD4+ T cell effectors, MSC exosome alleviated GVHD symptoms and increased survival. Surviving exosome-treated mice had a significantly higher level of human CD4+CD25+CD127low/- Tregs than surviving mice treated with Etanercept, a tumor necrosis factor inhibitor. CONCLUSIONS: MSC exosome enhanced Treg production in vitro and in vivo through an APC-mediated pathway. PMID- 29622484 TI - Mechanical Thrombectomy in an Infant With Acute Embolic Stroke. PMID- 29622486 TI - Autopsy Neuropathology Findings in a Child with Chronic Infantile Krabbe Leukoencephalopathy. PMID- 29622485 TI - The Association of Schizophrenia and Narcolepsy in Adolescents. PMID- 29622487 TI - Passing the Newborn Hearing Screen Does Not Always Exclude Acquired Hearing Loss Due to Congenital Infection. PMID- 29622488 TI - Cerebral Autoregulation and Conventional and Diffusion Tensor Imaging Magnetic Resonance Imaging in Neonatal Hypoxic-Ischemic Encephalopathy. AB - BACKGROUND: Deviation of mean arterial blood pressure (MAP) from the range that optimizes cerebral autoregulatory vasoreactivity (optimal MAP) could increase neurological injury from hypoxic-ischemic encephalopathy (HIE). We tested whether a global magnetic resonance imaging (MRI) brain injury score and regional diffusion tensor imaging (DTI) are associated with optimal MAP in neonates with HIE. METHODS: Twenty-five neonates cooled for HIE were monitored with the hemoglobin volume index. In this observational study, we identified optimal MAP and measured brain injury by qualitative and quantitative MRIs with the Neonatal Research Network (NRN) score and DTI mean diffusivity scalars. Optimal MAP and blood pressure were compared with brain injury. RESULTS: Neonates with blood pressure measurements within optimal MAP during rewarming had less brain injury by NRN score (P = 0.040). Longer duration of MAP within optimal MAP during hypothermia correlated with higher mean diffusivity in the anterior centrum semiovale (P = 0.008) and pons (P = 0.002). Blood pressure deviation below optimal MAP was associated with lower mean diffusivity in cerebellar white matter (P = 0.033). Higher optimal MAP values related to lower mean diffusivity in the basal ganglia (P = 0.021), the thalamus (P = 0.006), the posterior limb of the internal capsule (P = 0.018), the posterior centrum semiovale (P = 0.035), and the cerebellar white matter (P = 0.008). Optimal MAP values were not associated with the NRN score. CONCLUSIONS: The NRN score and the regional mean diffusivity scalars detected injury with mean arterial blood pressure deviations from the optimal MAP. Higher optimal MAP and lower mean diffusivity may be related because of cytotoxic edema and limited vasodilatory reserve at low MAP in injured brain. DTI detected injury with elevated optimal MAP better than the NRN score. PMID- 29622489 TI - The Association Between Maternal Age and Cerebral Palsy Risk Factors. AB - BACKGROUND: Advanced maternal age is associated with higher frequencies of antenatal and perinatal conditions, as well as a higher risk of cerebral palsy in offspring. We explore the association between maternal age and specific cerebral palsy risk factors. METHODS: Data were extracted from the Canadian Cerebral Palsy Registry. Maternal age was categorized as >=35 years of age and less than 20 years of age at the time of birth. Chi-square and multivariate logistic regressions were performed to calculate odds ratios and their 95% confidence intervals. RESULTS: The final sample consisted of 1391 children with cerebral palsy, with 19% of children having mothers aged 35 or older and 4% of children having mothers below the age of 20. Univariate analyses showed that mothers aged 35 or older were more likely to have gestational diabetes (odds ratio 1.9, 95% confidence interval 1.3 to 2.8), to have a history of miscarriage (odds ratio 1.8, 95% confidence interval 1.3 to 2.4), to have undergone fertility treatments (odds ratio 2.4, 95% confidence interval 1.5 to 3.9), and to have delivered by Caesarean section (odds ratio 1.6, 95% confidence interval 1.2 to 2.2). These findings were supported by multivariate analyses. Children with mothers below the age of 20 were more likely to have a congenital malformation (odds ratio 2.4, 95% confidence interval 1.4 to 4.2), which is also supported by multivariate analysis. CONCLUSIONS: The risk factor profiles of children with cerebral palsy vary by maternal age. Future studies are warranted to further our understanding of the compound causal pathways leading to cerebral palsy and the observed greater prevalence of cerebral palsy with increasing maternal age. PMID- 29622490 TI - Autoimmune GFAP-Associated Meningoencephalomyelitis: A Report of a Pediatric Patient. PMID- 29622463 TI - Genomic and Functional Approaches to Understanding Cancer Aneuploidy. AB - Aneuploidy, whole chromosome or chromosome arm imbalance, is a near-universal characteristic of human cancers. In 10,522 cancer genomes from The Cancer Genome Atlas, aneuploidy was correlated with TP53 mutation, somatic mutation rate, and expression of proliferation genes. Aneuploidy was anti-correlated with expression of immune signaling genes, due to decreased leukocyte infiltrates in high aneuploidy samples. Chromosome arm-level alterations show cancer-specific patterns, including loss of chromosome arm 3p in squamous cancers. We applied genome engineering to delete 3p in lung cells, causing decreased proliferation rescued in part by chromosome 3 duplication. This study defines genomic and phenotypic correlates of cancer aneuploidy and provides an experimental approach to study chromosome arm aneuploidy. PMID- 29622491 TI - The influence of age-policy changes on the relative age effect across the Australian Rules football talent pathway. AB - OBJECTIVES: To identify the influence of age-policy changes on the relative age effect (RAE) across the Australian Football League (AFL) talent pathway. DESIGN: Retrospective cross-sectional analysis of junior AFL players attending the National Draft (National), State, and State Under 16s (U16) combines between 1999 2016. METHODS: Birth-date data was obtained for players attending the AFL State U16 (n=663, age: 15.9+/-0.4years), State (n=803, age: 19.1+/-1.7years), National (n=1111, age: 18.3+/-0.8years) combines. Corresponding aged-matched Australian general population birth rate data was also collected. RESULTS: A chi-squared analysis comparing birth month distributions found all combine groups differed significantly from the general population (Under 16s: chi2=62.61, State: chi2=38.83, National: chi2=129.13, p<0.001). Specifically, Under 16s had greater birth frequencies for months January to March (>=2%, p<0.05), with more State players born in January (4.9%, p<0.05). Age-policy changes at the National level reduced birth distribution bias for some months, however the RAE remained for March, June and July (3.9%, 6.1%, 4.3%, p<0.05). State U16s and National players had 2-9% lower birth frequencies for November-December births compared general population. CONCLUSIONS: Selection bias exists towards older players is present at the AFL's State U16, and is maintained at State and National level combines. Age-policy changes are only partially successful at addressing the RAE at the National level, with alternative strategies also recommended in order to address the RAE across the AFL talent pathways. PMID- 29622465 TI - lncRNA Epigenetic Landscape Analysis Identifies EPIC1 as an Oncogenic lncRNA that Interacts with MYC and Promotes Cell-Cycle Progression in Cancer. AB - We characterized the epigenetic landscape of genes encoding long noncoding RNAs (lncRNAs) across 6,475 tumors and 455 cancer cell lines. In stark contrast to the CpG island hypermethylation phenotype in cancer, we observed a recurrent hypomethylation of 1,006 lncRNA genes in cancer, including EPIC1 (epigenetically induced lncRNA1). Overexpression of EPIC1 is associated with poor prognosis in luminal B breast cancer patients and enhances tumor growth in vitro and in vivo. Mechanistically, EPIC1 promotes cell-cycle progression by interacting with MYC through EPIC1's 129-283 nt region. EPIC1 knockdown reduces the occupancy of MYC to its target genes (e.g., CDKN1A, CCNA2, CDC20, and CDC45). MYC depletion abolishes EPIC1's regulation of MYC target and luminal breast cancer tumorigenesis in vitro and in vivo. PMID- 29622492 TI - Association analyses of variants of SIPA1L2, MIR4697, GCH1, VPS13C, and DDRGK1 with Parkinson's disease in East Asians. AB - A recent large-scale European-originated genome-wide association data meta analysis followed by a replication study identified 6 new risk loci for Parkinson's disease (PD), which include rs10797576/SIPA1L2, rs117896735/INPP5F, rs329648/MIR4697, rs11158026/GCH1, rs2414739/VPS13C, and rs8118008/DDRGK1. However, whether these new loci are associated with PD in Asian populations remain elusive. The INPP5F is nonpolymorphic in Asians. The present study aimed to understand the effects of the other 5 new loci in a Han Chinese population comprising 579 sporadic PD patients and 642 controls. Significant associations with PD were observed in the variants of SIPA1L2 (p = 0.001) and VPS13C (p = 0.007), where the T (odd ratio [OR] = 1.484, 95% confidence interval [CI] 1.186 1.858) and A (OR = 1.362, 95% CI 1.087-1.707) alleles serve as the risk alleles, respectively. The genotype distributions in the SIPA1L2 and VPS13C variants were also different between the patients and controls (p = 0.002 and p = 0.023, respectively). In contrast, no significant association with PD was found in the variants of MIR4697, GCH1, and DDRGK1 either in allele or genotype frequencies. Noteworthy, a followed meta-analysis of East Asian studies suggested an association of the GCH1 variant with PD (p = 0.04, OR 1.08, 95% CI 1.00-1.16), while the other results are in line with those of our cohort. In conclusion, our study together with meta-analyses demonstrates that the variants of SIPA1L2 and VPS13C, potentially GCH1, but not of MIR4697 and DDRGK1, are associated with PD susceptibility in East Asians. PMID- 29622493 TI - Hip Fracture Does Not Belong in the Elective Arthroplasty Bundle: Presentation, Outcomes, and Service Utilization Differ in Fracture Arthroplasty Care. AB - BACKGROUND: Center for Medicare and Medicaid Services reimbursement is the same for hip arthroplasty performed electively for arthritis and urgently for femoral neck fracture. METHODS: An analytic report of hip arthroplasty for a 5-hospital network identified 2362 cases performed from January 2014 to May 2016. Resource utilization was determined using 90-day charges. RESULTS: The fracture population (623 hips) was older (P < .01), had more medical comorbidities (28.3% vs 3.8%, P < .01), and was more likely to be anemic and malnourished (P < .01), and had longer hospital stay (5.7 vs 3.0 days, P < .0001), more frequent intensive care unit admission (4.5% vs 0.5%, P < .01), less frequent discharge to home (16.2% vs 83.6%, P < .01), more emergency department visits (26.5% vs 10.7%, P < .01), and more readmissions after hospital discharge (25.2% vs 12.2%, P < .01). Utilization of services ($50,875 vs $38,705, P < .0001) and the standard deviation of these services ($22,509 vs $9,847, P < .0001), from 90-day charges, were significantly greater in the fracture population. CONCLUSION: This study supports exclusion of fracture care from the Comprehensive Care for Joint Replacement bundled payment program. PMID- 29622464 TI - A Comprehensive Pan-Cancer Molecular Study of Gynecologic and Breast Cancers. AB - We analyzed molecular data on 2,579 tumors from The Cancer Genome Atlas (TCGA) of four gynecological types plus breast. Our aims were to identify shared and unique molecular features, clinically significant subtypes, and potential therapeutic targets. We found 61 somatic copy-number alterations (SCNAs) and 46 significantly mutated genes (SMGs). Eleven SCNAs and 11 SMGs had not been identified in previous TCGA studies of the individual tumor types. We found functionally significant estrogen receptor-regulated long non-coding RNAs (lncRNAs) and gene/lncRNA interaction networks. Pathway analysis identified subtypes with high leukocyte infiltration, raising potential implications for immunotherapy. Using 16 key molecular features, we identified five prognostic subtypes and developed a decision tree that classified patients into the subtypes based on just six features that are assessable in clinical laboratories. PMID- 29622494 TI - Evaluation of the Learning Curve When Transitioning From Posterolateral to Direct Anterior Hip Arthroplasty: A Consecutive Series of 1000 Cases. AB - BACKGROUND: The direct anterior approach (DAA) for primary hip replacement has been gaining more attention and widespread use in recent years. There are a number of published studies evaluating the learning curve when a surgeon changes technique; these studies typically look at complications during the initial cases. This study examines procedure and total operating room (OR) time along with all complications for a surgeon transitioning from the posterolateral approach (PA) to DAA. METHODS: A retrospective review of a single surgeon series of 1000 initial DAA procedures. Total OR time, procedure time, and complications were collected and analyzed. One-way analysis of variance and post hoc least significant difference tests were used for statistical analysis. RESULTS: There was an initial increase in both procedure and OR times compared with the mature PA, by 34% and 30%, respectively. The procedure time became statistically equivalent to the mature PA time after the 400th DAA case, and significantly shorter after the 850th case. The total OR time became statistically equivalent after the 900th DAA case. There were 18 early (<90 days) and 18 late reoperations performed in this series with a nonsignificant trend toward femoral complications occurring early in the series. Minimum follow-up time was 2 years. CONCLUSION: There was an initial increase in both total OR time and procedure time when an experienced surgeon introduced the DAA. By the end of the series, procedure time was significantly shorter and total OR time was equivalent. Complications overall were low and femoral complications decreased with time. PMID- 29622495 TI - Identification of Serine 119 as an Effective Inhibitor Binding Site of M. tuberculosis Ubiquitin-like Protein Ligase PafA Using Purified Proteins and M. smegmatis. AB - Owing to the spread of multidrug resistance (MDR) and extensive drug resistance (XDR), there is a pressing need to identify potential targets for the development of more-effective anti-M. tuberculosis (Mtb) drugs. PafA, as the sole Prokaryotic Ubiquitin-like Protein ligase in the Pup-proteasome System (PPS) of Mtb, is an attractive drug target. Here, we show that the activity of purified Mtb PafA is significantly inhibited upon the association of AEBSF (4-(2-aminoethyl) benzenesulfonyl fluoride) to PafA residue Serine 119 (S119). Mutation of S119 to amino acids that resemble AEBSF has similar inhibitory effects on the activity of purified Mtb PafA. Structural analysis reveals that although S119 is distant from the PafA catalytic site, it is located at a critical position in the groove where PafA binds the C-terminal region of Pup. Phenotypic studies demonstrate that S119 plays critical roles in the function of Mtb PafA when tested in M. smegmatis. Our study suggests that targeting S119 is a promising direction for developing an inhibitor of M. tuberculosis PafA. PMID- 29622498 TI - Clinical Outcomes After Extracorporeal Shock Wave Therapy for Chronic Plantar Fasciitis in a Predominantly Active Duty Population. AB - Chronic plantar fasciitis is a common cause of foot pain, with conservative treatment providing relief for most patients. However, because of the common occurrence of this pathology, this leaves many patients dissatisfied. The purpose of the present study was to determine the effectiveness of extracorporeal shock wave therapy (ESWT) to treat chronic plantar fasciitis (PF) in a largely active duty population. A review of 82 patients (115 heels) who had undergone ESWT for chronic PF was performed. Outcome data were obtained by patient telephone interviews. All ESWT was conducted at 24 kV for 2000 shocks. Of the 82 patients (115 heels), 76 (93%; 111 heels) agreed to participate. Their mean age was 42 +/- 10 years, with 41 males (54%) and 35 females (46%). The mean follow-up period was 42 +/- 22 months. Of the patients, 73.6% were active duty military personnel. The mean preoperative pain score of 7.8 +/- 2 had improved to 2.5 +/- 2 at the last follow-up visit (p <.0001). Active duty patients reported a mean improvement in pain of 4.8 +/- 3 compared with 6.8 +/- 3 in non-active duty patients (p = .005). Of the 76 patients, 75 (98%) underwent 1 ESWT session, and 1 (2%) requiring 2 sessions. Overall, 74% of patients rated the outcome of their procedure as either good or excellent, with 87% stating that ESWT was successful. Ten patients (18%) left the military because of continued foot pain, with 76% able to return to running. For patients with chronic PF, these results support the use of ESWT to relieve pain in >85% of patients, with a preponderance for better pain relief in patients who are not active duty military personnel. PMID- 29622496 TI - Multi-Site Diagnostic Classification of Schizophrenia Using Discriminant Deep Learning with Functional Connectivity MRI. AB - BACKGROUND: A lack of a sufficiently large sample at single sites causes poor generalizability in automatic diagnosis classification of heterogeneous psychiatric disorders such as schizophrenia based on brain imaging scans. Advanced deep learning methods may be capable of learning subtle hidden patterns from high dimensional imaging data, overcome potential site-related variation, and achieve reproducible cross-site classification. However, deep learning-based cross-site transfer classification, despite less imaging site-specificity and more generalizability of diagnostic models, has not been investigated in schizophrenia. METHODS: A large multi-site functional MRI sample (n = 734, including 357 schizophrenic patients from seven imaging resources) was collected, and a deep discriminant autoencoder network, aimed at learning imaging site shared functional connectivity features, was developed to discriminate schizophrenic individuals from healthy controls. FINDINGS: Accuracies of approximately 85.0% and 81.0% were obtained in multi-site pooling classification and leave-site-out transfer classification, respectively. The learned functional connectivity features revealed dysregulation of the cortical-striatal-cerebellar circuit in schizophrenia, and the most discriminating functional connections were primarily located within and across the default, salience, and control networks. INTERPRETATION: The findings imply that dysfunctional integration of the cortical striatal-cerebellar circuit across the default, salience, and control networks may play an important role in the "disconnectivity" model underlying the pathophysiology of schizophrenia. The proposed discriminant deep learning method may be capable of learning reliable connectome patterns and help in understanding the pathophysiology and achieving accurate prediction of schizophrenia across multiple independent imaging sites. PMID- 29622499 TI - Isolated Rupture of the Distal Plantaris Muscle. AB - In the present case, the plantaris tendon was ruptured in isolation and at the distal part of the tendon. An injury of the Achilles tendon, gastrocnemius muscle, or soleus muscle was not detected. To the best of our knowledge, a similar case has not yet been reported. Our case basically demonstrates that a rupture of the musculus plantaris does not have to occur at the myotendiouns junction or the muscle belly itself. The initial nonoperative treatment with physiotherapy, antiinflammatory medicine, and an early return to sports, even for this more distal plantaris tendon rupture, led to a good result. PMID- 29622500 TI - Max dD/Dt: A Novel Parameter to Assess Fetal Cardiac Contractility and a Substitute for Max dP/Dt. AB - Aortic pulse waveforms are composed of a forward wave from the heart and a reflection wave from the periphery. We focused on this forward wave and suggested a new parameter, the maximum slope of aortic pulse waveforms (max dD/dt), for fetal cardiac contractility. Max dD/dt was calculated from fetal aortic pulse waveforms recorded with an echo-tracking system. A normal range of max dD/dt was constructed in 105 healthy fetuses using linear regression analysis. Twenty-two fetuses with suspected fetal cardiac dysfunction were divided into normal and decreased max dD/dt groups, and their clinical parameters were compared. Max dD/dt of aortic pulse waveforms increased linearly with advancing gestational age (r = 0.93). The decreased max dD/dt was associated with abnormal cardiotocography findings and short- and long-term prognosis. In conclusion, max dD/dt calculated from the aortic pulse waveforms in fetuses can substitute for max dP/dt, an index of cardiac contractility in adults. PMID- 29622497 TI - Ebola Virus Persistence in Ocular Tissues and Fluids (EVICT) Study: Reverse Transcription-Polymerase Chain Reaction and Cataract Surgery Outcomes of Ebola Survivors in Sierra Leone. AB - BACKGROUND: Ebola virus disease (EVD) survivors are at risk for uveitis during convalescence. Vision loss has been observed following uveitis due to cataracts. Since Ebola virus (EBOV) may persist in the ocular fluid of EVD survivors for an unknown duration, there are questions about the safety and feasibility of vision restorative cataract surgery in EVD survivors. METHODS: We conducted a cross sectional study of EVD survivors anticipating cataract surgery and patients with active uveitis to evaluate EBOV RNA persistence in ocular fluid, as well as vision outcomes post cataract surgery. Patients with aqueous humor that tested negative for EBOV RNA were eligible to proceed with manual small incision cataract surgery (MSICS). FINDINGS: We screened 137 EVD survivors from June 2016 August 2017 for enrolment. We enrolled 50 EVD survivors; 46 with visually significant cataract, 1 with a subluxated lens, 2 with active uveitis and 1 with a blind painful eye due to uveitis. The median age was 24.0years (IQR 17-35) and 35 patients (70%) were female. The median logMAR visual acuity (VA) was 3.0 (Snellen VA Hand motions; Interquartile Range, IQR: 1.2-3.0, Snellen VA 20/320 - Hand motions). All patients tested negative for EBOV RNA by RT-PCR in aqueous humor/vitreous fluid and conjunctiva at a median of 19months (IQR 18-20) from EVD diagnosis in Phase 1 of ocular fluid sampling and 34months (IQR 32-36) from EVD diagnosis in Phase 2 of ocular fluid sampling. Thirty-four patients underwent MSICS, with a preoperative median VA improvement from hand motions to 20/30 at three-month postoperative follow-up (P<0.001). INTERPRETATION: EBOV persistence by RT-PCR was not identified in ocular fluid or conjunctivae of fifty EVD survivors with ocular disease. Cataract surgery can be performed safely with vision restorative outcomes in patients who test negative for EBOV RNA in ocular fluid specimens. These findings impact the thousands of West African EVD survivors at-risk for ocular complications who may also require eye surgery during EVD convalescence. PMID- 29622501 TI - Hepatic Steatosis Assessment with Ultrasound Small-Window Entropy Imaging. AB - Nonalcoholic fatty liver disease is a type of hepatic steatosis that is not only associated with critical metabolic risk factors but can also result in advanced liver diseases. Ultrasound parametric imaging, which is based on statistical models, assesses fatty liver changes, using quantitative visualization of hepatic steatosis-caused variations in the statistical properties of backscattered signals. One constraint with using statistical models in ultrasound imaging is that ultrasound data must conform to the distribution employed. Small-window entropy imaging was recently proposed as a non-model-based parametric imaging technique with physical meanings of backscattered statistics. In this study, we explored the feasibility of using small-window entropy imaging in the assessment of fatty liver disease and evaluated its performance through comparisons with parametric imaging based on the Nakagami distribution model (currently the most frequently used statistical model). Liver donors (n = 53) and patients (n = 142) were recruited to evaluate hepatic fat fractions (HFFs), using magnetic resonance spectroscopy and to evaluate the stages of fatty liver disease (normal, mild, moderate and severe), using liver biopsy with histopathology. Livers were scanned using a 3-MHz ultrasound to construct B-mode, small-window entropy and Nakagami images to correlate with HFF analyses and fatty liver stages. The diagnostic values of the imaging methods were evaluated using receiver operating characteristic curves. The results demonstrated that the entropy value obtained using small-window entropy imaging correlated well with log10(HFF), with a correlation coefficient r = 0.74, which was higher than those obtained for the B scan and Nakagami images. Moreover, small-window entropy imaging also resulted in the highest area under the receiver operating characteristic curve (0.80 for stages equal to or more severe than mild; 0.90 for equal to or more severe than moderate; 0.89 for severe), which indicated that non-model-based entropy imaging using the small-window technique-performs more favorably than other techniques in fatty liver assessment. PMID- 29622502 TI - Chronic pain medication management of older populations: Key points from a national conference and innovative opportunities for pharmacy practice. AB - OBJECTIVE: Inappropriate use of pain medication has serious consequences for older populations. Experts in the field have noted an increase in opioid prescriptions, and opioid-related hospitalisations and deaths among this vulnerable population. In the pursuit of educating pharmacists, physicians, allied healthcare professionals, researchers, academics and the public facing the challenges of chronic pain medication management, 'The Inaugural Monash University School of Public Health and Preventive Medicine (SPHPM) Best Practice in Chronic Pain Medication Management Day Conference' was held in December 2016 at the Alfred Medical Research and Education Precinct (Melbourne, Australia). METHODS: Fifteen experts presented on aspects of chronic pain epidemiology and current analgesic use in older Australians, and discussed current practice and associated challenges. RESULTS: Presenters highlighted the dramatic increase in opioid prescribing, development of tolerance and withdrawal symptoms, problems with abuse and addiction, increased risk of death from overdose or suicide, potentiation of sedative effects with concurrent use of anxiolytics/hypnotics, and medication diversion. CONCLUSIONS: Pharmacists are very accessible to patients and are crucial members of medication management teams. They have the necessary medication expertise to review medication regimens and provide patient education. Towards addressing chronic pain medication management of older populations, pharmacists can contribute in several ways, such as being aware of relevant guidelines and completing further training, contributing to policy and guideline development, participating in multidisciplinary panels, working groups and pain management teams, collaborating on research projects, and educating the community. With regards to opioid medication management, pharmacists are in an ideal position to: monitor prescription dispensing and potential misuse, provide education about overuse, and, if appropriate, provide access to naloxone. In order to fulfil these roles and responsibilities, allied healthcare professionals should be educated and informed, and opportunities for continuing professional education should be available and utilised. Pharmacists should have the necessary knowledge and skills to optimise chronic pain management, and to both deliver and inform policies and guidelines on pharmacological management of chronic pain in older people. PMID- 29622503 TI - Multidisciplinary management of an intra-sellar cavernous hemangioma: Case report and review of the literature. AB - Extra-axial cavernous hemangiomas (ECH) are rare vascular lesions with a tendency to grow within the medial structures of the middle cranial fossa. This pathological entity lacks specific symptoms, and falls into the category of differential diagnosis of space occupying lesions in the cavernous sinus (CS) with or without sellar involvement, including those of tumoral, vascular and inflammatory nature. Of note, ECH can also be indolent, and is at times discovered incidentally during autopsy investigations. On radiological studies, ECH with sellar extension are frequently mistaken at first for pituitary adenomas. Total removal of intrasellar-CS ECH is technically demanding and burdened by remarkable morbidity and mortality rates, mostly related to the complex neuroanatomy of the CS-sellar region (i.e., peri and postoperative bleeding, and transitory or permanent nerve palsies, hormonal deficits). Consequently, only a few cases of successful total removal have been reported so far in the literature. Surgical debulking with cranial nerve decompression followed by stereotactic radiosurgery is currently considered the best alternative to total removal when the latter carries excessive perioperative risks. We present a rare case of a mainly located intrasellar ECH extending to the left CS discussing its clinical features and focusing on the most relevant aspects of the surgical management along with a review of the pertinent literature. PMID- 29622466 TI - Comparative Molecular Analysis of Gastrointestinal Adenocarcinomas. AB - We analyzed 921 adenocarcinomas of the esophagus, stomach, colon, and rectum to examine shared and distinguishing molecular characteristics of gastrointestinal tract adenocarcinomas (GIACs). Hypermutated tumors were distinct regardless of cancer type and comprised those enriched for insertions/deletions, representing microsatellite instability cases with epigenetic silencing of MLH1 in the context of CpG island methylator phenotype, plus tumors with elevated single-nucleotide variants associated with mutations in POLE. Tumors with chromosomal instability were diverse, with gastroesophageal adenocarcinomas harboring fragmented genomes associated with genomic doubling and distinct mutational signatures. We identified a group of tumors in the colon and rectum lacking hypermutation and aneuploidy termed genome stable and enriched in DNA hypermethylation and mutations in KRAS, SOX9, and PCBP1. PMID- 29622505 TI - Preoperative lumbar drainage placement for surgical cranioplasty. AB - OBJECTIVE: Intraoperative reduction of cerebrospinal fluid may be required in patients undergoing cranioplasty (CP) surgery, especially in the presence of bulging cranial defects. Direct cannulation of the frontal horn of the lateral ventricle is associated with risks such as intracerebral haemorrhage or postoperative leakage of cerebrospinal fluid. Here we report our initial experiences with preoperative lumbar drain (LD) placement for cranioplasty surgery in patients with bulging cranial defects. METHOD: The medical records of patients who were treated with LD prior to CP surgery at our institution were retrospectively analysed. Pre-, intra- and postoperative modalities, complications and outcome parameters are described. RESULTS: A total of 14 patients (mean age 46 years) were included in this analysis. The majority of patients had received decompressive craniectomy due to space-occupying cerebral infarction (64.3%) and traumatic brain injury (14.3%). CP was performed unilaterally with autologous bone graft in 93% of cases. No complications occurred during lumbar drainage placement and the grafts were implanted without the need of dural opening and ventricle puncture. LDs were maintained for an average of 17 +/- 15 h (range, 1-48 h). There were no LD related complications in the further course. CONCLUSION: Our initial experiences demonstrate that preoperative LD placement facilitates CP in patients with bulging cranial defects requiring surgical cranioplasty. Intraoperative puncture of ventricles for reducing cerebrospinal fluid is avoided and therefore, the risk of intracerebral haemorrhage and brain damage is reduced. Further studies are needed to evaluate the advantages of this technique as an alternative to conventional methods of intraoperative CSF reduction. PMID- 29622504 TI - Effect of surgical decompression of spinal metastases in acute treatment - Predictors of neurological outcome. AB - OBJECTIVE: Space-occupying spinal metastases (SM), commonly diagnosed because of acute neurological deterioration, consequently lead to immediate decompression with tumor removal or debulking. In this study, we analyzed a series of patients with surgically treated spinal metastases and explicitly sought to determine individual predictors of functional outcome. PATIENTS AND METHODS: 94 patients (26 women, 68 men; mean age 64.0 years) with spinal metastases, who had been surgically treated at our department, were included retrospectively. We reviewed the pre- and postoperative charts, surgical reports, radiographic data for demographics, duration of symptoms, histopathology, stage of systemic disease, co morbidities, radiographic extension, surgical strategy, neurological performance (Frankel Grade Classification), and the Karnofsky Performance Index (KPI). RESULTS: Emergency surgery within <24 h after discharge had been conducted in 33% of patients. Prostate carcinoma (29.5%) and breast carcinoma (11.6%) were the most common histopathologies. Median KPI was 60% at admission that had significantly improved at discharge (KPI 70%; p = 0.01). The rate of complications without revision was 4.3%, the revision rate 4.2%. From admission to discharge, pain had been significantly reduced (p = 0.019) and motor deficits significantly improved (p = 0.003). KPI had been significantly improved during in hospital treatment (median 60 vs 70, p = 0.010). In the multivariable analysis, predictors of poor outcome (KPI < 70) were male sex, multiple metastases, and pre existing bowel and bladder dysfunction. Median follow up was 2 months. DISCUSSION: In our series, surgery for spinal metastases (laminectomy, tumor removal, and mass reduction) significantly reduced pain as well as sensory and motor deficits. We identified male sex, multiple metastases, and pre-existing bowel and bladder dysfunction as predictors of negative outcome. PMID- 29622507 TI - Serum neutrophil gelatinase-associated lipocalin (NGAL) concentration is independently associated with mortality in patients with acute coronary syndrome. AB - BACKGROUND: Circulating neutrophil gelatinase-associated lipocalin (NGAL) concentration increases in cardiovascular disease, but the long-term prognostic value of NGAL concentration has not been evaluated in acute coronary syndrome (ACS). We examined the association between NGAL concentration and prognosis in patients with ACS after non-ST-elevation myocardial infarction (NSTEMI) or STEMI. METHODS AND RESULTS: NGAL concentration was measured in blood from 1121 consecutive ACS patients (30% women, mean age 65 years) on the first morning after admission. After adjustment for 14 variables, NGAL concentration predicted long-term (median 167 months) mortality (hazard ratio [HR] 1.33, 95% confidence interval [CI] 1.10-1.61, P = 0.003) for quartile (q) 4 of NGAL concentration. NGAL concentrations also predicted long-term mortality (HR = 1.63, 95% CI 1.31 2.03, P < 0.001, N = 741) when adjusting for Global Registry of Acute Coronary Events (GRACE) score, left ventricular ejection fraction (LVEF), and pro-B-type natriuretic peptide (proBNP) and C-reactive protein (CRP) concentrations. With these adjustments, NGAL concentration predicted long-term mortality in NSTEMI patients (HR = 2.02, 95% CI 1.50-2.72, P < 0.001) but not in STEMI patients (HR = 1.32, 95% CI 0.95-1.83, P = 0.100). In all patients, the combination of NGAL concentration and GRACE score yielded an HR of 5.56 (95% CI 4.37-7.06, P < 0.001) for q4/q4 for both variables. CONCLUSION: NGAL concentration in ACS is associated with long-term prognosis after adjustment for clinical confounders. Measuring circulating NGAL concentration may help to identify patients-particularly those with NSTEMI-needing closer follow-up after ACS. PMID- 29622506 TI - Cost-effectiveness of a fixed dose combination (polypill) in secondary prevention of cardiovascular diseases in India: Within-trial cost-effectiveness analysis of the UMPIRE trial. AB - BACKGROUND: The Use of Multidrug Pill In Reducing cardiovascular Events (UMPIRE) trial, showed that access to a cardiovascular polypill (aspirin, statin and two blood pressure lowering drugs) significantly improved adherence, lowered systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDLc) in patients with or at high risk of cardiovascular disease (CVD). We aimed to analyze the within-trial cost-effectiveness of the polypill strategy versus usual care in India. METHODS: Relative effectiveness and costs of polypill versus usual care groups in UMPIRE were estimated from the health sector perspective. Only direct medical costs were considered. The effectiveness of the polypill was reported as a percentage increase in adherence and mean reductions in SBP, and LDL-c, over the 15-month trial period. Healthcare resource utilization and costs were collected for each patient during the trial. Polypill price was constructed using a range of scenarios: $0.06-$0.94/day. The cost-effectiveness of the polypill was measured as the additional cost for 10% increase in adherence, and per unit reduction in SBP and LDL-c. RESULTS: Overall, the mean cost per patient was significantly lower with the polypill strategy (-$203 per person, (95% CI: -286, 119, p < 0.01). In scenario analyses that varied polypill price assumptions, incremental cost-effectiveness ratios for a polypill strategy ranged between cost saving to $75 per 10% increase in adherence for polypill price of $0.94 per day. CONCLUSIONS: The polypill strategy was cost-saving compared to usual care among patients with or at high risk of CVD in India. PMID- 29622508 TI - Identifying novel phenotypes of acute heart failure using cluster analysis of clinical variables. AB - BACKGROUND: Acute heart failure (AHF) is a heterogeneous disease caused by various cardiovascular (CV) pathophysiology and multiple non-CV comorbidities. We aimed to identify clinically important subgroups to improve our understanding of the pathophysiology of AHF and inform clinical decision-making. METHODS: We evaluated detailed clinical data of 345 consecutive AHF patients using non hierarchical cluster analysis of 77 variables, including age, sex, HF etiology, comorbidities, physical findings, laboratory data, electrocardiogram, echocardiogram and treatment during hospitalization. Cox proportional hazards regression analysis was performed to estimate the association between the clusters and clinical outcomes. RESULTS: Three clusters were identified. Cluster 1 (n=108) represented "vascular failure". This cluster had the highest average systolic blood pressure at admission and lung congestion with type 2 respiratory failure. Cluster 2 (n=89) represented "cardiac and renal failure". They had the lowest ejection fraction (EF) and worst renal function. Cluster 3 (n=148) comprised mostly older patients and had the highest prevalence of atrial fibrillation and preserved EF. Death or HF hospitalization within 12-month occurred in 23% of Cluster 1, 36% of Cluster 2 and 36% of Cluster 3 (p=0.034). Compared with Cluster 1, risk of death or HF hospitalization was 1.74 (95% CI, 1.03-2.95, p=0.037) for Cluster 2 and 1.82 (95% CI, 1.13-2.93, p=0.014) for Cluster 3. CONCLUSIONS: Cluster analysis may be effective in producing clinically relevant categories of AHF, and may suggest underlying pathophysiology and potential utility in predicting clinical outcomes. PMID- 29622509 TI - Impact of BMI on clinical outcomes of NOAC therapy in daily care - Results of the prospective Dresden NOAC Registry (NCT01588119). AB - Direct acting non-Vitamin K antagonist oral anticoagulants (NOAC) are characterized by a fixed dosing regimen. Despite the potential for relative underdosing due to large distribution volumes, dose adjustments for patients with high body mass index (BMI) are not recommended. Since efficacy and safety data in obese patients are scarce, we evaluated the impact of BMI on clinical outcomes in daily care patients treated with NOAC for stroke prevention in atrial fibrillation or venous thromboembolism. Using prospectively collected data from a non-interventional registry, cardiovascular (CV), major bleeding events (MB) and all-cause mortality were evaluated according to BMI classes. All outcome events were centrally adjudicated using standard scientific definitions. Between November 1st 2011 and December 31st 2016, 3432 patients were enrolled into the registry (61.3% rivaroxaban; 20% apixaban; 10.1% dabigatran, 8.6% edoxaban; mean follow-up 998.1 +/- 542.9 days; median 1004 days). With increasing BMI (range 13.7-57.2 kg/m2), the proportion of patients receiving standard (vs. reduced) NOAC dose increased from 64.7% (underweight) to 78.9% (obesity). Although obese patients had more cardiovascular risk factors compared to normal weight patients, on-treatment rates of clinical outcomes (CV, MB, all-cause-mortality) were lowest in overweight and obese patients. In a large set of real-life NOAC recipients we found no indication that high BMI is associated with inferior NOAC effectiveness or safety, which is in line with recent epidemiological data of a "BMI paradox" that indicates a somewhat protective effect of higher BMI regarding unfavourable outcomes also in patients receiving fixed dose NOAC anticoagulation without dose adjustment for higher BMI. PMID- 29622510 TI - [In vitro susceptibility of cryptic species of Aspergillus fumigatus to isavuconazole, itraconazole and voriconazole by means of E-test]. PMID- 29622511 TI - A Novel Technique to Create an Arteriovenous Fistula During Total Percutaneous Deep Foot Venous Arterialisation Using an IVUS Guided Catheter. PMID- 29622513 TI - Endovascular Versus Open Surgical Intervention in Patients with Takayasu's Arteritis: A Meta-analysis. AB - OBJECTIVE/BACKGROUND: Although medical treatment has advanced, surgical treatment is needed to control symptoms of Takayasu's arteritis (TA), such as angina, stroke, hypertension, or claudication. Endovascular or open surgical intervention is performed; however, there are few comparative studies on these methods. This meta-analysis and systematic review aimed to examine the outcome of surgical treatment of TA. METHODS: A meta-analysis comparing outcomes of endovascular and open surgical intervention was performed using MEDLINE and Embase. This meta analysis included only observational studies, and the evidence level was low to moderate. Data were pooled and analysed using a fixed or random effects model with the I2 statistic. RESULTS: The included studies involved a total of 770 patients and 1363 lesions, with 389 patients treated endovascularly and 420 treated by surgical revascularization. Restenosis was more common with endovascular than open surgical intervention (odds ratio [OR] 5.18, 95% confidence interval [CI] 2.78-9.62; p < .001). In subgroup analysis according to the involved lesions, endovascular intervention patients showed more restenosis than open surgical intervention patients in the coronary artery, supra-aortic branches, and renal artery. In both the active and inactive stages, restenosis was more common in those treated endovascularly than in those treated by open surgery. However, stroke occurred less often with endovascular intervention than with open surgical intervention (OR 0.33, 95% CI 0.12-0.90; p = .003). Mortality and complications other than stroke and mortality did not differ between endovascular and open surgical intervention. CONCLUSION: This meta-analysis has shown a lower risk of restenosis with open surgical intervention than with endovascular intervention. Stroke was generally more common with open surgical intervention than with endovascular intervention. However, there were differences according to the location of the lesion, and the risk of stroke in open surgery is higher when the supra-aortic branches are involved rather than the renal arteries. PMID- 29622512 TI - Cost-Effectiveness Evaluation of Heparin Coated Versus Standard Graft for Bypass Surgery in Peripheral Artery Disease Alongside a Randomised Controlled Trial. AB - OBJECTIVE/BACKGROUND: Heparin coating has recently been shown to reduce the risk of graft failure in arterial revascularisation, at least transiently. The aim of this study was to assess the cost-effectiveness of heparin coated versus standard polytetrafluoroethylene grafts for bypass surgery in peripheral artery disease from a long-term healthcare system perspective. METHODS: Cost-effectiveness evaluation was conducted alongside the Danish part of the Scandinavian Propaten trial in which 431 patients planned for femoro-femoral or femoro-popliteal bypass surgery were randomised to either type of graft and followed for 5 years. Based on the intention to treat principle, the differences in healthcare costs (general practice, prescription medication, hospital admission, rehabilitation, and long term care in 2015 Euros), life years (LYs), and quality adjusted life years (QALYs) were analysed as arithmetic means with bootstrapped 95% confidence intervals. Cost-effectiveness acceptability curves were used to illustrate the probability of cost-effectiveness for a range of threshold values of willingness to pay (WTP). RESULTS: No statistically significant differences between the randomisation groups were observed for costs or gains of LYs or QALYs. The average cost per QALY was estimated at ?10,792. For a WTP threshold of ?40,000 per QALY, the overall probability of cost-effectiveness was estimated at 62%, but owing to cost savings in patients with critical ischaemia (cost per QALY 0.99), despite a tendency for overestimation by the new method (y=1.10 x +0.05). Bland-Altman plots confirmed this strong correlation by showing only two points outside the acceptable limits without clinical incidence, given the high PCT concentrations (over 10 ng/mL) in those samples. In conclusion, the new PCT assay on the Abbott Architect i2000-SR(r) shows excellent analytical performances, even at low concentrations. A slight positive bias compared to the Brahms Kryptor(r) was observed, but did not lead to inappropriate clinical decisions. PMID- 29622525 TI - Gamified Cognitive Control Training for Remitted Depressed Individuals: User Requirements Analysis. AB - BACKGROUND: The high incidence and relapse rates of major depressive disorder demand novel treatment options. Standard treatments (psychotherapy, medication) usually do not target cognitive control impairments, although these seem to play a crucial role in achieving stable remission. The urgent need for treatment combined with poor availability of adequate psychological interventions has instigated a shift toward internet interventions. Numerous computerized programs have been developed that can be presented online and offline. However, their uptake and adherence are oftentimes low. OBJECTIVE: The aim of this study was to perform a user requirements analysis for an internet-based training targeting cognitive control. This training focuses on ameliorating cognitive control impairments, as these are still present during remission and can be a risk factor for relapse. To facilitate uptake of and adherence to this intervention, a qualitative user requirements analysis was conducted to map mandatory and desirable requirements. METHODS: We conducted a user requirements analysis through a focus group with 5 remitted depressed individuals and individual interviews with 6 mental health care professionals. All qualitative data were transcribed and examined using a thematic analytic approach. RESULTS: Results showed mandatory requirements for the remitted sample in terms of training configuration, technological and personal factors, and desirable requirements regarding knowledge and enjoyment. Furthermore, knowledge and therapeutic benefits were key requirements for therapists. CONCLUSIONS: The identified requirements provide useful information to be integrated in interventions targeting cognitive control in depression. PMID- 29622526 TI - Impact of Low Back Pain Clinical Trials Measured by the Altmetric Score: Cross Sectional Study. AB - BACKGROUND: There is interest from authors and publishers in sharing the results of their studies over the Internet in order to increase their readership. In this way, articles tend to be discussed and the impact of these articles tends to be increased. In order to measure this type of impact, a new score (named Altmetric) was created. Altmetric aims to understand the individual impact of each article through the attention attracted online. OBJECTIVE: The primary objective of this study was to analyze potential factors related with the publishing journal and the publishing trial that could be associated with Altmetric scores on a random sample of low back pain randomized controlled trials (RCTs). The secondary objective of this study was to describe the characteristics of these trials and their Altmetric scores. METHODS: We searched for all low back pain RCTs indexed on the Physiotherapy Evidence Database (PEDro; www.pedro.org.au) published between 2010 and 2015. A total of 200 articles were randomly selected, and we extracted data related to the publishing trial, the publishing journal, methodological quality of the trials (measured by the 0-10 item PEDro scale), and total and individual scores of Altmetric mentioned and Altmetric reader. The study was a cross-sectional study, and multivariate regression models and descriptive statistics were used. RESULTS: A total of four variables were associated with Altmetric mentioned score: impact factor (beta-coefficient=3.4 points), number of years since publication (beta-coefficient=-4.9 points), number of citations divided by years since publication (beta-coefficient=5.2 points), and descriptive title (beta-coefficient=-29.4 points). Only one independent variable was associated with Altmetric reader score: number of citations divided by years since publication (beta-coefficient=10.1 points, 95% CI 7.74-12.46). We also found that the majority of articles were published in English, with a descriptive title, and published in open access journals endorsing the Consolidated Standards of Reporting Trials (CONSORT) statement. CONCLUSIONS: Researchers should preferably select high impact factor journals for submission and use declarative or interrogative titles, as these factors are likely to increase the visibility of their studies in social media. PMID- 29622527 TI - Epic Allies, a Gamified Mobile Phone App to Improve Engagement in Care, Antiretroviral Uptake, and Adherence Among Young Men Who Have Sex With Men and Young Transgender Women Who Have Sex With Men: Protocol for a Randomized Controlled Trial. AB - BACKGROUND: In the United States, young men who have sex with men (YMSM) and transgender women who have sex with men (YTWSM) bear a disproportionate burden of prevalent and incident HIV infections. Once diagnosed, many YMSM and YTWSM struggle to engage in HIV care, adhere to antiretroviral therapy (ART), and achieve viral suppression. Computer-based interventions, including those focused on behavior change, are recognized as effective tools for engaging youth. OBJECTIVE: The purpose of the study described in this protocol is to evaluate the efficacy of Epic Allies, a theory-based mobile phone app that utilizes game mechanics and social networking features to improve engagement in HIV care, ART uptake, ART adherence, and viral suppression among HIV-positive YMSM and YTWSM. The study also qualitatively assesses intervention acceptability, perceived impact, and sustainability. METHODS: This is a two-group, active-control randomized controlled trial of the Epic Allies app. YMSM and YTWSM aged 16 to 24 inclusive, with detectable HIV viral load are randomized 1:1 within strata of new to care (newly entered HIV medical care <=12 months of baseline visit) or ART nonadherent (first entered HIV medical care >12 months before baseline visit) to intervention or control conditions. The intervention condition addresses ART adherence barriers through medication reminders and adherence monitoring, tracking of select adherence-related behaviors (eg, alcohol and marijuana use), an interactive dashboard that displays the participant's adherence-related behaviors and provides tailored feedback, encouragement messages from other users, daily HIV/ART educational articles, and gamification features (eg, mini games, points, badges) to increase motivation for behavior change and app engagement. The control condition features weekly phone-based notifications to encourage participants to view educational information in the control app. Follow up assessments are administered at 13, 26, and 39 weeks for each arm. The primary outcome measure is viral suppression. Secondary outcome measures include engagement in care, ART uptake, ART adherence, and psychosocial barriers to engagement in care and ART adherence, including psychological distress, stigma, and social support. RESULTS: Baseline enrollment began in September 2015 and was completed in September 2016 (n=146), and assessment of intervention outcomes continued through August 2017. Results for primary and secondary outcome measures are expected to be reported in ClinicalTrials.gov by April 30, 2018. CONCLUSIONS: If successful, Epic Allies will represent a novel adherence intervention for a group disproportionately impacted by HIV in the United States. Adherent patients would require less frequent clinic visits and experience fewer HIV-related secondary infections, thereby reducing health care costs and HIV transmission. Epic Allies could easily be expanded and adopted for use among larger populations of YMSM and YTWSM, other HIV-positive populations, and for those diagnosed with other chronic diseases such as diabetes and hypertension. TRIAL REGISTRATION: ClinicalTrials.gov NCT02782130; https://clinicaltrials.gov/ct2/show/NCT02782130 (Archived by Webcite at http://www.webcitation.org/6yGODyerk). PMID- 29622528 TI - Impact of Mental Health Screening on Promoting Immediate Online Help-Seeking: Randomized Trial Comparing Normative Versus Humor-Driven Feedback. AB - BACKGROUND: Given the widespread availability of mental health screening apps, providing personalized feedback may encourage people at high risk to seek help to manage their symptoms. While apps typically provide personal score feedback only, feedback types that are user-friendly and increase personal relevance may encourage further help-seeking. OBJECTIVE: The aim of this study was to compare the effects of providing normative and humor-driven feedback on immediate online help-seeking, defined as clicking on a link to an external resource, and to explore demographic predictors that encourage help-seeking. METHODS: An online sample of 549 adults were recruited using social media advertisements. Participants downloaded a smartphone app known as "Mindgauge" which allowed them to screen their mental wellbeing by completing standardized measures on Symptoms (Kessler 6-item Scale), Wellbeing (World Health Organization [Five] Wellbeing Index), and Resilience (Brief Resilience Scale). Participants were randomized to receive normative feedback that compared their scores to a reference group or humor-driven feedback that presented their scores in a relaxed manner. Those who scored in the moderate or poor ranges in any measure were encouraged to seek help by clicking on a link to an external online resource. RESULTS: A total of 318 participants scored poorly on one or more measures and were provided with an external link after being randomized to receive normative or humor-driven feedback. There was no significant difference of feedback type on clicking on the external link across all measures. A larger proportion of participants from the Wellbeing measure (170/274, 62.0%) clicked on the links than the Resilience (47/179, 26.3%) or Symptoms (26/75, 34.7%) measures (chi2=60.35, P<.001). There were no significant demographic factors associated with help-seeking for the Resilience or Wellbeing measures. Participants with a previous episode of poor mental health were less likely than those without such history to click on the external link in the Symptoms measure (P=.003, odds ratio [OR] 0.83, 95% CI 0.02 0.44), and younger adults were less likely to click on the link compared to older adults across all measures (P=.005, OR 0.44, 95% CI 0.25-0.78). CONCLUSIONS: This pilot study found that there was no difference between normative and humor-driven feedback on promoting immediate clicks to an external resource, suggesting no impact on online help-seeking. Limitations included: lack of personal score control group, limited measures of predictors and potential confounders, and the fact that other forms of professional help-seeking were not assessed. Further investigation into other predictors and factors that impact on help-seeking is needed. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12616000707460; https://www.anzctr.org.au/ Trial/Registration/TrialReview.aspx?id=370187 (Archived by WebCite at http://www.webcitation.org/6y8m8sVxr). PMID- 29622530 TI - Randomised controlled trials may have many unrecognised potential biases. PMID- 29622532 TI - Blinatumomab for MRD+ B-ALL: the evidence strengthens. PMID- 29622533 TI - Et tu, E2F1? The assassins of CML stem cells. PMID- 29622529 TI - Alerting relatives about heritable risks: the limits of confidentiality. PMID- 29622534 TI - BAFF bestows longevity on splenic plasma cells. PMID- 29622535 TI - Biomarkers in AL amyloidosis: is the summit in sight? PMID- 29622536 TI - Patrolling the endothelium in sickle cell disease. PMID- 29622537 TI - Molecular mechanism of P1 antigen expression. PMID- 29622538 TI - Abnormalities of platelet aggregation associated with giant granules in a subset of platelets. PMID- 29622539 TI - A neonate presenting with jaundice, anemia, and thrombocytopenia. PMID- 29622540 TI - Doctor with list of "bad guys" he blamed for dismissal is jailed for 12 years. PMID- 29622541 TI - Impact of a provincial quality-improvement program on primary health care in Ontario: a population-based controlled before-and-after study. AB - BACKGROUND: In Ontario, a province-wide quality-improvement program (Quality Improvement and Innovation Partnership [QIIP]) was implemented between 2008 and 2010 to support improved outcomes in Family Health Teams, a care model that includes many features of the patient-centred medical home. We assessed the impact of this program on diabetes management, colorectal and cervical cancer screening and access to health care. METHODS: We used comprehensive linked administrative data sets to conduct a population-based controlled before-and after study. Outcome measures included diabetes process-of-care measures (test ordering, retinal examination, medication prescribing and completion of billing items specific to diabetes management), colorectal and cervical cancer screening measures and use of health care services (emergency department visits, hospital admission for ambulatory-care-sensitive conditions and rates of readmission to hospital). The control group consisted of Family Health Team physicians with at least 100 assigned patients during the study follow-up period (November 2009 February 2013). RESULTS: There were 53 physicians in the intervention group and 1178 physicians in the control group. Diabetes process-of-care measures improved more in the intervention group than in the control group: hemoglobin A1c testing 4.3% (95% confidence interval [CI] 1.2-7.5) more, retinal examination 2.5% (95% CI 0.8-4.4) more and preventive care visits 8.9% (95% CI 2.9-14.9) more. Medication prescribing also improved for use of statins (3.4% [95% CI 0.8-6.0] more) and angiotensin-converting-enzyme inhibitors or angiotensin receptor blockers (4.1% [95% CI 1.8-6.4] more). Colorectal cancer screening improved 5.4% (95% CI 3.1-7.8) more in the intervention group than in the control group, and cervical cancer screening improved 2.7% (95% CI 0.9-4.6) more. There were no significant differences in any of the measures of use of health care services. INTERPRETATION: This large controlled evaluation of a broadly implemented quality improvement initiative showed improvement for diabetes process of care and cancer screening outcomes, but not for proxy measures of access related to use of health care services. PMID- 29622542 TI - One-Hour Plasma Glucose Compared With Two-Hour Plasma Glucose in Relation to Diabetic Retinopathy in American Indians. AB - OBJECTIVE: We compared the ability of 1- and 2-h plasma glucose concentrations (1h-PG and 2h-PG, respectively), derived from a 75-g oral glucose tolerance test (OGTT), to predict retinopathy. 1h-PG and 2h-PG concentrations, measured in a longitudinal study of an American Indian community in the southwestern U.S., a population at high risk for type 2 diabetes, were analyzed to assess the usefulness of the 1h-PG to identify risk of diabetic retinopathy (DR). RESEARCH DESIGN AND METHODS: Cross-sectional (n = 2,895) and longitudinal (n = 1,703) cohorts were assessed for the prevalence and incidence of DR, respectively, in relation to deciles of 1h-PG and 2h-PG concentrations. Areas under the receiver operating characteristic (ROC) curves for 1h-PG and 2h-PG were compared with regard to predicting DR, as assessed by direct ophthalmoscopy. RESULTS: Prevalence and incidence of DR, based on direct ophthalmoscopy, changed in a similar manner across the distributions of 1h-PG and 2h-PG concentrations. ROC analysis showed that 1h-PG and 2h-PG were of similar value in identifying prevalent and incident DR using direct ophthalmoscopy. 1h-PG cut points of 230 and 173 mg/dL were comparable to 2h-PG cut points of 200 mg/dL (type 2 diabetes) and 140 mg/dL (impaired glucose tolerance), respectively. CONCLUSIONS: 1h-PG is a useful predictor of retinopathy risk, has a predictive value similar to that of 2h-PG, and may be considered as an alternative glucose time point during an OGTT. PMID- 29622543 TI - Postoperative Death After Lower-Limb Amputation in a National Prevalent Cohort of Patients With Diabetes. AB - OBJECTIVE: The objectives of this study were to 1) describe postoperative mortality after lower-limb amputation in a national prevalent cohort of patients with diabetes, and 2) investigate whether postoperative mortality differs by demographic subgroup, patient morbidity level, and health system factors related to the facility in which the amputation occurred. RESEARCH DESIGN AND METHODS: A national prevalent cohort of 302,339 individuals diagnosed with diabetes between 2005 and 2014 was followed until the end of 2014 for major and minor lower-limb amputation and subsequent postoperative mortality by using national health data collections. Kaplan-Meier survival analysis was used to determine postoperative survival, whereas Cox proportional hazards models were used to describe the relative hazard of postoperative mortality, adjusted for covariates. RESULTS: A total of 6,352 lower-limb amputations occurred over the study period (2,570 major amputations, 3,782 minor amputations). More than 11% of patients who underwent major amputation died within 30 days, whereas nearly 18% died within 90 days. Death was most common among older patients and indigenous Maori. Sex, deprivation, rurality, hospital volume, admission type, and patient comorbidity were not consistently or substantially independently associated with risk of postoperative mortality. CONCLUSIONS: In a national prevalent cohort of patients with diabetes, there was high risk of postoperative mortality as well as a differential risk of postoperative mortality by demographic subgroup. Further work is required to investigate the drivers of postoperative mortality among patients with diabetes who undergo amputation. PMID- 29622546 TI - Pushed out of a tough crowd: centrosome aberrations promote invasiveness. PMID- 29622547 TI - STOMP - time to make more noise. PMID- 29622545 TI - PAM50 and Risk of Recurrence Scores for Interval Breast Cancers. AB - Breast cancers detected after a negative breast screening examination and prior to the next screening are referred to as interval cancers. These cancers generally have poor clinical characteristics compared with screen-detected cancers, but associations between interval cancer and genomic cancer characteristics are not well understood. Mammographically screened women diagnosed with primary invasive breast cancer from 1993 to 2013 (n = 370) were identified by linking the Carolina Breast Cancer Study and the Carolina Mammography Registry. Among women with a registry-identified screening mammogram 0 to 24 months before diagnosis, cancers were classified as screen-detected (N = 165) or interval-detected (N = 205). Using logistic regression, we examined the association of mode of detection with cancer characteristics (clinical, IHC, and genomic), overall, and in analyses stratified on mammographic density and race. Interval cancer was associated with large tumors [>2 cm; OR, 2.3; 95% confidence interval (CI), 1.5-3.7], positive nodal status (OR, 1.8; 95% CI, 1.1-2.8), and triple-negative subtype (OR, 2.5; 95% CI, 1.1-5.5). Interval cancers were more likely to have non-Luminal A subtype (OR, 2.9; 95% CI, 1.5-5.7), whereas screen detected cancers tended to be more indolent (96% had low risk of recurrence genomic scores; 71% were PAM50 Luminal A). When stratifying by mammographic density and race, associations between interval detection and poor prognostic features were similar by race and density status. Strong associations between interval cancers and poor-prognosis genomic features (non-Luminal A subtype and high risk of recurrence score) suggest that aggressive tumor biology is an important contributor to interval cancer rates. Cancer Prev Res; 11(6); 327-36. (c)2018 AACR. PMID- 29622548 TI - Tight regulation of FOXO1 is essential for maintenance of B-cell precursor acute lymphoblastic leukemia. AB - The FOXO1 transcription factor plays an essential role in the regulation of proliferation and survival programs at early stages of B-cell differentiation. Here, we show that tightly regulated FOXO1 activity is essential for maintenance of B-cell precursor acute lymphoblastic leukemia (BCP-ALL). Genetic and pharmacological inactivation of FOXO1 in BCP-ALL cell lines produced a strong antileukemic effect associated with CCND3 downregulation. Moreover, we demonstrated that CCND3 expression is critical for BCP-ALL survival and that overexpression of CCND3 protected BCP-ALL cell lines from growth arrest and apoptosis induced by FOXO1 inactivation. Most importantly, pharmacological inhibition of FOXO1 showed antileukemia activity on several primary, patient derived, pediatric ALL xenografts with effective leukemia reduction in the hematopoietic, lymphoid, and central nervous system organ compartments, ultimately leading to prolonged survival without leukemia reoccurrence in a preclinical in vivo model of BCP-ALL. These results suggest that repression of FOXO1 might be a feasible approach for the treatment of BCP-ALL. PMID- 29622549 TI - Biomarkers for posttransplantation outcomes. AB - During the last decade, the development of biomarkers for the complications seen after allogeneic hematopoietic stem cell transplantation has expanded tremendously, with the most progress having been made for acute graft-versus-host disease (aGVHD), a common and often fatal complication. Although many factors are known to determine transplant outcome (including the age of the recipient, comorbidity, conditioning intensity, donor source, donor-recipient HLA compatibility, conditioning regimen, posttransplant GVHD prophylaxis), they are incomplete guides for predicting outcomes. Thanks to the advances in genomics, transcriptomics, proteomics, and cytomics technologies, blood biomarkers have been identified and validated for us in promising diagnostic tests, prognostic tests stratifying for future occurrence of aGVHD, and predictive tests for responsiveness to GVHD therapy and nonrelapse mortality. These biomarkers may facilitate timely and selective therapeutic intervention. However, such blood tests are not yet available for routine clinical care. This article provides an overview of the candidate biomarkers for clinical evaluation and outlines a path from biomarker discovery to first clinical correlation, to validation in independent cohorts, to a biomarker-based clinical trial, and finally to general clinical application. This article focuses on biomarkers discovered with a large scale proteomics platform and validated with the same reproducible assay in at least 2 independent cohorts with sufficient sample size according to the 2014 National Institutes of Health consensus on biomarker criteria, as well as on biomarkers as tests for risk stratification of outcomes, but not on their pathophysiologic contributions, which have been reviewed recently. PMID- 29622551 TI - Choroidal pericytes promote subretinal fibrosis after experimental photocoagulation. AB - Subretinal fibrosis results in local destruction of retinal structures and permanent vision loss, representing the end stage of neovascular age-related macular degeneration (AMD). Histological examination of fibrotic specimens from AMD patients has uncovered a wide range of cellular and acellular components. However, their origins and roles in fibrosis remain largely unexplored. Using a laser-induced photocoagulation model with collagen 1alpha1-GFP reporter mice, we demonstrate, by cell-lineage tracing, that pericytes associating with choroidal microvasculature are activated upon injury and infiltrate into the subretinal space as significant components of fibrotic lesions. In contrast to their choroidal precursors, infiltrating pericytes acquire stellate-like structures, upregulate expression of fibrogenic molecules and colocalize with extracellular fibrotic scar. Collectively, our results identify the choroidal perivascular niche as a novel source of subretinal fibrosis after photocoagulation, and suggest that collagen 1-expressing pericytes are potential targets for therapeutic intervention to suppress subretinal fibrosis and preserve vision. PMID- 29622552 TI - Clival Malformations in CHARGE Syndrome. AB - BACKGROUND AND PURPOSE: CHARGE syndrome is a multisystemic congenital disorder, most commonly including coloboma, heart malformations, choanal atresia, developmental delay, and genital and ear anomalies. The diagnostic criteria for CHARGE syndrome have been refined with time. However, limited reports describe skull base and craniocervical junction abnormalities. Recently, a coronal clival cleft has been identified in association with CHARGE syndrome. The aim of our study was to assess the prevalence of clival pathology in CHARGE syndrome. MATERIALS AND METHODS: In this retrospective study, the CT/MR imaging data base at a single academic children's hospital was queried for the phrase "CHARGE syndrome" during a 17-year period (2001-2017). Electronic medical records were reviewed to confirm the diagnosis. Images were assessed for skull base anomalies, specifically clival hypoplasia and dysplasia. RESULTS: The search yielded 42 examinations (21 CTs and 21 MRIs) from 15 distinct patients (mean age, 4.1 +/- 5.6 years; range, 2 days to 19 years). CHARGE syndrome diagnosis was confirmed either by clinical and genetic testing (n = 6) or by clinical diagnosis only (n = 9). A coronal clival cleft was identified in 87% of patients (37 examinations, n = 13 patients), either partial (53%) or complete (33%). Clival hypoplasia without clefting was present in all 5 examinations from the remaining 2 patients. CONCLUSIONS: Clival pathology is universal in CHARGE syndrome. Coronal clival clefts are extremely common, representing a useful additional diagnostic finding. Detection of a clival cleft should alert the radiologist to examine the palate, choana, eyes, ears, and olfactory centers for other signs of CHARGE syndrome. PMID- 29622550 TI - 14-3-3 proteins in platelet biology and glycoprotein Ib-IX signaling. AB - Members of the 14-3-3 family of proteins function as adapters/modulators that recognize phosphoserine/phosphothreonine-based binding motifs in many intracellular proteins and play fundamental roles in signal transduction pathways of eukaryotic cells. In platelets, 14-3-3 plays a wide range of regulatory roles in phosphorylation-dependent signaling pathways, including G-protein signaling, cAMP signaling, agonist-induced phosphatidylserine exposure, and regulation of mitochondrial function. In particular, 14-3-3 interacts with several phosphoserine-dependent binding sites in the major platelet adhesion receptor, the glycoprotein Ib-IX complex (GPIb-IX), regulating its interaction with von Willebrand factor (VWF) and mediating VWF/GPIb-IX-dependent mechanosignal transduction, leading to platelet activation. The interaction of 14-3-3 with GPIb IX also plays a critical role in enabling the platelet response to low concentrations of thrombin through cooperative signaling mediated by protease activated receptors and GPIb-IX. The various functions of 14-3-3 in platelets suggest that it is a possible target for the treatment of thrombosis and inflammation. PMID- 29622554 TI - Slow Collateral Flow Is Associated with Thrombus Extension in Patients with Acute Large-Artery Occlusion. AB - BACKGROUND AND PURPOSE: It is still poorly understood about the dynamic changes of the thrombus after intravenous thrombolysis and how the remaining thrombus affects clinical outcome in human stroke. Collateral flow was assumed to help to deliver endo/exogenous tissue-type plasminogen activator to the clot. We aimed to analyze the impact of collateral flow on the dynamic changes of the thrombus in patients with acute large-artery occlusion who received intravenous thrombolysis. MATERIALS AND METHODS: We reviewed consecutive patients with acute ischemic stroke with M1 segment or distal internal carotid artery occlusion who underwent multimodal MR imaging or CT perfusion before and 24 hours after intravenous thrombolysis without recanalization. Patients were divided into 3 groups (thrombus extension, shortening, and no change) according to thrombus-length change between baseline and 24 hours. Collateral flow was measured with arrival time delay and the collateral scoring system. Poor outcome was defined as a 3 month modified Rankin Scale score of >=3. RESULTS: Among 51 patients, 18 (35.3%) had thrombus extension, 14 (27%) had thrombus shortening, and 19 (37.3%) had thrombus without change. Arrival time delay was independently associated with thrombus extension (OR = 1.499; 95% CI, 1.053-2.135; P = .025). Similarly, the collateral score on the peak artery phase was independently associated with thrombus extension (OR = 0.456; 95% CI, 0.211-0.984; P = .045), whereas baseline National Institutes of Health Stroke Scale score (OR = 0.768; 95% CI, 0.614 0.961; P = .021) and baseline thrombus length (OR = 1.193; 95% CI, 1.021-1.394; P = .026) were associated with thrombus shortening. All patients with thrombus extension had poor outcomes. CONCLUSIONS: Slow collateral flow was related to thrombus extension in patients with large-artery occlusion without recanalization after intravenous thrombolysis. PMID- 29622553 TI - Edge Contrast of the FLAIR Hyperintense Region Predicts Survival in Patients with High-Grade Gliomas following Treatment with Bevacizumab. AB - BACKGROUND AND PURPOSE: Treatment with bevacizumab is standard of care for recurrent high-grade gliomas; however, monitoring response to treatment following bevacizumab remains a challenge. The purpose of this study was to determine whether quantifying the sharpness of the fluid-attenuated inversion recovery hyperintense border using a measure derived from texture analysis-edge contrast improves the evaluation of response to bevacizumab in patients with high-grade gliomas. MATERIALS AND METHODS: MRIs were evaluated in 33 patients with high grade gliomas before and after the initiation of bevacizumab. Volumes of interest within the FLAIR hyperintense region were segmented. Edge contrast magnitude for each VOI was extracted using gradients of the 3D FLAIR images. Cox proportional hazards models were generated to determine the relationship between edge contrast and progression-free survival/overall survival using age and the extent of surgical resection as covariates. RESULTS: After bevacizumab, lower edge contrast of the FLAIR hyperintense region was associated with poorer progression-free survival (P = .009) and overall survival (P = .022) among patients with high grade gliomas. Kaplan-Meier curves revealed that edge contrast cutoff significantly stratified patients for both progression-free survival (log-rank chi2 = 8.3, P = .003) and overall survival (log-rank chi2 = 5.5, P = .019). CONCLUSIONS: Texture analysis using edge contrast of the FLAIR hyperintense region may be an important predictive indicator in patients with high-grade gliomas following treatment with bevacizumab. Specifically, low FLAIR edge contrast may partially reflect areas of early tumor infiltration. This study adds to a growing body of literature proposing that quantifying features may be important for determining outcomes in patients with high-grade gliomas. PMID- 29622555 TI - MRI Planimetry and Magnetic Resonance Parkinsonism Index in the Differential Diagnosis of Patients with Parkinsonism. AB - BACKGROUND AND PURPOSE: Differential diagnosis of multiple system atrophy, progressive supranuclear palsy, and corticobasal degeneration from Parkinson disease on clinical grounds is often difficult. MR imaging biomarkers could assist in a more accurate diagnosis. We examined the utility of MR imaging surface measurements (MR imaging planimetry) in the differential diagnosis of patients with parkinsonism. MATERIALS AND METHODS: Fifty-two patients with Parkinson-plus (progressive supranuclear palsy, n = 24; corticobasal degeneration, n = 9; multiple system atrophy, n = 19), 18 patients with Parkinson disease, and 15 healthy controls were included. Corpus callosum, midbrain, and pons surfaces; relevant indices; and the Magnetic Resonance Parkinsonism Index were calculated. Corpus callosum subsection analysis was performed, and the corpus callosum posteroanterior gradient was introduced. RESULTS: A Magnetic Resonance Parkinsonism Index value of >12.6 discriminated progressive supranuclear palsy from other causes of parkinsonism with a 91% sensitivity and 95% specificity. No planimetry measurement could accurately discriminate those with multiple system atrophy with parkinsonism from patients with Parkinson disease. A corpus callosum posteroanterior gradient value of <=191 was highly specific (97%) and moderately sensitive (75%) for the diagnosis of corticobasal degeneration versus all other groups. A midbrain-to-corpus callosum posteroanterior gradient ratio of <=0.45 was highly indicative of progressive supranuclear palsy over corticobasal degeneration (sensitivity 86%, specificity 88%). CONCLUSIONS: MR imaging planimetry measurements are potent imaging markers of progressive supranuclear palsy and promising markers of corticobasal degeneration but do not seem to assist in the diagnosis of multiple system atrophy with parkinsonism. PMID- 29622556 TI - Accuracy of CT Angiography for Differentiating Pseudo-Occlusion from True Occlusion or High-Grade Stenosis of the Extracranial ICA in Acute Ischemic Stroke: A Retrospective MR CLEAN Substudy. AB - BACKGROUND AND PURPOSE: The absence of opacification on CTA in the extracranial ICA in acute ischemic stroke may be caused by atherosclerotic occlusion, dissection, or pseudo-occlusion. The latter is explained by sluggish or stagnant flow in a patent artery caused by a distal intracranial occlusion. This study aimed to explore the accuracy of CTA for differentiating pseudo-occlusion from true occlusion of the extracranial ICA. MATERIALS AND METHODS: All patients from the Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands (MR CLEAN) with an apparent ICA occlusion on CTA and available DSA images were included. Two independent observers classified CTA images as atherosclerotic cause (occlusion/high-grade stenosis), dissection, or suspected pseudo-occlusion. Pseudo-occlusion was suspected if CTA showed a gradual contrast decline located above the level of the carotid bulb, especially in the presence of an occluded intracranial ICA bifurcation (T-occlusion). DSA images, classified into the same 3 categories, were used as the criterion standard. RESULTS: In 108 of 476 patients (23%), CTA showed an apparent extracranial carotid occlusion. DSA was available in 46 of these, showing an atherosclerotic cause in 13 (28%), dissection in 16 (35%), and pseudo-occlusion in 17 (37%). The sensitivity for detecting pseudo-occlusion on CTA was 82% (95% CI, 57-96) for both observers; specificity was 76% (95% CI, 56-90) and 86% (95% CI, 68-96) for observers 1 and 2, respectively. The kappa value for interobserver agreement was .77, indicating substantial agreement. T-occlusions were more frequent in pseudo- than true occlusions (82% versus 21%, P < .001). CONCLUSIONS: On CTA, extracranial ICA pseudo-occlusions can be differentiated from true carotid occlusions. PMID- 29622557 TI - Cavitary Plaques in Otospongiosis: CT Findings and Clinical Implications. AB - BACKGROUND AND PURPOSE: Cavitary plaques have been reported as a manifestation of otospongiosis. They have been related to third window manifestations, complications during cochlear implantation, and sensorineural hearing loss. However, their etiology and clinical implications are not entirely understood. Our purpose was to determine the prevalence, imaging findings, and clinical implications of cavitary plaques in otospongiosis. MATERIALS AND METHODS: We identified patients with otospongiosis at a tertiary care academic medical center from January 2012 to April 2017. Cross-sectional CT images and clinical records of 47 patients (89 temporal bones) were evaluated for the presence, location, and imaging features of cavitary and noncavitary otospongiotic plaques, as well as clinical symptoms and complications in those who underwent cochlear implantation. RESULTS: Noncavitary otospongiotic plaques were present in 86 (97%) temporal bones and cavitary plaques in 30 (35%). Cavitary plaques predominated with increasing age (mean age, 59 years; P = .058), mostly involving the anteroinferior wall of the internal auditory canal (P = .003), and their presence was not associated with a higher grade of otospongiosis by imaging (P = .664) or with a specific type of hearing loss (P = .365). No patients with cavitary plaques had third window manifestations, and those with a history of cochlear implantation (n = 6) did not have complications during the procedure. CONCLUSIONS: Cavitary plaques occurred in one-third of patients with otospongiosis. Typically, they occurred in the anteroinferior wall of the internal auditory canal. There was no correlation with the degree of otospongiosis, type of hearing loss, or surgical complications. Cavitary plaques tended to present in older patients. PMID- 29622558 TI - Characteristic MR Imaging Findings of the Neonatal Brain in RASopathies. AB - BACKGROUND AND PURPOSE: Neuroimaging features in neonates with RASopathies are rarely reported, and to date, there are no neuroimaging studies conducted in this population. Our aim was to investigate the occurrence of supratentorial and posterior fossa abnormalities on brain MRIs of neonates with a RASopathy. MATERIALS AND METHODS: An observational case-control study of neonates with a confirmed RASopathy was conducted. The presence of an intraventricular and/or parenchymal hemorrhage and punctate white matter lesions and assessments of the splenium of the corpus callosum, gyrification of the cortical gray matter, and enlargement of the extracerebral space were noted. The vermis height, transverse cerebellar diameter, cranial base angle, tentorial angle, and infratentorial angle were measured. RESULTS: We reviewed 48 brain MR studies performed at 3 academic centers in 3 countries between 2009 and 2017. Sixteen of these infants had a genetically confirmed RASopathy (group 1), and 32 healthy infants were enrolled as the control group (group 2). An increased rate of white matter lesions, extracerebral space enlargement, simplification of the cortical gyrification, and white matter abnormalities were seen in group 1 (P < .001, for each). The vermis height of patients was significantly lower, and tentorial and infratentorial angles were significantly higher in group 1 (P = .01, P < .001, and P = .001, respectively). CONCLUSIONS: Neonates with a RASopathy had characteristic structural and acquired abnormalities in the cortical gray matter, white matter, corpus callosum, cerebellum, and posterior fossa. This study provides novel neuroimaging findings on supratentorial and posterior fossa abnormalities in neonates with a RASopathy. PMID- 29622559 TI - Who's Contributing Most to American Neuroscience Journals: American or Foreign Authors? AB - BACKGROUND AND PURPOSE: With globalization, the contributions of authors from abroad to the American published literature has increased. We sought to determine the changes with time in the proportional contributions of American and non American authors in the American neurosciences literature. We hypothesized the following: 1) During the past 21 years, manuscript contributions of American institutions have proportionally decreased in neuroradiology, more than in neurosurgery or neurology; 2) contributions of Asian institutions have affected neuroradiology more than neurosurgery and neurology; and 3) American articles garner more citations. MATERIALS AND METHODS: We reviewed the May issues of 2 of the highest impact American-based neurology, neurosurgery, and neuroradiology journals published from 1997 to 2017. We counted the number of articles published by nation based on the institution of origin. We looked at trends across time and compared neurology, neurosurgery, and neuroradiology journals. We also gathered data on the number of citations of each article by nationality. RESULTS: We reviewed 3025 articles. There was a significantly lower ratio of American to non American authorship in neuroradiology versus neurology/neurosurgery journals (odds ratio = 0.70; 95% confidence interval, 0.60-0.82). There was a significantly decreasing trend in American authorship across the 21 years in neuroradiology. Of the countries outside the United States, Japan contributed most for neuroradiology and neurosurgery journals, and the UK, for neurology. American-authored articles were cited, on average, 1.25 times more frequently than non-American-authored articles. CONCLUSIONS: Non-American contributions have impacted neuroradiology more than other clinical neuroscience fields with Asian authorship showing the greatest impact. That impact is growing, and the causes are manifold. Nonetheless American-authored articles are cited more. PMID- 29622561 TI - O-Linked beta-N-Acetylglucosamine Modification of A20 Enhances the Inhibition of NF-kappaB (Nuclear Factor-kappaB) Activation and Elicits Vascular Protection After Acute Endoluminal Arterial Injury. AB - OBJECTIVE: Recently, we have demonstrated that acute glucosamine-induced augmentation of protein O-linked beta-N-acetylglucosamine (O-GlcNAc) levels inhibits inflammation in isolated vascular smooth muscle cells and neointimal formation in a rat model of carotid injury by interfering with NF-kappaB (nuclear factor-kappaB) signaling. However, the specific molecular target for O GlcNAcylation that is responsible for glucosamine-induced vascular protection remains unclear. In this study, we test the hypothesis that increased A20 (also known as TNFAIP3 [tumor necrosis factor alpha-induced protein 3]) O-GlcNAcylation is required for glucosamine-mediated inhibition of inflammation and vascular protection. APPROACH AND RESULTS: In cultured rat vascular smooth muscle cells, both glucosamine and the selective O-linked N-acetylglucosaminidase inhibitor thiamet G significantly increased A20 O-GlcNAcylation. Thiamet G treatment did not increase A20 protein expression but did significantly enhance binding to TAX1BP1 (Tax1-binding protein 1), a key regulatory protein for A20 activity. Adenovirus-mediated A20 overexpression further enhanced the effects of thiamet G on prevention of TNF-alpha (tumor necrosis factor-alpha)-induced IkappaB (inhibitor of kappaB) degradation, p65 phosphorylation, and increases in DNA binding activity. A20 overexpression enhanced the inhibitory effects of thiamet G on TNF-alpha-induced proinflammatory cytokine expression and vascular smooth muscle cell migration and proliferation, whereas silencing endogenous A20 by transfection of specific A20 shRNA significantly attenuated these inhibitory effects. In balloon-injured rat carotid arteries, glucosamine treatment markedly inhibited neointimal formation and p65 activation compared with vehicle treatment. Adenoviral delivery of A20 shRNA to the injured arteries dramatically reduced balloon injury-induced A20 expression and inflammatory response compared with scramble shRNA and completely abolished the vascular protection of glucosamine. CONCLUSIONS: These results suggest that O-GlcNAcylation of A20 plays a key role in the negative regulation of NF-kappaB signaling cascades in TNF alpha-treated vascular smooth muscle cells in culture and in acutely injured arteries, thus protecting against inflammation-induced vascular injury. PMID- 29622560 TI - Role of ADAMTS-5 in Aortic Dilatation and Extracellular Matrix Remodeling. AB - OBJECTIVE: Thoracic aortic aneurysm (TAA), a degenerative disease of the aortic wall, is accompanied by changes in the structure and composition of the aortic ECM (extracellular matrix). The ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family of proteases has recently been implicated in TAA formation. This study aimed to investigate the contribution of ADAMTS-5 to TAA development. APPROACH AND RESULTS: A model of aortic dilatation by AngII (angiotensin II) infusion was adopted in mice lacking the catalytic domain of ADAMTS-5 (Adamts5Deltacat). Adamts5Deltacat mice showed an attenuated rise in blood pressure while displaying increased dilatation of the ascending aorta (AsAo). Interestingly, a proteomic comparison of the aortic ECM from AngII treated wild-type and Adamts5Deltacat mice revealed versican as the most upregulated ECM protein in Adamts5Deltacat mice. This was accompanied by a marked reduction of ADAMTS-specific versican cleavage products (versikine) and a decrease of LRP1 (low-density lipoprotein-related protein 1). Silencing LRP1 expression in human aortic smooth muscle cells reduced the expression of ADAMTS5, attenuated the generation of versikine, but increased soluble ADAMTS-1. A similar increase in ADAMTS-1 was observed in aortas of AngII-treated Adamts5Deltacat mice but was not sufficient to maintain versican processing and prevent aortic dilatation. CONCLUSIONS: Our results support the emerging role of ADAMTS proteases in TAA. ADAMTS-5 rather than ADAMTS-1 is the key protease for versican regulation in murine aortas. Further studies are needed to define the ECM substrates of the different ADAMTS proteases and their contribution to TAA formation. PMID- 29622562 TI - Settlement of Stenotic Site and Enhancement of Risk Factor Load for Atherosclerosis in Left Anterior Descending Coronary Artery by Myocardial Bridge. AB - OBJECTIVE: The aim of this study was to investigate the influence of a myocardial bridge (MB) on atherosclerosis development in the left anterior descending artery of the normal heart and the importance of traditional risk factors (RFs). An additional objective was to determine the correlation between intimal thickening and luminal narrowing. APPROACH AND RESULTS: The left anterior descending artery from 150 autopsied hearts was treated with formalin perfusion fixation, and each left anterior descending artery was serially cross-sectioned. The intima-media and luminal stenosis ratios were examined using computer-assisted histomorphometry. The luminal stenosis ratio was closely correlated with the intima-media ratio (r=0.792; P<0.001). When an MB was present, the luminal stenosis ratios proximal to the MB in the RF (+) group were significantly greater than those in the RF (-) group (P=0.022 by a multiple comparison test), but there were no differences between the RF (+) and RF (-) groups when an MB was absent. In addition, the site of the greatest stenosis in the MB (+) RF (+) group was 2.5 cm proximal to the MB entrance. Multivariate analyses indicated that age was an independent factor for luminal stenosis ratios >=50% and 60% (P=0.002 and 0.029, respectively). Furthermore, the presence of an MB plus RFs was an independent factor for a luminal stenosis ratio >=70% (P=0.037). CONCLUSIONS: An MB enhances left anterior descending artery atherosclerosis development at a site proximal to the MB entrance, particularly in subjects who have some RFs. PMID- 29622563 TI - Noncanonical Matrix Metalloprotease 1-Protease-Activated Receptor 1 Signaling Drives Progression of Atherosclerosis. AB - OBJECTIVE: Protease-activated receptor-1 (PAR1) is classically activated by thrombin and is critical in controlling the balance of hemostasis and thrombosis. More recently, it has been shown that noncanonical activation of PAR1 by matrix metalloprotease-1 (MMP1) contributes to arterial thrombosis. However, the role of PAR1 in long-term development of atherosclerosis is unknown, regardless of the protease agonist. APPROACH AND RESULTS: We found that plasma MMP1 was significantly correlated (R=0.33; P=0.0015) with coronary atherosclerotic burden as determined by angiography in 91 patients with coronary artery disease and acute coronary syndrome undergoing cardiac catheterization or percutaneous coronary intervention. A cell-penetrating PAR1 pepducin, PZ-128, currently being tested as an antithrombotic agent in the acute setting in the TRIP-PCI study (Thrombin Receptor Inhibitory Pepducin-Percutaneous Coronary Intervention), caused a significant decrease in total atherosclerotic burden by 58% to 70% (P<0.05) and reduced plaque macrophage content by 54% (P<0.05) in apolipoprotein E-deficient mice. An MMP1 inhibitor gave similar beneficial effects, in contrast to the thrombin inhibitor bivalirudin that gave no improvement on atherosclerosis end points. Mechanistic studies revealed that inflammatory signaling mediated by MMP1-PAR1 plays a critical role in amplifying tumor necrosis factor alpha signaling in endothelial cells. CONCLUSIONS: These data suggest that targeting the MMP1-PAR1 system may be effective in tamping down chronic inflammatory signaling in plaques and halting the progression of atherosclerosis. PMID- 29622566 TI - CORRECTION. PMID- 29622568 TI - Impact of age and comorbidity on risk stratification in idiopathic pulmonary arterial hypertension. AB - Recent reports from worldwide pulmonary hypertension registries show a new demographic picture for patients with idiopathic pulmonary arterial hypertension (IPAH), with an increasing prevalence among the elderly.We aimed to investigate the effects of age and comorbidity on risk stratification and outcome of patients with incident IPAH.The study population (n=264) was categorised into four age groups: 18-45, 46-64, 65-74 and >=75 years. Individual risk profiles were determined according to a risk assessment instrument, based on the European Society of Cardiology and the European Respiratory Society guidelines. The change in risk group from baseline to follow-up (median 5 months) and survival were compared across age groups. In the two youngest age groups, a significant number of patients improved (18-45 years, Z= -4.613, p<0.001; 46-64 years, Z= -2.125, p=0.034), but no significant improvement was found in the older patient groups. 5 year survival was highest in patients aged 18-45 years (88%), while the survival rates were 63%, 56% and 36% for patients in the groups 46-64, 65-74 and >=75 years, respectively (p<0.001). Ischaemic heart disease and kidney dysfunction independently predicted survival.These findings highlight the importance of age and specific comorbidities as prognostic markers of outcome in addition to established risk assessment algorithms. PMID- 29622565 TI - The cGAS-cGAMP-STING pathway connects DNA damage to inflammation, senescence, and cancer. AB - Detection of microbial DNA is an evolutionarily conserved mechanism that alerts the host immune system to mount a defense response to microbial infections. However, this detection mechanism also poses a challenge to the host as to how to distinguish foreign DNA from abundant self-DNA. Cyclic guanosine monophosphate (GMP)-adenosine monophosphate (AMP) synthase (cGAS) is a DNA sensor that triggers innate immune responses through production of the second messenger cyclic GMP-AMP (cGAMP), which binds and activates the adaptor protein STING. However, cGAS can be activated by double-stranded DNA irrespective of the sequence, including self DNA. Although how cGAS is normally kept inactive in cells is still not well understood, recent research has provided strong evidence that genomic DNA damage leads to cGAS activation to stimulate inflammatory responses. This review summarizes recent findings on how genomic instability and DNA damage trigger cGAS activation and how cGAS serves as a link from DNA damage to inflammation, cellular senescence, and cancer. PMID- 29622567 TI - Repression of Nitrogen Starvation Responses by Members of the Arabidopsis GARP Type Transcription Factor NIGT1/HRS1 Subfamily. AB - Nitrogen (N) is often a limiting nutrient whose availability determines plant growth and productivity. Because its availability is often low and/or not uniform over time and space in nature, plants respond to variations in N availability by altering uptake and recycling mechanisms, but the molecular mechanisms underlying how these responses are regulated are poorly understood. Here, we show that a group of GARP G2-like transcription factors, Arabidopsis thaliana NITRATE INDUCIBLE, GARP-TYPE TRANSCRIPTIONAL REPRESSOR1/HYPERSENSITIVE TO LOW Pi-ELICITED PRIMARY ROOT SHORTENING1 proteins (NIGT1/HRS1s), are factors that bind to the promoter of the N starvation marker NRT2.4 and repress an array of N starvation responsive genes under conditions of high N availability. Transient assays and expression analysis demonstrated that NIGT1/HRS1s are transcriptional repressors whose expression is regulated by N availability. We identified target genes of the NIGT1/HRS1s by genome-wide transcriptome analyses and found that they are significantly enriched in N starvation response-related genes, including N acquisition, recycling, remobilization, and signaling genes. Loss of NIGT1/HRS1s resulted in deregulation of N acquisition and accumulation. We propose that NIGT1/HRS1s are major regulators of N starvation responses that play an important role in optimizing N acquisition and utilization under fluctuating N conditions. PMID- 29622564 TI - The cell biology of systemic insulin function. AB - Insulin is the paramount anabolic hormone, promoting carbon energy deposition in the body. Its synthesis, quality control, delivery, and action are exquisitely regulated by highly orchestrated intracellular mechanisms in different organs or "stations" of its bodily journey. In this Beyond the Cell review, we focus on these five stages of the journey of insulin through the body and the captivating cell biology that underlies the interaction of insulin with each organ. We first analyze insulin's biosynthesis in and export from the beta-cells of the pancreas. Next, we focus on its first pass and partial clearance in the liver with its temporality and periodicity linked to secretion. Continuing the journey, we briefly describe insulin's action on the blood vasculature and its still-debated mechanisms of exit from the capillary beds. Once in the parenchymal interstitium of muscle and adipose tissue, insulin promotes glucose uptake into myofibers and adipocytes, and we elaborate on the intricate signaling and vesicle traffic mechanisms that underlie this fundamental function. Finally, we touch upon the renal degradation of insulin to end its action. Cellular discernment of insulin's availability and action should prove critical to understanding its pivotal physiological functions and how their failure leads to diabetes. PMID- 29622569 TI - Gadofosveset-enhanced lung magnetic resonance imaging to detect ongoing vascular leak in pulmonary fibrosis. PMID- 29622570 TI - Pulmonary haemodynamics and mortality in chronic hypersensitivity pneumonitis. PMID- 29622571 TI - Survival of patients with schistosomiasis-associated pulmonary arterial hypertension in the modern management era. PMID- 29622572 TI - What can we learn from patients' perspectives on the quality and safety of hospital care? PMID- 29622573 TI - Interaction of diabetes and smoking on stroke: a population-based cross-sectional survey in China. AB - OBJECTIVES: Diabetes and smoking are known independent risk factors for stroke; however, their interaction concerning stroke is less clear. We aimed to explore such interaction and its influence on stroke in Chinese adults. DESIGN: Cross sectional study. SETTING: Community-based investigation in Xuzhou, China. PARTICIPANTS: A total of 39 887 Chinese adults who fulfilled the inclusion criteria were included. METHODS: Participants were selected using a multistage stratified cluster method, and completed self-reported questionnaires on stroke and smoking. Type 2 diabetes mellitus (DM2) was assessed by fasting blood glucose or use of antidiabetic medication. Interaction, relative excess risk owing to interaction (RERI), attributable proportion (AP) and synergy index (S) were evaluated using a logistic regression model. RESULTS: After adjustment for age, sex, marital status, educational level, occupation, physical activity, body mass index, hypertension, family history of stroke, alcohol use and blood lipids, the relationships between DM2 and stroke, and between smoking and stroke, were still significant: ORs were 2.75 (95% CI 2.03 to 3.73) and 1.70 (95% CI 1.38 to 2.10), respectively. In subjects with DM2 who smoked, the RERI, AP and S values (and 95% CIs) were 1.80 (1.24 to 3.83), 0.52 (0.37 to 0.73) and 1.50 (1.18 to 1.84), respectively. CONCLUSIONS: The results suggest there are additive interactions between DM2 and smoking and that these affect stroke in Chinese adults. PMID- 29622574 TI - German-wide prospective DACAPO cohort of survivors of the acute respiratory distress syndrome (ARDS): a cohort profile. AB - PURPOSE: While most research focuses on the association between medical characteristics and residual morbidity of survivors of the acute respiratory distress syndrome (ARDS), little is known about the relation between potentially modifiable intensive care unit (ICU) features and the course of health-related quality of life (HRQoL). Accordingly, the DACAPO study was set up to elucidate the influence of quality of intensive care on HRQoL and return to work (RtW) in survivors of ARDS. The continued follow-up of these former ICU patients leads to the establishment of the DACAPO (survivor) cohort. PARTICIPANTS: Sixty-one ICUs all over Germany recruited patients with ARDS between September 2014 and April 2016. Inclusion criteria were: (1) age older than 18 years and (2) ARDS diagnosis according to the 'Berlin definition'. No further inclusion or exclusion criteria were applied. 1225 patients with ARDS could be included in the DACAPO ICU sample. Subsequently, the 876 survivors at ICU discharge form the actual DACAPO cohort. FINDINGS TO DATE: The recruitment of the participants of the DACAPO cohort and the baseline data collection has been completed. The care-related data of the DACAPO cohort reveal a high proportion of adverse events (in particular, hypoglycaemia and reintubation). However, evidence-based supportive measures were applied frequently. FUTURE PLANS: Three months, 6 months and 1 year after ICU admission a follow-up assessment is conducted. The instruments of the follow-up questionnaires comprise the domains: (A) HRQoL, (B) RtW, (C) general disability, (D) psychiatric symptoms and (E) social support. Additionally, an annual follow up of the DACAPO cohort focusing on HRQoL, psychiatric symptoms and healthcare utilisation will be conducted. Furthermore, several add-on projects affecting medical issues are envisaged. TRIAL REGISTRATION NUMBER: NCT02637011. PMID- 29622575 TI - Acupuncture for stable angina pectoris: a systematic review protocol. AB - INTRODUCTION: Previous reviews indicate that the effect of acupuncture on stable angina pectoris (SAP) remains controversial. The results of trials published in the past 5 years may possibly change this situation, but an updated systematic review is not available. We therefore designed this study to systematically assess the efficacy and safety of acupuncture for treating SAP. METHODS AND ANALYSIS: Nine online databases will be searched without language or publication status restrictions from their inception to September 2017. Randomised controlled trials that include patients with stable angina receiving acupuncture therapy versus a control group will be deemed eligible. The selection of studies, data extraction and risk of bias assessment will be carried out by two independent reviewers. Data synthesis will be performed using RevMan V.5.3 software with either a fixed effects model or random effects model, depending on the heterogeneity test. Evidence quality will be evaluated using the Grading of Recommendations Assessment, Development and Evaluation system. The efficacy effectiveness spectrum for each included trial will be rated using the Rating of Included Trials on the Efficacy-effectiveness Spectrum tool. Outcomes of interest include the improvement of weekly angina attacks and reduction of nitroglycerin medication use after receiving acupuncture treatment, the incidence of cardiovascular events, heart rate variability, pain intensity measured on a visual analogue scale, total workload and exercise duration at peak exercise, safety and adverse events. A meta-analysis will be conducted if no considerable heterogeneity is detected. The results will be presented as risk ratios with 95% CIs for dichotomous data and weighted mean differences or standardised mean differences with 95% CIs for continuous data. ETHICS AND DISSEMINATION: This systematic review will not involve private information from individuals or endanger their rights, and therefore does not necessarily require ethical approval. The results may be published in a peer-reviewed journal or disseminated in relevant conferences. TRIAL REGISTRATION NUMBER: CRD42015016201. PMID- 29622576 TI - Effect of maternal origin on the association between maternal height and risk of preterm birth in Belgium: a retrospective observational cohort study. AB - OBJECTIVES: To investigate the effect of maternal origin on the association between maternal height and the risk of preterm birth (PTB). DESIGN: Retrospective observational cohort study. SETTING: Two of the three Belgian regions, including Brussels-Capital and Walloon regions. PARTICIPANTS: A total of 245 204 women spontaneously delivered live singletons between 2009 and 2013. Maternal nationality at the time of birth included Belgium, Congo, French, Italy, Morocco, Poland, Romania and Turkey. OUTCOMES MEASURES: The outcome variable was spontaneous PTB, defined as childbirth occurring at less than 37 weeks' gestation. RESULTS: Average height, demographic characteristics and the spontaneous PTB rate differed according to maternal origin, defined as maternal nationality at birth. The pattern of association between maternal height and the risk of PTB was not uniform by maternal nationality at birth. The low maternal height category was associated with a statistically significant increased risk of spontaneous PTB for Belgian (adjusted OR (aOR) 1.23, 95% CI 1.16 to 1.32), Italian (aOR 1.48, 95% CI 1.12 to 1.96) and Polish (aOR 1.76, 95% CI 1.11 to 2.78), respectively. However, this association was not observed for the women from Congo, France, Morocco, Romania and Turkey. CONCLUSIONS: The association between height and the risk of PTB was modified by maternal nationality, even for mothers from the same region of the world. For example, there was a significant inverse association for the Belgians and Italians but not for French women. Our data suggest that PTB risk assessment should take into account the specific height of maternal origin. PMID- 29622577 TI - Analysis of caesarean sections using Robson 10-group classification system in a university hospital in eastern Ethiopia: a cross-sectional study. AB - OBJECTIVE: To analyse caesarean section (CS) using Robson 10-group classification system in an Ethiopian university hospital. DESIGN: Cross-sectional study. SETTING: A university hospital in eastern, Ethiopia. PARTICIPANTS: 980 women who underwent CS from January 2016 to April 2017. MAIN OUTCOME: Robson groups (1-10 based on gestational age, fetal presentation, number of fetus, onset of labour and history of CS) and indications for CS. RESULTS: Robson group 3 (multiparous women with single cephalic full-term pregnancy in spontaneous labour with no history of CS), group 5 (multiparous women with single cephalic full-term pregnancy with history of CS) and group 1 (single cephalic nulliparous women full term pregnancy in spontaneous labour) were the major contributors to the overall CS at 21.4%, 21.1% and 19.3%, respectively. The three major indications for CS were fetal compromise (mainly fetal distress), obstructed labour (mainly cephalopelvic disproportion) and previous CS. CONCLUSION: Robson groups 3, 5 and 1 were the major contributors to the overall CS rate. Fetal compromise, obstructed labour and previous CS were the underlying indications for performing CS. Further study is required to assess the appropriateness of the indications and to reduce CS among the low-risk groups (groups 1 and 3). PMID- 29622579 TI - High-throughput, nonperturbing quantification of lipid droplets with digital holographic microscopy. AB - In vitro differentiating adipocytes are sensitive to liquid manipulations and have the tendency to float. Assessing adipocyte differentiation using current microscopy techniques involves cell staining and washing, while using flow cytometry involves cell retrieval in suspension. These methods induce biases, are difficult to reproduce, and involve tedious optimizations. In this study, we present digital holographic microscopy (DHM) as a label-free, nonperturbing means to quantify lipid droplets in differentiating adipocytes in a robust medium- to high-throughput manner. Taking advantage of the high refractive index of lipid droplets, DHM can assess the production of intracellular lipid droplets by differences in phase shift in a quantitative manner. Adipocytic differentiation, combined with other morphological features including cell confluence and cell death, was tracked over 6 days in live OP9 mesenchymal stromal cells. We compared DHM with other currently available methods of lipid droplet quantification and demonstrated its robustness with modulators of adipocytic differentiation in a dose-responsive manner. This study suggests DHM as a novel marker-free nonperturbing method to study lipid droplet accumulation and may be envisioned for drug screens and mechanistic studies on adipocytic differentiation. PMID- 29622580 TI - Disruption of IFN-I Signaling Promotes HER2/Neu Tumor Progression and Breast Cancer Stem Cells. AB - Type I interferon (IFN-I) is a class of antiviral immunomodulatory cytokines involved in many stages of tumor initiation and progression. IFN-I acts directly on tumor cells to inhibit cell growth and indirectly by activating immune cells to mount antitumor responses. To understand the role of endogenous IFN-I in spontaneous, oncogene-driven carcinogenesis, we characterized tumors arising in HER2/neu transgenic (neuT) mice carrying a nonfunctional mutation in the IFNI receptor (IFNAR1). Such mice are unresponsive to this family of cytokines. Compared with parental neu+/- mice (neuT mice), IFNAR1-/- neu+/- mice (IFNAR-neuT mice) showed earlier onset and increased tumor multiplicity with marked vascularization. IFNAR-neuT tumors exhibited deregulation of genes having adverse prognostic value in breast cancer patients, including the breast cancer stem cell (BCSC) marker aldehyde dehydrogenase-1A1 (ALDH1A1). An increased number of BCSCs were observed in IFNAR-neuT tumors, as assessed by ALDH1A1 enzymatic activity, clonogenic assay, and tumorigenic capacity. In vitro exposure of neuT+ mammospheres and cell lines to antibodies to IFN-I resulted in increased frequency of ALDH+ cells, suggesting that IFN-I controls stemness in tumor cells. Altogether, these results reveal a role of IFN-I in neuT-driven spontaneous carcinogenesis through intrinsic control of BCSCs. Cancer Immunol Res; 6(6); 658 70. (c)2018 AACR. PMID- 29622582 TI - Sarcoid-Like Granulomatosis of the Lung Related to Immune-Checkpoint Inhibitors: Distinct Clinical and Imaging Features of a Unique Immune-Related Adverse Event. AB - With the rapidly expanding role of immune-checkpoint inhibitor therapy in advanced cancer treatment, an increasing number of new immune-related adverse events (irAEs) are being reported. The present report describes sarcoid-like granulomatosis of the lung as a distinct type of irAE with characteristic clinical, imaging, and histologic features. In patients treated with immune checkpoint inhibitors, sarcoid-like granulomatosis of the lung presented with a focal area of consolidation in the lung, which was often nodular or round, in the absence of new or enlarging lymphadenopathy on imaging. Histologic examination demonstrated nonnecrotizing granulomas and an absence of malignant cells. The patients were free of new or worsening respiratory symptoms, despite the development of lung parenchymal consolidations. Holding the immune-checkpoint inhibitors led to the spontaneous resolution of the findings, without any specific treatment for the abnormality. Awareness of the manifestations of sarcoid-like granulomatosis of the lung as a distinct type of irAE will improve management of patients treated with immune-checkpoint inhibitors. Cancer Immunol Res; 6(6); 630-5. (c)2018 AACR. PMID- 29622581 TI - Targeting Tissue Factor for Immunotherapy of Triple-Negative Breast Cancer Using a Second-Generation ICON. AB - Triple-negative breast cancer (TNBC) is a leading cause of breast cancer death and is often associated with BRCA1 and BRCA2 mutation. Due to the lack of validated target molecules, no targeted therapy for TNBC is approved. Tissue factor (TF) is a common yet specific surface target receptor for cancer cells, tumor vascular endothelial cells, and cancer stem cells in several types of solid cancers, including breast cancer. Here, we report evidence supporting the idea that TF is a surface target in TNBC. We used in vitro cancer lines and in vivo tumor xenografts in mice, all with BRCA1 or BRCA2 mutations, derived from patients' tumors. We showed that TF is overexpressed on TNBC cells and tumor neovasculature in 50% to 85% of TNBC patients (n = 161) and in TNBC cell line derived xenografts (CDX) and patient-derived xenografts (PDX) from mice, but was not detected in adjacent normal breast tissue. We then describe the development of a second-generation TF-targeting immunoconjugate (called L-ICON1, for lighter or light chain ICON) with improved efficacy and safety profiles compared with the original ICON. We showed that L-ICON1 kills TNBC cells in vitro via antibody dependent cell-mediated cytotoxicity and can be used to treat human and murine TNBC CDX as well as PDX in vivo in orthotopic mouse models. Thus, TF could be a useful target for the development of immunotherapeutics for TNBC patients, with or without BRCA1 and BRCA2 mutations. Cancer Immunol Res; 6(6); 671-84. (c)2018 AACR. PMID- 29622584 TI - Obstetrician who altered notes of patient who had stillbirth is struck off. PMID- 29622583 TI - A Pharmacogenetic Approach to the Treatment of Patients With PPARG Mutations. AB - Loss-of-function mutations in PPARG cause familial partial lipodystrophy type 3 (FPLD3) and severe metabolic disease in many patients. Missense mutations in PPARG are present in ~1 in 500 people. Although mutations are often binarily classified as benign or deleterious, prospective functional classification of all missense PPARG variants suggests that their impact is graded. Furthermore, in testing novel mutations with both prototypic endogenous (e.g., prostaglandin J2 [PGJ2]) and synthetic ligands (thiazolidinediones, tyrosine agonists), we observed that synthetic agonists selectively rescue function of some peroxisome proliferator-activated receptor-gamma (PPARgamma) mutants. We report on patients with FPLD3 who harbor two such PPARgamma mutations (R308P and A261E). Both PPARgamma mutants exhibit negligible constitutive or PGJ2-induced transcriptional activity but respond readily to synthetic agonists in vitro, with structural modeling providing a basis for such differential ligand-dependent responsiveness. Concordant with this finding, dramatic clinical improvement was seen after pioglitazone treatment of a patient with R308P mutant PPARgamma. A patient with A261E mutant PPARgamma also responded beneficially to rosiglitazone, although cardiomyopathy precluded prolonged thiazolidinedione use. These observations indicate that detailed structural and functional classification can be used to inform therapeutic decisions in patients with PPARG mutations. PMID- 29622578 TI - Relationship between islet autoantibody status and the clinical characteristics of children and adults with incident type 1 diabetes in a UK cohort. AB - OBJECTIVES: To describe the characteristics of children and adults with incident type 1 diabetes in contemporary, multiethnic UK, focusing on differences between the islet autoantibody negative and positive. DESIGN: Observational cohort study. SETTING: 146 mainly secondary care centres across England and Wales. PARTICIPANTS: 3312 people aged >=5 years were recruited within 6 months of a clinical diagnosis of type 1 diabetes via the National Institute for Health Research Clinical Research Network. 3021 were of white European ethnicity and 291 (9%) were non-white. There was a small male predominance (57%). Young people <17 years comprised 59%. MAIN OUTCOME MEASURES: Autoantibody status and characteristics at presentation. RESULTS: The majority presented with classical osmotic symptoms, weight loss and fatigue. Ketoacidosis was common (42%), especially in adults, and irrespective of ethnicity. 35% were overweight or obese. Of the 1778 participants who donated a blood sample, 85% were positive for one or more autoantibodies against glutamate decarboxylase, islet antigen-2 and zinc transporter 8. Presenting symptoms were similar in the autoantibody-positive and autoantibody-negative participants, as was the frequency of ketoacidosis (43%vs40%, P=0.3). Autoantibody positivity was less common with increasing age (P=0.0001), in males compared with females (82%vs90%, P<0.0001) and in people of non-white compared with white ethnicity (73%vs86%, P<0.0001). Body mass index was higher in autoantibody-negative adults than autoantibody-positive adults (median, IQR 25.5, 23.1-29.2vs23.9, 21.4-26.7 kg/m2; P=0.0001). Autoantibody-negative participants were more likely to have a parent with diabetes (28%vs16%, P<0.0001) and less likely to have another autoimmune disease (4%vs8%, P=0.01). CONCLUSIONS: Most people assigned a diagnosis of type 1 diabetes presented with classical clinical features and islet autoantibodies. Although indistinguishable at an individual level, autoantibody-negative participants as a group demonstrated features more typically associated with other diabetes subtypes. TRIAL REGISTRATION NUMBER: ISRCTN66496918; Pre-results. PMID- 29622585 TI - Prevalence and Progression of Late Gadolinium Enhancement in Children and Adolescents With Hypertrophic Cardiomyopathy. AB - BACKGROUND: Late gadolinium enhancement (LGE) on cardiac magnetic resonance imaging (CMR) is believed to represent dense replacement fibrosis. It is seen in ~60% of adult patients with hypertrophic cardiomyopathy (HCM). However, the prevalence of LGE in children and adolescents with HCM is not well established. In addition, longitudinal studies describing the development and evolution of LGE in pediatric HCM are lacking. This study assesses the prevalence, progression, and clinical correlations of LGE in children and adolescents with, or genetically predisposed to, HCM. METHODS: CMR scans from 195 patients <=21 years of age were analyzed in an observational, retrospective study, including 155 patients with overt HCM and 40 sarcomere mutation carriers without left ventricular (LV) hypertrophy. The extent of LGE was quantified by measuring regions with signal intensity >6 SD above nulled remote myocardium. RESULTS: Patients were 14.3+/-4.5 years of age at baseline and 68% were male. LGE was present in 70 (46%) patients with overt HCM (median extent, 3.3%; interquartile range, 0.8-7.1%), but absent in mutation carriers without LV hypertrophy. Thirty-one patients had >1 CMR (median interval between studies, 2.4 years; interquartile range, 1.5-3.2 years). LGE was detected in 13 patients (42%) at baseline and in 16 patients (52%) at follow-up CMR. The median extent of LGE increased by 2.4 g/y (range, 0-13.2 g/y) from 2.9% (interquartile range, 0.8-3.2%) of LV mass to 4.3% (interquartile range, 2.9-6.8%) ( P=0.02). In addition to LGE, LV mass and left atrial volume, indexed to body surface area, and z score for LV mass, as well, increased significantly from first to most recent CMR. CONCLUSIONS: LGE was present in 46% of children and adolescents with overt HCM, in contrast to ~60% typically reported in adult HCM. In the subset of patients with serial imaging, statistically significant increases in LGE, LV mass, and left atrial size were detected over 2.5 years, indicating disease progression over time. Further prospective studies are required to confirm these findings and to better understand the clinical implications of LGE in pediatric HCM. PMID- 29622586 TI - Heart Rate Recovery 10 Seconds After Cessation of Exercise Predicts Death. AB - BACKGROUND: Heart rate recovery (HRR) is commonly defined as the decrease of heart rate at 1 minute after cessation of exercise and is an important predictor of all-cause mortality and death associated with coronary artery disease. However, HRR at earlier time intervals after cessation has not been well evaluated and might better reflect PNS reactivation. We hypothesize that early HRR indices within the first minute is better associated with all-cause and coronary artery disease mortality compared with HRR at 1 minute. METHODS AND RESULTS: The prognostic value of HRR at 10, 20, 30, 40, and 50 seconds after cessation of exercise was investigated in 40 727 selected UK Biobank participants (mean age 56 years, 45% male) free from cardiovascular disease. During a median follow-up period of 6 years, 536 participants died (including 39 of coronary artery disease). In multivariable analyses, including adjustments for aerobic exercise capacity, cardiovascular risk factors, and factors associated with mortality in general, only HRR at 10 seconds remained predictive of both all cause and coronary artery disease mortality. Effects of HRR were larger and more significant when measured early after exercise cessation. Moreover, the association of change in heart rate between 10 seconds and 1 minute after exercise cessation with mortality was dependent on HRR at 10 seconds. CONCLUSIONS: We provide evidence that decreased HRR at 10 seconds after cessation of exercise is a superior predictor of outcome compared with HRR at later time intervals. This observation might have important implications for the future reporting and interpretation of exercise tests. PMID- 29622588 TI - Modeling the Transition From Decompensated to Pathological Hypertrophy. AB - BACKGROUND: Long-chain acyl-CoA synthetases (ACSL) catalyze the conversion of long-chain fatty acids to fatty acyl-CoAs. Cardiac-specific ACSL1 temporal knockout at 2 months results in a shift from FA oxidation toward glycolysis that promotes mTORC1-mediated ventricular hypertrophy. We used unbiased metabolomics and gene expression analyses to examine the early effects of genetic inactivation of fatty acid oxidation on cardiac metabolism, hypertrophy development, and function. METHODS AND RESULTS: Global cardiac transcriptional analysis revealed differential expression of genes involved in cardiac metabolism, fibrosis, and hypertrophy development in Acsl1H-/- hearts 2 weeks after Acsl1 ablation. Comparison of the 2- and 10-week transcriptional responses uncovered 137 genes whose expression was uniquely changed upon knockdown of cardiac ACSL1, including the distinct upregulation of fibrosis genes, a phenomenon not observed after complete ACSL1 knockout. Metabolomic analysis identified metabolites altered in hearts displaying partially reduced ACSL activity, and rapamycin treatment normalized the cardiac metabolomic fingerprint. CONCLUSIONS: Short-term cardiac specific ACSL1 inactivation resulted in metabolic and transcriptional derangements distinct from those observed upon complete ACSL1 knockout, suggesting heart-specific mTOR (mechanistic target of rapamycin) signaling that occurs during the early stages of substrate switching. The hypertrophy observed with partial Acsl1 ablation occurs in the context of normal cardiac function and is reminiscent of a physiological process, making this a useful model to study the transition from physiological to pathological hypertrophy. PMID- 29622587 TI - Efficacy and Safety of Apixaban, Dabigatran, Rivaroxaban, and Warfarin in Asians With Nonvalvular Atrial Fibrillation. AB - BACKGROUND: Whether non-vitamin K antagonist oral anticoagulants (NOACs) are superior to warfarin among Asians with nonvalvular atrial fibrillation remains unclear. METHODS AND RESULTS: In this nationwide retrospective cohort study collected from Taiwan National Health Insurance Research Database, there were 5843, 20 079, 27 777, and 19 375 nonvalvular atrial fibrillation patients taking apixaban, dabigatran, rivaroxaban and warfarin, respectively, from June 1, 2012 to December 31, 2016. Propensity-score weighting was used to balance covariates across study groups. Patients were followed until the first occurrence of any efficacy or safety outcome or the end date of study. Hazard ratios (95% confidence intervals) comparing apixaban, dabigatran, and rivaroxaban with warfarin were: ischemic stroke/systemic embolism (IS/SE), 0.55 (0.43-0.69), 0.82 (0.68-0.98), and 0.81 (0.67-0.97); major bleeding, 0.41 (0.31-0.53), 0.65 (0.53 0.80), and 0.58 (0.46-0.72); and all-cause mortality, 0.58 (0.51-0.66), 0.61 (0.54-0.68), and 0.57 (0.51-0.65). A total of 3623 (62%), 17 760 (88%), and 26 000 (94%) patients were taking low-dose apixaban (2.5 mg twice daily), dabigatran (110 mg twice daily), and rivaroxaban (10-15 mg once daily), respectively. Similar to all-dose NOACs, all low-dose NOACs had lower risk of IS/SE, major bleeding, and mortality when compared with warfarin. In contrast to other standard-dose NOACs, apixaban was associated with lower risks of IS/SE (0.45 [0.31-0.65]), major bleeding (0.29 [0.18-0.46]), and mortality (0.23 [0.17-0.31]) than warfarin. CONCLUSIONS: All NOACs were associated with lower risk of IS/SE, major bleeding, and mortality compared with warfarin in the largest real-world practice among Asians with nonvalvular atrial fibrillation. All low-dose NOACs had lower risk of IS/SE, major bleeding, and mortality when compared with warfarin. Standard-dose apixaban caused a lower risk of IS/SE, major bleeding, and mortality compared with warfarin. PMID- 29622589 TI - Genome-Wide Associations of Global Electrical Heterogeneity ECG Phenotype: The ARIC (Atherosclerosis Risk in Communities) Study and CHS (Cardiovascular Health Study). AB - BACKGROUND: ECG global electrical heterogeneity (GEH) is associated with sudden cardiac death. We hypothesized that a genome-wide association study would identify genetic loci related to GEH. METHODS AND RESULTS: We tested genotyped and imputed variants in black (N=3057) and white (N=10 769) participants in the ARIC (Atherosclerosis Risk in Communities) study and CHS (Cardiovascular Health Study). GEH (QRS-T angle, sum absolute QRST integral, spatial ventricular gradient magnitude, elevation, azimuth) was measured on 12-lead ECGs. Linear regression models were constructed with each GEH variable as an outcome, adjusted for age, sex, height, body mass index, study site, and principal components to account for ancestry. GWAS identified 10 loci that showed genome-wide significant association with GEH in whites or joint ancestry. The strongest signal (rs7301677, near TBX3) was associated with QRS-T angle (white standardized beta+0.16 [95% CI 0.13-0.19]; P=1.5*10-26), spatial ventricular gradient elevation (+0.11 [0.08-0.14]; P=2.1*10-12), and spatial ventricular gradient magnitude (-0.12 [95% CI -0.15 to -0.09]; P=5.9*10-15). Altogether, GEH-SNPs explained 1.1% to 1.6% of GEH variance. Loci on chromosomes 4 (near HMCN2), 5 (IGF1R), 11 (11p11.2 region cluster), and 7 (near ACTB) are novel ECG phenotype associated loci. Several loci significantly associated with gene expression in the left ventricle (HMCN2 locus-with HMCN2; IGF1R locus-with IGF1R), and atria (RP11-481J2.2 locus-with expression of a long non-coding RNA and NDRG4). CONCLUSIONS: We identified 10 genetic loci associated with ECG GEH. Replication of GEH GWAS findings in independent cohorts is warranted. Further studies of GEH loci may uncover mechanisms of arrhythmogenic remodeling in response to cardiovascular risk factors. PMID- 29622591 TI - Safety and Efficacy of Novel Oral Anticoagulants Versus Warfarin in Medicare Beneficiaries With Atrial Fibrillation and Valvular Heart Disease. AB - BACKGROUND: We examined a large community-based sample of patients with atrial fibrillation (AF) and valvular heart disease (VHD) (excluding prosthetic valves) with a goal to compare outcomes among patients with AF, with and without VHD, taking warfarin, dabigatran, and rivaroxaban. METHODS AND RESULTS: We identified Medicare beneficiaries enrolled in Medicare Part D benefit plan from 2011 to 2013 with newly diagnosed AF (18 137 patients with VHD [dabigatran, 1979; rivaroxaban, 2027; warfarin, 14 131] and 85 596 patients without VHD [dabigatran, 13 522; rivaroxaban, 14 257; warfarin, 57 817]). Primary outcomes of all-cause mortality, ischemic strokes, major bleeding, and myocardial infarction were compared across the 3 anticoagulants using 3-way propensity-matched samples. After propensity matching, a total of 5871 patients with VHD and 40 221 patients without VHD and AF were studied. Both dabigatran and rivaroxaban were associated with significantly lower risk of death in patients with VHD with AF (dabigatran versus warfarin: hazard ratio, 0.71; 95% confidence interval, 0.52-0.98; P=0.038; rivaroxaban versus warfarin: hazard ratio, 0.68; 95% confidence interval, 0.49 0.95; P=0.022). Nongastrointestinal bleeding was significantly reduced with dabigatran and rivaroxaban versus warfarin in those with VHD (dabigatran versus warfarin: hazard ratio, 0.17; 95% confidence interval, 0.06-0.49; P=0.001; rivaroxaban versus warfarin: hazard ratio, 0.37; 95% confidence interval, 0.17 0.84; P=0.017). Ischemic stroke and gastrointestinal bleeding rates did not differ between rivaroxaban, dabigatran, and warfarin in patients with VHD. The effects of the 3 anticoagulants on outcomes were comparable in patients with and without VHD and with AF. CONCLUSIONS: In this cohort of Medicare beneficiaries with VHD (excluding patients with prosthetic valves) and new-onset AF between 2011 and 2013, novel oral non-vitamin K anticoagulants were safe and effective options for prevention of systemic thromboembolism. PMID- 29622590 TI - Carotid Atherosclerosis Detected by Ultrasonography: A National Cross-Sectional Study. AB - BACKGROUND: Carotid atherosclerosis (CA) is a reflector of generalized atherosclerosis that is associated with systemic vascular disease. Data are limited on the epidemiology of carotid lesions in a large, nationally representative population sample. We aimed to evaluate the prevalence of CA detected by carotid ultrasonography and related risk factors based on a national survey in China. METHODS AND RESULTS: A total of 107 095 residents aged >=40 years from the China National Stroke Prevention Project underwent carotid ultrasound examination. Participants with carotid endarterectomy or carotid stenting and those with stroke or coronary heart disease were excluded. Data from 84 880 participants were included in the analysis. CA was defined as increased intima-media thickness (IMT) >=1 mm or presence of plaques. Of the 84 880 participants, 46.4% were men, and the mean age was 60.7+/-10.3 years. The standardized prevalence of CA was 36.2% overall, increased with age, and was higher in men than in women. Prevalence of CA was higher among participants living in rural areas than in urban areas. Approximately 26.5% of participants had increased IMT, and 13.9% presented plaques. There was an age-related increase in participants with increased IMT, plaque presence, and stenosis. In multiple logistic regression analysis, older age, male sex, residence in rural areas, smoking, alcohol consumption, physical inactivity, obesity, hypertension, diabetes mellitus, and dyslipidemia were associated with CA. CONCLUSIONS: CA was highly prevalent in a middle-aged and older Chinese population. This result shows the potential clinical importance of focusing on primary prevention of atherosclerosis progression. PMID- 29622592 TI - Contact-Free Screening of Atrial Fibrillation by a Smartphone Using Facial Pulsatile Photoplethysmographic Signals. AB - BACKGROUND: We aimed to evaluate a novel method of atrial fibrillation (AF) screening using an iPhone camera to detect and analyze photoplethysmographic signals from the face without physical contact by extracting subtle beat-to-beat variations of skin color that reflect the cardiac pulsatile signal. METHODS AND RESULTS: Patients admitted to the cardiology ward of the hospital for clinical reasons were recruited. Simultaneous facial and fingertip photoplethysmographic measurements were obtained from 217 hospital inpatients (mean age, 70.3+/-13.9 years; 71.4% men) facing the front camera and with an index finger covering the back camera of 2 independent iPhones before a 12-lead ECG was recorded. Backdrop and background light intensity was monitored during signal acquisition. Three successive 20-second (total, 60 seconds) recordings were acquired per patient and analyzed for heart rate regularity by Cardiio Rhythm (Cardiio Inc, Cambridge, MA) smartphone application. Pulse irregularity in >=1 photoplethysmographic readings or 3 uninterpretable photoplethysmographic readings were considered a positive AF screening result. AF was present on 12-lead ECG in 34.6% (n=75/217) patients. The Cardiio Rhythm facial photoplethysmographic application demonstrated high sensitivity (95%; 95% confidence interval, 87%-98%) and specificity (96%; 95% confidence interval, 91%-98%) in discriminating AF from sinus rhythm compared with 12-lead ECG. The positive and negative predictive values were 92% (95% confidence interval, 84%-96%) and 97% (95% confidence interval, 93%-99%), respectively. CONCLUSIONS: Detection of a facial photoplethysmographic signal to determine pulse irregularity attributable to AF is feasible. The Cardiio Rhythm smartphone application showed high sensitivity and specificity, with low negative likelihood ratio for AF from facial photoplethysmographic signals. The convenience of a contact-free approach is attractive for community screening and has the potential to be useful for distant AF screening. PMID- 29622593 TI - Transient Receptor Potential Melastatin-8 Activation Induces Relaxation of Pulmonary Artery by Inhibition of Store-Operated Calcium Entry in Normoxic and Chronic Hypoxic Pulmonary Hypertensive Rats. AB - Pulmonary hypertension (PH) is characterized by enhanced vasoconstriction and vascular remodeling, which are attributable to the alteration of Ca2+ homeostasis in pulmonary arterial smooth muscle cells (PASMCs). It is well established that store-operated Ca2+ entry (SOCE) is augmented in PASMCs during PH and that it plays a crucial role in PH development. Our previous studies showed that the melastatin-related transient receptor potential 8 (TRPM8) is down-regulated in PASMCs of PH animal models, and activation of TRPM8 causes relaxation of pulmonary arteries (PAs). However, the mechanism of TRPM8-induced PA relaxation is unclear. Here we examined the interaction of TRPM8 and SOCE in PAs and PASMCs of normoxic and chronic hypoxic pulmonary hypertensive (CHPH) rats, a model of human group 3 PH. We found that TRPM8 was down-regulated and TRPM8-mediated cation entry was reduced in CHPH-PASMCs. Activation of TRPM8 with icilin caused concentration-dependent relaxation of cyclopiazonic acid (CPA) and endothelin-1 contracted endothelium-denuded PAs, and the effect was abolished by the SOCE antagonist Gd3+ Application of icilin to PASMCs suppressed CPA-induced Mn2+ quenching and Ca2+ entry, which was reversed by the TRPM8 antagonist N-(3 aminopropyl)-2-([(3-methylphenyl)methyl])-oxy-N-(2-thienylmethyl)benzamide hydrochloride salt (AMTB). Moreover, the inhibitory effects of icilin on SOCE in PA and PASMCs of CHPH rats were significantly augmented due to enhanced SOCE activity in PH. Our results, therefore, demonstrated a novel mechanism of TRPM8 mediated inhibition of SOCE in pulmonary vasculature. Because SOCE is important for vascular remodeling and enhanced vasoconstriction, down-regulation of TRPM8 in PASMCs of CHPH rats may minimize its inhibitory influence to allow unimpeded SOCE activity for PH development. PMID- 29622594 TI - Clinical prediction rules for abusive head trauma: a systematic review. AB - OBJECTIVE: Misdiagnosis of abusive head trauma (AHT) has serious consequences for children and families. This systematic review identifies and compares clinical prediction rules (CPredRs) assisting clinicians in assessing suspected AHT. DESIGN: We searched MEDLINE, Embase, PubMed and Cochrane databases (January 1996 to August 2016). Externally validated CPredRs focusing on the detection of AHT in the clinical setting were included. RESULTS: Of 110 potential articles identified, three studies met the inclusion criteria: the Pediatric Brain Injury Research Network (PediBIRN) 4-Variable AHT CPredR, the Predicting Abusive Head Trauma (PredAHT) tool and the Pittsburgh Infant Brain Injury Score (PIBIS). The CPredRs were designed for different populations and purposes: PediBIRN: intensive care unit admissions (<3 years) with head injury, to inform early decisions to launch or forego an evaluation for abuse (sensitivity 0.96); PredAHT: hospital admissions (<3 years) with intracranial injury, to assist clinicians in discussions with child abuse specialists (sensitivity 0.72); and PIBIS: well appearing children (<1 year) in the emergency department with no history of trauma, temperature <38.3 degrees C, and >=1 symptom associated with high risk of AHT, to determine the need for a head CT scan (sensitivity 0.93). There was little overlap between the predictive variables. CONCLUSION: Three CPredRs for AHT were relevant at different stages in the diagnostic process. None of the CPredRs aimed to diagnose AHT but to act as aids/prompts to clinicians to seek further clinical, social or forensic information. None were widely validated in multiple settings. To assess safety and effectiveness in clinical practice, impact analyses are required and recommended. PMID- 29622595 TI - Does a Target Dose or a Target Heart Rate Matter to Outcomes When Prescribing beta-Blockers to Patients With Chronic Heart Failure? PMID- 29622597 TI - Alcohol and the heart: the good, the bad and the worse in heart failure. PMID- 29622596 TI - Risk stratifying chest pain patients in the emergency department using HEART, GRACE and TIMI scores, with a single contemporary troponin result, to predict major adverse cardiac events. AB - BACKGROUND: The majority of patients presenting to the ED with cardiac sounding chest pain have a non-diagnostic ECG and the problem of differentiating those suffering an acute coronary syndrome from those without is familiar to all ED clinical staff. To stratify risk in these patients, specific scores have been developed. Recent work has focused on incorporating newer high-sensitivity cardiac troponin (hs-cTn) assays; however, issues regarding performance and availability of these assays remain. AIM: Prospectively compare HEART, Global Registry of Acute Coronary Events (GRACE) and Thrombolysis in Myocardial Infarction (TIMI) scores, using a single contemporary cTn at admission, to predict a major adverse cardiac event (MACE) at 30 days. METHOD: Prospective observational cohort study performed in a UK tertiary hospital in patients with suspected cardiac chest pain and no significant ST elevation on initial ECG. Data collection took place 2 December 2014 to 8 February 2016. The treating clinician recorded risk score data real time and a single contemporary cTn taken at presentation was used in score calculation. The primary endpoint was 30-day MACE. C-statistic was determined for each score and diagnostic characteristics of high risk and low-risk cut-offs were calculated. RESULTS: 189/1000 patients in the study developed a 30-day MACE. The c-statistic of HEART for 30-day MACE (0.87 (95% CI 0.84 to 0.90)) was higher than TIMI (0.78 (95% CI 0.74 to 0.81)) and GRACE (0.74 (95% CI 0.70 to 0.78)).HEART score <=3 identified low-risk patients with sensitivity 99.5% (95% CI 97.1% to 99.9%) and negative predictive value (NPV) 99.6% (95% CI 97.3% to 99.9%) exceeding TIMI 0 (sensitivity 97.4% (95% CI 93.9% to 99.1%) and NPV 97.8% (95% CI 94.8% to 99.1%)) and GRACE score 0-55 (sensitivity 95.2% (95% CI 91.1% to 97.8%) and NPV 95.8% (95% CI 92.2% to 97.7%)). CONCLUSION: HEART outperformed both TIMI and GRACE in overall discriminative capacity for 30-day MACE. Using a single contemporary cTn at presentation, a HEART score of <=3 demonstrated sensitivity and NPV of >=99.5% for 30-day MACE. These results reach the threshold for a safe discharge strategy but should be interpreted thoughtfully in light of other work. PMID- 29622599 TI - Why and how to screen for atrial fibrillation. PMID- 29622598 TI - Impact of age on excess risk of coronary heart disease in patients with familial hypercholesterolaemia. AB - OBJECTIVE: The primary objective was to study the risk of acute myocardial infarction (AMI) and coronary heart disease (CHD) in patients with familial hypercholesterolaemia (FH) and compare with the risk in the general population. METHODS: Patients with an FH mutation but without prior AMI (n=3071) and without prior CHD (n=2795) were included in the study sample during 2001-2009. We obtained data on all AMI and CHD hospitalisations in Norway. We defined incident cases as first time hospitalisation or out-of-hospital death due to AMI or CHD. We estimated standardised incidence ratios (SIRs) with 95% CIs with indirect standardisation using incidence rates for the total Norwegian population stratified by sex, calendar year and 1 year age groups as reference rates. RESULTS: SIRs for AMI (95% CIs) were highest in the age group 25-39 years; 7.5 (3.7 to 14.9) in men and 13.6 (5.1 to 36.2) in women and decreased with age to 0.9 (0.4 to 2.1) in men and 1.8 (0.9 to 3.7) in women aged 70-79 years. Similarly, SIRs for CHD were highest among patients 25-39 years old; 11.1 (7.1 17.5) in men and 17.3 (9.6-31.2) in women and decreased 2.4 (1.4-4.2) in men and 3.2 (1.5-7.2) in women at age 70-79. For all age groups, combined SIRs for CHD were 4.2 (3.6-5.0) in men and 4.7 (3.9-5.7) in women. CONCLUSION: Patients with FH are at severely increased risk of AMI and CHD compared with the general population. The highest excess risk was in the youngest group aged 25-39 years, in both sexes. PMID- 29622600 TI - Estimated individual lifetime benefit from PCSK9 inhibition in statin-treated patients with coronary artery disease. AB - OBJECTIVE: In statin-treated patients with stable coronary artery disease (CAD), residual risk of cardiovascular events is partly explained by plasma levels of low-density lipoprotein cholesterol (LDL-C). This study aimed to estimate individual benefit of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition in CAD patients already treated with high-dose statin. METHODS: Individual lifetime benefit was estimated in months gain free of stroke or myocardial infarction (MI) until age 80 years. Predictions were based on two competing risk models developed in data from 4853 patients with CAD originating from the atorvastatin 80 mg arm of the Treating to New Targets (TNT) trial. The relative effect of PCSK9 inhibition was added to the models and was assumed based on average estimates from large clinical trials. We accounted for individual LDL C levels, assuming 50% LDL-C reduction by PCSK9 inhibition and 21% cardiovascular risk reduction per mmol/L (39 mg/dL) LDL-C lowering. RESULTS: Estimated individual gain was <6 months in 61% of the patients, 6-12 months in 28% of the patients and >=12 months in 10% of the patients (median 5, quartiles 2-8 months). Highest estimated benefit was observed in younger patients (aged 40-60 years) with high risk factor burden, particularly if LDL-C levels were >1.8 mmol/L (>70 mg/dL). Estimated benefit was lowest (<=5 months) in older patients (>=70 years), in particular if LDL-C and other risk factors levels were low. CONCLUSION: The individual estimated lifetime benefit from PCSK9 inhibition in patients with stable CAD on high-dose statin varied from <6 to >=12 months free of stroke or MI. Highest benefit is expected in younger patients (age 40-60 years) with high risk factor burden and relatively high LDL-C levels. TRIAL REGISTRATION NUMBER: NCT00327691; Post-results. PMID- 29622601 TI - Dual role of the RNA helicase DDX5 in post-transcriptional regulation of myelin basic protein in oligodendrocytes. AB - In the central nervous system, oligodendroglial expression of myelin basic protein (MBP) is crucial for the assembly and structure of the myelin sheath. MBP synthesis is tightly regulated in space and time, particularly at the post transcriptional level. We have identified the DEAD-box RNA helicase DDX5 (also known as p68) in a complex with Mbp mRNA in oligodendroglial cells. Expression of DDX5 is highest in progenitor cells and immature oligodendrocytes, where it localizes to heterogeneous populations of cytoplasmic ribonucleoprotein (RNP) complexes associated with Mbp mRNA in the cell body and processes. Manipulation of the amount of DDX5 protein inversely affects the level of MBP. We present evidence that DDX5 is involved in post-transcriptional regulation of MBP protein synthesis, with implications for oligodendroglial development. In addition, knockdown of DDX5 results in an increased abundance of MBP isoforms containing exon 2 in immature oligodendrocytes, most likely by regulating alternative splicing of Mbp Our findings contribute to the understanding of the complex nature of MBP post-transcriptional control in immature oligodendrocytes where DDX5 appears to affect the abundance of MBP proteins via distinct but converging mechanisms. PMID- 29622602 TI - Promotion of tobacco products on Facebook: policy versus practice. AB - BACKGROUND: Facebook has a comprehensive set of policies intended to inhibit promotion and sales of tobacco products. Their effectiveness has yet to be studied. METHODS: Leading tobacco brands (388) were identified via Nielsen and Ranker databases and 108 were found to maintain brand-sponsored Facebook pages. Key indicators of alignment with Facebook policy were evaluated. RESULTS: Purchase links (eg, 'shop now' button) on brand-sponsored pages were found for hookah tobaccos (41%), e-cigarettes (74%), smokeless (50%) and cigars (31%). Sales promotions (eg, discount coupons) were present in hookah tobacco (48%), e cigarette (76%) and cigar (69%) brand-sponsored pages. While conventional cigarettes did not maintain brand-sponsored pages, they were featured in 80% of online tobacco vendors' Facebook pages. The requirement for age gating, to exclude those <18 from viewing tobacco promotion, was absent in hookah tobacco (78%), e-cigarette (62%) and cigar (21%) brand-sponsored pages and for 90% of online tobacco stores which promote leading cigarette brands (eg, Marlboro, Camel). Many of the brand-sponsored tobacco product pages had thousands of 'likes'. CONCLUSIONS: It is laudable that Facebook has policies intended to interdict tobacco promotion throughout its platform. Nevertheless, widespread tobacco promotion and sales were found at variance with the company's policies governing advertising, commerce, page content and under age access. Vetting could be improved by automated screening in partnership with human reviewers. PMID- 29622603 TI - Cigarettes point of purchase patterns in 19 low-income and middle-income countries: Global Adult Tobacco Survey, 2008-2012. AB - BACKGROUND: There is little information on cigarette-purchasing behaviour among smokers globally. Understanding cigarette purchase and point-of-sale patterns can help guide the development and implementation of tobacco-control strategies in retail environments. OBJECTIVE: The purpose of this study was to identify where adults in 19 countries last purchased cigarettes. METHODS: Data were from 19 low income and middle-income countries that conducted the Global Adult Tobacco Survey (GATS) during 2008-2012. GATS is a nationally representative household survey of adults aged 15 years or older using a standardised protocol to measure tobacco related behaviours. Data were weighted to yield nationally representative estimates within each country and summarised by using descriptive statistics. RESULTS: Overall prevalence of current cigarette smoking ranged from 3.7% in Nigeria to 38.5% in the Russian Federation. Among current cigarette smokers, locations of last purchase were as follows: stores, from 14.6% in Argentina to 98.7% in Bangladesh (median=66.8%); street vendors, from 0% in Thailand to 35.7% in Vietnam (median=3.0%); kiosks, from 0.1% in Thailand to 77.3% in Argentina (median=16.1%); other locations, from 0.3% in China and Egypt to 57.5% in Brazil (median=2.6%). CONCLUSION: Cigarettes are purchased at various retail locations globally. However, stores and kiosks were the main cigarette purchase locations in 18 of the 19 countries assessed. Knowledge of where cigarette purchases occur could help guide interventions to reduce cigarette accessibility and use. PMID- 29622604 TI - Complete Genome Sequence of a New Ruminococcaceae Bacterium Isolated from Anaerobic Biomass Hydrolysis. AB - A new Ruminococcaceae bacterium, strain HV4-5-B5C, participating in the anaerobic digestion of grass, was isolated from a mesophilic two-stage laboratory-scale leach bed biogas system. The draft annotated genome sequence presented in this study and 16S rRNA gene sequence analysis indicated the affiliation of HV4-5-B5C with the family Ruminococcaceae outside recently described genera. PMID- 29622605 TI - Complete Genome Sequences of Two Methicillin-Resistant Staphylococcus haemolyticus Isolates of Multilocus Sequence Type 25, First Detected by Shotgun Metagenomics. AB - The emergence of nosocomial infections by multidrug-resistant Staphylococcus haemolyticus isolates has been reported in several European countries. Here, we report the first two complete genome sequences of S. haemolyticus sequence type 25 (ST25) isolates 83131A and 83131B. Both isolates were isolated from the same clinical sample and were first identified through shotgun metagenomics. PMID- 29622606 TI - Draft Genome Sequences of Marinobacter Strains Recovered from Utica Shale Produced Fluids. AB - The genomes of three Marinobacter strains, isolated from saline fluids produced from a Utica-Point Pleasant shale well, have been sequenced. These genomes provide novel information on the degradation of petroleum distillates and virulence mechanisms under microaerophilic conditions in fractured shale. PMID- 29622607 TI - Complete Genome Sequence of Epizootic hemorrhagic disease virus Serotype 6, Isolated from Florida White-Tailed Deer (Odocoileus virginianus). AB - Here, we report the complete genome sequence of Epizootic hemorrhagic disease virus (EHDV) serotype 6 (EHDV-6), isolated from a Florida white-tailed deer (Odocoileus virginianus) in 2016. To our knowledge, this is the first full genome sequence determined for an EHDV-6 isolate from Florida. PMID- 29622608 TI - Draft Genome Sequence of Candida pseudohaemulonii Isolated from the Blood of a Neutropenic Patient. AB - Candida pseudohaemulonii is phylogenetically close to the C. haemulonii complex and exhibits resistance to amphotericin B and azole agents. We report here the draft genome sequence of C. pseudohaemulonii UZ153_17 isolated from the blood culture of a neutropenic patient. The draft genome is 3,532,003,666 bp in length, with 579,838 reads, 130 contigs, and a G+C content of 47.15%. PMID- 29622609 TI - Draft Genome Sequences of Salmonella enterica Serovar Enteritidis and Kentucky Isolates from Retail Poultry Sources. AB - The draft genome sequences of four Salmonella enterica serovar Enteritidis and Kentucky isolates were evaluated for biofilm formation and antibiotic resistance. The Salmonella serovar Kentucky strains CFS84 and CFS85 and Salmonella serovar Enteritidis strains CFS86 and CFS87 were isolated from retail poultry sources in Arkansas. PMID- 29622610 TI - Draft Genome Sequence of the 1,4-Dioxane-Degrading Bacterium Pseudonocardia dioxanivorans BERK-1. AB - Pseudonocardia dioxanivorans strain BERK-1 grows aerobically with 1,4-dioxane as its sole substrate. Reported here is its draft genome sequence, with a size of 7.1 Mbp. Key genes are highlighted in this article. BERK-1 exhibits a reduced level of cell aggregation and adherence to surfaces compared to those of P. dioxanivorans CB1190, giving it an apparent advantage for movement through soil. PMID- 29622611 TI - Draft Genome Sequences of Megaplasmid-Bearing Streptomyces sp. Strains BF-3 and 4F, Isolated from the Great Salt Plains of Oklahoma. AB - Draft genome sequences of megaplasmid-bearing Streptomyces sp. strains BF-3 and 4F, isolated from the Great Salt Plains of Oklahoma, showed genome sizes of 7,950,134 and 7,550,992 bp, respectively. Both genomes revealed the presence of genes involved in osmoregulation and stress response, potentially helping their survival in such an extreme environment. PMID- 29622612 TI - Complete Genome Sequence of Lactobacillus plantarum subsp. plantarum Strain LB1 2, Isolated from the Hindgut of European Honeybees, Apis mellifera L., from the Philippines. AB - Lactobacillus plantarum subsp. plantarum strain LB1-2, isolated from the hindgut of European honeybees in the Philippines, is active against Paenibacillus larvae and has broad activity against several Gram-positive and Gram-negative bacteria. The complete genome sequence reported herein contains gene clusters for multiple bacteriocins and extensive gene inventories for carbohydrate metabolism. PMID- 29622613 TI - Draft Genome Sequence of Enterococcus faecium Strain J19, Isolated from Cabbage. AB - Herein, we report the draft genome sequence of a newly discovered probiotic strain, Enterococcus faecium J19, which was isolated from cabbage. Strain J19 has shown antagonistic effects against the human foodborne pathogen Listeria monocytogenes in coculture and in different food matrices. PMID- 29622614 TI - Draft Genome Sequence of Bowmanella denitrificans JL63, a Bacterium Isolated from Whiteleg Shrimp (Litopenaeus vannamei) That Can Inhibit the Growth of Vibrio parahaemolyticus. AB - Bowmanella denitrificans strain JL63 was isolated from a whiteleg shrimp (Litopenaeus vannamei) and was determined to have antibacterial activity against an acute hepatopancreatic necrosis disease (AHPND) strain of Vibrio parahaemolyticus Here, we report the draft genome sequence of this strain and identify genes that are potentially involved in its antibacterial activity. PMID- 29622615 TI - Genome Sequence of the Proteorhodopsin-Containing Bacterium Flavobacterium sp. Strain TH167, Isolated from Cyanobacterial Aggregates in a Eutrophic Lake. AB - Flavobacterium is the most abundant group of bacteria within the cyanobacterial aggregates in Lake Taihu, China. Here, we present the genome sequence and annotation of Flavobacterium sp. strain TH167. Genome analysis revealed the presence of a proteorhodopsin-encoding sequence, together with its retinal producing pathway, indicating a putative photoheterotrophic lifestyle that generates energy from light. PMID- 29622616 TI - Draft Genome Sequence of the Fish Pathogen Flavobacterium columnare Genomovar III Strain PH-97028 (=CIP 109753). AB - Flavobacterium columnare strain PH-97028 (=CIP 109753) is a genomovar III reference strain that was isolated from a diseased Ayu fish in Japan. We report here the analysis of the first available genomovar III sequence of this species to aid in identification, epidemiological tracking, and virulence studies. PMID- 29622617 TI - Genomic Sequence of Saccharomyces cerevisiae BAW-6, a Yeast Strain Optimal for Brewing Barley Shochu. AB - Here, we report the draft genome sequence of Saccharomyces cerevisiae strain BAW 6, which is used for the production of barley shochu, a traditional Japanese spirit. This genomic information can be used to elucidate the genetic basis underlying the high alcohol production capacity and citric acid tolerance of shochu yeast. PMID- 29622618 TI - Complete Genome Sequence of the Methanococcus maripaludis Type Strain JJ (DSM 2067), a Model for Selenoprotein Synthesis in Archaea. AB - Methanococcus maripaludis type strain JJ (DSM 2067) is an important organism because it serves as a model for primary energy metabolism and hydrogenotrophic methanogenesis and is amenable to genetic manipulation. The complete genome (1.7 Mb) harbors 1,815 predicted protein-encoding genes, including 9 encoding selenoproteins. PMID- 29622619 TI - Draft Genome Sequence and Annotation of the Lichen-Forming Fungus Arthonia radiata. AB - We report here the draft de novo genome assembly, transcriptome assembly, and annotation of the lichen-forming fungus Arthonia radiata (Pers.) Ach., the type species for Arthoniomycetes, a class of lichen-forming, lichenicolous, and saprobic Ascomycota. The genome was assembled using overlapping paired-end and mate pair libraries and sequenced on an Illumina HiSeq 2500 instrument. PMID- 29622621 TI - Letter by Chen et al Regarding Article, "Closure of Patent Foramen Ovale Versus Medical Therapy in Patients With Cryptogenic Stroke or Transient Ischemic Attack: Updated Systematic Review and Meta-Analysis". PMID- 29622620 TI - Draft Genome Sequence of the Basidiomycete White-Rot Fungus Phlebia centrifuga. AB - Here, we report the genome sequence of wood-decaying white-rot fungus Phlebia centrifuga strain FBCC195, isolated from Norway spruce (Picea abies) in Finnish Lapland. The 34.66-Mb genome containing 13,785 gene models is similar to the genome length reported for other saprobic white-rot species. PMID- 29622622 TI - Response by Ntaios et al to Letter Regarding Article, "Closure of Patent Foramen Ovale Versus Medical Therapy in Patients With Cryptogenic Stroke or Transient Ischemic Attack: Updated Systematic Review and Meta-Analysis". PMID- 29622623 TI - How to Review a Clinical Research Paper. PMID- 29622624 TI - Relationship Between Dual-Task Gait Speed and Walking Activity Poststroke. AB - BACKGROUND AND PURPOSE: Gait speed does not adequately predict whether stroke survivors will be active in the community. This may be because traditional single task gait speed does not sufficiently reproduce the demands of walking in the real world. This study assessed whether dual-task gait speed accounts for variance in daily ambulatory activity above what can be predicted with habitual (single task) gait speed in community-dwelling stroke survivors. METHODS: Twenty eight community-dwelling individuals, 58.2 years of age (SD=16.6), 8.9 months poststroke (interquartile range, 3.7-19.4), completed a gait and cognitive task in single- and dual-task conditions. Daily ambulatory activity was captured using a physical activity monitor. A regression analysis examined R2 changes with single- and dual-task gait speed. RESULTS: Single-task gait speed explained 15.3% of the variance in daily ambulatory activity (P=0.04). Adding dual-task gait speed to the regression model increased the variance explained by an additional 20.6% (P=0.04). CONCLUSIONS: Gait speed assessed under attention-demanding conditions may improve explanation of variance in daily ambulatory activity after stroke. PMID- 29622625 TI - Lipid-Lowering Agents and High HDL (High-Density Lipoprotein) Are Inversely Associated With Intracranial Aneurysm Rupture. AB - BACKGROUND AND PURPOSE: Growing evidence from experimental animal models and clinical studies suggests the protective effect of statin use against rupture of intracranial aneurysms; however, results from large studies detailing the relationship between intracranial aneurysm rupture and total cholesterol, HDL (high-density lipoprotein), LDL (low-density lipoprotein), and lipid-lowering agent use are lacking. METHODS: The medical records of 4701 patients with 6411 intracranial aneurysms diagnosed at the Massachusetts General Hospital and the Brigham and Women's Hospital between 1990 and 2016 were reviewed and analyzed. Patients were separated into ruptured and nonruptured groups. Univariable and multivariable logistic regression analyses were performed to determine the effects of lipids (total cholesterol, LDL, and HDL) and lipid-lowering medications on intracranial aneurysm rupture risk. Propensity score weighting was used to account for differences in baseline characteristics of the cohorts. RESULTS: Lipid-lowering agent use was significantly inversely associated with rupture status (odds ratio, 0.58; 95% confidence interval, 0.47-0.71). In a subgroup analysis of complete cases that includes both lipid-lowering agent use and lipid values, higher HDL levels (odds ratio, 0.95; 95% confidence interval, 0.93-0.98) and lipid-lowering agent use (odds ratio, 0.41; 95% confidence interval, 0.23-0.73) were both significantly and inversely associated with rupture status, whereas total cholesterol and LDL levels were not significant. A monotonic exposure-response curve between HDL levels and risk of aneurysmal rupture was obtained. CONCLUSIONS: Higher HDL values and the use of lipid lowering agents are significantly inversely associated with ruptured intracranial aneurysms. PMID- 29622626 TI - Triggered recruitment of ESCRT machinery promotes endolysosomal repair. AB - Endolysosomes can be damaged by diverse materials. Terminally damaged compartments are degraded by lysophagy, but pathways that repair salvageable organelles are poorly understood. Here we found that the endosomal sorting complex required for transport (ESCRT) machinery, known to mediate budding and fission on endolysosomes, also plays an essential role in their repair. ESCRTs were rapidly recruited to acutely injured endolysosomes through a pathway requiring calcium and ESCRT-activating factors that was independent of lysophagy. We used live-cell imaging to demonstrate that ESCRTs responded to small perforations in endolysosomal membranes and enabled compartments to recover from limited damage. Silica crystals that disrupted endolysosomes also triggered ESCRT recruitment. ESCRTs thus provide a defense against endolysosomal damage likely to be relevant in physiological and pathological contexts. PMID- 29622627 TI - Cryo-EM structure of a herpesvirus capsid at 3.1 A. AB - Structurally and genetically, human herpesviruses are among the largest and most complex of viruses. Using cryo-electron microscopy (cryo-EM) with an optimized image reconstruction strategy, we report the herpes simplex virus type 2 (HSV-2) capsid structure at 3.1 angstroms, which is built up of about 3000 proteins organized into three types of hexons (central, peripentonal, and edge), pentons, and triplexes. Both hexons and pentons contain the major capsid protein, VP5; hexons also contain a small capsid protein, VP26; and triplexes comprise VP23 and VP19C. Acting as core organizers, VP5 proteins form extensive intermolecular networks, involving multiple disulfide bonds (about 1500 in total) and noncovalent interactions, with VP26 proteins and triplexes that underpin capsid stability and assembly. Conformational adaptations of these proteins induced by their microenvironments lead to 46 different conformers that assemble into a massive quasisymmetric shell, exemplifying the structural and functional complexity of HSV. PMID- 29622630 TI - News at a glance. PMID- 29622629 TI - Science for state legislatures. PMID- 29622631 TI - In its second year, March for Science grows up. PMID- 29622628 TI - Structure of the herpes simplex virus 1 capsid with associated tegument protein complexes. AB - Herpes simplex viruses (HSVs) rely on capsid-associated tegument complex (CATC) for long-range axonal transport of their genome-containing capsids between sites of infection and neuronal cell bodies. Here we report cryo-electron microscopy structures of the HSV-1 capsid with CATC up to 3.5-angstrom resolution and atomic models of multiple conformers of capsid proteins VP5, VP19c, VP23, and VP26 and tegument proteins pUL17, pUL25, and pUL36. Crowning every capsid vertex are five copies of heteropentameric CATC, each containing a pUL17 monomer supporting the coiled-coil helix bundle of a pUL25 dimer and a pUL36 dimer, thus positioning their flexible domains for potential involvement in nuclear capsid egress and axonal capsid transport. Notwithstanding newly discovered fold conservation between triplex proteins and bacteriophage lambda protein gpD and the previously recognized bacteriophage HK97 gp5-like fold in VP5, HSV-1 capsid proteins exhibit extraordinary diversity in forms of domain insertion and conformational polymorphism, not only for interactions with tegument proteins but also for encapsulation of large genomes. PMID- 29622632 TI - University is quick to disclose misconduct. PMID- 29622634 TI - Rocky start for China's James Watson center. PMID- 29622633 TI - Humane studies of octopuses get a boost. PMID- 29622635 TI - NIH looks to punish reviewers who violate confidentiality. PMID- 29622636 TI - A delicate balance. PMID- 29622637 TI - Edge of extinction. PMID- 29622638 TI - A one-man fossil rescue mission. PMID- 29622639 TI - NextGen VOICES: A postdoc's purpose. PMID- 29622640 TI - Microplastics research-from sink to source. PMID- 29622641 TI - Supporting recovery from brain injury. PMID- 29622642 TI - Lattices for fractional Chern insulators. PMID- 29622643 TI - ESCRTs offer repair service. PMID- 29622644 TI - Up close with herpesviruses. PMID- 29622645 TI - LRRK2 kinase in Parkinson's disease. PMID- 29622646 TI - Testing international education assessments. PMID- 29622648 TI - Convergent evidence for widespread rock nitrogen sources in Earth's surface environment. AB - Nitrogen availability is a pivotal control on terrestrial carbon sequestration and global climate change. Historical and contemporary views assume that nitrogen enters Earth's land-surface ecosystems from the atmosphere. Here we demonstrate that bedrock is a nitrogen source that rivals atmospheric nitrogen inputs across major sectors of the global terrestrial environment. Evidence drawn from the planet's nitrogen balance, geochemical proxies, and our spatial weathering model reveal that ~19 to 31 teragrams of nitrogen are mobilized from near-surface rocks annually. About 11 to 18 teragrams of this nitrogen are chemically weathered in situ, thereby increasing the unmanaged (preindustrial) terrestrial nitrogen balance from 8 to 26%. These findings provide a global perspective to reconcile Earth's nitrogen budget, with implications for nutrient-driven controls over the terrestrial carbon sink. PMID- 29622647 TI - CRMP2-binding compound, edonerpic maleate, accelerates motor function recovery from brain damage. AB - Brain damage such as stroke is a devastating neurological condition that may severely compromise patient quality of life. No effective medication-mediated intervention to accelerate rehabilitation has been established. We found that a small compound, edonerpic maleate, facilitated experience-driven synaptic glutamate AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole-propionic-acid) receptor delivery and resulted in the acceleration of motor function recovery after motor cortex cryoinjury in mice in a training-dependent manner through cortical reorganization. Edonerpic bound to collapsin-response-mediator-protein 2 (CRMP2) and failed to augment recovery in CRMP2-deficient mice. Edonerpic maleate enhanced motor function recovery from internal capsule hemorrhage in nonhuman primates. Thus, edonerpic maleate, a neural plasticity enhancer, could be a clinically potent small compound with which to accelerate rehabilitation after brain damage. PMID- 29622649 TI - Light-induced lattice expansion leads to high-efficiency perovskite solar cells. AB - Light-induced structural dynamics plays a vital role in the physical properties, device performance, and stability of hybrid perovskite-based optoelectronic devices. We report that continuous light illumination leads to a uniform lattice expansion in hybrid perovskite thin films, which is critical for obtaining high efficiency photovoltaic devices. Correlated, in situ structural and device characterizations reveal that light-induced lattice expansion benefits the performances of a mixed-cation pure-halide planar device, boosting the power conversion efficiency from 18.5 to 20.5%. The lattice expansion leads to the relaxation of local lattice strain, which lowers the energetic barriers at the perovskite-contact interfaces, thus improving the open circuit voltage and fill factor. The light-induced lattice expansion did not compromise the stability of these high-efficiency photovoltaic devices under continuous operation at full spectrum 1-sun (100 milliwatts per square centimeter) illumination for more than 1500 hours. PMID- 29622651 TI - Cell cycle heterogeneity directs the timing of neural stem cell activation from quiescence. AB - Quiescent stem cells in adult tissues can be activated for homeostasis or repair. Neural stem cells (NSCs) in Drosophila are reactivated from quiescence in response to nutrition by the insulin signaling pathway. It is widely accepted that quiescent stem cells are arrested in G0 In this study, however, we demonstrate that quiescent NSCs (qNSCs) are arrested in either G2 or G0 G2-G0 heterogeneity directs NSC behavior: G2 qNSCs reactivate before G0 qNSCs. In addition, we show that the evolutionarily conserved pseudokinase Tribbles (Trbl) induces G2 NSCs to enter quiescence by promoting degradation of Cdc25String and that it subsequently maintains quiescence by inhibiting Akt activation. Insulin signaling overrides repression of Akt and silences trbl transcription, allowing NSCs to exit quiescence. Our results have implications for identifying and manipulating quiescent stem cells for regenerative purposes. PMID- 29622650 TI - Enzymatic construction of highly strained carbocycles. AB - Small carbocycles are structurally rigid and possess high intrinsic energy due to their ring strain. These features lead to broad applications but also create challenges for their construction. We report the engineering of hemeproteins that catalyze the formation of chiral bicyclobutanes, one of the most strained four membered systems, via successive carbene addition to unsaturated carbon-carbon bonds. Enzymes that produce cyclopropenes, putative intermediates to the bicyclobutanes, were also identified. These genetically encoded proteins are readily optimized by directed evolution, function in Escherichia coli, and act on structurally diverse substrates with high efficiency and selectivity, providing an effective route to many chiral strained structures. This biotransformation is easily performed at preparative scale, and the resulting strained carbocycles can be derivatized, opening myriad potential applications. PMID- 29622653 TI - No one is an island. PMID- 29622654 TI - Safety and efficacy of daratumumab in dialysis-dependent renal failure secondary to multiple myeloma. PMID- 29622652 TI - Hepatic thrombopoietin is required for bone marrow hematopoietic stem cell maintenance. AB - Hematopoietic stem cell (HSC) maintenance depends on extrinsic cues. Currently, only local signals arising from the bone marrow niche have been shown to maintain HSCs. However, it is not known whether systemic factors also sustain HSCs. We assessed the physiological source of thrombopoietin (TPO), a key cytokine required for maintaining HSCs. Using TpoDsRed-CreER knock-in mice, we showed that TPO is expressed by hepatocytes but not by bone marrow cells. Deletion of Tpo from hematopoietic cells, osteoblasts, or bone marrow mesenchymal stromal cells does not affect HSC number or function. However, when Tpo is deleted from hepatocytes, bone marrow HSCs are depleted. Thus, a cross-organ factor, circulating TPO made in the liver by hepatocytes, is required for bone marrow HSC maintenance. Our results demonstrate that systemic factors, in addition to the local niche, are a critical extrinsic component for HSC maintenance. PMID- 29622656 TI - A phase I study of romidepsin and ifosfamide, carboplatin, etoposide for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma. PMID- 29622655 TI - Repurposing tofacitinib as an anti-myeloma therapeutic to reverse growth promoting effects of the bone marrow microenvironment. AB - The myeloma bone marrow microenvironment promotes proliferation of malignant plasma cells and resistance to therapy. Activation of JAK/STAT signaling is thought to be a central component of these microenvironment-induced phenotypes. In a prior drug repurposing screen, we identified tofacitinib, a pan-JAK inhibitor Food and Drug Administration (FDA) approved for rheumatoid arthritis, as an agent that may reverse the tumor-stimulating effects of bone marrow mesenchymal stromal cells. Herein, we validated in vitro, in stromal-responsive human myeloma cell lines, and in vivo, in orthotopic disseminated xenograft models of myeloma, that tofacitinib showed efficacy in myeloma models. Furthermore, tofacitinib strongly synergized with venetoclax in coculture with bone marrow stromal cells but not in monoculture. Surprisingly, we found that ruxolitinib, an FDA approved agent targeting JAK1 and JAK2, did not lead to the same anti-myeloma effects. Combination with a novel irreversible JAK3-selective inhibitor also did not enhance ruxolitinib effects. Transcriptome analysis and unbiased phosphoproteomics revealed that bone marrow stromal cells stimulate a JAK/STAT-mediated proliferative program in myeloma cells, and tofacitinib reversed the large majority of these pro-growth signals. Taken together, our results suggest that tofacitinib reverses the growth-promoting effects of the tumor microenvironment. As tofacitinib is already FDA approved, these results can be rapidly translated into potential clinical benefits for myeloma patients. PMID- 29622657 TI - Fetal hemoglobin induction in sickle erythroid progenitors using a synthetic zinc finger DNA-binding domain. PMID- 29622658 TI - Value of cytogenetic abnormalities in post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a study of the MYSEC project. PMID- 29622659 TI - Clonal genetic evolution at relapse of favorable-risk acute myeloid leukemia with NPM1 mutation is associated with phenotypic changes and worse outcomes. PMID- 29622660 TI - RNase H eliminates R-loops that disrupt DNA replication but is nonessential for efficient DSB repair. AB - In Saccharomyces cerevisiae, genome stability depends on RNases H1 and H2, which remove ribonucleotides from DNA and eliminate RNA-DNA hybrids (R-loops). In Schizosaccharomyces pombe, RNase H enzymes were reported to process RNA-DNA hybrids produced at a double-strand break (DSB) generated by I-PpoI meganuclease. However, it is unclear if RNase H is generally required for efficient DSB repair in fission yeast, or whether it has other genome protection roles. Here, we show that S. pombe rnh1? rnh201? cells, which lack the RNase H enzymes, accumulate R loops and activate DNA damage checkpoints. Their viability requires critical DSB repair proteins and Mus81, which resolves DNA junctions formed during repair of broken replication forks. "Dirty" DSBs generated by ionizing radiation, as well as a "clean" DSB at a broken replication fork, are efficiently repaired in the absence of RNase H. RNA-DNA hybrids are not detected at a reparable DSB formed by fork collapse. We conclude that unprocessed R-loops collapse replication forks in rnh1? rnh201? cells, but RNase H is not generally required for efficient DSB repair. PMID- 29622661 TI - Isolation of a multipotent mesenchymal stem cell-like population from human adrenal cortex. AB - BACKGROUND: The highly plastic nature of adrenal cortex suggests the presence of adrenocortical stem cells (ACSC), but the exact in vivo identity of ACSC remains elusive. A few studies have demonstrated the differentiation of adipose or bone marrow-derived mesenchymal stem cells (MSC) into steroid-producing cells. We therefore investigated the isolation of multipotent MSC from human adrenal cortex. METHODS: Human adrenals were obtained as discarded surgical material. Single-cell suspensions from human adrenal cortex (n = 3) were cultured onto either complete growth medium (CM) or MSC growth promotion medium (MGPM) in hypoxic condition. Following ex vivo expansion, their multilineage differentiation capacity was evaluated. Phenotype markers were analysed by immunocytochemistry and flow cytometry for cell-surface antigens associated with bone marrow MSCs and adrenocortical-specific phenotype. Expression of mRNAs for pluripotency markers was assessed by q-PCR. RESULTS: The formation of colony forming unit fibroblasts comprising adherent cells with fibroblast-like morphology were observed from the monolayer cell culture, in both CM and MGPM. Cells derived from MGPM revealed differentiation towards osteogenic and adipogenic cell lineages. These cells expressed cell-surface MSC markers (CD44, CD90, CD105 and CD166) but did not express the haematopoietic, lymphocytic or HLA DR markers. Flow cytometry demonstrated significantly higher expression of GLI1 in cell population harvested from MGPM, which were highly proliferative. They also exhibited increased expression of the pluripotency markers. CONCLUSION: Our study demonstrates that human adrenal cortex harbours a mesenchymal stem cell like population. Understanding the cell biology of adrenal cortex- derived MSCs will inform regenerative medicine approaches in autoimmune Addison's disease. PMID- 29622663 TI - 16 kDa vasoinhibin binds to integrin alpha5 beta1 on endothelial cells to induce apoptosis. AB - Many functions of vasoinhibins have been reported, but its receptor has not been clarified yet. Vasoinhibins, 11-18 kDa N-terminal fragments of prolactin, have anti-angiogenic activity and act on endothelial cells to induce apoptosis and to inhibit migration and proliferation, which are opposite to the effects of prolactin. Although vasoinhibins bind to the prolactin receptor, its binding activity is very weak compared to prolactin. Therefore, in this study, we evaluated the binding activity between 16 kDa vasoinhibin and integrin beta1, alpha5 beta1, alpha1 beta1 and alphaV beta3 to identify a specific receptor for vasoinhibins. Moreover, we examined whether 16 kDa vasoinhibin induced apoptosis through integrin beta1 and alpha5 beta1 in endothelial cells. In this study, binding assays and co-immunoprecipitation experiments demonstrated that 16 kDa vasoinhibin could bind strongly to integrin beta1 and alpha5 beta1. Moreover, neutralizing with integrin beta1 and alpha5 beta1 antibody could inhibit 16 kDa vasoinhibin-induced apoptosis in endothelial cells. These findings suggest that vasoinhibins can act on endothelial cells through integrin alpha5 beta1 to induce apoptosis. PMID- 29622662 TI - Potential genetic polymorphisms predicting polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is a heterogenous endocrine disorder with typical symptoms of oligomenorrhoea, hyperandrogenism, hirsutism, obesity, insulin resistance and increased risk of type 2 diabetes mellitus. Extensive evidence indicates that PCOS is a genetic disease and numerous biochemical pathways have been linked with its pathogenesis. A number of genes from these pathways have been investigated, which include those involved with steroid hormone biosynthesis and metabolism, action of gonadotropin and gonadal hormones, folliculogenesis, obesity and energy regulation, insulin secretion and action and many others. In this review, we summarize the historical and recent findings in genetic polymorphisms of PCOS from the relevant publications and outline some genetic polymorphisms that are potentially associated with the risk of PCOS. This information could uncover candidate genes associating with PCOS, which will be valuable for the development of novel diagnostic and treatment platforms for PCOS patients. PMID- 29622665 TI - Shock attenuation in the human lumbar spine during walking and running. AB - During locomotion, each step generates a shock wave that travels through the body toward the head. Without mechanisms for attenuation, repeated shocks can lead to pathology. Shock attenuation (SA) in the lower limb has been well studied, but little is known about how posture affects SA in the spine. To test the hypothesis that lumbar lordosis (LL) contributes to SA, 27 adults (14 male, 13 female) walked and ran on a treadmill. Two lightweight, tri-axial accelerometers were affixed to the skin overlying T12/L1 and L5/S1. Sagittal plane accelerations were analyzed using power spectral density analysis, and lumbar SA was assessed within the impact-related frequency range. 3D kinematics quantified dynamic and resting LL. To examine the effects of intervertebral discs on spinal SA, supine MRI scans were used to measure disc morphology. The results showed no association between LL and SA during walking, but LL correlated with SA during running (P<0.01, R2=0.30), resulting in as much as 64% reduction in shock signal power among individuals with the highest LL. Patterns of lumbar spinal motion partially explain differences in SA: larger amplitudes of LL angular displacement and slower angular displacement velocity during running were associated with greater lumbar SA (P=0.008, R2=0.41). Intervertebral discs were associated with greater SA during running (P=0.02, R2=0.22) but, after controlling for disc thickness, LL remained strongly associated with SA (P=0.001, R2=0.44). These findings support the hypothesis that LL plays an important role in attenuating impact shocks transmitted through the human spine during high-impact, dynamic activities such as running. PMID- 29622664 TI - Multiple spectral channels in branchiopods. I. Vision in dim light and neural correlates. AB - Animals that have true color vision possess several spectral classes of photoreceptors. Pancrustaceans (Hexapoda+Crustacea) that integrate spectral information about their reconstructed visual world do so from photoreceptor terminals supplying their second optic neuropils, with subsequent participation of the third (lobula) and deeper centers (optic foci). Here, we describe experiments and correlative neural arrangements underlying convergent visual pathways in two species of branchiopod crustaceans that have to cope with a broad range of spectral ambience and illuminance in ephemeral pools, yet possess just two optic neuropils, the lamina and the optic tectum. Electroretinographic recordings and multimodel inference based on modeled spectral absorptance were used to identify the most likely number of spectral photoreceptor classes in their compound eyes. Recordings from the retina provide support for four color channels. Neuroanatomical observations resolve arrangements in their laminas that suggest signal summation at low light intensities, incorporating chromatic channels. Neuroanatomical observations demonstrate that spatial summation in the lamina of the two species are mediated by quite different mechanisms, both of which allow signals from several ommatidia to be pooled at single lamina monopolar cells. We propose that such summation provides sufficient signal for vision at intensities equivalent to those experienced by insects in terrestrial habitats under dim starlight. Our findings suggest that despite the absence of optic lobe neuropils necessary for spectral discrimination utilized by true color vision, four spectral photoreceptor classes have been maintained in Branchiopoda for vision at very low light intensities at variable ambient wavelengths that typify conditions in ephemeral freshwater habitats. PMID- 29622666 TI - Behavioral and physiological adaptations to high-flow velocities in chubs (Gila spp.) native to Southwestern USA. AB - Morphological streamlining is often associated with physiological advantages for steady swimming in fishes. Though most commonly studied in pelagic fishes, streamlining also occurs in fishes that occupy high-flow environments. Before the installation of dams and water diversions, bonytail (Cyprinidae, Gila elegans), a fish endemic to the Colorado River (USA), regularly experienced massive, seasonal flooding events. Individuals of G. elegans display morphological characteristics that may facilitate swimming in high-flow conditions, including a narrow caudal peduncle and a high aspect ratio caudal fin. We tested the hypothesis that these features improve sustained swimming performance in bonytail by comparing locomotor performance in G. elegans with that of the closely related roundtail chub (Gila robusta) and two non-native species, rainbow trout (Oncorhynchus mykiss) and smallmouth bass (Micropterus dolomieu), using a Brett-style respirometer and locomotor step-tests. Gila elegans had the lowest estimated drag coefficient and the highest sustained swimming speeds relative to the other three species. There were no detectible differences in locomotor energetics during steady swimming among the four species. When challenged by high-velocity water flows, the second native species examined in this study, G. robusta, exploited the boundary effects in the flow tank by pitching forward and bracing the pelvic and pectoral fins against the acrylic tank bottom to 'hold station'. Because G. robusta can station hold to prevent being swept downstream during high flows and G. elegans can maintain swimming speeds greater than those of smallmouth bass and rainbow trout with comparable metabolic costs, we suggest that management agencies could use artificial flooding events to wash non-native competitors downstream and out of the Colorado River habitat. PMID- 29622667 TI - Multiple spectral channels in branchiopods. II. Role in light-dependent behavior and natural light environments. AB - Light is a primary environmental factor used by aquatic invertebrates for depth selection behavior. Many branchiopod crustaceans live in ephemeral aquatic habitats. All branchiopod crustaceans studied to date express four or more visual opsins in their compound eyes. We asked whether two branchiopods, Triops longicaudatus and Streptocephalus mackini, use multiple spectral channels to regulate their position in the water column. At the lowest intensities that elicited photonegative behavior, both species had broad spectral bandwidths, suggesting they use multiple spectral photoreceptor classes. Male S. mackini were more likely to maintain a vertical position 8.0-12.0 cm below the surface than females, independently of whether females were present. Male photopositive behavior at low intensity was restricted to a narrow bandwidth centered at 532 nm, suggesting a single photoreceptor class is used to maintain position above females. We compared ephemeral pools from two regions in Arizona and found that diffuse light attenuation coefficients were two orders of magnitude greater than the most heavily attenuating coastal waters. At less than 1 m of depth, pools were often dimmer than terrestrial habitats under starlight. Soil particle size distribution in each region affected spectral light environments, and behavioral responses of field-caught shrimp were adapted to the spectral properties of their region. The results suggest that branchiopods predominantly use luminance vision summed from multiple spectral photoreceptor classes for depth selection in dim, spectrally variable environments. The neuroanatomical basis for summation is described in a companion paper. PMID- 29622668 TI - Utility of Electronic Medical Record Alerts to Prevent Drug Nephrotoxicity. AB - Nephrotoxin-induced AKI is an iatrogenic form of AKI that can be potentially avoided or ameliorated by prompt recognition and appropriate prescriber actions. Drug-targeted alerts, either for patients at risk of AKI or patients with existing AKI, may lead to more appropriate drug dosing and management and improved clinical outcomes. However, alerts of this type are complicated to create, have a high potential for error and off-target effects, and may be difficult to evaluate. Although many studies have shown that these alerts can reduce the rate of inappropriate prescribing, few studies have examined the utility of such alerts in terms of patient benefit. In this review, we examine the current state of the literature in this area, identify key technical challenges, and suggest methods of evaluation for drug-targeted AKI alerts. PMID- 29622670 TI - Pharmacology behind Common Drug Nephrotoxicities. AB - Patients are exposed to numerous prescribed and over-the-counter medications. Unfortunately, drugs remain a relatively common cause of acute and chronic kidney injury. A combination of factors including the innate nephrotoxicity of drugs, underlying patient characteristics that increase their risk for kidney injury, and the metabolism and pathway of excretion by the kidneys of the various agents administered enhance risk for drug-induced nephrotoxicity. This paper will review these clinically relevant aspects of drug-induced nephrotoxicity for the clinical nephrologist. PMID- 29622671 TI - Metabolic regulation of photosynthetic membrane structure tunes electron transfer function. AB - The photosynthetic chloroplast thylakoid membrane of higher plants is a complex three-dimensional structure that is morphologically dynamic on a timescale of just a few minutes. The membrane dynamics are driven by the phosphorylation of light-harvesting complex II (LHCII) by the STN7 kinase, which controls the size of the stacked grana region relative to the unstacked stromal lamellae region. Here, I hypothesise that the functional significance of these membrane dynamics is in controlling the partition of electrons between photosynthetic linear and cyclic electron transfer (LET and CET), which determines the ratio of NADPH/ATP produced. The STN7 kinase responds to the metabolic state of the chloroplast by sensing the stromal redox state. A high NADPH/ATP ratio leads to reduction of thioredoxin f (TRXf), which reduces a CxxxC motif in the stromal domain of STN7 leading to its inactivation, whereas a low NADPH/ATP ratio leads to oxidation of TRXf and STN7 activation. Phosphorylation of LHCII leads to smaller grana, which favour LET by speeding up diffusion of electron carriers plastoquinone (PQ) and plastocyanin (PC) between the domains. In contrast, dephosphorylation of LHCII leads to larger grana that slow the diffusion of PQ and PC, leaving the PQ pool in the stroma more oxidised, thus enhancing the efficiency of CET. The feedback regulation of electron transfer by the downstream metabolism is crucial to plant fitness, since perturbations in the NADPH/ATP ratio can rapidly lead to the inhibition of photosynthesis and photo-oxidative stress. PMID- 29622669 TI - Secular Trends in Infection-Related Mortality after Kidney Transplantation. AB - BACKGROUND AND OBJECTIVES: Infections are the most common noncardiovascular causes of death after kidney transplantation. We analyzed the current infection related mortality among kidney transplant recipients in a nationwide cohort in Finland. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Altogether, 3249 adult recipients of a first kidney transplant from 1990 to 2012 were included. Infectious causes of death were analyzed, and the mortality rates for infections were compared between two eras (1990-1999 and 2000-2012). Risk factors for infectious deaths were analyzed with Cox regression and competing risk analyses. RESULTS: Altogether, 953 patients (29%) died during the follow-up, with 204 infection-related deaths. Mortality rate (per 1000 patient-years) due to infections was lower in the more recent cohort (4.6; 95% confidence interval, 3.5 to 6.1) compared with the older cohort (9.1; 95% confidence interval, 7.6 to 10.7); the incidence rate ratio of infectious mortality was 0.51 (95% confidence interval, 0.30 to 0.68). The main causes of infectious deaths were common bacterial infections: septicemia in 38% and pulmonary infections in 45%. Viral and fungal infections caused only 2% and 3% of infectious deaths, respectively (such as individual patients with Cytomegalovirus pneumonia, Herpes simplex virus meningoencephalitis, Varicella zoster virus encephalitis, and Pneumocystis jirovecii infection). Similarly, opportunistic bacterial infections rarely caused death; only one death was caused by Listeria monocytogenes, and two were caused by Mycobacterium tuberculosis. Only 23 (11%) of infection-related deaths occurred during the first post-transplant year. Older recipient age, higher plasma creatinine concentration at the end of the first post-transplant year, diabetes as a cause of ESKD, longer pretransplant dialysis duration, acute rejection, low albumin level, and earlier era of transplantation were associated with increased risk of infectious death in multivariable analysis. CONCLUSIONS: The risk of death due to infectious causes after kidney transplantation in Finland dropped by one half since the 1990s. Common bacterial infections remained the most frequent cause of infection-related mortality, whereas opportunistic viral, fungal, or unconventional bacterial infections rarely caused deaths after kidney transplantation. PMID- 29622673 TI - An update on paediatric respiratory diseases. PMID- 29622672 TI - Viral infections in wheezing disorders. AB - Over the past year, studies into virus-induced wheeze in children have shifted towards investigations that examine the mechanisms by which respiratory viruses cause wheeze and an increase in studies examining the effects of novel interventions to reduce wheezing exacerbations. Studies on rhinovirus species (RV)-C infection have found that this is associated with a decrease in expression of CDHR3, the cellular receptor specific for this virus, and a decrease in interferon-beta expression, both of which are likely to favour RV-C infection. Recent clinical trials in children have found a decrease in wheezing exacerbations with both anti-respiratory syncytial virus antibody and anti immunoglobulin E antibody therapy, and a clinical trial of prednisolone in children with their first RV-induced wheeze showed that only those with an RV viral count >7000 copies.mL-1 responded. Further studies on the effects of bacterial lysates on immune system function continue to support the potential of this approach to reduce virus-induced wheezing exacerbations in children. These studies and many previous investigations into immunomodulation using bacterial lysates have led to the funding and commencement of a large study in which long term administration of a bacterial lysate in young children will be assessed for its ability to prevent asthma. PMID- 29622674 TI - Introduction to the Thematic Minireview Series: Redox metabolism and signaling. AB - In this sequel to the thematic collection of Minireviews on redox metabolism and signaling published last year, five articles plumb the redox metabolic pathways relevant to cell proliferation, stress response, and survival post-detachment from the extracellular matrix. The sixth article provides unexpected insights into the hepatic NAD(P)ome, revealing that more than half of these proteins reside outside the cytoplasmic and mitochondrial compartments, pointing to the paucity of knowledge on their functions. Collectively, these articles highlight the metabolic adaptability of proliferating cells to meet redox needs, the use of lipids to mediate mitochondrial stress responses, and the need for tools to interrogate compartment-specific pool sizes and oxidized/reduced ratios of antioxidants and lipids involved in redox homeostasis. PMID- 29622675 TI - Sorting nexin 9 (SNX9) regulates levels of the transmembrane ADAM9 at the cell surface. AB - ADAM9 is an active member of the family of transmembrane ADAMs (a disintegrin and metalloproteases). It plays a role in processes such as bone formation and retinal neovascularization, and importantly, its expression in human cancers correlates with disease stage and poor prognosis. Functionally, ADAM9 can cleave several transmembrane proteins, thereby shedding their ectodomains from the cell surface. Moreover, ADAM9 regulates cell behavior by binding cell-surface receptors such as integrin and membrane-type matrix metalloproteases. Because these functions are mainly restricted to the cell surface, understanding the mechanisms regulating ADAM9 localization and activity at this site is highly important. To this end, we here investigated how intracellular trafficking regulates ADAM9 availability at the cell surface. We found that ADAM9 undergoes constitutive clathrin-dependent internalization and subsequent degradation or recycling to the plasma membrane. We confirmed previous findings of an interaction between ADAM9 and the intracellular sorting protein, sorting nexin 9 (SNX9), as well as its close homolog SNX18. Knockdown of either SNX9 or SNX18 had no apparent effects on ADAM9 internalization or recycling. However, double knockdown of SNX9 and SNX18 decreased ADAM9 internalization significantly, demonstrating a redundant role in this process. Moreover, SNX9 knockdown revealed a nonredundant effect on overall ADAM9 protein levels, resulting in increased ADAM9 levels at the cell surface, and a corresponding increase in the shedding of Ephrin receptor B4, a well-known ADAM9 substrate. Together, our findings demonstrate that intracellular SNX9-mediated trafficking constitutes an important ADAM9 regulatory pathway. PMID- 29622676 TI - On the (un)coupling of the chromophore, tongue interactions, and overall conformation in a bacterial phytochrome. AB - Phytochromes are photoreceptors in plants, fungi, and various microorganisms and cycle between metastable red light-absorbing (Pr) and far-red light-absorbing (Pfr) states. Their light responses are thought to follow a conserved structural mechanism that is triggered by isomerization of the chromophore. Downstream structural changes involve refolding of the so-called tongue extension of the phytochrome-specific GAF-related (PHY) domain of the photoreceptor. The tongue is connected to the chromophore by conserved DIP and PRXSF motifs and a conserved tyrosine, but the role of these residues in signal transduction is not clear. Here, we examine the tongue interactions and their interplay with the chromophore by substituting the conserved tyrosine (Tyr263) in the phytochrome from the extremophile bacterium Deinococcus radiodurans with phenylalanine. Using optical and FTIR spectroscopy, X-ray solution scattering, and crystallography of chromophore-binding domain (CBD) and CBD-PHY fragments, we show that the absence of the Tyr263 hydroxyl destabilizes the beta-sheet conformation of the tongue. This allowed the phytochrome to adopt an alpha-helical tongue conformation regardless of the chromophore state, hence distorting the activity state of the protein. Our crystal structures further revealed that water interactions are missing in the Y263F mutant, correlating with a decrease of the photoconversion yield and underpinning the functional role of Tyr263 in phytochrome conformational changes. We propose a model in which isomerization of the chromophore, refolding of the tongue, and globular conformational changes are represented as weakly coupled equilibria. The results also suggest that the phytochromes have several redundant signaling routes. PMID- 29622677 TI - Heparan sulfate antagonism alters bone morphogenetic protein signaling and receptor dynamics, suggesting a mechanism in hereditary multiple exostoses. AB - Hereditary multiple exostoses (HME) is a pediatric disorder caused by heparan sulfate (HS) deficiency and is characterized by growth plate-associated osteochondromas. Previously, we found that osteochondroma formation in mouse models is preceded by ectopic bone morphogenetic protein (BMP) signaling in the perichondrium, but the mechanistic relationships between BMP signaling and HS deficiency remain unclear. Therefore, we used an HS antagonist (surfen) to investigate the effects of this HS interference on BMP signaling, ligand availability, cell-surface BMP receptor (BMPR) dynamics, and BMPR interactions in Ad-293 and C3H/10T1/2 cells. As observed previously, the HS interference rapidly increased phosphorylated SMAD family member 1/5/8 levels. FACS analysis and immunoblots revealed that the cells possessed appreciable levels of endogenous cell-surface BMP2/4 that were unaffected by the HS antagonist, suggesting that BMP2/4 proteins remained surface-bound but became engaged in BMPR interactions and SMAD signaling. Indeed, surface mobility of SNAP-tagged BMPRII, measured by fluorescence recovery after photobleaching (FRAP), was modulated during the drug treatment. This suggested that the receptors had transitioned to lipid rafts acting as signaling centers, confirmed for BMPRII via ultracentrifugation to separate membrane subdomains. In situ proximity ligation assays disclosed that the HS interference rapidly stimulates BMPRI-BMPRII interactions, measured by oligonucleotide-driven amplification signals. Our in vitro studies reveal that cell-associated HS controls BMP ligand availability and BMPR dynamics, interactions, and signaling, and largely restrains these processes. We propose that HS deficiency in HME may lead to extensive local BMP signaling and altered BMPR dynamics, triggering excessive cellular responses and osteochondroma formation. PMID- 29622678 TI - Calcium-induced structural rearrangements release autoinhibition in the Rap-GEF CalDAG-GEFI. AB - Platelets are recruited to sites of vascular injury, where they are activated and aggregate to form a hemostatic plug. This process requires the activation of the small GTPase Rap1B by its cognate guanine nucleotide exchange factor CalDAG-GEFI. Studies on platelet function suggest that CalDAG-GEFI activity is regulated by changes in cytosolic calcium, but the exact molecular mechanism is poorly understood. Here we show that purified CalDAG-GEFI is autoinhibited and directly regulated by calcium. Substitutions of putative calcium-binding residues within the canonical EF hands of CalDAG-GEFI diminish its capacity to activate Rap1B. Structural differences between active (WT) and inactive (EF hand variant) CalDAG GEFI protein were determined by hydrogen-deuterium exchange MS. The highest differential rates of deuterium uptake in WT over EF hand variant CalDAG-GEFI were observed in regions within the catalytic Cdc25 domain and a putative autoinhibitory linker connecting the Cdc25 and EF hand domains. Exchange activity in the EF hand variant was fully restored by an additional substitution, valine 406 to glutamate, which is thought to disrupt the interface between the autoinhibitory linker and the Cdc25 domain. Overall, our results suggest a model for how CalDAG-GEFI remains in an autoinhibited state when levels of cytosolic calcium in resting platelets are low. In response to cellular stimulation, calcium mobilization and binding to the EF hands causes conformational rearrangements within CalDAG-GEFI, including the autoinhibitory linker that frees the catalytic surface of CalDAG-GEFI to engage and activate Rap1B. The data from this study are the first evidence linking CalDAG-GEFI activity directly to calcium. PMID- 29622679 TI - An intersubunit electrostatic interaction in the GABAA receptor facilitates its responses to benzodiazepines. AB - Benzodiazepines are positive allosteric modulators of the GABAA receptor (GABAAR), acting at the alpha-gamma subunit interface to enhance GABAAR function. GABA or benzodiazepine binding induces distinct conformational changes in the GABAAR. The molecular rearrangements in the GABAAR following benzodiazepine binding remain to be fully elucidated. Using two molecular models of the GABAAR, we identified electrostatic interactions between specific amino acids at the alpha-gamma subunit interface that were broken by, or formed after, benzodiazepine binding. Using two-electrode voltage clamp electrophysiology in Xenopus laevis oocytes, we investigated these interactions by substituting one or both amino acids of each potential pair. We found that Lys104 in the alpha1 subunit forms an electrostatic bond with Asp75 of the gamma2 subunit after benzodiazepine binding and that this bond stabilizes the positively modified state of the receptor. Substitution of these two residues to cysteine and subsequent covalent linkage between them increased the receptor's sensitivity to low GABA concentrations and decreased its response to benzodiazepines, producing a GABAAR that resembles a benzodiazepine-bound WT GABAAR. Breaking this bond restored sensitivity to GABA to WT levels and increased the receptor's response to benzodiazepines. The alpha1 Lys104 and gamma2 Asp75 interaction did not play a role in ethanol or neurosteroid modulation of GABAAR, suggesting that different modulators induce different conformational changes in the receptor. These findings may help explain the additive or synergistic effects of modulators acting at the GABAAR. PMID- 29622680 TI - Mitochondrial Proteostasis in the Context of Cellular and Organismal Health and Aging. AB - As a central hub of cellular metabolism and signaling, the mitochondrion is a crucial organelle whose dysfunction can cause disease and whose activity is intimately connected to aging. We review how the mitochondrial network maintains proteomic integrity, how mitochondrial proteotoxic stress is communicated and resolved in the context of the entire cell, and how mitochondrial systems function in the context of organismal health and aging. A deeper understanding of how mitochondrial protein quality control mechanisms are coordinated across these distinct biological levels should help explain why these mechanisms fail with age and, ultimately, how routes to intervention might be attained. PMID- 29622682 TI - Auditory motion parallax. PMID- 29622681 TI - Heterochromatin protects retinal pigment epithelium cells from oxidative damage by silencing p53 target genes. AB - Oxidative stress (OS)-induced retinal pigment epithelium (RPE) cell apoptosis is critically implicated in the pathogenesis of age-related macular degeneration (AMD), a leading cause of blindness in the elderly. Heterochromatin, a compact and transcriptional inert chromatin structure, has been recently shown to be dynamically regulated in response to stress stimuli. The functional mechanism of heterochromatin on OS exposure is unclear, however. Here we show that OS increases heterochromatin formation both in vivo and in vitro, which is essential for protecting RPE cells from oxidative damage. Mechanistically, OS-induced heterochromatin selectively accumulates at p53-regulated proapoptotic target promoters and inhibits their transcription. Furthermore, OS-induced desumoylation of p53 promotes p53-heterochromatin interaction and regulates p53 promoter selection, resulting in the locus-specific recruitment of heterochromatin and transcription repression. Together, our findings demonstrate a protective function of OS-induced heterochromatin formation in which p53 desumoylation guided promoter selection and subsequent heterochromatin recruitment play a critical role. We propose that targeting heterochromatin provides a plausible therapeutic strategy for the treatment of AMD. PMID- 29622683 TI - Peak forelimb ground reaction forces experienced by dogs jumping from a simulated car boot. AB - Many dog owners allow their pets to jump out of a car boot; however, to date, there has been no study that has investigated whether this places dogs at risk of injury. The aim of this study was to investigate the relationship between height and peak vertical ground reaction force (vGRF) in static start jumps. Fifteen healthy adult dogs performed three jumps from a platform that represented common vehicle boot sill heights (0.55, 0.65, 0.75 m), landing on a single force platform. Kinetic data (mediolateral (Fx), craniocaudal (Fy) and vertical (Fz)) were normalised for body weight and analysed via a one-way repeated analysis of variance (ANOVA) and pairwise post hoc tests with a Bonferroni correction applied. There was a significant difference in peak forelimb vGRF between both the 0.55 m (27.35+/-4.14 N/kg) and the 0.65 m (30.84+/-3.66 N/kg) platform (P=0.001) and between the 0.65 and 0.75 m (34.12+/-3.63 N/kg) platform (P=0.001). There was no significant difference in mediolateral or craniocaudal forces between the heights examined. These results suggest that allowing dogs to jump from bigger cars with a higher boot sill may result in augmented levels of loading on anatomical structures. Further research is required to investigate the kinematic effects of height on static jump-down and how peak forelimb vGRF relates to anatomical loading and subsequent injury risk. PMID- 29622684 TI - Prevalence of feline urinary tract pathogens and antimicrobial resistance over five years. AB - The aim of this retrospective study was to document the prevalence of bacterial species in cats with significant bacteriuria and to compare their antimicrobial susceptibilities over five years. One hundred sixty-nine positive urine cultures from 150 cats were included. Fifty-five per cent showed clinical signs, while 40 per cent had subclinical bacteriuria. Escherichia coli, Staphylococcus species, Enterococcus species, Streptococcus species and Proteus mirabilis accounted for 50.5 per cent, 22.9 per cent, 15,1 per cent, 3.6 per cent and 2.6 per cent, respectively. Enterococcus species was significantly more common in cats with subclinical bacteriuria. Enterococcus species and Proteus mirabilis isolates were resistant to a significantly higher number of antimicrobials than other isolates. Applying the formula to select rational antimicrobial therapy, bacterial isolates were most likely to be susceptible to imipenem, nitrofurantoin, gentamicin and amoxicillin clavulanic acid. Over the study period, only minor differences were noted for the antimicrobial impact factors (IFs) between years and between cats with and without clinical signs. The cumulative IF increased significantly compared with the previous 10 years. Empirical treatment of bacterial cystitis should be avoided whenever possible and, if needed, based on the locally determined bacterial spectrum and antibiotic susceptibility. PMID- 29622685 TI - Evaluation of the cost-effectiveness of evolocumab in the FOURIER study: a Canadian analysis. AB - BACKGROUND: Evolocumab, a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor, has been shown to reduce low-density lipoprotein levels by up to 60%. Despite the absence of a reduction in overall or cardiovascular mortality in the Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk (FOURIER) trial, some believe that, with longer treatment, such a benefit might eventually be realized. Our aim was to estimate the potential mortality benefit over a patient's lifetime and the cost per year of life saved (YOLS) for an average Canadian with established coronary artery disease. We also sought to estimate the price threshold at which evolocumab might be considered cost-effective for secondary prevention in Canada. METHODS: We calibrated the Cardio-metabolic Model, a well-validated tool for predicting cardiovascular events and life expectancy, to the reduction in nonfatal events seen in the FOURIER trial. Assuming that long-term treatment will eventually result in mortality benefits, we estimated YOLSs and cost per YOLS with evolocumab treatment plus a statin compared to a statin alone. We then estimated the annual drug costs that would provide a 50% chance of being cost-effective at willingness to-pay values of $50 000 and $100 000. RESULTS: In secondary prevention in patients similar to those in the FOURIER study, evolocumab treatment would save an average of 0.34 (95% confidence interval [CI] 0.27-0.41) life-years at a cost of $101 899 (95% CI $97 325-$106 473), yielding a cost per YOLS of $299 482. We estimate that to have a 50% probability of achieving a cost per YOLS below $50 000 and $100 000 would require annual drug costs below $1200 and $2300, respectively. INTERPRETATION: At current pricing, the use of evolocumab for secondary prevention is unlikely to be cost-effective in Canada. PMID- 29622686 TI - VIPP1 Involved in Chloroplast Membrane Integrity Has GTPase Activity in Vitro. AB - VESICLE-INDUCING PROTEIN IN PLASTID1 (VIPP1) is conserved among oxygenic photosynthetic organisms and appears to have diverged from the bacterial PspA protein. VIPP1 localizes to the chloroplast envelope and thylakoid membrane, where it forms homooligomers of high molecular mass. Although multiple roles of VIPP1 have been inferred, including thylakoid membrane formation, envelope maintenance, membrane fusion, and regulation of photosynthetic activity, its precise role in chloroplast membrane quality control remains unknown. VIPP1 forms an oligomer through its amino-terminal domain and triggers membrane fusion in an Mg2+-dependent manner. We previously demonstrated that Arabidopsis (Arabidopsis thaliana) VIPP1 also exhibits dynamic complex disassembly in response to osmotic and heat stresses in vivo. These results suggest that VIPP1 mediates membrane fusion/remodeling in chloroplasts. Considering that protein machines that regulate intracellular membrane fusion/remodeling events often require a capacity for GTP binding and/or hydrolysis, we questioned whether VIPP1 has similar properties. We conducted an in vitro assay using a purified VIPP1-His fusion protein expressed in Escherichia coli cells. VIPP1-His showed GTP hydrolysis activity that was inhibited competitively by an unhydrolyzable GTP analog, GTPgammaS, and that depends on GTP binding. It is particularly interesting that the ancestral PspA from E. coli also possesses GTP hydrolysis activity. Although VIPP1 does not contain a canonical G domain, the amino-terminal alpha-helix was found to be important for both GTP binding and GTP hydrolysis as well as for oligomer formation. Collectively, our results reveal that the properties of VIPP1/PspA are similar to those of GTPases. PMID- 29622687 TI - The Linker Histone GH1-HMGA1 Is Involved in Telomere Stability and DNA Damage Repair. AB - Despite intensive searches, few proteins involved in telomere homeostasis have been identified in plants. Here, we used pull-down assays to identify potential telomeric interactors in the model plant species Arabidopsis (Arabidopsis thaliana). We identified the candidate protein GH1-HMGA1 (also known as HON4), an uncharacterized linker histone protein of the High Mobility Group Protein A (HMGA) family in plants. HMGAs are architectural transcription factors and have been suggested to function in DNA damage repair, but their precise biological roles remain unclear. Here, we show that GH1-HMGA1 is required for efficient DNA damage repair and telomere integrity in Arabidopsis. GH1-HMGA1 mutants exhibit developmental and growth defects, accompanied by ploidy defects, increased telomere dysfunction-induced foci, mitotic anaphase bridges, and degraded telomeres. Furthermore, mutants have a higher sensitivity to genotoxic agents such as mitomycin C and gamma-irradiation. Our work also suggests that GH1-HMGA1 is involved directly in the repair process by allowing the completion of homologous recombination. PMID- 29622688 TI - Palliative care in medical practice: medical students' expectations. AB - OBJECTIVES: During their careers, all doctors will be involved in the care of the dying, and this is likely to increase with current demographic trends. Future doctors need to be well-prepared for this. Little is known about medical students' expectations about providing palliative care. Our aim was to investigate how satisfying students expect palliative care to be, and any attitudes towards palliative care associated with a negative expectation. METHODS: Fifteen UK medical schools participated in the study, with 1898 first and final year students completing an online questionnaire which investigated how satisfying they expect providing palliative care to be and their attitudes towards palliative care. RESULTS: At both the beginning and end of their training, a significant proportion of students expect palliative care to be less satisfying than other care (19.3% first year, 16% final year). Students expecting palliative care to be less satisfying were more likely to be men, and their attitudes suggest that while they understand the importance of providing palliative care they are concerned about the potential impact of this kind of work on them personally. CONCLUSIONS: Medical student education needs to address why palliative care is important and how to deliver it effectively, and the strategies for dealing positively with the impact of this work on future clinicians. PMID- 29622690 TI - 'Malignant' pleural effusion with abdominal gossypiboma. PMID- 29622689 TI - Protein stabilization by RSUME accounts for PTTG pituitary tumor abundance and oncogenicity. AB - Increased levels of the proto-oncogene pituitary tumor-transforming gene 1 (PTTG) have been repeatedly reported in several human solid tumors, especially in endocrine-related tumors such as pituitary adenomas. Securin PTTG has a critical role in pituitary tumorigenesis. However, the cause of upregulation has not been found yet, despite analyses made at the gene, promoter and mRNA level that show that no mutations, epigenetic modifications or other mechanisms that deregulate its expression may explain its overexpression and action as an oncogene. We describe that high PTTG protein levels are induced by the RWD-containing sumoylation enhancer (RWDD3 or RSUME), a protein originally identified in the same pituitary tumor cell line in which PTTG was also cloned. We demonstrate that PTTG and RSUME have a positive expression correlation in human pituitary adenomas. RSUME increases PTTG protein in pituitary tumor cell lines, prolongs the half-life of PTTG protein and regulates the PTTG induction by estradiol. As a consequence, RSUME enhances PTTG transcription factor and securin activities. PTTG hyperactivity on the cell cycle resulted in recurrent and unequal divisions without cytokinesis, and the consequential appearance of aneuploidies and multinucleated cells in the tumor. RSUME knockdown diminishes securin PTTG and reduces its tumorigenic potential in a xenograft mouse model. Taken together, our findings show that PTTG high protein steady state levels account for PTTG tumor abundance and demonstrate a critical role of RSUME in this process in pituitary tumor cells. PMID- 29622691 TI - Seasonal temperature variability and emergency hospital admissions for respiratory diseases: a population-based cohort study. AB - BACKGROUND: Climate change increases global mean temperature and changes short term (eg, diurnal) and long-term (eg, intraseasonal) temperature variability. Numerous studies have shown that mean temperature and short-term temperature variability are both associated with increased respiratory morbidity or mortality. However, data on the impact of long-term temperature variability are sparse. OBJECTIVE: We aimed to assess the association of intraseasonal temperature variability with respiratory disease hospitalisations among elders. METHODS: We ascertained the first occurrence of emergency hospital admissions for respiratory diseases in a prospective Chinese elderly cohort of 66 820 older people (>=65 years) with 10-13 years of follow-up. We used an ordinary kriging method based on 22 weather monitoring stations in Hong Kong to spatially interpolate daily ambient temperature for each participant's residential address. Seasonal temperature variability was defined as the SD of daily mean summer (June August) or winter (December-February) temperatures. We applied Cox proportional hazards regression with time-varying exposure of seasonal temperature variability to respiratory admissions. RESULTS: During the follow-up time, we ascertained 12 689 cases of incident respiratory diseases, of which 6672 were pneumonia and 3075 were COPD. The HRs per 1 degrees C increase in wintertime temperature variability were 1.20 (95% CI 1.08 to 1.32), 1.15 (1.01 to 1.31) and 1.41 (1.15 to 1.71) for total respiratory diseases, pneumonia and COPD, respectively. The associations were not statistically significant for summertime temperature variability. CONCLUSION: Wintertime temperature variability was associated with higher risk of incident respiratory diseases. PMID- 29622692 TI - Predicting risk of unplanned hospital readmission in survivors of critical illness: a population-level cohort study. AB - BACKGROUND: Intensive care unit (ICU) survivors experience high levels of morbidity after hospital discharge and are at high risk of unplanned hospital readmission. Identifying those at highest risk before hospital discharge may allow targeting of novel risk reduction strategies. We aimed to identify risk factors for unplanned 90-day readmission, develop a risk prediction model and assess its performance to screen for ICU survivors at highest readmission risk. METHODS: Population cohort study linking registry data for patients discharged from general ICUs in Scotland (2005-2013). Independent risk factors for 90-day readmission and discriminant ability (c-index) of groups of variables were identified using multivariable logistic regression. Derivation and validation risk prediction models were constructed using a time-based split. RESULTS: Of 55 975 ICU survivors, 24.1% (95%CI 23.7% to 24.4%) had unplanned 90-day readmission. Pre-existing health factors were fair discriminators of readmission (c-index 0.63, 95% CI 0.63 to 0.64) but better than acute illness factors (0.60) or demographics (0.54). In a subgroup of those with no comorbidity, acute illness factors (0.62) were better discriminators than pre-existing health factors (0.56). Overall model performance and calibration in the validation cohort was fair (0.65, 95% CI 0.64 to 0.66) but did not perform sufficiently well as a screening tool, demonstrating high false-positive/false-negative rates at clinically relevant thresholds. CONCLUSIONS: Unplanned 90-day hospital readmission is common. Pre-existing illness indices are better predictors of readmission than acute illness factors. Identifying additional patient-centred drivers of readmission may improve risk prediction models. Improved understanding of risk factors that are amenable to intervention could improve the clinical and cost-effectiveness of post-ICU care and rehabilitation. PMID- 29622693 TI - Stratification by interferon-gamma release assay level predicts risk of incident TB. AB - INTRODUCTION: Targeted testing and treatment of latent TB infection (LTBI) are priorities on the global health agenda, but LTBI management remains challenging. We aimed to evaluate the prognostic value of the QuantiFERON TB-Gold (QFT) test for incident TB, focusing on the interferon (IFN)-gamma level, when applied in routine practice in a low TB incidence setting. METHODS: In this large population based prospective cohort, we linked QFT results in Norway (1 January 2009-30 June 2014) with national registry data (Norwegian Surveillance System for Infectious Diseases, Norwegian Prescription Database, Norwegian Patient Registry and Statistics Norway) to assess the prognostic value of QFT for incident TB. Participants were followed until 30 June 2016. We used restricted cubic splines to model non-linear relationships between IFN-gamma levels and TB, and applied these findings to a competing risk model. RESULTS: The prospective analyses included 50 389 QFT results from 44 875 individuals, of whom 257 developed TB. Overall, 22% (n=9878) of QFT results were positive. TB risk increased with the IFN-gamma level until a plateau level, above which further increase was not associated with additional prognostic information. The HRs for TB were 8.8 (95% CI 4.7 to 16.5), 19.2 (95% CI 11.6 to 31.6) and 31.3 (95% CI 19.8 to 49.5) times higher with IFN-gamma levels of 0.35 to <1.00, 1.00 to <4.00 and >4.00 IU/mL, respectively, compared with negative tests (<0.35 IU/mL). CONCLUSIONS: Consistently, QFT demonstrates increased risk of incident TB with rising IFN gamma concentrations, indicating that IFN-gamma levels may be used to guide targeted treatment of LTBI. PMID- 29622695 TI - Administration of mesenchymal stem cells during ECMO results in a rapid decline in oxygenator performance. AB - Mesenchymal stem cells (MSCs) have attracted attention as a potential therapy for Acute Respiratory Distress Syndrome (ARDS). At the same time, the use of extracorporeal membrane oxygenation (ECMO) has increased among patients with severe ARDS. To date, early clinical trials of MSCs in ARDS have excluded patients supported by ECMO. Here we provide evidence from an ex-vivo model of ECMO to suggest that the intravascular administration of MSCs during ECMO may adversely impact the function of a membrane oxygenator. The addition of clinical grade MSCs resulted in a reduction of flow through the circuit in comparison to controls (0.6 +/-0.35 L min-1vs 4.12 +/- 0.03 L min-1, at 240 minutes) and an increase in the transoygenator pressure gradient (101+/-9 mmHg vs 21+/-4 mmHg, at 240 minutes). Subsequent immunohistochemistry analysis demonstrated quantities of MSCs highly adherent to membrane oxygenator fibres. This study highlights the potential harm associated with MSC therapy during ECMO and suggests further areas of research required to advance the translation of cell therapy in this population. PMID- 29622694 TI - Airway epithelial phosphoinositide 3-kinase-delta contributes to the modulation of fungi-induced innate immune response. AB - BACKGROUND: Respiratory fungal exposure is known to be associated with severe allergic lung inflammation. Airway epithelium is an essential controller of allergic inflammation. An innate immune recognition receptor, nucleotide-binding domain, leucine-rich-containing family, pyrin-domain-containing-3 (NLRP3) inflammasome, and phosphoinositide 3 kinase (PI3K)-delta in airway epithelium are involved in various inflammatory processes. OBJECTIVES: We investigated the role of NLRP3 inflammasome in fungi-induced allergic lung inflammation and examined the regulatory mechanism of NLRP3 inflammasome, focusing on PI3K-delta in airway epithelium. METHODS: We used two in vivo models induced by exposure to Aspergillus fumigatus (Af) and Alternaria alternata (Aa), as well as an Af exposed in vitro system. We also checked NLRP3 expression in lung tissues from patients with allergic bronchopulmonary aspergillosis (ABPA). RESULTS: Assembly/activation of NLRP3 inflammasome was increased in the lung of Af-exposed mice. Elevation of NLRP3 inflammasome assembly/activation was observed in Af stimulated murine and human epithelial cells. Similarly, pulmonary expression of NLRP3 in patients with ABPA was increased. Importantly, neutralisation of NLRP3 inflammasome derived IL-1beta alleviated pathophysiological features of Af induced allergic inflammation. Furthermore, PI3K-delta blockade improved Af induced allergic inflammation through modulation of NLRP3 inflammasome, especially in epithelial cells. This modulatory role of PI3K-delta was mediated through the regulation of mitochondrial reactive oxygen species (mtROS) generation. NLRP3 inflammasome was also implicated in Aa-induced eosinophilic allergic inflammation, which was improved by PI3K-delta blockade. CONCLUSION: These findings demonstrate that fungi-induced assembly/activation of NLRP3 inflammasome in airway epithelium may be modulated by PI3K-delta, which is mediated partly through the regulation of mtROS generation. Inhibition of PI3K delta may have potential for treating fungi-induced severe allergic lung inflammation. PMID- 29622696 TI - COPD and cardiovascular diseases: now is the time for action! PMID- 29622697 TI - FDA Approval Summary: Tocilizumab for Treatment of Chimeric Antigen Receptor T Cell-Induced Severe or Life-Threatening Cytokine Release Syndrome. AB - : On August 30, 2017, the U.S. Food and Drug Administration approved Actemra (tocilizumab, Genentech, Inc., South San Francisco, CA) for the treatment of severe or life-threatening chimeric antigen receptor (CAR) T cell-induced cytokine release syndrome (CRS) in adults and in pediatric patients 2 years of age and older. The approval was based on a retrospective analysis of data for patients who developed CRS after treatment with CTL019 and KTE-C19 on prospective clinical trials. Evaluable patients had been treated with intravenous tocilizumab 8 mg/kg (12 mg/kg for patients <30 kg) for severe or life-threatening CRS; only the first episode of CRS was included in the analysis. The efficacy population for the CTL019 cohort included 24 male and 21 female patients (total 45 patients) of median age 12 years. The median time from the start of CRS to the first dose of tocilizumab was 4 days (range, 0-18 days). Patients were considered responders if CRS resolved within 14 days of the first dose of tocilizumab, if no more than 2 doses of tocilizumab were needed, and if no drugs other than tocilizumab and corticosteroids were used for treatment. Thirty-one patients (69%; 95% confidence interval, 53%-82%) achieved a response as defined. In an independent cohort of 15 patients with KTE-C19-induced CRS, 53% responded. Further study is needed to determine the optimal dose of tocilizumab and to confirm the safety of its use for treatment of patients with CAR T cell-induced CRS. IMPLICATIONS FOR PRACTICE: Severe or life-threatening chimeric antigen receptor (CAR) T cell-induced cytokine release syndrome (CRS) requires urgent treatment to prevent fatal outcomes. In two independent cohorts, the majority of patients with severe or life-threatening CAR T cell-induced CRS responded to treatment with one or two doses of tocilizumab in addition to advanced supportive care. More research is needed to determine the optimal dose and schedule of tocilizumab for treatment of CAR T cell-induced CRS. PMID- 29622698 TI - Value of Supportive Care Pharmacogenomics in Oncology Practice. AB - : Genomic medicine provides opportunities to personalize cancer therapy for an individual patient. Although novel targeted therapies prolong survival, most patients with cancer continue to suffer from burdensome symptoms including pain, depression, neuropathy, nausea and vomiting, and infections, which significantly impair quality of life. Suboptimal management of these symptoms can negatively affect response to cancer treatment and overall prognosis. The effect of genetic variation on drug response-otherwise known as pharmacogenomics-is well documented and directly influences an individual patient's response to antiemetics, opioids, neuromodulators, antidepressants, antifungals, and more. The growing body of pharmacogenomic data can now guide clinicians to select the safest and most effective supportive medications for an individual patient with cancer from the very first prescription. This review outlines a theoretical patient case and the implications of using pharmacogenetic test results to personalize supportive care throughout the cancer care continuum. IMPLICATIONS FOR PRACTICE: Integration of palliative medicine into the cancer care continuum has resulted in increased quality of life and survival for patients with many cancer types. However, suboptimal management of symptoms such as pain, neuropathy, depression, and nausea and vomiting continues to place a heavy burden on patients with cancer. As demonstrated in this theoretical case, pharmacogenomics can have a major effect on clinical response to medications used to treat these conditions. Recognizing the value of supportive care pharmacogenomics in oncology and application into routine practice offers an objective choice for the safest and most effective treatment compared with the traditional trial and error method. PMID- 29622699 TI - Comprehensive Computed Tomography Radiomics Analysis of Lung Adenocarcinoma for Prognostication. AB - BACKGROUND: In this era of personalized medicine, there is an expanded demand for advanced imaging biomarkers that reflect the biology of the whole tumor. Therefore, we investigated a large number of computed tomography-derived radiomics features along with demographics and pathology-related variables in patients with lung adenocarcinoma, correlating them with overall survival. MATERIALS AND METHODS: Three hundred thirty-nine patients who underwent operation for lung adenocarcinoma were included. Analysis was performed using 161 radiomics features, demographic, and pathologic variables and correlated each with patient survival. Prognostic performance for survival was compared among three models: (a) using only clinicopathological data; (b) using only selected radiomics features; and (c) using both clinicopathological data and selected radiomics features. RESULTS: At multivariate analysis, age, pN, tumor size, type of operation, histologic grade, maximum value of the outer 1/3 of the tumor, and size zone variance were statistically significant variables. In particular, maximum value of outer 1/3 of the tumor reflected tumor microenvironment, and size zone variance represented intratumor heterogeneity. Integration of 31 selected radiomics features with clinicopathological variables led to better discrimination performance. CONCLUSION: Radiomics approach in lung adenocarcinoma enables utilization of the full potential of medical imaging and has potential to improve prognosis assessment in clinical oncology. IMPLICATIONS FOR PRACTICE: Two radiomics features were prognostic for lung cancer survival at multivariate analysis: (a) maximum value of the outer one third of the tumor reflects the tumor microenvironment and (b) size zone variance represents the intratumor heterogeneity. Therefore, a radiomics approach in lung adenocarcinoma enables utilization of the full potential of medical imaging and could play a larger role in clinical oncology. PMID- 29622700 TI - Hybrid Capture-Based Tumor Sequencing and Copy Number Analysis to Confirm Origin of Metachronous Metastases in BRCA1-Mutant Cholangiocarcinoma Harboring a Novel YWHAZ-BRAF Fusion. AB - : Biliary tract cancers such as cholangiocarcinoma represent a heterogeneous group of cancers that can be difficult to diagnose. Recent comprehensive genomic analyses in large cholangiocarcinoma cohorts have defined important molecular subgroups within cholangiocarcinoma that may relate to anatomic location and etiology [1], [2], [3], [4] and may predict responsiveness to targeted therapies in development [5], [6], [7]. These emerging data highlight the potential for tumor genomics to inform diagnosis and treatment options in this challenging tumor type. We report the case of a patient with a germline BRCA1 mutation who presented with a cholangiocarcinoma driven by the novel YWHAZ-BRAF fusion. Hybrid capture-based DNA sequencing and copy number analysis performed as part of clinical care demonstrated that two later-occurring tumors were clonally derived from the primary cholangiocarcinoma rather than distinct new primaries, revealing an unusual pattern of late metachronous metastasis. We discuss the clinical significance of these genetic alterations and their relevance to therapeutic strategies. KEY POINTS: Hybrid capture-based next-generation DNA sequencing assays can provide diagnostic clarity in patients with unusual patterns of metastasis and recurrence in which the pathologic diagnosis is ambiguous.To our knowledge, this is the first reported case of a YWHAZ-BRAF fusion in pancreaticobiliary cancer, and a very rare case of cholangiocarcinoma in the setting of a germline BRCA1 mutation.The patient's BRCA1 mutation and YWHAZ-BRAF fusion constitute potential targets for future therapy. PMID- 29622702 TI - Perforated gastric remnant ulcer after laparoscopic gastric bypass. AB - Ulcer perforation in the excluded stomach and duodenum is a rare complication after Roux-en-Y gastric bypass (RYGB). Pathogenesis of these ulcers are multifactorial. We report a case of perforated gastric remnant ulcer in a 54-year old woman who had undergone a laparoscopic RYGB 5 years previously. The perforation was successfully repaired with an omental patch. We also present a review of the literature of similar cases. PMID- 29622703 TI - Immune stromal keratitis: a rare ocular presentation of tuberculosis. AB - An 11-year-old female patient presented with diminution of vision in both the eyes for the last 4 days. She had redness, watering and photophobia for the past 11 days. Slit lamp examination revealed multiple disc-shaped corneal stromal infiltrates with an overlying epithelial defect and hypopyon in both the eyes. A provisional diagnosis of infective keratitis was made. The patient was started on empirical antimicrobial therapy. However, no improvement was noted over the next 72 hours. Microbiological examination of the corneal scraping from both the eyes was negative. Considering the above, provisional diagnosis was changed to immune stromal keratouveitis and the patient was started on topical steroids. Further evaluation revealed a positive Mantoux test (30*20 mm) and contrast enhanced CT chest showing pulmonary nodules, suggestive of tuberculosis. The patient was subsequently started on antitubercular treatment. The infiltrates along with the ulcer and anterior uveitis responded dramatically to the revised treatment and resolved completely within 7 days of therapy. PMID- 29622704 TI - Mucinous adenocarcinoma arising from chronic perianal fistula mimicking horseshoe abscess. AB - Perianal fistulae are commonly seen clinical entity. Development of malignancy within a perianal fistula is rare. Even rarer is the development of mucinous adenocarcinoma in a chronic fistula-in-ano. Only a handful of such cases have been reported in the past. A case of mucinous adenocarcinoma arising in chronic perianal fistula in a 34-year-old woman is being described. She presented with complaints of perineal fullness, pain and recurrent pus discharge from perianal fistula for 4 years. On radiological workup, a large solid-cystic pelvic mass was seen in relation to the fistula. On MRI, the lesion was mimicking a large horseshoe abscess. Transrectal ultrasound-guided biopsy and subsequent histopathological examination confirmed the presence of mucinous adenocarcinoma with tumour cells immunopositive for CK7 and CK20. PMID- 29622701 TI - The Role of Notch3 in Cancer. AB - : The Notch family is a highly conserved gene group that regulates cell-cell interaction, embryogenesis, and tissue commitment. This review article focuses on the third Notch family subtype, Notch3. Regulation via Notch3 signaling was first implicated in vasculogenesis. However, more recent findings suggest that Notch3 signaling may play an important role in oncogenesis, tumor maintenance, and resistance to chemotherapy. Its role is mainly oncogenic, although in some cancers it appears to be tumor suppressive. Despite the wealth of published literature, it remains relatively underexplored and requires further research to shed more light on its role in cancer development, determine its tissue-specific function, and elaborate novel treatment strategies. Herein we summarize the role of Notch3 in cancer, possible mechanisms of its action, and current cancer treatment strategies targeting Notch3 signaling. IMPLICATIONS FOR PRACTICE: The Notch family is a highly conserved gene group that regulates cell-cell interaction, embryogenesis, and tissue commitment. This review summarizes the existing data on the third subtype of the Notch family, Notch3. The role of Notch3 in different types of cancers is discussed, as well as implications of its modification and new strategies to affect Notch3 signaling activity. PMID- 29622705 TI - Native valve endocarditis, fusarium and end-stage renal disease. AB - We would like to report a case of invasive Fusariosis involving the native mitral valve and complicated by septic thromboembolism. The patient was a known case of end-stage renal disease on maintenance haemodialysis and did not have any of the known risk factors for invasive Fusariosis like neutropaenia, severe T cell immunodeficiency, postsolid organ transplant recipients, posthaematopoietic stem cell transplant recipients and patients who received cytotoxic and/or high-dose corticosteroid therapy. PMID- 29622706 TI - Klebsiella endophthalmitis as the herald of occult colorectal cancer. AB - A 67-year-old Chinese man presented with acute loss of vision and pain in the left eye with hypopyon in the anterior chamber. The patient was afebrile with no systemic symptoms at presentation. Diagnosis of endogenous endophthalmitis was made with vitreous tap yielding Klebsiella pneumoniae Pars plana vitrectomy was performed twice to clear the infection. Thorough investigations showed no septic foci. Whole body positron emission tomography CT revealed a rectal tumour and biopsy showed adenocarcinoma. He was treated with neoadjuvant chemoirradiation followed by surgery to resect the tumour. Vision in the left eye was hand movement at 12 months postoperatively. This case illustrates Klebsiella endogenous endophthalmitis might be a herald of occult colorectal cancer. Bacteria might gain access into bloodstream via mucosal defect in the tumour. PMID- 29622707 TI - Paediatric non-ketotic hyperglycaemic hemichorea-hemiballismus. AB - Non-ketotic hyperglycaemic hemichorea-hemiballismus (NHHH) is commonly seen among elderly Asian women with type 2 diabetes mellitus. Here, we present a case of a 16-year-old Filipina with type 1 diabetes mellitus who is poorly compliant to her medications and subsequently developed right hemichorea-hemiballismus (HH). She was initially admitted with hyperglycaemia but was negative for ketonuria or metabolic acidosis. Neuroimaging showed bilateral lentiform nuclei and left caudate hyperdensities on CT and T1-weighted hyperintensity on MRI. Blood glucose was controlled with insulin. Haloperidol and clonazepam were started for the HH with gradual resolution of symptoms in 6 weeks. This is the fifth reported case of NHHH seen among the paediatric age group. NHHH in the paediatric population is clinically and radiographically similar to NHHH seen among adults. Correction of hyperglycaemia results in clinical improvement and radiographic resolution of lesions but persistent cases may necessitate specific treatment targeted towards the abnormal movements. PMID- 29622708 TI - Epidermoid cyst within an intrapancreatic accessory spleen. AB - This is a case of an epidermoid cyst in an intrapancreatic accessory spleen at the tail of the pancreas. Concurrent epidermoid cyst within the accessory spleen is an exceedingly rare entity. The patient initially presented with abdominal pain, nausea and vomiting. Imaging studies revealed a 3.6 cm cystic mass in the tail of the pancreas that was concerning for a mucinous cystic neoplasm (MCN). The patient underwent a robotic distal pancreatectomy for a suspected diagnosis of MCN, which following histologically examination was found to be an epidermoid cyst of an intrapancreatic accessory spleen. Further imaging characteristics are needed to characterise and differentiate these lesions from those of malignant potential. Robotic distal pancreatectomy is a safe alternative with many benefits including decreased length of stay and decreased blood loss. PMID- 29622709 TI - More than meets the eye: infant presenting with hypoxic ischaemic encephalopathy. AB - We report a newborn infant who presented with poor Apgar scores and umbilical artery acidosis leading to the diagnosis of hypoxic ischaemic encephalopathy. During the course of the infant's hospitalisation, subsequent workup revealed an underlying genetic cause that masqueraded as hypoxic ischaemic encephalopathy. PMID- 29622710 TI - Infectious causes of Addison's disease: 1 organ-2 organisms! PMID- 29622711 TI - Varicella-zoster virus necrotising retinitis, retinal vasculitis and panuveitis following uncomplicated chickenpox in an immunocompetent child. AB - A 4-year-old girl presented with acute left visual loss 4 weeks after uneventful chickenpox. She was found to have left necrotising retinitis and profound retinal vasculitis and vitritis. Aqueous humour was PCR positive for varicella-zoster virus. Combined intravenous and intravitreal antiviral treatment led to rapid improvement with settled retinitis, no vascular occlusion and good recovery of vision. Her recent coinfection with Epstein-Barr virus may have acted to provoke the retinitis. PMID- 29622712 TI - Isolated cystic lymphangiomatosis of spleen in an adult: a diagnostic conundrum. AB - Lymphangiomatosis is a rare developmental disorder characterised by diffuse proliferation of anastomosing lymphatic channels (lymphangiomas). It is believed to result from anomalous lymphatic development and usually presents in childhood. It typically occurs as a part of systemic lymphangiomatosis and isolated organ involvement is rare. Only nine cases of isolated cystic lymphangiomatosis of spleen have been reported between 1990 and 2010. Tuberculosis is a significant health problem in India and varied forms of this disease are seen in clinical practice. Isolated splenic tuberculosis, though a rare entity, has been described in the Indian population. We present a case of isolated splenic lymphangiomatosis in a 42-year-old woman that was initially misdiagnosed as splenic tuberculosis and was treated accordingly. Unresponsive to medical treatment, the patient underwent splenectomy and on histopathological examination, cystic lymphangiomatosis was diagnosed. The patient's symptoms resolved after surgery and she is doing well at a follow-up of 3 months. PMID- 29622713 TI - Uncommon presentation, rare complication and previously undescribed oncologic association of pheochromocytoma; the great masquerader. AB - We describe the case of a 67-year-old man presenting with ventricular tachycardia (VT) and systolic heart failure secondary to a left adrenal phaeochromocytoma. After treatment with amiodarone, the patient's VT resolved. However, his course was complicated by femoral deep venous thrombosis secondary to an incidentally discovered dedifferentiated liposarcoma of the thigh, for which he was prescribed a course of enoxaparin. The patient was discharged with plans for adrenalectomy following achievement of sufficient preoperative heart rate and blood pressure control with alpha-adrenergic receptor blockade, but re-presented to an outside facility in haemorrhagic shock, where he ultimately expired. Autopsy determined his death to be caused by spontaneous haemorrhage of the phaeochromocytoma. Cardiac manifestations, complications and oncological associations of phaeochromocytoma are discussed. PMID- 29622714 TI - Hypocalcaemia in an adult: the importance of not overlooking the cause. AB - A 58-year-old male patient was admitted at the Sao Bernardos's Hospital (Setubal, Portugal) with generalised muscle spasms, dyspnoea, laryngospasm and bronchospasm in the context of severe hypocalcaemia. Despite efforts to correct serum calcium, it remained below average, leading to question the true cause of hypocalcaemia. Low parathyroid hormone and 25-hydroxyvitamin D, along with facial anomalies, palate defect and cognitive impairment with concomitant psychiatric disorder led to a suspicion of a DiGeorge/velocardiofacial/22q11.2 deletion syndrome (DS), which was confirmed through genetic testing. The 22q11.2 DS has a wide phenotypic expression and there are growing reports of diagnosis being made in adulthood. This case report highlights the importance of understanding the cause of refractory hypocalcaemia and alerts medical community to carefully access these patients, for this metabolic disorder may only present in later stages of life. PMID- 29622715 TI - Chiari malformation and tuberculous meningitis: aetiology and management. AB - This is the first reported case of a Chiari 1 malformation in association with tuberculous (TB) meningitis. We present a case of a 23-year-old woman with a 2 week history nocturnal fever, vertigo, headache and projectile vomiting. She had nystagmus, scanning speech, bilateral papilloedema and ataxia. Cranial imaging showed a 10 mm tonsillar herniation. Posterior fossa decompression was done. Because the patient's gamut of symptoms was highly suspicious for a central nervous system infection, a lumbar tap was done which revealed TB meningitis. Four years later, after anti-TB medications and rehabilitation, all her symptoms except gait instability resolved. PMID- 29622716 TI - Bilateral multifocal acute lobar nephronia caused by Enterococcus faecalis. AB - An 8-year-old boy presented to our hospital with complaints of fever, epigastric pain and headache. Enterococcus faecalis were isolated from urine and blood culture, bacteraemic urinary tract infection was clinically diagnosed. Although vancomycin and ampicillin were administrated, fever did not subside. Contrast enhanced CT (CECT) revealed bilateral and multiple wedge-shaped defects, thus prompting a diagnosis of acute lobar nephronia (ALN). After 7 days of antibiotic treatment, the patient's fever subsided. ALN can be classified into two subgroups based on features of CECT; simple and complicated ALN. The treatment response to antibiotics tends to be delayed in complicated ALN, it is important that we understand the natural course of complicated ALN and should not escalate antibiotics hastily. According to previous studies, ALN has a wide regional variety of causative organisms. Therefore, the physician should recognise a local pattern of microbiological aetiology of ALN. PMID- 29622718 TI - Rapunzel syndrome: a tail too long to tell! PMID- 29622717 TI - Scorpion bite-induced unilateral pulmonary oedema. AB - A 24-year-old woman came to the emergency room of our hospital, 6 hours after a sting to the pulp of her middle finger of her left upper limb by an Indian red scorpion. On examination, she had tachycardia, tachypnoea, hypotension and low oxygen saturation at room temperature. On auscultation, there was poor air entry in all areas of the right lung along with crackles. The left lung field was normal on auscultation. Chest X-ray showed unilateral haziness of right lung field. Two-dimensional echocardiography showed clinical findings of myocarditis. Arterial blood gas showed metabolic acidosis with severe hypoxaemia, suggestive of type 1 respiratory failure. After intubation and initiating ventillatory support, the patient was given intravenous analgesics, antihistaminic and infiltrated of site of bite with 2% xylocaine. The patient was started on inotropes, alpha receptor blocker, intravenous steroids, bronchodilators and diuretics support. The patient clinically improved over the course of treatment and was subsequently discharged. PMID- 29622719 TI - Severe inflammatory ileitis resulting in ileal perforation in association with combination immune checkpoint blockade for metastatic malignant melanoma. AB - Immune checkpoint inhibitors have become standard of care in metastatic malignant melanoma management. Despite superior effectiveness to chemotherapy, significant immune-related adverse events (irAE) may occur, particularly if used in combination. Gastrointestinal irAEs were reported with different patterns of involvement. Here, we report the case of a patient who had ileal perforation as a complication of terminal ileitis, without colitis, induced by combination immune checkpoint blockade. PMID- 29622721 TI - Inpatient Asthma Care and Future Morbidity: A Role for Quality Improvement. PMID- 29622720 TI - Infant Pulmonary Function Testing and Phenotypes in Severe Bronchopulmonary Dysplasia. AB - BACKGROUND: The definition of severe bronchopulmonary dysplasia (sBPD) is based on respiratory support needs. The management of a patient with sBPD remains empirical and is highly variable among providers. Our objective in this study was to test the hypothesis that infant pulmonary function testing (iPFT) would reveal distinct phenotypes in patients with established sBPD during the initial NICU stay. METHODS: A prospective cohort study with data prospectively collected on infants with sBPD from May 1, 2003, to June 30, 2016. iPFT data were used to classify the patients as obstructive, restrictive, or mixed. RESULTS: The median gestational age at birth was 25 weeks (interquartile range [IQR], 24-27 weeks) and the median birth weight was 707 g (IQR, 581-925 g). At the time of iPFT, the median postmenstrual age was 52 weeks (IQR, 45-63 weeks), and the median weight was 4.4 kg (IQR, 3.7-6.0 kg). There were 56 (51%) patients with obstructive, 44 (40%) with mixed, and 10 (9%) with restrictive phenotypes. Moderate or severe obstruction was seen in 86% of the obstructive group and 78% of the mixed group. Of the restrictive patients, 70% had moderate and 30% had mild restriction. Bronchodilator response was seen in 74% of obstructive, 63% of mixed, and 25% of restrictive patients. CONCLUSIONS: Our findings reveal that sBPD as it is currently defined includes distinct phenotypes. Future researchers of diagnostic approaches to this population should consider the development of bedside tests to define phenotypes, and researchers in future therapeutic trials should consider the use of pulmonary function phenotyping in patient recruitment. PMID- 29622722 TI - Inpatient Quality Improvement Interventions for Asthma: A Meta-analysis. AB - CONTEXT: Despite the availability of evidence-based guidelines for the management of pediatric asthma, health care utilization remains high. OBJECTIVE: Systematically review the inpatient literature on asthma quality improvement (QI) and synthesize impact on subsequent health care utilization. DATA SOURCES: Medline and Cumulative Index to Nursing and Allied Health Literature (January 1, 1991-November 16, 2016) and bibliographies of retrieved articles. STUDY SELECTION: Interventional studies in English of inpatient-initiated asthma QI work. DATA EXTRACTION: Studies were categorized by intervention type and outcome. Random-effects models were used to generate pooled risk ratios for health care utilization outcomes after inpatient QI interventions. RESULTS: Thirty articles met inclusion criteria and 12 provided data on health care reutilization outcomes. Risk ratios for emergency department revisits were: 0.97 (95% confidence interval [CI]: 0.06-14.47) <30 days, 1.70 (95% CI: 0.67-4.29) for 30 days to 6 months, and 1.22 (95% CI: 0.52-2.85) for 6 months to 1 year. Risk ratios for readmissions were: 2.02 (95% CI: 0.73-5.61) for <30 days, 1.68 (95% CI: 0.88-3.19) for 30 days to 6 months, and 1.27 (95% CI 0.85-1.90) for 6 months to 1 year. Subanalysis of multimodal interventions suggested lower readmission rates (risk ratio: 1.49 [95% CI: 1.17-1.89] over a period of 30 days to 1 year after the index admission). Subanalysis of education and discharge planning interventions did not show effect. LIMITATIONS: Linkages between intervention and outcome are complicated by the multimodal approach to QI in most studies. CONCLUSIONS: We did not identify any inpatient strategies impacting health care reutilization within 30 days of index hospitalization. Multimodal interventions demonstrated impact over the longer interval. PMID- 29622723 TI - Catalytic enantioselective Minisci-type addition to heteroarenes. AB - Basic heteroarenes are a ubiquitous feature of pharmaceuticals and bioactive molecules, and Minisci-type additions of radical nucleophiles are a leading method for their elaboration. Despite many Minisci-type protocols that result in the formation of stereocenters, exerting control over the absolute stereochemistry at these centers remains an unmet challenge. We report a process for addition of prochiral radicals, generated from amino acid derivatives, to pyridines and quinolines. Our method offers excellent control of both enantioselectivity and regioselectivity. An enantiopure chiral Bronsted acid catalyst serves both to activate the substrate and induce asymmetry, while an iridium photocatalyst mediates the required electron transfer processes. We anticipate that this method will expedite access to enantioenriched small molecule building blocks bearing versatile basic heterocycles. PMID- 29622724 TI - Single-cell transcriptomics of the mouse kidney reveals potential cellular targets of kidney disease. AB - Our understanding of kidney disease pathogenesis is limited by an incomplete molecular characterization of the cell types responsible for the organ's multiple homeostatic functions. To help fill this knowledge gap, we characterized 57,979 cells from healthy mouse kidneys by using unbiased single-cell RNA sequencing. On the basis of gene expression patterns, we infer that inherited kidney diseases that arise from distinct genetic mutations but share the same phenotypic manifestation originate from the same differentiated cell type. We also found that the collecting duct in kidneys of adult mice generates a spectrum of cell types through a newly identified transitional cell. Computational cell trajectory analysis and in vivo lineage tracing revealed that intercalated cells and principal cells undergo transitions mediated by the Notch signaling pathway. In mouse and human kidney disease, these transitions were shifted toward a principal cell fate and were associated with metabolic acidosis. PMID- 29622726 TI - Morphogen gradient reconstitution reveals Hedgehog pathway design principles. AB - In developing tissues, cells estimate their spatial position by sensing graded concentrations of diffusible signaling proteins called morphogens. Morphogen sensing pathways exhibit diverse molecular architectures, whose roles in controlling patterning dynamics and precision have been unclear. In this work, combining cell-based in vitro gradient reconstitution, genetic rewiring, and mathematical modeling, we systematically analyzed the distinctive architectural features of the Sonic Hedgehog pathway. We found that the combination of double negative regulatory logic and negative feedback through the PTCH receptor accelerates gradient formation and improves robustness to variation in the morphogen production rate compared with alternative designs. The ability to isolate morphogen patterning from concurrent developmental processes and to compare the patterning behaviors of alternative, rewired pathway architectures offers a powerful way to understand and engineer multicellular patterning. PMID- 29622725 TI - SLAM-seq defines direct gene-regulatory functions of the BRD4-MYC axis. AB - Defining direct targets of transcription factors and regulatory pathways is key to understanding their roles in physiology and disease. We combined SLAM-seq [thiol(SH)-linked alkylation for the metabolic sequencing of RNA], a method for direct quantification of newly synthesized messenger RNAs (mRNAs), with pharmacological and chemical-genetic perturbation in order to define regulatory functions of two transcriptional hubs in cancer, BRD4 and MYC, and to interrogate direct responses to BET bromodomain inhibitors (BETis). We found that BRD4 acts as general coactivator of RNA polymerase II-dependent transcription, which is broadly repressed upon high-dose BETi treatment. At doses triggering selective effects in leukemia, BETis deregulate a small set of hypersensitive targets including MYC. In contrast to BRD4, MYC primarily acts as a selective transcriptional activator controlling metabolic processes such as ribosome biogenesis and de novo purine synthesis. Our study establishes a simple and scalable strategy to identify direct transcriptional targets of any gene or pathway. PMID- 29622727 TI - Current detection rates and time-to-detection of all identifiable BRCA carriers in the Greater London population. AB - BACKGROUND: BRCA carrier identification offers opportunities for early diagnoses, targeted treatment and cancer prevention. We evaluate BRCA- carrier detection rates in general and Ashkenazi Jewish (AJ) populations across Greater London and estimate time-to-detection of all identifiable BRCA carriers. METHODS: BRCA carrier data from 1993 to 2014 were obtained from National Health Service genetic laboratories and compared with modelled predictions of BRCA prevalence from published literature and geographical data from UK Office for National Statistics. Proportion of BRCA carriers identified was estimated. Prediction models were developed to fit BRCA detection rate data. BRCA carrier identification rates were evaluated for an 'Angelina Jolie effect'. Maps for four Greater London regions were constructed, and their relative BRCA detection rates were compared. Models developed were used to predict future time-to-identify all detectable BRCA carriers in AJ and general populations. RESULTS: Until 2014, only 2.6% (3072/111 742 estimated) general population and 10.9% (548/4985 estimated) AJ population BRCA carriers have been identified in 16 696 608 (AJ=190 997) Greater London population. 57% general population and 54% AJ mutations were identified through cascade testing. Current detection rates mirror linear fit rather than parabolic model and will not identify all BRCA carriers. Addition of unselected ovarian/triple-negative breast cancer testing would take >250 years to identify all BRCA carriers. Doubling current detection rates can identify all 'detectable' BRCA carriers in the general population by year 2181, while parabolic and triple linear rates can identify 'detectable' BRCA carriers by 2084 and 2093, respectively. The linear fit model can identify 'detectable' AJ carriers by 2044. We did not find an Angelina Jolie effect on BRCA carrier detection rates. There was a significant difference in BRCA detection rates between geographical regions over time (P<0.001). CONCLUSIONS: The majority of BRCA carriers have not been identified, missing key opportunities for prevention/earlier diagnosis. Enhanced and new strategies/approaches are needed. PMID- 29622728 TI - Encouraging responsible pet ownership. PMID- 29622729 TI - Licensing regulations passed by Parliament. PMID- 29622730 TI - Bid to update pet shop law in Scotland. PMID- 29622733 TI - Sniffer dogs unleashed. AB - A 10-year conservation project to restore the native bird populations of South Georgia has involved eradicating invasive rodent species. As Daniel Gillett explains, specially trained sniffer dogs are an important part of 'team rat'. PMID- 29622734 TI - Disease surveillance in England and Wales, March 2018. PMID- 29622735 TI - Sheep enteric diseases in 2017. AB - This article has been prepared by Amanda Carson of the APHA Small Ruminant Species Expert Group and Richard Irvine of the APHA's Surveillance Intelligence Unit. PMID- 29622738 TI - Learning techniques survey. PMID- 29622736 TI - Vitamin D therapy in canine atopic dermatitis. PMID- 29622739 TI - Encouraging responsible antibiotic use by pet owners. PMID- 29622740 TI - Are we asking enough questions? PMID- 29622741 TI - New RCVS junior vice-president elected. PMID- 29622743 TI - Is your CPD planning fit for purpose? PMID- 29622755 TI - Effects of pharmacological reversal of hyperuricemia on features of the metabolic syndrome in patients with gouty arthritis. AB - Hyperuricemia has been associated in epidemiological studies with the development of obesity, hypertension, insulin resistance and type 2 diabetes. Nevertheless, it remains unclear whether lowering of serum uric acid (UA) alters any of the features of the metabolic syndrome. In this prospective study (ClinicalTrials.gov identifier: NCT01654276), 24 patients with gouty arthritis and hyperuricemia were treated for 6 months with the xanthine oxidase inhibitor febuxostat to lower serum UA to <6 mg/dL. Measurements of 24 hours ambulatory blood pressure (ABP) and serum and urine markers of the metabolic syndrome were measured at baseline and at the end of 6 months of febuxostat. The study population consisted of 18 men and 6 women, 18 of which completed the baseline and 6 months visits. Serum UA decreased significantly from 8.7+/-1.5 mg/dL at baseline to 4.4+/-1.1 mg/dL at 6 months (P<0.0001). During that time frame, there was no significant change in body mass index, systolic or diastolic blood pressure measured by 24 hours ABP monitor, serum glucose, insulin or homeostatic model assessment for insulin resistance, serum total and high-density lipoprotein-cholesterol, serum triglycerides or urine pH (P>0.05 for all). There was no correlation between parameters of the metabolic syndrome and the decline in serum UA or serum UA achieved at study end. In conclusion, in patients with gouty arthritis, UA lowering with febuxostat below 6 mg/dL had no significant impact on features of the metabolic syndrome. PMID- 29622756 TI - HSV infection is associated with gestational hypertension: results from the US National inpatient sample. AB - The purpose of this study was to determine if there is an association between maternal herpes simplex virus (HSV) infection and pre-eclampsia/eclampsia or gestational hypertension. The US Nationwide Inpatient Sample database was searched for women aged 15-44 years who delivered in a hospital between 2005 and 2014. The patients were categorized into those with and without HSV and pre eclampsia/eclampsia and gestational hypertension were compared between the groups. The analytic sample size (n=8 264 076) was equivalent to a population based sample size of 40 653 030 patients. After adjusting for significant variables including age, race, income, insurance status, diabetes mellitus (DM), gestational DM, obesity, and multiple gestations, multivariate regression analysis indicated that HSV was associated with a higher OR for gestational hypertension (adjusted OR 1.038; 95% CI 1.004 to 1.072). However, HSV was not associated with pre-eclampsia/eclampsia (OR 1.001; 95% CI 0.968 to 1.035) in univariate regression analysis. The results of the current study suggest that HSV infection is associated with gestational hypertension but not pre-eclampsia. Given the prevalence of HSV infection and its potential association with hypertensive disorders of pregnancy, further study of HSV and hypertension in pregnancy is warranted. PMID- 29622757 TI - Significance of neurexin and neuroligin polymorphisms in regulating risk of Hirschsprung's disease. AB - By performing a basic case-control study among a Chinese population, the aims of this study were to explore if single nucleotide polymorphisms (SNPs) within neurexin and neuroligin were associated with susceptibility to Hirschsprung's disease (HD). Eleven SNPs within neurexin and neuroligin were selected in this basic case-control study, and this study recruited 210 children with HD and 187 healthy children. The t-test and Chi2 test were used to find the difference between case and control in their clinical variables. OR and 95% CI were used to assess the association between HD susceptibility and neurexin/neuroligin polymorphisms/haplotypes. Several SNPs were significantly associated with altered risk of HD in the Chinese Han population, including rs1421589 within NRXN1, rs11795613 and rs4844285 within NLGN3, as well as rs5961397, rs7157669 and rs724373 within NLGX4X (all P<0.05). Further studies presented that the effects of rs1421589 within NRXN1, rs4844285 and rs11795613 within NLGN3, as well as rs5961397 within NLGX4X on HD phenotypes were also statistically significant (all P<0.05). Conclusively, the polymorphisms and haplotypes situated within neurexin and neuroligin were markedly associated with the onset of HD, implying that mutations of neurexin and neuroligin might serve as the treatment target for HD for the Chinese children. PMID- 29622758 TI - Lumbar spine bone mineral density Z-score discrepancies by dual X-ray absorptiometry do not predict vertebral fractures in children. AB - Dual X-ray absorptiometry (DXA) remains the most common mode of bone mineral density (BMD) evaluation. In adults, presence of a lumbar spine (LS) BMD T-score discrepancy (>1 SD difference between adjacent vertebrae) can indicate a vertebral fracture. In children, however, the clinical significance of such discrepancies is unknown. We conducted a retrospective study to evaluate the association between LS DXA and LS morphology to elucidate the clinical significance of an LS BMD Z-score discrepancy. We identified 360 DXA scans performed between September 2014 and May 2016 in patients 5-18 years of age. DXA scans were cross-referenced against available LS radiographs and vertebral fracture assessment (VFA) within the 6 months preceding or following a DXA scan. After excluding 44 DXA scans because of spinal hardware, incomplete DXA, or repeat scans, 316 DXA scans were included; 81 (25.6%) had either an LS radiograph or a VFA. Twenty-five of 81 patients (30.9%) had >1 SD difference between adjacent vertebrae in LS BMD Z-score. Two of these 25 patients (8%) had a lumbar vertebral fracture documented by a spine radiograph. Of the remaining 56 patients who did not have a discrepancy >1 SD, 6 patients (11%) had a lumbar vertebral fracture. Discrepancies in LS BMD Z-scores were not associated with lumbar vertebral fractures and, in the absence of fractures, likely represented vertebral developmental variants in children whose skeletons are still growing. Therefore, it does not appear justified to recommend further imaging based solely on the results of a DXA scan without clinically meaningful indications. PMID- 29622759 TI - Endobronchial valve for treatment of persistent air leak complicating spontaneous pneumothorax. AB - INTRODUCTION: Endobronchial one-way valves have been proposed as treatment for persistent air leak complicating spontaneous pneumothorax in which surgical intervention is not feasible. However, published data on efficacy, safety, and factors associated with success are scanty. METHODS: This is a retrospective study of 37 patients at a general hospital from 2008 to 2016. The impact of endobronchial valve implantation on the time to air-leak cessation after bronchoscopy was evaluated. RESULTS: The median patient age was 71 years. The majority of patients were males (92%), were ever-smokers (83%), had at least one co-morbidity (97%), and had secondary spontaneous pneumothorax (89%). Nineteen patients (51%) had a mean of 2.6 endobronchial valves implanted (range, 1-6). The air leak ceased within 72 hours for only eight patients (22% of the complete cohort), with immediate air-leak cessation after completion of endobronchial valve implantation. All six successful cases that had computed tomographic data of the thorax were shown to have bilateral intact interlobar fissures. The median (interquartile range) Charlson co-morbidity index was 1 (0.25-1) and 2 (1-3) for the success group and failure group, respectively (P=0.029). All patients in the no-endobronchial valve group survived, whereas three patients in the endobronchial valve group died within 30 days of endobronchial valve implantation. CONCLUSION: Only a small proportion of cases of endobronchial valve implantation for air leak complicating pneumothorax had unequivocal success. Intact bilateral interlobar fissures appear to be a necessary, though not sufficient, condition for success. Patients with fewer medical co-morbidities and immediate air-leak cessation after endobronchial valve implantation have a higher likelihood of success. PMID- 29622760 TI - Effect of a financial incentive on the acceptance of a smoking cessation programme with service charge: a cluster-controlled trial. AB - INTRODUCTION: Frontline health care professionals in Hong Kong may encounter high refusal rates for the Hospital Authority's Smoking Counselling and Cessation Programme (SCCP) when smokers know it is subject to a service charge. We compared SCCP booking and attendance rates among smokers with or without a financial incentive. METHODS: In this multicentre non-randomised cluster-controlled trial, adult smokers who attended one of six general out-patient clinics between November 2015 and April 2016 were invited to join an SCCP. Attendees in the three intervention-group centres but not the three control-group centres received a supermarket coupon to offset the service charge. RESULTS: A total of 173 smokers aged 18 years or older (92 in the intervention group and 81 in the control group) were recruited into the study. In the intervention group, 47 smokers (51%) agreed via a questionnaire that they would join the SCCP, compared with only 23 smokers in the control group (28%). The booking rates were 83% (n=39) in the intervention group and 83% (n=19) in the control group. Among those who had booked a place, 19 (49%) intervention-group participants and 11 (58%) control-group participants attended an SCCP session. Multivariable logistic regression revealed that offering a coupon was associated with agreeing to join an SCCP (odds ratio=4.963, 95% confidence interval=2.173-11.334; P<0.001) and booking an SCCP place (odds ratio=4.244, 95% confidence interval=1.838-9.799; P<0.001). CONCLUSION: Provision of a financial incentive was positively associated with agreement to join an SCCP and booking an SCCP place. Budget holders should consider providing the SCCP free of charge to increase smokers' access to the service. PMID- 29622761 TI - Simultaneous Pancreas-Kidney Transplantation in a Patient with Heparin-Induced Thrombocytopenia on Dabigatran Therapy. AB - BACKGROUND New oral anticoagulants like direct thrombin inhibitors are an attractive alternative to vitamin K antagonists as anticoagulation therapy and can be used in heparin-induced thrombocytopenia. They are convenient in low-risk surgery, as there is no need for bridging with heparins. Patients who need urgent major surgery are at similar risk as on warfarin therapy, which, however, is much higher than in elective procedures. Due to their elimination profiles, these drugs are generally contraindicated in patients with severe renal insufficiency. On the other hand, pancreas transplantation is associated with high risk of bleeding and substantial risk of graft thrombosis. There are no recommendations on anticoagulation therapy in high-risk patients on kidney-pancreas waiting lists who cannot be given heparins. CASE REPORT We describe a case of simultaneous pancreas-kidney transplantation in a patient with heparin-induced thrombocytopenia on dabigatran treatment. CONCLUSIONS We conclude that, despite the high risk, pancreas transplantation in a patient with HIT can be safely done while on NOAC therapy, but an access to idarucizumab should be assured. PMID- 29622762 TI - Combination of Circulating miRNA-320a/b and D-Dimer Improves Diagnostic Accuracy in Deep Vein Thrombosis Patients. AB - BACKGROUND D-dimer tests have been widely used to rule-out deep venous thrombosis (DVT), but with low specificity. Circulating microRNAs (miRNAs) are novel promising biomarkers in diverse diseases. The purpose of our study was to identify the diagnostic abilities of circulating miRNA-320a/b and to assess their correlation with plasma D-dimer in DVT and post-thrombotic syndrome (PTS) patients. MATERIAL AND METHODS Plasma samples were taken from 30 DVT patients, 30 PTS patients, and 30 age- and sex-matched healthy volunteers. Quantitative real time PCR (qPCR) assay and turbidimetric immunoassay were conducted to assess the concentrations of miRNA-320a/b and D-dimer in plasma. RESULTS Circulating miRNA 320a and miRNA-320b were significantly upregulated in DVT patients with fold changes of 1.58 and 1.79, respectively. The receiver operating characteristic (ROC) curve analysis showed area under the curve (AUC) values of 0.70 (95% CI: 0.56-0.83) for miRNA-320a and 0.79 (95% CI: 0.67-0.90) for miRNA-320b. Moreover, plasma levels of miRNA-320b were associated with D-dimer values (r=0.52, 95% CI: 0.19-0.74) in DVT. However, no significant changes in plasma miRNA-320a/b and D dimer were detected in PTS patients. CONCLUSIONS Compared with controls, circulating miRNA-320a/b was differentially expressed in DVT. Simultaneous detection of miRNA-320a/b with D-dimer may improve diagnostic accuracy of DVT. PMID- 29622763 TI - Esophageal Mucosal Calcinosis: A Rare Site of Gastrointestinal Mucosal Calcinosis. AB - BACKGROUND Gastrointestinal tract mucosal calcinosis (MC) tends to affect the gastric mucosa, while esophageal involvement is rare. Gastric MC may be seen with solid organ transplantation, use of aluminum-containing antacids or sucralfate, malignancy, and chronic renal failure. While the incidence of gastric MC in renal transplant patients undergoing gastric biopsy is common (between 15-29%), to our knowledge esophageal MC has only been previously reported 3 times. CASE REPORT A 68-year-old male dialysis-dependent end stage renal disease status-post deceased donor kidney transplant underwent an esophagogastroduodenoscopy (EGD) for dysphagia and diffuse esophageal wall thickening seen on imaging studies. EGD demonstrated diffuse, circumferential thick white esophageal plaques and mucosal friability. Esophageal biopsies demonstrated erosive esophagitis with basophilic calcium deposits within the fibrinopurulent exudate and squamous mucosa. Stains for fungal organisms and viruses were negative. A diagnosis of esophageal MC was made. Although the patient had a protracted postoperative course after transplantation, he had improvement of the esophageal wall thickening on imaging after transplantation. CONCLUSIONS Esophageal MC is a rare phenomenon and all of the previously reported cases of esophageal MC, including our case, have been in patients with end stage renal disease who were on dialysis. Although prolonged hypercalcemia and hyperphosphatemia, an elevated calcium-phosphorus product, and associated underlying inflammation are likely key etiologic factors, the pathogenesis of esophageal MC is not fully understood and is likely due to multiple collective etiologies. Likewise, more reported cases are likely to increase our understanding of the clinical significance and management of this rare disorder. PMID- 29622764 TI - Glutathione disulfide sensitizes hepatocytes to TNFalpha-mediated cytotoxicity via IKK-beta S-glutathionylation: a potential mechanism underlying non-alcoholic fatty liver disease. AB - Oxidative stress and TNFalpha are critically involved in the initiation and progression of non-alcoholic fatty liver disease (NAFLD). In this study, we investigated the effects of dysregulated glutathione homeostasis, a principal feature of oxidative stress, on TNFalpha-induced hepatotoxicity and its mechanistic implications in NAFLD progression. We showed that mice fed a high-fat diet (HFD) for 12 weeks developed hepatic steatosis and liver injuries, which were associated with not only TNFalpha overproduction but also hepatic glutathione dysregulation, characterized by GSH reduction and GSSG elevation. Moreover, consuming a HFD increased protein S-glutathionylation (protein-SSG formation) in the liver. Subsequent cell culture studies revealed that GSSG accumulation, as opposed to GSH reduction, sensitized hepatocytes to TNFalpha killing by reducing the TNFalpha-triggered NF-kappaB activity. GSSG prevented TNFalpha-induced activation of IKK-beta, an upstream kinase in the NF-kappaB signaling pathway, by inducing IKK-beta glutathionylation (IKK-beta-SSG formation). In animal studies, in comparison to a control diet, HFD consumption resulted in increased hepatic IKK-beta-SSG formation, leading to suppressed IKK beta activation and subsequent NF-kappaB suppression. Furthermore, we found that HFD consumption also led to decreased hepatic expression of glutaredoxin, a key enzyme for de-glutathionylation. Similarly, CdCl2, a chemical inhibitor of glutaredoxin, sensitized hepatocytes to TNFalpha-mediated cytotoxicity. In conclusion, our data suggest that GSSG is a potent and clinically relevant sensitizer for TNFalpha-induced hepatotoxicity in NAFLD, which represents a potential therapeutic target for NAFLD. PMID- 29622766 TI - Olfactory marker protein regulates prolactin secretion and production by modulating Ca2+ and TRH signaling in lactotrophs. AB - Olfactory marker protein (OMP) is a marker of olfactory receptor-mediated chemoreception, even outside the olfactory system. Here, we report that OMP expression in the pituitary gland plays a role in basal and thyrotropin-releasing hormone (TRH)-induced prolactin (PRL) production and secretion. We found that OMP was expressed in human and rodent pituitary glands, especially in PRL-secreting lactotrophs. OMP knockdown in GH4 rat pituitary cells increased PRL production and secretion via extracellular signal-regulated kinase (ERK)1/2 signaling. Real time PCR analysis and the Ca2+ influx assay revealed that OMP was critical for TRH-induced PRL secretion. OMP-knockout mice showed lower fertility than control mice, which was associated with increased basal PRL production via activation of ERK1/2 signaling and reduced TRH-induced PRL secretion. However, both in vitro and in vivo results indicated that OMP was only required for hormone production and secretion because ERK1/2 activation failed to stimulate cell proliferation. Additionally, patients with prolactinoma lacked OMP expression in tumor tissues with hyperactivated ERK1/2 signaling. These findings indicate that OMP plays a role in PRL production and secretion in lactotrophs through the modulation of Ca2+ and TRH signaling. PMID- 29622765 TI - Identification of genomic aberrations associated with lymph node metastasis in diffuse-type gastric cancer. AB - Diffuse-type gastric cancer (DGC) is a GC subtype with heterogeneous clinical outcomes. Lymph node metastasis of DGC heralds a dismal progression, which hampers the curative treatment of patients. However, the genomic heterogeneity of DGC remains unknown. To identify genomic variations associated with lymph node metastasis in DGC, we performed whole exome sequencing on 23 cases of DGC and paired non-tumor tissues and compared the mutation profiles according to the presence (N3, n = 13) or absence (N0, n = 10) of regional lymph node metastasis. Overall, we identified 185 recurrently mutated genes in DGC, which included a significant novel mutation at CMTM2, as well as previously known mutations at CDH1, RHOA, and TP53. Noticeably, CMTM2 expression could predict the prognostic outcomes of DGC but not intestinal-type GC (IGC), indicating pivotal roles of CMTM2 in DGC progression. In addition, we identified a recurrent loss of heterozygosity (LOH) of DNA copy numbers at the 3p12-pcen locus in DGC. A comparison of N0 and N3 tumors showed that N3 tumors exhibited more frequent DNA copy number aberrations, including copy-neutral LOH and mutations of CpTpT trinucleotides, than N0 tumors (P = 0.2 * 10-3). In conclusion, DGCs have distinct profiles of somatic mutations and DNA copy numbers according to the status of lymph node metastasis, and this might be helpful in delineating the pathobiology of DGC. PMID- 29622767 TI - PEX5 regulates autophagy via the mTORC1-TFEB axis during starvation. AB - Defects in the PEX5 gene impair the import of peroxisomal matrix proteins, leading to nonfunctional peroxisomes and other associated pathological defects such as Zellweger syndrome. Although PEX5 regulates autophagy process in a stress condition, the mechanisms controlling autophagy by PEX5 under nutrient deprivation are largely unknown. Herein, we show a novel function of PEX5 in the regulation of autophagy via Transcription Factor EB (TFEB). Under serum-starved conditions, when PEX5 is depleted, the mammalian target of rapamycin (mTORC1) inhibitor TSC2 is downregulated, which results in increased phosphorylation of the mTORC1 substrates, including 70S6K, S6K, and 4E-BP-1. mTORC1 activation further suppresses the nuclear localization of TFEB, as indicated by decreased mRNA levels of TFEB, LIPA, and LAMP1. Interestingly, peroxisomal mRNA and protein levels are also reduced by TFEB inactivation, indicating that TFEB might control peroxisome biogenesis at a transcriptional level. Conversely, pharmacological inhibition of mTOR resulting from PEX5 depletion during nutrient starvation activates TFEB by promoting nuclear localization of the protein. In addition, mTORC1 inhibition recovers the damaged-peroxisome biogenesis. These data suggest that PEX5 may be a critical regulator of lysosomal gene expression and autophagy through the mTOR-TFEB-autophagy axis under nutrient deprivation. PMID- 29622768 TI - Role of phospholipase D in the lifespan of Caenorhabditis elegans. AB - We have previously shown that phospholipase D (PLD) downregulation accelerates cellular senescence, which is widely believed to play an important role in aging, by stimulating reactive oxygen species (ROS) accumulation in human cells. In this study, we examined the role of PLD in aging using the nematode Caenorhabditis elegans. The mRNA level of pld-1 was found to be inversely correlated with aging. RNAi-mediated knockdown of pld-1 expression in nematodes enhanced ROS and lipofuscin accumulation and decreased lifespan, motility, and resistance to stress compared to that in nematodes treated with control RNAi. Pld-1 knockdown repressed the long lifespan of age-1 and akt-1 mutants but did not further reduce the short lifespan of daf-16 mutants, suggesting that PLD functions between AKT-1 and DAF-16. The ROS scavenger N-acetyl-L-cysteine, a PLD effector phosphatidic acid and a possible CK2 activator spermidine attenuated the lifespan shortening and age-related biomarkers triggered by pld-1 knockdown. Pld-1 RNAi downregulated the expression of DAF-16 target genes such as sod-3, dod-11, and mtl-1 in nematodes. In human cells, furthermore, PLD2 downregulation decreased the transcription of FoxO3a target genes (Cu/ZnSOD, MnSOD, catalase, thioredoxin-2, and peroxiredoxin-5), whereas ectopic PLD2 expression elevated the mRNA levels of these antioxidant genes. Taken together, these results indicated that PLD downregulation shortens longevity and induces age-related biomarkers through ROS accumulation by inhibiting the DAF-16/FoxO3a pathway in nematodes. PMID- 29622769 TI - Alterations in the p53-SOCS2 axis contribute to tumor growth in colon cancer. AB - Altered expression of suppressor of cytokine signaling (SOCS) is found in various tumors. However, regulation of SOCS2 by upstream molecules has yet to be clearly elucidated, particularly in tumor cells. SCOCS2 expression was examined in tumor cells transfected with an inducible p53 expression system. The impact of SOCS2 on cell proliferation was measured with in vitro assays. Inhibition of tumorigenicity by SOCS2 knockdown was assessed via a mouse model. Expression profiles were compared and genes differentially expressed were identified using four types of p53-null cells (Saos, HLK3, PC3, and H1299) and the same cells stably expressing p53. Twelve kinds of target genes were simultaneously upregulated or downregulated by p53 in three or more sets of p53-null cells. SOCS2 expression was reciprocally inhibited by inducible p53 expression in p53 null cells, even colon cancer cells. SOCS2 promoter activity was inhibited by wild type but not mutant p53. SOCS2 knockdown inhibited tumor growth in vitro and in an animal xenograph model. SOCS2 overexpression was detected in a murine model of azoxymethane/dextran sulfate sodium-induced colitis-associated colon cancer compared to mock-treated controls. SOCS2 expression was heterogeneously upregulated in some human colon cancers. Thus, SOCS2 was upregulated by p53 dysfunction and seemed to be associated with the tumorigenic potential of colon cancer. PMID- 29622770 TI - TNF-alpha induces human neural progenitor cell survival after oxygen-glucose deprivation by activating the NF-kappaB pathway. AB - Neural progenitor cell (NPC) transplantation has been shown to be beneficial in the ischemic brain. However, the low survival rate of transplanted NPCs in an ischemic microenvironment limits their therapeutic effects. Tumor necrosis factor alpha (TNF-alpha) is one of the proinflammatory cytokines involved in the pathogenesis of various injuries. On the other hand, several studies have shown that TNF-alpha influences the proliferation, survival, and differentiation of NPCs. Our study investigated the effect of TNF-alpha pretreatment on human NPCs (hNPCs) under ischemia-related conditions in vitro. hNPCs harvested from fetal brain tissue were pretreated with TNF-alpha before being subjected to oxygen glucose deprivation (OGD) to mimic ischemia in vitro. TNF-alpha pretreatment improved the viability and reduced the apoptosis of hNPCs after OGD. At the molecular level, TNF-alpha markedly increased the level of NF-kappaB signaling in hNPCs, and an NF-kappaB pathway inhibitor, BAY11-7082, completely reversed the protective effects of TNF-alpha on hNPCs. These results suggest that TNF-alpha improves hNPC survival by activating the NF-kappaB pathway. In addition, TNF alpha significantly enhanced the expression of cellular inhibitor of apoptosis 2 (cIAP2). Use of a lentivirus-mediated short hairpin RNA targeting cIAP2 mRNA demonstrated that cIAP2 protected against OGD-induced cytotoxicity in hNPCs. Our study of intracellular NF-kappaB signaling revealed that inhibition of NF-kappaB activity abolished the TNF-alpha-mediated upregulation of cIAP2 in hNPCs and blocked TNF-alpha-induced cytoprotection against OGD. Therefore, this study suggests that TNF-alpha pretreatment, which protects hNPCs from OGD-induced apoptosis by activating the NF-kappaB pathway, provides a safe and simple approach to improve the viability of transplanted hNPCs in cerebral ischemia. PMID- 29622772 TI - Author Correction: Impacts of alpine wetland degradation on the composition, diversity and trophic structure of soil nematodes on the Qinghai-Tibetan Plateau. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29622771 TI - Glioblastoma-secreted soluble CD44 activates tau pathology in the brain. AB - During aggressive tumor growth and migration, glioblastoma cells secrete diverse molecules and adhesion proteins to the extracellular matrix. Yet, the biochemical effects of the glioblastoma secretome in the brain remain largely unknown. Here we show that soluble CD44 secreted from glioblastoma cells induces neuronal degeneration through the activation of tau pathology in the brain. Glioblastoma xenograft tissues showed a number of degenerating neurons bearing highly phosphorylated tau. Through a series of secretome-analyses, we identified that soluble CD44 was the responsible protein inducing tau phosphorylation and aggregation (EC50 = 19.1 ng/mL). The treatment of sCD44 to primary hippocampal neurons-induced tau hyperphosphorylation, leading to neuronal degeneration. Also, the injection of sCD44 into the brains of tau transgenic mice induced tau hyper phosphorylation in hippocampal neurons. Altogether, our data suggest a neurodegenerative role of sCD44 in promoting tau pathology and serving as a molecular link between glioblastoma and neurodegeneration. PMID- 29622773 TI - Author Correction: The epigenetic modifier Fam208a is required to maintain epiblast cell fitness. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29622774 TI - Author Correction: RPI-Bind: a structure-based method for accurate identification of RNA-protein binding sites. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29622775 TI - Author Correction: Analysis of inflammatory cytokine and TLR expression levels in Type 2 Diabetes with complications. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29622776 TI - Author Correction: Limited evidence on the effectiveness of interventions to reduce livestock predation by large carnivores. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29622777 TI - Author Correction: Maximizing energy coupling to complex plasmonic devices by injecting light into eigenchannels. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29622778 TI - Disparities in NICU quality of care: a qualitative study of family and clinician accounts. AB - OBJECTIVE: To identify how family advocates and clinicians describe disparities in NICU quality of care in narrative accounts. STUDY DESIGN: Qualitative analysis of a survey requesting disparity stories at the 2016 VON Quality Congress. Accounts (324) were from a sample of RNs (n = 114, 35%), MDs (n = 109, 34%), NNPs (n = 55, 17%), RN other (n = 4, 1%), clinical other (n = 25, 7%), family advocates (n = 16, 5%), and unspecified (n = 1, <1%). RESULTS: Accounts (324) addressed non-exclusive disparities: 151 (47%) language; 97 (30%) culture or ethnicity; 72 (22%) race; 41 (13%) SES; 28 (8%) drug use; 18 (5%) immigration status or nationality; 16 (4%) sexual orientation or family status; 14 (4%) gender; 10 (3%) disability. We identified three types of disparate care: neglectful care 85 (26%), judgmental care 85 (26%), or systemic barriers to care 139 (44%). CONCLUSIONS: Nearly all accounts described differential care toward families, suggesting the lack of equitable family-centered care. PMID- 29622779 TI - Author Correction: Predicting the potential distribution in China of Euwallacea fornicatus (Eichhoff) under current and future climate conditions. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29622780 TI - New biomarkers of postoperative neurocognitive disorders. PMID- 29622781 TI - Presenting models to policymakers: intention and perception. AB - The Seifu et al. article is a start to a timely inquiry on policymakers' perceptions of mathematical modeling and simulations aimed to guide obesity prevention programs. These computational tools have the potential to transform the fields of public health policy. Yet, to be effective, a broad Data and Information Literacy Initiative is needed to instill policymakers with the willingness to become life-long learners, to adapt and accept new technologies, attitudes, information, and creative ways of thinking. PMID- 29622782 TI - Multiple sgRNAs with overlapping sequences enhance CRISPR/Cas9-mediated knock-in efficiency. AB - The CRISPR/Cas9 system is widely applied in genome engineering due to its simplicity and versatility. Although this has revolutionized genome-editing technology, knockin animal generation via homology directed repair (HDR) is not as efficient as nonhomologous end-joining DNA-repair-dependent knockout. Although its double-strand break activity may vary, Cas9 derived from Streptococcus pyogenens allows robust design of single-guide RNAs (sgRNAs) within the target sequence; However, prescreening for different sgRNA activities delays the process of transgenic animal generation. To overcome this limitation, multiple sets of different sgRNAs were examined for their knockin efficiency. We discovered profound advantages associated with single-stranded oligo-donor-mediated HDR processes using overlapping sgRNAs (sharing at least five base pairs of the target sites) as compared with using non-overlapping sgRNAs for knock-in mouse generation. Studies utilizing cell lines revealed shorter sequence deletions near target mutations using overlapping sgRNAs as compared with those observed using non-overlapping sgRNAs, which may favor the HDR process. Using this simple method, we successfully generated several transgenic mouse lines harboring loxP insertions or single-nucleotide substitutions with a highly efficiency of 18-38%. Our results demonstrate a simple and efficient method for generating transgenic animals harboring foreign-sequence knockins or short-nucleotide substitutions by the use of overlapping sgRNAs. PMID- 29622783 TI - Genetics of male infertility. AB - Male infertility is a multifactorial pathological condition affecting approximately 7% of the male population. The genetic landscape of male infertility is highly complex as semen and testis histological phenotypes are extremely heterogeneous, and at least 2,000 genes are involved in spermatogenesis. The highest frequency of known genetic factors contributing to male infertility (25%) is in azoospermia, but the number of identified genetic anomalies in other semen and aetiological categories is constantly growing. Genetic screening is relevant for its diagnostic value, clinical decision making, and appropriate genetic counselling. Anomalies in sex chromosomes have major roles in severe spermatogenic impairment. Autosome-linked gene mutations are mainly involved in central hypogonadism, monomorphic teratozoospermia or asthenozoospermia, congenital obstructive azoospermia, and familial cases of quantitative spermatogenic disturbances. Results from whole-genome association studies suggest a marginal role for common variants as causative factors; however, some of these variants can be important for pharmacogenetic purposes. Results of studies on copy number variations (CNVs) demonstrate a considerably higher CNV load in infertile patients than in normozoospermic men, whereas whole exome analysis has proved to be a highly successful diagnostic tool in familial cases of male infertility. Despite such efforts, the aetiology of infertility remains unknown in about 40% of patients, and the discovery of novel genetic factors in idiopathic infertility is a major challenge for the field of androgenetics. Large, international, and consortium-based whole-exome and whole genome studies are the most promising approach for the discovery of the missing genetic aetiology of idiopathic male infertility. PMID- 29622784 TI - Author Correction: Revealing hidden complexities of genomic rearrangements generated with Cas9. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29622785 TI - Author Correction: Downregulation of PARP1 transcription by promoter-associated E2F4-RBL2-HDAC1-BRM complex contributes to repression of pluripotency stem cell factors in human monocytes. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper. PMID- 29622786 TI - INFORMED: an incubator at the US FDA for driving innovations in data science and agile technology. PMID- 29622787 TI - Mechanisms of improved specificity of engineered Cas9s revealed by single molecule FRET analysis. AB - Cas9 (from Streptococcus pyogenes) in complex with a guide RNA targets complementary DNA for cleavage. Here, we developed a single-molecule FRET analysis to study the mechanisms of specificity enhancement of two engineered Cas9s (eCas9 and Cas9-HF1). A DNA-unwinding assay showed that mismatches affect cleavage reactions through rebalancing the unwinding-rewinding equilibrium. Increasing PAM-distal mismatches facilitates rewinding, and the associated cleavage impairment shows that cleavage proceeds from the unwound state. Engineered Cas9s depopulate the unwound state more readily with mismatches. The intrinsic cleavage rate is much lower for engineered Cas9s, preventing cleavage from transiently unwound off-targets. Engineered Cas9s require approximately one additional base pair match for stable binding, freeing them from sites that would otherwise sequester them. Therefore, engineered Cas9s achieve their improved specificity by inhibiting stable DNA binding to partially matching sequences, making DNA unwinding more sensitive to mismatches and slowing down the intrinsic cleavage reaction. PMID- 29622789 TI - Psychological issues and alcohol misuse following bariatric surgery. PMID- 29622788 TI - S-nitrosylation of transglutaminase 2 impairs fatty acid-stimulated contraction in hypertensive cardiomyocytes. AB - The myocardium in hypertensive heart exhibits decreased fatty acid utilization and contractile dysfunction, leading to cardiac failure. However, the causal relationship between metabolic remodeling and cardiomyocyte contractility remains unestablished. Transglutaminase 2 (TG2) has been known to promote ATP production through the regulation of mitochondrial function. In this study, we investigated the involvement of TG2 in cardiomyocyte contraction under fatty acid supplementation. Using TG2 inhibitor and TG2-deficient mice, we demonstrated that fatty acid supplementation activated TG2 and increased ATP level and contractility of cardiac myocyte from the normal heart. By contrast, in cardiac myocytes from angiotensin-II-treated rats and mice, the effects of fatty acid supplementation on TG2 activity, ATP level, and myocyte contraction were abolished. We found that TG2 was inhibited by S-nitrosylation and its level increased in hypertensive myocytes. Treatment with inhibitor for neuronal NOS restored fatty acid-induced increase of TG2 activity and myocyte contraction. Moreover, intracellular Ca2+ levels were increased by fatty acid supplementation in both normal and hypertensive myocytes, showing that S-nitrosylation of TG2 but not alteration of intracellular Ca2+ levels is responsible for contractile dysfunction. These results indicate that TG2 plays a critical role in the regulation of myocyte contractility by promoting fatty acid metabolism and provide a novel target for preventing contractile dysfunction in heart with high workload. PMID- 29622790 TI - Performance of modified blood pressure-to-height ratio for identifying hypertension in Chinese and American children. AB - Blood pressure-to-height ratio (BPHR) has been reported to perform well for identifying hypertension (HTN) in adolescents but not in young children. Our study was aimed to evaluate the performance of BPHR and modified BPHR (MBPHR) for screening HTN in children. A total of 5268 Chinese children (boys: 53.1%) aged 6 12 years and 5024 American children (boys: 48.1%) aged 8-12 years were included in the present study. BPHR was calculated as BP/height (mmHg/cm). MBPHR7 was calculated as BP/(height + 7*(13-age)). MBPHR3 was calculated as BP/(height + 3*(13-age)). We used receiver-operating characteristic curve analysis to assess the performance of the three ratios for identifying HTN in children as compared to the 2017 U.S. clinical guideline as the "gold standard". The prevalence of HTN in Chinese and American children was 9.4% and 5.4%, respectively, based on the 2017 U.S. guideline. The AUC was larger for MBPHR3 than BPHR and MBPHR7. All three ratios had optimal negative predictive value (~100%). The positive predictive value (PPV) was higher for MBPHR3 than BPHR in both Chinese (43.9% vs. 37.9%) and American (39.1% vs. 26.3%) children. In contrast, the PPV was higher for MBPHR7 than BPHR in Chinese children (47.4% vs. 37.9%) but not in American children (24.8% vs. 26.3%). In summary, MBPHR3 overall performed better than MBPHR7 and BPHR for identifying HTN in children. However, the three ratios had low PPV (<50%) as compared to the 2017 U.S. guidelines, which makes these ratios of limited use for HTN screening in children. PMID- 29622791 TI - The Accutension Stetho, an automated auscultatory device to validate automated sphygmomanometer readings in individual patients. AB - The aim of this report is to describe a new device that can validate, by automated auscultation, individual blood pressure (BP) readings taken by automated sphygmomanometers.The Accutension Stetho utilizes a smartphone application in conjunction with a specially designed stethoscope that interfaces directly into the smartphone via the earphone jack. The Korotkoff sounds are recorded by the application and are analyzed by the operator on the screen of the smartphone simultaneously with the images from the sphygmomanometer screen during BP estimation. Current auscultatory validation standards require at least 85 subjects and strict statistical criteria for passage. A device that passes can make no guarantee of accuracy on individual patients. The Accutension Stetho is an inexpensive smartphone/stethoscope kit combination that estimates precise BP values by auscultation to confirm the accuracy of an automated sphygmomanometer's readings on individual patients. This should be of great value for both professional and, in certain circumstances, self-measurement BP. Patients will avoid both unnecessary treatment and errors of underestimation of BP, in which the patient requires therapy. The Stetho's software has been validated in an independent ANSI/AAMI/ISO standard study. The Stetho has been shown to perform without difficulty in multiple deflation-based devices by many manufacturers. PMID- 29622792 TI - The publication priorities of Spinal Cord. PMID- 29622795 TI - Antitumor activity of CD56-chimeric antigen receptor T cells in neuroblastoma and SCLC models. AB - The CD56 antigen (NCAM-1) is highly expressed on several malignancies with neuronal or neuroendocrine differentiation, including small-cell lung cancer and neuroblastoma, tumor types for which new therapeutic options are needed. We hypothesized that CD56-specific chimeric antigen receptor (CAR) T cells could target and eliminate CD56-positive malignancies. Sleeping Beauty transposon generated CD56R-CAR T cells exhibited alphabetaT-cell receptors, released antitumor cytokines upon co-culture with CD56+ tumor targets, demonstrated a lack of fratricide, and expression of cytolytic function in the presence of CD56+ stimulation. The CD56R-CAR+ T cells are capable of killing CD56+ neuroblastoma, glioma, and SCLC tumor cells in in vitro co-cultures and when tested against CD56+ human xenograft neuroblastoma models and SCLC models, CD56R-CAR+ T cells were able to inhibit tumor growth in vivo. These results indicate that CD56-CARs merit further investigation as a potential treatment for CD56+ malignancies. PMID- 29622793 TI - cAMP-independent non-pigmentary actions of variant melanocortin 1 receptor: AKT mediated activation of protective responses to oxidative DNA damage. AB - The melanocortin 1 receptor gene (MC1R), a well-established melanoma susceptibility gene, regulates the amount and type of melanin pigments formed within epidermal melanocytes. MC1R variants associated with increased melanoma risk promote the production of photosensitizing pheomelanins as opposed to photoprotective eumelanins. Wild-type (WT) MC1R activates DNA repair and antioxidant defenses in a cAMP-dependent fashion. Since melanoma-associated MC1R variants are hypomorphic in cAMP signaling, these non-pigmentary actions are thought to be defective in MC1R-variant human melanoma cells and epidermal melanocytes, consistent with a higher mutation load in MC1R-variant melanomas. We compared induction of antioxidant enzymes and DNA damage responses in melanocytic cells of defined MC1R genotype. Increased expression of catalase (CAT) and superoxide dismutase (SOD) genes following MC1R activation was cAMP-dependent and required a WT MC1R genotype. Conversely, pretreatment of melanocytic cells with an MC1R agonist before an oxidative challenge with Luperox decreased (i) accumulation of 8-oxo-7,8-dihydro-2'-deoxyguanine, a major product of oxidative DNA damage, (ii) phosphorylation of histone H2AX, a marker of DNA double-strand breaks, and (iii) formation of DNA breaks. These responses were comparable in cells WT for MC1R or harboring hypomorphic MC1R variants without detectable cAMP signaling. In MC1R-variant melanocytic cells, the DNA-protective responses were mediated by AKT. Conversely, in MC1R-WT melanocytic cells, high cAMP production downstream of MC1R blocked AKT activation and was responsible for inducing DNA repair. Accordingly, MC1R activation could promote repair of oxidative DNA damage by a cAMP-dependent pathway downstream of WT receptor, or via AKT in cells of variant MC1R genotype. PMID- 29622794 TI - Rab34 regulates adhesion, migration, and invasion of breast cancer cells. AB - The small GTPase Rab34 regulates spatial distribution of the lysosomes, secretion, and macropinocytosis. In this study, we found that Rab34 is over expressed in aggressive breast cancer cells, implying a potential role of Rab34 in breast cancer. Silencing Rab34 by shRNA inhibits cell migration, invasion, and adhesion of breast cancer cells. Rab34 specifically binds to the cytoplasmic tail of integrin beta3, and depletion of Rab34 promotes the degradation of integrin beta3. Interestingly, EGF induces the translocation of Rab34 to the membrane ruffle, which is greatly enhanced by the expression of Src kinase. Accordingly, Rab34 is tyrosine phosphorylated by Src at Y247 residue. A mutant mimicking phosphorylated form of Rab34 (Rab34Y247D) promotes cell migration and invasion. Importantly, the tyrosine phosphorylation of Rab34 is inhibited in cells in suspension, and increased with the cells re-adhesion. In addition, Rab34Y247D promotes cell adhesion, and enhances integrin beta3 endocytosis and recycling. The results uncover a role of Rab34 in migration and invasion of breast cancer cells and its involvement in cancer metastasis, and provide a novel mechanism of tyrosine phosphorylation of Rab34 in regulating cell migration, invasion, and adhesion through modulating the endocytosis, stability, and recycling of integrin beta3. PMID- 29622796 TI - NFkappaB regulates p21 expression and controls DNA damage-induced leukemic differentiation. AB - DNA damage exposure is a major modifier of cell fate in both normal and cancer tissues. In response to DNA damage, myeloid leukemia cells activate a poorly understood terminal differentiation process. Here, we show that the NFkappaB pathway directly activates expression of the proliferation inhibitor p21 in response to DNA damage in myeloid leukemia cells. In order to understand the role of this unexpected regulatory event, we ablated the NFkappaB binding site we identified in the p21 promoter, using CRISPR/Cas9-mediated genome editing. We found that NFkappaB-mediated p21 activation controls DNA damage-induced myeloid differentiation. Our results uncover a p53-independent pathway for p21 activation involved in controlling hematopoietic cell fate. PMID- 29622799 TI - Low-dose decitabine enhances the effect of PD-1 blockade in colorectal cancer with microsatellite stability by re-modulating the tumor microenvironment. AB - PD-1 blockade has demonstrated impressive clinical outcomes in colorectal cancers that have high microsatellite instability. However, the therapeutic efficacy for patients with tumors with low microsatellite instability or stable microsatellites needs further improvement. Here, we have demonstrated that low dose decitabine could increase the expression of immune-related genes such as major histocompatibility complex genes and cytokine-related genes as well as the number of lymphocytes at the tumor site in CT26 colorectal cancer-bearing mice. A more significant inhibition of tumor growth and a prolongation of survival were observed in the CT26 mouse model after treatment with a combination of PD-1 blockade and decitabine than in mice treated with decitabine or PD-1 blockade alone. The anti-tumor effect of the PD-1 blockade was enhanced by low-dose decitabine. The results of RNA sequencing and whole-genome bisulfite sequencing of decitabine-treated CT26 cells and tumor samples with microsatellite stability from the patient tumor-derived xenograft model have shown that many immune related genes, including antigen-processing and antigen-presenting genes, were upregulated, whereas the promoter demethylation was downregulated after decitabine exposure. Therefore, decitabine-based tumor microenvironment re modulation could improve the effect of the PD-1 blockade. The application of decitabine in PD-1 blockade-based immunotherapy may elicit more potent immune responses, which can provide clinical benefits to the colorectal cancer patients with low microsatellite instability or stable microsatellites. PMID- 29622798 TI - CD26 - The emerging role of a costimulatory molecule in allograft rejection. PMID- 29622800 TI - British Orthodontic Society's initiative on orthodontic retention, A GDP's perspective. AB - The British Orthodontic Society (BOS) recently published a number of news articles aimed at drawing attention to its 'Hold that Smile' campaign which promotes lifelong retainer wear. The BOS's stated intention is to 'generate a viral #HoldthatSmile campaign in order to build awareness of its message that retainers are for life'. The campaign also seeks to recruit the support of GDPs and DCPs, including nurses, in motivating patients to wear retainers for life. It suggests that orthodontists and GDPs need to work collaboratively and suggests that dentists would need to check patients are taking care of their retainers over the long term. This article discusses a number of aspects of the BOS's initiative on retention including the public campaign, the evidence base, long term retention care, retrospective support, the impact on consent, considerations for GDPs and record-keeping with suggestions on improving long-term support for patients. PMID- 29622797 TI - Novel bone morphogenetic protein receptor inhibitor JL5 suppresses tumor cell survival signaling and induces regression of human lung cancer. AB - BMP receptor inhibitors induce death of cancer cells through the downregulation of antiapoptotic proteins XIAP, pTAK1, and Id1-Id3. However, the current most potent BMP receptor inhibitor, DMH2, does not downregulate BMP signaling in vivo because of metabolic instability and poor pharmacokinetics. Here we identified the site of metabolic instability of DMH2 and designed a novel BMP receptor inhibitor, JL5. We show that JL5 has a greater volume of distribution and suppresses the expression of Id1 and pTak1 in tumor xenografts. Moreover, we demonstrate JL5-induced tumor cell death and tumor regression in xenograft mouse models without immune cells and humanized with adoptively transferred human immune cells. In humanized mice, JL5 additionally induces the infiltration of immune cells within the tumor microenvironment. Our studies show that the BMP signaling pathway is targetable in vivo and BMP receptor inhibitors can be developed as a therapeutic to treat cancer patients. PMID- 29622802 TI - Design and assessment of engineered CRISPR-Cpf1 and its use for genome editing. AB - Cpf1, a CRISPR endonuclease discovered in Prevotella and Francisella 1 bacteria, offers an alternative platform for CRISPR-based genome editing beyond the commonly used CRISPR-Cas9 system originally discovered in Streptococcus pyogenes. This protocol enables the design of engineered CRISPR-Cpf1 components, both CRISPR RNAs (crRNAs) to guide the endonuclease and Cpf1 mRNAs to express the endonuclease protein, and provides experimental procedures for effective genome editing using this system. We also describe quantification of genome-editing activity and off-target effects of the engineered CRISPR-Cpf1 in human cell lines using both T7 endonuclease I (T7E1) assay and targeted deep sequencing. This protocol enables rapid construction and identification of engineered crRNAs and Cpf1 mRNAs to enhance genome-editing efficiency using the CRISPR-Cpf1 system, as well as assessment of target specificity within 2 months. This protocol may also be appropriate for fine-tuning other types of CRISPR systems. PMID- 29622803 TI - Simultaneous reprogramming and gene editing of human fibroblasts. AB - The utility of human induced pluripotent stem cells (iPSCs) is enhanced by an ability to precisely modify a chosen locus with minimal impact on the remaining genome. However, the derivation of gene-edited iPSCs typically involves multiple steps requiring lengthy culture periods and several clonal events. Here, we describe a one-step protocol for reliable generation of clonally derived gene edited iPSC lines from human fibroblasts in the absence of drug selection or FACS enrichment. Using enhanced episomal-based reprogramming and CRISPR/Cas9 systems, gene-edited and passage-matched unmodified iPSC lines are obtained following a single electroporation of human fibroblasts. To minimize unwanted mutations within the target locus, we use a Cas9 variant that is associated with decreased nonhomologous end-joining (NHEJ) activity. This protocol outlines in detail how this streamlined approach can be used for both monoallelic and biallelic introduction of specific base changes or transgene cassettes in a manner that is efficient, rapid (~6-8 weeks), and cost-effective. PMID- 29622801 TI - Flapless dental implant surgery and use of cone beam computer tomography guided surgery. AB - Flapless implant surgery is increasing in popularity, particularly due to advances and increased usage of cone beam computed tomography (CBCT) and dental implant treatment planning software allowing three-dimensional assessment of the implant site. It is the aim of the article to provide an overview of flapless implant surgery and CBCT guided flapless implant surgery and summarise the literature with regard to the effectiveness of this surgical technique. PMID- 29622804 TI - Producing genome structure populations with the dynamic and automated PGS software. AB - Chromosome conformation capture technologies such as Hi-C are widely used to investigate the spatial organization of genomes. Because genome structures can vary considerably between individual cells of a population, interpreting ensemble averaged Hi-C data can be challenging, in particular for long-range and interchromosomal interactions. We pioneered a probabilistic approach for the generation of a population of distinct diploid 3D genome structures consistent with all the chromatin-chromatin interaction probabilities from Hi-C experiments. Each structure in the population is a physical model of the genome in 3D. Analysis of these models yields new insights into the causes and the functional properties of the genome's organization in space and time. We provide a user friendly software package, called PGS, which runs on local machines (for practice runs) and high-performance computing platforms. PGS takes a genome-wide Hi-C contact frequency matrix, along with information about genome segmentation, and produces an ensemble of 3D genome structures entirely consistent with the input. The software automatically generates an analysis report, and provides tools to extract and analyze the 3D coordinates of specific domains. Basic Linux command line knowledge is sufficient for using this software. A typical running time of the pipeline is ~3 d with 300 cores on a computer cluster to generate a population of 1,000 diploid genome structures at topological-associated domain (TAD)-level resolution. PMID- 29622805 TI - Generation and customization of biosynthetic excitable tissues for electrophysiological studies and cell-based therapies. AB - We describe a two-stage protocol to generate electrically excitable and actively conducting cell networks with stable and customizable electrophysiological phenotypes. Using this method, we have engineered monoclonally derived excitable tissues as a robust and reproducible platform to investigate how specific ion channels and mutations affect action potential (AP) shape and conduction. In the first stage of the protocol, we combine computational modeling, site-directed mutagenesis, and electrophysiological techniques to derive optimal sets of mammalian and/or prokaryotic ion channels that produce specific AP shape and conduction characteristics. In the second stage of the protocol, selected ion channels are stably expressed in unexcitable human cells by means of viral or nonviral delivery, followed by flow cytometry or antibiotic selection to purify the desired phenotype. This protocol can be used with traditional heterologous expression systems or primary excitable cells, and application of this method to primary fibroblasts may enable an alternative approach to cardiac cell therapy. Compared with existing methods, this protocol generates a well-defined, relatively homogeneous electrophysiological phenotype of excitable cells that facilitates experimental and computational studies of AP conduction and can decrease arrhythmogenic risk upon cell transplantation. Although basic cell culture and molecular biology techniques are sufficient to generate excitable tissues using the described protocol, experience with patch-clamp techniques is required to characterize and optimize derived cell populations. PMID- 29622807 TI - Author Correction: Ultrafast photonic reinforcement learning based on laser chaos. AB - A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has not been fixed in the paper. PMID- 29622809 TI - Viral hepatitis: OX40 signalling mediates effective HBV immune responses. PMID- 29622810 TI - Endoscopy: Autofluorescence inferior for dysplasia surveillance. PMID- 29622806 TI - Mechanisms of cancer resistance in long-lived mammals. AB - Cancer researchers have traditionally used the mouse and the rat as staple model organisms. These animals are very short-lived, reproduce rapidly and are highly prone to cancer. They have been very useful for modelling some human cancer types and testing experimental treatments; however, these cancer-prone species offer little for understanding the mechanisms of cancer resistance. Recent technological advances have expanded bestiary research to non-standard model organisms that possess unique traits of very high value to humans, such as cancer resistance and longevity. In recent years, several discoveries have been made in non-standard mammalian species, providing new insights on the natural mechanisms of cancer resistance. These include mechanisms of cancer resistance in the naked mole rat, blind mole rat and elephant. In each of these species, evolution took a different path, leading to novel mechanisms. Many other long-lived mammalian species display cancer resistance, including whales, grey squirrels, microbats, cows and horses. Understanding the molecular mechanisms of cancer resistance in all these species is important and timely, as, ultimately, these mechanisms could be harnessed for the development of human cancer therapies. PMID- 29622811 TI - Viral hepatitis: Maternal tenofovir use does not improve prevention of perinatal HBV transmission. PMID- 29622813 TI - Advances in the physiological assessment and diagnosis of GERD. AB - This corrects the article DOI: 10.1038/nrgastro.2017.130. PMID- 29622812 TI - Advances in the management of oesophageal motility disorders in the era of high resolution manometry: a focus on achalasia syndromes. AB - This corrects the article DOI: 10.1038/nrgastro.2017.132. PMID- 29622814 TI - NASH: Successful phase II trial of FGF19 analogue. PMID- 29622808 TI - Expert consensus document: Advances in the diagnosis and classification of gastric and intestinal motility disorders. AB - Disturbances of gastric, intestinal and colonic motor and sensory functions affect a large proportion of the population worldwide, impair quality of life and cause considerable health-care costs. Assessment of gastrointestinal motility in these patients can serve to establish diagnosis and to guide therapy. Major advances in diagnostic techniques during the past 5-10 years have led to this update about indications for and selection and performance of currently available tests. As symptoms have poor concordance with gastrointestinal motor dysfunction, clinical motility testing is indicated in patients in whom there is no evidence of causative mucosal or structural diseases such as inflammatory or malignant disease. Transit tests using radiopaque markers, scintigraphy, breath tests and wireless motility capsules are noninvasive. Other tests of gastrointestinal contractility or sensation usually require intubation, typically represent second line investigations limited to patients with severe symptoms and are performed at only specialized centres. This Consensus Statement details recommended tests as well as useful clinical alternatives for investigation of gastric, small bowel and colonic motility. The article provides recommendations on how to classify gastrointestinal motor disorders on the basis of test results and describes how test results guide treatment decisions. PMID- 29622815 TI - Spectroscopic Characterization of Key Aromatic Molecules: A Route toward The Origin of Life. AB - To gain information on the abiotic synthesis of the building blocks of life from simple molecules, and their subsequent chemical evolution to biological systems, the starting point is the identification of target species in Titan-like planets, i.e., planets that resemble the primitive Earth, as well as in Earth-like planets in the habitable zone of their star, namely planets where life can be already originated. In this scenario, molecular spectroscopy plays a crucial role because spectroscopic signatures are at the basis of an unequivocal proof for the presence of these target molecules. Thanks to the advances in many different techniques and to the NASA successful Kepler exoplanet transit mission, thousands of diverse planets outside of our solar system have been discovered. The James Webb Space Telescope (JWST), scheduled to be launched in 2018, will be very helpful in the identification of biosignature gases in Earth-like planets' atmospheres and of prebiotic molecule signatures in Titan-like atmospheres by observing their absorption during transits. While the search for key-target molecules in exoplanet atmospheres can be carried out by the JWST Transit Spectroscopy in the infrared (IR) region (0.6 - 29 um wavelength range), opportunities for their detection in protostellar cores, protoplanetary disks and on Titan are also offered by the interferometric high spectral and spatial resolution observations using the Atacama Large Millimeter/submillimeter Array (ALMA). In the present work, target molecules have been selected and their spectroscopic characterization presented in view of supporting their infrared and complementary millimeter/submillimeter-wave spectral observations. In detail, the selected target molecules include: (1) the three-membered oxygen-containing heterocycles: oxirane and protonated oxirane, (2) the cyclopropenyl cation and its methyl derivative, (3) two examples of ortho- and peri-fused tri-cyclic aromatic rings, i.e., the phenalenyl cation (C13H9+) and anion (C13H9-), and (4) uracil, a specific RNA base. PMID- 29622816 TI - Radial mixing and Ru-Mo isotope systematics under different accretion scenarios. AB - The Ru-Mo isotopic compositions of inner Solar System bodies may reflect the provenance of accreted material and how it evolved with time, both of which are controlled by the accretion scenario these bodies experienced. Here we use a total of 116 N-body simulations of terrestrial planet accretion, run in the Eccentric Jupiter and Saturn (EJS), Circular Jupiter and Saturn (CJS), and Grand Tack scenarios, to model the Ru-Mo anomalies of Earth, Mars, and Theia analogues. This model starts by applying an initial step function in Ru-Mo isotopic composition, with compositions reflecting those in meteorites, and traces compositional evolution as planets accrete. The mass-weighted provenance of the resulting planets reveals more radial mixing in Grand Tack simulations than in EJS/CJS simulations, and more efficient mixing among late-accreted material than during the main phase of accretion in EJS/CJS simulations. We find that an extensive homogenous inner disk region is required to reproduce Earth's observed Ru-Mo composition. EJS/CJS simulations require a homogeneous reservoir in the inner disk extending to >=3-4 AU (>=74-98% of initial mass) to reproduce Earth's composition, while Grand Tack simulations require a homogeneous reservoir extending to >=3-10 AU (>=97-99% of initial mass), and likely to >=6-10 AU. In the Grand Tack model, Jupiter's initial location (the most likely location for a discontinuity in isotopic composition) is ~3.5 AU; however, this step location has only a 33% likelihood of producing an Earth with the correct Ru-Mo isotopic signature for the most plausible model conditions. Our results give the testable predictions that Mars has zero Ru anomaly and small or zero Mo anomaly, and the Moon has zero Mo anomaly. These predictions are insensitive to wide variations in parameter choices. PMID- 29622817 TI - Optimal Electrocatalytic Pd/MWNTs Nanocatalysts toward Formic Acid Oxidation. AB - The operating conditions such as composition of electrolyte and temperature can greatly influence the formic acid (HCOOH) oxidation reaction (FAOR). Palladium decorated multi-walled carbon nanotubes (Pd/MWNTs) were successfully synthesized and employed as nanocatalysts to explore the effects of formic acid, sulfuric acid (H2SO4) concentration and temperature on FAOR. Both the hydrogen adsorption in low potential range and the oxidation of poisoning species during the high potential range in cyclic voltammetry were demonstrated to contribute to the enhanced electroactivity of Pd/MWNTs. The as-synthesized Pd/MWNTs gave the best performance under a condition with balanced adsorptions of HCOOH and H2SO4 molecules. The dominant dehydrogenation pathway on Pd/MWNTs can be largely depressed by the increased dehydration pathway, leading to an increased charge transfer resistance (Rct ). Increasing HCOOH concentration could directly increase the dehydration process proportion and cause the production of COads species. H2SO4 as donor of H+ greatly facilitated the onset oxidation of HCOOH in the beginning process but it largely depressed the HCOOH oxidation with excess amount of H+. Enhanced ion mobility with increasing the temperature was mainly responsible for the increased current densities, improved tolerance stabilities and reduced Rct values, while dehydration process was also increased simultaneously. PMID- 29622818 TI - Ultrathin layered double hydroxide nanosheets with Ni(III) active species obtained by exfoliation for highly efficient ethanol electrooxidation. AB - The development of non-precious metal electrocatalysts for renewable energy conversion and storage is compelling but greatly challenging due to low activity of the existing catalysts. Herein, the ultrathin NiAl-layered double hydroxide nanosheets (NiAl-LDH-NSs) are prepared by simple liquid-exfoliation of bulk NiAl LDHs and first used as ethanol electrooxidation catalysts. The ultrathin two dimensional (2D) structure ensures that the LDH nanosheets expose a greater number of active sites. More importantly, much Ni(III) active species (NiOOH) in the ultrathin nanosheets are formed by the exfoliation process, which play an authentic catalytic role in the ethanol oxidation reaction (EOR). The presence of NiOOH remarkably improves the reactivity and electrical conductivity of LDH nanosheets. These synergistic effects lead to strikingly more than 30 times enhanced EOR activity of NiAl-LDH-NSs compared to bulk NiAl-LDHs. The obtained electrocatalytic activity is also much better than those of most Ni- and LDH based EOR catalysts reported to date. In addition, the ultrathin NiAl-LDH-NS electrocatalyst also exhibits good long-term stability (maintain 81.8% of the original value after 10000 s). This study not only provides a highly competitive EOR catalyst, but also opens new avenues toward the design of highly efficient electrode materials that have various potential applications in supercapacitor, Ni-MH battery and other electrocatalytic systems. PMID- 29622819 TI - Mitigating the scourge of non-alcoholic fatty liver disease in Ghana. PMID- 29622820 TI - High risk of coagulopathy among Type-2 Diabetes Mellitus clients at a municipal hospital in Ghana. AB - Background: Persistent hyperglycaemia in diabetes mellitus causes coagulopathies due to glycation of haemoglobin, prothrombin, fibrinogen and other proteins involved in the clotting mechanism. Shortened activated partial thromboplastin time (APTT) and prothrombin time (PT) reflect hypercoagulable state, which is associated with an increased thrombotic risk and adverse cardiovascular effects. This study assessed the coagulation profile of type 2 diabetes mellitus (T2DM) clients at a municipal hospital in Ghana. Methods: A hospital-based case-control study was conducted from January to April 2015 at the Agona Swedru Municipal Hospital. Sixty (60) persons with T2DM and 40 without were recruited and screened using appropriate protocols. Blood samples were collected for coagulation and biochemical tests. Demographic and clinical information were collected using pre tested questionnaire. Data was analyzed with GraphPad Prism version 5. Results: APTT and PT were significantly shorter among patients with T2DM compared to those without (20.88 +/- 5.19 v 31.23 +/- 5.41, P=0.0001; and 11.03 +/- 2.06sec v 14.46 +/- 1.86, P=0.0001 respectively). INR was decreased among patients with T2DM compared to those without (0.83 +/- 0.18 v 1.13 +/- 0.17, P=0.0001). No significant difference was found in platelet count between T2DM and non-diabetics (179.85 +/- 66.15*103 /mm3 v 168.55 +/- 35.77*103 /mm3, P=0.326). Serum magnesium was lower among the T2DM patients compared to the non-diabetics, while serum ionized calcium was significantly higher among the T2DM patients (P<0.05). Conclusion: Clients with T2DM may have a high coagulation risk evidenced by shortened APTT, PT and a high ionized calcium compared with controls. Funding: Study was funded by Lord Ampomah and Solomon Panford. PMID- 29622821 TI - The burden and characteristics of peripheral arterial disease in patients undergoing amputation in Korle Bu Teaching Hospital, Accra, Ghana. AB - Background: To determine the prevalence of Peripheral Arterial Disease (PAD) and associated risk factors in patients undergoing amputation at the Korle Bu Teaching Hospital (KBTH), Accra, Ghana. Objectives: A cross- sectional study of all patients undergoing lower extremity amputation at the Department of Surgery, KBTH. Materials: A coded questionnaire was used to ascertain risk factors for PAD. The Edinburgh Claudication Questionnaire was used to determine symptomatic PAD and a 5 mmHz hand held Summit(r) Doppler together with an Accoson (r) sphygmomanometer was used to determine PAD and its severity. Method: Clinical diagnosis of symptomatic PAD was made using a symptom-based questionnaire and signs of PAD determined by measuring the ankle brachial pressure index (ABPI) by means of a handheld Doppler and sphygmomanometer. Risk factors were determined using the coded questionnaire and related to the occurrence and severity of PAD. Results: The prevalence of PAD among recruited participants was 71%. Twenty-eight per cent of participants with PAD in the index limb also showed signs of PAD in the other limb. The diagnosis of PAD was made in 71%, using ABPI, and 13%, using ECQ. Twenty-seven per cent of patient with hypertension, seventeen per cent with diabetes and all patients with hypercholesterolemia were not on any form of medication. Conclusion: There is a high prevalence of PAD among patients undergoing lower extremity amputation at the KBTH. The majority of PAD patients presented with moderate to severe PAD. Instituting measures to identify and control risk factors of PAD may reduce this high burden. Funding: Not declared. Funding source: Authors funded the study. PMID- 29622822 TI - Information gaps in surveillance data and effects on the Ghanaian response to the Ebola outbreak in West Africa. AB - Background: Complete and accurate information on disease occurrence is crucial for effective public health response to disease outbreaks. In response to the 2014 Ebola epidemic in West Africa, Ghana intensified surveillance for the disease across the country. However, the case definition provided by the Ministry of Health was not uniformly applied at all reporting health facilities. Objective: This paper analyses the accompanying Case Record Forms (CRFs) submitted to Noguchi Memorial Institute for Medical Research to determine its completeness and appropriateness for instituting an effective response to the epidemic. Methods: We determined the proportions of completeness in reporting for all criteria provided by the MOH for the clinical diagnosis of Ebola. New indicators were generated to measure the completeness of each variable. Tables and graphs of completeness of indicators were produced and presented. Results: Of the 156 samples, 69% were from males. Approximately 4.5% had no record for age. The date of specimen collection was filled for 96%; 34.6% (54) did not have date of onset of symptoms. In 37.8% (59) of cases, location was blank. In 12% of cases, no symptoms were recorded and about 30% had no record of fever. Travel history, especially to affected areas, was missing for 40.4%. Conclusions: Gaps on CRFs can significantly reduce the utility of results of laboratory analysis for outbreak control. Although all the samples analysed were negative for Ebola Virus, the high proportion of missing data on the forms should be a source of concern. We recommend that frontline health staff be trained on the importance of capturing all information required on the form. Source of funding: The funding for the analysis of suspected samples were provided partially by Ghana Health Servce and research funding from Noguchi Memorial Institute for Medical Research. PMID- 29622823 TI - Fasting plasma glucose and lipid profiles of diabetic patients improve with aerobic exercise training. AB - Objective: This study presents the effects of aerobic exercise training on fasting plasma glucose and lipid profiles (FPG/LP) of diabetic patients in Kumasi. Design: A randomised experimental with control design. Setting: The study was conducted at the diabetic unit of KATH in Kumasi, Ghana. Participants: Twelve diabetic patients [grouped into intervention (IG) and control (CG)] attending the diabetic unit of KATH with diabetes diagnosis durations less than fifty years, ambulant status/age of 20-68years, sedentary and free from complications. Interventions: Eight weeks aerobic exercise training between August 2015 and March 2016. Main outcome measures: Body weight (BW), Body mass index (BMI), fasting plasma glucose (FPG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglycerides (T) and total cholesterol (TC). Results: Body weight (4.85kg, 7.0%), body mass index (4.08kg/m2, 7.3%), FPG (5.28mmol/L, 43.5%), LDL-C (.33mmol/l, 11.9%), TC (.47 mmol/l, 5.3%) and T (.48mmol/l, 29.4%) profiles of the patients in IG declined while HDL-C (.11mmol/l, 7.1%) increased. IG patients improved significantly in FPG [6.27 +/- 0.91 < 8.00 +/- 0.96; t=-52.00, P = 0.000], BW [58.60 +/- 15.34 < 75.35 +/- 22.00; t= 3.29, P = 0.040] and BMI [23.45 +/-5.03<27.04 +/-4.78, t=4.24, P = .050] compared to CG. Conclusion: Patients in IG, in addition to conventional care, experienced non-significant decline in LDL-C, TC, T, increase in HDL-C and significant reduction in FPG, BW, and BMI over those receiving conventional care only. Exercise Scientists are recommended to handle exercise sessions for healthcare prevention and management routines of diabetic patients. Funding: Not declared. PMID- 29622824 TI - Traditional medicines and alternative practice in the management of prostate diseases in southern Ghana. AB - Objective: This study was aimed at identifying Ghanaian traditional medicines used for the management of prostate diseases and their constituents. Reviews of studies conducted on them are also presented. Methodology: This was a prospective study. Traditional Medicine samples from consecutive patients with either lower urinary symptoms (LUTS) presenting at the Urology Unit of the Korle Bu Teaching Hospital (KBTH) in Accra from January 2015 to June 2016 and had a prior treatment with traditional medicines, had the samples retrieved. Additionally, all the 58 licensed pharmaceutical shops in Okaishie, a whole sale and retail depot for medicines in the main business district of Accra, were visited and traditional medicines for the management of prostate diseases acquired. The products constituent as labeled were documented and entered once on a proforma. This study was part of a study on the management of benign prostate hyperplasia at the KBTH approved by the Medical Directorate.The findings were analyzed and presented using descriptive statistics and presented as a table. Results: Eleven products were identified with the main indigenous medicinal plant identified being the root extract of Croton membranaceus. This was the constituent in four products (Uro 500(r), UR-Quick mixture(r), Prostacure(r) and prostat(r)60). Although studies on the basic pharmacology and animal studies have confirmed its effect on the prostate, only one clinical study was identified. Conclusion: Croton membranaceus was the indigenous traditional medicine identified for relieving LUTS due to prostate disease. There is the need for empirical evidence on its efficacy in treating Prostate cancer. Funding: Not declared. PMID- 29622825 TI - Gastrointestinal food allergy in Ghanaian children: a case series. AB - Background: Food allergy is an adverse health effect arising from a specific immune response that occurs reproducibly on exposure to a given food. Food allergies are classified into three types: Ig(immunoglobulin)E mediated, mixed IgE and cell mediated and cell-mediated non IgE mediated. Gastrointestinal (GIT) food allergy has classically encompassed a number of different clinical entities: food protein-induced enterocolitis syndrome (FPIES), food protein-induced proctocolitis (FPIP), food protein-induced enteropathy and eosinophilic gastrointestinal disorders (EGID). Case presentations: These are 5 cases of infants and toddlers who presented with various features of gastrointestinal food allergies, the commonest of which is lower gastrointestinal bleed. Two infants on exclusive breast feeding, presented with lower gastrointestinal bleeding and these resolved with maternal dietary milk and all dairy elimination. The third infant had rectal bleeding at age 6 months after the introduction of infant formula. The bleeding and eczema resolved with the introduction of hydrolyzed formula. One of the toddlers presented with severe eczema and malnutrition which improved with 6 food elimination. The last case had massive lower gastrointestinal bleed which resulted in hemicolectomy with no improvement until dietary elimination was instituted. Conclusion: Gastrointestinal food allergy is not uncommon in children in Ghana. A high index of suspicion is required to make the right diagnosis, to minimize morbidity and unnecessary therapy. Source of funding: None. PMID- 29622826 TI - Hot Tub Lung: An Intriguing Diffuse Parenchymal Lung Disease. AB - In pulmonary medicine, identical pathogenesis due to varied etiological agents can present with indistinguishable clinical presentation, and produce similar laboratory and radiological changes. The importance of eliciting detailed occupational and social history from patients cannot be stressed enough when dealing with patients suffering from diffuse parenchymal lung diseases. Hot Tub Lung(HTL) is a perplexing pulmonary disease attributed to the Mycobacterium Avium intracellulare Complex (MAC). MAC is a ubiquitous atypical mycobacterium present in moist environment, and is not considered pathogenic, without the predisposing conditions like immunosuppression. However, HTL is a unique disease seen in healthy individuals following the exposure to contaminated hot water in spas. The less virulent MAC will, in healthy individual will elicit mild granulomatous inflammation particularly around the peribronchiolar region, which leads to the development of diffuse parenchymal lung. We report a case of HTL to increase the awareness of this rare and enigmatic disease among medical professionals, and to reiterate the importance of eliciting social and occupational details in clinical practice. PMID- 29622828 TI - Uncommon mixed outbreak of pneumococcal and meningococcal meningitis in Jirapa District, Upper West Region, Ghana, 2016. AB - Objective: The Jirapa District in Ghana falls within the African meningitis belt where over 500 million people are at risk of epidemic meningitis. The district suffered an outbreak of Neisseria meningitides, W (NMW) in 2012 and a mixed outbreak of Streptococcus pneumonia and NMW in early 2016. We investigated the outbreak to identify the source, causative agents, and magnitude and assess health facility preparedness and propose control measures. Design and Setting: We conducted a descriptive study in all sub-districts of Jirapa, between 28th February to 10th April 2016. We reviewed records at health facilities, assessed health facility preparedness, searched for cases, traced contacts of case to administer chemoprophylaxis and collect CSF for laboratory analysis. Data were entered in Microsoft excel cleaned, and exported to stata-13 for analysis by person place and time. Results: A total 233 meningitis cases were reported with mean age of 22.4years and standard deviation 21.6. Males were (57%), females (43%) and 60.8% were less than 19 years. Attack rate of meningitis was 214/100,000 with case fatality rate (CFR) of 12.4% (29/233). Causative agents were NMW (69.5%) and streptococcus pneumonia (27.1%), mainly serotype STN1 and H. influenza (3.4%). The index case had travel history to dollar power, close to Tain District which is the epicentre for the 2016 meningitis outbreak in Ghana. Conclusion: The Jirapa district experienced a mixed outbreak of streptococcal and meningococcal meningitis in early 2016, facilitated by migration. Active surveillance and mass vaccination with multivalent vaccines is required to protect the population. Funding: Ghana Field Epidemiology and Laboratory Training Programme (GFELTP). PMID- 29622829 TI - Factors influencing use of analgesics among construction workers in the Ga Eastmunicipality of the Greater Accra region, Ghana. AB - Background: Analgesics also known as painkillers are widely used for pain relief. There are severe health implications associated with excessive use of analgesics. This paper examines factors influencing the use of analgesics among construction workers in the Ga-East Municipality (GEM) of the Greater Accra region of Ghana. Methods: This is a cross-sectional study involving 206 construction workers randomly sampled from 7 construction sites in the GEM. A structured questionnaire was used to elicit responses on knowledge of analgesics, types of analgesics used and factors influencing the use of analgesics. Chi-square test analysis was used to examine factors influencing analgesic use. Results: The majority of workers were aged between 15 to 44 years (89.8%) and 51.9 percent of respondents had completed Junior high school. Many respondents (68.0%) used Brand 1 a locally manufactured analgesic with paracetamol, aspirin and caffeine as the active ingredients and 31.6 percent of respondents had no knowledge of possible side effects of continuous use of analgesics. Chi square analysis showed that age was significantly associated with use of analgesics (p<0.01). Knowledge of the types of analgesics, dosage and side effects did not influence use (p>0.05). Television and radio advertisements influenced use of analgesics (p<0.01). Conclusion: Knowledge on analgesic use and knowledge of probable serious side effects was inadequate. Pharmacists and chemists involvement in education of clients of the side effects of analgesics is highly recommended to minimise misuse. The Food and Drugs Authority should regulate the proliferation of advertisements for analgesics in the media. Funding: None declared. PMID- 29622830 TI - Prevalence, perception and correlates of low back pain among healthcare workers in tertiary health institutions in Sokoto, Nigeria. AB - Background: Low back pain (LBP) is a common cause of disability worldwide. Healthcare workers are particularly prone to it because of the physical and emotional factors associated with their profession. Objectives: To determine the prevalence, perception and correlates of LBP among healthcare workers in tertiary health institutions in Sokoto, Nigeria. Methods: A cross-sectional study was conducted among 320 healthcare workers selected by multistage sampling technique from July to September 2016. Anthropometry was done for the participants in addition to questionnaire administration. Results: The mean age of the study participants was 36.99 +/- 8.23 years. The lifetime, annual, and point prevalence of LBP among the participants were 56.2%, 39.1% and 17.2% respectively. Most, 151 (83.9%) of the 180 participants that have ever experienced LBP reported that it commenced after starting work, and they perceived it to be due to standing for long hours (57.2%), awkward postures (22.2%) and carrying heavy objects/patients at work (20.6%). Older age, female sex, longer duration of practice, overweight/obesity, and lifting heavy objects/patients at work were significantly associated with LBP among the participants. Conclusion: The prevalence of LBP is high among healthcare workers in Sokoto, Nigeria; although it was also associated with older age and female sex, being in practice for 10 years and above, overweight/obesity, and lifting heavy objects/patients at work were the predictors identified. Management of the respective hospitals should prevent workplace exposures to heavy weight/objects by establishing "lift teams" as a temporary measure, and also implement "zero lift programs" in their facilities. Funding: Nil. PMID- 29622833 TI - Fibreoptic gastro-intestinal endoscopy at the Korle Bu Teaching Hospital, Accra, Ghana: a historical perspective. AB - Fibreoptic (or Flexible) endoscopy has revolutionized and completely transformed practice of gastroenterology, and many other medical specialties, over the past half century or so. At the Korle Bu Teaching Hospital, Accra the development of this facility has evolved gradually, especially involving specialists from the Departments of Medicine and Surgery since the 1970s. This article is an attempt to trace and record this journey and to highlight some of the problems and challenges yet to be overcome. It is an anecdotal account based on the authors' recollection with attempts at verification of important dates. PMID- 29622831 TI - Experience with argon laser trabeculoplasty in Nigerians. AB - Aim: To report the safety and efficacy of Argon Laser Trabeculoplasty (ALT) in reducing intraocular pressure (IOP). Settings and Design: This was a retrospective study performed on 25 eyes of 25 patients. Methods and Materials: Consecutive patients who met the inclusion criteria for ALT were recruited from the ophthalmic clinic of the University College Hospital Ibadan, Nigeria and followed up for a minimum period of six months. Two criteria were used to define successful response. Criterion 1 was defined as IOP reduction of 3mmHg or more without additional intervention while criterion 2 was IOP reduction of 20% or more from the pretreatment IOP. Statistical Analysis: Data was analyzed using SPSS version 16. Frequencies and means were generated to observe patterns of variable distribution among the patients. P value < 0.05 was considered significant. Results: The mean pretreatment IOP was 19.9 +/-3.1mmHg, (range of 16 to 26 mmHg). Mean post treatment IOP at 6 months was 14.9 +/-2.2 mmHg, (range of 11 to 19 mmHg). Mean IOP reduction at one year was 4.6 mmHg, representing a 22.3% drop. There was a statistically significant greater IOP reduction in eyes (P<0.001) with higher pretreatment IOP. Based on criterion 1 and 2, 84.0% of the patients had successful outcome at six months while at one year, 76.9% were successful based on criterion one. Conclusion: To the best of our knowledge, this is the first study to report the efficacy of ALT in Nigerians. ALT is safe and effective in reducing IOP in Nigerians. Key messages: ALT is safe and effective in reducing intraocular pressure in this population of Nigerians. Funding: The present study did not receive any funds. PMID- 29622834 TI - Two cases of Pentalogy of Cantrell diagnosed antenatally at Korle Bu Teaching Hospital, Accra. AB - Pentalogy of Cantrell is a rare congenital malformation syndrome that may be associated with other congenital anomalies. The syndrome is said to affect males and females in equal numbers and the prognosis is generally poor. We report two cases of Cantrell's Pentalogy diagnosed antenatally at the Korle Bu teaching Hospital. The 2 cases described in this report demonstrate the complete and incomplete variant of the syndrome. The cases were referred as an omphalocoele and a detailed anomaly scan confirmed the diagnosis of Pentalogy of Cantrell. Both cases were females and neither survived beyond 24 hours. Although this condition is associated with a poor prognosis, there have been some reported cases of survival in the literature. Thus, accurate prenatal diagnosis and a multidisciplinary approach to the management may offer improved outcomes. PMID- 29622832 TI - Lunar cycle may have an effect on Shock Wave Lithotripsy related pain outcome. AB - Objectives: We tried to investigate the effects of lunar phase on Shock Wave Lithotripsy (SWL) related pain. In addition, correlation of various clinical parameters with the pain perception during SWL procedure, were also investigated. Methods: A total of 378 patients who underwent first SWL sessions for renal or ureteral stones were prospectively enrolled in the study. The degree of pain perception during the procedure was evaluated with 10-point visual analog scale (VAS) and pain questionnaires. The date of SWL was allocated to dates and times of lunar phases as: newmoon, waxing crescent, first quarter, waxing gibbus, fullmoon, waning gibbus, last quarter and waning gibbus. Results: Mean VAS scores in first quarter (2,41+/-1,06) were significantly lower when compared to mean VAS scores in waning crescent (3,58+/-1,83) and waning gibbus (3,42+/-1,98) (p=0,005 and 0,041, respectively). No statistically significant differences were observed when other lunar phases were compared between each other. Mean pain scores were not affected from gender, age, body mass index (BMI) and stone characteristics (stone laterality, burden and location). Conclusions: SWL procedure performed in first quarter of the lunar phase may become less painful. To the best of our knowledge, this is the first study which evaluated the effect of lunar phase on post-SWL pain outcome. Thus, additional randomized studies with larger series may be more informative. PMID- 29622835 TI - Diagnosing and treating rare lesions in a low resource setting: lessons from ahybrid epithelioid trophoblastic tumor and choriocarcinoma. AB - Objective: To raise awareness of the existence of a rare type of malignant trophoblastic tumor and discuss the diagnostic challenges and management of this lesion in a low resource setting. Case report and intervention: A 35 -year -old G6P3 woman was referred to our facility on account of persistent vaginal bleeding due to a suspected incomplete miscarriage with a cervical mass. Her serum beta HCG was elevated (36,900 mIU/ml) and examination showed a bleeding cervical mass. An initial histopathological diagnosis of moderately differentiated squamous cell carcinoma was reviewed to epithelioid trophoblastic tumor resulting in an extra fascial hysterectomy. A final histopathological diagnosis of hybrid Epithelioid Trophoblastic Tumor and Choriocarcinoma (ETT/CC) was made after external review and immunohistochemistry. She received subsequent chemotherapy. Conclusion: Epithelioid trophoblastic tumor and its hybrids are difficult to diagnose. They may be diagnosed as moderately differentiated squamous cell carcinoma especially in low resource settings where cervical squamous cell carcinoma is relatively more common. A high index of suspicion, a serum beta HCG test and close collaboration between clinicians and pathologists can help make the diagnosis. Funding: None. PMID- 29622836 TI - Impacted third molar transplantation on the malpracticed extraction socket. AB - : Autotransplantation with or without endodontic therapy is regarded as an alternative treatment option for the replacement of missing teeth. A primary responsibility of a maxillofacial surgeon is to reverse any malpractice to promote successful outcomes and improve the patient's quality of life. This paper presents a malpractice case of incorrect extraction of the lower second molar instead of the impacted third molar. A simple technique of transplanting the impacted third molar to the site of the extracted second molar is introduced by a maxillofacial specialist in Ghana. By making an intentional root socket and fixation without using additional appliances, a novel second molar was achieved with complete recovery. This patient was followed after transplant for a four year period with the best satisfaction. Funding: A grant of the Korean Health Technology R&D Project, Ministry of Health & Welfare, Republic of Korea. (HI15C0689). PMID- 29622837 TI - Hydatid cyst of the orbit in a young Nigerian female: a case report. AB - Objective: To report an unusual case of orbital hydatid cyst successfully managed by surgical excision. Case report: A 33-year-old female presented with gradual protrusion of the left eye associated with poor vision, cosmetic embarrassment and watering. She had excision biopsy of an encapsulated cystic lesion with cheesy tissue and serous content. Orbital hydatid cyst due to echinococcosis was confirmed at histopathological examination of the excised tissue. She subsequently became pregnant hence, could not undergo post-operative antihelminthic treatment, but was managed conservatively with no recurrence after five years of regular follow-up. Conclusion: Orbital hydatid cyst should be considered as a differential in a young patient presenting with unilateral proptosis. Funding: None. PMID- 29622838 TI - A Physical-Inorganic Approach for the Elucidation of Active Iron Species and Mechanism in Iron-Catalyzed Cross-Coupling. AB - Detailed studies of iron speciation and mechanism in iron-catalyzed cross coupling reactions are critical for providing the necessary fundamental insight to drive new reaction development. However, such insight is challenging to obtain due to the prevalence of mixtures of unstable, paramagnetic organoiron species that can form in this chemistry. A physical-inorganic research approach combining freeze-trapped inorganic spectroscopic studies, organometallic synthesis and GC/kinetic studies provides a powerful method for studying such systems. Mossbauer, EPR and MCD spectroscopy enable the direct investigation of in situ formed iron species and, combined with GC analysis, the direct correlation of reactions of specific iron species to the generation of organic products. This review focuses on a description of the key methods involved in this physical inorganic approach, as well as examples of its application to investigations of iron-SciOPP catalyzed cross-coupling catalysis. PMID- 29622839 TI - Social Exclusion and Parental Incarceration Impacts on Adolescents' Networks and School Engagement. AB - Although prior research links parental incarceration to deleterious outcomes for children over the life-course, few studies have examined whether such incarceration affects the social exclusion of children during adolescence. Drawing on several lines of scholarship, we examine whether adolescents with incarcerated parents have fewer or lower quality relationships, participate in more antisocial peer networks, and feel less integrated or engaged in school. The study applies propensity score matching to survey and network data from a national sample of youth. Analyses indicated that children with incarcerated parents have more antisocial peers; we found limited evidence, though, that parental incarceration adversely impacts peer networks and school integration domains. Generally, the results suggested that the impacts of parental incarceration on adolescents' social lives have less to do with isolation than with the types of peers adolescents befriend. Findings provide support for the idea that parental incarceration may adversely affect children's social exclusion. PMID- 29622841 TI - MDH volume 62 Issue 2 Cover and Front matter. PMID- 29622840 TI - Electromagnetic scattering by spheroidal volumes of discrete random medium. AB - We use the superposition T-matrix method to compare the far-field scattering matrices generated by spheroidal and spherical volumes of discrete random medium having the same volume and populated by identical spherical particles. Our results fully confirm the robustness of the previously identified coherent and diffuse scattering regimes and associated optical phenomena exhibited by spherical particulate volumes and support their explanation in terms of the interference phenomenon coupled with the order-of-scattering expansion of the far field Foldy equations. We also show that increasing nonsphericity of particulate volumes causes discernible (albeit less pronounced) optical effects in forward and backscattering directions and explain them in terms of the same interference/multiple-scattering phenomenon. PMID- 29622842 TI - Vessel detection and classification from spaceborne optical images: A literature survey. AB - *A review of 119 papers on ship detection and classification from optical satellite.*From 1978 to March 2017, showing an exponential growth in the number of papers.*Most published methods have very limited validation.*While big steps have been made, automatic algorithms are still far from perfect.*Increase in new observation and processing capabilities promises rapid advances. PMID- 29622843 TI - Rapid access to the core skeleton of the [3 + 2]-type dimeric pyrrole-imidazole alkaloids by triplet ketone-mediated C-H functionalization. AB - The ability of triplet ketones to abstract a hydrogen atom from hydrocarbons is reminiscent of that of the high-spin metal-oxo complexes in C-H oxidation enzymes. In practice, the reactivity of triplet ketones is easier to control and applicable to promoting a wider range of reactions. We demonstrate herein the synthetic utility of triplet ketone-mediated C-addition of methanol to cyclopentenone derivatives with an expedient synthesis of the core skeleton of the [3+2]-type dimeric pyrrole-imidazole alkaloids. Remarkably, this photochemical C-H functionalization reaction is highly regioselective and can tolerate a good range of functional groups. PMID- 29622844 TI - Isolation of amoenamide A and five antipodal prenylated alkaloids from Aspergillus amoenus NRRL 35600. AB - A new prenylated alkaloid, Amoenamide A (6), was isolated from the fungus Aspergillus amoenus NRRL 35600. Previously, 6 was postulated to be a precursor of Notoamide E4 (21) converted from Notoamide E (16), which was a key precursor of the prenylated indole alkaloids in the fungi of the genus Aspergillus. We previously succeeded in the isolation of two pairs of antipodes, Stephacidin A (1) and Notoamide B (2), from A. amoenus and A. protuberus MF297-2 and expected the presence of other antipodes in the culture of A. amoenus. We here report five new antipodes (7-11) along with a new metabolite (12), which was isolated as a natural compound for the first time, from A. amoenus. PMID- 29622845 TI - A Newly Defined Area of the Mouse Anterior Hypothalamus Involved in Septohypothalamic Circuit: Perifornical Area of the Anterior Hypothalamus, PeFAH. AB - Although the hypothalamus is classified into more than 10 compartments, it still contains uncharacterized areas. In this study, we identified a new triangular shaped area between the paraventricular hypothalamic nucleus (PVN) and the fornix area in the mouse anterior hypothalamus, which is enriched in chondroitin sulfate proteoglycans (CSPGs). We designated this region as the perifornical area of the anterior hypothalamus (PeFAH) based on its anatomical location. As evidenced by Nissl staining, the PeFAH was distinguishable as an area of relatively low density. Immunohistochemical and DNA microarray analyses indicated that PeFAH contains sparsely distributed calretinin-positive neurons and densely clustered enkephalin-positive neurons. Furthermore, the PeFAH was shown to have bidirectional neural connections with the lateral septum. Indeed, we confirmed enkephalinergic projections from PeFAH neurons to the lateral septum, and inversely, calbindin-positive lateral septum neurons as afferents to the PeFAH. Finally, c-Fos expression analysis revealed that the activity of certain PeFAH neuronal populations tended to be increased by psychological stressors, but not that of enkephalinergic neurons. We proposed PeFAH as a new region in the AH. PMID- 29622846 TI - Improved Serial Sectioning Techniques for Correlative Light-Electron Microscopy Mapping of Human Langerhans Islets. AB - Combined analysis of immunostaining for various biological molecules coupled with investigations of ultrastructural features of individual cells is a powerful approach for studies of cellular functions in normal and pathological conditions. However, weak antigenicity of tissues fixed by conventional methods poses a problem for immunoassays. This study introduces a method of correlative light and electron microscopy imaging of the same endocrine cells of compact and diffuse islets from human pancreatic tissue specimens. The method utilizes serial sections obtained from Epon-embedded specimens fixed with glutaraldehyde and osmium tetroxide. Double-immunofluorescence staining of thick Epon sections for endocrine hormones (insulin and glucagon) and regenerating islet-derived gene 1 alpha (REG1alpha) was performed following the removal of Epoxy resin with sodium ethoxide, antigen retrieval by autoclaving, and de-osmification treatment with hydrogen peroxide. The immunofluorescence images of endocrine cells were superimposed with the electron microscopy images of the same cells obtained from serial ultrathin sections. Immunofluorescence images showed well-preserved secretory granules in endocrine cells, whereas electron microscopy observations demonstrated corresponding secretory granules and intracellular organelles in the same cells. In conclusion, the correlative imaging approach developed by us may be useful for examining ultrastructural features in combination with immunolocalisation of endocrine hormones in the same human pancreatic islets. PMID- 29622847 TI - Estrogen Regulates Mitochondrial Morphology through Phosphorylation of Dynamin related Protein 1 in MCF7 Human Breast Cancer Cells. AB - Estrogen affects mitochondrial function in various tissues, but the precise mechanism remains unclear. We, therefore investigated the effect on estrogen regulated mitochondrial morphology by dynamin-related protein 1 (Drp1) and its Ser616-phosphorylated derivative (pDrp1Ser616) are involved in mitochondrial fission. MCF7 human breast cancer cells were treated with 17beta-estradiol (E2), an estrogen receptor (ER) alpha and beta antagonist (ICI 182, 780), an ERalpha antagonist (MPP), and an ERbeta antagonist (PHTPP) for 24 hr. The expression of Drp1 and pDrp1Ser616 was analyzed by western blotting and immunohistochemistry. Mitochondrial morphology was analyzed by transmission electron microscopy (TEM). In control cells, Drp1 was detected in the cytoplasm of all cells while pDrp1 was observed in the cytoplasm of 3.4 +/- 1.0% of the total population. After E2 treatment, pDrp1Ser616-positive cells comprised 30.6 +/- 5.6% of the total population, 10.5 +/- 1.7% after E2 + ICI treatment, 12.4 +/- 4.2% after E2 + MPP treatment, and 24.0 +/- 2.2% after E2 + PHTPP treatment. In ERalpha knockdown MCF7 cells, pDrp1 expression was decreased after E2 treatment compared to E2 treated wild type cells. Tubular pattern mitochondria were found in the control cells but the number of short and small pattern mitochondria (< 0.5 MUm2) was significantly increased after E2 treatment (as observed by TEM). We, therefore concluded that the phosphorylation of Drp1 is important for E2-dependent mitochondrial morphological changes through ERalpha. PMID- 29622848 TI - The HDAC Inhibitor, SAHA, Prevents Colonic Inflammation by Suppressing Pro inflammatory Cytokines and Chemokines in DSS-induced Colitis. AB - Inflammatory bowel disease (IBD) is an inflammatory disorder of the gastrointestinal tract that is caused by multiple factors, including dysfunction of the immune system and genetic and epigenetic alterations. Aberrant epigenetic regulation, especially histone acetylation, was found in biopsies from IBD patients and mouse models of colitis, suggesting that an epigenetic treatment approach may be useful for IBD therapy. Therefore, we investigated the effects of the histone deacetylase (HDAC) inhibitor, suberoylanilide hydroxamic acid (SAHA), in a mouse model of dextran sulfate sodium (DSS)-induced colitis. C57BL/6 mice were treated with 1.5% DSS for 5 days and/or SAHA (25 mg/kg BW/day) for 26 days. Levels of mRNA for the pro-inflammatory cytokines, interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha, and the chemokines, Ccl2, were examined by qRT-PCR. CD11b, a marker of dendritic cells, macrophages, and monocytes, as well as Ccl2 expression, were examined by immunohistochemistry. IL-6, TNF-alpha, and Ccl2 gene expression peaked on day 5 in DSS-treated mouse colon, whereas SAHA treatment significantly decreased pro-inflammatory gene expression. Ccl2 protein expression resembled Ccl2 gene expression results. Moreover, localization of CD11b showed that migratory inflammatory cells were dramatically decreased by SAHA treatment compared to DSS-treated mouse colon. Thus, we conclude that the HDAC inhibitor, SAHA, attenuates inflammatory changes in DSS-induced colitis by suppressing local secretion of pro-inflammatory cytokines and chemokines and also by suppressing mobilization and accumulation of inflammatory cells. PMID- 29622849 TI - Expression and Dynamics of Podoplanin in Cultured Osteoblasts with Mechanostress and Mineralization Stimulus. AB - This study investigates the significance of the expression and dynamics of podoplanin in mechanostress and mineralization in cultured murine osteoblasts. Podoplanin increased in osteoblasts subjected to straining in non-mineralization medium, suggesting that the mechanostress alone is a podoplanin induction factor. In osteoblasts subjected to vertical elongation straining in the mineralization medium, the mRNA amounts of podoplanin, osteopontin, and osteocalcin were significantly larger than those in cells not subjected to straining, suggesting that mechanostress is the cause of a synergistic effect in the expression of these proteins. In osteoblasts in the mineralization medium, significant increases in osteocalcin mRNA occurred earlier in cells subjected to straining than in the cells not subjected to straining, suggesting that the mechanostress is a critical factor to enhance the expression of osteocalcin. Western blot and ELISA analysis showed increased podoplanin production in osteoblasts with longer durations of straining. There was significantly less mineralization product in osteoblasts with antibodies for podoplanin, osteopontin, and osteocalcin. There was also less osteopontin and osteocalcin produced in osteoblasts with anti podoplanin. These findings suggest that mechanostress induces the production of podoplanin in osteoblasts and that podoplanin may play a role in mineralization in cooperation with bone-associated proteins. PMID- 29622850 TI - Expression of Draxin in Lung Carcinomas. AB - Guidance molecules, such as Netrin-1, and their receptors have important roles in controlling axon pathfinding, modulate biological activities of various cancer cells, and may be a useful target for cancer therapy. Dorsal repulsive axon guidance protein (Draxin) is a novel guidance molecule that binds not only common guidance molecule receptors with Netrin-1, but also directly binds the EGF domain of Netrin-1 through a 22-amino-acid peptide (22aa). By immunostaining, Draxin was positively expressed in small cell carcinoma, adenocarcinoma (ADC), and squamous cell carcinoma of the lung. In addition, western blot analysis revealed that Draxin was expressed in all histological types of lung cancer cell lines examined. Knockdown of Draxin in an ADC cell line H358 resulted in altered expression of molecules associated with proliferation and apoptosis. The Ki-67 labeling index of Draxin-knockdown ADC cells was increased compared to that of control ADC cells. In H358 cells, treatment of 22aa induced phosphorylation of histone H3, but did not change apoptosis-associated enzymes. These data suggest that Draxin might be involved in cell proliferation and apoptosis in lung adenocarcinoma cells. PMID- 29622851 TI - Distinguishing types of social withdrawal in children: Internalizing and externalizing outcomes of conflicted shyness versus social disinterest across childhood. AB - Little research has examined the effect of subtypes of social withdrawal on the development of psychopathology across childhood. Parents of 493 children (220 females) completed a measure of their child's conflicted shyness and social disinterest as well as the Child Behaviour Checklist (CBCL) when their child was age 3, and again at age 6. When children were age 9, parents completed the CBCL. From 3 to 6, conflicted shyness predicted increases in anxiety symptoms in boys and girls, and predicted depressive symptoms in boys. From 6 to 9, social disinterest predicted increases in anxiety symptoms in girls and boys, and predicted increases in depressive symptoms in boys. In addition, in boys, conflicted shyness at age 6 predicted increases in externalizing symptoms at age 9. Conflicted shyness appears to be particularly problematic in early to middle childhood, while social disinterest appears to be more maladaptive in later childhood, with some differences by gender. PMID- 29622852 TI - Effects of El Nino on summertime ozone air quality in the eastern United States. AB - We investigate the effect of El Nino on maximum daily 8-hour average surface ozone over the eastern United States in summer during 1980-2016. El Nino can influence the extra-tropical climate through the propagation of stationary waves, leading to (1) reduced transport of moist, clean air into the mid- and southern Atlantic states and greater subsidence, reduced precipitation, and increased surface solar radiation in this region, as well as (2) intensified southerly flow into the south central states, which here enhances flux of moist and clean air. As a result, each standard deviation increase in the Nino 1+2 index is associated with an increase of 1-2 ppbv ozone in the Atlantic states and a decrease of 0.5-2 ppbv ozone in the south central states. These influences can be predicted 4 month in advance. We show that U.S. summertime ozone responds differently to eastern type El Nino events compared to central-type events. PMID- 29622853 TI - For Whom the Bells Toll: Alonso and a Regional Science of Decline. AB - In his presidential address to the Regional Science Association over thirty years ago, William Alonso presented the case for "Five Bell Shapes in Development" and argued that "the developed countries will enter fully in to the realm of the right-hand tail of these curves" (p. 16) and that this transition might result in several surprises. He proposed, therefore, that we should study the right tail of these "curves" as well as interactions among them. Much of what Alonso suggested has come to pass, although his prognostications were not always exact. And although he touched on several issues of relevance to regional scientists, the discipline has been slow to move away from a growth-centered paradigm. The strength of regional science-the capacity to consider economic, demographic, and geographical aspects of an issue simultaneously-has yet to be focused on some of the "right-hand" challenges that have arisen, population loss, for example. In this article, we provide a review of regional science research within the context of Alonso's five bells and hypothesize how Alonso's propositions might differ in today's world. We then focus more specifically on one particular area: population loss. Using these examples allows us to highlight how regional science might contribute to the conceptualization of "right-hand tail" development challenges, especially where theory, issues of spatial scale, and interregional dependencies are concerned. PMID- 29622854 TI - Dynamic beam filtering for miscentered patients. AB - Purpose: Accurate centering of the patient within the bore of a CT scanner takes time and is often difficult to achieve precisely. Patient miscentering can result in significant dose and image noise penalties with the use of traditional bowtie filters. This work describes a system to dynamically position an x-ray beam filter during image acquisition to enable more consistent image performance and potentially lower dose needed for CT imaging. Methods: We propose a new approach in which two orthogonal low-dose scout images are used to estimate a parametric model of the object describing its shape, size, and location within the field of view (FOV). This model is then used to compute an optimal filter motion profile by minimizing the variance of the expected detector fluence for each projection. Dynamic filtration was implemented on a cone-beam CT (CBCT) test bench using two different physical filters: 1) an aluminum bowtie and 2) a structured binary filter called a multiple aperture device (MAD). Dynamic filtration performance was compared to a static filter in studies of dose and reconstruction noise as a function of the degree of miscentering of a homogeneous water phantom. Results: Estimated filter trajectories were found to be largely sinusoidal with an amplitude proportional to the amount of miscentering. Dynamic filtration demonstrated an improved ability to keep the spatial distribution of dose and reconstruction noise at baseline levels across varying levels of miscentering, reducing the maximum noise and dose deviation from 53% to 15% and 42% to 14% respectively for the bowtie filter, and 25% to 8% and 24% to 15% respectively for the MAD filter. Conclusion: Dynamic positioning of beam filters during acquisition improves dose utilization and image quality over static filters for miscentered patients. Such dynamic filters relax positioning requirements and have the potential to reduce set-up time and lower dose requirements. PMID- 29622855 TI - Prospective Image Quality Analysis and Control for Prior-Image-Based Reconstruction of Low-Dose CT. AB - Purpose: Prior-image-based reconstruction (PIBR) is a powerful tool for low-dose CT, however, the nonlinear behavior of such approaches are generally difficult to predict and control. Similarly, traditional image quality metrics do not capture potential biases exhibited in PIBR images. In this work, we identify a new bias metric and construct an analytical framework for prospectively predicting and controlling the relationship between prior image regularization strength and this bias in a reliable and quantitative fashion. Methods: Bias associated with prior image regularization in PIBR can be described as the fraction of actual contrast change (between the prior image and current anatomy) that appears in the reconstruction. Using local approximation of the nonlinear PIBR objective, we develop an analytical relationship between local regularization, fractional contrast reconstructed, and true contrast change. This analytic tool allows prediction bias properties in a reconstructed PIBR image and includes the dependencies on the data acquisition, patient anatomy and change, and reconstruction parameters. Predictions are leveraged to provide reliable and repeatable image properties for varying data fidelity in simulation and physical cadaver experiments. Results: The proposed analytical approach permits accurate prediction of reconstructed contrast relative to a gold standard based on exhaustive search based on numerous iterative reconstructions. The framework is used to control regularization parameters to enforce consistent change reconstructions over varying fluence levels and varying numbers of projection angles - enabling bias properties that are less location- and acquisition dependent. Conclusions: While PIBR methods have demonstrated a substantial ability for dose reduction, image properties associated with those images have been difficult to express and quantify using traditional metrics. The novel framework presented in this work not only quantifies this bias in an intuitive fashion, but it gives a way to predict and control the bias. Reliable and predictable reconstruction methods are a requirement for clinical imaging systems and the proposed framework is an important step translating PIBR methods to clinical application. PMID- 29622856 TI - Joint Optimization of Fluence Field Modulation and Regularization for Multi-Task Objectives. AB - This work investigates task-driven optimization of fluence field modulation (FFM) and regularization for model-based iterative reconstruction (MBIR) when different imaging tasks are presented by different organs. Example applications of the design framework were demonstrated in an abdomen phantom where the task of interest in the liver is a low-contrast, low-frequency detection task while that in the kidney is a high-contrast, high-frequency discrimination task. The global performance objective is based on maximizing local detectability index (d') at a discrete set of locations. Two objective functions were formulated based on different imaging needs: 1) a maxi-min objective where all tasks are equally important, and 2) a region-of-interest (ROI) objective to maximize imaging performance in an ROI while maintaining a minimum level of performance elsewhere. The FFM pattern for the maxi-min objective is determined by the most challenging task in the liver where both angular and spatial modulation resulted in a ~35% improvement in d' compared to an unmodulated case. The FFM for the ROI objective prescribes the most fluence to the organs of interest, boosting d' by ~59%, but manages to achieve the minimum d' target elsewhere. A spatially varying regularization was found to be important when tasks of different frequency content are present in different parts of the image - the optimal regularization strength for the two studied tasks differed by two orders of magnitude. Initial investigations in this work demonstrated that a multi-task objective is potentially important in shaping the optimal FFM and MBIR regularization, and that these tools may help to generalize task-based acquisition and reconstruction design for more complex diagnostic scenarios. PMID- 29622857 TI - Spatial Resolution and Noise Prediction in Flat-Panel Cone-Beam CT Penalized likelihood Reconstruction. AB - Purpose: Model based iterative reconstruction (MBIR) algorithms such as penalized likelihood (PL) methods have data-dependent and shift-variant image properties. Predictors of local reconstructed noise and resolution have found application in a number of methods that seek to understand, control, and optimize CT data acquisition and reconstruction parameters in a prospective fashion (as opposed to studies based on exhaustive evaluation). However, previous MBIR prediction methods have relied on idealized system models. In this work, we develop and validate new predictors using accurate physical models specific to flat-panel CT systems. Methods: Novel predictors for estimation of local spatial resolution and noise properties are developed for PL reconstruction that include a physical model for blur and correlated noise in flat-panel cone-beam CT (CBCT) acquisitions. Prospective predictions (e.g., without reconstruction) of local point spread function and and local noise power spectrum (NPS) model are applied, compared, and validated using a flat-panel CBCT test bench. Results: Comparisons between prediction and physical measurements show excellent agreement for both spatial resolution and noise properties. In comparison, traditional prediction methods (that ignore blur/correlation found in flat-panel data) fail to capture important data characteristics and show significant mismatch. Conclusion: Novel image property predictors permit prospective assessment of flat-panel CBCT using MBIR. Such predictors enable standard and task-based performance assessments, and are well-suited to evaluation, control, and optimization of the CT imaging chain (e.g., x-ray technique, reconstruction parameters, novel data acquisition methods, etc.) for improved imaging performance and/or dose utilization. PMID- 29622858 TI - The Relationship Context of Young Pregnancies. PMID- 29622859 TI - Performance improvement via bagging in probabilistic prediction of chaotic time series using similarity of attractors and LOOCV predictable horizon. AB - Recently, we have presented a method of probabilistic prediction of chaotic time series. The method employs learning machines involving strong learners capable of making predictions with desirably long predictable horizons, where, however, usual ensemble mean for making representative prediction is not effective when there are predictions with shorter predictable horizons. Thus, the method selects a representative prediction from the predictions generated by a number of learning machines involving strong learners as follows: first, it obtains plausible predictions holding large similarity of attractors with the training time series and then selects the representative prediction with the largest predictable horizon estimated via LOOCV (leave-one-out cross-validation). The method is also capable of providing average and/or safe estimation of predictable horizon of the representative prediction. We have used CAN2s (competitive associative nets) for learning piecewise linear approximation of nonlinear function as strong learners in our previous study, and this paper employs bagging (bootstrap aggregating) to improve the performance, which enables us to analyze the validity and the effectiveness of the method. PMID- 29622860 TI - Laboratory Monitoring of Chronic Myeloid Leukemia in Patients on Tyrosine Kinase Inhibitors. AB - Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm characterized by translocation of genetic material from chromosome 9 to chromosome 22 to form a fusion gene (BCR-ABL1) that is responsible for abnormal tyrosine kinase activity and alteration of various downstream signaling pathways. In addition to morphological diagnosis of CML phase, it is essential to detect BCR-ABL1 fusion by either metaphase cytogenetics or reverse transcriptase polymerase chain reaction that also determines type of mRNA transcript. Once treatment begins, monitoring the response to Tyrosine Kinase Inhibitor (TKI) using standardized techniques and guidelines is important to check for failure of response and thus, plan timely intervention by increasing the dose of TKI or opting for second line TKIs. The goal is to stop evolution of CML to accelerated phase or blast crisis that has poor response to treatment. Also, it is desirable to achieve good outcomes and even treatment free remission in patients of CML on TKI. Thus, molecular monitoring by reverse transcriptase quantitative PCR (RT-qPCR) is done at regular intervals. There are international recommendations and quality control measures to standardize the reporting of fusion gene transcript levels by quantitative PCR (RT-qPCR) in CML to achieve and maintain sensitivity in molecular detection of CML disease burden. Various state-of-the-art molecular techniques have emerged to accurately determine the number of fusion-gene transcript levels. This review highlights various methodologies and their practical implications in management of CML patients on TKI. PMID- 29622862 TI - The Effect and Safety of Bortezomib in the Treatment of AL Amyloidosis: A Systematic Review and Meta-Analysis. AB - Bortezomib began to be used in the treatment of light chain (AL) amyloidosis in recent years. We performed the first meta-analysis of randomized clinical trials and clinical controlled trials to evaluate the effect and safety of bortezomib treatment for AL amyloidosis. We conducted a search (until July 2016) in electronic databases (PubMed databases and the Cochrane Central Register of Controlled Trials bases from the year 2003). There were 205 records we searched and eight studies was included (n = 617 persons). We demonstrated that bortezomib treatment significantly improved overall response rate (ORR), complete response, a cardiac response rate, 2-year overall survival and the risk of neuropathy and reduced overall mortality compared to controls without bortezomib therapy. From the comparison and subgroup analysis of ORR between bortezomib group and no bortezomib group, the patients with bortezomib had a higher ORR, especially patients pretreated with bortezomib before high-dose melphalan followed by autologous stem cell transplant compared to no pretreatment. In addition, patients with bortezomib in standard dosage had significantly higher ORR. According to our results, bortezomib should be used in AL amyloidosis patients to improve response rate and survival rate and future relevant randomized controlled trials require to be performed. PMID- 29622861 TI - Management of Iron Deficiency Anemia in Pregnancy in India. AB - Iron deficiency anemia (IDA) continues to be the commonest etiology of anemia in pregnancy. The prevalence of iron deficiency (ID) in pregnant Indian women is amongst the highest in the world. Untreated iron deficiency (ID) has significant adverse feto-maternal consequences. Plethora of investigations are available for diagnosis of IDA, each having specific advantages and disadvantages when used in the pregnancy setting. Therapy for ID includes dietary modification, oral iron supplementation, intravenous iron and blood transfusion. Newer parenteral iron preparations are safe and there is mounting evidence to suggest their use in frontline settings for pregnancy associated IDA in the second and third trimester. Through this review, we suggest an algorithm for diagnosis and treatment of IDA in pregnancy depending on the severity of anemia and period of gestation suited for widespread use in resource limited settings. Also, we recommend ways for increasing public awareness and tackling this health issue including the observance of "National Anemia Awareness and Treatment Day." PMID- 29622863 TI - Summary and Review of the Abstracts on Philadelphia-Negative Myeloproliferative Neoplasms Presented at Haematocon 2017. AB - There are lot of grey zones in Philadelphia negative chronic myeloproliferative neoplasms (CMPNs) and that's the reason they are in hit list of researchers. Having a spectrum of disorders their diagnosis is very important and especially to differentiate from each other since they overlap with each other in many ways. Diagnosis doesn't start from lab but with clinical phenotype. Clinical phenotype not only able to provide us the diagnosis but also helps in management of the disease per se. When diagnosis comes, the old timer but an evergreen morphology plays an important role which along with the newer generation tool "molecular" helps in differentiating these disorders. Lot of studies have already come up from the world. Indian data has also started coming up. When we say about the Indian data nothing holds more important role than Indian Society of Haematology and Blood Transfusion, ISHBT. This small review will cover all papers with BCR ABL negative CMPNs which were presented at the annual national conference of the ISHBT (Haematocon 2017) which was conducted at Guwahati. These abstract papers from various reputed institutes and centres will provide a short academic journey towards ongoing research activities at these places and will able to guide us regarding Philadelphia negative CMPNs and also stimulate our brain for some left or conflicted areas. PMID- 29622864 TI - Comparison of Immunohistochemistry, Cytochemistry, and Flow Cytometry in AML for Myeloperoxidase Detection. AB - Acute Myeloid Leukemia (AML) as per World Health Organization (WHO 2008) classification is on the basis of the antigenic characterization, enzymes restriction in the neoplastic myeloid cells and the specific translocations/mutations. AML can be assessed and differentiated by flowcytometry (FCM)/immunohistochemistry (IHC)/cytochemistry techniques. Myeloperoxidase (MPO) is an unequivocal marker to differentiate AML from the acute lymphoblastic leukemia. Despite FCM popularity, it has its limitations, in form of 'dry-tap', cost, and inability of being performed by retrospective analysis. IHC, though an old technique has overcome these disadvantages of FCM. Cytochemistry, on the other hand has its own advantages in being cost-effective; technically easy to do while its disadvantages are its inability to be carried out in the old samples, 'dry-tap' conditions in aleukemic leukemia. There has been non-uniformity in the literature among these techniques especially concerning their sensitivity for MPO. A prospective study was done at All India Institute of Medical Sciences New Delhi from 01 July 2014 to 30 Nov 2015 to include 120 diagnosed acute myeloid leukemia cases. Myeloperoxidase stain was done by cytochemistry, immunohistochemistry and flow cytometry and results were compared. There were 28 cases which showed discrepancies. Out of these 28 cases immunohistochemistry showed positivity in majority (22 cases) followed by flow cytometry (14 cases). Therefore it is important to employ more than one technique and IHC must be included for detection of MPO in all suspected cases of AML especially when negative with FCM . PMID- 29622865 TI - The Synonymous Isocitrate Dehydrogenase 1 315C>T SNP Confers an Adverse Prognosis in Egyptian Adult Patients with NPM1-/CEBPA-Negative Acute Myeloid Leukemia. AB - Although the clinical features of isocitrate dehydrogenase (IDH) genetic aberrations have been well-characterized in acute myeloid leukemia (AML), definitive information on their prognostic significance is lacking. We aimed to explore the prognostic significance of IDH gene alterations in an Egyptian cohort of adult patients with de novo AML. Diagnostic peripheral blood samples from 51 AML patients were analyzed for the presence of mutations/SNPs in exon 4 of IDH1 and IDH2 genes using polymerase chain reaction amplification followed by direct sequencing. IDH mutational status had no impact on event-free survival (EFS) and overall survival (OS), whereas the presence of IDH1 315C>T SNP was significantly associated with inferior EFS (P = 0.037) and OS (P = 0.034) as compared with wild type IDH1. IDH1 315C>T SNP but not IDH mutations is associated with unfavorable outcomes, suggesting that AML patients with IDH1 315C>T SNP can represent a new subgroup of patients which allows refined risk stratification. PMID- 29622866 TI - The Inhibitory Effect of Epigallocatechin Gallate on the Viability of T Lymphoblastic Leukemia Cells is Associated with Increase of Caspase-3 Level and Fas Expression. AB - Acute lymphoblastic leukemia is the most prevalent cancer in children. Novel components to help struggle aggressive malignancies and overcome some side effects of conventional treatments could be a promising strategy. Epigallocatechingallate (EGCG), have attracted the attention of scientists for prevention or treatment of some cancers. Jurkat cells were incubated with the different concentrations of EGCG (30-100 um) for 24, 48, and 72 h and cell viability was investigated using MTS test. Apoptosis and the level of caspase 3 alterations were evaluated using flowcytometry and expression of Fas by Real Time PCR. EGCG decreased viability of cells with an inhibition concentration (IC50) of 82.8 +/- 3.1, 68.8 +/- 4 and 59.7 +/- 4.8 MUM in 24,48 and 72 h. 50, 70 and 100 uM concentrations of EGCG induced apoptosis in about 31, 40 and 71% of the cells, respectively. The mean value of caspase 3 positive cells in the presence of 50, 70 and 100 um concentrations of EGCG was 19.3 +/- 2.9, 29.5 +/- 3.1 and 61.2 +/- 3.4 respectively compared to 7.8 +/- 1.1 in control with a significant difference at 100 um concentration. Treatment with EGCG for 48 h enhanced the expression of Fas reaching to a significant level at 100 uM concentration. EGCG is effective in decrease cell viability, apoptosis induction and enhancement of caspase 3 and Fas expression level in jurkat cells. A comprehensive understanding of molecular events and pharmacokinetics of the component and experiments in animal models are required for dose determination and its interaction with other components of combination chemotherapy. PMID- 29622867 TI - Autologous Stem Cell Transplantation for Multiple Myeloma: Single Centre Experience from North India. AB - Autologous stem cell transplantation (ASCT) is considered as standard of care in patients with multiple myeloma (MM) patients aged 65 years or younger. We analyzed data of 94 patients of plasma cell dyscrasias who underwent 95 autologous transplants at our institute from October 2003 to Aug 2016. Other than 76 patients of newly diagnosed multiple myeloma, we also transplanted two patients of POEMS syndrome, two patients of plasma cell leukemia, three patients of concurrent light chain deposition disease, three patients of multifocal plasmacytomas, and eight patients of isolated light chain myeloma. One patient underwent transplant twice. The median age of patients was 53 years (range 21 65). The average interval between diagnosis and transplant was 10.51 +/- 5.42 months. The predominant stage in the study cohort was ISS-III. IgG kappa was the commonest subtype of plasma cell dyscrasia (27.9%) followed by IgG lambda (16.27%). Renal involvement was seen in 25% patients at the time of transplantation. Following chemotherapy, 42% patients were in CR, 39% in VGPR, 5% had PR and 14% had progressive disease at the time of transplantation. All patients were conditioned with melphalan (dose 120-200 mg/m2) except for one who received an additional bortezomib for his second transplant. The mean time to neutrophil and platelet engraftment was 11.09 +/- 1.82 and 12.69 +/- 4.55 days respectively. Mucositis was noted in all patients (grade 3 in 37.5% patients). The median PFS (biochemical) was 55.8% and PFS (clinical) was 76.7% at 6.5 years. Thirteen percent of the transplanted patients succumbed to their illness of which three patients died within 30 days of transplant. Median OS was 76.7% at 6.5 years. ASCT is a feasible option for MM in India and the results are comparable. PMID- 29622869 TI - Infusion Related Hypersensitivity Reactions with Bio-similar Anti CD-20 Monoclonal Antibody Rituximab in Indian Patients: A Retrospective Study. AB - There is paucity of data on infusion related hypersensitivity reactions (IRHR) pattern of bio-similar rituximab in B-cell lymphoma patients. As bio-similar molecules are independently developed monoclonal antibodies, they are likely to differ in immunogenicity and therefore, the hypersensitivity data of the innovator rituximab may not be directly applicable to patients treated with the biosimilar rituximab molecule. We analysed our data of 256 patients of B cell lymphoid neoplasm who received bio-similar rituximab (Reditux) based chemo immunotherapy for their treatment. Total 56/256 (21.8%) patients had >= grade II IRHR with first dose of rituximab. Grade II reactions were seen in 32/256 (12.5%) cases, grade III and grade IV reactions were seen in 21/256 (8.2%) and 3/256 (1.2%) cases, respectively. Rituximab was withdrawn from all further therapy in only 2 patients due to grade IV IRHR after attempting re-challenge of the drug under intensive monitoring. There was no difference in complete response rates in patients with or without IRHR during their first rituximab infusion. The IRHRs with bio-similar rituximab noted in our study were comparable with the previously published reactions associated with the original rituximab. PMID- 29622868 TI - Bufalin Enhances the Cytotoxity of Human Multiple Myeloma Cells H929 to AKT Inhibitor MK2206: The Role of Protein AKT Phosphorylation. AB - This study was purposed to investigate bufalin combined with AKT inhibitor MK2206 on growth inhibition and apoptosis of multiple myeloma cell line H929. CCK-8 assay and Annexin/PI staining were used to access the effects of bufalin and MK2206 in single or in combination, on inhibition of proliferation and induction of apoptosis in H929 cells. The apoptotic cells markedly increased after treated with nM bufalin and MUM MK2206, including caspase3 and PARP1 proteins activated. The difference was statistically significant (P < 0.05) when compared with these drugs in single use. The apoptosis associated proteins and AKT/p-AKT proteins were determined by Western blots. We confirmed that AKT performed contradictory results in H929 with the two agents, and concluded p-AKT was vital in the synergy. The underlying mechanisms warrant further investigation. PMID- 29622871 TI - Predictors of Mononuclear Cell Yield in Patients Undergoing Autologous Mononuclear Stem Cell Therapy in Non-haemopoietic Degenerative Disorders. AB - Cellular therapy outcomes are influenced by cellular composition of the product. We analyzed the cellular profiles (TNC, MNC and CD34+ cells) of patients receiving mononuclear cell therapy in terms of age, gender, BMI, pre-harvest haematological counts and clinical conditions. Cellular profiles of 262 patients were analyzed in terms of age (age < 40 year, age 41-60 year and age > 60 year), gender, BMI (BMI < 22 kg/m2, BMI 22-25 kg/m2 and BMI > 25 kg/m2), pre-harvest haematological profile and clinical conditions (chronic disorders, group A, acute vascular group B and traumatic events, group C). A steady decline was observed in TNC and MNC counts with increasing age and BMI. In clinical conditions, group C showed a highest cellular yield followed by group A and group B respectively. Amongst the three age groups, group I (age < 40 year) showed a better cellular profiles than group II (age 41-60 year) and group III (age > 60 year). Patients with Higher TLC (>7000/MUl) and platelet count (>200 * 103/MUl) yielded better cellular profile in the harvest. Patient age, BMI, haematological counts and clinical condition significantly affect the bone marrow cellular profile. PMID- 29622870 TI - Lower Total Leukocyte and Neutrophil Counts in Healthy Young Africans from Uganda. AB - The total leukocyte count (TLC) is an important component of the complete blood count and influences many clinical decisions. The effect of race or ethnicity on TLC is not well known. The African population has been reported to have lower than normal TLC and neutrophil counts. In this study, thirty eight African students referred for medical check up to a tertiary care hospital were included. Complete blood count was done on a three part automated hematology analyzer. Blood smear examination and manual differential count was also done. The control group included 38 age and sex matched healthy individuals. Student t test was used to compare the differences between the groups. The mean TLC in African students (4.95 +/- 1.09 * 109/l) was significantly lower (p < 0.0001) than that seen in the control group (7.42 +/- 1.7 * 109/l). The mean neutrophil percentage was also lower (49 +/- 7.5%) in African students compared to the control group (63.6 +/- 9.8%) [p < 0.0001] while lymphocyte percentage was higher (45.2 +/- 7.5%) in the African students as compared to the control group (31.0 +/- 9.3%) [p < 0.0001]. Absolute neutrophil count was also lower (2.45 +/- 0.76 * 109/l) in African students compared to the control group (4.76 +/- 1.47 * 109/l) while absolute lymphocyte count was comparable (2.21 +/- 0.5 * 109/l vs. 2.26 +/- 0.72 * 109/l) [p = 0.7212]. This study has shown lower leukocyte and neutrophil counts in apparently healthy African individuals. Knowledge of this variation from normal white cell and neutrophil counts is important in avoiding unnecessary investigations and influencing therapeutic decisions in these individuals. PMID- 29622872 TI - Beneficial Effect of Low Fixed Dose of Hydroxyurea in Vaso-occlusive Crisis and Transfusion Requirements in Adult HbSS Patients: A Prospective Study in a Tertiary Care Center. AB - Significant reduction in morbidity and mortality have been documented in patients with sickle cell disease (HbSS) by most of the studies using hydroxyurea at a dose of 25-35 mg/kg/day or maximum tolerated dose. But toxicities, need for frequent monitoring, compliance and cost are important hurdles particularly in Indian set up. We undertook this study to find out the efficacy, safety compliance rate of low fixed dose of hydroxyurea (10 mg/kg/day) in patients presenting to our hospital and its impact on clinical profile and laboratory parameters. A cohort of 128 (82 males, 46 females) confirmed HbSS cases (each >18 years age, vaso-occlusive crisis >2/years and/ or rate of transfusion 1-2 units/month) with no disease related end organ damage were assessed prospectively between 2013 and 2016. They were started on 10 mg/kg/day hydroxyurea along with other supportive care and followed up monthly for 1 year. Clinical and laboratory parameters before and after therapy were reviewed and compared. In 92% of cases presenting with repeated vaso-occlusive crisis, VOC disappeared completely during follow up and in 8% we found significant reduction in severity as well as frequency of attacks (p < 0.01). Again in 87%, no further transfusion was required during follow up and in 13%, it further reduced the rate of transfusion (p < 0.01). The median time of response for VOC was 3 months and in transfusion requirement was 5 months. There was also significant reduction in S.Billirubin, S.LDH, disease related complications and rate of hospitalisation with significant improvement in Hb, MCV, and MCH. There is insignificant increase in HbF with median (1.5-2.4)% and in 5 cases >5%. We did not find any remarkable adverse effect of the drug during the study period. Low fixed dose hydroxyurea (10 mg/kg/day) is beneficial in reducing the vaso-occlusive crisis and transfusion requirement in adult HbSS Patients (Arab-Indian Haplotype). It is safe, suitable and is a effective mode of treatment in resource poor setting like India. PMID- 29622873 TI - Clinico-Hematological Profile of Hb Q India: An Uncommon Hemoglobin Variant. AB - Inherited hemoglobin disorders include thalassemias and structural variants like HbS, HbE, and HbD, Hb Lepore, HbD-Iran, Hb-H disease and HbQ India. HbQ India is an uncommon alpha-chain structural hemoglobin variant seen in North and West India. Patients are mostly asymptomatic and often present in the heterozygous state or co-inherited with beta-thalassaemia. This study was done in a tertiary care teaching hospital in North India over a period of 7 years among patients referred from antenatal and other clinics for screening of hemoglobin disorders. Complete blood count, peripheral blood smear examination and cation exchange high performance liquid chromatography (HPLC) was done to quantify various hemoglobins. HbQ India was diagnosed if the unknown variant hemoglobin was detected within the characteristic retention window. Of a total of 7530 patients screened, 31 (0.4%) were detected to have HbQ India. Of these, 25 (0.3%) patients had HbQ India trait and 6 (0.1%) patients had compound heterozygosity for HbQ India and Beta Thalassemia trait (HbQ India-BTT). All patients were clinically asymptomatic and were detected as part of the screening for hemoglobin disorders. Only two patients with HbQ India-BTT had hemoglobin less than 10 g/dL. In 25 patients with HbQ India trait, HbQ ranged from 13.6 to 24.4% and in 6 patients with HbQ India-BTT, HbQ India ranged from 7.4 to 9.0%. HbQ India is an uncommon structural hemoglobin variant. Although asymptomatic, it may cause diagnostic difficulty in the compound heterozygous state with beta thalassemia. HPLC provides a rapid, accurate and reproducible method for screening of this condition to identify and counsel individuals. PMID- 29622875 TI - Study of Complete Haemogram and Iron Profile From Cord Blood of Newborn with Respect to Primigravida, Multigravida and Apgar Score. AB - Study of different parameters of cord blood usually reflects neonatal health status. One of the widely used system for assessing neonatal health is APGAR score. It is assed at 1 and 5 min from baby's birth. Immediate medical care may improve 5 min score of neonate who showed poor score at 1 min. The main objective of this study is to establish whether any correlation exists between complete hemogram and iron profile with APGAR score and gravid of mother. Cord blood was collected from 96 new born, delivered vaginally, mothers having no chronic medical disease. Different parameters of complete hemogram were assessed along with iron profile and statistical analysis was done by Graph pad Instat3 soft ware. Statistically significant correlation exists between APGAR score (5 min) and MCV (p = 0.005), MCHC (p = 0.016), nRBC (p = 0.002), platelet count (p = 0.001), RDW (p = 0.001). Statistically weak correlation exists between TLC (p = 0.08). Comparing complete blood count with gravid of mother by unpaired t test significant correlation was obtained for HCT (p = 0.035) and RDW (p = 0.03). Apgar score and complete hemogram from cord blood are both non-invasive procedure which help us to asses fetal wellbeing as well as requirement of immediate management. Further more studies are essential to establish the relationship. PMID- 29622874 TI - Utility of CD157 as a Common Leukocytes Marker for Paroxysmal Nocturnal Hemoglobinuria Screening in a Single Tube Five Color Combination. AB - To study the utility and advantage of CD157 in the paroxysmal nocturnal hemoglobinuria (PNH) screening along with its ability to replace CD24 and CD14. This was a confirmatory study to analyse the role and advantage of CD157 in a single tube five color combination to identify the PNH clones. A serial tenfold dilution experiments was carried out for sensitivity assessment. Reproducibility was checked in the intra-assay and inter-assay experiments. The results obtained with CD157 based assay were compared with the routinely used single tube six color CD24/CD14 based assay. CD157 showed a high degree of sensitivity at the level of 10-4. PNH positive clone sizes were precise with CVs of inter-assay and intra-assay precision analysis for polymorphs/monocytes ranging from 2.94 to 4.31/2.52 to 8.93, and 0.91 to 3.23/1.65 to 5.33%; respectively. The results were similar to those obtained from CD24/CD14 based assay (R2 > 0.993). There was no false positive or false negative result. CD157 was found better in delineating the type II clones. CD157 can be used as a common PNH leucocyte marker with high degree of sensitivity and precision. It can replace CD24 and CD14 from the currently used assays and thus bring down the cost of PNH screening. PMID- 29622876 TI - Cupincin: A Novel Cupin Domain Containing Protease from Rice (Oryza sativa L.) Bran Comprising of Procoagulant and Fibrinogenolytic Activity. AB - The current study was carried out to evaluate the pharmacological properties of cupincin- A novel cupin domain containing metalloprotease with limited proteolysis from rice bran on blood coagulation and hydrolysis of human fibrinogen. Cupincin preferentially hydrolyzed the Aalpha chain of fibrinogen and then the Bbeta-chain, but not the gamma-chain. Cupincin reduced the re calcification time of citrated human plasma dose dependently. Analysis of citrated whole blood in the presence of cupincin by rotem showed a decrease in coagulation time and clot formation time. Sonoclot analysis indicated that cupincin cleaved fibrinogen of whole citrated blood. SDS-PAGE and sonoclot analysis (LI-30) indicated that cupincin lacked plasmin-like activity. Global hemostasis tests like rotem and sonoclot analysis determined cupincin as a procoagulant enzyme. Cupincin did not show any effect on prothrombin time and activated partial thromboplastin time tests suggesting its action on the common pathway of coagulation. The involvement of proteases from rice (Oryza sativa L.) in haemostasis has never been exploited before. This study could provide the basis for the development of new procoagulant agents from a nontoxic source like rice. PMID- 29622877 TI - Prolonged Hemocoagulase Agkistrodon Halys Pallas Administration Induces Hypofibrinogenemia in Patients with Hematological Disorders: A Clinical Analysis of 11 Patients. AB - Hemocoagulase Agkistrodon Halys Pallas, a well-established hemostatic agent used in China, has widespread applications in various conditions of bleeding and hemorrhages. Although it presents a low risk of vascular thrombosis, the agent can be easily tolerated and does not show any harmful effects, except allergy. However, long-term use of hemocoagulase may induce hypofibrinogenemia in some patients. Herein, we report 11 patients of prolonged administration of hemocoagulase Agkistrodon, with particular attention to the dynamic changes in their coagulation functions. A marked decline in the level of fibrinogen was observed in patients suffering from hematological disorders, following an extended exposure to hemocoagulase. Nevertheless, the low fibrinogen levels increased after withdrawal of the agent. Since the D-dimer level did not show any significant increase, hemocoagulase inducing lower fibrinogen may be considered to be a process of primary fibrinolysis. In conclusion, we suggested that hemocoagulase must be cautiously used in patients with hematological disorders, because of the potential risk of fibrinolysis; and the coagulation functions should be carefully evaluated during the administration of hemocoagulase. PMID- 29622879 TI - Anxiety, Depression and Distress Among Children Undergoing Haematopoietic Stem Cell Transplantation and Its Correlation with Age and Socio-economic Status: A Single Centre Experience from India. PMID- 29622878 TI - The Influence of CYP2C9 and VKORC1 Gene Polymorphisms on the Response to Warfarin in Egyptians. AB - Warfarin is the most commonly used drug for chronic prevention of thromboembolic events, it also ranks high among drugs that cause serious adverse events. The variability in dose requirements has been attributed to inter-individual differences in medical, personal, and genetic factor. Cytochrome P-450 2C9 is the principle enzyme that terminates the anticoagulant effect of warfarin by catalyzing the conversion of the pharmacologically more potent S-enantiomer to its inactive metabolites. Warfarin exerts its effect by inhibition of vitamin K epoxide reductase. This protein is encoded by vitamin K epoxide reductase complex subunit 1 gene (VKORC1). The current study aimed to investigate the pharmacogenetic effect of CYP2C9 and VKORC1 gene polymorphisms on the patients response to warfarin. One hundred cases starting warfarin treatment and 20 healthy controls were enrolled. The mean daily dose of warfarin was calculated from patient's medical records. For each patient, less than 10 % variability in warfarin dose and a target international normalized ratio (INR) within the therapeutic target range were required for at least 3 months for one of the following indications (deep vein thrombosis, pulmonary embolism, cerebrovascular stroke and myocardial infarction) prior to inclusion in the study. Tetraprimer amplification refractory mutation system PCR was performed to determine CYP2C9*2, CYP2C9*3, and the VKORC1 1639 G > A genetic polymorphisms. Plasma warfarin determination was performed using rapid fluorometric assay. Plasma warfarin concentration ranged from 2.19 to 10.98 MUg/ml with a median 3.52 MUg/ml. Supratherpeutic INR was observed in 11 % of the cases. Thromboembolic complications occurred in 7 % of the cases and 8 % of cases experienced major bleeding. High maintenance dose (>7 mg/day) was associated with the combined non VKORC1*2 and homozygous wild type CYP2C9 (CYP2C9*1*1) alleles, while low maintenance dose was associated with the Variant (AG + AA)/Wild (*1/*1). (p value <0.001). CYP2C9 variant was a risk factor for supratherapeutic INR in the multivariate logistic regression model. Thromboembolic complication and incidence of supratherapeutic INR were observed in patients carrying combined VKORC1 Variant (AG + AA) and CYP2C9 Variant (*2/*3). Data from our study suggest that together with clinical factors, VKORC1 and CYP2C9 polymorphisms are important contributors to warfarin dosing and may help predict adverse effects in Egyptian patients. PMID- 29622880 TI - Fast Track Anaemia Clinic (FTAC) and Intravenous Iron Administration: Its Relevance and Application Today in India. PMID- 29622881 TI - Safety of Zoledronic Acid in Patients with Thalassemia Associated Low Bone Mineral Density. PMID- 29622882 TI - Peripheral Blood Monocyte Count is a Predictor of Successful Peripheral Blood Stem Cell Harvest After Chemo-Mobilization in Patients with Malignant Lymphoma. PMID- 29622884 TI - Refractory ALK-Positive Anaplastic Large Cell Lymphoma: Long Term Survival with Crizotinib. PMID- 29622883 TI - HbS/D-Punjab Disease: Report of 3 Cases from Sri Lanka. PMID- 29622885 TI - "Everything that Glows on PET is not Lymphoma": An Unheralded Intruder in a Case of Diffuse Large B Cell Lymphoma. PMID- 29622886 TI - B-acute Lymphoblastic Leukemia with Bright CD45 and Moderate Side Scatter Simulating Monocytoid Population: An Unusual Phenotype. PMID- 29622887 TI - Ibrutinib to Allogenic Stem Cell Transplant in a Case of Refractory Mantle Cell Lymphoma. PMID- 29622889 TI - De Novo Philadelphia Chromosome (BCR/ABL1) Positive Myelodysplastic Syndrome: Is it a Distinct Molecular and Clinical Entity? PMID- 29622888 TI - CD38-Negative Myeloma with Anaplastic Morphology at Presentation: A Case Report. PMID- 29622890 TI - Incidental Discovery of Anti-IH in a Patient Planned for Caesarean Section and it's Repercussions. PMID- 29622891 TI - Platelet Count, D-Dimer, Component Therapy and Dengue Hemorrhagic Fever. PMID- 29622892 TI - Myeloperoxidase Deficient Acute Promyelocytic Leukemia: Report of Two Cases. PMID- 29622893 TI - Extensive Platelet Phagocytosis in a Patient with Immune Thrombocytopenia (ITP) and Concomitant Tuberculosis. PMID- 29622894 TI - Budding Yeast Forms on Peripheral Blood Smear: An Intriguing Finding. PMID- 29622895 TI - Verrucous Skin Lesions in a Case of Acute Lymphoblastic Leukemia: A Rare Manifestation of Cytomegalovirus Infection. PMID- 29622896 TI - Howell-Jolly Body-Like Inclusions in Neutrophils and Monocytes of a Transplant Recipient. PMID- 29622897 TI - 8p11 Stem Cell Leukemia/Lymphoma Syndrome without Myeloproliferation: A Rare Clinical Entity. PMID- 29622898 TI - Nonconvex compressive video sensing. AB - High-speed cameras explore more details than normal cameras in the time sequence, while the conventional video sampling suffers from the trade-off between temporal and spatial resolutions due to the sensor's physical limitation. Compressive sensing overcomes this obstacle by combining the sampling and compression procedures together. A single-pixel-based real-time video acquisition is proposed to record dynamic scenes, and a fast nonconvex algorithm for the nonconvex sorted l1 regularization is applied to reconstruct frame differences using few numbers of measurements. Then, an edge-detection-based denoising method is employed to reduce the error in the frame difference image. The experimental results show that the proposed algorithm together with the single-pixel imaging system makes compressive video cameras available. PMID- 29622899 TI - [Ethics in clinical trials designs and alternative methods]. PMID- 29622900 TI - Unsuspected Small-Bowel Crohn's Disease in Elderly Patients Diagnosed by Video Capsule Endoscopy. AB - Background: Video capsule endoscopy (VCE) is increasingly performed among the elderly for obscure bleeding. Our aim was to report on the utility of VCE to uncover unsuspected Crohn's disease (CD) in elderly patients. Methods: Retrospective review of VCE performed in elderly patients (>=70 y) at a tertiary hospital (2010-2015). All underwent prior negative bidirectional endoscopies. CD diagnosis was based on consistent endoscopic findings, exclusion of other causes, and a Lewis endoscopic score (LS) > 790 (moderate-to-severe inflammation). Those with lower LS (350-790) required histological confirmation. Known IBD cases were excluded. Results: 197 VCE were performed (mean age 78; range 70-93). Main indications were iron deficiency anemia (IDA), occult GI bleeding (OGIB), chronic abdominal pain, or diarrhea. Eight (4.1%) were diagnosed as CD based on the aforementioned criteria. Fecal calprotectin (FCP) was elevated in 7/8 (mean 580 MUg/g). Mean LS was 1824. Small-bowel CD detected by VCE led to a change in management in 4/8. One patient had capsule retention secondary to NSAID induced stricture, requiring surgical retrieval. Conclusions: VCE can be safely performed in the elderly. A proportion of cases may have unsuspected small-bowel CD despite negative endoscopies. FCP was the best screening test. Diagnosis frequently changed management. PMID- 29622901 TI - The Triple Challenges of Low and Middle-Income Countries. PMID- 29622902 TI - Undiagnosed Diabetes Mellitus and Associated Factors among Psychiatric Patients Receiving Antipsychotic Drugs at The University of Gondar Hospital, Northwest Ethiopia. AB - Background: Undiagnosed diabetes mellitus cases are at higher risk for diabetic related complications. In low-income African countries, patients with undiagnosed diabetes mellitus account for 75% of diabetes cases. Psychiatric disorders have a greater impact on the global burden of diseases and disability associated with chronic diseases like diabetes mellitus and cardiovascular diseases. Methods: Institution based cross-sectional study was conducted at the University of Gondar Hospital from February to April 2016. A total of 205 psychiatric patients aged above 15 years that were taking antipsychotic were included by the simple random sampling method. Fasting blood glucose, triglycerides and cholesterol level were determined from venous blood samples to evaluate diabetes mellitus based on WHO criteria. Results: Among 205 psychiatric patients taking antipsychotics, 15(7.3%) had undiagnosed diabetes mellitus. Duration of antipsychotic treatment and sex had a statistically significant association with the prevalence of undiagnosed diabetes mellitus. As the duration of antipsychotic drug treatment increased by one year, the risk of having a diabetes mellitus increase by 1.47 times (AOR: 1.47 CI: 1.021-2.125). Conclusion: The prevalence of undiagnosed diabetes mellitus among psychiatry patients taking antipsychotics was higher than the estimated diabetes national prevalence of Ethiopia. Screening of diabetes mellitus in particular, patients having a longer duration of antipsychotic treatment is mandatory to bring more undiagnosed cases for medical attention. PMID- 29622904 TI - Non-Alcoholic Fatty Liver Disease and Associated Factors among Type 2 Diabetic Patients in Southwest Ethiopia. AB - Background: Non-alcoholic Fatty Liver Disease (NAFLD) among type 2 diabetic patients is completely ignored in developing regions like Africa paving the way for public health and economic burden in the region. Therefore, the main objective of this research was to evaluate non-alcoholic fatty liver disease and associated factors among type 2 diabetic patients in Southwestern Ethiopia attending Diabetic Clinic of Jimma University Specialized Hospital (JUSH). Methods: Facility based cross-sectional study design was used. Anthropometry, fatty liver (using utrasonography), liver enzymes, and lipid profiles were measured among type 2 diabetic patients who fulfilled the inclusion criteria. Socio-demographic and clinical characteristics were assessed using standard questionnaires. Results: Ninety-six (96) type 2 diabetic patients were enrolled and non-alcoholic fatty liver disease prevalence was 73%. Of non-alcoholic fatty Liver disease documented patients, 35.4%, 31.3% and 6.3% exhibited mild, moderate and severe fatty liver diseases, respectively. Alanine aminotransferase (p <=0.001), Triacyglycerol (p <=0.001), total bilirubin (p <=0.05), direct bilirubin (p <=0.05) and diabetic duration (p <=0.01) were significantly associated with non-alcoholic fatty liver disease among type 2 diabetic patients. The Aspartate aminotransferase/Alanine aminotransferase ratio among non alcoholic fatty liver disease patients was greater than one. Conclusions: The magnitude of non-alcoholic fatty liver disease is high among study groups and it needs urgent action by healthcare systems. Therefore, targeted treatment approach inclusive of non-alcoholic fatty liver disease should be designed. PMID- 29622905 TI - Patterns and Causes of Amputation in Ayder Referral Hospital, Mekelle, Ethiopia: A Three-Year Experience. AB - Background: Amputation is a surgical procedure for the removal of a limb which is indicated when limb recovery is impossible. There are different types of amputation, and their causes can vary from one area to the other. Therefor, the aim of this study is to find out the patterns and causes of amputations in patients presented to Ayder Referral Hospital, Mekelle, Ethiopia. Methods: the record of 87 patients who had amputation at different sites after admission to Ayder referral hospital, Mekelle, Ethiopia in three years period were reviewed retrospectively. Result: A total of 87 patients had amputation of which 78.2% were males. The age range was from 3 to 95 years, and the mean age was 40.6 in years. The most common indications were trauma (37.7%), tumor (24.1%), and peripheral arterial disease (PAD) (20.7%). The commonest type of amputation was major lower limb amputation (58.6%) which includes above knee amputation (35.6%)and below knee amputation (23%) followed by digital amputation (17.2%). There was 11.4% major upper limb amputation of which there was one patient who had re-amputation. Conclusion: Most of the indications for amputations in our setup are potentially preventable by increasing awareness in the society on safety measures both at home and at work and early presentation to health facilities. PMID- 29622903 TI - Prevalence and Associated Factors of Incidentally Diagnosed Prostatic Carcinoma among Patients Who Had Transurethral Prostatectomy in Tanzania: A Retrospective Study. AB - Background: Prostatic carcinoma carries a high morbidity and mortality if it is not diagnosed early. In resource limited countries, patients are at increased risk of being diagnosed late as they are operated for presumed benign prostatic hyperplasia. The information on the magnitude and risk factors of this problem in our setting could assist in the overall optimization of care of patients at risk. Methods: A retrospective study of patients who underwent prostatectomy for presumed benign prostatic enlargement was done at Bugando University Hspital in Tanzania. Patients' age, creatinine levels, urological Ultrasound, prostate specific antigen and Biopsy results were analyzed using STATA 11. The prevalence of incidental prostatic cancer was calculated and logistic regression was done for factors associated with incidental prostatic cancer. Results: In total, 152 patients were included in this study. The median age was 69 (SD 9.4) years, 16 (10.53%,) and 49 (32.24%) participants had Hydronephrosis and elevated creatinine levels respectively. Eighty six (58.56%) patients had PSA >10 ng/mL and in total; 33 (21.71%) had incidental prostatic carcinoma. The incidental prostatic carcinoma was independently associated with age of 70- 80years (AOR=2.8, p = 0.013) and PSA levels >10ng/mL (AOR=3.2, p=0.014). Conclusions: The prevalence of incidental prostatic carcinoma is high among patients undergoing transurethral prostatectomy for presumed benign prostatic hyperplasia in Tanzania with increased risk at age of 70-80 years and among those with PSA >10ng/mL. A national awareness campaign coupled with focused screening of patients above 60 years could increase the detection rate of prostatic carcinoma and reduce the magnitude of incidental diagnosis of this disease. PMID- 29622906 TI - Sexual and Reproductive Health Services Use, Perceptions, and Barriers among Young People in Southwest Oromia, Ethiopia. AB - Background: Utilizations of sexual and reproductive health (SRH) services among young people is vital in reducing sexual and reproductive health problems. This study investigated young people's perceptions and barriers towards the use of sexual and reproductive health services in Southwest Ethiopia. Methods: A cross sectional study was employed to collect data from 1,262 in-school youths. Simple random sampling technique was used to select schools and study participants. Fifteen focus group discussions and 22 key informant interviews were conducted. Multiple logistic regression analyses were conducted. P value <= 0.05 was set to determine statistical significance. Data were analyzed using SPSS v16. Qualitative data were triangulated with quantitative findings and also presented in themes. Results: Four hundred sixty (36.5%) of the respondents had utilized sexual and reproductive health services. Advice on sexual and reproductive health was the major (67.2%) service sought followed by seeking-treatments (23.3%). Health centers were the major (65.0%) source of SRH services. Being married, being sexually active, father-child communication, religion and place of residence were significantly associated with use of sexual and reproductive health services (p<0.05). Lack of information about SRH, poor perceptions about SRH, feeling of shame, fear of being seen by others, restrictive cultural norms, lack of privacy, confidentiality and unavailability of services were deterring use of sexual and reproductive health services. Conclusions: Only a small proportion of young people used sexual and reproductive health services. Hence, in addition to behavioral modification interventions, it is essential to consider multi-level and culturally sensitive interventions in a holistic approach. PMID- 29622907 TI - Sub-Optimal Breastfeeding and Its Associated Factors in Rural Communities of Hula District, Southern Ethiopia: A Cross-Sectional Study. AB - Background: Sub-optimal breast feeding contributed a significant number of infants' death. Although breast feeding is universal in Ethiopia, the practice is not optimal. Hence, this study assessed the prevalence of sub-optimal breast feeding practice and its associated factors in rural communities of Hula District, Southern Ethiopia. Methods: A community based cross-sectional study was conducted among 634 women with infants aged 6 to 12 months. Multistage sampling technique was employed to select study subjects. Interviewer administered structured questionnaire was used for data collection. Data were entered and analyzed by using SPSS version 20.0. Bivariate and multivariate logistic regression was used to identify predictors of delayed initiation of breastfeeding and non-exclusive breastfeeding. Results: The prevalence of suboptimal breast feeding of infants was found to be 56.9%. Nearly half (49.4%) of the mothers delayed initiation of breast feeding, and 13.4% of the infants were fed breast non-exclusively. Having formal education [AOR: 1.74; 95% CI (1.17, 2.59)], family size < 5 [AOR=1.59; 95% CI (1.03, 2.45)], having one under five child [AOR=1.88; 95% CI (1.29, 2.75)], lower number of antenatal care visits [AOR= 2.40; 95% CI (1.68, 3.43)] and lack of counseling on breastfeeding [AOR= 1.69; 95% CI (1.19, 2.41)] were negatively associated with delayed initiation of breast feeding. Similarly, not attending formal education, low birth order and lack of knowledge about exclusive breastfeeding were also negatively associated with exclusive breastfeeding practice. Conclusion: In this study, sub-optimal breast feeding was found to be high. Delayed initiation and non-exclusive breastfeeding practices were major contributors to sub-optimal breast feeding. PMID- 29622908 TI - Soil Contamination Rate, Prevalence, Intensity of Infection of Geohelminths and Associated Risk Factors among Residents in Bazou (West Cameroon). AB - Background: Soil-transmitted helminths (STH) infections remain an important public health problem in the tropics. This study aimed to evaluate the soil contamination rate and prevalence of infestations of geohelminth among residents in Bazou. Methods: Four hundred (400) soil samples and 182 stool specimens were collected respectively from four sites and from inhabitants aged 1 to 40 years and above in 12 households. A questionnaire was administered to evaluate risk factors of STH-infections. Soil samples were screened using sucrose centrifugal flotation method while stool specimens were analyzed using two techniques. Results: Out of the 400 soil and 182 stool samples examined, 13(3.3%) and 9(4.95%) were positive respectively after analyses. Soil contamination rates were 2%, 1% and 0.3% for Ascaris, Trichuris and hookworm eggs respectively while 4.95% of stool samples were positive to one species nematode (Ascaris lumbricoides). The soil contamination rate observed (5%) in the rainy season was significantly different (p>0.05) from the one observed (1.5%) in the dry season. Irrespectively of the season, the most frequent parasite identified was Ascaris spp. Soils around houses were more contaminated 6(12%) as compared to those collected from markets 5(10%) and roads 2(4%) while those around classrooms were not contaminated. Participants in the age group of 1-10 were more infected. Factors such as no hand washing habit and untrimmed finger nails were found to be important risk factors for STH. Conclusion: These results suggest the necessity to promote measures that could help to reduce STH infections. PMID- 29622909 TI - Anemia among HIV Infected Individuals Taking ART with and without Zidovudine at Addis Ababa, Ethiopia. AB - Background: Hematological complications such as Zidovudine(ZDV) associated anemia are among the commonly reported adverse drug reactions of Antiretroviral Therapy(ART). Little is known about ZDV associated anemia in developing countries like Ethiopia. Methods: Comparative retrospective cohort study was conducted at the ART Clinic of St. Paul Hospital Millennium Medical College from February 2011 to December 2012 to characterize anemia among HIV/AIDS patients initiated with ZDV and non-ZDV containing ART regimens. In each group, 197 HIV infected adults who had complete medical records were included. Medical records of participants were reviewed using pre-tested data collection format. Data were analyzed using SPSS version 19 for windows. For all statistical significance tests, the cut-off value was P<0.05. Results: Among ZDV group, anemia prevalence was 20.8 % (41/197), 33.5%(66 /197) and 13%(19/146) at baseline, six and twelve months of ART follow-up, respectively.On the other hand in non-ZDV group, anemia was present among 44.2% (87/197), 18.3% (36/197) and 12.4% (25 /202) of participants at baseline, six and twelve months of ART follow-up, respectively. After six months of follow-up, ZDV associated anemia was present among 32.7% (51/156) of the participants, and 43.1% of them were severe while about 45.2% were macrocytic type. Zidovudine group participants were 3.34 times more likely to develop severe anemia than non-ZDV group, P< 0.001. Conclusion: The prevalence, severity and characteristics of anemia were different between ZDV and non-ZDV group participants at different follow-up periods of ART. Zidovudine had significant contribution to severe anemia incidence after six months of ART; thus, hemoglobin level monitoring with red cell indices is suggested for improved detection of zidovudine associated anemia. PMID- 29622910 TI - Ethnomedicine Claim Directed in Silico Prediction of Anticancer Activity. AB - Background: The merits of ethnomedicine-led approach to identify and prioritize anticancer medicinal plants have been challenged as cancer is more likely to be poorly understood in traditional medicine practices. Nonetheless, it is also believed that useful data can be generated by combining ethnobotanical findings with available scientific studies. Thus, this study combined an ethnobtanical study with ligand based in silico screening to identify relevant medical plants and predict their anticancer potential based on their phytoconstiutents reported in scientific literatures. Methods: First, relevant medicinal plants were identified through an ethnobotanical survey. A list of phytochemicals was prepared based on literature review of articles which reported on the natural products of identified medicinal plants. Then, their phytochemicals were subjected to in silico evaluation, which included a hybrid score similarity measure, rule of five, Ghose-Viswanadhan-Wendoloski (GVW)-indices and structural features criteria, to predict their anticancer activity and drugability. Results: A total of 18 medicinal plants and 265 phytoconstituents were identified. The natural product pool constituted 109(41.13%) terpenoids, 67(25.28%) phenolics, 29(10.94%) simple and functionalized hydrocarbons, 26(9.81%) alkaloids, 25(9.43%) glycosides and 9(3.40%) compounds belonging to different phytochemical classes. The similarity measure using CDRUG identified 34(12.73%) phytochemicals with high (p-Value < 0.05) and 35(13.21%) with moderate possibility (p-Value < 0.1) of anticancer activity. In fact, three of the predicted compounds had the same structure with known anticancer compounds (HSCORE=1). The 80% GVW-indices based antineoplastic drugabilityranges were all mate by 25 of the predicted compounds. Predicted compounds were also shown to have ring structures and functional groups deemed important for anticancer activity. Conclusions: Given the findings, there is a promising anticancer activity by the traditionally used medicinal plants and a potential for the predicted phytochemicals to be pursued as possible hits or me too drugs. PMID- 29622911 TI - Submitral Left Ventricular Aneurysm Associated with Thrombus. AB - Background: Submitral left ventricular aneurysm is a rarely reported cardiac abnormality that is encountered commonly among blacks. So far, only one case has been reported from Ethiopia and East Africa.Our aim is to report an interesting and rare case that we encountered at St. Paul's Hospital Millennium Medical College. Methods: In April 2017, a 25-year-old patient havingsubmitral left ventricular aneurysm with New York Heart Association (NYHA) class IV heart failure and mild left ventricular systolic dysfunctionreceived medical treatment at our institution. She had severe mitral regurgitation and aneurysmal thrombus. The diagnosis was easily made using GE Vivid E9 transthoracic echocardiography. She was given drugs for management of heart failure and anticoagulation. Results: Our patient was discharged with a stable condition, and she had no early mortality. At 3 months' follow-up,shehad clinical improvement with NYHA class II heart failure, slight improvement of left ventricular systolic function, and resolution of the left ventricular thrombus. However, there waspersistent severe mitral regurgitation and aneurysm. Conclusion: Submitral left ventricular aneurysm is a rare cardiac abnormality. Diagnosis can be easily made with echocardiography. Surgery is the definitive treatment. However, it is not currently available in the country and patients cannot afford treatment abroad. PMID- 29622912 TI - Uncommon Pathogen Bacillus Cereus Causing Subdural Empyema in a Child. AB - Background: Subdural empyema (SDE) in children is a severe intracranial infection. Many pathogens can cause SDE. Case Details: In this articlewe present a 15-month old Indonesian boy diagnosed as SDE based on the clinical symptoms and neuroimaging. A complete blood count showed white blood cell count of 13.800/mm3 and the CRP level was 8.3 mg/L. Craniotomy following burr hole drainage procedure was performed to decrease intracranial pressure. The liquor culture indicated Bacillus cereus. A meropenem injection and metronidazole infusion were administered appropriately with antibiotic sensitivity for several weeks. Immediate initiation of appropriate antibiotic therapy related to an accelerated surgical drainage can improve the outcome. Conclusion: The combination of medication and surgery treatment for Bacillus cereus in SDE resulted in a good response, leaving neurological sequelae. PMID- 29622913 TI - The Difficult Rheumatology Diagnosis. AB - Background: Rheumatoid arthritis is a devastating condition. More so, the diagnosis of seronegative rheumatoid arthritis is often fraught off with much uncertainty and that leads to further suffering to the unfortunate patient. Case Details: This is a case of Madam A, who presented with many non-specific symptoms and signs involving many systems which was finally diagnosed as seronegative rheumatoid arthritis. This case explores the challenges in reaching this uncommon diagnosis and how anti-inflammatory drugs can bring a miraculous relief to the patient's suffering. Conclusion: The diagnosis of seronegative rheumatoid arthritis often presents a real challenge to the medical practitioner and often requires multiple visits and/or shared multidisciplinary care for confirmation of the diagnosis. Once diagnosed and treated with disease modifying anti- rheumatic drugs, often there is a miraculous relief to the patient's suffering. PMID- 29622914 TI - Tail-like Congenital Duplication of Lower Extremity (Extra Leg or Vestigial Parasitic Twin). AB - Background: Congenital duplication of lower extremity, either complete or incomplete is extremely rare. Only 26 cases had been reported till 2010, of which only 5 cases had feature of complete duplication. Theories have been proposed that the cause of this abnormality includes maternal factors like diabetes and usage of teratogenic drugs. Duplication of lower extremity may mimic that of vestigial parasitic twin; phenotypically, it appears as an individual with extra appendage or limbs. Vestigial parasitic twis are very rare comprising only 10% of all conjoined twins). Conjoined twin by itself is rare because the survival rate after birth is approximately 25%. Case Details: A 5-year old female patient came from a rural area of Ethiopia was referred to our hospital for radiological diagnosis and to assess the vascular supply. No family history of similar congenital abnormality was identified. No known history of chronic illness or maternal usage of teratogenic drugs was identified either. Conclusion: A child with parasitic twin and complete duplication of lower limb is reported. Tail-like soft tissue was found arising from sacral area. CT scan findings confirmed the duplication of the lower limb bones. Fatty tissue was the major component of the soft tissue almost replacing the muscle. Reconstructed CT angiography images showed major arterial blood supply of the parasite limb. Surgical intervention was done successfully. This type of case is unusual. It is the rarest type of lower limb duplication. PMID- 29622915 TI - Who cares? Experimental attention biases provide new insights into a mammalian sexual signal. AB - The effects of intrasexual and intersexual selection on male trait evolution can be difficult to disentangle, especially based on observational data. Male-male competition can limit an observer's ability to identify the effect of female mate choice independently from sexual coercion. Here, we use an experimental approach to explore whether an ornament, the red facial skin exhibited by male rhesus macaques (Macaca mulatta), might be involved in both female mate choice and male male competition. We used a noninvasive experimental approach based on the looking time paradigm in a free-ranging setting, showing images of differently colored male faces to both adult females (N = 91) and males (N = 77), as well as to juveniles (N = 94) as a control. Results show that both adult females and males looked longer at dark red faces compared with pale pink ones. However, when considering the proportion of subjects that looked longer at dark red faces regardless of preference strength, only females showed a significant dark red bias. In contrast, juveniles did not show any preferences between stimuli, suggesting that the adult bias is not a consequence of the experimental design or related to a general sensory bias for red coloration among all age-sex classes. Collectively, these results support the role the ornament plays in female mate choice in this species and provide the first evidence that this ornament may play a role in male-male competition as well, despite a general lack of observational evidence for the latter effect to date. PMID- 29622917 TI - Transparent and credible practices under the microscope: a response to comments on Ihle et al. PMID- 29622916 TI - Striving for transparent and credible research: practical guidelines for behavioral ecologists. AB - Science is meant to be the systematic and objective study of the world but evidence suggests that scientific practices are sometimes falling short of this expectation. In this invited idea, we argue that any failure to conduct research according to a documented plan (lack of reliability) and/or any failure to ensure that reconducting the same project would provide the same finding (lack of reproducibility), will result in a low probability of independent studies reaching the same outcome (lack of replicability). After outlining the challenges facing behavioral ecology and science more broadly and incorporating advice from international organizations such as the Center for Open Science (COS), we present clear guidelines and tutorials on what we think open practices represent for behavioral ecologists. In addition, we indicate some of the currently most appropriate and freely available tools for adopting these practices. Finally, we suggest that all journals in our field, such as Behavioral Ecology, give additional weight to transparent studies and therefore provide greater incentives to align our scientific practices to our scientific values. Overall, we argue that producing demonstrably credible science is now fully achievable for the benefit of each researcher individually and for our community as a whole. PMID- 29622918 TI - Consequences of sibling rivalry vary across life in a passerine bird. AB - Many studies have assessed the costs of sibling rivalry in systems where offspring always have competitors, but conclusions about sibling rivalry in these species are restricted to interpreting the cost of changes in the relative level of competition and are often complicated by the expression of potentially costly rivalry related traits. Additionally, the majority of studies focus on early-life sibling rivalry, but the costs of competition can also affect later-life performance. We test a suite of hypothesized immediate (early-life body mass, telomere length, and survival) and delayed (adult reproductive potential and lifespan) costs of sibling rivalry for offspring of differing competitive ability in Seychelles warblers, where most offspring are raised singly and hence competitor success can be compared to a competition-free scenario. Compared to those raised alone, all competing nestlings had lower body mass and weaker competitors experienced reduced survival. However, the stronger competitors appeared to have longer adult breeding tenures and lifespan than those raised alone. We propose that comparisons with competition-free groups, as well as detailed fitness measures across entire lifetimes, are needed to understand the evolution of sibling rivalry and thus individual reproductive strategy in wild systems. PMID- 29622919 TI - Environmental heterogeneity and population differences in blue tits personality traits. AB - Environmental heterogeneity can result in spatial variation in selection pressures that can produce local adaptations. The pace-of-life syndrome hypothesis predicts that habitat-specific selective pressures will favor the coevolution of personality, physiological, and life-history phenotypes. Few studies so far have compared these traits simultaneously across different ecological conditions. In this study, we compared 3 personality traits (handling aggression, exploration speed in a novel environment, and nest defense behavior) and 1 physiological trait (heart rate during manual restraint) across 3 Corsican blue tit (Cyanistes caeruleus) populations. These populations are located in contrasting habitats (evergreen vs. deciduous) and are situated in 2 different valleys 25 km apart. Birds from these populations are known to differ in life history characteristics, with birds from the evergreen habitat displaying a slow pace-of-life, and birds from the deciduous habitat a comparatively faster pace-of life. We expected personality to differ across populations, in line with the differences in pace-of-life documented for life-history traits. As expected, we found behavioral differences among populations. Despite considerable temporal variation, birds exhibited lower handling aggression in the evergreen populations. Exploration speed and male heart rate also differed across populations, although our results for exploration speed were more consistent with a phenotypic difference between the 2 valleys than between habitats. There were no clear differences in nest defense intensity among populations. Our study emphasizes the role of environmental heterogeneity in shaping population divergence in personality traits at a small spatial scale. PMID- 29622920 TI - Relative advantages of dichromatic and trichromatic color vision in camouflage breaking. AB - There is huge diversity in visual systems and color discrimination abilities, thought to stem from an animal's ecology and life history. Many primate species maintain a polymorphism in color vision, whereby most individuals are dichromats but some females are trichromats, implying that selection sometimes favors dichromatic vision. Detecting camouflaged prey is thought to be a task where dichromatic individuals could have an advantage. However, previous work either has not been able to disentangle camouflage detection from other ecological or social explanations, or did not use biologically relevant cryptic stimuli to test this hypothesis under controlled conditions. Here, we used online "citizen science" games to test how quickly humans could detect cryptic birds (incubating nightjars) and eggs (of nightjars, plovers and coursers) under trichromatic and simulated dichromatic viewing conditions. Trichromats had an overall advantage, although there were significant differences in performance between viewing conditions. When searching for consistently shaped and patterned adult nightjars, simulated dichromats were more heavily influenced by the degree of pattern difference than were trichromats, and were poorer at detecting prey with inferior pattern and luminance camouflage. When searching for clutches of eggs-which were more variable in appearance and shape than the adult nightjars-the simulated dichromats learnt to detect the clutches faster, but were less sensitive to subtle luminance differences. These results suggest there are substantial differences in the cues available under viewing conditions that simulate different receptor types, and that these interact with the scene in complex ways to affect camouflage breaking. PMID- 29622922 TI - Specialists and generalists coexist within a population of spider-hunting mud dauber wasps. AB - Individual foraging specialization describes the phenomenon where conspecifics within a population of generalists exhibit differences in foraging behavior, each specializing on different prey types. Individual specialization is widespread in animals, yet is understudied in invertebrates, despite potential impacts to food web and population dynamics. Sceliphron caementarium (Hymenoptera: Sphecidae) is an excellent system to examine individual specialization. Females of these mud dauber wasps capture and paralyze spiders which they store in mud nests to provision their offspring. Individuals may make hundreds of prey choices in their short lifespan and fully intact prey items can be easily excavated from their mud nests, where each distinct nest cell represents a discrete foraging bout. Using data collected from a single population of S. caementarium (where all individuals had access to the same resources), we found evidence of strong individual specialization; individuals utilized different resources (with respect to prey taxa, prey ecological guild, and prey size) to provision their nests. The extent of individual specialization differed widely within the population with some females displaying extreme specialization (taking only prey from a single species) while others were generalists (taking prey from up to 6 spider families). We also found evidence of temporal consistency in individual specialization over multiple foraging events. We discuss these findings broadly in the context of search images, responses to changing prey availability, and intraspecific competition pressure. PMID- 29622921 TI - Repeatable and heritable behavioural variation in a wild cooperative breeder. AB - Quantifying consistent differences in behaviour among individuals is vital to understanding the ecological and evolutionary significance of animal personality. To quantify personality, the phenotypic variation of a behavioural trait is partitioned to assess how it varies among individuals, which is also known as repeatability. If pedigree data are available, the phenotypic variation can then be further partitioned to estimate the additive genetic variance and heritability. Assessing the repeatability and heritability of personality traits therefore allows for a better understanding of what natural selection can act upon, enabling evolution. In a natural population of facultative cooperatively breeding Seychelles warbler (Acrocephalus sechellensis) on Cousin Island, a lack of breeding vacancies forces individuals into different life-history strategies, and these differences in reproductive state could generate behavioural differences among individuals in the population. We used this population to estimate the repeatability of 4 behavioural traits (novel environment exploration, novel object exploration, obstinacy/struggle rate, and escape response), and narrow-sense heritability (of behavior, h2B; behavior minus observer variance; and personality), and evolvability, of the repeatable behavioural traits. We also tested for an among-individual correlation between the repeatable traits. We found that, compared to estimates in other study species, the exploratory behaviours were moderately repeatable (0.23-0.37), there was a positive among-individual correlation (0.51) between novel environment and novel object exploration, and that novel environment exploration was moderately heritable (0.17; h2B was low as it includes observer variance). This study further clarifies the additive genetic variance available for selection to act upon in this cooperatively breeding bird. PMID- 29622923 TI - Avoiding the misuse of BLUP in behavioural ecology. AB - Having recognized that variation around the population-level "Golden Mean" of labile traits contains biologically meaningful information, behavioural ecologists have focused increasingly on exploring the causes and consequences of individual variation in behaviour. These are exciting new directions for the field, assisted in no small part by the adoption of mixed-effects modelling techniques that enable the partitioning of among- and within-individual behavioural variation. It has become commonplace to extract predictions of individual random effects from such models for use in subsequent analyses (for example, between a personality trait and other individual traits such as cognition, physiology, or fitness-related measures). However, these predictions are made with large amounts of error that is not carried forward, rendering further tests susceptible to spurious P values from these individual-level point estimates. We briefly summarize the problems with such statistical methods that are used regularly by behavioural ecologists, and highlight the robust solutions that exist within the mixed model framework, providing tutorials to aid in their implementation. PMID- 29622925 TI - Cut your losses: self-amputation of injured limbs increases survival. AB - Autotomy, self-induced limb loss, is an extreme trait observed throughout the animal kingdom; lizards drop their tails, crickets release their legs, and crabs drop their claws. These repeated evolutionary origins suggest that autotomy is adaptive. Yet, we do not have a firm understanding of the selective pressures that promote and maintain this extreme trait. Although multiple adaptive hypotheses exist, research has generally focused on autotomy's adaptive value as a form of predator escape. However, autotomy could also be selected to reduce the cost of an injured limb, which we investigate here. Previously, this alternative hypothesis has been challenging to directly test because when an injury occurs on an autotomizable limb, that limb is almost always dropped (i.e., autotomy is behaviorally fixed within populations). Recently, however, we have identified a species, Narnia femorata (Insecta: Hemiptera: Coreidae), where some individuals autotomize limbs in response to injury, but some do not. This natural variation allowed us to investigate both the survival costs of retaining an injured limb and the benefits of autotomizing it. In this study, we find a positive association between autotomizing injured limbs and survival, thereby quantifying a new and likely widespread benefit of autotomy-reducing the cost of injury. PMID- 29622924 TI - Mate choice in sticklebacks reveals that immunogenes can drive ecological speciation. AB - Adaptation to ecologically contrasting niches can lead to the formation of new species. Theoretically, this process of ecological speciation can be driven by pleiotropic "magic traits" that genetically link natural and sexual selection. To qualify as a true magic trait, the pleiotropic function of a gene must be reflected in biologically relevant mechanisms underlying both local adaptation and mate choice. The immune genes of the major histocompatibility complex (MHC) contribute to parasite resistance and also play a major role in sexual selection. Hence, the MHC may encode a candidate magic trait. Using diverging 3-spined stickleback populations from a connected lake-river habitat, we show with mate choice experiments in a flow channel that polymorphic MHC genes probably underlie assortative mating with respect to particular habitat-adapted ecotypes, potentially resulting in reproductive isolation. By manipulating olfactory cues in controlled experiments, we show that female sticklebacks employ MHC-dependent male olfactory signals to select mates with which they can achieve a habitat specific MHC gene structure that optimally protects their offspring against local parasites. By using MHC-based olfactory signals, females thus select individuals of their own population as mates. Our results demonstrate how mate choice and parasite resistance may be functionally linked. These findings suggest that MHC genes are pleiotropic and encode a true magic trait of biologically significant effect. PMID- 29622926 TI - Allopreening in birds is associated with parental cooperation over offspring care and stable pair bonds across years. AB - Individuals of many species form bonds with their breeding partners, yet the mechanisms maintaining these bonds are poorly understood. In birds, allopreening is a conspicuous feature of interactions between breeding partners and has been hypothesized to play a role in strengthening and maintaining pair bonds within and across breeding attempts. Many avian species, however, do not allopreen and the relationship between allopreening and pair bonding across species remains unexplored. In a comparative analysis of allopreening and pair bond behavior, we found that allopreening between breeding partners was more common among species where parents cooperate to rear offspring. The occurrence of allopreening was also associated with an increased likelihood that partners would remain together over successive breeding seasons. However, there was no strong evidence for an association between allopreening and sexual fidelity within seasons or time spent together outside the breeding season. Allopreening between partners was also no more common in colonial or cooperatively breeding species than in solitary species. Analyses of evolutionary transitions indicated that allopreening evolved from an ancestral state of either high parental cooperation or high partner retention, and we discuss possible explanations for this. Overall, our results are consistent with an important role for allopreening in the maintenance of avian pair bonds. PMID- 29622927 TI - Camouflaging moving objects: crypsis and masquerade. AB - Motion is generally assumed to "break" camouflage. However, although camouflage cannot conceal a group of moving animals, it may impair a predator's ability to single one out for attack, even if that discrimination is not based on a color difference. Here, we use a computer-based task in which humans had to detect the odd one out among moving objects, with "oddity" based on shape. All objects were either patterned or plain, and either matched the background or not. We show that there are advantages of matching both group-mates and the background. However, when patterned objects are on a plain background (i.e., no background matching), the advantage of being among similarly patterned distractors is only realized when the group size is larger (10 compared to 5). In a second experiment, we present a paradigm for testing how coloration interferes with target-distractor discrimination, based on an adaptive staircase procedure for establishing the threshold. We show that when the predator only has a short time for decision making, displaying a similar pattern to the distractors and the background affords protection even when the difference in shape between target and distractors is large. We conclude that, even though motion breaks camouflage, being camouflaged could help group-living animals reduce the risk of being singled out for attack by predators. PMID- 29622928 TI - Marginal predation: do encounter or confusion effects explain the targeting of prey group edges? AB - Marginal predation, also known as the edge effect, occurs when aggregations of prey are preferentially targeted on their periphery by predators and has long been established in many taxa. Two main processes have been used to explain this phenomenon, the confusion effect and the encounter rate between predators and prey group edges. However, it is unknown at what size a prey group needs to be before marginal predation is detectable and to what extent each mechanism drives the effect. We conducted 2 experiments using groups of virtual prey being preyed upon by 3-spined sticklebacks (Gasterosteus aculeatus) to address these questions. In Experiment 1, we show that group sizes do not need to be large for marginal predation to occur, with this being detectable in groups of 16 or more. In Experiment 2, we find that encounter rate is a more likely explanation for marginal predation than the confusion effect in this system. We find that while confusion does affect predatory behaviors (whether or not predators make an attack), it does not affect marginal predation. Our results suggest that marginal predation is a more common phenomenon than originally thought as it also applies to relatively small groups. Similarly, as marginal predation does not need the confusion effect to occur, it may occur in a wider range of predator-prey species pairings, for example those where the predators search for prey using nonvisual sensory modalities. PMID- 29622929 TI - Is male rhesus macaque facial coloration under intrasexual selection? AB - Exaggerated male traits can evolve under intra- or intersexual selection, but it remains less clear how often both mechanisms act together on trait evolution. While the males of many anthropoid primate species exhibit colorful signals that appear to be badges of status under intrasexual selection, the red facial coloration of male rhesus macaques (Macaca mulatta) appears to have evolved primarily under intersexual selection and female mate choice. Nonetheless, experiments show that red color is salient to males, raising the question of whether the signal may also be under intrasexual selection. Here, we examine whether males express this signal more strongly in competitive contexts. Facial images were collected on all 15 adult males of a free-ranging social group during the peak of the mating season, and coloration was quantified using visual models. Results show that males more similar in facial redness were more likely to interact aggressively than more dissimilar ones, suggesting that color may be involved in the assessment of rivals. Furthermore, males exhibited darker coloration on days they were observed copulating, and dominance rank predicted facial redness only on copulating days, suggesting that coloration may also advertise motivation to defend a mate. Male rhesus macaque facial coloration may thus mediate agonistic interactions with rivals during competition over reproductive opportunities, such that it is under both inter- and intrasexual selection. However, color differences were small, raising perceptibility questions. It remains possible that color variation reflects differences in male condition, which in turn alter investment towards male-male competition and mating effort. PMID- 29622931 TI - A case for considering individual variation in diel activity patterns. AB - There is a growing recognition of the role of individual variation in patterns emerging at higher levels of biological organization. Despite the importance of the temporal configuration of ecological processes and patterns, intraspecific individual variation in diel activity patterns is almost never accounted for in behavioral studies at the population level. We used individual-based monitoring data from 98 GPS-collared brown bears in Scandinavia to estimate diel activity patterns before the fall hunting season. We extracted 7 activity measures related to timing and regularity of activity from individual activity profiles. We then used multivariate analysis to test for the existence of distinct activity tactics and their environmental determinants, followed by generalized linear regression to estimate the extent of within-individual repeatability of activity tactics. We detected 4 distinct activity tactics, with a high degree of individual fidelity to a given tactic. Demographic factors, availability of key foraging habitat, and human disturbance were important determinants of activity tactics. Younger individuals and those with higher bear and road densities within their home range were more nocturnal and more likely to rest during the day. Good foraging habitat and increasing age led to more diurnal activity patterns and nocturnal resting periods. We did not find evidence of diel activity tactics influencing survival during the subsequent hunting season. We conclude that individual variation in activity deserves greater attention than it currently receives, as it may help account for individual heterogeneity in fitness and could facilitate within population niche partitioning that can have population- or community-level consequences. PMID- 29622930 TI - Cognition, personality, and stress in budgerigars, Melopsittacus undulatus. AB - To study the fitness effects of individual variation in cognitive traits, it is paramount to understand whether traits such as personality and physiological stress influence cognitive performance. We first tested whether budgerigars showed both consistent personalities and cognitive performance across time and tasks. We tested object and food neophobia, and exploratory behavior. We measured cognitive performance in habituation, ability to solve foraging problems, spatial memory, and seed discrimination tasks. Budgerigars showed consistency in their neophobic tendencies and these tendencies were associated with their exploratory behavior. Birds were also consistent in how they performed in most of the cognitive tasks (temporal consistency), but were not consistent in their performance across tasks (context consistency). Neither corticosterone levels (baseline and stress-induced) showed a significant relationship with either cognitive or personality measures. Neophobic and exploratory tendencies determined the willingness of birds to engage only in the seed discrimination task. Such tendencies also had a significant effect on problem-solving ability. Our results suggest that consistent individual differences in cognitive performance along with consistent differences in personality could determine response to environmental change and therefore have important fitness consequences. PMID- 29622932 TI - Selfish partners: resource partitioning in male coalitions of Asiatic lions. AB - Behavioral plasticity within species is adaptive which directs survival traits to take multiple pathways under varying conditions. Male-male cooperation is an evolutionary strategy often exhibiting an array of alternatives between and within species. African male lions coalesce to safeguard territories and mate acquisition. Unique to these coalitions is lack of strict hierarchies between partners, who have similar resource securities possibly because of many mating opportunities within large female groups. Skewed mating and feeding rights have only been documented in large coalitions where males were related. However, smaller modal prey coupled with less simultaneous mating opportunities for male Asiatic lions in Gir forests, India would likely result in a different coalition structure. Observations on mating events (n = 127) and feeding incidents (n = 44) were made on 11 male coalitions and 9 female prides in Gir, to assess resource distribution within and among different sized male coalitions. Information from 39 males was used to estimate annual tenure-holding probabilities. Single males had smaller tenures and appropriated fewer matings than coalition males. Pronounced dominance hierarchies were observed within coalitions, with one partner getting more than 70% of all matings and 47% more food. Competition between coalition partners at kills increased with decline in prey size, increase in coalition size and the appetite states of the males. However, immediate subordinates in coalitions had higher reproductive fitness than single males. Declining benefits to partners with increasing coalition size, with individuals below the immediate subordinates having fitness comparable to single males, suggest to an optimal coalition size of 2 lions. Lions under different competitive selection in Gir show behavioral plasticity to form hierarchical coalitions, wherein partners utilize resources asymmetrically, yet coalesce for personal gains. PMID- 29622934 TI - Joint care can outweigh costs of nonkin competition in communal breeders. AB - Competition between offspring can greatly influence offspring fitness and parental investment decisions, especially in communal breeders where unrelated competitors have less incentive to concede resources. Given the potential for escalated conflict, it remains unclear what mechanisms facilitate the evolution of communal breeding among unrelated females. Resolving this question requires simultaneous consideration of offspring in noncommunal and communal nurseries, but such comparisons are missing. In the Seychelles warbler Acrocephalus sechellensis, we compare nestling pairs from communal nests (2 mothers) and noncommunal nests (1 mother) with singleton nestlings. Our results indicate that increased provisioning rate can act as a mechanism to mitigate the costs of offspring rivalry among nonkin. Increased provisioning in communal broods, as a consequence of having 2 female parents, mitigates any elevated costs of offspring rivalry among nonkin: per-capita provisioning and survival was equal in communal broods and singletons, but lower in noncommunal broods. Individual offspring costs were also more divergent in noncommunal broods, likely because resource limitation exacerbates differences in competitive ability between nestlings. It is typically assumed that offspring rivalry among nonkin will be more costly because offspring are not driven by kin selection to concede resources to their competitors. Our findings are correlational and require further corroboration, but may help explain the evolutionary maintenance of communal breeding by providing a mechanism by which communal breeders can avoid these costs. PMID- 29622933 TI - Parental investment in Tibetan populations does not reflect stated cultural norms. AB - In this paper, we examined both stated norms of sex preference and actual sex biases in parental investment in a Tibetan pastoralist society. We collected detailed demographic data on infant mortality, infant feeding, the length of interbirth intervals, and a decision when giving gifts, to examine sex-biased parental investment. Our results indicate a mismatch between self-reported son preference and measures of actual parental investment that favor daughters. We interpret this female-biased parental investment as a possible response to daughters generating more economic resources. However, the stated sex preferences of both sexes reflect cultural norms that appear to have remained unchanged over a long period, which may reflect the importance of male roles in the past. Our behavioral measures of parental investment are those most likely to be in the control of women (such as breastfeeding and interbirth interval), so this mismatch between stated and actual investment may be especially true of women. PMID- 29622936 TI - Severe Harm and Death Associated With Errors and Drug Interactions Involving Low Dose Methotrexate. AB - Harm and death associated with methotrexate errors. PMID- 29622935 TI - Temporal migration patterns and mating tactics influence size-assortative mating in Rana temporaria. AB - Assortative mating is a common pattern in sexually reproducing species, but the mechanisms leading to assortment remain poorly understood. By using the European common frog (Rana temporaria) as a model, we aim to understand the mechanisms leading to size-assortative mating in amphibians. With data from natural populations collected over several years, we first show a consistent pattern of size-assortative mating across our 2 study populations. We subsequently ask if assortative mating may be explained by mate availability due to temporal segregation of migrating individuals with specific sizes. With additional experiments, we finally assess whether size-assortative mating is adaptive, i.e. influenced by mating competition among males, or by reduced fertilization in size mismatched pairs. We find that size-assortative mating is in accordance with differences in mate availability during migration, where larger individuals of both sexes reach breeding ponds earlier than smaller individuals. We observe an indiscriminate mate choice behavior of small males and an advantage of larger males pairing with females during scramble competition. The tactic of small males, to be faster and less discriminative than large males, may increase their chances to get access to females. Experimental tests indicate that the fertilization success is not affected by size assortment. However, since female fecundity is highly correlated with body size, males preferring larger females should maximize their number of offspring. Therefore, we conclude that in this frog species mate choice is more complex than formerly believed. PMID- 29622938 TI - Drug and Device News. AB - Approvals, new indications, regulatory activities, and more. PMID- 29622937 TI - CMS Consideration of Rebate Overhaul Elicits Strong Opinions Both Pro and Con. AB - CMS consideration of rebate overhaul elicits strong opinions. PMID- 29622939 TI - Pharmaceutical Approval Update. AB - Netarsudil ophthalmic solution (Rhopressa) for the reduction of elevated intraocular pressure; ertugliflozin (Steglatro) for adults with type-2 diabetes; and lutetium lu 177 dotatate (Lutathera) for certain gastroenteropancreatic neuroendocrine tumors. PMID- 29622940 TI - Plecanatide (Trulance) for Chronic Idiopathic Constipation and Irritable Bowel Syndrome With Constipation. AB - Plecanatide (Trulance) for chronic idiopathic constipation and irritable bowel syndrome with constipation. PMID- 29622941 TI - Frustration Over Generic Drug Shortages and Prices Prompts Federal and Private Actions: Health Systems Take Matters Into Their Own Hands. AB - Generic shortages are draining hospital resources throughout the U.S. and in some cases imperiling inpatient treatment. The author considers the FDA's performance and describes the approach some health systems are taking to create a solution. PMID- 29622943 TI - Management and Preventive Measures for Febrile Neutropenia. AB - Febrile neutropenia (FN) is an oncological emergency and serious complication often resulting from chemotherapy. In patients with a weak or completely suppressed immune system, a fever may be the only sign of an underlying infection and immediate treatment is needed. Using risk evaluation scores, it is possible to stratify individual patient degree of risk. However, all patients warrant immediate antibiotic coverage. Antibiotic treatment of FN is broadened or narrowed based on individualized clinical scenarios. Prophylactic antimicrobials may be used in specific high-risk situations. This article briefly reviews FN, describes risk assessment tools, and discusses treatment and prophylactic options. PMID- 29622942 TI - Pharmacological Agents Utilized in Patients With Type-2 Diabetes: Beyond Lowering A1c. AB - Staying up to date with evolving pharmacotherapies is important to providing optimal therapies to patients. The authors present available evidence to support the role of novel and existing agents in treating type-2 diabetes. PMID- 29622944 TI - Intense Focus Yet Many Setbacks for Alzheimer's Disease Drug Development. AB - Despite failures in late-phase trials, the pipeline of medications for Alzheimer's disease is robust as companies hope to be the first to bring an effective therapy to market. We review several investigational agents in late stage development. PMID- 29622945 TI - Genitourinary Cancers Symposium And Integrative Healthcare Symposium Annual Conference. AB - We present coverage of advances in renal cell carcinoma and prostate cancer, as well as sessions on addiction relapse prevention and the role of integrative care. PMID- 29622946 TI - Research Briefs. PMID- 29622947 TI - Adjustment Profiles of Low-Income Caregivers from the United States and South Africa: Contrasts and Commonalities. AB - Although low-income parents living in under-resourced communities in the United States and around the world face challenges, many do well while others struggle in one or more areas of functioning. The present study examined patterns of adjustment among maternal caregivers living in the United States (US) (N = 320) and South Africa (SA) (N = 324). Cluster analyses across four domains of functioning representing both positive and negative adjustment and conducted within country revealed similar patterns of adjustment, with a majority of caregivers (37.8% in the US; 47.5% in SA) landing in a "holding steady" pattern, exhibiting good but not exceptional adjustment. Other patterns of adjustment (three additional in the US sample; two additional in the SA sample) showed elevated impairment in somatic complaints, problems with alcohol, or life satisfaction. In both the US and SA, support from family, friends, and neighbors differentiated the adjustment profiles. Further, both current stressors within and outside of the family and previous stressors including direct and indirect exposure to violence discriminated caregivers who were "holding steady" from those who were struggling in one or more domains. Additionally, across both countries, caregivers who were "holding steady" evidenced less avoidant coping. Implications of this work for fostering resilience among caregivers and their children are discussed. PMID- 29622948 TI - "An Unusual and Fast Disappearing Opportunity": Infectious Disease, Indigenous Populations, and New Biomedical Knowledge in Amazonia, 1960-1970. AB - In the twentieth century, biomedical researchers believed the study of Indigenous Amazonians could inform global histories of human biological diversity. This paper examines the similarities and differences of two approaches to this mid century biomedical research, comparing the work of virologist and epidemiologist Francis Black with human geneticists James V. Neel and Francisco Salzano. While both groups were interested in Indigenous populations as representatives of the past, their perspectives on epidemics diverged. For Black, outbreaks of infectious diseases were central to his methodological and theoretical interests; for Neel and Salzano, epidemics could potentially compromise the epistemological value of their data. PMID- 29622950 TI - Assessment of mitral valve geometric deformity in patients with ischemic heart disease using three-dimensional echocardiography. AB - Background: A full understanding of the geometry of the nonplanar saddle-shaped mitral annulus can provide valuable information regarding the pathophysiology of mitral regurgitation (MR). Aim of the work: To investigate mitral annular geometric deformities using three-dimensional echocardiography among patients with ischemic coronary illness with and without mitral regurgitation. Methods: Three-dimensional transesophageal echocardiographic data were acquired intraoperatively from patients with ischemic heart disease with or without associated mitral regurgitation who experienced coronary artery bypass grafting and normal control subjects. The mitral annulus was analyzed for differences in geometry using QLAB software. Results: Left ventricular ejection fraction was reduced in patients with ischemic heart disease and MR (n = 21; Group 1) and without MR (n = 7; Group 2) compared with that in normal subjects (n = 14; Group 3) (43.4% +/- 11.8% and 35.9% +/- 13.6% vs. 52.6% +/- 9.3%, respectively; p = 0.015). Mitral annular height and mitral annular saddle-shaped nonplanarity were significantly lower in Group 1 compared to Group 2 and Group 3 (6.00 +/- 1.07 mm, 7.96 +/- 0.93 mm and 8.31 +/- 1.12 mm; p < 0.0001) and (0.19 +/- 0.04, 0.26 +/- 0.04 and 0.26 +/- 0.03; p < 0.0001) respectively while mitral annular ellipsicity and Mitral valve tenting volume were significantly higher in the same group (1) (114.82% +/- 22.47%, 100.21% +/- 9.87% and 97.29% +/- 14.37%; p = 0.0421) and (2.73 +/- 1.11, 2.20 +/- 1.39 and 0.87 +/- 0.67) respectively. Vena contracta diameter was inversely correlated with the mitral annular height (r = -0.82; p < 0.0001) and saddle-shaped nonplanarity of the annulus (r = -0.68; p < 0.0001). Conclusion: Among patients with ischemic heart disease, there are significant increases in mitral valve tenting volume and height, and those with mitral regurgitation exhibited a reduced mitral annular height, a shallower saddle shape annulus and losses of ellipsicity of the annulus. PMID- 29622949 TI - Relation between left atrial measurements and thromboembolic risk markers assessed by echocardiography in patients with nonvalvular atrial fibrillation: A cross-sectional study. AB - Background: Left atrium (LA) dilatation has been associated with adverse cardiovascular outcomes in patients with sinus rhythm and atrial fibrillation (AF). Aim of the study: We aimed to evaluate the accuracy of left atrial (LA) size to predict transesophageal echocardiographic (TEE) markers of increased thromboembolic risk left atrial appendage (LAA) thrombus, low LAA velocities and dense spontaneous echocardiographic contrast (SEC), and also to assess the best method to evaluate LA size. Patients and methods: Cross-sectional study included 64 patients with nonvalvular AF undergoing transthoracic and transesophageal echocardiographic (TTE and TEE) evaluation. LA size was measured on TTE by several methods including the following: anteroposterior diameter (AP), LA area in four and two apical chamber views and volumes by ellipsoid, single plane (1P) and biplane area-length (2P) formulas. All these measures were indexed to the body surface area (BSA). Thromboembolic markers including LAA thrombus, low LAA velocities, dense SEC and LA abnormality (LA ABN) which means the presence of one or more of the previous three parameters were evaluated by TEE. Results: There was statistically significant increase in indexed and non-indexed LA parameters in patients with LA ABN compared to patients without LA ABN. According to ROC curve, the study found that all indexed LA parameters were predictive for LAA thrombus with the highest AUC was indexed LA 1P area length volume (AUC 0.91, CI 95% 0.81-1.01, p < 0.000), for LAA low flow velocity were indexed and non-indexed LA AP diameters with the highest AUC was indexed LA AP diameter (AUC 0.89, CI 95% 0.80-0.98, p < 0.000), for LA dense SEC were indexed LA ellipsoid volume (AUC 0.78, CI 95% 0.66-0.96, p = 0.002) and indexed LA 1P area length volume (AUC 0.78, CI 95% 0.66-0.90, p = 0.002) and for LA ABN were all LA parameters with the highest AUC was indexed LA 1P area length volume (AUC 0.87, CI 95% 0.79-0.96, p < 0.000). On multivariate logistic regression analysis of TEE parameters, the study found that the most predictive LA measurement for LAA thrombus was indexed LA AP diameter with cutoff 3 cm/m2 (OR 7.5, 95% CI 1.24-45.2, p = 0.02), for LAA low flow velocity was LA AP diameter with cutoff 6 cm (OR 17.6, 95% CI 3.23-95.84, p = 0.001), for LA dense SEC was indexed LA ellipsoid volume with cutoff 42 cm3/m2 (OR 6.5, 95% CI 1.32-32.07, p = 0.02), and for LA ABN was indexed LA ellipsoid volume with cutoff 42 cm3/m2 (OR 10.45, 95% CI 2.18-51.9, p = 0.008). Conclusion: LA enlargement is suitable to predict thromboembolic markers in patients with non valvular AF. The indexed and non-indexed LA AP diameter and indexed LA ellipsoid volume were the most accurate parameters for predicting thromboembolic markers. PMID- 29622951 TI - Baseline characteristics of patients with heart failure and preserved ejection fraction at admission with acute heart failure in Saudi Arabia. AB - : Heart failure and preserved ejection fraction (HFpEF) is defined as heart failure symptoms and signs with a normal or near-normal ejection fraction (EF) with evidence of diastolic dysfunction. The few Middle Eastern studies that have been conducted were designed to compare patients with heart failure reduced ejection fraction (HFrEF) and HFpEF.The aim of this study was to study Saudi patients with HFpEF who presented with acute heart failure, and define their clinical characteristics and the signs and symptoms of heart failure, echocardiographic findings and medications at admission and at hospital discharge. Methods: This is a prospective observational study in which patients were included following an acute heart failure presentation with N-terminal pro BNP (NT-proBNP) > 300 ng/L and left ventricular ejection fraction (LVEF) > 50%. They were admitted to the coronary care unit of king Saud medical city from the period of March 2015 to September 2015. Results: 114 patients were enrolled in the study and assessed at acute admission. Of these, 4% died on day one of admission.The mean +/- SD age of 109 included patients was 59 +/- 8 years and 55% were women. Hypertension (64%), dyslipidemia (76%), atrial tachyarrhythmia (38%), prior heart failure (33%) and anemia (35%), median NT-proBNP was 2490 +/- 125 ng/l at admission. Mean (LVEF) was 61 +/- 3, mean LV mass index was 118 +/- 11, mean E/e' was 12.2 +/- 2, and left atrial volume index was 47 +/- 7 mL/m2. Mean global left ventricular strain was -13.5 +/- 1.5. At discharge the majority of patients were still symptomatic with high NT-proBNP 542 +/- 266. Conclusions: Patients with HFpEF were old with slight female dominance, a high rate of hypertension, diabetes, dyslipidemia and much comorbidity. LVEF was preserved despite depressed left ventricular longitudinal and diastolic functions with high filling pressure. At discharge the patients were still symptomatic calling for further research to reach the best strategy for proper management. PMID- 29622952 TI - Demographic features and prevalence of myocarditis in patients undergoing transarterial endomyocardial biopsy for unexplained cardiomyopathy. AB - Background: The diagnosis of myocarditis is still a challenge. The true incidence of the disease is unknown due to great variation in clinical manifestations. Objective: The aim of this study was to identify the demographic features and in hospital prevalence of myocarditis in patients undergoing transarterial endomyocardial biopsy (EMB) for unexplained cardiomyopathy. Patients and methods: This was a prospective observational study. We recruited all patients with unexplained cardiomyopathy presented at Assiut University Hospital from January 2014 till December 2014. The inclusion criteria were namely acute symptoms of heart failure, worsening of ejection fraction (EF) despite optimized therapy, hemodynamically significant arrhythmias, heart failure with concurrent rash, fever, or peripheral eosinophilia and new-onset cardiomyopathy in the presence of known amyloidosis. We excluded patients with uncontrolled hypertension, diabetes mellitus, ischemic, congenital, rheumatic heart disease, peripartum cardiomyopathy, cardiotoxic exposure, alcoholic and familial cardiomyopathies. All patients were subjected to full examination with ECG, echocardiography and coronary angiography, and then 3 EMB samples via femoral artery were taken from the LV. The histopathological examination of all biopsies was done. Results: Out of the 1100 patients admitted to our department, 15 patients (1.4%), who had unexplained cardiomyopathy were included in our study. Seventy-three percent were males with mean age 37.8 +/- 17 y. 87% were from rural areas, and 73.3% presented with dyspnea grade III to IV for a duration period that varied from 2 to 8 weeks. 33% had an EF > 40%. 33 EMB samples from 11 patients were examined. 7 out of 11 patients (63.6%) proved to have myocarditis on pathological examination, 5 of them had active myocarditis, 1 had chronic myocarditis and 1 had borderline myocarditis. Three patients (27.3%) had no pathological evidence of inflammation and one patient (9.1%) had cardiac amyloidosis. Four out of 15 patients (26.7%) did not undergo EMB because of LV thrombus or bleeding tendency. None of our patients had any complication from EMB. Conclusion: The in-hospital prevalence of myocarditis is high among patients with unexplained cardiomyopathy. EMB via femoral artery is safe and essential in confirming the diagnosis. PMID- 29622953 TI - Familial history of hypertension as a predictor of increased arterial stiffness in normotensive offspring. AB - Background: Increased arterial stiffness can be used as a prognostic marker of arterial hypertension. The relationship between arterial stiffness and arterial hypertension seems to be reciprocal. Objective: Evaluation of changes of the arterial elastic prosperities in normotensive subjects, with and without parental history of hypertension. Subjects and Methods: One hundred and ten normotensive individuals, aged 20-30 years, were divided into two groups: group-A (n = 57) and group-B (n = 53) subjects with positive and negative parental history of hypertension, respectively. Systolic, diastolic and pulse pressures were measured using mercury sphygmomanometer. The elastic properties of the ascending aorta and the common carotid arteries were assessed using M-mode echo and B-mode imaging, respectively. Stiffness index of the digital volume pulse (SIDVP) was measured in the right index finger using photoplethysmography. Results: Group A subjects showed higher aortic stiffness index (p = 0.002), carotid stiffness index (p = 0.001), carotid pulse wave velocity (p ? 0.001) and stiffness index of digital volume pulse (p = 0.001). Group A subjects showed lower aortic distensibility (p = 0.001), aortic strain (p = 0.004), changes in aortic diameter (p = 0.022), carotid distension (p = 0.026), carotid distensibility coefficient (p ? 0.001) and carotid compliance coefficient (p = 0.002). Conclusion: The aortic and carotid stiffness parameters and SIDVP were higher in normotensive offspring of hypertensive parents. This finding could direct the attention towards the increased cardiovascular risk in this group and thus prompt earlier and tighter prevention of cardiovascular risk factors. PMID- 29622954 TI - Predictors of intravenous amiodarone induced liver injury. AB - Background: Intravenous (IV) amiodarone may be associated with liver injury that may necessitate drug discontinuation. The prediction of amiodarone induced liver injury (AILI) and its severity may help careful patient monitoring or the choice of other measures alternative to amiodarone in high risk patients. Little is known regarding predictors of AILI. Objectives: To address the predictors of AILI and its severity. Methods: The study included 180 patients indicated for IV amiodarone therapy who were divided into 2 groups: cases (90 patients) who developed AILI, and controls (90 patients) who did not develop AILI. AILI was defined as aminotransferase (ALT and AST) elevation by ?2 folds of baseline levels. Severe AILI was defined as enzyme elevation by >5 folds of baseline values. Results: Multivariate analysis showed that the presence of cardiomyopathy (P = 0.032), congestive hepatomegaly (P = 0.001), increasing baseline total bilirubin (P < 0.0001), direct current cardioversion (P = 0.015), and increasing dose of amiodarone (P = 0.014) to be independent predictors for AILI. Regarding severity of AILI, inotropic support (P = 0.034), congestive hepatomegaly (P = 0.012), increasing baseline total bilirubin (P = 0.001), and increasing dose of amiodarone (P = 0.002) were found to be independent predictors for severe AILI. Among cases, linear regression analysis showed that baseline ALT was the only significant independent predictor of post-amiodarone ALT (P < 0.0001), while baseline AST (P < 0.0001) and EF (P = 0.012) were the only significant independent predictors of post-amiodarone AST. Conclusions: Compromised cardiac, hepatic, and hemodynamic conditions, with increasing dose of IV amiodarone were associated with AILI. Severity of liver injury had linear relationship with baseline aminotransferase levels and left ventricular systolic function. PMID- 29622955 TI - Radiation exposure, the forgotten enemy: Toward implementation of national safety program. AB - Radiation safety is an important counterpart in all facilities utilizing ionizing radiations. The concept of radiation safety has always been a hot topic, especially with the late reports pointing to increased hazards with chronic radiation exposure. Adopting a nationwide radiation safety program is considered one of the most urging topics, and is a conjoint responsibility of multiple disciplines within the health facility. PMID- 29622956 TI - Long-term prognostic implication of coronary plaque characterization as detected by 64-multidetector computed tomography in Egyptian population. AB - Objectives: We aimed to determine the role of multi-detector computed tomography (MDCT) in prognosis of patients with known or suspected coronary artery disease (CAD) by applying plaque characterization and whether obstructive versus non obstructive plaque volume is a predictor of future cardiac events. Background: Vulnerable plaques may occur across the full spectrum of severity of stenosis, underlining that also non-obstructive lesions may contribute to coronary events. Methods: We included 1000 consecutive patients with intermediate pretest likelihood of CAD who were evaluated by 64-MDCT. Coronary artery calcium scoring, assessment of degree of coronary stenosis and quantitative assessment of plaque composition and volume were performed. The end point was cardiac death, acute coronary syndrome, or symptom-driven revascularization. Results: After a median follow-up of 16 months, 190 patients had suffered cardiac events. In a multivariate regression analysis for events, the total amount of non-calcified plaque (NCP) in non-obstructive lesions was independently associated with an increased hazard ratio for non-fatal MI (1.01-1.9/100-mm3 plaque volume increase, p = 0.039), total amount of obstructive plaque was independently associated with symptoms driven revascularization (p = 0.04) and coronary artery calcium scoring (CACS) was independently associated with cardiac deaths (p = 0.001). Conclusion: MDCT is a non-invasive imaging modality with a prognostic utility in patients with known or suspected coronary artery disease by applying plaque characterization and it could identify vulnerable plaques by measuring the total amount of NCP in non-obstructive lesions which could be useful for detecting patients at risk of acute coronary syndrome (ACS) and guide further preventive therapeutic strategies. CACS was shown to be an independent predictor of mortality, while total amount of obstructive volume was shown to be an independent predictor of symptoms driven revascularization. PMID- 29622957 TI - Acute myocardial infarction following electroconvulsive therapy in a Schizophrenic patient. AB - Deaths due to acute coronary insufficiency have been reported during or following electroconvulsive therapy (ECT). Various mechanisms related to ECT related deaths also include cerebral, and respiratory complications; however, cardiovascular complication remains the most common. Here, we describe a 55 year old male with a longstanding psychiatric illness with multiple antipsychotics under regular follow-up and required repeated ECT therapy to have the disease symptoms under remission. This time he developed acute onset chest pain immediately post ECT shock and diagnosed as Acute anterior wall myocardial infarction and was taken up for successful primary coronary revascularization to left anterior descending (LAD) artery 2 h after the chest pain onset. He was later discharged in a stable state and advised for continuous psychiatric follow-up. PMID- 29622958 TI - Recurrent symptomatic ischemic stroke in a 46-year-old African male revealing Angio-Behcet with severe cardiovascular involvement. AB - Behcet'sdisease (BD) is a chronic, multisystem vasculitis. It is categorized under variable vessel vasculitis in the new Chapel Hill nomenclature as it involves blood vessels of any type and size. It is characterized by relapsing aphthous ulcers commonly occurring in the oral mucosa and genitalia with ocular involvement. Other organ systems may be involved any time throughout the course of the disease. The exact cause is unknown. However, combination of genetic and environmental factors is likely to play a role. Cardiac involvement may occur in the form of intracardiac thrombus, endocarditis, myocarditis, pericarditis, endomyocardial fibrosis, coronary arteritis, myocardial infarction, and valvular disease. We present a case of Angio-Behcet in a 46-year-old African male with severe cardiovascular involvement including pulmonary artery hypertension (PAH), right ventricular failure and left ventricular diastolic dysfunction diagnosed after 2 episodes of symptomatic ischemic stroke resulting from complete occlusion of the right internal carotid artery (ICA) up to its intracranial portion. Immunosuppressive and anticoagulant therapies have induced improvement in cardiac manifestations. Nevertheless, prompt recognition of the primarily vascular manifestation of BD without mucocutaneous manifestations was responsible for considerable delay that did not afford surgical therapy for the carotid occlusion. PMID- 29622959 TI - Fibromuscular dysplasia in an adult male as a cause of renal artery stenosis and secondary hypertension treated with renal artery stenting. AB - Background: Renovascular hypertension due to fibromuscular dysplasia is an uncommon cause of secondary hypertension and is more common in females. This entity is an important treatable cause of secondary hypertension. Case presentation: We report the case of a 21-year-old asymptomatic male found to have high blood pressure on routine checkup. Renal angiogram revealed fibromuscular dysplasia involving the right renal artery. He underwent percutaneous angioplasty with complete recovery. The single antihypertensive which he was on was stopped next month. Conclusion: Fibromuscular dysplasia causing stenosis of renal artery is uncommon. High degree of suspicion is required for the timely diagnosis and treatment of this potentially treatable cause of secondary hypertension. PMID- 29622960 TI - A case of multivessel PTCA in achondroplasia patient. PMID- 29622962 TI - Value of global longitudinal strain by two dimensional speckle tracking echocardiography in predicting coronary artery disease severity. AB - Background: Significant coronary artery stenosis might cause persistently impaired longitudinal left ventricle (LV) function at rest. LV global longitudinal strain (LVGLS) can be accurately assessed by 2D speckle-tracking strain echocardiography(2D-STE). Objective: We aimed to evaluate the diagnostic accuracy of LV global longitudinal strain obtained by 2D-STE in prediction of severity of CAD. Methods: Eighty patients with suspected stable angina pectoris were included. They underwent transthoracic echocardiography (TTE) to measure LV ejection fraction, 2-D-STE to measure GLS and coronary angiography (CA). The patients were divided into two groups: group 1 (58 patients) with significant (>70%) CAD, and group 2 (22 patients) with non-significant (<70%) CAD. Images were obtained in the apical long-axis, four-chamber, and two chamber views. Regional longitudinal systolic strain was measured in 17 myocardial segments and averaged to provide global longitudinal strain (LVGLS). Results: There was significant decrease in GLS in group 1 compared to group 2 (-11.86 +/- 2.89% versus -18.65 +/- 0.79%, P < 0.000). The optimal cutoff value of GLS for prediction of significant CAD was -15.6% [AUC 0.88, 95% CI 0.78-0.96 p < 0.000]. The sensitivity, specificity and accuracy of GLS for detecting significant CAD were 93.1%, 81.8%,and 90% respectively.There was a significant positive correlation between GLS and EF (r = 0.33; p = 0.036).There was incremental significant decrease in GLS with increasing number of coronary vessels involved. Conclusion: Measurement of global longitudinal strain using 2D speckle tracking echocardiography is sensitive and accurate tool in the prediction of severe CAD. PMID- 29622963 TI - Role of 2D speckle tracking echocardiography in predicting acute coronary occlusion in patients with non ST-segment elevation myocardial infarction. AB - Background: A substantial fraction of patients with non ST-elevation acute coronary syndrome have an occluded culprit vessel on coronary angiography. Acute coronary occlusion often results in myocardial infarction and loss of systolic function. Identification of these patients may have considerable impact on treatment and prognosis. Aim: The study aims at investigating role of 2D speckle tracking echocardiography as a non-invasive predictor of acute coronary artery occlusion in patients with non ST-segment elevation myocardial infarction. Patients: This study was carried on 60 patients with first attack non ST segment elevation myocardial infarction who were admitted to coronary care unit of Ain Shams University Hospitals. All patients underwent thorough history taking, full clinical examination, 12 leads surface ECG, full 2D, M-mode and Doppler echocardiographic study, two-dimensional speckle tracking strain study and coronary angiography. Results: 2D derived peak global longitudinal strain had a highly significant relationship in prediction of the presence of total occlusion, and also number of segments with reduced strain (functional risk area by strain) had a highly significant relationship in prediction of the presence of total occlusion. In this study, 2D derived peak longitudinal strain sensitivity and specificity were 68.9% and 77.7% respectively at a cutoff value of -15.5 while number of segments with reduced longitudinal strain sensitivity and specificity were 63.6% and 77.7% respectively at a cutoff value of 5 segments. Conclusion: Both global and regional peak longitudinal systolic strain can offer accurate, feasible, and non-invasive predictor for acute coronary artery occlusion in patients with non ST elevation myocardial infarction who may benefit from early revascularization. PMID- 29622961 TI - Data sharing: A new editorial initiative of the International Committee of Medical Journal Editors. Implications for the editors' network. AB - The International Committee of Medical Journal Editors (ICMJE) provides recommendations to improve the editorial standards and scientific quality of biomedical journals. These recommendations range from uniform technical requirements to more complex and elusive editorial issues including ethical aspects of the scientific process. Recently, registration of clinical trials, conflicts of interest disclosure, and new criteria for authorship -emphasizing the importance of responsibility and accountability-, have been proposed. Last year, a new editorial initiative to foster sharing of clinical trial data was launched. This review discusses this novel initiative with the aim of increasing awareness among readers, investigators, authors and editors belonging to the Editors' Network of the European Society of Cardiology. PMID- 29622964 TI - Correlation of corrected QT dispersion with the severity of coronary artery disease detected by SYNTAX score in non-diabetic patients with STEMI. AB - Introduction: Determination of the QT interval dispersion by means of a standard ECG at rest has been widely used for cardiovascular risk assessment during the last 15 years as one of the recent explanations for the development of life threatening ventricular arrhythmias. However, little is known about the relation between QT dispersion and the severity of coronary artery atherosclerosis as defined by SYNTAX score. Aim of work: The present study was done to assess the correlation between QTc dispersion and the severity of coronary artery disease in acute ST elevation myocardial infarction (STEMI) detected by SYNTAX score. Patients and methods: It included 50 patients who were non-diabetic, non hypertensive and diagnosed as acute STEMI within 6 months undergoing coronary angiography in the cath. lab. of Assiut University Hospital. QT dispersion was calculated as the difference between the longest (QT max) and the shortest QT (QTmin) interval recorded by standard 12 lead ECG. The QT interval was corrected by using Bazett's formula (QTc = QT/square root of R-R interval in seconds). Corrected QT dispersion (QTcd) was defined as the difference between the maximum and minimum QTc for a given heart rate. The SYNTAX score is calculated by syntax calculator, a new tool to grade the complexity of coronary artery disease. Results: Out of 50 participating patients, there were 43 (86%) males with mean age 53.9 +/- 12.1 years. The mean QTc dispersion was 83.1 +/- 20.3 ms, while mean SYNTAX score was 11.6 +/- 6.1. There is a strong positive correlation between QTc dispersion and SYNTAX score. This was not related to age, gender, risk factors or family history of ischemic heart disease. Of note, there was a relationship between QTc dispersion and serum creatinine. Conclusions: Our study concluded that there is a significant positive correlation between corrected QT dispersion and severity of coronary artery disease as assessed by SYNTAX score. PMID- 29622965 TI - The relation between coronary artery disease severity and fragmented QRS complex in patients with left bundle branch block. AB - Background: The diagnosis of coronary artery disease (CAD) in patients with LBBB represents a clinical challenge. The presence of fragmented QRS (fQRS) complex on surface ECG may be related to myocardial ischemia, scarring or fibrosis. Objectives: To investigate the relation between fQRS and the presence and severity of CAD in patients with LBBB. Patients and methods: 56 patients with symptoms suggesting CAD and complete LBBB were submitted to full history taking and clinical examination, complete 12-leads electrocardiography (ECG) to confirm the diagnosis of LBBB and to diagnose the fragmented wide QRS (f-wQRS) complex, echocardiography, and coronary angiography; lesions with ?70% narrowing in major epicardial artery or ?50% narrowing in the left main coronary artery were considered significant; and Gensini score was calculated. Patients were classified into two groups according to the presence or absence of f-wQRS. Results: There were significantly more patients with obstructive CAD among patients with f-wQRS (p = 0.000053). Gensini score was significantly higher in patients with than in patients without fwQRS (p < 0.00001). f-wQRS was the only significant independent predictor of obstructive CAD. Sensitivity of f-wQRS in predicting obstructive CAD was 80.1%, specificity was 73.3%, positive predictive value was 72.4%, negative predictive value was 81.5%, and overall accuracy was 76.8%, p = 0.0022. Conclusion: Seeking for f-wQRS in patients with LBBB and suspected CAD is a simple, easy, available, method that may be helpful in noninvasive prediction of obstructive CAD. PMID- 29622966 TI - Influence of collaterals on the left ventricular end-diastolic pressure and serum NT-proBNP levels in patients with coronary chronic total occlusion. AB - Objective: Although numerous studies have shown the protective effects of the well-developed coronary collaterals on left ventricular functions, the relationship between collateral grade and left ventricular end diastolic pressure has not been studied in chronic total occlusion patients. Also, there are conflicting data on the effect of collaterals on NT-proBNP levels. The aim of our study was to evaluate the relationship between coronary collateral circulation and left ventricular end diastolic pressure and NT-proBNP levels in chronic total occlusion patients. Methods: Study group was retrospectively selected from the patients who had undergone coronary angiography at our hospital between June 2011 and March 2013. Clinical, biochemical, angiographic and hemodynamic data of 199 consecutive patients having at least one totally occluded major epicardial coronary artery were evaluated. Coronary collateral circulation was graded according to Rentrop classification. While Rentrop grade 3 was defined as well developed, all the remaining collateral grades were regarded as poor collaterals. Results: Overall 87 patients were found to have good collaterals and 112 patients had poor collaterals. There was no significant difference between the patients with well- or poorly developed coronary collaterals with regard to left ventricular end diastolic pressure (16.84 +/- 5.40 mmHg vs 16.10 +/- 6.09, respectively, p = 0,632) and log NT-proBNP (2.46 +/- 0.58 vs 2.59 +/- 0.76, respectively, p = 0,335). Conclusion: In patients with coronary chronic total occlusion even well-developed coronary collaterals are not capable of protecting the rise of left ventricular end diastolic pressure and NT-proBNP levels which are reliable markers of the left ventricular dysfunction. PMID- 29622967 TI - The value of urotensin II in patients with left-sided rheumatic valvular regurgitation. AB - Aims: Rheumatic valve diseases are most common etiological valve diseases in developing countries. Urotensin II is cardiovascular autacoid/hormone and may be associated with patients of heart valve diseases. The present study was to measure plasma urotensin II concentrations in patients with left-sided rheumatic valve diseases such as mitral regurgitation (MR) and aortic regurgitation (AR), and to examine its correlation with severity of valve impairment, function (New York Heart association, NYHA) class and pulmonary artery pressure (PAP). Methods and results: Sixty patients with moderate to severe rheumatic left-sided valve regurgitation and 20 healthy controls were selected after performing the echocardiography. Plasma urotensin II level was measured in all subjects. The patients with MR and AR were significantly increased of left ventricular end diastolic dimension (LVEDD), left ventricular end systolic dimension (LVESD), left atrial diameter, PAP, but decreased of EF% versus the controls. Urotensin II level was highly significant in patients with MR (1.83 +/- 0.92 ng/ml, P < 0.001) and AR (0.79 +/- 0.3 ng/ml, P < 0.05) versus the controls (0.48 +/- 0.13 ng/ml). Also, there was significant correlation between Urotensin II level and LVEDD (MR, r = 0.318, P = 0.03; AR, r = 0.805, P < 0.001), LVESD (MR, r = -0.271, P = 0.115; AR, r = 0.614, P = 0.001), and PAP (MR, r = 0.706, P < 0.001; AR, r = 0.129, P = 0.538). Conclusion: Urotensin II was elevated in patients with rheumatic left sided valvular regurgitation, and positively correlated with increased LVEDD (in both MR and AR), LVESD (only AR) and pulmonary artery pressure (only MR). Therefore, urotensin II level may be used as diagnostic biomarker in patients with rheumatic valvular diseases for assessment of the severity in parallel with echocardiography. PMID- 29622969 TI - Relationship between serum osteoprotegerin and vascular calcifications in hemodialysis patients. AB - Background: Uremia is a vasculopathic process, and both cardiac calcification and vascular calcification seen from the early stages of chronic kidney disease. Osteoprotegerin could play a crucial role in atherosclerotic plaque formation, maturation and calcification. The goal of this study was to determine the relationship of serum osteoprotegerin with vascular calcification in patients with end stage kidney disease who were maintained on regular hemodialysis. Methods: Sixty clinically stable chronic renal failure patients undergoing regular hemodialysis were enrolled in this cross sectional study. Thirty patients (mean age 56.7 +/- 10.5 years) with abdominal aortic calcification were selected by basal abdominal X-ray who underwent multi-slice computerized tomography scan to measure coronary artery calcification score; and thirty patients (mean age 56.5 +/- 8.4 years) without abdominal aortic calcification. All patients were evaluated by serum calcium, phosphorus, albumin, lipid profile, intact parathyroid hormone (iPTH), serum creatinine, serum urea, serum uric acid, serum C-reactive protein, and hemoglobin. Serum osteoprotegerin samples were collected before dialysis and estimated by the ELISA kit. Results: Serum osteoprotegerin level was significantly higher in patients with vascular calcification than in those without calcifications. Serum osteoprotegerin correlated positively with serum phosphorus, calcium phosphorus product, alkaline phosphatase, iPTH, C reactive protein, serum uric acid, low-density lipoprotein (LDL) and left ventricular mass index (LVMI) (p < 0.005), and negatively with hemoglobin, ejection fraction (p < 0.005) and HDL (p < 0.05). Conclusions: These findings suggest that osteoprotegerin may be involved in the development of vascular calcification in hemodialysis patients. PMID- 29622968 TI - Atherosclerosis in chronic hepatitis C virus patients with and without liver cirrhosis. AB - Background: Chronic Hepatitis C virus (HCV) infection and liver cirrhosis may be associated with atherosclerosis and coronary artery disease (CAD). There are two phases to atherosclerosis, Subclinical and Clinical. Assessment of atherosclerosis may be started at its Subclinical phase by the evaluation of Epicardial Fat Thickness (EpFT) and Carotid Intima Thickness (CIMT). Aim of the study: The aim of the study was to evaluate Clinical and Subclinical atherosclerosis in chronic HCV patients with and without liver cirrhosis by evaluating CIMT and EpFT and correlating the results with Child-Pugh functional scoring of cirrhosis as well as with ultrasound and laboratory parameters that define the severity of liver disease. Patients and methods: This study involved 64 chronic HCV patients that were divided into two groups: 24 patients without liver cirrhosis and 40 patients with liver cirrhosis in addition to 20 apparently healthy volunteers serving as control. All of the 84 subjects were subjected to the following: Clinical evaluation; Routine Laboratory Evaluation (CBC, Liver Function Tests, Renal Function Tests, Serum electrolytes, Cholesterol, Triglycerides, HBs antigen and HCV antibody); ECG; Abdominal ultrasound; Echocardiographic evaluation of segmental wall motion abnormalities and EpFT and B-Mode Carotid ultrasonography for evaluation of CIMT. Results: In the cirrhotic HCV group, the CIMT and EpFT were both significantly increased [Compared to control group (p = 0.000), compared to the non-cirrhotic HCV group (p = 0.000)]. In the non-cirrhotic HCV group, the CIMT and EpFT were both significantly increased compared to the control group with a p-value of 0.003 for CIMT and 0.048 for EpFT. The CIMT and EpFT were also positively correlated with each other (r = 0.456, p = 0.001). There was a statistically significant increase in the EpFT and CIMT in Child class B patients compared to Child class A (p = 0.007 for CIMT and p = 0.028 for EpFT) and in Child class C patients compared to Child class B patients (p = 0.001 for CIMT and 0.005 for EpFT). CIMT and EpFT were correlated positively with AST (r = 0.385, p = 0.002 for CIMT, and r = 0.379, p = 0.003 for EpFT), Total Bilirubin (r = 0.378, p = 0.003 for CIMT, and r = 0.384, p = 0.002 for EpFT), INR% (r = 0.456, p = 0.001 for CIMT, and r = 0.384, p = 0.001 for EpFT), CRP (r = 0.378, p = 0.003 for CIMT, and r = 0.386, p = 0.002 for EpFT), spleen span (r = 0.417, p = 0.001 for CIMT, and r = 0.437, p = 0.001 for EpFT) and portal Vein Diameter (r = 0.372, p = 0.003 for CIMT, and r = 0.379, p = 0.003 for EpFT). CIMT and EpFT were correlated negatively with Albumin (r = 0.379, p = 0.003 for CIMT, and r = -0.370, p = 0.003 for EpFT), platelets count (r = -0.382, p = 0.002 for CIMT, and r = -0.378, p = 0.003 for EpFT) and Liver Span (r = -0.433, p = 0.001 for CIMT, and r = -0.424, p = 0.001 for EpFT). Conclusion: EpFT and CIMT significantly increased in chronic hepatitis C virus patients especially in those with cirrhosis and closely correlated with each other. Their thickness also correlated with the Child-Pugh functional scoring of cirrhosis as well as with ultrasound and laboratory parameters that define the severity of liver disease.The echocardiographic assessment of EpFT and the carotid Doppler assessment of CIMT may provide appropriate and simple screening markers for subclinical atherosclerosis and cardiovascular risk in chronic HCV patients with and without cirrhosis. PMID- 29622971 TI - Pattern of vascular remodeling of distal reference segment after recanalization of chronic total occlusion, long-term angiographic follow-up. AB - Chronic total occlusion (CTO) is probably caused by thrombus and lipid-rich cholesterol esters that are replaced over time by collagen and calcium deposition. Experimental models showed endothelial cell necrosis in response to vessel ligation, whereas more recent models suggest that the endothelium might retain viability guiding the subsequent development of CTO, including CTO neo revascularization, which occurs within the lumen and in various layers of the vessel wall, by the release of paracrine substances. It is uncertain whether after CTO recanalization the recovery of anterograde reverses endothelial dysfunction, thus promoting vasodilation and positive remodeling. PMID- 29622970 TI - Sudden cardiac death with triple pathologies: A case report. AB - Sudden cardiac death in young adults may be associated with rare cardiomyopathies such as left ventricular noncompaction (LVNC) and arrhythmogenic right ventricular (ARVC) cardiomyopathies. LVNC is characterised by hypertrabeculations and deep recesses of the left ventricle. ARVC presents with thin myocardium as a result of extensive fibro-fatty infiltrations. In both conditions, death may be due to arrhythmia, thromboembolic events or heart failure. We report a case of a 21-year old athletic young man who collapsed at the futsal court right after the game. He was resuscitated but expired at the hospital after a brief admission. A week earlier, he had a similar episode of syncope and revived through cardio pulmonary resuscitation at the site. Post mortem examination showed extensive acute myocardial infarction (AMI) involving the papillary muscles and the left ventricular wall. Features of LVNC were also observed. On top of that, the right ventricle showed patchy thin myocardium as the wall was largely comprised of fat. Histology examination confirmed the presence of AMI and massive fibro-fatty infiltrations of the right ventricle. This unfortunate young man had co-existing cardiomyopathies which is rare indeed. As he succumbed to AMI, this mechanism of death is also uncommonly associated with neither LVNC nor ARVC. In conclusion, young and physically active individuals may not be spared of sudden cardiac death. Mild and non-specific symptoms should not be taken lightly as it may be the subtle signs of cardiomyopathies. PMID- 29622972 TI - Elevated troponin in patients with acute stroke - Is it a true heart attack? AB - Although the prognostic value of a positive troponin in an acute stroke patient is still uncertain, it is a commonly encountered clinical situation given that Ischemic Heart Disease (IHD) and cerebrovascular disease (CVD) frequently co exist in the same patient and share similar risk factors. Our objectives in this review are to (1) identify the biologic relationship between acute cerebrovascular stroke and elevated troponin levels, (2) determine the pathophysiologic differences between positive troponin in the setting of acute stroke versus acute myocardial infarction (AMI), and (3) examine whether positive troponin in the setting of acute stroke has prognostic significance. We also will provide an insight analysis of some of the available studies and will provide guidance for a management approach based on the available data according to the current guidelines. PMID- 29622974 TI - Pre-hospital and hospital delay in patients with non-ST elevation acute coronary syndromes in tertiary care. AB - Background: Early presentation is desirable in all cases of acute prolonged chest pain. Causes of delayed presentation vary widely across geographic regions because of different patients' profile and different healthcare capabilities. Objectives: To detect causes of delay of Non-ST elevation acute coronary syndrome (NSTE-ACS) patients in our country. Methods: Patients admitted with NSTE-ACS were included. We recorded the time delay between the onsets of acute severe symptoms till their arrival to the hospital (Pre-hospital delay). We also recorded the time delay between the arrival to hospital and the institution of definitive therapy (hospital delay). Causes of pre-hospital delay are either patient- or transportation-related, while hospital delay causes are either staff- or system related. Results: We recruited 315 patients, 200 (63.5%) were males, 194 (61.6%) hypertensives, 180 (57.1%) diabetics, 106 (33.7%) current smokers and 196 (62.2%) patients had prior history of cardiac diseases. The mean pre-hospital delay time was 8.7 +/- 9.7 h. Sixty-six percent of this time was due to patient-related causes and 34% of pre-hospital delay time was spent in transportation. The mean hospital delay time was 2.3 +/- 0.95 h. In 89.8% of cases, the hospital delay was system-related while in 10.2% the reason was staff-related. The mean total delay time to definitive therapy was 11.0 +/- 9.8 h. Conclusion: Pre-hospital delay was mainly patient-related. Hospital delay was mainly related to healthcare resources. Governmental measures to promote ambulance emergency services may reduce the pre-hospital delay, while improving the utilization of healthcare resources may reduce hospital delay. PMID- 29622973 TI - Effect of chronic pretreatment with beta-blockers on no-reflow phenomenon in diabetic patients with acute ST-elevation myocardial infarction undergoing primary percutaneous coronary intervention. AB - Background: No-reflow is an important factor as it predicts a poor outcome in patients undergoing primary angioplasty. In comparison with patients attaining TIMI 3 flow, patients with no-reflow have an increased incidence of ventricular arrhythmias, early congestive cardiac failure, cardiac rupture and cardiac death. As such, it is of paramount importance to consider strategies to prevent the occurrence of no-reflow phenomenon. Previous evidence suggests that Beta (beta) blockers have multiple favorable effects on the vascular system not directly related to their effect on blood pressure. However, there are insufficient data regarding the effects of prior Beta blocker use on coronary blood flow after primary PCI in patients with AMI. Aim: The aim of this study was to test the hypothesis that Beta blocker treatment before admission would have beneficial effects on the development of the no-reflow phenomenon after acute myocardial infarction. Methods and results: The study included 107 diabetic patients who had presented with acute STEMI within 12 h from the onset of chest pain. All of them have undergone primary angioplasty at Ain Shams University hospitals or National Heart institute. The incidence of no-reflow phenomenon was 21%. No-reflow phenomenon was significantly lower in patients on chronic B-blocker therapy (12% vs. 28%; P = 0.04). The heart rate was significantly lower in the normal reflow group than in the no-reflow group (P = 0.03). The study also showed that B blocker pretreatment is an independent protective predictor for the no-reflow phenomenon (P = 0.045). Conclusion: Chronic pre-treatment with B-blocker in diabetic patients presenting with STEMI, is associated with lower rate of occurrence of no-reflow phenomenon after primary PCI. PMID- 29622975 TI - Ischemia modified albumin (IMA) in acute coronary syndrome (ACS) and left bundle branch block (LBBB). Does it make the difference? AB - Background: Management of patients with a suspected ACS and LBBB is a challenge to the clinician. Aim: To detect the ability of IMA to exclude myocardial ischemia in suspected patients with ACS and LBBB. Material and methods: A total of 68 patients with suspected ACS and LBBB (group I) and another twenty patients age and sex matched known to have LBBB with normal coronary angiography (group II) were included in this study and subjected to: routine laboratory tests, 12 lead ECG, echocardiography, and measurement of serum troponin I (TnI) and IMA (measured by ELISA). Diagnostic coronary angiography was performed on all patients and scored by severity and modified Gensini scores. Results: IMA and TnI levels are significantly increased in group I compared to group II (P value <0.001). IMA with a cutoff value >95 could predict significant CAD (lesions >50%) with AUC of 0.923, sensitivity of 88%, specificity of 83.33%, PPV of 93.6%, NPV of 71.4% and accuracy 86.76%. Moreover, by using both simple and multiple logistic regression analyses IMA could also independently detect significant CAD. The combined use of IMA and TnI significantly improved the sensitivity and the negative predictive value to 98% and 90.9% respectively. Conclusion: There was a distinct advantage of measuring IMA in patients presenting to the emergency department with acute chest pain and LBBB to rule out a final diagnosis of ACS. PMID- 29622976 TI - Patients with non-obstructive coronary artery disease admitted with acute myocardial infarction carry a better outcome compared to those with obstructive coronary artery disease. AB - Background: The characterization of patients who have acute myocardial infarction (AMI) and insignificant coronary stenosis is unclear. Aim: The present study aimed to investigate the clinical profile, in-hospital and 3-month outcome of AMI patients with insignificant coronary stenosis in comparison with those with significant disease. Methods: This prospective observational study included 200 consecutive patients admitted with AMI. Group I (100 patients) included patients with insignificant CAD (all lesions <50% stenosis). Group II (100 patients) included patients with one or more lesions >70% stenosis. Patients with previous CABG were excluded. Patients with significant CAD had successful total revascularization. Results: Patients with insignificant CAD were significantly younger (61 vs. 67 years, p < 0.001), more likely to be females (41% vs. 23%, p = 0.006), less likely to smoke (p = 0.006), less likely to have diabetes mellitus (p < 0.001), and less likely to have history of CAD (p = 0.042) or prior PCI (p = 0.037). They were also less likely to have typical anginal pain at presentation (61% vs 91%, p < 0.001), less likely to have heart failure at presentation (9% vs 30%, p < 0.001), less likely to have ischemic ST-segment changes on presentation (10% vs 46%, p < 0.001), lower peak troponin (p < 0.001) and CK-MB levels (p < 0.001), with lower LDL-C (p = 0.006), and higher HDL-C level (p = 0.020). They were less likely to be treated with b-blockers (p = 0.002), ACEI/ARBS (p = 0.007), and higher rates of calcium channel blocker therapy (p < 0.001). They had lower prevalence of major adverse clinical events at follow-up (readmission for ACS (p = 0.009), need for revascularization (p = 0.035), recurrent chest pain (p = 0.009), and cardiogenic shock (p = 0.029). Conclusion: Patients with AMI and insignificant CAD have different clinical profile and outcome compared to those with significant disease. PMID- 29622977 TI - Clinical and laboratory characteristics of short-term mortality in Egyptian patients with acute heart failure. AB - Objective: To identify the clinical and laboratory predictors of short-term mortality in patients with acute heart failure (AHF). Subjects and methods: We conducted a prospective, single center study on 120 consecutive patients presented with acute heart failure to the emergency department. All patients had clinical, laboratory, electrocardiographic and echocardiographic evaluation. Short-term mortality was reported within 30 days of presentation. Results: Mean age was 59.29 +/- 10.1 years, 55.8% were males and 50.8% were smokers. The common AHF presentations were dyspnea (91.7%), chest tightness (62.5%) and lower limb edema (54.2%). Ischemic heart disease, diabetes and hypertension were present in 72.5%, 43.3% and 35% of patients, respectively.Short-term mortality was reported in 29 patients (24.16%); most of them died in-hospital (19 patients, 65.52%). The following parameters were significantly associated with short-term mortality: hypoxia (P < 0.001), tachycardia (P < 0.01), raised jugular venous pressure (JVP) (P < 0.001), low systolic blood pressure (P < 0.01), prolonged PR interval (P < 0.007), atrial fibrillation (AF) (P < 0.038), left bundle branch block (LBBB) (P < 0.04), impaired kidney function (P < 0.007), anemia (P < 0.029), hyponatremia (P < 0.006), hypoalbuminemia (P < 0.005), dilated left ventricle (LV) (P < 0.001), low LV ejection fraction (LVEF) (P < 0.001), and dilated left atrium (LA) (P < 0.002).ROC curve analysis showed that low LVEF (<=24%), dilated LV end diastolic diameter (LVESD) >= 66.5 mm, dilated LV end systolic diameter (LVESD) >= 53.5 mm, dilated LA diameter >= 48 mm, increased serum creatinine >= 1.6 mg/dl, and decreased serum albumin <= 3 g/dl can significantly predict short-term mortality in patients with acute heart failure. Conclusion: Variable clinical, laboratory, electrocardiographic and echocardiographic parameters were associated with short-term mortality. Our study showed that low LVEF, dilated LV diameter, dilated LA diameter, impaired kidney function and low serum albumin can predict short-term mortality in patients with acute heart failure. PMID- 29622978 TI - Obesity paradox in heart failure patients - Female gender characteristics-KAMC single center experience. AB - Background/Introduction: The correlation between low body mass index (BMI) and congestive heart failure (obesity paradox) has been described in the literature; However, the association between BMI and clinical outcome measures is not well characterized. Little is known about CHF in the Middle Eastern female population; most of the gender-specific information on heart failure comes from higher income "Western" countries. Objectives: We aimed to identify the correlation between heart failure patients especially those with low BMI and clinical/safety outcome measures with focusing on female patients subgroup characteristics. Methods: We performed group comparisons of statistically relevant variables using prospectively collected data of HFrEF patients hospitalized over a 12 month period. Results: The 167 patients (Group I) enrolled by this study with mean age of 59.64 +/- 12.9 years, an EF score of 23.96 +/- 10.14, 62.9% had ischemic etiology, 12.5% were smoker, 18% had AF, 31.1% had received ICD/CRT-D and an estimated 8.85 +/- 9.5 days length of stay (LOS). The low BMI group of patients (Group II) had means age of 58.7 +/- 14.5 years, a significant lower EF score of 20.32 +/- 8.58, significantly higher 30, 90 days readmission rates and in-house mortality (22%, 36.6% and 17.1% vs 10.2%, 20.4% and 6.6% respectively) and higher rates of CVA, TIA and unexplained syncope (19.5% vs 7.2%). Similarly, female patients with low BMI (Group IV) had lower EF score of 22.0 +/- 53, higher 30,90 days readmission rates and in-house mortality (34.4%,43.8% and 25% vs 13.5%,21.6% and 5.4% respectively) and higher rates of CVA, TIA and unexplained syncope(10% vs 0%). Conclusion: Our findings showed that heart failure patients with low BMI had poor adverse clinical outcome measures (poor EF, recurrent readmission, mortality and composite rates of CVA, TIA and unexplained syncope) which reflect the effect of obesity paradox in those patients with HFrEF. Female patient subgroup showed similar characteristic findings which also might reflect the value of gender-specific BMI related clinical outcomes. PMID- 29622979 TI - Anomalous origin of left main coronary artery from the right sinus of Valsalva presenting as non ST elevation acute coronary syndrome: A case report. AB - Congenital anomalies of the coronary arteries are a cause of sudden cardiac death. Of the known anatomic variants, anomalous origination of a coronary artery from an opposite sinus of Valsalva (ACAOS) remains a major clinical issue and a challenging condition to treat. Congenital coronary anomalies are likely to be under-recognized, as completing an anatomic assessment in a very large portion of the population would seem unfeasible. However, we present a case report with image of a 49 year old male presented with acute non-ST elevation ACS for which he underwent diagnostic angiography of the coronary system which revealed a common origin of both right and left main coronary artery from right sinus of Valsalva with significant obstructive lesion in the mid segment of right coronary artery. However, due to financial constraints CT angiography could not be done in this patient to identify the detail anatomy and the course of the anomalous left coronary artery origin (L-ACAOS). He was managed medically with dual antiplatelets, beta blockers, nitrates and ACE inhibitors. PMID- 29622980 TI - Successful pregnancies after transvenous cardiac resynchronization therapy in a woman with congenitally corrected transposition of the great arteries. AB - Congenitally corrected transposition of the great arteries is a rare heart defect that can be associated with systemic ventricular dysfunction and conduction disturbances. The use of cardiac resynchronization therapy in patients with congenital heart disease is not fully established, and achievement of successful pregnancies after implantation of transvenous, biventricular system has never been described, and which resulted in a significant clinical improvement. We describe a 33-year-old female with congenitally corrected transposition of the great arteries, who achieved six pregnancies and successful vaginal deliveries. The two last pregnancies were achieved after cardiac resynchronization therapy for systemic ventricular dysfunction and complete heart block. A congenital cardiac disease has been identified in only one offspring. PMID- 29622981 TI - Acute triggers of myocardial infarction: A case-crossover study. AB - Background: Acute myocardial infarction (AMI) is one of the most preventable non communicable diseases in human. Identifying triggers of myocardial infarction (MI) and prevention ways of exposure-induced complications can reduce morbidity and mortality in people at risk. Aim: The aim of this study was to identify the emotional, environmental, physical and chemical dimensions of acute triggers in patients with AMI. Methods: This case-crossover study was conducted on 269 patients with AMI, hospitalized at two remedial centers in Rasht in 2015. The study samples were selected by convenient sampling method. Data were collected using researcher-made questionnaire through interviews. Hazard and control periods for each trigger and its effects on the development of MI were studied. The collected data were analyzed using descriptive and analytical statistical methods, Cochran test, and generalized estimating equation (GEE) model with logistics function default in SPSS version 21, and p < 0.05 was considered statistically significant. Results: The results showed that quarrel (P = 0.008, OR = 2.01) and hearing the sudden news (P = 0.001, OR = 2.19) were the most common emotional triggers. Respiratory infections (P = 0.0001, OR = 6.78) and exposure to hot or cold weather (P = 0.005, OR = 2.19) were the most frequent environmental triggers. Doing heavy activities (P = 0.005, OR = 1.66) and sexual activities (P = 0.003, OR = 2.36) were among the most common physical triggers. High-fat foods consumption and overeating (P = 0.0001, OR = 3.79) were the most frequent chemical triggers of AMI. Conclusion: It seems that given the importance of the triggers in the incidence of AMI, planning is necessary to train vulnerable individuals to reduce exposure to triggers. PMID- 29622983 TI - Myocardial bridging as one of the causes of atypical chest pain in young women. AB - Introduction: Myocardial bridging is congenital anomaly which usually has benign prognosis but there are also reports suggesting that it can be associated with ischemic clinical syndromes presenting with chest pain. Coronary computed tomography angiography is a well-established method for detecting myocardial bridging. However, clinical significance of this anomaly still remains unclear. Methods: We studied 977 patients who presented with recurrent typical or atypical chest pain in outpatient clinic. All patients have undergone detailed clinical examination, ECG stress testing and coronary computed tomography angiography. Results: Highest positive prediction for having myocardial bridging was for patients presenting with atypical chest pain with negative ECG stress test and who were younger women. Conclusion: Coronary computed tomography angiography may be preferable method for evaluation of chest pain in younger women presenting with atypical chest pain. PMID- 29622982 TI - Cardiovascular disease and ABO blood-groups in Africans. Are blood-group A individuals at higher risk of ischemic disease?: A pilot study. AB - Background: Since the discovery of the ABO blood group system by Karl Landsteiner in 1901, several reports have suggested an important involvement of the ABO blood group system in the susceptibility to thrombosis. Assessing that non-O blood groups in particular A blood group confer a higher risk of venous and arterial thrombosis than group O.Epidemiologic data are typically not available for all racial and ethnics groups.The purpose of this pilot study was to identify a link between ABO blood group and ischemic disease (ID) in Africans, and to analyze whether A blood group individuals were at higher risk of ischemic disease or not. Methods: A total of 299 medical records of patients over a three-year period admitted to the cardiology and internal medicine department of military hospital of Ouakam in Senegal were reviewed. We studied data on age, gender, past history of hypertension, diabetes, smoking, sedentarism, obesity, hyperlipidemia, use of estrogen-progestin contraceptives and blood group distribution.In each blood group type, we evaluated the prevalence of ischemic and non-ischemic cardiovascular disease. The medical records were then stratified into two categories to evaluate incidence of ischemic disease: Group 1: Patients carrying blood-group A and Group 2: Patients carrying blood group non-A (O, AB and B). Results: Of the 299 patients whose medical records were reviewed, 92 (30.8%) were carrying blood group A, 175 (58.5%) had blood group O, 13 (4.3%) had blood group B, and 19 (6.4%) had blood group AB.The diagnosis of ischemic disease (ID) was higher in patients with blood group A (61.2%) than in other blood groups, and the diagnosis of non-ischemic disease (NID) was higher in patients with blood group O (73.6%) compared to other groups. In patients with blood group B or AB compared to non-B or non-AB, respectively there was no statistically significant difference in ID incidence.Main risk factor for ID was smoking (56.5%), hypertension (18.4%) and diabetes (14.3%).In our study, there was no statistical difference between blood group A and non-A in myocardial infarction (MI) incidence (p = 0.09, 95% CI = 0.99-2.83) but a statistically significant difference between blood group A and non-A in stroke and coronary artery disease (CAD) incidence (p < 0.0001, 95% CI = 1.80-3.37 and p < 0.0001 95% CI = 1.82-3.41 respectively) was found.The incidence of ID in men was significantly higher in blood group A (95% CI = 2.26-4.57, p < 0.0001) compared with non-A group, while there was no statistically significant difference in women (p = 0.35). However, an overall effect was detected to be statistically significant regardless of gender (p < 0.0001). Conclusion: Our study suggests an association between blood group A and ID in sub-Sahara Africans.In African countries, where most of health facilities are understaffed, more rigorous studies with a larger population are needed to give a high level of evidence to confirm this association in order to establish the need to be more aggressive in risk factor control in these individuals. PMID- 29622984 TI - Tricuspid valve repair with Dacron band versus DeVega or segmental annuloplasty. Hospital outcome and short term results. AB - Background: The purpose of this study was to compare the hospital outcome and short term results of tricuspid valve (TV) repair with three repair techniques for functional tricuspid regurgitation (TR), namely, flexible Dacron band, DeVega and segmental annuloplasty. Methods: A total of 60 patients underwent TV repair at National Heart Institute from January 2013 to November 2014, of which 20 had DeVega procedure (DV), 20 had a segmental annuloplasty (SA) procedure and 20 had a Dacron band (DB) procedure. Concomitant procedures done for rheumatic left sided valve pathology consisted of mitral valve replacement in 70% of patients, and double valve replacement in 30% of patients. Clinical and echocardiographic follow-up data were obtained. Follow-up was 100% complete and was concluded after one year. Results: All demographic criteria and preoperative characteristics of the three studied groups were comparable except for preoperative right ventricular (RVEDD) size that was significantly bigger in Dacron band group as compared to the other two groups (3.18 +/- 0.43 cm compared to 3.00 +/- 0.33 cm (DV) and to 2.88 +/- 0.35 cm (SA), p value of (0.045)). Similarly, all operative and postoperative criteria were comparable among the study groups. Noticeably, (RVEDD) size remodeled better postoperatively in (DB) group as compared to the other two groups, (2.54 +/- 0.26 cm compared to 2.83 +/- 0.311 cm (DV) and to 2.72 +/- 0.29 cm (SA), mean difference values were group (0.64 +/- 0.47 cm) for (DB) compared to (0.18 +/- 0.29 cm) for (DV) or to (0.16 +/- 0.45 cm) for (SA) with p value of 0.000. The majority of patients in each group did not have tricuspid regurgitation (TR) or mild degree (+1) of (TR) on discharge. After one year of follow-up, most of the patient had either no regurgitation or grade (+1 TR). Two patients (10%) in DV group and one patient (5%) in SA group had (+3 TR). There was no statistical significance in the incidence of hospital mortality, only one patient died in DB and one in DV group (5%) and no death happened after hospital mortality for the three groups after one year. Conclusions: The three techniques are options to repair the tricuspid valve, however, placement of Dacron band in patients undergoing tricuspid valve repair is associated with better RV remodelling, and hence, a probable better right ventricular performance and better outcome of repair is expected. A higher number of patients are needed with longer follow up period to appreciate the effect on survival and rate of freedom from tricuspid regurgitation and re-intervention. PMID- 29622985 TI - The value of three-dimensional color Doppler trans-esophageal echocardiography in predicting the number of MitraClip devices needed during the procedure. AB - Purpose: During MitraClip procedure, one or more clips might be needed to effectively reduce the mitral regurgitation (MR). Three-dimensional vena contracta (3D-VC) assessed by color Doppler three-dimensional trans-esophageal echocardiography (3D-TEE) was proven to be well correlated with MR severity. However, its role in predicting the number of MitraClip devices needed during the procedure was not fully determined. Aim of this study is to assess the predictive value of 3D-VC area & length in determining the number of clips needed during the procedure. Methods: 3D-TEE with color Doppler was performed in 20 patients ( age: 68.9 +/- 2.5 years; 65% males; with functional severe/moderately severe MR) who underwent successful MitraClip procedure (reduction of MR to <2+). Manual tracing and measurement of the 3D-VC area (3D-VCA) as well as the 3D-VC length (3D-VCL) was done. These values were compared between patients who received 1 clip (n = 4) and >= 2 clips (n = 16). Results: Patients who received >= 2 clips had larger 3D VC area compared to patients who received 1 clip (0.39 +/- 0.23 cm2 vs. 0.13 +/- 0.03 cm2, p = 0.04, t = 2.22) . Patients who received >= 2 clips had bigger 3D-VC length compared to patients who received 1 clip (1.14 +/- 0.33 cm vs. p = 0.005, t = 3.25 ). A cut-off values of 0.20 cm2 & 1 cm for the VCA & VCL respectively, are suggestive that the patient will most likely require more than one MitraClip device to treat his mitral regurgitation. Conclusions: The 3D-VCA & 3D-VCA using 3D TEE is helpful indetermining the number of MitraClip devices needed during the procedure in functional mitral regurgitation. PMID- 29622986 TI - Clinical utility of a predictive model for paravalvular aortic regurgitation after transcatheter aortic valve implantation with a self-expandable prosthesis. AB - Background: A predictive model for Paravalvular aortic regurgitation (PAR) integrating the left ventricular outflow tract-to-ascending aorta angle (LVOT-AO) and depth to the non-coronary cusp (NCC) after TAVI with CoreValve prosthesis (MCP) was retrospectively identified (2 * ?LVOT-AO + [depth to NCC-10]2; cutoff = 50). However, the validity and clinical utility of this model remain unknown. Methods: A total of 100 patients (79.6 +/- 7 years, mean EuroScore 24.9 +/- 16.3%, 41 males) constituted a validation cohort for the predictive model. Both angle (LVOT-AO) and depth to NCC were considered during patient selection and device implantation. Results: Significant AR occurred in 16% (group A) vs. 84% (group B). Angle ?LVOT-AO and depth to NCC were larger in group A compared to group B (16.4 +/- 7.2 vs. 11.8 +/- 4.1, p < 0.001, and 9.1 +/- 4.8 mm vs. 6.6 +/- 2.7 mm, p = 0.004). The model showed a sensitivity of 68.7% and a specificity of 88.1% in prediction of PAR. Comparing the derivation cohort (initial experience, n = 50) and validation cohort (later experience, n = 100) it is showed that the ?LVOT-AO, valve depth and PAR were significantly lower (12.5 +/- 4.9 and 6.9 +/- 3.2 mm vs. 19.7 +/- 7.9 and 10.4 +/- 3.7 mm, 40% vs. 16% respectively, all p < 0.001) in the validation cohort. Conclusion: The predictive model for significant PAR after TAVI using MCP is valid with a reassuring specificity and an acceptable sensitivity. A strategy incorporating these anatomical and procedural variables improves PAR after TAVI. PMID- 29622987 TI - Outcome of transcatheter aortic valve implantation in high risk patients with severe aortic stenosis. AB - Aim: To assess outcome of TAVI in high risk patients with severe symptomatic aortic stenosis. Patients and methods: 40 patients with symptomatic severe aortic stenosis and high risk underwent TAVI with implantation of either Sapien XT valve or Core Valve and followed for 6 months. Device success, cardiovascular mortality, myocardial infarction, stroke, life-threatening bleeding and vascular complications were defined according to Valve Academic Research Consortium definitions. Results: The study included 40 patients, their mean age was 73.98 +/ 8.40, procedural success was 97.5%. One patient need valve in valve due to moderately severe paravalvular leak. Total mortality was 7.5%, cardiovascular death occurred in 2.5% and non cardiovascular death occurred in 5%. Myocardial infarction occurred in one patient (2.5%), stroke occurred in 2 patients (5%), minor bleeding occurred in 6 patients (15%), major bleeding occurred in 3 patients (7.5%), minor vascular complications occurred in 4 patients (10%) while major vascular complications occurred in 3 patients (7.5%). Permanent pacemaker was inserted for 5 patients (12.5%), new onset AF occurred in 4 patients (10%). Re hospitalization was needed for 2 patients (5%) due to heart failure. After TAVI there were significant improvement in NYHA functional class (p < 0.001), mean LV ejection fraction and LV mass index (p < 0.001), mean aortic valve area, mean and peak pressure gradient (p < 0.001), severity of aortic and mitral regurgitation (p < 0.001). When comparing types of valves used, both were nearly comparable. Conclusion: TAVI is a safe and effective procedure in selected high risk patients with severe symptomatic aortic stenosis without significant difference between used valves. PMID- 29622988 TI - Outflow tract ventricular premature beats ablation in the presence or absence of structural heart disease: Technical considerations and clinical outcomes. AB - Background: Premature ventricular beats (PVBs) are early depolarization of the myocardium originating in the ventricle. In case of very frequent PVBs, patients are severely symptomatic with impaired quality of life and are at risk of pre syncope, syncope, heart failure, and sudden cardiac death particularly in the presence of structural heart disease. Ventricular outflow tracts are the most common sites of origin of idiopathic PVBs especially in patients without structural heart disease. We examined the role of radiofrequency catheter ablation in suppression of monomorphic PVBs of outflow tract origin in the presence or absence of structural heart disease, and its impact on improvement of left ventricular (LV) systolic function. Methods: Thirty-seven highly symptomatic patients with PVBs burden exceeding 10% were enrolled, provided that PVBs are monomorphic, originating in ventricular outflow tracts and regardless the presence or absence of structural heart disease. Patients were divided into 2 groups according to PVB site origin (RVOT vs. LVOT). 3D electro-anatomical mapping modalities were used in all patients employing activation mapping technique in the majority of cases. Acute success was considered when PVBs completely disappeared or when residual sporadic PVBs <= 1 beats/min or <=10 beats/30 min after RF ablation. Patients were followed up for a mean period of 5.4 +/- 1.2 months with long-term success defined as complete disappearance or marked reduction by more than 75% in the PVBs absolute number on 24 h holter monitoring. Results: Mean age of the study group was 39.9 +/- 12.97 years, including 22 (59.4%) males. PVBs originated in RVOT in 17 cases and in LVOT in the remaining 20 cases. Prevalence of structural heart disease and consequently shortness of breath was higher in LVOT group. Initial ECG localization matched EP localization in the majority (94%) of cases. R wave duration index was the only significant independent predictor for RVOT origin with cut off value of <0.3 (P = 0.0057) upon multivariate analysis. Acute success was encountered in 32 (86%) patients with all cases of failure in the LVOT group. Recurrence occurred in 5 (15%) cases without significant difference between both groups. All cases of recurrence had residual PVBs at the end of the procedure. 18 cases out of the study group showed significant improvement of their EF (>5%) at the end of the follow-up period with no significant differences between both groups (p = 0.09). A linear correlation was observed between PVBs burden at follow up and magnitude of improvement of LV EF, particularly in patients with resting LV dysfunction and increased LV internal dimensions. Conclusions: RF ablation is an effective and safe method for elimination of outflow tract PVBs irrespective of their origin and the presence or absence of structural heart disease. PVBs burden after ablation appears to be the main determinant for reversal of PVB induced myopathy particularly in those with increased LV internal dimensions. PMID- 29622989 TI - Echocardiographic predictors of atrial fibrillation after mitral valve replacement. AB - Objectives: Detection of the echocardiographic predictors of post-operative atrial fibrillation in patients with rheumatic mitral valve disease undergoing mitral valve replacement. Methods: The study included 50 patients with rheumatic mitral valve disease undergoing mitral valve replacement. Preoperative assessment included standard two-dimensional echocardiography to assess LA diameter, volume, and emptying fraction, LV volume and ejection fraction. TDI derived velocity, strain of the left atrium and speckle tracking to assess left ventricular function then postoperative follow up for 1 month for occurrence of atrial fibrillation. Results: The incidence of postoperative AF was 44%; these patients were significantly older (P = 0.001) and show higher prevalence of DM (P = 0.001) and HTN (P = 0.001). Also, LA diameters (antero-posterior, transverse and longitudinal) and LA volumes (maximal and minimal) were increased (P < 0.001), but no difference in LA emptying fraction (P > 0.05). Systolic LA strain and left ventricular global longitudinal strain were significantly reduced in those patients (P value <0.001). Echocardiographic predictors of AF were LA systolic strain (P value <0.001) and LV global longitudinal strain (P value = 0.003). Cutoff value for systolic LA strain <=23 had sensitivity 90.91% and specificity 93.33% in predicting POAF. While, left ventricular global longitudinal strain <= 14.9% had sensitivity 63.6% and specificity 100.0% in predicting AF. Conclusion: LA systolic strain and LV global longitudinal strain were significant predictors of POAF. Echocardiographic parameters can identify patients at greater risk of developing POAF who can benefit from preventive measure and guide the selection of prosthesis. PMID- 29622990 TI - Transradial artery approach in STEMI patients reperfused early and late by either primary PCI or pharmaco-invasive approach. AB - The purpose of the study was to investigate the safety and efficacy of transradial artery approach (TRA) in STEMI patients who reperfused early (<=3 h from symptoms onset) or late (>3 h from symptoms onset) by either PPCI or pharmaco-invasive strategy (PI), thrombolysis followed by CA. Therefore, a total 143 STEMI patients (who were presented within 12 h from symptoms onset or 12-24 h with an evidence of ongoing ischemia or suffered from an acute STEMI were randomized for either PI or PPCI. Eighty-two patients were assigned to PI arm while the rest assigned were to PPCI arm. Patients who were taken to a non-PCI capable hospital received streptokinase and were then transferred to our Hospital for CA. TRA was used in the catheterization laboratory for all patients. Each arm was divided according to reperfusion time into early and late subgroups. A primary endpoint was death, shock, congestive heart failure, or reinfarction up to 30 days. There was a non-significant difference regarding LVEF in both arms. Myocardium wall preservation was significant in the early PI arm (P = 0.023). TIMI flow had no discrepancy between both arms (P = 0.569). Mean procedural and fluoroscopic time were 35.1 +/- 6.1 and 6.3 +/- 0.9 min. There were no reported entry site complications. There was no difference in primary endpoint complications (P = 0.326) considering the different times of patients' reperfusion (early; P = 0.696 vs. late; P = 0.424). In conclusion, it is safe and effective to use TRA in STEMI patients who reperfused by either early or late PPCI or PI. We recommend PI for STEMI patients with delay presentation if PPCI is not available. PMID- 29622991 TI - Tissue characterization of non-culprit intermediate coronary lesions in non ST elevation acute coronary syndromes. AB - Background: Disruption of vulnerable plaques is the most common cause of acute coronary syndromes. Intravascular ultrasound facilitates cross-sectional imaging of coronary arteries. We aimed at using IVUS to investigate the morphology and tissue characteristics of atherosclerotic plaques of non-culprit intermediate coronary lesions in non-ST elevation ACS setting. Methods: IVUS assessment of sixty-one intermediate coronary lesions in twenty-eight patients with the diagnosis of Non ST elevation acute coronary syndromes. Ultrasound signals were obtained by an IVUS system using a 40-MHz catheter. Results: Mean age was 53.2 +/ 9.1 years. Males = 20 (71.4%). Smoking in 17 (60.7%), hypertension in 16 (57.1%), Dyslipidemia in 12 (42.9%) and DM in 8 (28.6%). Culprit vessels represent 42% of affected vessels. Sixty-one intermediate lesions were detected. Twenty-nine lesions in culprit vessels and thirty-two lesions in non-culprit vessels with higher lipidic content in lesions of culprit vessels (P < 0.001) while a higher calcific content in lesions of non-culprit vessels (P < 0.001). Higher calcific content of proximal more than distal lesions (P = 0.048). Negative remodeling in 55.7% of lesions. Conclusions: A higher lipidic content in lesions of culprit vessels, while the lesions of non-culprit vessels were more calcific. Higher calcific content of proximal more than distal lesions was defined as well. PMID- 29622993 TI - Stent boost enhancement compared to intravascular ultrasound in the evaluation of stent expansion in elective percutaneous coronary interventions. AB - Background: Stent underexpansion is a major risk factor for in-stent restenosis and acute in-stent thrombosis1Intravascular ultrasound (IVUS) is one of the standards for detection of stent underexpansion (de Feyter et al. 1999; Mintz et al., 2001). StentBoost (SB) enhancement allows an improved angiographic visualization of the stent (Koolen et al., 2005). Aim of work: Comparison of stent expansion by IVUS and SB enhancement and detection of value of SB to guide dilatation post stent deployment. Methodology: IVUS, SB enhancement and QCA were done in 30 patients admitted for elective stenting procedures .We compared measurements of mean +/-standard deviations of (Max SD, Min SD, Mean SD, stent symmetry index) using IVUS, SB and QCA after stent deployment and after postdilatation whenever necessary to optimize stent deployment. The Stent symmetry index was calculated [(maximum stent diameter minus minimum stent diameter) divided by maximum stent diameter]. Results: The Max SD was (3.45 +/- 0.62 vs 3.55 +/- 0.56 vs 2.97 +/- 0.59) by IVUS vs SB vs QCA respectively. Max SD was significantly higher by IVUS vs QCA (p .009) and between SB vs QCA (p .001) while there was nonsignificant difference between IVUS vs SB (p .53). The Min SD was (2.77 +/- 0.53 vs 2.58 +/- 0.56 vs 1.88 +/- 0.60) by IVUS vs SB vs QCA respectively. Min SD was significantly higher by IVUS vs QCA (p .001) and between SB vs QCA (p .001) while there was nonsignificant difference between IVUS vs SB (p .07). The stent symmetry index was (0.24 +/-0.09 vs 0.34 +/- 0.09 vs 0.14 +/ 0.27) by IVUS vs SB vs QCA respectively. It was significantly higher by IVUS vs QCA (p .001) and between SB vs QCA (p .001) while there was nonsignificant difference between IVUS vs SB (p .32). SB was positively correlated with IVUS measurements of Max SD (p < .0001 & r 0.74) and Min SD (p < .0001 & r 0.68). QCA was positively correlated with IVUS measurements of Max SD correlation (p < .0001 & r 0.69) and Min SD (p < .0001 & r 0.63). QCA was positively correlated with SB measurements of Max SD (p < .0001 & r 0.61) and Min SD (p .003 & r 0.49). Conclusions: StentBoost enhancement has superior correlations for stent expansion measured by IVUS when compared with QCA. SB enhancement improved stent visualization and identification of stent underexpansion to guide stent postdilatation. PMID- 29622992 TI - The degree of hair graying as an independent risk marker for coronary artery disease, a CT coronary angiography study. AB - Background: Cardiovascular disease is a leading cause of death worldwide. Aging is an unavoidable coronary risk factor and is associated with dermatological signs that could be a marker for increased coronary risk. We tested the hypothesis that hair graying as a visible marker of aging is associated with risk of coronary artery disease (CAD) independent of chronological age. Methods: This cross-sectional study included 545 males who underwent a computed tomography coronary angiography (CTCA) for suspicious of CAD, patients were divided into subgroups according to the percentage of gray/white hairs (Hair Whitening Score, HWS: 1-5) and to the absence or presence of CAD. Results: CAD was prevalent in 80% of our studied population, 255 (46.8%) had 3 vessels disease with mean age of 53.2 +/- 10.7 yrs. Hypertension, diabetes and dyslipidemia were more prevalent in CAD group (P = 0.001, P = 0.001, and P = 0.003, respectively). Patients with CAD had statistically significant higher HWS (32.1% vs 60.1%, p < 0.001) and significant coronary artery calcification (<0.001). Multivariate regression analysis showed that age (odds ratio (OR): 2.40, 95% confidence interval (CI): [1.31-4.39], p = 0.004), HWS (OR: 1.31, 95% CI: [1.09-1.57], p = 0.004), hypertension (OR: 1.63, 95% CI: [1.03-2.58], p = 0.036), and dyslipidemia (OR: 1.61, 95% CI: [1.02-2.54], p = 0.038) were independent predictors of the presence of atherosclerotic CAD, and only age (p < 0.001) was significantly associated with HWS. Conclusions: Higher HWS was associated with increased coronary artery calcification and risk of CAD independent of chronological age and other established cardiovascular risk factors. PMID- 29622994 TI - Cardiovascular risk of circulating endotoxin level in prevalent hemodialysis patients. AB - Background: Cardiovascular diseases (CVDs) are a major cause of morbidity and mortality in patients with end stage renal disease (ESRD). Circulating endotoxins may have toxic effect on myocardial functions and are speculated as pathogens of accelerated atherosclerosis and hemodialysis (HD) patients. Objective: We aimed to assess the possible relation between circulating endotoxin levels and left ventricular functions parameters, common carotid artery intimal media thickness (CIMT) in prevalent HD patients. Patients and Methods: Forty stable prevalent HD patients with mean age (47.97 +/- 14.42) year using regular conventional hemodialysis sessions in Ain shams university hemodialysis unit, Cairo, Egypt were randomly selected. Diabetics, congestive heart failure and those with history of myocardial infarction or coronary artery disease were excluded from the study. All patients were studied by CBC and routine chemistry, as well as hs CRP, Intact PTH, lipid profile and endotoxin level by ELISA before and after the HD session, Delta change of endotoxin (pre dialysis endotoxin-post dialysis endotoxin) was calculated, resting Doppler echocardiographic and carotid duplex. Results: Mean of Pre-HD session serum endotoxin level was (0.356 +/- 0.090) EU/mL and the mean of post -HD endotoxin levels was (0.367 +/- 0.110) EU/mL. Significant positive correlation between post dialysis endotoxin, MV E/A ratio and grades of left ventricular diastolic dysfunction (P < 0.05) and significant correlation between delta change in endotoxin and EF% (r = -0.36,P = 0.02). By stepwise linear regression analysis for determinants of MVE/A post -HD endotoxin level independently associated with MV E/A ratio (beta = 0.350, P = 0.027). We did not detect any significant correlation between CCA atherosclerosis and neither pre nor post- HD endotoxin level nor with delta change of pre and post HD endotoxin levels. Conclusion: Acute increase in post dialytic circulating endotoxin level in prevalent HD patients may be associated with both left ventricular systolic and diastolic dysfunction and that attempts to reduce endotoxin level may have a positive impact on cardiovascular complications in HD Patients. PMID- 29622995 TI - Increased arterial stiffness in rheumatoid arthritis and Its relation to disease activity: A cross sectional study. AB - Background: Rheumatoid arthritis (RA) is associated with elevated plasma level of inflammatory markers. Chronic inflammation is known to predispose to endothelial dysfunction and increased arterial stiffness, which is an important marker of subclinical atherosclerosis and increased cardiovascular risk. Objective: The aim is to test for the relationship between disease activity and arterial stiffness in RA patients. Methods: The study included 90 RA patients, at different grades of disease activity and 45 healthy subjects, as a control group. Patients were subjected to full history taking and clinical examination, laboratory investigations including serum lipid profile and high sensitivity CRP (hs-CRP) measurements and plain x-rays of hands and feet. Modified Larsen method was used as radiographic scoring method. Disease activity score (DAS 28) was used for assessment of disease activity. Transthoracic echocardiography was performed to detect aortic stiffness parameters. Duplex ultrasound imaging of both common carotid arteries was performed to measure carotid stiffness parameters. Results: The mean age of RA patients was 39.86 +/- 9.39 years and most of them (83.3%) were females. RA patients had higher carotid stiffness index compared to control group patients (8.57 +/- 4.83 vs 4.08 +/- 1.13, p < .001). Very poor correlation was found between DAS-28 and aortic (r = 0.1, p = .28) as well as carotid (r = 0.05, p = .7) stiffness indices. No statistically significant correlation was found between hs-CRP and aortic stiffness index (r = 0.64, p = .55). Disease duration was significantly correlated to intima-media thickness (p < .01) as well as with other carotid stiffness parameters. Age also show a statistically significant positive correlation with carotid stiffness parameters. Conclusion: RA is associated with increased arterial stiffness, a well-recognized marker of cardiovascular risk. This is attributed to the inflammatory nature of the disease. It seems that the most important factors determining stiffness are patients' age and duration of illness. PMID- 29622996 TI - Clinical profile, management and outcome of pulmonary embolism in Shahid Gangalal National Heart Centre, Kathmandu, Nepal. AB - Background and aims: Pulmonary embolism (PE) is associated with a significant mortality and morbidity. We aim to study clinical profile, management and outcome of PE at Shahid Gangalal National heart Centre, Kathmandu, Nepal. Methods: It was a retrprospective, single centre study, conducted from January 2015 to December 2016. Haemodynamics was used for risk Simplified, PESI score, predisposing factors, symptoms, clinical features at the time of admission, ECG features, echocardiogram, treatment received and the outcome were reviewed. Results: During the study period 23 cases of PE were admitted. Nine were males and 14 were females. Eleven patients were diagnosed as provoked PE. High risk PE was diagnosed in four patients, Non-high risk in 19 patients. The most common clinical presentation was shortness of breath. The most common finding in ECG is sinus tachycardia followed by ST-T changes in V1-V3. Eight patient had SPO2 less than 90%. Most of the patients had a normal chest radiograph. Echocardiography revealed dilated RA and RV in 20 patients.All high risk PE patients were thrombolyzed with streptokinase. All patients who were diagnosed as Non-high risk PE were treated with LMWH. All the patients were treated with oral anticoagulants. Mean hospital stay was 9.7 +/- 4.9 days. Two patients died during hospital stay. S-PESI score was 1.4 +/- 0.9 respectively. Mean warfarin dose at the time of discharge was 5.9 +/- 1.6 mg. Conclusion: PE is an under diagnosed clinical problem world over. Suspicion is the most important part to come to the diagnosis of PE. PMID- 29622998 TI - Double right coronary artery detected on coronary computed tomography angiography: A case report. AB - Double right coronary artery is a relatively rare coronary anomaly. In this case report we aim to increase awareness of the importance of recognizing such anomaly and a brief literature review of similar cases and possible high risk features. Computed Tomography is well recognized modality to detect coronary anomaly and in our case we demonstrated this as well. PMID- 29622997 TI - Bleeding and asymptomatic overdose in patients under Vitamin K antagonist therapy: Frequency and risk factors. AB - Background: Vitamin K antagonists are widely used in the treatment and prevention of thromboembolic disease. However, these drugs can cause serious side effects, especially bleeding. This study aims to evaluate frequency and risk factors of both bleeding and asymptomatic overdose in North African patients undergoing Vitamin K antagonist therapy. Methods: We performed a cross-sectional study in patients undergoing Vitamin K antagonist therapy. A statistical analysis has been conducted to identify overdose and bleeding risk factors by using chi-square test (p < .05). Results: One hundred and eleven patients were included. We recorded 14 cases of bleeding and 26 cases of asymptomatic overdose. Advanced age, poor adherence, concomitant use of paracetamol and history of previous bleeding are significant risk factors of over-anticoagulation. An INR value over 6 at admission, a high therapeutic target range for INR, concomitant use of acetylsalicylic acid, lack of information on overdose signs and measures to be taken in case of bleeding were identified as risk factors for bleeding. Conclusion: Most of the risk factors identified in our study seem to be related to patients lack of information and education. These results highlight the importance of creating a therapeutic patient education program. PMID- 29622999 TI - Long-term efficacy of drug-coated balloon for renal artery in-stent restenosis. PMID- 29623001 TI - Proceedings from the Digital Innovation in Mental Health Conference, London, 2017. AB - Aims and Scope: The conference aims were two-fold: (1) to explore how digital technology is implemented into personalized and/or group mental health interventions and (2) to promote digital equality through developing culturally sensitive ways of bringing technological innovation to disadvantaged groups. A broad scope of perspectives were welcomed and encouraged, from lived experience, academic, clinical, media, the arts, policy-making, tech innovation, and other perspectives. PMID- 29623000 TI - Lipidomic Profiling of Plasma and Erythrocytes From Septic Patients Reveals Potential Biomarker Candidates. AB - Background: Sepsis remains the primary cause of death from infection, despite advances in modern medicine. The identification of reliable diagnostic biomarkers for the early detection of this disease is critical and may reduce the mortality rate as it could allow early treatment. The purpose of this study was to describe the changes in the plasma and red cells blood lipidome profiling of patients diagnosed with sepsis and septic shock with the aim to identify potentially useful metabolic markers. Methods: Lipids from plasma and erythrocytes from septic patients (n = 20) and healthy controls (n = 20) were evaluated by electrospray ionization quadrupole time-of-flight mass spectrometry, and the fatty acid composition of the phospholipids fraction of erythrocytes was determined by gas chromatography. The data were treated with multivariate data analysis, including principal component analysis and (orthogonal) partial least squares discriminant analysis. Results: Potential biomarkers including lysophosphatidylcholines (lyso-PCs) and sphingomyelin (SMs) with specific fatty acid chains were identified. Both Lyso-PCs and SMs were downregulated, whereas the saturated and unsaturated phosphatidylcholines (PCs) were upregulated in the plasma and erythrocytes of septic patients. An increase in oleic acid (C18:1 n-9) accompanied by a decrease in the unsaturation index as well as in the levels on n 3 polyunsaturated fatty acids was observed in erythrocytes phospholipids patients as compared with healthy controls. Conclusions: These results suggest that lipidome profiling has great potential in discovering potential clinical biomarkers for sepsis and helping to understand its underlying mechanisms. PMID- 29623002 TI - The Role for Exosomal microRNAs in Disruption of Regulatory T Cell Homeostasis in Multiple Sclerosis. AB - Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, in which myelin and oligodendrocytes are the main targets recognized by inflammatory CD4+ T cells reactive to myelin peptides. Regulatory CD4+ T (Treg) cells normally keep homeostasis of the immune system by inhibiting detrimental effects of inflammatory T cells. However, Treg cells are reduced in patients with MS for unknown reason. This commentary highlights a novel function of circulating exosomes to inhibit the differentiation of Treg cells in MS. Our recent work has demonstrated that the circulating exosomes, a member of extracellular vesicles, of patients with MS exert this effect by transferring let-7i to naive CD4+ T cells. The transferred let-7i subsequently causes a decreased expression of insulin like growth factor 1 receptor (IGF1R) and transforming growth factor beta receptor 1 (TGFBR1), leading to the inhibition of Treg cell differentiation. Thus, extrinsic microRNAs transferred by exosomes might have an active role in triggering autoimmune diseases. We hypothesize that extracellular vesicles including exosomes can be a communication tool between the gut microbiota and the host immune system. Further research in this area will expand the knowledge about the precise mechanism of autoimmune diseases and can lead to a new therapeutic approach. PMID- 29623003 TI - The Diving Bell and the Butterfly Revisited: A Fatal Case of Locked-in Syndrome in a Man With Epstein-Barr Virus-Positive Diffuse Large B-Cell Lymphoma, Not Otherwise Specified. AB - Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) is a rare variant of DLBCL. The natural history of this subtype is poorly understood. Incomplete literature in the era of rituximab suggests that patients with EBV positive DLBCL have similar outcomes to patients with EBV-negative DLBCL when treated with rituximab and anthracycline-based chemotherapy regimens; however, there are few prospective studies on this subtype and little is known about the risk of central nervous system (CNS) relapse with EBV-positive DLBCL. Herein, we describe the case of a 64-year-old man who presented with stage IIA EBV-positive DLBCL. His international age-adjusted International Prognostic Index (IPI) was 2. He achieved a complete response to 6 cycles of rituximab combined with chemotherapy consisting of dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin. After 10 days of completion of chemotherapy, he had a fulminant neurologic decline manifested by diffuse weakness followed by a locked-in syndrome; he could only communicate by moving his eyes. He had been deemed at low risk for CNS relapse based on the application of the recently developed CNS-IPI score of 2 (1 point for age >60 years and 1 point for lactate dehydrogenase higher than normal) and consequently did not receive therapy for CNS prophylaxis. A limited postmortem autopsy revealed extensive lymphoma throughout the brain, particularly in the deep basal nuclei, midbrain, pons, centrum semiovale, and corpus callosum. This presentation of CNS relapse is rare and has not yet been described in EBV-positive DLBCL. We discuss some of the unique aspects of this case including the clinical manifestations of locked-in syndrome and its differential diagnosis and the uncertain benefits of CNS prophylaxis in this clinical context. PMID- 29623004 TI - Populations of doubled haploids for genetic mapping in hexaploid winter triticale. AB - To create a framework for genetic dissection of hexaploid triticale, six populations of doubled haploid (DH) lines were developed from pairwise hybrids of high-yielding winter triticale cultivars. The six populations comprise between 97 and 231 genotyped DH lines each, totaling 957 DH lines. A consensus genetic map spans 4593.9 cM is composed of 1576 unique DArT markers. The maps reveal several structural rearrangements in triticale genomes. In preliminary tests of the populations and maps, markers specific to wheat segments of the engineered rye chromosome 1R (RM1B) were identified. Example QTL mapping of days to heading in cv. Krakowiak revealed loci on chromosomes 2BL and 2R responsible for extended vernalization requirement, and candidate genes were identified. The material is available to all parties interested in triticale genetics. PMID- 29623005 TI - Challenges and Opportunities for Biological Mass Spectrometry Core Facilities in the Developing World. AB - The developing world is seeing rapid growth in the availability of biological mass spectrometry (MS), particularly through core facilities. As proteomics and metabolomics becomes locally feasible for investigators in these nations, application areas associated with high burden in these nations, such as infectious disease, will see greatly increased research output. This article evaluates the rapid growth of MS in South Africa (currently approaching 20 laboratories) as a model for establishing MS core facilities in other nations of the developing world. Facilities should emphasize new services rather than new instruments. The reduction of the delays associated with reagent and other supply acquisition would benefit both facilities and the users who make use of their services. Instrument maintenance and repair, often mediated by an in-country business for an international vendor, is also likely to operate on a slower schedule than in the wealthiest nations. A key challenge to facilities in the developing world is educating potential facility users in how best to design experiments for proteomics and metabolomics, what reagents are most likely to introduce problematic artifacts, and how to interpret results from the facility. Here, we summarize the experience of 6 different institutions to raise the level of biological MS available to researchers in South Africa. PMID- 29623006 TI - Development of a Membrane-Based Method for Isolation of Genomic DNA from Human Blood. AB - High quality and sufficient quantity of genomic DNA (gDNA) are the primary requisites of several molecular biologic applications, including clinical studies related to genetics, genomics, gene polymorphism, and DNA fingerprinting. Whole blood is the primary source of gDNA in most of the clinical investigations. Currently, commercial kits are primarily used to achieve these goals. However, the use of kits is limited by the cost and involvement of several centrifugal steps. Other methods reported are either laborious or do not produce high quality or quantity of gDNA or both. Here, we present the data on the development of a centrifugation-free, cost-effective, and user-friendly method for the isolation of human gDNA from the buffy coat of human blood that involves limited numbers of steps with about 15 min of hands-on time per sample. PMID- 29623007 TI - Integrated Emotion Processing in Infancy: Matching of Faces and Bodies. AB - Accurate assessment of emotion requires the coordination of information from different sources such as faces, bodies, and voices. Adults readily integrate facial and bodily emotions. However, not much is known about the developmental origin of this capacity. Using a familiarization paired-comparison procedure, 6.5 month-olds in the current experiments were familiarized to happy, angry, or sad emotions in faces or bodies and tested with the opposite image type portraying the familiar emotion paired with a novel emotion. Infants looked longer at the familiar emotion across faces and bodies (except when familiarized to angry images and tested on the happy/angry contrast). This matching occurred not only for emotions from different affective categories (happy, angry) but also within the negative affective category (angry, sad). Thus, 6.5-month-olds, like adults, integrate emotions from bodies and faces in a fairly sophisticated manner, suggesting rapid development of emotion processing early in life. PMID- 29623008 TI - Consolidating the Academic End of a Community-Based Participatory Research Venture to Address Health Disparities. AB - Although there is strong support for community engagement and community-based participatory research (CBPR) from public health entities, medical organizations, and major grant-funding institutions, such endeavors often face challenges within academic institutions. Fostering the interest, skills, and partnerships to undertake participatory research projects and truly impact the community requires an interdisciplinary team with the competencies and values to engage in this type of research. Discussed in this article is how a CBPR-focused team evolved at a southern university, with emphasis on the activities that supported group identity, contributed to its evolution, and positioned the group to speak with authority in promoting CBPR as a tool for addressing health disparities. PMID- 29623010 TI - Male circumcision and human immunodeficiency virus infection: An update on randomized controlled trials and molecular evidences. PMID- 29623009 TI - Multifunctional biomedical imaging in physiological and pathological conditions using a NIR-II probe. AB - Compared with imaging in the visible (400 - 650 nm) and near-infrared window I (NIR-I, 650 - 900 nm) regions, imaging in near-infrared window II (NIR-II, 1,000 1,700 nm) is a highly promising in vivo imaging modality with improved resolution and deeper tissue penetration. In this work, a small molecule NIR-II dye,5,5' (1H,5H-benzo[1,2-c:4,5-c'] bis[1,2,5]thiadiazole)-4,8-diyl)bis(N,N-bis(4-(3 ((tert-butyldimethylsilyl)oxy)propyl)phenyl) thiophen-2-amine), has been successfully encapsulated into phospholipid vesicles to prepare a probe CQS1000. Then this novel NIR-II probe has been studied for in vivo multifunctional biological imaging. Our results indicate that the NIR-II vesicle CQS1000 can noninvasively and dynamically visualize and monitor many physiological and pathological conditions of circulatory systems, including lymphatic drainage and routing, angiogenesis of tumor and vascular deformity such as arterial thrombus formation and ischemia with high spatial and temporal resolution. More importantly, by virtue of the favorable half-life of blood circulation of CQS1000, NIR-II imaging is capable of aiding us to accomplish precise resection of tumor such as osteosarcoma, and to accelerate the process of lymph nodes dissection to complete sentinel lymph node biopsy for better decision-making during the tumor surgery. Overall, CQS1000 is a highly promising NIR-II probe for multifunctional biomedical imaging in physiological and pathological conditions, surpassing traditional NIR-I imaging modality and pathologic assessments for clinical diagnosis and treatment. PMID- 29623012 TI - Comparison between faculty and students perspectives on the qualities of a good medical teacher: A cross-sectional study. AB - Objectives: This study aimed to explore faculty and students perceptions on the qualities of good medical teachers, and to determine whether the opinions of faculty and students differed. Methods: Two quantitative surveys were performed at Qassim University College of Medicine using a pretested self-administered questionnaire distributed to the faculty and students of the college. It captured their opinions about qualities and attributes of good teachers. Each item was measured on a 5-point Likert scale. Data were entered and analyzed using SPSS. Results: A total of 90 faculty and 356 students responded with a response rate of 64%. Overall scores on the performance and personality scales were similar between faculty and students. Faculty and students agreed that "organizes good lectures/use of audiovisual aids" and "expert on the subject/knowledgeable" are important attributes and that telling jokes and the sense of humor or sharing personal experiences are not as important. Students felt it is important for an educator to be respectful, good planner and examiner, whereas faculty members felt that communication skills are of high importance. Conclusion: Faculty development programs should be designed to help faculty develop and improve on the identified qualities. PMID- 29623011 TI - Assessment of oral and dental health status in children with cerebral palsy: An exploratory study. AB - Objectives: Evaluating oral and dental health status in Egyptian children with cerebral palsy (CP) in relation to gross motor skills and types of CP. Methods: A Cross-sectional study was conducted at el-Shatby Hospital for Children, Alexandria-Egypt. Oral examination for 62 children with CP between the age ranges 3-12 years was performed and decay missing filling-tooth/decay filling-tooth (DMFT/dft), simplified oral hygiene index (OHI-S), and modified gingival index (MGI) indices were charted. Maxillofacial defects, dental problems and drooling of saliva were assessed. Children's CP type, motor milestone, and gross motor skills were determined. All statistical analyses were performed at P < 0.05 and 0.01. Results: About 84.0% of children had spastic quadriplegia, 41.9% were sit supported, 32.3% had Level IV gross motor function classification system (GMFCS), and 29.0% had Level V. No maxillofacial defects, 14.5% had dentine exposure >1/3 of the surface, and 22.6% had frequent/severe drooling saliva. Caries prevalence comprised 54.8%, 53.2% had poor oral hygiene (OHI-S index), and 43.6% had severe gingival inflammation (MGI index). The first best predictor variable for dft was "Motor Milestone." GMFCS (Level IV and V) was the first best predictor variable for DMFT, OHI-S, and MGI indices. Conclusion: The majority of children had dental caries, poor oral hygiene, and severe gingival inflammation. Children who were sit supported had no neck support and stand supported were suffering from dental caries (dft) more than children who were sitting and walking alone. Children with Levels IV/V GMFCS were prone to have dental caries (DMFT), susceptible to suffer from bad oral hygiene, and older children experiencing severe gingivitis more than younger ones. PMID- 29623013 TI - Human leukocyte antigens-DRB1*03 is associated with systemic lupus erythematosus and anti-SSB production in South Tunisia. AB - Introduction: Systemic lupus erythematosus (SLE) is an autoimmune disease with various presentations. This variation is due to the interaction of hormonal, environmental, and genetic factors. Associations between human leukocyte antigens and SLE have long been recognized in different ethnic populations and have been suggested to represent the most important association. Objectives: The objectives of this paper were to determine susceptibility and protection human leukocyte antigens (HLA) Class II markers for SLE and to highlight, for the first time, associations between HLA alleles and clinical and serological features in South Tunisia. Methods: We conducted a case-control study on 75 SLE patients and 123 healthy controls. The HLA Class II DRB1/DQB1 of all patients and controls was genotyped using polymerase chain reaction-sequence specific primer technique. Statistical analysis was performed using SPSS software. Results: HLA-DRB1*03 was the principal Class II allele associated with the genetic susceptibility to SLE (pc = 0.02; OR = 2.57; CI = [1.39-4.75]; this allele was also associated with anti-SSB production (P = 0.016; OR = 4.00; CI = [1.24-12.96]). HLA-DRB1*01 was significantly more expressed in SLE patients with neurologic disorders (P = 0.013; OR = 20.25; CI = [1.87-219.21]). No allele was found to be protective against SLE in our study group. Conclusion: Our results show that in South Tunisia SLE is associated with HLA-DRB1*03 and that some clinical features of SLE may be influenced by specific DRB1 and DQB1 alleles. PMID- 29623014 TI - Genetic alterations and PIK3CA gene mutations and amplifications analysis in cervical cancer by racial groups in the United States. AB - Introduction: A number of studies indicated racial differences in cervical cancer outcomes and several factors are associated with it such as stage, comorbidities, treatment pattern, and socioeconomic status. However, the associations of tumor genomic patterns such as phosphatidylinositol 3-kinase catalytic subunit alpha (PIK3CA) gene mutations and amplifications with cervical cancer racial disparities are largely unexplored. Objectives: Therefore, the present investigation aimed to identify genetic alterations (mutations and copy number variations) in cervical cancer and determine whether the PIK3CA gene mutations and amplifications in cervical cancer differ across racial/ethnic groups in the United States. Methods: This study made use of The Cancer Genome Atlas (TCGA) database. TCGA database is a publicly available database that was created by a joint effort between the National Cancer Institute and the National Human Genome Research Institute. The two-tailed Fisher's exact test was used to test for associations between the categorical variables, race, and PIK3CA gene mutation as well as PIK3CA gene amplification using the "Fisher test" function in R. Results: There were 309 cervical cancer samples, and of these, 194 samples had gene mutations and 295 samples had copy number alteration data. The top five mutated genes in TCGA dataset were PIK3CA, MUC4, KMT2C, SYNE1, and KMT2D. The top five amplified genes in TCGA dataset were MECOM, TP63, PRKCI, PIK3CA, and TRFC. The PIK3CA gene had the highest number of mutations with 53 mutation counts. The mutation rates were 62.5%, 31.3%, 25.4%, and 21.1% for American Indian, African American, White, and Asian, respectively. The amplification rates were 28.6%, 21.1%, 18.9%, and 12.5% for African American, Asian, White, and American Indian. Conclusions: There are many significantly mutated or amplified genes implicated in cervical cancer. Some of them are not grouped with the already known genes in relation to cervical cancer. For example, the KMT2C, SYNE1, KMT2D, EP300, RYR2, FLG, DMD, FBXW, MECOM, TRFC, RPL35A, LPP, TBL, FGF12, and SOX2 genes. They can be explored as therapeutic targets to improve cervical cancer treatment. PMID- 29623016 TI - Evaluation of diabetes care management in primary clinics based on the guidelines of American Diabetes Association. AB - Objective: There is a rapid increase in the incidence of diabetes mellitus in Saudi Arabia. Diabetes management is an essential constituent to prevent prognosis of diabetes complications. The main objective of this study was to assess diabetes care in primary clinics based on the guidelines of American Diabetes Association (ADA). Methods: A retrospective study at King Khaled University Hospitals, Riyadh, Saudi Arabia. A total of 200 patients were randomly selected from the databases of primary care clinics. An evaluation checklist was created based on the ADA treatment guidelines such as medical history, physical examination, laboratory evaluation, and referrals. Results: The result showed that elements achieving the ADA targets for overall care were medical history (44.9%), physical examination (59.6%), laboratory evaluation (36.3%), and referrals (19.3%). The other subelement indicators such as referral to diabetes self-management education clinics (10%), dental examination (2%), HbA1c regular monitoring (33.5%), and blood pressure determination (100%) were documented with adherence to ADA standards. Conclusions: Diabetes management standards are an essential element in the success of the management plan. Most of the elements examined are not in full compliance with the ADA standard. Continues monitoring and self-review are recommended. PMID- 29623015 TI - Association between Vitamin D deficiency and psoriasis: An exploratory study. AB - Introduction: Deficiency of Vitamin D is a widespread problem. Vitamin D could have important immune modulatory effects in psoriasis. Objective: Aimed to review and endeavored to establish the relationship, if any, between deficiency of Vitamin D and psoriasis. Methods: Leading studies that examined the relationship between deficiency of Vitamin D and psoriasis were reviewed from July2016 to October 2016. An electronic published work search was performed using PubMed, Ovid MEDLINE, Google Scholar, and Saudi Digital Library. Results: A total of 2132 eligible articles were identified by the electronic search. The titles and abstracts of 954 articles fulfilled the criteria of midline search. 20 articles were included after application of inclusion standards and full-text review. These 20 studies included 2046 psoriatic patients with or without arthritis and 6508 healthy controls. 14 studies show a positive correlation between Vitamin D deficiency and psoriasis. These 14 studies included 1249 psoriatic patients with or without arthritis and 680 healthy controls. Remaining six studies, including 797 psoriatic patients with or without arthritis and 5828 healthy controls do not depict a positive correlation between the two variables under study. Conclusion: There exists a correlation of psoriasis with deficiency of Vitamin D. However, there is a need for larger scale case-control studies to assess how far Vitamin D deficiency plays a role in psoriasis. PMID- 29623017 TI - Rising incidence of obesity in Saudi residents. A threatening challenge for the surgeons. AB - Objective: Obesity is thought to correlate very strongly with individuals general lifestyles. This study was conducted to determine whether lifestyle patterns were potential risk factors for morbid obesity in Saudi residents. Methods: This descriptive cross-sectional study was conducted in Unaizah City, Qassim Region, Kingdom of Saudi Arabia, over a 1-year period from March 2013 to March 2014. The study included 646 residents from the general public of Unaizah who were selected by convenient sampling at a mall and a public sector university, regardless of age and gender, and were given questionnaires regarding the details of their lifestyle patterns. The studied variables included demographic details, dietary habits, physical activity, occupation, body mass index, and unhealthy behavioral habits. The data were collected and statistically analyzed using SPSS version 20. Results: The study population had a mean age of 30.13 +/- 12.15 years and comprised 202 (31.3%) male and 444 (68.7%) female subjects. The study subjects were students (39.2%), general public included employed (35.3%), unemployed (23.8%), and others (1.7%). Overall, 79.4% comprised Saudi nationals and the majority (48.3%) had a university-level education. A reasonably high proportion of Saudi subjects were found to have sedentary habits and with physical activity levels far below the standard. Obesity was found in 42% of the study population with low physical activity levels and unhealthy dietary habits. Varying proportions of concomitant hypertension, hyperglycemia, and hypercholesterolemia were also observed in these subjects. Conclusion: Sedentary habits, low physical activity levels in younger populations, and unhealthy dietary habits are major factors causing obesity in the general public as well as in children and adolescents attending school and university. Serious insight into this problem at the governmental level is needed to improve the overall activity level and avoidance of a sedentary lifestyle by projecting the importance of a healthy lifestyle. PMID- 29623018 TI - Links between employment-related factors and physical and mental health among uninsured expatriate males in Saudi Arabia. AB - Objectives: The objectives were to determine whether employment-related factors had influence on physical and mental health outcomes among uninsured expatriates working in Saudi Arabia and to identify whether these factors act as facilitators or barriers to health. Methods: Cross-sectional face-to-face interviewsusing previously published methodswere conducted among a multistage stratified cluster sample of 1370 employees as their problemsin seeking health benefits have notbeen studied. Male expatriates working in different companies representing several trades in Riyadh were selected, for which tested questionnaires were administered to them. Results: Among 1370 uninsured expatriates, across various tested independent variables, age and income level were having most prominent influences on self-rated perceptions of physical and mental health. Uninsured expatriates with 60 plus age group have 71% more chances ofdeteriorating physical and mental health as compared to their younger age group uninsured expatriates. The expatriates earning less than SR 2000 had 68% more chances ofhaving poor physical and mental health as compared to their counterparts earning more than SR 6000, indicating more adverse outcomes among people in low-income categories. 74% of the expatriates having maximum education were found to have better physical and emotional outcomes than the less educated ones. Conclusion: The present study provides useful insights into the complex health-care system in Saudi Arabia and contributes to the exploration of health behaviors and the shaping of health perceptions among expatriates. PMID- 29623019 TI - Clinical presentation of atrial myxomas does it differ in left or right sided tumor? AB - Objective: This paper reports a 20 years' experience in the management of atrial myxomas at our institution. Apart from presenting our experience of their clinical presentation, surgical management, post-operative complication, and long term follow-up we investigated any correlation between left and right sided tumor with their symptom of presentation. Materials and Methods: The data were retrospectively collected for patients between the period 1995 and 2015 from the hospital database. The follow-up was conducted by questionnaire received from the patients describing their current status. Results: Fifty four consecutive patients underwent surgical resection for atrial myxomas. The mean age was 62 years (standard deviation [SD]: +/-14 years) with a larger number of female (55.5%) patients. The most common location for the tumor was the left atrium (70.3%) with the atrial septum being the most common (63%) site of attachment. The tumors presented in a variety of ways, namely, as shortness of breath (37.03%), transient ischemic attack (24.07%), and chest pains (22.2%) being the more common modes of presentation. Left heart tumors presented 6 years earlier with more severe shortness of breath as compared to right-sided tumors. Post operative atrial fibrillation occurred in 22.2% of patients. Concomitant surgical procedures were required in 26% of patient. The median length of post-operative hospital stay was 6 days (IQR: 5; 9). There were 2 (3.7%) in-hospital mortalities and 4 (7.4%) later deaths at 2, 3, 7, and 15 years, respectively. Long-term follow-up actuarial Kaplan-Meire survival for the whole group was 92.6 +/- 3.6% at 20 years with a significant reduction in the severity of shortness of breath. Conclusion: Cardiac myxoma is the most common form of the cardiac tumor with a slight female preponderance. Left-sided tumors present earlier than right-sided tumors with more severe shortness of breath. Excellent long-term results can be achieved with surgical intervention for cardiac myxomas, including any concomitant interventions. In particular, a sustained reduction in shortness of breath is observed. PMID- 29623020 TI - Atrial fibrillation among adult Saudi patients with chronic heart failure: Tertiary center experience. AB - Objective: To estimate the rate of atrial fibrillation (AF) among adult patients with chronic heart failure (HF) from Saudi Arabia, and to identify the clinical and the demographic characteristics. Methods: This study was performed using all medical records of patients registered in Prince Sultan Cardiac Center in Qassim, Saudi Arabia, and diagnosed with HF during the period from January 1, 2010 to June 30, 2014. The review process included patients diagnosed with chronic HF who were registered for follow-up during the study period. The rate of AF was calculated, and the associated risk factors were determined. Results: The rate of AF among chronic HF (n = 70) patients was 14.9%. The rate of AF was higher among males (15.7%) than females (12.5%). In both genders, the rate of AF rose with advancing age, and in each age stratum, it was higher in males than females. The rate of AF was higher if chronic HF was associated with chronic diseases, such as diabetes mellitus (DM, 14.3%), hypertension (HTN, 20%), and none of the patients had a history of chronic kidney disease. Conclusion: The rate of AF with chronic HF is high among Saudi Arabia patients. It is higher among male patients and HTN and DM patients. PMID- 29623021 TI - Biochemical aspects of mammalian melanocytes and the emerging role of melanocyte stem cells in dermatological therapies. AB - Skin color in animals is richer than human beings and is determined by different types of pigments. Melanin is the key pigment responsible for the diverse pigmentation found in animal and human skin, hair, and eyes. Melanin pigment is synthesized by melanocytes and is consecutively transferred to adjacent keratinocytes; here, it acts as an internal sunscreen to defend from ultraviolet (UV) damage. Any defect in the process of melanocytes development and/or melanin synthesis results in esthetic problem of abnormal pigmentation. Clinically, abnormal pigmentation displays distinct increased or reduced pigment levels, known as hyperpigmentation or hypopigmentation. These defects affect either the melanocyte number or its function. Herein, we discuss the fundamental aspects of melanocytes/melanin biology taken together the underlying cause of pigmentary disorders. The current chapter also gives an insight into the melanocyte stem cells biology, which in turn can facilitate the development of novel treatment regimens for dermatological disorders. PMID- 29623022 TI - Overview of dengue and Zika virus similarity, what can we learn from the Saudi experience with dengue fever? AB - There is high public health alert in the Kingdom of Saudi Arabia concerning Zika virus infection. So far, there is no reported outbreak. So are we at risk of this disease? Reviewing the literature of recent outbreaks of other infectious diseases in Saudi Arabia may clarify the situation. It is evident that there is some similarity between Zika and dengue regarding vector (Aedes aegypti) which is available in the Kingdom of Saudi Arabia. Furthermore, they have similar transmission process and the required environment for infection. It seems that the Kingdom has learned from previous outbreaks, so they are well prepared to face such challenges. The Saudi Ministry of Health built the command and control center to deal with the pandemic flues. Furthermore, they are trying to create a center for disease control, and they are recruiting local and international experts in monitoring the emerging infections. PMID- 29623023 TI - A case report of gustatory rhinorrhea after maxillectomy performed for squamous cell carcinoma. AB - A case of 75-year-old male presented with gustatory rhinorrhea for 3 months. Patient has positive history of maxillectomy performed 4 years back for squamous cell carcinoma of maxilla. PMID- 29623024 TI - Accessory scrotum and congenital perineal lipoma in a child with type 2 congenital pulmonary airway malformation: A report of an unusual. AB - Accessory scrotum and congenital perineal lipoma are unusual congenital anomalies. Congenital pulmonary airway malformation (CPAM) is a rare congenital disorder of the lung. There are five types of CPAM, each with a different clinical presentation and prognosis. The present report involves a case of type 2 CPAM associated with accessory scrotum and congenital perianal lipoma. PMID- 29623026 TI - The Association of Tau With Mitochondrial Dysfunction in Alzheimer's Disease. AB - Increasing evidence suggests that abnormally hyperphosphorylated tau plays a vital role in the pathogenesis of Alzheimer's disease (AD). Mitochondrial dysfunction also has a recognized role in the pathophysiology of AD. In recent years, mitochondrial dysfunction has been strongly associated with tau pathology in AD. Overexpression of hyperphosphorylated and aggregated tau appears to damage the axonal transport, leading to abnormal mitochondrial distribution. In addition, pathological tau impairs mitochondrial dynamics by regulating mitochondrial fission/fusion proteins, and further causes mitochondrial dysfunction and neuronal damage. Moreover, mitochondrial dysfunction is also involved in promoting tau pathology in AD. In this article, we evaluate the relationship between phosphorylated tau and mitochondrial dysfunction in AD. PMID- 29623025 TI - Impact of Powered Knee-Ankle Prosthesis on Low Back Muscle Mechanics in Transfemoral Amputees: A Case Series. AB - Regular use of prostheses is critical for individuals with lower limb amputations to achieve everyday mobility, maintain physical and physiological health, and achieve a better quality of life. Use of prostheses is influenced by numerous factors, with prosthetic design playing a critical role in facilitating mobility for an amputee. Thus, prostheses design can either promote biomechanically efficient or inefficient gait behavior. In addition to increased energy expenditure, inefficient gait behavior can expose prosthetic user to an increased risk of secondary musculoskeletal injuries and may eventually lead to rejection of the prosthesis. Consequently, researchers have utilized the technological advancements in various fields to improve prosthetic devices and customize them for user specific needs. One evolving technology is powered prosthetic components. Presently, an active area in lower limb prosthetic research is the design of novel controllers and components in order to enable the users of such powered devices to be able to reproduce gait biomechanics that are similar in behavior to a healthy limb. In this case series, we studied the impact of using a powered knee-ankle prostheses (PKA) on two transfemoral amputees who currently use advanced microprocessor controlled knee prostheses (MPK). We utilized outcomes pertaining to kinematics, kinetics, metabolics, and functional activities of daily living to compare the efficacy between the MPK and PKA devices. Our results suggests that the PKA allows the participants to walk with gait kinematics similar to normal gait patterns observed in a healthy limb. Additionally, it was observed that use of the PKA reduced the level of asymmetry in terms of mechanical loading and muscle activation, specifically in the low back spinae regions and lower extremity muscles. Further, the PKA allowed the participants to achieve a greater range of cadence than their predicate MPK, thus allowing them to safely ambulate in variable environments and dynamically control speed changes. Based on the results of this case series, it appears that there is considerable potential for powered prosthetic components to provide safe and efficient gait for individuals with above the knee amputation. PMID- 29623027 TI - Preclinical to Clinical Translation of Studies of Transcranial Direct-Current Stimulation in the Treatment of Epilepsy: A Systematic Review. AB - Epilepsy is a chronic brain syndrome characterized by recurrent seizures resulting from excessive neuronal discharges. Despite the development of various new antiepileptic drugs, many patients are refractory to treatment and report side effects. Non-invasive methods of brain stimulation, such as transcranial direct current stimulation (tDCS), have been tested as alternative approaches to directly modulate the excitability of epileptogenic neural circuits. Although some pilot and initial clinical studies have shown positive results, there is still uncertainty regarding the next steps of investigation in this field. Therefore, we reviewed preclinical and clinical studies using the following framework: (1) preclinical studies that have been successfully translated to clinical studies, (2) preclinical studies that have failed to be translated to clinical studies, and (3) clinical findings that were not previously tested in preclinical studies. We searched PubMed, Web of Science, Embase, and SciELO (2002 2017) using the keywords "tDCS," "epilepsy," "clinical trials," and "animal models." Our initial search resulted in 64 articles. After applying inclusion and exclusion criteria, we screened 17 full-text articles to extract findings about the efficacy of tDCS, with respect to the therapeutic framework used and the resulting reduction in seizures and epileptiform patterns. We found that few preclinical findings have been translated into clinical research (number of sessions and effects on seizure frequency) and that most findings have not been tested clinically (effects of tDCS on status epilepticus and absence epilepsy, neuroprotective effects in the hippocampus, and combined use with specific medications). Finally, considering that clinical studies on tDCS have been conducted for several epileptic syndromes, most were not previously tested in preclinical studies (Rasmussen's encephalitis, drug resistant epilepsy, and hippocampal sclerosis-induced epilepsy). Overall, most studies report positive findings. However, it is important to underscore that a successful preclinical study may not indicate success in a clinical study, considering the differences highlighted herein. Although most studies report significant findings, there are still important insights from preclinical work that must be tested clinically. Understanding these factors may improve the evidence for the potential use of this technique as a clinical tool in the treatment of epilepsy. PMID- 29623029 TI - Hypersensitivity of Prelimbic Cortex Neurons Contributes to Aggravated Nociceptive Responses in Rats With Experience of Chronic Inflammatory Pain. AB - Previous experience of chronic pain causes enhanced responses to upcoming noxious events in both humans and animals, but the underlying mechanisms remain unclear. In the present study, we found that rats with complete Freund's adjuvant (CFA) induced chronic inflammatory pain experience exhibited aggravated pain responses to later formalin test. Enhanced neuronal activation upon formalin assaults and increased phosphorylated cAMP-response element binding protein (CREB) were observed in the prelimbic cortex (PL) of rats with chronic inflammatory pain experience, and inhibiting PL neuronal activities reversed the aggravated pain. Inflammatory pain experience induced persistent p38 mitogen-activated protein kinase (MAPK; p38) but not extracellular regulated protein kinase (ERK) or c-Jun N-terminal kinase (JNK) hyperphosphorylation in the PL. Inhibiting the p38 phosphorylation in PL reversed the aggravated nociceptive responses to formalin test and down-regulated enhanced phosphorylated CREB in the PL. Chemogenetics identified PL-periaqueductal gray (PAG) but not PL-nucleus accumbens (NAc) as a key pathway in inducing the aggravated formalin pain. Our results demonstrate that persistent hyperphosphorylation of p38 in the PL underlies aggravated nociceptive responses in rats with chronic inflammatory pain experience. PMID- 29623031 TI - TAR DNA Binding Protein-43 Loss of Function Induced by Phosphorylation at S409/410 Blocks Autophagic Flux and Participates in Secondary Brain Injury After Intracerebral Hemorrhage. AB - This study aimed to determine the role of TAR DNA binding protein-43 (TDP-43) in intracerebral hemorrhage (ICH)-induced secondary brain injury (SBI) and its underlying mechanisms. After ICH, expression of TDP-43 in the nucleus was significantly decreased, and its expression in the cytoplasm increased both in vivo and in vitro, which indicates that TDP-43 translocates from the nucleus to the cytoplasm during SBI after ICH. In addition, mutations at S409/410 of TDP-43 could inhibit its phosphorylation, attenuate nuclear loss, and abolish the increase in neuronal apoptosis in the subcortex. Inhibition of TDP-43 phosphorylation attenuated ICH-induced downregulation of mTOR activity and dynactin1 expression, which may relieve blocking of autophagosome-lysosome fusion and the increase of autophagosomal and lysosomal biogenesis induced by ICH. However, knockdown of TDP-43 could worsen ICH-induced SBI. Furthermore, TDP-43 could be dephosphorylated by calcineurin (CN), and CN activity was increased by OxyHb treatment. In conclusion, this study demonstrated that TDP-43 loss-of function by phosphorylation at S409/410 may block autophagosome-lysosome fusion and induce elevation of LC3II and p62 levels by inhibiting the activity of mTOR and expression of dynactin1. This mechanism may play an important role in ICH induced SBI, and TDP-43 may be a potential therapeutic target. PMID- 29623032 TI - Cryopreservation of Primary Mouse Neurons: The Benefit of Neurostore Cryoprotective Medium. AB - Primary neuronal culture from rodents is a well-established model to investigate cellular neurobiology in vitro. However, for this purpose cell cultures need to be generated expressly, requiring extensive animal handling. Furthermore, often the preparation of fresh culture generates an excess of cells that are ultimately wasted. Therefore the ability to successfully cryopreserve primary neural cells would represent an important resource for neuroscience research and would allow to significantly reduce the sacrifice of animals. We describe here a novel freezing medium that allows long-term cryopreservation of primary mouse neurons prepared from E15.5 embryos. Combining imaging, biochemical and electrophysiological analyses, we found that cryopreserved cultures are viable and mature regarding morphology and functionality. These findings suggest that cryopreserved neurons are a valuable alternative to acutely dissociated neural cultures. PMID- 29623030 TI - On the Role of Store-Operated Calcium Entry in Acute and Chronic Neurodegenerative Diseases. AB - In both excitable and non-excitable cells, calcium (Ca2+) signals are maintained by a highly integrated process involving store-operated Ca2+ entry (SOCE), namely the opening of plasma membrane (PM) Ca2+ channels following the release of Ca2+ from intracellular stores. Upon depletion of Ca2+ store, the stromal interaction molecule (STIM) senses Ca2+ level reduction and migrates from endoplasmic reticulum (ER)-like sites to the PM where it activates the channel proteins Orai and/or the transient receptor potential channels (TRPC) prompting Ca2+ refilling. Accumulating evidence suggests that SOCE dysregulation may trigger perturbation of intracellular Ca2+ signaling in neurons, glia or hematopoietic cells, thus participating to the pathogenesis of diverse neurodegenerative diseases. Under acute conditions, such as ischemic stroke, neuronal SOCE can either re-establish Ca2+ homeostasis or mediate Ca2+ overload, thus providing a non-excitotoxic mechanism of ischemic neuronal death. The dualistic role of SOCE in brain ischemia is further underscored by the evidence that it also participates to endothelial restoration and to the stabilization of intravascular thrombi. In Parkinson's disease (PD) models, loss of SOCE triggers ER stress and dysfunction/degeneration of dopaminergic neurons. Disruption of neuronal SOCE also underlies Alzheimer's disease (AD) pathogenesis, since both in genetic mouse models and in human sporadic AD brain samples, reduced SOCE contributes to synaptic loss and cognitive decline. Unlike the AD setting, in the striatum from Huntington's disease (HD) transgenic mice, an increased STIM2 expression causes elevated synaptic SOCE that was suggested to underlie synaptic loss in medium spiny neurons. Thus, pharmacological inhibition of SOCE is beneficial to synapse maintenance in HD models, whereas the same approach may be anticipated to be detrimental to cortical and hippocampal pyramidal neurons. On the other hand, up regulation of SOCE may be beneficial during AD. These intriguing findings highlight the importance of further mechanistic studies to dissect the molecular pathways, and their corresponding targets, involved in synaptic dysfunction and neuronal loss during aging and neurodegenerative diseases. PMID- 29623028 TI - A Comparison of Pathophysiology in Humans and Rodent Models of Subarachnoid Hemorrhage. AB - Non-traumatic subarachnoid hemorrhage (SAH) affects an estimated 30,000 people each year in the United States, with an overall mortality of ~30%. Most cases of SAH result from a ruptured intracranial aneurysm, require long hospital stays, and result in significant disability and high fatality. Early brain injury (EBI) and delayed cerebral vasospasm (CV) have been implicated as leading causes of morbidity and mortality in these patients, necessitating intense focus on developing preclinical animal models that replicate clinical SAH complete with delayed CV. Despite the variety of animal models currently available, translation of findings from rodent models to clinical trials has proven especially difficult. While the explanation for this lack of translation is unclear, possibilities include the lack of standardized practices and poor replication of human pathophysiology, such as delayed cerebral vasospasm and ischemia, in rodent models of SAH. In this review, we summarize the different approaches to simulating SAH in rodents, in particular elucidating the key pathophysiology of the various methods and models. Ultimately, we suggest the development of standardized model of rodent SAH that better replicates human pathophysiology for moving forward with translational research. PMID- 29623034 TI - The Applicability of Standard Error of Measurement and Minimal Detectable Change to Motor Learning Research-A Behavioral Study. AB - Motor learning studies face the challenge of differentiating between real changes in performance and random measurement error. While the traditional p-value-based analyses of difference (e.g., t-tests, ANOVAs) provide information on the statistical significance of a reported change in performance scores, they do not inform as to the likely cause or origin of that change, that is, the contribution of both real modifications in performance and random measurement error to the reported change. One way of differentiating between real change and random measurement error is through the utilization of the statistics of standard error of measurement (SEM) and minimal detectable change (MDC). SEM is estimated from the standard deviation of a sample of scores at baseline and a test-retest reliability index of the measurement instrument or test employed. MDC, in turn, is estimated from SEM and a degree of confidence, usually 95%. The MDC value might be regarded as the minimum amount of change that needs to be observed for it to be considered a real change, or a change to which the contribution of real modifications in performance is likely to be greater than that of random measurement error. A computer-based motor task was designed to illustrate the applicability of SEM and MDC to motor learning research. Two studies were conducted with healthy participants. Study 1 assessed the test-retest reliability of the task and Study 2 consisted in a typical motor learning study, where participants practiced the task for five consecutive days. In Study 2, the data were analyzed with a traditional p-value-based analysis of difference (ANOVA) and also with SEM and MDC. The findings showed good test-retest reliability for the task and that the p-value-based analysis alone identified statistically significant improvements in performance over time even when the observed changes could in fact have been smaller than the MDC and thereby caused mostly by random measurement error, as opposed to by learning. We suggest therefore that motor learning studies could complement their p-value-based analyses of difference with statistics such as SEM and MDC in order to inform as to the likely cause or origin of any reported changes in performance. PMID- 29623033 TI - Aggression, Social Stress, and the Immune System in Humans and Animal Models. AB - Social stress can lead to the development of psychological problems ranging from exaggerated anxiety and depression to antisocial and violence-related behaviors. Increasing evidence suggests that the immune system is involved in responses to social stress in adulthood. For example, human studies show that individuals with high aggression traits display heightened inflammatory cytokine levels and dysregulated immune responses such as slower wound healing. Similar findings have been observed in patients with depression, and comorbidity of depression and aggression was correlated with stronger immune dysregulation. Therefore, dysregulation of the immune system may be one of the mediators of social stress that produces aggression and/or depression. Similar to humans, aggressive animals also show increased levels of several proinflammatory cytokines, however, unlike humans these animals are more protected from infectious organisms and have faster wound healing than animals with low aggression. On the other hand, subordinate animals that receive repeated social defeat stress have been shown to develop escalated and dysregulated immune responses such as glucocorticoid insensitivity in monocytes. In this review we synthesize the current evidence in humans, non human primates, and rodents to show a role for the immune system in responses to social stress leading to psychiatric problems such as aggression or depression. We argue that while depression and aggression represent two fundamentally different behavioral and physiological responses to social stress, it is possible that some overlapped, as well as distinct, pattern of immune signaling may underlie both of them. We also argue the necessity of studying animal models of maladaptive aggression induced by social stress (i.e., social isolation) for understanding neuro-immune mechanism of aggression, which may be relevant to human aggression. PMID- 29623035 TI - Maltreatment, the Oxytocin Receptor Gene, and Conduct Problems Among Male and Female Teenagers. AB - The oxytocin receptor gene (OXTR) influences human behavior. The G allele of OXTR rs53576 has been associated with both prosocial and maladaptive behaviors but few studies have taken account of environmental factors. The present study determined whether the association of childhood maltreatment with conduct problems was modified by OXTR rs53576 genotypes. In a general population sample of 1591 teenagers, conduct problems as well as maltreatment were measured by self-report. DNA was extracted from saliva samples. In males, there was a significant positive association between maltreatment and conduct problems independent of the genotype. In females, among G allele carriers, the level of conduct problems was significantly higher among those who had been maltreated as compared to those not maltreated. By contrast, among female AA carriers, conduct problems did not vary between those who were, and who were not, maltreated. The results indicate that OXTR rs53576 plays a role in antisocial behavior in females such that the G allele confers vulnerability for antisocial behavior if they experience maltreatment, whereas the A allele has a protective effect. PMID- 29623037 TI - Early-Life Cognitive Activity Is Related to Reduced Neurodegeneration in Alzheimer Signature Regions in Late Life. AB - Background: Although increased cognitive activity (CA), both current and past, is known to be associated with a decreased occurrence of Alzheimer's disease (AD) dementia in older adults, the exact neural mechanisms underlying the association between CA during different stages of life and human dementia remain unclear. Therefore, we investigated whether CA during different life stages is associated with cerebral amyloid-beta (Abeta) pathology and AD-related neurodegeneration in non-demented older adults. Methods: Cross-sectional analyses of data collected between April 2014 and March 2016 from the Korean Brain Aging Study for Early Diagnosis and Prediction of Alzheimer's Disease (KBASE), an ongoing prospective cohort. In total, 321 community-dwelling, non-demented older adults were involved in this study. Cerebral Abeta deposition and Abeta positivity were measured using 11C-Pittsburgh compound B (PiB)-positron emission tomography (PET). AD-signature region cerebral glucose metabolism (AD-CMglu) and AD-signature region neurodegeneration (AD-ND) positivity were measured using 18F-fluorodeoxyglucose (FDG)-PET. In addition, CA in early, mid, and late life was systematically evaluated using a structured questionnaire. Results: Of the 321 participants, 254 were cognitively normal (CN) and 67 had mild cognitive impairment (MCI). The mean age of participants was 69.6 years old [standard deviation (SD) = 8.0]. Higher early-life CA (CAearly) was associated with significantly increased AD-CMglu (B = 0.035, SE = 0.013, P = 0.009) and a decreasing trend of AD-ND positivity (OR = 0.65, 95% CI 0.43-0.98, P = 0.04) but was not associated with Abeta deposition or positivity. We observed no association between midlife CA (CAmid) and any AD related brain changes. Late-life CA (CAlate) showed an association with both global Abeta deposition and AD-CMglu, although it was not statistically significant. Sensitivity analyses controlling for current depression or conducted only for CN individuals revealed similar results. Conclusion: Our results suggest that CA in early life may be protective against late-life AD-related neurodegeneration, independently of cerebral Abeta pathology. PMID- 29623040 TI - Editorial: Adverse Effects of Cancer Chemotherapy: Anything New to Improve Tolerance and Reduce Sequelae? PMID- 29623039 TI - Simvastatin Therapy for Drug Repositioning to Reduce the Risk of Prostate Cancer Mortality in Patients With Hyperlipidemia. AB - Prostate cancer (PCa) is one of the most commonly diagnosed cancers in the western world, and the mortality rate from PCa in Asia has been increasing recently. Statins are potent inhibitors of 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase and are commonly used for treating hyperlipidemia, with beneficial effects for cardiovascular disease and they also exhibit anti-cancer activity. However, the protective effects of statins against PCa are controversial. In this study, we investigated the effect of two types of statins (simvastatin and lovastatin) and the mortality rate of PCa patients by using the Taiwan National Health Insurance Research Database (NHIRD). A total of 15,264 PCa patients with hyperlipidemia records and medical claims from the Registry of Catastrophic Illness were enrolled. The patients were divided into two cohorts based on their statin use before the diagnosis of PCa: statin users (n = 1,827) and non-statin users (n = 1,826). The results showed that patients who used statins exhibited a significantly reduced risk of mortality from PCa [adjusted hazard ratio (HR) = 0.84, 95% CI = 0.73-0.97]. Analysis of the cumulative defined daily dose (DDD) indicated that patients who were prescribed simvastatin >= 180 DDD had a dramatically decreased risk of death from PCa (adjusted HR = 0.63; 95% CI = 0.51-0.77). This population-based cohort study demonstrated that statin use significantly decreased the mortality of PCa patients, and that this risk was inversely associated with the cumulative DDD of simvastatin therapy. The results of this study revealed that statins may be used for drug repositioning and in the development of a feasible approach to prevent death from PCa. PMID- 29623041 TI - An Adaptogen: Withaferin A Ameliorates in Vitro and in Vivo Pulmonary Fibrosis by Modulating the Interplay of Fibrotic, Matricelluar Proteins, and Cytokines. AB - Pulmonary fibrosis (PF) is chronic lung disease with only two FDA approved clinically available drugs, with limited safety profile. Inadequate therapy motivated us to explore the effect of vimentin inhibitor Withaferin A, as an anti fibrotic agent against TGF-beta1-induced in vitro fibrotic events and Bleomycin induced in vivo fibrosis with an emphasis on epithelial to mesenchymal transition (EMT), extracellular matrix deposition (ECM), inflammation, and angiogenesis. In vitro EMT and fibrotic events were induced by TGF-beta1 in alveolar epithelial cells and human fetal lung fibroblasts followed by treatment with Withaferin A (0.25, 0.5, and 1 MUM concentrations) to explore its anti-fibrotic effects. In vivo potential of Withaferin A (2 and 4 mg/kg) was assessed in murine model of Bleomycin induced PF. All the parameters and molecular studies related to PF were performed at the end of treatment period. Withaferin A treatment reduced the progression of PF by modulating the EMT related cell markers both in vivo and in vitro. Withaferin A ameliorated the expression of inflammatory cytokines including NF-kappaB p65, IL-1beta and TNF-alpha, as well as attenuated the expression of pro-fibrotic proteins including CTGF, collagen 1A2, collagen 3A1, and fibronectin. Expression of angiogenic factors like VEGF, FAK, p38 MAPK, and PLC-gamma1 were also inhibited by Withaferin A. Phosphorylation of Smad 2/3 induced by TGF-beta1 and Bleomycin were significantly inhibited. Withaferin A suppressed expression of pro-inflammatory, pro-fibrotic, and pro-angiogenic mediators and also reduced the ECM deposition. In a nutshell, Withaferin A could probably prove as an efficient and potential therapeutic against PF. PMID- 29623042 TI - Estimation of Vertical Ground Reaction Forces and Sagittal Knee Kinematics During Running Using Three Inertial Sensors. AB - Analysis of running mechanics has traditionally been limited to a gait laboratory using either force plates or an instrumented treadmill in combination with a full body optical motion capture system. With the introduction of inertial motion capture systems, it becomes possible to measure kinematics in any environment. However, kinetic information could not be provided with such technology. Furthermore, numerous body-worn sensors are required for a full-body motion analysis. The aim of this study is to examine the validity of a method to estimate sagittal knee joint angles and vertical ground reaction forces during running using an ambulatory minimal body-worn sensor setup. Two concatenated artificial neural networks were trained (using data from eight healthy subjects) to estimate the kinematics and kinetics of the runners. The first artificial neural network maps the information (orientation and acceleration) of three inertial sensors (placed at the lower legs and pelvis) to lower-body joint angles. The estimated joint angles in combination with measured vertical accelerations are input to a second artificial neural network that estimates vertical ground reaction forces. To validate our approach, estimated joint angles were compared to both inertial and optical references, while kinetic output was compared to measured vertical ground reaction forces from an instrumented treadmill. Performance was evaluated using two scenarios: training and evaluating on a single subject and training on multiple subjects and evaluating on a different subject. The estimated kinematics and kinetics of most subjects show excellent agreement (rho>0.99) with the reference, for single subject training. Knee flexion/extension angles are estimated with a mean RMSE <5 degrees . Ground reaction forces are estimated with a mean RMSE < 0.27 BW. Additionaly, peak vertical ground reaction force, loading rate and maximal knee flexion during stance were compared, however, no significant differences were found. With multiple subject training the accuracy of estimating discrete and continuous outcomes decreases, however, good agreement (rho > 0.9) is still achieved for seven of the eight different evaluated subjects. The performance of multiple subject learning depends on the diversity in the training dataset, as differences in accuracy were found for the different evaluated subjects. PMID- 29623043 TI - Developmental Ethanol Exposure Causes Reduced Feeding and Reveals a Critical Role for Neuropeptide F in Survival. AB - Food intake is necessary for survival, and natural reward circuitry has evolved to help ensure that animals ingest sufficient food to maintain development, growth, and survival. Drugs of abuse, including alcohol, co-opt the natural reward circuitry in the brain, and this is a major factor in the reinforcement of drug behaviors leading to addiction. At the junction of these two aspects of reward are alterations in feeding behavior due to alcohol consumption. In particular, developmental alcohol exposure (DAE) results in a collection of physical and neurobehavioral disorders collectively referred to as Fetal Alcohol Spectrum Disorder (FASD). The deleterious effects of DAE include intellectual disabilities and other neurobehavioral changes, including altered feeding behaviors. Here we use Drosophila melanogaster as a genetic model organism to study the effects of DAE on feeding behavior and the expression and function of Neuropeptide F. We show that addition of a defined concentration of ethanol to food leads to reduced feeding at all stages of development. Further, genetic conditions that reduce or eliminate NPF signaling combine with ethanol exposure to further reduce feeding, and the distribution of NPF is altered in the brains of ethanol-supplemented larvae. Most strikingly, we find that the vast majority of flies with a null mutation in the NPF receptor die early in larval development when reared in ethanol, and provide evidence that this lethality is due to voluntary starvation. Collectively, we find a critical role for NPF signaling in protecting against altered feeding behavior induced by developmental ethanol exposure. PMID- 29623038 TI - Recent Advances: Decoding Alzheimer's Disease With Stem Cells. AB - Alzheimer's disease (AD) is an irreversible neurodegenerative disorder that destroys cognitive functions. Recently, a number of high-profile clinical trials based on the amyloid cascade hypothesis have encountered disappointing results. The failure of these trials indicates the necessity for novel therapeutic strategies and disease models. In this review, we will describe how recent advances in stem cell technology have shed light on a novel treatment strategy and revolutionized the mechanistic investigation of AD pathogenesis. Current advances in promoting endogenous neurogenesis and transplanting exogenous stem cells from both bench research and clinical translation perspectives will be thoroughly summarized. In addition, reprogramming technology-based disease modeling, which has shown improved efficacy in recapitulating pathological features in human patients, will be discussed. PMID- 29623036 TI - The Aging Brain With HIV Infection: Effects of Alcoholism or Hepatitis C Comorbidity. AB - As successfully treated individuals with Human Immunodeficiency Virus (HIV) infected age, cognitive and health challenges of normal aging ensue, burdened by HIV, treatment side effects, and high prevalence comorbidities, notably, Alcohol Use Disorders (AUD) and Hepatitis C virus (HCV) infection. In 2013, people over 55 years old accounted for 26% of the estimated number of people living with HIV (~1.2 million). The aging brain is increasingly vulnerable to endogenous and exogenous insult which, coupled with HIV infection and comorbid risk factors, can lead to additive or synergistic effects on cognitive and motor function. This paper reviews the literature on neuropsychological and in vivo Magnetic Resonance Imaging (MRI) evaluation of the aging HIV brain, while also considering the effects of comorbidity for AUD and HCV. PMID- 29623044 TI - Long-Term Intermittent Work at High Altitude: Right Heart Functional and Morphological Status and Associated Cardiometabolic Factors. AB - Background: Living at high altitude or with chronic hypoxia implies functional and morphological changes in the right ventricle and pulmonary vasculature with a 10% prevalence of high-altitude pulmonary hypertension (HAPH). The implications of working intermittently (day shifts) at high altitude (hypobaric hypoxia) over the long term are still not well-defined. The aim of this study was to evaluate the right cardiac circuit status along with potentially contributory metabolic variables and distinctive responses after long exposure to the latter condition. Methods: A cross-sectional study of 120 healthy miners working at an altitude of 4,400-4,800 m for over 5 years in 7-day commuting shifts was designed. Echocardiography was performed on day 2 at sea level. Additionally, biomedical and biochemical variables, Lake Louise scores (LLSs), sleep disturbances and physiological variables were measured at altitude and at sea level. Results: The population was 41.8 +/- 0.7 years old, with an average of 14 +/- 0.5 (range 5-29) years spent at altitude. Most subjects still suffered from mild to moderate symptoms of acute mountain sickness (mild was an LLS of 3-5 points, including cephalea; moderate was LLS of 6-10 points) (38.3%) at the end of day 1 of the shift. Echocardiography showed a 23% mean pulmonary artery pressure (mPAP) >25 mmHg, 9% HAPH (>=30 mmHg), 85% mild increase in right ventricle wall thickness (>=5 mm), 64% mild right ventricle dilation, low pulmonary vascular resistance (PVR) and fairly good ventricle performance. Asymmetric dimethylarginine (ADMA) (OR 8.84 (1.18-66.39); p < 0.05) and insulin (OR: 1.11 (1.02-1.20); p < 0.05) were associated with elevated mPAP and were defined as a cut-off. Interestingly, the correspondence analysis identified association patterns of several other variables (metabolic, labor, and biomedical) with higher mPAP. Conclusions: Working intermittently at high altitude involves a distinctive pattern. The most relevant and novel characteristics are a greater prevalence of elevated mPAP and HAPH than previously reported at chronic intermittent hypobaric hypoxia (CIHH), which is accompanied by subsequent morphological characteristics. These findings are associated with cardiometabolic factors (insulin and ADMA). However, the functional repercussions seem to be minor or negligible. This research contributes to our understanding and surveillance of this unique model of chronic intermittent high-altitude exposure. PMID- 29623045 TI - Relaxin Deficiency Leads to Uterine Artery Dysfunction During Pregnancy in Mice. AB - The uterine vasculature undergoes profound adaptations in response to pregnancy. Augmentation of endothelial vasodilator function and reduced smooth muscle reactivity are factors contributing to uterine artery adaptation and are critical for adequate placental perfusion. The peptide hormone relaxin has an important role in mediating the normal maternal renal vascular adaptations during pregnancy through a reduction in myogenic tone and an increase in flow-mediated vasodilation. Little is known however about the influence of endogenous relaxin on the uterine artery during pregnancy. We tested the hypothesis that relaxin deficiency increases myogenic tone and impairs endothelial vasodilator function in uterine arteries of late pregnant relaxin deficient (Rln-/-) mice. Reactivity of main uterine arteries from non-pregnant and late pregnant wild-type (Rln+/+) and Rln-/- mice was studied using pressure and wire myography and changes in gene expression explored using PCR. Myogenic tone was indistinguishable in arteries from non-pregnant mice. In late pregnancy uterine artery myogenic tone was halved in Rln+/+ mice (P < 0.0001), an adaptation that failed to occur in arteries from pregnant Rln-/- mice. The role of vasodilator prostanoids in the regulation of myogenic tone was significantly reduced in arteries of pregnant Rln-/- mice (P = 0.02). Agonist-mediated endothelium-dependent vasodilation was significantly impaired in non-pregnant Rln-/- mice. With pregnancy, differences in total endothelial vasodilator function were resolved, although there remained an underlying deficiency in the role of vasodilator prostanoids and alterations to the contributions of calcium-activated K+ channels. Fetuses of late pregnant Rln /- mice were ~10% lighter (P < 0.001) than those of Rln+/+ mice. In conclusion, relaxin deficiency is associated with failed suppression of uterine artery myogenic tone in pregnancy, which likely contributes to reduced uteroplacental perfusion and fetal growth restriction. PMID- 29623046 TI - Functional Changes Induced by Orexin A and Adiponectin on the Sympathetic/Parasympathetic Balance. AB - Obesity and lifestyle-related diseases are major problems faced by people in developed nations. Although exercise training prevents the progression of diabetes and obesity, the motivation for exercise is generally low in obese animals and humans. The autonomic nervous system (SNA) plays a crucial role in the regulation of eating behavior. Moreover, the SNA is involved in the body temperature regulation that is strictly related to body weight control, in accordance with the "thermoregulatory hypothesis" of food intake. Some neuronal peptides and hormones, like orexins and adiponectin, are also involved in the regulation of locomotion activity as well as food intake and metabolic rate. Furthermore, adiponectin as well as orexin A are involved in the control of body temperature, food intake and therefore in obesity-related diseases. The aim of this study was to investigate the changes in body temperature (Tc), and heart rate (HR) after an intracerebroventricular (ICV) injection of orexin A and adiponectin in animal model. The results of this study show that the orexin A levels are likely involved in the increase of Tc and HR. It is also clear that there is not a correlation between these parameters and adiponectin levels. Further studies are needed to assess adiponectin actions and outcome in the central nervous system in terms of energy expenditure, body temperature, heart rate and physical activity performance regulation. PMID- 29623048 TI - Editorial: Mesothelial Physiology and Pathophysiology. PMID- 29623047 TI - Sympathetic, Metabolic Adaptations, and Oxidative Stress in Autism Spectrum Disorders: How Far From Physiology? AB - Autism spectrum disorders (ASD) is a complex and multifaceted neurobehavioral syndrome with no specific cause still identified, despite the worldwide increasing (prevalence for 1,000 children from 6.7 to 14.6, between 2000 and 2012). Many biological and instrumental markers have been suggested as potential predictive factors for the precocious diagnosis during infancy and/or pediatric age. Many studies reported structural and functional abnormalities in the autonomic system in subjects with ASD. Sleep problems in ASD are a prominent feature, having an impact on the social interaction of the patient. Considering the role of orexins (A and B) in wake-sleep circadian rhythm, we could speculate that ASD subjects may present a dysregulation in orexinergic neurotransmission. Conversely, oxidative stress is implicated in the pathophysiology of many neurological disorders. Nonetheless, little is known about the linkage between oxidative stress and the occurrence or the progress of autism and autonomic functioning; some markers, such as heart rate (HR), heart rate variability (HRV), body temperature, and galvanic skin response (GSR), may be altered in the patient with this so complex disorder. In the present paper, we analyzed an autism case report, focusing on the rule of the sympathetic activity with the aim to suggest that it may be considered an important tool in ASD evaluation. The results of this case confirm our hypothesis even if further studies needed. PMID- 29623049 TI - Specific Changes in Young Soccer Player's Fitness After Traditional Bilateral vs. Unilateral Combined Strength and Plyometric Training. AB - The aim of this study was to compare changes in young soccer player's fitness after traditional bilateral vs. unilateral combined plyometric and strength training. Male athletes were randomly divided in two groups; both received the same training, including strength training for knee extensors and flexors, in addition to horizontal plyometric training drills. The only difference between groups was the mode of drills technique: unilateral (UG; n = 9; age, 17.3 +/- 1.1 years) vs. bilateral (TG; n = 9; age, 17.6 +/- 0.5 years). One repetition maximum bilateral strength of knee muscle extensors (1RM_KE) and flexors (1RM_KF), change of direction ability (COD), horizontal and vertical jump ability with one (unilateral) and two (bilateral) legs, and limb symmetry index were measured before and after an 8-week in-season intervention period. Some regular soccer drills were replaced by combination of plyometric and strength training drills. Magnitude-based inference statistics were used for between-group and within-group comparisons. Beneficial effects (p < 0.05) in 1RM_KE, COD, and several test of jumping performance were found in both groups in comparison to pre-test values. The limb symmetry index was not affected in either group. The beneficial changes in 1RM_KE (8.1%; p = 0.074) and 1RM_KF (6.7%; p = 0.004), COD (3.1%; p = 0.149), and bilateral jump performance (from 2.7% [p = 0.535] to 10.5% [p = 0.002]) were possible to most likely beneficial in the TG than in the UG. However, unilateral jump performance measures achieved likely to most likely beneficial changes in the UG compared to the TG (from 4.5% [p = 0.090] to 8.6% [p = 0.018]). The improvements in jumping ability were specific to the type of jump performed, with greater improvements in unilateral jump performance in the UG and bilateral jump performance in the TG. Therefore, bilateral strength and plyometric training should be complemented with unilateral drills, in order to maximize adaptations. PMID- 29623050 TI - Linear and Nonlinear Analyses of the Cardiac Autonomic Control in Children With Developmental Coordination Disorder: A Case-Control Study. AB - Children with Developmental Coordination Disorder (DCD) and children at risk for DCD (r-DCD) present motor impairments interfering in their school, leisure and daily activities. In addition, these children may have abnormalities in their cardiac autonomic control, which together with their motor impairments, restrict their health and functionality. Therefore, this study aimed to assess the cardiac autonomic control, by linear and nonlinear analysis, at supine and during an orthostatic stimulus in DCD, r-DCD and typically developed children. Thirteen DCD children (11 boys and 2 girls, aged 8.08 +/- 0.79 years), 19 children at risk for DCD (13 boys and 6 girls, aged 8.10 +/- 0.96 years) and 18 typically developed children, who constituted the control group (CG) (10 boys and 8 girls, aged 8.50 +/- 0.96 years) underwent a heart rate variability (HRV) examination. R-R intervals were recorded in order to assess the cardiac autonomic control using a validated HR monitor. HRV was analyzed by linear and nonlinear methods and compared between r-DCD, DCD, and CG. The DCD group presented blunted cardiac autonomic adjustment to the orthostatic stimulus, which was not observed in r-DCD and CG. Regarding nonlinear analysis of HRV, the DCD group presented lower parasympathetic modulation in the supine position compared to the r-DCD and CG groups. In the within group analysis, only the DCD group did not increase HR from supine to standing posture. Symbolic analysis revealed a significant decrease in 2LV (p < 0.0001) and 2UV (p < 0.0001) indices from supine to orthostatic posture only in the CG. In conclusion, r-DCD and DCD children present cardiac autonomic dysfunction characterized by higher sympathetic, lower parasympathetic and lower complexity of cardiac autonomic control in the supine position, as well as a blunted autonomic adjustment to the orthostatic stimulus. Therefore, cardiovascular health improvement should be part of DCD children's management, even in cases of less severe motor impairment. PMID- 29623051 TI - Melatonin Promotes Cheliped Regeneration, Digestive Enzyme Function, and Immunity Following Autotomy in the Chinese Mitten Crab, Eriocheir sinensis. AB - In the pond culture of juvenile Eriocheir sinensis, a high limb-impairment rate seriously affects the culture success. Therefore, it is particularly important to artificially promote limb regeneration. This study evaluated the effects of melatonin on cheliped regeneration, digestive ability, and immunity, as well as its relationship with the eyestalk. It was found that the injection of melatonin significantly increased the limb regeneration rate compared with the saline group (P < 0.05). The qRT-PCR results of growth-related genes showed that the level of EcR-mRNA (ecdysteroid receptor) and Chi-mRNA (chitinase) expression was significantly increased following the melatonin injection, while the expression of MIH-mRNA (molt-inhibiting hormone) was significantly decreased (P < 0.05). Melatonin significantly increased lipase activity (P < 0.05). We observed that the survival rates of limb-impaired and unilateral eyestalk-ablated crabs were substantially improved following melatonin treatment, whereas the survival of the unilateral eyestalk-ablated crabs was significantly decreased compared with the control group (P < 0.05). Furthermore, the results of serum immune and antioxidant capacity revealed that melatonin significantly increased the total hemocyte counts (THC), hemocyanin content, total antioxidant capacity (T-AOC), acid phosphatase (ACP), and glutathione peroxidase activity (GSH-Px), whereas the immune-related parameters were significantly decreased in eyestalk-ablated crabs (P < 0.05). Therefore, these findings indicate that melatonin exerts a protective effect on organism injury, which could promote limb regeneration by up-regulating the expression of growth-related genes, improve digestive enzyme activity, and strengthen the immune response, particularly antioxidant capacity. PMID- 29623052 TI - The Relationship Between Range of Motion and Injuries in Adolescent Dancers and Sportspersons: A Systematic Review. AB - Background: The frequent and intensive training and performance of pre professional ballet dancers and sportspersons is offered at a time when young ballet dancers and young athletes may be vulnerable to injury due to the progress through adolescence and growth spurts. Hypothesis: There are changes in range of motion during the progress through adolescence and growth periods in dancers and sportspersons. These changes in ROM can be linked to the increase of injury. Objectives: The primary aim of this systematic review is to determine whether there are changes in ROM during the progress through adolescence and growth spurts in dancers and sportspersons. The secondary aim is to determine whether these changes can predict the risk of injuries for adolescent dancers and sportspersons. Search strategy: Pubmed, Cochrane Register of Controlled Trails (CENTRAL), Cochrane Database of Systematic Reviews (CDSR), EBSCO Host databases: CINAHL Plus, MEDLINE, SPORTDiscus, Embase were searched using MeSH terms. Manual search in the Journal of Dance Medicine and Science and screening of the reference lists of identified studies and reviews was conducted. Selection criteria: Studies included adolescent dancers and sportspersons, aged 8-18, both sexes, growth spurt related to changes in ROM and injury incidence. Data collection and analysis: Search strategy was performed in the flow diagram of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). Two reviewers independently appraised each included study using Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) for methodological quality of the included studies. For data extraction, the following information was systematically extracted: first author and year of publication, study design, participants (sample size of mean age), age, maturation (if assessed), intervention, outcome(s), and some notes of each study. For evaluation of the risk of bias and precision the Research Triangle Institute Item Bank (RTI-IB) is included. Main results: Seven observational studies met the inclusion criteria of this current review. The results of this review suggest that there are changes in ROM during the progress through adolescence and growth spurts in dancers and sportspersons. These changes may lead to an increase in injury incidence. Conclusion: There is evidence linking to changes in ROM during the progress through adolescence and growth spurts in dancers and sportspersons. These changes in ROM may be related to injury incidence. PMID- 29623053 TI - Comparison of Methods for Factor Invariance Testing of a 1-Factor Model With Small Samples and Skewed Latent Traits. AB - A primary underlying assumption for researchers using a psychological scale is that scores are comparable across individuals from different subgroups within the population. In the absence of invariance, the validity of these scores for inferences about individuals may be questionable. Factor invariance testing refers to the methodological approach to assessing whether specific factor model parameters are indeed equivalent across groups. Though much research has investigated the performance of several techniques for assessing invariance, very little work has examined how methods perform under small sample size, and non normally distributed latent trait conditions. Therefore, the purpose of this simulation study was to compare invariance assessment Type I error and power rates between (a) the normal based maximum likelihood estimator, (b) a skewed-t distribution maximum likelihood estimator, (c) Bayesian estimation, and (d) the generalized structured component analysis model. The study focused on a 1-factor model. Results of the study demonstrated that the maximum likelihood estimator was robust to violations of normality of the latent trait, and that the Bayesian and generalized component models may be useful in particular situations. Implications of these findings for research and practice are discussed. PMID- 29623055 TI - Frequency of Home Numeracy Activities Is Differentially Related to Basic Number Processing and Calculation Skills in Kindergartners. AB - Home numeracy has been shown to play an important role in children's mathematical performance. However, findings are inconsistent as to which home numeracy activities are related to which mathematical skills. The present study disentangled between various mathematical abilities that were previously masked by the use of composite scores of mathematical achievement. Our aim was to shed light on the specific associations between home numeracy and various mathematical abilities. The relationships between kindergartners' home numeracy activities, their basic number processing and calculation skills were investigated. Participants were 128 kindergartners (Mage = 5.43 years, SD = 0.29, range: 4.88 6.02 years) and their parents. The children completed non-symbolic and symbolic comparison tasks, non-symbolic and symbolic number line estimation tasks, mapping tasks (enumeration and connecting), and two calculation tasks. Their parents completed a home numeracy questionnaire. Results indicated small but significant associations between formal home numeracy activities that involved more explicit teaching efforts (i.e., identifying numerals, counting) and children's enumeration skills. There was no correlation between formal home numeracy activities and non-symbolic number processing. Informal home numeracy activities that involved more implicit teaching attempts, such as "playing games" and "using numbers in daily life," were (weakly) correlated with calculation and symbolic number line estimation, respectively. The present findings suggest that disentangling between various basic number processing and calculation skills in children might unravel specific relations with both formal and informal home numeracy activities. This might explain earlier reported contradictory findings on the association between home numeracy and mathematical abilities. PMID- 29623054 TI - The Duration of Auditory Sensory Memory for Vowel Processing: Neurophysiological and Behavioral Measures. AB - Speech perception behavioral research suggests that rates of sensory memory decay are dependent on stimulus properties at more than one level (e.g., acoustic level, phonemic level). The neurophysiology of sensory memory decay rate has rarely been examined in the context of speech processing. In a lexical tone study, we showed that long-term memory representation of lexical tone slows the decay rate of sensory memory for these tones. Here, we tested the hypothesis that long-term memory representation of vowels slows the rate of auditory sensory memory decay in a similar way to that of lexical tone. Event-related potential (ERP) responses were recorded to Mandarin non-words contrasting the vowels /i/ vs. /u/ and /y/ vs. /u/ from first-language (L1) Mandarin and L1 American English participants under short and long interstimulus interval (ISI) conditions (short ISI: an average of 575 ms, long ISI: an average of 2675 ms). Results revealed poorer discrimination of the vowel contrasts for English listeners than Mandarin listeners, but with different patterns for behavioral perception and neural discrimination. As predicted, English listeners showed the poorest discrimination and identification for the vowel contrast /y/ vs. /u/, and poorer performance in the long ISI condition. In contrast to Yu et al. (2017), however, we found no effect of ISI reflected in the neural responses, specifically the mismatch negativity (MMN), P3a and late negativity ERP amplitudes. We did see a language group effect, with Mandarin listeners generally showing larger MMN and English listeners showing larger P3a. The behavioral results revealed that native language experience plays a role in echoic sensory memory trace maintenance, but the failure to find an effect of ISI on the ERP results suggests that vowel and lexical tone memory traces decay at different rates. Highlights: We examined the interaction between auditory sensory memory decay and language experience. We compared MMN, P3a, LN and behavioral responses in short vs. long interstimulus intervals. We found that different from lexical tone contrast, MMN, P3a, and LN changes to vowel contrasts are not influenced by lengthening the ISI to 2.6 s. We also found that the English listeners discriminated the non-native vowel contrast with lower accuracy under the long ISI condition. PMID- 29623056 TI - Using Behavioural Insights to Promote Food Waste Recycling in Urban Households Evidence From a Longitudinal Field Experiment. AB - Promoting pro-environmental behaviour amongst urban dwellers is one of today's greatest sustainability challenges. The aim of this study is to test whether an information intervention, designed based on theories from environmental psychology and behavioural economics, can be effective in promoting recycling of food waste in an urban area. To this end we developed and evaluated an information leaflet, mainly guided by insights from nudging and community-based social marketing. The effect of the intervention was estimated through a natural field experiment in Hokarangen, a suburb of Stockholm city, Sweden, and was evaluated using a difference-in-difference analysis. The results indicate a statistically significant increase in food waste recycled compared to a control group in the research area. The data analysed was on the weight of food waste collected from sorting stations in the research area, and the collection period stretched for almost 2 years, allowing us to study the short- and long term effects of the intervention. Although the immediate positive effect of the leaflet seems to have attenuated over time, results show that there was a significant difference between the control and the treatment group, even 8 months after the leaflet was distributed. Insights from this study can be used to guide development of similar pro-environmental behaviour interventions for other urban areas in Sweden and abroad, improving chances of reaching environmental policy goals. PMID- 29623057 TI - Passing Decisions in Football: Introducing an Empirical Approach to Estimating the Effects of Perceptual Information and Associative Knowledge. AB - The importance of various information sources in decision-making in interactive team sports is debated. While some highlight the role of the perceptual information provided by the current game context, others point to the role of knowledge-based information that athletes have regarding their team environment. Recently, an integrative perspective considering the simultaneous involvement of both of these information sources in decision-making in interactive team sports has been presented. In a theoretical example concerning passing decisions, the simultaneous involvement of perceptual and knowledge-based information has been illustrated. However, no precast method of determining the contribution of these two information sources empirically has been provided. The aim of this article is to bridge this gap and present a statistical approach to estimating the effects of perceptual information and associative knowledge on passing decisions. To this end, a sample dataset of scenario-based passing decisions is analyzed. This article shows how the effects of perceivable team positionings and athletes' knowledge about their fellow team members on passing decisions can be estimated. Ways of transfering this approach to real-world situations and implications for future research using more representative designs are presented. PMID- 29623058 TI - Cyberbullying Victimization, Self-Esteem and Suicidal Ideation in Adolescence: Does Emotional Intelligence Play a Buffering Role? AB - Cyberbullying has been linked to social, physical and psychological problems for adolescent victims but there has been no analysis of the specific role of emotional intelligence in protecting against the negative symptoms associated with cyberbullying victimization. This study examined the interaction between cyberbullying victimization and emotional intelligence (EI) as predictors of psychological maladjustment (operationalized as high suicidal ideation and low self-esteem) in 1,660 Spanish adolescents. We also investigated whether levels of EI moderated the relationship between cyberbullying victimization and mental health problems. The cyberbullying victimization x EI interaction contributed to variance in suicidal ideation and self-esteem in our sample of adolescent victims. Adolescent victims of cyberbullying with high EI scores reported lower suicidal ideation and higher self-esteem than their less emotionally intelligent counterparts. Thus, our data provide empirical support for theoretical and conceptual work connecting victimization, EI abilities and mental health associated with cyberbullying. This suggests that alone, but also in combination, EI may be particularly relevant in leading to increased levels of mental health issues in cyberbullying victims. Finally, the theoretical implications of our findings on the relationship between these variables and the mental health issues of adolescent victims of cyberbullying are discussed. PMID- 29623059 TI - Cognitive Impairments in Fibromyalgia Syndrome: Associations With Positive and Negative Affect, Alexithymia, Pain Catastrophizing and Self-Esteem. AB - Fibromyalgia syndrome (FMS) is a chronic condition characterized by widespread pain accompanied by symptoms like depression, anxiety, sleep disturbance and fatigue. In addition, affected patients frequently report cognitive disruption such as forgetfulness, concentration difficulties or mental slowness. Though cognitive deficits in FMS have been confirmed in various studies, not much is known about the mechanisms involved in their origin. This study aimed to investigate the contribution of affect-related variables to cognitive impairments in FMS. For this purpose, 67 female FMS patients and 32 healthy control subjects completed a battery of cognitive tests measuring processing speed, attention, visuospatial and verbal memory, cognitive flexibility and planning abilities. In addition, participants completed self-report questionnaires pertaining to positive and negative affect, alexithymia, pain catastrophizing and self-esteem. Clinical characteristics including pain severity, symptoms of depression and anxiety, insomnia and fatigue were also assessed. FMS patients showed markedly poorer performance than healthy controls in all of the cognitive domains assessed, in addition to greater levels of depression, anxiety, negative affect, alexithymia and pain catastrophizing, and lower self-esteem and positive affect. In exploratory correlation analysis in the FMS sample, lower cognitive performance was associated with higher pain severity, depression, anxiety, negative affect, alexithymia and pain catastrophizing, as well as lower self esteem and positive affect. However, in regression analyses, pain, self-esteem, alexithymia, and pain catastrophizing explained the largest portion of the variance in performance. While interference effects of clinical pain in cognition have been previously described, the present findings suggest that affective factors also substantially contribute to the genesis of cognitive impairments. They support the notion that affective disturbances form a crucial aspect of FMS pathology, whereas strategies aiming to improve emotional regulation may be a beneficial element of psychological therapy in the management of FMS. PMID- 29623060 TI - Perceived Stress in Adults Aged 65 to 90: Relations to Facets of Time Perspective and COMT Val158Met Polymorphism. AB - This study examined the relation between perceived stress and time perspective (views of past, present, future) in a population-based sample of older adults (65 90 years, N = 340). The Perceived Questionnaire (PSQ index) was used to measure stress and the Swedish version of the Zimbardo Time Perspective Inventory (S ZTPI) was used to operationalize time perspective. Unlike the original inventory, S-ZTPI separates positive and negative aspects of a future time perspective and we hypothesized that the Future Negative (FN) scale would be important to account for variations in stress. Additionally, associations with Catechol-O methyltransferase (COMT) Val158Met polymorphism were examined, motivated by prior associations of this single nucleotide polymorphism (SNP) with stress (or "anxiety") related personality traits. In line with the hypotheses, FN was the strongest predictor of PSQ index scores in multiple regression analyses. In a related vein, the dichotomization of the unitary Future scale increased the association between PSQ scores and a measure of deviations from a balanced time perspective, i.e., the difference between a proposed optimal and observed ZTPI profile. Finally, higher levels of stress as well as higher scores on FN were observed in COMT Val/Val carriers, at least among men. This suggests a shared dopaminergic genetic influence on these variables. Collectively, the results demonstrate that perceived stress is closely linked to time perspective and highlight the need to take negative aspects of a future temporal orientation into account to understand this relation. PMID- 29623061 TI - Explicit Versus Implicit "Halal" Information: Influence of the Halal Label and the Country-of-Origin Information on Product Perceptions in Indonesia. AB - Halal refers to what is permissible in traditional Islamic law. Food that meets halal requirements is marked by a halal label on the packaging and should be especially attractive to those Muslims who follow the set of dietary laws outlined in the Quran. This research examines the role of the halal label (explicit cue) and the country-of-origin (COO) (implicit cue) in predicting positive product perceptions among Muslim consumers. We hypothesized that when an explicit sign of "halalness" (i.e., halal label) relating to a particular product is accompanied by an implicit sign of anti-"halalness" (i.e., non-Islamic COO information), Muslim consumers who pay attention to the dietary laws of Islam would have negative perceptions of such a product. We tested our assumptions in an experiment conducted among Indonesian participants who declared themselves as Muslims (n = 444). We manipulated: (a) exposure to the halal label, and (b) the COO information. Religion-based purchase behavior was measured as a moderator variable. Positive product perceptions were measured as a dependent variable. The results showed that the halal label itself had limited influence on product perceptions. However, we found that positive product perceptions significantly decreased among people who were high in religion-based purchase behavior in response to exposure to non-Islamic COO information accompanied by a halal label. In conclusion, people who are high (vs. low) in religion-based purchase behavior do not seem to trust halal-labeled food produced in a country with other than an Islamic tradition. PMID- 29623062 TI - Lucid Dreaming: Intensity, But Not Frequency, Is Inversely Related to Psychopathology. AB - Lucid dreaming (LD) is awareness that one is dreaming, during the dream state. However, some define and assess LD relying also on controlling dream events, although control is present only in a subset of lucid dreams. LD has been claimed to represent well-being, and has even been used as a therapeutic agent. Conversely, LD is associated with mixed sleep-wake states, which are related to bizarre cognitions, stress, and psychopathology, and have been construed as arousal permeating and disrupting sleep. We propose that previous conflicting findings regarding relations between LD and both psychopathology and well-being, stem from the non-differentiated assessment of frequency and control. The present study aimed to develop an expansive measure of several LD characteristics (the Frequency and Intensity Lucid Dream questionnaire; FILD), and explore their relations with symptomatology. Undergraduate students (N = 187) self-reported trait LD, psychopathology (depression, anxiety, obsessive-compulsive symptoms, dissociation, and schizotypy), stress, and sleep problems; 2 months later, a subsample (n = 78) reported psychopathology again, and also completed a dream diary each morning for 14 days. Preliminary evidence supports the reliability and validity of the FILD. Items converged into four domains: frequency, intensity (e.g., control, activity, certainty of dreaming), emotional valence, and the use of induction techniques. We report an optimal frequency cutoff score to identify those likely to experience LD within a 2-week period. Whereas LD frequency was unrelated to psychopathology, LD intensity, and positive LD emotions, were inversely associated with several psychopathological symptoms. Use of deliberate induction techniques was positively associated with psychopathology and sleep problems. Additionally, we demonstrated directionality by employing a prospective longitudinal design, showing that deliberate LD induction predicted an increase in dissociation and schizotypy symptoms across 2 months. We conclude that lucidity should not be considered as necessarily suggestive of well-being; LD may be positive or negative, depending on lucidity characteristics. Additionally, deliberate LD induction may harbor negative long-term risk. PMID- 29623063 TI - Amyloid-beta Plaques in Clinical Alzheimer's Disease Brain Incorporate Stable Isotope Tracer In Vivo and Exhibit Nanoscale Heterogeneity. AB - Alzheimer's disease (AD) is a neurodegenerative disorder with clinical manifestations of progressive memory decline and loss of executive function and language. AD affects an estimated 5.3 million Americans alone and is the most common form of age-related dementia with a rapidly growing prevalence among the aging population-those 65 years of age or older. AD is characterized by accumulation of aggregated amyloid-beta (Abeta) in the brain, which leads to one of the pathological hallmarks of AD-Abeta plaques. As a result, Abeta plaques have been extensively studied after being first described over a century ago. Advances in brain imaging and quantitative measures of Abeta in biological fluids have yielded insight into the time course of plaque development decades before and after AD symptom onset. However, despite the fundamental role of Abeta plaques in AD, in vivo measures of individual plaque growth, growth distribution, and dynamics are still lacking. To address this question, we combined stable isotope labeling kinetics (SILK) and nanoscale secondary ion mass spectrometry (NanoSIMS) imaging in an approach termed SILK-SIMS to resolve plaque dynamics in three human AD brains. In human AD brain, plaques exhibit incorporation of a stable isotope tracer. Tracer enrichment was highly variable between plaques and the spatial distribution asymmetric with both quiescent and active nanometer sub regions of tracer incorporation. These data reveal that Abeta plaques are dynamic structures with deposition rates over days indicating a highly active process. Here, we report the first, direct quantitative measures of in vivo deposition into plaques in human AD brain. Our SILK-SIMS studies will provide invaluable information on plaque dynamics in the normal and diseased brain and offer many new avenues for investigation into pathological mechanisms of the disease, with implications for therapeutic development. PMID- 29623065 TI - In Situ Proximity Ligation Assay Reveals Co-Localization of Alpha-Synuclein and SNARE Proteins in Murine Primary Neurons. AB - The aggregation of alpha-synuclein (alphaSyn) is the pathological hallmark of Parkinson's disease, dementia with Lewy bodies and related neurological disorders. However, the physiological function of the protein and how this function relates to its pathological effects remain poorly understood. One of the proposed roles of alphaSyn is to promote the soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) complex assembly by binding to VAMP-2. The objective of this study was to visualize the co-localization between alphaSyn and the SNARE proteins (VAMP-2, SNAP-25, and syntaxin-1) for the first time using in situ proximity ligation assay (PLA). Cortical primary neurons were cultured from either non-transgenic or transgenic mice expressing human alphaSyn with the A30P mutation under the Thy-1 promoter. With an antibody recognizing both mouse and human alphaSyn, a PLA signal indicating close proximity between alphaSyn and the three SNARE proteins was observed both in the soma and throughout the processes. No differences in the extent of PLA signals were seen between non transgenic and transgenic neurons. With an antibody specific against human alphaSyn, the PLA signal was mostly located to the soma and was only present in a few cells. Taken together, in situ PLA is a method that can be used to investigate the co-localization of alphaSyn and the SNARE proteins in primary neuronal cultures. PMID- 29623064 TI - Predictability and Resetting in a Case of Convulsive Status Epilepticus. AB - In this case study, we present evidence of resetting of brain dynamics following convulsive status epilepticus (SE) that was treated successfully with antiepileptic medications (AEDs). The measure of effective inflow (EI), a novel measure of network connectivity, was applied to the continuously recorded multichannel intracranial stereoelectroencephalographic (SEEG) signals before, during and after SE. Results from this analysis indicate trends of progressive reduction of EI over hours up to the onset of SE, mainly at sites of the epileptogenic focus with reversal of those trends upon successful treatment of SE by AEDs. The proposed analytical framework is promising for elucidation of the pathology of neuronal network dynamics that could lead to SE, evaluation of the efficacy of SE treatment strategies, as well as the development of biomarkers for susceptibility to SE. PMID- 29623066 TI - Combined Analysis of Interleukin-10 Gene Polymorphisms and Protein Expression in Children With Cerebral Palsy. AB - Background: Interleukin-10 (IL-10) is an important anti-inflammatory and immunosuppressive cytokine, and it has indispensable functions in both the onset and development of inflammatory disorders. The association between persistent inflammation and the development of cerebral palsy (CP) has attracted much attention. Objective: The purpose of this study was to investigate whether IL-10 gene polymorphisms and plasma protein expression are associated with CP and to analyze the role of IL-10 in CP. Methods: A total of 282 CP patients and 197 healthy controls were genotyped for IL-10 polymorphisms (rs1554286, rs1518111, rs3024490, rs1800871, and rs1800896). Among them, 95 CP patients and 93 healthy controls were selected for plasma IL-10 measurement. Results: The differences in the rs3024490 (p = 0.033) and rs1800871 (p = 0.033) allele frequencies of IL-10 were determined between CP patients and controls. The frequencies of allele and genotype between CP patients with spastic tetraplegia and normal controls of IL 10 polymorphisms showed significant differences for rs1554286, rs151811, rs3024490, rs1800871, and rs1800896 (pallele = 0.015, 0.009, 0.006, 0.003, and 0.006, pgenotype = 0.039, 0.018, 0.027, 0.012, and 0.03, respectively). The plasma IL-10 protein level in CP patients was higher than normal controls (9.13 +/- 0.77 vs. 6.73 +/- 0.63 pg/ml, p = 0.017). IL-10 polymorphisms and protein association analysis showed that the TT genotype had higher plasma IL-10 protein levels compared to the GG + GT genotype at rs3024490 (11.14 +/- 7.27 vs. 7.44 +/- 6.95 pg/ml, p = 0.045, respectively) in CP cases. Conclusion: These findings provide an important contribution toward explaining the pleiotropic role of IL-10 in the complex etiology of CP. PMID- 29623067 TI - Cannabidiol to Improve Mobility in People with Multiple Sclerosis. PMID- 29623068 TI - Nuclear Insulin-Like Growth Factor Binding Protein-3 As a Biomarker in Triple Negative Breast Cancer Xenograft Tumors: Effect of Targeted Therapy and Comparison With Chemotherapy. AB - Triple-negative breast cancer (TNBC) typically has a worse outcome than other breast cancer subtypes, in part owing to a lack of approved therapeutic targets or prognostic markers. We have previously described an oncogenic pathway in basal like TNBC cells, initiated by insulin-like growth factor binding protein-3 (IGFBP 3), in which the epidermal growth factor receptor (EGFR) is transactivated by sphingosine-1-phosphate (S1P) resulting from sphingosine kinase (SphK)-1 activation. Oncogenic IGFBP-3 signaling can be targeted by combination treatment with the S1P receptor modulator and SphK inhibitor, fingolimod, and the EGFR kinase inhibitor, gefitinib (F + G). However, the interaction of this treatment with chemotherapy has not been documented. Since we observed nuclear localization of IGFBP-3 in some TNBC tumors, this study aimed to evaluate the prognostic significance of nuclear IGFBP-3 in pre-clinical models of basal-like TNBC treated with F + G and doxorubicin. Orthotopic xenograft tumors were grown in nude mice from the human basal-like TNBC cell lines MDA-MB-468 and HCC1806, and were treated with gefitinib, 25 mg/Kg, plus fingolimod, 5 mg/Kg, 3-times weekly. In some studies, doxorubicin was also administered once weekly for 6 weeks. Tumor tissue proteins were quantitated by immunohistochemistry (IHC). Interaction between doxorubicin and F + G was also studied in proliferation assays in vitro. In both tumor models, tissue staining for IGFBP-3 was predominantly nuclear. Combination of F + G significantly enhanced mouse survival, decreased nuclear IGFBP-3 and Ki67 staining, and increased apoptosis (cleaved caspase-3) staining. Kaplan-Meier survival analysis showed that a high tumor IGFBP-3 IHC score (>median), like a high Ki67 score, was significantly associated with shorter survival time, whereas a high apoptosis score was associated with prolonged survival. Studied in vitro in both cell lines, low-dose doxorubicin that had little effect alone, strongly enhanced the cytostatic effect of low-dose F + G combination. However, in both in vivo models, doxorubicin at maximum-tolerated dose neither inhibited tumor growth when administered alone, nor enhanced the significant inhibitory effect of F + G. We conclude that doxorubicin may not add benefit to the inhibitory effect of F + G unless its dose-limiting toxicity can be overcome. Nuclear IGFBP-3 appears to have potential as a prognostic marker in TNBC and could be evaluated for clinical utility. PMID- 29623069 TI - A Highly Efficient Xylan-Utilization System in Aspergillus niger An76: A Functional-Proteomics Study. AB - Xylan constituted with beta-1,4-D-xylose linked backbone and diverse substituted side-chains is the most abundant hemicellulose component of biomass, which can be completely and rapidly degraded into fermentable sugars by Aspergillus niger. This is of great value for obtaining renewable biofuels and biochemicals. To clarify the underlying mechanisms associated with highly efficient xylan degradation, assimilation, and metabolism by A. niger, we utilized functional proteomics to analyze the secreted proteins, sugar transporters, and intracellular proteins of A. niger An76 grown on xylan-based substrates. Results demonstrated that the complete xylanolytic enzyme system required for xylan degradation and composed of diverse isozymes was secreted in a sequential order. Xylan-backbone-degrading enzymes were preferentially induced by xylose or other soluble sugars, which efficiently produced large amounts of xylooligosaccharides (XOS) and xylose; however, XOS was more efficient than xylose in triggering the expression of the key transcription activator XlnR, resulting in higher xylanase activity and shortening xylanase-production time. Moreover, the substituted XOS was responsible for improving the abundance of side-chain-degrading enzymes, specific transporters, and key reductases and dehydrogenases in the pentose catabolic pathway. Our findings indicated that industries might be able to improve the species and concentrations of xylan-degrading enzymes and shorten fermentation time by adding abundant intermediate products of natural xylan (XOS) to cultures of filamentous fungi. PMID- 29623070 TI - A Review: The Styrene Metabolizing Cascade of Side-Chain Oxygenation as Biotechnological Basis to Gain Various Valuable Compounds. AB - Styrene is one of the most produced and processed chemicals worldwide and is released into the environment during widespread processing. But, it is also produced from plants and microorganisms. The natural occurrence of styrene led to several microbiological strategies to form and also to degrade styrene. One pathway designated as side-chain oxygenation has been reported as a specific route for the styrene degradation among microorganisms. It comprises the following enzymes: styrene monooxygenase (SMO; NADH-consuming and FAD-dependent, two-component system), styrene oxide isomerase (SOI; cofactor independent, membrane-bound protein) and phenylacetaldehyde dehydrogenase (PAD; NAD+ consuming) and allows an intrinsic cofactor regeneration. This specific way harbors a high potential for biotechnological use. Based on the enzymatic steps involved in this degradation route, important reactions can be realized from a large number of substrates which gain access to different interesting precursors for further applications. Furthermore, stereochemical transformations are possible, offering chiral products at high enantiomeric excess. This review provides an actual view on the microbiological styrene degradation followed by a detailed discussion on the enzymes of the side-chain oxygenation. Furthermore, the potential of the single enzyme reactions as well as the respective multi-step syntheses using the complete enzyme cascade are discussed in order to gain styrene oxides, phenylacetaldehydes, or phenylacetic acids (e.g., ibuprofen). Altered routes combining these putative biocatalysts with other enzymes are additionally described. Thus, the substrates spectrum can be enhanced and additional products as phenylethanols or phenylethylamines are reachable. Finally, additional enzymes with similar activities toward styrene and its metabolic intermediates are shown in order to modify the cascade described above or to use these enzyme independently for biotechnological application. PMID- 29623071 TI - Transcriptional Regulation of the Peripheral Pathway for the Anaerobic Catabolism of Toluene and m-Xylene in Azoarcus sp. CIB. AB - Alkylbenzenes, such as toluene and m-xylene, are an important class of contaminant hydrocarbons that are widespread and tend to accumulate in subsurface anoxic environments. The peripheral pathway for the anaerobic oxidation of toluene in bacteria consists of an initial activation catalyzed by a benzylsuccinate synthase (encoded by bss genes), and a subsequent modified beta oxidation of benzylsuccinate to benzoyl-CoA and succinyl-CoA (encoded by bbs genes). We have shown here that the bss and bbs genes, which are located within an integrative and conjugative element, are essential for anaerobic degradation of toluene but also for m-xylene oxidation in the denitrifying beta proteobacterium Azoarcus sp. CIB. New insights into the transcriptional organization and regulation of a complete gene cluster for anaerobic catabolism of toluene/m-xylene in a single bacterial strain are presented. The bss and bbs genes are transcriptionally coupled into two large convergent catabolic operons driven by the PbssD and PbbsA promoters, respectively, whose expression is inducible when cells grow anaerobically in toluene or m-xylene. An adjacent tdiSR operon driven by the PtdiS promoter encodes a putative two-component regulatory system. TdiR behaves as a transcriptional activator of the PbssD, PbbsA, and PtdiS promoters, being benzylsuccinate/(3-methyl)benzylsuccinate, rather than toluene/m-xylene, the inducers that may trigger the TdiS-mediated activation of TdiR. In addition to the TdiSR-based specific control, the expression of the bss and bbs genes in Azoarcus sp. CIB is under an overimposed regulation that depends on certain environmental factors, such as the presence/absence of oxygen or the availability of preferred carbon sources (catabolite repression). This work paves the way for future strategies toward the reliable assessment of microbial activity in toluene/m-xylene contaminated environments. PMID- 29623072 TI - Biodiversity and Microbial Resistance of Lactobacilli Isolated From the Traditional Greek Cheese Kopanisti. AB - Kopanisti is a Greek artisan cheese produced from raw milk in the island of Mykonos, Greece. The milk is left to rest for 12-24 h and then the rennet is added. After its formation the curd is left to drain for 2-3 days and is ready either for consumption (as tyrovolia fresh cheese), or with the addition of extra salt, the curd is left to ripen through further fermentation and surface development of Penicillium fungi, aprocess leading to the production of the traditional Greek cheese Kopanisti. From 120 samples of kopanisti, 574 Lactobacillus strains were isolated, distributed in 17 species (16 of them isolated from tyrovolia as well). Strains from 15 species were found resistant or multiresistant against 15 antimicrobial agents, representing all categories of antibiotics. Analysis revealed that the resistance was moderated during ripening of the curd from tyrovolia to Kopanisti. Resistance against penicillin G, ampicillin/sulbactam, clindamycin, chloramphenicol, streptomycin, trimethoprim, metronidazole, vancomycin, teichoplanin, and quinupristin/dalvopristin was significantly enhanced, while the resistance against ampicillin, erythromycin, oxytetracycline, gentamycin, and fucidic acid was significantly reduced. These changes during ripening suggest that resistance to antimicrobials is a dynamic process subjected to environmental factors. The biodiversity of isolated Lactobacillus strains is impressive and explains the exquisite sensorial characteristics of the cheese. However, the extent of the resistance is alarming. PMID- 29623073 TI - NS Segment of a 1918 Influenza A Virus-Descendent Enhances Replication of H1N1pdm09 and Virus-Induced Cellular Immune Response in Mammalian and Avian Systems. AB - The 2009 pandemic influenza A virus (IAV) H1N1 strain (H1N1pdm09) has widely spread and is circulating in humans and swine together with other human and avian IAVs. This fact raises the concern that reassortment between H1N1pdm09 and co circulating viruses might lead to an increase of H1N1pdm09 pathogenicity in different susceptible host species. Herein, we explored the potential of different NS segments to enhance the replication dynamics, pathogenicity and host range of H1N1pdm09 strain A/Giessen/06/09 (Gi-wt). The NS segments were derived from (i) human H1N1- and H3N2 IAVs, (ii) highly pathogenic- (H5- or H7-subtypes) or (iii) low pathogenic avian influenza viruses (H7- or H9-subtypes). A significant increase of growth kinetics in A549 (human lung epithelia) and NPTr (porcine tracheal epithelia) cells was only noticed in vitro for the reassortant Gi-NS-PR8 carrying the NS segment of the 1918-descendent A/Puerto Rico/8/34 (PR8 wt, H1N1), whereas all other reassortants showed either reduced or comparable replication efficiencies. Analysis using ex vivo tracheal organ cultures of turkeys (TOC-Tu), a species susceptible to IAV H1N1 infection, demonstrated increased replication of Gi-NS-PR8 compared to Gi-wt. Also, Gi-NS-PR8 induced a markedly higher expression of immunoregulatory and pro-inflammatory cytokines, chemokines and interferon-stimulated genes in A549 cells, THP-1-derived macrophages (dHTP) and TOC-Tu. In vivo, Gi-NS-PR8 induced an earlier onset of mortality than Gi-wt in mice, whereas, 6-week-old chickens were found to be resistant to both viruses. These data suggest that the specific characteristics of the PR8 NS segments can impact on replication, virus induced cellular immune responses and pathogenicity of the H1N1pdm09 in different avian and mammalian host species. PMID- 29623075 TI - Gut Microbiome Associates With Lipid-Lowering Effect of Rosuvastatin in Vivo. AB - : Background: Statin has been widely used to treat hyperlipidemia because of its high potency in decreasing cholesterol levels. The present study aimed to examine the lipid-lowering effect of rosuvastatin and the composition, diversity and species abundance of gut microbiome in association with rosuvastatin efficacy. TRIAL REGISTRATION: ChiCTR-ORC-17013212 at the First Affiliated Hospital of Dalian Medical University, November 2, 2017. Results: Totally 64 patients with hyperlipidemia were treated with 10 mg/day of rosuvastatin for 4-8 weeks. Blood lipid indicators triglycerides (TG), total cholesterol (TC), high density lipoprotein (HDL), low-density lipoprotein cholesterol (LDL-C) were measured before and after the treatment. Stool samples were collected right after the treatment. Following total DNA extraction and PCR amplification of 16S rRNA gene, Illumina sequencing was performed for gut microbiome identification, classification and characterization. All the patients showed a significant blood lipid reduction after the treatment. The patients were grouped according to parallel manner design. Group I had 33 patients whose blood lipid levels dropped to the normal levels from week 4, with 58.5% reduction in LDL-C and 26.6% reduction in TC. Group II had 31 patients whose blood lipid levels were still above the normal levels after 8 weeks therapy, but with 41.9% reduction in LDL-C and 31.2% reduction in TC. Based on Operational Taxonomic Unit data, Alpha diversity by Shannon Index was different between the two groups, and beta diversity by Principle Component Analysis exhibited separated patterns of the two groups. The differences were also observed in the relative-abundance at phylum, family, and genus levels of the two groups. Linear discriminate analysis illustrated that the abundance of 29 taxa was higher in group I, while the abundance of other 13 taxa was higher in group II. Phyla Firmicutes and Fusobacteria had negative correlation to LDL-C level, but Cyanobacteria and Lentisphaerae had a positive correlation to LDL-C level. Moreover, gender and age were also found somehow correlated to microbial community composition. Conclusion: Rosuvastatin therapy had different blood lipid-lowering effect on hyperlipidemia. The gut microbiota exhibited variation in community composition, diversity and taxa in association to rosuvastatin hypolipidemic effect. These results indicate that modulation of gut microflora, especially the negative/positive correlated species might strengthen statin efficacy in statin inadequate patients. PMID- 29623076 TI - Autoantibodies in Serum of Systemic Scleroderma Patients: Peptide-Based Epitope Mapping Indicates Increased Binding to Cytoplasmic Domains of CXCR3. AB - Systemic sclerosis (SSc) is a severe chronic autoimmune disease with high morbidity and mortality. Sera of patients with SSc contain a large variety of autoantibody (aab) reactivities. Among these are functionally active aab that bind to G protein-coupled receptors (GPCR) such as C-X-C motif chemokine receptor 3 (CXCR3) and 4 (CXCR4). Aab binding to the N-terminal portion of these two GPCRs have been shown to be associated with slower disease progression in SSc, especially deterioration of lung function. Aabs binding to GPCRs exhibit functional activities by stimulating or inhibiting GPCR signaling. The specific functional activity of aabs crucially depends on the epitopes they bind to. To identify the location of important epitopes on CXCR3 recognized by aabs from SSc patients, we applied an array of 36 overlapping 18-20mer peptides covering the entire CXCR3 sequence, comparing epitope specificity of SSc patient sera (N = 32, with positive reactivity with CXCR3) to healthy controls (N = 30). Binding of SSc patient and control sera to these peptides was determined by ELISA. Using a Bayesian model approach, we found increased binding of SSc patient sera to peptides corresponding to intracellular epitopes within CXCR3, while the binding signal to extracellular portions of CXCR3 was found to be reduced. Experimentally determined epitopes showed a good correspondence to those predicted by the ABCpred tool. To verify these results and to translate them into a novel diagnostic ELISA, we combined the peptides that represent SSc-associated epitopes into a single ELISA and evaluated its potential to discriminate SSc patients (N = 31) from normal healthy controls (N = 47). This ELISA had a sensitivity of 0.61 and a specificity of 0.85. Our data reveals that SSc sera preferentially bind intracellular epitopes of CXCR3, while an extracellular epitope in the N-terminal domain that appears to be target of aabs in healthy individuals is not bound by SSc sera. Based upon our results, we could devise a novel ELISA concept that may be helpful for monitoring of SSc patients. PMID- 29623077 TI - Influenza-Activated ILC1s Contribute to Antiviral Immunity Partially Influenced by Differential GITR Expression. AB - Innate lymphoid cells (ILCs) represent diversified subsets of effector cells as well as immune regulators of mucosal immunity and are classified into group 1 ILCs, group 2 ILCs, and group 3 ILCs. Group 1 ILCs encompass natural killer (NK) cells and non-NK ILCs (ILC1s) and mediate their functionality via the rapid production of IFN-gamma and TNF-alpha. The current knowledge of ILC1s mainly associates them to inflammatory processes. Much less is known about their regulation during infection and their capacity to interact with cells of the adaptive immune system. The present study dissected the role of ILC1s during early influenza A virus infection, thereby revealing their impact on the antiviral response. Exploiting in vitro and in vivo H1N1 infection systems, a cross-talk of ILC1s with cells of the innate and the adaptive immunity was demonstrated, which contributes to anti-influenza immunity. A novel association of ILC1 functionality and the expression of the glucocorticoid-induced TNFR related protein (GITR) was observed, which hints toward a so far undescribed role of GITR in regulating ILC1 responsiveness. Overexpression of GITR inhibits IFN gamma production by ILC1s, whereas partial reduction of GITR expression can reverse this effect, thereby regulating ILC1 functionality. These new insights into ILC1 biology define potential intervention targets to modulate the functional properties of ILC1s, thus contributing toward the development of new immune interventions against influenza. PMID- 29623074 TI - Retroviral RNA Dimerization: From Structure to Functions. AB - The genome of the retroviruses is a dimer composed by two homologous copies of genomic RNA (gRNA) molecules of positive polarity. The dimerization process allows two gRNA molecules to be non-covalently linked together through intermolecular base-pairing. This step is critical for the viral life cycle and is highly conserved among retroviruses with the exception of spumaretroviruses. Furthermore, packaging of two gRNA copies into viral particles presents an important evolutionary advantage for immune system evasion and drug resistance. Recent studies reported RNA switches models regulating not only gRNA dimerization, but also translation and packaging, and a spatio-temporal characterization of viral gRNA dimerization within cells are now at hand. This review summarizes our current understanding on the structural features of the dimerization signals for a variety of retroviruses (HIVs, MLV, RSV, BLV, MMTV, MPMV...), the mechanisms of RNA dimer formation and functional implications in the retroviral cycle. PMID- 29623078 TI - Physical Cues Controlling Seasonal Immune Allocation in a Natural Piscine Model. AB - Seasonal patterns in immunity are frequently observed in vertebrates but are poorly understood. Here, we focused on a natural piscine model, the three-spined stickleback (Gasterosteus aculeatus), and asked how seasonal immune allocation is driven by physical variables (time, light, and heat). Using functionally-relevant gene expression metrics as a reporter of seasonal immune allocation, we synchronously sampled fish monthly from the wild (two habitats), and from semi natural outdoors mesocosms (stocked from one of the wild habitats). This was repeated across two annual cycles, with continuous within-habitat monitoring of environmental temperature and implementing a manipulation of temperature in the mesocosms. We also conducted a long-term laboratory experiment, subjecting acclimated wild fish to natural and accelerated (*2) photoperiodic change at 7 and 15 degrees C. The laboratory experiment demonstrated that immune allocation was independent of photoperiod and only a very modest effect, at most, was controlled by a tentative endogenous circannual rhythm. On the other hand, experimentally-determined thermal effects were able to quantitatively predict much of the summer-winter fluctuation observed in the field and mesocosms. Importantly, however, temperature was insufficient to fully predict, and occasionally was a poor predictor of, natural patterns. Thermal effects can thus be overridden by other (unidentified) natural environmental variation and do not take the form of an unavoidable constraint due to cold-blooded physiology. This is consistent with a context-dependent strategic control of immunity in response to temperature variation, and points to the existence of temperature-sensitive regulatory circuits that might be conserved in other vertebrates. PMID- 29623079 TI - The Significance of Tumor Necrosis Factor Receptor Type II in CD8+ Regulatory T Cells and CD8+ Effector T Cells. AB - Tumor necrosis factor (TNF) is a pleiotropic cytokine that has both pro inflammatory and anti-inflammatory functions. The biological functions of TNF are mediated by two receptors, TNF receptor type I (TNFR1) and TNF receptor type II (TNFR2). TNFR1 is expressed universally on almost all cell types and has been extensively studied, whereas TNFR2 is mainly restricted to immune cells and some tumor cells and its role is far from clarified. Studies have shown that TNFR2 mediates the stimulatory activity of TNF on CD4+Foxp3+ regulatory T cells (Tregs) and CD8+Foxp3+ Tregs, and is involved in the phenotypic stability, proliferation, activation, and suppressive activity of Tregs. TNFR2 can also be expressed on CD8+ effector T cells (Teffs), which delivers an activation signal and cytotoxic ability to CD8+ Teffs during the early immune response, as well as an apoptosis signal to terminate the immune response. TNFR2-induced abolition of TNF receptor associated factor 2 (TRAF2) degradation may play an important role in these processes. Consequently, due to the distribution of TNFR2 and its pleiotropic effects, TNFR2 appears to be critical to keeping the balance between Tregs and Teffs, and may be an efficient therapeutic target for tumor and autoimmune diseases. In this review, we summarize the biological functions of TNFR2 expressed on CD8+Foxp3+ Tregs and CD8+ Teffs, and highlight how TNF uses TNFR2 to coordinate the complex events that ultimately lead to efficient CD8+ T cell mediated immune responses. PMID- 29623080 TI - Proapoptotic BIM Impacts B Lymphoid Homeostasis by Limiting the Survival of Mature B Cells in a Cell-Autonomous Manner. AB - The proapoptotic BH3-only protein BIM (Bcl2l11) plays key roles in the maintenance of multiple hematopoietic cell types. In mice, germline knockout or conditional pan-hematopoietic deletion of Bim results in marked splenomegaly and significantly increased numbers of B cells. However, it has remained unclear whether these abnormalities reflect the loss of cell-intrinsic functions of BIM within the B lymphoid lineage and, if so, which stages in the lifecycle of B cells are most impacted by the loss of BIM. Here, we show that B lymphoid specific conditional deletion of Bim during early development (i.e., in pro-B cells using Mb1-Cre) or during the final differentiation steps (i.e., in transitional B cells using Cd23-Cre) led to a similar >2-fold expansion of the mature follicular B cell pool. Notably, while the expansion of mature B cells was quantitatively similar in conditional and germline Bim-deficient mice, the splenomegaly was significantly attenuated after B lymphoid-specific compared to global Bim deletion. In vitro, conditional loss of Bim substantially increased the survival of mature B cells that were refractory to activation by lipopolysaccharide. Finally, we also found that conditional deletion of just one Bim allele by Mb1-Cre dramatically accelerated the development of Myc-driven B cell lymphoma, in a manner that was comparable to the effect of germline Bim heterozygosity. These data indicate that, under physiological conditions, BIM regulates B cell homeostasis predominantly by limiting the life span of non activated mature B cells, and that it can have additional effects on developing B cells under pathological conditions. PMID- 29623081 TI - A New In Vivo Model to Study Protective Immunity to Zika Virus Infection in Mice With Intact Type I Interferon Signaling. AB - The association between recent Zika virus (ZIKV) infection and neurological complications, microcephaly in the fetus, and Guillain-Barre syndrome in adults underscores the necessity for a protective vaccine. Rational vaccine development requires an in-depth understanding of the mechanisms which could protect against infection with this virus. However, so far, such an analysis has been hampered by the absence of a suitable small animal model. Unlike the situation in humans, ZIKV only replicates effectively in the peripheral organs of mice, if type I IFN signaling is interrupted. As type I IFN also impacts the adaptive immune response, mice with such a defect are not optimal for a comprehensive immunological analysis. In this report, we show that even in wild-type (WT) mice i.c. infection with low doses of virus causes marked local virus replication and lethal encephalitis in naive mice. Furthermore, peripheral infection of WT mice with low doses of virus induces a significant immune response, which provides long-lasting protection of WT mice from a fatal outcome of subsequent i.c. challenge. Therefore, combining peripheral priming with later i.c. challenge represents a new approach for studying the adaptive immune response to ZIKV in mice with an intact type I IFN response. In this study, we focused on the mechanisms underlying resistance to reinfection. Using a combination of adoptive transfer, antibody-based cell depletion, and gene targeting, we show that the key protective factor in type I IFN replete mice is humoral immunity. CD8 T cells are not essential in mice with preformed specific antibodies, but under conditions where initial antibody levels are low, effector CD8 T cells may play a role as a back-up system. These results have important implications for our understanding of natural immunity to ZIKV infection and for Zika vaccine design. PMID- 29623084 TI - Editorial: Mycorrhiza in Tropical and Neotropical Ecosystems. PMID- 29623083 TI - Robust Microplate-Based Methods for Culturing and in Vivo Phenotypic Screening of Chlamydomonas reinhardtii. AB - Chlamydomonas reinhardtii (Cr), a unicellular alga, is routinely utilized to study photosynthetic biochemistry, ciliary motility, and cellular reproduction. Its minimal culture requirements, unicellular morphology, and ease of transformation have made it a popular model system. Despite its relatively slow doubling time, compared with many bacteria, it is an ideal eukaryotic system for microplate-based studies utilizing either, or both, absorbance as well as fluorescence assays. Such microplate assays are powerful tools for researchers in the areas of toxicology, pharmacology, chemical genetics, biotechnology, and more. However, while microplate-based assays are valuable tools for screening biological systems, these methodologies can significantly alter the conditions in which the organisms are cultured and their subsequent physiology or morphology. Herein we describe a novel method for the microplate culture and in vivo phenotypic analysis of growth, viability, and photosynthetic pigments of C. reinhardtii. We evaluated the utility of our assay by screening silver nanoparticles for their effects on growth and viability. These methods are amenable to a wide assortment of studies and present a significant advancement in the methodologies available for research involving this model organism. PMID- 29623082 TI - Combination Immunotherapy: Taking Cancer Vaccines to the Next Level. AB - With the advent of checkpoint blockade therapies, immunotherapy is now a critical modality for the treatment of some cancers. While some patients respond well to checkpoint blockade, many do not, necessitating the need for other forms of therapy. Vaccination against malignancy has been a long sought goal of science. For cancers holding a microbial etiology, vaccination has been highly effective in reducing the incidence of disease. However, vaccination against established malignancy has been largely disappointing. In this review, we discuss efforts to develop diverse vaccine modalities in the treatment of cancer with a particular focus on melanoma. Recent work has suggested that vaccines targeting patient specific tumor mutations may be more relevant than those targeting unmutated proteins. Nonetheless, tumor cells utilize many strategies to evade host immunity. It is likely that the full potential of cancer vaccination will only be realized when vaccines are combined with other therapies targeting tumor immunoevasive mechanisms. By modulating inhibitory molecules, regulatory immune cells, and the metabolic resources and demands of T cells, scientists and clinicians can ensure vaccine-stimulated T cells are fully functional within the immunosuppressive tumor microevironment. PMID- 29623085 TI - Non-native Minnows Threaten Quillwort Populations in High Mountain Shallow Lakes. AB - Submersed aquatic plants are a key component of shallow, clear water lakes contributing to primary production and water quality. High mountain lakes are naturally fishless although invasive trout and most recently minnows have been introduced causing a major impact on fauna richness. The Pyrenean high mountain range has preserved soft-water oligotrophic boreal isoetids in their southern limit of distribution but the recent fish introduction is a potential factor of stress that needs to be addressed. We here work under the hypothesis that due to contrasting ecological features, trout will not be heavily affecting quillwort populations while minnows will have a stronger effect on zooplankton and zoobenthos that will promote algal growth and reduce light availability for the underwater meadows. Ten Pyrenean shallow lakes representative of three scenarios fishless, with trout and with minnows-, were sampled for meadow structure, water column and benthic environment characterization in mid-summer 2015 and 2016. Quillwort biomass allocation (above vs. belowground), epiphytic load, and composition of the algal community (abundant cyanobacteria) differed in the presence of minnows. In trout lakes biomass allocation and epiphytic load were average and the algal community composed by chlorophytes and diatoms as in fishless lakes. Biomass ratio was close to thresholds of negative buoyancy in minnow lakes indicating that meadows were at risk of uprooting and consequent de vegetation. Total and soluble carbohydrates were lower and the sporangia contained significantly less reserves to constrain growth and expansion in the presence of minnows. Lake scenarios were coupled to physicochemical differences with low light, high phosphorus and Chl-a (mesotrophia) in minnow lakes, while trout and fishless lakes remained oligotrophic. This is the first study assessing the impact of non-native fish on soft-water isoetids from mountain lakes and shows that minnows are a major threat to quillworts. The impaired light environment (from epiphytic algal overgrow and water column Chl-a) entails consequent regression (i.e., no recruitment) and de-vegetation (uprooting) of the meadows. Since soft-water oligotrophic mountain lakes are protected under the Habitats Directive, some action needs to be urgently implemented not only to preserve quillworts but to the overall ecological integrity of the lakes. PMID- 29623086 TI - Effects of N Fertilizer Sources and Tillage Practices on NH3 Volatilization, Grain Yield, and N Use Efficiency of Rice Fields in Central China. AB - Tillage practices and nitrogen (N) sources are important factors affecting rice production. Few studies, however, have examined the interactions between tillage practices and N fertilizer sources on NH3 volatilization, nitrogen use efficiency (NUE), and rice grain yield. This study aimed to investigate the effects of N fertilizer sources (no N fertilizer, inorganic N fertilizer, organic N fertilizer alone, organic N fertilizer plus inorganic N fertilizer, and slow-release N fertilizer plus inorganic N fertilizer) and tillage practices (no-tillage [NT] and conventional intensive tillage [CT]) on NH3 flux, grain yield, and NUE in the rice field of central China. N sources significantly affected NH3 volatilization, as the cumulative volatilization from the treatments of inorganic N fertilizer, organic N fertilizer, organic N fertilizer plus inorganic N fertilizer, slow release N fertilizer plus inorganic N fertilizer was 4.19, 2.13, 3.42, and 2.23 folds in 2013, and 2.49, 1.68, 2.08, and 1.85 folds in 2014 compared with that under no N fertilizer treatment, respectively. The organic N fertilizer treatment had the lowest grain yield and NUE among all N fertilizer treatments, while slow release N fertilizer plus inorganic N fertilizer treatment led to relatively higher grain yield and the greatest N use efficiency. Moreover, NT only markedly increased NH3 volatilization from basal fertilizer by 10-14% in average compared with CT, but had no obvious effects on total volatilization during the whole seasons. Tillage practices had no significant effects on grain yield and NUE. Our study suggested that the combination of slow-release N fertilizer plus inorganic N fertilizer and NT might be a sustainable method for mitigating greenhouse gas and NH3 emissions and improving grain yield and NUE in paddy fields of central China. PMID- 29623087 TI - EBG Based Microstrip Patch Antenna for Brain Tumor Detection via Scattering Parameters in Microwave Imaging System. AB - A microwave brain imaging system model is envisaged to detect and visualize tumor inside the human brain. A compact and efficient microstrip patch antenna is used in the imaging technique to transmit equivalent signal and receive backscattering signal from the stratified human head model. Electromagnetic band gap (EBG) structure is incorporated on the antenna ground plane to enhance the performance. Rectangular and circular EBG structures are proposed to investigate the antenna performance. Incorporation of circular EBG on the antenna ground plane provides an improvement of 22.77% in return loss, 5.84% in impedance bandwidth, and 16.53% in antenna gain with respect to the patch antenna with rectangular EBG. The simulation results obtained from CST are compared to those obtained from HFSS to validate the design. Specific absorption rate (SAR) of the modeled head tissue for the proposed antenna is determined. Different SAR values are compared with the established standard SAR limit to provide a safety regulation of the imaging system. A monostatic radar-based confocal microwave imaging algorithm is applied to generate the image of tumor inside a six-layer human head phantom model. S parameter signals obtained from circular EBG loaded patch antenna in different scanning modes are utilized in the imaging algorithm to effectively produce a high-resolution image which reliably indicates the presence of tumor inside human brain. PMID- 29623088 TI - A Cross-Domain Collaborative Filtering Algorithm Based on Feature Construction and Locally Weighted Linear Regression. AB - Cross-domain collaborative filtering (CDCF) solves the sparsity problem by transferring rating knowledge from auxiliary domains. Obviously, different auxiliary domains have different importance to the target domain. However, previous works cannot evaluate effectively the significance of different auxiliary domains. To overcome this drawback, we propose a cross-domain collaborative filtering algorithm based on Feature Construction and Locally Weighted Linear Regression (FCLWLR). We first construct features in different domains and use these features to represent different auxiliary domains. Thus the weight computation across different domains can be converted as the weight computation across different features. Then we combine the features in the target domain and in the auxiliary domains together and convert the cross-domain recommendation problem into a regression problem. Finally, we employ a Locally Weighted Linear Regression (LWLR) model to solve the regression problem. As LWLR is a nonparametric regression method, it can effectively avoid underfitting or overfitting problem occurring in parametric regression methods. We conduct extensive experiments to show that the proposed FCLWLR algorithm is effective in addressing the data sparsity problem by transferring the useful knowledge from the auxiliary domains, as compared to many state-of-the-art single-domain or cross-domain CF methods. PMID- 29623089 TI - Real-Time Human Detection for Aerial Captured Video Sequences via Deep Models. AB - Human detection in videos plays an important role in various real life applications. Most of traditional approaches depend on utilizing handcrafted features which are problem-dependent and optimal for specific tasks. Moreover, they are highly susceptible to dynamical events such as illumination changes, camera jitter, and variations in object sizes. On the other hand, the proposed feature learning approaches are cheaper and easier because highly abstract and discriminative features can be produced automatically without the need of expert knowledge. In this paper, we utilize automatic feature learning methods which combine optical flow and three different deep models (i.e., supervised convolutional neural network (S-CNN), pretrained CNN feature extractor, and hierarchical extreme learning machine) for human detection in videos captured using a nonstatic camera on an aerial platform with varying altitudes. The models are trained and tested on the publicly available and highly challenging UCF-ARG aerial dataset. The comparison between these models in terms of training, testing accuracy, and learning speed is analyzed. The performance evaluation considers five human actions (digging, waving, throwing, walking, and running). Experimental results demonstrated that the proposed methods are successful for human detection task. Pretrained CNN produces an average accuracy of 98.09%. S CNN produces an average accuracy of 95.6% with soft-max and 91.7% with Support Vector Machines (SVM). H-ELM has an average accuracy of 95.9%. Using a normal Central Processing Unit (CPU), H-ELM's training time takes 445 seconds. Learning in S-CNN takes 770 seconds with a high performance Graphical Processing Unit (GPU). PMID- 29623091 TI - The Prevalence and Underreporting of Needlestick Injuries among Dental Healthcare Workers in Pakistan: A Systematic Review. AB - Needlestick injuries (NSIs) are a major occupational health problem among dental healthcare workers (HCWs) in Pakistan, which places them at a significant risk of acquiring blood-borne infections. However, not all NSIs are reported, leading to an underestimation of the actual prevalence. The harmful impacts of NSIs on the healthcare delivery necessitate an urgent need to measure its actual prevalence. Objectives. The aim of this study was to review literature to estimate the prevalence and reporting rates of NSIs among dental-HCWs in Pakistan. Methods. 713 potentially relevant citations were identified by electronic databases and hand searching of articles. Nine primary studies were subsequently identified to be included in the review. Results. The results of the included studies indicate that the prevalence of NSIs among Pakistani dental-HCWs was between 30% and 73%. The rate of reporting of NSIs was between 15% and 76%, and the most common reason was found to be the lack of awareness regarding the reporting system, or of the need to report NSIs. Conclusion. It is evident from the review of the included studies that there is a significantly high prevalence and a low rate of reporting of NSIs among dental-HCWs in Pakistan, suggesting the need to setup an occupational health department in dental settings, for preventing, managing, recording, and monitoring NSIs. PMID- 29623092 TI - A Data Mining Approach to Improve Inorganic Characterization of Amanita ponderosa Mushrooms. AB - Amanita ponderosa are wild edible mushrooms that grow in some microclimates of Iberian Peninsula. Gastronomically this species is very relevant, due to not only the traditional consumption by the rural populations but also its commercial value in gourmet markets. Mineral characterisation of edible mushrooms is extremely important for certification and commercialization processes. In this study, we evaluate the inorganic composition of Amanita ponderosa fruiting bodies (Ca, K, Mg, Na, P, Ag, Al, Ba, Cd, Cr, Cu, Fe, Mn, Pb, and Zn) and their respective soil substrates from 24 different sampling sites of the southwest Iberian Peninsula (e.g., Alentejo, Andalusia, and Extremadura). Mineral composition revealed high content in macroelements, namely, potassium, phosphorus, and magnesium. Mushrooms showed presence of important trace elements and low contents of heavy metals within the limits of RDI. Bioconcentration was observed for some macro- and microelements, such as K, Cu, Zn, Mg, P, Ag, and Cd. A. ponderosa fruiting bodies showed different inorganic profiles according to their location and results pointed out that it is possible to generate an explanatory model of segmentation, performed with data based on the inorganic composition of mushrooms and soil mineral content, showing the possibility of relating these two types of data. PMID- 29623093 TI - Prevalence and Antibiotics Susceptibility Pattern of Salmonella and Shigella Species among Diarrheal Patients Attending Nekemte Referral Hospital, Oromia, Ethiopia. AB - The main objective of this study was determining the prevalence and antibiotics resistance pattern of Salmonella and Shigella sp. from diarrheal patients attending Nekemte Referral Hospital. A total of 422 patients were included in the study and their sociodemographic and clinical information was collected using questionnaire. Stool samples of the patients were collected and processed following standard bacteriological protocols. Presumptive colonies of Salmonella and Shigella species were identified and subcultured to their respective genera by standard biochemical tests. Antibiotics susceptibility of the isolates was tested using disk diffusion assay. The prevalences of Salmonella and Shigella sp. among the patients were 7.1% and 2.1%, respectively. The antimicrobial susceptibility test results of the isolates showed that they are highly resistant to amoxicillin (30 MUg). In contrast, the isolates showed relatively lower resistance level to ceftriaxone (30 MUg), nalidixic acid (30 MUg), norfloxacin (10 MUg), and ciprofloxacin (5 MUg). This study revealed 9.2% prevalence of Salmonella and Shigella sp. which were resistant to commonly prescribed antibiotics. Thus, intervention measures such as health education, provision of safe drinking water, improvement of waste disposal systems, and surveillance of antibiotics susceptibility of the pathogens should be done regularly. PMID- 29623090 TI - Liraglutide Activates the Nrf2/HO-1 Antioxidant Pathway and Protects Brain Nerve Cells against Cerebral Ischemia in Diabetic Rats. AB - This study aimed to determine the effect of liraglutide pretreatment and to elucidate the mechanism of nuclear factor erythroid 2-related factor (Nrf2)/heme oxygenase-1 (HO-1) signaling after focal cerebral ischemia injury in diabetic rats model. Adult male Sprague-Dawley rats were randomly divided into the sham operated (S) group, diabetes mellitus ischemia (DM + MCAO) group, liraglutide pretreatment normal blood glucose ischemia (NDM+MCAO+L) group, and liraglutide pretreatment diabetes ischemia (DM + MCAO + L) group. At 48 h after middle cerebral artery occlusion (MCAO), neurological deficits and infarct volume of brain were measured. Oxidative stress brain tissue was determined by superoxide dismutase (SOD) and myeloperoxidase (MPO) activities. The expression levels of Nrf2 and HO-1 of brain tissue were analyzed by western blotting. In the DM + MCAO + L group, neurological deficits scores and cerebral infarct volume seemed to decrease at 48 h after MCAO cerebral ischemia compared with those in DM + MCAO group (P < 0.05). In addition, the expression of Nrf2 and HO-1 increased in 48 h at liraglutide pretreatment groups after MCAO cerebral ischemia if compared with those in the DM + MCAO group (P < 0.05). Furthermore, the DM + MCAO + L group has no significant difference compared with the NDM + MCAO + L group (P > 0.05). To sum up, alleviating effects of liraglutide on diabetes complicated with cerebral ischemia injury rats would be related to Nrf2/HO-1 signaling pathway. PMID- 29623094 TI - Health Related Quality of Life among TB Patients: Question Mark on Performance of TB DOTS in Pakistan. AB - Due to long duration of treatment and use of several agents, tuberculosis can lead to poor health related quality of life among patients. Objective. The present study was designed to assess health related quality of life among pulmonary tuberculosis patients in Pakistan. Methodology. A descriptive cross sectional study design was used. SF-36 was self-administered to a sample of 382 pulmonary tuberculosis patients receiving self-administered or directly observed types of treatment, in baseline, initial, or continuous phase of treatment. After data collection, data was cleaned, coded, and statistically analyzed using SPSS version 21.0. Results. The results of the current study highlighted a significant impact on several domains of HRQoL of pulmonary TB patients. Highest HRQoL scores had been observed for the domain of physical functioning (60.03, +/-25.779) whereas lowest HRQoL scores were observed for the domain of general health (34.97, +/-14.286) perceptions of TB patients followed by bodily pain (43.40, +/ 24.594). Conclusion. The results of the present study concluded that TB patients had poor HRQoL in spite of the new therapeutic strategies and free availability of medicines. The disease had a negative impact on HRQoL of TB patients across all domains. PMID- 29623095 TI - Understanding Unlicensed Drug Vendor Practices Related to Childhood Malaria in One Rural District of Uganda: An Exploratory Study. AB - This study investigated unlicensed drug outlets' practices for the management of malaria in the rural district of Butaleja, Uganda. A qualitative design using semistructured interviews was used. Interviews were recorded, translated, transcribed, and analyzed using thematic analysis. A total of 75 vendors, representing 85% of the outlets in the study area, were interviewed. Most of the vendors were associated with a drug shop type of outfit. About three-quarters reported having completed some level of postsecondary education, but just one tenth of the vendors had qualifications that made them eligible to apply for a license to operate a drug shop. While most outlets stocked at least one type of antimalarial, only about one-quarter stocked an artemisinin-based combination therapy (ACT), one-quarter expressed a preference for ACTs, and less than one tenth attested to firmly adhering to the national malaria treatment guidelines on dispensing ACTs as the first-line option. In contrast, nine out of 10 vendors stocked quinine and well over a third stocked antimalarials no longer recommended, such as chloroquine and sulphadoxine-pyrimethamine. Given the ongoing gap between the national malaria policy and unlicensed drug outlet practices, this study calls for greater engagement of unlicensed vendors to improve the management of childhood malaria. PMID- 29623096 TI - Drinking Water Supply, Sanitation, and Hygiene Promotion Interventions in Two Slum Communities in Central Uganda. AB - Poor water, sanitation, and hygiene (WASH) continue to contribute to the high prevalence of diarrhoeal diseases in low-income countries such as Uganda particularly in slums. We implemented a 3-year WASH project in two urban slums in Uganda with a focus on safe drinking water and improvement in sanitation. The project implemented community and school interventions in addition to capacity building initiatives. Community interventions included home improvement campaigns, clean-up exercises, water quality assessment, promotion of drinking safe water through household point-of-use chlorination, promotion of hand washing, and support towards solid waste management. In schools, the project supported health clubs and provided them with "talking compound" messages. The capacity building initiatives undertaken included training of youth and community health workers. Project evaluation revealed several improvements in WASH status of the slums including increase in piped water usage from 38% to 86%, reduction in use of unprotected water sources from 30% to 2%, reduction in indiscriminate disposal of solid waste from 18% to 2%, and increase in satisfaction with solid waste management services from 40% to 92%. Such proactive and sustainable community interventions have the potential to not only improve lives of slum inhabitants in developing countries but also create lasting impact. PMID- 29623098 TI - High-density lipoprotein (HDL) functionality and its relevance to atherosclerotic cardiovascular disease. AB - Several prospective epidemiological studies have shown that there is a clear inverse relationship between serum high-density lipoprotein-cholesterol (HDL-C) concentrations and risk for coronary heart disease (CHD), even at low-density lipoprotein-cholesterol (LDL-C) levels below 70 mg/dL. However, more recent evidence from genetic studies and clinical research has come to challenge the long-standing notion that higher HDL-C levels are always beneficial, while lower HDL-C levels are always detrimental. Thus, it becomes apparent that HDL functionality plays a much more important role in atheroprotection than circulating HDL-C levels. HDL cholesterol efflux capacity (CEC) from macrophages is a key metric of HDL functionality and exhibits a strong inverse association with both carotid intima-media thickness and the likelihood of angiographic coronary artery disease (CAD), independent of the HDL-C level. Thus, extensive research is being conducted to identify new agents with a favorable side effect profile, which would be able to enhance CEC, improve HDL functionality and potentially decrease cardiovascular risk. This review aims to present and discuss the current clinical and scientific evidence pertaining to the significance of HDL functionality over the actual HDL-C concentration in mediating the favorable effects on the cardiovascular system. Thus, we conducted a PubMed search until December 2017 through the English literature using the search terms 'HDL function/functionality', 'HDL properties', 'cardiovascular risk' and 'cholesterol efflux capacity'. We also included references from the articles identified and publications available in the authors' libraries. PMID- 29623099 TI - Treatment of diverticular disease: an update on latest evidence and clinical implications. AB - Background: Diverticular disease (DD) is a common condition, especially in Western countries. In about 80% of patients, colonic diverticula remain asymptomatic (diverticulosis), while approximately 20% of patients may develop abdominal symptoms (symptomatic uncomplicated diverticular disease, SUDD) and, eventually complications as acute diverticulitis (AD). The management of this condition has been improved, and in the last five years European countries and the USA have published guidelines and recommendations. Scope: To summarize the latest evidence and clinical implication in treatment of DD focusing the attention either on the treatment of diverticulosis, SUDD and AD together with the primary and secondary prevention of diverticulitis. Findings: The present review was based on the latest evidence in the treatment of DD in the last 10 years. In the last 5 years, six countries issued guidelines on DD with differences regarding covered topics and recommendations regarding treatments. At present there is a lack of rationale for drug use in patients with asymptomatic diverticulosis, but there are limited indications to suggest an increase in dietary fibre to reduce risk of DD. To achieve symptomatic relief in SUDD patients, several therapeutic strategies with fibre, probiotics, rifaximin and mesalazine have been proposed even if a standard therapeutic approach remained to be defined. Agreement has been reached for the management of AD, since recent guidelines showed that antibiotics can be used selectively, rather than routinely in uncomplicated AD, although use of antibiotics remained crucial in the management of complicated cases. With regard to treatment for the primary and secondary prevention of AD, the efficacy of rifaximin and mesalazine has been proposed although with discordant recommendations among guidelines. Conclusion: Treatment of DD represented an important challenge in clinical practice, especially concerning management of SUDD and the primary and secondary prevention of AD. PMID- 29623100 TI - Youth health outcomes from the Connect-to-Protect Coalitions to prevent adolescent HIV infections. AB - We assessed the relationships among HIV-related social and behavioral outcomes resulting from an adolescent-focused HIV structural change initiative in eight urban sites operating Connect to Protect (C2P) coalitions. Over a 4-year period, annual cross-sectional panels of adolescents (N = 2,248) completed an audio computer-assisted interview, providing data on satisfaction with their communities as adolescent-supportive environments, internalized HIV stigma, lifetime HIV-testing, lifetime sexual risk-taking, and number of sexual partners in the prior year. We used structural equation modeling to estimate hypothesized links between time since coalition mobilization to our social and behavioral outcomes. Over the 4 years, adolescents perceived their communities to become more supportive (p < .05). Positive perceptions of community support were associated with lower lifetime HIV sexual risk (p < .05). The effect of time on risk behavior was mediated by perceptions of community support. Stigma was unchanged over time. Stigma had damaging effects on risk behavior, effects which were also mediated by perceptions of community support. Special efforts are needed to address the deleterious effect of HIV stigma on high-risk urban adolescents. PMID- 29623097 TI - Renal effects of non-tenofovir antiretroviral therapy in patients living with HIV. AB - A review of literature published regarding non-tenofovir antiretroviral agents causing renal adverse effects was conducted. The literature involving renal adverse effects and antiretroviral therapy is most robust with protease inhibitors, specifically atazanavir and indinavir, and includes reports of crystalluria, leukocyturia, nephritis, nephrolithiasis, nephropathy and urolithiasis. Several case reports describe potential nephropathy (including Fanconi syndrome) secondary to administration of abacavir, didanosine, lamivudine and stavudine. Case reports documented renal events such as acute renal failure, nephritis, proteinuria and renal stones with efavirenz administration. Regarding rilpivirine, a small increase of serum creatinine levels (SCr) was found in clinical trials; however, the clinical significance and impact on actual renal function is unknown. The integrase strand transfer inhibitors and enfuvirtide have a relatively safe renal profile, although studies have shown dolutegravir and raltegravir cause mild elevations in SCr without an impact on actual renal function. This is similar to the reaction observed with cobicistat, the pharmacokinetic enhancer frequently given with elvitegravir. PMID- 29623101 TI - Prediction of Pathological Subjects Using Genetic Algorithms. AB - This paper aims at estimating pathological subjects from a population through various physical information using genetic algorithm (GA). For comparison purposes, K-Means (KM) clustering algorithm has also been used for the estimation. Dataset consisting of some physical factors (age, weight, and height) and tibial rotation values was provided from the literature. Tibial rotation types are four groups as RTER, RTIR, LTER, and LTIR. Each tibial rotation group is divided into three types. Narrow (Type 1) and wide (Type 3) angular values were called pathological and normal (Type 2) angular values were called nonpathological. Physical information was used to examine if the tibial rotations of the subjects were pathological. Since the GA starts randomly and walks all solution space, the GA is seen to produce far better results than the KM for clustering and optimizing the tibial rotation data assessments with large number of subjects even though the KM algorithm has similar effect with the GA in clustering with a small number of subjects. These findings are discovered to be very useful for all health workers such as physiotherapists and orthopedists, in which this consequence is expected to help clinicians in organizing proper treatment programs for patients. PMID- 29623102 TI - Novel Signal Noise Reduction Method through Cluster Analysis, Applied to Photoplethysmography. AB - Physiological signals can often become contaminated by noise from a variety of origins. In this paper, an algorithm is described for the reduction of sporadic noise from a continuous periodic signal. The design can be used where a sample of a periodic signal is required, for example, when an average pulse is needed for pulse wave analysis and characterization. The algorithm is based on cluster analysis for selecting similar repetitions or pulses from a periodic single. This method selects individual pulses without noise, returns a clean pulse signal, and terminates when a sufficiently clean and representative signal is received. The algorithm is designed to be sufficiently compact to be implemented on a microcontroller embedded within a medical device. It has been validated through the removal of noise from an exemplar photoplethysmography (PPG) signal, showing increasing benefit as the noise contamination of the signal increases. The algorithm design is generalised to be applicable for a wide range of physiological (physical) signals. PMID- 29623103 TI - Linearized and Kernelized Sparse Multitask Learning for Predicting Cognitive Outcomes in Alzheimer's Disease. AB - Alzheimer's disease (AD) has been not only the substantial financial burden to the health care system but also the emotional burden to patients and their families. Predicting cognitive performance of subjects from their magnetic resonance imaging (MRI) measures and identifying relevant imaging biomarkers are important research topics in the study of Alzheimer's disease. Recently, the multitask learning (MTL) methods with sparsity-inducing norm (e.g., l2,1-norm) have been widely studied to select the discriminative feature subset from MRI features by incorporating inherent correlations among multiple clinical cognitive measures. However, these previous works formulate the prediction tasks as a linear regression problem. The major limitation is that they assumed a linear relationship between the MRI features and the cognitive outcomes. Some multikernel-based MTL methods have been proposed and shown better generalization ability due to the nonlinear advantage. We quantify the power of existing linear and nonlinear MTL methods by evaluating their performance on cognitive score prediction of Alzheimer's disease. Moreover, we extend the traditional l2,1-norm to a more general lql1-norm (q >= 1). Experiments on the Alzheimer's Disease Neuroimaging Initiative database showed that the nonlinear l2,1lq -MKMTL method not only achieved better prediction performance than the state-of-the-art competitive methods but also effectively fused the multimodality data. PMID- 29623104 TI - Academic Risk and Resilience in the Context of Homelessness. AB - Family homelessness in the United States has increased over the past two decades, raising concerns about associated risks for child development. In this article, we describe a translational research program focused on academic risk and resilience in homeless and highly mobile children. We find that although these children share many risk factors with other disadvantaged children, they are higher on an underlying continuum of risk. Additionally, marked variability has been observed among children who experience homelessness, both in risk level and achievement, with many children manifesting resilience. We discuss implications for research and efforts to address disparities in achievement. PMID- 29623105 TI - Subtherapeutic concentrations of infliximab and adalimumab are associated with increased disease activity in Crohn's disease. AB - Background: Low anti-tumor necrosis factor alpha (TNFalpha) serum concentrations may result in lack of treatment response in patients with inflammatory bowel disease. We determined the anti-TNFalpha drug concentrations in patients with inflammatory bowel disease and investigated whether or not subtherapeutic drug concentrations were associated with increased levels of disease activity. Methods: In a single-center cross-sectional study, we included patients with ulcerative colitis or Crohn's disease who were receiving infliximab or adalimumab maintenance therapy. Demographic data, disease activity symptom scores (Partial Mayo Score, Harvey Bradshaw Index), inflammatory markers [C-reactive protein (CRP), fecal calprotectin], antidrug antibodies and serum drug concentrations were recorded. Therapeutic drug concentrations were defined as 3-8 mg/liter for infliximab and 5-12 mg/liter for adalimumab. Results: Of 210 patients included, 137 (65.2%) had Crohn's disease. In the adalimumab group, subtherapeutic drug concentrations were measured in 16.7% of patients with ulcerative colitis and in 27.7% of patients with Crohn's disease. In the infliximab group, subtherapeutic drug concentrations were found in 23% (ulcerative colitis) and 30.3% (Crohn's disease) of patients. In Crohn's disease, subtherapeutic adalimumab concentrations were associated with higher fecal calprotectin and CRP concentrations compared with therapeutic concentrations. Subtherapeutic infliximab concentrations in patients with Crohn's disease were also associated with higher CRP concentrations compared with therapeutic concentrations. Conclusions: The prevalence of subtherapeutic drug levels ranged from 17% to 30%. In patients with Crohn's disease, subtherapeutic serum drug concentrations were associated with significantly higher disease activity with both anti-TNFalpha agents. These findings were not observed in patients with ulcerative colitis. Clinicaltrials.gov identifier [NCT02134054]. PMID- 29623107 TI - Intravesical instillations for the treatment of refractory recurrent urinary tract infections. AB - Background: Treatment options for refractory recurrent urinary tract infections (UTI) are limited; therefore, we sought to determine if intravesical instillations with heparin effectively treat recurrent UTIs. Methods: Patients at an academic medical center who received intravesical instillations with heparin for recurrent UTIs/chronic cystitis between January 2011 and December 2015 were identified via International Classification of Diseases, Ninth Revision (ICD-9) and Current Procedural Terminology (CPT) procedure codes. All cases were analyzed for frequency of UTIs during the treatment phase as well as for the subsequent 6 months after completion of therapy. Demographic, clinical and treatment related factors were then collected from the medical records to draw associations with success or failure of treatment. Results: Thirty-nine women were treated with heparin intravesical instillations for recurrent UTIs. The average age of the cohort was 68.38 years [range 25-88, standard deviation (SD) 12.92], with mean parity 2.38 (range 0-7, SD 1.55) and mean body mass index 27.85 (range 19.5-37.9, SD 4.84). A total of 84.6% completed the recommended 6-week treatment course while 69.2% went on to an additional maintenance phase. Twelve patients (30.8%) had a culture-proven UTI during the treatment phase. In the 6-month follow-up period, 46.2% of patients had at least one UTI with only seven patients (17.9%) meeting criteria for recurrent UTIs (two or more UTIs in 6 months). On univariable assessment, development of recurrent UTIs after completion of instillation therapy was associated with increasing age and vaginal estrogen use during the instillation treatment course. Conclusions: Intravesical instillation with heparin is an effective option to consider for the treatment of refractory recurrent UTIs. PMID- 29623106 TI - Defining distinct features of anti-MOG antibody associated central nervous system demyelination. AB - Extensive research over the last decades basically failed to identify a common cause of noninfectious inflammatory central nervous system (CNS) demyelinating disease. To a great extent, this may reflect that the group of inflammatory CNS demyelinating disorders likely contains multiple pathogenetically distinct disease entities. Indeed, the greatest success so far in deciphering the pathogenesis of a CNS demyelinating disorder resulted from the discovery of anti aquaporin (AQP)-4 antibodies (ab), which allowed progressive delineation of neuromyelitis optica (NMO), formerly considered a variant of the most common CNS demyelinating disorder, multiple sclerosis (MS), as a distinct disease. Nowadays, AQP-4+ NMO is considered an autoimmune astrocytopathy, in which CNS demyelination occurs only as a consequence of a primary destruction of astrocytes. Delineating these patients concomitantly revealed that not all patients presenting with clinically NMO-suggestive disease phenotype express AQP-4 ab, which created the pathogenetically undefined category of NMO spectrum disorders (NMOSD). Recent investigations discovered that a subgroup of these AQP-4- NMOSD patients produce an ab response against myelin oligodendrocyte glycoprotein (MOG), a molecule expressed on the outer lamella of the myelin sheath. Using pathophysiologically meaningful cell-based assays, this humoral response is extremely rare in adult MS and absent in classical AQP-4+ NMO, sharply differentiating the evolving group from both established disorders. In this review, we summarize available clinical, immunological and histopathological data on patients with MOG+ CNS demyelinating disease. By comparing this clearly distinct cohort to AQP-4+ NMO as well as MS, we propose that MOG+ CNS demyelinating disease represents a distinct novel disease entity. In addition to its diagnostic value, we furthermore provide mechanistic insight on how this peripheral anti-MOG ab response may be of pathogenetic relevance in triggering acute flares of inflammatory CNS demyelination. PMID- 29623108 TI - Electrical neuromodulation in the management of lower urinary tract dysfunction: evidence, experience and future prospects. AB - Lower urinary tract dysfunction (LUTD) is common and causes a spectrum of morbidity and decreased quality of life (QoL) for patients. LUTD can range from urinary retention to urge incontinence, and includes a variety of syndromes, with the most common and widely recognized being overactive bladder (OAB). The classic treatments of LUTD and OAB comprise different strategies including behavioral therapies, medications and minimally invasive or invasive surgical procedures. Generally, once patients have tried behavioral modifications and oral medical therapy, and have not experienced adequate relief of their symptoms, the next step is to consider minimally invasive therapies. In the last two decades since FDA approval, sacral nerve stimulation (SNS) has become an accepted intervention, with increasing use and evidence of effectiveness for LUTD, specifically OAB and non-obstructive urinary retention. SNS has shown both objective and subjective improvement in voiding symptoms in several randomized controlled trials (RCTs) when compared to sham or standard medical therapy. The main limitations for more extensive use include relatively high cost, implantation of a device and possibly reoperation secondary to adverse events (AE). Percutaneous tibial nerve stimulation (PTNS) is a less invasive, less direct and less expensive method for neuromodulation, which has also shown effectiveness in several randomized and non randomized trials, including comparable improvement rates to anticholinergics in OAB management. However, the efficacy of PTNS is only maintained for a short period after the stimulation is delivered. This technique has a much lower rate of AE compared to SNS, but with the inconvenience of weekly visits for stimulation, although implantable devices are on the horizon. In this article we review the mechanism of action, indications, effectiveness and complications related to SNS and PTNS therapy for LUTD. PMID- 29623109 TI - Quantified, Localized Health Benefits of Accelerated Carbon Dioxide Emissions Reductions. AB - Societal risks increase as Earth warms, but also for emissions trajectories accepting relatively high levels of near-term emissions while assuming future negative emissions will compensate even if they lead to identical warming [1]. Accelerating carbon dioxide (CO2) emissions reductions, including as a substitute for negative emissions, hence reduces long-term risks but requires dramatic near term societal transformations [2]. A major barrier to emissions reductions is the difficulty of reconciling immediate, localized costs with global, long-term benefits [3, 4]. However, 2 degrees C trajectories not relying on negative emissions or 1.5 degrees C trajectories require elimination of most fossil fuel related emissions. This generally reduces co-emissions that cause ambient air pollution, resulting in near-term, localized health benefits. We therefore examine the human health benefits of increasing ambition of 21st century CO2 reductions by 180 GtC; an amount that would shift a 'standard' 2 degrees C scenario to 1.5 degrees C or could achieve 2 degrees C without negative emissions. The decreased air pollution leads to 153+/-43 million fewer premature deaths worldwide, with ~40% occurring during the next 40 years, and minimal climate disbenefits. More than a million premature deaths would be prevented in many metropolitan areas in Asia and Africa, and >200,000 in individual urban areas on every inhabited continent except Australia. PMID- 29623111 TI - Case report: Whole exome sequencing of circulating cell-free tumor DNA in a follicular thyroid carcinoma patient with lung and bone metastases. AB - Metastatic follicular thyroid carcinoma (FTC), unresectable or resistance to radioactive iodine, is associated with poor survival. It is believed that this kind of FTC is driven by mutated genes. However, what kind of changes of genome and underlying mechanisms are elusive. The aim of this article is to understand whether there are somatic mutations in circulating cell-free tumor DNA (cfDNA) in a FTC patient with lung and bone metastases. A 55-year-old woman was diagnosed with FTC with bone and lung metastases. Appropriate amounts of DNA were extracted from formalin-fixed, paraffin-embedded thyroid tumor, peripheral cell-free plasma, and peripheral blood leukocytes and then sequenced. The significance of DNA sequencing was evaluated. There were 13,519 common variants in both tissue DNA and cfDNA. Fifty-five somatic mutations were identified in tumor, with 5 of them nonsynonymous. Seventy-two somatic mutations were found in cfDNA, with 2 of them causing amino acid change. Sixteen common alterations existed in both samples, that is, 31.3% of all the tissue somatic mutations. This pilot study provided proof that cfDNA represents the genomic characteristics of FTC primary tissue DNA well, but also metastatic tumors. Further studies are needed to better prove the effectiveness of cfDNA in the field of thyroid cancer metastatic mechanism research and real-time monitoring. PMID- 29623112 TI - Addition of dithi(ol)anylium tetrafluoroborates to alpha,beta-unsaturated ketones. AB - In the presented study, dithi(ol)anylium tetrafluoroborates are added to alpha,beta-unsaturated ketones in a Michael-type reaction yielding diverse substituted ketene diothi(ol)anes. The reactions proceed at room temperature in 1 or 13 h without the need of further additives. The presented procedure is in particular useful for dithi(ol)anylium tetrafluoroborates without electron withdrawing groups in alpha-position. This is advantageous with respect to previous approaches, which were limited to the use of ketene dithioacetals substituted with electron-withdrawing groups. Aiming for the systematic investigation of possible steric and electronic influences on the outcome of the reaction, various combinations of electrophiles and nucleophiles were used and the results of the reactions were compared based on the type of the used dithioacetal. The scope of the presented procedure is shown with four additional transformations including the use of additional electrophiles and nucleophiles, the use of a chiral auxiliary and subsequent reduction of selected products. Additionally, we extended the reaction to the synthesis of diene dithiolanes by addition of an ynone to alpha-alkyl or aryl-substitued dithiolanylium TFBs. PMID- 29623110 TI - Clinical assessment of immune-related adverse events. AB - Immunotherapy through checkpoint inhibitors is now standard practice for a growing number of cancer types, supported by overall improvement of clinical outcomes and better tolerance. One anti-CTLA-4 antibody (ipilimumab), two anti-PD 1 antibodies (pembrolizumab and nivolumab) and three anti-PD-L1 antibodies (atezolizumab, avelumab and durvalumab) have been approved for clear benefits across diverse trials. Adverse events of an immune nature associated with these agents frequently affect the skin, colon, endocrine glands, lungs and liver. Most of these effects are mild and can be managed through transient immunosuppression with corticosteroids, but high-grade events often require hospitalization and specialized treatment. However, since immunotherapy is recent, physicians with clinical experience in the diagnosis and management of immune toxicities are frequently those who actively participated in trials, but many practicing oncologists are still not familiarized with the assessment of these events. This review focuses on the incidence, diagnostic assessment and recommended management of the most relevant immune-related adverse events. PMID- 29623113 TI - Synthesis and stability of strongly acidic benzamide derivatives. AB - Reactivity studies of strong organic acids based on the replacement of one or both of the oxygens in benzoic acids with the trifluoromethanesulfonamide group are reported. Novel derivatives of these types of acids were synthesized in good yields. The generated N-triflylbenzamides were further functionalized through cross-coupling and nucleophilic aromatic substitution reactions. All compounds were stable in dilute aqueous solutions. Studies of stability under acidic and basic conditions are also reported. PMID- 29623114 TI - Oxidative cycloaddition of hydroxamic acids with dienes or guaiacols mediated by iodine(III) reagents. AB - [Bis(trifluoroacetoxy)iodo]benzene (BTI) and (diacetoxyiodo)benzene (DIB) efficiently promote the formation of acylnitroso species from hydroxamic acids in the presence of various dienes to give the corresponding hetero-Diels-Alder (HDA) adducts in moderate to high yields. The present method could be applied to the HDA reactions of acylnitroso species with o-benzoquinones generated by the oxidative dearomatization of guaiacols. PMID- 29623115 TI - An alternative to hydrogenation processes. Electrocatalytic hydrogenation of benzophenone. AB - The electrocatalytic hydrogenation of benzophenone was performed at room temperature and atmospheric pressure using a polymer electrolyte membrane electrochemical reactor (PEMER). Palladium (Pd) nanoparticles were synthesised and supported on a carbonaceous matrix (Pd/C) with a 28 wt % of Pd with respect to carbon material. Pd/C was characterised by transmission electron microscopy (TEM), and thermogravimetric analysis (TGA). Cathodes were prepared using Pd electrocatalytic loadings (LPd) of 0.2 and 0.02 mg cm-2. The anode consisted of hydrogen gas diffusion for the electrooxidation of hydrogen gas, and a 117 Nafion exchange membrane acted as a cationic polymer electrolyte membrane. Benzophenone solution was electrochemically hydrogenated in EtOH/water (90/10 v/v) plus 0.1 M H2SO4. Current densities of 10, 15 and 20 mA cm-2 were analysed for the preparative electrochemical hydrogenation of benzophenone and such results led to the highest fractional conversion (XR) of around 30% and a selectivity over 90% for the synthesis of diphenylmethanol upon the lowest current density. With regards to an increase by ten times the Pd electrocatalytic loading the electrocatalytic hydrogenation led neither to an increase in fractional conversion nor to a change in selectivity. PMID- 29623116 TI - Electrochemical Corey-Winter reaction. Reduction of thiocarbonates in aqueous methanol media and application to the synthesis of a naturally occurring alpha pyrone. AB - An electrochemical version of the Corey-Winter reaction was developed giving excellent results in aqueous methanol media (MeOH/H2O (80:20) with AcOH/AcONa buffer 0.5 M as supporting electrolyte), using a reticulated vitreous carbon as cathode in a divided cell. The electrochemical version is much more environmentally friendly than the classical reaction, where a large excess of trialkyl phosphite as reducing agent and high temperatures are required. Thus, cathodic reduction at room temperature of two cyclic thiocarbonates (-1.2 to -1.4 V vs Ag/AgCl) afforded the corresponding alkenes, trans-6-(pent-1-enyl)-alpha pyrone and trans-6-(pent-1,4-dienyl)-alpha-pyrone, which are naturally occurring metabolites isolated from Trichoderma viride and Penicillium, in high chemical yield and with excellent stereo selectivity. PMID- 29623117 TI - Investigations towards the stereoselective organocatalyzed Michael addition of dimethyl malonate to a racemic nitroalkene: possible route to the 4 methylpregabalin core structure. AB - Chiral derivatives of gamma-aminobutyric acid are widely used as medicines and can be obtained by organocatalytic Michael additions. We show here the stereoselective synthesis of 4-methylpregabalin stereoisomers using a Michael addition of dimethyl malonate to a racemic nitroalkene. The key step of the synthesis operates as a kinetic resolution with a chiral squaramide catalyst. Furthermore, specific organocatalysts can provide respective stereoisomers of the key Michael adduct in up to 99:1 er. PMID- 29623118 TI - Mannich base-connected syntheses mediated by ortho-quinone methides. AB - This article provides an overview about specifically modified Mannich reactions where the process involves an ortho-quinone methide (o-QM) intermediate. The reactions are classified on the basis of the o-QM source followed by the reactant, e.g., the dienophile partner in cycloaddition reactions (C=C or C=N dienophiles) or by the formation of multicomponent Mannich adducts. Due to the important pharmacological activities of these reactive o-QM intermediates, special attention is paid to the biological activity of these compounds. PMID- 29623119 TI - Copper-catalyzed asymmetric methylation of fluoroalkylated pyruvates with dimethylzinc. AB - The catalytic asymmetric methylation of fluoroalkylated pyruvates is shown with dimethylzinc as a methylating reagent in the presence of a copper catalyst bearing a chiral phosphine ligand. This is the first catalytic asymmetric methylation to synthesize various alpha-fluoroalkylated tertiary alcohols with CF3, CF2H, CF2Br, and n-C n F2n+1 (n = 2, 3, 8) groups in good-to-high yields and enantioselectivities. Axial backbones and substituents on phosphorus atoms of chiral phosphine ligands critically influence the enantioselectivity. Moreover, the methylation of simple perfluoroalkylated ketones is found to be facilitated by only chiral phosphines without copper. PMID- 29623120 TI - High-yielding continuous-flow synthesis of antimalarial drug hydroxychloroquine. AB - Numerous synthetic methods for the continuous preparation of fine chemicals and active pharmaceutical ingredients (API's) have been reported in recent years resulting in a dramatic improvement in process efficiencies. Herein we report a highly efficient continuous synthesis of the antimalarial drug hydroxychloroquine (HCQ). Key improvements in the new process include the elimination of protecting groups with an overall yield improvement of 52% over the current commercial process. The continuous process employs a combination of packed bed reactors with continuous stirred tank reactors for the direct conversion of the starting materials to the product. This high-yielding, multigram-scale continuous synthesis provides an opportunity to achieve increase global access to hydroxychloroquine for treatment of malaria. PMID- 29623121 TI - Diastereoselective auxiliary- and catalyst-controlled intramolecular aza-Michael reaction for the elaboration of enantioenriched 3-substituted isoindolinones. Application to the synthesis of a new pazinaclone analogue. AB - A new asymmetric organocatalyzed intramolecular aza-Michael reaction by means of both a chiral auxiliary and a catalyst for stereocontrol is reported for the synthesis of optically active isoindolinones. A selected cinchoninium salt was used as phase-transfer catalyst in combination with a chiral nucleophile, a Michael acceptor and a base to provide 3-substituted isoindolinones in good yields and diastereomeric excesses. This methodology was applied to the asymmetric synthesis of a new pazinaclone analogue which is of interest in the field of benzodiazepine-receptor agonists. PMID- 29623122 TI - Enzyme-free genetic copying of DNA and RNA sequences. AB - The copying of short DNA or RNA sequences in the absence of enzymes is a fascinating reaction that has been studied in the context of prebiotic chemistry. It involves the incorporation of nucleotides at the terminus of a primer and is directed by base pairing. The reaction occurs in aqueous medium and leads to phosphodiester formation after attack of a nucleophilic group of the primer. Two aspects of this reaction will be discussed in this review. One is the activation of the phosphate that drives what is otherwise an endergonic reaction. The other is the improved mechanistic understanding of enzyme-free primer extension that has led to a quantitative kinetic model predicting the yield of the reaction over the time course of an assay. For a successful modeling of the reaction, the strength of the template effect, the inhibitory effect of spent monomers, and the rate constants of the chemical steps have to be determined experimentally. While challenges remain for the high fidelity copying of long stretches of DNA or RNA, the available data suggest that enzyme-free primer extension is a more powerful reaction than previously thought. PMID- 29623123 TI - An air-stable bisboron complex: a practical bidentate Lewis acid catalyst. AB - We report an air-stable bisboron complex as an efficient catalyst for the inverse electron-demand Diels-Alder (IEDDA) reaction of 1,2-diazine as well as 1,2,4,5 tetrazine. Its stability towards air and moisture was demonstrated by NMR studies enabling its application in organic transformations without glovebox. A one-pot procedure for its synthesis was developed starting from 1,2 bis(trimethylsilyl)benzene greatly enhancing its practicality. Comparative reactions were carried out to evaluate its catalytic activity in IEDDA reactions of diazine including phthalazine as well as 1,2,4,5-tetrazine. PMID- 29623124 TI - Sequential Ugi reaction/base-induced ring closing/IAAC protocol toward triazolobenzodiazepine-fused diketopiperazines and hydantoins. AB - A practical three-step protocol for the assembly of triazolobenzodiazepine-fused diketopiperazines and hydantoins has been developed. The synthesis of these tetracyclic ring systems was initiated by an Ugi reaction, which brought together all necessary functionalities for further transformations. The Ugi adducts were then subjected to a base-induced ring closing and an intramolecular azide-alkyne cycloaddition reaction in succession to obtain highly fused benzodiazepine frameworks. PMID- 29623126 TI - Investigating radical cation chain processes in the electrocatalytic Diels-Alder reaction. AB - Single electron transfer (SET)-triggered radical ion-based reactions have proven to be powerful options in synthetic organic chemistry. Although unique chain processes have been proposed in various photo- and electrochemical radical ion based transformations, the turnover number, also referred to as catalytic efficiency, remains unclear in most cases. Herein, we disclose our investigations of radical cation chain processes in the electrocatalytic Diels-Alder reaction, leading to a scalable synthesis. A gram-scale synthesis was achieved with high current efficiency of up to 8000%. The reaction monitoring profiles showed sigmoidal curves with induction periods, suggesting the involvement of intermediate(s) in the rate determining step. PMID- 29623125 TI - Synthesis of a sucrose-based macrocycle with unsymmetrical monosaccharides "arms". AB - An efficient methodology for the selective substitution of both terminal positions (C6 and C6') in 1',2,3,3',4,4'-hexa-O-benzylsucrose with different unsaturated monosaccharide units is presented. Such a highly functionalized intermediate was cyclized under RCM conditions to afford a macrocyclic derivative containing a 31-membered ring in 26% yield. PMID- 29623127 TI - Heterogeneous Pd catalysts as emulsifiers in Pickering emulsions for integrated multistep synthesis in flow chemistry. AB - Within the "compartmentalised smart factory" approach of the ONE-FLOW project the implementation of different catalysts in "compartments" provided by Pickering emulsions and their application in continuous flow is targeted. We present here the development of heterogeneous Pd catalysts that are ready to be used in combination with biocatalysts for catalytic cascade synthesis of active pharmaceutical ingredients (APIs). In particular, we focus on the application of the catalytic systems for Suzuki-Miyaura cross-coupling reactions, which is the key step in the synthesis of the targeted APIs valsartan and sacubitril. An immobilised enzyme will accomplish the final product formation via hydrolysis. In order to create a large interfacial area for the catalytic reactions and to keep the reagents separated until required, the catalyst particles are used to stabilise Pickering emulsions of oil and water. A set of Ce-Sn-Pd oxides with the molecular formula Ce0.99-x Sn x Pd0.01O2-delta (x = 0-0.99) has been prepared utilising a simple single-step solution combustion method. The high applicability of the catalysts for different functional groups and their minimal leaching behaviour is demonstrated with various Suzuki-Miyaura cross-coupling reactions in batch as well as in continuous flow employing the so-called "plug & play reactor". Finally, we demonstrate the use of these particles as the sole emulsifier of oil-water emulsions for a range of oils. PMID- 29623128 TI - Enantioselective dioxytosylation of styrenes using lactate-based chiral hypervalent iodine(III). AB - A series of optically active hypervalent iodine(III) reagents prepared from the corresponding (R)-2-(2-iodophenoxy)propanoate derivative was employed for the asymmetric dioxytosylation of styrene and its derivatives. The electrophilic addition of the hypervalent iodine(III) compound toward styrene proceeded with high enantioface selectivity to give 1-aryl-1,2-di(tosyloxy)ethane with an enantiomeric excess of 70-96% of the (S)-isomer. PMID- 29623129 TI - Enhanced quantum yields by sterically demanding aryl-substituted beta-diketonate ancillary ligands. AB - Luminescent organometallic platinum(II) compounds are of interest as phosphors for organic light emitting devices. Their emissive properties can be tuned by variation of the ligands or by specific electron-withdrawing or electron-donating substituents. Different ancillary ligands can have a profound impact on the emission color and emission efficiency of these complexes. We studied the influence of sterically hindered, aryl-substituted beta-diketonates on the emission properties of C^C* cyclometalated complexes, employing the unsubstituted methyl-phenyl-imidazolium ligand. The quantum yield was significantly enhanced by changing the auxiliary ligand from acetylacetonate, where the corresponding platinum(II) complex shows only a very weak emission, to mesityl (mes) or duryl (dur) substituted acetylacetonates. The new complexes show very efficient emission with quantum yields >70% in the sky-blue spectral region (480 nm) and short decay times (<3 MUs). PMID- 29623130 TI - D-A-D-type orange-light emitting thermally activated delayed fluorescence (TADF) materials based on a fluorenone unit: simulation, photoluminescence and electroluminescence studies. AB - The design of orange-light emitting, thermally activated, delayed fluorescence (TADF) materials is necessary and important for the development and application of organic light-emitting diodes (OLEDs). Herein, two donor-acceptor-donor (D-A D)-type orange TADF materials based on fluorenone and acridine, namely 2,7 bis(9,9-dimethylacridin-10(9H)-yl)-9H-fluoren-9-one (27DACRFT, 1) and 3,6-bis(9,9 dimethylacridin-10(9H)-yl)-9H-fluoren-9-one (36DACRFT, 2), were successfully synthetized and characterized. The studies on their structure-property relationship show that the different configurations have a serious effect on the photoluminescence and electroluminescence performance according to the change in singlet-triplet splitting energy (DeltaEST) and excited state geometry. This indicates that a better configuration design can reduce internal conversion and improve triplet exciton utilization of TADF materials. Importantly, OLEDs based on 2 exhibited a maximum external quantum efficiency of 8.9%, which is higher than the theoretical efficiency of the OLEDs based on conventional fluorescent materials. PMID- 29623131 TI - AuBr3-catalyzed azidation of per-O-acetylated and per-O-benzoylated sugars. AB - Herein we report, for the first time, the successful anomeric azidation of per-O acetylated and per-O-benzoylated sugars by catalytic amounts of oxophilic AuBr3 in good to excellent yields. The method is applicable to a wide range of easily accessible per-O-acetylated and per-O-benzoylated sugars. While reaction with per O-acetylated and per-O-benzoylated monosaccharides was complete within 1-3 h at room temperature, the per-O-benzoylated disaccharides needed 2-3 h of heating at 55 degrees C. PMID- 29623132 TI - Liquid-assisted grinding and ion pairing regulates percentage conversion and diastereoselectivity of the Wittig reaction under mechanochemical conditions. AB - Mechanochemistry is maturing as a discipline and continuing to grow, so it is important to continue understanding the rules governing the system. In a mechanochemical reaction, the reactants are added into a vessel along with one or more grinding balls and the vessel is shaken at high speeds to facilitate a chemical reaction. The dielectric constant of the solvent used in liquid-assisted grinding (LAG) and properly chosen counter-ion pairing increases the percentage conversion of stilbenes in a mechanochemical Wittig reaction. Utilizing stepwise addition/evaporation of ethanol in liquid-assisted grinding also allows for the tuning of the diastereoselectivity in the Wittig reaction. PMID- 29623133 TI - Comparing Paper and Tablet Modes of Retrospective Activity Space Data Collection. AB - Individual actions are both constrained and facilitated by the social context in which individuals are embedded. But research to test specific hypotheses about the role of space on human behaviors and well-being is limited by the difficulty of collecting accurate and personally relevant social context data. We report on a project in Chitwan, Nepal, that directly addresses challenges to collect accurate activity space data. We test if a computer assisted interviewing (CAI) tablet-based approach to collecting activity space data was more accurate than a paper map-based approach; we also examine which subgroups of respondents provided more accurate data with the tablet mode compared to paper. Results show that the tablet approach yielded more accurate data when comparing respondent-indicated locations to the known locations as verified by on-the-ground staff. In addition, the accuracy of the data provided by older and less healthy respondents benefited more from the tablet mode. PMID- 29623134 TI - Generating Chondromimetic Mesenchymal Stem Cell Spheroids by Regulating Media Composition and Surface Coating. AB - INTRODUCTION: Spheroids of mesenchymal stem cells (MSCs) in cartilage tissue engineering have been shown to enhance regenerative potential owing to their 3D structure. In this study, we explored the possibility of priming spheroids under different media to replace the use of inductive surface coatings for chondrogenic differentiation. METHODS: Rat bone marrow-derived MSCs were organized into cell spheroids by the hanging drop technique and subsequently cultured on hyaluronic acid (HA) coated or non-coated well plates under different cell media conditions. Endpoint analysis included cell viability, DNA and Glycosaminoglycan (GAG) and collagen content, gene expression and immunohistochemistry. RESULTS: For chondrogenic applications, MSC spheroids derived on non-coated surfaces outperformed the spheroids derived from HA-coated surfaces in matrix synthesis and collagen II gene expression. Spheroids on non-coated surfaces gave rise to the highest collagen and GAG when primed with medium containing insulin-like growth factor (IGF) for 1 week during spheroid formation. Spheroids that were grown in chondroinductive raw material-inclusive media such as aggrecan or chondroitin sulfate exhibited the highest Collagen II gene expression in the non coated surface at 1 week. CONCLUSION: Media priming by growth factors and raw materials might be a more predictive influencer of chondrogenesis compared to inductive-surfaces. Such tailored bioactivity of the stem cell spheroids in the stage of the spheroid formation may give rise to a platform technology that may eventually produce spheroids capable of chondrogenesis achieved by mere media manipulation, skipping the need for additional culture on a modified surface, that paves the way for cost-effective technologies. PMID- 29623135 TI - Comparison of Mask Oxygen Therapy and High-Flow Oxygen Therapy after Cardiopulmonary Bypass in Obese Patients. AB - Background: To clarify the efficiency of mask O2 and high-flow O2 (HFO) treatments following cardiopulmonary bypass (CPB) in obese patients. Methods: During follow-up, oxygenization parameters including arterial pressure of oxygen (PaO2), peripheral oxygen saturation (SpO2), and arterial partial pressure of carbon dioxide (PaCO2) and physical examination parameters including respiratory rate, heart rate, and arterial pressure were recorded respectively. Presence of atelectasia and dyspnea was noted. Also, comfort scores of patients were evaluated. Results: Mean duration of hospital stay was 6.9 +/- 1.1 days in the mask O2 group, whereas the duration was significantly shorter (6.5 +/- 0.7 days) in the HFO group (p=0.034). The PaO2 values and SpO2 values were significantly higher, and PaCO2 values were significantly lower in patients who received HFO after 4th, 12th, 24th, 36th, and 48th hours. In postoperative course, HFO leads patients to achieve better postoperative FVC (p < 0.001). Also, dyspnea scores and comfort scores were significantly better in patients who received HFO in both postoperative day 1 and day 2 (p < 0.001, p < 0.001 and p=0.002, p=0.001, resp.). Conclusion: Our study demonstrated that HFO following CPB in obese patients improved postoperative PaO2, SpO2, and PaCO2 values and decreased the atelectasis score, reintubation, and mortality rates when compared with mask O2. PMID- 29623136 TI - The Effects of Continuous Positive Airway Pressure on Premature Ventricular Contractions and Ventricular Wall Stress in Patients with Heart Failure and Sleep Apnea. AB - Background: We aimed to investigate the effects of continuous positive airway pressure (CPAP) treatment on electrocardiography (ECG), premature ventricular contraction load on 24-hour Holter recordings, and implantable cardioverter defibrillator (ICD) shocks in patients with obstructive sleep apnea syndrome (OSAS) and heart failure. Methods: Patients with heart failure and ICD and patients with newly diagnosed OSAS were divided into two groups according to CPAP treatment. To compare the impact of CPAP on ECG parameters, both baseline and 6 month ECG, 24-hour Holter ECG, ambulatory blood pressure monitoring, echocardiography, polysomnography, and laboratory parameters were collected. Results: CPAP treatment significantly reduced the frequency of premature ventricular contractions, T-peak to T-end, corrected QT, corrected QT dispersion, and T-peak to T-end/corrected QT ratio in the study group (p < 0.001 for all). Although the baseline NT-pro-BNP levels were similar between study and control groups, after six months, the NT-pro-BNP levels of the study group were significantly lower than that of the control group (39.18 +/- 7.57 versus 46.11 +/- 7.65; p < 0.001). Conclusions: CPAP treatment in patients with heart failure and ICD and in patients with newly diagnosed OSAS may have beneficial effects on premature ventricular contractions and electrocardiographic arrhythmia indices and NT-pro-BNP levels. However, these results are needed to be clarified with further studies. PMID- 29623137 TI - Assessing a Novel Method to Reduce Anesthesia Machine Contamination: A Prospective, Observational Trial. AB - Background: Anesthesia machines are known reservoirs of bacterial species, potentially contributing to healthcare associated infections (HAIs). An inexpensive, disposable, nonpermeable, transparent anesthesia machine wrap (AMW) may reduce microbial contamination of the anesthesia machine. This study quantified the density and diversity of bacterial species found on anesthesia machines after terminal cleaning and between cases during actual anesthesia care to assess the impact of the AMW. We hypothesized reduced bioburden with the use of the AMW. Methods: In a prospective, experimental research design, the AMW was used in 11 surgical cases (intervention group) and not used in 11 control surgical cases. Cases were consecutively assigned to general surgical operating rooms. Seven frequently touched and difficult to disinfect "hot spots" were cultured on each machine preceding and following each case. The density and diversity of cultured colony forming units (CFUs) between the covered and uncovered machines were compared using Wilcoxon signed-rank test and Student's t tests. Results: There was a statistically significant reduction in CFU density and diversity when the AMW was employed. Conclusion: The protective effect of the AMW during regular anesthetic care provides a reliable and low-cost method to minimize the transmission of pathogens across patients and potentially reduces HAIs. PMID- 29623138 TI - Clinical, Serological, and Molecular Observations from a Case Series Study during the Asian Lineage Zika Virus Outbreak in Grenada during 2016. AB - This paper describes the spatial and temporal distribution of cases, demographic characteristics of patients, and clinical manifestations of Zika virus (ZIKV) during the 2016 outbreak in Grenada. The first reported case was recorded in St. Andrew Parish in April, and the last reported case was seen in November, with peak transmission occurring in the last week of June, based on test results. Data were collected from a total of 514 patients, of whom 207 (40%) tested positive for ZIKV. No evidence was found that testing positive for ZIKV infection was related to age, gender, or pregnancy status. Clinical presentation with rash (OR = 2.4, 95% CI = 1.5 to 3.7) or with lymphadenopathy (OR = 1.7, 95% CI = 1.0 to 2.9) were the only reported symptoms consistent with testing positive for ZIKV infection. During the Zika outbreak, the infection rate was 20 clinical cases per 10,000 in the population compared to 41 cases per 10,000 during the chikungunya outbreak in Grenada in 2014 and 17 cases per 10,000 during the dengue outbreak in 2001-2002. Even though the country has employed vector control programs, with no apparent decrease in infection rates, it appears that new abatement approaches are needed to minimize morbidity in future arbovirus outbreaks. PMID- 29623139 TI - RAPD PCR Profile, Antibiotic Resistance, Prevalence of armA Gene, and Detection of KPC Enzyme in Klebsiella pneumoniae Isolates. AB - The increasing prevalence of multidrug-resistant Klebsiella pneumoniae strains isolated from hospitals shows the limitation of recent antibiotics used for bacterial eradication. In this study, 81 K. pneumoniae isolates were collected from three hospitals in Tehran. Antibiotic susceptibility test showed the highest rates of resistance to cefotaxim (85.5%) and ceftazidime (78.3%), and the lowest rates of resistance were detected for colistin (16.9%), streptomycin (16.8%), and chloroamphenicol (21.7%). Eleven different resistance patterns were observed. Sixty-six out of 81 isolates (81.5%) were found to be multidrug resistant (MDR), and 35.8% of them belonged to A3 resistance pattern. 7.4% and 66.7% were KPC enzyme and armA gene positive, respectively. RAPD PCR assay of these bacteria showed 5 clusters, 16 single types, and 14 common types, and there was not any correlation between genetic patterns of the isolates and presence of resistance agents. Simultaneous detection of resistance-creating agents could be an important challenge for combination therapy of MDR K. pneumoniae-caused infections. PMID- 29623140 TI - Multidrug-Resistant Acinetobacter baumannii: An Emerging Health Threat in Aseer Region, Kingdom of Saudi Arabia. AB - Objective: The study aims to determine the prevalence of multidrug-resistant A. baumannii in Aseer Region, Kingdom of Saudi Arabia. Methods: This study evaluated the antibiotic susceptibility of ninety-four (n = 94) clinical isolates of A. baumannii. The isolates were collected from the south region of Saudi Arabia, and notably Aseer Region, during the period from 15 October 2014 to 15 January 2015. The isolates were tentatively identified as A. baumannii by routine bench tests and were confirmed by using VITEK(r) 2 Compact. The latest instrument was used to identify antibiotic susceptibility of these isolates. Results: Antibiotic susceptibility in this study showed that 69% of these isolates were multidrug resistant strains. Moreover, they were highly resistant to carbapenem drugs. Several strains of these isolates were found to be extremely resistant to test antibiotics and were only sensitive to one or two of them. Conclusion: High rate of multidrug-resistant A. baumannii bacteraemia has emerged in the south region of Saudi Arabia as an important health problem. Therefore, it is considered as a new threat in hospitals, which requires a tremendous effort to stop its escalation and spread. PMID- 29623141 TI - Functional Assessment of the Stomatognathic System, after the Treatment of Edentulous Patients, with Different Methods of Establishing the Centric Relation. AB - The study compares subjective experiences of patients, wearing complete dentures. Two different methods of determining a centric relation were performed: the traditional method using wax occlusal rims and the Gerber method, based on gothic arch tracings. The success rate of establishing a centric relation in both methods was evaluated (rentgenodiagnostics). The influence of the method used to obtain the centric relation on patients' stomatognathic system (condyle centralization, pain) was also evaluated. Better results were achieved in gothic arch tracing method. Before every prosthetic treatment of edentulous patients, a functional analysis of the TMJ is necessary. The lack of centric relation, in a long term adaptation patients, does not lead to TMD symptoms. This trial is registered with NCT03343015. PMID- 29623142 TI - Chronic Pain in the Emergency Department: A Pilot Interdisciplinary Program Demonstrates Improvements in Disability, Psychosocial Function, and Healthcare Utilization. AB - Objective: To evaluate the feasibility of an individualized interdisciplinary chronic pain care plan as an intervention to reduce emergency department (ED) visits and improve clinical outcomes among patients who frequented the ED with concerns related to chronic pain. Methods: A prospective cohort design was used in an urban tertiary care hospital. As a pilot program, fourteen patients with chronic pain who frequented the ED (i.e., >12 ED visits within the last year, of which >=50% were for chronic pain) received a rapid interdisciplinary assessment and individualized care plan that was uploaded to an electronic medical record system (EMR) accessible to the ED and patient's primary care provider. Patients were assessed at baseline and every three months over a 12-month period. Primary outcomes were self-reported pain and function assessed using psychometrically valid scales. Results: Nine patients completed 12-month follow-up. Missing data and attrition were handled using multiple imputation. Patients who received the intervention reported clinically significant improvements in pain, function, ED visits, symptoms of depression, pain catastrophizing, sleep, health-related quality of life, and risk of future aberrant opioid use. Discussion: Individualized care plans uploaded to an EMR may be worth implementing in hospital EDs for high frequency visitors with chronic pain. PMID- 29623143 TI - Efficacy of Nalbuphine with Flurbiprofen on Multimodal Analgesia with Transverse Abdominis Plane Block in Elderly Patients Undergoing Open Gastrointestinal Surgery: A Randomized, Controlled, Double-Blinded Trial. AB - Objective: To assess different doses of nalbuphine with flurbiprofen compared to sufentanil with flurbiprofen in multimodal analgesia efficacy for elderly patients undergoing gastrointestinal surgery with a transverse abdominis plane block (TAPB). Methods: 158 elderly patients scheduling for elective open gastrointestinal surgery under general anesthesia and TAPB were randomly assigned to four groups according to different doses of nalbuphine with flurbiprofen in postoperative intravenous analgesia (PCIA). Postoperative pain intensity, effective pressing numbers of PCIA, and adverse effects were recorded at 6, 12, 24, and 48 hours after surgery. Results: Postoperative pain intensity, effective pressing numbers, and the incidence of postoperative nausea and vomiting (PONV) were similar among the four groups after surgery, while the severity of PONV was decreased in Group L compared with Group S at 6, 12, and 48 h after surgery. No individual experienced pruritus, respiratory depression, or hypotension. Conclusions: Low dose of nalbuphine (15 MUg.kg-1.ml-1) combined with flurbiprofen is superior for elderly patients undergoing elective open gastrointestinal surgery with TAPB in terms of the efficient postoperative analgesia and decreased severity of PONV. This trial is registered with NCT02984865. PMID- 29623144 TI - Accuracy of Patient Opioid Use Reporting at the Time of Medical Cannabis License Renewal. AB - The decision to authorize a patient for continued enrollment in a state sanctioned medical cannabis program is difficult in part due to the uncertainty in the accuracy of patient symptom reporting and health functioning including any possible effects on other medication use. We conducted a pragmatic convenience study comparing patient reporting of previous and current prescription opioid usage to the opioid prescription records in the Prescription Monitoring Program (PMP) among 131 chronic pain patients (mean age = 54; 54% male) seeking the first annual renewal of their New Mexico Medical Cannabis Program (NMMCP) license. Seventy-six percent of the patients reported using prescription opioids prior to enrollment in the NMMCP, however, the PMP records showed that only 49% of the patients were actually prescribed opioids in the six months prior to enrollment. Of the 64 patients with verifiable opioid prescriptions prior to NMMCP enrollment, 35 (55%) patients reported having eliminated the use of prescription opioids by the time of license renewal. PMP records showed that 26 patients (63% of patients claiming to have eliminated the use of opioid prescriptions and 41% of all patients with verifiable preenrollment opioid use) showed no prescription opioid activity at their first annual NMMCP renewal visit. PMID- 29623145 TI - Water-Soluble Polymer Assists N-Methyl-D-Aspartic Acid Receptor 2B siRNA Delivery to Relieve Chronic Inflammatory Pain In Vitro and In Vivo. AB - We constructed a water-soluble lipopolymer (WSLP) as a nonviral gene carrier to deliver siRNA targeting NR2B. The cytotoxicity and serum stability of WSLP loaded with siRNA were evaluated, and the knockdown efficiency of WSLP/NR2B-siRNA in PC12 cells was examined. The results showed that WSLP could protect the loading siRNAs from enzymatic degradation in serum and exhibit low cytotoxicity to cells. After transfection, WSLP/NR2B-siRNA complexes reduced the NR2B transcriptional level by 50% and protein level by 55% compared to control siRNA. Moreover, 3 days after intrathecal injection of WSLP/NR2B-siRNA complexes into rats, the NR2B protein expression decreased significantly to 58%, compared to control treatment (p < 0.01). Injection of WSLP with scrambled siRNA or of polyethylenimine (PEI) with NR2B-siRNA did not show this inhibitory effect. Additionally, injection of WSLP/NR2B-siRNA complexes significantly relieved inflammatory pain in rats at 3, 4, and 5 days with reduced MWT and decreased TWL scores, while injection of WSLP with scrambled siRNA or of PEI with NR2B-siRNA did not. These results demonstrated that WSLP can efficiently deliver siRNA targeting NR2B to PC12 cells and relieve pain in rats with chronic inflammatory pain. PMID- 29623146 TI - Low Back Pain among Medical Students in Belgrade (Serbia): A Cross-Sectional Study. AB - Aim: To examine the prevalence of low back pain, to identify self-perceived triggers of low back pain, and to investigate the impact of perceived pain on the daily activities and mood among medical students. Methods: This cross-sectional study enrolled 459 fourth year students at the Faculty of Medicine in Belgrade during December 2014. The anonymous questionnaire was used for data collection. In data analysis, the chi-square test and t-test were used. Results: The lifetime prevalence of low back pain was 75.8%, 12-month prevalence 59.5%, and point prevalence 17.2%. Chronic low back pain was experienced by 12.4% of the students. Both the lifetime (p=0.001) and the 12-month (p=0.001) low back pain prevalence rates were significantly higher among female medical students. Mental stress during an exam period (p=0.001), sitting at the university (p=0.002), fatigue (p=0.043), improper body posture (p=0.005), and lack of exercise (p=0.001) as self-perceived triggers of low back pain were significantly more often reported by female students, compared to males. Regarding daily functioning, the experience of low back pain mostly affects students sleeping (14.6%) and walking (12.0%). Conclusions: The prevalence of LBP is high among Belgrade medical students and significantly affects their everyday functioning. PMID- 29623148 TI - Diclofenac Potassium in Acute Postoperative Pain and Dysmenorrhoea: Results from Comprehensive Clinical Trial Reports. AB - We compared the efficacy of diclofenac potassium in unpublished clinical study reports (CSRs) and published reports to examine publication bias, industry bias, and comprehensiveness. Novartis provided CSRs of randomised double-blind trials of diclofenac potassium involving postoperative patients following third molar extraction (3 trials, n=519), gynaecological surgery (3 trials, n=679), and dysmenorrhoea (2 trials, n=711) conducted in 1988-1990. Searches identified published reports of 6 trials. Information from 599/1909 patients was not published; trials with 846/1909 patients were published in a defunct journal. Greater methodological information in CSRs contributed to lesser risk of bias than published trials. Numbers needed to treat (NNT) from CSRs for all six postoperative trials for at least 50% of maximum pain relief over 6 h were 2.2 (95% confidence interval, 1.9-2.6) and 2.1 (1.8-2.4) for 50 and 100 mg diclofenac potassium, respectively. A Cochrane review of published trial data reported NNTs of 2.1 and 1.9, and one comprehensive analysis reported NNTs of 2.2 and 2.1, respectively. All analyses had similar results for patients remedicating within 8 h. No data from dysmenorrhoea CSRs appeared in a Cochrane review. CSRs provide useful information and increase confidence. Stable efficacy estimates with standard study designs reduce the need for updating reviews. PMID- 29623149 TI - Synthesis and Combined Experimental and Theoretical Characterization of Dihydro tetraaza-acenes. AB - We present a combined experimental and theoretical study of electronic and optical properties of dihydro-tetraaza-acenes (DHTAn). Using solvent-free condensation, we are able to synthesize not only DHTA5 but also the longer DHTA6 and DHTA7 molecules. We then investigate their gas-phase electronic structures by means of ab initio density functional calculations employing an optimally tuned range-separated hybrid functional. By comparing with the parent linear oligoacenes (nA) and based on computed ionization potentials and electron affinities, we predict DHTAn molecules to be more stable than acenes of the same length, where we expect DHTAn molecules to be persistent at least up to n = 7 rings. We further exploit the analogy with nA by analyzing the entire intramolecular pi-band structure of the DHTAn molecules. This clearly reveals that the additional two electrons donated by the dihydropyrazine group are delocalized over the entire molecule and contribute to its pi-electron system. As a consequence, the symmetry of the frontier orbitals of DHTAn differs from that of the parent nA molecule. This also affects the UV-vis absorption spectra which have been measured for DHTA5, 6, and 7 dissolved in dimethyl sulfoxide and analyzed by means of excited state calculations within a time-dependent density functional theory framework. PMID- 29623150 TI - Scalable Bayesian nonparametric regression via a Plackett-Luce model for conditional ranks. AB - We present a novel Bayesian nonparametric regression model for covariates X and continuous response variable Y ? R. The model is parametrized in terms of marginal distributions for Y and X and a regression function which tunes the stochastic ordering of the conditional distributions F (y|x). By adopting an approximate composite likelihood approach, we show that the resulting posterior inference can be decoupled for the separate components of the model. This procedure can scale to very large datasets and allows for the use of standard, existing, software from Bayesian nonparametric density estimation and Plackett Luce ranking estimation to be applied. As an illustration, we show an application of our approach to a US Census dataset, with over 1,300,000 data points and more than 100 covariates. PMID- 29623151 TI - Nipple-Areolar Complex Reconstruction: A Review of the Literature and Introduction of the Rectangle-to-Cube Nipple Flap. AB - Objective: There are many approaches to nipple-areola complex reconstruction. Tissue quality and thickness, desired nipple location and size, scar position, and surgeon preference all play a role in selecting a technique. We present the rectangle-to-cube nipple flap, a new technique for challenging nipple reconstruction. A review of published techniques is compared and contrasted with this flap design. Methods: Following bilateral total skin-sparing mastectomies, a patient with breast cancer underwent breast reconstruction with tissue expanders and subsequent nipple reconstruction with the rectangle-to-cube nipple flap. An inferiorly based rectangular flap with medial and lateral extensions is designed inferior to the transverse scar. Upon elevation and rotation, the medial and lateral flaps form a cube. Results: In all cases of rectangle-to-cube nipple flaps performed at our institution, adequate nipple projection and patient satisfaction have been achieved at 2-month postoperative evaluation. Conclusion: The rectangle-to-cube nipple flap provides sustained nipple projection due to the de-epithelialized base on which the flap sits. The rectangle-to-cube nipple flap also takes advantage of a long transverse scar, and it can be extended to include longer scars for scar revisions. PMID- 29623147 TI - Chronic Pain in Inflammatory Arthritis: Mechanisms, Metrology, and Emerging Targets-A Focus on the JAK-STAT Pathway. AB - Chronic pain is nowadays considered not only the mainstay symptom of rheumatic diseases but also "a disease itself." Pain is a multidimensional phenomenon, and in inflammatory arthritis, it derives from multiple mechanisms, involving both synovitis (release of a great number of cytokines) and peripheral and central pain-processing mechanisms (sensitization). In the last years, the JAK-STAT pathway has been recognized as a pivotal component both in the inflammatory process and in pain amplification in the central nervous system. This paper provides a summary on pain in inflammatory arthritis, from pathogenesis to clinimetric instruments and treatment, with a focus on the JAK-STAT pathway. PMID- 29623152 TI - Multiple Peripheral Schwannomas. PMID- 29623153 TI - Neurofibromas on the Hands. PMID- 29623154 TI - Choosing Wisely Together: Physical and Occupational Therapy Consultation for Acute Neurology Inpatients. AB - Background: Although many hospitalized neuroscience patients have physical and occupational therapy (rehabilitation) needs, patients with none or minimal physical impairments frequently receive rehabilitation consultation, diverting from patients with greatest need. Methods: A multidisciplinary team on the general and cerebrovascular neurology acute inpatient services mapped the rehabilitation consultation process, resulting in multiple implemented interventions including physician education on appropriate acute rehabilitation consultations, modification of multidisciplinary rounds, and discussion of patient rehabilitation needs throughout hospitalization. Nurses used the same functional impairment measurement tool used by physical and occupational therapists, the Activity Measure for Post-Acute Care Inpatient Short Forms (Basic Mobility and Activity domains). Results: The rate for initial rehabilitation consults for patients with no limitations in mobility or activity during the 6 month baseline period was 12%, which was decreased to 7% and 10% during the 6 month intervention and sustain periods, respectively (P < .001). The baseline rate for patients with no limitations receiving both physical therapy and occupational therapy consultations was 62% and was decreased to 21% and 39% in the intervention and sustain periods, respectively (P < .001). Rehabilitation sessions per hospital day increased for patients with high functional impairments, from 0.52 at baseline to 0.64 in the intervention and 0.66 in the sustain periods (P = .02), which equated to 1 more rehabilitation visit per patient hospitalization. Conclusions: A multifaceted intervention led to improved utilization of acute inpatient rehabilitation consultation while increasing the frequency of rehabilitation treatment for patients with highest functional impairment. PMID- 29623155 TI - Emergency Medicine Pharmacist Impact on Door-to-Needle Time in Patients With Acute Ischemic Stroke. AB - Background and Purpose: Decreased door-to-needle (DTN) time with tissue plasminogen activator (tPA) for acute ischemic stroke is associated with improved patient outcomes. Emergency medicine pharmacists (EMPs) can expedite the administration of tPA by assessing patients for contraindications, preparing, and administering tPA. The purpose of this study was to determine the impact of EMPs on DTN times and clinical outcomes in patients with acute ischemic stroke who receive tPA in the emergency department. Methods: A retrospective, single-center, cohort study of patients who received tPA between August 1, 2012, and August 30, 2014, was conducted to compare DTN times with or without EMP involvement in stroke care. Secondary outcomes included changes in neurological status as measured by the National Institutes of Health Stroke Scale (NIHSS), length of hospital stay, discharge disposition, symptomatic intracranial hemorrhage, and in hospital all-cause mortality. Results: A total of 100 patients were included. The EMPs were involved in the care of 49 patients. The EMP involvement was associated with a significant improvement in DTN time (median 46 [interquartile range IQR: 34.5-67] vs 58 [IQR: 45-79] minutes; P = .019) and with receiving tPA within 45 minutes of arrival (49% vs 25%, odds ratio [OR]: 2.81 [95% confidence interval [CI]: 1.21-6.52]). National Institutes of Health Stroke Scale scores were significantly improved at 24 hours post-tPA in favor of the EMP group (median NIHSS 1 [IQR: 0-4] vs 2 [IQR: 1-9.25]; P = .047). Conclusions: The EMP involvement in initial stroke care was associated with a significant improvement in DTN time. PMID- 29623156 TI - Prognostic Value of the Neurological Examination in Cardiac Arrest Patients After Therapeutic Hypothermia. AB - Objectives: Current prognostication guidelines for cardiac arrest (CA) survivors predate the use of therapeutic hypothermia (TH). The prognostic value and ideal timing of the neurological examination remain unknown in the setting of TH. Design: Patients (N = 291) admitted between 2007 and 2015 to Columbia University intensive care units for TH following CA had neurological examinations performed on days 1, 3, 5, and 7 postarrest. Absent pupillary light response (PLR), absent corneal reflexes (CRs), and Glasgow coma scores motor (GCS-M) no better than extension were considered poor examinations. Poor outcome was recorded as cerebral performance category score >=3 at discharge and 1 year. Predictive values of examination maneuvers were calculated for each time point. Main Results: Among the 137 survivors to day 7, sensitivities and negative predictive values were low at all time points. The PLR had false positive rates (FPRs) of 0% and positive predictive values (PPV) of 100% from day 3 onward. For the CR and GCS-M, the FPRs decreased from day 3 to 5 (9% vs 3%; 21% vs 9%), while PPVs increased (91% vs 96%; 90% vs 95%). Excluding patients who died due to withdrawal of life-sustaining therapy (WLST) did not significantly affect FPRs or PPVs, nor did assessing outcome at 1 year. Conclusions: A poor neurological examination remains a strong predictor of poor outcome, both at hospital discharge and at 1 year, independent of WLST. Following TH, the predictive value of the examination is insufficient at day 3 and should be delayed until at least day 5, with some additional benefit beyond day 5. PMID- 29623157 TI - Collaborative Comanagement Between Neurohospitalists and Internal Medicine Hospitalists Decreases Provider Costs and Enhances Satisfaction With Neurology Care at an Academic Medical Center. AB - Background and Purpose: The majority of academic medical centers are moving to a neurohospitalist model of care for hospital neurology coverage. Potential benefits over a more traditional academic model of patient care include greater expertise in acute neurologic disease, increased efficiency, and improved availability to patients, providers, and learners. Despite these perceived advantages, switching to a neurohospitalist model can come at substantial financial cost, so finding ways to maximize the positive impact of a limited number of neurohospitalists is very important to the future health of academic neurology departments. Over the past 7 years, we have implemented a model for inpatient neurological care based on an intimate collaborative relationship between the neurology and hospital medicine services at our main academic hospital. Our goal was to optimize the value of care by decreasing cost while improving quality. Methods: Cost and revenue associated with professional services was evaluated on a yearly basis. As part of ongoing quality improvement efforts, yearly surveys were administered to referring providers during the transition to a collaborative care model in which NHs and medicine hospitalists comanage neurology inpatients. Results: Net operating loss was dramatically decreased upon transition to the new care model. Concomitantly, there was a robust positive impact on perception of overall quality, timeliness, and communication skills of neurology services. Conclusions: Collaborative comanagement is an effective strategy to improve overall satisfaction with neurology services at a tertiary academic medical center while maintaining financial viability. PMID- 29623158 TI - Undiagnosed Partial Ornithine Transcarbamylase Deficiency Presenting Postoperatively as Agitated Delirium. AB - Partial ornithine transcarbamylase deficiency (pOTCD), an enzymatic defect within the urea cycle, is an increasingly recognized etiology for hyperammonemia of unclear source following a stressor within female adults. Here we present a case of newly diagnosed pOTCD following a systemic stressor and prolonged hospitalization course. From a neurological perspective, prompt recognition provided the patient with a swift and near complete recovery. We briefly review the pertinent literature pertaining to this genetically based condition including historical context and current therapeutic approaches. Given the potential morbidity of prolonged hyperammonemia, neurohospitalists need to be aware of partial ornithine transcarbamylase as an entity. PMID- 29623159 TI - Diagnosing Ring-Enhancing Lesions in the Brain of a Patient With AIDS Without Brain Biopsy: A Case of Central Nervous System Histoplasmoma. AB - We report a case of a Puerto Rican male with advanced AIDS who presented with multiple falls and pancytopenia. Magnetic resonance imaging (MRI) of the brain, as initial workup, revealed 2 ring-enhancing brain lesions. Initial cerebrospinal fluid analysis revealed minimal cells, mildly elevated protein, and no organism seen on gram stain. Due to prohibitive thrombocytopenia, brain biopsy was deferred. He had neither clinical nor radiographic improvement despite empiric therapy for both toxoplasmosis and bacterial abscesses. Indicated by pancytopenia, bone marrow (BM) aspiration was performed. Culture of BM aspirate grew Histoplasma capsulatum. Urine histoplasma antigen was markedly elevated. He was treated with liposomal amphotericin B (LamB) for progressive disseminated histoplasmosis with probable central nervous system involvement. Cerebrospinal fluid histoplasma antigen obtained after 2 months of LamB was detected. After prolonged course of LamB, he took itraconazole. Brain MRI at 7-month follow-up revealed significant improvement from baseline study. PMID- 29623161 TI - Bilateral Middle Cerebral Artery Occlusion In Rapid Succession During Thrombolysis. PMID- 29623160 TI - Geriatric Basics for the Neurohospitalist. AB - Due to the increasing age of the population, neurohospitalists are more frequently caring for old and very old people. Fundamental definitions and topics related to geriatric medicine are therefore of particular importance. In this review, common issues encountered in geriatric patients hospitalized on the neurology service are discussed. Focus is put on the geriatric assessment, multiprofessional diagnostic and therapeutic procedures, geriatric syndromes, pharmacotherapy of the aged, delirium, pain, and palliative management as they are relevant for the neurohospitalist. In addition, ethical questions are addressed. PMID- 29623162 TI - Tolosa-Hunt Syndrome. PMID- 29623163 TI - Encephalomyelitis After Varicella Zoster Reactivation in an Immunocompromised Patient. PMID- 29623164 TI - Wernicke's Encephalopathy 5 Years After a Whipple Procedure. PMID- 29623165 TI - Guest Editor Neal Kleiman Leads Issue on the Current Status of Stents. PMID- 29623166 TI - Stenting: the Latest Frontier in Percutaneous Intervention. PMID- 29623167 TI - Current Indications for Stenting: Symptoms or Survival CME. AB - The major goals of treating ischemic heart disease are to reduce angina, improve quality of life, and ultimately reduce mortality. While medical therapy can effectively address these aims, there is still much research and debate about the role of percutaneous coronary intervention in the treatment spectrum specifically, whether or not stenting prolongs life or simply treats symptoms without impacting survival. The data supporting revascularization for survival benefit came from patients who underwent bypass graft surgery prior to the introduction of effective medical management. Although both physicians and patients continue to believe in the life-saving ability of coronary stenting, little data exist to support this belief outside of when used during an acute myocardial infarction. Strategy trials designed to test the benefit of coronary stenting have limitations that have curbed physicians' willingness to accept the results, but they provide the best evidence for how to optimally manage these patients. In this article, we explore the data supporting the use of coronary stenting for various indications and the questions that remain to be answered. PMID- 29623168 TI - Stenting in Primary Percutaneous Coronary Intervention for Acute ST-Segment Elevation Myocardial Infarction. AB - The treatment of ST-segment elevation myocardial infarction (STEMI) has advanced dramatically over the past 30 years since the introduction of reperfusion therapies, such that mechanical reperfusion with primary percutaneous coronary intervention is now the standard of care. With STEMI, as with other forms of acute coronary syndrome, stent deployment in culprit lesions is the dominant form of reperfusion in the developed world and is supported by contemporary guidelines. However, the precise timing of stenting and the extent to which both culprit and non-culprit lesions should be treated continue to be active areas of study. In this review, we revisit key data that support the use of mechanical reperfusion therapy in STEMI patients and explore the optimal timing for and extent of stent implantation in this complex patient group. We also review data surrounding the deleterious effects of untreated residual myocardial ischemia, the importance of complete revascularization, and the recent data exploring culprit-only versus multivessel stenting in the STEMI setting. PMID- 29623169 TI - Mechanical Circulatory Support in High-Risk Percutaneous Coronary Intervention. AB - Due to advancing age and increasing comorbidities, the current population has a higher incidence of complex coronary artery disease, often without surgical options for revascularization. In this setting, hemodynamic support devices are an important adjunct in the interventionist's toolbox as they allow for a safer, more effective procedure. The following paper reviews the indications of various available mechanical support devices, highlights their clinical data and technical parameters, and offers a practical approach towards appropriate patient and device selection. PMID- 29623170 TI - A Practical Approach to Assessing Stent Results with IVUS or OCT. AB - Coronary angiography is routinely used to assess the extent and severity of coronary artery disease and for decision-making during percutaneous coronary interventions (PCI). However, it is sometimes inadequate for deciding a strategy and defining optimal stenting outcomes. In this review, we present a comprehensive and practical approach to PCI using intravascular ultrasound or optical coherence tomography to optimize stent deployment and assess procedural complications after stent implantation. PMID- 29623171 TI - Bioresorbable Coronary Scaffolds: Deployment Tips and Tricks and the Future of the Technology. AB - Bioresorbable scaffolds (BRS) were developed as an alternative to drug-eluting stents (DES) to facilitate vessel restoration and reduce the risk of future adverse events. However, recent meta-analyses and "real-world" registries have raised some concern about the safety of this novel technology, especially due to an increased risk of thrombosis within the first weeks of scaffold implantation. These devices appear to be less forgiving to poor implantation strategies when compared to contemporary DES. Moreover, problems with the first generation of these devices-bulky struts and high crossing prolife, prolonged resorption time, lack of x-ray visibility, and limited tolerance to postdilation-have restricted their clinical application and negatively impacted their short- to mid-term safety performance. However, the potential for long-term improvements has encouraged further research into strategies to overcome these limitations, and potentially safer next-generation devices are already undergoing in-human clinical evaluations. Based on the current literature and our center's experience with these devices, this review discusses various approaches to optimize BRS implantation, drawbacks related to current-generation BRS, and potentially advantageous features of three next-generation scaffold systems. PMID- 29623172 TI - Chronic Total Occlusion Coronary Intervention: In Search of a Definitive Benefit. AB - Percutaneous coronary intervention (PCI) of chronic coronary total occlusion is the latest frontier in percutaneous intervention. There are vast improvements in the initial success and safety of the procedure as well as a better understanding of appropriateness and benefits. Advances in technology and skill allow for increased utilization of PCI in cases of chronic coronary total occlusion, with benefits regarding symptoms and quality of life. Percutaneous coronary intervention for chronic coronary total occlusion can correct ischemia and achieve complete revascularization while avoiding traditional coronary bypass grafting, although survival benefits remain unclear. PMID- 29623173 TI - Spontaneous Closure of a Secundum Atrial Septal Defect. AB - Spontaneous closure of an atrial septal defect (ASD) is well described in pediatric cardiology but may be less familiar to adult internists and cardiologists. We report a moderately sized 6-mm ASD that closed spontaneously without intervention. A literature review found that a smaller defect size and an early age of diagnosis are the most important predictors of closure. Possible mechanisms of a spontaneous ASD closure include adaptive endothelial migration, limited myocardial proliferation, and fibroblast migration with extracellular matrix deposition. PMID- 29623174 TI - A Double Whammy: Severe Aortic Stenosis and Cocaine Overwhelm the Mitral Valve. AB - A 50-year-old man presented with acute onset dyspnea following cocaine use. He had severe aortic stenosis (AS), mild mitral regurgitation (MR) due to mitral valve prolapse, and no coronary artery disease on recent coronary angiography. He was in acute heart failure with signs of impending cardiogenic shock. Urgent bedside echocardiography revealed hyperdynamic left ventricular systolic function with acute severe MR from a ruptured chordae tendineae. The acute cocaine-induced spike of his already elevated left ventricular systolic pressure from severe AS likely precipitated chordal rupture of his vulnerable mitral valve. This patient underwent emergent mitral and aortic valve replacements. Although cocaine use has been associated with a myriad of cardiovascular complications, acute MR due to chordal rupture has not, to our knowledge, been previously reported in this setting. Prompt diagnosis with echocardiography and surgical intervention are of paramount importance in the management of acute MR. PMID- 29623175 TI - Ruptured Aortic Pseudoaneurysm: An Unusual Cause of Recurrent Lightheadedness and Cough. PMID- 29623176 TI - Renal Artery Stenosis: To Stent or Not to Stent. AB - The column in this issue is supplied by Hassan N. Ibrahim, M.D., director of the Division of Kidney Diseases and Hypertension in the Department of Medicine at Houston Methodist Hospital and a fellow of the American Society of Nephrology. Dr. Ibrahim joined Houston Methodist in May 2017 after serving as a professor of medicine and chief of nephrology at the University of Minnesota. PMID- 29623177 TI - Poet's Pen: Ulysses. AB - In the nineteenth century, when poetry was more widely read and memorized, Alfred, Lord Tennyson (1809-1833) was hugely popular, and no poem of his was more popular and better known than "Ulysses." Even today many know the rousing call to action, which closes the poem: "To strive, to seek, to find, and not to yield." Ulysses, the Roman name for Odysseus, has returned home an old man after 20 years of fighting in Troy and wandering, and he faces an existential crisis: the tension between his obligation to his wife Penelope, son Telemachus, and his kingdom and his need to continue a personal journey of discovery. PMID- 29623178 TI - Dr. Phil's Art Corner: Searching and Cobra Canyon. AB - Philip Alexander, M.D., is a native Texan, retired physician, and accomplished musician and artist. After 41 years as an internal medicine physician, Dr. Phil retired from his practice in College Station in 2016. A lifelong musician and former music professor, he often performs as an oboe soloist for the Brazos Valley Symphony Orchestra. He began exploring visual art in 1980, evolving from pencil sketches-including an official White House portrait of President Ronald Reagan-to the computer-generated drawings featured in this journal. His images, which first appeared in this journal in the spring of 2012, are his own original creations. PMID- 29623179 TI - Co-expression of MYC and BCL2 predicts poorer outcomes for relapsed/refractory diffuse large B-cell lymphoma with R-ICE and intent to transplant. AB - Diffuse large B-cell lymphoma (DLBCL) with co-expression of MYC and BCL2 protein by immunohistochemistry (IHC) - that is, double-expresser lymphoma (DEL) - is associated with poor outcomes after standard frontline therapy. Less is known about the prognostic impact of DEL in patients with relapsed/refractory disease treated with salvage therapy and autologous stem cell transplantation (ASCT). We analyzed the outcomes of 167 patients with relapsed/refractory DLBCL treated with R-ICE (rituximab, ifosfamide, carboplatin and etoposide), of whom 111 patients (66%) underwent ASCT. Using predefined cutoffs for positivity by IHC at relapse for MYC and BCL2 of ?40% and ?50% of positive tumor cells, respectively, 26 patients (16%) were categorized as DEL and the rest as non-DEL. Overall and complete response rates to R-ICE did not differ between DEL and non-DEL. With a median follow up of 20 months, the 3-year progression-free survival (PFS) and overall survival (OS) rates for DEL were inferior compared to non-DEL (for PFS: 6% versus 33%, p = 0.044, for OS: 39% versus 56%, p = 0.03). The negative impact of DEL on PFS and OS remained significant on multivariable analysis. In conclusion, positive DEL status predicts poorer outcomes following salvage therapy. PMID- 29623181 TI - Dealing with uncertainty in the treatment of Helicobacter pylori. AB - Helicobacter pylori treatment may be viewed as an uncertain situation, where current knowledge is insufficient to provide evidence-based recommendations for all possible scenarios. Evidence suggests that, under uncertainty conditions, a few simple rules of thumb tend to work better than complex algorithms. Overall, five evidence-based rules of thumb are suggested: (1) Use four drugs; (2) Use maximal acid inhibition; (3) Treat for 2 weeks; (4) Do not repeat antibiotics after treatment failure; and (5) If your treatment works locally, keep using it. These simple rules of thumb may help the reader to select the best alternative for a given patient, choosing between the heterogeneous recommendations provided by the many different consensus conferences on H. pylori treatment recently published. PMID- 29623180 TI - Pembrolizumab and its role in relapsed/refractory classical Hodgkin's lymphoma: evidence to date and clinical utility. AB - Immune evasion is a critical mechanism of malignant cell survival, and relies in part on molecular signaling through the programmed cell death 1 (PD-1)/PD-1 ligand (PD-L1) axis that contributes to T cell exhaustion. Immune modulatory therapy with monoclonal antibodies against PD-1 designed to enhance antitumor immune response have shown promise in the treatment of advanced solid tumors and hematologic malignancies. Classical Hodgkin's lymphoma (cHL), a unique B cell malignancy characterized by an extensive but ineffective immune cell infiltrate surrounding a small number of tumor cells, has shown significant response to anti PD-1 directed therapy. The anti-PD-1 monoclonal antibodies nivolumab and pembrolizumab have shown similarly remarkable activity in relapsed/refractory cHL and have been approved by the Food and Drug Administration for treatment of this disease. In this article we review the rationale of targeting the PD-1/PD-L1 axis in cHL and the pharmacology of pembrolizumab, and summarize the data on activity and safety profile of this agent in the treatment of relapsed/refractory cHL. We also discuss the potential benefits and pitfalls of using PD-1 blockade in the setting of allogeneic stem-cell transplantation, and summarize ongoing prospective trials of single-agent pembrolizumab and combination strategies as well as future directions. PMID- 29623182 TI - Metabolic responses to drought stress in the tissues of drought-tolerant and drought-sensitive wheat genotype seedlings. AB - An in-depth understanding of the effects of drought stress on plant metabolism is necessary to improve the drought tolerance of wheat and to utilize genetic resources for the development of drought stress-tolerant wheat varieties. In this study, the profiles of 58 key metabolites produced by wheat seedlings in response to drought stress were investigated to determine various physiological processes related to drought tolerance between drought-tolerant and drought-sensitive wheat genotypes. Results showed that the wheat metabolome was dominated by sugars, organic acids and amino acids; the wheat metabolome played important roles to enhance the drought tolerance of shoots. Under drought stress, JD17 exhibited higher growth indices and higher photosynthesis ability than JD8. A high level of compatible solutes and energy in shoots were essential for wheat to develop drought tolerance. Drought also caused system alterations in widespread metabolic networks involving transamination, tricarboxylic acid cycle, glycolysis, glutamate-mediated proline biosynthesis, shikimate-mediated secondary metabolisms and gamma-aminobutyric acid metabolisms. Long-term drought stress resulted in the drought-tolerant wheat genotype JD17, which induced metabolic shifts in the tricarboxylic acid cycle and glycolysis with the depletion of the gamma aminobutyric acid shut process. In JD17, the prolonged drought stress induced a progressive accumulation of osmolytes, including proline, sucrose, fructose, mannose and malic acid. This research extended our understanding of the mechanisms involved in wheat seedling drought tolerance; this study also demonstrated that gas chromatography-mass spectrometry metabolomics could be an effective approach to understand the drought effects on plant biochemistry. PMID- 29623183 TI - Geographic population structure in an outcrossing plant invasion after centuries of cultivation and recent founding events. AB - Population structure and genetic diversity of invasions are the result of evolutionary processes such as natural selection, drift and founding events. Some invasions are also molded by specific human activities such as selection for cultivars and intentional introduction of desired phenotypes, which can lead to low genetic diversity in the resulting invasion. We investigated the population structure, diversity and origins of a species with both accidental and intentional introduction histories, as well as long-term selection as a cultivar. Dyer's woad (Isatis tinctoria; Brassicaceae) has been used as a dye source for at least eight centuries in Eurasia, was introduced to eastern USA in the 1600s, and is now considered invasive in the western USA. Our analyses of amplified fragment length polymorphisms (AFLPs) from 645 plants from the USA and Eurasia did not find significantly lower gene diversity (Hj) in the invaded compared to the native range. This suggests that even though the species was under cultivation for many centuries, human selection of plants may not have had a strong influence on diversity in the invasion. We did find significantly lower genetic differentiation (Fst) in the invasive range but our results still suggested that there are two distinct invasions in the western USA. Our data suggest that these invasions most likely originated from Switzerland, Ukraine and Germany, which correlates with initial biological control agent survey findings. Genetic information on population structure, diversity and origins assists in efforts to control invasive species, and continued combination of ecological and molecular analyses will help bring us closer to sustainable management of plant invasions. PMID- 29623184 TI - Emerging properties of hydrogels in tissue engineering. AB - Hydrogels are three-dimensional polymeric networks filled with water and mimic tissue environments. Therefore, they are considered optimal to deliver cells and engineer damaged tissues. The hydrogel networks have been significantly modified to endow biochemical functionality with adhesive ligands, growth factors, or degradable sites that are helpful to drive proper cell functions. Recently, some of the biophysical properties of hydrogels have emerged as key players in dictating cell fate. Beyond static stiffness, time-dependent stress/strain changes in the interaction with cells and the cell-mediated degradation and matrix synthesis have been demonstrated to shape cell status and tissue repair process. We highlight here the emerging biophysical properties of hydrogels that can motivate tissue engineers to design and develop hydrogels optimally for tissue regeneration. PMID- 29623185 TI - Spontaneously reported adverse drug events related to tapentadol and oxycodone/naloxone in Australia. AB - Background: The rapid increase in prescribing and use of opioids for noncancer pain has coincided with an increase in opioid-related adverse drug events (ADEs). The objective of our study was to describe ADEs related to tapentadol and oxycodone/naloxone spontaneously reported to the Australian Therapeutic Goods Administration (TGA). Methods: Public case detail reports for tapentadol (September 2013-March 2017) and oxycodone/naloxone (April 2011-March 2017) were sourced from the TGA. The total number of public case detail reports for tapentadol were 104 and 249 for oxycodone/naloxone. Demographic characteristics of patients, concomitant medications, causality assessment and outcome were described for each opioid according to the Medical Dictionary for Regulatory Activities (MedDRA) system organ class. Results: The most prevalent ADEs for tapentadol were nervous system disorders (n = 52, 50%), psychiatric (n = 34, 32.7%), gastrointestinal (n = 18, 17.3%), and general disorders and administration site conditions (n = 21, 20.2%). Sixteen (23.2%) of 69 nervous system disorders reaction terms were consistent with serotonin syndrome of which 14 (87.5%) involved documented coadministration with another serotonergic medication. The most prevalent ADEs for oxycodone/naloxone were psychiatric disorders (n = 78, 31.3%), gastrointestinal (n = 73, 29.3%), general disorders and administration site conditions (n = 87, 35%), and nervous system disorders (n = 62, 24.9%). There were 40 (16%) public case detail reports for oxycodone/naloxone with the MedDRA reaction terms 'drug withdrawal syndrome' and 'withdrawal syndrome'. Conclusion: The profiles of spontaneous ADE reports for tapentadol and oxycodone/naloxone are largely consistent with their premarketing randomized controlled studies and profiles of opioids in general. Further research into the risk of serotonin syndrome with tapentadol use is warranted. The ADEs suggest clinicians should be cautious when switching patients to oxycodone/naloxone from other opioids. PMID- 29623186 TI - Trigger alerts associated with laboratory abnormalities on identifying potentially preventable adverse drug events in the intensive care unit and general ward. AB - Background: Medication safety strategies involving trigger alerts have demonstrated potential in identifying drug-related hazardous conditions (DRHCs) and preventing adverse drug events in hospitalized patients. However, trigger alert effectiveness between intensive care unit (ICU) and general ward patients remains unknown. The objective was to investigate trigger alert performance in accurately identifying DRHCs associated with laboratory abnormalities in ICU and non-ICU settings. Methods: This retrospective, observational study was conducted at a university hospital over a 1-year period involving 20 unique trigger alerts aimed at identifying possible drug-induced laboratory abnormalities. The primary outcome was to determine the positive predictive value (PPV) in distinguishing drug-induced abnormal laboratory values using trigger alerts in critically ill and general ward patients. Aberrant lab values attributed to medications without resulting in an actual adverse event ensuing were categorized as a DRHC. Results: A total of 634 patients involving 870 trigger alerts were included. The distribution of trigger alerts generated occurred more commonly in general ward patients (59.8%) than those in the ICU (40.2%). The overall PPV in detecting a DRHC in all hospitalized patients was 0.29, while the PPV in non-ICU patients (0.31) was significantly higher than the critically ill (0.25) (p = 0.03). However, the rate of DRHCs was significantly higher in the ICU than the general ward (7.49 versus 0.87 events per 1000 patient days, respectively, p < 0.0001). Although most DRHCs were considered mild or moderate in severity, more serious and life-threatening DRHCs occurred in the ICU compared with the general ward (39.8% versus 12.4%, respectively, p < 0.001). Conclusions: Overall, most trigger alerts performed poorly in detecting DRHCs irrespective of patient care setting. Continuous process improvement practices should be applied to trigger alert performance to improve clinician time efficiency and minimize alert fatigue. PMID- 29623187 TI - Moxifloxacin-induced tinnitus in an older adult. AB - An increased risk of bacterial resistance toward fluoroquinolones and the increased risk of disabling and serious adverse effects prompted the US Food and Drug Administration to recommend limiting fluoroquinolone use to the treatment of community-acquired pneumonia, skin and skin-structure infections, bacterial sinusitis, plague, chronic bronchitis exacerbations, and complicated intra abdominal infections. We report a case of moxifloxacin-induced tinnitus in an older adult prescribed oral moxifloxacin 400 mg for 5 days for the treatment of acute diverticulitis, due to allergies to nonfluoroquinolone preferred agents. A thorough literature review provided few other reported incidents of this rare and serious adverse event. PMID- 29623189 TI - Mitochondrial dysfunction in diabetic neuropathy may be involved in the development of neuropathic pain via a reduction in neurosteroid synthesis. AB - Background: Recent work in a model of diabetic neuropathy revealed that layer 2/3 cortical pyramidal neurones of the pain pathway exhibited reduced endogenous neurosteroid modulation of the GABA AR and exogenously applied neurosteroids had an exaggerated impact. It is postulated that this is related to reduced precursor synthesis, due to mitochondrial dysfunction in diabetic neuropathy. Benzodiazepines are also known to activate neurosteroidogenesis by binding to mitochondrial translocator protein (TSPO). This study explored the differential effect of diazepam on GABA AR modulation via neurosteroidogenesis in diabetic and wild type (WT) mice. Methods: Whole-cell patch-clamp technique was used on slices of neural tissue. Electrophysiological recordings were obtained from layer 2/3 cortical pyramidal neurons of the pain pathway from mice with type-II diabetic neuropathy ( ob/ob) and WT controls aged 60-80 days. Results: There was a key difference in the response of the WT and ob/ob cortical neurons to simultaneous incubation with diazepam and flumazenil. In contrast, diazepam and the 5a reductase inhibitor finasteride, individually or in combination, produced the same response in both strains. Conclusions: The exaggerated effect of diazepam on GABAergic inhibitory tone in the ob/ob, despite the presence of the GABA AR benzodiazepine antagonist flumazenil is likely observed due to physiological upregulation of key neurosteroidogenic enzymes in response to the reduced pregnenolone synthesis by the mitochondria. By increasing pregnenolone via TSPO activation, it is possible to promote enhanced neurosteroidogenesis and increase GABAergic inhibitory tone via an alternate route. In diabetic neuropathic pain, mitochondrial dysfunction may play an important role. Enhancing the GABAergic neurosteroid tone could be of potential therapeutic benefit. PMID- 29623188 TI - New chimeric RNAs in acute myeloid leukemia. AB - Background: High-throughput next generation sequencing (NGS) technologies enable the detection of biomarkers used for tumor classification, disease monitoring and cancer therapy. Whole-transcriptome analysis using RNA-seq is important, not only as a means of understanding the mechanisms responsible for complex diseases but also to efficiently identify novel genes/exons, splice isoforms, RNA editing, allele-specific mutations, differential gene expression and fusion-transcripts or chimeric RNA (chRNA). Methods: We used Crac, a tool that uses genomic locations and local coverage to classify biological events and directly infer splice and chimeric junctions within a single read. Crac's algorithm extracts transcriptional chimeric events irrespective of annotation with a high sensitivity, and CracTools was used to aggregate, annotate and filter the chRNA reads. The selected chRNA candidates were validated by real time PCR and sequencing. In order to check the tumor specific expression of chRNA, we analyzed a publicly available dataset using a new tag search approach. Results: We present data related to acute myeloid leukemia (AML) RNA-seq analysis. We highlight novel biological cases of chRNA, in addition to previously well characterized leukemia chRNA. We have identified and validated 17 chRNAs among 3 AML patients: 10 from an AML patient with a translocation between chromosomes 15 and 17 (AML-t(15;17), 4 from patient with normal karyotype (AML-NK) 3 from a patient with chromosomal 16 inversion (AML-inv16). The new fusion transcripts can be classified into four groups according to the exon organization. Conclusions: All groups suggest complex but distinct synthesis mechanisms involving either collinear exons of different genes, non-collinear exons, or exons of different chromosomes. Finally, we check tumor-specific expression in a larger RNA-seq AML cohort and identify new AML biomarkers that could improve diagnosis and prognosis of AML. PMID- 29623191 TI - Art in Science Competition invites artworks to the annual exhibition on ISMB 2018 in Chicago. AB - The International Society of Computational Biology and Bioinformatics (ISCB) brings together scientists from a wide range of disciplines, including biology, medicine, computer science, mathematics and statistics. Practitioners in these fields are constantly dealing with information in visual form: from microscope images and photographs of gels to scatter plots, network graphs and phylogenetic trees, structural formulae and protein models to flow diagrams, visual aids for problem-solving are omnipresent. The ISCB Art in Science Competition2017 at the ISCB/ECCB 2017 conference in Prague offered a way to show the beauty of science in art form. Past artworks in this annual exhibition at ISMB combined outstanding beauty and aesthetics with deep insight that perfectly validated the exhibit's approach or went beyond the problem's solution. Others were surprising and inspiring through the transition from science to art, opening eyes and minds to reflect on the work being undertaken. PMID- 29623192 TI - Classification of processes involved in sharing individual participant data from clinical trials. AB - Background: In recent years, a cultural change in the handling of data from research has resulted in the strong promotion of a culture of openness and increased sharing of data. In the area of clinical trials, sharing of individual participant data involves a complex set of processes and the interaction of many actors and actions. Individual services/tools to support data sharing are available, but what is missing is a detailed, structured and comprehensive list of processes/subprocesses involved and tools/services needed. Methods: Principles and recommendations from a published data sharing consensus document are analysed in detail by a small expert group. Processes/subprocesses involved in data sharing are identified and linked to actors and possible services/tools. Definitions are adapted from the business process model and notation (BPMN) and applied in the analysis. Results: A detailed and comprehensive list of individual processes/subprocesses involved in data sharing, structured according to 9 main processes, is provided. Possible tools/services to support these processes/subprocesses are identified and grouped according to major type of support. Conclusions: The list of individual processes/subprocesses and tools/services identified is a first step towards development of a generic framework or architecture for sharing of data from clinical trials. Such a framework is strongly needed to give an overview of how various actors, research processes and services could form an interoperable system for data sharing. PMID- 29623190 TI - Maize phyllosphere microbial community niche development across stages of host leaf growth. AB - Background: The phyllosphere hosts a variety of microorganisms, including bacteria, which can play a positive role in the success of the host plant. Bacterial communities in the phylloplane are influenced by both biotic and abiotic factors, including host plant surface topography and chemistry, which change in concert with microbial communities as the plant leaves develop and age. Methods: We examined how the Zea mays L. leaf microbial community structure changed with plant age. Ribosomal spacer length and scanning electron microscopic imaging strategies were used to assess microbial community composition across maize plant ages, using a novel staggered experimental design. Results: Significant changes in community composition were observed for both molecular and imaging analyses, and the two analysis methods provided complementary information about bacterial community structure within each leaf developmental stage. Conclusions: Both taxonomic and cell-size trait patterns provided evidence for niche-based contributions to microbial community development on leaves. PMID- 29623193 TI - Comparing organic versus conventional soil management on soil respiration. AB - Soil management has great potential to affect soil respiration. In this study, we investigated the effects of organic versus conventional soil management on soil respiration. We measured the main soil physical-chemical properties from conventional and organic managed soil in Ecuador. Soil respiration was determined using alkaline absorption according to Witkamp. Soil properties such as organic matter, nitrogen, and humidity, were comparable between conventional and organic soils in the present study, and in a further analysis there was no statically significant correlation with soil respiration. Therefore, even though organic farmers tend to apply more organic material to their fields, but this did not result in a significantly higher CO2 production in their soils in the present study. PMID- 29623194 TI - Case Report: Dermoscopic features of oral lichen planus - the evolution of mucoscopy. AB - Dermoscopy, a non-invasive technique for cutaneous diagnosis is being increasingly studied in various disorders of the skin, nails and scalp. However, it has been under-utilized for the diagnosis and characterization of mucosal disorders. The dermoscopic characterization of cutaneous lichen planus and its variants has been well documented with Wickham's striae constituting the hallmark of the condition. However, the dermoscopic features of oral lichen planus with hand-held or videodermoscopy remain to be elucidated. We present the case of a young adult man who presented with asymptomatic white lacy lesions over a bluish black background over the tongue, patchy hyperpigmentation of the buccal mucosa and gingivae, and longitudinal melanonychia involving some nails. History of intake of any drugs preceding the lesions, smoking, chewing of betel nut and dental implants was negative. Family history was non-contributory. There were no cutaneous lesions suggestive of lichen planus. Mucoscopy (dermoscopy of the mucosa, oral in this case) and onychoscopy were done followed by biopsy from the tongue that confirmed the diagnosis of lichen planus. Oral mucoscopy of the tongue revealed a tri-colored pattern with structureless veil-like grey-white areas (modified Wickham's striae), well-demarcated red glossy erosions, and violaceous-to-brown clods. Additionally, vascular pattern of dotted and linear to curved vessels along the borders of leukoplakia-like areas and erosions were observed. Onychoscopy confirmed lichen planus-associated melanonychia. Dermoscopy also proved useful in conveniently ruling out other disorders typified by mucosal and nail pigmentation such as Laugier Hunziker syndrome and drug-induced changes. Although direct oral microscopy has been used in defining features of oral lichen planus, to the best of our knowledge this case is the first report on mucoscopy or dermoscopy of oral lichen planus. PMID- 29623195 TI - Is panic disorder a disorder of physical fitness? A heuristic proposal. AB - Currently, panic disorder (PD) is considered a mental disorder based on the assumptions that panic attacks (PAs) are "false alarms" that arise from abnormally sensitive defense systems in the central nervous system and that PD is treated with therapies specifically acting on anxiety or fear mechanisms. This article aims to propose an alternative perspective based on the results of some experimental studies. Our heuristic proposal suggests not only that PD may be a mental disorder but also that patients with PD have real abnormal body functioning, mainly involving cardiorespiratory and balance systems, leading to a decline in global physical fitness. PAs, as well as physical symptoms or discomfort in some environmental situations, may be "real alarms" signaling that the adaptability resources of an organism are insufficient to respond appropriately to some internal or external changes, thus representing the transient conscious awareness of an imbalance in body functioning. The antipanic properties of several modern treatments for PD may include their beneficial effects on body functions. Although anxiety or fear mechanisms are evidently involved in PD, we hypothesize that a reduction of physical fitness is the "primum movens" of PD, while anxiety or fear is induced and sustained by repeated signals of impaired body functioning. We propose considering panic in a broader perspective that offers a central role to the body and to contemplate the possible role of somatic treatments in PD. PMID- 29623196 TI - Classic and recent advances in understanding amnesia. AB - Neurological amnesia has been and remains the focus of intense study, motivated by the drive to understand typical and atypical memory function and the underlying brain basis that is involved. There is now a consensus that amnesia associated with hippocampal (and, in many cases, broader medial temporal lobe) damage results in deficits in episodic memory, delayed recall, and recollective experience. However, debate continues regarding the patterns of preservation and impairment across a range of abilities, including semantic memory and learning, delayed recognition, working memory, and imagination. This brief review highlights some of the influential and recent advances in these debates and what they may tell us about the amnesic condition and hippocampal function. PMID- 29623197 TI - Recent advances in understanding West Nile virus host immunity and viral pathogenesis. AB - West Nile virus (WNV), a mosquito-borne flavivirus, has been a significant public health concern in the United States for nearly two decades. The virus has been linked to acute viral encephalitis, neurological sequelae, and chronic kidney diseases. Neither antiviral drugs nor vaccines are currently available for humans. In vitro cell culture and experimental animal models have been used to study WNV infection in humans. In this review, we will focus on recent findings and provide new insights into WNV host immunity and viral pathogenesis. PMID- 29623198 TI - Cluster headache: new targets and options for treatment. AB - Cluster headache is a severe headache disorder with considerable impact on quality of life. The pathophysiology of the disease remains poorly understood. With few specific targets for treatment, current guidelines mainly include off label treatment with medication. However, new targets for possible treatment options are emerging. Calcitonin gene-related peptide (CGRP)-targeted medication could become the first (cluster) headache-specific treatment option. Other exciting new treatment options include invasive and non-invasive neuromodulation techniques. Here, we provide a short overview of new targets and treatment options that are being investigated for cluster headache. PMID- 29623199 TI - The physiological functions of central nervous system pericytes and a potential role in pain. AB - Central nervous system (CNS) pericytes regulate critical functions of the neurovascular unit in health and disease. CNS pericytes are an attractive pharmacological target for their position within the neurovasculature and for their role in neuroinflammation. Whether the function of CNS pericytes also affects pain states and nociceptive mechanisms is currently not understood. Could it be that pericytes hold the key to pain associated with CNS blood vessel dysfunction? This article reviews recent findings on the important physiological functions of CNS pericytes and highlights how these neurovascular functions could be linked to pain states. PMID- 29623200 TI - Results of catheter-directed thrombolysis for acute ilio-femoral deep venous thrombosis - A retrospective cohort study. AB - Background: Catheter-directed thrombolysis may prevent post-thrombotic syndrome in patients with ilio-femoral deep venous thrombosis. We performed a retrospective review of prospectively collected follow-up data to evaluate the results of catheter-directed thrombolysis at our institution. Method: Patients admitted for venous thrombolysis were included in the study and their files screened for information regarding results and technical aspects of treatment and patient status on follow-up. A catheter was inserted under imaging guidance into the thrombosed vein. Through the catheter tissue plasminogen activator was administered. Daily catheter-based venographies were performed to monitor progression in thrombus resolution. After thrombolysis flow-limiting stenosis was stented. Patients started wearing compression stockings and were started on oral anticoagulant therapy. Follow-up visits with ultrasound, magnetic resonance venography and clinical assessment were scheduled at six weeks and three, six, 12 and 24 months. Results: A total of 48 patients underwent catheter-directed thrombolysis, including 36 female patients. Median age was 28 years. Complete lysis of the thrombus was achieved in 43 cases and partial lysis in two cases and 26 stents were placed. No deaths or life-threatening bleeding events occurred. Thirty-two of the patients who achieved full lysis and were followed up remained patent at follow-up. At 12 months seven patients had symptoms of post-thrombotic syndrome. Conclusion: Catheter-directed thrombolysis represents a safe and effective alternative to systemic anticoagulative treatment of deep venous thrombosis with rapid resolution of the thrombus and few complications. Long-term patency shows good validity and this study suggests that catheter-directed thrombolysis is effective in preventing post-thrombotic syndrome. PMID- 29623201 TI - Altered immunoglobulins (A and G) in Ghanaian patients with type 2 diabetes. AB - Objectives: Elevated immunoglobulin levels have been strongly linked to the development and progression of inflammatory disorders such as type 2 diabetes and obesity. This study aimed to evaluate circulating immunoglobulin levels and to identify other metabolic factors that influence humoral immune response among Ghanaian subjects with type 2 diabetes. Methods: A comparative cross-sectional study conducted at the National Diabetes Management and Research Center, Accra. Eighty persons with type 2 diabetes were age-matched with 78 controls. Immunoglobulin A, immunoglobulin G and immunoglobulin M; interleukin 6; fasting blood glucose; glycated hemoglobin; and lipid parameter concentrations were measured. Blood pressure, anthropometry and body composition indices were also assessed. Results: Median immunoglobulin A and immunoglobulin G (g/L) levels were higher in the case group compared with controls (0.89 vs 0.74, p = 0.043; 7.58 vs 7.29, p < 0.001). Immunoglobulin G, immunoglobulin A and interleukin 6 levels in the case cohort, respectively, associated weakly with fasting blood glucose (r = 0.252, p = 0.001; r = 0.170, p = 0.031; r = 0.296, p = 0.001). There were positive correlations within the control group for immunoglobulin A versus interleukin 6 (r = 0.366, p = 0.001) and within the case group for glycated hemoglobin versus interleukin 6 (r = 0.190, p = 0.020). Conclusion: Our data suggest that humoral immune response is altered in subjects with type 2 diabetes and that serum immunoglobulin levels could serve as useful biomarkers in the investigation and management of diabetes mellitus. PMID- 29623202 TI - Role of high-risk human papillomavirus in the etiology of oral and oropharyngeal cancers in Thailand: A case-control study. AB - Background: Among developing countries, Thailand shows no increase in the incidence of human papillomavirus-driven oropharyngeal cancer. The causal role of human papillomavirus infection in this pathology has not been researched thoroughly. Methods: A hospital-based, case-control study was performed which included 104 patients with newly diagnosed oral and oropharyngeal squamous cell carcinomas and 104 individuals without cancer. The Cervista high-risk human papillomavirus and 16/18 assays were used to detect human papillomavirus. Odds ratios were used to assess the association between high-risk genotypes of human papillomavirus and the cancers. Results: High-risk human papillomavirus was detected in 4 of 52 (7.7%) oral cancer cases, 6 of 52 (11.5%) oropharyngeal cancer cases, and 1 of 104 (0.96%) control subjects. Of 104 cancer patients in the study, 83 were smokers. High-risk human papillomavirus was significantly associated with oropharyngeal cancer (odds ratio = 13.44, 95% confidence interval = 1.6-114.8) but was nonsignificantly associated with oral cancer (odds ratio = 8.58, 95% confidence interval = 0.9-78.9). However, after adjustment for smoking, high-risk human papillomavirus was determined to be nonsignificantly associated with oropharyngeal cancer (adjusted odds ratio = 5.83, 95% confidence interval = 0.8-43.5). Conclusion: Although low human papillomavirus prevalence was observed, the rate of high-risk human papillomavirus infection in the cancer group was still higher than that in the control group. Smoking may have an influence on the etiology of human papillomavirus-related cancers. However, the study is underpowered to clarify the role of human papillomavirus as the independent risk factor for oral and oropharyngeal cancers in the Thai population. PMID- 29623203 TI - Squamous cell carcinoma arising from a thyroglossal duct cyst: A case report and review of the literature. AB - Objectives: Squamous cell carcinoma in a thyroglossal duct cyst is exceedingly rare with only 26 reported cases in the literature so far, which only account for 6% of the patients. Methods: We report a unique case of squamous cell carcinoma arising from a thyroglossal duct cyst in a 49-year-old male who was primarily diagnosed as a thyroglossal duct cyst with inflammation. The patient underwent Sistrunk procedure with wide local excision and radiation therapy as well as chemotherapy post-operatively and had no evidence of recurrence or metastasis for 24 months. In addition, we reviewed the relevant literatures. Results: Whether squamous cell carcinoma actually arises from thyroglossal duct cyst is still controversial; however, carcinoma originating from metaplasia of columnar and squamous epithelium in thyroglossal duct cyst has been well accepted. The gold standard diagnostic method is fine needle aspiration biopsy with ultrasound guidance. Sistrunk procedure alone or with wide excision is likely to be beneficial. Neck dissection is necessary in patients with positive cervical lymphadenopathy. Radiation therapy and chemotherapy have not yet been clearly defined. Conclusion: Squamous cell carcinoma arising from thyroglossal duct cyst is really a rare disease, whose origin, treatments and prognosis still remain uncertain. These are solely based on case reports, case series and expert opinions. Hence, more investigations about squamous cell carcinoma will be conducted in the near future. PMID- 29623204 TI - Cerebral venous thrombosis revealing Behcet's disease in a Moroccan patient: A case report and literature review. AB - Behcet's disease is an inflammatory disease, the origin of which still remains unclear, and it has multiple manifestations, one of them being thrombosis. In this report, we describe the case of a 24-year-old Moroccan patient who presented with headache persisting for more than 2 weeks, which was found to be caused by cerebral venous sinus thrombosis. His medical history of recurrent oral and genital ulcerations, epididymitis and one episode of pericarditis led to the diagnosis of Behcet's disease. We could observe an almost complete relief of symptoms with colchicine therapy, and anticoagulation with warfarin was started for secondary prevention of thrombosis. PMID- 29623205 TI - Near-fatal kinking of mammary graft due to emphysematous lung disease. AB - Left internal mammary artery grafting is commonly used in elective coronary artery bypass graft surgery. We report a near-fatal case with graft kinking upon sternal closure due to distended, emphysematous lungs impinging on the mammary graft. After the sternum was closed, the patient suffered a severe hemodynamic deterioration. Surgical examination revealed kinking of his left internal mammary artery upon sternal closure due to distended, emphysematous lungs impinging on the mammary graft. Using an off-bypass technique, the kink in the mammary graft to the left anterior descending artery was removed by moving the origin of the left internal mammary artery to a hooded graft of a saphenous vein graft instead. In this position, the graft no longer was impinged upon by the distended emphysematous lungs. Subsequently, the patient's sternum was closed without hemodynamic impingement. Although chronic obstructive pulmonary disease is well described to increase complications in coronary artery bypass graft surgery, it has not been previously associated with the kinking of a left internal mammary artery. This report highlights another contribution that chronic obstructive pulmonary disease can make to increased morbidity following coronary artery bypass graft surgery and alerts readers to watch for this complication in susceptible patients. PMID- 29623206 TI - Non-primary nail-plate syphilis in an HIV-infected patient. AB - A 37-year-old Caucasian male, HIV-infected (CDC A2) in 2012 and on antiretroviral therapy, presented for a follow-up visit. On physical examination, a barely discernible light-colored macular rash was observed on the trunk, not involving the palms and soles. However, clear maculo-papular lesions were present over the proximal volar aspect of both forearms. Furthermore, well-demarked purplish, opaque, rough, vertically ridged plaque-like lesions were observed over the proximal portions of fingernails. The patient reported that cutaneous and nail lesions had appeared about 2 months prior and that he had engaged in unprotected sex 5 months before. Serologic tests for syphilis resulted reactive. Intramuscular injection of benzathine penicillin G, 2.4 million units, was administered once a week for 3 weeks. One month after therapy, the rash was no longer present, and at 5 months, nail abnormalities had disappeared. The clinical findings, the serologic results, and the disappearance of skin and nail lesions after the administration of penicillin strongly suggest that this HIV-infected patient had secondary or early late syphilis with skin and nail-plate involvement. We are experiencing a resurgence of syphilis as well as an increase in unusual and/or forgotten clinical manifestations. Syphilis remains a diagnostically challenging disease. PMID- 29623207 TI - A rare case of hypercalcemia-induced pancreatitis in a first trimester pregnant woman. AB - : The objective of the study is to report a case of acute pancreatitis secondary to hypercalcemia induced by primary hyperparathyroidism in a pregnant woman at the end of the first trimester. The case included a 32-year-old woman who was diagnosed with acute pancreatitis and severe hypercalcemia refractory to many regimens of medical therapy in the first trimester of pregnancy. She was successfully treated with parathyroidectomy in the early second trimester with complete resolution of hypercalcemia and pancreatitis. Neonatal course was unremarkable. To our best knowledge, this is a rare case when primary hyperparathyroidism and its complications are diagnosed in the first trimester of pregnancy. In conclusion, primary hyperparathyroidism is a rare life-threatening condition to the fetus and mother especially when associated with complications such as pancreatitis. Early therapeutic intervention is important to reduce the morbidity and mortality. Parathyroidectomy performed in the second trimester can be the only solution. Learning points: Learning how to make diagnosis of primary hyperparathyroidism in a woman during the first trimester of pregnancy.Understanding the complications of hypercalcemia and be aware of the high mortality and sequelae in both fetus and mother.Providing the adequate treatment in such complicated cases with coordinated care between endocrinologists and obstetricians to ensure optimal outcomes. PMID- 29623208 TI - A rare challenging case of co-existent craniopharyngioma, acromegaly and squamous cell lung cancer. AB - : Co-existence of craniopharyngioma and acromegaly has been very rarely reported. A 65-year-old man presented with visual deterioration, fatigue and frontal headaches. Magnetic resonance imaging revealed a suprasellar heterogeneous, mainly cystic, 1.9 * 2 * 1.9 cm mass compressing the optic chiasm and expanding to the third ventricle; the findings were consistent with a craniopharyngioma. Pituitary hormone profile showed hypogonadotropic hypogonadism, mildly elevated prolactin, increased insulin-like growth factor 1 (IGF-1) and normal thyroid function and cortisol reserve. The patient had transsphenoidal surgery and pathology of the specimen was diagnostic of adamantinomatous craniopharyngioma. Post-operatively, he had diabetes insipidus, hypogonadotropic hypogonadism and adrenocorticotropic hormone and thyroid-stimulating hormone deficiency. Despite the hypopituitarism, his IGF-1 levels remained elevated and subsequent oral glucose tolerance test did not show complete growth hormone (GH) suppression. Further review of the pre-operative imaging revealed a 12 * 4 mm pituitary adenoma close to the right carotid artery and no signs of pituitary hyperplasia. At that time, he was also diagnosed with squamous cell carcinoma of the left upper lung lobe finally managed with radical radiotherapy. Treatment with long acting somatostatin analogue was initiated leading to biochemical control of the acromegaly. Latest imaging has shown no evidence of craniopharyngioma regrowth and stable adenoma. This is a unique case report of co-existence of craniopharyngioma, acromegaly and squamous lung cell carcinoma that highlights diagnostic and management challenges. Potential effects of the GH hypersecretion on the co-existent tumours of this patient are also briefly discussed. Learning points: Although an extremely rare clinical scenario, craniopharyngioma and acromegaly can co-exist; aetiopathogenic link between these two conditions is unlikely.Meticulous review of unexpected biochemical findings is vital for correct diagnosis of dual pituitary pathology.The potential adverse impact of GH excess due to acromegaly in a patient with craniopharyngioma (and other neoplasm) mandates adequate biochemical control of the GH hypersecretion. PMID- 29623209 TI - Concurrent primary hyperparathyroidism and pheochromocytoma in a Chinese lady with neurofibromatosis type 1. AB - : We report a case of elderly Chinese lady with neurofibromatosis type-1 presenting with longstanding palpitation, paroxysmal hypertension and osteoporosis. Biochemical testing showed mild hypercalcaemia with non-suppressed parathyroid hormone level suggestive of primary hyperparathyroidism, and mildly elevated urinary fractionated normetanephrine and plasma-free normetanephrine pointing to a catecholamine-secreting pheochromocytoma/paraganglioma. Further scintigraphic investigation revealed evidence of a solitary parathyroid adenoma causing primary hyperparathyroidism and a left pheochromocytoma. Resection of the parathyroid adenoma and pheochromocytoma resulted in normalization of biochemical abnormalities and hypertension. The rare concurrence of primary hyperparathyroidism and pheochromocytoma in neurofibromatosis type-1 is discussed. Learning points: All NF-1 patients who have symptoms suggestive of a pheochromocytoma/paraganglioma (PPGL), even remotely, should undergo biochemical testing.The initial biochemical tests of choice for PPGL in NF-1 are either plasma-free metanephrines or urinary fractionated metanephrines. Any elevations of metanephrines should be carefully evaluated for the presence of PPGLs in NF-1 patients.Primary hyperparathyroidism (PHPT) is described in subjects with NF-1. Due to the lack of epidemiological and functional studies, their association is yet to be substantiated. Meanwhile, PHPT may further exacerbate the metabolic bone defect in these patients and should be treated when present according to published guidelines.Coexistence of PPGL and PHPT can occur in subjects with NF 1, mimicking multiple endocrine neoplasia type 2 (MEN2). PMID- 29623210 TI - New-onset insulin-dependent diabetes due to nivolumab. AB - : Nivolumab, a monoclonal antibody against programmed cell death-1 receptor, is increasingly used in advanced cancers. While nivolumab use enhances cancer therapy, it is associated with increased immune-related adverse events. We describe an elderly man who presented in ketoacidosis after receiving nivolumab for metastatic renal cell carcinoma. On presentation, he was hyperpneic and laboratory analyses showed hyperglycemia and anion-gapped metabolic acidosis consistent with diabetic ketoacidosis. No other precipitating factors, besides nivolumab, were identified. Pre-nivolumab blood glucose levels were normal. The patient responded to treatment with intravenous fluids, insulin and electrolyte replacement. He was diagnosed with insulin-dependent autoimmune diabetes mellitus secondary to nivolumab. Although nivolumab was stopped, he continued to require multiple insulin injection therapy till his last follow-up 7 months after presentation. Clinicians need to be alerted to the development of diabetes mellitus and diabetic ketoacidosis in patients receiving nivolumab. Learning points: Diabetic ketoacidosis should be considered in the differential of patients presenting with metabolic acidosis following treatment with antibodies to programmed cell death-1 receptor (anti-PD-1).Autoimmune islet cell damage is the presumed mechanism for how insulin requiring diabetes mellitus can develop de novo following administration of anti-PD-1.Because anti-PD-1 works by the activation of T-cells and reduction of 'self-tolerance', other autoimmune disorders are likely to be increasingly recognized with increased use of these agents. PMID- 29623211 TI - Shewanella spp. infections in Gran Canaria, Spain: retrospective analysis of 31 cases and a literature review. AB - Introduction: Shewanella spp. can cause severe skin and soft-tissue infections, gastrointestinal infections, otitis and bacteraemia, generally upon contact with seawater or consumption of raw seafood. Recently, a new condition termed 'patera foot' characterized by acute skin and soft-tissue infection has been described in irregular immigrants arriving to the Canary Islands, Spain, in rudimentary boats. Most infections are caused by a single species, Shewanella algae. The improvement of the diagnostic capabilities in clinical microbiology laboratories has resulted in a growing number of cases being reported worldwide, most of them coming from warm regions. Case presentation: In this work, we reviewed the medical records of all the patients with Shewanella infections in the two university hospitals of Gran Canaria (the Canary Islands, Spain) during the period 2000-2016, resulting in the identification of 31 cases. We also conducted a literature review of Shewanella infections reported worldwide in recent years. Conclusion: This case series suggests that Shewanella infections are nosocomially acquired more frequently than previously thought. In addition, the unexpectedly high proportion of multidrug-resistant isolates raises concerns. PMID- 29623212 TI - First report of Lyme disease in Nepal. AB - Introduction: Lyme disease is a tick-borne illness caused by the spirochete Borrelia burgdorferi and is widely reported in the USA, Central Europe, South East Asia and Latin America. Until recently, no scientific report regarding Lyme disease in Nepal had been published. Case presentation: A 32-year-old, previously healthy female visited the hospital with a history of joint pains, fatigue, neck stiffness, tingling sensation and headache. She was initially treated for typhoid fever, brucellosis and malaria, but did not show significant improvement. Doxycycline was prescribed empirically for 3 weeks for the treatment of suspected tick-borne illness. A two-tiered immunoglobulin laboratory testing confirmed Borrelia burgdorferi. She developed post-treatment Lyme disease syndrome after completion of antibiotic therapy. Conclusion: To the best of our knowledge, this is the first report of Lyme disease in Nepal and probably the first documented case of post-treatment Lyme disease syndrome in Asia. Lyme disease might have been overlooked in Nepal and, therefore, patients having clinical signs and symptoms similar to Lyme disease should not be disregarded in differential diagnosis. PMID- 29623213 TI - A case of oropharyngeal Ureaplasma urealyticum infection in a human immunodeficiency virus positive bisexual male co-infected with human papilloma virus and Treponema pallidum. AB - Introduction: Management strategies for sexually transmitted infections (STIs) in their extragenital forms address Neisseria gonorrhoeae and Chlamydia trachomatis alone; whereas increased rates of isolation of other STI agents have been reported from various parts of the world. Their extragenital presence as a reservoir of infection emphasizes the need to screen and treat them at these sites. Case presentation: A 35-year-old human immunodeficiency virus 1 infected bisexual male presented with urethral discharge and multiple ano-genital warts. He was reactive for the venereal disease research laboratory (VDRL) test. He tested positive for Ureaplasma spp. both by culture and PCR at urethral and oropharyngeal sites, but was negative at the rectal site. The patient was successfully treated with doxycycline and penicillin, and was followed up with a test of cure at 6 weeks. Conclusion: In view of the disseminating infections that can be caused by Ureaplasma spp., it makes it important to screen for these infections even at non-genital sites, especially in the immunocompromised. STIs may be asymptomatic and can serve as a reservoir of infection in a population. This report should promote all efforts to formulate guidelines for extragenital screening of all STI pathogens. PMID- 29623214 TI - Mandibular osteomyelitis due to Raoultella species. AB - Introduction: Raoultella is a genus of aerobic Gram-negative bacilli belonging to the family Enterobacteriaceae that are commonly found in water, soil and aquatic environments. With improved bacterial identification techniques, Raoultella species (namely R. planticola and R. ornithinolytica) have been an increasingly reported cause of infections in humans. Case presentation: An 85-year-old man presented to hospital with a several-week history of left jaw pain and trismus. His medical history was significant for left mandibular osteomyelitis treated 1 year previously with amoxicillin-clavulanate. On admission, a computed tomography scan demonstrated a 2.6*1.7*1.6 cm peripherally enhancing collection surrounding the left posterior mandibular body. Two aspirates of the abscess grew a bacterium belonging to the genus Raoultella, with discordant species identification (R. ornithinolytica versus R. planticola) using two different techniques. A potential source of infection included a left lower molar tooth which was extracted months preceding the original diagnosis of osteomyelitis. Conclusion: This is the first case of mandibular osteomyelitis caused by Raoultella species reported in the literature. In contrast to other forms of osteomyelitis, the pathogenesis of mandibular osteomyelitis involves contiguous spread from an odontogenic focus. Risk factors for mandibular osteomyelitis include a history of fracture, irradiation, diabetes and steroid therapy. This report adds to the growing literature of infections caused by this genus of bacteria, and raises the possibility of this organism's role in odontogenic infections. PMID- 29623216 TI - Feasibility of mesenchymal stem cell culture expansion for a phase I clinical trial in multiple sclerosis. AB - Background: Multiple sclerosis is an inflammatory, neurodegenerative disease of the central nervous system for which therapeutic mesenchymal stem cell transplantation is under study. Published experience of culture-expanding multiple sclerosis patients' mesenchymal stem cells for clinical trials is limited. Objective: To determine the feasibility of culture-expanding multiple sclerosis patients' mesenchymal stem cells for clinical use. Methods: In a phase I trial, autologous, bone marrow-derived mesenchymal stem cells were isolated from 25 trial participants with multiple sclerosis and eight matched controls, and culture-expanded to a target single dose of 1-2 * 106 cells/kg. Viability, cell product identity and sterility were assessed prior to infusion. Cytogenetic stability was assessed by single nucleotide polymorphism analysis of mesenchymal stem cells from 18 multiple sclerosis patients and five controls. Results: One patient failed screening. Mesenchymal stem cell culture expansion was successful for 24 of 25 multiple sclerosis patients and six of eight controls. The target dose was achieved in 16-62 days, requiring two to three cell passages. Growth rate and culture success did not correlate with demographic or multiple sclerosis disease characteristics. Cytogenetic studies identified changes on one chromosome of one control (4.3%) after extended time in culture. Conclusion: Culture expansion of mesenchymal stem cells from multiple sclerosis patients as donors is feasible. However, culture time should be minimized for cell products designated for therapeutic administration. PMID- 29623217 TI - Carbon Nano-Structured Neural Probes Show Promise for Magnetic Resonance Imaging Applications. AB - Objective: Previous animal studies have demonstrated that carbon nanotube (CNT) electrodes provide several advantages of preferential cell growth and better signal-to-noise ratio when interfacing with brain neural tissue. This work explores another advantage of CNT electrodes, namely their MRI compatibility. MRI compatible neural electrodes that do not produce image artifacts will allow simultaneous co-located functional MRI and neural signal recordings, which will help improve our understanding of the brain. Approach: Prototype CNT electrodes on polyimide substrates are fabricated and tested in vitro and in vivo in rat brain at 9.4T. To understand the results of the in vitro and in vivo studies, a simulation model based on numerical computation of the magnetic field around a two-dimensional object in a tissue substrate is developed. Main Results: The prototype electrodes are found to introduce negligible image artifacts in structural and functional imaging sequences in vitro and in vivo. Simulation results confirm that CNT prototype electrodes produce less magnetic field distortion than traditional metallic electrodes due to a combination of both superior material properties and geometry. By using CNT films, image artifacts can be nearly eliminated at magnetic fields of strength up to 9.4T. At the same time, the high surface area of a CNT film provides high charge transfer and enables neural local field potential (LFP) recordings with an equal or better signal-to-noise ratio (SNR) than traditional electrodes. Significance: CNT film electrodes can be used for simultaneous MRI and electrophysiology in animal models to investigate fundamental neuroscience questions and clinically relevant topics such as epilepsy. PMID- 29623218 TI - The influence of a peritoneovenous shunt for cirrhotic and malignant intractable ascites on renal function. AB - Background: Peritoneovenous shunts (PVS) are widely used for palliation of intractable ascites caused by peritoneal carcinomatosis (PC) or liver cirrhosis (LC). Some patients who need PVS have renal dysfunction. However, renal dysfunction is considered a relative contraindication. Therefore, it is important to assess renal function before PVS placement. Purpose: To evaluate the relationship between PVS and renal function. Material and Methods: Between October 2007 and July 2015, 60 patients (PC = 47; LC = 10; others = 3) underwent PVS placement for intractable ascites. Changes in estimated glomerular filtration rate (eGFR) and other adverse events (AEs) were retrospectively analyzed. Results: Changes in eGFR before, one day after, and one week after PVS placement could be evaluated in 46 patients. The median eGFR before, one day after, and one week after was 56.5, 59.1, and 64.7 mL/min/1.73 m2, respectively (P < 0.05). These values were 61.6, 72, and 67.1 mL/min/1.73 m2, respectively, in PC patients (n = 34; P < 0.05) and 28.5, 27, and 37.2 mL/min/1.73 m2, respectively, in LC patients (n = 10; P < 0.05). In 17 patients with moderate to severe renal dysfunction (eGFR < 45), these values were 23.4, 23.7, and 30.5 mL/min/1.73 m2, respectively. The most frequent AE was PVS catheter obstruction, which occurred in 12 patients (20.7%). Clinical disseminated intravascular coagulation occurred in six patients (10.3%) and caused death in three patients (5.2%). Conclusion: PVS placement for intractable ascites is associated with various AEs. However, PVS appeared to promote renal function, especially in patients with renal impairment. PMID- 29623220 TI - High Prevalence of Hypertension in Ethiopian and Non-Ethiopian HIV-Infected Adults. AB - Objectives: Prevalence of hypertension has not been studied in the Ethiopian HIV infected population, which represents 60% of the patients in our AIDS unit. Our aim was to identify risk factors and characterize the prevalence of hypertension in the population monitored at our unit. Methods: A retrospective chart review categorized subjects according to their blood pressure levels. Hypertension prevalence was determined and stratified according to variables perceived to contribute to elevated blood pressure. Results: The prevalence of hypertension in our study population was significantly higher compared to the general population (53% versus 20%, P < 0.0001) and was associated with known risk factors and not with patients' viral load and CD4 levels. Ethiopian HIV-infected adults had a prominently higher rate of blood pressure rise over time as compared to non Ethiopians (P = 0.016). Conclusions: The high prevalence of hypertension in this cohort and the rapid increase in blood pressure in Ethiopians are alarming. We could not attribute high prevalence to HIV-related factors and we presume it is part of the metabolic syndrome. The lifelong cardiovascular risk associated with HIV infection mandates hypertension screening and close monitoring in this population. PMID- 29623221 TI - Efficacy of Dexmedetomidine versus Ketofol for Sedation of Postoperative Mechanically Ventilated Patients with Obstructive Sleep Apnea. AB - Patients with sleep apnea are prone to postoperative respiratory complications, requiring restriction of sedatives during perioperative care. We performed a prospective randomized study on 24 patients with obstructive sleep apnea (OSA) who underwent elective surgery under general anesthesia. The patients were equally divided into two groups: Group Dex: received dexmedetomidine loading dose 1 mcg/kg IV over 10 min followed by infusion of 0.2-0.7 mcg/kg/hr; Group KFL: received ketofol as an initial bolus dose 500 mcg/kg IV (ketamine/propofol 1 : 1) and maintenance dose of 5-10 mcg/kg/min. Sedation level (Ramsay sedation score), bispectral index (BIS), duration of mechanical ventilation, surgical intensive care unit (SICU) stay, and mean time to extubation were evaluated. Complications (hypotension, hypertension, bradycardia, postextubation apnea, respiratory depression, and desaturation) and number of patients requiring reintubation were recorded. There was a statistically significant difference between the two groups in BIS at the third hour only (Group DEX 63.00 +/- 3.542 and Group KFL 66.42 +/- 4.010, p value = 0.036). Duration of mechanical ventilation, SICU stay, and extubation time showed no statistically significant differences. No complications were recorded in both groups. Thus, dexmedetomidine was associated with lesser duration of mechanical ventilation and time to extubation than ketofol, but these differences were not statistically significant. PMID- 29623219 TI - Management Strategies for Posttransplant Diabetes Mellitus after Heart Transplantation: A Review. AB - Posttransplant diabetes mellitus (PTDM) is a well-recognized complication of heart transplantation and is associated with increased morbidity and mortality. Previous studies have yielded wide ranging estimates in the incidence of PTDM due in part to variable definitions applied. In addition, there is a limited published data on the management of PTDM after heart transplantation and a paucity of studies examining the effects of newer classes of hypoglycaemic drug therapies. In this review, we discuss the role of established glucose-lowering therapies and the rationale and emerging clinical evidence that supports the role of incretin-based therapies (glucagon like peptide- (GLP-) 1 agonists and dipeptidyl peptidase- (DPP-) 4 inhibitors) and sodium-glucose cotransporter 2 (SGLT2) inhibitors in the management of PTDM after heart transplantation. Recently published Consensus Guidelines for the diagnosis of PTDM will hopefully lead to more consistent approaches to the diagnosis of PTDM and provide a platform for the larger-scale multicentre trials that will be needed to determine the role of these newer therapies in the management of PTDM. PMID- 29623222 TI - The Role of Minimally Invasive Techniques in Scoliosis Correction Surgery. AB - Objective: Recently, minimally invasive surgery (MIS) has been included among the treatment modalities for scoliosis. However, literature comparing MIS to open surgery for scoliosis correction is limited. The objective of this study was to compare outcomes for scoliosis correction patients undergoing MIS versus open approach. Methods: We retrospectively collected data on demographics, procedure characteristics, and outcomes for 207 consecutive scoliosis correction surgeries at our institution between 2009 and 2015. Results: MIS patients had lower number of levels fused (p < 0.0001), shorter surgeries (p = 0.0023), and shorter overall lengths of stay (p < 0.0001), were less likely to be admitted to the ICU (p < 0.0001), and had shorter ICU stays (p = 0.0015). On multivariable regression, number of levels fused predicted selection for MIS procedure (p = 0.004), and multiple other variables showed trends toward significance. Age predicted ICU admission and VTE. BMI predicted any VTE, and DVT specifically. Comorbid disease burden predicted readmission, need for transfusion, and ICU admission. Number of levels fused predicted prolonged surgery, need for transfusion, and ICU admission. Conclusions: Patients undergoing MIS correction had shorter surgeries, shorter lengths of stay, and shorter and fewer ICU stays, but there was a significant selection effect. Accounting for other variables, MIS did not independently predict any of the outcomes. PMID- 29623223 TI - Predictors of Sun Protective Behaviors among Latino Day Laborers. AB - Objectives: Despite the substantial solar ultraviolet radiation experienced by Latino day laborers, little attention has been given to factors that are associated with sun protective behaviors. The purpose of this study was to examine psychological and nonpsychological predictors of sun protective behaviors among Latino day laborers. Methods: This cross-sectional study included a nonrandom sample of 137 Latino day laborers recruited from Mississippi and Illinois. Participants completed a self-report survey instrument, available in English and Spanish, on sun protective behaviors. Results: Multivariate regression results showed that sun protective behaviors were significantly greater among Latino day laborers: (a) who had greater perceptions that their supervisor also engaged in sun protective behaviors (beta = 0.25, p <= 0.01); (b) who reported higher levels of health literacy (beta = 0.23, p <= 0.001); (c) who have greater knowledge of skin cancer risk factors (beta = 0.21, p <= 0.01); and (d) who have skin tone that was self-perceived to be more prone to sunburns (beta = 0.19, p <= 0.01). Conclusions: Latino day laborers possess marginal levels of skin cancer knowledge and engage minimally in sun protective behaviors. Skin cancer prevention interventions are warranted for this high-risk group, particularly in the locations in which Latino day laborers work. PMID- 29623224 TI - Spinal Anaesthesia for Cesarean Section in a Patient with Vascular Type Ehlers Danlos Syndrome. AB - We report the administration of spinal anaesthesia for cesarean delivery in a parturient with vascular Ehlers-Danlos syndrome. Parturients who genetically inherit this disorder are at risk for significant morbidity and mortality. Risks during pregnancy include premature labor, uterine prolapse, and uterine rupture. Additionally, such laboring parturients are at increased risk of hemodynamic volatility, vascular stress, and severe postpartum hemorrhage. Instrumented delivery and cesarean delivery bring additional risks. Nonpregnancy-related complications include excessive bleeding, intestinal rupture, cardiac valvular dysfunction, and arterial dissection. Despite the complexity of this condition, literature focusing on specific intraoperative anaesthetic management is sparse. PMID- 29623225 TI - Ischemic Colitis in Sickle Cell Disease: A Case Report of a Diagnostic Challenge. AB - Microvascular occlusion serves as the underlying mechanism for the multitude of clinical manifestations of sickle cell disease, one of the most prevalent hemoglobinopathies worldwide. Recurrent painful episodes are the hallmark of this condition. Abdominal pain attributed to an acute painful episode can be indistinguishable from a separate and/or more serious intra-abdominal disease process, representing a significant diagnostic dilemma for clinicians. Here we present a rare case of ischemic colitis due to vascular occlusion in a 28-year old man with sickle cell disease. PMID- 29623226 TI - Acute Isolated Hyperbilirubinemia as a Presentation of Alcoholic Liver Disease: A Case Report and Literature Review. AB - Isolated hyperbilirubinemia as a manifestation of alcoholic liver disease without significant liver abnormalities is seen very rarely. We report such a case where a patient with chronic alcoholism presented to the ER with acute jaundice with bilirubin of 24.8 mg/dl, predominantly conjugated in nature along with mild elevation of AST (76 IU/L). There were no other abnormalities of the liver function. The patient underwent extensive laboratory and imaging tests that excluded extrahepatic cholestasis, viral and autoimmune hepatitis, ischemic hepatitis, and so forth. Liver biopsy excluded hemochromatosis, dysplasia, or malignancy and other differentials. Bilirubin gradually trended down to 7.3 mg/dl when alcohol consumption was stopped. PMID- 29623228 TI - Response after Infection-Associated Rise in Clozapine Levels in Treatment Resistant Schizoaffective Disorder. AB - The clinical management of patients with treatment-resistant psychotic disorders is still challenging despite years of extensive research. If first-line antipsychotic treatment proves ineffective, clozapine is considered golden standard. Herein, we report on a patient with schizoaffective disorder that initially showed no response to treatment with clozapine and ECT and therefore reached a therapeutic dead end. After an unintentional exposure to supratherapeutic clozapine levels, related to a pneumonia, a significant and persistent reduction of psychotic symptoms occurred. The report suggests a careful reevaluation of the clozapine dose in cases of treatment-resistant psychotic disorders with failed trials of clozapine. Further increase of dose may prove efficacious, although side effects should be closely monitored. Research to determine the upper threshold of clozapine for antipsychotic efficacy is warranted. PMID- 29623227 TI - Fulminant Diabetes in a Patient with Advanced Melanoma on Nivolumab. AB - Background: Anti-PD-1 agents were approved for advanced melanoma after the landmark trial Checkmate-037. Anti-PD-1 agents can breach immunologic tolerance. Fulminant diabetes is an immune endocrinopathy that results from a violent immune attack leading to complete destruction of pancreatic beta cells in genetically predisposed people. We present a rare case of fulminant diabetes precipitated by anti-PD-1 immunotherapy. Case: A 61-year-old male with advanced melanoma presented with a three-day history of nausea, vomiting, and malaise. He was started on nivolumab and ipilimumab. After the third dose, he developed a generalized rash and was prescribed high-dose prednisone. Labs revealed potassium 9.5 mmol/L, sodium 127 mmol/L, bicarbonate <10 mmol/L, blood glucose 1211 mg/dL, anion gap >31 mmol, arterial blood pH 7.14, and beta-hydroxybutyrate 13.7 mmol/L. He was diagnosed with diabetic ketoacidosis. Hemoglobin A1C was 6.9%. C-peptide was undetectable (<0.1 ng/ml). Glutamic acid decarboxylase autoantibodies, zinc transporter 8 autoantibodies, insulin autoantibodies, islet antigen 2 autoantibodies, and islet cell antibodies were all negative. Conclusion: Anti-PD 1 immunotherapy is effective in cancers refractory to standard chemotherapy. These agents can precipitate autoimmune disorders. As the use of anti-PD-1 agents is expected to rise, physicians should be educated about the potential side effects. We recommend conducting routine blood glucose checks in patients on these agents. PMID- 29623229 TI - Adenocarcinoma of the Colon Disguised as Abdominal Wall Abscess: Case Report and Review of the Literature. AB - Introduction: Abdominal wall invasion by cancerous cells arising from the colon with an overlying secondary infection that presents as an abdominal wall abscess has been encountered previously, but such a symptom is rarely the first presentation of colon cancer. There are very few cases reported in the literature. Case Presentation: In this case report, we present a case of a 66 year-old male presenting with abdominal wall abscess that was refractory to treatment. The patient later was found to have an abdominal wall invasion by an underlying colonic carcinoma. Conclusion: The purpose of this review is to set forth the proper approach when encountering such cases and emphasize on the significance of keeping a high index of suspicion. We also highlight the need for utilizing proper diagnostic imaging modalities prior to invasive intervention. PMID- 29623230 TI - Hepatic Rupture Induced by Spontaneous Intrahepatic Hematoma. AB - The etiology of hepatic rupture is usually secondary to trauma, and hepatic rupture induced by spontaneous intrahepatic hematoma is clinically rare. We describe here a 61-year-old female patient who was transferred to our hospital with hepatic rupture induced by spontaneous intrahepatic hematoma. The patient had no history of trauma and had a history of systemic lupus erythematosus for five years, taking a daily dose of 5 mg prednisone for treatment. The patients experienced durative blunt acute right upper abdominal pain one day after satiation, which aggravated in two hours, accompanied by dizziness and sweating. Preoperative diagnosis was rupture of the liver mass. Laparotomy revealed 2500 mL fluid consisting of a mixture of blood and clot in the peritoneal cavity. A 3.5 cm * 2.5 cm rupture was discovered on the hepatic caudate lobe near the vena cava with active arterial bleeding, and a 5 * 6 cm hematoma was reached on the right posterior lobe of the liver. Abdominal computed tomography (CT) and laparotomy revealed spontaneous rupture of intrahepatic hematoma with hemorrhagic shock. The patient was successfully managed by suturing the rupture of the hepatic caudate lobe and clearing part of the hematoma. The postoperative course was uneventful, and the patient was discharged after two weeks of hospitalization. PMID- 29623231 TI - African Orphan Crops under Abiotic Stresses: Challenges and Opportunities. AB - A changing climate, a growing world population, and a reduction in arable land devoted to food production are all problems facing the world food security. The development of crops that can yield under uncertain and extreme climatic and soil growing conditions can play a key role in mitigating these problems. Major crops such as maize, rice, and wheat are responsible for a large proportion of global food production but many understudied crops (commonly known as "orphan crops") including millets, cassava, and cowpea feed millions of people in Asia, Africa, and South America and are already adapted to the local environments in which they are grown. The application of modern genetic and genomic tools to the breeding of these crops can provide enormous opportunities for ensuring world food security but is only in its infancy. In this review, the diversity and types of understudied crops will be introduced, and the beneficial traits of these crops as well as their role in the socioeconomics of Africa will be discussed. In addition, the response of orphan crops to diverse types of abiotic stresses is investigated. A review of the current tools and their application to the breeding of enhanced orphan crops will also be described. Finally, few examples of global efforts on tackling major abiotic constraints in Africa are presented. PMID- 29623233 TI - Hydrolysis Activity of Virgin Coconut Oil Using Lipase from Different Sources. AB - Two types of lipase, Candida rugosa lipase (CRL) and porcine pancreas lipase (PPL), were used to hydrolyze virgin coconut oil (VCO). The hydrolysis process was carried out under four parameters, VCO to buffer ratio, lipase concentration, pH, and temperature, which have a significant effect on hydrolysis of lipase. CRL obtained the best hydrolysis condition at 1 : 5 of VCO to buffer ratio, 1.5% of CRL concentration, pH 7, and temperature of 40 degrees C. Meanwhile, PPL gave different results at 1 : 4 of VCO to buffer ratio, 2% of lipase concentration, pH 7.5, and 40 degrees C. The highest hydrolysis degree of CRL and PPL was obtained after 16 hours and 26 hours, reaching 79.64% and 27.94%, respectively. Besides, the hydrolysis process was controlled at different time course (every half an hour) at the first 4 hours of reaction to compare the initial hydrolysis degree of these two lipase types. FFAs from hydrolyzed products were isolated and determined the percentage of each fatty acid which contributes to the FFAs mixture. As a result, medium chain fatty acids (MCFAs) made up the main contribution in composition of FFAs and lauric acid (C12) was the largest segment (47.23% for CRL and 44.23% for PPL). PMID- 29623232 TI - Advances in the Preclinical Study of Some Flavonoids as Potential Antidepressant Agents. AB - Flavonoids are phenolic compounds found commonly in plants that protect them against the negative effects of environmental insults. These secondary metabolites have been widely studied in preclinical research because of their biological effects, particularly as antioxidant agents. Diverse flavonoids have been studied to explore their potential therapeutic effects in the treatment of disorders of the central nervous system, including anxiety and depression. The present review discusses advances in the study of some flavonoids as potential antidepressant agents. We describe their behavioral, physiological, and neurochemical effects and the apparent mechanism of action of their preclinical antidepressant-like effects. Natural flavonoids produce antidepressant-like effects in validated behavioral models of depression. The mechanism of action of these effects includes the activation of serotonergic, dopaminergic, noradrenergic, and gamma-aminobutyric acid-ergic neurotransmitter systems and an increase in the production of neural factors, including brain-derived neurotrophic factor and nerve growth factor. Additionally, alterations in the function of tropomyosin receptor kinase B and activity of the enzyme monoamine oxidase A have been reported. In conclusion, preclinical research supports the potential antidepressant effects of some natural flavonoids, which opens new possibilities of evaluating these substances to develop complementary therapeutic alternatives that could ameliorate symptoms of depressive disorders in humans. PMID- 29623234 TI - The Positive Benefits of Negative Movement Patterns Following Total Knee Arthroplasty. AB - Introduction: Eccentric (negative) resistance exercise of the legs using specialized machines has been reported to be useful and often superior to standard exercise following total knee arthroplasty (TKA). Movements that utilize body mass and gravity as a mode of eccentric resistance exercise in a more pragmatic rehabilitation paradigm may also be useful in reversing chronic muscle impairments observed years following surgery. This study explores whether an eccentrically biased, body mass resistance exercise induces greater magnitude of sagittal plane extensor angular impulse of the support torque and individual net joint torque contributions during both squatting and lunging movement patterns 6 weeks following TKA. Methods: Cross-sectional laboratory-based study design including 10 patients following primary unilateral TKA (6.5 +/- 0.8 weeks.). All patients completed 3 trials of the squat and lunge movement pattern under both a concentric and an eccentric condition. Extensor angular impulse of the support torque and net joint torque contributions were calculated by integrating the joint torque versus time curves. A Two-way analysis of covariance was conducted and contracts of clinical interest were computed using Wald posttest. P Values for all pairwise comparisons were adjusted for multiplicity using Bonferroni multiple comparison procedure. Results: The eccentric condition, compared to the concentric condition, displayed larger magnitude of extensor angular impulse during both the squat (P < .001) and lunge (P < .001) movement patterns for the support torques. Similarly, the eccentric condition, compared to the concentric condition, displayed larger magnitude of extensor angular impulse of the hip, knee, and ankle (P < .001) during both movement patterns. Conclusion: Eccentrically biased, body mass movement exercises can produce higher levels of extensor angular impulse on the surgical limb in patients early after TKA. Patients in this study were able to tolerate the higher extensor angular impulse demands and performed the eccentrically biased conditions (without specialized machines) that could be beneficial in postoperative rehabilitation. PMID- 29623235 TI - Is Excess Alcohol Consumption an Unrecognized Factor Contributing to Falls? PMID- 29623236 TI - Does Use of Oral Anticoagulants at the Time of Admission Affect Outcomes Following Hip Fracture. AB - Purpose: The purpose of this study was to compare hospital quality outcomes in patients over the age of 60 undergoing fixation of hip fracture based on their anticoagulation status. Materials and Methods: Patients aged 60 and older with isolated hip fracture injuries treated operatively at 1 academic medical center between October 2014 and September 2016 were analyzed. Patients on the following medications were included in the anticoagulation cohort: warfarin, clopidogrel, aspirin 325 mg, rivaroxaban, apixaban, dabigatran, and dipyridamole/aspirin. We compared outcome measures including time to surgery, length of stay (LOS), transfusion rate, blood loss, procedure time, complication rate, need for intensive care unit (ICU)/step-down unit (SDU) care, discharge disposition, and cost of admission. Outcomes were controlled for age, Charlson comorbidity index (CCI), and anesthesia type. Results: A total of 479 hip fracture patients met the inclusion criteria, with 367 (76.6%) patients in the nonanticoagulated cohort and 112 (23.4%) patients in the anticoagulated cohort. The mean LOS and time to surgery were longer in the anticoagulated cohort (8.3 vs 7.3 days, P = .033 and 1.9 vs 1.6 days, P = .010); however, after controlling for age, CCI, and anesthesia type, these differences were no longer significant. Surgical outcomes were equivalent with similar procedure times, blood loss, and need for transfusion. The mean number of complications developed and inpatient mortality rate in the 2 cohorts were similar; however, more patients in the anticoagulated cohort required ICU/SDU-level care (odds ratio = 2.364, P = .001, controlled for age, CCI, and anesthesia). There was increased utilization of post-acute care in the anticoagulated cohort, with only 10.7% of patients discharged home compared to 19.9% of the nonanticoagulated group (P = .026). Lastly, there was no difference in cost of care. Conclusion: This study highlights that anticoagulation status alone does not independently put patients at increased risk with respect to LOS, surgical outcomes, and cost of hospitalization. PMID- 29623237 TI - Cementless Stem for Femoral Neck Fractures in a Patient's 10th Decade of Life: High Rate of Periprosthetic Fractures. AB - Background: Subsidence of cementless femoral stems in hemiarthroplasty (HA) and increased fracture rates are ongoing concerns of orthopedic surgeons when treating fractures in very old patients. Additionally, bone cement implantation syndrome may result in perioperative cardiac or pulmonary complications, especially in older patients, leading to morbidity and mortality. This study was performed to analyze possible subsidence and intraoperative fractures in a cohort of very old patients treated with cementless stems. Methods: We retrospectively analyzed a consecutive cohort of patients aged >=90 years with femoral neck fractures treated by uncemented HA and an anterior minimally invasive approach. Immediate full-weight bearing was allowed postoperatively. Pelvic radiographs were examined for subsidence immediately postoperatively and 6 weeks later. Results: We treated 109 patients (74% women; mean age, 93 years; range, 90-102 years) by HA from January 2010 to March 2016. The 30-day mortality rate was 16%, and the morbidity rate was 47%. There were 11 (12%) intraoperative fractures: 8 (Vancouver B2) had to be addressed immediately during the primary operation, while 3 (1 Vancouver B1 and 2 Vancouver AG) were treated conservatively. One periprosthetic femoral fracture (Vancouver B1) was documented during follow-up. In 17 patients, subsidence of >2.0 mm (median, 3.9 mm; range, 2.5-9.0 mm) was documented. Conclusion: Early subsidence was low in this very old cohort treated with an uncemented stem and not showing a periprosthetic fracture. The risk of intraoperative periprosthetic fractures was high. The use of uncemented implants in osteoporotic bone continues to be an intervention with high risk and should only be performed by experienced surgeons. Level of Evidence: Level III, Therapeutic study. PMID- 29623239 TI - Increased resistance to apoptosis during differentiation and syncytialization of BeWo choriocarcinoma cells. AB - Transition from mononuclear villous cytotrophoblast into multinuclear syncytiotrophoblast in the human placenta is accompanied by changes in apoptosis related proteins and an apparent increased resistance to induced apoptosis. We investigated the specific nature and timing of changes in Bcl-2, Bax, p53, and caspases 3 and 8 in forskolin-treated BeWo choriocarcinoma cells, a model for villous cytotrophoblast differentiation. BeWo cells were treated with forskolin or vehicle alone for up to 72 h and evaluated at 24 h intervals for syncytialization and quantitative expression specific apoptosis-related proteins and mRNAs. Syncytialization was quantified using fluorescent staining of intercellular membranes and enumeration of the percentage of nuclei in multinucleate cells, and differential localization of apoptosis-related proteins to multinuclear or mononuclear cells was determined by quantitative immunofluorescence. Forskolin treatment for up to 72 h resulted in 80% syncytialization, increased expression of Bcl-2 protein (P < 0.01) and mRNA (P < 0.05), and significantly decreased expression of protein and mRNA for Bax, p53, and caspases 3 and 8. Syncytialized cells expressed higher levels of Bcl-2 protein concurrent with increased resistance to cisplatin-induced apoptosis. Thus, syncytialization of BeWo cells was accompanied by altered transcription of apoptotic-related proteins characteristic of increased apoptosis resistance secondary to increased expression of the anti-apoptotic protein Bcl-2 and diminish expression of pro-apoptotic proteins. PMID- 29623240 TI - Rio's Mountainous Region ("Regiao Serrana") 2011 Landslides: Impact on Public Mental Health System. AB - INTRODUCTION In January 2011 landslides and floods followed heavy rain in the Mountainous Region of Rio de Janeiro State ("Regiao Serrana"), in southeastern Brazil. These events led to the largest disaster registered in Brazilian recent history. Few studies addressed the impacts of this disaster on public health, and we found none addressing the impact on mental health. This study reviewed the consequences of the 2011 disaster in the "Regiao Serrana", by comparing the demand for public mental health assistance data from time periods before and after the even METHODS We performed an ecologic study, analysing the aggregate data from "Regiao Serrana" during the period two years before and after the disaster, exporting data from the Brazilian open access public health database. The primary outcome was defined as Mental Health Care Demand, and for that we calculated the number of mental health care visits per month, the proportion of visits due to mental health care and the monthly absolute number of mental health care visits per CAPS - "Centro de Atencao Psicossocial" (Psychosocial Care Centre). For secondary outcomes we evaluated the total number of deaths by any reason, and the total number of hospitalizations. The other health administrative regions of Rio de Janeiro state were used as control group. RESULTS We observed that there was an important increase in the rate of visits due to mental health in the six months after the landslides, from 13,875 to 17,690, reaching its maximum one year after the event totalizing 21,980 visits (Dec 2011). It was also observed that the proportion of visits due to mental health disorders increased after the event in the "Regiao Serrana", as well as the number of mental health care visits per CAPS. DISCUSSION In conclusion, we observed that the 2011 Landslides in "Regiao Serrana" led to a sustained higher burden to public mental health care. There was an increase in the demand for mental health visits, and the ratio of visits per CAPS was higher during most part of the studied period after the event, even with the region having more CAPS than before. PMID- 29623238 TI - The Effectiveness of Osteoporosis Screening and Treatment in the Midwest. AB - Introduction: With osteoporosis on the rise across the United States, the goal of this prospective study is to determine the effectiveness of our Midwest level-1 trauma center in diagnosing, treating, and educating osteoporosis patients after fracture with the use of questionnaires. Secondarily, we aimed to identify barriers that prevent our patients from complying with bone health recommendations. Methods: One hundred participants (>=55 years) were given 2 questionnaires (Fracture Risk Assessment Tool and a study-specific questionnaire) that were administered during the patient's visit to the orthopedic trauma clinic. A group of patients diagnosed with osteoporosis was compared to a group of patients not diagnosed with osteoporosis. Statistical analyses were performed using SPSS 24 (IBM Corp, Chicago, Illinois). Results: Patients who had been diagnosed with osteoporosis were significantly older (72.7 vs 66.5, P = .009) and more were women (86.2% vs 66.2%, P = .043). Significantly, fewer patients without the diagnosis of osteoporosis had a history of fragility fracture (56.3%) compared to 92.9% of those diagnosed with osteoporosis (P < .001). Of those with dual-energy X-ray absorptiometry (DXA) recommended by a healthcare provider, 20 (55.6%) of those without the diagnosis of osteoporosis and 13 (52%) of those with the diagnosis of osteoporosis had DXA screening before their fragility fracture (P = .499). More patients diagnosed with osteoporosis (93.1%) were taking calcium and vitamin D supplementation compared to 66.2% of those without the diagnosis of osteoporosis (P = .005). Only 37.9% of patients with the diagnosis of osteoporosis were receiving US Food and Drug Administration-approved medications for the management of their disease. Discussion: In patients without previous osteoporosis diagnosis, 59 (83.1%) of the 71 claimed that they did not receive any preventative education about osteoporosis, while 21 (72.4%) of the 29 patients with the diagnosis of osteoporosis claimed that they did not receive a preventative education (P = .165). Both groups lacked optimum diagnosis, treatment, and education of osteoporosis. Conclusion: Our study highlights the need for a deliberate effort of a multidisciplinary team to focus efforts in all stages of osteoporosis management. PMID- 29623241 TI - Collective Statement Regarding Patient Access to Approved Therapies from the Center Directors of Parent Project Muscular Dystrophy's Certified Duchenne Care Centers. AB - The dystrophinopathies (Duchenne [DMD] and Becker muscular dystrophy) are progressive diseases that until recently had no specific treatments. New FDA pathways to drug approval in rare diseases have resulted in a dramatic increase in the number of treatment trials for DMD and recently, two approved drugs. Health insurance policies for DMD products have been constructed with limited input from neuromuscular specialists directly involved in patient care and without patient input. These policies often reflect a lack of understanding of the disease, clinical population or the treatment. To ensure that policy determinations reflect best clinical practice, we recommend insurers work with neuromuscular specialists with expertise in care for patients with dystrophinopathy, as well as patients and families, and prominent advocacy organizations, such as Parent Project Muscular Dystrophy, in developing policies. PMID- 29623242 TI - The Impact of a Case of Ebola Virus Disease on Emergency Department Visits in Metropolitan Dallas-Fort Worth, TX, July, 2013-July, 2015: An Interrupted Time Series Analysis. AB - Background: The first Ebola virus disease (EVD) case in the United States (US) was confirmed September 30, 2014 in a man 45 years old. This event created considerable media attention and there was fear of an EVD outbreak in the US. Methods: This study examined whether emergency department (ED) visits changed in metropolitan Dallas-Fort Worth--, Texas (DFW) after this EVD case was confirmed. Using Texas Health Services Region 2/3 syndromic surveillance data and focusing on DFW, interrupted time series analyses were conducted using segmented regression models with autoregressive errors for overall ED visits and rates of several chief complaints, including fever with gastrointestinal distress (FGI). Date of fatal case confirmation was the "event." Results: Results indicated the event was highly significant for ED visits overall (P<0.05) and for the rate of FGI visits (P<0.0001). An immediate increase in total ED visits of 1,023 visits per day (95% CI: 797.0, 1,252.8) was observed, equivalent to 11.8% (95% CI: 9.2%, 14.4%) increase ED visits overall. Visits and the rate of FGI visits in DFW increased significantly immediately after confirmation of the EVD case and remained elevated for several months even adjusting for seasonality both within symptom specific chief complaints as well as overall. Conclusions: These results have implications for ED surge capacity as well as for public health messaging in the wake of a public health emergency. PMID- 29623243 TI - Analyzing the Local Epidemiological Profile of Malaria Transmission in the Brazilian Amazon Between 2010 and 2015. AB - Introduction: Malaria still is a public health problem in the Americas. In 2015, Brazil accounted for 37% of all cases in the Americas, and of these cases, 99.5% were located in the Brazilian Amazon. Despite the mobilization of resources from the Brazilian National Plan for Malaria Control, too many municipalities have high transmission levels. The objective of this study is to evaluate the local epidemiological profile of malaria and its trend between 2010 and 2015 in the Brazilian Amazon. This study also aims to recognize the epidemiological differences in the local temporo-spatial dynamics of malaria. Methods: Malaria data were stratified by the annual parasite incidence (API) over the six-year period and by municipality. We used the method of seasonal decomposition by Loess smoothing to capture trend, seasonal and irregular components. A generalized linear model was applied to quantify trends, and the Kruskal-Wallis Rank Sum was applied to test for seasonality significance. Results: The malaria API declined by 61% from 2010 to 2015, and there was a 40% reduction of municipalities with high transmission (determined as an API higher than 50). In 2015, 9.4% of municipalities had high transmission and included 62.8% of the total cases. The time-series analyses showed different incidence patterns by region after 2012; several states have minimized the effect of the seasonality in their incidence rates, thus achieving low rates of incidence. There were 13 municipalities with sustained high transmission that have become the principal focus of malaria control; these municipalities contained 40% of the cases between 2013 and 2015. Discussion: Brazil has achieved advances, but more sustained efforts are necessary to contain malaria resurgence. The use of malaria stratification has been demonstrated as a relevant tool to plan malaria programs more efficiently, and spatiotemporal analysis corroborates the idea that implementing any intervention in malaria should be stratified by time to interpret tendencies and by space to understand the local dynamics of the disease. PMID- 29623244 TI - The Relationship Between Bone Mineral Density and Cardiovascular Function in Duchenne Muscular Dystrophy: A Retrospective Cohort Study. AB - INTRODUCTION: Duchenne muscular dystrophy (DMD) is an X-linked genetic disorder that causes progressive skeletal and cardiac muscle weakness in boys. Cardiac dysfunction is a frequent cause of death in DMD. Glucocorticoids are the standard of care in DMD. The long-term use of oral glucocorticoids in DMD is complicated by poor bone health. Epidemiological studies suggest a biological link between the loss of bone mineral density (BMD) and cardiovascular disease, including coronary artery and cerebrovascular diseases. Whether an association between low BMD and cardiac dysfunction occurs in DMD boys has not yet been studied. The objective of this retrospective cohort study was to examine the relationship between BMD and cardiovascular health in DMD. METHODS: Retrospective data analyses was performed from de-identified medical records from a tertiary academic medical center. Whole body BMD was measured using dual-energy xray absorptiometry (DEXA) scan and left ventricular ejection fraction (LVEF) was measured using echocardiogram. Linear regression was used to evaluate the relationship between BMD and LVEF. RESULTS: Data was analyzed from a total of 32 boys with DMD. The mean age at which baseline BMD measurements was obtained of 11+/-3 (SD) years. The worst LVEF was measured at a mean of 23.7+/-21.8 (SD) months after the baseline BMD measurement. The final adjusted linear regression of the relationship between baseline BMD z-score and worst LVEF was not statistically significant (beta=0.41, p-value=0.6455). DISCUSSION: In this cohort of boys with DMD, BMD was not associated with LVEF dysfunction up to 79 months later. Future research with a longer longitudinal follow-up period is warranted to evaluate the relationship between BMD and cardiovascular disease in DMD. PMID- 29623245 TI - Human Orthobunyavirus Infections, Tefe, Amazonas, Brazil. AB - Introduction: Several orthobunyaviruses are important arthropod-borne pathogens, responsible for a variety of diseases in humans, from acute febrile illness to encephalitis. Methods: We collected serum samples from a series of dengue suspected cases in Tefe, a mid-size city located in the interior of the Amazonas state, Brazil. Viral RNA extraction was performed, and specimens were tested for dengue virus using RT-PCR. Thirty dengue negative samples were further tested for Mayaro virus (MAYV) and Oropouche virus (OROV) using an RT-qPCR protocol previously described. Positive samples were characterized by MegaBLAST analysis over the entire nucleotide collection of the main public databases, and also by maximum likelihood phylogenetic reconstruction of the S genome segment. Results: We detected nine OROV or OROV-like positive cases among 30 patients reporting fever and headache, as the most common symptoms. The closest nucleotide sequence returned from the MegaBLAST analysis belongs to an OROV isolated in Peru 2008. Moreover, all Tefe samples grouped in the same clade with the OROV reference sequence and other closely-related OROV-like viruses. Discussion: Dengue viruses are still the most important arbovirus worldwide, causing hundreds of millions of infections every year. Nonetheless, other arboviruses like chikungunya virus, Zika virus, and yellow fever virus have emerged in the last few years and are now a public health concern in several countries. OROV is believed to have caused more than 500,000 febrile infections in Brazil over recent decades. Therefore, the results described in this study strengthen that this arbovirus, and its closely-related recombinants, should be under continuous surveillance, at least in the endemic countries of Latin America. PMID- 29623247 TI - Chronic Rhinosinusitis-Related Smell Loss: Medical And Surgical Treatment Efficacy. AB - Chronic rhinosinusitis (CRS) is an inflammatory disorder of the nasal cavities and paranasal sinuses. Olfactory dysfunction is a common manifestation of CRS and one of its cardinal diagnostic features. A decreased sense of smell can have a profound impact on a CRS patient's quality of life and overall wellbeing. The treatment of CRS-associated olfactory dysfunction includes a wide range of medical interventions, including anti-inflammatory and antibiotic medications, and surgical interventions, including endoscopic sinus and nasal surgery. The evidence and treatment efficacy for these interventions is quite varied. This review provides a summary of the efficacy of the medical and surgical therapeutic options for CRS-associated olfactory dysfunction. PMID- 29623248 TI - Holistic classification of CT attenuation patterns for interstitial lung diseases via deep convolutional neural networks. AB - Interstitial lung diseases (ILD) involve several abnormal imaging patterns observed in computed tomography (CT) images. Accurate classification of these patterns plays a significant role in precise clinical decision making of the extent and nature of the diseases. Therefore, it is important for developing automated pulmonary computer-aided detection systems. Conventionally, this task relies on experts' manual identification of regions of interest (ROIs) as a prerequisite to diagnose potential diseases. This protocol is time consuming and inhibits fully automatic assessment. In this paper, we present a new method to classify ILD imaging patterns on CT images. The main difference is that the proposed algorithm uses the entire image as a holistic input. By circumventing the prerequisite of manual input ROIs, our problem set-up is significantly more difficult than previous work but can better address the clinical workflow. Qualitative and quantitative results using a publicly available ILD database demonstrate state-of-the-art classification accuracy under the patch-based classification and shows the potential of predicting the ILD type using holistic image. PMID- 29623246 TI - Obesity and Breast Cancer: A Complex Relationship. AB - As prevalence of obesity continues to rise in the United States, we are beginning to elucidate the complex role of obesity-associated chronic inflammation, endocrine dysfunction, and hormone production as a driver for increased breast cancer risk. Epidemiological data suggest that obesity (BMI > 30) is associated with increased breast cancer incidence, worse prognosis, and higher mortality rates. Mechanistically, obesity and excess fat mass represent a state of chronic inflammation, insulin resistance, adipokine imbalance, and increased estrogen signaling. This pro-tumorigenic environment stimulates cancer development through abnormal growth, proliferation, and survival of mammary tissue. Importantly, obesity is a modifiable risk factor; alterations in cell proliferation, apoptosis, circulating estrogen, and insulin sensitivity are observed in response to weight loss attainable through behavior modification including dietary and exercise changes. PMID- 29623250 TI - Enhanced saccharification of rice straw using combined ultra-high pressure and ionic liquid microemulsion pretreatments. AB - Energy efficiency ratio is significant in completely estimating lignocellulosic biomass pretreatment. In this work, rice straw (RS) was pretreated by ultra-high pressure (UHP), ionic liquid microemulsion (ILM), and a combination of UHP and ILM (ILM + UHP) at mild temperature. The chemical composition, crystalline structure, surface morphology, and enzymatic hydrolysis of untreated and pretreated RS samples were compared. After ILM pretreatment ([Emim]Ac/cyclohexane/Triton X-100/n-butanol = 0.25/0.15/0.45/0.15) at 500 MPa, 50 degrees C for 4 h, the cellulose content of the regenerated RS increased by 62.5, 66.2% of the lignin was removed, 37.3% of crystallinity index decreased, and the reducing sugar yield of 89.6% was achieved. All results show that the ILM + UHP pretreatments were more effective than sole UHP or ILM treatment at low temperature. PMID- 29623249 TI - Therapeutic applications of bacterial pigments: a review of current status and future opportunities. AB - Non-toxicity, biodegradability and non-carcinogenicity of the natural pigments, dyes and colorants make them an attractive source for human use. Bacterial pigments are colored metabolites secreted by bacteria under stress. The industrial uses of bacterial pigments have increased many folds because of several advantages over the synthetic pigments. Among natural resources, bacterial pigments are mostly preferred because of simple culturing and pigment extraction techniques, scaling up and being time economical. Generally, the bacterial pigments are safe for human use and therefore have a wide range of applications in pharmaceutical, textile, cosmetics and food industries. Therapeutic nature of the bacterial pigments is revealed because of their antimicrobial, anticancer, cytotoxic and remarkable antioxidant properties. Owing to the importance of bacterial pigments it was considered important to produce a comprehensive review of literature on the therapeutic and industrial potential of bacterial pigments. Extensive literature has been reviewed on the biomedical application of bacterial pigments while further opportunities and future challenges have been discussed. PMID- 29623251 TI - Central serous chorioretinopathy with angioid streaks: a rare combination. AB - Purpose: This rare case shows the presence of both angioid streaks (AS) and central serous chorioretinopathy (CSC) in the same eye. Methods: A 41-year-old Caucasian male who also has a positive family history of AS was diagnosed with angioid streaks. He was followed for few years, later developed CSC in his good eye. Results: Fundus fluorescein led to the diagnosis of CSC and indocyanine green angiography ruled out the possibility of idiopathic polypoidal choroidal vasculopathy (IPCV). The CSC followed a chronic course of non-resolution and finally half fluence photodynamic therapy was performed. Unfortunately, there was still some deterioration of vision with poor response. Conclusion: There is no known correlation between the two disorders and their presence in one eye has not been reported to our knowledge. PMID- 29623252 TI - Intraocular inflammation in a case of bee sting injury. AB - A19-year-old man presented with decreased vision in the right eye following a bee sting injury, ten days back. Examination revealed conjunctival hyperemia at the site of the sting, anterior uveitis, vitritis, mild disc hyperemia, ocular hypotony, and striae at macula. Treatment was initiated elsewhere with topical antibiotics, steroid, and cycloplegic. Systemic steroids were added. Three weeks later, vitiritis resolved, intraocular pressure became normal and the vision improved from 20/60 to 20/20. However, a chorioretinal atrophy in the vicinity of the sting site was noted. Global electroretinogram (ERG) revealed reduced scotopic responses and depressed oscillatory potentials; even though the photopic response was normal. Multifocal ERG and microperimetry were normal. Two months later, after discontinuation of medication, a traumatic mydriasis with a sluggish pupillary reaction was noted. Sixteen months later, the fundus remained stable. This is a rare case report of a bee sting injury leading to anterior uveitis, vitritis, and cilio-choroidal detachment, mimicking endophthalmitis. Timely recognition of the cause of the intraocular inflammation and appropriate treatment led to optimal recovery. PMID- 29623253 TI - Partial reversal of color vision impairment in type 2 diabetes associated with obstructive sleep apnea. AB - Objective: Tritan anomaly is a known acquired color defect seen in diabetic patients, with or without the evidence of clinical signs of diabetic retinopathy (DR). We report a case of a 45-year-old diabetic patient with tritan pattern color defect associated with obstructive sleep apnea and its partial reversal with continuous positive airway pressure (CPAP) ventilation. Methods: A 45-year old male with diabetes, wildlife photographer by profession, presented with specific complaints of seeing all objects in the surrounding with a greenish tinge in both the eyes. He underwent a comprehensive eye examination including Farnsworth-Munsel 100 (FM 100) hue test, multifocal electroretinogram, microperimetry, spectral domain optical coherence tomography (SDOCT), and arterial oxygen saturation. Results: The subject was found to have a low arterial oxygen saturation (PaO2) of 86%. He was then advised inhalation of 100% oxygen for 15 min, following which he reported improvement in his visual symptoms. FM 100, OCT, and microperimetry were repeated after oxygenation. He was referred to a specialty hospital for further evaluation of the cause for reduced blood oxygen saturation and was further advised for sleep study, where he was diagnosed to have obstructive sleep apnea (OSA) with an apnea-hypopnea index of 20.9. Conclusion: The subject was advised weight loss measures and oral application of continuous positive airway pressure. Since then, he is under our regular follow up and has never experienced or complained of any color vision problems. This case report highlights the presence of associated systemic disorders like obstructive sleep apnea in individuals with diabetes that can present with color vision problems. PMID- 29623255 TI - Use of pre-hospital medication in children presenting with malaria to the emergency unit of Mulago Hospital, Uganda: A descriptive study. AB - Background: Initiation of specific antimalarial treatment within 24 hrs of fever onset at home and before presentation to the hospital is one of the strategies to reduce mortality from malaria in sub-Saharan Africa. In order to determine whether this strategy is being implemented we describe the use and factors associated with the use of pre-hospital medications among children admitted with malaria in one of the tertiary hospitals in Uganda. Materials and methods: Use of pre-hospital medications was assessed in 205 children aged 6-59 months and diagnosed with malaria at admission in Mulago hospital. Data were obtained on the type, source, and dose adequacy of medicines used before presentation to the hospital as well as the socio-demographical characteristics of the children. The proportion of children using pre-hospital medication was determined and logistic regression analysis used to determine factors associated with use of pre-hospital medication. Results: Overall, 147/205 (72%) of the children were given some medication for their illness before presentation to the hospital. The common pre hospital medicines used were paracetamol (107/147, 72.8 %) and antimalarial medicines (91/147, 61.9 %). Antibiotics were used in only 12 (8.2 %) of the cases. The majority (62/91, 68%) of the cases got medicines from a health facility but only 41/91 (45%) received an adequate dose. Having fever for more than three days was significantly associated with use of pre-hospital medicines (OR = 2.2; 95% CI 1.12-4.35; p = 0.02). Conclusions: The pre-hospital use of medicines is common amongst children presenting with malaria to this tertiary Ugandan hospital. The practice is, however, associated with use of inadequate doses of antimalarials and delay in presentation to the hospital. More effort is therefore needed to educate communities on the importance of proper home management of malaria. PMID- 29623256 TI - Association Between Programmed Death-Ligand 1 Expression and the Vascular Endothelial Growth Factor Pathway in Angiosarcoma. AB - Angiosarcoma is a vascular malignancy associated with a poor prognosis and chemotherapy resistance. The tumor immune microenvironment of angiosarcoma has not been characterized. We investigated the expression of programmed death-ligand 1 (PD-L1) and programmed death 1 (PD-1) in angiosarcoma and correlated these findings with vascular endothelial growth factor (VEGF)-related gene expression and survival. Using archived formalin-fixed paraffin-embedded tissues of primary and metastatic angiosarcoma specimens, we characterized the immunohistochemical (IHC) expression of PD-L1 and PD-1. In addition, we extracted RNA from each tumor and quantified the expression of VEGF-related genes, and then tested if these genes were associated with PD-L1 and PD-1 expression and clinical outcomes. Retrospective review identified 27 angiosarcoma specimens collected between 1994 and 2012. IHC expression of tumor PD-L1, tumor-infiltrating immune cell PD-L1, and tumor-infiltrating immune cell PD-1 expression was identified in 5 (19%), 9 (33%), and 1 (4%) specimens, respectively. Expression of PD-L1 and PD-1 was not associated with VEGF-related gene expression or survival. PD-L1 tumor and tumor infiltrating immune cells expression was identified in a large proportion of patients. Though neither was associated with VEGF-related gene expression or prognosis, targeting PD-1/PD-L1 may be of benefit for a significant proportion of angiosarcomas that do not respond to surgery, chemotherapy, or radiation. PMID- 29623254 TI - CD8+ T Cells and NK Cells: Parallel and Complementary Soldiers of Immunotherapy. AB - CD8+ T cells and NK cells are both cytotoxic effector cells of the immune system, but the recognition, specificity, sensitivity, and memory mechanisms are drastically different. While many of these topics have been extensively studied in CD8+ T cells, very little is known about NK cells. Current cancer immunotherapies mainly focus on CD8+ T cells, but have many issues of toxicity and efficacy. Given the heterogeneous nature of cancer, personalized cancer immunotherapy that integrates the power of both CD8+ T cells in adaptive immunity and NK cells in innate immunity might be the future direction, along with precision targeting and effective delivery of tumor-specific, memory CD8+ T cells and NK cells. PMID- 29623258 TI - From Phagocytes to Immune Defense: Roles for Coronin Proteins in Dictyostelium and Mammalian Immunity. AB - Microbes have interacted with eukaryotic cells for as long as they have been co existing. While many of these interactions are beneficial for both the microbe as well as the eukaryotic cell, several microbes have evolved into pathogenic species. For some of these pathogens, host cell invasion results in irreparable damage and thus host cell destruction, whereas others use the host to avoid immune detection and elimination. One of the latter pathogens is Mycobacterium tuberculosis, arguably one of the most notorious pathogens on earth. In mammalian macrophages, M. tuberculosis manages to survive within infected macrophages by avoiding intracellular degradation in lysosomes using a number of different strategies. One of these is based on the recruitment and phagosomal retention of the host protein coronin 1, that is a member of the coronin protein family and a mammalian homolog of coronin A, a protein identified in Dictyostelium. Besides mediating mycobacterial survival in macrophages, coronin 1 is also an important regulator of naive T cell homeostasis. How, exactly, coronin 1 mediates its activity in immune cells remains unclear. While in lower eukaryotes coronins are involved in cytoskeletal regulation, the functions of the seven coronin members in mammals are less clear. Dictyostelium coronins may have maintained multiple functions, whereas the mammalian coronins may have evolved from regulators of the cytoskeleton to modulators of signal transduction. In this minireview, we will discuss the different studies that have contributed to understand the molecular and cellular functions of coronin proteins in mammals and Dictyostelium. PMID- 29623257 TI - Immune Dysregulation in Cancer Patients Undergoing Immune Checkpoint Inhibitor Treatment and Potential Predictive Strategies for Future Clinical Practice. AB - Realization of the full potential of immune checkpoint inhibitor-targeted onco immunotherapy is largely dependent on overcoming the obstacles presented by the resistance of some cancers, as well as on reducing the high frequency of immune related adverse events (IRAEs) associated with this type of immunotherapy. With the exception of combining therapeutic monoclonal antibodies, which target different types of immune checkpoint inhibitory molecules, progress in respect of improving therapeutic efficacy has been somewhat limited to date. Likewise, the identification of strategies to predict and monitor the development of IRAEs has also met with limited success due, at least in part, to lack of insight into mechanisms of immunopathogenesis. Accordingly, considerable effort is currently being devoted to the identification and evaluation of strategies which address both of these concerns and it is these issues which represent the major focus of the current review, particularly those which may be predictive of development of IRAEs. Following an introductory section, this review briefly covers those immune checkpoint inhibitors currently approved for clinical application, as well as more recently identified immune checkpoint inhibitory molecules, which may serve as future therapeutic targets. The remaining and more extensive sections represent overviews of: (i) putative strategies which may improve the therapeutic efficacy of immune checkpoint inhibitors; (ii) recent insights into the immunopathogenesis of IRAEs, most prominently enterocolitis; and (iii) strategies, mostly unexplored, which may be predictive of development of IRAEs. PMID- 29623259 TI - A CTP Synthase Undergoing Stage-Specific Spatial Expression Is Essential for the Survival of the Intracellular Parasite Toxoplasma gondii. AB - Cytidine triphosphate synthase catalyzes the synthesis of cytidine 5' triphosphate (CTP) from uridine 5'-triphosphate (UTP), the final step in the production of cytidine nucleotides. CTP synthases also form filamentous structures of different morphologies known as cytoophidia, whose functions in most organisms are unknown. Here, we identified and characterized a novel CTP synthase (TgCTPS) from Toxoplasma gondii. We show that TgCTPS is capable of substituting for its counterparts in the otherwise lethal double mutant (ura7Delta ura8Delta) of Saccharomyces cerevisiae. Equally, recombinant TgCTPS purified from Escherichia coli encodes for a functional protein in enzyme assays. The epitope-tagged TgCTPS under the control of its endogenous promoter displays a punctate cytosolic distribution, which undergoes spatial reorganization to form foci or filament-like structures when the parasite switches from a nutrient replete (intracellular) to a nutrient-scarce (extracellular) condition. An analogous phenotype is observed upon nutrient stress or after treatment with a glutamine analog, 6-diazo-5-oxo-L-norleucine (DON). The exposure of parasites to DON disrupts the lytic cycle, and the TgCTPS is refractory to a genetic deletion, suggesting an essential requirement of this enzyme for T. gondii. Not least, this study, together with previous studies, supports that CTP synthase can serve as a potent drug target, because the parasite, unlike human host cells, cannot compensate for the lack of CTP synthase activity. PMID- 29623260 TI - Population Genomics of Francisella tularensis subsp. holarctica and its Implication on the Eco-Epidemiology of Tularemia in Switzerland. AB - Whole genome sequencing (WGS) methods provide new possibilities in the field of molecular epidemiology. This is particularly true for monomorphic organisms where the discriminatory power of traditional methods (e.g., restriction enzyme length polymorphism typing, multi locus sequence typing etc.) is inadequate to elucidate complex disease transmission patterns, as well as resolving the phylogeny at high resolution on a micro-geographic scale. In this study, we present insights into the population structure of Francisella tularensis subsp. holarctica, the causative agent of tularemia in Switzerland. A total of 59 Fth isolates were obtained from castor bean ticks (Ixodes ricinus), animals and humans and a high resolution phylogeny was inferred using WGS methods. The majority of the Fth population in Switzerland belongs to the west European B.11 clade and shows an extraordinary genetic diversity underlining the old evolutionary history of the pathogen in the alpine region. Moreover, a new B.11 subclade was identified which was not described so far. The combined analysis of the epidemiological data of human tularemia cases with the whole genome sequences of the 59 isolates provide evidence that ticks play a pivotal role in transmitting Fth to humans and other vertebrates in Switzerland. This is further underlined by the correlation of disease risk estimates with climatic and ecological factors influencing the survival of ticks. PMID- 29623261 TI - Increased Relative Risk of Tick-Borne Encephalitis in Warmer Weather. AB - Tick-borne encephalitis (TBE) is a serious acute neuroinfection of humans caused by a tick-borne flavivirus. The disease is typically seasonal, linked to the host seeking activity of Ixodes ricinus (predominantly nymphs), the principal European tick vector species. To address the need for accurate risk predictions of contracting TBE, data on 4,044 TBE cases reported in the Czech Republic during 2001-2006 were compared with questing activity of I. ricinus nymphs monitored weekly at a defined location for the same 6-year period. A time shift of 21 days between infected tick bite and recorded disease onset provided the optimal model for comparing the number of cases of TBE with numbers of questing nymphs. Mean annual distribution of TBE cases and tick counts showed a similar bimodal distribution. Significantly, the ratio of TBE cases to questing nymphs was highest in the summer-autumn period even though the number of questing nymphs peaked in the spring-summer period. However, this pattern changed during a period of extreme meteorological events of flooding and abnormally high temperatures, indicating that changes in climate affect the incidence of TBE. Previous studies failed to link human behavior with changes in incidence of TBE but showed extrinsic temperature impacts arbovirus replication. Hence, we hypothesize the apparent discrepancy between peak nymphal tick activity and greatest risk of contracting TBE is due to the effect of temperature on virus replication in the tick vector. Relative proportions of questing nymphs and the numbers of weeks in which they were found were greater in summer-autumn compared with spring-summer at near-ground temperatures >5 degrees C and at standard day and weekly average temperatures of >15 degrees C. Thus, during the summer-autumn period, the virus dose in infected tick bites is likely greater owing to increased virus replication at higher microclimatic temperatures, consequently increasing the relative risk of contracting TBE per summer-autumn tick bite. The data support the use of weather-based forecasts of tick attack risk (based on daytime ambient temperature) supplemented with weekly average temperature (as a proxy for virus replication) to provide much-needed real-time forecasts of TBE risk. PMID- 29623264 TI - Bacterial Infection and Predictors of Mortality in Patients with Autoimmune Liver Disease-Associated Acute-On-Chronic Liver Failure. AB - Objective: To date, few studies are available on autoimmune liver disease associated acute-on-chronic liver failure (ACLF). The aim of this study is to investigate bacterial infection and predictors of mortality in these patients. Methods: We retrospectively studied patients with autoimmune liver disease from August 2012 to August 2017. Clinical data of the patients were retrieved for analysis. Results: There were 53 ACLF patients and 53 patients without ACLF in this study. The ACLF group had a higher prevalence of complications (P < 0.05). The 28-day and 90-day mortality rates were also obviously high in patients with ACLF (38.3% and 74.5%, resp.) (P < 0.05). No predictor was significantly associated with 28-day and 90-day transplant-free mortality. In 53ACLF patients, 40 (75.5%) patients showed bacterial infection. ACLF patients with bacterial infection showed high Child-Pugh score, MELD score, CLIF-SOFA score, 28-day mortality, and 90-day mortality (P > 0.05). Moreover, C-reactive protein (CRP) using 12.15 mg/L cut-off value proved to be more accurate than procalcitonin in identifying patients with infection. Conclusions: Autoimmune liver disease associated ACLF showed more complications and high mortality. Bacterial infection patients displayed a more severe condition than those without infection. Elevated CRP is an accurate marker for diagnosing bacterial infection in autoimmune liver disease-associated ACLF patients. PMID- 29623263 TI - A Contemporary Review of the Treatment Landscape and the Role of Predictive and Prognostic Biomarkers in Pancreatic Adenocarcinoma. AB - Pancreatic cancer continues to represent one of the leading causes of cancer related morbidity and mortality in the developed world. Over the past decade, novel systemic therapy combination regimens have contributed to clinically meaningful and statistically significant improvements in overall survival as compared to conventional monotherapy. However, the prognosis for most patients remains guarded secondary to the advanced stages of disease at presentation. There is growing consensus that outcomes can be further optimized with the use of predictive and prognostic biomarkers whereby the former can be enriching for patients who would benefit from therapies and the latter can inform decision making regarding the need and timing of advanced care planning. One of the challenges of current biomarkers is the lack of standardization across clinical practices such that comparability between jurisdictions can be difficult or even impossible. This inconsistency can impede widespread implementation of their use. In this review article, we provide a comprehensive overview of the contemporary treatment options for pancreatic cancer and we offer some insights into the existing landscape and future directions of biomarker development for this disease. PMID- 29623265 TI - Excessive Pretreatment Weight Loss Is a Risk Factor for the Survival Outcome of Esophageal Carcinoma Patients Undergoing Radical Surgery and Postoperative Adjuvant Chemotherapy. AB - Background: The prognostic values of weight loss and body mass index (BMI) in esophageal carcinoma remain controversial. This study aimed to evaluate the impacts of weight loss on the survival of patients undergoing radical surgery and adjuvant chemotherapy. Methods: The medical records of 189 consecutive patients with nonmetastatic esophageal carcinoma treated in our hospital between January 2012 and December 2013 were reviewed, and 121 patients were included for analysis. Results: Kaplan-Meier analysis revealed that the 3-year overall survival rate was significantly higher in the low pretreatment weight loss (pre LWL) group than in the high pretreatment weight loss (pre-HWL) group (P < 0.001). In addition, the 3-year overall survival rate of normal weight group was higher than that of overweight and underweight groups (P = 0.007). Multivariate Cox proportional hazards analysis showed that pre-LWL group had a significantly better 3-year overall survival than pre-HWL group (P = 0.027, HR = 1.89, and 95% CI = 1.07-3.32). pN stage and age were also the survival prognostic factors. Conclusions: Our study showed that low pretreatment weight loss predicted a better survival outcome in the esophageal carcinoma patients with radical surgery and adjuvant chemotherapy. However, BMI and weight loss during treatment had no impact on the survival outcome. PMID- 29623266 TI - The Potential Role of Liver Transplantation as a Treatment Option in Colorectal Liver Metastases. AB - Liver resection is the only potentially curative treatment option in patients with liver metastases from colorectal cancer, but only about 20% of the patients are resectable. Liver transplantation of patients with unresectable liver metastases was attempted in the early era but it was abandoned due to poor survival. During the last decade, several case reports, a controlled pilot study, and a retrospective cohort study indicated that prolonged disease-free survival and overall survival can be obtained in a proportion of these patients. Strict selection criteria have not yet been well defined, but tumor load, response to chemotherapy, pretransplant carcinoembryonic antigen level, and time interval from resection of the primary tumor to transplant are all factors related to outcome. Carefully selected patients may obtain 5-year overall survival that approaches conventional indications for liver transplant. The scarcity of liver grafts is a significant problem, but this can possibly to some extent be addressed by use of extended criteria grafts and novel surgical techniques. There is an increasing interest in liver transplantation in these patients in the transplant community, and currently 4 clinical trials are active and are recruiting. PMID- 29623262 TI - Choosing an Animal Model for the Study of Functional Dyspepsia. AB - Functional dyspepsia (FD) is a common functional gastrointestinal disorder with pain or discomfort in the upper abdomen as the main characteristic. The prevalence of FD worldwide varies between 5% and 11%. This condition adversely affects attendance and productivity in the workplace. Emerging evidence is beginning to unravel the pathophysiologies of FD, and new data on treatment are helping to guide evidence-based practice. In order to better understand the pathophysiologies of FD and explore better treatment options, various kinds of animal models of FD have been developed. However, it is unclear which of these models most closely mimic the human disease. This review provides a comprehensive overview of the currently available animal models of FD in relationship to the clinical features of the disease. The rationales, methods, merits, and disadvantages for modelling specific symptoms of FD are discussed in detail. PMID- 29623267 TI - Short-Term Outcome of Patients with Cirrhosis and Concurrent Portal Cavernoma Presenting with Acute Variceal Bleeding. AB - Background and Aim: The outcome of cirrhotic patients with main portal vein occlusion and portal cavernoma after the first episode of acute variceal bleeding (AVB) is unknown. We compared short-term outcomes after AVB in cirrhotic patients with and without portal cavernoma. Methods: Between January 2009 and September 2014, 28 patients with cirrhosis and portal cavernoma presenting with the first occurrence of AVB and 56 age-, sex-, and Child-Pugh score-matched cirrhotic patients without portal cavernoma were included. The primary endpoints were 5-day treatment failure and 6-week mortality. Results: The 5-day treatment failure rate was higher in the cavernoma group than in the control group (32.1% versus 12.5%; p = 0.031). The 6-week mortality rate did not differ between the cavernoma and control group (25% versus 12.5%, p = 0.137). Multivariable Cox proportional hazard regression analyses revealed that 5-day treatment failure (HR = 1.223, 95% CI = 1.082 to 1.384; p = 0.001) independently predicted 6-week mortality. Conclusions: Cirrhotic patients with AVB and portal cavernoma have worse short term prognosis than patients without portal cavernoma. The 5-day treatment failure was an independent risk factor for 6-week mortality in patients with cirrhosis and portal cavernoma. PMID- 29623268 TI - The New Era of Transplant Oncology: Liver Transplantation for Nonresectable Colorectal Cancer Liver Metastases. AB - Colorectal cancer (CRC) is the third most incident cancer worldwide. Most of CRC patients will develop distant metastases, mainly to the liver, and liver resection is the only potential chance for cure. On the other hand, only a small proportion of patients with hepatic CRC metastasis are candidates for upfront liver resection. Liver transplantation (LT) is an attractive option for patients with nonresectable CRC liver metastases (NRCLM) without extrahepatic involvement. Initial experiences with LT for NRCLM achieved very poor outcomes, with a 5-year overall survival (OS) lower than 20%. However, these initial studies did not have a standardized patient selection or neoadjuvant or adjuvant therapies. With recent advances in the surgical and medical oncology fields, the landscape has changed. Recent studies from Norway have shown an encouraging 5-year OS of 50% when transplanting patients with NRCLM. Nevertheless, the main concern when expanding the indications for LT is organ shortage. To manage this organ shortage, strategies utilizing live donor liver transplantation are gaining favor. A few ongoing trials are assessing the impact of LT in NRCLM patient survival. Therefore, the aim of this paper is to review the current status of LT for NRCLM. PMID- 29623269 TI - Cystic Kidney Diseases From the Adult Nephrologist's Point of View. AB - Cystic kidney diseases affect patients of all age groups with the onset spanning from prenatal disease to late adulthood. Autosomal-dominant polycystic kidney disease (ADPKD) is by far the most common renal cystic disease. However, there are various cystic kidney diseases, the onset of which occurs at different times in life and depends on the type of the disease and the causative genes involved. When genetic kidney diseases are discussed in the adult setting this view is usually limited on autosomal-dominant kidney disease, the most frequent genetic disorder causing adult onset ESRD. Other diseases-such as autosomal-recessive polycystic kidney disease-are often being viewed as a disorder only important in pediatric nephrology. However, more recent data has revealed that, despite clear age peaks of onset for each disorder, all of them can also show highly variable phenotypes with classical adult onset genetic diseases being of importance in pediatrics and vice versa. Furthermore, the affected children need to be seen by adult nephrologists in the long term after transition, requiring knowledge on the underlying pediatric disease, potential extrarenal manifestations, and genetic counseling. Consequently, the view on these diseases should be widened on both ends. Close interaction between pediatric and adult nephrology is key to appropriate care of patients suffering from genetic kidney disease to profit from each other's experience. PMID- 29623270 TI - RE-AIM in Clinical, Community, and Corporate Settings: Perspectives, Strategies, and Recommendations to Enhance Public Health Impact. AB - The RE-AIM Framework is a planning and evaluation model that has been used in a variety of settings to address various programmatic, environmental, and policy innovations for improving population health. In addition to the broad application and diverse use of the framework, there are lessons learned and recommendations for the future use of the framework across clinical, community, and corporate settings. The purposes of this article are to: (A) provide a brief overview of the RE-AIM Framework and its pragmatic use for planning and evaluation; (B) offer recommendations to facilitate the application of RE-AIM in clinical, community, and corporate settings; and (C) share perspectives and lessons learned about employing RE-AIM dimensions in the planning, implementation, and evaluation phases within these different settings. In this article, we demonstrate how the RE-AIM concepts and elements within each dimension can be applied by researchers and practitioners in diverse settings, among diverse populations and for diverse health topics. PMID- 29623271 TI - Continuous Quality Improvement and Comprehensive Primary Health Care: A Systems Framework to Improve Service Quality and Health Outcomes. AB - Continuous quality improvement (CQI) processes for improving clinical care and health outcomes have been implemented by primary health-care services, with resultant health-care impacts. But only 10-20% of gain in health outcomes is contributed by health-care services; a much larger share is determined by social and cultural factors. This perspective paper argues that health care and health outcomes can be enhanced through applying CQI as a systems approach to comprehensive primary health care. Referring to the Aboriginal and Torres Strait Islander Australian context as an example, the authors provide a systems framework that includes strategies and conditions to facilitate evidence-based and local decision making by primary health-care services. The framework describes the integration of CQI vertically to improve linkages with governments and community members and horizontally with other sectors to influence the social and cultural determinants of health. Further, government and primary health-care service investment is required to support and extend integration and evaluation of CQI efforts vertically and horizontally. PMID- 29623272 TI - Designing Place-Based Interventions for Sustainability and Replicability: The Case of GO! Austin/VAMOS! Austin. AB - Place-based health efforts account for the role of the community environment in shaping decisions and circumstances that affect population well-being. Such efforts, rooted as they are in the theory that health is socially determined, mobilize resources for health promotion that are not typically used, and offer a more informed and robust way of promoting health outcomes within a community. Common criticisms of place-based work include the difficulty of replication, since engagement is so specific to a place, and limited sustainability of the work, in the absence of continued institutional structures, both within the community and supporting structures outside the community, to keep these initiatives resilient. This paper describes a place-based initiative, GO! Austin/VAMOS! Austin (GAVA), which was designed to harness the strengths of place based work-namely, its specificity to place and community. From the start, the project was designed to balance this specificity with a focus on developing and utilizing a standardized set of evidence-informed implementation and evaluation approaches and tools that were flexible enough to be modified for specific settings. This was accompanied by an emphasis on leadership and capacity building within resident leaders, which provided for informed intervention and demand building capacity, but also for longevity as partners, philanthropic, and otherwise, moved in and out of the work. PMID- 29623273 TI - Mechanocatalytic Depolymerization of Cellulose With Perfluorinated Sulfonic Acid Ionomers. AB - Here, we investigated that the mechanocatalytic depolymerization of cellulose in the presence of Aquivion, a sulfonated perfluorinated ionomer. Under optimized conditions, yields of water soluble sugars of 90-97% were obtained using Aquivion PW98 and PW66, respectively, as a solid acid catalyst. The detailed characterization of the water soluble fraction revealed (i) the selective formation of oligosaccharides with a DP up to 11 and (ii) that depolymerization and reversion reactions concomitantly occurred during the mechanocatalytic process, although the first largely predominated. More importantly, we discussed on the critical role of water contained in Aquivion and cellulose on the efficiency of the mechanocatalytic process. PMID- 29623274 TI - Enzymatic Processes to Unlock the Lignin Value. AB - Main hurdles of lignin valorization are its diverse chemical composition, recalcitrance, and poor solubility due to high-molecular weight and branched structure. Controlled fragmentation of lignin could lead to its use in higher value products such as binders, coatings, fillers, etc. Oxidative enzymes (i.e., laccases and peroxidases) have long been proposed as a potentially promising tool in lignin depolymerization. However, their application was limited to ambient pH, where lignin is poorly soluble in water. A Finnish biotechnology company, MetGen Oy, that designs and supplies industrial enzymes, has developed and brought to market several lignin oxidizing enzymes, including an extremely alkaline lignin oxidase MetZyme(r) LIGNOTM, a genetically engineered laccase of bacterial origin. This enzyme can function at pH values as high as 10-11 and at elevated temperatures, addressing lignin at its soluble state. In this article, main characteristics of this enzyme as well as its action on bulk lignin coming from an industrial process are demonstrated. Lignin modification by MetZyme(r) LIGNOTM was characterized by size exclusion chromatography, UV spectroscopy, and dynamic light scattering for monitoring particle size of solubilized lignin. Under highly alkaline conditions, laccase treatment not only decreased molecular weight of lignin but also increased its solubility in water and altered its dispersion properties. Importantly, organic solvent-free soluble lignin fragmentation allowed for robust industrially relevant membrane separation technologies to be applicable for product fractionation. These enzyme-based solutions open new opportunities for biorefinery lignin valorization thus paving the way for economically viable biorefinery business. PMID- 29623275 TI - Wilms' Tumor Protein 1 and Enzymatic Oxidation of 5-Methylcytosine in Brain Tumors: Potential Perspectives. AB - The patterns of 5-methylcytosine (5mC) and its oxidized derivatives, 5 hydroxymethylcytosine, 5-formylcytosine, and 5-carboxylcytosine (5caC) are reportedly altered in a range of cancers. Likewise, Wilms' Tumor protein 1 (WT1), a transcription factor essential for urogenital, epicardium, and kidney development exhibits aberrant expression in multiple tumors. Interestingly, WT1 directly interacts with TET proteins that catalyze the enzymatic oxidation of 5mC and exhibits high affinity for 5caC-containing DNA substrates in vitro. Here we review recent developments in the fields of Tet-dependent 5mC oxidation and WT1 biology and explore potential perspectives for studying the interplay between TETs and WT1 in brain tumors. PMID- 29623277 TI - Worry About Caregiving Performance: A Confirmatory Factor Analysis. AB - Recent studies on the Zarit Burden Interview (ZBI) support the existence of a unique factor, worry about caregiving performance (WaP), beyond role and personal strain. Our current study aims to confirm the existence of WaP within the multidimensionality of ZBI and to determine if predictors of WaP differ from the role and personal strain. We performed confirmatory factor analysis (CFA) on 466 caregiver-patient dyads to compare between one-factor (total score), two-factor (role/personal strain), three-factor (role/personal strain and WaP), and four factor models (role strain split into two factors). We conducted linear regression analyses to explore the relationships between different ZBI factors with socio-demographic and disease characteristics, and investigated the stage dependent differences between WaP with role and personal strain by dyadic relationship. The four-factor structure that incorporated WaP and split role strain into two factors yielded the best fit. Linear regression analyses reveal that different variables significantly predict WaP (adult child caregiver and Neuropsychiatric Inventory Questionnaire (NPI-Q) severity) from role/personal strain (adult child caregiver, instrumental activities of daily living, and NPI-Q distress). Unlike other factors, WaP was significantly endorsed in early cognitive impairment. Among spouses, WaP remained low across Clinical Dementia Rating (CDR) stages until a sharp rise in CDR 3; adult child and sibling caregivers experience a gradual rise throughout the stages. Our results affirm the existence of WaP as a unique factor. Future research should explore the potential of WaP as a possible intervention target to improve self-efficacy in the milder stages of burden. PMID- 29623278 TI - An Innocent Esophageal Mucosal Bridge: Case Report and Literature Review. AB - An esophageal mucosal bridge is a rare finding that is seldom encountered on upper endoscopy. They most commonly present secondary to an underlying inflammatory disorder and cause chest pain and dysphagia, among other symptoms. More rarely, they present asymptomatically with no identifiable inflammatory conditions. Our case consists of a 31-year-old woman who presented with an asymptomatic, noninflammatory mucosal bridge of the esophagus. To our knowledge, this makes the third such case. The rarity of this condition coupled with the lack of epidemiologic data available make this case worthy for literature review. PMID- 29623276 TI - Coordination of Protein Kinase and Phosphoprotein Phosphatase Activities in Mitosis. AB - Dynamic changes in protein phosphorylation govern the transitions between different phases of the cell division cycle. A "tug of war" between highly conserved protein kinases and the family of phosphoprotein phosphatases (PPP) establishes the phosphorylation state of proteins, which controls their function. More than three-quarters of all proteins are phosphorylated at one or more sites in human cells, with the highest occupancy of phosphorylation sites seen in mitosis. Spatial and temporal regulation of opposing kinase and PPP activities is crucial for accurate execution of the mitotic program. The role of mitotic kinases has been the focus of many studies, while the contribution of PPPs was for a long time underappreciated and is just emerging. Misconceptions regarding the specificity and activity of protein phosphatases led to the belief that protein kinases are the primary determinants of mitotic regulation, leaving PPPs out of the limelight. Recent studies have shown that protein phosphatases are specific and selective enzymes, and that their activity is tightly regulated. In this review, we discuss the emerging roles of PPPs in mitosis and their regulation of and by mitotic kinases, as well as mechanisms that determine PPP substrate recognition and specificity. PMID- 29623279 TI - Clostridium difficile Colitis Leading to Reactive Arthritis: A Rare Complication Associated With a Common Disease. AB - The relationship between reactive arthritis and enteric infections caused by Yersinia enterocolitica, Campylobacter jejuni, and Salmonella typhimurium is well documented. Clostridium difficile colitis is a less recognized cause of reactive arthritis. We present a case of a 58-year-old woman with Clostridium difficile colitis complicated by reactive arthritis. A 58-year-old woman with no significant past medical history presented to our hospital with complaints of nonbloody watery diarrhea, abdominal pain for the past 1 week, and right knee pain starting 1 day prior. The patient had recently used antibiotics for a respiratory tract infection. On examination, the patient had a swollen and erythematous right knee. While in the hospital the patient also developed a similarly painful and swollen left knee. The patient was found to be positive for C difficile toxin in stool. Synovial fluid analysis of both the knee joints revealed a sterile and inflammatory fluid, negative for crystals and showing no growth on gram stain. We diagnosed the patient with reactive arthritis secondary to C difficile colitis once all other causes of the bilateral knee joint symptoms were ruled out with appropriate laboratory and imaging studies. Treatment with oral vancomycin and an anti-inflammatory was initiated, and the patient had complete resolution of symptoms. This case illustrates the importance of recognizing C difficile colitis as a potential differential for reactive arthritis under the appropriate circumstances. The treatment of reactive arthritis is mainly supportive and treating the underlying cause, which happens to be C difficile in this case. PMID- 29623280 TI - Neo Left Main Channel Creation Using Double Stenting Alongside a Sapien 3 Aortic Valve Bioprosthesis for Left Main Coronary Obstruction Following Valve-in-Valve Transcatheter Aortic Valve Replacement: A Case Report With Review of Literature. AB - Transcatheter aortic valve replacement in the setting of failed surgical bioprosthesis (valve-in-valve) is a valuable option for patients with bioprosthetic aortic stenosis or regurgitation who are deemed high risk for repeat open heart surgery. Although the procedure is successful with proper preprocedural assessment, instances of left main (LM) coronary artery ostium obstruction have been documented. We present a case of LM coronary obstruction in the immediate postoperative period following implantation of a 20-mm Edwards Sapien 3 valve inside the degenerated 21-mm Mitroflow bioprosthesis stenosis, which was treated with double stenting alongside the Edwards Sapien 3 valve creating a channel ("neo left main") that extended from mid-LM to the upper margin of the Edwards Sapien 3 valve. Although valve-in-valve in a Mitroflow degenerated bioprosthesis is a relatively safe procedure, 2 or more stents may be necessary to scaffold a channel to the coronary arteries between Edwards Sapien 3 prosthesis and aorta in the event of a coronary obstruction. PMID- 29623281 TI - Effect of Head Impact Exposures on Changes in Cognitive Testing. AB - Background: Gaining a better understanding of head impact exposures may lead to better comprehension of the possible effects of repeated impact exposures not associated with clinical concussion. Purpose: To assess the correlation between head impacts and any differences associated with cognitive testing measurements pre- and postseason. Study Design: Case-control study; Level of evidence, 3. Methods: A total of 34 National Collegiate Athletic Association Division I men's lacrosse players wore lacrosse helmets instrumented with an accelerometer during the 2014 competitive season and were tested pre- and postseason with the Sport Concussion Assessment Tool (SCAT 3) and Concussion Vital Signs (CVS) computer based neurocognitive tests. The number of head impacts >20g and results from the 2 cognitive tests were analyzed for differences and correlation. Results: There was no significant difference between pre- and postseason SCAT 3 scores, although a significant correlation between pre- and postseason cognitive scores on the SCAT 3 and total number of impacts sustained was noted (r = -0.362, P = .035). Statistically significant improvements on half of the CVS testing components included visual reaction time (P = .037, d = 0.37), reaction time (P = .001, d = 0.65), and simple reaction time (P = .043, d = 0.37), but no correlation with head impacts was noted. Conclusion: This study did not find declines in SCAT 3 or CVS scores over the course of a season among athletes who sustained multiple head impacts but no clinical concussion. Thus, it could not be determined whether there was no cognitive decline among these athletes or whether there may have been subtle declines that could not be measured by the SCAT 3 or CVS. PMID- 29623282 TI - Relationship Between Pitching a Complete Game and Spending Time on the Disabled List for Major League Baseball Pitchers. AB - Background: Injury rates among Major League Baseball pitchers have been increasing over the past several years. It is currently unknown whether pitching a complete game (CG) is a risk factor for spending time on the disabled list (DL). Purpose/Hypothesis: The purpose of this study was to determine the relationship between pitching a CG and time on the DL. We hypothesized that pitchers who threw a CG (1) would be at increased risk for spending time on the DL, which would be earlier in the season and for a longer period, than those who did not and (2) would be at further increased risk for spending time on the DL during subsequent seasons than matched controls. Study Design: Descriptive epidemiology study. Methods: Pitchers who threw a CG between 2010 and 2016 at the major league level and were placed on the DL during the same season were included. Timing and length of period on the DL were determined, as well as placement on the DL during subsequent seasons. Matched controls who did not throw a CG were assessed for time spent on the DL during that season and subsequent seasons. Results: Overall, 246 individual pitchers (501 pitcher-seasons) threw at least 1 CG between 2010 and 2016. Of the pitcher-seasons, 370 (73.9%) included a period on the DL, as compared with only 20% of controls. There were no differences in length of time on the DL (P = .928) or days from season start to time on the DL (P = .861) between pitchers who threw a CG and controls. Pitchers who threw a CG were significantly more likely than controls to spend subsequent seasons on the DL (1.9 +/- 1.1 vs 0.5 +/- 0.9, P < .001). Conclusion: Overall, 74% of pitchers who threw a CG spent time on the DL, as compared with 20% of controls. Pitchers who threw a CG during the study period spent more time in subsequent seasons on the DL than did matched controls who did not throw a CG. PMID- 29623283 TI - Does the Rotator Cuff Tear Pattern Influence Clinical Outcomes After Surgical Repair? AB - Background: Limited literature exists regarding the influence of rotator cuff tear morphology on patient outcomes. Purpose: To determine the effect of rotator cuff tear pattern (crescent, U-shape, L-shape) on patient-reported outcomes after rotator cuff repair. Study Design: Cohort study; Level of evidence, 3. Methods: Patients undergoing arthroscopic repair of known full-thickness rotator cuff tears were observed prospectively at regular intervals from baseline to 1 year. The tear pattern was classified at the time of surgery as crescent, U-shaped, or L-shaped. Primary outcome measures were the Western Ontario Rotator Cuff Index (WORC), the American Shoulder and Elbow Surgeons (ASES), and a visual analog scale (VAS) for pain. The tear pattern was evaluated as the primary predictor while controlling for variables known to affect rotator cuff outcomes. Mixed methods regression and analysis of variance (ANOVA) were used to examine the effects of tear morphology on patient-reported outcomes after surgical repair from baseline to 1 year. Results: A total of 82 patients were included in the study (53 male, 29 female; mean age, 58 years [range, 41-75 years]). A crescent shape was the most common tear pattern (54%), followed by U-shaped (25%) and L shaped tears (21%). There were no significant differences in outcome scores between the 3 groups at baseline. All 3 groups showed statistically significant improvement from baseline to 1 year, but analysis failed to show any predictive effect in the change in outcome scores from baseline to 1 year for the WORC, ASES, or VAS when tear pattern was the primary predictor. Further ANOVA also failed to show any significant difference in the change in outcome scores from baseline to 1 year for the WORC (P = .96), ASES (P = .71), or VAS (P = .86). Conclusion: Rotator cuff tear pattern is not a predictor of functional outcomes after arthroscopic rotator cuff repair. PMID- 29623284 TI - Extraction and Analysis of Pan-metabolome Polar Metabolites by Ultra Performance Liquid Chromatography-Tandem Mass Spectrometry (UPLC-MS/MS). AB - Modern triple quadrupole mass spectrometers provide the ability to detect and quantify a large number of metabolites using tandem mass spectrometry (MS/MS). Liquid chromatography (LC) is advantageous, as it does not require derivatization procedures and a large diversity in physiochemical characteristics of analytes can be accommodated through a variety of column chemistries. Recently, the comprehensive optimization of LC-MS metabolomics using design of experiments (COLMeD) approach has been described and used by our group to develop robust LC MS workflows (Rhoades and Weljie, 2016). The optimized LC-MS/MS method described here has been utilized extensively for metabolomics analysis of polar metabolites. Typically, tissue or biofluid samples are extracted using a modified Bligh-Dyer protocol (Bligh and Dyer, 1959; Tambellini et al., 2013). The protocol described herein describes this workflow using targeted polar metabolite multiple reaction monitoring (MRM) from tissues and biofluids via ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS). This workflow has been utilized extensively for chronometabolic analysis (Krishnaiah et al., 2017), with applications generalized to other types of analyses as well (Sengupta et al., 2017; Sivanand et al., 2017). PMID- 29623285 TI - Quantification of Bacterial Attachment to Tissue Sections. AB - Here we describe a method to test bacterial adhesion to paraffin embedded tissue sections. This method allows examining binding of different bacterial strains, transfected with a fluorescent protein reporter plasmid to various tissues, to better understand different mechanisms such as colonization. This assay provides a more physiological context to bacterial binding, than would have been achieved using adhesion assays to cell lines. The sections can be imaged using fluorescent microscopy and adhesion of various bacterial strains can be quantified and tested, simultaneously. PMID- 29623286 TI - Shared Care Models in the Treatment of Pediatric Attention-Deficit/Hyperactivity Disorder (ADHD): Are They Effective? AB - Objectives: The aim of this review is to evaluate the effectiveness of shared/collaborative care between mental health-care providers and primary care providers (PCPs) on the outcomes of children and adolescents with attention deficit/hyperactivity disorder (ADHD). This evaluation will be very helpful in the allocation of ADHD resources for models with the strongest evidence. Methods: Using the Preferred Reporting Items for Systematic Review and Meta-analysis statement, we searched for randomized controlled trials, cohort, case-control, and cross-sectional studies on shared/collaborative care models in the treatment of ADHD. Using MEDLINE, PsycINFO, and CENTRAL databases from January 2000 to December 2016, we retrieved English language articles for review. The validation search identified 75 records. Five studies met the inclusion criteria and were analyzed in this systematic review. There were insufficient data for a meta analysis. The included studies involved 655 children and adolescents who had a diagnosis of ADHD. The Cochrane Collaboration's tool for assessing risk of bias was used to estimate bias. Results: Overall, the results show that the effects of shared/collaborative care models were small to moderate (effect size: 0.1-0.6, P = .04) on symptom rating scales, but all positively affected functional outcomes (effect size: 0.3-0.7, P = .04-.01). The data indicated that the models were associated with increased PCPs' comfort levels, but the evidence for increased capacity for diagnosing and managing ADHD was weaker. Conclusions: This review concludes that the current studies do not show strong evidence for the outcome of collaboration between PCPs and mental health professionals on ADHD management. Future research should consider providing education to PCPs on management guidelines prior to conducting the trials, and more innovation is needed to discover methods of collaboration that affect the direct care of ADHD. PMID- 29623287 TI - Safe Surgery Checklist, Patient Safety, Teamwork, and Responsibility-Coequal Demands? A Focus Group Study. AB - The use of World Health Organization's (WHO's) Safe Surgery checklist is an established practice worldwide and contributes toward ensuring patient safety and collaborative teamwork. The aim of this study was to elucidate operating room nurses' and operating room nursing students' experiences and opinions about execution of and compliance with checklists. We chose a qualitative design with semistructured focus group discussions. Qualitative content analysis was conducted. Two main themes were identified; the Safe Surgery checklists have varied influence on teamwork and patient safety, and taking responsibility for executing the checks on the Safe Surgery checklist entails practical and ethical challenges. The experiences and opinions of operating room nurses and their students revealed differences of practices and attitudes toward checklist compliance and the intentions of checklist procedures. These differences are related to cultural and professional distances between team members and their understanding of the Safe Surgery checklists as a tool for patient safety. PMID- 29623288 TI - The Association Between Assisted Living Direct Care Worker End-of-Life Training and Hospice Use Patterns. AB - As resident acuity levels increase for those who reside in assisted living (AL), states allow for hospice care provision in AL. End-of-life care training for staff can potentially increase the awareness of benefits of hospice care for AL residents. This study examined the association between AL staff trained in end-of life care and hospice utilization in a sample of ALs (n = 45) in Florida. The sample included ALs (n = 21) with a low percentage (<=59%) and ALs (n = 24) with a high percentage (>=60%) of staff trained in end-of-life care as reported by AL directors. Zero-inflated negative binomial regression (ZINB) indicated that ALs in the high percentage of staff trained group were associated with a 3.64% greater utilization of hospice than ALs in the low percentage of staff trained group. Implementation of required staff training specific to care for the terminally ill as required in some states could potentially improve resident access to hospice care. PMID- 29623289 TI - Support for Self-Management and Prenatal Health Behavior Change: Implications for Pediatric Promotion of Interconception Care. AB - Pediatricians increasingly endorse a dual generation approach to health, in which parental health behaviors are recognized as critical to promoting child health. Positive parental behaviors often emerge during pregnancy, for reasons that remain incompletely described. We surveyed mothers in the immediate postpartum period to identify beliefs about health behavior change and characteristics of prenatal care associated with successful change. Sampling at a tertiary care hospital captured an English-speaking adult population with healthy infants. Respondents (n = 225) were predominantly non-Hispanic Black (64%) and Medicaid insured (44%). Most (71%) reported successful behavior change during pregnancy. Of those reporting change, 91% intended to sustain behaviors postnatally. Most believed that sustained change was important for their own health (94%) and their infant's health (93%). In logistic regression, support for self-management was associated with prenatal health behavior change (odds ratio = 1.64, 95% confidence interval = 1.09-2.46). Continued support for self-management by pediatricians may benefit long-term family health. PMID- 29623291 TI - Immune-related endocrine disorders in novel Immune checkpoint inhibition therapy. AB - Immune checkpoint inhibition against advance malignancies was named breakthrough discovery by the science magazine in 2013. In numerous clinical studies, monoclonal antibodies against the immune checkpoints, CTLA4, PD1 and PD1 ligand PDL1 have shown promising tumor response in different type of metastatic malignancies. The adverse events are autoimmune-related. The endocrine disorders, hypothysitis and thyroiditis are among the most common side effects associated with immune checkpoint inhibition treatment. Hypophysitis, a very rare endocrine disorder occurs in about one tenth of the patients receiving anti-CTLA4 treatment. Thyroiditis, on the other hand, is more commonly seen in patients receiving anti-PD1 treatment. In addition, both thyroiditis and hypophysitis are common in patients receiving combination treatment with anti-CTLA4 and anti-PD1 treatment. The time to onset of hypophysitis and thyroiditis is short. Most of the endocrine disorders occur within 12 weeks after initiation of the immune checkpoint inhibition therapy. Hypohysitis can manifest as total anterior pituitary hormone deficiency or isolated pituitary hormone deficiency. Diabetes insipidus is rare. TSH and gonadotropin deficiencies may be reversible but ACTH deficiency appears permanent. Thyroiditis can present as hypothyroidism or thyrotoxicosis followed by hypothyroidism. Hypothyroidism appears irreversible. Early identifying the onset of hypophysitis and thyroiditis and proper management of these endocrine disorders will improve the quality of the life and the outcome of this novel immunotherapy. PMID- 29623290 TI - Focusing light inside scattering media with magnetic-particle-guided wavefront shaping. AB - Optical scattering has traditionally limited the ability to focus light inside scattering media such as biological tissue. Recently developed wavefront shaping techniques promise to overcome this limit by tailoring an optical wavefront to constructively interfere at a target location deep inside scattering media. To find such a wavefront solution, a "guide-star" mechanism is required to identify the target location. However, developing guidestars of practical usefulness is challenging, especially in biological tissue, which hinders the translation of wavefront shaping techniques. Here, we demonstrate a guidestar mechanism that relies on magnetic modulation of small particles. This guidestar method features an optical modulation efficiency of 29% and enables micrometer-scale focusing inside biological tissue with a peak intensity-to-background ratio (PBR) of 140; both numbers are one order of magnitude higher than those achieved with the ultrasound guidestar, a popular guidestar method. We also demonstrate that light can be focused on cells labeled with magnetic particles, and to different target locations by magnetically controlling the position of a particle. Since magnetic fields have a large penetration depth even through bone structures like the skull, this optical focusing method holds great promise for deep-tissue applications such as optogenetic modulation of neurons, targeted light-based therapy, and imaging. PMID- 29623292 TI - MiRNA extraction from cell-free biofluid using protein corona formed around carboxyl magnetic nanoparticles. AB - MicroRNA (miRNA) in urine has been considered as a potential biomarker for early stage diagnosis of multiple diseases like urinary system cancer, kidney injury and diabetes, owing to their many demonstrated advantages including long-term stability and noninvasiveness. However, the traditional enrichment and extraction processes of miRNAs from urine are cumbersome and tedious due to the low concentration and multiple carriers of miRNAs. Herein, we present a novel method to collect low concentrations of miRNAs from dilute solutions such as urine and cell culture medium. 10-nm core sized magnetic nanoparticles with carboxylic acid coating can adsorb low-concentration proteins, and form protein corona which makes them easy to aggregate and precipitate for subsequent isolation. In urine and cell culture medium, these nanoparticles can aggregate with proteins, including miRNAs-associated protein Argonaute 2 and microvesicle-related proteins, to form precipitates, so that miRNAs can be easily extracted from pellets by small amount of lysis buffer for subsequent analysis such as real-time PCR. Our method provides a facile way to enrich miRNAs from biofluids without the need of ultracentrifugation and immunoprecipitations, bringing remarkable convenience to miRNAs-based biomarker research. PMID- 29623293 TI - Trends in Pathology Graduate Medical Education Programs and Positions, 2001 to 2017. AB - The US medical workforce is facing an impending physician shortage. This shortage holds special concern for pathologists, as many senior practitioners are set to retire in the coming years. Indeed, studies indicate a "pathologist gap" may grow through 2030. As such, it is important to understand current and future trends in US pathology. One key factor is graduate medical education. In this study, we analyzed data from the Accreditation Council of Graduate Medical Education, to determine the change in pathology graduate medical education programs and positions, from 2001 to 2017. We found that pathology programs and positions have increased since the 2001 to 2002 academic year, even after adjusting for population growth. However, this increase is much lower than that of total graduate medical education. Furthermore, many pathology subspecialties have declined in population-adjusted levels. Other subspecialties, such as selective pathology, have grown disproportionately. Our findings may be valuable for understanding the state of US pathology, now and in the future. They imply that more resources-or technological innovations-may be needed for specific pathology programs, in hopes of closing the pathologist gap for both this specialty and its subspecialties. PMID- 29623294 TI - A Novel Approach to Apply Gait Synchronized External Forces on the Pelvis using A TPAD to Reduce Walking Effort. AB - In this paper, we develop an intervention to apply external gait synchronized forces on the pelvis to reduce the user's effort during walking. A cable-driven robot was used to apply the external forces and an adaptive frequency oscillator scheme was developed to adapt the timing of force actuation to the gait frequency during walking. The external forces were directed in the sagittal plane to assist the trailing leg during the forward propulsion and vertical deceleration of the pelvis during the gait cycle. A pilot experiment with five healthy subjects was conducted. The results showed that the subjects applied lower ground reaction forces in the vertical and anterior-posterior directions during the late stance phase. In summary, the current work provides a novel approach to study the role of external pelvic forces in altering the walking effort. These studies can provide better understanding for designing exoskeletons and prosthetic devices to reduce the overall walking effort. PMID- 29623295 TI - Importance of intellectual property generated by biomedical research at universities and academic hospitals. AB - : Biomedical research has many different facets. Researchers and clinicians study disease biology and biochemistry to discover novel therapeutic targets, unravel biochemical pathways and identify biomarkers to improve diagnosis, or devise new approaches to clinically manage diseases more effectively. In all instances, the overall goal of biomedical research is to ensure that results thereof (such as a therapy, a device, or a method which may be broadly referred to as "inventions") are clinically implemented. Most of the researchers' efforts are centered on the advance of technical and scientific aspects of an invention. The development and implementation of an invention can be arduous and very costly. Historically, it has proven to be crucial to protect intellectual property rights (IPR) to an invention (i.e., a patent) to ensure that companies can obtain a fair return on their investment that is needed to develop an academic invention into a product for the benefit of patients. However, the importance of IPR is not generally acknowledged among researchers at academic institutions active in biomedical research. Therefore this paper aims to (1) raise IP awareness amongst clinical and translational researchers; (2) provide a concise overview of what the patenting trajectory entails; and (3) highlight the importance of patenting for research and the researcher. Importance for patients: Adequate patent protection of inventions generated through biomedical research at academic institutions increases the probability that patients will benefit from these inventions, and indirectly enables the financing of clinical studies, mainly by opening up funding opportunities (e.g. specific grants aimed at start-ups, pre-seed and seed capital) that otherwise would not be accessible. As a consequence, patented inventions are more likely to become clinically tested and reach the market, providing patients with more treatment options. PMID- 29623296 TI - EnLightenment: High resolution smartphone microscopy as an educational and public engagement platform. AB - We developed a simple, cost-effective smartphone microscopy platform for use in educational and public engagement programs. We demonstrated its effectiveness, and potential for citizen science through a national imaging initiative, EnLightenment. The cost effectiveness of the instrument allowed for the program to deliver over 500 microscopes to more than 100 secondary schools throughout Scotland, targeting 1000's of 12-14 year olds. Through careful, quantified, selection of a high power, low-cost objective lens, our smartphone microscope has an imaging resolution of microns, with a working distance of 3 mm. It is therefore capable of imaging single cells and sub-cellular features, and retains usability for young children. The microscopes were designed in kit form and provided an interdisciplinary educational tool. By providing full lesson plans and support material, we developed a framework to explore optical design, microscope performance, engineering challenges on construction and real-world applications in life sciences, biological imaging, marine biology, art, and technology. A national online imaging competition framed EnLightenment; with over 500 high quality images submitted of diverse content, spanning multiple disciplines. With examples of cellular and sub-cellular features clearly identifiable in some submissions, we show how young public can use these instruments for research-level imaging applications, and the potential of the instrument for citizen science programs. PMID- 29623297 TI - Provision of mental health care within primary care in Peru: A qualitative study exploring the perspectives of psychologists, primary health care providers, and patients. AB - Background: This study aimed to understand the offer of mental health care at the primary care level, collecting the views of psychologists, primary health care providers (PHCPs), and patients, with a focus on health services in which patients attend regularly and who present a higher prevalence of mental disorders. Methods: A qualitative study was conducted in antenatal care, tuberculosis, HIV/AIDS, and chronic diseases services from six primary health care centers. Semi-structured interviews were conducted with psychologists, PHCPs, and patients working in or attending the selected facilities. Results: A total of 4 psychologists, 22 PHCPs, and 37 patients were interviewed. A high perceived need for mental health care was noted. PHCPs acknowledged the emotional impact physical health conditions have on their patients and mentioned that referral to psychologists was reserved only for serious problems. Their approach to emotional problems was providing emotional support (includes listening, talk about their patients' feelings, provide advice). PHCPs identified system-level barriers about the specialized mental health care, including a shortage of psychologists and an overwhelming demand, which results in brief consultations and lack in continuity of care. Psychologists focus their work on individual consultations; however, consultations were brief, did not follow a standardized model of care, and most patients attend only once. Psychologists also mentioned the lack of collaborative work among other healthcare providers. Despite these limitations, interviewed patients declared that they were willing to seek specialized care if advised and considered the psychologist's care provided as helpful; however, they recognized the stigmatization related to seeking mental health care. Conclusions: There is a perceived need of mental health care for primary care patients. To attend these needs, PHCPs provide emotional support and refer to psychology the most severe cases, while psychologists provide one-to-one consultations. Significant limitations in the care provided are discussed. PMID- 29623298 TI - A murine model of Charcot-Marie-Tooth disease 4F reveals a role for the C terminus of periaxin in the formation and stabilization of Cajal bands. AB - Charcot-Marie-Tooth (CMT) disease comprises up to 80 monogenic inherited neuropathies of the peripheral nervous system (PNS) that collectively result in demyelination and axon degeneration. The majority of CMT disease is primarily either dysmyelinating or demyelinating in which mutations affect the ability of Schwann cells to either assemble or stabilize peripheral nerve myelin. CMT4F is a recessive demyelinating form of the disease caused by mutations in the Periaxin ( PRX) gene . Periaxin (Prx) interacts with Dystrophin Related Protein 2 (Drp2) in an adhesion complex with the laminin receptor Dystroglycan (Dag). In mice the Prx/Drp2/Dag complex assembles adhesive domains at the interface between the abaxonal surface of the myelin sheath and the cytoplasmic surface of the Schwann cell plasma membrane. Assembly of these appositions causes the formation of cytoplasmic channels called Cajal bands beneath the surface of the Schwann cell plasma membrane. Loss of either Periaxin or Drp2 disrupts the appositions and causes CMT in both mouse and man. In a mouse model of CMT4F, complete loss of Periaxin first prevents normal Schwann cell elongation resulting in abnormally short internodal distances which can reduce nerve conduction velocity, and subsequently precipitates demyelination. Distinct functional domains responsible for Periaxin homodimerization and interaction with Drp2 to form the Prx/Drp2/Dag complex have been identified at the N-terminus of Periaxin. However, CMT4F can also be caused by a mutation that results in the truncation of Periaxin at the extreme C-terminus with the loss of 391 amino acids. By modelling this in mice, we show that loss of the C-terminus of Periaxin results in a surprising reduction in Drp2. This would be predicted to cause the observed instability of both appositions and myelin, and contribute significantly to the clinical phenotype in CMT4F. PMID- 29623299 TI - Gender Differences in Clinical Outcomes after Catheter Ablation of Atrial Fibrillation. AB - Objective: To explore gender differences in real-world outcomes after catheter ablation of atrial fibrillation (AF). Background: Compared to men, women with AF have greater thromboembolic risk and tend to be more symptomatic. Catheter ablation is generally more effective than antiarrhythmic drug therapy alone. However, there is limited data on the influence of gender on AF ablation outcomes. Methods: We analyzed medical claims of 45 million United States patients enrolled in a variety of employee-sponsored and fee-for-service plans. We identified patients who underwent an AF ablation from 2007 to 2011 and evaluated 30-day safety and one-year effectiveness outcomes. Results: Of the 21,091 patients who underwent an AF ablation, 7,460 (29%) were female. Women, compared to men, were older (62+/-11 vs. 58+/-11 years), had higher CHADS2 (1.2+/ 1.1 vs. 1.0+/-1.0), higher CHA2DS2-VASc (2.9+/-1.5 vs. 1.6+/-1.4), and higher Charlson comorbidity index scores (1.2+/-1.3 vs. 1.0+/-1.2)(p<0.001 for all). Following ablation, women had higher risk of 30-day complications of hemorrhage (2.7 vs. 2.0%,p<0.001) and tamponade (3.8 vs. 2.9%,p<0.001). In multivariable analyses, women were more likely to have a re-hospitalization for AF (adjusted HR 1.12,p=0.009), but less likely to have repeat AF ablation (adjusted HR 0.92,p=0.04) or cardioversion (adjusted HR 0.75,p<0.001). Conclusion: Women have increased hospitalization rates after AF ablation and are more likely to have a procedural complication. Despite the higher rate of hospital admissions for AF after ablation, women were less likely to undergo repeat ablation or cardioversion. These data call for greater examination of barriers and facilitators to sustain rhythm control strategies in women. PMID- 29623300 TI - Identifying Noise Sources governing cell-to-cell variability. AB - Phenotypic differences often occur even in clonal cell populations. Many potential sources of such variation have been identified, from biophysical rate variance intrinsic to all chemical processes to asymmetric division of molecular components extrinsic to any particular signaling pathway. Identifying the sources of phenotypic variation and quantifying their contributions to cell fate variation is not possible without accurate single cell data. By combining such data with mathematical models of potential noise sources it is possible to characterize the impact of varying levels of each noise source and identify which sources of variation best explain the experimental observations. The mathematical framework of information theory provides metrics of the impact of noise on the reliability of a cell to sense its environment. While the presence of noise in a single cellular system reduces the reliability of signal transduction its impact on a population of varied single cells remains unclear. PMID- 29623301 TI - Peptide-Based Bioinspired Approach to Regrowing Multilayered Aprismatic Enamel. AB - The gradual discovery of functional domains in native enamel matrix proteins has enabled the design of smart bioinspired peptides for tooth enamel mimetics and repair. In this study, we expanded upon the concept of biomineralization to design smaller amelogenin-inspired peptides with conserved functional domains for clinical translation. The synthetic peptides displayed a characteristic nanostructured scaffold reminiscent of 'nanospheres' seen in the enamel matrix and effectively controlled apatite nucleation in vitro resulting in the formation of smaller crystallites. Following application of the peptides to sectioned human molar teeth, a robust, oriented, synthetic aprismatic enamel was observed after 7 days of incubation in situ. There was a two-fold increase in the hardness and modulus of the regrown enamel-like apatite layers and an increase in the attachment of the tooth-regrown layer interface compared to control samples. Repeated peptide applications generated multiple enamel-like hydroxyapatite (HAP) layers of limited thickness produced by epitaxial growth in which c-axis oriented nanorods evolved on the surface of native enamel. We conclude that peptide analogues with active domains can effectively regulate the orientation of regenerated HAP layers to influence functional response. Moreover, this enamel biofabrication approach demonstrates the peptide-mediated growth of multiple microscale HAP arrays of organized microarchitecture with potential for enamel repair. PMID- 29623302 TI - Novel Fully Organic Water Oxidation Electrocatalysts: A Quest for Simplicity. AB - Despite the growing need for readily available and inexpensive catalysts for the half-reactions involved in water splitting, water oxidation and reduction electrocatalysts are still traditionally based on noble metals. One long-standing challenge has been the development of an oxygen evolution reaction catalyzed by easily available, structurally simple, and purely organic compounds. Herein, we first generalize the performance of the known N-ethyl-flavinium ion to a number of derivatives. Furthermore, we demonstrate an unprecedented application of different pyridinium and related salts as very simple, inexpensive water oxidation organocatalysts consisting of earth-abundant elements (C, H, O, and N) exclusively. The results establish the prospects of heterocyclic aromatics for further design of new organic electrocatalysts for this challenging oxidation reaction. PMID- 29623303 TI - Bis(arylimidazole) Iridium Picolinate Emitters and Preferential Dipole Orientation in Films. AB - The straightforward synthesis and photophysical properties of a new series of heteroleptic iridium(III) bis(2-arylimidazole) picolinate complexes are reported. Each complex has been characterized by nuclear magnetic resonance, UV-vis, cyclic voltammetry, and photoluminescent angle dependency, and the emissive properties of each are described. The preferred orientation of transition dipoles in emitter/host thin films indicated more preferred orientation than homoleptic complex Ir(ppy)3. PMID- 29623304 TI - Toward Understanding Drug Incorporation and Delivery from Biocompatible Metal Organic Frameworks in View of Cutaneous Administration. AB - Although metal-organic frameworks (MOFs) have widely demonstrated their convenient performances as drug-delivery systems, there is still work to do to fully understand the drug incorporation/delivery processes from these materials. In this work, a combined experimental and computational investigation of the main structural and physicochemical parameters driving drug adsorption/desorption kinetics was carried out. Two model drugs (aspirin and ibuprofen) and three water stable, biocompatible MOFs (MIL-100(Fe), UiO-66(Zr), and MIL-127(Fe)) have been selected to obtain a variety of drug-matrix couples with different structural and physicochemical characteristics. This study evidenced that the drug-loading and drug-delivery processes are mainly governed by structural parameters (accessibility of the framework and drug volume) as well as the MOF/drug hydrophobic/hydrophilic balance. As a result, the delivery of the drug under simulated cutaneous conditions (aqueous media at 37 degrees C) demonstrated that these systems fulfill the requirements to be used as topical drug-delivery systems, such as released payload between 1 and 7 days. These results highlight the importance of the rational selection of MOFs, evidencing the effect of geometrical and chemical parameters of both the MOF and the drug on the drug adsorption and release. PMID- 29623305 TI - Dramatic Improvement of the Mechanical Strength of Silane-Modified Hydroxyapatite Gelatin Composites via Processing with Cosolvent. AB - Bone tissue engineering (BTE) requires a sturdy biomaterial for scaffolds for restoration of large bone defects. Ideally, the scaffold should have a mechanical strength comparable to the natural bone in the implanted site. We show that adding cosolvent during the processing of our previously developed composite of hydroxyapatite-gelatin with a silane cross-linker can significantly affect its mechanical strength. When processed with tetrahydrofuran (THF) as the cosolvent, the new hydroxyapatite-gelatin composite can demonstrate almost twice the compressive strength (97 vs 195 MPa) and biaxial flexural strength (222 vs 431 MPa) of the previously developed hydroxyapatite-gelatin composite (i.e., processed without THF), respectively. We further confirm that this mechanical strength improvement is due to the improved morphology of both the enTMOS network and the composite. Furthermore, the addition of cosolvents does not appear to negatively impact the cell viability. Finally, the porous scaffold can be easily fabricated, and its compressive strength is around 11 MPa under dry conditions. All these results indicate that this new hydroxyapatite-gelatin composite is a promising material for BTE application. PMID- 29623306 TI - Successful Targeted Therapy of Refractory Pediatric ETV6-NTRK3 Fusion-Positive Secretory Breast Carcinoma. PMID- 29623307 TI - Implications of DRG Classification in a Bundled Payment Initiative for COPD. AB - OBJECTIVES: Institutions participating in the Medicare Bundled Payments for Care Improvement (BPCI) initiative invest significantly in efforts to reduce readmissions and costs for patients who are included in the program. Eligibility for the BPCI initiative is determined by diagnosis-related group (DRG) classification. The implications of this methodology for chronic diseases are not known. We hypothesized that patients included in a BPCI initiative for chronic obstructive pulmonary disease (COPD) would have less severe illness and decreased hospital utilization compared with those excluded from the bundled payment initiative. STUDY DESIGN: Retrospective observational study. METHODS: We sought to determine the clinical characteristics and outcomes of Medicare patients admitted to the University of Alabama at Birmingham Hospital with acute exacerbations of COPD between 2012 and 2014 who were included and excluded in a BPCI initiative. Patients were included in the analysis if they were discharged with a COPD DRG or with a non-COPD DRG but with an International Classification of Diseases, Ninth Revision code for COPD exacerbation. RESULTS: Six hundred and ninety-eight unique patients were discharged for an acute exacerbation of COPD; 239 (34.2%) were not classified into a COPD DRG and thus were excluded from the BPCI initiative. These patients were more likely to have intensive care unit (ICU) admissions (63.2% vs 4.4%, respectively; P <.001) and require noninvasive (46.9% vs 6.5%; P <.001) and invasive mechanical ventilation (41.4% vs 0.7%; P <.001) during their hospitalization than those in the initiative. They also had a longer ICU length of stay (5.2 vs 1.8 days; P = .011), longer hospital length of stay (10.3 days vs 3.9 days; P <.001), higher in-hospital mortality (14.6% vs 0.7%; P <.001), and greater hospitalization costs (median = $13,677 [interquartile range = $7489-$23,054] vs $4281 [$2718-$6537]; P <.001). CONCLUSIONS: The use of DRGs to identify patients with COPD for inclusion in the BPCI initiative led to the exclusion of more than one-third of patients with acute exacerbations who had more severe illness and worse outcomes and who may benefit most from the additional interventions provided by the initiative. PMID- 29623308 TI - Novel Supercapacitor-Based Force Sensor Insensitive to Parasitic Noise. AB - Traditional capacitive sensors suffer from significant parasitic noise when used in liquid environments or inside the human body. The parasitic noise overwhelms the force response of the sensor and makes it impossible to calculate the absolute force experienced by the sensor. This article focuses on the development of a supercapacitor based force sensor that is immune to parasitic noise. The supercapacitor consists of co-planar electrodes and a solid state ionic gel electrolyte on a deformable membrane. Force exertion causes deformation of the electrolyte membrane, increases its area of contact with the electrodes, resulting in a change of capacitance. The sensor is sealed, waterproof, and shows absolutely no changes in capacitance when immersed in water or enclosed in extracted sheep tissue. At the same time, its force sensitivity of 0.13 MU F/N exceeds the 0.3 pF/N sensitivity of a traditional capacitive sensor by 6 orders of magnitude. The developed sensor could have many biomedical applications in which parasitic capacitance is a serious challenge. PMID- 29623309 TI - Cells on hierarchically-structured platforms hosting functionalized nanoparticles. AB - In this work, we report on a novel approach to develop hierarchically-structured cell culture platforms incorporating functionalized gold nanoparticles (AuNPs). In particular, the hierarchical substrates comprise primary pseudo-periodic arrays of silicon microcones combined with a secondary nanoscale pattern of homogeneously deposited AuNPs terminated with bio-functional moieties. AuNPs with various functionalities (i.e. oligopeptides, small molecules and oligomers) were successfully attached onto the microstructures. Experiments with PC12 cells on hierarchical substrates incorporating AuNPs carrying the RGD peptide showed an impressive growth and NGF-induced differentiation of the PC12 cells, compared to that on the NP-free, bare, micropatterned substrates. The exploitation of the developed methodology for the binding of AuNPs as carriers of specific bio functional moieties onto micropatterned culture substrates for cell biology studies is envisaged. PMID- 29623311 TI - The effect of KH on enhancing the dehydrogenation properties of the Li-N-H system and its catalytic mechanism. AB - Although recent works demonstrated that some potassium compounds that can be converted to KH during ball-milling or heat-treatment have obvious effects on enhancing the dehydrogenation properties of the Li-N-H system, the effect of KH on enhancing the dehydrogenation properties of the Li-N-H system and its catalytic mechanism remain unclear. In this study, the hydrogen desorption properties of the LiNH2-LiH system with alkali metal hydrides (LiH, NaH, or KH) were investigated and discussed. We find that the three types of hydrides are effective for enhancing the hydrogen desorption properties of the LiNH2-LiH system, among which, KH shows the best effect. In comparison with the broad shaped hydrogen desorption curve of the LiNH2-LiH composite without additive, the hydrogen desorption curve of the LiNH2-LiH-0.05KH composite becomes narrow. The dehydrogenation onset temperature of the LiNH2-LiH-0.05KH composite is decreased by approximately 20 degrees C, and the dehydrogenation peak temperature is lowered by approximately 30 degrees C. Moreover, the reversibility of the LiNH2 LiH system is enhanced drastically by the addition of KH. On the basis of previous reports and present experimental results, the mechanism for the enhancement of the dehydrogenation properties in the KH-added Li-N-H system is proposed. The reason for the improvement of the hydrogen desorption kinetics is that KH has superior reactivity with NH3 and plays the role of a catalyst to accelerate hydrogen release by cyclic reactions. PMID- 29623310 TI - Identification of PP1-Gadd34 substrates involved in the unfolded protein response using K-BIPS, a method for phosphatase substrate identification. AB - Phosphorylation is a key post-translational modification in cell signaling, which is regulated by the equilibrium activities of kinases and phosphatases. The biological significance of many phosphorylation events remains poorly characterized due to the scarcity of tools to discover phosphatases substrates. In prior work, we established kinase-catalyzed biotinylation where kinases accept the gamma-modified ATP analog, ATP-biotin, to label phosphoproteins. Here, we developed a novel method to study substrates of phosphatases using kinase catalyzed biotinylation termed K-BIPS (Kinase-catalyzed Biotinylation to Identify Phosphatase Substrates). In a proof-of-concept experiment, K-BIPS was initially used to explore the substrates of phosphatases inhibited by okadaic acid. Many known phosphatase substrates were observed, confirming K-BIPS as a valid phosphatase substrate identification tool. Then, as a further application, K-BIPS was used to discover the substrates of the PP1-Gadd34 phosphatase complex in the context of unfolded protein response (UPR). In addition to the known substrate eIF2alpha, K-BIPS revealed several novel substrates, suggesting a more prominent role for the PP1-Gadd34 complex in UPR than previously appreciated. Overall, the two studies establish K-BIPS as a powerful tool to discover the cellular substrates of phosphatases. PMID- 29623312 TI - Competition kinetics of OH radical reactions with oxygenated organic compounds in aqueous solution: rate constants and internal optical absorption effects. AB - Oxygenated organic compounds are omnipresent in the troposphere, due to their strong emissions from either biogenic or anthropogenic sources. Additionally, the degradation and oxidation processes of volatile organic compounds (VOCs) result in the production of oxygenated organic compounds in the troposphere. The degradation and conversion of these compounds are often initiated by radical reactions and occur in the gas phase as well as in the aqueous phase, including cloud droplets, fog, haze, rain or hygroscopic particles containing 'aerosol liquid water (ALW)'. In the present study, the temperature-dependent OH radical reactions with oxygenated organic compounds in the aqueous phase have been investigated by laser flash photolysis. To determine the rate constants, the OH radical - thiocyanate anion competition kinetics method has been used. Once the organic reactant has an absorption at the excitation wavelength of the photolysis laser, the initial OH concentration decreases. This internal absorption effect leads to an overestimated rate constant of the investigated compound. The present study considers this contribution in order to clarify the internal absorption effect of the investigated organic compounds. The following rate constants for OH radical oxidation reactions of the oxygenated organic compounds have been obtained: acetone (2-propanone) k298K = (7.6 +/- 1.0) * 107 L mol-1 s-1, 1 hydroxypropan-2-one k298K = (1.1 +/- 0.1) * 109 L mol-1 s-1, 1,3-dihydroxypropan 2-one k298K = (1.5 +/- 0.1) * 109 L mol-1 s-1, 2,3-dihydroxypropanal k298K = (1.3 +/- 0.1) * 109 L mol-1 s-1, butane-1,3-diol k298K = (2.5 +/- 0.1) * 109 L mol-1 s 1, butane-2,3-diol k298K = (2.0 +/- 0.1) * 109 L mol-1 s-1 and hexane-1,2-diol k298K = (4.6 +/- 0.4) * 109 L mol-1 s-1. With the rate constants obtained and their T-dependencies, the source and sink processes of oxygenated organic compounds in the tropospheric aqueous phase are arrived at precisely. These findings might enhance the predictive capabilities of models such as the chemical aqueous-phase radical mechanism (CAPRAM). PMID- 29623313 TI - Relevance of the deletion of the Tatri4 gene in the secondary metabolome of Trichoderma arundinaceum. AB - The fungus Trichoderma arundinaceum (Ta37) has a significant biocontrol application which has been related to the production of the trichothecene, harzianum A (2). Previous studies with a strain of T. arundinaceum which was blocked for the production of 2, revealed the existence of a chemical cross regulation between the biocontrol fungus and its target organism. A study of the secondary metabolome of a single culture of a mutant of T. arundinaceum TaDeltaTri4 which produces trichothecene biosynthetic intermediates, has now been carried out. The production of secondary metabolites in a co-culture with the phytopathogen, Botrytis cinerea, was then analyzed. The mutant produced a larger quantity of the aspinolides B (6) and C (7) and other derivatives when compared to the wild type Ta37. Ten new metabolites were isolated: three aspinolides 12 14, the gamma-lactones 15 and 16, two hemi-ketals 17 and 18 and three aspinolide degradation products, 19, 21 and 22. In the confrontation cultures involving the TaDeltaTri4 and the B. cinerea B05.10 strains, there was a higher production of the aspinolides B and C by the TaDeltaTri4 mutant while the production of the botryanes and botcinins by B. cinerea was reduced in the area of interaction between the cultures. These results shed light on the chemical cross-talk and ecological interactions between these fungi. PMID- 29623314 TI - A promising solution to the limits of microscopes for smooth surfaces: fluorophore-aided scattering microscopy. AB - Reflected light escape and mesoscopic penetration are two serious problems for optical characterization using microscopes. For specular samples with steep slopes, the detector does not receive enough light and the detection algorithm is not be able to detect the peak position, and would generate non-measured points. Moreover, the mesoscopic penetration phenomenon has been ignored when measuring and observing the shapes of samples with multi-layer structures. But this phenomenon, due to the transparency of materials to certain wavelengths of light, may result in serious errors in the measurements of the heights of samples, as well as errors in the descriptions of their shapes. Here we describe the use of fluorophore-aided scattering microscopy to significantly extend the magnitudes of slopes that can be detected, and to essentially eliminate errors in measurements of height caused by mesoscopic penetration. PMID- 29623315 TI - Correction: Adsorption of PAHs on interstellar ice viewed by classical molecular dynamics. AB - Correction for 'Adsorption of PAHs on interstellar ice viewed by classical molecular dynamics' by Eric Michoulier et al., Phys. Chem. Chem. Phys., 2018, DOI: 10.1039/c8cp00593a. PMID- 29623316 TI - High crystallization of a multiple cation perovskite absorber for low-temperature stable ZnO solar cells with high-efficiency of over 20. AB - ZnO as a promising electron transport layer (ETL) to TiO2 for perovskite solar cells (PSCs) has achieved a power conversion efficiency (PCE) of 18.9%; however, this is still lower than that obtained for TiO2-based PSCs (higher than 20%). Herein, we report the fabrication of high-efficiency methylammonium (MA) and Cs co-alloyed formamidinium (FA) triple cation perovskite based ZnO PSCs via delicate control of the cation compositions and annealing temperatures. By virtue of structural, morphological, spectral and electrochemical characterizations and analysis, we found that the incorporation of MA and Cs into FA perovskite enables the formation of a highly crystalline black phase perovskite with reduced surface roughness, which inhibits charge recombination and promotes electron transfer at the ZnO/perovskite/spiro-OMeTAD interfaces and hence improves Jsc and FF values of the cell. As a result, the ZnO PSC based on MA0.1FA0.75Cs0.15PbI3 annealed at 110 degrees C achieved a PCE as high as 20.09%, exceeding the previous highest efficiency recorded for ZnO ETL based PSCs. The optimized MA0.1FA0.75Cs0.15PbI3 material demonstrated excellent reproducibility and long-term cell durability under ambient conditions within 1000 h. Particularly, the incorporation of a small amount of Br into the triple cation perovskite, i.e., MA0.1FA0.75Cs0.15PbI2.9Br0.1 led to a further enhancement in PCE of up to 20.44%, which is comparable with the best-performing MA and Cs-containing FA-based lead halide TiO2 PSCs. PMID- 29623317 TI - Supramolecular assemblies of dinuclear alkynylplatinum(ii) terpyridine complexes with double-decker silsesquioxane nano-cores: the role of isomerism in constructing nano-structures. AB - Isomeric double-decker silsesquioxane-functionalized dinuclear alkynylplatinum(ii) terpyridine complexes demonstrate self-association behaviours via the stabilisation of hydrophobic, PtPt and/or pi-pi stacking interactions. These supramolecular architectures and molecular packings are found to be closely related to the isomeric configurations of the complexes and have been investigated using various spectroscopic studies. PMID- 29623318 TI - Readily functionalized AAA-DDD triply hydrogen-bonded motifs. AB - Herein we present a new, readily functionalized AAA-DDD hydrogen bond array. A novel AAA monomeric unit (3a-b) was obtained from a two-step synthetic procedure starting with 2-aminonicotinaldehyde via microwave radiation (overall yield of 52 66%). 1H NMR and fluorescence spectroscopy confirmed the complexation event with a calculated association constant of 1.57 * 107 M-1. Likewise, the usefulness of this triple hydrogen bond motif in supramolecular polymerization was demonstrated through viscosity measurements in a crosslinked supramolecular alternating copolymer. PMID- 29623324 TI - Reversible modulation of the redox characteristics of acid-sensitive molybdenum and tungsten scorpionate complexes. AB - The large-scale synthesis of the scorpionate ligand Ttz (hydrotris(1,2,4-triazol 1-yl)borate) is reported as well as syntheses of Group VI complexes K[M(L)(CO)3] and M(L)(NO)(CO)2 (L = Ttz or Tp (hydrotris(pyrazol-1-yl)borate), M = Mo or W). The redox characteristics of the metal in these Ttz complexes are shown to be reversibly modulated by interactions between the exo-4-N lone pairs of the triazolyl rings and Bronsted or Lewis acids. The basicity of the scorpionate ligand in [M(Ttz)(CO)3]- is quantified (pKaH2O values range from 1.1 to 4.6) and found to be dependent on both the oxidation state and identity of the metal. In the presence of Bronsted acids, the observed redox behavior for the one-electron oxidation of the Group VI metal center is consistent with a proton-coupled electron transfer (PCET). Indeed, for both Mo and W derivatives, a one-electron oxidation decreases the pKa by ~3.5 units. PMID- 29623325 TI - Synthesis, structural characterisation and antiproliferative activity of a new fluorescent 4-amino-1,8-naphthalimide Troger's base-Ru(ii)-curcumin organometallic conjugate. AB - The synthesis, photophysics and biological investigation of fluorescent 4-amino 1,8-naphthalimide Troger's bases (TB-1-TB-3) and a new Troger's base p-cymene Ru(ii)-curcumin organometallic conjugate (TB-Ru-Cur) are described; these compounds showed fast cellular uptake and displayed good luminescence and cytotoxicity against cervical cancer cells. PMID- 29623326 TI - Graphene-amplified femtosensitive aptasensing of estradiol, an endocrine disruptor. AB - We report the construction of a novel electrochemical femtomolar aptasensing APT ERGO/GCE interface based on the covalent immobilization of 38-mer amine functionalized (NH2-APT) 17beta-estradiol (E2) DNA aptamers on a graphene amplifying platform. Graphene oxide (GO) was synthesized and characterized by using FTIR, UV-vis spectroscopy, XRD spectroscopy, and SEM technique. The strategy for the construction of the E2-aptasensing interface involves in a three step modification process. (i) First, we carried out the electrochemical reduction of GO on the GCE electrode to form ERGO/GCE. (ii) Then, as an impact strategy, the E2-aptamers (NH2-APT) were further immobilized on the surface of the ERGO/GCE interface through electrochemical reduction of surface functionalized diazonium salts. This step includes electrografting of ERGO/GCE by electrochemical reduction of the diazonium salt (ClN2+-Ph-COOH) to obtain the ERGO/GCE-Ph-COOH-modified electrode. (iii) Finally, the free carboxyl groups on the ERGO/GCE-Ph-COOH surface were conjugated with NH2-APT through formation of carbodiimide to afford an aptasensing APT-ERGO/GCE interface. The presence of ERGO as an amplifying platform led to the successful immobilization of E2 aptamers with a surface coverage of 1.9 * 1013 molecule per cm2, which is higher than the values obtained in other reported methods. The constructed aptasensing APT-ERGO/GCE interface was appraised using cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS). The synergetic effect of high affinity and specificity of E2-aptamers and graphene platform was beneficial for the novel femtosensitive label-free electrochemical aptasensing APT-ERGO/GCE interface for the detection of [E2]. The oxidation current peaks at the aptasensing APT-ERGO/GCE interface were proportional to [E2] over two different concentration linearity ranges 1.0 * 10-15 mol L-1-9.0 * 10-12 mol L-1-1.2 * 10 11 mol L-1 to 2.3 * 10-10 mol L-1 with a limit of detection (LOD) of 0.5 * 10-15 mol L-1. This aptasensing APT-ERGO/GCE interface was employed as a femtomolar tool for the determination of [E2] in the environmental and pharmaceutical samples such as wastewater (spiked) and pharmaceutical dosages. PMID- 29623327 TI - alpha-Tocopherol-based cationic amphiphiles with a novel pH sensitive hybrid linker for gene delivery. AB - Endosomal escape is one of the barriers for the efficient liposomal gene delivery. To address this and based on earlier encouraging results using tocopherol cationic lipids, we elaborated chemical modifications on tocopherol cationic lipids by introducing a novel hybrid pH sensitive linker "ether-beta hydroxy-triazole" between tocopherol, the anchoring moiety and the basic tris(2 hydroxy ethyl)quaternary ammonium head group (Lp2). As control lipids we designed two lipids (Lp1 and Lp3), one is with only the ether-beta-hydroxy linker in between alpha-tocopherol and quaternary tris(2-hydroxyethyl)ammonium (Lp1) and the other is with the same novel hybrid linker i.e. "ether-beta-hydroxy-triazole" between the alpha-tocopherol linked and quaternary tris-ethyl ammonium head group (Lp3). Liposomes were formulated with a combination of a well-known co-lipid, 1,2 dioleoyl-sn-glycero-3-phosphoethanolamine (DOPE) and biophysical characteristics such as DNA binding, hydrodynamic diameters and global surface charges for liposomes and lipoplexes of respective lipids were evaluated. Cell viability assay and in vitro transfection studies were carried out in NIH3 T3, B16F10, HEK 293, and HepG2 cell lines. In vitro transfection data for the liposomes of lipids (Lp1, Lp2 and Lp3) revealed that the Lp2 lipid with a novel hybrid pH sensitive linker showed superior transfection efficiency when compared with the remaining two analogues. More importantly, Lp2 has shown a similar pattern of transfection efficiency in HepG2 and HEK-293 cell lines when compared with commercially available Lipofectamine 3000. PMID- 29623328 TI - Ultrasonication-assisted synthesis of high aspect ratio gold nanowires on a graphene template and investigation of their growth mechanism. AB - We report a facile synthesis of Au nanowires (AuNWs) with a high aspect ratio (l/D) of up to 5000 on a plasma activated graphene template with ultrasound assistance. We demonstrate that the ultrasonication induced symmetry breaking of Au clusters facilitates the growth of AuNWs from the embryonic stages. Furthermore, the growth mechanism of AuNWs is systematically investigated using high resolution electron transmission microscopy (HRTEM), which reveals the unique role of the defective graphene template in directing the growth of AuNWs. PMID- 29623329 TI - High light harvesting efficiency CuInS2 quantum dots/TiO2/MoS2 photocatalysts for enhanced visible light photocatalytic H2 production. AB - Expanding the photoresponse range of TiO2-based photocatalysts is of great interest for photocatalytic H2 production. Herein, noble-metal-free CuInS2 quantum dots were employed as a novel inorganic dye to expand the visible light absorption of TiO2/MoS2 for solar H2 generation. The as-prepared CuInS2/TiO2/MoS2 photocatalysts exhibit broad absorption from the ultraviolet to near-infrared region. Under visible light irradiation (lambda > 420 nm), the CuInS2/TiO2/MoS2 photocatalyst with 0.6 mmol g-1 CuInS2 and 0.5 wt% MoS2 showed the highest H2 evolution rate with a value of 1034 MUmol h-1 g-1. Moreover, a considerable H2 evolution rate of 141 MUmol h-1 g-1 was obtained under the irradiation of the optimized CuInS2/TiO2/MoS2 photocatalyst with >500 nm light. The reaction mechanism of the CuInS2/TiO2/MoS2 photocatalyst for photocatalytic H2 evolution was investigated in detail by photoluminescence decay study, and the results showed that the photoexcited electrons of CuInS2 can be transferred efficiently through TiO2 to MoS2 and then react with the absorbed protons to generate H2. The reported sensitization strategy tremendously improves the visible light absorption capacity and the photocatalytic performance of TiO2-based photocatalysts. PMID- 29623330 TI - Ruthenium(ii)-catalyzed remote C-H addition of 8 aminoquinoline amide to activated aldehyde. AB - Ruthenium(ii)-catalyzed regioselective remote C-H addition of 8-aminoquinoline amides at C-5 position to ethyl glyoxalate and 2,2,2-trifluoroacetaldehyde have been developed. The transformation affords C-5 functionalized quinolines in moderate to good yields. This method is applicable to various aryl, heteroaryl as well as aliphatic carboxamides. Experimental results suggest that the reaction very likely proceeds through an ionic pathway. PMID- 29623332 TI - Cooperativity in spin crossover materials as ligand's responsibility - investigations of the Fe(ii) - 1,3-bis((1H-tetrazol-1 yl)methyl)bicyclo[1.1.1]pentane system. AB - Criteria for a technologically relevant spin crossover (SCO) material include temperature and abruptness. A series of Fe(ii) - 1,3-bis((1H-tetrazol-1 yl)methyl)bicyclo[1.1.1]pentane SCO complexes with various anions (BF4-, ClO4-, and PF6-) designed using a structure-property based concept is reported. All complexes feature abrupt SCO-behavior with T1/2 between 170 K and 187 K. These materials demonstrate that without stabilizing the effects of incorporated solvents or a hydrogen bond-network, the observed cooperativity during high-spin low-spin transition is anion independent and originates only from the rigidity and internal strain of the propellane-moiety in the ligand. Spectroscopy and structural investigations of these materials are supported by quantum chemical calculations. PMID- 29623333 TI - Hierarchical SnS2/SnO2 nanoheterojunctions with increased active-sites and charge transfer for ultrasensitive NO2 detection. AB - SnS2 nanosheets with unique properties are excellent candidate materials for fabricating high-performance NO2 gas sensors. However, serious restacking and aggregation during sensor fabrication have greatly impacted the sensing response. In this study, flower-like hierarchical SnS2 was prepared by a simple microwave method and partially thermally oxidized to form hierarchical SnS2/SnO2 nanocomposites to further improve the sensing performance at low operating temperature. The fabricated SnS2/SnO2 sensor exhibited ultrahigh response (resistance ratio = 51.1) toward 1 ppm NO2 at 100 degrees C, roughly 10.2 times higher than that of pure SnS2 nanoflowers. The excellent and enhanced NO2 sensing performances of hierarchical SnS2/SnO2 nanocomposites were attributed to the novel hierarchical structure of SnS2 and the nanoheterojunction between SnS2 and the ultrafine SnO2 nanoparticles. The SnS2/SnO2 sensors also exhibited excellent selectivity and reliable repeatability. The simple fabrication of high performance sensing materials may facilitate the large-scale production of NO2 gas sensors. PMID- 29623331 TI - Recent trends in the structural revision of natural products. AB - Covering: 2012 to 2017 This article reviews recent reports on the structural revision of natural products. Through a critical assessment of the original and revised published structures, the article addresses why each structure was targeted for revision, discusses the techniques and key discrepancies that led to the proposal of the revised structure, and offers measures that may have been taken during the original structure determination to prevent error. With the revised structures in hand, weaknesses of original proposals are assessed, providing a better understanding on the logic behind structure determination. PMID- 29623337 TI - Rhodium(iii)-catalyzed CF3-carbenoid C-H functionalization of 6-arylpurines. AB - An efficient method for the CF3-carbenoid C-H functionalization of 6-arylpurines has been developed. This protocol uses readily available methyl 3,3,3-trifluoro-2 diazopropionate as a cross-coupling partner and proceeds smoothly under chelation controlled Rh(iii) catalysis. The reactions provide the corresponding carbene insertion products with high regioselectivity within a few hours and allow the introduction of both the CF3 and carboxylate functions into biologically important purine molecules including nucleoside derivatives. PMID- 29623338 TI - Lantern-like bismuth oxyiodide embedded typha-based carbon via in situ self template and ion exchange-recrystallization for high-performance photocatalysis. AB - Efficient photocatalysts induced by visible light (e.g. BiOI) have attracted wide attention for energy storage and environmental pollutant rehabilitation. In this work, N-doped bamboo tube-like carbon (NTC) was derived directly from the carbonization of bio-waste (withered typha grass) under an ammonia atmosphere. During fabrication, the BiOI/NTC material was used as a self-sacrificing template and I- ions were gradually replaced by OH- ions from NH3.H2O solution. Then Bi7O9I3/NTC was formed with micro-/nanohierarchical structures, which could exactly be explained by the in situ ion exchange-recrystallization mechanism. Thereinto, the well-defined hierarchical lantern-like Bi7O9I3 composed of interconnecting ultrathin nanosheets firmly embedded the "bamboo tubes" of NTC, which endow sufficient interface and high specific surface area (40 m2 g-1). The multiple synergistic effects of the lantern-like structure with ultrathin nanosheets, low iodine content and well-contacted interface endow the synthesized Bi7O9I3/NTC with outstanding visible-light catalytic activity. The results show that the obtained Bi7O9I3/NTC degraded 93.5% of methyl orange and 97.6% of rhodamine B within 2 hours, showing superior performance as compared to the pure BiOI. Therefore, our work demonstrates a controllable approach that can provide guidelines for designing optimized bismuth oxyiodide-based photocatalyst materials and has the potential for application in environmental remediation. PMID- 29623339 TI - Maintenance of Improved Attitudes Toward Stuttering. AB - Purpose: This study sought to determine the extent to which experimentally induced positive attitudes in high school students in a previous investigation were maintained 7 years later. Method: Authors and assistants recruited 36 adults in their early 20s (Follow-up group) who, in high school, had witnessed either a live oral talk by a person who stutters or a professionally made video on stuttering designed for teens followed by a short talk by the same speaker. The Public Opinion Survey of Human Attributes-Stuttering was administered before and after the interventions in high school and 7 years later such that pre-post group comparisons were made. Previously, the Follow-up group had demonstrated highly positive changes in their attitudes after the interventions. In addition, a control group of 56 former high school students from the same state, who did not participate in the interventions, were recruited and compared to the Follow-up group. Results: The Follow-up group, which was found to be representative of the original high school cohort, held more positive Public Opinion Survey of Human Attributes-Stuttering mean ratings than the Control group, although somewhat less positive than their previous postintervention ratings. Conclusions: The Follow-up group maintained many of the positive changes in their beliefs and self reactions regarding stuttering that were induced 7 years earlier after witnessing personal stories and facts about stuttering. PMID- 29623340 TI - Consonant and Vowel Identification in Cochlear Implant Users Measured by Nonsense Words: A Systematic Review and Meta-Analysis. AB - Purpose: The purpose of this systematic review and meta-analysis was to establish a baseline of the vowel and consonant identification scores in prelingually and postlingually deaf users of multichannel cochlear implants (CIs) tested with consonant-vowel-consonant and vowel-consonant-vowel nonsense syllables. Method: Six electronic databases were searched for peer-reviewed articles reporting consonant and vowel identification scores in CI users measured by nonsense words. Relevant studies were independently assessed and screened by 2 reviewers. Consonant and vowel identification scores were presented in forest plots and compared between studies in a meta-analysis. Results: Forty-seven articles with 50 studies, including 647 participants, thereof 581 postlingually deaf and 66 prelingually deaf, met the inclusion criteria of this study. The mean performance on vowel identification tasks for the postlingually deaf CI users was 76.8% (N = 5), which was higher than the mean performance for the prelingually deaf CI users (67.7%; N = 1). The mean performance on consonant identification tasks for the postlingually deaf CI users was higher (58.4%; N = 44) than for the prelingually deaf CI users (46.7%; N = 6). The most common consonant confusions were found between those with same manner of articulation (/k/ as /t/, /m/ as /n/, and /p/ as /t/). Conclusions: The mean performance on consonant identification tasks for the prelingually and postlingually deaf CI users was found. There were no statistically significant differences between the scores for prelingually and postlingually deaf CI users. The consonants that were incorrectly identified were typically confused with other consonants with the same acoustic properties, namely, voicing, duration, nasality, and silent gaps. A univariate metaregression model, although not statistically significant, indicated that duration of implant use in postlingually deaf adults predict a substantial portion of their consonant identification ability. As there is no ceiling effect, a nonsense syllable identification test may be a useful addition to the standard test battery in audiology clinics when assessing the speech perception of CI users. PMID- 29623341 TI - The updated German "Polytrauma - Guideline": an extensive literature evaluation and treatment recommendation for the care of the critically injured patient. PMID- 29623342 TI - Immune-mediated cholangitis: is it always nivolumab's fault? PMID- 29623343 TI - ? PMID- 29623344 TI - ? PMID- 29623346 TI - Chest wall mass in a 15 year old female patient. PMID- 29623345 TI - Lp-PLA2 activity is associated with increased risk of diabetic retinopathy: a longitudinal disease progression study. AB - AIMS/HYPOTHESIS: The aim of the study was to examine the association between lipoprotein-associated phospholipase A2 (Lp-PLA2) activity levels and incident diabetic retinopathy and change in retinopathy grade. METHODS: This was a cohort study of diabetic participants with serum collected at baseline and routinely collected diabetic retinal screening data. Participants with type 2 diabetes from the GoDARTS (Genetics of Diabetes Audit and Research in Tayside Scotland) cohort were used. This cohort is composed of individuals of white Scottish ancestry from the Tayside region of Scotland. Survival analysis accounting for informative censoring by modelling death as a competing risk was performed for the development of incident diabetic retinopathy from a disease-free state in a 3 year follow-up period (n = 1364) by stratified Lp-PLA2 activity levels (in quartiles). The same analysis was performed for transitions to more severe grades. RESULTS: The hazard of developing incident diabetic retinopathy was 2.08 times higher (95% CI 1.64, 2.63) for the highest quartile of Lp-PLA2 activity compared with the lowest. Higher Lp-PLA2 activity levels were associated with a significantly increased risk for transitions to all grades. The hazards of developing observable (or more severe) and referable (or more severe) retinopathy were 2.82 (95% CI 1.71, 4.65) and 1.87 (95% CI 1.26, 2.77) times higher for the highest quartile of Lp-PLA2 activity compared with the lowest, respectively. CONCLUSIONS/INTERPRETATION: Higher Lp-PLA2 levels are associated with increased risk of death and the development of incident diabetic retinopathy, as well as transitions to more severe grades of diabetic retinopathy. These associations are independent of calculated LDL-cholesterol and other traditional risk factors. Further, this biomarker study shows that the association is temporally sensitive to the proximity of the event to measurement of Lp-PLA2. PMID- 29623347 TI - [Intraoperative neuromonitoring in cervical deformity surgery]. AB - Correction of cervical deformity is associated with a considerable risk of neurological deterioration. The use of intraoperative neuromonitoring (IOM) can, however, significantly increase patient safety. Nonetheless, data on the effectiveness of IOM during reconstructive cervical surgery are very limited. Since the surgical maneuvers in reconstructive cervical surgery represent the same dangers to the spinal cord as in scoliosis correction, the same influence of IOM on the clinical outcome may be assumed. IOM has been shown to decrease the rate of neurological complications in scoliosis surgery. Herein, we discuss the current evidence for the efficacy of IOM during reconstructive cervical surgery as well as during scoliosis surgery. PMID- 29623348 TI - The sentinel loop sign. PMID- 29623349 TI - Three cases of intracystic papillary neoplasm of gallbladder. AB - Intracystic papillary neoplasm (ICPN) of gallbladder is a comparatively new concept and is described as pre-malignant lesions in Nakanuma et al. (In: Bosman et al. (eds) WHO Classification of Tumours of the Digestive System, World Health Organization of Tumours, IARC, Lyon, 2010). ICPN with high-grade intraepithelial neoplasia is understood to include intraepithelial carcinoma or noninvasive carcinoma. And lesions with invasive cancer components are classified as ICPN with an associated invasive carcinoma [1]. According to Adsay et al., more than half of patients diagnosed with ICPN have invasive cancer components (Adsay et al., Am J Surg Pathol 36:1279-1301, 2012).Polypoid masses in the gallbladder including benign, malignant, and non-neoplastic lesions have been called gallbladder polyps, and ICPN is also a polypoid lesion in the gallbladder. However, it is difficult to differentiate between them. In the literature, it is said that the possibility of malignancy is high in lesions exceeding 1 cm (Terzi et al., Surgery 127:622-627, 2000). And there are few reports on characteristic imaging findings of ICPN.We have experienced three cases (two females and one male) of ICPN and report our imaging findings. Contrast-enhanced computed tomography revealed large papillary polypoid lesions approximately 2-4 cm in size in the gallbladder. Findings suggestive of deformation of the gallbladder wall and extrinsic progression were absent in all cases. T2-weighted magnetic resonance imaging revealed intense signals and diffusion-weighted imaging showed high intensity. Expanding of the gallbladder was seen in case 1, and a tumor stalk-like appearance was seen in the papillary mass in cases 2 and 3. Surgery was performed in all three cases and ICPN was diagnosed pathologically. The cancer was localized to the mucosa, with no infiltration of surrounding tissue in all three cases. PMID- 29623350 TI - Group Selection May Explain Cancer Predisposition and Other Human Traits' Evolution. AB - Group selection is a matter of acute controversy among evolutionary biologists. The most well-publicized debate in this regard is that between Edward O. Wilson and Richard Dawkins. As is widely known, Edward O. Wilson is very excited about the idea of social selection and eusociality; by contrast Richard Dawkins favors the idea of gene selection. As is often the case, the truth is somewhere in the middle. Evolution is most likely a multilevel procedure, where selection forces act on genes, individuals, and groups. Here, I would like to emphasize that group selection may be a possible cause of increased genetic variation on DNA repair genes, subsequently this driving to high cancer incidence. Additionally, if group selection is indeed happening in humans, maybe this is the reason that few adaptive loci have been discovered in human genome, even though thousands of sequenced genomes exist today. PMID- 29623351 TI - Primitive Dark-Phase Cycle of Photosynthesis at the Origin of Life. AB - Simple phosphorylation, isomerization, and aldolisation reactions starting from glyceraldehyde have the potential to lead to the synthesis of pre-ribonucleotide polymers through a primitive form of the Calvin cycle (dark phase of photosynthesis) involving the unusual formation of phospho-nonulose phosphate and phospho-deculose phosphate, as key intermediates. These reactions involve activated phosphates which are generated from schreibersite minerals, geochemically available in Hadean times. PMID- 29623352 TI - Do we need gadolinium-based contrast medium for brain magnetic resonance imaging in children? AB - BACKGROUND: Brain imaging is the most common examination in pediatric magnetic resonance imaging (MRI), often combined with the use of a gadolinium-based contrast medium. The application of gadolinium-based contrast medium poses some risk. There is limited evidence of the benefits of contrast medium in pediatric brain imaging. OBJECTIVE: To assess the diagnostic gain of contrast-enhanced sequences in brain MRI when the unenhanced sequences are normal. MATERIALS AND METHODS: We retrospectively assessed 6,683 brain MR examinations using contrast medium in children younger than 16 years in the pediatric radiology department of the University Hospital Leipzig to determine whether contrast-enhanced sequences delivered additional, clinically relevant information to pre-contrast sequences. All examinations were executed using a 1.5-T or a 3-T system. RESULTS: In 8 of 3,003 (95% confidence interval 0.12-0.52%) unenhanced normal brain examinations, a relevant additional finding was detected when contrast medium was administered. Contrast enhancement led to a change in diagnosis in only one of these cases. CONCLUSION: Children with a normal pre-contrast brain MRI rarely benefit from contrast medium application. Comparing these results to the risks and disadvantages of a routine gadolinium application, there is substantiated numerical evidence for avoiding routine administration of gadolinium in a pre contrast normal MRI examination. PMID- 29623353 TI - An arthroscopic bone block procedure is effective in restoring stability, allowing return to sports in cases of glenohumeral instability with glenoid bone deficiency. AB - PURPOSE: A group of patients affected by bone loss in the context of recurrent anterior shoulder instability were treated arthroscopically with a modified Eden Hybinette technique since 2005. The last modification was made in 2013, consisting of fixation using a pair of specifically designed double round Endobuttons, which secure the bone graft to the glenoid rim placed through a guide. This report describes patients operated on after this last modification. No reports have described the results of this technique, and the purpose of this study was to assess early clinical and radiological results of an arthroscopic bone block procedure with double round Endobutton fixation. We hypothesized that this technique would restore shoulder stability in patients with anteroinferior glenohumeral instability with glenoid bone deficit, with excellent clinical and radiological results. METHODS: The clinical and radiological efficacy of this procedure was retrospectively evaluated in 26 patients with an average follow-up of 29.6 months (range 24-33 months). RESULTS: At minimum 2-year follow-up, we had no recurrent anterior dislocations, excellent clinical results [average Walch Duplay score 93.2, (SD 7.8); average Rowe score, 96.4 (SD 6.5); average SSV, 87.4 (SD 12.1); satisfaction rate, 88.5%; average loss of external rotation, 4.4 degrees (SD 8.7 degrees )] optimal graft positioning, and a healing rate of 92.3% on computed tomography scan. CONCLUSIONS: Arthroscopic bone block grafting combined with a standard Bankart repair restored shoulder stability in patients with anteroinferior glenohumeral instability with glenoid bone deficit, with excellent clinical and radiological results. This procedure did not substantially limit external rotation, allowing a high rate of return to sports even among competitive, overhead, and "at risk" athletes. PMID- 29623354 TI - Appetitive startle modulation in the human laboratory predicts Cannabis craving in the natural environment. AB - RATIONALE: Drug-related cues evoke craving and stimulate motivational systems in the brain. The acoustic startle reflex captures activation of these motivational processes and affords a unique measure of reactivity to drug cues. OBJECTIVES: This study examined the effects of cannabis-related cues on subjective and eye blink startle reactivity in the human laboratory and tested whether these effects predicted youth's cue-elicited cannabis craving in the natural environment. METHODS: Participants were 55 frequent cannabis users, ages 16 to 24 years (M = 19.9, SD = 1.9; 55% male; 56% met criteria for cannabis dependence), who were recruited from a clinical trial to reduce cannabis use. Eye blink electromyographic activity was recorded in response to acoustic probes that elicited startle reactivity while participants viewed pleasant, unpleasant, neutral, and cannabis picture cues. Following the startle assessment, participants completed an ecological momentary assessment protocol that involved repeated assessments of cue-elicited craving in real time in their real-world environments. RESULTS: Multilevel models included the presence or absence of visible cannabis cues in the natural environment, startle magnitude, and the cross-level interaction of cues by startle to test whether cue-modulated startle reactivity in the laboratory was associated with cue-elicited craving in the natural environment. Analyses showed that cannabis-related stimuli evoked an appetitive startle response pattern in the laboratory, and this effect was associated with increased cue-elicited craving in the natural environment, b = - 0.15, p = .022, 95% CI [- 0.28, - 0.02]. Pleasant stimuli also evoked an appetitive response pattern, but in this case, blunted response was associated with increased cue-elicited craving in the natural environment, b = 0.27, p < .001, 95% CI [0.12, 0.43]. CONCLUSIONS: Our findings support cue-modulated startle reactivity as an index of the phenotypic expression of cue-elicited cannabis craving. PMID- 29623355 TI - Clinical and laboratory features of patients with osteomalacia initially presenting with neurological manifestations. AB - : Patients with osteomalacia often visit the neurology department with conditions mimicking other myopathies. We analyzed clinical features of osteomalacia patients who visited the neurology department. These patients frequently presented with hypocalcemia, hypovitaminosis D, and pain with less severe weakness. Osteomalacia should be considered when patients present with pain and weakness. INTRODUCTION: Osteomalacia is a disease of bone metabolism; however, some patients with osteomalacia initially visit the neurology department. As these patients often complain of weakness and gait disturbance, osteomalacia can be confused with other myopathies. We analyzed the clinical features of patients with osteomalacia who visited the neurology department. METHODS: We retrospectively reviewed the medical records. Osteomalacia was diagnosed based on symptoms, laboratory features, and imaging results. We compared the characteristics of patients with osteomalacia who visited the neurology department with (1) those who did not visit the neurology department and (2) patients with idiopathic inflammatory myopathy. RESULTS: Eighteen patients with osteomalacia visited the neurology department (NR group). The common etiologies in the NR group included tumors or antiepileptic medication, whereas antiviral medication was the most common in patients who did not visit the neurology department (non-NR group). The NR group showed lower serum calcium (p = 0.004) and 25-hydroxyvitamin D (p = 0.006) levels than the non-NR group. When compared with patients with inflammatory myopathy, both groups showed proximal dominant weakness. However, pain was more common in osteomalacia than in myopathy (p = 0.008), and patients with osteomalacia showed brisk deep tendon reflex more often (p = 0.017). Serum calcium (p = 0.003) and phosphate (p < 0.001) levels were lower in osteomalacia than in myopathy. CONCLUSIONS: It was not uncommon for patients with osteomalacia to visit the neurology department. The clinical presentation of these patients can be more complex owing the superimposed neurological disease and accompanying hypocalcemia. Osteomalacia should be considered when patients present with pain and weakness. PMID- 29623356 TI - Exercise effects on bone mineral density in older men: a systematic review with special emphasis on study interventions. AB - This systematic review detected only limited positive effects of exercise on bone mineral density in older men. Further, based on the present literature, we were unable to suggest dedicated exercise prescriptions for this male cohort that might differ from recommendations based on studies with postmenopausal women. The primary aim of this systematic review was to determine the effect of exercise on bone mineral density (BMD) in healthy older men. A systematic review of the literature according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement included only randomized or non-randomized controlled trials of exercise training >= 6 months with study groups of >= eight healthy men aged 50 years or older, not using bone-relevant pharmacological therapy, that determined BMD by dual-energy X-ray absorptiometry. We searched PubMed, Scopus, Web of Science, Cochrane, Science Direct, and Eric up to November 2016. Risk of bias was assessed using the PEDro scale. We identified eight trials with 789 participants (PEDro-score, mean value 6 of 10) which satisfied our eligibility criteria. Studies vary considerably with respect to type and composition of exercise. Study interventions of six trials were considered to be appropriate for successfully addressing BMD in this cohort. Between-group differences were not or not consistently reported by three studies. Three studies reported significant exercise effects on BMD for proximal femur; one of them determined significant differences between the exercise groups. None of the exercise trials determined significant BMD effects at the lumbar spine. Based on the present studies, there is only limited evidence for a favorable effect of exercise on BMD in men. More well-designed and sophisticated studies on BMD in healthy older men have to address this topic. Further, there is a need to define intervention quality standards and implement a universal scoring system that allows this pivotal determinant to be addressed much more intensively. PMID- 29623358 TI - A Non-invasive Method to Collect Fecal Samples from Wild Birds for Microbiome Studies. AB - Over the past few decades, studies have demonstrated that the gut microbiota strongly influences the physiology, behavior, and fitness of its host. Such studies have been conducted primarily in humans and model organisms under controlled laboratory conditions. More recently, researchers have realized the importance of placing host-associated microbiota studies into a more ecological context; however, few non-destructive methods have been established to collect fecal samples from wild birds. Here, we present an inexpensive and easy-to-use kit for the non-invasive collection of feces from small birds. The portability of the collection kit makes this method amenable to field studies, especially those in remote areas. The main components of the collection kit include a flat bottomed paper bag, a large modified weigh boat (tray), vinyl-coated hardware cloth fencing (grate), a clothespin, and a 10% bleach solution (to sterilize the tray and grate). In the paper bag, a sterile tray is placed under a small grate, which prevents the birds from contacting the feces and reduces the risk of contamination. After capture, the bird is placed in the bag for 3-5 min until it defecates. After the bird is removed from the bag, the tray is extracted and the fecal sample is moved to a collection tube and frozen or preserved. We believe that our method is an affordable and easy option for researchers studying the gut microbiota of wild birds. PMID- 29623357 TI - Membrane microdomains regulate NLRP10- and NLRP12-dependent signalling in A549 cells challenged with cigarette smoke extract. AB - Chronic obstructive pulmonary disease (COPD) is predicted to become the third leading cause of death and disability worldwide by 2030; with cigarette smoking (active or passive) being one of the chief cause of its occurrence. Cigarette smoke exposure has been found to result in excessive inflammation and tissue injury, which might lead to COPD, although the exact pathophysiology of the disease remains elusive. While previous studies have demonstrated the role of membrane-bound Toll-like receptors (TLRs) in cigarette smoke (CS)-induced inflammation, scant information is available about the role of cytosolic NOD-like receptors (NLRs) in regulating CS-mediated inflammatory responses. Thus, we investigated the role of NLRP10 and NLRP12 in regulating inflammatory responses in human alveolar type II epithelial cells (A549) and human monocytic cells (THP 1) in response to a challenge with cigarette smoke extract (CSE). We observed CSE mediated increase in caspase-1 activity; production of IL-1beta and IL-18; and expression of NLRP10 and NLRP12 in A549 and THP-1 cells. Interestingly, immunofluorescence imaging results demonstrated an increase in the membrane recruitment of NLRP10 and NLRP12 proteins in CSE-challenged A549 cells. We also observed an increase in the expression of lipid raft proteins (caveolin-1, caveolin-2, and flotillin-1) and an induction of lipid raft assembly following CSE-exposure in A549 cells. Lipid rafts are cholesterol-rich membrane microdomains well known to act as harbours for signalling molecules. Here we demonstrate the recruitment of NLRP10 and NLRP12 in lipid raft entities as well as the interaction of NLRP12 with the lipid raft protein caveolin-1 in CSE challenged A549 cells. Furthermore, enrichment of lipid raft entities with poly unsaturated fatty acids (PUFA) rescued A549 cells from CSE-mediated membrane recruitment of NLRP10 and NLRP12, and also from inflammatory responses and inflammasome activation. Enrichment of membrane microdomains with PUFA was able to reverse filipin (chemical agent used for disrupting lipid rafts)-mediated enhanced inflammation in CSE-challenged A549 cells. Overall, our findings unveil a novel mechanism by identifying an important role of membrane microdomains (lipid rafts) in regulating CSE-induced inflammation and NLRP10/NLRP12-dependent signalling in A549 cells. PMID- 29623359 TI - Endocrine-Disrupting Activities and Organic Contaminants Associated with Oil and Gas Operations in Wyoming Groundwater. AB - Unconventional oil and natural gas (UOG) operations couple horizontal drilling with hydraulic fracturing to access previously inaccessible fossil fuel deposits. Hydraulic fracturing, a common form of stimulation, involves the high-pressure injection of water, chemicals, and sand to fracture the target layer and release trapped natural gas and/or oil. Spills and/or discharges of wastewater have been shown to impact surface, ground, and drinking water. The goals of this study were to characterize the endocrine activities and measure select organic contaminants in groundwater from conventional oil and gas (COG) and UOG production regions of Wyoming. Groundwater samples were collected from each region, solid-phase extracted, and assessed for endocrine activities (estrogen, androgen, progesterone, glucocorticoid, and thyroid receptor agonism and antagonism), using reporter gene assays in human endometrial cells. Water samples from UOG and conventional oil areas exhibited greater ER antagonist activities than water samples from conventional gas areas. Samples from UOG areas tended to exhibit progesterone receptor antagonism more often, suggesting there may be a UOG related impact on these endocrine activities. We also report UOG-specific contaminants in Pavillion groundwater extracts, and these same chemicals at high concentrations in a local UOG wastewater sample. A unique suite of contaminants was observed in groundwater from a permitted drinking water well at a COG well pad and not at any UOG sites; high levels of endocrine activities (most notably, maximal estrogenic activity) were noted there, suggesting putative impacts on endocrine bioactivities by COG. As such, we report two levels of evidence for groundwater contamination by both UOG and COG operations in Wyoming. PMID- 29623360 TI - Updated analysis on polypharmacy and mortality from the ESTHER study. PMID- 29623362 TI - [In memory of Prof. Dr. Maria Zabel]. PMID- 29623363 TI - ? PMID- 29623361 TI - [Ketogenic diet: insufficient study results and lack of positive clinical benefits]. PMID- 29623364 TI - ? PMID- 29623365 TI - ? PMID- 29623366 TI - ? PMID- 29623367 TI - ? PMID- 29623368 TI - ? PMID- 29623369 TI - ? PMID- 29623371 TI - ? PMID- 29623370 TI - ? PMID- 29623372 TI - ? PMID- 29623373 TI - ? PMID- 29623374 TI - ? PMID- 29623375 TI - Ability of FDG PET and CT radiomics features to differentiate between primary and metastatic lung lesions. AB - PURPOSE: To evaluate the ability of CT and PET radiomics features to classify lung lesions as primary or metastatic, and secondly to differentiate histological subtypes of primary lung cancers. METHODS: A cohort of 534 patients with lung lesions were retrospectively studied. Radiomics texture features were extracted using the LIFEx package from semiautomatically segmented PET and CT images. Histology data were recorded in all patients. The patient cohort was divided into a training and a validation group and linear discriminant analysis (LDA) was performed to classify the lesions using both direct and backward stepwise methods. The robustness of the procedure was tested by repeating the entire process 100 times with different assignments to the training and validation groups. Scoring metrics included analysis of the receiver operating characteristic curves in terms of area under the curve (AUC), sensitivity, specificity and accuracy. RESULTS: Radiomics features extracted from CT and PET datasets were able to differentiate primary tumours from metastases in both the training and the validation group (AUCs 0.79 +/- 0.03 and 0.70 +/- 0.04, respectively, from the CT dataset; AUCs 0.92 +/- 0.01 and 0.91 +/- 0.03, respectively, from the PET dataset). The AUC cut-off thresholds identified by LDA using direct and backward elimination strategies were -0.79 +/- 0.06 and -0.81 +/ 0.08, respectively (CT dataset) and -0.69 +/- 0.05 and -0.68 +/- 0.04, respectively (PET dataset). For differentiation between primary subgroups based on CT features, the AUCs in the training and validation groups were 0.81 +/- 0.02 and 0.69 +/- 0.04 for adenocarcinoma (Adc) vs. squamous cell carcinoma (Sqc) or "Other", 0.85 +/- 0.02 and 0.70 +/- 0.05 for Sqc vs. Adc or Other, and 0.77 +/- 0.03 and 0.57 +/- 0.05 for Other vs. Adc or Sqc. The same analyses for the PET data revealed AUCs of 0.90 +/- 0.10 and 0.80 +/- 0.04, 0.80 +/- 0.02 and 0.61 +/- 0.06, and 0.97 +/- 0.01 and 0.88 +/- 0.04, respectively. CONCLUSION: PET radiomics features were able to differentiate between primary and metastatic lung lesions and showed the potential to identify primary lung cancer subtypes. PMID- 29623376 TI - Trifunctional PSMA-targeting constructs for prostate cancer with unprecedented localization to LNCaP tumors. AB - PURPOSE: Treatment of late-stage prostate cancer by targeted radiotherapeutics such as 131I-MIP-1095 and 177Lu-PSMA-617 has shown encouraging early results. Lu 177 is preferred to I-131 in clinical settings, but targeted radioligand therapy (RLT) with 177Lu-PSMA-617 has not reached its full potential due to insufficient dose delivery to the tumor. We recently developed a dual-targeting radioiodinated ligand, RPS-027, that targets PSMA and uses albumin binding to enable good tumor uptake and significantly reduced kidney uptake in a preclinical model. Further development of this ligand is limited by the inability to independently modify PSMA and albumin binding and the requirement of I-131 for therapeutic application. We therefore sought to devise a new class of trifunctional ligands for RLT with (1) a high-affinity PSMA-binding domain, (2) an albumin-binding group (ABG), and (3) a chelator for radiometals such as 68Ga3+, 177Lu3+ and 225Ac3+. METHODS: Ligands incorporating a triazolylphenylurea-containing PSMA targeting group, an Nepsilon-(2-(4-iodophenyl)acetyl)lysine ABG and the bifunctional chelator p-SCN-Bn-DOTA linked by a PEG-containing polymer containing 0,3,4,6,8 or 12 repeats were prepared. PSMA affinity was determined in LNCaP cells and uptake and tissue distribution was studied in mice bearing LNCaP tumor xenografts and compared to 177Lu-PSMA-617. Imaging studies were performed up to 24 h post-injection (p.i.) using 66Ga3+ and biodistribution studies at 4 h, 24 h and 96 h p.i. with 177Lu3+. RESULTS: PSMA affinity was high (IC50 = 1-10 nM) and inversely proportional to the linker length. Tumor uptake correlated with binding affinity and was significantly greater than for 177Lu-PSMA-617 over 96 h. The highest uptake was achieved with 177Lu-RPS-063 (30.0 +/- 6.9 %ID/g; 4 h p.i.). Kidney uptake was generally high, with the exception of the lowest affinity ligand 177Lu-RPS-067. Each of the compounds showed slower blood clearance than 177Lu-PSMA-617, with clearance proportional to linker length. CONCLUSIONS: The high tumor uptake achieved with these trifunctional ligands predicts larger (up to 4*) doses delivered to the tumor than can be achieved with 177Lu-PSMA-617. Although PSMA-mediated kidney uptake was also observed, the exceptional area under the curve (AUC) in the tumor warrants further investigation of these novel ligands as candidates for RLT. PMID- 29623377 TI - The increase in posterior tibial slope provides a positive biomechanical effect in posterior-stabilized total knee arthroplasty. AB - PURPOSE: This study aims to clarify the influence of the posterior tibial slope (PTS) on knee joint biomechanics after posterior-stabilized (PS) total knee arthroplasty (TKA) using a computer simulation. METHODS: A validated TKA computational model was used to evaluate and quantify the effects of an increased PTS. In order to conduct a squat simulation, models with a - 3 degrees to 15 degrees PTS using increments of 3 degrees were developed. Forces on the quadriceps and collateral ligament, a tibial posterior translation, contact point on a polyethylene (PE) insert, and contact stress on the patellofemoral (PF) joint and post in a PE insert were compared. RESULTS: The maximum force on the quadriceps and the PF contact stress decreased with increases in the PTS. The kinematics on the tibiofemoral (TF) joint translated in an increasingly posterior manner, and the medial and lateral contact points on a PE insert were located in posterior regions with increases in the PTS. Additionally, increases in the PTS decreased the force on the collateral ligament and increased the contact stress on the post in a PE insert. A higher force on the quadriceps is required when the PTS decreases with an equivalent flexion angle. CONCLUSIONS: A surgeon should be prudent in terms of determining the PTS because an excessive increase in the PTS may lead to the progressive loosening of the TF joint due to a reduction in collateral ligament tension and failure of the post in a PE insert. Thus, we support a more individualized approach of optimal PTS determination given the findings of the study. PMID- 29623378 TI - ACL graft compression: a method to allow reduced tunnel sizes in ACL reconstruction. AB - PURPOSE: A common problem during ACL reconstruction is asymmetry of proximal distal graft diameter leading to tunnel upsizing and graft-tunnel mismatch. Compression downsizing provides a graft of uniform size, allowing easy passage into a smaller tunnel. The purpose of this study was to quantify the graft compression technique and its effects on graft biomechanics and stability. It was hypothesised that compression downsizing would significantly reduce cross sectional area (CSA); that no significant changes in graft biomechanics would occur; graft fixation stability would be improved. METHOD: Sixty-eight non irradiated peroneus longus (PL) tendons were investigated. Twenty were halved and paired into ten four-strand grafts, 20 strands were compressed by 0.5-1 mm diameter and changes in CSA recorded using an alginate mould technique. The following properties were compared with 20 control strands: cyclic strain when loaded 70-220 N for 1000 cycles; stiffness; ultimate tensile load and stress; Young's modulus. 24 PL tendons were quadrupled into grafts, 12 were compressed and all 24 were submerged in Ringer's solution at 37 degrees C and the CSA recorded over 12 h. Twelve compressed and 12 control quadrupled grafts were mounted in porcine femurs, placed in Ringer's solution for 12 h at 37 degrees C and graft displacement at the bone tunnel aperture recorded under cyclic loading. RESULTS: Mean decreases in CSA of 31% under a stress of 471 kPa and 21% under a stress of 447 kPa were observed for doubled and quadrupled grafts, respectively. Compressed grafts re-expanded by 19% over 12 h compared to 2% for controls. No significant differences were observed between compressed and control grafts in the biomechanical properties and graft stability; mean cyclic displacements were 0.3 mm for both groups. CONCLUSIONS: No detrimental biomechanical effects of graft compression on allograft PL tendons were observed. Following compression, the grafts significantly increased in size during in vitro joint simulation. No significant difference was observed in graft stability between groups. Graft compression did not cause adverse mechanical effects in vitro. Smaller tunnels for compressed grafts reduce bone loss and ease anatomical placement. PMID- 29623379 TI - Do perturbation-evoked responses result in higher reaction time costs depending on the direction and magnitude of perturbation? AB - To date, little work has focused on whether cognitive-task interference during postural response execution is influenced by the direction and/or magnitude of the perturbation applied. Hypothetically, the increased difficulty associated with a backward loss of balance could necessitate increased allocation of cognitive resources to counteract destabilizing forces. The current study investigated these relationships using a paradigm in which individuals performed a cognitive task (auditory Stroop task during quiet stance; baseline condition). In certain trials, a translation of the support surface was concurrently evoked (magnitude: small or large; direction: forward or backward) which required a postural response to maintain balance. Ten healthy young adults completed four blocks of these experimental trials (26 randomized trials/block). Postural stability during balance recovery was evaluated using the margin of stability (MoS), while Stroop task performance was based on reaction time cost (RTC) and differences between experimental conditions. Results showed no effect of perturbation direction on RTC, but there was an observed MoS increase at peak extrapolated center of mass excursion following a small perturbation evoked concurrently with the cognitive task. No effect of cognitive-task performance was detected for MoS during stepping strategies (followed large perturbations). Instead, increased RTC were observed relative to the fixed base of support responses. In general, young adults adopted a "posture-first" strategy, regardless of perturbation direction, reinforcing the importance of cognition in the maintenance of upright balance. PMID- 29623380 TI - Rate of recalibration to changing affordances for squeezing through doorways reveals the role of feedback. AB - Recalibration of affordance perception in response to changing motor abilities can only occur if observers detect appropriate perceptual information. Recent work suggests that although many affordances can be recalibrated without practicing the specific action to gather outcome feedback-information about whether the attempted action succeeded or failed-calibration of other affordances might depend on outcome feedback (Franchak, Attent Percept Psychophys 79:1816 1829, 2017). However, past work could not rule out the possibility that practicing the action produced perceptual-motor feedback besides outcome feedback that facilitated recalibration. The results of two experiments support the hypothesis that recalibration in a doorway squeezing task depends on outcome feedback as opposed to perceptual-motor feedback. After putting on a backpack that changed participants' doorway squeezing ability, affordance judgments were uncalibrated and remained so even after making repeated judgments. However, after practicing the action, which produced outcome feedback, judgments rapidly calibrated. Moreover, the order of feedback information directly impacted participants' judgments: Participants did not recalibrate if they received only success experience or only failure experience. Recalibration only occurred after participants received both types of feedback experiences, suggesting that outcome feedback is necessary for recalibration in the doorway squeezing task. More generally, the results of the current study support a key tenet of ecological psychology-that affordance perception depends on action-specific information about body-environment relations. PMID- 29623381 TI - The impact of perilaryngeal vibration on the self-perception of loudness and the Lombard effect. AB - The role of somatosensory feedback in speech and the perception of loudness was assessed in adults without speech or hearing disorders. Participants completed two tasks: loudness magnitude estimation of a short vowel and oral reading of a standard passage. Both tasks were carried out in each of three conditions: no masking, auditory masking alone, and mixed auditory masking plus vibration of the perilaryngeal area. A Lombard effect was elicited in both masking conditions: speakers unconsciously increased vocal intensity. Perilaryngeal vibration further increased vocal intensity above what was observed for auditory masking alone. Both masking conditions affected fundamental frequency and the first formant frequency as well, but only vibration was associated with a significant change in the second formant frequency. An additional analysis of pure-tone thresholds found no difference in auditory thresholds between masking conditions. Taken together, these findings indicate that perilaryngeal vibration effectively masked somatosensory feedback, resulting in an enhanced Lombard effect (increased vocal intensity) that did not alter speakers' self-perception of loudness. This implies that the Lombard effect results from a general sensorimotor process, rather than from a specific audio-vocal mechanism, and that the conscious self-monitoring of speech intensity is not directly based on either auditory or somatosensory feedback. PMID- 29623383 TI - [Mechanical circulatory support in terminal heart failure]. AB - BACKGROUND: After exhaustion of all conservative measures in the treatment of acute and chronic heart insufficiency, there is the possibility to temporarily or permanently support or replace the pump performance of the heart by mechanical circulatory support (MCS) systems. OBJECTIVE: Presentation of the most important cardiac support systems for intensive care medicine, their indications and important risk factors. MATERIAL AND METHODS: Critical review of device manufacturer's specifications, current research and expert opinions. RESULTS: The spectrum of available MCS procedures include mechanical chest compression devices, catheter-based micropumps and complete artificial hearts. Device selection depends on the severity of heart failure (monoventricular or biventricular pump failure), the expected duration of treatment and the degree of lung function impairment. The decision between minimally invasive and open surgical procedures depends on the options established at the specific healthcare institution and whether the heart function is to be temporarily or permanently replaced. Compliance with the anticoagulation regimens defined by the manufacturer is especially important as they differ vastly between devices and are critical to avoid bleeding or thromboembolic complications. CONCLUSION: Due to the increasing number of patients on long-term mechanical circulatory support, the chances are that physicians in the initial emergency admission are unfamiliar with these devices but need to operate them in emergency cases. Therefore, knowledge of these procedures and their complications becomes increasingly important. PMID- 29623382 TI - [The heart catheter table is not the operating table : Intraindividual comparison of pulmonary artery pressures]. AB - BACKGROUND: Patients undergoing cardiac surgery need extensive and invasive monitoring, which needs to be individually adapted for each patient and requires a diligent risk-benefit analysis. The use of a pulmonary artery catheter (PAC) seems to be justifiable in certain cases; therefore, the preoperative diagnosis of pulmonary hypertension represents an indication for perioperative monitoring with PAC in the S3 guidelines of the German Society for Anesthesiology and Intensive Care Medicine (DGAI). In many cases, however, this preoperative diagnosis cannot be confirmed intraoperatively. OBJECTIVE: We wanted to find out whether this is just an impression or whether there actually are significant differences between preoperative, intraoperative and postoperative pulmonary artery pressures. MATERIAL AND METHODS: After obtaining ethical approval, we retrospectively compared the pulmonary pressures of cardiac surgery patients with an elevated pulmonary pressure during preoperative right heart catheterization with those obtained intraoperatively and postoperatively by means of a PAC. All patients with a preoperatively documented pulmonary artery pressure of 40 mmHg or above and an intraoperative use of a PAC during a 4-year period were included. Exclusion criteria were intracardiac shunts, cardiogenic shock, emergency procedures, pulmonary hypertension of non-cardiac origin and a time span of more than 1 year between right heart catheterization and surgery. We included 90 patients. RESULTS: In the whole group and in the subgroups (according to diagnosis, time elapsed between heart catheterization and operation and pulmonary pressure), there were significant differences between preoperative and intraoperative pulmonary and systemic pressures. Systemic and pulmonary artery pressures were significantly higher during preoperative catheterization than intraoperatively. The systemic systolic pressure/systolic pulmonary pressure ratio, however, remained constant. The intraoperative and postoperative systemic and pulmonary artery pressures showed no significant differences. As a normal ejection fraction does not exclude heart failure with preserved ejection fraction and as we did not have any information on this condition, we did not group the patients according to the ejection fraction. CONCLUSION: An elevated pulmonary pressure obtained preoperatively during right heart catheterization is not indicative of an elevated pulmonary pressure either intraoperatively or postoperatively. There are various explanations for the differences (e.g., different physiological and pathophysiological settings, such as sedation with potential hypercapnia versus anesthesia with vasodilation when measured; newly prescribed medication coming into effect between the right heart catheterization and surgery; intraoperative positioning). Even though the inherent risks of a PAC seem to be low, we recommend refraining from using a PAC in patients with a once documented elevated pulmonary pressure by default. As an alternative we suggest estimating the pulmonary pressure by transesophageal echocardiography (TEE) as an aid to decide whether the patient will benefit from the use of a PAC. Especially if it is not possible to identify tricuspid valve regurgitation for determining the peak gradient, it is helpful to check for additional signs of pulmonary hypertension. But we also have to bear in mind that in the postoperative period only a PAC can provide continuous measurement of pulmonary pressure. PMID- 29623384 TI - Precise, accurate and user-independent blood collection system for dried blood spot sample preparation. AB - An accurate and precise 3 MUL blood collection and dispensing system is presented for the preparation of dried blood spot (DBS) samples. Using end-to-end glass capillaries in conjugation with pre-punched DBS pads, a blood micro collection system was developed to eliminate the haematocrit dispersion, widely associated with DBS technology, while providing better levels of accuracy and precision during sample preparation. This methodology is compared to traditional micro volume blood collection systems, such as a pipette and a digitally controlled analytical syringe. Results showed that % of recovery for the capillary methodology was closer to 100% across the three haematocrit (HCT) levels tested and when prepared by two users (98 to 100% for capillaries, 78 to 104% for pipette and 93 to 97% for digital syringe) attesting a higher accuracy. Additionally, by taking advantage of the capillary action mechanism to collect and dispense autonomously the desired volume of blood onto the DBS pad, coefficients of variation between two individuals were significantly lower than with standard methodologies (capillaries-0.05 to 0.77%, pipette-12.71 to 18.53% and digital syringe-0.72 to 1.77%). This alternate aspiration and dispensing methodology could be used by different users without compromising accuracy or precision when handling low volumes of blood during the pre-analytical steps. Graphical abstract Comparison of novel capillary dispensing methodology for dried blood spot sample preparation with pipette and digital syringe methodologies through accuracy and precision measurements of caffeine. PMID- 29623385 TI - Identification and quantification of glue-like off-odors in elastic therapeutic tapes. AB - Elastic therapeutic tapes are an important tool in the field of physical therapy and medicine. These tapes contain types of adhesive. However, sensory evaluations revealed the release of pronounced and irritating odors of the tapes. Negative odors were, amongst others, reported in elastic therapeutic tapes containing acrylic adhesives. In this study, the odor of four different tape samples was evaluated applying a descriptive analysis approach carried out by a trained sensory panel. Afterwards, the volatile compounds were recovered from the samples by solvent extraction and isolated by solvent-assisted flavor evaporation (SAFE). The obtained distillates were subsequently analyzed by gas chromatography olfactometry (GC-O) and two-dimensional GC-O coupled with mass spectrometry (2D GC-MS/O). To determine the most potent odorants in the distillates, odor extract dilution analyses (OEDA) were carried out. Thirty-one odorants were successfully identified using this approach, which were all described for the first time as odorants in tapes. Amongst the set of volatiles, unsaturated and saturated aldehydes were present, eliciting fatty, soapy, and citrus-like odor impressions, as well as a range of glue-like, moldy, and fruity smelling odor-active volatiles, such as 2-ethyl-1-hexanol, butyl benzoate, and 3-phenyltoluene. Based on their relative intensities, the concentrations of the glue-like smelling substances were determined: 2-ethyl-1-hexanol, present in all samples, was determined with concentrations ranging from 10 to 200 mg/kg in the investigated tapes. PMID- 29623386 TI - In vitro antibacterial activity of plant essential oils against Staphylococcus hyicus and Staphylococcus aureus, the causative agents of exudative epidermitis in pigs. AB - Greasy pig disease or exudative epidermitis, a generalized or localized skin disease affecting piglets, is mainly caused by Staphylococcus hyicus, although other staphylococcal species such as Staphylococcus aureus may also induce disease. Piglets with skin lesions can be treated systemically with antibiotics. However, antimicrobial resistance to beta-lactam antibiotics are now frequently observed in S. hyicus and S. aureus isolates. In this study, the antibacterial activity of plant essential oils as well as their ability to potentiate the effect of several antimicrobial compounds against S. hyicus and S. aureus were investigated with a view to a potential use as skin disinfectants. Among ten essential oils tested, those from cinnamon, thyme, and winter savory were the most active with minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) values ranging from 0.078 to 0.313% (v/v). Using a fluorescent probe with DNA affinity, it was found that thyme and winter savory oils act, at least in part, by disturbing the bacterial membrane integrity. At concentrations below the MIC, thyme and winter savory oils reduced biofilm formation by S. hyicus. Moreover, a treatment of pre-formed biofilms of S. hyicus with cinnamon or thyme oils significantly decreases its viability. Synergistic interactions between essential oils, more particularly from thyme and winter savory, and penicillin G, chlorhexidine or nisin, were observed. This study supports the therapeutic potential of essential oils as topical therapeutic agents against exudative epidermitis. PMID- 29623387 TI - Evolutionary engineering of industrial microorganisms-strategies and applications. AB - Microbial cells have been widely used in the industry to obtain various biochemical products, and evolutionary engineering is a common method in biological research to improve their traits, such as high environmental tolerance and improvement of product yield. To obtain better integrate functions of microbial cells, evolutionary engineering combined with other biotechnologies have attracted more attention in recent years. Classical laboratory evolution has been proven effective to letting more beneficial mutations occur in different genes but also has some inherent limitations such as a long evolutionary period and uncontrolled mutation frequencies. However, recent studies showed that some new strategies may gradually overcome these limitations. In this review, we summarize the evolutionary strategies commonly used in industrial microorganisms and discuss the combination of evolutionary engineering with other biotechnologies such as systems biology and inverse metabolic engineering. Finally, we prospect the importance and application prospect of evolutionary engineering as a powerful tool especially in optimization of industrial microbial cell factories. PMID- 29623388 TI - Construction of Halomonas bluephagenesis capable of high cell density growth for efficient PHA production. AB - High-cell-density cultivation is an effective way to improve the productivity of microbial fermentations and in turn reduce the cost of the final products, especially in the case of intracellular products. Halomonas bluephagenesis TD01 is a halophilic platform bacterium for the next generation of industrial biotechnology with a native PHA synthetic pathway, able to grow under non-sterile continuous fermentation conditions. A selection strategy for mutant strains that can grow to a high cell density was developed. Based on an error-prone DNA polymerase III epsilon subunit, a genome-wide random mutagenesis system was established and used in conjunction with an artificial high cell density culture environment during the selection process. A high-cell-density H. bluephagenesis TDHCD-R3 obtained after 3 rounds of selection showed an obvious enhancement of resistance to toxic metabolites including acetate, formate, lactate and ethanol compared to wild-type. H. bluephagenesis TDHCD-R3-8-3 constructed from H. bluephagenesis TDHCD-R3 by overexpressing an optimized phaCAB operon was able to grow to 15 g/L cell dry weight (CDW) containing 94% PHA in shake flask studies. H. bluephagenesis TDHCD-R3-8-3 was grown to more than 90 g/L CDW containing 79% PHA compared with only 81 g/L with 70% PHA by the wild type when incubated in a 7 L fermentor under the same conditions. PMID- 29623389 TI - Correction to: Lactococcus lactis as a safe and inexpensive source of bioactive silver composites. AB - The authors would like to inform readers of a mistake in the acknowledgement section of the original publication of this article. PMID- 29623390 TI - The role of genetics and epigenetics in rheumatic diseases: are they really a target to be aimed at? AB - To date, numerous genetic and epigenetic studies have been performed and provided a crucial step forward in our understanding of the pathogenesis of rheumatic diseases. However, most of the recent advances in the treatment of rheumatic diseases including biological therapies are not based on or even discrepant from these genetic and epigenetic findings. For example, tumor necrosis factor inhibitors are quite successful in the treatment of rheumatoid arthritis (RA), Behcet's disease (BD), ankylosing spondylitis (AS) and psoriatic arthritis (PsA) but not in that of systemic lupus erythematosus (SLE), systemic sclerosis (SSc), Sjogren's syndrome (SS) and antineutrophil cytoplasmic antibody-associated vasculitis (AAV), conversely, RA shares genetic backgrounds more with SLE, SSc, SS and AAV than BD, AS and PsA. In this review, we briefly highlight the findings from recent genetic and epigenetic studies and discuss what needs to be studied to provide a novel, more efficacious management of rheumatic diseases. PMID- 29623391 TI - Association between memory B-cells and clinical and immunological features of primary Sjogren's syndrome and Sicca patients. AB - B-cells play a pivotal role in primary Sjogren's syndrome (pSS) pathogenesis. We aim to (1) evaluate the distribution of B-lymphocyte subpopulations in pSS and Sicca patients, (2) establish cut-off points that discriminate pSS from controls, (3) evaluate the association between memory B-cells and phenotypic features in pSS. We included 57 pSS patients, 68 Sicca and 24 healthy controls. Circulating B cells were characterized by flow cytometry as naive and memory subsets and classified from Bm1 to Bm5. Compared to controls, pSS patients had lower percentages (29.5 vs 44.4%) and absolute numbers (47 vs 106 cells/ul) of memory B cells. Through ROC curves, a cut-off of <= 58 total memory B-cells/ul yielded a specificity of 0.88 and a sensitivity of 0.60 for pSS, and was met by 59.6% of pSS patients, 38.8% of Sicca and 12.5% of controls. A cut-off of < 23.5 Switched memory B-cells/ul yielded a specificity of 0.88 and a sensitivity of 0.54 and was met by 54.4% of pSS patients, 37.3% of Sicca and 12.5% of controls. In pSS, lower total memory B-cells count was associated with longer disease duration (14.3 vs 8.1 years, p = 0.006) and more active disease profile, as evaluated by the European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) (3.1 vs 1.4, p = 0.043). Decreased numbers of memory B-cells clearly discriminated pSS from controls and can also have prognostic value. It remains to be clarified whether Sicca patients with decreased memory B-cells represent pSS and if B-cell profiling could help in the diagnosis of pSS. PMID- 29623392 TI - Clinical utility of dynamic-enhanced MRI in salivary gland tumors: retrospective study and literature review. AB - PURPOSE: To improve the diagnoses of the salivary gland tumors, a dynamic enhanced MRI (dMRI) was investigated. METHODS: We conducted a retrospective chart review of 93 cases of salivary gland tumors. The histological diagnoses were obtained from all patients using a surgical specimen and/or an open biopsy specimen. The dMRI as well as fine-needle aspiration cytology (FNAC) and intraoperative frozen section (IFS) were analyzed. This study focused on the time intensity curve (TIC) after injection, peak time (Tpeak), washout ratio (WR) as well as the gradient of enhancement and washout profile. RESULTS: The histological diagnoses included pleomorphic adenoma (PMA) in 53 cases, the Warthin tumors (WT) in 14 cases and malignant tumors (MT) in 26 cases. Incorrect diagnosis rate of FNAC and IFS were 5.2 and 8.3%, respectively. The TIC revealed differences among the three types of tumors. Tpeak as well as WR also revealed significant differences (p < 0.001). Tpeak were lower in order of WT, MT, PMA, respectively. WR of TICs at 30, 45 and 105 s after Tpeak were higher in order of WT, MT, PMA, respectively (p < 0.001). The gradient of increment and washout in the TIC curve was also an important parameter to distinguish the three types of tumors. In MT, the rapid enhancement pattern was found in high or intermediate histological grade tumors, whereas the slow enhancement pattern was exhibited in low grade tumors. CONCLUSIONS: Our findings indicate that using Tpeak and WR, it is possible to distinguish between WT, PMA and MT. Additionally, a rapid enhancement pattern may be a potential marker for these tumors. PMID- 29623394 TI - Evaluation of Revised International Staging System (R-ISS) for transplant eligible multiple myeloma patients. AB - The International Myeloma Working Group has proposed the Revised International Staging System (R-ISS) for risk stratification of multiple myeloma (MM) patients. There are a limited number of studies that have validated this risk model in the autologous stem cell transplant (ASCT) setting. In this retrospective study, we evaluated the applicability and value for predicting survival of the R-ISS model in 134 MM patients treated with new agents and ASCT at the Mayo Clinic in Arizona and the University Hospital of Salamanca in Spain. The patients were reclassified at diagnosis according to the R-ISS: 44 patients (33%) had stage I, 75 (56%) had stage II, and 15 (11%) had stage III. After a median follow-up of 60 months, R ISS assessed at diagnosis was an independent predictor for overall survival (OS) after ASCT, with median OS not reached, 111 and 37 months for R-ISS I, II and III, respectively (P < 0.001). We also found that patients belonging to R-ISS II and having high-risk chromosomal abnormalities (CA) had a significant shorter median OS than those with R-ISS II without CA: 70 vs. 111 months, respectively. Therefore, this study lends further support for the R-ISS as a reliable prognostic tool for estimating survival in transplant myeloma patients and suggests the importance of high-risk CA in the R-ISS II group. PMID- 29623393 TI - Differences in laser lead extraction of infected vs. non-infected leads. AB - We investigated the effect of systemic infection or lead endocarditis on the complexity and the success of laser lead extraction (LLE) procedures. Medical records of all patients undergoing LLE between January 2012 and March 2017 were screened with regard to information on systemic infection or lead endocarditis. We treated 184 patients using high-frequency 80 Hz laser sheaths in patients with lead implant duration of >= 12 months. Indications for lead extraction were systemic infection and lead endocarditis in 52 cases (28.3%), local infection in 74 cases (40.2%), lead dysfunction in 37 cases (20.1%) and other indications in 21 cases (11.4%). 386 leads were scheduled for LLE: 235 (60.9%) pacing, 105 (27.2%) ICD and 46 (11.9%) CS leads. The mean time from initial lead implantation (systemic infection 96.8 +/- 74.7 months vs. 102.1 +/- 82.6 non-infected: months; p = 0.4155) and ratio of ICD leads (26.8 vs. 27.4%; p = 0.3411) did not differ significantly between the two groups. Complete procedural success was significantly higher in the systemic infection group (100 vs. 94.7%; p = 0.0077). The mean laser treatment (60.2 +/- 48.7 vs. 72.4 +/- 61.5 s; p = 0.2038) was numerically lower in the infection group, while fluoroscopy time (9.3 +/- 7.6 vs. 12.8 +/- 10.3 min; p = 0.0275) was significantly lower in this group. Minor and major complications were low in both groups and did not reveal any statistically significant difference (infected group: one minor complication; pocket hematoma, non-infected: three major complications; emergent sternotomy due to pericardial tamponade). No extraction related mortality was observed. The presence of systemic infection or lead endocarditis in LLE procedures allows for higher complete procedural success. When compared with LLE of non-infected leads, the infected leads require less laser and fluoroscopy times. Due to the scarcity of minor and major complications in general, no statistical significance was found in that regard. PMID- 29623397 TI - [Health service research in ophthalmology]. PMID- 29623396 TI - Resistance to eye opening in patients with disorders of consciousness. AB - INTRODUCTION: Resistance to eye opening (REO) is a commonly encountered phenomenon in clinical practice. We aim to investigate whether REO is a sign of consciousness or a reflex in severely brain-injured patients. METHODS: We recorded REO in chronic patients with disorders of consciousness during a multimodal diagnostic assessment. REO evaluations were performed daily in each patient and clinical diagnosis of unresponsive wakefulness syndrome (UWS), minimally conscious state with (MCS+) or without (MCS-) preserved language processing was made using the Coma Recovery Scale-Revised (CRS-R). RESULTS: Out of 150 consecutive patients, 79 patients fit inclusion criteria. REO was seen in 19 patients (24.1%). At the group level, there was a significant relationship between the presence of REO and the level of consciousness. We also observed a difference in the repeatability of REO between patients in UWS, MCS- and MCS+. Out of 23 patients in UWS, six showed REO, in whom five showed atypical brain patterns activation. CONCLUSION: Our findings suggest a voluntary basis for REO and stress the need for multiple serial assessments of REO in these patients, especially since most patients show fluctuating levels of consciousness. PMID- 29623395 TI - Variable X-chromosome inactivation and enlargement of pericentral glutamine synthetase zones in the liver of heterozygous females with OTC deficiency. AB - Ornithine transcarbamylase (OTC) deficiency is an X-linked disorder that causes recurrent and life-threatening episodes of hyperammonemia. The clinical picture in heterozygous females is highly diverse and derives from the genotype and the degree of inactivation of the mutated X chromosome in hepatocytes. Here, we describe molecular genetic, biochemical, and histopathological findings in the livers explanted from two female patients with late-onset OTC deficiency. Analysis of X-inactivation ratios by DNA methylation-based assays showed remarkable intra-organ variation ranging from 46:54 to 82:18 (average 70:30, n = 37), in favor of the active X chromosome carrying the mutation c.583G>C (p.G195R), in the first patient and from 75:25 to 90:10 (average 82:18, n = 20) in favor of the active X chromosome carrying the splicing mutation c.663+1G>A in the second patient. The X-inactivation ratios in liver samples correlated highly with the proportions of OTC-positive hepatocytes calculated from high-resolution image analyses of the immunohistochemically detected OTC in frozen sections that was performed on total area > 5 cm2. X-inactivation ratios in blood in both female patients corresponded to the lower limit of the liver values. Our data indicate that the proportion of about 20-30% of hepatocytes expressing the functional OTC protein is not sufficient to maintain metabolic stability. X inactivation ratios assessed in liver biopsies taken from heterozygous females with X-linked disorders should not be considered representative of the whole liver. PMID- 29623398 TI - Complete Genome Sequence of Alcaligenes Faecalis Strain JQ135, a Bacterium Capable of Efficiently Degrading Nicotinic Acid. AB - Nicotinic acid (NA), known as vitamin B3, is ubiquitous in nature and plays an important role in living organisms. The microbial catabolism of NA is highly diverse. However, the NA degradation by Alcaligenes faecalis strains has been poorly investigated. In this study, we report the complete genome sequence of A. faecalis JQ135 (4.08 Mbp) and several essential genes for NA degradation. This genome sequence will facilitate to elucidate the molecular metabolism of NA and advance the potential biotechnological applications of A. faecalis strains. PMID- 29623399 TI - Morphological and morphometric evaluation of intertendinous connections among extensor tendons in fetal hands. AB - PURPOSE: The purpose of this study was to determine morphometry and morphology of intertendinous connection on fetal cadavers and perform an evidence on tendon relationships. METHODS: Thirty dorsal fetal cadaveric hands were dissected. Morphometric measurements (length, width, beginning-ending angles and areas) of intertendinous connections were performed. The intertendinous connections were typed morphologically according to their shape and direction. Measurement values were obtained for the second, third and fourth intermetacarpal spaces. The measurement results were compared between right-left hand and male-female fetuses. RESULTS: No intertendinous connections were present in the first intermetacarpal space in any dissected hands. Statistical differences were observed between the sides in terms of width, and beginning and end angles. CONCLUSION: Anatomical results of this study would be helpful in identifying intertendinous connection types, dimensions and their relationships to the extensor tendons, and would assist surgeons when choosing intertendinous connection as an additional structural resource for tendon repair especially pediatric cases. PMID- 29623401 TI - The art of co-production of knowledge in environmental sciences and management: lessons from international practice. AB - This review paper addresses the challenging question of "how to" design and implement co-production of knowledge in climate science and other environmental and agricultural sciences. Based on a grounded theory review of nine (9) published case studies of transdisciplinary and collaborative research projects, the paper offers a set of common themes regarding specific components and processes for the design, implementation, and achievement of co-production of knowledge work, which represent the "Modus Operandi" of knowledge co-production. The analysis focuses on practical methodological guidance based on lessons from how different research teams have approached the challenges of complex collaborative research. We begin by identifying broad factors or actions that inhibit or facilitate the process, then highlight specific practices associated with co-production of knowledge and necessary competencies for undertaking co production. We provide insights on issues such as the integration of social and professional cultures, gender and social equity, and power dynamics, and illustrate the different ways in which researchers have addressed these issues. By exploring the specific practices involved in knowledge co-production, this paper provides guidance to researchers on how to navigate different possibilities of the process of conducting transdisciplinary and co-production of knowledge research projects that best fit their research context, stakeholder needs, and research team capacities. PMID- 29623400 TI - Biomechanical properties of the patellar tendon in children with heritable connective tissue disorders. AB - PURPOSE: Hereditary connective tissue disorders (HCTDs), such as classic Ehlers Danlos syndrome (cEDS) and Marfan syndrome (MS) share overlapping features like hypermobility and tissue fragility. In clinical practice it remains a challenge to distinguish children and adolescents with HCTD from healthy children. The purpose of this study was to investigate the biomechanical properties of the patellar tendon and joint laxity (Beighton score) in children with HCTDs (n = 7) compared to healthy controls (n = 14). METHODS: The mechanical properties of the patellar tendon were assessed using simultaneous force and ultrasonographic measurements during isometric ramp contractions. Ultrasonography was also used to measure tendon dimensions. The HCTD children were matched with 2 healthy controls with regard to age, body mass index (BMI), sex and physical activity level. RESULTS: The HCTD children had a greater degree of joint laxity (P < 0.01). Although, the patellar tendon dimensions did not differ significantly between the two groups, the HCTD children showed a tendency toward a larger patellar tendon cross-sectional area (CSA) (35%, P = 0.19). Moreover, stiffness did not differ between the two groups, but secant modulus was 27% lower in children with a HCTD (P = 0.05) at common force and 34% lower at maximum force (P = 0.02). CONCLUSIONS: The present study demonstrates for the first time that children with HCTDs have lower material properties (modulus) of their patellar tendon, which may be indicative of general impairment of connective tissue mechanics related to their increased joint laxity. PMID- 29623402 TI - Age estimation based on aspartic acid racemization in caries-affected teeth: need for further explorations. PMID- 29623403 TI - ["Digital Pathology in Diagnostics" guideline : Reporting on digital images]. AB - BACKGROUND: The digitization of medicine is gaining momentum in pathology. Long known technologies have reached such a degree of maturity that their use in primary diagnostics in routine pathology will be possible. In spite of the complexity of technological solutions and the far-reaching consequences in terms of diagnostic reliability, as well as due to the high investments, the decision for a specific product may become highly sophisticated for a pathologist. AIM: An implementation guide for Digital Diagnostics in Pathology is presented to describe technical and legal conditions for making this new technology feasible for the single pathologist. RESULTS AND DISCUSSION: For more than two years, the Digital Pathology Commission of the Federal Association of German Pathologists developed and discussed this implementation guide for digital diagnostics, especially for the use of virtual microscopy in the daily pathology routine in Germany. The key is the principal comparability of diagnostic reliability between conventional stained microscopic slides and their digital images, which have to be shown by the potential user. In eight chapters, the validation procedure as well as technical minimum requirements in slide scanners, the visualization pipeline, archiving, and integration in the pathology workflow are described. PMID- 29623404 TI - [Biobanking requirements from the perspective of the clinician : Experiences in hematology and oncology]. AB - The requirements for optimal biobanking from the point of view of the clinical partner can be highly variable. Depending on the material, processing, storage conditions, clinical data, and involvement of external partners, there will be special requirements for the participating clinician and specialist areas. What they all have in common is that the goal of any biobanking must be to improve clinical, translational, and basic research. While in the past biomaterials often had to be individually stored for each research project, modern biobanking offers decisive advantages: a comprehensive ethics vote fulfilling state-of-the-art data safety requirements, standardized processing and storage protocols, specialized biobank software for pseudonymization and localization, protection against power failures and defects of the equipment, centralized and sustainable storage, easy localization and return of samples, and their destruction or anonymization after completion of an individual project. In addition to this important pure storage function, central biobanking can provide a link to clinical data as well as the anonymous use of samples for project-independent research. Both biobank functions serve different purposes, are associated with specific requirements, and should be pursued in parallel. If successful, central biomaterial management can achieve a sustainable improvement of academic and non-academic biomedical research and the optimal use of resources. The close collaboration between clinicians and non clinicians is a crucial prerequisite for this. PMID- 29623405 TI - Surgical outcomes of pancreaticoduodenal injuries in children. AB - PURPOSE: To examine surgical outcomes of children with pancreaticoduodenal injuries at a Quaternary Level I pediatric trauma center. METHODS: We queried a prospectively maintained trauma database of a level one pediatric trauma center for all cases of pancreatic and/or duodenal injury from 2002 to 2017. Analysis was conducted using JMP 13.1.0. RESULTS: 170 children presented with pancreatic and/or duodenal injury. 13 (7.7%) suffered a combined injury and this group forms the basis for this report with mean ISS of 22.8 (+/- 15.1), RTS2 of 6.4(+/- 2.1), and median age of 6.6 (1.3-13.5) years. Child abuse (31%) and bicycle injuries (23%) were the most common mechanisms. 8/13 (61.5%) required operative intervention. Higher AAST pancreatic and duodenal injury grade (2.9 vs. 1.2, p = 0.05 and 3.6 vs. 1.4, p = < 0.01), lower RTS2 (7.84 vs. 5.49, p < 0.01), and lower GCS (9.6 vs. 15, p = 0.03) predicted operative intervention. 6/8 (75%) undergoing surgery survived to discharge with only (2/6) survivors suffering postoperative complications. Both mortalities were secondary to severe traumatic brain injury. CONCLUSION: Surgical management of complex pancreaticoduodenal injury is an uncommon traumatic event that is associated with high injury severity, but survival occurs in most scenarios. PMID- 29623406 TI - Monosegmental anterior column reconstruction using an expandable vertebral body replacement device in combined posterior-anterior stabilization of thoracolumbar burst fractures. AB - INTRODUCTION: In combined posterior-anterior stabilization of thoracolumbar burst fractures, the expandable vertebral body replacement device (VBRD) is typically placed bisegmentally for anterior column reconstruction (ACR). The aim of this study, however, was to assess feasibility, outcome and potential pitfalls of monosegmental ACR using a VBRD. In addition, clinical and radiological outcome of monosegmental ACR was related to that of bisegmental ACR using the same thoracoscopic technique. METHODS: Thirty-seven consecutive neurologically intact patients with burst fractures of the thoracolumbar junction (T11-L2) treated by combined posterior-anterior stabilization were included. Monosegmental ACR was performed in 18 and bisegmental ACR in 19 patients. Fracture type and extent of vertebral body comminution were determined on preoperative CT scans. Monosegmental and bisegmental kyphosis angles were analyzed preoperatively, postoperatively and at final radiological follow-up. Clinical outcome was assessed after a minimum of 2 years (74 +/- 45 months; range 24-154; follow-up rate 89.2%) using VAS Spine Score, RMDQ, ODI and WHOQOL-BREF. RESULTS: Monosegmental ACR resulted in a mean monosegmental and bisegmental surgical correction of - 15.6 +/- 7.7 degrees and - 14.7 +/- 8.1 degrees , respectively. Postoperative monosegmental and bisegmental loss of correction averaged 2.7 +/- 2.7 degrees and 5.2 +/- 3.7 degrees , respectively. Two surgical pitfalls of monosegmental ACR were identified: VBRD positioning (1) onto the weak cancellous bone (too far cranially to the inferior endplate of the fractured vertebra) and (2) onto a significantly compromised inferior endplate with at least two (even subtle) fracture lines. Ignoring these pitfalls resulted in VBRD subsidence in five cases. When relating the clinical and radiological outcome of monosegmental ACR to that of bisegmental ACR, no significant differences were found, except for frequency of VBRD subsidence (5 vs. 0, P = 0.02) and bisegmental loss of correction (5.2 +/- 3.7 degrees vs. 2.6 +/- 2.5 degrees , P = 0.022). After exclusion of cases with VBRD subsidence, the latter did not reach significance anymore (4.9 +/- 4.0 degrees vs. 2.6 +/- 2.5 degrees , P = 0.084). CONCLUSIONS: This study indicates that monosegmental ACR using a VBRD is feasible in thoracolumbar burst fractures if the inferior endplate is intact (incomplete burst fractures) or features only a single simple split fracture line (burst split fractures). If the two identified pitfalls are avoided, monosegmental ACR may be a viable alternative to bisegmental ACR in selected thoracolumbar burst fractures to spare a motion segment and to reduce the distance for bony fusion. PMID- 29623407 TI - Adding sleep restriction to the equation: impact on wildland firefighters' work performance and physiology in hot conditions. AB - PURPOSE: To examine the effects of sleep restriction on firefighters' physical task performance, physical activity, and physiological and perceived exertion during simulated hot wildfire conditions. METHODS: 31 firefighters were randomly allocated to either the hot (n = 18, HOT; 33 degrees C, 8-h sleep opportunity) or hot and sleep restricted (n = 13, HOT + SR; 33 degrees C, 4-h sleep opportunity) condition. Intermittent, self-paced work circuits of six firefighting tasks were performed for 3 days. Firefighters self-reported ratings of perceived exertion. Heart rate, core temperature, and physical activity were measured continuously. Fluids were consumed ad libitum, and all food and fluids consumed were recorded. Urine volume and urine specific gravity (USG) were analysed and sleep was assessed using polysomnography (PSG). RESULTS: There were no differences between the HOT and HOT + SR groups in firefighters' physical task performance, heart rate, core temperature, USG, or fluid intake. Ratings of perceived exertion were higher (p < 0.05) in the HOT + SR group for two of the six firefighting tasks. The HOT group spent approximately 7 min more undertaking moderate physical activity throughout the 2-h work circuits compared to the HOT + SR group. CONCLUSION: Two nights of sleep restriction did not influence firefighters' physical task performance or physiological responses during 3 days of simulated wildfire suppression. Further research is needed to explore firefighters' pacing strategies during real wildfire suppression. PMID- 29623408 TI - [Thromboembolism prophylaxis in old age]. AB - Anticoagulation in geriatric patients is challenging regarding the risk of bleeding complications and thromboembolic problems. Age, comorbidities, such as renal insufficiency and polymedication have a vital impact on bleeding and thromboembolic risks; however, age is not an exclusion criterion for withholding anticoagulation. Age is the main risk factor for deep vein thrombosis and atrial fibrillation becomes more relevant with aging. Older patients with atrial fibrillation have a particularly high risk of having a stroke. Therefore, very old patients benefit particularly from oral anticoagulation because the risk of bleeding is outweighed by the clinical benefit of stroke prevention. Risk of bleeding and thromboembolic problems can be easily assessed by established diagnostic tools. This article reviews the epidemiology of thromboembolic problems in the aged as well as current diagnostic and therapeutic steps for primary and secondary prevention. PMID- 29623409 TI - When less is more: costs and benefits of varied vs. fixed content and structure in short-term task switching training. AB - Training variability has been brought forward as one possible moderator for wider scale transfer effects in cognitive training. However, little is known about which aspects of task variability are important for optimizing training outcomes. This study systematically examined the impact of variability in the different task components on outcome measures, here manipulating content (whether the task stimuli remained fixed or changed between blocks) and the deeper structural task configuration (task sequence: whether the task sequence was fixed or random). Short-term task switching training was implemented with one of four training variability conditions: fixed content?fixed structure; fixed content? random structure; varied content?fixed structure and varied content?varied structure. The experiment consisted of a baseline block, seven training blocks (learning phase), followed by two transfer blocks, one with fixed and one with random task structure, respectively. In the learning phase, more rapid training gains were observed in the fixed content as compared to varied content. Interestingly, training with fixed content resulted in a trend for costs when transferred to a novel task switching context. In contrast, moderate transfer gains were noted in the varied content condition, manifested specifically on switch trials. These results suggest that task (content) variability is one of the means to improve positive transfer and avoid negative transfer. Additionally, and in agreement with the wide literature on training, this finding suggests that conditions that prevent training gains are in fact beneficial for learning generalization. PMID- 29623411 TI - Timing of rehabilitation in children with obstetric upper trunk brachial plexus palsy. AB - OBJECTIVES: The initiation timing of rehabilitation in children with obstetric brachial plexus palsy is controversial. The aim of the present study is to evaluate the effectiveness of rehabilitation timing to the functional outcomes of patients with obstetric upper trunk brachial plexus palsy. MATERIAL AND METHODS: Twenty-nine patients, who did not previously received any rehabilitation programme but attended our outpatient clinic, were included for the study. The electrophysiological findings, obstetric characteristics, and demographic features of the patients were recorded. The range of motion (ROM) of shoulders, elbows, and wrists and the strength of the muscles associated with these joints were evaluated. Modified Mallet Scale (MMS) was used for functional evaluation. A 4-week rehabilitation programme was performed twice at 2-month intervals. Patients were divided into three groups according to their ages as follows: 1-3 years old (group 1), 3-5 years old (group 2), and 5-7 years old (group 3). The ROMs, muscle strengths, and MMS scores of the patients were all evaluated. RESULTS: Two out of 29 patients were female (6.9%) and 27 were male (93.1%). All 29 patients had right upper extremity palsy (100%). The MMS scores, ROMs, and muscle strength of the upper extremities had improved in all the groups following the standardized rehabilitation programme. CONCLUSIONS: A rehabilitation programme is the best choice of treatment before surgical procedures in patients with mild to moderate obstetric upper trunk brachial plexus palsy regardless of age and the initiation time. PMID- 29623412 TI - Staying hot to fight the heat-high body temperatures accompany a diurnal endothermic lifestyle in the tropics. AB - Much of our knowledge of the thermoregulation of endotherms has been obtained from species inhabiting cold and temperate climates, our knowledge of the thermoregulatory physiology of tropical endotherms is scarce. We studied the thermoregulatory physiology of a small, tropical mammal, the large treeshrew (Tupaia tana, Order Scandentia) by recording the body temperatures of free ranging individuals, and by measuring the resting metabolic rates of wild individuals held temporarily in captivity. The amplitude of daily body temperature (~ 4 degrees C) was higher in treeshrews than in many homeothermic eutherian mammals; a consequence of high active-phase body temperatures (~ 40 degrees C), and relatively low rest-phase body temperatures (~ 36 degrees C). We hypothesized that high body temperatures enable T. tana to maintain a suitable gradient between ambient and body temperature to allow for passive heat dissipation, important in high-humidity environments where opportunities for evaporative cooling are rare. Whether this thermoregulatory phenotype is unique to Scandentians, or whether other warm-climate diurnal small mammals share similar thermoregulatory characteristics, is currently unknown. PMID- 29623410 TI - The clinical outcome and microbiological profile of bone-anchored hearing systems (BAHS) with different abutment topographies: a prospective pilot study. AB - PURPOSE: In this prospective clinical pilot study, abutments with different topologies (machined versus polished) were compared with respect to the clinical outcome and the microbiological profile. Furthermore, three different sampling methods (retrieval of abutment, collection of peri-abutment exudate using paper points, and a small peri-abutment soft-tissue biopsy) were evaluated for the identification and quantification of colonising bacteria. METHODS: Twelve patients, seven with machined abutment and five with polished abutment, were included in the analysis. Three different sampling procedures were employed for the identification and quantification of colonising bacteria from baseline up to 12 months, using quantitative culturing. Clinical outcome measures (Holgers score, hygiene, pain, numbness and implant stability) were investigated. RESULTS: The clinical parameters, and total viable bacteria per abutment or in tissue biopsies did not differ significantly between the polished and machined abutments. The total CFU/mm2 abutment and CFU/peri-abutment fluid space of anaerobes, aerobes and staphylococci were significantly higher for the polished abutment. Anaerobic bacteria were detected in the tissue biopsies before BAHS implantation. Anaerobes and Staphylococcus spp. were detected in all three compartments after BAHS installation. For most patients (10/12), the same staphylococcal species were found in at least two of the three compartments at the same time-point. The common skin coloniser Staphylococcus epidermidis was identified in all patients but one (11/12), whereas the pathogen Staphylococcus aureus was isolated in five of the patients. Several associations between clinical and microbiological parameters were found. CONCLUSIONS: There was no difference in the clinical outcome with the use of polished versus machined abutment at 3 and 12 months after implantation. The present pilot trial largely confirmed a suitable study design, sampling and analytical methodology to determine the effects of modified BAHS abutment properties. LEVEL OF EVIDENCE: 2. Controlled prospective comparative study. PMID- 29623413 TI - No effect of season on the electrocardiogram of long-eared bats (Nyctophilus gouldi) during torpor. AB - Heterothermic animals regularly undergo profound alterations of cardiac function associated with torpor. These animals have specialised tissues capable of withstanding fluctuations in body temperature > 30 degrees C without adverse effects. In particular, the hearts of heterotherms are able to resist fibrillation and discontinuity of the cardiac conduction system common in homeotherms during hypothermia. To investigate the patterns of cardiac conduction in small insectivorous bats which enter torpor year round, I simultaneously measured ECG and subcutaneous temperature (Tsub) of 21 Nyctophilus gouldi (11 g) during torpor at a range of ambient temperatures (Ta 1-28 degrees C). During torpor cardiac conduction slowed in a temperature dependent manner, primarily via prolongation along the atrioventricular pathway (PR interval). A close coupling of depolarisation and repolarisation was retained in torpid bats, with no isoelectric ST segment visible until animals reached Tsub <6 degrees C. There was little change in ventricular repolarisation (JT interval) with decreasing Tsub, or between rest and torpor at mild Ta. Bats retained a more rapid rate of ventricular conduction and repolarisation during torpor relative to other hibernators. Throughout all recordings across seasons (> 2500 h), there was no difference in ECG morphology or heart rate during torpor, and no manifestations of significant conduction blocks or ventricular tachyarrhythmias were observed. My results demonstrate the capacity of bat hearts to withstand extreme fluctuations in rate and temperature throughout the year without detrimental arrhythmogenesis. I suggest that this conduction reserve may be related to flight and the daily extremes in metabolism experienced by these animals, and warrants further investigation of cardiac electrophysiology in other flying hibernators. PMID- 29623414 TI - ILC2s in infectious diseases and organ-specific fibrosis. AB - Type 2 immune responses evolved to provide host protection against parasitic infections and to support the repair of infection-induced tissue injury. However, persistent chronic organ damage can result in dysregulated production of critical type 2 cytokines supporting tissue remodeling and fibrosis development. Recently, group 2 innate lymphoid cells (ILC2s) were newly described as central innate mediators of type 2 responses. In particular, by secretion of the cytokines IL-5, IL-9, and IL-13 and the growth factor amphiregulin in response to the release of tissue-derived alarmins, ILC2s have been shown to substantially contribute to both the dismissal of metazoan parasites and the repair of infection-dependent or sterile tissue damage. Conversely, cytokine production by ILC2s emerged as a driving force for tissue remodeling and excessive fibrosis in several organ systems including the lung, liver, and skin. In this review, we discuss how ILC2s are specifically implicated in the body's immune response to different pathogenic infections and how dysregulated ILC2s may promote organ-specific fibrosis. PMID- 29623415 TI - What have we learned in minimally invasive colorectal surgery from NSQIP and NIS large databases? A systematic review. AB - BACKGROUND: "Big data" refers to large amount of dataset. Those large databases are useful in many areas, including healthcare. The American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) and the National Inpatient Sample (NIS) are big databases that were developed in the USA in order to record surgical outcomes. The aim of the present systematic review is to evaluate the type and clinical impact of the information retrieved through NISQP and NIS big database articles focused on laparoscopic colorectal surgery. METHODS: A systematic review was conducted using The Meta-Analysis Of Observational Studies in Epidemiology (MOOSE) guidelines. The research was carried out on PubMed database and revealed 350 published papers. Outcomes of articles in which laparoscopic colorectal surgery was the primary aim were analyzed. RESULTS: Fifty-five studies, published between 2007 and February 2017, were included. Articles included were categorized in groups according to the main topic as: outcomes related to surgical technique comparisons, morbidity and perioperatory results, specific disease-related outcomes, sociodemographic disparities, and academic training impact. CONCLUSIONS: NSQIP and NIS databases are just the tip of the iceberg for the potential application of Big Data technology and analysis in MIS. Information obtained through big data is useful and could be considered as external validation in those situations where a significant evidence-based medicine exists; also, those databases establish benchmarks to measure the quality of patient care. Data retrieved helps to inform decision-making and improve healthcare delivery. PMID- 29623416 TI - Agreement between preload reserve measured by impedance cardiography and echocardiography during pregnancy. AB - PURPOSE: Accurate assessment of cardiac function is important during pregnancy. Echocardiography and impedance cardiography (ICG) are commonly used noninvasive methods to measure stroke volume (SV) and cardiac output (CO). The difference in stroke volume (DeltaSV) or cardiac output (DeltaCO) measured at baseline and after passive leg raising (PLR) is a measure of preload reserve that predicts volume responsiveness. However, the agreement between these two methods in measuring preload reserve during pregnancy is unclear. The aim of our study was to investigate the correlation and the agreement between Doppler echocardiography and ICG in assessing preload reserve in pregnant women. METHODS: In this prospective observational cross-sectional study, preload reserve was assessed by measuring the SV and CO during baseline and 90 s after PLR simultaneously by Doppler echocardiography and ICG in healthy pregnant women during the second and third trimesters. Bland-Altman analysis was used to determine the agreement between the two methods. Bias was calculated as the mean difference between two methods and precision as 1.96 SD of the difference. RESULTS: A total of 53 pregnant women were included. We found a statistically significant correlation between DeltaSV (R = 0.56, p < 0.0001) and DeltaCO (R = 0.39, p = 0.004) measured by ICG and Doppler echocardiography. The mean bias for DeltaSV was 2.52 ml, with a precision of 18.19 ml. The mean bias for DeltaCO was 0.21 l/min, with a precision of 1.51 l/min. CONCLUSION: There was a good agreement and a statistically significant correlation between ICG and Doppler echocardiography for measuring preload reserve. PMID- 29623417 TI - Peri-operative oral immunonutrition in malnourished ovarian cancer patients assessed by the nutritional risk screening. AB - OBJECTIVES: Aim of this study was to determine whether peri-operative immunonutrition can decrease complications and the length of stay (LOS) in malnourished ovarian cancer patients. STUDY DESIGN: Patients suspicious for advanced ovarian cancer before histopathological diagnosis and a nutritional risk score (NRS) >= 3 received oral immune-modulating diets (IMDs) for 5 days pre operative and at least 5 days post-operative. Parameters for clinical outcome were infectious and non-infectious complications during hospital stay, and time of hospitalization. The results were compared with malnourished ovarian cancer patients of a previous study without any additive nutritional support (standard clinical diet/nutrition). RESULTS: The infectious and non-infectious complication rate in the interventional group (IG) N = 28 was 42.9%, similar to the control group (CG) N = 19 with 42.1%, whereas the rate of infectious complications in the IG (21.4%) was slightly lower compared to the CG (26.3%). The median LOS of the IG was 18 days, and therefore, longer than LOS of the CG (15 days). Regarding the patients' compliance pre-operative 78.6% of the patients took the IMDs in an optimal and sufficient amount. Whereas after surgery, only eight (28.6%) patients were able to take IMDs in optimal and sufficient amount. CONCLUSIONS: The current study showed no improvement of the complication rate or the time of hospitalization due to additional peri-operative immunonutrition in malnourished ovarian cancer patients. However, a trend towards the reduction of infectious complications could be seen in the IG. PMID- 29623418 TI - Dentin sealing and antibacterial effects of silver-doped bioactive glass/mesoporous silica nanocomposite: an in vitro study. AB - OBJECTIVES: To synthesize a silver-doped bioactive glass/mesoporous silica nanoparticle (Ag-BGN@MSN), as well as to investigate its effects on dentinal tubule occlusion, microtensile bond strength (MTBS), and antibacterial activity. MATERIALS AND METHODS: Ag-BGN@MSN was synthesized using a modified "quick alkali mediated sol-gel" method. Demineralized tooth disc models were made and divided into four groups; the following treatments were then applied: group 1-no treatment, group 2-bioglass, group 3-MSN, group 4-Ag-BGN@MSN. Next, four discs were selected from each group and soaked into 6 wt% citric acid to test acid resistant stability. Dentinal tubule occlusion, as well as the occlusion ratio, was observed using field-emission scanning electron microscopy. The MTBS was also measured to evaluate the desensitizing effect of the treatments. Cytotoxicity was examined using the MTT assay. Antibacterial activity was detected against Lactobacillus casei, and ion dissolution was evaluated using inductively coupled plasma optical emission spectrometry. RESULTS: Ag-BGN@MSN effectively occluded the dentinal tubule and formed a membrane-like layer. After the acid challenge, Ag-BGN@MSN had the highest rate of dentinal tubule occlusion. There were no significant differences in MTBS among the four groups (P > 0.05). All concentrations of Ag-BGN@MSN used had a relative cell viability above 72%. CONCLUSIONS: Ag-BGN@MSN was successfully fabricated using a modified sol-gel method. The Ag-BGN@MSN biocomposite effectively occluded dentinal with acid resistant stability, did not decrease bond strength in self-etch adhesive system, had low cytotoxicity, and antibacterial effect. CLININAL RELEVANCE: Dentinal tubule sealing induced by Ag-BGN@MSN biocomposite with antibacterial effect is likely to increase long-term stability in DH. PMID- 29623419 TI - Axial plane dissimilarities of two identical Lenke-type 6C scoliosis cases visualized and analyzed by vertebral vectors. AB - PURPOSE: The global appearance of scoliosis in the horizontal plane is not really known. Therefore, the aims of this study were to analyze scoliosis in the horizontal plane using vertebral vectors in two patients classified with the same Lenke group, and to highlight the importance of the information obtained from these vertebral vector-based top-view images in clinical practice. METHODS: Two identical cases of scoliosis were selected, based on preoperative full-body standing anteroposterior and lateral radiographs obtained by the EOSTM 2D/3D system. Three-dimensional (3D) surface reconstructions of the spinal curves were performed by using sterEOSTM 3D software before and after surgery. In both patients, we also determined the vertebral vectors and horizontal plane coordinates for analyzing the curves mathematically before and after surgery. RESULTS: Despite the identical appearance of spinal curves in the frontal and sagittal planes, the horizontal views seemed to be significantly different. The vertebral vectors in the horizontal plane provided different types of parameters regarding scoliosis and the impact of surgical treatment: reducing lateral deviations, achieving harmony of the curves in the sagittal plane, and reducing rotations in the horizontal plane. CONCLUSIONS: Vertebral vectors allow the evolution of scoliosis curve projections in the horizontal plane before and after surgical treatment, along with representation of the entire spine. The top view in the horizontal plane is essential to completely evaluate the scoliosis curves, because, despite the similar representations in the frontal and sagittal planes, the occurrence of scoliosis in the horizontal plane can be completely different. These slides can be retrieved under Electronic Supplementary Material. PMID- 29623420 TI - Cancer survivors' experiences of a community-based cancer-specific exercise programme: results of an exploratory survey. AB - PURPOSE: Exercise levels often decline following cancer diagnosis despite growing evidence of its benefits. Treatment side effects, older age, lack of confidence and opportunity to exercise with others in similar circumstances influence this. Our study explored the experiences of people attending a cancer-specific community-based exercise programme (CU FitterTM). METHODS: A survey distributed to those attending the programme gathered demographic/clinical information, self reported exercise levels, information provision and barriers to/benefits of exercise. RESULTS: Sixty surveys were evaluable from 65/100 returned (62% female, 68% > 60 years, 66% breast/prostate cancer). Most (68%) were receiving treatment. Sixty-eight percent attended classes once or twice weekly. Fifty-five percent received exercise advice after diagnosis, usually from their hospital doctor/nurse. More (73%) had read about exercising, but less used the Internet to source information (32%). Self-reported exercise levels were higher currently than before diagnosis (p = 0.05). Forty-eight percent said their primary barrier to exercising was the physical impact of cancer/treatment. Improving fitness/health (40%) and social support (16%) were the most important gains from the programme. Many (67%) had made other lifestyle changes and intented to keep (50%) or increase (30%) exercising. CONCLUSIONS: This community-based cancer specific exercise approach engaged people with cancer and showed physical, psychological, and social benefits. IMPLICATIONS FOR CANCER SURVIVORS: Community grown exercise initiatives bring cancer survivors together creating their own supportive environment. Combining this with instructors familiar with the population and providing an open-ended service may prove particularly motivating and beneficial. Further work is required to provide evidence for this. PMID- 29623421 TI - Trabectedin plus pegylated liposomal doxorubicin (PLD) for patients with platinum sensitive recurrent ovarian cancer: a prospective, observational, multicenter study. AB - PURPOSE: The OVA-YOND study is the first prospective, non-interventional trial designed to evaluate trabectedin (1.1 mg/m2) plus PLD (30 mg/m2) in patients with platinum-sensitive recurrent ovarian cancer (ROC), given according to the marketing authorization in real-life clinical practice across Germany. METHODS: Eligible patients were adults with platinum-sensitive ROC, pretreated with >= 1 platinum-containing regimen/s. The primary endpoint was to assess safety/tolerability of the combination. RESULTS: Seventy-seven patients with platinum-sensitive relapse from 31 sites were evaluated. Patients received a median of 6 cycles (range 1-21) with 39 patients (50.6%) receiving >= 6 cycles. Median treatment duration was 4.2 months (range 0.7-18.8), mostly on an outpatient basis (88.3% of patients). Most common grade 3/4 trabectedin-related adverse events (AEs) were leukopenia (18.2%), neutropenia (15.6%), thrombocytopenia (9.1%), alanine (7.8%) and aspartate aminotransferase (6.5%) increase, and nausea/vomiting (5.2% each). Neutropenia (18.2%), leukopenia (15.6%), thrombocytopenia (10.4%), and nausea/vomiting (5.2% each) were the most frequent grade 3/4 PLD-related AEs. No deaths attributed to drug-related AEs or unexpected AEs occurred. Five patients (6.5%) had a complete response and 19 patients (24.7%) achieved a partial response for an objective response rate of 31.2% with median response duration of 6.25 months. Sixteen patients (20.8%) had disease stabilization for a disease control rate of 51.9%. Median progression free survival was 6.3 months and median overall survival was 16.4 months. CONCLUSION: Trabectedin plus PLD confer clinically meaningful benefit to pre treated patients with platinum-sensitive ROC, being comparable to those previously observed in selected populations from clinical trials and with a manageable safety profile. PMID- 29623422 TI - The role of citrate, lactate and transferrin in determining titanium release from surgical devices into human serum. AB - The presence of ionic titanium in the serum of patients with titanium implants is currently unexplained. This is presumed due to corrosion, and yet the serum titanium concentration measured in patients is far greater than that predicted by its solubility. The binding of titanium ion as Ti(IV) to human transferrin (hTF) in serum indicates that Ti(IV) ions interact with human physiology. This is an intriguing finding since there is currently no known role for titanium ions in human physiology. Thus, understanding the factors that determine in vivo titanium ion release is relevant to further understanding this metal's interactions with human biochemistry. The present study sought to determine the extent of titanium ion release of into human serum in vitro, and the role of citrate, lactate and hTF in this process. It was found that, when surgical devices of commercially pure titanium were placed into human serum, citrate and lactate concentrations were the prime determinants of titanium release. Crystallography revealed Ti(IV) bound to hTF in the presence of citrate alone, signalling that citrate can act as an independent ligand for Ti(IV) binding to hTF. Based on these findings, a two stage process of titanium ion release into human serum that is dependent upon both citrate and hTF is proposed to explain the ongoing presence of titanium ion in human subjects with implanted titanium devices. PMID- 29623423 TI - Clinical and genetic aspects of defects in the mitochondrial iron-sulfur cluster synthesis pathway. AB - Iron-sulfur clusters are evolutionarily conserved biological structures which play an important role as cofactor for multiple enzymes in eukaryotic cells. The biosynthesis pathways of the iron-sulfur clusters are located in the mitochondria and in the cytosol. The mitochondrial iron-sulfur cluster biosynthesis pathway (ISC) can be divided into at least twenty enzymatic steps. Since the description of frataxin deficiency as the cause of Friedreich's ataxia, multiple other deficiencies in ISC biosynthesis pathway have been reported. In this paper, an overview is given of the clinical, biochemical and genetic aspects reported in humans affected by a defect in iron-sulfur cluster biosynthesis. PMID- 29623425 TI - Unexpected Late Complication Causing Dysphagia. PMID- 29623426 TI - The sympathetic nervous system: malignancy, disease, and novel functions. PMID- 29623427 TI - Neuroinflammation in neurodegeneration: role in pathophysiology, therapeutic opportunities and clinical perspectives. PMID- 29623429 TI - 3D hollow porous CdFe2O4 microspheres as viable materials for magnetic solid phase extraction of azo colorants. AB - 3D magnetic hollow porous CdFe2O4 microspheres (3D MHPS-CdFe2O4) were prepared by a one-step and template-free hydrothermal method. The material was applied for magnetic solid phase extraction of three azo colorants (Acid Red, Congo Red, Sunset Yellow). Compared to conventional CdFe2O4 nanoparticles, the new 3D material exhibits superior extraction capability because of its unique hollow porous structure, high specific surface area, and the strong interaction between 3D microspheres and the colorants. A magnetic solid phase extraction (MPSE) combined with HPLC was established for simultaneous detection of the three azo colorants in food samples. Under optimum conditions, the detection limits are 0.54-1.00 ng mL-1, and good recoveries of 87.0-100.7% were obtained with spiked samples, with relative standard deviation of <= 3.8%. The combination of using the new 3D material and MPSE-HPLC results in an efficient, sensitive and inexpensive method for simultaneous determination of such colorants. Graphical abstract Schematic of the preparation of 3D magnetic hollow porous CdFe2O4 microspheres as solid phase extractant for simultaneous trace detection of three azo colorants in real samples. PMID- 29623428 TI - Frontal cortical control of posterior sensory and association cortices through the claustrum. AB - The claustrum is a telencephalic gray matter nucleus that is richly interconnected with the neocortex. This structure subserves top-down executive functions that require frontal cortical control of posterior cortical regions. However, functional anatomical support for the claustrum allowing for long-range intercortical communication is lacking. To test this, we performed a channelrhodopsin-assisted long-circuit mapping strategy in mouse brain slices. We find that anterior cingulate cortex input to the claustrum is transiently amplified by claustrum neurons that, in turn, project to parietal association cortex or to primary and secondary visual cortices. Additionally, we observe that claustrum drive of cortical neurons in parietal association cortex is layer specific, eliciting action potential generation briefly in layers II/III, IV, and VI but not V. These data are the first to provide a functional anatomical substrate through claustrum that may underlie top-down functions, such as executive attention or working memory, providing critical insight to this most interconnected and enigmatic nucleus. PMID- 29623424 TI - Fe-S cluster assembly in the supergroup Excavata. AB - The majority of established model organisms belong to the supergroup Opisthokonta, which includes yeasts and animals. While enlightening, this focus has neglected protists, organisms that represent the bulk of eukaryotic diversity and are often regarded as primitive eukaryotes. One of these is the "supergroup" Excavata, which comprises unicellular flagellates of diverse lifestyles and contains species of medical importance, such as Trichomonas, Giardia, Naegleria, Trypanosoma and Leishmania. Excavata exhibits a continuum in mitochondrial forms, ranging from classical aerobic, cristae-bearing mitochondria to mitochondria-related organelles, such as hydrogenosomes and mitosomes, to the extreme case of a complete absence of the organelle. All forms of mitochondria house a machinery for the assembly of Fe-S clusters, ancient cofactors required in various biochemical activities needed to sustain every extant cell. In this review, we survey what is known about the Fe-S cluster assembly in the supergroup Excavata. We aim to bring attention to the diversity found in this group, reflected in gene losses and gains that have shaped the Fe-S cluster biogenesis pathways. PMID- 29623430 TI - Relationship between serum apolipoproteins levels and retinopathy risk in subjects with type 2 diabetes mellitus. AB - AIMS: Prognostic significance of apolipoproteins in diabetic retinopathy risk has not been well investigated. The aim of this study was to reveal the relationship between the risk of diabetic retinopathy and the levels of several apolipoproteins and their ratios in a 10-year prospective cohort. METHODS: A total of 1023 diabetic patients without retinopathy were selected from a 10-year hospital-based diabetic cohort. In this cohort, all subjects had type 2 diabetes. Blood samples were obtained, and serum levels of several apolipoproteins were measured. In the follow-up period, diabetic retinopathy was diagnosed by two ophthalmologists through a series of ophthalmologic examinations. A Cox proportional hazard analysis was adopted to determine the relationship between the risk of diabetic retinopathy and the levels of several apolipoproteins and their ratios. RESULTS: In the follow-up period, 315 diabetic patients were suffered from diabetic retinopathy, and the remaining 708 patients did not. Baseline serum level of apoAI >= 7.4 MUmol/L was related to the decreased risk of diabetic retinopathy (HR 0.86, 95% CI 0.70-0.99). Baseline levels of apoCIII >= 6.3 MUmol/L, apoE >= 1.1 MUmol/L, apoCIII-to-apoAI ratio >= 0.9 and apoE-to-apoAI ratio >= 0.2 were associated with the increased risk of this complication (HR 1.25, 95% CI 1.04-1.49; HR 1.23, 95% CI 1.03-1.47; HR 1.34, 95% CI 1.11-1.60; HR 1.21, 95% CI 1.01-1.46). CONCLUSION: Elevated level of apoAI might be a protective factor for diabetic retinopathy. Increased levels of apoCIII, apoE, apoCIII-to-apoAI and apoE-to-apoAI ratios might be risk factors for this complication. PMID- 29623431 TI - Socio-demographic and clinical determinants of self-care in adults with type 2 diabetes: a multicentre observational study. AB - AIMS: To describe self-care as defined by the Middle Range Theory of Self-Care of Chronic Illness and to identify clinical and socio-demographic determinants in a T2DM population. METHODS: A multicentre observational cross-sectional study was conducted involving 540 adults with a confirmed diagnosis of T2DM from six outpatient diabetes services in Italy. Socio-demographic and clinical data were collected from medical records. The Self-Care of Diabetes Inventory (SCODI) was used to measure self-care maintenance, monitoring, management, and confidence dimensions. For each separate scale, scores were standardized 0-100 with higher SCODI scores indicating better self-care; a score >= 70 is adequate. Multiple quantile regression models were performed to identify determinants of each self care dimension. RESULTS: Self-care maintenance (median = 81.3) and self-care confidence (median = 79.5) were adequate in most of the subjects. Self-care monitoring was adequate in only half of the sample (median = 70.6). Self-care management was poor (median = 59.4). Lower self-care maintenance was associated with lower self-care confidence (p < 0.001). Lower self-care monitoring was associated with being male (p < 0.001), having lower self-care confidence (p < 001), and having diabetes for < 10 years (p < 0.001). Lower self-care management was associated with being male (p = 0.002), being older (p = 0.005), having a low income (p = 0.030), being employed (p = 0.008), having missed diabetes education in the last year (p = 0.002), and lower self-care confidence (p < 0.0001). Lower self-care confidence was associated with having diabetes for < 10 years (p = 0.008), and having at least one comorbid condition (p = 0.006). CONCLUSIONS: Determinants of self-care maintenance, monitoring, management and confidence include both clinical and socio-demographic variables. Modifiable determinants such as self-care confidence and diabetes self-care management education could be used to tailor interventions to improve diabetes self-care. PMID- 29623432 TI - Visual field deficits after epilepsy surgery: a new quantitative scoring method. AB - BACKGROUND: Anterior temporal lobectomy (ATL) as a treatment for drug-resistant temporal lobe epilepsy (TLE) frequently causes visual field deficits (VFDs). Reported VFD encompasses homonymous contralateral upper quadrantanopia. Its reported incidence ranges from 15 to 90%. To date, a quantitative method to evaluate postoperative VFD in static perimetry is not available. A method to quantify postoperative VFD, which allows for comparison between groups of patients, was developed. METHODS: Fifty-five patients with drug-resistant TLE, who underwent ATL with pre- and postoperative perimetry, were included. Temporal lobe resection length was measured on postoperative MRI. Percentage VFD was calculated for the total visual field, contralateral upper quadrant, or other three quadrants combined. RESULTS: Patients were divided into groups by resection size (< 45 and >= 45 mm) and side of surgery (right and left). We found significant higher VFD in the >= 45 vs. < 45 mm group (2.3 +/- 4.4 vs. 0.7 +/- 2.4%,p = 0.04) for right-sided ATL. Comparing VFD in both eyes, we found more VFD in the right vs. left eye following left-sided ATL (14.5 +/- 9.8 vs. 12.9 +/- 8.3%, p = 0.03). We also demonstrated significantly more VFD in the < 45 mm group for left- vs. right-sided surgery (6.7 +/- 6.7 vs. 13.1 +/- 7.0%, p = 0.016). A significant quantitative correlation between VFD and resection size for right sided ATL was shown (r = 0.52, p < 0.01). CONCLUSIONS: We developed a new quantitative scoring method for the assessment of postoperative visual field deficits after temporal lobe epilepsy surgery and assessed its feasibility for clinical use. A significant correlation between VFD and resection size for right sided ATL was confirmed. PMID- 29623434 TI - Full genotype constellations of six feline Rotavirus A strains isolated in Japan in the 1990s including a rare A15 NSP1 genotype. AB - Full genome sequencing of six feline Rotavirus A (RVA) strains isolated in Japan in the 1990s revealed three genotype constellations, one of which had a unique constellation of G3-P[3]-I3-R3-C3-M3-A15-N3-T3-E3-H6. Genotype A15, carried by RVA/Cat-tc/JPN/FRV348/1994/G3P[3], is a rare NSP1 genotype, and only one human and one canine RVA strains have thus far been reported to carry this genotype. The other three G3P[3] strains (FRV72, FRV73, and FRV303) possessed a constellation of I3-R3-C2-M3-A9-N2-T3-E3-H6, whereas two G3P[9] strains (FRV317 and FRV384) possessed a constellation of I3-R3-C3-M3-A3-N3-T3-E3-H3. PMID- 29623433 TI - Microevolution and independent incursions as main forces shaping H5 Hemagglutinin diversity during a H5N8/H5N5 highly pathogenic avian influenza outbreak in Czech Republic in 2017. AB - Here, we present a comprehensive analysis of the H5N8/H5N5 highly pathogenic avian influenza (HPAI) virus strains detected in the Czech Republic during an outbreak in 2017. Network analysis of the H5 Hemagglutinin (HA) from 99% of the outbreak localities suggested that the diversity of the Czech H5N8/H5N5 viruses was influenced by two basic forces: local microevolution and independent incursions. The geographical occurrence of the central node H5 HA sequences revealed three eco-regions, which apparently played an important role in the origin and further spread of the local H5N8/HPAI variants across the country. A plausible explanation for the observed pattern of diversity is also provided. PMID- 29623435 TI - Porcine-like G3P[6] and G4P[6] rotavirus A strains detected from children with diarrhoea in Vietnam. AB - Animal rotavirus A (RVA) strains can infect children and cause diarrhoea. We determined the full genome sequences of one G3P[6] strain (NT0001) and five G4P[6] strains (NT0042, NT0077, NT0205, NT0599, and NT0621) detected from children with diarrhoea in Vietnam in 2007-2008. Strain NT0001 had a genotype constellation of: G3-P[6]-I5-R1-C1-M1-A8-N1-T1-E1-H1, strain NT0042: G4-P[6]-I1 R1-C1-M1-A8-N1-T1-E1-H1, strain NT0077: G4-P[6]-I5-R1-C1-M1-A8-N1-T7-E1-H1, and strains NT0205, NT0599, and NT0621: G4-P[6]-I1-R1-C1-M1-A1-N1-T1-E1-H1. Sequence divergence data and phylogenetic analysis showed that they were different porcine RVA strains that independently and directly crossed the host species barrier to infect children. PMID- 29623436 TI - Molecular detection and phylogenetic analysis of megalocytivirus in Brazilian ornamental fish. AB - Megalocytiviruses have a worldwide distribution, causing serious economic loss to the global aquaculture industry. They also present a threat to ornamental fish trade because megalocytiviral infections have unspecified symptoms, making early diagnosis difficult. In this study, 100 ornamental fish from 24 different species were tested by PCR for megalocytivirus, with a 47% positive rate being identified. Phylogenetic reconstruction, based on the major capsid protein (MCP) gene, clustered all Brazilian samples into a single clade, showing identity values ranging from 99% to 100% when compared to each other. This is the first report of megalocytivirus infection in some ornamental fish species in Brazil. PMID- 29623438 TI - Reply to "Letter to Editor submitted by Rui Huang et al. entitled potential clinical application of strain elastography in chronic liver diseases". PMID- 29623437 TI - Molecular characterization of cosmopolitan and potentially co-invasive helminths of commensal, murid rodents in Gauteng Province, South Africa. AB - Concurrent studies of helminth parasites of introduced and native rodent species are few and miss the opportunity to identify potential co-invasive parasite species. This study employed molecular tools to infer the phylogeny and elucidate the origin of potentially co-invasive parasites of commensal, murid rodents by assessing introduced Rattus norvegicus, Rattus rattus, Rattus tanezumi, and native Mastomys coucha in Gauteng Province, South Africa. Genotypes of Nippostrongylus brasiliensis recovered from R. norvegicus are nearly identical to those recovered from elsewhere in the world. The pinworms, Aspiculurus tetraptera, recovered from introduced R. tanezumi and R. rattus, Syphacia muris recovered from R. tanezumi, and Syphacia obvelata recovered from indigenous M. coucha have affiliations to those recovered of laboratory rodents from the USA and China. Syphacia obvelata was previously only known as a commensal endoparasite of laboratory rodents, and the S. muris genotype recovered from R. tanezumi in this study shows an affiliation to a genotype recovered from the same host species in Indonesia which is part of the native range. The study emphasizes the need for surveillance of potential co-invasive species and contributes in documenting genetic diversity of endoparasites of well-known hosts. PMID- 29623439 TI - Potential clinical application of strain elastography in chronic liver diseases. PMID- 29623440 TI - Finding the K best synthesis plans. AB - In synthesis planning, the goal is to synthesize a target molecule from available starting materials, possibly optimizing costs such as price or environmental impact of the process. Current algorithmic approaches to synthesis planning are usually based on selecting a bond set and finding a single good plan among those induced by it. We demonstrate that synthesis planning can be phrased as a combinatorial optimization problem on hypergraphs by modeling individual synthesis plans as directed hyperpaths embedded in a hypergraph of reactions (HoR) representing the chemistry of interest. As a consequence, a polynomial time algorithm to find the K shortest hyperpaths can be used to compute the K best synthesis plans for a given target molecule. Having K good plans to choose from has many benefits: it makes the synthesis planning process much more robust when in later stages adding further chemical detail, it allows one to combine several notions of cost, and it provides a way to deal with imprecise yield estimates. A bond set gives rise to a HoR in a natural way. However, our modeling is not restricted to bond set based approaches-any set of known reactions and starting materials can be used to define a HoR. We also discuss classical quality measures for synthesis plans, such as overall yield and convergency, and demonstrate that convergency has a built-in inconsistency which could render its use in synthesis planning questionable. Decalin is used as an illustrative example of the use and implications of our results. PMID- 29623441 TI - Psychological Pain, Depression, and Suicide: Recent Evidences and Future Directions. AB - PURPOSE OF REVIEW: The definition of psychological pain is complex. It is a lasting unpleasant and unsustainable feeling characterized by a perception of inability or deficiency of the self, as well as frustrated psychological needs and social disconnection. The aim of our review was to summarize the most recent and updated findings supporting the role of psychological pain in the pathophysiology of depression and suicidal behavior. We also explored the relationship between psychological and physical pain in depression and suicide. RECENT FINDINGS: Psychological pain is a prominent dimension of depressive disorder and has been associated with higher risk of suicidal ideation and suicidal behavior. Sensitivity to psychological and physical pain is increased in depression. Conversely, higher tolerance to physical pain is associated with suicidal behavior. A better understanding of the pathophysiology of pain processing in depression and suicide offers new therapeutic options for the treatment of depression through the use of analgesic drugs. PMID- 29623442 TI - Therapeutic Drug Monitoring in Pediatric Inflammatory Bowel Disease. AB - PURPOSE OF REVIEW: Therapeutic drug monitoring (TDM) has emerged as a useful tool to optimize the use of drug therapies in adults with inflammatory bowel disease (IBD), including both Crohn's disease (CD) and ulcerative colitis (UC), especially during the use of biological therapies, for which the pharmacokinetics and pharmacodynamics are highly variable among patients. Fewer data exist in children. This review examines the current literature on TDM in pediatric IBD. RECENT FINDINGS: Drug clearance is affected by a number of patient and disease factors. For thiopurines, adjusting dosing by monitoring 6-thioguanine (6TGN) and 6-methylmercaptopurine ((6MMP) levels is demonstrated to maximize response and minimize toxicity, while monitoring metabolite levels when treating with anti tumor necrosis factor (anti-TNF) remain controversial. While in adults the use of TDM in the setting of loss of response to anti-TNF therapy is established, in children, only a small number of studies exist, but these too have encouraging results. There are however, conflicting data regarding the optimal timing of TDM, comparing "reactive" monitoring and "proactive" monitoring. No such data exist in pediatrics. TDM is cost-effective, and dose reduction may represent a safety benefit. There are limited adult data for use of TDM for the newer biologics, vedolizumab and ustekinumab, but early results suggest similarly promising utility. The use of TDM in pediatric IBD is increasing in clinical practice, with similar efficacy to adults demonstrated in children with loss of response to anti TNF therapy. More prospective studies are needed in children to examine proactive monitoring and utility of TDM with newer biologics. PMID- 29623443 TI - Pharmacokinetic and Pharmacodynamic Considerations of Antibiotics of Last Resort in Treating Gram-Negative Infections in Adult Critically Ill Patients. AB - PURPOSE OF REVIEW: We provide an overview of antimicrobials that are considered last resort for the treatment of resistant gram-negative infections in adult critically ill patients. The role in therapy, pharmacodynamic (PD) goals, and pharmacokinetic (PK) changes in critical illness for aminoglycosides, polymyxins, tigecycline, fosfomycin, and fluoroquinolones are summarized. RECENT FINDINGS: Altered PK in septic patients in the intensive care unit (ICU) is observed with many of our agents of last resort. Based on the available literature, dosage adjustments may be required to optimize PK parameters and meet PD targets for most effective bacterial killing. Data is limited, studies are conducted in heterogeneous patient populations, and conclusions are frequently conflicting. Strategic dosing regimens such as high-dose extended interval dosing of aminoglycosides or loading doses with colistin and polymyxin B are examples of ways to optimize antibiotic PK in critically ill patients. Benefits of these strategies must be balanced with risks of increased toxicity. Patients with resistant gram-negative infections may present with septic shock in the ICU. Sepsis can significantly alter the PK of antibiotics and require dosage adjustments to attain optimal drug levels. An understanding of PK and PD properties of these agents of last resort will help to maximize therapeutic efficacy while minimizing toxic effects. PMID- 29623444 TI - Polygenic risk score: use in migraine research. AB - BACKGROUND: The latest Genome-Wide Association Study identified 38 genetic variants associated with migraine. In this type of studies the significance level is very difficult to achieve (5 * 10- 8) due to multiple testing. Thus, the identified variants only explain a small fraction of the genetic risk. It is expected that hundreds of thousands of variants also confer an increased risk but do not reach significance levels. One way to capture this information is by constructing a Polygenic Risk Score. Polygenic Risk Score has been widely used with success in genetics studies within neuropsychiatric disorders. The use of polygenic scores is highly relevant as data from a large migraine Genome-Wide Association Study are now available, which will form an excellent basis for Polygenic Risk Score in migraine studies. RESULTS: Polygenic Risk Score has been used in studies of neuropsychiatric disorders to assess prediction of disease status in case-control studies, shared genetic correlation between co-morbid diseases, and shared genetic correlation between a disease and specific endophenotypes. CONCLUSION: Polygenic Risk Score provides an opportunity to investigate the shared genetic risk between known and previously unestablished co morbidities in migraine research, and may lead to better and personalized treatment of migraine if used as a clinical assistant when identifying responders to specific drugs. Polygenic Risk Score can be used to analyze the genetic relationship between different headache types and migraine endophenotypes. Finally, Polygenic Risk Score can be used to assess pharmacogenetic effects, and perhaps help to predict efficacy of the Calcitonin Gene-Related Peptide monoclonal antibodies that soon become available as migraine treatment. PMID- 29623445 TI - Role of the Microbiome in Food Allergy. AB - PURPOSE OF REVIEW: Resident microbial communities likely modify risk for allergic disorders, including food allergy. We review epidemiologic studies linking microbial exposures to food allergy risk and discuss the mechanisms by which the microbiome may modulate oral tolerance. We additionally address ongoing translational efforts in human microbiome studies. RECENT FINDINGS: Epidemiologic studies and murine models support that altered microbial exposures and colonization in early life modify food allergy risk. Differential microbiota confer protection or susceptibility to food allergy by modulating the regulatory tone of the mucosal immune system. Recent efforts are focused on the identification of bacterial strains necessary for oral tolerance in human and microbial-based clinical trials. Early childhood appears to be critical for the colonization of a diverse microbiota necessary for the induction and maintenance of oral tolerance. Identification and functional evaluation of protective commensal microbes will inform strategies for the prevention and treatment of food allergy. PMID- 29623446 TI - Regulatory phosphorylation of poly-gamma-glutamic acid with phosphate salts in the culture of Bacillus subtilis (natto). AB - Poly-gamma-glutamic acid (PGA) was easily phosphorylated by direct addition of phosphorylating agents into the culture medium of Bacillus subtilis (natto). Tetrapolyphosphate salt was the most incorporated into PGA molecules of all used reagents. Phosphorylation occurred at the alpha-carboxyl side chains of PGA molecule. The amounts of bound phosphate to PGA were dependent on the amounts of added phosphorylating agent. In low molecular weight regions of less than 100 kDa, a cross-linked peak was observed in the phosphorylated PGAs, whereas their peaks at approximately 1000 kDa shifted to a higher molecular weight due to the bound phosphate. The PGA derivatives had a wide range in viscosity up to 15/1000 to 15 times when compared to the native PGA, depending on the degree of phosphorylation (DP) in the PGA derivatives. The PGA with low DP had a high viscosity due to the unfolding conformation whereas highly phosphorylated PGA had aggregation with low viscosity. Heat treatment at 80 degrees C after the addition of phosphate salt elicited a novel collagen-like helix structure. These observations show that phosphorylation is an effective way to diversify the physicochemical properties of PGA. PMID- 29623447 TI - Decreased bone turnover in HIV-infected children on antiretroviral therapy. AB - : In this study, we evaluated the relationships between immune activation, bone turnover, and bone mass in virally suppressed HIV-infected children and HIV uninfected children in South Africa. We found that decreased bone mass may occur or persist independent of immune activation and altered bone turnover. PURPOSE: HIV-infected children and adolescents have deficits in skeletal growth which include decreases in bone mass and alterations in bone microarchitecture. However, the mechanism by which HIV infection compromises bone accrual in children and adolescents is unclear. The goal of this study was to evaluate the relationships between immune activation, bone turnover, and bone mass in a group of pre-pubertal HIV-infected children randomized to remain on ritonavir-boosted lopinavir (LPV/r)-based antiretroviral therapy (ART) or switch to efavirenz-based ART in South Africa virally suppressed at the time of this study. METHODS: This cross-sectional analysis included 219 HIV-infected and 180 HIV-uninfected children enrolled in the CHANGES Bone Study conducted in Johannesburg, South Africa. Whole body (WB) bone mineral content (BMC) was assessed by dual x-ray absorptiometry and WB BMC Z-scores adjusted for sex, age, and height were generated. Bone turnover markers, including C-telopeptide of type 1 collagen (CTx) and procollagen type I N-terminal propeptide (P1NP), were analyzed. Markers of immune activation were also measured, including cytokines IL-6 and TNF-alpha, as well as soluble CD14 and high-sensitivity C-reactive protein (CRP). RESULTS: Compared to uninfected controls, HIV-infected children had lower WB BMC Z-scores, similar IL-6 and TNF-alpha, higher soluble CD14 and high-sensitivity CRP, and lower markers of bone resorption (CTX) and bone formation (P1NP). Bone turnover markers were not different in those remaining on LPV/r or switched to efavirenz. CONCLUSIONS: Our findings suggest that in HIV-infected children with viral suppression, decreased bone accrual may occur or persist independent of immune activation and altered bone turnover. PMID- 29623449 TI - Role of matrix metalloproteinases in tumour invasion: immunohistochemistry of peritoneum from peritoneal carcinomatosis. AB - Colorectal cancer is one of the most common forms of cancer. Spread of tumour to the peritoneal cavity may lead to seeding of cancer cells that adhere to and invade the peritoneal membrane causing peritoneal carcinomatosis. Matrix metalloproteinases (MMPs) play an essential role in cancer cell invasion and dissemination. The aim of this study was to evaluate the morphology and presence of matrix metalloproteinases in peritoneal carcinomatosis. Biopsy samples of the parietal peritoneum were taken from patients undergoing cytoreductive surgery for peritoneal carcinomatosis. The samples were fixed in formalin, dehydrated and embedded in paraffin prior to cutting into 4-um slices. Staining with haematoxylin/eosin was used for morphology studies, and MMP-1, MMP-2 and TIMP-1 levels were evaluated using immunohistochemistry and light microscopy. The microscopically tumour-free areas of the peritoneal membrane were thin compared to the peripheral invasion zone and the areas invaded by tumour. Peritoneum invaded by tumour was richly vascularised and contained inflammatory cells. MMP-1 was expressed in tumour-free peritoneum and in the invasion zone between tumour and peritoneal tissue, but not in tumour-invaded areas. MMP-2 and TIMP-1 were mostly expressed in the proximity of blood vessels and inflammatory cells in tumour-invaded areas, but was not seen in tumour-free areas. MMPs play an important role in the process of cancer cell invasion of the peritoneum in peritoneal carcinomatosis. The peripheral zone of the tumour appears to be of importance for tumour invasion. PMID- 29623448 TI - Recent Genetics and Epigenetics Approaches to PTSD. AB - PURPOSE OF REVIEW: Following a life-threatening traumatic exposure, about 10% of those exposed are at considerable risk for developing posttraumatic stress disorder (PTSD), a severe and disabling syndrome characterized by uncontrollable intrusive memories, nightmares, avoidance behaviors, and hyperarousal in addition to impaired cognition and negative emotion symptoms. This review will explore recent genetic and epigenetic approaches to PTSD that explain some of the differential risk following trauma exposure. RECENT FINDINGS: A substantial portion of the variance explaining differential risk responses to trauma exposure may be explained by differential inherited and acquired genetic and epigenetic risk. This biological risk is complemented by alterations in the functional regulation of genes via environmentally induced epigenetic changes, including prior childhood and adult trauma exposure. This review will cover recent findings from large-scale genome-wide association studies as well as newer epigenome-wide studies. We will also discuss future "phenome-wide" studies utilizing electronic medical records as well as targeted genetic studies focusing on mechanistic ways in which specific genetic or epigenetic alterations regulate the biological risk for PTSD. PMID- 29623450 TI - The Role of Non-invasive Testing in Evaluation and Diagnosis of Pediatric Lower Urinary Tract Dysfunction. AB - PURPOSE OF REVIEW: The symptoms of lower urinary tract dysfunction (LUTD) including urinary incontinence, frequency, and urgency are among the most common reasons children are referred to pediatric urologists. Despite this, the workup for LUTD is often time consuming and a source of frustration for patients, parents, and clinicians alike. In the current review, we summarize the important role non-invasive testing plays in the diagnosis and management of children with LUTD and to show how use of these tests can help avoid the need for more invasive testing in the majority of children. RECENT FINDINGS: Non-invasive tests such urine studies, uroflowmetry +/- simultaneous electromyography, assessment of post void residual, renal/bladder ultrasound, and pelvic ultrasound when used appropriately can provide valuable information to facilitate decision making during the evaluation of children with LUTD. While these tests should be employed prior to more invasive testing such as urodynamic studies, they can often act as a surrogate for the more invasive tests. Non-invasive tests can help us in our goal of improving diagnostic ability to better classify the child's LUTD into an actual condition which allows targeted treatment in the hope of better outcomes and more satisfied patients and families. PMID- 29623452 TI - Rhabdomyolysis secondary to systemic lupus erythematosus. AB - Systemic lupus erythematous (SLE) is a systemic auto-immune disorder with a variety of presentations and wide spread organ involvement. We present a case report of a patient with an SLE exacerbation as well as concurrent rhabdomyolysis with massively elevated CPK (304,700 U/L). Though a rarely reported effect of SLE, rhabdomyolysis can be severe and potentially lethal secondary or concurrent to an acute SLE episode. This case report demonstrates the association between SLE and rhabdomyolysis, which is not well described in the current literature. PMID- 29623451 TI - Invasive pulmonary aspergillosis is associated with adverse clinical outcomes in critically ill patients receiving veno-venous extracorporeal membrane oxygenation. AB - To identify the incidence, risk factors and impact on long-term survival of invasive pulmonary aspergillosis (IPA) and Aspergillus colonisation in patients receiving vv-extracorporeal membrane oxygenation (ECMO). A retrospective evaluation was performed of patients receiving vv-ECMO at a tertiary hospital in Manchester (UK) between January 2012 and December 2016. Data collected included epidemiological data, microbiological cultures, radiographic findings and outcomes. Cases were classified as proven IPA, putative IPA or Aspergillus colonisation according to a validated clinical algorithm. One hundred thirty-four patients were supported with vv-ECMO, median age of 45.5 years (range 16.4-73.4). Ten (7%) patients had putative IPA and nine (7%) had Aspergillus colonisation. Half of the patients with putative IPA lacked classical host risk factors for IPA. The median number of days on ECMO prior to Aspergillus isolation was 5 days. Immunosuppression and influenza A infection were significantly associated with developing IPA in a logistic regression model. Cox regression model demonstrates a three times greater hazard of death associated with IPA. Overall 6-month mortality rate was 38%. Patients with putative IPA and colonised patients had a 6 month mortality rate of 80 and 11%, respectively. Immunosuppression and influenza A infection are independent risk factors for IPA. IPA, but not Aspergillus colonisation, is associated with high long-term mortality in patients supported with vv-ECMO. PMID- 29623453 TI - Omega-3 Supplementation as a Dietary Intervention to Reduce Aggressive and Antisocial Behavior. AB - PURPOSE OF REVIEW: Although there is an increasing body of literature on the relationship between omega-3 fatty acids and aggressive/antisocial behavior, evidence to date suggests that there are mixed findings on the efficacy of omega 3 supplementation as a dietary intervention to reduce such behaviors. This article describes the current state of the research regarding omega-3 supplementation and aggressive/antisocial behavior from intervention studies, with an emphasis on randomized controlled trials. RECENT FINDINGS: The current evidence base indicates a small effect size (approximately d = .20) for the efficacy of increased omega-3 intake in reducing aggressive and antisocial behavior in children and adults. How precisely omega-3 supplementation results in such behavioral improvement is an open question, although upregulation of dysfunctional prefrontal regions is one candidate mediator. Directions for further research include understanding the more basic mechanisms that may underlie any intervention effects, delineating dose-response relationships, ascertaining optimal treatment duration and composition, conducting follow-ups post-treatment, and testing the provisional hypothesis that more impulsive, reactive forms of aggression may be particularly amenable to omega-3 supplementation. PMID- 29623454 TI - Food Protein-Induced Enterocolitis Syndrome (FPIES): Review of Recent Guidelines. AB - PURPOSE OF REVIEW: To increase understanding of food protein-induced enterocolitis syndrome (FPIES), a non-immunoglobulin E (IgE)-mediated reaction to food, by reviewing a growing body of literature, including recently published international consensus guidelines. RECENT FINDINGS: FPIES primarily affects infants and young children and is characterized by the delayed onset of gastrointestinal symptoms, predominantly repetitive vomiting, in response to a trigger food. Symptoms are often severe and can lead to shock. Diagnosis can be challenging due to a wide differential diagnoses and lack of disease biomarkers. FPIES is a clinical diagnosis, with allergy testing playing a very limited role, if any. Medically supervised oral food challenges are used to monitor resolution of disease, which generally occurs in early childhood. FPIES is an important condition presenting to clinicians in a variety of settings. Recent international consensus guidelines and a growing body of literature can better equip practitioners to care for these often-challenging patients. PMID- 29623456 TI - Use of 5-azacytidine in a proof-of-concept study to evaluate the impact of pre natal and post-natal exposures, as well as within generation persistent DNA methylation changes in Daphnia. AB - Short-term exposures at critical stages of development can lead to delayed adverse effects long after the initial stressor has been removed, a concept referred to as developmental origin of adult disease. This indicates that organisms' phenotypes may epigenetically reflect their past exposure history as well as reflecting chemicals currently present in their environment. This concept has significant implications for environmental monitoring. However, there is as yet little or no implementation of epigenetics in environmental risk assessment. In a proof-of-principle study we exposed Daphnia magna to 5-azacytidine, a known DNA de-methylating agent. Exposures covered combinations of prenatal and postnatal exposures as well as different exposure durations and recovery stages. Growth, the transcription of genes and levels of metabolites involved in regulating DNA methylation, and methylation levels of several genes were measured. Our data shows that prenatal exposures caused significant changes in the methylome of target genes, indicating that prenatal stages of Daphnia are also susceptible to same level of change as post-natal stages of Daphnia. While the combination of pre- and postnatal exposures caused the most extreme reduction in DNA methylation compared to the control group. Furthermore, some of the changes in the methylation patterns were persistent even after the initial stressor was removed. Our results suggest that epigenetic biomarkers have the potential to be used as indicators of past chemical exposure history of organisms and provide strong support for implementing changes to the current regimes for chemical risk assessment to mimic realistic environmental scenarios. PMID- 29623457 TI - Prediction of respiratory function in patients with severe scoliosis on the basis of the novel individualized spino-pelvic index. AB - OBJECTIVE: Our study aimed to evaluate the pulmonary function of patients with severe scoliosis after correcting standing height with spino-pelvic index (SPI). METHODS: Inclusion criteria: (1) with a coronal Cobb angle of more than 90 degrees ; (2) diagnosed as congenital (CS) or idiopathic scoliosis (IS); (3) aged between ten and 20 years; (4) with pulmonary function test (PFT) at the primary consultation. Patients with previous surgical intervention, with angular kyphosis, and with neuromuscular disease were excluded. Length of spine (LOS), height of spine (HOS), and height of pelvis (HOP) were measured on coronal films. SPI was defined as the ratio between LOS and HOP. The corrected body height was calculated: corrected body height = body height + (SPI * HOP - HOS). The PFTs included the following parameters: VCmax, FVC, FVC% predicted, FEV1, FEV1% predicted, PEF, and MVV. PFT results were recalculated using the corrected body height. RESULTS: Thirty patients were diagnosed as IS and 27 as CS with average Cobb angles of 99.88 degrees +/- 11.83 and 98.06 degrees +/- 14.27, respectively. Significant differences were observed in VCmax and FVC between IS and CS patients (P < 0.05). All the corrected PFT parameters were significantly lower than the original PFT parameters (P < 0.05). CONCLUSION: For the first time, this study proposed a method to predict pulmonary function of patients with severe scoliosis using SPI, as an age-independent parameter in normal adolescents. After body height correction, pulmonary function of patients with severe scoliosis was found to be significantly decreased, indicating that pulmonary function impairment was underestimated in patients with severe scoliosis when evaluating pulmonary function with arm span. PMID- 29623455 TI - Managing Gait, Balance, and Posture in Parkinson's Disease. AB - PURPOSE OF REVIEW: Postural instability and gait difficulties inexorably worsen with Parkinson's disease (PD) progression and become treatment resistant, with a severe impact on autonomy and quality of life. We review the main characteristics of balance instability, gait disabilities, and static postural alterations in advanced PD, and the available treatment strategies. RECENT FINDINGS: It remains very difficult to satisfactorily alleviate gait and postural disturbances in advanced PD. Medical and surgical interventions often fail to provide satisfactory or durable alleviation of these axial symptoms, that may actually call for differential treatments. Exercise and adapted physical activity programs can contribute to improving the patients' condition. Gait, balance, and postural disabilities are often lumped together under the Postural Instability and Gait Difficulties umbrella term. This may lead to sub-optimal patients' management as data suggest that postural, balance, and gait problems might depend on distinct underlying mechanisms. We advocate for a multidisciplinary approach from the day of diagnosis. PMID- 29623458 TI - In vivo kinematics of gait in posterior-stabilized and bicruciate-stabilized total knee arthroplasties using image-matching techniques. AB - PURPOSE: This study aimed to evaluate the effects of two types of total knee arthroplasty (TKA) designs: posterior-stabilized (PS) and bicruciate-stabilized (BCS) on in vivo kinematics during gait. METHODS: Continuous X-ray images of the gait were taken using a flat panel detector for 23 PS and BCS TKAs. We analyzed the tibiofemoral implant flexion angle, anteroposterior (AP) translation, axial rotation, and anterior/posterior cam-post contact using image-matching techniques. RESULTS: Double knee actions were demonstrated for the PS and BCS design (35 and 61%, respectively, p = 0.08). The tibiofemoral AP positions were significantly more posterior at peak extension (- 1.7 +/- 2.2 and 1.0 +/- 2.5 mm, respectively, p < 0.01) and anterior at peak flexion (1.3 +/- 2.3 and - 0.8 +/- 2.8 mm, respectively, p = 0.01) for the PS design than for the BCS design, with a significant difference in AP translation (3.0 +/- 3.9 mm anterior and 1.7 +/- 2.8 mm posterior, respectively, p < 0.01). Anterior/posterior tibial post contacts were found in 83/4% and 74/30% for the PS and BCS designs, respectively, with a significant difference in posterior contact (p = 0.72/0.04, respectively). CONCLUSION: The knee flexion pattern, tibiofemoral AP translation, axial rotation, and cam-post contact during gait varied, depending on the type of implant, the PS and BCS designs. PMID- 29623459 TI - The importance of combining structure and function to measure rates of progression in glaucoma. PMID- 29623460 TI - Cryopreservation of amniotic membrane with and without glycerol additive. AB - PURPOSE: Amniotic membrane (AM) is an essential tool in ocular surface reconstruction. In this study, we analyzed the differential effects of glycerol and straight storage at - 80 degrees C for up to 6 months on the structural, biological, and mechanical properties of amniotic membrane (AM). METHODS: Human placentae of 11 different subjects were analyzed. AMs were stored at - 80 degrees C, either with a 1:1 mixture of Dulbecco's modified Eagle medium and glycerol (glycerol) or without any medium or additives (straight). Histological image analysis, tensile strength, cell viability, and basic fibroblast growth factor (bFGF) secretion were evaluated at 0.5, 1, 3, and 6 months. RESULTS: Histologically, neither glycerol nor straight storage significantly altered the epithelial or stromal structure of the AM. However, the cell number of the stroma was significantly reduced during the freezing process, independently of the storage method (p = 0.05-0.001). Tensile strength and Young's modulus were not influenced by the storage method, but longer storage periods significantly increased the tensile strength of the AMs (p = 0.028). Cell viability was higher in glycerol rather than straight AM samples for up to 3 months of storage (p = 0.047-0.03). Secretion of bFGF at 3 months of storage was significantly higher in glycerol versus straight frozen AM samples (p = 0.04). DISCUSSION: Glycerol led to higher cell viability and higher bFGF secretion for up to 3 months of AM storage. However, no significant differences between the two methods were observed at 6 months of storage at - 80 degrees C. PMID- 29623461 TI - Event-based analysis of visual field change can miss fast glaucoma progression detected by a combined structure and function index. AB - PURPOSE: To investigate the relationship between progression assessed by the visual field guided progression analysis (GPA) and rates of structural and functional change in glaucoma eyes. METHODS: This was a longitudinal observational study of 135 eyes of 97 patients with glaucoma followed for an average of 3.5 +/- 0.9 years. All patients had standard automated perimetry (SAP) and retinal nerve fiber layer (RNFL) analysis with spectral domain optical coherence tomography (SDOCT), with an average of 6.8 +/- 2.3 visits. A control group of healthy eyes followed longitudinally was used to estimate age-related change. Visual field progression was assessed using the Humphrey Field Analyzer GPA. Estimates of retinal ganglion cell counts from SAP and SDOCT were used to obtain a combined index of glaucomatous damage (RGC index) according to a previously described algorithm. Progression by SDOCT and the retinal ganglion cell (RGC) index were defined as statistically significant (P < 0.05) slopes of change that were also faster than age-related change estimated from healthy eyes. RESULTS: From the 135 eyes, 15 (11%) progressed by GPA, 21 (16%) progressed by SDOCT, and 31 (23%) progressed by the RGC index. Twenty-one eyes showed progression by the RGC index that was missed by the GPA. These eyes had an average rate of change in estimated RGC counts of - 28,910 cells/year, ranging from two to nine times faster than expected age-related losses. CONCLUSION: Many glaucomatous eyes that are not found to be progressing by GPA may actually have fast rates of change as detected by a combined index of structure and function. PMID- 29623462 TI - Long-term follow-up of lamellar macular holes and pseudoholes over at least 5 years. AB - PURPOSE: To assess morphological and functional changes of lamellar macular holes and pseudoholes with or without vitrectomy and membrane peeling with at least 5 years follow-up. METHODS: Retrospective study of 73 eyes with lamellar macular hole (LH, n = 28), macular pseudohole (PH, n = 31), and pseudohole with cleaved edges (cleavedPH, n = 14). Forty-six eyes were merely observed without vitreoretinal intervention (observation group), and 27 eyes underwent vitrectomy with membrane peeling (vitrectomy group). Outcome measures were best corrected visual acuity (BCVA) and morphological retinal parameters evaluated with optical coherence tomography (TD-OCT and SD-OCT). RESULTS: Mean follow-up was 8.3 years (5-12); mean age was 67 years (46-84). In the observation group, median BCVA (logMAR) at first exam was 0.2 (LH), 0.1 (PH), 0.2 (cleavedPH) and at last exam 0.3 (LH, p = 0.02), 0.2 (PH), 0.15 (cleavedPH). In the vitrectomy group, median BCVA at first exam was 0.4 (LH), 0.3 (PH), 0.25 (cleavedPH); before vitrectomy BCVA was 0.5 (LH), 0.35 (PH), 0.35 (cleavedPH); and at last exam BCVA increased to 0.3 (LH), 0.2 (PH, p < 0.05), 0.1 (cleavedPH, p < 0.05). At last exam, BCVA of LH was significantly worse compared to PH and cleavedPH. In the observation group, 6 of 29 eyes with PH or cleavedPH showed a spontaneous resolution of the epiretinal membrane with improvement of the foveal contour. Nine of 16 eyes with LH and 2/20 eyes with PH presented lamellar hole-associated epiretinal proliferation (LHEP) in SD-OCT. CONCLUSIONS: LH, PH, and cleavedPH are often stable over a very long time. LH tends to worse visual function compared to PH and cleavedPH. A spontaneous separation of epiretinal membranes in the long-term is not uncommon. Vitreoretinal intervention should be considered in cases with significant visual loss or functional and morphological progression. PMID- 29623465 TI - Does medical students' personality have an impact on their intention to show empathic behavior? AB - Several studies have demonstrated a correlation between specific personal traits and empathy. However, it is not clear if persons with certain personality traits lack the intent to show empathic behavior or if other factors independent of their intent are affecting their empathic behavior. To answer this question, we asked 132 medical students to fill out questionnaires evaluating the General Intention to Show Empathic Behavior (GISEB) and the five personality traits measured by NEO Five-Factor Inventory (NEO-FFI). Additionally, we evaluated the influence of other factors, such as age, gender, curricular progress (second versus fourth year), and preferred specialization after graduation. We performed a Pearson's correlation and a regression analysis. Results indicate that the five personality traits and gender have little influence on the General Intention (GISEB), only extraversion (r = .221, 95% CI [.013-.394], p = .027), and agreeableness (r = .229, 95% CI [.021-.428], p = .022) correlated with the intention. The only predictor for General Intention (GISEB) was curricular progress (beta = - .27, p < .05), showing a decrease of General Intention to Show Empathic Behavior from second to fourth year of university (U = 1203.5, p = .002). A further finding indicates that gender and personality influence the students' wish of specialization after graduation: Agreeableness (F(12, 53) = 2.376, p = .016) impacted the preferred specialization. Our study demonstrated that medical students' personality might not notably impact the intention to show empathic behavior. Further research is needed to investigate moderating effects. PMID- 29623463 TI - Current perspectives on corneal collagen crosslinking (CXL). AB - Corneal collagen crosslinking has revolutionized the treatment of keratoconus and post-refractive corneal ectasia in the past decade. Corneal crosslinking with riboflavin and ultraviolet A is proposed to halt the progression of keratectasia. In the original "Conventional Dresden Protocol" (C-CXL), the epithelium is removed prior to the crosslinking process to facilitate better absorption of riboflavin into the corneal stroma. Studies analyzing its short- and long-term outcomes revealed that although there are inconsistencies as to the effectiveness of this technique, the advantages prevail over the disadvantages. Therefore, corneal crosslinking (CXL) is widely used in current practice to treat keratoconus. In an attempt to improve the visual and topographical outcomes of C CXL and to minimize time-related discomfort and endothelial-related side effects, various modifications such as accelerated crosslinking and transepithelial crosslinking methods have been introduced. The comparison of outcomes of these modified techniques with C-CXL has also returned contradictory results. Hence, it is difficult to clearly identify an optimal procedure that can overcome issues associated with the CXL. This review provides an up-to-date analysis on clinical and laboratory findings of these popular crosslinking protocols used in the treatment of keratoconus. It is evident from this review that in general, these modified techniques have succeeded in minimizing the immediate complications of the C-CXL technique. However, there were contradictory viewpoints regarding their effectiveness when compared with the conventional technique. Therefore, these modified techniques need to be further investigated to arrive at an optimal treatment option for keratoconus. PMID- 29623466 TI - Is tumor volume reduction during radiotherapy prognostic relevant in patients with stage III non-small cell lung cancer? AB - PURPOSE/OBJECTIVE(S): Lung cancer tumor volume reduction is common during radiation treatment (RT). The purpose of this study was to investigate tumor volume reduction ratio (VRR) and its correlation with outcomes in a cohort of patients with stage III non-small cell lung cancer (NSCLC) who underwent image guided radiochemotherapy (RCTx). MATERIALS/METHODS: Fifty patients with NSCLC treated with fractionated RT at our institution between 2013 and 2017 were included. The relationship between gross tumor volume (GTV) changes during RT (week 1 vs. week 5) and outcomes were evaluated. RESULTS: The median radiation dose delivered was 59.4 Gy (median fraction dose, 1.8 Gy). The median GTV before treatment was 119 cm3, with a median GTV change of - 40%. Patients with more volume reduction had poorer tumor control. A VRR > 40% was associated with a poorer OS and PFS in patients with non-adenocarcinoma (non-ADC) histology. In multivariate analysis, VRR during RT, and chemotherapy (CTx) administration remained related to PFS and OS, while initial GTV remained a significant determinant for OS. In subgroup analyses, and CTx (p = 0.038) affected PFS among non-ADC patients, with initial GTV (p = 0.058) and VRR (p = 0.08) showing non significant trends. Initial GTV (p = 0.023), VRR (p = 0.038), and CTx (p = 0.01) remained significant predictors for OS in the non-ADC group. CONCLUSION: Worse tumor control and OS in non-ADC patients are observed with more marked RT-induced tumor shrinkage, supporting the development of response-adaptive treatment strategies, particularly in non-ADC NSCLC patients. PMID- 29623467 TI - Allogeneic haematopoietic cell transplantation offers the chance of cure for patients with transformed follicular lymphoma. AB - PURPOSE: In patients with follicular lymphoma, secondary transformation to aggressive lymphoma (tFL) implies a poor prognosis. In principle, allogeneic haematopoietic cell transplantation (allo-HCT) offers a chance of cure for tFL but is rarely practiced. Aim of this retrospective multicenter study was to define the actual significance of allo-HCT in treatment of tFL. METHODS: The database of the German Registry for Stem Cell Transplantation (DRST) was screened for patients who underwent allo-HCT for tFL 1998-2008. Confirmation of tFL diagnosis by local and/or pathologists of the National NHL Board was mandatory for enrolment. Gaps in reported EBMT Minimum Essential Data datasets (MED-A) were filled by local DRST data managers. Relevant HCT outcome variables were evaluated by uni- and multivariate statistical analysis. RESULTS: Median age of enrolled 33 patients was 51 years with a post allo-HCT median follow-up of 7.1 years of surviving patients. At time of HCT 24/33 patients had chemosensitive disease. In 24/33 patients reduced intensity conditioning (RIC) was used. Estimated 1, 2, 5 year overall survival (OS) and event-free survival rates were 49/39/33, and 33/30/24%. Cumulative 100 days non-relapse mortality was 25%. Chemosensitive disease, RIC, and limited chronic GvHD were identified as independent prognostic factors for OS. CONCLUSIONS: Allo-HCT offers the chance of cure for tFL. PMID- 29623468 TI - Misses and near misses in diagnosing nodular fasciitis and morphologically related reactive myofibroblastic proliferations: experience of a referral center with emphasis on frequency of USP6 gene rearrangements. AB - Although harmless, reactive and benign neoplastic myo-/fibroblastic proliferations represent a diagnostic challenge in routine surgical pathology practice as reflected by their frequency among consultation cases. In addition to resembling each other, the prototypical nodular fasciitis (NF) and NF-like lesions can be mistaken for low-grade or aggressive sarcomas. USP6 translocation was reported recently as the molecular driver and potential diagnostic marker of NF. We reviewed 71 lesions with a diagnosis of NF (n = 48) or NF-like myofibroblastic proliferations (n = 23) and screened them for USP6 translocation by fluorescence in situ hybridization (FISH). Only one third of NFs were correctly diagnosed by submitting pathologists while one third was initially judged as malignant. NF was mentioned in the differential diagnosis in only half of the cases. A high Ki67/mitotic index, misleading immunohistochemistry (false positive h-caldesmon), and unusual sites/circumscription were main causes behind overdiagnosis as malignant. FISH analysis revealed USP6 translocation in 74.4% of NF cases. None of the reactive/reparative myofibroblastic proliferations showed USP6 translocation. NF is still significantly misdiagnosed by general surgical pathologists, with a higher tendency toward overdiagnosis of malignancy. Inclusion of NF in the differential diagnosis of any fibromyxoid soft tissue lesion and awareness of its diverse morphology are mandatory to avoid misdiagnoses with the risk of disastrous overtreatment. In the appropriate clinicopathological context, USP6 gene translocation is a valuable adjunct for diagnosis of NF, particularly in limited biopsies. Absence of the USP6 gene translocation in NF-like reparative pseudosarcomatous myofibroblastic proliferations underlines their reactive nature and distinguishes them from NF which is currently considered a benign neoplasm with a self-limiting "transient" growth phase. PMID- 29623469 TI - Role of ancillary techniques in profiling unclassified laryngeal malignancies. AB - Laryngeal biopsies, contrary to biopsies from many other sites of the body, very often contain minute amounts of tumour tissue that may consist of morphologically undifferentiated tumour only. In haematoxylin- and eosin-stained sections, there may be no indicative features of what specific tumour entity that is present. In the larynx, particularly small round cell neoplasms, primary or metastatic, often cause a diagnostic dilemma and where an incorrect diagnosis can induce substantial clinical consequences for the patient (e.g., primary neuroendocrine carcinomas vs metastatic variants, certain sarcomas). If sufficient/representative material has been obtained, the application of immunohistochemistry and/or molecular techniques should in virtually every case reveal the true nature of the malignancy. In cases with sparse amount of material, and therefore a limited number of sections to be cut, a careful and thoughtful stepwise approach is necessary to ascertain a reliable diagnosis, or at least guide the clinician to the most likely diagnoses. With today's advanced and widely available technology with an abundance of markers to discriminate different tumours, the use of the term "undifferentiated" should be largely unnecessary. In the exceptional, and indeed exceedingly rare cases, when a classification is not possible, even after repeat biopsy, we suggest that the laryngeal neoplasm is better termed "unclassified malignant neoplasm" rather than "undifferentiated malignant neoplasm". PMID- 29623471 TI - Chronic captopril treatment reveals the role of ANG II in cardiovascular function of embryonic American alligators (Alligator mississippiensis). AB - Angiotensin II (ANG II) is a powerful vasoconstrictor of the renin-angiotensin system (RAS) that plays an important role in cardiovascular regulation in adult and developing vertebrates. Knowledge of ANG II's contribution to developmental cardiovascular function comes from studies in fetal mammals and embryonic chickens. This is the first study to examine the role of ANG II in cardiovascular control in an embryonic reptile, the American alligator (Alligator mississippiensis). Using chronic low (~ 5-mg kg embryo-1), or high doses (~ 450 mg kg embryo-1) of captopril, an angiotensin-converting enzyme (ACE) inhibitor, we disrupted the RAS and examined the influence of ANG II in cardiovascular function at 90% of embryonic development. Compared to embryos injected with saline, mean arterial pressure (MAP) was significantly reduced by 41 and 72% under low- and high-dose captopril treatments, respectively, a greater decrease in MAP than observed in other developing vertebrates following ACE inhibition. Acute exogenous ANG II injection produced a stronger hypertensive response in low dose captopril-treated embryos compared to saline injection embryos. However, ACE inhibition with the low dose of captopril did not change adrenergic tone, and the ANG II response did not include an alpha-adrenergic component. Despite decreased MAP that caused a left shifted baroreflex curve for low-dose captopril embryos, ANG II did not influence baroreflex sensitivity. This study demonstrates that ANG II contributes to cardiovascular function in a developing reptile, and that the RAS contributes to arterial blood pressure maintenance during development across multiple vertebrate groups. PMID- 29623473 TI - Copper complex derived from S-benzyldithiocarbazate and 3-acetylcoumarin induced apoptosis in breast cancer cell. AB - Copper complexes have been widely studied for the anti-tumour application as cancer cells are reported to take up greater amounts of copper than normal cells. Preliminary study revealed that the newly synthesised copper complex [Cu(SBCM)2] displayed marked anti-proliferative towards triple-negative MDA-MB-231 breast cancer cells. Therefore, Cu(SBCM)2 has great potential to be developed as an agent for the management of breast cancer. The present study was carried out to investigate the mode of cell death induced by Cu(SBCM)2 towards MDA-MB-231 breast cancer cells. The inhibitory and morphological changes of MDA-MB-231 cells treated with Cu(SBCM)2 was determined by using MTT assay and inverted light microscope, respectively. The safety profile of Cu(SBCM)2 was also evaluated towards human dermal fibroblast (HDF) normal cells. Confirmation of apoptosis and cell cycle arrest were determined by flow cytometry analysis. The expression of p53, Bax, Bcl-2 and MMP2 protein were detected with western blot analysis. Cu(SBCM)2 significantly inhibited the growth of MDA-MB-231 cells in a dose dependent manner with GI50 18.7 +/- 3.06 uM. Indeed, Cu(SBCM)2 was less toxic towards HDF normal cells with GI50 31.8 +/- 4.0 uM. Morphological study revealed that Cu(SBCM)2-treated MDA-MB-231 cells experienced cellular shrinkage, membrane blebbing, chromatin condensation and formation of apoptotic bodies, suggesting that Cu(SBCM)2 induced apoptosis in the cells, which was confirmed by Annexin V/PI flow cytometry analysis. It was also found that Cu(SBCM)2 induced G2/M phase cell cycle arrest towards MDA-MB-231 cells. The induction of apoptosis and cell cycle arrest in the present study is possibly due to the down-regulation of the mutant p53 and MMP2 protein. In conclusion, Cu(SBCM)2 can be developed as a targeted therapy for the treatment of triple-negative breast cancer. PMID- 29623472 TI - Downregulation of the CpSRP43 gene expression confers a truncated light harvesting antenna (TLA) and enhances biomass and leaf-to-stem ratio in Nicotiana tabacum canopies. AB - MAIN CONCLUSION: Downregulation in the expression of the signal recognition particle 43 (SRP43) gene in tobacco conferred a truncated photosynthetic light harvesting antenna (TLA property), and resulted in plants with a greater leaf-to stem ratio, improved photosynthetic productivity and canopy biomass accumulation under high-density cultivation conditions. Evolution of sizable arrays of light harvesting antennae in all photosynthetic systems confers a survival advantage for the organism in the wild, where sunlight is often the growth-limiting factor. In crop monocultures, however, this property is strongly counterproductive, when growth takes place under direct and excess sunlight. The large arrays of light harvesting antennae in crop plants cause the surface of the canopies to over absorb solar irradiance, far in excess of what is needed to saturate photosynthesis and forcing them to engage in wasteful dissipation of the excess energy. Evidence in this work showed that downregulation by RNA-interference approaches of the Nicotiana tabacum signal recognition particle 43 (SRP43), a nuclear gene encoding a chloroplast-localized component of the photosynthetic light-harvesting assembly pathway, caused a decrease in the light-harvesting antenna size of the photosystems, a corresponding increase in the photosynthetic productivity of chlorophyll in the leaves, and improved tobacco plant canopy biomass accumulation under high-density cultivation conditions. Importantly, the resulting TLA transgenic plants had a substantially greater leaf-to-stem biomass ratio, compared to those of the wild type, grown under identical agronomic conditions. The results are discussed in terms of the potential benefit that could accrue to agriculture upon application of the TLA-technology to crop plants, entailing higher density planting with plants having a greater biomass and leaf-to-stem ratio, translating into greater crop yields per plant with canopies in a novel agronomic configuration. PMID- 29623474 TI - Effects of iron on the aggregation propensity of the N-terminal fibrillogenic polypeptide of human apolipoprotein A-I. AB - Specific mutations in APOA1 gene lead to systemic, hereditary amyloidoses. In ApoA-I related amyloidosis involving the heart, amyloid deposits are mainly constituted by the 93-residue N-terminal region of the protein, here indicated as [1-93]ApoA-I. Oxidative stress is known to be an enhancing factor for protein aggregation. In healthy conditions, humans are able to counteract the formation and the effects of oxidative molecules. However, aging and atmospheric pollution increase the concentration of oxidative agents, such as metal ions. As the main effect of iron deregulation is proposed to be an increase in oxidative stress, we analysed the effects of iron on [1-93]ApoA-I aggregation. By using different biochemical approaches, we demonstrated that Fe(II) is able to reduce the formation of [1-93]ApoA-I fibrillar species, probably by stabilizing its monomeric form, whereas Fe(III) shows a positive effect on polypeptide fibrillogenesis. We hypothesize that, in healthy conditions, Fe(III) is reduced by the organism to Fe(II), thus inhibiting amyloid formation, whereas during ageing such protective mechanisms decline, thus exposing the organism to higher oxidative stress levels, which are also related to an increase in Fe(III). This alteration could contribute to the pathogenesis of amyloidosis. PMID- 29623475 TI - Diagnostic value of FDG-PET/CT for lateral pelvic lymph node metastasis in rectal cancer treated with preoperative chemoradiotherapy. AB - BACKGROUND: The aim of this study was to elucidate the diagnostic value of 18F fluorodeoxyglucose positron emission tomography (PET)-computed tomography (CT) for lateral pelvic lymph node (LPN) metastasis in rectal cancer treated with preoperative chemoradiotherapy (CRT). METHODS: Eighteen rectal cancer patients with enlarged (>= 8 mm) LPNs were treated with CRT followed by total mesorectal excision with LPN dissection during 2012-2015. After CRT, LPN maximum standard uptake values (SUVmax) were measured using PET/CT and long diameters of LPNs were measured using CT or magnetic resonance imaging (MRI). LPN size and SUVmax were compared with pathological status in the resected specimen. Radiologically identified nodes were matched with surgically resected nodes by separate examination of 4 lymph nodal regions: internal iliac, obturator, external iliac and common iliac lymph nodes. RESULTS: In total, 34 LPNs were located by CT or MRI. Metastatic LPNs were significantly larger than non-metastatic LPNs (size, mean +/- standard deviation: 13.0 +/- 8.3 vs. 4.9 +/- 3.5 mm, p < 0.01). SUVmax was determinable for 28 of the LPNs, among which metastatic LPNs were found to have significantly higher SUVmax than non-metastatic LPNs (mean +/- standard deviation: 2.2 +/- 1.3 vs. 1.2 +/- 0.3, p < 0.01). Receiver operating characteristic analysis suggested optimal cutoff values of size = 12 mm which had an accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 82.1, 70.6, 100, 100, and 68.8%, respectively. An SUVmax = 1.6 had an accuracy, sensitivity, specificity, PPV, and NPV of 85.7, 76.5, 100, 100, and 73.3%, respectively. When LPNs that were >= 12 mm in size and/or had an SUV >= 1.6, the accuracy, sensitivity, specificity, PPV, and NPV were 92.9, 88.2, 100, 100, and 84.6%, respectively. CONCLUSIONS: After CRT, PET/CT alone or in combination with CT and MRI can predict the presence of metastatic LPN with a high degree of accuracy. PET/CT may be useful in selecting patients with rectal cancer who would benefit from LPN dissection in addition to TME. These results need to be confirmed by larger studies. PMID- 29623477 TI - Future heat stress arising from climate change on Iran's population health. AB - Climate change-induced extreme heat events are becoming a major issue in different parts of the world, especially in developing countries. The assessment of regional and temporal past and future change in heat waves is a crucial task for public health strategies and managements. The historical and future heat index (HI) time series are investigated for temporal change across Iran to study the impact of global warming on public health. The heat index is calculated, and the nonparametric trend assessment is carried out for historical time series (1981-2010). The future change in heat index is also projected for 2020-2049 and 2070-2099 periods. A rise in the historical heat index and extreme caution conditions for summer and spring seasons for major parts of Iran are notable for historical (1981-2010) series in this study. Using different climate change scenarios shows that heat index will exceed the critical threshold for human adaptability in the future in the country. The impact of climate change on heat index risk in Iran is significant in the future. To cope with this crucial situation, developing early warning systems and health care strategies to deal with population growth and remarkable socio-economic features in future is essential. PMID- 29623476 TI - Transcription and microRNA Profiling of Cultured Human Tympanic Membrane Epidermal Keratinocytes. AB - The human tympanic membrane (TM) has a thin outer epidermal layer which plays an important role in TM homeostasis and ear health. The specialised cells of the TM epidermis have a different physiology compared to normal skin epidermal keratinocytes, displaying a dynamic and constitutive migration that maintains a clear TM surface and assists in regeneration. Here, we characterise and compare molecular phenotypes in keratinocyte cultures from TM and normal skin. TM keratinocytes were isolated by enzymatic digestion and cultured in vitro. We compared global mRNA and microRNA expression of the cultured cells with that of human epidermal keratinocyte cultures. Genes with either relatively higher or lower expression were analysed further using the biostatistical tools g:Profiler and Ingenuity Pathway Analysis. Approximately 500 genes were found differentially expressed. Gene ontology enrichment and Ingenuity analyses identified cellular migration and closely related biological processes to be the most significant functions of the genes highly expressed in the TM keratinocytes. The genes of low expression showed a marked difference in homeobox (HOX) genes of clusters A and C, giving the TM keratinocytes a strikingly low HOX gene expression profile. An in vitro scratch wound assay showed a more individualised cell movement in cells from the tympanic membrane than normal epidermal keratinocytes. We identified 10 microRNAs with differential expression, several of which can also be linked to regulation of cell migration and expression of HOX genes. Our data provides clues to understanding the specific physiological properties of TM keratinocytes, including candidate genes for constitutive migration, and may thus help focus further research. PMID- 29623479 TI - Age, sex, and puberty related development of the corpus callosum: a multi technique diffusion MRI study. AB - The corpus callosum is integral to the central nervous system, and continually develops with age by virtue of increasing axon diameter and ongoing myelination. Magnetic resonance imaging (MRI) techniques offer a means to disentangle these two aspects of white matter development. We investigate the profile of microstructural metrics across the corpus callosum, and assess the impact of age, sex and pubertal development on these processes. This study made use of two independent paediatric populations. Multi-shell diffusion MRI data were analysed to produce a suite of diffusion tensor imaging, neurite orientation dispersion and density imaging, and apparent fibre density (AFD) metrics. A multivariate profile analysis was performed for each diffusion metric across ten subdivisions of the corpus callosum. All diffusion metrics significantly varied across the length of the corpus callosum. AFD exhibited a strong relationship with age across the corpus callosum (partial eta2 = 0.65), particularly in the posterior body of the corpus callosum (partial eta2 = 0.72). In addition, females had significantly higher AFD compared with males, most markedly in the anterior splenium (partial eta2 = 0.14) and posterior genu (partial eta2 = 0.13). Age matched pubertal group differences were localised to the splenium. We present evidence of a strong relationship between apparent fibre density and age, sex, and puberty during development. These results are consistent with ex vivo studies of fibre morphology, providing insights into the dynamics of axonal development in childhood and adolescence using diffusion MRI. PMID- 29623478 TI - Continued Tumor Reduction of Metastatic Pheochromocytoma/Paraganglioma Harboring Succinate Dehydrogenase Subunit B Mutations with Cyclical Chemotherapy. AB - Patients harboring germline mutations in the succinate dehydrogenase complex subunit B (SDHB) gene present with pheochromocytomas and paragangliomas (PPGL) that are more likely malignant and clinically aggressive. The combination chemotherapy cyclophosphamide, vincristine, and dacarbazine (CVD) was retrospectively evaluated in patients with SDHB-associated metastatic PPGL.Query Twelve metastatic PPGL patients harboring SDHB mutations/polymorphisms with undetectable SDHB immunostaining were treated with CVD. CVD therapy consisted of 750 mg/m2 cyclophosphamide with 1.4 mg/m2 vincristine on day 1 and 600 mg/m2 dacarbazine on days 1 and 2, every 21-28 days. Treatment outcome was determined by RECIST criteria as well as determination of response duration and progression free and overall survivals. A median of 20.5 cycles (range 4-41) was administered. All patients had tumor reduction (12-100% by RECIST). Complete response was seen in two patients, while partial response was observed in 8. The median number of cycles to response was 5.5. Median duration of response was 478 days, with progression-free and overall survivals of 930 and 1190 days, respectively. Serial [18F]-fluorodeoxyglucose positron emission tomography and computed tomography imaging demonstrated continued incremental reduction in maximal standardized uptake values (SUVmax) values in 26/30 lesions. During treatment administration, the median SUV decreased from > 25 to < 6, indicating the efficacy of chemotherapy over a prolonged period of time. Prolonged therapy results in continued incremental tumor reduction, and is consistent with persistent drug sensitivity. CVD chemotherapy is recommended to be considered part of the initial management in patients with metastatic SDHB-related PPGL. PMID- 29623480 TI - The segmentation of the posterior cerebral artery: a microsurgical anatomic study. AB - There are still different descriptions of the segmentation of the posterior cerebral artery, although there is a radiological and anatomical consensus on the segmentation of the anterior and the middle cerebral artery. This study aims to define the most appropriate localization for origin and end points of the segments through reviewing the segmentation of the posterior cerebral artery. The segments and the cortical branches originating from those segments of the 40 posterior cerebral arteries of 20 cadaver brains were examined under operating microscope. In this research, the P1, P2, P3, P4, and P5 classification of the segmentation of the posterior cerebral artery is redefined. This redefinition was made to overcome the complexities of previous definitions. The P1 segment in this research takes its origin from the basilar tip and ends at the junction with the posterior communicating artery. The average diameter of this segment at the origin was 2.21 mm (0.9-3.3), and the average length was 6.8 mm (3-12). The P2 segment extends from the junction with the posterior communicating artery to the origin of the lateral temporal trunk. This point usually situates on one level of posterior of the cerebral peduncle. The average diameter of this segment at the origin was 2.32 mm (1.3-3.1), and the average length was 20.1 mm (11-26). The P3 segment extends from the origin of the lateral temporal trunk to the colliculus where both the posterior cerebral arteries are the nearest to each other (quadrigeminal point) and is located at the anterior-inferior of the splenium. The average diameter of this segment at the origin was 1.85 mm (1.2-2.7), and the average length was 16.39 mm (9-28). The P4 begins at the quadrigeminal point and ends at the top of the cuneus. The average diameter of this segment at the origin was 1.55 mm (1.1-2.2). While the P5 segment is named as the terminal branches of the major terminal branches of the posterior cerebral artery, no definite border was found between the P4 and the P5 segments. In this study, the segmentation of the posterior cerebral artery, developed by Krayenbuhl and Yasargil, was redefined to be more appropriate for radiological and anatomical purposes. PMID- 29623481 TI - Effect of Antazoline on Electrophysiological Properties of Atrial Muscle and Conduction System of the Heart. AB - PURPOSE: Antazoline is a first-generation antihistaminic agent with additional anticholinergic properties and antiarrhythmic potential. Recent data shows its high effectiveness in sinus rhythm restoration among patients with paroxysmal atrial fibrillation. The effect of antazoline on electrophysiological parameters of the heart in vivo has not yet been examined. The aim of this study was to evaluate changes in electrophysiological parameters of the heart muscle and conduction system as a response to increasing doses of antazoline. METHODS: After successful ablation of supraventricular arrhythmias, the electrophysiological parameters: sinus rhythm cycle length (SRCL), AH, HV, QRS, QT, QTc intervals, Wenckebach point (WP), sinus node recovery period (SNRT), intra- (hRA-CSos) and interatrial conduction time (hRA-CSd), right and left atrium refractory period (RA-; LA-ERP), and atrioventricular node refractory period (AVN-ERP) were assessed initially and after 100, 200, and 300 mg of antazoline given intravenously. RESULTS: Fifteen patients (8 males, 19-72 years old) undergoing EPS and RF ablation were enrolled. After 100 mg bolus, a significant reduction in SRCL was noticed. After antazoline administration, significant prolongation of HV, QRS, QTc, hRA-CSos, hRA-CSd intervals, RA- and LA-ERP and reduction of SRCL were observed. After a total dose of 300 mg, QT interval prolonged significantly. Increasing the dose of antazoline had no impact on AH, Wenckebach point, AVN-ERP, and SNRT. CONCLUSION: Antazoline has an effect on electrophysiological parameters of the atrial muscle and has rapid onset of action. No negative effect on sinus node function and atrioventricular conduction in a unique property among antiarrhythmic drugs. PMID- 29623482 TI - Nivolumab-induced acute granulomatous tubulointerstitial nephritis in a patient with gastric cancer. AB - We here report a case of nivolumab-induced acute granulomatous tubulointerstitial nephritis in a patient with gastric cancer. A 68-year-old woman with recurrent gastric cancer developed acute kidney injury associated with kidney enlargement and urinary leukocytes after 38 cycles of nivolumab treatment. A diagnosis of acute granulomatous tubulointerstitial nephritis was made based on kidney biopsy findings. Immunohistochemistry revealed expression of programmed cell death ligand 1 (PD-L1) in degenerated epithelial cells of collecting tubules. Among infiltrating immune cells, aggregation of T cells was more extensive than that of B cells, with CD4+ T cells outnumbering CD8+ T cells, consistent with the relative numbers of these cells in the circulation. Treatment with methylprednisolone (1.0 mg/kg daily) led to a rapid improvement in renal function and reduction in the number of circulating CD4+ T cells. Prompt administration of high-dose corticosteroid is thus recommended after diagnosis of this adverse event of nivolumab treatment by kidney biopsy. PMID- 29623483 TI - Genome instability syndromes caused by impaired DNA repair and aberrant DNA damage responses. AB - Maintenance of genome integrity is essential for all organisms because genome information regulates cell proliferation, growth arrest, and vital metabolic processes in cells, tissues, organs, and organisms. Because genomes are constantly exposed to intrinsic and extrinsic genotoxic stress, cellular DNA repair machinery and proper DNA damage responses (DDR) have evolved to quickly eliminate genotoxic DNA lesions, thus maintaining the genome integrity suitably. In human, germline mutations in genes involved not only in cellular DNA repair pathways but also in cellular DDR machinery frequently predispose hereditary diseases associated with chromosome aberrations. These genetic syndromes typically displaying mutations in DNA repair/DDR-related genes are often called "genome instability syndromes." Common features of these hereditary syndromes include a high incidence of cancers and developmental abnormalities including short stature, microcephaly, and/or neurological deficiencies. However, precisely how impaired DNA repair and/or dysfunctional DDR pathologically promote(s) these syndromes are poorly understood. In this review article, we summarize the clinical symptoms of several representatives "genome instability syndromes" and propose the plausible pathogenesis thereof. PMID- 29623484 TI - Symptoms of Internet Gaming Disorder in Youth: Predictors and Comorbidity. AB - Internet gaming disorder (IGD) was included in the Addendum to DSM-5 as a condition for further study. Studies of community samples using a diagnostic interview are lacking, and evaluations of the proposed symptoms, comorbidities, and predictors of IGD are scarce. To provide such information participants in a Norwegian prospective community study were assessed with a clinical interview at age 10 years. Symptoms of other psychiatric disorders were measured with the Child and Adolescent Psychiatric Assessment at ages 8 and 10 (n = 740). Children, parents, and teachers provided information on demographics, temperament, intelligence, executive functions, self-concept, social skills, victimization, emotion regulation, family climate, and parenting. Results indicated that IGD was present in 1.7% (95% confidence interval, 0.7-2.7) of the participants (3.0% boys and 0.5% girls). Factor analysis revealed two factors: heavy involvement and negative consequences. The positive predictive value of withdrawal, tolerance, and unsuccessful attempts to control gaming symptoms to the disorder was low. Symptoms of other common disorders correlated weakly with IGD-symptoms (i.e., from r = 0.07 to r = 0.15). Upon adjusting for gender and gaming at age 8, only limited social and emotion regulation skills at age 8 predicted more age-10 IGD symptoms. In conclusion, IGD is already present in a small percentage of Norwegian 10-year olds. At least three of the proposed symptoms -- withdrawal, tolerance and unsuccessful attempts to control gaming -- merit further study given their weak associations with the disorder. Symptoms of IGD are only marginally associated with symptoms of other psychiatric disorders and only predicted by social skills and emotion regulation deficits. PMID- 29623485 TI - Imaging of neurovascular emergencies in pregnancy and puerperium. AB - Acute neurovascular events, though rare, can complicate pregnancy and postpartum period. It is important to be aware of these clinical conditions for reducing maternal and fetal morbidity and mortality. In this review, we present a few important neurovascular emergencies and their imaging manifestations by various imaging modalities-computed tomography (CT), magnetic resonance imaging (MRI), and digital subtraction angiography (DSA)-which presented at our institution in the peripartum period. PMID- 29623486 TI - Darwin's two theories, 1844 and 1859. AB - Darwin's first two, relatively complete, explicit articulations of his theorizing on evolution were his Essay of 1844 and On the Origin of Species published in 1859. A comparative analysis concludes that they espoused radically different theories despite exhibiting a continuity of strategy, much common structure and the same key idea. Both were theories of evolution by means of natural selection. In 1844, organic adaptation was confined to occasional intervals initiated and controlled by de-stabilization events. The modified descendants rebalanced the particular "plant and animal forms ... unsettled by some alteration in their circumstances." But by 1859, organic adaptation occurred continuously, potentially modifying the descendants of all organisms. Even natural selection, the persistent core of Darwin's theorizing, does not prove to be a significant basis for theory similarity. Consequently, Darwin's Origin theory cannot reasonably be considered as a mature version of the Essay. It is not a modification based on adjustments, further justifications and the integration of a Principle of Divergence. The Origin announced a new "scientific paradigm" while the Essay did little more than seemingly misconfigure the operation of a novel mechanism to extend varieties beyond their accepted bounds, and into the realm of possible new species. Two other collections of Darwin's theorizing are briefly considered: his extensive notes of the late 1830s and his contributions to the famous meeting of 1 July 1858. For very different reasons, neither constitutes a challenge to the basis for this comparative study. It is concluded that, in addition to the much-debated social pressures, an unacknowledged further reason why Darwin did not publish his theorizing until 1859, could have been down to his perceptive technical judgement: wisely, he held back from rushing to publish demonstrably flawed theorizing. PMID- 29623487 TI - Atezolizumab in Metastatic Urothelial Carcinoma Outside Clinical Trials: Focus on Efficacy, Safety, and Response to Subsequent Therapies. AB - BACKGROUND: Little is known about the outcomes, safety, and response to subsequent therapies of patients with metastatic urothelial carcinoma (mUC) treated with atezolizumab outside clinical trials. OBJECTIVES: The objectives of the study include to report the clinical efficacy and safety of atezolizumab, and the response to future therapies in clinical practice outside clinical trials. PATIENT AND METHODS: This is a retrospective, single-center study including consecutive patients with confirmed mUC who received at least one dose of atezolizumab 1200 mg every 3 weeks between May 2016 and April 2017. RESULTS: Seventy-nine patients, median age 72 years (range 29-93), 71% men and 76% ECOG PS 0-1, were identified. Most patients (79%) had primary cancer in the bladder, 62% had prior surgery, and 75% received at least one prior line of treatment (34 patients had prior cisplatin-based chemotherapy). Best response included 18% partial response, 29% stable disease, and 53% progressive disease. Patients were on atezolizumab for a median of 2.7 months (95%CI, 1.8-3.6) and median PFS was 3.2 months (95%CI, 1.6-4.8). A total of 33 (42%) patients had significant (any cause) AEs, including grade 4 hyperbilirubinemia in two patients; no toxic deaths were reported. At time of data analysis, only 18% of patients received at least one subsequent line of treatment for a median of 1.8 months (95%CI, 0.0-5.0) while 42% were referred to palliative care/hospice or died. CONCLUSIONS: Patients with mUC who progressed on atezolizumab were unlikely to receive subsequent systemic treatments and the benefit of those treatments appeared limited in our cohort. The findings may impact timing and designs of clinical trials in mUC. PMID- 29623488 TI - Correction to: Inhalative sedation with small tidal volumes under venovenous ECMO. AB - In the original publication, the affiliations of fourth and fifth authors were published incorrectly. The corrected affiliations are given in this correction. PMID- 29623489 TI - BI1 is associated with microvascular protection in cardiac ischemia reperfusion injury via repressing Syk-Nox2-Drp1-mitochondrial fission pathways. AB - BACKGROUND: Mitochondrial fission has been identified as the pathogenesis underlying the development of cardiac microvascular ischemia reperfusion (IR) injury, although the regulatory signaling upstream from fission is far from clear. Bax inhibitor is a novel anti-apoptotic factor, and, however, its role of cardiac microvascular IR injury and mitochondrial homeostasis remains unclear. METHODS: The cardiac microvascular IR injury was performed in WT mice and BI1 transgenic (BITG) mice. The alterations of microvascular structure and function were detected via electron microscope, immunohistochemistry and immunofluorescence in vivo. Cardiac microvascular endothelial cells were isolated form WT and BITG mice and underwent hypoxia/reoxygenation injury in vitro. Cellular viability and apoptosis were analyzed via MTT assay and caspase-3 activity. Mitochondrial function, morphology and apoptosis were detected. Signaling pathways were analyzed via inhibitor, siRNA and mutant plasmid. RESULTS: Herein, we demonstrated that Bax inhibitor 1 (BI1) was downregulated following cardiac microvascular IR injury, and its expression correlated negatively with microvascular collapse, endothelial cell apoptosis and mitochondrial damage. However, compared to wild-type mice, BI1 transgenic mice were actually protected from the acute microvascular injury and mitochondrial dysfunction. Functional studies illustrated that reintroduced BI1 directly interacted with and inhibited the Syk pathway, leading to the inactivation of Nox2. Subsequently, less Nox2 was associated with ROS downregulation, inhibiting Drp1 phosphorylated activation. Through repression of the Syk-Nox2-Drp1 signaling axis, BI1 strongly disrupted mitochondrial fission, abolishing mitochondrial apoptosis and thus sustaining endothelial cell viability. CONCLUSIONS: In summary, our report illustrates that BI1 functions as a novel microvascular guardian in cardiac IR injury that operates via inhibition of the Syk-Nox2-Drp1 mitochondrial fission signaling axis. Thus, novel therapeutic strategies to regulate the balance between BI1 and mitochondrial fission could provide a survival advantage to microvasculature following IR stress. PMID- 29623490 TI - Food Allergy. AB - PURPOSE OF REVIEW: The goal of this review is to present an updated summary of the natural history of major childhood and adult food allergies and report recent advances in potential treatments for food allergy. RECENT FINDINGS: The most common childhood food allergies are typically outgrown by adolescence or adulthood. However, peanut/tree nut allergies appear to more commonly persist into adulthood. Adults can develop new IgE-mediated food allergies; the most common is oral allergy syndrome. There are multiple different approaches being tried as possible treatments for food allergy. The prevalence of food allergy appears to be increasing but the varied approaches to treatment are being actively pursued such that an approved modality may not be too far in the future. PMID- 29623491 TI - The complex alteration in the network of IL-17-type cytokines in patients with hereditary angioedema. AB - Hereditary angioedema (HAE) is a rare autosomic-dominant disorder characterized by a deficiency of C1 esterase inhibitor which causes episodic swellings of subcutaneous tissues, bowel walls and upper airways that are disabling and potentially life-threatening. We evaluated n = 17 patients with confirmed HAE diagnosis during attack and remission state and n = 19 healthy subjects. The samples were tested for a panel of IL (Interleukin)-17-type cytokines (IL-1beta, IL-6, IL-10, granulocyte-macrophage colony stimulating factor (GM-CSF), IL-17, IL 21, IL-22, IL-23) and transforming growth factor-beta (TGF-beta) subtypes. Data indicate that there are variations of cytokine levels in HAE subjects comparing the condition during the crisis respect to the value in the remission phase, in particular type 17 signature cytokines are increased, whereas IL-23 is unmodified and TGF-beta3 is significantly reduced. When comparing healthy and HAE subjects in the remission state, we found a significant difference for IL-17, GM-CSF, IL 21, TGF-beta1 and TGF-beta2 cytokines. These results confirm and extend our previous findings indicating that in HAE there is operating an inflammatory activation process, which involves also T helper 17 (Th17) cytokines and TGF-beta isoforms, associated with localized angioedema attacks and characterized by elevated bradykinin levels. PMID- 29623492 TI - Therapy for Crohn's Disease: a Review of Recent Developments. AB - PURPOSE OF REVIEW: To review recent advances in the treatment of Crohn's disease. RECENT FINDINGS: Several key advances are highlighted, including the increasing role of treatment algorithms and where new therapies can be used most effectively, the appropriate use of therapeutic drug monitoring, optimal management of post-surgical patients, and the role of multi-disciplinary clinics. The last several years have seen a number of exciting developments in the field of Crohn's therapy. This review covers research advances including updated treatment algorithms focusing on identifying patient risk as well as the role of drug monitoring in managing the disease. We also review the optimal management of post-surgical patients as well as new biologics and biosimilars. Finally, we describe innovations in care delivery including multi-disciplinary clinics and emerging evidence from developing therapeutics. PMID- 29623493 TI - Expert's comment concerning Grand Rounds case entitled "Management of a posterior gunshot injury with a floating pedicle and cerebrospinal fluid leak" by A. Bourghli, S. Abouhashem, R. Abo Wali, I. Obeid, L. Boissiere, J. M. Vital, M. Al Sarawan (Eur Spine J; 2018. DOI 10.1007/s00586-018-5537-9). PMID- 29623494 TI - Comment to: "Preventing parastomal hernia with modified stapled mesh stoma reinforcement technique (SMART) in patients who underwent surgery for rectal cancer: a case-control study." By Canda AE. (Hernia. 2018 Jan 5. doi: 10.1007/s10029-017-1723-7. [Epub ahead of print]). PMID- 29623495 TI - Reply to Comment to: Preventing parastomal hernia with modified stapled mesh stoma reinforcement technique (SMART) in patients who underwent surgery for rectal cancer: a case-control study. Li J, Zhang W. PMID- 29623496 TI - An update in international trends in incidence rates of thyroid cancer, 1973 2007. AB - PURPOSE: Over the past several decades, there has been a reported increase in the incidence of thyroid cancer in many countries. We previously reported an increase in thyroid cancer incidence across continents between 1973 and 2002. Here, we provide an update on the international trends in thyroid cancer between 2003 and 2007. METHODS: We examined thyroid cancer incidence data from the Cancer Incidence in Five Continents (CI5) database for the period between 1973 and 2007 from 24 populations in the Americas, Asia, Europe, Africa and Oceania, and report on the time trends as well as the distribution by histologic type and gender worldwide. RESULTS: The incidence of thyroid cancer increased during the period from 1998-2002 to 2003-2007 in the majority of populations examined, with the highest rates observed among women, most notably in Israel and the United States SEER registry, at over 14 per 100,000 people. This update suggests that incidence is rising in a similar fashion across all regions of the world. The histologic and gender distributions in the updated CI5 are consistent with the previous report. CONCLUSIONS: Our analysis of the published CI5 data illustrates that the incidence of thyroid cancer increased between 1998-2002 and 2003-2007 in most populations worldwide, and rising rates continue in all regions of the world. PMID- 29623497 TI - Poly(3,4-ethylenedioxythiophene) doped with engineered carbon quantum dots for enhanced amperometric detection of nitrite. AB - An electrochemical sensor for nitrite was fabricated by modifying a glassy carbon electrode (GCE) with the conducting polymer poly(3,4-ethylenedioxythiophene) (PEDOT) that is doped with carbon quantum dots (CQDs). The negatively charged CQDs were doped into PEDOT via electrodeposition to form a conducting polymer nanocomposite on the GCE. The electrode surface has a flake-like nanostructure and a large specific surface area. The elemental mapping analysis revealed that the CQDs are uniformly distributed across the whole nanocomposite. As a result of the superior catalytic activity of CQDs and the good conductivity of PEDOT, the modified GCE displays excellent electrocatalytic activity towards the oxidation of nitrite, and the oxidation peak current is ten times higher than that of a PEDOT modified GCE without CQDs. Under optimum conditions and at a working voltage of 0.80 V (vs. Ag/AgCl), the sensor has a linear response in the 0.5-1110 MUM nitrite concentration range, and an 88 nM limit of detection (at S/N = 3). Three different electrodes prepared under the same experimental conditions were applied for the detection of nitrite, and the RSD was 3.1%. The same sensor was employed to quantify nitrite in three replicate measurements, and the RSD was 2.2%. Graphical abstract Poly(3,4-ethylenedioxythiophene) (PEDOT) was doped with carbon quantum dots and deposited on a glassy carbon electrode to obtain an amperometric sensor for nitrite. PMID- 29623498 TI - The Function of Play for Coping and Therapy with Children Exposed to Disasters and Political Violence. AB - PURPOSE OF REVIEW: The objectives were to identify specific characteristics and patterns of children's play following events of political violence or disasters, examine their associations with risk and resilience, and explore their implications for preventive and therapeutic intervention. RECENT FINDINGS: Patterns of individual, dyadic, and social play are associated with measures of children's adaptation following collective traumatic events. Modifying the traditional child-centered play therapy, by integrating CBT principles or including parents, may increase efficacy. Preventive interventions in the aftermath of collective traumatic events must address children's need to play in safe spaces, with the support of significant adults. Recognizing that posttraumatic play is a multifaceted phenomenon implies the need for more individualized play therapy models, varying in level of therapist's activity and techniques employed. Research is needed to clarify the validity of play measures for assessing adaptation and to study the effectiveness of integrative play-based models. PMID- 29623499 TI - A low phase angle measured with bioelectrical impedance analysis is associated with osteoporosis and is a risk factor for osteoporosis in community-dwelling people: the Yakumo study. AB - : Although the phase angle has been reported to be related to predictive factors and therapeutic effects in various diseases, its relation with osteoporosis is unclear. In our large prospective survey of community-dwelling people, a low phase angle was related with osteoporosis, and it could be a predictor of osteoporosis. PURPOSE: The phase angle measured with bioelectrical impedance analysis (BIA) is one of the clinically important impedance parameters, and it is a predictor of prognosis and mortality for several diseases. The present cross sectional study aimed to elucidate the association between osteoporosis and variables measured with BIA, including the phase angle. METHODS: The study included 307 participants from an annual health checkup. All participants underwent measurement of bone status by quantitative ultrasound and body composition by BIA. Osteoporosis was diagnosed according to the WHO classification, and statistical comparisons were conducted between normal individuals and osteoporosis patients. RESULTS: Age, proteins, minerals, and the phase angle were significantly different between normal individuals and osteoporosis patients (p < 0.001). Furthermore, after controlling for age and sex, proteins, minerals, and the phase angle were significantly lower in osteoporosis patients than those in normal individuals (p < 0.001). In multivariate logistic regression analysis, older age and a low phase angle were risk factors for osteoporosis. Additionally, multiple regression analysis showed that age, sex, proteins, minerals, and the appendicular skeletal muscle index were significantly related to the phase angle. CONCLUSIONS: The phase angle is a predictor of osteoporosis, which is unaffected by age and sex, and a lower phase angle is associated with greater probability of osteoporosis. The phase angle can be easily measured, and osteoporosis can be confirmed even at home. This may facilitate early diagnosis and treatment, which may be useful for preventing diseases related to osteoporosis. PMID- 29623502 TI - Repurposing Waste Streams: Lessons on Integrating Hospital Food Waste into a Community Garden. AB - There have been increasing efforts in recent decades to divert institutional food waste into composting programs. As major producers of food waste who must increasingly demonstrate community benefit, hospitals have an incentive to develop such programs. In this article, we explain the emerging opportunity to link hospitals' food services to local community gardens in order to implement robust composting programs. We describe a partnership model at our hospital in central Pennsylvania, share preliminary outcomes establishing feasibility, and offer guidance for future efforts. We also demonstrate that the integration of medical students in such efforts can foster systems thinking in the development of programs to manage hospital waste streams in more ecologically-friendly ways. PMID- 29623500 TI - Oxaliplatin rechallenge in metastatic colorectal cancer patients after prior oxaliplatin treatment. AB - Because the number of cytotoxic agents available for the treatment of metastatic colorectal cancer (mCRC) is limited, rechallenge with the same chemotherapy agents can provide a continuum of treatment. This study investigated the efficacy and feasibility of oxaliplatin rechallenge in mCRC patients who had been previously exposed to oxaliplatin-based chemotherapy. Patients were included if they had mCRC and evaluable disease, had remained disease-free or progression free for at least 6 months after the last dose of prior oxaliplatin-based therapy, and were retreated with oxaliplatin therapy. Between January 2009 and May 2014, 110 patients were retreated with oxaliplatin-based regimens; of these, 42 (38.2%) had received prior oxaliplatin as adjuvant chemotherapy and 68 (61.8%) as palliative chemotherapy. The overall response rate to oxaliplatin rechallenge was 30.9% (34/110), and the disease control rate was 68.2% (75/110), with one patient achieving complete response, 33 achieving partial response, and 41 having stable disease. Median progression-free survival and overall survival following oxaliplatin rechallenge were 5.9 months (95% confidence interval [CI], 4.4-7.4 months) and 18.5 months (95% CI, 14.0-23.0 months), respectively. Sixteen patients experienced grade 2 or 3 neuropathy. Ten patients experienced any grade hypersensitivity reaction within four cycles of treatment, including six who stopped treatment due to grade 3 or 4 hypersensitivity reactions. Rechallenge with oxaliplatin-based therapy may be an option for patients who achieve at least 6 months of disease-free or progression-free survival with prior oxaliplatin based chemotherapy. However, neurotoxicity and hypersensitivity reactions should be carefully monitored in this setting. PMID- 29623503 TI - Barriers and Facilitators to Melanoma Prevention and Control Behaviors Among At Risk Children. AB - Melanoma prevention is essential for children who are at elevated risk for the disease due to family history. However, children who carry a familial risk for the disease do not optimally adhere to recommended melanoma preventive behaviors. The current study sought to identify perceived barriers to and facilitators of children's engagement in melanoma preventive behaviors among children at elevated risk for melanoma due to family history of the disease (i.e., having a parent with a history of melanoma) from both parents' and childrens' perspectives. Qualitative methods were employed and consisted of separate focus group discussions with children (ages 8-17 years, n = 37) and their parents (n = 39). Focus group transcripts were coded using content analysis. Parents and children reported a number of barriers and facilitators, including on the individual (e.g., knowledge and awareness, preferences), social (e.g., peer influences, family modeling and communication), and contextual (e.g., healthcare provider communication) levels. The identified categories of barriers and facilitators both confirm and extend the literature documenting the reasons children who are at elevated risk for melanoma do not engage in melanoma prevention and control behaviors. Programs aiming to decrease melanoma risk among children of melanoma survivors could help families address their barriers to preventive behavior implementation and build on facilitators. Melanoma survivors and their children could benefit from support on their interactions with healthcare providers, schools, peers, and other caregivers about melanoma prevention. PMID- 29623501 TI - Silymarin and celecoxib ameliorate experimental varicocele-induced pathogenesis: evidences for oxidative stress and inflammation inhibition. AB - BACKGROUND: The present study was done to investigate the ameliorative effect of silymarin (SMN) and celecoxib (CEL) on varicocele (VCL)-induced detrimental impact in testicular tissue. METHODS: Mature Wistar rats were divided into control and test groups. Following VCL induction, the animals in test group were subdivided into non-treated VCL-induced, SMN-treated (50 mg/kg, orally), CEL treated (10 mg/kg) and SMN + CEL-treated groups. Following 60 days, testicular total antioxidant capacity (TAC), malondialdehyde (MDA), nitric oxide (NO), superoxide dismutase (SOD), glutathione peroxidase (GSH-px), total thiol molecules (TTM), mRNA and protein levels of COX2 and mRNA level of iNos were analyzed. Moreover, the germinal cells apoptosis and mRNA damage were examined. RESULTS: Observations revealed that co-administration of SMN and CEL significantly (P < 0.05) up-regulated TAC, SOD, GSH-px and TTM levels and resulted in a remarkable (P < 0.05) reduction in iNos and COX2 expression, NO and MDA contents. The animals in SMN + CEL-treated group exhibited significantly (P < 0.05) lower number of apoptotic cells and cells with mRNA damage per one mm2. CONCLUSION: The SMN by up-regulating testicular TAC, SOD, GSH-px and TTM levels and the CEL by inhibiting COX2 and iNos expression as well as NO content could fairly ameliorate the VCL-decreased spermatogenesis. PMID- 29623504 TI - Coarse-grained molecular dynamics simulations of fibrin polymerization: effects of thrombin concentration on fibrin clot structure. AB - Studies suggest that patients with deep vein thrombosis and diabetes often have hypercoagulable blood plasma, leading to a higher risk of thromboembolism formation through the rupture of blood clots, which may lead to stroke and death. Despite many advances in the field of blood clot formation and thrombosis, the influence of mechanical properties of fibrin in the formation of thromboembolisms in platelet-poor plasma is poorly understood. In this paper, we combine the concepts of reactive molecular dynamics and coarse-grained molecular modeling to predict the complex network formation of fibrin clots and the branching of fibrin monomers. The 340-kDa fibrinogen molecule was converted into a coarse-grained molecule with nine beads, and using our customized reactive potentials, we simulated the formation and polymerization process of a fibrin clot. The results show that higher concentrations of thrombin result in higher branch-point formation in the fibrin clot structure. Our results also highlight many interesting properties, such as the formation of thicker or thinner fibers depending on the thrombin concentration. To the best of our knowledge, this is the first successful molecular polymerization study of fibrin clots to focus on thrombin concentration. PMID- 29623505 TI - Excessive Gambling and Online Gambling Communities. AB - The Internet provides an accessible context for online gambling and gambling related online communities, such as discussion forums for gamblers. These communities may be particularly attractive to young gamblers who are active Internet users. The aim of this study was to examine the use of gambling-related online communities and their relevance to excessive gambling among 15-25-year-old Finnish Internet users (N = 1200). Excessive gambling was assessed by using the South Oaks Gambling Screen. Respondents were asked in a survey about their use of various kinds of gambling-related online communities, and sociodemographic and behavioral factors were adjusted. The results of the study revealed that over half (54.33%) of respondents who had visited gambling-related online communities were either at-risk gamblers or probable pathological gamblers. Discussion in these communities was mainly based on sharing gambling tips and experiences, and very few respondents said that they related to gambling problems and recovery. In three different regression models, visiting gambling-related online communities was a significant predictor for excessive gambling (with 95% confidence level) even after adjusting confounding factors. The association of visiting such sites was even stronger among probable pathological gamblers than among at-risk gamblers. Health professionals working with young people should be aware of the role of online communities in terms of development and persistence of excessive gambling. Monitoring the use of online gambling communities as well as utilizing recovery-oriented support both offline and online would be important in preventing further problems. Gambling platforms should also include warnings about excessive gambling and provide links to helpful sources. PMID- 29623506 TI - Considerations When Treating Hepatitis C in a Cirrhotic Transplant Candidate. AB - PURPOSE OF REVIEW: This review examines the issues in determining the decision to treat a HCV-positive patient who is a liver transplant (LT) candidate with highly effective and well-tolerated direct-acting antiviral (DAA) therapies. RECENT FINDINGS: Cure of HCV with DAA can improve liver function and allow delisting in some patients. Beyond a threshold of hepatic impairment (likely MELD score > 16 to 20), patients may experience a decline in MELD score with HCV cure without improvement in liver-related complications resulting in decreased opportunity to receive a LT. Eradicating HCV from patients who need LT regardless also deprives them of the option of receiving HCV-positive donor organs. Patients with MELD > 16 or Child-Pugh B/C may also have reduced cure rates of HCV, increased risk of hepatic decompensation, and adverse events with DAA pre-LT compared to post-LT DAA therapy. Preliminary data demonstrates increase risk of hepatocellular carcinoma (HCC) recurrence after treatment with DAA with subsequent studies raising doubts about this association. Patients with HCV cirrhosis on the LT waiting list with MELD score > 16, CTP-B/C, and HCC are best treated after LT with better response, tolerability, and the ability to receive organs from a larger donor pool that includes HCV-positive donors. Larger, prospective studies are needed to assess whether increased HCC recurrence after DAA is a true effect. PMID- 29623507 TI - Molecular identification and transcriptional regulation of porcine IFIT2 gene. AB - IFN-induced protein with tetratricopeptide repeats 2 (IFIT2) plays important roles in host defense against viral infection as revealed by studies in humans and mice. However, little is known on porcine IFIT2 (pIFIT2). Here, we performed molecular cloning, expression profile, and transcriptional regulation analysis of pIFIT2. pIFIT2 gene, located on chromosome 14, is composed of two exons and have a complete coding sequence of 1407 bp. The encoded polypeptide, 468 aa in length, has three tetratricopeptide repeat motifs. pIFIT2 gene was unevenly distributed in all eleven tissues studied with the most abundance in spleen. Poly(I:C) treatment notably strongly upregulated the mRNA level and promoter activity of pIFIT2 gene. Upstream sequence of 1759 bp from the start codon which was assigned +1 here has promoter activity, and deltaEF1 acts as transcription repressor through binding to sequences at position - 1774 to - 1764. Minimal promoter region exists within nucleotide position - 162 and - 126. Two adjacent interferon stimulated response elements (ISREs) and two nuclear factor (NF)-kappaB binding sites were identified within position - 310 and - 126. The ISRE elements act alone and in synergy with the one closer to start codon having more strength, so do the NF-kappaB binding sites. Synergistic effect was also found between the ISRE and NF-kappaB binding sites. Additionally, a third ISRE element was identified within position - 1661 to - 1579. These findings will contribute to clarifying the antiviral effect and underlying mechanisms of pIFIT2. PMID- 29623508 TI - Chemical constituents from Canarium album Raeusch and their anti-influenza A virus activities. AB - Two new dyhydrophaseic acid glucoside isomers, (1'S, 3'R, 5'S, 8'R, 2Z, 4E) dihydrophaseic acid-3'-O-beta-D-glucopyranoside (2) and (1'R, 3'S, 5'R, 8'R, 2Z, 4E)-dihydrophaseic acid-3'-O-beta-D-glucopyranoside (4), together with 10 known compounds [myo-inositol (1), 3,4-dihydroxybenzoic acid (3), 3-O-galloyl quinic acid (5), ellagic acid (6), gallic acid (7), ethyl gallate (8), scopoletin (9), ellagic acid-4-O-beta-D-glucopyranoside (10), ellagic acid-4-O-alpha-L rhamnopyranoside (11), and isocorilagin (12)] were isolated from the chloroform extract of Canarium album Raeusch fruits by repeated chromatography on macroporous adsorption resin, silica gel, Sephadex LH-20, Toyopearl HW-40F, and reverse-phase C18 columns, etc. Their structures and absolute configurations were determined by comprehensive analysis of 1D- and 2D-nuclear magnetic resonance (NMR), high-resolution electron spray ionization mass spectrometry (HR-ESI-MS), ESI-MS, optical rotation, circular dichroism spectra, and comparison of NMR data with data of known compounds. Bioassay of their anti-influenza virus A activities showed that compounds 9 and 12 displayed a significant inhibitory effect with IC50 values of 22.9 +/- 3.7 and 5.42 +/- 0.97 MUg/ml, respectively. PMID- 29623509 TI - Rapid growth of thrombus formation in the unruptured sinus of Valsalva aneurysm following coronary angiography. PMID- 29623510 TI - To Explore a Representative Hypoxic Parameter to Predict the Treatment Response and Prognosis Obtained by [18F]FMISO-PET in Patients with Non-small Cell Lung Cancer. AB - PURPOSE: To explore a representative hypoxic parameter to predict the treatment response and prognosis for [18F]fluoromisonidazole ([18F]FMISO) positron emission tomography (PET)/X-ray computed tomography (CT) in patients with non-small cell lung cancer (NSCLC). PROCEDURES: Twenty-nine patients with NSCLC underwent FMISO PET scans before chemoradiotherapy (CRT). The maximum standard uptake values (SUVmax) in the tumor, normal lung, aortic arch, and vertical ridge muscle were measured, and the tumor-to-lung (T/L) ratios, tumor-to-blood (T/B) ratios, ands tumor-to-muscle (T/M) ratios were calculated and analyzed. Fractional hypoxic volume (FHV) was expressed as percentage of hypoxic volume. RESULTS: SUVmax, T/L ratio, T/B ratio, and FHV were all significantly different between the responders and the non-responders (SUVmax, 2.07 +/- 0.53 vs. 2.61 +/- 0.69, P = 0.026; T/L ratio, 3.16 +/- 0.85 vs. 4.09 +/- 1.46, P = 0.047; T/B ratio, 1.27 +/- 0.20 vs. 1.48 +/- 0.32, P = 0.042; 38.92 +/- 18.47 vs. 52.91 +/- 11.29 %, P = 0.020). However, the T/M ratio was not significantly different between the two populations (1.46 +/- 0.31 vs. 1.67 +/- 0.33, P = 0.098). The correlation ratio between hypoxic parameters and treatment responses ranged from high to low as FHV (r = 0.412); SUVmax (r = 0.400); T/L ratio (r = 0.379), P < 0.05; and T/B ratio (r = 0.355), P = 0.059. According to the area under curve (AUC) to predict response, the hypoxic parameters were arranged as FHV (AUC = 0.748), SUVmax (AUC = 0.731), T/L ratio (AUC = 0.719), and T/B ratio (AUC = 0.705). Binary logistic regression analyses showed that FHV was the only independent predictor for treatment response with the P value of 0.038. In the progression-free survival (PFS) prediction, both FHV and SUVmax reached statistical significance by Kaplan Meier plots (FHV, 46.99 %, P = 0.010; SUVmax, 1.99, P = 0.046) while only FHV was the independent prognostic factor in multivariate analysis by Cox proportional hazard model (P = 0.037). CONCLUSION: FHV may be a representative hypoxic parameter to predict the CRT response and PFS in patients with NSCLC. PMID- 29623511 TI - App Review: The Radiology Assistant 2.0. PMID- 29623513 TI - Primary Care Physician Referral to Physical Therapy for Musculoskeletal Conditions, 2003-2014. PMID- 29623512 TI - Incorporating PROMIS Symptom Measures into Primary Care Practice-a Randomized Clinical Trial. AB - BACKGROUND: Symptoms account for more than 400 million clinic visits annually in the USA. The SPADE symptoms (sleep, pain, anxiety, depression, and low energy/fatigue) are particularly prevalent and undertreated. OBJECTIVE: To assess the effectiveness of providing PROMIS (Patient-Reported Outcome Measure Information System) symptom scores to clinicians on symptom outcomes. DESIGN: Randomized clinical trial conducted from March 2015 through May 2016 in general internal medicine and family practice clinics in an academic healthcare system. PARTICIPANTS: Primary care patients who screened positive for at least one SPADE symptom. INTERVENTIONS: After completing the PROMIS symptom measures electronically immediately prior to their visit, the 300 study participants were randomized to a feedback group in which their clinician received a visual display of symptom scores or a control group in which scores were not provided to clinicians. MAIN MEASURES: The primary outcome was the 3-month change in composite SPADE score. Secondary outcomes were individual symptom scores, symptom documentation in the clinic note, symptom-specific clinician actions, and patient satisfaction. KEY RESULTS: Most patients (84%) had multiple clinically significant (T-score >= 55) SPADE symptoms. Both groups demonstrated moderate symptom improvement with a non-significant trend favoring the feedback compared to control group (between-group difference in composite T-score improvement, 1.1; P = 0.17). Symptoms present at baseline resolved at 3-month follow-up only one third of the time, and patients frequently still desired treatment. Except for pain, clinically significant symptoms were documented less than half the time. Neither symptom documentation, symptom-specific clinician actions, nor patient satisfaction differed between treatment arms. Predictors of greater symptom improvement included female sex, black race, fewer medical conditions, and receiving care in a family medicine clinic. CONCLUSIONS: Simple feedback of symptom scores to primary care clinicians in the absence of additional systems support or incentives is not superior to usual care in improving symptom outcomes. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT02383862. PMID- 29623514 TI - Pollution indices as useful tools for the comprehensive evaluation of the degree of soil contamination-A review. AB - The paper provides a complex, critical assessment of heavy metal soil pollution using different indices. Pollution indices are widely considered a useful tool for the comprehensive evaluation of the degree of contamination. Moreover, they can have a great importance in the assessment of soil quality and the prediction of future ecosystem sustainability, especially in the case of farmlands. Eighteen indices previously described by several authors (Igeo, PI, EF, Cf, PIsum, PINemerow, PLI, PIave, PIVector, PIN, MEC, CSI, MERMQ, Cdeg, RI, mCd and ExF) as well as the newly published Biogeochemical Index (BGI) were compared. The content, as determined by other authors, of the most widely investigated heavy metals (Cd, Pb and Zn) in farmland, forest and urban soils was used as a database for the calculation of all of the presented indices, and this shows, based on statistical methods, the similarities and differences between them. The indices were initially divided into two groups: individual and complex. In order to achieve a more precise classification, our study attempted to further split indices based on their purpose and method of calculation. The strengths and weaknesses of each index were assessed; in addition, a comprehensive method for pollution index choice is presented, in order to best interpret pollution in different soils (farmland, forest and urban). This critical review also contains an evaluation of various geochemical backgrounds (GBs) used in heavy metal soil pollution assessments. The authors propose a comprehensive method in order to assess soil quality, based on the application of local and reference GB. PMID- 29623470 TI - Laparoscopy in management of appendicitis in high-, middle-, and low-income countries: a multicenter, prospective, cohort study. AB - BACKGROUND: Appendicitis is the most common abdominal surgical emergency worldwide. Differences between high- and low-income settings in the availability of laparoscopic appendectomy, alternative management choices, and outcomes are poorly described. The aim was to identify variation in surgical management and outcomes of appendicitis within low-, middle-, and high-Human Development Index (HDI) countries worldwide. METHODS: This is a multicenter, international prospective cohort study. Consecutive sampling of patients undergoing emergency appendectomy over 6 months was conducted. Follow-up lasted 30 days. RESULTS: 4546 patients from 52 countries underwent appendectomy (2499 high-, 1540 middle-, and 507 low-HDI groups). Surgical site infection (SSI) rates were higher in low-HDI (OR 2.57, 95% CI 1.33-4.99, p = 0.005) but not middle-HDI countries (OR 1.38, 95% CI 0.76-2.52, p = 0.291), compared with high-HDI countries after adjustment. A laparoscopic approach was common in high-HDI countries (1693/2499, 67.7%), but infrequent in low-HDI (41/507, 8.1%) and middle-HDI (132/1540, 8.6%) groups. After accounting for case-mix, laparoscopy was still associated with fewer overall complications (OR 0.55, 95% CI 0.42-0.71, p < 0.001) and SSIs (OR 0.22, 95% CI 0.14-0.33, p < 0.001). In propensity-score matched groups within low /middle-HDI countries, laparoscopy was still associated with fewer overall complications (OR 0.23 95% CI 0.11-0.44) and SSI (OR 0.21 95% CI 0.09-0.45). CONCLUSION: A laparoscopic approach is associated with better outcomes and availability appears to differ by country HDI. Despite the profound clinical, operational, and financial barriers to its widespread introduction, laparoscopy could significantly improve outcomes for patients in low-resource environments. TRIAL REGISTRATION: NCT02179112. PMID- 29623516 TI - Sensitivity of supplementation of thyroid hormone on treatment of idiopathic short-stature children during therapy with recombinant human growth hormone. AB - This study aimed to evaluate the effects of thyroid hormone supplementation on growth rate of children with idiopathic short stature (ISS) and low-normal serum free thyroxine FT4 who were receiving growth hormone therapy. We selected 64 prepubertal children with FT4 levels in the lowest third of the normal range as the lower FT4 group, and these children were divided randomly into two subgroups: L-thyroxine (L-T4)-treated subgroup was treated with L-T4 (0.5-3.0 g/(kg.d)) from the beginning of the study, and the non-L-T4-treated subgroup received placebo. We also selected 39 ISS children with FT4 in the upper two-thirds of the normal range as the higher FT4 group. During the first year, the lower FT4 group featured lower FT3, FT4, thyroid stimulating hormone (TSH), and insulin-like growth factor-I standard deviation score (IGF-I SDS) and significantly lower height velocity (HV) compared with the higher FT4 group. However, in the lower FT4 group, the L-T4-treated subgroup presented higher FT4, FT3, TSH, and IGF-I SDS concentrations and significantly higher HV compared with children in the non L-T4-treated subgroup. In children with ISS, the negative effect of thyroid hormone deficiency on growth rate should be considered when FT4 level lies in the low-normal range prior to recombinant human growth hormone treatment. PMID- 29623515 TI - DNA methylation-based subclassification of psoriasis in the Chinese Han population. AB - Psoriasis (Ps) is an inflammatory skin disease caused by genetic and environmental factors. Previous studies on DNA methylation (DNAm) found genetic markers that are closely associated with Ps, and evidence has shown that DNAm mediates genetic risk in Ps. In this study, Consensus Clustering was used to analyze DNAm data, and 114 Ps patients were divided into three subclassifications. Investigation of the clinical characteristics and copy number variations (CNVs) of DEFB4, IL22, and LCE3C in the three subclassifications revealed no significant differences in gender ratio and in Ps area and severity index (PASI) score. The proportion of late-onset ( ? 40 years) Ps patients was significantly higher in type I than in types II and III (P = 0.035). Type III contained the smallest proportion of smokers and the largest proportion of non smoking Ps patients (P = 0.086). The CNVs of DEFB4 and LCE3C showed no significant differences but the CNV of IL22 significantly differed among the three subclassifications (P = 0.044). This study is the first to profile Ps subclassifications based on DNAm data in the Chinese Han population. These results are useful in the treatment and management of Ps from the molecular and genetic perspectives. PMID- 29623518 TI - Influence of a preventive program on the oral health-related quality of life (OHRQoL) of European pregnant women: a cohort study. AB - The aim of this study was to compare the impact of oral health on quality of life of a group of pregnant women enrolled in a program of oral health with respect to a control group of non-pregnant women. A cross-sectional study involving a sociodental indicator OHIP-14 and a dental examination was completed to assess pregnant women's knowledge of oral health, hygienic habits, periodontal and caries index. Data were collected from 113 pregnant women and 113 non-pregnant women. Sociodemographic data for both groups were homogeneous. Pregnant women have better values of general and oral health, even though they have not perceived need for dental treatment, compared with control group. A worse periodontal health was observed for the control group. Our results showed that quality of life in pregnant women has been influenced with a statistical significance (p < 0.05) by the variables age, unemployment, level of education, immigration, frequency of brushing, type of dental practice, self-reported general and oral health and perceived treatment needs. The oral quality of life of pregnant women seems to be positively influenced by the incorporation of preventive oral programs during pregnancy. PMID- 29623517 TI - Mini review on photosensitization by plants in grazing herbivores. AB - Photosensitization is severe dermatitis or oxidative/chemical changes in the epidermal tissues activated by the light-induced excitation of molecules within the tissue. It is a series of reactions mediated through light receptors and is more common when the plant-produced metabolites are heterocyclic/polyphenols in nature. The areas affected are exposed body parts and mostly non-pigmented areas with least ultraviolet protection. Similarly, cellular alteration also occurs in the affected animal's dermal tissues and body parts and grazing animals by the accumulation and activation of photodynamic molecules. Photo-oxidation can also occur within the plant due to the generation of reactive oxygen species causing damage and degradation in the form of free radicals and DNA. During the last few decades, many new tropical grass species have been introduced in the grazing lands which are genetically modified, and the animals grazing on them are facing various forms of toxicity including photosensitization. The plant's secondary metabolites/drugs may cause toxicity when bacteria, viral agents, fungi (Pithomyces chartarum), or neoplasia injures the liver and prevents the phylloerythrin excretion. All these may disturb the liver enzymes and blood profile causing a decrease in weight and production (wool and milk etc.) with severe dermal, digestive, and nervous problems. Recent advancements in OMICS (cellomics, ethomics, metabolomics, metabonomics, and glycomics) have enabled us to detect and identify the plants' secondary metabolites and changes in the animal's physiology and histopathology as a causative of photosensitivity. The review focuses on types of photosensitization, reasons, secondary metabolic compounds, chemistry, and environmental effect on plants. PMID- 29623519 TI - Comparisons of human risk assessment models for heavy metal contamination within abandoned metal mine areas in Korea. AB - This study was initiated to develop a model specialized to conduct human risk assessments (HRAs) of abandoned metal mine areas in Korea. The Korean guideline (KG) model used in study was formulated via modification of the original Korean guidelines on HRAs of soil contamination. In addition, the newly developed model was applied to the HRAs of two abandoned metal mines contaminated with arsenic (As) and heavy metals (Cd, Cu, Pb, and Zn). The results of the KG model were compared with those of two internationally renowned models [Contaminated land exposure assessment (CLEA) and CSOIL models]. The HRA results of the three models indicated that the areas of concern were unsafe when it came to both carcinogenic and non-carcinogenic hazards. Furthermore, the hazards in both areas were mostly attributed to As and the predominant exposure pathways were identified as crop intake in the KG model and surface soil dermal contact in CLEA and CSOIL models. Accordingly, measures to protect against As exposure should be established immediately to prevent adverse health effects on inhabitants in these areas. A comparison of HRA results revealed significant differences between KG, CLEA, and CSOIL models due to the various types of exposure pathways, contaminants, and input data, such as exposure factors and receptor parameters. This study suggests that set-up of an exposure scenario is crucial for the successful performance of HRAs, and the most relevant HRA model should be deliberately selected to attain risk assessment goals. PMID- 29623520 TI - CGRP Monoclonal Antibodies for the Preventative Treatment of Migraine. AB - PURPOSE OF REVIEW: CGRP is a key neuropeptide in migraine pathophysiology. The blockade of the CGRP pathway at the side of the CGRP receptor of the CGRP peptide leads to the interruption of trigeminal nerve system-mediated headache syndromes such as migraine. Monoclonal antibodies (mAbs) targeting the CGRP pathway have been developed and are currently under investigation for episodic (EM) and chronic migraine (CM) prevention. Here, we report data from these clinical trials. RECENT FINDINGS: Placebo-controlled, randomized double-blind phase studies of CGRP mAbs in episodic and chronic migraine have shown that the specific blockade of the peptide or the CGRP receptor are both powerful mechanisms to reduce migraine frequency. Along with the reduction of acute migraine-specific medication intake, early onset of efficacy of mAbs has been demonstrated. Most common adverse events are injection sider reactions. Depending on the mAb, the administration mode is a monthly or even less frequently s.c. or I.V. formulation. Phase II studies in EM and CM demonstrate that CGRP mAbs are effective anti-migraine preventatives with a beneficial adverse event profile. Further detailed results from larger phase III clinical trials are expected soon. PMID- 29623521 TI - High doses of laser phototherapy can increase proliferation in melanoma stromal connective tissue. AB - It is well established that laser phototherapy (LP) is contraindicated directly over cancer cells, due to its bio modulatory effects in cell and blood vessel proliferation. The aim of the present study was to analyze the influence of typical low-level laser therapy (LLLT) and high intensity laser therapy (HILT) and an in-between dose of 9 J on collagen fibers and blood vessels content in melanoma tumors (B16F10) implanted in mice. Melanoma tumor cells were injected in male Balb C mice which were distributed in four groups: control (no irradiated) or irradiated by 3, 9, or 21 J (150; 450, or 1050 J/cm2). LP was performed in daily sessions for 3 days with a InGaAlP-660 nm (mean output: 50 mW, spot size: 2 mm2). Tumor volume was analyzed using (1) picrosirius staining to quantify collagen fibers content and (2) Verhoeff's method to quantify blood vessels content. Tumor growth outcome measured in the 3-J group was not significantly different from controls. Nine and 21-J groups, presented significant and dose dependent increases in tumor volume. Quantitative analysis of the intensity of collagen fibers and their organization in stroma and peri-tumoral microenvironment showed significant differences between irradiated and control group. Blood vessels count of 21-J group outnumbered the other groups. High doses (>= 9 J) of LP showed a dose-dependent tumor growth, different collagen fibers characteristics, and eventually blood vessel growth, while a typical LLLT dose (3 J) appeared harmless on melanoma cell activity. PMID- 29623522 TI - Selection of growth-related genes and dominant genotypes in transgenic Yellow River carp Cyprinus carpio L. AB - Transgenic Yellow River carp is characterized by rapid growth rate and high feed conversion efficiency and exhibits a great application prospect. However, there is still a significant separation of growth traits in the transgenic Yellow River carp family; as such, growth-related genotypes must be screened for molecular marker-assisted selection. In this study, 23 growth-related candidate genes containing 48 SNP markers were screened through bulked segregant analysis (BSA) among transgenic Yellow River carp family members showing significant separation of growth traits. Then, two growth-related genes (Nos. 17 and 14 genes) were identified through combined genome-wide association study (GWAS) of candidate genes and validation of the full-sibling family approach. Nos. 17 and 14 genes encode BR serine/threonine-protein kinase 2 (BRSK2) and eukaryotic translation initiation factor 2-alpha kinase 3 (Eif2ak3), respectively. The average body weight of three subgroups carrying the genotypes 17GG, 17GG + 14CC, and 17GG + 14TT of these two genes increased by 27.96, 38.28, and 33.72%, respectively, compared with the controls. The proportion of individuals with body weight > 500 g in these subgroups increased by 19.22, 26.82, and 30.92%, respectively. The results showed that appropriate genotype carriers can be selected from the progeny population through BSA sequencing combined with simplified GWAS analysis. Hence, basic population for breeding can be constructed and transgenic Yellow River carp strains with stable production performance and uniform phenotypic properties can be bred. PMID- 29623523 TI - Visual evoked potentials can be reliably recorded using noninvasive epidermal electrodes in the anesthetized rat. AB - PURPOSE: Visual evoked potentials (VEPs) are a powerful tool to evaluate nervous conduction along the visual pathways, both in humans and in animal models. Traditionally, epidural screw electrodes are used to record VEPs in preclinical research. Here we tested the feasibility in the preclinical setting of the same noninvasive technique used for clinical VEP acquisition, by using epidermal cup electrodes with no surgical procedures. METHODS: Monocular flash VEPs were recorded bilaterally under sevoflurane anesthesia once a week for 6 weeks in 14 dark Agouti rats, 7 with implanted epidural screws and 7 with epidermal 6 mm O Ag/AgCl cups. RESULTS: VEP traces obtained with the two techniques were morphologically comparable. There were no significant differences in latency of the main visual component between screw-recorded VEPs (sVEPs) and cup-recorded VEPs (cVEPs). Amplitude values with epidermal cups were significantly lower than those with epidural screws. Both techniques provided latencies and amplitudes which were stable over time. Furthermore, with regard to latency both methods ensured highly repeatable measurements over time, with epidermal cups even providing slightly better results. On the other hand, considering amplitudes, cVEPs and sVEPs provided fairly acceptable repeatability. CONCLUSIONS: Epidermal cup electrodes can provide comparable results to those obtained with the "gold standard" epidural screws, while representing a simpler and less invasive technique to test nervous conduction along the visual pathways in the preclinical setting. PMID- 29623524 TI - Could Buerger's disease cause nonarteritic anterior ischemic optic neuropathy?: a rare case report. AB - We present an interesting case with nonarteritic anterior ischemic optic neuropathy (NAION) accompanied by Buerger's disease. A 43-year-old man was referred to our neuro-ophthalmology clinic with a complaint of visual deterioration in the left eye that started 5 days ago. He suffered from Buerger's disease, and he had acute pain in the right lower limb below the knee. His best corrected visual acuity was 10/10 in the right eye and 2/10 in the left eye by Snellen chart. There was a relative afferent pupil defect in the left eye. The right optic disc was normal on fundus examination, and blurring, hemorrhagic swelling was found at the left optic disc. Inferior altitudinal visual field defect was observed in the left eye. Neurological examination was normal. Computed tomography angiography scan revealed occlusion in the right posterior tibial artery. Brain imaging and laboratory tests such as blood analyses, genetic screening, coagulation, and lipid panels were unremarkable. NAION may occur in patients with Buerger's disease, but it is extremely rare. Therefore, clinicians should be aware of this rare association. PMID- 29623527 TI - Implementation of a Stress Intervention with Latino Immigrants in a Non traditional Migration City. AB - Stress negatively impacts health outcomes across all racial and ethnic groups, but the health disparities experienced by Latino immigrants in nontraditional migration cities are exacerbated by undeveloped infrastructure and weak social support networks. Immigrants in new migration cities can be difficult to engage in health interventions and are therefore underrepresented in the very research where their inclusion is most crucial. To effectively engage Latino immigrants, a team of academic and community researchers collaborated on a community-based participatory research project to design and implement a stress and coping intervention. Top stressors reported were family, children, and work, but health was most commonly identified as the primary stressor. Participants overwhelmingly chose physical activity goals for stress reduction. Pre- to post- intervention results revealed significant improvements in social support and stress management. Results demonstrate the effectiveness of a peer-led, community partnered approach to implementing a stress intervention with Latino immigrants in a nontraditional migration city. PMID- 29623525 TI - What are the caregivers' needs on dementia care? An integrated qualitative and quantitative assessment. AB - Dementia is one of the main causes of disability later in life. Interventions in support of patients with dementia aim at granting the highest level of independence in activities of daily living and at delivering the required facilities; formal and informal caregivers represent the interface between patients and health services. The aims of our study were to assess caregivers' perceived needs and to relate them to their own socio-cultural features and to patients' clinical characteristics. During three consecutive months, 50 caregivers of patients with dementia were interviewed about their needs in the assistance of subjects with dementia by means of three structured questionnaires (Caregiver Needs Assessment [CNA], Zarit Burden Inventory [ZBI], Neuropsychiatric Inventory-Questionnaire [NPI-Q]) and of two open-ended questions. Higher scores of CNA (suggestive of more needs) were associated with a major burden in caregiving and were related to a more severe behavioral and psychological profile of patients with dementia. ZBI was highly correlated with NPI distress score. Among caregivers, the children of patients reported more needs, particularly about information on disease and how to cope with it. CNA emerged as a complete and reliable instrument, with need for safety being the only item missing from the questionnaire and identified by means of the open-ended questions. Our results showed how the use of simple and brief instruments can increase the communication between health operators and caregivers and could thus improve the quality of formal and informal assistance. PMID- 29623526 TI - What is the Impact of Placement Type on Educational and Health Outcomes of Unaccompanied Refugee Minors? A Systematic Review of the Evidence. AB - Record numbers of unaccompanied refugee minors have been arriving in high-income countries since 2015. Child welfare agencies and non-governmental organisations tasked with providing services have struggled to cope with demands on their services as a result. Despite this, there is little research on how best to meet their needs and in particular what services can mitigate the psychological difficulties they face. As a result, the evidence base for social services for refugee children remains very limited. This paper is a systematic review and meta analysis of the evidence on the relationship between care placement type and the educational, mental health and physical health outcomes of unaccompanied refugee minors. We searched ten databases and identified 3877 citations which were screened for inclusion. Nine studies were included in the final review, with seven included in the meta-analysis. Eight studies examined the link between accommodation type and mental health outcomes, and two analysed the relationship between accommodation type and education. There were no studies looking at physical health outcomes. Included studies suggest that foster care and placements that are culturally sensitive may be associated with better mental health outcomes. This review highlights the paucity of research on the impact of services provided by child welfare agencies and non-governmental organisations. PMID- 29623528 TI - A Multi-Institutional Validation of Gleason Score Derived from Tissue Microarray Cores. AB - To test the agreement between high-grade PCa at RP and TMA, and the ability of TMA to predict BCR. Validation of concordance between tissue microarray (TMA) and radical prostatectomy (RP) high-grade prostate cancer (PCa) is crucial because latter determines the treated natural history of PCa. We hypothesized that TMA Gleason score is in agreement with RP pathology and capable of accurately predicting biochemical recurrence (BCR). Data were provided from a multi institutional Canadian sample of 1333 TMA and RP specimens with complete clinicopathological data. First, rate of agreement between TMA and high-grade Gleason at RP or biopsy and RP was tested. Second, ability of RP, TMA and biopsy to predict BCR was compared. Multivariable (MVA) Cox regression models were fitted and BCR rates were illustrated with Kaplan-Meier plots. Agreement between RP and TMA and between RP and biopsy was 72.6% (95% CI:69.7-75.5) and 60.4% (95% CI:57.2-63.6), respectively. In MVA predicting BCR, the accuracy for RP, TMA and biopsy was 0.73, 0.72 and 0.68, respectively. TMA added discriminatory ability among exclusively low-grade Gleason RP patients (p = 0.02), but did not improve BCR discrimination in exclusive high-grade PCa RP patients (p = 0.8). TMA Gleason grade accurately reflects presence of high-grade Gleason in RP specimen, accurately predicts BCR rates after RP and improves prediction of BCR in low grade Gleason patients at RP. PMID- 29623529 TI - Nutritional Interventions in Heart Failure: Challenges and Opportunities. AB - PURPOSE OF REVIEW: There is a growing body of evidence that nutritional factors influence the incidence of heart failure (HF). The current manuscript aims to collate evidence relating to nutritional intervention in the treatment of HF as well as to provide context regarding challenges and opportunities in the field. RECENT FINDINGS: Despite the accepted importance of nutritional factors relating to cardiovascular disease severity, there is surprisingly little human intervention research regarding dietary intake and HF. Further, existing nutritional interventions in HF were mostly pilot studies with small samples and short follow-up. There is consistent evidence that nutritional factors majorly influence HF. Despite limited research, there is evidence that nutritional modification can rapidly and profoundly influence multiple aspects of HF. There is an urgent need for well-conducted research to ascertain if nutritional modification can alter the long-term course of HF. PMID- 29623530 TI - Novel Insights and Treatment Strategies for Right Heart Failure. AB - PURPOSE OF REVIEW: The function of the right ventricle (RV) is intimately linked to its preload (systemic volume status) and afterload (pulmonary vasculature). In this review, we explore current knowledge in RV physiology, RV function assessment, causes of right heart failure (RHF), and specific treatment strategies for RHF. RECENT FINDINGS: We examine the evidence behind new pharmacological therapies available, such as macitentan and riociguat in the treatment of specific etiologies of RHF. We will also focus on RHF in the setting of heart failure with preserved ejection fraction (HFpEF) and in the presence of left ventricular assist devices (LVAD), looking at current treatment recommendations, including mechanical circulatory support. Lastly, we will look to the horizon for the latest research on RHF, including the molecular basis of RHF and potential novel treatment methods for this old yet poorly understood syndrome. Disturbances in this complex relationship result in the clinical syndrome of RHF. Despite advances in the management of left heart diseases, much work remains to be done to understand and manage RHF. PMID- 29623531 TI - Initial evaluation of the validity and reliability of the culturally adapted Spanish CaSUN (S-CaSUN). AB - PURPOSE: There is a dearth of knowledge and limited research on the needs of Hispanic male cancer survivors (HMCSs). There is a clear need for the development of culturally and linguistically adapted needs assessment tools that are valid and reliable for use among the growing HMCS population. Thus, the purpose of this paper is to describe the field testing and psychometric evaluation of the translated and culturally adapted Spanish Cancer Survivor Unmet Needs Measure (S CaSUN). METHODS: Hispanic male cancer survivors (n = 84) completed the Spanish CaSUN (S-CaSUN), the Hospital Anxiety and Depression Scale (HADS), and the Functional Assessment of Cancer Therapy-General Population (FACT-GP). Construct validity of the S-CaSUN was assessed by correlation analysis among aforesaid measures. A test-retest procedure with 2-week delay was used to examine reproducibility with a participant subsample (n = 50). Cronbach's alpha was computed to assess internal consistency of the S-CaSUN. RESULTS: Construct validity of the S-CaSUN was estimated by moderate correlation with the HADS anxiety (r = 0.55, P < 0.001) and depression scales (r = 0.60, P < 0.001) and the FACT-GP (r = - 0.62, P < 0.001). The test-retest correlation coefficient for the S-CaSUN was 0.78. Cronbach's alpha was 0.96. Field testing yielded a mean S-CaSUN score of 38.3 (SD = 26.2); all needs and positive change items were endorsed. CONCLUSION: Findings from field testing and preliminary psychometric evaluation of the S-CaSUN provide initial evidence of validity and reliability of the measure and highlight the importance of going beyond translation when adapting measures to take culture, literacy, and language into consideration. IMPLICATIONS FOR CANCER SURVIVORS: Reliable, culturally, and linguistically valid instruments facilitate identification of unique unmet needs of Hispanic cancer survivors that, in turn, can be addressed with evidence-based interventions. As cancer centers continue to develop survivorship programs, the S-CaSUN may be useful for a growing group of cancer survivors. PMID- 29623533 TI - Psychosocial Health Disparities Among Black Bisexual Men in the U.S.: Effects of Sexuality Nondisclosure and Gay Community Support. AB - Compared with Black gay men, Black bisexual men experience psychosocial health disparities, including depression, polydrug use, physical assault, and intimate partner violence (IPV). Black bisexual men are also less likely to disclose their sexuality, which may result in them receiving less sexual minority community support, exacerbating psychosocial health disparities. We assessed relationships between bisexual behavior, bisexual identity, sexuality nondisclosure, gay community support, and psychosocial morbidities among Black men who have sex with men (MSM). Between 2014 and 2017, survey data were collected from Black MSM >= 18 years old (n = 4430) at Black Pride events in six U.S. cities. We differentiated between bisexual-identified men reporting past-year sex with men and women (bisexual MSMW, 8.4%); gay-identified men reporting sex with men only (gay MSMO, 73.1%); gay MSMW (8.0%); and bisexual MSMO (8.4%). Multivariable regressions contrasted these groups by psychosocial morbidities, sexuality nondisclosure, and gay community support. Structural equation models assessed total, direct, and indirect effects. Compared with gay MSMO, bisexual MSMW and gay MSMW were significantly more likely to report polydrug use, depression symptoms, IPV, physical assault, sexuality nondisclosure, and lack of gay community support. Lack of gay community support had significant indirect effects on the relationships between bisexual behavior and psychosocial morbidity (p < .001) and between bisexual identity and psychosocial morbidity (p < .001). Sexuality nondisclosure had significant indirect effects on relationships between bisexual behavior (p < .001), bisexual identity (p < .001), and lack of gay community support. Psychosocial health disparities experienced by Black bisexual men are associated with both bisexual behavior and bisexual identity. Interventions decreasing biphobia will facilitate opportunities for protective sexuality disclosure and access to sexual minority community support. PMID- 29623534 TI - Don't believe everything you hear: Routine validation of audiovisual information in children and adults. AB - Previous research has shown that the validation of incoming information during language comprehension is a fast, efficient, and routine process (epistemic monitoring). Previous research on this topic has focused on epistemic monitoring during reading. The present study extended this research by investigating epistemic monitoring of audiovisual information. In a Stroop-like paradigm, participants (Experiment 1: adults; Experiment 2: 10-year-old children) responded to the probe words correct and false by keypress after the presentation of auditory assertions that could be either true or false with respect to concurrently presented pictures. Results provide evidence for routine validation of audiovisual information. Moreover, the results show a stronger and more stable interference effect for children compared with adults. PMID- 29623535 TI - Henoch Schonlein Purpura Nephritis Developing in a Child with Known IgA Nephropathy. PMID- 29623532 TI - Genome Editing in Induced Pluripotent Stem Cells using CRISPR/Cas9. AB - The development of the reprogramming technology led to generation of induced Pluripotent Stem Cells (iPSC) from a variety of somatic cells. Ever since, fast growing knowledge of different efficient protocols enabled the differentiation of these iPSCs into different cells types utilized for disease modeling. Indeed, iPSC-derived cells have been increasingly used for investigating molecular and cellular pathophysiological mechanisms underlying inherited diseases. However, a major barrier in the field of iPSC-based disease modeling relies on discriminating between the effects of the causative mutation and the genetic background of these cells. In the past decade, researchers have made great improvement in genome editing techniques, with one of the latest being CRISPR/Cas9. Using a single non-sequence specific protein combined with a small guiding RNA molecule, this state-of-the-art approach enables modifications of genes with high efficiency and accuracy. By so doing, this technique enables the generation of isogenic controls or isogenic mutated cell lines in order to focus on the pathologies caused by a specific mutation. In this article, we review the latest studies combining iPSC and CRISPR/Cas9 technologies for the investigation of the molecular and cellular mechanisms underlying inherited diseases including immunological, metabolic, hematological, neurodegenerative and cardiac diseases. PMID- 29623536 TI - A practical multi-step synthesis of ethyl N-functionalized [Formula: see text] amino benzimidazole acrylate derivatives as promising cytotoxic agents. AB - A series of 16 new ethyl [Formula: see text]-amino benzimidazole acrylate derivatives 12(a-p) with a (2E)-s-cis/trans conformation and bearing two points of diversity was designed and synthesized by using a multi-step strategy (reductive amination, deprotection in acidic media and transamination) in moderate to good yields from ethyl 3-dimethylamino-2-(1H-benzimidazol-2 yl)acrylate (5) and monosubstituted N-Boc diamines (7a,7b) as starting building blocks. Products 12 were evaluated for their in vitro cytotoxic potential against six selected human cell lines (Huh7-D12, Caco2, MDA-MB231, HCT116, PC3 and NCI H727). Compounds 12a, 12e and 12l exhibited selective and micromolar antitumor activities against Huh7-D12 and Caco2 cell lines. PMID- 29623537 TI - Glutaraldehyde Cross-linking Modification of Decellularized Rat Kidney Scaffolds. AB - The decellularized (DC) scaffolds retain three-dimensional structures for the stimulation of cell growth, with components of the extracellular matrix (ECM) relatively conserved between species. The strategy based on decellularized scaffolds provides a new way for organ regeneration, with a number of prominent advances having been reported in the past few years. While their lack of biomechanical strength and excessive degradation limit the clinical applications, therefore it is urgent to modify the DC scaffolds to improve the performance.In this article we describe a simple and robust modification protocol for DC rat kidney scaffolds. To modify, we perfuse DC rat kidneys with glutaraldehyde through the perfusion circulation of the decellularization. After cross-linking, kidney scaffolds are harvested for evaluation of histology, structural stability, and biocompatibility, involving water absorption testing, biomechanical testing, scanning electron microscopy, and several different histological and immunofluorescent analyses. PMID- 29623538 TI - Optimization for Peptide Sample Preparation for Urine Peptidomics. AB - Analysis of native or endogenous peptides in biofluids can provide valuable insight into disease mechanisms. Furthermore, the detected peptides may also have utility as potential biomarkers for noninvasive monitoring of human diseases. The noninvasive nature of urine collection and the abundance of peptides in the urine make analysis by high-throughput "peptidomics" methods an attractive approach for investigating the pathogenesis of renal disease. However, urine peptidomics methodologies can be problematic with regard to difficulties associated with sample preparation. The urine matrix can provide significant background interference in making the analytical measurements, in that it hampers both the identification of peptides and the depth of the peptidomics read when utilizing LC-MS-based peptidome analysis. We report on a novel adaptation of the standard solid-phase extraction (SPE) method to a modified SPE (mSPE) approach for improved peptide yield and analysis sensitivity with LC-MS-based peptidomics, in terms of time, cost, clogging of the LC-MS column, peptide yield, peptide quality, and number of peptides identified by each method. The mSPE method provides significantly improved efficiencies for the preparation of samples from urine. The mSPE method is found to be superior to the conventional, standard SPE method for urine peptide sample preparation when applying LC-MS peptidomics analysis, due to optimized sample cleanup that provides improved experimental inference from confidently identified peptides. PMID- 29623539 TI - Registration of 3D freehand ultrasound to a bone model for orthopedic procedures of the forearm. AB - PURPOSE: For guidance of orthopedic surgery, the registration of preoperative images and corresponding surgical plans with the surgical setting can be of great value. Ultrasound (US) is an ideal modality for surgical guidance, as it is non ionizing, real time, easy to use, and requires minimal (magnetic/radiation) safety limitations. By extracting bone surfaces from 3D freehand US and registering these to preoperative bone models, complementary information from these modalities can be fused and presented in the surgical realm. METHODS: A partial bone surface is extracted from US using phase symmetry and a factor graph based approach. This is registered to the detailed 3D bone model, conventionally generated for preoperative planning, based on a proposed multi-initialization and surface-based scheme robust to partial surfaces. RESULTS: 36 forearm US volumes acquired using a tracked US probe were independently registered to a 3D model of the radius, manually extracted from MRI. Given intraoperative time restrictions, a computationally efficient algorithm was determined based on a comparison of different approaches. For all 36 registrations, a mean (+/- SD) point-to-point surface distance of [Formula: see text] was obtained from manual gold standard US bone annotations (not used during the registration) to the 3D bone model. CONCLUSIONS: A registration framework based on the bone surface extraction from 3D freehand US and a subsequent fast, automatic surface alignment robust to single-sided view and large false-positive rates from US was shown to achieve registration accuracy feasible for practical orthopedic scenarios and a qualitative outcome indicating good visual image alignment. PMID- 29623540 TI - Patient-specific catheter shaping for the minimally invasive closure of the left atrial appendage. AB - PURPOSE: The minimally invasive closure of the left atrial appendage is a promising alternative to anticoagulation for stroke prevention in patients suffering from atrial fibrillation. One of the challenges of this procedure is the correct positioning and the coaxial alignment of the tip of the catheter sheath to the implant landing zone. METHOD: In this paper, a novel preoperative planning system is proposed that allows patient-individual shaping of catheters to facilitate the correct positioning of the catheter sheath by offering a patient-specific catheter shape. Based on preoperative three-dimensional image data, anatomical points and the planned implant position are marked interactively and a patient-specific catheter shape is calculated if the standard catheter is not considered as suitable. An approach to calculate a catheter shape with four bends by maximization of the bending radii is presented. Shaping of the catheter is supported by a bending form that is automatically generated in the planning program and can be directly manufactured by using additive manufacturing methods. RESULTS: The feasibility of the planning and shaping of the catheter could be successfully shown using six data sets. The patient-specific catheters were tested in comparison with standard catheters by physicians on heart models. In four of the six tested models, the participating physicians rated the patient individual catheters better than the standard catheter. CONCLUSION: The novel approach for preoperatively planned and shaped patient-specific catheters designed for the minimally invasive closure of the left atrial appendage could be successfully implemented and a feasibility test showed promising results in anatomies that are difficult to access with the standard catheter. PMID- 29623541 TI - Nonparametric change point estimation for survival distributions with a partially constant hazard rate. AB - We present a new method for estimating a change point in the hazard function of a survival distribution assuming a constant hazard rate after the change point and a decreasing hazard rate before the change point. Our method is based on fitting a stump regression to p values for testing hazard rates in small time intervals. We present three real data examples describing survival patterns of severely ill patients, whose excess mortality rates are known to persist far beyond hospital discharge. For designing survival studies in these patients and for the definition of hospital performance metrics (e.g. mortality), it is essential to define adequate and objective end points. The reliable estimation of a change point will help researchers to identify such end points. By precisely knowing this change point, clinicians can distinguish between the acute phase with high hazard (time elapsed after admission and before the change point was reached), and the chronic phase (time elapsed after the change point) in which hazard is fairly constant. We show in an extensive simulation study that maximum likelihood estimation is not robust in this setting, and we evaluate our new estimation strategy including bootstrap confidence intervals and finite sample bias correction. PMID- 29623542 TI - Parenting Stress Plays a Mediating Role in the Prediction of Early Child Development from Both Parents' Perinatal Depressive Symptoms. AB - Maternal postnatal depression has been associated with a broad range of developmental risk among children. However, there has been less focus on disentangling the effects of pre- and postnatal depressive symptoms, as well as examining the symptoms of both parents. This study aims to investigate the separate effects of pre- and postnatal depressive symptoms in mothers and fathers, and parents' differential effects on child social-emotional, cognitive, and language development at 18 months of age. Further, we investigate whether effects of depressive symptomatology on child outcomes are particularly strong when both parents evinced high symptom loads and whether parenting stress mediates associations between perinatal depressive symptoms and child developmental outcomes. The study used data from 1036 families participating in a community-based study from mid-pregnancy until 18 months postpartum. Depressive symptoms were assessed at seven time points (four prenatally). Within a structural equation framework, we found that parental perinatal depressive symptoms predicted child social-emotional functioning, specifically externalizing, internalizing, and dysregulation problems, as well as language developmental delay at 18 months. Controlling for postnatal symptoms we found no independent effect of prenatal depressive symptoms on any child outcomes. A differential effect was evident, linking maternal symptoms to social-emotional outcomes, and paternal symptoms to language outcomes. There was no evidence of stronger associations between depressive symptoms and child outcomes when both parents showed high symptom loads. However, parenting stress mediated most relations between parental depressive symptoms and child outcomes. Findings demonstrate the importance of including paternal depressive symptoms in both clinical and research contexts. PMID- 29623543 TI - Comparison of visual acuity, metamorphopsia, and aniseikonia in patients with an idiopathic epiretinal membrane. AB - PURPOSE: The clinical course of reduced visual acuity, metamorphopsia, and aniseikonia are dissimilar in patients with an epiretinal membrane (ERM). We measured and compared the best-corrected visual acuity (BCVA), metamorphopsia, and aniseikonia of patients with ERM. METHODS: We measured metamorphopsia and aniseikonia horizontally as well as vertically with the M-CHART (MH and MV) and New Aniseikonia Test (NATH and NATV) in 61 patients with unilateral idiopathic ERM. We compared the BCVA with the other values. Comparisons between the MH and the NATV and between the MV and the NATH were performed, because the MH assesses vertical metamorphopsia, and the MV, horizontal metamorphopsia. RESULTS: BCVA was not significantly correlated with the other values (MH vs BCVA: P = .69; MV vs BCVA: P = .114; NATH vs BCVA: P = .656; NATV vs BCVA: P = .935). The MH and NATV magnitudes were significantly correlated, but the correlation coefficient was small (P = .007, r = 0.343); no significant correlation was found between the MV and NATH magnitudes (P = .065). We found patients with aniseikonia, but no metamorphopsia (n = 6), and more patients with metamorphopsia, but no aniseikonia (n = 11). Only 23 patients had coincident directions of metamorphopsia and aniseikonia. CONCLUSIONS: The magnitudes of metamorphopsia and aniseikonia were not closely correlated and their directions did not coincide in most patients. Neither the M-CHARTS nor the NAT measurements correlated with the BCVA. Quantitative testing of metamorphopsia and aniseikonia in addition to that for BCVA is necessary to assess visual function in patients with ERM. PMID- 29623544 TI - SOCS1 gene therapy has antitumor effects in imatinib-resistant gastrointestinal stromal tumor cells through FAK/PI3 K signaling. AB - BACKGROUND: Most of the gastrointestinal stromal tumors (GIST) have mutations in the KIT gene, encoding a receptor tyrosine kinase. Imatinib, a receptor tyrosine kinase inhibitor, is the first-line therapy for unresectable and metastatic GISTs. Despite the revolutionary effects of imatinib, some patients are primarily resistant to imatinib and many become resistant because of acquisition of secondary mutations in KIT. This study investigated the antitumor effects of SOCS1 gene therapy, which targets several signaling pathways. METHODS: We used GIST-T1 (imatinib-sensitive) and GIST-R8 (imatinib-resistant) cells. We infected both cell lines with an adenovirus expressing SOCS1 (AdSOCS1) and examined antitumor effect and mechanisms of its agent. RESULTS: The latter harboured with secondary KIT mutation and had imatinib resistance > 1000-fold higher than the former cells. We demonstrated that AdSOCS1 significantly decreased the proliferation and induced apoptosis in both cell lines. Moreover, SOCS1 overexpression inhibited the phosphorylation of signal transducer and activator of transcription 3 (STAT3), AKT, and focal adhesion kinase (FAK) in both of them. Inhibition of JAK signaling did not affect the proliferation enough. However, inhibition of the FAK signaling with an FAK inhibitor or RNA interference significantly showed inhibitory effect on cell growth and suppressed the phosphorylation of AKT, indicating a cross-talk between the AKT and FAK pathways in both the imatinib-sensitive and imatinib-resistant GIST cells. CONCLUSIONS: Our results indicate that the activation of FAK signaling is critical for proliferation of both imatinib-sensitive and -resistant GIST cells and the interference with FAK/AKT pathway might be beneficial for therapeutic target. PMID- 29623546 TI - Exercise rehabilitation in ventricular assist device recipients: a meta-analysis of effects on physiological and clinical outcomes. AB - Exercise rehabilitation in heart failure patients has been shown to improve quality of life (QoL) and survival. It is also recommended in clinical practice guidelines for ventricular assist device (VAD) recipients. However, there have only been two meta-analyses on the effects of exercise rehabilitation in VAD patients, on only two outcomes. The objective of the review was to quantitatively evaluate the effect of exercise rehabilitation in VAD recipients on functional capacity, exercise physiology parameters, chronotropic responses, inflammatory biomarkers and neurohormones, heart structure and function, and clinical outcomes. The following databases were systematically searched: CCTR, CDSR, CINAHL, EMBASE, PsycInfo, and Medline through to November 2015, for studies reporting on VAD recipients receiving >= 2 sessions of aerobic training. Citations were considered for inclusion, and data were extracted in included studies as well as quality assessed, each by two investigators independently. Random-effects meta-analyses were performed where possible. The meta-analysis showed that compared to usual care, exercise rehabilitation significantly improved peak VO2 (n = 74, mean difference = 1.94 mL kg-1 min-1, 95% CI 0.63 3.26, p = 0.004) and 6-min walk test distance (n = 52, mean difference = 42.46 m, 95% CI 8.45-76.46, p = 0.01). No significant differences were found for the ventilatory equivalent slope (VE/VCO2) or ventilatory anaerobic threshold (VAT). In the six studies which reported QoL, exercise rehabilitation was beneficial in four, with no difference observed in two studies. Exercise rehabilitation is associated with improved outcomes in VAD recipients, and therefore should be more systematically delivered in this population. PMID- 29623545 TI - Glial Fatty Acid-Binding Protein 7 (FABP7) Regulates Neuronal Leptin Sensitivity in the Hypothalamic Arcuate Nucleus. AB - The hypothalamus is involved in the regulation of food intake and energy homeostasis. The arcuate nucleus (ARC) and median eminence (ME) are the primary hypothalamic sites that sense leptin and nutrients in the blood, thereby mediating food intake. Recently, studies demonstrating a role for non-neuronal cell types, including astrocytes and tanycytes, in these regulatory processes have begun to emerge. However, the molecular mechanisms involved in these activities remain largely unknown. In this study, we examined in detail the localization of fatty acid-binding protein 7 (FABP7) in the hypothalamic ARC and sought to determine its role in the hypothalamus. We performed a phenotypic analysis of diet-induced FABP7 knockout (KO) obese mice and of FABP7 KO mice treated with a single leptin injection. Immunohistochemistry revealed that FABP7+ cells are NG2+ or GFAP+ in the ARC and ME. In mice fed a high-fat diet, weight gain and food intake were lower in FABP7 KO mice than in wild-type (WT) mice. FABP7 KO mice also had lower food intake and weight gain after a single injection of leptin, and we consistently confirmed that the number of pSTAT3+ cells in the ARC indicated that the leptin-induced activation of neurons was significantly more frequent in FABP7 KO mice than in WT mice. In FABP7 KO mice-derived primary astrocyte cultures, the level of ERK phosphorylation was lower after leptin treatment. Collectively, these results indicate that in hypothalamic astrocytes, FABP7 might be involved in sensing neuronal leptin via glia-mediated mechanisms and plays a pivotal role in controlling systemic energy homeostasis. PMID- 29623547 TI - First Analysis of SERPING1 Gene in Patients with Hereditary Angioedema in Colombia Reveals Two Genotypic Variants in a Highly Symptomatic Individual. AB - Hereditary angioedema (HAE) is a heterogeneous genetic disease caused by a deficit in C1 inhibitor (C1-INH) and clinically characterized by sudden events of edema, swelling, and pruritus. Here, we describe the first SERPING1 genotyping in 22 subjects from 4 non-related families, all from southern Colombia. The previously reported heterozygous gene mutations, c.1081C>T (p.Gln361*), c.1396C>G (p.Arg466Gly), c.1029+84G>A, or c.106_107del (p.Ser36Phefs*21), were found in 12 patients. Of note, a single patient clinically characterized as severe HAE type 2 expressed mutations in exon 8 and intron 6, whereas all the others have type 1 HAE and expressed one pathogenic variant. One of the subjects, a 5-year-old girl was discovered to have a pathogenic variant, and she is still asymptomatic. This is the first report focused on HAE genetic analysis in a Colombian population. PMID- 29623548 TI - Nanomedicine for obesity treatment. AB - Obesity, as a chronic condition, has been a serious public health issue over the last decades both in the affluent Western world and developing countries. As reported, the risk of several serious diseases increases with weight gain, including type 2 diabetes, coronary heart disease, cancer, and respiratory diseases. In addition to lifestyle modifications, pharmacotherapy has become an important strategy to control weight gain. However, most of the anti-obesity drugs often show poor outcome for weight-loss and cause severe adverse effects. This review surveys recent advances in nanomedicine as an emerging strategy for obesity treatment with an emphasis on the enhanced therapeutic efficiency and minimized side effects. The insights for future development are also discussed. PMID- 29623549 TI - Defect-related luminescent bur-like hydroxyapatite microspheres induced apoptosis of MC3T3-E1 cells by lysosomal and mitochondrial pathways. AB - When orthopedic joints coated by hydroxyapatite (HA) were implanted in the human body, they release wear debris into the surrounding tissues. The generation and accumulation of wear particles will induce aseptic loosening. However, the potential bioeffect and mechanism of HA-coated orthopedic implants on bone cells are poorly understood. In this study, defect-related luminescent bur-like hydroxyapatite (BHA) microspheres with the average diameter of 7-9 MUm which are comparable to that of the wear-debris particles from aseptically loosened HA implants or HA debris have been synthesized by hydrothermal synthesis and the MC3T3-E1 cells were set as a cells model to study the potential bioeffect and mechanism of BHA microspheres. The studies demonstrated that BHA microspheres could be taken into MC3T3-E1 cells via endocytosis involved in micropinocytosis- and clathrin-mediated endocytosis process, and exert cytotoxicity effect. BHA microspheres could induce the cell apoptosis by intracellular production of reactive oxygen species (ROS), which led to not only an increase in the permeability of lysosome and release of cathepsins B, but also mitochondrial dysfunction and DNA damage. Our results provide novel evidence to elucidate their toxicity mechanisms and might be helpful for more reasonable applications of HA based orthopaedic implants in the future. PMID- 29623550 TI - Evaluation of adaptive radiotherapy (ART) by use of replanning the tumor bed boost with repeated computed tomography (CT) simulation after whole breast irradiation (WBI) for breast cancer patients having clinically evident seroma. AB - PURPOSE: The aim of this study is to evaluate adaptive radiotherapy (ART) by use of replanning the tumor bed boost with repeated computed tomography (CT) simulation after whole breast irradiation (WBI) for breast cancer patients having clinically evident seroma. MATERIALS AND METHODS: Forty-eight patients with clinically evident seroma at the time of planning CT simulation for WBI were included. Two RT treatment plannings were generated for each patient based on the initial CT simulation and tumor bed boost CT simulation to assess seroma and boost target volume (BTV) changes during WBI. Also, dosimetric impact of ART was analyzed by comparative evaluation of critical organ doses in both RT treatment plannings. RESULTS: Median time interval between the two CT simulations was 35 days. Statistically significant reduction was detected in seroma volume and BTV during the conventionally fractionated WBI course along with statistically significant reduction in critical organ doses with ART (p < 0.0001). CONCLUSION: Our data suggest significant benefit of ART by use of replanning the tumor bed boost with repeated CT simulation after WBI for patients with clinically evident seroma. PMID- 29623551 TI - Classification of uterine artery angiographic images: a predictive factor of failure in uterine artery embolization for postpartum hemorrhage. AB - PURPOSE: To justify a classification system for angiographic images of uterine artery embolization (UAE) for postpartum hemorrhage (PPH) and identify new risk factors associated with failed embolization. MATERIALS AND METHODS: A retrospective analysis of 63 consecutive patients who underwent UAE for severe PPH was performed. Uterine artery angiography (UA) before embolization was classified into two types: type 1 was defined as complete staining and type 2 was defined as partial staining of the uterine arteries. The clinical outcome, UA classification, and other possible factors previously reported were evaluated. Univariate and multivariate analyses were performed to determine the factors related to clinical outcomes. RESULTS: Sixty-three patients were enrolled (type 1, 22; type 2, 41). The clinical success rates of the primary UAE session were 90.9% (20/22) for type 1 and 61.0% (25/41) for type 2 (p = 0.018). Univariate and multivariate analyses demonstrated that the only UA classification was significantly associated with primary UAE failure (p = 0.033). CONCLUSIONS: The UA classification is an independent predictive factor of the clinical success rate of the primary UAE session for PPH; thus, it is an intuitive and optimal predictor for interventional radiologists to decide whether additional therapy is necessary. PMID- 29623552 TI - First-in-human intraoperative near-infrared fluorescence imaging of glioblastoma using cetuximab-IRDye800. AB - INTRODUCTION: Maximizing extent of surgical resection with the least morbidity remains critical for survival in glioblastoma patients, and we hypothesize that it can be improved by enhancements in intraoperative tumor detection. In a clinical study, we determined if therapeutic antibodies could be repurposed for intraoperative imaging during resection. METHODS: Fluorescently labeled cetuximab IRDye800 was systemically administered to three patients 2 days prior to surgery. Near-infrared fluorescence imaging of tumor and histologically negative peri tumoral tissue was performed intraoperatively and ex vivo. Fluorescence was measured as mean fluorescence intensity (MFI), and tumor-to-background ratios (TBRs) were calculated by comparing MFIs of tumor and histologically uninvolved tissue. RESULTS: The mean TBR was significantly higher in tumor tissue of contrast-enhancing (CE) tumors on preoperative imaging (4.0 +/- 0.5) compared to non-CE tumors (1.2 +/- 0.3; p = 0.02). The TBR was higher at a 100 mg dose than at 50 mg (4.3 vs. 3.6). The smallest detectable tumor volume in a closed-field setting was 70 mg with 50 mg of dye and 10 mg with 100 mg. On sections of paraffin embedded tissues, fluorescence positively correlated with histological evidence of tumor. Sensitivity and specificity of tumor fluorescence for viable tumor detection was calculated and fluorescence was found to be highly sensitive (73.0% for 50 mg dose, 98.2% for 100 mg dose) and specific (66.3% for 50 mg dose, 69.8% for 100 mg dose) for viable tumor tissue in CE tumors while normal peri tumoral tissue showed minimal fluorescence. CONCLUSION: This first-in-human study demonstrates the feasibility and safety of antibody based imaging for CE glioblastomas. PMID- 29623553 TI - Hypertension and Pharmacological Therapy in Women. AB - Cardiovascular (CV) disease is the leading cause of morbidity and mortality for women all over the world. The role and weight of risk factors in relation to gender are not completely clarified as well as their treatment. Pathophysiology of hypertension in woman presents different aspects in relation to phase of life, with an impact on treatment. The only certainties that we have nowadays regarding hypertension therapy in women are really few and may be summarized in: how to treat or, better, what not to use in hypertension in pregnancy and how to treat acute severe hypertension in pregnancy. We have some certainties also on treatment of hypertension associated to some women's comorbidities. Considering guidelines and analyzing what happens in the real world, we report in this review that women have similar major CV risk factors of men, although a minor CV global risk. However, there are some data that suggest that hypertension and diabetes are more important risk factors in women than in men. Blood pressure reduction and benefit by treatment appear similar in women and men, suggesting that we should aim for similar target of blood pressure, although the lower global risk profile should imply different target. Theoretically, recommended drugs are similar in women and men, but in women we must take in account CV risk profile, comorbidity, side effects, and reproductive health. Finally, registries and observational studies show that fewer women reach the target values of blood pressure and that women receive more frequently prescription of "other" classes of drugs than those recommended by guidelines, even after normalization by age and comorbidities. PMID- 29623554 TI - Documenting Resistance and Physiological Changes in Soybean Challenged by Aphis glycines Matsumura (Hemiptera: Aphididae). AB - The soybean aphid, Aphis glycines Matsumura (Hemiptera: Aphididae), is a limiting factor in soybean production in the North Central region of the USA. The objectives of this work were to identify sources of resistance to A. glycines in 14 soybean genotypes, and also document changes in total protein, peroxidase, and chlorophyll in response to aphid feeding. A reduced number of A. glycines was observed on the genotypes UX 2569-159-2-01 and UX 2570-171- 04, indicating the presence of antixenosis and/or antibiosis. UX 2569-159-2-01 expressed the highest level of resistance; whereas, UX 2570-171-04 had moderate levels of resistance to A. glycines. Chlorophyll content was relatively unaffected by A. glycines, except for a reduction in UX 2569-159-2-01 infested plants at 5 and 15 days after infestation (DAI). No changes were detected in total protein content between infested and control plants for the genotypes analyzed; however, peroxidase activity was higher in infested UX 2570-171-04 at both 5 and 10 DAI. This improvement in peroxidase content in infested UX 2570-171-04 may be playing multiple roles in the plant tolerance. PMID- 29623555 TI - The Power of Knowledge, Responses to Change, and the Gymnastics of Causation. PMID- 29623556 TI - Anesthesia for interventional pulmonology procedures: a review of advanced diagnostic and therapeutic bronchoscopy. AB - PURPOSE: Interventional pulmonology is a growing subspecialty of pulmonary medicine with flexible and rigid bronchoscopies increasingly used by interventional pulmonologists for advanced diagnostic and therapeutic purposes. This review discusses different technical aspects of anesthesia for interventional pulmonary procedures with an emphasis placed on pharmacologic combinations, airway management, ventilation techniques, and common complications. SOURCE: Relevant medical literature was identified by searching the PubMed and Google Scholar databases for publications on different anesthesia topics applicable to interventional pulmonary procedures. Cited literature included case reports, original research articles, review articles, meta analyses, guidelines, and official society statements. PRINCIPAL FINDINGS: Interventional pulmonology is a rapidly growing area of medicine. Anesthesiologists need to be familiar with different considerations required for every procedure, particularly as airway access is a shared responsibility with pulmonologists. Depending on the individual case characteristics, a different selection of airway method, ventilation mode, and pharmacologic combination may be required. Most commonly, airways are managed with supraglottic devices or endotracheal tubes. Nevertheless, patients with central airway obstruction or tracheal stenosis may require rigid bronchoscopy and jet ventilation. Although anesthetic approaches may vary depending on factors such as the length, complexity, and acuity of the procedure, the majority of patients are anesthetized using a total intravenous anesthetic technique. CONCLUSIONS: It is fundamental for the anesthesia provider to be updated on interventional pulmonology procedures in this rapidly growing area of medicine. PMID- 29623557 TI - Late right ventricular performance after mitral valve repair assessed by exercise echocardiography. AB - OBJECTIVES: The aim of the study was to evaluate the right ventricular (RV) performance during exercise in patients who underwent mitral valve repair for chronic mitral valve insufficiency relative to healthy individuals and to assess exercise capacity using a semisupine ergometer. METHODS: We studied 56 patients who underwent mitral valve repair for degenerative posterior mitral leaflet prolapse between 2005 and 2014 and a control group of 13 healthy individuals. Clinical data were collected prospectively, and echocardiographic measurements of RV function were obtained at rest and at peak exercise. RESULTS: One-third of the study patients had RV systolic dysfunction as indicated by tricuspid annular plane excursion (TAPSE) at rest. Resting TAPSE was lower in the study group (16.7 +/- 3.3 mm) than in the control group (24.4 +/- 4.3 mm), p < 0.001. TAPSE increased in both groups during exercise and exercise was shown to have a significant main effect on TAPSE F(1, 52) = 80, p < 0.001. TAPSE increased more in the control group and an interaction was detected between the participant groups (study group vs. control group) and exercise, F(1, 52) = 24, p < 0.001. In the study group, Poor postoperative RV function was associated with preoperative left ventricular dilatation but was not correlated with impaired maximum exercise capacity. CONCLUSIONS: Despite the excellent clinical outcome during rest and exercise after mitral valve repair, our results suggest patients that have undergone mitral valve repair due to posterior leaflet prolapse have significantly reduced RV function at rest and during exercise compared to healthy controls at long-term follow-up, as measured by TAPSE. PMID- 29623558 TI - Why I choose to repair and not to replace the aortic valve? AB - Aortic valve replacement whether surgical or transcutaneous remains an option for the treatment of severe aortic valve disease; however, current prosthetic devices are associated with complications including, but no limited to, valve thrombosis and thromboembolic events, bleeding events associated with anticoagulation use, prosthetic valve endocarditis and structural valve deterioration. In this effect, aortic valve repair (AVr) has become an attractive alternative in circumventing these potential complications by preservation of the native aortic valve apparatus. In this article, we attempt to present the progress made for AVr over the last two decades. We also wish to highlight the critical steps for successful AVr and the outcome data that demonstrate that can be first-choice treatment in selected patients and finally to emphasize on the key steps for further future development. PMID- 29623559 TI - Head-to-Head Comparison of EQ-5D-3L and EQ-5D-5L Health Values. AB - BACKGROUND: The EQ-5D is a widely used preference-based instrument to measure health-related quality of life. Some methodological drawbacks of its three-level version (EQ-5D-3L) prompted development of a new format (EQ-5D-5L). There is no clear evidence that the new format outperforms the standard version. OBJECTIVE: The objective of this study was to make a head-to-head comparison of the EQ-5D-3L and EQ-5D-5L in a discrete choice model setting giving special attention to the consistency and logical ordering of coefficients for the attribute levels and to the differences in health-state values. METHODS: Using efficient designs, 240 pairs of EQ-5D-3L health states and 240 pairs of EQ-5D-5L health states were generated in a pairwise choice format. The study included 3698 Dutch general population respondents, analyzed their responses using a conditional logit model, and compared the values elicited by EQ-5D-3L and EQ-5D-5L for different health states. RESULTS: No inconsistencies or illogical ordering of level coefficients were observed in either version. The proportion of severe health states with low values was higher in the EQ-5D-5L than in the EQ-5D-3L, and the proportion of mild/moderate states was lower in the EQ-5D-5L than in the EQ-5D-3L. Moreover, differences were observed in the relative weights of the attributes. CONCLUSION: Overall distribution of health-state values derived from a large representative sample using the same measurement framework for both versions showed differences between the EQ-5D-3L and EQ-5D-5L. However, even small differences in the phrasing (language) of the descriptive system or in the valuation protocol can produce differences in values between these two versions. PMID- 29623560 TI - Middle East respiratory syndrome coronavirus in pediatrics: a report of seven cases from Saudi Arabia. AB - Infection with Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in 2012 as an important respiratory disease with high fatality rates of 40%-60%. Despite the increased number of cases over subsequent years, the number of pediatric cases remained low. A review of studies conducted from June 2012 to April 19, 2016 reported 31 pediatric MERS-CoV cases. In this paper, we present the clinical and laboratory features of seven patients with pediatric MERS. Five patients had no underlying medical illnesses, and three patients were asymptomatic. Of the seven cases, four (57%) patients sought medical advice within 1-7 days from the onset of symptoms. The three other patients (43%) were asymptomatic and were in contact with patients with confirmed diagnosis of MERS CoV. The most common presenting symptoms were fever (57%), cough (14%), shortness of breath (14%), vomiting (28%), and diarrhea (28%). Two (28.6%) patients had platelet counts of < 150 * 109/L, and one patient had an underlying end-stage renal disease. The remaining patients presented with normal blood count, liver function, and urea and creatinine levels. The documented MERS-CoV Ct values were 32-38 for four of the seven cases. Two patients (28.6%) had abnormal chest radiographic findings of bilateral infiltration. One patient (14.3%) required ventilator support, and two patients (28.6%) required oxygen supplementation. All the seven patients were discharged without complications. PMID- 29623562 TI - Decline in Buprenorphine/Naloxone Prescriptions in a State Medicaid Population Following Formulary Conversion from Suboxone to Bunavail. AB - INTRODUCTION: A large, statewide, fee-for-service Medicaid plan recently (October 2015) executed a complete switch from sublingual buprenorphine-naloxone [(SLBN), Suboxone(r)] to buccal buprenorphine-naloxone [(BBN), Bunavail(r)] on its preferred drug formulary. This complete formulary switch provided an opportunity to assess dynamic changes in prescribing patterns, patient/physician acceptance, and indices of potential misuse/diversion. METHODS: For the period January 1, 2015 through December 31, 2016, two datasets were analyzed: prescriptions and associated costs for buprenorphine-naloxone (BN) products and urine toxicology test results for patients in the Medicaid plan. The dataset comprised 1370 unique providers ordering 643,225 prescriptions for opioid addiction therapy. Patient and order volumes, and the rate of monthly positive laboratory values for opioid molecules and cocaine were reviewed. A targeted survey of physicians treating opioid-dependent patients with state Medicaid plan coverage was also conducted. RESULTS: Upon plan conversion to BBN, there was a rapid increase in monthly BBN prescriptions mirrored by a rapid decrease in SLBN prescriptions. Peak in BBN prescriptions (2633 in November 2015) was approximately 60% lower than peak in SLBN prescriptions (6531 in July 2015). An unexpected finding was a 68% reduction of the overall BN market, indicating that many BN prescriptions were abandoned. The reduction was associated with quarterly cost savings to the Medicaid plan of approximately $3.5 million. Toxicology results indicated a reduction in drug positivity (defined as positivity for cocaine and/or any opioids except buprenorphine and methadone) from 13-16% in 2015 to less than 10% in 2016. Heroin positivity decreased from approximately 9% in December 2015 to an average of less than 1% during the last quarter of 2016, while positivity for norbuprenorphine, the major metabolite of buprenorphine, showed a marked increase in 2016 vs 2015. Among physicians who responded to the targeted survey most rated BBN as more difficult to abuse or misuse than SLBN. CONCLUSION: The rapid reduction in the overall BN market following a complete formulary switch from SLBN to BBN was associated with quarterly savings of $3.5 million for the state Medicaid plan. Toxicology data suggest that this cost saving was realized in the context of improved physician and patient adherence to treatment protocols. The changing market dynamics can potentially be explained by a number of contributory factors, including a reduction of diversion and illicit distribution of BN following formulary conversion. These results are considered hypothesis-generating and future research should systematically compare the propensity for diversion and abuse of BN products using various epidemiological tracking tools. FUNDING: BioDelivery Sciences International, Inc. PMID- 29623563 TI - Assessment of Radiology Training During Radiation Oncology Residency. AB - A strong foundation in diagnostic imaging is essential to the practice of radiation oncology. This study evaluated radiology training in radiation oncology residency. An online survey was distributed to current radiation oncology residents in the USA by e-mail in 2017. Responses were summarized using frequency and percentages and compared with chi-square test and Spearman's rank correlation when appropriate. One hundred five residents completed the survey. Although most residents felt that a strong knowledge base in diagnostic radiology was moderately or extremely important (87%, n = 90/104), the majority were only somewhat confident in their radiology skills (61%, n = 63/104) and were only somewhat, minimally, or not at all satisfied with their training (79%, n = 81/103). Although there was an association between increasing post-graduate training and confidence level (p = 0.01062, rho = 0.24959), the majority of graduating residents feel only somewhat confident in radiology skills (63%, n = 12/19). Residents were most commonly exposed to radiology via multidisciplinary conferences (96%, n = 100/104), though only 15% (n = 16/104) of residents ranked these as the most beneficial component of their radiology training and 13% (n = 13/101) of residents felt these were the least beneficial. Most residents (60%, n = 63/105) believe there is a need for dedicated radiology training during residency, preferring monthly formal didactics (68%, n = 71/105) co-taught by a radiologist and radiation oncologist (58%, n = 61/105). Radiation oncology residents feel their radiology training is suboptimal, suggesting a need for more guidance and standardization of radiology curriculum. A preferred option may be monthly didactics co-taught by radiologists and radiation oncologists; however, future studies should assess the effectiveness of this model. PMID- 29623564 TI - Brief Report: Memory for Self-Performed Actions in Adults with Autism Spectrum Disorder: Why Does Memory of Self Decline in ASD? AB - The decline in self-related memory in ASD was investigated by using encoding, forgetting, and source monitoring. Participants memorized action sentences verbally, observationally, or by enacted encoding. Then, they underwent recall, recognition, and source monitoring memory tests immediately and 1 week later. If the information were properly encoded, memory performance in the enacted encoding would be the highest (enactment effect). The result of memory tests in ASD and TD people showed that enacted encoding was superior. However, recall and source monitoring in ASD was significantly lower than in TD, which was not the case for recognition and forgetting. These results suggest that the decline in memory of self in ASD is associated with a deficit in memory reconstruction and source monitoring. PMID- 29623561 TI - NKT cells in liver diseases. AB - Natural killer T cells are innate-like and tissue-resident lymphocytes, which recognize lipid antigens and are enriched in the liver. Natural killer T cells play important roles in infections, tumors, autoimmune diseases, and metabolic diseases. In this study, we summarize recent findings on biology of natural killer T cells and their roles in hepatitis B virus and hepatitis C virus infection, autoimmune liver diseases, alcoholic liver disease, nonalcoholic fatty liver disease, and hepatocellular carcinoma. Controversial results from previous studies are discussed, and indicate the dynamic alteration in the role of natural killer T cells during the progression of liver diseases, which might be caused by changes in natural killer T subsets, factors skewing cytokine responses, and intercellular crosstalk between natural killer T cells and CD1d-expressing cells or bystander cells. PMID- 29623567 TI - Clear Cell Sarcoma-Like Tumor of the Gastrointestinal Tract. PMID- 29623565 TI - Effect of master mixes on the measurement of telomere length by qPCR. AB - Alterations in telomere length (TL) have been associated with several diseases and a method based on qPCR, the Monochrome Multiplex Real-Time Quantitative PCR (MMQPCR) technique, has been used extensively for the analysis of TL. Some previous studies have been found that certain methodological conditions can affect the measurement of TL. The aim of the study was to evaluate the performance of eight different commercially available SYBR Green and High Resolution Melting (HRM) mixes on the measurement of TL by the MMQPCR method. Four SYBR Green and four HRM mixes were tested and the measurement of TL was expressed by the T/S ratio. It was found that the type of master mix used in MMQPCR influences the measurement of TL, affecting aspects such as the specificity and consistency of the results. Our results are the first description of the effects of different master mixes on TL analysis by MMQPCR and highlight the importance of the future methodological improvement of this broadly used technique. PMID- 29623568 TI - Metachronous Hepatic Angiosarcoma Presenting as a Mimic of Recurrent Hepatocellular Carcinoma. PMID- 29623566 TI - The effect of QTL-rich region polymorphisms identified by targeted DNA-seq on pig production traits. AB - The aim of the present study was to analyse the effect of PLCD4, PECR, FN1 and PNKD mutations on pig productive traits and tested the usefulness of targeted enrichment DNA sequencing method as tool for preselection of genetic markers. The potential genetic markers for pig productive traits were identified by using targeted enrichment DNA sequencing of chromosome 15 region that is QTL-rich. The selected mutations were genotyped by using HRM, Sanger sequencing and PCR-ACRS methods. The association study was performed by using GLM model in SAS program and included over 500 pigs of 5 populations maintained in Poland. The variation (C/T) of PLCD4 gene affected feed conversion, intramuscular fat and water exudation. The PNKD mutations were associated with texture parameters measured after cooking. In turn, the variation rs792423408 (C/T) in the FN1 gene influenced toughness measured in semimembranosus muscle and growth traits that was observed particularly in Duroc breed. Summarizing, the investigated gene variants delivered valuable information that could be used during developing SNP microarray for genomic estimated breeding value procedure in pigs. Moreover, the study showed that the TEDNA-seq method could be used to preselect the molecular markers associated with pig traits. However, the further association study that included large number animal populations is necessary. PMID- 29623569 TI - Advances in computer-assisted syndrome recognition by the example of inborn errors of metabolism. AB - Significant improvements in automated image analysis have been achieved in recent years and tools are now increasingly being used in computer-assisted syndromology. However, the ability to recognize a syndromic facial gestalt might depend on the syndrome and may also be confounded by severity of phenotype, size of available training sets, ethnicity, age, and sex. Therefore, benchmarking and comparing the performance of deep-learned classification processes is inherently difficult. For a systematic analysis of these influencing factors we chose the lysosomal storage diseases mucolipidosis as well as mucopolysaccharidosis type I and II that are known for their wide and overlapping phenotypic spectra. For a dysmorphic comparison we used Smith-Lemli-Opitz syndrome as another inborn error of metabolism and Nicolaides-Baraitser syndrome as another disorder that is also characterized by coarse facies. A classifier that was trained on these five cohorts, comprising 289 patients in total, achieved a mean accuracy of 62%. We also developed a simulation framework to analyze the effect of potential confounders, such as cohort size, age, sex, or ethnic background on the distinguishability of phenotypes. We found that the true positive rate increases for all analyzed disorders for growing cohorts (n = [10...40]) while ethnicity and sex have no significant influence. The dynamics of the accuracies strongly suggest that the maximum distinguishability is a phenotype-specific value, which has not been reached yet for any of the studied disorders. This should also be a motivation to further intensify data sharing efforts, as computer-assisted syndrome classification can still be improved by enlarging the available training sets. PMID- 29623570 TI - Food Security and Diet Among American Indians in the Midwest. AB - The purpose of this study was to determine levels of food security among American Indians (AI) living in the Midwest and possible correlations between food security levels and various health outcomes, diet, and demographic variables. This study used a cross-sectional design to determine health behaviors among AI. Participants (n = 362) were recruited by AI staff through various cultural community events in the Midwest, such as powwows and health fairs. Inclusion criteria included the following: age 18 years or older, self-identify as an AI, and willing to participate in the survey. Of all participants, 210 (58%) had either low or very low food security, with 96 in the very low category (26.5%). Participants with very low food security tended to have significantly more chronic conditions. Additional significant differences for very low food security existed by demographic variables, including having no insurance (p < 0.0001) or having a regular primary care provider (p = 0.0354). There was also a significant difference between food security levels and the consumption of fast food within the past week (p value = 0.0420), though no differences were found in fruit and vegetable consumption. AI in our sample had higher levels of food insecurity than those reported in the literature for other racial/ethnic groups. AI and non Native health professionals should be aware of the gravity of food insecurity and the impact it has on overall health. Additional research is needed to determine specific aspects of food insecurity affecting different Native communities to develop appropriate interventions. PMID- 29623571 TI - Introducing Students of Color to Health Sciences Research: An Evaluation of the Health Disparities Summer Internship Program. AB - The goal of this analysis is to assess the effectiveness of a summer program designed to introduce high school students of color to health disparities research. A total of 73 students (69.9% Black, 68.5% female and 80.6% either junior/senior) participated in the 4-week Health Disparities Summer Internship Program (HDSIP) during the years 2012-2015. Students attended lectures covering topics such as health disparities, community-based participatory research (CBPR), immigrant health, and policy and advocacy. While working with community-based organizations, students gained hands-on experience related to issues discussed in class. Students completed research projects and provided suggestions for health policy change. Pre/post surveys were completed to evaluate the program. After participating in the HDSIP, students demonstrated heightened awareness of the social determinants of health, especially in regards to racial discrimination (p = .023); borderline statistically significant increases were shown for income (p = .082), community safety (p = .058), and healthcare access (p = .076). Most students (82.1%) planned to advocate for changes in their community; an increase from the initial 65.2% (p = .052). About nine out of ten students (89.6%) reported being satisfied with the summer program; the majority reported improvement in analytical skills, CBPR methods, and oral/communication skills. Increasing diversity in the health workforce has widely been proposed as a means of addressing health disparities. Introducing minority students to health professions can serve as a catalyst for lasting changes in health outcomes. The HDSIP has increased students' awareness of social determinants of health and has fostered their interest in improving the health of minority populations. PMID- 29623572 TI - Disarming the gunslinger effect: Reaction beats intention for cooperative actions. AB - According to the famous physicist Niels Bohr, gunfights at high noon in Western movies not only captivate the cinema audience but also provide an accurate illustration of a psychophysical law. He suggested that willed actions come with slower movement execution than reactions, and therefore that a film's hero is able to get the upper hand even though the villain normally draws first. A corresponding "gunslinger effect" has been substantiated by empirical studies. Because these studies used a markedly competitive setting, however, it is currently unclear whether the gunslinger effect indeed reflects structural differences between willed actions and reactive movements, or whether it is a by product of the competitive setting. To obtain bullet-proof evidence for a true reactive advantage, we investigated willed and reactive movements during a cooperative interaction of two participants. A pronounced reactive advantage emerged, indicating that two independent systems indeed control willed and reactive movements. PMID- 29623573 TI - Bioactive Oleic Derivatives of Dopamine: A Review of the Therapeutic Potential. AB - Lipid derivatives of dopamine are a novel class of compounds raising a research interest due to the potential of their being a vehicle for dopamine delivery to the brain. The aim of the present paper is to review the main features of the two most prominent bioactive members of this family, namely, N-oleoyl-dopamine (OLDA) and 3'-O-methyl-N-oleoyl-dopamine (OMe-OLDA), with emphasis on the possible therapeutic properties. PMID- 29623574 TI - Does Patient-Specific Instrumentation Improve Femoral and Tibial Component Alignment in Total Knee Arthroplasty? A Prospective Randomized Study. AB - Alignment of the prosthesis is one of the most significant factors that affect the long-term clinical outcome following total knee arthroplasty (TKA). There is conflicting evidence whether patient-specific instrumentation (PSI) for TKA improves the component position compared to standard instrumentation. This study aimed to compare the rotational alignment of the femoral and tibial components in TKA patients when performed with either conventional or PSI. Sixty patients with primary knee osteoarthritis were randomly divided into two groups treated surgically with TKA: one with conventional instrumentation and the other with the Visionaire PSI system (Smith and Nephew, Memphis, TN). Computerized tomography (CT) and X-ray imaging were performed preoperatively and 12 weeks after surgery. The rotational alignment of the femoral and tibial component in all patients was assessed postsurgically using CT imaging according to the Berger protocol. Both groups were clinically assessed in a blinded fashion using the Knee Society Score (KSS) and a visual analog scale (VAS). Fifty-eight patients were prospectively assessed. The mean postsurgical follow-up was 3.0 +/- 0.4 months. CT images did not reveal any significant improvement in the rotational alignment of the implant components between the groups. X-rays revealed a significant improvement in the deviation from the optimal alignment range of the femoral component in the coronal plane in both groups. Patients operated with Visionaire PSI assistance had poorer functional outcomes. We conclude that there were no improvements in clinical outcomes or knee component alignment in patients treated with PSI compared with those treated with standard instruments. In addition, clinical and functional assessment showed inferior results in terms of KSS and VAS scores at the midterm follow-up in patients treated with PSI. PMID- 29623575 TI - Effect of eribulin on patients with metastatic breast cancer: multicenter retrospective observational study in Taiwan. AB - PURPOSE: The aim of this study was to confirm the therapeutic role of eribulin on Taiwanese women with metastatic breast cancer. METHODS: This retrospective study examined 449 females who received eribulin between March 2014 and June 2017 at 14 hospitals in Taiwan for treatment of locally advanced or metastatic breast cancer. RESULTS: The survival rate at 24 months was 57.2% (95% CI 51.0-62.9%) and the median time to treatment failure (TTF) was 3.91 months (95% CI 3.45-3.94). A total of 175 patients (40.1%) received eribulin for fewer than 90 days and the others received it for 90 days or more. Eight patients (1.83%) had complete remission, 82 (18.8%) had partial remission, 202 (46.3%) had stable disease, and 144 (33.0%) had progressive disease (PD). Patients' tumors with the luminal A subtype had a significantly better objective response rate. Kaplan-Meier analysis indicated that hormone receptor positivity, luminal A subtype, receipt of eribulin as the 1st to 3rd line therapy, and metastasis to fewer than 4 organs were significantly associated with longer TTF. Stepwise multivariate analysis showed that only receipt of eribulin as the 1st to 3rd line therapy was significantly associated with TTF (HR 1.49, p < 0.001). All toxicities were manageable and only 18 patients (4.1%) discontinued treatment due to adverse events. CONCLUSIONS: Eribulin appears to have better efficacy and cause fewer adverse events, especially neutropenia, in Taiwanese women than Western women. PMID- 29623576 TI - Understanding racial/ethnic differences in breast cancer-related physical well being: the role of patient-provider interactions. AB - PURPOSE: Racial/ethnic differences in cancer symptom burden are well documented, but limited research has evaluated modifiable factors underlying these differences. Our objective was to examine the role of patient-provider interactions to help explain the relationship between race/ethnicity and cancer specific physical well-being (PWB) among women with breast cancer. METHODS: The Pathways Study is a prospective cohort study of 4505 women diagnosed with breast cancer at Kaiser Permanente Northern California between 2006 and 2013. Our analysis included white, black, Hispanic, and Asian participants who completed baseline assessments of PWB, measured using the Functional Assessment of Cancer Therapy for Breast Cancer, and patient-provider interactions, measured by the Interpersonal Processes of Care Survey (IPC) (N = 4002). Using step-wise linear regression, we examined associations of race/ethnicity with PWB, and changes in associations when IPC domains were added. RESULTS: We observed racial/ethnic differences in PWB, with minorities reporting lower scores than whites (beta, black: - 1.79; beta, Hispanic: - 1.92; beta, Asian: - 1.68; p < 0.0001 for all comparisons). With the addition of health and demographic covariates to the model, associations between race/ethnicity and PWB score became attenuated for blacks and Asians (beta: - 0.63, p = 0.06; beta: - 0.68, p = 0.02, respectively) and, to a lesser extent, for Hispanic women (beta: - 1.06, p = 0.0003). Adjusting for IPC domains did not affect Hispanic-white differences (beta: - 1.08, p = 0.0002), and slightly attenuated black-white differences (beta: - 0.51, p = 0.14). Asian-white differences narrowed substantially (beta: - 0.31, p = 0.28). CONCLUSIONS: IPC domains, including those capturing perceived discrimination, respect, and clarity of communication, appeared to partly explain PWB differences for black and Asian women. Results highlight opportunities to improve providers' interactions with minority patients, and communication with minority patients about their supportive care needs. PMID- 29623577 TI - Use of dual mTOR inhibitor MLN0128 against everolimus-resistant breast cancer. AB - PURPOSE: HR+/HER2- aromatase inhibitor-resistant metastatic breast cancer can be treated with everolimus and a second AI until the cancer recurs. Targeting these everolimus-resistant patients with the latest standard of care, CDK4/6 inhibitors, has not been clearly addressed. Understanding the signaling transduction pathways, which everolimus resistance activates, will elucidate the mechanisms and offer treatment strategies of everolimus resistance. METHODS: To mimic the clinical setting, letrozole-resistant cells were used to generate an everolimus-resistant model (RAD-R). Reverse phase protein array (RPPA) was performed to reveal changes in the signaling transduction pathways, and expression levels of key proteins were analyzed. Inhibitors targeting the major signaling pathways, a CDK4/6 inhibitor palbociclib and a mTORC1/2 inhibitor (MLN0128), were evaluated to establish resistance mechanisms of RAD-R. RESULTS: RPPA results from RAD-R indicated changes to significant regulatory pathways and upregulation of p-AKT expression level associating with everolimus resistance. MLN0128, that inhibits the AKT phosphorylation, effectively suppressed the proliferation of RAD-R cells while treatment with palbociclib had no effect. CONCLUSION: Among the many signaling transduction pathways, which are altered post everolimus resistance, targeting dual mTORC1/2 is a possible option for patients who have recurrent disease from previous everolimus treatment. PMID- 29623578 TI - Trajectories of Depressive Symptoms Among a Population of HIV-Infected Men and Women in Routine HIV Care in the United States. AB - Depressive symptoms vary in severity and chronicity. We used group-based trajectory models to describe trajectories of depressive symptoms (measured using the Patient Health Questionnaire-9) and predictors of trajectory group membership among 1493 HIV-infected men (84%) and 292 HIV-infected women (16%). At baseline, 29% of women and 26% of men had depressive symptoms. Over a median of 30 months of follow-up, we identified four depressive symptom trajectories for women (labeled "low" [experienced by 56% of women], "mild/moderate" [24%], "improving" [14%], and "severe" [6%]) and five for men ("low" [61%], "mild/moderate" [14%], "rebounding" [5%], "improving" [13%], and "severe" [7%]). Baseline antidepressant prescription, panic symptoms, and prior mental health diagnoses were associated with more severe or dynamic depressive symptom trajectories. Nearly a quarter of participants experienced some depressive symptoms, highlighting the need for improved depression management. Addressing more severe or dynamic depressive symptom trajectories may require interventions that additionally address mental health comorbidities. PMID- 29623579 TI - Pharmacokinetics, Safety and Tolerability of Oral Semaglutide in Subjects with Renal Impairment. AB - BACKGROUND: Semaglutide, a glucagon-like peptide-1 (GLP-1) analogue, has been co formulated with the absorption enhancer sodium N-(8-[2-hydroxybenzoyl] amino) caprylate (SNAC) as a tablet for oral administration. This trial (NCT02014259) investigated the pharmacokinetics, safety and tolerability of oral semaglutide in subjects with and without renal impairment. METHODS: Subjects were categorised as having normal renal function (n = 24), mild (n = 12), moderate (n = 12) or severe (n = 12) renal impairment, or end-stage renal disease (ESRD) requiring haemodialysis (n = 11) and received once-daily oral semaglutide (5 mg for 5 days followed by 10 mg for 5 days) in the fasting state, followed by 30 min fasting after dosing. Semaglutide plasma concentrations were measured during dosing and for up to 21 days after the last dose. RESULTS: Semaglutide exposure (area under the plasma concentration-time curve from time zero to 24 h after the tenth dose and maximum concentration after the tenth dose) did not vary in a consistent pattern across the renal function groups. Similarly, there was no apparent effect of renal impairment on the semaglutide half-life (geometric mean range 152-165 h). Except for one subject in the ESRD group, semaglutide was not detected in urine. Haemodialysis did not affect the pharmacokinetics of semaglutide. Adverse events were in line with those observed for other GLP-1 receptor agonists and no safety concerns were identified. CONCLUSION: There was no apparent effect of renal impairment or haemodialysis on the pharmacokinetics of oral semaglutide. Based on this trial, renal impairment should not affect dose recommendations for oral semaglutide. PMID- 29623581 TI - Clinical presentation of cashew nut allergy in a paediatric cohort attending an allergy clinic in the West of Ireland. AB - BACKGROUND: Cashew nut (CN) allergy appears to be increasing. Reactions are variable and may include anaphylaxis. AIM: To describe the clinical features of CN allergy in a group of children attending an allergy clinic with suspected peanut allergy and confirmed sensitisation to CN. METHODS: Patients were identified retrospectively by reviewing the Immunology Database at University Hospital Galway over a 5-year period, Oct. 2010 to Sept. 2015. Patients confirmed sensitised to CN (specific IgE > 0.35 kUa/L, ImmunoCAP Assay) were selected and contacted. RESULTS: Over the 5-year period, 115 children were identified; 102/115 were individually contacted. Of the 102 children, 55 had a history of prior CN exposure with confirmed clinical reaction, 43 had no prior CN exposure, and 4 were sensitised and tolerating CN. For those with clinical CN allergy (N = 55), 30 (55%) were male and median age of onset was 2 years (lower quartile 1.5, upper quartile 4.8). Severity of reaction was graded as mild for 13 children, moderate in 13 additional children, and severe in 29 children. Median CN serum IgE level was 3.2 kUa/L (range 0.36 to > 100) in the clinical reaction group, 2.91 kUa/L (range 0.36 to > 100) in the sensitised group, and 3.4 kUa/L (range 0.94 to 5.21) in those tolerating CN. IgE values were not significantly different between those with mild, moderate, or severe reaction to CN (p = 0.346). CONCLUSION: Children are ingesting CN at a young age with more than half of allergic reactions reportedly severe in nature. The specific CN IgE value was not helpful in predicting severity of reactions. PMID- 29623580 TI - Management and consequences of postoperative fluctuations in plasma sodium concentration after pediatric brain tumor surgery in the sellar region: a national cohort analysis. AB - PURPOSE: Severe fluctuations in plasma sodium concentration and plasma osmolarity, including central diabetes insipidus (CDI), may have significant influence on postoperative morbidity and mortality after pediatric brain tumor surgery.The aim of this study was to describe the frequency, severity and neurological consequences of these fluctuations in pediatric brain tumor survivors. METHODS: A retrospective, multi-institutional chart review was conducted among all children who underwent brain tumor surgery in the sellar or suprasellar region in seven university hospitals in the Netherlands between January 2004 and December 2013. RESULTS: Postoperative CDI was observed in 67.5% of 120 included children. Fluctuations of plasma sodium concentration >= 10 mmol/L/24 h during the first ten postoperative days were seen in 75.3% of patients with CDI, with a maximum delta of 46 mmol/L/24 h. When compared to patients without CDI, altered mental status occurred more frequently in patients with postoperative CDI (5.1 vs. 23.5% respectively, p = 0.009). Low plasma sodium concentration was related to altered mental status and the occurrence of seizures. Frequency and severity of fluctuations in plasma sodium concentration during the first ten postoperative days were significantly higher in patients with permanent CDI at last follow-up than in patients with transient CDI or without CDI (p = 0.007). CONCLUSION: Postoperative CDI is a common complication after pediatric brain tumor surgery in the sellar or suprasellar region. Extreme plasma sodium concentrations and large intra-day fluctuations still occur and seem to influence the postoperative neurological course. These results illustrate the need for intensive monitoring in a highly experienced center. PMID- 29623583 TI - Pathology findings and clinical outcomes after risk reduction salpingo oophorectomy in BRCA mutation carriers: a multicenter Spanish study. AB - OBJECTIVE: To determine the incidence of serous tubal intraepithelial carcinoma (STIC) after risk reduction salpingo-oophorectomy(RRSO), and to describe oncological outcomes after RRSO. MATERIALS AND METHODS: BRCA pathogenic mutation carriers who had undergone an RRSO were evaluated in this retrospective multicenter observational study. Patients were only included when fallopian tubes were analyzed following the protocol for Sectioning and Extensively Examining the FIMbria (SEE-FIM). Surgeries were performed between June 2010 and April 2017 at eight Spanish hospitals. RESULTS: A total of 359 patients met the inclusion criteria. STIC was diagnosed in 3 (0.8%) patients; one of them underwent surgical staging due to positive peritoneal washing, with absence of disease at the final pathology report. None of the three patients received adjuvant chemotherapy and were free of disease at last follow-up. Fallopian tube and ovarian carcinoma were diagnosed in 5 (1.4%) and 1 (0.3%), respectively. At a median (range) follow-up time of 29 (3-92) months, five patients had a newly diagnosed breast cancer. Other types of cancer, which were diagnosed during the follow-up time, included: serous primary peritoneal carcinoma (n = 1), serous endometrial carcinoma (n = 1), colon (n = 1), pancreas (n = 1), jaw (n = 1), and lymphoma (n = 1). Seven patients died due to different types of cancer: breast (n = 4), pancreas (n = 1), jaw (n = 1), and colon (n = 1). CONCLUSION: The incidence of STIC after RRSO in BRCA mutation carriers is low (0.8%) and it presents an excellent oncological outcome. Patients after RRSO, however, run the risk to develop other types of cancer during follow-up and should be properly advised before the prophylactic surgery. PMID- 29623582 TI - Childhood and adolescent lymphoma in Spain: incidence and survival trends over 20 years. AB - BACKGROUND: Lymphoma is the third most common malignancy in children (0-14 years) and the first in adolescents (15-19 years). This population-based study-the largest ever done in Spain-analyses incidence and survival of lymphomas among Spanish children and adolescents. PATIENTS AND METHODS: 1664 lymphoma cases (1983 2007) for incidence and 1030 for survival (1991-2005) followed until 31/12/2010, were provided by 11 cancer registries. Age-adjusted incidence rates (ASRw) to the world standard population were obtained; incidence trends were modelled using the Joinpoint programme, observed survival (OS) was estimated with Kaplan-Meier and trends tested with a log-rank test. Results are presented according to the International Classification of Childhood Cancer-3. RESULTS: In Spain, the ASRw0 14 for lymphomas was 17.5 per 1.000.000 child-years and 50.0 the specific rate for adolescents. Overall incidence increased significantly during 1983-1997 with no increases thereafter. Patients over 9 years old showed significant rising trends for all subtypes, except for Burkitt lymphoma (BL) in adolescents. During 2001-2005 (age 0-19 years), 5-year OS was 94 (90-98), 73 (64-83) and 86 (78-94) for Hodgkin lymphoma (HL), non-Hodgkin lymphoma (NHL) and BL, respectively. No improvement in survival was found. The incidence in Spain was higher than overall European rates, but within the range of that in Southern Europe. Comparing OS in Spain 1991-1995 and 2001-2005 with results for Europe of the Automated Childhood Cancer Information System (ACCIS) (1988-1997) and the European cancer registry based study on survival and care of cancer patients (EUROCARE) (2000-2007), it was similar for HL and lower for NHL and BL. CONCLUSIONS: Systematic monitoring and analysis of lymphoma paediatric data would provide clinical and epidemiological information to improve the health care of these patients and the outcomes for these malignancies in Spain. PMID- 29623584 TI - Dosimetry study of 18F-FMISO + PET/CT hypoxia imaging guidance on intensity modulated radiation therapy for non-small cell lung cancer. AB - OBJECTIVES: This study was to evaluate the feasibility of simultaneous integrated boost on tumor hypoxia area by studying the dosimetric change of hypoxia imaging guidance on intensity-modulated radiation therapy for non-small cell lung cancer (NSCLC). METHODS: Five NSCLC patients with large hypoxic volume participated in this study. FDG PET/CT images were fused with CT localization images to delineate gross tumor volume. FMISO PET/CT images were fused with CT localization images to delineate hypoxic biological target volume (BTV) (tissue maximum ratio >= 1.3) by threshold. BTV was irradiated with 72, 78 and 84 Gy, respectively, 30 times. The dosimetry differences were compared in target volume and organ at risk between simultaneous integrated boost plans and conventional radiotherapy plans. RESULTS: Dosages on BTV of NSCLC hypoxic area were increased to 72, 78 and 84 Gy, respectively, by simultaneous integrated boost intensity-modulated radiation therapy. There was no obvious difference in dosage distributions on original target volume compared with those in conventional radiotherapy. Dosages on main organ at risk in chest met the dosimetric constraint, and there was no significant difference compared with those in conventional radiotherapy. CONCLUSION: It is feasible in dosiology that the dosages in NSCLC hypoxic area were added to 72, 78 and 84 Gy by simultaneous integrated boost with the guidance of 18F-FMISO PET/CT. PMID- 29623585 TI - The effect of dose escalation for large squamous cell carcinomas of the anal canal. AB - PURPOSE: Chemoradiation allows for organ preservation in patients with anal cancer, but patients with large tumors (> 5 cm) have elevated rates of locoregional recurrence. With conformal radiation techniques, there is interest in dose escalation to decrease local recurrence in patients with large tumor size. METHODS/PATIENTS: The National Cancer Database (NCDB) was used to identify patients with anal cancer from 2004 to 2013 with tumors > 5 cm. Adult patients who received definitive chemoradiation were included. Patients with prior resection were excluded. High dose was defined as greater than or equal to 5940 cGy. Statistical analyses were performed using logistic regression, Kaplan-Meier, and Cox proportional hazards for overall survival (OS). RESULTS: In total, 1349 patients were analyzed with 412 (30.5%) receiving high-dose radiation therapy (RT). 5-year OS was 58 and 60% for high and standard dose RT, respectively (p = 0.9887). On univariate analysis, high-dose RT was not associated with improved OS (HR = 0.998, CI 0.805-1.239, p = 0.9887). On multivariate analysis, high-dose RT (HR = 0.948, CI 0.757-1.187, p = 0.6420) was not associated with improved OS but older age (HR = 1.535, CI 1.233-1.911, p = 0.0001), male sex (HR = 1.695, CI 1.382-2.080, p < 0.0001), comorbidities (HR = 1.389, CI 1.097-1.759, p = 0.0064), and long RT (HR = 1.299, CI 1.047-1.611, p = 0.0173) were significantly associated with decreased OS. CONCLUSIONS: There was no observed difference in OS for dose escalation of anal cancers > 5 cm in this population-based analysis. Differences in local control and salvage therapy cannot be assessed through the NCDB. Whether dose escalation of large tumors may improve local control and colostomy-free survival remains an important question and is the subject of ongoing trials. PMID- 29623586 TI - Comparison of plasma ctDNA and tissue/cytology-based techniques for the detection of EGFR mutation status in advanced NSCLC: Spanish data subset from ASSESS. AB - PURPOSE: The analysis of epidermal growth factor receptor (EGFR) mutations in many patients with advanced non-small-cell lung cancer (aNSCLC) has provided the opportunity for successful treatment with specific, targeted EGFR tyrosine kinase inhibitors. However, this therapeutic decision may be challenging when insufficient tumor tissue is available for EGFR mutation testing. Therefore, blood surrogate samples for EGFR mutation analysis have been suggested. METHODS: Data were collected from the Spanish cohort of patients in the large, non interventional, diagnostic ASSESS study (NCT01785888) evaluating the utility of circulating free tumor-derived DNA from plasma for EGFR mutation testing. The incidence of EGFR mutation in Spain and the level of concordance between matched tissue/cytology and plasma samples were evaluated. RESULTS: In a cohort of 154 eligible patients, EGFR mutations were identified in 15.1 and 11.0% of tumor and plasma samples, respectively. The most commonly used EGFR mutation testing method for the tumor tissue samples was the QIAGEN Therascreen(r) EGFR RGQ PCR kit (52.1%). Fragment Length Analysis + PNA LNA Clamp was used for the plasma samples. The concordance rate for EGFR mutation status between the tissue/cytology and plasma samples was 88.8%; the sensitivity was 45.5%, and the specificity was 96.7%. CONCLUSIONS: The high concordance between the different DNA sources for EGFR mutation testing supports the use of plasma samples when tumor tissue is unavailable. PMID- 29623587 TI - Postoperative intra-abdominal infection is an independent prognostic factor of disease-free survival and disease-specific survival in patients with stage II colon cancer. AB - BACKGROUND: Recurrence occurs in up to 20% of patients with stage II colon cancer operated on for cure. Although postoperative intra-abdominal infection has been linked with an increased risk of recurrence, the association is controversial. The aim was to investigate the impact of postoperative intra-abdominal infection on disease-free survival and disease-specific survival in patients with stage II colon cancer. METHODS: Patients undergoing elective surgery for colon cancer stage II, between 2003 and 2014, were included. Patients with anastomotic leak or intra-abdominal abscess were included in the infection group. We used the Kaplan Meier method to represent the distribution of survival and the Cox proportional hazards model to estimate the contribution of relevant clinicopathological factors with prognosis. RESULTS: Postoperative intra-abdominal infection was diagnosed in 37 of 363 (10.2%) patients. Perioperative blood transfusion was more frequent in patients with infection (p = 0.008). Overall 5-year disease-free survival rate was 85.1%. Disease-free survival at 5 years was lower in patients with postoperative intra-abdominal infection (52.8 vs 88.7%; p < 0.001), perineural invasion (p = 0.001), lymphovascular invasion (p = 0.001), pT4 (p = 0.013), and in patients with adjuvant chemotherapy (p = 0.013). Multivariate analysis showed that postoperative intra-abdominal infection (HR 4.275; p < 0.001), perineural invasion (HR 2.230; p = 0.007), and lymphovascular invasion (HR 2.052; p = 0.016) were all significant independent predictors of reduced disease-free survival. Regarding specific survival, independent significant prognostic factors were the number of lymph nodes, lymphovascular invasion, and postoperative intra-abdominal infection. CONCLUSION: In this series of patients with stage II colon cancer, postoperative intra-abdominal infection has an independent negative impact on disease-free survival and disease-specific survival. PMID- 29623588 TI - Recurrent non-functioning pituitary adenomas: a review on the new pathological classification, management guidelines and treatment options. AB - At least 50% of surgically resected non-functioning pituitary adenomas (NFPA) recur. Either early or late adjuvant radiotherapy is highly efficacious in controlling recurrent NFPA but associates potentially burdensome complications like hypopituitarism, vascular complications or secondary neoplasm. Reoperation is indicated in bulky tumor rests compressing the optic pathway. To date, no standardized medical therapy is available for recurrent NFPA although cabergoline and temozolomide show promising results. Guidelines on the management of recurrent NFPAs are now available. The new 2017 WHO pituitary tumor classification, based on immunohistochemistry and transcription factor assessment, identifies a group of aggressive NFPA variants that may benefit from earlier adjuvant therapy. Nevertheless, NFPA patients exhibit a reduced overall life expectancy largely due to hypopituitarism and treatment-related morbidity. The management of recurrent NFPA benefits from a multidisciplinary teamwork of surgeons, endocrinologists, radiation oncologists, ophthalmologists, pathologists and neuro-radiologists in order to provide individualized therapy and anticipate deterioration. PMID- 29623589 TI - Linear Mixed Effects Analysis Reveals the Significant Impact of Preoperative Diet Success on Postoperative Weight Loss in Gastric Bypass Surgery. AB - BACKGROUND: Several studies investigated the impact of preoperative weight loss on bariatric surgery outcome. However, they mostly focus on small groups of patients or lack updated statistical support. METHODS: Two hundred and thirty nine consecutive patients undergoing laparoscopic, proximal Roux-en-Y gastric bypass at our institution between September 2009 and November 2015 were studied. Patients were operated by the same surgeon, applying a standardized technique and followed a 500-kcal/day preoperative diet, starting 14 days before surgery. Body weight was measured before diet, at surgery, and at least three times postoperatively. A linear mixed effects (LME) model and Benedict and Harris formula were used to assess association of pre- and postoperative weight loss up to 2 years postoperatively. RESULTS: Patients' (184 females) initial weight was 121.7 kg (females 117.2 kg; males 136.6 kg). They lost on average 5.3 kg (females 4.7 kg; males 7.0 kg) pre- and 36.8 kg (females 36.7 kg; males 37.0 kg) postoperatively, within 2 years. Average excess weight loss (EWL) was 67.2% (females 66.6%; males 67.4%). In 205 patients (154 females), EWL exceeded 50%. Longitudinal data analysis according to LME showed a significant impact of pre- on postoperative weight loss (p < 0.001, likelihood-ratio test, LRT). These effects were undetectable if patients were evaluated by non-parametric analysis based on application of the Benedict and Harris formula. CONCLUSIONS: Preoperative dietary success is associated with postoperative weight loss. Effects predicted by the LME model are most pronounced in the first 4-6 months after surgery and are fading away within 24 months postoperatively. External factors not considered in this study might dominate in later phases. PMID- 29623590 TI - Improvement of Body Composition and Quality of Life Following Intragastric Balloon. AB - BACKGROUND: The aim is to evaluate the effects of IGB in overweight or class I obese patients, by analyzing body composition and quality of life (QOL). METHODS: Prospective study including patients with BMI 27-34.9 kg/m2.body composition analysis (BCA) was performed before IGB implantation and its removal, after 6 months of treatment. QOL was assessed by the Short Form 36 (SF-36) Health Survey at baseline and after treatment. RESULTS: Forty patients were included in this study, but four were excluded. The total weight decreased by 12.29 kg after 6 months of use of IGB, which corresponds to loss of 13.69% of the total weight. There was a significant reduction in body fat mass and fat area. QOL improved in all eight sections analyzed (p < 0.001 to 0.041): functional capacity, physical aspects, pain, general health status, vitality, social aspects, emotional aspects, and mental health. CONCLUSIONS: IGB induces not only weight loss but changes in body composition through the reduction of body fat mass and fat area. Furthermore, it improves QOL. PMID- 29623591 TI - Correction to: Intramuscular clodronate in erosive osteoarthritis of the hand is effective on pain and reduces serum COMP: a randomized pilot trial-The ER.O.D.E. study (ERosive Osteoarthritis and Disodium-clodronate Evaluation). AB - One of the author names on this article was incorrectly tagged during the article mark-up; Luca Dalle Carbonare's name has now been correctly tagged, with first name 'Luca' and last name 'Dalle Carbonare'. PMID- 29623593 TI - Efficacy and Safety of Rapid-Acting Insulin Analogs in Special Populations with Type 1 Diabetes or Gestational Diabetes: Systematic Review and Meta-Analysis. AB - INTRODUCTION: To assess the efficacy and safety of three available rapid-acting insulin analogs (insulins lispro, aspart and glulisine, respectively) in pregnant women, children/adolescents and people using continuous subcutaneous insulin infusion (CSII) with type 1 diabetes. METHODS: PubMed, EMBASE and Cochrane Reviews were searched electronically, and their bibliographies examined to identify suitable studies for review and inclusion in a meta-analysis. Eligible studies were randomized controlled trials that reported data on relevant clinical outcomes. A different reviewer abstracted data for each of the three subpopulations, and one reviewer abstracted data for all three. Any differences were resolved by consensus or by consulting a fourth reviewer. RESULTS: In people on CSII, rapid-acting insulin analogs lowered postprandial plasma glucose post breakfast to a greater extent than did regular human insulin (RHI) (mean difference: - 1.63 mmol/L [95% confidence interval - 1.71; - 1.54]), with a comparable risk of hypoglycemia and a trend for lower glycated hemoglobin. In the pediatric population, glycemic control was similar with rapid-acting insulin analogs and RHI, with no safety concerns. Meta-analysis indicated severe hypoglycemic events were comparable for rapid-acting insulin analogs versus RHI (risk difference: 0.00 [95% confidence interval - 0.01; 0.01]). In the pregnancy group, insulin lispro and insulin aspart were safe and effective for both mother and fetus, with glycemic control being at least as good as with RHI. There were no data on insulin glulisine during pregnancy. CONCLUSION: Rapid-acting insulin analogs appear generally safe and effective in these special populations; however, additional trials would be helpful. FUNDING: Novo Nordisk A/S. PMID- 29623592 TI - A Retrospective Cohort Study of Patients with Type 2 Diabetes in China: Associations of Hypoglycemia with Health Care Resource Utilization and Associated Costs. AB - INTRODUCTION: This study aimed to examine the associations of hypoglycemia with health care resource utilization (HCRU) and health care costs among patients with type 2 diabetes mellitus (T2DM) in China. METHODS: This retrospective cohort study was conducted with 23,680 T2DM patients >18 years old who visited the Second Affiliated Hospital of Nanchang University between 1 January 2011 and 31 December 2015. Univariate descriptive statistics were used to relate the HCRU and associated costs to patient characteristics, and regression analysis was used to examine the association between hypoglycemia and HCRU, controlling for other confounding factors. RESULTS: In the T2DM patients with or without insulin treatment, when compared with nonhypoglycemic patients, hypoglycemia was associated with more medical visits (all T2DM patients 19.48 vs. 10.46, insulin users 23.45 vs. 14.12) and higher diabetes-related medical costs (all T2DM patients Y5187.54 vs. Y3525.00, insulin users Y6948.84 vs. Y3401.15) and medication costs (T2DM patients Y1349.40 vs. Y641.92, insulin users: Y1363.87 vs. Y853.96). Controlling for age, gender, and Charlson comorbidity index (CCI) score, hypoglycemia and insulin intake were associated with greater health care resource utilization. As compared to nonhypoglycemic patients, hypoglycemic T2DM patients and those on insulin therapy performed more outpatient visits (proportions of hypoglycemic vs nonhypoglycemic T2DM patients performing 3+ visits: 72.69% vs. 65.49%; proportions of hypoglycemic vs nonhypoglycemic patients on insulin therapy performing 3+ visits: 78.26% vs. 71.73%) and were hospitalized more often (proportions of hypoglycemic vs nonhypoglycemic T2DM patients with 3+ admissions 75.90% vs. 50.24%; proportions of hypoglycemic vs nonhypoglycemic patients on insulin therapy with 3+ admissions: 83.19% vs. 58.51%). CONCLUSION: Hypoglycemia in diabetes patients was associated with increased healthcare resource utilization and health-related expenditure, especially for patients on insulin treatment. Insulin treatment regimens should be more individualized and account for hypoglycemia risk. PMID- 29623594 TI - Combination Treatment of SGLT2 Inhibitors and GLP-1 Receptor Agonists: Symbiotic Effects on Metabolism and Cardiorenal Risk. AB - INTRODUCTION: When treating type 2 diabetes, drugs that cause hypoglycemia and weight gain should, if possible, be avoided. In addition, due to the increased incidence and prevalence of cardiovascular disease, cardiac events and heart failure, as well as the accelerated renal decompensation that may occur with type 2 diabetes, hypoglycemic agents that have the potential to lower cardiac and renal risk should be utilized as early as possible in the course of the disease. METHODS: This is a literature review of the efficacy of combined treatment with a glucagon-like peptide 1 (GLP-1) agonist and a sodium glucose cotransporter-2 (SGLT2) inhibitor in lowering glycated hemoglobin (HbA1c) level, cardiac risk, cardiac events and renal decompensation. RESULTS: Evidence is presented which shows that the efficacy of combined SGLT2 inhibitor/GLP-1 receptor agonist therapy is additive in lowering HbA1c level, systolic blood pressure and body weight. This combined therapy also has the potential to cause further reductions in major cardiovascular events and renal decompensation than those achieved with either drug used as monotherapy or in combination with other hypoglycemic agents. CONCLUSION: The combination of a GLP-1 agonist and an SGLT2-inhibitor has additive effects on lowering HbA1c and systolic blood pressure, body weight and cardiac risk and has the potential to synergistically reduce cardiovascular events and decelerate renal decompensation. A large prospective study of this combination is needed to prove that this synergism, especially as it applies to cardiac risk factors, cardiac events and mortality and preservation of renal function, is proven. PMID- 29623596 TI - Clinical challenges of glioma and pregnancy: a systematic review. AB - INTRODUCTION: This review aims to summarize challenges in clinical management of concomitant gliomas and pregnancy and provides suggestions for this management based on current literature. METHODS: PubMed and Embase databases were systematically searched for studies on glioma and pregnancy. Observational studies and articles describing expert opinions on clinical management were included. The strength of evidence was categorized as arguments from observational studies, consensus in expert opinions, or single expert opinions. Risk of bias was assessed by the Newcastle-Ottawa Scale (NOS). RESULTS: 27 studies were selected, including 316 patients with newly diagnosed (n = 202) and known (n = 114) gliomas during pregnancy. The median sample size was 6 (range 1 65, interquartile range 1-9). Few recommendations originated from observational studies; the remaining arguments originated from consensus in expert opinions. CONCLUSION: Findings from observational studies of adequate quality include (1) There is no known effect of pregnancy on survival in low-grade glioma patients; (2) Pregnancy can provoke clinical deterioration and tumor growth on MRI; (3) In stable women at term, there is no benefit of cesarean section over vaginal delivery, with respect to adverse events in mother or child. Unanswered questions include when pregnancy should be discouraged, what best monitoring schedule is for both mother and fetus, and if and how chemo- and radiation therapy can be safely administered during pregnancy. A multicenter individual patient level meta analysis collecting granular information on clinical management and related outcomes is needed to provide scientific evidence for clinical decision-making in pregnant glioma patients. PMID- 29623597 TI - Coping mediates the relationship between sense of coherence and mental quality of life in patients with chronic illness: a cross-sectional study. AB - PURPOSE: The aim of the present study was to investigate relationships between sense of coherence, emotion-focused coping, problem-focused coping, coping efficiency, and mental quality of life (QoL) in patients with chronic illness. A model based on Lazarus' and Folkman's stress and coping theory tested the specific hypothesis: Sense of coherence has a direct and indirect effect on mental QoL mediated by emotion-focused coping, problem-focused coping, and coping efficiency in serial adjusted for age, gender, educational level, comorbidity, and economic status. METHODS: The study used a cross-sectional and correlational design. Patients (n = 292) with chronic diseases (chronic heart failure, end stage renal disease, multiple sclerosis, stroke, and Parkinson) completed three questionnaires and provided background data. Data were collected in 2012, and a serial multiple mediator model was tested using PROCESS macro for SPSS. RESULTS: The test of the conceptual model confirmed the hypothesis. There was a significant direct and indirect effect of sense of coherence on mental QoL through the three mediators. The model explained 39% of the variance in mental QoL. CONCLUSIONS: Self-perceived effective coping strategies are the most important mediating factors between sense of coherence and QoL in patients with chronic illness, which supports Lazarus' and Folkman's stress and coping theory. PMID- 29623599 TI - A Rapidly Developing Diffuse Large B cell Lymphoma of the Stomach. PMID- 29623598 TI - Accuracy of two-dimensional pharyngeal airway space prediction for bimaxillary orthognathic surgery. AB - PURPOSE: The aim of this retrospective study was to evaluate the accuracy of two dimensional (2D) virtual surgical planning (VSP) of pharyngeal airway space (PAS) in patients submitted to bimaxillary orthognathic surgery. METHODS: This study was conducted with lateral cephalograms acquired through cone-beam computed tomography records of 33 patients, divided into group 1-patients submitted to maxillary advancement and mandibular setback (n = 17) and group 2-patients submitted to maxillomandibular advancement (n = 16). Records were taken 1 to 2 months prior to surgery, which was used to perform the 2D VSP (Tp), and 6 to 8 months after surgery (T1). In Dolphin Imaging software, the anteroposterior size of the PAS was calculated at the level of four craniometric points: A, occlusal plane (Mx), B, and pogonion (Pog). Two previously calibrated examiners performed these measurements. Statistical analyses were conducted using Kendall and t tests at a 5% level of significance. RESULTS: There was a concordance between the two examiners at all points and times. In group 1, points A and B have statistically significant differences between the PAS measurements performed in Tp and T1, while in group 2, none of the PAS points showed statistically significant differences when comparing Tp to T1. CONCLUSIONS: 2D computer-based cephalometric prediction in Dolphin Imaging software offers a good orientation to professionals during the surgical procedure of bimaxillary surgeries since its use is considered clinically relevant in daily practice. PMID- 29623600 TI - Significance of Glypican-3 in Early Detection of Hepatocellular Carcinoma in Cirrhotic Patients. AB - BACKGROUND: Egypt has high incidence of hepatocellular carcinoma (HCC). This is due to wide spread of hepatitis C virus (HCV) infection which is responsible for most of the cases of liver cirrhosis. The major diagnostic techniques for HCC include serum markers and various imaging modalities. Glypican 3 (GPC3) protein is highly expressed in HCC, but not in normal liver tissue. The significance of GPC3 as a predictor or diagnostic tool for human tumors other than HCC is unclear. AIM: To quantitatively assess the role of GPC3 in diagnosis of HCC in comparison to alpha-fetoprotein (AFP), ultrasonography (US), and computerized tomography (CT). PATIENTS AND METHODS: This cross-sectional study enrolled 85 subjects: 40 cirrhotic patients with primary HCC, 30 cirrhotic patients without HCC, and 15 healthy individuals. All patients were recruited from the Gastroenterology and Tropical Departments and outpatient clinics of New Damietta Hospital during the period from November 2010 to August 2012. RESULTS: GPC3 is positive in some HCC patients with normal levels of AFP. AFP has lower sensitivity (67.5%) compared to higher sensitivity of GPC3 (82.5%), and near specificity (61.2%) to GPC3 (57.8%). CONCLUSION AND SIGNIFICANCE: The combined serum AFP and GPC3 significantly increased the sensitivity of HCC diagnosis. Although GPC3 is better than AFP in diagnosis of HCC, it still lacks the 100% sensitivity and specificity because some patients have negative or normal level of GPC3 (below the cutoff point 1.5 ng/ml) despite being diagnosed by triphasic CT. PMID- 29623601 TI - Effects of minimally invasive approaches on chronic subdural hematoma by novel YL 1 puncture needle and burr-hole methods. AB - The objective of this study is to investigate effects of minimally invasive approaches on outcome of chronic subdural hematoma (CSDH) by novel YL-1 puncture needle and burr-hole methods. A retrospective analysis was performed in 158 hospitalized CSDH patients from January, 2013 to December, 2017 in Kunshan Hospital of Traditional Chinese Medicine. Patients' gender, age, history of trauma, volume of hematoma, hematoma location, application of urokinase, surgical approach, the operation time, hospitalized time, and CT scans 3 months after discharge were recorded. Prognostic indicators including symptom relief and post hospital neuro-imaging findings were extracted to evaluate surgical efficacy. Statistical methods were conducted to evaluate surgical efficacy. Both YL-1 puncture needle and burr-hole surgeries had a satisfying follow-up (93.67%). There was non-significant group difference in follow-up results (p > 0.05). While YL-1 needle group needs less operation time ((p < 0.001) and hospitalized time (p < 0.001), gender (p = 0.144), age (p = 0.394), history of head trauma (p = 0.445), volume of hematoma (p = 0.068), hematoma location (p = 0.281), and application of urokinase (p = 0.545) were shown non-significantly associated with these two minimally invasive approaches. Volume of hematoma was significantly associated with follow-up outcomes (p = 0.016). Novel YL-1 puncture needle and classic burr-hole craniotomy are both proved to be safe and effective minimally invasive surgeries, which can provide an early intervention and minimally invasive strategy for neurosurgeons. PMID- 29623603 TI - Injury Risk (Burden), Risk Matrices and Risk Contours in Team Sports: A Review of Principles, Practices and Problems. AB - The aim of this review was to provide insights into and a critical assessment of injury burden, risk matrices and risk contours in the context of team sports. Injury burden is the product of injury incidence and mean severity, and is normally reported as days' absence/1000 player-hours. An important feature of injury burden is that equal values can reflect quite different numerical combinations of injury incidence and severity. The timeframe over which injury burden affects a team depends on the incidence and severity values of the injuries sustained. Injury burden is evaluated through the use of risk matrices and risk contours. The main benefits of using risk matrices, and the reasons for their widespread acceptance, are the minimal data inputs required, the ease of understanding the visual data presentation, the transparent nature of the evaluation criteria and the simplicity with which the conclusions can be communicated to stakeholders. Injury burden is most often used for the identification of injuries that cause the greatest loss of time for players, ranking the importance of injury risk factors and prioritising injury prevention plans. Although risk matrices are commonly used for evaluating risks during the risk assessment process, there is little evidence to demonstrate that they improve decision-making, as they have a number of limitations, including potential inconsistencies and discrepancies when evaluating and ranking risks. These limitations suggest that physicians, physiotherapists and sports scientists should only use injury burden, risk matrices and risk contours when they fully understand their strengths and weaknesses. PMID- 29623604 TI - Mental Fatigue and Soccer: Current Knowledge and Future Directions. AB - Fatigue is a complex state with multiple physiological and psychological origins. However, fatigue in soccer has traditionally been investigated from a physiological perspective, with little emphasis on the cognitive demands of competition. These cognitive demands may induce mental fatigue, which could contribute to the fatigue-related performance decrements observed during and after soccer matches. Recent research investigating the relationship between mental fatigue and soccer-specific performance supports this suggestion. This leading article provides an overview of the research in this emerging field, outlining the impact of mental fatigue on soccer-specific physical, technical, decision-making, and tactical performances. The second half of this review provides directions for future research in response to the limitations of the existing research. Emphasis is placed on translating the current body of knowledge into practical applications and developing a greater understanding of the mechanisms underpinning the negative impact of mental fatigue on soccer performance. A conceptual model is presented to help direct this future research. PMID- 29623602 TI - Inhibition of Astrocyte Connexin 43 Channels Facilitates the Differentiation of Oligodendrocyte Precursor Cells Under Hypoxic Conditions In Vitro. AB - Oligodendrocyte precursor cells (OPCs) proliferation and differentiation are essential for remyelination after white matter injury. Astrocytes could promote oligodendrogenesis after white matter damage whereas the underlying mechanisms are unknown. In this study, the role of astrocytic connexin43 (Cx43) hemichannels involved in OPC proliferation and differentiation in chronic hypoxia was evaluated. In an astrocyte-OPC co-culture chronic hypoxia model, OPCs became proliferative but failed to mature into oligodendrocytes. Application of astrocytic Cx43 blockers attenuated astrocyte activation, suppressed Cx43 hemichannel uptake activity and glutamate release induced by hypoxia, as well as improved OPC differentiation. Moreover, AMPA but not NMDA glutamate receptor antagonist rescued OPC differentiation in hypoxia. In conclusion, these findings suggested that astrocytic Cx43 hemichannel inhibition could potentially improve OPC maturation by attenuating AMPAR-mediated glutamate signaling. Astrocytic Cx43 hemichannels could serve as a potential therapeutic target for remyelination after chronic hypoxia. PMID- 29623605 TI - Co-Editors' Note. PMID- 29623606 TI - Is Demography Just a Numerical Exercise? Numbers, Politics, and Legacies of China's One-Child Policy. PMID- 29623595 TI - Hiding in Plain Sight? It's Time to Investigate Other Possible Transmission Routes for Hepatitis E Virus (HEV) in Developed Countries. AB - Historically in developed countries, reported hepatitis E cases were typically travellers returning from countries where hepatitis E virus (HEV) is endemic, but now there are increasing numbers of non-travel-related ("autochthonous") cases being reported. Data for HEV in New Zealand remain limited and the transmission routes unproven. We critically reviewed the scientific evidence supporting HEV transmission routes in other developed countries to inform how people in New Zealand may be exposed to this virus. A substantial body of indirect evidence shows domesticated pigs are a source of zoonotic human HEV infection, but there is an information bias towards this established reservoir. The increasing range of animals in which HEV has been detected makes it important to consider other possible animal reservoirs of HEV genotypes that can or could infect humans. Foodborne transmission of HEV from swine and deer products has been proven, and a large body of indirect evidence (e.g. food surveys, epidemiological studies and phylogenetic analyses) support pig products as vehicles of HEV infection. Scarce data from other foods suggest we are neglecting other potential sources of foodborne HEV infection. Moreover, other transmission routes are scarcely investigated in developed countries; the role of infected food handlers, person to-person transmission via the faecal-oral route, and waterborne transmission from recreational contact or drinking untreated or inadequately treated water. People have become symptomatic after receiving transfusions of HEV-contaminated blood, but it is unclear how important this is in the overall hepatitis E disease burden. There is need for broader research efforts to support establishing risk based controls. PMID- 29623607 TI - Making Demography Astonishing: Lessons in the Politics of Population Science. PMID- 29623608 TI - Socioeconomic Factors Have Been the Major Driving Force of China's Fertility Changes Since the Mid-1990s. PMID- 29623609 TI - If Science Had Come First: A Billion Person Fable for the Ages (A Reply to Comments). PMID- 29623610 TI - Relation Between Attention-Deficit Hyperactivity Disorder and IgE-Dependent Allergy in Pediatric Patients. AB - Food allergy is a common condition in children and adolescent, remitting with time. Few clinical studies have emphasized the link between food allergies and psychosocial conditions, suggesting a profound impact of atopic diseases on the development of attention-deficit hyperactivity disorder (ADHD) in children. The objective of this study was to compile and assess available studies on the comorbidity or causality between ADHD and atopic food allergy in children. We discuss epidemiology, interrelated mechanisms, and potential dietary interventions in the management of children with ADHD. PMID- 29623611 TI - m-Trifluoromethyl-diphenyl Diselenide Regulates Prefrontal Cortical MOR and KOR Protein Levels and Abolishes the Phenotype Induced by Repeated Forced Swim Stress in Mice. AB - The present study aimed to investigate the m-trifluoromethyl-diphenyl diselenide [(m-CF3-PhSe)2] effects on prefrontal cortical MOR and KOR protein levels and phenotype induced by repeated forced swim stress (FSS) in mice. Adult Swiss mice were subjected to repeated FSS sessions, and after that, they performed the spontaneous locomotor/exploratory activity, tail suspension, and splash tests. (m CF3-PhSe)2 (0.1 to 5 mg/kg) was administered to mice 30 min before the first FSS session and 30 min before the subsequent repeated FSS. (m-CF3-PhSe)2 abolished the phenotype induced by repeated FSS in mice. In addition, a single FSS session increased MU but reduced delta-opioid receptor contents, without changing the kappa content. Mice subjected to repeated FSS had an increase in the MU content when compared to those of naive group or subjected to single FSS. Repeated FSS induced an increase of delta-opioid receptor content compared to those mice subjected to single FSS. However, the delta-opioid receptor contents were lower than those found in the naive group. The mice subjected to repeated FSS showed an increase in the kappa-opioid receptor content when compared to that of the naive mice. (m-CF3-PhSe)2 regulated the protein contents of MU and kappa receptors in mice subjected to repeated FSS. These findings demonstrate that (m-CF3-PhSe)2 was effective to abolish the phenotype induced by FSS, which was accompanied by changes in the contents of cortical MU- and kappa-opioid receptors. PMID- 29623612 TI - The Stem Cell Factor Sox2 Is a Positive Timer of Oligodendrocyte Development in the Postnatal Murine Spinal Cord. AB - Myelination in the central nervous system takes place predominantly during the postnatal development of humans and rodents by myelinating oligodendrocytes (OLs), which are differentiated from oligodendrocyte progenitor cells (OPCs). We recently reported that Sox2 is essential for developmental myelination in the murine brain and spinal cord. It is still controversial regarding the role of Sox2 in oligodendroglial lineage progression in the postnatal murine spinal cord. Analyses of a series of cell- and stage-specific Sox2 mutants reveal that Sox2 plays a biphasic role in regulating oligodendroglial lineage progression in the postnatal murine spinal cord. Sox2 controls the number of OPCs for subsequent differentiation through regulating their proliferation. In addition, Sox2 regulates the timing of OL differentiation and modulates the rate of oligodendrogenesis. Our experimental data prove that Sox2 is an intrinsic positive timer of oligodendroglial lineage progression and suggest that interventions affecting oligodendroglial Sox2 expression may be therapeutic for overcoming OPC differentiation arrest in dysmyelinating and demyelinating disorders. PMID- 29623613 TI - Analytical variability in the determination of anti-double-stranded DNA antibodies: the strong need of a better definition of the old and new tests. AB - Anti-dsDNA antibodies are a heterogeneous group of antibodies, quite specific for SLE. Their variability is related to the assay used, the immunoglobulin class secondary antibody, and the dsDNA source. The standardization of measuring anti dsDNA antibodies is still poor and different methods yield different results. Several novel technologies were developed during the last decades that represent viable alternatives to the traditional methods such as the chemiluminescent immunoassay (CIA) and multiplex flow immunoassay (MFI). Additionally, positive results for anti-dsDNA antibodies can be detected in patients with inflammatory arthritis (IA) treated with different biologics reducing its clinical specificity for SLE. Anti-dsDNA antibody levels were evaluated in 246 patient samples: 70 SLE and 176 disease control (including 96 IA during treatment with different biologics), using three enzyme immunoassays (indirect enzyme immunoassay, Bio-Rad Laboratories; chemiluminescent immunoassay, Inova Diagnostics; multiplex flow immunoassay, Bio-Rad Laboratories) and three Crithidia luciliae immunofluorescence tests (CLIFT) (Euroimmun AG, Bio-Rad Laboratories, INOVA Diagnostics). Diagnostic performances were assessed both including and excluding the IA patients. Agreements, measured by the Cohen's Kappa between all methods, ranged from moderate to substantial (0.47-0.68). The clinical sensitivities for the anti-dsDNA antibody tests varied from 5.7% by CLIFT A up to 33.3% provided by EIA while the clinical specificities varied from 89.8% by MFI to 98.9% provided by CLIFT B and C. Newer technologies, such as MFI and CIA, showed great potential as a diagnostic application. Significant variations among anti-dsDNA antibody assays were observed confirming the lack of standardization. PMID- 29623615 TI - Raise the Bar, Not the Threshold Value: Meeting Patient Preferences for Palliative and End-of-Life Care. PMID- 29623614 TI - Effects of halogenated contaminants on reproductive development in wild mink (Neovison vison) from locations in Canada. AB - The concept of the Anthropocene, that humans are now re-engineering global ecosystems, is in part evidenced by the pervasive pollution by persistent organic pollutants (POPs). Certain POPs are hormone mimics and can disrupt endocrine and hence reproductive processes, shown mainly by laboratory studies with model species. There are, in contrast, fewer confirmations of such disruption from eco epidemiological studies of wild mammals. Here we used the American mink (Neovison vison) as a sentinel species for such a study. Over the period 1998-2006, 161 mink carcasses were obtained from commercial trappers in the Canadian provinces of British Columbia and Ontario. Mink were aged, sexed, measured, and body condition assessed. Livers were analyzed either individually or pooled for organochlorine (OC) pesticides, polychlorinated biphenyls (PCBs), and subsets for polybrominated diphenyl ethers (PBDEs). We primarily addressed whether contaminants affected male reproductive development by measuring baculum size and assessing the influences of age and body condition. We also considered the influence of spatial variation on relative exposure and size of baculum. Statistical models separated by age class revealed that significant relationships between baculum length or mass and juvenile mink were mostly positive, whereas for adults and first year mink they were mostly negative. A significant negative relationship for adult mink was determined between DDE and both baculum length and mass. For juvenile mink we found significant positive relationships between ?PCBs, DDE and ?PBDEs with baculum length. Our results provide some indication of negative effects of halogenated contaminants on male reproductive development in wild mink, and the most likely candidate chemical is the confirmed anti androgenic compound, DDE, rather than PCBs or other compounds. PMID- 29623616 TI - Does Methodological Guidance Produce Consistency? A Review of Methodological Consistency in Breast Cancer Utility Value Measurement in NICE Single Technology Appraisals. AB - Since 2004, National Institute for Health and Care Excellence (NICE) methodological guidance for technology appraisals has emphasised a strong preference for using the validated EuroQol 5-Dimensions (EQ-5D) quality-of-life instrument, measuring patient health status from patients or carers, and using the general public's preference-based valuation of different health states when assessing health benefits in economic evaluations. The aim of this study was to review all NICE single technology appraisals (STAs) for breast cancer treatments to explore consistency in the use of utility scores in light of NICE methodological guidance. A review of all published breast cancer STAs was undertaken using all publicly available STA documents for each included assessment. Utility scores were assessed for consistency with NICE-preferred methods and original data sources. Furthermore, academic assessment group work undertaken during the STA process was examined to evaluate the emphasis of NICE preferred quality-of-life measurement methods. Twelve breast cancer STAs were identified, and many STAs used evidence that did not follow NICE's preferred utility score measurement methods. Recent STA submissions show companies using EQ 5D and mapping. Academic assessment groups rarely emphasized NICE-preferred methods, and queries about preferred methods were rare. While there appears to be a trend in recent STA submissions towards following NICE methodological guidance, historically STA guidance in breast cancer has generally not used NICE's preferred methods. Future STAs in breast cancer and reviews of older guidance should ensure that utility measurement methods are consistent with the NICE reference case to help produce consistent, equitable decision making. PMID- 29623617 TI - Health-Related Quality of Life in Patients Treated with Continuous Ambulatory Peritoneal Dialysis and Automated Peritoneal Dialysis in Singapore. AB - OBJECTIVE: This study aimed to compare the health-related quality of life (HRQOL) in patients with end-stage renal disease (ESRD) treated with continuous ambulatory peritoneal dialysis (CAPD) and automated peritoneal dialysis (APD) in Singapore. METHODS: The data used in this study were from two cross-sectional surveys of ESRD patients. HRQOL was assessed using the Kidney Disease Quality of Life (KDQOL) instrument. Socio-demographic characteristics and clinical data were collected. The physical component summary (PCS) and mental component summary (MCS) scores, kidney disease component summary (KDCS) score and its three scales (symptoms, effects, burden), and one health utility score [EuroQol 5-dimension (EQ-5D)] were calculated and compared between CAPD and APD using multivariate linear regression. RESULTS: In total, 266 patients were included, with 145 on CAPD (mean age 60.8 years) and 121 on APD (mean age 57.4 years). After adjustment for all variables collected, APD patients had significant higher scores in PCS and KDQOL symptoms than CAPD patients, suggesting that APD was associated with better physical health and milder dialysis-related symptoms. CONCLUSION: The HRQOL of CAPD and APD patients was largely equivalent in Singapore, but APD patients seemed to experience better physical health and be less bothered by dialysis-related symptoms. PMID- 29623618 TI - Cost of Intensive Care Treatment for Liver Disorders at Tertiary Care Level in India. AB - BACKGROUND: Liver diseases contribute significantly to the health and economic burden globally. We undertook this study to assess the health system costs, out of-pocket (OOP) expenditure and extent of financial risk protection associated with treatment of liver disorders in a tertiary care public sector hospital in India. METHODOLOGY: The present study was undertaken in an intensive care unit (ICU) of a tertiary care hospital in North India. It comprised an ICU and an HDU (high dependency unit). Bottom-up micro-costing was undertaken to assess the health system costs. Data on OOP expenditure and indirect costs were collected for 150 liver disorder patients admitted to the ICU or HDU from December 2013 to October 2014. Per-patient and per-bed-day costs of treatment were estimated from both health system and patient perspectives. Financial risk protection was assessed by computing prevalence of catastrophic health expenditure as a result of OOP expenditure. RESULTS: In 2013-2014, health system costs per patient treated in the ICU and HDU were US$2728 [Indian National Rupee (INR) 1,63,664] and US$1966 (INR 1,17,985), respectively. The mean OOP expenditures for treatment in the ICU and HDU were US$2372 (INR 1,42,297) and US$1752 (INR 1,05,093), respectively. Indirect costs of hospitalization in ICU and HDU patients were US$166 (INR 9952) and US$182 (INR 10,903), respectively. CONCLUSION: Treatment of chronic liver disorders poses an economic challenge for both the health system and patients. There is a need to focus on prevention of liver disorders, and finding ways to treat patients without exposing their households to the catastrophic effect of OOP expenditure. PMID- 29623619 TI - Risk-Sharing Agreements in the EU: A Systematic Review of Major Trends. AB - OBJECTIVE: Our objectives were to explore the changes in the level of interest in risk-sharing agreements (RSAs) in the EU during the last 15 years and the underlying reasons for these changes. METHODS: A systematic literature review was conducted using PubMed, Scopus, Web of Science, and Embase. Articles identified were divided into 'quantitative articles' used to establish the level of interest and 'qualitative articles' used to identify the underlying trends in RSAs. RESULTS: The literature search retrieved 2144 scientific articles. Data were extracted from 238 articles. Of these, 100 contained quantitative data and 138 contained qualitative data. The pace of articles being published about RSAs grew significantly in 2015, which related to the increase in interest in and knowledge about RSAs. The underlying reasons for the fluctuations were condensed into four overall themes: (1) push for value-based pricing, (2) economic crisis and further push to contain costs, (3) criticism of RSAs in the real world, and (4) diversification of RSAs to fit the purpose. CONCLUSION: The overall level of interest in RSAs in the EU has been increasing since 2000; therefore, articles reporting the number of RSAs implemented and case studies have been steadily growing as evidence is becoming more readily available. The number of qualitative articles reporting and discussing the underlying reasons for these changes in interest has largely fluctuated over the last 15 years. Despite these fluctuations, interest in RSAs remains high. PMID- 29623620 TI - Economic Evaluation of Midazolam-Droperidol Combination, Versus Droperidol or Olanzapine for the Management of Acute Agitation in the Emergency Department: A Within-Trial Analysis. AB - BACKGROUND: The combination of midazolam and droperidol has proven superior to droperidol or olanzapine monotherapy in the management of acute agitation in emergency departments (EDs). OBJECTIVE: This is the first economic analysis to evaluate the cost-benefit and cost effectiveness of the midazolam-droperidol combination compared with droperidol or olanzapine for the management of acute agitation in EDs. METHODS: This analysis used data derived from a randomised, controlled, double-blind clinical trial conducted in two metropolitan Australian EDs between October 2014 and August 2015. The economic evaluation was from the perspective of Australian public hospital EDs. The main outcomes included agitation management time and the agitation-free time gained. Sensitivity analyses were undertaken. RESULTS: The midazolam-droperidol combination was the least costly regimen (Australian dollars [AU$]46.25 per patient) compared with the droperidol and olanzapine groups (AU$92.18 and AU$110.45 per patient, respectively). The main cost driver for all groups was the cost of the labour required during the initial adequate sedation. The combination afforded an additional 10-13 min of mean agitation-free time gained, which can be translated to additional savings of AU$31.24-42.60 per patient compared with the droperidol and olanzapine groups. The benefit-cost ratio for the midazolam-droperidol combination was 12.2:1.0, or AU$122,000 in total benefit for every AU$10,000 spent on management of acute agitation. Sensitivity analyses over key variables indicated these results were robust. CONCLUSIONS: The midazolam-droperidol combination may be a cost-saving and dominant cost-effective regimen for the treatment of acute agitation in EDs as it is more effective and less costly than either droperidol or olanzapine monotherapy. PMID- 29623621 TI - Resources and Costs Associated with the Treatment of Advanced and Metastatic Gastric Cancer in the Mexican Public Sector: A Patient Chart Review. AB - BACKGROUND: Little evidence is available on the management and cost of treating patients with advanced or metastatic gastric cancer (GC). This study evaluates patient characteristics, treatment patterns, and resource utilization for these patients in Mexico. METHODS: Data were collected from three centers of investigation (tertiary level). Patients were >=18 years of age, diagnosed between 1 January 2009 and 1 January 2015, had advanced or metastatic GC, received first-line fluoropyrimidine/platinum, and had >=3 months follow-up after discontinuing first-line treatment. Data were summarized using descriptive statistics. RESULTS: The study sample totaled 180. Patients' mean age was 57.2 years (+/-12.4) and 57.0% were male; 151 (83.9%) patients received second-line chemotherapy. A total of 16 and 19 regimens were identified in first- and second line therapy. Of the sample, 51 (28.3%) received third-line therapy, and <10% received more than three lines of active chemotherapy. Supportive care received in first- and second-line chemotherapy, included pain interventions (12.2 and 7.9%), nutritional support (3.3 and 1.3%), radiotherapy (6.1 and 16.6%), and transfusions (13.3 and 10.6%), respectively. Using Mexican Institute of Social Security (IMSS) tariffs, the average total cost per patient-month in first- and second-line therapy was US$1230 [95% confidence interval (CI) 1034-1425] and US$1192 (95% CI 913-1471), respectively. Administration and acquisition of chemotherapy comprised the majority of costs. CONCLUSIONS: This study shows considerable variation in first- and second-line chemotherapy regimens of patients with advanced or metastatic GC. Understanding GC treatment patterns in Mexico will help address unmet needs. PMID- 29623622 TI - Direct Medical Costs of Type 2 Diabetes in France: An Insurance Claims Database Analysis. AB - OBJECTIVES: Our objects was to estimate the direct healthcare costs of type 2 diabetes mellitus (T2DM) in France in 2013. METHODS: Data were drawn from a random sample of ~600,000 patients registered in the French national health insurances database, which covers 90% of the French population. An algorithm was used to select patients with T2DM. Direct healthcare costs from a collective perspective were derived from the database and compared with those from a control group to estimate the cost of diabetes and related comorbidities. Overall direct costs were also compared according to the diabetes therapies used throughout the year 2013. RESULTS: Cost analysis was available for a sample of 25,987 patients with T2DM (mean age 67.5 +/- standard deviation 12.5; 53.9% male) matched with a control group of 76,406 individuals without diabetes. Overall per patient per year medical expenditures were ?6506 +/- 10,106 in the T2DM group as compared with ?3668 +/- 6954 in the control group. The cost difference between the two groups was ?2838 per patient per year, mainly due to hospitalizations, medication and nursing care costs. Total per capita annual costs were lowest for patients receiving metformin monotherapy (?4153 +/- 6170) and highest for those receiving insulin (?12,890). However, apart from patients receiving insulin, costs did not differ markedly across the different oral treatment patterns. CONCLUSION: Extrapolating these results to the whole T2DM population in France, total direct costs of diagnosed T2DM in 2013 was estimated at over ?8.5 billion. This estimate highlights the substantial economic burden of this condition on society. PMID- 29623623 TI - Direct Mapping of the QLQ-C30 to EQ-5D Preferences: A Comparison of Regression Methods. AB - BACKGROUND: Several mapping or cross-walking algorithms for deriving utilities from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire for Cancer (EORTC QLQ-C30) scores have been published in recent years. However, the large majority used ordinary least squares (OLS) regression, which proved to be not very accurate because of the specifics of the quality-of-life measures. OBJECTIVE: Our objective was to compare regression methods that have been used to map EuroQol 5 Dimensions 3 Levels (EQ-5D-3L) utility values from the general EORTC QLQ-C30 using OLS as a benchmark while fixing the number of explanatory variables and to explore an alternative three part model. METHODS: We conducted a regression analysis of predicted EQ-5D-3L utilities generated using data from an observational study in ambulatory patients with non-small-cell lung cancer in a Toronto hospital. Six alternative regression methods were compared with a simple OLS regression as benchmark. The six alternative regression models were Tobit, censored least absolute deviation, normal mixture, beta, zero-one inflated beta and a mix of piecewise OLS and logistic regression. RESULTS: The best predictive fit was obtained by a mix of OLS regression(s) for utilities lower than 1 with a cut-off point of 0.50 and a separate binary logistic regression for utilities equal to one. Zero-one inflated beta regression was also promising. However, OLS regression proved to be the most accurate for the mean. The prediction of utilities equal to one was poor in all regression approaches. CONCLUSIONS: Three-part regression methods that separately target low, medium and high (<0.50, 0.51-0.99 or 1) utilities seem to have better prediction power than OLS with EQ-5D-3L data, although OLS also seems quite robust. Exploration of three-part approaches compared with single (OLS) regression should be further tested in other similar datasets or using individual pooled data from various clinical or observational studies. The use of alternative goodness-of-fit measures for mapping studies and their influence on the choice of the best performing methods should also be investigated. PMID- 29623624 TI - The Economic Burden of Small Cell Lung Cancer: A Systematic Review of the Literature. AB - BACKGROUND: Small cell lung cancer (SCLC), the most aggressive form of lung carcinoma, represents approximately 15% of all lung cancers; however, the economic and healthcare burden of SCLC is not well-defined. OBJECTIVE: The aim of this study was to explore the impact of SCLC on healthcare costs through a systematic literature review (SLR). METHODS: Using the OVID search engine, the SLR was conducted in PubMed, MEDLINE In-Process, EMBASE, EconLIT and the National Health Service Economic Evaluation Database (NHS EED). Searches were limited to studies published between January 2005 and 24 February 2016, and excluded preclinical studies. Additional internet-based searches were conducted. In total, 229 abstracts were retrieved and systematically screened for eligibility, with 17 publications retained. RESULTS: The majority of publications provided data on limited and extensive disease of SCLC. The reported burden was categorised as direct costs and indirect costs, with the majority of the publications (n = 16) reporting on direct costs and one reporting on both direct and indirect costs. The only indirect costs reported for SCLC were lost productivity (premature mortality costs) and caregiver burden. Chemotherapy, diagnostic costs and treatment costs were identified as significant costs when managing SCLC patients, including the associated treatment costs such as hospitalisation, nurse visits, emergency room visits, follow-up appointments and outpatient care. CONCLUSIONS: SCLC and its treatment have a substantial impact on costs. The scarcity and heterogeneity of economic cost data negated meaningful cost comparison, highlighting the need for further research. Capturing the economic burden of SCLC may help patients and clinicians make informed treatment choices and improve SCLC management. PMID- 29623625 TI - Applying a Multicriteria Decision Analysis (MCDA) Approach to Elicit Stakeholders' Preferences in Italy: The Case of Obinutuzumab for Rituximab Refractory Indolent Non-Hodgkin Lymphoma (iNHL). AB - BACKGROUND: Healthcare decision makers need to make trade-offs between different elements of value of new treatments. Multicriteria decision analysis (MCDA) provides a framework that can help decision makers to understand stakeholders' preferences and be explicit about the trade-offs that are being made. OBJECTIVE: The objective of this study was to use MCDA to obtain preferences and views on decision criteria across three stakeholder groups (patients, clinicians and payers) in Italy and to use these to assess the performance of obinutuzumab for rituximab-refractory indolent non-Hodgkin lymphoma (iNHL). METHODS: We used EVIDEM V3.0, an MCDA framework, and collected participants' preferences via an online survey and structured meetings. RESULTS: Patients and clinicians expressed a preference for interventions targeting severe conditions. Payers expressed preference for treatments targeting areas with an unmet need, which are cheaper than the comparator, and with high-quality evidence. Obinutuzumab in combination with bendamustine, compared with bendamustine alone, received high positive scores for the criteria 'disease severity' and 'type of therapeutic benefit' by all three groups, and negative scores on the economic-related criteria, according to all stakeholder groups. CONCLUSIONS: MCDA can be used to elicit the views of different stakeholder groups and has the potential to structure and inform reimbursement decisions. PMID- 29623626 TI - Healthcare Resource Uses and Out-of-Pocket Expenses Associated with Pulmonary TB Treatment in Thailand. AB - BACKGROUND: In Thailand, pharmaceutical care has been recently introduced to a tertiary hospital as an approach to improve adherence to tuberculosis (TB) treatment in addition to home visit and modified directly observed therapy (DOT). However, the economic impact of pharmaceutical care is not known. OBJECTIVE: The aim of this study was to estimate healthcare resource uses and costs associated with pharmaceutical care compared with home visit and modified DOT in pulmonary TB patients in Thailand from a healthcare sector perspective inclusive of out-of pocket expenditures. METHODS: We conducted a retrospective study using data abstracted from the hospital billing database associated with pulmonary TB patients who began treatment between 2010 and 2013 in three hospitals in Thailand. We used generalized linear models to compare the costs by accounting for baseline characteristics. All costs were converted to international dollars (Intl$) RESULTS: The mean direct healthcare costs to the public payer were $519.96 (95%confidence interval [CI] 437.31-625.58) associated with pharmaceutical care, $1020.39 (95% CI 911.13-1154.11) for home visit, and $887.79 (95% CI 824.28-955.91) for modified DOT. The mean costs to patients were $175.45 (95% CI 130.26-230.48) for those receiving pharmaceutical care, $53.77 (95% CI 33.25-79.44) for home visit, and $49.33 (95% CI 34.03-69.30) for modified DOT. After adjustment for baseline characteristics, pharmaceutical care was associated with lower total direct costs compared with home visit (-$354.95; 95% CI -285.67 to -424.23) and modified DOT (-$264.61; 95% CI -198.76 to -330.46). CONCLUSION: After adjustment for baseline characteristics, pharmaceutical care was associated with lower direct costs compared with home visit and modified DOT. PMID- 29623627 TI - Cost Effectiveness of Stapled Haemorrhoidopexy and Traditional Excisional Surgery for the Treatment of Haemorrhoidal Disease. AB - OBJECTIVE: Our objective was to compare the cost effectiveness of stapled haemorrhoidopexy (SH) and traditional haemorrhoidectomy (TH) in the treatment of grade II-IV haemorrhoidal disease from the perspective of the UK national health service. METHODS: An economic evaluation was conducted alongside an open, two arm, parallel-group, pragmatic, multicentre, randomised controlled trial conducted in several hospitals in the UK. Patients were randomised into either SH or TH surgery between January 2011 and August 2014 and were followed up for 24 months. Intervention and subsequent resource use data were collected using case review forms and questionnaires. Benefits were collected using the EQ-5D-3L (EuroQoL-five dimensions-three levels) instrument. The primary economic outcome was incremental cost measured in pounds (L), year 2016 values, relative to the incremental benefit, which was estimated using quality-adjusted life-years (QALYs). Cost and benefits accrued in the second year were discounted at 3.5%. The base-case analysis was based on imputed data. Uncertainty was explored using univariate sensitivity analyses. RESULTS: Participants (n = 777) were randomised to SH (n = 389) or TH (n = 388). The mean cost of SH was L337 (95% confidence interval [CI] 251-423) higher than that of TH and the mean QALYs were -0.070 (95% CI -0.127 to -0.011) lower than for TH. The base-case cost-utility analysis indicated that SH has zero probability of being cost effective at both the L20,000 and the L30,000 threshold. Results from the sensitivity analyses were similar to those from the base-case analysis. CONCLUSIONS: The evidence suggests that, on average, the total mean costs over the 24-month follow-up period were significantly higher for the SH arm than for the TH arm. The QALYs were also, on average, significantly lower for the SH arm. These results were supported by the sensitivity analyses. Therefore, in terms of cost effectiveness, TH is a superior surgical treatment for the management of grade II-IV haemorrhoids when compared with SH. PMID- 29623628 TI - Using Cerebrospinal Fluid Biomarker Testing to Target Treatment to Patients with Mild Cognitive Impairment: A Cost-Effectiveness Analysis. AB - OBJECTIVE: Cerebrospinal fluid (CSF) biomarkers are shown to facilitate a risk identification of patients with mild cognitive impairment (MCI) into different risk levels of progression to Alzheimer's disease (AD). Knowing a patient's risk level provides an opportunity for earlier interventions, which could result in potential greater benefits. We assessed the cost effectiveness of the use of CSF biomarkers in MCI patients where the treatment decision was based on patients' risk level. METHODS: We developed a state-transition model to project lifetime quality-adjusted life-years (QALYs) and costs for a cohort of 65-year-old MCI patients from a US societal perspective. We compared four test-and-treat strategies where the decision to treat was based on a patient's risk level (low, intermediate, high) of progressing to AD with two strategies without testing, one where no patients were treated during the MCI phase and in the other all patients were treated. We performed deterministic and probabilistic sensitivity analyses to evaluate parameter uncertainty. RESULTS: Testing and treating low-risk MCI patients was the most cost-effective strategy with an incremental cost effectiveness ratio (ICER) of US$37,700 per QALY. Our results were most sensitive to the level of treatment effectiveness for patients with mild AD and for MCI patients. Moreover, the ICERs for this strategy at the 2.5th and 97.5th percentiles were US$18,900 and US$50,100 per QALY, respectively. CONCLUSION: Based on the best available evidence regarding the treatment effectiveness for MCI, this study suggests the potential value of performing CSF biomarker testing for early targeted treatments among MCI patients with a narrow range for the ICER. PMID- 29623629 TI - Impact of Fluid Choice in Systemic Inflammatory Response Syndrome Patients on Hospital Cost Savings. AB - BACKGROUND: There is growing evidence of the benefits of intravenous fluid therapy with balanced crystalloids over 0.9% 'normal' saline. This analysis evaluated the economic impact of increasing usage of a calcium-free balanced crystalloid solution (BAL) in patients with systemic inflammatory response syndrome (SIRS) on an annual hospital budget. METHODS: An Excel(r)-based economic model was developed to estimate costs associated with increased BAL usage (i.e., use in a greater proportion of patients), from the US hospital perspective, over a 5-year time horizon. Clinical inputs were based on the results of a retrospective Electronic Health Record (EHR) database analysis identifying significantly fewer complications among SIRS patients receiving predominantly BAL versus saline. Complication-associated costs, adjusted to 2015, were obtained from published reports. Scenario analyses examined cost impacts for hospitals of various sizes, with different BAL adoption levels and rates. RESULTS: Base-case scenario analysis (300-bed hospital, 80% occupancy, current and year 5 BAL usage in 5 and 75% of SIRS patients, respectively, exponential year-over-year adoption) showed year 1 hospital savings of US$29,232 and cumulative 5-year savings of US$1.16M. Cumulative 5-year pharmacy savings were US$172,641. Scenario analyses demonstrated increasing cumulative 5-year savings with increasing hospital size, year 5 BAL usage in greater proportions of patients, and rapid/early BAL adoption. CONCLUSIONS: Increased BAL usage represents an opportunity for hospitals and pharmacy departments to reduce complication-related costs associated with managing SIRS patients. The model suggests that savings could be expected across a range of scenarios, likely benefiting hospitals of various sizes and with different adoption capabilities. PMID- 29623631 TI - Evaluation of Health Status of Type 2 Diabetes Outpatients Receiving Care in a Tertiary Hospital in Nigeria. AB - OBJECTIVES: The aim of this study was to determine the health status of type 2 diabetes patients in a Nigerian tertiary hospital, and examine the sociodemographic and clinical variables that predicted the health status of type 2 diabetes patients in terms of utility valuations and EuroQol Visual Analogue Scale (EQ-VAS) score. METHODS: This was a cross-sectional study of 147 diabetes patients attending the University of Nigeria Teaching Hospital, Enugu State, Nigeria. The EQ-5D-5L instrument, version 2.1, was used to evaluate patients' self-reported health status, and patients who gave informed consent completed the questionnaire while waiting to see a doctor. Descriptive and multiple linear regression analyses were performed using SPSS version 20. RESULTS: Overall, 147 patients participated in this study, with a mean age (+/- standard deviation) of 56.7 years (+/- 10.33). Over half of the respondents were females (55.1%) and more than half were older than 60 years of age. The mean EQ-VAS and utility valuations of respondents were 72.59 +/- 10.51 and 0.72 +/- 0.13, respectively. The age of respondents independently and significantly predicted EQ-VAS by -2.659 per year, while the age of respondents, level of education, duration of diabetes, and presence of other illnesses independently and significantly predicted utility valuations by -0.020 per year, +0.029 per level of education, -0.008 per year, and -0.044 per illness, respectively. Less than 39% of patients experienced no problems for each of the dimensions, except self-care (68%). CONCLUSION: The results of this study revealed a relatively low health status among type 2 diabetic patients in Nigeria. Old age, duration of diabetes and the presence of other illnesses were major contributors to the negative impact on health status, while a higher level of education contributed positively to health status. Adequate family support, as well as regular and effective patient counseling and education, may be worthwhile. PMID- 29623632 TI - Out-of-Pocket Expenditures, Indirect Costs and Health-Related Quality of Life of Patients with Pulmonary Tuberculosis in Thailand. AB - BACKGROUND: Thailand's hospitals may adopt different supervision approaches to improve tuberculosis (TB) treatment adherence. OBJECTIVE: The aim of this study was to compare out-of-pocket (OOP) expenditures, indirect costs, and health related quality of life (HRQoL) among TB patients who received pharmaceutical care (pharmacist-led patient education and telephone consultation), home visit, and self-administered therapy (SAT) in Thailand. METHODS: We conducted a prospective study to collect OOP expenditures, indirect costs, and HRQoL from a subsample of 104 adult pulmonary TB patients who started treatment between January and May 2014 in three hospitals. The three sources of data included patient interviews, patient medical records, and the hospital billing database. Patients were followed from January 2014 to March 2015. Relevant OOP expenditures collected during the interviews included (1) healthcare costs and other medications costs (e.g. vitamins, antibiotics, anti-cough) occurring in private healthcare units; and (2) costs of transportation, food, and accommodation. Productivity loss was measured using the self-reported amount of time a patient was unable to work due to TB, travel time to and from the hospital, time spent at the hospital (waiting time, consultation time, and hospitalizations), and time spent accompanying family members on outpatient visits or during hospitalizations. Cost differences among treatment strategies were adjusted for baseline characteristics by generalized linear models (GLMs). All costs were converted to international dollars (I$). RESULTS: A total of 256 eligible patients who started pulmonary TB treatment during the specified period were approached, with 104 patients being included in the analysis (29, 38, and 37 patients receiving pharmaceutical care, home visit, and SAT, respectively). Mean OOP expenditures per patient receiving pharmaceutical care, home visit, and SAT were I$907.56 [confidence interval (CI) I$603.80-I$1269.41], I$148.47 (CI I$109.49-I$194.89), and I$95.35 (CI I$69.11-I$129.63), respectively. The GLM indicated statistically significantly lower OOP expenditures for patients receiving either home visit or SAT (ratio of mean costs 0.247, CI 0.142-0.427; and 0.318, CI 0.187-0.540, respectively) than those receiving pharmaceutical care. Patient's indirect costs for receiving pharmaceutical care, home visit, and SAT were I$1925.68 (CI I$922.06-I$3284.94), I$2393.66 (CI I$1435.01-I$3501.98), and I$833.33 (CI I$453.87-I$1263.45), respectively. The GLM found no statistically significant differences in indirect costs for the home visit and SAT groups (ratio of mean costs 1.904, CI 0.754-4.802; and 0.792, CI 0.289-2.175, respectively) when pharmaceutical care was set as the reference. Mean utility scores [EuroQol five-dimensional three-level (EQ-5D-3L)] at baseline and treatment end were 0.679 and 0.830, 0.713 and 0.905, and 0.708 and 0.913 for patients receiving pharmaceutical care, home visit, and SAT, respectively. CONCLUSION: Pharmaceutical care patients experienced the highest OOP expenditures, compared with home visit and SAT patients. Home-visit patients reached the highest indirect costs and utility score improvements. A large-scale prospective study is required in order to strengthen evidence to support policy making regarding the most efficient use of limited resources for the management of TB. PMID- 29623630 TI - The Potential Clinical and Economic Value of Primary Tumour Identification in Metastatic Cancer of Unknown Primary Tumour: A Population-Based Retrospective Matched Cohort Study. AB - PURPOSE: Several genomic tests have recently been developed to identify the primary tumour in cancer of unknown primary tumour (CUP). However, the value of identifying the primary tumour in clinical practice for CUP patients remains questionable and difficult to prove in randomized trials. OBJECTIVE: We aimed to assess the clinical and economic value of primary tumour identification in CUP using a retrospective matched cohort study. METHODS: We used the Manitoba Cancer Registry to identify all patients initially diagnosed with metastatic cancer between 2002 and 2011. We defined patients as having CUP if their primary tumour was found 6 months or more after initial diagnosis or never found during the course of disease. Otherwise, we considered patients to have metastatic cancer from a known primary tumour (CKP). We linked all patients with Manitoba Health databases to estimate their direct healthcare costs using a phase-of-care approach. We used the propensity score matching technique to match each CUP patient with a CKP patient on clinicopathologic characteristics. We compared treatment patterns, overall survival (OS) and phase-specific healthcare costs between the two patient groups and assessed association with OS using Cox regression adjustment. RESULTS: Of 5839 patients diagnosed with metastatic cancer, 395 had CUP (6.8%); 1:1 matching created a matched group of 395 CKP patients. CUP patients were less likely to receive surgery, radiation, hormonal and targeted therapy and more likely to receive cytotoxic empiric chemotherapeutic agents. Having CUP was associated with reduced OS (hazard ratio [HR] 1.31; 95% confidence interval 1.1-1.58), but this lost statistical significance with adjustment for treatment differences. CUP patients had a significant increase in the mean net cost of initial diagnostic workup before diagnosis and a significant reduction in the mean net cost of continuing cancer care. CONCLUSION: Identifying the primary tumour in CUP patients might enable the use of more effective therapies, improve OS and allow more efficient allocation of healthcare resources. PMID- 29623633 TI - Cost Analysis of a Digital Health Care Model in Sweden. AB - BACKGROUND: Digital technologies in health care are expected to increase in scope and to affect ever more parts of the health care system. It is important to enhance the knowledge of whether new digital methods and innovations provide value for money compared with traditional models of care. OBJECTIVE: The objective of the study was to evaluate whether a digital health care model for primary care is a less costly alternative compared with traditional in-office primary care in Sweden. METHODS: Cost data for the two care models were collected and analyzed to obtain a measure in local currency per care contact. RESULTS: The comparison showed that the total economic cost of a digital consultation is 1960 Swedish krona (SEK) (SEK100 = US$11.29; February 2017) compared with SEK3348 for a traditional consultation at a health care clinic. Cost differences arose on both the provider side and on the user side. CONCLUSION: The digital health care model may be a less costly alternative to the traditional health care model. Depending on the rate of digital substitution, gross economic cost savings of between SEK1 billion and SEK10 billion per year could be realized if more digital consultations were made. Further studies are needed to validate the findings, assess the types of care most suitable for digital care, and also to obtain various quality-adjusted outcome measures. PMID- 29623634 TI - A Review of Clinical and Economic Evaluations Applied to Psychotropic Therapies Used in the Treatment of Schizophrenia in Argentina. AB - Schizophrenia is considered a serious mental disorder that affects over 21 million people worldwide, and is associated with disability that frequently affects the patient's educational and working performance. In Argentina, two of the most widely used antipsychotics in the treatment of this disorder are haloperidol and risperidone. Both are provided free to patients without health coverage in public healthcare facilities. In this paper we seek to review the clinical and economic benefits of prescribing psychotropic therapies based on haloperidol (a first-generation antipsychotic that is part of the butyrophenone group of drugs) versus risperidone [an atypical or second-generation antipsychotic (neuroleptic) drug] in adult patients who have been diagnosed with schizophrenia. To achieve this objective, an exhaustive search of relevant articles published between 2006 and April 2017 was conducted. This literature search showed that intermittent treatment usually fails to prevent relapses due to irregular protection, therefore continuous treatment is more effective. Although the injectable formats of both drugs [haloperidol depot and long-acting injectable risperidone (LAIR)] have not proven to have significant differences with regard to clinical effectiveness vis-a-vis the tablet formats, they showed a lower cost-effectiveness ratio by reducing patients' relapses. Moreover, LAIR exhibits superior cost effectiveness compared with haloperidol depot. Haloperidol is less expensive than risperidone but is less cost effective; in comparison with haloperidol, treatment with risperidone produces (1) an improvement in quality adjusted life-years, and (2) a significant reduction in negative symptoms. In most cases, antipsychotic treatments are effective in controlling the positive and negative symptoms associated with schizophrenia, allowing patients to live in their communities without any impairments. However, it is extremely important to combine pharmacological treatment with other measures that constitute psychosocial therapy. PMID- 29623635 TI - The Healthcare Cost Burden of Acute Myocardial Infarction in Alberta, Canada. AB - OBJECTIVES: Little is known about the cost burden of acute myocardial infarction (AMI) on healthcare systems. Accordingly, we examined the long-term trends of healthcare costs for AMI in the province of Alberta, Canada. METHODS: We linked five Albertan health databases, including ambulatory care, hospitalization, practitioner claims, pharmaceutical information network, and population registry to identify patients with a primary diagnosis of AMI between 2004 and 2013. We used the Alberta Interactive Health Data Application to provide unit costs for ambulatory care and inpatient services, claim paid amounts for physician services, and the Alberta Drug Benefit List for drug prices. Healthcare costs for AMI were grouped into ambulatory care, hospitalization, physician costs, and drug costs. All costs were converted to 2016 Canadian dollar values ($Can). RESULTS: A total of 52,912 patients with AMI were included in the analysis. Patient age decreased over time, as did the proportion of females. AMI cost the Alberta healthcare system Can$1033 million during the study period; of which the largest proportion was hospitalization costs (Can$716.4 million, 63.1%), followed by drug costs (Can$147.2 million, 21.1%), ambulatory care costs (Can$94.5 million, 8.8%) and physician costs (Can$74.9 million, 7.0%). The cost per AMI hospitalization decreased from Can$14,116 in 2004 to Can$11,792 in 2013 (p < 0.001). CONCLUSIONS: Healthcare costs for AMI are significant; however, they decreased slightly during the study period. Hospital services accounted for the largest share of the costs. There are opportunities for further savings in AMI care. PMID- 29623636 TI - An Exploratory Study: A Head-to-Head Comparison of the EQ-5D-5L and AQoL-8D for Long-Term Publicly Waitlisted Bariatric Surgery Patients Before and 3 Months After Bariatric Surgery. AB - BACKGROUND: Choice of a multi-attribute utility instrument (MAUI) that appropriately assesses an intervention's health-related quality-of-life (HRQoL) impacts is a vital part of healthcare resource allocation and clinical assessment. OBJECTIVE: Our exploratory study compared the EuroQol (EQ)-5D-5L and Assessment of Quality of Life (AQoL)-8D MAUIs, which were used to assess the effect of bariatric surgery for a cohort of long-term publicly waitlisted, severely obese patients. METHODS: The study was conducted at the Hobart Private Hospital (Tasmania, Australia). To compare the sensitivity and instrument content of the two MAUIs, we used dimensional comparisons by investigating the distribution of patient-reported responses (number/percentage) across the MAUIs' levels and dimensions; summary health-state utility valuations (utilities); and individual/super-dimension scores (AQoL-8D) to investigate discriminatory power and HRQoL improvements preoperatively and 3 months postoperatively. RESULTS: Participants' (n = 23) overall MAUI completion rate was 74%. Postoperative total weight loss was 9.9%. EQ-5D-5L utilities were relatively higher pre- and postoperatively than AQoL-8D utilities [mean standard deviation (SD) EQ-5D-5L 0.70 (0.25) to 0.80 (0.25); AQoL-8D 0.51 (0.24) to 0.61 (0.24)]. AQoL-8D Psychosocial super dimension was relatively low postoperatively [0.37 (0.25)], driving the instrument's lower utility. These results were supported by the dimensional comparisons that revealed an overall greater dispersion for the AQoL 8D. Nevertheless, there were clinical improvements in utilities for both instruments. AQoL-8D utilities were lower than population norms; not so the EQ-5D 5L utilities. The AQoL-8D dimensions of Happiness, Coping, and Self-worth improved the most. CONCLUSIONS: AQoL-8D more fully captured the impact of obesity and bariatric surgery on HRQoL (particularly psychosocial impacts) for long-term waitlisted bariatric surgery patients, even 3 months postoperatively. AQoL-8D preoperative utility revealed our population's HRQoL was lower than people with cancer or heart disease. PMID- 29623637 TI - Healthcare Cost Development in a Type 2 Diabetes Patient Population on Glucose Lowering Drug Treatment: A Nationwide Observational Study 2006-2014. AB - OBJECTIVE: The objective of this study was to describe healthcare resource use and cost development in Sweden during 2006-2014 in a type 2 diabetes (T2D) population receiving glucose-lowering drugs (GLDs). METHODS: In- and outpatient healthcare resource use and costs were extracted from mandatory national registries: the Cause of Death Register; the National Patient Register; and the Prescribed Drug Register. Primary care data were estimated based on an observational study including patients from 84 primary care centers in Sweden. Numbers of any cause inpatient, outpatient, and primary care contacts were extracted and direct healthcare costs were estimated. RESULTS: During 2006-2014, the number of inpatient and primary care contacts increased by approximately 70% (from 45,559 to 78,245 and from 4.9 to 8.8 million, respectively) and outpatient care contacts almost doubled (from 105,653 to 209,417). Mean annual per patient costs increased by 13%, reaching ?4594. Total healthcare costs increased from ?835 million to ?1.684 billion. Inpatient care costs constituted 47% of total costs in 2014 (?783 million), primary care accounted for 24% (?405 million), outpatient care 18% (?303 million), non-GLD medications 6% (?109 million), and GLDs 5% (?84 million). Cardiovascular diseases (CVDs) were the most costly disease group in inpatient care (26%), whereas managing unspecified factors influencing health and T2D-associated diseases were the most costly in outpatient care (16 and 11%, respectively). CONCLUSIONS: The healthcare costs of the GLD treated T2D population doubled during 2006-2014, mostly driven by the increasing size of this population, of which inpatient care accounted for 47%. GLDs constituted the smallest share of costs. CVD was the most resource-requiring disease group. PMID- 29623638 TI - The Cost of Patients with Chronic Kidney Failure Before Dialysis: Results from the IRIDE Observational Study. AB - BACKGROUND: Chronic kidney disease (CKD) is an important public health problem. Most of the evidence on its costs relates to patients receiving dialysis or kidney transplants, which shows that, in these phases, CKD poses a high burden to payers. Less evidence is available on the costs of the predialytic phase. OBJECTIVE: The aim of this study was to estimate the annual cost of patients with CKD not receiving dialysis treatment, using the Italian healthcare system perspective and a prospective approach. METHODS: A 3-year observational study (December 2010-September 2014) was carried out to collect data on resource consumption for 864 patients with CKD. Costs were estimated for both patients who completed the follow-up and dropouts. RESULTS: The mean annual total (healthcare) cost per patient equalled ?2723 (95% confidence interval 2463.0-2983.3). Disease severity (higher CKD stage), multiple comorbidities, dropout status and belonging to the southern region are predictive of higher costs. Pharmaceuticals, hospitalisation, and outpatient services account for 71.5, 18.8 and 9.7% of total healthcare expenditure, respectively. Recent estimates of Italian costs of patients receiving dialysis are nine times the unit costs of CKD for patients estimated in this study. Unit costs at stage 5 CKD (the highest level of severity) equals 4.7 times the costs for patients at stage 1 CKD. CONCLUSION: Despite its limitations, this study provides further evidence on the opportunity to invest in the first phases of CKD to avoid progression and an increase in healthcare costs. PMID- 29623640 TI - Mixed strategy to allocate resources with air pollution treatment in China: based on the analytic network process and large-group decision-making method. AB - The resource allocation of air pollution treatment in China is a complex problem, since many alternatives are available and many criteria influence mutually. A number of stakeholders participate in this issue holding different opinions because of the benefits they value. So a method is needed, based on the analytic network process (ANP) and large-group decision-making (LGDM), to rank the alternatives considering interdependent criteria and stakeholders' opinions. In this method, the criteria related to air pollution treatment are examined by experts. Then, the network structure of the problem is constructed based on the relationships between the criteria. Further, every participant in each group provide comparison matrices by judging the importance between criteria according to dominance, regarding a certain criteria (or goal), and the geometric average comparison matrix of each group is obtained. The decision weight of each group is derived by combining the subjective weight and the objective weight, in which the subjective weight is provided by organizers, while the objective weight is determined by considering the consensus levels of groups. The final comparison matrices are obtained by the geometric average of comparison matrices and the decision weights. Next, the resource allocation is made according to the priorities of the alternatives using the super decision software. Finally, an example is given to illustrate the use of the proposed method. PMID- 29623639 TI - Pharmacogenetics of Opioid Use Disorder Treatment. AB - Opioid use disorder (OUD) is a significant health problem in the United States and many other countries. A combination of issues, most notably increased prescription of opioid analgesics, has resulted in climbing rates of opioid abuse and overdose over the last decade. This ongoing epidemic has produced a growing population of patients requiring treatment for OUD. Medications such as methadone and buprenorphine have well documented success rates in treating the disorder compared with placebo. However, significant percentages of the population still fail to maintain abstinence or reduce illicit opioid use while using such medications. Genetic variation may play a role in this variability in outcome through pharmacokinetic or pharmacodynamic effects on OUD medications, or by affecting the rate of negative side effects and adverse events. This review focuses on the existing literature on the pharmacogenetics of OUD treatment, with specific focus on medication metabolism, treatment outcomes, and adverse events. PMID- 29623641 TI - Cathodic microbial community adaptation to the removal of chlorinated herbicide in soil microbial fuel cells. AB - The microbial fuel cell (MFC) that uses a solid electrode as the inexhaustible electron acceptor is an innovative remediation technology that simultaneously generates bioelectricity. Chlorinated pollutants are better metabolized by reductive dechlorination in proximity to the cathode. Here, the removal efficiency of the herbicide metolachlor (ML) increased by 262 and 176% in soil MFCs that were spiked with 10 (C10) and 20 mg/kg (C20) of ML, respectively, relative to the non-electrode controls. The bioelectricity output of the C10 and C20 increased by over two- and eightfold, respectively, compared to that of the non-ML control, with maximum current densities of 49.6 +/- 2.5 (C10) and 78.9 +/- 0.6 mA/m2 (C20). Based on correlations between ML concentrations and species abundances in the MFCs, it was inferred that Azohydromonas sp., Sphingomonas sp., and Pontibacter sp. play a major role in ML removal around the cathode, with peak removal efficiencies of 56 +/- 1% (C10) and 58 +/- 1% (C20). Moreover, Clostridium sp., Geobacter sp., Bacillus sp., Romboutsia sp., and Terrisporobacter sp. may be electricigens or closely related microbes due to the significant positive correlation between the bioelectricity generation levels and their abundances around the anode. This study suggests that a directional adaptation of the microbial community has taken place to increase both the removal of chlorinated herbicides around the cathode and the generation of bioelectricity around the anode in bioelectrochemical remediation systems. PMID- 29623642 TI - Trends on PM2.5 research, 1997-2016: a bibliometric study. PMID- 29623643 TI - Reduction mechanism of hexavalent chromium by functional groups of undissolved humic acid and humin fractions of typical black soil from Northeast China. AB - Soil organic matters (SOM) have a great retention effect on Cr(VI) migration in subsurface environment, which act as the main electron donors for Cr(VI) reduction; however, Cr(VI) reduction mechanism by different SOM fractions is still unclear, such as undissolved humic acid (HA) and humin (HM). In this study, HA and HM fractions extracted from typical black soil from Northeast China were used to investigate the reaction mechanism between humus functional groups and Cr(VI). According to the results, phenol and hydroxyl were determined as the main electron donors for Cr(VI) reduction by HA and HM instead of carboxyl and carbonyl, which were more likely involved in Cr complexation. Furthermore, Cr(VI) reduction was more dependent on aromatic carbon, rather than aliphatic carbon, and functional groups on the particle surfaces of HA and HM were much more active for Cr(VI) reduction than their interior part. Additionally, HM was found to have a relatively low Cr(VI) reduction capability compared with HA resulting from its high content of cellulose structures that are quite resistant to Cr(VI) oxidation. These results suggest that in the soil environment, undissolved HA tends to play a much more important role than HM in Cr(VI) reduction and retention in the condition that their mass contents are comparable. PMID- 29623644 TI - Intranasal instillation of iron oxide nanoparticles induces inflammation and perturbation of trace elements and neurotransmitters, but not behavioral impairment in rats. AB - Over the last decades, engineered nanomaterials have been widely used in various applications due to their interesting properties. Among them, iron oxide nanoparticles (IONPs) are used as theranostic agents for cancer, and also as contrast agents in magnetic resonance imaging. With the increasing production and use of these IONPs, there is an evident raise of IONP exposure and subsequently a higher risk of adverse outcome for humans and the environment. In this work, we aimed to investigate the effects of sub-acute IONP exposure on Wistar rat, particularly (i) on the emotional and learning/memory behavior, (ii) on the hematological and biochemical parameters, (iii) on the neurotransmitter content, and (vi) on the trace element homeostasis. Rats were treated during seven consecutive days by intranasal instillations at a dose of 10 mg/kg body weight. The mean body weight increased significantly in IONP-exposed rats. Moreover, several hematological parameters were normal in treated rats except the platelet count which was increased. The biochemical study revealed that phosphatase alkaline level decreased in IONP-exposed rats, but no changes were observed for the other hepatic enzymes (ALT and AST) levels. The trace element homeostasis was slightly modulated by IONP exposure. Sub-acute intranasal exposure to IONPs increased dopamine and norepinephrine levels in rat brain; however, it did not affect the emotional behavior, the anxiety index, and the learning/memory capacities of rats. PMID- 29623646 TI - Different relationships between personal exposure and ambient concentration by particle size. AB - Ambient particulate matter (PM) concentrations at monitoring stations were often used as an indicator of population exposure to PM in epidemiological studies. The correlation between personal exposure and ambient concentrations of PM varied because of diverse time-activity patterns. The aim of this study was to determine the relationship between personal exposure and ambient concentrations of PM10 and PM2.5 with minimal impact of time-activity pattern on personal exposure. Performance of the MicroPEM, v3.2 was evaluated by collocation with central ambient air monitors for PM10 and PM2.5. A field technician repeatedly conducted measurement of 24 h personal exposures to PM10 and PM2.5 with a fixed time activity pattern of office worker over 26 days in Seoul, Korea. The relationship between the MicroPEM and the ambient air monitor showed good linearity. Personal exposure and ambient concentrations of PM2.5 were highly correlated with a fixed time-activity pattern compared with PM10. The finding implied a high infiltration rate of PM2.5 and low infiltration rate of PM10. The relationship between personal exposure and ambient concentrations of PM10 and PM2.5 was different for high level episodes. In the Asian dust episode, staying indoors could reduce personal exposure to PM10. However, personal exposure to PM2.5 could not be reduced by staying indoors during the fine dust advisory episode. PMID- 29623645 TI - Contrasting congener profiles for persistent organic pollutants and PAH monitoring in European storm petrels (Hydrobates pelagicus) breeding in Ireland: a preen oil versus feathers approach. AB - Persistent organic pollutants (POPs) and polycyclic aromatic hydrocarbons (PAHs) are anthropogenic contaminants of environmental concern due to their persistence in the environment and capacity to accumulate in biota. Many of these contaminants have been found to have ill effects over wildlife and humans. Birds are known to be particularly affected through endocrine disruption and eggshell thinning. POPs have been banned or restricted through the Stockholm Convention (2001), making monitoring essential for tracking effects of regulation. Seabirds have been used as monitoring tools for being top predators and consuming a diverse array of prey in different trophic levels. Non-destructive sampling has become widely popular using feathers and preen oil, as opposed to carcasses and internal organs. This study aimed to set baseline levels of POP and PAH concentration in a highly pelagic and abundant seabird in Ireland and the Atlantic, the European storm petrel, Hydrobates pelagicus, and to investigate the profiles of contaminant congeners in preen oil and feathers, comparatively. Mean concentrations in preen oil followed: PCB (10.1 ng/g ww) > PAH (7.1 ng/g ww) > OCP (5.4 ng/g ww) > PBDE (3.9 ng/g ww), whilst mean concentrations in feathers followed the order: PAH (38.9 ng/g ww) > PCB (27.2 ng/g ww) > OCP (17.9 ng/g ww) > PBDE (4.5 ng/g ww). Congener profiles highly differed between preen oil and feathers, and little correlation was found between the matrices. These results demonstrate that the sampling of a single matrix alone (preen oil or feathers) might produce confounding results on contamination in seabirds and that more than one matrix is recommended to obtain a full picture of contamination by persistent organic pollutants. PMID- 29623647 TI - The association between serum copper concentrations and cardiovascular disease risk factors in children and adolescents in NHANES. AB - Copper is an essential element in human beings, alterations in serum copper levels could potentially have effect on human health. To date, no data are available regarding how serum copper affects cardiovascular disease (CVD) risk factors in children and adolescents. We examined the association between serum copper levels and CVD risk factors in children and adolescents. We analyzed data consisting of 1427 subjects from a nationally representative sample of the US population in the National Health and Nutrition Examination Survey (NHANES) from 2011 to 2014. The CVD risk factors included total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, fasting glucose, glycohemoglobin, fasting insulin, and blood pressure. Multivariate and generalized linear regressions were performed to investigate associations adjusted for age, gender, ethnicity, poverty:income ratio (PIR), BMI, energy intake, and physical activity. We found significant associations between serum copper and total cholesterol (coefficient = 0.132; 95% CI 0.081, 0.182; P for trend < 0.001), glycohemoglobin (coefficient = 0.044; 95% CI 0.020, 0.069; P < 0.001), and fasting insulin (coefficient = 0.730; 95% CI 0.410, 1.050; P < 0.001) among the included participants. Moreover, in the generalized linear models, subjects with the highest copper levels demonstrated a 0.83% (95% CI 0.44%, 1.24%) greater increase in serum total cholesterol (p for trend < 0.001) when compared to participants with the lowest copper concentrations. Our results provide the first epidemiological evidence that serum copper concentrations are associated with total cholesterol concentrations in children and adolescents. However, the underlying mechanisms still need further exploration. PMID- 29623648 TI - Osteoporosis-Related Fractures in HIV-Infected Patients Receiving Long-Term Tenofovir Disoproxil Fumarate: An Observational Cohort Study. AB - INTRODUCTION: Patients with HIV infection may have a higher prevalence of osteoporosis and osteopenia, as well as an increased risk of bone fracture compared with non-HIV-infected individuals. Antiretroviral therapy is thought to be one of factors associated to osteoporosis-related bone fractures. OBJECTIVE: The aim of this study was to assess the effects of long-term exposure to tenofovir disoproxil fumarate (TDF) on the cumulative risk of osteoporosis related bone fractures in Japanese patients with HIV infection. DESIGN: This observational cohort study comprised a joint HIV-related drug survey of patients treated with TDF between April 2004 and March 2013. METHODS: Thirty-five healthcare facilities in Japan participated in the survey. The incidence of osteoporosis-related fractures was extracted from all adverse events (AEs) using standardized Medical Dictionary for Regulatory Activities queries, and used to calculate the fracture rate per 10,000 patient-years (PY). Kaplan-Meier analysis was used to estimate the cumulative probability of fracture during the study period. RESULTS: A total of 3251 patients who received TDF or TDF/emtricitabine between April 2004 and March 2013 were analyzed in this study; 93.5% of patients were male. The fracture rate was 13.5 per 10,000 PY in males and 42.2 per 10,000 PY in females. The mean age for male patients with osteoporosis-related fracture was 43.2 years, whereas it was 65.7 years in female patients. The cumulative probability of osteoporosis-related fracture increased after >= 5 years of TDF exposure. The rate of hip fracture (95% confidence interval) was 7.2 (3.1-14.2) per 10,000 PY. CONCLUSIONS: Among HIV-infected patients in Japan, treatment with TDF for >= 5 years increases the risk of bone fractures in younger men, in addition to that seen in older post-menopausal women. PMID- 29623649 TI - Influence of an Acute Exercise Until Exhaustion on Serum and Urinary Concentrations of Molybdenum, Selenium, and Zinc in Athletes. AB - The aim of the present study was to determine changes occurring in serum and urine concentrations of essential trace elements with proven essentiality (molybdenum, selenium, and zinc) as a result of performing an acute physical activity until exhaustion in middle- and long-distance runners who live in the same area of Extremadura (Spain). Twenty-one Spanish national middle- and long distance runners and 26 sedentary students of a similar age were recruited for the study. Both groups ran on a treadmill until exhaustion, starting at a speed of 10 and 8 km/h, respectively, and increasing the speed at 1 km/h every 400 m, without modifying the slope, always within the recommended parameters. Serum and urine samples were obtained from all subjects before and after the tests. Analysis of trace metals was performed by inductively coupled plasma mass spectrometry (ICP-MS). Resting serum and urinary concentrations between groups were compared using the Student t test, and the Wilcoxon test was used to analyze the trends of changes before and after the effort. The results showed that molybdenum concentrations were significantly higher in athletes than in controls (p < 0.01). Selenium (p < 0.05) and zinc (p < 0.01) concentrations were significantly lower in athletes than in controls. When we compared the serum concentrations before and after the test in the controls, only in the case of selenium (p = 0.006), a significant increase was observed after the test. However, this signification disappears with the corrections for hematocrit. Athletes' serum concentrations of Se (p = 0.004) and Zn (p = 0.005) lowered at the end of the test. Also, the results showed that there were no statistical urinary concentration (expressed in MUg/g creatinine) changes in Mo and Se. Zn urinary concentration increased at the end of exercise (p = 0.018), since an incremental exercise to exhaustion in middle- and long-distance elite athletes produces a decrease in Se and Zn serum concentrations but Zn urinary concentration increased. In conclusion, athletes show higher serum concentrations of molybdenum and lower serum concentrations of selenium and zinc than sedentary subjects. Additionally, a treadmill test until exhaustion provokes a decrease in serum concentration of selenium and zinc and a higher excretion of urinary zinc. Serum concentrations of Se and Zn should be carried out in order to avoid any possible deficit cases and to establish the optimal supplementation. PMID- 29623650 TI - Multi-Scale Approach for the Evaluation of Bone Mineralization in Strontium Ranelate-Treated Diabetic Rats. AB - Long-term diabetes mellitus can induce osteopenia and osteoporosis, an increase in the incidence of low-stress fractures, and/or delayed fracture healing. Strontium ranelate (SrR) is a dual-action anti-osteoporotic agent whose use in individuals with diabetic osteopathy has not been adequately evaluated. In this study, we studied the effects of an oral treatment with SrR and/or experimental diabetes on bone composition and biomechanics. Young male Wistar rats (half non diabetic, half with streptozotocin/nicotinamide-induced diabetes) were either untreated or orally administered 625 mg/kg/day of SrR for 6 weeks. After sacrifice, femora from all animals were evaluated by a multi-scale approach (X ray diffraction, Fourier transform infrared spectroscopy, inductively coupled plasma optical-emission spectrometry, static histomorphometry, pQCT, and mechanical testing) to determine chemical, crystalline, and biomechanical properties. Untreated diabetic animals (versus untreated non-diabetic) showed a decrease in femoral mineral carbonate content, in cortical thickness and BMC, in trabecular osteocyte density, in maximum load supported at rupture and at yield point, and in overall toughness at mid-shaft. Treatment of diabetic animals with SrR further affected several parameters of bone (some already impaired by diabetes): crystallinity index (indicating less mature apatite crystals); trabecular area, BMC, and vBMD; maximum load at yield point; and structural elastic rigidity. However, SrR was also able to prevent the diabetes-induced decreases in trabecular osteocyte density (completely) and in bone ultimate strength at rupture (partially). Our results indicate that SrR treatment can partially but significantly prevent some bone structural mechanical properties as previously affected by diabetes, but not others (which may even be worsened). PMID- 29623651 TI - Is Iron Accumulation a Possible Risk Factor for Sarcopenia? AB - Sarcopenia has a high incidence among the elderly, with significant negative effects on the quality of life. The pathogenesis of sarcopenia is complex, and many factors are involved in its development and progression. Sarcopenia might be associated with iron accumulation given that (1) age-related iron accumulation was found in the skeletal muscle, (2) excess iron could cause skeletal muscle damage or atrophy, and (3) patients with sarcopenia showed higher levels of serum ferritin. Understanding the etiology and pathogenesis of sarcopenia would help to develop new treatment and preventive methods, thereby improving the quality of life of the elderly patients. PMID- 29623652 TI - Baloxavir: First Global Approval. AB - Baloxavir marboxil (XofluzaTM; baloxavir) is an oral cap-dependent endonuclease inhibitor that has been developed by Roche and Shionogi. The drug blocks influenza virus proliferation by inhibiting the initiation of mRNA synthesis. In February 2018, baloxavir received its first global approval in Japan for the treatment of influenza A or B virus infections. Phase III development is underway in the USA, EU and other countries for this indication. This article summarized the milestones in the development of baloxavir leading to this first global approval for influenza A or B virus infections. PMID- 29623653 TI - Infliximab Pharmacokinetics are Influenced by Intravenous Immunoglobulin Administration in Patients with Kawasaki Disease. AB - BACKGROUND: Infliximab, a monoclonal antibody directed against tumor necrosis factor-alpha, is being evaluated as adjunctive therapy to intravenous immunoglobulin (IVIG) for treatment of young children with acute Kawasaki disease (KD). OBJECTIVE: The aim of this study was to develop a population pharmacokinetic (PopPK) model for infliximab in children with KD, and to evaluate the impact of covariates on infliximab disposition. Specifically, we wanted to investigate the effect of body weight and IVIG administration on PK parameters. METHODS: In the current PopPK analysis, 70 subjects with a median (interquartile range) age of 2.9 years (1.3-4.4) were included from two randomized controlled trials. Infliximab concentration-time data were best described by a two compartment model with first-order elimination using non-linear mixed-effects modeling (NONMEM 7.3). RESULTS: The clearance, volume of distribution of the central (V1) and peripheral (V2) compartment, and intercompartmental clearance estimates (95% confidence interval) from the PopPK analysis were 0.117 (0.091 0.134) L/day, 0.801 (0.545-0.960) L, 0.962 (0.733-1.759) L, and 0.692 (0.482 1.779) L/day, respectively. Allometric body weight was included on all parameters of the structural model and a covariate analysis revealed that administering infliximab after IVIG, as opposed to before, resulted in a 50% decrease in V2. CONCLUSIONS: Our study shows that the timing of infliximab administration relative to IVIG administration affects the disposition of the monoclonal antibody. These results may have important implications for other monoclonal antibodies administered in combination with IVIG for treating inflammatory diseases. PMID- 29623655 TI - Transitions between Housing States among Urban Homeless Adults: a Bayesian Markov Model. AB - The purpose of this study is to explore how marginalization, substance abuse, and service utilization influence the transitions between streets, shelters, and housed states over the course of 2 years in a population of urban homeless adults. Survey responses from three yearly interviews of 400 homeless adults were matched with administrative services data collected from regional health, mental health, and housing service providers. To estimate the rates of transition between housed, street, and shelter status, a multi-state Markov model was developed within a Bayesian framework. These transition rates were then regressed on a set of independent variables measuring demographics, marginalization, substance abuse, and service utilization. Transitions from housing to shelters or streets were associated with not being from the local area, not having friends or family to count on, and unemployment. Pending charges and a recent history of being robbed were associated with the shelters-to-streets transition. Remaining on the streets was uniquely associated with engagement in "shadow work" and, surprisingly, a high use of routine services. These findings paint a picture of unique and separate processes for different types of housing transitions. These results reinforce the importance of focusing interventions on the needs of these unique housing transitions, paying particular attention to prior housing patterns, substance abuse, and the different ways that homeless adults are marginalized in our society. PMID- 29623656 TI - Access to Health Care Services among Young People Exchanging Sex in Detroit. AB - Within the related epidemics of sex exchange, drug use, and poverty, access to health care is shaped by intersecting identities, policy, and infrastructure. This study uses a unique survey sample of young adults in Detroit, who are exchanging sex on the street, in strip clubs, and at after-hours parties and other social clubs. Factors predicting access to free or affordable health care services, such as venue, patterns of sexual exchange influence, drug use and access to transportation, were examined using multivariable logistic regression and qualitative comparative analysis. The most significant predictors of low access to health care services were unstable housing and lack of access to reliable transportation. In addition, working on the street was associated with decreased access to services. Coordinated policy and programming changes are needed to increase health care access to this group, including improved access to transportation, housing, and employment, and integration of health care services. PMID- 29623654 TI - Tapentadol Extended Release in the Treatment of Severe Chronic Low Back Pain and Osteoarthritis Pain. AB - Tapentadol is a novel pain reliever with apparently synergistic dual mechanisms of action, capable of addressing both nociceptive and neuropathic components of chronic pain. As an effective analgesic with good tolerability, tapentadol may be appropriate for patients suffering from severe chronic pain associated with low back pain (LBP) or osteoarthritis (OA). Efficacy studies of tapentadol in populations of patients with severe chronic LBP or OA pain suggest that tapentadol is non-inferior to oxycodone. Its tolerability, especially with respect to gastrointestinal (GI) side effects, may be better than that of other strong opioids in clinical trials and analyses of multiple trials. Patient satisfaction with tapentadol extended release for chronic noncancer pain syndromes is good. Although tapentadol has an opioid component with abuse liability, it appears to be a difficult opioid for tampering with less appeal to abusers than other opioids. For patients with severe LBP and OA pain, tapentadol appears to hold promise as a safe, effective therapeutic option. PMID- 29623657 TI - A case of primary familial congenital polycythemia with a novel EPOR mutation: possible spontaneous remission/alleviation by menstrual bleeding. AB - A 10-year-old girl with persistent erythrocytosis and ruddy complexion was diagnosed with primary familial congenital polycythemia (PFCP) involving a novel heterozygous mutation of c.1220C>A, p.Ser407X in exon 8 of the erythropoietin receptor gene (EPOR). This mutation causes truncation of EPOR, resulting in loss of the cytoplasmic region, which is necessary for negative regulation of erythropoietin signal transmission. Genetic analysis showed that the mutated EPOR was inherited from her mother. Her mother had polycythemia and had undergone venesection several times when she was young, but her polycythemic state appeared to have resolved. Venesection was not needed to maintain Hct levels within normal range. For the case reported here, venesection was also conducted to maintain the blood Hct level below 50%. We observed that after the patient experienced menarche, the volume and frequency of venesection needed to maintain Hct level < 50% were clearly reduced compared with those before menarche. These findings suggest that, in female patients with this type of EPOR mutation, menstruation might reduce blood volume in a manner similar to venesection. Spontaneous remission of erythrocytosis may thus occur after the start of menstrual bleeding. PMID- 29623658 TI - Atrial Fibrillation in Patients with Heart Failure: Current State and Future Directions. AB - Heart failure affects nearly 26 million people worldwide. Patients with heart failure are frequently affected with atrial fibrillation, and the interrelation between these pathologies is complex. Atrial fibrillation shares the same risk factors as heart failure. Moreover, it is associated with a higher-risk baseline clinical status and higher mortality rates in patients with heart failure. The mechanisms by which atrial fibrillation occurs in a failing heart are incompletely understood, but animal studies suggest they differ from those that occur in a healthy heart. Data suggest that heart failure-induced atrial fibrosis and atrial ionic remodeling are the underlying abnormalities that facilitate atrial fibrillation. Therapeutic considerations for atrial fibrillation in patients with heart failure include risk factor modification and guideline directed medical therapy, anticoagulation, rate control, and rhythm control. As recommended for atrial fibrillation in the non-failing heart, anticoagulation in patients with heart failure should be guided by a careful estimation of the risk of embolic events versus the risk of hemorrhagic episodes. The decision whether to target a rate-control or rhythm-control strategy is an evolving aspect of management. Currently, both approaches are good medical practice, but recent data suggest that rhythm control, particularly when achieved through catheter ablation, is associated with improved outcomes. A promising field of research is the application of neurohormonal modulation to prevent the creation of the "structural substrate" for atrial fibrillation in the failing heart. PMID- 29623660 TI - Outstanding JASMS Manuscript Reviewers, 2016-2017. PMID- 29623659 TI - Directed-Backbone Dissociation Following Bond-Specific Carbon-Sulfur UVPD at 213 nm. AB - Ultraviolet photodissociation or UVPD is an increasingly popular option for tandem-mass spectrometry experiments. UVPD can be carried out at many wavelengths, and it is important to understand how the results will be impacted by this choice. Here, we explore the utility of 213 nm photons for initiating bond-selective fragmentation. It is found that bonds previously determined to be labile at 266 nm, including carbon-iodine and sulfur-sulfur bonds, can also be cleaved with high selectivity at 213 nm. In addition, many carbon-sulfur bonds that are not subject to direct dissociation at 266 nm can be selectively fragmented at 213 nm. This capability can be used to site-specifically create alaninyl radicals that direct backbone dissociation at the radical site, creating diagnostic d-ions. Furthermore, the additional carbon-sulfur bond fragmentation capability leads to signature triplets for fragmentation of disulfide bonds. Absorption of amide bonds can enhance dissociation of nearby labile carbon-sulfur bonds and can be used for stochastic backbone fragmentation typical of UVPD experiments at shorter wavelengths. Several potential applications of the bond selective fragmentation chemistry observed at 213 nm are discussed. Graphical Abstract ?. PMID- 29623661 TI - Editorial and Review: 29th ASMS Sanibel Conference on Mass Spectrometry Peptidomics: Bridging the Gap between Proteomics and Metabolomics by MS. PMID- 29623662 TI - Gas-Phase Enrichment of Multiply Charged Peptide Ions by Differential Ion Mobility Extend the Comprehensiveness of SUMO Proteome Analyses. AB - The small ubiquitin-like modifier (SUMO) is a member of the family of ubiquitin like modifiers (UBLs) and is involved in important cellular processes, including DNA damage response, meiosis and cellular trafficking. The large-scale identification of SUMO peptides in a site-specific manner is challenging not only because of the low abundance and dynamic nature of this modification, but also due to the branched structure of the corresponding peptides that further complicate their identification using conventional search engines. Here, we exploited the unusual structure of SUMO peptides to facilitate their separation by high-field asymmetric waveform ion mobility spectrometry (FAIMS) and increase the coverage of SUMO proteome analysis. Upon trypsin digestion, branched peptides contain a SUMO remnant side chain and predominantly form triply protonated ions that facilitate their gas-phase separation using FAIMS. We evaluated the mobility characteristics of synthetic SUMO peptides and further demonstrated the application of FAIMS to profile the changes in protein SUMOylation of HEK293 cells following heat shock, a condition known to affect this modification. FAIMS typically provided a 10-fold improvement of detection limit of SUMO peptides, and enabled a 36% increase in SUMO proteome coverage compared to the same LC-MS/MS analyses performed without FAIMS. Graphical Abstract ?. PMID- 29623663 TI - Experimental Observation of the Effects of Translational and Rotational Electrode Misalignment on a Planar Linear Ion Trap Mass Spectrometer. AB - The performance of miniaturized ion trap mass analyzers is limited, in part, by the accuracy with which electrodes can be fabricated and positioned relative to each other. Alignment of plates in a two-plate planar LIT is ideal to characterize misalignment effects, as it represents the simplest possible case, having only six degrees of freedom (DOF) (three translational and three rotational). High-precision motorized actuators were used to vary the alignment between the two ion trap plates in five DOFs-x, y, z, pitch, and yaw. A comparison between the experiment and previous simulations shows reasonable agreement. Pitch, or the degree to which the plates are parallel along the axial direction, has the largest and sharpest impact to resolving power, with resolving power dropping noticeably with pitch misalignment of a fraction of a degree. Lateral displacement (x) and yaw (rotation of one plate, but plates remain parallel) both have a strong impact on ion ejection efficiency, but little effect on resolving power. The effects of plate spacing (y-displacement) on both resolving power and ion ejection efficiency are attributable to higher-order terms in the trapping field. Varying the DC (axial) trapping potential can elucidate the effects where more misalignments in more than one DOF affect performance. Implications of these results for miniaturized ion traps are discussed. Graphical Abstract ?. PMID- 29623664 TI - Reply to IFSO Worldwide Survey 2014. PMID- 29623666 TI - Food Tolerance and Eating Behavior After Roux-en-Y Gastric Bypass Surgery. AB - BACKGROUND: Roux-en-Y gastric bypass (RYGB) surgery often leads to food intolerance, especially protein intake. AIM: This is to investigate the association of food intolerance with protein intake and chewing parameters in patients who underwent RYGB surgery 2 years prior. METHODS: An observational study was carried out in 30 patients aged between 18 and 60 years old with at least a 2-year postoperative period since undergoing RYGB surgery. A specific questionnaire was applied to obtain a food tolerance score; a masticatory efficiency, chewing cycles, and time were evaluated with a standard test based on the size of the fragmentation of almonds and of meat after a certain chewing time. Protein intake was evaluated by 24-h dietary recall. RESULTS: Mean age was 42.3 +/- 11.2 years; mean body mass index was 33 +/- 6 kg/m2; and mean time since surgery was 4.9 years. The food tolerance score was 23.4 +/- 3.3 points. There was no evidence of an association between food tolerance and chewing efficiency for meat (p = 0.28) nor between food tolerance and protein intake (Spearman correlation coefficient 0.03, p = 0.86). Regarding chewing efficiency with almonds, tolerance was higher in patients with optimal efficiency than among those with good and acceptable efficiency (p = 0.01). CONCLUSIONS: In the evaluation of mastication using almonds, food tolerance increased with the number of chewing cycles and with greater chewing efficiency; the same association was not found in the evaluation using red meat. PMID- 29623665 TI - Laparoscopic Gastric Bypass with Fundectomy and Gastric Remnant Exploration (LRYGBfse): Results at 5-Year Follow-up. AB - BACKGROUND: The laparoscopic Roux-en-Y gastric bypass (LRYGB) is the gold standard treatment for morbid obesity. After LRYGB, the endoscopic access to the gastric remnant and pancreaticobiliary system is challenging. The laparoscopic gastric bypass with fundectomy and exploration of the gastric remnant (LRYGBfse) was introduced in an attempt to overcome this limitation. The purpose of this study was to analyze the medium-term outcomes and safety of LRYGBfse. METHODS: Observational prospective single-arm multicenter cohort study. Patients with BMI > 35 kg/m2 were included. Previous open abdominal surgery was an exclusion criterion. Postoperative 1, 2, 3, and 5-year weight loss, BMI decrease, and percentage of excess weight loss (%EWL) were recorded. Wilcoxon signed rank sum test was used for paired data. RESULTS: Among 653 enrolled patients, 229 completed the 5-year follow-up. Preoperative median body weight (kg) and BMI (kg/m2) were 133.4 kg (interquartile range (IQR) = 12.0) and 48.2 kg/m2 (IQR = 10.1), respectively. Median 5-year body weight, BMI, and %EWL were 83.7 (IQR = 17.3), 31.2 (IQR = 7.7), and 74.8 (IQR = 23.4), respectively, all significantly improved compared to baseline (p = 0.002, p = 0.001, and p = 0.012, respectively). Comorbid improvement or resolution was observed in 88% of the patients. No major intraoperative complications were reported. Postoperative overall morbidity and mortality rates were 1 and 0%, respectively. Banding removal was necessary in one patient 62 months after the index operation. CONCLUSIONS: The LRYGBfse seems safe and effective with durable results at 5-year follow-up. Endoscopic exploration of the gastric remnant is an additional valuable tool. PMID- 29623669 TI - The (un)reliability of item-level semantic priming effects. AB - Many researchers have tried to predict semantic priming effects using a myriad of variables (e.g., prime-target associative strength or co-occurrence frequency). The idea is that relatedness varies across prime-target pairs, which should be reflected in the size of the priming effect (e.g., cat should prime dog more than animal does). However, it is only insightful to predict item-level priming effects if they can be measured reliably. Thus, in the present study we examined the split-half and test-retest reliabilities of item-level priming effects under conditions that should discourage the use of strategies. The resulting priming effects proved extremely unreliable, and reanalyses of three published priming datasets revealed similar cases of low reliability. These results imply that previous attempts to predict semantic priming were unlikely to be successful. However, one study with an unusually large sample size yielded more favorable reliability estimates, suggesting that big data, in terms of items and participants, should be the future for semantic priming research. PMID- 29623670 TI - Epidemiology in wonderland: Big Data and precision medicine. AB - Big Data and precision medicine, two major contemporary challenges for epidemiology, are critically examined from two different angles. In Part 1 Big Data collected for research purposes (Big research Data) and Big Data used for research although collected for other primary purposes (Big secondary Data) are discussed in the light of the fundamental common requirement of data validity, prevailing over "bigness". Precision medicine is treated developing the key point that high relative risks are as a rule required to make a variable or combination of variables suitable for prediction of disease occurrence, outcome or response to treatment; the commercial proliferation of allegedly predictive tests of unknown or poor validity is commented. Part 2 proposes a "wise epidemiology" approach to: (a) choosing in a context imprinted by Big Data and precision medicine-epidemiological research projects actually relevant to population health, (b) training epidemiologists, PMID- 29623667 TI - A Review of the Opioid Epidemic: What Do We Do About It? AB - The opioid epidemic, with its noticeable increase in opioid prescriptions and related misuse, abuse and resultant deaths in the previous 12 years, is a particularly North American phenomenon. Europe, and particularly low- and middle income countries, appear to be less influenced by this problem. There is undisputable value in using opioids not only in the treatment of acute pain, but in cancer pain as well. However, opioids are progressively being prescribed more and more for chronic non-cancer pain, despite inadequate data on their efficacy. In this paper, we describe the current prevalence of opioid misuse in a number of countries and the rationale for the commencement of opioid therapy. The safe initiation and monitoring of opioid therapy as well as the need for concurrent use of interdisciplinary multimodal therapy is discussed. The possible consequences of long-term use and predictors of high opioid use and overdose are presented. In particular, the management of opioid use disorders and the prevention of opioid abuse and dependence in the young, the old and the pregnant are discussed. Measures to prevent overprescribing and to alleviate risk are described, including the tapering of opioids and the use of opioid deterrents. Finally, the paper looks at the future development of pioneering medications and technologies to potentially treat abuse. In those parts of the world with an opioid epidemic, coroners and medical examiners, private and public health agencies, and agencies that enforce the law need to cooperate in an effort to slow down and reverse the indiscriminate use of prescribing opioids in the long term for chronic non-cancer pain. Ongoing research is needed to create ways to minimise risks of opioid use, and to provide evidence for effective strategies for treating chronic pain. PMID- 29623672 TI - A Systematic Review on the Protective Effect of N-Acetyl Cysteine Against Diabetes-Associated Cardiovascular Complications. AB - INTRODUCTION: Heart failure is the leading cause of death in patients with diabetes. No treatment currently exists to specifically protect these patients at risk of developing cardiovascular complications. Accelerated oxidative stress induced tissue damage due to persistent hyperglycemia is one of the major factors implicated in deteriorated cardiac function within a diabetic state. N-acetyl cysteine (NAC), through its enhanced capacity to endogenously synthesize glutathione, a potent antioxidant, has displayed abundant health-promoting properties and has a favorable safety profile. OBJECTIVE: An increasing number of experimental studies have reported on the strong ameliorative properties of NAC. We systematically reviewed the data on the cardioprotective potential of this compound to provide an informative summary. METHODS: Two independent reviewers systematically searched major databases, including PubMed, Cochrane Library, Google scholar, and Embase for available studies reporting on the ameliorative effects of NAC as a monotherapy or in combination with other therapies against diabetes-associated cardiovascular complications. We used the ARRIVE and JBI appraisal guidelines to assess the quality of individual studies included in the review. A meta-analysis could not be performed because the included studies were heterogeneous and data from randomized clinical trials were unavailable. RESULTS: Most studies support the ameliorative potential of NAC against a number of diabetes-associated complications, including oxidative stress. We discuss future prospects, such as identification of additional molecular mechanisms implicated in diabetes-induced cardiac damage, and highlight limitations, such as insufficient studies reporting on the comparative effect of NAC with common glucose-lowering therapies. Information on the comparative analysis of NAC, in terms of dose selection, administration mode, and its effect on different cardiovascular-related markers is important for translation into clinical studies. CONCLUSIONS: NAC exhibits strong potential for the protection of the diabetic heart at risk of myocardial infarction through inhibition of oxidative stress. The effect of NAC in preventing both ischemia and non-ischemic-associated cardiac damage is also of interest. Consistency in dose selection in most studies reported remains important in dose translation for clinical relevance. PMID- 29623671 TI - One- and two-stage surgical revision of peri-prosthetic joint infection of the hip: a pooled individual participant data analysis of 44 cohort studies. AB - One-stage and two-stage revision strategies are the two main options for treating established chronic peri-prosthetic joint infection (PJI) of the hip; however, there is uncertainty regarding which is the best treatment option. We aimed to compare the risk of re-infection between the two revision strategies using pooled individual participant data (IPD). Observational cohort studies with PJI of the hip treated exclusively by one- or two-stage revision and reporting re-infection outcomes were retrieved by searching MEDLINE, EMBASE, Web of Science, The Cochrane Library, and the WHO International Clinical Trials Registry Platform; as well as email contact with investigators. We analysed IPD of 1856 participants with PJI of the hip from 44 cohorts across four continents. The primary outcome was re-infection (recurrence of infection by the same organism(s) and/or re infection with a new organism(s)). Hazard ratios (HRs) for re-infection were calculated using Cox proportional frailty hazards models. After a median follow up of 3.7 years, 222 re-infections were recorded. Re-infection rates per 1000 person-years of follow-up were 16.8 (95% CI 13.6-20.7) and 32.3 (95% CI 27.3 38.3) for one-stage and two-stage strategies respectively. The age- and sex adjusted HR of re-infection for two-stage revision was 1.70 (0.58-5.00) when compared with one-stage revision. The association remained consistently absent after further adjustment for potential confounders. The HRs did not vary importantly in clinically relevant subgroups. Analysis of pooled individual patient data suggest that a one-stage revision strategy may be as effective as a two-stage revision strategy in treating PJI of the hip. PMID- 29623673 TI - The Relationship Between Age and Chronic Kidney Disease in Patients Undergoing Pancreatic Resection. AB - BACKGROUND: Severe chronic kidney disease (CKD) predicts adverse outcomes in patients undergoing pancreatectomy, but the impact of milder CKD is unknown. Additionally, some authors have suggested that, due to physiologic changes of aging, CKD is over-diagnosed in patients above age 65. METHODS: Patients undergoing pancreatectomy for malignancy from 2005 to 2014 were identified from the National Surgical Quality Improvement Program. Primary outcomes were all cause mortality and major complication, defined as myocardial infarction, cardiac arrest, stroke, venous thromboembolism, respiratory failure, deep surgical site infection, pneumonia, acute kidney injury, coma > 24 h, or re-operation occurring within 30 days of surgery. RESULTS: The mean age of 16,173 participants was 66 (range 18-90). Median preoperative creatinine was 0.80 mg/dL (0.10-11.0), and median preoperative eGFR was 86.36 mL/min/1.73m2 (2.98-182.2). Mortality and major complication occurred in 3 and 23% of patients, respectively. In adjusted analyses, CKD stages 2 (adjusted odds ratio (aOR) 1.24, 95% confidence interval (CI) 1.10-1.40), 3a (aOR 1.50, 95% CI 1.24-1.82), 3b (aOR 1.56, 95% CI 1.19 2.06), and 4 (aOR 2.17, 95% CI 1.25-3.76) were associated with increased major complication, and CKD stage 4 was associated with increased mortality (aOR 2.68, 95% CI 1.10-6.56). Age did not influence the relationship between CKD and either outcome. CONCLUSION: CKD of any stage was associated with an increased risk of postoperative major complication, and severe CKD was associated with increased mortality among patients undergoing pancreatectomy for malignancy. These associations were not diminished in elderly patients. Our findings could inform preoperative counseling and decision-making. PMID- 29623676 TI - Cost-effectiveness of the BRECONDA decision aid for women with breast cancer: Results from a randomized controlled trial. AB - OBJECTIVE: To report on the cost-effectiveness of BRECONDA (Breast RECONstruction Decision Aid), a web-based decision aid to facilitate decisions regarding breast reconstruction surgery, with usual care for women with breast cancer. METHODS: The economic evaluation was conducted alongside a randomized controlled trial. Women diagnosed with breast cancer or ductal carcinoma in situ and eligible for breast reconstruction following mastectomy were randomized to access BRECONDA for 6 months + usual care (n = 106) or usual care (n = 116) and were assessed at baseline preintervention, and then 1-month and 6-months post-randomization. Decisional conflict, satisfaction with information, decisional regret, and utilities were assessed by using maximum-likelihood linear mixed effects models. Costs included the fixed costs of BRECONDA, health care provider time, and health care resource use. Nonparametric bootstrapping was used to estimate incremental cost-effectiveness ratios. RESULTS: BRECONDA resulted in significantly less decisional conflict and greater satisfaction with information over time. Quality adjusted life years did not differ between participants who received the decision aid compared with usual care. The cost of BRECONDA was estimated to be small (AUD$10) relative to other health care interventions and resulted in decreased health care costs overall (AUD$764). Based on the point estimates, the decision aid was more effective and less costly (dominant) for all measures of effectiveness. It was estimated that the decision aid has an 87% probability of being cost-effective at $60 000 per quality-adjusted life year gained. CONCLUSIONS: The BRECONDA web-based intervention designed to facilitate decisions regarding breast reconstruction surgery is likely to be cost-effective compared with usual care for women with breast cancer. PMID- 29623674 TI - Current State of Knowledge on Implications of Gut Microbiome for Surgical Conditions. AB - The role of the microbiome in human health has become a central tenant of current medical research, infiltrating a diverse disciplinary base whereby microbiology, computer science, ecology, gastroenterology, immunology, neurophysiology and psychology, metabolism, and cardiovascular medicine all intersect. Traditionally, commensal gut microbiota have been assumed to play a significant role only in the metabolic processing of dietary nutrients and host metabolites, the fortification of gut epithelial barrier function, and the development of mucosal immunity. However, over the last 20 years, new technologies and renewed interest have uncovered a considerably broader influence of the microbiota on health maintenance and disease development, many of which are of particular relevance for surgeons. This article provides a broad overview of the current state of knowledge and a review of the technology that helped in their formation. PMID- 29623677 TI - Population-based study of the sensitivity of axillary ultrasound imaging in the preoperative staging of node-positive invasive lobular carcinoma of the breast. AB - BACKGROUND: Preoperative staging of the axilla is important to allow decisions regarding neoadjuvant treatment and the management of the axilla. Invasive lobular carcinoma metastases are difficult to detect because of the infiltrative pattern of the nodal spread. In this study the sensitivity of preoperative axillary staging between invasive lobular (ILC) and ductal (IDC) carcinoma was compared. METHODS: All women diagnosed with pure ILC or IDC in the West of Scotland in 2012-2014 were identified from a database maintained prospectively within the Managed Clinical Network. Pretreatment axillary ultrasound imaging (AUS), core biopsy and fine-needle aspiration cytology (FNAC) results were compared between ILC and IDC. RESULTS: Some 602 women with ILC and 4199 with IDC had undergone axillary surgery, of whom 209 and 1402 respectively had nodal metastases. Pretreatment AUS sensitivity was significantly lower in ILC than in IDC (32.1 versus 50.1 per cent respectively, P < 0.001; OR 0.47, 95 per cent c.i. 0.34 to 0.64). Core biopsy had equally high sensitivity of 86 per cent in both subtypes; however, FNAC was significantly less sensitive in both ILC (55 per cent; P = 0.003) and IDC (75.6 per cent; P = 0.006). Multivariable analysis revealed that cT3-4 status and symptomatic presentation were both significant in predicting nodal metastasis in patients with ILC and false-negative AUS findings (OR 3.77, 95 per cent c.i. 1.69 to 8.42, P = 0.001; and OR 1.92, 1.24 to 2.98, P = 0.003, respectively). CONCLUSION: AUS is inferior in detecting axillary node metastasis in ILC compared with IDC. Women with cT3-4 lobular carcinoma may benefit from ultrasound-guided axillary biopsy regardless of the ultrasonographic appearance of the nodes. PMID- 29623675 TI - Abdominal imaging findings in adult patients with Fontan circulation. AB - : The Fontan procedures, designed to treat paediatric patients with functional single ventricles, have markedly improved the patient's survival into adulthood. The physiology of the Fontan circuit inevitably increases systemic venous pressure, which may lead to multi-system organ failure in the long-term follow up. Fontan-associated liver disease (FALD) can progress to liver cirrhosis with signs of portal hypertension. Focal nodular hyperplasia-like nodules commonly develop in FALD. Imaging surveillance is often performed to monitor the progression of FALD and to detect hepatocellular carcinoma, which infrequently develops in FALD. Other abdominal abnormalities in post-Fontan patients include protein losing enteropathy and pheochromocytoma/paraganglioma. Given that these abdominal abnormalities are critical for patient management, it is important for radiologists to become familiar with the abdominal abnormalities that are common in post-Fontan patients on cross-sectional imaging. TEACHING POINTS: * Fontan procedure for functional single ventricle has improved patient survival into adulthood. * Radiologists should be familiar with unique imaging findings of Fontan-associated liver disease. * Focal nodular hyperplasia-like nodules commonly develop in Fontan-associated liver disease. * Hepatocellular carcinoma, protein-losing enteropathy, pheochromocytoma/paraganglioma may develop. PMID- 29623678 TI - Routine histopathological examination after female-to-male gender-confirming mastectomy. AB - BACKGROUND: The number of transmen seeking gender-confirming surgery has risen steadily throughout the last decade. Pathologists are increasingly confronted with transmale mastectomy specimens. It is not clear whether routine histopathological examination is useful. This study explored the possible benefit of routine investigation through detailed description of lesions encountered in mastectomy specimens after female-to-male gender-confirming surgery. METHODS: Breast tissue from a cohort of transmen was reviewed. The presence of benign and malignant breast lesions was recorded. The number of terminal duct-lobule units (TDLUs) per ten low-power fields (LPFs) was quantified. Information on hormone therapy and morphometry was retrieved for selected patients. RESULTS: The cohort included 344 subjects with a mean age of 25.8 (range 16-61) years at the time of surgery; the age at surgery decreased significantly over time. Older individuals presented with a significantly higher number of breast lesions. The number of TDLUs per LPF was lower in heavier breasts, but did not correlate with age. Breast lesions, either benign or malignant, were present in 166 individuals (48.3 per cent). Invasive breast cancer was found in two (0.6 per cent); one tumour was an unexpected finding. The number of breast lesions encountered on histopathological examination increased significantly when more tissue blocks were taken. CONCLUSION: The discovery of an unexpected breast cancer in a 31-year old transman emphasizes the importance of thorough routine histopathological examination of mastectomy specimens. The number of tissue blocks taken should be based on age and breast weight. PMID- 29623679 TI - Pregnancy Outcomes After Exposure to Certolizumab Pegol: Updated Results From a Pharmacovigilance Safety Database. AB - OBJECTIVE: Anti-tumor necrosis factor (anti-TNF) medications are effective in controlling chronic inflammatory diseases, but information about their use and safety in pregnancy is limited. Consequently, anti-TNF agents are often discontinued early in gestation. Certolizumab pegol (CZP), a PEGylated, Fc-free anti-TNF agent approved for the treatment of rheumatic diseases and/or Crohn's disease, has minimal to no active placental transfer. This analysis was undertaken to evaluate pregnancy outcomes in women receiving CZP, especially those exposed during early pregnancy. METHODS: Prospective and retrospective data on maternal CZP exposure were extracted from the UCB Pharma safety database through March 6, 2017. Analysis was limited to prospective reports to avoid potential bias associated with retrospective submissions. The numbers of live births, miscarriages, elective abortions, stillbirths, and major congenital malformations were ascertained. RESULTS: Of 1,137 prospectively reported pregnancies with maternal exposure to CZP, 528 (including 10 twin pregnancies) had 538 known outcomes: 459 live births (85.3%), 47 miscarriages (8.7%), 27 elective abortions (5.0%), and 5 stillbirths (0.9%). There were 8 major congenital malformations (1.7%) among the 459 infants. First trimester exposure occurred in 367 (81.2%) of 452 pregnancies resulting in 459 live births. Exposure during all 3 trimesters occurred in 201 (44.5%) of 452 pregnancies. CONCLUSION: This analysis represents the largest cohort of pregnant women exposed to an anti TNF agent for management of chronic inflammatory diseases. Analysis of pregnancy outcomes does not indicate a teratogenic effect of CZP, compared to the general population, nor an increased risk of fetal death. The data are reassuring for women of childbearing age considering treatment with CZP. PMID- 29623681 TI - Erratum: "BMPR1A antagonist differentially affects cartilage and bone formation during fracture healing" [J Orthop Res. Vol 34, 2096-2105 (2016)]. PMID- 29623682 TI - Adult immunisation: A key element of public health programs: Synopsis of Asia Pacific Adult Immunisation Meeting, Tokyo, 1-2 December 2016. AB - OBJECTIVES: To (i) improve scientific knowledge and understanding of the importance of adult vaccination within a public health framework; (ii) share an understanding of the principles of good practice that have improved adult vaccination uptake rates; (iii) appreciate the diverse nature of country-specific barriers; and (iv) reach consensus on principles of a call to action to increase adult vaccination uptake rates. METHODS: Non-governmental organisations, the International Federation on Ageing and Friends of International Federation on Ageing Japan, convened the Asia Pacific Adult Immunisation Meeting, herein referred to as the 'Asia Pacific Meeting'. RESULTS: Delegates identified fundamental barriers to adult vaccination similar to those reported at previous meetings in Latin America and Europe and formed a road map to respond to key barriers in countries represented at the Asia Pacific Meeting. CONCLUSION: Older people are uniquely vulnerable to vaccine-preventable diseases and therefore need to be the target of a series of actions intended to improve uptake rates in this subpopulation. PMID- 29623680 TI - A Critical Review of Methods and Results in the Search for Genetic Contributors to Alcohol Sensitivity. AB - Attributes of alcohol sensitivity are present before alcohol use disorders (AUDs) develop, they predict those adverse alcohol outcomes, are familial in nature, and many are heritable. Whether measured by alcohol challenges or retrospective reports of numbers of drinks required for effects, alcohol sensitivity reflects multiple phenotypes, including low levels of alcohol response and alcohol-related stimulation. Identification of genes that contribute to alcohol sensitivity could help identify individuals carrying risks for AUDs through their alcohol responses for whom early intervention might mitigate their vulnerability. Such genes could also improve understanding of biological underpinnings of AUDs, which could lead to new treatment approaches. However, the existing literature points to a wide range of genetic mechanisms that might contribute to alcohol responses, and few such genetic findings have been widely replicated. This critical review describes the potential impact of the diverse methods used to study sensitivity on the diversity of genetic findings that have been reported, places the genetic variants mentioned in the literature into broader categories rather than isolated results, and offers suggestions regarding how to advance the field by interpreting findings in light of the methods used to select research subjects and to measure alcohol sensitivity. To date, the most promising results have been for GABA, glutamate, opioid, dopamine, serotonin, and cholinergic system genes. The more gene variants that can be identified as contributors to sensitivity the better future gene screening platforms or polygenic scores are likely to be. PMID- 29623683 TI - Essential ocean variables for global sustained observations of biodiversity and ecosystem changes. AB - Sustained observations of marine biodiversity and ecosystems focused on specific conservation and management problems are needed around the world to effectively mitigate or manage changes resulting from anthropogenic pressures. These observations, while complex and expensive, are required by the international scientific, governance and policy communities to provide baselines against which the effects of human pressures and climate change may be measured and reported, and resources allocated to implement solutions. To identify biological and ecological essential ocean variables (EOVs) for implementation within a global ocean observing system that is relevant for science, informs society, and technologically feasible, we used a driver-pressure-state-impact-response (DPSIR) model. We (1) examined relevant international agreements to identify societal drivers and pressures on marine resources and ecosystems, (2) evaluated the temporal and spatial scales of variables measured by 100+ observing programs, and (3) analysed the impact and scalability of these variables and how they contribute to address societal and scientific issues. EOVs were related to the status of ecosystem components (phytoplankton and zooplankton biomass and diversity, and abundance and distribution of fish, marine turtles, birds and mammals), and to the extent and health of ecosystems (cover and composition of hard coral, seagrass, mangrove and macroalgal canopy). Benthic invertebrate abundance and distribution and microbe diversity and biomass were identified as emerging EOVs to be developed based on emerging requirements and new technologies. The temporal scale at which any shifts in biological systems will be detected will vary across the EOVs, the properties being monitored and the length of the existing time-series. Global implementation to deliver useful products will require collaboration of the scientific and policy sectors and a significant commitment to improve human and infrastructure capacity across the globe, including the development of new, more automated observing technologies, and encouraging the application of international standards and best practices. PMID- 29623685 TI - Specific bioactive collagen peptides (PETAGILE(r) ) as supplement for horses with osteoarthritis: A two-centred study. AB - The aim of the study was to evaluate the clinical efficacy of specific bioactive collagen peptides (BCP), here administered orally as PETAGILE(r) , on horses with mild to moderate, naturally occurring osteoarthritis. Data from a two-centred pilot study were used for the meta-analysis. Thirty-eight privately owned horses of various breeds were available. In one centre, 18 of these patients (6 +/- 3 years; 519 +/- 100 kg BW) received either 25 g (n = 6) or 50 g (n = 12) BCP/day orally for 12 weeks. In the second centre, 20 horses (18 +/- 4 years; 413 +/- 94 kg BW) received either a placebo (control; n = 10) or 25 g BCP/day. The attending veterinarians performed an orthopaedic examination including flexion tests and evaluated the degree of lameness, rotation pain, step length and arc of foot flight during trot (8 parameters) at the beginning and after 6 and 12 weeks. The horse owners answered a weekly questionnaire about their perception of lameness, mobility and the horses' willingness to run. In the 50 g BCP group, in six of eight parameters, a strong effect (Cohen's r > .5) was detected with two parameters (lameness and flexion pain) significantly improved already after 6 weeks. In the 25 g BCP group, a moderate effect (Cohen's r = .3-0.5) was seen in six parameters, with three parameters improved already after 6 weeks. The owners reported a strong effect for mobility and willingness to run (Cohen's r = .69 and .62, respectively) and a moderate effect (Cohen's r = .49 and 0.41) for the development of lameness in the 50 g and 25 g BCP group in comparison with the placebo treatment. This study revealed promising effects of the safe oral specific BCP supplementation on symptoms of osteoarthritis in horses already after 3 months. The higher dosage of 50 g BCP/day had superior impact. Further long-term investigations on specific BCP efficacy in horses with osteoarthritis, preferably in blinded and placebo-controlled studies, should be performed to confirm these first positive results. PMID- 29623684 TI - Social Support Moderates Effects of Natural Disaster Exposure on Depression and Posttraumatic Stress Disorder Symptoms: Effects for Displaced and Nondisplaced Residents. AB - Social support is a known protective factor against the negative psychological impact of natural disasters. Most past research has examined how the effects of exposure to traumatic events influences whether someone meets diagnostic criteria for depression and posttraumatic stress disorder (PTSD); it has also suggested sequelae of disaster exposure depends on whether survivors are displaced from their homes. To capture the full range of the psychological impact of natural disasters, we examined the buffering effects of social support on depressive symptoms and cluster-specific PTSD symptoms, with consideration of displacement status. In a survey conducted 18 to 24 months after Hurricane Katrina, 810 adults exposed to the disaster reported the number of Katrina-related traumatic events experienced, perceived social support 2 months post-Katrina, and cluster-specific PTSD and depressive symptoms experienced since Katrina. Analyses assessed the moderating effects of social support and displacement and the conditional effects of displacement status. Social support significantly buffered the negative effect of Katrina-related traumatic events on depressive symptoms, B = -0.10, p = .001, and avoidance and arousal PTSD symptoms, B = -0.02, p = .035 and B = -0.02, p = .042, respectively. Three-way interactions were nonsignificant. Conditional effects indicated social support buffered development of depressive symptoms across all residents; however, the moderating effects of support on avoidance and arousal symptoms only appeared significant for nondisplaced residents. Results highlight the protective effects of disaster-related social support among nondisplaced individuals, and suggest displaced individuals may require more formal supports for PTSD symptom reduction following a natural disaster. PMID- 29623686 TI - Effect of a montmorillonite-bentonite-based product on faecal parameters of horses. AB - Free faecal water (fluid excreted separate from normal faeces) is a common problem of unknown origin in horses. Multifactorial causes are assumed. This study assessed the effect of a commercial product (EMP) sold to help support intestinal health of horses, particularly regarding the occurrence of free faecal water. The hypothesis was that water-binding capacity and microbial activity are improved in the large intestine of horses fed EMP. EMP contained montmorillonite bentonite, whey and extracts from hop and absinthium. Eight adult and healthy horses kept on the same diet and bedding were additionally fed EMP. In a complete crossover study design, all horses participated as control (C) and as test animal receiving EMP (E). Faecal score was assessed. Faecal samples were analysed for pH, ammonia, dry matter content (DM), crude fibre (CF), soxhlet fat (SF), crude protein (CP), crude ash (CA), neutral detergent fibre (NDF), acid detergent fibre (ADF), acid detergent lignin (ADL) and volatile fatty acids (VFAs). None of the assessed parameters measured in the faeces showed a significant treatment effect. This study was conducted in healthy horses without any gastrointestinal disorders. VFA analysis did not show treatment effects. However, apparent higher variability in CP in the faeces of E might be a hint for changes in the intestinal microbiota. Further studies and analysis of additional parameters for example the differentiation of the faecal microbial profile in horses susceptible to free faecal water are necessary to evaluate the effect of EMP. PMID- 29623687 TI - Qualitative and quantitative detection of chicken deoxyribonucleic acid (DNA) in dry dog foods. AB - Chicken is a common protein source in pet foods and is concurrently listed among food allergens. Commercial over-the-counter (OTC) diets with an alternative animal protein source are considered suitable for dietary elimination trials by pet owners. The potential presence of undeclared chicken-derived ingredients in these diets can compromise the outcome of the trial during the diagnosis of adverse food reactions. The aim of this study was to selectively verify the absence or presence of chicken DNA in 10 OTC dry canine foods, using qualitative and quantitative approaches. The method of identification of chicken-derived protein was elaborated with the polymerase chain reaction (PCR) technology, whereas quantitative real-time PCR was used for the quantitative assessment. In most of the analysed samples, the chicken DNA was detectable; however, the quantified amounts were predominantly low, although differences between batches were observed. PMID- 29623688 TI - Dietary approaches reducing boar taint-Importance of Lawsonia intracellularis colonisation for interpreting results. AB - In the fattening of male pigs, boar odour is a major problem with regard to the acceptance of the meat by consumers. Skatole can be one cause. Tryptophan from non-digested feed ingredients and intestinal cell debris can be the precursor in skatole formation. Lawsonia intracellularis, one of the most widespread pathogens in swine, promotes the epithelial cell turnover and might favour the tryptophan influx into the hindgut. Therefore, the question arises how far the severity of a Lawsonia intracellularis infection has an effect on results of dietary experiments with specific issues. Fifty finishing boars from a specific pathogen free farm were randomly allotted to ten boxes in five feeding groups. Natural developing Lawsonia intracellularis colonisation was monitored serologically (twice individually) and molecular biologically (weekly individually). Over 4 weeks, animals were fed either a finely ground pelleted diet (FP), a coarsely ground meal diet (CM), a meal diet either with 22% cracked corn (CORN), 16.9% dried whey (WHEY) or 30% raw potato starch (RPS). Fifty % of animals showing lower differences in serological Lawsonia intracellularis values between the start and the end of the trial were characterised by a higher dry matter content in faeces (256 +/- 29.4 vs. 239 +/- 23.6 g/kg). Lawsonia intracellularis-negative caecal samples showed the highest butyrate concentrations (27.2 +/- 7.53 mmol/kg). Lawsonia intracellularis-negative faecal samples of group FP showed the highest DM levels in faeces (neg: 290 +/- 46.1/pos: 250 +/- 52.2 g/kg); negative samples from group RPS had the lowest values (217 +/- 24.4 g/kg). Lawsonia intracellularis-negative faecal samples from the group CM were lower in skatole than positive samples (82.8 +/- 32.8 vs. 119 +/- 29.3 MUg/g DM). RPS group samples without pathogen detection had the lowest skatole concentrations (30.5 +/ 36.3 MUg/g DM). This study provides first evidence that clinically unremarkable colonisation with intestinal pathogens might influence the results of dietary approaches. PMID- 29623689 TI - In vitro evaluation of Saccharomyces cerevisiae cell wall fermentability using a dog model. AB - Six Saccharomyces cerevisiae cell wall samples were tested by the in vitro gas production technique using dog faeces as inoculum. In particular, the substrates resulted from three different production processes (alcoholic_A, bakers_BA and brewers_BR) and were characterized by two different carbohydrates (mannans + glucans) concentrations nitrogen-free extract (NFE high and low). Gas production of fermenting cultures was recorded for 72 hr to estimate the fermentation profiles. The organic matter degradability (OMD), fermentation liquor pH, short chain fatty acids (SCFA) and ammonia (NH3 ) productions were also measured. All substrates presented a high percentage of OMD (>92%) and moderate fermentability in terms of cumulative volume of gas related to incubated OM (OMCV >50 ml/g) and short-chain fatty acids production (>25 mmol/g), proving their functional properties. Comparing the substrates, it seems evident that the production process affects the chemical composition of the yeast cell wall in terms of crude protein, ether extract and ash content. Consequently, the in vitro fermentation process was significantly different among substrates for volume of gas, SCFA and ammonia production. Regarding the fermentation rate profiles, the production process influenced mainly the curve shape, whereas the NFE concentration affected the quantity of gas produced per hour. In particular, both S. cerevisiae_BR showed very high percentage of OM degradability, gas and SCFA productions and a fast fermentation process due to their high content of fermentable carbohydrates. On the contrary, both S. cerevisiae_BA yeast cell walls appeared to be less degradable and fermentable, probably due to their high content of ether extract. Regarding both S. cerevisiae_A, the high protein content of these substrates could explain the contrasting in vitro results (high degradability with low gas and SCFA production). PMID- 29623690 TI - Observation about phosphorus and protein supply in cats and dogs prior to the diagnosis of chronic kidney disease. AB - There is evidence that nutritional phosphorus (P) excess may be a risk factor for chronic kidney disease (CKD) in humans and pets (Advances in Nutrition: An International Review Journal (2014), 5, 104; The American Journal of Clinical Nutrition, (2013), 98, 6; Journal of Feline Medicine and Surgery, (2017); The source of phosphorus influences serum PTH, apparent digestibility and blood levels of calcium and phosphorus in dogs fed high phosphorus diets with balanced Ca/P ratio. Proc. Waltham International Nutritional Sciences Symposium, USA; Clinical aspects of natural and added phosphorus in foods, 2017, Springer Science+Business, Media). A retrospective study was conducted in order to gather data about P and protein intake in the feeding history of dogs and cats prior to the diagnosis of CKD. Cases of 75 dogs and 16 cats with CKD with comprehensive nutritional history presented to the nutrition consultation service of the Chair of Animal Nutrition and Dietetics, Ludwig-Maximilians-University Munich, between October 2009 and March 2016, were evaluated. Cases of age-matched dogs (n = 57) and cats (n = 18) without diagnosed or suspected CKD served as controls. The most frequent type of diet used in the four groups (cats CKD, cats control, dogs CKD and dogs control) was home-made. In all groups, P and protein supply was in excess (>150%) of the recommended daily allowances (RDA; Nutrient requirements of dogs and cats (2006), National Research Council, National Academy Press). Between the dog groups, no differences regarding P and protein intake existed. The P and protein intake relative to the RDA was altogether higher in cats than in dogs. Cats with CKD showed significantly higher P and protein intakes prior to diagnosis than the control cats (170 +/- 36 vs. 123 +/- 34 mg P/kg BW0.67 ; p < .05). These observations call for further investigations into the long-term effects of P excess. PMID- 29623691 TI - Urinary incontinence and sexual health in a population sample of older people. AB - OBJECTIVES: To investigate the association between self-reported urinary incontinence (UI) and sexual health in a representative sample of older people. SUBJECTS AND METHODS: Participants were community-dwelling women and men aged 50 90+ years from the English Longitudinal Study of Ageing (ELSA) who reported any sexual activity in the last year. The prevalence of UI was assessed both cross sectionally (ELSA Wave 6; 2012) and retrospectively over the preceding 8 years (ELSA Waves 2-6; 2004-2012). Sexual activities, difficulties and concerns were assessed using a validated Sexual Relationships and Activities Questionnaire. The association between UI and sexual health outcomes was examined using weighted logistic regressions, with adjustments made for demographic, health, and lifestyle factors. RESULTS: At Wave 6, 391 (20.0%) women and 141 (6.9%) men reported 'any UI' in the last 12 months. Compared to those without UI, women with UI reported declines in sexual activity and arousal over the last year, and increased concern about their frequency of sexual activity and ability to become sexually aroused. Men with 'any UI' reported declines in sexual desire, increased erectile and orgasm difficulties, and were more concerned about these sexual functions compared to men without UI. Differences in the patterns of association with sexual health were seen, dependent upon whether UI was reported as sporadic or persistent, and also with respect to the duration of retrospectively reported UI. CONCLUSION: Self-reported UI was associated with impairment in sexual health in women and men, and mainly linked to recent declines in sexual activity and function along with elevated sexual concerns. Our findings highlight that the sexual health of older people should be considered when managing UI. PMID- 29623693 TI - Increase in diagnosis of depressive disorders contributes to the increase in antidepressant use in adolescents. AB - OBJECTIVE: To study if the observed increase in use of antidepressants (AD) among adolescents may be explained by higher incidence of depressive disorder diagnosis, increasing treatment of other mental disorders or more liberal prescribing practice. METHODS: We used three different study populations of girls and boys aged 13-17 years in Norway: 1) individuals who were diagnosed with depressive disorders in primary health care, 2) individuals who were diagnosed with depressive disorders in secondary health care; 3) individuals who were dispensed ADs as recorded in the prescription database. Dataset 2) and 3) were linked. RESULTS: Incidence of depressive disorders increased from 2010 to 2015 both in primary and secondary health care, especially in girls. One in four girls with incident depressive disorders was prescribed ADs and this proportion was stable over time. Among girls treated with ADs the proportion with a diagnosis where AD treatment is indicated increased from 61.1% to 66.0%. Furthermore, the proportion with moderate or severe episodes of major depressive disorders was stable and high, 72.9% in 2014. CONCLUSION: The only issue studied that could explain increasing AD use in girls was increasing incidence of depressive disorders. Most adolescents with incident diagnosis of depressive disorders were not treated with ADs. PMID- 29623692 TI - Daily muscle stretching enhances blood flow, endothelial function, capillarity, vascular volume and connectivity in aged skeletal muscle. AB - KEY POINTS: In aged rats, daily muscle stretching increases blood flow to skeletal muscle during exercise. Daily muscle stretching enhanced endothelium dependent vasodilatation of skeletal muscle resistance arterioles of aged rats. Angiogenic markers and capillarity increased in response to daily stretching in muscles of aged rats. Muscle stretching performed with a splint could provide a feasible means of improving muscle blood flow and function in elderly patients who cannot perform regular aerobic exercise. ABSTRACT: Mechanical stretch stimuli alter the morphology and function of cultured endothelial cells; however, little is known about the effects of daily muscle stretching on adaptations of endothelial function and muscle blood flow. The present study aimed to determine the effects of daily muscle stretching on endothelium-dependent vasodilatation and muscle blood flow in aged rats. The lower hindlimb muscles of aged Fischer rats were passively stretched by placing an ankle dorsiflexion splint for 30 min day-1 , 5 days week-1 , for 4 weeks. Blood flow to the stretched limb and the non stretched contralateral limb was determined at rest and during treadmill exercise. Endothelium-dependent/independent vasodilatation was evaluated in soleus muscle arterioles. Levels of hypoxia-induced factor-1alpha, vascular endothelial growth factor A and neuronal nitric oxide synthase were determined in soleus muscle fibres. Levels of endothelial nitric oxide synthase and superoxide dismutase were determined in soleus muscle arterioles, and microvascular volume and capillarity were evaluated by microcomputed tomography and lectin staining, respectively. During exercise, blood flow to plantar flexor muscles was significantly higher in the stretched limb. Endothelium-dependent vasodilatation was enhanced in arterioles from the soleus muscle from the stretched limb. Microvascular volume, number of capillaries per muscle fibre, and levels of hypoxia-induced factor-1alpha, vascular endothelial growth factor and endothelial nitric oxide synthase were significantly higher in the stretched limb. These results indicate that daily passive stretching of muscle enhances endothelium dependent vasodilatation and induces angiogenesis. These microvascular adaptations may contribute to increased muscle blood flow during exercise in muscles that have undergone daily passive stretch. PMID- 29623694 TI - Which Exercise Is Better for Increasing Serum Testosterone Levels in Patients with Erectile Dysfunction? AB - PURPOSE: We investigated the correlations of serum total testosterone (TT) levels with body composition and physical fitness parameters in patients with erectile dysfunction (ED) to know the best exercise for testosterone deficiency. MATERIALS AND METHODS: Eighty-seven ED patients underwent serum TT assessment as well as body composition and basic exercise testing. The bioelectrical impedance analysis was used to assess body composition. Seven types of basic exercise tests were used to determine physical fitness. Correlations between serum TT levels and body composition/physical function parameters were evaluated using partial correlation analyses. A serum TT cut-off value was obtained for the parameters significantly correlated with serum TT levels. RESULTS: The subjects had a mean serum TT level of 342.1 ng/dL. Among the body composition parameters, body and abdominal fat percentages showed statistically significant negative correlations with serum TT levels. Among the basic exercise test parameters, only the cycle ergometer test for cardiorespiratory fitness showed a statistically significant positive correlation with serum TT levels. CONCLUSIONS: Serum TT levels in patients with ED, may be increased by reducing fat percentage and improving cardiorespiratory fitness via aerobic exercise. PMID- 29623696 TI - Sperm Bank: From Laboratory to Patient. PMID- 29623695 TI - A Case Series of Patients Who Underwent Laparoscopic Extraperitoneal Radical Prostatectomy with the Simultaneous Implant of a Penile Prosthesis: Focus on Penile Length Preservation. AB - PURPOSE: There are many grey areas in the field of penile rehabilitation after radical prostatectomy (RP). The preservation of the full dimensions of the penis is an important consideration for improving patients' compliance for the treatment. We present the first case series of patients treated by laparoscopic extraperitoneal RP and simultaneous penile prosthesis implantation (PPI) in order to preserve the full length of the penis and to improve patients' satisfaction. MATERIALS AND METHODS: From June 2013 to June 2014, 10 patients underwent simultaneous PPI (with an AMS InhibiZone prosthesis) and RP. Patients were evaluated by means of urological visits, questionnaires, and objective measurements before surgery, at discharge from the hospital, on postoperative days 21 to 28, each 3 months for the first year, and each 6 months thereafter. The main outcome measures were biochemical recurrence-free rate, penile length, and quality of life. RESULTS: Ten patients (mean age of 61 years; completed the study follow-up period (median, 32.2 months). No difference was found between the time of surgery and the 2-year follow-up evaluation in terms of penile length. The pre-surgery 36-Item Short Form Health Survey (SF-36) median score was 97. Patients were satisfied with their penile implants, and couples' level of sexual satisfaction was rated median 8. The median postoperative SF-36 score was 99 at 3 months follow-up. CONCLUSIONS: Laparoscopic extraperitoneal RP surgery with simultaneous PPI placement seems to be an interesting possibility to propose to motivated patients for preserving the length of the penis and improving their satisfaction. PMID- 29623697 TI - Efficacy and Safety of a Mixed Extract of Trigonella foenum-graecum Seed and Lespedeza cuneata in the Treatment of Testosterone Deficiency Syndrome: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. AB - PURPOSE: The aim of this study was to investigate the efficacy and safety of a mixed extract of Trigonella foenum-graecum seed and Lespedeza cuneata (TFGL) for the treatment of testosterone deficiency syndrome (TDS). MATERIALS AND METHODS: Patients were instructed to take a placebo or 200 mg TFGL capsule twice per day for 8 weeks. The primary efficacy variable was the change from baseline in the Aging Males' Symptoms scale (AMS), as well as levels of serum total and free testosterone. Secondary efficacy measurements included changes from baseline in the number of 'yes' answers on the Androgen Deficiency in the Aging Male (ADAM) questionnaire, levels of serum total cholesterol, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triglyceride, all domain scores of the International Index of Erectile Function (IIEF), perceived stress scale-10 (PSS-10), as well as changes in body composition. RESULTS: The TFGL group exhibited a significant improvement in the AMS scores at 8 weeks, total testosterone at 8 weeks, and free testosterone at 4 and 8 weeks. At 4 weeks, 25% of the TFGL group changed to negative in terms of ADAM scores and 34.1% of the TFGL group had negative scores at the end of the study. The TFGL group exhibited a significant improvement in total cholesterol, HDL-C, LDL-C, triglyceride, IIEF scores, and PSS-10 scores at 8 weeks. CONCLUSIONS: The mixed extract of TFGL resulted in significant improvements in symptoms of TDS, as measured by the AMS, ADAM, PSS-10 and testosterone levels. PMID- 29623698 TI - Shifting the Paradigm of Testosterone Replacement Therapy in Prostate Cancer. AB - Historically, testosterone and prostate cancer have been demonstrated to have a positive association leading providers to forgo testosterone replacement therapy (TRT) in men with concurrent histories of hypogonadism and prostate cancer. This paradigm has been gradually shifting with our evolving understanding of the relationship between testosterone and prostate cancer and the gaining popularity of the saturation model. Newer data suggests improved quality of life for men with hypogonadism after TRT leading to a more tempered view of the effects of this treatment and its risk in prostate cancer. As more reports emerge of TRT in men who have either undergone definitive treatment for prostate cancer or are on active surveillance, some providers see a role for TRT in these patients despite non-consensus in clinical guidelines. It is critical that we examine evidence currently available, while we await more rigorous data to emerge. PMID- 29623699 TI - Current Issues in Adolescent Varicocele: Pediatric Urological Perspectives. AB - While varicocele is the most common cause of surgically correctable infertility in adult males, with repair resulting in improved semen parameters in 60% to 80% of men and a higher likelihood of conception in up to 60% of men, the rationale for varicocele repair in the pediatric population is less clear. Additionally, prepubertal varicoceles are much less common and their management is controversial. Adolescents with a varicocele are often in the midst of a progressive disease process. Despite the high prevalence of varicocele and its association with progressive disease processes, the indications for adolescent varicocele repair and the effects thereof on paternity have been persistently challenging to study. This review will briefly present some of the current issues regarding adolescent varicocele from a pediatric urological point of view, including the evaluation of adolescent varicocele, the optimal surgical indications, the optimal choice of surgical intervention to be performed, and outcomes. PMID- 29623700 TI - The Relationship between Neonatal Circumcision, Urinary Tract Infection, and Health. AB - The risk-benefit profile of neonatal circumcision is not clear. Most studies have focused on urinary tract infections but other health sequelae have not been evaluated. While evidence supports benefits of circumcision, a lack of randomized trials has been cited as a weakness. National guidelines provide mixed recommendations regarding neonatal circumcision. We review the weight of evidence and utilize current statistical methodology on observational data to examine the risks and benefits of neonatal circumcision. PMID- 29623701 TI - Let's Take Advantage of Mixtures of Bupivacaine or Ropivacaine in Urologic Inguinal and Scrotal Surgery. PMID- 29623703 TI - Penile Reconstructive Surgery in Peyronie Disease: Challenges in Restoring Normal Penis Size, Shape, and Function. AB - PURPOSE: To provide an overview of current approaches to penile reconstructive surgery in Peyronie disease (PD), and to discuss the challenges in restoring normal penile size and function. METHODS: A systematic literature search was conducted to identify the published literature relevant to PD and penile reconstructive surgery. A summary of the published guidelines from major organisations is included in this review paper. DISCUSSION: Penile plication is simple and minimally invasive, and tends to preserve potency in most patients. However, plication invariably results in penile length loss and may, in fact, worsen the existing hour-glass or hinge effect. In contrast, graft reconstructive surgery can address issues relating to the loss of penile length and complex penile deformities, but long-term data highlight the risks of altered glans sensation, recurrent curvature, and/or loss of penile length from graft contracture, as well as the development of erectile dysfunction. Complex penile reconstruction with the concurrent placement of a penile prosthesis and/or graft material is a demanding operation that should be performed by surgeons with extensive prosthetic and reconstructive experience, as the risk of sensory loss, glans ischemia/necrosis, prosthesis-related complications, and failure to gain any meaningful length are serious concerns and cannot be underestimated. CONCLUSIONS: While surgical approaches remain the standard of care, they pose considerable risks and require prolonged postoperative rehabilitation. Obtaining proper informed consent and establishing realistic outcome expectations are imperative for successful postoperative outcomes. PMID- 29623704 TI - High-speed cell recognition algorithm for ultrafast flow cytometer imaging system. AB - An optical time-stretch flow imaging system enables high-throughput examination of cells/particles with unprecedented high speed and resolution. A significant amount of raw image data is produced. A high-speed cell recognition algorithm is, therefore, highly demanded to analyze large amounts of data efficiently. A high speed cell recognition algorithm consisting of two-stage cascaded detection and Gaussian mixture model (GMM) classification is proposed. The first stage of detection extracts cell regions. The second stage integrates distance transform and the watershed algorithm to separate clustered cells. Finally, the cells detected are classified by GMM. We compared the performance of our algorithm with support vector machine. Results show that our algorithm increases the running speed by over 150% without sacrificing the recognition accuracy. This algorithm provides a promising solution for high-throughput and automated cell imaging and classification in the ultrafast flow cytometer imaging platform. PMID- 29623702 TI - Testosterone Replacement, Muscle Strength, and Physical Function. AB - Muscle strength and physical function decrease in older men, as do testosterone levels. Nonetheless, the effects of testosterone replacement therapy on muscle strength and physical function remain inconclusive and equivocal. We conducted a rapid systematic review, the results of which showed that testosterone replacement does not affect muscle strength (measured by hand grip strength and leg muscle strength), although it may increase physical function (measured by the 6-minute walk test, Physical Activity Scale for the Elderly score, and other physical performance tests). However, most of the studies were conducted in the United States or Europe and did not include participants from Asian or other ethnic backgrounds; therefore, further studies are needed to evaluate the effects of testosterone replacement in a broader population. PMID- 29623706 TI - pH-Induced Rotation of Lidless Lipase LipA from Bacillus subtilis at Lipase Detergent Interface. AB - Lipases exhibit a unique process during the catalysis of the hydrolysis of triglyceride substrates called interfacial activation. Surfactants are used as cosolvents with water not only to offer a less polar environment to the lipases needed for their interfacial activation but also to solvate the substrate which are poorly soluble in water. However, the presence of detergent in the medium can affect both the lipase and the substrate, making the construction of a microkinetic model for lipase activity in the presence of the detergent difficult. Herein, we study the interfacial activation of a lidless lipase LipA from Bacillus subtilis using extensive atomistic molecular dynamics simulations at different concentrations of the surfactant, Thesit (C12E8), at two pH values. Residues which bind to the monomeric detergent are found to be the same as the ones which have been reported earlier to bind to the substrate. Very importantly, a pH-induced rotation of the enzyme with respect to surfactant aggregate has been observed which not only explains the experimentally observed pH-dependent enzymatic activity of this lidless lipase, but also suggests its reorientation at an aqueous-lipodophilic interface. PMID- 29623705 TI - Centella asiatica (Centellicum(r)) facilitates the regular healing of surgical scars in subjects at high risk of keloids. AB - BACKGROUND: Formation of scars after surgical incisions requires the proper appositions of elements contributing to the scarring process. The structural rebuilding of damaged tissues is essential in producing a linear scar. The excess of blood, foreign particles, exuberant sutures, necrotic tissue, possible infective agents, as well as the ongoing inflammatory process may produce a non linear, sometimes painful keloidal scar. Centella asiatica (CA) extracts have been used topically since ancient times for preventing keloids (i.e. after extensive burns) and for other applications including ulcer healing. The aim of this registry study was to evaluate the effect of supplementation with Centellicum(r) (Horphag Research Ltd.) on the healing of surgical wounds in subjects with previous hypertrophic or keloid scars, and to identify with ultrasound the collagen components of the scar in order to assess the quality (or linearity) of surgical wounds. METHODS: Subjects with history of hypertrophic scars or keloid following previous surgery were included in this registry. Short term antibiotic prophylaxis was used as per surgical standards with cephalosporins for three days maximum after surgery. Only patients receiving abdominal or knee surgery were included. A total of 129 patients were included: 64 in the control group treated only with standard management, and 65 in the active treatment group where CA supplementation with Centellicum(r) was used at the dose of two 225 mg capsules/day from the 2nd to 6th week after surgery. RESULTS: A total of 64 scars were analyzed within the control group and 65 in the supplement group. The tolerability to Centellicum(r) was overall good, and no side effects were reported. Compliance to treatment was optimal, with >98% of the CA capsules correctly used. The ultrasound-assessed scar tissue regularity was on average lower in controls than in supplemented subjects (P<0.05). Scars also appeared to be significantly more homogeneous in CA patients than in controls. CONCLUSIONS: Supplementation with Centellicum(r) is safe and does not interfere with other concomitant treatments. It is well tolerated and compliance to treatment is optimal. PMID- 29623708 TI - [Gut microbiota: its development and relation to certain diseases]. AB - Coexistence of humans with microorganisms is well known for a long time. Besides the association with infectious diseases, personal microbiota is important for human health, possibly for some non-infectious diseases. Colonization of the human body with appropriate microorganisms after delivery is essential for physiological immune system maturation and also has an influence on central nervous system development. The composition of the gut microbiota is affected by the mode of delivery, early life nutrition and last but not least by lifestyle and drug, especially antibiotics intake. A comparison of gut microbiomes between individuals living in different parts of the world showed a cardinal variation in its composition and basic enterotypes were defined. Interestingly, it has been found out that the different microbiota species composition covers the same, respectively similar metabolic pathways. It is suggested that gut microbiota composition and its dysbiosis may influence civilization diseases development, e. g. diabetes mellitus, obesity, asthma, inflammatory bowel disease, allergy, and autoimmune diseases.Key words: gut microbiota microbiome health immune system dysbiosis. PMID- 29623709 TI - The size-reduced Eudragit(r) RS microparticles prepared by solvent evaporation method - monitoring the effect of selected variables on tested parameters. AB - Size-reduced microparticles were successfully obtained by solvent evaporation method. Different parameters were applied in each sample and their influence on microparticles was evaluated. As a model drug the insoluble ibuprofen was selected for the encapsulation process with Eudragit(r) RS. The obtained microparticles were inspected by optical microscopy and scanning electron microscopy. The effect of aqueous phase volume (600, 400, 200 ml) and the concentration of polyvinyl alcohol (PVA; 1.0% and 0.1%) were studied. It was evaluated how those variations and also size can affect microparticle characteristics such as encapsulation efficiency, drug loading, burst effect and microparticle morphology. It was observed that the sample prepared with 600 ml aqueous phase and 1% concentration of polyvinyl alcohol gave the most favorable results.Key words: microparticles solvent evaporation sustained drug release Eudragit RS(r). PMID- 29623707 TI - Quantitative SIMS Imaging of Agar-Based Microbial Communities. AB - After several decades of widespread use for mapping elemental ions and small molecular fragments in surface science, secondary ion mass spectrometry (SIMS) has emerged as a powerful analytical tool for molecular imaging in biology. Biomolecular SIMS imaging has primarily been used as a qualitative technique; although the distribution of a single analyte can be accurately determined, it is difficult to map the absolute quantity of a compound or even to compare the relative abundance of one molecular species to that of another. We describe a method for quantitative SIMS imaging of small molecules in agar-based microbial communities. The microbes are cultivated on a thin film of agar, dried under nitrogen, and imaged directly with SIMS. By use of optical microscopy, we show that the area of the agar is reduced by 26 +/- 2% (standard deviation) during dehydration, but the overall biofilm morphology and analyte distribution are largely retained. We detail a quantitative imaging methodology, in which the ion intensity of each analyte is (1) normalized to an external quadratic regression curve, (2) corrected for isomeric interference, and (3) filtered for sample specific noise and lower and upper limits of quantitation. The end result is a two-dimensional surface density image for each analyte. The sample preparation and quantitation methods are validated by quantitatively imaging four alkyl quinolone and alkyl-quinoline N-oxide signaling molecules (including Pseudomonas quinolone signal) in Pseudomonas aeruginosa colony biofilms. We show that the relative surface densities of the target biomolecules are substantially different from values inferred through direct intensity comparison and that the developed methodologies can be used to quantitatively compare as many ions as there are available standards. PMID- 29623710 TI - [Development of dissolution method for warfarin sodium tablets]. AB - Warfarin is intensively discussed drug with narrow therapeutic index. In the past, its generic substitution was identified as a cause of bleeding. Altered quality of the active substance or varying drug content was discussed. The substance quality can be evaluated with adequate dissolution method. An official dissolution method with aqueous medium exists, however this method is non discriminatory. In the first 15 minutes the whole amount of the active pharmaceutical ingredient is released from a tested dosage form, which does not allow comparison between tablets from different producers and it also makes difficult to track the changes throughout stability testing. In the literature, there is a well known method using pH 6.8 buffer, which seems to be a suitable alternative to water. The aim of this study was to prove, that this alternative medium, when two stirring speeds for dissolution (50 or 25 rpm) are used, will be suitable for calculation of similarity and difference factor and if it will be eventually discriminatory with regard to particle size and radial hardness. For this purpose we prepared tablets with 10 mg of warfarin sodium in form of crystalline clathrate with isopropanol. Tablets differed by particle size of active pharmaceutical ingredient (d50 = 4.8, or d50 = 22.5 MUm respectively) and by radial hardness (30, or 100 N respectively). The content uniformity of the tablets was determined using process capability index (Cpk) and Bergum method. It was confirmed that the dissolution medium with pH of 6.8 allows comparison of dissolution profiles by similarity and difference factors but under given conditions it is not discriminatory.Key words: warfarin dissolution method particle size distribution radial hardness similarity factor difference factor. PMID- 29623711 TI - Carboxylic acids from brown algae Fucus vesiculosus and Padina pavonica. AB - Using the gas chromatographic-mass spectrometric method, the content of 28 carboxylic acids was determined in the thalli of Fucus vesiculosus, palmitic, oxalic and malic acids predominating. In the thalli of Padina pavonica, the content of 27 carboxylic acids was determined. Palmitic, oxalic and oleic acids prevail.Key words: brown algae Fucus vesiculosus Padina pavonica, carboxylic acids gas chromatography mass spectrometry. PMID- 29623712 TI - ? PMID- 29623713 TI - [Active substances from marine organisms in clinical trials and practice]. AB - Oceans cover a large part of our planet and they are a home for an enormous amount of species. A lot of them are still waiting to be discovered by man, much like the chemicals they synthesize. Marine pharmacology concerns itself with the study of these chemicals and their potential use in medicine. Origin in marine species is for the most part the only thing this large and diverse group of substances have in common, so the spectrum of possible applications is quite wide. Many of these substances have a unique mechanism of action, offering new therapeutic possibilities. Although just a few of them are used in a clinical practice today (e.g. eribulin, cytarabine), the future looks quite promising. Current clinical trials focus mostly on the therapy of cancer, but trials for therapy of pain or Alzheimers disease and many others are also underway.Key words: marine pharmacology. PMID- 29623714 TI - [Herbs for increasing breast-milk production]. AB - Subjective perception of insufficient milk supply is one of the most common problems of nursing mothers. For centuries, herbs have been used to increase lactation and remain popular even today. There is only a limited number of studies proving their safety and effectivity, so their use is based primarily on previous experience. The use of certain herbs has shown that they could be effective and safe, but further research is needed to define terms of use. This paper describes preliminary findings on the mechanism of action, adverse effects and possible interactions observed in some herbs frequently used to promote lactation.Key words: phytotherapy lactation herbal galactagogue. PMID- 29623715 TI - Fatty acid composition of lipids of Iris sibirica. AB - Different Iris species are a rich source of secondary metabolites and they are widely used due to their medicinal properties, i.e. such as antibacterial, cytotoxic, hepatoprotective, antiplasmodial, and immunomodulatory effects. Determination of the fatty acid composition is necessary to create complex phytopreparations on their basis, and also, it is important for understanding of the adaptive capabilities of the plant. In our study, a comparative analysis of fatty acids composition of total lipids of the leaves and rhizomes of Iris sibirica was carried out by the gas chromatography-mass spectrometry method. The degree of unsaturated fatty acids and the activity of acyl-lipid desaturases were determined by the Lyons method. 14 fatty acids were identified in the leaves of I. sibirica, their content being 6.1 mg/g; 18 acids were found in the rhizomes, their content being 6.9 mg/g. Among the saturated fatty acids palmitic acid dominates (C16:0), and among the unsaturated ones, it is linoleic (C18:2omega6) and alpha-linolenic (C18:3omega3) acids. The content of the unsaturated fatty acids in the leaves is higher (45%) due to a high content of the polyunsaturated fatty acids, as well as the reduced share of the saturated and the monounsaturated acids, compared to the rhizomes (the content of the unsaturated fatty acids is 40%), which causes a higher value of the double bonds index (1.10), and the coefficient of unsaturation (0.81), which indicate the relative cold resistance of the plants. By contrast, in the rhizomes the concentration of the saturated fatty acids increases and the level of the unsaturated fatty acids reduces. The fatty acids composition of the leaves and rhizomes of Iris sibirica was established for the first time.Key words: Iris sibirica fatty acids acyl lipid desaturases gas chromatography-mass spectrometry. PMID- 29623716 TI - Development of the composition of intramammary combined preparation based on silver citrate for veterinary use. AB - The goal of the present study was to develop a new intramammary combination preparation for veterinary use based on silver citrate, arginine and dexpanthenol for the treatment and prophylaxis of subclinical mastitis in cattle. When creating combined medicines for veterinary use, attention must be paid to the factors that influence their stability in a combined presence, and the composition of drugs, as well as the technology for their preparation should be determined. In the current study, a qualitative and quantitative control of model mixtures of active ingredients, as well as of a silver citrate-based combined preparation was carried out. The following parameters that define intramammary drug stability were studied: clarity, pH, and the quantitative content of the active ingredient. Based on the experimental studies, optimal pH limits for a new preparation were determined ranging from 6.4 to 6.7. Considering the instability of solutions based on silver citrate, studies on the stabilization of the preparation were conducted at the obtained pH values. As the result, we used povidone, which possessed the stabilizing properties. The amount of arginine that provides the optimum pH level for the selected combination of active ingredients was also determined. In conclusion, the optimal composition of an intramammary preparation for veterinary medicine in 10 ml ampoules with a shelf life of 6 months was developed.Key words: silver citrate arginine dexpanthenol intramammary dosage form stability. PMID- 29623718 TI - ? PMID- 29623717 TI - [Idiopathic thrombocytopenia refractery to therapy of cyclosporine A in clinical practice - case report]. AB - Primary immune thrombocytopenia (idiopathic thrombocytopenic purpura; ITP) is an autoimmune disorder characterized by isolated thrombocytopenia without abnormalities in the erythroid and myeloid/lymphoid lineages. The incidence of ITP in adults is estimated at approximately 1.6-3.9 per 100 000 persons/year. The aim of this study was to analyze a case report of a patient with diagnosed immune thrombocytopenia (D69.3) resistant to cyclosporine A therapy as well as an evaluation of factors that could contribute to an inadequate response to cyclosporine A. The results show a multifactorial origin of thrombocytopenia and a possible effect on refractivity to cyclosporine A therapy caused by long-term smoking, MDR-1 gene polymorphism, genetic predisposition to autoimmune diseases, allergic reactions as a manifestation of hypersensitivity in the immune system, controversial compliance of the patient, overcome infections as well as impact of drugs taken.Key words: immune thrombocytopenia refractery form cyclosporine A therapy platelets. PMID- 29623719 TI - Standardized care by redesign of an intravitreal injection pathway. AB - PURPOSE: Intravitreal injection of medication is a rapid rising surgical intervention in modern ophthalmological care. With increasing numbers, the caseload of complications follows and the burden on daily clinical organization increases. This study focuses on developing a standardized treatment protocol to improve care and reduce hazard. METHODS: A standardized treatment protocol was designed and educated to the involved medical doctor and registered nurse. An independent observer used this protocol to evaluate the actions performed during the intravitreal injection. Data on the included patients and products injected were collected. RESULTS: In total, 180 injections of 134 patients were observed between 1 December 2011 and 18 October 2012, divided over 16 measurements. From the fifth measurement on, a 100% protocol adherence for the time out procedure was achieved and maintained over time, with a transient insignificant decrease. The performance of actions of the medical doctor and assisting registered nurse followed the same trend with a rapid increase and 100% protocol adherence. No microorganism caused development of endophthalmitis was recorded. CONCLUSION: The optimization of an intravitreal injection care pathway leads to a more standardized intervention process with no apparent reduction in clinical efficiency and safety. PMID- 29623720 TI - Optical coherence tomography angiography in age-related macular degeneration: The game changer. AB - Optical coherence tomography angiography is one of the biggest advances in ophthalmic imaging. It enables a depth-resolved assessment of the retinal and choroidal blood flow, far exceeding the levels of detail commonly obtained with dye angiographies. One of the first applications of optical coherence tomography angiography was in detecting the presence of choroidal neovascularization in age related macular degeneration and establishing its position in relation to the retinal pigmented epithelium and Bruch's membrane, and thereby classifying the CNV as type 1, type 2, type 3, or mixed lesions. Optical coherence tomography angiograms, due to the longer wavelength used by optical coherence tomography, showed a more distinct choroidal neovascularization vascular pattern than fluorescein angiography, since there is less suffering from light scattering or is less obscured by overlying subretinal hemorrhages or exudation. Qualitative and quantitative assessments of optical coherence tomography angiography findings in exudative and nonexudative age-related macular degeneration have been largely investigated within the past 3 years both in clinical and experimental settings. This review constitutes an up-to-date of all the potential applications of optical coherence tomography angiography in age-related macular degeneration in order to better understand how to translate its theoretical usefulness into the current clinical practice. PMID- 29623721 TI - Evaluation of ocular perforation during retrobulbar block using high-resolution spectral domain-optical coherence tomography and optical coherence tomography angiography. AB - INTRODUCTION: This article reports a case of ocular perforation during a retrobulbar block in a patient who underwent scleral buckle for retinal detachment. METHODS: Sterile air was immediately injected into the vitreous cavity to restore intraocular pressure and the scleral buckle operation was quickly finished. One week later, a laser retinopexy was performed on the two retinal holes that were outside the foveal area. After 6 months, spectral domain optical coherence tomography and optical coherence tomography angiography were performed on the perforated wall centered on the exit hole area. RESULTS: The visual acuity was maintained 20/20 and the retina was totally attached. Spectral domain-optical coherence tomography showed a localized interruption of inner retina, retinal pigment epithelium, and choroid, with a higher posterior reflectivity in correspondence with the sclera. Optical coherence tomography angiography was able to detect atrophic alterations in the choroidal slab with a good visualization of large and rarefied choroidal vessels due to lack of retinal pigment epithelium and choriocapillaris. CONCLUSION: When ocular perforation by a needle is outside the foveal area and when there is an early awareness of the perforation, the complications may be avoided, and we could observe a good final visual acuity result. Furthermore, using spectral domain-optical coherence tomography and optical coherence tomography angiography, we could observe the perforated eyeball wall and study the effects of a 25-gauge needle perforation in the retinal and choroidal blood stream. PMID- 29623722 TI - New visual field indices of disharmony for early diagnosis of glaucoma, alone or associated with conventional parameters. AB - PURPOSE: To evaluate the specificity of new perimetric indices based on harmony, alone and in combination with structural data, for glaucoma detection. METHODS: In this prospective observational cross-sectional study, one eye of 105 healthy subjects and 97 early and suspect glaucomas were sequentially included and examined with Cirrus optical coherence tomography, twice with OCULUS Smartfield perimeter (SPARK strategy) and twice with Humphrey Analyzer (24-2 SITA-Fast) at the Ophthalmology Department from the University Hospital La Candelaria. Disharmony in the visual field was evaluated including vertical threshold symmetry, threshold rank), and homogeneity (threshold standard deviation from its maximum) using the patient himself/herself as a reference. We also evaluated disharmony in combination with the mean deviation and the pattern standard deviation in a single index (mismatch) and various combinations of morphological and functional indices. Combinations used a new score based on values above certain critical cut-off levels of each index. RESULTS: For 95% specificity, the highest sensitivities were as follows: vertical cup/disc ratio: 28.9%; SPARK threshold rank: 29.9%; and SITA-Fast threshold standard deviation: 28.9%. For the combined indices and 100% specificity, they were 5 SPARK indices mismatch: 10.3%; 5 SITA-Fast indices mismatch: 11.3%; 8 optical coherence tomography indices: 21.9%; 13 SPARK and optical coherence tomography indices: 27.8%; and 13 SITA-Fast and optical coherence tomography indices: 32.0%. CONCLUSION: Disharmony combined with normative value-based indices and/or optical coherence tomography indices is useful for very specific early diagnosis of glaucoma. PMID- 29623723 TI - Macular toxicity and blind spot enlargement during a treatment by voriconazole: A case report. AB - PURPOSE: To report a case of macular toxicity and blind spot enlargement during voriconazole treatment. METHODS: This is a case report. RESULTS: We describe a 77 year-old man treated by voriconazole for pulmonary aspergillosis, who complained of visual disorders such as dyschromatopsia and visual hallucinations 3 days after voriconazole initiation. Initial ophthalmological examination found no loss of visual acuity. The anterior and posterior segments presented no anomalies. The chromatic vision evaluated with the Lanthony 15-Hue Desaturated Test demonstrated dyschromatopsia in the left eye along the tritan axis, and the Goldmann visual field examination found a blind spot enlargement in both eyes. The multifocal electroretinogram found a global decrease in the foveal peak in both eyes. Visual evoked potential showed asymmetric data and lower amplitudes of the P(100) wave on the left eye. No anomalies were observed on spectral domain macular optical coherence tomography. As a first step, based on presumed dose-dependent toxicity, voriconazole dose was reduced. No improvements were noted. The voriconazole treatment was then discontinued and replaced with itraconazole. After 1 month, visual field and multifocal electroretinogram had improved and visual hallucinations had disappeared. CONCLUSION: Voriconazole can cause potentially serious visual side effects. Adapting treatment based on plasma concentrations of voriconazole did not prevent the appearance of visual side effects in this case. Therapeutic drug switching within the same drug family seems to be an effective alternative to preserve ocular function. PMID- 29623724 TI - Management of oncological patients in the digital era: anatomic pathology and nuclear medicine teamwork. PMID- 29623725 TI - An overview of hypocretin based therapy in narcolepsy. AB - INTRODUCTION: Narcolepsy with cataplexy is most commonly caused by a loss of hypocretin/orexin peptide-producing neurons in the hypothalamus (i.e., Narcolepsy Type 1). Since hypocretin deficiency is assumed to be the main cause of narcoleptic symptoms, hypocretin replacement will be the most essential treatment for narcolepsy. Unfortunately, this option is still not available clinically. There are many potential approaches to replace hypocretin in the brain for narcolepsy such as intranasal administration of hypocretin peptides, developing small molecule hypocretin receptor agonists, hypocretin neuronal transplantation, transforming hypocretin stem cells into hypothalamic neurons, and hypocretin gene therapy. Together with these options, immunotherapy treatments to prevent hypocretin neuronal death should also be developed. Areas covered: In this review, we overview the pathophysiology of narcolepsy and the current and emerging treatments of narcolepsy especially focusing on hypocretin receptor based treatments. Expert opinion: Among hypocretin replacement strategies, developing non-peptide hypocretin receptor agonists is currently the most encouraging since systemic administration of a newly synthesized, selective hypocretin receptor 2 agonist (YNT-185) has been shown to ameliorate symptoms of narcolepsy in murine models. If this option is effective in humans, hypocretin cell transplants or gene therapy technology may become realistic in the future. PMID- 29623726 TI - The effect of biological DMARDs on the risk of congestive heart failure in rheumatoid arthritis: a systematic review. AB - INTRODUCTION: A common cardiovascular manifestation in rheumatoid arthritis (RA) is congestive heart failure (CHF) in which inflammation is considered to play a pivotal role. Although anti-inflammatory therapy such as biological disease modifying anti-rheumatic drugs (bDMARDs) have the potential of improving the cardiac function and reducing the risk of CHF, the published studies showed contrasting results. This review aims to systematically summarize and analyze literature regarding the effect of bDMARDs on the cardiac function and on the risk of CHF in RA. Areas covered: Observational cohort, randomized controlled trials and case-controlled studies were included. The systematic literature search was conducted in PubMed, Wiley/Embase, Cochrane, Web of Science and clinicaltrials.gov (up to 2017). Two authors assessed abstracts for inclusion and methodological quality was assessed by one reviewer. Expert opinion: RA patients have a clinically relevant increased risk of developing CHF needing further attention. However, we found a lack of high quality studies. Future studies should focus on distinguishing the effect of myocardial inflammation reduction versus antibody-specific myocardial cellular effects of bDMARDs to improve the understanding of the effects of bDMARDs in RA patients and the relation with the development of CHF. PMID- 29623727 TI - Myxoid Emboli. AB - Emboli are common clinicopathologic findings. Recognition of the type of arterial emboli could be the first clue to the original source. Emboli with myxomatous changes are rare. Myxoma-like features in mural organizing thrombi have been reported. The most challenging differential diagnosis is between embolic cardiac myxomas and myxomatous thromboemboli. Emboli from sarcomas and arteriosclerotic plaques with myxoid features are also potential pitfalls. There is scarcity of studies focusing on myxoid emboli and their clinical and pathologic importance. We performed a retrospective study over 12 years. We retrieved all of the embolectomy specimens. We histologically screened the emboli for myxoid stroma, myxomatous changes, and mucinous degeneration. We retrieved 12 cases (3%) of myxoid emboli out of 391 embolectomy specimens. We found 4 cases of thromboemboli, 5 cases of atrial myxomas, 2 cases of atheromatous plaques, and a myxoid liposarcoma. The age range was between 35 and 71 years, with a mean age of 51 years. The male-to-female ratio was 3:2. Myxoid thromboemboli and myxomas were large, while atheromatous plaque emboli were small. Myxoid emboli arising from organizing mural thrombi can be histologically confused with cardiac myxomas and vice versa. Myxoid emboli from atheromatous plaque and myxoid sarcomas can mimic embolizing myxomas. Certain histologic features are helpful hints to differentiate between myxoid emboli. In doubtful cases, immunohistochemistry is helpful. Correct histologic recognition of the different types of myxoid emboli helps guide the clinicians to the most likely etiology and appropriate management in occlusive peripheral vascular diseases with clinically unrecognized lesions. PMID- 29623728 TI - Poorly Differentiated Chordomas Showing Loss of INI1/SMARCB1: A Report of 2 Rare Cases With Diagnostic Implications. AB - Poorly differentiated chordomas are rare musculoskeletal tumors. Case 1. A 42 year-old lady presented with quadriparesis of 2 months' duration. Radiologic imaging disclosed a soft tissue mass in her left prevertebral- and paravertebral cervical region. Case 2. A 4-year-old male child presented with neck pain and restricted head movements of 1-year duration. Radiologic imaging revealed a contrast enhancing, paraspinal soft tissue mass in his cervical region. Microscopic examination in both the cases revealed a cellular malignant tumor composed of moderate to markedly pleomorphic cells with interspersed mitotic figures, along with focal myxoid change and necrosis. By immunohistochemistry, tumor cells in both cases were diffusely positive for pan cytokeratin (AE1/AE3) and brachyury, whereas these were negative for INI1/SMARCB1. Tumor cells in the second case were also positive for glypican3. The first case developed pulmonary metastasis, while the second case developed recurrence. Poorly differentiated chordomas are uncommon tumors, invariably characterized by loss of INI1. These tumors can be rarely seen in adults and need to be differentiated from their diagnostic mimics, in view of treatment implications and their relatively aggressive clinical outcomes. PMID- 29623730 TI - New lignans from Urticae Fissae Herba. AB - Two new lignans named neourticol A (1) and neourticol B (2), together with seven known compounds (3-9), were isolated from Urticae Fissae Herba, a folk medicine for rheumatism arthritis in China. The active evaluation results showed that 1 and 2 possessed the potent anti-complement and anti-inflammatory activities. PMID- 29623729 TI - Pharmacokinetic considerations for pediatric patients receiving analgesia in the intensive care unit; targeting postoperative, ECMO and hypothermia patients. AB - INTRODUCTION: Adequate postoperative analgesia in pediatric patients in the intensive care unit (ICU) matters, since untreated pain is associated with negative outcomes. Compared to routine postoperative patients, children undergoing hypothermia (HT) or extracorporeal membrane oxygenation (ECMO), or recovering after cardiac surgery likely display non-maturational differences in pharmacokinetics (PK) and pharmacodynamics (PD). These differences warrant additional dosing recommendations to optimize pain treatment. Areas covered: Specific populations within the ICU will be discussed with respect to expected variations in PK and PD for various analgesics. We hereby move beyond maturational changes and focus on why PK/PD may be different in children undergoing HT, ECMO or cardiac surgery. We provide a stepwise manner to develop PK-based dosing regimens using population PK approaches in these populations. Expert opinion: A one-dose to size-fits-all for analgesia is suboptimal, but for several commonly used analgesics the impact of HT, ECMO or cardiac surgery on average PK parameters in children is not yet sufficiently known. Parameters considering both maturational and non-maturational covariates are important to develop population PK-based dosing advices as part of a strategy to optimize pain treatment. PMID- 29623731 TI - Elevated lead level from a tobacco source requiring chelation in a 12-year-old child. AB - CONTEXT: Across the world, tobacco is used in a variety of forms, including being smoked or added to a "quid" that is then chewed. We report a case of lead poisoning in a child from tobacco imported from Thailand. CASE DETAILS: A 12-year old Thai immigrant boy had a blood lead level (BLL) of 6 mcg/dL on routine testing upon arrival to the United States, but which increased to 72 mcg/dL six months after his arrival. He was asymptomatic with unremarkable workup. At this time his father, mother and two siblings were also found to have elevated BLLs of 53, 16, 22, and 11 mcg/dL, respectively. Water, paint, food and cookware sources tested negative for lead, whereas samples of the father's dried tobacco leaves imported from Thailand contained 36.12 ppm (mcg/g) of lead. The mother admitted that both she and the patient used the tobacco as well. The child was chelated with oral succimer and his BLL decreased. DISCUSSION: In our case, the source of the lead exposure was from the tobacco that the patient was chewing. Tobacco is often overlooked as a source of lead exposure, though it has been reported in the literature, both from direct smoking and from chewing, as well as through secondhand smoke. Toxicologists and health care professionals should consider cultural practices when evaluating patients with elevated BLLs. PMID- 29623733 TI - Necrotizing Enterocolitis With Systemic Gas Embolism. PMID- 29623732 TI - Clinical outcome and higher order aberrations after bilateral implantation of an extended depth of focus intraocular lens. AB - PURPOSE: The purpose of this study was to assess the clinical outcome after a bilateral implantation of an extended depth of focus intraocular lens in comparison to a monofocal intraocular lens. SETTING: Department of Ophthalmology, Charite-Medical University Berlin, Germany. PATIENTS AND METHODS: A total of 60 eyes of 30 patients were enrolled in this prospective, single-center study. The cataract patients underwent phacoemulsification with bilateral implantation of a TECNIS(r) Symfony (Abbott Medical Optics, Santa Ana, CA, USA, 15 patients) or a TECNIS Monofocal ZCB00 (Abbott Medical Optics, Santa Ana, CA, USA, 15 patients). Postoperative evaluations were performed after 1 and 3 months, including visual acuities at far, intermediate, and near distance. Mesopic, scotopic vision, and contrast sensitivity were investigated. Aberrometry was performed using an iTrace aberrometer with a pupil scan size of 5.0 mm. RESULTS: After 3 months, the TECNIS Symfony group reached an uncorrected visual acuity at far distance of -0.02 logMAR compared to -0.06 logMAR in the TECNIS Monofocal group ( p = 0.03). Regarding the uncorrected vision at intermediate and near distance the following values were obtained: intermediate visual acuity -0.13 versus 0.0 logMAR (TECNIS Symfony vs TECNIS Monofocal, p = 0.001) and near visual acuity 0.11 versus 0.26 logMAR (TECNIS Symfony vs TECNIS Monofocal, p = 0.001). Low-contrast visual acuities were 0.27 versus 0.20 logMar (TECNIS Symfony vs TECNIS Monofocal, p = 0.023). CONCLUSION: The TECNIS Symfony intraocular lens can be considered an appropriate alternative to multifocal intraocular lenses because of good visual results at far, intermediate, and near distance as well as in low-contrast vision. PMID- 29623734 TI - Effects of environmental enrichment on activity and lameness in commercial broiler production. AB - The aim of this pilot study was to investigate the effects of commercially applied environmental enrichments on behavior and lameness in broilers. Two consecutive flocks of broilers were observed at 16 days and 30 days of age to investigate differences between enriched (peat, bales of lucerne hay, and elevated platforms) and control birds with regards to behavioral activities and lameness. More running (p < .001), worm running (p = .006), play fighting (p = .015), dust bathing (p = .009), and ground pecking while standing (p < .001) were observed at 16 days than at 30 days. Across both ages, enriched birds showed more wing flapping (p = .016), wing stretching (p = .002), body shaking (p = .002), ground scratching (p < .001), and ground pecking while standing (p < .001) and lying (p = .003) compared with control birds. Even when no enrichments were close, enriched birds showed more body shaking (p = .008) and ground pecking while standing (p < 0.001) and lying (p = .010) than birds in comparable locations in control pens. There was a tendency for a lower gait score (i.e., reduced lameness) with the enriched treatment (p = .077). In conclusion, enriched birds showed higher levels of several activities compared with control birds, and demonstrated higher levels in areas where no enrichments were present. PMID- 29623735 TI - Reducing the risk of post-surgical cancer recurrence: a perioperative anti inflammatory anti-stress approach. PMID- 29623737 TI - Epithelioid Inflammatory Myofibroblastic Sarcoma. PMID- 29623736 TI - Treatment of venous stenosis in oncologic patients. AB - Symptomatic obstruction related to malignant involvement of large veins may occur in central veins both in the thoracic and pelvic regions, and in the abdominal region of the body. Both cases represent a therapeutic challenge, and endovascular revascularization, consisting of angioplasty and stent placement, is safe and effective. Superior vena cava stenting has become widespread in the management of occlusive venous disease. The percutaneous placement of large expandable metal stents allows rapid restoration of normal blood flow in the majority of patients, thus improving symptoms. Published data on the diagnosis and treatment of symptomatic cancer-related iliocaval obstructions are limited and mainly consist of case reports and small case series. The present review reports the current state of endovascular treatment for both superior vena cava occlusion and iliac compression syndrome in cancer patients. PMID- 29623740 TI - 2018 Council of Business Advisor Members. PMID- 29623739 TI - Predictors of Timely Prenatal Care Initiation and Adequate Utilization in a Sample of Late Adolescent Texas Latinas. AB - INTRODUCTION: Little is known of late adolescent Texas Latinas' prenatal care perceptions or how these perceptions predict timely prenatal care initiation or adequate utilization. Hence, the purpose of this study is to describe and compare these perceptions between participants with timely versus late prenatal care initiation and adequate, intermediate, and inadequate prenatal care utilization; and to determine predictors of timely prenatal care initiation and adequate utilization. METHODS: Fifty-four postpartum Latinas were recruited through social media. Eligibility criteria were 18 to 21 years old, Texas-born, primiparous, uncomplicated pregnancy/delivery, and English literate. Prenatal care perceptions were measured with the Revised Better Babies Survey and Access Barriers to Care Index. RESULTS: Participants had favorable views of prenatal care benefits; however, not living with the baby's father predicted inadequate prenatal care, Wald chi2(1) = 4.93, p = .026. Perceived benefits of timely and adequate prenatal care predicted timely prenatal care initiation, chi2(1) = 7.47, p = .006. Self reported depression during pregnancy predicted timely entry into prenatal care, chi2(1) = 4.73, p = .03. CONCLUSION: Participants' positive prenatal care perceptions did not predict adequate prenatal care utilization, indicating that barriers serve as powerful obstacles in late adolescent Texas Latinas. PMID- 29623741 TI - Nursing Leadership at this Juncture in History. PMID- 29623742 TI - Intranasal Rhinofacial Conidiobolomycosis (Entomophthoromycosis) With Splendore Hoeppli Phenomenon. PMID- 29623743 TI - Immunoexpression of BAP1, ROS1, and ALK in Spitzoid Melanocytic Tumors. AB - BACKGROUND: Spitzoid tumors are a heterogeneous group of melanocytic neoplasms that frequently imposes diagnostic difficulties. Lately, several advances in molecular biology afforded significant discoveries on the pathogenesis of these tumors. BAP1 (BRCA-1 associated protein-1) inactivation and anomalous expression of kinase translocation-related proteins are among the main criteria launched by new classification proposals. Our aim was to systematically assess the immunoexpression of BAP1, ROS1 (receptor tyrosine kinase c-Ros oncogene 1), and ALK (anaplastic lymphoma receptor tyrosine kinase) proteins in an unpublished series of spitzoid tumors. METHODS: Retrospective study based on 47 formalin fixed paraffin-embedded tissue samples from 3 different institutions. BAP1, ROS1, and ALK immunostains were performed in all cases. We included 27 Spitz tumors without significant abnormality, 15 atypical spitzoid tumors, and 5 spitzoid melanomas. RESULTS: We observed loss of BAP1 nuclear immunolabeling in 4.3% of evaluable cases (2/46), both of them atypical spitzoid tumors. The proportional frequency of BAP1-inactivated cases among atypical spitzoid tumors was 14.2% (2/14). No immunoexpression of ROS1 or ALK was found. CONCLUSIONS: Our study revealed 2 additional BAP1-inactived cases and described its respective frequency. The absence of anomalous expression of translocation-related proteins ALK and ROS1 in this series, composed predominantly of low-grade/low-risk tumors, indicates that translocated spitzoid lesions may not be as prevalent as initially suggested, at least in some populations. Furthermore, our findings encourage additional investigation on unequal occurrence of such immunomarkers among different diagnostic categories of spitzoid neoplasms. PMID- 29623744 TI - Endometrial Stromal Sarcoma With Hyalinizing Giant Rosettes, Mimicking Low-Grade Fibromyxoid Sarcoma. AB - We highlight a rare variant pattern of low-grade endometrial stromal sarcoma showing extensive collagenous rosette formation, closely mimicking low-grade fibromyxoid sarcoma. Additionally, this neoplasm showed diffuse and strong expression of muscle markers, favoring an initial diagnosis of leiomyosarcoma. Reverse transcription-polymerase chain reaction showed the presence of JAZF1 SUZ12 fusion transcripts, and this highlights the broad morphologic and immunophenotypic spectrum of endometrial stromal sarcoma. PMID- 29623745 TI - Eosinophilic Myocarditis With Hypersegmented Granulocytes and Neutrophilia Without Eosinophilia: A Case Mimicking Neutrophilic Myocarditis. AB - We report a case of a 78-year-old woman with neutrophilia without eosinophilia who was pathologically diagnosed with eosinophilic myocarditis by myocardial biopsy. The biopsy specimen showed infiltrating granulocytes with hypersegmentation, mimicking neutrophils; however, they were confirmed to be eosinophils by Giemsa staining. PMID- 29623746 TI - Synchronous Pancreatic Serous Cystic Neoplasm and Duodenal Neuroendocrine Tumor: Case Report and Review of the Literature. AB - Simultaneous presence of pancreatic serous cystic neoplasms and neuroendocrine neoplasms is rare. We present a case with the incidental finding of a duodenal neuroendocrine tumor (NET) with 2 lymph node metastases in a Whipple resection specimen performed to remove a pancreatic cystic neoplasm that postoperatively turned out to represent a serous cystic neoplasm (SCN). The patient was a 75-year old female. She presented with loss of appetite and weight. Preoperative contrast enhanced computed tomography scan of the abdomen showed a multicystic lesion in the head of pancreas. On histologic examination of the resection specimen, a pancreatic SCN was found, and in addition in 2 peripancreatic lymph nodes, metastases from a NET. Further examination of the resected specimen revealed a duodenal NET. Review of the literature revealed only one prior study with 4 cases of pancreatic SCN associated with a duodenal NET. In 1 of the 4 cases, the patient had von Hippel-Lindau disease. Our report emphasizes the importance of careful examination of pancreatic resection specimens including the peripancreatic lymph nodes also when dealing with SCNs, as coexisting and more malignant tumors may otherwise be missed. PMID- 29623747 TI - Attachment styles and secure base priming in relation to emotional reactivity after frustration induction. AB - In two experimental studies, we explored the role of attachment in predicting emotional reactivity after frustration induction. In the first study, using a cognitive frustration task, we examined in a college sample (N = 134) how attachment styles related to the experience and expression of emotions after frustration induction. In the second study, we investigated in college students (N = 198) the effect of conscious priming of the secure base schema on mood disturbance after the performance of a cognitive frustration task. Results showed that individuals experienced and expressed emotions after frustration induction independent of their attachment styles. Conscious priming of the secure base script attenuated self-reported emotional reactivity after frustration induction independent of individuals' attachment styles. These findings suggest that the mechanism of attachment-related emotional reactivity might not pertain to frustration during an unsolvable cognitive task, but that the activation of the sense of having a secure base is useful in reducing mood disturbance in the context of a frustrating performance task. PMID- 29623750 TI - Considerations in the Diagnosis and Accelerated Return to Sport of a Professional Basketball Player With a Triceps Surae Injury: A Case Report. AB - Study Design Case report. Background Acute injuries of the triceps surae and Achilles tendon are common in sports. Rupture of the plantaris tendon can be challenging to diagnose. There is limited evidence detailing the diagnosis, rehabilitation, and accelerated return to sport of elite professional basketball players who have sustained calf injuries. Case Description A 25-year-old male professional basketball player sustained an injury to his calf during a professional basketball game. This case report details the presumptive diagnosis, graduated progression of intervention, and return to play of a professional athlete with a likely isolated plantaris tendon tear. Outcomes The patient returned to postseason competition 10 days post injury. Objective measures were tracked throughout rehabilitation and compared to baseline assessments. Before returning to play, the athlete showed improvements beyond the minimal clinically important difference for calf girth (2 cm) and numeric pain-rating scale score (4 points, 0-10 scale). Functional testing was conducted that included the Y Balance Test lower quarter and the Functional Movement Screen, with results that exceeded or returned the athlete to preseason levels. Discussion This report details the case of a professional basketball player who returned to competitive play in an accelerated time frame following injury to his calf. Diagnosing a plantaris tendon rupture can be challenging, and anatomical variations of this muscle should be considered. It was demonstrated in this case that physical therapy rehabilitation was helpful in making a treatment-based clinical diagnosis when imaging was unclear. Level of Evidence Therapy, level 5. J Orthop Sports Phys Ther 2018;48(5):388-397. Epub 6 Apr 2018. doi:10.2519/jospt.2018.7192. PMID- 29623749 TI - Effects of a program to strengthen general practice care on hospitalisation rates: a comparative observational study. AB - OBJECTIVE: To determine the effect of a large-scale program to strengthen general practice on hospitalisation rates. METHODS: This observational study compared enrolled patients in the program and a sample of non-participating patients from non-participating GPs in the same geographic area in Germany. Key components of the program are: prompt access to care, comprehensiveness, continuity, empanelment, data-driven quality improvement, computerized decision support, and additional reimbursement of general practices. The outcomes in this study were hospitalisation, rehospitalisation, and avoidable hospital admission up to four years after patient inclusion. Poisson regression models and generalized estimating equations were used to estimate intervention effects. RESULTS: In the baseline year, 19.1% were hospitalised and 13.6% had a potentially avoidable hospitalisation, 14.5% were rehospitalised within 4 weeks. Across the four observed years, yearly hospitalisations were 9.8 to 14.9% lower in enrolled patients, yearly re-hospitalisations were 5.3 to 11.5% lower, and yearly avoidable hospitalisations were 6.8 to 8.6% lower compared to the control cohort (all differences were statistically significant). The trend in the between-group difference for hospitalisations and re-hospitalisations increased, while it remained stable for avoidable hospitalisations. CONCLUSION: This study provides strong indications for the positive impact of strong general practice care on population outcomes. Key points A program to strengthen general practice in Germany comprised of prompt access to care, comprehensiveness, continuity, empanelment, data-driven quality improvement, computerized decision support, and additional reimbursement of general practices. Patients who remained in the program during 4 years had increasingly lowered rates of hospitalisation and rehospitalisation compared to a control group of patients. Avoidable hospitalisations were also lower, but no trend of further lowering was found. This might suggest a ceiling effect to impact of strong general practice on hospitalisations. PMID- 29623748 TI - Neisseria meningitidis disease-associated clones in Amazonas State, Brazil. AB - BACKGROUND: The aim of this study is to describe the molecular epidemiology of Neisseria meningitidis invasive disease before the introduction of serogroup C conjugate vaccine in Amazonas State in 2010. METHODS: Meningococcal disease reported cases were investigated in Amazonas State during the period 2000-2010. N. meningitidis isolates (n = 196) recovered from patients were genotyped by multilocus sequence typing (MLST) and sequencing of porB, porA, fetA, fHbp and penA. Antimicrobial susceptibility was determined using E-test. RESULTS: In the study period, 948 cases were reported; the incidence was 2.8 for the entire state and 4.8 per 100,000 in the capital of Manaus. Most meningococcal disease was caused by N. meningitidis belonging to ST-32 (72%; 141/196) or ST-103 (21%; 41/196) clonal complexes. Capsular switching (B->C) was suggested within clonal complex (cc) 32. There were 6 (3%; 6/196) strains with intermediate susceptibility to penicillin and a single strain was resistant to rifampicin. Since 2007, serogroup C strains belonging to the cc103 have predominated and case fatality has increased. CONCLUSION: We demonstrate a high rate of meningococcal disease in Amazonas State, where, like other parts of Brazil, serogroup C replaced serogroup B during 2000s. These data serve as a baseline to measure impact of serogroup C conjugate vaccine introduction in 2010. This study emphasizes the need for enhanced surveillance to monitor changes in meningococcal disease trends following the introduction of meningococcal vaccines. PMID- 29623751 TI - Scapular Muscle Activity During Static Yoga Postures. AB - Study Design Controlled, cross-sectional laboratory study. Background Despite the growing popularity of yoga, little is known about the muscle activity of the scapular stabilizers during isometric yoga postures and their potential utility in shoulder rehabilitation. Objectives To examine scapular stabilizer muscle activation during various yoga postures. Methods Twenty women with yoga experience and no shoulder pain or injury participated. Electromyography was used to record the muscle activity of the upper, middle, and lower trapezius, as well as of the serratus anterior, during 15 yoga postures. Results Muscle activity varied between yoga postures (3%-57% maximum voluntary isometric contraction [MVIC]). Overall, the "locust arms forward" posture elicited the highest activity from the upper (22.4% MVIC), middle (41.8% MVIC), and lower (56.8% MVIC) trapezius, while several postures elicited moderate activity (greater than 20% MVIC) from the serratus anterior. Conversely, the "dancer's pose right," "reverse tabletop," and "warrior II" postures demonstrated low activity (less than or equal to 15.7% MVIC) of the scapular stabilizers. Conclusion Strengthening the scapular stabilizer muscles is an important component of shoulder rehabilitation. Yoga postures have been identified that activate the scapular stabilizer muscles at varying levels of activity. J Orthop Sports Phys Ther 2018;48(6):504-509. Epub 6 Apr 2018. doi:10.2519/jospt.2018.7311. PMID- 29623752 TI - Developing and evaluating a course programme to enhance existential communication with cancer patients in general practice. AB - OBJECTIVE: Our objective was to describe the development and evaluation of a course programme in existential communication targeting general practitioners (GPs). DESIGN: The UK Medical Research Council's (MRC) framework for complex intervention research was used as a guide for course development and evaluation and was furthermore used to structure this paper. The development phase included: identification of existing evidence, description of the theoretical framework of the course, designing the intervention and deciding for types of evaluation. In the evaluation phase we measured self-efficacy before and after course participation. To explore further processes of change we conducted individual, semi-structured telephone interviews with participants. SUBJECTS AND SETTING: Twenty practising GPs and residentials in training to become GPs from one Danish region (mean age 49). RESULTS: The development phase resulted in a one-day vocational training/continuing medical education (VT/CME) course including the main elements of knowledge building, self-reflection and communication training. Twenty GPs participated in the testing of the course, nineteen GPs answered questionnaires measuring self-efficacy, and fifteen GPs were interviewed. The mean scores of self-efficacy increased significantly. The qualitative results pointed to positive post course changes such as an increase in the participants' existential self-awareness, an increase in awareness of patients in need of existential communication, and an increase in the participants' confidence in the ability to carry out existential communication. CONCLUSIONS: A one-day VT/CME course targeting GPs and including the main elements of knowledge building, self reflection and communication training showed to make participants more confident about their ability to communicate with patients about existential issues and concerns. Key points Patients with cancer often desire to discuss existential concerns as part of clinical care but general practitioners (GPs) lack confidence when discussing existential issues in daily practice. In order to lessen barriers and enhance existential communication in general practice, we developed a one-day course programme. Attending the course resulted in an increase in the participants' confidence in the ability to carry out existential communication. This study adds knowledge to how confidence in existential communication can be increased among GPs. PMID- 29623753 TI - Trait rumination and response to negative evaluative lab-induced stress: neuroendocrine, affective, and cognitive outcomes. AB - Theoretical models of depression posit that, under stress, elevated trait rumination predicts more pronounced or prolonged negative affective and neuroendocrine responses, and that trait rumination hampers removing irrelevant negative information from working memory. We examined several gaps regarding these models in the context of lab-induced stress. Non-depressed undergraduates completed a rumination questionnaire and either a negative-evaluative Trier Social Stress Test (n = 55) or a non-evaluative control condition (n = 69), followed by a modified Sternberg affective working memory task assessing the extent to which irrelevant negative information can be emptied from working memory. We measured shame, negative and positive affect, and salivary cortisol four times. Multilevel growth curve models showed rumination and stress interactively predicted cortisol reactivity; however, opposite predictions, greater rumination was associated with blunted cortisol reactivity to stress. Elevated trait rumination interacted with stress to predict augmented shame reactivity. Rumination and stress did not significantly interact to predict working memory performance, but under control conditions, rumination predicted greater difficulty updating working memory. Results support a vulnerability stress model of trait rumination with heightened shame reactivity and cortisol dysregulation rather than hyper-reactivity in non-depressed emerging adults, but we cannot provide evidence that working memory processes are critical immediately following acute stress. PMID- 29623755 TI - Epidemiology of fishing related upper extremity injuries presenting to the emergency department in the United States. AB - OBJECTIVE: Fishing injuries commonly affect the hands. The goal of this study was to quantify the incidence of fishing-related upper extremity injuries that present to emergency departments in the United States. METHODS: We examined the reported cases of fishing-related upper extremity injuries in the National Electronic Injury Surveillance System database. Analysis was performed based on age, sex and the type of injury reported. RESULTS: The national incidence of fishing-related upper extremity injuries was 119.6 per 1 million person-years in 2014. The most common anatomic site for injury was the finger (63.3%), followed by the hand (20.3%). The most common type of injury in the upper extremity was the presence of a foreign body (70.4%). The incidence of fishing-related upper extremity injuries in males was 200 per 1 million person-years, which was significantly higher than the incidence in females (41 per 1 million person years). CONCLUSION: The incidence of fishing-related upper extremity injuries that present to the Emergency Department was 120 per 1 million person-years. The incidence was significantly higher in males. With the widespread popularity of the activity, it is important for Emergency Physicians and Hand Surgeons to understand how to properly evaluate and manage these injuries. PMID- 29623754 TI - Bone mineral density in primary care patients related to serum calcium concentrations: a longitudinal cohort study from Sweden. AB - OBJECTIVE: Elevated calcium concentration is a commonly used measure in screening analyses for primary hyperparathyroidism (pHPT) and cancer. Low bone mineral density (BMD) and osteoporosis are common features of pHPT and strengthen the indication for parathyroidectomy. It is not known whether an elevated calcium concentration could be a marker of low BMD in suspected pHPT patients with a normal parathyroid hormone concentration. PURPOSE: To study if low BMD and osteoporosis are more common after ten years in patients with elevated compared with normal calcium concentrations at baseline. DESIGN: Prospective case control study. SETTING: Primary care, southern Sweden. SUBJECTS: One hundred twenty-seven patients (28 men) with baseline elevated, and 254 patients (56 men) with baseline normal calcium concentrations, mean age 61 years, were recruited. After ten years, 77% of those still alive (74 with elevated and 154 with normal calcium concentrations at baseline) participated in a dual energy x-ray absorptiometry measurement for BMD assessment and analysis of calcium and parathyroid hormone concentrations. MAIN OUTCOME MEASURES: Association between elevated and normal calcium concentration at base-line and BMD at follow-up. Correlation between calcium and parathyroid hormone concentrations and BMD at follow-up. RESULTS: A larger proportion of the patients with elevated baseline calcium concentrations who participated in the follow-up had osteoporosis (p value = 0.036), compared with the patients with normal concentrations. In contrast, no correlation was found between calcium or parathyroid hormone concentrations and BMD at follow-up. CONCLUSIONS: In this study, patients with elevated calcium concentrations at baseline had osteoporosis ten years later more often than controls (45% vs. 29%), which highlights the importance of examining these patients further using absorptiometry, even when their parathyroid hormone level is normal. Key Points Osteoporosis is common, difficult to detect and usually untreated. It is not known whether elevated calcium concentrations, irrespective of the PTH level, could be a marker of low bone mineral density. No correlation was found between calcium or parathyroid hormone concentrations and bone mineral density at follow up. In this study, patients with elevated calcium concentrations at baseline had osteoporosis ten years later more often than controls (45% vs. 29%). PMID- 29623756 TI - An explorative study on potent Gram-negative specific LpxC inhibitors: CoMFA, CoMSIA, HQSAR and molecular docking. AB - Pathogenic Gram-negative bacteria are responsible for nearly half of the serious human infections. Hologram quantitative structure-activity relationships (HQSAR), comparative molecular field analysis (CoMFA), and comparative molecular similarity index analysis (CoMSIA) were implemented on a group of 32 of potent Gram-negative LpxC inhibitors. The most effective HQSAR model was obtained using atoms, bonds, donor, and acceptor as fragment distinction. The cross-validated correlation coefficient (q2), non-cross-validated correlation coefficient (r2), and predictive correlation coefficient (r2Pred) for test set of HQSAR model were 0.937, 0.993, and 0.892, respectively. The generated models were found to be statistically significant as the CoMFA model had (r2 = 0.967, q2 = 0.804, r2Pred = 0.827); the CoMSIA model had (r2 = 0.963, q2 = 0.752, r2Pred = 0.857). Molecular docking was employed to validate the results of the HQSAR, CoMFA, and CoMSIA models. Based on the obtained information, six new LpxC inhibitors have been designed. PMID- 29623757 TI - Icariin, a flavonoid with anti-cancer effects, alleviated paclitaxel-induced neuropathic pain in a SIRT1-dependent manner. AB - Background One of the most common side effects of paclitaxel was dosage dependently painful neuropathy. Various reports indicated that spinal neuroinflammation was involved in paclitaxel-induced neuropathic pain. This study investigated the effect of icariin on paclitaxel-induced neuroinflammation and peripheral neuropathy in rats. Methods Two parts were included in this study. In part one, the effect of icariin on paclitaxel-induced neuropathic pain was investigated. Mechanical thresholds were measured as primary outcomes. Production of proinflammatory factors (tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-6), activation of nuclear factor-kappaB (NF-kappaB(p65)) signal, and activation of astrocytes were detected as secondary outcomes. Spinal Sirtuin 1 (SIRT1) expression, H4 acetylation, and NAD+ content were measured to investigate the effect of icariin on spinal SIRT1 signal pathway. In part two, the role of SIRT1 signal on icariin-induced effect in rats was investigated, and EX527, a SIRT1 inhibitor, was employed. Results The results showed paclitaxel treatment induced significant decrease in mechanical thresholds. Paclitaxel treatment also induced NF-kappaB(p65) activation and upregulation of proinflammatory factors (TNF-alpha, IL-1beta, and IL-6). Paclitaxel also induced astrocyte activation in the spinal cord. However, 100 mg/kg icariin treatment significantly alleviated paclitaxel-induced mechanical allodynia and spinal neuroinflammation. Furthermore, icariin treatment dosage-dependently reversed paclitaxel-induced SIRT1 downregulation and H4 acetylation. EX527, a selective SIRT1 inhibitor, completely reversed icariin-induced anti-neuroinflammation and anti-allodynia effects in paclitaxel-induced neuropathic pain rats. Conclusions This meant that spinal SIRT1 activation was involved in icariin-induced effects in paclitaxel induced neuropathic pain rats. Icariin could be a potential agent for the treatment of paclitaxel-induced neuropathic pain. PMID- 29623758 TI - Targeting altered cancer methionine metabolism with recombinant methioninase (rMETase) overcomes partial gemcitabine-resistance and regresses a patient derived orthotopic xenograft (PDOX) nude mouse model of pancreatic cancer. AB - Pancreatic cancer is a recalcitrant disease. Gemcitabine (GEM) is the most widely used first-line therapy for pancreatic cancer, but most patients eventually fail. Transformative therapy is necessary to significantly improve the outcome of pancreatic cancer patients. Tumors have an elevated requirement for methionine and are susceptible to methionine restriction. The present study used a patient derived orthotopic xenograft (PDOX) nude mouse model of pancreatic cancer to determine the efficacy of recombinant methioninase (rMETase) to effect methionine restriction and thereby overcome GEM-resistance. A pancreatic cancer obtained from a patient was grown orthotopically in the pancreatic tail of nude mice to establish the PDOX model. Five weeks after implantation, 40 pancreatic cancer PDOX mouse models were randomized into four groups of 10 mice each: untreated control (n = 10); GEM (100 mg/kg, i.p., once a week for 5 weeks, n = 10); rMETase (100 units, i.p., 14 consecutive days, n = 10); GEM+rMETase (GEM: 100 mg/kg, i.p., once a week for 5 weeks, rMETase: 100 units, i.p., 14 consecutive days, n = 10). Although GEM partially inhibited PDOX tumor growth, combination therapy (GEM+rMETase) was significantly more effective than mono therapy (GEM: p = 0.0025, rMETase: p = 0.0010). The present study is the first demonstrating the efficacy of rMETase combination therapy in a pancreatic cancer PDOX model to overcome first-line therapy resistance in this recalcitrant disease. PMID- 29623759 TI - An update on clinical significance of use of THSD7A in diagnosing idiopathic membranous nephropathy: a systematic review and meta-analysis of THSD7A in IMN. AB - BACKGROUND: THSD7A is a new target antigen of idiopathic membranous nephropathy (IMN). Moreover, malignancies are also found in patients with THSD7A-positive membranous nephropathy. We aimed to systematically evaluate the prevalence of THSD7A in IMN patients and malignancies in THSD7A-positive patients. METHODS: We searched English and Chinese database to 31 December 2017 with the term 'THSD7A' or 'thrombospondin type 1 domain-containing 7A'. Meta-analysis was used to explore the positive rate of THSD7A in the IMN patients. Subgroup analysis was performed according to the race, sample size, and detecting method of THSD7A. RESULTS: Ten studies involving 4121 participants were eventually included. The prevalence of THSD7A was 3% (95% CI, 3%-4%) in all patients and 10% (95% CI, 6% 15%) in PLA2R-negative patients. 77 patients had positive circulating antibodies, and the prevalence of THSD7A was also low at 3% (95% CI, 2%-4%). Overall, 72 patients had positive THSD7A staining on renal biopsy, and the prevalence was 3% (95% CI 2%-4%). Subgroup analysis showed significant differences in the prevalence of THSD7A based on the study sample sizes, however, no significant differences were seen in different ethnic groups. Furthermore, among THSD7A positive patients, 3/10 studies reported malignancies with the incidence varied from 6% to 25%. CONCLUSIONS: The prevalence of THSD7A is more common in the PLA2R negative patients than the IMN patients. Screening for malignancies in THSD7A positive MN patients is recommended. PMID- 29623760 TI - Associations between working environment and weight control efforts among workers with obesity in Korea. AB - Objective The aim of this study was to investigate the relationship between working environment and weight control efforts among obese workers in Korea. Methods This study was based on the 2011 3rd Korean Working Conditions Survey, which was conducted on workers aged 15 years or older. A sample of 484 obese workers was included in the study. Multivariable logistic regression analysis was used to investigate the relationship between working environment and weight control efforts after controlling for individual variables. Adjusted odds ratios (ORs) and 95% confidence intervals were calculated. Results Of the participants, 63.4% reported that they made efforts to control their weight. After controlling for personal factors, the OR of weight control efforts for individuals working 40 49 hours per week was 2.4 times that for individuals working 60 hours or more per week. The OR of regular employment workers was 2.2 times that of non-regular workers. Conclusion We established that working hours and employment type were significantly related to weight control efforts. Therefore, we recommend that working conditions should be considered in designing effective workplace health promotion programs. PMID- 29623761 TI - Every Day is a New Day: Legislative Strides for Organ Donation and Transplantation Continue in Washington, DC. PMID- 29623762 TI - Degraded melanocores are incompetent to protect epidermal keratinocytes against UV damage. AB - Melanosomes are membrane-bound intracellular organelles that are uniquely generated by melanocytes (MCs) in the basal layer of human epidermis. Highly pigmented mature melanosomes are transferred from MCs to keratinocytes (KCs), and then positioned in the supra-nuclear region to ensure protection against ultraviolet radiation (UVR). However, the molecular mechanism underlying melanosome (or melanin pigment) transfer remains enigmatic. Emerging evidence shows that exo-/endo-cytosis of the melanosome core (termed melanocore) has been considered as the main transfer manner between MCs and KCs. As KCs in the skin migrate up from the basal layer and undergo terminal differentiation, the melanocores they have taken up from MCs are subjected to degradation. In this study, we isolated individual melanocores from human MCs in culture and then induced their destruction/disruption using a physical approach. The results demonstrate that the ultrastructural integrity of melanocores is essential for their antioxidant and photoprotective properties. In addition, we also show that cathepsin V (CTSV), a lysosomal acid protease, is involved in melanocore degradation in calcium-induced differentiated KCs and is also suppressed in KCs following exposure to UVA or UVB radiation. Thus, our study demonstrates that change in the proportion of melanocores in the intact/undegraded state by CTSV related degradation in KCs affects photoprotection of the skin. PMID- 29623764 TI - "Good, better, creative": the influence of creativity on goal scoring in elite soccer. AB - This study investigated the level of creativity of goals scored in football. Therefore, all goals in the Football FIFA World Cup 2010 and 2014, as well as the Football UEFA Euro 2016 were qualitatively examined. Three Football experts evaluated the last eight actions before each goal using a creativity scale ranging from 0 to 10 (0 = not creative, 10 = highly creative) of all goals scored via open play (311 goals in 153 matches). Level of creativity was revealed using an Analysis of Variance and the frquency of high highly creative goals using a Kruskall- Wallis Test. The results showed that the closer the actions to a goal, the more creative they were evaluated. Teams that advanced to the later rounds of the tournament demonstrated greater creativity than teams that failed to do so. High creativity in the last two actions before the actual shot on goal proved to be the best predictor for game success. In conclusion, this study is the first one to show that creativity seems to be a factor for success in high level football. Thereby it provides an empirical basis for the ongoing debate on the importance of creativity training in football. PMID- 29623765 TI - Long venous cannula on the arterial position for VA-ECMO. AB - Differential hypoxia and the arterial mixing zone are two important factors in managing peripheral veno-arterial extracorporeal membrane oxygenation (VA-ECMO). With the aim of improving perfusion to the aortic arch branches and coronaries, we describe our approach for VA-ECMO cannulation: bicaval drainage through the femoral vein and proximal retrograde ECMO flow using a multi-stage venous cannula inserted in the femoral artery and the tip placed at the proximal descending thoracic aorta. We report the use of this VA-ECMO approach on a 15-year-old female with combined cardiorespiratory failure and on a 12-year-old male with acute cardiac failure. PMID- 29623763 TI - Polysaccharide hydrolase of the hadal zone amphipods Hirondellea gigas. AB - Hirondellea species are common inhabitants in the hadal region deeper than 7,000 m. We found that Hirondellea gigas thrived in the Challenger Deep possessed polysaccharide hydrolases as digestive enzymes. To obtain various enzymes of other H. gigas, we captured amphipods from the Japan Trench, and Izu-Ogasawara (Bonin) Trench. A phylogenetic analysis based on the cytochrome oxidase I gene showed close relationships among amphipods, despite the geographic distance between the localities. However, several differences in enzymatic properties were observed in these H. gigas specimens. We also carried out RNA sequencing of H. gigas from the Izu-Ogasawara Trench. The cellulase gene of H. gigas was highly homologous to cellobiohydrolase of Glucosyl Hydrolase family 7 (GH7). On the other hand, enzymatic properties of H. gigas's cellulase were different from those of typical GH7 cellobiohydrolase. Thus, these results indicate that hadal zone amphipod can be good candidates as the new enzyme resource. PMID- 29623766 TI - A retrospective analysis of the mixed venous oxygen saturation as the target for systemic blood flow control during cardiopulmonary bypass. AB - OBJECTIVES: The patient's body surface area serves as the traditional reference for the determination of systemic blood flow during cardiopulmonary bypass (CPB). New strategies refer to different algorithms of oxygen delivery. This study reports on the mixed venous oxygen saturation (SvO2) as the target for systemic blood flow control. We hypothesise that an SvO2>75% (SvO275) is associated with better preservation of renal function and improved short-term survival. METHODS: This retrospective, 10-year, observational study analysed 6945 consecutive cardiac surgical cases requiring CPB. Endpoints included rates of acute kidney injury (AKI) and short-term survival, also the estimated glomerular filtration rate (eGFR), lactate levels and blood transfusions. RESULTS: Seventy-seven percent of the patients attained the SvO275 target. For this group, the median SvO2 was 78.1 (5.8) %, with a mean oxygen delivery of 331 (78) ml/min per m2 body surface area. Overall incidence of AKI levels (I-III): 7.5% - 2.6% - 0.6%. Incidence of eGFR (<50%): 3.9%, increasing to 6% for haemoglobin levels <80 g/L (p<0.001). Red cell transfusion was more frequent (p<0.001) within this group (30.6%) compared to levels >100 g/L (0.3%). Further, women (52.8%) were transfused more often than men (14.6%). Lactate level at weaning from CPB was 1.3 (0.7) mmol/L. The SvO275 target demonstrated a relative risk reduction of 22.5% (p=0.032) for AKI (I), increasing to 32.3% (p=0.026) for procedures extending >90 minutes. In addition, the risk for death 90-days postop was lower (p=0.039). CONCLUSION: The SvO275 target showed a decreased risk for postoperative AKI and prolonged short-term survival. Good clinical outcomes were also linked to measures of lactate and the eGFR. However, anaemia remains a risk factor for AKI. PMID- 29623767 TI - Validation of a New Methodology to Determine 3-Dimensional Endograft Apposition, Position, and Expansion in the Aortic Neck After Endovascular Aneurysm Repair. AB - PURPOSE: To validate a novel methodology employing regular postoperative computed tomography angiography (CTA) scans to assess essential factors contributing to durable endovascular aneurysm repair (EVAR), including endograft deployment accuracy, neck adaptation to radial forces, and effective apposition of the fabric within the aortic neck. METHODS: Semiautomatic calculation of the apposition surface between the endograft and the infrarenal aortic neck was validated in vitro by comparing the calculated surfaces over a cylindrical silicon model with known dimensions on CTA reconstructions with various slice thicknesses. Interobserver variabilities were assessed for calculating endograft position, apposition, and expansion in a retrospective series of 24 elective EVAR patients using the repeatability coefficient (RC) and the intraclass correlation coefficient (ICC). The variability of these calculations was compared with variability of neck length and diameter measurements on centerline reconstructions of the preoperative and first postoperative CTA scans. RESULTS: In vitro validation showed accurate calculation of apposition, with deviation of 2.8% from the true surface for scans with 1-mm slice thickness. Excellent agreement was achieved for calculation of the endograft dimensions (ICC 0.909 to 0.996). Variability was low for calculation of endograft diameter (RC 2.3 mm), fabric distances (RC 5.2 to 5.7 mm), and shortest apposition length (RC 4.1 mm), which was the same as variability of regular neck diameter (RC 0.9 to 1.1 mm) and length (RC 4.0 to 8.0 mm) measurements. CONCLUSION: This retrospective validation study showed that apposition surfaces between an endograft and the infrarenal neck can be calculated accurately and with low variability. Determination of the (ap)position of the endograft in the aortic neck and detection of subtle changes during follow-up are crucial to determining eventual failure after EVAR. PMID- 29623768 TI - Methionine residues lining the substrate pathway in prolyl oligopeptidase from Pleurotus eryngii play an important role in substrate recognition. AB - Family S9 prolyl oligopeptidases (POPs) are of interest as pharmacological targets. We recently found that an S9 POP from Pleurotus eryngii showed altered substrate specificity following H2O2 treatment. Oxidation of Met203 on the non catalytic beta-propeller domain resulted in decreased activity toward non aromatic aminoacyl-para-nitroanilides (pNAs) while maintaining its activity toward aromatic aminoacyl-pNAs. Given that the other Met residues should also be oxidized by H2O2 treatment, we constructed mutants in which all the Met residues were substituted with other amino acids. Analysis of the mutants showed that Met570 in the catalytic domain is another potent residue for the altered substrate specificity following oxidation. Met203 and Met570 lie on the surfaces of two different domains and form part of a funnel from the surface to the active center. Our findings indicate that the funnel forms the substrate pathway and plays a role in substrate recognition. PMID- 29623769 TI - Investigating Perceptual Biases, Data Reliability, and Data Discovery in a Methodology for Collecting Speech Errors From Audio Recordings. AB - This work describes a methodology of collecting speech errors from audio recordings and investigates how some of its assumptions affect data quality and composition. Speech errors of all types (sound, lexical, syntactic, etc.) were collected by eight data collectors from audio recordings of unscripted English speech. Analysis of these errors showed that: (i) different listeners find different errors in the same audio recordings, but (ii) the frequencies of error patterns are similar across listeners; (iii) errors collected "online" using on the spot observational techniques are more likely to be affected by perceptual biases than "offline" errors collected from audio recordings; and (iv) datasets built from audio recordings can be explored and extended in a number of ways that traditional corpus studies cannot be. PMID- 29623770 TI - Atypical presentation of acute coronary syndrome (ACS): a case report. AB - CASE: A 45-year-old man presented at the emergency department (ED) with stomach pain since eight days. The patient was not worried about his symptoms and requested only pain relief. The emergency physician requested a consult of the gastroenterologist. Clinical examination was unremarkable. However, 12-lead ECG and ischemic markers were suggestive of acute coronary syndrome (ACS) which led to admission at the cardiology department. Despite delayed presentation, the patient was still referred for urgent coronary angiogram after receiving heparin, ticagrelor and acetylsalicylic acid because of persistent pain. An acute occlusion of the posterior descending artery was visualized and a percutaneous coronary intervention (PCI) with implantation of a drug-eluting stent was performed. DISCUSSION: Atypical presentation of ACS can range from non-chest pain to an epileptic seizure. Risk factors for atypical presentation include female gender, old age, comorbidities and severe mental illness. Troponin testing plays a central role when confronted with ACS but has only limited added-value with non chest pain ACS. In cohort studies 1-2.2% of diagnosis of ACS is missed by emergency physicians. Possible explanations include atypical symptoms, non diagnostic ECG and failure to interpret subtle ECG changes. ACS without chest pain frequently gets underdiagnosed and undertreated, which leads to more complications and a higher in-hospital mortality rate. PMID- 29623773 TI - Continuing education for general practitioners working in rural practice: a review of the literature. AB - Background Studies demonstrate that the CME/CPD (continuing medical education/continuing professional development) needs of rural general practitioners (GPs) are unique. Little research has focused specifically on the effectiveness of CME/CPD programmes for rural practice. Aims To review the literature on CME/CPD for GPs in rural areas, focussing on studies which examined impact on doctor performance or patient outcomes. Methods A search of peer reviewed English language literature and relevant grey literature was conducted: identified literature was reviewed. Results Nineteen articles met the pre specified inclusion criteria. Educational delivery approaches examined include regional CME/CPD small-group learning programmes, workshops and distance learning. Most articles report on participant experience or satisfaction while doctor performance and patient outcomes are seldom reported. Distance learning programmes found it difficult to recruit or engage doctors, two out of six studies found improvements in self-reported knowledge or performance, while none reported measurable changes in doctor performance/patient care. PMID- 29623772 TI - Screening, management, and treatment of intimate partner violence among women in low-resource settings. AB - The prevention of intimate partner violence continues to be a high priority for health practitioners and researchers around the world. Screening practices and intervention efforts utilized within high- and/or middle-income areas may not translate effectively to low-resource areas due to differences in financial, social, and physical context. However, little is known about the evidence-base of intervention efforts in such areas. Using the Arksey and O'Malley framework for scoping reviews, the purpose of this review was to synthesize what is known about intimate partner violence screening, management, and treatment in low-resource areas. A total of 31 programs reported across 34 articles were included in this scoping review. The programs incorporated a range of intervention activities, including group-based education and skill-development combined with microfinance to screening and referral to community resources. Slightly less than half of the studies (n = 14) were randomized controlled trials or clustered randomized controlled trials. Many barriers were common across the programs, including limited financial support, lack of community support, and lack of coordination across programs. Despite considerable barriers related to the limited available resources, the literature base had many strengths, such as strong evaluation methodologies, inclusion of a theoretical or conceptual framework to guide the intervention, and community engagement before and during the intervention implementation. However, insufficient statistical power and barriers related to cultural differences or inadequate cultural sensitivity were also common. With a variety of barriers to program implementation noted within the articles, it is important for researchers and practitioners to consider the geographic, social, cultural, and economic contexts when implementing intimate partner violence programs in low-resource areas. Given the significant differences in context across low-resource areas, additional research to establish effective protocols for tailoring and implementing evidence-based programs using a community-engaged framework would be beneficial to future research and practice. PMID- 29623771 TI - Interaural Time-Difference Discrimination as a Measure of Place of Stimulation for Cochlear-Implant Users With Single-Sided Deafness. AB - Current clinical practice in programming a cochlear implant (CI) for individuals with single-sided deafness (SSD) is to maximize the transmission of speech information via the implant, with the implicit assumption that this will also result in improved spatial-hearing abilities. However, binaural sensitivity is reduced by interaural place-of-stimulation mismatch, a likely occurrence with a standard CI frequency-to-electrode allocation table (FAT). As a step toward reducing interaural mismatch, this study investigated whether a test of interaural-time-difference (ITD) discrimination could be used to estimate the acoustic frequency yielding the best place match for a given CI electrode. ITD discrimination performance was measured by presenting 300-ms bursts of 100-pulses per-second electrical pulse trains to a single CI electrode and band-limited pulse trains with variable carrier frequencies to the acoustic ear. Listeners discriminated between two reference intervals (four bursts each with constant ITD) and a moving target interval (four bursts with variable ITD). For 17 out of the 26 electrodes tested across eight listeners, the function describing the relationship between ITD-discrimination performance and carrier frequency had a discernable peak where listeners achieved 70% to 100% performance. On average, this peak occurred 1.15 octaves above the CI manufacturer's default FAT. ITD discrimination shows promise as a method of estimating the cochlear place of stimulation for a given electrode, thereby providing information to optimize the FAT for SSD-CI listeners. PMID- 29623774 TI - Intimate Partner Violence in Urban, Rural, and Remote Areas: An Investigation of Offense Severity and Risk Factors. AB - This study compared the severity of intimate partner violence (IPV) and the relationship between risk factors for IPV and overall risk judgments of future IPV in urban, rural, and remote areas. IPV risk assessments conducted by the Swedish police between 2010 and 2014 in urban ( n = 564), rural ( n = 456), and remote ( n = 196) areas were examined. Rurality was associated with the severity of IPV reported, as well as the presence of risk factors and their relationship to overall risk judgments. Cases in remote areas included more severe IPV as well as more risk factors. PMID- 29623775 TI - Culturally Sensitive Assessment of Anxious-Depressive Distress in Vietnam: Avoiding Category Truncation. AB - The present study investigated what complaints are prominent in psychologically distressed Vietnamese in Vietnam beyond standard symptoms assessed by Western diagnostic instruments for anxiety and depression. To form the initial Vietnamese Symptom and Cultural Syndrome Addendum (VN SSA), we reviewed the literature, consulted experts, and conducted focus groups. The preliminary VN SSA was then used in a general survey (N = 1004) of five provinces in Vietnam. We found that the VN SSA items were highly and significantly correlated with a measure of anxious-depressive psychopathology (a composite measure of the General Anxiety Disorder-7; Posttraumatic Diagnostic Scale; and Patient Health Questionnaire-9). The VN SSA item most highly correlated to anxious-depressive psychopathology was "thinking a lot" ( r = .54), reported by 15.8% of the sample. Many other symptoms in the addendum also were prominent, such as orthostatic dizziness (i.e., dizziness upon standing up; r = .41), reported by 22.9% of the sample. By way of comparison, somatic complaints more typically assessed to profile Western anxious depressive distress, such as palpitations, were less prominent, as evidenced by being less strongly correlated to Western psychiatric symptoms and being less frequent (e.g., palpitations: r = .31, 7.1% of the sample). Study results suggest that to avoid category truncation when profiling anxious-depressive distress among Vietnamese that items other than those in standard psychopathology measures should also be assessed. PMID- 29623776 TI - Some comparative psychiatric studies in the 19th century. AB - This article analyses 19th-century publications which dealt with the social and cultural aspects of psychiatric disorders in different parts of the world. Systematic reviews were conducted of three German medical journals, one Russian medical journal, and a relevant monograph. All these archives were published in the 19th century. Our work highlights the fact that long before Kraepelin, several, mostly forgotten, publications had already discussed cultural aspects, social conditions, the influence of religion, the influence of climate, and also "race" as a trigger or amplifier of psychiatric diseases. These publications also reflect racist notions of the colonial period. PMID- 29623777 TI - What keeps Maya from eating? A case study of disordered eating from North India. AB - Anthropologists have paid much attention to food and eating practices in India, but surprisingly few scholars in any discipline have examined eating disorders. This article presents an ethnographic case study of disordered eating, based on a story of a young female pharmacist from one of the Northern Indian states. Advocating ethnography as an essential method to uncovering the multiple facets of "not eating," I first show how this phenomenon may reflect resistance to Brahmanical patriarchy, especially the institution of arranged marriage. Secondly, I illustrate how "not eating" may be an embodied expression of distress, in this case related to the inability to fulfil filial obligations of reciprocity. Finally, I argue that "not eating" in India may be associated with the ways in which personhood, as locally understood, is influenced by regional socioeconomic development. Thus, while young, unmarried, and highly educated women have increasingly better opportunities for formal employment, they may find themselves at the crossroads of conflicting social expectations, and "not eating" may arise as an after-effect. While making large-scale generalizations of these findings across India would be inappropriate, this case study sheds light on the complexity of disordered eating in this country and calls for further ethnographic studies, sensitive to local meanings of (not) eating. PMID- 29623778 TI - Involvement of dopamine system in the regulation of the brain corticotropin releasing hormone in paraventricular nucleus in a rat model of chronic visceral pain. AB - Objective We aimed to investigate the mechanism of paraventricular nucleus (PVN) and ventral tegmental area (VTA) circuit in the pathogenesis of visceral pain depression with a rat model induced by neonatal and adult colorectal distension (CRD). Methods Neonate male Sprague-Dayley (SD) rats underwent CRD on postnatal days 8, 10, and 12, and when matured, were tested for adult abdominal withdrawal reflex (AWR) scores to assess visceral hypersensitivity. The forced swimming test was employed to evaluate depression-like behaviors. The rats exhibiting visceral pain-depressive behaviors underwent lidocaine injection in the VTA to explore the relationship between VTA and visceral pain. Moreover, double immunofluorescence was employed to evaluate the qualitative and quantitative expression of dopamine/ c-Fos in CRD rats. After verifying the existed fiber projection from PVN to VTA, the intra-PVN microinjection of CRH-RNAi lentivirus to inhibit corticotropin releasing hormone (CRH) expression, behavioral changes were assessed by AWR score and FST. Thereafter, with the sacrifice of the rats, the variations of TH protein in rats were evaluated by immunofluorescence and Western blot. Results Intra-VTA microinjection of lidocaine increased the pain threshold of CRD group. After intra-VTA microinjection of green retrograde tracer, immunofluorescence photomicrographs visualized the PVN with a typical green retrograde tracer. Intra PVN microinjection of CRH-RNAi lentivirus alleviated the visceral pain-depression behaviors and decreased the TH protein expression in the VTA. Conclusion These data demonstrated that the VTA played a functional role in chronic visceral pain and depression, and the CRH-containing neurons in hypothalamic PVN may be implicated in the onset and maintenance of the chronic visceral pain and depression via the activation of dopamine in the VTA. PMID- 29623779 TI - Long-term use of darunavir/ritonavir-containing regimens in daily practice in Belgium: retrospective observational cohort data of 1701 HIV-patients. AB - Background Once daily (QD) ritonavir or cobicistat-boosted darunavir (DRV/b), in combination with other antiretrovirals (ARVs), is recommended as a first-line option for human immunodeficiency virus-infected patients in European and USA guidelines. The objective of this study was to analyse the outcomes of DRV/r QD based antiretroviral therapy (ART) regimens in real-life settings. Methods This is an observational, non-interventional, non-comparative, retrospective, multicentre cohort study. Data were collected from the databases of eight Belgian AIDS Reference Centres. All patients who received at least one dose of DRV/r QD, regardless of background ARV regimen, with a minimum follow-up of 6 months were included. Results Data from 1701 subjects were collected. Most were male (66.5%) with a mean age of 42.9 years, 33.1% were treatment-naive and 66.9% were ART experienced. During a median follow-up of 2.45 years (95% CI: 1.50-3.34), the probability to remain on treatment was 87% for the first year, 79% for the second year. DRV/r was well tolerated with few discontinuations due to adverse events (6.9%) or virological failure (0.8%). Among the 1138 treatment-experienced patients, 111 (9.8%) patients received DRV/r QD monotherapy. Conclusions This retrospective cohort analysis confirms the long-term effectiveness and good tolerability of DRV/r QD in a real-life setting. No unexpected adverse events were reported. PMID- 29623780 TI - Justification of Wife Beating in Adolescents: Associated Beliefs and Behaviors. AB - Socioeconomically disadvantaged adolescents who are exposed to social norms related to violence against women are more likely to experience or be perpetrators of intimate partner violence. This study evaluated factors hypothesized to be associated with acceptance of wife beating among 240 male and female adolescents aged 10-16 years participating in a World Vision program in Armenia. Acceptance of wife beating was associated with relational victimization, perceived social support, and parent and community boundaries and expectations, but was not associated with overt victimization or aggression. These findings highlight several areas that may be important for violence prevention research. PMID- 29623781 TI - Sildenafil protective effects on high glucose-induced neurotoxicity in PC12 cells: the role of oxidative stress, apoptosis, and inflammation pathways in an in vitro cellular model for diabetic neuropathy. AB - Objectives Diabetic neuropathy (DN) induces lifetime disability and there is currently no effective therapy to treat or to minimize patients suffering, so it is thereby imperative to develop therapeutic strategies for this disease. Since oxidative stress, mitochondrial dysfunction, apoptosis, and inflammation are crucial mechanisms in development and progression of DN, it is important to explore tools by which one can reduce factors related to these pathways. Herein, the understandings of the sildenafil neuroprotective effect through increase of cGMP level and the mediation of oxidative stress, apoptosis, and inflammation pathways on neurotoxicity induced by high glucose (HG) in PC12 cells as an in vitro cellular model for DN were investigated. Methods We reported that the PC12 cells pre-treatment with sildenafil (0.008 MUM) for 60 min and then exposing the cells to HG (25 mM for 72 h) or normal glucose (NG) (5 mM for 72 h) condition, show: Results (1) significant attenuation in reactive oxygen species, MDA and TNF a levels, Bax/Bcl-2 ratio, expression of caspase 3 and UCP2 proteins; (2) significant increase in viability, GSH/GSSG ratio, mitochondrial membrane potential, and ATP levels. Conclusion All these data together led us to propose neuroprotective effect of sildenafil is probably through its antioxidant, antiapoptotic, and anti-inflammatory activities. Of course, further studies are required to explain the underlying mechanism of the sildenafil effects. PMID- 29623782 TI - Local Introgression of Mitochondrial DNA in Eight-Barbel Loaches of the Genus Lefua (Balitoridae, Cypriniformes). AB - The evolutionary history of eight-barbel loaches of the genus Lefua was investigated to resolve the faunal formation and evolutionary history of Japanese and East Asian freshwater fishes. In the present study, we found that seven Lefua specimens obtained from western Japan could not be assigned genetically to any population recognized so far, although they were morphologically and ecologically indistinguishable from Lefua sp 1. We tentatively designated the specimens as the Nihonkai population. Sequencing of the mitochondrial D-loop region showed that five specimens of the Nihonkai population were allied with the Kinki and Tokai populations of L. echigonia and other two with Lefua sp. 2, indicating a discrepancy between morphological-ecological and genetic traits. In order to determine whether the population experienced parallel evolution or introgression of mitochondrial DNA, we sequenced the nuclear ribosomal S7 subunit, and demonstrated that the Nihonkai population is included within Lefua sp. 1. These results indicate that the Nihonkai population can be identified as Lefua sp. 1, possessing introgressive mitochondrial DNA, and suggest that the evolutionary history and faunal formation of Japanese and East Asian freshwater fishes are more complicated than previously thought. PMID- 29623783 TI - Evaluating Movement Patterns and Microhabitat Selection of the Japanese Common Toad (Bufo japonicus formosus) Using Fluorescent Powder Tracking. AB - Bufo japonicus formosus (Eastern-Japanese common toad) is endemic to Eastern Japan. As with many Japanese amphibians, little is known about its terrestrial life, especially during the nonbreeding season. This species persists even in highly disturbed urban areas where many other amphibian species have already been extirpated. An understanding of how such species use habitats within remnant landscapes may help to inform management strategies for the conservation of urban ecosystems. We examined the nightly movement patterns, distance traveled, movement range, and microhabitat selection of non-breeding adult B. j. formosus at an urbanized site, using fluorescent powder tracking. We evaluated the usefulness of this tracking method through this survey. We found that the nightly distances traveled by these toads varied greatly among individuals and nights. No sexual differences in movement pattern, distance traveled, and movement range were detected. However, body size significantly affected distance traveled and movement range. We found that toads tended to use areas covered with grasses and mosses more frequently than expected, and to avoid paved areas. Fluorescent powder tracking was effective for the elucidation of movement patterns and habitat selection of amphibians. Our results provide useful information for the conservation of amphibians, especially for species inhabiting urbanized areas. PMID- 29623784 TI - Metals Differentially Activate Ovarian Cancer G Protein-Coupled Receptor 1 in Various Species. AB - Human, mouse, and zebrafish ovarian cancer G protein-coupled receptors (OGR1s) are activated by both metals and extracellular protons. In the present study, we examined whether pig, rat, chicken, and Xenopus OGR1 homologs could sense and be activated by protons and metals. We found that all homologs stimulated serum response element (SRE)-driven promoter activities when they are stimulated by protons. On the other hand, metals differentially activated the homologs. The results using chimeric receptors of human and zebrafish OGR1s indicate that the specificity of the metal-induced activation lies in the extracellular region. These results suggest that protons are an evolutionally conserved agonist of OGR1. However, the types of metals that activated the receptor differed among the homologs. PMID- 29623785 TI - Genetic Structure of Dytiscus sharpi in North and South Hokuriku in Japan Inferred from Mitochondrial and Nuclear Gene Sequence. AB - Dytiscus sharpi is a critically endangered diving beetle endemic to Japan that is distributed in five distant areas today. Information on the population genetics of this species is crucial for its conservation. We investigated the genetic differentiation and divergence of the D. sharpi in seven populations in North and South Hokuriku on the Sea of Japan side, using mitochondrial cytochrome oxidase subunit I (COI) and nuclear Histone 3 and 28S rRNA gene sequences. Although the nuclear markers showed little geographic genetic differentiation, nine COI haplotypes were identified from 31 individuals, and these haplotypes were divided into two distinct networks A and B. The network A consisted of a single haplotype, and network B consisted of eight haplotypes. The populations in North Hokuriku possessed the haplotypes of both networks, whereas those in South Hokuriku possessed only the haplotypes of network B. The genetic diversity was relatively high in South and North Hokuriku. However, populations in South Hokuriku showed low genetic diversity and the isolation-by-distance pattern was observed among the populations, suggesting a restricted gene flow. Phylogenetic analysis including the data from a previous study revealed that the network A was closely related to a haplotype from Kanto, which is on the Pacific side. These results suggested that in the past this species was distributed widely across the Hokuriku area and the fragmentation of its distribution areas is a recent event. These results will contribute to strategies for the preservation of the current genetic diversity of D. sharpi. PMID- 29623786 TI - Identification of Two Additional Genomic Loci Responsible for experimentally induced testicular teratoma 2 and 3 (ett2 and ett3). AB - Experimental testicular teratomas (ETTs) can be induced in 129/Sv mouse by E12.5 fetal testes transplant into adult testes. Previously, we conducted linkage analysis to explore candidate genes possibly involved in ETT development using F2 intercross fetuses derived from F1[LTXBJ * 129/Sv- + /Ter (+ /+)] hybrids. By linkage analysis on Chr 18 and Chr 19, we identified the genomic locus for experimental testicular teratoma 1 (ett1) on Chr 18. In the present study, we conducted additional mapping and linkage analysis on teratoma susceptibility and genome composition on Chr 1-17. The results revealed two new candidate loci, experimental testicular teratoma 2 (ett2) and experimental testicular teratoma 3 (ett3), on Chr 3 and 7. Interestingly, the rates of ETT generation were increased in the case of ett2 and ett3 regions replaced with LTXBJ strain. To determine whether a polymorphic gene was present, we performed exome analysis of 129/Sv- + /Ter (+ /+) and LTXBJ. This revealed the presence of SNPs in all three loci, ett1 to ett3. ett1 contains polymorphic Mc4r; ett2 contains polymorphic Polr3c, Cd160, and Pdzk1; and ett3 contains polymorphic Prmt3. We found additional loci responsible for ETT formation, namely, ett2 and ett3, and identified candidate genes in these regions by exome analysis. PMID- 29623787 TI - Description of a New Subfamily, Astrocloninae (Ophiuroidea: Euryalida: Gorgonocephalidae), Based on Molecular Phylogeny and Morphological Observations. AB - Previous phylogenetic studies of the family Gorgonocephalidae (brittle stars and basket stars) have identified three subfamilies, Astrotominae, Astrothamninae, and Gorgonocephalinae. The genus Astroclon was tentatively assigned to the subfamily Astrothamninae in previous studies, but its morphology is enigmatic and molecular data of the genus was insufficient. Therefore, the systematic position of Astroclon required confirmation to reconstruct the accurate systematics of the Euryalida. In the present study, we sought to clarify the subfamilial classification in the family Gorgonocephalidae (Echinodermata: Ophiuroidea: Euryalida). We revisited molecular phylogenetics of the Gorgonocephalidae including Astroclon and the major taxa in the family. The molecular analysis supported monophyly of the two species of Astroclon and its clear separation from Astrothamninae. The two Astroclon species were also distinguished from the other two subfamilies, Astrotominae and Gorgonocephalinae. Astroclon and three other subfamilies were divided in the basal position of the Gorgonocephalidae, and were assigned to subfamilies. A new subfamily, Astrocloninae was monotypically established for Astroclon in addition to the previous three subfamilies. Morphology of the first ventral arm plates and tentacle pores also supported distinctiveness of the new subfamily. PMID- 29623788 TI - On the Occurrence of the Invasive Freshwater Limpet Ferrissia californica (Mollusca: Gastropoda: Planorbidae) in Japan. AB - Two members of the genus Ferrissia Walker, 1903, namely Ferrissia nipponica (Kuroda, 1949) and F. japonica Habe and Burch, 1965, have been reported to occur in Japan, but due to a lack of molecular data, doubts have been expressed as to their validity. Furthermore, the possible presence of allochthonous Ferrissia taxa has been stated under a variety of names, so that even now there is no consensus on their presence and identity. Recently, freshwater limpets belonging to the planorbid genus Ferrissia were collected in an irrigation trough on the Izu island of Hachijojima, Tokyo, Japan. Molecular identification of the collected specimens, based on a fragment of the large ribosomal subunit 16S (mtDNA), unequivocally proved that they belong to the allochthonous, invasive species Ferrissia californica (Rowell, 1863), the protagonist of a relentless cryptic invasion worldwide to which can Japan can now be added. The shells of the collected specimens show some scars, which bear testimony to the fragile nature of the shell and, possibly, to the paucity of calcium in the inland waters of Hachijojima. PMID- 29623789 TI - Light Microscopy of Development of the Olfactory Organ of European Weatherfish Misgurnus fossilis (Teleostei: Cobitidae). AB - We studied the formation of the olfactory organ of European weatherfish Misgurnus fossilis (Linnaeus, 1758) from the formation of its placodes to the formation of lamellae using light microscopy. The aim of the present investigation was to determine which morphogenetic features of the olfactory organ ate associated with the demersal lifestyle. The olfactory organ of European weatherfish goes through such developmental stages as olfactory placode, olfactory pit, and olfactory chamber with lamellae. Formation of the olfactory pit occurs in prolarvae, but a considerable increase in size takes place during the switch to exogenous feeding. In late larva, lamellae are formed in the aboral part olfactory chamber as an outward fold at its bottom. At the same time, incurrent and excurrent nostrils start being formed as the result of approximation of lateral and medial margins in the rostal part above the olfactory cavity. In contrast to other fishes, the peculiarity of morphogenesis of olfactory organ of M. fossilis is its late formation followed by intensive postembryonic development. PMID- 29623790 TI - Molecular Phylogeny Demonstrates the Need for Taxonomic Reconsideration of Species Diversity of the Hydrocoral Genus Millepora (Cnidaria: Hydrozoa) in the Pacific. AB - Millepora (Cnidaria: Hydrozoa: Milleporidae) spp. are distributed throughout shallow subtropical and tropical marine environments in the Indo-Pacific and Caribbean-Atlantic, and have traditionally been identified using pore characteristics and colony form. Until now, representatives of Millepora spp. on the island of Okinawa-jima, Japan, have been divided into five species; three branching species (Millepora intricata, M. tenera, M. dichotoma), one species with plate-like morphology (M. platyphylla), and one encrusting species (M. exaesa). There have been only a few reports from the Indo-Pacific that have studied the genetic diversity within Millepora spp., although phylogenetic analyses in the Caribbean-Atlantic have proven useful in delimiting closely related species, while demonstrating that morphologically-based identification systems may have problems. In the present study, we sought to clarify taxonomic confusion of Millepora spp. in the Pacific by using sequence data of the ribosomal internal transcribed spacer (ITS-rDNA) of specimens from Okinawa, Japan and other localities (Johnston Atoll, Great Barrier Reef). Four separate clades were recovered from the ITS-rDNA analyses. Although we examined specimens of all three branching Millepora spp. previously reported from Okinawa-jima Island, in our phylogenetic analyses they were concentrated within a single clade, with only three specimens in other clades. Encrusting Millepora specimens were found within all clades, although it should be noted all species initially start as encrusting forms, and plate-like specimens were found within three clades. Our data also point to the existence of a previously unknown lineage within Millepora characterized by its ability to overgrow live scleractinian corals. PMID- 29623791 TI - First Detailed Record of Symbiosis Between a Sea Anemone and Homoscleromorph Sponge, With a Description of Tempuractis rinkai gen. et sp. nov. (Cnidaria: Anthozoa: Actiniaria: Edwardsiidae). AB - A new species in a new genus of sea anemone, Tempuractis rinkai gen. et sp. nov., was discovered at several localities along the temperate rocky shores of Japan. The new species is approximately 4 mm in length and has been assigned to family Edwardsiidae, because it has eight macrocnemes, lacks sphincter and basal muscles, and possesses rounded aboral end. The sea anemone, however, also has a peculiar body shape unlike that of any other known taxa. This new species resembles some genera, especially Drillactis and Nematostella, in smooth column surface without nemathybomes or tenaculi, but is distinguishable from them by several morphological features: the presence of holotrichs and absence of nematosomes. Furthermore, this edwardsiid species exhibits a peculiar symbiotic ecology with sponges. Therefore, a new genus, Tempuractis, is proposed for this species. In the field, T. rinkai sp. nov. was always found living inside homosclerophorid sponge of the genus Oscarella, which suggests a possible obligate symbiosis between Porifera and Actiniaria. The benefit of this symbiosis is discussed on the basis of observations of live specimens, both in the aquarium and field. This is the first report of symbiosis between a sea anemone and a homoscleromorph sponge. PMID- 29623792 TI - A Unique Seminal Plasma Protein, Zona Pellucida 3-Like Protein, has Ca2+ Dependent Sperm Agglutination Activity. AB - Identification of seminal proteins provides a means of investigating their roles. Despite their importance in the study of protein function, such as regulation of sperm motility, it is difficult to select candidates from the large number of proteins. Analyzing the rate of molecular evolution is a useful strategy for selecting candidates, and expressing the protein allows the examination of its function. In the present study, we investigated seminal plasma proteins of the cichlid Oreochromis mossambicus, which exhibits a unique mode of fertilization and a rapidly evolving gene that encodes a seminal plasma protein, zona-pellucida 3-like (ZP3-like), which does not belong to the same molecular family as other ZPs. Seminal plasma proteins of O. mossambicus were separated by two-dimensional electrophoresis, and 19 major proteins were identified by mass spectrometry (MALDI-Tof Mass). Because proteins that are under positive selection often impact sperm function, the rates of molecular evolution of these proteins were analyzed in terms of non-synonymous/synonymous substitutions (omega). Among the 19 proteins, positive selection was supported for five genes; functional assays were carried out on four of the proteins encoded by these genes. Of the four positively selected proteins, only ZP3-like protein agglutinated sperm in a dose- and Ca2+ -dependent manner. The other three proteins did not affect sperm motility. Because of the unique fertilization type, in which fertilization occurs in the buccal cavity, the need to retain sperm within the cavity during spawning, and the agglutination of sperm, which may be partly assisted by ZP3-like protein, may contribute to fertilization success. Fertilization in the buccal cavity may be related to its rapid molecular evolution. PMID- 29623793 TI - There's a Freedom in Accepting Self as Carbon. PMID- 29623795 TI - On Being: Podcasts to Explore. PMID- 29623794 TI - Examination of Spiritual Needs in Hurricane Sandy Disaster Recovery Through Clinical Pastoral Education Verbatims. AB - Objectives Spiritual support is an essential component to disaster response and recovery. The goals of this study were to (a) provide a qualitative examination of spiritual needs of recipients of disaster relief after Hurricane Sandy, as observed by spiritual care interns in "verbatims"; (b) demonstrate the feasibility of conducting research with providers of disaster spiritual care. Methods The study was accomplished through analysis (including codebook development and transcript coding) of written pastoral reports-aka "verbatims" ( n = 18)-as well as audio-recorded, transcribed seminars ( n = 23). Clinical Pastoral Education verbatims offer qualitative data in the form of confidential, anonymous reports of what the students do in the field. Results Analysis of coded transcripts yielded several themes and subthemes as results. Significance of Results Major themes include: (a) the feasibility of research for CPE students as subject; (b) the discussion of magnitude of the storm and aftermath, as a spiritual need in disaster; PMID- 29623797 TI - Transforming Chaplaincy Requires Transforming Clinical Pastoral Education. AB - Clinical Pastoral Education (CPE) is a process focused on developing students' personal integration. Outcomes for CPE need to expand to reflect current research in religion and spirituality because religion and spirituality impacts coping, meaning making, decision-making, and health care outcomes. Focusing CPE outcomes on religious/spiritual beliefs and practices used by patients will equip chaplains to provide research-informed spiritual care for families and discipline specific information for the interdisciplinary team. PMID- 29623798 TI - The Art of Response Post Hurricane Maria. PMID- 29623799 TI - Voice of the Clergy Wife: A Phenomenological Study. AB - The clergy wife is an understudied and silenced population. While the minister himself is well represented in the literature concerning burnout, psychological distress, and diminishing years of service, his wife remains unheard and desperate for her needs to be understood and addressed. The lived experience of nine Wesleyan pastors' wives was investigated using a qualitative methodology and phenomenological approach. Themes arose surrounding both protective factors (faith, calling, support) and stressors (performance expectations and loss of identity, loneliness, low income, sacrifice of time). The theoretical underpinnings of Kanter's (1977) Work-Family Agenda are applied in relation to the occupation of one family member affecting the entire family system. Kanter claims work and family as mutually exclusive entities is a myth. Her framework, including five concepts (rewards/resources, absorption, time/timing, occupational cultures/worldview, emotional climate), allowed for exploration of the results. Interestingly, the stressors in the role of pastor's wife far outweighed the protective factors; yet, clergy wives remain positive and even willing to continue apparent hardships. This is discussed and future research is suggested. PMID- 29623800 TI - Heraclitus, Heisenberg, and Spiritual Care. PMID- 29623802 TI - Spiritual Counseling Program For Children with Anxiety Disorders: A multi-city experiment. AB - This article reports on a multi-city two-year long experiment on the effect of a spiritual counseling program (SCP) on children diagnosed with anxiety disorders. The two-year customized SCP was conducted with 1238 children from 20 private schools in five cities across five countries, with an equal number in a control group. Results showed that post-treatment self-reported and counselor-tested anxiety outcome measure scores were lower for the treatment group. Girls, children from more affluent cities, middle-class children, and those who had one stay-at-home parent and no siblings showed reduced anxiety disorders post treatment. Children who voluntarily attended more SCP rounds than those prescribed and those who regularly self-practiced also showed lower anxiety symptoms post-treatment. Child-focused spiritual counseling intervention comprising components of connection with God within, recognizing and annihilating fear through introspection and breath control, stilling, centering, and consciousness seemed effective. Socio-cultural factors, parental involvement, and child's own engagement with the treatment were significant determinants of effectiveness. PMID- 29623803 TI - TED Talks: Learning Through Podcasts. PMID- 29623804 TI - The Journal of Pastoral Care & Counseling Quiz: (Continuing Education Quiz). PMID- 29623805 TI - For Caregivers of Children with Cancer And All Those Who Catch Falling Stars. PMID- 29623806 TI - Cancer Storytelling: A Study of Well-Being Expressions Made by Patients. AB - Many cancer patients tell their story to help others. This paper reports a study of 160 such stories, which were processed using a grounded theory methodology. The stories were rich in emotional words and in metaphors and these, along with self-talk and meaning-for-life, provided the commonest indications of the patients' well-being. Cancer patients, through the process of telling their story, help themselves and enhance their well-being. The method of active listening is described, with associated risks for professionals. PMID- 29623807 TI - Chance Encounters: Rap Music as a Relational and Pedagogical Resource in Clinical Pastoral Education. AB - Music has long been regarded as a valuable tool for educators. Over the last three decades, rap music has grown to become a global phenomenon. However, due to historical and cultural factors, rap music is often underutilized in Clinical Pastoral Education. This article discusses the social significance of rap music, highlights how rap music informed my supervision of a clinical pastoral education student, and examines Chance the Rapper's mixtape Coloring Book as a case study on the utilization of rap music as a relational and pedagogical resource in spiritual education. PMID- 29623808 TI - Alternative Medicine in North America: A Christian Pastoral Response. AB - Complementary and Alternative Medicine is popular among North Americans. However, there are many areas of concern, both scientific and spiritual, about its appropriate use. Those involved in pastoral care may be consulted for advice and therefore should be knowledgeable about Complementary and Alternative Medicine. This paper reviews and evaluates it from a Christian perspective, and offers suggestions for a pastoral response. PMID- 29623809 TI - Participation in active play of children who use lower extremity prostheses: An exploratory questionnaire. AB - BACKGROUND: Through play, children develop motor, cognitive, social, and other life skills. Play barriers can impede physical and psychosocial benefits. OBJECTIVES: We describe participation in active play, fundamental movement skills, play environment characteristics, and potential play barriers for school aged children (6-12 years) who use lower extremity prostheses. STUDY DESIGN: Cross-sectional questionnaire study. METHODS: A questionnaire was developed and administered online to parents of children 6-12 years who use lower extremity prostheses. Questions focused on children's valued play activities, participation in active play, fundamental movement skills, body positions for play, and characteristics of play environments. RESULTS: Parents (n = 26) reported their children who use lower extremity prostheses participated in a range of activities including active play (e.g. playgrounds, swimming). Fundamental movement skill limitations were identified (e.g. walking long distances, running fast, hopping on one foot, and skipping). Mobility limitations with floor positions, movement transitions, and uneven or sloped surfaces were reported. Active play with equipment such as roller skating, climbing structures, and bicycling presented challenges. CONCLUSION: Parents of children who use lower extremity prostheses reported participation restrictions associated with mobility limitations, activity type, and built environment characteristics (e.g. surfaces and equipment). Challenges made it difficult for children who use lower extremity prostheses to keep up with peers in schools and communities. Clinical relevance Understanding potential barriers to participation in active play of children who use lower extremity prostheses may contribute to enhanced prosthetic design, rehabilitation strategies, universal design of play and built environments, and improved outcome measures ultimately enabling these children to participate fully in active play in diverse contexts. PMID- 29623810 TI - Step count accuracy of StepWatch and FitBit OneTM among individuals with a unilateral transtibial amputation. AB - BACKGROUND: Step counts, obtained via activity monitors, provide insight into activity level in the free-living environment. Accuracy assessments of activity monitors are limited among individuals with lower-limb amputations. OBJECTIVES: (1) To evaluate the step count accuracy of both monitors during forward-linear and complex walking and (2) compare monitor step counts in the free-living environment. STUDY DESIGN: Cross-sectional study. METHODS: Adult prosthetic users with a unilateral transtibial amputation were equipped with StepWatch and FitBit OneTM. Participants completed an in-clinic evaluation to evaluate each monitor's step count accuracy during forward linear and complex walking followed by a 7-day step count evaluation in the free-living environment. RESULTS: Both monitors showed excellent accuracy during forward, linear walking (intraclass correlation coefficients = 0.97-0.99, 95% confidence interval = 0.93-0.99; percentage error = 4.3%-6.2%). During complex walking, percentage errors were higher (13.0%-15.5%), intraclass correlation coefficients were 0.88-0.90, and 95% confidence intervals were 0.69-0.96. In the free-living environment, the absolute percentage difference between monitor counts was 25.4%, but the counts had a nearly perfect linear relationship. CONCLUSION: Both monitors accurately counted steps during forward linear walking. StepWatch appears to be more accurate than FitBit during complex walking but a larger sample size may confirm these findings. FitBit consistently counted fewer steps than StepWatch during free-living walking. Clinical relevance The StepWatch and FitBit are acceptable tools for assessing forward, linear walking for individuals with transtibial amputation. Given the results' consistenty in the free-living enviorment, both tools may ultimiately be able to be used to count steps in the real world, but more research is needed to confirm these findings. PMID- 29623811 TI - Assessment of the compressive and tensile mechanical properties of materials used in the Jaipur Foot prosthesis. AB - BACKGROUND: Designed by Dr. Sethi, the Jaipur Foot prosthesis is ideally suited for amputees in developing countries as it utilizes locally sourced, biodegradable, inexpensive materials and is focused on affordability and functionality. To date, however, no data have been reported on the material properties of the foot components. OBJECTIVES: The goal of this work was to evaluate mechanical properties of the Jaipur Foot components to guide foot design and manufacturing and reduce weight. STUDY DESIGN: Experimental. METHODS: Mechanical testing was conducted on two types of woods (ardu and cheed), microcellular rubber, tire cord, cushion compound, tread compound, and skin colored rubber. Each material was subjected to testing in either tension or compression based on its location and function in the foot. Samples were tested before and after vulcanization. Two-sample t-tests were used to assess statistical differences. RESULTS: Cheed compressed perpendicular to the grain had a significantly higher modulus of elasticity than ardu ( p < 0.05); however, cheed had a higher density. Vulcanization significantly increased the modulus of skin-colored rubber, cushion compound, and tread compound ( p < 0.05) and decreased the moduli of both microcellular rubber and tire cord ( p < 0.05). CONCLUSION: The material property results from this study provide information for computer modeling to assess material construction on overall foot mechanics for design optimization. Ardu wood was ideal based on the desire to reduce weight, and the tire cord properties serve well to hold the foot together. Clinical relevance With new knowledge on the material properties of the components of the Jaipur Foot, future design modifications and standardized fabrication can be realized, making the Jaipur Foot more available on a global scale. PMID- 29623812 TI - The efficacy of the Ankle Mimicking Prosthetic Foot prototype 4.0 during walking: Physiological determinants. AB - BACKGROUND: Evaluating the effectiveness of a novel prosthetic device during walking is an important step in product development. OBJECTIVE: To investigate the efficacy of a novel quasi-passive ankle prosthetic device, Ankle Mimicking Prosthetic Foot 4.0, during walking at different speeds, using physiological determinants in transtibial and transfemoral amputees. STUDY DESIGN: Nonrandomized crossover design for amputees. METHODS: Six able-bodied subjects, six unilateral transtibial amputees, and six unilateral transfemoral amputees underwent a 6-min walk test at normal speed, followed by series of 2-min walking at slow, normal, and fast speeds. The intensity of effort and subjective measures were determined. Amputees performed all walking tests on a treadmill with current and novel prostheses. Shapiro-Wilk normality tests and parametric and nonparametric tests were conducted (p < 0.05). RESULTS: Compared to able-bodied individuals, the rating of perceived exertion levels were significantly elevated in transtibial and transfemoral amputees for both prostheses (p <= 0.016). Compared to able-bodied individuals transfemoral amputees also showed significantly elevated heart rate for both prostheses at normal speed (p <= 0.043). Within-group comparisons demonstrated that walking with Ankle Mimicking Prosthetic Foot significantly increased the heart rate in transfemoral amputees and transtibial compared to current prosthesis (p = 0.002). Furthermore, transfemoral amputees reached a significantly higher rating of perceived exertion levels. CONCLUSION: Intensity of effort during walking with Ankle Mimicking Prosthetic Foot is higher compared to current prostheses. Clinical relevance Ankle Mimicking Prosthetic Foot 4.0 is a novel quasi-passive ankle prosthesis with state-of-the-art technological parts. Subjective measures show the importance of this technology, but the intensity of effort during walking still remains higher compared to current passive prostheses, especially in transfemoral amputees. PMID- 29623813 TI - Analysis of erythrocyte membrane proteins in patients with hereditary spherocytosis and other types of haemolytic anaemia. AB - OBJECTIVES: In order to investigate the pathophysiology of erythrocyte membrane proteins, 10 patients (6 pre- and 4 post-splenectomy) with hereditary spherocytosis (HS) and other patients with haemolytic anaemia were examined. METHODS: The membrane proteins were analysed by biochemical and mass spectrometry. RESULTS: Reductions in the extracellular membrane of band 3 protein by eosin-5'-maleimide (EMA) binding test were greater in patients with pre splenectomy HS than in patients with post-splenectomy HS, other types of haemolytic anaemia, and controls. Compared to patients with haemolytic anaemia and healthy controls, the band 3 protein of patients with HS pre- or post splenectomy was more easily decomposed with N-glycosidase F and by mass spectrometry interactions with degraded low-molecular-weight spectrin and ankyrin. The resulting fragments were observed more frequently in pre-splenectomy than post-splenectomy HS. Haemoglobin-derived peptides were present in patients with haemoglobinopathy (Hb Evans, Hb Sabine) but not in those with haemolytic anaemia and healthy controls. CONCLUSION: Haemolysis in patients with HS occurred because the fragile proteins in erythrocytes (band 3, spectrin, and ankyrin) collapsed due to compression during blood circulation in the spleen. Further, haemolysis in patients with haemoglobinopathy occurred owing to membrane damage due to combined spectrin, band 3 with denatured haemoglobin in the vessel during blood circulation. PMID- 29623814 TI - Expanding opportunities to educate and deliver HIV pre-exposure prophylaxis training for gay, bisexual and other men who have sex with men. PMID- 29623815 TI - Urban farming: an innovative intervention to enhance engagement in HIV care. PMID- 29623816 TI - Who should be tested for syphilis? Rationalising syphilis screening in sexual health clinics. PMID- 29623817 TI - Restless legs syndrome in patients infected with Helicobacter pylori. AB - Objective Although the etiology of restless legs syndrome (RLS) is yet to be discovered, some studies have mentioned the effect of infectious diseases in occurrence of RLS. This study aims to determine the association between common Helicobacter pylori (H. pylori) infection and occurrence of RLS. Methods In this descriptive analytical cross-sectional study, patients with RLS who were referred to the Internal Medicine Clinic of Fayazbakhsh Hospital in Tehran from September to December 2016 were evaluated. Patients with underlying diseases that would lead to secondary RLS were excluded from the study. The control group were matched with the patients group regarding their age and gender, but did not have RLS or diseases that would lead to secondary RLS. All participants underwent serologic tests for evaluating serum levels of IgA and IgG antibodies against H. pylori. Data were analyzed using Chi-Square test and Logistic Regression with SPSS Software Version 20. The significance level was <=0.05. Results Fifty-seven RLS patients and 64 healthy controls were included in the study. In the RLS group, 36 participants (29.8%) had H. pylori infection. This number was 27 participants (22.3%) in the control group. Data analysis using logistic regression showed a significant relation between H. pylori and occurrence of RLS (p value <= 0.05). Conclusions Results of the present study indicated that infection with H. pylori is related with the occurrence of RLS. It seems that releasing inflammatory factors, iron deficiency, and small intestinal bacterial overgrowth are some of the involved mechanisms in this pathogenesis. PMID- 29623818 TI - Midwest Nursing Research Society News. PMID- 29623819 TI - Register-Based Ecologic Evaluation of Safety Signals Related to Pneumococcal Conjugate Vaccine in Children. AB - BACKGROUND: In clinical trials of Pneumococcal Conjugate Vaccines (PCV), some adverse events have been reported more frequently in the PCV vaccinated. Ten valent PCV (PCV10) was introduced into the Finnish National Vaccination Programme (NVP) in September 2010. OBJECTIVE: We conducted an ecologic register-based study to investigate further the reported adverse events after PCV. METHODS: This study included data obtained from the Finnish nationwide, population-based registers. First diagnoses of febrile seizures, breath-holding, urticarial rash, asthma and Kawasaki's disease were included as outcomes obtained from the hospital discharge register. Data from Finnish Population Register during 2000-2014 for children age from 3 months to 10 years were used to estimate annual incidence rates. Incidence rate ratios of the outcomes were calculated between the target cohort of children eligible for PCV10 during 2010-2014 and a reference cohort before the NVP introduction (2004-2008). RESULTS: No increases in the incidence of the adverse events after PCV10 introduction were found except for urticarial rash (incidence rate 2.48 vs. 1.60/1000 pyrs; incidence rate ratio, 1.54;95% CI 1.42-1.67). This increase was seen also in the unvaccinated older age groups in the post vaccination era. The higher incidence of urticarial rash after the PCV10 introduction was due to the inclusion of diagnoses made in general medicine specialty in the discharge register because of a concomitant administrative change. CONCLUSION: The results do not support public health concerns related to the previously reported adverse events. Concomitant changes in health care administration and coding introduced bias, which was controlled after further evaluation of the data. We consider this register-based approach with realworld data feasible in the signal validation process after any signal detection. PMID- 29623820 TI - Chickpea Lectin Inhibits Human Breast Cancer Cell Proliferation and Induces Apoptosis Through Cell Cycle Arrest. AB - BACKGROUND: Breast cancer demands safe adjuvant to overcome the side effects of standard drug tamoxifen. Diet derived bioactive compounds are reported to exhibit modulation of cancer growth leading to cell death. Chickpea is a protein rich edible legume with several bioactive compounds that includes lectin as well. Characterization of chickpea lectin for its effect against cancer cells has been investigated in this study. METHOD: Cicer arietinum L. lectin (CAL) agglutinating trypsin-treated rabbit blood cells was purified employing DEAE-cellulose and SP sephadex ion exchange chromatography. The lectin was characterized for its biological activity vis-a-vis antiproliferative and apoptotic effects through cell cycle arrest in MCF-7 human breast cancer cells. RESULT: There is a significant inhibition of the survival of breast cancer cells due to chickpea lectin in a dose dependent manner for 24 hr. Lectin treated cells revealed distinct features of apoptosis. Flow cytometric analysis at 80 ug/ml of lectin induced S and G2 phase cell cycle arrest. CAL induced apoptosis in MCF-7 cells associated with lactate dehydrogenase leakage, cell cycle arrest and reactive oxygen species generation. CONCLUSION: Our studies show that chickpea lectin exerted anticancer activity and could be exploited as an essential source for medicine leading to the treatment of breast cancer. PMID- 29623821 TI - Long-term Effects of Lysine Restriction on Liver Global Proteins, Meat Quality, and Blood Biochemical Parameters in Pigs. AB - BACKGROUND: Our previous study suggested that short-term lysine restriction improved feed intake and gut microbiota in piglets. Thus, in this study, we further used proteomics technology to investigate the potential mechanism associated with long-term lysine restriction in pigs. In addition, blood biochemical parameters, meat quality, and muscle nutrient transporters were also evaluated in lysine restricted pigs. RESULTS: The results showed that 131 proteins in the liver were markedly altered in response to dietary lysine restriction, with 54 being downregulated and 77 being upregulated, which mainly involved in neurodegenerative diseases, oxidative phosphorylation, and metabolic pathways. In addition, lysine restriction markedly reduced serum BUN, CHOL, and HDL abundances. Dietary lysine restriction enhanced meat color lightness and upregulated SLC7A2 expression. CONCLUSION: Lysine restriction affected meat quality, blood biochemical parameters, and liver global protein expressions. This study is the first attempt to evaluate the liver protein profile of lysine restricted pigs, and the current results may provide valuable information with respect to better understanding the host response to lysine restriction in pigs. PMID- 29623822 TI - Mass Spectrometric Analysis of Proteins of L6 Skeletal Muscle Cells Under Different Glucose Conditions and Vitamin D Supplementation. AB - BACKGROUND: Type 2 Diabetes (T2D) is a metabolic disease which affects glucose homeostasis caused due to inability of the target cells to respond to insulin. Role of vitamin D in the pathogenesis and prevention of T2D has sparked widespread interest. Vitamin D plays a classical role in Ca++ homeostasis as well as regulates insulin secretion from beta-cells and its action on various target cells. Proteins are the vital components of all cellular processes and their expression alters in response to various external or internal stimuli. Alteration in protein structure, function may contribute to the pathogenesis of many diseases including diabetes. Protein expression during the exposure of the cells to different glucose concentrations may alter and can give vital information about the pathogenesis of T2D. OBJECTIVE: To study the effect of different glucose concentrations and supplementation of vitamin D on proteomic profile of L6 cell lines. METHOD: L6 skeletal muscle cells were exposed to different Glucose (G) concentrations (0mM, 8mM, 16mM and 25mM) supplemented with Vitamin D (VD) for 48 hours. Total cell protein was extracted and protein profile was studied using SDS-PAGE. Three distinct bands observed in SDSPAGE in samples obtained from cells which were exposed to 8mM (G), 8mM (G) + VD and 16mM (G). The distinct bands were excised, in gel digestion were performed and MALDI-TOF analysis of the samples were done. RESULTS: MALDI-TOF analysis revealed these bands as mitochondrial uncoupling protein 3 (UCP3 MOUSE), Insulin gene enhancer protein 2 (ISL2 MOUSE) and Tubulin polyglutamylase complex1 (TPGS1 MOUSE) respectively. UCP3 protein is primarily expressed in the skeletal muscle cells and is involved in energy homeostasis and modulates insulin sensitivity. ISL2 protein plays an important role in differentiation and maintenance of the tissues. TPGS1 helps in microtubule polymerization might be helping in glucose transport and also play crucial role in the cellular movement, organization of intracellular structure, and intracellular transport. CONCLUSION: These identified proteins may provide information about disease pathophysiology and can serve as potential targets for therapeutic intervention of T2D. Further studies on the changes of protein expression under high glucose concentration and supplementation with vitamin D will lead to better understanding of the molecular mechanisms of T2D. PMID- 29623823 TI - Low 25 Hydroxyvitamin D Levels are Independently Associated with Autoimmune Thyroiditis in a Cohort of Apparently Healthy Overweight and Obese Subjects. AB - BACKGROUND: Low vitamin D levels have been associated with autoimmune disorders and, then, with the Hashimoto's autoimmune thyroiditis (AT), the most common autoimmune disease. Obesity is characterized by lower vitamin D levels and higher risk to develop autoimmune diseases. The aim of the study was to examine the possibility of an association between AT and decreased 25(OH) vitamin D (25(OH)D) levels in a cohort of otherwise healthy overweight and obese subjects. MATERIALS AND METHODS: Two hundred sixty one overweight subjects (mean age: 40.9 + 15.6 years, 200 women and 61 men) were enrolled for this study. All of them did not show any clinically evident metabolic or chronic diseases (i.e. hypertension, diabetes mellitus, renal failure, etc.) and did not use any kind of drug. Serum fasting levels of 25(OH)D, anti-thyroid peroxidase (TPO-Ab) and antithyroglobulin (TG-Ab) antibodies, free triiodothyronine (FT3), free thyroxine (FT4), thyroid stimulating hormone (TSH), glucose, uric acid and lipids (triglycerides, total, HDL and LDL cholesterol) were measured. Demographic, anthropometric and clinical parameters (age, body mass index (BMI), waist circumference, blood pressure) were also assessed. RESULTS: Fifty five percent of all subjects (144/261) showed vitamin D deficiency (<= 20 ng/ml), and 17% of all individuals had AT (45/261). The percentage of subjects having vitamin D deficiency was significantly higher among those with AT (31 of 45, 69%) than in those without AT (113 of 216, 52%) (chi2= 4.1, p = 0.042). TSH levels were significantly higher in subjects with AT as compared to those without AT (M-W = 7715.5, p < 0.0001). The final logistic model of a multivariate analysis, performed with AT as the dependent variable and sex, age, BMI category, 25(OH)D category, and HDLcholesterol and TSH levels as the independent ones, showed that patients with AT were more likely to have deficiency of 25(OH)D (p = 0.031) and higher TSH (p < 0.005) levels. Seventy six percent of patients with vitamin D deficiency (110 of 144) were obese whereas 59% of patients without vitamin D deficiency were obese (69 of 117) (p=0.003). Waist circumference was different between subjects with deficiency or normal 25 (OH) D levels (p=0.016). CONCLUSION: This study clearly shows that vitamin D deficiency is significantly associated to AT in overweight and obese subjects and confirms that obesity is associated to lower vitamin D circulating levels. We suggest that screening for AT should be suggested in all obese subjects with vitamin D deficiency and that vitamin D deficiency should be researched in all obese subjects with AT. PMID- 29623824 TI - The Design of New HIV-IN Tethered Bifunctional Inhibitors using Multiple Microdomain Targeted Docking. AB - Currently used antiretroviral HIV therapy drugs exclusively target critical groups in the enzymes essential for the viral life cycle. Increased mutagenesis of their genes, changes these viral enzymes which once mutated can evade therapeutic targeting, effects which confer drug resistance. To circumvent this, our review addresses a strategy to design and derive HIV-Integrase (HIV-IN) inhibitors which simultaneously target two IN functional domains, rendering it inactive even if the enzyme accumulates many mutations. First we review the enzymatic role of IN to insert the copied viral DNA into a chromosome of the host T lymphocyte, highlighting its main functional and structural features to be subjected to inhibitory action. From a functional and structural perspective we present all classes of HIV-IN inhibitors with their most representative candidates. For each chosen compound we also explain its mechanism of IN inhibition. We use the recently resolved cryo EM IN tetramer intasome DNA complex [1] onto which we dock various reference IN inhibitory chemical scaffolds such as to target adjacent functional IN domains. Pairing compounds with complementary activity, which dock in the vicinity of a IN structural microdomain, we design bifunctional new drugs which may not only be more resilient to IN mutations but also may be more potent inhibitors than their original counterparts. In the end of our review we propose synthesis pathways to link such paired compounds with enhanced synergistic IN inhibitory effects. PMID- 29623825 TI - Functional neuroimaging biomarkers in migraine: diagnostic, prognostic and therapeutic implications. AB - INTRODUCTION: in current migraine clinical practice conventional neuroimaging examinations are often sought to exclude possible causes of secondary headaches or migraine-associated disorders. Contrariwise, although advanced magnetic resonance imaging (MRI) has improved tremendously our understanding of human brain processes in migraine patients, to the state of the art they have not superseded the conventional neuroimaging techniques in the migraine clinical setting. METHODS: a comprehensive review was conducted of PubMed citations by entering the key word "marker" AND/OR "biomarker" combined with "migraine" AND/OR "headache." Other key words included "imaging" OR "neuroimaging", "structural" OR "functional". The only restriction was English-language publication. The abstracts of all articles meeting these criteria were reviewed, and full text was retrieved and examined for relevant references. RESULTS: several authors tried to identify imaging biomarkers able to identify different migraine phenotypes or, even better, to follow-up the same migraine patients during the course of the disease, to predict the evolution into more severe phenotypes and, finally, the response to specific treatment. CONCLUSIONS: the identification of diagnostic, prognostic and therapeutic advanced neuroimaging biomarkers in the migraine clinical setting, in order to approach to patients in a more and more rational and "tailored" way, is extremely intriguing and futuristic. Unfortunately, reliable and robust neuroimaging biomarkers are still lacking for migraine, probably due to both not completely understood pathogenesis and clinical and neuroimaging heterogeneity. Although further longitudinal advanced neuroimaging studies, aimed to identify effective neuroimaging biomarkers, are needed, this review aims to collect the main and most recent works on this topic. PMID- 29623826 TI - Targeting AMPK in Diabetes and Diabetic Complications: Energy homeostasis, Autophagy and Mitochondrial health. AB - Adenosine 5'-monophosphate activated protein kinase (AMPK) is a key enzymatic protein involved in linking the energy sensing to the metabolic manipulation. It is a serine/threonine kinase activated by several upstream kinases. AMPK is a heterotrimeric protein complex regulated by AMP, ADP, and ATP allosterically. AMPK is ubiquitously expressed in various tissues of the living system such as heart, kidney, liver, brain and skeletal muscles. Thus malfunctioning of AMPK is expected to harbor several human pathologies especially diseases associated with metabolic and mitochondrial dysfunction. AMPK activators including synthetic derivatives and several natural products that have been found to show therapeutic relief in several animal models of disease. AMP, 5-Aminoimidazole-4-carboxamide riboside (AICA riboside) and A769662 are important activators of AMPK which have potential therapeutic importance in diabetes and diabetic complications. AMPK modulation has shown beneficial effects against diabetes, cardiovascular complications and diabetic neuropathy. The major impact of AMPK modulation ensures healthy functioning of mitochondria and energy homeostasis in addition to maintaining a strict check on inflammatory processes, autophagy and apoptosis. Structural studies on AMP and AICAR suggest that the free amino group is imperative for AMPK stimulation. A769662, a non-nucleoside thienopyridone compound which resulted from the lead optimization studies on A-592107 and several other related compounds are reported to exhibit promising effect on diabetes and its complications through activation of AMPK. Subsequent to the discovery of A769662, several thienopyridones, hydroxybiphenyls pyrrolopyridones have been reported as AMPK modulators. The review will explore the structure function relationships of these analogues and the prospect of targeting AMPK in diabetes and diabetic complications. PMID- 29623827 TI - Comparative Assay of 2D and 3D Cell Culture Models: Proliferation, Gene Expression and Anticancer Drug Response. AB - BACKGROUND: In vitro tests allow establishing experimental variables. However, in vitro results cannot be extrapolated to in vivo tests. Considering that three dimensional (3D) culture has been one of the best ways to portray the in vivo system of most cell types, it is possible to carry out assays with a great clinical relevance for the analysis of the screening, action and resistance of antitumor drugs. OBJECTIVE: Thus, the objective of the present study was to compare between 2D and 3D cell culture forms to conclude which is the most suitable model for preclinical in vitro drug testing. METHOD: We evaluated the proliferation, genetic expression and chemoresistance of prostate tumor cell lines, PC- 3, LNCaP and DU145. Prostate tumor cell lines PC-3, LNCaP and DU145 were treated with the antineoplastic drugs paclitaxel and docetaxel and evaluated with cytotoxicity, cell proliferation and gene expression assays in 2D and magnetic 3D bioprinting cultures. RESULTS: Lower cell proliferation rate, more resistance to paclitaxel and docetaxel and altered gene expression profile was shown in 3D cell culture comparing with its 2D counterpart. CONCLUSION: 3D cell culture exhibited a more similar behavior to in vivo systems, being a promising and more reliable tool for the development of new drugs. PMID- 29623828 TI - A Novel Fluorescence-Labeled Curcumin Conjugate: Synthesis, Evaluation and Imaging on Human Cell Lines. AB - Curcumin, as the main ingredient of the curcuma spice, has increasingly become the target of scientific research. The turmeric root where the spice is obtained from has been widely used in the traditional medicine. Moreover, scientific studies have found that curcumin has anti-inflammatory, anti-cancer, anti angiogenic effects as well as antibacterial properties. Recently, curcumin has gathered interest as a potential therapeutic agent in the research on Alzheimer's disease. A consistent problem in the investigative and therapeutic applications of curcumin is its poor solubility in aqueous solutions. In the present study, we synthesized a conjugate of curcumin, the amino acid lysine and the fluorescent dye fluorescein. This conjugate was soluble in cell culture medium and facilitated the examination of curcumin with fluorescence imaging methods. We studied the cell growth impact of unmodified curcumin on seven different human cell lines and then analyzed the uptake and cellular localization of our curcumin conjugate with confocal laser scanning imaging and flow cytometry on the seven cell lines. We found that unbound curcumin inhibited cell growth in vitro and was not taken up into the cells. The curcumin conjugate was internalized into the cell cytoplasm in a dot-like pattern and cellular uptake correlated with the cell membrane damage which was measured using propidium iodide. The CAL-72 osteosarcoma cell exhibited 3-4fold increased conjugate uptake and a strong uniform fluorescein staining in addition to the dot-like pattern observed in all cell lines. In conclusion, we successfully synthesized a novel water-soluble fluorescent curcumin conjugate which showed a strong preference for CAL-72 osteosarcoma cells in vitro. PMID- 29623829 TI - The Potential Mechanisms of Exercise-induced Cognitive Protection: A Literature Review. AB - Dementia has become a major health concern for the aging population of the United States. Studies indicate that participation in moderate exercise, with training, has been shown to have a beneficial impact on cognition. Thus, exercise and its effects on cognitive function has become an important area of research. This review summarizes the current literature on the potential mechanisms of the benefits of exercise for cognitive function. PMID- 29623830 TI - The Effects of Coenzyme Q10 Supplementation on Lipid Profiles Among Patients with Metabolic Diseases: A Systematic Review and Meta-analysis of Randomized Controlled Trials. AB - BACKGROUND AND OBJECTIVE: Oxidative stress and inflammation are key parameters in developing metabolic disorders. Hence, antioxidant intake might be an appropriate approach. Several studies have evaluated the effect of coenzyme Q10 (CoQ10) supplementation on lipid profile among patients with metabolic diseases, though findings are controversial. The aim of this systematic review and meta-analysis was to determine the effects of CoQ10 supplementation on lipid profile in patients with metabolic disorders. METHODS: We searched PubMed, EMBASE, Web of Science and Cochrane Library databases until July 2017. Prospective clinical trials were selected assessing the effect of CoQ10 supplementation on different biomarkers. Two reviewers independently assessed the eligibility of studies, extracted data, and evaluated the risk of bias of included studies. A fixed- or random-effects model was used to pool the data, which expressed as a standardized mean difference with 95% confidence interval. Heterogeneity was measured using a Q-test and with I2 statistics. RESULTS: A total of twenty-one controlled trials (514 patients and 525 controls) were included. The meta-analysis indicated a significant reduction in serum triglycerides levels (SMD -0.28; 95% CI, -0.56, 0.005). CoQ10 supplementation also decreased total-cholesterol (SMD -0.07; 95% CI, -0.45, 0.31), increased LDL- (SMD 0.04; 95% CI, -0.27, 0.36), and HDL cholesterol levels (SMD 0.10; 95% CI, -0.32, 0.51), not statistically significant. CONCLUSION: CoQ10 supplementation may significantly reduce serum triglycerides levels, and help to improve lipid profiles in patients with metabolic disorders. Additional prospective studies are recommended using higher supplementation doses and longer intervention period. PMID- 29623831 TI - Proteomics Approach for Biomarker Research in Major Depression: Antidepressant Effects. AB - BACKGROUND: The proteomics approach is the new mantra in disease biomarker research in areas such as major depression (MD). Current protocols for investigating biomarkers in biological fluid often employ both immuno- based and non-immuno-based technologies. METHOD: The immuno-based method is used normally in measuring well-known disease biomarkers, and commercial kits are often available. Immuno-based methods such as radio-immunoassay and enzyme-linked immunosorbent assay are sensitive and specific. However, tedious sample preparations such as filtration and centrifugation are required. Non-immuno-based technologies, such as matrix-assisted laser desorption/ionization- time of flight mass spectrometry has been proven to be useful techniques to rapidly screen disease biomarkers in human biological fluids. The mass spectrometer provides a powerful research tool in the proteomics field, not only in biomarker discovery but also in biomarker validation. A bioinformation tool like principal component analysis is a statistical procedure that utilizes proteomics data. CONCLUSION: In this article, we review the proteomics approaches in MD biomarker research and the data after the antidepressants treatment. And it covers a selection of advances in the realm of proteomics and its promise for major depression biomarker discovery and antidepressant effects. These technologies have opened new approaches to identifying signaling biomarkers associated with the cellular metabolism, cell life cycle, and detection of disease. PMID- 29623832 TI - Herbs with Potential Nephrotoxic Effects According to the Traditional Persian Medicine: Review and Assessment of Scientific Evidence. AB - BACKGROUND: The increased use of herbal remedies particularly in patients with kidney diseases indicated the importance of studies, which focused on nephrotoxic plants. OBJECTIVE: The present study aimed to review and assess the kidney damaging herbs mentioned in the Persian medicine [PM] books. METHOD: The main PM books were searched for nephrotoxic herbs and their relevant reformers traditionally proposed for preventing renal damage. PubMed, Scopus and Google Scholar were investigated for evaluation of the scientific evidence relating to the nephrotoxicity of herbs. RESULTS: A total of 64 plants with kidney damage potential and their reformer medicaments were recorded in 7 sources included in this review. Allium schoenoprasum and Marrubium vulgare were the most repeated and emphasized nephrotoxic plants in PM books, but there was no relevant scientific evidence. Despite the lack of clinical studies, some evidence was found for 38% of plants that were related to renal damage. The most repeated reformers for reducing the renal side effects mainly consisted of gum tragacanth, gum Arabic, mastic gum, anise, jujube and honey and some evidence was found for their nephroprotective activities. CONCLUSION: The present study reviewed and assessed the herbs with adverse renal effects in the main PM books. Some evidence was in line with the potential nephrotoxicity of plants and their .reformers. Despite the lack of clinical research for evaluation of their renal damage, the herbs may be focused in term of their nephrotoxicity; and there is a need for further studies on the scientific basis of their nephrotoxicity. PMID- 29623833 TI - New Therapeutic Drugs from Bioactive Natural Molecules: The Role of Gut Microbiota Metabolism in Neurodegenerative Diseases. AB - BACKGROUND: The gut-brain axis is considered a neuroendocrine system, which connects the brain and gastrointestinal tract and plays an important role in stress response. The homeostasis of gut-brain axis is important for health conditions and its alterations are associated to neurological disorders and neurodegenerative diseases. METHOD: We selected recent papers analysing the association among alterations in the homeostasis of the gut-brain axis and neurological disorders. In addition, we described how bioactive natural molecules - such as polyphenols - by influencing gut microbiota composition may help rescue neural signalling pathways impaired in neurodegenerative diseases. RESULTS: Recent studies show that gut microbiota is a dynamic ecosystem that can be altered by external factors such as diet composition, antibiotics or xenobiotics. Gut bacterial community plays a key role in maintaining normal brain functions. Metagenomic analyses have elucidated that the relationship between gut and brain, either in normal or in pathological conditions, reflects the existence of a "microbiota-gut-brain" axis. Gut microbiota composition can be influenced by dietary ingestion of probiotics or natural bioactive molecules such as prebiotics and polyphenols. Their derivatives coming from microbiota metabolism can affect both the gut bacterial composition and brain biochemistry. CONCLUSION: This review highlights the role of gut microbiota in regulating regulates brain biochemistry and the role of microbiota metabolites on neuropathologies. Dietary ingestion of probiotics, prebiotics and polyphenols affect gut microbiota composition underlining the key role played by specific metabolites not only in the gut microbiota composition but also in the brain health maintenance. PMID- 29623834 TI - The Molecular Targets of Swertiamarin and its Derivatives Confer Anti- Diabetic and Anti-Hyperlipidemic Effects. AB - The herbal plant extract of Enicostemma littorale is widely used to medicate and treat type II Diabetes. This extract in medicine has shown its value in reducing blood glucose & lipid levels, and improving the kidney functioning, lipid profile, controlling blood pressure and heart rate. The well characterized chemical components such as iridoid and secoiridoid glycosides are present in aqueous and ethanolic extracts of the plant. Swertiamarin, a secoiridoid glycoside, is identified as the lead compound that confers anti-hyperglycemic & anti-hyperlipidemic effects. The swertiamarin binds with one or more molecular targets to alter their expression and/or activity. The in silico, in vivo and in vitro studies have been carried out to uncover the underlying molecular mechanism of action of swertiamarin and its derivatives for showing the better anti diabetic & anti-hyperlipidemic activities. In brief, the present review focuses on unraveling the information about molecular targets of swertiamarin. Our review will open new avenues to develop therapeutic approaches and drugs to treat diabetes and other inflammatory diseases. PMID- 29623835 TI - ApoE4 May be a Promising Target for Treatment of Coronary Heart Disease and Alzheimer's Disease. AB - Alzheimer disease (AD) is most common neurodegenerative disorder of dementia, as we all know that ApoE4 is the greatest genetic risk factor of late-onset Alzheimer's disease (LOAD). Coronary heart disease (CHD) leads to one-fourth of all deaths in industrialized countries, it is reported that ApoE4 increases the risk of coronary heart disease as well. Furthermore, evidence show that coronary heart disease also increases the incidence of Alzheimer's disease. Whether ApoE4 is a bridge connecting AD with CHD or not? And what are the special mechanism and therapeutic methods? Researchers found that cholesterol metabolic disorder is the common cause and risk factor of AD and CHD. Epidemiological studies demonstrate that carriers of the ApoE4 allele have higher cholesterol plasma concentration. More evidence indicate that hypercholesterolemia accelerates the progression of coronary atherosclerosis, damages the central nervous system blood-brain barrier, promotes Abeta protein production and Tau deposition in brain. Therefore, ApoE4 is likely to be the bridge between AD and CHD, and may be a potentially promising therapeutic target. PMID- 29623836 TI - Microbial Biofilm and Quorum Sensing Inhibition: Endowment of Medicinal Plants to Combat Multidrug-Resistant Bacteria. AB - Continued emergence and spread of multidrug-resistant bacteria behooved the development of alternative treatment strategies, including antimicrobial drugs. A hopeful approach is to target cellto- cell communications, commonly known as quorum-sensing (QS) and microbial biofilm formation. Quorum Sensing is a method used on bacteria to determine their physiological behavior and coordinate gene expression based on the cell to cell signaling. Many physiological functions of bacteria are controlled by quorum sensings such as virulence, motility, sporulation, luminescence, and biofilm formation. Microbial biofilms are organized aggregations of cells attached to a substratum and surrounded by a self produced extrapolymeric substance (EPS) matrix. Currently, biofilm formation and quorum sensing are considered as a prospective novel target for antimicrobial therapy to control multidrug- resistant infections. Plant-based natural products have been comprehensively studied in this context. In this review, a comprehensive overview of various research papers published in the last decade on plant-derived molecules that are capable of inhibiting quorum sensing or microbial biofilm formation is reviewed, mentioning the biosynthetic classes of active compounds and their biological activity in the performed assays. PMID- 29623837 TI - New Light on An Old Friend: Targeting PUMA in Radioprotection and Therapy of Cardiovascular and Neurodegenerative Diseases. AB - This review summarizes recent progress in understanding the role of p53 upregulated mediator of apoptosis (PUMA) in molecular pathways with respect to its potential therapeutic applications. Particular emphasis is given to the PUMA's role in ionizing radiation-induced signalling as radiotoxicity of normal tissue is mediated mostly via apoptosis. PUMA and its p53-dependent and p53- independent induction are described and potential use as a new target for the development of radioprotective agents is suggested. Further implications, including targeting PUMA to prevent and treat cardiovascular and neurodegenerative diseases, are also discussed together with an overview of other therapeutic applications. Finally, basic chemical structures for the development of novel PUMA modulators such as pifithrine derivatives, kinase inhibitors or modulators of Bcl-2 protein family are described. PMID- 29623838 TI - MiR-29 Targets PUMA to Suppress Oxygen and Glucose Deprivation/Reperfusion (OGD/R)-induced Cell Death in Hippocampal Neurons. AB - INTRODUCTION: We previously demonstrated that microRNAs (miRNA) play an important role in Hypothermic Circulatory Arrest (DHCA)-associated neural injury. However, the specific role of miRNAs in the pathogenesis of DHCA-induced neuron death is still unclear. MATERIAL AND METHODS: Thus, in the present study, we investigated miR-29 expression and roles in neuronal HT-22 cells with Oxygen-glucose Deprivation/reoxygenation (OGD/R). In this study, the model of OGD/R was established using an airtight culture container and the anaeropack. Measurement of Reactive Oxygen Species (ROS) production and Mitochondrial Membrane Potential (MMP) was done using the probes of JC-1 and H2DCFDA. The microRNA (miRNA) profile in hippocampal neurons from rat model of DHCA was determined by miRNA deep sequencing. RESULTS: We found that the expression of the miR-29 family (miR 29a/b/c) was significantly reduced in model of DHCA and OGD/R. Overexpression of the miR-29 family inhibited the OGD/R-induced elevation of ROS and reduction of MMP in HT-22 cells. In addition, administration of the miR-29 family suppressed proteins of Keap1, Bax and PUMA and increased Nrf2 expression. We further demonstrated that the miR-29 family targeted the PUMA by luciferase reporter assay and Western blot analysis. CONCLUSION: In conclusion, our data suggest that by targeting a pro-apoptotic BCL2 family member PUMA, the miR-29 family might emerge as a strategy for protection against DHCA-mediated neural cell injury. PMID- 29623839 TI - Identifying Patterns in Signs and Symptoms Preceding the Clinical Diagnosis of Alzheimer's Disease: Retrospective Medical Record Review Study and a Nested Case control Design. AB - OBJECTIVE: Evidence suggests that individuals with Alzheimer's disease (AD) are often diagnosed in the later stages of their disease with a poor prognosis. This study is aimed to identify patterns in signs and symptoms preceding the clinical diagnosis of AD to suggest a predictive model for earlier diagnosis of the disease in the primary care. DESIGN: A retrospective medical record review; nested case control design. PARTICIPANTS: Participants included one hundred and nine patients from three general practice (GP) surgeries in Milton Keynes and Luton Clinical Commissioning Groups (CCG) (37 cases with AD and 72 controls without AD). MAIN OUTCOME MEASURE: A retrospective analysis using the logistic regression of the presence of signs and symptoms before the diagnosis of AD was attained. Identification of the timing and sequence of appearance of these presentations as first reported before the clinical diagnosis was measured. RESULT: Episodic memory with an odds ratio of 1.85 was the most frequent presentation, documented in 1.38% of the controls and 75.6% in cases. Auditory disturbance with an odds ratio of 3.03, which has not previously been noted except in the form of auditory hallucination, could have a diagnostic value. CONCLUSION: Auditory disturbance, which occurred mostly in the Caucasian females, could discriminate individuals with AD from those without the disease. The symptom, which presented up to 14.5 (mean time) years prior to clinical diagnosis, was identified in Caucasians and mixed race individuals only. Strengths: The study demonstrates that auditory disturbance could allow an earlier diagnosis of AD in Caucasian females. Episodic memory was confirmed as being frequently noted in AD patients prior to a clinical diagnosis as per previous publications. This study supports the development of a scoring system for the earlier diagnosis of AD. The data used was free from the confounding effects of misinformation, as this was written at the point of collection, thereby benefitting from the use of GP data that is diversified, reliable and valid. LIMITATIONS: Limited sample size that will not allow for generalization of less frequent observations due to their low prevalence in case notes. Randomisation was not achieved; however, the best available nonrandomisation which is consecutive sampling was used. Patterns identified were in LOAD, the baseline could vary with other geographical areas. PMID- 29623840 TI - Fruitless Wolfberry-Sprout Extract Rescued Cognitive Deficits and Attenuated Neuropathology in Alzheimer's Disease Transgenic Mice. AB - BACKGROUND: Alzheimer's disease (AD) is a neurodegenerative disease featured by memory loss, neuroinflammation and oxidative stress. Overproduction or insufficient clearance of Abeta leads to its pathological aggregation and deposition, which is considered the predominant neuropathological hallmark of AD. Therefore, reducing Abeta levels and inhibiting Abeta-induced neurotoxicity are feasible therapeutic strategies for AD treatment. Wolfberry has been traditionally used as a natural antioxidant and anti-aging product. However, whether wolfberry species has therapeutic potential on AD remains unknown. METHOD: The effects of fruitless wolfberry-sprout extract (FWE) on Abeta fibrillation and fibril disaggregation was measured by thioflavin T fluorescence and transmission electron microscope imaging; Abeta oligomer level was determined by dot-blot; Cell viability and apoptosis was assessed by MTT and TUNEL assay. The levels of Abeta40/42, oxidative stress biomarkers and inflammatory cytokines were detected by corresponding kits. 8-month-old male APP/PS1 mice and their age matched WT littermates were treated with FWE or vehicle by oral administration (gavage) once a day for 4 weeks. Then the cognitive performance was determined using object recognition test and Y-maze test. The Abeta burden and gliosis was evaluated by immunostaining and immunoblotting, respectively. RESULTS: FWE significantly inhibited Abeta fibrillation and disaggregated the formed Abeta fibrils, lowered Abeta oligomer level and Abeta-induced neuro-cytotoxicity, and attenuated oxidative stress in vitro. Oral administration of FWE remarkably improved cognitive function, reduced Abeta burden, decreased gliosis and inflammatory cytokines release, and ameliorated oxidative stress in the brains of APP/PS1 mice. CONCLUSION: These findings indicate that FWE is a promising natural agent for AD treatment. PMID- 29623841 TI - Changes in Speech Chunking in Reading Aloud is a Marker of Mild Cognitive Impairment and Mild-to-Moderate Alzheimer's Disease. AB - BACKGROUND: Speech and Language Impairments, generally attributed to lexico semantic deficits, have been documented in Mild Cognitive Impairment (MCI) and Alzheimer's disease (AD). This study investigates the temporal organisation of speech (reflective of speech production planning) in reading aloud in relation to cognitive impairment, particularly working memory and attention deficits in MCI and AD. The discriminative ability of temporal features extracted from a newly designed read speech task is also evaluated for the detection of MCI and AD. METHOD: Sixteen patients with MCI, eighteen patients with mild-to-moderate AD and thirty-six healthy controls (HC) underwent a battery of neuropsychological tests and read a set of sentences varying in cognitive load, probed by manipulating sentence length and syntactic complexity. RESULTS: Our results show that Mild-to Moderate AD is associated with a general slowness of speech, attributed to a higher number of speech chunks, silent pauses and dysfluences, and slower speech and articulation rates. Speech chunking in the context of high cognitive linguistic demand appears to be an informative marker of MCI, specifically related to early deficits in working memory and attention. In addition, Linear Discriminant Analysis shows the ROC AUCs (Areas Under the Receiver Operating Characteristic Curves) of identifying MCI vs. HC, MCI vs. AD and AD vs. HC using these speech characteristics are 0.75, 0.90 and 0.94 respectively. CONCLUSION: The implementation of connected speech-based technologies in clinical and community settings may provide additional information for the early detection of MCI and AD. PMID- 29623842 TI - Platelet Tau Protein as a Potential Peripheral Biomarker in Alzheimer's Disease: An Explorative Study. AB - BACKGROUND: Cerebrospinal fluid (CSF) measures of tau and amyloid proteins have now been largely accepted to be a diagnostic tool to aid the clinical diagnosis of Alzheimer's disease (AD), but CSF is not routinely obtained in most clinical settings. There is a need, therefore, to uncover additional readily accessible peripheral biomarkers that will enable comprehensive detection of AD-specific proteins in blood and blood derivates. OBJECTIVES: Blood platelets contain proteins found in neuronal cell lines, including tau protein. Since tau protein is a characteristic of AD-neuropathology, platelet tau protein may be closely related to the central nervous process occurring in neurodegeneration. METHOD: Platelets from 25 AD and 26 control subjects were analysed for the microtubule binding and C-terminal region, as well as two tau phosphorylation sites (Ser202/Thr205 and Thr181). RESULTS: Tau protein measures did not discriminate between AD and control individuals. However, subjects with MMSE 24-27 had elevated C-terminal end tau protein (p=0.049) compared to those with MMSE >27, whereas older AD subjects (>80 years) showed higher t-tau protein in comparison to younger AD (<80 years; p=0.009) and control (<80 years; p=0.011) participants. CONCLUSIONS: These initial findings not only confirm that platelet tau protein can be measured, but also indicate that platelet tau measures merit further study as they may be useful in indicating early stages of cognitive impairment. Further studies on larger number of participants are needed to confirm our findings. PMID- 29623843 TI - Differential Cued-Stroop Performance in Cognitively Asymptomatic Older Adults with Biomarker-Identified Risk for Alzheimer's Disease: A Pilot Study. AB - BACKGROUND: There exists a need for more sensitive measures capable of detecting subtle cognitive decline due to Alzheimer's disease. OBJECTIVE: To advance the literature in Alzheimer's disease by demonstrating that performance on a cued Stroop task is impacted by preclinical Alzheimer's disease neuropathology. METHOD: Twenty-nine cognitively asymptomatic older adults completed a computerized, cued-Stroop task in which accuracy rates and intraindividual variability in reaction times were the outcomes of interest. Cerebrospinal fluid biomarkers of Abeta42 and tau were measured and participants were then grouped according to a published p-tau/Abeta42 cutoff reflecting risk for Alzheimer's disease (preclinical Alzheimer's disease = 14; control = 15). RESULTS: ANOVAs indicated that accuracy rates did not differ between the groups but 4-second delay incongruent color-naming Stroop coefficient of variation reaction times were higher in the preclinical Alzheimer's disease group compared to the control group, reflecting increased within-person variability. Moreover, partial correlations showed no relationships between cerebrospinal fluid biomarkers and accuracy rates. However, increases in coefficient of variation reaction times correlated with decreased Abeta42 and increases in p-tau and the p-tau/Abeta42 ratio. CONCLUSION: Results supported the ability of the computerized, cued-Stroop task to detect subtle Alzheimer's disease neuropathology using a small cohort of cognitively asymptomatic older adults. The ongoing measurement of cued-Stroop coefficient of variation reaction times has both scientific and clinical utility in preclinical Alzheimer's disease. PMID- 29623844 TI - In vitro and in vivo Assessment of Silver Nanoparticles against Clostridium botulinum type A botulinum. AB - BACKGROUND: Clostridium botulinum causes botulism, resulting from the ingestion of a botulinal toxin, which is a serious paralytic illness. Due to strong antimicrobial activity of silver nanoparticles' products, the applications of silver nanoparticles in the field of healthcare in particular are being expanded. Therefore, the objective of current study was to assess a therapeutic strategy for the treatment of botulism toxicity using silver nanoparticles. METHODS: A preliminary test was conducted, based on the ranges that produce illness in laboratory animals, to determine absolute lethal dose (LD100) of botulinum toxin type A (BoNT/A) in mice. Then, the test animals were divided into six groups containing six mice in each group. Group I, II and III were considered as the negative (botulinum toxin only), the positive control-1 (nano-silver only), and positive control-2 (no treatment); and the remaining groups were allocated to the toxin that supplemented with three nano-silver treatments. RESULTS: The mortality rates of mice caused by BoNT/A significantly reduced in the treatment groups with different doses and injection intervals of nan-osilver when compared to the negative control group. BoNT/A toxicity induced by intraperitoneal injection of the toxin of Clostridium botulinum causes rapid death while when coupled with nan osilver results in delayed death in mice. CONCLUSION: These results, while open to future improvements, represent a preliminary step towards the satisfactory control of BoNT/A by silver nanoparticles for human protection against the challenges bioterrorism threat. Further study in this area will be promising enough to elucidate the underlying mechanism for detoxifying BoNT/A by silver nanoparticles. PMID- 29623845 TI - Is treat-to-target in lupus nephritis realistic in clinical practice? AB - The treat-to-target (T2T) principle has been advocated in a number of inflammatory and non-inflammatory medical illnesses. Tight control of disease activity has been shown to improve the outcome of rheumatoid arthritis and psoriatic arthritis as compared to the conventional approach. However, whether T2T can be applied to patients with lupus nephritis is still under hot discussion. Treatment of lupus nephritis should target at inducing and maintaining remission of the kidney inflammation so as to preserve renal function and improve survival in the long-term. In real life, therapeutic options for lupus nephritis are limited. There is no universal agreement on the definition of remission or low disease activity state of nephritis, as well as the time points for switching of therapies. Despite the availability of objective parameters for monitoring such as proteinuria and urinary sediments, differentiation between ongoing activity and damage in some patients with persistent urinary abnormalities remains difficult without a renal biopsy. A large number of serum and urinary biomarkers have been tested in lupus nephritis but none of them have been validated for routine clinical use. As patients with lupus nephritis are more prone to infective complications, tight disease control with the use of more aggressive immunosuppressive therapies has to be tested for its safety and cost effectiveness by randomized controlled trials. PMID- 29623846 TI - Immune mediated necrotizing myopathy: where do we stand? AB - Immune-mediated necrotizing myopathies (IMNMs) are a group of acquired autoimmune muscle disorders that have been recently defined. They are characterized by proximal muscle weakness, high levels of creatinine kinase, and myopathic findings on electromyogram (EMG). Muscle biopsy in IMNM differentiates it from the other subgroups of idiopathic inflammatory myositis (IIM) by the presence of myofibre necrosis and prominent regeneration without substantial lymphocytic inflammatory infiltrates. Anti-signal recognition particle (SRP) and anti 3hydroxy-3 methylglutaryl-coenzyme A reductase (HMGCR) autoantibodies were found in two thirds of IMNM patients. In terms of treatment, IMNM is more resistant to conventional immunosuppressive treatment, therefore, other modalities of treatment such as intravenous immunoglobulin (IVIG) and rituximab are often required. PMID- 29623847 TI - Adenosine Deaminase activity and HLA-DRB as diagnostic markers for Rheumatoid Arthritis. AB - BACKGROUND AND OBJECTIVE: Rheumatoid Arthritis (RA) is a chronic multi systemic disorder with the unclarified ethiopathology. Although several markers have been presented for recognition of RA, but none of them has been specific. New markers such as HLA typing and activity of Adenosine deaminase (ADA) isoenzymes could be useful and specific. The aim of this study is to evaluate the pattern of ADA isoenzymes activity and HLA typing in both RA patients and healthy cases. METHODS: Blood samples were collected from 55 RA patients and 60 healthy subjects, over a period of 6 months. Levels of C-reactive protein (CRP), rheumatoid factor (RF) and ADA (ADA1, ADA2, total ADA) were measured using AVITEX kit and HITACHI Auto Analyzer. In addition, HLA-DRB1*1,*04 and *010 was detected using PCR-SSP. RESULTS: ADA activity, particularly ADA2 level, was significantly higher among RA group (P<0.05). The concentrations of tADA in patients with RF and CRP positive were significantly higher (P <0.05). The allele prevalence of DRB1*10 and *01 was significantly higher in RA patients (8.3% and 13.1%, respectively) compared with control group (2.51% and 5.5%, respectively) (P <0.05). Calculated sensitivity and specificity for diagnostic tests in this study are listed as: CRP (75%), RF (80%), ADA (84%) and RF (90%), ADA (83%), CRP (72%), respectively. CONCLUSION: Increase tADA level and the frequency of DRB1*010 and *01 caused to susceptibility to RA. PMID- 29623848 TI - The Complications of Bariatric Surgery Patients with Type 2 Diabetes in the World: A systematic Review and Meta-Analysis. AB - BACKGROUND: In this Meta-analysis, we aimed to quantify the incidence of complications of different methods of bariatric surgery on diabetic patients. INTRODUCTION: Type 2 Diabetes mellitus (T2DM) is increasing worldwide specifically in obese cases. Additionally, obesity worsens T2DM. Complications of each bariatric surgery method were assessed separately; but, meta-analysis of these complications and comparison between procedures in T2DM patients has not been investigated previously. The result of this study will help surgeons to choose the most appropriate surgical technique, considering individual conditions for a diabetic patient. METHOD: We searched PubMed, Scopus, and ISI for original papers including bariatric surgical procedures for diabetic population and the reported consequences. Data analyses were done using Stata software. RESULTS: Mortality percentage between diabetic and non-diabetic patients was statistically non-significant (P = 0.987). Early and late complications were higher in diabetic group in comparison with non-diabetic (6.0% vs. 1.8%, P = 0.024 and 0.6% vs. 0.3%, P = 0.04, respectively). Most prevalent findings in malabsorptive (7.8%, P < 0.001) and restrictive procedures (80%, P < 0.001) were major complications and hypoglycemic episodes, respectively. CONCLUSION: As our study showed, most of the complications are not necessarily higher in diabetic population but dependent on the method of surgery. PMID- 29623849 TI - Cardiac Imaging in Systemic Diseases: What the Clinician should Know. AB - IMPORTANCE: Systemic diseases that affect the cardiovascular system constitute a diagnostic and therapeutic challenge for all specialists involved; imaging tools along with clinical suspicion play an essential role in their evaluation. These entities share neurological, immunological, renal, hematologic, oncologic, infectious and endocrine processes, all of which may have associated cardiac involvement. OBSERVATIONS: Recent advances in cardiac ultrasound, Computed Tomography (CT), cardiac Magnetic Resonance (CMR) and nuclear scintigraphy have impacted the management of these conditions when involving the heart since they provide valuable anatomical and functional information while avoiding the use of invasive techniques. For this review, bibliographic sources were gathered from diverse databases, including PubMed, Cochrane, EBSCO and Google Scholar, concentrating on English language publications dealing with the clinical use of these tools. CONCLUSION: Clinical suspicion should always guide the use of imaging since in many instances, these techniques only play a supportive role rather than representing a diagnostic gold standard. Early diagnosis is critical due to the fact that cardiac manifestations are commonly a late phenomenon. PMID- 29623850 TI - Treatment of Metastatic, Castration-resistant, Docetaxel-resistant Prostate Cancer: A Systematic Review of Literature With a Network Meta-analysis of Randomized Clinical Trials. AB - INTRODUCTION: To compare the efficacy of abiraterone acetate, enzalutamide, cabazitaxel and Radium-223 in the treatment of castration-resistant, docetaxel resistant metastatic prostate cancer. METHODS: An indirect comparison of Overall Survival (OS) and time to PSA progression among abiraterone acetate, enzalutamide, cabazitaxel and Radium-223 was performed with a network metaanalysis. OS in the entire population of patients was the primary endpoint. OS in ECOG 0-1/2, BPISF<= 4/>4, pretreated with 1 or 2 courses of chemotherapy, age<=65/>65 patients, patients with only bone metastases or bone and visceral metastases, and time to PSA progression were the secondary endpoints. An indirect comparison of the Hazard Ratio and the 95% Confidence Interval was performed, assuming an alpha error of 5% as an index of statistical significance. The among the-trial heterogeneity was assessed using a qualitative methodological and clinical analysis. RESULTS: Four trials were selected. In three trials, the comparator was placebo, in one trial it was mitoxantrone, the effect of which in improving survival was considered negligible. No significant difference in OS among abiraterone acetate, enzalutamide, cabazitaxel and radium 223 was observed in neither the entire population nor all the subgroups of patients. Enzalutamide resulted significantly better than abiraterone acetate, cabazitaxel or radium-223 in time to PSA progression. CONCLUSION: Since no significant difference in efficacy seems to exist between the four therapeutic options in the treatment of castration-resistant, docetaxel-resistant, metastatic prostate cancer, the safety of the treatment, patient's compliance and costs should represent the criteria to guide clinicians' choice in clinical practice. PMID- 29623851 TI - Mesenchymal Stem Cells-Derived Exosomes: A Possible Therapeutic Strategy for Osteoporosis. AB - Osteoporosis is a common age-related disorder characterized by low bone mass and deterioration in bone microarchitecture, leading to increased skeletal fragility and fracture risk. The pathophysiology of osteoporosis is multifactorial. It is related to the imbalance between osteoblasts and osteoclasts; reduced bone mass and increased adipogenesis in the bone marrow. Moreover, angiogenesis, inflammatory process and miRNAs have shown effects in the formation of osteoporosis. In the recent years, mesenchymal stem cells (MSCs) have been regarded as an excellent choice for cell-based tissue engineering therapy of osteoporosis. Growing evidence showed that paracrine effect has been considered as the predominant mechanism for the role of MSCs in tissue repair. Recently, many studies have proposed that MSCs-derived exosomes are effective for a variety of diseases like cancer, cardiovascular diseases, etc. However, whether the MSCs derived exosomes could serve as a novel therapeutic tool for osteoporosis has not clearly described. In this review, we summarize the MSCs-derived exosomes and the relationship with osteogenesis, osteoclast differentiation, angiogenesis, immune processes and miRNAs. Finally, we suggest that MSCs-derived exosomes might be a promising therapeutic method for osteoporosis in the future. PMID- 29623852 TI - Potential Future of New Glutamate Agonists and Antagonists Development. AB - Receptors of glutamic acid are known for over 30 years for their action and for about 20 years for their structure. Presence of at least three classes of ionotropic receptors was confirmed at the beginning of 80'. Recognition of the sequence and first cloning were done at the beginning of 90'. In 1994 ligand binding site was recognized at the junction of two subunits S1-S2 in the ligand binding domain. Since then, many subtypes of ionotropic and metabotropic glutamate receptors were recognized, together with their localization and functions. In the meantime numerous orthosteric ligands, both agonists and antagonists were developed especially for NMDA ion channels. Their usefulness as drugs was rather low, due to the involvement in the excitatory tract. More interest was focused on metabotropic receptors, which are GPSR's and can be modulated both by orthosteric and allosteric modulators. It seems like allosterism could be considered as promising future for glutamate receptors and ion channels, especially when first allosteric negative modulators of the mGluR2 went close into the clinical trial. PMID- 29623853 TI - Repositioning of difluorinated propanediones as inhibitors of histone methyltransferases and their biological evaluation in human leukemic cell lines. AB - Cancer chemotherapy is associated with limitations like dose dependent host tissue toxicity, multiple drug resistance and tumor heterogeneity. Hence, it is imperative to unearth novel targets to cure cancer. At present, 'pharmaco epigenomics' constitutes the hope in cancer treatment owing to epigenetic deregulation- a reversible process, suspected of playing a role in malignancy. In this research work, we have used the fundamentals of drug repurposing for a set of our previously synthesized difluorinated propanediones and evaluated them for their histone methyltransferase inhibitory potential in leukemic cell lines. A small molecule inhibitor PR-4, at a concentration of 1 and 10MUM, has shown to alter the methylation levels in two leukemic cell lines, one of histiocytic lymphoma (U937) and other of acute T-cell leukemia (JURKAT). Treatment with the compound shows an increase in G2/M population and a subsequent decrease in the G0/G1 population 24h post treatment in U937. In JURKAT, an increase in both G2/M and S phase population at 16 and 24h time point was observed. The sub-G1 population showed a steady rise with increase in dose and prolonged time intervals in U937 and JURKAT cell lines. In SRB assay, the moiety showed a cell growth of 42.6 % and 53.4% comparable to that of adriamycin; 44.5% and 53.2% in U937 and JURKAT, respectively. The apoptosis pattern suggests that this molecule could emerge as a potential anticancer agent by targeting histone methyltransferases. The molecule PR-4 could be a lead in developing more histone lysine methyltransferases inhibitors with potential to be anti-carcinogenic agents. PMID- 29623854 TI - Cytotoxic effect of 5-Fluorouracil-loaded polymer-coated magnetite nanographene oxide combined with radiofrequency. AB - : Despite the development of conventional therapies, include surgery, radiotherapy, chemotherapy and hyperthermia, the prognosis remains very poor. Recently, integration of conventional therapy and multifunctional nanoparticles have attracted a lot of attention because it produces a synergistic effect and better diagnostic and therapeutic efficiency. OBJECTIVE: This study aimed to investigate the uptake and cytotoxic effects of polycaprolactone (PCL)/chitosan (CHI)-coated superparamagnetic iron oxide nano-graphene oxide (SPION-NGO) as a carrier of 5-fluorouracil (5-Fu) and radiofrequency (RF) hyperthermia using an alternate magnetic field (AMF) with 13.56 MHz frequency on the proliferation capacity level of CT26 colon cancer cell line in monolayer culture. METHOD: The release of the newly synthesised 5-Fu-loaded PCL/CHI-SPION-NGO was measured in phosphate buffered saline (PBS) using the dialysis bag method. The cellular uptake of 5-Fu-loaded PCL/CHI-SPION-NGO was measured using atomic absorption spectroscopy (AAS). The cytotoxic effects of 5-Fu, 5-Fu-PCL/CHI-SPION-NGO and PCL/CHI-SPION-NGO with and without RF hyperthermia were determined using the colony formation assay. RESULTS: Particle size and zeta potential of 5-Fu-PCL/CHI SPION-NGO and PCL/CHI-SPION-NGO were 61.2 nm and -1.87 mV and 43.4 nm and -10.19 mV, respectively. Spectroscopy results demonstrated that the cellular uptake of 5 Fu-PCL/CHI-SPION-NGO increased with elevated nanostructure concentrations. The results revealed that the proliferation capacity of the cells decreased with 5-Fu or 5-Fu-PCL/CHI-SPION-NGO in combination with RF hyperthermia. Furthermore, extend of reduction in colony number following treatment with 5-Fu-PCL/CHI-SPION NGO in combination with AMF was significantly more than 5-Fu + hyperthermia. CONCLUSION: Therefore, PCL/CHI-SPION-NGO can deliver 5-Fu more efficiently into the CT26 cells. PMID- 29623855 TI - How Does Plasma Activated Media Treatment Differ From Direct Cold Plasma Treatment? AB - OBJECTIVE: The aim of the paper is to investigate the optimum condition for generation of Plasma Activated Media (PAM), where it can deactivate the cancer cells while minimum damage for normal cells. BACKGROUND: Over past few years, cold atmospheric Plasma-Activated Media (PAM) have shown its promising application in plasma medicine for treatment of cancer. PAM has a tremendous ability for selective anti-cancer capacity in vitro and in vivo. METHODS: We have analyzed the radicals in air using the optical emission spectroscopy and in culture media using chemical analysis. Further, we have tested the toxicity of PAM using MTT assay. RESULTS: We observed that more cancer cell death is for the Ar plasma followed by the Ar-N2 plasma, and the least cell death was observed for the Ar-O2 plasma at all treatment times both by direct treatment and through PAM treatment. The concentration of the RNS species is high for Ar-N2 plasma in gas as well as inside the culture media compared to that for pure Ar plasma. However, the difference is significantly less between the Ar plasma treatments and the Ar N2 plasma treatments, showing that ROS is the main factor contributing to cell death. CONCLUSION: Among all three feeding gas plasmas the best system is Ar-O2 plasma for direct treatments towards the cancer cells. In addition, the best system for PAM preparation is Ar-N2 at low time treatments (1 min and 2 min) because it has no effect on normal cells, but kills the cancer cells. PMID- 29623856 TI - Investigation of the roles of non-neuronal acetylcholine in chronic myeloid leukemic cells and their erythroid or megakaryocytic differentiated lines. AB - Many studies suggested that acetylcholine (ACh) might serve as an autocrine/ paracrine growth factor in several types of tumors or tumor cell lines. Therefore, cholinergic signaling seems to be functionally important in cancer. High levels of acetylcholinesterase (AChE) activity have been reported in primary brain tumors, ovarian, colon and lung tumors. K562 cells were derived from a chronic myelogenous leukemia patient during blast crisis serving as pluripotent hematopoietic stem cells. K562 cells were incubated with various cholinergic agonists or antagonists to investigate the role of ACh in different differentiated cell lines. Our experiments showed that AChE activity was increased in response to ACh in undifferentiated K562 cells, but in the erythroid differentiated K562 cells a high concentration of ACh (1 mM) decreased the AChE activity. ACh failed to elevate the AChE activity in the megakaryotic differentiated K562 cells. An AChE inhibitor, eserine, also suppressed the AChE activity in a concentration-dependent manner. Choline uptake inhibition by hemicholinium did not affect the AChE activity but not in the erythroid differentiated K562 cell line. Choline uptake inhibition by hemicholinium did increase the AChE activity but not in the erythroid differentiated K562 cell line. PMID- 29623857 TI - The Large Conductance Calcium- and Voltage-activated Potassium Channel (BK) and Epilepsy. AB - BACKGROUND & OBJECTIVE: The large conductance, calcium- and voltage-activated potassium channels (BK) are widely distributed channel proteins which exist in virtually every cell type of mammals and function to influence membrane excitability and Ca2+ signaling. BK channels can be activated by the increase of the intracellular Ca2+ concentration, a consequence of neuronal excitation, and then terminate the action potential with the outward K+ flux. Moreover, after hyperpolarization induced by BK channels closes Cav channels and thus precludes excessive Ca2+ influx. Considering this negative feedback effect, BK channel seemly acts to decrease membrane excitability in order to prevent hyperexcitation which is a typical characteristic of epilepsy. Therefore, one may reasonably suppose that membrane excitability would increase when the BK channel activity decreases. However, the membrane excitability displays elevation when the function of BK channel is under either upregulated or down-regulated status. Factors altering the activity of BK channels, such as gene mutations, polymorphism, channel openers or blockers that lead to loss- or gain-of-function, have all been linked to epilepsy onset. CONCLUSION: The aim of this review is to summarize existing knowledge and recent findings on the molecular properties, signaling complex and channel dysfunction of the BK channels with a particular attention to the possible relevance to the pathophysiology of epilepsy. PMID- 29623859 TI - Non-invasive Cerebellar Stimulation in Cerebellar Disorders. AB - BACKGROUND & OBJECTIVE: Non-invasive brain stimulation (NIBS) might be a valuable therapeutic approach for neurological diseases by modifying the cortical activity in the human brain and promoting neural plasticity. Currently, researchers are exploring the use of NIBS on the cerebellum to promote functional neural changes in cerebellar disorders. In the presence of cerebellar dysfunction, several movement disorders, such as kinetic tremor, ataxia of gait, limb dysmetria and oculomotor deficits, become progressively more disabling in daily life, and no pharmacological treatments currently exist. CONCLUSION: In the present mini review, we report the main evidence concerning the use of NIBS in three specific cerebellar dysfunctions, cerebellar ataxias (CA), essential tremor (ET) and ataxic cerebral palsy, in which abnormalities of neuroplasticity and cortical excitability can be important pathophysiological factors. PMID- 29623860 TI - Adenosine and Adenosine 5'-triphosphate Catabolism in Systemic Blood as a Potential Biomarker for Doxorubicin Cardiotoxicity in an Experimental Rat Model in vivo. AB - BACKGROUND: Previous studies have shown that metabolism of adenosine 5' triphosphate (ATP) in systemic blood is a potential surrogate biomarker for cardiovascular toxicity. OBJECTIVE: To investigate the acute effect of high dose of doxorubicin (DOX) on adenosine and ATP catabolism in systemic blood in vivo. METHOD: Sprague Dawley (SD) rats were each given either 10 mg/kg of DOX (n = 8) or normal saline (1 mL/kg, n = 11) twice daily for 4 doses by subcutaneous (sc) injection. Blood samples were collected sequentially for up to 6 hours for measuring circulating concentrations of ATP, adenosine and their metabolites. Hemodynmic recording was obtained continuously after the last injection. The difference in response between groups was considered significant at p < 0.05 (t test). RESULTS: Diastolic blood pressure (DBP) was significantly lower in the DOX treated rats than in the control before the final injection (87 +/- 12 vs. 104 +/ 11 mmHg, p < 0.05). Blood pressure fell gradually after the last injection and the decrease was significantly greater in the DOX treated group (p < 0.05). Plasma concentration of adenosine was significantly lower in the DOX treated group. In contrast, plasma concentrations of uric acid and hypoxanthine, as well as Red Blood Cell (RBC) concentrations of AMP, were significantly higher (p < 0.05). CONCLUSION: Acute cardiotoxicity induced by DOX may be measured by the increased breakdown of ATP to AMP in the RBC and also breakdown of adenosine to hypoxanthine and uric acid in plasma. PMID- 29623861 TI - [Proposal for an anonymous reporting code organ trafficking: how transplant professionals can play a role in preventing this trafficking]. AB - Patients travel worldwide to undergo kidney transplantations. Care providers in the Netherlands encounter these patients, both before and after the transplantation. We present the results of a survey that was distributed among Dutch transplant professionals about their experiences with patients who have undergone a kidney transplantation abroad. We propose that care providers should report illegal transplantations. Of the 241 surveyed professionals, 100 treated patients who travelled to a country outside the European Union for a kidney transplant. Thirty-one professionals were certain that patients purchased their kidney, and sixty-five had suspicions that it had been purchased. The majority reported a conflict of duties. Professionals can help prevent organ purchase by detecting and disclosing information about organ trafficking networks. The aim of reporting is two-fold. Firstly, such disclosure can lead to increased knowledge and information about organ trafficking. Secondly, it can support the police and law enforcement agencies to investigate if networks are involved in facilitation of these transplantations. In this manner, those who facilitate organ trafficking can be prosecuted and exploitation of donors can be prevented. PMID- 29623862 TI - [Sepsis and a swollen hand]. AB - We describe a 53-year-old man presenting at the emergency department with sepsis and a swollen right hand. Over the course of a day a large haemorrhagic bulla developed on the back of the hand. The blood cultures were positive for Streptococcus pyogenes. Our diagnosis was bullous cellulitis leading to S. pyogenes sepsis. PMID- 29623863 TI - [Fibronectin test in threatened preterm labour: cost-saving but not yet widely implemented in the Netherlands]. AB - OBJECTIVE: Analysis of national implementation of the foetal fibronectin test in the diagnostics of threatened preterm labour in the Netherlands, and indication of the possible obstacles and consequences of implementation or no implementation. DESIGN: National questionnaire, retrospective cohort study and cost-effectiveness calculation. METHODS: We approached all hospitals in the Netherlands (n = 86) with a questionnaire on use of the fibronectin test. We also collected data on women who were referred to the Academic Medical Center (AMC), a tertiary care centre in Amsterdam, with symptoms of threatened preterm labour. We investigated whether the referred patients gave birth within 7 days, and whether unnecessary transfer to a centre with a neonatal intensive care unit (NICU) could have been avoided by implementation of the fibronectin test in the referring hospital. RESULTS: The fibronectin test was used in 34% of the hospitals and an additional 17% were in the process of implementation. The most important reasons not to use the fibronectin test were of a financial nature (50%). The cohort study included 96 women who were referred from secondary care. In our cohort, 36% of all transfers could have been avoided by implementation of the fibronectin test in secondary care. CONCLUSION: The fibronectin test can greatly reduce overtreatment and unnecessary transfer in threatened preterm labour, but implementation remains limited. Costs of the test are an obstacle for the referring hospitals, while implementation prevents unnecessary transport, admission and treatment of pregnant women, giving a potential saving of at least EUR 1,027,930 per year. Inclusion in the Netherlands Society for Obstetrics and Gynaecology (Nederlandse Vereniging voor Obstetrie en Gynaecologie, NVOG) guidelines would be a first step towards wider implementation. Slow implementation exemplifies a more widespread problem: the current reimbursement system does not stimulate such cost-saving innovations. PMID- 29623864 TI - [Clinical drug profiles: an instrument to improve shared decision-making]. AB - Doctors and patients are increasingly choosing treatment options by means of the shared decision-making process. However, human decisions are subject to cognitive bias, i.e. systematic and predictable errors in probability estimation and information synthesis. Decision-making may also be hampered by incomplete information. Clinical Drug Profiles (CDPs) aim to provide up-to-date, evidence based and independent information about drug characteristics that are relevant to doctors and patients alike in the context of shared decision-making. They contain information about mechanisms of action, mode and frequency of administration, clinical efficacy, therapeutic effectiveness, side effects, persistence and adherence, and safety monitoring. CDPs are to be made freely available on the internet, thus enabling doctors and patients to obtain drug-specific information on potential benefits and risks, before or during the decision-making process. In addition, the patient can make a subjective appraisal of the chances of success and the risk of side effects. In all, CDPs increase the likelihood that two major conditions of successful shared decision-making are met: minimisation of cognitive bias and complete information. PMID- 29623865 TI - [Stroke mimicking acute peripheral vertigo: how to avoid misdiagnosis - importance of alarm symptoms and assessment of eye movements]. AB - Identifying the occurrence of stroke in patients with isolated vertigo is difficult for general practitioners (GPs) as well as for physicians working in the Emergency Department. Three patients with acute vestibular syndrome are presented in this clinical lesson. The importance of an adequate neuro-otological examination is emphasised. However, many GPs lack knowledge of the nystagmus and the head impulse test. Alternative strategies for GPs are discussed. PMID- 29623866 TI - [Gifts from patients: to accept or not?] AB - Most physicians receive gifts from their patients during their careers, but what to think of these presents and how to react to them? For many years, generous patients led to uneasiness: they might expect special services from the physician; or other patients - who did not give anything - could feel disadvantaged over generous patients. These are good reasons not to be too keen on gifts. They still lead to uneasiness now, but the situation has nevertheless been reappraised as it goes against the general tendency to complain about everything: a token of appreciation is welcome. We should keep in mind that many patients have sincere intentions when giving presents. Just as in our clinical decision-making, we should trust our common sense when appreciating and accepting presents. However, verbal or written expressions of gratitude are preferable to physical presents since the former ones are far less complicated. PMID- 29623867 TI - Image-based food portion size estimation using a smartphone without a fiducial marker. AB - OBJECTIVE: Current approaches to food volume estimation require the person to carry a fiducial marker (e.g. a checkerboard card), to be placed next to the food before taking a picture. This procedure is inconvenient and post-processing of the food picture is time-consuming and sometimes inaccurate. These problems keep people from using the smartphone for self-administered dietary assessment. The current bioengineering study presents a novel smartphone-based imaging approach to table-side estimation of food volume which overcomes current limitations. DESIGN: We present a new method for food volume estimation without a fiducial marker. Our mathematical model indicates that, using a special picture-taking strategy, the smartphone-based imaging system can be calibrated adequately if the physical length of the smartphone and the output of the motion sensor within the device are known. We also present and test a new virtual reality method for food volume estimation using the International Food UnitTM and a training process for error control. RESULTS: Our pilot study, with sixty-nine participants and fifteen foods, indicates that the fiducial-marker-free approach is valid and that the training improves estimation accuracy significantly (P0.05). CONCLUSIONS: Elimination of a fiducial marker and application of virtual reality, the International Food UnitTM and an automated training allowed quick food volume estimation and control of the estimation error. The estimated volume could be used to search a nutrient database and determine energy and nutrients in the diet. PMID- 29623868 TI - The nutritional content of supermarket beverages: a cross-sectional analysis of New Zealand, Australia, Canada and the UK - CORRIGENDUM. PMID- 29623869 TI - Mixed deep learning and natural language processing method for fake-food image recognition and standardization to help automated dietary assessment. AB - OBJECTIVE: The present study tested the combination of an established and a validated food-choice research method (the 'fake food buffet') with a new food matching technology to automate the data collection and analysis. DESIGN: The methodology combines fake-food image recognition using deep learning and food matching and standardization based on natural language processing. The former is specific because it uses a single deep learning network to perform both the segmentation and the classification at the pixel level of the image. To assess its performance, measures based on the standard pixel accuracy and Intersection over Union were applied. Food matching firstly describes each of the recognized food items in the image and then matches the food items with their compositional data, considering both their food names and their descriptors. RESULTS: The final accuracy of the deep learning model trained on fake-food images acquired by 124 study participants and providing fifty-five food classes was 92.18 %, while the food matching was performed with a classification accuracy of 93 %. CONCLUSIONS: The present findings are a step towards automating dietary assessment and food choice research. The methodology outperforms other approaches in pixel accuracy, and since it is the first automatic solution for recognizing the images of fake foods, the results could be used as a baseline for possible future studies. As the approach enables a semi-automatic description of recognized food items (e.g. with respect to FoodEx2), these can be linked to any food composition database that applies the same classification and description system. PMID- 29623870 TI - Comparative evidence of the consumption from fast-food restaurants between normal weight and obese Saudi schoolchildren. AB - OBJECTIVE: To provide an in-depth analysis of the relationship between obesity and fast-food consumption by comparing urban obese and normal-weight Saudi Arabian children. DESIGN: A multicentre cross-sectional study was conducted from December 2015 to March 2016. Participants were divided into two groups (normal weight and obese) and further stratified by sex. Groups were randomly selected using a multistage stratified cluster-sampling technique. A self-paced questionnaire was used to collect data relating to food consumption. Weight height and waist circumference were measured and bioelectrical impedance analysis was performed in all children. SETTING: Capital of Saudi Arabia, Riyadh. SUBJECTS: Children aged 9.00-11.99 years (n 1023). RESULTS: Compared with normal weight groups, intake frequency of fast food/week was higher among the obese groups (P<0.001), irrespective of fast-food consumption outside (P<0.001) or inside (P<0.001) the home; and larger portion sizes were preferred in obese groups (P<0.001). Families eating fast-food meals together was a protective factor against obesity (OR; 95 % CI: 2.67; 1.44, 4.96, P<0.001), with similar results for families ordering from a 'healthy meals menu' for their children (1.90; 1.24, 2.90, P=0.002). Taste of fast foods (P=0.021), child-friendly menu (P=0.020) and meal cost (P<0.001) were identified as main reasons why parents took their children to fast-food restaurants; these data were replicated for parents with obese boys, but not girls. CONCLUSIONS: Development of effective interventions to reduce fast-food consumption in Saudi Arabian schoolchildren requires greater research-based evidence of fast-food consumption habits and practices associated with increased childhood obesity. PMID- 29623871 TI - Health-promoting lifestyle and quality of life among Chinese nursing students. AB - : AimThis study aimed to examine the relationships between socio-economic status, health-promoting lifestyles, and quality of life among Chinese nursing students. BACKGROUND: Nursing students will be future health promoters, but they may not always adopt the recommended healthy lifestyle. Currently, there are insufficient studies examining the health-promoting lifestyles of Chinese nursing students, and the impact of socio-economic status and health-promoting lifestyle on their health. METHODS: This was a cross-sectional survey. Data were collected from nursing students studying in pre-registration nursing programs of a university in Hong Kong. The survey was conducted through a self-administered questionnaire that solicited information regarding their socio-economic status, health promoting lifestyle, quality of life, and perceptions of the barriers to adopting a health-promoting lifestyle.FindingsA total of 538 students returned completed questionnaires for analysis. Among the health-promoting lifestyle subscales, the participants performed best in interpersonal relations and worst in physical activity, and the vast majority of them did not actively engage in health-risk behaviors. Hierarchical regression analyses revealed that only 5% of the variance in quality of life was explained by socio-economic variables, whereas a total of 24% of the variance was explained when health-promoting lifestyle variables were added. In particular, health responsibility, physical activity, spiritual growth, and stress management were statistically significant predictors of quality of life. CONCLUSIONS: Early concerns about how prepared nurses are to take on the role of promoting health still apply today. School administrators should plan the nursing curriculum to include activities that encourage student nurses to participate in health-promoting lifestyles. Future studies are needed to explore the barriers that prevent students from practicing health-promoting behavior. PMID- 29623873 TI - Antimicrobial Resistance in Campylobacter spp. AB - Campylobacter is a major foodborne pathogen and has become increasingly resistant to clinically important antimicrobials. To cope with the selection pressure from antimicrobial use in both veterinary and human medicine, Campylobacter has developed multiple mechanisms for antibiotic resistance, including modification or mutation of antimicrobial targets, modification or inactivation of antibiotics, and reduced drug accumulation by drug efflux pumps. Some of these mechanisms confer resistance to a specific class of antimicrobials, while others give rise to multidrug resistance. Notably, new antibiotic resistance mechanisms continuously emerge in Campylobacter, and some examples include the recently discovered multidrug resistance genomic islands harboring multiple genes involved in the resistance to aminoglycosides and macrolides, a novel Cfr(C) conferring resistance to phenicols and other drugs, and a potent multidrug efflux pump CmeABC variant (RE-CmeABC) that shows a significantly enhanced function in multidrug resistance and is associated with exceedingly high-level resistance to fluoroquinolones. These newly emerged resistance mechanisms are horizontally transferable and greatly facilitate the adaptation of Campylobacter in the food producing environments where antibiotics are frequently used. In this article, we will discuss how Campylobacter resists the action of various classes of antimicrobials, with an emphasis on newly discovered mechanisms. PMID- 29623872 TI - Origin, Evolution, and Loss of Bacterial Small RNAs. AB - Despite the central role of bacterial noncoding small RNAs (sRNAs) in posttranscriptional regulation, little is understood about their evolution. Here we compile what has been studied to date and trace a life cycle of sRNAs-from their mechanisms of emergence, through processes of change and frequent neofunctionalization, to their loss from bacterial lineages. Because they possess relatively unrestrictive structural requirements, we find that sRNA origins are varied, and include de novo emergence as well as formation from preexisting genetic elements via duplication events and horizontal gene transfer. The need for only partial complementarity to their mRNA targets facilitates apparent rapid change, which also contributes to significant challenges in tracing sRNAs across broad evolutionary distances. We document that recently emerged sRNAs in particular evolve quickly, mirroring dynamics observed in microRNAs, their functional analogs in eukaryotes. Mutations in mRNA-binding regions, transcriptional regulator or sigma factor binding sites, and protein-binding regions are all likely sources of shifting regulatory roles of sRNAs. Finally, using examples from the few evolutionary studies available, we examine cases of sRNA loss and describe how these may be the result of adaptive in addition to neutral processes. We highlight the need for more-comprehensive analyses of sRNA evolutionary patterns as a means to improve novel sRNA detection, enhance genome annotation, and deepen our understanding of regulatory networks in bacteria. PMID- 29623874 TI - RNA Thermometers in Bacterial Pathogens. AB - Temperature variation is one of the multiple parameters a microbial pathogen encounters when it invades a warm-blooded host. To survive and thrive at host body temperature, human pathogens have developed various strategies to sense and respond to their ambient temperature. An instantaneous response is mounted by RNA thermometers (RNATs), which are integral sensory structures in mRNAs that modulate translation efficiency. At low temperatures outside the host, the folded RNA blocks access of the ribosome to the translation initiation region. The temperature shift upon entering the host destabilizes the RNA structure and thus permits ribosome binding. This reversible zipper-like mechanism of RNATs is ideally suited to fine-tune virulence gene expression when the pathogen enters or exits the body of its host. This review summarizes our present knowledge on virulence-related RNATs and discusses recent developments in the field. PMID- 29623876 TI - Averaging in time-frequency domain reveals the temporal and spatial extent of seizures recorded by scalp EEG. AB - To demonstrate the importance of averaging in time-frequency space and the added localizing value in time and space in a case of cortical myoclonus. One hundred myoclonic jerks were averaged in time series and in spectral domain. For the latter, we chose 100 (10-second) segments from interictal background and used the unpaired t-test for the jerk-related and control spectral data to obtain the t value and corresponding p value at each pixel. We corrected for multiple comparisons using false discovery rate procedure. We generated maps of spectral significance per electrode. All insignificant t-values were converted to 0 for easier visual analysis. Standard back-averaging of 100 jerks disclosed a single spike preceding EMG activity by 19-27 milliseconds. No other definite ictal patterns were discernible in the time domain. Statistical analysis of the same 100 epochs in the time-frequency domain disclosed a greater temporal extent of the seizure, as well as a more detailed rendering of rhythms and frequencies involved. Valproate was added and led to substantial improvement. Averaging in the spectral domain may reveal frequency-specific changes that may not be otherwise appreciated in the time domain. Future studies may elucidate the effect on the sensitivity of diagnosis of simple partial seizures and auras. PMID- 29623877 TI - Long-term seizure outcome following epilepsy surgery in the parietal lobe: a meta analysis. AB - Due to a limited number of patients with drug-resistant parietal lobe epilepsy in surgical series, there are insufficient data about long-term seizure outcome following surgery restricted to the parietal lobe. We performed a meta-analysis to asses long-term outcomes in patients with parietal lobe epilepsy who underwent surgery confined to the parietal lobe or resection with major involvement of the parietal cortex. An English language literature search for studies on parietal lobe surgery and outcome was conducted using the MEDLINE database, followed by a manual search based on specific criteria. An inverse variance random effect meta analysis model was used to estimate the pooled proportion of Engel Class I. Meta regression models were used to examine the association between outcome and potential predictors. The search yielded seven retrospective studies with a total sample size of 253 patients (mean follow-up: 104.9+/-74.8 months). Following surgery, Engel Class I surgical outcome was achieved in 62.4% (95% CI: 0.492 0.755). Two independent predictors were identified for positive long-term outcome: interictal EEG localized to the parietal region (p=0.007) and the presence of tumour (p=0.022). Following surgery confined to the parietal lobe or resection with major involvement of the parietal cortex, the long-term prognosis of patients with parietal lobe epilepsy is favourable. PMID- 29623875 TI - Use of a leukocyte-targeted peptide probe as a potential tracer for imaging the tuberculosis granuloma. AB - Granulomas are the histopathologic hallmark of tuberculosis (TB), both in latency and active disease. Diagnostic and therapeutic strategies that specifically target granulomas have not been developed. Our objective is to develop a probe for imaging relevant immune cell populations infiltrating the granuloma. We report the binding specificity of Cyanine 3 (Cy3)-labeled cFLFLFK-PEG12 to human leukocytes and cellular constituents within a human in vitro granuloma model. We also report use of the probe in in vivo studies using a mouse model of lung granulomatous inflammation. We found that the probe preferentially binds human neutrophils and macrophages in human granuloma structures. Inhibition studies showed that peptide binding to human neutrophils is mediated by the receptor formyl peptide receptor 1 (FPR1). Imaging the distribution of intravenously administered cFLFLFK-PEG12-Cy3 in the mouse model revealed probe accumulation within granulomatous inflammatory responses in the lung. Further characterization revealed that the probe preferentially associated with neutrophils and cells of the monocyte/macrophage lineage. As there is no current clinical diagnostic imaging tool that specifically targets granulomas, the use of this probe in the context of latent and active TB may provide a unique advantage over current clinical imaging probes. We anticipate that utilizing a FPR1-targeted radiopharmaceutical analog of cFLFLFK in preclinical imaging studies may greatly contribute to our understanding of granuloma influx patterns and the biological roles and consequences of FPR1-expressing cells in contributing to disease pathogenesis. PMID- 29623878 TI - 2009-2017 report on the attractiveness of laboratory medicine among young doctors. PMID- 29623879 TI - About genetic diagnosis of hereditary hemochromatosis. PMID- 29623881 TI - The role of the clinical biologist in the patient care chain. PMID- 29623880 TI - Serum GH concentration must now be expressed in mass units in France like in the rest of the world. PMID- 29623882 TI - Myoglobin: still a useful biomarker in 2017? AB - The clinical biologist plays a role as a consultant for the relevant use of biological examination. Advisory activities of the medical laboratory may help physician in diagnosis or therapeutic algorithm, avoiding redundant ordering or useless tests. In this context, we performed a review of literature about the clinically interest of myoglobin assays. The indications of myoglobin's assays appear fairly limited. It is no longer mentioned in the European guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. In patients with rhabdomyolysis myoglobin is neither a diagnostic nor a prognostic criterion. Its interest in predicting the occurrence of acute renal failure is also discussed. The most recent clinico biological score (such as the McMahon score) do not integrate it. In this context, we decided to stop performing myoglobin assay. PMID- 29623883 TI - Evaluation of the coagulometer STA R Max(r) (Stago) for routine coagulation parameters. AB - The STA R Max(r) is a fully automated multiparameter coagulometer using clotting (viscosity-based detection system), chromogenic and immunologic assays. STA R Max(r) is equipped with an innovative software (STA Coag Expert(r)) designed to assist laboratory in accreditation. The aim of this study was to evaluate its performances for the certification according to ISO 15189 quality standard in the haemostasis unit of our university hospital. The following tests were evaluated: prothrombin time (PT), activated partial thromboplastin time (aPTT), kaolin cephalin clotting time (KCCT), fibrinogen, anti-Xa assay and D-dimers. In normal and pathological range, the intra-assay coefficients of variation (CV) for PT, aPTT, KCCT and fibrinogen were below 4.0%. Intra-assay CV was of 4.0% for the anti-Xa assay and intra-assay CV was of 7.9% for D-dimers. Inter-assay CV were below 5.0% for PT, aPPT, KCCT and fibrinogen, 14.9% for anti-Xa assay and 8.6% for D-dimers. The interlaboratory comparisons were below 8.7% for PT, aPPT and KCCT, 5.0% for fibrinogen and 15.5% for anti-Xa assay. All results were acceptable according to suitable CV established by GFHT and the provider. The concordance between all coagulometers was excellent, with correlation coefficient close to 1 (0.99 for all parameters except for aPPT which was 0.98) calculated thanks to an intra-class correlation study. In conclusion, the STA R Max(r) analyser is suitable for haemostasis laboratories and facilitates certification of a laboratory. PMID- 29623884 TI - Tryptophan metabolism: utility of plasmatic assay in phenylketonuria, a study in 6 adult patients. AB - Phenylketonuria (PKU, OMIM 261600) is an autosomal recessive inborn error of metabolism caused by a deficiency of the hepatic enzyme phenylalanine hydroxylase (PAH; EC 1.14.16.1). If untreated, the disease leads to an important intellectual disability (IQ <50). Although many facts are common between phenylalanine (Phe) and tryptophan (Trp) metabolism, little is known about Trp metabolism modification in PKU. Our aim was to evaluate the modifications of Trp metabolism in a phenylketonuric population. A monocentric study was conducted between October 2016 and March 2017. Every phenylketonuric fasting adults were included during their annual follow up. For each patient, 9 analytes of Trp metabolism were quantified in peripheral blood using liquid chromatography coupled with tandem mass spectrometry. Mann and Whitney tests (p <0.05) were carried out in StatView 5.0 software. A total of 6 PKU patients were studied. Significant modification of Trp metabolism was shown. Indeed, three analytes, i.e. tryptophan, kynurenine and 3-hydroxykynurenic acid, were significantly lower in phenylketonuric than in healthy population (p-value <0.05), without known confounding factors. This study shows a significant modification of Trp metabolism in peripheral blood of phenylketonuric patients. Nevertheless, more investigations are necessary to confirm the modification of Trp metabolism in PKU and to determine how this metabolism is involved in neurological symptoms. PMID- 29623885 TI - Flagging threshold optimization for manual blood smear review in primary care laboratory. AB - Manual blood smear review is required when an anomaly detected by the automated hematologic analyzer triggers a flag. Our will through this study is to optimize these flagging thresholds for manual slide review in order to limit workload, while insuring clinical care through no extra false-negative. Flagging causes of 4,373 samples were investigated by manual slide review, after having been run on ADVIA 2120i. A set of 6 user-adjustments is proposed. By implementing all recommendations that we made, false-positive rate falls from 81.8% to 58.6%, while PPV increases from 18.2% to 23.7%. Hence, use of such optimized thresholds enables us to maximize efficiency without altering clinical care, but each laboratory should establish its own criteria to take into consideration local distinctive features. PMID- 29623886 TI - Contribution of cutlery and serving dishes to the human daily intake of silver An in vitro assessment. AB - Silver cutlery and serving dishes are a potential source of exposure of humans that was never quantified. Release of silver was assessed in vitro in an acidic solution mimicking food fluid in two conditions: i] the JRC guidelines for hot fill conditions with stable high temperature over a 2 hour-period of time, and ii] a more realistic condition with spontaneous progressive decline from 90C to ambient temperature over the same period of time. Massive silver 95% strips were exposed to a 5% citric acid solution: i) cooling down from 90C to ambient or ii) 70C maintained, during 2 hours. Spectrometry with optical emission was used to measure silver in solution. In the spontaneous cooling down study, the time course of temperature was close to the Newton's law of cooling and the released quantities were detected but too low to be measured. The 70C exposition resulted in a non-linear release that became quantifiable after one hour of heating up to an apparent plateau at 120 min with a mean concentration [extreme] of 24.6 [22.3 26.8] MUg/L. The results of the present study allow concluding that 95% silver used for cutlery and serving dishes may be released in foods. However, the extent of release depends on the condition of use. At a stable 70C temperature over a 2 h-period of time, silver is released in a non-linear model up to a mean concentration of 24.6 MUg/L. In contrast, in conditions fitting with the routine recommendations of use, infinitesimal detectable amounts of silver were released. PMID- 29623887 TI - Clinical and biological study of the 31 cases of gallstones. AB - This study reports the clinical and biological signs, as well as the morphological aspect and the chemical composition of the calculus during the biliary stones. The study population consisted of 31 patients with an average age of 49 years (30 women and one man) with biliary lithiasis and who had cholecystectomy. Hepatic colic and epigastralgia were the most evocative clinical signs. The calculus were pigmentary (n=6), cholesterolic and mostly single (n=18), and mixed (n=6) and one infectious multiple lithiasis. Cholesterol was found in 22 calculi (70.96%). We have found a significant increase in liver enzymes and total bilirubin, which is more pronounced in pigmentary lithiasis. Our results showed that most gallstones were composed of cholesterol. These results indicate the influence of diet and chronic hemolysis in calculus formation. More investigation should allow knowing the nutritional and environmental factors influencing gallstones formation in Tunisia, in order to prevent this disease. PMID- 29623888 TI - Comparative study of the tissue distribution of equimolar repeated doses of hydroxocobalamin and cobalt chloride in the rats. AB - High dose of the cobalt atom is toxic for mammals. Hydroxocobalamin is considered safe due to the inclusion of the cobalt atom into the heminic moiety. The tissue distribution of cobalt following repeated doses of either hydroxocobalamin or cobalt chloride was studied in Wistar rats. In both cases, cobalt was administered in equimolar doses daily for an overall period of three weeks. Three groups were designed. In the hydroxocobalamin treated group, ten rats received hydroxocobalamin 17.5 mg by intraperitoneal route daily. In the cobalt-treated group, ten rats received cobalt chloride 3 mg i.p. daily. In the control group, six rats received a daily injection of 0.35 mL isotonic sodium chloride i.p. Cobalt concentrations were measured by Inductively Coupled Plasma Atomic Emission. Ours results showed that in rats having received either hydroxocobalamin or cobalt chloride, the tissue concentrations of cobalt were greater than those in the control group. The present study documented that in naive rats, the repeated administration of high doses of cobalt as hydroxocobalamin leads to tissue concentrations of the atom of cobalt significantly lower than those induced by equimolar doses of cobalt administered as cobalt chloride (p <0.05). We conclude that hydroxocobalamin reduced the tissue distribution of the cobalt atom in comparison with cobalt chloride. PMID- 29623889 TI - Research and identification of antinuclear antibodies: analysis of a questionnaire from the European EASI group and confrontation of French practices to international recommendations. AB - Antinuclear antibodies (ANA) are prescribed as first-line autoantibodies in suspicion of mainly systemic autoimmune diseases. They include antibodies recognizing antigenic structures localized in the nucleus of cells, but also in the cytoplasm, at the membranes or transitional structures related to the cell cycle. Their research is based on screening and identification tests. For these tests, there is little or no standardization and harmonization of professional practices is necessary. From a questionnaire sent to healthcare professionals involved in the realization and interpretation of tests of autoimmunity, an overwiew of routine practices for the research of the ANA and their identification, was directed by the EASI Group International. Here, we present the results of the survey carried out in France. The analysis of these results faced with that of other countries as well as international recommendations allowed us to propose a synthesis of the main recommendations adapted to the regulatory texts of the NABM in France. These recommendations are addressed to those who prescribe, to those who perform biological analysis and to clinicians and biologists who interpret the results. They allow better understanding and admitting the methodological differences and their evolutions, to encourage the choice of the best technique based on the clinical context, to inform the clinician of the characteristics of the tests used. PMID- 29623890 TI - Journees nationales 2017 de la SFBC. PMID- 29623891 TI - Premiere edition du CoBioMe Congres des internes de biologie medicale. PMID- 29623892 TI - Deep venous thrombosis treated by rivaroxaban in a young patient with type Ia carbohydrate-deficient glycoprotein (CDG) syndrome. AB - Congenital disorders of glycosylation (CDG) are rare inborn diseases of glycan component of N-glycosylated proteins. We report here the case of a 28-year-old patient with CDG syndrome type Ia, who presented with a deep venous thrombosis in the left suro-popliteal vein with no known triggers or antecedents. The patient was treated with rivaroxaban for six months. Blood tests performed after discontinuing anticoagulant treatment showed multiple abnormalities affecting the proteins involved in haemostasis (both coagulation factors and inhibitors), i.e. a combined factor XI, antithrombin and protein C deficiency (35%, 41%, and 42% respectively) associated with a moderate increase of FVIII (179%) and VWFAg (163%) without inflammation. Patient results are here discussed with regard to the limited number of articles addressing haemostasis in this rare disease, as the occurrence of deep venous thrombosis remains uncommon in the literature. PMID- 29623893 TI - Immunoanalytical characteristics of HE4 protein. AB - Besides structural and physiological data of HE4 protein, this paper points out the optimal conditions for sampling, assays and interpretation of results for the management of ovarian cancer. PMID- 29623894 TI - Aseptic meningitis caused by the Varicella-zoster virus after primary infection in an immunocompetent child: a case report. PMID- 29623895 TI - High-sensitivity cardiac troponin T and hemodialysis: influence of gender, age and diabetes. PMID- 29623897 TI - Hesperidin attenuates influenza A virus (H1N1) induced lung injury in rats through its anti-inflammatory effect. AB - BACKGROUND: Influenza A viruses (IAV) can cause pandemics and are big threats to human health. Inflammation is the main pathological process in the lungs after IAV infection. We aimed to investigate whether hesperidin, a well-known anti inflammatory compound, could be effective in improving IAV-induced lung injury. METHODS: We generated a rat model using H1N1 virus infection, and intraperitoneally injected different doses of hesperidin for 5 days. Pulmonary function was analysed. Local inflammatory state was profiled by immune cells and cytokines. Pulmonary microvascular endothelial cells were isolated from rats and used to test the effects of hesperidin in vitro. RESULTS: Hesperidin showed efficacy in improving H1N1-induced impairment of pulmonary function in a dose dependent manner. Local numbers of immune cells and concentrations of cytokines were significantly limited by hesperidin. However, we found that hesperidin neither inhibited virus replication, nor rescued infected pulmonary microvascular endothelial cells. Rather, we observed that hesperidin reduced pro-inflammatory cytokine production by suppressing mitogen-activated protein kinase (MAPK) signalling pathways. CONCLUSIONS: Hesperidin could alleviate H1N1-induced impairment of pulmonary function by inhibiting cytokine production in pulmonary microvascular endothelial cells through MAPK signalling pathways. PMID- 29623898 TI - Nature of magnetization and lateral spin-orbit interaction in gated semiconductor nanowires. AB - Semiconductor nanowires are interesting candidates for realization of spintronics devices. In this paper we study electronic states and effects of lateral spin orbit coupling (LSOC) in a one-dimensional asymmetrically biased nanowire using the Hartree-Fock method with Dirac interaction. We have shown that spin polarization can be triggered by LSOC at finite source-drain bias,as a result of numerical noise representing a random magnetic field due to wiring or a random background magnetic field by Earth magnetic field, for instance. The electrons spontaneously arrange into spin rows in the wire due to electron interactions leading to a finite spin polarization. The direction of polarization is, however, random at zero source-drain bias. We have found that LSOC has an effect on orientation of spin rows only in the case when source-drain bias is applied. PMID- 29623899 TI - Critical exponents and universal magnetic behavior of noncentrosymmetric Fe0.6Co0.4Si. AB - The critical magnetic properties of a non-centrosymmetric B20 cubic helimagnet Fe0.6Co0.4Si are investigated using magnetization isotherms. It belongs to the 3D Heisenberg universality class with short range magnetic coupling as inferred from the self-consistent critical exponents [Formula: see text], [Formula: see text], [Formula: see text] and [Formula: see text] in combination with exchange interaction [Formula: see text]. Itinerant magnetic nature of the compound is realized by the Rhodes-Wholfarth analysis. Field-induced weak first (para[Formula: see text]helical) to second (para[Formula: see text]field polarized) order transition is reported to occur at low critical field due to the weak spin-orbit coupling arising from the weak Dzyaloshinksii-Moriya interactions. Our study suggests the distinct phenomenological magnetic structures for Fe-based cubic magnets (Fe1-x Co x Si and FeGe) and MnSi which cause contrasting physical properties. PMID- 29623901 TI - Summaries of articles in this issue. AB - Summaries of the articles in this issue are given in the PDF file. PMID- 29623902 TI - A continuous time-resolved measure decoded from EEG oscillatory activity predicts working memory task performance. AB - OBJECTIVE: Working memory (WM), crucial for successful behavioral performance in most of our everyday activities, holds a central role in goal-directed behavior. As task demands increase, inducing higher WM load, maintaining successful behavioral performance requires the brain to work at the higher end of its capacity. Because it is depending on both external and internal factors, individual WM load likely varies in a continuous fashion. The feasibility to extract such a continuous measure in time that correlates to behavioral performance during a working memory task remains unsolved. APPROACH: Multivariate pattern decoding was used to test whether a decoder constructed from two discrete levels of WM load can generalize to produce a continuous measure that predicts task performance. Specifically, a linear regression with L2-regularization was chosen with input features from EEG oscillatory activity recorded from healthy participants while performing the n-back task, [Formula: see text]. MAIN RESULTS: The feasibility to extract a continuous time-resolved measure that correlates positively to trial-by-trial working memory task performance is demonstrated (r = 0.47, p < 0.05). It is furthermore shown that this measure allows to predict task performance before action (r = 0.49, p < 0.05). We show that the extracted continuous measure enables to study the temporal dynamics of the complex activation pattern of WM encoding during the n-back task. Specifically, temporally precise contributions of different spectral features are observed which extends previous findings of traditional univariate approaches. SIGNIFICANCE: These results constitute an important contribution towards a wide range of applications in the field of cognitive brain-machine interfaces. Monitoring mental processes related to attention and WM load to reduce the risk of committing errors in high-risk environments could potentially prevent many devastating consequences or using the continuous measure as neurofeedback opens up new possibilities to develop novel rehabilitation techniques for individuals with degraded WM capacity. PMID- 29623903 TI - Single-particle fusion of influenza viruses reveals complex interactions with target membranes. AB - The first step in infection of influenza A virus is contact with the host cell membrane, with which it later fuses. The composition of the target bilayer exerts a complex influence on both fusion efficiency and time. Here, an in vitro, single particle approach is used to study this effect. Using total internal reflection fluorescence (TIRF) microscopy and a microfluidic flow cell, the hemifusion of single virions is visualized. Hemifusion efficiency and kinetics are studied while altering target bilayer cholesterol content and sialic-acid donor. Cholesterol ratios tested were 0%, 10%, 20%, and 40%. Sialic-acid donors GD1a and GYPA were used. Both cholesterol ratio and sialic-acid donors proved to have a significant effect on hemifusion efficiency. Furthermore, comparison between GD1a and GYPA conditions shows that the cholesterol dependence of the hemifusion time is severely affected by the sialic-acid donor. Only GD1a shows a clear increasing trend in hemifusion efficiency and time with increasing cholesterol concentration of the target bilayer with maximum rates for GD1A and 40% cholesterol. Overall our results show that sialic acid donor and target bilayer composition should be carefully chosen, depending on the desired hemifusion time and efficiency in the experiment. PMID- 29623900 TI - Pattern separation and completion of distinct axonal inputs transmitted via micro tunnels between co-cultured hippocampal dentate, CA3, CA1 and entorhinal cortex networks. AB - OBJECTIVE: Functions ascribed to the hippocampal sub-regions for encoding episodic memories include the separation of activity patterns propagated from the entorhinal cortex (EC) into the dentate gyrus (DG) and pattern completion in CA3 region. Since a direct assessment of these functions is lacking at the level of specific axonal inputs, our goal is to directly measure the separation and completion of distinct axonal inputs in engineered pairs of hippocampal sub regional circuits. APPROACH: We co-cultured EC-DG, DG-CA3, CA3-CA1 or CA1-EC neurons in a two-chamber PDMS device over a micro-electrode array (MEA60), inter connected via distinct axons that grow through the micro-tunnels between the compartments. Taking advantage of the axonal accessibility, we quantified pattern separation and completion of the evoked activity transmitted through the tunnels from source into target well. Since pattern separation can be inferred when inputs are more correlated than outputs, we first compared the correlations among axonal inputs with those of target somata outputs. We then compared, in an analog approach, the distributions of correlation distances between rate patterns of the axonal inputs inside the tunnels with those of the somata outputs evoked in the target well. Finally, in a digital approach, we measured the spatial population distances between binary patterns of the same axonal inputs and somata outputs. MAIN RESULTS: We found the strongest separation of the propagated axonal inputs when EC was axonally connected to DG, with a decline in separation to CA3 and to CA1 for both rate and digital approaches. Furthermore, the digital approach showed stronger pattern completion in CA3, then CA1 and EC. SIGNIFICANCE: To the best of our knowledge, these are the first direct measures of pattern separation and completion for axonal transmission to the somata target outputs at the rate and digital population levels in each of four stages of the EC-DG-CA3-CA1 circuit. PMID- 29623904 TI - Role of random magnetic anisotropy on the valence, magnetocaloric and resistivity properties in a hexagonal Sm2Ni0.87Si2.87 compound. AB - In this work, we report the effect of random magnetic anisotropy (RMA) on the valence, magnetocaloric and resistivity properties in a glassy intermetallic material Sm2Ni0.87Si2.87. On the basis of detailed studies on the valence band and core level electronic structure, we have established that both the Sm3+ and Sm2+ ions are present in the system, suggesting the compound to be of mixed valence in nature. The significant observation of positive magnetic entropy change in zero-field cooled measurement has been argued due to the presence of RMA that develops due to local electronic environmental variations between the rare-earth ions in the system. The quantum interference effect caused by the elastic electron-electron interaction is responsible for the resistivity upturn at low-temperature for this disordered metallic conductor. PMID- 29623905 TI - Compact standalone platform for neural recording with real-time spike sorting and data logging. AB - OBJECTIVE: Longitudinal observation of single unit neural activity from large numbers of cortical neurons in awake and mobile animals is often a vital step in studying neural network behaviour and towards the prospect of building effective brain-machine interfaces (BMIs). These recordings generate enormous amounts of data for transmission and storage, and typically require offline processing to tease out the behaviour of individual neurons. Our aim was to create a compact system capable of: (1) reducing the data bandwidth by circa 2 to 3 orders of magnitude (greatly improving battery lifetime and enabling low power wireless transmission in future versions); (2) producing real-time, low-latency, spike sorted data; and (3) long term untethered operation. APPROACH: We have developed a headstage that operates in two phases. In the short training phase a computer is attached and classic spike sorting is performed to generate templates. In the second phase the system is untethered and performs template matching to create an event driven spike output that is logged to a micro-SD card. To enable validation the system is capable of logging the high bandwidth raw neural signal data as well as the spike sorted data. MAIN RESULTS: The system can successfully record 32 channels of raw neural signal data and/or spike sorted events for well over 24 h at a time and is robust to power dropouts during battery changes as well as SD card replacement. A 24 h initial recording in a non-human primate M1 showed consistent spike shapes with the expected changes in neural activity during awake behaviour and sleep cycles. SIGNIFICANCE: The presented platform allows neural activity to be unobtrusively monitored and processed in real-time in freely behaving untethered animals-revealing insights that are not attainable through scheduled recording sessions. This system achieves the lowest power per channel to date and provides a robust, low-latency, low-bandwidth and verifiable output suitable for BMIs, closed loop neuromodulation, wireless transmission and long term data logging. PMID- 29623906 TI - Universal shape characteristics for the mesoscopic star-shaped polymer via dissipative particle dynamics simulations. AB - In this paper we study the shape characteristics of star-like polymers in various solvent quality using a mesoscopic level of modeling. The dissipative particle dynamics simulations are performed for the homogeneous and four different heterogeneous star polymers with the same molecular weight. We analyse the gyration radius and asphericity at the poor, good and theta-solvent regimes. Detailed explanation based on interplay between enthalpic and entropic contributions to the free energy and analyses on of the asphericity of individual branches are provided to explain the increase of the apsphericity in theta solvent regime. PMID- 29623907 TI - Recurrent paratesticular dedifferentiated liposarcoma after contralateral radical orchiectomy. PMID- 29623908 TI - The risk of human papillomavirus infection for male fertility abnormality: a meta analysis. AB - Human papillomavirus (HPV) is the most common sexually transmitted virus in males and females worldwide; yet its impact upon male fertility remains unclear. The objective of this study was to evaluate the potential impact of HPV infection in semen on male fertility abnormality. A systematic literature search was performed in PubMed, Medline, Embase, Web of Science, and the Cochrane Library database for relevant publications up to May 6, 2017. The odds ratio (OR), and its corresponding 95% confidence interval (CI), was selected to represent the effect size. Statistical analysis was conducted using STATA 12.0. In total, eight articles, providing data on 1955 participants, were included in this meta analysis. Collectively, the data suggested that HPV infection of semen was a risk factor for male fertility abnormality with an OR of 3.02 (95% CI: 2.11-4.32; I2 = 6.9%). Sensitivity analysis revealed that the results of this study were robust. In conclusion, HPV infection of semen represents a risk factor for male fertility abnormality. PMID- 29623909 TI - China Endeavors to Guarantee the Implementation of the Healthy China Initiative through Legislation. PMID- 29623910 TI - Evaluation of the SharkCore(r) needle for EUS-guided core biopsy of pancreatic neuroendocrine tumors. AB - Background and Objectives: EUS guided core biopsy was once rarely performed but is now entering mainstream practice. Neuroendocrine tumors often warrant core biopsy as sufficient tissue must be obtained to allow for special staining to ensure a correct diagnosis. Traditionally these lesions were sampled with FNA needles. We performed a retrospective pilot study to evaluate the clinical value and efficacy of the a new EUS core needle biopsy needle as compared to a standard EUS FNA needle in the evaluation of patients with known or suspected neuroendocrine tumors. Methods: A retrospective analysis of the first 10 patients (between January 2015 and April 2016) to undergo EUS-FNA with the SharkCore(r) needle at the University of Utah School of Medicine/Huntsman Cancer Center with neuroendocrine tumors. Each case was retrospectively reviewed by a board certified cytopathologist (BLW) for the following cytologic parameters on the aspirate smears or touch/squash preparations: overall cellularity [1 (low) to 3 (high)], percentage of obtained cells that were lesional/representative (<25%, 26%-50%, and >50%), relative ease of interpretation [1 (difficult) to 3 (easy)]. Pathologic material and reporting records were also reviewed for each case to confirm the number of needle passes to achieve diagnostic adequacy, the presence or absence diagnostic material on H&E slide (from cell block, if prepared), whether a definitive diagnosis was able to be rendered, and the presence or absence of a true core/core fragments (within the cell block, if prepared). Results: A total of 20 patients underwent EUS-FNA for suspected neuroendocrine lesions. Ten patients underwent either transgastric or transduodenal EUS-FNA with the 22 gauge SharkCore(r) needle. The comparison cohort of 10 patients underwent either transgastric or transduodenal EUS-FNA with the standard 22 gauge Echotip(r) needle. The SharkCore(r) needle required a fewer mean number of needle passes to obtain diagnostic adequacy than the Echotip(r) (P=0.0074). For cases with cell blocks, the SharkCore(r) needle produced diagnostic material in 100% of cases, whereas Echotip(r) produced diagnostic material in 60% of cases. There was no significant difference between specimen cellularity, percentage of lesional material, or ease of interpretation between the two needle types. Conclusion: Our pilot investigation targeting patients with known or suspected pancreatic NETs indicates that the SharkCore(r) needle shows promise in obtaining suitable tissue for ancillary testing that can allow for more definitive pathologic interpretations on EUS FNA specimens. Fewer passes were needed with the core needle when compared to a standard needle. PMID- 29623911 TI - A multicenter evaluation of a new EUS core biopsy needle: Experience in 200 patients. AB - Background and Objectives: We present a multicenter study of a new endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) needle (Acquire, Boston Scientific, Natick, MA). The aim of the study was to analyze the needle's clinical performance when sampling solid lesions and to assess the safety of this device. Methods: We performed a multicenter retrospective study of patients undergoing EUS-FNB during July 1-November 15, 2016. Results: Two hundred patients (121 males and 79 females) underwent EUS-FNB of solid lesions with the Acquire needle. Lesions included solid pancreatic masses (n = 109), adenopathy (n = 45), submucosal lesions (n = 34), cholangiocarcinoma (n = 8), liver lesions (n = 6), and other (n = 8). Mean lesion size was 30.6 mm (range: 3-100 mm). The mean number of passes per target lesion was 3 (range: 1-7). Rapid onsite cytologic evaluation (ROSE) by a cytologist was performed in all cases. Tissue obtained by EUS-FNB was adequate for evaluation and diagnosis by ROSE in 197/200 cases (98.5%). Data regarding the presence or absence of a core of tissue obtained after EUS-FNB were available in 145/200 procedures. In 131/145 (90%) of cases, a core of tissue was obtained. Thirteen out of 200 patients (6.5%) underwent some form of repeat EUS-based tissue acquisition after EUS-FNB with the Acquire needle. There were no adverse events. Conclusion: Overall, this study showed a high rate of tissue adequacy and production of a tissue core with this device with no adverse events seen in 200 patients. Comparative studies of different FNB needles are warranted in the future to help identify which needle type and size is ideal in different clinical settings. PMID- 29623915 TI - The relaxin peptide family - potential future hope for neuroprotective therapy? A short review. AB - Since its discovery in the 1920's the relaxin peptide hormone family has not only grown in number to now seven members (relaxin-1, relaxin-2, relaxin-3, insulin like peptide (INSL) 3, INSL4, INSL5 and INSL6), but ever more effects, suchs as vasodilatory, angiogenic, anti-apoptopic, anti-fibriotic and anti-inflammatory, have been linked to them. While relaxin-2 has mainly been investigated in the context of cardiac protection, most comprehensively in the RELAX-AHF and RELAX AHF2 studies, a small number of studies have furthermore assessed the potential neuroprotective effects of especially relaxin-2 and other members of the relaxin family. In this short review we summarise and discuss recent efforts to utilize relaxin hormones for neuroprotection and point out potential future fields of research and translational applications. While many questions still need to be answered, the promising results of the available studies definitely warrant future well-designed studies on neuroprotection by relaxin peptides. PMID- 29623916 TI - Roles of neural regeneration in memory pharmacology. PMID- 29623914 TI - Heterozygous carriers of galactocerebrosidase mutations that cause Krabbe disease have impaired microglial function and defective repair of myelin damage. AB - This review addresses two puzzling findings related to mutations in galactocerebrosidase (GALC) that cause Krabbe disease (KD), a severe lysosomal storage disorder characterized by extensive myelin damage in children with mutations in both GALC alleles. First, heterozygous carriers of KD-causing mutations, which include the biological parents of children with KD, exhibit increased risk for developing other diseases. Second, variants in the GALC locus increase the risk of developing multiple sclerosis (MS), another disease characterized by extensive myelin damage. What explains these correlations? In studies on cuprizone-induced myelin damage in heterozygous (GALC+/-) mice carrying one copy of a mutation that causes KD-like disease, the extent of damage was similar in GALC+/- and wild-type (WT) mice. In contrast, GALC+/- mice had striking defects in repair of cuprizone-induced damage. We further found unexpected microglial defects in myelin debris clearance and in the ability to up regulate the Trem2 microglial protein critical for debris uptake. These defects were rescued by exposure to a lysosomal re-acidifying drug discovered in our studies on KD, and which provides multiple clinically relevant benefits in the twitcher (GALC+/-) mouse model of KD. Thus, heterozygous GALC mutations cause effects on biological function that may help to understand the increased disease risk in heterozygous carriers of such mutations and to understand why GALC variations increase the risk of MS. Our findings indicate that while some genetic risk factors may contribute to complex diseases by increasing the risk of tissue damage, others may do so by compromising tissue repair. PMID- 29623917 TI - Towards frequency adaptation for delayed feedback deep brain stimulations. PMID- 29623913 TI - SNARE complex in axonal guidance and neuroregeneration. AB - Through complex mechanisms that guide axons to the appropriate routes towards their targets, axonal growth and guidance lead to neuronal system formation. These mechanisms establish the synaptic circuitry necessary for the optimal performance of the nervous system in all organisms. Damage to these networks can be repaired by neuroregenerative processes which in turn can re-establish synapses between injured axons and postsynaptic terminals. Both axonal growth and guidance and the neuroregenerative response rely on correct axonal growth and growth cone responses to guidance cues as well as correct synapses with appropriate targets. With this in mind, parallels can be drawn between axonal regeneration and processes occurring during embryonic nervous system development. However, when studying parallels between axonal development and regeneration many questions still arise; mainly, how do axons grow and synapse with their targets and how do they repair their membranes, grow and orchestrate regenerative responses after injury. Major players in the cellular and molecular processes that lead to growth cone development and movement during embryonic development are the Soluble N-ethylamaleimide Sensitive Factor (NSF) Attachment Protein Receptor (SNARE) proteins, which have been shown to be involved in axonal growth and guidance. Their involvement in axonal growth, guidance and neuroregeneration is of foremost importance, due to their roles in vesicle and membrane trafficking events. Here, we review the recent literature on the involvement of SNARE proteins in axonal growth and guidance during embryonic development and neuroregeneration. PMID- 29623918 TI - Linking axon transport to regeneration using in vitro laser axotomy. PMID- 29623919 TI - Targeting microthrombosis and neuroinflammation with vepoloxamer for therapeutic neuroprotection after traumatic brain injury. PMID- 29623921 TI - Metabolism, neurodegeneration and epigenetics: Emerging role of Sirtuins. PMID- 29623920 TI - Drugging SUMOylation for neuroprotection and oncotherapy. PMID- 29623912 TI - Cerebral ischemia and neuroregeneration. AB - Cerebral ischemia is one of the leading causes of morbidity and mortality worldwide. Although stroke (a form of cerebral ischemia)-related costs are expected to reach 240.67 billion dollars by 2030, options for treatment against cerebral ischemia/stroke are limited. All therapies except anti-thrombolytics (i.e., tissue plasminogen activator) and hypothermia have failed to reduce neuronal injury, neurological deficits, and mortality rates following cerebral ischemia, which suggests that development of novel therapies against stroke/cerebral ischemia are urgently needed. Here, we discuss the possible mechanism(s) underlying cerebral ischemia-induced brain injury, as well as current and future novel therapies (i.e., growth factors, nicotinamide adenine dinucleotide, melatonin, resveratrol, protein kinase C isozymes, pifithrin, hypothermia, fatty acids, sympathoplegic drugs, and stem cells) as it relates to cerebral ischemia. PMID- 29623922 TI - Melastatin-related transient receptor potential 2 channel in Abeta42-induced neuroinflammation: implications to Alzheimer's disease mechanism and development of therapeutics. PMID- 29623923 TI - Microcebus murinus: A novel promising non-human primate model of spinal cord injury. PMID- 29623924 TI - Immunomodulation as a neuroprotective strategy after spinal cord injury. PMID- 29623925 TI - Diffusion tensor imaging as a tool to detect presymptomatic axonal degeneration in a preclinical spinal cord model of amyotrophic lateral sclerosis. PMID- 29623926 TI - The protocadherin alpha cluster is required for axon extension and myelination in the developing central nervous system. AB - In adult mammals, axon regeneration after central nervous system injury is very poor, resulting in persistent functional loss. Enhancing the ability of axonal outgrowth may be a potential treatment strategy because mature neurons of the adult central nervous system may retain the intrinsic ability to regrow axons after injury. The protocadherin (Pcdh) clusters are thought to function in neuronal morphogenesis and in the assembly of neural circuitry in the brain. We cultured primary hippocampal neurons from E17.5 Pcdhalpha deletion (del-alpha) mouse embryos. After culture for 1 day, axon length was obviously shorter in del alpha neurons compared with wild-type neurons. RNA sequencing of hippocampal E17.5 RNA showed that expression levels of BDNF, Fmod, Nrp2, OGN, and Sema3d, which are associated with axon extension, were significantly down-regulated in the absence of the Pcdhalpha gene cluster. Using transmission electron microscopy, the ratio of myelinated nerve fibers in the axons of del-alpha hippocampal neurons was significantly decreased; myelin sheaths of P21 Pcdhalpha del mice showed lamellar disorder, discrete appearance, and vacuoles. These results indicate that the Pcdhalpha cluster can promote the growth and myelination of axons in the neurodevelopmental stage. PMID- 29623927 TI - Progesterone modulates mTOR in the hippocampus of mice after traumatic brain injury. AB - The mechanistic target of rapamycin (mTOR) is an intracellular protein kinase that functions as an energy and nutrient sensor in the cellular microenvironment of neurons. Modulation of mTOR is vital when nutrient and energy sources become limited. Hypoxia, traumatic brain injury, cellular energy states, and growth factors all regulate the phosphorylation and total levels of mTOR in cells. Alterations in the microenvironment induce transduction of signals to downstream proteins by mTOR allowing for cells to make the necessary adjustments to counteract stressors and survive. Progesterone, a hydrophobic steroid hormone, has been shown in studies of non-neural tissue to be a suppressor of mTOR and modulator of mTOR phosphorylation. Our study tested the effects of progesterone on mTOR expression following traumatic brain injury. C57BL/6 mice were treated with progesterone (8 mg/kg) at 1 (intraperitoneal), 6 (subcutaneous), 24 (subcutaneous), and 48 (subcutaneous) hours post closed skull traumatic brain injury. The hippocampus was then harvested 72 hours post injury and prepared for western blot analysis. We found that progesterone significantly decreased total mTOR levels in all groups compared to sham treated with vehicle. This was further confirmed by immunostaining showing decreased cytoplasmic mTOR levels compared to sham. Our study shows progesterone is a significant modulator of mTOR levels in the hippocampus of mice following traumatic brain injury. PMID- 29623928 TI - Effect of tibolone pretreatment on kinases and phosphatases that regulate the expression and phosphorylation of Tau in the hippocampus of rats exposed to ozone. AB - Oxidative stress (OS) is a key process in the development of many neurodegenerative diseases, memory disorders, and other pathological processes related to aging. Tibolone (TIB), a synthetic hormone used as a treatment for menopausal symptoms, decreases lipoperoxidation levels, prevents memory impairment and learning disability caused by ozone (O3) exposure. However, it is not clear if TIB could prevent the increase in phosphorylation induced by oxidative stress of the microtubule-associated protein Tau. In this study, the effects of TIB at different times of administration on the phosphorylation of Tau, the activation of glycogen synthase kinase-3beta (GSK3beta), and the inactivation of Akt and phosphatases PP2A and PTEN induced by O3 exposure were assessed in adult male Wistar rats. Rats were divided into 10 groups: control group (ozone-free air plus vehicle [C]), control + TIB group (ozone-free air plus TIB 1 mg/kg [C + TIB]); 7, 15, 30, and 60 days of ozone exposure groups [O3] and 7, 15, 30, and 60 days of TIB 1 mg/kg before ozone exposure groups [O3 + TIB]. The effects of O3 exposure and TIB administration were assessed by western blot analysis of total and phosphorylated Tau, GSK3beta, Akt, PP2A, and PTEN proteins and oxidative stress marker nitrotyrosine, and superoxide dismutase activity and lipid peroxidation of malondialdehyde by two different spectrophotometric methods (Marklund and TBARS, respectively). We observed that O3 exposure increases Tau phosphorylation, which is correlated with decreased PP2A and PTEN protein levels, diminished Akt protein levels, and increased GSK3beta protein levels in the hippocampus of adult male rats. The effects of O3 exposure were prevented by the long-term treatment (over 15 days) with TIB. Malondialdehyde and nitrotyrosine levels increased from 15 to 60 days of exposure to O3 in comparison to C group, and superoxide dismutase activity decreased. Furthermore, TIB administration limited the changes induced by O3 exposure. Our results suggest a beneficial use of hormone replacement therapy with TIB to prevent neurodegeneration caused by O3 exposure in rats. PMID- 29623930 TI - In vivo observation of cerebral microcirculation after experimental subarachnoid hemorrhage in mice. AB - Acute brain injury caused by subarachnoid hemorrhage is the major cause of poor prognosis. The pathology of subarachnoid hemorrhage likely involves major morphological changes in the microcirculation. However, previous studies primarily used fixed tissue or delayed injury models. Therefore, in the present study, we used in vivo imaging to observe the dynamic changes in cerebral microcirculation after subarachnoid hemorrhage. Subarachnoid hemorrhage was induced by perforation of the bifurcation of the middle cerebral and anterior cerebral arteries in male C57/BL6 mice. The diameter of pial arterioles and venules was measured by in vivo fluorescence microscopy at different time points within 180 minutes after subarachnoid hemorrhage. Cerebral blood flow was examined and leukocyte adhesion/albumin extravasation was determined at different time points before and after subarachnoid hemorrhage. Cerebral pial microcirculation was abnormal and cerebral blood flow was reduced after subarachnoid hemorrhage. Acute vasoconstriction occurred predominantly in the arterioles instead of the venules. A progressive increase in the number of adherent leukocytes in venules and substantial albumin extravasation were observed between 10 and 180 minutes after subarachnoid hemorrhage. These results show that major changes in microcirculation occur in the early stage of subarachnoid hemorrhage. Our findings may promote the development of novel therapeutic strategies for the early treatment of subarachnoid hemorrhage. PMID- 29623929 TI - Quinacrine pretreatment reduces microwave-induced neuronal damage by stabilizing the cell membrane. AB - Quinacrine, widely used to treat parasitic diseases, binds to cell membranes. We previously found that quinacrine pretreatment reduced microwave radiation damage in rat hippocampal neurons, but the molecular mechanism remains poorly understood. Considering the thermal effects of microwave radiation and the protective effects of quinacrine on heat damage in cells, we hypothesized that quinacrine would prevent microwave radiation damage to cells in a mechanism associated with cell membrane stability. To test this, we used retinoic acid to induce PC12 cells to differentiate into neuron-like cells. We then pretreated the neurons with quinacrine (20 and 40 mM) and irradiated them with 50 mW/cm2 microwaves for 3 or 6 hours. Flow cytometry, atomic force microscopy and western blot assays revealed that irradiated cells pretreated with quinacrine showed markedly less apoptosis, necrosis, and membrane damage, and greater expression of heat shock protein 70, than cells exposed to microwave irradiation alone. These results suggest that quinacrine stabilizes the neuronal membrane structure by upregulating the expression of heat shock protein 70, thus reducing neuronal injury caused by microwave radiation. PMID- 29623931 TI - Associations between thromboxane A synthase 1 gene polymorphisms and the risk of ischemic stroke in a Chinese Han population. AB - Thromboxane A synthase 1 (TBXAS1) catalyses the synthesis of thromboxane A2 (TXA2), which plays an important role in the pathogenesis of ischemic stroke. Thus, the TBXAS1 gene was investigated as a candidate gene involved in the formation of atherosclerosis. This case-control study collected peripheral blood specimens and clinical data of 370 ischemic stroke patients and 340 healthy controls in the Northern Chinese Han population from October 2010 to May 2011. Two TBXAS1 single-nucleotide polymorphisms, rs2267682 and rs10487667, were analyzed using a SNaPshot Multiplex sequencing assay to explore the relationships between the single-nucleotide polymorphisms in TBXAS1 and ischemic stroke. The TT genotype frequency and T allele frequency of rs2267682 in the patients with ischemic stroke were significantly higher than those in the controls (P < 0.01 and P = 0.02). Furthermore, compared with the GG + GT genotype, the TT rs2267682 genotype was associated with increased risk of ischemic stroke (odds ratio (OR) = 1.80, 95% confidence interval (CI): 1.16-2.79, P < 0.01). Multivariate logistic analysis with adjustments for confounding factors revealed that rs2267682 was still associated with ischemic stroke (OR = 1.94, 95% CI : 1.13-3.33, P = 0.02). The frequency of the T-G haplotype in the patients was significantly higher than that in the controls according haplotype analysis (OR = 1.49, 95% CI: 1.10-2.00, P < 0.01). These data reveal that the rs2267682 TBXAS1 polymorphism is associated with ischemic stroke. The TT genotype of TBXAS1 and T allele of rs2267682 increase susceptibility to ischemic stroke in this Northern Chinese Han population. The protocol has been registered with the Chinese Clinical Trial Registry (registration number: ChiCTR-COC-17013559). PMID- 29623932 TI - Evaluation of nerve transfer options for treating total brachial plexus avulsion injury: A retrospective study of 73 participants. AB - Despite recent great progress in diagnosis and microsurgical repair, the prognosis in total brachial plexus-avulsion injury remains unfavorable. Insufficient number of donors and unreasonable use of donor nerves might be key factors. To identify an optimal treatment strategy for this condition, we conducted a retrospective review. Seventy-three patients with total brachial plexus avulsion injury were followed up for an average of 7.3 years. Our analysis demonstrated no significant difference in elbow-flexion recovery between phrenic nerve-transfer (25 cases), phrenic nerve-graft (19 cases), intercostal nerve (17 cases), or contralateral C7-transfer (12 cases) groups. Restoration of shoulder function was attempted through anterior accessory nerve (27 cases), posterior accessory nerve (10 cases), intercostal nerve (5 cases), or accessory + intercostal nerve transfer (31 cases). Accessory nerve + intercostal nerve transfer was the most effective method. A significantly greater amount of elbow extension was observed in patients with intercostal nerve transfer (25 cases) than in those with contralateral C7 transfer (10 cases). Recovery of median nerve function was noticeably better for those who received entire contralateral C7 transfer (33 cases) than for those who received partial contralateral C7 transfer (40 cases). Wrist and finger extension were reconstructed by intercostal nerve transfer (31 cases). Overall, the recommended surgical treatment for total brachial plexus-avulsion injury is phrenic nerve transfer for elbow flexion, accessory nerve + intercostal nerve transfer for shoulder function, intercostal nerves transfer for elbow extension, entire contralateral C7 transfer for median nerve function, and intercostal nerve transfer for finger extension. The trial was registered at ClinicalTrials.gov (identifier: NCT03166033). PMID- 29623933 TI - Electroacupuncture and moxibustion promote regeneration of injured sciatic nerve through Schwann cell proliferation and nerve growth factor secretion. AB - Using electroacupuncture and moxibustion to treat peripheral nerve injury is highly efficient with low side effects. However, the electroacupuncture- and moxibustion-based mechanisms underlying nerve repair are still unclear. Here, in vivo and in vitro experiments uncovered one mechanism through which electroacupuncture and moxibustion affect regeneration after peripheral nerve injury. We first established rat models of sciatic nerve injury using neurotomy. Rats were treated with electroacupuncture or moxibustion at acupoints Huantiao (GB30) and Zusanli (ST36). Each treatment lasted 15 minutes, and treatments were given six times a week for 4 consecutive weeks. Behavioral testing was used to determine the sciatic functional index. We used electrophysiological detection to measure sciatic nerve conduction velocity and performed hematoxylin-eosin staining to determine any changes in the gastrocnemius muscle. We used immunohistochemistry to observe changes in the expression of S100-a specific marker for Schwann cells-and an enzyme-linked immunosorbent assay to detect serum level of nerve growth factor. Results showed that compared with the model-only group, sciatic functional index, recovery rate of conduction velocity, diameter recovery of the gastrocnemius muscle fibers, number of S100-immunoreactive cells, and level of nerve growth factor were greater in the electroacupuncture and moxibustion groups. The efficacy did not differ between treatment groups. The serum from treated rats was collected and used to stimulate Schwann cells cultured in vitro. Results showed that the viability of Schwann cells was much higher in the treatment groups than in the model group at 3 and 5 days after treatment. These findings indicate that electroacupuncture and moxibustion promoted nerve regeneration and functional recovery; its mechanism might be associated with the enhancement of Schwann cell proliferation and upregulation of nerve growth factor. PMID- 29623934 TI - Acetyl-11-keto-beta-boswellic acid extracted from Boswellia serrata promotes Schwann cell proliferation and sciatic nerve function recovery. AB - Frankincense can promote blood circulation. Acetyl-11-keto-beta-boswellic acid (AKBA) is a small molecule with anti-inflammatory properties that is derived from Boswellia serrata. Here, we hypothesized that it may promote regeneration of injured sciatic nerve. To address this hypothesis, we established a rat model of sciatic nerve injury using a nerve clamping method. Rats were administered AKBA once every 2 days at doses of 1.5, 3, and 6 mg/kg by intraperitoneal injection for 30 days from the 1st day after injury. Sciatic nerve function was evaluated using the sciatic functional index. Degree of muscle atrophy was measured using the triceps surae muscle Cuadros index. Neuropathological changes were observed by hematoxylin-eosin staining. Western blot analysis was used to detect expression of phospho-extracellular signal-regulated kinase 1 and 2 (p-ERK1/2) in injured nerve. S100 immunoreactivity in injured nerve was detected by immunohistochemistry. In vivo experiments showed that 3 and 6 mg/kg AKBA significantly increased sciatic nerve index, Cuadros index of triceps muscle, p ERK1/2 expression, and S100 immunoreactivity in injured sciatic nerve of sciatic nerve injury model rats. Furthermore, for in vitro experiments, Schwann cells were treated with AKBA at 0-20 MUg/mL. Proliferation of Schwann cells was detected by Cell Counting Kit-8 colorimetry assay. The results showed that 2 MUg/mL AKBA is the optimal therapeutic concentration. In addition, ERK phosphorylation levels increased following 2 MUg/mL AKBA treatment. In the presence of the ERK1/2 inhibitor, PD98059 (2.5 MUL/mL), the AKBA-induced increase in p-ERK1/2 protein expression was partially abrogated. In conclusion, our study shows that AKBA promotes peripheral nerve regeneration with ERK protein phosphorylation playing a key role in this process. PMID- 29623935 TI - Neuroprotective effect of ischemic postconditioning on sciatic nerve transection. AB - Ischemic preconditioning or postconditioning has been shown to have neuroprotective effect on cerebral ischemia, but it has not been studied in peripheral nerve injury. In this study, a rat model of sciatic nerve transection was established, and subjected to three cycles of ischemia for 10 minutes + reperfusion for 10 minutes, once a day. After ischemic postconditioning, serum insulin-like growth factor 1 expression increased; sciatic nerve Schwann cell myelination increased; sensory function and motor function were restored. These findings indicate that ischemic postconditioning can effectively protect injured sciatic nerve. The protective effect is possibly associated with upregulation of insulin-like growth factor 1. PMID- 29623936 TI - Cell proliferation during hair cell regeneration induced by Math1 in vestibular epithelia in vitro. AB - Hair cell regeneration is the fundamental method of correcting hearing loss and balance disorders caused by hair cell damage or loss. How to promote hair cell regeneration is a hot focus in current research. In mammals, cochlear hair cells cannot be regenerated and few vestibular hair cells can be renewed through spontaneous regeneration. However, Math1 gene transfer allows a few inner ear cells to be transformed into hair cells in vitro or in vivo. Hair cells can be renewed through two possible means in birds: supporting cell differentiation and transdifferentiation with or without cell division. Hair cell regeneration is strongly associated with cell proliferation. Therefore, this study explored the relationship between Math1-induced vestibular hair cell regeneration and cell division in mammals. The mouse vestibule was isolated to harvest vestibular epithelial cells. Ad-Math1-enhanced green fluorescent protein (EGFP) was used to track cell division during hair cell transformation. 5-Bromo-2'-deoxyuridine (BrdU) was added to track cell proliferation at various time points. Immunocytochemistry was utilized to determine cell differentiation and proliferation. Results demonstrated that when epithelial cells were in a higher proliferative stage, more of these cells differentiated into hair cells by Math1 gene transfer. However, in the low proliferation stage, no BrdU-positive cells were seen after Math1 gene transfer. Cell division always occurred before Math1 transfection but not during or after Math1 transfection, when cells were labeled with BrdU before and after Ad-Math1-EGFP transfection. These results confirm that vestibular epithelial cells with high proliferative potential can differentiate into new hair cells by Math1 gene transfer, but this process is independent of cell proliferation. PMID- 29623937 TI - Efficacy of chitosan and sodium alginate scaffolds for repair of spinal cord injury in rats. AB - Spinal cord injury results in the loss of motor and sensory pathways and spontaneous regeneration of adult mammalian spinal cord neurons is limited. Chitosan and sodium alginate have good biocompatibility, biodegradability, and are suitable to assist the recovery of damaged tissues, such as skin, bone and nerve. Chitosan scaffolds, sodium alginate scaffolds and chitosan-sodium alginate scaffolds were separately transplanted into rats with spinal cord hemisection. Basso-Beattie-Bresnahan locomotor rating scale scores and electrophysiological results showed that chitosan scaffolds promoted recovery of locomotor capacity and nerve transduction of the experimental rats. Sixty days after surgery, chitosan scaffolds retained the original shape of the spinal cord. Compared with sodium alginate scaffolds- and chitosan-sodium alginate scaffolds-transplanted rats, more neurofilament-H-immunoreactive cells (regenerating nerve fibers) and less glial fibrillary acidic protein-immunoreactive cells (astrocytic scar tissue) were observed at the injury site of experimental rats in chitosan scaffold-transplanted rats. Due to the fast degradation rate of sodium alginate, sodium alginate scaffolds and composite material scaffolds did not have a supporting and bridging effect on the damaged tissue. Above all, compared with sodium alginate and composite material scaffolds, chitosan had better biocompatibility, could promote the regeneration of nerve fibers and prevent the formation of scar tissue, and as such, is more suitable to help the repair of spinal cord injury. PMID- 29623938 TI - Delayed xenon post-conditioning mitigates spinal cord ischemia/reperfusion injury in rabbits by regulating microglial activation and inflammatory factors. AB - The neuroprotective effect against spinal cord ischemia/reperfusion injury in rats exerted by delayed xenon post-conditioning is stronger than that produced by immediate xenon post-conditioning. However, the mechanisms underlying this process remain unclear. Activated microglia are the main inflammatory cell type in the nervous system. The release of pro-inflammatory factors following microglial activation can lead to spinal cord damage, and inhibition of microglial activation can relieve spinal cord ischemia/reperfusion injury. To investigate how xenon regulates microglial activation and the release of inflammatory factors, a rabbit model of spinal cord ischemia/reperfusion injury was induced by balloon occlusion of the infrarenal aorta. After establishment of the model, two interventions were given: (1) immediate xenon post-conditioning after reperfusion, inhalation of 50% xenon for 1 hour, 50% N2/50%O2 for 2 hours; (2) delayed xenon post-conditioning-after reperfusion, inhalation of 50% N2/50%O2 for 2 hours, 50% xenon for 1 hour. At 4, 8, 24, 48 and 72 hours after reperfusion, hindlimb locomotor function was scored using the Jacobs locomotor scale. At 72 hours after reperfusion, interleukin 6 and interleukin 10 levels in the spinal cord of each group were measured using western blot assays. Iba1 levels were determined using immunohistochemistry and a western blot assay. The number of normal neurons at the injury site was quantified using hematoxylin eosin staining. At 72 hours after reperfusion, delayed xenon post-conditioning remarkably enhanced hindlimb motor function, increased the number of normal neurons at the injury site, decreased Iba1 levels, and inhibited interleukin-6 and interleukin-10 levels in the spinal cord. Immediate xenon post-conditioning did not noticeably affect the above-mentioned indexes. These findings indicate that delayed xenon post-conditioning after spinal cord injury improves the recovery of neurological function by reducing microglial activation and the release of interleukin-6 and interleukin-10. PMID- 29623939 TI - Cell cycle and complement inhibitors may be specific for treatment of spinal cord injury in aged and young mice: Transcriptomic analyses. AB - Previous studies have reported age-specific pathological and functional outcomes in young and aged patients suffering spinal cord injury, but the mechanisms remain poorly understood. In this study, we examined mice with spinal cord injury. Gene expression profiles from the Gene Expression Omnibus database (accession number GSE93561) were used, including spinal cord samples from 3 young injured mice (2-3-months old, induced by Impactor at Th9 level) and 3 control mice (2-3-months old, no treatment), as well as 2 aged injured mice (15-18-months old, induced by Impactor at Th9 level) and 2 control mice (15-18-months old, no treatment). Differentially expressed genes (DEGs) in spinal cord tissue from injured and control mice were identified using the Linear Models for Microarray data method, with a threshold of adjusted P < 0.05 and |logFC(fold change)| > 1.5. Protein-protein interaction networks were constructed using data from the STRING database, followed by module analysis by Cytoscape software to screen crucial genes. Kyoto encyclopedia of genes and genomes pathway and Gene Ontology enrichment analyses were performed to investigate the underlying functions of DEGs using Database for Annotation, Visualization and Integrated Discovery. Consequently, 1,604 and 1,153 DEGs were identified between injured and normal control mice in spinal cord tissue of aged and young mice, respectively. Furthermore, a Venn diagram showed that 960 DEGs were shared among aged and young mice, while 644 and 193 DEGs were specific to aged and young mice, respectively. Functional enrichment indicates that shared DEGs are involved in osteoclast differentiation, extracellular matrix-receptor interaction, nuclear factor-kappa B signaling pathway, and focal adhesion. Unique genes for aged and young injured groups were involved in the cell cycle (upregulation of PLK1) and complement (upregulation of C3) activation, respectively. These findings were confirmed by functional analysis of genes in modules (common, 4; aged, 2; young, 1) screened from protein-protein interaction networks. Accordingly, cell cycle and complement inhibitors may be specific treatments for spinal cord injury in aged and young mice, respectively. PMID- 29623940 TI - DTI and pathological changes in a rabbit model of radiation injury to the spinal cord after 125I radioactive seed implantation. AB - Excessive radiation exposure may lead to edema of the spinal cord and deterioration of the nervous system. Magnetic resonance imaging can be used to judge and assess the extent of edema and to evaluate pathological changes and thus may be used for the evaluation of spinal cord injuries caused by radiation therapy. Radioactive 125I seeds to irradiate 90% of the spinal cord tissue at doses of 40-100 Gy (D90) were implanted in rabbits at T10 to induce radiation injury, and we evaluated their safety for use in the spinal cord. Diffusion tensor imaging showed that with increased D90, the apparent diffusion coefficient and fractional anisotropy values were increased. Moreover, pathological damage of neurons and microvessels in the gray matter and white matter was aggravated. At 2 months after implantation, obvious pathological injury was visible in the spinal cords of each group. Magnetic resonance diffusion tensor imaging revealed the radiation injury to the spinal cord, and we quantified the degree of spinal cord injury through apparent diffusion coefficient and fractional anisotropy. PMID- 29623941 TI - Endoplasmic reticulum stress transducer old astrocyte specifically induced substance contributes to astrogliosis after spinal cord injury. AB - Old astrocyte specifically induced substance (OASIS) is an endoplasmic reticulum (ER) stress transducer specifically expressed in astrocytes and osteoblasts. OASIS regulates the differentiation of neural precursor cells into astrocytes in the central nervous system. This study aimed to elucidate the involvement of ER stress responses stimulated via OASIS in astrogliosis following spinal cord injury. In a mouse model of spinal cord contusion injury, OASIS mRNA and protein expression were evaluated at days 7 and 14. A significant increase in OASIS mRNA on day 7 and an increase in protein on days 7 and 14 was observed in injured spinal cords. Immunostaining on day 7 revealed co-localization of OASIS and astrocytes in the periphery of the injury site. Furthermore, anti-OASIS small interfering RNA (siRNA) was injected at the injury sites on day 5 to elucidate the function of OASIS. Treatment with anti-OASIS siRNA caused a significant decrease in OASIS mRNA on day 7 and protein on days 7 and 14, and was associated with the inhibition of astrogliosis and hindlimb motor function recovery. Results of our study show that OASIS expression synchronizes with astrogliosis and is functionally associated with astrogliosis after spinal cord injury. PMID- 29623942 TI - Combined acupuncture and HuangDiSan treatment affects behavior and synaptophysin levels in the hippocampus of senescence-accelerated mouse prone 8 after neural stem cell transplantation. AB - Sanjiao acupuncture and HuangDiSan can promote the proliferation, migration and differentiation of exogenous neural stem cells in senescence-accelerated mouse prone 8 (SAMP8) mice and can improve learning and memory impairment and behavioral function in dementia-model mice. Thus, we sought to determine whether Sanjiao acupuncture and HuangDiSan can elevate the effect of neural stem cell transplantation in Alzheimer's disease model mice. Sanjiao acupuncture was used to stimulate Danzhong (CV17), Zhongwan (CV12), Qihai (CV6), bilateral Xuehai (SP10) and bilateral Zusanli (ST36) 15 days before and after implantation of neural stem cells (5 * 105) into the hippocampal dentate gyrus of SAMP8 mice. Simultaneously, 0.2 mL HuangDiSan, containing Rehmannia Root and Chinese Angelica, was intragastrically administered. Our results demonstrated that compared with mice undergoing neural stem cell transplantation alone, learning ability was significantly improved and synaptophysin mRNA and protein levels were greatly increased in the hippocampus of mice undergoing both Sanjiao acupuncture and intragastric administration of HuangDiSan. We conclude that the combination of Sanjiao acupuncture and HuangDiSan can effectively improve dementia symptoms in mice, and the mechanism of this action might be related to the regulation of synaptophysin expression. PMID- 29623943 TI - The ROCK pathway inhibitor Y-27632 mitigates hypoxia and oxidative stress-induced injury to retinal Muller cells. AB - Rho kinase (ROCK) was the first downstream Rho effector found to mediate RhoA induced actin cytoskeletal changes through effects on myosin light chain phosphorylation. There is abundant evidence that the ROCK pathway participates in the pathogenesis of retinal endothelial injury and proliferative epiretinal membrane traction. In this study, we investigated the effect of the ROCK pathway inhibitor Y-27632 on retinal Muller cells subjected to hypoxia or oxidative stress. Muller cells were subjected to hypoxia or oxidative stress by exposure to CoCl2 or H2O2. After a 24-hour treatment with Y-27632, the 3-(4,5-dimethylthiazol 2-yl)-2,5-diphenyl tetrazolium bromide assay was used to assess the survival of Muller cells. Hoechst 33258 was used to detect apoptosis, while 2',7' dichlorodihydrofluorescein diacetate was used to measure reactive oxygen species generation. A transwell chamber system was used to examine the migration ability of Muller cells. Western blot assay was used to detect the expression levels of alpha-smooth muscle actin, glutamine synthetase and vimentin. After treatment with Y-27632, Muller cells subjected to hypoxia or oxidative stress exhibited a morphology similar to control cells. Y-27632 reduced apoptosis, alpha-smooth muscle actin expression and reactive oxygen species generation under oxidative stress, and it reduced cell migration under hypoxia. Y-27632 also upregulated glutamine synthetase expression under hypoxia but did not impact vimentin expression. These findings suggest that Y-27632 protects Muller cells against cellular injury caused by oxidative stress and hypoxia by inhibiting the ROCK pathway. PMID- 29623946 TI - The biological clock: Future of neurological disorders therapy. PMID- 29623945 TI - Optic radiation injury in patients with aneurismal subarachnoid hemorrhage: A preliminary diffusion tensor imaging report. AB - Visual field defect is one of the various clinical manifestations in patients with subarachnoid hemorrhage (SAH). Little is known about the pathogenic mechanism of visual field defect in SAH. In the current study, we investigated the diffusion tensor imaging (DTI) finding of the optic radiation in patients with SAH following rupture of a cerebral artery aneurysm. We recruited 21 patients with aneurismal SAH (12 males, 9 females, mean age, 52.67 years; range, 41-68 years) who showed no definite lesion along the visual pathway. Twenty-one age-and sex-matched normal control subjects were also recruited. DTI data were acquired at an average of 5.9 weeks (range: 3-12 weeks) after onset and reconstruction of the optic radiation was performed using DTI-Studio software. The fractional anisotropy value, apparent diffusion coefficient value, and fiber number of the optic radiation were measured. The fractional anisotropy value of the optic radiation was significantly decreased, and the apparent diffusion coefficient value was significantly increased, in patients with aneurismal SAH than in normal control subjects. However, there was no significant difference in the fiber number of the optic radiation between patients with aneurismal SAH and normal control subjects. The decrement of fractional anisotropy value and increment of apparent diffusion coefficient value of the optic radiation in patients with aneurismal SAH suggest optic radiation injury. Therefore, we recommend a thorough evaluation for optic radiation injury in patient with aneurismal SAH. PMID- 29623944 TI - Regulatory role of calpain in neuronal death. AB - Calpains are a group of calcium-dependent proteases that are over activated by increased intracellular calcium levels under pathological conditions. A wide range of substrates that regulate necrotic, apoptotic and autophagic pathways are affected by calpain. Calpain plays a very important role in neuronal death and various neurological disorders. This review introduces recent research progress related to the regulatory mechanisms of calpain in neuronal death. Various neuronal programmed death pathways including apoptosis, autophagy and regulated necrosis can be divided into receptor interacting protein-dependent necroptosis, mitochondrial permeability transition-dependent necrosis, pyroptosis and poly (ADP-ribose) polymerase 1-mediated parthanatos. Calpains cleave series of key substrates that may lead to cell death or participate in cell death. Regarding the investigation of calpain-mediated programed cell death, it is necessary to identify specific inhibitors that inhibit calpain mediated neuronal death and nervous system diseases. PMID- 29623947 TI - Genetic Polymorphisms of the Mitochondrial Aldehyde Dehydrogenase ALDH2 Gene in a Large Ethnic Hakka Population in Southern China. AB - BACKGROUND Human mitochondrial aldehyde dehydrogenase 2 (ALDH2) plays a critical role in the detoxification of the ethanol metabolite acetaldehyde. The ALDH2*2 (rs671) gene variant is mainly absent among Europeans but is prevalent in populations in East Asia. The aim of this study was to investigate ALDH2*2 mutant alleles and genotype frequencies in the Hakka population of China. MATERIAL AND METHODS Between January 2016 and June 2017, 7,966 unrelated individuals were recruited into the study from the Hakka ethnic population residing in the Meizhou area of Guangdong Province, China, who provided venous blood samples. Genotyping of ALDH2 genotypes were determined using a gene chip platform and confirmed by DNA sequencing. RESULTS In the 7,966 individuals from the Hakka population of China in this study, the frequencies of the ALDH2 genotypes *1/*1, *1/*2 and *2/*2 were 52.03%, 39.67%, and 8.30%, respectively; 47.97% of the individuals were found to carry the ALDH2*2 genotype, which was associated with a deficiency in the aldehyde dehydrogenase (ALDH2) enzyme activity. The frequency of the ALDH2*2 allele was lower than that previously reported in the Japanese population but higher than that reported in other Oriental populations. CONCLUSIONS The findings of this study have provided new information on the ALDH2 gene polymorphisms in the Hakka ethnic population residing in the Meizhou area of Guangdong Province, China, including an understanding of the origin of the atypical ALDH2*2 allele. Also, the study findings may be relevant to the primary care of patients in China. PMID- 29623948 TI - Corrigendum: Hypertension and the risk of endometrial cancer: a systematic review and meta-analysis of case-control and cohort studies. AB - This corrects the article DOI: 10.1038/srep44808. PMID- 29623950 TI - Erratum: miR-2478 inhibits TGFbeta1 expression by targeting the transcriptional activation region downstream of the TGFbeta1 promoter in dairy goats. AB - This corrects the article DOI: 10.1038/srep42627. PMID- 29623951 TI - Erratum: Impairment of PDGF-induced chemotaxis by extracellular alpha-synuclein through selective inhibition of Rac1 activation. AB - This corrects the article DOI: 10.1038/srep37810. PMID- 29623952 TI - Corrigendum: Atrasentan increased the expression of klotho by mediating miR-199b 5p and prevented renal tubular injury in diabetic nephropathy. AB - This corrects the article DOI: 10.1038/srep19979. PMID- 29623949 TI - Teleneurology and mobile technologies: the future of neurological care. AB - Neurological disorders are the leading cause of global disability. However, for most people around the world, current neurological care is poor. In low-income countries, most individuals lack access to proper neurological care, and in high income countries, distance and disability limit access. With the global proliferation of smartphones, teleneurology - the use of technology to provide neurological care and education remotely - has the potential to improve and increase access to care for billions of people. Telestroke has already fulfilled this promise, but teleneurology applications for chronic conditions are still in their infancy. Similarly, few studies have explored the capabilities of mobile technologies such as smartphones and wearable sensors, which can guide care by providing objective, frequent, real-world assessments of patients. In low-income settings, teleneurology can increase the capacity of local care systems through professional development, diagnostic support and consultative services. In high income settings, teleneurology is likely to promote the expansion and migration of neurological care away from institutions, incorporate systems of asynchronous communication (such as e-mail), integrate clinicians with diverse skill sets and reach new populations. Inertia, outdated policies and social barriers - especially the digital divide - will slow this progress at considerable cost. However, a future increasingly will be possible in which neurological care can be accessed by anyone, anywhere. Here, we examine the emerging evidence regarding the benefits of teleneurology for chronic conditions, its role and risks in low income countries and the promise of mobile technologies to measure disease status and deliver care. We conclude by discussing the future trends, barriers and timing for the adoption of teleneurology. PMID- 29623953 TI - Erratum: Extracellular alpha-synuclein induces sphingosine 1-phosphate receptor subtype 1 uncoupled from inhibitory G-protein leaving beta-arrestin signal intact. AB - This corrects the article DOI: 10.1038/srep44248. PMID- 29623955 TI - Introducing cancer convergence. PMID- 29623954 TI - Probing three-dimensional collective cancer invasion with DIGME. AB - Background: Multicellular pattern formation plays an important role in developmental biology, cancer metastasis and wound healing. While many physical factors have been shown to regulate these multicellular processes, the role of ECM micro-to-meso scale geometry has been poorly understood in 3D collective cancer invasion. Results: We have developed a mechanical-based strategy, Diskoid In Geometrically Micropatterned ECM (DIGME). DIGME allows easy engineering of the shape of 3D tissue organoid, the mesoscale ECM heterogeneity, and the fiber alignment of collagen-based ECM all at the same time. We have employed DIGME to study the 3D invasion of MDA-MB-231 diskoids in engineered collagen matrix. We find that the collective cancer invasion is closely regulated by the micro-to meso scale geometry of the ECM. Conclusions: We conclude that DIGME provides a simple yet powerful tool to probe 3D dynamics of tissue organoids in physically patterned microenvironments. PMID- 29623956 TI - Cancer dormancy and criticality from a game theory perspective. AB - Background: The physics of cancer dormancy, the time between initial cancer treatment and re-emergence after a protracted period, is a puzzle. Cancer cells interact with host cells via complex, non-linear population dynamics, which can lead to very non-intuitive but perhaps deterministic and understandable progression dynamics of cancer and dormancy. Results: We explore here the dynamics of host-cancer cell populations in the presence of (1) payoffs gradients and (2) perturbations due to cell migration. Conclusions: We determine to what extent the time-dependence of the populations can be quantitively understood in spite of the underlying complexity of the individual agents and model the phenomena of dormancy. PMID- 29623958 TI - Correction to: The Influence of CYP2C9 and VKORC1 Gene Polymorphisms on the Response to Warfarin in Egyptians. AB - [This corrects the article DOI: 10.1007/s12288-016-0725-4.]. PMID- 29623957 TI - Non-randomness of the anatomical distribution of tumors. AB - Background: Why does a tumor start where it does within an organ? Location is traditionally viewed as a random event, yet the statistics of the location of tumors argues against this being a random occurrence. There are numerous examples including that of breast cancer. More than half of invasive breast cancer tumors start in the upper outer quadrant of the breast near the armpit, even though it is estimated that only 35 to 40% of breast tissue is in this quadrant. This suggests that there is an unknown microenvironmental factor that significantly increases the risk of cancer in a spatial manner and that is not solely due to genes or toxins. We hypothesize that tumors are more prone to form in healthy tissue at microvascular 'hot spots' where there is a high local concentration of microvessels providing an increased blood flow that ensures an ample supply of oxygen, nutrients, and receptors for growth factors that promote the generation of new blood vessels. Results: To show the plausibility of our hypothesis, we calculated the fractional probability that there is at least one microvascular hot spot in each region of the breast assuming a Poisson distribution of microvessels in two-dimensional cross sections of breast tissue. We modulated the microvessel density in various regions of the breast according to the total hemoglobin concentration measured by near infrared diffuse optical spectroscopy in different regions of the breast. Defining a hot spot to be a circle of radius 200 MUm with at least 5 microvessels, and using a previously measured mean microvessel density of 1 microvessel/mm2, we find good agreement of the fractional probability of at least one hot spot in different regions of the breast with the observed invasive tumor occurrence. However, there is no reason to believe that the microvascular distribution obeys a Poisson distribution. Conclusions: The spatial location of a tumor in an organ is not entirely random, indicating an unknown risk factor. Much work needs to be done to understand why a tumor occurs where it does. PMID- 29623960 TI - The formative design of Epilepsy Journey: A web-based executive functioning intervention for adolescents with epilepsy. AB - This case study discusses the design, development, and formative evaluation of Epilepsy Journey, an individually-tailored, web-based intervention designed to address the unique executive functioning (EF) needs of adolescents with epilepsy. This intervention was designed through a three-phase iterative, patient-centered participatory action research process. First, a front-end analysis was completed to identify the unique needs of adolescents with epilepsy and initial design ideas via focus groups. Second, a preliminary design of the intervention was developed from focus group results. Finally, we iteratively incorporated revisions and refinements based on patient-centered feedback collected during usability sessions. Findings based on usage analytics, user reports, and coded qualitative themes from usability sessions suggest that our iterative, patient centered approach to design, development, and evaluation resulted in a visually appealing interactive and brief intervention that is both engaging and individually tailored to the needs of adolescents with epilepsy. PMID- 29623962 TI - N-Aryltrifluoromethanesulfonimides as new trifluoromethylating agents for the (photo)catalyst-free functionalization of (hetero)aromatics. AB - The photoinduced (by UV or sunlight) catalyst-free radical trifluoromethylation of (hetero)aromatics (up to 87% yield) has been successfully achieved by using N aryltrifluoromethanesulfonimides as the trifluoromethylating agents. The process likewise occurred under continuous flow conditions. PMID- 29623959 TI - A network modeling approach to elucidate drug resistance mechanisms and predict combinatorial drug treatments in breast cancer. AB - Background: Mechanistic models of within-cell signal transduction networks can explain how these networks integrate internal and external inputs to give rise to the appropriate cellular response. These models can be fruitfully used in cancer cells, whose aberrant decision-making regarding their survival or death, proliferation or quiescence can be connected to errors in the state of nodes or edges of the signal transduction network. Results: Here we present a comprehensive network, and discrete dynamic model, of signal transduction in ER+ breast cancer based on the literature of ER+, HER2+, and PIK3CA-mutant breast cancers. The network model recapitulates known resistance mechanisms to PI3K inhibitors and suggests other possibilities for resistance. The model also reveals known and novel combinatorial interventions that are more effective than PI3K inhibition alone. Conclusions: The use of a logic-based, discrete dynamic model enables the identification of results that are mainly due to the organization of the signaling network, and those that also depend on the kinetics of individual events. Network-based models such as this will play an increasing role in the rational design of high-order therapeutic combinations. PMID- 29623963 TI - Simple bond patterns predict the stability of Diels-Alder adducts of empty fullerenes. AB - We present an extensive and systematic study on the regioselectivity of Diels Alder (DA) cycloadditions to empty fullerenes, covering the whole range of cage sizes from C60 to C180. Reaction energies obtained from DFT calculations, which correlate with activation barriers, can be well reproduced by using a simple Huckel model, indicating that pi electronic effect is the key factor determining the relative stability of DA adducts. Based on these results, we propose a couple of simple rules of thumb, in terms of a set of bond patterns, as a visual guide for approximate prediction of DA reactive sites. Moreover, we suggest two quantitative descriptors for the stability of DA regioadducts of empty fullerenes; one combines the pi free valences and bond orders involved in the DA addition, and the other characterizes the local pi aromaticity around the addition site. The latter criterion allows us to easily rationalize the proposed rules. PMID- 29623964 TI - Unexpected phase separation in Li1-xNi0.5Mn1.5O4 within a porous composite electrode. AB - The Ni oxidation state in Li1-xNi0.5Mn1.5O4 (LNMO) within a composite electrode mapped by soft X-ray scanning transmission X-ray microscopy (STXM) has shown unexpected distinct variations in phase separation among and within individual battery particles, which has been experimentally correlated to both their morphology and interface structure for the first time. The obtained new insights will assist the further development of long-life high voltage LNMO batteries. PMID- 29623965 TI - Monitoring the chemical and electronic properties of electrolyte-electrode interfaces in all-solid-state batteries using operando X-ray photoelectron spectroscopy. AB - Understanding the degradation of the solid electrolyte-electrodes interface during cycling is currently one of the most challenging obstacles in the development of all-solid-state batteries. Here, we introduce operando X-ray photoelectron spectroscopy (XPS) as a combined approach for real-time monitoring of the (i) (electro-) chemical interfacial reactions between different components of the composites electrode and (ii) surface electronic properties. The dedicated electrochemical cell, capable of maintaining high mechanical pressure, offers reliable electrochemistry and versatility in terms of materials application. We propose a fundamental physical model to explain the effect of applied cell voltage on core level binding energy shifts, which allows direct contactless measurement of the surface potentials. Such a fundamental understanding is also an essential prerequisite for (i) accurate interpretation of the XPS core level peaks, (ii) the assignment of solid electrolyte decomposition byproducts and (iii) an improved description of the interfacial reaction mechanisms in all-solid state batteries. A mixture of LiCoO2 (LCO) and (Li2S)3-P2S5 (LPS) cycled vs. InLix is investigated revealing that the LPS oxidation begins above 2.1 V vs. InLix and the byproducts passivate the composite surface against further oxidation. Moreover, we confirm that LCO particles are electronically conductive even in the absence of conductive additives by measuring directly its surface potential during cycling. PMID- 29623961 TI - Distinguishing mechanisms underlying EMT tristability. AB - Background: The Epithelial-Mesenchymal Transition (EMT) endows epithelial-looking cells with enhanced migratory ability during embryonic development and tissue repair. EMT can also be co-opted by cancer cells to acquire metastatic potential and drug-resistance. Recent research has argued that epithelial (E) cells can undergo either a partial EMT to attain a hybrid epithelial/mesenchymal (E/M) phenotype that typically displays collective migration, or a complete EMT to adopt a mesenchymal (M) phenotype that shows individual migration. The core EMT regulatory network - miR-34/SNAIL/miR-200/ZEB1 - has been identified by various studies, but how this network regulates the transitions among the E, E/M, and M phenotypes remains controversial. Two major mathematical models - ternary chimera switch (TCS) and cascading bistable switches (CBS) - that both focus on the miR 34/SNAIL/miR-200/ZEB1 network, have been proposed to elucidate the EMT dynamics, but a detailed analysis of how well either or both of these two models can capture recent experimental observations about EMT dynamics remains to be done. Results: Here, via an integrated experimental and theoretical approach, we first show that both these two models can be used to understand the two-step transition of EMT - E->E/M->M, the different responses of SNAIL and ZEB1 to exogenous TGF beta and the irreversibility of complete EMT. Next, we present new experimental results that tend to discriminate between these two models. We show that ZEB1 is present at intermediate levels in the hybrid E/M H1975 cells, and that in HMLE cells, overexpression of SNAIL is not sufficient to initiate EMT in the absence of ZEB1 and FOXC2. Conclusions: These experimental results argue in favor of the TCS model proposing that miR-200/ZEB1 behaves as a three-way decision-making switch enabling transitions among the E, hybrid E/M and M phenotypes. PMID- 29623966 TI - Oxidation of a germanium(ii) dication to access cationic germanium(iv) fluorides. AB - The synthesis and characterization of the tris(1-ethyl-benzoimidazol-2 ylmethyl)amine (BIMEt3 = L) complex of Ge(ii)2+ is described. Oxidation of [LGe]2+ with Selectfluor gives [LGeF2]2+, in a process that is envisaged to involve a tricationic complex [LGeF]3+ as an intermediate, which has been isolated by fluoride ion abstraction from [LGeF2]2+. PMID- 29623967 TI - Low-voltage-driven soft actuators. AB - Soft actuators based on electroactive polymers (EAPs) are the core constituents of future soft robots owing to their fascinating properties such as lightweight, compactness, easy fabrication into various forms, and low cost. Ionic EAP actuators are particularly attractive owing to the low driving voltages (<3 V) as compared to those of electronic EAP actuators (usually kilovolts). This paper presents a brief overview of the recent progress in a range of EAP actuators by focusing on low voltage operation, in addition to the challenges and future strategies for their wide applicability in artificial muscles and various innovative soft robot technologies. PMID- 29623968 TI - Order in disorder: solution and solid-state studies of [MM] wheels (MIII = Cr, Al; MII = Ni, Zn). AB - A family of heterometallic Anderson-type 'wheels' of general formula [MIII2MII5(hmp)12](ClO4)4 (where MIII = Cr or Al and MII = Ni or Zn giving [Cr2Ni5] (1), [Cr2Zn5] (2), [Al2Ni5] (3) and [Al2Zn5] (4); hmpH = 2 pyridinemethanol) have been synthesised solvothermally. The metallic skeleton common to all structures describes a centred hexagon with the MIII sites disordered around the outer wheel. The structural disorder has been characterised via single crystal X-ray crystallography, 1-3D 1H and 13C solution-state NMR spectroscopy of the diamagnetic analogue (4), and solid-state 27Al MAS NMR spectroscopy of compounds (3) and (4). Alongside ESI mass spectrometry, these techniques show that structure is retained in solution, and that the disorder is present in both the solution and solid-state. Solid-state dc susceptibility and magnetisation measurements on (2) and (3) reveal the Cr-Cr and Ni-Ni exchange interactions to be JCr-Cr = -1 cm-1 and JNi-Ni,r = -5 cm-1, JNi-Ni,c = 10 cm-1. Fixing these values allows us to extract JCr-Ni,r = -1.2 cm-1, JCr-Ni,c = 2.6 cm 1 for (1), the exchange between adjacent Ni and Cr ions on the ring is antiferromagnetic and between Cr ions on the ring and the central Ni ion is ferromagnetic. PMID- 29623969 TI - Synthesis, characterization and properties of a glycol-coordinated epsilon-Keggin type Al13 chloride. AB - Herein we present the first example of a glycol-coordinated epsilon-Keggin Al13 chloride (gl-epsilon-Al13), which is the first chelated version since discovery of Al13 in 1960. The molecular structure consists of [AlO4Al12(OH)12(OC2H4OH)12]Cl7.H2O units with chelating mono-anionic ethylene glycol units replacing one bridging and one terminal oxygen site. PMID- 29623970 TI - Regulating structural dimensionality and emission colors by organic conjugation between SmIII at a fixed distance. AB - The conjugation of bridging bis(diphenylphosphine oxide) alkane or arene ligands was found to control the structural dimensionality and the emission color of complexes from reactions with SmIII(hfac)3(H2O)2 (hfac- = hexafluoroacetylacetonato) while retaining the SmSm distances. Bis(diphenylphosphine oxide)-1,4-butane (L1) affords a one-dimensional (1D) ribbon {Sm(hfac)3(L1)}infinity (1) that emits red color, while bis(diphenyl phosphinoyl)-1,4-benzene (L2) results in a two-dimensional (2D) network {Sm(hfac)2(CF3COO)(L2)3}infinity (2) and near-white emission, but bis(diphenyl phosphinoyl)-9,10-anthracene (L3) forms a zero-dimensional (0D) cyclic structure {Sm(hfac)3(L3)}2 (3) with strong pipi interactions that emit green color. Noticeably, the conjugation change is accompanied by a configurational change of coordination from trans for 1 and 2 to cis for 3. The color change is associated with the superposition of ligand and Sm based electronic band energies and their intensities. Such white light emission by a single compound having contributions from different building components is quite rare. PMID- 29623971 TI - The impact of tumor receptor heterogeneity on the response to anti-angiogenic cancer treatment. AB - Multiple promoters and inhibitors mediate angiogenesis, the formation of new blood vessels, and these factors represent potential targets for impeding vessel growth in tumors. Vascular endothelial growth factor (VEGF) is a potent angiogenic factor targeted in anti-angiogenic cancer therapies. In addition, thrombospondin-1 (TSP1) is a major endogenous inhibitor of angiogenesis, and TSP1 mimetics are being developed as an alternative type of anti-angiogenic agent. The combination of bevacizumab, an anti-VEGF agent, and ABT-510, a TSP1 mimetic, has been tested in clinical trials to treat advanced solid tumors. However, the patients' responses are highly variable and show disappointing outcomes. To obtain mechanistic insight into the effects of this combination anti-angiogenic therapy, we have constructed a novel whole-body systems biology model including the VEGF and TSP1 reaction networks. Using this molecular-detailed model, we investigated how the combination anti-angiogenic therapy changes the amounts of pro-angiogenic and anti-angiogenic complexes in cancer patients. We particularly focus on answering the question of how the effect of the combination therapy is influenced by tumor receptor expression, one aspect of patient-to-patient variability. Overall, this model complements the clinical administration of combination anti-angiogenic therapy, highlights the role of tumor receptor variability in the heterogeneous responses to anti-angiogenic therapy, and identifies the tumor receptor profiles that correlate with a high likelihood of a positive response to the combination therapy. Our model provides novel understanding of the VEGF-TSP1 balance in cancer patients at the systems-level and could be further used to optimize combination anti-angiogenic therapy. PMID- 29623972 TI - Stereoselective synthesis of N-ethyl-2-arylvinyl-5-methyl fulleropyrrolidines: reaction of [60]fullerene with aromatic aldehydes and triethylamine/diethylamine in the absence or presence of manganese(iii) acetate. AB - The reaction of [60]fullerene with aromatic aldehydes and triethylamine/diethylamine in the absence or presence of manganese(iii) acetate under air conditions afforded a series of N-ethyl-2-arylvinyl-5-methyl fulleropyrrolidines in moderate to good yields, which would be difficult to synthesize by reported protocols. The in situ generation of arylvinyl aldehydes by the aldol reaction of aromatic aldehydes with acetaldehyde from an unusual C-N bond cleavage of triethylamine/diethylamine played a crucial role in the successful preparation of the corresponding fulleropyrrolidines. Depending on the reaction conditions, both cis and trans isomers of fulleropyrrolidines could be selectively synthesized. Cis isomers as major products could be obtained by reacting with triethylamine at 160 degrees C without the addition of manganese(iii) acetate, while trans isomers as major products, with rare exceptions, could be observed via the reaction with diethylamine at 120 degrees C under the assistance of manganese(iii) acetate. Moreover, the in situ generated arylvinyl aldehydes displayed higher reactivity towards diethylamine as compared with aryl aldehydes, leading to the formation of arylvinyl-substituted fulleropyrrolidines. A plausible formation mechanism for fulleropyrrolidines was provided based on the experimental observations. PMID- 29623973 TI - Fabrication and evaluation of hemoglobin-based polydopamine microcapsules as oxygen carriers. AB - Polydopamine-hemoglobin (PDA-Hb) microcapsules as suitable oxygen carriers are fabricated easily by templating decomposable MnCO3 particles in collaboration with self-polymerization of dopamine on pure Hb spheres. The PDA-Hb microcapsules possess a high oxygen affinity and are able to bind and release oxygen reversibly as demonstrated by electrochemical methods. PMID- 29623974 TI - Mechanistic insights into Pd(0)-catalyzed intermolecular and intramolecular hydroamination of methylenecyclopropanes: a computational study. AB - The mechanisms of transition metal-catalyzed methylenecyclopropanes (MCPs) involved reactions are rather complicated due to the diverse pathways for the activation of MCPs. Herein, computational studies were carried out to investigate the detailed mechanisms of Pd(0)-catalyzed intermolecular and intramolecular hydroamination of MCPs. The initial activation of the three-membered ring of MCPs readily occurs via the insertion of Pd(0) into the distal C-C bond, leading to a metallacyclobutane intermediate. The commonly proposed oxidative addition of amine/amide nucleophile (Nu-H) onto the Pd(0) center to afford a hydrido-Pd(ii) complex, however, is less favorable in comparison with the Pd(0)-mediated cleavage of the distal C-C bond of MCPs. Subsequently, for the Pd(0)-catalyzed intermolecular hydroamination of 1,1-diphenyl MCP with 2-pyrrolidone, it is more favorable for the C1 of the metallacyclobutane intermediate to undergo protonation to yield a pi-allylpalladium intermediate, from which the final allylamine product is afforded via reductive elimination. For the Pd(0)-catalyzed intramolecular hydroamination of aniline-tethered MCP, the intramolecular nucleophilic attack of the amine moiety to C3/C4 of the corresponding metallacyclobutane intermediate is preferable to generate a cyclic intermediate. Subsequent proton transfer steps could occur to complete the hydroamination reaction. The different pKa values of the N-H bonds of amide/amine are mainly responsible for the mechanistic difference in the Pd(0)-catalyzed hydroamination of MCPs. PMID- 29623975 TI - Injectable self-assembled peptide hydrogels for glucose-mediated insulin delivery. AB - Closed-loop glucose-responsive insulin delivery with excellent biocompatibility has the potential to improve the health and quality of life of diabetic patients. Herein, we developed an excellent glucose-responsive insulin delivery system using a pH-sensitive peptide hydrogel loaded with insulin and a glucose-specific enzyme. The designed peptide can be used as a carrier that is loaded with insulin and enzyme via a self-assembly process under physiological conditions. When hyperglycemia is encountered, the enzymatic conversion of glucose into gluconic acid leads to a decrease in the local pH, and the hydrogel is disassembled because of the strong inter- and intramolecular electrostatic repulsions between ornithine (Orn) residues; this is followed by the release of insulin. The glucose responsive hydrogel system was characterized by studying its structure, conformation, rheology, morphology, acid sensitivity and the amounts of consistent release of insulin in vitro and in vivo. In vivo experiments indicated that the closed-loop insulin glucose-responsive system could efficiently regulate blood glucose in streptozocin-induced (STZ-induced) type 1 diabetic rats for 8 days. PMID- 29623976 TI - Pt-Free microengines at extremely low peroxide levels. AB - Herein, we demonstrate that iron oxide modified MnO2 (FeOx-MnO2) catalyzed micromotors can be fabricated via electrochemical co-reduction and exhibit exceptional high performance at an extremely low hydrogen peroxide (H2O2) fuel concentration. We observed that graphene/FeOx-MnO2 microtubes could show motion behaviors at fuel concentration as low as 0.03% H2O2, which is nearly one order of magnitude lower than Pt-based micromotors (normally at above 0.2% H2O2). Moreover, the micromotors exhibit higher speeds than any other reported catalytic micro/nanomotors (MNMs) at low peroxide levels. The FeOx-MnO2 systems are better catalytic MNMs, due to their excellent catalytic activity, easy fabrication, robust structure and movement, as well as low-cost, biocompatible and abundance nature, showing great potential for future applications. PMID- 29623977 TI - Safer lithium-sulfur battery based on nonflammable electrolyte with sulfur composite cathode. AB - The Li-S batteries have been rewarded as the one of the most promising candidates due to their high energy densities. In this study, the common nonflammable solvent triethyl phosphate (TEP) is used for the first time as a co-solvent in Li S battery. In the highly safe electrolyte system of 1 M LiBOB/TEP + FEC (7 : 3, v/v), the sulfur composite cathodes show enhanced cycling performance with a satisfactory capacity retention of 91.3% after 500 cycles at 1C. PMID- 29623978 TI - In vitro elucidation of the role of pericellular matrix in metastatic extravasation and invasion of breast carcinoma cells. AB - Numerous studies have demonstrated the importance of altered hyaluronan metabolism to malignant progression of multiple tumor types, including breast carcinomas. Increased hyaluronan (HA) metabolism in the stroma of primary tumors promotes activation of oncogenic signaling pathways that impact tumor initiation, growth, and invasion. Carcinoma cell synthesis and assembly of HA-rich pericellular matrices induces a stromal-independent phenotype, which is associated with cancer progression. Although the pro-tumorigenic role of stromal HA is well established, a novel but unexplored hypothesis is that carcinoma cell associated HA pericellular matrices promote metastasis of circulating tumor cells. Here, we report the development of an in vitro assay that employs microfluidic techniques to directly measure the importance of an HA-rich pericellular matrix in the entry of carcinoma cells into ectopic sites. This model provides the capability to visualize specific steps in metastasis, which is difficult using animal models. The results show that the presence of a HA-rich pericellular matrix correlates to the invasive and metastatic potential of breast carcinoma cells. Furthermore, enzymatic removal or pharmacologic inhibition of HA synthesis significantly inhibits carcinoma cell extravasation and invasion in this model system. These results implicate pericellular HA-rich carcinoma cell associated pericellular matrices in colonization of ectopic sites by circulating tumor cells and support specific targeting of this matrix to limit metastasis in patients. PMID- 29623979 TI - Field-cycling NMR experiments in an ultra-wide magnetic field range: relaxation and coherent polarization transfer. AB - An experimental method is described allowing fast field-cycling Nuclear Magnetic Resonance (NMR) experiments over a wide range of magnetic fields from 5 nT to 10 T. The method makes use of a hybrid technique: the high field range is covered by positioning the sample in the inhomogeneous stray field of the NMR spectrometer magnet. For fields below 2 mT a magnetic shield is mounted on top of the spectrometer; inside the shield the magnetic field is controlled by a specially designed coil system. This combination allows us to measure T1-relaxation times and nuclear Overhauser effect parameters over the full range in a routine way. For coupled proton-carbon spin systems relaxation with a common T1 is found at low fields, where the spins are "strongly coupled". In some cases, experiments at ultralow fields provide access to heteronuclear long-lived spin states. Efficient coherent polarization transfer is seen for proton-carbon spin systems at ultralow fields as follows from the observation of quantum oscillations in the polarization evolution. Applications to analysis and the manipulation of heteronuclear spin systems are discussed. PMID- 29623980 TI - Impact of limited English proficiency on presentation and outcomes of patients undergoing primary percutaneous coronary intervention for ST-elevation myocardial infarction. AB - Doctor-patient language discordance has been shown to lead to worse clinical outcomes. In this study of patients undergoing primary percutaneous coronary intervention for ST-elevation myocardial infarction at an Australian health service, we demonstrated that limited English proficiency (LEP) is an independent predictor of prolonged symptom-to-door time, but does not lead to worse 30-day mortality compared with English-proficient patients. More effort needs to be placed in providing public health education in varied languages to encourage early presentation to hospital for patients with LEP. PMID- 29623981 TI - Anti-type M phospholipase A2 receptor antibody-positive membranous nephropathy as a part of multi-system autoimmune syndrome post-allogeneic stem cell transplantation. PMID- 29623982 TI - Back pain and fever: when the diagnosis becomes crystal clear. PMID- 29623983 TI - Symptomatic hypereosinophilia associated with Necator americanus self inoculation. PMID- 29623984 TI - Breathlessness and palliative oxygen therapy in advanced chronic obstructive pulmonary disease. PMID- 29623985 TI - The unique aspects of chronic hepatitis B infection in Aboriginal and Torres Strait Islander people. PMID- 29623986 TI - Transcatheter mitral valve intervention: an emerging treatment for mitral regurgitation. AB - Mitral regurgitation (MR) is a valvular heart disease associated with significant morbidity and mortality. Transcatheter mitral valve intervention (TMVI) repairs or replaces the mitral valve through small arterial and venous entry sites and so avoids risks associated with open heart surgery. Transcatheter devices targeting components of the mitral apparatus are being developed to repair or replace it. Numerous challenges remain including developing more adaptable devices and correction of multiple components of the mitral annulus to attain durable results. The mitral valve apparatus is a complex structure and understanding of the mechanisms of MR is essential in the development of TMVI. There will likely be a complementary role between surgery and TMVI in the near future. PMID- 29623987 TI - Electronic cigarettes in physician practice. AB - There is growing evidence for the effectiveness of e-cigarettes as a quitting aid and, although not completely harmless, the scientific consensus is that they are substantially less harmful than smoking tobacco. More research is needed, but there is now sufficient empirical evidence and real-world experience over more than a decade to consider their use as a legitimate tobacco harm reduction tool for smokers who are unable or unwilling to quit with conventional strategies. Smokers should be advised that the highest success rates occur with daily use with nicotine e-liquid and newer e-cigarette models. After quitting smoking, it is preferable to aim ultimately to cease vaping if possible, but long-term use of e-cigarettes is safer than relapsing to smoking. PMID- 29623988 TI - Levodopa-carbidopa intestinal gel: is the naso-jejunal phase a redundant convention? AB - Levodopa-carbidopa intestinal gel (LCIG) is an effective treatment for Parkinson disease. Initiating therapy involves an initial naso-jejunal (NJ) titration phase. The NJ phase is prolonged with significant morbidity. The aim of this study is to assess the impact of proceeding without the NJ phase on resource utilisation and the outcomes of patients. Twenty-five patients were started on LCIG using the patients existing levodopa equivalent dose (LED). We recorded change in LED, length of hospital stay, readmission rates and use of outpatient services and clinical outcomes within 6 months. The median length of stay was 4.5 days. Patients had four outpatient clinic reviews and 2.5 community nurse contacts within 6 months. There was no significant change in daily LED on discharge (P = 0.56). There were significant improvements in all Unified Parkinson Disease Rating Scale subscores (P < 0.05), the Freezing of Gait scale (P < 0.01) and Parkinson Disease Quality Of Life 39 score (P < 0.01). Initiating LCIG without the NJ phase resulted in short admissions, a minimal outpatient burden and no significant requirement for dose titration while producing good clinical outcomes. PMID- 29623989 TI - Author reply. PMID- 29623990 TI - Author reply. PMID- 29623991 TI - Paul Lee, 1977-2017. PMID- 29623992 TI - Diagnostic utility of an age-specific cut-off for d-dimer for pulmonary embolism assessment when used with various pulmonary embolism risk scores. AB - This retrospective cohort study compared the diagnostic utility (sensitivity, specificity and negative predictive value (NPV)) of the age-times-10 adjusted d dimer cut-off used in combination with the original and simplified Well's pulmonary embolism (PE) scores and the original and simplified revised Geneva scores to identify patients in whom PE is classified as unlikely according to each score. The PE risk scores performed similarly with high sensitivity (97.6, 97.1, 96.9 and 97.1% respectively) and NPV (99.3, 99.3, 99.2 and 99.2% respectively). Each missed only one PE. The age-times-10 age-adjusted d-dimer assay cut-off performed similarly with each of the clinical risk scores tested with high sensitivity and NPV. PMID- 29623993 TI - Levodopa-carbidopa intestinal gel: 'dismantling the road blocks of a journey'. AB - Levodopa-carbidopa intestinal gel offers superior treatment to standard oral therapy in selective patients with advanced Parkinson disease. The costs involved in instituting and maintaining this treatment are high but largely mitigated with the quality of life years the treatment offers. Key to this is ensuring a high retention rate once the treatment is instituted. We outline factors and considerations from our experience and viewpoints at each stage of the process to address in this 'journey' patients undertake that can help maximise retention rates and benefits. PMID- 29623995 TI - Corrigendum. PMID- 29623994 TI - Clinical features and outcome of patients with cutaneous melioidosis during a nosocomial outbreak in a temperate region of Australia. AB - Six cases of cutaneous melioidosis from southwestern Australia, a non-endemic region occurred as a result of Burkholderia pseudomallei contamination of normal saline that was used for irrigating superficial wounds. Treatment with parenteral meropenem, given by continuous infusion for 2 weeks, followed by oral antibiotics was successful in all cases. PMID- 29623996 TI - Ibrutinib and antimicrobial therapy in a heavily pretreated patient with chronic lymphocytic leukaemia and disseminated cutaneous non-tuberculous mycobacterial infection: successful surgery-free approach. PMID- 29623997 TI - Collaborative research between emergency medicine and physicians. PMID- 29623998 TI - Prevalence of pathogenicity island ETT2 in Escherichia coli isolated from piglets with diarrhea in northeast of China. AB - Our aim was to investigate the prevalence of the pathogenicity island ETT2 and to examine the relationship between the ETT2 locus and other virulence factors in Escherichia coli (E. coli) isolated from piglets with diarrhea. A total of 354 E. coli strains isolated from scouring piglets were tested using PCR for the presence of the ETT2 locus. The E. coli strains were also analyzed for enterotoxins, fimbriae, non-fimbrial adhesin, Shiga toxins, pathogenicity islands, alpha-haemolysin (hlyA), afa8 gene cluster and autotransporter protease (sepA) genes. The results showed that 215 (60.7%) of the isolates possessed the ETT2 island. In 215 ETT2-positive E. coli strains, the virulence genes found were EAST1 (27.0%), irp2 (18.6%), paa (15.4%), STb (7.9%), LT (6.5%), ler (4.7%), hlyA (3.7%), AIDA-I (3.7%), K88 (3.7%), eae (3.3%), STa (2.8%), afaD (1.4%), afaE (1.4%), K99 (0.9%) and sepA (0.47%), respectively, and the isolates could be assigned into 25 different virulence factor patterns. In 139 ETT2-negative E. coli strains, the virulence genes detected were EAST1 (38.9%), paa (14.4%), STb (11.5%), AIDA-I (10.1%), irp2 (7.9%), sepA (2.16%), LT (0.7%), STa (0.7%), eae (0.7%), ler (0.7%), hlyA (0.7%) and K88 (0.7%), respectively, and the isolates could be classified into 13 different virulence factor patterns. Moreover, the occurrence of LT gene of ETT2-positive E. coli strains was far more than that of ETT2-negative E. coli strains. PMID- 29623999 TI - Evaluation of changes in periodontal bacteria in healthy dogs over 6 months using quantitative real-time PCR. AB - Porphyromonas gulae, Tannerella forsythia and Campylobacter rectus are considered dominant periodontal pathogens in dogs. Recently, quantitative real-time PCR (qRT PCR) methods have been used for absolute quantitative determination of oral bacterial counts. The purpose of the present study was to establish a standardized qRT-PCR procedure to quantify bacterial counts of the three target periodontal bacteria (P. gulae, T. forsythia and C. rectus). Copy numbers of the three target periodontal bacteria were evaluated in 26 healthy dogs. Then, changes in bacterial counts of the three target periodontal bacteria were evaluated for 24 weeks in 7 healthy dogs after periodontal scaling. Analytical evaluation of each self-designed primer indicated acceptable analytical imprecision. All 26 healthy dogs were found to be positive for P. gulae, T. forsythia and C. rectus. Median total bacterial counts (copies/ng) of each target genes were 385.612 for P. gulae, 25.109 for T. forsythia and 5.771 for C. rectus. Significant differences were observed between the copy numbers of the three target periodontal bacteria. Periodontal scaling reduced median copy numbers of the three target periodontal bacteria in 7 healthy dogs. However, after periodontal scaling, copy numbers of all three periodontal bacteria significantly increased over time (p<0.05, Kruskal-Wallis test) (24 weeks). In conclusion, our results demonstrated that qRT-PCR can accurately measure periodontal bacteria in dogs. Furthermore, the present study has revealed that qRT-PCR method can be considered as a new objective evaluation system for canine periodontal disease. PMID- 29624000 TI - The occurrence of dynamic structural disorders in the pharynx and larynx, at rest and during exercise, in horses diagnosed with mild and moderate Equine Asthma (Inflammatory Airway Disease). AB - : The goal of the present study was to establish the occurrence of structural disorders in the larynx and pharynx during treadmill exercise tests in horses diagnosed with Equine Asthma (EA). Investigation was performed in 29 horses, patients of the Equine Clinic of the Warsaw University of Life Sciences in Poland, admitted with poor exercise performance. Upper and lower airway examinations were performed in all patients revealing both mild to moderate Equine Asthma (13 horses), and no lower airway abnormalities (16 animals). In the group of horses with EA, 11 did not have structural disorders of the pharynx and larynx at rest. During exercise two horses were free of abnormalities, while 11 had structural disorders, eight of them solely in the pharynx, two in the larynx, and one in both the pharynx and larynx. In the non- asthmatic group, 11 horses had no structural disorders during resting endoscopy. Endoscopy performed during exercise revealed disorders of the larynx in 10 horses, of the pharynx in three horses, and in both the larynx and pharynx in the remaining three horses. IN CONCLUSION: horses with diagnosed EA frequently have disorders of the pharynx during treadmill exercise tests, while without EA, often have disorders of the larynx. Endoscopy of upper airways during exercise testing is a valuable tool in the diagnosis of poor performance in horses with lower airway inflammatory disease. PMID- 29624001 TI - Magnolol inhibits Streptococcus suis-induced inflammation and ROS formation via TLR2/MAPK/NF-kappaB signaling in RAW264.7 cells. AB - Our previous studies have shown that Magnolol (Mag) improves the symptoms and decreases the levels of cytokines during infection induced by Streptococcus suis (S. suis) in mice. Although some reports show that Mag inhibits lipopolysaccharide-induced inflammatory responses via downregulating mitogen activated protein kinases (MAPK) and nuclear factor-kappaB (NF-kappaB) signaling pathways, the molecular mechanisms underlying Mag-mediated inhibition of S. suis induced inflammatory responses are poorly understood. Here, RAW264.7 cells were stimulated with S. suis in the presence or absence of Mag. Cell viability and bactericidal effects were examined, and the concentrations of tumor necrosis factor-a (TNF-alpha), IL-1beta (interleukin-1beta), IL-6 (interleukin-6), and IL 8 (interleukin- 8) were determined by ELISA. The change in ROS (reactive oxygen species) was determined by fluorescence microscopy and ELISA. The levels of Toll like receptor 2 (TLR2) and MAPK family proteins and NF-kappaB signaling were determined by Western blot analysis. S. suis induced massive RAW264.7 cell death, a decline in bactericidal activity, the release of inflammatory cytokines, increased oxidative stress, and activation of TLR2/MAPK/NF-kappaB signaling pathways. Mag treatment significantly suppressed macrophage cell death and caused a decline in bactericidal activity. Furthermore, Mag decreased inflammatory cytokines production and ROS generation. It also prevented p38, extracellular regulated protein kinases (ERK), c-Jun N-terminal kinase (JNK), inhibitor of NF kappaB (IkappaB), and NF-kappaB phosphorylation induced by S. suis in a dose dependent manner. Our results indicate that Mag exerts anti-inflammatory and cell protective effects and mediates the activation of MAPK and NF-kappaB signaling by downregulating the expression of TLR2 upregulated by S. suis. PMID- 29624002 TI - Expression of ADAMTS-7 in myocardial dystrophy associated with white muscle disease in lambs. AB - The aim of the present study was to investigate the role of ADAMTS-7 gene in the pathogenesis of myocardial dystrophy associated with white muscle disease (WMD) in lambs. A total of 217 cardiac tissue samples from lambs with WMD were used in the study. Histopathological sections of the samples were stained with hematoxylin-eosin (HE) and examined using Western-blot, real-time PCR (RT-PCR) and immunohistochemistry for ADAMTS-7 gene expression, and the findings were statistically evaluated. Histopathological examinations revealed fibrosis associated with hyalinization, necrosis and granular calcifications in cardiomyocytes. Western blot and RT-PCR showed a statistically significant upregulation of ADAMTS-7 (p<0.05) (p<0.05). Immunohistochemical analyses showed that immunopositive cell numbers significantly high for ADAMTS-7 (p<0.05). The study has revealed that ADAMTS-7 gene is significantly expressed in myocardial dystrophy associated with WMD in addition to its role in the pathogenesis of this disease. PMID- 29624003 TI - Investigation of the correlation between virulence factors and genotypic profiles of Candida albicans isolated from turkeys. AB - Candida albicans exists as an element of the normal flora in the skin, mucosa, and gastrointestinal tract, which is the principal reservoir for this organism. When the delicate balance in the host-yeast relationship is tipped in favour of the microorganism by antimicrobial treatment, illness, or other debilities of the host, fungi may overgrow and cause disease, such as candidiasis. The aim of this study was to analyse three virulence factors, haemolysin, proteinase, and phospholipase, with the genotypic profiles of C. albicans isolated from turkeys and to investigate if any correlation between these features exists. The genotypic profiles were generated using the polymerase chain reaction (PCR) with the RDS6 primer, and the enzymatic activity was evaluated in culture. Among the C. albicans isolates, four genotypic profiles using random amplified polymorphic DNA (RAPD) and three enzymatic profiles were defined. Genotypic profile A was characterised by seven bands, genotypic profile B was characterised by nine bands, genotypic profile C was characterised by nine bands, and genotypic profile D was characterised by four bands. Enzymatic profile I demonstrated no haemolysin or proteinase activity, but phospholipase activity was present; enzymatic profile II displayed no proteinase activity, but haemolysin and phospholipase activity were produced; and enzymatic profile III revealed all three types of enzymatic activity. The genotypic profiles were strictly correlated with the enzymatic profiles among the C. albicans isolates from poultry. PMID- 29624004 TI - A method for tracing exogenous DNA uptake in live spermatozoa and embryos. AB - Sperm-mediated gene transfer(SMGT) is a simple method for producing transgenic animals. Due to the lack of repeatability in spermatozoa binding and internalization of exogenous DNA, the efficiency of SMGT is still low. Considering this point, the present work aims to develop a method for evaluating the spermatozoa capacity of binding exogenous DNA after co-incubation with DNA. The main approach is using a Cy5-labelled DNA to trace the exogenous DNA and assess the ability of spermatozoa to take up exogenous DNA. Using this technique, we found that the percentage of spermatozoa that are binding and uptaking DNA is higher at concentration of 10 MUg/mL and 100 MUg/mL than 5 MUg/mL, 1 MUg/mL and 0 MUg/mL after incubation with Cy5-DNA for 30min at 37oC. After fertilization, the DNA fluorescence signal was also detected in zygotes in groups where spermatozoa were incubated with 10 MUg/mL and 100 MUg/mL of Cy5-DNA. These results showed a simple and convenient method to trace the exogenous DNA in spermatozoa and zygote when compared to conventional methods of labeling DNA during fertilization, resulting in a real-time observation of the exogenous DNA in spermatozoa and zygote. PMID- 29624005 TI - Effects of seminal plasma concentration on sperm motility and plasma and acrosome membrane integrity in chilled canine spermatozoa. AB - Depending on the mammal species, the use of seminal plasma during semen processing for cryopreservation has been found to have both beneficial and detrimental effects. This study was designed to determine the effects of seminal plasma concentration on the motility, sperm movement characteristics, and plasma and acrosome membrane integrity of chilled canine spermatozoa. After pooling the semen from seven dogs, samples for each assay were preserved at 4oC for 96h in extenders containing different seminal plasma concentrations (0, 25, 50, 75 and 100% (v/v) seminal plasma). After 96h cold storage, group 25% (v/v) seminal plasma showed significantly higher percentages of sperm cells with motility [46.4 +/- 1.65% (p<0.05)], intact plasma membrane [46.5 +/- 3.11% (p<0.05)] and intact acrosome[58.5 +/- 1.86 % (p<0.05)] than other groups. In conclusion, supplementing semen extender with an appropriate seminal plasma concentration (25% (v/v) seminal plasma) is able to adequately preserve the sperm motility, integrity of the plasma and acrosome membrane in canine spermatozoa chilled at 4oC. PMID- 29624006 TI - Intrinsic and extrinsic molecular determinants or modulators for epigenetic remodeling and reprogramming of somatic cell-derived genome in mammalian nuclear transferred oocytes and resultant embryos. AB - The efficiency of somatic cell cloning in mammals remains disappointingly low. Incomplete and aberrant reprogramming of epigenetic memory of somatic cell nuclei in preimplantation nuclear- transferred (NT) embryos is one of the most important factors that limit the cloning effectiveness. The extent of epigenetic genome wide alterations, involving histone or DNA methylation and histone deacetylation, that are mediated by histone-lysine methyltransferases (HMTs) or DNA methyltransferases (DNMTs) and histone deacetylases (HDACs) can be modulated/reversed via exogenous inhibitors of these enzymes throughout in vitro culture of nuclear donor cells, nuclear recipient oocytes and/or cloned embryos. The use of the artificial modifiers of epigenomically-conditioned gene expression leads to inhibition of both chromatin condensation and transcriptional silencing the genomic DNA of somatic cells that provide a source of nuclear donors for reconstruction of enucleated oocytes and generation of cloned embryos. The onset of chromatin decondensation and gene transcriptional activity is evoked both through specific/selective inactivating HMTs by BIX-01294 and through non specific/non-selective blocking the activity of either DNMTs by 5-aza-2' deoxycytidine, zebularine, S-adenosylhomocysteine or HDACs by trichostatin A, valproic acid, scriptaid, oxamflatin, sodium butyrate, m-carboxycinnamic acid bishydroxamide, panobinostat, abexinostat, quisinostat, dacinostat, belinostat and psammaplin A. Epigenomic modulation of nuclear donor cells, nuclear recipient cells and/or cloned embryos may facilitate and accelerate the reprogrammability for gene expression of donor cell nuclei that have been transplanted into a host ooplasm and subsequently underwent dedifferentiating and re-establishing the epigenetically dependent status of their transcriptional activity during pre- and postimplantation development of NT embryos. Nevertheless, a comprehensive additional work is necessary to determine whether failures in the early-stage reprogramming of somatic cell-inherited genome are magnified downstream in development of cloned conceptuses and neonates. PMID- 29624007 TI - Haptoglobin as a treatment monitoring factor in feline plasmacytic gingivostomatitis. AB - INTRODUCTION: feline plasmacytic gingivostomatitis is an important and fairly common chronic disease. Its complex aetiology - which involves infectious agents, immunological disorders, and even genetic factors adds to the considerable difficulty of its treatment. MATERIALS AND METHODS: the study was performed on 33 cats, 26 animals diagnosed with plasmacytic gingivostomatitis (study group) and 7 clinically healthy cats (control group). The study extended over four examination periods during which clinical and X-ray examinations, morphological and biochemical blood tests, as well as haptoglobin essays were performed. RESULTS: the biochemical and haematological parameters were within normal limits. Blood serum haptoglobin measured on the first day of the treatment was above physiological levels, however its serum concentration decreased as the treatment progressed. CONCLUSIONS: in the present study, despite the bacterial inflammatory condition of periodontal pockets, after the treatment was concluded and symptoms alleviated, neither clinical examinations nor haptoglobin essays revealed deviations from values commonly accepted as normal. Fluctuations in blood serum haptoglobin levels proved to be a useful prognostic in determining the duration of necessary treatment. PMID- 29624008 TI - Age-related changes in mRNA expression of selected surface receptors in lymphocytes of dairy calves. AB - The aim of this study was to determine age-related changes in the mRNA expression of four clusters of differentiation (CD: e.g. CD5, CD21, CD22 and CD23) in lymphocytes of calves. Blood samples were collected from 10 Holstein heifers on day 2, 22 and 56 of life and used for lymphocyte isolation. Subsequently, the mRNA was isolated from lymphocytes and the relative expression of CD5, CD21, CD22 and CD23 was investigated using quantitative real-time PCR with GAPDH as a reference gene. CD5, CD21 and CD23 mRNA expression increased linearly (p <= 0.04) with calf age, whereas CD22 mRNA expression did not change in the investigated period (p > 0.05). Age related changes in CD5, CD21 and CD23 mRNA expression suggest their importance in the process of lymphocyte maturation in calves. PMID- 29624009 TI - The concentration of free amino acids in blood serum of dairy cows with primary ketosis. AB - Ketosis is a common condition found in the initial stages of lactation in high yielding dairy cows. The major cause of ketosis is a negative energy balance. During the energy deficiency, proteolysis processes develop parallel to lipolysis. During proteolysis, muscle tissue can be used as a source of amino acid. To date, the participation of amino acids in gluconeogenesis (glucogenic amino acids) and ketogenesis (ketogenic amino acids) has not been determined in detail. This paper presents the study on determination of the parameters of protein and free amino acid metabolism in blood serum of dairy cows with primary ketosis compared to healthy cows. This study contributes to better understanding of the role of amino acids in pathogenesis of ketosis. A total of 30 cows, divided into two groups: experimental (15 cows with ketosis) and control (15 healthy cows), were included in the study. The concentrations of glucose, beta hydroxybutyrate, total protein, albumin, urea, and free amino acids were determined in peripheral blood. Statistically significantly higher concentrations of glutamine, glutamic acid, isoleucine (p<=0.001), and tyrosine (p<=0.05) were found in cows with primary ketosis compared to healthy cows. Significant decrease in the concentrations of asparagine, histidine, methionine, and serine (p<=0.001), alanine, leucine, lysine and proline (p<=0.05) was observed. Significant increase of total ketogenic and glucogenic amino acids (p<=0.05), and an increased ratio of total ketogenic and glucogenic amino acids to total amino acids (p<=0.001) were noted in cows with ketosis. In our study, the changes, in particular observed in amino acid concentration in cows with primary ketosis, indicate its intensive use in both ketogenesis and gluconeogenesis processes. Therefore, a detailed understanding of the role that amino acids play in gluconeogenesis and ketogenesis will improve ketosis diagnostics and monitoring the course of a ketosis episode. Perhaps, the prevention of this disease is possible by balancing the appropriate feed ration in terms of amino acid content. PMID- 29624010 TI - Molecular characterization and expression patterns of ghrelin in the reindeer (Rangifer tarandus). AB - Ghrelin is a novel growth hormone (GH)-releasing peptide, which has been identified as an endogenous ligand for the GH-sretagogue receptor. The sequence and expression of ghrelin has been determined in many species. In this study, to reveal the molecular characterization and expression patterns of ghrelin in the reindeer (Rangifer tarandus), the full-length DNA and cDNA encoding ghrelin were cloned from reindeer stomach using genome walking and rapid amplification of complementary deoxyribonucleic acid ends (RACE). The expression of ghrelin in almost all tissues was examined by real-time quantitative PCR (RT-qPCR). The 4076 bp amplicon of the ghrelin gene consisting of 4 exons and 3 introns was cloned from reindeer. Results of cDNA cloning and sequence analysis revealed that the full-length ghrelin cDNA was composed of 539 bp that included a 5'-untranslated region (46 bp), an open reading frame (ORF) (351 bp), and a 3'-untranslated region (142 bp). In addition, ghrelin was expressed in the all tissues examined, with the expression in the abomasum significantly higher than that in other tissues (p<0.05), followed by the pancreas, duodenum, testis and oesophagus. The results show that the expression of ghrelin in the reindeer gastrointestinal tract is extensive, suggesting its may have a role in regulating the digestive function. PMID- 29624011 TI - Comparison of the cardiovascular and respiratory effects and sevoflurane requirement in dogs premedicated with two doses of medetomidine and butorphanol undergoing surgical sterilization. AB - The aim of this study was to compare the cardiovascular and respiratory effects and sevoflurane requirement in dogs premedicated with two doses of medetomidine and butorphanol undergoing surgical sterilization. The dogs were randomly assigned to two different groups: group 1 received a lower dose of medetomidine (0.014 mg/kg) and butorphanol (0.14 mg/kg) and group 2 received a higher dose of medetomidine (0.024 mg/kg) and butorphanol (0.24 mg/kg). Anesthesia was induced with intravenous propofol and maintained with sevoflurane 2% in pure oxygen. Heart rate, SpO2, respiratory rate, EtCO2, esophageal temperature, systolic and diastolic arterial blood pressures, capillary refill time, reflexes (palpebral, pedal), jaw tone, and eye position (straight, down) were assessed. Anesthesia was monitored continuously by an anesthesiologist, and variables were recorded every 5 min. During general anesthesia, the median sevoflurane (SVO) concentrations and the median HR were significantly lower in group 2 than group 1 (p<0.05). The median HR was 96.3 (85.8-100.8) in group 1, whereas in group 2 it was 77.0 (67.5 84.6) (p<0.05). It might be concluded that the higher dose of medetomidine and butorphanol allows the use of a lower sevoflurane concentration during routine surgical treatments and ensures stable work of the cardiovascular and respiratory systems. PMID- 29624012 TI - Comparison of pathological lesions in navicular bone (os sesamoideum distale) and analysis of remodelling capacity in warmblood and coldblood horses. AB - The problem of navicular bone lesions is better understood in warmblood horses. The aim of our research was to compare pathologic lesions of navicular bone of different types of horses divided into age groups. An extra goal was to compare radiographs with anatomical status of navicular bone dissected from the hoof capsule. The study group included 161 horses, out of which 100 individuals were warmbloods, and 61 - coldbloods. In total 280 navicular bones were analysed. The flexor surface, distal border fragments, enthesophytes and the process of obliteration of nutrient foramina were analysed. Some navicular bones were also subject to histology test. A greater tendency for the obliteration of nutrient foramina was observed in coldblood horses than in warmbloods. This fact can be explained as increased remodelling, covering the phenomenon of closure of synovial invaginations and canaliculi within the navicular bone. As a result, the synovial groove disappears and blood vessels cannot enter the distal border. New bone formation on the distal border is more frequently observed in coldblood horses. The development of enthesophytes both on the distal and proximal borders depends to a large extent on the age of horses of both types. Warmbloods, however, are more prone to have the lesions located on the flexor surface, leading as a consequence to deep erosions. They might be found even in very young horses in the form of grooves crossing the sagittal ridge. The frequency of lesions varies depending on the type of the horse. Post-mortem analysis of navicular bones helped interpret radiographs in a more precise manner. PMID- 29624013 TI - Influence of hair clipping on transepidermal water loss values in horses: a pilot study. AB - The measurement of transepidermal water loss (TEWL) is one of the biophysical skin parameters used to assess skin barrier function. Assessment of transepidermal water loss, may depend on such factors as body region, age, sex or breed and the hair coat has been considered as one of the factors that may cause variation of TEWL values. The aim of our research was an examination of the influence of clipping on the amount of TEWL. The examination was performed with 12 Wielkopolska horses with Courage Khazaka Multi Probe Adapter 5 and a TEWL TM 300 probe. The TEWL values were statistically constant in the clipped site, while the values in the unclipped sites were not. Hair clipping of examined sites is recommended for TEWL measurement in horses. PMID- 29624014 TI - The effect of feeding system and sex on the performance and selected gastrointestinal features of fattening pigs. AB - The aim of the study was to evaluate the efficiency of two feeding systems for fattening pigs (wet and dry), taking into account their sex, on performance, nutrient digestibility, and some histological and microbiological parameters of the gut. The study was conducted on 450 fattening pigs, divided into 6 groups (n = 75) and housed in pens with 15 pigs per pen. The first three groups, divided according to sex, i.e. gilts, barrows and boars subjected to immunocastration (B I), received complete dry feed, while the next three, divided in the same manner according to sex, were fed a fermented liquid diet. The nutritional value of the feeds, calculated on a dry weight basis, was similar for the two feeding systems in both stages of the fattening period. The best weight gains were observed in the group B-I pigs which received the liquid diet, and the poorest in the gilts fed the dry feeds. The best feed conversion ratio (FCR) was observed in the boars treated with Improvac(r), especially those receiving the liquid diet. The feeding system significantly influenced the digestibility of nutrients, with higher apparent digestibility coefficients for crude protein, fat and fibre noted in the animals fed in the wet system. The liquid feeding system caused an increase in crypt depth in the colon in all groups of pigs, as well as an increase in the width of the muscular layer. A significant decrease in the total bacterial count was observed in the calcium, especially in the animals fed in the wet system. PMID- 29624015 TI - Photodynamic therapy of red and blue lights on Malassezia pachydermatis: an in vitro study. AB - In veterinary medicine, infection caused by Malassezia pachydermatis is spreading and necessity of alternative treatment is emphasized. Photodynamic therapy (PDT) is therapeutic method using specific spectrum of light with photosensitizer. In this study, applying PDT not only using red light which is used in human medicine commonly, but also using blue light into skin infection causative microorganism with photosensitizer, confirm the effect of PDT and possibility of being an alternative treatment. Four isolates of M. pachyderematis were collected from canine skin and used into this study. Light emitting diode with 495 nm, 625 nm spectrum was applied, and final concentration of delta-aminolevulinic acid (ALA), which is used as a photosensitizer, was adjusted into 20%. To confirm effectiveness of PDT, the number of colony forming unit was checked and variation of optical density values was measured. Antifungal effect of PDT on both spectrums was presented in all condition, and it makes best result when using blue light applied with ALA. Through outcome of this study, PDT using light in 465 nm, 625 nm wavelength combinations with ALA can interrupt proliferation of M. pachydermatis considerably. In consequence, PDT can be alterative treatment of canine Malassezia infection. PMID- 29624016 TI - Dietary supplementation with mannan oligosaccharide and clinoptilolite modulates innate and adaptive immune parameters of weaned pigs. AB - The aim of this study was to assess modulatory effects of dietary supplements mannan oligosaccharide (MOS) and clinoptilolite (CPL) as potential alternatives to antibiotic growth promoters (AGP) given to 4-week old pigs at weaning (Day 0) on their innate/adaptive immunity by determining: alterations in C-reactive protein (CRP) and haptoglobin (HpG) serum levels, efficiency of blood monocytes (MO) and neutrophilic granulocytes (GR) for in vitro phagocytosis (PHC)/microbicidity (MBC) and proportion of extrathymic double positive CD4 CD8 (CD4+CD8+) T cells throughout 35 days of the study. Neither MOS nor CPL changed the serum concentrations of CRP, whereas that of HpG was significantly increased in the CPL supplemented pigs (p<0.05) at Day 35. Activity of PHA of GR was significantly increased by both dietary supplements (p<0.05) from Day 7 to Day 35. Also, the GR from pigs fed with both supplements had significantly increased MBC at Day 7 (p<0.05), but at Day 35 such an increase was observed only for CPL. The in vitro PHC/MBC of MO did not change in either group of supplemented pigs. The pigs supplemented with MOS had a significantly higher proportion of CD4+CD8+ T lymphocytes at Day 28 (p<0.05). Although both supplements showed a promising ability to stimulate rather innate than adaptive cellular immunity, it does not appear that any solely applied natural substance such as MOS or CPL in the current study could be a competitive alternative to conventional AGP for improving health and promoting growth in weaned pigs. PMID- 29624017 TI - Characteristics of advanced methods used for typing bacterial isolates from mastitis with particular reference to Staphylococci. AB - Staphylococci are very common human and animal pathogens. A variety of staphylococcal virulence determinates leads to vast range of infections. One of them is mastitis which is a common disease of the mammary glands. The incidence of this disease is widespread all over the world and depends on bacterial virulence and on prevention programs. The influence of mastitis on human health is not globally evaluated, however, in veterinary fields loses in milk production caused by bovine mastitis are a constant economic problem. One of the most important parts of the mastitis control programs is accurate diagnosis of the inflammation and characterization of the etiological factors which leads to reduction of mastitis spread. Recent reports show that staphylococci are common bacterial etiological factors of mastitis, and this paper is an overview of the diagnostic typing methods used for characterization of staphylococcal isolates. A number of different techniques available to applicate is described. Phenotypic methods to identify and to differentiate isolates or discriminate virulence factors are still in use, however, some advanced genetic methods offering higher discriminatory power are reported as more accurate. In fact, nowadays the most powerful tool on that field is next generation sequencing (NGS) of the whole genome, but its high cost and requirement of special laboratory equipment makes it hard to use for routine diagnostics. That is why standard PCR techniques-based methods, and the sequencing of particular genes, are mostly used for typing bacterial isolates. Most of these techniques are characterized by a high discriminatory power, big epidemiological concordance, and repeatable results. The presented report describes the techniques used most frequent in mastitis diagnostics related to staphylococci typing and shows their advantages and disadvantages. PMID- 29624018 TI - Development of a rapid immunochromatographic assay for detection of antibodies against porcine epidemic diarrhea virus. AB - An immunochromatographic test strip was developed for the detection of antibodies against porcine epidemic diarrhea virus (PEDV) in porcine serum. In this test, the recombinant nucleocapsid protein of PEDV was expressed in soluble form and purified by using Ni-NTA resin and gel filtration chromatography. The purified recombinant N protein conjugated with colloidal gold was dispensed on a conjugate pad as the detector. Staphylococcal protein A and rabbit anti-N protein IgG were blotted on a nitrocellulose membrane for the test and control lines, respectively. The immunochromatographic test strip specifically detected PEDV antibodies within 10 min and had higher sensitivity (96.0%) and specificity (90.8%) than those of commercial enzyme-linked immunosorbent assay (ELISA) kits. Our newly developed strip has great potential for the early diagnosis of PEDV infection. PMID- 29624019 TI - Therapeutic activity of chlorhexidine-poloxamer antiseptic gel on wound healing in rats: a preclinical study. AB - Despite the progress in curative and preventive medicine, skin lesions after injuries or surgical interventions are still a big problem. The aim of wound care is to get damaged tissues to heal as soon as possible. A gel-forming material helps to maintain proper humidity in the wound and promotes the healing process. For this purpose, a healing gel containing the active substance chlorhexidine based on poloxamer was prepared. The aim of this study was to assess in vivo the therapeutic efficacy of chlorhexidine-poloxamer gel in treatment of wounds caused experimentally and inoculated with bacteria, and the effect of an antiseptic gel applied on a healthy rat skin. Wistar albino rats were selected for these studies. The effect of an antiseptic gel on the healing excision and incision wounds, as well as the irritating effect on the healthy skin were assessed. Cross sectional full-thickness specimens from each group were collected at the end of the experiment to assess the histopathological alterations. Chlorhexidine poloxamer gels accelerate the healing of infected skin wounds because the active ingredient chlorhexidine remains at the application site, and systemic effects are avoided. Moreover, chlorhexidine-poloxamer gels are easy to use because they can be easily washed off from the wound surface by water. The present study has revealed that chlorhexidine-poloxamer gels promote healing of full-thickness skin wounds without skin irritation. This makes it possible to plan further clinical trials in the target species. PMID- 29624020 TI - Effect of chlorpyrifos and enrofloxacin on selected enzymes in rats. AB - This study examined the effect of chlorpyrifos and/or enrofloxacin on the activity of acetylcholinesterase (AChE) in the blood and brain, and the activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) in serum. The experiment was conducted on Wistar strain rats. Chlorpyrifos was administered with a stomach tube at a dose of 0.04 LD50 for 28 days and enrofloxacin at a dose of 5 mg/kg bw for 5 consecutive days. The experiment found that enrofloxacin changed the activity of the enzymes under study only to a small extent. At the dose applied in the experiment, chlorpyrifos decreased the activity of AChE significantly, both in blood and in the brain, and increased the activity of ALT and AST in rat serum. The administration of chlorpyrifos in combination with enrofloxacin changed the activity of the enzymes under study only slightly. A weaker, but longer, inhibition of AChE activity in both blood and the brain was observed in this group compared to the animals exposed only to chlorpyrifos. However, although enrofloxacin, like chlorpyrifos, increases the activity of ALT and AST in serum, their combined administration did not increase the hepatotoxic effect. PMID- 29624021 TI - Construction of a recombinant baculovirus expressing swine hepatitis E Virus ORF2 and preliminary research on its immune effect. AB - In the swine hepatitis E virus (HEV), open reading frame 2 (ORF2) is rich in antigenic determinants and neutralizing epitopes that could induce immune protection. We chose the Bac-to-Bac(r) Baculovirus Expression System to express fragments containing the critical neutralizing antigenic sites within the HEV ORF2 protein of pigs to obtain a recombinant baculovirus. The fragment of swine HEV ORF2 region (1198-1881bp) was cloned into vector pFastBacTM. A recombinant baculovirus, rBacmid-ORF2, was obtained after transposition and transfection. The molecular mass of the recombinant protein was 26 kDa. Mice were immunized by the intraperitoneal and oral routes with cell lysates of recombinant baculovirus rBacmid-ORF2. Serum and feces of the mice were collected separately at 0, 14, 28, and 42 d after immunization and the antibody levels of IgG and secretory IgA against swine HEV were determined using an enzyme-linked immunosorbent assay. The results suggested that rBacmid-ORF2 induced antibodies of the humoral and mucosal immune responses in mice and that the oral route was significantly superior to the intraperitoneal route. This is the first study to demonstrate that that recombinant baculovirus swine HEV ORF2 could induce humoral and mucosal immune responses in mice. PMID- 29624022 TI - Simvastatin modulates beta-catenin/MDR1 expression on spheres derived from CF41.Mg canine mammary carcinoma cells. AB - The presence of cancer stem-like cells (CSC) within canine mammary tumors, may explain partly local recurrence and spreading, since their ability to resist conventional antitumor treatments as chemo and radiotherapy. It has been recently described that simvastatin - a drug that inhibits synthesis of cholesterol - attenuates the proliferation of canine mammary CSC derived from CF41.Mg canine mammary carcinoma cells, promoting their chemosensitizing and apoptosis. The canonical Wnt/beta-catenin pathway is usually activated at CSC and up-regulates multidrug resistance protein 1 (MDR1), triggering chemoresistance. In the present study, we analyze the effect of simvastatin on beta-catenin/MDR1 expression in spheres obtained from the CF41.Mg cell line as a model of CSC. Simvastatin increased phosphorylation of beta-catenin without affecting its total expression. Moreover, MDR1 expression was decreased by simvastatin. These results suggest that simvastatin would facilitate the degradation of beta-catenin, decreasing MDR1 expression and contributing to the chemosensitizing effects of the statin on canine mammary CSC. PMID- 29624023 TI - Effect of nitric oxide on boar sperm motility, membrane integrity, and acrosomal status during semen storage. AB - Nitric oxide (NO) is a major gasotransmitter involved in several physiological processes of male reproduction. There is, nevertheless, little information concerning the role of NO during semen storage. The aim of this study was to evaluate the effect of NO on boar semen stored at 17oC for 72 h. For this purporse, sperm samples were treated with 0.625, 1.25, 2.5, 5, and 10 mM aminoguanidine (AG) or Nomega-Nitro-L-arginine methyl ester hydrochloride (L NAME), a selective and non-selective NO synthase (NOS) inhibitor, respectively. Moreover, sodium nitroprusside (SNP), a NO donor, was used at the dose of 18.75, 37.5, 75, and 150 MUM. Sperm motility, membrane integrity, and acrosomal status were evaluated at 0, 4, 24, 48, and 72 h of semen storage. A significant increase of the amplitude of lateral sperm head displacement (ALH), and both curvilinear and straight-line velocity (VCL and VSL, respectively) was observed at 72 h of semen storage in samples treated with 0.625 mM AG, probably because of the antioxidant properties of this NOS inhibitor. Contrarily, 0.625 mM L-NAME showed no effect on boar sperm parameters during the entire period of semen storage. Moreover, AG and L-NAME at 10 mM negatively affected sperm kinetics and acrosome integrity, which may provide further support to the notion that low NO levels are necessary for a normal sperm function. The concentrations of SNP used in this study had mostly no or negative effects on boar sperm parameters during semen storage. In conclusion, the results from this study increase the understanding of the role of NO on boar sperm physiology. PMID- 29624024 TI - Morphology and elemental analysis of free range and stabled Polish Konik horses hair using Energy-dispersive X-ray spectroscopy (EDS). AB - Hair is a more biologically stable material than other tissues and contains a relatively constant level of minerals, drugs or toxins. The content of essential elements in hair depends on dietary and non-dietary factors. The aim of this study was to assess and compare the effect of diet on the elemental composition and morphological properties of the hair of healthy Polish Konik horses. Mane hair was collected from 19 horses living in The National Park in Popielno in Poland. Six of these horses were free-ranged all year with permanent access to pasture, while 13 horses were kept in the stable and fed oats, hay and straw. The samples were analyzed using a Scanning Electron Microscope combined with Energy dispersive X-ray spectroscopy (SEM-EDS). Each hair was analyzed for its microscopic appearance and elemental Mg, Si, S, Ca, Mn, Co, Zn and Se content. No significant changes in the morphological properties and elemental composition were observed. There was inter- individual variability in element content between horses in both groups, but this did not affect their health. The comparison of the present results with other studies shows that the level of elements in the hair of Polish Konik horses is significantly lower than in healthy horses of other breeds. The traditional feeding plan containing pasture, oats and hay does not contain a sufficient amount of main mineral elements. Further investigation is needed to explain the effect of diet and maintenance on the mineral balance of horses. PMID- 29624025 TI - Hepatic encephalopathy and cirrhotic cardiomyopathy in Intensive Care Unit. AB - Acute and chronic liver diseases may escalate to hepatic encephalopathy (HE) and multiple organ failure, requiring admission and organ support in Intensive Care Unit (ICU). Hepatic dysfunction in ICU is a broad and complex topic; unfortunately, up to now, the understanding of its underlying pathophysiology is far from complete. HE and cirrhotic cardiomyopathy (CCM) need timely diagnostic and therapeutic measures aiming at the identification and elimination of causative factors, to improve patients' prognosis. Through this short review, we tried to answer the most asked questions about clinical features of HE and CCM at the ICU stage. PMID- 29624026 TI - Preoperative anxiety and implications on postoperative recovery: what can we do to change our history. AB - Preoperative anxiety can influence the intensity of postoperative pain and anesthesia and analgesia requirement. In certain types of surgery, anxiety may even increase postoperative morbidity and mortality. The goal of this narrative review is to remind anesthesiologists that anxiety measurement using specific tools can be done in clinical practice, to present the implications of preoperative anxiety on postoperative patient recovery, and to acknowledge the importance of a dedicated anesthesia plan in the management of anxious adult patients. Preoperative assessment performed several weeks before surgery in an outpatient clinic is a reasonable option to give information about surgery, anesthesia and postoperative pain. This is the time to assess patient preoperative anxiety by using VAS-A. If high anxiety level is detected early, the patient can be referred to a psychologist for preoperative preparation. This is consistent with the guidelines for enhanced recovery after surgeries, which underline the importance of patient-doctor discussion about hospitalization and perioperative care. Patients with preoperative anxiety could benefit from multimodal analgesia, including non-pharmacological methods, such as cognitive therapy and music therapy and relaxation. The authors' opinion is that greater education about preoperative anxiety consequences in the surgical community is needed. A systemized approach and guidelines about the management of preoperative anxiety should be followed. PMID- 29624027 TI - Percussive ventilation rescue after HFOV failure in severe ARDS due to burn injury. PMID- 29624028 TI - Uncommon occurrence of high piperacillin-tazobactam and meropenem plasma concentrations and concomitant absence of neurotoxicity in pediatrics. PMID- 29624029 TI - Pressure, volume and temperature: Boyle's law rules airways. PMID- 29624030 TI - The ultrasound-guided C2-C4 compartment block combined to dexmedetomidine sedation: an ideal approach for carotid endarterectomy in awake patients. PMID- 29624031 TI - Fluid therapy and endothelial glycocalyx layer. On the track of the water-phobic Bigfoot. PMID- 29624033 TI - EFFECT OF DISEASE-MODIFYING ANTIRHEUMATIC DRUGS ON THE VALUES OF APOLIPOPROTEIN A 1 AND ACUTE PHASE REACTANTS IN PATIENTS WITH ACTIVE RHEUMATOID ARTHRITIS. AB - In this observational study we examined the impact of disease-modifying antirheumatic drugs (DMARDS) on thedisease activity as well as the values of acute phase reactants and the apolipoprotein A1 (Apo A1) in patients with activerheumatoid arthritis (RA). Eighty patients with active RA and newly discovered RA patients who meet the AmericanRheumatology Association (ARA) 1987 revised criteria were treated with disease modifying anti-rheumatic drugs -DMARDs according to the standard protocol of everyday clinical practice. At 6 and 12 months of treatment the patientsachieved a signifi cant decrease in the disease activity score 28 (DAS28), C-reactive protein (CRP), and erythrocytesedimentation rate (ESR) values. On the other hand, the levels of Apo A-1, which were low at baseline, were signifi -cantly higher. In conclusion, the use of DMARDs in patients with RA reduced disease activity and infl ammation, butalso had a benefi cial eff ect in increasing the levels of atheroprotective Apo A-1 lipoprotein, which can reduce CV risksin these patients. PMID- 29624032 TI - [VAGAL NERVE STIMULATION IN THE TREATMENT OF PATIENTS WITH RHEUMATOID ARTHRITIS - RESULTS THROUGH DAY 84 OBTAINED AT THE CROATIAN CENTER OF AN INTERNATIONAL PILOT STUDY]. AB - Objective: Electrical stimulation of the vagus has proven effective in various inflammatory conditions in animalmodels. The aim of this study is to show the effect of vagal nerve neurostimulation on clinical and laboratory parameters in two patients with active rheumatoid arthritis (RA) and an inadequate response to methotrexate. Patients and methods: The research was conducted as part of an international pilot study. Patients were implanted with the Cyberonics system for electrical stimulation of the vagus. After an initial in-clinic stimulation, the patientsperformed the stimulations at home for 42 days, when the device was inactivated. On day 56 the stimulations were reinitiated. The following parameters were evaluated: tender and swollen joint count, physician's (PGA) and patient's (PtGA) global score, intensity of pain, disease activity (DAS28), functional ability (HAQ), serum CRP level, and EULAR response. Results: In the period from the screening visit to the day 42 visit, both patients experienced an improvement ofDAS28 (7.00 and 6.22 vs. 4.03 and 2.13), PGA (70 and 53 vs. 27 and 16), PtGA (48 and 43 vs. 15 and 14), tender joint count (26 and 28 vs. 4 and 0), swollen joint count (24 and 14 vs. 8 and 2), intensity of pain (72 and 87 vs 21 and 7), HAQ score (2.25 and 2.25 vs. 1.5 and 1.375), and CRP levels (23.8 and 5.58 vs. 13 and 4.61). After the device deactivation, DAS28 and VAS pain worsened in both patients. Conclusion: Vagal neural stimulation in the treatment of patients with active RA and an inadequate response tomethotrexate is effective in reducing clinical symptoms and parameters of inflammation. Our results are in accordance with the results obtained in other centers. Research on a larger number of subjects is necessary for a better evaluation of the effect of this new approach to the treatment of patients with rheumatoid arthritis. PMID- 29624034 TI - [MYOCARDIAL INFARCTION AS A CONSEQUENCE OF CHILDHOOD POLYARTERITIS NODOSA - CASE REPORT]. AB - Polyarteritis nodosa (PAN) is a systemic vasculitis histologically characterized by necrotic lesions of small and medium-sized arteries occurring mostly in their bifurcations. PAN is a multi-organ disorder that affects numerous visceralarteries and leads to inflammation and necrosis, which may result in ischemia of vital organs. The etiology of the diseaseis unknown. It occurs in four forms - cutaneous (most common), classic, systemic, and microscopic. PAN preferablyaffects the renal and coronary arteries. The most common findings in the affected blood vessels are aneurysm, thrombosis,and stenosis. Cardiac complications are rare in children, but 35% of patients develop a complication in adulthood. Themost common complication in adulthood is cardiac decompensation, which can be explained as a consequence of longstandinghypertension and changes in coronary blood vessels. The incidence of myocardial infarction is low, particularlyin young patients. This paper describes a 25-year-old patient with acute myocardial infarction accompanied by changesin the coronary blood vessels and persistent arterial hypertension as a result of PAN diagnosed in childhood. PMID- 29624035 TI - PERICARDIAL FEATURES OF IN-HOSPITAL RHEUMATOLOGY PATIENTS: AN OBSERVATIONAL STUDY. AB - Rheumatic disorders can be associated with pericarditis, but severe forms of pericarditis are rare. The aim of thisobservational study was to evaluate pericardial features in patients with different rheumatic diseases. Thirty fivepatients hospitalized at the Clinic of Rheumatology, University Clinical Center of Kosovo, from October 1 to October21, 2014 were included in the study. Demographic data, history, laboratory, ECG, and echocardiography data, withspecial emphasis on the analysis of the pericardium, were obtained from each patient. Echocardiography was especiallyfocused on the amount of pericardial fluid and pericardial thickness in the posterior wall of the heart.Mean patient age was 51.5 +/- 13.8 years. 65.7% of the patients were women. Out of the patients that we analyzed,88.6% had an inflammatory rheumatologic disease. 11.3% of the patients had mild symptoms, in 68.7% the symptomswere moderate, and in 20% severe. In all patients, pericardial hyperechogenicity was marked, with a mean pericardialthickness of 4.68 +/- 1.66 mm. Pericardial effusion in a small amount was present in 57.1% of patients, with a meanpericardial fluid amount of 3.3 +/- 1.9 mm. The severity of rheumatic disease had a positive and significant correlationwith the presence of pericardial effusion (r= 0.29, p=0.04) and its amount (r= 0.28, p=0.05). The patients had not beenaware of the pericardial involvement and did not have any clinical symptoms.In conclusion, in this short term small observational study pericardial changes were a frequent finding in therheumatology patients. In general, the pericarditis was subclinical and with small amounts of effusion. The diseaseactivity of rheumatic disorders can be associated with pericarditis. Further studies with larger samples of patients andof longer duration are needed to further explore this issue. PMID- 29624036 TI - Carbon Nanotube Inkjet Printing Based Resettable Sensor for Online Scale Monitoring. AB - In this paper, a new type of sensor and associated system for complete online monitoring of scale deposition with great accuracy and reliability is fabricated and characterized. The system is based on carbon nanotubes (CNTs), which have unique sensing/electronic properties along with physical and chemical stability in corrosive and hostile environments required for the oil and gas application. CNTs inkjet printing technique is used to fabricate the CNTs sensor. The sensitivity of the films, real time monitoring of brine solution, stability of the films in various solvents and fluids and the ability of setting and resetting of the sensor are studied. The results of these studies indicate that adding of one brine solution on the surface of the CNTs inkjet printing increases the resistance from 0.50 kOmega to 1.50 kOmega. The CNTs inkjet printing sample is found to be stable even after 48 hours of soaking the whole sample in DI-water. This sensor not only shows good sensing response for detection of the deposition of brine, but can also be easily reset back many times by just wash it with DI water. This simple sensor is ideally suited for real time monitoring and the response time of the film is found to be from 15-30 s. PMID- 29624037 TI - Effect of Illumination Intensities on the Visible and Infrared Photoresponse of Cu2SnS3 Nanostructures. AB - We report the synthesis of Cu(2)SnS(3) nanostructures using solvothermal technique and the study of its visible and infrared (IR) photoresponse under different illumination intensities. The CTS nano-crystals were found to have tetragonal crystal structure using X-ray Diffraction (XRD). Both flower and sphere shaped structures of around 1.5 MUm were obtained as seen using scanning electron microscopy (SEM). Transmission electron microscopy (TEM) was used to study the crystalline nature as well as the different planes present in the crystal. The band gap of the obtained crystals was found to be 1.4 eV using optical studies. The visible photocurrent increased from 0.25 MUA at dark to 0.42 MUA at 1.05 suns and 1 V applied bias. The sensitivity increased from 1.25 at 0.88 suns to 1.68 at 1.05 suns. The IR photocurrent increased from 0.13 MUA at dark to 0.66 MUA at 477.7 mWcm(-2). The device exhibited an increase in the sensitivity, responsivity, external quantum efficiency and specific detectivity from 1.23, 0.10 mA/W, 0.016% and 5.02 * 10(8) Jones respectively at 127.4 mWcm(-2 ) to 4.95, 0.46 mA/W, 0.071% and 2.22*10(9) Jones respectively at 477.7 mWcm(-2). The time response of the photocurrent was measured over different ON-OFF cycles and the cyclic stability of the device was verified. PMID- 29624038 TI - [CLASSIFICATION AND DIAGNOSIS OF AXIAL SPONDYLOARTHRITIDES - HISTORY, PRESENT STATE, AND PERSPECTIVES]. AB - Spondyloarthritis (SpA) is a group of inflammatory rheumatic diseases that share some common genetic,clinical, serological, radiological, and prognostic features. Since the early 1960s, several classification criteria forSpA have been proposed, and some of them were also used for diagnostic purposes. The ASAS international group ofexperts established a set of classification criteria for SpA, dividing them into axial or peripheral, according to predominantinvolvement. The paradigmatic entity of axial SpA is ankylosing spondylitis, which is diagnosed in clinicalpractice with significant delay. Therefore the ASAS classification introduced the term "non-radiographic axial SpA",which refers to changes in the sacroiliac joints seen on MRI, but not on radiograph. Although the ASAS classificationhas been widely accepted in the professional community, recently initiatives were raised suggesting changes and aimingat improvements. In this paper these objections are discussed, as well as the responses of experts who consider thatthese changes are not necessary. PMID- 29624039 TI - Fabrication of Self-Cleaning and Anti-Icing Durable Surface on Glass. AB - Ice accumulation on insulators affected the safety of power system and may inflict serious consequences such as insulator flashover accidents and power failure. This article reported a simple method to prepare anti-icing polydimethylsiloxane superhydrophobic surface on glass by utilizing nano-particle filling method. The effect of concentration of silica nanoparticles on superhydrophobicity of the samples was investigated. The wettability, surface morphology and anti-icing property of the as-prepared superhydrophobic surface were characterized by corresponding methods. Results show that the as-prepared surface with addition amount of 7 g silica nanoparticles exhibited self-cleaning property and excellent superhydrophobicity with a contact angle of 165.7 +/- 2.4 degrees and a sliding angle of 3.8 degrees . It was found that the ice formation was delayed for 29 min at -5 degrees C. Moreover, the as-prepared superhydrophobic surface showed superhydrophobicity in the pH range of 1-13 and exhibited excellent drop impact stability. The as-prepared superhydrophobic surface may be suitable for applications in cold regions owing to its flexibility, durability and anti-icing property. PMID- 29624040 TI - [ETIOLOGY AND PATHOGENESIS OF PAIN IN RHEUMATIC DISEASES]. AB - Rheumatic diseases are chronic inflammatory disorders with ongoing inflammation that causes tissuedamage. Inflammatory and damaged cells synthetize and release many diff erent intracellular substances which canactivate highly specialized subsets of primary sensory neurons called nociceptors. Some of these proinflammatorymediators directly activate the nociceptor terminal and produce pain (such as hydrogen ion, adenosine triphosphate,and bradykinin), and others sensitize the terminal so that it becomes hypersensitive to subsequent and non noxiousstimuli (such as prostaglandin E2 and bradykinin). Acute pain has a protective role since it induces behavior that promoteshealing and recovery, such as immobilization which limits tissue damage. Chronic pain is unhelpful pain thattends to be out of proportion to the actual tissue damage and persists long after the tissues have healed, so that the painbecomes the problem rather than the tissues of origin. Chronic pain affects the physical and mental status and causesimpairment of quality of life as well as work disability. For rheumatologists the assessment and treatment of pain is avery important integral part of patient care, and understanding the etiology and pathogenesis of pain is necessary tofi nd adequate modalities of treatment to prevent suffering. PMID- 29624041 TI - TiO2 Nanolayer-Enhanced Fluorescence for Simultaneous Multiplex Mycotoxin Detection by Aptamer Microarrays on a Porous Silicon Surface. AB - A new aptamer microarray method on the TiO2-porous silicon (PSi) surface was developed to simultaneously screen multiplex mycotoxins. The TiO2 nanolayer on the surface of PSi can enhance the fluorescence intensity 14 times than that of the thermally oxidized PSi. The aptamer fluorescence signal recovery principle was performed on the TiO2-PSi surface by hybridization duplex strand DNA from the mycotoxin aptamer and antiaptamer, respectively, labeled with fluorescence dye and quencher. The aptamer microarray can simultaneously screen for multiplex mycotoxins with a dynamic linear detection range of 0.1-10 ng/mL for ochratoxin A (OTA), 0.01-10 ng/mL for aflatoxins B1 (AFB1), and 0.001-10 ng/mL for fumonisin B1 (FB1) and limits of detection of 15.4, 1.48, and 0.21 pg/mL for OTA, AFB1, and FB1, respectively. The newly developed method shows good specificity and recovery rates. This method can provide a simple, sensitive, and cost-efficient platform for simultaneous screening of multiplex mycotoxins and can be easily expanded to the other aptamer-based protocol. PMID- 29624042 TI - Self-Assembled Supramolecular Hybrid of Carbon Nanodots and Polyoxometalates for Visible-Light-Driven Water Oxidation. AB - Water splitting is considered the most attractive pursuit in the field of solar energy conversion. In this study, we report the synthesis and application of a supramolecular hybrid of carbon nanodot (CD) and cobalt polyoxometalate (Co-POM) to solar water oxidation. The self-assembly of the alginate-based CD and Co-POM led to the formation of a spherical hybrid of CD/Co-POM. Owing to the facile transfer of photogenerated holes from CD under visible light irradiation, the hybrid donor-acceptor type of CD/Co-POM enabled the rapid scavenging of holes and accumulation of a long-lived oxidation state of Co-POM for efficient solar water oxidation, outperforming conventional [Ru(bpy)3]2+-based systems. We believe that this study offers new insights into the development of CD-based nanocomposites with various photocatalytic and optoelectronic applications. PMID- 29624043 TI - Macroscopic X-ray Powder Diffraction Scanning: Possibilities for Quantitative and Depth-Selective Parchment Analysis. AB - At or below the surface of painted works of art, valuable information is present that provides insights into an object's past, such as the artist's technique and the creative process that was followed or its conservation history but also on its current state of preservation. Various noninvasive techniques have been developed over the past 2 decades that can probe this information either locally (via point analysis) or on a macroscopic scale (e.g., full-field imaging and raster scanning). Recently macroscopic X-ray powder diffraction (MA-XRPD) mapping using laboratory X-ray sources was developed. This method can visualize highly specific chemical distributions at the macroscale (dm2). In this work we demonstrate the synergy between the quantitative aspects of powder diffraction and the noninvasive scanning capability of MA-XRPD highlighting the potential of the method to reveal new types of information. Quantitative data derived from a 15th/16th century illuminated sheet of parchment revealed three lead white pigments with different hydrocerussite-cerussite compositions in specific pictorial elements, while quantification analysis of impurities in the blue azurite pigment revealed two distinct azurite types: one rich in barite and one in quartz. Furthermore, on the same artifact, the depth-selective possibilities of the method that stem from an exploitation of the shift of the measured diffraction peaks with respect to reference data are highlighted. The influence of different experimental parameters on the depth-selective analysis results is briefly discussed. Promising stratigraphic information could be obtained, even though the analysis is hampered by not completely understood variations in the unit cell dimensions of the crystalline pigment phases. PMID- 29624044 TI - Dichroic Mirror-Assisted Electrochemiluminescent Assay for Simultaneously Detecting Wild-type and Mutant p53 with Photomultiplier Tubes. AB - The electrochemical-dependent and unstable intensity of electrochemiluminescence (ECL) makes it difficult to identify ECL in a waveband-resolved way on photomultiplier tube (PMT)-based traditional ECL analyzers. Herein, a dual-color ECL strategy is proposed by transferring ECL to two PMTs in a waveband-resolved way via dichroic mirror, simultaneously detecting wild-type p53 (WTp53) in near infrared wavebands with CdTe (lambdamax = 782 nm) nanocrystals as tag and mutant p53 (MUp53) in eye-visible wavebands with CdSe (lambdamax = 554 nm) nanocrystals as tag. The two targets can be color-selectively determined from 10 fM to 100 pM with a limit of detection at 5 fM for MUp53 and from 50 fM to 100 pM with a limit of detection at 10 fM for WTp53, respectively. The dichroic mirror-involved ECL setup is easy to assemble for popularization, which would not only eventually enable PMT-based multiple-color ECL analysis but also make it is possible to directly determine the changed level of tumor suppressors for cancer diagnosis and therapeutic evaluation via one-pot ECL assay. PMID- 29624045 TI - High-Crystallinity Urchin-like VS4 Anode for High-Performance Lithium-Ion Storage. AB - VS4 anode materials with controllable morphologies from hierarchical microflower, octopus-like structure, seagrass-like structure to urchin-like structure have been successfully synthesized by a facile solvothermal synthesis approach using different alcohols as solvents. Their structures and electrochemical properties with various morphologies are systematically investigated, and the structure property relationship is established. Experimental results reveal that Li+ ion storage behavior in VS4 significantly depends on physical features such as the morphology, crystallite size, and specific surface area. According to this study, electrochemical performance degrades on the order of urchin-like VS4 > octopus like VS4 > seagrass-like VS4 > flower-like VS4. Among them, urchin-like VS4 demonstrates the best electrochemical performance benefiting from its peculiar structure which possesses large surface area that accommodates the volume change to a certain extent, and single-crystal thorns that provide fast electron transportation. Kinetic parameters derived from EIS spectra and sweep-rate dependent CV curves, such as charge-transfer resistances, Li+ ion apparent diffusion coefficients and stored charge ratio of capacitive and intercalation contributions, both support this claim well. In addition, the EIS measurement was conducted during the first discharge/charge process to study the solid electrolyte interface (SEI) formation on urchin-like VS4 and kinetics behavior of Li+ ion diffusion. A better fundamental understanding on Li+ storage behavior in VS4 is promoted, which is applicable to other vanadium-based materials as well. This study also provides invaluable guidance for morphology-controlled synthesis tailored for optimal electrochemical performance. PMID- 29624046 TI - Chromium Trioxide Hole-Selective Heterocontacts for Silicon Solar Cells. AB - A high recombination rate and high thermal budget for aluminum (Al) back surface field are found in the industrial p-type silicon solar cells. Direct metallization on lightly doped p-type silicon, however, exhibits a large Schottky barrier for the holes on the silicon surface because of Fermi-level pinning effect. As a result, low-temperature-deposited, dopant-free chromium trioxide (CrO x, x < 3) with high stability and high performance is first applied in a p type silicon solar cell as a hole-selective contact at the rear surface. By using 4 nm CrO x between the p-type silicon and Ag, we achieve a reduction of the contact resistivity for the contact of Ag directly on p-type silicon. For further improvement, we utilize a CrO x (2 nm)/Ag (30 nm)/CrO x (2 nm) multilayer film on the contact between Ag and p-type crystalline silicon (c-Si) to achieve a lower contact resistance (40 mOmega.cm2). The low-resistivity Ohmic contact is attributed to the high work function of the uniform CrO x film and the depinning of the Fermi level of the SiO x layer at the silicon interface. Implementing the advanced hole-selective contacts with CrO x/Ag/CrO x on the p-type silicon solar cell results in a power conversion efficiency of 20.3%, which is 0.1% higher than that of the cell utilizing 4 nm CrO x. Compared with the commercialized p-type solar cell, the novel CrO x-based hole-selective transport material opens up a new possibility for c-Si solar cells using high-efficiency, low-temperature, and dopant-free deposition techniques. PMID- 29624047 TI - Parallel Proteomic Workflow for Mass Spectrometric Analysis of Tissue Samples Preserved by Different Methods. AB - Formalin-fixed and paraffin-embedded (FFPE) and optimal cutting temperature (OCT) embedded and frozen tissue specimens in biobanks are highly valuable in clinical studies but proteomic and post-translational modification (PTM) studies using mass spectrometry (MS) have been limited due to structural arrangement of proteins and contaminations from embedding material. This study aims to develop a parallel proteomic workflow for FFPE and OCT/frozen samples that allows for large scale, quick, reproducible, qualitative, and quantitative high-resolution MS analysis. The optimized protocol gives details on removal of embedding material, protein extraction, and multienzyme digestion using filter-aided sample preparation method. The method was evaluated by investigating the protein expression levels in nonmuscle-invasive and muscle-invasive bladder cancer samples in two cohorts and MS spectra were carefully reviewed for contaminations. More than 2000 and 3000 proteins in FFPE and OCT/frozen samples, respectively, were identified, and samples could be clustered in different tumor stages based on their protein expression. Furthermore, more than 250 and 400 phosphopeptides could be identified from specific patient samples of FFPE and OCT/frozen, respectively, using titanium dioxide enrichment. The paper presents unique data describing the similarities and differences observed in FFPE and OCT/frozen samples and shows the feasibility to detect proteins and site-specific phosphorylation even after long-term storage of clinical samples. PMID- 29624048 TI - OEGylated Cyclodextrins Responsive to Temperature, Redox, and Metal Ions. AB - The present work provides a versatile access for "smart" cyclodextrins (CDs) that are responsive to temperature, redox, and metal ions. These CDs are modified with oligoethylene glycols through thiol-ene click chemistry, which are inherently thermoresponsive in aqueous solutions. At the same time, their thermoresponsiveness is tunable through oxidation or metal ion chelation of thioether moieties. Significantly, these stimuli-responsive CDs retained strong inclusion abilities to guest dyes, and the inclusion complexation can be tuned by thermally induced phase transitions, oxidation, as well as metal chelation. The stimuli-responsive complexation with dyes allows to fabricate colorimetric/fluorescent sensors for temperature or for soft metal ions, such as Ag+ and Hg2+. With multiple responsiveness integrated in one material, these monodisperse CDs have formed a new class of stimuli-responsive macrocycles, which can reversibly encapsulate and release guest species through multiple switches. PMID- 29624049 TI - Skin-Attachable, Stretchable Electrochemical Sweat Sensor for Glucose and pH Detection. AB - As part of increased efforts to develop wearable healthcare devices for monitoring and managing physiological and metabolic information, stretchable electrochemical sweat sensors have been investigated. In this study, we report on the fabrication of a stretchable and skin-attachable electrochemical sensor for detecting glucose and pH in sweat. A patterned stretchable electrode was fabricated via layer-by-layer deposition of carbon nanotubes (CNTs) on top of patterned Au nanosheets (AuNS) prepared by filtration onto stretchable substrate. For the detection of glucose and pH, CoWO4/CNT and polyaniline/CNT nanocomposites were coated onto the CNT-AuNS electrodes, respectively. A reference electrode was prepared via chlorination of silver nanowires. Encapsulation of the stretchable sensor with sticky silbione led to a skin-attachable sweat sensor. Our sensor showed high performance with sensitivities of 10.89 MUA mM-1 cm-2 and 71.44 mV pH 1 for glucose and pH, respectively, with mechanical stability up to 30% stretching and air stability for 10 days. The sensor also showed good adhesion even to wet skin, allowing the detection of glucose and pH in sweat from running while being attached onto the skin. This work suggests the application of our stretchable and skin-attachable electrochemical sensor to health management as a high-performance healthcare wearable device. PMID- 29624050 TI - Zwitterionic Rhodium and Iridium Complexes Based on a Carboxylate Bridge Functionalized Bis-N-heterocyclic Carbene Ligand: Synthesis, Structure, Dynamic Behavior, and Reactivity. AB - A series of water-soluble zwitterionic complexes featuring a carboxylate bridge functionalized bis-N-heterocyclic carbene ligand of formula [Cp*MIIICl{(MeIm)2CHCOO}] and [MI(diene){(MeIm)2CHCOO}] (Cp* = 1,2,3,4,5 pentamethylcyclopentadienyl; M = Rh, Ir; MeIm = 3-methylimidazol-2-yliden-1-yl; diene = 1,5-cyclooctadiene (cod), norbornadiene (nbd)) were prepared from the salt [(MeImH)2CHCOO]Br and suitable metal precursor. The solid-state structure of both types of complexes shows a boat-shaped six-membered metallacycle derived of the kappa2C,C' coordination mode of the bis-NHC ligand. The uncoordinated carboxylate fragment is found at the bowsprit position in the Cp*MIII complexes, whereas in the MI(diene) complexes it is at the flagpole position of the metallacycle. The complexes [RhI(diene){(MeIm)2CHCOO}] (diene = cod, nbd) exist as two conformational isomers in dichloromethane, bowsprit and flagpole, that interconvert through the boat-to-boat inversion of the metallacycle. An inversion barrier of ~17 kcal.mol-1 was determined by two-dimensional exchange spectroscopy NMR measurements for [RhI(cod){(MeIm)2CHCOO}]. Reaction of zwitterionic Cp*MIII complexes with methyl triflate or tetrafluoroboric acid affords the cationic complexes [Cp*MIIICl{(MeIm)2CHCOOMe}]+ or [Cp*MIIICl{(MeIm)2CHCOOH}]+ (M = Rh, Ir) featuring carboxy and methoxycarbonyl functionalized methylene-bridged bis NHC ligands, respectively. Similarly, complexes [MI(diene){(MeIm)2CHCOOMe}]+ (M = Rh, Ir) were prepared by alkylation of the corresponding zwitterionic MI(diene) complexes with methyl triflate. In contrast, reaction of [IrI(cod){(MeIm)2CHCOO}] with HBF4.Et2O (Et = ethyl), CH3OTf, CH3I, or I2 gives cationic iridium(III) octahedral complexes [IrIIIX(cod){(MeIm)2CHCOO}]+ (X = H, Me, or I) featuring a tripodal coordination mode of the carboxylate bridge-functionalized bis-NHC ligand. The switch from kappa2C,C' to kappa3C,C',O coordination of the bis-NHC ligand accompanying the oxidative addition prevents the coordination of the anions eventually formed in the process that remain as counterions. PMID- 29624051 TI - Soil Bacterial Diversity Is Associated with Human Population Density in Urban Greenspaces. AB - Urban greenspaces provide extensive ecosystem services, including pollutant remediation, water management, carbon maintenance, and nutrient cycling. However, while the urban soil microbiota underpin these services, we still have limited understanding of the factors that influence their distribution. We characterized soil bacterial communities from turf-grasses associated with urban parks, streets, and residential sites across a major urban environment, including a gradient of human population density. Bacterial diversity was significantly positively correlated with the population density; and species diversity was greater in park and street soils, compared to residential soils. Population density and greenspace type also led to significant differences in the microbial community composition that was also significantly correlated with soil pH, moisture, and texture. Co-occurrence network analysis revealed that microbial guilds in urban soils were well correlated. Abundant soil microbes in high density population areas had fewer interactions, while abundant bacteria in high moisture soils had more interactions. These results indicate the significant influence of changes in urban demographics and land-use on soil microbial communities. As urbanization is rapidly growing across the planet, it is important to improve our understanding of the consequences of urban zoning on the soil microbiota. PMID- 29624052 TI - Macroscopic X-ray Powder Diffraction Scanning, a New Method for Highly Selective Chemical Imaging of Works of Art: Instrument Optimization. AB - In the past decade macroscopic X-ray fluorescence imaging (MA-XRF) has become established as a method for the noninvasive investigation of flat painted surfaces, yielding large scale elemental maps. MA-XRF is limited by a lack of specificity, only allowing for indirect pigment identification based on the simultaneous presence of chemical elements. The high specificity of X-ray powder diffraction (XRPD) mapping is already being exploited at synchrotron facilities for investigations at the (sub)microscopic scale, but the technique has not yet been employed using lab sources. In this paper we present the development of a novel MA-XRPD/XRF instrument based on a laboratory X-ray source. Several combinations of X-ray sources and area detectors are evaluated in terms of their spatial and angular resolution and their sensitivity. The highly specific imaging capability of the combined MA-XRPD/XRF instrument is demonstrated on a 15th/16th century illuminated manuscript directly revealing the distribution of a large number of inorganic pigments, including the uncommon yellow pigment massicot ( o PbO). The case study illustrates the wealth of new mapping information that can be obtained in a noninvasive manner using the laboratory MA-XRPD/XRF instrument. PMID- 29624053 TI - Large-Scale Differentiation and Site Specific Discrimination of Hydroxyproline Isomers by Electron Transfer/Higher-Energy Collision Dissociation (EThcD) Mass Spectrometry. AB - 3- and 4-Hydroxyprolines (HyP) are regioisomers that play different roles in various species and organs. Despite their distinct functions inside cells, they are generally considered indistinguishable using mass spectrometry due to their identical masses. Here, we demonstrate, for the first time, that characteristic w ions can be produced by electron-transfer/higher energy collision dissociation (EThcD) dual fragmentation technique to confidently discriminate 3-HyP/4-HyP isomers. An integrated and high throughput strategy was developed which combined online LC separation with EThcD for large-scale differentiation of 3-HyP/4-HyP in complex samples. An automated algorithm was developed for charge state dependent characterization of 3-HyP/4-HyP isomers. Using this combined discrimination approach, we identified 108 3-HyP sites and 530 4-HyP sites from decellularized pancreas, allowing more than 5-fold increase of both 3-HyP and 4-HyP identifications compared to previous reports. This approach outperformed ETD and HCD in the analysis of HyP-containing peptides with unique capacity to generate w ions for HyP discrimination, improved fragmentation of precursor ions, as well as unambiguous localization of modifications. A high content of 3-HyP was observed in the C-terminal (GPP)n domain of human CO1A1, which was previously only identified in vertebrate fibrillar collagens from tendon. Unexpectedly, some unusual HyP sites at Xaa position in Gly-HyP-Ala, Gly-HyP-Val, Gly-HyP-Gln, Gly HyP-Ser, and Gly-HyP-Arg were also confirmed to be 3-hydroxylated, whose functions and enzymes are yet to be discovered. Overall, this novel discrimination strategy can be readily implemented into de novo sequencing or other proteomic search engines. PMID- 29624054 TI - Highly Tunable Hollow Gold Nanospheres: Gaining Size Control and Uniform Galvanic Exchange of Sacrificial Cobalt Boride Scaffolds. AB - In principle, the diameter and surface plasmon resonance (SPR) frequency of hollow metal nanostructures can be independently adjusted, allowing the formation of targeted photoactivated structures of specific size and optical functionality. Although tunable SPRs have been reported for various systems, the shift in SPR is usually concomitant with a change in particle size. As such, more advanced tunability, including constant diameter with varying SPR or constant SPR with varying diameter, has not been properly achieved experimentally. Herein, we demonstrate this advanced tunability with hollow gold nanospheres (HGNs). HGNs were synthesized through galvanic exchange using cobalt-based nanoparticles (NPs) as sacrificial scaffolds. Co2B NP scaffolds were prepared by sodium borohydride nucleation of aqueous cobalt chloride and characterized using UV-vis, dynamic light scattering, X-ray absorption spectroscopy, and X-ray photoelectron spectroscopy. Careful control over the size of the Co2B scaffold and its galvanic conversion is essential to realize fine control of the resultant HGN diameter and shell thickness. In pursuit of size control, we introduce B(OH)4- (the final product of NaBH4 hydrolysis) as a growth agent to obtain hydrodynamic diameters ranging from ~17-85 nm with relative standard deviation <3%. The highly monodisperse Co2B NPs were then used as scaffolds for the formation of HGNs. In controlling HGN shell thickness and uniformity, environmental oxygen was shown to affect both the structural and optical properties of the resultant gold shells. With careful control of these key factors, we demonstrate an HGN synthesis that enables independent variation of diameter and shell thickness, and thereby SPR, with unprecedented uniformity. The new synthesis method creates a truly tunable plasmonic nanostructure platform highly desirable for a wide range of applications, including sensing, catalysis, and photothermal therapy. PMID- 29624055 TI - Constant Isothiocyanate-Release Potentials across Biofumigant Seeding Rates. AB - Biofumigation is an integrated pest-management method involving the mulching of a glucosinolate-containing cover crop into a field in order to generate toxic isothiocyanates (ITCs), which are effective soil-borne-pest-control compounds. Variation in biofumigation efficacy demonstrates a need to better understand the factors affecting pest-control outcomes and develop best practices for choosing biofumigants, growth conditions, and mulching methods that allow the greatest potential isothiocyanate release. We measured the glucosinolate concentrations of six different commercial varieties of three biofumigant plant species: Brassica juncea (ISCI99, Vitasso, and Scala) Raphanus sativus (Diablo and Bento), and Sinapis alba (Ida Gold). The plants were grown in the range of commercially appropriate seeding rates and sampled at three growth stages (early development, mature, and 50% flowering). Within biofumigant species, the highest ITC-release potentials were achieved with B. juncea cv. ISCI99 and R. sativus cv. Bento. The highest ITC-release potential occurred at the 50% flowering growth stage across the species. The seeding rate had a minor impact on the ITC-release potential of R. sativus but had no significant effects on the ITC-release potentials of the B. juncea or S. alba cultivars. PMID- 29624057 TI - The Role of Excitation Energy in Photobrightening and Photodegradation of Halide Perovskite Thin Films. AB - We study the impact of excitation energy on the photostability of methylammonium lead triiodide (CH3NH3PbI3 or MAPI) perovskite thin films. Light soaking leads to a transient increase of the photoluminescence efficiency at excitation wavelengths longer than 520 nm, whereas light-induced degradation occurs when exciting the films with wavelengths shorter than 520 nm. X-ray diffraction and extinction measurements reveal the light-induced decomposition of CH3NH3PbI3 to lead iodide (PbI2) for the high-energy excitation regime. We propose a model explaining the energy dependence of the photostability that involves the photoexcitation of residual PbI2 species in the perovskite triggering the decomposition of CH3NH3PbI3. PMID- 29624056 TI - Measurement of Kinetics and Active Site Distances in Metalloenzymes Using Paramagnetic NMR with 13C Hyperpolarization. AB - Paramagnetic relaxation enhancement (PRE) conjoint with hyperpolarized NMR reveals structural information on the enzyme-product complex in an ongoing metalloenzyme-catalyzed reaction. Substrates of pseudouridine monophosphate glycosidase are hyperpolarized using the dynamic nuclear polarization (DNP) method. Time series of 13C NMR spectra are subsequently measured with the enzyme containing diamagnetic Mg2+ or paramagnetic Mn2+ ions in the active site. The differences of the signal evolution and line widths in the Mg2+ vs Mn2+ reactions are explained through PRE in the enzyme-bound product, which is in fast exchange with its free form. Here, a strong distance dependence of the paramagnetically enhanced relaxation rates enables the calculation of distances from product atoms to the metal center in the complexed structure. The same method can be used to add structural information to real-time characterizations of chemical processes involving compounds with naturally present or artificially introduced paramagnetic sites. PMID- 29624058 TI - Slowing the Starch Digestion by Structural Modification through Preparing Zein/Pectin Particle Stabilized Water-in-Water Emulsion. AB - Slowing the digestion of starch is one of the dominant concerns in the food industry. A colloidal structural modification strategy for solving this problem was proposed in this work. Due to thermodynamic incompatibility between two biopolymers, water/water emulsion of waxy corn starch (WCS) droplets dispersed in a continuous aqueous guar gum (GG) was prepared, and zein particles (ZPs), obtained by antisolvent precipitation and pectin modification, were used as stabilizer. As the ratio of zein to pectin in the particles was 1:1, their wetting properties in the two polysaccharides were similar, which made them accumulate at the interface and cover the WCS-rich droplets. The analysis of digestibility curves indicated that a rapid (rate constant k1: 0.145 min-1) and a slow phase ( k2: 0.022 min-1) existed during WCS digestion. However, only one slow phase ( k2: 0.019 min-1) was found in the WCS/GG emulsion, suggesting that this structure was effective in slowing starch digestion. PMID- 29624059 TI - In Situ Generation of Nitrilimines from Aryldiazonium Salts and Diazo Esters: Synthesis of Fully Substituted Pyrazoles under Room Temperature. AB - A novel one-pot synthesis for fully substituted pyrazoles has been well developed via the in situ generation of nitrilimines from aryldiazonium salts and diazo esters and a subsequent cycloaddition with 1,3-dicarbonyl compounds. High yields, mild conditions, wide substrate scope, and operational simplicity are the significant advantages of this methodology. PMID- 29624060 TI - Cobalt-Catalyzed Diastereoselective Cross-Couplings between Alkynylzinc Pivalates and Functionalized Cyclic Iodides or Bromides. AB - Various 1,2-, 1,3-, and 1,4-substituted cyclic iodides or bromides undergo highly diastereoselective cross-couplings (diastereoselectivity (dr) up to 99:1) with a range of alkynylzinc pivalates, using CoCl2 (20 mol %) and trans- N, N, N', N' tetramethylcyclohexane-1,2-diamine as a catalytic system. PMID- 29624061 TI - Asymmetric Bisvinylogous Aldolation of Aldehydes via 2-Oxonia-Cope Rearrangement Enabling Total Stereochemical Control. AB - Highly stereoselective 2-oxonia-Cope rearrangement reactions between newly designed bisvinylogous aldolation synthons and aldehydes, which can provide epsilon-hydroxy-alpha,beta,gamma,delta-unsaturated esters with excellent enantioselectivities, as well as with unprecedented E- and Z-selectivities without regioselectivity issues, are described. PMID- 29624062 TI - Secondary Metabolites, Monoterpene-Polyketides Containing a Spiro[3.5]nonane from Cryptocarya laevigata. AB - Six novel lactone derivatives, cryptolaevilactones A-F (1-6), were isolated from Cryptocarya laevigata. Their unique spiro[3.5]nonane moiety by hetero [2 + 2] cyclization with monoterpene and polyketide was found for the first time in nature. Structural elucidation using various nuclear magnetic resonance (NMR) techniques revealed that 1-3 and 4-6 are diastereomers and partially established the absolute configurations. PMID- 29624063 TI - Diastereoselective Synthesis of a Dyn[3]arene with Distinct Binding Behaviors toward Linear Biogenic Polyamines. AB - The extension of the family of dyn[ n]arenes toward a three-membered macrocycle is reported. Through a templated approach, a single diastereoisomer of a dyn[3]arene that bears six carboxyl groups could be isolated by precipitation in 59-63% yield and excellent purity (>=95%). A combination of experimental and computational experiments in water at physiological pH revealed that the macrocycle could bind parent biogenic polyamines with a unique diversity of surface-binding modes. Whereas no binding event could be accurately measured with 1,3-diaminopropane, spermidine formed a classical stoichiometric complex with the dyn[3]arene in the millimolar concentration range. On the other hand, the data obtained for spermine could only be attributed to a more complex binding event with the formation of a 2:1 complex at high [host]/[guest] ratios and redistribution toward a 1:1 complex upon further addition of guest. PMID- 29624064 TI - Metal-Free and User-Friendly Regioselective Hydroxyfluorination of Olefins. AB - A simple, user-friendly, metal-free protocol for the regioselective anti Markovnikov hydrofluorination of olefins using readily available and inexpensive reagents has been developed. This new approach displays a broader scope than previously reported methodologies and has been applied to the late-stage fluorination of a complex molecule, giving rise to a fluorosteroid derivative. The stereochemistry of the process has also been studied in some detail. PMID- 29624066 TI - Ferric(III) Chloride Catalyzed Halogenation Reaction of Alcohols and Carboxylic Acids Using alpha,alpha-Dichlorodiphenylmethane. AB - A new method for chlorination of alcohols and carboxylic acids, using alpha,alpha dichlorodiphenylmethane as the chlorinating agent and FeCl3 as the catalyst, was developed. The method enables conversions of various alcohols and carboxylic acids to their corresponding alkyl and acyl chlorides in high yields under mild conditions. Particulary interesting is the observation that the respective alkyl bromides and iodides can be generated from alcohols when either LiBr or LiI are present in the reaction mixtures. PMID- 29624065 TI - Acaulins A and B, Trimeric Macrodiolides from Acaulium sp. H-JQSF. AB - Acaulin A (1) and its macrolactone ring-opened congener acaulin B (2) were characterized from the culture of Acaulium sp. H-JQSF (an isopod-associated fungus) as architecturally undescribed trimeric macrodiolides, with the former being antiosteoporotic at 0.4 MUM in the prednisolone-induced osteoporotic zebrafish. Identification of acaudiolic acid (3) as the monomeric macrodiolide precursor facilitated the proposal of the acaulin biosynthetic pathway. PMID- 29624067 TI - Ru(II)-Catalyzed C-H Activation and Annulation Reaction via Carbon-Carbon Triple Bond Cleavage. AB - An unprecedented Ru(II)-catalyzed C-H activation and annulation reaction, which proceeds via C-C triple bond cleavage, is reported. This reaction of 2 phenyldihydrophthalazinediones with alkynes, which works most efficiently in the presence of bidented ligand 1,3-bis(diphenylphosphino)propane, affords good yields of substituted quinazolines. PMID- 29624068 TI - Radical Borylative Cyclization of 1,6-Dienes: Synthesis of Boron-Substituted Six Membered Heterocycles and Carbocycles. AB - A radical borylative cyclization reaction of 1,6-dienes was developed to assemble boron-handled six-membered heterocycles and carbocycles. This reaction was initiated by the chemo- and regio-controlled addition of an N-heterocyclic carbene-boryl radical to one of the alkene tethers, followed by an intramolecular 6- exo cyclization to afford a six-membered ring framework. The utility of this method was demonstrated in the synthesis of diverse paroxetine analogues through late-stage derivatization of the boryl functional unit. PMID- 29624069 TI - Pd-Catalyzed Decarboxylative Sonogashira Reaction via Decarboxylative Bromination. AB - The decarboxylative alkynylation of (hetero)aryl carboxylic acids with terminal alkynes has been achieved by using a Pd(PPh3)4/PCy3 catalyst. This Pd-catalyzed method exhibits good functional group tolerance for both coupling partners and enables chemical modification of complex molecules. The establishment of this decarboxylative alkynylation reaction is attributed to the discovery of a highly selective decarboxylative bromination of (hetero)aryl carboxylic acids with NBS ( N-bromosuccinimide). PMID- 29624070 TI - Fluoroalkylsulfonyl Chlorides Promoted Vicinal Chloro-fluoroalkylthiolation of Alkenes and Alkynes. AB - The unprecedented use of CF3SO2Cl for direct bifunctional chloro trifluoromethylthiolation of alkenes and alkynes is reported. CF3SCl, which is generated by the reduction of PPh3, undergoes electrophilic addition and then chlorination to give the bifunctionalized products without using an additional chlorine source. The method is also applicable for chloro difluoromethylthiolation using CF2HSO2Cl. PMID- 29624072 TI - Enhanced Patient Satisfaction With Cellular-Enabled Glucose Meters in Pregnancy. PMID- 29624073 TI - Diagnostic Test for Incipient Tuberculosis: A Step Forward, Many More to Go. PMID- 29624071 TI - Four-gene Pan-African Blood Signature Predicts Progression to Tuberculosis. AB - RATIONALE: Contacts of tuberculosis (TB) patients constitute an important target population for preventative measures as they are at high risk of infection with Mycobacterium tuberculosis and progression to disease. OBJECTIVES: We investigated biosignatures with predictive ability for incident tuberculosis. METHODS: In a case-control study nested within the Grand Challenges 6-74 longitudinal HIV-negative African cohort of exposed household contacts, we employed RNA sequencing, polymerase chain reaction (PCR) and the Pair Ratio algorithm in a training/test set approach. Overall, 79 progressors, who developed tuberculosis between 3 and 24 months following exposure, and 328 matched non progressors, who remained healthy during 24 months of follow-up, were investigated. MEASUREMENTS AND MAIN RESULTS: A four-transcript signature (RISK4), derived from samples in a South African and Gambian training set, predicted progression up to two years before onset of disease in blinded test set samples from South Africa, The Gambia and Ethiopia with little population-associated variability and also validated on an external cohort of South African adolescents with latent Mycobacterium tuberculosis infection. By contrast, published diagnostic or prognostic tuberculosis signatures predicted on samples from some but not all 3 countries, indicating site-specific variability. Post-hoc meta analysis identified a single gene pair, C1QC/TRAV27, that would consistently predict TB progression in household contacts from multiple African sites but not in infected adolescents without known recent exposure events. CONCLUSIONS: Collectively, we developed a simple whole blood-based PCR test to predict tuberculosis in household contacts from diverse African populations, with potential for implementation in national TB contact investigation programs. PMID- 29624074 TI - Implications of Plasmodium glycosylation on vaccine efficacy and design. PMID- 29624075 TI - Molecular Testing for Early Lung Cancer. PMID- 29624076 TI - Performance Characteristics of Cerebrospinal Fluid Cytology: An Analysis of Responses From the College of American Pathologists Nongynecologic Cytopathology Education Program. AB - CONTEXT: - Cerebrospinal fluid cytology is a critical diagnostic tool for the diagnosis of many conditions affecting the central nervous system. OBJECTIVE: - To assess the performance characteristics of cerebrospinal fluid cytology samples by evaluating participant interpretations within the College of American Pathologists Nongynecologic Cytopathology Education program. DESIGN: - Participant interpretations (N = 46 264) evaluated in the College of American Pathologists Nongynecologic Cytopathology Education Program were examined for concordance with the general category and with the reference diagnosis. Two nonlinear mixed models were used to analyze the concordance rates. RESULTS: - The overall concordance rates for the general category and reference diagnosis were 92.1% and 81.0%, respectively. In the malignant category, the concordance rates with the reference diagnosis were lowest for diagnoses of nonhematopoietic small blue round cell tumors (54.8%) and metastatic malignancy (77.5%); the concordance rate with the reference diagnosis was highest for leukemia/lymphoma (94.0%). In the benign category, the concordance rate was lowest for normal cerebrospinal fluid reference diagnoses (58.6%), followed by acute and chronic inflammation (64.6%), fungal infection (80.8%), and macrophages (85.3%). Significant differences in concordance were uncovered when performance was evaluated by participant type and stain technique. Leukemia/lymphoma was the most common diagnosis for misclassified nonhematopoietic small blue round cell tumor cases and negative or inflammatory cerebrospinal fluid cases. CONCLUSIONS: - This study illustrates the difficulties in achieving accurate diagnoses from cerebrospinal fluid specimens, particularly for nonhematopoietic small blue round cell tumors and normal and inflammatory cerebrospinal fluid specimens. PMID- 29624077 TI - Molecular Testing in Lung Cancer: Where to Draw the Line? PMID- 29624078 TI - The Effect of 3.2% and 3.8% Sodium Citrate on Specialized Coagulation Tests. AB - CONTEXT: - Coagulation testing is challenging and depends on preanalytic factors, including the citrate buffer concentration used. OBJECTIVE: - To better estimate preanalytic effects of the citrate buffer concentration in use, the difference between results obtained by samples with 3.2% and 3.8% citrate was evaluated. DESIGN: - In a prospective observational study with 76 volunteers, differences related to the citrate concentration were evaluated. For both buffer concentrations, reference range intervals were established according to the recommendations of the C28-A3 guideline published by the Clinical and Laboratory Standards Institute. RESULTS: - In our reagent-analyzer settings, most parameters evaluated presented good comparability between citrated samples taken with 3.2% and 3.8% trisodium buffer. The ellagic acid containing activated partial thromboplastin time reagent (aPTT-FS) indicated a systemic and proportional difference between both buffer concentrations, leading to an alteration in its reference ranges. Further, a confirmation test for lupus anticoagulant assessment (Staclot LA) showed only a moderate correlation ( rrho = 0.511) with a proportional deviation between both citrate concentrations. Further, a statistically significant difference was found in the diluted Russell viper venom time confirmation testing, coagulation factors V and VIII, and the protein C activity, which was found to be of minor clinical relevance. CONCLUSIONS: - With caution regarding the potential impact of the reagent-analyzer combination, our findings demonstrate the comparability of data assessed with 3.2% and 3.8% buffered citrated plasma. As an exception, the aPTT-FS and the Staclot LA assay were considerably affected by the citrate concentration used. Further studies are required to confirm our finding using different reagent-analyzer combinations. PMID- 29624079 TI - Cross-Sectional Analysis of Longitudinal Mediation Processes. AB - Statistical mediation analysis can help to identify and explain the mechanisms behind psychological processes. Examining a set of variables for mediation effects is a ubiquitous process in the social sciences literature; however, despite evidence suggesting that cross-sectional data can misrepresent the mediation of longitudinal processes, cross-sectional analyses continue to be used in this manner. Alternative longitudinal mediation models, including those rooted in a structural equation modeling framework (cross-lagged panel, latent growth curve, and latent difference score models) are currently available and may provide a better representation of mediation processes for longitudinal data. The purpose of this paper is twofold: first, we provide a comparison of cross sectional and longitudinal mediation models; second, we advocate using models to evaluate mediation effects that capture the temporal sequence of the process under study. Two separate empirical examples are presented to illustrate differences in the conclusions drawn from cross-sectional and longitudinal mediation analyses. Findings from these examples yielded substantial differences in interpretations between the cross-sectional and longitudinal mediation models considered here. Based on these observations, researchers should use caution when attempting to use cross-sectional data in place of longitudinal data for mediation analyses. PMID- 29624080 TI - Supporting the Sexual Rights of Women Living With HIV: A Critical Analysis of Sexual Satisfaction and Pleasure Across Five Relationship Types. AB - In the context of human immunodeficiency virus (HIV), a focus on protecting others has overridden concern about women's own sexual well-being. Drawing on feminist theories, we measured sexual satisfaction and pleasure across five relationship types among women living with HIV in Canada. Of the 1,230 women surveyed, 38.1% were completely or very satisfied with their sexual lives, while 31.0% and 30.9% were reasonably or not very/not at all satisfied, respectively. Among those reporting recent sexual experiences (n = 675), 41.3% always felt pleasure, with the rest reporting usually/sometimes (38.7%) or seldom/not at all (20.0%). Sex did not equate with satisfaction or pleasure, as some women were completely satisfied without sex, while others were having sex without reporting pleasure. After adjusting for confounding factors, such as education, violence, depression, sex work, antiretroviral therapy, and provider discussions about transmission risk, women in long-term/happy relationships (characterized by higher levels of love, greater physical and emotional intimacy, more equitable relationship power, and mainly HIV-negative partners) had increased odds of sexual satisfaction and pleasure relative to women in all other relational contexts. Those in relationships without sex also reported higher satisfaction ratings than women in some sexual relationships. Findings put focus on women's rights, which are critical to overall well-being. PMID- 29624081 TI - Metal Resurfacing Inlay Implant for Osteochondral Talar Defects After Failed Previous Surgery: A Midterm Prospective Follow-up Study. AB - BACKGROUND: Treatment of osteochondral talar defects (OCDs) after failed previous surgery is challenging. Promising short-term results have been reported with use of a metal resurfacing inlay implant. PURPOSE: To evaluate the midterm clinical effectiveness of the metal implant for OCDs of the medial talar dome after failed previous surgery. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: We prospectively studied all patients who met the inclusion criteria and received a metal resurfacing inlay implant between 2007 and 2014. The primary outcome measure was implant survival, as measured by reoperation rate. Secondary outcome measures were numeric rating scales for pain at rest and during walking, running, and stair climbing; the Foot and Ankle Outcome Score (FAOS); the American Orthopaedic Foot and Ankle Society Ankle Hindfoot Scale; the 36-Item Short Form Health Survey (SF-36); return to work and sports; and radiographic evaluation. RESULTS: This study included 38 patients with a mean age of 39 years (SD, +/-13 years) and a mean follow-up of 5.1 years (SD, +/-1.5 years). Two patients (5%) underwent revision surgery by means of an ankle arthrodesis (2 and 6 years postoperatively). In 8 patients, computed tomography scanning was conducted to assess postoperative complaints. These scans showed impression of the tibial plafond (n = 4), a small tibial cyst (<2.5 mm; n = 1), and cyst formation around the implant screw (n = 4). A total of 21 reoperations were performed, including medial malleolar screw removal (n = 12), arthroscopic removal of bony anterior impingement (n = 7), and calcaneal realignment osteotomy (n = 2). All secondary outcome measures improved significantly, apart from pain at rest, the FAOS symptoms subscale, and the SF-36 mental component scale. The mean time for return to sport was 4.1 months (SD, +/-3 months), and 77% of patients resumed sporting activities postoperatively. Only 1 patient did not return to work postoperatively. Radiographs at final follow-up showed cyst formation (n = 2), subchondral periprosthetic radiolucency (n = 2), and non-preexisting joint space narrowing (n = 2). CONCLUSION: This study shows that the metal implant is an effective technique when assessed at midterm follow-up for OCDs of the medial talar dome after failed previous surgery. PMID- 29624082 TI - Legalised non-consensual sterilisation - eugenics put into practice before 1945, and the aftermath. Part 1: USA, Japan, Canada and Mexico. AB - In the late 19th century, eugenics, a pseudo-scientific doctrine based on an erroneous interpretation of the laws of heredity, swept across the industrialised world. Academics and other influential figures who promoted it convinced political stakeholders to enact laws authorising the sterilisation of people seen as 'social misfits'. The earliest sterilisation Act was enforced in Indiana, in 1907; most states in the USA followed suit and so did several countries, with dissimilar political regimes. The end of the Second World War saw the suspension of Nazi legislation in Germany, including that regulating coerced sterilisation. The year 1945 should have been the endpoint of these inhuman practices but, in the early post-war period, the existing sterilisation Acts were suspended solely in Germany and Austria. Only much later did certain countries concerned - not Japan so far - officially acknowledge the human rights violations committed, issue apologies and develop reparation schemes for the victims' benefit. PMID- 29624083 TI - Orally disintegrating tablets, fast-dissolving, buccal and sublingual formulations. PMID- 29624084 TI - Recent developments in interferon-based therapies for multiple sclerosis. AB - INTRODUCTION: Multiple sclerosis (MS) is a chronic and disabling immune-mediated disease of the central nervous system. Beta-interferons are the first approved and still the most widely used first-line disease-modifying treatment in MS. Areas covered: Here we focus on recent developments in pharmacology and delivery systems of beta-interferons, and discuss their place within current state of the art therapeutic approaches. We briefly review the clinical trials for classical and PEGylated formulations, emphasizing effectiveness, safety concerns, and tolerability. The mechanisms of action of IFN-beta in view of MS pathogenesis are also debated. Expert opinion: Though only modestly efficient in reducing the annualized relapse rate, beta-interferons remain a valid first-line option due to their good long-term safety profile and cost-efficacy. Moreover, they are endogenous class II cytokines essential for mounting an effective antiviral response, and they may interact with putative MS triggering factors such as Epstein-Barr virus infection and human endogenous retroviruses. Recent improvements in formulations, delivery devices and drug regimens tackle the tolerability and adherence issues frequently seen with these drugs, and scientific advances may offer means for a better selection of patients. Although a well-established immunomodulatory treatment, beta-interferons have not said their last word in the management of MS. PMID- 29624085 TI - On the Computation of the RMSEA and CFI from the Mean-And-Variance Corrected Test Statistic with Nonnormal Data in SEM. AB - A new type of nonnormality correction to the RMSEA has recently been developed, which has several advantages over existing corrections. In particular, the new correction adjusts the sample estimate of the RMSEA for the inflation due to nonnormality, while leaving its population value unchanged, so that established cutoff criteria can still be used to judge the degree of approximate fit. A confidence interval (CI) for the new robust RMSEA based on the mean-corrected ("Satorra-Bentler") test statistic has also been proposed. Follow up work has provided the same type of nonnormality correction for the CFI (Brosseau-Liard & Savalei, 2014). These developments have recently been implemented in lavaan. This note has three goals: a) to show how to compute the new robust RMSEA and CFI from the mean-and-variance corrected test statistic; b) to offer a new CI for the robust RMSEA based on the mean-and-variance corrected test statistic; and c) to caution that the logic of the new nonnormality corrections to RMSEA and CFI is most appropriate for the maximum likelihood (ML) estimator, and cannot easily be generalized to the most commonly used categorical data estimators. PMID- 29624086 TI - Does acute myocardial infarction kill more people on weekends? Analysis of in hospital mortality rates for weekend admissions in Portugal. AB - Objectives To investigate a possible weekend effect in the in-hospital mortality rate for acute myocardial infarction in Portugal, and whether the delay in invasive intervention contributes to this effect. Methods Data from the National 2011-2015 Diagnostic-Related-Group databases were analysed. The focus was on adult patients admitted via the emergency department and with the primary diagnosis of acute myocardial infarction. Patients were grouped according to ST elevation myocardial infarction and non-ST-elevation myocardial infarction episodes. We employed multivariable logistic regressions to determine the association between weekend admission and in-hospital mortality, controlling for episode complexity (through a severity index and acute comorbidities), demographic characteristics and hospital identifications. The association between the probability of a prompt surgery (within one day) and the day of admission was investigated to explore the possible delay of care delivery for patients admitted during weekends. Results Our results indicate that in-hospital mortality rates were not significantly higher for weekend admissions than for weekday admissions in both ST-elevation myocardial infarction (STEMI) and non-STEMI episodes. This result is robust to the inclusion of a number of potential confounding mechanisms. Patients admitted on weekends had lower probabilities of undergoing invasive cardiac surgery within the day after admission, but delay in care delivery during the weekend was not associated with worse outcomes in terms of in hospital mortality. Conclusions There is no evidence for the existence of a weekend effect due to admission for acute myocardial infarction in Portugal, in both STEMI and non-STEMI episodes. PMID- 29624087 TI - What does meaningful look like? A qualitative study of patient engagement at the Pan-Canadian Oncology Drug Review: perspectives of reviewers and payers. AB - Objectives While there is wide support for patient engagement in health technology assessment, determining what constitutes meaningful (as opposed to tokenistic) engagement is complex. This paper explores reviewer and payer perceptions of what constitutes meaningful patient engagement in the Pan-Canadian Oncology Drug Review process. Methods Qualitative interview study comprising 24 semi-structured telephone interviews. A qualitative descriptive approach, employing the technique of constant comparison, was used to produce a thematic analysis. Results Submissions from patient advocacy groups were seen as meaningful when they provided information unavailable from other sources. This included information not collected in clinical trials, information relevant to clinical trade-offs and information about aspects of lived experience such as geographic differences and patient and carer priorities. In contrast, patient submissions that relied on emotional appeals or lacked transparency about their own methods were seen as detracting from the meaningfulness of patient engagement by conflating health technology assessment with other functions of patient advocacy groups such as fundraising or public awareness campaigns, and by failing to provide credible information relevant to deliberations. Conclusions This study suggests that misalignment of stakeholder expectations remains an issue even for a well-regarded health technology assessment process that has promoted patient engagement since its inception. Support for the technical capacity of patient groups to participate in health technology assessment is necessary but not sufficient to address this issue fully. There is a fundamental tension between the evidence-based nature of health technology assessment and the experientially oriented culture of patient advocacy. Divergent notions of what constitutes evidence and how it should be used must also be addressed. PMID- 29624088 TI - Intrastate Variation in Treatment and Outcomes of Out-of-Hospital Cardiac Arrest. AB - OBJECTIVE: Our objective was to analyze and compare out-of-hospital cardiac arrest (OHCA) system of care performance and outcomes at the Medical Control Authority (MCA) level in the state of Michigan. We hypothesized that clinically and statistically significant variations in treatment and outcomes of OHCA exists within a single U.S. state. METHODS: We performed a retrospective, observational study of all non-traumatic EMS-treated OHCA from the state of Michigan CARES registry for 2014-2015. Geocoding of the OHCA incident address was used to assign records to individual MCAs. MCA-based demographics, arrest characteristics, system of care performance and outcomes were quantified and compared. Associations between demographics, system of care parameters, and outcomes were examined at the MCA level. RESULTS: A total of 8,115 records with complete data were available for analysis. Eleven MCAs met study inclusion criteria of >100 cases, producing a final sample size of 7,788 records (96%). Statistically significant variations in survival to hospital discharge ranged from 4.5% to 15% (p < 0.001) (Adjusted odds ratio [AOR] range 0.6-2.0) and survival with good neurologic outcome 2.7-12.5% (p < 0.001; AOR range 0.5-2.2,) were observed across MCAs. Bystander CPR ranged from 32% to 53% (p < 0.001) and bystander AED application ranged from 3.5% 11.5% (p < 0.05). Of patients admitted to the hospital alive, 29-68% received targeted temperature management. In hospital mortality ranged from 53.1% to 73.9% (p < 0.05). CONCLUSION: Significant intrastate variability in OHCA system of care performance and outcomes currently exist and are similar to what has been previously reported across North America almost a decade ago. This degree of variability highlights the opportunity to optimize modifiable factors within local systems of care to improve OHCA outcomes. PMID- 29624089 TI - Geriatric Interdisciplinary Team Training 2.0: A collaborative team-based approach to delivering care. AB - Interprofessional collaborative education and practice has become a cornerstone of optimal person-centered management in the current complex health care climate. This is especially important when working with older adults, many with multiple chronic conditions and challenging health care needs. This paper describes a feasibility study of the Geriatric Interdisciplinary Team Training 2.0 (GITT 2.0) program focused on providing interprofessional care to complex and frail older adults with multiple chronic conditions. A concurrent triangulation mixed-methods design facilitated program implementation and evaluation. Over three years (2013 2016), 65 graduate students from nursing, midwifery, social work, and pharmacy participated along with 25 preceptors. Participants were surveyed on their attitudes toward interprofessional collaboration pre and post-intervention and participated in focus groups. While attitudes toward interprofessional collaboration did not change quantitatively, focus groups revealed changes in language and enhanced perspectives of participants. Based on the evaluation data, the GITT 2.0 Toolkit was refined for use in interprofessional education and practice activities related to quality initiatives. PMID- 29624090 TI - Cryoprotectant choice and analyses of freeze-drying drug suspension of nanoparticles with functional stabilisers. AB - Freeze-drying is an effective way to improve long-term physical stability of nanosuspension in drug delivery applications. Nanosuspension also known as suspension of nanoparticles. In this study, the effect of freeze-drying with different cryoprotectants on the physicochemical characteristics of resveratrol (RSV) nanosuspension and quercetin (QUE) nanosuspension was evaluated. D-alpha tocopheryl polyethylene glycol succinate (TPGS) and folate-modified distearoylphosphatidyl ethanolamine-polyethylene glycol (DSPE-PEG-FA) were selected as functional stabilisers formulated nanosuspension which were prepared by anti-solvent precipitation method. RSV nanoparticle size and QUE nanoparticle size were about 210 and 110 nm, respectively. The AFM and TEM results of nanosuspension showed uniform and irregular shape particles. After freeze-drying, the optimal concentration of four cryoprotectants was determined by the particle size of re-dispersed nanoparticles. The dissolution profile of drug nanoparticle significantly showed approximately at a 6-8-fold increase dissolution rate. Moreover, TPGS and DSPE-PEG-FA stabilised RSV nanosuspension and QUE nanosuspension samples showed better effect on long-term physical stability. PMID- 29624091 TI - Excess visceral adiposity is associated with diabetic retinopathy in a multiethnic Asian cohort with longstanding type 2 diabetes. AB - : Purpose/Aim: Diabetic retinopathy (DR) is the most common diabetic microvascular complication, and it typically develops after 10 years of diabetes diagnosis. The primary aim of this study was to evaluate the association between adiposity and DR susceptibility among individuals with longstanding type 2 diabetes mellitus (T2D). MATERIALS AND METHODS: In this cross-sectional study, DR was assessed by fundus photography in 953 T2D subjects. DR prevalence by categories of T2D duration was evaluated. In a sub-cohort analysis, subjects having T2D for >=10 years were divided into DR (N = 241) and non-DR (N = 377) groups. Measures of adiposity including body mass index (BMI), waist circumference (WC), and visceral fat area (VFA) were analyzed. Urinary albumin:creatinine ratio (ACR) and estimated glomerular filtration rate (eGFR) were measured. RESULTS: DR prevalence markedly increased 10 years after T2D diagnosis (p < 0.001). Among subjects with T2D duration >=10 years, BMI, WC, and VFA were elevated in DR compared with non-DR (all p < 0.05). Contrasting with BMI and WC, the association between VFA and DR sustained adjustment for demographics, metabolic factors, and insulin treatment (OR: 1.060, 95% CI: 1.004-1.119, p = 0.035). However, the association became insignificant after controlling for ACR and eGFR. Mediation analysis revealed that ACR and eGFR explained 47.3% of the relationship between VFA and DR. CONCLUSIONS: The findings suggest that visceral adiposity is associated with DR in individuals with longstanding T2D. This relationship may be attributable to generalized vascular injury as reflected by coexisting renal burden. Therefore, effective management of visceral adiposity and ameliorating renal burden may ameliorate susceptibility to DR. PMID- 29624092 TI - At the Frontiers of Modeling Intensive Longitudinal Data: Dynamic Structural Equation Models for the Affective Measurements from the COGITO Study. AB - With the growing popularity of intensive longitudinal research, the modeling techniques and software options for such data are also expanding rapidly. Here we use dynamic multilevel modeling, as it is incorporated in the new dynamic structural equation modeling (DSEM) toolbox in Mplus, to analyze the affective data from the COGITO study. These data consist of two samples of over 100 individuals each who were measured for about 100 days. We use composite scores of positive and negative affect and apply a multilevel vector autoregressive model to allow for individual differences in means, autoregressions, and cross-lagged effects. Then we extend the model to include random residual variances and covariance, and finally we investigate whether prior depression affects later depression scores through the random effects of the daily diary measures. We end with discussing several urgent-but mostly unresolved-issues in the area of dynamic multilevel modeling. PMID- 29624093 TI - Robustness of Parameter Estimation to Assumptions of Normality in the Multidimensional Graded Response Model. AB - A central assumption that is implicit in estimating item parameters in item response theory (IRT) models is the normality of the latent trait distribution, whereas a similar assumption made in categorical confirmatory factor analysis (CCFA) models is the multivariate normality of the latent response variables. Violation of the normality assumption can lead to biased parameter estimates. Although previous studies have focused primarily on unidimensional IRT models, this study extended the literature by considering a multidimensional IRT model for polytomous responses, namely the multidimensional graded response model. Moreover, this study is one of few studies that specifically compared the performance of full-information maximum likelihood (FIML) estimation versus robust weighted least squares (WLS) estimation when the normality assumption is violated. The research also manipulated the number of nonnormal latent trait dimensions. Results showed that FIML consistently outperformed WLS when there were one or multiple skewed latent trait distributions. More interestingly, the bias of the discrimination parameters was non-ignorable only when the corresponding factor was skewed. Having other skewed factors did not further exacerbate the bias, whereas biases of boundary parameters increased as more nonnormal factors were added. The item parameter standard errors recovered well with both estimation algorithms regardless of the number of nonnormal dimensions. PMID- 29624094 TI - PERCUTANEOUS ETHANOL INJECTION FOR BENIGN CYSTIC AND MIXED THYROID NODULES. AB - OBJECTIVE: We aimed to determine the effect of percutaneous ethanol injection (PEI) on volume of cystic and mixed thyroid nodules, thyroid function tests (TFTs), antibody titers, and cytologic changes for 1 year. METHODS: Fifty-five nodules from 53 patients with cystic and mixed properties treated with PEI were included. Nodule volumes, TFTs, and thyroid autoantibodies were analyzed at baseline, 6 months, and 12 months. Fine-needle aspiration biopsy (FNAB) was performed to PEI-treated nodules in the 12th month. Thyroid nodules were classified into three groups by structural properties (purely cystic, predominantly cystic, predominantly solid). RESULTS: PEI caused a volume reduction of 80.7% at 6 months and 82.1% at 12 months, without any serious complications. PEI was repeated 1.4 +/- 0.4 times with a mean total ethanol amount of 3.6 +/- 3.1 mL. Volume reduction in the purely cystic nodules in the 6th and 12th months after PEI was greater than the volume reductions in predominantly cystic and predominantly solid nodules. We found that smaller nodules had greater volume reductions after PEI in the 12th month. During the study, patients remained euthyroid. Antithyroglobulin levels were decreased at 12 months. None of the FNAB results were compatible with a malignant or suspicious for malignancy cytology at the 12th month. CONCLUSION: PEI is an effective means of treatment for benign cystic and mixed thyroid nodules, without any serious side effects. We can also assume that PEI is not a trigger for autoimmunity and malignancy development over the short term. ABBREVIATIONS: anti-TG = anti thyroglobulin; anti-TPO = anti-thyroperoxidase; AUS = atypia of unknown significance; CV = coefficient of variation; FNAB = fine-needle aspiration biopsy; fT3 = free triiodothyronine; fT4 = free thyroxine; PEI = percutaneous ethanol injection; TFT = thyroid function test; TSH = thyroid-stimulating hormone; US = ultrasonography. PMID- 29624095 TI - EXTERNAL VALIDATION OF THE DIABETES EARLY RE-ADMISSION RISK INDICATOR (DERRITM). AB - OBJECTIVE: The Diabetes Early Re-admission Risk Indicator (DERRITM) was previously developed and internally validated as a tool to predict the risk of all-cause re-admission within 30 days of discharge (30-day re-admission) of hospitalized patients with diabetes. In this study, the predictive performance of the DERRITM with and without additional predictors was assessed in an external sample. METHODS: We conducted a retrospective cohort study of adult patients with diabetes discharged from two academic medical centers between January 1, 2000 and December 31, 2014. We applied the previously developed DERRITM, which includes admission laboratory results, sociodemographics, a diagnosis of certain comorbidities, and recent discharge information, and evaluated the effect of adding metabolic indicators on predictive performance using multivariable logistic regression. Total cholesterol and hemoglobin A1c (A1c) were selected based on clinical relevance and univariate association with 30-day re-admission. RESULTS: Among 105,974 discharges, 19,032 (18.0%) were followed by 30-day re admission for any cause. The DERRITM had a C-statistic of 0.634 for 30-day re admission. Total cholesterol was the lipid parameter most strongly associated with 30-day re-admission. The DERRITM predictors A1c and total cholesterol were significantly associated with 30-day re-admission; however, their addition to the DERRITM did not significantly change model performance (C-statistic, 0.643 [95% confidence interval, 0.638 to 0.647]; P = .92). CONCLUSION: Performance of the DERRITM in this external cohort was modest but comparable to other re-admission prediction models. Addition of A1c and total cholesterol to the DERRITM did not significantly improve performance. Although the DERRITM may be useful to direct resources toward diabetes patients at higher risk, better prediction is needed. ABBREVIATIONS: A1c = hemoglobin A1c; CI = confidence interval; DERRITM = Diabetes Early Re-admission Risk Indicator; GEE = generalized estimating equation; HDL-C = high-density-lipoprotein cholesterol; ICD-9-CM = International Classification of Diseases, Ninth Revision, Clinical Modification; LDL-C = low-density-lipoprotein cholesterol. PMID- 29624096 TI - INTERLEUKIN-6-PRODUCING PHEOCHROMOCYTOMA AS A NEW REASON FOR FEVER OF UNKNOWN ORIGIN: A RETROSPECTIVE STUDY. AB - OBJECTIVE: To explore the fever of unknown origin (FUO) in patients with interleukin-6 (IL-6)-producing pheochromocytoma. METHODS: Patients with pheochromocytoma were enrolled from June 2014 to April 2017. Clinical characteristics were recorded including sex, age, 24-h urinary catecholamines (norepinephrine, epinephrine, dopamine), tumor size, axillary temperature (AT), white blood cells (WBC), and serum IL-6 and high-sensitivity C-reactive protein (hsCRP) levels. IL-6 secretion by pheochromocytoma was analyzed by immunohistochemistry (IHC). RESULTS: We identified 29 cases of pheochromocytoma (7 with high AT and 22 with normal AT). Serum IL-6 and hsCRP levels were increased in the high AT group compared with the normal AT group (both P = .001). After pheochromocytoma resection, AT and IL-6 and hsCRP levels decreased significantly ( P<.001, P = .002 and P = .003, respectively). IHC revealed significantly higher IL-6 expression in the high AT group ( P = .002). CONCLUSION: IL-6-producing pheochromocytoma should be included in the differential diagnosis of FUO. ABBREVIATIONS: AT = axillary temperature; CT = computed tomography; FUO = fever of unknown origin; IHC = immunohistochemistry; IL-6 = interleukin-6; hsCRP = high-sensitivity C-reactive protein; WBC = white blood cells. PMID- 29624097 TI - POSITIVE THYROTROPIN RECEPTOR ANTIBODIES IN PATIENTS WITH TRANSIENT THYROTOXICOSIS. AB - OBJECTIVE: Thyrotropin (TSH) receptor antibody (TRAb) testing is considered accurate for the diagnosis of Graves disease (GD) and has been identified rarely in thyrotoxic patients without GD. We describe 4 patients with transient thyrotoxicosis and positive TRAb to highlight this clinical possibility. METHODS: Patient demographics, symptoms, laboratory findings, and time to resolution of thyrotoxicosis are summarized. TRAb testing was performed by either a third generation thyrotropin-binding inhibitory immunoglobulin (TBII) competitive binding assay or a thyroid-stimulating immunoglobulin (TSI) bioassay from either Mayo Clinic Laboratory or Quest Diagnostics. RESULTS: Four patients with transient thyrotoxicosis and positive TRAb testing were identified. Of these, three were female, and the median age was 44 years (range, 25 to 49 years). Median symptom duration at evaluation was 6.5 weeks (range, 3 to 12 weeks). No patient had any clinical manifestations unique to GD or exposure to biotin, thyroid hormone, supplements, iodine, or relevant medications. The TSH was <0.1 mIU/L in all patients. Three patients had a positive TSI, which was elevated less than twice the upper limit of the reference range in all cases, and 1 patient had a strongly positive TBII. None of the patients were treated with thionamides or radioactive iodine. Spontaneous resolution occurred in all patients at a median of 5.5 weeks (range, 2 to 14.4 weeks). CONCLUSION: These cases demonstrate that TSI or TBII may be present in thyrotoxic patients with transient thyrotoxicosis. For clinically stable patients presenting without pathognomonic evidence of GD, mildly elevated TRAb results may require cautious interpretation, and alterative diagnostic testing or close monitoring should be considered. ABBREVIATIONS: cAMP = cyclic adenosine monophosphate; FT4 = free thyroxine; GD = Graves disease; TBII = thyrotropin-binding inhibitory immunoglobulin (also known as TBI); TRAb = thyrotropin receptor antibody; TSH = thyrotropin; TSHR = thyrotropin receptor; TSI = thyroid-stimulating immunoglobulin; TT3 = total triiodothyronine; TT4 = total thyroxine. PMID- 29624098 TI - VISUAL VIGNETTE. PMID- 29624099 TI - USE OF ELECTRONIC HEALTH RECORDS TO CHARACTERIZE A RARE DISEASE IN THE U.S.: TREATMENT, COMORBIDITIES, AND FOLLOW-UP TRENDS AMONG PATIENTS WITH A CONFIRMED DIAGNOSIS OF ACROMEGALY. AB - OBJECTIVE: Understanding of acromegaly disease management is hampered in the U.S. by the lack of a national registry. We describe medical management in a population with confirmed acromegaly. METHODS: Inpatient and outpatient electronic health records (EHRs) were used to create a database of de-identified patients assigned the Acromegaly and Gigantism International Classification of Diseases, 9th revision (ICD-9) code and/or an appropriate pituitary procedure code at 1 of 4 regional hospital systems over a 6- to 11-year period. Information regarding demographics, medical history, labs, procedures, and medications was collected and supplemented with a chart review to validate the diagnosis of acromegaly. RESULTS: Of 367 patients with validated acromegaly, available records showed that during the years studied, pituitary surgery was performed on 31%, 4% received radiosurgery, and 22% were prescribed a drug indicated for acromegaly. Insulin-like growth factor-1 (IGF-1) levels were measured in 62% of patients, 83% of whom had at least 1 normal value. Coded comorbidities reflect those reported previously in patients with acromegaly, with the exception of esophageal reflux in 20% of patient records. Fewer data regarding acromegaly-specific medications and testing were available for patients aged 65 and older. CONCLUSION: AcroMEDIC is a U.S. multisite retrospective study of acromegaly that captured medical management in the majority of patients included in the cohort. Chart review highlighted the importance of verification of coded diagnoses. Most of the acromegaly-related comorbidities identified here are known to increase with age and obesity. Patients >=65 appeared to have less active management/monitoring of their disease. Medical attention should be directed to this population to address evolving needs over time. ABBREVIATIONS: AcroMEDIC = Acromegaly Multisite Electronic Data Innovative Consortium; BMI = body mass index; CCI = Charlson Comorbidity Index; EHR = electronic health record; GH = growth hormone; GHRA = growth hormone receptor antagonist; ICD-9 = International Classification of Diseases, 9th revision; IGF-1 = insulin-like growth factor-1; SSA = somatostatin analogue. PMID- 29624100 TI - Ipilimumab-Induced Secondary Hypophysitis. PMID- 29624101 TI - VISUAL VIGNETTE. PMID- 29624102 TI - EXOGENOUS TESTOSTERONE DOES NOT INDUCE OR EXACERBATE THE METABOLIC FEATURES ASSOCIATED WITH PCOS AMONG TRANSGENDER MEN. AB - OBJECTIVE: Polycystic ovary syndrome (PCOS) is a complex condition which can include menstrual irregularity, metabolic derangement, and increased androgen levels. The mechanism of PCOS is unknown. Some suggest that excess production of androgens by the ovaries may cause or exacerbate the metabolic findings. The purpose of this study was to assess the role of increased testosterone on metabolic parameters for individuals presumed to be chromosomally female by examination of these parameters in hormone-treated transgender men. METHODS: In 2015 and 2016, we asked all transgender men who visited the Endocrinology Clinic at Boston Medical Center treated with testosterone for consent for a retrospective anonymous chart review. Of the 36 men, 34 agreed (94%). Serum metabolic factors and body mass index (BMI) levels for each patient were graphed over time, from initiation of therapy through 6 years of treatment. Bivariate analyses were conducted to analyze the impact of added testosterone. RESULTS: Regressions measuring the impact of testosterone demonstrated no significant changes in levels of glycated hemoglobin (HbA1c), triglycerides, or low-density lipoprotein cholesterol. There was a statistically significant decrease in BMI with increasing testosterone. There was also a statistically significant decrease in high-density lipoprotein levels upon initiation of testosterone therapy. CONCLUSION: Testosterone therapy in transgender men across a wide range of doses and over many years did not result in the dyslipidemia or abnormalities in HbA1c seen with PCOS. Instead, treatment of transgender men with testosterone resulted only in a shift of metabolic biomarkers toward the average physiologic male body. ABBREVIATIONS: BMI = body mass index; HbA1c = glycated hemoglobin; HDL = high density lipoprotein; LDL = low-density lipoprotein; PCOS = polycystic ovary syndrome. PMID- 29624103 TI - Detecting Kerogen as a Biosignature Using Colocated UV Time-Gated Raman and Fluorescence Spectroscopy. AB - The Mars 2020 mission will analyze samples in situ and identify any that could have preserved biosignatures in ancient habitable environments for later return to Earth. Highest priority targeted samples include aqueously formed sedimentary lithologies. On Earth, such lithologies can contain fossil biosignatures as aromatic carbon (kerogen). In this study, we analyzed nonextracted kerogen in a diverse suite of natural, complex samples using colocated UV excitation (266 nm) time-gated (UV-TG) Raman and laser-induced fluorescence spectroscopies. We interrogated kerogen and its host matrix in samples to (1) explore the capabilities of UV-TG Raman and fluorescence spectroscopies for detecting kerogen in high-priority targets in the search for possible biosignatures on Mars; (2) assess the effectiveness of time gating and UV laser wavelength in reducing fluorescence in Raman spectra; and (3) identify sample-specific issues that could challenge rover-based identifications of kerogen using UV-TG Raman spectroscopy. We found that ungated UV Raman spectroscopy is suited to identify diagnostic kerogen Raman bands without interfering fluorescence and that UV fluorescence spectroscopy is suited to identify kerogen. These results highlight the value of combining colocated Raman and fluorescence spectroscopies, similar to those obtainable by SHERLOC on Mars 2020, to strengthen the confidence of kerogen detection as a potential biosignature in complex natural samples. Key Words: Raman spectroscopy-Laser-induced fluorescence spectroscopy-Mars Sample Return Mars 2020 mission-Kerogen-Biosignatures. Astrobiology 18, 431-453. PMID- 29624104 TI - Characterization of Bacteriophages Targeting Non-O157 Shiga Toxigenic Escherichia coli. AB - Non-O157 Shiga toxigenic Escherichia coli (STEC) are an important group of foodborne pathogens, implicated in several outbreaks and recalls in the past 2 decades. It is therefore crucial to devise effective control strategies against these pathogens. Bacteriophages present an attractive alternative to conventional pathogen control methods in the food industry. Bacteriophages, targeting non-O157 STEC (O26, O45, O103, O111, O121, O145), were isolated from beef cattle operations in Oklahoma. Their host range and lytic ability were determined against several ( n = 21) non-O157 STEC isolates, by using the spot-on-lawn assay. Isolated phages were purified, and their morphology was determined under a transmission electron microscope. Infection kinetics of selected phages ( n = 19), particularly adsorption rate, rise period, latent period, and burst size, were determined. Phages were also evaluated for stability at a wide pH range (1 to 11) and temperature range (-80 to 90 degrees C). In total, 45 phages were isolated and classified into Myoviridae, Siphoviridae, or Tectiviridae. The phages had a latent period between 8 and 37 min, a rise period between 19 and 40 min, and a large burst size (12 to 794 virions per infected cell), indicating high lytic activity. Tested phages were stable at pH 5 to 9 for 24 h, whereas a decrease in phage titer was observed at pHs 1, 2, and 11. Phages were stable at 40 and 60 degrees C, except for O103-specific phages. At 70 degrees C, all the phages lost viability after 20 min, except three phages targeting O26 and O121 and one phage targeting O45 and O111 STEC, which remained viable for 60 min. All the phages lost activity after 10 min at 90 degrees C, except one each of O26 and O121 STEC-infecting phages that remained viable for 60 min. Phages remained stable for 90 days under refrigerated (4 degrees C) and frozen (-20 and -80 degrees C) storage. Characterization of phages, targeting diverse non-O157 STEC serotypes, could help in the development of effective biocontrol strategies for this group of pathogens in the food industry. PMID- 29624105 TI - Safety and Quality Assessment of Smallholder Farmers' Maize in the Western Highlands of Guatemala. AB - Maize ( Zea mays) is a staple in many developing countries but is known to be prone to pest (insects, birds, and rodents) and fungal infestation. In Guatemala, mycotoxin contamination of cultivated products may occur owing to such factors as environmental conditions and the use of traditional agriculture operations. To assess the current maize conditions in Guatemala, a small-scale study was performed. Mold and insect counts and mycotoxin (aflatoxin and fumonisin) concentrations were determined on 25 farms in two townships (Chiantla and Todos Santos) of the Huehuetenango Department. Total fungal counts were 3.6 to 6.83 log CFU/g with no significant differences ( P > 0.05) across farms at different altitudes. Farms where maize was not produced but was purchased were at higher risk of fumonisin contamination, whereas local producers were mostly affected by aflatoxins. Aflatoxin was present in maize from 100% of farms at 1.0 to 85.3 ppb, and fumonisin was detected on 52% of farms at 0.4 to 31.0 ppm. Average mycotoxin consumption amounts were above the recommended maximum intake for aflatoxin in both produced and purchased maize and above the provisional maximum tolerable daily intake for fumonisin in purchased maize. Estimated daily intake was 0.01 to 0.85 MUg/kg of body weight per day for aflatoxin and 2.9 to 310.0 MUg/kg of body weight per day for fumonisin. An entomological analysis revealed overall 32% prevalence of Ephestia kuehniella (flour moth), 16% prevalence of Sitophilus zeamais (maize weevil), and 8% prevalence of Tribolium sp. (flour beetle) on the analyzed farms. This study highlighted poor agricultural practices used in the highlands of Guatemala. Current practices should be revised for the production of maize that is safe for consumption by the population in this region. PMID- 29624106 TI - Behavior of Listeria monocytogenes on Mortadella Formulated Using a Natural, Clean-Label Antimicrobial Agent during Extended Storage at 4 or 12 degrees C. AB - All-pork mortadella, an Italian-style deli meat, was produced by a local artisanal meat producer with or without 1.0 or 1.5% liquid buffered vinegar (LBV), 0.4, 0.6, or 1.0% dry buffered vinegar (DBV), or a 2.5% blend of potassium lactate and sodium diacetate (KLac). In each of three trials, mortadella was sliced (ca. 1.5 cm thick, ca. 30 g) and surface inoculated with 250 MUL per side of a five-strain mixture of Listeria monocytogenes (ca. 3.8 log CFU per slice). The packages were vacuum sealed and then stored at 4 or 12 degrees C. In the absence of antimicrobials, L. monocytogenes levels increased by ca. 2.6 and 6.0 log CFU per slice after up to 120 or 28 days at 4 or 12 degrees C, respectively. With inclusion of 1.0 or 1.5% LBV, 1.0% DBV, or 2.5% KLac as ingredients, pathogen levels decreased by ca. 0.3 to 0.7 log CFU per slice after 120 days at 4 degrees C, whereas with inclusion of 0.4 or 0.6% DBV, L. monocytogenes levels increased by ca. 1.2 and 0.8 log CFU per slice, respectively. After 28 days at 12 degrees C, inclusion of 2.5% KLac, 1.0 or 1.5% LBV, or 0.4 or 0.6% DBV resulted in a ca. 1.4- to 5.7-log increase in L. monocytogenes levels. When 1.0% DBV was included in the formulation, pathogen levels remained unchanged after 28 days at 12 degrees C. However, product quality was lessened at this abusive storage temperature (12 degrees C) for all treatments by the end of storage. Thus, inclusion of LBV or DBV, as clean-label ingredients, in mortadella is equally effective as KLac for controlling L. monocytogenes during storage at 4 degrees C without adversely affecting product quality. PMID- 29624107 TI - RNA capping by mitochondrial and multi-subunit RNA polymerases. AB - Recently, it was found that bacterial and eukaryotic transcripts are capped with cellular cofactors installed by their respective RNA polymerases (RNAPs) during transcription initiation. We now show that mitochondrial RNAP efficiently caps transcripts with ADP - containing cofactors. However, a functional role of universal RNAP - catalysed capping is not yet clear. PMID- 29624108 TI - An Examination of Gender Differences in the Association of Adolescent Substance use with Eating and Weight Loss Attitudes. AB - OBJECTIVE: To assess gender differences in the relationship between eating and weight loss attitudes (EWAs), and 30-day tobacco and alcohol use among adolescents, while controlling for potential confounds (age, country of birth, psychological distress, pubertal development, peer alcohol and tobacco use, and sexual activity). METHODS: School students aged between 11 and 17 years (N = 10,273) from high schools in the State of Victoria (Australia) completed surveys in class under conditions of anonymity and confidentiality. RESULTS: The interaction between EWAs and gender was significant for tobacco use but not for alcohol use, indicating that the effect of EWAs on tobacco use, but not alcohol use, vary by gender. CONCLUSIONS: Tobacco use was related to EWAs in adolescent females but not males, and this is consistent with the possibility that females use tobacco in an instrumental fashion to control weight. Implications and Contribution: Female adolescents high in eating and weight loss attitudes were more likely to engage in tobacco use. In contrast, eating and weight loss attitudes were not related to male tobacco use. These results point to the potential importance of developing gender-specific approaches towards addressing problematic behaviors in adolescent populations. PMID- 29624109 TI - Corrigendum. PMID- 29624110 TI - Women's Attitude and Its Influence on Violence During Pregnancy in Northern State of Peninsular Malaysia: Cross-Sectional Study. AB - The objective of this study was to determine the prevalence of men's violence against pregnant women and whether it is influenced by women's attitude. A cross sectional study was carried out in a hospital in northern state of Peninsular Malaysia. A total of 1,200 postnatal women aged 18 years and above who had been admitted to the hospital were recruited in the study. Universal sampling was performed, and participants were interviewed face-to-face by using a validated Malay version of WHO Women's Health and Life Experiences Questionnaire. The main outcome measures in the study were emotional, physical or sexual violence. The study results showed that more than one third of women (35.9%; confidence interval [CI] = [0.33, 0.39]) had experienced any type of violence during pregnancy with the commonest was psychological violence (29.8%; CI = [0.27, 0.32]) followed by physical (12.9%; CI = [0.11, 0.15]) and sexual violence (9.8%; CI = [0.08, 0.12]). Women who were drug users, had an exposure to violence during childhood, had higher parity, and had inadequate antenatal care were at greater risk. Agree that husband is justified to hit his wife in certain conditions and agree that women has a right to refuse sex in certain conditions were among violence-supporting attitudes. It can be concluded that men's violence against pregnant women is extremely prevalent. Sensitive assessment, attitude modification, and intervention (primary, secondary, and tertiary) are of great value in combating men's violence against pregnant women. PMID- 29624111 TI - Synthetic and Other Drug Use among High School Students: The Role of Perceived Prevalence, Access, and Harms. AB - BACKGROUND: Synthetic and other drugs have become available to teens, yet little is known about risk factors of use. OBJECTIVE: To examine adolescent use of one class of synthetic drugs and its association with perceptions about its prevalence, access, and risk of substance use. METHODS: Adolescents from a convenience sample of 104 middle and high schools (N = 59,218) participated in an anonymous survey to assess school climate and substance use in 2013-2014. Multilevel logistic regression examined the association between risk for synthetic and other drug use, perceptions of substance use, and school-level characteristics. RESULTS: Results indicated that 2,407 (4.3%) students reported synthetic and other drug use in the past 30 days. A large proportion of youth perceived drugs to be problematic at school but underestimated the harms associated with drug use. Participants also perceived tobacco, alcohol, marijuana, and prescription drugs are easy to obtain. Risk factors for synthetic and other drug use included the perception that substance use was a large problem at school, ease of access to drugs, and limited harm associated with drug use. School enrollment and socio-economic status of students reduced odds of drug use. Similar trends were found regarding marijuana use. Conclusion/Importance: Synthetic and other drug use is an emerging public health concern. Many youth identified substances as problematic and easily accessible in their schools but underestimated their potential harms. Health and education professionals need to increase effective education around substance use, including common risk factors for synthetic drug use. PMID- 29624113 TI - Clinician Experience and Attitudes toward Safety Planning with Adolescents At Risk for Suicide. AB - OBJECTIVES: This study examined clinician experiences and attitudes toward safety planning in a large urban pediatric psychiatry department serving primarily Latino youth. METHODS: Forty-six clinicians completed a survey assessing their experience with and attitudes toward safety planning with adolescents at-risk for suicide. RESULTS: The majority of clinicians were female (78%), non-Latino White (54%), and aged 30-39 (52%). Clinicians' attitudes were largely positive (M = 3.69 SD = 0.47, Range = 2.42-4.42). However, many clinicians (n = 24) were not convinced that safety planning reduces the imminent risk of suicidal behavior in patients. CONCLUSION: This study provides more depth to our understanding of the way in which safety planning is perceived by clinicians. PMID- 29624112 TI - Cathepsin S is associated with degradation of collagen I in abdominal aortic aneurysm. AB - BACKGROUND: Cathepsins have been described in the pathogenesis of abdominal aortic aneurysm (AAA), their exact role, especially in collagen degradation, is still unclear. The aim of the present study was therefore to analyse relevant cathepsins in human AAA tissue samples in relation to collagen I, III, and their degradation products. MATERIALS AND METHODS: Samples from 37 AAA patients obtained from elective open surgical repair and eight healthy non-aneurysmatic aortas from kidney donors were included. Expression of cathepsins B, D, K, L, S, cystatin C, collagen I and III, their degraded products C-Telopeptide of type 1 and 3 collagen (CTX-I, CTX-III), cellular markers for leukocytes (CD45), T cells (CD3), macrophage scavenger receptor-1 (MSR-1), synthetic, and contractile smooth muscle cells (SMCs) (smoothelin: SMTH, collagen I and III, myosin heavy chain: MHC, embryonic smooth muscle myosin heavy chain: SMemb) were determined at messenger RNA (mRNA) level, using SYBRGreen-based quantitative PCR and at protein level using enzyme-linked immunosorbent assay (ELISA). RESULTS: Expression of cathepsins B, D, L, and S at mRNA level was significantly elevated in AAA compared to control aorta (1.7-fold, p = 0.025; 2.5-fold, p = 0.002; 2.6-fold, p = 0.034; and 7.0-fold, p = 0.003). Expression of cathepsin S correlated significantly with leukocytes and macrophages (rho = 0.398, p = 0.033 and rho = 0.422, p = 0.020), synthetic SMCs were significantly associated with cathepsins B, D, and L (rho = 0.522, p = 0.003; rho = 0.431, p = 0.015 and rho = 0.467, p = 0.008). At protein level, cathepsins B and S were elevated in AAA compared to controls (5.4-fold, p = 0.001 and 7.3-fold, p < 0.001). Significant correlations were observed between collagen I, its degraded product, and cathepsin S (r = 0.350, p = 0.034 and r = +0.504, p < 0.001). Expression of cathepsin B was associated with SMCs, expression of cathepsin S with inflammatory cells. CONCLUSIONS: Particularly cathepsin S was associated with the degradation product of collagen I and thus might be involved in the progression of AAA. Furthermore, cathepsin S correlated with inflammatory cells. PMID- 29624114 TI - Ultrastructural analysis of human umbilical cord derived MSCs at undifferentiated stage and during osteogenic and adipogenic differentiation. AB - Mesenchymal stem cells (MSCs) are considered as an important tool for regenerative medicine and experimental treatments. Unveiling the ultrastructural changes during the differentiation of MSCs might help us to understand the nature of the process and to develop novel therapeutic approaches. For this purpose, human umbilical cord (hUC) was chosen as MSC source. In the first place, MSCs were isolated from sub-amniotic, intervascular and perivascular areas of hUC by enzymatic and tissue explant method to determine the most favorable region of hUC and technique for further processing. Therefore, microscopic and growth kinetics analyses showed that there was no clear difference in the morphologies and proliferation rates among the hUC-MSC groups. Flow cytometric analysis showed that CD44 and CD90 MSC markers were highly expressed, while CD34 and CD45 hematopoietic stem cells markers were expressed at low degree. Because our preliminary results showed that there was no conspicuous superiority among the hUC-MSCs groups, whole UC was utilized as a source, and tissue explant method was applied to isolate MSCs for further differentiation analysis. At the 1st and 3rd week of osteogenic and adipogenic differentiation, ultrastructural analysis showed an increase in the number of secondary lysosomes in comparison with the undifferentiated status. Increase in the mitochondrial content was also detected at the 1st week of adipogenic differentiation. Consequently, ultrastructural changes including increase in the number of mitochondria and secondary lysosomes during the adipogenic and osteogenic differentiation could be attributed to the switch in energy metabolism of the MSCs and increment in the lysosomal activity respectively. PMID- 29624115 TI - Cadmium-induced conformational changes in type 2 metallothionein of medicinal plant Coptis japonica: insights from molecular dynamics studies of apo, partially and fully metalated forms. AB - Plants play an important role in the removal of excess heavy metals from soil and water. Medicinal plants can also have non-traditional use in phytoremediation technologies. Among the heavy metals, Cadmium (Cd) is the most abundant and readily taken up by the crop plants. Plant metallothioneins (MTs) are small proteins having cysteine-rich residues and appear to play key roles in metal homoeostasis. Plant metallothionein 2 (MT 2) from Coptis japonica (Gold-thread; CjMT 2) is a typical member of this subfamily and features two cysteine-rich regions containing eight and six cysteine residues, respectively, separated by 42 amino acids long linker region. In-silico analysis of MT 2 protein sequences of C. japonica was performed. In this study, ab initio methods were utilised for the prediction of three-dimensional structure of CjMT 2. After structure validation, heavy metal-binding sites were predicted for the selected modelled structures of CjMT 2. To obtain Cdi-CjMT 2 (i = 1-7), metalated complex individual docking experiments were performed. The stability of the metalated docked structures was assessed by molecular dynamics (MD) simulation studies. Our study showed that CjMT 2 binds up to 4 Cd2+ ions in two distinct domains: a N-terminal beta-domain that binds to 2 Cd2+ ions and a C-terminal alpha-domain that binds with 2 Cd2+ ions. Our analysis revealed that Cys residues of alpha and beta domain and some residues of spacer region of CjMT 2 protein might be important for the cadmium interaction. MD simulation studies provided insight into metal-induced conformational changes and mechanism of metalation of CjMT 2, an intrinsically disordered protein. This study provides useful insights into mechanism of cadmium type 2 metallothionein interaction. PMID- 29624117 TI - Scandalous: Christian identification, sex guilt, and the mediated demonization of the participants in the AshleyMadison scandal. AB - In 2015, AshleyMadison.com (AshleyMadison) was hacked, leading to the release of site members' personal information. The exposed members faced public scrutiny, judgment, and other negative outcomes. In this study, we examined predictors of the demonization of the AshleyMadison participants (i.e., AshleyMadison members, owners, hackers) to help explain victim derogation. We attempted to discern the role religiosity and sexual guilt played in the demonization of the AshleyMadison hacking participants. We predicted sexual guilt would mediate between religiosity and demonization of the AshleyMadison hacking participants. Our findings indicate that religiosity alone does not predict demonization. Instead, sex guilt was a necessary part of the equation and mediated between participants' religiosity and the amount they demonized the different groups. PMID- 29624116 TI - Evaluation of Congo Red Staining in Degenerating Porcine Photoreceptors In Vitro: Protective Effects by Structural and Trophic Support. AB - Congo red (CR) is a histological stain used for the detection of extracellular amyloids mediating various neurodegenerative diseases. Given that damaged photoreceptors appear to degenerate similarly to other nerve cells, CR staining was evaluated in experimentally injured porcine retina. CR staining appeared mostly as discrete cytosolic deposits with no obvious plaque formation during the investigated time period. Increases of CR labeling coincided temporally with the known accumulation of mislocalized opsins and increases of cell death. Coculture, either with human retinal pigment epithelium (ARPE) or human neural progenitor (ReN) cells, was accompanied by a significant reduction of CR labeling. Of particular interest was the reduction of CR labeling in cone photoreceptors, which are important for the perception of color and fine details and afflicted in age-related macular degeneration (AMD). Electron microscopy revealed inclusions in the inner segment, cell body, and occasionally synaptic terminals of photoreceptor cells in cultured specimens. Closer examinations indicated the presence of different types of inclusions resembling protein aggregates as well as inclusion bodies. The current results indicate that injury-related response resulted in accumulation of CR deposits in photoreceptor cells, and that trophic and/or structural support attenuated this response. PMID- 29624118 TI - EphrinB2 activation enhances angiogenesis, reduces amyloid-beta deposits and secondary damage in thalamus at the early stage after cortical infarction in hypertensive rats. AB - Cerebral infarction causes secondary neurodegeneration and angiogenesis in thalamus, which impacts functional recovery after stroke. Here, we hypothesize that activation of ephrinB2 could stimulate angiogenesis and restore the secondary neurodegeneration in thalamus after cerebral infarction. Focal cerebral infarction was induced by middle cerebral artery occlusion (MCAO). Secondary damage, angiogenesis, amyloid-beta (Abeta) deposits, levels of ephrinB2 and receptor for advanced glycation end product (RAGE) in the ipsilateral thalamus were determined by immunofluorescence and immunoblot. The contribution of ephrinB2 to angiogenesis was determined by siRNA-mediated knockdown of ephrinB2 and pharmacological activation of ephrinB2. The results showed that formation of new vessels and ephrinB2 expression was markedly increased in the ipsilateral thalamus at seven days after MCAO. EphrinB2 knockdown markedly suppressed angiogenesis coinciding with increased Abeta accumulation, neuronal loss and gliosis in the ipsilateral thalamus. In contrast, clustered EphB2-Fc significantly enhanced angiogenesis, alleviated Abeta accumulation and the secondary thalamic damage, which was accompanied by accelerated function recovery. Additionally, activation of ephrinB2 significantly reduced RAGE levels in the ipsilateral thalamus. Our findings suggest that activation of ephrinB2 promotes angiogenesis, ameliorates Abeta accumulation and the secondary thalamic damage after cerebral infarction. Additionally, RAGE might be involved in Abeta clearance by activating ephrinB2 in the thalamus. PMID- 29624119 TI - How Different Guilt Feelings Can Affect Social Competence Development in Childhood. AB - The authors examined how the two different dimensions of guilt feelings, needed for reparation and fear of punishment, could influence social conduct, such as prosocial and aggressive behaviors, and how they are linked to popularity in childhood. The authors hypothesized a theoretical model that they tested, fitting it with empirical data obtained from a sample of 242 Italian children 9-11 years old. Both dimensions of guilt predict prosocial and aggressive behaviors. Specifically, the feeling of guilt linked to the need for reparation tends to negatively predict aggressive behaviors, and positively predict prosocial behaviors. The feeling of guilt linked to the fear of punishment, on the contrary, tends to positively affect aggressive and negatively affect prosocial conducts in children. These results highlight that the different feelings of guilt can represent a relevant risk or protective factor for the development of social competence in childhood. Limitations, strengths, and further development of the present study are discussed. PMID- 29624120 TI - Density functional theory based probe of the affinity interaction of saccharide ligands with extra-cellular sialic acid residues. AB - Changes in glycosylation pattern leads to malignant transformations among the cells. In combination with upregulated actions of sialyltransferases, it ultimately leads to differential expression of sialic acid (SA) at cell surface. Given its negative charge and localization to extracellular domain, SA has been exploited for the development of targeted theranostics using approaches, such as, cationization and appending recognition saccharides on carrier surface. In this study, we have performed quantum mechanical calculations based on density functional theory (DFT) to study the interaction of saccharides with extracellular SA. Gradient-corrected DFT with the three parameter function (B3) was utilized for the calculation of Lee-Yang-Parr (LYP) correlation function. Atomic charge, vibrational frequencies and energy of the optimized structures were calculated through B3LYP. Our calculations demonstrate a stronger galactose sialic acid interaction at tumour-relevant low pH and hyperthermic condition. These results support the application of pH responsive delivery vehicles and targeted hyperthermic chemotherapy for eradicating solid tumour deposits. These studies, conducted a priori, can guide the formulation scientists over appropriate choice of ligands and their applications in the design of 'smart' theranostic tools. PMID- 29624121 TI - Childhood Abuse, Religious Involvement, and Lifetime Substance Use Disorders among Latinas Nationwide. AB - BACKGROUND: Childhood abuse is a major behavioral health concern and imposes lasting sequelae on mental and physical health, including lifetime substance use disorders (LT-SUD). Yet, gender-specific research examining this early trauma and substance use in Latina-Americans (Latinas) is scarce. No study has explored the relationship between collectivist cultural factors and LT-SUD in this largest minority-female subgroup of the United States' population. OBJECTIVES: Based on coping theory, this study investigated the association between childhood abuse, cultural factors, and LT-SUD among Latinas nationwide. METHODS: Using the National Latino and Asian American Study we performed three-step logistic regressions to investigate LT-SUD for 1,427 Latinas, following three preplanned steps: (1) childhood physical and sexual abuse (CPA and CSA) with LT-SUD; (2) known correlates as controls; and (3) cultural strength factors. RESULTS: The prevalence rates of CPA and CSA were 28.0% and 18.4%, and that of LT-SUD was 4.8%. Religious attendance at a weekly level was negatively related to LT-SUD. Alongside English proficiency, discrimination, and social support, however, CPA and religious coping were positively associated with LT-SUD. Conclusion/Importance: Childhood physical abuse is an early risk factor for long term substance use, viewed as a negative coping strategy. Religious attendance may have potential protection for Latinas. The victimization history may lead to coexisting positive (e.g., pursing social support, religious coping) and negative (e.g., SUD) coping behaviors within Latino communities. PMID- 29624122 TI - Docking, steered molecular dynamics, and QSAR studies as strategies for studying isoflavonoids as 5-, 12-, and 15-lipoxygenase inhibitors. AB - Lipoxygenases (LOX) are enzymes that catalyze polyunsaturated fatty acid peroxidation and have a non-heme iron atom located in their active site. They are implicated in the arachidonic acid pathway and involved in inflammation, fever, pain production, and in the origins of several diseases such as cancer, asthma, and psoriasis. The search for inhibitors of these enzymes has emerged in the last years, and isoflavonoids have a broad spectrum of biological activity with low cytotoxicity. Our previous results have shown that isoflavonoids inhibited different LOX isoforms in vitro. For this reason, we studied the most important interactions that govern the potency and selectivity of some isoflavones and isoflavans toward different LOX isoforms using computational methods. The docking results have shown that all the molecules can be located in different zones in the LOX active site. Steered molecular dynamics indicated that selectivity was present at the cavity entry, but not at its exit. We also observed the correlation between the potential mean force and the best (HIR-303) and worst inhibitors (IR-213) in 5-LOX. Finally, structure-activity relationship (QSAR) studies showed a good correlation between theoretical IC50 values and experimental data for 5-LOX and 12-LOX with 96 and 95%, respectively, and a lower correlation for 15-LOX (79%). Conclusively, pharmacophore analysis showed that our proposed molecules should possess a donor-acceptor and aromatic centers to encourage interactions in the active site. PMID- 29624123 TI - The Mediating Role of Coping Self-Efficacy in Hope Box Use and Suicidal Ideation Severity. AB - In this study, we examined the indirect effect of the Virtual Hope Box (VHB) smartphone application on suicidal ideation, mediated through coping self efficacy. A total of 117 veterans with suicidal ideation completed measures on coping self-efficacy and suicidal ideation at baseline and weeks 3, 6, and 12. Participants were randomly assigned to either the VHB or enhanced treatment as usual (eTAU) condition. Parallel process growth curve modeling (-0.20 [95% CI = 0.44, 0.00]) and auto-regressive modeling (-0.12 [95% CI = -0.35, -0.01]) revealed that a higher rate of change in coping self-efficacy in the VHB group was associated with a decrease in suicidal ideation severity, as compared to the eTAU group. Findings suggest that coping self-efficacy may be one mechanism by which the VHB operates to help reduce suicidal ideation. More broadly, the role of coping self-efficacy in reducing suicidal ideation is worthy of future study. PMID- 29624124 TI - Architecture of the RNA polymerase II elongation complex: new insights into Spt4/5 and Elf1. AB - Transcription by RNA polymerase II (Pol II) is accomplished with the aid of numerous accessory factors specific to each transcriptional stage. The structure of the Pol II elongation complex (EC) bound with Spt4/5, Elf1, and TFIIS unveiled the sophisticated basal EC architecture essential for transcription elongation and other transcription-related events. PMID- 29624125 TI - Examining the contraceptive decisions of young, HIV-infected women: A qualitative study. AB - This study qualitatively examined factors that influenced contraceptive choices in a sample of young, HIV-infected women. Individual qualitative interviews were conducted among 30 vertically and horizontally HIV-infected women (n = 26 African American) from the ages of 14 to 24 years (Mean age = 20.9 years). We recruited sample groups with the following characteristics: (a) current contraceptive/condom use with >=1 child (n = 11); (b) current contraceptive/condom use with no children (n = 12); and (c) no current contraceptive/condom use with no children (n = 7). A semi-structured interview guide was used to ask participants about factors influencing past and current contraceptive choices. Individual interviews were digitally recorded and transcribed verbatim; analyses to identify core themes were informed by the Grounded Theoretical approach. Young, HIV-infected women did not identify their HIV serostatus or disease-related concerns as influential in their contraceptive decisions. However, they reported that recommendations from health-care providers and input from family and friends influenced their contraceptive choices. They also considered a particular method's advantages (e.g., menstrual cycle improvements) and disadvantages (e.g., increased pill burden) when selecting a method. Findings suggested that HIV-infected young women's contraceptive decisions were influenced by factors other than those related to their infection. PMID- 29624126 TI - Health-Related Quality of Life and Personal Life Goals of Adults With Sickle Cell Disease After Hematopoietic Stem Cell Transplantation. AB - Allogeneic hematopoietic stem cell transplantation (HSCT) from a human leukocyte antigen (HLA)-matched sibling donor offers a unique therapy to reverse SCD. This mixed-methods study explores recipients' perception of HSCT success, personal life goals, and associated health-related quality of life (HRQOL) more than 1 year after HSCT. Recipients completed the Short Form-36, version 1 (SF-36v1) HRQOL survey followed by a 60- to 90-min face-to-face or telephone audio-recorded interview. Eleven of 15 eligible recipients participated in the study. Although the eight HRQOL subscale scores varied, the three recipients with a successful HSCT and the highest scores were pursuing their personal life goals. The four with avascular necrosis (AVN) had lower scores related to AVN limitations, yet they were pursuing their personal goals. The two reporting a failed HSCT had reverted back to having SCD, and their subscale scores were among the lowest. Our results show that HSCT success, ability to pursue goals, and HRQOL align in predictable ways. PMID- 29624127 TI - Depolarized Hepatocytes Express the Stem/Progenitor Cell Marker Neighbor of Punc E11 After Bile Duct Ligation in Mice. AB - There is a medical need of biomarkers for disease stratification in cholestatic liver diseases that come along with changes in hepatocyte polarity. Neighbor of Punc E11 (Nope) is an oncofetal marker that is lost after final differentiation and polarization of hepatocytes. We analyzed the expression pattern of Nope and connexin (Cx) 26 as markers of hepatocyte polarization during murine liver development as well as in adult liver with or without bile duct ligation (BDL) by quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), western blotting (WB), and immunohistochemistry. Nope is highly expressed in fetal and postnatal liver but barely detectable thereafter. Cx26, however, is much higher expressed in adult than in fetal liver. Postnatally, Nope is directed to the sinusoidal membrane of early hepatocytes while Cx26 remains distributed over the whole membrane indicating limited polarization. In the adult liver, only Cx26 is detectable and restricted to the bile canalicular domain indicating fully polarized hepatocytes. After BDL, Nope is again >300-fold upregulated while Cx26 is reduced rapidly. By immunohistochemistry, Nope identifies a subset of hepatocytes with randomly distributed Cx26. In summary, Nope identifies depolarized adult hepatocytes after cholestatic liver injury resembling early postnatal hepatocytes. Therefore, Nope might be a valuable histochemical biomarker allowing stage-specific stratifications in cholestatic liver diseases. PMID- 29624129 TI - The relationship of older age and perioperative outcomes following thoracolumbar three-column osteotomy for adult spinal deformity: an analysis of 300 consecutive cases. AB - OBJECTIVE Three-column osteotomies are increasingly being used in the elderly population to correct rigid spinal deformities. There is hesitation, however, in performing the technique in older patients because of the high risk for blood loss, longer operative times, and complications. This study assesses whether age alone is an independent risk factor for complications and length of stay. METHODS All patients with thoracolumbar adult spinal deformity (ASD) who underwent 3 column osteotomy (vertebral column resection or pedicle subtraction osteotomy) performed by the senior author from 2006 to 2016 were identified. Demographics, clinical baseline, and surgical details were collected. Outcomes of interest included perioperative complication, ICU stay, and hospital stay. Bivariate and multivariate analyses were used to assess the association of age with outcomes of interest. RESULTS A total of 300 patients were included, and 38.3% were male. The mean age was 63.7 years: 10.3% of patients were younger than 50 years, 36.0% were 50-64 years, 45.7% were 65-79 years, and 8.0% were 80 years or older. The overall mean EBL was 1999 ml. The overall perioperative complication rate was 24.7%: 18.0% had a medical complication and 7.0% had a surgical complication. There were no perioperative or 30-day deaths. Age was associated with overall complications (p = 0.002) and medical-specific complications (p < 0.001); there were higher rates of overall and medical complications with increased age: 9.7% and 6.5%, respectively, for patients younger than 50 years; 16.7% and 10.2%, respectively, for patients 50-64 years; 31.4% and 22.6%, respectively, for patients 65-79 years; and 41.7% and 41.7%, respectively, for patients 80 years or older. However, after adjusting for relevant covariates on multivariate analysis, age was not an independent factor for perioperative complications. Surgical complication rates were similar among the 4 age groups. Longer ICU and total hospital stays were observed in older age groups, and age was an independent factor associated with longer ICU stay (p = 0.028) and total hospital stay (p = 0.003). ICU stays among the 4 age groups were 1.6, 2.3, 2.0, and 3.2 days for patients younger than 50 years, 50-64 years, 65-79 years, and 80 years or older, respectively. The total hospital stays stratified by age were 7.3, 7.7, 8.2, and 11.0 days for patients younger than 50 years, 50-64 years, 65-79 years, and 80 years or older, respectively. CONCLUSIONS Older age was associated with higher perioperative complication rates, but age alone was not an independent risk factor for complications following the 3-column osteotomy for ASD. Comorbidities and other unknown variables that come with age are likely what put these patients at higher risk for complications. Older age, however, is independently associated with longer ICU and hospital stays. PMID- 29624128 TI - The use of patient-reported preoperative activity levels as a stratification tool for short-term and long-term outcomes in patients with adult spinal deformity. AB - OBJECTIVE Given the recent shift in health care toward quality reporting requirements and a greater emphasis on a cost-quality approach, patient stratification with respect to long-term outcomes and the use of health care resources is of increasing value. Stratification tools may be effective if they are simple and evidence based. The authors hypothesize that preoperative patient reported activity levels might independently predict postoperative outcomes in patients with adult spinal deformity. METHODS This is a retrospective cohort. A total of 575 patients in a prospective adult spinal deformity surgical database were identified with complete data regarding the preoperative level of activity. Answers to question 5 of the Scoliosis Research Society-22r Patient Questionnaire (SRS-22r) were used to stratify patients into active and inactive groups. Outcomes were length of hospital stay (LOS), level of activity, and reaching the minimum clinically important difference (MCID) for SRS-22r domains and the Physical Component Summary (PCS) of the SF-36 at 2 years postoperatively. The 2 groups were compared with respect to several potential confounders. Covariates with p < 0.1 were controlled for. The impact of activity on LOS was assessed using multivariate negative binomial regression analysis. Multivariate logistic regression models additionally controlling for the respective baseline health related quality of life (HRQOL) scores were used to assess the association between preoperative activity levels and reaching the MCID at 2 years postoperatively. RESULTS A total of 420 (73%) of the 575 patients who met the inclusion criteria had complete data at 2 years postoperatively. The inactive group was more likely to be significantly older, have a higher Charlson Comorbidity Index, worse baseline radiographic deformity, and greater correction of most radiographic parameters. After controlling for possible confounders, the active group had a significantly shorter LOS (incidence risk ratio 0.91, p = 0.043). After adding respective baseline HRQOL scores to the models, active patients were significantly more likely to reach the MCID for the SRS-22r pain domain (OR 1.72, p = 0.026) and PCS (OR 1.94, p = 0.013). Active patients were also significantly more likely to be active at 2 years postoperatively on multivariate analysis (OR 8.94, p < 0.001). CONCLUSIONS The authors' results show that patients who belong to the inactive group are likely to have a longer LOS and lower odds of reaching the MCID in HRQOL or being active at 2 years postoperatively. Inquiring about patients' preoperative activity levels might be a reliable and simple stratification tool in terms of long- and short-term outcomes in ASD patients. PMID- 29624130 TI - Treatment strategy for rod fractures following corrective fusion surgery in adult spinal deformity depends on symptoms and local alignment change. AB - OBJECTIVE Despite the significant incidence of rod fractures (RFs) following long segment corrective fusion surgery, little is known about the optimal treatment strategy. The objectives of this study were to investigate the time course of clinical symptoms and treatments in patients with RFs following adult spinal deformity (ASD) surgery and to establish treatment recommendations. METHODS This study was a retrospective case series of patients with RFs whose data were retrieved from a prospectively collected single-center database. The authors reviewed the cases of 304 patients (mean age 62.9 years) who underwent ASD surgery. Primary symptoms, time course of symptoms, and treatments were investigated by reviewing medical records. Standing whole-spine radiographs obtained before and after RF development and at last follow-up were evaluated. Osseous union was assessed using CT scans and intraoperative findings. RESULTS There were 54 RFs in 53 patients (mean age 68.5 years [range 41-84 years]) occurring at a mean of 21 months (range 6-47 months) after surgery. In 1 patient RF occurred twice, with each case at a different time and level, and the symptoms and treatments for these 2 RFs were analyzed separately (1 case of revision surgery and 1 case of nonoperative treatment). The overall rate of RF observed on radiographs after a minimum follow-up of 1 year was 18.0% (54 of 300 cases). The clinical symptoms at the time of RF were pain in 77.8% (42 of 54 cases) and no onset of new symptoms in 20.5% (11 of 54 cases). The pain was temporary and had subsided in 19 of 42 cases (45%) within 2 weeks. In 36 of the 54 cases (66.7%) (including the first RF in the patient with 2 RFs), patients underwent revision surgery at a mean of 116 days (range 5-888 days) after diagnosis. In 18 cases patients received only nonoperative treatment as of the last follow-up, including 17 cases in which the patients experienced no pain and no remarkable progression of deformity (mean 18.5 months after RF development). CONCLUSIONS This analysis of 54 RFs in 53 patients following corrective fusion surgery for ASD demonstrates a relationship between symptoms and alignment change. Revision surgeries were performed in a total of 36 cases. Nonoperative care was offered in 18 (33.3%) of 54 cases at the last follow-up, with no additional symptoms in 17 of the 18 cases. These data offer useful information regarding informed decision making for patients in whom an RF occurs after ASD surgery. PMID- 29624131 TI - Team performance in the Italian NHS: the role of reflexivity. AB - Purpose The purpose of this paper is twofold: first, to investigate the goodness of the input-process-output (IPO) model in order to evaluate work team performance within the Italian National Health Care System (NHS); and second, to test the mediating role of reflexivity as an overarching process factor between input and output. Design/methodology/approach The Italian version of the Aston Team Performance Inventory was administered to 351 employees working in teams in the Italian NHS. Mediation analyses with latent variables were performed via structural equation modeling (SEM); the significance of total, direct, and indirect effect was tested via bootstrapping. Findings Underpinned by the IPO framework, the results of SEM supported mediational hypotheses. First, the application of the IPO model in the Italian NHS showed adequate fit indices, showing that the process mediates the relationship between input and output factors. Second, reflexivity mediated the relationship between input and output, influencing some aspects of team performance. Practical implications The results provide useful information for HRM policies improving process dimensions of the IPO model via the mediating role of reflexivity as a key role in team performance. Originality/value This study is one of a limited number of studies that applied the IPO model in the Italian NHS. Moreover, no study has yet examined the role of reflexivity as a mediator between input and output factors in the IPO model. PMID- 29624132 TI - Collaboration in a competitive healthcare system: negotiation 101 for clinicians. AB - Purpose The purpose of this paper is to evaluate the effectiveness of negotiation training delivered to senior clinicians, managers and executives, by exploring whether staff members implemented negotiation skills in their workplace following the training, and if so, how and when. Design/methodology/approach This is a qualitative study involving face-to-face interviews with 18 senior clinicians, managers and executives who completed a two-day intensive negotiation skills training course. Interviews were transcribed verbatim, and inductive interpretive analysis techniques were used to identify common themes. Research setting was a large tertiary care hospital and health service in regional Australia. Findings Participants generally reported positive affective and utility reactions to the training, and attempted to implement at least some of the skills in the workplace. The main enabler was provision of a Negotiation Toolkit to assist in preparing and conducting negotiations. The main barrier was lack of time to reflect on the principles and prepare for upcoming negotiations. Participants reported that ongoing skill development and retention were not adequately addressed; suggestions for improving sustainability included provision of refresher training and mentoring. Research limitations/implications Limitations include self-reported data, and interview questions positively elicited examples of training translation. Practical implications The training was well matched to participant needs, with negotiation a common and daily activity for most healthcare professionals. Implementation of the skills showed potential for improving collaboration and problem solving in the workplace. Practical examples of how the skills were used in the workplace are provided. Originality/value To the authors' knowledge, this is the first international study aimed at evaluating the effectiveness of an integrative bargaining negotiation training program targeting executives, senior clinicians and management staff in a large healthcare organization. PMID- 29624133 TI - Telephone consultation in primary care. AB - Purpose The purpose of this paper is to describe and analyze a teleconsultation modality based on a simple telephone call, using either landline or mobile phone, made available to more than two million people. Telecommunication systems are an increasingly common feature in modern healthcare. However, making teleconsultations available to the entire population covered by a public health system is a challenging goal. Design/methodology/approach This retrospective longitudinal observational study analyzed how this modality was used at the primary care level in Galicia, a region in the Northwest of Spain, in 2014 and 2015, focusing on demand, gender and age preferences, rural vs urban population and efficiency. Findings Of 28,472,852 consultations requested in this period, 9.0 percent were telephone consultations. Women requested more telephone consultations (9.9 percent of total consultations) than men (7.7 percent of total consultations). The highest demand occurred for the over 85 age group for both men and women. In both years, 2014 and 2015, the number of telephone consultations per inhabitant was higher in urban (0.53 and 0.69) than in rural areas (0.34 and 0.47). In 10.9 percent of cases, the telephone consultations required further face-to-face consultation. Originality/value Conventional voice telephone calls can efficiently replace conventional face-to-face consultations in primary healthcare in roughly 10 percent of cases. Women are more likely than men to use primary care services in both face-to-face and telephone consultation modalities. Public healthcare systems should consider implementing telephone consultations to deliver their services. PMID- 29624134 TI - Development of an instrument to measure organisational culture in community pharmacies in Great Britain. AB - Purpose Organisational culture (OC) shapes individuals' perceptions and experiences of work. However, no instrument capable of measuring specific aspects of OC in community pharmacy exists. The purpose of this paper is to report the development and validation of an instrument to measure OC in community pharmacy in Great Britain (GB), and conduct a preliminary analysis of data collected using it. Design/methodology/approach Instrument development comprised three stages: Stage I: 12 qualitative interviews and relevant literature informed instrument design; Stage II: 30 cognitive interviews assessed content validity; and Stage III: a cross-sectional survey mailed to 1,000 community pharmacists in GB, with factor analysis for instrument validation. Statistical analysis investigated how community pharmacists perceived OC in their place of work. Findings Factor analysis produced an instrument containing 60 items across five OC dimensions - business and work configuration, social relationships, personal and professional development, skills utilisation, and environment and structures. Internal reliability for the dimensions was high (0.84 to 0.95); item-total correlations were adequate ( r=0.46 to r=0.76). Based on 209 responses, analysis suggests different OCs in community pharmacy, with some community pharmacists viewing the environment in which they worked as having a higher frequency of aspects related to patient contact and safety than others. Since these aspects are important for providing high healthcare standards, it is likely that differences in OC may be linked to different healthcare outcomes. Originality/value This newly developed and validated instrument to measure OC in community pharmacy can be used to benchmark existing OC across different pharmacies and design interventions for triggering change to improve outcomes for community pharmacists and patients. PMID- 29624135 TI - Flavored E-cigarette Use and Cigarette Smoking Reduction and Cessation-A Large National Study among Young Adult Smokers. AB - BACKGROUND: E-cigarette use prevalence has increased drastically among young adult cigarette smokers in recent years. OBJECTIVES: This study seeks to understand which e-cigarette flavors-sweet and fruity or tobacco and menthol/mint are more likely to be associated with smoking reduction and cessation among young adults. METHODS: Longitudinal data (waves 1 and 2) of the Population Assessment of Tobacco and Health (PATH) Study from young adult (aged 18-34) cigarette smokers (n = 4,645) at wave 1 and current e-cigarette users (n = 844) at wave 2 were used. Univariate and multivariate regressions were conducted to examine the associations between past-year smoking reduction and cessation and current e cigarette flavor use at wave 2. RESULTS: At wave 2, 25.9% of respondents either reduced or quit smoking, and 6.7%, 5.2%, and 6.3% of them reported currently using e-cigarettes with tobacco/menthol (TM) flavors, one non-tobacco/non-menthol (NTM) flavor, and multiple NTM flavors, respectively. E-cigarette users with one (AOR = 2.5, p < 0.001) and multiple NTM flavors (AOR = 3.0, p < 0.001) were more likely to have reduced or quit smoking over the past year compared to non-e cigarette users. NTM flavor use was positively associated with e-cigarette use of a higher frequency and larger amount. CONCLUSIONS: The positive association between past-year smoking reduction and cessation and current NTM flavored e cigarette use may be explained by young adults' escalated e-cigarette use with NTM flavors. Public health professionals should prevent and reduce multiple tobacco use through enhanced education about the harm of vaping NTM flavors and by advising young adult smokers to quit tobacco altogether using evidence-based methods. PMID- 29624136 TI - How hospital survey teams function. AB - Purpose The purpose of this paper is to understand how inspection team members work together to conduct surveys of hospitals, the challenges teams may face and how these might be addressed. Design/methodology/approach Data were gathered through an evaluation of a new regulatory model for acute hospitals in England, implemented by the Care Quality Commission (CQC) during 2013-2014. The authors interviewed key stakeholders, observed inspections and surveyed and interviewed inspection team members and hospital staff. Common characteristics of temporary teams provided an analytical framework. Findings The temporary nature of the inspection teams hindered the conduct of some inspection activities, despite the presence of organisational citizenship behaviours. In a minority of sub-teams, there were tensions between CQC employed inspectors, healthcare professionals, lay people and CQC data analysts. Membership changes were infrequent and did not appear to inhibit team functioning, with members displaying high commitment. Although there were leadership authority ambiguities, these were not problematic. Existing processes of recruitment and selection, training and preparation and to some extent leadership, did not particularly lend themselves to addressing the challenges arising from the temporary nature of the teams. Research limitations/implications Conducting the research during the piloting of the new regulatory approach may have accentuated some challenges. There is scope for further research on inspection team leadership. Practical implications Issues may arise if inspection and accreditation agencies deploy temporary, heterogeneous survey teams. Originality/value This research is the first to illuminate the functioning of inspection survey teams by applying a temporary teams perspective. PMID- 29624137 TI - Multi-disciplinary decision making in general practice. AB - Purpose Internationally, healthcare systems are moving towards delivering care in an integrated manner which advocates a multi-disciplinary approach to decision making. Such an approach is formally encouraged in the management of Atrial Fibrillation patients through the European Society of Cardiology guidelines. Since the emergence of new oral anticoagulants switching between oral anticoagulants (OACs) has become prevalent. This case study considers the role of multi-disciplinary decision making, given the complex nature of the agents. The purpose of this paper is to explore Irish General Practitioners' (GPs) experience of switching between all OACs for Arial Fibrillation (AF) patients; prevalence of multi-disciplinary decision making in OAC switching decisions and seeks to determine the GP characteristics that appear to influence the likelihood of multi disciplinary decision making. Design/methodology/approach A probit model is used to determine the factors influencing multi-disciplinary decision making and a multinomial logit is used to examine the factors influencing who is involved in the multi-disciplinary decisions. Findings Results reveal that while some multi disciplinary decision-making is occurring (64 per cent), it is not standard practice despite international guidelines on integrated care. Moreover, there is a lack of patient participation in the decision-making process. Female GPs and GPs who have initiated prescriptions for OACs are more likely to engage in multi disciplinary decision-making surrounding switching OACs amongst AF patients. GPs with training practices were less likely to engage with cardiac consultants and those in urban areas were more likely to engage with other (non-cardiac) consultants. Originality/value For optimal decision making under uncertainty multi-disciplinary decision-making is needed to make a more informed judgement and to improve treatment decisions and reduce the opportunity cost of making the wrong decision. PMID- 29624138 TI - The role of academic health centres in improving health equity: a systematic review. AB - Purpose Academic health centres (AHCs) are organisations that pursue a "tripartite" mission to deliver high-quality care to patients, undertake clinical and laboratory research, and train future health professionals. The last decade has seen a global spread of AHC models and a growing interest in the role of AHCs in addressing health system equity. The purpose of this paper is to synthesise and critically appraise the evidence on the role of AHCs in improving health equity. Design/methodology/approach Peer-reviewed and grey literature published in English between 2000 and 2016 were searched. Articles that identified AHCs as the primary unit of analysis and that also addressed health equity concepts in relation to the AHC's activity or role were included. Findings In total, 103 publications met the inclusion criteria of which 80 per cent were expert opinion. Eight descriptive themes were identified through which health equity concepts in relation to AHCs were characterised, described and operationalised: population health, addressing health disparities, social determinants of health, community engagement, global health, health system reform, value-based and accountable financing models, and role clarification/recalibration. There was consensus that AHCs can and should address health disparities, but there is a lack of empirical evidence to show that AHCs have a capacity to contribute to health equity goals or are demonstrating this contribution. Originality/value This review highlights the relevance of health equity concepts in discussions about the role and missions of AHCs. Future research should improve the quality of the evidence base by empirically examining health equity strategies and interventions of AHCs in multiple countries and contexts. PMID- 29624139 TI - Knowledge exchange in the UK CLAHRCs. AB - Purpose The purpose of this paper is to examine how knowledge exchange between academics and clinicians in Collaborations for Leadership in Applied Health Research and Care (CLAHRCs) is influenced by their social position based on their symbolic and social capitals, that is, their personal professional status and connections to high-status professional peers, knowledge brokers, and unfamiliar professional peers. Design/methodology/approach Using an online survey, the author triangulates the cross-sectional measurement of the effects of academic and clinicians' social position in the initial and later phases of CLAHRCs with the longitudinal measurement of these effects over a two-year period. Findings First, academics and clinicians with a higher personal professional status are more likely to develop joint networks and decision making both in the early and later phases of a CLAHRC. Second, academics and clinicians who are more connected to higher status occupational peers are more likely to develop joint networks in the early phase of a knowledge exchange partnership but are less likely to become engaged in joint networks over time. Third, involvement of knowledge brokers in the networks of academics and clinicians is likely to facilitate their inter professional networking only in the later partnership phase. Practical implications Academics and clinicians' capitals have a distinctive influence on knowledge exchange in the early and later phases of CLAHRCs and on a change in knowledge exchange over a two-year period. Originality/value Prior research on CLAHRCs has examined how knowledge exchange between academics and clinicians can be encouraged by the creation of shared governance mechanisms. The author advances this research by highlighting the role of their social position in facilitating knowledge exchange. PMID- 29624140 TI - Population health management guiding principles to stimulate collaboration and improve pharmaceutical care. AB - Purpose A range of strategies to improve pharmaceutical care has been implemented by population health management (PHM) initiatives. However, which strategies generate the desired outcomes is largely unknown. The purpose of this paper is to identify guiding principles underlying collaborative strategies to improve pharmaceutical care and the contextual factors and mechanisms through which these principles operate. Design/methodology/approach The evaluation was informed by a realist methodology examining the links between PHM strategies, their outcomes and the contexts and mechanisms by which these strategies operate. Guiding principles were identified by grouping context-specific strategies with specific outcomes. Findings In total, ten guiding principles were identified: create agreement and commitment based on a long-term vision; foster cooperation and representation at the board level; use layered governance structures; create awareness at all levels; enable interpersonal links at all levels; create learning environments; organize shared responsibility; adjust financial strategies to market contexts; organize mutual gains; and align regional agreements with national policies and regulations. Contextual factors such as shared savings influenced the effectiveness of the guiding principles. Mechanisms by which these guiding principles operate were, for instance, fostering trust and creating a shared sense of the problem. Practical implications The guiding principles highlight how collaboration can be stimulated to improve pharmaceutical care while taking into account local constraints and possibilities. The interdependency of these principles necessitates effectuating them together in order to realize the best possible improvements and outcomes. Originality/value This is the first study using a realist approach to understand the guiding principles underlying collaboration to improve pharmaceutical care. PMID- 29624141 TI - Management simulations for Lean healthcare: exploiting the potentials of role playing. AB - Purpose The purpose of this paper is to investigate the potentials of role playing (RP) both in training healthcare (HC) professionals to implement tools and improvement actions based on Lean principles, and in supporting group discussion and the sharing of different competencies for the development of Lean HC. Design/methodology/approach The paper presents the case study of an RP simulation called LEAN HEALTHCARE LAB, which is used to train HC professionals at Siena University Hospital. The paper reports and discusses the results of a specific two-day simulation session and of a questionnaire that was distributed to gather feedback from the participants. Findings The paper verifies the potentials of RP to be a powerful educational and training tool that is able to stimulate the HC participants to apply Lean thinking principles and share their competencies in collaborative decision-making processes. Research limitations/implications The study provides data in reference to one single simulation session, although the game has already been applied several times in different HC organizations with very similar outcomes. Moreover, a more in-depth analysis of players' perceptions and decisions could be performed using different tools in addition to the adopted questionnaire. Practical implications RP games (RPGs) are effective training and educational tools for HC professionals. They offer benefits and learning conditions which are definitely different if compared with more conventional education programs for HC professionals. Originality/value While previous studies have extensively discussed the potentialities of RPG and simulations in training programs, only a few articles have discussed the RP adoption for Lean thinking and even less to educate HC professionals on Lean principles and tools. PMID- 29624142 TI - Leading with compassion in health care organisations. AB - Purpose The purpose of this paper is to report an evaluation of a leading-with compassion recognition scheme and to present a new framework for compassion derived from the data. Design/methodology/approach Qualitative semi-structured interviews, a focus group and thematic data analysis. Content analysis of 1,500 nominations of compassionate acts. Findings The scheme highlighted that compassion towards staff and patients was important. Links to the wider well being strategies of some of the ten organisations involved were unclear. Awareness of the scheme varied and it was introduced in different ways. Tensions included the extent to which compassion should be expected as part of normal practice and whether recognition was required, association of the scheme with the term leadership, and the risk of portraying compassion as something separate, rather than an integral part of the culture. A novel model of compassion was developed from the analysis of 1,500 nominations. Research limitations/implications The number of respondents in the evaluation phase was relatively low. The model of compassion contributes to the developing knowledge base in this area. Practical implications The model of compassion can be used to demonstrate what compassion "looks like", and what is expected of staff to work compassionately. Originality/value A unique model of compassion derived directly from descriptions of compassionate acts which identifies the impact of compassion on staff. PMID- 29624143 TI - Development and validation of health service management competencies. AB - Purpose The importance of managerial competencies in monitoring and improving the performance of organisational leaders and managers is well accepted. Different processes have been used to identify and develop competency frameworks or models for healthcare managers around the world to meet different contextual needs. The purpose of the paper is to introduce a validated process in management competency identification and development applied in Australia - a process leading to a management competency framework with associated behavioural items that can be used to measure core management competencies of health service managers. Design/methodology/approach The management competency framework development study incorporated both qualitative and quantitative methods, implemented in four stages, including job description analysis, focus group discussions and online surveys. Findings The study confirmed that the four-stage process could identify management competencies and the framework developed is considered reliable and valid for developing a management competency assessment tool that can measure management competence amongst managers in health organisations. In addition, supervisors of health service managers could use the framework to distinguish perceived superior and average performers among managers in health organisations. Practical implications Developing the core competencies of health service managers is important for management performance improvement and talent management. The six core management competencies identified can be used to guide the design professional development activities for health service managers. Originality/value The validated management competency identification and development process can be applied in other countries and different industrial contexts to identify core management competency requirements. PMID- 29624144 TI - Pilot study of intracranial venous physiology in craniosynostosis. AB - OBJECTIVE In addition to craniocerebral disproportion, other factors, such as Chiari malformation type I, obstructive sleep apnea, and venous outflow obstruction, are considered to have a role in the occurrence of intracranial hypertension in craniosynostosis. This pilot study examined cerebral venous flow velocity to better characterize the complex intracranial venous physiology of craniosynostosis. METHODS The authors performed a prospective cohort study of craniosynostosis patients (n = 34) referred to a single national (tertiary) craniofacial unit. Controls (n = 28) consisted of children who were referred to the unit's outpatient clinic and did not have craniosynostosis. Transfontanelle ultrasound scans with venous Doppler flow velocity assessment were performed at the first outpatient clinic visit and after each surgery, if applicable. Mean venous blood flow velocities of the internal cerebral vein (ICVv) and the superior sagittal sinus (SSSv) were recorded and blood flow waveform was scored. RESULTS Preoperatively, SSSv was decreased in craniosynostosis patients compared with controls (7.57 vs 11.31 cm/sec, p = 0.009). ICVv did not differ significantly between patients and controls. Postoperatively, SSSv increased significantly (7.99 vs 10.66 cm/sec, p = 0.023). Blood flow waveform analyses did not differ significantly between patients and controls. CONCLUSIONS Premature closure of cranial sutures was associated with decreased SSSv but not ICVv; indicating an effect on the superficial rather than deep venous drainage. Further Doppler ultrasound studies are needed to test the hypothesis that at an early stage of craniosynostosis pathology SSSv, but not pulsatility, is abnormal, and that abnormality in both SSSv and the superficial venous waveform reflect a more advanced stage of evolution in suture closure. PMID- 29624145 TI - Surgical decision-making in the management of childhood tumors of the CNS disseminated at presentation. AB - OBJECTIVE It is relatively unusual for pediatric CNS tumors to be disseminated at presentation, and the literature on the clinical features, management, and outcomes of this specific group is scarce. Surgical management in this population is often challenging, particularly in the presence of hydrocephalus. The authors present their recent experience of treating pediatric CNS tumors that were disseminated at presentation, and they compare these lesions with focal tumors. METHODS The authors performed a retrospective review of prospectively collected data on children presenting to a tertiary center between 2003 and 2016 inclusive. RESULTS Of 361 children with CNS tumors, the authors identified 53 patients with disease dissemination at presentation (male/female ratio 34:19, median age 3.8 years, age range 7 days to 15.6 years) and 308 without dissemination at presentation (male/female ratio 161:147, median age 5.8 years, age range 1 day to 16.9 years). Five tumor groups were studied: medulloblastoma (disseminated n = 29, focal n = 74), other primitive neuroectodermal tumor (n = 8, n = 17), atypical teratoid rhabdoid tumor (n = 8, n = 22), pilocytic astrocytoma (n = 6, n = 138), and ependymoma (n = 2, n = 57). The median follow-up duration in survivors was not significantly different between those with disease dissemination at presentation (64.0 months, range 5.2-152.0 months) and those without it (74.5 months, range 4.7-170.1 months) (p > 0.05). When combining data from all 5 tumor groups, dissemination status at presentation was significantly associated with a higher risk of requiring CSF diversion, a higher surgical complication rate, and a reduced likelihood of achieving gross-total resection of the targeted lesion (all variables p < 0.05). Differences between the 5 tumor groups were evident. No factors that predicted the need for permanent CSF diversion following temporary external ventricular drainage were identified on multivariate analysis, and there was no clear superiority of either ventriculoperitoneal shunt surgery or endoscopic third ventriculostomy as a permanent CSF diversion procedure. CONCLUSIONS Tumor type and dissemination status at initial presentation significantly affect outcomes across a range of measures. The management of hydrocephalus in patients with CNS tumors is challenging, and further prospective studies are required to identify the optimal CSF diversion strategy in this population. PMID- 29624146 TI - Posterior cerebral artery stenosis and posterior circulation revascularization surgery in pediatric patients with moyamoya disease. AB - OBJECTIVE Some pediatric patients with moyamoya disease (MMD) present with posterior cerebral artery (PCA) stenosis before and after anterior circulation revascularization surgery and require posterior circulation revascularization surgery. This study evaluated the factors associated with PCA stenosis and assessed the efficacy of posterior circulation revascularization surgery, including occipital artery (OA)-PCA bypass, in pediatric patients with MMD. METHODS The presence of PCA stenosis before and after anterior circulation revascularization surgery and its clinical characteristics were investigated in 62 pediatric patients (< 16 years of age) with MMD. RESULTS Twenty-three pediatric patients (37%) with MMD presented with PCA stenosis at the time of the initial diagnosis. A strong correlation between the presence of infarction and PCA stenosis before anterior revascularization was observed (p < 0.001). In addition, progressive PCA stenosis was observed in 12 patients (19.4%) after anterior revascularization. The presence of infarction and a younger age at the time of initial diagnosis were risk factors for progressive PCA stenosis after anterior revascularization (p < 0.001 and p = 0.002, respectively). Posterior circulation revascularization surgery, including OA-PCA bypass, was performed in 9 of the 12 patients with progressive PCA stenosis, all of whom showed symptomatic and/or radiological improvement. CONCLUSIONS PCA stenosis is an important clinical factor related to poor prognosis in pediatric MMD. One should be aware of the possibility of progressive PCA stenosis during the postoperative follow-up period and consider performing posterior circulation revascularization surgery. PMID- 29624147 TI - Risk factors for surgical site infection after intracranial electroencephalography monitoring for epilepsy in the pediatric population. AB - OBJECTIVE Intracranial electroencephalography (iEEG) monitoring is an important method of identifying the seizure focus in patients with medically refractory epilepsy. While previous studies have demonstrated low rates of surgical complications, reported rates of surgical site infection (SSI) are highly variable. To date, no studies have specifically evaluated the patient or operative risk factors contributing to SSI. The goals of this study were to examine the rate of SSI after iEEG monitoring for epilepsy workup in pediatric patients and to determine the variables that might contribute to the development of SSI. METHODS A retrospective analysis of hospital charts at the Hospital for Sick Children was performed for all patients who had undergone iEEG monitoring between 2000 and 2016. Univariate and multivariate analyses were performed to look for statistically significant variables in relation to SSI. RESULTS Among 199 patients eligible for analysis, 8 (4.0%) developed SSIs within a period ranging from 21 to 51 days postoperatively. Univariate analysis yielded 4 factors related to SSI: number of people present in the operating room on electrode insertion (p = 0.02), length of insertion surgery (p = 0.04), previous operation at the same surgical site (p = 0.04), and number of depth electrodes inserted (p = 0.01). Multivariate analysis revealed that both the number of people present during the implant operation (OR 0.08, 95% CI 0.01-0.70) and the number of depth electrodes inserted (OR 3.52, 95% CI 1.44-8.59) independently contributed to SSI. CONCLUSIONS This is the largest case series and the first comprehensive review of both patient and operative risk factors in the development of SSI from iEEG monitoring in a pediatric population. The authors' institution had a lower rate of infection than those in most other studies, which could be explained by their protocol of administering intravenous antibiotics perioperatively and post implant removal antibiotics for 14 days. The authors found a correlation between SSI and the number of people present during the implant operation, as well as the number of depth electrodes; both may contribute to breaks in sterility. PMID- 29624148 TI - Reliability of MRI for predicting characteristics of neurovascular conflicts in trigeminal neuralgia: implications for surgical decision making. AB - OBJECTIVE The choice of microvascular decompression (MVD), among the several other surgical options, for treating refractory classical trigeminal neuralgia (TN) relies mostly on preoperative imaging, but the degree of reliability of MRI remains a matter of debate. The authors approached the question of predictability of neurovascular conflict (NVC) in a series of 100 protocolized MRI studies from patients with TN who underwent MVD, by reexamination of MR images, blinded to the clinical data and surgical findings, including the side of the neuralgia. METHODS Patients included in the study were those who underwent MVD after surgical indication had been determined based on a protocolized imagery workup (3D high resolution T2-weighted cisternography centered on the trigeminal nerve, 3D time of-flight angiography, and 3D gadolinium-enhanced T1-weighted imaging) performed at our institution. All MR images were blindly reexamined, and neurovascular relationships were described on both sides, noting the existence of compression, vessels involved, situation along the root, and degree of compression. The results of MRI evaluation were then compared with actual surgical findings. The extent of agreement and quality of the prediction were expressed with Cohen's kappa coefficient (kappa) and receiver operating characteristic (ROC) statistics. RESULTS A conflict had actually been found during surgery in 94 of 100 patients. The sensitivity of MRI to detect a conflict was 97% and the specificity was 50%. Vessel type was identified with high reliability (kappa = 0.80), while the grade of the conflict and its situation along the root showed poor to average reliability (kappa = 0.38 and kappa = 0.40, respectively). The area under the ROC curve for predicting the presence of a conflict according to the grades of conflict seen on MRI was 0.93, which is considered very good. The positive predictive value was differentiated according to the grade of conflict, with a very high value for high grades of vascular conflict. CONCLUSIONS This study shows an overall good reliability of MRI to predict the existence of an NVC. The prediction value is excellent for high grades of compression. Some apparent low grade compressions on MRI may be revealed as false positives in surgical exploration. This raises the question of what other imaging methods might be used to determine not only the existence of a conflict but also its degree of compression. The degree of compression is of paramount importance to predict the probability of long-term pain relief, and therefore in the decision to propose MVD as the first choice of surgical treatment. PMID- 29624149 TI - Detection rates and sites of unruptured intracranial aneurysms according to sex and age: an analysis of MR angiography-based brain examinations of 4070 healthy Japanese adults. AB - OBJECTIVE The purpose of this study was to evaluate the detection rate and occurrence site according to patient sex and age of unruptured intracranial aneurysms detected through MRI and MR angiography (MRA). METHODS A total of 4070 healthy adults 22 years or older (mean age [+/- SD] 50.6 +/- 11.0 years; 41.9% women) who underwent a brain examination known as "Brain Dock" in the central Tokyo area between April 2014 and March 2015 were checked for unruptured saccular aneurysm using 3-T MRI/MRA. The following types of cases were excluded: 1) protrusions with a maximum diameter < 2 mm at locations other than arterial bifurcations, 2) conical protrusions at arterial bifurcations with a diameter < 3 mm, and 3) cases of suspected aneurysms with unclear imaging of the involved artery. When an aneurysm was definitively diagnosed, the case was included in the aneurysm group. The authors also investigated the relationship between aneurysm occurrence and risk factors (age, sex, smoking history, hypertension, diabetes, and hyperlipidemia). RESULTS One hundred eighty-eight aneurysms were identified in 176 individuals (detection rate 4.32%), with the detection rate for women being significantly higher (6.2% vs 3.0%, p < 0.001). The average age in the aneurysm group was significantly higher than in the patients in whom aneurysms were not detected (53.0 +/- 11.1 vs 50.5 +/- 11.0 years). The detection rate tended to increase with age. The detection rates were 3.6% for people in their 30s, 3.5% for those in their 40s, 4.1% for those in their 50s, 6.9% for those in their 60s, and 6.8% for those in their 70s. Excluding persons in their 20s and 80s-age groups in which no aneurysms were discovered-the detection rate in women was higher in all age ranges. Of the individuals with aneurysms, 12 (6.81%) had multiple cerebral aneurysms; no sex difference was observed with respect to the prevalence of multiple aneurysms. Regarding aneurysm size, 2.0-2.9 mm was the most common size range, with 87 occurrences (46.3%), followed by 3.0-3.9 mm (67 [35.6%]) and 4.0-4.9 mm (20 [10.6%]). The largest aneurysm was 13 mm. Regarding location, the internal carotid artery (ICA) was the most common aneurysm site, with 148 (78.7%) occurrences. Within the ICA, C1 was the site of 46 aneurysms (24.5%); C2, 57 (30.3%); and C3, 29 (15.4%). The aneurysm detection rates for C2, C3, and C4 were 2.23%, 1.23%, and 0.64%, respectively, for women and 0.68%, 0.34%, and 0.21%, respectively, for men; ICA aneurysms were significantly more common in women than in men (5.27% vs 2.20%, p < 0.001). Multivariate logistic regression analysis revealed that age (p < 0.001, OR 1.03, 95% CI 1.01-1.04), female sex (p < 0.001, OR 2.28, 95% CI 1.64-3.16), and smoking history (p = 0.011, OR 1.52, 95% CI 1.10-2.11) were significant risk factors for aneurysm occurrence CONCLUSIONS In this study, both female sex and older age were independently associated with an increased aneurysm detection rate. Aneurysms were most common in the ICA, and the frequency of aneurysms in ICA sites was markedly higher in women. PMID- 29624150 TI - Frequency and characteristics associated with inherited thrombophilia in patients with intracranial dural arteriovenous fistula. AB - OBJECTIVE The pathogenesis of dural arteriovenous fistulas (DAVFs) remains poorly defined. Prior studies on thrombophilia as a risk factor for DAVF development are limited by small sample sizes and poor generalizability. METHODS In this longitudinal observational study, all patients with intracranial DAVFs evaluated at the University of California, San Francisco from December 1994 through April 2014 were identified. After obtaining patient consent, 3 thrombophilic mutations, factor V Leiden (rs6025), MTHFR (rs1801133), and prothrombin G20210A, were genotyped. The authors evaluated the association of thrombophilia status (presence of any thrombophilic mutation) and clinical and angiographic characteristics using either a 2-sample t-test or Fisher's exact test. RESULTS A total of 116 patients with diagnosed intracranial DAVFs were included in the study. Twenty-five (22%) patients met criteria for thrombophilia. Focal neurological deficits tended to occur more frequently in the thrombophilia group (78% vs 57%, p = 0.09). Angiographic characteristics of DAVFs, including high risk venous flow pattern, multiplicity of DAVF, and the presence of venous sinus thrombosis, did not differ significantly between the 2 groups but tended to be more common in the thrombophilic than in the nonthrombophilic group. CONCLUSIONS This study is one of the largest of thrombophilia and DAVF to date. The frequency of mutations associated with thrombophilia in this study was higher than that in the general population. PMID- 29624151 TI - Histopathological features predictive of local control of atypical meningioma after surgery and adjuvant radiotherapy. AB - OBJECTIVE The goal of this study was to investigate the impact of adjuvant radiotherapy (RT) on local recurrence and overall survival in patients undergoing primary resection of atypical meningioma, and to identify predictive factors to inform patient selection for adjuvant RT. METHODS One hundred eighty-two patients who underwent primary resection of atypical meningioma at a single institution between 1993 and 2014 were retrospectively identified. Patient, meningioma, and treatment data were extracted from the medical record and compared using the Kaplan-Meier method, log-rank tests, multivariate analysis (MVA) Cox proportional hazards models with relative risk (RR), and recursive partitioning analysis. RESULTS The median patient age and imaging follow-up were 57 years (interquartile range [IQR] 45-67 years) and 4.4 years (IQR 1.8-7.5 years), respectively. Gross total resection (GTR) was achieved in 114 cases (63%), and 42 patients (23%) received adjuvant RT. On MVA, prognostic factors for death from any cause included GTR (RR 0.4, 95% CI 0.1-0.9, p = 0.02) and MIB1 labeling index (LI) <= 7% (RR 0.4, 95% CI 0.1-0.9, p = 0.04). Prognostic factors on MVA for local progression included GTR (RR 0.2, 95% CI 0.1-0.5, p = 0.002), adjuvant RT (RR 0.2, 95% CI 0.1-0.4, p < 0.001), MIB1 LI <= 7% (RR 0.2, 95% CI 0.1-0.5, p < 0.001), and a remote history of prior cranial RT (RR 5.7, 95% CI 1.3-18.8, p = 0.03). After GTR, adjuvant RT (0 of 10 meningiomas recurred, p = 0.01) and MIB1 LI <= 7% (RR 0.1, 95% CI 0.003-0.3, p < 0.001) were predictive for local progression on MVA. After GTR, 2.2% of meningiomas with MIB1 LI <= 7% recurred (1 of 45), compared with 38% with MIB1 LI > 7% (13 of 34; p < 0.001). Recursive partitioning analysis confirmed the existence of a cohort of patients at high risk of local progression after GTR without adjuvant RT, with MIB1 LI > 7%, and evidence of brain or bone invasion. After subtotal resection, adjuvant RT (RR 0.2, 95% CI 0.04-0.7, p = 0.009) and <= 5 mitoses per 10 hpf (RR 0.1, 95% CI 0.03 0.4, p = 0.002) were predictive on MVA for local progression. CONCLUSIONS Adjuvant RT improves local control of atypical meningioma irrespective of extent of resection. Although independent validation is required, the authors' results suggest that MIB1 LI, the number of mitoses per 10 hpf, and brain or bone invasion may be useful guides to the selection of patients who are most likely to benefit from adjuvant RT after resection of atypical meningioma. PMID- 29624152 TI - Barriers to participation in global surgery academic collaborations, and possible solutions: a qualitative study. AB - OBJECTIVE There is a global lack of access to surgical care, and this issue disproportionately affects those in low- and middle-income countries. Global surgery academic collaborations (GSACs) between surgeons in high-income countries and those in low- and middle-income countries are one possible sustainable way to address the global surgical need. The objective of this study was to examine the barriers to participation in GSACs and to suggest ways to increase involvement. METHODS A convenience sample of 86 surgeons, anesthesiologists, other physicians, residents, fellows, and nurses from the US, Canada, and Norway was used. Participants were all health care providers from multiple specialties and multiple academic centers with varied involvement in GSACs. More than half of the participants were neurosurgeons. Participants were interviewed in person or over Skype in Toronto over the course of 2 months by using a predetermined set of open ended questions. Thematic content analysis was used to evaluate the participants' responses. RESULTS Based on the data, 3 main themes arose that pointed to individual, community, and system barriers for involvement in GSACs. Individual barriers included loss of income, family commitments, young career, responsibility to local patients, skepticism of global surgery efforts, ethical concerns, and safety concerns. Community barriers included insufficient mentorship and lack of support from colleagues. System barriers included lack of time, minimal academic recognition, insufficient awareness, insufficient administrative support and organization, and low political and funding support. CONCLUSIONS Steps can be taken to address some of these barriers and to increase the involvement of surgeons from high-income countries in GSACs. This could lead to a necessary scale-up of global surgery efforts that may help increase worldwide access to surgical care. PMID- 29624153 TI - Occlusion rates of intracranial aneurysms treated with the Pipeline embolization device: the role of branches arising from the sac. AB - OBJECTIVE The aim of this study was to compare the clinical and angiographic outcomes of intracranial aneurysms with and without branches arising from the sac after Pipeline embolization device (PED) treatment. METHODS This retrospective 2 center comparative study included 116 patients with 157 aneurysms that were treated with PEDs. Aneurysms were divided into 2 groups: one group had branches arising from the sac and the other group did not. Study end points included total aneurysm occlusion assessed by angiography at 6 and 12 months, death or stroke, technical complications, in-stent stenosis, patency of covered branches, and transient ischemia. RESULTS One hundred fifty-one aneurysms (96%) were located in the internal carotid artery. A branch arising from the sac was observed in 26 aneurysms. Complete occlusion was found in 120 of 156 aneurysms at 6 months (76.92% [95% CI 69.71%-82.84%]) and in 136 of 155 aneurysms at 12 months (87.74% [95% CI 81.28%-92.27%]). Total occlusion was more frequently observed in the group without a branch arising from the sac (84% vs 40% at 6 months, p < 0.001; 93.10% vs 60% at 1 year, p < 0.001). There were 4 (3.45% [95% CI 1.11%-9.12%]) cases of death or major stroke. Amaurosis fugax occurred in 3 patients. One patient experienced worsening of mass effect after treatment. No occlusion of branches arising from the aneurysm was observed. In-stent stenosis greater than 50% was observed in 1 case. CONCLUSIONS Aneurysms treated with PEDs are less likely to be totally occluded if they have a branch arising from the sac than are aneurysms without these branches. PMID- 29624154 TI - The diagnostic accuracy of detecting malignant transformation of low-grade glioma using O-(2-[18F]fluoroethyl)-l-tyrosine positron emission tomography: a retrospective study. AB - OBJECTIVE The diagnostic accuracy of O-(2-[18F]fluoroethyl)-l-tyrosine (FET) PET scanning in detecting the malignant transformation of low-grade gliomas (LGGs) is controversial. In this study, the authors retrospectively assessed the diagnostic potential of FET PET in patients with MRI-suspected malignant progression of LGGs that had previously been treated and the relationship between FET uptake and MRI and molecular biomarkers. METHODS Forty-two patients who had previously undergone surgical or multimodal treatment for a histologically verified LGG were referred for FET PET assessment because of clinical signs and/or MRI findings suggestive of tumor progression. Maximal and mean tumor-to-brain ratios (TBRmax and TBRmean, respectively) on FET PET as well as kinetic FET PET parameters (time to peak [TTP] and time-activity curve [TAC]) were determined. Final diagnoses were confirmed histologically. The diagnostic accuracy of FET parameters, separately and combined, for the detection of malignant progression was evaluated using receiver operating characteristic (ROC) curve analysis. Possible predictors that might influence the diagnostic accuracy of FET PET were assessed using multiple linear regression analysis. Spearman's rank correlation r method was applied to determine the correlation between TBRmax and TAC, and molecular biomarkers from tumor tissues. RESULTS A total of 47 FET PET scans were obtained and showed no significant association between FET parameters and contrast enhancement on MRI. ROC curve analyses overall were unable to demonstrate any significant differentiation between nontransformed LGGs and LGGs that had transformed to high grade gliomas when evaluating FET parameters separately or combined. After excluding the oligodendroglial subgroup, a significant difference was observed between nontransformed and transformed LGGs when combining FET parameters (i.e., TBRmax > 1.6, TAC describing a plateau or decreasing pattern, and TTP < 25 minutes), with the best result yielded by a combined analysis of TBRmax > 1.6 and TAC with a plateau or decreasing pattern (sensitivity 75% and specificity 83%, p = 0.003). The difference was even greater when patients who had previously undergone oncological treatment were also excluded (sensitivity 93% and specificity 100%, p = 0.001). Multiple linear regression analysis revealed that the presence of an oligodendroglial component (p = 0.029), previous oncological treatment (p = 0.039), and the combined FET parameters (p = 0.027) were significant confounding factors in the detection of malignant progression. TBRmax was positively correlated with increasing cell density (p = 0.040) and inversely correlated with IDH1 mutation (p = 0.006). CONCLUSIONS A single FET PET scan obtained at the time of radiological and/or clinical progression seems to be of limited value in distinguishing transformed from nontransformed LGGs, especially if knowledge of the primary tumor histopathology is not known. Therefore, FET PET imaging alone is not adequate to replace histological confirmation, but it may provide valuable information on the location and delineation of active tumor tissue, as well as an assessment of tumor biology in a subgroup of LGGs. PMID- 29624155 TI - Preface. PMID- 29624156 TI - Letter to the Editor: International Consensus Radiochemistry Nomenclature Guidelines. PMID- 29624157 TI - Editorial: A Possible Chemo-biodescriptor Framework for the Prediction of Toxicity of Nanosubstances: An Integrated Computational Approach. PMID- 29624158 TI - Editorial: Beware of Naive q2, use True q2: Some Comments on QSAR Model Building and Cross Validation. PMID- 29624159 TI - Occurrence of IMP-1 in non-baumannii Acinetobacter clinical isolates from Brazil. AB - The aim of this study was to characterize the presence of carbapenemase-encoding genes in distinct species of Acinetobacter spp. isolated from Brazilian hospitals. Five carbapenem-resistant Acinetobacter spp. isolates (two Acinetobacter pittii, two Acinetobacter bereziniae and one Acinetobacter junii) recovered from two distinct hospitals between 2000 and 2016 were included in this study. All of the isolates harboured blaIMP-1, which was inserted into In86, a class 1 integron. Pulsed field gel eletrophoresis analysis showed that both A. pittii were identical, while the two A. berezinae isolates were considered to be clonally related. In this study, we demonstrated that mobile elements carrying carbapenemase-encoding genes such as In86 may persist for a long period, allowing their mobilization from A. baumannii to other Acinetobacter spp. that are usually susceptible to multiple antimicrobials. PMID- 29624160 TI - Tabrizicola fusiformis sp. nov., isolated from an industrial wastewater treatment plant. AB - The translucent white-coloured, Gram-stain-negative, aerobic, non-motile, fusiform-shaped bacterium (designated strain SY72T) was isolated from waste activated sludge. Optimal growth occurred at 30-37 degrees C and pH 6.0-7.0. Phylogenetic analysis based on the 16S rRNA gene sequences revealed that the novel isolate belonged to the family Rhodobacteraceae of the class Alphaproteobacteria. Strain SY72T is closely related to Tabrizicola aquatica KCTC 23724T (97.8 % 16S rRNA gene sequence similarity) and Pseudorhodobacter aquaticus DC2N1-10T (96.4 %), respectively. DNA-DNA relatedness between strain SY72T and the closest phylogenetically related strain, Tabrizicola aquatica KCTC 23724T, was 18.0+/-0.7 %. In strain SY72T, the predominant respiratory quinone was ubiquinone Q-10, and the cellular fatty acids consisted mainly of C18 : 1omega7c and C18 : 1omega7c-11 methyl. The major polar lipids were phosphatidylcholine, phosphatidylglycerol, diphosphatidylglycerol and phosphatidylethanolamine. Photoautotrophic and photoheterotrophic growth did not occur in strain SY72T. Furthermore, strain SY72T did not produce photosynthetic pigments or contain the photosynthetic genes pufL and pufM, by which it differed from the phototrophic species of the family Rhodobacteraceae. On the basis of distinct phenotypic and phylogenetic properties, strain SY72T represents a novel species of the genus Tabrizicola, for which the name Tabrizicola fusiformis sp. nov. is proposed. The type strain is SY72T (=KCTC 62105T=NBRC 113021T). PMID- 29624161 TI - E5 can be expressed in anal cancer and leads to epidermal growth factor receptor induced invasion in a human papillomavirus 16-transformed anal epithelial cell line. AB - We detected the first human papillomavirus (HPV)-16-immortalized anal epithelial cell line, known as AKC2 cells to establish an in vitro model of HPV-16-induced anal carcinogenesis. Consistent with detection of E6, E7 and E5 expression in anal cancer biopsies, AKC2 cells expressed high levels of all three HPV oncogenes. Also, similar to findings in anal cancer biopsies, epidermal growth factor receptor (EGFR) was overexpressed in AKC2 cells. AKC2 cells exhibited a poorly differentiated and invasive phenotype in three-dimensional raft culture and inhibition of EGFR function abrogated AKC2 invasion. Reducing E5 expression using E5-targeted siRNAs in AKC2 cells led to knockdown of E5 expression, but also HPV-16 E2, E6 and E7 expression. AKC2 cells treated with E5-targeted siRNA had reduced levels of total and phosphorylated EGFR, and reduced invasion. Rescue of E6/E7 expression with simultaneous E5 knockdown confirmed that E5 plays a key role in EGFR overexpression and EGFR-induced invasion. PMID- 29624163 TI - RelA/DTD-mediated regulation of spore formation and toxin production by Clostridium perfringens type A strain SM101. AB - RelA is a global regulator for stationary phase development in the model bacterium Bacillus subtilis. The relA gene forms a bicistronic operon with the downstream dtd gene. In this study, we evaluated the significance of RelA and DTD proteins in spore formation and toxin production by an important gastrointestinal pathogen Clostridium perfringens. Our beta-glucuronidase assay showed that in C. perfringens strain SM101, relA forms a bicistronic operon with its downstream dtd gene, and the relA promoter is expressed during both vegetative and sporulation conditions. By constructing double relA dtd and single dtd mutants in C. perfringens SM101, we found that: (1) RelA is required for maintaining the efficient growth capacity of SM101 cells during vegetative conditions; (2) both RelA and DTD are required for spore formation and enterotoxin (CPE) production by SM101; (3) RelA/DTD activate CodY, which is known to activate spore formation and CPE production in SM101 by activating a key sporulation-specific sigma factor F; (4) as expected, RelA/DTD activate sporulation-specific sigma factors (sigmaE, sigmaF, sigmaG and sigmaK) by positively regulating Spo0A production; and finally (5) RelA, but not DTD, negatively regulates phospholipase C (PLC) production by repressing plc gene expression. Collectively, our results demonstrate that RelA modulates cellular physiology such as growth, spore formation and toxin production by C. perfringens type A strain SM101, although DTD also plays a role in these pleiotropic functions in coordination with RelA during sporulation. These findings have implications for the understanding of the mechanisms involved in the infectious cycle of C. perfringens. PMID- 29624162 TI - Streptomyces boninensis sp. nov., isolated from soil from a limestone cave in the Ogasawara Islands. AB - Actinomycete strain K11-0400T was isolated from a soil sample collected in the Ogasawara Islands (also known as the Bonin Islands), Tokyo, Japan. Mature spore chains of strain K11-0400T had more than 20 spores per chain. The strain contained ll-diaminopimelic acid as the diamino acid in whole-cell hydrolysates, and MK-9(H6) and MK-9(H4) were the predominant menaquinones. The polar lipids were phosphatidylethanolamine, diphosphatidylglycerol and phosphatidylinositol, and no diagnostic whole-cell sugar was detected. The G+C content of the genomic DNA was 72 mol%. These morphological and chemical features of strain K11-0400T indicated that it belonged to the genus Streptomyces. Strain K11-0400T showed the highest 16S rRNA gene sequence similarity to Streptomyces naganishii NBRC 12892T (97.58 %). However, the DNA-DNA relatedness value between strain K11-0400T and the related strain was below 70 %. Based on morphological, cultural and physiological characteristics, and DNA-DNA relatedness data, strain K11-0400T should be classified as a new species of the genus Streptomyces, for which the name Streptomyces boninensis sp. nov. is proposed. The type strain of S. boninensis is K11-0400T (=NBRC 113073T, TBRC 7755T). PMID- 29624165 TI - Bombyx mori nucleopolyhedrovirus orf133 and orf134 are involved in the embedding of occlusion-derived viruses into polyhedra. AB - Bombyx mori nucleopolyhedrovirus (BmNPV) orf133 (bm133) and orf134 (bm134), the orthologues of Autographa californica multiple nucleopolyhedrovirus (AcMNPV) ac4 and ac5, are two adjacent genes with opposite transcriptional orientations and are highly conserved in all sequenced group I nucleopolyhedroviruses (NPVs). A double bm133-bm134 knockout bacmid was generated to enable the functional study of each gene independently or together. Compared with wild-type and double-repair viruses, deletion of both bm133 and bm134 did not affect budded virus (BV) production or viral DNA replication in transfected BmN cells. Electron microscopy revealed that the double knockout did not affect nucleocapsid assembly, virus induced intranuclear microvesicle formation or occlusion-derived virus (ODV) production, but the number of virions embedded in the polyhedra decreased significantly. Further investigations showed that disruption of either gene was unable to recover the defect of ODV occlusion, suggesting that Bm133 and Bm134 are indispensable to the embedding of ODVs into polyhedra. Confocal microscopy analysis showed that Bm133 and Bm134 distributed throughout the whole cell during viral infection and Bm134 concentrated on the mature polyhedra in lysed cells. These results suggest that although Bm133 and Bm134 are not essential for BV or ODV development, they play vital roles in polyhedra morphogenesis. PMID- 29624164 TI - Campylobacter blaseri sp. nov., isolated from common seals (Phoca vitulina). AB - During a study to assess the faecal microbiome of common seals (Phoca vitulina) in a Dutch seal rehabilitation centre, 16S rRNA gene sequences of an unknown Campylobacter taxon were identified. Campylobacter isolates, which differed from the established Campylobacter taxa, were cultured and their taxonomic position was determined by a polyphasic study based on ten isolates. The isolates were characterized by 16S rRNA and atpA gene sequence analyses and by conventional phenotypic testing. Based on the whole genome sequences, the average nucleotide identity and core genome phylogeny were determined. The isolates formed a separate phylogenetic clade, divergent from all other Campylobacter taxa and most closely related to Campylobacter corcagiensis, Campylobacter geochelonis and Campylobacter ureolyticus. The isolates can be distinguished phenotypically from all other Campylobacter taxa based on their lack of motility, growth at 25 degrees C and growth on MacConkey agar. This study shows that these isolates represent a novel species within the genus Campylobacter, for which the name Campylobacter blaseri sp. nov. is proposed. The type strain for this novel species is 17S00004-5T (=LMG 30333T=CCUG 71276T). PMID- 29624166 TI - Addressing the diversity of the honeybee gut symbiont Gilliamella: description of Gilliamella apis sp. nov., isolated from the gut of honeybees (Apis mellifera). AB - The gut microbiota of honeybees (Apis) and bumblebees (Bombus) include the symbiotic bacterial genus Gilliamella. This genus shows a high degree of functional and genomic diversity and separates into distinct lineages. Gilliamella apicola wkB1T, which was isolated from Apis, was the first species to be described. Recently four new species, isolated from Bombus, were identified. In this paper, we compare several genomes/strains from previous studies spanning this diversity, which gives insight into the phylogenetic relationship among different Gilliamella species. We show that one lineage, isolated only from Apis, is different from other gilliamellas described, based on average nucleotide identity calculation (about 80 %) and phenotypic characterizations. We propose the new species name for this lineage: Gilliamella apis sp. nov. We present the characterization of the type strain NO3T (=DSM 105629T=LMG 30293T), a strain isolated from the Western honeybee Apis mellifera, which clusters within this lineage. Cells of strain NO3T grow best in a microaerophilic atmosphere with enhanced CO2 levels at 36 degrees C and pH 7.0-7.5. Cells also grow well in anaerobic conditions, but not in aerobic conditions. Cells are approximately 1 um in length and rod-shaped, and the genomic G+C content is 34.7 mol%. Differential characteristics between strain NO3T and the different type strains of Gilliamella were revealed based on API kit tests and genomic content comparisons. The main respiratory quinone of strain NO3T was ubiquinone-8, and the predominant fatty acids were C18 : 1omega7c/C18 : 1omega6c, C16 : 0, consistent with the genus Gilliamella. PMID- 29624167 TI - Proteasome storage granules protect proteasomes from autophagic degradation upon carbon starvation. AB - 26S proteasome abundance is tightly regulated at multiple levels, including the elimination of excess or inactive particles by autophagy. In yeast, this proteaphagy occurs upon nitrogen starvation but not carbon starvation, which instead stimulates the rapid sequestration of proteasomes into cytoplasmic puncta termed proteasome storage granules (PSGs). Here, we show that PSGs help protect proteasomes from autophagic degradation. Both the core protease and regulatory particle sub-complexes are sequestered separately into PSGs via pathways dependent on the accessory proteins Blm10 and Spg5, respectively. Modulating PSG formation, either by perturbing cellular energy status or pH, or by genetically eliminating factors required for granule assembly, not only influences the rate of proteasome degradation, but also impacts cell viability upon recovery from carbon starvation. PSG formation and concomitant protection against proteaphagy also occurs in Arabidopsis, suggesting that PSGs represent an evolutionarily conserved cache of proteasomes that can be rapidly re-mobilized based on energy availability. PMID- 29624168 TI - Age-related islet inflammation marks the proliferative decline of pancreatic beta cells in zebrafish. AB - The pancreatic islet, a cellular community harboring the insulin-producing beta cells, is known to undergo age-related alterations. However, only a handful of signals associated with aging have been identified. By comparing beta-cells from younger and older zebrafish, here we show that the aging islets exhibit signs of chronic inflammation. These include recruitment of tnfalpha-expressing macrophages and the activation of NF-kB signaling in beta-cells. Using a transgenic reporter, we show that NF-kB activity is undetectable in juvenile beta cells, whereas cells from older fish exhibit heterogeneous NF-kB activity. We link this heterogeneity to differences in gene expression and proliferation. Beta cells with high NF-kB signaling proliferate significantly less compared to their neighbors with low activity. The NF-kB signalinghi cells also exhibit premature upregulation of socs2, an age-related gene that inhibits beta-cell proliferation. Together, our results show that NF-kB activity marks the asynchronous decline in beta-cell proliferation with advancing age. PMID- 29624171 TI - The humble case report: bottom of the evidence-based medical pyramid or the foundation of clinical research? PMID- 29624169 TI - A comprehensive and quantitative exploration of thousands of viral genomes. AB - The complete assembly of viral genomes from metagenomic datasets (short genomic sequences gathered from environmental samples) has proven to be challenging, so there are significant blind spots when we view viral genomes through the lens of metagenomics. One approach to overcoming this problem is to leverage the thousands of complete viral genomes that are publicly available. Here we describe our efforts to assemble a comprehensive resource that provides a quantitative snapshot of viral genomic trends - such as gene density, noncoding percentage, and abundances of functional gene categories - across thousands of viral genomes. We have also developed a coarse-grained method for visualizing viral genome organization for hundreds of genomes at once, and have explored the extent of the overlap between bacterial and bacteriophage gene pools. Existing viral classification systems were developed prior to the sequencing era, so we present our analysis in a way that allows us to assess the utility of the different classification systems for capturing genomic trends. PMID- 29624172 TI - Mechanical circulatory support: the last resort in cardiogenic shock? PMID- 29624170 TI - Segmentation of the zebrafish axial skeleton relies on notochord sheath cells and not on the segmentation clock. AB - Segmentation of the axial skeleton in amniotes depends on the segmentation clock, which patterns the paraxial mesoderm and the sclerotome. While the segmentation clock clearly operates in teleosts, the role of the sclerotome in establishing the axial skeleton is unclear. We severely disrupt zebrafish paraxial segmentation, yet observe a largely normal segmentation process of the chordacentra. We demonstrate that axial entpd5+ notochord sheath cells are responsible for chordacentrum mineralization, and serve as a marker for axial segmentation. While autonomous within the notochord sheath, entpd5 expression and centrum formation show some plasticity and can respond to myotome pattern. These observations reveal for the first time the dynamics of notochord segmentation in a teleost, and are consistent with an autonomous patterning mechanism that is influenced, but not determined by adjacent paraxial mesoderm. This behavior is not consistent with a clock-type mechanism in the notochord. PMID- 29624173 TI - Closing congenital vascular connections: the novel and the traditional... both at risk of developing ventricular dysfunction? PMID- 29624174 TI - Shining light on calcified lesions, plaque stabilisation and physiologic significance: new insights from intracoronary OCT. PMID- 29624175 TI - Is it time for national systems of care for valvular heart disease? PMID- 29624176 TI - Genital mucosal melanoma with somatic SF3B1 R625C mutation. PMID- 29624177 TI - A case of red lunulae after haematopoietic stem cell transplantation. PMID- 29624178 TI - Correlation of T cell and IL-17+ cell subsets in lesional skin of different subtypes of psoriasis. PMID- 29624179 TI - Tolerance of methotrexate in a daily practice cohort of adults with atopic dermatitis. PMID- 29624180 TI - Unilateral abdominal clonic seizures of parietal lobe origin: EEG findings. AB - Unilateral abdominal clonic seizures represent a peculiar and rare manifestation of focal onset epilepsy. We present the case of a 26-year-old man with right sided abdominal clonic movements associated with seizures arising from the left parietal area. We show the ictal EEG correlates of these events, including source localization of early ictal spikes; findings that have not been demonstrated in previously reported cases. The electro-clinical features in this patient suggested that clinical onset occurred after anterior propagation of ictal activity from a region posterior to the neck and trunk area of the sensory homunculus of the postcentral gyrus. [Published with video sequence on www.epilepticdisorders.com]. PMID- 29624181 TI - Identification of gene regulation models from single-cell data. AB - In quantitative analyses of biological processes, one may use many different scales of models (e.g. spatial or non-spatial, deterministic or stochastic, time varying or at steady-state) or many different approaches to match models to experimental data (e.g. model fitting or parameter uncertainty/sloppiness quantification with different experiment designs). These different analyses can lead to surprisingly different results, even when applied to the same data and the same model. We use a simplified gene regulation model to illustrate many of these concerns, especially for ODE analyses of deterministic processes, chemical master equation and finite state projection analyses of heterogeneous processes, and stochastic simulations. For each analysis, we employ Matlab and Python software to consider a time-dependent input signal (e.g. a kinase nuclear translocation) and several model hypotheses, along with simulated single-cell data. We illustrate different approaches (e.g. deterministic and stochastic) to identify the mechanisms and parameters of the same model from the same simulated data. For each approach, we explore how uncertainty in parameter space varies with respect to the chosen analysis approach or specific experiment design. We conclude with a discussion of how our simulated results relate to the integration of experimental and computational investigations to explore signal-activated gene expression models in yeast (Neuert et al 2013 Science 339 584-7) and human cells (Senecal et al 2014 Cell Rep. 8 75-83)5. PMID- 29624182 TI - Morphology and dynamics of tumor cell colonies propagating in epidermal growth factor supplemented media. AB - The epidermal growth factor (EGF) plays a key role in physiological and pathological processes. This work reports on the influence of EGF concentration (c EGF) on the modulation of individual cell phenotype and cell colony kinetics with the aim of perturbing the colony front roughness fluctuations. For this purpose, HeLa cell colonies that remain confluent along the whole expansion process with initial quasi-radial geometry and different initial cell populations, as well as colonies with initial quasi-linear geometry and large cell population, are employed. Cell size and morphology as well as its adhesive characteristics depend on c EGF. Quasi-radial colonies (QRC) expansion kinetics in EGF-containing medium exhibits a complex behavior. Namely, at the first stages of growth, the average QRC radius evolution can be described by a t 1/2 diffusion term coupled with exponential growth kinetics up to a critical time, and afterwards a growth regime approaching constant velocity. The extension of each regime depends on c EGF and colony history. In the presence of EGF, the initial expansion of quasi-linear colonies (QLCs) also exhibits morphological changes at both the cell and the colony levels. In these cases, the cell density at the colony border region becomes smaller than in the absence of EGF and consequently, the extension of the effective rim where cell duplication and motility contribute to the colony expansion increases. QLC front displacement velocity increases with c EGF up to a maximum value in the 2-10 ng ml-1 range. Individual cell velocity is increased by EGF, and an enhancement in both the persistence and the ballistic characteristics of cell trajectories can be distinguished. For an intermediate c EGF, collective cell displacements contribute to the roughening of the colony contours. This global dynamics becomes compatible with the standard Kardar-Parisi Zhang growth model, although a faster colony roughness saturation in EGF containing medium than in the control medium is observed. PMID- 29624183 TI - Comparative study of the compensated semi-metals LaBi and LuBi: a first principles approach. AB - We have investigated the electronic structures of LaBi and LuBi, employing the full-potential all electron method as implemented in Wien2k. Using this, we have studied in detail both the bulk and the surface states of these materials. From our band structure calculations we find that LuBi, like LaBi, is a compensated semi-metal with almost equal and sizable electron and hole pockets. In analogy with experimental evidence in LaBi, we thus predict that LuBi will also be a candidate for extremely large magneto-resistance (XMR), which should be of immense technological interest. Our calculations reveal that LaBi, despite being gapless in the bulk spectrum, displays the characteristic features of a [Formula: see text] topological semi-metal, resulting in gapless Dirac cones on the surface, whereas LuBi only shows avoided band inversion in the bulk and is thus a conventional compensated semi-metal with extremely large magneto-resistance. PMID- 29624184 TI - Self-powered vision electronic-skin basing on piezo-photodetecting Ppy/PVDF pixel patterned matrix for mimicking vision. AB - The development of multifunctional electronic-skin that establishes human-machine interfaces, enhances perception abilities or has other distinct biomedical applications is the key to the realization of artificial intelligence. In this paper, a new self-powered (battery-free) flexible vision electronic-skin has been realized from pixel-patterned matrix of piezo-photodetecting PVDF/Ppy film. The electronic-skin under applied deformation can actively output piezoelectric voltage, and the outputting signal can be significantly influenced by UV illumination. The piezoelectric output can act as both the photodetecting signal and electricity power. The reliability is demonstrated over 200 light on-off cycles. The sensing unit matrix of 6 * 6 pixels on the electronic-skin can realize image recognition through mapping multi-point UV stimuli. This self powered vision electronic-skin that simply mimics human retina may have potential application in vision substitution. PMID- 29624185 TI - Reactive multi-particle collision dynamics with reactive boundary conditions. AB - In the present study, an off-lattice particle-based method called the reactive multi-particle collision (RMPC) dynamics is extended to model reaction-diffusion systems with reactive boundary conditions in which the a priori diffusion coefficient of the particles needs to be maintained throughout the simulation. To this end, the authors have made use of the so-called bath particles whose purpose is only to ensure proper diffusion of the main particles in the system. In order to model partial adsorption by a reactive boundary in the RMPC, the probability of a particle being adsorbed, once it hits the boundary, is calculated by drawing an analogy between the RMPC and Brownian Dynamics. The main advantages of the RMPC compared to other molecular based methods are less computational cost as well as conservation of mass, energy and momentum in the collision and free streaming steps. The proposed approach is tested on three reaction-diffusion systems and very good agreement with the solutions to their corresponding partial differential equations is observed. PMID- 29624186 TI - Hybrid nanomembrane-based capacitors for the determination of the dielectric constant of semiconducting molecular ensembles. AB - Considerable advances in the field of molecular electronics have been achieved over the recent years. One persistent challenge, however, is the exploitation of the electronic properties of molecules fully integrated into devices. Typically, the molecular electronic properties are investigated using sophisticated techniques incompatible with a practical device technology, such as the scanning tunneling microscopy. The incorporation of molecular materials in devices is not a trivial task as the typical dimensions of electrical contacts are much larger than the molecular ones. To tackle this issue, we report on hybrid capacitors using mechanically-compliant nanomembranes to encapsulate ultrathin molecular ensembles for the investigation of molecular dielectric properties. As the prototype material, copper (II) phthalocyanine (CuPc) has been chosen as information on its dielectric constant (k CuPc) at the molecular scale is missing. Here, hybrid nanomembrane-based capacitors containing metallic nanomembranes, insulating Al2O3 layers, and the CuPc molecular ensembles have been fabricated and evaluated. The Al2O3 is used to prevent short circuits through the capacitor plates as the molecular layer is considerably thin (<30 nm). From the electrical measurements of devices with molecular layers of different thicknesses, the CuPc dielectric constant has been reliably determined (k CuPc = 4.5 +/- 0.5). These values suggest a mild contribution of the molecular orientation on the CuPc dielectric properties. The reported nanomembrane-based capacitor is a viable strategy for the dielectric characterization of ultrathin molecular ensembles integrated into a practical, real device technology. PMID- 29624187 TI - Predictors of Long-Term Opioid Use After Opioid Initiation at Discharge From Medical and Surgical Hospitalizations. AB - Opioid analgesics may be initiated following surgical and medical hospitalization or in ambulatory settings; rates of subsequent long-term opioid (LTO) use have not been directly compared. This retrospective cohort study of the Veterans Health Administration (VHA) included all patients receiving a new outpatient opioid prescription from a VHA provider in fiscal year 2011. If a new outpatient prescription was filled within 2 days following hospital discharge, the initiation was considered a discharge prescription. LTO use was defined as an episode of continuous opioid supply lasting a minimum of 90 days and beginning within 30 days of the initial prescription. We performed bivariate and multivariate analyses to identify the factors associated with LTO use following surgical and medical discharges. Following incident prescription, 5.3% of discharged surgical patients, 15.2% of discharged medical patients, and 19.3% of outpatient opioid initiators received opioids long term. Medical and surgical patients differed; surgical patients were more likely to receive shorter prescription durations. Predictors of LTO use were similar in medical and surgical patients; the most robust predictor in both groups was the number of days' supply of the initial prescription (odds ratio [OR] = 1.24 and 95% confidence interval [CI], 1.12-1.37 for 8-14 days; OR = 1.56 and 95% CI, 1.39 1.76 for 15-29 days; and OR = 2.59 and 95% CI, 2.35-2.86 for >30 days) compared with the reference group receiving =7days. Rates of subsequent LTO use are higher among discharged medical patients than among surgical patients. Characteristics of opioid prescribing within the initial 30 days, including initial dose and days prescribed, were strongly associated with LTO use. PMID- 29624188 TI - Safe Opioid Prescribing for Acute Noncancer Pain in Hospitalized Adults: A Systematic Review of Existing Guidelines. AB - BACKGROUND: Pain is common among hospitalized patients. Inpatient prescribing of opioids is not without risk. Acute pain management guidelines could inform safe prescribing of opioids in the hospital and limit associated unintended consequences. PURPOSE: To evaluate the quality and content of existing guidelines for acute, noncancer pain management. DATA SOURCES: The National Guideline Clearinghouse, MEDLINE via PubMed, websites of relevant specialty societies and other organizations, and selected international search engines. STUDY SELECTION: Guidelines published between January 2010 and August 2017 addressing acute, noncancer pain management among adults were considered. Guidelines that focused on chronic pain, specific diseases, and the nonhospital setting were excluded. DATA EXTRACTION: Quality was assessed using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument. DATA SYNTHESIS: Four guidelines met the selection criteria. Most recommendations were based on expert consensus. The guidelines recommended restricting opioids to severe pain or pain that has not responded to nonopioid therapy, using the lowest effective dose of short acting opioids for the shortest duration possible, and co-prescribing opioids with nonopioid analgesics. The guidelines generally recommended checking the prescription drug monitoring program when prescribing opioids, developing goals for patient recovery, and educating patients regarding the risks and side effects of opioid therapy. Additional recommendations included using an opioid dose conversion guide, avoidance of co-administration of parenteral and oral opioids, and using caution when co-prescribing opioids with other central nervous system depressants. CONCLUSIONS: Guidelines, based largely on expert opinion, recommend judicious prescribing of opioids for severe, acute pain. Future work should assess the implications of these recommendations on hospital-based pain management. PMID- 29624190 TI - Hospitalist Value in an ACO World. AB - The accountable care organization (ACO) concept is advocated as a promising value based payment model that could successfully realign the current payment system to financially reward improvements in quality and efficiency. Focusing on the care of hospitalized patients and controlling a substantive portion of variable hospital expenses, hospitalists are poised to play an essential role in system level transformational change to achieve clinical integration. Especially through hospital and health system quality improvement (QI) initiatives, hospitalists can directly impact and share accountability for measures ranging from care coordination to implementation of evidence-based care and the patient and family caregiver experience. Regardless of political terrain, financial constraints in healthcare will foster continued efforts to promote formation of ACOs that aim to deliver coordinated, evidence-based, and patient-centered care. Hospitalists possess the clinical experience of caring for complex patients with multiple comorbidities and the QI skills needed to lead efforts in this new ACO era. PMID- 29624189 TI - Improving the Safety of Opioid Use for Acute Noncancer Pain in Hospitalized Adults: A Consensus Statement From the Society of Hospital Medicine. AB - Hospital-based clinicians frequently treat acute, noncancer pain. Although opioids may be beneficial in this setting, the benefits must be balanced with the risks of adverse events, including inadvertent overdose and prolonged opioid use, physical dependence, or development of opioid use disorder. In an era of epidemic opioid use and related harms, the Society of Hospital Medicine (SHM) convened a working group to develop a consensus statement on opioid use for adults hospitalized with acute, noncancer pain, outside of the palliative, end-of-life, and intensive care settings. The guidance is intended for clinicians practicing medicine in the inpatient setting (eg, hospitalists, primary care physicians, family physicians, nurse practitioners, and physician assistants). To develop the Consensus Statement, the working group conducted a systematic review of relevant guidelines, composed a draft Statement based on extracted recommendations, and obtained feedback from external experts in hospital-based opioid prescribing, SHM members, the SHM Patient-Family Advisory Council, other professional societies, and peer-reviewers. The iterative development process resulted in a final Consensus Statement consisting of 16 recommendations covering 1) whether to use opioids in the hospital, 2) how to improve the safety of opioid use during hospitalization, and 3) how to improve the safety of opioid prescribing at hospital discharge. As most guideline recommendations from which the Consensus Statement was derived were based on expert opinion alone, the working group identified key issues for future research to support evidence-based practice. PMID- 29624191 TI - Reducing SNF Readmissions: At What Cost? PMID- 29624192 TI - Attachment and Growth of Periodontal Cells on Smooth and Rough Titanium. AB - Besides bone, two other tissues directly contact an osseous implant and/or attachments to it: epithelium and soft connective tissues including the gingival connective tissue. These tissues have received less attention than bone, but are required because of the transmucosal nature of endosseous dental implant restorations. The attachment and growth of human gingival and periodontal ligament fibroblasts and an epithelial cell line to titanium with various surface textures have been examined. Of the three cell types examined, gingival fibroblasts attached best, followed by periodontal ligament fibroblasts and the epithelial cells. Both fibroblast cell types had more cells attached to control (tissue culture plastic) and smooth titanium than either of two rough surfaces. However, once attached, the fibroblast cells grew well on smooth and rough titanium. Epithelial cells did not attach well to any of the surfaces but after a lag period proliferated on control and smooth titanium, although not on either rough titanium surface. This study demonstrates that, as has been found in vivo, human fibroblast and epithelial cell attachment and proliferation are significantly affected by surface characteristics of titanium. These studies suggest that surface texture could be used to guide specific cell attachment to the dental implant. They also provide an in vitro model in which agents such as inflammatory mediators and growth factors could be examined on specific cell function on titanium with distinct surface characteristics. PMID- 29624193 TI - Tuning the emission of a water-soluble 3-hydroxyflavone derivative by host-guest complexation. AB - 3-Hydroxyflavone derivatives have great potential as fluorescent probes for bio labeling in aqueous medium. They were extensively studied in various organic solvents for the "excited state intramolecular proton transfer" process, but seldom addressed in aqueous solution due to the poor water solubility. Herein, an amphiphilic molecule bearing 3-hydroxyflavone and oligo(ethylene oxide) (denoted as 3HF-EO) was designed and synthesized. Different from the fluorescence in organic solvents, 3HF-EO in aqueous solution showed a remarkable single fluorescence emission, which is ascribed to the fluorescence of its anionic species. We found that the fluorescence intensity could be efficiently tuned via host-guest complexation. alpha-CD has little effect on the emission, while beta CD and gamma-CD lead to enhanced and reduced emissions of 3HF-EO, respectively. The 1H NMR and 2D NOESY NMR spectra indicate that alpha-CD barely had any interaction with 3HF-EO, while beta-CD and gamma-CD formed complexes with one and two 3HF-EO molecules, respectively. These results provide a sound explanation for the modulated fluorescence intensity. PMID- 29624194 TI - On the nature of organic and inorganic centers that bifurcate electrons, coupling exergonic and endergonic oxidation-reduction reactions. AB - Bifurcating electrons to couple endergonic and exergonic electron-transfer reactions has been shown to have a key role in energy conserving redox enzymes. Bifurcating enzymes require a redox center that is capable of directing electron transport along two spatially separate pathways. Research into the nature of electron bifurcating sites indicates that one of the keys is the formation of a low potential oxidation state to satisfy the energetics required of the endergonic half reaction, indicating that any redox center (organic or inorganic) that can exist in multiple oxidation states with sufficiently separated redox potentials should be capable of electron bifurcation. In this Feature Article, we explore a paradigm for bifurcating electrons down independent high and low potential pathways, and describe redox cofactors that have been demonstrated or implicated in driving this unique biochemistry. PMID- 29624195 TI - Molecular dynamics study on calcium silicate hydrate subjected to tension loading and water attack: structural evolution, dynamics degradation and reactivity mechanism. AB - The coupled effects of mechanical loading and chemical attack can dramatically weaken the durability of a material. In this study, reactive force field molecular dynamics and the GCMC method were utilized to investigate the degradation mechanism for a deformed C-S-H gel subjected to water attack. In the elastic region of the stress-strain relation, no water molecules invaded the deformed C-S-H gel tensioned along the y-direction. On the other hand, in the failure stage, the tension loading stretched/broke the Si-O-Si bond, resulting in the distortion of the "dreierketten" silicate chain distribution and ordered zigzag sheets built by the calcium oxygen octahedron. More water molecules penetrated into the defective silicate sheets and dissociated into the Si-OH and Ca-OH surrounding the highly reactive non-bridging oxygen sites induced by the silicate chain breakage. The water invasion and hydrolytic reaction reduced the cohesive stress of the tensioned C-S-H structure. Furthermore, the cracks in the calcium silicate sheet connected with the interlayer region, enhancing the channel connectivity for the water transport. This resulted in the water dynamic transformation from the cage stage to the diffusive stage. The high mobility of confined water molecules further weakened the stability of the hydrogen bonds in the calcium silicate skeleton. Moreover, the tensile loading and water attack contributed to the silicate morphological rearrangement. The long silicate chains were first destroyed to form shorter chains and then re-polymerized to form a branch and ring structure to strengthen the weak interlayer regions. PMID- 29624196 TI - Highly concentrated collagen solutions leading to transparent scaffolds of controlled three-dimensional organizations for corneal epithelial cell colonization. AB - This study aimed at controlling both the organization and the transparency of dense collagen scaffolds making use of the lyotropic mesogen properties of collagen. Cholesteric or plywood-like liquid crystal phases were achieved using mixtures of acetic and hydrochloric acids as solvents. The critical pH at which the switch between the two phases occurred was around pH = 3. The use of the two acids led to fibrillated collagen I scaffolds, whose visual aspect ranged from opaque to transparent. Rheological investigations showed that viscoelastic properties of the plywood-like solutions were optimized for molding due to faster recovery. They also confirmed the correlation between the elastic modulus and the diameter of collagen fibrils obtained after fibrillogenesis under ammonia vapor. Human corneal epithelial cells, grown from donor limbal explants, were cultured both on transparent plywood-like matrices and on human amniotic membranes for 14 days. The development of corneal epithelium and the preservation of epithelial stem cells were checked by optical microscopy, colony formation assay, immuno fluorescence and quantitative polymerase chain reaction. A higher level of amplification of limbal stem cells was obtained with collagen matrices compared with amniotic membranes, showing the high biocompatibility of our scaffolds. We therefore suggest that collagen solutions presenting both plywood-like organization and transparency might be of interest for biomedical applications in ophthalmology. PMID- 29624197 TI - Self-assembly of hairy disks in two dimensions - insights from molecular simulations. AB - We report the results of large scale molecular dynamics simulations conducted for sparsely grafted disks in two-dimensional systems. The main goal of this work is to show how the ligand mobility influences the self-assembly of particles decorated with short chains. We also analyze the impact of the chain length on the structure of dense phases. A crossover between the systems controlled by the core-core or by the segment-segment interactions is discussed. We prove that the ligand mobility determines the structure of the system. The particles with fixed tethers are found to order into different structures, an amorphous phase, hexagonal or honeycomb lattices, and a "spaghetti"-like phase containing single strings of cores, depending on the length of attached chains. The disks with mobile monomers assemble into a hexagonal structure, while the particles with longer mobile chains attached to them form a lamellar phase consisting of double strings of cores. PMID- 29624198 TI - Sequence dependence on DNA photochemistry: a computational study of photodimerization pathways in TpdC and dCpT dinucleotides. AB - The excited states involved in the main photodimerization paths in TpdC and dCpT are mapped by PCM/TD-M052X calculations, considering different dinucleotide conformers. As for TT steps, a cyclobutane pyrimidine dimer (CPD) is formed on the PES of the lowest energy exciton, delocalized over two stacked pyrimidines; 6 4 pyrimidine-pyrimidone (64-PP) adduct's formation involves instead a 5'-ter -> 3'-ter charge transfer state. For dCpT, 64-PP dimerization occurs via a two-step reaction, which proceeds through an oxetane intermediate. For TpdC, instead, the final 64-PP product is obtained in a single step and it is as stable as the CPD photoproduct, explaining the relatively large yield of 64-PP found experimentally for TC steps in DNA. PMID- 29624199 TI - Patterning nonisometric origami in nematic elastomer sheets. AB - Nematic elastomers dramatically change their shape in response to diverse stimuli including light and heat. In this paper, we provide a systematic framework for the design of complex three dimensional shapes through the actuation of heterogeneously patterned nematic elastomer sheets. These sheets are composed of nonisometric origami building blocks which, when appropriately linked together, can actuate into a diverse array of three dimensional faceted shapes. We demonstrate both theoretically and experimentally that the nonisometric origami building blocks actuate in the predicted manner, and that the integration of multiple building blocks leads to complex, yet predictable and robust, shapes. We then show that this experimentally realized functionality enables a rich design landscape for actuation using nematic elastomers. We highlight this landscape through examples, which utilize large arrays of these building blocks to realize a desired three dimensional origami shape. In combination, these results amount to an engineering design principle, which provides a template for the programming of arbitrarily complex three dimensional shapes on demand. PMID- 29624200 TI - Rational construction of a 3D hierarchical NiCo2O4/PANI/MF composite foam as a high-performance electrode for asymmetric supercapacitors. AB - A 3D hierarchical NiCo2O4/PANI/MF composite foam with a macroporous 3D skeleton, a conductive PANI coating and highly electrochemically active NiCo2O4 nanosheets is synthesized as a lightweight and low-cost electrode material. Due to the collaborative contribution of all the components, the prepared composite foam exhibits excellent capacitive performances when incorporated into an asymmetric supercapacitor. PMID- 29624206 TI - Paracetamol (acetaminophen) for patent ductus arteriosus in preterm or low birth weight infants. AB - BACKGROUND: In preterm newborns, the ductus arteriosus frequently fails to close and the infants require medical or surgical closure of the patent ductus arteriosus (PDA). A PDA can be treated surgically; or medically with one of two prostaglandin inhibitors, indomethacin or ibuprofen. Case reports suggest that paracetamol may be an alternative for the closure of a PDA. An association between prenatal or postnatal exposure to paracetamol and later development of autism or autism spectrum disorder has been reported. OBJECTIVES: To determine the effectiveness and safety of intravenous or oral paracetamol compared with placebo or no intervention, intravenous indomethacin, intravenous or oral ibuprofen, or with other cyclo-oxygenase inhibitors for treatment of an echocardiographically diagnosed PDA in preterm or low birth weight infants. SEARCH METHODS: We used the standard search strategy of Cochrane Neonatal to search the Cochrane Central Register of Controlled Trials (CENTRAL 2017, Issue 10), MEDLINE via PubMed (1966 to 6 November 2017), Embase (1980 to 6 November 2017), and CINAHL (1982 to 6 November 2017). We searched clinical trial databases, conference proceedings, and the reference lists of retrieved articles for randomised controlled trials (RCT) and quasi-randomised trials. SELECTION CRITERIA: We included RCTs in which paracetamol was compared to no intervention, placebo or other agents used for closure of PDA irrespective of dose, duration and mode of administration in preterm (<= 34 weeks' postmenstrual age) infants. We both reviewed the search results and made a final selection of potentially eligible articles by discussion. We included studies of both prophylactic and therapeutic use of paracetamol. DATA COLLECTION AND ANALYSIS: We performed data collection and analyses in accordance with the methods of the Cochrane Neonatal Review Group. We used the GRADE approach to assess the quality of evidence for the following outcomes when data were available: failure of ductal closure after the first course of treatment; neurodevelopmental impairment; all-cause mortality during initial hospital stay (death); gastrointestinal bleed or stools positive for occult blood; and serum levels of creatinine after treatment (umol/L). MAIN RESULTS: We included eight studies that reported on 916 infants. One of these studies compared paracetamol to both ibuprofen and indomethacin. Five studies compared treatment of PDA with paracetamol versus ibuprofen and enrolled 559 infants. There was no significant difference between paracetamol and ibuprofen for failure of ductal closure after the first course of drug administration (typical risk ratio (RR) 0.95, 95% confidence interval (CI) 0.75 to 1.21; typical risk difference (RD) -0.02, 95% CI -0.09 to 0.09); I2 = 0% for RR and RD; moderate quality of evidence. Four studies (n = 537) reported on gastrointestinal bleed which was lower in the paracetamol group versus the ibuprofen group (typical RR 0.28, 95% CI 0.12 to 0.69; typical RD -0.06, 95% CI -0.09 to -0.02); I2 = 0% for RR and RD; number needed to treat for an additional beneficial outcome (NNTB) 17 (95% CI 11 to 50); moderate quality of evidence. The serum levels of creatinine were lower in the paracetamol group compared with the ibuprofen group in four studies (moderate quality of evidence), as were serum bilirubin levels following treatment in two studies (n = 290). Platelet counts and daily urine output were higher in the paracetamol group compared with the ibuprofen group. One study reported on long-term follow-up to 18 to 24 months of age following treatment with paracetamol versus ibuprofen. There were no significant differences in the neurological outcomes at 18 to 24 months (n = 61); (low quality of evidence).Two studies compared prophylactic administration of paracetamol for a PDA with placebo or no intervention in 80 infants. Paracetamol resulted in a lower rate of failure of ductal closure after 4 to 5 days of treatment compared to placebo or no intervention which was of borderline significance for typical RR 0.49 (95% CI 0.24 to 1.00; P = 0.05); but significant for typical RD -0.21 (95% CI -0.41 to -0.02); I2 = 0 % for RR and RD; NNTB 5 (95% CI 2 to 50); (low quality of evidence).Two studies (n = 277) compared paracetamol with indomethacin. There was no significant difference in the failure to close a PDA (typical RR 0.96, 95% CI 0.55 to 1.65; I2 = 11%; typical RD -0.01, 95% CI 0.09 to 0.08; I2 = 17%) (low quality of evidence). Serum creatinine levels were significantly lower in the paracetamol group compared with the indomethacin group and platelet counts and daily urine output were significantly higher in the paracetamol group. AUTHORS' CONCLUSIONS: Moderate-quality evidence according to GRADE suggests that paracetamol is as effective as ibuprofen; low-quality evidence suggests paracetamol to be more effective than placebo or no intervention; and low-quality evidence suggests paracetamol as effective as indomethacin in closing a PDA. There was no difference in neurodevelopmental outcome in children exposed to paracetamol compared to ibuprofen; however the quality of evidence is low and comes from only one study. In view of concerns raised regarding neurodevelopmental outcomes following prenatal and postnatal exposure to paracetamol, long-term follow-up to at least 18 to 24 months' postnatal age must be incorporated in any studies of paracetamol in the newborn population. At least 19 ongoing trials have been registered. Such trials are required before any recommendations for the possible routine use of paracetamol in the newborn population can be made. PMID- 29624207 TI - Large differences in neonatal drug use between NICUs are common practice: time for consensus? AB - AIMS: Evidence for drug use in newborns is sparse, which may cause large differences in drug prescriptions. We aimed to investigate the differences between neonatal intensive care units (NICUs) in the Netherlands in currently prescribed drugs. METHODS: This multicentre study included neonates admitted during 12 months to four different NICUs. Drugs were classified in accordance with the Anatomical Therapeutic Chemical (ATC) classification system and assessed for on/off-label status in relation to neonatal age. The treatment protocols for four common indications for drug use were compared: pain, intubation, convulsions and hypotension. RESULTS: A total of 1491 neonates (GA range 23+6 -42+2 weeks) were included with a total of 32 182 patient days, 181 different drugs and 10 895 prescriptions of which 23% was off-label in relation to neonatal age. Overall, anti-infective drugs were most frequently used with a total of 3161 prescriptions, of which 4% was off-label in relation to neonatal age. Nervous system drugs included 2500 prescriptions of which 31% was off-label in relation to neonatal age. Nervous system drugs, blood and blood forming organs, and cardiovascular drugs showed the largest differences between NICUs with ranges of 919-2278, 554-1465, and 238-952 total prescriptions per 1000 patients per ATC class, respectively. CONCLUSIONS: We showed that drug use varies widely in neonatal clinical practice. The drug classes with the highest proportion of off label drugs in relation to neonatal age showed the largest differences between NICUs, i.e. cardiovascular and nervous system drugs. Drug research in neonates should receive high priority to guarantee safe and appropriate medicines and optimal treatment. PMID- 29624209 TI - WITHDRAWN: Grommets (ventilation tubes) for recurrent acute otitis media in children. AB - BACKGROUND: This is an update of a Cochrane review first published in The Cochrane Library in Issue 4, 2008 and previously updated in 2011.Acute suppurative otitis media is one of the most common infectious diseases in childhood. Recurrent acute otitis media is defined for the purposes of this review as either three or more acute infections of the middle ear cleft in a six month period, or at least four episodes in a year. Strategies for managing the condition include the assessment and modification of risk factors where possible, repeated courses of antibiotics for each new infection, antibiotic prophylaxis and the insertion of ventilation tubes (grommets). OBJECTIVES: To establish whether grommet insertion reduces the frequency of episodes of recurrent acute otitis media and the proportion of symptomatic children. SEARCH METHODS: The Cochrane Ear, Nose and Throat Disorders Group (CENTDG) Trials Search Co-ordinator searched the CENTDG Trials Register; Central Register of Controlled Trials (CENTRAL 2014, Issue 10); PubMed; EMBASE; CINAHL; Web of Science; Clinicaltrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 6 November 2014. SELECTION CRITERIA: Randomised controlled trials comparing grommet insertion versus control (antibiotics/other treatments/no treatment) for recurrent acute otitis media in children aged from 0 to 16 years. DATA COLLECTION AND ANALYSIS: Two authors independently selected studies. Three authors independently assessed study quality and extracted data. We synthesised data descriptively. MAIN RESULTS: Two randomised controlled trials with a total of 148 participants are included in this review. The overall risk of bias in the studies is unclear.The first study randomised 95 children to grommets or control (antibiotic treatment of acute otitis media episodes). For the primary outcome, this study showed that grommet insertion leads to a mean reduction of 1.5 episodes of acute otitis media in the first six months after treatment. In six months of follow-up significantly more children in the grommet group had no episodes of acute otitis media (P value < 0.001). Complications of surgery included grommet blockage with acute otitis media requiring re-operation within six months in 3/54 children who underwent grommet insertion. Adverse effects were not documented in the control group. The following pre-defined secondary outcomes were not reported: change in symptom scores for otalgia or otorrhoea, alteration in the frequency of otalgia or otorrhoea, and number of days at nursery or school lost secondary to acute otitis media.The second study reported on 53 of 68 children who were randomised to grommet insertion or six months of once a day sulfamethoxazole and trimethoprim antibiotic prophylaxis. There was no significant difference in the primary outcome, number of episodes of acute otitis media, during the six-month follow-up between grommet insertion and antibiotic treatment groups (64.5% in the surgical group versus 45.4% in the antibiotic group had no recurrence, P value = 0.4). Two participants underwent grommet re-insertion to replace extruded tubes during the follow-up period. The only other adverse effect reported was the development of a skin rash in two patients in the medical group. Other pre-defined secondary outcome measures were not reported. The study has a high risk of bias and the results should be interpreted cautiously. AUTHORS' CONCLUSIONS: Grommets significantly increase the number of acute otitis media-free children in the first six months after insertion compared to children who receive no treatment. Grommet insertion maybe of equivalent efficacy to once a day antibiotic prophylaxis. Further research is required to confirm the advantage of grommets over no treatment, investigate the effect beyond six months, compare grommet effectiveness against alternative active treatments and confirm the low risk of adverse effects compared to no treatment and all active treatments in recurrent acute otitis media. In the interim clinicians should consider the possible adverse effects of grommet insertion and alternative treatments before recommending surgery. PMID- 29624208 TI - Gemcitabine-based chemotherapy for advanced biliary tract carcinomas. AB - BACKGROUND: Biliary tract cancers are a group of rare heterogeneous malignant tumours. They include intrahepatic and extrahepatic cholangiocarcinomas, gallbladder carcinomas, and ampullary carcinomas. Surgery remains the optimal modality of therapy leading to long-term survival for people diagnosed with resectable biliary tract carcinomas. Unfortunately, most people with biliary tract carcinomas are diagnosed with either unresectable locally-advanced or metastatic disease, and they are only suitable for palliative chemotherapy or supportive care. OBJECTIVES: To assess the benefits and harms of intravenous administration of gemcitabine monotherapy or gemcitabine-based chemotherapy versus placebo, or no intervention, or other treatments (excluding gemcitabine) in adults with advanced biliary tract carcinomas. SEARCH METHODS: We performed electronic searches in the Cochrane Hepato-Biliary Group Controlled Trials Register, CENTRAL, MEDLINE, Embase, LILACS, Science Citation Index Expanded, and Conference Proceedings Citation Index - Science up to June 2017. We also checked reference lists of primary original studies and review articles manually, for further related articles (cross-references). SELECTION CRITERIA: Eligible studies include randomised clinical trials, irrespective of language or publication status, comparing intravenous administration of gemcitabine monotherapy or gemcitabine-based combination to placebo, to no intervention, or to treatments other than gemcitabine. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. We assessed risks of bias of the included trials using definitions of predefined bias risk domains, and presented the review results incorporating the methodological quality of the trials using GRADE. MAIN RESULTS: We included seven published randomised clinical trials with 600 participants. All included trials were at high risk of bias, and we rated the evidence as very low quality. Cointerventions were equally applied in three trials (gemcitabine plus S-1 (a combination of tegafur, gimeracil, and oteracil) versus S-1 monotherapy; gemcitabine plus S-1 versus gemcitabine monotherapy versus S-1 monotherapy; and gemcitabine plus vandetanib versus gemcitabine plus placebo versus vandetanib monotherapy), while four trials compared gemcitabine plus cisplatin versus S-1 plus cisplatin; gemcitabine plus mitomycin C versus capecitabine plus mitomycin C; gemcitabine plus oxaliplatin versus chemoradiotherapy; and gemcitabine plus oxaliplatin versus 5-fluorouracil plus folinic acid versus best supportive care. The seven trials were conducted in India, Japan, France, China, Austria, South Korea, and Italy. The median age of the participants in the seven trials was between 50 and 60 years, and the male/female ratios were comparable in most of the trials. Based on these seven trials, we established eight comparisons. We could not perform all planned analyses in all comparisons because of insufficient data.Gemcitabine versus vandetanibOne three-arm trial compared gemcitabine versus vandetanib versus both drugs in combination. It reported no data for mortality, health-related quality of life, or tumour progression outcomes. We rated the increased risk of serious adverse events, anaemia, and overall response rate as very low-certainty evidence.Gemcitabine plus cisplatin versus S-1 plus cisplatinFrom one trial of 96 participants, we found very low-certainty evidence that gemcitabine can lower the risk of mortality at one year when used with cisplatin versus S-1 plus cisplatin (risk ratio (RR) 0.76, 95% confidence interval (CI) 0.58 to 0.98; P = 0.04; participants = 96). The trial did not report data for serious adverse events, quality of life, or tumour response outcomes. There is very low-certainty evidence that gemcitabine plus cisplatin combination leads to a higher risk of high-grade thrombocytopenia compared with S-1 plus cisplatin combination (RR 5.28, 95% CI 1.23 to 22.55; P = 0.02; participants = 96).Gemcitabine plus S-1 versus S-1From two trials enrolling 151 participants, we found no difference between the two groups in terms of risk of mortality at one year or risk of serious adverse events. Gemcitabine plus S-1 combination was associated with a higher overall response rate compared with S-1 alone (RR 2.46, 95% CI 1.27 to 4.75; P = 0.007; participants = 140; trials = 2; I2 = 0%; very low certainty of evidence). Neither of the trials reported data for health-related quality of life or time to progression of the tumour.Gemcitabine plus oxaliplatin versus 5 fluorouracil plus folinic acid versus best supportive careOne three-arm trial compared gemcitabine plus oxaliplatin versus 5-fluorouracil plus folinic acid versus best supportive care. It reported no data for serious adverse events, health-related quality of life, or tumour progression. We rated the evidence for mortality and for overall response rate as of very low certainty.Gemcitabine plus oxaliplatin versus 5-fluorouracil plus cisplatin plus radiotherapyOne trial of 34 participants compared gemcitabine plus oxaliplatin versus 5-fluorouracil plus cisplatin plus radiotherapy. It reported no data for quality of life, overall response rate, or tumour progression outcomes. We rated the evidence for mortality and serious adverse events as of very low certainty.Gemcitabine plus mitomycin C versus capecitabine plus mitomycin COne trial of 51 participants compared gemcitabine plus mitomycin C versus capecitabine plus mitomycin C. It reported no data for serious adverse events, quality of life, or tumour progression. We rated the evidence for mortality, overall response rate and thrombocytopenia as of very low certainty.We also identified three ongoing trials evaluating outcomes of interest for our review, which we can incorporate in future updates.For-profit bias: there was a high risk of for-profit bias in two trials (because of industry sponsorship) while there was a low risk of for-profit bias in another three trials, and unclear risk in two trials. AUTHORS' CONCLUSIONS: In adults with advanced biliary tract carcinomas, the effects of gemcitabine or gemcitabine-based chemotherapy are uncertain on mortality and overall response compared with a range of inactive or active controls. The very low certainty of evidence is due to risk of bias, lack of information in the analyses and hence large imprecision, and possible publication bias. The confidence intervals do not rule out meaningful benefits or lack of effect of gemcitabine in all comparisons but one on mortality where gemcitabine plus cisplatin is compared with S-1 plus cisplatin. Gemcitabine-based regimens showed an increase in non-serious adverse events (particularly haematological toxicities). Further randomised clinical trials are mandatory, to further explore the best therapeutic options for adults with advanced biliary tract carcinomas. PMID- 29624210 TI - April 2018. PMID- 29624211 TI - Influence of maternal negative emotion reactivity and cognitive reappraisal on child anxiety disorder. AB - BACKGROUND: Anxiety disorders are among the most common psychopathologies in childhood. Two underlying contributors to child anxiety disorders (ADs) are negative emotional hyper-reactivity and deficits in reappraisal, a cognitive strategy of emotion regulation. Given that emotion regulation develops in the context of parent-child interaction, the aim of this study was to fill a research gap regarding the association between maternal negative emotional reactivity (NER) and reappraisal and child anxiety by examining (a) whether mothers of children with ADs display abnormalities in emotional reactivity and reappraisal compared to mothers of children without ADs; (b) whether maternal NER and reappraisal are associated with child anxiety; and (c) whether maternal reactivity and reappraisal significantly explain the variance in the level of child anxiety beyond the level of maternal anxiety. METHOD: Forty-nine mothers and their AD children (aged 10-17) were assessed at admission to an anxiety disorder clinic and were compared to a control group of 42 mothers and their non anxious (NA) children. Child and maternal anxiety were assessed, as well as maternal NER and reappraisal. RESULTS: Mothers of AD children showed a higher NER as well as reappraisal deficits compared to the control group. Self-rated child anxiety was associated with maternal deficits in reappraisal. The variance in child anxiety was significantly explained by the level of maternal anxiety as well as maternal reappraisal deficits. CONCLUSIONS: This study suggests that maternal NER and reappraisal play an important role in child anxiety and should be considered in prevention and intervention of childhood ADs. PMID- 29624213 TI - Should breast cancer screening programs routinely measure mammographic density? PMID- 29624212 TI - Effectiveness of base-of-skull immobilization system in a compact proton therapy setting. AB - PURPOSE: The purpose of this study was to investigate daily repositioning accuracy by analyzing inter- and intra-fractional uncertainties associated with patients treated for intracranial or base of skull tumors in a compact proton therapy system with 6 degrees of freedom (DOF) robotic couch and a thermoplastic head mask indexed to a base of skull (BoS) frame. MATERIALS AND METHODS: Daily orthogonal kV alignment images at setup position before and after daily treatments were analyzed for 33 patients. The system was composed of a new type of thermoplastic mask, a bite block, and carbon-fiber BoS couch-top insert specifically designed for proton therapy treatments. The correctional shifts in robotic treatment table with 6 DOF were evaluated and recorded based on over 1500 planar kV image pairs. Correctional shifts for patients with and without bite blocks were compared. RESULTS: Systematic and random errors were evaluated for all 6 DOF coordinates available for daily vector corrections. Uncertainties associated with geometrical errors and their sources, in addition to robustness analysis of various combinations of immobilization components were presented. CONCLUSIONS: Analysis of 644 fractions including patients with and without a bite block shows that the BoS immobilization system is capable of maintaining intra fraction localization with submillimeter accuracy (in nearly 83%, 86%, 95% of cases along SI, LAT, and PA, respectively) in translational coordinates and subdegree precision (in 98.85%, 98.85%, and 96.4% of cases for roll, pitch, and yaw respectively) in rotational coordinates. The system overall fares better in intra-fraction localization precision compared to previously reported particle therapy immobilization systems. The use of a mask-attached type bite block has marginal impact on inter- or intra-fraction uncertainties compared to no bite block. PMID- 29624214 TI - Continuing Professional Development. PMID- 29624215 TI - Current information about vaccination practice in pediatric rheumatic diseases and recommendations for future applications. AB - Acari C, Unsal E. Current information about vaccination practice in pediatric rheumatic diseases and recommendations for future applications. Turk J Pediatr 2017; 59: 357-368. Pediatric patients with autoinflammatory or rheumatic diseases are at increased risk of infections; therefore, safe and effective immunizations are crucial in the management of these group of patients. Current aggressive treatments involving the early use of immunosuppressive drugs and biological agents have further increased the susceptibility to infections in this group of patients. Therefore, effective and safe vaccination with adequate serological responses is important. In patients with rheumatic diseases, immunogenicity of a vaccine can differ from the healthy population, because of the disease itself or the immunosuppressive treatment received. Moreover, possible effects of vaccination on the underlying disease should be considered. In general, live attenuated vaccines should not be administered when high-dose immunosuppressive drugs are used for immunosuppressed patients. Inactivated vaccine agents have proven to be generally safe in patients with RD. The immune-modulating of biologic agents effects can last for weeks to months after discontinuation, depending on their half lifes. Also, live virus vaccines are contraindicated during therapy and for weeks to months following discontinuation of the biologics. The aim of this review is to cover the current information about vaccination practice in pediatric rheumatologic diseases and to give recommendations for future applications. PMID- 29624216 TI - Esophageal eosinophilia in children: A 6-year single-center experience. AB - Cakir M, Sag E, Mungan S, Akbulut UE, Orhan F. Esophageal eosinophilia in children: A 6-year single-center experience. Turk J Pediatr 2017; 59: 369-378. Esophageal eosinophilia (EE) and eosinophilic esophagitis (EoE) are emerging clinical entities, the prevalence of which has increased during the last 15 years. However, there is a lack of data concerning the etiology and outcomes of EE in children. The aim of this study was therefore to analyze the clinical findings and outcomes of children with EE and EoE in our pediatric gastroenterology unit over a 6-year period. The study included children undergoing esophagogastroduodenoscopy (EGD) during this 6-year period (January 2010 to December 2015) in our pediatric gastroenterology unit. The files of patients with EE were re-evaluated in detail to elicit demographic features, clinical, laboratory and histopathological findings, treatment modalities and outcomes. EE was determined in 33 patients [0.95% (95% CI: 0.63-1.27) among all children, and in 4.66% (95% CI: 3.11-6.21) of children undergoing esophageal biopsy] (8.6+/-4.2 years and 72.7% male). EoE was the most common cause of EE (n=11, 33.3%), followed by eosinophilic gastroenteropathy (n=6, 18.1%) and proton pump inhibitor responsive esophageal eosinophilia (n=4, 12.1%). Patients with EoE (n=11) were followed up for 21.2+/-18 (range: 1-60) months, and treatment was discontinued in 2 patients (18.1%). Additionally, 5 patients (45.5%) received diet elimination only and 1 patient (9%) received a combination of low dose steroids and diet. Three patients (27.2%) are still being treated under the initial regimen. The overall incidence of EE increased in 2014-2015 compared to 2010-2011 (0.41% vs. 1.33, p=0.047, OR: 3.22 and 95% CI: 0.94-10.98, p=0.06). EE is an increasingly common clinical entity with a wide spectrum of etiology and clinical presentations in children. PMID- 29624217 TI - Assessment of sleep in pediatric cancer patients. AB - Ince D, Demirag B, Karapinar TH, Oymak Y, Ay Y, Kaygusuz A, Toret E, Vergin C. Assessment of sleep in pediatric cancer patients. Turk J Pediatr 2017; 59: 379 386. The purpose of the study is to describe sleep habits, assess the prevalence of sleep disturbances in pediatric cancer patients and healthy controls, and to compare sleep patterns, sleep problems. One hundred-thirty-five patients and 190 healthy controls were evaluated. Healthy children matched for age, sex, economic status, parental education and family structure constituted the control group. Sleep was evaluated by using the Children's Sleep Habits Questionnaire (CSHQ). Sleep problems were detected in half of patients. There were no significant differences in total sleep score and subscale scores between patients and controls. Solely the wake-time was found significantly different between patients and controls. Although our results indicated that neither childhood cancer survivors nor patients with cancer during treatment period had more sleep problems than their healthy peers, sleep problems were not uncommon in whole study group. This study underlines the need to screen, assess and manage sleep problems in children with diagnosis of cancer. PMID- 29624218 TI - Ectopic intrathyroidal thymus in children: Prevalence, imaging findings and evolution. AB - Erol OB, Sahin D, Bayramoglu Z, Yilmaz R, Akpinar YE, Unal OF, Yekeler E. Ectopic intrathyroidal thymus in children: Prevalence, imaging findings and evolution. Turk J Pediatr 2017; 59: 387-394. The aim of this study was to evaluate the ultrasound (US) features of intrathyroidal ectopic thymus (IET) and demonstrate the alterations after follow-up. This study included 36 lesions of 32 patients (mean age 95 +/- 58 months) diagnosed with IET. The patients underwent follow-up US examination at least 22-months without a medication or surgical intervention. A total of 36 IETs with an incidence of 0.91% were detected among 3914 thyroid ultrasound (US) examinations. The mean of anteroposterior (ap), transverse (tr), and craniocaudal (cc) diameters in the initial US examinations were 3.1+/-1.19 mm, 4.89+/-1.86 mm, and 6.45+/-3.92 mm respectively. All of the lesions were well demarcated, hypoechoic to the thyroid gland, and contained uniformly distributed punctate echogenic foci. Follow-up US examinations were performed after 684+/-85 days. The alterations between the initial and follow-up diameters for ap and cc direction were not statistically significant. However, a significant difference (p=0.007) was found for transverse diameters and the IETs were found to be smaller at follow-up US than in the initial US. Most of the IETs were located in the left lobe (64%), middle portion (83%), and extended to a border of thyroid gland (69%) and nonspherical in shape (89%). The descriptive findings of IETs are uniform distribution of punctate echogenic foci, absence of a rim, and the presence of vessels traversing through the lesion without parenchymal displacement. Given our findings, healthcare professionals should be aware of the diagnosis of IET. Patients with an IET could be safely managed with follow-up US and any surgical treatment would not be required. PMID- 29624219 TI - Evaluation of antimicrobial susceptibilities and virulence factors of Staphylococcus aureus strains isolated from community-acquired and health-care associated pediatric infections. AB - Karbuz A, Karahan ZC, Aldemir-Kocabas B, Tekeli A, Ozdemir H, Guriz H, Gokdemir R, Ince E, Ciftci E. Evaluation of antimicrobial susceptibilities and virulence factors of Staphylococcus aureus strains isolated from community-acquired and health-care associated pediatric infections. Turk J Pediatr 2017; 59: 395-403. The aim of this study was to investigate the enterotoxins and Panton-Valentine leukocidin (PVL) gene as virulence factor, identification if antimicrobial sensitivity patterns, agr (accessory gene regulator) types and sequence types and in resistant cases to obtain SCCmec (staphylococcal cassette chromosome mec) gene types which will be helpful to decide empirical therapy and future health politics for S. aureus species. Total of 150 isolates of S. aureus were isolated from the cultures of the child patients in January 2011 and December 2012. In this study, the penicillin resistance was observed as 93.8%. PVL and mecA was detected positive in 8.7% and in 6% of all S. aureus strains, respectively. Two MRSA (methicillin resistant S.aureus) strains were detected as SCCmec type III and SCCmec type V and five MRSA strains were detected as SCCmec type IV. SET-I and SET-G were the most common detected enterotoxins. In both community associated and healthcare-associated MRSA strains, agr type 1 was detected most commonly. The most common sequence types were ST737 in 13 patients than ST22 in eight patients and ST121 in six patients. This study highlights a necessity to review the cause of small changes in the structural genes in order to determine whether it is a cause or outcome; community-acquired and healthcare associated strains overlap. PMID- 29624220 TI - Vitamin D receptor gene polymorphisms in children with kidney stone disease. AB - Subasi B, Gokce I, Delil K, Alpay H. Vitamin D receptor gene polymorphisms in children with kidney stone disease. Turk J Pediatr 2017; 59: 404-409. Kidney stone disease has a multifactorial etiology involving the interaction of genetic and environmental factors. There is an increased risk of stone formation in the relatives of idiopathic stone patients, which can be explained up to 60% by genetic factors. This study was conducted to explore the association of vitamin D receptor (VDR) gene polymorphisms with the risk of urolithiasis (UL) in Turkish children. We investigated the VDR gene polymorphisms: ApaI, BsmI, TagI, Cdx2, FokI, in 52 children (26 boys, 26 girls) with UL and in 51 healthy children (22 boys, 29 girls) without UL. Apa I, BsmI, TagI, Cdx2, FokI genotypes were analyzed by Apa I, BsmI, TagI, Cdx2, FokI restriction enzyme digestion, respectively. The resulting alleles are designated as ABTCF (ApaI, BsmI, TagI, Cdx2, and FokI restriction site is absent), or abtcf (ApaI, BsmI, TagI, Cdx2, FokI restriction site is present), respectively. Genotype and allele frequencies were calculated, and the association with UL, hypercalciuria and hypocitraturia was investigated. Our data provide no statistically significant evidence for an association between UL and VDR ApaI, BsmI, TagI, Cdx2, and FokI genotype and allele frequencies. Patients with hypocitraturia and hypercalciuria were compared with the control group and no statistically significant difference was detected in terms of VDR gene ApaI, BsmI, TagI, Cdx2, and FokI polymorphisms and allele frequencies. Our data suggest that the VDR ApaI, BsmI, TagI, Cdx2, and FokI polymorphisms do not indicate a significant risk for UL. PMID- 29624221 TI - Clinical and epidemiological characteristics of children with germ cell tumors: A single center experience in a developing country. AB - Incesoy-Ozdemir S, Ertem U, Sahin G, Bozkurt C, Yuksek N, Oren AC, Balkaya E, Alkan A. Clinical and epidemiological characteristics of children with germ cell tumors: A single center experience in a developing country. Turk J Pediatr 2017; 59: 410-417. Germ cell tumor (GCT) is a rare malignancy accounting for 2-3% of all pediatric tumors. The overall survival rate of children and adolescents with GCT is more than 80% after adopting combined therapy. The aim of this study is to review clinical presentation, management, and outcome in a single-center series with extracranial GCT. Clinical characteristics, pathologic presentations, and survival outcomes of 101 children with GCT, treated at our hospital from 1988 to 2011, were analyzed. Sixty-two of patients were female and 39 of them were male. Fifty-eight (57%) patients had gonadal tumor (24 testicular, 34 ovarian), 43 (43%) extragonadal. Histologically, teratomas were found most frequently (26 mature, 10 immature), followed by yolk sac tumors (n: 33), mixed malignant tumors (n: 13), embryonal carcinoma (n: 10), disgerminoma (n: 8) and seminoma (n: 1). Twenty-six patients were diagnosed as mature teratoma and we excluded them in the evaluation of staging and survival. Five-year overall and relaps-free survival were 80.3% (mean follow-up time: 215.8 months) and 73.4% (mean follow-up time: 176.2 months), respectively. Five-year survival rates were 93.2% and 90.2% in malign GCTs diagnosed after 1999. PMID- 29624222 TI - The diagnostic and prognostic value of angiopoietins compared with C-reactive protein and procalcitonin in children with febrile neutropenia. AB - Mimaroglu E, Citak EC, Kuyucu N, Eskendari G. The diagnostic and prognostic value of angiopoietins compared with C-reactive protein and procalcitonin in children with febrile neutropenia. Turk J Pediatr 2017; 59: 418-425. In this study, we aimed to determine serum angiopoetin (Ang) levels and compare them with levels of C-reactive protein (CRP) and procalcitonin (PCT). Cancer patients (aged 0-18 years) who experienced febrile neutropenia attacks were included in the study. Ang-1, Ang-2, CRP, and PCT were analyzed at admission and 2nd day. Ninety-four episodes of febrile neutropenia that developed in 62 patients were analyzed in this study. The mean age of the patients was 7.56 +/- 4.8 (0.5-17) years. The patients had lymphoma (33.9%), solid tumors (48.4%), and other cancer (17.7%). The percentages of the patients with fever of unknown origin (FUO), clinically documented infection (CDI), and microbiologically documented infection (MDI) categories were 45.7%, 22.3%, and 31.9%, respectively. During the study period 11 patients were lost to follow-up. The levels of CRP, PCT and Ang-2 were significantly higher; and that of Ang-1 was significantly lower, compared to the controls. The differentiation cannot be made between the groups by CRP and PCT levels. The level of Ang-1 was the lowest in MDI group; the level of Ang-2 and the ratio of Ang-2/Ang-1 were high in each group. Ang-1, Ang-2 and the ratio of Ang-2/Ang-1 were significantly associated with mortality. Angs correlated with the severity of infection. PMID- 29624223 TI - Risks associated with mother-to-child transmission of HIV infection. AB - Nguefack F, Koki-Ndombo P, Ngoh R, Soh Fru F, Kinkela MN, Chiabi A. Risks associated with mother-to-child transmission of HIV infection. Turk J Pediatr 2017; 59: 426-433. Early infant diagnosis (EID) permits the detection of Human Immunodeficiency Virus (HIV) infection in exposed children from 4-6 weeks by polymerase chain reaction (PCR). The aim of this study was to assess some maternal and infant characteristics associated with HIV infected children in an EID program. A retrospective study was performed using records of HIV exposed children enrolled in the EID program from 2009 to 2013. Patients recruited were from various health structures and at different clinical stages; some for the Prevention of Mother-to-Child Transmission (PMTCT) follow up, others with signs of HIV infection. Data was collected from completed hospital records of children aged 6 weeks to 18 months containing at least two PCR, one PCR and one serologic test, or one PCR test and viral load. HIV infection was considered if one of the of tests was positive. In all, 130 (5.3%) exposed children with only one positive PCR test, and 1,442 (59%) others with information lacking in their record were excluded. A total 107 out of 871 infants enrolled (12.2%) were infected. Only, 32.7% of the mothers were on antiretroviral therapy (ART). Of these, 53.3% had their first PCR performed between 6 weeks and 6 months. Children were less likely to be HIV infected when their mothers received antiretroviral (ARV) (OR=0.15, 95% CI 0.07-0.30, P=0.000). Factors associated with HIV infection in the children were the lack of ARV prophylaxis (OR=2.07, 95%CI 1.05-4.09, P=0.035) and having mixed feeding (OR=3.91, 95% CI 1.66-9.24, P=0.002) in multivariate analysis. The high rate of infection associated with the maternal and infant correlates of HIV infected children would result from the poor implementation of the PMTCT. Systematic screening of pregnant and breastfeeding women should be reinforced and the lifelong ARVs for PMTCT (Option B+) be promoted. PMID- 29624224 TI - Impaired glucose tolerance in Fanconi-Bickel syndrome: Eight patients with two novel mutations. AB - Seker-Yilmaz B, Kor D, Bulut FD, Yuksel B, Karabay-Bayazit A, Topaloglu AK, Ceylaner G, Onenli-Mungan N. Impaired glucose tolerance in Fanconi-Bickel syndrome: Eight patients with two novel mutations. Turk J Pediatr 2017; 59: 434 441. Fanconi-Bickel syndrome (FBS) is a rare, autosomal recessive disorder of carbohydrate metabolism caused by defects in the facilitative glucose transporter 2 (GLUT2 or SLC2A2) gene. Prominent findings are failure to thrive, renal tubular acidosis, hypoglycemia and postprandial hyperglycemia even mimicking diabetes mellitus. Eight patients from 6 families with FBS were included in this study. c.482_483insC homozygous mutation was detected in six patients from four different families. Mutation analysis of SLC2A2 gene revealed two novel homozygous mutations; c.1069delGinsAATAA and c.575A > G. Standard oral glucose tolerance test with 1.75 g/kg oral glucose was performed in six of the patients who were older than 3-years of age. Impaired glucose tolerance was found in all patients as expected and two of them had overt diabetes. None of the antidiabetic medications were given to them in order to avoid significant hypoglycemia. Beside the conservative treatment, follow up with frequent oral glucose tolerance tests are planned. We report these cases of FBS, as GSD XI is rare, two novel mutations were detected and also to highlight the risk of diabetes mellitus; although there is not a consensus about the treatment. PMID- 29624225 TI - Nutritional rehabilitation for children with congenital heart disease with left to right shunt. AB - El-Koofy N, Mahmoud AM, Fattaouh AM. Nutritional rehabilitation for children with congenital heart disease with left to right shunt. Turk J Pediatr 2017; 59: 442 451. Children with congenital heart disease (CHD) are prone to malnutrition. We aimed to assess the nutritional status of infants with CHD and evaluate the role of nutritional counseling. A cohort study included 50 patients with acyanotic CHD causing increased pulmonary blood flow consecutively enrolled from the cardiology clinic in Cairo University Children Hospital. The patients were subjected to clinical evaluation, nutritional assessment with detailed nutritional history, anthropometric measurements and subjective global assessment (SGA) score and complete blood count, serum albumin and total protein assessment. Degree of failure to thrive (FTT) was assessed and nutritional counselling was offered to those patients; followed up for 3 months then re-evaluated. The mean age was (8.6+/-4.8 months) with male: female ratio 1:1. The overall prevalence of malnutrition was 62%. Fourteen patients had mild FTT and 17 patients had severe FTT [47.1% with mild heart failure (HF) and 47.1% had moderate or severe HF]. All patients with moderate to severe HF had severe FTT and 80% of those with mild HF had severe FTT. Anemia was present in 96% of the patients. Patients with moderate or severe FTT had more severe degree of HF (p < 0.001), more complications (p < 0.001), more frequent hospital admission (p < 0.001) and less optimum breast feeding (p < 0.001). It was found that 76.5% of those with moderate to severe FTT were formula fed (p 0.002) and significantly lower rate of optimum weaning among (p 0.037). There was significant improvement in the anthropometry, the SGA and degree of FTT, level of albumin with decrease in the percent of anemia among the included patients after nutritional rehabilitation. Malnutrition represents serious problem to children with CHD. Nutritional assessment and proper counseling help to improve the nutritional status of those patients. PMID- 29624226 TI - Clinical and imaging features of malignant infantile osteopetrosis. AB - Tfifha M, Gaha M, Gamaoun W, Chemli J, Mabrouk S, Hassayoun S, Zouari N, Jemni H, Abroug S. Clinical and imaging features of malignant infantile osteopetrosis. Turk J Pediatr 2017; 59: 452-457. Human osteopetrosis is a rare genetic disorder caused by osteoclast failure. It encompasses a group of highly heterogeneous forms, ranged widely in severity. Patients with autosomal recessive osteopetrosis are the most severely affected osteopetrotic patients. Here we describe Tunisian children with severe phenotype. They are native from the same geographic region, born to consanguineous parents. Clinical features were cranio-facial dysmorphy, macrocephaly, hepatosplenomegaly, severe anemia and thrombocytopenia with precocious onset of neuronopathic complications, blindness and deafness. Retinal atrophy, reported in a minority of forms is highlighted. Skeletal radiographs revealed generalized increase in bone density and abnormal metaphyseal remodeling, and superimposed rickets resulting from the defect in osteoclasts to provide a normal Ca/P balance. We report an exceptional association with congenital hypothyroidism. Multi-organ failure due to sepsis is one the most severe complications observed. The issue was fatal without hematopoietic stem cell transplantation. PMID- 29624227 TI - Conventional insulin pump therapy in two neonatal diabetes patients harboring the homozygous PTF1A enhancer mutation: Need for a novel approach for the management of neonatal diabetes. AB - Kurnaz E, Aycan Z, Yildirim N, Cetinkaya S. Conventional insulin pump therapy in two neonatal diabetes patients harboring the homozygous PTF1A enhancer mutation: Need for a novel approach for the management of neonatal diabetes. Turk J Pediatr 2017; 59: 458-462. The enhancer of PTF1A mutation causes developmental defects of the pancreas. This condition can result in insulin-requiring diabetes and exocrine pancreatic insufficiency. We report two patients with diabetes mellitus harboring the homozygous PTF1A enhancer mutation. The patients had hyperglycemia in the first month of life and were started with subcutaneous insulin injections with NPH insulin. When blood glucose (BG) exceeded 250 mg/dl, a conservative dose of rapid-acting insulin was administered to restore BG to the target range. In cases with documented poor control (persistent hypoglycemia and rebound hyperglycemia), it was decided that the baby would benefit from a continuous subcutaneous insulin infusion pump. But our experience shows that wide fluctuations in BG concentrations despite the strict follow-up was probably due to the absence of circulating glucagon. Further treatment options would overcome this problem, especially for children with pancreas agenesis. We could say theoretically that using diluted insulin, a sensor-augmented insulin pump system and single-hormone (insulin alone) and dual-hormone (insulin and glucagon) artificial pancreas systems may mitigate the severity of hypogylcemia. PMID- 29624228 TI - Febrile infection-related epilepsy syndrome (FIRES) treated with immunomodulation in an 8-year-old boy and review of the literature. AB - Alparslan C, Kamit-Can F, Anil AB, Olgac-Dundar N, Cavusoglu D, Goc Z. Febrile infection-related epilepsy syndrome (FIRES) treated with immunomodulation in an 8 year-old boy and review of the literature. Turk J Pediatr 2017; 59: 463-466. Febrile infection-related epilepsy syndrome (FIRES) is a catastrophic epilepsy syndrome which is characterized by acute onset of refractory status epilepticus following a febrile infection occurring in previously normal children. Despite the various treatment options that have been tried, exact treatment strategy is still undetermined. This is the first pediatric case of FIRES from Turkey which was successfully treated with intravenous immunoglobulin (IVIG). A previously healthy 8-year-old boy was referred to our hospital with a pre-diagnosis of status epilepticus and encephalitis. He presented with acute onset of convulsions and unconsciousness following fever and malaise lasting 7 days. On physical examination Glasgow coma scale was 12, his pupils were miotic. He had cafe-au lait spots on his body. His fundus examination, cerebrospinal fluid findings and cranial magnetic resonance imaging did not reveal any abnormality. Results of comprehensive search for metabolic, toxicological, infectious and autoimmune etiologies were all negative. Generalized slowing was seen on the electroencephalography (EEG) of the patient indicating possible encephalopathy. The patient developed convulsive status epilepticus and was intubated on day 5. His seizures were controlled by continuous infusion of midazolam, thiopental and used for 4 days. Phenytoin, levetiracetam, topiramate were used simultaneously. IVIG was administered as an immunomodulator for refractory seizures on day-9. The patient was extubated on day 11. The diagnosis was made after a comprehensive negative search for central nervous system infection, autoimmune and metabolic diseases. At follow up it was learnt that he had had only two seizures in two years. Status epilepticus did not recur. Clinicians should keep in mind FIRES which is a diagnosis of exclusion especially in refractory status epilepticus. IVIG treatment could have a benefit in these patients. PMID- 29624229 TI - Two cases of periodic fever syndrome with coexistent mevalonate kinase and Mediterranean fever gene mutations. AB - Cakan M, Aktay-Ayaz N, Keskindemirci G, Karadag SG. Two cases of periodic fever syndrome with coexistent mevalonate kinase and Mediterranean fever gene mutations. Turk J Pediatr 2017; 59: 467-470. The periodic fever syndromes are autoinflammatory diseases that present with recurrent fever, serositis and rash. Familial Mediterranean fever is the most common periodic fever syndrome and characterized by recurrent attacks of fever, arthritis, peritonitis, pleuritis that typically last 1-3 days. Hyperimmunoglobulinemia D syndrome is another example of periodic fever syndromes and patients have recurrent fever attacks for 3-7 days accompanied by abdominal pain, rash, vomiting, diarrhea, arthralgia, arthritis, aphthous ulcers, and cervical lymphadenopathy. In some cases the clinical picture of the patient does not fit to one autoinflammatory syndrome because of the digenic inheritance. This may cause to overlap or atypical clinical features or an unexpected response to treatment. Herein we report two cases of hyperimmunoglobulinemia D syndrome that also had MEFV gene mutations and familial Mediterranean fever phenotype. PMID- 29624230 TI - Beta-ketothiolase deficiency: An unusual cause of recurrent ketoacidosis. AB - Kilic-Yildirim G, Durmus-Aydogdu S, Ceylaner S, Sass JO. Beta-ketothiolase deficiency: An unusual cause of recurrent ketoacidosis. Turk J Pediatr 2017; 59: 471-474. Beta-ketothiolase deficiency (mitochondrial acetoacetyl-CoA thiolase, MAT or T2 deficiency) is a rare autosomal recessive disorder of isoleucine and ketone body metabolism due to acetyl-CoA acetyltransferase-1 (ACAT1) gene mutations. The disease is characterized by recurrent episodes of ketoasidosis which starts with vomiting and followed by dehydration and tachypnea. Here, we present a patient who was admitted to the hospital with severe acidosis and dehydration because of vomiting induced by protein rich nutrient and was diagnosed with MAT deficiency. 3-hydroxy-butyric acid, acetoacetic acid and 3 hydroxy-iso-valeric acid levels were significantly increased and tiglyglycine as trace amount in the urine organic acid analysis of the patient. Genetic analysis for ACAT-1 showed compound heterozygosity for the mutations c.949G > A (p.D317N) and c.951C > T (p.D317D), which both are known to cause exon 10 skipping and to be pathogenic missense mutations. PMID- 29624231 TI - Identification of two novel PNPLA1 mutations in Turkish families with autosomal recessive congenital ichthyosis. AB - Dokmeci-Emre S, Taskiran ZE, Yuzbasioglu A, Onal G, Akarsu AN, Karaduman A, Ozguc M. Identification of two novel PNPLA1 mutations in Turkish families with autosomal recessive congenital ichthyosis. Turk J Pediatr 2017; 59: 475-482. Autosomal recessive congenital ichthyosis (ARCI) is a group of inherited keratinization disorders that are characterized by abnormal epidermal keratinization. ARCI patients generally represent serious symptoms including collodion baby phenotype accompanied by dehydration, heat loss, electrolytic imbalance, and sepsis. ARCI shows high degree of clinical and genetic heterogeneity. To date, nine genes were shown to be responsible for ARCI phenotype. One of these genes, patatin-like phospholipase domain containing protein-1 (PNPLA1) was suggested to be involved in the synthesis of omega-O acylceramides related to epidermal cornified lipid envelope organization. In addition to previously reported PNPLA1 mutations, we report two novel PNPLA1 mutations including one novel missense mutation c.335C > A (p.Ser112Tyr) and one novel deletion mutation c.733_735delTAC (p.Tyr245del) in Turkish ARCI patients from unrelated consanguineous families. We also report previously reported missense mutation c.514G > A (p.Asp172Asn) in Turkish ARCI patients. Novel PNPLA1 mutations were shown to be located in the catalytic patatin domain of PNPLA1 gene. Identification of novel mutations in PNPLA1 gene expands the mutational spectrum in the causative gene. Increase in the total number of cases has high diagnostic value in terms of genotype-phenotype correlation in ARCI patients. PMID- 29624232 TI - A rare large mutation involving two exons of the SP-B gene in an infant with severe respiratory distress. AB - Takci S, Anuk-Ince D, Louha M, Couderc R, Cakar N, Koseoglu RD, Ates O. A rare large mutation involving two exons of the SP-B gene in an infant with severe respiratory distress. Turk J Pediatr 2017; 59: 483-486. Hereditary surfactant protein-B (SP-B) deficiency is a rare autosomal recessive disease of newborn infants causing severe respiratory failure and death within the first year of life. The most common cause of SP-B deficiency is a frameshift mutation in exon 4 (121ins2) in the gene encoding SP-B. We report a term infant with unremitting respiratory distress who was unresponsive to all treatment modalities. The parents were consanguineous and a term sibling of the infant had died due to respiratory failure without a certain diagnosis. In the first step of the diagnostic work-up, common genetic mutations for SP-B, surfactant protein C and ATP-binding cassette s3 were absent, however sequencing of SP-B gene revealed a large homozygous genomic deletion covering exon 8 and 9. In this case report, we aimed to emphasize further genetic evaluation in all cases suggestive of surfactant dysfunction, even if common mutations are absent. PMID- 29624233 TI - ARC syndrome. AB - Mutlu M, Aslan Y, Akturk-Acar F, Cakir M, Erduran E, Kalyoncu M. ARC syndrome. Turk J Pediatr 2017; 59: 487-490. Arthrogryposis-renal dysfunction-cholestasis (ARC) is an autosomal recessive multisystem disorder characterized by arthrogryposis, renal tubular dysfunction and neonatal cholestasis with low gamma glutamyl transpeptidase activity. Most of the mutations in ARC syndrome are associated with the vacuolar protein sorting 33B (VPS33B) gene on chromosome 15q26.1. Herein, we report a female newborn with ARC syndrome caused by homozygous mutations in VPS33B [IVS1-2A > C (c.97-2A > C)]. PMID- 29624234 TI - The role of plasmapheresis in organophosphate poisoning: Case reports of three pediatric patients. AB - Yukselmis U, Ozcetin M, Cag Y, Yildizdas D, Yilmaz HL. The role of plasmapheresis in organophosphate poisoning: Case reports of three pediatric patients. Turk J Pediatr 2017; 59: 491-496. The aim of the study was to assess the impact of plasmapheresis treatment in the management of three pediatric patients with organophosphate poisoning who did not respond to standard treatment. The treatment of signs and symptoms, and supportive treatment has been evaluated in this paper. Patients were initially given atropine infusion and 0.05 mg/kg atropine with five-minute intervals. Despite pralidoxime loading and three consecutively infusions clinical symptoms did not respond to the treatment and plasma pseudocholinesterase levels did not decrease. At this point, plasmapheresis was used on three consecutive days. Accordingly, the clinical signs improved and mechanical ventilation was no longer necessary. Patients were discharged on the sixteenth day after their admission to the hospital. Plasmapheresis may be an option for the patients who do not respond to atropine and pralidoxime treatment in organophosphate poisoning. PMID- 29624235 TI - A rare situation in acute rheumatic carditis: Involvement of all four valves. AB - Guvenc O, Cimen D. A rare situation in acute rheumatic carditis: Involvement of all four valves. Turk J Pediatr 2017; 59: 497-500. Acute rheumatic fever continues to be an important health problem, especially in countries that are socioeconomically underdeveloped. Carditis, which develops in approximately half of the patients, is responsible for both early-stage mortality as well as late stage surgical treatment due to heart valve insufficiency or stenosis. The most frequent and severe valve involvement is with the mitral valve, while the aortic valve has the second highest incidence of involvement. Pulmonary and tricuspid valves are rarely involved. The literature cites a few adult cases in which all four valves are affected by rheumatic carditis; however, to the best of our knowledge, there have been no acute-stage rheumatic carditis pediatric cases reported. This article presents a 13-year-old male patient of Syrian origin who escaped to Turkey from the war in his country, and who was in the acute stage of rheumatic carditis in which all four valves were involved. PMID- 29624236 TI - REMEDIAL APPLICATIONS OF EXOSOMES IN CANCER, INFECTIONS AND DIABETES. AB - Different cell types under normal and diseased states constantly secrete numerous membrane vesicles including exosomes into extracellular space wkich can be isolated from various biological fluids and cell culture supernatants. Exosomal diameter ranges between 40-100 nm. In current research, exosomes are being exploited as biomarkers for pathological diagnosis and potential remedy against various disease conditions such as infections and autoimmune disorders. In cancer immunotherapy, exosomes have promisingly been employed due to the identical immunogenic antigens of exosomes produced by neoplastic cells and the originating tissues. Antigen-specific T-cell activation and immunomodulatory activity is observed to be performed by exosomes isolated from tumor and dendritic cells (DCs). However, more research is still required to uncover the realistic uses of exosomes, particularly as drug delivery tool in autoimmune diseases, cancers and diabetes. PMID- 29624237 TI - CAPSAICIN: ITS BIOLOGICAL ACTIVITIES AND IN SILICO TARGET FISHING. AB - Capsicum annuum L. is a rich source of capsaicin, an alkaloid, which is a very pungent compound. Due to ever growing need of capsaicin, an extensive research on its efficient cultivation as well as chemical synthesis is underway. Owing to the pungent nature of capsaicin, its analogous molecules without pungent effect are being explored. The objective of this descriptive review is to comprehensively present the updates on the bioactivities of capsaicin. Additionally, the in silico target fishing approach has been used to identify the possible protein targets of capsaicin. This article will definitely provide future perspectives of research on capsaicin. PMID- 29624238 TI - ANALYSIS OF BASIC PSYCHOTROPIC DRUGS IN BIOLOGICAL FLUIDS AND TISSUES BY REVERSED PHASE HIGH PERFORMANCE LIQUID CHROMATOGRAPHY. AB - The review of the RP HPLC analysis of basic psychotropic drugs is presented. It contains sample preparation methods with centrifugation, protein precipitation, liquid-liquid extraction (LLE), dispersive liquid-liquid microextraction (DLLME), solid-phase extraction (SPE), solid-phase microextraction (SPME), microwave assisted extraction (MAE) and RP-HPLC analysis. Chromatographic behavior of basic drugs in aqueous media - eluents used in reversed phase systems is discussed. Methods of blocking of residue surface silanols' interaction are mentioned. Analytical methods used for the analysis are divided into parts according with the above methods: the use of low-pH eluents, the use of high-pH eluents, the use of silanol blockers, special stationary phases for basic analytes. Literature connected with the sample preparation methods and analytical systems for the drug analysis are cited in details and presented also in Table 1. PMID- 29624239 TI - APPLICATION OF VARIOUS POLYMERS AND POLYMERS BASED TECHNIQUES USED TO IMPROVE SOLUBILITY OF POORLY WATER SOLUBLE DRUGS: A REVIEW. AB - Solubility is concerned with solute and solvent to form a homogenous mixture. If solubility of a drug is low, then usually it is difficult to achieve desired therapeutic level of drug. Most of the newly developed entities have solubility problems and encounter difficulty in dissolution. Basic aim of solubility enhancement is to achieve desired therapeutic'level of drug to produce required pharmacological response. Different techniques are being used to enhance the solubility of water insoluble drugs. These techniques include particle size reduction, spray drying, kneading method, solvent evaporation method, salt formation, microemulsions, co-solven- cy, hydrosols, prodrug approach, supercritical fluid process, hydrogel micro particles etc. Selection of solubility improving method depends on drug properties, site of absorption, and required dosage form characteristics. Variety of polymers are also used to enhance solubility of these drugs like polyethylene glycol 300, polyvinyl pyrrolidone, chitosan, beta-cyclodextrins etc. PMID- 29624240 TI - DEVELOPMENT AND VALIDATION OF HPLC ANALYTICAL METHODS USED-FOR DETERMINATION OF ASSAY, CONTENT UNIFORMITY AND DISSOLUTION OF IMMEDIATE RELEASE CANDESARTAN CILEXETIL 32 MG TABLETS. AB - New analytical methods have been developed and validated on high performance liquid chromatography (HPLC) to assess the assay, content uniformity and dissolution of immediate release candesartan cilexetil 32 mg tablets. Method development studies were performed on cyano column. Mobile phase of assay and content uniformity test consisted of mixture of 0.05 M phosphate buffer, pH 4.5 and methanol (40 : 60, v/v) adjusted to pH 4.0 with trifluoroacetic acid, whereas mobile phase of dissolution test consisted of mixture of I mM phosphate buffer and acetonitrile (50 : 50, v/v) adjusted to pH 2.0 with trifluoroacetic acid. Mobile phases were pumped at flow rate of 1.0 mL/min, ultraviolet-visible (UV) detector was operated at 254 nm, injection volume was set at 20 MUL, column temperature was held at 250C. Dissolution medium was 0.05 M phosphate buffer, pH 6.5 including 0.70% (w/v) polysorbate 20. Validation studies met acceptance criteria of system suitability, specificity, linearity and range, accuracy, precision, detection limit (LOD), quantitation limit (LOQ) and robustness parameters. PMID- 29624241 TI - POTENTIOMETRIC STUDY OF Pd(II) COMPLEXES OF SOME FLAVONOIDS IN WATER-METHANOL-1,4 DIOXANE-ACETONITRILE (MDM) MIXTURE. AB - The potentiometric method was used to determine the protonation (dissociation) constants for morin, rutin and chrysin and the composition and formation constants of the Pd(II)-flavonoid complexes in the water/methanol/acetonitrile/1,4-dioxane mixture (water/MDM). All investigations were carried out at a constant ionic strength of I = 0.2 (KCI) at 298 K. Morin, rutin and chrysin are polyprotic acids (polihydroxy-flavones) practically insoluble in water, but they are soluble in organic solvents. The mixture of water/MDM is interesting because several solvents were mixed together to produce a solvent having a physical and chemical properties different of the pure components. The two (chrysin) and three (morin, rutin) dissociation constants were obtained by the Bjerrum method (graphic approximations) and numeric data analysis by Hyperquad2008 computer program. Obtained results provide evidence to show that investigated flavonoids in water-MDM solutions form with Pd(II) complexes of composition ML and MI.. The values of the stability constants suggest that the complexes of chrysin, rutin and morin with Pd(II) ions are of medium stability. Moreover, obtained result implies that morin forms the strongest complexes with Pd(II), subsequently rutin and chrysin. PMID- 29624242 TI - REVERSE PHASE HIGH PERFORMANCE LIQUID CHROMATOGRAPHY METHOD FOR DETERMINATION OF 5-FLUOROURACIL IN RABBIT PLASMA. AB - A simple, efficient, accurate and selective HPLC method has been developed and validated successfully for the estimation of 5-fluorouracil in rabbit plasma. The drug was eluted by using Supelco C18 column (1.5 cm x 4.6 mm, 5 MUm) with a mobile phase consisting of methanol and water (20: 80, v/v) by adjusting pH at 3.2, using perchloric acid solution. The retention time was found to be 4.107 with a flow rate of I mL/min. Multiple validation parameters evaluated with high accuracy indicating that the current method sufficiently qualifies the recommended criteria. Regression value obtained from linearity curve was R2 = 0.999 and percentage recovery obtained was ranged from 96.6 to 102.5%. A fine response in short run time with perfect resolution made the method highly suitable for pharmacokinetic studies. PMID- 29624243 TI - DEVELOPMENT AND VALIDATION OF FAST REVERSED-PHASE HPLC METHOD FOR ANALYSIS OF ESOMEPRAZOLE IN RABBIT PLASMA. AB - The present study focused to develop rapid, accurate and sensitive reversed-phase high pressure liquid chromatography method for the quantification of esomeprazole (ESO) magnesium in rabbit plasma. Chromatographic separation was achieved isocratically on a reversed-phase C,, column using simple mobile phase consisting of of methanol : acetonitrile: 0.05 M phosphate buffer, pH 7 adjusted with potassium hydroxide (45 : 10 : 45, v/v/v) at a flow rate of 1.0 mL/min and UV detection at 302 nm. The method was validated for system suitability, linearity, precision, accuracy, stability, robustness, LOD and LOQ. The described method stated good linearity over the range of 0.01 to 2.5 pg/mL (r = 0.999). The extraction recovery of esomeprazole was more than 95.3%. The method was precise with relative standard deviation < 1% with more than 90% accuracy and limit of quantification 0.0309 MUg/mL. The freeze thaw stability studies indicated that the rabbit plasma samples containing esomeprazole could be stored in freezer at 200C and handled under normal laboratory conditions without significant loss of drug. In conclusion, the developed method is simple, cost effective and reproducible, with improved sensitivity and running time of analysis. PMID- 29624244 TI - NEW RENIN INHIBITORS - STABILITY AND ACTIVITY DETERMINATION. PART IV. AB - A series of new seven potential renin inhibitors containing pseudodipeptides were synthesized. Stability for all compounds (1-7) in homogenates of liver, kidney, lung and in serum, gastric, intestinal juice and in the presence of alpha chymotrypsin was determined. Compound 1 was unstable in all determined mediums. Compounds 2, 4, 5 and 7 were unstable, compound 3 was stable, compound 6 was unstable only in alpha-chy-motrypsin solution. Inhibitory activity of the compounds was measured in vitro by HPLC determination of low-ering concentration of substrate (angiotensinogen) in the presence of renin and the potential renin inhibitor (compounds 1-7). Compounds 1, 2, 4, 5, 6 and 7 showed inhibitory activity (1.12 x 10-7, 0.96 x 10-6, 1.58 x10-7,1.68 x 10-6, 1.30 x 10-6, 0.96 x 10-7M, respectively). PMID- 29624245 TI - DEVELOPMENT AND VALIDATION OF BROMATOMETRIC, DIAZOTIZATION AND VIS SPECTROPHOTOMETRIC METHODS FOR THE DETERMINATION OF MESALAZINE IN PHARMACEUTICAL FORMULATION. AB - Three new methods were developed for the quantitative determination of mesalazine in the form of the pure substance or in the form of suppositories and tablets - accordingly: bromatometric, diazotization and visible light spectrophotometry method. Optimizing the time and the temperature of the bromination reaction (500C, 50 min) 4-amino-2,3,5,6-tetrabromophenol was obtained. The results obtained were reproducible, accurate and precise. Developed methods were compared to the pharmacopoeial approach - alkalimetry in an aqueous medium. The validation parameters of all methods were comparable. Developed methods for quantification of mesalazine are a viable alternative to other more expensive approaches. PMID- 29624246 TI - SIMULTANEOUS ASSAY OF ARIPIPRAZOLE AND ITS ACTIVE METABOLITE IN SERUM BY HPLC. AB - A rapid, convenient, precise HPLC method was developed for the simultaneous determination of aripiprazole and its active metabolite dehydroaripiprazole in blood serum. The separation was carried out by RP HPLC on Symmetry C18 column (150 x 4.6 mm; 5 MUm). The mobile phase was composed of acetonitrile: water (30 : 70, v/v), pH 3.0 adjusted with o-phosphoric acid. The detection was monitored at 220 nm. PMID- 29624247 TI - INCREASED OXIDATIVE STRESS AND DOWN REGULATION OF ENDOTHELIAL NITRIC OXIDE SYNTHASE (ENOS) IN THE KIDNEY ATTEN- UATE THE RESPONSIVENESS OF (XlB ADRENERGIC RECEPTORS IN THE KIDNEY OF RATS WITH LEFT VENTRICULAR HYPERTROPHY. AB - Present study explored endothelial nitric oxide synthase/nitric oxide (eNOS/NO) pathway in the kidney and role of alphaIB adrenergic receptor in the regulation of renal vasculature in the rats with left ventricular hypertrophy (LVH). LVH was induced by administering isoprenaline 5 mg/kg (s.c. 72 h. apart) and caffeine (62 mg/L in drinking water) for 14 days. Quantification of molecular expression of eNOS in kidney was performed by quantitative Real Time Polymerase Chain Reaction (qPCR). Renal vasoconstrictor responses were measured by administering noradrenaline (NA), phenylephrine (PE) and methoxamine (ME) in pre-drug phase, low dose and high dose phases of chloroethylelonidine (CEC), a selective of (alphaIB adrenergic receptor antagonist. In the kidney of LVH male Wistar Kyoto (WKY) rats eNOS was significantly down regulated (p < 0.05) by 74% relative to Control WKY (taken as 100%). The high dose 5 CEC attenuated the vasoconstrictor responses to NA by 41%, PE by 43% and ME by 33% in the LVH-WKY when compared to the same dose phase in Control WKY group. In LVH, increased oxidative stress in kidney and increased ACE activity in the plasma resulted in down regulation of eNOS/NO in the kidney. The renal vasoconstrictor responses to adrenergic agonist are blunted in LVH and (alphaIB adrenergic receptor is functional subtype in renal vasculature in LVH. PMID- 29624248 TI - ANTIOXIDANTS AND ANTIFUNGAL ACTIVITIES OF SUBSTITUTED GUANIDINES AND THEIR COPPER COMPLEXES. AB - A series of guanidines and their copper (II) complexes were investigated for their radical scavenging activity including peroxyl radicals (ROO), superoxide anion (O2), hydroxyl ('OH), and reactive hydrogen per- oxide (H202) species. Among the Cu(II) complexes, Cu-MR-9-2 shows the highest, Cu-MR-9-3, Cu-MR-9-6 less and Cu-MR-9-1 least antioxidant potential. The Cu(II) complexes show better Fea'-chelating activity than that of ligands. Among the Cu(II) complexes Cu-MR-9 2 was found to have the highest, Cu-MR-9-6 moderate, MR-9-3 less and Cu-MR-9-1 least ferric reducing capacity. The IC50 values for ligands (MR-9-1, MR-9-2, MR- 9-3, MR-9-6) were determined to be 197.53 +/- 7.13, 189.07 +/- 7.34, 207.98 +/- 6.78 and 233.38 +/-6.37 pM, which showed lower antioxidant activity than their Cu(II) complexes. The IC,o values for ascorbic acid were found to be 51.60 +/- 13.18 pM. The Cu(I) metal compounds (Cu-MR-9-1,Cu-MR-9-2, Cu-MR-9-3 and Cu-MR-9 6) were detected to be the most powerful scavengers of the hydroxyl radical with IC50 up to 108.03 +/- 11.34 pM, 101.41 +/-12.10 pM, 90.59 +/- 11.53 pM and 88.86 +/- 13.16 pM, respectively. PMID- 29624249 TI - SYNTHESIS AND BIOLOGICAL ACTIVITY OF NOVEL 6-PHENYL-1H-PYRROLO[3,4-c]PYRIDINE-1,3 DIONE DERIVATIVES. AB - The new pyrrolo[3,4-c]pyridines have been synthesized. 4-Methyl-6-phenyl-1H pyrrolo[3,4-cpyridine-1,3-dione (1) was the key intermediate for the synthesis of the novel derivatives of various chemical structures. In the first step, the pyrrolo[3,4-c]pyridine-1,3-dione 1 was alkylated to the corresponding N-alkyl-4- methyl-6-phenyl-IH-pyrrolo[3,4-c]pyridine-1,3-dione derivatives 2a-f. The Mannich bases 3a-j were synthesized by treating pyrrolo[3,4-c]pyridine-1,3-dione 1 with appropriate amines and formaldehyde. Hydrolysis of ester 2a gave the appropriate acid 5. Next, amides 4a-e have been obtained. The structures of the new compounds were confirmed by elemental analysis, IR and NMR spectra. The antitumor and antimicrobial activities in vitro of the obtained derivatives were examined. Mannich bases 3c and 3g showed activity against C. albicans and S. aureus. PMID- 29624250 TI - DESIGN, SYNTHESIS AND BIOLOGICAL EVALUATION OF 2,3-DISUBSTITUTED AND FUSED QUINOXALINES AS POTENTIAL ANTICANCER AND ANTIMICROBIAL AGENTS. AB - This article describes the synthesis of new bioactive quinoxalines as potential anticancer and antimicrobial agents; 2,3-dichloroquinoxaline was used as the key molecule for the preparation of various mono or disubstituted quinoxalines 2-7, pyridoimidazoquinoxaline derivative 8, thiazolo[4,5-b]quinoxaline derivatives 9 11, piperazinoquinoxaline derivatives 12, 13 and 1,4-benzoxazino[2,3 b]quinoxaline 15. The newly synthesized compounds were evaluated for their anticancer and antimicrobial activity. Assay results showed the compounds 6-bromo 2-chloro-N-[4-(trifluoromethyl)phenyl]-3-aminoquinoxaline (4), 7-bromo-2-[2-(4 methoxy-benzylidene) hydrazinyl]thiazolo[5,4-b]quinoxaline (9d) and 7-bromo 1,2,3,4-tetrahydropyrazino[2,3- blquinoxaline (12) proved to possess dual effects as potential anti-cancer and antimicrobial agents. PMID- 29624251 TI - STABILITY OF SOLUTIONS OF 2,3-DIPHENYLCYCLOPROPENONE IN VARIOUS SOLVENTS. A NOVEL FORMULA - DIPHENYLCYCLOPROPENONE IN ISOPROPANOL MAY BE USEFUL IN TOPICAL THERAPY OF PATIENTS WITH ALOPECIA AREATA. AB - The aim of this study was to evaluate the chemical stability of diphenylcyclopropenone (DCP) in var- ious solvents. DCP is being used in topical therapy in patients with alopecia areata (AA). The solvents for DCP used so far were acetone, ethanol and propylene glycol. DCP is supposed to be an immune modulating thera- peutic agent, however the studies on it's pharmacokinetics including chemical stability are lacking. In a pres- ent study, DCP was dissolved in acetone (A), ethanol (E), propylene glycol (PG) and isopropanol (I). Solutions at two concentrations: 0.1 and 3.0% were prepared in each of these solvents. Then, the solutions were divided into two parts - one'of which was stored at room temperature and the other in a refrigerator (at about 40C) with- out the access of light. In determined time intervals the solutions were analyzed and the content of DCP and it's main decomposition product DPA was assessed. The stability of solutions of DCP with all the solvents kept in a refrigerator (at about 40C) without light was maintained, the decomposition rate after 60 days was negligible. In contrary, DCP solutions kept at room temperature after 60 days decomposed visibly and in different rates according to a solvent (PG > I > E > A). The most surprising finding was that DCP solutions in acetone, which was supposed to be a good solvent for the purpose of AA treatment, decomposed completely (100%) after just 45 days at room temperature. The most stable solutions at room temperature turned out to be the ones in propy- lene glycol and isopropanol. Results suggest: 1. the preferable storage condition for all DCP solutions is at a temperature of about 40C without the access of light; 2. there is a limited benefit from'using acetone as a DCP solvent; 3. the novel solvent for DCP - isopropanol, showed good stability in both temperatures and has favor- able cosmetic qualities. In conclusion, authors suggest to make further investigations on DCP in isopropanol solutions in clinical studies regarding treatment of AA. PMID- 29624252 TI - DEVELOPMENT OF COMPRESSED COATED POLYPILL WITH MUCOADHESIVE CORE COMPRISING OF ATORVASTATIN/CLOPIDOGREL/ASPIRIN USING COMPRESSION COATING TECHNIQUE. AB - The study was conducted to formulate and assess a novel polypill comprising of atorvastatin calci- um (ATVC), clopidogrel bisulfate (CLB) and aspirin (ASP) which, after in vivo correlation, can be intended for use in hyperlipidemic chronic heart disease patients. Polypill was made by the compression coating technique (CCT) with multiple active ingredients along with different concentrations of mucoadhesive and sustained release polymers, i.e., Carbopol 934 (CAB), Methocel k15 (MTH) and sodium carboxymethyl cellulose (NaCMC). The effect of different concentration of polymers on physical properties, wash off time, mucoadhe- sion strength, swelling behavior, surface pH and drug release kinetics were investigated. In vitro drug release studies showed that combination of CAB NaCMC (1 : 1) retarded drug release up to 96.7 +/- 1.15%, while com- bination of CAB-MTH and MTH-NaCMC retarded drug release up to 81.9 +/- 1.5% and 101.4 +/- 1.3%, respec- tively, at the same polymer concentration. Core enteric coated tablet of ATVC (K 11) was compressed over with CLB and ASP granules with the help of CCT and produced the desired results with zero order release rate thus indicating successful formulation of proposed polypill. PMID- 29624253 TI - ASSESSMENT OF A STABLE COSMETIC PREPARATION BASED ON ENZYMATIC INTERESTERIFIED FAT, PROPOSED IN THE PREVENTION OF ATOPIC DERMATITIS. AB - Atopic dermatitis is one of the most common skin disorders seen in infants, children and adults. Proper prevention might slow the atopic symptoms. The purpose of the work was a sensory analysis, an evaluation of moistening properties and stability of emulsions based on an enzymatic interesterified fat blend (mutton tallow and walnut oil) and homogenized at different revolutions and different contents of thickener. The emulsions were evaluated with respect to sensory and skin moisturizing properties by 78 respondents. Stability tests, particle size, distribution, dispersity index, morphology structure of the emulsions were determinated too. Taking into consideration all properties of the emulsions, emulsion IV (containing 0.9 g carboxymethyl cellulose and homogenized at 18000 rpm) and emulsion V (1.5 g of carboxymethyl cellulose and homogenized at 24000 rpm) were found to be of optimum composition. The emulsions exhibited good stability, were highly rated in sensory terms and displayed optimum moistening properties. It has been proven that model emulsions based on interesterified fats containing partial acylglicerols, with optimum carboxymethyl cellulose content and specific revolutions at the time of homogenization are an opportunity for developing preparations targeted at skins requiring special care (e.g., with atopic dermatitis or psoriasis). The work proved the use of enzymatic process to create the emulsifier, which represents the innovative contribution of this work. Also it showed an additional application of enzymatic interesterified fats which since has been used only in food industries. PMID- 29624254 TI - PHARMACOKINETICS AND BIOEQUIVALENCE STUDIES OF TWO NIMESULIDE 100 mg TABLETS: UNIT DOSE, RANDOMIZED-SEQUENCE, TWO-WAY CROSSOVER STUDY IN HEALTHY VOLUNTEERS OF PAKISTANI POPULATION. AB - Single centered crossover, two cycles volunteer study was performed on 12 healthy male volunteers. Both reference and test, immediate release nimesulide formulation was given in a randomized manner with a washout period of 15 days and 5 mL of blood samples were drawn at 0.5, 1, 1.5, 2, 4, 8, 12 and 24 h. Plasma after centrifugation and deproteination, 100 MUL of the sample was injected using already validated HPLC method. In plasma LOQ was 0.01 +/- 0.012 MUg/mL, LOD was 0.001 MUg/mL and linearity was observed from 10 to 0.001 pg/mL. Pharmacokinetic parameters including in vivo bioequivalence were studied by using Kinetica 4.4.1. software. The average values of AUC,, was found to be 23.654 +/- 0.688 and 23.532 +/- 0.662 mg/L x h while C.. values were 6.101 +/- 0.403 and 6.072 +/- 0.403 pg/mL, respectively. Mean clearance and volume of distribution of reference formulation were 64.062 +/- 3.086 mL/h/kg and 9.416 +/- 4.767 L, respectively. The disposition rate constant in reference formulation was 0.339 +/- 0.598 h' while in immediate release it was 0.467 +/- 0.481 h-'. Absorption rate constant and distribution rate constant for reference brand were 1.409 +/- 0.251 h- and 1.201 +/- 0.283 h' while in immediate release formulation these values were 1.420 +/- 0.214 h-' and 1.227 +/- 0.263 h', respectively. Bioequivalence results showed 90% confidence of interval for compartmental parameters like Cmax was 99.1 to 100.3%, Tmax. was 98.198 to 99.658% and AUClast, was 99.88 to 100.08% and all were within range. PMID- 29624255 TI - FORMULATION AND ASSESSMENT OF SEMI-SOLID CARRIER INCORPORATED WITH HERBAL EXTRACT OF LAWSONIA INERMIS. AB - The development of an optimal microemulsion of lawsone for transdermal delivery was the core objective of the study. Effects of formulation variable including oils, surfactants and co-surfactants on the per- cutaneous delivery of lawsone microemulsion have also been inspected. Pseudotemary phase diagrams with oil, cosurfactant-surfactant mixtures (Smix) were constructed to recognize the microemulsion areas. Microemulsion prepared was of 5%. The in vitro transdermal penetration of microemulsion of lawsone was determined by Franz diffusion cell. These profiles indicated that the absorption and rate of penetration of lawsone microemul- sion was far better than the saturated solution of lawsone. The formulation was characterized for pH, conduc- tivity, viscosity and passed stability tests. A non-irritant formulation to skin was prepared in this way. The out- comes specify that the transdermal drug delivery ability and phase behavior of microemulsion is affected by the type of cosurfactant and surfactant. PMID- 29624256 TI - COLOCASIA ESCULENTA CORMS MUCILAGE-ALGINATE MICROSPHERES OF OXCARBAZEPINE: DESIGN, OPTIMIZATION AND EVALUATION. AB - The present investigation was undertaken with an objective of formulating sustained release microspheres of oxcarbazepine (OXC), an anti-epileptic drug, to overcome poor patient compliance and exposure to high doses associated with currently marketed OXC dosage forms. Ionic gelation technique was used to prepare OXC microspheres by using sodium alginate along with rate controlling polymer Colocasia esculenta mucilage (CEM) matrix as well coated form. The microspheres have been characterized by differential scanning calorimetry (DSC) for understanding thermal stability and Fourier transform infrared (FT-IR) spectroscopy to investigate the chemical interaction as well as to assess the structure of drug-loaded formulation. Surface morphology of the microspheres was investigated by scanning electron microscope (SEM). The size distribution of OXC microspheres as studied by optical microscopy was in the range of 394-575 pm. The microspheres exhibited encapsulating efficiency from 75 to 92%. The release of drug from the microspheres at pH 1.2 is negligible. Under neutral conditions, the microspheres were swell and release was attributed mainly to polymer relaxation. The release pattern from microspheres followed Korsmeyer-Peppas model and the value of n > 1 showed that drug released by anomalous (non-Fickian) diffusion. The data obtained thus suggest that a microparticulate system can be successfully designed by using CEM with alginate for sustained delivery of OXC. PMID- 29624257 TI - NANOEMULSION WITH CLOTRIMAZOLE - DESIGN AND OPTIMALIZATION OF MEAN DROPLET SIZE USING MICROFLUIDIZATION TECHNIQUE. AB - Poor water solubility of clotrimazole (CLO) hinders development of the effective pharmaceutical dosage forms. Many different concepts and approaches, including lipid based formulations, have been undertaken to improve delivery of CLO. The purpose of this study was to design the composition of nanoemulsion with CLO for topical use, which could be processed by microfluidization method. Based on the solubility study and the results obtained from the pseudotemary phase diagrams, the optimal compositions of nanoemulsions with CLO were selected (Capryol 90/Tween 80 and oleic acid/Tween 80). The coarse emulsions were prepared by using high shear mixer and then processing by microfluidization technique. It was shown that formulation containing oleic acid and Tween 80, because of gelling properties, was not suitable for microfluidization. The stable nanoemulsion was obtained by mixing Capryol 90 as oil phase and Tween 80 as surfactant. The mean diameter of the droplets of nanoemulsion with CLO was 45.7 nm, polydispersity index was 0.27 and zeta potential -40.3 mV. The mean droplet size,of CLO nanoemulsion was significantly decreased with the increment of microfluidization passes (from 75.4 +/- 3.2 nm to 63.2 +/- 3.4 nm, and to 45.7 +/- UR 2.8 nm after 5 and 10 passes. PMID- 29624258 TI - MICROWAVE RADIATION INDUCED SYNTHESIS OF HYDROXYPROPYL METHYLCELLULOSE-GRAFT- (POLYVINYLALCOHAL-CO-ACRYLIC ACID) POLYMERIC NETWORK AND ITS IN VITRO EVALUATION. AB - A microwave induced irradiation synthesis, was proposed for the preparation of hydroxypropyl methylcellulose-graft-(polyvinylalcohal-co-acrylic acid) hydrogels. The hydrogels were separately synthesized by using microwave irradiation method and conventional water bath heating method. Moreover, the prepared hydrogels were loaded with an antihypertensive drug, captopril. Chemical groups, thermal stability and surface morphology of these hydrogels were characterized by FT-IR, DSC and SEM. Swelling ratios of the gels were measured gravimetrically at'pH 1.2 and 7.4. Results showed that micrographs obtained from scanning electron microscopy (SEM), revealed that gels synthesized using microwave irradiation had more uniformly porous network structures. The uniformity in porosity was due to rapid and instantaneous penetration of microwave energy throughout the surface and they had higher swelling ratios in comparison to hydrogels synthesized by water bath method. Thermal analysis (DCS and TGA) depicted that crosslinked polymers were more stable. FT-IR analysis had confirmed the formation of the new polymeric network. X-ray diffractogram revealed that crystallinity of HPMC was reduced in hydrogel prepared by microwave radiation. It had also been observed that high crosslinking density diminish swelling of hydrogel. A stable network of hydroxypropyl methylcellulose (HPMC), poly(vinylalcohal) (PVA) and acrylic acid was developed in shorter time period under influence of microwave radiations. PMID- 29624259 TI - MODELLING AND BIOPHARMACEUTICAL EVALUATION OF CICLOPIROX OLAMINE GELS. AB - The ciclopirox olamine (CPO) has a broad antimicrobial profile including dermatophytes, yeasts and is used in various pharmaceutical forms. The aim of this study is to evaluate the quality of the CPO gels according to biopharmaceutial tests in vitro and antifungal activity assay. Hydroxypropyl cellulose, chitosan and poloxamer 407 were selected as agents gelificants. The effects of gelling agent properties and concentration on the consistency and flow characteristics have been studied by rheometer. CPO release rates from gel were measured with Franz type diffusion cells. The antifungal activity of gels was tested using agar well diffusion technique. The results of the experimental study have shown that the rheological properties of the medications depend on the selected gelling agent and the amount of it. The higher amounts of CPO were released from the poloxamer 407 gels. Though all tested CPO gels showed great inhibition of Microsporn canis. PMID- 29624260 TI - HIGH SHEAR GRANULATION PROCESS: ASSESSING IMPACT OF FORMULATION VARIABLES ON GRANULES AND TABLETS CHARACTERISTICS OF HIGH DRUG LOADING FORMULATION USING DESIGN OF EXPERIMENT METHODOLOGY. AB - High shear wet granulation is a significant component procedure in the pharmaceutical industry. The objective of the study was to investigate the influence of two independent formulation variables; polyvinypyrrolidone (PVP) as a binder (X,) and croscarmellose sodium (CCS) as a disintegrant (X2) on the crit- ical quality attributes of acetaminophen granules and their corresponding tablets using design of experiment (DoE) approach. A two factor, three level (32) full factorial design has been applied; each variable was investi- gated at three levels to characterize their strength and interaction. The dried granules have been analyzed for their density, granule size and flowability. Additionally, the produced tablets have been investigated for: break- ing force, friability, disintegration time and t. of drug dissolution. The analysis of variance (ANOVA) showed that the two variables had a significant impact (p < 0.05) on granules and tablets characteristics, while only the binder concentration influenced the tablets friability. Furthermore, significant interactions (p < 0.05) between the two variables, for granules and tablets attributes, were also found. However, variables interaction showed minimal effect for granules flowability as well as tablets friability. Desirability function was carried out to opti- mize the variables under study to obtain product within the USP limit. It was found that the higher desirability (0.985) could be obtained at the medium level of PVP and low level of CCS. Ultimately, this study supplies the formulator with beneficial tools in selecting the proper level of binder and disintegrant to attain product with desired characteristics. PMID- 29624261 TI - DEVELOPMENT AND EVALUATION OF IVABRADINE HCI-LOADED POLYMERIC MICROSPHERES PREPARED WITH EUDRAGIT L100-55 (METHACRYLIC ACID-ETHYL ACRYLATE COPOLYMER) AND ETHYL CELLULOSE FOR CONTROLLED DRUG RELEASE. AB - The objective of this study was to prepare and evaluate ivabradine HCl-loaded microspheres consisting of Eudragit LIOO-55 and ethyl cellulose prepared by oil in-oil solvent evaporation method. Ivabradine HCl was encapsulated into microspheres by in situ method. The resultant microspheres were characterized with respect to drug loading, flow properties, Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), X-ray diffractometry (XRD), thermal analysis and release behavior. Chemical stability of IBH after being encapsulated into microspheres was confirmed by FTR, DSC and XRD. FTIR spectra reflect- ed no interaction between drug and excipients. TGA indicates that prepared microspheres showed much better thermal stability than pure drug ivabradine. SEM images showed formulation of microspheres in spherical shape. The maximum perceniage entrapment efficiency was found to be 81 +/- 2.15 and percentage yield was 88 +/- 2.65. The maximum in vito drug release was 94.5% for the pH 7.4 and demonstrated that all drug-loaded formulations had a pH-dependent drug release. The cumulative drug release data were analyzed by applying different kinetic models. Korsmeyer-Peppas equation was used to determine value of n which follows non-Fickian diffusion. PMID- 29624262 TI - COMPARISON OF THE EFFECTS OF MARSANIDINE DERIVATIVES ON RAT CARDIOVASCULAR SYSTEM. AB - Since clonidine was introduced in clinical practice, attempts are still made to obtain substances capable of centrally controlling blood pressure, however with pharmacological profile better than currently avail- able, such as moxonidine and rilmenidine. Recently synthesized indazole derivatives exert promising action on blood pressure and heart rate in Wistar rats. In the present study, our aim was to check which of tested substituted compound exerts the best effect on basic circulatory parameters. Effects of marsanidine (M), 7-Me- marsanidine (7-Me-M), 7 Cl-marsanidine (7-Cl-M) and 7-F-marsanidine (7-F-M) on blood pressure, heart rate and diuresis were compared. Male Wistar rats were receiving iv. tested compounds in two doses: 10 or 100 pg/kg b.w. Mean arterial pressure (MAP), heart rate (HR) and ECG were recorded continuously. Urine samples were collected before and after administration of tested imidazolines. Obtained data were filtered and subjected to statistical analysis. All tested compounds caused a profound decrease of MAP. 7-M-M reduced blood pressure to the highest extent when used in 10 MUg/kg b.w. dose. 7-F-M in dose of 100 MUg/kg b.w. caused the strongest drop of MAP. The weakest and the shortest effect in duration was observed after M administration. HR was reduced after administration of each compound while the strongest effect was observed after 7-M-M administration in dose of 10 MUg/kg b.w. and after 7-Cl M administered in dose of 100 MUg/kg b.w. Again, the weakest and the shortest in duration effect was observed after M administration. The highest increase of diuresis was observed after 7-M-M administration. These data suggest that methyl substituent in 7 position of indazole ring is the most effective in improving hypotensive effects of newly synthesized imidazolidine derivatives. PMID- 29624263 TI - WHAT MOTIVATES POLISH COMMUNITY PHARMACISTS TO PURSUIT OF POSTGRADUATE EDUCATION?. AB - Due to increasing importance of the advisory role for physicians and patients played by the pharmacist over the last decade, it seems appropriate to evaluate if and why pharmacists are interested in postgraduate medical education. The purpose of the study was to develop and validate an instrument to assess such motives, with special interest to Polish community pharmacists. A self administered questionnaire was completed by a sample of participants of community pharmacist specialization programs and it was analyzed in relation to participants of other postgraduate courses. They were asked to rank their motives on a Likert-like scale and the underlying dimensions for study motives were identified using exploratory and confirmatory techniques. The reasons for taking specialization for community pharmacists were similar as compared to participants of other postgraduate studies. However, the autotelic factor was not so strong and the crucial reason was that such postgraduate training was required to be promoted in work. Basing on Polish results, we propose the division of motives into three groups - autotelic, instrumental and coincidental. The validated self administered questionnaire based on this division displayed acceptable construct validity and internal consistency, and therefore can be proposed as an example tool to assess the particular motives and expectations of potential postgraduate students and employees in the pharmaceutical job market. The promotion of postgraduate education among pharmacists can improve the quality of pharmaceutical service. PMID- 29624264 TI - INFLUENCE OF EXTRACTION PROCEDURE FROM EDIBLE MUSHROOM SPECIES BOLETUS BADIUS ON ZINC QUANTITY RELEASED INTO SIMULATED GASTRIC FLUID. PMID- 29624265 TI - CURCUMA LONGA AS MEDICINAL HERB IN THE TREATMENT OF DIABET- IC COMPLICATIONS. AB - Curcuma longa L. (turmeric) of ginger family (Zingiberaceae) belongs to the group of oldest cultivated spice plants in the south-east Asian countries. For many years rhizome of this plant has been used also as a safe and active drug for the treatment of various.chronic diseases, especially of diabetes mellitus (DM). The active substance of turmeric - curcumin (diferuloylmethane), possesses multiple therapeutic properties. In recent years, many detailed research (tests in vito and in vivo) along with clinical trials have revealed its very valuable biological activities related to its anti-inflammatory, antioxidant and cancer preventive properties, which are presented in numerous publications (1-6). At the molecular level it has been stated that curcumin inhibits cell proliferation, metastasis creation and apoptosis. Currently, great attention has been focused on curcumin as a blocker of TNF-s, which are the principal mediators of most inflammation-related disturbances (7). The main cause of blocking the broadly extended pharmacological and clinical investigations of curcumin is its extremely low solubility in water and in organ fluids. This feature consequently limits its systemic bioavailability and makes use of curcumin as a therapeutic remedy (to date) difficult. The primary aim of presently conducted research is to achieve increased solubilization and bioavailability of this promising nontoxic agent. PMID- 29624266 TI - INFLUENCE OF ORGANIC FOLIAR FERTILIZATION ON ANTIOXIDANT ACTIVITY AND CONTENT OF POLYPHENOLS IN OCIMUM BASILICUM L. AB - Basil is an important medicinal and culinary herb, cultivated on large areas in many countries. With the growing necessity of ecological products, organic crops need to be expanded, but a more complete characterization of such agriculture systems is required. The present paper aims to evaluate total phenolics and flavonoid contents, antioxidant activity of Ocimum basilicum L. under organic fertilization with four different foliar fertilizers (Fylo(r), Geolino Plants&Flowers(r), Cropmax(r), Fitokondi(r)). The total content of phenolic compounds was stimulated by all foliar fertilizers used in the experiment. In the first year, the highest increase was obtained in plants fertilized with Fylo (29%) and Fitokondi (27%) while in the second year Fitokondi fertilizer treatment lead to the highest increase of total phenolics (28%) compared to the control plants. The production of total phenolics was enhanced in the second year probably because the experiment was started earlier on April compared to first year. Foliar fertilization of basil plants can thus be used to obtain increased yield and phenolic compounds synthesis with little effect on the physiological parameters that were analyzed, allowing better performance of basil under organic fertilization. PMID- 29624267 TI - ANTICANCER ACTIVITY OF OAT beta-GLUCAN IN COMBINATION WITH ELECTROPORATION ON HUMAN CANCER CELLS. AB - The currently available data suggest that natural products may exert significant cytotoxic and immunomodulatory effects. Plant-derived chemotherapeutic agents such as taxol, etoposide or vincristine, currently used in cancer therapy, are prominent examples in this regard. However, there is a need for new and nat- ural anticancer compounds with low or without toxicity to normal cells. One of the active compounds responsible for the immune effects is beta-glucan derived from cereals, fungi, seaweeds, yeasts and bacteria. The recent data suggest that beta glucans are potent immunomodulators with anticancer properties. Antitumor properties of fungi and yeast derived beta-glucans have been widely recognized, but those polysaccharides are mostly insoluble, creating several problems especially in topical formulation. To overcome the issue of low water solubility, in the current study a more soluble beta-glucan type from oats was chosen for the investigation of its antitumor activities. Cytotoxic effects were studied using a human melanoma cell line (Me45). The effect of electroporation on the antitumor activity of oat beta-glucan was investigated as well. Cellular viability assessment, immuno-cytochemistry and immunofluochemistry were employed to evaluate biologic effects. Our results indicate strong anticancer properties of oat beta-glucan, enhanced by electroporation. PMID- 29624268 TI - INFLUENCE OF POMEGRANATE SEED OIL AND GRAPE SEED OIL ON CHOLESTEROL CONTENT AND FATTY ACIDS PROFILE IN LIVERS OF CHICKENS. AB - Oils are important food ingredients, mainly as a source of unsaturated fatty acids. The offer of novel edible oils from herbs, spices and fruit seeds has grown and many of them are used as functional food and dietary supplements but also as feed additives in animal feeding. Poultry meat is recommended.in properly balanced diet and its consumption in Poland has been growing. The objective of present study was to verify if the supplementation of chickens' diet with grape seed oil or pomegranate seed oil influences cholesterol content and fatty acids (FA) profile in their livers. Ross 308 chickens (n = 24) were fed with fodder enriched with grape seed oil (G group) or pomegranate seed oil (P group). Diet of control group (C group) was based on soybean oil. FA analysis in livers as well as cholesterol content was made with gas chromatography. We observed significant increase in fat content when part of soybean oil was replaced by grape seed oil (p = 0.0002). Its highest amount was detected in G group (4.44 +/- 1.53%) whereas the lowest in C group (1.73 +/- 0.53%). Applied supplementation did not change total cholesterol content. Its content ranged from 233.0 +/- 12.2 mg/100 g in G group to 234.6 +/- 29.7 mg1100 g in C group. However, chickens' diet modification with grape seed oil and pomegranate seed oil influenced the FA profile in livers. We detected the presence of punicic acid (cis-9, trans-11, cis-13 C18:3, PA) in livers of chicken fed with pomegranate seed oil. Pomegranate seed oil is one of natural sources of conjugated linolenic acids (CLnA), which predominate in this oil (PA >70% of all FA). However, in livers PA constituted only 0.90 +/- 0.10% of all fatty acids. Furthermore, we detected substantial amounts of rumenic acid (cis-9, trans-11 C18:2, RA) - the major isomer of conjugated linoleic acids (CLA). Its natural sources in diet are meat and milk of ruminants, but incorporation of pomegranate seed oil into chickens' diet caused a significant increase of its share in fatty acids pool in their livers (3.73 ? 0.79% in P group in relation to 0.08 +/- 0.03% in G group and 0.02 +/- 0.00% in C group, p < 0.0001). It proves that PA is effectively converted into RA in chickens organisms. Pomegranate seed oil seems to be an interesting feed additive in chicken feeding which can improve FA profile of poultry meat. PMID- 29624269 TI - IN VIVO STUDIES AND STABILITY STUDY OF CLADOPHORA GLOMERATA EXTRACT AS A COSMETIC ACTIVE INGREDIENT. AB - Marine algae are widely used as cosmetics raw materials. Likewise, freshwater alga Cladophora glomerata may be a good source of fatty acids and others bioactive agents. The aims of this study was to find out if the addition of the extract from the freshwater C. glonerata affects the stability of prepared cosmetic emulsions and to investigate in vivo effects of the extract in cosmetic formulations on hydration and elasticity of human skin. Extract from the freshwater C. glonierata was obtained using supercritical fluid extraction (SFE). Two forms of O/W emulsions were prepared: placebo and emulsion containing 0.5% of Cladophora SFE extract. The stability of obtained emulsions was investigated by using Turbiscan Lab Expert. Emulsions were applied by .volunteers daily. Corneometer was used to evaluate skin hydration and cutometer to examine skin elasticity. Measurements were conducted at reference point (week 0) and after 1st, 2nd, 3rd and 4th week of application. The addition of Cladophora extract insignificantly affected stability of the emulsion. The extract from C. glomerata in the emulsion influenced the improvement of both skin hydration and its elasticity. Thus, freshwater C. glonierata extract prepared via SFE method may be considered as an effective cosmetic raw material used as a moisturizing and firming agent. PMID- 29624270 TI - IMPACT OF FABRICS FROM TRANSGENIC FLAX PLANT ON HUMAN DERMAL FIBROBLASTS IN VITRO PROLIFERATION. AB - Previously it was documented that transgenic flax plants, which contained an increased level of polyphenolic compounds, significantly improved healing of skin wounds lesions. In order to recognize mechanisms of beneficial action of transgenic flax fabrics on wound healing, in the present study the impact of flax fabric pieces/cuts from three types of transgenic flax on normal human dermal fibroblasts primary culture (NHDF) was investigated. NHDF cell cultures were exposed for 48 h to specific area of flax fabric cuts, made from M50, B 14 and M50+B14 (intertwined fibers of M and B), or parallely, extracts from fibers of the tested flax materials to cell culture medium. Cultures were inspected for cell viability, proliferation, cell cycle changes and for their resistance to oxidative stress (consecutive addition of H2,O2, to harvested cell cultures). None of the tested flax fabrics were cytotoxic to fibroblast cultures and also did not increase significantly a frequency of apoptotic cells in cultures. In the comet assay, the tested flax fabrics revealed significant protective effect on DNA damage ciused by addition of H202 to the cultures at the end of incubation time. Fabrics from transgenic flax significantly enhanced fibroblasts proliferation in vitro estimated with the SRB test. Flow cytometric analysis revealed higher frequency of cells in the S phase, in the presence of transgenic flax fabrics. Fabrics from B14 and M50+B14 flax are the most potent activators of NHDF cells in applied in vityo tests, hence they could be recommended for elaboration of new type bandage, able to improve skin wound healing. PMID- 29624271 TI - FLAX OIL FROM TRANSGENIC LINUM USITATISSIMUM SELECTIVELY INHIBITS IN VITRO PROLIFERATION OF HUMAN CANCER CELL LINES. AB - Emulsions made of oils from transgenic flaxseeds significantly decreased in vitro proliferation of six tested human cancer cell lines in 48-h cultures, as assessed with the standard sulforhodamine assay. However, the emulsions also increased proliferation rate of normal human dermal fibroblasts and, to a lower extend, of keratinocytes. Both inhibition of in vitro proliferation of human cancer cell lines and stimulation of proliferation of normal dermal fibroblasts and keratinocytes were especially strong with the emulsion type B and with emulsion type M. Oils from seeds of transgenic flax type B and M should be considered as valuable adjunct to standard cytostatic therapy of human cancers and also could be applied to improve the treatment of skin lesions in wound healing. PMID- 29624272 TI - POLYPHENOL CONTENT AND BIOACTIVITY OF SASKATOON (AMELANCHIER ALNIFOLIA NUTT.) LEAVES AND BERRIES. AB - The studies were designed to determine the polyphenolic composition and biological activity of extracts from fruits (SFE) and leaves (SLE) of Saskatoon (Amelanchier alnifolia Nutt.) in relation to erythrocyte membranes. A detailed quantitative and qualitative analysis of extracts was conducted, using the chro- matographic (UPLC-DAD, UPLC-ESI-MS) and spectrophotometric (Folin-Ciocalteu) methods. The biological activity of the extracts was investigated in relation to erythrocytes and isolated membranes of erythrocytes by using spectrophotometric, fluorimetric and microscopic methods and determined on the basis of hemolytic and antioxidant activity of the extracts and their impact on physical properties of the membrane such as: osmotic resistance, shape of erythrocytes, packing order of the polar head of lipids and fluidity of the membrane. The results showed that the tested extracts are rich sources of polyphenols, primarily from the group of flavonoids; in leaves dominating flavonols and anthocyanins in fruits. The SFE and SLE extracts to varying degree modify the physical properties of the erythrocyte membrane, causing formation of echinocytes, an increase in osmotic resistance and changes in the polar part of the membrane. Furthermore, the substances markedly protect erythrocytes and their membranes against oxidation induced by different physico-chemical factors. The findings indicate that the polyphenolic compounds contained in extracts of Saskatoon do not destroy biological membranes but effectively protect them against oxidation by way of interacting with the membrane surface. The extracts could effectively protect the organism and food products from the harmful effects of free radicals. PMID- 29624273 TI - CONDITIONS OF PROOXIDANT ACTIVITY OF CISTUS AND POMEGRANATE POLYPHENOLS IN V79 CELL CULTURES. AB - Polyphenol rich extracts obtained from cistus herb (Cistus incanus L.) and pomegranate peels (Punica granatunm L.) added at high concentrations (25-100 pg/mL) to V79 (Chinese hamster lung fibroblast) cell cultures, markedly increased intracellular level of ROS (reactive oxygen species). Also in cells exposed to the exogenous oxidant - H202, [100 MUM, 30 min., 37'C] intracellular ROS level was augmented, although to a lower extent than in resting cells not exposed to H202. Additionally, cistus and pomegranate extracts at high concentration (25-100 MUg/mL) inhibited the P-gp protein efflux function in V79 cell cultures. Both pro oxidant activity of polyphenols at high concentrations and their ability to decrease efflux function of P-gp (cellular multidrug resistance protein) could be exploited for improving anticancer adjuvant therapy. PMID- 29624274 TI - ACTIVITY OF BLACKCURRANT AND CHOKEBERRY EXTRACTS AND TWO MAJOR CYANIDIN GLYCOSIDES AGAINST LIPID MEMBRANE OXIDATION AND THEIR BINDING PROPERTIES TO ALBUMIN. AB - The purpose of this study was to explain how extracts from chokeberry and blackcurrant interact with the lipid phase of biological membrane and with human albumin - the main protein of blood. Aiming at better understanding of the observed biological activity of the extracts, we also conducted experiments with their main components: cyanidin-3-0-galactoside and cyanidin-3-0-ruthinoside. Antioxidant activities of extracts and cyanidin derivatives were investigated with phosphatidy1choline liposomes and AAPH as oxidation inducing factor. Fluorescent probes (merocyanin and N-phenyl-1-naphthylamine) that were located at different depths within the membrane lipid bilayer were also used. The interaction between the compounds and human serum albumin was investigated using natural fluorescence quenching. According to our study it is highly likely that the significant antioxidant activity of chokeberry and blackcurrant extracts (IC50chokeberry = 4.92 pg/mL; IC50blackbcurrant = 7.04 MUg/mL) is probably due to cyjanidin's main derivatives, which protect the lipid membrane more than the extracts. In addition, it has been suggested that the compounds are anchored mainly on the membrane surface and rigidify/order the lipids in the membrane. That rigidifying effect is the key factor for understanding their antioxidant properties. Experimental results have proved that all the study compounds quench the fluorescence of HSA through a static mechanism and the main interaction forces are the Van der Waals and hydrogen bonding interactions. The results of the study have improved our knowledge on how to protect membranes against lipid peroxidation using extracts rich in anthocyanins. The results can be relevant to pharmacists and nutritionists. PMID- 29624275 TI - ANTIOXIDANT AND CANCER CHEMOPREVENTIVE ACTIVITIES OF CISTUS AND POMEGRANATE POLYPHENOLS. AB - Polyphenol rich extracts obtained from cistus herb (Cistus incanus L.) and pomegranate peel (Punica granatum L.) exhibited significant antioxidant activity in V79 cell culture (Chinese hamster lung fibroblasts) -cistus extract reduced intracellular content of reactive oxygen species (ROS) by 30-40% and pomegranate extract by 29-36%. In human breast (MCF-7) and colon (LOVO) cancer cell lines cistus and pomegranate extracts decreased cancer cell growth both in drug sensitive cells by 15-30% and in drug resistant (doxorubicin-resistant; DX) sublines by 5-20%. However, the extracts did not influence on cell growth%f normal hamster fibroblast cultures (V79). The extracts induced apoptosis in the tested cancer cell lines. Significantly higher proapoptotic impact of the extracts was observed in drug-sensitive than in drug-resistant sublines. The results suggest potential usefulness of the tested polyphenol rich extracts in people exposed to oxidative stress. Their potential use as adjuvant therapy of human cancers needs further studies. PMID- 29624276 TI - CHEMICAL COMPOSITION AND ANTIMICROBIAL ACTIVITY OF GERANIUM ROBERTIANUM L. ESSENTIAL OIL. PMID- 29624277 TI - DEVELOPMENT OF AROMA IN SPROUTING SATUREJA HORTENSIS. PMID- 29624278 TI - IN VITRO ACTIVITY OF PEPTIDE FRACTIONS FROM IMPATIENS GLAN- DULIFERA AGAINST CARIES CAUSING BACTERIA. PMID- 29624279 TI - ANTIMICROBIAL ACTIVITY, CYTOTOXICITY AND TOTAL PHENOLIC CONTENT OF DIFFERENT EXTRACTS OF PROPOLIS FROM THE WEST POMERANIAN REGION IN POLAND. PMID- 29624280 TI - ANTIMICROBIAL ACTIVITY OF ESSENTIAL OIL AND FURANOCOUMARIN FRACTION OF THREE HERACLEUM SPECIES. PMID- 29624281 TI - CHROMATOGRAPHIC ANALYSIS OF ORGANIC ACIDS, AMINO ACIDS, AND SUGARS IN OCIMUM AMERICANUM L. PMID- 29624282 TI - Moving Beyond Cancer: Immediate Impact on-the Health-Related Quality of Life of Breast Cancer Patients After Mastectomy. AB - During the last decade, survival rates for breast cancer have increased as a result of earlier detection and increased use of adjuvant therapy. Limited data exist on the post mastectomy quality of life in the process of transition from health to cancer in its different phases of treatment. The aim of current study was to evaluate the changes of health-related quality of life (HRQoL) after mastectomy and to measure their impression about future perspectives in Bangladeshi Breasts cancer patients. A group of 250 women with a diagnosis of primary breast cancer who was admitted in the department of surgical oncology in National Institute of Cancer Research and Hospital, Dhaka were enrolled in this study from January 2012 to March 2013. Two-point interview like pre(MI) and post mastectomy(M2) was taken using the structured questionnaire made by European Organization for Research and Treatment of Cancer (EORTC)- EORTC Q30 and BR23. The mean age of the patients was 44.7?9.87 years, 52.6% were locally advanced. HRQoL scores of breast cancer patients deteriorated after mastectomy, general features like presence of fatigability, nausea, apatite loss, sleeplessness and pain has got tremendous effect on the quality of life(p<.005). Financial difficulties and sleep disorders did not affect much. Four of the Global Health status/QOL parameters like physical functioning, role functioning, emotional functioning, cognitive functioning deteriorated but only physical functioning status affected significantly(p<0.005). Breast symptoms like body image problem, general breast symptoms like pain, arm swelling and sexual feeling affected their (HRQOL) after mastectomy. A diagnosis of cancer and associated treatments affects multiple domains of life. The complicated transitions between health, illness and living with cancer can often be challenged with a preoperative information for the patient confronted with breast cancer should include possible psychological effects of cancer diagnosis, surgery, and other treatment. Breast conservation particularly in the young group may give a better outcome in the treatment protocol of breast cancer patients. PMID- 29624283 TI - Sociocultural and host factors related to extra-pulmonary tuberculosis in rural Bangladesh: A case control study. AB - Bangladesh ranks sixth among higher TB burden countries. Extra-pulmonary TB contributes 12% of all tuberculosis cases in 2008. Risk factors for EPTB in Bangladesh are hypothesized to be different from pulmonary tuberculosis as seen in other high-burden countries. A case control study was conducted to compare the sociodemographic, household condition and lifestyle characteristics between extra pulmonary and pulmonary tuberculosis. This case control study was conducted in thirteen sub districts of Pabna, Shirajgonj and Cox's Bazar districts from January to June 2013. The samples were classified as either extra pulmonary tuberculosis EPTB (cases) or pulmonary tuberculosis PTB (controls). A total of 490 participants including 245 extra pulmonary tuberculosis (cases) and 245 pulmonary tuberculosis (controls), who were being enrolled in DOTS treatment for last six months, were interviewed for epidemiological and clinical information using a standardized questionnaire. Children, adolescent and younger adults had four-time higher risk of being manifested with extra pulmonary tuberculosis [Adjusted odds ratio (AOR) 3.97; 95% Confidence Interval (CI) 1.10 to 14.35] and (AOR 4.50; 95% CI 1.48 to 13.72). Respondents, who lived in their own houses showed three times more chance of getting extra pulmonary disease (AOR 3.11; 95% CI 1.15 to 8.39). Extra pulmonary tuberculosis was seven to eight times more likely to occur among those whose resided in bedrooms ventilated with one (p= .001) or more windows (p =.004) and having window shutter made of glasses or wood slit raised the probability of getting extra pulmonary involvement by twenty times. Households using grain husk and leaves as cooking fuel revealed seven times higher chance of being manifested as extra pulmonary tuberculosis (P <.001). Extra pulmonary cases were three times more common among respondents, who had no history of exposure with known tuberculosis cases than those who had frequent exposure history (AOR 3.01; 95% CI 1.24 to 7.34). Extra pulmonary tuberculosis was found 1.5 times more common among BCG vaccinated respondents than pulmonary tuberculosis (AOR 1.66; 95% CI 1.06 to 2.58). Younger age, house ownership, bedroom ventilation, fuel material used for cooking, contact history and BCG vaccination status might be the important risk factors for the extra pulmonary manifestation of tuberculosis relative to pulmonary tuberculosis. PMID- 29624284 TI - Detection of potential pathogenic aerobic bacteria from egg shell and egg contents of hen collected from poultry. AB - This study was done to identify different pathogenic aerobic bacteria from egg shell and egg contents of hen. Egg shells and egg contents of 150 eggs collected from poultry were tested. Of 150 egg shells, 130 (86.67%) yielded growth of bacteria and 60 (40%) Esch. coli,.25 (16.67%) Providencia rettgeri, 5 (3.33%) Providencia alkalifaciens, 20 (13.33%) Citrobacter freundii, 10 (6.67%) Salmonella spp, 10 (6.67%) Enterobacter aerogenes were isolated. No bacteria were isolated from 150 egg contents. Total 14 (9.33%) Salmonella spp. from egg shells and 7 (4.67%) Salmonella spp. from egg contents were identified by PCR. Most of the identified serotypes were Salmonella Enteritidis (42.86% from egg shells and 71.43% from egg contents). All (100%) Salmonella Typhi and Salmonella Paratyphi A were sensitive to ciprofloxacin and ceftriaxone. PMID- 29624285 TI - Silkworm as an animal infection model for the screening of environmental, clinical and veterinary pathogens. AB - Silkworm, Bombyx mori, has passive immunity and can be infected by pathogenic bacteria. Therefore, it can be used as a robust bacterial infection model for screening of pathogenic isolates from various sources. In this work, 11 environmental, clinical and veterinary isolates were screened for pathogenicity using silkworm larvae by injecting bacterial suspension through their dorsal surface and observing response. Experimental conditions were established by using Bacillus thuringiensis SW_R_F_1, Escherichia coli 0157:H7, E. coli DH5a and 0.6% saline. Nine out of 11 isolates were detected pathogenic after screening. The biochemical and genomic analysis of the nine test isolates confirmed their pathogenicity. The LD50 of Pseudomonas aeruginosa 47D and Salmonella Typhimurium 77 were 4.63x107 at 12 hours was 8.02x107 cells/lOOMUI/gram at 24 hours respectively. These results indicated that silkworm exhibits differential pathological response for pathogenic and nonpathogenic bacteria, and can be used as an alternative to animal model for screening diverse isolates. PMID- 29624286 TI - Role of ultrasonography in diagnosis of solid space occupying lesion in the liver correlation with FNAC. AB - This cross sectional study was carried enrolling 47 subjects with suspected solid liver mass, in the Department of Radiology and Imaging, Dhaka Medical College Hospital, Dhaka, over a period of twelve months. The aim of this study was to evaluate the diagnostic usefulness of transabdominal ultrasonography in the diagnosis of solid SOL in the liver. Majority of the respondents (42.55%) were found between 41-60 years of age. Five (10.63%) subjects were found below 20 years of age. There were 31 men (65.95%) and 16 women (34.05%). Majority of the metastasis were multiple (85%), hypoechoic (35%) and only 15% had internal calcifications. HCC was single lesion (61.53%) with hyperechoic (38.35%) echogenicity, with a central halo (76.92%) and 15.38% had internal calcifications. Majority of the cholangiocarcinoma were solitary (80%), hypoechoic (60%) and 60% had internal calcifications. Hepatoblastoma were solitary and had calcifications (60%) with mixed echogenicity (60%). Majority of the adenomas were solitary (80%), hypoechoic (60%) and only 20 % had internal calcifications. The validity of transabdominal sonography for the diagnosis of metastasis was confirmed by calculating sensitivity (100%), specificity (96.42%), accuracy (97.87%), positive (95%) and negative predictive (100%) values by using the standard formula given. The sensitivity, specificity, accuracy, positive and negative predictive values for HCC were 92.3%, 97.05%, 95.74%, 92.3% and 97.05% respectively. The sensitivity, specificity, accuracy, positive and negative predictive values for cholangiocarcinoma and hepatoblastoma were 80%, 97.61%, 95.74%, 80% and 97.61% respectively. Sensitivity, specificity, accuracy, positive and negative predictive values were 80%, 100%, 97.87%, 100% and 97.67% respectively for adenoma. From the study result it was concluded that transabdominal ultrasonography could be reliable, non- ionizing and relatively cheap procedure for diagnosis solid hepatic mass lesion. PMID- 29624287 TI - Central venous catheter-related bloodstream infections (CVC-BSI) in patients of clinically suspected septicemia. AB - Central venous catheter-related bloodstream infections (CVC-BSI) are associated with morbidity and mortality especially in critically ill patients. This study was performed to find out the rate of CVC-BSI and CVC colonization, causative organism and their antibiogram in patients of Intensive Care Unit (ICU) and Department of Nephrology of tertiary care hospitals. A total of 100 patients from Bangabandhu Sheikh Mujib Medical University (BSMMU) and Dhaka Medical College Hospital (DMCH) who had-CVC and clinically suspected of septicemia were included in the study. Paired CVC blood and peripheral venous blood (PVB) samples were collected from each patient and were cultured by automated blood culture method. CVC-BSI was diagnosed in 11% and CVC colonization in 43% patients by Differential time to positivity (DTP) method. Rate of CVC-BSI was 8/1000 CVC days and 11/1000 CVC days in BSMMU and DMCH respectively whereas CVC colonization rate was 32/1000 CVC days and 47.5/1000 CVC days in BSMMU and DMCH. The most common bacteria causing CVC-BSI was Klebsiella spp. (36.4%) followed by Acinetobacter spp. (27.3%), Pseudomonas spp. (18.2%) and E. coli (18.2%). Among bacteria isolated from CVC colonization majority were Pseudomonas spp. (30.23%) and Staphylococcus epidermidis (30.23%) followed by Acinetobacter spp. (27.91%), Enterococcus spp. (6.98%). Most of the isolated bacteria causing CVC-BSI were resistant to commonly used antibiotics, but showed good sensitivity to imipenem and colistin. Information about CVC-BSI, -colonization and antibiogram of this study can help to guide the selection of suitable antibiotics for empirical therapy and to improve infection control measures of the hospital. PMID- 29624288 TI - The overview of cancer patients attending in a specialized hospital: A cross sectional study. AB - According to National Institute of Cancer Research and Hospital most frequently observed cancers in Bangladeshi population are lungs, breast, cervix, lymph node, esophagus, larynx and stomach. The point of epidemiological background, the rate of incidence and mortality are likely unavailable due to lack of population based cancer registry system in Bangladesh. This cross-sectional study was conducted from 2003 to 2012 with an aim to describe trends and pattern of cancer cases attended a specialized hospital in Dhaka city. A total of 29,999 cancer cases was enrolled and among them the male and female ratio was 1.2:1. The study revealed that around half of the patients attended from Dhaka division, followed by Chittagong division (22.9%) and Sylhet division (8.8%). According to the organ involvement most frequently reported malignancies in males were lung cancer (24.2%), followed by eight percent larynx cancer and six percent lymph node cancer, whereas in females were breast cancer (27.5%), followed by cervix cancer (19.5%) and five percent lung cancer. It has been found that the system involvement was observed of cancers among male's respifatory system (33.5%) followed by the digestive organs (20.0%) and oral cavity (14.2%) whereas in females were reproductive organs (26.3%), followed by fourteen percent digestive organs and eight percent oral cancer. The overall cancer trend showed a gradual rise of cancer cases in both sexes. The rate was higher in females rather than male. Without the availability of population based registries, incidence and mortality figures; studies like the present one may provide useful leads for health planning and future exploration. PMID- 29624289 TI - Molecular characterization and resistance profile of nosocomial Acinetobacter baumannii intensive care unit of tertiary care hospital in Bangladesh. AB - This study was designed to investigate the resistance profile along with the genetic background of resistance to beta-lactam antibiotics among the nosocomial A. baumannii in Bangladesh. A. baumannii was confirmed by detecting blaoXA-51 like. Antibiotic susceptibility was determined by disk diffusion method. Agar dilution method was used to determine MIC of ceftazidime and imipenem. All A. baumannii were phenotypically screened for ampC, ESBL and MBL production. Genetic markers of antibiotic resistance. such as blaampC, blaOXA-51, 23, 40, 58 and 143, blaKPc, blaMp, blavi and blaNDM-j, genetic environment around blaADc and ISAbal upstream of blaoXA, were evaluated by PCR. Twenty-four (96%) A. baumannii were considered as MDR. 96% A. baumanii were resistant to amoxiclav, ceftazidime, ciprofloxacin and cefoxitin, 92% to cefotaxime and piperacillin-tazobactam, 88% to cefepime, amikacin and imipenem, 52% to sulbactam- cefoperazone and 40% were resistant to aztreonam. Everything were sensitive to colistin. The distribution of several beta-lactamase genes such as blaoxa-51 (100%), blaADC-like (92%), blaNDM-i (92%), EBC group (84%), blaoxa-23 (76%), blavm (72%), blacpc (44%), DHA group (24%), blaoxa-58 (16%), ACC group (8%) and CIT group (4%) were observed among the 25 A. baumannii. This is the first reported plasmid mediated ampC beta lactamases in A. baumannii. blaoxa-51 was positive in 100%, blandm-i in 95.45%, blaoxa-23 in 77.27%, blavim in 72.73%, blakpc in 50% and blaOXA-58 in 18.18% of imipenem resistant isolates. MDR profile of nosocomial A. baumannii would highlight the importance of standard guideline of antimicrobials use and infection control policy in the hospitals of Bangladesh. PMID- 29624290 TI - Fabrication of Self-Cleaning and Anti-Icing Durable Surface on Glass. AB - Ice accumulation on insulators affected the safety of power system and may inflict serious consequences such as insulator flashover accidents and power failure. This article reported a simple method to prepare anti-icing polydimethylsiloxane superhydrophobic surface on glass by utilizing nano-particle filling method. The effect of concentration of silica nanoparticles on superhydrophobicity of the samples was investigated. The wettability, surface morphology and anti-icing property of the as-prepared superhydrophobic surface were characterized by corresponding methods. Results show that the as-prepared surface with addition amount of 7 g silica nanoparticles exhibited self-cleaning property and excellent superhydrophobicity with a contact angle of 165.7 +/- 2.4 degrees and a sliding angle of 3.8 degrees . It was found that the ice formation was delayed for 29 min at -5 degrees C. Moreover, the as-prepared superhydrophobic surface showed superhydrophobicity in the pH range of 1-13 and exhibited excellent drop impact stability. The as-prepared superhydrophobic surface may be suitable for applications in cold regions owing to its flexibility, durability and anti-icing property. PMID- 29624293 TI - Application of Nano-SiO2 and Nano-Fe2O3 for Protection of Steel Rebar in Chloride Contaminated Concrete: Epoxy Nanocomposite Coatings and Nano-Modified Mortars. AB - The effect of incorporating nanoparticles on the corrosion resistance of epoxy coated steel in salt contaminated mortars was investigated using potentiodynamic polarization and electrochemical impedance spectroscopy. Researchers conducted electrochemical monitoring of the coated steel embedded in mortar over 100 days of immersion in 0.1 M NaOH solutions. The chloride permeability and microstructure of Portland cement mortar with admixed nano-materials (at 1% by weight of cement) were examined using an electromigration test and field emission scanning electron microscopy (FESEM). Electrochemical monitoring showed that nano Fe2O3 improved the corrosion resistance of the coated rebar. The incorporation of a small amount of nano Fe2O3 (1% by total weight of resin and hardener) into the epoxy coating reduced the corrosion current of the epoxy-coated steel in chloride contaminated mortar (0.3% chloride by weight of cement). After 100 days of immersion, the nanoparticles reduced the corrosion current of epoxy-coated steel by a factor of 6. The FESEM test revealed that admixing of nano-materials not only led to denser cement mortar but also changed the morphology of cement hydration products. The test results of compressive strength showed that nanoparticles increased the strength of cement mortar. The electromigration test showed that the incorporation of nanoparticles improved the chloride penetration resistance of the mortar, as indicated by the reduced apparent diffusion coefficients of the chloride anion. When nano-SiO2 and nano-Fe2O3 were admixed into fresh cement mortar at 1% by weight of cement, the value of D(Cl-) was decreased by 83%, from 7.35*10(-11) m2/s (control specimen) to 1.21*10(-11) m2/s and 1.36*10(-11) m2/s, respectively. PMID- 29624291 TI - Neonatal Genistein Exposure and Glucocorticoid Signaling in the Adult Mouse Uterus. AB - BACKGROUND: Female reproductive tract development is sensitive to the endocrine disrupting potential of environmental estrogens. Early-life exposure to the dietary phytoestrogen genistein impairs fertility and persistently alters the transcriptome in the oviduct and uterus of rodents. Glucocorticoid signaling, which has recently been shown to be essential for normal fertility in the female mouse uterus, is antagonized by genistein. OBJECTIVE: Our goal was to determine whether early-life exposure to genistein disrupts glucocorticoid signaling in the mouse uterus, which may contribute to infertility. METHODS: Female C57Bl/6 mice were exposed to either 50 mg/kg per day genistein, 10 MUg/kg per day estradiol, or vehicle (corn oil) on postnatal days 1-5 (PND1-5), and then treated with the synthetic glucocorticoid dexamethasone (Dex: 1 mg/kg) or vehicle (saline) on PND5, at weaning on PND21, or as adults on PND56 following adrenalectomy and ovariectomy to evaluate glucocorticoid responsiveness. Uteri were isolated following treatment for gene expression or chromatin immunoprecipitation. RESULTS: Neonatal exposure to genistein altered the uterine transcriptome of adult mice and caused substantial changes to the transcriptional response to glucocorticoids. Although expression of the glucocorticoid receptor was not affected, genistein exposure disrupted glucocorticoid receptor recruitment to specific regulatory sites in target genes. Many genes involved in chromatin remodeling were dysregulated in genistein-exposed mice, suggesting that epigenetic reprograming may contribute to the altered glucocorticoid response of the uterus following early-life exposure to genistein. These changes affected the biological activity of glucocorticoids within the uterus, as glucocorticoids antagonized the proliferative effects of estradiol in the uterus of control mice but not genistein-exposed mice. CONCLUSIONS: Our findings suggest that disruption of glucocorticoid signaling due to early-life exposure to environmental estrogens may in part render the uterus unable to support implantation. https://doi.org/10.1289/EHP1575. PMID- 29624292 TI - Bias Amplification in Epidemiologic Analysis of Exposure to Mixtures. AB - BACKGROUND: The analysis of health effects of exposure to mixtures is a critically important issue in human epidemiology, and increasing effort is being devoted to developing methods for this problem. A key feature of environmental mixtures is that some components can be highly correlated, raising the issues of confounding by coexposure and colinearity. A relatively unexplored topic in epidemiologic analysis of mixtures is the impact of residual confounding bias due to unmeasured or unknown variables. OBJECTIVES: This paper examines the potential amplification of such biases when correlated exposure variables are included in regression models. METHODS: We use directed acyclic graphs (DAGs) to describe different simple scenarios involving residual confounding. We derive expressions for the expected value of the resulting bias using linear models and multiple linear regression. RESULTS: Approaches to the analysis of mixtures that involve regressing the outcome on several exposures simultaneously can in some cases amplify rather than reduce confounding bias. DISCUSSIONS: The problem of bias amplification can worsen with stronger correlation between mixture components or when more mixture components are included in the model. CONCLUSIONS: Investigators must consider steps to minimize possible bias amplification in the design and analysis of epidemiologic studies of multiple correlated exposures. This may be particularly important when biomarkers of exposure are used. https://doi.org/10.1289/EHP2450. PMID- 29624294 TI - [CLINICAL ENTITIES AND CHARACTERISTICS OF PAIN IN PATIENTS WITH RHEUMATIC DISEASES]. AB - Musculoskeletal pain is the most common symptom present in almost all rheumatic diseases. Rheumaticdiseases include more than 150 clinical entities. There is no uniform classification of rheumatic diseases. In general, wedistinguish inflammatory rheumatic diseases, non-inflammatory degenerative articular diseases, systemic connective tissuediseases, metabolic disorders with articular manifestations, and regional and extended pain syndromes. According tothe International Association for the Study of Pain (IASP), pain is defined as an unpleasant sensation associated with tissuedamage or reported simultaneously with such damage. Pain has a physical, mental, and social component. In rheumaticdiseases the pain is mostly chronic and may severely impair the patient's general condition. The defining criteria involve aperiod of more than 3 or 6 months, and according to some definitions more than 6 weeks. In most cases the pain is nociceptiverather than neuropathic. Musculoskeletal pain, especially chronic pain, is a global public health problem because of itsprevalence, as well as the frequently associated muslculoskeletal function impairment and development of chronic painsyndrome, which can be considered as a separate clinical entity and requires a biopsychosocial treatment approach. PMID- 29624295 TI - Enhanced Photoelectrochemical Water Splitting Behaviour of Tuned Band Gap CdSe QDs Sensitized LaB6. AB - We report the fabrication of tuned band gap quantum dots sensitized LaB6 hybrid nanostructures and their application as a photoanode for photoelectrochemical water splitting. The lanthanum hexaboride (LaB6) obtained by molten salt electrolysis method is sensitized with different sized CdSe quantum dots, which form a multiple-level hierarchical heterostructure and such design enhance the light absorption and charge carrier separation, which in turn showed higher photocurrent density compared to that of pristine LaB6. When LaB6 is sensitized with CdSe quantum dots of different band gaps, which have the absorption in the green and red (530 and 605 nm) regions in visible light, developed a ten times higher photocurrent density (11.0 mA cm(-2)) compared to that of pristine LaB6 (0.5 mA cm(-2) at 0.75 V vs. Ag/AgCl) in 1 M Na2S electrolyte under illumination. These results prove that the tuned band gap quantum dots sensitized LaB6 heterostructures are an ideal candidate for a photoanode in solar water splitting applications. PMID- 29624297 TI - Surface Modification of Electrospun Poly(vinylidene fluoride) Fibrous Membrane Based on Layer-by-Layer Assembly of TiO 2 Nanoparticles. AB - A facile surface modification method of improving hydrophilicity of poly(vinylidene fluoride) (PVDF) membranes was presented by layer-by-layer assembly. Various layers of anatase TiO2 nanoparticles were successfully deposited on electrospun PVDF fibrous membranes. FTIR, SEM, TEM and droplet scanning analysis were used to investigate microstructure and contact angle (CA) of modified membranes. TiO2 modified PVDF fibers showed rougher surface and greater diameter compared to uncoated ones. The CA of modified membranes was significantly decreased. For instance, the CA of the 4 layers of TiO2 modified membranes through two pretreatment methods (viz., ethanol-water displacement or KMnO4 modification) could be decreased to 0 degrees while the unmodified PVDF had CA of 114.4 degrees . Moreover, the modification through ethanol-water pre treatment formed TiO2 coating owing to hydrogen bonds without damaging strength of PVDF. Therefore, this presents a facile and effective hydrophilic modification method for PVDF in water treatment, filtration and other fields. PMID- 29624296 TI - [FIBROMYALGIA: IS IT A RHEUMATIC DISEASE?] AB - Fibromylagia (FM) is a complex chronic condition usually presenting with symptoms of widespreadpain and fatigue, as well as sleep and cognitive disorders. The diagnosis is made by exclusion of other diseases and accordingto the EULAR criteria. The treatment of the disease is multidisciplinary and associated with a better understanding ofthe disease pathophysiology. The most commonly used drugs are tricylic antidepressants (TCA), serotonin and noradrenalinuptake inhibitors (SNRI), anticonvulsants, and opioids. For the purpose of reducing the patient's overall symptomburden, adjunctive therapy with medicines targeted at specific symptoms, including sleep disorders, symptoms ofirritable bowel syndrome, or autoimmune diseases, should be considered. Current therapeutic models neither completelytreat FM symptoms nor benefit all patients; therefore, further research on new therapeutic approaches is needed. PMID- 29624298 TI - [EVALUATION OF PAIN AND LOCAL PHARMACOLOGICAL PAIN TREATMENT IN RHEUMATOLOGY]. AB - The objective of this review is to present outcome measurement tools for chronic musculoskeletalpain in rheumatology patients and to provide an overview of local pharmacological pain treatment.Reliable and valid assessment of pain is fundamental for both clinical trials and effective pain management. Thecomplex nature of pain makes objective measurement impossible. Evaluation of chronic musculoskeletal pain and itsimpact on physical, emotional, and social functions requires multidimensional qualitative tools and health-relatedquality of life instruments. The main recommendation concerning outcome measurements of pain is that they shouldinclude an evaluation of pain, fatigue, disturbed sleep, physical functioning, emotional functioning, and patient globalratings of satisfaction and quality of life. Despite the growing field of new instruments and publications related to measuringthe various aspects of chronic pain, there is still little agreement on the topic among researchers and clinicalexperts and no unified approach has been adopted. There is still considerable need for the development of a core set ofmeasurement tools and response criteria regarding chronic pain management.It is well known that pain in articular joints and soft tissues of the musculoskeletal system represents the mostcommon symptom presenting to rheumatologists. Therefore, local pharmacological pain tretment has an importantrole in rheumatology treatment algorithms. Topical administration, as well as injection administration in joints andsoft tissue trigger points, can be done under the control of musculoskeletal ultrasound. The most frequently prescribeddrugs include NSARs and corticosteroids, with their effectiveness being well-proven in evidence-based practice. PMID- 29624299 TI - [SYSTEMIC PHARMACOLOGICAL TREATMENT OF PAIN IN RHEUMATIC DISEASE]. AB - Pain is a cardinal symptom of rheumatic diseases and the most common reason for seeking medicalhelp. Pain relief has many benefi cial eff ects and is necessary for the functional recovery. A variety of drugs are used forthe treatment of pain in rheumatic diseases. Th ey usually include acetaminophen, nonsteroidal anti rheumatic drugs,and opioids (mostly weak opioids). Antidepressants and anticonvulsants can be used in cases with a predominantneuropathic component. In this descriptive review we present up-to-date results of trials with systemic analgesic drugsin rheumatic diseases, including nerve growth factor inhibitors and symptomatic slow-acting drugs for osteoarthritis. PMID- 29624300 TI - [NON-PHARMACOLOGICAL PAIN MANAGEMENT OF RHEUMATIC DISEASES]. AB - Rheumatic diseases are a leading cause of chronic painful conditions, which, if not recognized andtreated in a timely manner, cause inability and consequently reduce the quality of life of individuals. Chronic pain inrheumatic patients has a multifactorial background. Therefore, it is oft en accompanied by sleep and mood disturbances,fatigue, and reduced functional capacity of joints and the spine. Recent studies suggest that rheumatic pain isnot exclusively nociceptive, and that in a large number of patients it may have the characteristics of neuropathic andcentral pain. Thus, the current approach to the treatment of rheumatic pain oft en had very modest results. For thesereasons, rheumatic pain can no longer be treated only as a symptom, but should rather be viewed as a separate disease.Effective treatment of rheumatic pain requires a multidisciplinary, biopsychosocial approach taking into account thecause and nature of the pain, the disease characteristics, lifestyle, and psychological ability of an individual to deal withpainful conditions. Careful selection of different modes of non-pharmacological treatment should be the fi rst step inthe treatment of rheumatic pain with the use of available pharmacological interventions. A small number of systematicreviews, which included only a small number of causes and treatments for rheumatic pain with questionable qualityof evidence, indicates the need to develop new high-quality randomized controlled trials, in order to enable realinsight into the effectiveness of non pharmacological methods for the treatment of rheumatic pain. PMID- 29624301 TI - Light Absorption and Luminescence Quenching Properties of Hybrid Bulk Heterojunction Materials Based on the Blend Conducting Polymers. AB - We have investigated the enhancement absorption light and luminescence quenching properties of the hybrid bulk heterojunction systems which were fabricated using poly[2-methoxy-5-(2'-ethyl-hexyloxy)-1,4-phenylene vinylene] (MEH-PPV); poly(3 hexylthiophene) (P3HT); fullerene derivative 1-(3-methoxycarbonyl) propyl-1 phenyl-[6,6] C61 (PCBM) and TiO2 nanocrystals. The optimized material showed a broad absorption in the region of 350 to 670 nm and the luminescence quenching higher 85%. The obtained results provide further insight into photophysics of the heterojunction system and device performance improvement by using this system as an active layer. PMID- 29624302 TI - [JUVENILE IDIOPATHIC ARTHRITIS]. AB - Juvenile idiopathic arthritis (JIA) is the most common rheumatic disorder in children and one of themost common causes of part-time or long-term disability. The term juvenile idiopathic arthritis defines the main characteristicsof the disease: joint inflammation of unknown origin manifested before the 16th birthday and lasting for morethan six weeks. JIA is very rare in infancy, with highest frequency in preschool age. It is not a single disease, but a groupof disorders with some common features of different immunopathogenesis and with different clinical manifestations. Accordingto the revised International League of Associations for Rheumatology (ILAR) criteria, JIA is classified into 8subtypes, but this classification is still a "work in progress" because with new knowledge gained in genetics and immunology,the classification will obviously have to be changed and refined. New research of the disease pathogenesis is the basisfor the development of new and better treatments for JIA. The goal of such treatments is not just to relieve pain, but alsoto control inflammation and stop irreversible joint damage and long-term disability. Biological agents have significantlyimproved the disease prognosis. PMID- 29624303 TI - [JUVENILE SPONDYLOARTHRITIS]. AB - Juvenile spondyloartrhritis is a group of multifactorial diseases in which a disturbed interplay occursbetween the immune system and environmental factors on a predisposing genetic background, which leads to inflammationand structural damage of the target tissue. First symptoms of jSpA rarely involve the spine, while asymmetricaloligoarthritis of lower extremities, dactylitis, and peripheral enthesitis are much more common. There are many classificationcriteria for jSpA, but the majority of pediatric rheumatologists currently use the International League AgainstRheumatism (ILAR) criteria according to which most patients with jSpA are classified into the enthesitis-related arthritisgroup of juvenile idiopathic arthritis. To meet these criteria, a patient should have arthritis and/or enthesitis,with two or more symptoms such as sacroiliac joint tenderness and/or inflammatory back pain, HLAB27 genotype,HLA B27 genotype-associated disease in a first- or second-degree relative, uveitis, and male sex with eight or moreyears of age. Therefore, diagnosis is most oft en made only based on clinical examination and medical history. Anti-nuclear antibodies (ANA), rheumatoid factor (RF), and HLA testing with B27, B7, and DR4 alleles are preferred. Sincesubclinical gut inflammation is present in many patients, it is recommended to check fecal calprotectin levels. In patientswith signs of peripheral enthesitis it is warranted to perform power Doppler musculoskeletal ultrasound (PDUS),and in patients with signs of axial involvement radiographic and contrast-enhanced magnetic resonance imaging.Most patients are treated with nonsteroidal anti-inflammatory drugs (NSAIDs) and physical therapy, while in refractorycases with peripheral disease synthetic disease- modifying antirheumatic drugs (DMARDs), such as sulfasalazine,are used. In patients with axial involvement, biological DMARDs such as adalimumab, infliximab, and etanercept areobligatory. Although a number of studies gave us a good insight into the disease pathogenesis, the response to treatmentand prognosis are still difficult to predict. PMID- 29624304 TI - Reduced Graphene Oxide/Single-Walled Carbon Nanotube Hybrid Films Using Various p Type Dopants and Their Application to GaN-Based Light-Emitting Diodes. AB - This article reports the electrical and optical properties of the reduced graphene oxide (RGO)/single-walled carbon nanotube (SWCNT) films using various p type dopants and their application to GaN-based light-emitting diodes. To enhance the current injection and spreading of the RGO/SWCNT films on the light-emitting diodes (LEDs), we increased the work function (Phi) of the films using chemical doping with AuCl3, poly(3,4-ethylenedioxythiophene) oxidized with poly(4 styrenesulfonate) (PEDOT:PSS) and MoO3; thereby reduced the Schottky barrier height between the RGO/SWCNT films and p-GaN. By comparison, LEDs fabricated with work-function-tuned RGO/SWCNT film doped with MoO3 exhibited the decrease of the forward voltage from 5.3 V to 5.02 V at 20 mA and the increase of the output power up to 1.26 times. We also analyzed the current injection mechanism using ultraviolet photoelectron spectroscopy and X-ray photoelectron spectroscopy. PMID- 29624305 TI - [AUTOIMMUNITY AND IMMUNODEFICIENCIES]. AB - Autoimmune diseases and primary immunodeficiencies share a common pathogenesis characterizedby dysregulation of immunity. Although most autoimmune diseases show a polygenic inheritance pattern, it has beenshown that monogenic defects of various immune system components could lead to autoimmunity as well. These findingshave opened a new pathway for understanding the development of autoimmune diseases and the overlap betweenimmunodeficiency and autoimmunity. Th e mechanism of how a single gene defect leads to autoimmunity is not completelyknown. The purpose of this clinically-oriented review is to describe the incidence, clinical presentation, andpossible mechanisms of autoimmunity in patients with primary immunodeficiencies relevant to rheumatologists. PMID- 29624306 TI - [RADIOLOGICAL FEATURES IN PEDIATRIC IMAGING]. AB - Juvenile idiopathic arthritis (JIA) is an autoimmune disease usually occurring in children before theage of 16. As one of the most prevalent rheumatic diseases in the pediatric population, with an estimated prevalence of2 to 20 and an incidence of 16 to 150 per 100,000 children, it is defined as an inflammation of one or more joints, witha duration of 6 weeks minimum. JIA is primarily diagnosed clinically, confirmed by laboratory and radiological findings,with the goal of early detection and assessment of the spread and progress of the disease as well as the response tomedication. The current International League of Associations for Rheumatology (ILAR) classification defines eighttypes of arthritis. PMID- 29624307 TI - [VASCULITIDES IN CHILDHOOD]. AB - Primary systemic vasculitides in children are relatively rare diseases. In most cases, they have an unknownetiology and are defined as the presence of inflammation in the blood vessel wall. Establishing the diagnosis ofvasculitis is oft en challenging, since the disorder is multisystem in nature with mostly nonspecific symptoms. The last10 years have seen significant advances in the field of pediatric vasculitis: the development and validation of classificationcriteria as well as tools to assess clinical disease activity and disease outcome, the inclusion of pediatric patients ininternational multicentre randomized controlled trial designs for therapies of vasculitis, clinical trials for very rarepediatric vasculitides, and identification of a special group of monogenic vasculitides. In this paper we want to introducereaders to the giant leap in the field of pediatric vasculitis as a result of the hard work of pediatric rheumatologistsin vasculitis work groups. PMID- 29624308 TI - [RHEUMATOLOGY IN PEDIATRIC CARDIOLOGY FROM FETAL STAGE TO ADULTHOOD. THE ROLE OF FETAL ECHOCARDIOGRAPHY]. AB - Even though in the last ten years pediatric cardiology and rheumatology have formally separated inCroatia as well, strong links still remain between them. They are no longer manifested through rheumatic fever, butthrough other rheumatic entities: systemic lupus erythematosus, antiphospholipid syndrome, systemic scleroderma,Kawasaki disease, polyarteritis nodosa, and some forms of granulomatous vasculitis. We take special note of the occurrenceof complete congenital atrioventricular block (CCAVB) in pregnant women who, due to systemic connectivetissue diseases, develop distinctive ANA antibodies (anti-SSA/Ro and/or anti SSB/La), but who are also likely to havethe same inflammation within the heart, leading to the development of restricted cardiomyopathy associated withCCAVC. Although rheumatology has thus been involved with early fetal age for some time now, there are also someissues relating to the embryonal stage (the association between methotrexate/folic acid and heart development in embryos),as well as to the late fetal stage (antiprostaglandin anti-infl ammatory agent impact on premature ductus arteriosusclosure). We gave special attention to the neonatal lupus syndrome, the most serious complication in the fetalperiod. Thus the multiple association between cardiology and rheumatology in all age groups, from the embryonal andfetal stage to adulthood, is being realized. The aim of this paper is to present some important links and thus furtheremphasize the new cooperation between pediatric cardiology and rheumatology from fetal stage to adulthood. PMID- 29624309 TI - [THE IMPORTANCE OF TRANSITION IN RHEUMATOLOGY]. AB - Rheumatic diseases are among the most common chronic diseases of childhood. Between 30 and 70%of pediatric rheumatology patients reach adulthood with some disease activity, functional limitations, or psychosocialproblems. Transition is the purposeful, planned move of chronic pediatric patients from pediatric to adult care. It is aprocess in which adolescents with chronic conditions prepare for independent care for their health and life in general.Th e establishment of transitional services will ensure better disease control, limit long-term complications, work loss,and unnecessary health care costs, and increase quality of life. PMID- 29624311 TI - Breakfast with Jared PMID- 29624310 TI - AIDS Quartet PMID- 29624313 TI - Ethiopian Love Song PMID- 29624312 TI - This Zoonotic World PMID- 29624314 TI - [DIAGNOSTIC ULTRASOUND OF MUSCULOSKELETAL SYSTEM IN RHEUMATOLOGY IN CROATIA - CURRENT STATUS AND NEW PERSPECTIVES]. AB - In recent years, diagnostic ultrasound of the musculoskeletal system (MSUS) has become almost inevitablein everyday clinical practice in rheumatology. Due to the efforts of the European League Against Rheumatism(EULAR), the use of MSUS has significantly increased in Europe. Unfortunately, there are still certain open issues relatedto MSUS, primarily regarding different ways of interpretation of US findings, the standardization of MSUS findings,and the lack of clear criteria for assessing the competency of sonographers and their certification. PMID- 29624315 TI - A Passion for Parasites PMID- 29624316 TI - [Hepatitis B virus and APOBEC family]. PMID- 29624317 TI - Influence of the Supramolecular Arrangement in the Electrical Conductivity of Poly(thiophene) Thin Films. AB - Thin films of regioregular polythiophene derivatives have had their optical, structural and morphological properties characterized, but there is still a lack of comparative studies to determine the effect from deposition techniques, especially on the electrical properties. In this study, we produced Langmuir Schaefer and spin-coated films of regioregular alkyl-substituted polythiophene derivatives (P3AT) to investigate how distinct supramolecular arrangements can affect their properties. The Langmuir-Schaefer films deposited on indium-tin oxide substrates were observed to grow linearly with the number of layers, according to UV-visible absorption spectroscopy. Atomic force microscopy and Brewster angle microscopy were carried out for morphological characterization. From electrical transport measurements, the DC electrical conductivity of Langmuir-Schaefer films of P3AT was higher than the corresponding spin-coated films, which can be related to the dissimilar roughness and molecular-level organization provided by the Langmuir-Schaefer technique. PMID- 29624318 TI - [Structural basis of APOBEC3-Vif Interaction in the host-virus arms race]. PMID- 29624319 TI - [Interplay between HIV-1 and APOBEC]. PMID- 29624320 TI - [APOBEC3B-induced mutagenesis in cancers]. PMID- 29624321 TI - [Functional polymorphisms and molecular evolution of mouse APOBEC3]. PMID- 29624322 TI - Camphor Sulfonic Acid Doped Poly(3-hexylthiophene) Nanofilms: Optical and Electrical Properties. AB - Herein, we report the fabrication and characterization of Camphor Sulfonic Acid (CSA) doped Poly(3-hexylthiophene) (P3HT) nanofilms prepared at different substrate temperature on glass by simple wire bar coating method. Spectroscopic, optic, structural and electrical properties of the prepared nanofilms were characterized by atomic force microscopy (AFM), UV-Visible spectroscopy, fluorescence spectroscopy, X-ray diffraction, NKD spectroscopy, SEM and DC electrical measurements. The detailed electrical characterizations revealed that the conductivity of the P3HT nanofilms increased when the films are doped with CSA and the conductivity increased from 5.89*10-5 S/cm to 1.39 * 10-4 S/cm for 40 degrees C preparation temperature. Thus, it was confirmed that the substrate temperature plays an important role on the film structure and spectroscopic properties. Additionally CSA-doping changes the optical properties, especially when the films prepared at 40 degrees C. PMID- 29624323 TI - [Pathophysiological role of A-to-I RNA editing enzyme ADAR1 in human diseases]. PMID- 29624324 TI - [Abnormal RNA editing and treatment strategy in neurological diseases; towards cure for ALS]. PMID- 29624325 TI - [DYW domain and RNA editing in plant organelles]. PMID- 29624326 TI - Controllable Fabrication of Ag Nanoparticles-Coated Silica Core-Shell Microspheres and Its Optical Properties. AB - This paper described a one-step shell growth and extraordinarily facile method for the preparation of Ag nanoparticles-coated silica core-shell microspheres. The Ag nanoparticles could deposit on the silica microspheres to form continuous and compact shell layers at a balanced amount of polyvinyl pyrrolidone after the surface modification of the silica microspheres by (3-Mercaptopropyl) trimethoxysilane. The strong interactions between the thiol groups and Ag nanoparticles make it difficult to peel off the Ag shell from the core microspheres, obtaining extremely stable and homogeneous Ag nanoparticles-coated silica core-shell microspheres. Besides, the coating effect was controlled by varying the content of coupling agent, the type and amount of stabilizing agent, the quantity of silica microspheres as well as the mixing time between silica and silver ammonia solution. In addition, these Ag nanoparticles-coated silica core shell microspheres were characterized using laser particle size analyzer (LPS), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The optical properties of the composite microspheres were observed by UV-vis spectroscopy. PMID- 29624327 TI - Characterization of Carbon Nanotube Based Infrared Photodetector Using Digital Microscopy. AB - The state-of-the-art infrared camera suffers from the trade-off between sensitivity and cost. The bolometer infrared sensors are low resolution and slow speed while the quantum photodetectors are bulky and expensive. In this paper, the novel low dimensional material Carbon Nanotube (CNT) based non-cryogenic photodetector is proposed to detect infrared (IR) irradiance. The photoconductance and photovoltaic effect need to be distinguished to fully understand and improve nano IR detector performance. The robust test bench using digital microscope and precise five axis substage is used to measure detector photoresponse. The relative position between nanoscale sensor and IR beam is localized by mapping the photocurrent on laser spot. The distance between photodetector and infrared laser lens is leveraged by digital microscope. The experimental results show photovoltaic quantum effect dominates CNT-Metal Schottky based IR detector and the photoresponse is dependent on contact size and metal materials. The photoresponsivity can reach to 16.8 MUA/mW at 808 nm wavelength. The proposed method will be applicable for 1D/2D nanoscale material based photodiode characterization. PMID- 29624328 TI - [Lymph node microenvironment controls high-speed T cell migration]. PMID- 29624329 TI - [Mechanisms of synapse pruning in the developing cerebellum]. PMID- 29624330 TI - Synthesis and Photoluminescence of Red to Near-Infrared-Emitting CdTe( x) Se(1 x) /CdZnS Core/Shell Quantum Dots. AB - Red to near-infrared (NIR)-emitting ternary-alloyed CdTe (x) Se(1-x) (x = 0 0.3) quantum dots (QDs) with tetrapod and dot morphologies have been synthesized by a facile method using oleic acid (OA) as single capping agent. The controlled dot-shaped and tetrapod-shaped CdTe( x) Se(1-x) QDs can be successfully obtained by adjusting the content of Te element. It is clear that CdTe (x) Se(1 x) QDs display the tunable emission peaks from the visible light (613.4 nm) to the NIR range (791.6 nm). With an inorganic CdZnS shell coated on the surface of CdTe(0.1)Se(0.9) cores, the stability and PL efficiency of the resulting core/shell QDs can be improved dramatically, accompanied with the red-shift of emission peaks to longer wavelength (795.6 nm). Peculiarly, a large blue shift of emission spectrum of CdTe(0.3)Se(0.7)/CdZnS core/shell QDs is observed, which is mainly ascribed to the shrink of the size of QDs by the fracture of tetrapod arms. PMID- 29624331 TI - [Integrated regulation of Nrf2 by two protein degradation systems]. PMID- 29624332 TI - [Microsystems allow highly sensitive analysis of membrane protein functions]. PMID- 29624333 TI - Aging and health AB - For the Instituto Mexicano del Seguro Social (IMSS), population aging represents a major challenge as a social security institution. This is why the Epidemiological Research and Health Care Services Unit/Aging Area has developed multi-disciplinary research concerning the older adult population, in order to contribute with programs of prevention, detection and attention of that age group and develop policies with plural perspective in which the voices of the older adults can be heard. PMID- 29624334 TI - [The application of epigenetic regulation for natural products discovery]. PMID- 29624335 TI - [Interactions between microbiota and pathogenesis during malaria]. PMID- 29624336 TI - [New mechanism for chronic itch in the nervous system]. PMID- 29624337 TI - [Regulation of feedback signaling by anti-inflammatory drugs]. PMID- 29624338 TI - [Unique macrophages induced by infection with Mycobacterium avium complex regulate the mitogenesis and differentiation of T cells]. PMID- 29624340 TI - [Proteins capturing the tail of chitosan]. PMID- 29624339 TI - Relationship between bone remodeling and metabolism in the elderly AB - Background: Recent studies have shown that osteocalcin (OC) is related to not only bone metabolism but also energy metabolism. The aim of the present study was to investigate whether OC was associated with metabolic factors and bone mineral density (BMD) in elderly men. Methods: A cross-sectional study was done including 122 healthy men aged 60 years or older. Serum glucose, lipids, insulin, adiponectin and OC were measured and BMD was estimated using dual energy X-ray absorptiometry. Results: 42.8% of men had metabolic syndrome (MetS). OC levels were not significantly different between men with and without MetS. OC concentrations were inversely associated with body mass index (BMI) (r = -0.226, p = 0.04), waist circumference (r = -0.261, p = 0.02), glucose (r = -0.245, p = 0.03), insulin (r = -0.235, p = 0.03), and HOMA-IR (r = -0.211, p = 0.04). In addition, OC levels were higher in patients with diminished BMD compared with those with normal BMD. Conclusions: OC levels correlate negatively with BMI, waist circumference, glucose, insulin and HOMA-IR in elderly men, which suggests a connection between bone and energy metabolism. PMID- 29624341 TI - [Development and applications of three color variants of bright luminescent protein probes]. PMID- 29624342 TI - [Cytohesin regulation of axonal myelination by Schwann cells and oligodendrocytes]. PMID- 29624343 TI - Oxidative stress in the elderly with diabetes mellitus or hypertension AB - Background: Mexico City has the highest aging rate in the country, as well as a high prevalence of diabetes mellitus (DM) and hypertension (HT). It is known that each one of these conditions increase oxidative stress (OS) independently. Methods: With this study we described changes in OS of 18 patients without DM or HT (controls), 12 with DM, 23 with HT, and 18 with DM and HT, all of them members of the COSFAMM (Cohorte de Obesidad, Sarcopenia y Fragilidad en Adultos Mayores de Mexico). OS was measured by the quantification of reactive oxygen species (ROS), by the oxidation of diclorofluorosceine, and by determination of lipid peroxidation by product malondialdehyde (MDA). Results: HT patients showed increased ROS levels, as did men with HT compared with the respective DM and HT groups. Also, women of control group showed higher levels of ROS compared with men. Conclusions: Generally, HT turned out to be the most influential factor for the increase of oxidative stress in the elderly while DM has no effect whatsoever. PMID- 29624344 TI - [Does calpain inhibition always rescue us?]. PMID- 29624345 TI - [Tumor growth regulation by cell competition and cooperation]. PMID- 29624346 TI - [Structure-function studies between the hormone-disrupting chemical bisphenols and the nuclear receptors]. PMID- 29624347 TI - [MPIase, a multi-functional glycolipid involved in protein insertion into and protein translocation across membranes]. PMID- 29624348 TI - [Mitotic nucleoporin orchestrates colorectal carcinogenesis]. PMID- 29624349 TI - [Recent advances in functional analysis of plant Nudix hydrolase family-novel roles of metabolic regulation of GDP-D-mannose and NADH-]. PMID- 29624350 TI - [Mechanism of mitotic cell death during telomere crisis]. PMID- 29624351 TI - [Stem cell glycomics: Structure, function, and application]. PMID- 29624352 TI - [Embryonic origin of adult neural stem cells]. PMID- 29624353 TI - [Regulation of Abeta production by angiotensin receptor type Ia]. PMID- 29624354 TI - [Intracellular thiol contents and fatty acid metabolism pathways are regulated by the Nrf1 (NFE2L1) with its transcriptional suppressor activity]. PMID- 29624355 TI - [Electrostatic interaction between ganglioside and membrane proteins]. PMID- 29624356 TI - [The new lipid mediators that modulate skin homeostasis and diseases]. PMID- 29624357 TI - [Tethering effect by which improves protein folding in the chaperonin cage]. PMID- 29624358 TI - Toxicity of beta-amyloid protein during aging: Influence of synaptosomal energy metabolism AB - Background: Recent evidence suggests that early neurodegenerative events associated with Alzheimer's disease (AD) probably begin in the synaptic terminal, where it has been reported a large accumulation of beta-amyloid protein (Abeta), one of the main factors described in the development of AD. We analyzed the influence of energy metabolism on the toxic effects of Abeta during aging on synaptosomes from neocortex and hippocampus of rats exposed to inhibitors of glycolytic and mitochondrial metabolism and we evaluated the protective effects of some antioxidant compounds. Methods: Synaptosomes were obtained by differential centrifugation in sucrose gradients and their redox activity was determined with the MTT assay. Results: The mitochondrial activity of synaptosomes from young rats was not altered by the presence of Abeta; the ones obtained from old rats showed an increase in susceptibility to Abeta; this activity was greater in the synaptic terminals of the hippocampus. Conclusions: These results provide experimental support for the hypothesis that certain risk factors, such as energy metabolism dysfunction or the aging process itself, may increase vulnerability to Abeta. Hippocampal region is more susceptible to Abeta and its effect increases with age in relation to the neocortex, which would agree with the damage gradient reported in the AD. PMID- 29624359 TI - [Membrane translocation of arginine-rich cell-penetrating peptides]. PMID- 29624360 TI - [Screening and design of short length functional peptide by peptide array]. PMID- 29624361 TI - [The application of cell penetrating peptides to the nervous systems]. PMID- 29624363 TI - Improvement of Corrosion and Tribocorrosion Behavior of Pure Titanium by Subzero Anodic Spark Oxidation. AB - The present investigation reports corrosion and tribocorrosion behavior of anodic spark oxidation (ASO) coatings formed at 20 and -10 degrees C. Despite the numerous open pores on the layers formed at 20 degrees C , the plasma discharged channels were blocked on the surfaces of the subzero ASO coatings. According to polarization curves, the samples treated at -10 degrees C showed a significant increase in the corrosion resistance ( jcorr of 0.75 nA cm-2). Electrochemical impedance spectroscopy experiments illustrated lower capacitance and higher resistance of both inner and porous layers formed at low temperature. Subzero ASO coatings also demonstrated the lowest overall open circuit potential drop in tribocorrosion studies. PMID- 29624362 TI - Reorganization and clinical management for hypertension control at primary healthcare AB - Background: In Mexico, 40% of hypertensive patients see their blood pressure under control. The evidence to keep hypertension (HT) under control is scarce, particularly in older adults who have the highest prevalence and require more health services. The objective was to determine the impact of a double intervention to increase the percentage of hypertensive patients with blood pressure levels under control and estimate differences among adults and older adults. Methods: Quasi-experimental design including reorganization and training to physicians using clinical guidelines in four primary healthcare units at the Instituto Mexicano del Seguro Social (IMSS). We included adults who participated whether in the intervention group (IG) or in the control group without equivalence (CGNE). We used regression models for longitudinal data for systolic pressure (SP) and diastolic pressure (DP) variables and proportion of patients with hypertension under control. Results: 530 participants, 272 in the IG; 57.5% were >= 60 years. In the IG decreased the SP, beta= -5.93 (95%CI -9.59, -2.28) and increased the proportion with blood pressure under control in young adults (OR 1.48, 95%CI 1.02, 2.14). In the elderly the intervention decreased the DP among those with HT and other comorbidities, beta= -3.57(95%CI -6.72, -0.41), p < 0.05. Conclusion: The interventions reduced SP among adults and DP among older adults with hypertension and other comorbidities. Actions of secondary prevention addressed to each group of age are needed to achieve the control of hypertension at IMSS. PMID- 29624364 TI - Interfacial Electron Transfer of Ferrocene Immobilized onto Indium Tin Oxide through Covalent and Noncovalent Interactions. AB - The immobilization of molecular species onto electrodes presents a direct route to modifying surface properties with molecular fidelity. Conventional methods include direct covalent attachment and physisorption of pyrene-appended molecular compounds to electrodes with aromatic character through pi-pi interactions. A recently reported hybrid approach extends the synthetic flexibility of the latter to a broader range of electrode materials. We report an application of this approach to immobilization of pyrene-appended ferrocene onto pyrene functionalized indium tin oxide (ITO). The modified ITO surfaces were characterized using X-ray photoelectron spectroscopy, fluorescence spectroscopy, and electrochemical techniques. An electron-transfer rate constant ( kapp) of 100 +/- 8 s-1 was measured between the electrode and immobilized ferrocene using electrochemical methods. For comparison, a ferrocene-modified electrode using conventional covalent attachment of vinylferrocene was also prepared, and kapp was measured to be 9 +/- 2 s-1. PMID- 29624365 TI - General Observation of Photocatalytic Oxygen Reduction to Hydrogen Peroxide by Organic Semiconductor Thin Films and Colloidal Crystals. AB - Low-cost semiconductor photocatalysts offer unique possibilities for industrial chemical transformations and energy conversion applications. We report that a range of organic semiconductors are capable of efficient photocatalytic oxygen reduction to H2O2 in aqueous conditions. These semiconductors, in the form of thin films, support a 2-electron/2-proton redox cycle involving photoreduction of dissolved O2 to H2O2, with the concurrent photooxidation of organic substrates: formate, oxalate, and phenol. Photochemical oxygen reduction is observed in a pH range from 2 to 12. In cases where valence band energy of the semiconductor is energetically high, autoxidation competes with oxidation of the donors, and thus turnover numbers are low. Materials with deeper valence band energies afford higher stability and also oxidation of H2O to O2. We found increased H2O2 evolution rate for surfactant-stabilized nanoparticles versus planar thin films. These results evidence that photochemical O2 reduction may be a widespread feature of organic semiconductors, and open potential avenues for organic semiconductors for catalytic applications. PMID- 29624367 TI - Large Dielectric Constant Enhancement in MXene Percolative Polymer Composites. AB - We demonstrate that poly(vinylidene fluoride) (PVDF)-based percolative composites using two-dimensional (2D) MXene nanosheets as fillers exhibit significantly enhanced dielectric permittivity. The poly(vinylidene fluoride-trifluoro-ethylene chlorofluoroehylene) (P[VDF-TrFE-CFE]) polymer embedded with 2D Ti3C2T x nanosheets reaches a dielectric permittivity as high as 105 near the percolation limit of about 15.0 wt % MXene loading, which surpasses all previously reported composites made of carbon-based fillers in the same polymer. With up to 10 wt % MXene loading, the dielectric loss of the MXene/P(VDF-TrFE-CFE) composite indicates only an approximately 5-fold increase (from 0.06 to 0.35), while the dielectric constant increased by 25 times over the same composition range. Furthermore, the ratio of permittivity to loss factor of the MXene-polymer composite is superior to that of all previously reported fillers in this same polymer. The dielectric constant enhancement effect is demonstrated to exist in other polymers as well when loaded with MXene. We show that the dielectric constant enhancement is largely due to the charge accumulation caused by the formation of microscopic dipoles at the surfaces between the MXene sheets and the polymer matrix under an external applied electric field. PMID- 29624366 TI - Electrospun Polyhydroxybutyrate/Poly(epsilon-caprolactone)/Sol-Gel-Derived Silica Hybrid Scaffolds with Drug Releasing Function for Bone Tissue Engineering Applications. AB - Electrospun hybrid scaffolds are an effective platform to deliver drugs site specifically for the prevention and treatment of diseases in addition to promote tissue regeneration because of the flexibility to load drugs therein. In the present study, electrospun hybrid scaffolds containing antibiotics were developed to support cellular activities and eliminate potential postoperative inflammation and infection. As a model drug, levofloxacin (LFX) was successfully incorporated into pure polyhydroxybutyrate/poly(epsilon-caprolactone) (PHB/PCL) scaffolds and PHB/PCL/sol-gel-derived silica (SGS) scaffolds. The influence of LFX on the morphology, mechanical performance, chemical structure, drug release profile, and antibacterial effect of the scaffolds was thoroughly and comparatively investigated. MG-63 osteoblast-like cell cultivation on both scaffolds certified that LFX inclusion did not impair the biocompatibility. In addition to the favorable cellular proliferation and differentiation, scaffolds containing both LFX and SGS displayed highly increased mineralization content. Therefore, the present multifunctional hybrid scaffolds are promising in tissue engineering applications. PMID- 29624368 TI - Hybrid Surface and Bulk Resonant Acoustics for Concurrent Actuation and Sensing on a Single Microfluidic Device. AB - While many microfluidic devices have been developed for sensing and others for actuation, few devices can perform both tasks effectively and simultaneously on the same platform. In piezoelectric sensors and actuators, this is due to the opposing operating requirements for sensing and actuation. Sensing ideally requires narrow resonant peaks characterized by high quality factors, such as those found in quartz crystals. However, these materials usually have poor electromechanical coupling coefficients that are not ideal for actuation. In this work, we show that it is possible to achieve both sensing and actuation simultaneously on a shared device by exploiting the distinct advantages of both bulk waves for effective mass sensing and surface waves for highly efficient microfluidic actuation through a unique hybrid surface and bulk acoustic wave platform. In light of the recent resurgence of interest in portable inhaled insulin devices for personalized diabetes management, we demonstrate the use of this technology for efficient aerosolization of insulin for inhalation without denaturing the protein, while being able to concurrently detect the residual mass of the un-nebulized insulin remaining on the device such that the actual dose delivered to the patient can be determined in real time. PMID- 29624369 TI - Ultrasensitive and Facile Detection of MicroRNA via a Portable Pressure Meter. AB - The upregulation of microRNA (miRNA) is highly related with some kinds of tumor, such as breast, prostate, lung, and pancreatic cancers. Therefore, for an important tumor biomarker, the point-of-care testing (POCT) of miRNA is of significant importance and is in great demand for disease diagnosis and clinical prognoses. Herein, a POCT assay for miRNA detection was developed via a portable pressure meter. Two hairpin DNA probes, H1 and H2, were ingeniously designed and functionalized with magnetic beads (MBs) and platinum nanoparticles (PtNPs), respectively, to form MBs-H1 and PtNPs-H2 complexes. In the presence of target microRNA 21 (miR-21), the cyclic strand displacement reaction (SDR) between MBs H1 and PtNPs-H2 was triggered to continuously form the MBs-H1/PtNPs-H2 duplex. Owing to the amplification of cyclic SDR, numerous PtNPs were enriched onto the surface of MBs to catalytically decompose H2O2 for the generation of much O2. The gas pressure value has a linear relationship with the logarithmic value of miR-21 concentration in the range of 10 fM to 10 pM. The limit of detection is 7.6 fM, which is more sensitive than that in a number of previous reports. Hairpin DNA probes and magnetic separation highly ensured the specificity and reliability. Single-base mutation was easily discriminated, and the detection of miR-21 in the serum sample achieved satisfactory result. Therefore, it offers a reliable POCT strategy for the detection of miRNA, which is of great theoretical and practical importance for POCT clinical diagnostics. PMID- 29624371 TI - High-Resolution High Kinetic Energy Ion Mobility Spectrometer Based on a Low Discrimination Tristate Ion Shutter. AB - High kinetic energy ion mobility spectrometry (HiKE-IMS) allows for sensitive trace gas analysis within seconds, mitigating many disadvantages of standard ion mobility spectrometers through operation at reduced pressure and high electric field strengths. However, these advantages usually come at the cost of reduced resolving power, ranging from a maximum of 75 down to 50 at a reduced field strength of 120 Td for the original device. In this work, we present an extended theory for HiKE-IMS resolving power and a novel tristate ion shutter principle able to achieve initial ion packet widths of 1 MUs without significant mobility discrimination. Such an ultrashort injection time allows for improving the resolving power of the HiKE-IMS to 140 for a wide range of reduced electric field strengths. With this resolving power, separating all ion species generated from a mixture of benzene, toluene, and xylene is possible. Furthermore, a resolving power of 140 is sufficient to partially separate isotopologues under high electric field strengths. PMID- 29624370 TI - Polarizable Force Field for Molecular Ions Based on the Classical Drude Oscillator. AB - Development of accurate force field parameters for molecular ions in the context of a polarizable energy function based on the classical Drude oscillator is a crucial step toward an accurate polarizable model for modeling and simulations of biological macromolecules. Toward this goal we have undertaken a hierarchical approach in which force field parameter optimization is initially performed for small molecules for which experimental data exists that serve as building blocks of macromolecular systems. Small molecules representative of the ionic moieties of biological macromolecules include the cationic ammonium and methyl substituted ammonium derivatives, imidazolium, guanidinium and methylguanidinium, and the anionic acetate, phenolate, and alkanethiolates. In the present work, parameters for molecular ions in the context of the Drude polarizable force field are optimized and compared to results from the nonpolarizable additive CHARMM general force field (CGenFF). Electrostatic and Lennard-Jones parameters for the model compounds are developed in the context of the polarizable SWM4-NDP water model, with emphasis on assuring that the hydration free energies are consistent with previously reported parameters for atomic ions. The final parameters are shown to be in good agreement with the selected quantum mechanical (QM) and experimental target data. Analysis of the structure of water around the ions reveals substantial differences between the Drude and additive force fields indicating the important role of polarization in dictating the molecular details of aqueous solvation. The presented parameters represent the foundation for the charged functionalities in future generations of the Drude polarizable force field for biological macromolecules as well as for drug-like molecules. PMID- 29624372 TI - Bond Covalency and Oxidation State of Actinide Ions Complexed with Therapeutic Chelating Agent 3,4,3-LI(1,2-HOPO). AB - The hydroxypyridinone ligand 3,4,3-LI(1,2-HOPO) is a promising agent for biological decorporation of radionuclides, and allows spectroscopic detection of many lanthanide (Ln) and actinide (An) species via sensitized luminescence. Despite the manifest uses of this ligand, the structural and thermodynamic properties of its complexes across the An series remain understudied. Theoretical investigations of the binding of An(III) and An(IV) ions, from actinium to einsteinium, by the 3,4,3-LI(1,2-HOPO) ligand, as well as experimental extended X ray absorption fine structure (EXAFS) studies on the trivalent americium, curium, and californium complexes were employed to address the resulting structures, thermodynamic parameters, redox properties, and corresponding electronic configurations. An(IV) ions were found to form much stronger complexes than An(III) ions, consistent with experimental measurements. Complexation of both An(III) and An(IV) ions generally becomes more favorable for heavier actinides, reflecting increased energy degeneracy driven covalency and concomitant orbital mixing between the 5f orbitals of the An ions and the pi orbitals of the ligand. Notably, the ability of this ligand to either accept or donate electron density as needed from its pyridine rings is found to be key to its extraordinary stability across the actinide series. PMID- 29624373 TI - An Affordable and Portable Thermocycler for Real-Time PCR Made of 3D-Printed Parts and Off-the-Shelf Electronics. AB - The polymerase chain reaction (PCR) is a sought-after nucleic acid amplification technique used in the detection of several diseases. However, one of the main limitations of this and other nucleic acid amplification assays is the complexity, size, maintenance, and cost of their operational instrumentation. This limits the use of PCR applications in settings that cannot afford the instruments but that may have access to basic electrical, electronic, and optical components and the expertise to build them. To provide a more accessible platform, we developed a low-cost, palm-size, and portable instrument to perform real-time PCR (qPCR). The thermocycler leverages a copper-sheathed power resistor and a computer fan, in tandem with basic electronic components controlled from a single-board computer. The instrument incorporates a 3D-printed chassis and a custom-made fluorescence optical setup based on a CMOS camera and a blue LED. Results are displayed in real-time on a tablet. We also fabricated simple acrylic microdevices consisting of four wells (2 MUL in volume each) where PCR reactions take place. To test our instrument, we performed qPCR on a series of cDNA dilutions spanning 4 orders of magnitude, achieving similar limits of detection as those achieved by a benchtop thermocycler. We envision our instrument being utilized to enable routine monitoring and diagnosis of certain diseases in low resource areas. PMID- 29624374 TI - pH-Responsive Nanoparticle Superlattices with Tunable DNA Bonds. AB - Stimuli-responsive nanomaterials with reconfigurable structures and properties have garnered significant interest in the fields of optics, electronics, magnetics, and therapeutics. DNA is a powerful and versatile building material that provides programmable structural and dynamic properties, and indeed, sequence-dependent changes in DNA have already been exploited in creating switchable DNA-based architectures. However, rather than designing a new DNA input sequence for each intended dynamic change, it would be useful to have one simple, generalized stimulus design that could provide multiple different structural outputs. In pursuit of this goal, we have designed, synthesized, and characterized pH-dependent, switchable nanoparticle superlattices by utilizing i motif DNA structures as pH-sensitive DNA bonds. When the pH of the solution containing such superlattices is changed, the superlattices reversibly undergo: (i) a lattice expansion or contraction, a consequence of the pH-induced change in DNA length, or (ii) a change in crystal symmetry, a consequence of both pH induced DNA "bond breaking" and "bond forming" processes. The introduction of i motifs in DNA colloidal crystal engineering marks a significant step toward being able to dynamically modulate crystalline architectures and propagate local molecular motion into global structural change via exogenous stimuli. PMID- 29624375 TI - Computational Chemistry: A Rising Tide of Women. AB - The authors were inspired to explore the topic of gender diversity in computational chemistry on the basis of similar recent publications in the related fields of medicinal chemistry ( Huryn , D. M. ; et al. ACS Med. Chem. Lett. 2017 , 8 , 900 ) and computational biology ( Bonham , K. S. ; Stefan , M. I. PLoS Comput. Biol. 2017 , 13 , e1005134 ). To do so, we examined historical demographics in two different professional settings, i.e., attendance/participation at the Gordon Research Conferences on Computer-Aided Drug Design and Computational Chemistry and membership in the Computers in Chemistry Division of the American Chemical Society. We conclude that female representation in computational chemistry has risen steadily over the last 40 years and likely stands at around 25%, which appears to slightly exceed that of the neighboring fields of computer science and medicinal chemistry. In accordance with the old slogan that "a rising tide lifts all boats", here a rising tide of women scientists is having an impact on the field of computational chemistry. Tactics to ensure that this number continues to improve are highlighted. PMID- 29624376 TI - Isomerism in Au-Ag Alloy Nanoclusters: Structure Determination and Enantioseparation of [Au9Ag12(SR)4(dppm)6X6]3. AB - Revealing structural isomerism in a nanocluster remains significant but challenging. Herein, we have obtained a pair of structural isomers, [Au9Ag12(SR)4(dppm)6X6]3+-C and [Au9Ag12(SR)4(dppm)6X6]3+-Ac [dppm = bis(diphenyphosphino)methane; HSR = 1-adamantanethiol/ tert-butylmercaptan; X = Br/Cl; C stands for one of the structural isomers being chiral; Ac stands for another being achiral], that show different structures as well as different chiralities. These structures are determined by single-crystal X-ray diffraction and further confirmed by high-resolution electrospray ionization mass spectrometry. On the basis of the isomeric structures, the most important finding is the different arrangements of the Au5Ag8@Au4 metal core, leading to changes in the overall shape of the cluster, which is responsible for structural isomerism. Meanwhile, the two enantiomers of [Au9Ag12(SR)4(dppm)6X6]3+-C are separated by high-performance liquid chromatography. Our work will contribute to a deeper understanding of the structural isomerism in noble-metal nanoclusters and enrich the chiral nanocluster. PMID- 29624377 TI - Hydroboration Reactivity of Niobium Bis(N-heterocyclic carbene)borate Complexes. AB - The syntheses of high-valent niobium imido complexes [H2B(MesIm)2]Nb(N tBu)Cl2 (2) and [H2B(MesIm)2]Nb(N tBu)Me2 (3) bearing a bis(NHC)borate (NHC = N heterocyclic carbene) supporting ligand are described. The reaction of the dimethyl complex (3) with excess CO generates an equivalent of acetone, which inserts into a B-H bond of the bis(NHC)borate ligand to form a boryl isopropoxide/niobium(III) dicarbonyl complex (4). This mode of hydroboration reactivity also occurs readily upon the treatment of either 2 or 3 with ketones, aldehydes, and isocyanates. Modification of the bis(carbene) ligand of 3 via the hydroboration of benzophenone produces the dimethylniobium complex [(OCHPh2)2B(MesIm)2]Nb(N tBu)Me2 (12), which undergoes intramolecular eta6-arene coordination upon hydrogenation. PMID- 29624378 TI - MoFi: A Software Tool for Annotating Glycoprotein Mass Spectra by Integrating Hybrid Data from the Intact Protein and Glycopeptide Level. AB - Hybrid mass spectrometry (MS) is an emerging technique for characterizing glycoproteins, which typically display pronounced microheterogeneity. Since hybrid MS combines information from different experimental levels, it crucially depends on computational methods. Here, we describe a novel software tool, MoFi, which integrates hybrid MS data to assign glycans and other post-translational modifications (PTMs) in deconvoluted mass spectra of intact proteins. Its two stage search algorithm first assigns monosaccharide/PTM compositions to each peak and then compiles a hierarchical list of glycan combinations compatible with these compositions. Importantly, the program only includes those combinations which are supported by a glycan library as derived from glycopeptide or released glycan analysis. By applying MoFi to mass spectra of rituximab, ado-trastuzumab emtansine, and recombinant human erythropoietin, we demonstrate how integration of bottom-up data may be used to refine information collected at the intact protein level. Accordingly, our software reveals that a single mass frequently can be explained by a considerable number of glycoforms. Yet, it simultaneously ranks proteoforms according to their probability, based on a score which is calculated from relative glycan abundances. Notably, glycoforms that comprise identical glycans may nevertheless differ in score if those glycans occupy different sites. Hence, MoFi exposes different layers of complexity that are present in the annotation of a glycoprotein mass spectrum. PMID- 29624380 TI - Rapid In Situ Profiling of Lipid C?C Location Isomers in Tissue Using Ambient Mass Spectrometry with Photochemical Reactions. AB - Rapid and in situ profiling of lipids using ambient mass spectrometry (AMS) techniques has great potential for clinical diagnosis, biological studies, and biomarker discovery. In this study, the online photochemical reaction involving carbon-carbon double bonds was coupled with a surface sampling technique to develop a direct tissue-analysis method with specificity to lipid C?C isomers. This method enabled the in situ analysis of lipids from the surface of various tissues or tissue sections, which allowed the structural characterization of lipid isomers within 2 min. Under optimized reaction conditions, we have established a method for the relative quantitation of lipid C?C location isomers by comparing the abundances of the diagnostic ions arising from each isomer, which has been proven effective through the established linear relationship ( R2 = 0.999) between molar ratio and diagnostic ion ratio of the FA 18:1 C?C location isomers. This method was then used for the rapid profiling of unsaturated lipid C?C isomers in the sections of rat brain, lung, liver, spleen, and kidney, as well as in normal and diseased rat tissues. Quantitative information on FA 18:1 and PC 16:0-18:1 C?C isomers was obtained, and significant differences were observed between different samples. To the best of our knowledge, this is the first study to report the direct analysis of lipid C?C isomers in tissues using AMS. Our results demonstrated that this method can serve as a rapid analytical approach for the profiling of unsaturated lipid C?C isomers in biological tissues and should contribute to functional lipidomics and clinical diagnosis. PMID- 29624381 TI - Disodium Benzodipyrrole Sulfonate as Neutral Hole-Transporting Materials for Perovskite Solar Cells. AB - Hole-transporting material (HTM) is an indispensable constituent in organic electronic devices, generally comprising a donor/dopant combination. We report that a disodium salt of substituted benzo[1,2- b:4,5- b']dipyrrole bearing two racemic alkanediylsulfonate anion side chains (BDPSOs) serves as a neutral, nonhygroscopic, dopant-free HTM for lead perovskite (MAPbI3) solar cells. These organic/inorganic hybrid molecules are useful for tunable orbital level and controllable solubility. A fluorinated BDPSO has an energy level matched with MAPbI3, affording an inverted-structure solar cell that performs with 17.2% efficiency with minimal hysteresis. The solar cell devices fabricated using BDPSOs showed remarkable storage and operational stability. PMID- 29624382 TI - In Vitro Bioaccessibility of Carotenoids and Vitamin E in Rosehip Products and Tomato Paste As Affected by Pectin Contents and Food Processing. AB - Limited bioavailability of antioxidants present in food from fruits and vegetables matrices is determined by their low bioaccessibility due to the physical and chemical interactions of the antioxidants with the indigestible polysaccharides of cell walls. Therefore, this in vitro investigation aimed to assess the bioaccessibility of carotenoids and vitamin E from rosehips as well as from tomato paste and to investigate several aspects of effects of pectin contents and food processing on bioaccessibility. Following the addition of the enzyme mixture Fructozym P6-XL, the bioaccessibility of carotenoids from rosehips as well as from tomato paste significantly increased. The average relative increase in bioaccessibility from rosehips was lower for ( all-E)-beta-carotene compared with ( all-E)-lycopene and ( all-E)-rubixanthin. In contrast, increases of bioaccessibility of alpha-tocopherol were comparable for rosehip samples and tomato paste. PMID- 29624384 TI - Semisynthetic Organisms with Expanded Genetic Codes. PMID- 29624383 TI - Chromophore Dipole Directs Morphology and Photocatalytic Hydrogen Generation. AB - The spontaneous self-assembly of chromophores into light-harvesting antennae provides a potentially low-cost approach to building solar-to-fuel conversion materials. However, designing such supramolecular architectures requires a better understanding of the balance between noncovalent forces among the molecular components. We investigated here the aqueous assembly of perylene monoimide chromophore amphiphiles synthesized with different substituents in the 9 position. The molecular dipole strength decreases as the nature of the substituent is altered from electron donating to electron withdrawing. Compounds with stronger molecular dipoles, in which dipolar interactions stabilize assemblies by 10-15 kJ.mol-1, were found to form crystalline nanoribbons in solution. In contrast, when the molecular dipole moment is small, nanofibers were obtained. Highly blue-shifted absorption maxima were observed in assemblies with large dipoles, indicating strong electronic coupling is present. However, only the moderate dipole compound had the appropriate molecular packing to access charge-transfer excitons leading to enhanced photocatalytic H2 production. PMID- 29624385 TI - Well-Defined Oligo- and Polysaccharides as Ideal Probes for Structural Studies. AB - Polysaccharides are the most abundant organic materials in nature, yet correlations between their three-dimensional structure and macroscopic properties have not been established. Automated glycan assembly enables the preparation of well-defined oligo- and polysaccharides resembling natural as well as unnatural structures. These synthetic glycans are ideal probes for the fundamental study of polysaccharides. According to molecular modeling simulations and NMR analysis, different classes of polysaccharides adopt fundamentally different conformations that are drastically altered by single-site substitutions. Larger synthetic polysaccharides are obtained via a "LEGO"-like approach as a first step toward the production of tailor-made carbohydrate-based materials. PMID- 29624386 TI - How Does the Surface Tension Depend on the Surface Area with Coarse-Grained Models? AB - We propose to investigate the size-effects on the surface tension calculated with coarse-grained (CG) models. We investigate different liquid-vapor (LV) and liquid liquid (LL) interfaces with the MARTINI force field and original CG models designed for the dissipative particle dynamics (DPD) and multibody particle dynamics (MDPD) simulations. We also test a realistic CG potential developed for the DPD method to investigate the LV interface of n-pentane. Concerning the MARTINI force field, we observe a weak oscillatory effect of the interfacial tension with the surface area for the LV interfaces of n-octane and water. This weak dependence of the surface tension with the box dimension is also observed in the LL interface of n-octane-water (MARTINI, DPD) and in the LV interface of water with the MDPD model. PMID- 29624387 TI - Computer-Aided Discovery and Characterization of Novel Ebola Virus Inhibitors. AB - The Ebola virus (EBOV) causes severe human infection that lacks effective treatment. A recent screen identified a series of compounds that block EBOV-like particle entry into human cells. Using data from this screen, quantitative structure-activity relationship models were built and employed for virtual screening of a ~17 million compound library. Experimental testing of 102 hits yielded 14 compounds with IC50 values under 10 MUM, including several sub micromolar inhibitors, and more than 10-fold selectivity against host cytotoxicity. These confirmed hits include FDA-approved drugs and clinical candidates with non-antiviral indications, as well as compounds with novel scaffolds and no previously known bioactivity. Five selected hits inhibited BSL-4 live-EBOV infection in a dose-dependent manner, including vindesine (0.34 MUM). Additional studies of these novel anti-EBOV compounds revealed their mechanisms of action, including the inhibition of NPC1 protein, cathepsin B/L, and lysosomal function. Compounds identified in this study are among the most potent and well characterized anti-EBOV inhibitors reported to date. PMID- 29624388 TI - A Versatile Multiple Time Step Scheme for Efficient ab Initio Molecular Dynamics Simulations. AB - We present here our implementation of a time-reversible, multiple time step (MTS) method for full QM and hybrid QM/MM Born-Oppenheimer molecular dynamics simulations. The method relies on a fully flexible combination of electronic structure methods, from density functional theory to wave function-based quantum chemistry methods, to evaluate the nuclear forces in the reference and in the correction steps. The possibility of combining different electronic structure methods is based on the observation that exchange and correlation terms only contribute to low frequency modes of nuclear forces. We show how a pair of low/high level electronic structure methods that individually would lead to very different system properties can be efficiently combined in the reference and correction steps of this MTS scheme. The current MTS implementation makes it possible to perform highly accurate ab initio molecular dynamics simulations at reduced computational cost. Stable and accurate trajectories were obtained with time steps of several femtoseconds, similar to and even exceeding the ones usually adopted in classical molecular dynamics, in particular when using a generalized Langevin stochastic thermostat. Compared to the standard Velocity Verlet integration, the present MTS scheme allows for a 5- to 6-fold overall speedup, at an unaltered level of accuracy. PMID- 29624389 TI - Correction to Application of Structure-Based Design and Parallel Chemistry to Identify a Potent, Selective, and Brain Penetrant Phosphodiesterase 2A Inhibitor. PMID- 29624390 TI - Understanding Fast and Robust Thermo-osmotic Flows through Carbon Nanotube Membranes: Thermodynamics Meets Hydrodynamics. AB - Following our recent theoretical prediction of the giant thermo-osmotic response of the water-graphene interface, we explore the practical implementation of waste heat harvesting with carbon-based membranes, focusing on model membranes of carbon nanotubes (CNT). To that aim, we combine molecular dynamics simulations and an analytical model considering the details of hydrodynamics in the membrane and at the tube entrances. The analytical model and the simulation results match quantitatively, highlighting the need to take into account both thermodynamics and hydrodynamics to predict thermo-osmotic flows through membranes. We show that, despite viscous entrance effects and a thermal short-circuit mechanism, CNT membranes can generate very fast thermo-osmotic flows, which can overcome the osmotic pressure of seawater. We then show that in small tubes confinement has a complex effect on the flow and can even reverse the flow direction. Beyond CNT membranes, our analytical model can guide the search for other membranes to generate fast and robust thermo-osmotic flows. PMID- 29624392 TI - Self-Interaction Error in Density Functional Theory: An Appraisal. AB - Self-interaction error (SIE) is considered to be one of the major sources of error in most approximate exchange-correlation functionals for Kohn-Sham density functional theory (KS-DFT), and it is large with all local exchange-correlation functionals and with some hybrid functionals. In this work, we consider systems conventionally considered to be dominated by SIE. For these systems, we demonstrate that by using multiconfiguration pair-density functional theory (MC PDFT), the error of a translated local density-functional approximation is significantly reduced (by a factor of 3) when using an MCSCF density and on-top density, as compared to using KS-DFT with the parent functional; the error in MC PDFT with local on-top functionals is even lower than the error in some popular KS-DFT hybrid functionals. Density-functional theory, either in MC-PDFT form with local on-top functionals or in KS-DFT form with some functionals having 50% or more nonlocal exchange, has smaller errors for SIE-prone systems than does CASSCF, which has no SIE. PMID- 29624391 TI - Membrane Deformation Induces Clustering of Norovirus Bound to Glycosphingolipids in a Supported Cell-Membrane Mimic. AB - Quartz crystal microbalance with dissipation monitoring and total internal reflection fluorescence microscopy have been used to investigate binding of norovirus-like particles (noroVLPs) to a supported (phospho)lipid bilayer (SLB) containing a few percent of H or B type 1 glycosphingolipid (GSL) receptors. Although neither of these GSLs spontaneously form domains, noroVLPs were observed to form micron-sized clusters containing typically up to about 30 VLP copies, especially for B type 1, which is a higher-affinity receptor. This novel finding is explained by proposing a model implying that VLP-induced membrane deformation promotes VLP clustering, a hypothesis that was further supported by observing that functionalized gold nanoparticles were able to locally induce SLB deformation. Because similar effects are likely possible also at cellular membranes, our findings are interesting beyond a pure biophysicochemical perspective as they shed new light on what may happen during receptor-mediated uptake of viruses as well as nanocarriers in drug delivery. PMID- 29624393 TI - Temperature Dependent Rate Coefficients for the Gas-Phase Reaction of the OH Radical with Linear (L2, L3) and Cyclic (D3, D4) Permethylsiloxanes. AB - Permethylsiloxanes are emitted into the atmosphere during production and use as personal care products, lubricants, and cleaning agents. The predominate atmospheric loss process for permethylsiloxanes is expected to be via gas-phase reaction with the OH radical. In this study, rate coefficients, k(T), for the OH radical gas-phase reaction with the two simplest linear and cyclic permethylsiloxanes were measured using a pulsed laser photolysis-laser induced fluorescence technique over the temperature range of 240-370 K and a relative rate method at 294 K: hexamethyldisiloxane ((CH3)3SiOSi(CH3)3, L2), k1; octamethyltrisiloxane ([(CH3)3SiO]2Si(CH3)2, L3), k2; hexamethylcyclotrisiloxane ([-Si(CH3)2O-]3, D3), k3; and octamethylcyclotetrasiloxane ([-Si(CH3)2O-]4, D4), k4. The obtained k(294 K) values and temperature-dependence expressions for the 240-370 K temperature range are (cm3 molecule-1 s-1, 2sigma absolute uncertainties): k1(294 K) = (1.28 +/- 0.08) * 10-12, k1( T) = (1.87 +/- 0.18) * 10-11 exp(-(791 +/- 27)/ T); k2(294 K) = (1.72 +/- 0.10) * 10-12, k2( T) = 1.96 * 10-13 (T/298)4.34 exp(657/ T); k3(294 K) = (0.82 +/- 0.05) * 10-12, k3( T) = (1.29 +/- 0.19) * 10-11 exp(-(805 +/- 43)/ T); and k4(294 K) = (1.12 +/- 0.10) * 10-12, k4( T) = (1.80 +/- 0.26) * 10-11 exp(-(816 +/- 43)/ T). The cyclic molecules were found to be less reactive than the analogous linear molecule with the same number of -CH3 groups, while the linear and cyclic permethylsiloxane reactivity both increase with the increasing number of CH3- groups. The present results are compared with previous rate coefficient determinations where available. The permethylsiloxanes included in this study are atmospherically short-lived compounds with estimated atmospheric lifetimes of 11, 8, 17, and 13 days, respectively. PMID- 29624394 TI - Ultrahigh Flux Thin Film Boiling Heat Transfer Through Nanoporous Membranes. AB - Phase change heat transfer is fundamentally important for thermal energy conversion and management, such as in electronics with power density over 1 kW/cm2. The critical heat flux (CHF) of phase change heat transfer, either evaporation or boiling, is limited by vapor flux from the liquid-vapor interface, known as the upper limit of heat flux. This limit could in theory be greater than 1 kW/cm2 on a planar surface, but its experimental realization has remained elusive. Here, we utilized nanoporous membranes to realize a new "thin film boiling" regime that resulted in an unprecedentedly high CHF of over 1.2 kW/cm2 on a planar surface, which is within a factor of 4 of the theoretical limit, and can be increased to a higher value if mechanical strength of the membranes can be improved (demonstrated with 1.85 kW/cm2 CHF in this work). The liquid supply is achieved through a simple nanoporous membrane that supports the liquid film where its thickness automatically decreases as heat flux increases. The thin film configuration reduces the conductive thermal resistance, leads to high frequency bubble departure, and provides separate liquid-vapor pathways, therefore significantly enhances the heat transfer. Our work provides a new nanostructuring approach to achieve ultrahigh heat flux in phase change heat transfer and will benefit both theoretical understanding and application in thermal management of high power devices of boiling heat transfer. PMID- 29624395 TI - Rhodium-Catalyzed Enantioselective Alkenylation of Cyclic Ketimines: Synthesis of Multifunctional Chiral alpha,alpha-Disubstituted Allylic Amine Derivatives. AB - By employing a simple open-chain chiral phosphite-olefin ligand, a highly enantioselective rhodium-catalyzed alkenylation of 1,2,5-thiadiazole 1,1-dioxide type cyclic ketimines with diverse vinylboronic acids was achieved under mild conditions at room temperature. This protocol provides an efficient and practical access to multifunctional alpha,alpha-disubstituted chiral allylic amines bearing quaternary stereocenters in high yields (up to 99%) with good to excellent ee's (up to 99%). PMID- 29624396 TI - Excitonic Emission of Monolayer Semiconductors Near-Field Coupled to High-Q Microresonators. AB - We present quantum yield measurements of single layer WSe2 (1L-WSe2) integrated with high-Q ( Q > 106) optical microdisk cavities, using an efficient (eta > 90%) near-field coupling scheme based on a tapered optical fiber. Coupling of the excitonic emission is achieved by placing 1L-WSe2 in the evanescent cavity field. This preserves the microresonator high intrinsic quality factor ( Q > 106) below the bandgap of 1L-WSe2. The cavity quantum yield is QYc ~ 10-3, consistent with operation in the broad emitter regime (i.e., the emission lifetime of 1L-WSe2 is significantly shorter than the bare cavity decay time). This scheme can serve as a precise measurement tool for the excitonic emission of layered materials into cavity modes, for both in plane and out of plane excitation. PMID- 29624397 TI - Supported Mn3O4 Nanosystems for Hydrogen Production through Ethanol Photoreforming. AB - Photoreforming promoted by metal oxide nanophotocatalysts is an attractive route for clean and sustainable hydrogen generation. In the present work, we propose for the first time the use of supported Mn3O4 nanosystems, both pure and functionalized with Au nanoparticles (NPs), for hydrogen generation by photoreforming. The target oxide systems, prepared by chemical vapor deposition (CVD) and decorated with gold NPs by radio frequency (RF) sputtering, were subjected to a thorough chemico-physical characterization and utilized for a proof-of-concept H2 generation in aqueous ethanolic solutions under simulated solar illumination. Pure Mn3O4 nanosystems yielded a constant hydrogen production rate of 10 mmol h-1 m-2 even for irradiation times up to 20 h. The introduction of Au NPs yielded a significant enhancement in photocatalytic activity, which decreased as a function of irradiation time. The main phenomena causing the Au containing photocatalyst deactivation have been investigated by morphological and compositional analysis, providing important insights for the design of Mn3O4 based photocatalysts with improved performances. PMID- 29624398 TI - Autoxidation Photoredox Catalysis for the Synthesis of 2-Phosphinoylindoles. AB - A new approach to the synthesis of 2-phosphinoylindoles through photoredox catalysis without external oxidants has been developed. Promoted by a ruthenium photoredox catalyst, a broad scope of 2-phosphinoylindoles can be synthesized through phosphinoylation/cyclization of diphenylphosphine oxide at room temperature under irradiation without external oxidants. The estrone skeleton isocyan is also an amenable substrate for this cyclization, yielding a molecule that has potential medicinal applications. PMID- 29624399 TI - Templating Synthesis of Mesoporous Fe3C-Encapsulated Fe-N-Doped Carbon Hollow Nanospindles for Electrocatalysis. AB - Developing cost-efficient alternatives to the noble metal catalysts toward oxygen reduction reaction (ORR) has attracted much attention. Herein, a kind of mesoporous hollow spindlelike Fe-N-C electrocatalysts with iron carbide nanoparticles encased in the N-doped graphitic layers has been synthesized by a novel "reactive hard template" strategy through the Fe3+-assisted polymerization of dopamine on the Fe2O3 cores and the following calcinations. The Fe2O3 nanospindles not only as the hard template guide the formation of well-defined shape and structure of the catalyst but also as the reactive template provide Fe reservoir to generate Fe3C nanoparticles in the catalyst during the thermochemical process. The superiority in accessible active sites of Fe-N x species, Fe3C nanoparticles in graphenelike layers, and highly mesoporous hollow structure enables the catalysts to exhibit excellent ORR performances including high catalytic activity, outstanding long-term cycling stability, and good tolerance to methanol. PMID- 29624400 TI - Molecular Size Distribution of Fluorophores in Aquatic Natural Organic Matter: Application of HPSEC with Multi-Wavelength Absorption and Fluorescence Detection Following LPSEC-PAGE Fractionation. AB - Analytical high performance size exclusion liquid chromatography (HPSEC) with multiwavelength absorbance and fluorescence detections was used for the analysis of molecular size distribution and optical properties of dissolved natural organic matter. Experiments were conducted on Suwannee River organic matter (SRNOM) and its fractions A, B, C+D preliminary obtained by combination of preparative low pressure size exclusion chromatography and polyacrylamide gel electrophoresis (LPSEC-PAGE) and purified by dialysis on membrane with nominal cutoff 10 kDa, the fractions molecular size varied in order A > B > C + D > 10 kDa. The multistep fractionation of SRNOM enabled the size-separation of at least five types of humic-like fluorophores within NOM showing emission maxima at 465, 450, 435, 420, and 405 nm. The decrease of the humic-like emission maxima paralleled the decrease of the nominal molecular size of fluorescent SRNOM. The protein-like fluorescence was split into tyrosine-like and tryptophan-like fluorophores and only detected in fractions A and B. This work provides new data on the optical properties of size-fractionated NOM, which consistent with the formation of supramolecular NOM assemblies, likely controlled by association of low-molecular size components. It is clearly observed for the high molecular size fraction A, containing free amino acids or short peptides. The combination of several different fractionation procedures is very useful for obtaining less complex NOM compounds and understanding the NOM function in the environment. PMID- 29624401 TI - Autoassemblies of alpha-Cyclodextrin and Grafted Polysaccharides: Crystal Structure and Specific Properties of the Platelets. AB - Cyclodextrins (CDs) are a family of oligosaccharides with a toroid shape, which exhibit a remarkable ability to include guest molecules in their internal cavity, providing a hydrophobic environment for poorly soluble molecules. Recently, new types of inclusions of alpha CDs with alkyl grafted polysaccharide chains (pullulan, chitosan, dextran, amylopectin, chondroitin sulfate...) have been prepared which are autoassembled into micro- and nanoplatelets. We report in this paper an extensive investigation of platelets with different compositions, including their reversible hydration (thermogravimetric analysis), crystalline structure (powder X-ray diffraction), dimensions and shapes (scanning electron microscopy-field emission gun), thermal properties, solubility, and melting (micro-differential scanning calorimetry). The crystalline platelets exhibit layered structures intercalating the polysaccharide backbones and CD complexes hosting the grafted alkyl chains. The monoclinic symmetry of columnar-type crystals suggests a head-to-tail arrangement of the CDs. The platelets have a preferentially hexagonal shape with sharp edges, variable sizes, and thicknesses and sometimes show incomplete layers (terraces). The crystal parameters change upon dehydration. Melting temperatures of platelets in aqueous solutions exceed 100 degrees C. Finally, we discuss the potential relation between the platelet structure and applications for mucoadhesive devices. PMID- 29624403 TI - "Nickel Nanoflowers" with Surface-Attached Fluoropolymer Networks by C,H Insertion for the Generation of Metallic Superhydrophobic Surfaces. AB - Metallic superhydrophobic surfaces (SHSs) combine the attractive properties of metals, such as ductility, hardness, and conductivity, with the favorable wetting properties of nanostructured surfaces. Moreover, they promise additional benefits with respect to corrosion protection. For the modification of the intrinsically polar and hydrophilic surfaces of metals, a new method has been developed to deposit a long-term stable, highly hydrophobic coating, using nanostructured Ni surfaces as an example. Such substrates were chosen because the deposition of a thin Ni layer is a common choice for enhancing corrosion resistance of other metals. As the hydrophobic coating, we propose a thin film of an extremely hydrophobic fluoropolymer network. To form this network, a thin layer of a fluoropolymer precursor is deposited on the Ni substrate which includes a comonomer that is capable of C,H insertion cross-linking (CHic). Upon UV irradiation or heating, the cross-linker units become activated and the thin glassy film of the precursor is transformed into a polymer network that coats the surface conformally and permanently, as shown by extensive extraction experiments. To achieve an even higher stability, the same precursor film can also be transformed into a chemically surface-attached network by depositing a self-assembled monolayer of an alkane phosphonic acid on the Ni before coating with the precursor. During cross-linking, by the same chemical process, the growing polymer network will simultaneously attach to the alkane phosphonic acid layer at the surface of the metal. This strategy has been used to turn fractal Ni "nanoflower" surfaces grown by anisotropic electroplating into SHSs. The wetting characteristics of the obtained nanostructured metallic surfaces are studied. Additionally, the corrosion protection effect and the significant mechanical durability are demonstrated. PMID- 29624402 TI - MOMD Analysis of NMR Line Shapes from Abeta-Amyloid Fibrils: A New Tool for Characterizing Molecular Environments in Protein Aggregates. AB - The microscopic-order-macroscopic-disorder (MOMD) approach for 2H NMR line shape analysis is applied to dry and hydrated 3-fold- and 2-fold-symmetric amyloid Abeta40 fibrils and protofibrils of the D23N mutant. The methyl moieties of L17, L34, V36 (C-CD3), and M35 (S-CD3) serve as probes. Experimental 2H spectra acquired previously in the 147-310 K range are used. MOMD describes local probe motion as axial diffusion ( R tensor) in the presence of a potential, u, which represents the spatial restrictions exerted by the molecular surroundings. We find that R? = (0.2-3.3) * 104 s-1, R? = (2.2-2.5) * 102 s-1, and R is tilted from the 2H quadrupolar tensor at 60-75 degrees . The strength of u is in the (2.0-2.4) kT range; its rhombicity is substantial. The only methyl moieties affected by fibril hydration are those of M35, located at fibril interfaces. The associated local potentials change form abruptly around 260 K, where massive water freezing occurs. An independent study revealed unfrozen "tightly-peptide bound" water residing at the interfaces of the 3-fold-symmetric Abeta40 fibrils and at the interfaces of the E22G and E22Delta Abeta40-mutant fibrils. Considering this to be the case in general for Abeta40-related fibrils, the following emerges. The impact of water freezing is transmitted selectively to the fibril structure through interactions with tightly-peptide-bound water, in this case of M35 methyl moieties. The proof that such waters reside at the interfaces of the 2-fold-symmetric fibril, and the protofibril of the D23N mutant, is new. MOMD provides information on the surroundings of the NMR probe directly via the potential, u, which is inherent to the model; a prior interpretation of the same experimental data does so partially and indirectly (see below). Thus, MOMD analysis of NMR line shapes as applied to amyloid fibrils/protein aggregates emerges as a consistent new tool for elucidating the properties of, and processes associated with, molecular environments in the fibril. PMID- 29624404 TI - Stable Defects in Semiconductor Nanowires. AB - Semiconductor nanowires are commonly described as being defect-free due to their ability to expel mobile defects with long-range strain fields. Here, we describe previously undiscovered topologically protected line defects with null Burgers vector that, unlike dislocations, are stable in nanoscale crystals. We analyze the defects present in semiconductor nanowires in regions of imperfect crystal growth, i.e., at the nanowire tip formed during consumption of the droplet in self-catalyzed vapor-liquid-solid growth and subsequent vapor-solid shell growth. We use a form of the Burgers circuit method that can be applied to multiply twinned material without difficulty. Our observations show that the nanowire microstructure is very different from bulk material, with line defects either (a) trapped by locks or other defects, (b) arranged as dipoles or groups with a zero total Burgers vector, or (c) have a zero Burgers vector. We find two new line defects with a null Burgers vector, formed from the combination of partial dislocations in twinned material. The most common defect is the three-monolayer high twin facet with a zero Burgers vector. Studies of individual nanowires using cathodoluminescence show that optical emission is quenched in defective regions, showing that they act as strong nonradiative recombination centers. PMID- 29624405 TI - Catalytic Nanotruss Structures Realized by Magnetic Self-Assembly in Pulsed Plasma. AB - Tunable nanostructures that feature a high surface area are firmly attached to a conducting substrate and can be fabricated efficiently over significant areas, which are of interest for a wide variety of applications in, for instance, energy storage and catalysis. We present a novel approach to fabricate Fe nanoparticles using a pulsed-plasma process and their subsequent guidance and self-organization into well-defined nanostructures on a substrate of choice by the use of an external magnetic field. A systematic analysis and study of the growth procedure demonstrate that nondesired nanoparticle agglomeration in the plasma phase is hindered by electrostatic repulsion, that a polydisperse nanoparticle distribution is a consequence of the magnetic collection, and that the formation of highly networked nanotruss structures is a direct result of the polydisperse nanoparticle distribution. The nanoparticles in the nanotruss are strongly connected, and their outer surfaces are covered with a 2 nm layer of iron oxide. A 10 MUm thick nanotruss structure was grown on a lightweight, flexible and conducting carbon-paper substrate, which enabled the efficient production of H2 gas from water splitting at a low overpotential of 210 mV and at a current density of 10 mA/cm2. PMID- 29624406 TI - Endotracheal Intubation in Critically III Patients: Direct Laryngoscopy, Complications, and Cardiac Arrest. PMID- 29624407 TI - Exploring the Multiple Roles of Acupuncture in Alleviating the Opioid Crisis. PMID- 29624408 TI - Patient and Family Engagement in the ICU. Untapped Opportunities and Underrecognized Challenges. AB - The call for meaningful patient and family engagement in health care and research is gaining impetus. Healthcare institutions and research funding agencies increasingly encourage clinicians and researchers to work actively with patients and their families to advance clinical care and research. Engagement is increasingly mandated by healthcare organizations and is becoming a prerequisite for research funding. In this article, we review the rationale and the current state of patient and family engagement in patient care and research in the ICU. We identify opportunities to strengthen engagement in patient care by promoting greater patient and family involvement in care delivery and supporting their participation in shared decision-making. We also identify challenges related to patient willingness to engage, barriers to participation, participant risks, and participant expectations. To advance engagement, clinicians and researchers can develop the science behind engagement in the ICU context and demonstrate its impact on patient- and process-related outcomes. In addition, we provide practical guidance on how to engage, highlight features of successful engagement strategies, and identify areas for future research. At present, enormous opportunities remain to enhance engagement across the continuum of ICU care and research. PMID- 29624410 TI - Ginseng as a Treatment for Fatigue: A Systematic Review. AB - BACKGROUND: Millions of people with chronic illness suffer from fatigue. Fatigue is a complex, multidimensional symptom with poorly understood causes, wide variations in severity among individuals, and negative effects on multiple domains of daily life. Many patients with fatigue report the use of herbal remedies. Ginseng is one of the most widely used because it is believed to improve energy, physical and emotional health, and well-being. OBJECTIVE: To systematically review the published evidence to evaluate the safety and effectiveness of the two types of Panax ginseng (Asian [Panax ginseng] and American [Panax quinquefolius]) as treatments for fatigue. DESIGN: PubMed, CINAHL (Cumulative Index to Nursing and Allied Health), Ovid MEDLINE, and EMBASE databases were searched using Medical Subject Heading and keyword terms, including ginseng, Panax, ginsenosides, ginsenoside* (wild card), fatigue, fatigue syndrome, cancer-related fatigue, and chronic fatigue. Studies were included if participants had fatigue, had used one of the two Panax ginsengs as an intervention, and had scores from a self-report fatigue measure. Two reviewers independently assessed each article at each review phase and met to develop consensus on included studies. Risk of bias was assessed using version 5.3 of the Cochrane Collaboration Review Manager (RevMan), and results were synthesized in a narrative summary. RESULTS: The search strategy resulted in 149 articles, with 1 additional article located through review of references. After titles, abstracts, and full text were reviewed, 139 articles did not meet inclusion criteria. For the 10 studies reviewed, there was a low risk of adverse events associated with the use of ginseng and modest evidence for its efficacy. CONCLUSIONS: Ginseng is a promising treatment for fatigue. Both American and Asian ginseng may be viable treatments for fatigue in people with chronic illness. Because of ginseng's widespread use, a critical need exists for continued research that is methodologically stronger and that includes more diverse samples before ginseng is adopted as a standard treatment option for fatigue. PMID- 29624409 TI - Validation of a Host Response Assay, SeptiCyte LAB, for Discriminating Sepsis from Systemic Inflammatory Response Syndrome in the ICU. AB - RATIONALE: A molecular test to distinguish between sepsis and systemic inflammation of noninfectious etiology could potentially have clinical utility. OBJECTIVES: This study evaluated the diagnostic performance of a molecular host response assay (SeptiCyte LAB) designed to distinguish between sepsis and noninfectious systemic inflammation in critically ill adults. METHODS: The study employed a prospective, observational, noninterventional design and recruited a heterogeneous cohort of adult critical care patients from seven sites in the United States (n = 249). An additional group of 198 patients, recruited in the large MARS (Molecular Diagnosis and Risk Stratification of Sepsis) consortium trial in the Netherlands ( www.clinicaltrials.gov identifier NCT01905033), was also tested and analyzed, making a grand total of 447 patients in our study. The performance of SeptiCyte LAB was compared with retrospective physician diagnosis by a panel of three experts. MEASUREMENTS AND MAIN RESULTS: In receiver operating characteristic curve analysis, SeptiCyte LAB had an estimated area under the curve of 0.82-0.89 for discriminating sepsis from noninfectious systemic inflammation. The relative likelihood of sepsis versus noninfectious systemic inflammation was found to increase with increasing test score (range, 0-10). In a forward logistic regression analysis, the diagnostic performance of the assay was improved only marginally when used in combination with other clinical and laboratory variables, including procalcitonin. The performance of the assay was not significantly affected by demographic variables, including age, sex, or race/ethnicity. CONCLUSIONS: SeptiCyte LAB appears to be a promising diagnostic tool to complement physician assessment of infection likelihood in critically ill adult patients with systemic inflammation. Clinical trial registered with www.clinicaltrials.gov (NCT01905033 and NCT02127502). PMID- 29624411 TI - Investigating Matrix-Fibroblast Regulation of MicroRNAs. A Dice(r)y Proposition. PMID- 29624413 TI - Motorcycle crashes potentially preventable by three crash avoidance technologies on passenger vehicles. AB - OBJECTIVE: The objective of this study was to identify and quantify the motorcycle crash population that would be potential beneficiaries of 3 crash avoidance technologies recently available on passenger vehicles. METHODS: Two vehicle crashes between a motorcycle and a passenger vehicle that occurred in the United States during 2011-2015 were classified by type, with consideration of the functionality of 3 classes of passenger vehicle crash avoidance technologies: frontal crash prevention, lane maintenance, and blind spot detection. Results were expressed as the percentage of crashes potentially preventable by each type of technology, based on all known types of 2-vehicle crashes and based on all crashes involving motorcycles. RESULTS: Frontal crash prevention had the largest potential to prevent 2-vehicle motorcycle crashes with passenger vehicles. The 3 technologies in sum had the potential to prevent 10% of fatal 2-vehicle crashes and 23% of police-reported crashes. However, because 2-vehicle crashes with a passenger vehicle represent fewer than half of all motorcycle crashes, these technologies represent a potential to avoid 4% of all fatal motorcycle crashes and 10% of all police-reported motorcycle crashes. DISCUSSION: Refining the ability of passenger vehicle crash avoidance systems to detect motorcycles represents an opportunity to improve motorcycle safety. Expanding the capabilities of these technologies represents an even greater opportunity. However, even fully realizing these opportunities can affect only a minority of motorcycle crashes and does not change the need for other motorcycle safety countermeasures such as helmets, universal helmet laws, and antilock braking systems. PMID- 29624412 TI - Prenatal Development and Adolescent Obesity: Two Distinct Pathways to Diabetes in Adulthood. AB - OBJECTIVE: Higher body-mass index (BMI) and lower birth weight (BW) are associated with elevated risk of diabetes in adulthood, but the extent to which they compose two distinct pathways is unclear. METHODS: We used data from the National Longitudinal Study of Adolescent to Adult Health, a cohort of adolescents (1994-1995) followed for 14 years over four waves into adulthood (n = 13,413). Sex-stratified path analysis was used to examine pathways from BW [kg; linear (BW) and quadratic (BW2)] to latent trajectories in BMI from adolescence to adulthood to prevalent diabetes or prediabetes (pre/diabetes) in adulthood, adjusting for sociodemographic characteristics. RESULTS: Two pathways from BW to pre/diabetes were characterized: one from higher BW to elevated BMI and pre/diabetes and a second from lower BW, independent of BMI. In the BMI independent pathway, greater BW was associated with marginally lower odds of pre/diabetes in women, but not men. Girls born at lower and higher BW exhibited elevated BMI in adolescence [coeff (95% CI): BW: -2.1 (-4.1, -0.05); BW2: 0.43 (0.09, 0.76)]; higher BW predicted marginally faster BMI gain and higher adolescent BMI and faster BMI gain were associated with pre/diabetes [coeff (95% CI): BMI intercept: 0.09 (0.06, 0.11); BMI slope: 0.11 (0.07, 0.15)]. In boys, BW was weakly associated with BMI intercept and slope; BMI slope, but not BMI intercept, was positively associated with pre/diabetes [coeff (95% CI): 0.29 (0.19, 0.39)]. CONCLUSIONS: Findings suggest that in girls, slowing BMI gain is critical for diabetes prevention, yet it may not address distinct pathology stemming from early life. PMID- 29624414 TI - Health Outcomes from Multidrug-Resistant Salmonella Infections in High-Income Countries: A Systematic Review and Meta-Analysis. AB - BACKGROUND: Salmonella is a leading cause of foodborne enterocolitis worldwide. Antimicrobial use in food animals is the driving force for antimicrobial resistance among Salmonella particularly in high-income countries. Nontyphoidal Salmonella (NTS) infections that are multidrug resistant (MDR) (nonsusceptible to >=1 agent in >=3 antimicrobial categories) may result in more severe health outcomes, although these effects have not been systematically examined. We conducted a systematic review and meta-analysis to examine impacts of MDR NTS on disease outcomes in high-income settings. METHODS: We systematically reviewed the literature from scientific databases, including PubMed, Scopus, and grey literature sources, using preferred reporting items for systematic reviews and meta-analyses (PRISMA) guidelines. We included peer-reviewed publications of case control and cohort studies, outbreak investigations, and published theses, imposing no language restriction. We included publications from January 1, 1990 through September 15, 2016 from high-income countries as classified by the World Bank, and extracted data on duration of illness, hospitalization, morbidity and mortality of MDR, and pan-susceptible NTS infections. RESULTS: After removing duplicates, the initial search revealed 4258 articles. After further screening, 16 eligible studies were identified for the systematic review, but, only 9 of these were included in the meta-analysis. NTS serotypes differed among the reported studies, but serotypes Typhimurium, Enteritidis, Newport, and Heidelberg were the most often reported MDR pathogens. Salmonella infections that were MDR were associated with excess bloodstream infections (odds ratio [OR] 1.73; 95% confidence interval [CI] 1.32-2.27), more frequent hospitalizations (OR 2.51; 95% CI 1.38-4.58), and higher mortality (OR 3.54; 95% CI 1.10-11.40) when compared with pan-susceptible isolates. CONCLUSIONS: Our study suggests that MDR NTS infections have more serious health outcomes compared with pan-susceptible strains. With the emergence of MDR Salmonella strains in high-income countries, it is crucial to reduce the use of antimicrobials in animals and humans, and intervene to prevent foodborne infections. PMID- 29624415 TI - A Beginner's Guide to Analysis of RNA Sequencing Data. AB - Since the first publications coining the term RNA-seq (RNA sequencing) appeared in 2008, the number of publications containing RNA-seq data has grown exponentially, hitting an all-time high of 2,808 publications in 2016 (PubMed). With this wealth of RNA-seq data being generated, it is a challenge to extract maximal meaning from these datasets, and without the appropriate skills and background, there is risk of misinterpretation of these data. However, a general understanding of the principles underlying each step of RNA-seq data analysis allows investigators without a background in programming and bioinformatics to critically analyze their own datasets as well as published data. Our goals in the present review are to break down the steps of a typical RNA-seq analysis and to highlight the pitfalls and checkpoints along the way that are vital for bench scientists and biomedical researchers performing experiments that use RNA-seq. PMID- 29624417 TI - Consumption of green coffee and the risk of chronic diseases. AB - Green coffee contains macro nutrients such as carbohydrates, protein, fat, as well as minor components such as caffeine, trigonelin and chlorogenic acid. Phenolics, chlorogenic acids and brown pigments are sources of natural antixodants. High polypehonic materials found in green coffee and especially chlorogenic acid in it have an important place. It is considered that; green coffee has effects on body mass, blood glucose and lipid levels, blood pressure, prevention from cardiovascular diseases which is based on chlorogenic acid consisting antioxidant activity. However, many topics like toxicological effects, doses, amounts, usage in the body, advantages and disadvantages, etc. of these active molecules need to be examined. For these reasons this article was rewieved to evaluate health effects of green coffee. PMID- 29624416 TI - Traditional Chinese Patent Medicine for Treating Impaired Glucose Tolerance: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. AB - INTRODUCTION/AIM: To assess the effectiveness and safety of Traditional Chinese patent medicines (TCPMs) for managing impaired glucose tolerance (IGT). METHODS: Seven databases were searched to identify eligible trials published from incepting to May 1, 2016. Randomized controlled trials (RCTs) involving TCPM for IGT with a minimum follow-up duration of 6 months were included for analysis. Data extraction and quality assessment were performed by two reviewers independently. Data synthesis was analyzed using Review Manager 5.3 software. Subgroup analysis was carried out to assess the robustness of results of meta analysis. RESULTS: Eighteen trials with a total of 3172 participants met the inclusion criteria. The methodological quality of the RCTs was variable. Comparing with receiving lifestyle modification (LM) alone, TCPM plus LM was significantly better at reducing the incidence of diabetes (risk ratio [RR] 0.45; 95% confidence interval [CI] 0.36-0.57, p < 0.00001) and normalizing the blood glucose (RR 0.72; 95% CI 0.64-0.82, p < 0.00001). TCPM plus LM was superior in decreasing the levels of 2hPG, body mass index (BMI), fasting insulin, and 2 h insulin compared with LM alone (2hPG: mean difference [MD] -1.13; 95% CI -1.68 to -0.58, p < 0.0001; BMI: MD -0.42; 95% CI -0.71 to -0.14, p = 0.004; fasting insulin: MD -2.44; 95% CI -3.79 to -1.09, p = 0.0004; and 2 h insulin: MD -8.26; 95% CI -8.47 to -8.05, p < 0.00001). Compared with placebo plus LM, TCPM plus LM was superior in reducing diabetes (RR 0.54; 95% CI 0.42-0.69, p < 0.00001) and normalizing blood glucose (RR 0.55; 95% CI 0.41-0.73, p < 0.00001; the interventions were also associated with a decline in the two-hour postprandial blood glucose (2hPG) levels (MD -1.45; 95% CI -2.11 to -0.79, p < 0.0001) and BMI levels (MD -1.12; 95% CI -2.00 to -0.24, p < 0.0001). There were no significant differences in adverse events between two groups. Subgroup analysis found no significant difference in overall effects among all study characteristics, indicating that the overall effects were stable. CONCLUSIONS: The study indicated that TCPM combined with moderate lifestyle modification had significant effect on IGT. Further studies are needed to provide more reliable evidence. The PROSPERO registration is No. CRD42016039312. PMID- 29624418 TI - Welcome and Opening Remarks. PMID- 29624419 TI - Multidisciplinary Studies on Rotavirus-Human Milk Oligosaccharide Interactions. PMID- 29624420 TI - Human Milk to Prevent and Heal Gastrointestinal Tract Injury in Children After Bone Marrow Transplantation. PMID- 29624421 TI - Human Milk Oligosaccharides at the Interface of Maternal-Infant Health. PMID- 29624422 TI - Breast Milk Fats and Lipids: Expanding Benefits to Fragile Infant Populations. PMID- 29624423 TI - Human Milk-Based Industry in the Muslim World: Religioethical Challenges. PMID- 29624424 TI - History of Milk Banking: From Origin to Present Time. PMID- 29624425 TI - Variations in Human Milk Composition: Impact on Immune Development and Allergic Disease Susceptibility. PMID- 29624426 TI - Integrated Approaches to Analyze Big Data in the Perinatal/Neonatal Space. PMID- 29624427 TI - Human Milk and Preterm Infant Brain Development. PMID- 29624428 TI - Cardiac Remodeling in Preterm-Born Adults: Long-Term Benefits of Human Milk Consumption in Preterm Neonates. PMID- 29624429 TI - Probiotic Intervention Through the Pregnant and Breastfeeding Mother to Reduce Disease Risk in the Child. PMID- 29624430 TI - Do Transfusions Cause Necrotizing Enterocolitis? Evidence and Potential Mechanisms. PMID- 29624431 TI - Editor-in-Chief's Welcoming Comments. PMID- 29624432 TI - ABM Clinical Protocol #8: Human Milk Storage Information for Home Use for Full Term Infants, Revised 2017. PMID- 29624433 TI - Pharmacological potential of methylxanthines: Retrospective analysis and future expectations. AB - Methylated xanthines (methylxanthines) are available from a significant number of different botanical species. They are ordinarily included in daily diet, in many extremely common beverages and foods. Caffeine, theophylline and theobromine are the main methylxanthines available from natural sources. The supposedly relatively low toxicity of methylxanthines, combined with the many beneficial effects that have been attributed to these compounds through time, generated a justified attention and a very prolific ground for dedicated scientific reports. Methylxanthines have been widely used as therapeutical tools, in an intriguing range of medicinal scopes. In fact, methylxanthines have been/were medically used as Central Nervous System stimulants, bronchodilators, coronary dilators, diuretics and anti-cancer adjuvant treatments. Other than these applications, methylxanthines have also been hinted to hold other beneficial health effects, namely regarding neurodegenerative diseases, cardioprotection, diabetes and fertility. However, it seems now consensual that toxicity concerns related to methylxanthine consumption and/or therapeutic use should not be dismissed. Taking all the knowledge and expectations on the potential of methylxanthines into account, we propose a systematic look at the past and future of methylxanthine pharmacologic applications, discussing all the promise and anticipating possible constraints. Anyways, methylxanthines will still substantiate considerable meaningful research and discussion for years to come. PMID- 29624434 TI - ABM Clinical Protocol #22: Guidelines for Management of Jaundice in the Breastfeeding Infant 35 Weeks or More of Gestation-Revised 2017. PMID- 29624435 TI - ABM Clinical Protocol #15: Analgesia and Anesthesia for the Breastfeeding Mother, Revised 2017. PMID- 29624436 TI - Amniotic Band Syndrome: A Multidisciplinary Care Approach to the Treatment of a Rare Case. AB - Amniotic band syndrome (ABS) is a rare developmental disorder associated with defects such as syndactyly, facial and/or palatal clefts, and dental anomalies like malformed or impacted teeth. In this report, a patient with ABS was successfully treated with orthodontic, endodontic, and periodontal therapies. Cone beam computed tomography revealed a unique eruptive path of the impacted central incisor through the incisive canal and cleft area. The tooth was occlusally and functionally stable after 1 year of treatment. Multidisciplinary care was critical to the success of this case. Available literature on ABS is also briefly reviewed. PMID- 29624437 TI - Burden of Care of Various Infant Orthopedic Protocols for Improvement of Nasolabial Esthetics in Patients With CUCLP. AB - OBJECTIVES: 1. To evaluate the orthodontic burden of care of nasoalveolar molding (NAM) and modified McNeil for the treatment of patients with complete unilateral cleft lip and palate (CUCLP). 2. To compare the esthetic outcomes of each with those of centers not utilizing infant orthopedics (IO). DESIGN: Retrospective cohort study. SETTING: Institutional. PARTICIPANTS: Four cohorts with repaired CUCLP (n = 149) from 3 centers. INTERVENTIONS: Two cohorts were treated in the same center and had either traditional infant orthopedics (TIO) or NAM and 2 were treated in centers not employing IO. MAIN OUTCOME MEASURES: Burden of care data for the IO groups were compared using t tests. Frontal and profile photographs at approximately age 5 were collected for ratings of nasolabial esthetics, using a modification of the Asher-McDade method. Intrarater and interrater reliabilities were determined using weighted kappa statistics. Median ratings were compared using a Kruskal-Wallis test. RESULTS: The burden of care of NAM was significantly greater than TIO for both the number of visits (9.9 vs 6.6, [ P < .001]); and treatment duration (127 vs 112 days, [ P < .05]). Significant differences in nasolabial esthetic ratings were noted among the 3 centers. No significant differences were observed in the nasolabial esthetic outcomes between the NAM and TIO groups. CONCLUSIONS: 1. NAM required more visits and longer overall duration compared with TIO. 2. The center employing IO showed favorable nasolabial esthetics compared to those not utilizing IO. 3. No significant differences were found in the nasolabial esthetics of patients who have received NAM compared with TIO. PMID- 29624438 TI - The Implications of Nasal Substitutions in the Early Phonology of Toddlers With Repaired Cleft Palate. AB - OBJECTIVE: To examine the implications of nasal substitutions in the early words of toddlers with cleft palate. DESIGN: Retrospective. PATIENTS: Thirty-four toddlers with nonsyndromic cleft palate and 20 noncleft toddlers, followed from ages 13 to 39 months. MAIN OUTCOME MEASURES: The groups were compared for the percentage of toddlers who produced nasal substitutions in their early words. The percentage of toddlers with repaired cleft palate who produced nasal substitutions and were later suspected of having velopharyngeal dysfunction (VPD) was also examined. RESULTS: Seventy-six percent of the toddlers in the cleft group (n = 26) and 35% of toddlers in the noncleft group (n = 7) produced nasal substitutions on one or more of their early words. Only 38% (10/26) of the toddlers with cleft palate who produced nasal substitutions in their early words were later diagnosed as having moderate-severe hypernasality and suspected VPD. CONCLUSIONS: The presence of nasal substitutions following palatal surgery was not always an early sign of VPD. These substitutions were present in the early lexicon of children with and without cleft palate. PMID- 29624439 TI - Predicting Individual Characteristics from Digital Traces on Social Media: A Meta Analysis. AB - The increasing utilization of social media provides a vast and new source of user generated ecological data (digital traces), which can be automatically collected for research purposes. The availability of these data sets, combined with the convergence between social and computer sciences, has led researchers to develop automated methods to extract digital traces from social media and use them to predict individual psychological characteristics and behaviors. In this article, we reviewed the literature on this topic and conducted a series of meta-analyses to determine the strength of associations between digital traces and specific individual characteristics; personality, psychological well-being, and intelligence. Potential moderator effects were analyzed with respect to type of social media platform, type of digital traces examined, and study quality. Our findings indicate that digital traces from social media can be studied to assess and predict theoretically distant psychosocial characteristics with remarkable accuracy. Analysis of moderators indicated that the collection of specific types of information (i.e., user demographics), and the inclusion of different types of digital traces, could help improve the accuracy of predictions. PMID- 29624440 TI - Altered Heart Rate Variability During Gaming in Internet Gaming Disorder. AB - Internet gaming disorder (IGD) is characterized by addiction to online gaming and reduced executive control, particularly when individuals are exposed to gaming related cues. Executive control can be measured as vagally mediated heart rate variability (HRV), which corresponds to variability in the time interval between heart beats. In this study, we investigated whether individuals with IGD have altered HRV while playing online games. We hypothesized that while gaming, individuals with IGD would exhibit phasic suppression of vagally mediated HRV, which would reflect executive control dysfunction during game play. To test this, we measured the changes of HRV when young males with IGD were engaged in real time online gaming. The changes of HRV were associated with the severity of IGD assessed by self-reports and prefrontal gray matter volume (GMV) calculated by voxel-based morphometry. We included 23 IGD subjects and 18 controls in our analyses. Changes in HRV were not statistically different between IGD subjects and controls. Within the IGD group, however, subjects showed significant decreases in high-frequency (HF) HRV during gaming. Furthermore, the degree of decrease correlated with IGD severity and prefrontal GMV. Importantly, this phasic suppression of HF-HRV in response to gaming did not occur in control subjects. In conclusion, young males with IGD showed an altered HRV response while playing an online game, reflecting their difficulties in executive control over gaming. The dynamics between executive control and reward seeking may be out of balance during game play in IGD. PMID- 29624441 TI - Motives and Concerns Associated with Geosocial Networking App Usage: An Exploratory Study Among Heterosexual College Students in the United States. AB - Geosocial network application (GSNA) use is common among young adults. However, there is little empirical research into patterns of use, motives, and potential concerns among app users. A total of 409 heterosexual students from a public university in the southeast United States participated in an online survey. Sample composition was primarily Caucasian and in their first 2 years of college. Average age was 19.7 years. Results revealed that 39 percent of participants had used a GSN app, and 60 percent of these were regular users. Tinder was the most popular GSNA. Top reasons for app use were for fun (31 percent) and to meet people (11 percent). Very few users reported using them for casual sex encounters (4 percent), although many users (72 percent of men and 22 percent of women) were open to meeting a sexual partner with a GSNA. Regular users were less likely to be in dating relationships. In-person meetings of matches were relatively infrequent among app users. Those who did meet matches were very likely to vet them online in advance, and women were more likely to do so than men. App users rated them as relatively unsafe, women in particular. Top concerns included safety (44 percent), others misrepresenting their identities (35 percent), and privacy (18 percent). Overall, regular app users perceived their use as normative among peers, but they did not view the apps as particularly useful for meeting matches. Although there are few surveys of GSNA use among emerging adults in the United States, some limitations are noted, along with suggestions for future research. PMID- 29624443 TI - Interpersonal Communication Motives for Flirting Face to Face and Through Texting. AB - The objective of this study was to investigate specific interpersonal communication motives that college students use to flirt through texting versus face to face (FtF). Four hundred college students (101 men, 299 women) were surveyed and reported using various communication motives to flirt using texting with a potential romantic partner. College students reported specific motives for flirting. Women reported flirting through text and FtF for pleasure motives significantly more than men, whereas men reported flirting for control and relaxation. In addition, men were more likely to flirt FtF for escape compared with women. Findings suggest that individuals are likely to flirt for pleasure if they are in a committed romantic relationship compared with those not in a committed relationship. PMID- 29624444 TI - The Effects of Social Environments on Time Spent Gaming: Focusing on the Effects of Communities and Neighborhoods. AB - This study examined the impact of community and neighborhood on time spent computer gaming. Computer gaming for over 20 hours a week was set as the cutoff line for "engaged use" of computer games. For the analysis, this study analyzed data for about 1,800 subjects who participated in the Korean Children and Youth Panel Survey. The main findings are as follows: first, structural community characteristics and neighborhood social capital affected the engaged use of computer games. Second, adolescents who reside in regions with a higher divorce rate or higher residential mobility were likely to exhibit engaged use of computer games. Third, adolescents who highly perceive neighborhood social capital exhibited lower possibility of engaged use of computer games. Based on these findings, practical implications and directions for further study are suggested. PMID- 29624445 TI - Event-Related Potential Measures of Smartphone Distraction. AB - The effect of smartphone use on cognitive function was quantified using measures of neural activity called event-related potentials (ERPs). Participants engaged in a primary task ( Exp. 1a : executive function; Exp. 1b : gambling) with no distraction and while using their smartphone to read online news articles. Smartphone use slowed behavioral responses and reduced the P300 ERP amplitudes by ~50 percent and provides evidence that smartphones have a large distracting effect. Experiment 2 compared executive function ERPs from smartphone-experienced users ( Exp. 1a ) with those collected on smartphone-naive subjects (collected in late 2006 and early 2007; Scisco et al.). This comparison provides preliminary evidence that smartphone use may be improving visual spatial attention. Collectively, the data highlight some costs and benefits of smartphone use. PMID- 29624448 TI - The Tenuous Relationship Between Instagram and Teen Self-Identity. PMID- 29624446 TI - Longitudinal Associations in Youth Involvement as Victimized, Bullying, or Witnessing Cyberbullying. AB - Although cyberbullying has been linked to cyber victimization, it is unknown whether witnessing cyberbullying impacts and is impacted by experiences of cyberbullying and victimization. In the current study, we examine the frequency of youth involved as victimized, bullying, and witnessing cyberbullying and how these experiences are associated across three academic years. Participants comprised 670 Canadian students who began the longitudinal study in grades 4, 7, or 10 at Time 1 (T1). Cyber witnessing represented the largest role of youth involvement in cyberbullying. Cyber witnessing was positively associated with both cyberbullying and victimization. Cyber victimization at T1 was positively associated with cyber witnessing at T2, which was positively related to both cyberbullying and victimization at T3. Findings highlight the significance of addressing the role of cyber witnesses in cyberbullying prevention and intervention efforts. PMID- 29624449 TI - Defining Impaired Respiratory Health. A Paradigm Shift for Pulmonary Medicine. PMID- 29624455 TI - Assessment of Antihyperlipidemic and Antitumor Effect of Isolated Active Phytoconstituents from Apium graveolens L. through Bioassay-Guided Procedures. AB - The seeds of A. graveolens yielded coumarin derivatives such as seselin, methoxsalen, and 3H-isobenzofuran-1-one through chromatographic separation techniques. The structure of the components has been established on the basis of spectral data analysis. The present study was undertaken to explore the antihyperlipidemic and antitumor effects of ethanolic extract and phytoconstituents of A. graveolens in rodents. Albino rats were administered intraperitoneal (i.p.) injection of Triton WR 1339 for the induction of hyperlipidemia at a dose of 400 mg/kg body weight. After 24 h of Triton administration, the test drugs were administered orally at dose of 50 mg/kg body weight in rats. The extract and isolated components were further investigated for the tumor take inhibitory activity in hybrid mice (of C57BL strain + Swiss albino strain). Preventive group animals were injected daily with the extract and isolated components at a dose of 50 mg/kg body weight i.p. for 10 consecutive days. The animals were observed for the growth of tumor after injection of B16F10 melanoma cells into the dorsal skin of mice. The study showed significant reduction in total cholesterol (p < .001), triglycerides (p < .001) and low density lipoprotein (LDL) level (bp < .01) and significantly increased high density lipoprotein (HDL) level (p < .01) after the treatment. Pretreatment showed delay in tumor growth by increasing the volume-doubling time (p < .01), growth delay (p < .01), and mean survival time (p < .001). Acute treatment caused stimulatory effect on HDL level and inhibition in total cholesterol (TC) and triglyceride (TG) elevation induced by Triton. Tumor regression studies showed a regression response for tumor growth in vivo of murine mouse melanoma tumor cell lines. PMID- 29624454 TI - A Growing Consensus for Change in Interpretation of Clinical Research Evidence. AB - CONTEXT: The paradigm of evidence-based practice (EBP) is well established among the health care professions, but perspectives on the best methods for acquiring, analyzing, appraising, and using research evidence are evolving. BACKGROUND: The EBP paradigm has shifted away from a hierarchy of research evidence quality to recognize that multiple research methods can yield evidence to guide clinicians and patients through a decision-making process. Whereas the "frequentist" approach to data interpretation through hypothesis testing has been the dominant analytical method used by and taught to athletic training students and scholars, this approach is not optimal for integrating evidence into routine clinical practice. Moreover, the dichotomy of rejecting, or failing to reject, a null hypothesis is inconsistent with the Bayesian-like clinical decision-making process that skilled health care providers intuitively use. We propose that data derived from multiple research methods can be best interpreted by reporting a credible lower limit that represents the smallest treatment effect at a specified level of certainty, which should be judged in relation to the smallest effect considered to be clinically meaningful. Such an approach can provide a quantifiable estimate of certainty that an individual patient needs follow-up attention to prevent an adverse outcome or that a meaningful level of therapeutic benefit will be derived from a given intervention. CONCLUSIONS: The practice of athletic training will be influenced by the evolution of the EBP paradigm. Contemporary practice will require clinicians to expand their critical-appraisal skills to effectively integrate the results derived from clinical research into the care of individual patients. Proper interpretation of a credible lower limit value for a magnitude ratio has the potential to increase the likelihood of favorable patient outcomes, thereby advancing the practice of evidence-based athletic training. PMID- 29624457 TI - Low Seroprevalence of Neutralizing Antibodies Targeting Two Clade F AAV in Humans. AB - To assess the therapeutic utility of AAVHSC15 and AAVHSC17, two recently described Clade F adeno-associated viruses (AAVs), the seroprevalence of neutralizing antibodies (NAbs) to these AAVs was assessed in a representative human population and compared to that of AAV9. NAb levels were measured in 100 unique human sera of different races (34, Black, 33 Caucasian, and 33 Hispanic) and sex (49% female, 51% male) collected within the United States. Fifty-six sera were tested in Huh7 cells and 44 sera were tested in 2V6.11 cells with vectors packaged with either a CMV-promoter upstream of LacZ or a CBA-promoter upstream of Firefly Luciferase, respectively. For AAVHSC15, AAVHSC17, and AAV9, 24/100 (24%), 21/100 (21%), and 17/100 (17%), respectively, of all sera tested were seropositive for NAbs using 50% inhibition of cellular transduction at a 1/16 dilution of serum as cutoff for seropositivity. Only 6% of positive sera had titers of 1/150 to 1/340, indicating that the majority of positive sera were of low titer. Significant cross-reactivity of NAbs across all three AAV serotypes was observed. These data show that approximately 80% of humans evaluated were seronegative for pre-existing NAbs to the AAV serotypes tested, suggesting that the vast majority of human subjects would be amenable to therapeutic intervention with Clade F AAVs. PMID- 29624456 TI - Enhanced stability of vitamin A palmitate microencapsulated by gamma-cyclodextrin metal-organic frameworks. AB - gamma-Cyclodextrin metal-organic frameworks (gamma-CD-MOFs) are highly porous and bio-friendly novel materials formed by gamma-CD as an organic ligand and potassium ion as an inorganic metal centre. The aim of this study was to enhance the stability of vitamin A palmitate (VAP) using gamma-CD-MOFs as the carrier. Herein, gamma-CD-MOFs displayed VAP microencapsulating capacity of 9.77 +/- 0.24% with molar ratio as nMOFs:nVAP = 3.2:1.0. It was important to find that the improved stability of VAP microencapsulated by gamma-CD-MOFs without addition of any antioxidant(s) was better than that of the best available reference product in the market, with 1.6-fold elongated half-life. The protecting mechanism of gamma-CD-MOFs for VAP contributed that VAP molecules preferentially curled inside the cavities of dual gamma-CD pairs in gamma-CD-MOFs. It was proved that gamma-CD MOFs were an efficient new carrier to deliver and protect VAP for food and pharmaceutical applications. PMID- 29624458 TI - Burden of asthma among patients adherent to ICS/LABA: A real-world study. AB - OBJECTIVES: Asthma is a chronic respiratory condition with a U.S. prevalence of 7.4%. Despite numerous treatment options, asthma remains poorly controlled in some patients. Uncontrolled asthma is associated with high healthcare resource utilization (HCRU) and reduced productivity. This study assessed symptoms, productivity, and HCRU of patients adherent to medium/high-dosage inhaled corticosteroid/long-acting beta2-agonist (ICS/LABA) treatment, and the relationship of asthma control with these parameters. METHODS: Data were collected in the U.S. in 2013-2016 in the Adelphi Respiratory Disease Specific Programme, a cross-sectional survey. Participating physicians (n = 258) each completed a record form for eligible patients, who were receiving medium/high dosage ICS/LABA treatment with self-reported moderate/high adherence, completed the Asthma Control Test (ACT) and the Work Productivity and Activity Impairment (WPAI) questionnaire, and were included in the analyses. RESULTS: Patients (n = 428) had a mean of 59% symptom-free days in the past month. Wheezing was the most troublesome symptom for 25% of patients. In the previous 12 months, the mean number of exacerbations was 1.3; 15% of exacerbations required emergency room treatment and/or hospitalization. Mean physician visits for asthma was 5.7. Asthma impacted leisure/personal time frequently/constantly for 11% of patients, with 20% overall work impairment. Asthma was poorly controlled (ACT score <=15) in 18% of patients; poorer asthma control was associated with higher rates of exacerbations, work impairment, and HCRU. CONCLUSION: Given the substantial burden described, greater attention to asthma monitoring and management is necessary. Identification of novel treatments may be important for patients not responding to medium/high-dosage ICS/LABA treatment. PMID- 29624450 TI - National Athletic Trainers' Association Position Statement: Evaluation, Management, and Outcomes of and Return-to- Play Criteria for Overhead Athletes With Superior Labral Anterior-Posterior Injuries. AB - OBJECTIVE: To present recommendations for the diagnosis, management, outcomes, and return to play of athletes with superior labral anterior-posterior (SLAP) injuries. BACKGROUND: In overhead athletes, SLAP tears are common as either acute or chronic injuries. The clinical guidelines presented here were developed based on a systematic review of the current evidence and the consensus of the writing panel. Clinicians can use these guidelines to inform decision making regarding the diagnosis, acute and long-term conservative and surgical treatment, and expected outcomes of and return-to-play guidelines for athletes with SLAP injuries. RECOMMENDATIONS: Physical examination tests may aid diagnosis; 6 tests are recommended for confirming and 1 test is recommended for ruling out a SLAP lesion. Combinations of tests may be helpful to diagnose SLAP lesions. Clinical trials directly comparing outcomes between surgical and nonoperative management are absent; however, in cohort trials, the reports of function and return-to-sport outcomes are similar for each management approach. Nonoperative management that includes rehabilitation, nonsteroidal anti-inflammatory drugs, and corticosteroid injections is recommended as the first line of treatment. Rehabilitation should address deficits in shoulder internal rotation, total arc of motion, and horizontal-adduction motion, as well as periscapular and glenohumeral muscle strength, endurance, and neuromuscular control. Most researchers have examined the outcomes of surgical management and found high levels of satisfaction and return of shoulder function, but the ability to return to sport varied widely, with 20% to 94% of patients returning to their sport after surgical or nonoperative management. On average, 55% of athletes returned to full participation in prior sports, but overhead athletes had a lower average return of 45%. Additional work is needed to define the criteria for diagnosing and guiding clinical decision making to optimize outcomes and return to play. PMID- 29624459 TI - "Introducing Modified Dakkak and Bennett Grading System for Indian Food in Oral Submucous Fibrosis": A Dharwad Study. AB - Oral submucous fibrosis (OSMF) is one of the "diseases of civilization" because of the large differences in prevalence among races, geographic areas, and individuals at different socioeconomic levels. It is a premalignant condition strongly associated with the habit of chewing areca nuts. This study is to compare the scoring system in relation to the burning sensation of mouth and dysphagia using the visual analog scale (VAS) and Dakkak and Bennett grading system for Indian food, respectively, in OSMF patients. This study was a randomized clinical trial incorporating a total of 50 cases of OSMF divided into a control group (antioxidant therapy) and pentoxifylline test cases. Values for burning sensation of the mouth using the VAS and modified Dakkak and Bennett grading system for Indian food were recorded. Statistical analyses were done using t test, Mann -Whitney U test, and one-way analysis of variance (ANOVA) test. Patients subjected to pentoxifylline when compared to the control group showed significant reduction in dysphagia for Indian food. Burning sensation was recorded according to the visual analogue scale. Significant reduction in burning sensation was seen in the pentoxifylline group when compared to the control group. This grading system provides quantitative and qualitative parameters in patients with OSMF. PMID- 29624461 TI - National Standards and State Variation in Physician Orders for Life-Sustaining Treatment Forms. AB - BACKGROUND: The Physician Orders for Life-Sustaining Treatment (POLST) Paradigm is used across the country to document the treatment preferences of seriously ill or frail patients as medical orders. The National POLST Paradigm Task Force maintains consensus-based standards for POLST programs and uses these to determine whether a state POLST program is developing, endorsed, or mature. OBJECTIVES: To evaluate state program form adherence to national standards. DESIGN: Document review. MEASUREMENTS: Forms from endorsed/mature (n = 21) and developing (n = 23) states were compared with national standards to assess adherence to required and optional form elements. RESULTS: Required elements were present on 84% of endorsed/mature state POLST forms and 73% of the developing state POLST forms. Compliance with required elements in endorsed states ranged from 50% to 100%. Three endorsed/mature states (14%) had forms that met all of the required elements fully and 14 (67%) had forms that met the all of the elements fully or partially. CONCLUSIONS: There is variability in adherence to required and optional standards as well as challenges in interpreting and applying existing standards. Although there may be legal and logistical barriers to the existence of a national POLST form, standardization remains an important goal to support patient-centered care. PMID- 29624460 TI - Novel Quinoxaline-2-Carbonitrile-1,4-Dioxide Derivatives Suppress HIF1alpha Activity and Circumvent MDR in Cancer Cells. AB - A series of 3-aryl/hetarylquinoxaline-2-carbonitrile-1,4-dioxides was synthesized and evaluated against breast cancer cell lines in normoxia and hypoxia. Selected compounds in this series demonstrated better cytotoxicity and comparable hypoxia selectivity than tirapazamine. In contrast to Dox, quinoxaline-1,4-dioxides showed potent cytotoxicity against different MDR cells. Compound 2g inhibits of cancer cell growth through p53-independent mechanisms. Our results showed that compound 2g sensitized MCF-7 cells to metformin in hypoxia. Treatment with 2g results in the increase of ROS accumulation in cancer cells. Compound 2g can be considered as the lead compound for further anticancer drug design, evaluation, and development of new potent antitumor agents. PMID- 29624462 TI - Minimal Residual Disease Testing After Induction Chemotherapy for Acute Myeloid Leukemia: Moving Beyond Prognostication? PMID- 29624464 TI - Curing More Prostate Cancer: Thinking Through the Options. PMID- 29624465 TI - Practical Implications of Factor IX Gene Transfer for Individuals with Hemophilia B: A Clinical Perspective. AB - Gene therapy for severe hemophilia is on the cusp of entering clinical practice. However, there is limited clinical experience in this area given that gene transfer is a relatively recent technology. Therefore, this clinical perspective article will review the evidence supporting gene therapy in this field, examine ways to open a dialogue about gene therapy with patients in the clinic setting, and present a case of a participant in a recent clinical trial of gene therapy for hemophilia. Clinical trials in hemophilia using adeno-associated virus (AAV) vectors to transfer functional factor IX (FIX) have reported increases in FIX activity to functional levels, reduced bleed frequency, and a lessening or abrogation of the need for costly FIX replacement. The safety profile of AAV mediated gene therapy also appears positive, with manageable, asymptomatic increases in liver enzymes being the most commonly described adverse event. Examining a clinical case in hemophilia B more closely, gene transfer decreased annualized bleeds from six (unknown or spontaneous) bleeds before treatment to three (spontaneous) bleeds after treatment alongside a 55% reduction in FIX replacement. The participant experienced an increase in traumatic bleeds after treatment, which appears to reflect increased physical activity and early prophylaxis discontinuation. After the gene transfer, the participant considered his hemophilia to be "cured," which emphasizes the need to manage patient expectations, particularly regarding activity levels and bleed risk in the immediate post-treatment period. Gene therapy for hemophilia has the potential to transform the lives of affected individuals and is likely to create a new class of hemophilia patient who has shifted from a severe to a mild phenotype. Despite having a mild phenotype, these individuals may retain a legacy of increased bleed risk and joint damage from their years with severe hemophilia and will need different clinical management compared to a more typical individual with mild hemophilia. PMID- 29624466 TI - Degradation of polyethylene microplastics in seawater: Insights into the environmental degradation of polymers. AB - Microplastic contamination of aquatic environments has become an increasingly alarming problem. These, defined as particles <5 mm, are mostly formed due to the cracking and embrittlement of larger plastic particles. Recent reports show that the increasing presence of microplastics in the environment could have significant deleterious consequences over the health of marine organisms, but also across the food chain. Herein, we have studied the effects of artificial seawater on polyethylene (PE)-based beads by exposing them up to eight weeks to saltwater in stirred batch reactors in the dark and examined the structural and morphological changes these endured. Electron microscopy observations showed that artificial seawater induces severe microcracking of the pellets' surfaces. Additionally, Fourier transform infrared spectroscopy (FTIR) analyses evidenced the formation of oxidized groups whenever these particles were exposed to water and an increase in organic matter content of the waters in which the pellets were kept was evidenced by Raman spectroscopy. There were also noticeable consequences in the thermal stability of the polyethylene pellets, as determined by thermogravimetric studies (TGA). Furthermore, the parallel exposure of polyethylene pellets to UV radiation yielded less pronounced effects, thus underscoring its lower preponderance in the degradation of this material. These results highlight the importance of determining the mechanisms of degradation of microplastics in marine settings and what the implications may be for the environment. Overall, the herein presented results show that a relatively short period of time of accelerated exposure can yield quantifiable chemical and physical impacts on the structural and morphological characteristics of PE pellets. PMID- 29624467 TI - Potential immediate hypersensitivity reactions following immunization in preschool aged children in Victoria, Australia. AB - Immediate hypersensitivity reactions (IHR) are rare but potentially serious adverse events following immunization (AEFI). Surveillance of Adverse Events following Vaccination in the Community (SAEFVIC) is an enhanced passive surveillance system that collects, analyses and reports information about AEFI in Victoria, Australia. We describe the incidence, timing and type of potential IHR following vaccination in preschool children reported over an 8-year period. A total of 2110 AEFI were reported in 1620 children, of which 23.5% (496) were classified as potential IHR. Of these, 37.1% (184) were suspected to be IgE mediated, (including anaphylaxis, angioedema and/or urticaria) and 83.5% (414) occurred within 15 minutes of vaccination. The incidence of potential IHR was 5.4 per 100,000 doses, with that of suspected IgE-mediated IHR being 2.0 per 100,000 doses. The incidence of anaphylaxis was extremely low (0.13 per 100,000 doses) and is consistent with other published studies. Potential IHR following immunization should be reported to appropriate local pharmacovigilance systems and patients reviewed by specialists able to evaluate, investigate and manage future vaccinations. PMID- 29624463 TI - Phase III Intergroup Trial of Adjuvant Androgen Deprivation With or Without Mitoxantrone Plus Prednisone in Patients With High-Risk Prostate Cancer After Radical Prostatectomy: SWOG S9921. AB - Purpose Patients with high-risk prostate cancer after radical prostatectomy are at risk for death. Adjuvant androgen-deprivation therapy (ADT) may reduce this risk. We hypothesized that the addition of mitoxantrone and prednisone (MP) to adjuvant ADT could reduce mortality compared with adjuvant ADT alone. Methods Eligible patients had cT1-3N0 prostate cancer with one or more high-risk factors after radical prostatectomy (Gleason score [GS] >= 8; pT3b, pT4, or pN+ disease; GS 7 and positive margins; or preoperative prostate-specific antigen [PSA] > 15 ng/mL, biopsy GS score > 7, or PSA > 10 ng/mL plus biopsy GS > 6. Patients with PSA <= 0.2 ng/mL after radical prostatectomy were stratified by pT/N stage, GS, and adjuvant radiation plan and randomly assigned to ADT (bicalutamide and goserelin for 2 years) or ADT plus six cycles of MP. The primary end point was overall survival (OS). Median OS was projected to be 10 years in the ADT arm, requiring 680 patients per arm to detect a hazard ratio of 1.30 with 92% power and one-sided alpha = .05. Results Nine hundred sixty-one eligible intent-to treat patients were randomly assigned to ADT or ADT + MP from October 1999 to January 2007, when the Data Safety Monitoring Committee recommended stopping accrual as a result of higher leukemia incidence with ADT + MP. Median follow-up was 11.2 years. The 10-year OS estimates were 87% with ADT (expected 50%) and 86% with ADT + MP (hazard ratio, 1.06; 95% CI, 0.79 to 1.43). The 10-year estimate for disease-free survival was 72% for both arms. Prostate cancer was the cause of death in 18% of patients in the ADT arm and 22% in the ADT + MP arm. More patients in the MP arm died of other cancers (36% v 18% in ADT alone arm). Conclusion MP did not improve OS and increased deaths from other malignancies. The DFS and 10-year OS in these patients treated with 2 years of ADT were encouraging compared with historical estimates, although a definitive conclusion regarding value of ADT may not be made without a nontreatment control arm. PMID- 29624468 TI - Effects of glyphosate on the non-target leaf beetle Cerotoma arcuata (Coleoptera: Chrysomelidae) in field and laboratory conditions. AB - This study aimed to assess the glyphosate application effects on the Cerotoma arcuata Oliver (Coleoptera: Chrysomelidae) population in glyphosate-resistant soybean crops. Field studies were conducted with glyphosate and the insecticide endosulfan to observe the effects of these pesticides on C. arcuata, on its damages in the crop and on the populations of natural enemies in glyphosate resistant soybean crops. Moreover, the lethal and behavioral sublethal response of C. arcuata to glyphosate and endosulfan was conducted in the laboratory. The results of the field and laboratory experiments showed that glyphosate caused moderate toxicity and high irritability in C. arcuata and that endosulfan caused high toxicity and irritability. Therefore, the direct effect of glyphosate on C. arcuata was negative and does not explain the population increases of this pest in glyphosate-resistant soybean. However, the glyphosate also decreased the density of predators. Thus, the negative effect of glyphosate on the predators may be related to population increases of C. arcuata in glyphosate-resistant soybean crops, however, more studies are needed to better evidence this relationship. This study suggests that glyphosate can impact other non-target organisms, such as herbivorous insects and natural enemies and that the use of this herbicide will need to be carefully stewarded to prevent potential disturbances in beneficial insect communities in agricultural systems. PMID- 29624469 TI - Laparoscopic Enteropexy for Prolapsing Stoma: A Case Series Describing a Novel Technique. AB - BACKGROUND: Ileostomy prolapse has a cumulative risk of 11% and represents a significant complication with associated morbidity, which may result in multiple admissions and procedures requiring a general anesthetic. We have developed a laparoscopic technique for managing stoma prolapse-so-called laparoscopic enteropexy for prolapsing stoma (LEPS). METHODS: Retrospective analysis of a prospectively maintained departmental surgical logbook was performed alongside clinical case history review for patients undergoing LEPS. Primary outcome was defined as recurrent prolapse. Secondary outcomes were any postoperative complication or complication occurring at the time of stoma closure. RESULTS: A total of 15 LEPS procedures were performed on 14 patients with stoma prolapse-13 were patients with ileostomy and 1 with a loop colostomy. Median operative time was 75 minutes (range 50-95). Median postoperative stay was 1 day (1-4 days). There was one return to theater for a small bowel intussusception on the second postoperative day wherein taking down of the bowel and repeat LEPS were necessary. There was one recurrence of prolapse in a separate patient (1/14 [7%]). Three patients have since had their stoma closed without complication. CONCLUSION: We describe here the initial case series of our LEPS procedure for managing stoma prolapse. This is a reproducible and technically straightforward laparoscopic procedure with an excellent success rate in preventing further prolapse. PMID- 29624471 TI - An integrated approach for assessing the migration behavior of chlorpyrifos and carbaryl in the unsaturated soil zone. AB - Chlorpyrifos (O, O-diethyl O-3,5,6-trichloropyridin-2-yl phosphorothioate) and carbaryl (1-naphthyl methylcarbamate) are often applied concurrently as insecticides in food production. The aim of this study was to research their migration behavior in a real environment. We researched the leaching of both pesticides by setting up field lysimeters on a farm with the typical soil used in fruit production today. In order to analyze the variables involved in this process, we performed complementary adsorption studies, we performed complementary adsorption studies using batches and undisturbed soil laboratory columns for both compounds. The results for pesticide transport through the lysimeters showed that less than 1% of chlorpyrifos was recovered in the leachates, while almost 17% was recovered for carbaryl. Having completed the experiment in undisturbed laboratory columns, soil analysis showed that chlorpyrifos mainly remained in the first 5 cm, while carbaryl moved down to the lower sections. These results can be explained in view of the sorption coefficient values (KD) obtained in horizons A and B for chlorpyrifos (393 and 184 L kg-1) and carbaryl (3.1 and 4.2 L kg-1), respectively. By integrating the results obtained in the different approaches, we were able to characterize the percolation modes of these pesticides in the soil matrix, thus contributing to the sustainable use of resources. PMID- 29624472 TI - Efficacy and safety of baroreflex activation therapy for treatment of resistant hypertension: a systematic review and meta-analysis. AB - To provide definite evidence for the anti-hypertensive benefit of Baroreflex Activation Therapy (BAT) for resistant hypertension, we performed a systematic review and meta-analysis to evaluate the efficacy and safety of BAT. Electronic searches were conducted in PubMed, EMBASE, The Cochrane Library and Web of Science. Two reviewers independently determined the eligibility of studies and extracted the data. The quality of all included studies was evaluated by the use of the Newcastle Ottawa Scale (NOS). Disagreements were settled through discussion. Twelve studies, included one randomized clinical trials (RCTs) and eleven prospective studies were eligible for qualitative analysis and five prospective studies were selected for meta-analysis. The data of analysis showed office systolic blood pressure (SBP)(WMD = -24.01, 95% CI = -28.65 to -19.36, P= 0.753I2 = 0.0%) and diastolic blood pressure (DBP)(WMD = -12.53, 95% CI = -15.82 to -9.24,P = 0.893,I2 = 0.893) decreased by BAT treatment.The effect on SBP was both significant in the Barostim neo TM device (WMD = -22.49, 95% CI = -29.13 to 15.84, P= 0.443; I2 = 0.0%) and Rheos System (WMD = 25.46, 95% CI = -31.96 to 18.96, P= 0.703; I2 = 0.0%). Our study found office BP were significantly decreased by BAT treatment, but available evidence is limited by risk of bias, small sample size, and few RCTs. Thus, there is presently insufficient evidence to fully evaluate the efficacy and safety of BAT for Patients with Resistant Hypertension. Additional high-quality RCT research with long-term follow-up is required. PMID- 29624473 TI - Preferential allelic deletion of RBSP3, LIMD1 and CDC25A in head and neck squamous cell carcinoma: Implication in cancer screening and early detection. AB - Head and neck squamous cell carcinoma is one of the leading cancers in terms of incidence and mortality. However, no reliable marker till date accurately predicts its progression when altered in healthy tissues. The study aims to identify alleles of microsatellites adjacent to important cell cycle regulatory, tumor suppressor genes altered in early head and neck lesions, viz. RBSP3, LIMD1 and CDC25A, which undergo frequent deletion and can be used for population screening and early detection. DNA for tumors and normal tissues was isolated from 143 patients in different stages of head and neck squamous cell carcinoma. The size of microsatellite present in normal tissues and their deletion in the corresponding tumor was identified, along with the correlation of expression in normal epithelium with respect to allele size. The results revealed a range of alleles (CA9 to CA32) for the different microsatellites of the genes in normal tissues. The larger alleles were significantly deleted with differential deletion of alleles observed in tumors, except for LIMD1, in which the smaller allele was significantly deleted. In normal tissues, some alleles represented as stable alleles with high prevalence, while in tumours, specific sizes showed greater propensity for deletion. However, similar expression of the proteins in normal epithelium adjacent to tumors was observed despite variations in allele size, possibly due to the location of the microsatellites. Thus, those alleles when present in normal tissues and undergoing persistent deletion in tumours could be used as markers for screening and early identification of populations at risk of developing head and neck lesions. PMID- 29624470 TI - Noninvasive vaccination against infectious diseases. AB - The development of a successful vaccine, which should elicit a combination of humoral and cellular responses to control or prevent infections, is the first step in protecting against infectious diseases. A vaccine may protect against bacterial, fungal, parasitic, or viral infections in animal models, but to be effective in humans there are some issues that should be considered, such as the adjuvant, the route of vaccination, and the antigen-carrier system. While almost all licensed vaccines are injected such that inoculation is by far the most commonly used method, injection has several potential disadvantages, including pain, cross contamination, needlestick injury, under- or overdosing, and increased cost. It is also problematic for patients from rural areas of developing countries, who must travel to a hospital for vaccine administration. Noninvasive immunizations, including oral, intranasal, and transcutaneous administration of vaccines, can reduce or eliminate pain, reduce the cost of vaccinations, and increase their safety. Several preclinical and clinical studies as well as experience with licensed vaccines have demonstrated that noninvasive vaccine immunization activates cellular and humoral immunity, which protect against pathogen infections. Here we review the development of noninvasive immunization with vaccines based on live attenuated virus, recombinant adenovirus, inactivated virus, viral subunits, virus-like particles, DNA, RNA, and antigen expression in rice in preclinical and clinical studies. We predict that noninvasive vaccine administration will be more widely applied in the clinic in the near future. PMID- 29624474 TI - Cationic pullulan nanogel as a safe and effective nasal vaccine delivery system for respiratory infectious diseases. AB - The mucosal surfaces of the respiratory and gastrointestinal tracts are continuously exposed to countless beneficial and pathologic antigens. These mucosal surfaces are thus equipped with an immune system that is unique from those elsewhere in the body; this unique system provides the first line of immune surveillance and defense against pathogen invasion. The sophisticated immune induction machinery in the aero-digestive tract involves mucosa-associated lymphoid tissues, including nasopharyngeal- and gut-associated lymphoid tissues, for the generation of antigen-specific humoral and cellular immune responses. Consequently, nasal or oral immunization with an appropriate vaccine delivery vehicle prompts the induction of protective immunity in both the mucosal and systemic compartments, leading to a double layer of protection against pathogens. To harness the benefits of mucosal vaccines, various mucosal antigen delivery vehicles are under development, and a cationic cholesteryl-group-bearing pullulan nanogel (cCHP nanogel) has emerged as a potent nasal vaccine delivery system for the induction of protective immunity against respiratory infections. PMID- 29624475 TI - Access to Strong Opioid Analgesics in the Context of Legal and Regulatory Barriers in Eleven Central and Eastern European Countries. AB - BACKGROUND: In 2011-2013, >95% of the global opioid analgesics consumption occurred in three regions, accounting for 15% of the world population. Despite abundant literature on barriers to access, little is known on the correlation between actual access to opioid analgesics and barriers to access, including legal and regulatory barriers. OBJECTIVE: This study aimed to evaluate the correlation between access to strong opioid analgesics and barriers to access in national legislation and regulations in 11 central and eastern European countries that participated in the Access to Opioid Medication in Europe (ATOME) project. DESIGN: Two variables were contrasted to assess their correlation: the country level of access to strong opioid analgesics indicated by the Adequacy of Consumption Measure (ACM) and the number of potential legal and regulatory barriers identified by an external review of legislation and regulations. MEASUREMENTS: A linear correlation was evaluated using a squared linear correlation coefficient. RESULTS: Evaluation of the correlation between the ACM and the number of potential barriers produces an R2 value of 0.023 and a correlation plot trend line gradient of -0.075, indicating no correlation between access to strong opioid analgesics and the number of potential barriers in national legislation and regulations in the countries studied. CONCLUSIONS: No correlation was found, which indicates that other factors besides potential legal and regulatory barriers play a critical role in withholding prescribers and patients essential pain medication in the studied countries. More research is needed toward better understanding of the complex interplay of factors that determine access to strong opioid analgesics. PMID- 29624476 TI - Immunotherapy in inflammatory bowel disease: Novel and emerging treatments. AB - Inflammatory bowel disease (IBD) is a chronic disabling inflammatory process that affects young individuals, with growing incidence. The etiopathogenesis of IBD remains poorly understood. A combination of genetic and environmental factors triggers an inadequate immune response against the commensal intestinal flora in IBD patients. Thus, a better understanding of the immunological mechanisms involved in IBD pathogenesis is central to the development of new therapeutic options. Current pharmacological treatments used in clinical practice like thiopurines or anti-TNF are effective but can produce significant side effects and their efficacy may diminish over time. In fact, up to one third of the patients do not have a satisfactory response to these therapies. Consequently, the search for new therapeutic strategies targeting alternative immunological pathways has intensified. Several new oral and parenteral substances are in the pipeline for IBD. In this review we discuss novel therapies targeting alternative pro-inflammatory pathways like IL-12/23 axis, IL-6 pathway or Janus Kinase inhibitors; as well as others modulating anti-inflammatory signalling pathways like transforming growth factor-beta1 (TGF-beta1). We also highlight new emerging therapies targeting the adhesion and migration of leukocytes into the inflamed intestinal mucosa by blocking selectively different subunits of alpha4beta7 integrins or binding alternative adhesion molecules like MAdCAM-1. Drugs reducing the circulating lymphocytes by sequestering them in secondary lymphoid organs (sphingosine-1-phosphate (S1P) receptor modulators) are also discussed. Finally, the latest advances in cell therapies using mesenchymal stem cells or engineered T regs are reviewed. In addition, we provide an update on the current status in clinical trials of these new immune-regulating therapies that open a new era in the treatment of IBD. PMID- 29624477 TI - The immunization status of children with chronic neurological disease and serological assessment of vaccine-preventable diseases. AB - The aim of this study was to evaluate the age-appropriate immunization coverage in 366 children with chronic neurological disease (CND), to evaluate the use of vaccines not included in routine program, to evaluate serological tests for vaccine-preventable diseases and to describe the related factors in unvaccinated children. 95.6% of all children with had received age-appropriate vaccinations according to the actual National Immunization Program (NIP) during childhood. 12 children (3.6%) had not received vaccines; only two had true contraindications. Because most of the vaccines have been implemented through the NIP for 10 years in Turkey, 88% of children required these new vaccines or booster doses. Moreover, 86.6% of the children and 92.6% of household contacts had no prior history of influenza vaccine. Furthermore, 88% of the patients had not received the varicella vaccine, and the anti-varicella IgG levels were only negative in 27.9%. In addition, 18.6% of the children were negative for anti-mumps IgG, 23.7% for anti-measles IgG, and 6.3% for anti-rubella IgG. Anti-HBs IgG level was 0-10 IU/L in 45.6% of the patients (most of them previously vaccinated) and 79.8% were negative for hepatitis A IgG antibodies. For pertussis infection, the antibody titers of 54.1% of patients were below the protective level, and 10% of patients had a prior acute pertussis infection. Therefore, it is suggested that children with CND should be evaluated for their vaccination status during their first and follow-up visits at certain intervals, and their primary immunization should be completed; moreover, many will need revaccination or booster doses. PMID- 29624478 TI - Assessment and ecological indicators of total and polycyclic aromatic hydrocarbons in the aquatic environment of lake Manzala, Egypt. AB - The study objective was to assess the profile of aliphatic and polycyclic aromatic hydrocarbons in the aquatic environment of Lake Manzala and to determine the potential sources and effects of these hydrocarbons. To reach these objectives 24 surface sediment and 24 tilapia fish were collected and analyzed using GC-FID and GC-MS. The highest concentrations for n-alkanes (?n-C15-35) (19,625 ng g-1) and PAHs (?45PAHs) (5,153 ng g-1) were found in sediments collected from Bahr Al-Baqar drain while Al-Temsah and Al-Hamra sites contained the lowest concentrations. Different diagnostic molecular ratios for hydrocarbons were used to evaluate sources of the hydrocarbons. The hydrocarbons were found to have differing proportions of petrogenic, pyrogenic, and biogenic sources. Comparison to sediment quality guidelines indicated PAHs were below the effect range low (ERL) with the exception of acenaphthene, fluorine, and ?45PAHs in Bahr Al-Baqar drain sediments. Tissue samples had moderate PAH concentrations for ?45PAHs ranging from 302.5 ng g-1 West of Bashteer (S3) to 596 ng g-1 in Legam (S5). Since fish metabolize PAH quickly, their detection suggest continual or very recent exposure. The PAH in sediment and fish from Lake Manzala are at a low or below level of environmental concern. PMID- 29624479 TI - In Vivo and In Vitro Anti-Bacterial Efficacy of Absorbable Barbed Polydioxanone Monofilament Tissue Control Device with Triclosan. AB - BACKGROUND: This study evaluated the in vitro and in vivo anti-bacterial efficacy of STRATAFIXTM Symmetric PDSTM Plus Knotless Tissue Control Devices in comparison with standard absorbable polydioxanone devices lacking triclosan, utilizing challenges by gram-positive and gram-negative bacteria. METHODS: The STRATAFIXTM Symmetric PDSTM Plus Knotless Tissue Control Device was tested for in vitro efficacy against Staphylococcus aureus, methicillin-resistant S. aureus (MRSA), S. epidermidis, methicillin-resistant S. epidermidis (MRSE), Klebsiella pneumoniae, and Escherichia coli using a zone of inhibition (ZOI) assay. The ZOI was used to determine: immediate anti-bacterial efficacy at 24 hours, sustained efficacy for as long as 23 days, and stability for as long as 36 months. Bacterial colonization of the device in vitro was evaluated by scanning electron microscopy and enumerating viable adherent bacteria, expressed as colony-forming units (CFU) per centimeter on the device. In vivo evaluations were conducted in guinea pigs and mice where 3 to 4 cm of the test device and the control suture (commercial QuillTM PDO without triclosan) were implanted subcutaneously through separate catheters into opposite sides of the dorsolateral region. Each implantation site was challenged directly through the indwelling catheter with 106 CFU of S. aureus (guinea pigs) or 107 CFU of E. coli (mice). At 48 hours post implantation, the test device and control suture were explanted for bacterial enumeration. RESULTS: The STRATAFIXTM Symmetric PDSTM Plus Knotless Tissue Control Device demonstrated in vitro anti-bacterial activity against all test organisms. This activity was maintained for 11 and 23 days when tested against E. coli and S. aureus, respectively. The device was not colonized by test bacteria in vitro. The anti-bacterial activity remained stable for as long as 36 months of storage at 30 degrees C and 75% relative humidity. In vivo evaluation in animal models demonstrated a 1.16-log reduction in S. aureus and a 1.83-log reduction in E. coli relative to the control device. (p < 0.05) Conclusion: The STRATAFIXTM Symmetric PDSTM Plus Knotless Tissue Control Device exhibited anti-bacterial efficacy in vitro against a wide range of clinically significant bacterial species with long-lasting inhibition of colonization by S. aureus, and E. coli. It inhibited colonization by S. aureus and E. coli in vitro and in vivo. Thus, the STRATAFIXTM Symmetric PDSTM Plus Knotless Tissue Control Device represents a powerful technology to help mitigate one of the risk factors for surgical site infections. PMID- 29624480 TI - Comparison and analysis of several wet scrubbing solutions to remove methyl mercaptan. AB - Wet scrubbing is regarded as an effective method to remove hydrophobic organic odorants. The focus of wet scrubbing is to choose an appropriate scrubbing liquid. In this study, methyl mercaptan (CH3SH) was selected as a representative hydrophobic organic odorant for treatment by wet scrubbing using several types of scrubbing solution: ethanol (C2H5OH), lead acetate ((CH3COO)2Pb), sodium hypochlorite (NaClO), and sodium hydroxide (NaOH). A comparative analysis of the treatment efficiency, operation cost, and environmental impact was conducted. Results of the technical and economic comparison indicate that the C2H5OH solution is the best choice of scrubbing solution among those tested. These findings serve as a reference for engineering design and operation for the removal of hydrophobic organic odorants. PMID- 29624481 TI - Craniofacial Manifestations of Systemic Disorders: CT and MR Imaging Findings and Imaging Approach. AB - Many systemic diseases or conditions can affect the maxillofacial bones; however, they are often overlooked or incidentally found at routine brain or head and neck imaging performed for other reasons. Early identification of some conditions may significantly affect patient care and alter outcomes. Early recognition of nonneoplastic hematologic disorders, such as thalassemia and sickle cell disease, may help initiate earlier treatment and prevent serious complications. The management of neoplastic diseases such as lymphoma, leukemia, or Langerhans cell histiocytosis may be different if diagnosed early, and metastases to the maxillofacial bones may be the first manifestation of an otherwise occult neoplasm. Endocrinologic and metabolic disorders also may manifest with maxillofacial conditions. Earlier recognition of osteoporosis may alter treatment and prevent complications such as insufficiency fractures, and identification of acromegaly may lead to surgical treatment if there is an underlying growth hormone-producing adenoma. Bone dysplasias sometimes are associated with skull base foraminal narrowing and subsequent involvement of the cranial nerves. Inflammatory processes such as rheumatoid arthritis and sarcoidosis may affect the maxillofacial bones, skull base, and temporomandibular joints. Radiologists should be familiar with the maxillofacial computed tomographic and magnetic resonance imaging findings of common systemic disorders because these may be the first manifestations of an otherwise unrevealed systemic process with potential for serious complications. Online supplemental material is available for this article. (c)RSNA, 2018. PMID- 29624482 TI - Automated Three-dimensional Breast US for Screening: Technique, Artifacts, and Lesion Characterization. AB - Automated breast (AB) ultrasonography (US) scanners have recently been brought to market for breast imaging. AB US devices use mechanically driven wide linear array transducers that can image whole-breast US volumes in three dimensions. AB US is proposed for screening as a supplemental modality to mammography in women with dense breasts and overcomes important limitations of whole-breast US using handheld devices, such as operator dependence and limited reproducibility. A literature review of supplemental whole-breast US for screening was performed, which showed that both AB US and handheld US allow detection of mammographically negative early-stage invasive breast cancers but also increase the false-positive recall rate. Technicians with limited training can perform AB US; nevertheless, there is a learning curve for acquiring optimal images. Proper acquisition technique may allow avoidance of common artifacts that could impair interpretation of AB US results. Regardless, interpretation of AB US results can be challenging. This article reviews the US appearance of common benign and malignant lesions and presents examples of false-positive and false-negative AB US results. In situ breast cancers are rarely detected with supplemental whole breast US. The most discriminating feature that separates AB US from handheld US is the retraction phenomenon on coronal reformatted images. The retraction phenomenon is rarely seen with benign findings but accompanies almost all breast cancers. In conclusion, women with dense breasts may benefit from supplemental AB US examinations. Understanding the pitfalls in acquisition technique and lesion interpretation, both of which can lead to false-positive recalls, might reduce the potential harm of performing supplemental AB US. Online supplemental material is available for this article. (c)RSNA, 2018. PMID- 29624483 TI - Analysis of Radiation-Induced Chromosomal Aberrations on a Cell-by-Cell Basis after Alpha-Particle Microbeam Irradiation: Experimental Data and Simulations. AB - There is a continued need for further clarification of various aspects of radiation-induced chromosomal aberration, including its correlation with radiation track structure. As part of the EMRP joint research project, Biologically Weighted Quantities in Radiotherapy (BioQuaRT), we performed experimental and theoretical analyses on chromosomal aberrations in Chinese hamster ovary cells (CHO-K1) exposed to alpha particles with final energies of 5.5 and 17.8 MeV (absorbed doses: ~2.3 Gy and ~1.9 Gy, respectively), which were generated by the microbeam at the Physikalisch-Technische Bundesanstalt (PTB) in Braunschweig, Germany. In line with the differences in linear energy transfer (approximately 85 keV/MUm for 5.5 MeV and 36 keV/MUm for 17.8 MeV alpha particles), the 5.5 MeV alpha particles were more effective than the 17.8 MeV alpha particles, both in terms of the percentage of aberrant cells (57% vs. 33%) and aberration frequency. The yield of total aberrations increased by a factor of ~2, although the increase in dicentrics plus centric rings was less pronounced than in acentric fragments. The experimental data were compared with Monte Carlo simulations based on the BIophysical ANalysis of Cell death and chromosomal Aberrations model (BIANCA). This comparison allowed interpretation of the results in terms of critical DNA damage [cluster lesions (CLs)]. More specifically, the higher aberration yields observed for the 5.5 MeV alpha particles were explained by taking into account that, although the nucleus was traversed by fewer particles (nominally, 11 vs. 25), each particle was much more effective (by a factor of ~3) at inducing CLs. This led to an increased yield of CLs per cell (by a factor of ~1.4), consistent with the increased yield of total aberrations observed in the experiments. PMID- 29624484 TI - Early Inflammatory Biomarkers as Predictive Factors for Freedom from Infection after Colorectal Cancer Surgery: A Prospective Cohort Study. AB - PURPOSE: Different biomarkers are useful in diagnosing infections. The aim of this work was to clarify the relation between different inflammatory biomarkers (white blood cell [WBC] count, C-reactive protein [CRP], procalcitonin [PCT], and C-reactive protein-to-albumin ratio [CAR]) and early infectious complications after colorectal surgery. METHODS: This prospective single-center cohort study included 130 patients undergoing elective colorectal surgery. The WBC count, CRP, and PCT were measured at post-operative day one (POD1) and POD3 and albumin on POD3. RESULTS: Patients with surgical site infections (SSI) exhibited significantly higher CRP concentrations on POD1 and CRP and CAR on POD3 than did patients without SSI. According to receiver operating characteristic analysis, the CRP concentration on POD1 and the CRP and CAR on POD3 showed the highest area under the curve (AUC) for predicting SSI (AUC 0.639, 0.736, and 0.729, respectively). Multivariable logistic regression analysis showed that CRP on POD1 and CRP and CAR on POD3 were independent predictors of SSI (odds ratio 7.355, 7.605, and 8.337, respectively). CONCLUSIONS: The CRP concentration on PO1 and CRP and CAR on POD3 can positively identify patients at low risk of SSI. They can be used as a prognostic tool to predict an uneventful post-operative period and therefore have been incorporate into our discharge criteria after elective colorectal resection, improving clinical decision-making. PMID- 29624486 TI - Public Safety and National Security Implications of the Horsepox Study. PMID- 29624485 TI - Microbial Glucuronidase Inhibition Reduces Severity of Diclofenac-Induced Anastomotic Leak in Rats. AB - BACKGROUND: The non-steroidal anti-inflammatory drug diclofenac has been associated with intestinal anastomotic leakage, although the underlying pathophysiology is unclear. Previous data suggest that reactivation of biliary diclofenac metabolites by microbial beta-glucuronidases in the gut plays a role in harming the intestinal mucosa, and that microbiome-targeted glucuronidase inhibition prevents this damage. Here, the microbial glucuronidase inhibitor Inh1 was examined for its ability to reduce diclofenac-induced anastomotic leakage in rats. METHODS: Ninety male Wistar rats were allocated to five groups. In the two diclofenac groups, group DCF received diclofenac (3 mg/kg per day) and group DCF Inh1 additionally received 800 mcg/kg per day of glucuronidase inhibitor Inh1 solution orally. In non-diclofenac groups, animals received either Inh1 (800 mcg/kg per day; group Inh1) solution, the vehicle (methylcellulose; group Veh), or no solution (group Ctrl). All solutions were provided from the day of surgery until sacrifice on day three. Plasma concentrations of diclofenac were determined. Outcomes were anastomotic leakage, leak severity, and anastomotic strength. RESULTS: Anastomotic leak rates were 89% in group DCF and 44% in group DCF-Inh1 (p = 0.006). Leak severity was reduced in group DCFic-Inh1 (p = 0.029). In non-diclofenac cohorts, mostly minor leakage signs were observed in 25% in group Ctrl, 39% in group Inh1 (0.477), and 24% in group Veh (p = 1.000). Bursting pressure and breaking strength were not significantly different. Plasma concentrations of diclofenac were not changed by Inh1. CONCLUSION: Microbial glucuronidase inhibitor reduces diclofenac-induced anastomotic leakage severity, which suggests a harmful effect of diclofenac metabolite reactivation in the gut. This finding improves the understanding of the pathogenesis of anastomotic leakage. PMID- 29624487 TI - Avian Influenza Is a Catalyst for Economic and Political Destabilization in Iran. PMID- 29624488 TI - Correction to: Health Secur 2018:16(1):1-7. PMID- 29624489 TI - Outbreak Protection and the Importance of Paid Sick Leave. AB - From the Field is a semi-regular column that explores what it means to be a local health professional on the front lines of an emergency. Typically, National Association of County and City Health Officials (NACCHO) members share their stories of preparing for and responding to disasters, epidemics, and other major health issues. Through exploring the analysis of the challenges faced and the solutions developed, readers can learn how these public health champions keep their communities safe even in extreme situations. Readers may submit topics of interest to the column's editor, Meghan McGinty, PhD, MPH, MBA, at mmcginty@naccho.org. PMID- 29624490 TI - Identifying Potential Provider and Environmental Contamination on a Clinical Biocontainment Unit Using Aerosolized Pathogen Simulants. AB - The Johns Hopkins Hospital created a biocontainment unit (BCU) to care for patients with highly infectious diseases while assuring healthcare worker safety. Research to date for BCU protocols and practices are based on case reports and lessons learned from patient care and exercises. This study seeks to be the first to explore the influences of healthcare worker movement and personal protective equipment (PPE) doffing on the transport of simulant pathogen particles in a BCU. A cough device released 1 MUm fluorescent polystyrene beads (PSLs) in the patient room. PSL transport was then examined under 2 scenarios: (1) PSL release only, no healthcare workers; and (2) PSL release during 5-minute simulated activity by healthcare workers. Airborne PSL concentrations were quantified every second for 30 minutes per scenario by 7 optical particle sensors located throughout the BCU. PSLs were not detected in the donning room at any time nor in the doffing room during the first test scenario where no healthcare worker was present. The main difference detected between the tested scenarios was the presence of PSLs in the doffing room when healthcare workers were removing PPE, potentially due to re aerosolization of PSLs off the exterior PPE surface or opening of the patient room door. Future work will further explore the potential for re-aerosolization of particles off of PPE during doffing. The present study provides the groundwork for a systematic method for evaluating the BCU and doffing procedures for their respective safety, and it also pilots a systematic method for evaluating potential pathogen exposure pathways for BCU healthcare workers. PMID- 29624492 TI - Eyes on New Product Development. PMID- 29624491 TI - Determination of mineral contents of wild Boletus edulis mushroom and its edible safety assessment. AB - This study aimed to determine the contents of main mineral elements of wild Boletus edulis and to assess its edible safety, which may provide scientific evidence for the utilization of this species. Fourteen mineral contents (Ba, Ca, Cd, Co, Cr, Cu, Fe, Mg, Mn, Na, Ni, Sr, V and Zn) in the caps and stipes of B. edulis as well as the corresponding surface soils collected from nine different geographic regions in Yunnan Province, southwest China were determined. The analyses were performed using inductively coupled plasma atomic emission spectrometer (ICP-AES) after microwave digestion. Measurement data were analyzed using variance and Pearson correlation analysis. Edible safety was evaluated according to the provisionally tolerable weekly intake (PTWI) of heavy metals recommended by United Nations Food and Agriculture Organization and World Health Organization (FAO/WHO). Mineral contents were significantly different with the variance of collection areas. B. edulis showed relative abundant contents of Ca, Fe, Mg and Na, followed by Ba, Cr, Cu, Mn and Zn, and the elements with the lower content less were Cd, Co, Ni, Sr and V. The elements accumulation differed significantly in caps and stipes. Among them, Cd and Zn were bioconcentrated (BCF > 1) while others were bioexcluded (BCF < 1). The mineral contents in B. edulis and its surface soil were positively related, indicating that the elements accumulation level was related to soil background. In addition, from the perspective of food safety, if an adult (60 kg) eats 300 g fresh B. edulis per week, the intake of Cd in most of tested mushrooms were lower than PTWI value whereas the Cd intakes in some other samples were higher than this standard. The results indicated that the main mineral contents in B. edulis were significantly different with respect to geographical distribution, and the Cd intake in a few of regions was higher than the acceptable intakes with a potential risk. PMID- 29624493 TI - Efficacy and Safety of 0.6% Pazufloxacin Ophthalmic Solution Versus Moxifloxacin 0.5% and Gatifloxacin 0.5% in Subjects with Bacterial Conjunctivitis: A Randomized Clinical Trial. AB - PURPOSE: The purpose of this study was to evaluate the clinical efficacy and safety of a novel ophthalmic solution of pazufloxacin on the ocular surface of patients with bacterial conjunctivitis after 7 days of intervention. METHODS: This is a phase 2, double-blind, controlled, multicenter, clinical trial of 300 subjects, randomized to either a 3 dosing regimen of pazufloxacin 0.6% ophthalmic solution (twice a day [BID], n = 90; 3 times a day [TID], n = 76; 4 times a day [QID], n = 68), moxifloxacin 0.3% TID (n = 82), or gatifloxacin 0.5% TID (n = 72). Follow-up was set on days 0, 3, and 7. Assessments of ocular signs were performed, both anterior and posterior segments. The primary outcome measures included conjunctival culture and clinical signs. Safety variables included adverse events (AEs), lisamine green, fluorescein ocular surface stains, and clinical signs of tolerability. RESULTS: After intervention, bacterial eradication was reported in all groups: pazufloxacin BID 79%, pazufloxacin TID 84%, pazufloxacin QID 84%, moxifloxacin 80%, and gatifloxacin 82%. There were no significant differences between treatments. Similar results were reported in clinical remission: pazufloxacin BID 89%, pazufloxacin TID 98%, pazufloxacin QID 92%, moxifloxacin 91%, and gatifloxacin 92% (P = 0.03 comparing pazufloxacin BID vs. TID). There were no differences between female and male responses. The AEs were not related to the interventions. CONCLUSIONS: A simplified dosing regimen was selected to follow the development of ophthalmic pazufloxacin based on its efficacy and safety profile. Pazufloxacin, 1 drop 3 times daily, showed similar rates of bacterial eradication and clinical remission compared with other fluoroquinolones. PMID- 29624494 TI - Pesticides impact on Clavibacter michiganensis ssp. sepedonicus biofilm formation. AB - The effect of various pesticides on the biofilm formation by the phytopathogenic bacterium Clavibacter michiganensis ssp. sepedonicus (Cms), the potato ring rot causative agent, was explored for the first time. Systemic herbicides: 2,4-D, diuron, glyphosate, clopyralid, fluorodifen, as well as the commercial preparations "Lazurite," "Ridomil Gold," and the mitochondria inhibiting pesticides analog, sodium monoiodoacetate, were studied. These pesticides' effect on the Cms biofilm formation was shown to be distinct and dependent on the agent under question. Cms biofilm formation was reduced when exposed to sodium monoiodoacetate, as well as "Lazurite" preparation, that could be due to the bactericidal effect of these agents. 2,4-D and "Ridomil Gold" preparation stimulated the biofilm formation. Systemic herbicides diuron, glyphosate, clopyralid, fluorodifen did not exert appreciable influence on the process of bacterial biofilm formation. PMID- 29624495 TI - Implant Success and Failure Is Dependent Upon the Bone Response. Show a Little Respect for Those Bone Cells! PMID- 29624496 TI - Advances in deformity correction, limb lengthening and reconstruction. AB - This article summarizes the content of this special issue of the journal about: deformity correction, limb lengthening and reconstruction. PMID- 29624498 TI - Mutations Conferring Increased Sensitivity to Tripartite Motif 22 Restriction Accumulated Progressively in the Nucleoprotein of Seasonal Influenza A (H1N1) Viruses between 1918 and 2009. AB - Influenza A viruses (IAVs) can cause zoonotic infections with pandemic potential when most of the human population is immunologically naive. After a pandemic, IAVs evolve to become seasonal in the human host by acquiring adaptive mutations. We have previously reported that the interferon (IFN)-inducible tripartite motif 22 (TRIM22) protein restricts the replication of seasonal IAVs by direct interaction with the viral nucleoprotein (NP), leading to its polyubiquitination and proteasomal degradation. Here we show that, in contrast to seasonal H1N1 IAVs, the 2009 pandemic H1N1 strain as well as H1N1 strains from the 1930s are resistant to TRIM22 restriction. We demonstrate that arginine-to-lysine substitutions conferring an increased sensitivity to TRIM22-dependent ubiquitination accumulated progressively in the NP of seasonal influenza A (H1N1) viruses between 1918 and 2009. Our findings suggest that during long-term circulation and evolution of IAVs in humans, adaptive mutations are favored at the expense of an increased sensitivity to some components of the innate immune response.IMPORTANCE We have uncovered that long-term circulation of seasonal influenza A viruses (IAV) in the human population resulted in the progressive acquisition of increased sensitivity to a component of the innate immune response: the type I interferon-inducible TRIM22 protein, which acts as a restriction factor by inducing the polyubiquitination of the IAV nucleoprotein (NP). We show that four arginine residues present in the NP of the 1918 H1N1 pandemic strain and early postpandemic strains were progressively substituted for by lysines between 1918 and 2009, rendering NP more susceptible to TRIM22 mediated ubiquitination. Our observations suggest that during long-term evolution of IAVs in humans, variants endowed with increased susceptibility to TRIM22 restriction emerge, highlighting the complexity of selection pressures acting on the NP. PMID- 29624497 TI - Pseudotyping of HIV-1 with Human T-Lymphotropic Virus 1 (HTLV-1) Envelope Glycoprotein during HIV-1-HTLV-1 Coinfection Facilitates Direct HIV-1 Infection of Female Genital Epithelial Cells: Implications for Sexual Transmission of HIV 1. AB - Female genital epithelial cells cover the genital tract and provide the first line of protection against infection with sexually transmitted pathogenic viruses. These cells normally are impervious to HIV-1. We report that coinfection of cells by HIV-1 and another sexually transmitted virus, human T-lymphotropic virus 1 (HTLV-1), led to production of HIV-1 that had expanded cell tropism and was able to directly infect primary vaginal and cervical epithelial cells. HIV-1 infection of epithelial cells was blocked by neutralizing antibodies against the HTLV-1 envelope (Env) protein, indicating that the infection was mediated through HTLV-1 Env pseudotyping of HIV-1. Active replication of HIV-1 in epithelial cells was demonstrated by inhibition with anti-HIV-1 drugs. We demonstrated that HIV-1 derived from peripheral blood of HIV-1-HTLV-1-coinfected subjects could infect primary epithelial cells in an HTLV-1 Env-dependent manner. HIV-1 from subjects infected with HIV-1 alone was not able to infect epithelial cells. These results indicate that pseudotyping of HIV-1 with HTLV-1 Env can occur in vivo Our data further reveal that active replication of both HTLV-1 and HIV-1 is required for production of pseudotyped HIV-1. Our findings indicate that pseudotyping of HIV-1 with HTLV-1 Env in coinfected cells enabled HIV-1 to directly infect nonpermissive female genital epithelial cells. This phenomenon may represent a risk factor for enhanced sexual transmission of HIV-1 in regions where virus coinfection is common.IMPORTANCE Young women in certain regions of the world are at very high risk of acquiring HIV-1, and there is an urgent need to identify the factors that promote HIV-1 transmission. HIV-1 infection is frequently accompanied by infection with other pathogenic viruses. We demonstrate that coinfection of cells by HIV-1 and HTLV-1 can lead to production of HIV-1 pseudotyped with HTLV-1 Env that is able to directly infect female genital epithelial cells both in vitro and ex vivo Given the function of these epithelial cells as genital mucosal barriers to pathogenic virus transmission, the ability of HIV-1 pseudotyped with HTLV-1 Env to directly infect female genital epithelial cells represents a possible factor for increased risk of sexual transmission of HIV-1. This mechanism could be especially impactful in settings such as Sub Saharan Africa and South America, where HIV-1 and HTLV-1 are both highly prevalent. PMID- 29624499 TI - Adaptation of cardiovascular system stent implants. AB - Time-consuming design and manufacturing processes are a serious disadvantage when adapting human cardiovascular implants as they cause unacceptable delays after the decision to intervene surgically has been made. An ideal cardiovascular implant should have a broad range of characteristics such as strength, viscoelasticity and blood compatibility. The present research proposes the sequence of the geometrical adaptation procedures and presents their results. The adaptation starts from the identification of a person's current health status while performing abdominal aortic aneurysm (AAA) imaging, which is a point of departure for the mathematical model of a cardiovascular implant. The computerized tomography scan shows the patient-specific geometry parameters of AAA and helps to create a model using COMSOL Multiphysics software. The initial parameters for flow simulation are taken from the results of a patient survey. The simulation results allow choosing the available shape of an implant which ensures a non-turbulent flow. These parameters are essential for the design and manufacturing of an implant prototype which should be tested experimentally for the assurance that the mathematical model is adequate to a physical one. The article gives a focused description of competences and means that are necessary to achieve the shortest possible preparation of the adapted cardiovascular implant for the surgery. PMID- 29624500 TI - Homocysteine is the confounding factor of metabolic syndrome-confirmed by siMS score. AB - BACKGROUND: Abdominal adiposity has a central role in developing insulin resistance (IR) by releasing pro-inflammatory cytokines. Patients with metabolic syndrome (MS) have higher values of homocysteine. Hyperhomocysteinemia correlates with IR, increasing the oxidative stress. Oxidative stress causes endothelial dysfunction, hypertension and atherosclerosis. The objective of the study was to examine the correlation of homocysteine with siMS score and siMS risk score and with other MS co-founding factors. METHODS: The study included 69 obese individuals (age over 30, body mass index [BMI] >25 kg/m2), classified into two groups: I-with MS (33 patients); II-without MS (36 patients). Measurements included: anthropometric parameters, lipids, glucose regulation parameters and inflammation parameters. IR was determined by homeostatic model assessment for insulin resistance (HOMA-IR). ATP III classification was applied for diagnosing MS. SiMS score was used as continuous measure of metabolic syndrome. RESULTS: A significant difference between groups was found for C-reactive protein (CRP) (p<0.01) apolipoprotein (Apo) B, HOMA-IR and acidum uricum (p<0.05). siMS risk score showed a positive correlation with homocysteine (p=0.023), while siMS score correlated positively with fibrinogen (p=0.013), CRP and acidum uricum (p=0.000) and homocysteine (p=0.08). Homocysteine correlated positively with ApoB (p=0.036), HbA1c (p=0.047), HOMA-IR (p=0.008) and negatively with ApoE (p=0.042). CONCLUSIONS: Correlation of siMS score with homocysteine, fibrinogen, CRP and acidum uricum indicates that they are co-founding factors of MS. siMS risk score correlation with homocysteine indicates that hyperhomocysteinemia increases with age. Hyperhomocysteinemia is linked with genetic factors and family nutritional scheme, increasing the risk for atherosclerosis. PMID- 29624501 TI - Effect of the African-specific promoter polymorphisms on the SLC22A2 gene expression levels. AB - BACKGROUND: Single nucleotide polymorphisms in promoter regions have been shown to alter the transcription of genes. Thus, SNPs in SLC22A2 can result in inter individual variable response to medication. METHODS: The objective of the study was to investigate the effect of the African-specific promoter polymorphisms on the SLC22A2 gene expression levels in vitro. These included rs572296424 and rs150063153, which have been previously identified in the Xhosa population of South Africa. The promoter region (300 bp) for the two haplotypes was cloned into the pGLOW promoterless GFP reporter vector. The GFP expression levels of each haplotype was determined in the HEK293 cells using a GlowMax Multi-Detection E7031 luminometer in the form of light emission. RESULTS: The relative promoter activity suggests that no significant variation exists between the expression levels of the WT and -95 haplotypes and the -95 and -156 haplotypes (p=0.498). However, the relative promoter activity of the WT haplotype in comparison to the 156 haplotype displayed a significant difference in expression level (p=0.016). CONCLUSIONS: The data presented here show that the African-specific promoter polymorphisms can cause a decrease in the SLC22A2 gene expression levels in vitro, which in turn, may influence the pharmacokinetic profiles of cationic drugs. PMID- 29624502 TI - Editorial. PMID- 29624503 TI - Magnetically-focusing biochip structures for high-speed active biosensing with improved selectivity. AB - We report a magnetically-focusing biochip structure enabling a single layered magnetic trap-and-release cycle for biosensors with an improved detection speed and selectivity. Here, magnetic beads functionalized with specific receptor molecules were utilized to trap target molecules in a solution and transport actively to and away from the sensor surfaces to enhance the detection speed and reduce the non-specific bindings, respectively. Using our method, we demonstrated the high speed detection of IL-13 antigens with the improved detection speed by more than an order of magnitude. Furthermore, the release step in our method was found to reduce the non-specific bindings and improve the selectivity and sensitivity of biosensors. This method is a simple but powerful strategy and should open up various applications such as ultra-fast biosensors for point-of care services. PMID- 29624504 TI - Magnetically tunable liquid dielectric with giant dielectric permittivity based on core-shell superparamagnetic iron oxide. AB - A liquid dielectric based on a core-shell architecture having a superparamagnetic iron oxide core and a shell of silicon dioxide was synthesized. The frequency dependence of dielectric properties was evaluated for different concentrations of iron oxide. The dependence of magnetic field on the dielectric properties was also studied. Aqueous ferrofluid exhibited a giant dielectric constant of 6.4 * 105 at 0.1 MHz at a concentration of 0.2 vol% and the loss tangent was 3. The large rise in dielectric constant at room temperature is modelled and explained using percolation theory and Maxwell-Wagner-Sillars type polarization. The ferrofluid is presumed to consist of nanocapacitor networks which are wired in series along the lateral direction and parallel along longitudinal direction. On the application of an external magnetic field, the chain formation and its alignment results in the variation of dielectric permittivity. PMID- 29624505 TI - Impact of Concomitant Urologic Intervention on Clinical Outcomes After Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy. AB - INTRODUCTION: The impact of concomitant urologic procedures (UPs) on perioperative and long-term outcomes after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is uncertain. METHODS: In total, 935 consecutive CRS/HIPEC procedures were performed between 1996 and 2016 in Sydney, Australia. Among these, 73 (7.8%) involved concomitant UP. The association of concomitant UP with 21 perioperative outcomes and overall survival was assessed using univariate and multivariate analyses. RESULTS: In-hospital mortality was 1.8%. Patients requiring UP were more likely to require transfusion of >=5 units of red blood cells (P=0.031) and have a complete cytoreduction (79% vs. 60%, P<0.001). On multivariate analysis, UP was not associated with in-hospital mortality (2.7% vs. 1.7%, P=0.407) or grade III/IV morbidity (52% vs. 41%, P=0.376). The incidence of ureteric fistula (4% vs. 1%, P=0.004), return to theater (26% vs. 14%, P=0.005) and digestive fistula (22% vs. 11%, P=0.005) was higher in the UP group. The addition of a UP did not significantly impact overall survival for appendiceal cancer (P=0.162), colorectal cancer (P=0.315), or pseudomyxoma peritonei (P=0.120). CONCLUSIONS: Addition of a UP was not associated with an increased risk of grade III/IV morbidity or poorer long-term survival after CRS/HIPEC. PMID- 29624506 TI - Laparoscopic Assessment to Determine the Likelihood of Achieving Optimal Cytoreduction in Patients Undergoing Primary Debulking Surgery for Ovarian, Fallopian Tube, or Primary Peritoneal Cancer. AB - OBJECTIVE: The objective of this study was to evaluate the safety and efficacy of laparoscopic assessment to determine the likelihood of achieving optimal cytoreduction (OC) in patients undergoing primary debulking surgery (PDS) for ovarian cancer. METHODS: All patients who underwent diagnostic laparoscopy and PDS at our institution from January 2008 to December 2013 were identified. We determined the likelihood of achieving optimal cytoreduction by laparoscopic assessment based on tumor site, pattern of spread, and disease burden. Sensitivity was defined as the number of patients who achieved optimal cytoreduction after laparoscopic assessment divided by the number of patients with disease deemed resectable by laparoscopy. RESULTS: We identified 55 patients during study period. Twenty-one of the 55 patients (38%) were early stage disease. Six (10.9%) patients had disease deemed unresectable and 49 (89.1%) had disease deemed resectable at the time of laparoscopy. OC was achieved in 48 of 49 (97.9%) patients. The sensitivity of laparoscopy in predicting OC was 98% (95% confidence interval, 89.3%-99.9%). The operation was completed laparoscopically in 23 of 49 patients (47%); in 26 of 49 (53%), PDS was performed by laparotomy. There were no port site metastases reported. The rate of postoperative complications was 16%. With a median follow-up of 30 months, the median overall survival was not reached and the 75th percentile for overall survival was 37 months. CONCLUSIONS: Laparoscopy was shown to have a high sensitivity in predicting OC and is a feasible tool in triaging patients with ovarian cancer. Laparoscopy is not associated with adverse surgical outcomes. PMID- 29624507 TI - A rare symptom of a very rare disease: a case report of a oculodentodigital dysplasia with lymphedema. PMID- 29624508 TI - Viscoelastic Tamponade Applied to the Ocular Surface for Enhanced Control of Gaseous Egress From the Anterior Chamber During Final Bubble Titration in DMEK Surgery: The "Polite" Burp. AB - PURPOSE: To present a novel technique for enhancing the surgeon's control over the volume of air or gas that is "burped" from the anterior chamber during final bubble and intraocular pressure (IOP) titration in Descemet membrane endothelial keratoplasty. METHODS: After ascertaining that the intracameral bubble is either too large and/or has rendered IOP too high, a bead of ophthalmic viscoelastic is applied to the ocular surface over a paracentesis incision, which is then depressed in the usual fashion to burp gas from the anterior chamber. RESULTS: The weight and viscosity of the viscoelastic create a tamponade that slows the egress of gas from the anterior chamber, thereby making it more controllable. CONCLUSIONS: If the bubble size or IOP needs to be reduced at the conclusion of the Descemet membrane endothelial keratoplasty procedure, application of ophthalmic viscoelastic over the paracentesis can enhance the surgeon's control over the volume of gas burped from the anterior chamber, thereby reducing the tendency to swing between a bubble that is too large or too small. PMID- 29624509 TI - Graft Detachment Pattern After Descemet Membrane Endothelial Keratoplasty Comparing Air Versus 20% SF6 Tamponade. AB - PURPOSE: The change from air to 20% sulfur hexafluoride (SF6) as anterior chamber tamponade for Descemet membrane endothelial keratoplasty (DMEK) significantly reduced the rebubbling rate. Nonetheless, underlying mechanisms are not completely understood. In this study, we investigate the morphology of graft detachments after DMEK depending on the tamponade and its influence on postoperative rebubbling. METHODS: In this retrospective analysis of prospective data of 204 consecutive patients who underwent DMEK with 100% air, or 20% SF6, we compared the SF6 group with the air group regarding the number, lateral and axial diameter and localization of detachments, visual acuity (BSCVA), and incidence of rebubbling after 1 week (T1), after 1 (T2), 3 (T3), 6 (T4), and 12 (T5) months postoperatively. RESULTS: The air group showed more detachments at all time points. Detachments in this group were of a larger axial diameter at T1, T4, and T5 and of a larger lateral diameter at T1, T3, T4, and T5 compared with the SF6 group. Patients receiving SF6 needed fewer rebubblings at T1 compared with patients receiving air (12.1% vs. 29.1%, P = 0.003), but not at T2 (15.1% vs. 19.1%, P = 0.56). There was no difference in postoperative BSCVA between the groups. CONCLUSIONS: Early graft attachment after DMEK, which is improved by the use of SF6 as anterior chamber tamponade, is important for the overall rebubbling rate and improves wound-healing mechanisms between the graft and recipient cornea. Faster resolving air tamponade is associated with extended detachments especially inferiorly and mid-peripherally, but has no negative effect on the long-term BSCVA. PMID- 29624510 TI - Genetic risk stratification in cardiac arrhythmias. AB - PURPOSE OF REVIEW: The current article provides a concise summary of the possibilities and limitations of genotype-based risk stratification of cardiac arrhythmias. We will outline the most important findings of the recent years in the light of their chronological and conceptual development. RECENT FINDINGS: Genotype-phenotype association studies in families with single-gene disorders as well as in the general population led to the discovery of several DNA variants significantly associated with the risk of sudden death or life-threatening arrhythmias. In genetic (monogenic) diseases, the disease-causing mutations modulate the risk of events and response to antiarrhythmic therapy according to the specific gene involved, to their position of the mutation and to their functional effects. These causal relationships have been quite well characterized in the case of long QT syndrome but are still less defined in the case of other inherited conditions. Quantitatively, the risk associated with a single genetic variant is large for DNA variants that cause monogenic inherited arrhythmias. Much different is the case of more common variants associated with the risk of arrhythmias in the general population as they are generally associated with a small effect size. SUMMARY: Genetic profiling identifies arrhythmogenic risk even if a complete picture allowing high-granularity risk stratification is yet to come. PMID- 29624512 TI - Gastrointestinal Tract Vasculopathy: Clinicopathology and Description of a Possible "New Entity" With Protean Features. AB - Noninfectious gastrointestinal (GI) vasculopathic disorders are rare and are often overlooked in histopathologic examination or when forming differential diagnoses due to their rarity. However, involvement of the GI tract may lead to serious complications, including ischemia and perforation. Since awareness of the types of vasculopathy that may involve the GI tract is central to arriving at a correct diagnosis, we reviewed our institutional experience with GI tract vasculopathy in order to enhance diagnostic accuracy of these rare lesions. We report the clinical and histologic features of 16 cases (excluding 16 cases of immunoglobulin A vasculitis) diagnosed over a 20-year period. Of the 16 patients, 14 presented with symptoms related to the GI vasculopathy (including 2 presenting with a mass on endoscopic examination). The remaining 2 patients presented with incarcerated hernia and invasive adenocarcinoma. The vasculopathy was not associated with systemic disease and appeared limited to the GI tract in 8 patients. Eight had associated systemic disease, but only 6 had a prior diagnosis. The underlying diagnoses in these 6 patients included systemic lupus erythematosus (1), dermatomyositis (2), rheumatoid arthritis (1), eosinophilic granulomatosis with polyangiitis (1), and Crohn disease (1). One patient with granulomatous polyangiitis and 1 patient with systemic lupus erythematosus initially presented with GI symptoms. The 8 cases of isolated GI tract vasculopathy consisted of enterocolic lymphocytic phlebitis (4), idiopathic myointimal hyperplasia of the sigmoid colon (1), idiopathic myointimal hyperplasia of the ileum (1), granulomatous vasculitis (1), and polyarteritis nodosa-like arteritis (1). Isolated GI tract vasculopathy is rare, but appears to be almost as common as that associated with systemic disease. The chief primary vasculopathies are enterocolic lymphocytic colitis and idiopathic myointimal hyperplasia. Although the latter occurs predominantly in the left colon, rare examples occur in the small bowel and likely represent a complex, more protean disorder. PMID- 29624511 TI - Poorly Differentiated Clusters Predict Colon Cancer Recurrence: An In-Depth Comparative Analysis of Invasive-Front Prognostic Markers. AB - This study aimed to compare common histologic markers at the invasive front of colon adenocarcinoma in terms of prognostic accuracy and interobserver agreement. Consecutive patients who underwent curative resection for stages I to III colon adenocarcinoma at a single institution in 2007 to 2014 were identified. Poorly differentiated clusters (PDCs), tumor budding, perineural invasion, desmoplastic reaction, and Crohn-like lymphoid reaction at the invasive front, as well as the World Health Organization (WHO) grade of the entire tumor, were analyzed. Prognostic accuracies for recurrence-free survival (RFS) were compared, and interobserver agreement among 3 pathologists was assessed. The study cohort consisted of 851 patients. Although all the histologic markers except WHO grade were significantly associated with RFS (PDCs, tumor budding, perineural invasion, and desmoplastic reaction: P<0.001; Crohn-like lymphoid reaction: P=0.021), PDCs (grade 1 [G1]: n=581; G2: n=145; G3: n=125) showed the largest separation of 3 year RFS in the full cohort (G1: 94.1%; G3: 63.7%; hazard ratio [HR], 6.39; 95% confidence interval [CI], 4.11-9.95; P<0.001), stage II patients (G1: 94.0%; G3: 67.3%; HR, 4.15; 95% CI, 1.96-8.82; P<0.001), and stage III patients (G1: 89.0%; G3: 59.4%; HR, 4.50; 95% CI, 2.41-8.41; P<0.001). PDCs had the highest prognostic accuracy for RFS with the concordance probability estimate of 0.642, whereas WHO grade had the lowest. Interobserver agreement was the highest for PDCs, with a weighted kappa of 0.824. The risk of recurrence over time peaked earlier for worse PDCs grade. Our findings indicate that PDCs are the best invasive-front histologic marker in terms of prognostic accuracy and interobserver agreement. PDCs may replace WHO grade as a prognostic indicator. PMID- 29624514 TI - National Nurses Week 2018: Inspire, innovate, influence. PMID- 29624513 TI - Mice with diet-induced obesity demonstrate a relative prothrombotic factor profile and a thicker aorta with reduced ex-vivo function. AB - : Classical risk factors such as cholesterol and lipoproteins are currently not sufficient to explain all physiopathological processes of obesity-related vascular dysfunction as well as atherosclerosis and arteriosclerosis. Therefore, the discovery of potential markers involved in vascular dysfunction in the obese state is still needed. Disturbances in hemostatic factors may be involved in the developmental processes associated with obesity-related cardiovascular disorders. We hypothesized that alterations of several hemostatic factors in the obese state could correlate with the function and morphology of the aorta and it could play an important role in the development of vascular dysfunction. To test this, we fed mice with a high-fat diet for 18 weeks and investigated the relationships between selected hemostatic factors (in either plasma or in the liver), metabolic hormones and morphology, and ex-vivo function of the aorta. Here, we show that 18 week exposure to a high-fat diet results in a higher plasma fibrinogen and prolonged prothrombin time in diet-induced obese mice compared to the controls. In addition, liver levels or activities of FII, FX, activated protein C, AT-III, and protein S are significantly different in diet-induced obese mice as compared to the controls. Curiously, FII, FVIII, FX, activated protein C, PTT, and protein S are correlated with both the aorta histology (aortic thickness and diameter) and ex-vivo aortic function. Notably, ex-vivo studies revealed that diet-induced obese mice show a marked attenuation in the functions of the aorta. Taken together, aforementioned hemostatic factors may be considered as critical markers for obesity-related vascular dysfunction and they could play important roles in diagnosing of the dysfunction. PMID- 29624515 TI - Screening women for intimate partner violence: Creating proper practice habits. AB - Intimate partner violence continues to be a challenge for advanced practice registered nurses to address and manage in their daily practice. This article reviews current healthcare concerns in heterosexual, bisexual, transgender, and lesbian women, and explores screening guidelines and resources for developing successful screening habits. Additionally, the article discusses how the Transtheoretical Model and Stages of Change offers insight into the behavior of women who experience intimate partner violence and provides safety strategies for these women. PMID- 29624516 TI - Neural pathways in medial septal cholinergic modulation of chronic pain: distinct contribution of the anterior cingulate cortex and ventral hippocampus. AB - One specific behavior can be synergistically modulated by different neural pathways. Medial septal (MS) cholinergic system innervates widespread cortical and subcortical regions and participates in pain modulation, but the underlying neural pathways are not fully understood. This study examined the contribution of MS cholinergic neurons and 2 neural pathways: MS-rostral anterior cingulate cortex (rACC) and MS-ventral hippocampal CA1 (vCA1), in modulating perceptual and affective pain behaviors in a mouse model of chronic inflammatory pain. We found that chronic pain activated MS cholinergic neurons and pyramidal neurons in the rACC, but suppressed pyramidal neuronal activities in the vCA1, all of which contributed to the maintenance of pathological pain. Chemogenetic inhibition of MS cholinergic neurons or the MS-rACC pathway inhibited rACC pyramidal neuronal activities and attenuated perceptual and affective dimensions of chronic pain. By contrast, chemogenetic activation of MS cholinergic neurons also produced analgesia, but by rescuing hypofunctional pyramidal neurons in vCA1. These results clearly demonstrate that the MS cholinergic system differentially modulates chronic inflammatory pain through MS-rACC or MS-vCA1 pathways. More significantly, our research provides evidence for a novel paradigm of neural circuit modulation: MS cholinergic inhibition and activation induce similar analgesia but through distinct neural pathways. PMID- 29624517 TI - Sources of opioid medication for misuse in older adults: results from a nationally representative survey. AB - Despite increasing rates of prescription opioid (PO) misuse in adults 50 years of age and older, little research has investigated such misuse in this population. This work aimed to examine sources of misused opioid medication in adults 50 years and older, with comparisons to younger groups. Data were from the 2009 to 2014 National Survey on Drug Use and Health surveys. Prevalence rates of PO sources, misuse, and PO use disorder (POUD) symptoms were estimated. Design-based logistic regression investigated age-based differences in these factors and the association of sources with POUD symptoms and other concurrent substance use. Nearly half (47.7%) of adults 65 years and older used physician sources for past 30-day PO misuse, with the second highest rates in those 50 to 64 years old (39.2%). Conversely, use of theft (5.3%), purchases (8.5%), or friends/family (for free; 23.2%) to obtain opioids were least common in adults 65 years and older, with prevalence rates of these sources in those 50 years and older closer to those of younger groups. Across those 50 years and older, use of purchases, physician, or multiple sources were associated with elevated POUD symptom prevalence. Older adults, particularly those 65 years and older, use a different pattern of PO sources than adolescents or younger adults, and those using physician sources have elevated POUD symptoms. Physicians are a key avenue for older adults to obtain opioids for misuse, highlighting the potential role of clinicians in limiting such misuse. PMID- 29624518 TI - Novice and Expert Clinical Instructors: A Method to Enhance Teaching Capabilities. AB - Due to scarce opportunities for professional development in clinical teaching, an online learning community was developed to provide initial and ongoing education for novice and experienced clinical instructors. Asynchronous learning modules were developed that included discussion boards to share best practices. Results demonstrated a significant change in the participants' knowledge of clinical teaching as well as the identification of a lack of confidence among novice instructors (p < .05). This research establishes the benefit of a learning community for both new and experienced clinical instructors and the need to increase confidence in their teaching abilities. PMID- 29624519 TI - The Relationship Between Experiences of Lateral Violence and Career Choice Satisfaction Among Nursing Students. AB - This article explores associate degree nursing students' experiences with lateral violence and its impact on career choice satisfaction. Lateral violence has been linked to decreased professional identity, increased errors, and poor self esteem, leading to a negative culture and attrition. A nonexperimental, quantitative, cross-sectional, correlational design was used; 13.4 percent of respondents (n = 32) met the criteria for intermittent bullying. Analysis confirmed a significant negative correlation between experiences of lateral/vertical violence and career choice satisfaction (r = - .140, p < .05) even after controlling for affect and support. Improved efforts are needed to prevent lateral violence. PMID- 29624520 TI - Inhibition of microRNA-429 attenuates oxygen-glucose deprivation/reoxygenation induced neuronal injury by promoting expression of GATA-binding protein 4. AB - MicroRNAs (miRNAs) have been documented as critical regulators in ischemia/reperfusion-induced neuronal death. A better understanding of miRNA mediated molecular mechanisms in ischemia/reperfusion-induced neuronal death may provide therapeutic targets for cerebral ischemia/reperfusion injury. A growing body of evidence suggests that miR-429 is a apoptosis-related miRNA that is also induced by hypoxia. However, whether miR-429 is involved in regulating neuronal apoptosis during cerebral ischemia/reperfusion injury remains unclear. In this study, the effect of miR-429 on oxygen-glucose deprivation and reoxygenation (OGD/R)-induced neuronal injury was investigated in vitro. The results showed that miR-429 expression levels were upregulated in cultured neurons with OGD/R treatment. The downregulation of miR-429 significantly alleviated OGD/R-induced neuronal injury, whereas upregulation of miR-429 aggravated it. Bioinformatic analysis showed that miR-429 could directly target the 3'-untranslated region of GATA-binding protein 4 (GATA4), which was verified by dual-luciferase reporter assay. Moreover, we found that miR-429 negatively regulated GATA4 expression. Overexpression of GATA4 also significantly alleviated OGD/R-induced neuronal injury. However, knockdown of GATA4 partially reversed the protective effect induced by miR-429 downregulation. Overall, our data showed that downregulation of miR-429 protected neurons against OGD/R-induced injury by promoting GATA4 and suggested a potential therapeutic target for the treatment of cerebral ischemia/reperfusion injury. PMID- 29624521 TI - Development and Pilot Testing of a Measure of Potential Barriers and Facilitators to the Use of a Standardized Assessment Tool. AB - INTRODUCTION: Standardized assessment tools (SATs) are essential to evidence based assessment practices. Identifying what impedes clinicians' use of a SAT can help tailor strategies promoting its use in clinical practice. This article presents the development of the "Measure of potential barriers and facilitators to the Use of a Standardized assessment Tool (MUST)" questionnaire. Preliminary findings are also reported from pilot testing in which the MUST was used to investigate occupational therapists' (OTs) perceptions of potential barriers and facilitators to the use of the Activities of Daily Living Profile (ADL Profile), a SAT evaluating independence in everyday activities of cognitively impaired adults. METHODS: The MUST was administered to 41 OTs attending continuing education workshops on the ADL Profile. Internal consistency was explored using Chronbach alpha. Descriptive statistics were used to analyze scores for each statement. RESULTS: Internal consistency for subscales related to clinicians' characteristics (alpha = 0.7) and to the SAT's characteristics (alpha = 0.8) were adequate but lower for the subscale related to the clinical setting (alpha = 0.6). OTs' perceptions of potential barriers were associated with: OTs' perceived self-efficacy; ADL Profile's applicability to OTs' clienteles; ADL Profile's compatibility with values promoted in the work setting and with clients' preferences; limited peer support; time to implement the ADL Profile. DISCUSSION: The MUST, a theory-informed questionnaire, may prove useful in identifying potential barriers needing to be addressed in continuing education training promoting the use of SATs by clinicians. The MUST is quick to administer and initial testing provides support for its internal consistency. PMID- 29624522 TI - Low Energy Availability, Plasma Lipids, and Hormonal Profiles of Recreational Athletes. AB - Black, K, Slater, J, Brown, RC, and Cooke, R. Low energy availability, plasma lipids, and hormonal profiles of recreational athletes. J Strength Cond Res 32(10): 2816-2824, 2018-It has been postulated that low energy availability (LEA) impacts bone health, hormonal concentrations, and cardiovascular function. This study describes the lipid levels, hormonal profiles, and nutrient intakes of recreationally active adults at risk of LEA compared with those not at risk. Thirty-eight women who meet or exceed the New Zealand guidelines for physical activity participated. Each participant completed an online questionnaire including the Low Energy Availability in Females questionnaire (LEAF-Q), demographic questions, and daily exercise to determine energy expenditure. Participants also provided a weighed 3-day diet record, a blood sample analyzed for total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglycerides, and cortisol, and a saliva sample analyzed for testosterone. Body composition was assessed using bioelectrical impedance. Those classed as at risk of LEA according to the LEAF-Q showed very likely lower energy availability (at risk: mean, 36.3 [95% confidence interval, 30.8-41.7] kcal.kg.FFMd vs. not at risk: mean, 47.5 [95% CI, 39.5-55.4] kcal.kg.FFMd) and lower calcium intakes (mean, 847 [95% CI, 695-998] mg, vs. mean, 1488 [95% CI, 690-2,286] mg). Those at risk also had a likely small lower T3 concentration of 1.78 (SD: 0.36) nmol.L compared with 2.01 (SD: 0.53) nmol.L for those not at risk. These data suggest that recreationally active female subjects classed as at risk of LEA according to the LEAF-Q also have lower energy availability as determined by diet records and exercise diaries. The results also suggests that those at risk of LEA have reductions in T3, and their low energy intake, in addition to a low calcium intake, could put them at an increased risk of poor bone health. PMID- 29624524 TI - Blood Pressure Coefficient of Variation and Its Association With Cardiac Surgical Outcomes. AB - BACKGROUND: Multiple studies completed in the ambulatory nonsurgical setting show a significant association between short- and long-term blood pressure variability and poor outcomes. However, perioperative blood pressure variability outcomes have not been well studied, especially in the cardiac surgical setting. In this study, we sought to assess whether systolic and mean arterial blood pressure variability were associated with 30-day mortality and in-hospital renal failure in patients undergoing cardiac surgery requiring cardiopulmonary bypass. Furthermore, blood pressure variability has not been evaluated specifically during each phase of surgery, namely in the pre-, intra- and postbypass phases; thus, we aimed also to assess whether outcomes were associated with phase specific systolic and mean arterial blood pressure variability. METHODS: All patients undergoing cardiac surgery from January 2008 to June 2014 were enrolled in this retrospective, single-center study. Demographic, intraoperative, and postoperative outcome data were obtained from the institution's Society of Thoracic Surgery database and Anesthesia Information Management System. Systolic and mean arterial blood pressure variability were assessed using the coefficient of variation (CV). The primary outcomes were 30-day mortality and in-hospital renal failure in relation to the entire duration of a case, while the secondary outcomes assessed phase-specific surgical periods. In an effort to control the family-wise error rate, P values <.0125 were considered significant for the primary outcomes. RESULTS: Of the 3687 patients analyzed, 2.7% of patients died within 30 days of surgery and 2.8% experienced in-hospital renal failure. After adjusting for significant covariates, we found a statistically significant association between increasing CV for systolic blood pressure (CVSBP) and 30-day mortality and in-hospital renal failure. For every 0.10 increase in CVSBP, there was a 150% increase in the odds of death (odds ratio, 2.50; 95% confidence interval, 1.60-3.92; P < .0001) and there was a 104% increase in odds of experiencing renal failure (odds ratio, 2.04; 95% confidence interval, 1.33-3.14; P = .001). The association with mortality was driven primarily by the prebypass period, because the association between CVSBP and mortality during the prebypass phase was significant (P = .01), and not during the postbypass phase (P = .08). There was no significant association between CV for mean arterial blood pressure and either death or renal failure during any period of surgery, including the bypass phase. CONCLUSIONS: Increasing systolic blood pressure variability was associated with 30-day mortality and development of renal failure, with surgery phase-specific relationships observed. Further research is required to determine how to prospectively detect blood pressure variability and elucidate opportunities for intervention. PMID- 29624525 TI - New Visions and Current Evidence for Safety in Anesthesia. PMID- 29624523 TI - Optimizing a Positive Psychology Intervention to Promote Health Behaviors After an Acute Coronary Syndrome: The Positive Emotions After Acute Coronary Events III (PEACE-III) Randomized Factorial Trial. AB - OBJECTIVE: Despite the clear benefits of physical activity and related behaviors on prognosis, most patients experiencing an acute coronary syndrome (ACS) remain nonadherent to these behaviors. Deficits in positive psychological constructs (e.g., optimism) are linked to reduced participation in health behaviors, supporting the potential utility of a positive psychology (PP)-based intervention in post-ACS patients. Accordingly, we aimed to identify optimal components of a PP-based intervention to promote post-ACS physical activity. METHODS: As part of a multiphase optimization strategy, we completed a randomized factorial trial with eight conditions in 128 post-ACS patients to efficiently identify best performing intervention components. All participants received a PP-based intervention, with conditions varying in duration (presence/absence of booster sessions), intensity (weekly/daily PP exercises), and content (PP alone or combined with motivational interviewing), allowing three concurrent comparisons within the trial. The study aims included assessments of the overall feasibility, acceptability, and impact of the intervention, along with the primary aim of determining which components were associated with objectively measured physical activity and self-reported health behavior adherence at 16 weeks, assessed using longitudinal models. RESULTS: The intervention was well accepted and associated with substantial improvements in behavioral and psychological outcomes. Booster sessions were associated with greater activity to a nearly significant degree (beta = 8.58, 95% confidence interval = -0.49-17.65, effect size difference = .43, p = .064), motivational interviewing was associated with overall adherence (beta = 0.95, 95% confidence interval = 0.02-1.87, effect size difference = .39, p = .044), and weekly exercise completion was generally superior to daily. CONCLUSIONS: These findings will enable optimization of the PP-based intervention in preparation for a well-powered controlled trial. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov, NCT02754895. PMID- 29624526 TI - American Society for Enhanced Recovery: Advancing Enhanced Recovery and Perioperative Medicine. AB - As the population ages, the increasing surgical volume and complexity of care are expected to place additional care delivery burdens in the perioperative setting. In this age of integrated multidisciplinary care of the surgical patients, there is increasing recognition that an evidence-based perioperative pathway is associated with the optimal outcomes. These pathways, collectively referred to as Enhanced Recovery Pathways, have resulted in shortened length of hospital stay, reduced complications, and variance in outcomes, as well as earlier return to baseline activities. The American Society for Enhanced Recovery (ASER) is a multispecialty, nonprofit international organization, dedicated to the practice of enhanced recovery in perioperative patients through education and research. Perioperative Quality Initiatives were formed whose intent is to organize a series of consensus conferences on topics of interest related to perioperative medicine. The journal affiliation between American Society for Enhanced Recovery and Anesthesia & Analgesia will enable these evidence-based practices to be disseminated widely and swiftly to the practicing perioperative health care professionals so they can be adopted to improve the quality of perioperative surgical care. PMID- 29624528 TI - Lack of Evidence for Ceiling Effect for Buprenorphine Analgesia in Humans. PMID- 29624527 TI - Dezocine Alleviates Morphine-Induced Dependence in Rats. AB - BACKGROUND: Opioid dependence is a major public health issue without optimal therapeutics. This study investigates the potential therapeutic effect of dezocine, a nonaddictive opioid, in opioid dependence in rat models. METHODS: Dezocine was administered intraperitoneally to a morphine-dependent rat model to investigate its effect on withdrawal and conditioned place preference (CPP). Effect of dezocine on morphine withdrawal syndrome and CPP was analyzed using 2 way analysis of variance (ANOVA) followed by Tukey's post hoc test. Buprenorphine and vehicle solution containing 20% (v/v) dimethyl sulfoxide were used for positive and negative control, respectively. The astrocytes activation in nucleus accumbens was assessed by immunofluorescence assay of glial fibrillary acidic protein. Effect of dezocine and buprenorphine on the internalization of kappa opioid receptor (KOR) was investigated using Neuro2A expressing KOR fused to red fluorescent protein tdTomato (KOR-tdT). Buprenorphine and dezocine were screened against 44 G-protein-coupled receptors, ion channels, and transporter proteins using radioligand-binding assay to compare the molecular targets. RESULTS: The mean withdrawal score was reduced in rats treated with 1.25 mg.kg dezocine compared to vehicle-treated control animals starting from the day 1 (mean difference: 7.8; 95% confidence interval [CI], 6.35-9.25; P < .0001 by 2-way ANOVA). Significance was observed at all treatment days, including day 7 (mean difference: 2.13; 95% CI, 0.68-3.58; P < .001 by 2-way ANOVA). Furthermore, dezocine inhibited the reinstatement of morphine-induced CPP (mean difference: 314; 95% CI, 197.9-430.1; P < .0001 by 2-way ANOVA) compared to the control group. Chronic morphine administration induced astrocytes activation in nucleus accumbens, which was attenuated by dezocine. Dezocine blocked the agonist-induced KOR internalization in vitro, 1 of the mechanisms involved in the downstream signaling and development of opioid dependence. Dezocine had affinity to norepinephrine and serotonin transporters and sigma-1 receptor, whereas buprenorphine showed no activity against these targets. CONCLUSIONS: Dezocine could potentially be used to alleviate opioid dependence. Due to the unique molecular target profile different from buprenorphine, it might have important value in studying the mechanisms of morphine dependence and developing novel therapeutic approaches. PMID- 29624529 TI - Potential Benefits of Sodium-Glucose Cotransporter-2 Inhibitors in the Perioperative Period. PMID- 29624530 TI - Diagnostic Accuracy of Point-of-Care Gastric Ultrasound. AB - BACKGROUND: Pulmonary aspiration of gastric contents is associated with significant perioperative morbidity and mortality. Previous studies have investigated the validity, reliability, and possible clinical impact of gastric ultrasound for the assessment of gastric content at the bedside. In the present study, we examined the accuracy (evaluated as sensitivity, specificity, and likelihood ratios) of point-of-care gastric ultrasound to detect a "full stomach" in a simulated scenario of clinical equipoise. METHODS: After a minimum fasting period of 8 hours, 40 healthy volunteers were randomized in a 1:1 ratio to either remain fasted or ingest a standardized quantity of clear fluid or solid. Each subject was randomized twice on 2 independent study sessions at least 24 hours apart. A gastric ultrasound examination was performed by a blinded sonographer following a standardized scanning protocol. Using a combination of qualitative and quantitative findings, the result was summarized in a dichotomous manner as positive (any solid or >1.5 mL/kg of clear fluid) or negative (no solid and <=1.5 mL/kg of clear fluid) for full stomach. RESULTS: Data from 80 study sessions were analyzed. In this simulated clinical scenario with a pretest probability of 50%, point-of-care gastric ultrasound had a sensitivity of 1.0 (95% confidence interval [CI], 0.925-1.0), a specificity of 0.975 (95% CI, 0.95-1.0), a positive likelihood ratio of 40.0 (95% CI, 10.33-infinity), a negative likelihood ratio of 0 (95% CI, 0-0.072), a positive predictive value of 0.976 (95% CI, 0.878-1.0), and a negative predictive value of 1.0 (95% CI, 0.92-1.0). CONCLUSIONS: Our results suggest that bedside gastric ultrasound is highly sensitive and specific to detect or rule out a full stomach in clinical scenarios in which the presence of gastric content is uncertain. PMID- 29624531 TI - In Response. PMID- 29624532 TI - Reduced Ketobemidone Usage in Quadratus Lumborum Block Patients After Cesarean Delivery: Clinical Pharmacology Views. PMID- 29624533 TI - Profound Intraoperative Hypotension Associated With Transfusion via the Belmont Fluid Management System. AB - This retrospective observational case series conducted at 2 large academic centers over a 4-year period consists of 15 cases of profound hypotension in surgical patients immediately after initiation of the Belmont Fluid Management System for rapid transfusion of blood products. Halting the infusion and administering vasoactive agents led to resolution of hypotension. Repeat transfusion with the Belmont system resulted in repeat hypotension unless counteracted with vasopressors. No etiology was elucidated. This represents the largest documented association of acute hypotensive transfusion reaction with any rapid infusion system in surgical patients. PMID- 29624534 TI - In Response. PMID- 29624535 TI - Comparison of Intraoperative Sedation With Dexmedetomidine Versus Propofol on Acute Postoperative Pain in Total Knee Arthroplasty Under Spinal Anesthesia: A Randomized Trial. AB - BACKGROUND: In patients undergoing total knee arthroplasty under spinal anesthesia, we compared the postoperative analgesic effect of intraoperative sedation with dexmedetomidine versus propofol. We hypothesized that sedation with dexmedetomidine would result in lower postoperative opioid analgesic consumption than with propofol. METHODS: Forty-eight patients were enrolled and randomly assigned to either a dexmedetomidine group (n = 24), which received a loading dose of 1 MUg/kg dexmedetomidine over 10 minutes, followed by a continuous infusion of 0.1-0.5 MUg.kg.hour, or a propofol group (n = 24), which received a continuous infusion of propofol via a target-controlled infusion to maintain the effect-site concentration within a range of 0.5-2.0 MUg/mL. The drug infusion rate was determined according to the sedation level, targeting a modified observer's assessment of alertness/sedation score of 3 or 4. The cumulative amounts of fentanyl administered via intravenous patient-controlled analgesia were recorded at 24 and 48 hours postoperatively (primary outcome). The postoperative numerical rating scale for pain was assessed at 6, 12, 24, and 48 hours (secondary outcome). The postoperative use of additional rescue analgesic (ketoprofen) and antiemetic drugs was also compared between the 2 groups at 24 and 48 hours. RESULTS: Dexmedetomidine significantly reduced postoperative fentanyl consumption (median [interquartile range]) during 0-24 hours (45 [30-71] vs 150 [49-248] MUg, P = .004; median difference = -105 MUg [99.98% CI, 210 7.5]), 24-48 hours (90 [45-143] vs 188 [75-266] MUg, P = .005; median difference = -98 MUg [99.98% CI, 195-45]), and 0-48 hours (135 [68-195] vs 360 [146-480] MUg, P = .003; median difference = -225 MUg [99.98% CI, 405-7.5]). The numerical rating scale (median [interquartile range]) was lower at 6 hours (1 [0-2] vs 2 [1 3], P = .003), 12 hours (1 [1-2] vs 3 [2-3], P < .001), 24 hours (1 [1-2] vs 3 [2 3], P < .001), and 48 hours (2 [2-3] vs 3 [3-4], P < .001) after surgery in the dexmedetomidine group compared to the propofol group. No significant intergroup differences were observed in the amount of rescue analgesics and antiemetics at 24 hours (P = .155 and P = .482) and 48 hours (P = .082 and P = .153) after surgery. CONCLUSIONS: Intraoperative dexmedetomidine sedation was associated with a small but clinically important reduction in postoperative opioid use after total knee arthroplasty. PMID- 29624536 TI - Working Memory Training Following Neonatal Critical Illness: A Randomized Controlled Trial. AB - OBJECTIVES: To test the immediate and long-term effectiveness of Cogmed Working Memory Training following extracorporeal membrane oxygenation and/or congenital diaphragmatic hernia. DESIGN: A nationwide randomized controlled trial assessing neuropsychologic outcome immediately and 1 year post Cogmed Working Memory Training, conducted between October 2014 and June 2017. Researchers involved in the follow-up assessments were blinded to group allocation. SETTING: Erasmus MC Sophia Children's Hospital, Rotterdam, and Radboud University Medical Center, Nijmegen, the Netherlands. PATIENTS: Eligible participants were neonatal extracorporeal membrane oxygenation and/or congenital diaphragmatic hernia survivors (8-12 yr) with an intelligence quotient greater than or equal to 80 and a z score less than or equal to -1.5 on at least one (working) memory test at first assessment. INTERVENTIONS: Cogmed Working Memory Training, comprising 25 45 minute training sessions for 5 consecutive weeks at home. MEASUREMENTS AND MAIN RESULTS: Participants were randomized to Cogmed Working Memory Training (n = 19) or no intervention (n = 24) (two dropped out after T0). Verbal working memory (estimated coefficient = 0.87; p = 0.002) and visuospatial working memory (estimated coefficient=0.96, p = 0.003) significantly improved at T1 post Cogmed Working Memory Training but was similar between groups at T2 (verbal, p = 0.902; visuospatial, p = 0.416). Improvements were found at T2 on long-term visuospatial memory following Cogmed Working Memory Training (estimated coefficient = 0.95; p = 0.003). Greater improvements in this domain at T2 following Cogmed Working Memory Training were associated with better self-rated school functioning (r = 0.541; p = 0.031) and parent-rated attention (r = 0.672; p = 0.006). CONCLUSIONS: Working memory improvements after Cogmed Working Memory Training disappeared 1 year post training in neonatal extracorporeal membrane oxygenation and/or congenital diaphragmatic hernia survivors. Gains in visuospatial memory persisted 1 year post intervention. Cogmed Working Memory Training may be beneficial for survivors with visuospatial memory deficits. PMID- 29624537 TI - Feasibility and Safety of Intravascular Temperature Management for Severe Heat Stroke: A Prospective Multicenter Pilot Study. AB - OBJECTIVES: Heat stroke is a life-threatening condition with high mortality and morbidity. Although several cooling methods have been reported, the feasibility and safety of treating heat stroke using intravascular temperature management are unclear. This study evaluated the efficacies of conventional treatment with or without intravascular temperature management for severe heat stroke. DESIGN: Prospective multicenter study. SETTING: Critical care and emergency medical centers at 10 tertiary hospitals. PATIENTS: Patients with severe heat stroke hospitalized during two summers. INTERVENTIONS: Conventional cooling with or without intravascular temperature management. MEASUREMENTS AND MAIN RESULTS: Cooling efficacy, Sequential Organ Failure Assessment score, occurrence rate of serious adverse events, and prognosis based on the modified Rankin Scale and Cerebral Performance Category. Patient outcomes were compared between five centers that were prospectively assigned to perform conventional cooling (control group: eight patients) and five centers that were assigned to perform conventional cooling plus intravascular temperature management (intravascular temperature management group: 13 patients), based on equipment availability. Despite their higher initial temperatures, all patients in the intravascular temperature management group reached the target temperature of 37 degrees C within 24 hours, although only 50% of the patients in the control group reached 37 degrees C (p < 0.01). The intravascular temperature management group also had a significant decrease in the Sequential Organ Failure Assessment score during the first 24 hours after admission (4.0 vs 1.5; p = 0.04). Furthermore, the intravascular temperature management group experienced fewer serious adverse events during their hospitalization, compared with the control group. The percentages of favorable outcomes at discharge and 30 days after admission were not statistically significant. CONCLUSIONS: The combination of intravascular temperature management and conventional cooling was safe and feasible for treating severe heat stroke. The results indicate that better temperature management may help prevent organ failure. A large randomized controlled trial is needed to validate our findings. PMID- 29624539 TI - Tinnitus, Depression, Anxiety, and Suicide in Recent Veterans: A Retrospective Analysis. AB - OBJECTIVES: The purpose of this project was to investigate whether there is an association between tinnitus diagnosis and suicide and whether depression and anxiety strengthen that association. Given that tinnitus is the top service connected disability among U.S. Veterans () and that suicide among Veterans has been occurring at a higher frequency as compared with community suicide rates (), the possible associations between tinnitus and suicide will be explored. Co occurring physical conditions also will be examined to determine if they increase the risk of suicide in the context of tinnitus. DESIGN: Administrative health care data related to Operations Enduring Freedom/Iraqi Freedom/New Dawn (OEF/OIF/OND) were used to identify Veterans who accessed the Veterans Administration (VA) health care system from January 1, 2002, to December 31, 2011. Veterans who were deceased as of December 2011 were identified using the National Death Index (NDI) files. Tinnitus cases were followed until either they were deceased or to the end of the study period. The International Classification of Diseases 9th Revision Clinical Modification (ICD-9-CM) codes were used to identify all conditions and diseases. As per mortality research standards, International Classification of Diseases 10th Revision (ICD-10) codes were used to identify cause of death. RESULTS: Of 769,934 OEF/OIF/OND Veterans receiving VA care January 2002 to December 2011, 15% (n =116,358) were diagnosed with tinnitus. Of these Veterans diagnosed with tinnitus, 21% were also diagnosed with depression, another 8% with anxiety, and another 17% with both depression and anxiety. Fifty-four percentage were identified as having tinnitus without depression or anxiety. Among individuals with tinnitus, 41.9% had co-occurring hearing loss. Suicide rates were lower among Veterans with tinnitus than Veterans without tinnitus. Co-occurring diagnoses of mental-health conditions did not significantly increase the risk of suicide. CONCLUSIONS: The study results do not confirm clinical and anecdotal reports that tinnitus could be related to suicide among Veterans. However, tenets from rehabilitation psychology suggest that the onset of chronic impairment or disability does not predict an individual's subsequent psychological states; other personal attributes may be more influential. Health care professionals, such as audiologists and psychologists, should be cognizant of the associations between tinnitus and mental health issues and be prepared to address the psychological needs of individuals who have tinnitus. PMID- 29624538 TI - Comparisons of IQ in Children With and Without Cochlear Implants: Longitudinal Findings and Associations With Language. AB - OBJECTIVES: To make longitudinal comparisons of intelligence quotient (IQ) in children with cochlear implants (CIs) and typical hearing peers from early in development to the school-age period. Children with additional comorbidities and CIs were also evaluated. To estimate the impact of socioeconomic status and oral language on school-age cognitive performance. DESIGN: This longitudinal study evaluated nonverbal IQ in a multicenter, national sample of 147 children with CIs and 75 typically hearing peers. IQ was evaluated at baseline, prior to cochlear implantation, using the Bayley Scales of Infant and Toddler Development and the Leiter International Performance Scale. School-age IQ was assessed using the Wechsler Intelligence Scales for Children. For the current study, only the Perceptual Reasoning and Processing Speed indices were administered. Oral language was evaluated using the Comprehensive Assessment of Spoken Language. RESULTS: Children in the CI group scored within the normal range of intelligence at both time points. However, children with additional comorbidities scored significantly worse on the Processing Speed, but not the Perceptual Reasoning Index. Maternal education and language were significantly related to school-age IQ in both groups. Importantly, language was the strongest predictor of intellectual functioning in both children with CIs and normal hearing. CONCLUSION: These results suggest that children using cochlear implants perform similarly to hearing peers on measures of intelligence, but those with severe comorbidities are at-risk for cognitive deficits. Despite the strong link between socioeconomic status and intelligence, this association was no longer significant once spoken language performance was accounted for. These results reveal the important contributions that early intervention programs, which emphasize language and parent training, contribute to cognitive functioning in school-age children with CIs. For families from economically disadvantaged backgrounds, who are at-risk for suboptimal outcomes, these early intervention programs are critical to improve overall functioning. PMID- 29624540 TI - Evaluation of Speed and Accuracy of Next-Generation Auditory Steady State Response and Auditory Brainstem Response Audiometry in Children With Normal Hearing and Hearing Loss. AB - OBJECTIVES: The first objective of this study was to compare the predicted audiometric thresholds obtained by auditory steady state response (ASSR) and auditory brainstem response (ABR) in infants and toddlers when both techniques use optimal stimuli and detection algorithms. This information will aid in determining the basis for large discrepancies in ABR and ASSR measures found in past studies. The hypothesis was that advancements in ASSR response detection would improve (lower) thresholds and decrease discrepancies between the thresholds produced by the two techniques. The second objective was to determine and compare test times required by the two techniques to predict thresholds for both ears at the 4 basic audiometric frequencies of 500, 1000, 2000, and 4000 Hz. DESIGN: A multicenter clinical study was implemented at three university-based children's hospital audiology departments. Participants were 102 infants and toddlers referred to the centers for electrophysiologic testing for audiometric purposes. The test battery included wideband tympanometry, distortion-product otoacoustic emissions, and threshold measurements at four frequencies in both ears using ABR and ASSR (randomized) as implemented on the Interacoustics Eclipse systems with "Next-Generation" ASSR detection and FMP analysis for ABR. Both methods utilized narrow band CE-Chirp stimuli. Testers were trained on a specialized test battery designed to minimize test time for both techniques. Testing with both techniques was performed in one session. Thresholds were evaluated and confirmed by the first author and correction factors were applied. Test times were documented in system software. RESULTS: Corrected thresholds for ABR and ASSR were compared by regression, by the Bland-Altman technique and by matched pairs t tests. Thresholds were significantly lower for ASSR than ABR. The ABR-ASSR discrepancy at 500 Hz was 14.39 dB, at 1000 Hz was 10.12 dB, at 2000 Hz was 3.73 dB, and at 4000 Hz was 3.67 dB. The average test time for ASSR of 19.93 min (for 8 thresholds) was found to be significantly lower (p < 0.001) than the ABR test time of 32.15 min. One half of the subjects were found to have normal hearing. ASSR thresholds plotted in dB nHL for normal-hearing children in this study were found to be the lowest yet described except for one study which used the same technology. CONCLUSIONS: This study found a reversal of previous findings with up to 14 dB lower thresholds found when using the ASSR technique with "Next-Generation" detection as compared with ABR using an automated detection (FMP). The test time for an audiogram prediction was significantly lower when using ASSR than ABR but was excellent by clinical standards for both techniques. ASSRs improved threshold performance was attributed to advancements in response detection including utilization of information at multiple harmonics of the modulation frequency. The stimulation paradigm which utilized narrow band CE-Chirps also contributed to the low absolute levels of the thresholds in nHL found with both techniques. PMID- 29624541 TI - Toward Optimizing VEMP: Calculating VEMP Inhibition Depth With a Generic Template. AB - OBJECTIVES: Cervical vestibular evoked myogenic potentials (cVEMP) indirectly reveal the response of the saccule to acoustic stimuli through the inhibition of sternocleidomastoid muscle electromyographic response. VEMP inhibition depth (VEMPid) is a recently developed metric that estimates the percentage of saccular inhibition. VEMPid provides both normalization and better accuracy at low response levels than amplitude-normalized cVEMPs. Hopefully, VEMPid will aid in the clinical assessment of patients with vestibulopatholgy. To calculate VEMPid a template is needed. In the original method, a subject's own cVEMP was used as the template, but this method can be problematic in patients who do not have robust cVEMP responses. We hypothesize that a "generic" template, created by assembling cVEMPs from healthy subjects, can be used to compute VEMPid, which would facilitate the use of VEMPid in subjects with pathological conditions. DESIGN: A generic template was created by averaging cVEMP responses from 6 normal subjects. To compare VEMPid calculations using a generic versus a subject-specific template, cVEMPs were obtained in 40 healthy subjects using 500, 750, and 1000 Hz tonebursts at sound levels ranging from 98 to 123 dB peSPL. VEMPids were calculated both with the generic template and with the subject's own template. The ability of both templates to determine whether a cVEMP was present or not was compared with receiver operating characteristic curves. RESULTS: No significant differences were found between VEMPid calculations using a generic template versus using a subject-specific template for all frequencies and sound levels. Based on the receiver operating characteristic curves, the subject-specific and generic template did an equally good job at determining threshold. Within limits, the shape of the generic template did not affect these results. CONCLUSIONS: A generic template can be used instead of a subject-specific template to calculate VEMPid. Compared with cVEMP normalized by electromyographic amplitudes, VEMPid is advantageous because it averages zero when there is no sound stimulus and it allows the accumulating VEMPid value to be shown during data acquisition as a guide to deciding when enough data has been collected. PMID- 29624542 TI - Effects of Combined Lower Thoracic Epidural/General Anesthesia on Pain Control in Patients Undergoing Elective Lumbar Spine Surgery: A Randomized Controlled Trial. AB - STUDY DESIGN: Randomized controlled trial. OBJECTIVE: Our objective was to compare postoperative pain relief and operating field condition of single-shot, low-thoracic epidural anesthesia combined with general anesthesia versus general anesthesia alone. SUMMARY OF BACKGROUND DATA: Prior studies have suggested that continuous epidural analgesia provides better postoperative pain relief and less intraoperative blood loss, but with the risk of the epidural catheter contaminating the surgical field. METHODS: A total of 22 patients scheduled for elective lumbar spine surgery were enrolled and randomly allocated into two groups. Group B (block) received a single-shot epidural block with 0.25% bupivacaine plus 4 mg of morphine with a total volume of 10 mL before receiving general anesthesia with desflurane, and cisatracurium. Group G (general) received general anesthesia alone with desflurane, cisatracurium, and any systemic analgesia deemed appropriate by the attending anesthesiologist. Postoperative pain score, opioid consumption, intraoperative blood loss, surgical field rating score, and other side effects were recorded at the postanesthesia care unit (PACU) and at 24 hours postoperatively. RESULTS: Both groups were comparable for age, sex, body mass index, and American Society of Anaesthesiologists physical status. Fentanyl consumption was significantly lower (P < 0.05) for group B (block) at the PACU and 24 hours. Mean fentanyl consumption at PACU was 20 MUg for group B and 85 MUg for group G. At 24 hours mean fentanyl consumption was 80 MUg for group B and 386 MUg for group G. Pain measured with numerical rating scale, surgical field rating score, blood loss, and complications were similar in both groups. CONCLUSION: Single-shot low-thoracic epidural anesthesia combined with general anesthesia provides better pain control than general anesthesia alone. LEVEL OF EVIDENCE: 2. PMID- 29624543 TI - INJECTION FREQUENCY OF AFLIBERCEPT VERSUS RANIBIZUMAB IN A TREAT-AND-EXTEND REGIMEN FOR CENTRAL RETINAL VEIN OCCLUSION: A Randomized Clinical Trial. AB - PURPOSE: To prospectively investigate the injection frequency of aflibercept and ranibizumab in the treatment of macular edema in central retinal vein occlusion. METHODS: Patients with treatment-naive central retinal vein occlusion and macular edema were randomized to receive intravitreal injections with aflibercept (n = 22) or ranibizumab (n = 23) in a treat-and-extend regimen with a follow-up time of 18 months. After 3 loading doses, the treatment intervals were extended by 2 weeks to a maximum of 12 weeks. Intervals were shortened by 2 weeks if macular edema recurred. RESULTS: The number of injections was significantly lower in the aflibercept group with a mean of 10.9 injections (95% confidence interval, 9.6 12.3) compared with 14.4 in the ranibizumab group (95% confidence interval 12.7 16.1) at study completion (P = 0.0017). The mean treatment interval was significantly longer in the aflibercept group compared with the ranibizumab group 10.0 (95% confidence interval, 8.7-11.3) and 6.6 (95% confidence interval, 5.2 8.0) weeks, respectively (P < 0.001). No significant difference between the groups regarding visual acuity or central retinal thickness was observed. CONCLUSION: Patients with macular edema secondary to central retinal vein occlusion required significantly fewer intravitreal injections of aflibercept compared with ranibizumab when treated with a treat-and-extend regimen. This may reduce the treatment burden and, to some extent, the need for close monitoring of patients. PMID- 29624544 TI - DIFFERENCES IN REFRACTIVE OUTCOMES BETWEEN PHACOEMULSIFICATION FOR CATARACT ALONE AND COMBINED PHACOEMULSIFICATION AND VITRECTOMY FOR EPIRETINAL MEMBRANE. AB - PURPOSE: To determine whether preoperative adjustments are required for intraocular lens calculations in combined phacovitrectomy surgery. METHODS: A single-center, retrospective study of 50 eyes that underwent combined phacovitrectomy and a control group of 50 eyes after cataract surgery over a 3 year period by a single anterior segment surgeon and a single posterior segment surgeon. Main outcome measures were predicted refractive error (RE), as determined by SRK/T and Holladay 1 formulas, change compared with actual RE, surgically induced astigmatism, and the relationships between preoperative central foveal thickness or change in central foveal thickness and final RE. RESULTS: The differences in predicted and final RE between groups were not statistically significant between groups when both SRK/T and Holladay 1 formulas were used (P > 0.05). Regardless of the formula used, final RE was neither significantly hyperopic nor myopic as compared to the target. There was no difference in surgically induced astigmatism between the two groups. Increased preoperative central foveal thickness was correlated with greater difference between predicted and actual RE. No relationship was noted between change in central foveal thickness and RE. CONCLUSION: Combined phacovitrectomy for concurrent cataract epiretinal membrane by experienced cataract and vitreoretinal surgeons seems to deliver as predictable refractive results as cataract surgery alone. PMID- 29624545 TI - HIV Infection Is Not Associated With Aortic Stiffness. Traditional Cardiovascular Risk Factors Are the Main Determinants-Cross-sectional Results of INI-ELSA BRASIL. AB - INTRODUCTION: Aortic stiffness measured by carotid-femoral pulse wave velocity (cf-PWV) is a marker of subclinical atherosclerosis. We propose to assess whether HIV infection is associated with arterial stiffness and their determinants in HIV infected subjects. METHODS: We compared data from an HIV cohort (644 patients, HIV+) in Rio de Janeiro with 2 groups: 105 HIV-negative (HIV-) individuals and 14,873 participants of the ELSA-Brasil study. We used multivariable linear regression to investigate factors associated with cf-PWV and whether HIV was independently associated with aortic stiffness and propensity score weighting to control for imbalances between groups. RESULTS: From 15,860 participants, cf-PWV was obtained in 15,622 (98.5%). Median age was 51 (interquartile range 45-58), 44.41 (35.73, 54.72), and 43.60 (36.01, 50.79) years (P < 0.001), and median cf PWV (m/s; interquartile range) was 9.0 (8.10, 10.20), 8.70 (7.90, 10.20), and 8.48 (7.66, 9.40) for ELSA-Brasil, HIV- and HIV+, respectively (P < 0.001). In the final weighted multivariable models, HIV group was not associated with cf-PWV when compared either with ELSA-Brasil [beta = -0.05; 95% confidence interval (CI) = -0.23; P = 0.12; P = 0.52] or with the HIV- groups (beta = 0.10; 95% CI = 0.10; 0, 31; P = 0.32). Traditional risk factors were associated with higher cf PWV levels in the HIV+ group, particularly waist-to-hip ratio (beta = 0.20; 95% CI = 0.10; 0.30; P < 0.001, result per one SD change). CONCLUSIONS: HIV infection was not associated with higher aortic stiffness according to our study. In HIV infected subjects, the stiffness of large arteries is mainly associated with traditional risk factors and not to the HIV infection per se. PMID- 29624546 TI - Missing the Boat? Appreciating the Importance of the Pathophysiology of Perianal Crohn's Disease in Guiding Biological and Surgical Therapy. PMID- 29624547 TI - Expert Commentary on Prevention, Diagnosis, and Treatment of Complications of the IPAA for Ulcerative Colitis. PMID- 29624548 TI - Disparities in Colon Cancer Survival by Insurance Type: A Population-Based Analysis. AB - BACKGROUND: Colon cancer is a common cancer with a relatively high survival for nonmetastatic disease if appropriate treatment is given. A lower survival rate for patients with no or inadequate insurance has previously been documented, but the differences have not been explored in detail on a population level. OBJECTIVE: The purpose of this study was to examine survival for patients with colon cancer by insurance type. DESIGN: Complete analysis was used to examine 1-, 2-, and 3-year survival rates. SETTINGS: This was a population-level analysis. PATIENTS: Patients were drawn from the in-patients diagnosed with colon cancer at ages 15 to 64 years between 2007 and 2012 in the Surveillance, Epidemiology, and End Results 18 database by insurance type (Medicaid, uninsured, or other insurance) MAIN OUTCOME MEASURE:: This study measured overall survival. RESULTS: A total of 57,790 cases were included, with insurance information available for 55,432. Of those, 7611 (13.7%), 4131 (7.5%), and 43,690 (78.8%) had Medicaid, no insurance, or other insurance. Patients with Medicaid or without insurance were more likely to have metastatic disease compared with those with other insurance. Survival was higher for patients with insurance other than Medicaid, with 3-year survival estimates of 57.0%, 61.2%, and 75.6% for Medicaid, uninsured, and other insurance. Significant disparities continued to be observed after adjustment for stage, especially for later-stage disease. When only patients with stage I to II disease who had definitive surgery and resection of >=12 lymph nodes were included in the analysis, the discrepancy was decreased, especially for uninsured patients. LIMITATIONS: Information on chemotherapy use and biological markers of disease severity are not available in the database. CONCLUSIONS: Colon cancer survival is lower for patients with no insurance or with Medicaid than for those with private insurance. Differences in rates of definitive surgery and adequate lymph node dissection explain some of this disparity. See Video Abstract at http://links.lww.com/DCR/A585. PMID- 29624549 TI - Phase II Clinical Trial to Evaluate the Efficacy of Transanal Endoscopic Total Mesorectal Excision for Rectal Cancer. AB - BACKGROUND: Total mesorectal excision has become the standard treatment for rectal cancer, and several investigators have shown that a transanal approach is a feasible option. OBJECTIVE: This study aimed to evaluate the efficacy of transanal endoscopic total mesorectal excision in patients with rectal cancer. DESIGN: This study was a prospective, single-arm phase II trial. It was registered on clinicaltrials.gov under identifier NCT02406118. SETTINGS: Inpatients at a hospital specializing in oncology were selected. PATIENTS: This prospective study enrolled 49 patients with rectal cancer located 3 to 12 cm from the anal verge who were scheduled to undergo radical surgery. INTERVENTIONS: Laparoscopy-assisted transanal total mesorectal excision was performed. MAIN OUTCOME MEASURES: The primary end point was total mesorectal excision quality and circumferential resection margin. Secondary end points included the number of harvested lymph nodes, operation time, and 30-day postoperative complications. RESULTS: From March 2015 to April 2016, 32 men and 17 women with rectal cancer were enrolled. The mean age was 61.2 years, and mean BMI was 23.3 kg/m. The mean operating time was 158 minutes, and the mean estimated blood loss was 89.3 mL. There were no intraoperative complications and no conversions to open surgery. Successful treatment based on total mesorectal excision quality and circumferential resection margin was achieved in 45 patients (91.8%). Fifteen patients (30.6%) had 30-day postoperative complications, including 7 (14.3%) with anastomotic dehiscence, 5 (10.2%) with urinary retention, 2 (4.1%) with abdominal wound complications, and 1 (2.0%) with ileus. There was no postoperative mortality. LIMITATIONS: This was a noncomparative single-arm trial conducted at a single institution. CONCLUSIONS: Transanal endoscopic total mesorectal excision showed acceptable results based on perioperative and short-term oncologic outcomes. Further investigations are necessary to show the benefits and long-term outcomes of this procedure. See Video Abstract at http://links.lww.com/DCR/A563. PMID- 29624550 TI - Urgent Pelvic Exenteration: Should the Indication Be Extended? AB - BACKGROUND: Pelvic exenteration carries significant risks of morbidity and mortality. Preoperative management is therefore crucial, and the exenteration procedure is usually performed in an elective setting. In cases of rectal cancer, however, tumor-related complications may cause a patient's condition to deteriorate rapidly, despite optimal management. Urgent pelvic exenteration then may be an option for these patients. OBJECTIVE: This study aims to compare the outcomes of pelvic exenteration between the urgent and elective settings. DESIGN: This is a retrospective study. SETTING: This study was conducted at King Chulalongkorn Memorial Hospital between February 2006 and June 2012. PATIENTS: Fifty-three patients with locally advanced rectal cancer were included. INTERVENTION: All patients underwent pelvic exenteration for locally advanced rectal cancer. They were assigned to urgent and elective setting groups according to their preoperative conditions. The urgent setting group included patients who required urgent pelvic exenteration because of intestinal obstruction, bowel perforation, bleeding, or uncontrolled sepsis, despite optimal management preoperatively. MAIN OUTCOME MEASURES: Twenty-six patients were classified in the urgent setting group, and 27 were classified in the elective setting group. Three year overall and disease-free survivals were compared between the 2 groups. Thirty-day postoperative morbidity and mortality were also studied. RESULTS: Three-year overall survival was 62.2% and 54.4% in the elective and urgent groups (p = 0.7), whereas three-year disease-free survival was 43% and 63.8% (p = 0.33). The median follow-up time was 33 months. Thirty-day morbidity did not differ between the 2 groups (p = 0.49). A low serum albumin level was a significant risk factor for complications. There was no postoperative mortality in this study. LIMITATIONS: This was a retrospective study performed at 1 institution, and it lacked quality-of-life scores. CONCLUSION: Pelvic exenteration in an urgent setting is feasible and could offer acceptable outcomes. See Video Abstract at http://links.lww.com/DCR/A591. PMID- 29624551 TI - Three-Dimensional Modeling for Crohn's Fistula-in-Ano: A Novel, Interactive Approach. AB - BACKGROUND: Pelvic MRI allows for clear delineation of anatomy in Crohn's fistula in-ano, although its interpretation is often difficult for nonradiologists. OBJECTIVE: The aim was to develop a 3-dimensional model where fistula tracts and their relationship to the sphincter complex can be accurately defined, which can then be rotated in multiple axes by the surgeon. DESIGN: A 3-dimensional model was created based on MRI images. An additional 3-dimensional T2-weighted sequence was added to the existing MRI protocol to obtain high-resolution images. Segmentation of the fistula tract and volume rendering of the segmented tract were performed to create the final model. SETTINGS: This was a single-center study conducted in Victoria, Australia. PATIENTS: All of the patients who had pelvic MRI for fistulating Crohn's disease between March 2016 and March 2017 had the additional MRI sequence. INTERVENTIONS: Postprocessing of MRI images was performed by a single radiologist. RESULTS: Total acquisition time for MRI images was extended to 31 minutes compared with the standard 2-dimensional protocol lasting 25 minutes. Additional postprocessing time used to create the model was ~15 minutes. Two clinical vignettes using this model are presented and compared with conventional 2-dimensional MRI images to highlight the use of the 3 dimensional modeling technique. LIMITATIONS: This technique involves a semiautomatic process of fistula tract segmentation that requires radiologist expertise and additional postprocessing time. CONCLUSIONS: This 3-dimensional modeling technique enables accurate identification of tracts in Crohn's fistula in-ano and improves spatial orientation for the surgeon. The model has the potential to be an invaluable preoperative tool to guide operative decision making, as well as enabling the assessment of response to medical or surgical therapy. PMID- 29624552 TI - Adjuvant Chemotherapy After Preoperative Chemoradiation Improves Survival in Patients With Locally Advanced Rectal Cancer. PMID- 29624553 TI - Does Adjuvant Chemotherapy After Preoperative Chemoradiation Improve Overall Survival in Patients With Rectal Cancer? PMID- 29624555 TI - Corrigendum. PMID- 29624554 TI - Response to Letter to the Editor. PMID- 29624556 TI - Erratum. PMID- 29624558 TI - A Phase 1 Pharmacokinetic and Safety Study of Extended-Duration, High-dose Cefixime for Cephalosporin-resistant Neisseria gonorrhoeae in the Pharynx. AB - BACKGROUND: There are no fully oral recommended treatment regimens for gonorrhea. Inadequately treated pharyngeal gonococcal infections are a likely reservoir for transmission and development of antimicrobial resistance. We sought to determine an oral cefixime dosing regimen that would theoretically treat pharyngeal infections by gonococci with minimum inhibitory concentrations 0.5 MUg/mL. METHODS: We conducted an open-label, nonrandomized, phase I pharmacokinetic and safety study of cefixime in 25 healthy male and female volunteers divided into 4 dosing cohorts (cohort A, 400 mg; cohort B, 800 mg; cohort C, 1200 mg; and cohort D, 800 mg every 8 hours * 3 doses [total dose 2400 mg]) with a target serum concentration of at least 2.0 MUg/mL for more than 20 hours. Cefixime concentrations from serum and pharyngeal fluid were determined with use of a validated liquid chromatography-tandem mass spectrometry assay. Safety measures included laboratories, physical examinations, and symptom diaries. RESULTS: None of the single-dose regimens attained the target concentration; however, 50% of subjects in cohort D attained the target concentration. Variation in absorption and protein binding contributed to differences in concentrations. Pharyngeal fluid concentrations were negligible. The single-dose regimens were well tolerated; the multidose regimen resulted in mild to moderate gastrointestinal symptoms in 43% of subjects. CONCLUSIONS: None of the dosing regimens achieved the target concentration. However, the proposed theoretical target was extrapolated from penicillin data; there are no empirically derived pharmacokinetic/pharmacodynamic criteria for pharyngeal gonorrhea. Under alternative cephalosporin-specific therapeutic goals, the multidose regimen may be effective, although the absence of cefixime in pharyngeal fluid is concerning. A clinical trial evaluating efficacy and defining pharmacokinetic/pharmacodynamic outcomes may be warranted. PMID- 29624561 TI - Recent Changes in Prevention Funding to Areas With High Racial and Ethnic Disparities in Sexually Transmitted Disease Rates. AB - We examined changes in federal sexually transmitted disease funding allocations to areas with high racial/ethnic disparities in sexually transmitted diseases after the implementation of a funding formula in 2014. The funding formula increased prevention funding allocations to areas with high relative racial/ethnic disparities. Results were mixed for areas with high absolute disparities. PMID- 29624560 TI - Sexual behaviors of HIV-infected pregnant women and factors associated with sexual transmitted infection in South Africa. AB - BACKGROUND: Sexual behaviors in HIV-infected pregnant women in South Africa are not well understood. METHODS: HIV-infected pregnant women were recruited into a prospective cohort at first antenatal care visit. Sociodemographic information and self-collected vulvovaginal swab samples were collected from participants. Vulvovaginal swab samples were tested for Chlamydia trachomatis (CT), Neisseria gonorrhoea (NG) and Trichomonas vaginalis (TV) using GeneXpert(r). We investigated sexual behaviors, alcohol use and factors associated with condomless sex during pregnancy and prevalent sexually transmitted infection (STI) among our cohort. We report descriptive, univariate and multivariable logistic regression results of sexual behaviors and alcohol use, factors associated with condomless sex at last sex, and having any STI during pregnancy adjusting for a priori confounders. RESULTS: We recruited and enrolled 430 HIV-infected pregnant women. Median age was 30-years; median gestational age was 20-weeks. 89% of women reported sex during pregnancy. At last sex, 68% reported condomless sex; 18% reported having >1 sex partner in the past 12-months. Adjusting for age, income and relationship status, condom use at last sex was associated with prior knowledge of HIV status (aOR=2.46;95%CI=1.54-3.92) and being in a concordant HIV positive (aOR=3.17;95%CI=1.84-5.50), or serodiscordant relationship (aOR=6.50;95%CI=3.59-11.80). The prevalence of any STI was 41% (95%CI=36%-45%). Adjusting for mothers' age and employment, odds of having a STI increased if the woman reported alcohol use during pregnancy (aOR=1.96;95%CI=1.06-3.64) or if the father of the child was a non-cohabiting or casual partner (aOR=1.42;95%CI=0.97 2.03). CONCLUSION: Almost all HIV-infected pregnant women were sexually active during pregnancy and most women reported condomless sex at last sex. Condom use was associated with knowledge of serostatus and/or partner's serostatus before first ANC visit. Factors associated with having a STIs included: alcohol use during pregnancy and father of child being a non-cohabiting partner. PMID- 29624562 TI - Congenital Syphilis Prevention: Strategies, Evidence, and Future Directions. AB - BACKGROUND: Congenital syphilis (CS)-the preventable transmission of Treponema pallidum from infected mother to fetus-remains a significant problem worldwide. METHODS: From July through November 2017, 239 articles relevant to CS prevention were identified via keyword searches in PubMed and Google Scholar, ancestry searches, and expert recommendation. Articles were then assessed for (1) measurement of a specified CS or adverse pregnancy outcomes (APOs) and (2) geographic setting in high/upper middle income countries according to United Nations criteria. In total, 119 articles met inclusion criteria. These were then vetted for 1 of 3 arms of CS prevention, after which additional ancestral searches were conducted within each arm to arrive at the final collection of articles per CS prevention strategy-maternal prenatal treatment (n = 33), prenatal screening (n = 24), and public health interventions that support screening and treatment (n = 15). RESULTS: Of the 7 studies that evaluated treatment with benzathine penicillin G (BPG) use within the context of a modern health care system, all showed BPG to be highly effective in CS prevention; 3 additional studies demonstrated BPG effectiveness in preventing APOs. Ten studies revealed early disease detection through prenatal screening significantly reduces CS and APOs when paired with BPG. There was limited literature evaluating public health interventions, such as partner notification, surveillance, and prenatal screening laws. CONCLUSIONS: Congenital syphilis is a preventable disease, effectively avoided with appropriate prenatal screening and BPG therapy. Increasing syphilis rates among all adults, accompanied by gaps in the provision of prenatal care to women at high risk of infection, are major contributors to CS persistence. PMID- 29624563 TI - Different Faces of Neurosyphilis. PMID- 29624564 TI - Syphilitic Alopecia. PMID- 29624566 TI - JOEM 2017 Reviewers - Thank You and Perspectives. PMID- 29624565 TI - The Impact of a Novel Structured Health Intervention for Truckers (SHIFT) on Physical Activity and Cardiometabolic Risk Factors. AB - OBJECTIVE: The aim of this study was to examine the effects of implementing a lifestyle health behavior intervention on cardiovascular risk markers in a sample of lorry drivers. METHODS: Fifty-seven males participated in the pre-post evaluation of a multicomponent 12-week intervention. RESULTS: Favorable changes in several cardiovascular health indicators were observed, including fasting blood glucose (-0.6 mmol/L), LDL-Cholesterol (-0.7 mmol/L), total cholesterol ( 0.7 mmol/L), waist-hip ratio (-0.10), and waist circumference (-2.5 cm) (P < 0.01). The proportion of participants with a more than 10% risk of a cardiovascular event in the next 10 years was reduced by 12% (P < 0.05). A 21%, 12%, and 7.5% reduction in drivers with pre-diabetes (P < 0.001), undiagnosed diabetes (P < 0.05), and the metabolic syndrome (P < 0.05), respectively, was observed. CONCLUSION: This study highlights the feasibility of implementing a multicomponent health intervention within the transport setting and provides preliminary evidence of its beneficial effects on some markers of health. PMID- 29624567 TI - Clinical Value of Dorsal Medulla Oblongata Involvement Detected with Conventional MRI for Prediction of Outcome in Children with Enterovirus 71-related Brainstem Encephalitis. AB - BACKGROUND: Brainstem encephalitis is the most common neurologic complication after enterovirus 71 infection. The involvement of brainstem, especially the dorsal medulla oblongata, can cause severe sequelae or death in children with enterovirus 71 infection. We aimed to determine the prevalence of dorsal medulla oblongata involvement in children with enterovirus 71-related brainstem encephalitis (EBE) by using conventional MRI and to evaluate the value of dorsal medulla oblongata involvement in outcome prediction. METHODS: 46 children with EBE were enrolled in the study. All subjects underwent a 1.5 Tesla MR examination of the brain. The disease distribution and clinical data were collected. Dichotomized outcomes (good versus poor) at longer than 6 months were available for 28 patients. Logistic regression was used to determine whether the MRI confirmed dorsal medulla oblongata involvement resulted in improved clinical outcome prediction when compared with other location involvement. RESULTS: Of the 46 patients, 35 had MRI evidence of dorsal medulla oblongata involvement, 32 had pons involvement, 10 had midbrain involvement, and 7 had dentate nuclei involvement. Patients with dorsal medulla oblongata involvement or multiple area involvement were significantly more often in the poor outcome group than in the good outcome group. Logistic regression analysis showed that dorsal medulla oblongata involvement was the most significant single variable in outcome prediction (predictive accuracy, 90.5%), followed by multiple area involvement, age, and initial glasgow coma scale score. CONCLUSIONS: Dorsal medulla oblongata involvement on conventional MRI correlated significantly with poor outcomes in EBE children, improved outcome prediction when compared with other clinical and disease location variables, and was most predictive when combined with multiple area involvement, glasgow coma scale score and age. PMID- 29624568 TI - Resveratrol Attenuates Lipopolysaccharides (LPS)-Induced Inhibition of Osteoblast Differentiation in MC3T3-E1 Cells. AB - BACKGROUND LPS-inhibited osteoblastic differentiation plays an important role in the pathogenesis of osteomyelitis. Thus, searching for drugs that affect LPS mediated osteoblastic differentiation may be crucial in developing therapies for osteomyelitis. The purpose of this study was to investigate the role and mechanisms of resveratrol, a natural polyphenol present in red wine, on LPS inhibited osteoblastic differentiation. MATERIAL AND METHODS Cell viability was measured by MMT assay. Mitochondrial ATP levels, membrane potential, and superoxide production were measured to evaluate the effects of LPS and resveratrol on mitochondrial functions in osteoblast-like MC3T3-E1 cells. Osteoblast-related genes, including ALP, OCN, OPN, and RUNX2, were measured by ELISA analysis and RT-PCR in differentiated osteoblast cells treated with LPS and resveratrol. Cellular Sirt1 and PCG-1alpha levels were measured by Western blot to probe the impact of resveratrol treatment in LPS-stimulated MC3T3-E1 osteoblasts. RESULTS The results showed that LPS caused significant mitochondrial dysfunctions of MC3T3-E1 cells in a dose-dependent manner, which were attenuated by resveratrol. Furthermore, LPS markedly decreased the expression of ALP, OCN, OPN, and RUNX2 in MC3T3-E1 cells cultivated in osteoblast differentiation medium, suggesting that LPS inhibited the osteoblastic differentiation of MC3T3-E1 cells. However, resveratrol obviously alleviated the suppressive impact of LPS on osteoblast differentiation. In addition, resveratrol increased expression of Sirt1 and PGC-1alpha in MC3T3-E1 cells treated with LPS. CONCLUSIONS Taken together, these results show that resveratrol alleviated the suppression of LPS on osteoblast differentiation by improving, at least in part, mitochondrial function. PMID- 29624569 TI - Are probiotics effective in preventing urinary tract infection? AB - INTRODUCTION: Urinary tract infection is the most common bacterial infection and recurrences are common. Probiotics have been proposed as an alternative to decrease this risk. However, it is not clear if they are really effective. METHODS: To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified six systematic reviews including nine studies overall, of which seven were randomized trials. We concluded it is not clear whether probiotics decrease the risk of symptomatic urinary tract infection, because the certainty of the evidence is very low. PMID- 29624570 TI - Are diuretics effective for Meniere's disease? AB - INTRODUCTION: Meniere's disease is an inner ear disorder characterized by episodes of spontaneous vertigo, fluctuating hearing loss and tinnitus. Diuretics have been widely used for the treatment of attacks, but there is controversy about their effectiveness. METHODS: To answer this question we used Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. RESULTS AND CONCLUSIONS: We identified three systematic reviews including nineteen studies overall, of which four were randomized trials. We concluded it is not clear whether diuretics lead to a symptomatic improvement of vertigo or an objective decrease in hearing loss in patients with Meniere's disease, because the certainty of the evidence is very low. PMID- 29624571 TI - Frequency and characteristics of gallbladder cancer at a referral hospital in southern Peru, 2009-2014: a descriptive study. AB - INTRODUCTION: Gallbladder cancer is a rare neoplasm, its frequency is variable in the regions of Peru. OBJECTIVE: To determine the frequency and describe the clinical characteristics of gallbladder cancer in southern Peru. METHODS: The reports of the anatomopathological department of the Honorio Delgado Regional Hospital were selected from all samples of cholecystectomies performed between 2009 and 2014 and those that had some result compatible with gallbladder cancer were looked for. Subsequently, the clinical histories were searched to obtain the characteristics of these patients. RESULTS: Of 2991 cholecystectomies, 75 (2.5%) had gall bladder cancer. The most frequent symptom in both groups was pain (96.7%), followed by nausea (87.5%) and vomiting (65.0%). The majority of patients were women (83.3%) older than 60 years (65.0%). The most frequent histological type was the adenocarcinoma (80.0%). CONCLUSION: The frequency of gallbladder cancer in a reference hospital in southern Peru is 2.51%, higher than that reported in other studies in the central and northern regions of Peru. PMID- 29624572 TI - Maternal body mass index and risk of intraventricular hemorrhage in preterm infants. AB - BackgroundIntraventricular hemorrhage (IVH) and pre-pregnancy obesity and underweight have been linked to inflammatory states. We hypothesize that IVH in preterm infants is associated with pre-pregnancy obesity and underweight due to an inflammatory intrauterine environment.MethodsPopulation-based study of infants born between 22 and 32 weeks' gestation from 2007 to 2011. Data were extracted from vital statistics and the California Perinatal Quality Care Collaborative. Results were examined for all cases (any IVH) and for severe IVH.ResultsAmong 20,927 infants, 4,818 (23%) had any IVH and 1,514 (7%) had severe IVH. After adjustment for confounders, there was an increased risk of IVH associated with pre-pregnancy obesity, relative risk 1.14 (95% confidence interval (CI) 1.06, 1.32) for any IVH, and 1.25 (85% CI 1.10, 1.42) for severe IVH. The direct effect of pre-pregnancy obesity on any IVH was significant (P<0.001) after controlling for antenatal inflammation-related conditions, but was not significant after controlling for gestational age (P=0.56).ConclusionPre-pregnancy obesity was found to be a risk factor for IVH in preterm infants; however, this relationship appeared to be largely mediated through the effect of BMI on gestational age at delivery. The etiology of IVH is complex and it is important to understand the contributing maternal factors. PMID- 29624573 TI - Emotion computing using Word Mover's Distance features based on Ren_CECps. AB - In this paper, we propose an emotion separated method(SeTF.IDF) to assign the emotion labels of sentences with different values, which has a better visual effect compared with the values represented by TF.IDF in the visualization of a multi-label Chinese emotional corpus Ren_CECps. Inspired by the enormous improvement of the visualization map propelled by the changed distances among the sentences, we being the first group utilizes the Word Mover's Distance(WMD) algorithm as a way of feature representation in Chinese text emotion classification. Our experiments show that both in 80% for training, 20% for testing and 50% for training, 50% for testing experiments of Ren_CECps, WMD features get the best f1 scores and have a greater increase compared with the same dimension feature vectors obtained by dimension reduction TF.IDF method. Compared experiments in English corpus also show the efficiency of WMD features in the cross-language field. PMID- 29624574 TI - Need for speed: An optimized gridding approach for spatially explicit disease simulations. AB - Numerical models for simulating outbreaks of infectious diseases are powerful tools for informing surveillance and control strategy decisions. However, large scale spatially explicit models can be limited by the amount of computational resources they require, which poses a problem when multiple scenarios need to be explored to provide policy recommendations. We introduce an easily implemented method that can reduce computation time in a standard Susceptible-Exposed Infectious-Removed (SEIR) model without introducing any further approximations or truncations. It is based on a hierarchical infection process that operates on entire groups of spatially related nodes (cells in a grid) in order to efficiently filter out large volumes of susceptible nodes that would otherwise have required expensive calculations. After the filtering of the cells, only a subset of the nodes that were originally at risk are then evaluated for actual infection. The increase in efficiency is sensitive to the exact configuration of the grid, and we describe a simple method to find an estimate of the optimal configuration of a given landscape as well as a method to partition the landscape into a grid configuration. To investigate its efficiency, we compare the introduced methods to other algorithms and evaluate computation time, focusing on simulated outbreaks of foot-and-mouth disease (FMD) on the farm population of the USA, the UK and Sweden, as well as on three randomly generated populations with varying degree of clustering. The introduced method provided up to 500 times faster calculations than pairwise computation, and consistently performed as well or better than other available methods. This enables large scale, spatially explicit simulations such as for the entire continental USA without sacrificing realism or predictive power. PMID- 29624575 TI - Montelukast for bronchiolitis obliterans syndrome after lung transplantation: A randomized controlled trial. AB - Bronchiolitis obliterans syndrome (BOS) remains the major problem which precludes long-term survival after lung transplantation. Previously, an open label pilot study from our group demonstrated a possible beneficial effect of montelukast in progressive BOS patients with low airway neutrophilia (<15%), and already on azithromycin treatment, in whom the further decline in pulmonary function was attenuated. This was, however, a non-randomized and non-placebo controlled trial. The study design is a single center, prospective, interventional, randomized, double blind, placebo-controlled trial, with a two arm parallel group design and an allocation ratio of 1:1. Randomization to additional montelukast (10 mg/day, n = 15) or placebo (n = 15) was performed from 2010 to 2014 at the University Hospitals Leuven (Leuven, Belgium) in all consecutive patients with late-onset (>2years posttransplant) BOS >=1. Primary end-point was freedom from graft loss 1 year after randomization; secondary end-points were acute rejection, lymphocytic bronchiolitis, respiratory infection rate; and change in FEV1, airway and systemic inflammation during the study period. Graft loss at 1 y and 2y was similar in both groups (respectively p = 0. 981 and p = 0.230). Montelukast had no effect on lung function decline in the overall cohort. However, in a post-hoc subanalysis of BOS stage 1 patients, montelukast attenuated further decline of FEV1 during the study period, both in absolute (L) (p = 0.008) and % predicted value (p = 0.0180). A linear mixed model confirmed this association. Acute rejection, lymphocytic bronchiolitis, respiratory infections, systemic and airway inflammation were comparable between groups over the study period. This randomized controlled trial showed no additional survival benefit with montelukast compared to placebo, although the study was underpowered. The administration of montelukast was associated with an attenuation of the rate of FEV1 decline, however, only in recipients with late-onset BOS stage 1. PMID- 29624576 TI - Quantification of pathogenic Leptospira in the soils of a Brazilian urban slum. AB - BACKGROUND: Leptospirosis is an important zoonotic disease that causes considerable morbidity and mortality globally, primarily in residents of urban slums. While contact with contaminated water plays a critical role in the transmission of leptospirosis, little is known about the distribution and abundance of pathogenic Leptospira spp. in soil and the potential contribution of this source to human infection. METHODS/PRINCIPAL FINDINGS: We collected soil samples (n = 70) from three sites within an urban slum community endemic for leptospirosis in Salvador, Brazil. Using qPCR of Leptospira genes lipl32 and 16S rRNA, we quantified the pathogenic Leptospira load in each soil sample. lipl32 qPCR detected pathogenic Leptospira in 22 (31%) of 70 samples, though the median concentration among positive samples was low (median = 6 GEq/g; range: 4-4.31*102 GEq/g). We also observed heterogeneity in the distribution of pathogenic Leptospira at the fine spatial scale. However, when using 16S rRNA qPCR, we detected a higher proportion of Leptospira-positive samples (86%) and higher bacterial concentrations (median: 4.16*102 GEq/g; range: 4-2.58*104 GEq/g). Sequencing of the qPCR amplicons and qPCR analysis with all type Leptospira species revealed that the 16S rRNA qPCR detected not only pathogenic Leptospira but also intermediate species, although both methods excluded saprophytic Leptospira. No significant associations were identified between the presence of pathogenic Leptospira DNA and environmental characteristics (vegetation, rat activity, distance to an open sewer or a house, or soil clay content), though samples with higher soil moisture content showed higher prevalences. CONCLUSION/SIGNIFICANCE: This is the first study to successfully quantify the burden of pathogenic Leptospira in soil from an endemic region. Our results support the hypothesis that soil may be an under-recognized environmental reservoir contributing to transmission of pathogenic Leptospira in urban slums. Consequently, the role of soil should be considered when planning interventions aimed to reduce the burden of leptospirosis in these communities. PMID- 29624577 TI - A decade of the World Register of Marine Species - General insights and experiences from the Data Management Team: Where are we, what have we learned and how can we continue? AB - The World Register of Marine Species (WoRMS) celebrated its 10th anniversary in 2017. WoRMS is a unique database: there is no comparable global database for marine species, which is driven by a large, global expert community, is supported by a Data Management Team and can rely on a permanent host institute, dedicated to keeping WoRMS online. Over the past ten years, the content of WoRMS has grown steadily, and the system currently contains more than 242,000 accepted marine species. WoRMS has not yet reached completeness: approximately 2,000 newly described species per year are added, and editors also enter the remaining missing older names-both accepted and unaccepted-an effort amounting to approximately 20,000 taxon name additions per year. WoRMS is used extensively, through different channels, indicating that it is recognized as a high-quality database on marine species information. It is updated on a daily basis by its Editorial Board, which currently consists of 490 taxonomic and thematic experts located around the world. Owing to its unique qualities, WoRMS has become a partner in many large-scale initiatives including OBIS, LifeWatch and the Catalogue of Life, where it is recognized as a high-quality and reliable source of information for marine taxonomy. PMID- 29624578 TI - Semantic representation in the white matter pathway. AB - Object conceptual processing has been localized to distributed cortical regions that represent specific attributes. A challenging question is how object semantic space is formed. We tested a novel framework of representing semantic space in the pattern of white matter (WM) connections by extending the representational similarity analysis (RSA) to structural lesion pattern and behavioral data in 80 brain-damaged patients. For each WM connection, a neural representational dissimilarity matrix (RDM) was computed by first building machine-learning models with the voxel-wise WM lesion patterns as features to predict naming performance of a particular item and then computing the correlation between the predicted naming score and the actual naming score of another item in the testing patients. This correlation was used to build the neural RDM based on the assumption that if the connection pattern contains certain aspects of information shared by the naming processes of these two items, models trained with one item should also predict naming accuracy of the other. Correlating the neural RDM with various cognitive RDMs revealed that neural patterns in several WM connections that connect left occipital/middle temporal regions and anterior temporal regions associated with the object semantic space. Such associations were not attributable to modality-specific attributes (shape, manipulation, color, and motion), to peripheral picture-naming processes (picture visual similarity, phonological similarity), to broad semantic categories, or to the properties of the cortical regions that they connected, which tended to represent multiple modality-specific attributes. That is, the semantic space could be represented through WM connection patterns across cortical regions representing modality specific attributes. PMID- 29624579 TI - Seagrass on the brink: Decline of threatened seagrass Posidonia australis continues following protection. AB - Seagrasses are in decline globally due to sustained pressure from coastal development, water quality declines and the ongoing threat from climate change. The result of this decline has been a change in coastal productivity, a reduction in critical fisheries habitat and increased erosion. Attempts to slow this decline have included legislative protection of habitat and direct restoration efforts. Monitoring the success of these approaches requires tracking changes in the abundance of seagrasses, but such monitoring is frequently conducted at either too coarse a spatial scale, or too infrequently to adequately detect changes within individual meadows. Here, we used high resolution aerial imagery to quantify the change in meadows dominated by Posidonia australis over five years at 14 sites in five estuaries in south-eastern Australia. Australia has some of the world's most diverse and extensive seagrass meadows, but the widely distributed P. australis has a slow growth rate, recovers poorly after disturbance, and suffers runaway attrition if the conditions for recovery are not met. In 2010, after declines of 12-57% between the 1940s and 1980s, P. australis was listed as a threatened ecological community in New South Wales. We quantified changes in area at fine spatial scales and, where loss was observed, describe the general patterns of temporal decline within each meadow. Our results demonstrate that seagrass meadows dominated by P. australis underwent declines of ~ 2-40% total area at 11 out of 14 study sites between 2009 and 2014. In the iconic Sydney Harbour, our analyses suggest that P. australis meadows are declining at an average rate greater than 10% yr-1, exceeding the global rate of seagrass decline. Highlighting these alarming declines across the study region should serve as means to prioritise management action and review the effectiveness of legislative listing as a method to limit impacts at an ecosystem level. PMID- 29624580 TI - Estimating the response and economic burden of rheumatoid arthritis patients treated with biologic disease-modifying antirheumatic drugs in Taiwan using the National Health Insurance Research Database (NHIRD). AB - BACKGROUND: Previous studies in Taiwan utilizing the Taiwan's National Health Insurance Database (NHIRD) have estimated the direct healthcare costs of RA patients, but they have not focused on patients on bDMARDs, or considered patients' response to therapy. OBJECTIVES: The objective of this study was to estimate the rate of inadequate response for patients newly treated with biologic disease-modifying antirheumatic drugs (bDMARDs) as well as their costs and resource use. METHODS: Data were from the catastrophic illness file within the NHIRD from 1/1/2009 to 12/31/2013. Patients with RA, which was categorized by the presence of a catastrophic illness card, that were previously bDMARD-naive, were included in this study if they initiated their first bDMARD during the index period. The index period included all of 2010, a pre-index period consisting of the index date- 365 days, and a follow-up period including the index date to 365 days post-index, were also included. Previously biologically-naive patients were indexed into the study on the date of their first claim for a bDMARD. A validated algorithm was used to examine the rate of inadequate response (IR) in the biologically-naive cohort of patients. Inadequate responders met one or more of the following criteria during their year of follow-up: low adherence (proportion of days covered <0.80); switched to or added a second bDMARD; added a new conventional synthetic DMARD (csDMARD); received >=1 glucocorticoid injection; or increased oral glucocorticoid dosing. All-cause mean annual direct costs and resource use were measured in the year of follow-up. Costs were converted from NT$ to USD using 1 NT$ = 0.033 USD. RESULTS: A total of 818 patients with RA initiated their first bDMARD (54% etanercept and 46% adalimumab) in 2010. After one year of follow-up, 32% (n = 258) were classified as stable, 66% (n = 540) had an IR, and 2% (n = 20) were lost to follow-up. During the follow-up period mean annual total direct costs were $16,136 for stable patients compared to $14,154 for patients with IR. Mean annual non-medication direct costs were $937 for stable patients and $1,574 for patients with IR. Mean annual hospitalizations were higher for patients with IR (0.46) compared to stable patients (0.10) during the one year follow-up period. CONCLUSIONS: The majority of patients that were previously naive to bDMARDs had an IR to their first bDMARD during the year of follow-up. Patients with an IR had numerically increased all-cause resource utilization and non-medication costs during the follow-up period compared to patients with stable disease. This level of IR suggests an unmet need in the RA treatment paradigm. PMID- 29624581 TI - Efficacy of Aedes aegypti control by indoor Ultra Low Volume (ULV) insecticide spraying in Iquitos, Peru. AB - BACKGROUND: Aedes aegypti is a primary vector of dengue, chikungunya, Zika, and urban yellow fever viruses. Indoor, ultra low volume (ULV) space spraying with pyrethroid insecticides is the main approach used for Ae. aegypti emergency control in many countries. Given the widespread use of this method, the lack of large-scale experiments or detailed evaluations of municipal spray programs is problematic. METHODOLOGY/PRINCIPAL FINDINGS: Two experimental evaluations of non residual, indoor ULV pyrethroid spraying were conducted in Iquitos, Peru. In each, a central sprayed sector was surrounded by an unsprayed buffer sector. In 2013, spray and buffer sectors included 398 and 765 houses, respectively. Spraying reduced the mean number of adults captured per house by ~83 percent relative to the pre-spray baseline survey. In the 2014 experiment, sprayed and buffer sectors included 1,117 and 1,049 houses, respectively. Here, the sprayed sector's number of adults per house was reduced ~64 percent relative to baseline. Parity surveys in the sprayed sector during the 2014 spray period indicated an increase in the proportion of very young females. We also evaluated impacts of a 2014 citywide spray program by the local Ministry of Health, which reduced adult populations by ~60 percent. In all cases, adult densities returned to near baseline levels within one month. CONCLUSIONS/SIGNIFICANCE: Our results demonstrate that densities of adult Ae. aegypti can be reduced by experimental and municipal spraying programs. The finding that adult densities return to approximately pre-spray densities in less than a month is similar to results from previous, smaller scale experiments. Our results demonstrate that ULV spraying is best viewed as having a short-term entomological effect. The epidemiological impact of ULV spraying will need evaluation in future trials that measure capacity of insecticide spraying to reduce human infection or disease. PMID- 29624582 TI - Geospatial-temporal distribution of Tegumentary Leishmaniasis in Colombia (2007 2016). AB - BACKGROUND: Tegumentary Leishmaniasis (TL) is a neglected disease with worldwide distribution and considered a public health problem, especially in Latin America. In Colombia, the governmental epidemiological surveillance system (SIVIGILA) is responsible for collecting information on the presentation of cases of TL from each of the municipalities and departments. In absence of a study compiling and analyzing currently available metadata of TL in Colombia, this study describes the geospatial-temporal distribution of TL and identifies the regions of the country on which prevention measures should be established in order to control the disease. METHODOLOGY/PRINCIPAL FINDINGS: This is an exploratory descriptive analysis of the distribution of TL in Colombia. Information was collected on new cases of the disease during the years 2007-2016 from the Colombian reporting system (SIVIGILA). Incidence calculations were made based on population estimates by departments and biogeographical regions. Time evolution is shown in biennial maps. A 10-year series was analyzed, showing that the Amazon region is the most affected in terms of incidence, while the Andean region has the highest number of cases with a high variability among the departments that make it up. In those departments where there is a greater reported diversity of vector species, a large number of cases was observed. CONCLUSIONS/SIGNIFICANCE: Transmission dynamics of TL in Colombia in the past 10 years have been variable, with a greater concentration of cases in the central and southern departments. The present study contributes to improve the understanding of the patterns of distribution of TL in Colombia and can be a basis for future studies of impact evaluation of Health policies in the country and the region. PMID- 29624583 TI - The life cycle of a zoonotic parasite reassessed: Experimental infection of Melanoides tuberculata (Mollusca: Thiaridae) with Centrocestus formosanus (Trematoda: Heterophyidae). AB - Centrocestus formosanus is a foodborne intestinal trematode that is native to Asia and has been introduced into the Americas and Europe. Although there are several studies of C. formosanus in definitive vertebrate hosts (birds and mammals, including humans), and in intermediate vertebrate hosts (fish and amphibians), there is little published information regarding interaction with its transmitting mollusc. In this study we studied the miracidial development of C. formosanus using a mouse as a source of eggs. Adult parasites were maintained in water in order to develop miracidia in intrauterine eggs. Miracidia appeared at 12 days of incubation, with no hatching observed for up to 40 days. Subsequently, we placed dead C. formosanus containing eggs with miracidia individually in contact with 48 specimens of Melanoides tuberculata, and observed the absence of the parasites after 1h of exposure, suggesting that they were ingested by the snails. Of the 33 experimentally-infected snails that were alive after 84-89 days post-infection (DPI), seven (21%) shed cercariae. We detected young C. formosanus rediae in 21/33 (64%) M. tuberculata at 90 DPI. To our knowledge, this report is the first to show that, in the life cycle of C. formosanus, infection of molluscs occurs passively by ingestion of eggs, followed by a long intramolluscan phase. We compare these data with those described for other Heterophyidae, and discuss on the phylogenetic background of the pattern of miracidial development verified in these parasites. PMID- 29624584 TI - The impact of passive case detection on the transmission dynamics of gambiense Human African Trypanosomiasis. AB - Gambiense Human African Trypanosomiasis (HAT), or sleeping sickness, is a vector borne disease affecting largely rural populations in Western and Central Africa. The main method for detecting and treating cases of gambiense HAT are active screening through mobile teams and passive detection through self-referral of patients to dedicated treatment centres or hospitals. Strategies based on active case finding and treatment have drastically reduced the global incidence of the disease over recent decades. However, little is known about the coverage and transmission impact of passive case detection. We used a mathematical model to analyse data from the period between active screening sessions in hundreds of villages that were monitored as part of three HAT control projects run by Medecins Sans Frontieres in Southern Sudan and Uganda in the late 1990s and early 2000s. We found heterogeneity in incidence across villages, with a small minority of villages found to have much higher transmission rates and burdens than the majority. We further found that only a minority of prevalent cases in the first, haemo-lymphatic stage of the disease were detected passively (maximum likelihood estimate <30% in all three settings), whereas around 50% of patients in the second, meningo-encephalitic were detected. We estimated that passive case detection reduced transmission in affected areas by between 30 and 50%, suggesting that there is great potential value in improving rates of passive case detection. As gambiense HAT is driven towards elimination, it will be important to establish good systems of passive screening, and estimates such as the ones here will be of value in assessing the expected impact of moving from a primarily active to a more passive screening regime. PMID- 29624585 TI - Genome dynamics and evolution in yeasts: A long-term yeast-bacteria competition experiment. AB - There is an enormous genetic diversity evident in modern yeasts, but our understanding of the ecological basis of such diversifications in nature remains at best fragmented so far. Here we report a long-term experiment mimicking a primordial competitive environment, in which yeast and bacteria co-exist and compete against each other. Eighteen yeasts covering a wide phylogenetic background spanning approximately 250 million years of evolutionary history were used to establish independent evolution lines for at most 130 passages. Our collection of hundreds of modified strains generated through such a rare two species cross-kingdom competition experiment re-created the appearance of large scale genomic rearrangements and altered phenotypes important in the diversification history of yeasts. At the same time, the methodology employed in this evolutionary study would also be a non-gene-technological method of reprogramming yeast genomes and then selecting yeast strains with desired traits. Cross-kingdom competition may therefore be a method of significant value to generate industrially useful yeast strains with new metabolic traits. PMID- 29624586 TI - Hidden danger: Unexpected scenario in the vector-parasite dynamics of leishmaniases in the Brazil side of triple border (Argentina, Brazil and Paraguay). AB - Every year about 3 million tourists from around the world visit Brazil, Argentina and Paraguay's triple border region where the Iguacu Falls are located. Unfortunately, in recent years an increasing number of autochthonous canine and human visceral leishmaniasis (VL) cases have been reported. The parasite is Leishmania (Leishmania) infantum and it is transmitted by sand flies (Phlebotominae). To assess the risk factors favorable for the establishment and spread of potential vectors the Centers for Disease Control and Prevention light trap (CDC-light trap) collections were made in the Foz do Iguacu (FI) and Santa Terezinha de Itaipu (STI) townships and along two transects between them. Our study determined the Phlebotominae fauna, the factors that affect the presence and abundance of Lutzomyia longipalpis and Nyssomyia whitmani, the presence of L. infantum in different sand fly species and which Leishmania species are present in this region. Lutzomyia longipalpis was the prevalent species and its distribution was related to the abundance of dogs. Leishmania infantum was found in Lu. longipalpis, Ny. whitmani, Ny. neivai and a Lutzomyia sp. All the results are discussed within the Stockholm Paradigm and focus on their importance in the elaboration of public health policies in international border areas. This region has all the properties of stable VL endemic foci that can serve as a source of the disease for neighboring municipalities, states and countries. Most of the urban areas of tropical America are propitious for Lu. longipalpis establishment and have large dog populations. Pan American Health Organization's initiative in supporting the public health policies in the border areas of this study is crucial and laudable. However, if stakeholders do not act quickly in controlling VL in this region, the scenario will inevitable become worse. Moreover, L. (Viannia) braziliensis found in this study supports the need to develop public health policies to avoid the spread of cutaneous leishmaniasis. The consequences of socioeconomic attributes, boundaries and frontiers on the spread of diseases cannot be neglected. For an efficient control, it is essential that urban planning is articulated with the neighboring cities. PMID- 29624587 TI - Germanium as a scalable sacrificial layer for nanoscale protein patterning. AB - We demonstrate the use of germanium (Ge) films as water-soluble features that allow the patterning of proteins onto surfaces with commonly used organic solvents. This technique is scalable for manufacturing and is compatible with nano- and microfabrication processes, including standard lithography. We use Ge as a sacrificial layer to mask and protect areas of the substrate during surface functionalization. Since Ge dissolves in 0.35% hydrogen peroxide (H2O2) in water but not in organic solvents, Ge can be removed after patterning without significantly affecting protein activities. In this paper, we present examples of protein patterning with two different techniques. We show that 50 nm thick Ge layers can be completely removed in 10 min without residues and, importantly, nanoscale resolution and misalignment can be achieved with conventional photolithography equipment. Both biotin and streptavidin maintain ~80% and >50% activity after 10 min and 360 min incubation in 0.35% H2O2, respectively. Lastly, the process can be used to functionalize sidewalls with proteins, a capability of recent interest for cell-cell adhesion studies. PMID- 29624588 TI - Factors determining the social participation of older adults: A comparison between Japan and Korea using EASS 2012. AB - AIMS: Japan and Korea are the world's most aged and most rapidly aging nations. They both have low fertility rates, thereby intensifying the importance of social structures to aid a large, dependent population of older adults. Common strategies involve improving their social participation, which enhances their physical and mental health, so they are supporting society rather than being supported. Since the social participation rates in both countries are not as high as those of Western countries, it is critical to shed light on the factors related to social participation of the elderly. METHODS: A secondary analyses were performed using Japanese and Korean data from the 2012 East Asia Social Survey (EASS), which includes nationally representative samples through random sampling. The analyses only include data from those 65 and older (Japan: N = 683, Korea: N = 362). RESULTS: Social participation is classified into four types: 1) no affiliation; 2) inactive participation; 3) active recreational; and 4) active social. The Japanese respondents had a higher participation rate than Koreans, but more Japanese were inactive. Though the rates of active participations were similar in both countries. Multinomial logistic regressions were conducted to examine the related factors among the four types of social participation. Basic attributes (e.g., living alone) and other factors (e.g., network size) were included as independent variables. The results show that larger non-family networks were linked with increased social participation in both societies. Men were more vulnerable to engaging in no social activities and at a higher risk of social isolation in both countries. One difference between the two nations is that among the Japanese, people with higher social orientations engage in more active social type participation. CONCLUSION: This study reveals that non-kin social networks are important for social participation in Japan and Korea. PMID- 29624590 TI - Taxonomic revision of the long-nosed armadillos, Genus Dasypus Linnaeus, 1758 (Mammalia, Cingulata). AB - Dasypus is the most speciose genus of the order Cingulata, including approximately 40% of known living armadillos. Nine species are currently recognized, although comprehensive analyses of the entire genus have never been done. Our aim is to revise the taxonomy of the long-nosed armadillos and properly define the taxa. We examined 2126 specimens of Dasypus preserved in 39 different museum collections, including 17 type specimens. Three complementary methods were applied to explore morphological datasets both qualitatively and quantitatively. Qualitative morphological variation in discrete characters was assessed by direct observations of specimens. Linear morphometric variation was based on external data and cranial measurements of 887 adult skulls. The shape and size of the skull was abstracted through two-dimensional geometric morphometric analyses of dorsal, lateral and ventral views of respectively 421, 211, and 220 adult specimens. Our results converge on the recognition of eight living species (D. beniensis, D. kappleri, D. mazzai, D. novemcinctus, D. pastasae, D. pilosus, D. sabanicola, and D. septemcinctus), and three subspecies of D. septemcinctus (D. s. septemcinctus, D. s. hybridus, and a new subspecies from Cordoba described here). Information on type material, diagnosis, distribution, and taxonomic comments for each taxon are provided. We designate a lectotype for D. novemcinctus; and a neotype for Loricatus hybridus (= D. septemcinctus hybridus). PMID- 29624589 TI - Toll-like receptor 3 (TLR3) promotes the resolution of Chlamydia muridarum genital tract infection in congenic C57BL/6N mice. AB - Chlamydia trachomatis urogenital serovars primarily replicate in epithelial cells lining the reproductive tract. Epithelial cells recognize Chlamydia through cell surface and cytosolic receptors, and/or endosomal innate receptors such as Toll like receptors (TLRs). Activation of these receptors triggers both innate and adaptive immune mechanisms that are required for chlamydial clearance, but are also responsible for the immunopathology in the reproductive tract. We previously demonstrated that Chlamydia muridarum (Cm) induces IFN-beta in oviduct epithelial cells (OE) in a TLR3-dependent manner, and that the synthesis of several cytokines and chemokines are diminished in Cm-challenged OE derived from TLR3-/- 129S1 mice. Furthermore, our in vitro studies showed that Cm replication in TLR3 /- OE is more efficient than in wild-type OE. Because TLR3 modulates the release inflammatory mediators involved in host defense during Cm infection, we hypothesized that TLR3 plays a protective role against Cm-induced genital tract pathology in congenic C57BL/6N mice. Using the Cm mouse model for human Chlamydia genital tract infections, we demonstrated that TLR3-/- mice had increased Cm shedding during early and mid-stage genital infection. In early stage infection, TLR3-/- mice showed a diminished synthesis of IFN-beta, IL-1beta, and IL-6, but enhanced production of IL-10, TNF-alpha, and IFN-gamma. In mid-stage infection, TLR3-/- mice exhibited significantly enhanced lymphocytic endometritis and salpingitis than wild-type mice. These lymphocytes were predominantly scattered along the endometrial stroma and the associated smooth muscle, and the lamina propria supporting the oviducts. Surprisingly, our data show that CD4+ T-cells are significantly enhanced in the genital tract TLR3-/- mice during mid-stage Chlamydial infection. In late-stage infections, both mouse strains developed hydrosalpinx; however, the extent of hydrosalpinx was more severe in TLR3-/- mice. Together, these data suggest that TLR3 promotes the clearance of Cm during early and mid-stages of genital tract infection, and that loss of TLR3 is detrimental in the development hydrosalpinx. PMID- 29624591 TI - Optimal cut-off for neutrophil-to-lymphocyte ratio: Fact or Fantasy? A prospective cohort study in metastatic cancer patients. AB - This study assessed the prognostic value of pre-treatment neutrophil-to lymphocyte ratio (NLR) in patients with metastatic solid tumors. Clinical and biological data for patients with metastatic solid tumors treated in an oncology outpatient department and prospectively followed by a call center (PROCHE program) between January 2008 and December 2011 were analyzed. All patients with an NLR value within 28 days before the first cycle of first-line of chemotherapy were included (cohort 1). To assess influence of chemotherapy line on NLR prognostic value, data from patients treated with later chemotherapy lines were also analyzed (cohort 2). Adjusted multivariate Cox regressions with or without non-linear and time-dependent effects were performed. Optimal NLR cut-off was investigated by time-dependent sensitivity analysis using several indices. There were 317 and 134 patients in cohorts 1 and 2, respectively. Elevated NLR was associated with worse survival (hazard ratio [HR] for death, 1.35 [95% confidence interval 1.19-1.54]; p<0.0001). The optimal NLR cut-off in cohort 1 was dependent on index used and time of assessment: HR values were non-significant at a cut-off of 3.0 (1.34 [0.99-1.32], but significant when the cut-off was 4.0 (1.53 [1.11 2.10]). NLR was linearly related to mortality risk; in subgroup analysis, no significant interaction was found with co-variables or tumor localization overall (cohorts 1+2). Pre-treatment NLR is a useful prognostic tool in patients with metastatic solid tumors, irrespective of primary tumor site, chemotherapy line, age, gender and performance status. However, using an NLR cut-off value for clinical decision-making requires extreme caution. PMID- 29624593 TI - Work routines moderate the association between eveningness and poor psychological well-being. AB - : Well-being is a useful screening method for the detection of mood disorders. Evidence associating psychological well-being with sleep-wake patterns exists, as well as associations with sleep-wake patterns, work-related parameters, and perceived self-efficacy. Despite the growing research regarding the relationship between these factors and mental health, there are few studies that analyze them together. OBJECTIVE: To investigate if the association between sleep-wake patterns and psychological well-being is mediated or moderated by perceived self efficacy, work flexibility and work routines. MATERIAL AND METHODS: This cohort study was performed in southern Brazil. A sample of 987 individuals was analyzed (66.9% women; mean age = 43.9 years). Work routines parameters and work schedule flexibility were evaluated, most participants were farmers (46%) and most worked 7 days a week (69.1%). Munich Chronotype Questionnaire (MCTQ) was administered for evaluation of sleep-wake patterns, General Self-Efficacy Scale (GSE) for assessment the participants' beliefs about how they coped with daily hassles, and World Health Organization Five-item Well-being Index (WHO-5) for evaluation of psychological well-being levels. Moderation and mediation models were tested. RESULTS: The moderation model showed influences of work end time on the relationship between sleep onset time and psychological well-being (R2 = 0.147; F = 24.16; p<0.001). The final regression model showed an association of psychological well-being with sex (Beta = -0.086; p = 0.004), sleep onset time (Beta = -0.086; p = 0.006), and self-efficacy (Beta = 0.316; p<0.001); the work end time showed association in the interaction with sleep onset time (Beta = 0.075; p = 0.016). CONCLUSION: The findings support the direct association of psychological well-being with sleep-wake patterns and self-efficacy, and show an interaction between work routines and sleep-wake patterns. Our results draw attention to the importance of the interplay between individual and social rhythms in relation to psychological well-being. PMID- 29624592 TI - Anti-O-specific polysaccharide (OSP) immune responses following vaccination with oral cholera vaccine CVD 103-HgR correlate with protection against cholera after infection with wild-type Vibrio cholerae O1 El Tor Inaba in North American volunteers. AB - BACKGROUND: Cholera is an acute voluminous dehydrating diarrheal disease caused by toxigenic strains of Vibrio cholerae O1 and occasionally O139. A growing body of evidence indicates that immune responses targeting the O-specific polysaccharide (OSP) of V. cholerae are involved in mediating protection against cholera. We therefore assessed whether antibody responses against OSP occur after vaccination with live attenuated oral cholera vaccine CVD 103-HgR, and whether such responses correlate with protection against cholera. METHODOLOGY: We assessed adult North American volunteers (n = 46) who were vaccinated with 5 * 108 colony-forming units (CFU) of oral cholera vaccine CVD 103-HgR and then orally challenged with approximately 1 * 105 CFU of wild-type V. cholerae O1 El Tor Inaba strain N16961, either 10 or 90 days post-vaccination. PRINCIPAL FINDINGS: Vaccination was associated with induction of significant serum IgM and IgA anti-OSP and vibriocidal antibody responses within 10 days of vaccination. There was significant correlation between anti-OSP and vibriocidal antibody responses. IgM and IgA anti-OSP responses on day 10 following vaccination were associated with lower post-challenge stool volume (r = -0.44, P = 0.002; r = 0.36, P = 0.01; respectively), and none of 27 vaccinees who developed a >=1.5 fold increase in any antibody isotype targeting OSP on day 10 following vaccination compared to baseline developed moderate or severe cholera following experimental challenge, while 5 of 19 who did not develop such anti-OSP responses did (P = 0.01). CONCLUSION: Oral vaccination with live attenuated cholera vaccine CVD 103-HgR induces antibodies that target V. cholerae OSP, and these anti-OSP responses correlate with protection against diarrhea following experimental challenge with V. cholerae O1. TRIAL REGISTRATION: ClinicalTrials.gov NCT01895855. PMID- 29624594 TI - A systematic scoping review on the consequences of stress-related hyperglycaemia. AB - BACKGROUND: Stress-related hyperglycaemia (SHG) is commonly seen in acutely ill patients and has been associated with poor outcomes in many studies performed in different acute care settings. We aimed to review the available evidence describing the associations between SHG and different outcomes in acutely ill patients admitted to an ICU. Study designs, populations, and outcome measures used in observational studies were analysed. METHODS: We conducted a systematic scoping review of observational studies following the Joanna Briggs methodology. Medline, Embase, and the Cochrane Library were searched for publications between January 2000 and December 2015 that reported on SHG and mortality, infection rate, length of stay, time on ventilation, blood transfusions, renal replacement therapy, or acquired weakness. RESULTS: The search yielded 3,063 articles, of which 43 articles were included (totalling 536,476 patients). Overall, the identified studies were heterogeneous in study conduct, SHG definition, blood glucose measurements and monitoring, treatment protocol, and outcome reporting. The most frequently reported outcomes were mortality (38 studies), ICU and hospital length of stay (23 and 18 studies, respectively), and duration of mechanical ventilation (13 studies). The majority of these studies (40 studies) compared the reported outcomes in patients who experienced SHG with those who did not. Fourteen studies (35.9%) identified an association between hyperglycaemia and increased mortality (odds ratios ranging from 1.13 to 2.76). Five studies identified hyperglycaemia as an independent risk factor for increased infection rates, and one identified it as an independent predictor of increased ICU length of stay. DISCUSSION: SHG was consistently associated with poor outcomes. However, the wide divergences in the literature mandate standardisation of measuring and monitoring SHG and the creation of a consensus on SHG definition. A better comparability between practices will improve our knowledge on SHG consequences and management. PMID- 29624595 TI - Social determinants, their relationship with leprosy risk and temporal trends in a tri-border region in Latin America. AB - BACKGROUND: Brazil is the only country in Latin America that has adopted a national health system. This causes differences in access to health among Latin American countries and induces noticeable migration to Brazilian regions to seek healthcare. This phenomenon has led to difficulties in the control and elimination of diseases related to poverty, such as leprosy. The aim of this study was to evaluate social determinants and their relationship with the risk of leprosy, as well as to examine the temporal trend of its occurrence in a Brazilian municipality located on the tri-border area between Brazil, Paraguay and Argentina. METHODS: This ecological study investigated newly-diagnosed cases of leprosy between 2003 and 2015. Exploratory analysis of the data was performed through descriptive statistics. For spatial analysis, geocoding of the data was performed using spatial scan statistic techniques to obtain the Relative Risk (RR) for each census tract, with their respective 95% confidence intervals calculated. The Bivariate Moran I test, Ordinary Least Squares (OLS) and Geographically Weighted Regression (GWR) models were applied to analyze the spatial relationships of social determinants and leprosy risk. The temporal trend of the annual coefficient of new cases was obtained through the Prais-Winsten regression. A standard error of 5% was considered statistically significant (p < 0.05). RESULTS: Of the 840 new cases identified in the study, there was a predominance of females (n = 427, 50.8%), of white race/color (n = 685, 81.6%), age range 15 to 59 years (n = 624, 74.3%), and incomplete elementary education (n = 504, 60.0%). The results obtained from multivariate analysis revealed that the proportion of households with monthly nominal household income per capita greater than 1 minimum wage (beta = 0.025, p = 0.036) and people of brown race (beta = 0.101, p = 0.024) were statistically-significantly associated with risk of illness due to leprosy. These results also confirmed that social determinants and risk of leprosy were significantly spatially non-stationary. Regarding the temporal trend, a decrease of 4% (95% CI [-0.053, -0.033], p = 0.000) per year was observed in the rate of detection of new cases of leprosy. CONCLUSION: The social determinants income and race/color were associated with the risk of leprosy. The study's highlighting of these social determinants can contribute to the development of public policies directed toward the elimination of leprosy in the border region. PMID- 29624597 TI - Correction: Diabetes-related changes in the protein composition and the biomechanical properties of human retinal vascular basement membranes. AB - [This corrects the article DOI: 10.1371/journal.pone.0189857.]. PMID- 29624596 TI - Embodied pain in fibromyalgia: Disturbed somatorepresentations and increased plasticity of the body schema. AB - Fibromyalgia syndrome (FMS) is a highly prevalent, chronic musculoskeletal condition characterized by widespread pain and evoked pain at tender points. This study evaluated various aspects of body awareness in a sample of 14 women with FMS and 13 healthy controls, such as plasticity of the body schema, body esteem, and interoceptive awareness. To this end, the Rubber Hand Illusion (RHI), the Body Esteem Scale (BES), and the Body Perception Questionnaire (BPQ) were used, respectively. Consistent with increased plasticity of the body schema, FMS patients scored higher, with large or very large effect sizes, across all three domains evaluated in the RHI paradigm, namely proprioceptive drift and perceived ownership and motor control over the rubber hand. Scores on all items addressed by the BES were consistently lower among FMS subjects (2.52, SEM .19 vs 3.89, SEM .16, respectively, p < .01, Cohen's d = .38-.66). In the FMS sample, BES scores assigned to most painful regions also were lower than those assigned to the remaining body sites (1.58, SEM .19 vs 2.87, SEM .18, respectively, p < .01). Significantly higher scores (p < .01, Cohen's d = .51-.87) were found in the FMS sample across awareness (3.57 SEM .15 vs 1.87 SEM .11), stress response (3.76 SEM .11 vs 1.78 SEM .11), autonomic nervous system reactivity (2.59 SEM .17 vs 1.35 SEM .07), and stress style 2 (2.73 SEM .27 vs 1.13 SEM .04) subscales of the BPQ. Intensity of ongoing clinical pain was found to be strongly correlated with interoceptive awareness (r = .75, p = .002). The results suggest a disturbed embodiment in FMS, characterized by instability of the body schema, negatively biased cognitions regarding one's own body, and increased vigilance to internal bodily cues. These manifestations may be interpreted as related with the inability of incoming sensory inputs to adequately update negatively biased off line somatorepresentations stored as long-term memory. PMID- 29624600 TI - Spatial variations of soil respiration and temperature sensitivity along a steep slope of the semiarid Loess Plateau. AB - The spatial heterogeneity of soil respiration and its temperature sensitivity pose a great challenge to accurately estimate the carbon flux in global carbon cycling, which has primarily been researched in flatlands versus hillslope ecosystems. On an eroded slope (35 degrees ) of the semiarid Loess Plateau, soil respiration, soil moisture and soil temperature were measured in situ at upper and lower slope positions in triplicate from 2014 until 2016, and the soil biochemical and microbial properties were determined. The results showed that soil respiration was significantly greater (by 44.2%) at the lower slope position (2.6 MUmol m-2 s-1) than at the upper slope position, as were soil moisture, carbon, nitrogen fractions and root biomass. However, the temperature sensitivity was 13.2% greater at the upper slope position than at the lower slope position (P < 0.05). The soil fungal community changed from being Basidiomycota-dominant at the upper slope position to being Zygomycota-dominant at the lower slope position, corresponding with increased beta-D-glucosidase activity at the upper slope position than at the lower slope position. We concluded that soil respiration was enhanced by the greater soil moisture, root biomass, carbon and nitrogen contents at the lower slope position than at the upper slope position. Moreover, the increased soil respiration and decreased temperature sensitivity at the lower slope position were partially due to copiotrophs replacing oligotrophs. Such spatial variations along slopes must be properly accounted for when estimating the carbon budget and feedback of future climate change on hillslope ecosystems. PMID- 29624598 TI - High costs of infection: Alphavirus infection reduces digestive function and bone and feather growth in nestling house sparrows (Passer domesticus). AB - Increasingly, ecoimmunology studies aim to use relevant pathogen exposure to examine the impacts of infection on physiological processes in wild animals. Alphaviruses are arthropod-borne, single-stranded RNA (ssRNA) viruses ("arboviruses") responsible for millions of cases of human illnesses each year. Buggy Creek virus (BCRV) is a unique alphavirus that is transmitted by a cimicid insect, the swallow bug, and is amplified in two avian species: the house sparrow (Passer domesticus) and the cliff swallow (Petrochelidon pyrrhonota). BCRV, like many alphaviruses, exhibits age-dependent susceptibility where the young are most susceptible to developing disease and exhibit a high mortality rate. However, alphavirus disease etiology in nestling birds is unknown. In this study, we infected nestling house sparrows with Buggy Creek virus and measured virological, pathological, growth, and digestive parameters following infection. Buggy Creek virus caused severe encephalitis in all infected nestlings, and the peak viral concentration in brain tissue was over 34 times greater than any other tissue. Growth, tissue development, and digestive function were all significantly impaired during BCRV infection. However, based on histopathological analysis performed, this impairment does not appear to be the result of direct tissue damage by the virus, but likely caused by encephalitis and neuronal invasion and impairment of the central nervous system. This is the first study to examine the course of alphavirus diseases in nestling birds and these results will improve our understanding of age-dependent infections of alphaviruses in vertebrate hosts. PMID- 29624599 TI - A snapshot of gut microbiota of an adult urban population from Western region of India. AB - The human gut microbiome contributes to a broad range of biochemical and metabolic functions that directly or indirectly affect human physiology. Several recent studies have indicated that factors like age, geographical location, genetic makeup, and individual health status significantly influence the diversity, stability, and resilience of the gut microbiome. Of the mentioned factors, geographical location (and related dietary/socio-economic context) appears to explain a significant portion of microbiome variation observed in various previously conducted base-line studies on human gut microbiome. Given this context, we have undertaken a microbiome study with the objective of cataloguing the taxonomic diversity of gut microbiomes sampled from an urban cohort from Ahmedabad city in Western India. Computational analysis of microbiome sequence data corresponding to 160 stool samples (collected from 80 healthy individuals at two time-points, 60 days apart) has indicated a Prevotella dominated microbial community. Given that the typical diet of participants included carbohydrate and fibre-rich components (predominantly whole grains and legume-based preparations), results appear to validate the proposed correlation between diet/geography and microbiome composition. Comparative analysis of obtained gut microbiome profiles with previously published microbiome profiles from US, China, Finland, and Japan additionally reveals a distinct taxonomic and (inferred) functional niche for the sampled microbiomes. PMID- 29624601 TI - Sleep apnea detection by a cardiac resynchronization device integrated thoracic impedance sensor: A validation study against the gold standard polysomnography. AB - BACKGROUND: Sleep disordered breathing is a common but often undiagnosed comorbidity in heart failure patients. Cardiac implantable electronic devices used for cardiac resynchronization therapy (CRT) may detect sleep apnea by use of a transthoracic impedance sensor. Validation of the AP scan(r) algorithm (Boston Scientific(r)) was performed by using the diagnostic gold standard polysomnography (PSG). METHODS: Forty-one patients with impaired left ventricular ejection fraction, frequent right ventricular pacing due to atrioventricular block and heart failure symptoms despite optimal medical therapy underwent upgrading to biventricular pacing. Within one month after left ventricular lead implantation, sleep apnea was assessed by single-night PSG and AP scan(r) measurements. RESULTS: AP scan(r) measurements were valid in only 21 of 41 (51.2%) patients in the index night of the PSG. The PSG determined apnea-hypopnea index did not correlate statistically significant with the AP scan(r) measurements (r = 0.41, 95% confidence interval -0.05-0.72, p = 0.07). The degree of overestimation is displayed by using the Bland-Altman method: mean difference 12.4, standard deviation +/- 15.8, 95% confidence interval -43.3-18.6. CONCLUSIONS: In heart failure patients receiving CRT upgrading, the AP scan(r) algorithm may need further improvement before it can be recommended for sleep apnea detection. PMID- 29624603 TI - Factors associated with tuberculosis treatment delay in patients co-infected with HIV in a high prevalence area in Brazil. AB - BACKGROUND: Worldwide, about 11% of Tuberculosis (TB) cases occur in people living with HIV (PLHIV) and it is the leading cause of death in this population. An important step towards reducing the incidence and mortality of TB in PLHIV is to reduce the time from onset of symptoms to treatment. Factors related to TB treatment delay therefore need to be understood. METHODS: Using data from a prospective cohort study of patients diagnosed with TB at the National Institute of Infectious Disease, at the Oswaldo Cruz Foundation, Rio de Janeiro, Brazil we conducted a survival analysis to identify factors associated with patient and health care treatment delay. In our analysis we included patients who were co infected with TB and HIV (n = 201). Patients were followed during the course of their TB treatment and information regarding duration of symptoms, sociodemographics and clinical characteristics were collected at the baseline visit. RESULTS: The median time from onset of initial symptoms to prescription of TB treatment (total delay) was 82 days. From initiation of symptoms to first visit at INI clinic (patient delay), the median was 51 days. From first visit to initiation of treatment (health care delay) the median was 16 days. Illiteracy was associated with greater patient delay [Hazard Ratio (HR) = 2.25, CI 95% 1.29 3.94]. Having had a previous episode of TB (HR = 0.53, CI 95% 0.37-0.74) and being married (HR = 0.71, CI 95% 0.54-0.94) were inversely related to patient delay. Illiteracy was also associated with greater health care delay (HR = 2.83, CI 95% 1.25-5.47) in contrast to high viral load (HR = 0.37, CI 95% 0.24-0.54) and weight loss greater than 10% (HR = 0.54, CI 95% 0.37-0.8), both of which were inversely related to health care delay. CONCLUSIONS: This study highlights the existence of factors that lead to greater risk of delayed treatment of TB among patients co-infected with HIV and TB. These include factors that can be assessed through targeted interventions which have implications for improving treatment outcomes and, through reduced duration of infectiousness, reduce the incidence of TB in Brazil. PMID- 29624602 TI - Early intervention of tau pathology prevents behavioral changes in the rTg4510 mouse model of tauopathy. AB - Although tau pathology, behavioral deficits, and neuronal loss are observed in patients with tauopathies, the relationship between these endpoints has not been clearly established. Here we found that rTg4510 mice, which overexpress human mutant tau in the forebrain, develop progressive age-dependent increases in locomotor activity (LMA), which correlates with neurofibrillary tangle (NFT) pathology, hyperphosphorylated tau levels, and brain atrophy. To further clarify the relationship between these endpoints, we treated the rTg4510 mice with either doxycycline to reduce mutant tau expression or an O-GlcNAcase inhibitor Thiamet G, which has been shown to ameliorate tau pathology in animal models. We found that both doxycycline and Thiamet G treatments starting at 2 months of age prevented the progression of hyperactivity, slowed brain atrophy, and reduced brain hyperphosphorylated tau. In contrast, initiating doxycycline treatment at 4 months reduced neither brain hyperphosphorylated tau nor hyperactivity, further confirming the relationship between these measures. Collectively, our results demonstrate a unique behavioral phenotype in the rTg4510 mouse model of tauopathy that strongly correlates with disease progression, and that early interventions which reduce tau pathology ameliorate the progression of the locomotor dysfunction. These findings suggest that better understanding the relationship between locomotor deficits and tau pathology in the rTg4510 model may improve our understanding of the mechanisms underlying behavioral disturbances in patients with tauopathies. PMID- 29624604 TI - Acute myocardial infarction occurring while on chronic clopidogrel therapy ('clopidogrel failure') is associated with high incidence of clopidogrel poor responsiveness and stent thrombosis. AB - OBJECTIVES: The clinical significance of the laboratory-based phenomenon of clopidogrel hypo-responsiveness and platelet reactivity associated with acute myocardial infarction, despite chronic clopidogrel therapy, is largely unknown. We aimed to determine platelet reactivity and clinical and angiographic features in 29 consecutive patients sustaining an acute myocardial infarction despite chronic (>=1 month) clopidogrel therapy. METHODS: Platelet reactivity was determined on admission using conventional aggregometry. All patients underwent coronary angiography within 24 hours of admission. Patients were matched with clopidogrel-naive acute myocardial infarction patients. Clopidogrel-naive patients received a 600 mg clopidogrel loading dose and 75 mg/day thereafter. RESULTS: Of the 29 study patients, 19 (66%) presented with ST-elevation myocardial infarction, and in 25% the infarction was related to angiographically proved definite stent thrombosis. Two-thirds of these patients were poor responders to clopidogrel (adenosine diphosphate-induced platelet aggregation >50%) and dual antiplatelet poor responsiveness was found in 57% in the chronic clopidogrel therapy group. Compared with clopidogrel-naive patients, chronic clopidogrel therapy patients were more likely to demonstrate clopidogrel poor responsiveness (66% versus 38%, p = 0.02), to be diabetic (52% versus 33%, p = 0.1) and to have multi-vessel coronary disease (79% versus 55%, p = 0.03). CONCLUSIONS: Patients sustaining acute coronary syndrome despite chronic clopidogrel therapy are more likely to exhibit inadequate platelet inhibition with clopidogrel. PMID- 29624605 TI - Frequency of occurrence of HIV-1 dual infection in a Belgian MSM population. AB - INTRODUCTION: HIV-1 dual infection is a condition that results from infection with at least two HIV-1 variants from different sources. The scarceness of information on this condition is partly due to the fact that its detection is technically challenging. Using next-generation sequencing we defined the extent of HIV-1 dual infection in a cohort of men who have sex with men (MSM). MATERIAL & METHODS: Eighty-six MSM, diagnosed with HIV-1 subtype B infection between 2008 and 2013 were selected for next-generation sequencing of the HIV-1 envelope V3. Sequencing was performed on 2 plasma samples collected with an interval of > 6 months before the initiation of antiretroviral therapy. Maximum likelihood phylogenetic trees were inspected for dual infection, defined as the presence of two or more monophyletic clusters with >= 90% bootstrap support and a mean between-cluster genetic distance of >= 10%. To confirm dual infection, deep V3 sequencing of intermediate samples was performed as well as clonal sequencing of the HIV-1 protease-reverse transcriptase gene. RESULTS: Five of the 74 patients (6.8%) for whom deep sequencing was successful, showed clear evidence of dual infection. In 4 of them, the second strain was absent in the first sample but occurred in subsequent samples. This was highly suggestive for superinfection. In 3 patients both virus variants were of subtype B, in 2 patients at least one of the variants was a subtype B/non-B recombinant virus. CONCLUSIONS: Dual infection was confirmed in 6.8% of MSM diagnosed with HIV-1 in Belgium. This prevalence is probably an underestimation, because stringent criteria were used to classify viral variants as originating from a new infection event. PMID- 29624606 TI - Diel hysteresis between soil respiration and soil temperature in a biological soil crust covered desert ecosystem. AB - Soil respiration induced by biological soil crusts (BSCs) is an important process in the carbon (C) cycle in arid and semi-arid ecosystems, where vascular plants are restricted by the harsh environment, particularly the limited soil moisture. However, the interaction between temperature and soil respiration remains uncertain because of the number of factors that control soil respiration, including temperature and soil moisture, especially in BSC-dominated areas. In this study, the soil respiration in moss-dominated crusts and lichen-dominated crusts was continuously measured using an automated soil respiration system over a one-year period from November 2015 to October 2016 in the Shapotou region of the Tengger Desert, northern China. The results indicated that over daily cycles, the half-hourly soil respiration rates in both types of BSC-covered areas were commonly related to the soil temperature. The observed diel hysteresis between the half-hourly soil respiration rates and soil temperature in the BSC-covered areas was limited by nonlinearity loops with semielliptical shapes, and soil temperature often peaked later than the half-hourly soil respiration rates in the BSC-covered areas. The average lag times between the half-hourly soil respiration rates and soil temperature for both types of BSC-covered areas were two hours over the diel cycles, and they were negatively and linearly related to the volumetric soil water content. Our results highlight the diel hysteresis phenomenon that occurs between soil respiration rates and soil temperatures in BSC-covered areas and the negative response of this phenomenon to soil moisture, which may influence total C budget evaluations. Therefore, the interactive effects of soil temperature and moisture on soil respiration in BSC-covered areas should be considered in global carbon cycle models of desert ecosystems. PMID- 29624607 TI - Shedding light on eDNA: neither natural levels of UV radiation nor the presence of a filter feeder affect eDNA-based detection of aquatic organisms. AB - The use of environmental DNA (eDNA) as a species detection tool is attracting attention from both scientific and applied fields, especially for detecting invasive or rare species. In order to use eDNA as an efficient and reliable tool, however, we need to understand its origin and state as well as factors affecting its degradation. Various biotic and abiotic environmental factors have been proposed to affect degradation of eDNA in aquatic environments and thus to influence detection rates of species. Here, we were interested in two of them, namely UV light, which can break down DNA, and the presence of filter feeders, which can remove DNA and DNA-bound particles. A few, mostly laboratory-based studies have found minor effects of UVB on the degradation of eDNA. Ultraviolet A radiation (UVA), however, has been neglected although it also causes DNA lesions and is 10- to 100-fold more prevalent than UVB when reaching the earth's surface. Filter feeders are common in aquatic ecosystem, but their effects on eDNA has hitherto been ignored. We conducted a full-factorial aquatic mesocosm experiment under near-natural outdoor conditions manipulating UV radiation as well as the presence of Dreissena polymorpha, a strong filter feeder capable of filtering cells or organelles containing DNA. Surprisingly, we found that neither UV radiation nor the presence of the filter feeder affected eDNA-based detection rates of macroinvertebrates, even though the experiment took place in summer when UV radiation intensity and filtration activity is high for the chosen experimental site and conditions. These results, in combination with studies from marine or laboratory settings finding no effect of sunlight and its UV components on the detectability of eDNA, suggest that eDNA based species assessments could be relatively robust with respect to our two factors studied. PMID- 29624608 TI - Intramembranous bone formation after callus distraction is augmented by increasing axial compressive strain. AB - The mechanical environment is a primary factor in the success of distraction osteogenesis. It is known that the interfragmentary movement during the distraction and maturation phase effects the callus formation. In addition to cyclic compression, other movements like shear and bending influence the bone formation process as shown in previous callus distraction studies. Reports of cartilage presence and endochondral ossification in the regenerative zone have been associated with a lack of fixation stability and delayed healing. So far the effects of the direction of interfragmentary movements could not be studied separately. By means of a unique lateral callus distraction model, we investigated the effects of small (0.1 mm) and moderate (0.6 mm), purely axial compression on ossification during callus maturation in sheep. A distraction device incorporating a mobile titanium plate was mounted on the tibia. Following lateral callus distraction, electromechanically controlled movements allowed purely axial cyclic compression of the tissue regenerate. Seven weeks post operatively, the tissue regenerates were investigated using MUCT, histology and immunohistochemistry. The larger amplitude significantly increased bone formation (Fractional bone volume: 19.4% vs. 5.2%, p = 0.03; trabecular thickness: 0.1 mm vs. 0.06 mm, p = 0.006; mean spicule height: 2.6 mm vs. 1.1 mm, p = 0.02) however, no endochondral ossification occurred. The elimination of shear movement, unimpaired neovascularization as well as the tensile strain stimuli during the distraction phase suppressing chondrogenic differentiation may all contribute to the absence of cartilage. In clinical application of distraction osteogenesis, moderate axial interfragmentary movement augments intramembranous ossification provided shear strain is minimized. PMID- 29624609 TI - Integrated approach for identifying and evaluating the quality of Marsdenia tenacissima in the medicine market. AB - The accurate identification and quality evaluation of herbal medical plants is highly necessary to ensure their safety and efficacy. In present study, a new strategy combining DNA barcoding techniques with thin-layer chromatography (TLC) and high-performance liquid chromatography (HPLC) was proposed to facilitate the identification and quality control of M. tenacissima. In present work, the internal transcribed spacer 2 (ITS2) barcode was successfully used to identify 58 M. tenacissima samples and its adulterants. TLC successfully identified the other three M. tenacissima samples that failed to produce ITS2 regions. An adulterant was found in all the 62 samples. Moreover, the content of active medicinal ingredients is important for herbal plants quality. The content of tenacissoside H (TS-H) of M. tenacissima samples was determined by HPLC to range from 0.39% to 1.09%, which meets the criterion of the Chinese Pharmacopoeia. Thus, DNA barcoding coupled with TLC and HPLC is very promising to identify and evaluate the quality of M. tenacissima in the medicine market. PMID- 29624610 TI - Chemically defined, ultrasoft PDMS elastomers with selectable elasticity for mechanobiology. AB - Living animal cells are strongly influenced by the mechanical properties of their environment. To model physiological conditions ultrasoft cell culture substrates, in some instances with elasticity (Young's modulus) of only 1 kPa, are mandatory. Due to their long shelf life PDMS-based elastomers are a popular choice. However, uncertainty about additives in commercial formulations and difficulties to reach very soft materials limit their use. Here, we produced silicone elastomers from few, chemically defined and commercially available substances. Elastomers exhibited elasticities in the range from 1 kPa to 55 kPa. In detail, a high molecular weight (155 kg/mol), vinyl-terminated linear silicone was crosslinked with a multifunctional (f = 51) crosslinker (a copolymer of dimethyl siloxane and hydrosilane) by a platinum catalyst. The following different strategies towards ultrasoft materials were explored: sparse crosslinking, swelling with inert silicone polymers, and, finally, deliberate introduction of dangling ends into the network (inhibition). Rheological experiments with very low frequencies led to precise viscoelastic characterizations. All strategies enabled tuning of stiffness with the lowest stiffness of ~1 kPa reached by inhibition. This system was also most practical to use. Biocompatibility of materials was tested using primary cortical neurons from rats. Even after several days of cultivation no adverse effects were found. PMID- 29624611 TI - Urinary type IV collagen excretion is involved in the decline in estimated glomerular filtration rate in the Japanese general population without diabetes: A 5-year observational study. AB - Urinary type IV collagen (U-Col4) and albumin excretion is evaluated to monitor the development of diabetic kidney disease. However, U-Col4 excretion in the general population without diabetes has not yet been fully elucidated. In this study, 1067 participants without diabetes and with urinary albumin-creatinine ratio <300 mg/gCr (normo- or microalbuminuria) who underwent an annual health examination in 2004 were enrolled and observed for 5 years. They were divided according to the amount of U-Col4 or urinary albumin excreted. The decline in estimated glomerular filtration rate (eGFR) was calculated. In participants with eGFR >=80 mL/min, abnormal U-Col4 excretion was indicated as a significant independent risk factor for 10% eGFR change per year, which is one of the prognostic factors for the development of end-stage kidney disease. Moreover, in contrast to urinary albumin excretion, U-Col4 excretion was not related to age or kidney function, suggesting that some individuals with abnormal U-Col4 excretion can have an independent hidden risk for the development of kidney dysfunction. In conclusion, it is important to measure U-Col4 excretion in the general population without diabetes to determine changes in renal features in every individual and help detect future complications such as diabetic kidney disease. If U-Col4 excretion is abnormal, kidney manifestation should be carefully followed up, even if the kidney function and urinalysis findings are normal. PMID- 29624612 TI - Childhood traumas as a risk factor for HIV-risk behaviours amongst young women and men living in urban informal settlements in South Africa: A cross-sectional study. AB - : Childhood traumas, in the form of physical, sexual, and emotional abuse and neglect, are globally widespread and highly prevalent, and associated with a range of subsequent poor health outcomes. This study sought to understand the relationship between physical, sexual and emotional childhood abuse and subsequent HIV-risk behaviours amongst young people (18-30) living in urban informal settlements in Durban, South Africa. Data came from self-completed questionnaires amongst 680 women and 677 men comprising the baseline of the Stepping Stones and Creating Futures intervention trial. Men and women were analysed separately. Logistic regression models assessed the relationship between six HIV-risk behaviours and four measures of trauma: the form of trauma, the severity of each trauma, the range of traumas, and overall severity of childhood trauma. Childhood traumas were incredibly prevalent in this population. All childhood traumas were associated with a range of HIV-risk behaviours. This was for the ever/never trauma, as well as the severity of each type of trauma, the range of trauma, and overall severity of childhood trauma. Despite the wider harsh contexts of urban informal settlements, childhood traumas still play a significant role in shaping subsequent HIV-risk behaviours amongst young people. Interventions to reduce childhood traumas for populations in informal settlements need to be developed. In addition, trauma focused therapies need to be considered as part of wider HIV-prevention interventions for young adults. TRIAL REGISTRATION: ClinicalTrials.gov NCT03022370. PMID- 29624613 TI - Quantifying differences in water and carbon cycling between paddy and rainfed rice (Oryza sativa L.) by flux partitioning. AB - Agricultural crops play an important role in the global carbon and water cycle. Global climate change scenarios predict enhanced water scarcity and altered precipitation pattern in many parts of the world. Hence, a mechanistic understanding of water fluxes, productivity and water use efficiency of cultivated crops is of major importance, i.e. to adapt management practices. We compared water and carbon fluxes of paddy and rainfed rice by canopy scale gas exchange measurements, crop growth, daily evapotranspiration, transpiration and carbon flux modeling. Throughout a monsoon rice growing season, soil evaporation in paddy rice contributed strongly to evapotranspiration (96.6% to 43.3% from initial growth to fully developed canopy and amounted to 57.9% of total water losses over the growing seasons. Evaporation of rainfed rice was significantly lower (by 65% on average) particularly before canopy closure. Water use efficiency (WUE) was significantly higher in rainfed rice both from an agronomic (WUEagro, i.e. grain yield per evapotranspiration) and ecosystem (WUEeco, i.e. gross primary production per evapotranspiration) perspective. However, our results also show that higher WUE in rainfed rice comes at the expense of higher respiration losses compared to paddy rice (26% higher on average). Hence, suggestions on water management depend on the regional water availability (i.e. Mediterranean vs. Monsoon climate) and the balance between higher respiratory losses versus a potential reduction in CH4 and other greenhouse gas emissions. Our results suggest that a shift from rainfed/unsaturated soil to waterlogged paddy conditions after closure of the rice canopy might be a good compromise towards a sustainable use of water while preserving grain yield, particularly for water-limited production areas. PMID- 29624614 TI - Rapid regeneration offsets losses from warming-induced tree mortality in an aspen dominated broad-leaved forest in northern China. AB - Worldwide tree mortality as induced by climate change presents a challenge to forest managers. To successfully manage vulnerable forests requires the capacity of regeneration to compensate for losses from tree mortality. We observed rapid regeneration and the growth release of young trees after warming-induced mortality in a David aspen-dominated (Populus davidiana) broad-leaved forest in Inner Mongolia, China, as based on individual tree measurements taken in 2012 and 2015 from a 6-ha permanent plot. Warming and drought stress killed large trees 10 15 m tall with a total number of 2881 trees during 2011-2012, and also thinned the upper crowns. David aspen recruitment increased 2 times during 2012-2015 and resulted in a high transition probability of David aspen replacing the same or other species, whereas the recruitment of Mongolian oak (Quercus mongolica) was much lower: it decreased from 2012 to 2015, indicating that rapid regeneration represented a regrowth phase for David aspen, and not succession to Mongolian oak. Further, we found that the recruitment density increased with canopy openness, thus implying that warming-induced mortality enhanced regeneration. Our results suggest that David aspen has a high regrowth ability to offset individual losses from warming-induced mortality. This important insight has implications for managing this vulnerable forest in the semi-arid region of northern China. PMID- 29624615 TI - Efficacy and synergy of live-attenuated and inactivated influenza vaccines in young chickens. AB - Outbreaks of novel highly pathogenic avian influenza viruses have been reported in poultry species in the United States since 2014. These outbreaks have proven the limitations of biosecurity control programs, and new tools are needed to reinforce the current avian influenza control arsenal. Some enzootic countries have implemented inactivated influenza vaccine (IIV) in their control programs, but there are serious concerns that a long-term use of IIV without eradication may result in the selection of novel antigenically divergent strains. A broadly protective vaccine is needed, such as live-attenuated influenza vaccine (LAIV). We showed in our previous studies that pc4-LAIV (a variant that encodes a C terminally truncated NS1 protein) can provide significant protection against heterologous challenge virus in chickens vaccinated at 2-4 weeks of age through upregulation of innate and adaptive immune responses. The current study was conducted to compare the performances of pc4-LAIV and IIV in young chickens vaccinated at 1 day of age. A single dose of pc4-LAIV was able to induce stronger innate and mucosal IgA responses and protect young immunologically immature chickens better than a single dose of IIV. Most importantly, when 1-day-old chickens were intranasally primed with pc4-LAIV and subcutaneously boosted with IIV three weeks later, they showed a rapid, robust, and highly cross-reactive serum antibody response and a high level of mucosal IgA antibody response. This vaccination regimen warrants further optimization to increase its range of protection. PMID- 29624616 TI - Sequence, genome organization, annotation and proteomics of the thermophilic, 47.7-kb Geobacillus stearothermophilus bacteriophage TP-84 and its classification in the new Tp84virus genus. AB - Bacteriophage TP-84 is a well-characterized bacteriophage of historical interest. It is a member of the Siphoviridae, and infects a number of thermophilic Geobacillus (Bacillus) stearothermophilus strains. Its' 47.7-kbp double-stranded DNA genome revealed the presence of 81 coding sequences (CDSs) coding for polypeptides of 4 kDa or larger. Interestingly, all CDSs are oriented in the same direction, pointing to a dominant transcription direction of one DNA strand. Based on a homology search, a hypothetical function could be assigned to 31 CDSs. No RNA or DNA polymerase-coding genes were found on the bacteriophage genome indicating that TP-84 relies on the host's transcriptional and replication enzymes. The TP84 genome is tightly packed with CDSs, typically spaced by several to-tens of bp or often overlapping. The genome contains five putative promoter like sequences showing similarity to the host promoter consensus sequence and allowing for a 2-bp mismatch. In addition, ten putative rho-independent terminators were detected. Because the genome sequence shows essentially no similarity to any previously characterised bacteriophage, TP-84 should be considered a new species in an undefined genus within the Siphoviridae family. Thus a taxonomic proposal of a new Tp84virus genus has been accepted by the International Committee on Taxonomy of Viruses. The bioinformatics genome analysis was verified by confirmation of 33 TP-84 proteins, which included: a) cloning of a selected CDS in Escherichia coli, coding for a DNA single-stranded binding protein (SSB; gene TP84_63), b) purification and functional assays of the recombinant TP-84 SSB, which has been shown to improve PCR reactions, c) mass spectrometric (MS) analysis of TP-84 bacteriophage capsid proteins, d) purification of TP-84 endolysin activity, e) MS analysis of the host cells from infection time course. PMID- 29624617 TI - Reference values for hand grip strength in the South Korean population. AB - OBJECTIVE: To establish reference values for hand grip strength (HGS) in a healthy Korean population and to identify the dependent anthropometric variables that affect HGS. METHODS: Based on the sixth Korea National Health and Nutrition Examination Survey from 2014 to 2015, we analyzed the HGS data of 7,969 South Koreans. Individuals with specific chronic diseases and who reported poor subjective health status were excluded to ensure a healthy population sample. Means with standard deviations (SDs) and 95% confidence intervals were calculated for each 5-year interval starting from 10 years of age. To determine the relationship between HGS and anthropometric variables, we performed correlation analyses between HGS and height, weight, and body mass index (BMI). Additionally, based on these findings, the cut-off value for low HGS was presented by deriving 2SD values of healthy young adults as recommended by the European Working Group on Sarcopenia in Older People. RESULTS: The mean age and BMI of men and women were 38.3 and 38.2 years and 23.8 and 22.4 kg/m2, respectively. Mean HGS of the dominant hand in men and women was 39.5 and 24.2 kg, respectively. The peak in HGS was at 35-39 years of age, after which HGS decreased in both sexes. HGS was significantly correlated with height, weight, and BMI. The cut-off values for weak HGS were < 28.9 and < 16.8 kg in men and women, respectively. CONCLUSION: These results provide useful reference values to assess HGS in patients who undergo hand surgery or who have various diseases that affect HGS. Moreover, a cut-off value for low HGS may help in defining sarcopenia among the Korean population. PMID- 29624618 TI - Invasive infection caused by Klebsiella pneumoniae is a disease affecting patients with high comorbidity and associated with high long-term mortality. AB - Klebsiella pneumoniae (KP) is after Escherichia coli (EC) the most common gram negative species causing invasive infections. Herein, we analyzed risk factors and prognosis in invasive infections caused by KP versus EC, in an area with low antimicrobial resistance. Moreover, we compared antimicrobial resistance and relative prevalence of KP and EC (KP/EC-ratio) in different European countries, using EARS-Net data. Adult patients admitted to Karolinska University Hospital 2006-2012 with invasive infection caused by KP (n = 599) were matched regarding sex and age with patients infected by EC. The medical records were retrospectively reviewed. Comorbidity was adjusted for with multivariable analysis. European data were retrieved from the EARS-Net database. No differences were observed in 7- and 30-day mortality between the groups. The 90-day mortality was significantly higher in the KP cohort (26% versus 17%, p<0.001), but not after adjusting for comorbidity. Malignancy was seen in 53% of the patients with KP versus 38% with EC, OR 1.86 (1.34-2.58). A significant increase in the rate of ESBL-production was observed in EC, but not in KP. The KP/EC-ratio remained stable. In contrast, European data showed increasing percentages of isolates non susceptible to third-generation cephalosporins in EC and KP, and increasing KP/EC ratio. Invasive infection caused by KP is a disease affecting patients with high comorbidity and associated with high 90-d mortality. The stable KP/EC-ratio and low occurrence of antimicrobial resistance in data from Karolinska University Hospital compared to aggregate data from 20 EARS-Net countries could be related to absence of clonal spread of multidrug-resistant KP. PMID- 29624619 TI - Time estimation and beta segregation: An EEG study and graph theoretical approach. AB - Elucidation of the neural correlates of time perception constitutes an important research topic in cognitive neuroscience. The focus to date has been on durations in the millisecond to seconds range, but here we used electroencephalography (EEG) to examine brain functional connectivity during much longer durations (i.e., 15 min). For this purpose, we conducted an initial exploratory experiment followed by a confirmatory experiment. Our results showed that those participants who overestimated time exhibited lower activity of beta (18-30 Hz) at several electrode sites. Furthermore, graph theoretical analysis indicated significant differences in the beta range (15-30 Hz) between those that overestimated and underestimated time. Participants who underestimated time showed higher clustering coefficient compared to those that overestimated time. We discuss our results in terms of two aspects. FFT results, as a linear approach, are discussed within localized/dedicated models (i.e., scalar timing model). Second, non localized properties of psychological interval timing (as emphasized by intrinsic models) are addressed and discussed based on results derived from graph theory. Results suggested that although beta amplitude in central regions (related to activity of BG-thalamocortical pathway as a dedicated module) is important in relation to timing mechanisms, the properties of functional activity of brain networks; such as the segregation of beta network, are also crucial for time perception. These results may suggest subjective time may be created by vector units instead of scalar ticks. PMID- 29624620 TI - Clinical risk factors of extracorporeal membrane oxygenation support in older adults. AB - BACKGROUND: The ageing population and the expected increase in the number of elderly patients make an evidence-based assessment of Extracorporeal Membrane Oxygenation (ECMO) therapy in old patients progressively more important. Veno arterial (VA) ECMO results for patient aged <65 years is well known. However, the risk profile and in-hospital prognosis of advanced age patients with ECMO still need more investigation. The aim of this study was to identify risk factors that predicted the outcomes for elderly patients who received VA-ECMO. METHODS: In this retrospective study, medical records for patients with ECMO aged 65 years and over were collected between 2009 and 2012 at a tertiary hospital. RESULTS: A total of 99 patients (mean age: 76.4+/-6.4 years) were included. The most common condition requiring VA-ECMO support was cardiogenic shock. Among survivors on VA ECMO, 28 (28.3%) patients were successfully weaned from support. Thirteen (13.1%) patients were successfully discharged. We found that cardiogenic shock (OR = 3.158, P = 0.013), acute physiology and chronic health evaluation II (APACHE II) score (OR = 1.147, P<0.001), and simplified acute physiology score II (SAPS II) score (OR = 1.054, P = 0.001) were risk factors associated with survival on VA ECMO. By using the areas under the receiver operating characteristic (AUC) curve, the APACHE II score and SAPS II score displayed acceptable discriminative power (AUC 0.722; 0.715, respectively). CONCLUSION: Our findings indicate that the risk of mortality increases with cardiogenic shock, higher APACHE II score, and higher SAPS II score. These risk factors can be utilized as potential predictors to identify the potential candidates for ECMO support. PMID- 29624621 TI - Hormonal and neuromuscular responses during a singles match in male professional tennis players. AB - We sought to measure the response of cortisol concentrations around a professional tennis match and its association with hydration status and neuromuscular performance. Nine professional male tennis players were tested in a rest day, and 2-week after, during the first match of a professional tournament played in a clay-court. Salivary concentrations of cortisol (SalCC) were measured in a resting day (9:00 am and 8:00 pm), at the match day (9:00 am and 8:00 pm) and immediately before and after the match. Hydration status was assessed before the match (urine specific gravity; USG) while fluid turnover was tracked during the match. Finally, counter movement jump (CMJ) and handgrip isometric strength (HS) were measured before and after the match. SalCC, either in the morning (P = 0.161) and afternoon (P = 0.683) was similar in rest and match days. However, SalCC increased after the match (P = 0.033). Participants started the match hypohydrated (USG = 1.026+/-0.002) and during the match lost 1.0+/-0.3% of body weight despite 1.035+/-0.124 L/h of fluid ingested. CMJ and HS did not change post-match (P = 0.210 and P = 0.881, respectively). Correlations between the elevations in SalCC and dehydration (% BW loss) during the match were significant (r = -0.632; P = 0.034). Professional male tennis players did not show an anticipatory increase in SalCC the day of the match and neither signs of neuromuscular fatigue after it. During the match, the mild dehydration (i.e., <1.5%) was associated with the increases in cortisol levels which suggests that dehydration may be an added stress to be considered. PMID- 29624622 TI - Methodology and results of integrated WNV surveillance programmes in Serbia. AB - Studies conducted during the past few years have confirmed active West Nile virus (WNV) circulation in Serbia. Based on these studies and the epidemiological situation, the Veterinary Directorate of the Ministry of Agriculture and Environmental Protection launched national WNV surveillance programmes in 2014 and 2015. The programmes encompassed the territory of Serbia and were conducted by the veterinary service in collaboration with entomologists and ornithologists. The objective of the programmes was early detection of WNV and timely reporting to the public health service and local authorities to increase both clinical and mosquito control preparedness. The WNV surveillance programmes were based on direct and indirect surveillance of the presence of WNV by the serological testing of initially seronegative sentinel horses and chickens as well as through viral detection in pooled mosquito and wild bird samples. The most intense WNV circulation was observed in all seven districts of Vojvodina Province (northern Serbia) and Belgrade City, where most of the positive samples were detected among sentinel animals, mosquitoes and wild birds. The West Nile virus surveillance programmes in 2014 and 2015 showed satisfactory results in their capacity to indicate the spatial distribution of the risk for humans and their sensitivity to early detect viral circulation at the enzootic level. Most of the human cases were preceded by the detection of WNV circulation as part of the surveillance programmes. According to the existing data, it can be reasonably assumed that WNV infection, now an endemic infection in Serbia, will continue to present a significant problem for the veterinary service and public health. PMID- 29624623 TI - Motion and dural sac compression in the upper cervical spine during the application of a cervical collar in case of unstable craniocervical junction-A study in two new cadaveric trauma models. AB - BACKGROUND: Unstable conditions of the craniocervical junction such as atlanto occipital dislocation (AOD) or atlanto-axial instability (AAI) are severe injuries with a high risk of tetraplegia or death. Immobilization by a cervical collar to protect the patient from secondary damage is a standard procedure in trauma patients. If the application of a cervical collar to a patient with an unstable craniocervical condition may cause segmental motion and secondary injury to the spinal cord is unknown. The aim of the current study is (i) to analyze compression on the dural sac and (ii) to determine relative motion of the cervical spine during the procedure of applying a cervical collar in case of ligamentous unstable craniocervical junction. METHODS AND FINDINGS: Ligamentous AOD as well as AOD combined with ligamentous AAI was simulated in two newly developed cadaveric trauma models. Compression of the dural sac and segmental angulation in the upper cervical spine were measured on video fluoroscopy after myelography during the application of a cervical collar. Furthermore, overall three-dimensional motion of the cervical spine was measured by a motion tracking system. In six cadavers each, the two new trauma models on AOD and AOD combined with AAI could be implemented. Mean dural sac compression was significantly increased to -1.1 mm (-1.3 to -0.7 mm) in case of AOD and -1.2 mm (-1.6 to -0.6 mm) in the combined model of AOD and AAI. Furthermore, there is a significant increased angulation at the C0/C1 level in the AOD model. Immense three dimensional movement up to 22.9 degrees of cervical spine flexion was documented during the procedure. CONCLUSION: The current study pointed out that applying a cervical collar in general will cause immense three-dimensional movement. In case of unstable craniocervical junction, this leads to a dural sac compression and thus to possible damage to the spinal cord. PMID- 29624624 TI - Genetic modulation of atrial fibrillation risk in a Hispanic/Latino cohort. AB - Atrial fibrillation (AF) is the most prevalent cardiac rhythm disorder worldwide but the underlying genetic and molecular mechanisms and the response to therapies is not fully understood. Despite a greater burden of AF risk factors in Hispanics/Latinos the prevalence of AF remains low. Over the last decade, genome wide association studies have identified numerous AF susceptibility loci in mostly whites of European descent. The goal of this study was to determine if the top 9 single nucleotide polymorphisms (SNPs) associated with AF in patients of European descent also increase susceptibility to AF in Hispanics/Latinos. AF cases were prospectively enrolled in the University of Illinois at Chicago (UIC) AF Registry and control subjects were identified from the UIC Cohort of Patients, Family and Friends. AF cases and controls were genotyped for 9 AF risk SNPs at chromosome 1q21: rs13376333, rs6666258; chr1q24: rs3903239; chr4q25: rs2200733; rs10033464; chr10q22: rs10824026; chr14q23: rs1152591; chr16q22: rs2106261 and rs7193343. The study sample consisted of 713 Hispanic/Latino subjects including 103 AF cases and 610 controls. Among the 8 AF risk SNPs genotyped, only rs10033464 SNP at chromosome (chr) 4q25 (near PITX2) was significantly associated with development of AF after multiple risk factor adjustment and multiple testing (adj. odds ratio [OR] 2.27, 95% confidence interval [CI] 1.31-3.94; P = 3.3 x 10 3). Furthermore, the association remained significant when the analysis was restricted to Hispanics of Mexican descent (adj. OR 2.32, 95% CI 1.35-3.99; P = 0.002. We confirm for the first time the association between a chromosome 4q25 SNP and increased susceptibility to AF in Hispanics/Latinos. While the underlying molecular mechanisms by which the chr4q25 SNP modulates AF risk remains unclear, this study supports a genetic basis for non-familial AF in patients of Hispanic descent. PMID- 29624625 TI - Clinical management of seronegative and seropositive rheumatoid arthritis: A comparative study. AB - Both rheumatoid factor (RF) and anti-cyclic citrullinated peptide antibody (ACPA) are associated with poor radiologic outcomes in patients with rheumatoid arthritis (RA). In general, RA patients positive for RF or ACPA (SPRA) are considered to manifest an aggressive disease course compared with seronegative RA patients (SNRA). However, the relationship between seropositivity and measures of disease severity other than radiologic outcome is disputed. In this study, we sought to compare the clinical presentations and treatment outcomes of SNRA and SPRA patients. A total of 241 patients diagnosed with DMARD-naive RA under either 1987 American College of Rheumatology (ACR) criteria or 2010 ACR/European League Against Rheumatism (EULAR) criteria were identified (40 with SNRA and 201 with SPRA). We investigated the disease activity measures including ESR, CRP, patient VAS, 28 tender/swollen joint count (28 TJC, 28 SJC) and DAS28 as well as radiologic outcomes at baseline, 1 and 2 years after conventional treatment with DMARD. Age, sex and disease duration were similar between SNRA and SPRA. However, the baseline 28 TJC (4.7+/-2.9 vs. 3.3+/-2.7, p = 0.004), 28 SJC (4.3+/-3.0 vs. 2.9+/-2.3, p = 0.001) and DAS28 (5.1+/-1.0 vs. 4.7+/-1.0, p = 0.043) components were significantly higher in SNRA than in SPRA. Over 2 years of similar treatment with DMARDs, all disease activity measures significantly improved in both groups. Comparison among populations matched for baseline disease activity showed that DeltaDAS28 at 1 year was greater in SNRA than in SPRA (-2.84+/-1.32 vs. -3.70+/ 1.29, p = 0.037) in high disease activity population (DAS28-ESR>5.1). Radiologic outcomes at baseline and at 1- or 2-year follow-up were similar between the 2 groups. In conclusion, SNRA patients manifested more active disease at baseline, but showed a better response to treatment compared with SPRA. SNRA does not appear to be a benign subtype of RA. PMID- 29624626 TI - Effect of Software Version on the Accuracy of an Intraoral Scanning Device. AB - PURPOSE: To investigate the impact of software version on the accuracy of an intraoral scanning device. MATERIALS AND METHODS: A master tooth was scanned with a high-precision optical scanner and then 10 times with a CEREC Omnicam scanner with software versions 4.4.0 and 4.4.4. Discrepancies were measured using quality control software. RESULTS: Mean deviation for 4.4.0 was 36.2 +/- 35 MUm and for 4.4.4 was 20.7 +/- 14.2 MUm (P <= .001). CONCLUSION: Software version has a significant impact on the accuracy of an intraoral scanner. It is important that researchers also publish the software version of scanners when publishing their findings. PMID- 29624627 TI - Influence of Iatrogenic Gaps, Cement Type, and Time on Microleakage of Cast Posts Using Spectrophotometer and Glucose Filtration Measurements. AB - PURPOSE: To determine the influence of iatrogenic gaps, type of cement, and time on microleakage of cast posts using spectrophotometer and glucose filtration measurements. MATERIALS AND METHODS: Forty-eight single-rooted teeth were divided into eight groups of six teeth each. Teeth were instrumented and obturated, and a cast post was fabricated. In addition to two control groups (positive and negative), a total of six groups were prepared: In four groups, an artificial 2- to 3-mm gap was created between post and residual gutta percha (GP), and two groups were prepared with intimate contact between post and residual GP. Posts were cemented with either zinc phosphate cement or resin cement. Leakage through the post after 1, 8, 14, and 20 days was measured using a glucose penetration model with two different reading methods. Mixed analysis of variance tests were performed to analyze the data. RESULTS: The presence of a gap between the apical end of the post and the most coronal portion of the GP remaining in the root canal after post space preparation increased microleakage significantly. However, microleakage was significantly less when the gap was refilled with GP compared to no gap. There was no difference in leakage between luting cements used. CONCLUSION: It was concluded that none of the cements were able to prevent microleakage. However, the addition of GP to residual GP did increase the sealing ability. PMID- 29624628 TI - Comparison of Cemented vs Screw-Retained, Customized Computer-Aided Design/Computer-Assisted Manufacture Zirconia Abutments for Esthetically Located Single-Tooth Implants: A 10-Year Randomized Prospective Study. AB - PURPOSE: To compare the clinical outcomes of screw-retained vs cemented single crowns supported by customized zirconia abutments on implants. MATERIALS AND METHODS: Thirty-two patients received implant-supported (Regular Neck, Tissue Level, Straumann AG), single-tooth restorations with customized zirconia abutments in the anterior areas. Participants were randomly assigned to the screw retained (full-crown abutment [FCA]) group or the cemented (zirconia crown [ZrC]) group and followed up over a 10-year period. Prosthetic and biologic complications, marginal bone level (MBL), mucosal recession, and pink and white esthetic scores (PES and WES, respectively) were evaluated. RESULTS AND CONCLUSION: There were no implant failures during the study period; after 10 years, 94% of crowns were functional. Prosthetic complications were recorded in both groups (three FCA and two ZrC), and no significant difference was found (P = .65). Two cases of mucositis were recorded, one in each group. Esthetic outcomes were assessed using PES and WES scores. MBL was 0.95 mm in the ZrC group and 0.82 mm in the FCA group, with no significant difference between groups. These encouraging preliminary results need to be confirmed with long-term follow-up on larger study samples. PMID- 29624629 TI - Using Intraoral Scanning to Capture Complete Denture Impressions, Tooth Positions, and Centric Relation Records. AB - Intraoral scanning was used to capture the soft tissue surfaces of both maxillary and mandibular edentulous ridges and the denture borders. Additionally, an intraoral scanner was used to digitize existing dentures with their tooth positions and base forms and a centric relation record obtained with a Gothic arch-tracing device. These scans provided all the required records for fabrication of computer-aided design/computer-assisted manufacturing of complete dentures. PMID- 29624630 TI - Changes in Quality of Life Induced by Tooth Whitening are Moderated by Perfectionism: A Randomized, Double-Blind, Placebo-Controlled Trial. AB - PURPOSE: To explore the influence of perfectionism on the short-term changes in satisfaction with smile esthetics and quality of life (QoL) induced by tooth whitening. MATERIALS AND METHODS: A total of 60 subjects were analyzed: 30 in the active group, in which the subject's anterior teeth were whitened with a photoactivated gel, and 30 in the placebo group. The Smile Esthetics-Related Quality of Life and Multidimensional Perfectionism Scale questionnaires were administered to all participants. RESULTS: The active group demonstrated an increase in dental self-confidence and a decrease in dissatisfaction with color (P < .05). The amount of color change did not correlate linearly with change in dissatisfaction or with QoL. In subjects with higher perfectionism, increasing the color change led to more decrease in dental self-consciousness. CONCLUSION: Perfectionism moderates perception of smile esthetics. PMID- 29624632 TI - Advances in industrial biopharmaceutical batch process monitoring: Machine learning methods for small data problems. AB - Biopharmaceutical manufacturing comprises of multiple distinct processing steps that require effective and efficient monitoring of many variables simultaneously in real-time. The state-of-the-art real-time multivariate statistical batch process monitoring (BPM) platforms have been in use in recent years to ensure comprehensive monitoring is in place as a complementary tool for continued process verification to detect weak signals. This article addresses a longstanding, industry-wide problem in BPM, referred to as the "Low-N" problem, wherein a product has a limited production history. The current best industrial practice to address the Low-N problem is to switch from a multivariate to a univariate BPM, until sufficient product history is available to build and deploy a multivariate BPM platform. Every batch run without a robust multivariate BPM platform poses risk of not detecting potential weak signals developing in the process that might have an impact on process and product performance. In this article, we propose an approach to solve the Low-N problem by generating an arbitrarily large number of in silico batches through a combination of hardware exploitation and machine-learning methods. To the best of authors' knowledge, this is the first article to provide a solution to the Low-N problem in biopharmaceutical manufacturing using machine-learning methods. Several industrial case studies from bulk drug substance manufacturing are presented to demonstrate the efficacy of the proposed approach for BPM under various Low-N scenarios. PMID- 29624631 TI - Temporal trends in disease presentation and survival of patients with hepatocellular carcinoma: A real-world experience from 1998 to 2015. AB - BACKGROUND: Hepatocellular carcinoma (HCC) is one of the few cancers whose incidence continues to increase. The goal of the current study was to investigate the presentation and survival trends of patients with HCC presenting to a university hospital between 1998 and 2015. METHODS: Study data were ascertained by individual chart review with survival data also supplemented by National Death Index query up to December 31, 2015. Patients were divided into three 6-year groups by diagnosis date (1998-2003, 2004-2009, and 2010-2015). RESULTS: A total of 2106 consecutive patients with HCC were included. The majority of patients had either hepatitis C (56.7%) or hepatitis B (22.1%), but cases of nonalcoholic steatohepatitis HCC increased by 68% over the most recent time period. Screening/surveillance identified 61% of HCC cases, but only 31% of these patients underwent curative treatment, which did not increase significantly over time. The overall median survival was 29.8 months (2.48 years) and without improvement over time. On multivariable analysis, Asian or Hispanic ethnicity, meeting Milan criteria, and receiving any of the standard HCC treatments were found to be significantly associated with improved survival, but diagnosis time period and liver disease etiology were not. CONCLUSIONS: Over the last 18 years, the percentage of cases of nonalcoholic steatohepatitis HCC has increased but not overall survival. It is interesting to note that only 31% of patients with HCC identified via screening/surveillance received any curative treatment. Further research is needed to better understand the barriers to curative care for patients with HCC and the causes of the lack of improvement in survival in the more recent patient cohort. Cancer 2018;124:2588-98. (c) 2018 American Cancer Society. PMID- 29624634 TI - The efficacy of a nested polymerase chain reaction in detecting the cytochrome c oxidase subunit 1 gene of Sarcoptes scabiei var. hominis for diagnosing scabies. AB - BACKGROUND: A widespread scabies infestation, associated with long-term residence in nursing homes, is becoming an issue in high-income countries. Mineral oil examination is regarded as the gold standard in diagnosing scabies, but the sensitivity of this method is generally low - approximately 50%. Molecular techniques may contribute to enhancing the sensitivity of current tests for laboratory diagnosis of human scabies. OBJECTIVES: To develop new primers for a nested polymerase chain reaction (PCR) for the cytochrome c oxidase subunit 1 (cox1) gene of Sarcoptes scabiei var. hominis to increase the sensitivity of a previously developed conventional PCR. METHODS: Patients with clinically suspected scabies underwent dermoscopy-guided skin scraping with microscopic examination. The diagnosis was positive for scabies when mites or eggs were found under the microscope, and patients were then designated as 'microscopy positive'. Patients who presented with negative microscopic results were placed in the 'microscopy-negative' group. Skin scrapings were collected from both groups for PCR. RESULTS: Of the total 63 samples, 28 were microscopy positive and 35 were negative with no differences in sex and age between the two groups. All microscopically proven cases of scabies were positive using the cox1 nested PCR. Among microscopy-negative samples, S. scabieiDNA was detected in nine. If sensitivity of the cox1 nested PCR is considered 100% [95% confidence interval (CI) 90.5-100], then sensitivity of microscopy is 75.7% (95% CI 58.8-88.2; P = 0.004). CONCLUSIONS: Nested PCR can be successfully used as an alternative method for diagnosing suspected scabies. Therefore, infection control measures and treatments can be initiated before significant transmission occurs, minimizing the risk of outbreaks. PMID- 29624633 TI - Disparities in the survivorship experience among Latina survivors of breast cancer. AB - BACKGROUND: The authors investigated disparities in the survivorship experience among Latinas with breast cancer (BC) in comparison with non-Latinas. METHODS: A cross-sectional bilingual telephone survey was conducted among 212 Latina and non Latina women within 10 to 24 months after a diagnosis of BC (AJCC TNM staging system stage 0-III) at 2 Los Angeles County public hospitals. Data were collected using the Preparing for Life as a (New) Survivor (PLANS) scale, Perceived Efficacy in Patient-Physician Interactions Questionnaire (PEPPI), Breast Cancer Prevention Trial (BCPT) Symptom Checklist, Satisfaction with Care and Information Scale, Consumer Assessment of Healthcare Providers and Systems (CAHPS) tool, Charlson Comorbidity Index adapted for patient self-report, and the 12-item Short Form Health Survey. Controlling variables included age, stage as determined by the American Joint Committee on Cancer (AJCC) TNM staging system, educational level, and study site in multivariate analyses. RESULTS: The mean ages of Latinas and non-Latinas were 51.5 years and 56.6 years, respectively. Compared with non Latinas, Latinas reported less BC survivorship knowledge (27.3 vs 30.7; P<.0001), were more dissatisfied with BC care information (2.3 vs 3.4; P<.0001), reported lower PEPPI scores (38.2 vs 42.2; P = .03), and experienced more BCPT symptoms (6.4 vs 5.0; P = .04). No differences were noted regarding their confidence in survivorship care preparedness (42.7 vs 41; P = .191), satisfaction with BC survivorship care (9.6 vs 8.8; P = .298), or their discussion with physicians (9.6 vs 8.1; P = .07). These ethnic group differences persisted in multivariate analyses, with the exception of PEPPI. CONCLUSIONS: Latina survivors of BC experienced disparities in BC knowledge and satisfaction with information received, but believed themselves to be prepared for survivorship and were as satisfied with providers, care received, and discussions with physicians as non Latinas. Cancer 2018;124:2373-80. (c) 2018 American Cancer Society. PMID- 29624636 TI - Prognostic importance of lymphovascular invasion in urothelial carcinoma of the renal pelvis. AB - BACKGROUND: The current study was conducted to assess the impact of lymphovascular invasion on the survival of patients with urothelial carcinoma of the renal pelvis. METHODS: Patients with urothelial carcinoma of the renal pelvis who underwent radical nephroureterectomy from 2010 through 2015 were identified in the National Cancer Data Base. Patients were characterized according to demographic and clinical factors, including pathologic tumor stage and lymphovascular invasion. Associations with overall survival were assessed through proportional hazards regression analysis. RESULTS: A total of 4177 patients were identified; 1576 had lymphovascular invasion. Patients with T3 disease and lymphovascular invasion had 5-year survival that was significantly worse than that of patients with T3 disease without lymphovascular invasion (34.7% vs 52.6; P < .001 by the log-rank test), and approached that of patients with T4 disease without lymphovascular invasion (34.7% vs 26.5%; P = .002). On multivariate analysis controlling for age, comorbidities, grade, lymph node status, surgical margin status, race, sex, and chemotherapy administration, patients with T3 disease and lymphovascular invasion also were found to have significantly worse survival compared with patients with T3 disease without lymphovascular invasion (hazard ratio, 1.7; 95% confidence interval, 1.4-1.91). CONCLUSIONS: Lymphovascular invasion status is a key prognostic marker that can stratify the risk of patients with pT3 upper tract urothelial carcinoma further. Patients with this pathologic feature should be carefully considered for clinical trials exploring existing and novel therapies. Cancer 2018;124:2507-14. (c) 2018 American Cancer Society. PMID- 29624635 TI - Symptoms of anxiety and depression among colorectal cancer survivors from the population-based, longitudinal PROFILES Registry: Prevalence, predictors, and impact on quality of life. AB - BACKGROUND: The aims of this study were to prospectively assess symptoms of anxiety and depression among survivors of colorectal cancer (CRC), to compare these survivors with a normative population, and to identify subgroups at risk for experiencing symptoms of anxiety and/or depression across a 4-year time period. Also, the impact on health-related quality of life (HRQOL) was studied. METHODS: The population-based Eindhoven Cancer Registry was used to select patients diagnosed with CRC between 2000 and 2009. The Hospital Anxiety and Depression Scale and the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (HRQOL) were completed by patients in 2010 (n = 2625 [73% response rate]), 2011, 2012, and 2013 and by an age- and sex-matched normative sample (n = 315) in 2011. RESULTS: Patients reported a significantly higher prevalence of depression (19.0% vs 12.8%) and anxiety (20.9% vs 11.8%) in comparison with the norm. Anxiety was stable, whereas depression scores changed over time, although this was not clinically relevant. A longer time since diagnosis was associated with fewer depressive symptoms over time, whereas older age and being male were associated with less anxiety and more depression. Being married was associated with less anxiety and depression, and a low education level and comorbid conditions were associated with more anxiety and depression. Higher levels of symptoms of depression and anxiety were associated with a lower global quality of life and lower physical, role, cognitive, emotional, and social functioning over time. CONCLUSIONS: Because of the increased prevalence of depression and anxiety among patients with CRC and their negative effect on HRQOL, screening and referral are of the utmost importance, especially among those who are single, have a low educational level, and have comorbid conditions, even years after diagnosis and treatment. Cancer 2018;124:2621-8. (c) 2018 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. PMID- 29624637 TI - MiR-146a-5p correlates with clinical efficacy in patients with psoriasis treated with the tumour necrosis factor-alpha inhibitor adalimumab. PMID- 29624638 TI - Medical management of miscarriage: Predictive factors of success. AB - Medical management of miscarriage is an acceptable option available to women, and has advantages of providing timely treatment, while avoiding exposure to surgery and anaesthesia. This retrospective cohort study aimed to determine factors predictive of successful medical management, utilising a single dose protocol of 800 ug vaginal misoprostol. In this cohort, the success rate was 67% (199/296), and smaller mean gestational sac diameter independent of gestational age predicted success (P = 0.046). Success is not significantly related to parity, miscarriage type, pelvic pain or vaginal bleeding at the outset of treatment. PMID- 29624639 TI - Detection of anti-BP180 NC16A autoantibodies after the onset of dipeptidyl peptidase-IV inhibitor-associated bullous pemphigoid: a report of three patients. PMID- 29624640 TI - Why we prefer levetiracetam over phenytoin for treatment of status epilepticus. AB - Over last fifty years, intravenous (iv) phenytoin (PHT) loading dose has been the treatment of choice for patients with benzodiazepine-resistant convulsive status epilepticus and several guidelines recommended this treatment regimen with simultaneous iv diazepam. Clinical studies have never shown a better efficacy of PHT over other antiepileptic drugs. In addition, iv PHT loading dose is a complex and time-consuming procedure which may expose patients to several risks, such as local cutaneous reactions (purple glove syndrome), severe hypotension and cardiac arrhythmias up to ventricular fibrillation and death, and increased risk of severe allergic reactions. A further disadvantage of PHT is that it is a strong enzymatic inducer and it may make ineffective several drugs that need to be used simultaneously with antiepileptic treatment. In patients with a benzodiazepine resistant status epilepticus, we suggest iv administration of levetiracetam as soon as possible. If levetiracetam would be ineffective, a further antiepileptic drug among those currently available for iv use (valproate, lacosamide, or phenytoin) can be added before starting third line treatment. PMID- 29624641 TI - Feasibility, safety, and efficacy of aerobic training in pretreated patients with metastatic breast cancer: A randomized controlled trial. AB - BACKGROUND: The investigation of exercise training in metastatic breast cancer has received minimal attention. This study determined the feasibility and safety of aerobic training in metastatic breast cancer. METHODS: Sixty-five women (age, 21-80 years) with metastatic (stage IV) breast cancer (57% were receiving chemotherapy, and >40% had >= 2 lines of prior therapy) were allocated to an aerobic training group (n = 33) or a stretching group (n = 32). Aerobic training consisted of 36 supervised treadmill walking sessions delivered thrice weekly between 55% and 80% of peak oxygen consumption (VO2peak ) for 12 consecutive weeks. Stretching was matched to aerobic training with respect to location, frequency, duration, and intervention length. The primary endpoint was aerobic training feasibility, which was a priori defined as the lost to follow-up (LTF) rate (<20%) and attendance (>=70%). Secondary endpoints were safety, objective outcomes (VO2peak and functional capacity), and patient-reported outcomes (PROs; quality of life). RESULTS: One of the 33 patients (3%) receiving aerobic training was LTF, whereas the mean attendance rate was 63% +/- 30%. The rates of permanent discontinuation and dose modification were 27% and 49%, respectively. Intention to-treat analyses indicated improvements in PROs, which favored the attention control group (P values > .05). Per protocol analyses indicated that 14 of 33 patients (42%) receiving aerobic training had acceptable tolerability (relative dose intensity >= 70%), and this led to improvements in VO2peak and functional capacity (P values < .05). CONCLUSIONS: Aerobic training at the dose and schedule tested is safe but not feasible for a significant proportion of patients with metastatic breast cancer. The acceptable feasibility and promising benefit for select patients warrant further evaluation in a dose-finding phase 1/2 study. Cancer 2018;124:2552-60. (c) 2018 American Cancer Society. PMID- 29624643 TI - Lichen planus pigmentosus - An appraisal. PMID- 29624642 TI - Cannabidiol regulates behavioural alterations and gene expression changes induced by spontaneous cannabinoid withdrawal. AB - BACKGROUND AND PURPOSE: Cannabidiol (CBD) represents a promising therapeutic tool for treating cannabis use disorder (CUD). This study aimed to evaluate the effects of CBD on the behavioural and gene expression alterations induced by spontaneous cannabinoid withdrawal. EXPERIMENTAL APPROACH: Spontaneous cannabinoid withdrawal was evaluated 12 h after cessation of CP-55,940 treatment (0.5 mg.kg-1 every 12 h, i.p.; 7 days) in C57BL/6J mice. The effects of CBD (5, 10 and 20 mg.kg-1 , i.p.) on withdrawal-related behavioural signs were evaluated by measuring motor activity, somatic signs and anxiety-like behaviour. Furthermore, gene expression changes in TH in the ventral tegmental area, and in the opioid MU receptor (Oprm1), cannabinoid CB1 receptor (Cnr1) and CB2 receptor (Cnr2) in the nucleus accumbens, were also evaluated using the real-time PCR technique. KEY RESULTS: The administration of CBD significantly blocked the increase in motor activity and the increased number of rearings, rubbings and jumpings associated with cannabinoid withdrawal, and it normalized the decrease in the number of groomings. However, CBD did not change somatic signs in vehicle treated animals. In addition, the anxiogenic-like effect observed in abstinent mice disappeared with CBD administration, whereas CBD induced an anxiolytic-like effect in non-abstinent animals. Moreover, CBD normalized gene expression changes induced by CP-55,940-mediated spontaneous withdrawal. CONCLUSIONS AND IMPLICATIONS: The results suggest that CBD alleviates spontaneous cannabinoid withdrawal and normalizes associated gene expression changes. Future studies are needed to determine the relevance of CBD as a potential therapeutic tool for treating CUD. PMID- 29624644 TI - Producing 'internal suspect bodies': divisive effects of UK counter-terrorism measures on Muslim communities in Leeds and Bradford. AB - Research on UK government counter-terrorism measures has claimed that Muslims are treated as a 'suspect community'. However, there is limited research exploring the divisive effects that membership of a 'suspect community' has on relations within Muslim communities. Drawing from interviews with British Muslims living in Leeds or Bradford, I address this gap by explicating how co-option of Muslim community members to counter extremism fractures relations within Muslim communities. I reveal how community members internalize fears of state targeting which precipitates internal disciplinary measures. I contribute the category of 'internal suspect body' which is materialized through two intersecting conditions within preventative counter-terrorism: the suspected extremist for Muslims to look out for and suspected informer who might report fellow Muslims. I argue that the suspect community operates through a network of relations by which terrors of counter-terrorism are reproduced within Muslim communities with divisive effects. PMID- 29624645 TI - Lipidomics reveals skin surface lipid abnormity in acne in young men. AB - BACKGROUND: Acne is a complex and multifactorial skin disorder. Alterations in skin surface lipid (SSL) are believed to be an important factor in the pathogenesis of acne and SSL plays a key role in the initiation of acne lesions. OBJECTIVES: To analyse the lipidome profiles of SSL in patients with acne and in healthy controls in order to understand SSL abnormity in acne in young men. METHODS: Ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF-MS) and multivariate data analysis were used to investigate the SSL variations in main lipid classes, subclasses and individual species. RESULTS: Results showed that there were significant differences in the lipidome between the two groups. Significantly increased levels of three main classes of glycerophospholipids, fatty acyls and sterol lipids and significantly decreased levels of two main classes of prenol lipids and saccharolipids were observed in patients with acne. Subsequent analysis showed that there were 18 subclasses, which varied significantly and shared the same changing trends of the main classes to which they belonged. Multivariate data analysis indicated that 36 individual species were mostly responsible for this discrimination and the majority of differentiating lipid species were phosphatidylserines. Furthermore, it was observed that the chain length of ceramides were reduced and unsaturated free fatty acids were increased in patients with acne. CONCLUSIONS: SSL sampled from young male patients with acne had significantly higher levels of phosphatidylserines. Additionally, the reduction in the chain length of ceramides and the increase in unsaturated free fatty acids contributed to an altered lipid organization and decreased skin barrier function in acne. PMID- 29624646 TI - 'Post-finasteride syndrome': what to tell our female patients? PMID- 29624647 TI - Maculopapular drug eruption induced by linagliptin. PMID- 29624649 TI - Lymphocytic thrombophilic arteritis complicated by systemic involvement. AB - Lymphocytic thrombophilic arteritis (LTA) is a recently described entity defined by primary lymphocytic vasculitis; it typically has a chronic indolent course. We describe a patient who presented with clinical and histological findings consistent with LTA and later developed bilateral focal testicular infarcts as well as an acute median nerve neuropathy. PMID- 29624648 TI - CNS Langerhans cell histiocytosis: Common hematopoietic origin for LCH-associated neurodegeneration and mass lesions. AB - BACKGROUND: Central nervous system Langerhans cell histiocytosis (CNS-LCH) brain involvement may include mass lesions and/or a neurodegenerative disease (LCH-ND) of unknown etiology. The goal of this study was to define the mechanisms of pathogenesis that drive CNS-LCH. METHODS: Cerebrospinal fluid (CSF) biomarkers including CSF proteins and extracellular BRAFV600E DNA were analyzed in CSF from patients with CNS-LCH lesions compared with patients with brain tumors and other neurodegenerative conditions. Additionally, the presence of BRAFV600E was tested in peripheral mononuclear blood cells (PBMCs) as well as brain biopsies from LCH ND patients, and the response to BRAF-V600E inhibitor was evaluated in 4 patients with progressive disease. RESULTS: Osteopontin was the only consistently elevated CSF protein in patients with CNS-LCH compared with patients with other brain pathologies. BRAFV600E DNA was detected in CSF of only 2/20 (10%) cases, both with LCH-ND and active lesions outside the CNS. However, BRAFV600E+ PBMCs were detected with significantly higher frequency at all stages of therapy in LCH patients who developed LCH-ND. Brain biopsies of patients with LCH-ND demonstrated diffuse perivascular infiltration by BRAFV600E+ cells with monocyte phenotype (CD14+ CD33+ CD163+ P2RY12- ) and associated osteopontin expression. Three of 4 patients with LCH-ND treated with BRAF-V600E inhibitor experienced significant clinical and radiologic improvement. CONCLUSION: In LCH-ND patients, BRAFV600E+ cells in PBMCs and infiltrating myeloid/monocytic cells in the brain is consistent with LCH-ND as an active demyelinating process arising from a mutated hematopoietic precursor from which LCH lesion CD207+ cells are also derived. Therapy directed against myeloid precursors with activated MAPK signaling may be effective for LCH-ND. Cancer 2018;124:2607-20. (c) 2018 American Cancer Society. PMID- 29624650 TI - Neurofilament light protein levels in cerebrospinal fluid predict long-term disability of Guillain-Barre syndrome: A pilot study. AB - OBJECTIVES: Although the recovery from Guillain-Barre syndrome (GBS) is good in most patients, some develop permanent severe disability or even die. Early predictors would increase the likelihood to identify patients at risk for poor outcome at the acute stage, allowing them intensified therapeutic intervention. MATERIALS AND METHOD: Eighteen patients with a history of GBS 9-17 years ago were reassessed with scoring of neurological disability and quality of life assessment (QoL). Their previous diagnostic work-up included clinical examination with scoring of disability, neurophysiological investigation, a battery of serology tests for infections, and cerebrospinal fluid (CSF) examination. Aliquots of CSF were frozen, stored for 20-28 years, and analyzed by ELISA for determination of neurofilament light protein (NFL) and glial fibrillary acidic protein (GFAP). RESULTS: Patients with poor outcome (n = 3) had significantly higher NFL and GFAP levels at GBS nadir than those with good outcome (n = 15, P < .01 and P < .05, respectively). High NFL correlated with more prominent disability and worse QoL at long-term follow-up (r = .694, P < .001, and SF 36 dimension physical component summary (PCS) (r =-.65, P < .05), respectively, whereas GFAP did not correlate with clinical outcome or QoL. CONCLUSION: High NFL in CSF at the acute stage of GBS seems to predict long-term outcome and might, together with neurophysiological and clinical measures, be useful in treatment decisions and clinical care of GBS. PMID- 29624651 TI - A case of pigmentary mosaicism associated with diploid/triploid mixoploidy. PMID- 29624652 TI - Religious stigmata: a dermato-psychiatric approach and differential diagnosis. AB - BACKGROUND: Stigma refers to the wounds reproduced on the human body, similar to the ones inflicted on the Christ during his crucifixion, on the palms, soles, and head, as well as the right or the left side of the chest, the lips and, the back. Whether they are genuine or fabricated, stigmata are still considered a medical enigma. OBJECTIVE: To summarize and analyze all available medical data about stigmata, integrating both its dermatological and psychiatric features. METHODS AND MATERIALS: A systematic search of Pubmed and Embase databases was conducted on August 19, 2016, using the terms stigma, stigmata, and religious. RESULTS: Around 300 cases of stigma have been described since the 13th century. Hematidrosis, hemolacria, bloody otorrhea, vicarious menstruation, and Gardner Diamond syndrome were all dermatological disorders that resulted in signs and symptoms similar to that of stigma. Stigma was often associated with the occurrence of intense emotion or great psychological stress. It also occurred in the context of simulation, factitious disorder, conversion disorder, and functional neurological symptom disorder. CONCLUSION: Stigma remains an example of the intricate relationships existing between medicine, psychiatry, psychology, spirituality, and the human body. PMID- 29624653 TI - Reduction in pain following treatment with ranolazine in primary erythromelalgia: a case report. PMID- 29624654 TI - Skin ultrasound is a useful tool for evaluating and monitoring eosinophilic fasciitis. PMID- 29624655 TI - Novel use of combination therapeutic plasma exchange and rituximab in the treatment of nivolumab-induced bullous pemphigoid. PMID- 29624656 TI - Topical timolol for Kaposi sarcoma: An innovation. PMID- 29624657 TI - Development and evaluation of a patient-centred measurement tool for surgeons' non-technical skills. AB - BACKGROUND: Non-technical skills are essential for safe and effective surgery. Several tools to assess surgeons' non-technical skills from the clinician's perspective have been developed. However, a reliable measurement tool using a patient-centred approach does not currently exist. The aim of this study was to translate the existing Non-Technical Skills for Surgeons (NOTSS) tool into a patient-centred evaluation tool. METHODS: Data were gathered from four cohorts of patients using an iterative four-stage mixed-methods research design. Exploratory and confirmatory factor analyses were performed to establish the psychometric properties of the tool, focusing on validity, reliability, usability and parsimony. RESULTS: Some 534 patients were recruited to the study. A total of 24 patient-centred non-technical skill items were developed in stage 1, and reduced to nine items in stage 2 using exploratory factor analysis. In stage 3, confirmatory factor analysis demonstrated that these nine items each loaded on to one of three factors, with excellent internal consistency: decision-making, leadership, and communication and teamwork. In stage 4, validity testing established that the new tool was independent of physician empathy and predictive of surgical quality. Surgical leadership emerged as the most dominant skill that patients could recognize and evaluate. CONCLUSION: A novel nine-item assessment tool has been developed. The Patients' Evaluation of Non-Technical Skills (PENTS) tool allows valid and reliable measurement of surgeons' non-technical skills from the patient perspective. PMID- 29624658 TI - Primary visual cortex in neandertals as revealed from the occipital remains from the El Sidron site, with emphasis on the new SD-2300 specimen. AB - The comparative analysis of the endocranial surface of the El Sidron new occipital fragment SD-2300 shows meaningful differences in the configuration of the occipital pole region between neandertals and anatomically modern humans (AMH). The particular asymmetries found in neandertals in the venous sinus drainage and the petalial patterns are recognizable in this new specimen as well. In addition, the supra- and infracalcarine fossae of the occipital pole region appear to deviate obliquely from the mid-line when compared with sapiens. Due to the excellent preservation conditions of SD-2300, the main sulci and gyri of the occipital pole area have been identified, this degree of detail being uncommon in a fossil specimen; in general, the gyrification pattern is similar to AMH, but with some notable differences. Particularly interesting is the description of the lunate and the calcarine sulci. The lunate sulcus is located close to the occipital pole, in a similar posterior position to in other Homo species. Regarding the calcarine sulcus, there are significant differences in the primary visual cortex, with the V1 area, or Brodmann area 17, being larger in Homo neanderthalensis than in Homo sapiens. This may lead to greater visual acuity in neandertals than in sapiens. PMID- 29624659 TI - Sociodemographic factors associated with oral health in 12-year-old adolescents: hygiene behaviours and health appointments. A cross-sectional national study in Portugal. AB - OBJECTIVES: The aim of this study was to characterise the daily oral hygiene behaviours and the frequency of, and reasons for, oral health appointments, among 12-year-old adolescents in Portugal. We also investigated whether there were any associations between these behaviours and sociodemographic factors. METHODS: We conducted an observational descriptive study based on 1,309 Portuguese adolescents from rural, peri-urban and urban populations. Data were drawn from the III National Prevalence Study of Oral Health Diseases. After descriptive analyses, binary logistic regression models were used. RESULTS: In this study, 70.6% (n = 924) of adolescents reported that they brushed 'twice a day or more', and this behaviour was associated with all sociodemographic variables. Multivariate analysis revealed that male gender [odds ratio (OR) = 2.124; 95% confidence interval (95% CI): 1.616-2.793], rural residence (OR = 1.647; 95% CI: 1.169-2.321), peri-urban residence (OR = 1.926; 95% CI: 1.319-2.812), low level of maternal educational (OR = 2.139; 95% CI: 1.446-3.164) and father's unemployment (OR = 1.671; 95% CI: 1.127-2.478) were associated with not brushing at least twice a day (P < 0.05). Approximately 94% (n = 1,217) of participants had already visited an oral health professional, and 74.5% (n = 860) did so in the last 12 months. CONCLUSION: Our results are in agreement with the literature; the oral health behaviours of 12-year-old Portuguese adolescents can be regarded as satisfactory, although there are important variations across different subpopulations. The influence of sociodemographic factors suggests that tailored strategies must be developed for specific subpopulations, at both individual and community levels. PMID- 29624660 TI - Social decision making mediates the association between anger and externalising problems in Chinese adolescents. AB - The goal of this study was to test the mediating effect of social decision making in the relations of anger and anger control to externalising and internalising problems. A sample of 174 Chinese adolescents (mean age = 15.36 years) completed self-reports of trait anger, anger control, externalising problems, internalising problems and social decision making, which was operationalized as situational judgement reflecting an individual's ability to interact effectively with parents, teachers and peers. Findings indicated that adolescents' trait anger and anger control were positively related to both externalising and internalising problems. In addition, path analysis revealed that social decision making mediated the relationship between trait anger, anger control and externalising problems. Findings on the mediating effect will be discussed by referencing appraisal tendency theory and response evaluation and decision. PMID- 29624661 TI - Codon harmonization - going beyond the speed limit for protein expression. AB - Codon usage distribution has been soundly used by nature to fine tune protein biogenesis. Alteration of the mRNA structure or sequential scheduling of codons can profoundly affect translation, thus altering protein yield, functionality, solubility, and proper folding. Building on these observations, here, we present an evaluation of different recently designed algorithms of sequence adaptation based on Codon Adaptation Index (CAI) profiling. The first algorithm globally harmonizes synonymous codons in the original sequence in full respect to the heterologous expression host codon usage. The second recodes the sequence in accordance with the native sequence CAI profile. Our data, generated on three model proteins, highlights the importance to consider gene recoding as a parameter itself for recombinant protein expression improvement. PMID- 29624662 TI - Dyshidrosiform pemphigoid restricted to the soles. PMID- 29624663 TI - The fluctuating resource hypothesis explains invasibility, but not exotic advantage following disturbance. AB - Invasibility is a key indicator of community susceptibility to changes in structure and function. The fluctuating resource hypothesis (FRH) postulates that invasibility is an emergent community property, a manifestation of multiple processes that cannot be reliably predicted by individual community attributes like diversity or productivity. Yet, research has emphasized the role of these individual attributes, with the expectation that diversity should deter invasibility and productivity enhance it. In an effort to explore how these and other factors may influence invasibility, we evaluated the relationship between invasibility and species richness, productivity, resource availability, and resilience in experiments crossing disturbance with exotic seed addition in 1-m2 plots replicated over large expanses of grasslands in Montana, USA and La Pampa, Argentina. Disturbance increased invasibility as predicted by FRH, but grasslands were more invasible in Montana than La Pampa whether disturbed or not, despite Montana's higher species richness and lower productivity. Moreover, invasibility correlated positively with nitrogen availability and negatively with native plant cover. These patterns suggested that resource availability and the ability of the community to recover from disturbance (resilience) better predicted invasibility than either species richness or productivity, consistent with predictions from FRH. However, in ambient, unseeded plots in Montana, disturbance reduced native cover by >50% while increasing exotic cover >200%. This provenance bias could not be explained by FRH, which predicts that colonization processes act on species' traits independent of origins. The high invasibility of Montana grasslands following disturbance was associated with a strong shift from perennial to annual species, as predicted by succession theory. However, this shift was driven primarily by exotic annuals, which were more strongly represented than perennials in local exotic vs. native species pools. We attribute this provenance bias to extrinsic biogeographic factors such as disparate evolutionary histories and/or introduction filters selecting for traits that favor exotics following disturbance. Our results suggest that (1) invasibility is an emergent property best explained by a community's efficiency in utilizing resources, as predicted by FRH but (2) understanding provenance biases in biological invasions requires moving beyond FRH to incorporate extrinsic biogeographic factors that may favor exotics in community assembly. PMID- 29624664 TI - Effectiveness of a trauma-focused group intervention for young refugees: a randomized controlled trial. AB - BACKGROUND: As access to evidence-based treatments for young refugees with posttraumatic stress symptoms (PTSS) is limited, we developed the trauma-focused group intervention Mein Weg to be delivered by trained social workers. A recently published pilot study delivered preliminary evidence of the intervention with regard to symptom reduction and its feasibility. The aim of this study was, therefore, to determine whether the intervention, in addition to usual care (UC), is more effective in reducing PTSS (primary outcome) compared to UC alone. METHODS: A parallel group randomized controlled trial was conducted in seven German child and adolescent welfare agencies. Participants were randomly assigned to either six sessions Mein Weg (n = 50; Mage = 17.00, 94% male) or UC (n = 49; Mage = 16.92, 92% male). Mixed effect models, with fixed effects of group and time as well as their interaction, were performed on the relevant outcome measures. This trial was registered in the German Clinical Trials Registry (#DRKS00010915, https://www.drks.de/drks_web/). RESULTS: Intention-to-treat analyses showed that Mein Weg was significantly superior to UC regarding symptom improvement of self-reported PTSS (Mein Weg: d = .61, UC: d = .15) and depression (Mein Weg: d = .63, UC: d = -.06), but not regarding caregiver-reported symptoms and self-reported dysfunctional posttraumatic cognitions. CONCLUSIONS: Mein Weg is effective for young refugees according to self-reports and can be viewed as a valuable component in a stepped care approach for this vulnerable population. The findings need to be replicated with independent clinical assessments. PMID- 29624665 TI - Interspecific geographic range size-body size relationship and the diversification dynamics of Neotropical furnariid birds. AB - Among the earliest macroecological patterns documented, is the range and body size relationship, characterized by a minimum geographic range size imposed by the species' body size. This boundary for the geographic range size increases linearly with body size and has been proposed to have implications in lineages evolution and conservation. Nevertheless, the macroevolutionary processes involved in the origin of this boundary and its consequences on lineage diversification have been poorly explored. We evaluate the macroevolutionary consequences of the difference (hereafter the distance) between the observed and the minimum range sizes required by the species' body size, to untangle its role on the diversification of a Neotropical species-rich bird clade using trait dependent diversification models. We show that speciation rate is a positive hump shaped function of the distance to the lower boundary. The species with highest and lowest distances to minimum range size had lower speciation rates, while species close to medium distances values had the highest speciation rates. Further, our results suggest that the distance to the minimum range size is a macroevolutionary constraint that affects the diversification process responsible for the origin of this macroecological pattern in a more complex way than previously envisioned. PMID- 29624667 TI - The response of big sagebrush (Artemisia tridentata) to interannual climate variation changes across its range. AB - Understanding how annual climate variation affects population growth rates across a species' range may help us anticipate the effects of climate change on species distribution and abundance. We predict that populations in warmer or wetter parts of a species' range should respond negatively to periods of above average temperature or precipitation, respectively, whereas populations in colder or drier areas should respond positively to periods of above average temperature or precipitation. To test this, we estimated the population sensitivity of a common shrub species, big sagebrush (Artemisia tridentata), to annual climate variation across its range. Our analysis includes 8,175 observations of year-to-year change in sagebrush cover or production from 131 monitoring sites in western North America. We coupled these observations with seasonal weather data for each site and analyzed the effects of spring through fall temperatures and fall through spring accumulated precipitation on annual changes in sagebrush abundance. Sensitivity to annual temperature variation supported our hypothesis: years with above average temperatures were beneficial to sagebrush in colder locations and detrimental to sagebrush in hotter locations. In contrast, sensitivity to precipitation did not change significantly across the distribution of sagebrush. This pattern of responses suggests that regional abundance of this species may be more limited by temperature than by precipitation. We also found important differences in how the ecologically distinct subspecies of sagebrush responded to the effects of precipitation and temperature. Our model predicts that a short term temperature increase could produce an increase in sagebrush cover at the cold edge of its range and a decrease in cover at the warm edge of its range. This prediction is qualitatively consistent with predictions from species distribution models for sagebrush based on spatial occurrence data, but it provides new mechanistic insight and helps estimate how much and how fast sagebrush cover may change within its range. PMID- 29624666 TI - Manual dexterity, but not cerebral palsy, predicts cognitive functioning after neonatal stroke. AB - AIM: To disentangle the respective impacts of manual dexterity and cerebral palsy (CP) in cognitive functioning after neonatal arterial ischaemic stroke. METHOD: The population included 60 children (21 females, 39 males) with neonatal arterial ischaemic stroke but not epilepsy. The presence of CP was assessed clinically at the age of 7 years and 2 months (range 6y 11mo-7y 8mo) using the definition of the Surveillance of CP in Europe network. Standardized tests (Nine-Hole Peg Test and Box and Blocks Test) were used to quantify manual (finger and hand respectively) dexterity. General cognitive functioning was evaluated with the Wechsler Intelligence Scale for Children, Fourth Edition. Simple and multiple linear regression models were performed while controlling for socio-economic status, lesion side, and sex. RESULTS: Fifteen children were diagnosed with CP. In simple regression models, both manual dexterity and CP were associated with cognitive functioning (beta=0.41 [p=0.002] and beta=0.31 [p=0.019] respectively). However, in multiple regression models, manual dexterity was the only associated variable of cognitive functioning, whether or not a child had CP (beta=0.35; p=0.007). This result was reproduced in models with other covariables (beta=0.31; p=0.017). INTERPRETATION: As observed in typically developing children, manual dexterity is related to cognitive functioning in children having suffered a focal brain insult during the neonatal period. WHAT THIS PAPER ADDS: Manual dexterity predicts cognitive functioning after neonatal arterial ischaemic stroke. Correlations between manual dexterity and cognitive functioning occur irrespective of sex, lesion side, presence of cerebral palsy, and socio-economic status. Residual motor ability may support cognitive functioning. PMID- 29624668 TI - Evolution of cranial telescoping in echolocating whales (Cetacea: Odontoceti). AB - Odontocete (echolocating whale) skulls exhibit extreme posterior displacement and overlapping of facial bones, here referred to as retrograde cranial telescoping. To examine retrograde cranial telescoping across 40 million years of whale evolution, we collected 3D scans of whale skulls spanning odontocete evolution. We used a sliding semilandmark morphometric approach with Procrustes superimposition and PCA to capture and describe the morphological variation present in the facial region, followed by Ancestral Character State Reconstruction (ACSR) and evolutionary model fitting on significant components to determine how retrograde cranial telescoping evolved. The first PC score explains the majority of variation associated with telescoping and reflects the posterior migration of the external nares and premaxilla alongside expansion of the maxilla and frontal. The earliest diverging fossil odontocetes were found to exhibit a lesser degree of cranial telescoping than later diverging but contemporary whale taxa. Major shifts in PC scores and centroid size are identified at the base of Odontoceti, and early burst and punctuated equilibrium models best fit the evolution of retrograde telescoping. This indicates that the Oligocene was a period of unusually high diversity and evolution in whale skull morphology, with little subsequent evolution in telescoping. PMID- 29624669 TI - Effects of hurricanes and climate oscillations on annual variation in reproduction in wet forest, Puerto Rico. AB - Interannual changes in global climate and weather disturbances may influence reproduction in tropical forests. Phenomena such as the El Nino Southern Oscillation (ENSO) are known to produce interannual variation in reproduction, as do severe storms such as hurricanes. Using stationary trap-based phenology data collected fortnightly from 1993 to 2014 from a hurricane-affected (1989 Hugo, 1998 Georges) subtropical wet forest in northeastern Puerto Rico, we conducted a time series analysis of flowering and seed production. We addressed (1) the degree to which interannual variation in flower and seed production was influenced by global climate drivers and time since hurricane disturbance, and (2) how long-term trends in reproduction varied with plant lifeform. The seasonally de-trended number of species in flower fluctuated over time while the number of species producing seed exhibited a declining trend, one that was particularly evident during the second half of the study period. Lagged El Nino indices and time series hurricane disturbance jointly influenced the trends in numbers of flowering and fruiting species, suggesting complex global influences on tropical forest reproduction with variable periodicities. Lag times affecting flowering tended to be longer than those affecting fruiting. Long-term patterns of reproduction in individual lifeforms paralleled the community-wide patterns, with most groups of lifeform exhibiting a long-term decline in seed but not flower production. Exceptions were found for hemiepiphytes, small trees, and lianas whose seed reproduction increased and then declined over time. There was no long-term increase in flower production as reported in other Neotropical sites. PMID- 29624670 TI - Spasticity in children with cerebral palsy: what are we treating? PMID- 29624671 TI - Practitioner Review: Emotional dysregulation in attention-deficit/hyperactivity disorder - implications for clinical recognition and intervention. AB - BACKGROUND: Because emotional symptoms are common in attention deficit/hyperactivity disorder (ADHD) patients and associate with much morbidity, some consider it to be a core feature rather than an associated trait. Others argue that emotional symptoms are too nonspecific for use as diagnostic criteria. This debate has been difficult to resolve due, in part, to the many terms used to describe emotional symptoms in ADHD and to concerns about overlap with mood disorders. METHODS: We sought to clarify the nature of emotional symptoms in ADHD by reviewing conceptual and measurement issues and by examining the evidence base regarding specificity of such symptoms for ADHD. We reviewed the various terms used to define emotional symptoms in ADHD, clarify how these symptoms are demarcated from mood disorders, and assess the possibility that symptoms of emotional impulsivity and deficient emotional self-regulation should be considered as core symptoms. We addressed psychiatric comorbidities, the effects of ADHD treatments on associated emotional dysregulation, and the utility of current rating scales to assess emotional symptoms associated with ADHD. RESULTS: Emotional symptoms are common and persistent in youth and adults with ADHD. Although emotional symptoms are common in other psychiatric disorders, emotional impulsivity (EI), and deficient emotional self-regulation (DESR) may be sufficiently specific for ADHD to function as diagnostic criteria. CONCLUSIONS: Emotional symptoms in ADHD cause clinically significant impairments. Although there is a solid theoretical rationale for considering EI and DESR to be core symptoms of ADHD, there is no consensus about how to define these constructs sin a manner that would be specific to the disorder. An instrument to measure EI and DESR which demarcates them from irritability and other emotional symptoms could improve the accuracy of diagnostic criteria for ADHD. PMID- 29624672 TI - Mohs micrographic surgery for basal cell carcinoma of the scrotum. PMID- 29624673 TI - The bone marrow is patrolled by NK cells that are primed and expand in response to systemic viral activation. AB - The bone marrow hosts NK cells whose distribution, motility and response to systemic immune challenge are poorly understood. At steady state, two-photon microscopy of the bone marrow in Ncr1gfp/+ mice captured motile NK cells interacting with dendritic cells. NK cells expressed markers and effector molecules of mature cells. Following poly (I:C) injection, RNA-Seq of NK cells revealed three phases of transcription featuring immune response genes followed by posttranscriptional processes and proliferation. Functionally, poly (I:C) promoted upregulation of granzyme B, enhanced cytotoxicity in vitro and in vivo, and, in the same individual cells, triggered proliferation. Two-photon imaging revealed that the proportion of sinusoidal NK cells decreased, while at the same time parenchymal NK cells accelerated, swelled and divided within the bone marrow. MVA viremia induced similar responses. Our findings demonstrate that the bone marrow is patrolled by mature NK cells that rapidly proliferate in response to systemic viral challenge while maintaining their effector functions. PMID- 29624674 TI - Cytochemical features of the digestive tract mucosa of Hemisorubim platyrhynchos (Siluriformes: Pimelodidae). AB - Membranous organelles, acid glycoconjugates and lipids were characterized in the digestive tract mucosa of Hemisorubim platyrhynchos by cytochemistry techniques. Two types of mucous-secreting cells were observed in the digestive tract epithelium: goblet cells in the oesophagus and intestine and epithelial cells in the stomach. These cells had a Golgi apparatus more developed than the other cell types. The cytochemical analysis revealed that secretory granules are reactive to acid glycoconjugates, varying in reaction intensity according to the region of the digestive tract. Acid glycoconjugate reactions were also observed in oesophageal epithelial cell microridges and in enterocyte microvilli. In the digestive tract, acid glycoconjugates act to protect the epithelial surface, increasing mucous viscosity, which facilitates the passage of food, prevents the binding of parasites and facilitates their removal. Through lipid staining, a coated membrane was observed around each secretory granule of the oesophageal and intestinal goblet cells, while gastric epithelial cells granules were fully reactive. Oxynticopeptic cells of the gastric glands showed lipid droplets in the cytoplasm and also in the mitochondrial matrix, which act as an energy reserve for these cells that have a high energy demand. Enterocytes showed a well developed smooth endoplasmic reticulum, especially in the apical region of the cell, being related to absorption and resynthesis of lipids. PMID- 29624675 TI - Parasympathetic and sympathetic activity are associated with individual differences in neural indices of selective attention in adults. AB - Multiple theoretical frameworks posit that interactions between the autonomic nervous system and higher-order neural networks are crucial for cognitive and emotion regulation. However, few studies have directly examined the relationship between measures of autonomic physiology and brain activity during cognitive tasks, and fewer studies have examined both the parasympathetic and sympathetic autonomic branches when doing so. Here, 93 adults completed an ERP auditory selective attention task concurrently with measures of parasympathetic activity (high-frequency heart rate variability; HF-HRV) and sympathetic activity (preejection period; PEP). We focus on the well-studied N1 ERP component to test for associations with baseline values of HF-HRV and PEP. Individuals with higher resting HF-HRV and shorter resting PEP showed larger effects of selective attention on their ERPs. Follow-up regression models demonstrated that HF-HRV and PEP accounted for unique variance in selective attention effects on N1 mean amplitude. These results are consistent with the neurovisceral integration model, such that greater parasympathetic activity is a marker of increased selective attention, as well as other theoretical models that emphasize the role of heightened sympathetic activity in more efficient attention-related processing. The present findings highlight the importance of autonomic physiology in the study of individual differences in neurocognitive function and, given the foundational role of selective attention across cognitive domains, suggest that both parasympathetic and sympathetic activity may be key to understanding variability in brain function across a variety of cognitive tasks. PMID- 29624676 TI - Validity of self-reported periodontal measures, demographic characteristics, and systemic medical conditions. AB - BACKGROUND: The objective of the present study was to assess self-reported periodontal screening questions, demographic characteristics, systemic medical conditions, and tobacco use for predicting periodontal disease among individuals seeking dental therapy in a university dental clinic. METHODS: In this retrospective study, a total of 4,890 randomly selected dental charts were evaluated from among patients who had attended the University of Minnesota School of Dentistry clinics for treatment. Radiographic bone loss measurements were used to assess the severity of periodontal disease. Demographic characteristics as well as medical history of the patients were also recorded. Five self-reported periodontal screening questions were included, with answers limited to Yes/No. Generalized logit models were used to assess the association between bone loss and the predictors. RESULTS: The sample's mean age was 54.1 years and included 52.6% males and 14.9% smokers, with a mean of 3.5 missing teeth. Self-reported tooth mobility, history of "gum treatment," and the importance of retaining teeth as well as age, tobacco use, and cancer were statistically significant predictors (P < 0.05) of a radiographic diagnosis of moderate and severe periodontal disease. With respect to severe periodontal disease, significant associations (P < 0.05) were also found with "bleeding while brushing," gender, diabetes, anxiety, and arthritis. CONCLUSIONS: Self-reported periodontal screening questions as well as demographic characteristics, smoking, and systemic medical conditions were significant predictors of periodontal disease, and they could be used as valid, economic, and practical measures. PMID- 29624677 TI - Logistical and safety implications of temperature-based acceptance of returned red blood cell units. AB - BACKGROUND: AABB requires that red blood cells (RBCs) are maintained at 1 to 10 degrees C during transport. Historically, blood banks used the 30-minute rule for returned RBCs transported outside of validated containers. The implications of this policy have not been previously reported in a real-life hospital setting. STUDY DESIGN AND METHODS: A 2-year, retrospective review of RBC units returned outside of qualified containers was conducted. During the first year, the 30 minute rule was used to accept RBCs back into inventory. Sequentially, the following year, a temperature-based approach was implemented using a thermometer with an accuracy of +/-1 degrees C. Time out of the blood bank, temperature upon return, wastage, and transfusion reactions associated with the reissued RBCs were analyzed. RESULTS: In our practice, the 30-minute rule would have accepted 15.2% of RBC units outside of the allowed temperature. Compared to the 30-minute rule, temperature-based acceptance was associated with a 13% increase in wastage (p < 0.001). During the 30-minute rule period, transfusion of returned and subsequently reissued RBCs was associated with a nonsignificant trend toward a higher transfusion reaction rate compared to the overall RBC transfusion reaction rate (1.4% vs. 0.6%, p = 0.084). During the temperature period, transfusion of returned and subsequently reissued RBCs had the same transfusion reaction rate compared to the overall RBC transfusion reaction rate (0.5% vs. 0.5%, p = 1.0). CONCLUSION: Temperature-based acceptance of returned RBCs is associated with significantly higher wastage compared to the 30-minute rule. A temperature-based acceptance practice mitigates the risk of accepting RBCs with unacceptable temperatures returned within 30 minutes of issue. PMID- 29624678 TI - Response acquisition by zebrafish (Danio rerio) with delayed reinforcement. AB - Zebrafish (Danio rerio) is a common vertebrate animal model in biomedical research and is a promising species for studying how genes interact with environmental factors in determining behavior. The present study investigated how reinforcement parameters affect zebrafish behavior by assessing response acquisition with delayed reinforcement, which has been studied with other species (e.g., rats, pigeons, humans, etc.) but not with zebrafish. Twenty-four experimentally naive subjects were exposed to a tandem fixed-ratio 1 differential reinforcement-of-other-behavior x-s schedule of reinforcement, where x varied across subjects. There were six different delay-to-reinforcement durations and sets of four fish were assigned to each delay duration. All of the fish assigned to a 0-, 0.5-, or 1-s delay acquired responding. Two fish acquired responding with a 3-s delay and one fish appeared to have acquired it with a 6-s delay although the latter result was less clear. None acquired responding with a 12-s delay. These results suggest that zebrafish behavior is sensitive to delays to reinforcement and the time frame over which reinforcement is effective may be limited approximately to 6 s. This time frame is shorter than that found with other species. Practical and theoretical implications of the present finding are discussed. PMID- 29624680 TI - A new species of Anchoviella (Clupeiformes: Engraulidae) from the western Amazon River in Peru, with comments on congeners in the Peruvian Amazon River. AB - Anchoviella hernanni sp. nov. is described from the upper Amazon River basin, in tributaries of the Maranon, Ucayali and Madre de Dios river drainages that drain the Peruvian Andes. The new taxon can be distinguished from all congeners except Anchoviella jamesi, Anchoviella manamensis and Anchoviella perezi, by having 12 15 gill rakers in the lower branch of the first gill arch (v.16-35) and from those species by the distance between verticals through the posterior margin of the orbit to the posterior margin of the upper jaw 9.5-14.8% head length; LH (v. up to 6.0% LH ). An updated identification key of all freshwater species of Anchoviella and morphological comparisons between all species of the genus occurring in Peru are provided. PMID- 29624679 TI - Metabolic effect of alkaline additives and guanosine/gluconate in storage solutions for red blood cells. AB - BACKGROUND: Over a century of advancements in the field of additive solutions for red blood cell (RBC) storage has made transfusion therapy a safe and effective practice for millions of recipients worldwide. Still, storage in the blood bank results in the progressive accumulation of metabolic alterations, a phenomenon that is mitigated by storage in novel storage additives, such as alkaline additive solutions. While novel alkaline additive formulations have been proposed, no metabolomics characterization has been performed to date. STUDY DESIGN AND METHODS: We performed UHPLC-MS metabolomics analyses of red blood cells stored in SAGM (standard additive in Europe), (PAGGSM), or alkaline additives SOLX, E-SOL 5 and PAG3M for either 1, 21, 35 (end of shelf-life in the Netherlands), or 56 days. RESULTS: Alkaline additives (especially PAG3M) better preserved 2,3-diphosphoglycerate and adenosine triphosphate (ATP). Deaminated purines such as hypoxanthine were predictive of hemolysis and morphological alterations. Guanosine supplementation in PAGGSM and PAG3M fueled ATP generation by feeding into the nonoxidative pentose phosphate pathway via phosphoribolysis. Decreased urate to hypoxanthine ratios were observed in alkaline additives, suggestive of decreased generation of urate and hydrogen peroxide. Despite the many benefits observed in purine and redox metabolism, alkaline additives did not prevent accumulation of free fatty acids and oxidized byproducts, opening a window for future alkaline formulations including (lipophilic) antioxidants. CONCLUSION: Alkalinization via different strategies (replacement of chloride anions with either high bicarbonate, high citrate/phosphate, or membrane impermeant gluconate) results in different metabolic outcomes, which are superior to current canonical additives in all cases. PMID- 29624681 TI - A new species of Astyanax (Characiformes: Characidae) from Costa Rica and Panama, with a key to the lower Central American species of the genus. AB - Astyanax anai, a new species of characid fish, is described from the Sixaola River basin, eastern Costa Rica-western Panama, Central America. The new species can be distinguished from all other congeners by the following combination of characters: premaxillary teeth 4-5 at the inner series and 4-6 at the outer series; maxillary teeth tricuspid, 2-4; predorsal scale series irregular and incomplete, with an unscaled space behind tip of supraoccipital process and 12-14 scales; lateral line scales 34-39; humeral region with a conspicuous black and rounded to horizontally ovate spot and two diffuse brown and vertically elongate bars (the first through the rounded to horizontally ovate spot, the second 2-4 scales behind the first); body depth 36.6-42.3% of standard length (LS ); midlateral stripe formed by a series of 10-14 anteriorly-directed dermal herringbone, or chevron-shaped, marks, most apparent in juveniles and in preserved specimens, extending above the lateral line from the black humeral spot or just behind it (from the second vertical bar) to the caudal peduncle; scale rows from lateral line to base of first dorsal-fin ray 8-9; scale rows from lateral line to base of pelvic fin 7-8; pre-anal distance 53.9-61.9% of LS ; total anal-fin elements 29-33; caudal spot elongated, rhomboid or rectangular, with its anterior margin surpassing the middle of the caudal peduncle, usually reaching the anal-fin insertion, posteriorly covering 4-7 principal caudal-fin rays and not extending onto the ventral and dorsal margins of the caudal peduncle, covering 3-5 horizontal scale rows. In order to test the phylogenetic relationships of the new taxon in relation to the other North and Central American species of the genus, a new phylogenetic hypothesis based on a reanalysis of the morphological matrix by Schmitter-Soto (2016) is proposed. A key to the lower Central American (southern Nicaragua to eastern Panama) species of Astyanax is also provided. PMID- 29624682 TI - ABO incompatibility and RhIG immunoprophylaxis protect against non-D alloimmunization by pregnancy. AB - BACKGROUND: Hemolytic disease of the fetus and newborn (HDFN) is caused by maternal antibodies against fetal red blood cell antigens, most often anti-D, -K, or -c. ABO incompatibility between mother and child and anti-D immunoprophylaxis (RhIG) are known to reduce the risk of D immunization and subsequent HDFN. However, no immunoprophylaxis has been developed to prevent non-D immunizations. STUDY DESIGN AND METHODS: We evaluated whether ABO incompatibility has a preventive effect on formation of non-D alloantibodies, by performing a case control study including pregnant women with newly detected non-D antibodies, identified within a nationwide data set, immunized during their first pregnancy and/or delivery. Subsequently, we assessed a possible protective effect of RhIG in a subgroup with non-Rh antibodies only. The proportions of previous ABO incompatibility and of RhIG administrations of these women were compared to the known rate of 19.4% ABO incompatibility and 9.9% RhIG administrations (D- women carrying a D+ child) in the general population of pregnant women. RESULTS: A total of 11.9% of the 232 included immunized women had a possible ABO incompatibility in their first pregnancy (vs. expected 19.4%; 95% confidence interval [CI], 7.3-18.8; p = 0.036). Furthermore, 1.0% women with non-Rh antibodies were D-, delivered a D+ child, and had therefore received RhIG, whereas 9.9% was expected (95% CI, 0.18-5.50; p = 0.003). CONCLUSION: We found that ABO incompatibility and RhIG reduce the risks not only for D, but also for non-Rh immunizations, suggesting that antibody-mediated immune suppression in this condition is not antigen specific. PMID- 29624683 TI - Evaluation of the association between the number of natural teeth and anemia among Korean adults using nationally representative data. AB - BACKGROUND: Anemia as a chronic disease is defined as anemia occurring in chronic infections with inflammatory conditions. The purpose of this study is to assess the association between the number of natural teeth and anemia using nationally representative data. METHODS: This study involved a cross-sectional analysis using data from the Korean National Health and Nutrition Examination Survey from 2010 to 2012. A total of 16,875 respondents aged > 19 years without missing values were included in this study. The association between the number of natural teeth and anemia was evaluated by multivariable logistic regression analyses after adjusting for age, sex, body mass index, smoking habits, drinking habits, exercise levels, income levels, education levels, vitamin D levels, diabetes, toothbrushing frequency, energy intake, and percentage of fat in total energy intake among Korean adults. RESULTS: There was a significant decrease in prevalence of anemia and a significant increase in hemoglobin levels in participants with more natural teeth (P < 0.05). Adjusted odds ratios and their 95% confidence intervals for anemia in participants with numbers of natural teeth of < 15, 15 to 19, 20 to 24, or 24 to 28 were 1 (reference), 0.856(0.591 to 1.24), 0.659(0.5 to 0.868), and 0.607(0.463 to 0.797), respectively, with adjustment for confounding factors (P < 0.05). CONCLUSION: The number of natural teeth is negatively associated with anemia in Korean adults, and the number of natural teeth may be considered an independent risk indicator of anemia. PMID- 29624684 TI - The ectomycorrhizal basidiomycete Laccaria bicolor releases a secreted beta-1,4 endoglucanase that plays a key role in symbiosis development. AB - In ectomycorrhiza, root ingress and colonization of the apoplast by colonizing hyphae is thought to rely mainly on the mechanical force that results from hyphal tip growth, but this could be enhanced by secretion of cell-wall-degrading enzymes, which have not yet been identified. The sole cellulose-binding module (CBM1) encoded in the genome of the ectomycorrhizal Laccaria bicolor is linked to a glycoside hydrolase family 5 (GH5) endoglucanase, LbGH5-CBM1. Here, we characterize LbGH5-CBM1 gene expression and the biochemical properties of its protein product. We also immunolocalized LbGH5-CBM1 by immunofluorescence confocal microscopy in poplar ectomycorrhiza. We show that LbGH5-CBM1 expression is substantially induced in ectomycorrhiza, and RNAi mutants with a decreased LbGH5-CBM1 expression have a lower ability to form ectomycorrhiza, suggesting a key role in symbiosis. Recombinant LbGH5-CBM1 displays its highest activity towards cellulose and galactomannans, but no activity toward L. bicolor cell walls. In situ localization of LbGH5-CBM1 in ectomycorrhiza reveals that the endoglucanase accumulates at the periphery of hyphae forming the Hartig net and the mantle. Our data suggest that the symbiosis-induced endoglucanase LbGH5-CBM1 is an enzymatic effector involved in cell wall remodeling during formation of the Hartig net and is an important determinant for successful symbiotic colonization. PMID- 29624685 TI - Timing of Atlantic salmon Salmo salar smolt migration predicts successful passage through a reservoir. AB - Around 30% of Atlantic salmon Salmo salar smolts successfully survived passage through Loch Meig, a reservoir in the north of Scotland, en route to the sea. However, this survival rate was in turn dependent on the timing of migration, with the earliest migrants in the spring having the best chance of survival. This could have implication for fisheries management, since the estimation of smolt downstream survival may be influenced by which time period of the smolt run is analysed. PMID- 29624686 TI - Juvenile migration of the exclusively pelagic cyprinid, Gnathopogon caerulescens (Honmoroko) in Lake Biwa, Central Japan. AB - Migration of wild and cultivated juvenile honmoroko Gnathopogon caerulescens of from the spawning and nursery areas in Lake Biwa were investigated, both in the Ibanaiko Lagoon and its outlet to Daido River, using beam-trawl surveys in 2013 and 2014. The study demonstrated migration of G. caerulescens from a nursery lagoon toward Lake Biwa after the juvenile stage. These findings appear to be the first direct evidence for migration of an exclusively pelagic cyprinid species from a littoral nursery to a pelagic adult habitat in a large deep lake. PMID- 29624687 TI - [Development of molecular targeted anti-cancer hybrid peptide for novel cancer therapy ]. PMID- 29624688 TI - Characteristics of an beta-N-Acetylhexosaminidase from Bacillus sp. CH11, Including its Transglycosylation Activity. AB - : beta-N-Acetylhexosaminidase was identified from Bacillus sp. CH11 and found to have relatively high transferring activity. In this study, its enzymatic properties and transglycosylation activity including its acceptor specificity were investigated. Its molecular weight was estimated to be 90 kDa by SDS-PAGE and its optimal pH was approximately 7 with good stability from pH 6 to 8. Its optimal temperature was 40 degrees C, and its activity was stable at temperatures of up to 40 degrees C. To analyze its acceptor specificity for transglycosylation, N, N'-diacetylchitobiose was used as a donor substrate and alcohols, sugar alcohols, sugars and polyphenols were used as acceptors. Dialcohols, which have 2 hydroxyl groups on the outside of the carbon chains, were good acceptors. The molecular size of the acceptor did not influence the transglycosylation up to at least 1,5-pentanediol (carbon number: C5). Glycerin (C3), erythritol (C4), and xylitol (C5), all small molecular weight sugar alcohols, had high acceptor specificity. Transglycosylation to mono- and disaccharides and polyphenols was not observed except for L-fucose. For the beta N-acetylhexosaminidase-catalyzed transglycosylation of chitin oligosaccharides and xylitol, the transfer product was identified as 1-O-beta-D-N acetylglucosaminyl xylitol. The optimal ratio of xylitol was 24% to 2% N, N' diacetylchitobiose and 226 mg per 1 g N, N'-diacetylchitobiose was produced. CH11 beta-N-acetylhexosaminidase efficiently produced 1-O-beta-D-N-acetylglucosaminyl xylitol via transglycosylation. PRACTICAL APPLICATION: The new transfer products including 1-O-beta-D-N-acetylglucosaminyl xylitol are attractive compounds for their potential physiological functions. 1-O-beta-D-N-Acetylglucosaminyl xylitol was produced effectively from chitin-oligosaccharides and xylitol by beta-N acetylhexosaminidase from Bacillus sp. CH11. This enzyme may be useful for the development of food materials for health-related applications such as oligosaccharides with intestinal functions and noncariogenic sugars. PMID- 29624689 TI - Effects of Fat Polymorphic Transformation and Nonfat Particle Size Distribution on the Surface Changes of Untempered Model Chocolate, Based on Solid Cocoa Mass. AB - : This study aims to understand the bloom process in untempered chocolate by investigating the polymorphic transformation of cocoa butter and changes in chocolate surface. Cocoa mass with varying particle size distributions (PSD) were used to produce untempered model chocolate. Optical microscopy showed that during 25 d of storage, the chocolate surface gradually became honeycombed in appearance with dark spots surrounded by white sandy bloom areas. In conjunction with X-ray diffraction this indicates that the polymorphic transformation of form IV cocoa butter to more stable form V crystals caused the observed surface changes with the most significant changes occurring within 6 d. As bloom developed the surface whiteness increased, but the PSD of nonfat particles showed limited impact on the changes in whiteness. Moreover, scanning electron microscopy showed separated fat crystals on fat-rich dark spots and empty spaces between particles in bloom areas suggesting redistribution of fat in the chocolate matrix. PRACTICAL APPLICATION: The results reported in this work can facilitate the understanding of fat bloom formation in untempered chocolate with respect to the changes in microstructure and surface appearances. It also contributes to show the details of IV-to-V polymorphic transformation in the fat phase as time went by. PMID- 29624690 TI - Sleep disturbances are associated with frailty in older adults AB - Background: Sleep plays a vital role in good health. Since sleep disturbances have been linked to a series of adverse physical health outcomes, the objective was to analyze the association between sleep disturbances and the frailty criteria in Mexican older adults from Mexico City. Methods: The study design was cross-sectional. A total of 1252 people aged 60 years or older were assessed according to Fried criteria for defining frailty. Sleep disturbances (sleeping without rest, sleeping more than usual and having trouble sleeping) were collected by self-report through a face to face questionnaire. The association between sleep disturbances and frailty was estimated with ordinal logistic regression controlled by covariates. Results: It was found that 6.9% of older people reported sleeping more than usual, 18.9% slept without rest and 16.3% had trouble sleeping. There was a statistically significant association between sleeping more than usual (OR = 1.96, 95% CI: 1.23-3.12) and having trouble sleeping (OR = 1.53, 95%CI: 1.09-2.17) with frailty. Conclusion: Sleeping more than usual or having trouble sleeping contribute to increase frailty in older people from Mexico City. PMID- 29624691 TI - Early developmental and allometric patterns in the electric yellow cichlid Labidochromis caeruleus. AB - The electric yellow cichlid Labidochromis caeruleus is a mouth-brooding haplochromine cichlid from Lake Malawi and one of the most popular cichlids in the ornamental fish industry. To investigate the early development of L. caeruleus from hatching until the juvenile stage, we studied its morphological development and allometric growth patterns. In newly-hatched larvae, most organs and body parts were not yet differentiated and continued to develop until 15 days post hatching (dph). The yolk sac was depleted at 13 dph. There was allometric growth, primarily in the anterior and posterior regions of the body, and inflection points when trajectories of allometric growth changed. Head and tail growth was prioritized, suggesting that body parts linked to feeding and swimming behaviour mature earlier than the rest of the body. Additionally, growth patterns revealed that development of organs related to vital functions such as branchial respiration, sensation, exogenous feeding and swimming was prioritized. Comparisons with other African and Neotropical cichlids revealed differences in ontogenetic processes and allometric growth along the anterior-posterior axis as well as variation in developmental timing. These results indicate how early morphological development and ontogenic processes might respond to the distinctive parental care observed in mouth-brooding cichlids. PMID- 29624692 TI - Photo-identification as a tool to study small-spotted catshark Scyliorhinus canicula. AB - Photo-identification (photo-ID) was tested as a means to identify individual small-spotted catsharks Scyliorhinus canicula. The spotting pattern of the caudal region of S. canicula was used for the tests and revealed that photo-ID is an efficient method to identify individuals. Photo-ID is logistically simple, making it a potential alternative to traditional tagging to provide information on the distribution patterns and population dynamics of S. canicula and related species. PMID- 29624693 TI - Accuracy of 2D shear wave elastography in the diagnosis of liver fibrosis in patients with chronic hepatitis C. AB - PURPOSE: This prospective study was conducted to assess the diagnostic accuracy of two-dimensional shear wave elastography (2D SWE) in the diagnosis of liver fibrosis in patients with chronic liver disease and hepatitis C virus (HCV) compared with the serum liver fibrosis biomarkers using the results of liver biopsy as the reference standard. METHODS: We analyzed 233 consecutive HCV patients. On the same day, 2D SWE m, biochemical tests, and liver biopsy were performed. We used the METAVIR staging system and receiver operating characteristic curves for the analysis. RESULTS: The success rate of 2D-SWE was 98.7%. The median shear wave velocities (SWVs) of patients in the F0, F1, F2, F3, and F4 stages were 1.35 m/s, 1.42 m/s, 1.58 m/s, 1.83 m/s, and 2.13 m/s, respectively, demonstrating a stepwise increase (P < .0001). The accuracy of 2D SWE in the prediction of >=F1, >=F2, >=F3, and F4 was .888 (95% CI: .85-.93), .915 (95% CI: .88-095), .940 (95% CI: .91-.97), and .949 (95% CI: .92-.97), respectively. 2D-SWE was significantly superior to serum liver fibrosis biomarkers. CONCLUSION: 2D-SWE was positively correlated with the severity of liver fibrosis and was more useful for to predict all liver fibrosis grades in HCV patients than liver fibrosis biomarkers. PMID- 29624694 TI - The impact of cognitive training on spontaneous gamma oscillations in schizophrenia. AB - Schizophrenia patients exhibit less gamma-frequency EEG/MEG activity (>30 Hz), a finding interpreted as evidence of poor temporal neural organization and functional network communication. Research has shown that neuroplasticity oriented training can improve task-related oscillatory dynamics, indicating some reorganization capacity in schizophrenia. Demonstrating a generalization of such task training effects to spontaneous oscillations at rest would not only enrich understanding of this neuroplastic potential but inform the interpretation of spontaneous gamma oscillations in the service of normal cognitive function. In the present study, neuromagnetic resting-state oscillatory brain activity and cognitive performance were assessed before and after training in 61 schizophrenia patients, who were randomly assigned to 4 weeks of neuroplasticity-oriented targeted cognitive training or treatment as usual (TAU). Gamma power of 40-90 Hz increased after training, but not after TAU, in a frontoparietal network. Across two types of training, this increase was related to improved cognitive test performance. These results indicate that abnormal oscillatory dynamics in schizophrenia patients manifested in spontaneous gamma activity can be changed with neuroplasticity-oriented training parallel to cognitive performance. PMID- 29624695 TI - Effect of Passive Drying on Ascorbic Acid, alpha-Tocopherol, and beta-Carotene in Tomato and Mango. AB - : The effect of two passive drying methods on the degradation of ascorbic acid (vitamin C), alpha-tocopherol (vitamin E), and beta-carotene (provitamin A) in ripe mango and tomato was determined. Samples of both commodities were dried outdoors in a solar drying cabinet or indoors in sealed plastic boxes containing ceramic zeolite drying beads in a bead-to-fruit ratio of 1:10. Nutrient content of the dried samples was compared to fresh samples (undried control) obtained from the same batch of fruit. Mango samples tended to reach an equilibrium weight of approximately 18% of their initial weight after 28 to 30 hr of drying in both drying methods, while tomatoes equilibrated at 5% to 6% of their initial weight after 8 to 10 hr of drying in the solar drying cabinet and after approximately 30 hr using drying beads. The content of all three nutrients in solar dried tomato, and of beta-carotene in mango were significantly (P < 0.05) lower than the control. alpha-Tocopherol and beta-carotene content in tomato and beta-carotene content in mango were significantly lower than the control in samples dried using drying beads. Drying method had a significant (P < 0.05) effect on nutrient content; ascorbic acid and beta-carotene content were lower in solar dried tomato than in tomato dried with drying beads. For mango, beta-carotene content was lower after solar drying as compared to drying with drying beads. Drying fruit at lower temperatures using drying beads resulted in higher overall nutrient content of the dried fruit. PRACTICAL APPLICATION: Agriculturalists in developing countries still depend largely on solar drying methods as a means of extending the shelf life and increasing the value of fruit and vegetable products. Zeolite drying beads are reusable and are capable of drying fruit relatively quickly in a controlled environment, and may reduce the degradation of certain nutrients due to heat during solar drying. PMID- 29624696 TI - Consistency of fish-shoal social network structure under laboratory conditions. AB - We investigated the consistency of association network structure for groups of sticklebacks Gasterosteus aculeatus. Each group was observed twice and we varied the duration between observations and the size of the experimental arena that they were observed in. At the dyad level, we found positive correlations between dyad interaction frequencies across observations. At the group level we found variation in four network metrics between observations, but only in treatments where the duration between observations was short. Specifically, fish formed more and smaller groups in the second observation in this treatment. Fish were also organized into more subunits in the larger arenas. Finally, we saw positive correlations between some group network metrics across observations suggesting relative consistency at the group level. There are several processes that might drive these interaction patterns. Our findings have implications for experimental design and the comparison and integration of findings of experiments from different studies carried out under different conditions. PMID- 29624697 TI - A new Myleus species (Characiformes: Serrasalmidae) from the Rio Tapajos basin, Brazil. AB - Myleus pachyodus, a new serrasalmid species, is described from the Rio Teles Pires and Rio Jamanxim, both tributaries of the Rio Tapajos in Mato Grosso and Para states, Brazil. The new species differs from all congeners by having a remarkable ontogenetic thickening of the teeth shifting from slender incisiform in juveniles to thick bulky teeth at standard length >= 100 mm, whereas congeners present slender, antero-posteriorly flat teeth throughout all life stages. The new species further differs from congeners by having 18-20 branched dorsal-fin rays, by the lack of a diastema between contralateral outer series of premaxillary teeth and by the presence of 16-25 prepelvic spines, with the anteriormost spine never reaching the vertical through the pectoral-fin origin. PMID- 29624698 TI - Accelerated diversification is related to life history and locomotion in a hyperdiverse lineage of microbial eukaryotes (Diatoms, Bacillariophyta). AB - Patterns of species richness are commonly linked to life history strategies. In diatoms, an exceptionally diverse lineage of photosynthetic heterokonts important for global photosynthesis and burial of atmospheric carbon, lineages with different locomotory and reproductive traits differ dramatically in species richness, but any potential association between life history strategy and diversification has not been tested in a phylogenetic framework. We constructed a time-calibrated, 11-gene, 1151-taxon phylogeny of diatoms - the most inclusive diatom species tree to date. We used this phylogeny, together with a comprehensive inventory of first-last occurrences of Cenozoic fossil diatoms, to estimate ranges of expected species richness, diversification and its variation through time and across lineages. Diversification rates varied with life history traits. Although anisogamous lineages diversified faster than oogamous ones, this increase was restricted to a nested clade with active motility in the vegetative cells. We propose that the evolution of motility in vegetative cells, following an earlier transition from oogamy to anisogamy, facilitated outcrossing and improved utilization of habitat complexity, ultimately leading to enhanced opportunity for adaptive divergence across a variety of novel habitats. Together, these contributed to a species radiation that gave rise to the majority of present-day diatom diversity. PMID- 29624699 TI - Diagnosis, Staging, and Management of Hepatocellular Carcinoma: 2018 Practice Guidance by the American Association for the Study of Liver Diseases. PMID- 29624700 TI - Sarcomatoid pilomatrix carcinoma. AB - Pilomatrix (pilomatrical) carcinoma is a rare cutaneous adnexal tumor with matrical differentiation and recurrent and metastatic potential. Sarcomatoid pilomatrix carcinoma is a rare variant which shows a sarcomatoid component intermingling with the epithelial one. There are only 4 cases previously published. We present an additional case on the hand of a 78 year-old man which appeared as a 6 mm hyperkeratotic, focally ulcerated plaque. A shave biopsy demonstrated a dermal infiltrative neoplasm, composed of markedly atypical appearing basaloid cells with focal necrotic/ghost cells, as well as an intimately associated population of atypical oval to spindle-shaped cells. Both the epithelial and the sarcomatoid components expressed cytokeratins (CKs) AE1/AE3, CK 5/6 and CAM 5.2, as well as beta-catenin and LEF-1. The tumor failed to express CK7, CK20, S100, thyroid transcription factor 1 (TTF1), CDX2, prostate specific antigen (PSA) and CD34. The tumor was completely excised with Mohs surgery, and there has been no recurrence in the 8 months of follow-up to date. PMID- 29624701 TI - Identification of the mutation causing progressive retinal atrophy in Old Danish Pointing Dog. AB - Progressive retinal atrophy (PRA) is a common cause of blindness in many dog breeds. It is most often inherited as a simple Mendelian trait, but great genetic heterogeneity has been demonstrated both within and between breeds. In many breeds the genetic cause of the disease is not known, and until now, the Old Danish Pointing Dog (ODP) has been one of those breeds. ODP is one of the oldest dog breeds in Europe. Seventy years ago the breed almost vanished, but today a population still exists, primarily in Denmark but with some dogs in Germany and Sweden. PRA has been diagnosed in ODP since the late 1990s. It resembles late onset PRA in other dog breeds, and it is inherited as an autosomal recessive trait. In the present study, we performed whole-genome sequencing and identified a single base insertion (c.3149_3150insC) in exon 1 of C17H2orf71. This is the same mutation previously found to cause PRA in Gordon Setters and Irish Setters, and it was later found in Tibetan Terrier, Standard Poodle and the Polski Owczarek Nizinny. The presence of the mutation in such a diverse range of breeds indicates an origin preceding creation of modern dog breeds. Hence, we screened 262 dogs from 44 different breeds plus four crossbred dogs, and can subsequently add Miniature Poodle and another polish sheepdog, the Polski Owczarek Podhalanski, to the list of affected breeds. PMID- 29624704 TI - Implementation Science to Advance Care Delivery: A Primer for Pharmacists and Other Health Professionals. AB - Health care is experiencing increasing pressure to implement evidence-based interventions that improve quality, control costs, and maximize value. Unfortunately, many clinical services and interventions to optimize medication use do not consistently produce the intended humanistic, clinical, and economic outcomes. The lack of conclusive results is believed to stem from the widely recognized research-to-practice gap. The field of implementation science seeks to discover and apply strategies designed to accelerate successful integration of interventions into routine practice. This primer provides an overview of implementation science principles for pharmacists and other health care providers interested in accelerating practice transformation to improve health care delivery and, ultimately, patient care. PMID- 29624702 TI - Prediction of pathological nodal involvement by CT-based Radiomic features of the primary tumor in patients with clinically node-negative peripheral lung adenocarcinomas. AB - PURPOSE: The purpose of this study was to investigate the potential of computed tomography (CT) based radiomic features of primary tumors to predict pathological nodal involvement in clinically node-negative (N0) peripheral lung adenocarcinomas. METHODS: A total of 187 patients with clinical N0 peripheral lung adenocarcinomas who underwent preoperative CT scan and subsequently received systematic lymph node dissection were retrospectively reviewed. 219 quantitative 3D radiomic features of primary lung tumor were extracted; meanwhile, nine radiological semantic features were evaluated. Univariate and multivariate logistic regression analysis were used to explore the role of these features in predicting pathological nodal involvement. The areas under the ROC curves (AUCs) were compared between multivariate logistic regression models. RESULTS: A total of 153 patients had pathological N0 status and 34 had pathological lymph node metastasis. On univariate analysis, fissure attachment and 17 radiomic features were significantly associated with pathological nodal involvement. Multivariate analysis revealed that semantic features of pleural retraction (P = 0.048) and fissure attachment (P = 0.023) were significant predictors of pathological nodal involvement (AUC = 0.659); and the radiomic feature F185 (Histogram SD Layer 1) (P = 0.0001) was an independent prognostic factor of pathological nodal involvement (AUC = 0.73). A logistic regression model produced from combining radiomic feature and semantic feature showed the highest AUC of 0.758 (95% CI: 0.685-0.831), and the AUC value computed by fivefold cross-validation method was 0.737 (95% CI: 0.73-0.744). CONCLUSIONS: Features derived on primary lung tumor described by semantic and radiomic could provide information of pathological nodal involvement in clinical N0 peripheral lung adenocarcinomas. PMID- 29624703 TI - Epidemiology, outcome, and risk factors for infectious complications in myelofibrosis patients receiving ruxolitinib: A multicenter study on 446 patients. AB - Infections represent one of the major concerns regarding the utilization of ruxolitinib (RUX) in patients with myelofibrosis. With the aim to investigate epidemiology, outcome and risk factors for infections in RUX-exposed patients, we collected clinical and laboratory data of 446 myelofibrosis patients treated with RUX between June 2011 and November 2016 in 23 European Hematology Centers. After a median RUX exposure of 23.5 months (range, 1-56), 123 patients (28%) experienced 161 infectious events (grades 3-4 32%, fatal 9%), for an incidence rate of 17 cases per 100 pts/y. The rate of infections tended to decrease over time: 14% of patients developed the first infection within 6 months, 5% between 6 and 12 months, 3.7% between 12 and 18 months, 3.4% between 18 and 24 months, and 7.9% thereafter (P < .0001). Respiratory tract infections were more frequently observed (81 events, 50%), and bacteria were the most frequent etiological agents (68.9%). However, also viral (14.9%) and fungal infections (2.5%) were observed. In multivariate analysis, previous infectious event (HR 2.54; 95% CI, 1.51-4.28; P = .0005) and high international prognostic score system category (IPSS) (HR 1.53; 95% CI, 1.07-2.20; P = .021) significantly correlated with higher infectious risk. On the contrary, spleen reduction >=50% from baseline after 3 months of treatment (P = .02) was associated with better infection-free survival. Taken together, these findings reinforce the concept of disease severity as the most important risk factor for infections, and describe, for the first time, that a positive therapeutic effect in reducing splenomegaly may also reduce subsequent infectious complications. PMID- 29624705 TI - Genomic breeding values, SNP effects and gene identification for disease traits in cow training sets. AB - Holstein Friesian cow training sets were created according to disease incidences. The different datasets were used to investigate the impact of random forest (RF) and genomic BLUP (GBLUP) methodology on genomic prediction accuracies. In addition, for further verifications of some specific scenarios, single-step genomic BLUP was applied. Disease traits included the overall trait categories of (i) claw disorders, (ii) clinical mastitis and (iii) infertility from 80 741 first lactation Holstein cows kept in 58 large-scale herds. A subset of 6744 cows was genotyped (50K SNP panel). Response variables for all scenarios were de regressed proofs (DRPs) and pre-corrected phenotypes (PCPs). Initially, all sick cows were allocated to the testing set, and healthy cows represented the training set. For the ongoing cow allocation schemes, the number of sick cows in the training set increased stepwise by moving 10% of the sick cows from the testing to the training set in each step. The size of training and testing sets was kept constant by replacing the same number of cows in the testing set with (randomly selected) healthy cows from the training set. For both the RF and GBLUP methods, prediction accuracies were larger for DRPs compared to PCPs. For PCPs as a response variable, the largest prediction accuracies were observed when the disease incidences in training sets reflected the disease incidence in the whole population. A further increase in prediction accuracies for some selected cow allocation schemes (i.e. larger prediction accuracies compared to corresponding scenarios with RF or GBLUB) was achieved via single-step GBLUP applications. Correlations between genome-wide association study SNP effects and RF importance criteria for single SNPs were in a moderate range, from 0.42 to 0.57, when considering SNPs from all chromosomes or from specific chromosome segments. RF identified significant SNPs close to potential positional candidate genes: GAS1, GPAT3 and CYP2R1 for clinical mastitis; SPINK5 and SLC26A2 for laminitis; and FGF12 for endometritis. PMID- 29624707 TI - Population structure and ancestry of Qinchuan cattle. AB - The aim of this study was to estimate population structure and ancestry of Qinchuan cattle by genotyping 27 individuals using the GeneSeek HD 77k BeadChip, and another 1355 cattle representing breeds distributed worldwide, which had been genotyped using the Illumina Bovine 50k BeadChip. Qinchuan cattle were characterized by a dominant Bos taurus ancestry, accompanied by a considerable proportion of Bos indicus ancestry based on principal components analysis and supervised admixture analysis. A small proportion of Bos javanicus ancestry was detected as well. A similar admixture pattern in both Qinchuan and Turkish cattle breeds reflects their similar degrees of zebu introgression. Our study presents a relatively clear view of the population structure and ancestry of Qinchuan cattle, serving to benefit our understanding of this breed and leading to better targeted conservation approaches moving forward. PMID- 29624706 TI - Pharmacokinetics of efavirenz in patients on antituberculosis treatment in high human immunodeficiency virus and tuberculosis burden countries: A systematic review. AB - AIMS: Efavirenz (EFV) and rifampicin-isoniazid (RH) are cornerstone drugs in human immunodeficiency virus (HIV)-tuberculosis (TB) coinfection treatment but with complex drug interactions, efficacy and safety challenges. We reviewed recent data on EFV and RH interaction in TB/HIV high-burden countries. METHODS: We conducted a systematic review of studies conducted in the high TB/HIV-burden countries between 1990 and 2016 on EFV pharmacokinetics during RH coadministration in coinfected patients. Two reviewers conducted article screening and data collection. RESULTS: Of 119 records retrieved, 22 were included (two conducted in children), reporting either EFV mid-dose or pre-dose concentrations. In 19 studies, median or mean concentrations of RH range between 1000 and 4000 ng ml-1 , the so-called therapeutic range. The proportion of patients with subtherapeutic concentration of RH ranged between 3.1 and 72.2%, in 12 studies including one conducted in children. The proportion of patients with supratherapeutic concentration ranged from 19.6 to 48.0% in six adult studies and one child study. Five of eight studies reported virological suppression >80%. The association between any grade hepatic and central nervous system adverse effects with EFV/RH interaction was demonstrated in two and three studies, respectively. The frequency of the CYP2B6 516G > T polymorphism ranged from 10 to 28% and was associated with higher plasma EFV concentrations, irrespective of ethnicity. CONCLUSIONS: Anti-TB drug coadministration minimally affect the EFV exposure, efficacy and safety among TB-HIV coinfected African and Asian patients. This supports the current 600 mg EFV dosing when coadministered with anti-TB drugs. PMID- 29624708 TI - Accuracy of electron density, effective atomic number, and iodine concentration determination with a dual-layer dual-energy computed tomography system. AB - PURPOSE: This study aimed to quantitate the accuracy of the determination of electron density (ED), effective atomic number (Zeff ), and iodine concentration, directed for more accurate radiation therapy planning, with a new dual-layer dual energy computed tomography (DL-DECT) system. The dependence of the accuracy of these values on the scan and reconstruction parameters, as well as on the phantom size, was also examined. METHODS: Measurements were performed on a commercial DECT system with a DL detector (IQon Spectral CT, Philips Healthcare), using phantoms with various tissue-equivalent inserts as well as iodine and calcium inserts of different concentrations. The expected values of ED and Zeff for the insert materials were derived from the chemical compositions provided by the vendors. The nominal scan condition for the accuracy measurements was 120 kVp, 20 mGy CTDIvol, 0.812 pitch, 16 * 0.625 mm collimation, and 0.33-second gantry rotation. RESULTS: The median deviation of ED ranged from -0.1% to 1.1% for all Gammex tissue inserts. The median deviation of Zeff ranged from -2.3% to 1.7% for soft tissue and bone inserts and was <=7% for lung inserts. The absolute deviations for ED and Zeff in lung inserts were within 1% of the ED of water and 1 a.u., respectively. For two different phantom sizes, the ED values agreed to within 0.7% and the Zeff values agreed to within 2%, except for the lung inserts. When the scan parameters were changed from 120 kVp/20 mGy to 140 kVp/30 mGy, the ED differed within [-0.51%, 0.65%] and the Zeff differed within [-1.1%, 0.23%] for all materials except lungs, in which Zeff increased by 2.4%. The accuracy of ED and Zeff measurement at 120 kVp was no worse than that at 140 kVp. For iodine quantitation, the median absolute deviations from the nominal values were up to 0.3 mg/mL for iodine concentrations of 2-20 mg/mL, with an overall median deviation of -0.1 mg/mL. Iodine and calcium were well separated on the ED-Zeff scatter plot, even at the lowest concentrations (2 mg/mL for iodine and 50 mg/mL for calcium). CONCLUSIONS: The accuracy of ED measurement, Zeff determination, and iodine quantitation derived from DL-DECT was demonstrated with phantom measurements. The accuracies were not sensitive to scan and reconstruction parameters, namely tube potential, dose, rotation time, and spectral reconstruction level, especially in the case of electron density. PMID- 29624709 TI - RE: Preissner F, et al. extent of lymph node dissection improves survival in prostate cancer patients treated with radical prostatectomy without lymph node invasion. The Prostate. 2018;1-7. PMID- 29624710 TI - Nasal hyperreactivity in rhinitis: A diagnostic and therapeutic challenge. AB - Although nasal hyperreactivity (NHR) is a common feature in patients suffering from allergic and nonallergic rhinitis, it is widely neglected during history taking, underdiagnosed in the majority of patients with rhinitis and rhinosinusitis, not considered as an outcome parameter in clinical trials on novel treatments for rhinitis and rhinosinusitis, and no target for routine treatment. In contrast to the simple nature of diagnosing NHR by a history of nasal symptoms induced by nonspecific exogenous and/or endogenous triggers, quantification is hardly performed in routine clinic given the lack of a simple tool for its diagnosis. So far, limited efforts have been invested into gaining better insight in the underlying pathophysiology of NHR, helping us to explain why some patients with inflammation develop NHR and others not. Of note, environmental and microbial factors have been reported to influence NHR, contributing to the complex nature of understanding the development of NHR. As a consequence of the neglect of NHR as a key clinical feature of rhinitis and chronic rhinosinusitis (CRS), patients with NHR might be suboptimally controlled and/or dissatisfied with current treatment. We here aim to provide a comprehensive overview of current knowledge on the pathophysiology, and the available tools to diagnose and treat NHR. PMID- 29624711 TI - Lessons learnt on the analysis of large sequence data in animal genomics. AB - The 'omics revolution has made a large amount of sequence data available to researchers and the industry. This has had a profound impact in the field of bioinformatics, stimulating unprecedented advancements in this discipline. Mostly, this is usually looked at from the perspective of human 'omics, in particular human genomics. Plant and animal genomics, however, have also been deeply influenced by next-generation sequencing technologies, with several genomics applications now popular among researchers and the breeding industry. Genomics tends to generate huge amounts of data, and genomic sequence data account for an increasing proportion of big data in biological sciences, due largely to decreasing sequencing and genotyping costs and to large-scale sequencing and resequencing projects. The analysis of big data poses a challenge to scientists, as data gathering currently takes place at a faster pace than does data processing and analysis, and the associated computational burden is increasingly taxing, making even simple manipulation, visualization and transferring of data a cumbersome operation. The time consumed by the processing and analysing of huge data sets may be at the expense of data quality assessment and critical interpretation. Additionally, when analysing lots of data, something is likely to go awry-the software may crash or stop-and it can be very frustrating to track the error. We herein review the most relevant issues related to tackling these challenges and problems, from the perspective of animal genomics, and provide researchers that lack extensive computing experience with guidelines that will help when processing large genomic data sets. PMID- 29624712 TI - Incremental update of electrostatic interactions in adaptively restrained particle simulations. AB - The computation of long-range potentials is one of the demanding tasks in Molecular Dynamics. During the last decades, an inventive panoply of methods was developed to reduce the CPU time of this task. In this work, we propose a fast method dedicated to the computation of the electrostatic potential in adaptively restrained systems. We exploit the fact that, in such systems, only some particles are allowed to move at each timestep. We developed an incremental algorithm derived from a multigrid-based alternative to traditional Fourier-based methods. Our algorithm was implemented inside LAMMPS, a popular molecular dynamics simulation package. We evaluated the method on different systems. We showed that the new algorithm's computational complexity scales with the number of active particles in the simulated system, and is able to outperform the well established Particle Particle Particle Mesh (P3M) for adaptively restrained simulations. (c) 2018 Wiley Periodicals, Inc. PMID- 29624713 TI - Clinical and imaging hallmarks of the MYH7-related myopathy with severe axial involvement. AB - INTRODUCTION: MYH7 gene mutations are related to a heterogeneous group of skeletal and cardiac myopathies. METHODS: We evaluated clinical and muscle MRI changes in patients with mutations in the rod domain of MYH7, including 1 with mosaicism and 3 with novel missense mutations. RESULTS: Patients presented in childhood with a distal and axial phenotype. Biopsy findings were variable. Half of the cases displaying some type of core pathology, including minicores and eccentric cores. Most patients demonstrated internal bands of infiltration ("inverted-collagen-VI sign") in multiple muscles, particularly the soleus, and prominent atrophy and fatty infiltration of the tongue and the paraspinal, gluteus minimus, sartorius, gracilis, tibialis anterior, and extensor digitorum longus muscles. DISCUSSION: Muscle imaging findings in patients with axial involvement provide significant clues permitting the distinction between MYH7 related myopathies and other axial myopathies such as those related to SEPN1 and LMNA genes. Muscle Nerve 58: 224-234, 2018. PMID- 29624714 TI - Two cases of discrete adenoid pseudogland formation within benign intradermal melanocytic nevi. AB - We report 2 cases of benign intradermal melanocytic nevi with discrete glandular elements and mucin deposition engendering a diagnostic dilemma. The preliminary differential included entrapment of adnexal structures, collision with an adnexal neoplasm such as adenoid cystic carcinoma or metastatic adenocarcinoma. A colloidal iron special stain confirmed the deposition of mucin; however, a pankeratin AE1/AE3 immunohistochemical cocktail was surprisingly negative. Closer cytological examination of the discrete "glands" combined with nearby pseudoangiomatous (almost kaposiform) change hinted at melanocytic origin, which was confirmed with a positive melanoma antigen recognized by T-cells 1 immunohistochemical stain. Histopathological variations in melanocytic morphology include balloon cell formation, pseudoangiomatous change, lipomatous change, nevus of Nanta (osteonevus) with osseous metaplasia, neurotization, cartilaginous nevus, calcification, increased elastic tissue, psamomma body formation, amyloid deposition, eczematous changes (Meyerson nevus), granular cell change and ancient change/atypia. Mucin deposition, tubule and pseudoacini formation, and now discrete adenoid cystic-like "glands" may also be seen, all of which are important to recognize to avoid misdiagnosis. PMID- 29624715 TI - Multifunctional properties of novel tacrine congeners: cholinesterase inhibition and cytotoxic activity. AB - This review describes the synthesis of a wide range of novel tetrahydroacridine derivatives (tiocyanates, selenocyanates, ureas, selenoureas, thioureas, isothioureas, disulfides, diselenides and several tacrine homo- and hetro hybrids). These tacrine congeners exhibit significant anticholinesterase and cytotoxic properties and may therefore be of considerable potential for the development of new drugs for the treatment of Alzheimer's disease. PMID- 29624716 TI - Oral juvenile xanthogranuloma in a child: Clinical, histological and immunohistochemical profile of a rare entity. AB - Juvenile xanthogranuloma (JXG) is a non-Langerhans cell histiocytosis (non-LCH) affecting normolipemic infants and children most frequently in the first year of life, often showing spontaneous regression within 3 to 6 years. Classic JXG is characterized by a yellowish asymptomatic papule or nodule, often located in the skin of the head, neck and upper trunk. Oral JXG has been reported, but is rare. Histologically, JXG is composed mainly of an infiltrate of macrophages with a variable degree of lipidization (foamy macrophages), and (most of the time) scattered Touton-type giant cells. Because of the rarity of oral lesions and possible variations in the clinical and histological presentation, the correct diagnosis can be challenging, requiring a careful clinical and histopathological evaluation with adjuvant immunohistochemical studies. Our review of the English language literature disclosed 33 cases of oral JXG, including this case report. The purpose of this study is to present a new case of this uncommon entity as well as to review and discuss its main clinicopathologic features and immunohistochemical findings. PMID- 29624718 TI - The distribution of neuralgic amyotrophy lesions is overwhelmingly extraplexal. PMID- 29624717 TI - SIRT3 restricts hepatitis B virus transcription and replication through epigenetic regulation of covalently closed circular DNA involving suppressor of variegation 3-9 homolog 1 and SET domain containing 1A histone methyltransferases. AB - : Hepatitis B virus (HBV) infection remains a major health problem worldwide. Maintenance of the covalently closed circular DNA (cccDNA), which serves as a template for HBV RNA transcription, is responsible for the failure of eradicating chronic HBV during current antiviral therapy. cccDNA is assembled with cellular histone proteins into chromatin, but little is known about the regulation of HBV chromatin by histone posttranslational modifications. In this study, we identified silent mating type information regulation 2 homolog 3 (SIRT3) as a host factor restricting HBV transcription and replication by screening seven members of the sirtuin family, which is the class III histone deacetylase. Ectopic SIRT3 expression significantly reduced total HBV RNAs, 3.5-kb RNA, as well as replicative intermediate DNA in HBV-infected HepG2-Na+ /taurocholate cotransporting polypeptide cells and primary human hepatocytes. In contrast, gene silencing of SIRT3 promoted HBV transcription and replication. A mechanistic study found that nuclear SIRT3 was recruited to the HBV cccDNA, where it deacetylated histone 3 lysine 9. Importantly, occupancy of SIRT3 on cccDNA could increase the recruitment of histone methyltransferase suppressor of variegation 3 9 homolog 1 to cccDNA and decrease recruitment of SET domain containing 1A, leading to a marked increase of trimethyl-histone H3 (Lys9) and a decrease of trimethyl-histone H3 (Lys4) on cccDNA. Moreover, SIRT3-mediated HBV cccDNA transcriptional repression involved decreased binding of host RNA polymerase II and transcription factor Yin Yang 1 to cccDNA. Finally, hepatitis B viral X protein could relieve SIRT3-mediated cccDNA transcriptional repression by inhibiting both SIRT3 expression and its recruitment to cccDNA. CONCLUSION: SIRT3 is a host factor epigenetically restricting HBV cccDNA transcription by acting cooperatively with histone methyltransferase; these data provide a rationale for the use of SIRT3 activators in the prevention or treatment of HBV infection. (Hepatology 2018). PMID- 29624719 TI - Development of a patient-centric food allergy research program: A model for action. PMID- 29624720 TI - Case study: Behavior changes in the family-focused obesity prevention HOME Plus program. AB - OBJECTIVE: The purpose of this case study is to describe two successful HOME Plus participants and highlight how an intervention with individual and group components can help families make lifestyle changes that result in improvements in child weight status. DESIGN: One hundred and sixty families participated in the HOME Plus study, and were randomized to either a control or intervention group. SAMPLE: Two successful HOME Plus participants were chosen because of their healthful changes in weight status and behavior and high engagement in the program. MEASUREMENTS: Data were collected at baseline and postintervention, 1 year later. Data included height, weight, home food inventory, dietary recalls, and psychosocial surveys. INTERVENTION: Families in the intervention group participated in cooking and nutrition education sessions, goal-setting activities, and motivational interviewing telephone calls to promote behavioral goals associated with meal planning, family meal frequency, and healthfulness of meals and snacks. RESULTS: Analysis of the families' behaviors showed that Oliver (fictitious name) experienced changes in nutritional knowledge and cooking skill development while Sophia's (fictitious name) changes were associated with healthful food availability and increased family meal frequency. CONCLUSION: These cases show that offering a multicomponent, family-focused program allows participants to select behavior strategies to fit their unique family needs. PMID- 29624721 TI - Serologic and fecal markers to predict response to induction therapy in dogs with idiopathic inflammatory bowel disease. AB - BACKGROUND: Little information is available of markers that assess the disease course in dogs with idiopathic inflammatory bowel disease (IBD). OBJECTIVES: Evaluate relationship between disease severity and serum and fecal biomarkers in dogs with idiopathic IBD before and after treatment. ANIMALS: Sixteen dogs with idioptahic IBD and 13 healthy dogs. METHODS: Prospective case control study. Canine IBD activity index (CIBDAI) clinical score, serum concentrations of C reactive protein (CRP), perinuclear antineutrophil cytoplasmic antibodies (pANCA), and serum and fecal canine calprotectin (cCP) were measured before and after 21 days of treatment. RESULTS: Serum CRP (median 3.5 mg/L; range: 0.1-52.4 mg/L), fecal cCP (median 92.3 MUg/g; range: 0.03-637.5 MUg/g), and CIBDAI scores significantly increased in dogs with IBD before treatment compared with serum CRP (median 0.2 mg/L; range: 0.1-11.8 mg/L; P < .001), fecal cCP (median 0.67 MUg/g; range: 0.03-27.9 MUg/g; P < .001) and CIBDAI (P < .001) after treatment. No significant associations between CIBDAI scores and before or after treatment serum biomarkers. There was a significant association between fecal cCP and CIBDAI scores before treatment (rho = 0.60, P = .01). CRP and fecal cCP significantly decreased after treatment (median 3.5 mg/L v. 0.2 mg/L; P < .001 and 92.3 MUg/g v. 0.67 MUg/g; P = .001, respectively). CONCLUSIONS AND CLINICAL IMPORTANCE: Our data indicate that measurement of fecal cCP concentration is a useful biomarker for noninvasive evaluation of intestinal inflammation. Dogs with severe signs of GI disease more often have abnormal markers than dogs having less severe disease. PMID- 29624723 TI - Randomized, clinical trial of RT001: Early signals of efficacy in Friedreich's ataxia. AB - BACKGROUND: RT001 is a deuterated ethyl linoleate that inhibits lipid peroxidation and is hypothesized to reduce cellular damage and recover mitochondrial function in degenerative diseases such as Friedreich's ataxia. OBJECTIVE: To evaluate the safety, pharmacokinetics, and preliminary efficacy of RT001 in Friedreich's ataxia patients. DESIGN/METHODS: We conducted a phase I/II double-blind, comparator-controlled trial with 2 doses of RT001 in Friedreich's ataxia patients (9 subjects each cohort). Subjects were randomized 2:1 to receive either RT001 (1.8 or 9.0 g/day), or a matching dose of nondeuterated ethyl linoleate as comparator for 28 days. The primary endpoints were safety, tolerability, and pharmacokinetic analysis. Secondary endpoints included cardiopulmonary exercise testing and timed 25-foot walk. RESULTS: Nineteen patients enrolled in the trial, and 18 completed all safety and efficacy measurements. RT001 was found to be safe and tolerable, with plasma levels approaching saturation by 28 days. One subject with a low body mass index experienced steatorrhea taking a high dose and discontinued the study. Deuterated arachidonic acid (a brain-penetrant metabolite of RT001) was found to be present in plasma on day 28. There was an improvement in peak workload in the drug group compared to placebo (0.16 watts/kg; P = 0.008), as well as an improvement trend in peak oxygen consumption (change of 0.16 L/min; P = 0.116), and in stride speed (P = 0.15). CONCLUSIONS: RT001 was found to be safe and tolerable over 28 days, and improved peak workload. Further research into the effect of RT001 in Friedreich's ataxia is warranted. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29624722 TI - Volumetric Bone Mineral Density and Failure Load of Distal Limbs Predict Incident Clinical Fracture Independent HR-pQCT BMD and Failure Load Predicts Incident Clinical Fracture of FRAX and Clinical Risk Factors Among Older Men. AB - Our objective was to determine the associations of peripheral bone strength and microarchitecture with incident clinical and major osteoporotic fracture among older men after adjusting for major clinical risk factors. We used a prospective cohort study design with data from 1794 men (mean age 84.4 years) in the Osteoporotic Fractures in Men (MrOS) study. Eligible men attended the year 14 visit, had high-resolution peripheral quantitative computed tomography (HR-pQCT) scans of the distal radius and distal or diaphyseal tibia, DXA measured BMD, and were followed for mean 1.7 years for incident fracture. Failure load was estimated using finite element analysis. We used Cox proportional hazards models with standardized HR-pQCT parameters as exposure variables. Primary outcome was clinical fracture (n = 108). Covariates included either Fracture Risk Assessment Tool (FRAX) major osteoporotic fracture probability calculated with BMD (FRAX BMD), or individual clinical risk factors (CRF) including age, total hip BMD, race, falls, and prevalent fracture after age 50 years. Lower failure load was associated with higher risk of incident clinical fracture and incident major osteoporotic fracture. For clinical fracture with FRAX-BMD adjustment, the associations ranged from hazard ratio (HR) 1.58 (95% CI, 1.25 to 2.01) to 2.06 (95% CI, 1.60 to 2.66) per SD lower failure load at the diaphyseal tibia and distal radius. These associations were attenuated after adjustment for individual CRFs, but remained significant at the distal sites. Associations of volumetric BMD with these outcomes were similar to those for failure load. At the distal radius, lower trabecular BMD, number, and thickness, and lower cortical BMD, thickness, and area were all associated with higher risk of clinical fracture, but cortical porosity was not. Among community-dwelling older men, HR-pQCT measures including failure load, volumetric BMD, and microstructure parameters at peripheral sites (particularly distal radius) are robust independent predictors of clinical and major osteoporotic fracture. (c) 2018 American Society for Bone and Mineral Research. PMID- 29624724 TI - Inflammatory compound lipopolysaccharide promotes the survival of GM-CSF cultured dendritic cell via PI3 kinase-dependent upregulation of Bcl-x. AB - As professional antigen-presenting cells, dendritic cells (DCs) initiate and regulate immune responses against inflammation. The invasion of pathogens into the body, however, can in turn cause the change of DCs in both activity and viability, which ultimately affect immune homeostasis. The exact mechanisms that the bacteria utilize to alter the lifespan of DCs, however, are far from clear. In this study, we found that the bacterial wall compound lipopolysaccharide (LPS) can promote the survival of GM-CSF-differentiated DCs (GM-DCs). At molecular levels, we demonstrated that GM-DCs had distinct pattern of mRNA expression for anti-apoptotic BCL-2 family members, of which, Bcl-x increased significantly following LPS stimulation. Interestingly, specific inhibition of BCL-XL protein alone was sufficient to remove the anti-apoptotic effects of LPS on BM-DCs. Further study of the signaling mechanisms revealed that although LPS can activate both Erk MAP kinase and PI3 kinase pathways, only blocking of PI3K abolished both Bcl-x upregulation and the enhanced survival phenotype, suggesting that the PI3K signaling mediated the upregulation of Bcl-x for the LPS-induced pro-survival in GM-DCs. Collectively, this study unveils a molecular mechanism that DCs adapt to maintain innate immunity against the invasion of pathogens. PMID- 29624725 TI - Narratives in the Immediate Aftermath of Traumatic Injury: Markers of Ongoing Depressive and Posttraumatic Stress Disorder Symptoms. AB - In this study, we considered connections between the content of immediate trauma narratives and longitudinal trajectories of negative symptoms to address questions about the timing and predictive value of collected trauma narratives. Participants (N = 68) were individuals who were admitted to the emergency department of a metropolitan hospital and provided narrative recollections of the traumatic event that brought them into the hospital that day. They were then assessed at intervals over the next 12 months for depressive and posttraumatic symptom severity. Linguistic analysis identified words involving affect (positive and negative emotions), sensory input (sight, sound, taste, touch, and smell), cognitive processing (thoughts, insights, and reasons), and temporal focus (past, present, and future) within the narrative content. In participants' same-day narratives of the trauma, past-focused utterances predicted greater decreases in depressive symptom severity over the next year, d = -0.13, whereas cognitive process utterances predicted more severe posttraumatic symptom severity across time points, d = 0.32. Interaction analyses suggested that individuals who used fewer past-focused and more cognitive process utterances within their narratives tended to report more severe depressive and posttraumatic symptom severity across time, ds = 0.31 to 0.34. Overall, these findings suggest that, in addition to other demographics and baseline symptom severity, early narrative content can serve as an informative marker for longitudinal psychological symptoms, even before extensive narrative processing and phenomenological meaning-making have occurred. PMID- 29624728 TI - Respective role of membrane and nuclear estrogen receptor (ER) alpha in the mandible of growing mice: Implications for ERalpha modulation. AB - Estrogens play an important role in bone growth and maturation as well as in the regulation of bone turnover in adults. Although the effects of 17beta-estradiol (E2) are well documented in long bones and vertebrae, little is known regarding its action in the mandible. E2 actions could be mediated by estrogen receptor (ER) alpha or beta. ERs act primarily as transcriptional factors through two activation functions (AFs), AF1 and AF2, but they can also elicit membrane initiated steroid signaling (MISS). The aim of the present study was to define ER pathways involved in E2 effects on mandibular bone. Using mice models targeting ERbeta or ERalpha, we first show that E2 effects on mandibular bone are mediated by ERalpha and do not require ERbeta. Second, we show that nuclear ERalphaAF2 is absolutely required for all the actions of E2 on mandibular bone. Third, inactivation of ERalphaMISS partially reduced the E2 response on bone thickness and volume, whereas there was no significant impact on bone mineral density. Altogether, these results show that both nuclear and membrane ERalpha are requested to mediate full estrogen effects in the mandible of growing mice. Finally, selective activation of ERalphaMISS is able to exert an effect on alveolar bone but not on the cortical compartment, contrary to its protective action on femoral cortical bone. To conclude, these results highlight similarities but also specificities between effects of estrogen in long bones and in the mandible that could be of interest in therapeutic approaches to treat bone mass reduction. (c) 2018 American Society for Bone and Mineral Research. PMID- 29624726 TI - Differential Mortality and the Excess Rates of Hip Fracture Associated With Type 2 Diabetes: Accounting for Competing Risks in Fracture Prediction Matters. AB - Type 2 diabetes (T2DM) is associated with a reduced life expectancy. The latest published evidence suggests an increased risk of fractures among T2DM patients. We conducted a population-based cohort study to determine the impact of mortality as a competing risk in the study of the association between T2DM and hip fracture rates. Participants were all diagnosed T2DM patients registered in the Sistema de Informacion para el Desarrollo de la Investigacion en Atencion Primaria (SIDIAP) database aged 65 years and older; up to two non-T2DM were matched by age, sex, and primary care facility. We used Cox regression models to estimate cause specific hazard ratio (HR) of death or hip fracture according to T2DM status. Fine and Gray models were then fitted to estimate the subhazard ratio (SHR) of hip fracture while accounting for competing risk with death and to estimate the probability of hip fracture within 5 years. A total of 55,891 T2DM and 103,093 matched non-T2DM patients were observed for a median of 8 years. Mortality was 48.8 per 1000 person years (py) in T2DM, and 33.8 per 1000 py in non-T2DM; hip fracture rates were 6.0 per 1000 py and 4.9 per 1000 py, respectively. Cox models confirmed a significant association for death and hip fracture: HR 1.51 (95% CI, 1.48 to 1.55), and HR 1.32 (95% CI, 1.24 to 1.40), respectively. Accounting for death as a competing event (Fine-Gray models), the association between T2DM and hip fracture risk remained statistically significant (SHR 1.15; 95% CI, 1.09 to 1.21) and the probability of a hip fracture within 5 years was 2.3% for TD2M and 1.9% for non-TD2M patients compared to 2.6% and 2.1% respectively using Kaplan Meier (KM) estimates. T2DM patients have a 50% increased mortality and, after adjusting for differential survival at 5 years, a 21% increased incidence of hip fracture when compared to matched non-T2DM. Failing to account for differential mortality leads to an overestimation of fracture risk. (c) 2018 American Society for Bone and Mineral Research. PMID- 29624727 TI - AutoVOI: real-time automatic prescription of volume-of-interest for single voxel spectroscopy. AB - PURPOSE: To develop a fast and automated volume-of-interest (VOI) prescription pipeline (AutoVOI) for single-voxel MRS that removes the need for manual VOI placement, allows flexible VOI planning in any brain region, and enables high inter- and intra-subject consistency of VOI prescription. METHODS: AutoVOI was designed to transfer pre-defined VOIs from an atlas to the 3D anatomical data of the subject during the scan. The AutoVOI pipeline was optimized for consistency in VOI placement (precision), enhanced coverage of the targeted tissue (accuracy), and fast computation speed. The tool was evaluated against manual VOI placement using existing T1 -weighted data sets and corresponding VOI prescriptions. Finally, it was implemented on 2 scanner platforms to acquire MRS data from clinically relevant VOIs that span the cerebrum, cerebellum, and the brainstem. RESULTS: The AutoVOI pipeline includes skull stripping, non-linear registration of the atlas to the subject's brain, and computation of the VOI coordinates and angulations using a minimum oriented bounding box algorithm. When compared against manual prescription, AutoVOI showed higher intra- and inter subject spatial consistency, as quantified by generalized Dice coefficients (GDC), lower intra- and inter-subject variability in tissue composition (gray matter, white matter, and cerebrospinal fluid) and higher or equal accuracy, as quantified by GDC of prescribed VOI with targeted tissues. High quality spectra were obtained on Siemens and Philips 3T systems from 6 automatically prescribed VOIs by the tool. CONCLUSION: Robust automatic VOI prescription is feasible and can help facilitate clinical adoption of MRS by avoiding operator dependence of manual selection. PMID- 29624729 TI - KIKI-net: cross-domain convolutional neural networks for reconstructing undersampled magnetic resonance images. AB - PURPOSE: To demonstrate accurate MR image reconstruction from undersampled k space data using cross-domain convolutional neural networks (CNNs) METHODS: Cross domain CNNs consist of 3 components: (1) a deep CNN operating on the k-space (KCNN), (2) a deep CNN operating on an image domain (ICNN), and (3) an interleaved data consistency operations. These components are alternately applied, and each CNN is trained to minimize the loss between the reconstructed and corresponding fully sampled k-spaces. The final reconstructed image is obtained by forward-propagating the undersampled k-space data through the entire network. RESULTS: Performances of K-net (KCNN with inverse Fourier transform), I net (ICNN with interleaved data consistency), and various combinations of the 2 different networks were tested. The test results indicated that K-net and I-net have different advantages/disadvantages in terms of tissue-structure restoration. Consequently, the combination of K-net and I-net is superior to single-domain CNNs. Three MR data sets, the T2 fluid-attenuated inversion recovery (T2 FLAIR) set from the Alzheimer's Disease Neuroimaging Initiative and 2 data sets acquired at our local institute (T2 FLAIR and T1 weighted), were used to evaluate the performance of 7 conventional reconstruction algorithms and the proposed cross domain CNNs, which hereafter is referred to as KIKI-net. KIKI-net outperforms conventional algorithms with mean improvements of 2.29 dB in peak SNR and 0.031 in structure similarity. CONCLUSION: KIKI-net exhibits superior performance over state-of-the-art conventional algorithms in terms of restoring tissue structures and removing aliasing artifacts. The results demonstrate that KIKI-net is applicable up to a reduction factor of 3 to 4 based on variable-density Cartesian undersampling. PMID- 29624730 TI - Structure-retention relationship for enantioseparation of selected fluoroquinolones. AB - Fluoroquinolones are popular class of antibiotics with distinct chemical functionality. Most of them are ampholytes with one chiral center. Stereogeneic center is located either in the side ring of Gatifloxacin (GFLX) or in the quinolone core of Ofloxacin (OFLX). These two amphoteric fluoroquinolones have terminal amino groups in common. The unusual Nadifloxacin (NFLX) is an acidic fluoroquinolone with a core chiral center. Owing to chirality and functionality differences among GFLX, OFLX, and NFLX, we mapped these enantiomers onto structure-retention relationship. Amount of acetic acid modifier was studied in screened mobile phase and cellulose tris(3-chloro-4-methyl phenyl carbamate) (Lux cellulose-2) stationary phase. Experimental design of acetic acid% along with column temperature have been applied. Resolution and enantioselectivity have been related to structural features of the studied enantiomers. High amount of acid (0.4%) was optimum for the separation of either side chirality with a proximate amino group (GFLX) or core chirality without basic functionality (NFLX), while low amount (0.2%) is optimum for core chiral center with distal amino group (OFLX). Temperature has no significant effect on resolution and retention of enantiomers except for OFLX. Enantio-retention explains possible chiral selective and nonselective interactions. The proposed methods have been validated for pharmaceutical analyses. PMID- 29624731 TI - A novel microsurgical rodent model for the transplantation of engineered cardiac muscle flap. AB - BACKGROUND: The survival of engineered cardiac muscle 'grafts' to the epicardium is limited by vascularization post-transplantation in rat models. In this article, we describe the methodology of a novel rat model that allows for the transplantation of an engineered cardiac muscle flap (ECMF) onto the epicardium. MATERIALS AND METHODS: A total of 40 rats were used. Twenty-four neonatal rats were used to harvest cardiomyocytes. At week 1, ECMF were generated by seeding cardiomyocytes into the arteriovenous loop (AVL) tissue engineering chamber implanted into the right groin of adult rats (n = 8). At week 6, the ECMF were harvested based on a pedicle along the femoral-iliac-abdominal vessel and anastomosed to the neck vessels of the recipient syngeneic adult rats (n = 8). The flaps were delivered into the thoracic cavity and onto the epicardium. The transplanted flaps were harvested at week 10. Survival of the flaps was assessed by the patency of anastomoses and viability of the cardiomyocytes through histological analysis (hematoxylin and eosin [H&E], desmin, and von Willebrand factor [vWF] immunostaining). RESULTS: Six out of 8 rats survived the transplantation procedure. These remaining 6 recipient rats survived until harvest time point at 4 weeks post-transplantation. The mean area of the flap was 46.7mm2 . Six out of 6 flaps harvested at week 10 showed viable cardiomyocytes using desmin immunostaining and vascular channels were seen at the interface between flap and epicardium. CONCLUSION: This is a technically feasible model that will be useful for future assessment of different cardiac stem cell implants and their functional significance in rat heart models. PMID- 29624732 TI - Effect of a 5-HT2c receptor agonist on urethral closure mechanisms in female rats. AB - AIMS: The serotonin (5-HT2c) receptor is known to be involved in the mechanism of urethral closure in a model of stress incontinence. Lorcaserin (Belviq(r)) has received Food and Drug Administration approval for the treatment of obesity. However, it is unclear whether this selective 5-HT2c receptor agonist enhances urethral closure in stress urinary incontinence (SUI) models. Therefore, we investigated whether lorcaserin could enhance urethral closure in female rats with vaginal distention (VD). METHODS: Normal female rats and rats with stress incontinence induced by VD were tested. We evaluated the effect of a single dose of lorcaserin (0.03, 0.3, or 0.9 mg/kg with cumulative administration) on the urethral pressure amplitude during electrical stimulation (A-URE) and on the urethral baseline pressure (UBP). The manual compression-induced leak point pressure (LPP) was also measured. RESULTS: In VD rats, a single intravenous injection of lorcaserin (0.3 and 0.9 mg/kg) significantly increased both A-URE and LPP compared to saline (P < 0.05). In normal rats, intravenous lorcaserin (0.3 and 0.9 mg/kg) also significantly increased A-URE and LPP compared to saline (P < 0.05). The changes of A-URE and LPP, which are parameters of active urethral closure, were significantly larger in normal rats than in VD rats. CONCLUSIONS: We showed that lorcaserin can activate the external urethral sphincter and pelvic floor muscles, suggesting an influence on active closure mechanisms. 5-HT2c receptors agonists may have dual effects in patients with SUI, not only by reducing obesity but also by enhancing active urethral closure. PMID- 29624733 TI - Strong correlations among four measures of disease progression in Friedreich's ataxia. PMID- 29624734 TI - Predominant role of microglia in brain iron retention in Sanfilippo syndrome, a pediatric neurodegenerative disease. AB - Neuroinflammation and iron accumulation are hallmarks of a variety of adult neurodegenerative diseases. In Sanfilippo syndrome (mucopolysaccharidosis type III, MPSIII, a pediatric neurodegenerative disease that shares some features with adult neurodegenerative diseases), the progressive accumulation of heparan sulfate oligosaccharides (HSOs) induces microglia and astrocytes to produce pro inflammatory cytokines leading to severe neuroinflammation. The objectives of the present study were (1) to measure the local iron concentration and to assess iron metabolism in the brain of a MPSIIIB murine model and (2) to identify the brain cells involved in this accumulation. We found that iron accumulation in MPSIIIB mice primarily affected the cerebral cortex where hepcidin levels were higher than in wild-type mice, and increased with aging. This increase was correlated with low expression of ferroportin 1 (FPN1), and thus brain iron retention. Moreover, we showed in vitro that HSOs are directly responsible for the production of hepcidin and the relative decrease in FPN1 expression when added to cultures of microglia and, to a lesser extent, to cultures of astrocytes. In contrast, no significant differences were observed in neurons. Hepcidin induction results from activation of the TLR4 pathway and STAT3 signaling, and leads to iron retention within microglia. Our results show that microglia have a key role in cerebral hepcidin overexpression and thus in the brain iron accumulation observed in the MPSIIIB model. PMID- 29624735 TI - Cx3cr1-deficiency exacerbates alpha-synuclein-A53T induced neuroinflammation and neurodegeneration in a mouse model of Parkinson's disease. AB - Parkinson's disease (PD) is the second most common neurodegenerative disorder characterized by the degeneration of dopaminergic neurons of the substantia nigra and the accumulation of protein aggregates, called Lewy bodies, where the most abundant is alpha-synuclein (alpha-SYN). Mutations of the gene that codes for alpha-SYN (SNCA), such as the A53T mutation, and duplications of the gene generate cases of PD with autosomal dominant inheritance. As a result of the association of inflammation with the neurodegeneration of PD, we analyzed whether overexpression of wild-type alpha-SYN (alpha-SYNWT ) or mutated alpha-SYN (alpha SYNA53T ) are involved in the neuronal dopaminergic loss and inflammation process, along with the role of the chemokine fractalkine (CX3CL1) and its receptor (CX3CR1). We generated in vivo murine models overexpressing human alpha SYNWT or alpha-SYNA53T in wild type (Cx3cr1+/+ ) or deficient (Cx3cr1-/- ) mice for CX3CR1 using unilateral intracerebral injection of adeno-associated viral vectors. No changes in CX3CL1 levels were observed by immunofluorescence or analysis by qRT-PCR in this model. Interestingly, the expression alpha-SYNWT induced dopaminergic neuronal death to a similar degree in both genotypes. However, the expression of alpha-SYNA53T produced an exacerbated neurodegeneration, enhanced in the Cx3cr1-/- mice. This neurodegeneration was accompanied by an increase in neuroinflammation and microgliosis as well as the production of pro-inflammatory markers, which were exacerbated in Cx3cr1-/- mice overexpressing alpha-SYNA53T . Furthermore, we observed that in primary microglia CX3CR1 was a critical factor in the modulation of microglial dynamics in response to alpha-SYNWT or alpha-SYNA53T . Altogether, our study reveals that CX3CR1 plays an essential role in neuroinflammation induced by alpha-SYNA53T . PMID- 29624736 TI - MR fingerprinting Deep RecOnstruction NEtwork (DRONE). AB - PURPOSE: Demonstrate a novel fast method for reconstruction of multi-dimensional MR fingerprinting (MRF) data using deep learning methods. METHODS: A neural network (NN) is defined using the TensorFlow framework and trained on simulated MRF data computed with the extended phase graph formalism. The NN reconstruction accuracy for noiseless and noisy data is compared to conventional MRF template matching as a function of training data size and is quantified in simulated numerical brain phantom data and International Society for Magnetic Resonance in Medicine/National Institute of Standards and Technology phantom data measured on 1.5T and 3T scanners with an optimized MRF EPI and MRF fast imaging with steady state precession (FISP) sequences with spiral readout. The utility of the method is demonstrated in a healthy subject in vivo at 1.5T. RESULTS: Network training required 10 to 74 minutes; once trained, data reconstruction required approximately 10 ms for the MRF EPI and 76 ms for the MRF FISP sequence. Reconstruction of simulated, noiseless brain data using the NN resulted in a RMS error (RMSE) of 2.6 ms for T1 and 1.9 ms for T2 . The reconstruction error in the presence of noise was less than 10% for both T1 and T2 for SNR greater than 25 dB. Phantom measurements yielded good agreement (R2 = 0.99/0.99 for MRF EPI T1 /T2 and 0.94/0.98 for MRF FISP T1 /T2 ) between the T1 and T2 estimated by the NN and reference values from the International Society for Magnetic Resonance in Medicine/National Institute of Standards and Technology phantom. CONCLUSION: Reconstruction of MRF data with a NN is accurate, 300- to 5000-fold faster, and more robust to noise and dictionary undersampling than conventional MRF dictionary-matching. PMID- 29624737 TI - WAIF1 Is a Cell-Surface CTHRC1 Binding Protein Coupling Bone Resorption and Formation. AB - The osteoclast-derived collagen triple helix repeat containing 1 (CTHRC1) protein stimulates osteoblast differentiation, but the underlying mechanism remains unclear. Here, we identified Wnt-activated inhibitory factor 1 (WAIF1)/5T4 as a cell-surface protein binding CTHRC1. The WAIF1-encoding Trophoblast glycoprotein (Tpbg) gene, which is abundantly expressed in the brain and bone but not in other tissues, showed the same expression pattern as Cthrc1. Tpbg downregulation in marrow stromal cells reduced CTHRC1 binding and CTHRC1-stimulated alkaline phosphatase activity through PKCdelta activation of MEK/ERK, suggesting a novel WAIF1/PKCdelta/ERK pathway triggered by CTHRC1. Unexpectedly, osteoblast lineage specific deletion of Tpbg downregulated Rankl expression in mouse bones and reduced both bone formation and resorption; importantly, it impaired bone mass recovery following RANKL-induced resorption, reproducing the phenotype of osteoclast-specific Cthrc1 deficiency. Thus, the binding of osteoclast-derived CTHRC1 to WAIF1 in stromal cells activates PKCdelta-ERK osteoblastogenic signaling and serves as a key molecular link between bone resorption and formation during bone remodeling. (c) 2018 American Society for Bone and Mineral Research. PMID- 29624738 TI - Meniscal extrusion and degeneration during the course of osteoarthritis in the Murine collagenase-induced osteoarthritis model. AB - Meniscal damage is, despite its major role in knee osteoarthritis (OA), often neglected in OA animal models. We evaluated structural meniscal degeneration during the course of OA in the murine collagenase-induced OA (CIOA) model. To investigate this, OA was induced in the knee joints of 33 male C57BL/6 mice by an intra-articular injection of 10U collagenase. The mice were sacrificed after 1, 3, 7, 14, 28, and 56 days, and the knees were harvested and processed for histological analysis. As control, six knees were obtained from 16-week-old mice in which no OA was induced. Meniscal damage, meniscal extrusion, and articular cartilage damage were evaluated on thionin-stained sections. Associations between parameters of interest were evaluated with Spearman rho correlation tests. When compared to non-OA knees, meniscal extrusion was visible from day 1 onwards and meniscal degeneration had a tendency to increase over time. The meniscus damage appeared around the same time as articular cartilage damage (day 14-28) and was statistically significantly more pronounced anterior than posterior, and no differences were seen between medial and lateral menisci. Meniscus and articular cartilage damage were moderately associated in the CIOA knees (rho = 0.57; 95%CI [0.23-0.78]). Our findings suggest that the CIOA model is a valuable model to study the role of meniscal damage during OA progression and can support the development of future preventative treatment strategies. (c) 2018 The Authors. Journal of Orthopaedic Research(r) Published by Wiley Periodicals, Inc. on behalf of the Orthopaedic Research Society. J Orthop Res 36:2416-2420, 2018. PMID- 29624740 TI - Significant Effect of Pore Sizes on Energy Storage in Nanoporous Carbon Supercapacitors. AB - Mesoporous carbon can be synthesized with good control of surface area, pore-size distribution, and porous architecture. Although the relationship between porosity and supercapacitor performance is well known, there are no thorough reports that compare the performance of numerous types of carbon samples side by side. In this manuscript, we describe the performance of 13 porous carbon samples in supercapacitor devices. We suggest that there is a "critical pore size" at which guest molecules can pass through the pores effectively. In this context, the specific surface area (SSA) and pore-size distribution (PSD) are used to show the point at which the pore size crosses the threshold of critical size. These measurements provide a guide for the development of new kinds of carbon materials for supercapacitor devices. PMID- 29624741 TI - Usefulness of the "continuous insufflation method" for observing the cervical esophagus. PMID- 29624739 TI - Hemodialysis-induced cardiovascular disease. AB - More than half of all deaths among end stage renal disease (ESRD) patients are due to cardiovascular disease (CVD). Cardiovascular changes secondary to renal dysfunction, including fluid overload, uremic cardiomyopathy, secondary hyperparathyroidism, anemia, altered lipid metabolism, and accumulation of gut microbiota-derived uremic toxins like trimethylamine N-oxidase, contribute to the high risk for CVD in the ESRD population. In addition, conventional hemodialysis (HD) itself poses myocardial stress and injury on the already compromised cardiovascular system in uremic patients. This review will provide an overview of cardiovascular changes in chronic kidney disease and ESRD, a description of reported mechanisms for HD-induced myocardial injury, comparison of HD with other treatment modalities in the context of CVD, and possible management strategies. PMID- 29624742 TI - Temporary non-flared fully covered self-expandable metal stent placement for refractory benign choledochojejunal anastomotic stricture. PMID- 29624744 TI - Underwater endoscopic mucosal resection for gastric polyp. PMID- 29624743 TI - Absence of interaction between porcine endogenous retrovirus and porcine cytomegalovirus in pig-to-baboon renal xenotransplantation in vivo. AB - BACKGROUND: Studies of xenotransplantation from swine have identified porcine viruses as potential barriers to clinical trials. The biology of these viruses has not been extensively investigated in the in vivo xeno-environment. Enhancement of viral gene expression by viral and cellular factors acting in trans has been demonstrated for certain viruses, including bidirectional interactions between human herpesviruses and endogenous (HERV) and exogenous (HIV) retroviruses. Both porcine cytomegalovirus (PCMV) and porcine endogenous retrovirus (PERV) infections have been identified in xenografts from swine. PERV receptors exist on human cells with productive infection in vitro in permissive human target cell lines. PCMV is largely species-specific with infection restricted to the xenograft in pig-to-baboon transplants. It is unknown whether coinfection by PCMV affects the replication of PERV within xenograft tissues which might have implications for the risk of retroviral infection in the human host. METHODS: A series of 11 functioning, life-supporting pig-to-baboon kidney xenografts from PERV-positive miniature swine were studied with and without PCMV co-infection. Frozen biopsy samples were analyzed using quantitative, real-time PCR with internal controls. RESULTS: PERV replication was not altered in the presence of PCMV coinfection (P = .70). The absence of variation with coinfection was confirmed when PERV quantitation was expressed relative to simultaneous cellular GAPDH levels with or without PCMV coinfection (P = .59). CONCLUSIONS: PCMV coinfection does not alter the replication of PERV in life-supporting renal xenotransplantation in vivo in baboons. PMID- 29624745 TI - Atopic dermatitis: Interaction between genetic variants of GSTP1, TNF, TLR2, and TLR4 and air pollution in early life. AB - BACKGROUND: Associations between traffic-related air pollution (TRAP) and childhood atopic dermatitis (AD) remain inconsistent, possibly due to unexplored gene-environment interactions. The aim of this study was to examine whether a potential effect of TRAP on AD prevalence in children is modified by selected single nucleotide polymorphisms (SNPs) related to oxidative stress and inflammation. METHODS: Doctor-diagnosed AD up to age 2 years and at 7-8 years, as well as AD symptoms up to age 2 years, was assessed using parental-reported questionnaires in six birth cohorts (N = 5685). Associations of nitrogen dioxide (NO2 ) estimated at the home address of each child at birth and nine SNPs within the GSTP1, TNF, TLR2, or TLR4 genes with AD were examined. Weighted genetic risk scores (GRS) were calculated from the above SNPs and used to estimate combined marginal genetic effects of oxidative stress and inflammation on AD and its interaction with TRAP. RESULTS: GRS was associated with childhood AD and modified the association between NO2 and doctor-diagnosed AD up to the age of 2 years (P(interaction) = .029). This interaction was mainly driven by a higher susceptibility to air pollution in TNF rs1800629 minor allele (A) carriers. TRAP was not associated with the prevalence of AD in the general population. CONCLUSIONS: The marginal genetic association of a weighted GRS from GSTP1, TNF, TLR2, and TLR4SNPs and its interaction with air pollution supports the role of oxidative stress and inflammation in AD. PMID- 29624747 TI - Fecal microbiome signatures are different in food-allergic children compared to siblings and healthy children. AB - BACKGROUND: Intestinal microbes have been shown to influence predisposition to atopic disease, including food allergy. The intestinal microbiome of food allergic children may differ in significant ways from genetically similar non allergic children and age-matched controls. The aim was to characterize fecal microbiomes to identify taxa that may influence the expression of food allergy. METHODS: Stool samples were collected from children with IgE-mediated food allergies, siblings without food allergy, and non-allergic controls. Stool microbiome characterization was performed via next-generation sequencing (Illumina) of the V1V3 and V4 variable regions of the 16S rRNA gene. Bacterial diversity, evenness, richness, and relative abundance of the operational taxonomic units (OTUs) were evaluated using QIIME. ANOVA and Welch's t test were utilized to compare groups. RESULTS: Sixty-eight children were included: food allergic (n = 22), non-food-allergic siblings (n = 25), and controls (n = 21). When comparing fecal microbial communities across groups, differences were noted in Rikenellaceae (P = .035), Actinomycetaceae (P = .043), and Pasteurellaceae (P = .018), and nine other distinct OTUs. Food-allergic subjects had enrichment for specific microbes within the Clostridia class and Firmicutes phylum (Oscillobacter valericigenes, Lachnoclostridium bolteae, Faecalibacterium sp.) compared to siblings and controls. Identification of Clostridium sp. OTUs revealed differences in specific Clostridia drive the separation of the allergic from the siblings and controls. Alistipes sp. were enriched in non-allergic siblings. CONCLUSIONS: Comparisons in the fecal microbiome of food-allergic children, siblings, and healthy children point to key differences in microbiome signatures, suggesting the role of both genetic and environmental contributors in the manifestation of food-allergic disease. PMID- 29624746 TI - Hyperleukocytosis is associated with distinct genetic alterations and is an independent poor-risk factor in de novo acute myeloid leukemia patients. AB - OBJECTIVES: Acute myeloid leukemia (AML) with hyperleukocytosis (HL) is intuitively thought as a unique group with dismal prognosis. However, comprehensive studies regarding the genetic landscape and clinical outcome in this group of patients are limited. METHODS: A total of 693 newly diagnosed de novo non-M3 AML patients were consecutively enrolled. We compared relevant mutations in 20 genes between AML patients with or without HL and exposed their prognostic implications. RESULTS: Hyperleukocytosis, defined as initial white blood cell counts above 50 000/MUL, occurred in 28.9% of AML patients. HL patients had higher incidences of FLT3-ITD, NPM1, DNMT3A, CEBPA, and TET2 mutations. Multivariate analysis demonstrated that HL was an independent poor prognostic factor for overall survival and disease-free survival in total patients, those with intermediate-risk cytogenetics and normal karyotype irrespective of genetic alterations. Intriguingly, HL predicted poor survival in CEBPA double mutated, NPM1 + /FLT3-ITD- and NPM1-/FLT3-ITD- patients. Further, HL patients who received allogeneic hematopoietic stem cell transplantation (allo HSCT) in first complete remission (CR) had a significantly longer overall survival and disease-free survival than those without allo-HSCT. CONCLUSIONS: Hyperleukocytosis is an independent poor prognostic factor irrespective of cytogenetics and mutation status. Allo-HSCT in first CR seems to ameliorate the poor prognostic impact of HL. PMID- 29624749 TI - Sleep-deprivation and autobiographical memory: evidence from sleep-deprived nurses. AB - Negative effects of sleep deprivation on different types of memory are well documented, but the specific effects on autobiographical memory performance are not well studied. In this study, we investigated performance on the autobiographical memory test in a group of sleep-deprived and well-rested nurses. One-hundred participants divided into sleep-deprived (N = 50, 25 females) and well-rested (N = 50, 25 females) groups took part in the study. The sleep deprived group included night-shift nurses with 8-12 hr sleep deprivation, while the well-rested group had the usual night sleep before performance assessment. All participants were matched for gender, age, education and employment status. They completed depression and anxiety inventories, and underwent the autobiographical memory test, which included 18 cue words with positive, negative and neutral valence. The sleep-deprived group scored significantly higher in depression scores. Analysis of covariance (ANCOVA) results showed that sleep deprived participants had a significantly poorer autobiographical memory compared with the well-rested group. Additionally, specific memories were significantly declined in the sleep-deprived group. This group remembered significantly less positive and more negative memories. Findings implicate that sleep deprivation has detrimental effects on autobiographical memory specificity and valence, and is associated with mood dysregulation. PMID- 29624748 TI - Nivolumab maintenance after salvage autologous stem cell transplantation results in long-term remission in multiple relapsed primary CNS lymphoma. AB - Recurrence of primary central nervous system lymphoma (PCNSL) after high-dose chemotherapy with autologous stem cell transplantation (ASCT) usually has a poor overall prognosis with limited treatment options. Data on repeated ASCT are sparse. Checkpoint inhibitor maintenance therapy has also not been reported in PCNSL. Here, we report the first documented case of a successful third ASCT in second relapse of PCNSL. Whole-exome sequencing identified a hypermutated tumor genotype. Additionally, immunohistochemistry on pretreatment tumor tissue revealed infiltrates of PD-1+ cytolytic T cells. These alterations provided a rationale for subsequent nivolumab maintenance treatment. Therapy led to a long term, ongoing complete remission. In eligible patients with recurrent MTX sensitive PCNSL, multiple long-term remissions can be induced by repetition of high-dose MTX-based chemotherapy followed by autologous retransplantation. Subsequent immune checkpoint inhibitor maintenance therapy might be able to prolong or maintain remission. PMID- 29624750 TI - Feline herpesvirus ulcerative dermatitis: an atypical case? AB - BACKGROUND: Feline herpesvirus ulcerative dermatitis is an uncommon skin disease in cats, with a predominantly facial distribution characterized by massive infiltration of eosinophils and, occasionally, predominant neutrophils. OBJECTIVE: To describe the clinical and histopathological features of a putative atypical case of feline herpesvirus dermatitis. ANIMAL: A 10-month-old, intact male, European cat was presented with chronic monolateral ulcerative dermatitis with adherent crusts on the left pinna. The lesion had been present for six months and worsened after the administration of corticosteroids. METHODS: Clinical and histopathological examination, immunohistochemistry, nested PCR and transmission electron microscopy (TEM). RESULTS: Histological examination of skin biopsies showed multifocal ulcerative and necrotic lesions, involving the superficial and deep dermis covered by thick haemorrhagic and serocellular crusts. The superficial, medium and deep dermis was heavily infiltrated with mast cells and plasma cells, with a lower number of neutrophils and eosinophils. In the nuclei of some cells in the deep dermis, whose histotype was unrecognizable with routine haematoxylin and eosin stain, intranuclear eosinophilic inclusion bodies were noticed. Nested PCR and TEM supported the hypothesis of FeHV-1 induced dermatitis. CONCLUSIONS AND CLINICAL IMPORTANCE: This case is noteworthy for the infrequent location on the pinna and the atypical histopathological features of the lesion, with a predominant infiltration of mast cells and plasma cells. Our findings suggest that herpesvirus dermatitis should be listed as a differential diagnosis in case of ulcerative dermatitis when the location and histological features are atypical. PMID- 29624752 TI - Biomarkers for cognitive impairment in Lewy body disorders: Status and relevance for clinical trials. AB - Biomarkers have the potential to improve diagnosis and prognosis, and guide clinical treatment decisions. In research, biomarkers can be used for patient selection and as outcome measures in clinical trials. A range of biochemical and imaging biomarkers are relevant to patients with Lewy body disorders, including PD, PD dementia, and dementia with Lewy bodies. Dopaminergic imaging is used for differential diagnosis of parkinsonian disorders versus tremor disorders without dopamingeric deficits, and also to differentiate dementia with Lewy bodies from Alzheimer's disease. Markers of underlying Alzheimer's disease pathology have been applied to PD patients experiencing cognitive decline to determine the extent of mixed pathology in these cases. Assessment of alpha-synuclein species in spinal fluid is possible, and more specific assays attempt to identify alpha synuclein aggregates or phosphorylated alpha-synuclein. While alpha-synuclein markers are intended to measure the pathology most central to PD dementia and dementia with Lewy bodies, convincing evidence of robust reliability and validity from multiple laboratories is lacking. Similarly, alpha-synuclein imaging by PET or single-photon emission computed tomography, while an important research goal, is not yet available. In addition to their uses in the clinic, biomarkers have natural uses in therapeutic trials that target cognitive and neuropsychiatric features of Lewy body disorders. The biomarkers most likely to be incorporated into trials are dopaminergic and amyloid imaging for the purpose of accurate patient selection, and possibly to demonstrate the utility of antiamyloid treatments in Lewy body disorders patients with mixed pathology. (c) 2018 International Parkinson and Movement Disorder Society. PMID- 29624753 TI - Identification of neuronal autophagy regulators: Combined use of iKAP and THANATOS. PMID- 29624751 TI - Analysis of the genomic basis of functional diversity in dinoflagellates using a transcriptome-based sequence similarity network. AB - Dinoflagellates are one of the most abundant and functionally diverse groups of eukaryotes. Despite an overall scarcity of genomic information for dinoflagellates, constantly emerging high-throughput sequencing resources can be used to characterize and compare these organisms. We assembled de novo and processed 46 dinoflagellate transcriptomes and used a sequence similarity network (SSN) to compare the underlying genomic basis of functional features within the group. This approach constitutes the most comprehensive picture to date of the genomic potential of dinoflagellates. A core-predicted proteome composed of 252 connected components (CCs) of putative conserved protein domains (pCDs) was identified. Of these, 206 were novel and 16 lacked any functional annotation in public databases. Integration of functional information in our network analyses allowed investigation of pCDs specifically associated with functional traits. With respect to toxicity, sequences homologous to those of proteins found in species with toxicity potential (e.g., sxtA4 and sxtG) were not specific to known toxin-producing species. Although not fully specific to symbiosis, the most represented functions associated with proteins involved in the symbiotic trait were related to membrane processes and ion transport. Overall, our SSN approach led to identification of 45,207 and 90,794 specific and constitutive pCDs of, respectively, the toxic and symbiotic species represented in our analyses. Of these, 56% and 57%, respectively (i.e., 25,393 and 52,193 pCDs), completely lacked annotation in public databases. This stresses the extent of our lack of knowledge, while emphasizing the potential of SSNs to identify candidate pCDs for further functional genomic characterization. PMID- 29624754 TI - Asymmetric Synthesis of Hispidanin A and Related Diterpenoids. AB - We report on our accomplishment of the asymmetric synthesis of hispidanin A and its natural precursor, a labdane diterpenoid. In the first generation of synthesis, a semi-synthesis strategy was employed to construct a labdane-type diterpenoid, a natural precursor of hispidanin A, in which Barton's photolytic remote functionalization was employed as a key transformation. In addition, the totarane-type dienophile counterpart was derived from commercially available (-) scalareol. In the second generation of synthesis, key elements included an iron catalyzed radical cascade to access the labdane-type diene on the basis of hydrogen atom transfer, and an enantioselective cationic polyene cyclization furnished the totarane-type dienophile. Reaction optimization and mechanistic analysis of the radical cascade reaction was conducted. Furthermore, the [4+2] cycloaddition reaction was achieved in excellent yield and selectivity under thermal conditions, which has been rationalized by using DFT transition-state analysis and paved the way for final accomplishment of the total synthesis of hispidanin A. PMID- 29624755 TI - Searching for unknown transfusion-transmitted hepatitis viruses: a binational cohort study of 1.5 million transfused patients. AB - BACKGROUND: Both hepatitis B and C viruses were transmitted through blood transfusion before implementation of donor screening. The existence of additional, yet unknown transfusion transmittable agents causing liver disease could have important public health implications. METHODS: Analyses were based on the Scandinavian Donations and Transfusions (SCANDAT2) database. Cox regression models were used to estimate the hazard ratio (HR) of developing chronic liver disease in recipients of blood from donors who later developed any chronic liver disease compared to recipients who received blood transfusion from healthy donors. We also studied whether the risk of liver disease was increased in patients who received units from 'high-risk' donors, defined as donors who had a higher than expected occurrence of liver disease amongst their previous recipients. All analyses were stratified before and after 1992 to account for the effect of screening for hepatitis C virus. RESULTS: A total of 1 482 922 transfused patients were included in the analyses. Analyses showed evidence of transfusion transmission of liver diseases before, but not after the implementation of hepatitis C virus screening in 1992, with HRs for any liver disease of 1.38 [95% confidence interval (CI), 1.30-1.46] and 0.99 (95% CI, 0.91 1.07), before and after 1992, respectively. Similarly, blood components from 'high-risk' donors conferred increased risks before, but not after 1992. CONCLUSIONS: Our data provide no evidence for transfusion transmission of agents causing liver disease after the implementation of screening for hepatitis B and C, and suggest that if such transmission does occur, it is rare. PMID- 29624756 TI - Sex chromosome repeats tip the balance towards speciation. AB - Because sex chromosomes, by definition, carry genes that determine sex, mutations that alter their structural and functional stability can have immediate consequences for the individual by reducing fertility, but also for a species by altering the sex ratio. Moreover, the sex-specific segregation patterns of heteromorphic sex chromosomes make them havens for selfish genetic elements that not only create suboptimal sex ratios but can also foster sexual antagonism. Compensatory mutations to mitigate antagonism or return sex ratios to a Fisherian optimum can create hybrid incompatibility and establish reproductive barriers leading to species divergence. The destabilizing influence of these selfish elements is often manifest within populations as copy number variants (CNVs) in satellite repeats and transposable elements (TE) or as CNVs involving sex determining genes, or genes essential to fertility and sex chromosome dosage compensation. This review catalogs several examples of well-studied sex chromosome CNVs in Drosophilids and mammals that underlie instances of meiotic drive, hybrid incompatibility and disruptions to sex differentiation and sex chromosome dosage compensation. While it is difficult to pinpoint a direct cause/effect relationship between these sex chromosome CNVs and speciation, it is easy to see how their effects in creating imbalances between the sexes, and the compensatory mutations to restore balance, can lead to lineage splitting and species formation. PMID- 29624757 TI - An assessment of a Western blot method for the investigation of canine cutaneous adverse food reactions. AB - BACKGROUND: Adverse food reaction (AFR) is diagnosed with a two month elimination diet (ED), followed by challenge with the original food. HYPOTHESIS/OBJECTIVES: To evaluate reactivity of selected EDs and performance of a Western blot serological test for the diagnosis of AFR. ANIMALS: Twenty five food reactive (FR) and 13 non food reactive (NFR) privately owned dogs. METHODS: Sera were tested for antibodies against hydrolyzed poultry feather (RCA), hydrolyzed soy (PHA), hydrolyzed fish (FUH), limited antigen horse and potato (THP), fresh horse meat and the offending food for each FR dog as documented by provocative challenge. RESULTS: Fourteen sera were negative and two positive to all foods. Sera from five of 13 NFR and three of 25 FR dogs were reactive to hydrolyzed foods. The RCA diet was recognized by four of 38, FUH by six of 38 and PHA by one of 28 samples. THP was recognized by 14 of 33 and fresh horse by one of ten dogs that had never eaten horse meat. The test correctly identified one of 15 dogs allergic to FUH. Twenty of 25 FR sera were negative for the dogs' respective offending foods (20% sensitivity), whereas four of 13 NFR sera were positive to the dogs' usual diets (69% specificity). CONCLUSION AND CLINICAL IMPORTANCE: Western blot analysis cannot be considered as a valid tool for the diagnosis of AFR; it may serve as an aid in selecting an ED. PMID- 29624760 TI - Nurse turnover in the Kingdom of Saudi Arabia: An integrative review. AB - AIM: To appraise and synthesise existing literature on nurse turnover in the Saudi Arabian context. BACKGROUND: Saudi Arabia is notably one of the nations with a health care system that is bombarded by high rates of turnover and turnover intention. Moreover, rapid population growth and the expansion of the health care system increase the demand on registered nurses in the kingdom. EVALUATION: Eleven primary sources were reviewed using Whittemore and Knafl's (Journal of Advanced Nursing, 2005; 52, 546-553) integrative review method. KEY ISSUES: There is variation in the reported turnover rates across the studies. The identified determinants of nurse turnover in the Saudi Arabian context included nurses' demographics, satisfaction, leadership and management, and job-related factors. CONCLUSION: There is a need for more studies that focus on the cost and outcome of nurse turnover and turnover intention in the Saudi Arabian context. IMPLICATIONS FOR NURSING MANAGEMENT: The review highlights the alarming rates of nurse turnover and its determinants in Saudi Arabia. Nurse managers in Saudi Arabia should consider this information, as they make daily assignments. PMID- 29624759 TI - Recent Advances in Liquid Metal Manipulation toward Soft Robotics and Biotechnologies. AB - Interest has grown significantly in the field of soft robotics, which seeks to develop machinery capable of duplicating the elastic and rheological properties of typically polymeric or elastomeric biological tissues and organs. As a result of a number of unique properties, gallium-based liquid metals (LMs) are emerging as materials used in the forefront of soft robotics research. Finding methods to enable the sophisticated manipulation of LMs will be essential for further progress in the field. This review provides a critical discussion of the manipulation of LMs and on important biotechnological applications of LMs including microfluidics, healthcare devices, biomaterials, and nanomedicines. PMID- 29624758 TI - Gonadotrophin-inhibitory hormone and its mammalian orthologue RFamide-related peptide-3: Discovery and functional implications for reproduction and stress. AB - At the turn of the millennium, a neuropeptide with pronounced inhibitory actions on avian pituitary gonadotrophin secretion was identified and named gonadotrophin inhibitory hormone (GnIH). Across bird species, GnIH acts at the level of the pituitary and the gonadotrophin-releasing hormone (GnRH) neuronal system to inhibit reproduction. Subsequent to this initial discovery, orthologues of GnIH have been identified and characterised across a broad range of species. In many vertebrates, the actions of GnIH and its orthologues serve functional roles analogous to those seen in birds. In other cases, GnIH and its orthologues exhibit more diverse actions dependent on sex, species, season and reproductive condition. The present review highlights the discovery and functional implications of GnIH across species, focusing on research domains in which the significance of this neuropeptide has been explored most. PMID- 29624762 TI - Dynamic Ureas with Fast and pH-Independent Hydrolytic Kinetics. AB - Low cost, high performance hydrolysable polymers are of great importance in biomedical applications and materials industries. While many applications require materials to have a degradation profile insensitive to external pH to achieve consistent release profiles under varying conditions, hydrolysable chemistry techniques developed so far have pH-dependent hydrolytic kinetics. This work reports the design and synthesis of a new type of hydrolysable polymer that has identical hydrolysis kinetics from pH 3 to 11. The unprecedented pH independent hydrolytic kinetics of the aryl ureas were shown to be related to the dynamic bond dissociation controlled hydrolysis mechanism; the resulting hindered poly(aryl urea) can be degraded with a hydrolysis half-life of 10 min in solution. More importantly, these fast degradable hindered aromatic polyureas can be easily prepared by addition polymerization from commercially available monomers and are resistant to hydrolysis in solid form for months under ambient storage conditions. The combined features of good stability in solid state and fast hydrolysis at various pH values is unprecedented in polyurea material, and will have implications for materials design and applications, such as sacrificial coatings and biomaterials. PMID- 29624761 TI - Pancake Bonding in pi-Stacked Trimers in a Salt of Tetrachloroquinone Anion. AB - The crystal structure of [4-damp])2 [Cl4 Q]3 (4-damp=4-dimethylamino-N methylpyridinium, Cl4 Q=tetrachloroquinone) salt is built up from slipped columnar stacks of quinoid rings composed of closely bound trimers with the intra trimer separation distance of 2.84 A and total charge of -2 whereas the inter trimer distance is 3.59 A. The individual rings exhibit partial negative charges that are distributed unevenly among the three Cl4 Qs in the trimer. The strong interactions within a trimer (Cl4 Q)32- have a partially covalent character with two-electron/multicentered bonding, that is extended over three rings, plausibly termed as "pancake bonding". The electron pairing within this multicentre bond leads to the fact that the crystals are diamagnetic and act as insulators. The studies of the structure and nature of bonding are based on X-ray charge density analysis and density functional theory. PMID- 29624763 TI - Hydrogen peroxide production and myo-inositol metabolism as important traits for virulence of Mycoplasma hyopneumoniae. AB - Mycoplasma hyopneumoniae is the causative agent of enzootic pneumonia. In our previous work, we reconstructed the metabolic models of this species along with two other mycoplasmas from the respiratory tract of swine: Mycoplasma hyorhinis, considered less pathogenic but which nonetheless causes disease and Mycoplasma flocculare, a commensal bacterium. We identified metabolic differences that partially explained their different levels of pathogenicity. One important trait was the production of hydrogen peroxide from the glycerol metabolism only in the pathogenic species. Another important feature was a pathway for the metabolism of myo-inositol in M. hyopneumoniae. Here, we tested these traits to understand their relation to the different levels of pathogenicity, comparing not only the species but also pathogenic and attenuated strains of M. hyopneumoniae. Regarding the myo-inositol metabolism, we show that only M. hyopneumoniae assimilated this carbohydrate and remained viable when myo-inositol was the primary energy source. Strikingly, only the two pathogenic strains of M. hyopneumoniae produced hydrogen peroxide in complex medium. We also show that this production was dependent on the presence of glycerol. Although further functional tests are needed, we present in this work two interesting metabolic traits of M. hyopneumoniae that might be directly related to its enhanced virulence. PMID- 29624765 TI - N-Heterocyclic Carbene-Catalyzed Annulation of alpha-Chloroaldehydes with gamma /delta-Amino-alpha,beta-Unsaturated Ketones: Enantioselective Synthesis of Pyrrolidones and Piperidones. AB - The N-heterocyclic carbene-catalyzed [2+3] and [2+4] annulations of alpha chloroaldehydes with gamma-/delta-amino-alpha,beta-unsaturated ketones were developed, giving the corresponding pyrrolidones and piperidones in good yields with exclusive trans-selectivities and excellent enantioselectivities. PMID- 29624764 TI - Porphyrin Cyclodextrin Conjugates Modulate Amyloid Beta Peptide Aggregation and Cytotoxicity. AB - Although fibrillar amyloid beta peptide (Abeta) aggregates are one of the major hallmarks of Alzheimer's disease, increasing evidence suggests that soluble Abeta oligomers are the primary toxic species. Targeting the oligomeric species could represent an effective strategy to interfere with Abeta toxicity. In this work, the biological properties of 5[4-(6-O-beta-cyclodextrin)-phenyl],10,15,20-tri(4 hydroxyphenyl)-porphyrin and its zinc complex were tested, as new molecules that interact with Abeta and effectively prevent its cytotoxicity. We found that these systems can cross the cell membrane to deliver Abeta intracellularly and promote its clearance. Our results provide evidence for the use of cyclodextrin-porphyrin derivatives as a promising strategy to target amyloid aggregation. PMID- 29624766 TI - The protective role of self-esteem, perceived social support and job satisfaction against psychological distress among Chinese nurses. AB - AIM: To determine the prevalence of psychological distress, and to explore the combined protective roles of self-esteem, perceived social support and job satisfaction against psychological distress. BACKGROUND: Few studies have explored the combined protective effect of self-esteem, perceived social support and job satisfaction on nurses' mental health in the same theoretical framework. METHODS: The Rosenberg Self-Esteem Scale, the Multidimensional Scale of Perceived Social Support, a self-developed Job Satisfaction Questionnaire and the Kessler Psychological Distress Scale were used to survey 581 nurses. The hypothesized model of the relationships among self-esteem, perceived social support, job satisfaction and psychological distress was tested with structural equation modelling. RESULTS: The prevalence of psychological distress was 92.3%. Job satisfaction exerted the strongest direct protective effect against psychological distress, with perceived social support and self-esteem exerting the second and third strongest direct protective effects, respectively. Additionally, self esteem had an indirect protective effect. CONCLUSIONS: Chinese nurses showed a surprisingly high prevalence of psychological distress. Job satisfaction, self esteem and perceived social support were identified, in this order of importance, as protective factors against psychological distress. IMPLICATIONS FOR NURSING MANAGEMENT: Nurse administrators should take measures to improve nurses' job satisfaction and social support, and hire individuals with high self-esteem as nurses. PMID- 29624768 TI - GNAT toxins of bacterial toxin-antitoxin systems: acetylation of charged tRNAs to inhibit translation. AB - GCN5-related N-acetyltransferase (GNAT) is a huge superfamily of proteins spanning the prokaryotic and eukaryotic domains of life. GNAT proteins usually transfer an acetyl group from acetyl-CoA to a wide variety of substrates ranging from aminoglycoside antibiotics to large macromolecules. Type II toxin-antitoxin (TA) modules are typically bicistronic and widespread in bacterial and archael genomes with diverse cellular functions. Recently, a novel family of type II TA toxins was described, which presents a GNAT-fold and functions by acetylating charged tRNA thereby precluding translation. These GNAT toxins are usually associated with a corresponding ribbon-helix-helix-fold (RHH) antitoxin. In this issue, Qian et al. describes a unique GNAT-RHH TA system, designated KacAT, from a multidrug resistant strain of the pathogen, Klebsiella pneumoniae. As most type II TA loci, kacAT is transcriptionally autoregulated with the KacAT complex binding to the operator site via the N-terminus region of KacA to repress kacAT transcription. The crystal structure of the KacT toxin is also presented giving a structural basis for KacT toxicity. These findings expand our knowledge on this newly discovered family of TA toxins and the potential role that they may play in antibiotic tolerance and persistence of bacterial pathogens. PMID- 29624767 TI - Systemic exertion intolerance disease/chronic fatigue syndrome is common in sleep centre patients with hypersomnolence: A retrospective pilot study. AB - Symptoms of the central disorders of hypersomnolence extend beyond excessive daytime sleepiness to include non-restorative sleep, fatigue and cognitive dysfunction. They share much in common with myalgic encephalomyelitis/chronic fatigue syndrome, recently renamed systemic exertion intolerance disease, whose additional features include post-exertional malaise and orthostatic intolerance. We sought to determine the frequency and correlates of systemic exertion intolerance disease in a hypersomnolent population. One-hundred and eighty-seven hypersomnolent patients completed questionnaires regarding sleepiness and fatigue; questionnaires and clinical records were used to assess for systemic exertion intolerance disease. Sleep studies, hypocretin and cataplexy were additionally used to assign diagnoses of hypersomnolence disorders or sleep apnea. Included diagnoses were idiopathic hypersomnia (n = 63), narcolepsy type 2 (n = 25), persistent sleepiness after obstructive sleep apnea treatment (n = 25), short habitual sleep duration (n = 41), and sleepiness with normal sleep study (n = 33). Twenty-one percent met systemic exertion intolerance disease criteria, and the frequency of systemic exertion intolerance disease was not different across sleep diagnoses (p = .37). Patients with systemic exertion intolerance disease were no different from those without this diagnosis by gender, age, Epworth Sleepiness Scale, depressive symptoms, or sleep study parameters. The whole cohort reported substantial fatigue on questionnaires, but the systemic exertion intolerance disease group exhibited more profound fatigue and was less likely to respond to traditional wake-promoting agents (88.6% versus 67.7%, p = .01). Systemic exertion intolerance disease appears to be a common co-morbidity in patients with hypersomnolence, which is not specific to hypersomnolence subtype but may portend a poorer prognosis for treatment response. PMID- 29624769 TI - Synthetic Approaches to Tetracyclic Indolines as Versatile Building Blocks of Diverse Indole Alkaloids. AB - Indole alkaloids bearing the tetracyclic indoline scaffolds of 1H-pyrrolo[2,3 d]carbazole have shown fascinating chemical diversity and significant biological activities. The development of efficient synthetic methodologies for such a tetracyclic scaffold remains highly desirable in both synthetic chemistry and medicinal chemistry. This review outlines key strategies for the construction of the tetracyclic indoline scaffolds in total syntheses of many indole alkaloids. The key strategies include nucleophilic additions, Diels-Alder reactions, radical cyclizations, and palladium-catalyzed coupling reactions. The representative examples and their applications in the total syntheses are described here and discussed in depth. PMID- 29624770 TI - Hot Off the Press: Topical Tranexamic Acid Compared With Anterior Nasal Packing for Treatment of Epistaxis in Patients Taking Antiplatelet Drugs. PMID- 29624771 TI - Assessing cognitive function in patients treated with immune checkpoint inhibitors: A feasibility study. PMID- 29624773 TI - Sleep disorders in spinocerebellar ataxia type 10. AB - As sleep disturbances have been reported in spinocerebellar ataxias (SCAs), including types SCA1, SCA2, SCA3, SCA6 and SCA13, identification and management of these disturbances can help minimise their impact on SCA patients' overall body functions and quality of life. To our knowledge, there are no studies that investigate sleep disturbances in SCA10. Therefore, the aim of this study was to assess sleep disturbances in patients with SCA10. Twenty-three SCA10 patients and 23 healthy controls were recruited. Patients were evaluated in terms of their demographic and clinical data, including disease severity (Scale for the Assessment and Rating of Ataxia, SARA) and excessive daytime sleepiness (Epworth Sleepiness Scale, ESS), and underwent polysomnography. SCA10 patients had longer rapid eye movement (REM) sleep (p = .04) and more REM arousals than controls (p< .0001). There was a correlation of REM sleep onset with the age of onset of symptoms (r = .459), and with disease duration (r = -.4305). There also was correlation between the respiratory disturbance index (RDI) and SARA (r = .4013), and a strong indirect correlation between arousal index and age at onset of symptoms (r = -.5756). In conclusion, SCA10 patients had sleep abnormalities that included more REM arousals and higher RDI than controls. Our SCA10 patients had sleep disorders related to shorter disease duration and lower severity of ataxia, in a pattern similar to that of other neurodegenerative diseases. PMID- 29624772 TI - Separation of trait and state in stuttering. AB - Stuttering is a disorder in which the smooth flow of speech is interrupted. People who stutter show structural and functional abnormalities in the speech and motor system. It is unclear whether functional differences reflect general traits of the disorder or are specifically related to the dysfluent speech state. We used a hierarchical approach to separate state and trait effects within stuttering. We collected sparse-sampled functional MRI during two overt speech tasks (sentence reading and picture description) in 17 people who stutter and 16 fluent controls. Separate analyses identified indicators of: (1) general traits of people who stutter; (2) frequency of dysfluent speech states in subgroups of people who stutter; and (3) the differences between fluent and dysfluent states in people who stutter. We found that reduced activation of left auditory cortex, inferior frontal cortex bilaterally, and medial cerebellum were general traits that distinguished fluent speech in people who stutter from that of controls. The stuttering subgroup with higher frequency of dysfluent states during scanning (n = 9) had reduced activation in the right subcortical grey matter, left temporo occipital cortex, the cingulate cortex, and medial parieto-occipital cortex relative to the subgroup who were more fluent (n = 8). Finally, during dysfluent states relative to fluent ones, there was greater activation of inferior frontal and premotor cortex extending into the frontal operculum, bilaterally. The above differences were seen across both tasks. Subcortical state effects differed according to the task. Overall, our data emphasise the independence of trait and state effects in stuttering. PMID- 29624774 TI - Multicystic mucinous adenocarcinoma of the uterine cervix compared with benign multicystic lesions: Multiparametric MR features. AB - BACKGROUND: Multicystic mucinous adenocarcinoma is rarely recognized and has a high misdiagnosis rate. PURPOSE: To distinguish malignant multicystic mucinous adenocarcinomas from benign multicystic lesions in the uterine cervix using multiparametric MR. STUDY TYPE: Retrospective. POPULATION: Forty patients with seven cystic mucinous adenocarcinomas and 33 benign multicystic lesions. FIELD STRENGTH/SEQUENCE: 3.0T. Diffusion-weighted images (DWI) and dynamic contrast enhanced (DCE) images. ASSESSMENT: Lesion size, intracystic hemorrhage, solid component, and heterogeneous enhancement were subjectively assessed, and apparent diffusion coefficient (ADC) values, Ktrans , Kep , and Ve parameters were compared. STATISTICAL ANALYSIS: Student's t-test was used to compare age, tumor size, ADC values, and DCE parameters. Pearson's chi-square test was used to compare intracystic hemorrhage, solid component, and heterogeneous enhancement. Receiver-operating-characteristic (ROC) analysis of ADC values, tumor size, and Ktrans were performed. RESULTS: The size of mucinous adenocarcinomas was larger than benign multicystic lesions (4.09 +/- 2.09 vs. 2.23 +/- 0.58 cm, P < 0.001); the area under the curve (AUC) for tumor size was 0.859 with a sensitivity of 71.4% and specificity of 90.9%. Stromal ADC value was lower for mucinous adenocarcinomas (1.19 +/- 0.22 vs. 1.68 +/- 0.22 * 10-3 mm2 /s, P < 0.001); AUC for stromal ADC value was 0.970, with a sensitivity of 86.4% and specificity of 100.0%. Among quantitative DCE parameters, only ktrans offered a discriminative value (1.72 +/- 1.42 vs. 0.69 +/- 0.30 min-1 , P = 0.031); the AUC for ktrans was 0.831 with a sensitivity of 71.4% and specificity of 97.0%. Intracystic hemorrhage (3/7), solid component (5/7), and heterogeneous enhancement (4/7) were only found in mucinous adenocarcinomas. Five patients (71.4%) had lymphovascular space invasion and three (42.9%) had lymph node metastasis. The 1-year tumor recurrence or metastasis rate was 28.5% (2/7). DATA CONCLUSION: Awareness of multiparametric MR features can assist in the differentiation of mucinous adenocarcinomas from benign multicystic lesions. LEVEL OF EVIDENCE: 4 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1336-1343. PMID- 29624775 TI - Highly efficient ssODN-mediated homology-directed repair of DSBs generated by CRISPR/Cas9 in human 3PN zygotes. PMID- 29624776 TI - TRPC3 overexpression and intervention in airway smooth muscle of ovalbumin induced hyperresponsiveness and remodeling. AB - Transient receptor potential canonical channel 3 (TRPC3) proteins function as non voltage-gated Ca2+ -permeable channels and play divergent roles in many processes of pathophysiology. The purpose of this study was to determine the relationship between TRPC3 expression and airway hyperresponsiveness and remodeling in ovalbumin-induced asthmatic Kunming mice. Mice were sensitized and challenged by ovalbumin to establish asthmatic model. Hematoxylin-eosin staining, hydroxyproline assay, and isometric tracheal ring force measurement were used to evaluate airway remodeling and hyperresponsiveness in asthmatic mice. Western blot was performed to detect the expression of TRPC3 proteins. MTT assay was used to measure the proliferation of airway smooth muscle cells. TRPC3 protein expression increased in airway smooth muscle of asthmatic mice. GdCl3 , a nonspecific TRPC blocker, attenuated the contractile force of airway smooth muscle. Fetal bovine serum stimulated airway smooth muscle cells proliferation and augmented TRPC3 protein expression. Both TRPC3 blockade by GdCl3 or specific TRPC3 antibodies and gene silencing by siRNA inhibited the proliferation of airway smooth muscle cells. In contrast, the current drugs treatment for asthma such as Dexamethasone and Aminophylline had no effects on TRPC3 protein overexpression. Therefore, TRPC3 protein overexpression may be involved in airway smooth muscle hyperresponsiveness and remodeling in asthmatic mice, providing evidence for a new direction of asthma pathogenesis research and a new target for drug intervention. PMID- 29624777 TI - De novo tetrahydrobiopterin biosynthesis is impaired in the inflammed striatum of parkin(-/-) mice. AB - Parkinson's disease (PD), the second-most prevalent neurodegenerative disease, is primarily characterized by neurodegeneration in the substantia nigra pars compacta, resulting in motor impairment. Loss-of-function mutations in parkin are the major cause of the early onset familial form of the disease. Although rodents deficient in parkin (parkin(-/-) ) have some dopaminergic system dysfunction associated with central oxidative stress and energy metabolism deficiencies, these animals only display nigrostriatal pathway degeneration under inflammatory conditions. This study investigated the impact of the inflammatory stimulus induced by lypopolisaccharide (LPS) on tetrahydrobiopterin (BH4) synthesizing enzymes (de novo and salvage pathways), since this cofactor is essential for dopamine synthesis. The mitochondrial content and architecture was investigated in the striatum of LPS-exposed parkin(-/-) mice. As expected, the LPS (0.33 mg/kg; i.p.) challenge compromised spontaneous locomotion and social interaction with juvenile parkin(-/-) and WT mice. Moreover, the genotype impacted the kinetics of the investigation of the juvenile. The inflammatory scenario did not induce apparent changes in mitochondrial ultrastructure; however, it increased the quantity of mitochondria, which were of smaller size, and provoked the perinuclear distribution of the organelle. Furthermore, the BH4 de novo biosynthetic pathway failed to be up-regulated in the LPS challenge, a well-known stimulus for its activation. The LPS treatment increased sepiapterin reductase (SPR) expression, suggesting compensation by the salvage pathway. This might indicate that dopamine synthesis is compromised in parkin(-/-) mice under inflammatory conditions. Finally, this scenario impaired the striatal expression of the transcription factor BDNF, possibly favoring cell death. PMID- 29624779 TI - A single-session intervention (the Mini-AFTERc) for fear of cancer recurrence: A feasibility study. PMID- 29624778 TI - Ultrastructure of sensilla on the maxillary and labial palps of the adult Xylotrechus grayii (Coleoptera: Cerambycidae). AB - The longhorn beetle, Xylotrechus grayii (White, 1855), is a serious woodborer pest of many economic and medicinal plants. The maxillary and labial palps of X. grayii adults are strongly involved in mating and host selection behaviors. To further develop control strategies of the pest, sensilla on the palps were studied with scanning and transmission electron microscopy. Five types of sensilla (nine subtypes) were identified: sensilla styloconica (four subtypes, Sty1-4), sensilla chaetica (2 subtypes, SC1-2), sensilla digitiformia (Di), sensilla basiconica (Ba), and Bohm sensilla (Bm). Sty and Ba have dendrites and wall pores. SC2 has a tubular body. Di exist only on the terminal segment of the maxillary palp. Sty numbers are the highest in both palps, followed by SC. The number of sensilla in the maxillary palp is significantly higher than that in the labial palp. There are no significant sexual differences in sensilla types, characteristics, distribution, and quantity in the maxillary or labial palps, except for the number of SC sensilla on the maxillary palp. Sensilla functions were compared with correlative sensilla in previous studies. Sty may be sense gustation and olfaction stimulation, while SC are mechanoreceptors. Ba are likely thermo- and hygroreceptors. The phylliform depression area formed by Di may exert multiple functions. Bm may sense palp position and movement. These results contribute to the study of the electrophysiology and behavior mechanisms of X. grayii. PMID- 29624780 TI - The association of irregular sleep habits with the risk of being overweight/obese in a sample of Portuguese children aged 6-9 years. AB - OBJECTIVES: The consequences of irregular sleep duration at younger ages remains uncertain, especially when we consider shorter and longer than recommended sleep durations. Therefore, the present study aimed to analyze the association between healthy sleep duration and risk of obesity in Portuguese children. METHODS: The sample for this cross-sectional study comprised 8273 children (4183 females) aged 6-9 years. Height and weight were measured and body mass index (BMI) was calculated. Sleep habits and sedentary behaviors (i.e., TV viewing) were assessed by questionnaire. Logistic regressions were used. RESULTS: After adjustments for confounders, males who have irregular sleep duration were 1.28 times more likely to be classified as overweight or obese than their counterparts who had normal sleep duration on weekdays. No associations between sleep duration and overweight/obesity risk were found for girls, neither on weekdays nor on the weekend. For both boys and girls, the final model showed a significant inverse association between overweight/obesity risk and the educational level of fathers (males: 95% CI 0.51 to 0.79, P < .001; females: 95% CI 0.57 to 0.87, P < .01). CONCLUSION: Findings revealed that shorter and longer than recommended sleep duration was positively associated with risk of obesity in boys on weekdays. Furthermore, pediatric obesity risk could be highly influenced by the education level of fathers of both males and females. Future research should extend a similar design, using objective measures of sleep duration to confirm some of the afore-mentioned results. PMID- 29624781 TI - Predictive analytics in secure settings. PMID- 29624782 TI - A molecular pathological study of four cases of ciliated muconodular papillary tumors of the lung. AB - Ciliated muconodular papillary tumors (CMPTs) are a recently categorized benign or low-grade malignant neoplasm that develops in the peripheral lung. Only about 40 cases have been reported to date, and the clinicopathological characteristics have yet to be defined in detail. Here, we present four cases of CMPTs with a focus on their immunohistochemical profiles and driver gene mutations. These tumors were a papillary proliferation of a mixture of ciliated, mucous, and basal cells located in the peripheral lung. Ciliated, mucous and basal cells were positive for TTF-1 when using the clone SPT24, but negative for HNF-4alpha. Basal cells were positive for p40. Mucous cells in some tumors were positive for MUC5AC and MUC6. The Ki-67 index was less than 5%, and strong expression of p53 was not detected. Three of the four tumors had a BRAF (V600E) driver mutation, an EGFR (del E746-T751/S752V) driver mutation, or driver mutations in both EGFR (E709G) and KRAS (G12V). These mutation types are rare for any histological type of lung cancer. The present results confirmed that CMPT is a neoplasm with immunohistochemical features and driver gene mutations that are distinct from those of common lung tumors. PMID- 29624783 TI - Caring for the person with cancer: Information and support needs and the role of technology. AB - OBJECTIVE: Informal carers experience a variety of information and support needs when providing care to someone with cancer. It is unclear when carers seek information and what resources they access to support themselves throughout the cancer trajectory. METHODS: A sample of 45 carers and 15 oncology nurses were recruited to participate in either focus groups or phone interviews. RESULTS: Carers in the study were more likely to be women (60%), caring for a spouse or partner (64.4%), living with the patient (86.7%), and hold a university degree (46.7%). The majority of oncology nurses were females (66.6%). Findings showed that carers had limited access to adequate information as needs arose. Supports used to address information needs included information booklets, the Internet, and communication with healthcare professionals or with other carers. Barriers in communication between nurses and carers impacted on the adequacy of information received. Participants reported that technology, such as smartphone applications, might be appropriate for improving information and support needs. CONCLUSIONS: Caring for someone with cancer is multifaceted. Carers need access to timely information to help them effectively manage patients' needs. Future studies should assess the role of contemporary approaches, such as digital technology, as a solution to the delivery of information and support for carers of people with cancer. PMID- 29624784 TI - Non-thermal plasma as a simple ferroptosis inducer in cancer cells: A possible role of ferritin. PMID- 29624785 TI - Relationship between adrenal steroid hormones in cord blood and birth weight: The Sapporo Cohort, Hokkaido Study on Environment and Children's Health. AB - OBJECTIVES: We investigated the relationship between steroid hormone levels in cord blood and birth weight. METHODS: Among 514 participants in a prospective birth cohort study in Sapporo, the following hormone levels were measured in 294 stored cord blood samples from 135 males and 159 females: androstenedione, dehydroepiandrosterone (DHEA), cortisol, and cortisone. Birth weight information was obtained from medical records. RESULTS: Androstenedione/DHEA was significantly higher in males than in females, while DHEA was significantly higher in females. Birth weight was significantly higher in males than in females. Regarding cortisone, androstenedione/DHEA, and cortisone/cortisol, a correlation was observed with birth weight in males but not in females. CONCLUSIONS: Prenatal adrenal steroids as well as converting enzymes such as 11beta-hydrosteroid dehydrogenase type 2 and 3beta-hydrosteroid dehydrogenase may have an impact on prenatal physical development. PMID- 29624786 TI - Impact of oncogene panel results on surgical management of cytologically indeterminate thyroid nodules. AB - BACKGROUND: The impact of oncogene panel results on the surgical management of indeterminate thyroid nodules (ITNs) is currently unknown. METHODS: Surgical management of 649 patients consecutively evaluated from October 2008 to April 2016 with a single nodule biopsied and indeterminate cytology (193 evaluated with and 456 without oncogene panels) was assessed and compared. Histological features of 629 consecutively resected ITNs (164 evaluated with and 465 without oncogene panels) were also characterized and compared. RESULTS: Oncogene panel evaluation was associated with higher rates of total thyroidectomy (45% vs 28%; P = .006), and central lymph node dissection (19% vs 12%; P = .03) without increasing the yield of malignancy or decreasing the rate of completion thyroidectomy. Most malignancies (64%), including 83% of those with driver mutation identified, were low-risk cancers for which a lobectomy could have been sufficient initial treatment. CONCLUSION: Current oncogene panel results seem insufficient to guide the surgical extent of solitary ITNs. PMID- 29624787 TI - Insights into the helix-sense inversion of poly(beta-phenethyl-L-aspartate) by two-dimensional Raman correlation spectroscopy. AB - In this study, the transition process of the helix-sense inversion of poly(beta phenethyl-L-aspartate) was investigated by Raman scattering and 2-dimensional correlation spectroscopy. Temperature-dependent Raman spectra were obtained during the helix-sense inversion. The results of 2-dimensional correlation analysis in the spectral regions of 1600-1800 and 3200-3400 cm-1 showed that the intensity changes of the side-chain ester C?O stretching bands occurred prior to those of amide A and amide I bands in the unwinding process of alphaR-helix on heating. The sequential order of the intensity changes for amide A, amide I, and the side-chain ester C?O stretching bands during the inversion process was determined. It was found that the conformation change of the side chain occurred prior to that of the main chain for the alphaR-helix on heating. Thus, we concluded that the transformation of the backbone chain from right-handed to left handed is triggered by the conformational change of the side chains. PMID- 29624788 TI - Rural and remote health research: Does the investment match the need? AB - OBJECTIVE: To determine the percentage of research projects funded by the National Health and Medical Research Council in the period 2000-2014 that aimed specifically to deliver health benefits to Australians living in rural and remote areas and to estimate the proportion of total funding this represented in 2005 2014. DESIGN: This is a retrospective analysis of publicly available datasets. SETTING: National Health and Medical Research Council Rural and Remote Health Research 2000-2014. OUTCOME MEASURES: 'Australian Rural Health Research' was defined as: research that focussed on rural or remote Australia; that related to the National Health and Medical Research Council's research categories other than Basic Science; and aimed specifically to improve the health of Australians living in rural and remote areas. Grants meeting the inclusion criteria were grouped according to the National Health and Medical Research Council's categories and potential benefit. Funding totals were aggregated and compared to the total funding and Indigenous funding for the period 2005-2014. RESULTS: Of the 16 651 National Health and Medical Research Council-funded projects, 185 (1.1%) that commenced funding during the period 2000-2014 were defined as 'Australian Rural Health Research'. The funding for Australian Rural Health Research increased from 1.0% of the total in 2005 to 2.4% in 2014. A summary of the funding according to the National Health and Medical Research Council's research categories and potential benefit is presented. CONCLUSION: Addressing the health inequality experienced by rural and remote Australians is a stated aim of the Australian Government. While National Health and Medical Research Council funding for rural health research has increased over the past decade, at 2.4% by value, it appears very low given the extent of the health status and health service deficits faced by the 30% who live in rural Australia. PMID- 29624789 TI - Eph/ephrin family anchored on exosome facilitate communications between cells. AB - Interactions of Ephrins and Eph receptors at cell membranes play crucial role in boundary formation and axon guidance. Extracellular vesicles (EVs), such as exosomes, are formed by cells communicating with each other in paracrine or endocrine manner. Until now, it is thought that direct cell-cell contact is necessary for ephrin and Eph receptor signal transduction. In this review, we discuss recent data that indicate the existence of a novel Eph-ephrin family anchored exosome signaling pathway in long-range intercellular communication and provide evidence that this type of signaling elicits cellular responses in cancer cells, independent of juxtacrine interactions. We emphasize that exosome-anchored Eph/ephrin involves a variety of biological processes and transduction signals, which may serve as a potential diagnostic biomarker. PMID- 29624790 TI - Gene therapy for Glut1-deficient mouse using an adeno-associated virus vector with the human intrinsic GLUT1 promoter. AB - BACKGROUND: We generated an adeno-associated virus (AAV) vector in which the human SLC2A1 gene, encoding glucose transporter type 1 (GLUT1), was expressed under the human endogenous GLUT1 promoter (AAV-GLUT1). We examined whether AAV GLUT1 administration could lead to functional improvement in GLUT1-deficient mice. METHODS: We extrapolated human endogenous GLUT1 promoter sequences from rat minimal Glut1 promoter sequences. We generated a tyrosine-mutant AAV9/3 vector in which human SLC2A1-myc-DDK was expressed under the human GLUT1 promoter (AAV GLUT1). AAV-GLUT1 was administered to GLUT1-deficient mice (GLUT1+/- mice) via intracerebroventricular injection (1.85 * 1010 vg/mouse or 6.5 * 1010 vg/mouse). We analyzed exogenous GLUT1 mRNA and protein expression in the brain and other major organs. We also examined improvements of cerebral microvasculature, motor function using rota-rod and footprint tests, as well as blood and cerebrospinal fluid (CSF) glucose levels. Additionally, we confirmed exogenous GLUT1 protein distribution in the brain and other organs after intracardiac injection (7.8 * 1011 vg/mouse). RESULTS: Exogenous GLUT1 protein was strongly expressed in the cerebral cortex, hippocampus and thalamus. It was mainly expressed in endothelial cells, and partially expressed in neural cells and oligodendrocytes. Motor function and CSF glucose levels were significantly improved following intracerebroventricular injection. Exogenous GLUT1 expression was not detected in other organs after intracerebroventricular injection of AAV-GLUT1, whereas it was detected in the liver and muscle tissue after intracardiac injection. CONCLUSIONS: Exogenous GLUT1 expression after AAV-GLUT1 injection approximated that of physiological human GLUT1 expression. Local central nervous system administration of AAV-GLUT1 improved CSF glucose levels and motor function of GLUT1-deficient mice and minimized off-target effects. PMID- 29624791 TI - A Taxonomy of Value. PMID- 29624792 TI - Circumstances of suicide among individuals with a history of cancer. AB - OBJECTIVE: Cancer can trigger psychological distress, which may be associated with risk of suicide. We explored precipitating circumstances of suicides among decedents with and without a history of cancer. METHODS: Coroner or medical examiner and law enforcement narratives of adult suicides were coded from 17 participating states in Centers for Disease Control and Prevention's National Violent Death Reporting System during 2004 to 2013. Bivariate and multivariate analyses examined associations between cancer history and factors that precipitated suicide. RESULTS: Of 90 581 suicides, 4182 decedents (4.6%) had a history of cancer. Significantly more decedents with a history of cancer (versus without) were male, non-Hispanic white, married, veterans, and aged 55 or older (P < .001). Decedents with a history of cancer were more likely to die of suicide by firearm and less likely to die of suicide by suffocation compared to poisoning. In matched case analyses controlling for demographic and recent circumstances, fewer decedents with a history of cancer had mental health problems, history of suicide attempts, alcohol use problems, intimate partner problems, financial problems, job problems, and recent crisis. CONCLUSIONS: Findings highlight the potential to identify high-risk populations for suicide prevention in clinical practice. PMID- 29624793 TI - Electron microscopic observations of stomata, epicuticular waxes, and papillae in Chamaecyparis obtusa: Reconsidering the traditional concept of Y-shaped white stomatal bands. AB - The foliar morphological characters of hinoki (Chamaecyparis obtusa) were revisited using optical and scanning electron microscopy. In C. obtusa, typical Y shaped white stomatal bands were evident on the abaxial leaf surfaces. Two facial leaves and two lateral leaves were observed at the same node. Waxy papillae and oval stomata were arranged in two or three rows with protuberant rims on the abaxial leaf surfaces. Higher magnifications revealed the deposition of epicuticular waxes (tubules) on the Y-shaped white stomatal bands. Given the absence of stomatal bands after dewaxing with organic solvents, the white stomatal bands in C. obtusa were related to the epicuticular waxes rather than the presence of aggregated stomata alone. In contrast to C. obtusa, a single median leaf and two lateral leaves were observed at the same node of oriental arborvitae (Platycladus koraiensis). Neither stomatal bands nor papillae were observed on P. koraiensis leaves. The stomatal density and epicuticular waxes in the stomatal regions of C. obtusa were higher than those of P. koraiensis. This study suggests that the traditional concept of Y-shaped white stomatal bands in C. obtusa should be revised to describe the arrangement of the aggregated waxy stomata that occur in rows. PMID- 29624794 TI - Socio-demographic differences in Colombian children's muscular fitness: Does scaling for differences in body size present a challenge to conventional thinking? AB - OBJECTIVES: In low- to middle-income countries, children from less-deprived areas (from families of higher socio-economic status [SES]) have superior muscular fitness than those from low-SES groups. They are also taller and heavier, factors associated with muscular fitness. The purpose of this study was to identify any socio-demographic differences in Colombian children's muscular fitness and examine how these conclusions can be modified by scaling for differences in body size. METHODS: A total of 38,098 youths (46% girls), ninth grade students (aged 14-15 years), participated in a study of cross-sectional design. We recorded SES and family incomes, stature, and mass. Standing broad jump and handgrip strength were used to assess muscular fitness. A multiplicative allometric model was adopted to adjust for body-size differences. RESULTS: Children from the mid- to high-SES groups jumped significantly higher than children from the lowest SES group, although no SES group difference in grip strength was observed. After adjusting for body size, children from higher SES and with higher family incomes had significantly lower handgrip strength, and their superior jump height performances remained but were greatly reduced. Only children from the highest SES now jumped significantly higher that the lowest SES group. CONCLUSIONS: The superior jump performance and no difference in handgrip strength of Colombian children from higher SES may simply reflect their superior physiques. When body size is accounted for, these differences are reduced or even reversed, suggesting that children from higher SES groups should not be complacent regarding their apparent superior muscular fitness. PMID- 29624795 TI - Reconstruction of a buttock defect after excision of inflammatory linear verrucous epidermal nevus. PMID- 29624796 TI - Beyond left ventricular ejection fraction there is a right heart that pumps: reply. PMID- 29624797 TI - Prosocial and self-interested intra-twin pair behavior in monozygotic and dizygotic twins in the early to middle childhood transition. AB - Several related and complementary theoretical frameworks have been proposed to explain the existence of prosocial behavior, despite its potential fitness cost to the individual. These include kin selection theory, proposing that organisms have a propensity to help those to whom they are genetically related, and reciprocity, referring to the benefit of being prosocial, depending on past and future mutual interactions. A useful paradigm to examine prosociality is to compare mean levels of this behavior between monozygotic (MZ) and dizygotic (DZ) twins. Here, we examined the performance of 883 6.5-year-old twins (139 MZ and 302 DZ same-sex 6.5-year-old full twin pairs) in the Differential Productivity Task. In this task, the twins' behaviors were observed under two conditions: working for themselves vs. working for their co-twin. There were no significant differences between the performances of MZ and DZ twins in the prosocial condition of the task. Correlations within the twin dyads were significantly higher in MZ than DZ twins in the self-interested condition. However, similar MZ and DZ correlations were found in the prosocial condition, supporting the role of reciprocity in twins' prosociality towards each other. PMID- 29624798 TI - ASHRM's commitment to improving diagnosis in health care. PMID- 29624799 TI - A checklist for managed access programmes for reimbursement co-designed by Canadian patients and caregivers. AB - INTRODUCTION: Reimbursement decisions on orphan drugs carry significant uncertainty, and as the amount increases, so does the risk of making a wrong decision, where harms outweigh benefits. Consequently, patients often face limited access to orphan drugs. Managed access programmes (MAPs) are a mechanism for managing risk while enabling access to potentially beneficial drugs. Patients and their caregivers have expressed support for these programmes and see patient input as critical to successful implementation. However, they have yet to be systematically involved in their design. OBJECTIVE: The aim of this study was to co-design with patients and caregivers a tool for the development of managed access programmes. METHODS: Building upon established relationships with the Canadian Organization for Rare Disorders, the project team collaborated with patients and caregivers using the principles of participatory action research. Data were collected at two workshops and analysed using a thematic network approach. RESULTS: Patients and caregivers co-designed a checklist comprised of six aspects of an ideal MAP relating to accountability (programme goals); governance (MAP-specific committee oversight, patient input, international collaboration); and evidence collection (outcome measures and continuation criteria, on-going monitoring and registries). They recognized that health-care resources are finite and considered disease or drug eligibility criteria for deciding when to use a MAP (eg drugs treating diseases for which there are no other legitimate alternatives). CONCLUSIONS: A patient and caregiver-designed checklist was created, which emphasized patient involvement and transparency. Further research is needed to examine the feasibility of this checklist and roles for other stakeholders. PMID- 29624801 TI - Application of ozone during grape drying for the production of straw wine. Effects on the microbiota and compositive profile of grapes. AB - AIMS: Straw wine is a highly valuable oenological production, affected by relevant economical losses due to proliferation of spoilage micro-organisms during drying grapes, after being harvested. In this work, ozone was evaluated as a tool to preserve grapes during drying, in terms of both qualitative and quantitative changes induced in the epiphytic microflora. In addition, the alteration exerted by ozone on grapes' chemical composition was analysed. METHODS AND RESULTS: Grapes from four vine varieties were treated with ozone produced by a cold plasma generator during the entire drying period (6 weeks). The microflora was quantified weekly by plate counts and characterized by 454-pyrosequencing, and was compared with identical, untreated grape samples. At the end of drying, an extensive chemical characterization of the whole mass of grapes by FT-IR and GC-MS was performed. Ozone counteracted the growth of microflora by reducing the microbial population up to 3 log units. From the qualitative point of view, ozone reduced the incidence of spoilage micro-organisms, such as Acetobacter and Botrytis cinerea, among the microbiota of grapes. CONCLUSIONS: The statistical analysis discriminates grape samples based on the residual epiphytic microflora at the end of drying and not on their chemical composition. These evidences confirmed that ozone did control spoilage micro-organisms without altering the volatile profile of grapes. Chemical analysis revealed that untreated grapes are less suitable for winemaking owing to the deprivation of some valuable compounds during the microbial proliferation. SIGNIFICANCE AND IMPACT OF THE STUDY: Ozone is an emerging tool in winemaking, recently applied for controlling spoilage micro-organisms in winery. The present study describes a new application of ozone as an effective and safe alternative to chemical preservatives which are actually involved in the control of microbial alterations of grapes. PMID- 29624800 TI - Efficacy and safety of 3-month dosing regimen of degarelix in Japanese subjects with prostate cancer: A phase III study. AB - Non-inferiority in the cumulative castration rate of the 3-month formulation of degarelix compared with the 3-month formulation of goserelin was evaluated in subjects with prostate cancer. A phase III, open-label, parallel-arm study was carried out. An initial dose of 240 mg degarelix or 3.6 mg goserelin was given s.c.; after day 28, a maintenance dose of 480 mg degarelix or 10.8 mg goserelin was given once every 84 days. Non-inferiority in castration rate and safety of degarelix to goserelin were evaluated. The primary end-point was the cumulative castration rate from day 28 to day 364 and the non-inferiority margin was set to be 10%. A total of 234 subjects with prostate cancer were randomized to the degarelix group (n = 117) and the goserelin group (n = 117). The cumulative castration rate was 95.1% in the degarelix group and 100.0% in the goserelin group. As there were no events in the goserelin group, an additional analysis was carried out using 95% confidence intervals of the difference in the proportion of subjects with castration. Analyses indicated the non-inferiority of the 3-month formulation of degarelix to goserelin. Degarelix showed more rapid decreases in testosterone, luteinizing hormone, follicle stimulating hormone, and prostate specific antigen levels compared with goserelin. The most common adverse events in the degarelix group were injection site reactions. Non-inferiority of the 3 month formulation of degarelix to goserelin was shown for testosterone suppression. The 3-month formulation of degarelix was also found to be tolerated as an androgen deprivation therapy for patients with prostate cancer. This trial was registered with ClinicalTrials.gov (identifier NCT01964170). PMID- 29624804 TI - Dialysis facility screening and testing practices in the era of improved hepatitis C treatment. PMID- 29624803 TI - Towards co-designing active ageing strategies: A qualitative study to develop a meaningful physical activity typology for later life. AB - BACKGROUND: Physical activity levels decline in later life despite the known benefits for physical, cognitive and mental health. Older people find it difficult to meet activity targets; therefore, more realistic and meaningful strategies are needed. We aimed to develop a typology of older people's motivations and lifelong habits of being active as a starting point to co designing active ageing strategies in a workshop. METHODS: We conducted semi structured interviews with 27 participants aged 65-80 in Norfolk, UK, and participant observation with 17 of them. At a workshop with 13 study participants and 6 government and civil society representatives, we invited reflections on preliminary findings. RESULTS: Three types were developed. "Exercisers" had engaged in sport and exercise throughout their life but experienced physical ill health and limitations as barriers. "Out-and-about-ers" pursued social engagement and a variety of interests but experienced biographical disruption through retirement and loss of companions that limited social activities in later life. A final type characterized people who preferred "sedentary/solitary" activities. A workshop elicited suggestions for new strategies relating to these types that addressed people's specific motivations. An example was to combine social engagement and physical activity in "dog-parent"-walking schemes to link people through shared responsibility for a dog. CONCLUSIONS: We suggest that these potential strategies map more closely onto the everyday life-worlds in which public health might seek to intervene than common physical activity interventions. Most notably, this means a more differentiated understanding of barriers, and acknowledging that intellectual, social or solitary pursuits can include incidental physical activity. PMID- 29624802 TI - Serum hepatitis B surface antigen correlates with fibrosis and necroinflammation: A multicentre perspective in China. AB - The kinetics of serum hepatitis B surface antigen (HBsAg) during the natural history of hepatitis B virus (HBV) infection has been studied, but the factors affecting them remain unclear. We aimed to investigate the factors affecting HBsAg titres, using data from multicentre, large-sized clinical trials in China. The baseline data of 1795 patients in 3 multicentre trials were studied, and the patients were classified into 3 groups: hepatitis B early antigen (HBeAg) positive chronic HBV infection (n = 588), HBeAg-positive chronic hepatitis B (n = 596), and HBeAg-negative chronic hepatitis B (n = 611). HBsAg titres in the different phases were compared, and multiple linear progression analyses were performed to investigate the implicated factors. HBsAg titres varied significantly in different phases (P = .000), with the highest (4.60 log10 IU/mL [10%-90% confidence interval: 3.52 log10 IU/mL-4.99 log10 IU/mL]) in patients with HBeAg-positive chronic HBV infection. In all phases, age and HBV DNA were correlated with serum HBsAg level. In HBeAg-positive chronic hepatitis B patients, a negative correlation between HBsAg titres and fibrosis stage was observed. Alanine amonitransferase or necroinflammatory activity was also correlated with HBsAg titres in HBeAg-negative chronic hepatitis B patients. In conclusion, decreased HBsAg titres may be associated with advancing fibrosis in HBeAg-positive chronic hepatitis B patients or increased necroinflammation in those with HBeAg-negative chronic hepatitis B. Our findings may help clinicians better understand the kinetics of HBsAg and provide useful insights into the management of this disease. PMID- 29624805 TI - Characterization and antimicrobial activity of silver nanoparticles mycosynthesized by Aspergillus brasiliensis. AB - AIMS: Since mycosynthesis of metal nanoparticles (NPs) is advertised as a promising and ecofriendly approach. Thus, this study aims to investigate the capability of Aspergillus brasiliensis ATCC 16404 for mycosynthesis of silver NPs (AgNPs). METHODS AND RESULTS: One-factor-at-a-time-technique was used to study the effect of different physicochemical parameters: the reaction time, pH, temperature, different stirring rates, illumination, and finally, the different concentrations of silver nitrate and fungal biomass on the mycosynthesis of AgNPs. The visual observation showed the characteristic brown colour formation due to the bioreduction of Ag+ ions to Ag0 by the mycelial cell-free filtrate (MCFF). The UV/visible spectrophotometric technique displayed a characteristic sharp peak at y440 confirming the mycosynthesis of AgNPs. The zeta potential value -16.7 mV assured the long-term stability of AgNPs and the dynamic light scattering analysis revealed good dispersion and average particle size 77 nm. The energy dispersive X-ray spectroscopy displayed a maximum elemental distribution of silver elements. The X-ray diffraction spectroscopy demonstrated the crystallinity of the mycosynthesized AgNPs. The field emission scanning electron microscope and high-resolution transmission electron microscope revealed monodispersed spherical shaped AgNPs with average particle size of 6-21 nm. The FTIR analysis showed the major peaks of proteins providing the possible role of MCFF in the synthesis and stabilization of the AgNPs. The mycosynthesized AgNPs expressed good biocidal activity against different pathogenic micro-organisms causing some water-related diseases and health problems to local residents. CONCLUSIONS: This study proved that A. brasiliensis ATCC 16404 MCFF has good potential for mycosynthesis of AgNPs, which exhibited good antimicrobial effect on different pathogenic micro-organisms; thus, it can be applied for water disinfection. SIGNIFICANCE AND IMPACT OF THE STUDY: This research provides a helpful insight into the development of a new mycosynthesized antimicrobial agent. PMID- 29624808 TI - Perspectives of Attosecond Spectroscopy for the Understanding of Fundamental Electron Correlations. AB - The description of the electronic structure of molecules in terms of molecular orbitals is a highly successful concept in chemistry. However, it commonly fails if the electrons in a molecule are strongly correlated and cannot be treated as independent particles. Electron correlation is essential to understand inner valence X-ray spectroscopies, it can drive ultrafast charge migration in molecules, and it is responsible for many exotic properties of strongly correlated materials. Time-resolved spectroscopy with attosecond resolution is generally capable of following electronic motion in real time and can thus provide experimental access to electron-correlation-driven phenomena. High harmonic spectroscopy in particular uses the precisely timed laser-driven recollision of electrons to interrogate the electronic structure and dynamics of the investigated system on a sub-femtosecond timescale. In this Review, the capabilities of high-harmonic spectroscopy to follow electronic motion in molecules are discussed. Both qualitative and quantitative approaches to unraveling the detailed dynamical responses of molecular systems following ionization are presented. A new theoretical formalism for the reconstruction of correlation-driven charge migration is introduced. The importance of electron-ion entanglement and electronic coherence in the reconstruction of attosecond hole dynamics are discussed. These advances make high-harmonic spectroscopy a promising technique to decode fundamental electron correlations and to provide experimental data on the complex manifestations of multi-electron dynamics. PMID- 29624806 TI - Kruppel-like factor 4 promotes c-Met amplification-mediated gefitinib resistance in non-small-cell lung cancer. AB - Gefitinib has been widely used in the first-line treatment of advanced EGFR mutated non-small-cell lung cancer (NSCLC). However, many NSCLC patients will acquire resistance to gefitinib after 9-14 months of treatment. This study revealed that Kruppel-like factor 4 (KLF4) contributes to the formation of gefitinib resistance in c-Met-overexpressing NSCLC cells. We observed that KLF4 was overexpressed in c-Met-overexpressing NSCLC cells and tissues. Knockdown of KLF4 increased tumorigenic properties in gefitinib-resistant NSCLC cell lines without c-Met overexpression, but it reduced tumorigenic properties and increased gefitinib sensitivity in gefitinib-resistant NSCLC cells with c-Met overexpression, whereas overexpression of KLF4 reduced gefitinib sensitivity in gefitinib-sensitive NSCLC cells. Furthermore, Western blot analysis revealed that KLF4 contributed to the formation of gefitinib resistance in c-Met-overexpressing NSCLC cells by inhibiting the expression of apoptosis-related proteins under gefitinib treatment and activating the c-Met/Akt signaling pathway by decreasing the inhibition of beta-catenin on phosphorylation of c-Met to prevent blockade by gefitinib. In summary, this study's results suggest that KLF4 is a promising candidate molecular target for both prevention and therapy of NSCLC with c-Met overexpression. PMID- 29624807 TI - Cost-utility analysis of meaning-centered group psychotherapy for cancer survivors. AB - BACKGROUND: Meaning-centered group psychotherapy for cancer survivors (MCGP-CS) improves meaning, psychological well-being, and mental adjustment to cancer and reduces psychological distress. This randomized controlled trial was conducted to investigate the cost-utility of MCGP-CS compared with supportive group psychotherapy (SGP) and care-as-usual (CAU). METHODS: In total, 170 patients were randomized to MCGP-CS, SGP, or CAU. Intervention costs, direct medical and nonmedical costs, productivity losses, and health-related quality of life were measured until 6 months follow-up, using the TIC-P, PRODISQ, data from the hospital information system, and the EQ-5D. The cost-utility was calculated by comparing mean cumulative costs and quality-adjusted life years (QALYs). RESULTS: Mean total costs ranged from ?4492 (MCGP-CS) to ?5304 (CAU). Mean QALYs ranged .507 (CAU) to .540 (MCGP-CS). MCGP-CS had a probability of 74% to be both less costly and more effective than CAU, and 49% compared with SGP. Sensitivity analyses showed these findings are robust. If society is willing to pay ?0 for one gained QALY, MCGP-CS has a 78% probability of being cost-effective compared with CAU. This increases to 85% and 92% at willingness-to-pay thresholds of ?10 000 and ?30 000, which are commonly accepted thresholds. CONCLUSIONS: MCGP-CS is highly likely a cost-effective intervention, meaning that there is a positive balance between the costs and gains of MCGP-CS, in comparison with SGP and CAU. PMID- 29624809 TI - Characterization of demographics and NS5A genetic diversity for hepatitis C virus genotype 4-infected patients with or without cirrhosis treated with ombitasvir/paritaprevir/ritonavir. AB - Hepatitis C virus (HCV) genotype 4 (GT4) is genetically diverse with 17 confirmed and 4 provisional subtypes. In this report, HCV GT4-infected patient samples from Phase 2/3 clinical studies were analysed to characterize global demographics and genetic diversity of GT4 infection among patients treated with ombitasvir (OBV, NS5A inhibitor) plus paritaprevir/r (NS3/4A inhibitor codosed with ritonavir). Among 17 subtypes isolated from GT4-infected patients in the PEARL-I and AGATE-I studies, subtype prevalence by country of enrolment and country of origin suggested that subtypes 4a and 4d were likely circulating in Europe, while heterogeneous GT4 subtypes and a portion of GT4a detected in European and North American countries were likely due to immigration of HCV-infected patients from Africa. The distributions of birth cohort and race were also significantly different across GT4 subtypes 4a, 4d, and non-4a/4d. In addition, phylogenetic analyses of NS5A sequences revealed clustering within subtype 4a which segregated by the patient-reported country of origin and the presence of the L30R/S polymorphism. HCV NS5A sequences derived from GT4a-infected patients who originated from Europe and the United States clustered separately from sequences derived from patients who originated from Egypt, suggesting that genetically distinct strains of subtype 4a may be circulating globally. Finally, NS5A baseline polymorphisms were frequently detected at amino acid positions of interest for the inhibitor-class and OBV retained activity against 37 of 39 NS5A GT4 clinical isolates, with no impact on treatment outcome in the PEARL-I and AGATE-I studies. PMID- 29624810 TI - Immunodetection of the toxic portion of Vip3A reveals differential temporal regulation of its secretion among Bacillus thuringiensis strains. AB - AIMS: To devise a protocol for heterologous expression and purification of a partial toxic portion of the Bacillus thuringiensis (Bt) vegetative insecticidal protein Vip3A and using it as an antigen for anti-Vip3A polyclonal antibody development. Also, to evaluate the regulation of Vip3A secretion into culture supernatants (SNs) of different Bt strains based on this antibody. METHODS AND RESULTS: A primer pair was designed to amplify partially the toxic portion of the vip3A gene from the HD125 strain. The amplicon was cloned in expressing vector to produce a ~35 kDa peptide, which was HPLC-purified prior to rabbit immunizations. The serum containing the polyclonal anti-Vip3A antibody demonstrated a detection sensitivity of 0.4 ng mm-2 for the antigen in slot-blot experiments. Seven Bt strains from different origins were assessed regarding their temporal secretion of Vip3A toxin. ELISA results showed a strain-specific temporal regulation of Vip3A secretion in culture for the temperate isolates, with no detection of the toxin for the tropical strains, even when the presence of the gene was confirmed by PCR and sequencing. CONCLUSIONS: Conformational variation in the toxic portion of Vip3A may explain lack of its detection in the tropical strains. Isolates from the same subspecies display physiological variability in proteins' secretion into culture SNs, which can affect screening procedures for more effective strains/toxins. SIGNIFICANCE AND IMPACT OF THE STUDY: Immunoassays based on the developed anti-Vip3A antibody can be useful in a variety of basic studies. This method can be also coupled with toxicity assays on target insects, for more efficient screening methods of novel Bt strains/toxins with biocontrol applicability. PMID- 29624811 TI - Bilateral adrenal hemorrhage in a neonatal kidney donor. AB - EKT from neonatal donors remains rare despite successful outcome being reported. The surgical aspects of neonatal abdominal organ recovery remain unfamiliar to the vast majority of abdominal organ recovery teams and renal transplant surgeons. BAH is not uncommon in newborn babies suffering distress in the perinatal period. BAH is often also associated with RVT and will impact on utilization of kidneys for transplantation. We present a case of a neonatal kidney donor with massive BAHs discovered at the time of organ recovery. This made the procurement challenging. Both kidneys were recovered en bloc with pancreas and the liver with aorta and inferior vena cave as vascular conduits. The kidneys were successfully implanted into an adult recipient with good function at 1-year follow-up. Association between adrenal hemorrhage and RVT needs to be considered before utilizing such kidneys. This case exemplifies successful outcome after careful assessment and transplantation of such kidneys. PMID- 29624812 TI - Treatment of nevoid hyperkeratosis of the areola and nipple with topical tacalcitol: A case report. PMID- 29624813 TI - Feasibility of reaching world health organization targets for hepatitis C and the cost-effectiveness of alternative strategies. AB - New drugs for treating hepatitis C have considerably increased the probability of being cured. Treatment uptake, however, is still low. The objectives of this study were to analyse the impact of initiatives that may increase the proportion of infected people on treatment and interventions aimed at reducing the incidence of new infection among people who inject drugs. A compartmental model for Norway was used to simulate hepatitis C and related complications. We analysed 2 different screening initiatives aimed to increase the proportion of infected people on treatment. Interventions aiming at reducing the hepatitis C incidence analysed were opioid substitution therapy (OST), a clean needle and syringe programme and a combination of both. The most cost-effective strategy for increasing hepatitis C treatment uptake was screening by general practitioners while simultaneously allowing for all infected people to be treated. We estimated that this intervention reduces the incidence of hepatitis C by 2030 by 63% compared with the current incidence. The 2 harm reduction strategies both reduced the incidence of hepatitis C by about 70%. Combining an increase in the current clean needles and syringe programme with OST was clearly the most cost-effective option. This strategy would reduce the incidence of hepatitis C by 80% compared with the current incidence by 2030. Thus, interventions to reduce the burden and spread of hepatitis C are cost-effective. Reaching the WHO target of a 90% reduction in hepatitis C incidence by 2030 may be difficult without combining different initiatives. PMID- 29624815 TI - Responding effectively to adult mental health patient feedback in an online environment: A coproduced framework. AB - BACKGROUND: Responding to online patient feedback is considered integral to patient safety and quality improvement. However, guidance on how to respond effectively is limited, with limited attention paid to patient perceptions and reactions. OBJECTIVES: To identify factors considered potentially helpful in enhancing response quality; coproduce a best-practice response framework; and quality-appraise existing responses. DESIGN: A four-stage mixed methodology: (i) systematic search of stories published on Care Opinion about adult mental health services in the South West of England; (ii) collaborative thematic analysis of responses to identify factors potentially helpful in enhancing response quality; (iii) validation of identified factors by a patient-carer group (n = 12) leading to the coproduction of a best-practice response framework; and (iv) quality appraisal of existing responses. RESULTS: A total of 245 stories were identified, with 183 (74.7%) receiving a response. Twenty-four (9.8%) had been heard but not yet responded to. 1.6% (n = 4/245) may lead to a change. Nineteen factors were considered influential in response quality. These centred around seven subject areas: (i) introductions; (ii) explanations; (iii) speed of response; (iv) thanks and apologies; (v) response content; (vi) signposting; and (vii) response sign off that were developed into a conceptual framework (the Plymouth, Listen, Learn and Respond framework). Quality appraisal of existing responses highlighted areas for further improvement demonstrating the framework's utility. CONCLUSION: This study advances existing understanding by providing previously unavailable guidance. It has clear practical and theoretical implications for those looking to improve health-care services, patient safety and quality of care. Further validation of the conceptual framework is encouraged. PMID- 29624816 TI - Myocarditis in a girl with mixed connective tissue disease. PMID- 29624817 TI - Fatal hyperammonemia associated with disseminated Serratia marcescens infection in a pediatric liver transplant recipient. AB - Hyperammonemia is a rare and important complication post-liver transplantation. We review a case of a 5-month-old boy with biliary atresia who received a split liver transplant following a variceal bleed. The transplant was complicated by recurrent portal vein thrombosis. Colonized with Serratia marcescens pretransplant, he developed disseminated infection associated with very high levels of ammonia that led to his death. It is important to be aware of serum ammonia levels in patients with portal vein thrombosis, particularly in the setting of gastrointestinal bleeding and sepsis. PMID- 29624814 TI - eIF2beta, a subunit of translation-initiation factor EIF2, is a potential therapeutic target for non-small cell lung cancer. AB - To identify novel therapeutic targets for non-small cell lung cancer (NSCLC), we conducted an integrative study in the following 3 stages: (i) identification of potential target gene(s) through shRNA functional screens in 2 independent NSCLC cell lines; (ii) validation of the clinical relevance of identified gene(s) using public databases; and (iii) investigation of therapeutic potential of targeting the identified gene(s) in vitro. A semi-genome-wide shRNA screen was performed in NCI-H358 cells, and was integrated with data from our previous screen in NCI-H460 cells. Among genes identified in shRNA screens, 24 were present in both NCI-H358 and NCI-H460 cells and were considered potential targets. Among the genes, we focused on eIF2beta, which is a subunit of heterotrimeric G protein EIF2 and functions as a transcription initiation factor. The eIF2beta protein is highly expressed in lung cancer cell lines compared with normal bronchial epithelial cells, and gene copy number analyses revealed that eIF2beta is amplified in a subset of NSCLC cell lines. Gene expression analysis using The Cancer Genome Atlas (TCGA) dataset revealed that eIF2beta expression is significantly upregulated in lung cancer tissues compared with corresponding normal lung tissues. Furthermore, high eIF2beta expression was correlated with poor survival in patients with lung adenocarcinoma, as shown in other cohorts using publicly available online tools. RNAi-mediated depletion of eIF2beta suppresses growth of lung cancer cells independently of p53 mutation status, in part through G1 cell cycle arrest. Our data suggest that eIF2beta is a therapeutic target for lung cancer. PMID- 29624819 TI - Use of S17 fragment containing hepatitis E virus infectious clones in cell culture experiments: The fine print does matter. PMID- 29624818 TI - Incidence of hepatitis B virus infection in young Chinese blood donors born after mandatory implementation of neonatal hepatitis B vaccination nationwide. AB - This study was carried out to determine the incidence of hepatitis B virus (HBV) infection in the young generation born after mandatory implementation of hepatitis B vaccination since 1992. Repeat blood donors born between 1992 and 1997 were enrolled, who gave blood at least twice during the past 3 years. Donors were tested for HBV infection markers of HBsAg, anti-HBc, anti-HBs and viral DNA by immunoassays (EIAs) and nucleic acid tests (NAT). A total of 14 937 pre donation screening qualified young repeat donors aged 18-23 years were tested with 9 (0.06%) being HBsAg by EIA and 10 (1:1494) HBV DNA positive by Ultrio NAT (10.4 IU/mL), respectively. HBV DNA was further detected in 1:192 (9/1732) anti HBc+ repeat donors with Ultrio Plus NAT (3.4 IU/mL). Most cases were identified as occult HBV infection (OBI). Of 14 937 repeat donors, 20.9% were anti-HBc+ positive, while approximately 50% of 12 024 repeat donors were anti-HBs negative or had levels <100 IU/L. HBsAg+ or OBI strains were classified as wild type of genotype B or genotype C. Incident HBV infection in repeat donors was approximately 1:18.5 person-years (1.1%/year) but significantly less frequent in donors with confirmed HBV vaccination (2.4%-3.3%) than those unsure of vaccination status (10.5%; P = .0023). Hepatitis B virus vaccination appears largely protective of HBV infection, but incidence of infections increases in young adults with mostly undetectable or low anti-HBs or occasionally high anti HBs. A boost of hepatitis B vaccine for adolescents prior to age 18 years may reduce HBV infection, and implementation of more sensitive NAT in blood donation screening may improve HBV safety in blood transfusion. PMID- 29624820 TI - Escherichia coli cellular responses to exposure to atmospheric-pressure dielectric barrier discharge plasma-treated N-acetylcysteine solution. AB - AIM: To understand the underlying cellular mechanisms during inactivation of Escherichia coli in response to antimicrobial solution of nonthermal plasma activated N-acetylcysteine (NAC). METHODS AND RESULTS: The recommended techniques were used to demonstrate E. coli cellular and transcriptomic changes caused associated with peroxynitrite and compared with plasma-treated NAC solution. The findings demonstrate that E. coli cells respond to plasma-treated NAC and undergo severe oxidative and nitrosative stress, and leading to stress-induced damages to different components of bacterial cells, which includes loss of membrane potential, formation of oxidized glutathione (GSSG), formation of nitrotyrosine (a known marker of nitrosative stress), DNA damage, and generated a prominent pool of peroxynitrite. Reverse-transcriptase (RT)-polymerase chain reaction analysis of reactive nitrogen species (RNS) responsive genes indicated their differential expressions. CONCLUSION: For the first time, we report that the plasma-treated NAC solution activates predominantly nitrosative stress-responsive genes in E. coli and is responsible for cell death. SIGNIFICANCE AND IMPACT OF THE STUDY: The reactive species generated in solutions by nonthermal plasma treatment depends on the type of solution or solvent used. The plasma-treated NAC solution rapidly inactivates E. coli, mostly involving highly RNS generated in NAC solution, and has high potential as disinfectant. PMID- 29624822 TI - O->S Relay Deprotection: A General Approach to Controllable Donors of Reactive Sulfur Species. AB - Reactive sulfur species (RSS) are biologically important molecules. Among them, H2 S, hydrogen polysulfides (H2 Sn, n>1), persulfides (RSSH), and HSNO are believed to play regulatory roles in sulfur-related redox biology. However, these molecules are unstable and difficult to handle. Having access to their reliable and controllable precursors (or donors) is the prerequisite for the study of these sulfur species. Reported in this work is the preparation and evaluation of a series of O-silyl-mercaptan-based sulfur-containing molecules which undergo pH- or F- -mediated desilylation to release the corresponding H2 S, H2 Sn , RSSH, and HSNO in a controlled fashion. This O->S relay deprotection serves as a general strategy for the design of pH- or F- -triggered RSS donors. Moreover, we have demonstrated that the O-silyl groups in the donors could be changed into other protecting groups like esters. This work should allow the development of RSS donors with other activation mechanisms (such as esterase-activated donors). PMID- 29624821 TI - Systematic review of risk factors of hepatocellular carcinoma after hepatitis B surface antigen seroclearance. AB - There is no consensus about factors that increase risk of hepatocellular carcinoma (HCC) among patients with chronic hepatitis B who have achieved seroclearance of hepatitis B surface antigen (HBsAg). To assess the available evidence about risk factors for HCC after HBsAg seroclearance, Scopus, EMBASE, PubMed and Cochrane Library databases were systematically searched for relevant studies published through 15 September 2017. A total of 28 studies involving more than 105 411 patients with chronic hepatitis B were included. HBsAg seroclearance occurred spontaneously in 7656, while it occurred after interferon or nucleos(t)ide analogue therapy in 1248. The rate of HBsAg seroclearance was 6.77%. Incidence of HCC was significantly lower among patients who experienced HBsAg seroclearance than among those who remained HBsAg-positive (1.86% vs 6.56%, P < .001). Risk factors of HCC occurrence included cirrhosis (incidence with vs without: 9.51% vs 1.66%), male gender (2.34% vs 0.64%) and age >= 50 year at HBsAg seroclearance (2.34% vs 0.63%) (all P < .001). The available evidence suggests that HCC can develop at a low rate after HBsAg seroclearance, so periodic surveillance is recommended, especially for male patients, patients with cirrhosis and patients who experience HBsAg seroclearance when at least 50 years old. PMID- 29624823 TI - Cyclic beta-glucans at the bacteria-host cells interphase: One sugar ring to rule them all. AB - Cyclic beta-1,2-D-glucans (CbetaG) are natural bionanopolymers present in the periplasmic space of many Proteobacteria. These molecules are sugar rings made of 17 to 25 D-glucose units linked exclusively by beta-1,2-glycosidic bonds. CbetaG are important for environmental sensing and osmoadaptation in bacteria, but most importantly, they play key roles in complex host-cell interactions such as symbiosis, pathogenesis, and immunomodulation. In the last years, the identification and characterisation of the enzymes involved in the synthesis of CbetaG allowed to know in detail the steps necessary for the formation of these sugar rings. Due to its peculiar structure, CbetaG can complex large hydrophobic molecules, a feature possibly related to its function in the interaction with the host. The capabilities of the CbetaG to function as molecular boxes and to solubilise hydrophobic compounds are attractive for application in the development of drugs, in food industry, nanotechnology, and chemistry. More importantly, its excellent immunomodulatory properties led to the proposal of CbetaG as a new class of adjuvants for vaccine development. PMID- 29624824 TI - Prognostic value of nutritional risk screening 2002 scale in nasopharyngeal carcinoma: A large-scale cohort study. AB - Little is known about the value of the nutritional risk screening 2002 (NRS2002) scale in nasopharyngeal carcinoma (NPC). We conducted a large-scale study to address this issue. We employed a big-data intelligence database platform at our center and identified 3232 eligible patients treated between 2009 and 2013. Of the 3232 (12.9% of 24 986) eligible patients, 469 (14.5%), 13 (0.4%), 953 (29.5%), 1762 (54.5%) and 35 (1.1%) had NRS2002 scores of 1, 2, 3, 4 and 5, respectively. Survival outcomes were comparable between patients with NRS2002 <3 and >=3 (original scale). However, patients with NRS2002 <=3 vs >3 (regrouping scale) had significantly different 5-year disease-free survival (DFS; 82.7% vs 75.0%, P < .001), overall survival (OS; 88.8% vs 84.1%, P = .001), distant metastasis-free survival (DMFS; 90.2% vs 85.9%, P = .001) and locoregional relapse-free survival (LRRFS; 91.6% vs 87.2%, P = .001). Therefore, we proposed a revised NRS2002 scale, and found that it provides a better risk stratification than the original or regrouping scales for predicting DFS (area under the curve [AUC] = 0.530 vs 0.554 vs 0.577; P < .05), OS (AUC = 0.534 vs 0.563 vs 0.582; P < .05), DMFS (AUC = 0.531 vs 0.567 vs 0.590; P < .05) and LRRFS (AUC = 0.529 vs 0.542 vs 0.564; P < .05 except scale A vs B). Our proposed NRS2002 scale represents a simple, clinically useful tool for nutritional risk screening in NPC. PMID- 29624825 TI - The Rho signalling pathway mediates the pathogenicity of AHPND-causing V. parahaemolyticus in shrimp. AB - An emerging bacterial disease, acute hepatopancreatic necrosis disease (AHPND), is caused by strains of Vibrio parahaemolyticus with an additional AHPND associated plasmid pVA1 encoding a virulent toxin (Pirvp ) that damages the shrimp's hepatopancreas. Like other species of Vibrio, these virulent strains initially colonise the shrimp's stomach, but it is not yet understood how the bacteria or toxins are subsequently able to cross the epithelial barrier and reach the hepatopancreas. Here, by using transcriptomics and system biology methods, we investigate AHPND-induced changes in the stomach of AHPND-causing V. parahaemolyticus (5HP)-infected shrimp and identify host molecular mechanisms that might explain how the integrity of the stomach barrier is compromised. We found that the expression of 376 unique genes was differentially regulated by AHPND infection. Gene ontology, protein interaction, and gene-to-gene correlation expression interaction analyses indicated that in addition to the immune system, a number of these genes were involved in cytoskeleton regulation by Rho GTPase. The involvement of Rho pathway regulation during AHPND pathogenesis was further supported by experiments showing that while Rho inhibitor pretreatment delayed the infection, pretreatment with Rho activator enhanced the pathogenicity of 5HP, and both the bacteria and toxin were detected sooner in the hepatopancreas. Further, disruption of the stomach epithelial structure was found in both Rho preactivated shrimp and in 5HP-infected shrimp. Taken together, we interpret our results to mean that Rho signalling helps to mediate AHPND pathogenesis in shrimp. PMID- 29624827 TI - Photocatalytic Deuteration of Halides Using D2 O over CdSe Porous Nanosheets: A Mild and Controllable Route to Deuterated Molecules. AB - A facile and efficient method for deuterium incorporation has been developed by merging photocatalytic C-X bond dissociation and water splitting with porous CdSe nanosheets as the photocatalyst under mild reaction conditions. This reaction displays good functional group tolerance and high selectivity with regard to the number and position of incorporated deuterium atoms, and can be used for the construction of complex molecules in tandem processes. PMID- 29624826 TI - Site-Specific Incorporation of Chemical Fluorescence on Live Enterovirus-71 Virion by Using an Organometallic Palladium Reagent To Monitor Virus Entry. AB - Imaging live virus to monitor the viral entry process is essential to understand virus-host interactions during pathogen infection. However, methods for efficient labeling of live viruses, in particular labeling non-enveloped viruses and tracing virus entry processes, remain limited. Recently, labeling by using organometallic palladium reagents has provided a highly efficient and selective way to bioconjugate cysteines of virus proteins. Here, site-specific bioorthogonal labeling mediated by an organometallic palladium reagent on the surface of live enterovirus-71 (EV71) was used to visualize its entry into live cells. In contrast to currently used immunofluorescence and membrane-anchored dyes, this site-specific and quantitative labeling of live EV71 allows temporal imaging of its entry into host cell membranes on the timescale of seconds with little negative impact on its virulence. This method revealed details of EV71 virus entry and has broad applicability for monitoring virus entry that is difficult to assess by using conventional protein-labeling approaches. PMID- 29624828 TI - Polymeric Nanoparticles with a Glutathione-Sensitive Heterodimeric Multifunctional Prodrug for In Vivo Drug Monitoring and Synergistic Cancer Therapy. AB - Polymeric micelle-based drug delivery systems have dramatically improved the delivery of small molecular drugs, yet multiple challenges remain to be overcome. A polymeric nanomedicine has now been engineered that possesses an ultrahigh loading (59 %) of a glutathione (GSH)-sensitive heterodimeric multifunctional prodrug (HDMP) to effectively co-deliver two synergistic drugs to tumors. An HDMP comprising of chemotherapeutic camptothecin (CPT) and photosensitizer 2-(1 hexyloxyethyl)-2-devinyl pyropheophorbide-alpha (HPPH) was conjugated via a GSH cleavable linkage. The intrinsic fluorogenicity and label-free radio-chelation (64 Cu) of HPPH enabled direct drug monitoring by fluorescence imaging and positron emission tomography (PET). Through quantitative PET imaging, HDMP significantly improves drug delivery to tumors. The high synergistic therapeutic efficacy of HDMP-loaded NPs highlights the rational design of HDMP, and presents exciting opportunities for polymer NP-based drug delivery. PMID- 29624829 TI - Direct Synthesis of a Covalent Triazine-Based Framework from Aromatic Amides. AB - There have been extensive efforts to synthesize crystalline covalent triazine based frameworks (CTFs) for practical applications and to realize their potential. The phosphorus pentoxide (P2 O5 )-catalyzed direct condensation of aromatic amide instead of aromatic nitrile to form triazine rings. P2 O5 catalyzed condensation was applied on terephthalamide to construct a covalent triazine-based framework (pCTF-1). This approach yielded highly crystalline pCTF 1 with high specific surface area (2034.1 m2 g-1 ). At low pressure, the pCTF-1 showed high CO2 (21.9 wt % at 273 K) and H2 (1.75 wt % at 77 K) uptake capacities. The direct formation of a triazine-based COF was also confirmed by model reactions, with the P2 O5 -catalyzed condensation reaction of both benzamide and benzonitrile to form 1,3,5-triphenyl-2,4,6-triazine in high yield. PMID- 29624830 TI - Asymmetric Synthesis of Silicon-Stereogenic Vinylhydrosilanes by Cobalt-Catalyzed Regio- and Enantioselective Alkyne Hydrosilylation with Dihydrosilanes. AB - The strategic carbon-to-silicon substitution at a stereogenic center can produce chiral silanes with significantly improved properties relative to their carbon congeners. We herein report an unprecedented cobalt-catalyzed asymmetric hydrosilylation of unsymmetric alkynes with dihydrosilanes that furnishes silicon stereogenic vinylhydrosilanes with high regio- and enantioselectivity. The absolute configurations of the products were determined by chiroptical methods in combination with DFT calculations. The synthetic versatility of the vinylhydrosilanes as chiral building blocks was further demonstrated by asymmetric Si-H insertion and catalytic hydroboration reactions. PMID- 29624831 TI - Biology by the Bay. PMID- 29624832 TI - Metacognitive Interpersonal Therapy in group (MIT-G) for young adults with personality disorders: A pilot randomized controlled trial. AB - Young adults with personality disorders (PD) other than borderline are in urgent need of validated treatments to help them in managing important life transitions. Therapeutic interventions focused upon social and interpersonal difficulties may facilitate these individuals in maximizing opportunities for employment, forming stable romantic relationships, and belong to social groups. It is also important that they are offered evidence-based, first-line time-limited treatments in order to maximize effectiveness and reduce costs. We developed a 16-session programme of group-based Metacognitive Interpersonal Therapy (MIT-G) including psychoeducation on the main interpersonal motives, an experiential component enabling practice of awareness of mental states; and use of mentalistic knowledge for purposeful problem-solving. We report a feasibility, acceptability, and clinical significance randomized clinical trial. Participants meeting inclusion criteria were randomized to receive MIT-G (n = 10) or waiting list+TAU (n = 10). Dropout rate was low and session attendance high (92.19%). Participants in the MIT-G arm had symptomatic and functional improvements consistent with large effect sizes. In the MIT-G arm similarly large effects were noted for increased capacity to understand mental states and regulate social interactions using mentalistic knowledge. Results were sustained at follow-up. Our findings suggest potential for applying MIT-G in larger samples to further test its effectiveness in reducing PD-related symptoms and problematic social functioning. PMID- 29624833 TI - Infants' visual sustained attention is higher during joint play than solo play: is this due to increased endogenous attention control or exogenous stimulus capture? AB - Previous research has suggested that when a social partner, such as a parent, pays attention to an object, this increases the attention that infants pay to that object during spontaneous, naturalistic play. There are two contrasting reasons why this might be: first, social context may influence increases in infants' endogenous (voluntary) attention control; second, social settings may offer increased opportunities for exogenous attentional capture. To differentiate these possibilities, we compared 12-month-old infants' naturalistic attention patterns in two settings: Solo Play and Joint Play with a social partner (the parent). Consistent with previous research, we found that infants' look durations toward play objects were longer during Joint Play, and that moments of inattentiveness were fewer, and shorter. Follow-up analyses, conducted to differentiate the two above-proposed hypotheses, were more consistent with the latter hypothesis. We found that infants' rate of change of attentiveness was faster during Joint Play than Solo Play, suggesting that internal attention factors, such as attentional inertia, may influence looking behaviour less during Joint Play. We also found that adults' attention forwards-predicted infants' subsequent attention more than vice versa, suggesting that adults' behaviour may drive infants' behaviour. Finally, we found that mutual gaze did not directly facilitate infant attentiveness. Overall, our results suggest that infants spend more time attending to objects during Joint Play than Solo Play, but that these differences are more likely attributable to increased exogenous attentional scaffolding from the parent during social play, rather than to increased endogenous attention control from the infant. PMID- 29624834 TI - Selective Imaging of Lipids in Adipocytes by Using an Imidazolyl Derivative of Perylene Bisimide. AB - A small molecule, perylene bisimide imidazolyl derivative (PBI-ID), has been identified and developed as a specific marker for labelling multifunctional fat bodies in various organisms, including Drosophila and mammalian adipocytes. Interestingly, PBI-ID neither labels the plasma membranes nor cell nuclei by trapping into it. A remarkable feature of unbound PBI-ID is diminished fluorescence, which reduces the background emission noise, while contrasting the bound state effectively. PMID- 29624835 TI - Electrochemical Aziridination by Alkene Activation Using a Sulfamate as the Nitrogen Source. AB - The first direct aziridination of triaryl-substituted alkenes was achieved by means of an electrochemical process that could extend to multisubstituted styrenes. Specifically, hexafluoroisopropanol sulfamate was used as a nucleophilic nitrogen source. Mechanistic experiments suggest that this electrochemical process proceeds by stepwise formation of two C-N bonds through reactions between cationic carbon species and the sulfamate. PMID- 29624836 TI - Behaviors of active sunbeds users and their knowledge on the potential health risks; results of cross-sectional study in Poland. AB - BACKGROUND: Current literature review indicates that there is an increase in risk of skin melanoma due to the use of sunbeds. AIMS: To assess behaviors and opinions about health risk related to tanning. METHODS: From March 2012 to June of the same year, nonrepresentative cross-sectional study was conducted online concerning knowledge and behaviors during tanning. Data from 4919 people (80% of women, median age 25 years [IQR: 20-36]) were analyzed statistically with R software (level of significance at alpha = .05). We used the authors "active users of sunbeds" (AUS) criterion, denoting person using it >=2 times per year with an average sessions lasting >=5 minutes (cutoff values above 1 quartile). The reference was those not meeting above criteria. RESULTS: A total of 926 persons (18.8%) stated that they use sunbeds, while 680 (13.8%) met the criterion of AUS. Within the AUS group, the median number of visits in the tanning beds rooms was 10 (IQR: 5-15) per year, with single session lasting 9 (IQR: 7-10) minutes. The majority (83.5%) of AUS tanned naked indoors, with only 47.4% to have used safety glasses. These individuals were significantly more likely to be women, better educated, and were considered outdoor tanners. AUS were less aware of the risks associated with sunburns, with equal use of sunscreen and reapplication more frequently (as non-AUS). CONCLUSIONS: The level of knowledge in the field of prevention of melanoma was similar in both groups; however, AUS group more frequently took risky behaviors related to sun exposure. PMID- 29624837 TI - Two Histidines in an alpha-Helix: A Rigid Co2+ -Binding Motif for PCS Measurements by NMR Spectroscopy. AB - Pseudocontact shifts (PCS) generated by paramagnetic metal ions present valuable long-range information in the study of protein structural biology by nuclear magnetic resonance (NMR) spectroscopy. Faithful interpretation of PCSs, however, requires complete immobilization of the metal ion relative to the protein, which is difficult to achieve with synthetic metal tags. We show that two histidine residues in sequential turns of an alpha-helix provide a binding site for a Co2+ ion, which positions the metal ion in a uniquely well-defined and predictable location. Exchange between the bound and free cobalt is slow on the timescale defined by chemical shifts, but the NMR resonance assignments are nonetheless readily transferred from the diamagnetic to the paramagnetic NMR spectrum by an Iz Sz -exchange experiment. The double-histidine-Co2+ motif offers a straightforward, inexpensive, and convenient way of generating precision PCSs in proteins. PMID- 29624838 TI - The N-Methylpyrrolidone (NMP) Effect in Iron-Catalyzed Cross-Coupling with Simple Ferric Salts and MeMgBr. AB - The use of N-methylpyrrolidone (NMP) as a co-solvent in ferric salt catalyzed cross-coupling reactions is crucial for achieving the highly selective, preparative scale formation of cross-coupled product in reactions utilizing alkyl Grignard reagents. Despite the critical importance of NMP, the molecular level effect of NMP on in situ formed and reactive iron species that enables effective catalysis remains undefined. Herein, we report the isolation and characterization of a novel trimethyliron(II) ferrate species, [Mg(NMP)6 ][FeMe3 ]2 (1), which forms as the major iron species in situ in reactions of Fe(acac)3 and MeMgBr under catalytically relevant conditions where NMP is employed as a co-solvent. Importantly, combined GC analysis and 57 Fe Mossbauer spectroscopic studies identified 1 as a highly reactive iron species for the selective formation generating cross-coupled product. These studies demonstrate that NMP does not directly interact with iron as a ligand in catalysis but, alternatively, interacts with the magnesium cations to preferentially stabilize the formation of 1 over [Fe8 Me12 ]- cluster generation, which occurs in the absence of NMP. PMID- 29624839 TI - Proximal hypospadias treated with a transverse preputial island tube: long-term functional, sexual, and cosmetic outcomes. AB - OBJECTIVE: To study long-term urinary and sexual function, and cosmetic outcomes in adult patients who underwent single-stage transverse preputial island tube (TPIT) for proximal hypospadias repair in childhood. Long-term data on outcomes of patients with proximal hypospadias with severe coexisting curvature and insufficient urethral plate are scarce, but are necessary to decide which repair technique is most beneficial. PATIENTS, SUBJECTS AND METHODS: Patients with proximal hypospadias operated with TPIT (TPIT Group) were compared to patients with distal hypospadias repair (Distal Group) and to a control group of male medical students (Control Group). Participants completed the International Prostate Symptom Score, the International Index of Erectile Function (IIEF-15), additional non-validated questions, and performed uroflowmetry. Cosmesis was assessed in the patients with hypospadias using the Pediatric Penile Perception Score (PPPS); stretched penile length was also measured. RESULTS: Of the 121 eligible patients with hypospadias, 54 with either TPIT or distal hypospadias repairs participated. The TPIT Group comprised 12 patients (median age of 20.0 years) and the Distal Group comprised 42 patients (median age of 19.6 years). The complication rates were similar, at 8 of the 12 patients in the TPIT Group vs 26/42 (62%) in the Distal Group (P = 0.76). Urinary outcomes were similar in the TPIT, Distal, and the Control (comprised of 148 medical students with a median age of 21.0 years) groups. The TPIT Group had a lower maximum urinary flow rate compared to the Control Group, at 24.1 vs 28.6 mL/s (P < 0.05). IIEF-15 scores were similar in the TPIT, Distal and Control groups, except for 'Orgasmic Function' (7.5 vs 10.0 vs 10.0, respectively; P < 0.01). Although the TPIT Group had a smaller penile length compared to the Distal Group (10.1 vs 12.9 cm, P < 0.01), PPPS outcomes were similar. CONCLUSION: In these TPIT patients, long-term urinary, sexual and cosmetic outcomes were similar to those in patients with distal hypospadias repairs and controls. PMID- 29624840 TI - A Planar-Chiral Rhodium(III) Catalyst with a Sterically Demanding Cyclopentadienyl Ligand and Its Application in the Enantioselective Synthesis of Dihydroisoquinolones. AB - The rapid development of enantioselective C-H activation reactions has created a demand for new types of catalysts. Herein, we report the synthesis of a novel planar-chiral rhodium catalyst [(C5 H2t Bu2 CH2t Bu)RhI2 ]2 in two steps from commercially available [(cod)RhCl]2 and tert-butylacetylene. Pure enantiomers of the catalyst were obtained through separation of its diastereomeric adducts with natural (S)-proline. The catalyst promoted enantioselective reactions of aryl hydroxamic acids with strained alkenes to give dihydroisoquinolones in high yields (up to 97 %) and with good stereoselectivity (up to 95 % ee). PMID- 29624841 TI - Enantioselective Synthesis of Medium-Sized Lactams via Chiral alpha,beta Unsaturated Acylammonium Salts. AB - Medium-sized lactams are important structural motifs found in a variety of bioactive compounds and natural products but are challenging to prepare, especially in optically active form. A Michael addition/proton transfer/lactamization organocascade process is described that delivers medium sized lactams, including azepanones, benzazepinones, azocanones, and benzazocinones, in high enantiopurity through the intermediacy of chiral alpha,beta-unsaturated acylammonium salts. An unexpected indoline synthesis was also uncovered, and the benzazocinone skeleton was transformed into other complex heterocyclic derivatives, including spiroglutarimides, isoquinolinones, and delta lactones. PMID- 29624842 TI - Thiophene-Fused-Heteroaromatic Diones as Promising NIR Reflectors for Radiative Cooling. AB - Developing appropriate NIR-reflective materials to combat near-infrared (NIR) heat radiation (700-2500 nm) from sunlight, avoiding energy accumulation and reduce energy consumption, is important and highly desirable. In this research, four thiophene-fused-heteroaromatic diones were used as basic reflectors to investigate the relationship between their intrinsic molecular structures and NIR reflective properties. The reflectance intensity can be readily tuned by adjusting the length of the appended aliphatic side chains, as well as the strength of the electron-donating groups. A methoxy-substituted thiophene-fused heteroaromatic dione showed the best performance in reflecting NIR, and it was used as a coating for a model glass house. The comparison of the internal temperature difference relative to a control house was measured and the maximum temperature was 12 degrees C lower than that in the control house. PMID- 29624844 TI - A Vastly Increased Chemical Variety of RNA Modifications Containing a Thioacetal Structure. AB - Recently discovered new chemical entities in RNA modifications have involved surprising functional groups that enlarge the chemical space of RNA. Using LC-MS, we found over 100 signals of RNA constituents that contained a ribose moiety in tRNAs from E. coli. Feeding experiments with variegated stable isotope labeled compounds identified 37 compounds that are new structures of RNA modifications. One structure was elucidated by deuterium exchange and high-resolution mass spectrometry. The structure of msms2 i6 A (2-methylthiomethylenethio-N6 isopentenyl-adenosine) was confirmed by methione-D3 feeding experiments and by synthesis of the nucleobase. The msms2 i6 A contains a thioacetal, shown in vitro to be biosynthetically derived from ms2 i6 A by the radical-SAM enzyme MiaB. This enzyme performs thiomethylation, forming ms2 i6 A from i6 A in a first turnover. The new thioacetal is formed by a second turnover. Along with the pool of 36 new modifications, this work describes a new layer of RNA modification chemistry. PMID- 29624843 TI - A novel multimarker assay for the phenotypic profiling of circulating tumor cells in hepatocellular carcinoma. AB - Current clinicopathologic staging systems and serum biomarkers poorly discriminate tumor biology in hepatocellular carcinoma (HCC), with high recurrence rates following curative-intent surgical resection and liver transplantation (LT). Identification of accurate biomarkers for improved prognostication and treatment selection is a critical unmet need. We sought to develop a novel "liquid-biopsy" assay capable of detecting HCC circulating tumor cells (CTCs) and characterizing phenotypic subpopulations with prognostic significance. Using HCC cell lines, a tissue microarray, and human blood samples, an antibody cocktail targeting the cell-surface markers asialoglycoprotein receptor (ASGPR), glypican-3, and epithelial cell adhesion molecule was optimized for HCC CTC capture using the NanoVelcro CTC Assay. The ability of HCC CTCs and vimentin (VIM)-positive CTCs (a subpopulation expressing an epithelial-to mesenchymal phenotype) to accurately discriminate tumor stage, recurrence, progression, and overall survival (OS) was evaluated in a prospective study of 80 patients. Multimarker capture detected greater numbers of CTCs than any individual antibody alone for both cell line and patient samples (P < 0.001). HCC CTCs were identified in 59/61 (97%) patients, and HCC (median, 6 CTCs) and non HCC patients (median, 1 CTC; area under the receiver operating characteristic curve [AUROC] = 0.92; P < 0.001; sensitivity = 84.2%; specificity = 88.5%) were accurately discriminated. VIM-positive CTCs accurately discriminated early-stage, LT eligible patients (median, 0 CTCs) from locally advanced/metastatic, LT ineligible patients (median, 6 CTCs; AUROC = 0.89; P = 0.001; sensitivity = 87.1%; specificity = 90.0%), and predicted OS for all patients (hazard ratio [HR], 2.21; P = 0.001), and faster recurrence after curative-intent surgical or locoregional therapy in potentially curable early-stage HCC (HR, 3.14; P = 0.002). In conclusion, we developed a novel multimarker CTC enrichment assay that detects HCC CTCs with high efficiency and accuracy. A phenotypic subpopulation of VIM-positive CTCs appears to signify the presence of aggressive underlying disease and occult metastases and may have important implications for treatment selection. Liver Transplantation 24 946-960 2018 AASLD. PMID- 29624845 TI - Neuroprotective Potential and Chemical Profile of Alternatively Cultivated Ganoderma lucidum Basidiocarps. AB - Various neurodegenerative diseases are the main challenges to the modern medicine and there is a great need for novel, natural, neuroprotective agents. Ganoderma lucidum is a well-known medicinal mushroom, which health benefits have been confirmed by numerous studies. As demand for its basidiocarps is increased and traditional cultivation on hardwoods is not environmentally friendly and economically justified, finding of alternative substrates is necessary. The aim of the study was to assess the effect of alternative cultivation substrates on the chemical profile of G. lucidum basidiocarps and their capacity to inhibit acetylcholinesterase and tyrosinase, which higher activity is directly associated with neurodegenerative processes. Extracts of basidiocarps cultivated on alternative substrates, especially on clear wheat straw, showed significantly higher inhibition capacities than extracts of commercially-grown ones. These extracts were considerably different chemically from commercial basidiocarps extracts and even nine new compounds were isolated from them. Our results suggest that cultivation substrate greatly affect the chemical profile and neuroprotective capacity of obtained basidiocarps and wheat straw is a promising cultivation substrate. PMID- 29624846 TI - New Acetophenone Derivatives from Acronychia oligophlebia and Their Anti inflammatory and Antioxidant Activities. AB - Seven new acetophenone derivatives (acroliones A - G, 1 - 7) and three known ones (8 - 10) were isolated from the leaves of Acronychia oligophlebia. Their structures were elucidated based on extensive spectroscopic analyses (IR, UV, HR ESI-MS, 1D- and 2D-NMR), X-ray diffraction and comparison with literature data. The anti-inflammatory and antioxidant activities of all isolates were evaluated. PMID- 29624847 TI - Use of direct oral anticoagulants in antiphospholipid syndrome. AB - The direct oral anticoagulants (DOACs) are therapeutic alternatives to warfarin and other vitamin K antagonists (VKAs), and constitute the standard of care for many indications. VKAs constitute the conventional therapy for the treatment and secondary thromboprophylaxis of thrombotic antiphospholipid syndrome (APS), but are often problematic, owing to the variable sensitivity of thromboplastins to lupus anticoagulant. Thus, the International Normalized Ratio may not accurately reflect anticoagulation intensity, or be clinically effective. Definition of the current role of DOACs in the treatment of APS is based on limited clinical trial data and information from other sources, including manufacturers' data, case series or cohort studies, and expert consensus. The Rivaroxaban in Antiphospholipid Syndrome (RAPS) randomized controlled trial (RCT), which had a laboratory surrogate primary outcome measure, suggests that rivaroxaban has the potential to be an effective and convenient alternative to warfarin in thrombotic APS patients with a single venous thromboembolism event requiring standard intensity anticoagulation. However, further studies, in particular to provide better long-term efficacy and safety data, are needed before it can be widely recommended. APS patients are clinically heterogeneous, with the risk of recurrent thrombosis and the intensity of anticoagulation being influenced by their clinical phenotype and risk profile. DOAC trials involving homogeneous thrombotic APS populations, with the antiphospholipid antibody status well defined, will help to optimize the appropriate treatment in APS patient subgroups. Ongoing and emerging DOAC RCTs should provide further information to guide the use of DOACs in APS patients. Optimal identification of APS patients is a key step in working towards improved therapeutic strategies in these individuals. PMID- 29624848 TI - Autofluorescence-based optical biopsy: An effective diagnostic tool in hepatology. AB - Autofluorescence emission of liver tissue depends on the presence of endogenous biomolecules able to fluoresce under suitable light excitation. Overall autofluorescence emission contains much information of diagnostic value because it is the sum of individual autofluorescence contributions from fluorophores involved in metabolism, for example, NAD(P)H, flavins, lipofuscins, retinoids, porphyrins, bilirubin and lipids, or in structural architecture, for example, fibrous proteins, in close relationship with normal, altered or diseased conditions of the liver. Since the 1950s, hepatocytes and liver have been historical models to study NAD(P)H and flavins as in situ, real-time autofluorescence biomarkers of energy metabolism and redox state. Later investigations designed to monitor organ responses to ischaemia/reperfusion were able to predict the risk of dysfunction in surgery and transplantation or support the development of procedures to ameliorate the liver outcome. Subsequently, fluorescent fatty acids, lipofuscin-like lipopigments and collagen were characterized as optical biomarkers of liver steatosis, oxidative stress damage, fibrosis and disease progression. Currently, serum AF is being investigated to improve non-invasive optical diagnosis of liver disease. Validation of endogenous fluorophores and in situ discrimination of cancerous from non-cancerous tissue belong to the few studies on liver in human subjects. These reports along with other optical techniques and the huge work performed on animal models suggest many optically based applications in hepatology. Optical diagnosis is currently offering beneficial outcomes in clinical fields ranging from the respiratory and gastrointestinal tracts, to dermatology and ophthalmology. Accordingly, this review aims to promote an effective bench to bedside transfer in hepatology. PMID- 29624849 TI - Catalytic Asymmetric Dearomatization by Visible-Light-Activated [2+2] Photocycloaddition. AB - A novel method for the catalytic asymmetric dearomatization by visible-light activated [2+2] photocycloaddition with benzofurans and one example of a benzothiophene is reported, thereby providing chiral tricyclic structures with up to four stereocenters including quaternary stereocenters. The benzofurans and the benzothiophene are functionalized at the 2-position with a chelating N acylpyrazole moiety which permits the coordination of a visible-light-activatable chiral-at-rhodium Lewis acid catalyst. Computational molecular modeling revealed the origin of the unusual regioselectivity and identified the heteroatom in the heterocycle to be key for the regiocontrol. PMID- 29624850 TI - Association of advanced glycation end products with peri-implant inflammation in prediabetes and type 2 diabetes mellitus patients. AB - BACKGROUND: It is postulated that peri-implant sulcular fluid (PISF) levels of advanced glycation end products (AGEs) are higher with high glycemic levels. PURPOSE: In the present clinico-biochemical study, we explored the clinical and radiographic peri-implant parameters and levels of AGEs among prediabetic, type 2 diabetic (T2DM), and non-diabetic patients and to evaluate the correlation of AGEs with clinical peri-implant parameters. MATERIALS AND METHODS: Ninety patients were divided into three groups of 30 patients each; group 1: patients with prediabetes; group 2: patients with T2DM; and group 3: non-diabetic individuals. Clinical and radiographic peri-implant parameters assessed included plaque index (PI), bleeding on probing (BOP), probing depth (PD), and marginal bone loss (MBL). PISF was collected and analyzed for AGEs levels using enzyme linked immunosorbent assay. Between-group comparison of means was verified with Kruskal-Wallis test and Pearson correlation coefficient for correlations of AGE levels with peri-implant parameters. RESULTS: Mean peri-implant PI, BOP, PD, and MBL was significantly higher in group 1 and 2 as compared with non-diabetic patients (P < .05). Mean PI, BOP, PD, and MBL were comparable between group 1 and group 2 patients (P > .05). Mean levels of AGEs in PISF were significantly higher among prediabetic and T2DM patients as compared with non-diabetic patients (P < .05). Between group 1 and group 2, mean levels of AGEs was significantly higher in group 2 (P < .05). A significant positive correlations were found between levels of AGEs and PD (P = .0371) and MBL (P = .0117) in T2DM patients, respectively. CONCLUSION: Clinical and radiographic peri-implant parameters were worse and levels of AGEs in PISF were increased in individuals with prediabetes and T2DM. AGEs may play an important role in peri-implant inflammation in prediabetes and T2DM. PMID- 29624851 TI - Diversity of Listeria monocytogenes strains isolated from Agaricus bisporus mushroom production. AB - AIMS: The aims of this study were to characterize the genetic diversity of Listeria monocytogenes isolates obtained from commercial mushroom production, to establish the persistence, recontamination and the risk of cross-contamination from the working environment to the final products, creating awareness about the presence of L. monocytogenes thus helping to prevent the possibility of cross contamination. METHODS AND RESULTS: From an extensive analysis of commercial mushroom production, analysed with BS EN ISO 11290-1:1996/Amd 1:2004 and BS EN ISO 11290-2:1998/Amd 1:2004, 279 L. monocytogenes isolates were obtained. All of the isolates were characterized by pulsed-field gel electrophoresis, species PCR and serogroup PCR. All the isolates were confirmed as L. monocytogenes; 30.1% were serogroup 1/2b-3b-7, 40.8% were serogroup 1/2a-3a and 29.1% were serogroup 4b-4d-4e. There were 77 pulsotypes from the 279 isolates, 40 of the pulsotypes had only one strain and 37 had two or more strains, indicating great diversity in the isolates. CONCLUSIONS: The high genetic diversity is indicative of the fact that current hygiene practices are successful at removing L. monocytogenes but that recontamination of the production environment is frequent. SIGNIFICANCE AND IMPACT OF THE STUDY: The results obtained are very valuable in creating awareness of L. monocytogenes in mushroom production and for the improvement of hygiene practices. PMID- 29624852 TI - Cryopreserved whole blood for the quantification of monocyte, T-cell and NK-cell subsets, and monocyte receptor expression by multi-color flow cytometry: A methodological study based on participants from the canadian longitudinal study on aging. AB - Immunophenotyping by multi-color flow cytometry is arguably the best tool to identify and quantify distinct cell lineages from the peripheral blood and other biological fluids/tissues. Effective in both clinical and research settings, it can be used to estimate the frequency of a given cell type or measure its phenotypic or functional properties. Normally, immunophenotyping is performed in fresh or fractionated blood (i.e., PBMCs) the same day, or within 24 hours of collection; however, this may not be feasible for all study designs. We have previously shown that cryopreserved blood, a biospecimen that is simple and inexpensive to prepare, is comparable to fresh blood for the enumeration of major leukocyte cell types. For the following study, we sought to extend these observations to distinct subsets of: monocytes (classical, intermediate, and non classical), T-cells (CD4/CD8 naive, central and effector memory, senescent, and terminally differentiated, and regulatory T-cells), and NK-cells (CD56 bright and dim); we also examined the expression of monocyte cell-surface receptors CX3CR1, CCR2, TLR2, and TLR4. Our results indicate that cryopreserved blood is comparable to fresh blood; with exception to relatively rare subsets and lowly expressed receptors, the absolute or relative frequency of cell subsets generally correlated >0.80 between blood types, while monocyte receptor expressed was mostly >0.70. Furthermore, the day-to-day coefficient of variation for most cell subsets and parameters was below 20%. Given these findings, we suggest that cryopreserved peripheral blood be given greater consideration for studies in which the quantification of distinct leukocyte subsets is required. (c) 2018 International Society for Advancement of Cytometry. PMID- 29624853 TI - Impact of salt reduction in meals consumed during hemodialysis sessions on interdialytic weight gain and hemodynamic stability. AB - INTRODUCTION: Patients on hemodialysis (HD) are advised to limit daily water- and salt intake to reduce interdialytic weight gain (IDWG). To counterbalance protein losses, protein-rich meals are sometimes provided during HD sessions, but their salt content is not always taken into account. The aim of this study was to assess the influence of a lower salt content of meals provided during HD sessions on IDWG, blood pressure (BP), and hemodynamic stability during dialysis. METHODS: This monocentric, interventional study was proposed to all the patients treated with three weekly HD sessions. The first two months of the study (high salt period), the patients continued to receive one sandwich containing 2.4 g of salt per session. Then, we reduced its salt content from 2.4 to 1.4 g, and patients received this "low-salt sandwich" at each dialysis session for four months. The mean values of IDWG, BP, and dry weight of the first two months were compared with those collected during the low salt periods (2-6 months). FINDINGS: Forty out of 76 patients who initially agreed to participate were free of hospitalization, transplantation, and transfer to another center or death during the study period and were included in the final analysis (35% women). Median age was 63 years (range 28-90), 22.5% had a residual diuresis > 0.5 L/day. IDWG baseline decreased from 2.17 +/- 0.98 to 2.03 +/- 1 kg (P = 0.001) two months and to 2.09 +/- 1.01 kg (P = 0.009) four months after we had lowered the salt content of the sandwich. The number of symptomatic intradialytic hypotension was also reduced (6.1% vs., respectively, 3.2% and 3.3% of HD sessions; P = 0.004). DISCUSSION: IDWG was reduced and hemodynamic stability improved after the reduction of the salt content of perdialytic meals. This suggests that salt consumed during HD matters and might influence salt and water intake outside the dialysis unit. PMID- 29624854 TI - An evaluation of the trimmed mean approach in clinical trials with dropout. AB - The trimmed mean is a method of dealing with patient dropout in clinical trials that considers early discontinuation of treatment a bad outcome rather than leading to missing data. The present investigation is the first comprehensive assessment of the approach across a broad set of simulated clinical trial scenarios. In the trimmed mean approach, all patients who discontinue treatment prior to the primary endpoint are excluded from analysis by trimming an equal percentage of bad outcomes from each treatment arm. The untrimmed values are used to calculated means or mean changes. An explicit intent of trimming is to favor the group with lower dropout because having more completers is a beneficial effect of the drug, or conversely, higher dropout is a bad effect. In the simulation study, difference between treatments estimated from trimmed means was greater than the corresponding effects estimated from untrimmed means when dropout favored the experimental group, and vice versa. The trimmed mean estimates a unique estimand. Therefore, comparisons with other methods are difficult to interpret and the utility of the trimmed mean hinges on the reasonableness of its assumptions: dropout is an equally bad outcome in all patients, and adherence decisions in the trial are sufficiently similar to clinical practice in order to generalize the results. Trimming might be applicable to other inter-current events such as switching to or adding rescue medicine. Given the well-known biases in some methods that estimate effectiveness, such as baseline observation carried forward and non-responder imputation, the trimmed mean may be a useful alternative when its assumptions are justifiable. PMID- 29624855 TI - Evaluation of movement behaviors to inform toxic baiting strategies for invasive wild pigs (Sus scrofa). AB - BACKGROUND: Invasive wild pigs damage agriculture, property, and natural ecosystems. To curtail damage, an effective and humane toxic bait containing microencapsulated sodium nitrite is under development. Strategies for delivering the toxic bait are needed to establish adequate spacing of bait sites, and for simultaneously accustoming wild pigs to the novel bait and wild pig-specific bait stations designed to exclude non-target species. RESULTS: We monitored movements of 32 Global Positioning System (GPS)-collared wild pigs relative to 41 bait sites containing placebo bait. Among the bait sites, we compared three experimental baiting strategies (and a control) to evaluate which strategy led to the most wild pigs accessing the placebo bait inside bait stations. We found that bait sites should be spaced 0.5-1 km apart to maximize opportunities for all wild pigs to find and utilize the bait sites. Baiting strategies that allowed >= 15 days for accustoming wild pigs to bait stations were most effective and resulted in nearly 90% of wild pigs accessing the placebo bait inside the bait stations. Bait stations excluded all non-target animals, except one instance with a raccoon (Procyon lotor). CONCLUSION: These results demonstrate the potential for toxic bait to be an effective tool for reducing populations of wild pigs with minimal risks to non-target species, if optimized delivery procedures are followed. (c) 2018 Society of Chemical Industry. PMID- 29624856 TI - A cross-sectional analysis of Wits and Riedel in adults with skeletal III malocclusion: How informative are they? AB - OBJECTIVES: To compare the relationship between Riedel and Wits appraisal in skeletal III malocclusions and to assess the effect of variation in the vertical skeletal measurements. SETTING AND SAMPLE POPULATION: One-hundred and twenty consecutive subjects with Class III malocclusions attending orthognathic clinics were analysed. MATERIALS AND METHODS: Lateral cephalograms were hand-traced under standardized conditions. Cephalometric measurements included Riedel analysis, Wits appraisal, A point/B point to Frankfurt plane (AF-BF) and vertical measurements. RESULTS: The mean ANB and Wits values were -3.22 degrees and 11.39 mm, respectively. A positive correlation was found between ANB and Wits overall (r = -.49; P < .001). However, there was poor agreement between both Wits (r = .087) and Riedel (r = .089) with AF-BF (P > .05). A negative correlation existed between Wits and LAFH% (r = -.64, P-value < .001); however, no relationship was observed between ANB and LAFH% (P > .05) based on linear regression analysis. CONCLUSIONS: There is a positive relationship between ANB and Wits; however, neither correlated well with a purer antero-posterior assessment (AF-BF). Furthermore, variations in the vertical skeletal measurements affect the strength of agreement. Caution is advised in the interpretation of antero-posterior analysis especially in the presence of vertical discrepancy. PMID- 29624857 TI - Impact of wedelolactone in the anti-glycation and anti-diabetic activity in experimental diabetic animals. AB - The glycation reaction is the addition of free carbonyl group of reducing sugar to the free amino groups of proteins, lipoproteins and nucleic acids which results in the formation of an Amadori product which may ultimately lead to the generation of advanced glycation products (AGEs). The impact of AGEs on proteins consequently generates free radicals, "a key player" for the pathogenesis of diabetes mellitus. Gel electrophoresis was carried out to see the visual changes taking place as a result of the glycation reaction. In this study, the anti glycation and anti-diabetic effect of wedelolactone (WED) was seen both in vitro and in vivo. WED reverted various biochemical markers in streptozotocin-induced diabetic rats along-with the improvements in the oxidative stress markers. It also decreased the levels of the glycated serum protein and fasting blood glucose. Broadly, WED not only inhibited glycation in vitro but also proved to be an effective in vivo anti-glycating agent. (c) 2018 IUBMB Life, 70(6):547-552, 2018. PMID- 29624858 TI - Being targeted as a "severely overweight pregnant woman" -A qualitative interview study. AB - BACKGROUND: Pregnant women with a body mass index (BMI) >= 30 kg/m2 have been targeted in health-care systems in many western countries as a high-risk group. However, we have limited knowledge of the long-term significance of this prenatal care policy. OBJECTIVE: To investigate accounts women give of their experiences of being targeted as severely overweight during pregnancy when they look back at the intervention 4-5 years later. DESIGN: Interpretive analysis based on 21 semi structured interviews conducted 4-5 years after the pregnancy with Danish mothers categorized as having a pre-pregnancy BMI >= 30. FINDINGS: In the women's retrospective accounts three phases were identified and separated: (i) Being identified as a "severely overweight pregnant woman." The women differed over whether they accepted this categorization, but all believed that an approach based on weight was acceptable. (ii) Encounters with health-care professionals. The women differed here: some reported no negative experiences; others reported experiences of prejudice and silence. (iii) Reflections on long-term outcomes. Most women reported that the interventions during their pregnancies did not lead to any lasting lifestyle change. The women disagreed over whether, in principle, pregnancy was a suitable time to be targeted. DISCUSSION AND CONCLUSION: Our study illustrates the importance of critically considering whether pregnancy is a suitable window of opportunity for obesity prevention, and shows that women's experiences should be examined in relation to each phase of intervention. More interdisciplinary studies are needed to map potential benefits and other consequences over the short- and long-term. PMID- 29624859 TI - Comparison between open and pharmacomechanical repair of acutely thrombosed arteriovenous hemodialysis fistulae within a decade. AB - INTRODUCTION: Different declotting techniques are available for acutely thrombosed arteriovenous hemodialysis fistulae (AVF). The aim of this single center study was to compare immediate and follow-up results between surgical repair and a modified interventional lyse-and-wait technique characterized by prolonged local reaction times of recombinant tissue-plasminogen activator (rtPA). MATERIALS AND METHODS: We retrospectively analyzed medical records of 110 consecutively treated patients between the years 2003 and 2013. All patients were on hemodialysis (HD) and suffered from an acutely thrombosed AVF. The treatment standards changed in the course of time, wherefore we compared 2 groups: the open repair (OR) (N = 50) and the endovascular repair (ER) group (N = 60). FINDINGS: We found no significant differences in success rates (OR 92%/ER 96.7%; P = 0.28), immediate failures (IFs) (OR 8%/ER 10%; P = 0.71), and temporary catheter placements (TCPs) (OR 10%/ER 6.7%; P = 0.52). Furthermore, there were no differences in cumulative primary patency rates (P = 0.42) and secondary patency rates (P = 0.97).The infection rate was significantly increased after OR (8%) compared to ER (0%); P = 0.026. The hospital stay in days was shorter after ER (5.2 +/-2.8) vs. OR (9.0 +/- 3.5); P < 0.001. CONCLUSION: The modified lyse-and wait technique with prolonged local reaction times is a successful alternative to surgical repair for acutely thrombosed AVF. Clear benefits are less infections and significant shorter hospital stays after ER. However, OR remains the preferred treatment for aneurysms and anastomotic stenoses. PMID- 29624860 TI - Hepatic encephalopathy: Diagnosis and management. AB - Hepatic encephalopathy (HE) is a peculiar kind of brain dysfunction caused by liver insufficiency and/or portal-systemic shunting. It is related to gut-derived substances. It is a relevant cause of morbidity and hospitalisation for patients with cirrhosis. The prognosis of HE is important in terms of survival and re hospitalisation. It is related to impaired quality of life, falls and poor driving; presents a relevant burden for caregivers and health services; and may negatively impact on patient's job and income. Proper diagnosis and classification are expected to improve HE management. Once diagnosed, the management and therapeutic options for HE are generally clear. The improvement of knowledge in recent years has also clarified which are the further aims of research in this field of medicine. Prophylaxis of overt HE should always be performed, and this is generally secondary prophylaxis. Primary prophylaxis should be done immediately after upper gastrointestinal bleeding. Great advances in the detection and treatment of mild forms of HE are expected to lead to further improvement in patient management. PMID- 29624861 TI - Proteinuria and risk of stroke in patients with hypertension: The Kailuan cohort study. AB - Proteinuria is associated with stroke, but the effects of changes in proteinuria on stroke risk are not well understood in the hypertensive population. This study examined whether proteinuria changes across 2-year assessments were associated with incident stroke in individuals with hypertension. We used visit data from 24 300 participants with hypertension of the Kailuan study who were stroke free at baseline. Based on the baseline and 2-year dipstick screening results, participants were classified as having no, remittent, incident, or persistent proteinuria. The relationship between proteinuria and stroke was analyzed using Cox proportional-hazards models after adjusting for potential variables. During a median of 6.89-year follow-up, we identified 1197 people with stroke. Compared to those with no proteinuria, stroke risk was significantly increased in participants with incident (hazard ratio [HR] 1.41, 95% CI, 1.05-1.77) and persistent proteinuria (HR 1.49, 95% CI, 1.25-1.89) after adjustment for other factors, which was consistent in ischemic stroke and intracerebral hemorrhage. No interaction was found between changes of proteinuria and diabetes mellitus in the hypertensive population. Changes in proteinuria exposure, particularly persistent proteinuria, play a role in reflecting the risk of stroke in patients with hypertension. PMID- 29624864 TI - Takayasu arteritis and giant cell arteritis: are they a spectrum of the same disease? PMID- 29624863 TI - Prevalence and measurement of anterior loop of the mandibular canal using CBCT: A cross sectional study. AB - BACKGROUND: Anterior loop of the mental nerve is a very important anatomic landmark in implant placement and anterior mandibular osteotomies. PURPOSE: Two dimensional imaging techniques are not competent enough to locate and measure the mental nerve loop in majority of the cases. Any injury to this loop results in pain/paresthesia/numbness in the region supplied by the mental nerve. The aim of this study is to analyze the prevalence and measure the length of the loop using cone beam computerized tomography (CBCT) and calculate the average length and prevalence so that a safe margin can be given while placing the implants or the osteotomy cuts in the premolar region. MATERIALS AND METHODS: A cross-sectional study was done using CBCT images of 85 patients taken for impaction surgery. The length of the loop was measured in mm using standardized lines drawn along specific anatomic landmarks. RESULTS: In our study 11.76% of patients had anterior loop in their mental nerve. Mean length of the mental nerve loop was calculated and found to be 2.79 mm. CONCLUSION: A margin of 4 mm anterior to the mental foramen should be safe to avoid any damage to the mental nerve loop bundle in majority of the cases where the loop is present. PMID- 29624862 TI - The oxidoreductase p66Shc acts as tumor suppressor in BRAFV600E-transformed cells. AB - Metabolic reprogramming, as exemplified by the shift from oxidative phosphorylation to glycolysis, is a common feature of transformed cells. In many tumors, altered metabolism is also reflected in increased reactive oxygen species (ROS) levels, which contribute to proliferation and survival signaling. However, despite high ROS levels, cancer cells can be efficiently killed by further increasing ROS production. We have shown previously that both wild-type and oncogenic CRAF and BRAF prevent excessive mitochondrial ROS production. Subsequently, it has been demonstrated that raising ROS levels in BRAFV600E transformed melanoma cells by inhibiting BRAF or MEK rendered them susceptible to cell death induction. To understand how oncogenic BRAF affects mitochondrial ROS production in melanoma, we studied the mitochondrial ROS-producing oxidoreductase p66Shc, which is frequently overexpressed in tumors. Using NIH 3T3 BRAFV600E fibroblasts and the melanoma cell lines A375 and M238 carrying the same BRAF mutation, we show that under treatment with the ROS-inducing agent phenethyl isothiocyanate (PEITC), oncogenic BRAF renders cells refractory to p66ShcS36 phosphorylation, which is essential for p66Shc activation and mitochondrial ROS production. Consistent with this, the activation of JNK1/2, which phosphorylate S36, was blunted, while other mitogen-activated protein kinases were not affected. Inhibition of JNK1/2 efficiently prevented ROS production, while BRAF and MEK inhibitors increased ROS levels. Vemurafenib-resistant M238R melanoma cells were impaired in S36 phosphorylation and ROS production following PEITC treatment. Moreover, they failed to increase ROS levels after MEK/BRAF inhibition. Finally, shRNA-mediated knockdown of p66Shc led to increased growth of BRAFV600E-transformed NIH 3T3 cells in soft agar assay. Taken together, these data suggest that phosphorylation-activated p66Shc functions as a tumor suppressor in melanoma cells. PMID- 29624865 TI - Infection-associated vasculitides. PMID- 29624867 TI - Cell-autonomous astrocytopathy in Alzheimer's disease. PMID- 29624866 TI - Factors associated with recovery delay in a sample of patients diagnosed by MERS CoV rRT-PCR: A Saudi Arabian multicenter retrospective study. AB - BACKGROUND: Research evidence exists that poor prognosis is common in Middle East respiratory syndrome coronavirus (MERS-CoV) patients. OBJECTIVES: This study estimates recovery delay intervals and identifies associated factors in a sample of Saudi Arabian patients admitted for suspected MERS-CoV and diagnosed by rRT PCR assay. METHODS: A multicenter retrospective study was conducted on 829 patients admitted between September 2012 and June 2016 and diagnosed by rRT-PCR procedures to have MERS-CoV and non-MERS-CoV infection in which 396 achieved recovery. Detailed medical charts were reviewed for each patient who achieved recovery. Time intervals in days were calculated from presentation to the initial rRT-PCR diagnosis (diagnosis delay) and from the initial rRT-PCR diagnosis to recovery (recovery delay). RESULTS: The median recovery delay in our sample was 5 days. According to the multivariate negative binomial model, elderly (age >= 65), MERS-CoV infection, ICU admission, and abnormal radiology findings were associated with longer recovery delay (adjusted relative risk (aRR): 1.741, 2.138, 2.048, and 1.473, respectively). Camel contact and the presence of respiratory symptoms at presentation were associated with a shorter recovery delay (expedited recovery) (aRR: 0.267 and 0.537, respectively). Diagnosis delay is a positive predictor for recovery delay (r = .421; P = .001). CONCLUSIONS: The study evidence supports that longer recovery delay was seen in patients of older age, MERS-CoV infection, ICU admission, and abnormal radiology findings. Shorter recovery delay was found in patients who had camel contact and respiratory symptoms at presentation. These findings may help us understand clinical decision making on directing hospital resources toward prompt screening, monitoring, and implementing clinical recovery and treatment strategies. PMID- 29624868 TI - Design, Synthesis, and in vitro antitubercular activity of 1,2,3-triazolyl dihydroquinoline derivatives. AB - In the quest for new active molecules against Mycobacterium tuberculosis, a series of dihydroquinoline derivatives possessing triazolo substituents were efficiently synthesized using click chemistry. The structure of 6l was evidenced by X-ray crystallographic study. The newly synthesized compounds were evaluated for their in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv (ATCC27294). The compounds 6a, 6g, and 6j (MIC: 3.13 MUg/ml) showed promising activity when compared to the first-line drug such as ethambutol. In addition, the structure and antitubercular activity relationship were further supported by in silico molecular docking studies of the active compounds against 3IVX.PDB (crystal structure of pantothenate synthetase in complex with 2-(2 (benzofuran-2-ylsulfonylcarbamoyl)-5-methoxy-1H-indol-1-yl)acetic acid). PMID- 29624869 TI - A Highly Efficient Near-Infrared-Emissive Copolymer with a N=N Double-Bond pi Conjugated System Based on a Fused Azobenzene-Boron Complex. AB - Fused azobenzene-boron complexes (BAzs) show highly efficient near-infrared (NIR) emission from the nitrogen-nitrogen double bond (N=N) containing pi-conjugated copolymer. Optical measurements showed that BAz worked as a strong electron acceptor because of the intrinsic electron deficiency of the N=N double bond and the boron-nitrogen (B-N) coordination which dramatically lowered the energy of the lowest unoccupied molecular orbital (LUMO) of the azobenzene ligand. The simple donor-acceptor (D-A) type copolymer of bithiophene (BT) and BAz exhibited intense photoluminescence (PL) in the NIR region both in the dilute solution (lambdaPL =751 nm, PhiPL =0.25) and in the film (lambdaPL =821 nm, PhiPL =0.038). The BAz monomer showed slight PL in the dilute solution, and aggregation-induced emission (AIE) was detected. We proposed that N=N double bonds should be attractive and functional building blocks for designing pi-conjugated materials. PMID- 29624871 TI - Utilization of aspirin and statin in management of coronary artery disease in patients with cirrhosis undergoing liver transplant evaluation. AB - Coronary artery disease (CAD) assessment is a vital part of liver transplantation (LT) evaluation, as it allows for identification and medical optimization prior to transplantation. Although aspirin and statins are standard of care for CAD, they are not universally used in cirrhosis due to concerns about adverse events. Per protocol, coronary angiography was performed as part of the LT evaluation in all patients over the age of 50 years or with CAD risk factors, even if they were younger than 50. Optimal CAD medical management was defined as the use of both statin and aspirin, unless a contraindication was documented. Impact of these medications on hepatic decompensation, renal function, gastrointestinal bleeding, and need for transfusion was evaluated. CAD was detected in 84/228 (36.8%) patients. Lipid profile was similar in patients with and without CAD. In patients with CAD, statins were started in 19 (23%), while aspirin was used in 30 (36%) patients. In patients with obstructive or multivessel CAD, statin therapy was used only in 41% and 65%, respectively. Statins were more likely to be prescribed in patients with diabetes (32% versus 15%, P = 0.05) and history of dyslipidemia (38% versus 15%, P = 0.02). Use of statin therapy was not linked to hepatic decompensation, hospitalization, or rise in Model for End-Stage Liver Disease (MELD). Similarly, use of aspirin therapy was not associated with increased risk acute variceal hemorrhage, gastrointestinal bleeding, or worsening anemia. In conclusion, in decompensated cirrhosis, lipid profile alone is unable to risk stratify patients with CAD. Statin and aspirin appear to be safe. However, they are significantly underutilized for the management of CAD in this patient population. Liver Transplantation 24 872-880 2018 AASLD. PMID- 29624870 TI - Characteristics and risk factors of pulmonary arterial hypertension in patients with primary Sjogren's syndrome. AB - AIM: To describe baseline characteristics of patients with primary Sjogren's syndrome (pSS) with right heart catheterization (RHC)-confirmed pulmonary arterial hypertension (PAH) and explore risk factors for PAH in pSS. METHODS: This case-control study included consecutive patients hospitalized with pSS-PAH from 2007 to 2015, and pSS patients without PAH (in a 4 : 1 ratio) as controls. All patients fulfilled the 2002 American-European Consensus Group classification criteria for pSS-PAH was defined according to RHC-based European Society of Cardiology/European Respiratory Society guidelines. Associated variables were analyzed by univariate binary logistic regression to identify possible risk factors for PAH. RESULTS: Twenty-nine patients with RHC-confirmed pSS-PAH were included (mean age at onset, 38.4 +/- 8.3 years; mean pSS duration, 54.6 months). PAH was the initial manifestation of pSS in 12 patients (41.4%), and shortness of breath was the most common symptom (29/29, 100%). Mean pulmonary arterial pressure was 51.8 +/- 10.0 mmHg, mean cardiac index was 2.3 +/- 0.8 L/min/m2 , and mean pulmonary vascular resistance was 13.0 +/- 6.0 Wood units in this group. Treatments included immunosuppressive agents (93.1%) and PAH-targeted therapies (86.2%). We identified four independent risk factors for PAH in pSS: Raynaud's phenomenon (odds ratio [OR] = 9.660, P = 0.000), rheumatoid factor >= 200 U/mL (OR = 6.691, P = 0.001), hepatic injury (OR = 3.284, P = 0.008) and pericardial effusion (OR = 3.279, P = 0.016). CONCLUSIONS: PAH can be the first manifestation of pSS. The pSS patients with Raynaud's phenomenon, high-titer rheumatoid factor, hepatic injury or pericardial effusion should be screened for PAH. PMID- 29624873 TI - Regional patterns of genetic diversity in swine influenza A viruses in the United States from 2010 to 2016. AB - BACKGROUND: Regular spatial and temporal analyses of the genetic diversity and evolutionary patterns of influenza A virus (IAV) in swine informs control efforts and improves animal health. Initiated in 2009, the USDA passively surveils IAV in U.S. swine, with a focus on subtyping clinical respiratory submissions, sequencing at minimum the hemagglutinin (HA) and neuraminidase (NA) genes, and sharing these data publicly. OBJECTIVES: In this study, our goal was to quantify and describe regional and national patterns in the genetic diversity and evolution of IAV in U.S. swine from 2010 to 2016. METHODS: A comprehensive phylogenetic and epidemiological analysis of publicly available HA and NA genes generated by the USDA surveillance system collected from January 2010 to December 2016 was conducted. RESULTS: The dominant subtypes and genetic clades detected during the study period were H1N1 (H1-gamma/1A.3.3.3, N1-classical, 29%), H1N2 (H1-delta1/1B.2.2, N2-2002, 27%), and H3N2 (H3-IV-A, N2-2002, 15%), but many other minor clades were also maintained. Year-round circulation was observed, with a primary epidemic peak in October-November and a secondary epidemic peak in March-April. Partitioning these data into 5 spatial zones revealed that genetic diversity varied regionally and was not correlated with aggregated national patterns of HA/NA diversity. CONCLUSIONS: These data suggest that vaccine composition and control efforts should consider IAV diversity within swine production regions in addition to aggregated national patterns. This article is protected by copyright. All rights reserved. PMID- 29624872 TI - Greater University Identification-But not Greater Contact-Leads to More Life Satisfaction: Evidence from a Spanish Longitudinal Study. AB - BACKGROUND: A growing body of literature has highlighted the relationship between group identification (a subjective sense of belonging to one's social group, coupled with a subjective sense of commonality with the group's members) and well being. However, little of this work is longitudinal, and few studies address reciprocal causality or control for intensity of contact with fellow group members. METHOD: We investigated the effect of university identification on satisfaction with life (SWL) over time (and vice versa) in 216 Spanish undergraduates, with seven months between T1 and T2. RESULTS: While greater university identification T1 predicted higher SWL T2, SWL T1 did not predict university identification T2. University contact T1 was unrelated to SWL T2. CONCLUSIONS: These results show that university identification impacts positively on SWL over time (rather than SWL impacting positively on university identification over time), and this is not reducible to the effects exerted by university contact. The implications for those who work with students are discussed. PMID- 29624875 TI - Radiology and biomarkers in assessing disease activity in Takayasu arteritis. PMID- 29624874 TI - Biological and Biomechanical Evaluation of Autologous Tendon Combined with Ligament Advanced Reinforcement System Artificial Ligament in a Rabbit Model of Anterior Cruciate Ligament Reconstruction. AB - OBJECTIVE: To compare the biomechanical and histological changes in a rabbit model after reconstructing the anterior cruciate ligament (ACL) with solely autologous tendon and with autologous tendon combined with the ligament advanced reinforcement system (LARS) artificial ligament. METHODS: Anterior cruciate ligament reconstruction was performed in 72 knees from 36 healthy New Zealand white rabbits (bodyweight, 2500-3000 g). The Achilles tendons were harvested bilaterally. The left ACL were reconstructed solely with autografts (autologous tendon group), while the right ACL were reconstructed with autografts combined with LARS ligaments (combined ligaments group). The gross observation, histological determination, and the tension failure loads in both groups were evaluated at 12 weeks (n = 18) and 24 weeks (n = 18) postoperatively. RESULTS: Gross examination of the knee joints showed that all combined ligaments were obviously covered by a connective tissue layer at 12 weeks, and were completely covered at 24 weeks. Fibrous tissue ingrowth was observed between fascicles and individual fibers in the bone-artificial ligament interface at both time points; this fibrovascular tissue layer localized at the bone-artificial ligament interface tended to be denser in specimens obtained at 24 weeks compared with those obtained at 12 weeks. The tension failure loads of the knees were similar in the autologous tendon group and the combined ligaments group at 12 weeks (144.15 +/- 3.92 N vs. 140.88 +/- 2.75 N; P > 0.05), and at 24 weeks (184.15 +/- 1.96 N vs. 180.88 +/- 3.21 N; P > 0.05). CONCLUSION: Reconstructing the ACL in rabbits using autologous tendon combined with the LARS artificial ligament results in satisfactory biointegration, with no obvious immunological rejection between the autologous tendon and the artificial ligament, and is, therefore, a promising ACL reconstruction method. PMID- 29624876 TI - Very long-term Voice Handicap Index Voice Outcomes after Montgomery Thyroplasty: A cross-sectional study. AB - OBJECTIVE: The aim of this multicentric cross-sectional study was to examine the permanency of Montgomery thyroplasty (MTIS) results from a patient's perspective. DESIGN: The study consisted of collecting Voice Handicap Index (VHI-30) questionnaires from patients who had previously been operated with MTIS between 2 and 12 years before. Very long-term (>2 years) postoperative data were compared with the previously acquired preoperative and early postoperative VHI results. Influence of factors such as age, gender, size/side of the prosthesis and length of the follow-up were also analysed. SETTING: Multicentric study involving three tertiary European voice centres. PARTICIPANTS: Forty-nine unilateral vocal fold paralysis (UVFP) patients, treated by MTIS, were included in the study. MAIN OUTCOME MEASURES: The Voice Handicap Index-30 score. RESULTS & CONCLUSIONS: The median VHI was significantly different over time-points (Friedman's test P < .001), with a significant difference between preoperative and early postoperative time-points (median VHI: 70 vs 21, respectively; P < .001) and between preoperative and very long-term postoperative time-points (median VHI: 70 vs 16, respectively; P < .001). The median VHI did not differ for the early and very long-term postoperative time-points (median VHI: 21 vs 16; P = .470). Age differences, gender differences and size/side differences of the prostheses, centres where surgery took place and length of the follow-up showed no significant influence. Medialisation thyroplasty (MT) overall and MTIS, in particular, should be considered as a possible standard of care for UVFP when permanency of voice results is sought. PMID- 29624877 TI - Electron acceptors for anaerobic oxidation of methane drive microbial community structure and diversity in mud volcanoes. AB - Mud volcanoes (MVs) emit globally significant quantities of methane into the atmosphere, however, methane cycling in such environments is not yet fully understood, as the roles of microbes and their associated biogeochemical processes have been largely overlooked. Here, we used data from high-throughput sequencing of microbial 16S rRNA gene amplicons from six MVs in the Junggar Basin in northwest China to quantify patterns of diversity and characterize the community structure of archaea and bacteria. We found anaerobic methanotrophs and diverse sulfate- and iron-reducing microbes in all of the samples, and the diversity of both archaeal and bacterial communities was strongly linked to the concentrations of sulfate, iron and nitrate, which could act as electron acceptors in anaerobic oxidation of methane (AOM). The impacts of sulfate/iron/nitrate on AOM in the MVs were verified by microcosm experiments. Further, two representative MVs were selected to explore the microbial interactions based on phylogenetic molecular ecological networks. The sites showed distinct network structures, key species and microbial interactions, with more complex and numerous linkages between methane-cycling microbes and their partners being observed in the iron/sulfate-rich MV. These findings suggest that electron acceptors are important factors driving the structure of microbial communities in these methane-rich environments. PMID- 29624878 TI - Elastographic ultrasound: an additional image tool in Sjogren's syndrome. AB - AIM: To evaluate the stiffness of parotid and submandibular glands using elastography ultrasound and to correlate it with B-mode ultrasonographical, clinical and serological features, salivary profibrotic and inflammatory chemokines, and salivary gland fibrosis. METHODS: We performed B-mode and elastography ultrasound of major salivary glands of 26 patients with primary Sjogren's syndrome. We registered the shear wave velocity (SWV) and correlated it with the morphologic ultrasonographic changes assessed by the Hocevar scale. We assessed the European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI), EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI), non-stimulated whole salivary flow rate (NSWSF), C3 and C4 levels, anti Ro/La antibodies, salivary inflammatory (C-X-C motif ligand 13 [CXCL13], CXCL10, CXCL8, C-C motif ligand 2 [CCL2], interleukin 10 [IL-10] and IL-6) and pro fibrotic (CXCL14, CCL28, tumor necrosis factor-related apoptosis-inducing ligand and transforming growth factor beta) chemokines and cytokines and evaluated the presence of fibrosis in the minor salivary gland. RESULTS: Ninety-two percent of patients were women; mean age was 51.1 +/- 11 years; median disease duration was 6.1 years; 92.3% had oral symptoms and 26.9% fibrosis. The median B-mode score was 22.2 points and the median SWV 2.5 m/s (tau = 0.53, P = 0.001). The SWV correlated with the NSWSF (tau = -0.53, P = 0.001), ESSDAI (tau = 0.31, P = 0.03), glandular ESDDAI domain (tau = 0.36, P = 0.02), C4 levels (tau = -0.32, P = 0.04), salivary CXCL13 (tau = 0.29, P = 0.03) and CXCL10 (tau = 0.30, P = 0.003), but not with age and fibrosis. CONCLUSION: WV correlated with the B-mode ultrasound score, systemic and glandular activity and in a large degree with CXCL10, an inflammatory chemokine, but not with fibrosis. An increased SWV might represent chronic glandular inflammation rather than fibrotic changes in these patients. PMID- 29624879 TI - Financial burdens and mental health needs in families of children with congenital heart disease. AB - OBJECTIVE: To examine the financial burdens and mental health needs of families of children with special healthcare needs (CSHCN) with congenital heart disease (CHD). METHODS: Data from the 2009-2010 National Survey of Children with Special Health Care Needs (NS-CSHCN) were used to examine parent-reported financial burdens (out-of-pocket expenses, financial problems, employment impact, caregiving hours) and family members' need for mental health services in families of CSHCN with CHD. Multivariable logistic regression was used to compare financial burdens and family members' need for mental health services among CSHCN with and without CHD. Among CSHCN with CHD, multivariable logistic regression, stratified by age (0-5 and 6-17 years), was used to assess characteristics associated with the outcomes. RESULTS: Overall, families of 89.1% of CSHCN with CHD experienced at least one financial burden and 14.9% needed mental health services due to the child's condition. Compared with CSHCN without CHD, those with CHD had families with a higher prevalence of all financial burdens (adjusted prevalence ratio [aPR] range: 1.4-1.8) and similar family member need for mental health services (aPR = 1.3, 95% CI [1.0, 1.6]). Across both age groups, insurance type, activity limitations, and comorbidities were significantly associated with financial burdens and/or family members' need for mental health services. CONCLUSIONS: CSHCN with CHD, compared with those without CHD, lived in families with more financial burdens. Interventions that reduce financial burdens and improve mental health of family members are needed, especially among CSHCN with CHD who are uninsured and have comorbidities or activity limitations. PMID- 29624880 TI - Translation initiation by cap-dependent ribosome recruitment: Recent insights and open questions. AB - Gene expression universally relies on protein synthesis, where ribosomes recognize and decode the messenger RNA template by cycling through translation initiation, elongation, and termination phases. All aspects of translation have been studied for decades using the tools of biochemistry and molecular biology available at the time. Here, we focus on the mechanism of translation initiation in eukaryotes, which is remarkably more complex than prokaryotic initiation and is the target of multiple types of regulatory intervention. The "consensus" model, featuring cap-dependent ribosome entry and scanning of mRNA leader sequences, represents the predominantly utilized initiation pathway across eukaryotes, although several variations of the model and alternative initiation mechanisms are also known. Recent advances in structural biology techniques have enabled remarkable molecular-level insights into the functional states of eukaryotic ribosomes, including a range of ribosomal complexes with different combinations of translation initiation factors that are thought to represent bona fide intermediates of the initiation process. Similarly, high-throughput sequencing-based ribosome profiling or "footprinting" approaches have allowed much progress in understanding the elongation phase of translation, and variants of them are beginning to reveal the remaining mysteries of initiation, as well as aspects of translation termination and ribosomal recycling. A current view on the eukaryotic initiation mechanism is presented here with an emphasis on how recent structural and footprinting results underpin axioms of the consensus model. Along the way, we further outline some contested mechanistic issues and major open questions still to be addressed. This article is categorized under: Translation > Translation Mechanisms Translation > Translation Regulation RNA Interactions with Proteins and Other Molecules > Protein-RNA Interactions: Functional Implications. PMID- 29624881 TI - Study on association of human leukocyte antigen-DRB1 alleles amongst Bangladeshi patients with rheumatoid arthritis. AB - INTRODUCTION: Rheumatoid arthritis (RA) is a chronic, systemic and autoimmune disease affecting 0.5-1% of the world population. Genetic and environmental factors are already established as being involved in the development of RA. Different human leukocyte antigen (HLA)-DRB1 alleles have major pathogenic effects to the development of RA. OBJECTIVE: To determine the HLA-DRB1 allelic frequency of RA in one Bangladeshi tertiary care center. METHODS: This case control study was conducted at the Microbiology and Rheumatology Department of Bangabandhu Sheikh Mujib Medical University (BSMMU). Fifty-two patients diagnosed as having RA and 52 healthy controls were enrolled. Buccal swabs were collected from all subjects and HLA-DRB1 typing was carried out with polymerase chain reaction with sequence-specific primers (PCR-SSP) of low resolution. Blood was also collected for auto-antibodies (rheumatoid factor [RF] and anti-cyclic citrullinated peptide [anti-CCP]) detection from all subjects. RF was detected by nephelometry and anti-CCP was detected by using the enzyme-linked immunosorbent assay method. Statistical associations of HLA antigen between the groups were determined by chi-square test. RESULTS: In RA patients DR*04 and DR*10 were found at the DRB1 locus at higher frequencies (20.5%, P = 0.0035 and 18.3%, P = 0.0045, respectively). However, the frequency of DR*15 was significantly lower (P = 0.005) in RA cases (18.3%) than the control group (35.6%). The frequencies of autoantibodies (anti-CCP and RF) were compared between approximate shared epitope (SE) positive and SE negative patients, and no significant association was found. CONCLUSIONS: In this study DRB1*04 and DRB1*10 alleles were significantly associated with RA patients while DRB1*15 was found more in the control group. PMID- 29624883 TI - Diagnosis and management of ADA2 deficient polyarteritis nodosa. PMID- 29624882 TI - The potential economic value of influenza vaccination for healthcare workers in The Netherlands. AB - BACKGROUND: Despite the clinical evidence, influenza vaccination coverage of healthcare workers remains low. To assess the health economic value of implementing an influenza immunization program among healthcare workers (HCW) in University Medical Centers (UMCs) in the Netherlands, a cost-benefit model was developed using a societal perspective. METHODS/PATIENTS: The model was based on a trial performed among all UMCs in the Netherlands that included both hospital staff and patients admitted to the pediatrics and internal medicine departments. The model structure and parameters estimates were based on the trial and complemented with literature research, and the impact of uncertainty explored with sensitivity analyses. RESULTS: In a base-case scenario without vaccine coverage, influenza-related annual costs were estimated at ? 410 815 for an average UMC with 8000 HCWs and an average occupancy during the influenza period of 6000 hospitalized patients. Of these costs, 82% attributed to the HCWs and 18% were patient-related. With a vaccination coverage of 15.47%, the societal program's savings were ? 2861 which corresponds to a saving of ? 270.53 per extended hospitalization. Univariate sensitivity analyses show that the results are most sensitive to changes in the model parameters vaccine effectiveness in reducing influenza-like illness (ILI) and the vaccination-related costs. CONCLUSION: In addition to the decreased burden of patient morbidity among hospitalized patients, the effects of the hospital immunization program slightly outweigh the economic investments. These outcomes may support healthcare policymakers' recommendations about the influenza vaccination program for healthcare workers. PMID- 29624884 TI - The molecular mechanism of two coreceptor binding site antibodies X5 and 17b neutralizing HIV-1: Insights from molecular dynamics simulation. AB - The coreceptor binding site of gp120 plays an important role in HIV entry into host cell. X5 and 17b are typical coreceptor binding site antibodies with the ability to broadly neutralize HIV. Thus, here, to study the neutralizing mechanism of two antibodies and identify the source of two antibodies with different neutralizing ability, we performed molecular dynamics simulations for the complexes of X5 and 17b with gp120 and CD4. The simulation results indicate X5 and 17b mainly affects CD4 and coreceptor binding sites. Specifically, for CD4 binding site (CD4bs), the binding of antibodies has different effects on CD4bs with and without CD4. However, for coreceptor binding sites, the binding of the antibodies has consistent influence on the region adjacent to loop V3 despite of the simulated systems with or without CD4. The binding of the antibodies enhances the interactions of gp120 region adjacent to loop V3 with other region of gp120, which are unfavorable for conformational rearrangements of the region adjacent to loop V3 and further binding the coreceptor. Additionally, the interactions of loop V3 and bridging sheet with X5 lead to the close motion of loop V3 in X5 bound form, which further influences the rearrangements in gp120. PMID- 29624885 TI - Procedure-related tumour seeding in lung cancer with malignant pleural effusion: Radiological features and outcomes. AB - INTRODUCTION: Pleural procedures are performed to prove the diagnosis of pleural effusion. This study was to assess the incidence and outcome of pleural procedure related tumour seeding in lung cancer with malignant pleural effusion, and to review the characteristics of the implanted tumours on computed tomography (CT) images. METHODS: From January 2008 to December 2010, 165 patients with the diagnosis of lung cancer with malignant pleural effusion, who underwent at least one pleural procedure and had follow-up CT, were included. Two radiologists retrospectively reviewed the presence of implanted tumours and their manifestations on CT images. The incidence of tumour seeding, the time to tumour seeding, and hazard ratios for death associated with the procedures and presence of tumour seeding were evaluated. Multivariable logistic regression analysis was used to identify variables that were independently associated with procedure related tumour seeding. RESULTS: The incidence of procedure-related tumour seeding was 22.4%. Conventional intercostal drainage (ICD) was the independent predictor of tumour seeding. Patients with a history of ICD rapidly developed implanted tumours (P = 0.0319). The estimated mean time of tumour seeding was 2.9 months. There was an increased risk of death with the presence of tumour seeding (HR: 3.35, 95% CI: 1.87-6.01). The majority of CT features showed ill-defined margins with heterogeneous enhancement. CONCLUSION: Pleural procedure-related tumour seeding in lung cancer with malignant pleural effusion is common. There was a significantly increased risk of death with the presence of tumour seeding. The majority of the CT features in implanted tumours were ill-defined margins with heterogeneous enhancement. PMID- 29624887 TI - G protein-coupled receptor 119 agonist DS-8500a effects on pancreatic beta-cells in Japanese type 2 diabetes mellitus patients. AB - AIMS/INTRODUCTION: Pancreatic beta-cell dysfunction contributes to type 2 diabetes mellitus progression. Drugs that improve insulin secretion might be a valuable treatment approach. The present study aimed to evaluate the effect of the G protein-coupled receptor 119 agonist DS-8500a on insulin secretory capacity in Japanese type 2 diabetes mellitus patients. MATERIALS AND METHODS: This single center, 4-week, randomized, double-blind, cross-over study enrolled 21 Japanese drug-naive type 2 diabetes mellitus patients aged >=20 years with glycated hemoglobin >=7.0 and <9.0% (NCT02669732, JapicCTI 163126). Patients received 75 mg of DS-8500a or a placebo orally daily for 4 weeks in a random order. A combined euglycemic-hyperinsulinemic and hyperglycemic clamp test was carried out to assess insulin secretion and insulin sensitivity before and after each 4-week treatment period. Primary end-points were first-phase insulin secretion (insulin area under the curve [AUC]180-190 min and C-peptide AUC180-190 min during the clamp test) and second-phase insulin secretion (insulin AUC190-300 min and C peptide AUC190-300 min ). Insulin sensitivity (M and M/I values), disposition index and changes in lipid profile were also assessed. RESULTS: DS-8500a significantly increased first- and second-phase insulin AUC (P = 0.0011, P = 0.0112) and C-peptide AUC (P = 0.0012, P < 0.0001) compared with the placebo. At day 28, M and M/I values were comparable with those of the placebo, whereas the disposition index for insulin and C-peptide was significantly increased (P = 0.0108, P = 0.0002). Total cholesterol, low-density lipoprotein cholesterol and triglyceride concentrations were significantly reduced, and high-density lipoprotein cholesterol concentrations were significantly increased compared with the placebo. No significant treatment-emergent adverse events occurred. CONCLUSION: DS-8500a enhanced insulin secretory capacity, but not insulin sensitivity. PMID- 29624888 TI - Polysulfide Binding to Several Nanoscale Magneli Phases Synthesized in Carbon for Long-Life Lithium-Sulfur Battery Cathodes. AB - In Li-S batteries, it is important to ensure efficient reversible conversion of sulfur to lithium polysulfide (LiPS). Shuttling effects caused by LiPS dissolution can lead to reduced performance and cycle life. Although carbon materials rely on physical trapping of polysulfides, polar oxide surfaces can chemically bind LiPS to improve the stability of sulfur cathodes. We show a simple synthetic method that allows high sulfur loading into mesoporous carbon preloaded with spatially localized nanoparticles of several Magneli-phase titanium oxide (Tin O2n-1 ). This material simultaneously suppresses polysulfide shuttling phenomena by chemically binding Li polysulfides onto several Magneli phase surfaces in a single cathode and ensures physical confinement of sulfur and LiPS. The synergy between chemical immobilization of significant quantities of LiPS at the surface of several Tin O2n-1 phases and physical entrapment results in coulombically efficient high-rate cathodes with long cycle life and high capacity. These cathodes function efficiently at low electrolyte-to-sulfur ratios to provide high gravimetric and volumetric capacities in comparison with their highly porous carbon counterparts. Assembled coin cells have an initial discharge capacity of 1100 mAh g-1 at 0.1C and maintain a reversible capacity of 520 mAh g 1 at 0.2C for more than 500 cycles. Even at 1C, the cell loses only 0.06 % per cycle for 1000 cycles with a coulombic efficiency close to 99 %. PMID- 29624889 TI - PhyMet2 : a database and toolkit for phylogenetic and metabolic analyses of methanogens. AB - The vast biodiversity of the microbial world and how little is known about it, has already been revealed by extensive metagenomics analyses. Our rudimentary knowledge of microbes stems from difficulties concerning their isolation and culture in laboratory conditions, which is necessary for describing their phenotype, among other things, for biotechnological purposes. An important component of the understudied ecosystems is methanogens, archaea producing a potent greenhouse-effect gas methane. Therefore, we created PhyMet2 , the first database that combines descriptions of methanogens and their culturing conditions with genetic information. The database contains a set of utilities that facilitate interactive data browsing, data comparison, phylogeny exploration and searching for sequence homologues. The most unique feature of the database is the web server MethanoGram, which can be used to significantly reduce the time and cost of searching for the optimal culturing conditions of methanogens by predicting them based on 16S RNA sequences. The database will aid many researchers in exploring the world of methanogens and their applications in biotechnological processes. PhyMet2 with the MethanoGram predictor is available at http://metanogen.biotech.uni.wroc.pl. PMID- 29624890 TI - Biological Evaluation and X-ray Co-crystal Structures of Cyclohexylpyrrolidine Ligands for Trypanothione Reductase, an Enzyme from the Redox Metabolism of Trypanosoma. AB - The tropical diseases human African trypanosomiasis, Chagas disease, and the various forms of leishmaniasis are caused by parasites of the family of trypanosomatids. These protozoa possess a unique redox metabolism based on trypanothione and trypanothione reductase (TR), making TR a promising drug target. We report the optimization of properties and potency of cyclohexylpyrrolidine inhibitors of TR by structure-based design. The best inhibitors were freely soluble and showed competitive inhibition constants (Ki ) against Trypanosoma (T.) brucei TR and T. cruzi TR and in vitro activities (half maximal inhibitory concentration, IC50 ) against these parasites in the low micromolar range, with high selectivity against human glutathione reductase. X ray co-crystal structures confirmed the binding of the ligands to the hydrophobic wall of the "mepacrine binding site" with the new, solubility-providing vectors oriented toward the surface of the large active site. PMID- 29624891 TI - Two-Dimensional Co@N-Carbon Nanocomposites Facilely Derived from Metal-Organic Framework Nanosheets for Efficient Bifunctional Electrocatalysis. AB - Metal-organic frameworks (MOFs) and MOF-derived nanomaterials have recently attracted great interest as highly efficient, non-noble-metal catalysts. In particular, two-dimensional MOF nanosheet materials possess the advantages of both 2D layered nanomaterials and MOFs and are considered to be promising nanomaterials. Herein, we report a facile and scalable in situ hydrothermal synthesis of Co-hypoxanthine (HPA) MOF nanosheets, which were then directly carbonized to prepare uniform Co@N-Carbon nanosheets for efficient bifunctional electrocatalytic hydrogen-evolution reactions (HERs) and oxygen-evolution reactions (OERs). The Co embedded in N-doped carbon shows excellent and stable catalytic performance for bifunctional electrocatalytic OERs and HERs. For OERs, the overpotential of Co@N-Carbon at 10 mA cm-2 was 400 mV (vs. reversible hydrogen electrode, RHE). The current density of Co@N-Carbon reached 100 mA cm-2 at an overpotential of 560 mV, which showed much better performance than RuO2 ; the largest current density of RuO2 that could be reached was only 44 mA cm-2 . The Tafel slope of Co@N-Carbon was 61 mV dec-1 , which is comparable to that of commercial RuO2 (58 mV dec-1 ). The excellent electrocatalytic properties can be attributed to the nanosheet structure and well-dispersed carbon-encapsulated Co, CoN nanoparticles, and N-dopant sites, which provided high conductivity and a large number of accessible active sites. The results highlight the great potential of utilizing MOF nanosheet materials as promising templates for the preparation of 2D Co@N-Carbon materials for electrocatalysis and will pave the way to the development of more efficient 2D nanomaterials for various catalytic applications. PMID- 29624894 TI - Should organs from hepatitis C-positive donors be used in hepatitis C-negative recipients for liver transplantation? AB - Given the scarcity of donated organs and the frequency of death on the waiting list, strategies that could improve the available supply of high-quality liver grafts are much needed. Direct-acting antiviral agent (DAA) regimens have proved to be highly effective to treat hepatitis C virus (HCV), even in the setting of posttransplantation. The question arises as to whether transplant communities should consider the utilization of HCV-positive donors into HCV-negative recipients. This review summarizes risk of transmission, treatment options with success rate, and ethical considerations for usage of HCV-positive donors. Liver Transplantation 24 831-840 2018 AASLD. PMID- 29624892 TI - Antibiotic-mediated bacteriome depletion in ApcMin/+ mice is associated with reduction in mucus-producing goblet cells and increased colorectal cancer progression. AB - Recent epidemiological evidence suggests that exposure to antibiotics in early-to middle adulthood is associated with an increased risk of colorectal adenoma. However, mechanistic studies in established preclinical cancer to examine these claims are extremely limited. Therefore, we investigated the effect of long-term exposure of an antibiotic cocktail composed of Vancomycin, Neomycin, and Streptomycin, on tumor development and progression in the ApcMin/+ mouse, an established genetic model for familial adenomatous polyposis. Clinical pathologies related to tumor development as well as intestinal and colon tissue histopathology were studied at ages 8, 12, and 16 weeks of age, which correspond to the approximate ages of development of neoplasia, gut inflammation with polyposis, and cancer progression, respectively, in this animal model. We show that the antibiotics significantly increase the severity of clinical symptoms, including effects on intestinal histology and goblet cell numbers. In addition, they promote small intestinal polyposis. Finally, metagenomic analysis of fecal samples demonstrated that antibiotic exposure is associated with a significant but nonuniform depletion of the animal's natural gut flora. Overall, these findings support the premise that long-term antibiotic exposure mediates the selected depletion of gut microbial communities and the concomitant thinning of the protective mucus layer, resulting in an increase in tumor development. PMID- 29624893 TI - The emotion dysregulation inventory: Psychometric properties and item response theory calibration in an autism spectrum disorder sample. AB - : Individuals with autism spectrum disorder (ASD) often present with prominent emotion dysregulation that requires treatment but can be difficult to measure. The Emotion Dysregulation Inventory (EDI) was created using methods developed by the Patient-Reported Outcomes Measurement Information System (PROMIS(r) ) to capture observable indicators of poor emotion regulation. Caregivers of 1,755 youth with ASD completed 66 candidate EDI items, and the final 30 items were selected based on classical test theory and item response theory (IRT) analyses. The analyses identified two factors: (a) Reactivity, characterized by intense, rapidly escalating, sustained, and poorly regulated negative emotional reactions, and (b) Dysphoria, characterized by anhedonia, sadness, and nervousness. The final items did not show differential item functioning (DIF) based on gender, age, intellectual ability, or verbal ability. Because the final items were calibrated using IRT, even a small number of items offers high precision, minimizing respondent burden. IRT co-calibration of the EDI with related measures demonstrated its superiority in assessing the severity of emotion dysregulation with as few as seven items. Validity of the EDI was supported by expert review, its association with related constructs (e.g., anxiety and depression symptoms, aggression), higher scores in psychiatric inpatients with ASD compared to a community ASD sample, and demonstration of test-retest stability and sensitivity to change. In sum, the EDI provides an efficient and sensitive method to measure emotion dysregulation for clinical assessment, monitoring, and research in youth with ASD of any level of cognitive or verbal ability. Autism Res 2018, 11: 928 941. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: This paper describes a new measure of poor emotional control called the Emotion Dysregulation Inventory (EDI). Caregivers of 1,755 youth with ASD completed candidate items, and advanced statistical techniques were applied to identify the best final items. The EDI is unique because it captures common emotional problems in ASD and is appropriate for both nonverbal and verbal youth. It is an efficient and sensitive measure for use in clinical assessments, monitoring, and research with youth with ASD. PMID- 29624896 TI - The use and effectiveness of interactive progressive drawing in anatomy education. AB - Anatomical relationships are challenging concepts for first-year medical students. The use of progressive drawing, where an image is created from a blank template, has long been utilized for outlining anatomical relationships and continuity from one region to another, and has shown positive outcomes for student learning. More recently, computerized progressive drawing has been introduced; however, challenges, including issues with visual clarity, have been described. In this study, 17 computerized screencasts of drawings covering neurovasculature of the limbs, abdomen, pelvis, head, and neck were created and provided to first-year medical students at Morehouse School of Medicine. An animated method for drawing was utilized to increase visual clarity. Surveys were provided to 181 first-year medical students to collect feedback about these screencasts. Sixty percent (n = 108) of students completed at least one survey. Respondents rated all 17 screencasts with a minimum of 4.7/5 for helpfulness in learning the material for course examinations. A majority of students (77.8%) reported viewing the screencasts more than once on at least one survey, and students reported varying methods for utilizing the screencasts. A majority of students provided positive feedback relating to technical quality. Some significant differences in course performance were seen based on screencast usage. The positive responses from students indicate that this is a useful method in medical education. Anat Sci Educ 11: 445-460. (c) 2018 American Association of Anatomists. PMID- 29624895 TI - How I investigate Clonal cytogenetic abnormalities of undetermined significance. AB - Myelodysplastic syndromes are a group of hematopoietic stem cell diseases characterized by cytopenia(s), morphological dysplasia, and clonal hematopoiesis. In some patients, the cause of cytopenia(s) is uncertain, even after thorough clinical and laboratory evaluation. Evidence of clonal hematopoiesis has been used to support a diagnosis of myelodysplastic syndrome in this setting. In patients with cytopenia(s), the presence of clonal cytogenetic abnormalities, except for +8, del(20q) and -Y, can serve as presumptive evidence of myelodysplastic syndrome. Recent advances in next-generation sequencing have detected myeloid neoplasm-related mutations in patients who do not meet the diagnostic criteria for myelodysplastic syndrome. Various terms have been adopted to describe these cases, including clonal hematopoiesis of indeterminate potential (CHIP) and clonal cytopenia of undetermined significance (CCUS). Similarly, studies have shown that certain chromosomal abnormalities, including ones commonly detected in myelodysplastic syndrome, may not be associated necessarily with an underlying myelodysplastic syndrome. These clonal cytogenetic abnormalities of undetermined significance (CCAUS) are similar to CHIP and CCUS. Here, we review the features of CCAUS, distinguishing CCAUS from clonal cytogenetic abnormalities associated with myelodysplastic syndrome, and the potential impact of CCAUS on patient management. PMID- 29624897 TI - Palladium-Catalyzed Functionalization of Kraft Lignin: Ether Linkages through the Telomerization Reaction. AB - Kraft lignin was efficiently functionalized with octadienyl ether linkages through the palladium-catalyzed telomerization of 1,3-butadiene. Comparison with molecular model substrates assessed the grafting of phenols and alcohols and an optimization study led to up to 69 % conversion of the total number of hydroxyl groups present in lignin. This catalytic study evidenced the partial oxidation of triphenylphosphine into triphenylphosphine oxide and triphenylphosphine sulfide by contaminants present in the industrial grade kraft lignin. The telomerised lignin is a malleable material and a preliminary study of the thermal properties showed a decrease in the glass transition in comparison with the starting material. PMID- 29624898 TI - A novel null allele, HLA-DRB1*15:148N, identified in a Chinese family. AB - A single nucleotide deletion at position 187 of HLA-DRB1*15:01:01:01 results in a null allele, HLA-DRB1*15:148N. PMID- 29624899 TI - Phylogenetic distribution of roseobacticides in the Roseobacter group and their effect on microalgae. AB - The Roseobacter-group species Phaeobacter inhibens produces the antibacterial tropodithietic acid (TDA) and the algaecidal roseobacticides with both compound classes sharing part of the same biosynthetic pathway. The purpose of this study was to investigate the production of roseobacticides more broadly in TDA producing roseobacters and to compare the effect of producers and non-producers on microalgae. Of 33 roseobacters analyzed, roseobacticide production was a unique feature of TDA-producing P. inhibens, P. gallaeciensis and P. piscinae strains. One TDA-producing Phaeobacter, 27-4, did not produce roseobacticides, possibly due to a transposable element. TDA-producing Ruegeria and Pseudovibrio did not produce roseobacticides. Addition of roseobacticide-containing bacterial extracts affected the growth of the microalgae Rhodomonas salina, Thalassiosira pseudonana and Emiliania huxleyi, while growth of Tetraselmis suecica was unaffected. During co-cultivation, growth of E. huxleyi was initially stimulated by the roseobacticide producer DSM 17395, while the subsequent decline in algal cell numbers during senescence was enhanced. Strain 27-4 that does not produce roseobacticides had no effect on algal growth. Both bacterial strains, DSM 17395 and 27-4, grew during co-cultivation presumably utilizing algal exudates. Furthermore, TDA-producing roseobacters have potential as probiotics in marine larviculture and it is promising that the live feed Tetraselmis was unaffected by roseobacticides-containing extracts. PMID- 29624900 TI - Air bronchogram in pleomorphic carcinoma of the lung is associated with favorable prognosis. AB - BACKGROUND: Pleomorphic carcinoma (PC) of the lung is a rare histological type of lung carcinoma. The association between computed tomography (CT) findings and histology with outcome remains unclear. We examined the relationships between CT features and histopathologic findings, and evaluated the impact of CT features and other clinicopathologic factors on survival. METHODS: Thirty-five consecutive patients with PC of the lung who underwent surgery between October 2010 and December 2015 were enrolled in this study. The 35 tumors were classified with or without air bronchogram in the tumors, and with or without intratumoral ground glass opacity (GGO) on CT. RESULTS: Air bronchogram and GGO were detected in 12 (34.3%) and 5 (14.3%) tumors, respectively. Multivariate analysis revealed that air bronchogram was significantly associated with the presence of adenocarcinoma components with lepidic growth patterns (P = 0.005), and predominance of adenocarcinomas (P = 0.026). GGO was significantly associated with the presence of adenocarcinoma component with lepidic growth pattern (P = 0.010). Air bronchogram was an independent favorable prognostic factor for overall survival, whereas GGO did not have a significant effect on survival. CONCLUSION: Air bronchogram observed in PCs of the lung is strongly related with histological components of the tumor and favorable outcome. PMID- 29624901 TI - [Development of tumor-lineage homing peptide for their tailored application to diverse malignancies ]. PMID- 29624902 TI - One-hour oral glucose tolerance test plasma glucose at gestational diabetes diagnosis is a common predictor of the need for insulin therapy in pregnancy and postpartum impaired glucose tolerance. AB - AIMS/INTRODUCTION: Gestational diabetes mellitus (GDM) is a risk for adverse perinatal outcomes, and patients with a history of GDM have an increased risk of impaired glucose tolerance (IGT). Here, we carried out two non-interventional and retrospective studies of GDM patients in Japan. MATERIALS AND METHODS: In the first study, we enrolled 529 GDM patients and assessed predictors of the need for insulin therapy. In the second study, we enrolled 185 patients from the first study, and assessed predictors of postpartum IGT. RESULTS: In the first study, gestational weeks at GDM diagnosis and history of pregnancy were significantly lower, and pregestational body mass index, family history of diabetes mellitus, 1 and 2-h glucose levels in a 75-g oral glucose tolerance test (OGTT), the number of abnormal values in a 75-g OGTT, and glycated hemoglobin were significantly higher in participants receiving insulin therapy. In the second study, 1- and 2-h glucose levels in a 75-g OGTT, the number of abnormal values in a 75-g OGTT, glycated hemoglobin, and ketone bodies in a urine test were significantly higher in participants with OGT. Logistic regression analysis showed that gestational weeks at GDM diagnosis, 1-h glucose levels in a 75-g OGTT and glycated hemoglobin were significant predictors of the need for insulin therapy, and 1-h glucose levels in a 75-g OGTT at diagnosis and ketone bodies in a urine test were significant predictors for postpartum IGT. CONCLUSIONS: Antepartum 1-h glucose levels in a 75-g OGTT was a predictor of the need for insulin therapy in pregnancy and postpartum IGT. PMID- 29624904 TI - Identification of the novel HLA-B*08:01:01:02 allele in a Saudi individual. AB - HLA-B*08:01:01:02 differs from HLA-B*08:01:01:01 by a T to C substitution at position 3086. PMID- 29624903 TI - Lupus nephritis: low urinary DNase I levels reflect loss of renal DNase I and may be utilized as a biomarker of disease progression. AB - Renal DNase I is lost in advanced stages of lupus nephritis. Here, we determined if loss of renal DNase I reflects a concurrent loss of urinary DNase I, and whether absence of urinary DNase I predicts disease progression. Mouse and human DNase I protein and DNase I endonuclease activity levels were determined by western blot, gel, and radial activity assays at different stages of the murine and human forms of the disease. Cellular localization of DNase I was analyzed by immunohistochemistry, immunofluorescence, confocal microscopy, and immunoelectron microscopy. We further compared DNase I levels in human native and transplanted kidneys to determine if the disease depended on autologous renal genes, or whether the nephritic process proceeded also in transplanted kidneys. The data indicate that reduced renal DNase I expression level relates to serious progression of lupus nephritis in murine, human native, and transplanted kidneys. Notably, silencing of renal DNase I correlated with loss of DNase I endonuclease activity in the urine samples. Thus, urinary DNase I levels may therefore be used as a marker of lupus nephritis disease progression and reduce the need for renal biopsies. PMID- 29624905 TI - Hydride Shuttle Formation and Reaction with CO2 on GaP(110). AB - Adsorbed hydrogenated N-heterocycles have been proposed as co-catalysts in the mechanism of pyridine (Py)-catalyzed CO2 reduction over semiconductor photoelectrodes. Initially, adsorbed dihydropyridine (DHP*) was hypothesized to catalyze CO2 reduction through hydride and proton transfer. Formation of DHP* itself, by surface hydride transfer, indeed any hydride transfer away from the surface, was found to be kinetically hindered. Consequently, adsorbed deprotonated dihydropyridine (2-PyH- *) was then proposed as a more likely catalytic intermediate because its formation, by transfer of a solvated proton and two electrons from the surface to adsorbed Py, is predicted to be thermodynamically favored on various semiconductor electrode surfaces active for CO2 reduction, namely GaP(111), CdTe(111), and CuInS2 (112). Furthermore, this species was found to be a better hydride donor for CO2 reduction than is DHP*. Density functional theory was used to investigate various aspects of 2-PyH- * formation and its reaction with CO2 on GaP(110), a surface found experimentally to be more active than GaP(111). 2-PyH- * formation was established to also be thermodynamically viable on this surface under illumination. The full energetics of CO2 reduction through hydride transfer from 2-PyH- * were then investigated and compared to the analogous hydride transfer from DHP*. 2-PyH- * was again found to be a better hydride donor for CO2 reduction. Because of these positive results, full energetics of 2-PyH- * formation were investigated and this process was found to be kinetically feasible on the illuminated GaP(110) surface. Overall, the results presented in this contribution support the hypothesis of 2 PyH- *-catalyzed CO2 reduction on p-GaP electrodes. PMID- 29624906 TI - Stress effects of cyanotoxin beta-methylamino-L-alanine (BMAA) on cyanobacterial heterocyst formation and functionality. AB - Various species of cyanobacteria, diatoms and dinoflagellates are capable of synthesizing the non-proteinogenic neurotoxic amino acid beta-N-methylamino-L alanine (BMAA), which is known to be a causative agent of human neurodegeneration. Similar to most cyanotoxins, the biological and ecological functions of BMAA in cyanobacteria are unknown. In this study, we show for the first time that BMAA, in micromolar amounts, inhibits the formation of heterocysts (specialized nitrogen-fixing cells) in heterocystous, diazotrophic cyanobacteria [Anabaena sp. PCC 7120, Nostoc punctiforme PCC 73102 (ATCC 29133), Nostoc sp. strain 8963] under conditions of nitrogen starvation. The inhibitory effect of BMAA is abolished by the addition of glutamate. To understand the genetic reason for the observed phenomenon, we used qPCR to study the expression of key genes involved in cell differentiation and nitrogen metabolism in the model cyanobacterium Anabaena sp. PCC 7120. We observed that in the presence of BMAA, Anabaena sp. PCC 7120 does not express two essential genes associated with heterocyst differentiation, namely, hetR and hepA. We also found that addition of BMAA to cyanobacterial cultures with mature heterocysts inhibits nifH gene expression and nitrogenase activity. PMID- 29624907 TI - Laparoscopic right hemicolectomy for a colon cancer patient with an ileal conduit. AB - Here, we describe our experience of laparoscopic surgery in a colon cancer patient with an ileal conduit. To our knowledge, this is the second case presented in the English-language literature. A 71-year-old woman with a history of both open anterior exenteration with ileal conduit reconstruction for bladder cancer and open cholecystectomy for cholecystitis was diagnosed with ascending colon cancer (cT3N1M0). Laparoscopic right hemicolectomy with conduit preservation was planned. After adhesiolysis, complete mesocolic excision and central vascular ligation were achieved laparoscopically without injury to the conduit or other structures. Laparoscopic surgery for patients with an ileal conduit can be technically demanding. A preoperative plan based on preoperative imaging and the patient's previous operative record is crucial, especially when considering the optimal balance between oncological radicality and functional outcomes. PMID- 29624908 TI - Iodine-Mediated Direct Generation of o-Quinone Methides at Room Temperature: A Facile Protocol for the Synthesis of ortho-Hydroxybenzyl Thioethers. AB - An iodine-mediated preparation of ortho-quinone methides (o-QMs) from ortho hydroxybenzyl alcohols by a C-O bond scission strategy is described. The in situ generated o-QMs were then employed for C-S bond formation by thio-Michael addition of thiols to provide the ortho-hydroxybenzyl thioethers (o-HBT) in moderate to excellent yields. PMID- 29624909 TI - Exposure to liquid sweetness in early childhood: artificially-sweetened and sugar sweetened beverage consumption at 4-5 years and risk of overweight and obesity at 7-8 years. AB - BACKGROUND: A significant gap exists in longitudinal evidence on early exposure to artificially sweetened beverages (ASBs) and weight outcomes for paediatric populations. OBJECTIVE: The objective of this study is to examine the relationship between ASB/sugar-sweetened beverage (SSB) consumption at 4-5 years and risk of overweight and obesity at 7-8 years. METHODS: Data from a nationally representative cohort (n = 2986) in Scotland were analysed using logistic regression to evaluate the association between exposure to ASBs/SSBs at 4-5 years and risk of overweight and obesity at 7-8 years. RESULTS: There were positive unadjusted associations between ASB consumption and risk of obesity, and following adjustment for confounders, ASB associations attenuated, and only the middle consumption category (1 to 6 times per week) remained significant (odds ratio 1.57, 95% confidence interval {CI} 1.05-2.36). For SSB consumption, there were no significant unadjusted associations, and following adjustment for confounders, only the middle consumption category was significant (odds ratio 1.65, 95% CI 1.12-2.44). There were no significant associations for risk of overweight. CONCLUSIONS: Longitudinal analysis from 4-5 to 7-8 years demonstrated some evidence of associations between ASBs/SSB consumption and risk of obesity. However, non-linear patterns and wide CIs suggest cautious interpretation and need for future studies with long-term follow-up. PMID- 29624910 TI - Skeletal Growth Dysregulation in Australian Male Infants and Toddlers With Autism Spectrum Disorder. AB - : Recent findings suggest that children with Autism Spectrum Disorder (ASD) are larger in size for head circumference (HC), height, and weight compared to typically developing (TD) children; however, little is known about their rate of growth, especially in height and weight. The current study aimed to: (a) confirm and extend upon previous findings of early generalized overgrowth in ASD; and (b) determine if there were any differences in the rate of growth between infants and toddlers with ASD compared to their TD peers. Measurements of HC, height, and weight were available for 135 boys with ASD and 74 TD boys, from birth through 3 years of age. Size and growth rate in HC, height, and weight were analyzed using a linear mixed-effects model. Infants with ASD were significantly smaller in size at birth for HC, body length, and weight compared to TD infants (all P < 0.05); however, they grew at a significantly faster rate in HC and height in comparison to the TD children (P < 0.001); there was no significant difference between the groups in growth rate for weight (P > 0.05). The results confirmed that male infants and toddlers with ASD exhibit skeletal growth dysregulation early in life. Autism Res 2018, 11: 846-856. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: Recent findings suggest that infants with Autism Spectrum Disorder (ASD) are smaller in size at birth compared to typically developing infants but grow larger than their peers during the first year. Little is known about their rate of growth, especially for height and weight. Our findings confirmed that infants with ASD are smaller in size at birth for head circumference (HC), height, and weight, but grow at a faster rate in HC and height than their peers from birth to 3 years. PMID- 29624911 TI - Efficiently Exploring Adsorption Space to Identify Privileged Adsorbents for Chemical Separations of a Diverse Set of Molecules. AB - Although computational models have been used to predict adsorption of molecules in large libraries of porous adsorbents, previous work of this kind has focused on a small number of molecules as potential adsorbates. In this study, molecular simulations were used to consider the adsorption of a diverse range of molecules in a large collection of metal-organic framework (MOF) materials. Specifically, 11 304 isotherms were obtained from molecular simulations of 24 different adsorbates in 471 MOFs. This information provides insight into several interesting questions that could not be addressed with previously available data. Highly computationally efficient methods are introduced that can predict isotherms for a wide range of adsorbing molecules with far less computation than traditional molecular simulations. By characterizing the 276 binary mixtures defined by the molecules considered, "privileged" adsorbents are shown to exist, which are effective for separating many different molecular mixtures. Finally, correlations that were developed previously to predict molecular solubility in polymers are found to be surprisingly effective in predicting the average properties of molecules adsorbing in MOFs. PMID- 29624912 TI - Antichagasic, Leishmanicidal, and Trichomonacidal Activity of 2-Benzyl-5 nitroindazole-Derived Amines. AB - Three different series of new 5-nitroindazole derivatives-1-(omega-aminoalkyl)-2 benzylindazolin-3-ones (series A; ten compounds), 3-(omega-aminoalkoxy)-2 benzylindazoles (series B; four compounds) and 3-alkylamino-2-benzylindazoles (series C; five compounds)-have been synthesized and evaluated against the protozoan parasites Trypanosoma cruzi, Leishmania amazonensis, and Trichomonas vaginalis: etiological agents of Chagas disease, cutaneous leishmaniasis, and trichomoniasis, respectively. Many indazoles of series A, B, and C were efficient against T. cruzi. Some compounds in series A, after successfully passing the preliminary screening for epimastigotes, exhibited activity values against amastigotes of several T. cruzi strains that were better than or similar to those shown by the reference drug benznidazole and displayed low nonspecific toxicity against mammalian cells. On the other hand, preliminary studies against promastigotes of L. amazonensis showed high leishmanicidal activity for some derivatives of series A and C. With regard to activity against T. vaginalis, some indazoles of series B and C were rather efficient against trophozoites of a metronidazole-sensitive isolate and showed low nonspecific toxicities toward Vero cell cultures. Additionally, some of these compounds displayed similar activity against metronidazole-sensitive and resistant isolates, showing the absence of cross-resistance between these derivatives and the reference drug. PMID- 29624913 TI - Role of radiation therapy in primary breast diffuse large B-cell lymphoma in the Rituximab era: a SEER database analysis. AB - Primary breast diffuse large B-cell lymphoma (PB-DLBCL) is an uncommon extranodal non-Hodgkin's lymphoma (NHL), which was traditionally treated with anthracycline containing regimens followed by consolidative radiation therapy (RT) to add therapeutic benefits. The introduction of anti-CD20 antibody rituximab for the treatment of B-cell NHLs has significantly improved the clinical outcome of these malignant diseases. It is unclear, however, whether consolidative RT could still add therapeutic benefits for PB-DLBCL patients treated with rituximab. To answer this important question, we used the Surveillance, Epidemiology, and End Results (SEER) database to evaluate the impact of RT on the clinical outcomes of PB-DLBCL patients in the rituximab era. Information on patient age, year of diagnosis, stage, race, laterality, and RT status for PB-DLBCL patients diagnosed between 2001 and 2014 were extracted. Kaplan-Meier survival curves were plotted, and log rank test was used to compare the potential survival difference. Multivariate analysis using Cox proportional hazards model was employed to determine the impact of RT and other factors such as age, race, tumor laterality, stage, and year of diagnosis on survival. Among the 386 patients identified, the median follow-up time was 45 months (range, 0-167 months); the median age was 64 years (range, 19-93 years); 33.9% of the patients were younger than 60 years of age; 69.9% of the patients were stage I; 79.0% were white; 51.8% received RT. The 5 year OS and cause-specific survival (CSS) for the whole cohort were 72.3% and 82.5%, respectively. The 5-year OS was significantly superior for patients who received RT compared to those who did not receive RT (78.1% vs. 66.0%, P = 0.031). In multivariable analysis, RT remained significantly associated with improved OS (P = 0.026). In summary, our study suggests that RT still adds significant therapeutic benefits for patients with PB-DLCBL in the rituximab era. PMID- 29624914 TI - Fragile X checklists: A meta-analysis and development of a simplified universal clinical checklist. AB - BACKGROUND: Clinical checklists available have been developed to assess the risk of a positive Fragile X syndrome but they include relatively small sample sizes. Therefore, we carried out a meta-analysis that included statistical pooling of study results to obtain accurate figures on the prevalence of clinical predictors of Fragile X syndrome among patients with intellectual disability, thereby helping health professionals to improve their referrals for Fragile X testing. METHODS: All published studies consisting of cytogenetic and/or molecular screening for fragile X syndrome among patients with intellectual disability, were eligible for the meta-analysis. All patients enrolled in clinical checklists trials of Fragile X syndrome were eligible for this review, with no exclusion based on ethnicity or age. Odds ratio values, with 95% confidence intervals as well as Cronbach coefficient alpha, was reported to assess the frequency of clinical characteristics in subjects with intellectual disability with and without the fragile X mutation to determine the most discriminating. RESULTS: The following features were strongly associated with Fragile X syndrome: skin soft and velvety on the palms with redundancy of skin on the dorsum of hand [OR: 16.85 (95% CI 10.4-27.3; alpha:0.97)], large testes [OR: 7.14 (95% CI 5.53-9.22; alpha: 0.80)], large and prominent ears [OR: 18.62 (95% CI 14.38-24.1; alpha: 0.98)], pale blue eyes [OR: 8.97 (95% CI 4.75-16.97; alpha: 0.83)], family history of intellectual disability [OR: 3.43 (95% CI 2.76-4.27; alpha: 0.81)] as well as autistic-like behavior [OR: 3.08 (95% CI 2.48-3.83; alpha: 0.77)], Flat feet [OR: 11.53 (95% CI 6.79-19.56; alpha:0.91)], plantar crease [OR: 3.74 (95% CI 2.67 5.24; alpha: 0.70)]. We noted a weaker positive association between transverse palmar crease [OR: 2.68 (95% CI 1.70-4.18; alpha: 0.51)], elongated face [OR: 3.69 (95% CI 2.84-4.81; alpha: 0.63)]; hyperextensible metacarpo-phalangeal joints [OR: 2.68 (95% CI 2.15-3.34; alpha: 0.57)] and the Fragile X syndrome. CONCLUSION: This study has identified the highest risk features for patients with Fragile X syndrome that have been used to design a universal clinical checklist. PMID- 29624916 TI - Production of Plant Phthalate and its Hydrogenated Derivative from Bio-Based Platform Chemicals. AB - Direct transformation of bio-based platform chemicals into aromatic dicarboxylic acids and their derivatives, which are widely used for the manufacture of polymers, is of significant importance for the sustainable development of the plastics industry. However, limited successful chemical processes have been reported. This study concerns a sustainable route for the production of phthalate and its hydrogenated derivative from bio-based malic acid and erythritol. The key Diels-Alder reaction is applied to build a substituted cyclohexene structure. The dehydration reaction of malic acid affords fumaric acid with 96.6 % yield, which could be used as the dienophile, and 1,3-butadiene generated in situ through erythritol deoxydehydration serves as the diene. Starting from erythritol and dibutyl fumarate, a 74.3 % yield of dibutyl trans-4-cyclohexene-1,2-dicarboxylate is obtained. The palladium-catalyzed dehydrogenation of the cycloadduct gives a 77.8 % yield of dibutyl phthalate. Dibutyl trans-cyclohexane-1,2-dicarboxylate could be formed in nearly 100 % yield under mild conditions by hydrogenation of the cycloadduct. Furthermore, fumaric acid and fumarate, with trans configurations, were found to be better dienophiles for this Diels-Alder reaction than maleic acid and maleate, with cis configuration, based on the experimental and computational results. This new route will pave the way for the production of environmental friendly plastic materials from plants. PMID- 29624915 TI - Present and changing trends in surgical modalities and neoadjuvant chemotherapy administration for female breast cancer in Beijing, China: A 10-year (2006-2015) retrospective hospitalization summary report-based study. AB - BACKGROUND: This study was conducted to describe present and changing trends in surgical modalities and neoadjuvant chemotherapy (NACT) in female breast cancer patients in China from 2006 to 2015. METHODS: Data of 44 299 female breast cancer patients from 15 tertiary hospitals in Beijing were extracted from hospitalization summary reports. Surgeries were categorized into five modalities: breast-conserving surgery (BCS), simple mastectomy (SM), modified radical mastectomy (MRM), radical mastectomy (RM), and extensive radical mastectomy (ERM). RESULTS: In total, 38 471 (86.84%) breast cancer patients underwent surgery: 22.64% BCS, 8.22% SM, 63.97% MRM, 4.24% RM, and 0.93% ERM. Older patients (> 60) underwent surgery more frequently than younger patients (< 60). The proportion of patients who underwent BCS was highest in the age >= 80 (39.24%) and < 40 (28.69%) subgroups and in patients with papillary carcinoma (35.48%), and lowest in the age 60- subgroup (18.17%) and in patients with Paget's disease (19.05%). SM was most frequently performed in patients with Paget's disease (29.00%), and MRM for ductal (64.99%), and lobular (63.78%) carcinomas. During the study period, the proportion of patients who underwent MRM dropped by 29.04%, SM and BCS increased from 15.78% and 30.83%, respectively, and NACT increased in all subgroups, particularly in patients with lymph node involvement (26.72%). CONCLUSIONS: Surgical modalities varied significantly by age and histologic group. The use of BCS and SM increased dramatically, while MRM declined significantly. The proportion of patients treated with NACT has increased significantly, especially in patients with lymph node involvement. PMID- 29624917 TI - Essential ingredients of engagement when working alongside people after their first episode of psychosis: A qualitative meta-synthesis. AB - AIM: Early intervention services (EISs) for first-episode psychosis (FEP) have been established internationally, however, service disengagement is a recurrent concern resulting in unplanned treatment cessation. The implications of this are far-reaching due to the financial and personal costs associated with untreated symptoms. The aim of this meta-synthesis was to collect, interpret and synthesize qualitative research about how engagement is experienced within EISs for FEP. METHODS: A systematic search was conducted in PsycINFO, Ovid MEDLINE and Ovid Emcare from date of conception to November 2016. Following initial screening, 91 abstracts and 13 full texts were reviewed for eligibility. Nine studies were then critically appraised using the CASP tool for qualitative studies, data were systematically extracted and results were synthesized using constant comparison and reciprocal translational analysis. RESULTS: Nine qualitative studies explored engagement with EISs, from the perspectives of service users and their caregivers. No studies were found from the perspectives of clinicians or services. All 9 studies employed an inductive methodology, within an interpretivist epistemology. Five main themes were identified: experiences of finding help; factors promoting engagement; the therapeutic relationship; the role of caregivers in supporting engagement; and factors impacting ongoing engagement. CONCLUSIONS: There is a critical need to stimulate discussion around this multifaceted phenomenon, including a continued focus on the roles of key stakeholders and clinical models that may further facilitate collaboration in treatment plans and recovery. PMID- 29624918 TI - Fine-needle aspiration of tubulocystic renal cell carcinoma. AB - We report two cases of tubulocystic renal cell carcinoma, a rare renal tumor the cytology of which has not been previously reported. Both aspirates were cellular and contained large sheets of cells with abundant granular cytoplasm, distinct cell borders and intracellular windows, distinct to prominent nucleoli, rare intracytoplasmic vacuoles, and rare nuclear grooves. Cells with variable amounts of cytoplasm were also arranged in small groups, some of which resembled spherules. The large sheets of cells with windows appeared specific for tubulocystic carcinoma; the spherules could easily be confused with a papillary renal cell carcinoma. PMID- 29624919 TI - Increased cytokines in cystic fibrosis patients' upper airways during a new P. aeruginosa colonization. AB - OBJECTIVES: Previously, we found linkages of inflammatory mediator levels in CF upper airways (UAW) sampled by nasal lavage (NL) to disease severity and to chronic pathogen colonization such as Pseudomonas aeruginosa (PsA). Here, we assess UAW cytokine dynamics in CF patients with a new PsA colonization. METHODS: We measured cytokines in 149 longitudinally obtained NL samples from 34 CF patients. Cytokine concentrations determined prior to, at the time of de novo PsA detection in either UAW or lower airways (LAW), and in a subsequent PsA free period in newly colonized patients (PsA-new/n = 7) were compared to levels of not (PsA-free/n = 13) and chronically colonized patients (PsA-chron/n = 14). Moreover, serological and clinical data were compiled. RESULTS: Concentrations of IL-1beta, IL-6, and IL-8 in samples taken prior to new PsA detection were comparable with PsA-free patients. At the time of PsA detection and, most interestingly, irrespective of whether PsA occurred in the UAW or LAW, IL-8 increased (P = 0.009) and IL-6 tended to increase (P = 0.081). In these patients, detection of PsA was not related to elevated PsA antibody-titers. In comparison, NL of PsA-chron patients revealed generally lower IL-8 and IL-1beta concentrations as in PsA-free patients, most likely due to a consequent antibiotic and anti-inflammatory therapy (eg, with azithromycin). CONCLUSIONS: Monitoring cytokine dynamics in the UAW by serial NL sampling may be valuable in the early phase of PsA acquisition and, thus, increase the chance to adjust treatment options early and more specifically. PMID- 29624920 TI - Lack of association between vitamin D receptor genes BsmI as well as ApaI polymorphisms and osteoporosis risk: A pooled analysis on Chinese individuals. AB - BACKGROUND: As for the association between vitamin D receptor (VDR) gene polymorphisms and osteoporosis, the current results have yielded conflicts. Therefore, we performed a pooled analysis based on Chinese individuals to provide comprehensive data on the association between VDR BsmI, ApaI, Tru9I polymorphisms and osteoporosis risk. METHODS: Studies were identified using PubMed, Springer Link, Ovid, Chinese Wanfang Data Knowledge Service Platform, Chinese National Knowledge Infrastructure and Chinese Biology Medicine databases through to January 2017. Studies were screened according to the predefined inclusion and exclusion criteria. The association between VDR BsmI, ApaI, Tru9I polymorphisms and osteoporosis was evaluated by calculating pooled odds ratios (ORs) based on the individual ORs. The significance of the pooled OR was evaluated by a Z-test. All statistical analyses were conducted using Stata 12.0 software (StataCorp, College Station, TX, USA). RESULTS: A total of 13 studies with 1141 osteoporosis cases and 1263 controls were included in this meta-analysis. It revealed that VDR Tru9I polymorphism was associated with an increased risk of osteoporosis in a common model (OR = 2.67, CI 95% = 1.59-4.49). No significant association was observed between VDR BsmI, ApaI and osteoporosis. CONCLUSION: In conclusion, this meta-analysis suggests that VDR Tru9I polymorphism may be associated with osteoporosis risk in Chinese individuals, while BsmI, ApaI polymorphisms might not be a risk factor for osteoporosis. PMID- 29624922 TI - Impact of pharmacy services on cystic fibrosis medication adherence: Update. PMID- 29624923 TI - Neutrophil elastase correlates with increased sphingolipid content in cystic fibrosis sputum. AB - INTRODUCTION: Sphingolipids are associated with the regulation of pulmonary inflammation. Although sphingolipids have been investigated in the context of cystic fibrosis (CF), the focus has been on loss of CF transmembrane conductance regulator (CFTR) function in mice, and in CF human lung epithelial cell lines. The sphingolipid content of CF sputum and the potential link between ceramide and airway inflammation in CF remain relatively unexplored. METHODS: Fifteen patients with CF provided two spontaneously expectorated sputum samples, one collected during a hospitalization for an acute pulmonary exacerbation and one from an outpatient visit at a time of clinical stability. Sputum was processed, and the supernatant assessed for active neutrophil elastase (NE) using a chromogenic microplate assay and sphingolipid content using reverse phase high-performance liquid chromatography/electrospray ionization tandem mass spectrometry (HPLC-ESI MS/MS). Relevant demographic data including age, sex, CF genotype, FEV1 % predicted, and sputum bacteriology were assessed as possible modifying factors that could influence the correlation between NE and sputum sphingolipids. Data were analyzed for linear correlation, with statistical significance pre-defined as P < 0.05. RESULTS: There was a significant association between the concentration of active NE and ceramide, sphingomyelin, and monohexosylceramide moieties as well as sphingosine-1-phosphate. The presence of Methicillin resistant Staphylococcus aureus (MRSA), FEV1 % predicted, and female gender further strengthened the association of NE and sphingolipids, but Pseudomonas aeruginosa had no effect on the association between NE and sphingolipids. CONCLUSIONS: These data suggest that NE may increase pro-inflammatory sphingolipid signaling, and the association is strengthened in female patients and patients with MRSA. PMID- 29624921 TI - A genetic variant in IL-15Ralpha correlates with physical activity among European American adults. AB - BACKGROUND: Interleukin-15 (IL-15) is a myokine associated with muscle strength, possibly by attenuating protein breakdown. A variant in the alpha-receptor (IL 15Ralpha 1775 A>C, rs2228059) partially modulates the muscle strength and size response to resistance training. We examined if this polymorphism associated with habitual physical activity among European-American adults. METHODS: Men (n = 240, 23.7 +/- 0.3 year, body mass index [BMI] 25.3 +/- 0.3 kg/m2 ) and women (n = 292, 23.2 +/- 0.3 year, 24.0 +/- 0.3 kg/m2 ) were genotyped. Physical activity phenotypes were derived from the Paffenbarger Physical Activity Questionnaire. Analysis of covariance (ancova) tested log-transformed differences between the IL 15Ralpha genotype and physical activity phenotypes by gender with age and BMI as covariates. RESULTS: Men with the IL-15Ralpha 1775AA genotype spent more time in light intensity physical activity (39.4 +/- 2.4 hr/week) than men with the CC genotype (28.6 +/- 2.3 hr/week, (p = .009). CONCLUSION: Further research is needed to confirm our finding and determine the possible mechanisms by which the IL-15Ralpha variant modulates light intensity physical activity. PMID- 29624924 TI - Brief report: Poor self-regulation as a predictor of individual differences in adaptive functioning in young children with autism spectrum disorder. AB - The present study examined the link between poor self-regulation (measured by the child behavior checklist dysregulated profile [DP]) and core autism symptoms, as well as with developmental level, in a sample of 107 children with autism spectrum disorder (ASD) aged 19-46 months. We further examined the utility of DP in predicting individual differences in adaptive functioning, relative to the influence of ASD severity, chronological age (CA), and developmental level. Poor self-regulation was unrelated to CA, developmental level, and severity of ADOS-2 restricted and repetitive behaviors, but was associated with lower ADOS-2 social affect severity. Hierarchical regression identified poor self-regulation as a unique independent predictor of adaptive behavior, with more severe dysregulation predicting poorer adaptive functioning. Results highlight the importance of early identification of deficits in self-regulation, and more specifically, of the utility of DP, when designing individually tailored treatments for young children with ASD. Autism Res 2018, 11: 1157-1165. (c) 2018 International Society for Autism Research, Wiley Periodicals, Inc. LAY SUMMARY: This study explored the relationship between poor self-regulation and age, verbal and non-verbal developmental level, severity of autism symptoms and adaptive functioning in 107 children with autism under 4 years of age. Poor self-regulation was unrelated to age, developmental level, and severity of restricted and repetitive behaviors but was associated with lower social affect severity. Importantly, more severe self regulation deficits predicted poorer adaptive functioning. PMID- 29624925 TI - Experiences with Universal Health Coverage of Maternal Health Care in Ondo State, Nigeria, 2009-2017. PMID- 29624926 TI - Maternal Education and Diarrhea among Children aged 0-24 Months in Nigeria. AB - Childhood diarrhea remains a problem in countries like Nigeria where access to potable water, good hygiene and sanitation are lacking. Maternal education is an important determinant of health status of under-five children. Very few studies have investigated the relationship between maternal education and diarrhea in children in Nigeria. Therefore, this study was implemented to fill the gap. The study design was cross-sectional and 2013 National Survey was used. Children aged 0-24 months were investigated and the dependent variable was diarrhea status of the index child in the last two weeks prior the survey. The main independent variable was maternal education. Data were analyzed using Chi-square and Logistic regression models (alpha=0.05). Diarrhea prevalence was 13.7% and higher (15.5%) among children of women who have no formal education, and mothers living in the North East region of Nigeria experienced the highest prevalence (26.4%). Children whose mothers had no formal education were 2.69(CI= 1.800-4.015, p <0.001) more likely to have diarrhea as compared to those who had higher education. Maternal education is an important predictor of diarrhea among children aged 0-24 months in Nigeria. Policies to reduce diarrhea among children in Nigeria should target children of the illiterate, less educated mothers and those living in the North West. PMID- 29624927 TI - Strengthening Youth Friendly Health Services through Expanding Method Choice to include Long-Acting Reversible Contraceptives for Ethiopian Youth. AB - Despite robust evidence regarding long-acting reversible contraceptive (LARC) low failure rates, immediate return to fertility and safety, LARC uptake among youth is low. We evaluated the effect on contraceptive uptake of training youth friendly service providers to counsel and provide all contraceptive methods including LARCs in the same unit. A convenience purposive sampling technique was used to select 20 youth friendly health units; ten each in Amhara and Tigray regions, Ethiopia; randomly allocated to the intervention (five) and non intervention (five) arms. Data were abstracted from the family planning registers over an eleven-month period: three months pre-intervention and eight months post intervention. Analysis of contraceptive uptake and chi-square tests of association were conducted. The number of LARCs new acceptors in the intervention arm was 781 (pre-intervention=116; post intervention=665) as compared to 358 in the non-intervention arm (pre-intervention=95; post intervention=263). Odds of adopting LARCs at pre-intervention (0.70); rose to 1.30 for the post-intervention phase (p-value <0.0001); comparing intervention to non-intervention study arms. Training youth friendly service providers to counsel and provide all contraceptive methods including LARCs in one location resulted in higher LARCs uptake for all sexually active young women; including those planning on delaying their first pregnancy. PMID- 29624928 TI - HIV/AIDS Knowledge, Attitude and Practice among Dilla University Students, Ethiopia. AB - The growing rate of educational institutions and student population at the tertiary level in Ethiopia is remarkable; this may lead to a corresponding increase to exposure to HIV/AIDS. Based on this orientation, this study estimated the level of knowledge, attitude and practice of HIV/AIDS among university students in Ethiopia. Four hundred forty one students were chosen through multi stage probability sampling technique. Data was collected through five point measurement scale. One sample t-test and Structural Equation Modelling based on Confirmatory Factor Analysis (CFA) were employed for data analysis. It was found that the level of HIV/AIDS knowledge, attitude, and practice were 53%, 95%CI = .03- .06, p = .55; 58 %, 95%CI = .01- .10, p <.05; and = 92 %, 95%CI = .37- .42, p <.001 respectively. Apart from knowledge, the observed value of attitude and practice were higher than their corresponding expected values with the effect size, d = 0.12 for attitude and d = 0.82 for practice. Implications were discussed to assist students develop comprehensive knowledge and desirable attitude towards self-protective skills against HIV infection. PMID- 29624929 TI - Barriers to Antenatal Care in an Urban Community in the Gambia: An In-depth Qualitative Interview Study. AB - This qualitative study investigated the barriers to obtaining access to antenatal care in a small, urban government-supported health centre in the Gambia. It thus addresses an important issue related to maternal health and the prevention of maternal deaths. In-depth interviews were conducted with 25 pregnant women, 13 healthcare workers and 9 male partners. Three areas were identified for study: recognition and acknowledgment of pregnancy, recognition of the need for care and practical barriers to attendance. Intentional concealment of early pregnancy was common to avoid adverse social consequences or for fear that malign interventions would cause a miscarriage. In the absence of symptoms many women considered it unnecessary to attend the antenatal clinic until well into the second trimester. Practical barriers to attendance included conflicting domestic demands and the attitude of some healthcare workers. Access to antenatal care in the Gambia throughout pregnancy should be considered in a stepwise fashion and barriers to care were identified at each stage. Interviews with male partners and health workers highlighted their key role. PMID- 29624930 TI - User Satisfaction with Family Planning Services in Government Health Centres in the Congo. AB - Patient satisfaction is considered an indicator of quality of care. This study aimed to assess the degree of clients' satisfaction with family planning (FP) services in government health centers in Congo. A cross-sectional study was conducted. A total of 635 clients nested in 27 health facilities were included in the analysis. Satisfaction was defined as "having a good perception of provider technical skills, being satisfied with the service organization and having a general positive appreciation of FP services. Statistical analyses were performed using SPSS v15. Among 635 clients, 57% perceived lack of technical competence in providers, 88% perceived good organization in FP services and 77% declared having general positive appreciation of FP services. Global level of client satisfaction was 42%. In conclusion client satisfaction with FP service was low and strengthening health workers technical competence is crucial. But, as the quality is multidimensional, other aspects especially significant funding investment and quality-assurance interventions must be taken into account. PMID- 29624931 TI - Influence of Knowledge of Spousal Fertility Cycles on Male Reproductive Health Participation in Ibadan Metropolis, Nigeria. AB - In spite of the established roles and influence of men on women's uptake and utilization of reproductive health care interventions, the degree of involvement with intimate issues within the household which could help to understand male involvement and support remains an under-researched topic. The aim of this study was to investigate the degree of involvement at the family level of men within sub-urban communities of Ibadan in South-West Nigeria. A cross sectional survey design was conducted among 380 men selected from sub-urban communities in Ibadan, Oyo State using multi-stage sampling. Data was obtained using pre-tested, semi structured, interviewer administered questionnaires. Data were analysed using descriptive statistics, bivariate analysis and logistic regression with level of significance set at 5%. Mean age of respondents was 41.1 +/- 7.6 years. Men who were knowledgeable of spouse's menstrual cycles and ovulation dates were significantly more likely to have supported some form of public health intervention before (p <0.001). Age over 30, above secondary education, and men aware of menstrual dates of spouse were significant predictors of reproductive health interventions. Men who were aware of menstrual cycles of spouse were 96.6% more likely to be supportive or involved in reproductive health matters compared to those who were not (OR =0.034; 95% CI = 0.02 - 0.07; p <0.001). Involvement of men at family level as demonstrated in this study serves to influence and explain the level of involvement with reproductive health. Further research investigating other proximal factors that influence male participation is recommended. PMID- 29624932 TI - Determinants of Modern Contraceptive Uptake among Nigerian Women: Evidence from the National Demographic and Health Survey. AB - Family planning is a key strategy in the control of fertility among women. This study sought to determine various factors that influence modern family planning use in Nigeria. The study used data from Nigeria Demographic and Health Survey (NDHS) 2013. Analysis was carried out using Stata version 12.1. Multivariate logistic regression was used to determine association between various factors and use of modern family planning methods. A total of 119,386 women aged 15-49 years participated in the study. The mean age of respondents was 35.9 +/- 8.1 years. Overall, contraceptive prevalence rate of modern methods was 10.3%. The highest proportion of use was 26.7% in the South West, while the lowest was 2.7% in the North West. Predictors of modern family planning use were higher education (OR=4.49, 95% CI: 4.10-4.92), richest wealth quintile (OR=3.71 CI: 3.29-4.19), being from South West (OR=3.42, 95% CI: 3.15-3.70), age 25-49 years (OR=1.55, 95% CI: 1.42-1.69) and urban residence (OR=1.08, 95% CI: 1.03-1.13) (p <0.001). The highest predictors of modern contraceptive use were education and wealth index. These indices were poorest in North Western Nigeria. Measures should be taken to improve female literacy and employment as these will most likely improve uptake of modern contraceptives among women in Nigeria. PMID- 29624933 TI - Effects of Vaginal Lubricants on In-Vitro Progressive Spermatozoa Motility. AB - Vaginal lubricants are used to solve intercourse difficulties or as sexual enhancers, but recent reports raise questions about their safety in terms of fertility. In this study, twenty semen samples were tested against commercially available vaginal lubricants for progressive spermatozoa motility and vitality with varying exposure time intervals. Results showed that the vaginal lubricant which least affected progressive spermatozoa motility was the oil-based vaginal lubricant, which kept the mean percentage of progressive spermatozoa motility within the minimum normal range of 32%, following 60 minutes of exposure. The silicone-based vaginal lubricant produced similar results to the oil-based vaginal lubricant, however the progressive spermatozoa motility dropped below the minimum normal range within 60 minutes of exposure. The fertility lubricant did not produce mean progressive motilities that were within the normal minimum range at any of the three time intervals, producing poor results overall. The vaginal lubricant which produced the poorest results was the water-based, which immobilized all of the spermatozoa within 5 minutes of exposure and killed on average 95.23% within 60 minutes. Although further assessment is required, these results highlight potential fertility issues related to the formulation of commercially available vaginal lubricants. PMID- 29624934 TI - Saving the Lives of Women, Newborns, and Children: A Formative Study Examining Opportunities to Improve Reproductive, Maternal, Neonatal, and Child Health Outcomes in Nigeria. AB - Despite economic growth in Nigeria, maternal and infant mortality rates remain among the highest in the world. Civil society organisations (CSOs) play a critical role in ensuring governmental accountability to fulfil commitments that improve health outcomes for women, newborns, and children. This formative study was undertaken to identify: a) policy advocacy priorities b) advocacy challenges, and, c) opportunities for strategic advocacy. Methods consisted of a desk review of key reproductive, maternal, neonatal, child and adolescent health (RMNCAH) policies, surveys with CSOs working on RMNCAH, and key informants from non governmental organisations (NGOs), and United Nations agencies. Participants identified the need for improved funding for RMNCAH policy implementation, increased civil society input in policy creation, and greater accountability. Increased investment in advocacy capacity building and accountability play an important role in improving health outcomes in Nigeria. PMID- 29624935 TI - Scientific Knowledge Dissemination and Reproductive Health Promotion in Africa: The Case of AJRH. PMID- 29624936 TI - Promoting Early Detection of Breast Cancer and Care Strategies for Nigeria. AB - Breast cancer is the most common cancer in women particularly in developing countries like Nigeria, with high mortality, and economic costs. Worldwide, it is predicted that more than one million women are diagnosed with breast cancer, and more than 400,000 will die from the disease every year. A comparative integrative review of the literature from Nigeria and Canada showed that in Canada, there is positive association between wide spread education, early detection, the disease stage at diagnosis, and survival rates. In Nigeria, presentation with the advanced stage of the disease makes survival very low. The primary factors responsible for the late presentations are lack of awareness, misconceptions about breast cancer causes, and treatment outcomes. It is recommended that guidelines and policies about breast cancer early detection, care strategies, and ongoing management pathways be produced, disseminated, and adopted. The guidelines will assist practitioners and patients in making informed decisions and choices about the most appropriate health care for their specific clinical situations. The implementation of evidence-based guidelines will most likely help to improve care processes, the quality of clinical decisions and patient treatment outcome. PMID- 29624937 TI - Trends and Determinants of Comprehensive Knowledge of HIV among Adolescents and Young Adults in Nigeria: 2003 - 2013. AB - This study examined comprehensive knowledge of HIV (CKH) and its determinants among young people aged 15-24 years in Nigeria between 2003 and 2013. Secondary analysis was conducted on three rounds of NDHS 2003, 2008 and 2013 data. CKH increased significantly between 2003 and 2013, but the level reached in 2013 fell short of the global expectation for young people. Its significant determinants included gender, age, educational attainment, place and region of residence, household wealth status and uptake of HIV test. There is need to sustain all on going effective youth-focused interventions and programmes to meet the comprehensive knowledge needs for all young people in Nigeria. PMID- 29624938 TI - Partner Support for Family Planning and Modern Contraceptive Use in Luanda, Angola. AB - Husband's/partner's support for family planning may influence a women's modern contraceptive use. Socio-demographic factors, couple communication about family planning, and fertility preferences are known to play a role in contraceptive use. We conducted logistic regression analysis to investigate the relationship between perceived husband's/partner's approval and husband's/partner's encouragement of modern contraceptive use, adjusting for socio-demographic factors and recent couple communication about family planning. We also examined mediating roles potentially played by perceived contraceptive accessibility and contraceptive self-efficacy (using index created by principal component analysis). Perceived husband's/partner's approval was associated with triple the odds of women's modern contraceptive use and remained significantly associated with 1.6 times the odds, after controlling for contraceptive accessibility and contraceptive self-efficacy. Husband's/partner's encouragement, while initially significantly associated with contraceptive use, became non-significant after adjustments for socio-demographic factors and couple communication. Perceived husband's/partner's approval, separate from a woman's sense of self-efficacy and perceived accessibility of contraceptives, appears strongly and positively associated with current modern contraceptive use. Increased couple communication may help women identify their husband's/partner's approval. Difference between the meaning of approval and encouragement should be explored. Interventions involving information education and communication campaigns geared to men and promoting male involvement in family planning could increase contraceptive prevalence. PMID- 29624939 TI - Associated Factors and Quality of Care Received among Maternal Deaths at a Regional Hospital in Ghana: Maternal Death Audit Review. AB - Maternal death audits are crucial to the reduction of maternal deaths. The aim of this study was to identity factors contributing to maternal deaths at Eastern Regional Hospital of Ghana. Quantitative and qualitative methods were used. Quantitative data on all the maternal deaths from January to December 2012 was extracted from completed audit forms and patients records using a standardized questionnaire. The data were analyzed in Epi-info. Qualitative data was collected through in-depth interviews and focus group discussions with health staff to assess care received and factors leading to death. A total of 43 maternal deaths occurred out of which 37 (86%) were audited. Major causes of deaths were pregnancy induced hypertension (27%) and abortion (21%). Late referrals, poor supervision of junior staff, inadequate numbers of senior clinicians, lack of intensive care facility as well as unavailability and insufficient blood and blood products were the main contributory factors to the deaths. Tertiary health institutions should be adequately equipped, staffed, and funded to address these causes of maternal death. PMID- 29624940 TI - Exploring the Causes of Change in Adolescent Girls' Sexual Behaviour in Begoro, Ghana. AB - There is a changing trend in adolescent girls' sexual and reproductive behaviour in Ghana. However, contemporary perspectives on adolescent girls' sexual behaviours are largely missing hence this study. Thematic analysis of data collected through in-depth interviews with adolescent girls and community members as well as focus group discussions with adolescent boys identified several factors accounting for the changes in adolescent girls' sexual and reproductive behaviour. These factors include changes in girls' attitudes to traditional practices, diversity in the agents of socialization as well as the age at menarche. This has resulted in a clash of value system between girls' sexual behaviours and that of the elderly. Thus, the social context in which girls are experiencing sexual and reproductive life in Ghana is changing and this must be taken into consideration when designing any intervention to help adolescent girls become resilient in their sexual and reproductive lives. PMID- 29624941 TI - High rates of Unintended Pregnancies among Young Women Sex Workers in Conflict affected Northern Uganda: The Social Contexts of Brothels/Lodges and Substance Use. AB - This study aimed to examine the correlates of unintended pregnancies among young women sex workers in conflict-affected northern Uganda. Data were drawn from the Gulu Sexual Health Study, a cross-sectional study of young women engaged in sex work. Bivariable and multivariable logistic regression was used to examine the correlates of ever having an unintended pregnancy. Among 400 sex workers (median age=20 years; IQR 19-25), 175 (43.8%) reported at least one unintended pregnancy. In multivariable analysis, primarily servicing clients in lodges/brothels [Adjusted Odds Ratio (AOR= 2.24; 95% Confidence Interval: 1.03-4.84)], hormonal contraceptive usage [AOR=1.68; 95%CI 1.11-2.59] and drug/alcohol use while working [AOR= 1.64; 95%CI 1.04-2.60] were positively correlated with previous unintended pregnancy. Given that unintended pregnancy is an indicator of unmet reproductive health need, these findings highlight a need for improved access to integrated reproductive health and HIV services, catered to sex workers' needs. Sex work-led strategies (e.g., peer outreach) should be considered, alongside structural strategies and education targeting brothel/lodge owners and managers. PMID- 29624942 TI - Integrating Family Planning and HIV Services at the Community Level: Formative Assessment with Village Health Teams in Uganda. AB - Little is known on integrating HIV and family planning (FP) services in community settings. Using a cluster randomized controlled design, we conducted a formative assessment in two districts in Uganda where community health workers, called VHTs, already offered FP. Thirty-six trained VHTs also provided HIV testing and counseling (HTC) during the intervention. We surveyed all 36 VHTs and 256 FP clients, and reviewed service statistics. In the intervention group, VHTs tested 80% of surveyed clients for HIV, including 76% they already saw for FP and 22% who first came to them for HTC before receiving FP. Comparing clients' experiences in the intervention and control groups, adding HTC does not appear to have negatively affected FP service quality. VHTs reported more monthly clients, but rated their workload as easy to manage. This integrated model seems feasible and beneficial for both VHTs and clients, while not resulting in any negative effects. This study was registered with ClinicalTrials.gov, number [NCT02244398]. PMID- 29624943 TI - Context-specific Factors and Contraceptive Use: A Mixed Method Study among Women, Men and Health Providers in a Rural Ghanaian District. AB - Suitable options for improving women's access to effective, safe and context specific contraceptive methods must be explored to curtail rising unmet needs for contraceptive use in rural Ghana. The study aimed to outline context-specific factors associated with contraceptive use, access on demand and future use intentions among women in one district of Ghana. Using mixed method approach, quantitative data (n=720) was collected among women aged 18-28. Focus group discussions and in-depth interviews were also conducted among women (n=30) aged 18-49 and men (n=10) respectively. IDIs were conducted among 3 midwives. Women who received focused counseling on contraceptive use were twice likely to have ever used (OR=2 95% CI 1.163-3.467) or be current users (OR=2, 95% CI 1.146 4.010) of contraceptives. Male partner support can drive cultural sensitivities towards accepting use of contraception (OR=34.5, CI% 19.01-64.22). Covert use is still preferred by most in the study. Services delivered on good provider relational grounds and convenient clinic hours encourage contraceptive use among women. Male targeting for improving contraceptive service use must first identify context-specific preferences of the woman, since covert use is highly valued. Ascertaining the prevalence of covert use and how community systems can address this for improved contraceptive uptake is further recommended. PMID- 29624944 TI - Demand for Women's Health Services in Northern Nigeria: A Review of the Literature. AB - Demand for and utilization of women's health services in northern Nigeria are consistently low and health indicators in the region are among the poorest in the world. This literature review focuses on social and cultural barriers to contraceptive use, antenatal care, and facility births in northern Nigeria, and influencers of young women's health-seeking behavior. A thorough search of peer reviewed and grey literature yielded 41 publications that were synthesized and analyzed. The region's population is predominantly Muslim, practicing Islam as a complete way of life. While northern Nigerian society is slowly changing, most women still lack formal education, with a significant proportion married in their teens, and the majority neither socially nor economically empowered. The husband largely makes most household decisions, including utilization of healthcare services by members of his household. These practices directly impact women's health-seeking behaviors for themselves and for their children. Programs seeking to improve women's health outcomes in northern Nigeria should involve women's influencers to affect behavior change, including husbands, religious leaders, and others. More research is needed to identify pathways of information that can be utilized by programs designed to increase demand for health services. PMID- 29624945 TI - The Threat of Aerobic Vaginitis to Pregnancy and Neonatal Morbidity. AB - Aerobic vaginitis (AV) is an endogenous opportunistic infection brought about by the disruption of the normal vaginal microbiota. Its early diagnosis and treatment during pregnancy may reduce the risk of negative pregnancy outcomes. The aim of this review was to report on the aerobic bacteria most prevalent in AV and to provide evidence of the threat of untreated AV on pregnancy outcomes. More than 300 papers on preterm delivery were extracted from several research domains and filtered to include only AV-associated bacteria such as Staphylococcus aureus, Enterococcus faecalis, Escherichia coli and Group B streptococci and their association with adverse pregnancy outcomes. Due to the diverse sample groups, study techniques and outcomes, a meta-analysis was not conducted. The review revealed that the association of AV with adverse pregnancy outcomes has not been as widely researched as bacterial vaginosis (BV) and needs further investigation. Furthermore, the frequent misdiagnosis of AV coupled with the emerging antimicrobial resistance associated with bacteria implicated in AV and neonatal nosocomial infections pose a problem for prophylaxis and treatment to reduce the risk of maternal and neonatal morbidity and mortality. PMID- 29624947 TI - The Need for Societal Investment to Improve Cervical Cancer Outcomes in Nigeria: A commentary. AB - Although cervical cancer is a preventable cancer with a well-known natural history, it remains a huge burden in developing countries of sub-Saharan Africa where organized cervical cancer screening services are lacking. Developed countries that have invested on providing organized screening programs have made substantial progress in reducing both incidence and mortality due to cervical cancer. Implementing evidence-based interventions such as human papillomavirus (HPV) vaccination of young girls, early detection and treatment of premalignant conditions of the cervix through conventional Pap cytology, HPV screening or visual aided inspection with acetic acid could significantly reduce incidence of new cases at population level. Societal investment for such preventive services and provision of effective treatment for those diagnosed at early stages will yield economic benefits in reducing premature deaths of women at the prime of their productive lives. From a societal perspective, this should be a priority area for national investment towards the achievement of sustainable development in Nigeria and similar settings in Africa. PMID- 29624946 TI - Potentials for Use of Medicinal Plants in Female Reproductive Disorders - The Way Forward. PMID- 29624948 TI - Changing Face of Family Planning Funding in Kenya: A Cross-Sectional Survey of Two Urban Counties. AB - As international development partners reduce funding for family planning (FP) programs, the need to estimate the financial resources devoted to FP is becoming increasingly important both at all levels. This cross-sectional assessment examined the FP financing sources, agents, and expenditures in two counties of Kenya for fiscal years 2010/2011 and 2011/2012 to guide local decision-making on financial allocations. Data were collected through a participatory process. This involved stakeholder interviews, review of financial records and service statistics, and a survey of facilities offering FP services. Financing sources and agents were identified, and source amounts calculated. Types of FP provider organizations and the amounts spent by expenditure categories were identified. Overall, five financing sources and seven agents for FP were identified. Total two-year expenditures were KSh 307.8 M (US$ 3.62 M). The government's share of funding rose from 12% to 21% over the two years (p=0.029). In 2010/2011, the largest expense categories were administration, commodities, and labor; however, spending on commodities increased by 47% (p=0.042). This study provides local managers with FP financing and expenditure information for use in budget allocation decision-making. These analyses can be done routinely and replicated in other local counties or countries in a context of devolution. PMID- 29624950 TI - Intimate Partner Violence and HIV Status among Ever-Married and Cohabiting Zimbabwean Women: An Examination of Partners' Traits. AB - This study examines the connection between intimate partner violence (IPV) and Human Immunodeficiency Virus status among married and cohabitating women in Zimbabwe using an African feminist framework. Stata 13.0 was used to analyze data from the 2010-2011 Zimbabwe Demographic and Health Survey, which used a national probability sample of households in the country of Zimbabwe. This study used logistic regression to analyze the 2,830 ever-married or cohabitating women who also answered the violence and spousal traits questionnaire as well as provided blood samples. The logistic regression revealed that women who had experienced any type of intimate partner violence (odds ratio=1.29, CI [1.00, 1.67]) or broken bones (odds ratio=2.39, CI [1.19, 4.77]) were more likely to be HIV positive; relative to those with bruises bruises (odds ratio=- .64 CI [.41, .99]) were less likely. Women with partners who are trackers (odds ratio=1.28, CI [1.04, 1.59]) were more likely to be HIV positive. Patriarchal, hypermasculist culture, shown through violence against women, contributes to the likelihood of HIV in wives and partners. A cultural shift at the highest levels may help to prevent IPV and reduce the spread of HIV. PMID- 29624949 TI - Medicinal Plants used during Antenatal Care by Pregnant Women in Eastern Uganda. AB - Plants are commonly used during the antenatal stage in pregnancy to manage different ailments in Africa. In Uganda, both medicinal and food plants are used to handle common pregnancy related conditions. An ethnobotanical survey was conducted in Iganga district, eastern Uganda. Seven traditional birth attendants (TBA) and 46 mothers were interviewed. Data was collected using structured questionnaires and household interviews. The TBAs were identified using snowball sampling. A total of 33 plant species, belonging to 23 families were documented. Out of these, the pregnant mothers used 45.5 % as both food and medicine. The most frequently used plant life form was herbs (58.8%). The leaves are the most commonly used plant parts (59%). Most of the plants (58.8%) were semi cultivated and were being domesticated in crop fields and home gardens. Most of the plants were used to manage anaemia and for child development and good health among the pregnant women. The pregnant women and TBAs in Namungalwe sub County have diverse knowledge on medicinal and nutri-medicinal plants in the management of common pregnancy related diseases, which can be used to supplement modern antenatal services, inspite of the ban of the activities of TBA. Further research on the bioavailability of nutrients, efficacy and safety of the medicinal plants used by pregnant women should be done. PMID- 29624951 TI - Perceptions of Infertility and In Vitro Fertilization Treatment among Married Couples in Anambra State, Nigeria. AB - There is a high rate of infertility among couples in Nigeria. This challenge is perceived differently in each socio-cultural context in which it is experienced but solution to the problem is adversely affected by the people's perception of the phenomenon. This study thus explored the perceptions of infertility and in vitro fertilization (IVF) and how to enhance the use of IVF treatment among married couples. This was a cross-sectional survey in Anambra State, Nigeria involving household respondents (married couples) and hospital respondents (couples undergoing infertility evaluation). Structured questionnaire and key informant interview (KII) guide were used for data collection. Altogether 600 questionnaires were administered and 589 were validly completed and analysed. The main outcome measures included perceptions of infertility and IVF treatment, utilization of IVF treatment and association between some demographic variables and IVF utilization. The results showed that infertility was perceived majorly as - destiny/supernatural powers (17.1%), threat to men's procreativity/continuity of lineage (14.3%), women's problem only (15.6%). Solutions to the challenges were adversely affected by perception. The use of IVF treatment was low with misconceptions like it's too costly (15.4%) and unnatural (7.6%), giving rise to unmet need for assisted reproductive technology. Women (especially above 35 years) were more likely to accept IVF treatment than men. Reproductive health education and awareness creation should target the misconceptions about infertility/IVF and fertility treatment should be covered by national health insurance to reduce the cost of IVF treatment and improve its use in Anambra State. PMID- 29624952 TI - An Audit of Perineal Trauma and Vertical Transmisson Of HIV. AB - Restrictive episiotomy is recommended for the prevention of vertical transmission of HIV. The study compared the frequency of episiotomy use and the occurrence of perineal tears; and related factors in HIV positive and HIV negative women and to assess their effect on Mother-to-child transmission (MTCT) of HIV. A total of 110 HIV positive and 134 HIV negative parturients were enrolled in the study. The incidence of episiotomy was more in the HIV negative group (p=0.0000) while that of perineal tear was not affected by HIV status (p=0.17). The rate of episiotomy was significantly affected by primigravidity in HIV negative subjects (OR= 0.032, 95% CI 0.0072-0.13). The rate of perineal tear was significantly affected by primigravidity in HIV positive subjects (OR=8.55, 95% CI 1.91-38.7) and multigravidity in HIV negative subjects (OR= 0.030, 95% CI 0.133-0.71). Gestational age and mean birth weight had no effect on the rate of episiotomy (p value =0.57 and 0.30) and perineal tear (p value= 0.79 and 0.061). There was no mother-to-child HIV transmission. Episiotomies should be given when needed irrespective of HIV status because of the risk of consequent perineal tear and with HAART the risk of MTCT from perineal trauma is minimal. PMID- 29624953 TI - Determinants of Home Delivery among Women attending Antenatal Care in Bagwai Town, Kano Nigeria. AB - Unskilled home delivery is a threat to maternal and child health. In northern Nigeria, many pregnant women attend antenatal care but opt to deliver at home despite knowing the potential consequences. An institutional delivery, helps reduce various complications during childbirth, and therefore decreases the rates of maternal and child mortality. To explore the determinants of home delivery after attending antenatal services, this study employed a cross-sectional design and a non-probability purposive sampling technique. Findings of the study revealed that, majority (74.1%) of the women predominantly between the ages of 25 35 years, (29+/-6.4) quit antenatal care to deliver at home mainly due to maternity staff attitude and presence of male healthcare workers during delivery. The study concluded that, pregnant women are aware of the importance of antenatal care and, do deliver at home due to behavioural, sociocultural and religious preferences. To combat the maternal mortality in this region, values and beliefs of the women and families should be put into cognizance. Additionally, healthcare workers should be respectful and create a conducive environment in the maternity centres. More maternity centres including waiting homes should be provided. PMID- 29624954 TI - Empowerment of Adolescent Girls for Sexual and Reproductive Health Care: A Qualitative Study. AB - Adolescent girls should be empowered to acquire the ability to take care of their sexual and reproductive health. The present study aimed to improve the understanding of the factors affecting the empowerment of Iranian adolescent girls in terms of taking care of their sexual and reproductive health (e.g. pubertal and menstrual health, preventing high risk sexual behaviors, treatment seeking for sexual and reproductive complaints such as dysmenorrhea, genitalia infection). The present qualitative study was performed using conventional content analysis method. Eight key informants were purposively selected and interviewed. Data collection was performed through unstructured and in-depth interviews. The qualitative content was analyzed simultaneously with data collection based on Graneheim and Lundman method using MAXQDA 2010 software. Data analysis led to the emergence of the main theme of empowerment for care with four classes of reinforcing the foundations of sexual and reproductive health, providing services in health system, reinforcing educational institutions, and consolidating the interaction between adolescent and family, as well as thirteen sub-classes. Results of the present study showed the need for inter-sectional interaction and collaboration among authorities of health systems, education systems, and policymaking institutions to achieve a model for empowering adolescent girls via a multi-level and comprehensive approach. PMID- 29624955 TI - Examining the Role of Couples' Characteristics in Contraceptive use in Nigeria and Zambia. AB - Relationship-related characteristics influence diverse health and demographic outcomes. This study examined the role of couples' characteristics in contraceptive use. Data were obtained from 2013 Nigeria and 2013-14 Zambia Demographic and Health Surveys. The study population consisted of couples in monogamous union (married or living together) who had at least one live birth and the wife was not pregnant at the time of the survey. Prevalence of contraceptive use among couples in Nigeria was 27% and 63% in Zambia. Couples' educational attainment, religious affiliation, the frequency of listening to the radio, reported number of children, fertility preference, region of residence and household wealth index were significant predictors of contraceptive use among couples in Nigeria and Zambia. Given the significant role of couples' characteristics in the uptake of contraceptives, there is the need to encourage interventions that target couples, particularly those of poor socioeconomic status. PMID- 29624956 TI - Gender-Based Violence among Married Women in Debre Tabor Town, Northwest Ethiopia: A Qualitative Study. AB - Gender-based violence is one of the major public health problems in Ethiopia. This study aimed to assess the perception and attitude of the community towards gender-based violence among married women in Northwest Ethiopia. A qualitative study was conducted using the purposive sampling technique for the three focus group discussions and ten in-depth interviews among married women. Data was analyzed thematically using version 3.4 of the Open Code Software. Most of the participants perceived that gender-based violence was acceptable in the community, violent acts needed to be considerably tolerated rather than condemned. Additionally, participants perceived that the consequences of gender based violence were mild, and its elimination was difficult. Domestic violence was found to be common, marital rape was not clearly understood, and there was no tendency to disapprove it. This study revealed that the attitude of people and traditional norms played the major role in determining the acceptability of gender-based violence on married women. Increasing awareness on the consequences of gender-based violence, strengthening of women empowerment, involving different stakeholders on the provision of education, amending and enforcing the existing laws, and providing professional help to stop or reduce violence against women are recommended. PMID- 29624957 TI - [Development of targetable drug delivery systems with peptide ligands]. PMID- 29624958 TI - [Novel function of MeCP2 in the pathophysiology of Rett syndrome: Regulation of mTOR signaling mediated by MeCP2-dependent microRNA processing]. PMID- 29624959 TI - [Organization and function of glycosphingolipid-enriched lipid raft: Lactosylceramide-enriched lipid raft-mediated innate immune responses]. PMID- 29624960 TI - Associated factors with sarcopenia among Mexican elderly: 2012 National Health and Nutrition Survey AB - Background: Sarcopenia involves the loss of skeletal muscle mass and age-related functionality; it diminishes physical independence, health and quality of life. In 2016 it was added to the International Classification of Diseases (ICD-10). Information about the frequency of sarcopenia among Mexican older adults is scarce. The objective was to analyze associated factors with sarcopenia in Mexican older adults through the 2012 National Health and Nutrition Survey data. Methods: Cross-sectional study which included subjects of 60 years of age or more with simultaneous information on health and anthropometry questionnaires from the 2012 National Health and Nutrition Survey. Sarcopenia was diagnosed through a gait speed test and calf circumference. It was assessed the prevalence of sarcopenia and its association with sociodemographic characteristics and variables related to health, tobacco use and alcohol consumption. The analysis was performed with SPSS v. 16. Results: We analyzed a sample of 5046 older adults who represented 7 439 686 older adults nationwide. Among subjects 53.9% (n = 2718) were women (mean age 69.92 +/- 7.56 years) and 46.1% (n = 2328), men (mean age 70.43 +/- 7.73 years). Prevalence of presarcopenia was 8.70% and sarcopenia, 13.30%. Conclusion: Sarcopenia was more prevalent in women and it increases with age. It has a significant relationship with falls, cognitive impairment, central obesity and high levels of marginalization. PMID- 29624961 TI - [Unexpected roles of Shugoshin at chromosome ends]. PMID- 29624962 TI - [Diversity of the molecular mechanisms of synapse formation in the central nervous system]. PMID- 29624963 TI - [Oxidative damage on blood cells and blood-associated autoimmune diseases]. PMID- 29624964 TI - [Dynamic modification of sphingomyelin evokes a novel membrane dynamism in the plasma membrane]. PMID- 29624966 TI - [Diagnostic biomarker of major depression based on DNA methylation]. PMID- 29624965 TI - [Control of switching between migration modes in cancer invasion]. PMID- 29624967 TI - [Regulation of energy metabolism by BOSS/GPRC5B]. PMID- 29624968 TI - Self-perception of oral health in older adults from Mexico City AB - Background: Quality of life related to oral health is assessed through the individual's self-perceived oral health (SPOH). The objective is to determine SPOH in relation to socio-demographic and health characteristics in older adults beneficiaries from the Instituto Mexicano del Seguro Social (IMSS) in Mexico City. Methods: Cross-sectional study. We used data collection with questionnaire and assessment scales related to socio-demographic, health and dependency variables, as well as the visit to the dentist, the use of removable dental prostheses and SPOH. The self-perception means (Geriatric/General Oral Health Assessment Index-GOHAI) were calculated, and we used Student's t, ANOVA and Bonferroni post hoc tests. Results: 60.5% were women; the average age of population was 68.23 +/- 7.0. GOHAI total mean was 48.07 (48.05-48.08). Compared to their counterparts, people with the next features showed marked improvement in SPOH: of 60-69 years of age, separated or divorced, >= 7 years of study, paid work, living alone, no smoking, drinking alcohol, with a good health perception, low weight, no cognitive impairment, no depression, no anxiety, no comorbidity, consumption < 5 drugs, with limitations in basic activities, without limitations in instrumental activities, who did not visit the dentist and who did not use removable prosthesis. Conclusion: The concept of quality of life essentially incorporates the SPOH as a need in the evaluation of health outcomes. PMID- 29624969 TI - [Mechanism for efficient chromosome alignment in mitosis]. PMID- 29624970 TI - [Pathophysiological role of sigma-1 receptor in Amyotrophic lateral sclerosis]. PMID- 29624971 TI - [Novel mechanism of contact inhibition of cell movement and proliferation]. PMID- 29624972 TI - [ZIP tag-probe system: A fluorescence imaging tool for intercellular proteins]. PMID- 29624973 TI - [Investigation of raft dynamics by single-molecule observation of ganglioside probes]. PMID- 29624974 TI - Cost of hospitalizations for older adults at one IMSS regional general hospital AB - Background: Population aging has a direct impact on the increasing demand of health services and on medical care costs. The objective was to carry out a cost analysis of health care costs in older adults in a regional general hospital of the Instituto Mexicano del Seguro Social. Methods: A calculation of the costs was done based on a retrospective collection of health care data. Unit prices were used to estimate costs. These were reported in 2016 Mexican pesos. A cost analysis was carried out by means of a regression model. Explanatory variables were sex, age and comorbidity level, the latter measured by using the Charlson index. Results: The average cost of all the 509 patients was 34 769 Mexican pesos (SD = 2869 pesos). Age variable explains the costs; however, sex and comorbidity variables were not significant. Cost predictions with the statistical model show differences mainly by age. In the case of females, the model predicts greater costs compared with those of males. Costs for older adults of 85 years or more were greater than those for the group of younger people (75-84). Conclusion: The hospitalization costs estimated are high and they differ according to the age group. We suggest to make further research in order to know the factors associated with high hospital costs for this age group. PMID- 29624975 TI - [Biochemical simulations at the molecular level reveal novel effects of cellular environments]. PMID- 29624976 TI - [TMEPAI family that inhibits TGF-beta signal]. PMID- 29624977 TI - [Golgi stress response]. PMID- 29624978 TI - [Roles of ceramide and its metabolites in cutaneous tissues]. PMID- 29624979 TI - Inappropriate prescribing in older adults: Critical review of the literature and safety alerts AB - Background: Prescribing errors are a risk factor for patients to present adverse events and a strategy that has been incorporated into medical care to reduce them is the use of computer tools. The objective was to obtain the scientific basis for the development of prescribing error alerts for four chronic diseases with a higher prevalence in population >= 65 years. Methods: We reviewed the literature from 2010 to 2015 to obtain information about adverse events and adverse drug reactions associated with the use of drugs for the treatment of diabetes mellitus type 2 (DM2), hypertension, osteoarticular diseases (OD) and depression; the review included these databases: PubMed, OVID, Cochrane Library, LILACS, MEDES, Portal Mayores and SIETES. A group of physicians reviewed and analyzed the papers that were identified and in a meeting they developed the alerts for the treatments used in the included diseases. Results: We obtained 76 papers, out of which 47 were analyzed by the group of physicians, who eliminated 18. With the remaining 29 were integrated 55 alerts: five for DM2, 16 for hypertension, 15 for OD and 19 for depression. Conclusion: The safety alerts that were developed mainly were drug-drug interactions and adverse reactions. PMID- 29624980 TI - [Structure and function relationships of a heme sensor, HRI, and heme-based oxygen sensors, EcDOS, YddV and AfGcHK, and related heme sensors]. PMID- 29624981 TI - [Regulation and physiological functions of phospholipase C]. PMID- 29624983 TI - Flavonoids in the treatment of hypertension in geriatric patients AB - Background: Geriatric patients belong to a group over 65 years old. In general these patients present multiple chronic diseases and impairments with disability, body mass diminished and generalized fatigue. On the other hand, a high percentage of these patients have cardiovascular diseases. For this reason, several studies suggest that associated with drugs treatment consumption of natural products such as flavonoids, contribute to improve the quality of life of geriatric patients. The aim of this work is to review in literature the effect of flavonoids in vascular protection of older adults. Results: Literature review indicates that the intake of flavonoids significantly reduces the risk of hypertension and cardiovascular disease. Likewise, its consumption is associated with an improvement in endothelial function, since they act regulating different kinases like protein kinase B, nitric oxide synthase and the consequent synthesis of nitric oxide (NO), which leads to improve vasodilation. Finally, flavonoids also act to regulate the functioning of other kinases, phophodiesterases, ion channels diminishing vascular inflammation. Conclusion: Foods enriched in polyphenols improve endothelial function by promoting vascular dilation and lowering blood pressure. PMID- 29624982 TI - Clinical interventions in osteosarcopenic obesity: nutrition, physical and psychological activity AB - Osteosarcopenic obesity (OSO) is a condition associated with adverse outcomes in older adults. Since it is a condition which includes three tissues (obesity, sarcopenia and osteopenia/osteoporosis), it requires simultaneous and multidisciplinary clinical interventions to revert it. Until this moment, there have been published review articles only focused on nutrition or physical activity. However, we believe that assembling the existing evidence on potential treatments (nutritional intervention with micro- and macronutrients), physical activity, farmacological treatment for osteopenia/osteoporosis, possible farmacological treatment for sarcopenia, and, finally, psychological interventions focused on the treatment of psychiatric comorbidities (such as anxiety or depression) will help healthcare providers to improve the body composition of older adults. PMID- 29624984 TI - Geriatric intervention: Strategy to enhance the social roles of the elderly AB - At the global level, population aging is an issue that is becoming increasingly important due to the great impact it will have on the 21st century society. It is essential to develop policies, strategies and actions aimed at addressing the issues that will arise from the rapid increase in this segment of population. The aim of this paper is to propose the geriatric intervention as a strategy for the development of the older people in their community. We expose the epistemological frame, the theoretical and methodological support and the need to find a language to incorporate the older adult actively to society, in a condition of total equality. The moments of the situation analysis for strategic planning (explanatory, normative, strategic, tactical and operational) are explained. The model has been implemented in Chile and inspired the community development centers (CDC). It has been implemented as well in community interventions of social work. Working from this perspective implies to overcome the approaches that visualize older adults only as sick or disabled people, to assume the dynamics of life that these people experience in their communitarian spaces, as well as the possibility to continue with their development, to exercise citizenship, to demand respect for their rights and enhance their social roles. PMID- 29624985 TI - [Hexokinase 2 mediated cellular protection: interaction with Akt/mTORC1 to regulate mitochondrial protection and autophagy]. PMID- 29624986 TI - [Bioengineering utilizing microorganisms ]. PMID- 29624987 TI - [Analysis of ASK3 that regulates bidirectional osmotic stress response]. PMID- 29624988 TI - [Production of the neuron-specific enolase in astrocytes, but not in neurons, under the neuronal inflammation]. PMID- 29624989 TI - [A sexy scent of prostaglandin F(2alpha): Identification of pheromone receptor mediating male courtship behavior in zebrafish]. PMID- 29624990 TI - [Functional roles of VAMP family proteins in pancreatic beta-cells]. PMID- 29624991 TI - [Analyses of entry mechanisms of targeted viruses by pseudotype VSV system]. PMID- 29624992 TI - [Regulation of polarized trafficking by Rab small GTPases in epithelial cells]. PMID- 29624993 TI - [Proteoglycan linkeropathies caused by defect in glycosaminoglycan-protein linker region]. PMID- 29624994 TI - [Comprehensive analysis of disease-related glycosylation, leading to glyco therapy]. PMID- 29624995 TI - [The effect of polyunsaturated fatty acids on neocortical development]. PMID- 29624996 TI - [Overall architecture of the intraflagellar transport (IFT)-B complex revealed by a visible immunoprecipitation (VIP) assay]. PMID- 29624997 TI - [CNC-small Maf heterodimer: Unique cis-element recognition and biological functions]. PMID- 29624998 TI - [Molecular architecture and function of mitochondrial protein entry gate]. PMID- 29624999 TI - [Regulation of cellular function by ROCO family kinase LRRK1 in a manner dependent on its substrates]. PMID- 29625000 TI - [Chondroitin sulfate cluster involves in the binding specificity to collagen]. PMID- 29625001 TI - [Functional analyses of specific protein-protein interaction networks using affinity clamping technology]. PMID- 29625002 TI - [The Importance of N-glycosylation on integrins for its biological functions]. PMID- 29625003 TI - [AGIA tag system: a super-sensitive detection and capture peptide tag suitable for cell biology]. PMID- 29625004 TI - [Cell-free translation system: Development in biochemistry and advance in synthetic biology]. PMID- 29625005 TI - One-Step Preparation of pH-Responsive Polymeric Nanogels as Intelligent Drug Delivery Systems for Tumor Therapy. AB - In this work, pH-responsive polypeptide-based nanogels are reported as potential drug delivery systems. By the formation of pH-sensitive benzoic imine bonds, pH responsive nanogels are constructed using hydrophilic methoxy poly(ethylene glycol)- b-poly[ N-[ N-(2-aminoethyl)-2-aminoethyl]-l-glutamate] (MPEG- b-PNLG) and hydrophobic terephthalaldehyde (TPA) as a cross-linker. At pH 7.4, MPEG- b PNLG nanogels exhibit high stabilities with hydrophobic inner cores, which allow encapsulation of hydrophobic therapeutic agents. Under tumoral acidic environments (pH ~6.4), the cleavage of benzoic imine bonds induces the destruction of MPEG- b-PNLG nanogels and leads to rapid release of their payloads. The formation and pH sensitivity of the nanogels are investigated by dynamic light scattering. These nanogels exhibit excellent stabilities in the presence of salt or against dilution. The globular morphologies of the nanogels are confirmed using transmission electron microscopy. Doxorubicin is used as a model drug to evaluate drug encapsulation and release. Finally, the anticancer activities of the drug-encapsulated nanogels are assessed in vitro. PMID- 29625006 TI - SpyCatcher-NTEV: A Circularly Permuted, Disordered SpyCatcher Variant for Less Trace Ligation. AB - The SpyTag/SpyCatcher reaction has emerged as a powerful way for bioconjugation, but it leaves a folded complex in the product after the formation of the isopeptide bond. To vary the location of the reactive residue and reduce the size of the complex and its potential immunogenicity, we engineer two circularly permuted SpyCatcher variants, SpyCatcher-N and SpyCatcher-NTEV, the latter of which possesses a TEV-recognition site for removal of the fragment containing the catalytic site. Surprisingly, both variants are found to be disordered in solution, yet still retain the ability to form an ordered complex upon reaction with SpyTag with second-order rate constants of ~10 M-1 s-1. Cellular expression of a telechelic protein bearing SpyCatcher-NTEV at the N-terminus and SpyTag at the C-terminus gives both cyclized and chain-extended products. Notably, the monomers exist almost exclusively in the cyclic form owing to its high reactivity in vivo. The fragment containing the catalytic site of SpyCatcher-NTEV can then be removed by TEV digestion, giving a circular protein with minimal trace from the ligation reaction. The plasticity of SpyTag/SpyCatcher reactive pair has promised an ever-expanding toolbox of genetically encoded peptide-protein reaction with versatile features. PMID- 29625007 TI - Synthetic Gene Network with Positive Feedback Loop Amplifies Cellulase Gene Expression in Neurospora crassa. AB - Second-generation or lignocellulosic biofuels are a tangible source of renewable energy, which is critical to combat climate change by reducing the carbon footprint. Filamentous fungi secrete cellulose-degrading enzymes called cellulases, which are used for production of lignocellulosic biofuels. However, inefficient production of cellulases is a major obstacle for industrial-scale production of second-generation biofuels. We used computational simulations to design and implement synthetic positive feedback loops to increase gene expression of a key transcription factor, CLR-2, that activates a large number of cellulases in a filamentous fungus, Neurospora crassa. Overexpression of CLR-2 reveals previously unappreciated roles of CLR-2 in lignocellulosic gene network, which enabled simultaneous induction of approximately 50% of 78 lignocellulosic degradation-related genes in our engineered Neurospora strains. This engineering results in dramatically increased cellulase activity due to cooperative orchestration of multiple enzymes involved in the cellulose degradation pathway. Our work provides a proof of principle in utilizing mathematical modeling and synthetic biology to improve the efficiency of cellulase synthesis for second generation biofuel production. PMID- 29625008 TI - Study of the Lyase Activity of Human DNA Polymerase beta Using Analogues of the Intermediate Schiff Base Complex. AB - DNA polymerase beta (Pol beta) participates in mammalian base excision repair. The enzyme has a two-domain architecture, reflecting its dual functionality. The polymerase activity, which replaces damaged nucleosides removed during an initial excision process, is within the C-terminal 31 kDa domain, while the N-terminal 8 kDa domain participates in a lyase function, working to remove a 5'-deoxyribose phosphate (5'-dRP) moiety from the damaged DNA substrate. The currently accepted mechanism of the lyase reaction involves a transient covalent enzyme-DNA intermediate in the form of a Schiff base connecting Lys72 of the enzyme with the 5'-dRP moiety. The Schiff base intermediate is resolved via a beta-elimination reaction, initiated by abstraction of a C2'-H atom from the 5'-dRP moiety. Presently, we describe the preparation of three Pol beta enzymes modified at position 72 with aminooxy or hydrazinyl analogues of lysine. These enzymes form transient covalent bonds with the 5'-dRP moiety of the damaged DNA, in the form of an oxime or hydrazone, respectively. Both types of enzyme DNA intermediates are ultimately resolved by the lyase activities of each of the modified enzymes. Unsurprisingly, the formation and resolution of these E-S complexes proceed with diminished kinetics, and with an altered pH profile. The performed experiments provide additional support for Schiff base formation as an obligatory intermediate on the pathway to DNA repair, as well as for the proposed participation of Lys72 in effecting opening of the 5'-dRP ring via protonation of the ring oxygen atom, and for complex resolution via a beta-elimination reaction. PMID- 29625009 TI - D iCE: Diastereomeric in Silico Chiral Elucidation, Expanded DP4 Probability Theory Method for Diastereomer and Structural Assignment. AB - NMR chemical shift prediction at the B3LYP/cc-pVDZ level of theory was used to develop a highly accurate probability theory algorithm for the determination of the stereochemistry of diastereomers as well as the regiochemistry. DFT-GIAO calculations were performed for each conformer using geometry optimization and a CPCM solvent model. Boltzmann averaged shielding constants were converted to chemical shifts for 1H and 13C, using the generalized linear scaling terms determined in four different solvents for 1H and 13C and extended to 15N in DMSO. The probability theory algorithm, D iCE, was based on the DP4 method and developed for 1H, 13C, and 15N NMR using individual and combined probability data. The chemical shift calculation errors were fitted to a Student's t distribution for 1H and 13C and a normal distribution for 15N. The application yielded a high accuracy for structural assignment with a low computational cost. PMID- 29625010 TI - On Grounds of the Memory Effect in Amorphous and Crystalline Apatite: Kinetics of Crystallization and Biological Response. AB - Memory effects, despite being intrinsic to biological systems, are rarely potentiated in biomaterials. By exploring the transition between amorphous calcium phosphate (ACP) and hydroxyapatite (HAp) from different empirical angles, here, we attempt to set the basis for elicitation of structural memory effects in CPs. Two CPs precipitated under different degrees of saturation (DS), yielding HAp at a low DS and ACP at a high DS, were shown to evolve into structures with a high level of crystallographic similarity after their prolonged aging in the solution and served as the basis for this study. Amorphous-to-crystalline transition was abrupt in both precipitates, indicating an autocatalytic process preceded by considerable nucleation lag times, but it was more dynamic and proceeded in multiple stages in the precipitate formed at a higher DS, involving a greater degree of lattice rearrangements. ACP was found to exist in one of the two stoichiometrically and crystallographically different forms, one of which, amounting to >=60 wt %, resembled tricalcium phosphate and transformed to HAp through the surface dissolution/reprecipitation mechanism and the other one, amounting to <=20 wt %, was apatitic, enabling the transformation of ACP to HAp via martensitic, bulk lattice reordering phenomena. Large density of stacking faults was responsible for the comparatively high lattice strain, the property to which biogenic apatite owes its ability to accommodate foreign ions and act as a mineral reservoir for the body. Being the precursor for biogenic apatite during biomineralization and a thermodynamically logical intermediate in the ripening of HAp per the Ostwald law of stages, ACP proved to be more prone to structural transformation than the final and the most stable of the CP phases in this sequence of events: HAp. Amorphized upon gelation, two CPs transformed into HAp, albeit at different rates, which were higher for the material that had been crystalline prior to amorphization than for the one that had initially been amorphous, indicating the presence of a definite memory effect. The two HAp powders with different histories of formation also elicited different biological responses, including a Runx2 transcription factor expression in MC3T3-E1 osteoblasts, cell uptake efficiency, and antibacterial activity, extending the memory effect in HAp to the biological domain. The biological response was typically indistinct between the final products and their respective precursors but markedly different between the two products obtained by following different formation paths, confirming the presence of the given memory effect. It is suggested that the key to explaining the difference in the response between the materials differing in their route of formation lies in the direct dependence between the DS at which precipitation occurs and the rate of exchange of hydrated ions and ionic clusters across the particle surface in contact with a solution. PMID- 29625011 TI - Construction of Porphyrin-Containing Metallacycle with Improved Stability and Activity within Mesoporous Carbon. AB - The successful construction of porphyrin functionalized metallacycle in the confined cavity of mesoporous carbon FDU-16 (3?C) is presented in this study. Because of high dispersity of metallacycles within the mesoporous cavities, the stability and activity of porphyrin-containing metallacycles were obviously improved. For example, 1O2 generation efficiency of 3?C is ca. 6-fold faster than that of free metallaycles in solution. Thus, the resultant hybrid material has been successfully employed as a heterogeneous catalyst for photooxidation of sulfides. PMID- 29625012 TI - Home-Based Physical Activity Program Improves Depression and Anxiety in Older Adults. AB - BACKGROUND: Late-life depression and anxiety among older adults is an important public health concern. This study examined the effect of a DVD-delivered exercise intervention on the secondary outcomes of depression and anxiety in older adults and the extent to which physical self-worth mediated the relationship between leisure-time physical activity and depression and anxiety. METHODS: Older adults (N = 307) were randomized to a 6-month flexibility, toning, and balance DVD (FlexToBaTM, FTB) or healthy aging DVD control. Self-reported physical activity and questionnaires were administered at baseline and postintervention. Statistical analyses were conducted in the total sample and in a subsample of participants with elevated levels of depression or anxiety. RESULTS: FTB participants with elevated depression and anxiety symptoms at baseline had significantly greater reductions in depression and anxiety (d = 1.66 and 2.90) than the control condition (d = 0.77 and 0.73). The effect of physical activity on depression and anxiety was partially mediated by increases in physical self worth in the total sample but not in those with elevated depression or anxiety. CONCLUSION: A home-based physical activity intervention may be a viable treatment for reducing depression and anxiety in older adults with elevated baseline scores. PMID- 29625015 TI - Rapidly Progressive Cystic Lung Disease. PMID- 29625014 TI - Group Influences on Engaging Self-Control: Children Delay Gratification and Value It More When Their In-Group Delays and Their Out-Group Doesn't. AB - Self-control emerges in a rich sociocultural context. Do group norms around self control influence the degree to which children use it? We tested this possibility by assigning 3- to 5-year-old children to a group and manipulating their beliefs about in-group and out-group behavior on the classic marshmallow task. Across two experiments, children waited longer for two marshmallows when they believed that their in-group waited and their out-group did not, compared with children who believed that their in-group did not wait and their out-group did. Group behavior influenced children to wait more, not less, as indicated by comparisons with children in a control condition who were assigned to a group but received no information about either groups' delay behavior (Experiment 1). Children also subsequently valued delaying gratification more if their in-group waited and their out-group did not (Experiment 2). Childhood self-control behavior and related developmental outcomes may be shaped by group norms around self-control, which may be an optimal target for interventions. PMID- 29625013 TI - Successful Establishment of Primary Type II Alveolar Epithelium with 3D Organotypic Coculture. AB - Alveolar type II (AT2) epithelial cells are uniquely specialized to produce surfactant in the lung and act as progenitor cells in the process of repair after lung injury. AT2 cell injury has been implicated in several lung diseases, including idiopathic pulmonary fibrosis and bronchopulmonary dysplasia. The inability to maintain primary AT2 cells in culture has been a significant barrier in the investigation of pulmonary biology. We have addressed this knowledge gap by developing a three-dimensional (3D) organotypic coculture using primary human fetal AT2 cells and pulmonary fibroblasts. Grown on top of matrix-embedded fibroblasts, the primary human AT2 cells establish a monolayer and have direct contact with the underlying pulmonary fibroblasts. Unlike conventional two dimensional (2D) culture, the structural and functional phenotype of the AT2 cells in our 3D organotypic culture was preserved over 7 days of culture, as evidenced by the presence of lamellar bodies and by production of surfactant proteins B and C. Importantly, the AT2 cells in 3D cocultures maintained the ability to replicate, with approximately 60% of AT2 cells staining positive for the proliferation marker Ki67, whereas no such proliferation is evident in 2D cultures of the same primary AT2 cells. This organotypic culture system enables interrogation of AT2 epithelial biology by providing a reductionist in vitro model in which to investigate the response of AT2 epithelial cells and AT2 cell fibroblast interactions during lung injury and repair. PMID- 29625016 TI - Feeling Is Believing: Inspiration Encourages Belief in God. AB - Even without direct evidence of God's existence, about half of the world's population believes in God. Although previous research has found that people arrive at such beliefs intuitively instead of analytically, relatively little research has aimed to understand what experiences encourage or legitimate theistic belief systems. Using cross-cultural correlational and experimental methods, we investigated whether the experience of inspiration encourages a belief in God. Participants who dispositionally experience more inspiration, were randomly assigned to relive or have an inspirational experience, or reported such experiences to be more inspirational all showed stronger belief in God. These effects were specific to inspiration (instead of adjacent affective experiences) and a belief in God (instead of other empirically unverifiable claims). Being inspired by someone or something (but not inspired to do something) offers a spiritually transcendent experience that elevates belief in God, in part because it makes people feel connected to something beyond themselves. PMID- 29625017 TI - Adipose transcriptome analysis provides novel insights into molecular regulation of prolonged fasting in northern elephant seal pups. AB - The physiological and cellular adaptations to extreme fasting in northern elephant seals ( Mirounga angustirostris, NES) are remarkable and may help to elucidate endocrine mechanisms that regulate lipid metabolism and energy homeostasis in mammals. Recent studies have highlighted the importance of thyroid hormones in the maintenance of a lipid-based metabolism during prolonged fasting in weaned NES pups. To identify additional molecular regulators of fasting, we used a transcriptomics approach to examine changes in global gene expression profiles before and after 6-8 wk of fasting in weaned NES pups. We produced a de novo assembly and identified 98 unique protein-coding genes that were differentially expressed between early and late fasting. Most of the downregulated genes were associated with lipid, carbohydrate, and protein metabolism. A number of downregulated genes were also associated with maintenance of the extracellular matrix, consistent with tissue remodeling during weight loss and the multifunctional nature of blubber tissue, which plays both metabolic and structural roles in marine mammals. Using this data set, we predict potential mechanisms by which NES pups sustain metabolism and regulate adipose stores throughout the fast, and provide a valuable resource for additional studies of extreme metabolic adaptations in mammals. PMID- 29625018 TI - Sugar sensor genes in the murine gastrointestinal tract display a cephalocaudal axis of expression and a diurnal rhythm. AB - Distributed along the length of the gastrointestinal (GI) tract are nutrient sensing cells that release numerous signaling peptides influencing GI function, nutrient homeostasis and energy balance. Recent studies have shown a diurnal rhythm in GI nutrient sensing, but the mechanisms responsible for rhythmicity are poorly understood. In this report we studied murine GI sugar sensor gene and protein expression levels in the morning (7 AM) and evening (7 PM). Sweet taste receptor ( tas1r2/tas1r3/gnat3/gnat1) sugar transporter ( slc5a1, slc2a2, slc2a5) and putative sugar sensor ( slc5a4a and slc5a4b) gene expression levels were highest in tongue and proximal and distal small intestine, respectively. Clock gene ( cry2/arntl) activity was detected in all regions studied. Slc5a4a and slc5a4b gene expression showed clear diurnal rhythmicity in the small intestine and stomach, respectively, although no rhythmicity was detected in SGLT3 protein expression. Tas1r2, tas1r3, gnat1, and gcg displayed a limited rhythm in gene expression in proximal small intestine. Microarray analysis revealed a diurnal rhythm in gut peptide gene expression in tongue (7 AM vs. 7 PM) and in silico promoter analysis indicated intestinal sugar sensors and transporters possessed the canonical E box elements necessary for clock gene control over gene transcription. In this report we present evidence of a diurnal rhythm in genes that are responsible for intestinal nutrient sensing that is most likely controlled by clock gene activity. Disturbances in clock gene/nutrient sensing interactions may be important in the development of diet-related diseases, such as obesity and diabetes. PMID- 29625019 TI - Beta-hydroxybutyrate infusion identifies acutely differentially expressed genes related to metabolism and reproduction in the hypothalamus and pituitary of castrated male sheep. AB - To identify molecular pathways that couple metabolic imbalances and reproduction, we randomly assigned 10 castrated male sheep to be centrally injected into the lateral ventricle through intracerebroventricular cannulas with 1 ml of beta hydroxybutyric acid sodium salt solution (BHB; 12,800 umol/l) or saline solution (CON; 0.9% NaCl). Approximately 2 h postinjection, sheep were humanely euthanized, and hypothalamus and pituitary tissues were harvested for transcriptome characterization by RNA sequencing. RNA was extracted from the hypothalamus and pituitary and sequenced at a high depth (hypothalamus: 468,912,732 reads; pituitary: 515,106,092 reads) with the Illumina Hi-Seq 2500 platform and aligned to Bos taurus and Ovis aries genomes. Of the total raw reads, 87% (hypothalamus) and 90.5% (pituitary) mapped to the reference O. aries genome. Within these read sets, ~56% in hypothalamus and 69% in pituitary mapped to either known or putative protein coding genes. Fragments per kilobase of transcripts per million normalized counts were averaged and ranked to identify the transcript expression level. Gene Ontology analysis (DAVID Bioinformatics Resources) was utilized to identify biological process functions related to genes shared between tissues, as well as functional categories with tissue-specific enrichment. Between CON- and BHB-treated sheep, 11 and 44 genes were differentially expressed (adj. P < 0.05) within the pituitary and hypothalamus, respectively. Functional enrichment analyses revealed BHB altered expression of genes in pathways related to stimulus perception, inflammation, and cell cycle control. The set of genes altered by BHB creates a foundation from which to identify the signaling pathways that impact reproduction during metabolic imbalances. PMID- 29625020 TI - Comparison of Axillary and Temporal Artery Thermometry in Preterm Neonates. AB - OBJECTIVE: To compare the accuracy of infrared temporal artery thermometry with axillary thermometry in a cohort of preterm neonates between 28 and 36 weeks postmenstrual age. DESIGN: Descriptive repeated measures design with randomization to temperature measurement order. SETTING: Level III NICU in the Central/Southeastern United States. PARTICIPANTS: Sixty-eight neonates born between 28 weeks and 36 weeks postmenstrual age cared for in incubators or open cribs. METHODS: Neonates were randomly assigned to temperature measurement order (axillary followed by temporal artery or temporal artery followed by axillary). Temperature pairs were taken once during the day shift and once during the night shift. Behavioral states were assessed before, during, and after temperature measurement. RESULTS: Neonates were predominantly female (64.7%) with a mean age of 6.6 days and a mean gestational age of 32.7 weeks, and most were cared for in incubators (n = 55). Noninferiority was observed between the two temperature methods (Holm-Bonferroni criterion = .025, p < .001). There was no statistically significant difference in the behavioral states of the neonates between the two temperature methods. It took nurses significantly longer to use the axillary thermometer than to use the temporal artery thermometer (p < .001). CONCLUSION: Temporal artery temperature measurements were as accurate as axillary temperature measurements in low-birth-weight neonates in the NICU. Nurses spent less time measuring with the temporal artery method than with the axillary method. PMID- 29625021 TI - Hepatitis C viral load in HCV-monoinfected and HCV/HIV-1-, HCV/HTLV-1/-2-, and HCV/HIV/HTLV-1/-2-co-infected patients from Sao Paulo, Brazil. AB - Co-infections of hepatitis C virus (HCV) and either human immunodeficiency virus type 1 (HIV-1), human T-cell lymphotropic virus type 1 (HTLV-1) or type 2 (HTLV 2) have been described as having an impact on HCV viremia and subsequent disease progression. HCV load in serum samples from 622 patients (343 males, 279 females; median age 50.8 years) from Sao Paulo/southeast Brazil was analyzed using the Abbott Real Time HCV assay (Abbott Molecular Inc., IL, USA). Samples were obtained from HCV-monoinfected (n=548), HCV/HIV-1- (n=41), HCV/HTLV-1- (n=16), HCV/HTLV-2- (n=8), HCV/HIV/HTLV-1- (n=4), and HCV/HIV/HTLV-2-co-infected (n=5) patients, and results were compared among the groups and according to sex. The median HCV load in HCV-monoinfected patients was 5.23 log10 IU/mL and 0.31 log10 higher in men than in women. Increases in viral load of 0.51 log10, 0.54 log10, and 1.43 log10 IU/mL were detected in HCV/HIV-1-, HCV/HTLV-1- and HCV/HIV/HTLV-1 co-infected individuals, respectively, compared with HCV-monoinfected counterparts. In contrast, compared to HCV/HIV co-infected patients, HCV/HTLV-2 co-infected patients had an HCV load of 5.0 log10 IU/mL, whereas HCV/HIV/HTLV-2 co-infected patients had a median load 0.37 log10 IU/mL lower. Significant differences in HCV loads were detected, with males and HCV/HIV-1- and HCV/HIV/HTLV-1-co-infected patients presenting the highest values. Conversely, females and HCV/HTLV-2-co-infected patients exhibited lower HCV loads. Overall, HCV viremia is increased in HIV and/or HTLV-1-co-infection and decreased in HTLV 2 co-infection. PMID- 29625022 TI - L-GATOR: Genetic Association Testing for a Longitudinally Measured Quantitative Trait in Samples with Related Individuals. AB - In complex-trait mapping, when each subject has multiple measurements of a quantitative trait over time, power for detecting genetic association can be gained by the inclusion of all measurements and not just single time points or averages in the analysis. To increase power and control type 1 error, one should account for dependence among observations for a single individual as well as dependence between observations of related individuals if they are present in the sample. We propose L-GATOR, a retrospective, mixed-effects method for association mapping of longitudinally measured traits in samples with related individuals. L GATOR allows arbitrary time points for different individuals, incorporates both time-varying and static covariates, and properly addresses various types of dependence. In simulations, we show that L-GATOR outperforms existing prospective methods in terms of both type 1 error and power when there is phenotype model misspecification or missing data. Compared with the previously proposed longGWAS method, L-GATOR was more than ten times faster for association testing in our simulations and almost 100 times faster for parameter estimation. L-GATOR is applicable to essentially arbitrary combinations of related and unrelated individuals, including small families as well as large, complex pedigrees. We apply the method to data from the Framingham Heart Study to identify association between longitudinal systolic blood pressure measurements and genome-wide SNPs. Of the smallest p values, one-third occur in or near genes that have been previously identified as associated with pulse pressure (such as PIK3CG) and systolic and diastolic blood pressure (such as C10orf107), showing that L-GATOR is able to prioritize relevant loci in a genome screen. PMID- 29625023 TI - Identification of Misclassified ClinVar Variants via Disease Population Prevalence. AB - There is a significant interest in the standardized classification of human genetic variants. We used whole-genome sequence data from 10,495 unrelated individuals to contrast population frequency of pathogenic variants to the expected population prevalence of the disease. Analyses included the ACMG recommended 59 gene-condition sets for incidental findings and 463 genes associated with 265 OrphaNet conditions. A total of 25,505 variants were used to identify patterns of inflation (i.e., excess genetic risk and misclassification). Inflation increases as the level of evidence supporting the pathogenic nature of the variant decreases. We observed up to 11.5% of genetic disorders with inflation in pathogenic variant sets and up to 92.3% for the variant set with conflicting interpretations. This improved to 7.7% and 57.7%, respectively, after filtering for disease-specific allele frequency. The patterns of inflation were replicated using public data from more than 138,000 genomes. The burden of rare variants was a main contributing factor of the observed inflation, indicating collective misclassified rare variants. We also analyzed the dynamics of re classification of variant pathogenicity in ClinVar over time, which indicates progressive improvement in variant classification. The study shows that databases include a significant proportion of wrongly ascertained variants; however, it underscores the critical role of ClinVar to contrast claims and foster validation across submitters. PMID- 29625025 TI - LTBP3 Pathogenic Variants Predispose Individuals to Thoracic Aortic Aneurysms and Dissections. AB - The major diseases affecting the thoracic aorta are aneurysms and acute dissections, and pathogenic variants in 11 genes are confirmed to lead to heritable thoracic aortic disease. However, many families in which multiple members have thoracic aortic disease do not have alterations in the known aortopathy genes. Genes highly expressed in the aorta were assessed for rare variants in exome sequencing data from such families, and compound rare heterozygous variants (p.Pro45Argfs*25 and p.Glu750*) in LTBP3 were identified in affected members of one family. A homozygous variant (p.Asn678_Gly681delinsThrCys) that introduces an additional cysteine into an epidermal growth factor (EGF)-like domain in the corresponding protein, latent TGF-beta binding protein (LTBP-3), was identified in a second family. Individuals with compound heterozygous or homozygous variants in these families have aneurysms and dissections of the thoracic aorta, as well as aneurysms of the abdominal aorta and other arteries, along with dental abnormalities and short stature. Heterozygous carriers of the p.Asn678_Gly681delinsThrCys variant have later onset of thoracic aortic disease, as well as dental abnormalities. In these families, LTBP3 variants segregated with thoracic aortic disease with a combined LOD score of 3.9. Additionally, heterozygous rare LTBP3 variants were found in individuals with early onset of acute aortic dissections, and some of these variants disrupted LTBP-3 levels or EGF-like domains. When compared to wild-type mice, Ltbp3-/- mice have enlarged aortic roots and ascending aortas. In summary, homozygous LTBP3 pathogenic variants predispose individuals to thoracic aortic aneurysms and dissections, along with the previously described skeletal and dental abnormalities. PMID- 29625026 TI - Biallelic Mutations in MRPS34 Lead to Instability of the Small Mitoribosomal Subunit and Leigh Syndrome. PMID- 29625024 TI - A Common Type 2 Diabetes Risk Variant Potentiates Activity of an Evolutionarily Conserved Islet Stretch Enhancer and Increases C2CD4A and C2CD4B Expression. AB - Genome-wide association studies (GWASs) and functional genomics approaches implicate enhancer disruption in islet dysfunction and type 2 diabetes (T2D) risk. We applied genetic fine-mapping and functional (epi)genomic approaches to a T2D- and proinsulin-associated 15q22.2 locus to identify a most likely causal variant, determine its direction of effect, and elucidate plausible target genes. Fine-mapping and conditional analyses of proinsulin levels of 8,635 non-diabetic individuals from the METSIM study support a single association signal represented by a cluster of 16 strongly associated (p < 10-17) variants in high linkage disequilibrium (r2 > 0.8) with the GWAS index SNP rs7172432. These variants reside in an evolutionarily and functionally conserved islet and beta cell stretch or super enhancer; the most strongly associated variant (rs7163757, p = 3 * 10-19) overlaps a conserved islet open chromatin site. DNA sequence containing the rs7163757 risk allele displayed 2-fold higher enhancer activity than the non risk allele in reporter assays (p < 0.01) and was differentially bound by beta cell nuclear extract proteins. Transcription factor NFAT specifically potentiated risk-allele enhancer activity and altered patterns of nuclear protein binding to the risk allele in vitro, suggesting that it could be a factor mediating risk allele effects. Finally, the rs7163757 proinsulin-raising and T2D risk allele (C) was associated with increased expression of C2CD4B, and possibly C2CD4A, both of which were induced by inflammatory cytokines, in human islets. Together, these data suggest that rs7163757 contributes to genetic risk of islet dysfunction and T2D by increasing NFAT-mediated islet enhancer activity and modulating C2CD4B, and possibly C2CD4A, expression in (patho)physiologic states. PMID- 29625027 TI - Bi-allelic Mutations in KLHL7 Cause a Crisponi/CISS1-like Phenotype Associated with Early-Onset Retinitis Pigmentosa. PMID- 29625028 TI - Effectiveness of Drainage in Mandibular Third Molar Surgery: A Systematic Review and Meta-Analysis. AB - PURPOSE: The purpose of this study was to provide an evidence-based evaluation of the impact of surgical drainage after the removal of mandibular third molars. MATERIALS AND METHODS: The Medline (PubMed), Cochrane Library, and Web of Science databases were searched to identify randomized controlled trials up to September 1, 2017. Postoperative variables, including facial swelling, trismus, and pain, were calculated early (2 to 3 days) and late (5 to 7 days) after the removal of impacted mandibular third molars. Weighted mean differences for trismus and standardized mean differences (SMDs) for swelling and pain were pooled for the included studies. RESULTS: The samples consisted of 592 extractions (297 with surgical drainage and 295 controls) in 409 participants. The included studies were published from 1988 to 2016. Participants who received surgical drainage had significantly less facial swelling during the early stage (SMD, -0.46; 95% confidence interval [CI], -0.67 to -0.26; P < .0001) and the late stage (SMD, 0.36; 95% CI, -0.55 to -0.16; P = .0004) after the removal of an impacted mandibular third molar. They also had better mouth opening than controls during the early and late stages (early MD, 5.55 mm; 95% CI, 2.31-8.79; P = .0008; late MD, 2.38 mm; 95% CI, 1.47-3.29; P < .0001). The level of pain was significantly different between the 2 groups in the early stage (SMD, -0.55; 95% CI, -1.00 to 0.10; P = .01); however, there were no significant differences in the late stage (SMD, -0.13; 95% CI, -0.38 to 0.12; P = .30). CONCLUSION: The use of surgical drainage has an obviously positive effect on postoperative reactions after the removal of a mandibular third molar. Given the need for additional time for clinic visits, surgical drainage presents an alternative for the perioperative management of impacted mandibular third molar surgery, especially in cases of a fully bony tooth with poor drainage. PMID- 29625029 TI - How Much Noise Is an Oral and Maxillofacial Surgeon Exposed to? AB - PURPOSE: A common concern among oral and maxillofacial surgeons (OMSs) is progressive hearing loss throughout their careers. Although this has not been critically studied, there could be several factors that contribute to this detriment, including drills, saws, suction, music, and other sounds within the closed operating environment. This study observed the intensity of noise in operating rooms (ORs) and clinical settings during the use of drills, saws, surgical handpieces, and other tools. MATERIALS AND METHODS: In this cross sectional study, sound intensities were measured in decibels using a CEM DT-8851 industrial high-accuracy digital sound noise level meter data logger in clinics and ORs. The device measured sound intensities during the entire duration of the procedures. The recorded drilling periods were extracted from the data and t tests were run to determine whether a statistically relevant difference existed between the non-drilling and drilling periods. In addition, the duration during which intensity was greater than or equal to 85 dB was measured. RESULTS: Fifty procedures were recorded in the clinical setting and 50 were recorded in the OR. The results of this study proved that OMSs were indeed exposed to sound intensities in decibels that exceeded Occupational Safety and Health Administration (OSHA) guidelines, but these exposures occurred less than 1% of the time. The maximum recorded intensities in the clinic and OR were during a non drilling period and these were attributed to suction. CONCLUSION: OSHA guidelines were exceeded in clinical and OR settings, but the results were not relevant. The authors believe this is a very promising study for future endeavors. They found that the threshold set by OSHA was exceeded at points during surgical procedures in the clinic and OR. This will prompt future studies focusing on recordings when suction is used and longitudinal studies of individual OMSs. PMID- 29625030 TI - Is Counterclockwise Rotation With Double Jaw Orthognathic Surgery Stable in the Long-Term in Hyperdivergent Class III Patients? AB - PURPOSE: To evaluate the long-term postsurgical stability of counterclockwise rotation of the occlusal plane (OP) in double-jaw orthognathic surgery in patients with hyperdivergent Class III malocclusion. MATERIALS AND METHODS: This retrospective cohort study evaluated the postsurgical stability of orthognathic surgery in patients with skeletal Class III malocclusion and counterclockwise rotation of the maxillomandibular complex with an OP change of at least -2 degrees . Patients were evaluated with lateral cephalometric analysis before surgery, immediately after surgery, and at longest follow-up. The primary predictor variable was the change in angle of the OP and the Frankfort horizontal (FH) after surgery. The primary outcome variable was stability of the OP at longest follow-up. Other study variables were age, gender, and the following cephalometric measurements: mandibular plane angle; gonial angle; angle formed by the sella, nasion, and B point; maxillary height; angle of the palatal plane to the line connecting the sella and nasion; and distances of the posterior nasal spine and A point to the FH and of the A point to the vertical line passing from the nasion. The Mann-Whitney U test was used to compare stability between groups because the variables were not normally distributed. Bonferroni correction was used to evaluate P values. The chi2 test and Fisher exact test, where appropriate, were used to compare the proportions of groups. A P value less than .05 was accepted as statistically significant. RESULTS: The sample was composed of 15 adult patients (mean age at surgery, 23.5 yr; 40% men). The median duration of follow-up was 48 months (interquartile range, 36 to 60 months). The groups had similar demographic properties and similar surgical changes. Ten patients showed very stable results with an OP-FH change no greater than 1 degrees . Four patients showed unstable results with an OP-FH change of 2.25 +/- 0.5 degrees during the follow-up period. The change in the mandibular plane angle was notable between patients with stability and those with instability, which was the variable most affected by relapse of the OP. CONCLUSION: This study found long term postsurgical skeletal stability of counterclockwise rotation of the OP during double-jaw orthognathic surgery in patients with high angle Class III malocclusion after a median follow-up of 48 months. PMID- 29625031 TI - In a Class of Its Own: A New Family of Deubiquitinases Promotes Genome Stability. AB - Several proteins are ubiquitylated in response to genotoxic stress; however, the roles of deubiquitinases (DUBs) in reversing these modifications are less well characterized. Two independent studies by Kwasna et al. (2018) and Haahr et al. (2018) identify a new type of cysteine protease DUB called ZUFSP, which cleaves K63-linked polyubiquitin chains at DNA damage sites to promote genome stability. PMID- 29625032 TI - Separating Actin-Dependent Chemokine Receptor Nanoclustering from Dimerization Indicates a Role for Clustering in CXCR4 Signaling and Function. AB - A current challenge in cell motility studies is to understand the molecular and physical mechanisms that govern chemokine receptor nanoscale organization at the cell membrane, and their influence on cell response. Using single-particle tracking and super-resolution microscopy, we found that the chemokine receptor CXCR4 forms basal nanoclusters in resting T cells, whose extent, dynamics, and signaling strength are modulated by the orchestrated action of the actin cytoskeleton, the co-receptor CD4, and its ligand CXCL12. We identified three CXCR4 structural residues that are crucial for nanoclustering and generated an oligomerization-defective mutant that dimerized but did not form nanoclusters in response to CXCL12, which severely impaired signaling. Overall, our data provide new insights to the field of chemokine biology by showing that receptor dimerization in the absence of nanoclustering is unable to fully support CXCL12 mediated responses, including signaling and cell function in vivo. PMID- 29625034 TI - Injury Activates Ca2+/Calmodulin-Dependent Phosphorylation of JAV1-JAZ8-WRKY51 Complex for Jasmonate Biosynthesis. AB - Insect herbivory causes severe damage to plants and threatens the world's food production. During evolutionary adaptation, plants have evolved sophisticated mechanisms to rapidly accumulate a key defense hormone, jasmonate (JA), that triggers plant defense against herbivory. However, little is known about how plants initially activate JA biosynthesis at encounter with herbivory. Here, we uncover that a novel JAV1-JAZ8-WRKY51 (JJW) complex controls JA biosynthesis to defend against insect attack. In healthy plants, the JJW complex represses JA biosynthesis to restrain JA at a low basal level to ensure proper plant growth. When plants are injured by insect attack, injury rapidly triggers calcium influxes to activate calmodulin-dependent phosphorylation of JAV1, which disintegrates JJW complex and activates JA biosynthesis, giving rise to the rapid burst of JA for plant defense. Our findings offer new insights into the highly sophisticated defense systems evolved by plants to defend against herbivory. PMID- 29625035 TI - Inter-chromosomal Contact Properties in Live-Cell Imaging and in Hi-C. PMID- 29625033 TI - Galectins Control mTOR in Response to Endomembrane Damage. AB - The Ser/Thr protein kinase mTOR controls metabolic pathways, including the catabolic process of autophagy. Autophagy plays additional, catabolism independent roles in homeostasis of cytoplasmic endomembranes and whole organelles. How signals from endomembrane damage are transmitted to mTOR to orchestrate autophagic responses is not known. Here we show that mTOR is inhibited by lysosomal damage. Lysosomal damage, recognized by galectins, leads to association of galectin-8 (Gal8) with the mTOR apparatus on the lysosome. Gal8 inhibits mTOR activity through its Ragulator-Rag signaling machinery, whereas galectin-9 activates AMPK in response to lysosomal injury. Both systems converge upon downstream effectors including autophagy and defense against Mycobacterium tuberculosis. Thus, a novel galectin-based signal-transduction system, termed here GALTOR, intersects with the known regulators of mTOR on the lysosome and controls them in response to lysosomal damage. VIDEO ABSTRACT. PMID- 29625036 TI - Coordinated Activity of Y Family TLS Polymerases and EXO1 Protects Non-S Phase Cells from UV-Induced Cytotoxic Lesions. PMID- 29625037 TI - A Much-Needed Boost for the Dwindling Antibiotic Pipeline. AB - In this issue of Molecular Cell, Pantel et al. (2018) identify and synthetically optimize a novel ribosome-targeting antimicrobial from a potentially rich new source of bioactive natural products. PMID- 29625038 TI - Finding Sugar in the Pantry: How Galectins Detect and Signal Lysosomal Damage. AB - In this issue of Molecular Cell, Jia et al. (2018) identify a lysosomal damage response pathway centered on galectin 8 and 9 that feeds back on mTORC1 signaling. In response to lysosome-damaging agents, galectins inhibits mTORC1, triggering a stress response that may help restore cellular homeostasis. PMID- 29625039 TI - Terminal Uridylyltransferases Execute Programmed Clearance of Maternal Transcriptome in Vertebrate Embryos. AB - During the maternal-to-zygotic transition (MZT), maternal RNAs are actively degraded and replaced by newly synthesized zygotic transcripts in a highly coordinated manner. However, it remains largely unknown how maternal mRNA decay is triggered in early vertebrate embryos. Here, through genome-wide profiling of RNA abundance and 3' modification, we show that uridylation is induced at the onset of maternal mRNA clearance. The temporal control of uridylation is conserved in vertebrates. When the homologs of terminal uridylyltransferases TUT4 and TUT7 (TUT4/7) are depleted in zebrafish and Xenopus, maternal mRNA clearance is significantly delayed, leading to developmental defects during gastrulation. Short-tailed mRNAs are selectively uridylated by TUT4/7, with the highly uridylated transcripts degraded faster during the MZT than those with unmodified poly(A) tails. Our study demonstrates that uridylation plays a crucial role in timely mRNA degradation, thereby allowing the progression of early development. PMID- 29625040 TI - Odilorhabdins, Antibacterial Agents that Cause Miscoding by Binding at a New Ribosomal Site. AB - Growing resistance of pathogenic bacteria and shortage of antibiotic discovery platforms challenge the use of antibiotics in the clinic. This threat calls for exploration of unconventional sources of antibiotics and identification of inhibitors able to eradicate resistant bacteria. Here we describe a different class of antibiotics, odilorhabdins (ODLs), produced by the enzymes of the non ribosomal peptide synthetase gene cluster of the nematode-symbiotic bacterium Xenorhabdus nematophila. ODLs show activity against Gram-positive and Gram negative pathogens, including carbapenem-resistant Enterobacteriaceae, and can eradicate infections in animal models. We demonstrate that the bactericidal ODLs interfere with protein synthesis. Genetic and structural analyses reveal that ODLs bind to the small ribosomal subunit at a site not exploited by current antibiotics. ODLs induce miscoding and promote hungry codon readthrough, amino acid misincorporation, and premature stop codon bypass. We propose that ODLs' miscoding activity reflects their ability to increase the affinity of non-cognate aminoacyl-tRNAs to the ribosome. PMID- 29625041 TI - Mechanistic View and Genetic Control of DNA Recombination during Meiosis. AB - Meiotic recombination is essential for fertility and allelic shuffling. Canonical recombination models fail to capture the observed complexity of meiotic recombinants. Here, by combining genome-wide meiotic heteroduplex DNA patterns with meiotic DNA double-strand break (DSB) sites, we show that part of this complexity results from frequent template switching during synthesis-dependent strand annealing that yields noncrossovers and from branch migration of double Holliday junction (dHJ)-containing intermediates that mainly yield crossovers. This complexity also results from asymmetric positioning of crossover intermediates relative to the initiating DSB and Msh2-independent conversions promoted by the suspected dHJ resolvase Mlh1-3 as well as Exo1 and Sgs1. Finally, we show that dHJ resolution is biased toward cleavage of the pair of strands containing newly synthesized DNA near the junctions and that this bias can be decoupled from the crossover-biased dHJ resolution. These properties are likely conserved in eukaryotes containing ZMM proteins, which includes mammals. PMID- 29625043 TI - Charting a Course to a Cure. PMID- 29625042 TI - Activation of the Stringent Response by Loading of RelA-tRNA Complexes at the Ribosomal A-Site. AB - RelA/SpoT homologs (RSHs) are ubiquitous bacterial enzymes that synthesize and hydrolyze (p)ppGpp in response to environmental challenges. Bacteria cannot survive in hosts and produce infection without activating the (p)ppGpp-mediated stringent response, but it is not yet understood how the enzymatic activities of RSHs are controlled. Using UV crosslinking and deep sequencing, we show that Escherichia coli RelA ((p)ppGpp synthetase I) interacts with uncharged tRNA without being activated. Amino acid starvation leads to loading of cognate tRNA?RelA complexes at vacant ribosomal A-sites. In turn, RelA is activated and synthesizes (p)ppGpp. Mutation of a single, conserved residue in RelA simultaneously prevents tRNA binding, ribosome binding, and activation of RelA, showing that all three processes are interdependent. Our results support a model in which (p)ppGpp synthesis occurs by ribosome-bound RelA interacting with the Sarcin-Ricin loop of 23S rRNA. PMID- 29625044 TI - The TCGA Legacy. PMID- 29625045 TI - The Cancer Genome Atlas: Creating Lasting Value beyond Its Data. AB - The Cancer Genome Atlas (TCGA) team now presents the Pan-Cancer Atlas, investigating different aspects of cancer biology by analyzing the data generated during the 10+ years of the TCGA project. PMID- 29625046 TI - Pipped at the Post: Pipecolic Acid Derivative Identified as SAR Regulator. AB - The non-protein amino acid pipecolic acid (Pip) is a lysine catabolite involved in plant systemic acquired resistance (SAR). In this issue of Cell, Hartmann et al. (2018) demonstrate that a flavin-dependent monooxygenase converts Pip to N hydroxypipecolic acid (NHP), which functions as a critical metabolic regulator of SAR in Arabidopsis. PMID- 29625047 TI - Coupling Neurogenesis to Circuit Formation. AB - A central question in neuroscience is how developmental programs instruct the formation of complex neural circuits with temporal, spatial, and numerical precision. Pinto-Teixeira et al. (2018) reveal simple developmental rules that govern sequential neurogenesis to concurrently establish highly organized retinotopic maps in the Drosophila visual system. PMID- 29625048 TI - Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer. AB - We conducted comprehensive integrative molecular analyses of the complete set of tumors in The Cancer Genome Atlas (TCGA), consisting of approximately 10,000 specimens and representing 33 types of cancer. We performed molecular clustering using data on chromosome-arm-level aneuploidy, DNA hypermethylation, mRNA, and miRNA expression levels and reverse-phase protein arrays, of which all, except for aneuploidy, revealed clustering primarily organized by histology, tissue type, or anatomic origin. The influence of cell type was evident in DNA methylation-based clustering, even after excluding sites with known preexisting tissue-type-specific methylation. Integrative clustering further emphasized the dominant role of cell-of-origin patterns. Molecular similarities among histologically or anatomically related cancer types provide a basis for focused pan-cancer analyses, such as pan-gastrointestinal, pan-gynecological, pan-kidney, and pan-squamous cancers, and those related by stemness features, which in turn may inform strategies for future therapeutic development. PMID- 29625049 TI - Perspective on Oncogenic Processes at the End of the Beginning of Cancer Genomics. AB - The Cancer Genome Atlas (TCGA) has catalyzed systematic characterization of diverse genomic alterations underlying human cancers. At this historic junction marking the completion of genomic characterization of over 11,000 tumors from 33 cancer types, we present our current understanding of the molecular processes governing oncogenesis. We illustrate our insights into cancer through synthesis of the findings of the TCGA PanCancer Atlas project on three facets of oncogenesis: (1) somatic driver mutations, germline pathogenic variants, and their interactions in the tumor; (2) the influence of the tumor genome and epigenome on transcriptome and proteome; and (3) the relationship between tumor and the microenvironment, including implications for drugs targeting driver events and immunotherapies. These results will anchor future characterization of rare and common tumor types, primary and relapsed tumors, and cancers across ancestry groups and will guide the deployment of clinical genomic sequencing. PMID- 29625056 TI - Influenza Infection in Humans Induces Broadly Cross-Reactive and Protective Neuraminidase-Reactive Antibodies. AB - Antibodies to the hemagglutinin (HA) and neuraminidase (NA) glycoproteins are the major mediators of protection against influenza virus infection. Here, we report that current influenza vaccines poorly display key NA epitopes and rarely induce NA-reactive B cells. Conversely, influenza virus infection induces NA-reactive B cells at a frequency that approaches (H1N1) or exceeds (H3N2) that of HA-reactive B cells. NA-reactive antibodies display broad binding activity spanning the entire history of influenza A virus circulation in humans, including the original pandemic strains of both H1N1 and H3N2 subtypes. The antibodies robustly inhibit the enzymatic activity of NA, including oseltamivir-resistant variants, and provide robust prophylactic protection, including against avian H5N1 viruses, in vivo. When used therapeutically, NA-reactive antibodies protected mice from lethal influenza virus challenge even 48 hr post infection. These findings strongly suggest that influenza vaccines should be optimized to improve targeting of NA for durable and broad protection against divergent influenza strains. PMID- 29625059 TI - SnapShot: TCGA-Analyzed Tumors. AB - This SnapShot provides a list of the tumor types characterized by The Cancer Genome Atlas (TCGA) program. Key findings shown are the most relevant discoveries described in each marker paper for the tumor type. PMID- 29625060 TI - De Novo DNA Methylation: Marking the Path from Stem Cell to Neural Fate. AB - DNA methylation is an epigenetic mark that plays pivotal roles in gene regulation, but its functions in neural fate decisions are poorly understood. In this issue of Cell Stem Cell, Ziller et al. (2018) show that the de novo methyltransferase Dnmt3a ensures efficient generation of motor neurons from stem cells. PMID- 29625061 TI - Orchestrating Ribosomal Subunit Coordination to Control Stem Cell Fate. AB - The mechanisms responsible for maintaining ribosomal component stoichiometry, which is critical during cell fate transitions, are currently not well understood. In this issue of Cell Stem Cell, Corsini et al. (2018) demonstrate that the transcription and splicing-associated factor HTATSF1 controls stem cell fate by coordinately regulating ribosomal protein and RNA production. PMID- 29625058 TI - Retraction Notice to: FMN2 Makes Perinuclear Actin to Protect Nuclei during Confined Migration and Promote Metastasis. PMID- 29625062 TI - Building Bonds: Cancer Stem Cells Depend on Their Progeny to Drive Tumor Progression. AB - Little is currently known about how cancer stem-like cells (CSCs) interact with their more restricted progeny. In this issue of Cell Stem Cell, Wang et al. (2018) demonstrate a novel bidirectional signaling axis between CSCs and their progeny that is mediated by brain-derived neurotrophic factor and VGF accelerating glioma progression. PMID- 29625063 TI - To Be Young at Heart. AB - Recently in Cell, Mohamed et al. (2018) report a cell-cycle regulator gene cocktail identified from young cardiomyocytes that enables mouse, rat, and human cardiomyocyte proliferation and promotes heart regeneration after infarction, defying the non-dividing nature of adult mammalian cardiomyocytes and implying a new way to treat or prevent heart failure. PMID- 29625057 TI - Tumor Evolution and Drug Response in Patient-Derived Organoid Models of Bladder Cancer. AB - Bladder cancer is the fifth most prevalent cancer in the U.S., yet is understudied, and few laboratory models exist that reflect the biology of the human disease. Here, we describe a biobank of patient-derived organoid lines that recapitulates the histopathological and molecular diversity of human bladder cancer. Organoid lines can be established efficiently from patient biopsies acquired before and after disease recurrence and are interconvertible with orthotopic xenografts. Notably, organoid lines often retain parental tumor heterogeneity and exhibit a spectrum of genomic changes that are consistent with tumor evolution in culture. Analyses of drug response using bladder tumor organoids show partial correlations with mutational profiles, as well as changes associated with treatment resistance, and specific responses can be validated using xenografts in vivo. Our studies indicate that patient-derived bladder tumor organoids represent a faithful model system for studying tumor evolution and treatment response in the context of precision cancer medicine. PMID- 29625064 TI - The Rules of Successful Speed Dating Are Complex, Even for Super-Enhancers. AB - Super-enhancers (SEs) are important for regulating cell identity genes and oncogenes, but correctly assigning target genes to SEs is difficult. Recently in Cell Reports, Lopes Novo et al. (2018) map interactions between SEs and promoters and observe a significant rewiring of complex SE-promoter networks between different pluripotent states. PMID- 29625065 TI - Sending Cancer into the Fetal Position. AB - Malignant cells gain the ability to self-renew and reacquire expression of proteins associated with embryonic development. In this issue of Cell Stem Cell, Kooreman et al. (2018) demonstrate that vaccination of mice with syngeneic inactivated iPSCs generates T cell immunity against embryonic antigens and provides resistance to several different types of cancers. PMID- 29625051 TI - Machine Learning Identifies Stemness Features Associated with Oncogenic Dedifferentiation. AB - Cancer progression involves the gradual loss of a differentiated phenotype and acquisition of progenitor and stem-cell-like features. Here, we provide novel stemness indices for assessing the degree of oncogenic dedifferentiation. We used an innovative one-class logistic regression (OCLR) machine-learning algorithm to extract transcriptomic and epigenetic feature sets derived from non-transformed pluripotent stem cells and their differentiated progeny. Using OCLR, we were able to identify previously undiscovered biological mechanisms associated with the dedifferentiated oncogenic state. Analyses of the tumor microenvironment revealed unanticipated correlation of cancer stemness with immune checkpoint expression and infiltrating immune cells. We found that the dedifferentiated oncogenic phenotype was generally most prominent in metastatic tumors. Application of our stemness indices to single-cell data revealed patterns of intra-tumor molecular heterogeneity. Finally, the indices allowed for the identification of novel targets and possible targeted therapies aimed at tumor differentiation. PMID- 29625066 TI - Human Pluripotent Stem Cell-Derived Endoderm for Modeling Development and Clinical Applications. AB - The liver, lung, pancreas, and digestive tract all originate from the endoderm germ layer, and these vital organs are subject to many life-threatening diseases affecting millions of patients. However, primary cells from endodermal organs are often difficult to grow in vitro. Human pluripotent stem cells thus hold great promise for generating endoderm cells and their derivatives as tools for the development of new therapeutics against a variety of global healthcare challenges. Here we describe recent advances in methods for generating endodermal cell types from human pluripotent stem cells and their use for disease modeling and cell-based therapy. PMID- 29625068 TI - Chromatin Accessibility Dynamics during Chemical Induction of Pluripotency. AB - Despite its exciting potential, chemical induction of pluripotency (CIP) efficiency remains low and the mechanisms are poorly understood. We report the development of an efficient two-step serum- and replating-free CIP protocol and the associated chromatin accessibility dynamics (CAD) by assay for transposase accessible chromatin (ATAC)-seq. CIP reorganizes the somatic genome to an intermediate state that is resolved under 2iL condition by re-closing previously opened loci prior to pluripotency acquisition with gradual opening of loci enriched with motifs for the OCT/SOX/KLF families. Bromodeoxyuridine, a critical ingredient of CIP, is responsible for both closing and opening critical loci, at least in part by preventing the opening of loci enriched with motifs for the AP1 family and facilitating the opening of loci enriched with SOX/KLF/GATA motifs. These changes differ markedly from CAD observed during Yamanaka-factor-driven reprogramming. Our study provides insights into small-molecule-based reprogramming mechanisms and reorganization of nuclear architecture associated with cell-fate decisions. PMID- 29625069 TI - Coordinated Control of mRNA and rRNA Processing Controls Embryonic Stem Cell Pluripotency and Differentiation. AB - Stem cell-specific transcriptional networks are well known to control pluripotency, but constitutive cellular processes such as mRNA splicing and protein synthesis can add complex layers of regulation with poorly understood effects on cell-fate decisions. Here, we show that the RNA binding protein HTATSF1 controls embryonic stem cell differentiation by regulating multiple aspects of RNA processing during ribosome biogenesis. HTATSF1, in a complex with splicing factor SF3B1, controls intron removal from ribosomal protein transcripts and regulates ribosomal RNA transcription and processing, thereby controlling 60S ribosomal abundance and protein synthesis. HTATSF1-dependent protein synthesis is essential for naive pre-implantation epiblast to transition into post implantation epiblast, a stage with transiently low protein synthesis, and further differentiation toward neuroectoderm. Together, these results identify coordinated regulation of ribosomal RNA and protein synthesis by HTATSF1 and show that this essential mechanism controls protein synthesis during early mammalian embryogenesis. PMID- 29625067 TI - Reciprocal Signaling between Glioblastoma Stem Cells and Differentiated Tumor Cells Promotes Malignant Progression. AB - Glioblastoma is the most lethal primary brain tumor; however, the crosstalk between glioblastoma stem cells (GSCs) and their supportive niche is not well understood. Here, we interrogated reciprocal signaling between GSCs and their differentiated glioblastoma cell (DGC) progeny. We found that DGCs accelerated GSC tumor growth. DGCs preferentially expressed brain-derived neurotrophic factor (BDNF), whereas GSCs expressed the BDNF receptor NTRK2. Forced BDNF expression in DGCs augmented GSC tumor growth. To determine molecular mediators of BDNF-NTRK2 paracrine signaling, we leveraged transcriptional and epigenetic profiles of matched GSCs and DGCs, revealing preferential VGF expression by GSCs, which patient-derived tumor models confirmed. VGF serves a dual role in the glioblastoma hierarchy by promoting GSC survival and stemness in vitro and in vivo while also supporting DGC survival and inducing DGC secretion of BDNF. Collectively, these data demonstrate that differentiated glioblastoma cells cooperate with stem-like tumor cells through BDNF-NTRK2-VGF paracrine signaling to promote tumor growth. PMID- 29625070 TI - A CLK3-HMGA2 Alternative Splicing Axis Impacts Human Hematopoietic Stem Cell Molecular Identity throughout Development. AB - While gene expression dynamics have been extensively cataloged during hematopoietic differentiation in the adult, less is known about transcriptome diversity of human hematopoietic stem cells (HSCs) during development. To characterize transcriptional and post-transcriptional changes in HSCs during development, we leveraged high-throughput genomic approaches to profile miRNAs, lincRNAs, and mRNAs. Our findings indicate that HSCs manifest distinct alternative splicing patterns in key hematopoietic regulators. Detailed analysis of the splicing dynamics and function of one such regulator, HMGA2, identified an alternative isoform that escapes miRNA-mediated targeting. We further identified the splicing kinase CLK3 that, by regulating HMGA2 splicing, preserves HMGA2 function in the setting of an increase in let-7 miRNA levels, delineating how CLK3 and HMGA2 form a functional axis that influences HSC properties during development. Collectively, our study highlights molecular mechanisms by which alternative splicing and miRNA-mediated post-transcriptional regulation impact the molecular identity and stage-specific developmental features of human HSCs. PMID- 29625072 TI - Large-Scale Clonal Analysis Resolves Aging of the Mouse Hematopoietic Stem Cell Compartment. AB - Aging is linked to functional deterioration and hematological diseases. The hematopoietic system is maintained by hematopoietic stem cells (HSCs), and dysfunction within the HSC compartment is thought to be a key mechanism underlying age-related hematopoietic perturbations. Using single-cell transplantation assays with five blood-lineage analysis, we previously identified myeloid-restricted repopulating progenitors (MyRPs) within the phenotypic HSC compartment in young mice. Here, we determined the age-related functional changes to the HSC compartment using over 400 single-cell transplantation assays. Notably, MyRP frequency increased dramatically with age, while multipotent HSCs expanded modestly within the bone marrow. We also identified a subset of functional cells that were myeloid restricted in primary recipients but displayed multipotent (five blood-lineage) output in secondary recipients. We have termed this cell type latent-HSCs, which appear exclusive to the aged HSC compartment. These results question the traditional dogma of HSC aging and our current approaches to assay and define HSCs. PMID- 29625073 TI - Vascular Tissue Engineering: Progress, Challenges, and Clinical Promise. PMID- 29625074 TI - Regenerative Rehabilitation: Applied Biophysics Meets Stem Cell Therapeutics. PMID- 29625071 TI - Human Hippocampal Neurogenesis Persists throughout Aging. AB - Adult hippocampal neurogenesis declines in aging rodents and primates. Aging humans are thought to exhibit waning neurogenesis and exercise-induced angiogenesis, with a resulting volumetric decrease in the neurogenic hippocampal dentate gyrus (DG) region, although concurrent changes in these parameters are not well studied. Here we assessed whole autopsy hippocampi from healthy human individuals ranging from 14 to 79 years of age. We found similar numbers of intermediate neural progenitors and thousands of immature neurons in the DG, comparable numbers of glia and mature granule neurons, and equivalent DG volume across ages. Nevertheless, older individuals have less angiogenesis and neuroplasticity and a smaller quiescent progenitor pool in anterior-mid DG, with no changes in posterior DG. Thus, healthy older subjects without cognitive impairment, neuropsychiatric disease, or treatment display preserved neurogenesis. It is possible that ongoing hippocampal neurogenesis sustains human specific cognitive function throughout life and that declines may be linked to compromised cognitive-emotional resilience. PMID- 29625075 TI - A novel and sensitive functional assay for complement Factor I based on the third proteolytic clip of C3b. AB - A sensitive assay for the functional activity of complement Factor I is described. This is based on its third proteolytic clip whereby Factor I cleaves cell-bound iC3b to cell-bound C3dg and soluble C3c, thereby abolishing conglutination of the cells. Factor H is required as a co-factor for Factor I activity. Because of the low affinity of iC3b for Factor H, the assay needs to be performed at low ionic strength. This assay is easier to perform than those based on the conversion of C3b to iC3b (the first two Factor I clips), there being no need for the unstable intermediate EAC142 or for purified C3. PMID- 29625050 TI - Oncogenic Signaling Pathways in The Cancer Genome Atlas. AB - Genetic alterations in signaling pathways that control cell-cycle progression, apoptosis, and cell growth are common hallmarks of cancer, but the extent, mechanisms, and co-occurrence of alterations in these pathways differ between individual tumors and tumor types. Using mutations, copy-number changes, mRNA expression, gene fusions and DNA methylation in 9,125 tumors profiled by The Cancer Genome Atlas (TCGA), we analyzed the mechanisms and patterns of somatic alterations in ten canonical pathways: cell cycle, Hippo, Myc, Notch, Nrf2, PI-3 Kinase/Akt, RTK-RAS, TGFbeta signaling, p53 and beta-catenin/Wnt. We charted the detailed landscape of pathway alterations in 33 cancer types, stratified into 64 subtypes, and identified patterns of co-occurrence and mutual exclusivity. Eighty nine percent of tumors had at least one driver alteration in these pathways, and 57% percent of tumors had at least one alteration potentially targetable by currently available drugs. Thirty percent of tumors had multiple targetable alterations, indicating opportunities for combination therapy. PMID- 29625076 TI - Lymphatic cannulation models in sheep: Recent advances for immunological and biomedical research. AB - Lymphatic cannulation models are useful tools for studying the immunobiology of the lymphatic system and the immunopathology of specific tissues in diseases. Sheep cannulations have been used extensively, as models for human physiology, fetal and neonatal development, human diseases, and for studies of ruminant pathobiology. The development of new and improved cannulation techniques in recent years has meant that difficult to access sites, such as mucosal associated tissues, are now more readily available to researchers. This review highlights the new approaches to cannulation and how these, in combination with advanced omics technologies, will direct future research using the sheep model. PMID- 29625054 TI - A Pan-Cancer Analysis of Enhancer Expression in Nearly 9000 Patient Samples. AB - The role of enhancers, a key class of non-coding regulatory DNA elements, in cancer development has increasingly been appreciated. Here, we present the detection and characterization of a large number of expressed enhancers in a genome-wide analysis of 8928 tumor samples across 33 cancer types using TCGA RNA seq data. Compared with matched normal tissues, global enhancer activation was observed in most cancers. Across cancer types, global enhancer activity was positively associated with aneuploidy, but not mutation load, suggesting a hypothesis centered on "chromatin-state" to explain their interplay. Integrating eQTL, mRNA co-expression, and Hi-C data analysis, we developed a computational method to infer causal enhancer-gene interactions, revealing enhancers of clinically actionable genes. Having identified an enhancer ~140 kb downstream of PD-L1, a major immunotherapy target, we validated it experimentally. This study provides a systematic view of enhancer activity in diverse tumor contexts and suggests the clinical implications of enhancers. PMID- 29625077 TI - Optimising the collection of female genital tract fluid for cytokine analysis in pregnant women. AB - INTRODUCTION: To better understand the immunology of pregnancy, study of female genital tract fluid (FGF) is desirable. However the optimum method of collection of FGF in pregnant women for immunological methods, specifically cytokine measurement, is unknown. METHODS: A prospective study of HIV-uninfected pregnant women comparing two methods of FGF collection: polyvinyl acetal sponge collection of cervical fluid (CF) and menstrual cup collection of cervicovaginal fluid (CVF). Samples were collected at 3 time points across the second and third trimesters: 14-21, 22-25 and 26-31 weeks. Multiplex chemi-luminescent assays were used to measure: IFN-gamma, IL-1beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-13 and TNF-alpha. Optimal methodology for cytokine normalisation (sample weight, volume and total protein) was explored. RESULTS: All cytokines were measurable in both fluid types. IL-1beta, IL-8 and IL-6 were detected at the highest concentrations (ranking order CF > CVF > plasma). CVF collection was simpler, provided the largest volume of sample (median 0.5 g) with the potential for undiluted usage, and allowed for self-insertion. CF cytokine concentrations were intrinsically associated with sample weight and protein concentration however CVF cytokines were independent of these. CONCLUSION: Both methods of collection are robust for measurement of FGF cytokines during pregnancy. We recommend CVF collection using a menstrual cup as a viable option in pregnant women for high dimensional biological techniques. PMID- 29625078 TI - Automated generation of immature dendritic cells in a single-use system. AB - Dendritic cells (DCs) are an indispensable part of studying human responses that are important for protective immunity against cancer and infectious diseases as well as prevention of autoimmunity and transplant rejection. These cells are also key elements of personalized vaccines for cancer and infectious diseases. Despite the vital role of DCs in both clinical and basic research contexts, methods for obtaining these cells from individuals remains a comparatively under-developed and inefficient process. DCs are present in very low concentrations (<1%) in blood, thus they must be generated from monocytes and the current methodology in DC generation involves a laborious process of static culture and stimulation with cytokines contained in culture medium. Herein, we describe an automated fluidic system, MicroDEN, that allows for differentiation of monocytes into immature-DCs (iDCs) utilizing continuous perfusion of differentiation media. Manual steps associated with current ex vivo monocyte differentiation are vastly reduced and an aseptic environment is ensured by the use of an enclosed cartridge and tubing network. Benchmark phenotyping was performed on the generated iDCs along with allogeneic T-cell proliferation and syngeneic antigen-specific functional assays. MicroDEN generated iDCs were phenotypically and functionally similar to well plate generated iDCs, thereby demonstrating the feasibility of utilizing MicroDEN in the broad range of applications requiring DCs. PMID- 29625081 TI - On Becoming a Woman. PMID- 29625079 TI - DPD functional tests in plasma, fresh saliva and dried saliva samples as predictors of 5-fluorouracil exposure and occurrence of drug-related severe toxicity. AB - OBJECTIVE: to evaluate plasma and salivary uracil (U) to dihydrouracil (UH2) ratios as tools for predicting 5-fluorouracil systemic exposure and drug-related severe toxicity, and clinically validate the use of dried saliva spots (DSS) as an alternative sampling strategy for dihydropyrimidine dehydrogenase (DPD) deficiency assessment. METHODS: Pre-chemotherapy plasma, fresh saliva and DSS samples were obtained from gastrointestinal patients (N = 40) for measurement of endogenous U and UH2 concentrations by LC-MS/MS. A second plasma sample collected during 5FU infusion was used for 5FU area under the curve (AUC) determination by HPLC-DAD. Data on toxicity was reported according to CTCAE. RESULTS: 15% of the patients developed severe 5FU-related toxicity, with neutropenia accounting for 67% of the cases. U, UH2 and [UH2,]/[U] were highly correlated between fresh and dried saliva samples (rs = 0.960; rs = 0.828; rs = 0.910, respectively). 5FU AUC ranged from 11.3 to 37.31 mg h L-1, with 46.2% of under-dosed and 10.3% over dosed patients. The [UH2]/[U] ratios in plasma, fresh saliva and dried saliva samples were moderately correlated with 5FU AUC and adverse events grade, indicating a partial contribution of the variables to drug exposure (r = -0.412, rs = -0.373, rs = 0.377) and toxicity (r = -0.363, rs = -0.523, rs = 0.542). Metabolic ratios were lower in patients with severe toxicity (P < .01 salivary ratios, and P < .5 plasma ratios), and 5FU AUC were in average 47% higher in this group than in moderate toxicity. The diagnostic performance of [UH2]/[U] ratios in fresh saliva and DSS for the identification of patients with severe toxicity were comparable. CONCLUSIONS: The [UH2]/[U] metabolic ratios in plasma, fresh saliva and DSS were significantly associated with 5FU systemic exposure and toxicity degree. This study also demonstrated the applicability of DSS as alternative sampling for evaluating DPD activity. PMID- 29625080 TI - The effects of age on mitochondria, axonal transport, and axonal degeneration after chronic IOP elevation using a murine ocular explant model. AB - The purpose of this study was to compare younger and older mice after chronic intraocular pressure (IOP) elevation lasting up to 4 days with respect to mitochondrial density, structure, and movement, as well as axonal integrity, in an ex vivo explant model. We studied 2 transgenic mouse strains, both on a C57BL/6J background, one expressing yellow fluorescent protein (YFP) in selected axons and one expressing cyan fluorescent protein (CFP) in all mitochondria. Mice of 4 months or 14 months of age were exposed to chronic IOP by anterior chamber microbead injection for 14 h, 1, 3, or 4 days. The optic nerve head of globe- optic nerve explants were examined by laser scanning microscopy. Mitochondrial density, structure, and movement were quantified in the CFP explants, and axonal integrity was quantified in YFP explants. In control mice, there was a trend towards decreased mitochondrial density (# per mm2) with age when comparing younger to older, control mice, but this was not significant (1947 +/- 653 vs 1412 +/- 356; p = 0.19). Mitochondrial density decreased after IOP elevation, significantly, by 31%, in younger mice (p = 0.04) but trending towards a decrease, by 22%, in older mice (p = 0.82) compared to age matched controls. Mitochondrial mean size was not altered after chronic IOP elevation for 14 h or more (p >= 0.16). When assessing mitochondrial movement, in younger mice, 5% were mobile at any given time; 4% in the anterograde direction and 1% retrograde. In younger untreated tissue, only 75% of explants had moving mitochondria (mean = 15.8 moving/explant), while after glaucoma induction only 24% of explants had moving mitochondria (mean = 4.2 moving/explant; difference from control, p = 0.03). The distance mitochondria traveled in younger mice was unchanged after glaucoma exposure, but in older glaucoma explants the distance traveled was less than half of older controls (p < 0.0003). In younger mice, mitochondrial speed increased after 14 h of elevated IOP (p = 0.006); however, in older glaucoma explants, movement was actually slower than controls (p = 0.02). In RGC-YFP explants, axonal integrity declined significantly after 4 days of IOP elevation to a similar degree in both younger and older mice. Older mice underwent greater loss of mitochondrial movement with chronic IOP elevation than younger mice, but suffered similar short-term axonal fragmentation in C57BL/6J mice. These transgenic strains, studied in explants, permit observations of alterations in intracellular structure and organelle activity in experimental glaucoma. PMID- 29625082 TI - Oral Anticoagulation for Primary Prophylaxis of Venous Thromboembolism in Patients with Cancer. PMID- 29625053 TI - Comprehensive Characterization of Cancer Driver Genes and Mutations. AB - Identifying molecular cancer drivers is critical for precision oncology. Multiple advanced algorithms to identify drivers now exist, but systematic attempts to combine and optimize them on large datasets are few. We report a PanCancer and PanSoftware analysis spanning 9,423 tumor exomes (comprising all 33 of The Cancer Genome Atlas projects) and using 26 computational tools to catalog driver genes and mutations. We identify 299 driver genes with implications regarding their anatomical sites and cancer/cell types. Sequence- and structure-based analyses identified >3,400 putative missense driver mutations supported by multiple lines of evidence. Experimental validation confirmed 60%-85% of predicted mutations as likely drivers. We found that >300 MSI tumors are associated with high PD-1/PD L1, and 57% of tumors analyzed harbor putative clinically actionable events. Our study represents the most comprehensive discovery of cancer genes and mutations to date and will serve as a blueprint for future biological and clinical endeavors. PMID- 29625083 TI - Comparative Trends in Heart Disease, Stroke, and All-Cause Mortality in the United States and a Large Integrated Healthcare Delivery System. AB - OBJECTIVES: Heart disease and stroke remain among the leading causes of death nationally. We examined whether differences in recent trends in heart disease, stroke, and total mortality exist in the United States and Kaiser Permanente Northern California (KPNC), a large integrated healthcare delivery system. METHODS: The main outcome measures were comparisons of US and KPNC total, age specific, and sex-specific changes from 2000 to 2015 in mortality rates from heart disease, coronary heart disease, stroke, and all causes. The Centers for Disease Control and Prevention Wide-Ranging Online Data for Epidemiologic Research data system was used to determine US mortality rates. Mortality rates for KPNC were determined from health system, Social Security vital status, and state death certificate databases. RESULTS: Declines in age-adjusted mortality rates were noted in KPNC and the United States for heart disease (36.3% in KPNC vs 34.6% in the United States), coronary heart disease (51.0% vs 47.9%), stroke (45.5% vs 38.2%), and all-cause mortality (16.8% vs 15.6%). However, steeper declines were noted in KPNC than the United States among those aged 45 to 65 years for heart disease (48.3% KPNC vs 23.6% United States), coronary heart disease (55.6% vs 35.9%), stroke (55.8% vs 26.0%), and all-cause mortality (31.5% vs 9.1%). Sex-specific changes were generally similar. CONCLUSIONS: Despite significant declines in heart disease and stroke mortality, there remains an improvement gap nationally among those aged less than 65 years when compared with a large integrated healthcare delivery system. Interventions to improve cardiovascular mortality in the vulnerable middle-aged population may play a key role in closing this gap. PMID- 29625052 TI - Pathogenic Germline Variants in 10,389 Adult Cancers. AB - We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in MET, RET, and PTPN11 associated with high gene expression. We nominated 47 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer. PMID- 29625084 TI - Vitamin C deficiency aggravates tumor necrosis factor alpha-induced insulin resistance. AB - Chronic low-grade inflammation plays a major role in the development of insulin resistance. The potential role and underlying mechanism of vitamin C, an antioxidant and anti-inflammatory agent, was investigated in tumor necrosis factor-alpha (TNF-alpha)-induced insulin resistance. Gulonolactone oxidase knockout (Gulo-/-) mice genetically unable to synthesize vitamin C were used to induce insulin resistance by continuously pumping small doses of TNF-alpha for seven days, and human liver hepatocellular carcinoma cells (HepG2 cells) were used to induce insulin resistance by treatment with TNF-alpha. Vitamin C deficiency aggravated TNF-alpha-induced insulin resistance in Gulo-/- mice, resulting in worse glucose tolerance test (GTT) results, higher fasting plasma insulin level, and the inactivation of the protein kinase B (AKT)/glycogen synthase kinase-3beta (GSK3beta) pathway in the liver. Vitamin C deficiency also worsened liver lipid accumulation and inflammation in TNF-alpha-treated Gulo-/- mice. In HepG2 cells, vitamin C reversed the TNF-alpha-induced reduction of glucose uptake and glycogen synthesis, which were mediated by increasing GLUT2 levels and the activation of the insulin receptor substrate (IRS-1)/AKT/GSK3beta pathway. Furthermore, vitamin C inhibited the TNF-alpha-induced activation of not only the mitogen-activated protein kinase (MAPKs), but also nuclear factor-kappa B (NF-kappaB) signaling. Taken together, vitamin C is essential for preventing and improving insulin resistance, and the supplementing with vitamin C may be an effective therapeutic intervention for metabolic disorders. PMID- 29625085 TI - Progranulin ameliorates coxsackievirus-B3-induced viral myocarditis by downregulating Th1 and Th17 cells. AB - Viral myocarditis, which is caused by Coxsackievirus B3 (CVB3) infection, is a leading reason of sudden cardiac death in young adults. Progranulin (PGRN), a pleiotropic growth factor, has been shown to exert anti-inflammatory function in a variety of inflammatory diseases. However, the expression and function of PGRN in the pathogenesis of viral myocarditis remain largely unknown. In this study, we found that PGRN levels in plasma and cardiac tissues were significantly upregulated post CVB3 infection, and negative correlated with disease severity. PGRN deficiency significantly exacerbated, whereas recombinant PGRN treatment attenuated CVB3-induced myocarditis in mice. PGRN downregulated Th1 and Th17 cell responses and cytokine production in vitro and in vivo, whereas its effect on viral myocarditis was Treg cell independent. Furthermore, PGRN regulated Th1 and Th17 cells differentiation through inhibition of the JAK/STAT pathway. Therefore, our findings reveal a critical role for PGRN in reducing CVB3-induced myocarditis and suggest that PGRN maybe a novel therapeutic treatment for viral myocarditis. PMID- 29625086 TI - Tr1 responses are elevated in asymptomatic H. pylori-infected individuals and are functionally impaired in H. pylori-gastric cancer patients. AB - Gastric cancer is one of the most lethal malignancies worldwide. Chronic Helicobacter pylori (H. pylori) infection can induce an inflammatory response that promotes atrophic gastritis, a preceding event to cancer development. The type 1 regulatory T (Tr1) cells have recently emerged as a critical participant in maintaining self-tolerance. In this study, we examined Tr1 cells in H. pylori infection and gastric cancer development. While H. pylori-uninfected (uninfected) subjects presented low Tr1 frequency in the peripheral blood, H. pylori-infected asymptomatic (infected) individuals and H. pylori-infected gastric cancer (cancer) individuals both presented elevated Tr1 frequency. Although the Tr1 cells from infected asymptomatic subjects were functionally more potent than those from uninfected healthy subjects, the Tr1 cells in cancer individuals demonstrated several functional impairments, such as reduced interleukin 10 (IL 10) expression, lower secretion of cytolytic factors including granzyme B and perforin, and lower capacity to suppress CD4+CD25- T cell and CD8+ T cell proliferation. In addition, the frequency and function of Tr1 cells were positively correlated with the disease-free survival of the gastric cancer patients. These results suggest that Tr1 cells might be involved in the regulating immune responses in H. pylori infection and gastric cancer development. The fact that Tr1 cells could suppress inflammation and produce cytotoxic molecules at the same time has made them attractive potential candidates for future immunotherapies. PMID- 29625055 TI - An Integrated TCGA Pan-Cancer Clinical Data Resource to Drive High-Quality Survival Outcome Analytics. AB - For a decade, The Cancer Genome Atlas (TCGA) program collected clinicopathologic annotation data along with multi-platform molecular profiles of more than 11,000 human tumors across 33 different cancer types. TCGA clinical data contain key features representing the democratized nature of the data collection process. To ensure proper use of this large clinical dataset associated with genomic features, we developed a standardized dataset named the TCGA Pan-Cancer Clinical Data Resource (TCGA-CDR), which includes four major clinical outcome endpoints. In addition to detailing major challenges and statistical limitations encountered during the effort of integrating the acquired clinical data, we present a summary that includes endpoint usage recommendations for each cancer type. These TCGA-CDR findings appear to be consistent with cancer genomics studies independent of the TCGA effort and provide opportunities for investigating cancer biology using clinical correlates at an unprecedented scale. PMID- 29625087 TI - The peculiar NPQ regulation in the stramenopile Phaeomonas sp. challenges the xanthophyll cycle dogma. AB - In changing light conditions, photosynthetic organisms develop different strategies to maintain a fine balance between light harvesting, photochemistry, and photoprotection. One of the most widespread photoprotective mechanisms consists in the dissipation of excess light energy in the form of heat in the photosystem II antenna, which participates to the Non Photochemical Quenching (NPQ) of chlorophyll fluorescence. It is tightly related to the reversible epoxidation of xanthophyll pigments, catalyzed by the two enzymes, the violaxanthin deepoxidase and the zeaxanthin epoxidase. In Phaeomonas sp. (Pinguiophyte, Stramenopiles), we show that the regulation of the heat dissipation process is different from that of the green lineage: the NPQ is strictly proportional to the amount of the xanthophyll pigment zeaxanthin and the xanthophyll cycle enzymes are differently regulated. The violaxanthin deepoxidase is already active in the dark, because of a low luminal pH, and the zeaxanthin epoxidase shows a maximal activity under moderate light conditions, being almost inactive in the dark and under high light. This light-dependency mirrors the one of NPQ: Phaeomonas sp. displays a large NPQ in the dark as well as under high light, which recovers under moderate light. Our results pinpoint zeaxanthin epoxidase activity as the prime regulator of NPQ in Phaeomonas sp. and therefore challenge the deepoxidase-regulated xanthophyll cycle dogma. PMID- 29625088 TI - Dissecting the pattern of proton release from partial process involved in ubihydroquinone oxidation in the Q-cycle. AB - A key feature of the modified Q-cycle of the cytochrome bc1 and related complexes is a bifurcation of QH2 oxidation involving electron transfer to two different acceptor chains, each coupled to proton release. We have studied the kinetics of proton release in chromatophore vesicles from Rhodobacter sphaeroides, using the pH-sensitive dye neutral red to follow pH changes inside on activation of the photosynthetic chain, focusing on the bifurcated reaction, in which 4H+are released on complete turnover of the Q-cycle (2H+/ubiquinol (QH2) oxidized). We identified different partial processes of the Qo-site reaction, isolated through use of specific inhibitors, and correlated proton release with electron transfer processes by spectrophotometric measurement of cytochromes or electrochromic response. In the presence of myxothiazol or azoxystrobin, the proton release observed reflected oxidation of the Rieske iron-sulfur protein. In the absence of Qo-site inhibitors, the pH change measured represented the convolution of this proton release with release of protons on turnover of the Qo-site, involving formation of the ES-complex and oxidation of the semiquinone intermediate. Turnover also regenerated the reduced iron-sulfur protein, available for further oxidation on a second turnover. Proton release was well-matched with the rate limiting step on oxidation of QH2 on both turnovers. However, a minor lag in proton release found at pH 7 but not at pH 8 might suggest that a process linked to rapid proton release on oxidation of the intermediate semiquinone involves a group with a pK in that range. PMID- 29625089 TI - A possible molecular basis for photoprotection in the minor antenna proteins of plants. AB - The bioenergetics of light-harvesting by photosynthetic antenna proteins in higher plants is well understood. However, investigation into the regulatory non photochemical quenching (NPQ) mechanism, which dissipates excess energy in high light, has led to several conflicting models. It is generally accepted that the major photosystem II antenna protein, LHCII, is the site of NPQ, although the minor antenna complexes (CP24/26/29) are also proposed as alternative/additional NPQ sites. LHCII crystals were shown to exhibit the short excitation lifetime and several spectral signatures of the quenched state. Subsequent structure-based models showed that this quenching could be explained by slow energy trapping by the carotenoids, in line with one of the proposed models. Using Fluorescence Lifetime Imaging Microscopy (FLIM) we show that the crystal structure of CP29 corresponds to a strongly quenched conformation. Using a structure-based theoretical model we show that this quenching may be explained by the same slow, carotenoid-mediated quenching mechanism present in LHCII crystals. PMID- 29625090 TI - DNA barcoding of five Japanese encephalitis mosquito vectors (Culex fuscocephala, Culex gelidus, Culex tritaeniorhynchus, Culex pseudovishnui and Culex vishnui). AB - Culex mosquitoes can act as vectors of several important diseases, including Japanese encephalitis, West Nile virus, St. Louis encephalitis and equine encephalitis. Besides the neurological sequelae caused in humans, Japanese encephalitis can lead to abortion in sows and encephalitis in horses. Effective vector control and early diagnosis, along with continuous serosurveillance in animals, are crucial to fight this arboviral disease. However, the success of vector control operations is linked with the fast and reliable identification of targeted species, and knowledge about their biology and ecology. Since the DNA barcoding of Culex vectors of Japanese encephalitis is scarcely explored, here we evaluated the efficacy of this tool to identify and analyze the variations among five overlooked Culex vectors of Japanese encephalitis, Culex fuscocephala, Culex gelidus, Culex tritaeniorhynchus, Culex pseudovishnui and Culex vishnui, relying to the analysis of mitochondrial CO1 gene. Variations in their base pair range were elucidated by the entropy Hx plot. The differences among individual conspecifics and on base pair range across the same were studied. The C (501-750 bp) region showed a moderate variation among all the selected species. C. tritaeniorhynchus exhibited the highest variation in all the ranges. The observed genetic divergence was partially non-discriminatory. i.e., the overall intra- and inter nucleotide divergence was 0.0920 (0.92%) and 0.125 (1.25%), respectively. However, 10X rule fits accurately intraspecies divergence <3% for the five selected Culex species. The analysis of individual scatter plots showed threshold values (10X) of 0.008 (0.08%), 0.005 (0.05%), 0.123 (1.23%), 0.033 (0.33%) and 0.019 (0.19%) for C. fuscocephala, C. gelidus, C. tritaeniorhynchus, C. pseudovishnui and C. vishnui, respectively. The C. tritaeniorhynchus haplotypes KU497604, KU497603, AB690847 and AB690854 exhibited the highest divergence range, i.e., from 0.465 -0.546. Comparatively, the intra-divergence among the other haplotypes of C. tritaeniorhynchus ranged from 0-0.056. The maximum parsimony tree was formed by distinctive conspecific clusters with appreciable branch values illustrating their close congruence and extensive genetic deviations. Overall, this study adds valuable knowledge to the molecular biology and systematics of five overlooked mosquito species acting as major vectors of Japanese encephalitis in Asian countries. PMID- 29625091 TI - What makes an effective Chagas disease vector? Factors underlying Trypanosoma cruzi-triatomine interactions. AB - The Chagas disease is caused by the parasite Trypanosoma cruzi, which infect blood-feeding triatomine bugs to finally reach mammal hosts. Chagas disease is endemic in Latin America, and is ranked among the 13 neglected tropical diseases worldwide. Currently, an estimate of 7 million people is infected by T. cruzi, leading to about 22 000 deaths per year throughout the Americas. As occurs with other vectors, a major question towards control programs is what makes a susceptible bug. In this review, we focus on findings linked to insect gut structure and microbiota, immunity, genetics, blood sources, abiotic factors (with special reference to ambient temperature and altitude) to understand the interactions occurring between T. cruzi and triatomine bugs, under a co evolutionary scenario. These factors lead to varying fitness benefits and costs for bugs, explaining why infection in the insect takes place and how it varies in time and space. Our analysis highlights that major factors are gut components and microbiota, blood sources and temperature. Although their close interaction has never been clarified, knowledge reviewed here may help to boost the success of triatomine control programs, reducing the use of insecticides. PMID- 29625092 TI - Artificial blood feeders for mosquito and ticks-Where from, where to? AB - Mosquito and tick feeding activity represent a key threat for humans, livestock, pets and wildlife worldwide. Rearing these vectors in laboratory conditions is extremely important to investigate basic facets of their biology, vector competence, new control strategies, as well as mechanisms of pesticide resistance. However, the use of animals or humans to provide blood for hematophagous arthropod feeding poses a strict limit to these researches, due to the accidental transmission of diseases, ethical problems concerning animal welfare, as well as expensive and time-consuming animal rearing procedures. The use of devices to artificially feed arthropod vectors can importantly leverage progresses in parasitology and entomology. The aim of this review is to summarize current knowledge about artificial feeding of mosquitoes and ticks, focusing on key concepts and case studies about the design and fabrication of blood feeding devices. From a technical standpoint, the literature analyzed here showed little standardization of materials used for fabricating membrane interfaces, as well as in the strategy used to heat the "biomimetic host". In addition, a lack of uniform methods to design an architecture merging complex and realistic cues with an easy-to-assemble approach have been found. Some commercial products are available, but they are quite expensive, thus hard to reach for many laboratories, especially in developing countries. An important challenge for future research is represented by the introduction of automation and bioinspired engineered solutions in these devices, improving the effectiveness of blood feeding systems by increasing their host-mimicking features. Automation can reduce labor costs and provide interesting solutions - in line with the 3R principle "reduce, replace and refine" - aimed to minimize the employ of experimental animals in research. PMID- 29625093 TI - Is Going Beyond Rasch Analysis Necessary to Assess the Construct Validity of a Motor Function Scale? AB - OBJECTIVE: To examine whether a Rasch analysis is sufficient to establish the construct validity of the Motor Function Measure (MFM) and discuss whether weighting the MFM item scores would improve the MFM construct validity. DESIGN: Observational cross-sectional multicenter study. SETTING: Twenty-three physical medicine departments, neurology departments, or reference centers for neuromuscular diseases. PARTICIPANTS: Patients (N=911) aged 6 to 60 years with Charcot-Marie-Tooth disease (CMT), facioscapulohumeral dystrophy (FSHD), or myotonic dystrophy type 1 (DM1). INTERVENTIONS: None. MAIN OUTCOME MEASURE(S): Comparison of the goodness-of-fit of the confirmatory factor analysis (CFA) model vs that of a modified multidimensional Rasch model on MFM item scores in each considered disease. RESULTS: The CFA model showed good fit to the data and significantly better goodness of fit than the modified multidimensional Rasch model regardless of the disease (P<.001). Statistically significant differences in item standardized factor loadings were found between DM1, CMT, and FSHD in only 6 of 32 items (items 6, 27, 2, 7, 9 and 17). CONCLUSIONS: For multidimensional scales designed to measure patient abilities in various diseases, a Rasch analysis might not be the most convenient, whereas a CFA is able to establish the scale construct validity and provide weights to adapt the item scores to a specific disease. PMID- 29625094 TI - Conceptual Underpinnings of the Quality of Life in Neurological Disorders (Neuro QoL): Comparisons of Core Sets for Stroke, Multiple Sclerosis, Spinal Cord Injury, and Traumatic Brain Injury. AB - OBJECTIVE: To determine the extent to which the content of the Quality of Life in Neurological Disorders (Neuro-QoL) covers the International Classification of Functioning, Disability and Health (ICF) Core Sets for multiple sclerosis (MS), stroke, spinal cord injury (SCI), and traumatic brain injury (TBI) using summary linkage indicators. DESIGN: Content analysis by linking content of the Neuro-QoL to corresponding ICF codes of each Core Set for MS, stroke, SCI, and TBI. SETTING: Three academic centers. PARTICIPANTS: None. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Four summary linkage indicators proposed by MacDermid et al were estimated to compare the content coverage between Neuro-QoL and the ICF codes of Core Sets for MS, stroke, MS, and TBI. RESULTS: Neuro-QoL represented 20% to 30% Core Set codes for different conditions in which more codes in Core Sets for MS (29%), stroke (28%), and TBI (28%) were covered than those for SCI in the long-term (20%) and early postacute (19%) contexts. Neuro-QoL represented nearly half of the unique Activity and Participation codes (43%-49%) and less than one third of the unique Body Function codes (12%-32%). It represented fewer Environmental Factors codes (2%-6%) and no Body Structures codes. Absolute linkage indicators found that at least 60% of Neuro-QoL items were linked to Core Set codes (63%-95%), but many items covered the same codes as revealed by unique linkage indicators (7%-13%), suggesting high concept redundancy among items. CONCLUSIONS: The Neuro-QoL links more closely to ICF Core Sets for stroke, MS, and TBI than to those for SCI, and primarily covers activity and participation ICF domains. Other instruments are needed to address concepts not measured by the Neuro-QoL when a comprehensive health assessment is needed. PMID- 29625095 TI - Predictive Validity of the STarT Back Tool for Risk of Persistent Disabling Back Pain in a U.S. Primary Care Setting. AB - OBJECTIVE: To examine the predictive validity of the Subgrouping for Targeted Treatment (STarT Back) tool for classifying people with back pain into categories of low, medium, and high risk of persistent disabling back pain in U.S. primary care. DESIGN: Secondary analysis of data from participants receiving usual care in a randomized clinical trial. SETTING: Primary care clinics. PARTICIPANTS: Adults (N = 1109) >=18 years of age with back pain. Those with specific causes of back pain (pregnancy, disc herniation, vertebral fracture, spinal stenosis) and work-related injuries were not included. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The original 9-item version of the STarT Back tool, administered at baseline, stratified patients by their risk (low, medium, high) of persistent disabling back pain (STarT Back risk group). Persistent disabling back pain was defined as Roland-Morris Disability Questionnaire scores of >=7 at 6-month follow-up. RESULTS: The STarT Back risk group was a significant predictor of persistent disabling back pain (P<.0001) at 6-month follow-up. The proportion of individuals with persistent disabling back pain at follow-up was 22% (95% confidence interval [CI] 18-25) in the low-risk group, 62% (95% CI 57-67) in the medium-risk group, and 80% (95% CI 75-85) in the high-risk group. The relative risk of persistent disabling back pain was 2.9 (95% CI 2.4-3.5) in the medium risk group compared to the low-risk group, and 3.7 (95% CI 3.1-4.4) in the high risk group. CONCLUSIONS: The STarT Back risk groups successfully separated people with back pain into distinct categories of risk for persistent disabling back pain at 6-month follow-up in U.S. primary care. These results were very similar to those in the original STarT Back validation study. This validation study is a necessary first step toward identifying whether the entire STarT Back approach, including matched/targeted treatment, can be effectively used for primary care in the United States. PMID- 29625096 TI - Molecular characterization and functional analysis of components of the TOR pathway of the salmon louse, Lepeophtheirus salmonis (Kroyer, 1838). AB - The salmon louse Lepeophtheirus salmonis (Copepods, Caligida) is a marine ectoparasite infecting salmonid fishes in the northern hemisphere. At present, salmon lice infections are the most severe disease problem in the salmon farming industry causing significant economic losses. Due to development of resistance towards available chemotherapeutants, it is clear that new chemotherapeutants or non-chemical control methods are essential to manage the parasite in the future. The TOR signaling pathway is present in all metazoans and is a major regulator of cellular activity according to nutrient availability. In this study, we identified the TOR pathway genes in salmon louse; LsTSC1, LsTSC2, LsRheb, LsTOR, LsRaptor and LsRictor. RNA interference mediated gene silencing was performed to elucidate the functional role of each member of the pathway. Our results show that interference of the TOR signaling pathway either directly or indirectly inhibits many biological processes including egg maturation. In addition, the effect of gene knock-down results in more comprehensive physiological defects when targeting TORC1 and the upstream regulator Rheb. This is the first report on the TOR pathway in the salmon louse and that our research contributes to the basic knowledge of the parasite that could lead to development of novel treatment methods. PMID- 29625097 TI - Chloroquine as a possible disinfection adjunct of disinfection solutions against Acanthamoeba. AB - Acanthamoeba keratitis is commonly encountered by contact lens wearers. Contact lens solution plays an important role in the safe use of contact lenses. The most popular products for disinfecting lenses are multipurpose disinfecting solutions (MPDS). However, almost all MPDS retailed in Korea are ineffective in killing Acanthamoeba. The objective of this study was to determine the possibility of using autophagy inhibitor chloroquine as a disinfecting agent to improve the amoebicidal activity of MPDS against Acanthamoeba, especially the cyst. Amoebicidal effects of eight different MPDSs combined with chloroquine (CQ), an autophagy inhibitor, and their cytotoxicities to human corneal epithelium cells were determined. Almost all MPDS showed strong amoebicidal effect on trophozoites after 8 h of exposure. However, they showed inadequate amoebicidal effect on cysts even after 24 h of exposure. MPDSs combined with 100 MUM CQ increased their amoebicidal effects on immature cyst by inhibiting formation of mature cysts. Incubation with 100 MUM CQ for 30 min did not have cytotoxicity to human corneal epithelial cells. PMID- 29625098 TI - Evaluation of kinase-inhibitors nilotinib and everolimus against alveolar echinococcosis in vitro and in a mouse model. AB - Infection with the larval stage (metacestode) of the fox tapeworm Echinococcus multilocularis leads to a primary hepatic disease referred to as alveolar echinococcosis (AE). The progressive disease can be lethal if untreated. In cases where complete parasite resection by surgery is not feasible, the current treatment regimens of AE consist of chemotherapy with the parasitostatic benzimidazoles albendazole or mebendazole over decades. Kinase-inhibitors currently administered in various cancer treatments are of increasing interest also as anti-parasitic drugs due to previous promising in vitro results. In order to search for novel drug targets and treatment regimens, nilotinib (AMN107; Tasigna(r)), an Abl-tyrosine kinase inhibitor and everolimus (RAD001; Afinitor(r)), a serine/threonine-kinase inhibitor, were tested for their treatment efficacy against metacestode vesicles of E. multilocularis in vitro and in BALB/c mice. In vitro treatment with 200 MUM nilotinib caused drug-induced alterations after 12 days, and everolimus exerted parasite damage at concentrations dosing from 40 to 100 MUM after 5 and 12 days of in vitro exposure. Nilotinib (100 mg/kg) + erythromycin (to increase nilotinib plasma levels: 10 mg/kg intraperitoneal) or everolimus (5 mg/kg) were formulated in honey and administered daily for three weeks and subsequently twice a week for an additional three weeks in experimentally infected mice. Treatments did not result in any reduction of parasite growth compared to untreated control groups, whereas oral treatment with albendazole (200 mg/kg) was highly effective. Combined application of the kinase-inhibitors with albendazole did not lead to a synergistic or additive treatment efficacy compared to albendazole treatment alone. These results show that neither nilotinib nor everolimus represent valuable alternatives to the current treatment regimens against AE. PMID- 29625099 TI - Sinergism between alkaloids piperine and capsaicin with meglumine antimoniate against Leishmania infantum. AB - The primary choice of drugs to treat Leishmaniasis are the pentavalent antimony based compounds, nevertheless these drugs presented undesirable side effects. However, safe natural compounds could be used in combination with these drugs to enhance their activity. The aim of this study was to evaluate the sinergism of capsaicin and piperine, isolated from Capsicum frutescens and Piper nigrum, respectively, in combination with meglumine antimoniate against Leishmania infantum promastigote and amastigote forms. Each compound was mixed with the standard drug in several percentage mixtures and tested at various concentrations. Capsaicin and piperine in combination with meglumine antimoniate (25% + 75%) showed better anti-leishmanial activity with EC50 = 4.31 +/- 0.44 e 7.25 +/- 4.84 MUg/mL against promastigote and amastigote forms, respectively. The results point that these spice alkaloids are suitable compounds to be administered in combinations with antileishmanial drugs to improve their action. PMID- 29625100 TI - National Comparison of Hospital Performances in Lung Cancer Surgery: The Role of Case Mix Adjustment. AB - BACKGROUND: When comparing hospitals on outcome indicators, proper adjustment for case mix (a combination of patient and disease characteristics) is indispensable. This study examines the need for case mix adjustment in evaluating hospital outcomes for non-small cell lung cancer surgery. METHODS: Data from the Dutch Lung Cancer Audit for Surgery were used to validate factors associated with postoperative 30-day mortality and complicated course with multivariable logistic regression models. Between-hospital variation in case mix was studied by calculating medians and interquartile ranges for separate factors on the hospital level and the "expected" outcomes per hospital as a composite measure. RESULTS: A total of 8,040 patients, distributed over 51 Dutch hospitals, were included for analysis. Mean observed postoperative mortality and complicated course were 2.2% and 13.6%, respectively. Age, American Society of Anesthesiologists classification, Eastern Cooperative Oncology Group performance score, lung function, extent of resection, tumor stage, and postoperative histopathologic findings were individual significant predictors for both outcomes of postoperative mortality and complicated course. A considerable variation of these case mix factors among hospital populations was observed, with the expected mortality and complicated course per hospital ranging from 1.4% to 3.2% and from 11.5% to 17.1%, respectively. CONCLUSIONS: The between-hospital variation in case mix of patients undergoing surgical treatment for non-small cell lung cancer emphasizes the importance of proper adjustment when comparing hospitals on outcome indicators. PMID- 29625101 TI - Spread Through Air Spaces Is a Prognostic Factor in Sublobar Resection of Non Small Cell Lung Cancer. AB - BACKGROUND: Spread through air spaces (STAS) identified in lung cancer is considered to be a risk factor for recurrence after surgery. The purpose of this study is to clarify the prognostic impact of STAS in sublobar resections. METHODS: We studied 514 patients with clinical stage IA cancers: 329 underwent lobectomies and 185 underwent sublobar resections. We assessed the prognostic impact of STAS in the cases with a sublobar resection for stage IA lung cancer versus the cases with a lobectomy. RESULTS: STAS was found in 73 of 329 (22.2%) lobectomy cases and 31 of 185 (16.8%) sublobar resection cases. For overall survival, univariate analysis revealed that STAS was not a prognostic factor in the lobectomy group, but it was a significantly worse prognostic factor for the sublobar resection group in both univariate and multivariate analyses. For the recurrence-free rate, multivariate analysis showed STAS was not a risk factor in the lobectomy group, but it was a significant risk factor for the sublobar resection group in both univariate and multivariate analyses. Patients with STAS and sublobar resection had a significantly higher rate of pulmonary metastases than did patients with STAS and lobectomy (8 of 31 [25.8%] vs 6 of 73 [8.2%]). CONCLUSIONS: STAS is a prognostic factor of poor outcomes for sublobar resection in patients with lung cancer. The worse prognosis for sublobar resection would be associated with STAS. PMID- 29625102 TI - Tricuspid Valve Detachment in Ventricular Septal Defect Closure Does Not Impact Valve Function. AB - BACKGROUND: Although tricuspid valve detachment (TVD) facilitates improved exposure during transatrial ventricular septal defect (VSD) closure, few have analyzed the impact of TVD on long-term valve durability. METHODS: Pediatric patients undergoing VSD closure at our institution from 1997 to 2013 were identified, and charts were retrospectively reviewed. Patients were separated into groups based on utilization of TVD. Propensity score matching was then performed using a nonparsimonious logistic regression model involving 7 variables. Primary outcome was residual TV dysfunction at long-term follow-up, defined as mild (2+) and moderate (3+) TV regurgitation (TR) on follow-up echocardiography. Secondary outcomes included postoperative atrioventricular dissociation, residual VSD, and reinterventions. RESULTS: A total of 247 patients underwent VSD closure; 164 (66.4%) without TVD and 83 (33.6%) with TVD. Median follow-up time was 2,343 days (interquartile range, 1,237 to 3,963.5 days) in the group without TVD versus 1,606 days (interquartile range, 826 to 3,017 days) in those with TVD. After successfully matching 83 patients, 29 of 83 (34.9%) patients in the non-TVD group had mild TR versus 28 of 83 (33.7%) patients in the TVD group (p = 0.87). 2 patients in the non-TVD group had moderate TR versus 1 patient in the TVD group at long-term follow-up. One patient in each group suffered transient atrioventricular block, but neither required pacemaker insertion. CONCLUSIONS: TVD did not compromise long-term valve durability and did not impose increased morbidity. Patients who underwent TVD had a similar prevalence of mild TR to patients without TVD. Moderate TR was exceptionally rare in both groups. When exposure is difficult, TVD is a safe and effective technical adjunct. PMID- 29625103 TI - Aortic Valve Reoperation After Stentless Bioprosthesis: Short- and Long-Term Outcomes. AB - BACKGROUND: Limited data are available regarding outcomes for stentless aortic valve reoperation. The reported reoperative mortality has been unacceptably high. METHODS: Between 1997 and 2017, a retrospective analysis was performed on 143 patients who underwent open aortic valve reoperations for failed stentless aortic valve bioprostheses. We evaluated both short-term and long-term outcomes on this cohort of patients. RESULTS: Bicuspid aortic valve was present in 107 of 143 patients (75%) at the time of the initial Freestyle (Medtronic, Minneapolis, MN) procedure, and 120 of 143 patients (84%) underwent a modified inclusion aortic root replacement procedure. The interval from first operation to reoperation was 9 years (range, 5.4 to 11.8), which was significantly shorter for patients with infectious endocarditis (4.1 years; range, 1.8 to 7.1) compared with patients with structural valvular deterioration (10.4 years; range, 8.1 to 12.4, p < 0.001). The median age at the time of reoperation was 59 years (range, 50 to 67). Aortic valve reoperation was performed for structural valve deterioration in 68% cases compared with 32% for infectious prosthetic valve endocarditis. Concomitant surgery included coronary artery bypass (13%), mitral valve surgery (4%), and ascending aorta and arch replacement (42%). The 30-day and inhospital mortality was 1% and 2%, respectively. The composite outcome including myocardial infarction, stroke, new-onset renal failure on hemodialysis, and operative mortality was 4%. The 5-year and 10-year Kaplan-Meier survival after reoperation for failed stentless valve was 83% (95% confidence interval: 73% to 89%) and 57% (95% confidence interval: 36% to 74%). CONCLUSIONS: Aortic valve reoperation after stentless valve implantation can be performed with low operative mortality and favorable long-term survival. PMID- 29625104 TI - Structural requirement of the hydrophobic region of the Bordetella pertussis CyaA hemolysin for functional association with CyaC-acyltransferase in toxin acylation. AB - Previously, we demonstrated that the ~130-kDa CyaA-hemolysin (CyaA-Hly, Met482 Arg1706) from Bordetella pertussis was palmitoylated at Lys983 when co-expressed with CyaC-acyltransferase in Escherichia coli, and thus activated its hemolytic activity. Here, further investigation on a possible requirement of the N-terminal hydrophobic region (HP, Met482-Leu750) for toxin acylation was performed. The ~100-kDa RTX (Repeat-in-ToXin) fragment (CyaA-RTX, Ala751-Arg1706) containing the Lys983-acylation region (AR, Ala751-Gln1000), but lacking HP, was co-produced with CyaC in E. coli. Hemolysis assay indicated that CyaA-RTX showed no hemolytic activity. Additionally, MALDI-TOF/MS and LC-MS/MS analyses confirmed that CyaA RTX was non-acylated, although the co-expressed CyaC-acyltransferase was able to hydrolyze its chromogenic substrate-p-nitrophenyl palmitate and acylate CyaA-Hly to become hemolytically active. Unlike CyaA-RTX, the ~70-kDa His-tagged CyaA HP/BI fragment which is hemolytically inactive and contains both HP and AR was constantly co-eluted with CyaC during IMAC-purification as the presence of CyaC was verified by Western blotting. Such potential interactions between the two proteins were also revealed by semi-native PAGE. Moreover, structural analysis via electrostatic potential calculations and molecular docking suggested that CyaA-HP comprising alpha1-alpha5 (Leu500-Val698) can interact with CyaC through several hydrogen and ionic bonds formed between their opposite electrostatic surfaces. Overall, our results demonstrated that the HP region of CyaA-Hly is conceivably required for not only membrane-pore formation but also functional association with CyaC-acyltransferase, and hence effective palmitoylation at Lys983. PMID- 29625105 TI - Myoclonus epilepsy, retinitis pigmentosa, leukoencephalopathy and cerebral calcifications associated with a novel m.5513G>A mutation in the MT-TW gene. AB - We sequenced the mitochondrial genome from a 40-year-old woman with myoclonus epilepsy, retinitis pigmentosa, leukoencephalopathy and cerebral calcifications. Histological and biochemical features of mitochondrial respiratory chain dysfunction were present. Direct sequencing showed a novel heteroplasmic mutation at nucleotide 5513 in the MT-TW gene that encodes tRNATrp. Restriction Fragment Length Polymorphism analysis confirmed that about 80% of muscle mtDNA harboured the mutation while it was present in minor percentages in mtDNA from other tissues. The mutation is predicted to disrupt a highly conserved base pair within the aminoacyl acceptor stem of the tRNA. This is the 17 degrees mutation in MT TW gene and expands the known causes of late-onset mitochondrial diseases. PMID- 29625106 TI - Full-length RPB1 is required in two-step shoot regeneration. AB - Regeneration is a complicated progress in plants and animals. Most multicellular organisms can regenerate new tissue when wounded, and plants excel most animals in their ability to regenerate whole new growth module from adult tissues. Regeneration in Arabidopsis includes two steps. Firstly, the explants from differentiated plant tissues such as roots or hypocotyls are induced to generate callus, then the shoots regenerate upon the callus. The phytohormone auxin and cytokinin play important parts in this process. And genes related to auxin and cytokinin siganls involved in the regeneration have been studied widely. As we reported before, in Arabidopsis the full-length CTD of RNA Polymerase II's largest subunit RPB1 is necessary in keeping normal cell cycling and maintaining stem cell niches. Here, we report that the mutants of card1s have significant defects in the regeneration progress both in the induction of callus and the formation of shoot. All the results further proved the importance of intact RPB1 from a distinctive perspective. PMID- 29625107 TI - Cephalosporin antibiotics are weak blockers of GABAa receptor-mediated synaptic transmission in rat brain slices. AB - Cephalosporins are beta-lactam antibiotics that are extensively used in medical practice and are reported to cause epileptic seizures in some patients. The primary cause of cephalosporin-induced convulsions is believed to be their ability to block GABAa receptors. However, direct evidence for the involvement of this mechanism has not yet been provided. The present study aims to investigate the ability of two cephalosporins - cefepime and ceftriaxone - to block inhibitory synaptic transmission in entorhinal cortex slices of rats. Using the whole-cell patch-clamp method, we found that millimolar concentrations of cefepime (IC50 = 1.6 +/- 0.1 mM) and ceftriaxone (2.0 +/- 0.1 mM) were required to block the evoked inhibitory postsynaptic currents (IPSCs). These concentrations are almost two orders of magnitude higher than cerebrospinal fluid concentrations of antibiotics achieved during treatment. We also found that while ceftriaxone did not affect the IPSC decay kinetics, cefepime significantly slowed the decays of the evoked currents, which may be attributed to the diverse mechanisms of the GABAa receptor inhibition of cefepime and ceftriaxone. The experiments involving the fast application of GABA at various concentrations to isolated neurons suggests that cefepime blocks receptors competitively, while ceftriaxone does so noncompetitively. Cefepime, at a concentration of up to 4 mM, was unable to produce seizure-like events in brain slices. However, this antibiotic could induce epileptiform activity in combination with the altered ionic composition of the perfusing media, which may be the case for patients with renal insufficiency. Our results suggest that cefepime and ceftriaxone are weak GABAa receptor blockers and that it is unlikely that the inhibition of GABAa receptors by antibiotics is the primary cause of the seizures. PMID- 29625108 TI - Oncogenic MicroRNA-20a is downregulated by the HIF-1alpha/c-MYC pathway in IDH1 R132H-mutant glioma. AB - Mutations in the isocitrate dehydrogenase 1 (IDH1) gene have been identified as one of the earliest events in gliomagenesis, occurring in over 70% of low grade gliomas and are present in the vast majority of secondary glioblastoma (GBM) that develop from these low-grade lesions. The aim of this study was to investigate whether the IDH1 R132H mutation influences the expression of oncogenic miR-20a and shed light on the underlying molecular mechanisms. The findings of the current study demonstrate presence of the IDH1 R132H mutation in primary human glioblastoma cell lines with upregulated HIF-1alpha expression, downregulating c MYC activity and resulting in a consequential decrease in miR-20a, which is responsible for cell proliferation and resistance to standard temozolomide treatment. Elucidating the mechanism of oncogenic miR-20a activity introduces its role among well-established signaling pathways (i.e. HIF/c-MYC) and may be a meaningful prognostic biomarker or target for novel therapies among patients with IDH1-mutant glioma. PMID- 29625109 TI - Generation of splice switching oligonucleotides targeting the Cockayne syndrome group B gene product in order to change the diseased cell state. AB - Cockayne syndrome (CS) is a severe disorder with no effective treatment. The Cockayne syndrome group B (CSB) gene is one gene responsible for CS and also causes UV sensitive syndrome (UVSS), a disorder that causes mild symptoms. How the CSB gene determines a patient's fate is unknown, but one intriguing point is that in UVSS patient cell, there are nonsense mutations in both alleles at the same position in each upstream region of the PiggyBac transposable element derived 3 (PGBD3) inserted region. In contrast, in CS patient cells, there is at least one allele with several mutations downstream of the PGBD3 inserted region, or there are homozygous mutations in exon 1. Here, we designed and synthesized 24 splice switching oligonucleotides (SSOs) to skip exon 3 in CSB mRNA. Use of these SSOs induced a frame shift in order to generate an alternative stop codon at the upstream region of the PGBD3 invasion site. As a result, a reduction of mitochondrial membrane potential following H2O2 treatment in CS cell was recovered. It was demonstrated that up-regulation of several gene expression brought about by SSOs are related to mitochondrial dysfunction in CS cells. PMID- 29625110 TI - LncRNA TP73-AS1 predicts the prognosis of bladder cancer patients and functions as a suppressor for bladder cancer by EMT pathway. AB - Long noncoding RNAs (lncRNAs) have been identified to have more and more important roles in tumorigenesis and may be novel biomarker for cancer therapy. LncRNA TP73-AS1 is a novel identified lncRNA that has been demonstrated to be increased in several cancers, however, its function in bladder cancer remains unknown. The aim of this work was to examine the expression and role of lncRNA TP73-AS1 in bladder cancer. The expression levels of lncRNA TP73-AS1 in bladder cancer tissues and cell lines were determined by quantitative real-time PCR (qRT PCR), and its clinical significance was assessed by statistical analysis. Moreover, by gain-of-function assay, the effect of TP73-AS1 on proliferation, cell cycle, apoptosis, migration and invasion was examined in bladder cancer cells. We identified that the expression level of TP73-AS1 was significantly down regulated in bladder cancer tissues and cells compared to adjacent non-tumor tissues. Kaplan-Meier survival analysis found that patients with low TP73-AS1 expression level had shorter overall survival and progression-free survival than those with high TP73-AS1 expression. Moreover, we showed that overexpression of TP73-AS1 could inhibit cell growth, arrest cell cycle, reduce cell migration and invasion, and promote cell apotosis in vitro study. In addition, overexpression of TP73-AS1 diminished epithelial-mesenchymal transition (EMT) through inhibiting the expression of vimentin, snail, MMP-2, and MMP-9 and upregulating the expression levels of E-cadherin. Collectively, our findings for the first time elucidated that lncRNA TP73-AS1 may serve as a tumor suppressor participated in bladder cancer progression, which provided a promising therapy strategy for patients with bladder cancer. PMID- 29625111 TI - Insect taste receptors relevant to host identification by recognition of secondary metabolite patterns of non-host plants. AB - The taste sensing system is crucial for food recognition in insects and other animals. It is commonly believed that insect gustatory receptors (Grs) expressed in gustatory organs are indispensable for host plant selection. Many behavioral studies have shown that mono- or oligo-phagous lepidopteran insects use the balance between feeding attractants and feeding deterrents in host plants and that these are sensed by taste organs for host plant recognition. However, the molecular mechanism underlying taste recognition, especially of feeding deterrents, remains to be elucidated. To better understand this mechanism, we studied orphan Grs, including Bombyx mori Gr (BmGr) 16, BmGr18, and BmGr53, from the mono-phagous insect, Bombyx mori. Using Calcium imaging in mammalian cells, we first confirmed in lepidoptera insects that three of the putative bitter Grs widely responded to structurally different feeding deterrents. Although the phylogenetic distance of these Grs was considerable, they responded to partially overlapping deterrents of plant secondary metabolites. These findings suggest that not only these three Grs but also most of the Grs that have been assigned to putative bitter Grs are feeding-deterrent receptors that play a role in host plant recognition. PMID- 29625112 TI - The transcriptional factor Apt regulates neuroblast differentiation through activating CycE expression. AB - In Drosophila, the thoracic neuroblast 6-4 (NB6-4T) divides asymmetrically into a glial precursor and a neuronal precursor, while the abdominal neuroblast 6-4 (NB6 4A) divides symmetrically to produce two glial cells. The underlying mechanism by which NB6-4T and NB6-4A undergo distinct differentiation is still elusive. Here, we find that the transcription factor Apontic (Apt) exclusively expresses in NB6 4T cells and is involved in regulating NB6-4T differentiation. Loss of Apt results in neuronal precursor loss. Epistasis analysis shows that Apt controls NB6-4T differentiation through activating CycE expression. On the other hand, Gcm suppresses Apt expression in the NB6-4A cell, thus inhibiting CycE expression. Taken together, our findings reveal a Gcm-Apt-CycE axis that regulates neuroblast and glia cell differentiation. PMID- 29625113 TI - Exosomal proteome analysis of human plasma to monitor sepsis progression. AB - Exosomes are cell-derived vesicles containing RNA, lipid, and protein, which act in body immune response, intercellular signaling and some other important biological processes. Exosomes have been extensively studied in the past several years on their disease related mechanisms and potential roles to monitor disease progression as biomarkers. Compared with analyzing exosome RNA, comprehensive proteome profiling of exosomes in clinical samples (e.g. blood) are highly demanded but limited mainly due to lack of a reproducible method for efficient exosome extraction. In this study, we evaluated and optimized an exosome preparation approach using one-step ultracentrifugation through an OptiprepTM cushion. Exosomes prepared via this method and analyzed by mass spectrometry using Q-Exactive plus, has led to reproducible identification and quantification of 200 + proteins from human plasma samples of as little as 300 MUL. Therefore, such a straightforward exosome extract method has enable us to deeply profile exosome proteomes from human blood at a scale of clinical studies. As a proof of principal, we practiced this approach in analyzing the exosome proteomic profiles of blood samples collected from a sepsis patient during six time points after diagnosis. Among the 238 proteins identified and quantified across the 6 samples, protein SPTLC3 involved in the sphingolipid metabolism, shows a negative correlation (p = 0.02, correlation coefficient = -0.984) with disease progression indicated by body temperature (BD) and C-reactive protein (CRP). Therefore, SPTLC3 could be an interesting target for future study on molecular mechanism of sepsis development, as well as potential classifier to monitor clinical progression of sepsis. PMID- 29625114 TI - Memantine treatment of juvenile rats with kaolin-induced hydrocephalus. AB - Memantine is a selective, non-competitive N-methyl-D-aspartate (NMDA) receptor antagonist that has previously been shown to have neuroprotective qualities in some animal models of neurologic disease. We hypothesized that memantine therapy would improve behavioral, neuropathological, and/or biochemical outcomes in juvenile rats with kaolin-induced hydrocephalus. Three-week old rats received an injection of kaolin (aluminum silicate) into the cisterna magna. Magnetic resonance imaging was performed one week later to assess ventricle size and stratify rats to three treatment groups. Rats were blindly treated daily for three weeks with saline or 10 or 30 mg/kg/day memantine. Behavior measures were performed weekly. Histologic and biochemical evaluations were performed at termination. Hydrocephalic rats showed no differences in weight among treatment groups. Memantine treatment stabilized ventricular enlargement in both low and high dose groups. The high dose group exhibited increased motor activity in open field chambers compared to the vehicle-treated group. However, there were no significant differences between the three hydrocephalic treatment groups for other behavioral tasks. Ventriculomegaly was associated with periventricular white matter damage. Glial fibrillary acidic protein (GFAP) content was higher in the low dose memantine group compared to vehicle-treated group, but there were no differences in GFAP-immunoreactive astrocytes or Iba-1- immunoreactive microglia between groups. Memantine therapy stabilized ventricular expansion and improved some behavioral measures but did not reduce brain tissue changes in juvenile rats with kaolin-induced hydrocephalus. PMID- 29625115 TI - Administration of placenta-derived mesenchymal stem cells counteracts a delayed anergic state following a transient induction of endogenous neurogenesis activity after global cerebral ischemia. AB - BACKGROUND: Global cerebral ischemia (GCI) is a major obstacle for cardiac arrest survival. Recent studies have suggested the possibility of mesenchymal stem cell (MSC) as a novel therapeutic option for GCI, but these results were limited to the neuroprotective effects of MSCs. Therefore, we aimed to investigate specific characteristics of neurogenesis after transient GCI, and to assess the effect of MSC on these characteristics. METHODS: Adult male Sprague-Dawley rats were subjected to 7 min of transient GCI and randomized into 7 groups: baseline, MSC, and control administered groups, to be analyzed at 2, 3, and 4 weeks after GCI, respectively. The same interventions were repeated for sham operated animals. Rats were euthanized at the designated time after GCI. RESULTS: A comparison of GCI and sham groups without MSC treatment, showed that the counts of bromodeoxyuridine (BrdU)- and doublecortin (DCX)-positive cells were significantly increased in the GCI group at 1 week after insult, but the trend was reversed at 3 weeks after insult. The counts of BrdU-, Ki67- and DCX-positive cells and the intensity of zinc translocator 3 (ZnT3) were all significantly higher in the MSC-treated group than those in the control group at 3 weeks after GCI. The count of NeuN-positive cells in the hippocampus was significantly increased in the MSC group at 4 weeks after GCI. CONCLUSIONS: GCI induces transient neurogenesis, followed by an anergic state. MSC may counteract this anergy of neurogenesis and result in an increase in intact neurons in later stages. PMID- 29625116 TI - Neuropeptide Y (NPY) or cocaine- and amphetamine-regulated transcript (CART) fiber innervation on central and medial amygdaloid neurons that project to the locus coeruleus and dorsal raphe in the rat. AB - The amygdaloid nuclear complex has been linked to the regulation of emotional behavior and energy regulation in that emotional stress might cause either reduction or enhancement of eating. We examined hypothalamic neuronal origin of feeding/arousal-related peptidergic fibers containing cocaine- and amphetamine regulated transcript (CART) and neuropeptide Y (NPY) located in the rat amygdala along with its efferent projections to the brainstem monoaminergic nuclei. First, central (CeA) as well as medial (MeA) amygdala, among several amygdaloid subdivisions, exhibited the most prominent NPY or CART immunostaining which consisted of a substantial number of somata as well as labeled fibers. When we examined hypothalamic neuronal origin of NPY or CART fibers projecting to the CeA and MeA, medial and lateral arcuate nuclei were neuronal origins of NPY and CART fibers, respectively. However, the majority (>70%) of amygdala-projecting CART neurons which co-contained melanin-concentrating hormone (MCH) originated from the lateral hypothalamus (LH), zona incerta (ZI), and dorsal hypothalamic area (DA). This observation implied that the CeA as well as the MeA might receive potent second-order (and downstream) feeding-related CART input from the lateral hypothalamic regions in addition to first-order CART or NPY input from the Arc. Second, a large number of CeA neurons projected to the locus coeruleus (LC), whereas only a small number of MeA cells projected to the dorsal raphe (DR); none of the CeA or MeA cells provided dual projections to the LC and DR. Finally, a portion of MCH cells in the LH, ZI, and DA sent divergent axon collaterals to the CeA and LC. Considering that the CeA sends substantial GABAergic input to the LC, the present observation might serve as an anatomical substrate to support the potent hypnogenic role of MCH neurons in the LH regions during cataplexy and REM sleep. PMID- 29625117 TI - The role of ventral striatum in reward-based attentional bias. AB - INTRODUCTION: Models of attention suggest that endogenous and exogenous factors can bias attention. However, recent data suggest that reward can also enhance attention towards relevant stimulus features as a function of involuntary biases. In this study, we utilized the additional singleton task to determine the neural circuitry that biases perceptual processing as a function of reward history. METHODS: Participants searched for a unique shape amongst an array of differently shaped objects. All shapes, including the target shape, had the same color except one distractor shape. Participants randomly received a low or high reward after correct trials. From one trial to the next, target colors could stay the same or swap with the distractor color. Interestingly, and despite the irrelevancy of reward magnitude for task accuracy, the difference in reaction time between swap and non-swap trials usually is more pronounced following a high compared to a low reward. RESULTS: In the current study, we showed that reward modulated attention is larger for individuals with enhanced reward magnitude sensitivity in the ventral striatum. In addition, connectivity data shows that ventral striatum was more positively connected with visual cortex during high reward non-swap trials compared to high reward swap trials for participants showing stronger reward modulated attention. CONCLUSIONS: This suggests that involuntary reward modulated attention might be implemented by direct influences of the ventral striatum on visual cortex. PMID- 29625118 TI - FUS causes synaptic hyperexcitability in Drosophila dendritic arborization neurons. AB - Mutations in the nuclear localization signal of the RNA binding protein FUS cause both Frontotemporal Dementia (FTD) and Amyotrophic Lateral Sclerosis (ALS). These mutations result in a loss of FUS from the nucleus and the formation of FUS containing cytoplasmic aggregates in patients. To better understand the role of cytoplasmic FUS mislocalization in the pathogenesis of ALS, we identified a population of cholinergic neurons in Drosophila that recapitulate these pathologic hallmarks. Expression of mutant FUS or the Drosophila homolog, Cabeza (Caz), in class IV dendritic arborization neurons results in cytoplasmic mislocalization and axonal transport to presynaptic terminals. Interestingly, overexpression of FUS or Caz causes the progressive loss of neuronal projections, reduction of synaptic mitochondria, and the appearance of large calcium transients within the synapse. Additionally, we find that overexpression of mutant but not wild type FUS results in a reduction in presynaptic Synaptotagmin, an integral component of the neurotransmitter release machinery, and mutant Caz specifically disrupts axonal transport and induces hyperexcitability. These results suggest that FUS/Caz overexpression disrupts neuronal function through multiple mechanisms, and that ALS-causing mutations impair the transport of synaptic vesicle proteins and induce hyperexcitability. PMID- 29625119 TI - The exosome of adipose-derived stem cells reduces beta-amyloid pathology and apoptosis of neuronal cells derived from the transgenic mouse model of Alzheimer's disease. AB - Adipose-derived stem cells (ADSC) have a therapeutic potential for the treatment of neurodegenerative disorders such as Alzheimer's disease (AD). Exosomes are extracellular vesicles secreted from various types of cells, and stem cell derived exosomes are known to have beneficial effects in many diseases. Many studies have suggested that amyloid beta (Abeta) peptides have a pivotal role in AD progression, by mitochondrial dysfunction of neuronal cells. We examined the therapeutic potential of exosomes derived from ADSCs (ADSC-Exo) in preventing the disease phenotypes induced by the Abeta cascade in an AD in vitro model. Neuronal stem cells (NSCs) from the brains of TG2576 AD mice were used to examine the effects of ADSC-Exo on AD phenotypes. NSCs from AD mice can be grown as a neurosphere and differentiated. Differentiated NSCs of TG2576 mice showed increase of Abeta42 and Abeta40 levels, and Abeta42/40 ratio. Apoptotic molecules such as p53, Bax and caspase-3 were increased and Bcl2, an anti-apoptotic molecule, was decreased in AD cells compared with wild-type littermate cells. Lower viable cell population and higher necrotic cells were examined in AD neuronal cells. ELISA result showed that ADSC-Exo treatment resulted in reduced Abeta42 levels, Abeta40 levels, and the Abeta42/40 ratio of AD cells. Increased apoptotic molecules, p53, Bax, pro-caspase-3 and cleaved-caspase-3, and decreased Bcl-2 protein level were normalized by ADSC-Exo treatment. Flow cytometry analysis revealed that increased cell apoptosis of AD neuronal cells was reduced by ADSC-Exo. In addition, neurite growth, which is impaired by Abeta in the brains of patients with AD, was augmented by ADSC-Exo treatment. Taken together, these findings implicate the disease-modulating effects of ADSC-Exo in the transgenic mice-derived AD in vitro model, and ADSC-Exo can be a therapeutic source to ameliorate the progression of Abeta-induced neuronal death and AD. PMID- 29625120 TI - Impact of transcranial direct current stimulation on somatosensory transfer learning: When the secondary somatosensory cortex comes into play. AB - Transfer learning is an immanent feature of perceptual learning. Yet, despite the increasingly widespread application of transcranial direct current stimulation (tDCS) to study learning, transfer effects in response to tDCS have not been studied. Therefore, the present study investigated the transfer of tactile acuity evoked by repeatedly applied anodal tDCS over the left primary somatosensory cortex (S1) over the course of five days from the dominant (right) to the non dominant (left) index finger (IF). There was a complete transfer of improvement of the right IF to its contralateral homologue by follow-up four weeks later. Changes in tactile acuity of the left IF in the tDCSanodal condition were accompanied by a significant longitudinal change in functional connectivity between the left S1 and the right secondary somatosensory cortex (S2) assessed at day five of tDCS delivery and four week later. Moreover, we observed a close link between tactile acuity and (changes of) functional connectivity of the right S2 in the tDCSanodal condition identifying the S2 as neural correlate to mediate the transfer of tDCS effects in the somatosensory domain. These findings provide unprecedented evidence of transfer effects evoked by tDCS, implicate the S2 in somatosensory transfer learning and provide evidence in support of models of perceptual learning allocating learning to the reweighting of connections between different levels of processing. PMID- 29625121 TI - Is there any value in measuring vertebrate steroids in invertebrates? AB - This brief review questions the belief that just because it is possible to measure vertebrate steroids (such as estradiol-17beta, testosterone and progesterone) in the tissues of invertebrates, this necessarily means that they are endogenously derived or are hormones. There is a surprisingly large number of studies, mainly on mollusks, showing that they can readily absorb vertebrate steroids from the environment. They are also able to conjugate these steroids to fatty acids with great efficiency, and subsequently retain them for very long periods (with half-lives measured in weeks rather than days). This, plus the fact that key enzymes that are required for the biosynthesis of vertebrate steroids (e.g. aromatase) do not appear to be present in invertebrates, calls into doubt the claims in many studies on invertebrates that steroid concentrations are functionally linked to reproductive cycles or that invertebrates can be used as biomarker for vertebrate-type endocrine disrupters. PMID- 29625122 TI - Periodic regulation of expression of genes for kisspeptin, gonadotropin inhibitory hormone and their receptors in the grass puffer: Implications in seasonal, daily and lunar rhythms of reproduction. AB - The seasonal, daily and lunar control of reproduction involves photoperiodic, circadian and lunar changes in the activity of kisspeptin, gonadotropin inhibitory hormone (GnIH) and gonadotropin-releasing hormone (GnRH) neurons. These changes are brought through complex networks of light-, time- and non photic signal-dependent control mechanisms, which are mostly unknown at present. The grass puffer, Takifugu alboplumbeus, a semilunar spawner, provides a unique and excellent animal model to assess this question because its spawning is synchronized with seasonal, daily and lunar cycles. In the diencephalon, the genes for kisspeptin, GnIH and their receptors showed similar expression patterns with clear seasonal and daily oscillations, suggesting that they are regulated by common mechanisms involving melatonin, circadian clock and water temperature. For implications in semilunar-synchronized spawning rhythm, melatonin receptor genes showed ultradian oscillations in expression with the period of 14.0-15.4 h in the pineal gland. This unique ultradian rhythm might be driven by circatidal clock. The possible circatidal clock and circadian clock in the pineal gland may cooperate to drive circasemilunar rhythm to regulate the expression of the kisspeptin, GnIH and their receptor genes. On the other hand, high temperature (over 28 degrees C) conditions, under which the expression of the kisspeptin and its receptor genes is markedly suppressed, may provide an environmental signal that terminates reproduction at the end of breeding period. Taken together, the periodic regulation of the kisspeptin, GnIH and their receptor genes by melatonin, circadian clock and water temperature may be important in the precisely-timed spawning of the grass puffer. PMID- 29625123 TI - Expression profiling of c-kit and its impact after esiRNA silencing during gonadal development in catfish. AB - Receptor, c-Kit is a member of a family of growth factor receptors that have tyrosine kinase activity, and are involved in the transduction of growth regulatory signals across plasma membrane by activation of its ligand, kitl/scf. The present study analyzed mRNA and protein expression profiles of c-kit in the gonads of catfish, Clarias gariepinus, using real time PCR, in situ hybridization and immunohistochemistry. Tissue distribution analysis revealed higher expression mainly in the catfish gonads. Ontogeny studies showed minimal expression during early developmental stages and highest during 50-75 days post hatch, and the dimorphic expression in gonads decreased gradually till adulthood, which might suggest an important role for this gene around later stages of sex differentiation and gonadal development. Expression of c-kit was analyzed at various phases of gonadal cycle in both male and female, which showed minimal expression during the resting phase, and higher expression during the pre spawning phase in male compared to females. In vitro and in vivo induction using human chorionic gonadotropin elevated the expression of c-kit indicating the regulatory influence of hypothalamo-hypophyseal axis. In vivo transient gene silencing using c-kit-esiRNA in adult catfish during gonadal recrudescence showed a decrease in c-kit expression, which affected the expression levels of germ cell meiotic marker sycp3, as well as several factors and steroidogenic enzyme genes that are involved in germ cell development. Decrease in the levels of 11 ketotestosterone and testosterone in serum were also observed after esiRNA silencing. The findings suggests that c-kit has an important role in the process of germ cell proliferation, development and maturation during gonadal development and recrudescence in catfish. PMID- 29625124 TI - Theophylline suppresses interleukin-6 expression by inhibiting glucocorticoid receptor signaling in pre-adipocytes. AB - Adipose tissues in obese individuals are characterized by a state of chronic low grade inflammation. Pre-adipocytes and adipocytes in this state secrete pro inflammatory adipokines, such as interleukin 6 (IL-6), which induce insulin resistance and hyperglycemia. Theophylline (1,3-dimethylxanthine) exerts anti inflammatory effects, but its effects on pro-inflammatory adipokine secretion by pre-adipocytes and adipocytes have not been examined. In this study, we found that theophylline decreased IL-6 secretion by 3T3-L1 pre-adipocytes and mouse derived primary pre-adipocytes. The synthetic glucocorticoid dexamethasone (DEX) induced IL-6 expression in 3T3-L1 pre-adipocytes, and this effect was suppressed by theophylline at the mRNA level. Knockdown of CCAAT/enhancer binding protein (C/EBP) delta inhibited DEX-induced IL-6 expression, and theophylline suppressed C/EBPdelta expression. Furthermore, theophylline suppressed transcriptional activity of the glucocorticoid receptor (GR) through suppression of nuclear localization of GR. In vivo, glucocorticoid corticosterone treatment (100 MUg/mL) increased fasting blood glucose and plasma IL-6 levels in C57BL/6 N mice. Theophylline administration (0.1% diet) reduced corticosterone-increased fasting blood glucose, plasma IL-6 levels, and Il6 gene expression in adipose tissues. These results show that theophylline administration attenuated glucocorticoid induced hyperglycemia and IL-6 production by inhibiting GR activity. The present findings indicate the potential of theophylline as a candidate therapeutic agent to treat insulin resistance and hyperglycemia. PMID- 29625125 TI - Pork as a source of transmission of Toxoplasma gondii to humans: a parasite burden study in pig tissues after infection with different strains of Toxoplasma gondii as a function of time and different parasite stages. AB - Toxoplasma gondii is an ubiquitous apicomplexan parasite which can infect any warm-blooded animal including humans. Humans and carnivores/omnivores can also become infected by consumption of raw or undercooked infected meat containing muscle cysts. This route of transmission is considered to account for at least 30% of human toxoplasmosis cases. To better assess the role of pork as a source of infection for humans, the parasite burden resulting from experimental infection with different parasite stages and different strains of T. gondii during the acute and chronic phases was studied. The parasite burden in different tissues was measured with a ISO 17025 validated Magnetic Capture-quantitative PCR. A high burden of infection was found in heart and lungs during the acute phase of infection and heart and brain were identified as the most parasitised tissues during the chronic phase of infection, independent of the parasite stage and the strain used. Remarkably, a higher parasite burden was measured in different tissues following infection with oocysts of a type II strain compared with a tissue cyst infection with three strains of either type II or a type I/II. However, these results could have been affected by the use of different strains and euthanasia time points. The parasite burden resulting from a tissue cyst infection was not significantly different between the two strains. PMID- 29625126 TI - Primers targeting mitochondrial genes of avian haemosporidians: PCR detection and differential DNA amplification of parasites belonging to different genera. AB - Haemosporida is a diverse group of vector-borne parasitic protozoa, ubiquitous in terrestrial vertebrates worldwide. The renewed interest in their diversity has been driven by the extensive use of molecular methods targeting mitochondrial genes. Unfortunately, most studies target a 478 bp fragment of the cytochrome b (cytb) gene, which often cannot be used to separate lineages from different genera found in mixed infections that are common in wildlife. In this investigation, an alignment constructed with 114 mitochondrial genome sequences belonging to four genera (Leucocytozoon, Haemoproteus, Plasmodium and Hepatocystis) was used to design two different sets of primers targeting the cytb gene as well as the other two mitochondrial DNA genes: cytochrome c oxidase subunit 1 and cytochrome c oxidase subunit 3. The design of each pair of primers required consideration of different criteria, including a set for detection and another for differential amplification of DNA from parasites belonging to different avian haemosporidians. All pairs of primers were tested in three laboratories to assess their sensitivity and specificity under diverse practices and across isolates from different genera including single and natural mixed infections as well as experimental mixed infections. Overall, these primers exhibited high sensitivity regardless of the differences in laboratory practices, parasite species, and parasitemias. Furthermore, those primers designed to separate parasite genera showed high specificity, as confirmed by sequencing. In the case of cytb, a nested multiplex (single tube PCR) test was designed and successfully tested to differentially detect lineages of Plasmodium and Haemoproteus parasites by yielding amplicons with different sizes detectable in a standard agarose gel. To our knowledge, the designed assay is the first test for detection and differentiation of species belonging to these two genera in a single PCR. The experiments across laboratories provided recommendations that can be of use to those researchers seeking to standardise these or other primers to the specific needs of their field investigations. PMID- 29625127 TI - Toxoplasma CRISPR/Cas9 constructs are functional for gene disruption in Neospora caninum. AB - Herein we describe, to our knowledge for the first time the use of the clustered regularly interspaced short palindromic repeats/CRISPR-associated gene 9 (CRISPR/Cas9) system for genome editing of Neospora caninum, an apicomplexan parasite considered one of the main causes of abortion in cattle worldwide. By using plasmids containing the CRISPR/Cas9 components adapted to the closely related parasite Toxoplasma gondii, we successfully knocked out a green fluorescent protein (GFP) in an Nc-1 GFP-expressing strain, and efficiently disrupted the NcGRA7 gene in the Nc-Spain7 isolate by insertion of a pyrimethamine resistance cassette. The successful use of this technology in N. caninum lays the foundation for an efficient, targeted gene modification tool in this parasite. PMID- 29625128 TI - Physical properties of DNA may direct the binding of nucleoid-associated proteins along the E. coli genome. AB - Nucleoid-associated proteins (NAPs) play important roles in both chromosome packaging and gene regulation in bacteria. The underlying mechanisms, however, remain elusive particularly for how NAPs contribute to chromosome packaging. We report here a characterization of the binding sites for several major NAPs in E. coli, namely HNS, IHF, Fis, Dps and a non-NAP protein, FNR, in terms of the physical properties of their binding DNA. Our study shows that (i) as compared with flanking regions, the binding sites for IHF, Fis and FNR tend to have high intrinsic curvature, while no characterized pattern of intrinsic curvature distribution around those of HNS and Dps; (ii) all the binding sites analyzed in this study except those of HNS are characterized by high structural flexibility; (iii) the intrinsic curvature and flexibility at the binding sites for Fis and IHF are found to be coupled with the sequence specificity required in their binding, while the physical properties of the binding regions for both Dps and FNR are independent of sequence specificity. Our data suggest that physical properties of DNA sequence may contribute to binding of NAPs and mediate genome packaging and transcriptional regulation of the downstream genes. Our results should be informative for prediction of NAPs binding sites and understanding of the bacterial chromosome packaging. PMID- 29625129 TI - A negative feedback loop between microRNA-378 and Nrf1 promotes the development of hepatosteatosis in mice treated with a high fat diet. AB - BACKGROUNDS: The incidence of nonalcoholic fatty liver disease (NAFLD) is rapidly increasing due to the prevalence of obesity. NAFLD is a major risk factor of hepatocellular carcinoma (HCC). Even with successful surgical removal, the presence of NAFLD is associated with an increased recurrence of HCC. Despite the extensive study of NAFLD, its underlying mechanism(s) remains essentially unknown and there are no FDA-approved drugs for its treatment. Alterations in microRNA (miR) expression have been observed in human fatty livers. However, regulatory mechanism(s) of miRNA biogenesis and their role in regulating the development of NAFLD is poorly described. METHODS: We used immunohistochemistry, luciferase assays and immunoblotting to study the regulatory mechanism of miR-378 biogenesis. Wild-type mice kept on a high fat diet (HFD) were injected with miR 378 inhibitors or a mini-circle expression system containing miR-378 to study loss and gain-of functions of miR-378. RESULTS: miR-378 was significantly increased in fatty livers of dietary obese mice and human hepatoma HepG2 cells with accumulated lipid. Further studies identified NRF1 (Nuclear receptor factor 1), a key regulator of fatty acid oxidation (FAO), as a direct target of miR-378. Overexpression of miR-378 impaired FAO and promoted lipid accumulation in murine hepatoma Hepa1-6 cells. In contrast, knockdown of miR-378 using its ASO (anti sense oligo) improved FAO and reduced intracellular lipid content in Hepa1-6 cells. Liver-specific expression of miR-378 impaired FAO, which subsequently promoted the development of hepatosteatosis. Antagonizing miR-378 via injecting miR-378-ASO into HFD-treated mice led to increased expression of Nrf1, improved FAO and decreased hepatosteatosis. Additional knockdown of up-regulated Nrf1 offset the effects of miR-378-ASO, suggesting that Nrf1 mediated the inhibitory effect of miR-378-ASO on hepatosteatosis. Furthermore, Nrf1 was identified as a transcriptional repressor of miR-378. Ablation of Nrf1 using its shRNA in livers led to increased miR-378, which subsequently resulted in reduced FAO and elevated hepatic lipid content. CONCLUSIONS: These findings identified a negative feedback loop between miR-378 and Nrf1 that promotes the pathogenesis of hepatosteatosis, and suggests the use of miR-378 as a potential therapeutic target for NAFLD. PMID- 29625130 TI - State-level minimum wage and heart disease death rates in the United States, 1980 2015: A novel application of marginal structural modeling. AB - Despite substantial declines since the 1960's, heart disease remains the leading cause of death in the United States (US) and geographic disparities in heart disease mortality have grown. State-level socioeconomic factors might be important contributors to geographic differences in heart disease mortality. This study examined the association between state-level minimum wage increases above the federal minimum wage and heart disease death rates from 1980 to 2015 among 'working age' individuals aged 35-64 years in the US. Annual, inflation-adjusted state and federal minimum wage data were extracted from legal databases and annual state-level heart disease death rates were obtained from CDC Wonder. Although most minimum wage and health studies to date use conventional regression models, we employed marginal structural models to account for possible time varying confounding. Quasi-experimental, marginal structural models accounting for state, year, and state * year fixed effects estimated the association between increases in the state-level minimum wage above the federal minimum wage and heart disease death rates. In models of 'working age' adults (35-64 years old), a $1 increase in the state-level minimum wage above the federal minimum wage was on average associated with ~6 fewer heart disease deaths per 100,000 (95% CI: -10.4, -1.99), or a state-level heart disease death rate that was 3.5% lower per year. In contrast, for older adults (65+ years old) a $1 increase was on average associated with a 1.1% lower state-level heart disease death rate per year (b = 28.9 per 100,000, 95% CI: -71.1, 13.3). State-level economic policies are important targets for population health research. PMID- 29625131 TI - A Prostate Cancer Composite Score to Identify High Burden Neighborhoods. AB - This study presents a novel geo-based metric to identify neighborhoods with high burdens of prostate cancer, and compares this metric to other methods to prioritize neighborhoods for prostate cancer interventions. We geocoded prostate cancer patient data (n = 10,750) from the Pennsylvania cancer registry from 2005 to 2014 by Philadelphia census tract (CT) to create standardized incidence ratios (SIRs), mortality ratios (SMRs), and mean prostate cancer aggressiveness. We created a prostate cancer composite (PCa composite) variable to describe CTs by mean-centering and standard deviation-scaling the SMR, SIR, and mean aggressiveness variables and summing them. We mapped CTs with the 25 highest PCa composite scores and compared these neighborhoods to CTs with the 25 highest percent African American residents and the 25 lowest median household incomes. The mean PCa composite score among the 25 highest CTs was 4.65. Only seven CTs in Philadelphia had both one of the highest PCa composite scores and the highest percent African American residents. Only five CTs had both the highest PCa composites and the lowest median incomes. Mean PCa composite scores among CTs with the highest percent African American residents and lowest median incomes were 2.08 and 1.19, respectively. The PCa composite score is an accurate metric for prioritizing neighborhoods based on burden. If neighborhoods were prioritized based on percent African American or median income, priority neighborhoods would have been very different and not based on PCa burden. These methods can be utilized by public health decision-makers when tasked to prioritize and select neighborhoods for cancer interventions. PMID- 29625132 TI - Modernizing regulation of cosmetic products: Reintroduction of the Personal Care Products Safety Act. PMID- 29625133 TI - Commentary: Does biologic treatment of psoriasis lower the risk of cardiovascular events and mortality?: A critical question that we are only just beginning to answer. PMID- 29625134 TI - IL-17-producing ST2+ group 2 innate lymphoid cells play a pathogenic role in lung inflammation. AB - BACKGROUND: IL-17 plays a pathogenic role in asthma. ST2- inflammatory group 2 innate lymphoid cells (ILC2s) driven by IL-25 can produce IL-17, whereas ST2+ natural ILC2s produce little IL-17. OBJECTIVE: We characterized ST2+IL-17+ ILC2s during lung inflammation and determined the pathogenesis and molecular regulation of ST2+IL-17+ ILC2s. METHODS: Lung inflammation was induced by papain or IL-33. IL-17 production by lung ILC2s from wild-type, Rag1-/-, Rorcgfp/gfp, and aryl hydrocarbon receptor (Ahr)-/- mice was examined by using flow cytometry. Bone marrow transfer experiments were performed to evaluate hematopoietic myeloid differentiation primary response gene-88 (MyD88) signaling in regulating IL-17 production by ILC2s. mRNA expression of IL-17 was analyzed in purified naive ILC2s treated with IL-33, leukotrienes, and inhibitors for nuclear factor of activated T cells, p38, c-Jun N-terminal kinase, or nuclear factor kappa light chain enhancer of activated B cells. The pathogenesis of IL-17+ ILC2s was determined by transferring wild-type or Il17-/- ILC2s to Rag2-/-Il2rg-/- mice, which further induced lung inflammation. Finally, expression of 106 ILC2 signature genes was compared between ST2+IL-17+ ILC2s and ST2+IL-17- ILC2s. RESULTS: Papain or IL-33 treatment boosted IL-17 production from ST2+ ILC2s (referred to by us as ILC217s) but not ST2- ILC2s. Ahr, but not retinoic acid receptor-related orphan receptor gammat, facilitated the production of IL-17 by ILC217s. The hematopoietic compartment of MyD88 signaling is essential for ILC217 induction. IL-33 works in synergy with leukotrienes, which signal through nuclear factor of activated T-cell activation to promote IL-17 in ILC217s. Il17-/- ILC2s were less pathogenic in lung inflammation. ILC217s concomitantly expressed IL-5 and IL-13 but expressed little GM-CSF. CONCLUSION: During lung inflammation, IL 33 and leukotrienes synergistically induce ILC217s. ILC217s are a highly pathogenic and unexpected source for IL-17 in lung inflammation. PMID- 29625136 TI - Surgical Management of Adult-acquired Buried Penis: Impact on Urinary and Sexual Quality of Life Outcomes. AB - OBJECTIVE: To assess postoperative patient-reported quality of life outcomes after surgical management of adult-acquired buried penis (AABP). We hypothesize that surgical treatment of AABP results in improvements in urinary and sexual quality of life. METHODS: Patients that underwent surgical treatment of AABP were retrospectively identified. The Expanded Prostate Cancer Index (EPIC) questionnaire was completed at >=3 months postoperatively, and completed retrospectively to define preoperative symptoms. EPIC is validated for local treatment of prostate cancer. Urinary and sexual domains were utilized. Questions are scored on a 5-point Likert scale, with higher scores indicating better quality of life. Preoperative scores were compared with postoperative scores. RESULTS: Sixteen patients completed pre- and postoperative questionnaires. Mean time from surgery to questionnaire was 12.6 months. There was a significant improvement in 10 of 12 urinary domain questions and 10 of 13 sexual domain questions. Fourteen of 16 patients (87.5%) reported significant improvement in overall sexual function (median score changed from 1.5 to 5, P <.0001). Similarly, 14 of 16 patients (87.5%) reported significant improvement in overall urinary function (median score changed from 1 to 4, P <.0001). CONCLUSION: AABP is a challenging condition to treat and often requires surgical intervention to improve hygiene and function. There are limited data on patient-reported quality of life outcomes. We found that surgical management of AABP results in significant improvements in both urinary and sexual quality of life outcomes. PMID- 29625135 TI - Effect of heterochromatin stability on intestinal stem cell aging in Drosophila. AB - Chromatin change is one of the crucial causes of aging. Specifically, maintenance of heterochromatin stability is critical for cellular integrity, and its loss induces genomic instability and cellular aging. However, the causes and effects of heterochromatin instability in multicellular tissue aging still remain unclear. Here, in the adult Drosophila midgut, we report age-related loss of heterochromatin stability in enterocytes (ECs) due to the loss and dispersion of tri-methylated histone H3 Lys9 (H3K9me3) and heterochromatin protein 1 (HP1). Our study further shows that EC-specific knockdown of Su(var)3-9, histone lysine methyltransferase for H3K9me3 formation, or HP1a leads to intestinal stem cell (ISC) aging through genomic stress, JNK signaling, and apoptotic death in ECs. Our findings revealed the plausible causes of age-related loss of heterochromatin stability in ECs, including oxidative stress and nutrient-sensing AKT/TOR signaling. Taken together, the loss of heterochromatin stability may be the crucial niche aging mechanism for ISC aging which is the prime determinant of intestinal tissue aging. Furthermore, our study provides new clues on the link between heterochromatin and aging. PMID- 29625137 TI - Sensitivity of Noncontrast Computed Tomography for Small Renal Calculi With Endoscopy as the Gold Standard. AB - OBJECTIVE: To compare the sensitivity of noncontrast computed tomography (CT) with endoscopy for detection of renal calculi. Imaging modalities for detection of nephrolithiasis have centered on abdominal x-ray, ultrasound, and noncontrast CT. Sensitivities of 58%-62% (abdominal x-ray), 45% (ultrasound), and 95%-100% (CT) have been previously reported. However, these results have never been correlated with endoscopic findings. METHODS: Idiopathic calcium oxalate stone formers with symptomatic calculi requiring ureteroscopy were studied. At the time of surgery, the number and the location of all calculi within the kidney were recorded followed by basket retrieval. Each calculus was measured and sent for micro-CT and infrared spectrophotometry. All CT scans were reviewed by the same genitourinary radiologist who was blinded to the endoscopic findings. The radiologist reported on the number, location, and size of each calculus. RESULTS: Eighteen renal units were studied in 11 patients. Average time from CT scan to ureteroscopy was 28.6 days. The mean number of calculi identified per kidney was 9.2 +/- 6.1 for endoscopy and 5.9 +/- 4.1 for CT (P <.004). The mean size of total renal calculi (sum of the longest stone diameters) per kidney was 22.4 +/- 17.1 mm and 18.2 +/- 13.2 mm for endoscopy and CT, respectively (P = .06). CONCLUSION: CT scan underreports the number of renal calculi, probably missing some small stones and being unable to distinguish those lying in close proximity to one another. However, the total stone burden seen by CT is, on average, accurate when compared with that found on endoscopic examination. PMID- 29625138 TI - Controlled release technology for anti-angiogenesis treatment of posterior eye diseases: Current status and challenges. AB - Antiangiogenic therapeutics, such as corticosteroids, VEGF targeting antibodies and aptamers have been demonstrated effective in controlling retinal and choroidal neovascularization related vision loss. However, to manage the chronic conditions, it requires long term and frequent intravitreal injections of these drugs, resulting in poor patient compliance and suboptimal treatment. In addition, emerging drugs such as tyrosine kinase inhibitors and siRNAs received much expectations, but the late stage clinical trials encountered various obstacles. Controlled release technology could improve the existing treatment regimen by extending therapeutic duration, reducing risks and burdens caused by frequent injections, and enabling new drugs to overcome the hurdles of translation. Here, we give qualitative and quantitative discussions about the principle mechanisms of polymeric reservoir, polymeric matrix and hydrogel systems. We also reveal the design rationales of the existing drug delivery and release systems in preclinical and clinical stages. Lastly, the animal models of ocular angiogenesis diseases are critically reviewed, which could help to facilitate the translation of controlled release technologies from bench to bedside. PMID- 29625139 TI - Perspectives on the physiological roles of microRNAs in immune-metabolism: Where are we now? PMID- 29625140 TI - Circular RNAs (circRNAs) in cancer. AB - Circular RNAs (circRNAs) are a class of non-coding RNAs that do not have 5' end caps or 3' end poly (A) tails. There are more than one hundred thousand genes that encode circRNAs. Clinical data show that there are differences in the expression of circRNAs in a variety of diseases, including cancer, suggesting that circRNA has a regulatory effect on some diseases. Further studies reveal that circRNA can be used as an endogenous competitive RNA, thereby regulating the proliferation, invasion or other physiological activities of tumor cells. In addition, some circRNAs located in the nucleus can regulate the transcription of the parental gene by binding to RNA polymerase II. circRNA can also combine with proteins to influence the cell cycle. Furthermore, recent studies have shown that circRNA can encode proteins, similarly to mRNA. circRNAs are found extensively in human cells and have tissue specificity. They have the potential to be used in clinical applications as tumor markers and therapeutic targets. PMID- 29625141 TI - Optimal cutoff values of fasting plasma glucose (FPG) variability for detecting retinopathy and the threshold of FPG levels for predicting the risk of retinopathy in type 2 diabetes: A longitudinal study over 27 years. AB - AIMS: To determine the cutoff values of fasting plasma glucose (FPG) variability for detecting retinopathy and examine the threshold of FPG levels for predicting retinopathy incidence in type 2 diabetes. METHODS: Subjects comprised 170 patients with type 2 diabetes who had no retinopathy at their first visit, and continuously visited thereafter for 27 years. Retinopathy was evaluated by ophthalmologists at least annually. RESULTS: 114 patients developed retinopathy. 46 of them had advanced retinopathy. The optimal cutoff values of intrapersonal mean and standard deviation (SD) of FPG over 27 years and intrapersonal mean HbA1c from the initial measurement to the last visit for detecting retinopathy were 7.4 mmol/L, 1.4 mmol/L, and 7.2% (56 mmol/mol), respectively. Similarly, for advanced retinopathy, 7.7 mmol/L, 1.9 mmol/L, and 7.5% (59 mmol/mol), respectively. Hazard ratios of deciles of intrapersonal mean FPG (mmol/L) during the initial 2 years for retinopathy incidence significantly increased from eighth decile (6.9-7.4), and were sharply elevated from ninth-decile (7.4-8.7). CONCLUSIONS: Our study provides new cutoff values for FPG variability. Cutoff values of FPG and HbA1c were slightly higher than recommended targets of the current guideline. The threshold of FPG levels (6.9 mmol/L) is proposed to predict retinopathy incidence during the subsequent 25 years. PMID- 29625143 TI - Neo-clerodane and abietane diterpenoids with neurotrophic activities from the aerial parts of Salvia leucantha Cav. AB - Four new neoclerodane diterpenoids, leucansalvialins FI (1-4), and one rare 18(4 > 3)-abeo-abietane diterpenoid, leucansalvialin J (5), were isolated from the aerial part of Salvia leucantha Cav., along with 14 known analogues. Leucansalvialin F (1) represents the first rearranged salvigenane type clerodane 17,12:18,6-diolide. Their structures were elucidated by 1D and 2D NMR spectroscopic data analysis, and the absolute configurations of 1, 2, 3, and 5 were determinded by X-ray diffraction crystal analysis and the ECD technique. All of the isolated components were evaluated for their neurotrophic activities on PC12 cells and all new compounds were evaluated for their cytotoxicity against five human cancer cell lines (HL-60, A-549, SMMC-7721, MCF-7, and SW480). Compounds 2 and 5 showed moderate neuroprotective effects in an in vitro assay. PMID- 29625144 TI - The synthesis and anti-metastatic effects of optical isomers of ionone alkaloid 9 (N,N-dimethyl)-4,7-megastigmedien-3-one. AB - Ionone alkaloid 9-(N,N-dimethyl)-4,7-megastigmedien-3-one (compound 1) is a new anti-metastatic natural product. However, it was previously reported as optical isomers mixture. Herein, the optical isomers (6a-6d) of compound 1 were synthesized. The absolute configurations of 6a-6d were determined by ECD experiments and calculated spectra with time-dependent density functional theory (TDDFT). The anti-metastatic effects of the optical isomers were examined by transwell assay. These results revealed that compound 6a had potential anti metastatic activity with an IC50 value of 0.512 +/- 0.093 MUM. PMID- 29625142 TI - Substituents at the C3' and C3'N positions are critical for taxanes to overcome acquired resistance of cancer cells to paclitaxel. AB - We tested the role of substituents at the C3' and C3'N positions of the taxane molecule to identify taxane derivatives capable of overcoming acquired resistance to paclitaxel. Paclitaxel-resistant sublines SK-BR-3/PacR and MCF-7/PacR as well as the original paclitaxel-sensitive breast cancer cell lines SK-BR-3 and MCF-7 were used for testing. Increased expression of the ABCB1 transporter was found to be involved in the acquired resistance. We tested three groups of taxane derivatives: (1) phenyl group at both C3' and C3'N positions, (2) one phenyl at one of the C3' and C3'N positions and a non-aromatic group at the second position, (3) a non-aromatic group at both C3' and C3'N positions. We found that the presence of phenyl groups at both C3' and C3'N positions is associated with low capability of overcoming acquired paclitaxel resistance compared to taxanes containing at least one non-aromatic substituent at the C3' and C3'N positions. The increase in the ATPase activity of ABCB1 transporter after the application of taxanes from the first group was found to be somewhat higher than after the application of taxanes from the third group. Molecular docking studies demonstrated that the docking score was the lowest, i.e. the highest binding affinity, for taxanes from the first group. It was intermediate for taxanes from the second group, and the highest for taxanes from the third group. We conclude that at least one non-aromatic group at the C3' and C3'N positions of the taxane structure, resulting in reduced affinity to the ABCB1 transporter, brings about high capability of taxane to overcome acquired resistance of breast cancer cells to paclitaxel, due to less efficient transport of the taxane compound out of the cancer cells. PMID- 29625145 TI - Antiprotozoan sesterterpenes and triterpenes isolated from two Ghanaian mushrooms. AB - Bioassay-guided compound isolation led to the discovery of two new scalarane sesterterpenes (1 and 2) and two new triterpenes (3 and 4) from two mushroom species, Pleurotus ostreatus (edible) and Scleroderma areolatum, collected from Ghana. Their structures, including absolute stereochemistry, were established by spectroscopic methods, particularly (+)-ESI-TOF mass spectrometry and 1D and 2D NMR. The four compounds exhibited IC50 values of 1.65-7.63 MUM against Plasmodium falciparum 3D7 and 5.04-13.65 MUM against Trypanosoma cruzi Tulahuen C4 parasites and were also non-cytotoxic against HepG2 tumoral human liver cells. This is the first report describing the isolation of sesterterpenes belonging to the scalarane structural class from a terrestrial source. PMID- 29625146 TI - Selenium-dependent gene expression in Methanococcus maripaludis: Involvement of the transcriptional regulator HrsM. AB - BACKGROUND: The archaeon Methanococcus maripaludis strain JJ employs several selenocysteine (Sec)-containing proteins in its primary energy metabolism, methanogenesis. Upon selenium deprivation, or when the pathway for selenoprotein synthesis is disrupted, they are replaced by cysteine (Cys)-containing isoforms, thus allowing for selenium-independent growth. METHODS: Expression of a fusion of the promoter region of frcA (encoding a subunit of the selenium-independent hydrogenase Frc) and bla [encoding beta-lactamase (Bla)] in M. maripaludis JJ was assessed in response to the selenium supply, growth substrate, and growth phase. Random transposon mutants of the reporter strain were screened for deregulated bla expression, which identified HrsM, a LysR-type transcriptional regulator (LTTR). Its involvement in selenium-dependent gene regulation was further assessed by analyzing in vivo transcription, synthesis of selenoproteins and of HrsM, and by analyzing in vitro binding of HrsM to DNA. RESULTS: HrsM, which is not required for selenoprotein synthesis, acts as a positive effector of selenoprotein gene expression and as a negative effector of Cys-encoding isogene expression, but its own expression is independent of the selenium availability. Specific binding in vitro of HrsM to a promoter region under in vivo HrsM control verified its role in selenium-dependent gene regulation. CONCLUSIONS: HrsM exerts a key role in regulating expression of selenoprotein genes and their Cys-encoding isogenes in M. maripaludis in a selenium-dependent fashion. However, this activity is not achieved via autoregulation but probably by a mechanism, which modulates the DNA-binding of HrsM. GENERAL SIGNIFICANCE: Although LTTRs are abundant in Bacteria, HrsM represents only the second characterized member of this group in Archaea. PMID- 29625147 TI - The role of Treg population in pathogenesis of Crimean Congo hemorrhagic fever. AB - Crimean-Congo hemorrhagic fever (CCHF) is a severe human infection caused by CCHF virus (CCHFV). Today, although the literature on CCHF pathogenesis is still limited, it is thought to be associated with immunosuppression in the early phase of infection followed by pro-inflammatory immune response that may lead to fatal outcomes. The aim of this study is to investigate the role of regulatory T-cells (Treg cells) in the pathogenesis of CCHFV. Peripheral blood mononuclear cell samples collected from 14 acute CCHF patients with mild disease course and 13 healthy subjects were included in this study. Treg expression and functional levels were analyzed by flow cytometry. Treg cells were identified as CD4+CD25 + CD127dim cells, and their functional levels were compared by measuring their ability to suppress CD69 and CD154 expression by activated T-cells. The flow cytometry analysis revealed that total T-cell and helper T-cell levels did not vary between the two groups. In contrast, CCHF patients displayed higher Treg cell levels but lower Treg suppressive activities when compared with control subjects. This is the first study on the involvement of Treg cells in CCHF pathogenesis. Our results indicate that even though Treg cell levels are elevated during acute phase of CCHF infection, not all generated Treg cells has immunosuppressive capacity, and therefore may not represent 'true' Treg cell population. Future studies on the intrinsic mechanisms responsible for the reduced Treg inhibitory activities are required for further enlightening the CCHF pathogenesis, especially in the acute phase of the disease. PMID- 29625148 TI - Genome scale screening identification of SaCas9/gRNAs for targeting HIV-1 provirus and suppression of HIV-1 infection. AB - The CRISPR/Cas9 gene-editing approach has been widely used in anti-HIV-1 gene therapy research. However, the major challenges facing the therapeutic application of CRISPR/Cas9 are the precise genome cleavage efficacy and efficient delivery of Cas9/gRNA specifically to the HIV-infected cells. Recently, a small size Cas9 from Staphylococcus aureus (SaCas9) has shown promise in genome editing in eukaryotic cells, suggesting a potential usage in blocking HIV-1 infection by targeting the HIV-1 genome. Here, we designed 43 guide RNAs (gRNAs) against the HIV-1 genome, thereby identifying 8 gRNAs that efficiently and specifically disrupt the target DNA by SaCas9. In addition, we found the selected gRNAs induce SaCas9 to disrupt the latent HIV-1 provirus and suppress HIV-1 proviral reactivation in latently infected Jurkat C11 cells. We further confirmed that the dual or triple gRNAs in an all-in-one lentiviral vector could reduce viral production in TZM-bl cells as well as in Jurkat T cells. Moreover, we did not detect any off-target cleavages in the predicted sites, suggesting that through all-in-one lentiviral vector-mediated HIV-1 genome editing, the selected SaCas9/gRNAs can provide an alternative and flexible strategy for anti-HIV gene therapy. PMID- 29625149 TI - Identification and characterization of natural viruses associated with the invasive insect pest Drosophila suzukii. AB - The invasive insect pest Drosophila suzukii infests ripening fruits and causes extensive damage to crops in the northern hemisphere. Novel, environmentally friendly strategies to control the spread of this species are urgently needed, and one promising approach is the deployment of entomopathogenic viruses. Here we report the identification and characterization of two natural viruses associated with D. suzukii: Drosophila A virus (DAV) and La Jolla virus (LJV). Our work provides new tools for the development of biological control agents that protect crops against D. suzukii without a harmful impact on biodiversity. PMID- 29625150 TI - Nimodipine represses AMPK phosphorylation and excessive autophagy after chronic cerebral hypoperfusion in rats. AB - Chronic cerebral hypofusion (CCH) after bilateral carotid artery occlusion (2VO) causes cognitive damage and neuronal degeneration in the cortex and hippocampal CA1 area, and influences the oxygen and glucose supply in the brain which often results in metabolic alterations and oxidative stress. AMP-activated protein kinase (AMPK) phosphorylation, a sensor of cellular energy status, directs metabolic adaptation to support cellular growth and survival after CCH. Autophagy is also likely to be involved in metabolic adaptation and plays an important role in neuronal deterioration and cognitive decline after CCH. Nimodipine, an L-type calcium channel antagonist, has been reported to exert neuroprotective effects. However, the potential role of nimodipine in autophagy and the energy sensing AMPK signal is not well understood. In addition, little is known about the relationship between autophagy and AMPK signal. Here, we designed a way to evaluate these issues. Adult male Wistar rats were subjected to 2VO and randomly divided into three groups: the Vehicle (2VO), Nimodipine (2VO + nimodipine 10 mg/kg) groups. A third group served as sham controls. Each group was investigated at 2 and 4 weeks post gavage and tested using the Morris water maze. The activities of LC3B and AMPK signal were examined using immunohistochemistry and western blotting. Nimodipine significantly alleviated spatial learning and memory impairments and the number of lesion neurons. At 2 weeks of durg administration, these drug effects, suppressing AMPK activation and excessive autophagy, were more pronounced at the cortex than at hippocampal CA1 area. The effects of nimodipine were significant in the hippocampal CA1 area after 4 weeks of administration. Furthermore, nimodipine inhibited expression of eIF2alpha/ATF4 signaling related to energy deficit stress in 2VO rats. These results suggest that excessive autophagy has promoted neuronal and tissue injury after 2VO in rats. Nimodipine protected the brain from CCH by inhibiting the autophagy activity. The p-AMPK and eIF2alpha/ATF4 pathway is likely part of an integrated pro-autophagy signaling network after CCH. PMID- 29625151 TI - 1 mA cathodal tDCS shows excitatory effects in children and adolescents: Insights from TMS evoked N100 potential. AB - In children and adolescents, 1 mA transcranial direct current stimulation (tDCS) may cause "paradoxical" effects compared with adults: both 1 mA anodal and cathodal tDCS increase amplitude of the motor evoked potential (MEP) as revealed by a single pulse transcranial magnetic stimulation (TMS) of the motor cortex. Here, EEG based evoked potentials induced by a single pulse TMS, particularly the N100 component as marker of motor cortex inhibition, were investigated in order to explain effects of tDCS on the developing brain. In nineteen children and adolescents (11-16 years old), 1 mA anodal, cathodal, or sham tDCS was applied over the left primary motor cortex for 10 min. The TMS-evoked N100 was measured by 64-channel EEG before and immediately after stimulation as well as every 10 min after tDCS for one hour. 1 mA Cathodal stimulation suppressed the N100 amplitude compared with sham stimulation. In contrast, anodal tDCS did not modify the N100 amplitude. It seems likely that the increase of the motor cortex activity under cathodal tDCS in children and adolescents as shown in previous studies can be attributed to a reduce inhibition. Based on TMS evoked N100, the study provides an insight into neuromodulatory effects of tDCS on the developing brain. PMID- 29625152 TI - G-protein-coupled receptor genes of Dirofilaria immitis. AB - The diversity and uniqueness of nematode heterotrimeric G-protein-coupled receptors (GPCRs) provides impetus for identifying ligands that can be used as therapeutics for treating diseases caused by parasitic nematode infections. In human medicine, GPCRs have represented the largest group of 'drugable' targets exploited in the market today. In the filarial nematode Dirofilaria immitis, which causes heartworm disease, the macrocyclic lactones (ML) have been used as the sole preventatives for more than 25 years and now there is confirmed ML resistance in this parasite. A novel anthelmintic emodepside, with antifilarial activity, can act on a GPCR. In view of the ML resistance, there is an urgent need to identify new drug targets and GPCRs of D. immitis may be promising receptors. Knowledge of polymorphism within the GPCR superfamily is of interest. A total of 127 GPCR genes have been identified, so far, in the genome of D. immitis. Whole genome sequencing data from four ML susceptible and four ML loss of efficacy populations was used to identify 393 polymorphic loci in 35 D. immitis GPCR genes. Out of 57 SNPs in exonic regions, 36 of them caused a change in an amino acid, out of which 2 changed the predicted secondary structure of the protein. Knowledge about GPCR genes and their polymorphism is valuable information for drug design processes. Further studies need to be carried out to more fully understand the implications of each of the SNPs identified by this study. PMID- 29625153 TI - Brain CT perfusion improves intracranial vessel occlusion detection on CT angiography. AB - BACKGROUND AND PURPOSE: To evaluate whether brain CT perfusion (CTP) aids in the detection of intracranial vessel occlusion on CT angiography (CTA) in acute ischemic stroke. MATERIALS AND METHODS: Medical-ethical committee approval of our hospital was obtained and informed consent was waived. Patients suspected of acute ischemic stroke who underwent non-contrast CT(NCCT), CTA and whole-brain CTP in our center in the year 2015 were included. Three observers with different levels of experience evaluated the imaging data of 110 patients for the presence or absence of intracranial arterial vessel occlusion with two strategies. In the first strategy, only NCCT and CTA were available. In the second strategy, CTP maps were provided in addition to NCCT and CTA. Receiver-operating-characteristic (ROC) analysis was used for the evaluation of diagnostic accuracy. RESULTS: Overall, a brain perfusion deficit was scored present in 87-89% of the patients with an intracranial vessel occlusion, more frequently observed in the anterior than in the posterior circulation. Performance of intracranial vessel occlusion detection on CTA was significantly improved with the availability of CTP maps as compared to the first strategy (P=0.023), due to improved detection of distal and posterior circulation vessel occlusions (P-values of 0.032 and 0.003 respectively). No added value of CTP was found for intracranial proximal vessel occlusion detection, with already high accuracy based on NCCT and CTA alone. CONCLUSION: The performance of intracranial vessel occlusion detection on CTA was improved with the availability of brain CT perfusion maps due to the improved detection of distal and posterior circulation vessel occlusions. PMID- 29625154 TI - Experimental evaluation of the NeVaTM thrombectomy device a novel stent retriever conceived to improve efficacy of organized clot removal. AB - BACKGROUND AND PURPOSE: Stent retrievers are recognized as the most effective devices for intracranial thrombectomy. Although highly effective, such devices fail in clot removal when the brain vessel occlusion is due to organized, firm clots. The mechanism of failure is that during the retrieval, devices remain compressed by the organized clot and slide between it and the vessel wall without any removal effect. The aim of the current study is to present the preclinical evaluation of the NevaTM device, a novel stent retriever designed to improve the incorporation and removal of organized thrombi. MATERIALS AND METHODS: Preclinical evaluation of the NevaTM device was divided in three main chapters: efficacy analysis, mechanical analysis and safety analysis. Efficacy and mechanical analysis aimed to investigate the behavior during the retrieval of the NevaTM device and its interaction with experimental organized clots. Safety analysis was conducted on animals in order to investigate the effect of the NevaTM device on real arteries after simulated thrombectomy maneuvers. RESULTS: NevaTM device showed a high rate of "optimal clot integration" and "effective clot removal" which was related to constant cohesion to the vessel wall during retrievals. Safety analysis showed as the most frequent finding the disruption of the intima of the tested vessels with, in some cases, minimal disruption of the internal elastic lamina. CONCLUSIONS: The NevaTM device has demonstrated safety and efficacy in a pre-clinical study. Such encouraging, preliminary results have to be compared with those of clinical trials. PMID- 29625155 TI - Speculation on the naming of Moyamoya disease. PMID- 29625156 TI - A schizophrenia-like behavioral trait in the SHR model: Applying confirmatory factor analysis as a new statistical tool. AB - Questionnaires that assess symptoms of schizophrenia patients undergo strict statistical validation, often using confirmatory factor analysis (CFA). CFA allows testing the existence of a trait that both collectively explains the symptoms and gathers the information in a single general index. In rodents, some behaviors are used to model psychiatric symptoms, but no single test or paradigm adequately captures the disorder's phenotype in toto. This work investigated the existence of a behavioral trait in the SHR strain underlying five behavioral tasks used in schizophrenia animal studies and altered in this strain: locomotor activity, rearing behavior, social interaction, prepulse inhibition of startle and contextual fear conditioning. The analysis was conducted on a sample of Wistar (n = 290) and Spontaneously Hypertensive Rats (SHRs, n = 290). CFA showed the existence of a continuous trait in both strains, and higher values among SHRs. This work is the first to demonstrate the existence of a schizophrenia-like trait in an animal model. We suggest that using CFA to evaluate behavioral parameters in animals might facilitate the pre-clinical investigation of psychiatric disorders, diminishing the gap between animal and human studies. PMID- 29625157 TI - Role of Cyclodextrins in Nanoparticle-Based Drug Delivery Systems. AB - Cyclodextrins (CDs) are cyclic oligosaccharides with unique hydrophobic interior surfaces. Three parent CDs, alpha-CD, beta-CD, and gamma-CD, are further chemically modified primarily to make them suitable for parenteral administration, and these are used for many pharmaceutical applications. CDs offer distinctive advantages due to their unique ability to form inclusion complexes with a variety of organic and inorganic lipophilic molecules. This attribute is promising for a wide range of fields such as drug delivery, cancer therapy, gene delivery, and biosensing. In recent years, CDs have become more commonly used functional materials in nanoparticle (NP)-based drug delivery. The properties of NPs can be advantageously modified by the inclusion of CDs or their derivatives. CD-conjugated NPs (CD-NPs) have many benefits such as improved drug solubility and serve as drug carriers to specific locations such as cancer cells, which reduces toxicity to normal cells. In addition, CDs can overcome the limitations of NPs such as low encapsulation efficiency and drug loading. This review will discuss the various uses of CDs as it applies to NP-based drug carriers. Specifically, how CDs enhance the characteristics of polymeric, magnetic, lipid, metallic, and mesoporous NPs are discussed. PMID- 29625158 TI - Effects of selected bacterial cultures on safety and sensory traits of Nocellara Etnea olives produced at large factory scale. AB - This work investigates the effects of different combinations of selected lactic acid bacteria strains on Lactobacillus species occurrence, on safety and on sensory traits of natural green table olives, produced at large factory scale. Olives belonging to Nocellara Etnea cv were processed in a 6% NaCl brine and inoculated with six different bacterial cultures, using selected strains belonging to Lactobacillus plantarum, Lactobacillus paracasei and Lactobacillus pentosus species. The fermentation process was strongly influenced by the added starters and the identification of lactic acid bacteria isolated throughout the process confirms that L. pentosus dominated all fermentations, followed by L. plantarum, whereas L. casei was never detected. Pathogens were never found, while histamine and tyrosine were detected in control and in two experimental samples. The samples with the lowest final pH values showed a safer profile and the most appreciated sensory traits. The present study highlights that selected starters promote prevalence of L. pentosus over the autochthonous microbiota throughout the whole process of Nocellara Etnea olives. PMID- 29625159 TI - The revelation of selective sphingolipid pathway inhibition mechanism on fumonisin toxin binding to ceramide synthases in susceptible organisms and survival mechanism in resistant species. AB - Fumonisin B1 toxin (FB1) is a well-known competitive inhibitor of ceramide synthase (CS) in yeast. However, FB1 is unable to obstruct CS from Trichoderma spp., which are well-known biocontrol agents. To explore the contrasting binding modes, a comparative structural analysis of complexes of FB1 with these two CS proteins was carried out. Formation of activation loop on the binding of substrates with the CS from yeast was observed but when inhibitor interacted with the activation loop, it transformed into helix leading to the potentially inactivated state of the enzyme. In yeast homologue of the enzyme, the inhibitor and substrates compete for the same binding site. Whereas, in the CS protein from Trichoderma guizhouense, no such competition for substrate binding site was observed and the binding pocket of the enzyme could easily accommodate FB1 molecule along with the two interacting native substrates, which may lead to the successful catalysis. PMID- 29625160 TI - Noninvasive monitoring of nanoparticle clearance and aggregation in blood circulation by in vivo flow cytometry. AB - Nanoparticles have been widely used in biomedical research as drug carriers or imaging agents for living animals. Blood circulation is crucial for the delivery of nanoparticles, which enter the bloodstream through injection, inhalation, or dermal exposure. However, the clearance kinetics of nanoparticles in blood circulation has been poorly studied, mainly because of the limitations of conventional detection methods, such as insufficient blood sample volumes or low spatial-temporal resolution. In addition, formation of nanoparticle aggregates is a key determinant for biocompatibility and drug delivery efficiency. Aggregation behavior of nanoparticles in blood is studied using dynamic light scattering in serum or serum protein solutions, which is still very different from in vivo condition. In this work, we monitored the dynamics of nanoparticle concentration and formation of nanoparticle aggregates in the bloodstream in live animals using in vivo flow cytometry (IVFC). The results indicated that nanoparticles in smaller size could stay longer in the bloodstream. Polyethylene glycol (PEG) modification could prolong circulating time and reduce the formation of aggregates in the blood circulation. Our work shows that IVFC can be a powerful tool for pharmacokinetic studies of nanoparticles and other drug carriers, assessing cell-targeting efficiency, as well as potentially measuring cardiac output and hepatic function in vivo. PMID- 29625161 TI - Development of a TaqMan-based real-time PCR assay for the rapid and specific detection of pigeon torque teno virus. AB - Pigeon torque teno virus (PTTV), a recently discovered circular DNA virus. Here, we developed a TaqMan-based real-time PCR for rapid and specific detection of PTTV infections with sensitivity up to 49.3 copies/MUl. Positive signals can be observed by the assay in pigeon embryonated eggs, which indicted that PTTV can be transmitted vertically. Our findings play important implications for a better understanding the transmission of torque teno virus in pigeons. PMID- 29625162 TI - Effective delivery of hydrophobic drugs to breast and liver cancer cells using a hybrid inorganic nanocarrier: A detailed investigation using cytotoxicity assays, fluorescence imaging and flow cytometry. AB - This study was focused on developing a drug carrier system composed of a polymer containing hydroxyapatite (HAp) shell and a magnetic core of iron oxide nanoparticles. Doxorubicin and/or curcumin were loaded into the carrier via a simple diffusion deposition approach, with encapsulation efficiencies (EE) for curcumin and doxorubicin of 93.03 +/- 0.3% and 97.37 +/- 0.12% respectively. The co-loading of curcumin and doxorubicin led to a total EE of 76.02 +/- 0.48%. Release studies were carried out at pH 7.4 and 5.3, and revealed a greater extent of release at pH 5.3, showing the formulations to have potential applications in tumor microenvironments. Cytotoxicity assays, fluorescence imaging and flow cytometry demonstrated that the formulations could effectively inhibit the growth of MCF-7 (breast) and HEpG2 (liver) cancer cells, being more potent than the free drug molecules both in terms of dose and duration of action. Additionally, hemolysis tests and cytotoxicity evaluations determined the drug-loaded carriers to be non-toxic towards non-cancerous cells. These formulations thus have great potential in the development of new cancer therapeutics. PMID- 29625163 TI - Severe diarrhoea due to Cystoisospora belli infection in a Good syndrome patient. PMID- 29625164 TI - Very low concentration of cerium dioxide nanoparticles induce DNA damage, but no loss of vitality, in human spermatozoa. AB - Cerium dioxide nanoparticles (CeO2NP) are widely used for industrial purposes, as in diesel, paint, wood stain and as potential therapeutic applications. The Organization for Economic Cooperation and Development included CeO2NP in the priority list of nanomaterials requiring urgent evaluation. As metal nanoparticles can cross the blood-testis barrier, CeO2NP could interact with spermatozoa. The genotoxicity of CeO2NP was demonstrated in vitro on human cell lines and mouse gametes. However, the effects of CeO2NP on human spermatozoa DNA remain unknown. We showed significant DNA damage induced in vitro by CeO2NP on human spermatozoa using Comet assay. The genotoxicity was inversely proportional to the concentration (0.01 to 10 mg.L-1). TEM showed no internalization of CeO2NP into the spermatozoa. This study shows for the first time that in vitro exposure to very low concentrations of cerium dioxide nanoparticles can induce significant DNA damage in human spermatozoa. These results add new and important insights regarding the reproductive toxicity of priority nanomaterials, which require urgent evaluation. PMID- 29625165 TI - Minocycline induces apoptosis in acute lymphoblastic leukemia Jurkat cells. PMID- 29625166 TI - Neuroprotective effect of a physiological ratio of testosterone and estradiol on corticosterone-induced apoptosis in PC12 cells via Traf6/TAK1 pathway. AB - Clinical and experimental studies suggested that testosterone or estradiol alone supplementation may have antidepressant-like effects. However, the synergistic effect of testosterone/estradiol on the treatment of depression and the underlying mechanism remain largely unknown. Here, we hypothesized that an appropriate dosage of testosterone combined with estradiol may became a new therapeutic strategy in depression. Our results indicated that an appropriate testosterone/estradiol ratio of 10:1 (10-8 mol/L testosterone and 10-9 mol/L estradiol) was found, which has a significant synergistic anti-apoptotic effect on PC12 cells injury stimulated by corticosterone. We then confirmed the synergistic effect of the defined testosterone/estradiol ratio in PC12 cells mainly depend on the inhibitory activation of Traf6/TAK1 signaling pathway. Furthermore, we found that the defined testosterone/estradiol ratio could suppress the expression and ubiquitination of Traf6 protein through AR/ERalpha mediated pathways. Finally, endogenous interactions of Traf6 with AR/ERalpha in PC12 cells were found using co-immunoprecipitation assays, and further verified how the defined testosterone/estradiol ratio plays a synergistic role in injury of PC12 cells. The current study demonstrated that an appropriate testosterone/estradiol ratio has a synergistic effect on PC12 cells injury induced by corticosterone through suppressing the activation of Traf6/TAK1 signaling pathway, suggesting that testosterone/estradiol might synergistically protect against neuronal apoptosis to ameliorate depressive symptoms. PMID- 29625169 TI - Effects of cationic liposomes with stearylamine against virus infection. AB - In this study, we demonstrated that cationic liposomes with incorporated stearylamine (SA) inhibit viral infectivity without preloaded active pharmaceutical ingredients. Specifically, we correlated physiochemical properties of liposomes, such as zeta potentials and particle sizes, with virus infectivity using the BacMamTM reagent, which is based on recombinant baculovirus (BV). Compared with neutral or negatively-charged liposomes, SA liposomes suppressed BV infectivity in several mammalian cell lines, including A549 cells. SA liposomes inhibited BV infection over 80% by optimizing the liposomal concentration and exposure time with cells. Moreover, these antiviral SA liposomes were not cytotoxic, and reducing the embedded cholesterol contents intensified the antiviral effects and simultaneously increased the binding of SA liposomes to the cell membranes. These data indicate that binding of SA liposomes to cell membranes may block virus entry. Finally, we also demonstrated the antiviral effects of SA liposomes on herpes simplex virus type 1 in A549 cells, and showed comparable efficacy to that of the antiviral drug acyclovir. PMID- 29625168 TI - Improved properties of fine active pharmaceutical ingredient powder blends and tablets at high drug loading via dry particle coating. AB - It has been shown that dry coating cohesive active pharmaceutical ingredients (APIs) with nano-silica can improve packing and flow of their blends, facilitating high speed direct compression tableting. This paper examines the broader scope and generality of previous work by examining three fine APIs; micronized Acetaminophen (mAPAP), coarse Acetaminophen (cAPAP) and micronized Ibuprofen (mIBU), and considers dry coating with both hydrophobic or hydrophilic nano-silica to examine the effect not only on packing density and flow of their blends, but also dissolution and tensile strength of their tablets. The impact of the excipient size on blend and tablet properties are also investigated, indicating blend flow is most improved when matching API particle size with excipient particle size. In all cases where the API is dry coated, the blend packing and flow improve, so as to suggest such high drug loaded blends could enable direct compression. Using dry coated API along with finer excipients in blends lead to improved hardness of the corresponding tablets. Interestingly, dissolution profiles show dry coated API tablets generally have faster dissolution rates, regardless of silica hydrophilicity, suggesting API powder deagglomeration via nano-silica coating plays a crucial role. The most significant conclusion is that, although there are differences in properties of blends that depend on the API, hydrophobic or hydrophilic nano-silica coating, as well as large or fine excipients, in all cases, dry coating of APIs significantly improves the possibility of using the specific blend at high drug loading in direct compression tableting. PMID- 29625170 TI - Developing core elements and checklist items for global hospital antimicrobial stewardship programmes: a consensus approach. AB - OBJECTIVES: With increasing global interest in hospital antimicrobial stewardship (AMS) programmes, there is a strong demand for core elements of AMS to be clearly defined on the basis of principles of effectiveness and affordability. To date, efforts to identify such core elements have been limited to Europe, Australia, and North America. The aim of this study was to develop a set of core elements and their related checklist items for AMS programmes that should be present in all hospitals worldwide, regardless of resource availability. METHODS: A literature review was performed by searching Medline and relevant websites to retrieve a list of core elements and items that could have global relevance. These core elements and items were evaluated by an international group of AMS experts using a structured modified Delphi consensus procedure, using two-phased online in-depth questionnaires. RESULTS: The literature review identified seven core elements and their related 29 checklist items from 48 references. Fifteen experts from 13 countries in six continents participated in the consensus procedure. Ultimately, all seven core elements were retained, as well as 28 of the initial checklist items plus one that was newly suggested, all with >=80% agreement; 20 elements and items were rephrased. CONCLUSIONS: This consensus on core elements for hospital AMS programmes is relevant to both high- and low-to middle-income countries and could facilitate the development of national AMS stewardship guidelines and adoption by healthcare settings worldwide. PMID- 29625171 TI - The role of nitric oxide (NO) donors in anxiety. Lights and shadows. AB - Anxiety-related disorders are a common public health issues. Current medication for this affective disorder involves the GABA-ergic or the serotonergic transmission. Different forms of anxiety, however, are resistant to treatment with GABA-ergic or serotonergic agents and the use of these compounds can be associated with severe side effects. Thus, almost 60 years after the discovery of the benzodiazepines there is need not only for fresh medications but also alternative targets. The nitrergic system has emerged as a promising target since several lines of evidence suggest that nitric oxide (NO), an intra- and inter cellular messenger in the brain, is implicated in anxiety. Therefore, NO modulators might be beneficial. Here I critically review advances in research of agents acting on the nitrergic system, such as the NO donors, for the treatment of anxiety. Present analysis suggests that although NO donors are involved in anxiety their potential anxiolytic effect remains to be established. PMID- 29625167 TI - Idiosyncrasies of hnRNP A1-RNA recognition: Can binding mode influence function. AB - The heterogeneous nuclear ribonucleoproteins (hnRNPs) are a diverse family of RNA binding proteins that function in most stages of RNA metabolism. The prototypical member, hnRNP A1, is composed of three major domains; tandem N-terminal RNA Recognition Motifs (RRMs) and a C-terminal mostly intrinsically disordered region. HnRNP A1 is broadly implicated in basic cellular RNA processing events such as splicing, stability, nuclear export and translation. Due to its ubiquity and abundance, hnRNP A1 is also frequently usurped to control viral gene expression. Deregulation of the RNA metabolism functions of hnRNP A1 in neuronal cells contributes to several neurodegenerative disorders. Because of these roles in human pathologies, the study of hnRNP A1 provides opportunities for the development of novel therapeutics, with disruption of its RNA binding capabilities being the most promising target. The functional diversity of hnRNP A1 is reflected in the complex nature by which it interacts with various RNA targets. Indeed, hnRNP A1 binds both structured and unstructured RNAs with binding affinities that span several magnitudes. Available structures of hnRNP A1 RNA complexes also suggest a degree of plasticity in molecular recognition. Given the reinvigoration in hnRNP A1, the goal of this review is to use the available structural biochemical developments as a framework to interpret its wide-range of RNA functions. PMID- 29625172 TI - Oxidant-specific biomarkers of oxidative stress. Association with atherosclerosis and implication for antioxidant effects. AB - The unregulated oxidative modification of lipids, proteins, and nucleic acids induced by multiple oxidants has been implicated in the pathogenesis of many diseases. Antioxidants with diverse functions exert their roles either directly or indirectly in the physiological defense network to inhibit such deleterious oxidative modification of biological molecules and resulting damage. The efficacy of antioxidants depends on the nature of oxidants. Therefore, it is important to identify the oxidants which are responsible for modification of biological molecules. Some oxidation products produced selectively by specific oxidant enable to identify the responsible oxidants, while other products are produced by several oxidants similarly. In this review article, several oxidant-specific products produced selectively by peroxyl radicals, peroxynitrite, hypochlorous acid, lipoxygenase, and singlet oxygen were summarized and their potential role as biomarker is discussed. It is shown that the levels of specific oxidation products including hydroxylinoleate isomers, nitrated and chlorinated products, and oxysterols produced by the above-mentioned oxidants are elevated in the human atherosclerotic lesions, suggesting that all these oxidants may contribute to the development of atherosclerosis. Further, it was shown that the reactivities of physiological antioxidants toward the above-mentioned oxidants vary extensively, suggesting that multiple antioxidants effective against these different oxidants are required, since no single antioxidant alone can cope with these multiple oxidants. PMID- 29625174 TI - Hyponatremia is associated with occurrence of atrial fibrillation in outpatients with heart failure and reduced ejection fraction. AB - OBJECTIVES: Hyponatremia and atrial fibrillation (AF) have been established as strong predictors for worse clinical outcomes in patients with heart failure (HF). However, little is known about hyponatremia in relation to the occurrence of AF. This study aims to investigate the possible relationship between hyponatremia and AF in patients with chronic HF and reduced ejection fraction (HFrEF). METHODS: Turkish research team-HF (TREAT-HF) is a network that has been undertaking multicenter, observational cohort studies on HF. A total of 880 patients who had plasma sodium measurement in TREAT-HF data set were included in this study. Hyponatremia was defined as a plasma sodium level of <=135 mmol/L. The patients were classified into hyponatremia (n=213) or normonatremia (n=667) based on the sodium level. RESULTS: The rate of AF was found to be 33.3% in patients with hyponatremia and 18.8% in patients with normonatremia (p<0.001). Univariate analysis demonstrated an association between hyponatremia and AF. Furthermore, in multivariate logistic regression model, hyponatremia was also found to be significantly and independently associated with the occurrence of AF (odds ratio [OR]=2.457, 95% confidence interval [CI]=1.586-3.806, p<0.001) in addition to other well-known risk factors for AF. CONCLUSION: The results of this study showed that AF was more prevalent in outpatients with HFrEF and hyponatremia than in those with HFrEF and normonatremia. These results also suggest that hyponatremia is independently associated with the occurrence of AF. PMID- 29625175 TI - MAGI proteins can differentially regulate the signaling pathways of 5-HT2AR by enhancing receptor trafficking and PLC recruitment. AB - MAGI proteins are Membrane-Associated Guanylate Kinase Inverted proteins that belong to the MAGUK family. They are scaffolding proteins that were shown to mediate the trafficking and signaling of various G protein-coupled receptors (GPCRs). They contain PDZ domains in their structure and many GPCRs interact with these proteins via the PDZ motifs on the carboxyl terminal end of a receptor. In a PDZ overlay assay performed with the carboxyl terminal tail of 5-HT2AR, we were able to detect all three members of the MAGI subfamily, MAGI-1, MAGI-2 and MAGI-3 as interacting PDZ proteins. The PDZ motif of 5-HT2AR consists of three amino acids; serine (S), cysteine (C) and valine (V). In this study, we characterize these 5-HT2AR interactions with MAGI proteins. We first confirm the interaction using co-immunopricipitation and illustrate that the interaction is PDZ motif dependent in human embryonic kidney (HEK 293) cells. We then assess the effects of overexpression and knockdown of the MAGI proteins on the internalization, trafficking and signaling of 5-HT2AR. We find that knockdown of either MAGI-1 or MAGI-3 using siRNA results in a significant reduction in the internalization of 5 HT2AR. As for signaling, we report here that MAGI proteins can modulate the signaling via the two transduction pathways that 5-HT2AR can activate. We illustrate a significant effect of modulating MAGI proteins expression on 5-HT stimulated IP formation. We demonstrate an enhancement in 5-HT2AR-stimulated IP formation upon MAGI proteins overexpression. In addition, we show that knockdown of MAGI proteins with siRNA leads to a significant reduction in 5-HT2AR stimulated IP formation. Furthermore, we illustrate a significant increase in 5 HT-stimulated ERK1/2 phosphorylation upon MAGI proteins knockdown. Interestingly, this effect on ERK1/2 activation is PDZ motif-independent. We also suggest two possible mechanisms of regulation for the effect of MAGI proteins on 5-HT2AR function. One mechanism involves the regulation of cell surface expression since we show that both MAGI-2 and MAGI-3 can enhance receptor trafficking to the plasma membrane when overexpressed in HEK 293 cells. The other mechanism points to regulation of second messengers in the signaling pathways. Specifically, we show that overexpression of any of the three MAGI proteins can enhance the recruitment of PLCbeta3 to 5-HT2AR. In addition, we report a negative effect for knocking down MAGI-3 on beta-arrestin recruitment to the receptor and this effect is PDZ motif-independent. Taken together, our findings document distinct roles for the three MAGI proteins in regulating 5-HT2AR trafficking and signaling and emphasize the importance of studying PDZ proteins and their interactions with GPCRs to regulate their function. PMID- 29625173 TI - Brain mitochondrial iron accumulates in Huntington's disease, mediates mitochondrial dysfunction, and can be removed pharmacologically. AB - Mitochondrial bioenergetic dysfunction is involved in neurodegeneration in Huntington's disease (HD). Iron is critical for normal mitochondrial bioenergetics but can also contribute to pathogenic oxidation. The accumulation of iron in the brain occurs in mouse models and in human HD. Yet the role of mitochondria-related iron dysregulation as a contributor to bioenergetic pathophysiology in HD is unclear. We demonstrate here that human HD and mouse model HD (12-week R6/2 and 12-month YAC128) brains accumulated mitochondrial iron and showed increased expression of iron uptake protein mitoferrin 2 and decreased iron-sulfur cluster synthesis protein frataxin. Mitochondria-enriched fractions from mouse HD brains had deficits in membrane potential and oxygen uptake and increased lipid peroxidation. In addition, the membrane-permeable iron-selective chelator deferiprone (1 MUM) rescued these effects ex-vivo, whereas hydrophilic iron and copper chelators did not. A 10-day oral deferiprone treatment in 9-week R6/2 HD mice indicated that deferiprone removed mitochondrial iron, restored mitochondrial potentials, decreased lipid peroxidation, and improved motor endurance. Neonatal iron supplementation potentiates neurodegeneration in mouse models of HD by unknown mechanisms. We found that neonatal iron supplementation increased brain mitochondrial iron accumulation and potentiated markers of mitochondrial dysfunction in HD mice. Therefore, bi-directional manipulation of mitochondrial iron can potentiate and protect against markers of mouse HD. Our findings thus demonstrate the significance of iron as a mediator of mitochondrial dysfunction and injury in mouse models of human HD and suggest that targeting the iron-mitochondrial pathway may be protective. PMID- 29625177 TI - An examination of group size and valence in delay discounting of shared outcomes. AB - Previous research has examined delay discounting in a group context, where the outcomes are shared with others. These studies indicate shallow delay discounting in a group context compared to an individual context. The present set of studies aimed to explore the impact of two factors, group size (the number of others in the group) and group valence (liked or disliked others in the group), that may affect delay discounting in a group context. Results of the two studies replicated previous results, where shallow delay discounting was observed in the group context compared to the individual context. While Study 1 indicated no effects of group size nor of valence, Study 2 indicated shallow delay discounting for a larger group compared to a smaller group and for liked others compared to disliked others. These results contribute the nascent literature on delay discounting in group contexts. PMID- 29625176 TI - High doses of Antisecretory Factor stop diarrhea fast without recurrence for six weeks post treatment. AB - BACKGROUND: Diarrheal illnesses in young children cause morbidity and preventable deaths in developing countries. We evaluated two high doses of Salovum(r) [Antisecretory Factor] to treat diarrhea in young children and followed up for recurrence 6 weeks post treatment. METHODS: Forty children, 6-24 months old, admitted with acute diarrhea, to the Outpatient Department of Children's Hospital in Lahore, Pakistan were selected. The patients were randomly allocated to either Group A given 2 sachets, or to Group B, given 4 sachets. Each sachet contained 4gram of Salovum(r) and was mixed with Oral Rehydration Salt solution. This mixture was administered perorally within the first 30min of treatment. The trained nursing staff observed them for number of stools and consistency over every half hour for a total of 4hours. Follow up for 6 weeks was done daily by telephone, or visits by the mothers. The results demonstrate that Salovum provides a protective effect irrespective of the diarrhea causes. RESULTS: Group B, given 4 sachets of Salovum(r) showed improved fecal consistency in 80% of the children compared to 50% in Group A within 30minutes of treatment, p=0.004. The number of diarrheal stools decreased over this time from seven to one/two over 4hours in the two groups [p=0.234]. None of the children showed a recurrence of diarrhea over the follow up period. CONCLUSION: Peroral high doses of Salovum(r) rapidly and safely counteract diarrhea in children followed by a diarrhea-free period of 6 weeks. PMID- 29625178 TI - Impact of Hajj on the S. pneumoniae carriage among Indian pilgrims during 2016- a longitudinal molecular surveillance study. AB - BACKGROUND: The population flow dynamics of Hajj increases the probability of pneumococcal acquisition and amplification among Hajis. This multi-site longitudinal molecular surveillance study was designed to assess the impact and potential variations of pneumococcal carriage in a single cohort of pre and post Hajj pilgrims from India. METHOD: A total of 3228 pre and post-Hajj, nasopharyngeal and oropharyngeal swabs were collected from 807 pilgrims with an interval of 40 +/- 5 days. The carriage was detected by culture and qmPCR. Quellung test, mPCR-FAF, PCRseqTyping, and MLST was used for typing. Antibiogram was performed by MIC method. RESULTS: An increased incidence of pneumococcal carriage was detected in post Hajj cohort by qmPCR (19% vs 21.8%) (p-value = 0.0487) and culture (6.5% vs 8.2%) (p-value = 0.0645). Fragment analysis could identify multiple serotype carriage in 76 pilgrims. Increase in drug resistance was also observed in post-hajj cohort for Tetracycline (29% vs 51%), Erythromycin (26% vs 46%) and Levofloxacin (6% vs 17%). Multidrug resistant strains in post Hajj group was 32% compared to 11% in pre Hajj group (p-value = 0.0002). CONCLUSION: Our results confirm high acquisition rate of multidrug-resistant S. pneumoniae in Hajj pilgrims and highlight its potential spread to home countries upon their return. Surveillance studies are needed to evaluate modifiable factors associated with carriage. PMID- 29625179 TI - Proteostasis in epicardial versus subcutaneous adipose tissue in heart failure subjects with and without diabetes. AB - BACKGROUND: Cardiovascular diseases (CVDs) are leading cause of death and primary cause of morbidity and mortality in diabetic population. Epicardial adipose tissue (EAT) covers the heart's surface and is a source of biomolecules regulating heart and blood vessel physiology. The protective activation of the unfolded protein response (UPR) and autophagy allows the cardiomyocyte reticular network to restore energy and/or nutrient homeostasis and to avoid cell death. However, an excessive or prolonged UPR activation can trigger cell death. UPR activation is an early event of diabetic cardiomyopathies and deregulated autophagy is associated with CVDs. RESULTS: An upregulation of UPR markers (glucose-regulated protein 78 KDa, glucose-regulated protein 94 KDa, inositol requiring enzyme 1alpha, protein kinase RNA-like ER kinase and CCAAT/-enhancer binding protein homologous protein (CHOP) gene) in EAT compared to subcutaneous adipose tissue (SAT), was observed as well as the UPR-related apoptosis marker caspase-4/procaspase-4 ratio but not in CHOP protein levels. Additionally, levels of ubiquitin and ubiquitinated proteins were decreased in EAT. Moreover, upregulation of autophagy markers (5' adenosine monophosphate-activated protein kinase, mechanistic target of rapamycin, Beclin 1, microtubule-associated protein light chain 3-II, lysosome-associated membrane protein 2, and PTEN-induced putative kinase 1) was observed, as well as an increase in the apoptotic Bim but not the ratio between Bim and the anti-apoptotic Bcl-2 in EAT. Diabetic patients show alterations in UPR activation markers but not in autophagy or apoptosis markers. CONCLUSION: UPR and autophagy are increased in EAT compared to SAT, opening doors to the identification of early biomarkers for cardiomyopathies and novel therapeutic targets. PMID- 29625180 TI - Abeta-oligomer uptake and the resulting inflammatory response in adult human astrocytes are precluded by an anti-Abeta single chain variable fragment in combination with an apoE mimetic peptide. AB - An imbalance between production and clearance of soluble amyloid-beta (Abeta) initiates the pathological process in sporadic Alzheimer's disease (AD). Abeta specific antibodies seemed promising as therapeutic option in AD mouse models. In patients, however, vascular side-effects and Abeta-antibody complex-induced microglial and/or perivascular macrophage inflammatory responses were encountered. To prevent inflammatory reactions, we designed a single chain variable fragment (scFv-h3D6), based on monoclonal antibody bapineuzumab (mAb h3D6), but lacking the Fc region. ScFv-h3D6 reduced Abeta-oligomer burden and prevented AD-associated behavioral and cellular changes in 3xTg-AD mice. As scFv h3D6 lacks the Fc-tail, it cannot enhance Fc-receptor mediated Abeta clearance by microglia and probably exerts its beneficial effects in 3xTg-AD mice through other mechanisms. ScFv-h3D6 restored the increased apoE and apoJ levels in 3xTg AD brains back to normal. ApoE and apoJ influence cholesterol transport, Abeta aggregation and clearance, and their genetic variants are risk factors for sporadic AD. Astrocytes are constitutive scavengers of soluble Abeta from the CNS. We previously found apoE and apoJ to inhibit Abeta uptake by adult human astrocytes, in vitro, and thus to potentially protect astrocytes from Abeta cytotoxicity. In the present study, scFv-h3D6 and mAb-h3D6 inhibited Abeta oligomer uptake by adult human astrocytes. ApoE- and apoJ- mimetic peptides (MP) affected Abeta uptake as well as Abeta-induced cytokine release similar to intact apoE and apoJ, without interfering with the strong inhibitory effects of scFv h3D6 on Abeta-oligomer uptake. These results suggest that combining Abeta specific scFv and apoE-MP, that inhibits Abeta oligomer-induced cytokine release by astrocytes, could offer advantages over currently used therapeutics. PMID- 29625184 TI - Clinical results of peroneal tendon repair in a retrospective series of 30 patients. AB - INTRODUCTION: Peroneal tendinopathy is an under-diagnosed pathology, mainly triggered by ankle sprain. Failure of medical treatment often leads to surgery, with modalities adapted to the lesion type. The present study aimed to assess clinical and functional results of tendon repair and to analyze the influence of hindfoot alignment on quality of outcome. The study hypothesis was that hindfoot varus impairs medium-term results. MATERIALS AND METHODS: A retrospective series of 30 patients undergoing peroneal tendon repair or tenodesis was analyzed at a mean 20 months' follow-up. All patients had preoperative ultrasound scan or NMRI. Clinical assessment was based on AOFAS and FAAM scores. Hindfoot alignment was assessed on Meary view; 2 groups were distinguished: valgus (n=11) and varus (n=17). RESULTS: Mean AOFAS score improved, from 74.5+/-11.2 preoperatively to 86.7+/-9.4 at follow-up. There was a significant intergroup difference (p=0.0003) in AOFAS at follow-up: valgus, 93/100; varus, 82/100. There was no significant intergroup difference in FAAM score. Time to surgery, lesion type and surgical technique did not influence clinical results. DISCUSSION/CONCLUSION: Clinical results for surgical repair of peroneal tendons were satisfactory and in line with literature reports. However, hindfoot varus was associated with poorer results, raising the possibility of correction by opening wedge calcaneal osteotomy. LEVEL OF EVIDENCE: IV, retrospective case series. PMID- 29625181 TI - Hyaluronan in immune dysregulation and autoimmune diseases. AB - The tissue microenvironment contributes to local immunity and to the pathogenesis of autoimmune diseases - a diverse set of conditions characterized by sterile inflammation, immunity against self-antigens, and destruction of tissues. However, the specific factors within the tissue microenvironment that contribute to local immune dysregulation in autoimmunity are poorly understood. One particular tissue component implicated in multiple autoimmune diseases is hyaluronan (HA), an extracellular matrix (ECM) polymer. HA is abundant in settings of chronic inflammation and contributes to lymphocyte activation, polarization, and migration. Here, we first describe what is known about the size, amount, and distribution of HA at sites of autoimmunity and in associated lymphoid structures in type 1 diabetes, multiple sclerosis, and rheumatoid arthritis. Next, we examine the recent literature on HA and its impact on adaptive immunity, particularly in regards to the biology of lymphocytes and Foxp3+ regulatory T-cells (Treg), a T-cell subset that maintains immune tolerance in healthy individuals. We propose that HA accumulation at sites of chronic inflammation creates a permissive environment for autoimmunity, characterized by CD44-mediated inhibition of Treg expansion. Finally, we address potential tools and strategies for targeting HA and its receptor CD44 in chronic inflammation and autoimmunity. PMID- 29625185 TI - Epigenetic modifications in the embryonic and induced pluripotent stem cells. AB - Epigenetic modifications are involved in global reprogramming of the cell transcriptome. Therefore, synchronized major shifts in the expression of many genes could be achieved through epigenetic changes. The regulation of gene expression could be implemented by different epigenetic events including histone modifications, DNA methylation and chromatin remodelling. Interestingly, it has been documented that reprogramming of somatic cells to induced pluripotent stem (iPS) cells is also a typical example of epigenetic modifications. Additionally, epigenetic would determine the fates of almost all cells upon differentiation of stem cells into somatic cells. Currently, generation of iPS cells through epigenetic modifications is a routine laboratory practice. Despite all our knowledge, inconsistency in the results of reprogramming and differentiation of stem cells, highlight the need for more thorough investigation into the role of epigenetic modification in generation and maintenance of stem cells. Besides, subtle differences have been observed among different iPS cells and between iPS and ES cells. Although, a handful of detailed review regarding the status of epigenetics in stem cells has been published previously, in the current review, an abstracted and rather simplified view has been presented for those who want to gain a more general overview on this subject. However, almost all key references and ground breaking studies were included, which could be further explored to gain more in depth knowledge regarding this topic. The most dominant epigenetic changes have been presented followed by the impacts of such changes on the global gene expression. Epigenetic status in iPS and ES cells were compared. In addition to including the issues related to X-chromosome reactivation in the stem cells, we have also included loss of imprinting for some genes as a major drawback in generation of iPS cells. Finally, the overall impacts of epigenetic modifications on different aspects of stem cells has been discussed, including their use in cell therapy. PMID- 29625183 TI - Extracellular matrix: The driving force of mammalian diseases. AB - Like the major theme of a Mozart concerto, the immense and pervasive extracellular matrix drives each movement and ultimately closes the symphony, embracing a unique role as the fundamental mediator for most, if not all, ensuing intracellular events. As such, it comes as no surprise that the mechanism of just about every known disease can be traced back to some part of the matrix, typically in the form of an abnormal amount or activity level of a particular matrix component. These defects considerably affect downstream signaling axes leading to overt cellular dysfunction, organ failure, and death. From skin to bone, from vessels to brain, from eyes to all the internal organs, the matrix plays an incredible role as both a cause and potential means to reverse diseases. Human malaises including connective tissue disorders, muscular dystrophy, fibrosis, and cancer are all extracellular matrix-driven diseases. The ability to understand and modulate these matrix-related mechanisms may lead to the future discovery of novel therapeutic options for these patients. PMID- 29625186 TI - Bimodal fuzzy analytic hierarchy process (BFAHP) for coronary heart disease risk assessment. AB - Rooted deeply in medical multiple criteria decision-making (MCDM), risk assessment is very important especially when applied to the risk of being affected by deadly diseases such as coronary heart disease (CHD). CHD risk assessment is a stochastic, uncertain, and highly dynamic process influenced by various known and unknown variables. In recent years, there has been a great interest in fuzzy analytic hierarchy process (FAHP), a popular methodology for dealing with uncertainty in MCDM. This paper proposes a new FAHP, bimodal fuzzy analytic hierarchy process (BFAHP) that augments two aspects of knowledge, probability and validity, to fuzzy numbers to better deal with uncertainty. In BFAHP, fuzzy validity is computed by aggregating the validities of relevant risk factors based on expert knowledge and collective intelligence. By considering both soft and statistical data, we compute the fuzzy probability of risk factors using the Bayesian formulation. In BFAHP approach, these fuzzy validities and fuzzy probabilities are used to construct a reciprocal comparison matrix. We then aggregate fuzzy probabilities and fuzzy validities in a pairwise manner for each risk factor and each alternative. BFAHP decides about being affected and not being affected by ranking of high and low risks. For evaluation, the proposed approach is applied to the risk of being affected by CHD using a real dataset of 152 patients of Iranian hospitals. Simulation results confirm that adding validity in a fuzzy manner can accrue more confidence of results and clinically useful especially in the face of incomplete information when compared with actual results. Applying the proposed BFAHP on CHD risk assessment of the dataset, it yields high accuracy rate above 85% for correct prediction. In addition, this paper recognizes that the risk factors of diastolic blood pressure in men and high-density lipoprotein in women are more important in CHD than other risk factors. PMID- 29625182 TI - Idiopathic pulmonary fibrosis: Epithelial-mesenchymal interactions and emerging therapeutic targets. AB - Idiopathic pulmonary fibrosis (IPF) is a chronic fibrotic disease of the lung that is marked by progressive decline in pulmonary function and ultimately respiratory failure. Genetic and environmental risk factors have been identified that indicate injury to, and dysfunction of the lung epithelium is central to initiating the pathogenic process. Following injury to the lung epithelium, growth factors, matrikines and extracellular matrix driven signaling together activate a variety of repair pathways that lead to inflammatory cell recruitment, fibroblast proliferation and expansion of the extracellular matrix, culminating in tissue fibrosis. This tissue fibrosis then leads to changes in the biochemical and biomechanical properties of the extracellular matrix, which potentiate profibrotic mechanisms through a "feed-forward cycle." This review provides an overview of the interactions of the pathogenic mechanisms of IPF with a focus on epithelial-mesenchymal crosstalk and the extracellular matrix as a therapeutic target for idiopathic pulmonary fibrosis. PMID- 29625187 TI - Using insurance claims to predict and improve hospitalizations and biologics use in members with inflammatory bowel diseases. AB - OBJECTIVE: Inflammatory Bowel Disease (IBD) is an inflammatory disorder of the gastrointestinal tract that can necessitate hospitalization and the use of expensive biologics. Models predicting these interventions may improve patient quality of life and reduce expenditures. MATERIALS AND METHODS: We used insurance claims from 2011 to 2013 to predict IBD-related hospitalizations and the initiation of biologics. We derived and optimized our model from a 2011 training set of 7771 members, predicting their outcomes the following year. The best performing model was then applied to a 2012 validation set of 7450 members to predict their outcomes in 2013. RESULTS: Our models predicted both IBD-related hospitalizations and the initiation of biologics, with average positive predictive values of 17% and 11%, respectively - each a 200% improvement over chance. Further, when we used topic modeling to identify four member subpopulations, the positive predictive value of predicting hospitalization increased to 20%. DISCUSSION: We show that our hospitalization model, in concert with a mildly-effective interventional treatment plan for members identified as high-risk, may both improve patient outcomes and reduce insurance expenditures. CONCLUSION: The success of our approach provides a roadmap for how claims data can complement traditional medical decision making with personalized, data-driven predictive medicine. PMID- 29625188 TI - Building ER-PM contacts: keeping calm and ready on alarm. AB - It is well over half a century since contacts between organelles such as the endoplasmic reticulum (ER), mitochondria, and the plasma membrane (PM) were first observed in electron microscopy studies. Still, these early images of seemingly rare organelle interactions continue to capture the attention and curiosity of cell biologists even today. From seminal studies first proposing roles for organelle cross talk in excitable cells, the field has now expanded to cover nearly all aspects of eukaryotic cell biology, from calcium and membrane lipid transport to vesicular trafficking, cell signaling, metabolism, and homeostasis. This review highlights recent discoveries pointing to vital roles for ER-PM contacts in membrane lipid dynamics and organization. PMID- 29625189 TI - The dystrophin isoform Dp71eDelta71 is involved in neurite outgrowth and neuronal differentiation of PC12 cells. AB - : The Dp71 protein is the most abundant dystrophin in the central nervous system (CNS). Several dystrophin Dp71 isoforms have been described and are classified into three groups, each with a different C-terminal end. However, the functions of Dp71 isoforms remain unknown. In the present study, we analysed the effect of Dp71eDelta71 overexpression on neuronal differentiation of PC12 Tet-On cells. Overexpression of dystrophin Dp71eDelta71 stimulates neuronal differentiation, increasing the percentage of cells with neurites and neurite length. According to 2-DE analysis, Dp71eDelta71 overexpression modified the protein expression profile of rat pheochromocytoma PC12 Tet-On cells that had been treated with neuronal growth factor (NGF) for nine days. Interestingly, all differentially expressed proteins were up-regulated compared to the control. The proteomic analysis showed that Dp71eDelta71 increases the expression of proteins with important roles in the differentiation process, such as HspB1, S100A6, and K8 proteins involved in the cytoskeletal structure and HCNP protein involved in neurotransmitter synthesis. The expression of neuronal marker TH was also up regulated. Mass spectrometry data are available via ProteomeXchange with identifier PXD009114. SIGNIFICANCE: This study is the first to explore the role of the specific isoform Dp71eDelta71. The results obtained here support the hypothesis that the dystrophin Dp71eDelta71 isoform has an important role in the neurite outgrowth by regulating the levels of proteins involved in the cytoskeletal structure, such as HspB1, S100A6, and K8, and in neurotransmitter synthesis, such as HCNP and TH, biological processes required to stimulate neuronal differentiation. PMID- 29625190 TI - Patients with sacroiliac joint dysfunction exhibit altered movement strategies when performing a sit-to-stand task. AB - OF BACKGROUND DATA: The ability to rise from a chair is a basic functional task that is frequently compromised in individuals diagnosed with orthopedic disorders in the low back and hip. There is no published literature that describes how this task is altered by sacroiliac joint dysfunction (SIJD). PURPOSE: The objective of this study was to compare lower extremity biomechanics and the onset of muscle activity when rising from a chair in subjects with SIJD and in healthy persons. STUDY DESIGN: Six women with unilateral SIJD and six age-matched healthy controls performed a sit-to-stand task while we measured kinematics, kinetics, and muscle activity. MATERIALS AND METHODS: Subjects stood up at a preferred speed from a seated position on an armless and backless adjustable stool. We measured kinematics with a 10-camera motion capture system, ground reaction forces for each leg with force plates, and muscle activity with surface electromyography. Joint angles and torques were calculated using inverse dynamics. Leg-loading rate was quantified as the average slope of vertical ground reaction (VGRF) force during the 500-millisecond interval preceding maximal knee extension. RESULTS: Between-leg differences in loading rates and peak VGRFs were significantly greater for the SIJD group than for the control group. Maximal hip angles were significantly less for the SIJD group (p=.001). Peak hip moment in the SIJD group was significantly greater in the unaffected leg (0.75+/-0.22 N?m/kg) than in the affected leg (0.47+/-0.29 N?m/kg, p=.005). There were no between-leg or between group differences for peak knee or ankle moments. The onset of activity in the latissimus dorsi muscle on the affected side was delayed and the erector spinae muscles were activated earlier in the SIJD group than in the control group. CONCLUSIONS: Subjects with SIJD have a greater VGRF on the unaffected leg, generate a greater peak hip moment in the unaffected leg, use a smaller range of motion at the hip joint of the affected leg, and delay the onset of a key muscle on the affected side when rising from a seated position. PMID- 29625191 TI - GSK3-like Kinases Are a Class of Positive Components in the Core ABA Signaling Pathway. PMID- 29625192 TI - Bioactive carbazole and quinoline alkaloids from Clausena dunniana. AB - Nine undescribed carbazole and quinoline alkaloids, named dunnines A-E, and 14 known analogues were isolated from the leaves and stems of Clausena dunniana. Their structures were elucidated on the basis of comprehensive analysis of NMR and HRMS spectroscopic data, and the absolute configurations were assigned via comparison of their specific rotations and calculated and experimental ECD data. (+/-)-Dunnines A-C and (+/-)-clausenawalline A are four pairs of biscarbazole atropisomers and (+/-)-dunnine D is a pair of dihydropyranocarbazole enantiomers. They were separated by chiral HPLC to obtain the optically pure compounds. Three compounds showed weak inhibitory effects on nitric oxide production stimulated by lipopolysaccharide in BV-2 microglial cells (IC50 > 50 MUM); five compounds could significantly promote insulin secretion in HIT-T15 cell line (1.9-3.1-fold of the control, p < 0.01) at 40 MUM, and nine compounds could inhibit the apoptosis of PC12 cell induced by 6-hydroxydopamine with IC50 values in the range of 10.9-47.2 MUM. PMID- 29625193 TI - Icaritin induces ovarian cancer cell apoptosis through activation of p53 and inhibition of Akt/mTOR pathway. AB - AIMS: Ovarian cancer (OC) has the highest mortality rate of all gynecological cancers. Currently, the first-line OC treatment consists of cytoreductive surgery and platinum-based chemotherapy. However, most patients develop chemoresistance after the first-line treatment limits the success of treatment. Therefore, there is an urgent need to identify effective therapeutic agents. MAIN METHODS: Cell viabilities were detected by MTS assay; Annexin V-FITC/PI assay and western blotting assay were performed to analyze the apoptotic cells in vitro; An immunofluorescence assay was performed to analyze the TUNEL+ apoptotic cells in vivo; Patient-derived xenografts were established to test the in vivo antitumor effects; The key proteins of p53, caspase-mediated apoptotic pathway and Akt/mTOR pathway were detected by Western blotting. KEY FINDINGS: Icaritin, a prenylflavonoid derivative from Epimedium Genus, inhibited the proliferation of drug-sensitive OC cells (OV2008 and C13*) and cisplatin resistant OC cells A2780cp. Icaritin induced OC cell apoptosis in vitro, as indicated by the increase of Annexin V+/PI+ apoptotic cells analyzed with flow cytometry, and the cleavage of caspase 9, caspase 3 and poly-ADP-ribose polymerase (PARP) detected with western blotting. Icaritin also inhibited tumor growth and induced OC cells apoptosis in patient-derived xenografts, as indicated by the tumor growth delay and increase of TUNEL-positive cells in tumor tissues. The icaritin-induced OC cell apoptosis may be associated with the activation of p53 and the suppression of Akt/mTOR pathway. SIGNIFICANCE: This study sheds light on the underlying mechanisms of antitumor effect of icaritin, and warrants clinical trial for treatment of OC. PMID- 29625194 TI - Titanium dioxide nanoparticle stimulating pro-inflammatory responses in vitro and in vivo for inhibited cancer metastasis. AB - AIMS: The interaction of engineered nanoparticles (NPs) with the immune system and the possibility of inflammation induction are of particularly interest. Titanium dioxide nanoparticles (TiO2 NPs) are one of the most popular manufactured nanomaterials. In this study, we focused on the immune-modulatory effect of commercial P-25 TiO2 NPs in vivo and in vitro and their crucial role in cancer metastasis. MAIN METHODS: The female C57BL/6 mice were injected into abdominal cavity with PBS or P-25 TiO2 to investigate the immune-modulatory function of P-25. And breast cancer cells were intravenously (i.v.) injected into mouse to establish the liver and lung cancer metastasis model. Peritoneal macrophage was used to investigate the macrophage polarization in vitro. KEY FINDINGS: Results showed us that peritoneal macrophage exposed to P-25 TiO2 NPs displayed activated M1 macrophage response, as evidenced by the increased mRNA expression of interleukin-1beta (IL1beta), IL6, TNFalpha, CCR7 and inducible nitric oxide synthase (iNOS). After exposure of TiO2 NPs in vivo for 21 days, the body weights of mice decreased significantly, which were accompanied by an infiltration of immune cells in liver and spleen in 20 mg/kg BW treated group. Importantly, the production of pro-inflammatory cytokines in liver, spleen and the serum were amplified, which indicated the tissue and systemic inflammation induced by TiO2 NPs. In addition, the activation of immune response induced by P 25 TiO2 NPs was correlated with their ability to inhibit cancer metastasis. SIGNIFICANCE: Our results delineated the stimulating pro-inflammatory response induced by P-25 TiO2 NPs and their outcome in vivo for cancer metastasis. PMID- 29625195 TI - Idiopathic premature ventricular complexes originating from the distal great cardiac vein: Clinical, cardiac and electrophysiological characteristics and catheter ablation outcome. AB - AIMS: Although catheter ablation for idiopathic ventricular arrhythmia (VA) has been generally well-established, VA originating from the great cardiac vein (GCV) may be clinically challenging due to its epicardial origin, proximity to coronary arteries and limited accessibility. The purpose of this study was to explore its electrophysiological characteristics and identify effective mapping/ablation strategies for idiopathic premature ventricular complexes (PVCs) originating from the GCV. MATERIALS AND METHODS: Between January 2013 to January 2018, 12 patients (who were diagnosed with PVCs originating from the GCV) among the 305 patients with idiopathic left ventricular outflow tract tachycardia were included. The origin of the ectopy was localized by mapping, the characteristics of the electrocardiogram (ECG) were analyzed, and all the patients with PVCs originating from GCV were treated by radiofrequency catheter ablation (RFCA). The safety and efficacy of RFCA were evaluated. KEY FINDINGS: The origin of the ectopy was successfully localized in GCV for all 12 patients by mapping, and access to GCV via the coronary sinus was feasible. Successful RFCA was achieved in 11 of 12 patients (91.67% acute procedural success) without perioperative complications. During a median follow-up of 12.6 +/- 6.5 months, only one patient had recurrent VA (recurrence rate: 9.1%). SIGNIFICANCE: ECG characteristics may be helpful for identifying patients with PVCs originating from the GCV. RFCA within the coronary venous system appears to be safe and effective for these patients, and should be considered when routine RFCA from the endocardium or aortic sinus of the Valsalva is not effective. PMID- 29625196 TI - Sex modulated effects of sarin exposure in rats: Toxicity, hypothermia and inflammatory markers. AB - This work focused on sex differences in rats exposed to sarin. Females were found to be more sensitive to sarin toxicity (LD50 67 MUg/kg) than males (88 MUg/kg), showed less acute hypothermic effects than males (at 120 min post sarin, 3.1 +/- 1.1 and 4.5 +/- 1 degrees C decrease, respectively), but with a significant slower recovery over days. Females' temperature response to the cholinergic agonist oxotremorine (0.25 mg/kg, im) was more pronounced than that of males (at 30 min, 3.13 +/- 0.27 and 2.13 +/- 0.19 degrees C decrease, respectively) and both sexes recovered within 2 h of exposure. 24 h after sarin exposure (80 MUg/kg) followed 1 min later by TA treatment (TMB4 7.5 mg/kg and atropine 5 mg/kg) a 255% increase in plasma MCP-1 in males but not in females was recorded. In the brain, TIMP-1 increased 43 fold in females and 25 fold in males, compared to control rats. MCP-1 increased 8 fold in females only. TNFalpha increased in both sexes, but the increase in female brain was higher than that recorded in males. IL-6 increased in females but not in males. IL-1beta increased in both sexes. This work clearly demonstrates significant sex modulation effects on measures of toxicity, hypothermia and inflammatory markers in brain and plasma 24 h following exposure to sarin. In general, females seem to be more sensitive to the toxicity of sarin, but may be better protected against its brain damage. In light of these and other findings, the efficacy of the various available treatments, as well as those being developed, should be evaluated in both sexes. PMID- 29625197 TI - A single subconvulsant dose of domoic acid at mid-gestation does not cause temporal lobe epilepsy in mice. AB - Harmful blooms of domoic acid (DA)-producing algae are a problem in oceans worldwide. DA is a potent glutamate receptor agonist that can cause status epilepticus and in survivors, temporal lobe epilepsy. In mice, one-time low-dose in utero exposure to DA was reported to cause hippocampal damage and epileptiform activity, leading to the hypothesis that unrecognized exposure to DA from contaminated seafood in pregnant women can damage the fetal hippocampus and initiate temporal lobe epileptogenesis. However, development of epilepsy (i.e., spontaneous recurrent seizures) has not been tested. In the present study, long term seizure monitoring and histology was used to test for temporal lobe epilepsy following prenatal exposure to DA. In Experiment One, the previous study's in utero DA treatment protocol was replicated, including use of the CD-1 mouse strain. Afterward, mice were video-monitored for convulsive seizures from 2 to 6 months old. None of the CD-1 mice treated in utero with vehicle or DA was observed to experience spontaneous convulsive seizures. After seizure monitoring, mice were evaluated for pathological evidence of temporal lobe epilepsy. None of the mice treated in utero with DA displayed the hilar neuron loss that occurs in patients with temporal lobe epilepsy and in the mouse pilocarpine model of temporal lobe epilepsy. In Experiment Two, a higher dose of DA was administered to pregnant FVB mice. FVB mice were tested as a potentially more sensitive strain, because they have a lower seizure threshold, and some females spontaneously develop epilepsy. Female offspring were monitored with continuous video and telemetric bilateral hippocampal local field potential recording at 1 11 months old. A similar proportion of vehicle- and DA-treated female FVB mice spontaneously developed epilepsy, beginning in the fourth month of life. Average seizure frequency and duration were similar in both groups. Seizure frequency was lower than that of positive-control pilocarpine-treated mice, but seizure duration was similar. None of the mice treated in utero with vehicle or DA displayed hilar neuron loss or intense mossy fiber sprouting, a form of aberrant synaptic reorganization that develops in patients with temporal lobe epilepsy and in pilocarpine-treated mice. FVB mice that developed epilepsy (vehicle- and DA treated) displayed mild mossy fiber sprouting. Results of this study suggest that a single subconvulsive dose of DA at mid-gestation does not cause temporal lobe epilepsy in mice. PMID- 29625198 TI - RelA-Containing NFkappaB Dimers Have Strikingly Different DNA-Binding Cavities in the Absence of DNA. AB - The main nuclear factor kappa B transcription factor family members RelA-p50 heterodimer and RelA homodimer have different biological functions and show different transcriptional activation profiles. To investigate whether the two family members adopt a similar conformation in their free states, we performed hydrogen-deuterium exchange mass spectrometry, all-atom molecular dynamics simulations, and stopped-flow binding kinetics experiments. Surprisingly, the N terminal DNA-binding domains adopt an open conformation in RelA-p50 but a closed conformation in RelA homodimer. Both hydrogen-deuterium exchange mass spectrometry and molecular dynamics simulations indicate the formation of an interface between the N-terminal DNA-binding domains only in the RelA homodimer. Such an interface would be expected to impede DNA binding, and stopped-flow binding kinetics show that association of DNA is slower for the homodimer as compared to the heterodimer. Our results show that the DNA-binding cavity in the RelA-p50 heterodimer is open for DNA binding, whereas in the RelA homodimer, it is occluded. PMID- 29625199 TI - Crystal Structure of Human Rpp20/Rpp25 Reveals Quaternary Level Adaptation of the Alba Scaffold as Structural Basis for Single-stranded RNA Binding. AB - Ribonuclease P (RNase P) catalyzes the removal of 5' leaders of tRNA precursors and its central catalytic RNA subunit is highly conserved across all domains of life. In eukaryotes, RNase P and RNase MRP, a closely related ribonucleoprotein enzyme, share several of the same protein subunits, contain a similar catalytic RNA core, and exhibit structural features that do not exist in their bacterial or archaeal counterparts. A unique feature of eukaryotic RNase P/MRP is the presence of two relatively long and unpaired internal loops within the P3 region of their RNA subunit bound by a heterodimeric protein complex, Rpp20/Rpp25. Here we present a crystal structure of the human Rpp20/Rpp25 heterodimer and we propose, using comparative structural analyses, that the evolutionary divergence of the single-stranded and helical nucleic acid binding specificities of eukaryotic Rpp20/Rpp25 and their related archaeal Alba chromatin protein dimers, respectively, originate primarily from quaternary level differences observed in their heterodimerization interface. Our work provides structural insights into how the archaeal Alba protein scaffold was adapted evolutionarily for incorporation into several functionally-independent eukaryotic ribonucleoprotein complexes. PMID- 29625200 TI - Reciprocal Interactions between Membrane Bilayers and S. aureus PSMalpha3 Cross alpha Amyloid Fibrils Account for Species-Specific Cytotoxicity. AB - Phenol-soluble modulin alpha3 (PSMalpha3) is a functional amyloid secreted by the pathogenic bacterium Staphylococcus aureus. This 22-residue peptide serves as a key virulence determinant, toxic to human cells via the formation of unique cross alpha amyloid-like fibrils. We demonstrate that bilayer vesicles accelerated PSMalpha3 fibril formation, and the fibrils, in turn, inserted deeply into bilayers mimicking mammalian cell membranes, accounting for PSMalpha3 cellular toxicity. Importantly, a mere amphipathic helical conformation was not a sufficient determinant for membrane-activity of PSMalpha3, pointing to the functional role of cross-alpha fibrils. In contrast to deep insertion of PSMalpha3 into mammalian membrane bilayers, the peptide only interacted with the surface of bilayers mimicking bacterial membranes, which might be related to its lack of antibacterial activity. Together, our data provide mechanistic insight into species-specific toxicity of a key bacterial amyloid virulence factor via reciprocal interactions with membranes, and open new perspectives into amyloid related cytotoxicity mediated by helical fibril structures. PMID- 29625201 TI - saRNAdb: Resource of Small Activating RNAs for Up-regulating the Gene Expression. AB - RNA activation (RNAa) is the process of enhancing selective gene expression at transcriptional level using double-stranded RNAs, targeting gene promoter. These RNA molecules are usually 21 nucleotides long and termed as small activating RNAs (saRNAs). They are involved in gene regulation, epigenetics, gain-of-function studies and have potential therapeutic applications for various diseases especially cancer. RNAa is opposite to RNA interference in functionality; however, both processes share some protein machinery. There are many RNA interference centered online resources but no one for saRNAs; therefore, we developed "saRNAdb" database (http://bioinfo.imtech.res.in/manojk/sarna/). It contains 2150 manually curated saRNA entries with detailed information about their nucleotide sequences, activities, corresponding target gene, promoter and other experimental data. Besides, saRNA-promoter binding location, predicted saRNA features, tools (off-target, map) and RNAa-related proteins with their interacting partners are provided. saRNAdb is expected to assist in RNA research especially for nucleic acid-based therapeutics development. PMID- 29625202 TI - Yeast Inner-Subunit PA-NZ-1 Labeling Strategy for Accurate Subunit Identification in a Macromolecular Complex through Cryo-EM Analysis. AB - Cryo-electron microscopy (cryo-EM) has been established as one of the central tools in the structural study of macromolecular complexes. Although intermediate- or low-resolution structural information through negative staining or cryo-EM analysis remains highly valuable, we lack general and efficient ways to achieve unambiguous subunit identification in these applications. Here, we took advantage of the extremely high affinity between a dodecapeptide "PA" tag and the NZ-1 antibody Fab fragment to develop an efficient "yeast inner-subunit PA-NZ-1 labeling" strategy that when combined with cryo-EM could precisely identify subunits in macromolecular complexes. Using this strategy combined with cryo-EM 3D reconstruction, we were able to visualize the characteristic NZ-1 Fab density attached to the PA tag inserted into a surface-exposed loop in the middle of the sequence of CCT6 subunit present in the Saccharomyces cerevisiae group II chaperonin TRiC/CCT. This procedure facilitated the unambiguous localization of CCT6 in the TRiC complex. The PA tag was designed to contain only 12 amino acids and a tight turn configuration; when inserted into a loop, it usually has a high chance of maintaining the epitope structure and low likelihood of perturbing the native structure and function of the target protein compared to other tagging systems. We also found that the association between PA and NZ-1 can sustain the cryo freezing conditions, resulting in very high occupancy of the Fab in the final cryo-EM images. Our study demonstrated the robustness of this strategy combined with cryo-EM in efficient and accurate subunit identification in challenging multi-component complexes. PMID- 29625203 TI - CRISPys: Optimal sgRNA Design for Editing Multiple Members of a Gene Family Using the CRISPR System. AB - The development of the CRISPR-Cas9 system in recent years has made eukaryotic genome editing, and specifically gene knockout for reverse genetics, a simple and effective task. The system is directed to a genomic target site by a programmed single-guide RNA (sgRNA) that base-pairs with it, subsequently leading to site specific modifications. However, many gene families in eukaryotic genomes exhibit partially overlapping functions, and thus, the knockout of one gene might be concealed by the function of the other. In such cases, the reduced specificity of the CRISPR-Cas9 system, which may lead to the modification of genomic sites that are not identical to the sgRNA, can be harnessed for the simultaneous knockout of multiple homologous genes. We introduce CRISPys, an algorithm for the optimal design of sgRNAs that would potentially target multiple members of a given gene family. CRISPys first clusters all the potential targets in the input sequences into a hierarchical tree structure that specifies the similarity among them. Then, sgRNAs are proposed in the internal nodes of the tree by embedding mismatches where needed, such that the efficiency to edit the induced targets is maximized. We suggest several approaches for designing the optimal individual sgRNA and an approach to compute the optimal set of sgRNAs for cases when the experimental platform allows for more than one. The latter may optionally account for the homologous relationships among gene-family members. We further show that CRISPys outperforms simpler alignment-based techniques by in silico examination over all gene families in the Solanum lycopersicum genome. PMID- 29625204 TI - Bifurcation analysis of a mathematical model of atopic dermatitis to determine patient-specific effects of treatments on dynamic phenotypes. AB - Atopic dermatitis (AD) is a common inflammatory skin disease, whose incidence is currently increasing worldwide. AD has a complex etiology, involving genetic, environmental, immunological, and epidermal factors, and its pathogenic mechanisms have not yet been fully elucidated. Identification of AD risk factors and systematic understanding of their interactions are required for exploring effective prevention and treatment strategies for AD. We recently developed a mathematical model for AD pathogenesis to clarify mechanisms underlying AD onset and progression. This model describes a dynamic interplay between skin barrier, immune regulation, and environmental stress, and reproduced four types of dynamic behaviour typically observed in AD patients in response to environmental triggers. Here, we analyse bifurcations of the model to identify mathematical conditions for the system to demonstrate transitions between different types of dynamic behaviour that reflect respective severity of AD symptoms. By mathematically modelling effects of topical application of antibiotics, emollients, corticosteroids, and their combinations with different application schedules and doses, bifurcation analysis allows us to mathematically evaluate effects of the treatments on improving AD symptoms in terms of the patients' dynamic behaviour. The mathematical method developed in this study can be used to explore and improve patient-specific personalised treatment strategies to control AD symptoms. PMID- 29625205 TI - A sex-structured model with birth pulse and release strategy for the spread of Wolbachia in mosquito population. AB - Dengue fever is one of the most important diseases causing illness and death all over the world, which brings tremendous threat to peoples' life and property security, especially in the undeveloped areas. The main vector, Aedes aegypti, must be controlled to prevent the transmission of dengue. There are a variety of methods to control it. Wolbachia is an innovative bacterium which breaks the dengue transmission cycle for its characteristics of cytoplasmic incompatibility and maternal transmission. In this paper, a sex-structured model with birth pulse is established to study the spread of Wolbachia in mosquito population. The results show that if the maternal transmission is perfect, Wolbachia will spread successfully. Moreover, all the mosquitoes will be infected with Wolbachia. If the maternal transmission is imperfect, there are two locally asymptotically stable periodic solutions. One is Wolbachia-extinction periodic solution, and the other is part replacement periodic solution. Numerical simulations show that the initial occupancy of Wolbachia-infected mosquitoes has an important effect on the success of part replacement strategy. If the initial occupancy is relatively large, the part replacement strategy can be successful. Furthermore, in consideration of the fact that the initial occupancy cannot be always large enough in the wild nature, to release Wolbachia-infected mosquitoes artificially into the wild nature becomes necessary. Therefore, we add a release strategy into the sex-structured model with birth pulse for further analysis. The condition to ensure the stability of the Wolbachia total replacement periodic solution is obtained. Finally, the effect of the release quantity is simulated numerically. PMID- 29625206 TI - Toward a model-free feedback control synthesis for treating acute inflammation. AB - An effective and patient-specific feedback control synthesis for inflammation resolution is still an ongoing research area. A strategy consisting of manipulating a pro and anti-inflammatory mediator is considered here as used in some promising model-based control studies. These earlier studies, unfortunately, suffer from the difficultly of calibration due to the heterogeneity of individual patient responses even under similar initial conditions. We exploit a new model free control approach and its corresponding "intelligent" controllers for this biomedical problem. A crucial feature of the proposed control problem is as follows: the two most important outputs which must be driven to their respective desired states are sensorless. This difficulty is overcome by assigning suitable reference trajectories to the other two outputs that do have sensors. A mathematical model, via a system of ordinary differential equations, is nevertheless employed as a "virtual" patient for in silico testing. We display several simulation results with respect to the most varied situations, which highlight the effectiveness of our viewpoint. PMID- 29625207 TI - Synaptic organization and division of labor in the exceptionally polymorphic ant Pheidole rhea. AB - Social insect polyphenisms provide models to examine the neural basis of division of labor and anatomy of the invertebrate social brain. Worker size-related behavior is hypothesized to enhance task performance, raising questions concerning the integration of morphology, behavior, and cellular neuroarchitecture, and how variation in sensory inputs and cognitive demands of behaviorally differentiated workers is reflected in higher-order processing ability. We used the highly polymorphic ant Pheidole rhea, which has three distinct worker size classes - minors, soldiers, and supersoldiers - to examine variation in synaptic circuitry across worker size and social role. We hypothesized that the density and size of synaptic complexes (microglomeruli, MG) would be positively associated with behavioral repertoire and the relative size of the mushroom bodies (MB). Supersoldiers had significantly larger and less dense MG in the lip (olfactory region) of the MB calyx (MBC), and larger MG in the collar (visual region) compared to minors. Soldiers were intermediate in synaptic phenotype: they did not differ significantly in MG density from minors and supersoldiers, had MG of similar size to minors in the lip, and did not differ from these two worker groups in MG size in the collar. Results suggest a complex relationship between MG density, size, behavior, and worker body size involving a conserved and plastic neurobiological development plan, although workers show strong variation in size and social role. PMID- 29625208 TI - Development of the human lateral geniculate nucleus: A morphometric and computerized 3D-reconstruction study. AB - INTRODUCTION: The lateral geniculate nucleus (LGN) is the major relay center of the visual pathway in humans. There are few quantitative data on the morphology of LGN in prenatal infants. In this study, using serial brain sections, the author investigated the morphology of this nucleus during the second half of fetal period. MATERIAL AND METHODS: Eleven human brains were obtained at routine autopsy from preterm infants aged 20-39 postmenstrual weeks. After fixation, the brain was embedded en bloc in celloidin and cut serially at 30 MUm in the horizontal plane. The sections were stained at regular intervals using the Kluver Barrera method. RESULTS: At 20-21 weeks, the long axis of LGN declined obliquely from the vertical to horizontal plane, while a deep groove was noted on the ventro-lateral surface of the superior half. At this time, an arcuate cell-sparse zone appeared in the dorso-medial region, indicating the beginning of lamination. From 25 weeks onwards, the magnocellular and parvocellular layers were distinguishable, and the characteristic six-layered structure was recognized. The magnocellular layer covered most of the dorsal surface, and parts of the medial, lateral, and inferior surfaces but not the ventral and superior surfaces. Nuclear volume increased exponentially with age during 20-39 weeks, while the mean neuronal profile area increased linearly during 25-39 weeks. CONCLUSION: Human LGN develops a deep groove on the ventro-lateral surface at around mid-gestation, when the initial lamination is recognized in the prospective magnocellular layer. Thereafter, the nuclear volume increases with age in an exponential function. PMID- 29625209 TI - Elevated expression of ageing and immunity genes in queens of the black garden ant. AB - Studies in model organisms have identified a variety of genes whose expression can be experimentally modulated to produce changes in longevity, but whether these genes are the same as those involved in natural variation in lifespan remains unclear. Social insects boast some of the largest lifespan differences known between plastic phenotypes, with queen and worker lifespans differing by an order of magnitude despite no systematic nucleotide sequence differences between them. The contrasting lifespans of queens and workers are thus the result of differences in gene expression. We used RNA sequencing of brains and legs in 1 day-old and 2-month-old individuals of the ant Lasius niger to determine whether genes with queen-biased expression are enriched for genes linked to ageing in model organisms. Because the great longevity of queens may require investment into immune processes, we also investigated whether queen-biased genes are enriched for genes with known roles in immunity. Queen-biased genes in legs were enriched for ageing genes and for genes associated with increasing rather than decreasing lifespan. Queen-biased genes in legs were also enriched for immune genes, but only in 1-day-old individuals, perhaps linked to the changing roles of workers with age. Intriguingly, the single most differentially expressed gene between 1-day-old queen and worker brains was an extra-cellular form of CuZn Superoxide Dismutase (SOD3), raising the possibility of an important role of anti oxidant genes in modulating lifespan. PMID- 29625210 TI - Application of Quality by Design to optimize a stability-indicating LC method for the determination of ticagrelor and its impurities. AB - Simultaneous analysis of drug compounds and their impurities of degradation and synthesis became constant in the modern pharmaceutical analysis. Likewise, analytical techniques must improve sensitivity and selectivity for the monitoring of pharmaceutical products, allowing a full assessment of impurities in drug products and, therefore, ensure safety and efficacy of pharmacological treatments. The application of Quality by Design (QbD) principles has proved to be feasible on the elaboration of analytical methods, allowing the comprehensive evaluation and measurement of different analytical parameters and their effects on critical properties of the methodology in development. QbD approach was applied to the development of a fast and selective HPLC method for the analysis of the antiplatelet aggregation drug ticagrelor and its degradation products in presence of three impurities of synthesis. Fractional factorial resolution V was the screening experimental design applied to five method parameters. Response surface methodology was carried by central composite star face design on the two critical method parameters selected. Analytical design space, established after the application of Monte-Carlo simulations, verified whether predicted results were in accordance with critical quality attributes. The developed and validated HPLC method with DAD detection at 225 nm was able to resolve eight related compounds in less than three minutes. PMID- 29625211 TI - Corneal and conjunctival drug permeability: Systematic comparison and pharmacokinetic impact in the eye. AB - On the surface of the eye, both the cornea and conjunctiva are restricting ocular absorption of topically applied drugs, but barrier contributions of these two membranes have not been systemically compared. Herein, we studied permeability of 32 small molecular drug compounds across an isolated porcine cornea and built a quantitative structure-property relationship (QSPR) model for the permeability. Corneal drug permeability (data obtained for 25 drug molecules) showed a 52-fold range in permeability (0.09-4.70 * 10-6 cm/s) and the most important molecular descriptors in predicting the permeability were hydrogen bond donor, polar surface area and halogen ratio. Corneal permeability values were compared to their conjunctival drug permeability values. Ocular drug bioavailability and systemic absorption via conjunctiva were predicted for this drug set with pharmacokinetic calculations. Drug bioavailability in the aqueous humour was simulated to be <5% and trans-conjunctival systemic absorption was 34-79% of the dose. Loss of drug across the conjunctiva to the blood circulation restricts significantly ocular drug bioavailability and, therefore, ocular absorption does not increase proportionally with the increasing corneal drug permeability. PMID- 29625212 TI - Development and characterization of high payload combination dry powders of anti tubercular drugs for treating pulmonary tuberculosis. AB - This study aimed to develop a high payload dry powder inhalation formulation containing a combination of the first line anti-tubercular drug, pyrazinamide, and the second line drug, moxifloxacin HCl. Individual powders of pyrazinamide (PSD) and moxifloxacin (MSD) and combination powders of the two drugs without (PM) and with 10% l-leucine (PML) and 10% DPPC (PMLD) were produced by spray drying. PSD contained >10 MUm crystalline particles and showed poor aerosolization behaviour with a fine particle fraction (FPF) of 18.7 +/- 3.4%. PM produced spherical hollow particles with aerodynamic diameter < 5 MUm and PML showed improved aerosolization with a high FPF of ~70%. However, PMLD showed a significantly reduced FPF (p > 0.05) compared to PML. Solid state studies and surface elemental analysis by X-ray photoelectron spectroscopy and time-of-flight secondary ion mass spectrometry confirmed the surface coating of particles contained amorphous moxifloxacin and both l-leucine and DPPC over crystalline pyrazinamide. Furthermore, pyrazinamide, moxifloxacin, PML and PMLD were found to display low toxicity to both A549 and Calu-3 cell lines even at a concentration of 100 MUg/mL. In conclusion, a combination powder formulation of PML has the potential to deliver a high drug dose to the site of infection resulting in efficient treatment. PMID- 29625213 TI - Mechanistic insights of the controlled release properties of amide adhesive and hydroxyl adhesive. AB - Although interactions between drugs and acrylate pressure sensitive adhesives (PSAs) containing amide groups were reported in the previous studies, detailed studies elucidating their mechanism of action are still lacking. In the present study, an amide PSA (AACONH2) and a hydroxyl PSA (AAOH, as the control) were synthesized, and their molecular mechanism of controlled drug release was described. Using zolmitriptan (ZOL) and etodolac (ETO) as model drugs, in vitro drug release and skin permeation experiments were performed. Intermolecular interactions between drugs and PSAs were determined by Flory-Huggins model, FT-IR spectroscopic analysis and molecular modeling. In addition, PSA mobility was evaluated using differential scanning calorimetry and rheology study. Release percent of ZOL and ETO from AACONH2 were 43.9 +/- 0.3% and 50.0 +/- 2.0% respectively, while from AAOH, the release percent of ZOL and ETO were 61.4 +/- 1.2% and 81.0 +/- 1.2% separately. As a consequence of controlled drug release, skin permeation of both drugs was significantly controlled by AACONH2. It was demonstrated that AACONH2 markedly interacted with drugs, especially with ETO, through hydrogen bonding and weak intermolecular forces (e.g. dipole-dipole and van der waals). PSA mobility of AACONH2 was significantly increased due to drug PSA interactions. In conclusion, AACONH2 had stronger controlled release properties compared with AAOH, which was mainly caused by the stronger interactions between amide groups and drugs. The amide PSA synthesized in the present study was a potential sustained-release excipient for transdermal drug delivery system. PMID- 29625214 TI - Blast Exposure Disrupts the Tonotopic Frequency Map in the Primary Auditory Cortex. AB - Blast exposure can cause various auditory disorders including tinnitus, hyperacusis, and other central auditory processing disorders. While this is suggestive of pathologies in the central auditory system, the impact of blast exposure on central auditory processing remains poorly understood. Here we examined the effects of blast shockwaves on acoustic response properties and the tonotopic frequency map in the auditory cortex. We found that multiunits recorded from the auditory cortex exhibited higher acoustic thresholds and broader frequency tuning in blast-exposed animals. Furthermore, the frequency map in the primary auditory cortex was distorted. These changes may contribute to central auditory processing disorders. PMID- 29625215 TI - H3K9 Acetylation of Tph2 Involved in Depression-like Behavior in Male, but not Female, Juvenile Offspring Rat Induced by Prenatal Stress. AB - Increasing evidence has shown that prenatal stress (PS) could cause depression like behavior in the offspring, which is sex-specific. However, the underlying mechanisms remain to be elucidated. This study is to investigate the involvement of tryptophan hydroxylase 2 (Tph2) H3K9 acetylation (H3K9ac) modification on PS induced depression-like behavior in juvenile offspring rats (JOR). PS models were established, with or without trichostatin A (TSA) treatment. Animal behavior was assessed by the sucrose preference test (SPT) and forced swimming test (FST). The mRNA and protein expression levels of TPH2 in the dorsal raphenucleus (DRN), hippocampus, and prefrontal cortex were detected with quantitative real-time PCR and Western blot analysis, respectively. The Tph2 H3K9ac levels in the hippocampus were also analyzed. SPT and FST showed significantly reduced sucrose preference and significantly prolonged immobility in PS-induced male juvenile offspring rats (MJOR). Moreover, the mRNA and protein expression levels of TPH2 in the DRN and hippocampus were significantly declined, while the hippocampal Tph2 H3K9ac levels were significantly declined in the PS-induced MJOR. Furthermore, the PS-induced effects in MJOR could be reversed by the microinjection of TSA. However, no significant effects were observed for the female juvenile offspring rats (FJORs). In conclusion, our results showed that the Tph2 H3K9ac modification is only involved in PS-induced depression-like behavior in MJOR, in a sex-specific manner. These findings might contribute to the understanding of the disease pathogenesis and clinical treatment in future. PMID- 29625216 TI - Receptor for Advanced Glycation End Products (RAGE) is Expressed Predominantly in Medium Spiny Neurons of tgHD Rat Striatum. AB - Receptor for advanced glycation end products (RAGE) is a multi-ligand receptor involved in the pathology of several progressive neurodegenerative disorders including Huntington's disease (HD). We previously showed that the expression of RAGE and its colocalization with ligands were increased in the striatum of HD patients, increasing with grade severity, and that the pattern of RAGE expression coincided with the medio-lateral pattern of neurodegeneration. However, the exact role of RAGE in HD remains elusive. In order to address the necessity for a direct functional study, we aimed to characterize the pattern of RAGE expression in the transgenic rat model of HD (tgHD rats). Our results showed that RAGE expression was expanded laterally in tgHD rat caudate-putamen (CPu) compared to wildtype littermates, but the expression was unchanged by disease severity. The rostro-caudal location did not affect RAGE expression. RAGE was predominantly expressed in the medium spiny neurons (MSN) where it colocalized most extensively with N-carboxymethyllysine (CML), which largely contradicts with observations from human HD brains. Overall, the tgHD rat model only partially recapitulated the pattern in striatal RAGE expression in human brains, raising a question about its reliability as an animal model for future functional studies. PMID- 29625217 TI - The expression of three opsin genes and phototactic behavior of Spodoptera exigua (Lepidoptera: Noctuidae): Evidence for visual function of opsin in phototaxis. AB - Phototaxis in nocturnal moths is widely utilized to control pest populations in practical production. However, as an elusive behavior, phototactic behavior is still not well understood. Determination of whether the opsin gene plays a key role in phototaxis is an interesting topic. This study was conducted to analyze expression levels and biological importance of three opsin genes (Se-uv, Se-bl, and Se-lw) and phototactic behavior of Spodoptera exigua. The three opsin genes exhibited higher expression levels during daytime, excluding Se-bl in females, whose expression tended to increase at night. And cycling of opsin gene levels tended to be upregulated at night, although the magnitude of increase in females was lower than that in males exposed to constant darkness. The results of western blotting were consistent with those of qRT-PCR. Furthermore, opsin gene expression was not influenced by light exposure during the scotophase, excluding Se-uv in males, and tended to be downregulated by starvation in females and copulation in both female and male moths. To determine the relationship between opsin gene expression and phototactic behavior, Se-lw was knocked down by RNA interference. Moths with one opsin gene knocked down showed enhanced expression of the other two opsin genes, which may play important roles in compensation in vision. The Se-lw-knockdown moths exhibited reduced phototactic efficiency to green light, suggesting that Se-LW contributes to phototaxis, and increases phototactic efficiency to green light. Our finding provides a sound theoretical basis for further investigation of visual expression pattern and phototactic mechanisms in nocturnal moths. PMID- 29625218 TI - Shirazi balangu (Lallemantia royleana) seed mucilage: Chemical composition, molecular weight, biological activity and its evaluation as edible coating on beefs. AB - In this study, Lallemantia royleana seed mucilage (LRSM) was extracted from whole seeds using hot-water extraction. The structural information (monosaccharide compositions and molecular weight analysis), chemical composition (moisture, protein, ash, fat and carbohydrate), biological activity (antimicrobial, total phenol content and antioxidant activity) and effect LRSM edible coating on population of microbial pathogens (total viable count (TVC), psychrotrophic bacteria, Escherichia coli, Staphylococcus aureus and fungi), chemical changes (thiobarbituric acid, peroxide value and pH) and sensory attributes (color, odor and total acceptability) of the beef slices at 4 degrees C for 18days (0, 3, 6, 9, 12, 15 and 18) were determined. The LRSM had 76.74% carbohydrate, 3.86% protein, 9.92% ash and 9.48% moisture. LRSM is a high molecular weight (1.19*106Da) polysaccharide, composed of galactose (36.28%), arabinose (35.96%), rhamnose (15.18%), xylose (7.38%) and glucose (5.20%). The LRSM total phenolic content and antioxidant activity (IC50) were equal to 82.56+/-1.6MUgGAE/mg and 528.54+/-0.35MUg/ml, respectively. The results showed that, the beef shelf life based on TVC for samples control, LRSM, LRSM+1% AHEO, LRSM+1.5% AHEO, and LRSM+2% AHEO were 6, 9, 9, 12, and 15days, respectively. There was no significant difference between LRSM+1% AHEO and LRSM samples, but the TVC in first one had slight changes than LRSM. Compared to the control samples, LRSM extended the microbial shelf life, oxidative stability and sensorial acceptability of beef by 3, 6 and 6days, respectively. PMID- 29625219 TI - Optimization of ultrasound-assisted extraction of okra (Abelmoschus esculentus (L.) Moench) polysaccharides based on response surface methodology and antioxidant activity. AB - This study determined the optimal conditions for ultrasound-assisted extraction of a water-soluble polysaccharide, Raw Okra Polysaccharide, from the fruit of okra using response surface methodology. The optimal extraction temperature, extraction time and ultrasonic power were 59 degrees C, 30min and 522W, respectively, giving a yield of 10.35+/-0.11%. ROP was further isolated, lyophilized and purified using a DEAE-Sepharose Fast Flow column and Sepharose CL 6B column, revealing three elution peaks subsequently designated ROP -1, -2, and 3, respectively. Of these, ROP-2 showed the highest yield, and was therefore selected for physicochemical analysis and evaluation of antioxidant activity. Gas chromatography, fourier transform infrared spectroscopy, and high-performance liquid chromatography were used to characterize the primary structural features and molecular weight, revealing that ROP-2 is composed of glucose, mannose, galactose, arabinose, xylose, fructose, and rhamnose (molar percentages: 28.8, 12.5, 13.1, 15.9, 9.2, 13.7, and 6.8%, respectively) and has an average molecular weight of 1.92*105Da. A superoxide radical scavenging assay and DPPH radical scavenging assay further revealed the significant in vitro antioxidant activity of ROP-2. These findings present an effective technique for extraction of the natural antioxidant ROP-2, warranting further analysis of its potential application in the food industry. PMID- 29625220 TI - Synthesis and characterization of starch-g-poly(vinyl acetate-co-butyl acrylate) bio-based adhesive for wood application. AB - Enhancing the performance of wood adhesive is important for its industrial applications. Accordingly, we designed and demonstrated the use of two co monomers vinyl acetate (VAc) and butyl acrylate (BA) for promoting the graft copolymerization while improving the bonding performance of wood adhesive. The results showed that the addition of co-monomers in the ratio of VAc/BA 6:4 (v/v, volume basis of VAc) could improve the shear strength to 6.68MPa and 3.32MPa in dry and wet states, respectively. 1H-nuclear magnetic resonance (1H NMR) and fourier transform infrared spectroscopy (FT-IR) analysis revealed successful graft copolymerization reaction while the morphologies were observed by scanning electron microscopy (SEM) and transmission electron microscopy (TEM). Furthermore, the grafting reaction and thermal stabilities of wood adhesive were analyzed by X-ray photoelectron spectroscopy (XPS) and thermogravimetric analysis (TGA). The results showed that the properties of wood adhesive could improve dramatically by using two co-monomers VAc and BA during the graft copolymerization reaction. PMID- 29625221 TI - Synthesis, characterization and antifungal efficacy of chitosan derivatives with triple quaternary ammonium groups. AB - A novel type of water soluble chitosan derivatives (TQCSPX) were synthesized including 3-aminopyridine (TQCSP1) and 3-Amino-4-methylpyridine (TQCSP2). The theoretical structures of TQCSPX were calculated by Gaussian 09 and confirmed by FT-IR, 1H NMR, 13C NMR, elemental analysis and XRD. The antifungal properties of TQCSPX against Phytophthora capsici (P. capsici), Rhizoctonia solani (R. solani), Fusarium oxysporum (F. oxysporum) and Fusarium solani (F. solani) were evaluated at concentrations ranging from 0.2mg/mL to 0.8mg/mL. Antifungal results indicated that the derivatives have significantly enhanced antifungal activity after quaternized compared with the original chitosan (CS). Moreover, TQCSP1 inhibited the growth of P. capsici with inhibitory indices of 91.94% at 0.8mg/mL. The experimental results demonstrated that the increasing number of the positive charge would improve the antifungal efficiency of chitosan, which may provide a novel direction for the development of fungicides. PMID- 29625222 TI - Enhanced direct electron transfer of redox protein based on multiporous SnO2 nanofiber-carbon nanotube nanocomposite and its application in biosensing. AB - A novel third generation H2O2 biosensor is fabricated using multiporous SnO2 nanofiber/carbon nanotubes (CNTs) composite as a matrix for the immobilization of redox protein onto glassy carbon electrode. The multiporous nanofiber (MPNFs) of SnO2 is synthesized by electrospinning technique from the tin precursor. This nanofiber shows high surface area and good electrical conductivity. The SnO2 nanofiber/CNT composite increases the efficiency of biomolecule loading due to its high surface area. The morphology of the nanofiber has been evaluated by scanning electron microscopy (SEM). Cyclic Voltammetry and amperometry technique are employed to study and optimize the performance of the fabricated electrode. A direct electron transfer between the protein's redox centre and the glassy carbon electrode is established after fabrication of the electrode. The fabricated electrode shows excellent electrocatalytic reduction to H2O2. The catalysis currents increases linearly to the H2O2 concentration in a wide range of 1.0 10-6 1.4*10-4M and the lowest detection limit was 30nM (S/N=3). Moreover, the biosensor showed a rapid response to H2O2, a good stability and reproducibility. PMID- 29625223 TI - Antioxidant and hepatoprotective effects of intracellular mycelium polysaccharides from Pleurotus geesteranus against alcoholic liver diseases. AB - In the present study, we investigated the antioxidant and hepatoprotective effects of intracellular mycelium polysaccharides from Pleurotus geesteranus (IMPP) to address acute alcoholic liver diseases (ALD). Animal studies have demonstrated that the hepatic parameters of CYP2E1, MPO, TC, ALT, AST and ALP, HDLC, LDL-C and VLDL-C were improved; the inflammatory factor levels, including TNF-alpha, IL-1beta and IL-6, were decreased; the hepatic ADH and ALDH activities were inhibited; the activities of the antioxidant enzymes SOD, GSH-Px, CAT and T AOC were enhanced; and the MDA and LPO contents were reduced by IMPP treatment. Furthermore, the liver histopathology confirmed the beneficial effects of IMPP against ALD in mice, demonstrating that IMPP had the potential to remediate alcoholic hepatitis. Besides the properties of typical pyran-type polysaccharides obtained by beta-glycosidic bonding rich in fucose, the results demonstrated that IMPP might be used as a functional food and natural medicine for preventing ALD and its complications. PMID- 29625224 TI - An engineered Calvin-Benson-Bassham cycle for carbon dioxide fixation in Methylobacterium extorquens AM1. AB - Organisms are either heterotrophic or autotrophic, meaning that they cover their carbon requirements by assimilating organic compounds or by fixing inorganic carbon dioxide (CO2). The conversion of a heterotrophic organism into an autotrophic one by metabolic engineering is a long-standing goal in synthetic biology and biotechnology, because it ultimately allows for the production of value-added compounds from CO2. The heterotrophic Alphaproteobacterium Methylobacterium extorquens AM1 is a platform organism for a future C1-based bioeconomy. Here we show that M. extorquens AM1 provides unique advantages for establishing synthetic autotrophy, because energy metabolism and biomass formation can be effectively separated from each other in the organism. We designed and realized an engineered strain of M. extorquens AM1 that can use the C1 compound methanol for energy acquisition and forms biomass from CO2 by implementation of a heterologous Calvin-Benson-Bassham (CBB) cycle. We demonstrate that the heterologous CBB cycle is active, confers a distinct phenotype, and strongly increases viability of the engineered strain. Metabolic 13C-tracer analysis demonstrates the functional operation of the heterologous CBB cycle in M. extorquens AM1 and comparative proteomics of the engineered strain show that the host cell reacts to the implementation of the CBB cycle in a plastic way. While the heterologous CBB cycle is not able to support full autotrophic growth of M. extorquens AM1, our study represents a further advancement in the design and realization of synthetic autotrophic organisms. PMID- 29625225 TI - Metabolic engineering of Escherichia coli for producing adipic acid through the reverse adipate-degradation pathway. AB - Adipic acid is an important dicarboxylic acid mainly used for the production of nylon 6-6 fibers and resins. Previous studies focused on the biological production of adipic acid directly from different substrates, resulting in low yields and titers. In this study, a five-step reverse adipate-degradation pathway (RADP) identified in Thermobifida fusca has been reconstructed in Escherichia coli BL21 (DE3). The resulting strain (Mad136) produced 0.3 g L-1 adipic acid with a 11.1% theoretical yield in shaken flasks, and we confirmed that the step catalyzed by 5-Carboxy-2-pentenoyl-CoA reductase (Tfu_1647) as the rate-limiting step of the RADP. Overexpression of Tfu_1647 by pTrc99A carried by strain Mad146 produced with a 49.5% theoretical yield in shaken flasks. We further eliminated pathways for major metabolites competing for carbon flux by CRISPR/Cas9 and deleted the succinate-CoA ligase gene to promote accumulation of succinyl-CoA, which is the precursor for adipic acid synthesis. The final engineered strain Mad123146, which could achieve 93.1% of the theoretical yield in the shaken flask, was able to produce 68.0 g L-1 adipic acid by fed-batch fermentation. To the best of our knowledge, these results constitute the highest adipic acid titer reported in E. coli. PMID- 29625226 TI - Long noncoding RNA BC200 regulates cell growth and invasion in colon cancer. AB - Colon cancer is the third most commonly diagnosed and deadly cancer worldwide. Efforts have been made to characterize its pathological mechanisms and to explore new therapeutic targets of this disease. Aberrant expression of long noncoding RNAs (lncRNAs) has been associated with the pathogenesis of colon cancer. In the current study, we aimed to define the biological mechanism of the lncRNA BC200 in colon cancer. Here, we found that expression of BC200 was up-regulated in colon cancer tissues as compared with adjacent non-cancerous tissues. The BC200 level was positively correlated with advanced TNM stage. The Kaplan-Meier method indicated that the cumulative survival rate was significantly lower in patients with high BC200 expression than in those with low BC200 expression. Interestingly, we found that knockdown of BC200 inhibited proliferation of HCT 116 and HT29 colon cancer cell lines and reduce the expression of cell proliferation markers, such as Ki-67 and PCNA. In addition, silencing of BC200 could induce obvious G0/G1 arrest and cause apoptosis in HCT-116 and HT29 cells and reduced the expression of cyclin D1, cyclin E, and c-Myc through inhibiting the expression of beta-catenin. Importantly, we found that knockdown of BC200 reduced invasion of HCT-116 and HT29 cells and epithelial-mesenchymal transition (EMT) by reducing the expression of MMP-2 and MMP-9. Mechanistically, silencing of BC200 significantly reduced the phosphorylation of STAT3. Overall, the findings presented here suggest that lncRNA BC200 may serve as a novel oncogene and a new therapeutic target for colon cancer. PMID- 29625228 TI - Phylogeny, evolution and mitochondrial gene order rearrangement in scale worms (Aphroditiformia, Annelida). AB - Next-generation sequencing (NGS) has become a powerful tool in phylogenetic and evolutionary studies. Here we applied NGS to recover two ribosomal RNA genes (18S and 28S) from 16 species and 15 mitochondrial genomes from 16 species of scale worms representing six families in the suborder Aphroditiformia (Phyllodocida, Annelida), a complex group of polychaetes characterized by the presence of dorsal elytra or scales. The phylogenetic relationship of the several groups of scale worms remains unresolved due to insufficient taxon sampling and low resolution of individual gene markers. Phylogenetic tree topology based on mitochondrial genomes is comparable with that based on concatenated sequences from two mitochondrial genes (cox1 and 16S) and two ribosomal genes (18S and 28S) genes, but has higher statistical support for several clades. Our analyses show that Aphroditiformia is monophyletic, indicating the presence of elytra is an apomorphic trait. Eulepethidae and Aphroditidae together form the sister group to all other families in this suborder, whereas Acoetidae is sister to Iphionidae. Polynoidae is monophyletic, but within this family the deep-sea subfamilies Branchinotogluminae and Macellicephalinae are paraphyletic. Mitochondrial genomes in most scale-worm families have a conserved gene order, but within Polynoidae there are two novel arrangement patterns in the deep-sea clade. Mitochondrial protein-coding genes in polynoids as a whole have evolved under strong purifying selection, but substitution rates in deep-sea species are much higher than those in shallow-water species, indicating that purifying selection is relaxed in deep sea polynoids. There are positive selected amino acids for some mitochondrial genes of the deep-sea clade, indicating they may involve in the adaption of deep sea polynoids. Overall, our study (1) provided more evidence for reconstruction of the phylogeny of Aphroditiformia, (2) provided evidence to refute the assumption that mitochondrial gene order in Errantia is conserved, and (3) indicated that the deep-sea extreme environment may have affected the mitochondrial genome evolution rate and gene order arrangement in Polynoidae. PMID- 29625229 TI - Comprehensive molecular phylogeny of the grassbirds and allies (Locustellidae) reveals extensive non-monophyly of traditional genera, and a proposal for a new classification. AB - The widespread Old World avian family Locustellidae ('grassbirds and allies') comprises 62 extant species in 11 genera. In the present study, we used one mitochondrial and, for most species, four nuclear loci to infer the phylogeny of this family. We analysed 59 species, including the five previously unsampled genera plus two genera that had not before been analysed in a densely sampled dataset. This study revealed extensive disagreement with current taxonomy; the genera Bradypterus, Locustella, Megalurus, Megalurulus and Schoenicola were all found to be non-monophyletic. Non-monophyly was particularly pronounced for Megalurus, which was widely scattered across the tree. Three of the five monotypic genera (Amphilais, Buettikoferella and Malia) were nested within other genera; one monotypic genus (Chaetornis) formed a clade with one of the two species of Schoenicola; whereas the position of the fifth monotypic genus (Elaphrornis) was unresolved. Robsonius was confirmed as sister to the other genera. We propose a phylogenetically informed revision of genus-level taxonomy, including one new generic name. Finally, we highlight several non-monophyletic species complexes and deep intra-species divergences that point to conflict in taxonomy and suggest an underestimation of current species diversity in this group. PMID- 29625227 TI - Anxiety-like behavior and other consequences of early life stress in mice with increased protein kinase A activity. AB - Anxiety disorders are associated with abnormalities in fear-learning and bias to threat; early life experiences are influential to the development of an anxiety like phenotype in adulthood. We recently reported that adult mice (Prkar1a+/-) with haploinsufficiency for the main regulatory subunit of the protein kinase A (PKA) exhibit an anxiety-like phenotype associated with increased PKA activity in the amygdala. PKA is the main effector of cyclic adenosine mono-phosphate signaling, a key pathway involved in the regulation of fear learning. Since anxiety has developmental and genetic components, we sought to examine the interaction of a genetic defect associated with anxiety phenotype and early life experiences. We investigated the effects of neonatal maternal separation or tactile stimulation on measures of behavior typical to adolescence as well as developmental changes in the behavioral phenotype between adolescent and adult wild-type (WT) and Prkar1a+/- mice. Our results showed developmental differences in assays of anxiety and novelty behavior for both genotypes. Adolescent mice showed increased exploratory and novelty seeking behavior compared to adult counterparts. However, early life experiences modulated behavior in adolescent WT differently than in adolescent Prkar1a+/- mice. Adolescent WT mice exposed to early life tactile stimulation showed attenuation of anxiety-like behavior, whereas an increase in exploratory behavior was found in Prkar1a+/- adolescent mice. The finding of behavioral differences that are apparent during adolescence in Prkar1a+/- mice suggests that long-term exposure of the brain to increased PKA activity during critical developmental periods contributes to the anxiety-like phenotype noted in the adult animals with increased PKA activity. PMID- 29625230 TI - Pleistocene land bridges act as semipermeable agents of avian gene flow in Wallacea. AB - Cyclical periods of global cooling have been important drivers of biotic differentiation throughout the Quaternary. Ice age-induced sea level fluctuations can lead to changing patterns of land connections, both facilitating and disrupting gene flow. In this study, we test if species with differing life histories are differentially affected by Quaternary land connections. We used genome-wide SNPs in combination with mitochondrial gene sequences to analyse levels of divergence and gene flow between two songbird complexes across two Wallacean islands that have been repeatedly connected during glaciations. Although the two bird complexes are similar in ecological attributes, the forest and edge-inhabiting golden whistler Pachycephala pectoralis is comparatively flexible in its diet and niche requirements as compared to the henna-tailed jungle-flycatcher Cyornis colonus, which is largely restricted to the forest interior. Using population-genomic and coalescent approaches, we estimated levels of gene flow, population differentiation and divergence time between the two island populations. We observed higher levels of differentiation, an approximately two to four times deeper divergence time and near-zero levels of gene flow between the two island populations of the more forest-dependent henna tailed jungle-flycatcher as compared to the more generalist golden whistler. Our results suggest that Quaternary land bridges act as semipermeable agents of gene flow in Wallacea, allowing only certain taxa to connect between islands while others remain isolated. Quaternary land bridges do not accommodate all terrestrial species equally, differing in suitability according to life history and species biology. More generalist species are likely to use Quaternary land connections as a conduit for gene flow between islands whereas island populations of more specialist species may continue to be reproductively isolated even during periods of Quaternary land bridges. PMID- 29625231 TI - The oxidized linoleic acid metabolite 12,13-DiHOME mediates thermal hyperalgesia during inflammatory pain. AB - Eicosanoids play a crucial role in inflammatory pain. However, there is very little knowledge about the contribution of oxidized linoleic acid metabolites in inflammatory pain and peripheral sensitization. Here, we identify 12,13-dihydroxy 9Z-octadecenoic acid (12,13-DiHOME), a cytochrome P450-derived linoleic acid metabolite, as crucial mediator of thermal hyperalgesia during inflammatory pain. We found 12,13-DiHOME in increased concentrations in peripheral nervous tissue during acute zymosan- and complete Freund's Adjuvant-induced inflammatory pain. 12,13-DiHOME causes calcium transients in sensory neurons and sensitizes the transient receptor potential vanilloid 1 (TRPV1)-mediated intracellular calcium increases via protein kinase C, subsequently leading to enhanced TRPV1-dependent CGRP-release from sensory neurons. Peripheral injection of 12,13-DiHOME in vivo causes TRPV1-dependent thermal pain hypersensitivity. Finally, application of the soluble epoxide hydrolase (sEH)-inhibitor TPPU reduces 12,13-DiHOME concentrations in nervous tissue and reduces zymosan- and CFA-induced thermal hyperalgesia in vivo. In conclusion, we identify a novel role for the lipid mediator 12,13-DiHOME in mediating thermal hyperalgesia during inflammatory pain and propose a novel mechanism that may explain the antihyperalgesic effects of sEH inhibitors in vivo. PMID- 29625232 TI - Shared Care: Using an Electronic Consult Form to Facilitate Primary Care Provider Specialty Care Coordination. AB - OBJECTIVE: The quality of children's health is compromised by poor care coordination between primary care providers (PCPs) and specialists. Our objective was to determine how an electronic consultation and referral system impacts referral patterns and PCP-specialist communication. METHODS: The primary care clinic at Boston Children's Hospital piloted an electronic referral and consultation system with the neurology and gastroenterology departments from April 1, 2014, to October 31, 2016. PCPs completed an electronic consult form, and if needed, specialists replied with advice or facilitated expedited appointments. Specialist response times, referral rates, wait times, and completion rates for specialty visits were tracked. PCPs and specialists also completed a survey to evaluate feasibility and satisfaction. RESULTS: A total of 82 PCPs placed 510 consults during the pilot period. Specialists responded to 88% of requests within 3 business days. Eighteen percent of specialty visits were deferred and 21% were expedited. Wait times for specialty appointments to both departments significantly decreased, from 48 to 34 days (P < .001), and completion rates improved from 58% to 70% (P < .01), but referral volumes remained stable (25 per month to 23 per month; P = .29). Most PCPs said the Shared Care system facilitated better communication with specialists (89%) and enabled them to provide superior patient care (92%). Specialists reported that the system required a minimal amount of time and enabled them to educate PCPs and triage referrals. CONCLUSIONS: Implementation of an electronic referral and consultation system was feasible and provided timely access to specialty care, but did not affect referral volume. This system could serve as a model for other health care organizations and specialties. PMID- 29625233 TI - Directed functional connectivity using dynamic graphical models. AB - There are a growing number of neuroimaging methods that model spatio-temporal patterns of brain activity to allow more meaningful characterizations of brain networks. This paper proposes dynamic graphical models (DGMs) for dynamic, directed functional connectivity. DGMs are a multivariate graphical model with time-varying coefficients that describe instantaneous directed relationships between nodes. A further benefit of DGMs is that networks may contain loops and that large networks can be estimated. We use network simulations and human resting-state fMRI (N = 500) to investigate the validity and reliability of the estimated networks. We simulate systematic lags of the hemodynamic response at different brain regions to investigate how these lags potentially bias directionality estimates. In the presence of such lag confounds (0.4-0.8 s offset between connected nodes), our method has a sensitivity of 72%-77% to detect the true direction. Stronger lag confounds have reduced sensitivity, but do not increase false positives (i.e., directionality estimates of the opposite direction). In human resting-state fMRI, the default mode network has consistent influence on the cerebellar, the limbic and the auditory/temporal networks. We also show a consistent reciprocal relationship between the visual medial and visual lateral network. Finally, we apply the method in a small mouse fMRI sample and discover a highly plausible relationship between areas in the hippocampus feeding into the cingulate cortex. We provide a computationally efficient implementation of DGM as a free software package for R. PMID- 29625235 TI - Supervoxel based method for multi-atlas segmentation of brain MR images. AB - Multi-atlas segmentation has been widely applied to the analysis of brain MR images. However, the state-of-the-art techniques in multi-atlas segmentation, including both patch-based and learning-based methods, are strongly dependent on the pairwise registration or exhibit huge spatial inconsistency. The paper proposes a new segmentation framework based on supervoxels to solve the existing challenges of previous methods. The supervoxel is an aggregation of voxels with similar attributes, which can be used to replace the voxel grid. By formulating the segmentation as a tissue labeling problem associated with a maximum-a posteriori inference in Markov random field, the problem is solved via a graphical model with supervoxels being considered as the nodes. In addition, a dense labeling scheme is developed to refine the supervoxel labeling results, and the spatial consistency is incorporated in the proposed method. The proposed approach is robust to the pairwise registration errors and of high computational efficiency. Extensive experimental evaluations on three publically available brain MR datasets demonstrate the effectiveness and superior performance of the proposed approach. PMID- 29625236 TI - Statistical learning of multisensory regularities is enhanced in musicians: An MEG study. AB - The present study used magnetoencephalography (MEG) to identify the neural correlates of audiovisual statistical learning, while disentangling the differential contributions of uni- and multi-modal statistical mismatch responses in humans. The applied paradigm was based on a combination of a statistical learning paradigm and a multisensory oddball one, combining an audiovisual, an auditory and a visual stimulation stream, along with the corresponding deviances. Plasticity effects due to musical expertise were investigated by comparing the behavioral and MEG responses of musicians to non-musicians. The behavioral results indicated that the learning was successful for both musicians and non musicians. The unimodal MEG responses are consistent with previous studies, revealing the contribution of Heschl's gyrus for the identification of auditory statistical mismatches and the contribution of medial temporal and visual association areas for the visual modality. The cortical network underlying audiovisual statistical learning was found to be partly common and partly distinct from the corresponding unimodal networks, comprising right temporal and left inferior frontal sources. Musicians showed enhanced activation in superior temporal and superior frontal gyrus. Connectivity and information processing flow amongst the sources comprising the cortical network of audiovisual statistical learning, as estimated by transfer entropy, was reorganized in musicians, indicating enhanced top-down processing. This neuroplastic effect showed a cross modal stability between the auditory and audiovisual modalities. PMID- 29625237 TI - Scale-freeness or partial synchronization in neural mass phase oscillator networks: Pick one of two? AB - Modeling and interpreting (partial) synchronous neural activity can be a challenge. We illustrate this by deriving the phase dynamics of two seminal neural mass models: the Wilson-Cowan firing rate model and the voltage-based Freeman model. We established that the phase dynamics of these models differed qualitatively due to an attractive coupling in the first and a repulsive coupling in the latter. Using empirical structural connectivity matrices, we determined that the two dynamics cover the functional connectivity observed in resting state activity. We further searched for two pivotal dynamical features that have been reported in many experimental studies: (1) a partial phase synchrony with a possibility of a transition towards either a desynchronized or a (fully) synchronized state; (2) long-term autocorrelations indicative of a scale-free temporal dynamics of phase synchronization. Only the Freeman phase model exhibited scale-free behavior. Its repulsive coupling, however, let the individual phases disperse and did not allow for a transition into a synchronized state. The Wilson-Cowan phase model, by contrast, could switch into a (partially) synchronized state, but it did not generate long-term correlations although being located close to the onset of synchronization, i.e. in its critical regime. That is, the phase-reduced models can display one of the two dynamical features, but not both. PMID- 29625234 TI - Baby brain atlases. AB - The baby brain is constantly changing due to its active neurodevelopment, and research into the baby brain is one of the frontiers in neuroscience. To help guide neuroscientists and clinicians in their investigation of this frontier, maps of the baby brain, which contain a priori knowledge about neurodevelopment and anatomy, are essential. "Brain atlas" in this review refers to a 3D-brain image with a set of reference labels, such as a parcellation map, as the anatomical reference that guides the mapping of the brain. Recent advancements in scanners, sequences, and motion control methodologies enable the creation of various types of high-resolution baby brain atlases. What is becoming clear is that one atlas is not sufficient to characterize the existing knowledge about the anatomical variations, disease-related anatomical alterations, and the variations in time-dependent changes. In this review, the types and roles of the human baby brain MRI atlases that are currently available are described and discussed, and future directions in the field of developmental neuroscience and its clinical applications are proposed. The potential use of disease-based atlases to characterize clinically relevant information, such as clinical labels, in addition to conventional anatomical labels, is also discussed. PMID- 29625238 TI - Infection, genetic and virulence characteristics of porcine epidemic diarrhea virus in northwest China. AB - From September 2015 to May 2016, epidemic outbreaks of a diarrheal disease caused severe economic losses to the swine industry in northwest China. Typical clinical symptoms of the disease included severe diarrhea, vomiting, dehydration and death. In order to identify the pathogen, 27 intestinal samples were collected from dead piglets in Shaanxi, Gansu and Qinghai provinces and from Ningxia Hui Autonomous Region. All samples were tested using RT-PCR to detect rotavirus (RV), porcine epidemic diarrhea virus (PEDV) and transmissible gastroenteritis virus (TGEV). Twenty-five fecal samples were PEDV positive and five were TGEV positive; no piglets were infected with RV, indicating PEDV was the major pathogenic agent of viral diarrheal disease in these areas. Six strains were successfully isolated from positive samples and were serially passaged 40 times in Vero cells, with obvious cytopathic effects observed after 24 h post inoculation (hpi) and virus titers reaching 1.0 * 107 to 5.62 * 108. Sequence analysis ruled out that isolated strains were vaccine PEDV strains or strains derived from vaccine strains. Five strains belonged to classical strains, while one strain was a novel variant strain. The virulence of new novel variant strain SX1 and classical strain NX1 were tested in vivo using 10-day-old nursing piglets, revealing that both strains were highly pathogenic for piglets with destruction to small intestinal villi. Hematoxylin and eosin staining demonstrated markedly increased mucosal thickness, reduced villus length and villus/crypt (V/C) ratio in infected piglets. These pathological changes correlated with observed significantly reduced intestinal digestion and absorption functions that led to anorexia, dehydration, diarrhea and emaciation. Collectively, this study first reported the PEDV epidemic and phylogenetic analysis in northwest China and the results were important to understanding the infectivity, genetic characteristics, evolution and pathogenicity of PEDV strains, therefore, this experiment had important public health significance. PMID- 29625239 TI - Retrospective genome-wide comparisons of Salmonella enterica serovar Enteritidis from suspected outbreaks in Singapore. AB - The number of salmonellosis cases in Singapore has increased over the years. Salmonella enterica serovar Enteritidis has always been the most predominant serovar in the last five years. The National Public Health Laboratory assisted outbreak investigations by performing multilocus variable number tandem repeat analysis (MLVA) on isolates that were collected at the time of the investigations. Isolates were defined as belonging to a particular cluster if they had identical MLVA patterns. Whilst MLVA has been instrumental in outbreak investigations, it may not be useful when outbreaks are caused by an endemic MLVA type. In this study, we analysed 67 isolates from 12 suspected outbreaks with known epidemiological links to explore the use of next-generation sequencing (NGS) for defining outbreaks. We found that NGS can confidently group isolates into their respective outbreaks. The isolates from each suspected outbreak were closely related and differed by a maximum of 3 single nucleotide polymorphisms (SNPs). They were also clearly separated from isolates that belonged to different suspected outbreaks. This study provides an important insight and further evidence on the value of NGS for routine surveillance and outbreak detection of S. Enteritidis. PMID- 29625240 TI - Predicting the receptor-binding domain usage of the coronavirus based on kmer frequency on spike protein. PMID- 29625241 TI - Phenotype and genotype alteration during adaptive evolution of Enterococcus faecalis to antimicrobials. AB - The current worldwide emergence of resistance to antibiotics in bacteria constitutes an important growing public health threat. The mechanisms of the emergence and dissemination of resistance remain to be elucidated. Adaptation laboratory evolution provide an approach to investigate the acquisition of de novo mutations that confers drug resistance. In our study, 3 Enterococcus faecalis clinical isolates and E. faecalis ATCC29212 were evolved resistant to 8 kinds of antimicrobials spanning five chemical classes, including ciprofloxacin, levofloxacin, gatifloxacin, penicillin, imipenem, vancomycin, chloramphenicol and gentamicin. After 10 passages for 40 days, strains exhibited high level resistance to selected drugs except for imipenem. The greatest increase was observed in those evolved to quinolones, which caused >256-fold increase in MIC compared to the wild type. Cross-resistance and collateral-sensitivity were widely found after evolution. Through genotypic analysis of quinolones resistance strains, amino acid changes were observed in the QRDR region of GyrA and ParC. Substitutions occurred at GyrA were detected as Ser84Asn/Ser84Ile/Ser84Arg/Gly106Asp. However, Substitutions in ParC were found as Ser82Ile/Glu86Lys/Glu86Gly/His105Tyr. Compared with ancestral strains, the growth rates of evolved resistant strains slowed down and the logarithmic phase was delayed >7 h. While, the biofilm formation capacity of strains was not significantly changed by evolutionary adaptation. Our data verified that long term exposure to sub-lethal concentrations of antimicrobial agents could selectively enrich drug resistant mutant of E. faecalis, conferring to cross resistance and collateral-sensitivity towards other antimicrobials and fitness costs. Defining these effects can provide alternative antimicrobial strategies directed to mitigate the selection of antibiotic resistant microbes. PMID- 29625242 TI - Soya-saponins induce intestinal inflammation and barrier dysfunction in juvenile turbot (Scophthalmus maximus). AB - Soybean meal-induced enteritis (SBMIE) is a well-described condition in the distal intestine (DI) of several cultured fish species, but the exact cause is still unclear. The work on Atlantic salmon and zebrafish suggested soya-saponins, as heat-stable anti-nutritional factors in soybean meal, are the major causal agents. However, this conclusion was not supported by the research on some other fish, such as gilthead sea bream and European sea bass. Our previous work proved that soybean could induce SBMIE on turbot and the present work aimed to investigate whether soya-saponins alone could cause SBMIE and the effects of soya saponins on the intestinal barrier function in juvenile turbot. Turbots with initial weight 11.4 +/- 0.02 g were fed one of four fishmeal-based diets containing graded levels of soya-saponins (0, 2.5, 7.5, 15 g kg-1) for 8 weeks. At the end of the trial, all fish were weighed and plasma was obtained for diamine oxidase (DAO) activity and d-lactate level analysis and DI was sampled for histological evaluation and quantification of antioxidant parameters and inflammatory marker genes. The activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and intestinal glutathione level were selected to evaluated intestinal antioxidant system. The distal intestinal epithelial cell (IEC) proliferation and apoptosis were investigated by proliferating cell nuclear antigen (PCNA) labelling and TdT-mediated dUTP nick end labeling (TUNEL), respectively. The results showed that soya-saponins caused significantly dose-dependent decrease in the growth performance and nutrient utilization (p < 0.05). Enteritis developed in DI of the fish fed diet containing soya-saponins. Significantly dose-dependent increases in severity of the inflammation concomitant with up-regulated expression of il-1beta, il-8, and tnf alpha, increased IEC proliferation and apoptosis, and decreases in selected antioxidant parameters were detected (p < 0.05). The epithelial permeability (evaluated by the plasma DAO activity and d-lactate level) was significantly increased with the increasing of dietary level of soya-saponins (p < 0.05), which was concomitant with the destroyed the intracellular junctions. In conclusion, the present work proved that soya-saponins induced enteritis and compromised the intestinal barrier functions. Based on the present work, strategies focus on regulation of cell apoptosis, epithelial permeability, intracellular junctions and redox homeostasis worth further investigating to develop new and efficient ways for SBMIE alleviation. PMID- 29625243 TI - beta-1,3 glucan derived from Euglena gracilis and AlgamuneTM enhances innate immune responses of red drum (Sciaenops ocellatus L.). AB - To reduce susceptibility to stressors and diseases, immune-modulators such as beta-glucans have been proven effective tools to enhance the innate immune responses of fish. Consequently, commercial sources of this polysaccharide are becoming increasingly more available. AlgamuneTM is a commercial additive produced from Euglena gracilis, as a source of linear beta-1,3-glucan. In order to evaluate the immunomodulatory effects of this beta-glucan product, the present study assessed the innate immune parameters of red drum (Sciaenops ocellatus) exposed to AlgamuneTM ex vivo and in vivo. Isolated kidney phagocytes were incubated with graded concentrations (0, 0.2, 0.4, 0.8, 1.6 and 3.2 mg L-1) of dried Euglena gracilis (AlgamuneTM) as well as purified Paramylon (linear beta 1,3 glucan). Increased bactericidal activity against Streptococcus iniae, and production of intracellular O2- anion superoxide were stimulated by both beta glucan sources. A reduced activity of extracellular anion superoxide was observed by the phagocytes incubated with Algamune TM. After corroborating the effectiveness of the glucan source ex vivo, a feeding trial was conducted using red drum juveniles (~26.6 g initial weight). Fish were fed diets with graded levels of AlgamuneTM (0, 100, 200, 400 and 800 mg kg-1) twice daily for 21 days. No significant differences were detected regarding production performance parameters. At the end of the feeding trial, blood, intestinal content, and kidney were sampled. Intestinal microbiota from fecal material was analyzed through denaturing gradient gel electrophoresis (DGGE) and found to be similar among all treatments. No significant differences were detected for oxidative radical production from whole blood, and isolated phagocytes, and plasma lysozyme activity. However, the total hemolytic activity of red drum plasma was increased in fish fed 100 and 200 mg kg-1 of dietary AlgamuneTM when compared to fish fed the basal diet. Based on results from both ex vivo and in vivo trials, beta glucan from AlgamuneTM was demonstrated to have a moderate immunostimulatory effects on red drum. PMID- 29625244 TI - Molecular characterization, expression and functional analysis of peptidoglycan recognition protein-SC2 from rock bream, Oplegnathus fasciatus. AB - Peptidoglycan recognition proteins are members of the family of pattern recognition receptors (PRRs), that play important roles in the recognition of peptidoglycan and various biological processes. In this study, we have characterized peptidoglycan recognition protein-SC2 (PGRP-SC2) in rock bream (Oplegnathus fasciatus) (RbPGRP-SC2) and analysed its expression in various tissues after pathogen challenge. A sequence alignment revealed that the residues essential to zinc binding of the deduced protein were highly conserved among all the organisms. Phylogenetic analysis revealed that RbPGRP-SC2 is most closely related to the large yellow croaker PGRP-SC2. RbPGRP-SC2 was ubiquitously expressed in all tissues analysed, predominantly distributed in muscle and skin. After challenge with microbial pathogens (Edwardsiella piscicida), Streptococcus iniae or red seabream iridovirus [RSIV]), RbPGRP-SC2 was up-regulated in all the tissues examined, especially in liver. We produced recombinant RbPGRP-SC2 (rRbPGRP-SC2) using an Escherichia coli expression system. The rRbPGRP-SC2 had agglutination activity towards both Gram-negative (E. piscicida) and Gram positive bacteria (S. iniae). In addition, rRbPGRP-SC2 induced leukocyte apoptosis and promoted leukocyte phagocytosis. These results suggest that the RbPGRP-SC2 plays an important role in the immune system and in maintaining cellular homeostasis of rock bream. PMID- 29625245 TI - iTRAQ-based quantitative proteomic analysis of Procambarus clakii hemocytes during Spiroplasma eriocheiris infection. AB - As a new-found aquaculture pathogen, Spiroplasma eriocheiris, has resulted in inconceivable economic losses in aquaculture. In the infection of S. eriocheiris, the Procambarus clakii hemocytes have indicated to be major target cells. What was designed to examine in our study is the hemocytes' immune response at the protein levels. Before the pathogen was injected and after 192 h of post injection, the differential proteomes of the crayfish hemocytes were analyzed immediately by isobaric tags for relative and absolute quantization (iTRAQ) labeling, followed by liquid chromatogramphytandem mass spectrometry (LC-MS/MS). This research had identified a total of 285 differentially expressed proteins. Eighty-three and 202 proteins were up-regulated and down-regulated, respectively, caused by the S. eriocheiris infection. Up-regulated proteins included alpha-2 macroglobulin (alpha2M), vitellogenin, ferritin, etc. Down-regulated proteins, involved with serine protease, peroxiredoxin 6, 14-3-3-like protein, C-type lectin, cdc42 homolog precursor, etc. The prophenoloxidase-activating system, antimicrobial action involved in the immune responses of P. clarkii is considered to be damaged due to S. eriocheiris infection. The present work could lay the foundation for future research on the proteins related to the susceptibility/resistance of P. clarkii to S. eriocheiris. In addition, it is helpful for our understanding molecular mechanism of disease processes in crayfishes. PMID- 29625246 TI - Droplet Digital PCR Is a Robust Tool for Monitoring Minimal Residual Disease in Adult Philadelphia-Positive Acute Lymphoblastic Leukemia. AB - The breakpoint cluster region-abelson 1 p190 fusion transcript is the most frequent variant observed in Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL). Qualitative-PCR and real-time quantitative PCR are the currently used methods to monitor minimal residual disease (MRD) in Ph+ ALL patients; for the latter, full standardization and an international quality validation are lacking. Here, we developed a droplet digital PCR (ddPCR) assay for MRD monitoring in p190+ ALL cases. The analytical performance was assessed by the limit-of-detection determination, showing a reliability, sensitivity, and precision of the assay of up to 0.001%. Comparison of results obtained with qualitative PCR and ddPCR in 117 follow-up samples from 16 of 26 Ph+ ALL patients showed discordant results in 27% of cases (32 of 117). Real-time quantitative PCR analysis of 19 ddPCR-positive samples with a low tumor burden failed to provide quantitative results in 63% of cases (12 of 19). These results highlight that in p190+ ALL the ddPCR method has a sufficient analytical performance for very low MRD monitoring and for predicting molecular relapse several months before hematologic relapse. In conclusion, MRD monitoring by ddPCR may better stratify Ph+ ALL patients at risk of disease progression. PMID- 29625247 TI - Added Value of 50-Gene Panel Sequencing to Distinguish Multiple Primary Lung Cancers from Pulmonary Metastases: A Systematic Investigation. AB - Differentiation between multiple primary lung cancers and pulmonary metastases (PM) has important implications in staging, prognosis, and treatment strategies. Clinical and immunohistopathologic criteria have been standardized; however, a substantial number of cases remain difficult to classify. Using next-generation sequencing, it is now possible to improve the classification of multiple lung cancer lesions. This study systematically investigated the value of routine morphologic and IHC characteristics, p53 protein expression, TP53 mutation analysis, and 50-gene panel sequencing (GPS) in 111 lesions from 50 patients with multiple lung lesions. Based on immunohistopathologic criteria, 32 paired lesions were classified as multiple primary lung cancer (MPLC) and 21 as PM. TP53 mutation analysis indicated MPLC in 23 and PM in 6 pairs, but in the majority of cases (n = 28, 49%) no mutation was observed and no conclusion could be drawn. In contrast, only 2 pairs were not conclusive using GPS. In a significant number of matching tumor samples (n = 19, 39%), sequencing results were contradictory to the initial immunohistopathology diagnosis. No separation in overall survival for classifications based on immunohistopathology was observed, while a clear but nonsignificant trend was observed concerning survival in MPLC patients (hazard ratio = 3.98) using 50-gene GPS. In about one-third of the patients, GPS provided additional information to improve the differentiation between MPLC and PM. PMID- 29625248 TI - Transferring a Quantitative Molecular Diagnostic Test to Multiple Real-Time Quantitative PCR Platforms. AB - Quantitative gene expression assays are increasingly used for diagnosis and research, but are often restricted to specific instrumentation. We propose a robust technical and statistical framework that enables transferring of established real-time quantitative PCR assays across real-time quantitative PCR platforms without compromising analytical and clinical validity. The feasibility of our approach was tested on MammaTyper, an in vitro diagnostic assay that quantifies breast cancer biomarkers and dichotomizes results according to cutoff points. CFX96, Applied Biosystems 7500 Fast, and Mx3000P were chosen as the candidate platforms, whereas the LightCycler 480 II was used as a reference. Two instruments were used per platform, and they were tested initially for equivalence via Bland-Altman and Deming regression analyses. A method comparison approach was adapted to adjust cutoffs for the new systems and the cross-platform agreement was evaluated. Finally, precision was estimated for each platform. The performance on the candidate devices was highly comparable to the reference platform, with a 7 log quantification range and amplification efficiencies of 97% to 103%. The equivalence tests successfully prequalified instruments, preventing constant and proportional errors and enabling reliable adjustments of cutoffs, which resulted in cross-platform marker and subtype agreements of 91% to 100% and kappa values between 0.78 and 1.00. Provided that platform-specific adjustments are implemented, the described process can help expand the operability of quantitative diagnostic tests while maintaining assay performance characteristics. PMID- 29625249 TI - Accurate Typing of Human Leukocyte Antigen Class I Genes by Oxford Nanopore Sequencing. AB - Oxford Nanopore Technologies' MinION has expanded the current DNA sequencing toolkit by delivering long read lengths and extreme portability. The MinION has the potential to enable expedited point-of-care human leukocyte antigen (HLA) typing, an assay routinely used to assess the immunologic compatibility between organ donors and recipients, but the platform's high error rate makes it challenging to type alleles with accuracy. We developed and validated accurate typing of HLA by Oxford nanopore (Athlon), a bioinformatic pipeline that i) maps nanopore reads to a database of known HLA alleles, ii) identifies candidate alleles with the highest read coverage at different resolution levels that are represented as branching nodes and leaves of a tree structure, iii) generates consensus sequences by remapping the reads to the candidate alleles, and iv) calls the final diploid genotype by blasting consensus sequences against the reference database. Using two independent data sets generated on the R9.4 flow cell chemistry, Athlon achieved a 100% accuracy in class I HLA typing at the two field resolution. PMID- 29625250 TI - External Quality Assessment Identifies Training Needs to Determine the Neoplastic Cell Content for Biomarker Testing. AB - Neoplastic cell content determination is crucial for biomarker testing. It is known that interobserver variation exists, but largescale data are missing about variation in tumor delineation and cell content determination. Results were obtained from the external quality assessment program for metastatic colorectal cancer from the European Society of Pathology (N = 5776 observations). The study included three parts: current practices were surveyed, neoplastic cell content estimations and delineations were retrieved from stained slides, and clinical reports were analyzed. Seventeen of 43 pathologists determined the neoplastic cell content in a tumor-rich area for DNA extraction and took immune cells (n = 37), tumor cell distribution (n = 33), desmoplastic stroma (n = 30), necrosis (n = 29), and mucus (n = 23) into account. The selected area was highly variable, and the average difference between the highest and lowest estimation ranged between 51% and 78% (2011 to 2017). The number of overestimations was alarmingly high in samples containing <30% tumor cells. Of concern is that 33 of 105 laboratories reported a wild-type result in a sample without tumor in 2017. Standardization of neoplastic cell content determination is needed for test outcome interpretation. The authors' data show variation in estimation practices, tumor delineations and estimations, and interpretation problems (n = 226 reports). Further training for selecting the most suitable block and creating clear reports is urgently needed. PMID- 29625251 TI - The influence of temporomandibular joint movement parameters on dental morphology. AB - : Association between tooth morphology, occlusal relations and mandibular condyle/glenoid fossa morphology is still a controversial issue in dentistry. The aim of the present study was to examine the influence of three important articular parameters on the dental morphology and the crown volume, quantifying the variation for each tooth group: incisor, canine, premolar and molar. MATERIALS AND METHODS: All maxillary teeth from a set of basic study models were prepared for zirconia single crowns. The models were scanned and then, using a computer aided design software, they were mounted in a virtual articulator and specific mandibular movements were defined. The crown morphology was designed and statically adapted. Ten models were obtained by dynamical adjustment of the basic model for successively modified articular parameters: sagittal condylar inclination (SCI)=30 degrees , Bennett angle (BA)=10 degrees , Immediate side shift (ISS)=0.5mm - for control and SCI: 40 degrees , 50 degrees and 60 degrees with BA and ISS as control, BA: 15 degrees , 20 degrees and 25 degrees with SCI and ISS as control, ISS: 1.5mm, 1.0mm and 0.0mm with SCI and BA as control - for the nine test models. The following measurements were performed three times on the right side of each model: volume for each tooth group, slope (S) for the central incisor, S and mesio-distal angle (MDA) for canine, S, MDA and vestibulo oral angle (VOA) for the first premolar and molar. RESULTS: When SCI was varied, statistically significant changes as compared to the controls were found for incisor's and premolar's S, premolar's VOA and, for 50 degrees and 60 degrees , MDA and molar's MDA (for 50 degrees ) and VOA (for 60 degrees ). When BA was varied, significant changes were found for S (canine) and, in certain models, MDA (premolar, molar). Variations of ISS significantly changed mainly MDA for molars and, in two models, premolars. CONCLUSIONS: Within the limits of this study, among the articular parameters, SCI mostly influenced the dynamic tooth morphology, but canine and molar morphology was stronger influenced by BA and/or ISS. PMID- 29625252 TI - The deep lymphatic anatomy of the hand. AB - BACKGROUND: The deep lymphatic anatomy of the hand still remains the least described in medical literature. METHODS: Eight hands were harvested from four nonembalmed human cadavers amputated above the wrist. A small amount of 6% hydrogen peroxide was employed to detect the lymphatic vessels around the superficial and deep palmar vascular arches, in webs from the index to little fingers, the thenar and hypothenar areas. A 30-gauge needle was inserted into the vessels and injected with a barium sulphate compound. Each specimen was dissected, photographed and radiographed to demonstrate deep lymphatic distribution of the hand. RESULTS: Five groups of deep collecting lymph vessels were found in the hand: superficial palmar arch lymph vessel (SPALV); deep palmar arch lymph vessel (DPALV); thenar lymph vessel (TLV); hypothenar lymph vessel (HTLV); deep finger web lymph vessel (DFWLV). Each group of vessels drained in different directions first, then all turned and ran towards the wrist in different layers. CONCLUSION: The deep lymphatic drainage of the hand has been presented. The results will provide an anatomical basis for clinical management, educational reference and scientific research. PMID- 29625253 TI - Liposome-chaperoned cell-free synthesis for the design of proteoliposomes: Implications for therapeutic delivery. AB - : Cell-free (CF) protein synthesis has emerged as a powerful technique platform for efficient protein production in vitro. Liposomes have been widely studied as therapeutic carriers due to their biocompatibility, biodegradability, low toxicity, flexible surface manipulation, easy preparation, and higher cargo encapsulation capability. However, rapid immune clearance, insufficient targeting capacity, and poor cytoplasmic delivery efficiency substantially restrict their clinical application. The incorporation of functional membrane proteins (MPs) or peptides allows the transfer of biological properties to liposomes and imparts them with improved circulation, increased targeting, and efficient intracellular delivery. Liposome-chaperoned CF synthesis enables production of proteoliposomes in one-step reaction, which not only substantially simplifies the production procedure but also keeps protein functionality intact. Building off these observations, proteoliposomes with integrated MPs represent an excellent candidate for therapeutic delivery. In this review, we describe recent advances in CF synthesis with emphasis on detailing key factors for improving CF expression efficiency. Furthermore, we provide insights into strategies for rational design of proteoliposomal nanodelivery systems via CF synthesis. STATEMENT OF SIGNIFICANCE: Liposome-chaperoned CF synthesis has emerged as a powerful approach for the design of recombinant proteoliposomes in one-step reaction. The incorporation of bioactive MPs or peptides into liposomes via CF synthesis can facilitate the development of proteoliposomal nanodelivery systems with improved circulation, increased targeting, and enhanced cellular delivery capacity. Moreover, by adapting lessons learned from natural delivery vehicles, novel bio-inspired proteoliposomes with enhanced delivery properties could be produced in CF systems. In this review, we first give an overview of CF synthesis with focus on enhancing protein expression in liposome-chaperoned CF systems. Furthermore, we intend to provide insight into harnessing CF-synthesized proteoliposomes for efficient therapeutic delivery. PMID- 29625254 TI - Oligoaniline-based conductive biomaterials for tissue engineering. AB - : The science and engineering of biomaterials have improved the human life expectancy. Tissue engineering is one of the nascent strategies with an aim to fulfill this target. Tissue engineering scaffolds are one of the most significant aspects of the recent tissue repair strategies; hence, it is imperative to design biomimetic substrates with suitable features. Conductive substrates can ameliorate the cellular activity through enhancement of cellular signaling. Biocompatible polymers with conductivity can mimic the cells' niche in an appropriate manner. Bioconductive polymers based on aniline oligomers can potentially actualize this purpose because of their unique and tailoring properties. The aniline oligomers can be positioned within the molecular structure of other polymers, thus painter acting with the side groups of the main polymer or acting as a comonomer in their backbone. The conductivity of oligoaniline-based conductive biomaterials can be tailored to mimic the electrical and mechanical properties of targeted tissues/organs. These bioconductive substrates can be designed with high mechanical strength for hard tissues such as the bone and with high elasticity to be used for the cardiac tissue or can be synthesized in the form of injectable hydrogels, particles, and nanofibers for noninvasive implantation; these structures can be used for applications such as drug/gene delivery and extracellular biomimetic structures. It is expected that with progress in the fields of biomaterials and tissue engineering, more innovative constructs will be proposed in the near future. This review discusses the recent advancements in the use of oligoaniline-based conductive biomaterials for tissue engineering and regenerative medicine applications. STATEMENT OF SIGNIFICANCE: The tissue engineering applications of aniline oligomers and their derivatives have recently attracted an increasing interest due to their electroactive and biodegradable properties. However, no reports have systematically reviewed the critical role of oligoaniline-based conductive biomaterials in tissue engineering. Research on aniline oligomers is growing today opening new scenarios that expand the potential of these biomaterials from "traditional" treatments to a new era of tissue engineering. The conductivity of this class of biomaterials can be tailored similar to that of tissues/organs. To the best of our knowledge, this is the first review article in which such issue is systematically reviewed and critically discussed in the light of the existing literature. Undoubtedly, investigations on the use of oligoaniline-based conductive biomaterials in tissue engineering need further advancement and a lot of critical questions are yet to be answered. In this review, we introduce the salient features, the hurdles that must be overcome, the hopes, and practical constraints for further development. PMID- 29625255 TI - Genetic enhancement of macroautophagy in vertebrate models of neurodegenerative diseases. AB - Most of the neurodegenerative diseases that afflict humans manifest with the intraneuronal accumulation of toxic proteins that are aggregate-prone. Extensive data in cell and neuronal models support the concept that such proteins, like mutant huntingtin or alpha-synuclein, are substrates for macroautophagy (hereafter autophagy). Furthermore, autophagy-inducing compounds lower the levels of such proteins and ameliorate their toxicity in diverse animal models of neurodegenerative diseases. However, most of these compounds also have autophagy independent effects and it is important to understand if similar benefits are seen with genetic strategies that upregulate autophagy, as this strengthens the validity of this strategy in such diseases. Here we review studies in vertebrate models using genetic manipulations of core autophagy genes and describe how these improve pathology and neurodegeneration, supporting the validity of autophagy upregulation as a target for certain neurodegenerative diseases. PMID- 29625256 TI - Epileptogenesis, traumatic brain injury, and biomarkers. AB - Epilepsy is one of the most common brain disorders, causing serious disability and premature death worldwide. Approximately 1.2% of the U.S. population has active epilepsy, and 30 to 40% have seizures that do not respond to antiseizure drugs. There currently is no treatment available that prevents epilepsy following a potential epileptogenic insult, and the search for disease or syndrome modifying interventions for epilepsy is a high priority of neurobiological research. This requires better understanding of neuronal mechanisms underlying the development of epilepsy, and biomarkers of this process that would permit cost-effective drug discovery, and validation in clinical trials, for potential antiepileptogenic compounds. EpiBioS4Rx is an NIH-funded Center without Walls consisting of collaborative investigations in the United States, Europe, and Australia of traumatic brain injury in patients, and a standardized animal model, to identify biomarkers of epileptogenesis and to determine their ability to assess the effectiveness of potential antiepileptogenic agents. Successful completion of this project is expected to result in design of an economically feasible, full-scale clinical trial of at least one antiepileptogenic intervention. PMID- 29625257 TI - 5-year overall survival after early breast cancer diagnosed during pregnancy: A retrospective case-control multicentre French study. AB - BACKGROUND: Breast cancer diagnosed during pregnancy (BCP) is rare, but the prevalence is expected to rise. Long-term follow-up data regarding this clinically challenging condition are scarce. The main objective of this multicentre case-control French study was to compare the survival between pregnant patients and matched controls. METHODS: Patients from 27 centres diagnosed between 2000 and 2009 with histologically proven invasive breast cancer occurring during pregnancy were retrospectively included. Controls were matched to BCP patients on age, clinical T stage, hormone receptor, HER2, administration of neo-adjuvant chemotherapy and pathological node involvement in the absence of neo-adjuvant chemotherapy. Five-year overall survival (OS), disease-free survival (DFS) and metastasis-free survival (MFS) rates were estimated using the Kaplan Meier method. RESULTS: One hundred and eleven BCP patients and 253 controls were included. Median age was 33 and 35 years, respectively. Both populations were managed similarly, except for less frequent sentinel node dissection (p = 0.026) and taxane administration (p = 0.03) among BCP patients. Median follow-up was 7.5 years. Survival rates were similar between both BCP and control patients: 5-year OS rates were 83.1% (95% CI: 74.5-89.0) vs 85.5% (95% CI: 80.4-89.4), respectively, p = 0.31; 5-year DFS rates 60.0% (95% CI: 50.1-68.6) vs 68.5% (95% CI: 62.3-73.9), respectively, p = 0.12 and 5-year MFS rates 71.0% (95% CI: 61.3 78.6) and 74.5% (95% CI: 68.6-79.5), respectively, p = 0.21. CONCLUSION: Our study showed that the survival outcomes of patients diagnosed with BCP were not significantly different as compared to those of matched non-pregnant controls. A proper management of women diagnosed with BCP is crucial. PMID- 29625258 TI - Chemical characterization with in vitro biological activities of Gypsophila species. AB - Methanol-aqueous extracts from the aerial parts of Gypsophila glomerata (GGE), G. trichotoma (GTE) and G. perfoliata (GPE) were investigated for antioxidant potential using different in vitro models, as well as for phenolic and flavonoid contents. The possible anti-cholinesterase, anti-tyrosinase, anti-amylase and anti-glucosidase activities were also tested. The flavonoid variability was analyzed using ultra high-performance liquid chromatography (UHPLC) coupled with hybrid quadrupole-Orbitrap high resolution mass spectrometry (HRMS). Eleven C glycosyl flavones and 4 O-glycosyl flavonoids, including 2"-O-pentosyl-6-C hexosyl-apigenin/methylluteolin, as well as their mono(di)-acetyl derivatives were found in GGE. Both GGE and GTE shared 2"-pentosyl-6-C-hexosyl-luteolin together with the common saponarin, homoorientin, orientin, isovitexin and vitexin, while di C-glycosyl flavones were evidenced only in GPE. The highest radical scavenging in both ABTS and DPPH assays was noted in GPE, as well as ferric and cupric reducing abilities. However, GTE had the strongest metal chelating activity (17.44 +/- 0.51 mg EDTAE/g extract). GPE and GGE were more potent as acetylcholinesterases inhibitors witnessed by 2.09 +/- 0.02 mg GALAE/g extract and 1.59 +/- 0.09 mgGALAE/g extract, respectively. All flavonoids were found in G. glomerata for the first time. Therefore, further isolation and structural elucidation of newly described acetylated flavonoids are needed in order to determine their relevance in the beneficial properties of the plant. PMID- 29625259 TI - Effective methodologies for enantiomeric separations of 150 pharmacology and toxicology related 1 degrees , 2 degrees , and 3 degrees amines with core-shell chiral stationary phases. AB - Core-shell particles (superficially porous particles, SPPs) have been proven to provide high-throughput and effective separations of a variety of chiral molecules. However, due to their limited commercialization, many separations have not been reported with these stationary phases. In this study, four SPP chiral stationary phases (CSPs) were utilized for the enantiomeric separation of 150 chiral amines. These amines encompass a variety of structural and drug classes, which are particularly important to the pharmaceutical industry and in forensics. This comprehensive evaluation demonstrates the power of these CSPs and the ease of method development and optimization. The CSPs used in this study included the macrocyclic glycopeptide-based CSPs (VancoShell and NicoShell), the cyclodextrin based CSP (CDShell-RSP), and the cyclofructan-based CSP (LarihcShell-P). These CSPs offered versatility for a variety of applications and worked in a complementary fashion to baseline separate all 150 amines. The LarihcShell-P was highly effective for separating primary amines. VancoShell, NicoShell, and CDShell-RSP were useful for separating all types of amines. These CSPs are multi modal and can be utilized with mass spectrometry compatible solvents. Eighteen racemic controlled substances were simultaneously baseline separated in a single liquid chromatography-mass spectrometry (LC-MS) analysis. Details in high performance liquid chromatography (HPLC) parameters will be discussed as well as the improved chromatographic performance afforded by the SPP CSPs. PMID- 29625260 TI - Protective effects of Polygonum multiflorum on ischemic stroke rat model analysed by 1H NMR metabolic profiling. AB - Stroke is the third most common cause of death in most industrialized countries. Polygonum multiflorum (He-Shou-Wu, HSW) is one of the traditional Chinese medicines with multiple pharmacological activities which is widely used in Chinese recipe. This study aims to explore the protective effect of HSW on ischemic stroke rat model and to elucidate the underlying mechanisms. The mortality rate, neurological deficit, cerebral infarct size, histopathology, immunohistochemistry, biochemical parameters, quantitative real-time polymerase chain reaction and western blotting were used to access the treatment effects of HSW on ischemic stroke. Proton nuclear magnetic resonance (1H NMR) based metabolomics analysis disclosed that HSW could relieve stroke rats suffering from the ischemia/reperfusion injury by ameliorating the disturbed energy and amino acids metabolisms, alleviating the oxidative stress from reactive oxygen species and reducing the inflammation. HSW treatment increased levels of cellular antioxidants that scavenged reactive oxygen species during ischemia-reperfusion via the nuclear erythroid 2-related factor 2 signaling pathway, and exert anti inflammatory effect by decreasing the levels of inflammatory factors such as cyclooxygenase-2, interleukin-1beta, interleukin-6 and tumor necrosis factor alpha. The integrated metabolomics approach showed its potential in understanding mechanisms of HSW in relieving ischemic stroke. Further study to develop HSW as an effective therapeutic agent to treat ischemic stroke is warranted. PMID- 29625261 TI - Acute and chronic effect of physical activity on cognition and behaviour in young people with ADHD: A systematic review of intervention studies. AB - BACKGROUND: Young people with attention deficit hyperactivity disorder (ADHD) often have learning and behavioral control difficulties. AIM: The aim of this review is analyse the acute and chronic effect of physical activity (PA) on the cognition and behaviour of children and adolescents with ADHD. METHODS: Studies were identified in five databases (PubMed, SPORTDiscus, ProQuest, Web of Science, and SCOPUS), from January 2000 through to January 2017. A total of 16 interventional studies met the inclusion criteria. RESULTS/CONCLUSIONS: PA practice of 20-30 min (intensity 40-75%) produces a positive acute effect on processing speed, working memory, planning and problem solving in young people with ADHD. However, these effects on behaviour are contradictory and vary depending on age. Chronic PA practice (>=30 min per day, >=40% intensity, >=three days per week, >=five weeks) further improves attention, inhibition, emotional control, behaviour and motor control. The results must be treated with caution, because only 25% of the studies used confounders. IMPLICATION: More research is needed to justify the causes of these effects. It is necessary to establish programs with regard to the duration, intensity, kind of exercise, and time of PA to improve cognition and behaviour in young people with ADHD taking into account potential confounders. PMID- 29625263 TI - Difference between car-to-cyclist crash and near crash in a perpendicular crash configuration based on driving recorder analysis. AB - Analyzing a crash using driving recorder data makes it possible to objectively examine factors contributing to the occurrence of the crash. In this study, car to-cyclist crashes and near crashes recorded on cars equipped with advanced driving recorders were compared with each other in order to examine the factors that differentiate near crashes from crashes, as well as identify the causes of the crashes. Focusing on cases where the car and cyclist approached each other perpendicularly, the differences in the car's and cyclist's parameters such as velocity, distance and avoidance behavior were analyzed. The results show that car-to-cyclist crashes would not be avoidable when the car approaching the cyclist enters an area where the average deceleration required to stop the car is more than 0.45 G (4.4 m/s2). In order for this situation to occur, there are two types of cyclist crash scenarios. In the first scenario, the delay in the drivers' reaction in activating the brakes is the main factor responsible for the crash. In this scenario, time-to-collision when the cyclist first appears in the video is more than 2.0 s. In the second scenario, the sudden appearance of a cyclist from behind an obstacle on the street is the factor responsible for the crash. In this case, the time-to-collision is less than 1.2 s, and the crash cannot be avoided even if the driver exhibited avoidance maneuvers. PMID- 29625264 TI - Improving ancestry distinctions among Southwest Asian populations. AB - The Kidd Lab panel of 55 AISNPs can provide up to 10 statistically relevant biogeographic groupings of a global set of populations. A second-tier panel would be useful for increasing the accuracy for further differentiation of populations within a specific global grouping. Because recent advances in massively parallel sequencing (MPS) methods allow the genotyping of many more SNPs, we are now identifying additional SNPs to provide refined discrimination among regional subsets of populations; Southwest Asia and the nearby Mediterranean region (SWA) is our current target for such a "second tier" panel. We selected the potentially best SNPs from various sources: our own laboratory database (>4600 SNPs), AISNP panels (Kidd 55 and Seldin 128 SNP panels), and published papers reporting European and SW Asian populations. Rosenberg's Informativeness, Fst, and allele frequency heatmap matrices are used to determine the best SNPs for the region. A total of 2568 individuals, from 39 different populations ranging from North-East Africa through the SW Asia and Europe to the Ural Mountains, were included in the refinement processes and analyses. Heatmap, PCA, Structure (K = 4), and ancestry inference for selected individuals with an in-lab version of FROG-kb analyses indicate that these 86 AISNPs provide the basis for building an improved, optimized panel of AISNPs that collectively provide additional information on differences among populations in that part of the world. Testing this panel with additional populations from the area and with new SNPs and/or microhaplotypes is expected to improve the panel. PMID- 29625262 TI - Difficulties regulating positive emotions and alcohol and drug misuse: A path analysis. AB - INTRODUCTION: Alcohol and drugs are widely used among college students. Emotion dysregulation has been identified as a key mechanism in the etiology, maintenance, and treatment of alcohol and drug misuse. Yet, research in this area has been limited by its narrow focus on dysregulation stemming from negative emotions. The goal of the current study was to extend past research by examining the relation of difficulties regulating positive emotions to alcohol and drug misuse. METHODS: Participants were 311 college students (Mage = 19.24; 66.1% female; 66.0% White) who completed measures assessing difficulties regulating positive emotions and alcohol and drug misuse. RESULTS: Structural equational modeling was used to model the relation between difficulties regulating positive emotions and alcohol and drug misuse. In a hypothesized structural model, higher levels of difficulties regulating positive emotions were found to relate to greater alcohol and drug misuse. Moreover, an alternative model provided support for an association of greater drug (but not alcohol) misuse to higher levels of difficulties regulating positive emotions. CONCLUSIONS: If replicated, findings may suggest the utility of targeting difficulties regulating positive emotions in treatments aimed at reducing alcohol and drug misuse among college students. PMID- 29625265 TI - Network-based meta-analysis in the identification of biomarkers for papillary thyroid cancer. AB - Papillary thyroid carcinoma (PTC) has been increasing across the world with incomplete understanding of its pathogenesis. We aimed to investigate gene alterations and biomarkers contributing to PTC development. A total of five eligible microarray datasets including 94 PTC and 81 normal thyroid samples were included to identify gene expression signatures. Using integrative meta-analysis of expression data (INMEX) program, we identified a total of 2699 differentially expressed genes (DEGs) (1333 overexpressed and 1366 underexpressed genes) in PTC relative to normal thyroid samples. The top 100 upregualted and downregulated DEGs identified in the meta-analysis were further validated in The Cancer Genome Atlas (TCGA) dataset for PTC with high consistency. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed pathways in cancer, proteoglycans in cancer, focal adhesion, axon guidance, and ECM-receptor interaction among the top 5 most enriched pathways. Network-based meta-analysis identified FN1 and TRAF6 to be the most highly ranked hub genes among the overexpressed and underexpressed genes, respectively, both of which are involved in pathways in cancer. The most enriched terms for Gene Ontology (GO) of biological processes, cellular component, and molecular function were signal transduction, cytoplasm, and protein binding, respectively. Our meta-analysis comprehensively investigated DEGs, hub genes, enriched pathways and GO terms for PTC, which might provide additional approaches to explore the molecular mechanisms underlying the pathophysiology of PTC, and identify biomarkers and therapeutic targets toward PTC. PMID- 29625266 TI - De novo transcriptomic analysis to identify differentially expressed genes during the process of aerenchyma formation in Typha angustifolia leaves. AB - Lysigenous aerenchyma is formed through programmed cell death (PCD) in Typha angustifolia leaves. However, the genome and transcriptome data for this species are unknown. To further elucidate the molecular basis of PCD during aerenchyma formation in T. angustifolia leaves, transcriptomic analysis of T. angustifolia leaves was performed using Illumina sequencing technology, revealing 73,821 unigenes that were produced by assembly of the reads in T1, T2 and T3 samples. The important pathways, such as programmed cell death (PCD), aerenchyma formation, and ethylene responsiveness were regulated by these unigenes. 1 aminocyclopropane-1-carboxylate synthase (ACS) and 1-aminocyclopropane-1 carboxylate oxidase (ACO) were highly up-regulated as key enzymes for ethylene synthesis, along with respiratory burst oxidase homolog (RBOH), metallothionein, calmodulin-like protein (CML), and polygalacturonase (PG), may collectively explain the PCD involved in T. angustifolia aerenchyma formation. We hypothesize that fermentation, metabolism and glycolysis generate ATP for PCD. We searched the 73,821 unigenes against protein databases, and 24,712 were annotated. Based on sequence homology, 16,012 of the 73,821 annotated unigenes were assigned to one or more Gene Ontology (GO) terms. Meanwhile, a total of 9537 unigenes were assigned to 126 pathways in the KEGG database. In summary, this investigation provides important guidelines for exploring the molecular mechanisms of aerenchyma formation in aquatic plants. PMID- 29625267 TI - Identification of small-molecule ligands that bind to MiR-21 as potential therapeutics for endometriosis by screening ZINC database and in-vitro assays. AB - MicroRNA-21 (miR-21) is an important regulator of cell signaling pathways involved in the pathogenesis of endometriosis. Here, we attempted to discover new ligands of miR-21 pre-element by carrying out stepwise high-throughput virtual screening against a chemical library consisting of over 4 million lead-like compounds. In the procedure, a synthetic strategy that integrated empirical exclusion, molecular docking, druglikeness evaluation, consensus scoring and manual culling was employed to computationally identify seven promising hits from the large compound library, of which four were determined to have moderate or high affinity for miR-21 pre-element (KD range between 3.7 and 109 MUM). We also evaluated the putative binding site and predicted interaction mode of pre-element with its identified compound ligands by inversion mutation of the wild-type pre element to mutant [U11A/A20U], and explored the sequence-specific recognition in pre-element-ligand interactions by generating a background of numerous random RNA decoys. It was revealed that most of identified pre-element binders are positively charged to meet the electrostatic complementarity with the negative electrostatic potential surface of RNA molecule, and the compound selectivity seems related partially to their affinity. PMID- 29625268 TI - Trunk muscle activation patterns during walking among persons with lower limb loss: Influences of walking speed. AB - Persons with lower limb amputation (LLA) walk with altered trunk-pelvic motions. The underlying trunk muscle activation patterns associated with these motions may provide insight into neuromuscular control strategies post LLA and the increased incidence of low back pain (LBP). Eight males with unilateral LLA and ten able bodied controls (CTR) walked over ground at 1.0 m/s, 1.3 m/s, 1.6 m/s, and self selected speeds. Trunk muscle onsets/offsets were determined from electromyographic activity of bilateral thoracic (TES) and lumbar (LES) erector spinae. Trunk-pelvic kinematics were simultaneously recorded. There were no differences in TES onset times between groups; however, LLA demonstrated a second TES onset during mid-to-terminal swing (not seen in CTR), and activation for a larger percentage of the gait cycle. LLA (vs. CTR) demonstrated an earlier onset of LES and activation for a larger percentage of the gait cycle at most speeds. LLA walked with increased frontal plane trunk ROM, and a more in-phase inter segmental coordination at all speeds. These data collectively suggest that trunk neuromuscular control strategies secondary to LLA are driven by functional needs to generate torque proximally to advance the affected limb during gait, though this strategy may have unintended deleterious consequences such as increasing LBP risk over time. PMID- 29625269 TI - Design, synthesis and evaluation of pterostilbene beta-amino alcohol derivatives as multifunctional agents for Alzheimer's disease treatment. AB - A series of pterostilbene beta-amino alcohol derivatives were designed, synthesized and evaluated as multifunctional agents for the treatment of Alzheimer's disease (AD). In vitro assays demonstrated that most of the derivatives were selective acetylacholinesterase (AChE) inhibitors with moderate multifunctional properties. Among them, compound 5f exhibited the best inhibitory activity for EeAChE (IC50 = 24.04 MUM), that was better than pterostilbene under our experimental condition. In addition, compound 5f displayed reasonable antioxidant activity and could confer significant neuroprotective effect against H2O2-induced PC-12 cell injury. Moreover, 5f also showed self-induced Abeta1-42 aggregation inhibitory potency and displayed high BBB permeability in vitro. These multifunctional properties highlight 5f as a promising candidate for further studies directed to the development of novel drugs against AD. PMID- 29625270 TI - Acetylenic fatty acids from Porcelia macrocarpa (Annonaceae) against trypomastigotes of Trypanosoma cruzi: Effect of octadec-9-ynoic acid in plasma membrane electric potential. AB - Porcelia macrocarpa (Warm.) R. E. Fries (Annonaceae) is an endemic plant in Brazil where its tasty pulp has been eaten fresh. The hexane extract from its flowers was subjected to chromatographic procedures to afford four acetylene derivatives identified as octadec-9-ynoic (stearolic acid - 1), (11E)-octadec-11 en-9-ynoic (santalbic acid - 2), 8-hydroxyoctadec-9,11-diynoic (3) and 8 hydroxyoctadec-17-en-9,11-diynoic (isanolic acid - 4) acids by NMR and HRESIMS. Among tested compounds against trypomastigote forms of T. cruzi, octadec-9-ynoic acid (1) displayed higher potential with IC50 = 27.6 uM and a selectivity index (SI) higher than 7. Compounds 2 and 3 showed IC50 of approximately 60 uM while compound 4 was inactive. The lethal action of the compound 1 was investigated using spectrofluorometric techniques to detect ROS content, plasma membrane permeability and plasma membrane potential by flow cytometry. Compound 1 showed no alteration in the production of ROS of treated trypomastigotes and no alteration of the plasma membrane permeability was observed as detected by the fluorescent probe SYTOX-green after 120 min of incubation. However, by using the potential-sensitive fluorescent probe DiSBAC2(3), compound 1 caused depolarization of the plasma membrane potential when compared to untreated parasites. Our results demonstrated the anti-T. cruzi effects of compounds 1-3 isolated from flowers of P. macrocarpa and indicated that the lethal effect of compound 1 in T. cruzi could be associated to the plasma membrane disturbance of the parasite. PMID- 29625271 TI - Tyrosine kinase inhibition effects of novel Pyrazolo[1,5-a]pyrimidines and Pyrido[2,3-d]pyrimidines ligand: Synthesis, biological screening and molecular modeling studies. AB - Tyrosine kinases are one of the most critical mediators in the signaling path way. Late studies have proved the part of tyrosine kinases in the pathophysiology of cancer diseases. This current research paper has focused on investigating the novel Pyrazolo[1,5-a]pyrimidines and Pyrido[2,3-d]pyrimidines as a small molecules that can inhibit tyrosine kinase in cancer cells. NCI protocol was applied to test the antitumor activity of such compounds. Leukemia and renal cancer cell lines proved to be sensitive to some derivatives such as 6b-d, 9a and 11 with GI% values ranging from 30.4 to 41.3%. In addition, compound 11 proved to be the most active against MCF-7 with GI% 62.5. The synthesized compounds were also evaluated for their inhibitory effects against EGFR kinase enzyme. Compound 9b proved to be the most active one among the synthesized series with inhibition % value of 81.72 at 25 nM concentration and IC50 8.4 nM which is very close to the reference drug Sorafenib. In vitro cytotoxicity test was also performed using the MCF-7 breast cell line. Computer modeling using the active site of tyrosine kinase as a template and the most active tyrosine kinase inhibitors were calculated. Docking studies of the synthesized compounds into the active site of EGFR kinase domain showed good agreement with the obtained biological results. PMID- 29625272 TI - Reporting bias in completed epilepsy intervention trials: A cross-sectional analysis. AB - OBJECTIVE: To explore the evidence of reporting bias among completed epilepsy intervention trials (EITs) and compliance of applicable EITs to Food and Drug Administration Amendments Act (FDAAA). METHODS: We included consecutive EITs registered as completed on ClinicalTrials.gov from 2008 to 2015. Descriptive data was collected including study type, study phase, funding source, primary completion date, and result reporting date. Time to result reporting was analyzed using Kaplan-Meier estimates for two time periods (2008-2011 and 2012-2015). PubMed, Web of Science, and Google scholar databases were manually searched for publication details. RESULTS: Overall, 95/126 EITs (75%) reported, while remaining 31/126 (25%) did not report their results. Time to reporting was significantly lower for trials completed during 2012-2015 (16.5 months; 95% CI: 13.60-19.40; p = .002; Cohen's d = 0.68) as compared to the trials completed during 2008-2011 (25.9 months; 95% CI: 21.56-30.22). 72/126 trials were conducted in at least one U.S. center. 56/72 (78%) of the trials met the FDAAA criteria, while only 19/56 (34%) reported within the mandated one-year time frame. CONCLUSION: The lack of reporting of nearly one-quarter of completed epilepsy intervention trials suggests existence of reporting bias. As such, it should be considered an important criterion for determining risk of bias in epilepsy systematic reviews. PMID- 29625273 TI - Botany, ethnomedicines, phytochemistry and pharmacology of Himalayan paeony (Paeonia emodi Royle.). AB - ETHNOPHARMACOLOGICAL RELEVANCE: Himalayan paeony (Paeonia emodi Royle.) is an important species used to treat various diseases. This study aimed to compile the detailed traditional medicinal uses, phytochemistry, pharmacology and toxicological investigations on P. emodi. This study also highlights taxonomic validity, quality of experimental designs and shortcomings in previously reported information on Himalayan paeony. METHODS: The data was extracted from unpublished theses (Pakistan, China, India and Nepal), and different published research articles confined to pharmacology, phytochemistry and antimicrobial activities using different databases through specific keywords. The relevant information regarding medicinal uses, taxonomic/common names, part used, collection and identification source, authentication, voucher specimen number, plant extracts and their characterization, isolation and identification of phytochemicals, methods of study in silico, in vivo or in vitro, model organism used, dose and duration, minimal active concentration, zone of inhibition (antimicrobial study), bioactive compound(s), mechanism of action on single or multiple targets, and toxicological information. RESULTS: P. emodi is reported for diverse medicinal uses with pharmacological properties like antioxidant, nephroprotective, lipoxygenase inhibitory, cognition and oxidative stress release, cytotoxic, anti inflammatory, antiepileptic, anticonvulsant, haemaglutination, alpha-chymotrypsin inhibitory, hepatoprotective, hepatic chromes and pharmacokinetics of carbamazepine expression, beta-glucuronidase inhibitory, spasmolytic and spasmogenic, and airway relaxant. Data confined to its taxonomic validity, shows 10% studies with correct taxonomic name while 90% studies with incorrect taxonomic, pharmacopeial and common names. The literature reviewed, shows lack of collection source (11 reports), without proper source of identification (15 reports), 33 studies without voucher specimen number, 26 reports lack information on authentic herbarium submission and most of the studies (90%) without validation of taxonomic names using recognized databases. In reported methods, 67% studies without characterization of extracts, 25% lack proper dose, 40% without duration and 31% reports lack information on proper controls. Similarly, only 18% studies reports active compound(s) responsible for pharmacological activities, 14% studies show minimal active concentration, only 2.5% studies report mechanism of action on target while none of the reports mentioned in silico approach. CONCLUSION: P. emodi is endemic to Himalayan region (Pakistan, China, India and Nepal) with diverse traditional therapeutic uses. Majority of reviewed studies showed confusion in its taxonomic validity, incomplete methodologies and ambiguous findings. Keeping in view the immense uses of P. emodi in various traditional medicinal systems, holistic pharmacological approaches in combination with reverse pharmacology, system biology, and "omics" technologies are recommended to improve the quality of research which leads to natural drug discovery development at global perspectives. PMID- 29625274 TI - Assessment of genotoxic activity of oleoresins and leaves extracts of six Copaifera species for prediction of potential human risks. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Copaifera species are used in folk medicine for a wide variety of pharmacological properties. This paper reports the cytotoxic and genotoxic analyses of oleoresins and leaves extracts of Copaifera species: C. duckei, C. multijuga, C. paupera, C. pubiflora, C. reticulata and C. trapezifolia. MATERIALS AND METHODS: In vitro assays were performed using Chinese hamster lung fibroblasts (V79 cells). The clonogenic efficiency and cytokinesis block micronucleus assays were employed for the cytotoxicity and genotoxicity assessment, respectively. The mouse bone marrow micronucleus test was used for in vivo studies. RESULTS: The cytotoxicity results using the clonogenic efficiency assay showed IC50 values ranging from 9.8 to 99.2 ug/mL for oleoresins and 66.4 721.5 for leaves extracts. However, no cytotoxic effect was observed in the in vivo studies. Additionally, the treatments with oleoresins and leaves extracts did not significantly increase the frequency of micronuclei in both in vitro and in vivo mammalian cells. The UPLC-MS/MS and CG/MS analyses of Copaifera oleoresins allowed the identification of 10 acid diterpenes and 11 major volatile sesquiterpenes. Leaves are rich in phenolic compounds including two flavonoid heterosides and 16 galloylquinic acid derivatives. CONCLUSIONS: The oleoresins and leaves extracts of studied Copaifera species were not cytotoxic in vivo, as well as not genotoxic in both in vitro and vivo assays, under the experimental conditions used. Therefore, the obtained results should be sufficient to demonstrate the absence of significant genotoxic risk of these Copaifera products for human use in the evaluated concentrations range. PMID- 29625276 TI - Biomarkers to noninvasively determine the atrial fibrillation progression phenotype: A bridge to individualized ablative therapy? PMID- 29625275 TI - Mutation analysis of 19 commonly used short tandem repeat loci in a Guangdong Han population. AB - Short tandem repeats (STRs) are the most widely used genetic markers in current forensic practice. However, STR mutations have troubled paternity test all the time. To ensure the accuracy in parentage testing, it is important to obtain population mutation data and identify factors that affect STR mutation rates. In the present study, we performed a comprehensive analysis on 322 mutation events in 19 autosomal STR loci from 12,752 meiotic events in 9,626 parentage test cases. The average mutation rate for the 19 STR loci was estimated at 1.3290/00 per meiosis. Most mutations were single-step and occurred in the male germline. Further, the mutation rates increased with the paternal age at child birth, but not the maternal age. Multidimensional scaling analysis showed differences in the profiles of the mutation rates of the 13 CODIS STR loci among several different worldwide populations. Our findings also showed that locus-specific mutation rates were correlated with heterozygosity, and longer alleles have higher mutation rates than shorter alleles do. The data from our study may provide useful information for parentage testing, kinship analysis, and population genetics. PMID- 29625277 TI - Loss of p21-activated kinase 1 (Pak1) promotes atrial arrhythmic activity. AB - BACKGROUND: Atrial fibrillation (AF) is initiated through arrhythmic atrial excitation from outside the sinus node or remodeling of atrial tissue that allows reentry of excitation. Angiotensin II (AngII) has been implicated in the initiation and maintenance of AF through changes in Ca2+ handling and production of reactive oxygen species (ROS). OBJECTIVE: We aimed to determine the role of p21-activated kinase 1 (Pak1), a downstream target in the AngII signaling cascade, in atrial electrophysiology and arrhythmia. METHODS: Wild-type and Pak1 /- mice were used to determine atrial function in vivo on the organ and cellular level by quantification of electrophysiological and Ca2+ handling properties. RESULTS: We demonstrate that reduced Pak1 activity increases the inducibility of atrial arrhythmia in vivo and in vitro. On the cellular level, Pak1-/- atrial myocytes (AMs) exhibit increased basal and AngII (1 MUM)-induced ROS production, sensitivity to the NADPH oxidase-2 (NOX2) inhibitors gp91ds-tat and apocynin (1 MUM), and enhanced membrane translocation of Ras-related C3 substrate 1 (Rac1) that is part of the multimolecular NOX2 complex. Upon stimulation with AngII, Pak1-/- AMs exhibit an exaggerated increase in the intracellular Calcium concentration ([Ca2+]i) and arrhythmic events that were sensitive to sodium calcium exchanger (NCX) inhibitors (KB-R7943 and SEA0400; 1 MUM) and suppressed in AMs from NOX2-deficient (gp91phox-/-) mice. Pak1 stimulation (FTY720; 200 nM) in wild-type AMs and AMs from a canine model of ventricular tachypacing-induced AF prevented AngII-induced arrhythmic Ca2+ overload by attenuating NCX activity in a NOX2-dependent manner. CONCLUSION: The experimental results support that Pak1 stimulation can attenuate NCX-dependent Ca2+ overload and prevent triggered arrhythmic activity by suppressing NOX2-dependent ROS production. PMID- 29625278 TI - Right atrial dual-loop reentrant tachycardia after cardiac surgery: Prevalence, electrophysiological characteristics, and ablation outcomes. AB - BACKGROUND: Right atrial (RA) dual-loop reentrant tachycardia has been described in patients who have undergone open heart surgery. However, the prevalence, electrophysiological (EP) substrate, and ablation outcomes have been poorly characterized. OBJECTIVE: The purpose of this study was to investigate the prevalence, EP substrate, and ablation outcomes for RA dual-loop reentrant tachycardia after cardiac surgery. METHODS: We identified all patients with atrial tachycardia (AT) after cardiac surgery. We compared EP findings and outcomes of those with RA dual-loop reentrant tachycardia to a control group of patients with RA macroreentrant arrhythmias in the setting of linear RA free-wall (FW) scar. RESULTS: Of the 127 patients with 152 postsurgical ATs, 28 of the ATs (18.4%) had RA dual-loop reentry and 24 of 28 (85.7%) had tricuspid annular reentry combined with FW incisional reentry. An incision length >51.5 mm along the FW predicted the substrate for a second loop. In 22 of 23 patients (95.7%) with initial ablation in the cavotricuspid isthmus, a change in the interval between Halod to CSp could be recorded, and 15 of 23 patients (65.2%) had coronary sinus activation pattern change. Complete success was achieved in 25 of 28 patients (89.3%) in the dual-loop reentry group and in 64 of 69 patients (92.8%) in the control group. After mean follow-up of 33.9 +/- 24.2 months, 24 of 28 patients (85.7%) and 60 of 69 patients (86.95%) were free of arrhythmias after the initial procedure in the 2 groups, respectively. CONCLUSION: The prevalence of RA dual-loop reentry is 18.4% of ATs with prior atriotomy scar. A long incision should alert physicians to the possibility of a second loop at the FW. Halo and coronary sinus activation patterns provide important clues to circuit transformation. PMID- 29625279 TI - Rhythm management in myotonic dystrophy: Progress has been made, but unsettled issues remain. PMID- 29625280 TI - Long QT syndrome type 5-Lite: Defining the clinical phenotype associated with the potentially proarrhythmic p.Asp85Asn-KCNE1 common genetic variant. AB - BACKGROUND: Long QT syndrome (LQTS) genetic test reports commonly exclude potentially proarrhythmic common variants such as p.Asp85Asn-KCNE1. OBJECTIVE: The purpose of this study was to determine whether a discernible phenotype is associated with p.Asp85Asn-KCNE1 and whether relatively common KCNE1 variants underlie transient QT prolongation pedigrees with negative commercial LQTS genetic tests. METHODS: Retrospective review was used to compare demographics, symptomatology, and QT parameters of individuals with p.Asp85Asn-KCNE1 in the absence of other rare/ultra-rare variants in LQTS-susceptibility genes and those who underwent comprehensive LQTS genetic testing. RESULTS: Compared to the Genome Aggregation Database, p.Asp85Asn-KCNE1 was more prevalent in individuals undergoing LQTS genetic testing (33/1248 [2.6%] vs 1552/126,652 [1.2%]; P = .0001). In 19 of 33 patients (58%), only p.Asp85Asn-KCNE1 was observed. These patients were predominantly female (90% vs 62%; P = .01) and were less likely to experience syncope (0% vs 34%; P = .0007), receive beta-blockers (53% vs 85%; P = .001), or require an implantable cardioverter-defibrillator (5.3% vs 33%; P = .01). However, they exhibited a similar degree of QT prolongation (QTc 460 ms vs 467 ms; P = NS). Whole exome sequencing of 2 commercially genotype-negative pedigrees revealed that p.Asp85Asn-KCNE1 and p.Arg36His-KCNE1 traced with a transient QT prolongation phenotype. Functional characterization of p.Arg36His KCNE1 demonstrated loss of function, with a 47% reduction in peak IKs current density in the heterozygous state. CONCLUSION: We provide further evidence that relatively common variants in KCNE1 may result in a mild QT phenotype designated as "LQT5-Lite" to distinguish such potentially proarrhythmic common variants (ie, functional risk alleles) from rare pathogenic variants that truly confer monogenic disease susceptibility, albeit with incomplete penetrance. PMID- 29625281 TI - Full-scale production of VFAs from sewage sludge by anaerobic alkaline fermentation to improve biological nutrients removal in domestic wastewater. AB - A full-scale project of thermal-alkaline pretreatment and alkaline fermentation of sewage sludge was built to produce volatile fatty acids (VFAs) which was then used as external carbon source for improving biological nitrogen and phosphorus removals (BNPR) in wastewater plant. Results showed this project had efficient and stable performances in VFA production, sludge reduce and BNPR. Hydrolysis rate in pretreatment, VFAs yield in fermentation and total VS reduction reached 68.7%, 261.32 mg COD/g VSS and 54.19%, respectively. Moreover, fermentation liquid with VFA presented similar efficiency as acetic acid in enhancing BNPR, obtaining removal efficiencies of nitrogen and phosphorus up to 72.39% and 89.65%, respectively. Finally, the project also presented greater economic advantage than traditional processes, and the net profits for VFAs and biogas productions are 9.12 and 3.71 USD/m3 sludge, respectively. Long-term operation indicated that anaerobic alkaline fermentation for VFAs production is technically and economically feasible for sludge carbon recovery. PMID- 29625282 TI - Effect of hydrothermal carbonization on storage process of woody pellets: Pellets' properties and aldehydes/ketones emission. AB - Effect of hydrothermal carbonization (HTC) on the hydrochar pelletization and the aldehydes/ketones emission from pellets during storage was investigated. Pellets made from the hydrochar were stored in sealed apparatuses for sampling. The energy consumption during pelletization and the pellets' properties before/after storage, including dimension, density, moisture content, hardness, aldehyde/ketones emission amount/rate and unsaturated fatty acid amount, were analyzed. Compared with untreated-sawdust-pellets, the hydrochar-pellets required more energy consumption for pelletization, and achieved the improved qualities, resulting in the higher stability degree during storage. The species and amount of unsaturated fatty acids in the hydrochar-pellets were higher than those in the untreated-sawdust-pellets. The unsaturated fatty acids content in the hydrochar pellets was decreased with increasing HTC temperature. Higher aldehydes/ketones emission amount and rates with a longer emission period were found for the hydrochar-pellets, associated with variations of structure and unsaturated fatty acid composition in pellets. PMID- 29625283 TI - Screening of chemical modulators for lipid accumulation in Schizochytrium sp. S31. AB - Schizochytrium sp. is a promising candidate for docosahexaenoic acid (DHA) production due to its high content of lipid and DHA proportions. To further enhance the lipid accumulation, seven chemical modulators were screened to evaluate their roles on lipid accumulation. Notably, among the seven tested chemical modulators, the addition of naphthoxyacetic acid (BNOA) or jasmonic acid (JA) was able to increase the lipid accumulation of Schizochytrium sp. S31. In addition, the effects of BNOA and JA were demonstrated dose-dependent and time dependent, achieving a highest increase in lipid content by 11.16% and 12.71% when 2.0 mg/L of BNOA or 20 mg/L of JA was added into culture at 48 h after inoculation, respectively. In addition, the combination of 2 mg/L BNOA and 20 mg/L JA further increased lipid accumulation up to 16.79%. These results provided valuable strategy on promoting the lipid accumulation and DHA production by chemical modulators in Schizochytrium sp. S31. PMID- 29625284 TI - Electricity generation and removal performance of a microbial fuel cell using sulfonated poly (ether ether ketone) as proton exchange membrane to treat phenol/acetone wastewater. AB - The microbial fuel cell (MFC) has emerged as a promising technology for wastewater treatment and energy recovery, but the expensive cost of proton exchange membranes (PEMs) is a problem that need to be solved. In this study, a two-chamber MFC based on our self-made PEM sulfonated poly (ether ether ketone) membrane was set up to treat phenol/acetone wastewater and synchronously generate power. The maximum output voltage was 240-250 mV. Using phenol and acetone as substrates, the power generation time in an operation cycle was 289 h. The MFC exhibited good removal performance, with no phenol or acetone detected, respectively, when the phenol concentration was lower than 50 mg/L and the acetone concentration was lower than 100 mg/L. This study provides a cheap and eco-friendly way to treat phenol/acetone wastewater and generate useful energy by MFC technology. PMID- 29625285 TI - Enhancing the Fock reactivity of dissolving pulp by the combined prerefining and poly dimethyl diallyl ammonium chloride-assisted cellulase treatment. AB - Dissolving pulp is an important source of cellulose raw material, and its key quality parameter is the Fock reactivity for viscose rayon application. Cellulase treatment is an effective method for improving the Fock reactivity of kraft-based dissolving pulp. In this study, a novel process concept of improving the cellulase treatment for this purpose was developed, and it consists of mechanical pre-refining and PDADMAC-assisted cellulase treatment. The hypothesis is based on: 1) opening up the fiber structures to improve the cellulase accessibility by pulp prerefining, 2) the addition of cationic poly DADMAC to the subsequent cellulase stage enhances the cellulase adsorption onto anionic fibers due to favorable electrostatic interactions. The results showed that the Fock reactivity of the resultant pulp from the combined treatment is much higher than that of the control, yet, achieved at a much lower cellulase dosage. PMID- 29625286 TI - Complete genome sequence provides insights into the biodrying-related microbial function of Bacillus thermoamylovorans isolated from sewage sludge biodrying material. AB - To enable the development of microbial agents and identify suitable candidate used for biodrying, the existence and function of Bacillus thermoamylovorans during sewage sludge biodrying merits investigation. This study isolated a strain of B. thermoamylovorans during sludge biodrying, submitted it for complete genome sequencing and analyzed its potential microbial functions. After biodrying, the moisture content of the biodrying material decreased from 66.33% to 50.18%, and B. thermoamylovorans was the ecologically dominant Bacillus, with the primary annotations associated with amino acid transport and metabolism (9.53%) and carbohydrate transport and metabolism (8.14%). It contains 96 carbohydrate-active enzyme-encoding gene counts, mainly distributed in glycoside hydrolases (33.3%) and glycosyl transferases (27.1%). The virulence factors are mainly associated with biosynthesis of capsule and polysaccharide capsule. This work indicates that among the biodrying microorganisms, B. thermoamylovorans has good potential for degrading recalcitrant and readily degradable components, thus being a potential microbial agent used to improve biodrying. PMID- 29625287 TI - Kinetics study of levulinic acid production from corncobs by tin tetrachloride as catalyst. AB - Levulinic acid (LA) is an ideal platform chemical that can be produced through acid-catalyzed dehydration and hydrolysis of hexose sugars obtained from lignocellulosic materials. In this study, SnCl4 was identified as an efficient catalyst for LA production and the reaction kinetics was investigated in a single water phase under different reaction conditions. The Box-Behnken design response surface methodology (RSM) was applied to determine the optimized reaction conditions and three individual variables including reaction temperature, duration, and catalyst concentration were evaluated. An appealing LA yield of 76.0% was achieved at 193 degrees C and 17 min with 82 mM SnCl4 catalyst. A kinetics model was developed to predict the yields of glucose, HMF, and LA, which are tally with the experimental results. The analysis of the related kinetic parameters and the results of the RSM experiment helped to provide insights into the interplay between various reaction steps with SnCl4 as catalysts. PMID- 29625288 TI - Addition of granular activated carbon and trace elements to favor volatile fatty acid consumption during anaerobic digestion of food waste. AB - The effect of supplementing granular activated carbon and trace elements on the anaerobic digestion performance of consecutive batch reactors treating food waste was investigated. The results from the first batch suggest that addition of activated carbon favored biomass acclimation, improving acetic acid consumption and enhancing methane production. Adding trace elements allowed a faster consumption of propionic acid. A second batch proved that a synergy existed when activated carbon and trace elements were supplemented simultaneously. The degradation kinetics of propionate oxidation were particularly improved, reducing significantly the batch duration and improving the average methane productivities. Addition of activated carbon favored the growth of archaea and syntrophic bacteria, suggesting that interactions between these microorganisms were enhanced. Interestingly, microbial analyses showed that hydrogenotrophic methanogens were predominant. This study shows for the first time that addition of granular activated carbon and trace elements may be a feasible solution to stabilize food waste anaerobic digestion. PMID- 29625289 TI - Degradative solvent extraction of biomass using petroleum based solvents. AB - The aim of this study was to examine the possibility to use two petroleum based solvents, kerosene and a distillate rich in benzene (A150), as practical solvents for the degradative solvent extraction at 350 degrees C in reference to 1-MN. It was found that the thermal degradation behavior of two biomass samples, a rice straw and Leucaena, in the three solvents was rather similar and that only the distribution of Soluble, Deposit, and Residue was affected by the difference of solubility of the solvents. Preparation of solvent treated biomass (STB) using the three solvents gave the yields close to the sum of the yields of Soluble, Deposit, and Residue. It was judged that A150 may be used to preparing Soluble and that Kerosene can well be used to prepare STB. PMID- 29625290 TI - Correlation of microbial community structure with pollutants removal, sludge reduction and sludge characteristics in micro-aerobic side-stream reactor coupled membrane bioreactors under different hydraulic retention times. AB - A micro-aerobic side-stream reactor (MSSR) was inserted in returned sludge line of a membrane bioreactor (MBR) for sludge reduction. Three MSSR coupled MBRs (M MBRs) and an anoxic/oxic MBR (AO-MBR) were operated in parallel to investigate effects of micro-aerobic condition and hydraulic retention time (HRT) of MSSR (HRTM) on process performance. M-MBRs and AO-MBR were equally effective in COD and NH4-N removal. Rising HRTM from 3.3 to 6.7 h increased sludge reduction from 10.8% to 47.5%, and promoted dissolved organic matters release and utilization by enriching hydrolytic, fermentative and predatory bacteria. M-MBR at HRTM of 3.3 h obtained the highest nitrogen removal, and enriched denitrifiers (Thauera and Hyphomicrobium) in the MSSR. The highest relative abundance of polyphosphate accumulating organisms was observed in M-MBR at HRTM of 5.0 h, which achieved the highest phosphorus removal. Prolonging HRTM to 6.7 h improved sludge dewaterability by enriching floc-formation bacteria (Nannocystis) and inhibiting filamentous bacteria (Candidatus_Alysiosphaera). PMID- 29625291 TI - Effects of temperature on anammox performance and community structure. AB - A lab-scale anammox up-flow anaerobic sludge blanket (UASB) reactor was run to investigate the influence of temperature on anammox performance and community structure. The anammox system had a higher substrate tolerance at 13 degrees C than at 18 degrees C. The adverse effects caused by the use of a lower temperature (8 degrees C) could be restored. The nitrogen removal rate (NRR) decreased with decreasing in situ specific anammox activity (SAA). Interestingly, the ex situ SAA acclimated at 23 degrees C, when exposed to ex situ temperatures of 33 and 28 degrees C, was higher than for those acclimated at 33 and 28 degrees C. No shift was observed in the optimum temperature for ex situ SAA in the whole lowering process of anammox UASB. More extracellular polymeric substances were produced in response to cooler conditions (18 degrees C and 13 degrees C). Ca. Kuenenia became much more abundant (55.18% of the microbial community) and had a competitive advantage over other anammox bacteria (AnAOB) at 13 degrees C. PMID- 29625292 TI - Magnetic bionanoparticles of Penicillium sp. yz11-22N2 doped with Fe3O4 and encapsulated within PVA-SA gel beads for atrazine removal. AB - A novel magnetic bionanomaterial, Penicillium sp. yz11-22N2 doped with nano Fe3O4 entrapped in polyvinyl alcohol-sodium alginate gel beads (PFEPS), was successfully synthesized. The factors including nutrient substance, temperature, pH, initial concentrations of atrazine and rotational speeds were presented and discussed in detail. Results showed that the highest removal efficiency of atrazine by PFEPS was 91.2% at 8.00 mg/L atrazine. The maximum removal capacity for atrazine was 7.94 mg/g. Meanwhile, it has been found that most of atrazine were removed by metabolism and degradation of Penicillium sp. yz11-22N2, which could use atrazine as the sole source of either carbon or nitrogen. Degradation kinetics of atrazine conformed to first-order kinetics model. The intermediates indicated that the possible pathway for atrazine degradation by PFEPS mainly included hydrolysis dechlorination, dealkylation, side-chain oxidation and ring opening. PMID- 29625293 TI - Modelling of an anaerobic plug-flow reactor. Process analysis and evaluation approaches with non-ideal mixing considerations. AB - This study shows the implementation of the Anaerobic Digestion Model (ADM1) in an anaerobic plug-flow reactor (PFR) with two approaches based on the use of consecutive continuous stirred tank reactors (CSTR) connected in serie for considering non-ideal mixing. The two-region (TR) model splits each CSTR into two regions, while the particulate retention (PR) model adds a retention parameter. The models were calibrated and validated based on experimental data from a bench scale reactor treating cow manure. The PFR conventional model slightly outperformed the non-ideal mixing approaches. However, the PR model showed an increase in biomass retention time treating high solid content substrate. Biogas production was not sensitive to variations of the mixing parameters. The liquid fraction content was better represented by the PR model than the PFR and TR models. The study shows how reactor modelling is useful for monitoring and supervising biogas plants. PMID- 29625294 TI - Overexpressing human GPR109A leads to pronounced reduction in plasma triglyceride levels in BAC transgenic rats. AB - BACKGROUND AND AIMS: Nicotinic acid administration causes plasma non-esterified fatty acid (NEFA) reduction and plasma lipid changes, including reduced triglyceride levels. GPR109A, which is expressed mainly in adipose tissue and has anti-lipolytic activity, was reported to be a molecular target for nicotinic acid. However, recent clinical reports have shown that most GPR109A agonists failed to induce clinically meaningful plasma lipid changes. In addition, a recent study has shown that the TG lowering effect of nicotinic acid was not diminished in Gpr109a deficient mice, which is different from the original finding. Therefore, whether GPR109A activation can lead to plasma lipid changes is unclear. METHODS: We created a bacterial artificial chromosome (BAC) transgenic rat expressing human GPR109A (Tg rat) and examined the in vivo role of GPR109A. RESULTS: Under fasted conditions, plasma NEFA and triglyceride levels in Tg rats were lower than those in non-Tg rats. In this condition, a positive correlation between plasma NEFA and triglyceride or beta-hydroxybutyrate levels was observed. Furthermore, insulin levels in Tg rats were lower than those in non Tg rats only when a reduction in NEFAs was observed, which is a phenomenon also reported for nicotinic acid. Interestingly, body weight gain in Tg rats was significantly lower than in non-Tg rats. CONCLUSIONS: These results suggest that GPR109A signaling leads to a reduction in triglyceride and insulin levels, and that the triglyceride-lowering effect of nicotinic acid is at least partially mediated by GPR109A signaling. PMID- 29625295 TI - Decreased iron stores are associated with cardiovascular disease in patients with type 2 diabetes both cross-sectionally and longitudinally. AB - BACKGROUND AND AIMS: The possible contribution of iron to cardiovascular complications of type 2 diabetes (T2D) has been scarcely investigated. We aimed to study whether serum ferritin is linked to prevalent/incident cardiovascular disease (CVD) in T2D. METHODS: The prevalence of coronary heart disease (CHD), cerebrovascular disease (CEVD) and CVD was evaluated in the SIDIAP study (n = 38,617) and prevalence and 7-year incidence were analysed in the Edinburgh Type 2 Diabetes Study (ET2DS) (n = 821). Logistic and Cox regressions were used to describe associations between serum ferritin and CVD adjusting for confounding variables. RESULTS: Increase of 1 SD unit in log-ferritin was associated with lower CVD prevalence in fully-adjusted models (ET2DS odds ratio (OR) 95% confidence interval (CI): 0.81 (0.68-0.96), p = 0.018; SIDIAP study: 0.91 (0.88 0.94), p < 0.001). In ET2DS, ferritin in the highest (vs. the lowest) quintile was associated with lower incidence of CVD (fully adjusted HR 95% CI: 0.46 (0.26 0.83), p = 0.010). This association persisted after removing subjects with CVD at baseline (n = 536) (HR 95% CI: 0.34 (0.14-0.81), p = 0.016). CONCLUSIONS: Low iron status was associated with CVD risk in T2D. This pattern was consistent in populations at different cardiovascular risk. Low iron status seems to be harmful for cardiovascular health in T2D and it may be a target for intervention. PMID- 29625297 TI - Rationally designed core-shell and yolk-shell magnetic titanate nanosheets for efficient U(VI) adsorption performance. AB - The hierarchical core-shell and yolk-shell magnetic titanate nanosheets (Fe3O4@TNS) were successfully synthesized by employing magnetic nanoparticles (NPs) as interior core and intercrossed titanate nanostructures (NSs) as exterior shell. The as-prepared magnetic Fe3O4@TNS nanosheets had high specific areas (114.9 m2 g-1 for core-shell Fe3O4@TNS and 130.1 m2 g-1 for yolk-shell Fe3O4@TNS). Taking advantage of the unique multilayer structure, the nanosheets were suitable for eliminating U(VI) from polluted water environment. The sorption was strongly affected by pH values and weakly influenced by ionic strength, suggesting that the sorption of U(VI) on Fe3O4@TNS was mainly dominated by ion exchange and outer-sphere surface complexion. The maximum sorption capacities (Qmax) calculated from the Langmuir model were 68.59, 121.36 and 264.55 mg g-1 for core-shell Fe3O4@TNS and 82.85, 173.01 and 283.29 mg g-1 for yolk-shell Fe3O4@TNS, at 298 K, 313 K and 328 K, respectively. Thermodynamic parameters (DeltaH0, DeltaS0 and DeltaG0) demonstrated that the sorption process was endothermic and spontaneous. Based on X-ray photoelectron spectroscopy (XPS) analyses, the sorption mechanism was confirmed to be cation-exchange between interlayered Na+ and UO22+. The yolk-shell Fe3O4@TNS had more extraordinary sorption efficiency than core-shell Fe3O4@TNS since the yolk-shell structure provided internal void space inside the titanate shell to accommodate more exchangeable active sites. The flexible recollection and high efficient sorption capacity made core-shell and yolk-shell Fe3O4@TNS nanosheets promising materials to eliminate U(VI) or other actinides in wastewater cleanup applications. PMID- 29625298 TI - eDNA-based bioassessment of coastal sediments impacted by an oil spill. AB - Oil spills offshore can cause long-term ecological effects on coastal marine ecosystems. Despite their important ecological roles in the cycling of energy and nutrients in food webs, effects on bacteria, protists or arthropods are often neglected. Environmental DNA (eDNA) metabarcoding was applied to characterize changes in the structure of micro- and macro-biota communities of surface sediments over a 7-year period since the occurrence of Hebei Spirit oil spill on December 7, 2007. Alterations in diversities and structures of micro- and macro biota were observed in the contaminated area where concentrations of polycyclic aromatic hydrocarbons were greater. Successions of bacterial, protists and metazoan communities revealed long-term ecological effects of residual oil. Residual oil dominated the largest cluster of the community-environment association network. Presence of bacterial families (Aerococcaceae and Carnobacteriaceae) and the protozoan family (Platyophryidae) might have conferred sensitivity of communities to oil pollution. Hydrocarbon-degrading bacterial families (Anaerolinaceae, Desulfobacteraceae, Helicobacteraceae and Piscirickettsiaceae) and algal family (Araphid pennate) were resistant to adverse effects of spilt oil. The protistan family (Subulatomonas) and arthropod families (Folsomia, Sarcophagidae Opomyzoidea, and Anomura) appeared to be positively associated with residual oil pollution. eDNA metabarcoding can provide a powerful tool for assessing effects of anthropogenic pollution, such as oil spills on sediment communities and its long-term trends in coastal marine environments. PMID- 29625296 TI - JH6 downstream intronic sequence is dispensable for RNA polymerase II accumulation and somatic hypermutation of the variable gene in Ramos cells. AB - Activation-induced deaminase (AID) introduces nucleotide substitutions within the variable region of immunoglobulin genes to promote antibody diversity. This activity, which is limited to 1.5 kb downstream of the variable gene promoter, mutates both the coding exon and downstream intronic sequences. We recently reported that RNA polymerase II accumulates in these regions during transcription in mice. This build-up directly correlates with the area that is accessible to AID, and manipulation of RNA polymerase II levels alters the mutation frequency. To address whether the intronic DNA sequence by itself can regulate RNA polymerase II accumulation and promote mutagenesis, we deleted 613 bp of DNA downstream of the JH6 intron in the human Ramos B cell line. The loss of this sequence did not alter polymerase abundance or mutagenesis in the variable gene, suggesting that most of the intronic sequence is dispensable for somatic hypermutation. PMID- 29625299 TI - Spatiotemporal variability of polybrominated diphenyl ether concentration in atmospheric fine particles in Shenzhen, China. AB - Polybrominated diphenyl ethers (PBDEs) are widely used as flame retardants for various products and have become ubiquitous pollutants in environmental media. However, little is known about PBDE levels in Shenzhen, a manufacturing center of electronic products. This study aimed to investigate spatiotemporal variability of PBDE concentration in atmospheric fine particles (PM2.5) and to estimate the daily inhalation exposure doses for local residents in Shenzhen, China. A total of 36 samples were collected and 8 PBDE compounds (BDE-28, 47, 99, 100, 153, 154, 183 and 209) were analyzed by isotope dilution high-resolution gas chromatograph/high-resolution mass spectrometer (HRGC/HRMS). Mean concentrations of Sigma8PBDEs and BDE-209 in PM2.5 in Shenzhen were 33.47 pg/m3 and 24.75 pg/m3, respectively, which were lower than those for other reported cities from China. The mean concentration of Sigma8PBDEs was higher in the winter + spring than that in summer + autumn, and both concentrations of BDE-28 and BDE-47 in PM2.5 were significantly higher in winter + spring than those in summer + autumn. Among the 8 congeners, BDE-209 was predominant, accounting for 73.9% of the Sigma8PBDEs concentrations. Traffic area, industrial area, residential area and discharge of electronic industries had significant positive influences on PBDE concentrations in PM2.5. Both vegetation area and water area were significantly negatively correlated with PBDE levels in PM2.5. Significantly negative correlation was also found between PBDE concentrations in PM2.5 and the relative humidity. The ranking of estimated inhalation exposure doses of PBDEs via PM2.5 inhalation were toddlers (1.74 pg/kg b.w./day) > children (1.33 pg/kg b.w./day) > adults (1.26 pg/kg b.w./day) > teenagers (0.64 pg/kg b.w./day), and toddlers had a highest risk to expose to PBDEs by PM2.5. To our knowledge, the present study is the first to reveal the spatiotemporal variability of PBDEs in PM2.5 of Shenzhen, China. PMID- 29625300 TI - Effects of elevated ozone concentration and nitrogen addition on ammonia stomatal compensation point in a poplar clone. AB - The stomatal compensation point of ammonia (chis) is a key factor controlling plant-atmosphere NH3 exchange, which is dependent on the nitrogen (N) supply and varies among plant species. However, knowledge gaps remain concerning the effects of elevated atmospheric N deposition and ozone (O3) on chis for forest species, resulting in large uncertainties in the parameterizations of NH3 incorporated into atmospheric chemistry and transport models (CTMs). Here, we present leaf scale measurements of chis for hybrid poplar clone '546' (Populusdeltoides cv. 55/56 x P. deltoides cv. Imperial) growing in two N treatments (N0, no N added; N50, 50 kg N ha-1 yr-1 urea fertilizer added) and two O3 treatments (CF, charcoal filtered air; E-O3, non-filtered air plus 40 ppb) for 105 days. Our results showed that chis was significantly reduced by E-O3 (41%) and elevated N (19%). The interaction of N and O3 was significant, and N can mitigate the negative effects of O3 on chis. Elevated O3 significantly reduced the light-saturated photosynthetic rate (Asat) and chlorophyll (Chl) content and significantly increased intercellular CO2 concentrations (Ci), but had no significant effect on stomatal conductance (gs). By contrast, elevated N did not significantly affect all measured photosynthetic parameters. Overall, chis was significantly and positively correlated with Asat, gs and Chl, whereas a significant and negative relationship was observed between chis and Ci. Our results suggest that O3 induced changes in Asat, Ci and Chl may affect chis. Our findings provide a scientific basis for optimizing parameterizations of chis in CTMs in response to environmental change factors (i.e., elevated N deposition and/or O3) in the future. PMID- 29625301 TI - Phthalates contamination in China: Status, trends and human exposure-with an emphasis on oral intake. AB - Despite the extensive production and use of phthalates in Asian countries, especially China, limited information is available about the current situation of human exposure in this region, and thus identification of further research needs is warranted. This review summarized the current trends of phthalates related to industrial production and human exposure by conducting a comprehensive assessment of phthalates contaminations in air, indoor dust, personal care products (PCPs), foodstuff and internal exposure in China, with comparisons with other countries. The concentrations of phthalates in indoor dust and PCPs in China were moderate, while concentrations in foods and air were among the highest worldwide. Dietary intake of phthalates varied with location, with hotspots in the southern and eastern coastal regions of China which correlated with the extensive industrial production recorded in these regions. This review firstly revealed the significantly differentiated food-type contribution profiles for phthalates in China and in other countries, which were affected by dietary habits and food contamination. The internal exposure for the Chinese population was found to be moderate, however there is a paucity of data available. Knowledge gaps identified concerning phthalates in China include trends in phthalates exposure, sources (e.g. PCPs, pharmaceuticals and medical treatment), and internal exposure derived from biomonitoring, warranting phthalates a research priority. PMID- 29625302 TI - Estimating the age of Lucilia illustris during the intrapuparial period using two approaches: Morphological changes and differential gene expression. AB - Lucilia illustris (Meigen, 1826) (Diptera: Calliphoridae) is a cosmopolitan species of fly that has forensic and medical significance. However, there is no relevant study regarding the determination of the age of this species during the intrapuparial period. In this study, we investigated the changes in both morphology and differential gene expression during intrapuparial development, with an aim to estimate the age of L. illustris during the intrapuparial stage. The overall intrapuparial morphological changes of L. illustris were divided into 12 substages. Structures such as the compound eyes, mouthparts, antennae, thorax, legs, wings, and abdomen, each capable of indicating age during the intrapuparial stage, were observed in detail, and the developmental progression of each of these structures was divided into six to eight stages. We recorded the time range over which each substage or structure appeared. The differential expression of the three genes 15_2, actin, and tbp previously identified for predicting the timing of intrapuparial development was measured during L. illustris metamorphosis. The expression of these genes was quantified by real-time PCR, and the results revealed that these genes can be used to estimate the age of L. illustris during the intrapuparial period, as they exhibit regular changes and temperature dependence. This study provides an important basis for estimating the minimum postmortem interval (PMImin) in forensic entomology according to changes in intrapuparial development and differential gene expression. Furthermore, combination of the two approaches can generate a more precise PMImin than either approach alone. PMID- 29625303 TI - Ocular chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation in an Italian referral center. AB - PURPOSE: This study aimed to assess the prevalence and clinical manifestations of ocular graft-versus-host disease (GVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). METHODS: 269 patients who received allo-HSCT for hematologic malignancies were evaluated between December 2013 and April 2017 in this prospective observational study. Subjects underwent ophthalmologic examination at 6, 12 and 24 months after allo-HSCT. We evaluated the ophthalmologic and hematological data using the NIH consensus criteria definition and the International Chronic Ocular GVHD Consensus Group scoring systems. RESULTS: According to NIH consensus criteria definition, ocular GVHD developed in 46.1%, 51.9% and 54.7% of patients at the follow-up visits. According to the International Chronic Ocular GVHD Consensus Group, ocular GVHD developed in 41.3%, 47.7% and 51.9% of patients at the follow-up visits. We found a strong association between the presence of systemic GVHD and the development of chronic ocular GVHD throughout the entire follow-up period. Weaker associations were found between the presence of a female donor, matched related donor, conjunctival hyperemia and conjunctival fibrosis. CONCLUSIONS: More than 50% of subjects develop chronic ocular GVHD after allo-HSCT. The presence of active systemic GVHD, female donor and matched related donor are associated with ocular GVHD development. PMID- 29625304 TI - Independent Factors Affecting Postoperative Complication Rates After Custom-Made Porous Hydroxyapatite Cranioplasty: A Single-Center Review of 109 Cases. AB - BACKGROUND: Cranioplasties are an important neurosurgical procedure not only for improved cosmesis but also for improved functional recovery after craniectomy with a large cranial defect. The aim of this study was to identify predictive factors of postcranioplasty complications using custom-made porous hydroxyapatite cranioplasty. METHODS: Retrospective review was performed of all patients who underwent a reconstructive cranioplasty using custom-made hydroxyapatite at our institution between February 2008 and September 2017. Postoperative complications considered included bacterial infection, seizures, hydrocephalus requiring ventricular shunt placement, and cranioplasty-to-bone shift. Variables associated at P < 0.1 level in unadjusted analysis were entered into backward stepwise logistic regression models. RESULTS: Of 109 patients included, 15 (13.8%) experienced postoperative infection, with craniectomy performed at an outside institution (adjusted odds ratio [OR] 10.37 [95% confidence interval [CI], 2.03 75.27], P = 0.012) and a previous infection at the surgical site (adjusted OR 6.15 [95%CI, 1.90-19.92], P = 0.003) identified as independent predictors. Six patients (5.5%) experienced postoperative seizures, with stroke (ischemic and hemorrhagic) as a reason for craniectomy (adjusted OR 11.68 [95% CI, 2.56-24.13], P < 0.001) and the presence of seizures in the month before cranioplasty (adjusted OR 9.39 [95% CI, 2.04-127.67], P = 0.002) identified as independent predictors. Four patients (3.7%) experienced postcranioplasty hydrocephalus necessitating shunt placement, and 5 patients (4.6%) experienced cranioplasty-to bone shift >=5 mm, but no significant predictive factors were identified for either complication. CONCLUSIONS: This study identified possible predictive factors for postcranioplasty complications to help identify at-risk patients, guide prophylactic care, and improve morbidity of this important surgical procedure. PMID- 29625305 TI - Patient Motivation and Long-Term Satisfaction with Treatment Choice in Vestibular Schwannoma. AB - OBJECTIVES: To ascertain primary motivation and long-term satisfaction with treatment selection in patients with vestibular schwannoma. METHODS: A multicenter, cross-sectional survey was performed. Patients with small- to medium sized sporadic vestibular schwannoma who underwent stereotactic radiosurgery (SRS; n = 247), microsurgery (n = 144), or observation (n = 148) between 1998 and 2008 were surveyed regarding their motivation behind treatment selection and hindsight satisfaction with their choice of management. RESULTS: "Physician recommendation" was the most commonly stated reason for modality selection in all 3 groups. The second and third most common reasons for selecting SRS included "less invasive option than surgery" in 80 patients (32%) and "less recovery time than surgery" in 16 patients (6%). The second and third most common reasons for selecting observation included "to avoid side-effects of treatment" in 25 patients (17%) and "symptoms not severe enough to warrant intervention" in 22 patients (15%). The second and third most common reasons for selecting microsurgery included "do not want tumor in head" in 35 patients (24%) and "most definitive treatment" in 15 patients (10%). Overall, 232 patients (96%) treated with SRS, 141 observed patients (97%), and 121 patients (85%) who underwent microsurgical treatment were satisfied with their original decision (P < 0.001). CONCLUSIONS: Motivation behind treatment selection varies between individuals. Those who select observation and SRS commonly reference less invasiveness and lower risk, whereas those who select microsurgery are commonly motivated by having their tumor physically removed and the more definitive nature of treatment. Posttreatment satisfaction is highest in patients who undergo SRS and observation, although all 3 groups report high levels of satisfaction. PMID- 29625306 TI - Low-Grade Glioma of the Neurohypophysis: Clinical Characteristics and Surgical Outcomes. AB - BACKGROUND: Low-grade glioma (LGG) of the neurohypophysis is an extremely rare tumor arising from the pituicytes of the posterior pituitary or the infundibulum. The preoperative imaging findings of these tumors mimic those of pituitary adenomas, and radical resection is often challenging in affected patients due to the hypervascularity of the tumor. Here we describe the clinical and radiologic features of this clinical entity. METHODS: We identified 8 patients with LGG of the neurohypophysis who underwent surgery at Toranomon Hospital between January 2007 and March 2017. We retrospectively reviewed the clinical and radiologic data for these patients. RESULTS: The patient cohort comprised 5 men and 3 women, with a mean age of 57 years. The presenting symptoms included visual disturbance in 7 patients and anterior pituitary dysfunction in 7 patients. No patient had diabetes insipidus (DI). Preoperative magnetic resonance imaging (MRI) showed a thick anterior pituitary gland located anterior to the tumor in 3 patients and flow voids on T2-weighted images in 6 patients. All patients underwent transsphenoidal surgery, and gross total resection was achieved in 4 patients. Postoperative morbidities included deterioration of anterior pituitary function in 4 patients and permanent DI in 3 patients. CONCLUSIONS: Anterior displacement of a thick anterior pituitary by a tumor combined with evidence of flow voids on preoperative MRI is helpful in the preoperative diagnosis of LGG of the neurohypophysis. Radical resection should be attempted in these tumors, especially during primary surgery, even though it is associated with postoperative pituitary dysfunction. PMID- 29625307 TI - Surgical Management of Giant Retrocerebellar Arachnoid Cysts with a Cystoventricular Stent After Long-Term, Independent, and Simultaneous Intracystic and Intraventricular Pressure Monitoring. AB - BACKGROUND: Outcomes of surgical treated patients with giant retrocerebellar arachnoid cysts with the available typically preferred techniques frequently are unsatisfactory. OBJECTIVES: We hypothesized that a pressure gradient may exist between the cyst and the ventricular system that may be responsible for the posterior fossa-related symptoms and headaches, and, if so, that connecting both cavities by means of a shunt catheter (i.e., cystoventricular stent), the pressure differences would equilibrate and the symptoms resolve. To prove our hypothesis, we decided to simultaneously monitor the intracyst pressure and the intraventricular pressure. METHODS: This was a retrospective chart review analysis of 5 consecutive patients with giant retrocerebellar arachnoid cysts treated between 2014 and 2016. RESULTS: Four patients underwent 3 days of continuous intracranial pressure monitoring, and 1 patient was monitored in the surgical suit. Cyst and ventricular pressures tended to be within normal accepted values in all patients, and a pressure gradient was noticed only in the 2 patients with previous cyst surgeries. All patients were treated with a cystoventricular stent, and overall, had long-term sustained good outcomes, with resolution of symptoms in 3 and significant improvement in 2. CONCLUSIONS: Patients with symptomatic large retrocerebellar arachnoid cysts do not seem to have increased intracranial pressure, and regardless of the presence or absence of a pressure gradient between the cyst and the ventricles, a cystoventricular stent seems to be effective and the best first surgical option to offer. PMID- 29625308 TI - The Effect of Underlying Liver Disease on Perioperative Outcomes Following Craniotomy for Tumor: An American College of Surgeons National Quality Improvement Program Analysis. AB - BACKGROUND: The association between underlying liver disease and poor surgical outcomes has been well documented across a wide variety of surgical disciplines. However, little is known about the importance of liver disease in neurosurgery. In this report, we assess the independent effect of liver disease on perioperative outcomes in patients undergoing craniotomy for tumor. METHODS: The American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database was queried for patients undergoing craniotomy for tumor from 2006 to 2015. Presence and severity of underlying liver disease was assessed with the aspartate aminotransferase-to-platelet ratio index and the Model for End Stage Liver Disease-Sodium scores, computed from preoperative laboratory values. RESULTS: Among 11,897 patients, mild and advanced disease was identified in 2.4% and 1.9% of patients, respectively. Rates of 30-day mortality were 4.5% and 15.8% in these patients, compared with 3.1% in patients with healthy livers. The 30-day complication rate was 40.3%, 28.0%, and 19.8% in patients with advanced, mild, and no liver disease, respectively. In multivariate analysis, the presence of any liver disease (mild or advanced) was independently associated with mortality (OR = 2.46; 95% confidence interval [CI], 1.68-3.59; P < 0.001), morbidity (OR, 1.49; 95% CI, 1.18-1.87; P = 0.001), and length of hospital stay over 10 days (OR, 1.35; 95% CI, 1.07-1.70; P = 0.012), when compared with 13 covariates. Liver disease showed the strongest independent association with mortality of all risk factors analyzed. CONCLUSIONS: Liver disease is an independent predictor of poor 30-day outcomes following craniotomy for tumor. Consideration of underlying liver function can have a role in surgical decision making and postoperative care for these patients. PMID- 29625309 TI - Risk Factors for Significant Intraoperative Blood Loss During Unilateral Expansive Open-Door Cervical Laminoplasty for Cervical Compressive Myelopathy. AB - OBJECTIVE: Unilateral expansive open-door cervical laminoplasty is an effective and safe procedure for cervical compressive myelopathy but occasionally is accompanied with significant intraoperative blood loss (SIBL). The aim of the present study was to elucidate the risk factors for SIBL in patients undergoing cervical laminoplasty for multilevel cervical compressive myelopathy and to identify the effect of SIBL on neurologic complications. METHODS: A total of 215 patients who received cervical laminoplasty between January 2010 and August 2016 were enrolled in the study. SIBL was defined as 500 mL or more of blood volume during surgery. Patients were subdivided into 2 groups according to whether they suffered from SIBL (n = 26) or not (n = 189). Patient characteristics and clinical data were collected. Univariate and multivariable analysis were performed to identify independent risk factors for SIBL. RESULTS: The incidence of SIBL during unilateral expansive open-door cervical laminoplasty was 12.1%. The multivariable logistic regression analysis showed Pavlov ratio (odds ratio [OR] 0.002, P = 0.009), ossification of the posterior longitudinal ligament (OR 2.677, P = 0.038), and number of complete hinge fractures (OR 1.842, P = 0.015) were independent risk factors for SIBL during cervical laminoplasty. Patients with SIBL during cervical laminoplasty had a greater rate of neurologic complications during hospitalization (P = 0.012), worse neurologic recovery rate at discharge (P = 0.01), and longer postoperative length of stay (P = 0.003). CONCLUSIONS: This study suggested that Pavlov ratio, ossification of the posterior longitudinal ligament, and number of complete hinge fractures were independent risk factors for SBIL during cervical laminoplasty. SIBL in cervical laminoplasty was associated with greater neurologic complications and worse neurologic functional recovery. PMID- 29625310 TI - Glioneuronal Heterotopia Presenting as Cerebellopontine Angle Tumor of Cranial Nerve VIII. AB - BACKGROUND: Vestibular schwannomas and meningiomas account for the great majority of lesions arising in the cerebellopontine angle. In this report, we present a case of glioneuronal heterotopia, also known as glioneuronal hamartoma, arising from cranial nerve VIII, which is an extremely uncommon lesion. Important radiologic and surgical aspects are reviewed, which may help in early recognition and intraoperative decision making when these lesions are encountered. CASE DESCRIPTION: A healthy 29-year-old female presented with intermittent right facial numbness. Magnetic resonance imaging showed an incidental, minimally enhancing cerebellopontine angle lesion on the right cranial nerve VII-VIII complex. The patient declined serial observation and opted for operative intervention for resection. Intraoperatively, the lesion resembled neural tissue and was continuous with the VIII cranial nerve. Pathologic analysis demonstrated mature glioneuronal tissue consistent with hamartomatous brain tissue. The patient maintained normal hearing and facial nerve function after surgery. Radiologic, surgical, and pathologic characteristics are described. CONCLUSIONS: Ectopic glioneuronal tissue of cranial nerve VIII is a rare non-neoplastic lesion and should be considered in the differential diagnosis of unusual-appearing intracanalicular and cerebellopontine angle lesions. The congenital and benign nature of this entity makes observation a valid option for these cases, although they are so infrequent that they are often presumptively managed as vestibular schwannomas. Attempts to radically resect these lesions may result in higher rates of hearing loss or facial palsy due to their continuity with cranial nerves. PMID- 29625311 TI - Accuracy of 18F-FDOPA Positron Emission Tomography and 18F-FET Positron Emission Tomography for Differentiating Radiation Necrosis from Brain Tumor Recurrence. AB - BACKGROUND: Distinguishing radiation necrosis from brain tumor recurrence remains challenging. We performed a meta-analysis to assess the diagnostic accuracy of 2 different amino acid tracers used in positron emission tomography/computed tomography scans: 18F-FDOPA (6-[18F]-fluoro-L-3,4-dihydroxyphenylalanine) and 18F FET (O-(2-18F-fluoroethyl)-L-tyrosine). METHODS: We searched for studies in 3 databases: PubMed, Embase, and Chinese Biomedical databases. The data were extracted from eligible studies and then processed with heterogeneity test, threshold effect test, and calculations of sensitivity, specificity, and area under the summary receiver operating characteristic curve. Meta-regression and subgroup analyses were performed to explore the source of heterogeneity. RESULTS: A total of 48 studies (18F-FDOPA, n = 21; 18F-FET, n = 27) were included. Quantitative synthesis determined pooled weight values in the 18F-FDOPA and 18F FET groups: sensitivity, 0.85 versus 0.82; specificity, 0.77 versus 0.80; diagnostic odds ratio, 21.7 versus 23.03; area under the curve (AUC) values, 0.8771 versus 0.8976 (P = 0.46). Moreover, the type of tumor was identified as the possible source of the significant heterogeneity (I2 = 52%; P = 0.003) found in the 18F-FDOPA group. In meta-regression and subgroup analyses, 18F-FDOPA showed better diagnostic accuracy in patients with glioma compared with patients with brain metastases (AUC values, 0.9691 vs. 0.837; P < 0.01). 18F-FDOPA also showed a significant advantage in the diagnosis of glioma recurrence compared with 18F-FET (AUC values, 0.9691 vs. 0.9124; P = 0.015). CONCLUSIONS: Both 18F FDOPA and 18F-FET exhibit moderate overall accuracy in diagnosing brain tumor recurrence from radiation necrosis. However, 18F-FDOPA is more adept at diagnosing glioma recurrence compared with brain metastases, and it is more effective than 18F-FET in diagnosing glioma recurrence. PMID- 29625312 TI - Strokectomy and Extensive Cerebrospinal Fluid Drainage for the Treatment of Space Occupying Cerebellar Ischemic Stroke. AB - BACKGROUND: Cerebellar ischemia may lead to space-occupying edema, resulting in potentially fatal complications. Different surgical procedures are available to create space for the swollen ischemic brain; however, the type and timing of surgical treatments remain topics of debate in the literature. Here we report a case series of patients treated with a unilateral craniotomy to perform a cerebellar strokectomy and extensive cerebrospinal fluid (CSF) drainage without osteodural posterior fossa decompression. METHODS: We retrospectively analyzed the clinical and radiographic data of 11 patients with posterior fossa ischemia who underwent surgery at one of our institutions. A statistical analysis was performed to identify potential predictive factors for functional outcome. RESULTS: The mean patient age was 64.7 years. The involved vascular territory was the Posterior inferior cerebellar artery in 9 patients (82%) and the anterior inferior cerebellar artery/superior cerebellar artery in 2 patients (18%). The mean Glasgow Coma Scale score was 13.6 on admission, but 9.3 immediately before surgery. The surgical procedure was performed in a mean of 36.8 minutes after the radiologic diagnosis of space-occupying edema. Clinical outcome at 6 months was good (modified Rankin Scale [mRS] score <=2) in 9 patients (82%). Surgery-related complications occurred in 2 patients (18%), and these was a single death (9%) not related to the procedure or posterior fossa compression. Matching patients with their mRS outcome evaluation, the sole variable significantly associated with good outcome was age at admission (62.1 vs. 76.5 years; P < 0.05). CONCLUSIONS: Unilateral suboccipital craniotomy with strokectomy and extensive CSF drainage may allow for satisfactory decompression of the ischemic posterior fossa with acceptable morbidity and mortality rates, especially in younger patients. PMID- 29625313 TI - An Unusual Case of Lhermitte-Duclos Disease Manifesting with Intratumoral Hemorrhage. AB - BACKGROUND: Lhermitte-Duclos disease (LDD) is a rare neurologic disease that causes a hamartomatous lesion in the cerebellum. LDD is usually associated with mass lesion effects, but with appropriate surgical treatment, the clinical course is usually benign. We report a rare case of a patient with LDD with contrast enhancement on magnetic resonance imaging (MRI) who died as a result of intratumoral hemorrhage. CASE DESCRIPTION: LDD was diagnosed in a 59-year-old woman after a routine MRI. She did not present with any symptoms initially or after follow-up MRI suggested minor hemorrhage in the tumor. Eleven months after her first visit to our department, she suddenly lost consciousness, and computed tomography revealed massive intratumoral hemorrhage. Surgical decompression was done, but she died 17 days after surgery. Histopathologic findings were consistent with LDD. CONCLUSIONS: Hemorrhagic events can occur with LDD, even though the growth of the lesion is slow. Long-term close follow-up of patients with LDD is needed, especially patients in whom MRI shows atypical enhancement. To avoid possible hemorrhagic events, surgical treatment should be considered even if only subtle changes are seen on neuroimaging. PMID- 29625314 TI - Polybrominated diphenyl ethers in the dissolved and suspended phases of seawater from Sanggou Bay, east China. AB - The levels and profiles of polybrominated diphenyl ethers (PBDEs) in dissolved phase (DP) and suspended particulate matter (SPM) in seawater of Sanggou Bay (SGB) in four seasons were determined. The distribution and potential sources of these compounds were analyzed, and the ecological risk was assessed. The total concentrations of 14 PBDEs (?14PBDE) in DP and SPM in the surface water ranged from 0.10 ng L-1 to 2.20 ng L-1 and from 0.51 ng L-1 to 6.15 ng L-1, respectively. The highest value was obtained in August. The concentrations of ?14PBDE in the surface water were higher than those in the bottom water, and PBDEs were mainly partitioned into the SPM fraction. BDE209 was the most dominant PBDE congener, having average relative contributions of 86.5%-94.8% in DP and 40.5%-56.5% in SPM, followed by BDE47. The profiles of PBDEs in seawater of SGB were different from those of commercial PBDE products. The concentrations of ?14PBDE were higher in the inner bay than in the outer bay, suggesting that the terrestrial input and human activities affected the PBDE distribution in SGB. Results of nonparametric multidimensional scaling suggested that BDE209 and BDE47 were important congeners discriminating PBDE contamination in SGB. The potential sources of PBDEs in SGB included commercial PentaBDE and DecaBDE products from the land, the atmospheric transport of commercial OctaBDE, and the degradation of high brominated congeners. The ecological risks from PentaBDE and OctaBDE were low, and those from DecaBDE were moderate in seawater of SGB. PMID- 29625315 TI - Efficient removal of perfluorooctane sulfonate from aqueous film-forming foam solution by aeration-foam collection. AB - Aqueous film-forming foams (AFFFs) used in fire-fighting are one of the main contamination sources of perfluorooctane sulfonate (PFOS) to the subterranean environment, requiring high costs for remediation. In this study, a method that combined aeration and foam collection was presented to remove PFOS from a commercially available AFFF solution. The method utilized the strong surfactant properties of PFOS that cause it to be highly enriched at air-water interfaces. With an aeration flow rate of 75 mL/min, PFOS removal percent reached 96% after 2 h, and the PFOS concentration in the collected foam was up to 6.5 mmol/L, beneficial for PFOS recovery and reuse. Increasing the aeration flow rate, ionic strength and concentration of co-existing surfactant, as well as decreasing the initial PFOS concentration, increased the removal percents of PFOS by increasing the foam volume, but reduced the enrichment of PFOS in the foams. With the assistance of a co-existing hydrocarbon surfactant, PFOS removal percent was above 99.9% after aeration-foam collection for 2 h and the enrichment factor exceeded 8400. Aeration-foam collection was less effective for short-chain perfluoroalkyl substances due to their relatively lower surface activity. Aeration-foam collection was found to be effective for the removal of high concentrations of PFOS from AFFF-contaminated wastewater, and the concentrated PFOS in the collected foam can be reused. PMID- 29625316 TI - The adsorption of Cs+ from wastewater using lithium-modified montmorillonite caged in calcium alginate beads. AB - The increasing nuclear energy consumption has posed serious environmental concerns (e.g. nuclear leakage), and the removal of radionuclides such as cesium becomes an urgent issue to be solved currently. In this research, a novel non toxic adsorbent lithium-modified montmorillonite clay encapsulated in calcium alginate microbeads (MCA/Li) was fabricated by using ion-exchange method and then used successfully in the remediation of cesium-contaminated wastewater. Analyses of scanning electron microscopy, X-ray diffraction, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy were used to characterize the physicochemical properties of adsorbent MCA/Li, such as internal crystal structure, constituent elements, and functional groups. The effects of concentration ratios (sodium alginate/montmorillonite), solution pH, contacting time and initial Cs+ concentration on the adsorption behavior were carefully investigated via batch adsorption experiments. The adsorbent MCA/Li exhibited higher selectivity and removal efficiency towards Cs+ with the maximum adsorption capacity of 100.25 mg/g. In the kinetics study, the pseudo-first-order fitted the cesium adsorption data of MCA/Li better than the pseudo-second-order. The adsorption mechanism studies revealed the process followed the Langmuir isotherm model, which suggested that Cs+ adsorption onto MCA/Li is a monolayer homogeneous adsorption process. The research findings indicated this novel adsorbent MCA/Li demonstrated great potential in radioactive wastewater treatment due to its convenience in synthesis, high adsorption capacity, and low cost. PMID- 29625317 TI - A novel method to delaminate nitrate-intercalated MgAl layered double hydroxides in water and application in heavy metals removal from waste water. AB - Nitrate-intercalated MgAl layered double hydroxide (LDH) was successfully delaminated in water by a facile and effective method upon reflux at 120 degrees C for 24 h followed by sonication at 40 degrees C for 5 h. This process is environmentally friendly since water is the only solvent used. The delaminated nanosheets were characterized by microscopic, spectroscopic, and particle size analyses. The delamination process successfully produced octahedron-shaped single layer nanosheets 50-150 nm in size. X-ray photoelectron spectroscopy (XPS) data confirmed that the surface elements and their chemical status are consistent with the basic layer of MgAl LDH. The delaminated nanosheets displayed higher adsorption capacity for removing heavy metals from waste water than the original powdered LDH. After treating the waste water, a sharp and intense peak in the X ray powder diffraction (XRD) pattern of the precipitate confirms the restacking of the LDH nanosheets. PMID- 29625318 TI - Halogenated flame retardants in building and decoration materials in China: Implications for human exposure via inhalation and dust ingestion. AB - In this study, polybrominated diphenyl ethers (PBDEs), novel brominated flame retardants (NBFRs), and dechlorane plus (DPs) were analyzed in seven categories of building and decoration materials. The total concentrations of analyzed FRs ranged from 1.19 ng/g (diatomite powder) to 9532 ng/g (expanded polystyrene panel). Relatively high concentrations were detected in foam samples and PVC materials, followed by sealing materials, boards, wallpaper, paints, and wall decoration powders. BDE209 was the most detected compound with the highest concentrations in almost all materials, followed by decabromodiphenyl ethane (DBDPE), which was consistent with their productions and consumptions in China. The estimated PBDE concentrations in air and dust based on material concentration and emission rate were comparable with those detected in real samples. Adult and infant exposures via inhalation and dust ingestion were assessed. The estimated exposures to BDE209 via dust ingestion were 1.36 and 0.12 ng/(kg bw d), which were 19- and 4-fold higher than those via inhalation for infants and adults, respectively. This suggested that dust ingestion was a significant pathway of human BDE209 exposure, especially for infants. For the other PBDE congeners (?7PBDEs), the estimated exposures via inhalation were 2.60 and 1.32 ng/(kg bw d) for infants and adults, respectively. Despite the low estimated human exposures to PBDEs compared to the oral reference doses, the exposure associated with building and decoration materials still requires more attention because of the potential risks from other exposure pathways and undetected FRs in those materials. PMID- 29625319 TI - Fast and simple determination and exposure assessment of bisphenol A, phenol, p tert-butylphenol, and diphenylcarbonate transferred from polycarbonate food contact materials to food simulants. AB - Polycarbonate (PC) plastics find extensive use in baby bottles, food storage containers, and various kitchen items. Possibly hazardous chemicals, bisphenol A (BPA), phenol, p-tert-butylphenol (TBP), and diphenylcarbonate (DPC), are source materials or by-products from PC production. Therefore, a fast and simple analytical method was developed to determine and assess the exposure of BPA, phenol, TBP, and DPC transferred from PC food-contact materials to four different food simulants (water, 4% acetic acid, 50% ethanol, and n-heptane) at different temperatures. The method was validated in terms of limit of detection (LOD) and quantification (LOQ), recovery, and precision for the detection of BPA, phenol, and TBP using HPLC-FLD and of DPC using HPLC-UV. BPA, phenol, TBP, and DPC concentrations transferred from 200 PC samples to food simulants were determined. The highest migration levels of BPA (54.3 MUg L-1) and phenol (43.8 MUg L-1) were found in 50% ethanol at 70 degrees C. TBP did not migrate to any simulant. DPC did not show any migration from PC samples into water and only migrated from a cup to 4% acetic acid at 70 degrees C and 100 degrees C, whereas migration occurred from several cups, ladles, spoons, and tongs to 50% ethanol and to n heptane at 25 degrees C. Food simulants and temperature were the crucial factors for the migration of BPA and phenol from PC samples. Estimated daily intakes (EDIs), based on food consumption and food-type distribution factors, for BPA, phenol, and DPC were calculated to be 0.007, 0.001, and 2.5 * 10-4 MUg kg-1 bw day-1, respectively. PMID- 29625320 TI - Prognostic factors for thrombosis-free survival and overall survival in polycythemia vera: A retrospective analysis of 623 PTS With long follow-up. PMID- 29625321 TI - Secreted Wnt antagonists in leukemia: A road yet to be paved. AB - Wnt signaling has been a topic of research for many years for its diverse and fundamental functions in physiological (such as embryogenesis, organogenesis, proliferation, tissue repair and cellular differentiation) and pathological (carcinogenesis, congenital/genetic diseases, and tissue degeneration) processes. Wnt signaling pathway aberrations are associated with both solid tumors and hematological malignancies. Unregulated Wnt signaling observed in malignancies may be due to a wide spectrum of abnormalities, from mutations in the genes of key players to epigenetic modifications of Wnt antagonists. Of these, Wnt antagonists are gaining significant attention for their potential of being targets for treatment and inhibition of Wnt signaling. In this review, we discuss and summarize the significance of Wnt signaling antagonists in the pathogenesis and treatment of hematological malignancies. PMID- 29625322 TI - Novel p-n heterojunction copper phosphide/cuprous oxide photocathode for solar hydrogen production. AB - A Copper phosphide (Cu3P) micro-rod (MR) array, with coverage by an n-Cu2O thin layer by electrodeposition as a photocathode, has been directly fabricated on copper foil via simple electro-oxidation and phosphidation for photoelectrochemical (PEC) hydrogen production. The morphology, structure, and composition of the Cu3P/Cu2O heterostructure are systematically analyzed using a scanning electron microscope (SEM), X-ray diffraction and X-ray photoelectron spectra. The PEC measurements corroborate that the p-Cu3P/n-Cu2O heterostructural photocathode illustrates efficient charge separation and low charge transfer resistance to achieve the highest photocurrent of 430 MUA cm-2 that is greater than other transition metal phosphide materials. In addition, a detailed energy diagram of the p-Cu3P/n-Cu2O heterostructure was investigated using Mott-Schottky analysis. Our study paves the way to explore phosphide-based materials in a new class for solar energy applications. PMID- 29625323 TI - Enhanced physical and biological properties of silk fibroin nanofibers by layer by-layer deposition of chitosan and rectorite. AB - The search for biodegradable and biocompatible materials applied to the antibacterial field has become a significant topic of interest worldwide. In this study, the electrospinning and electrostatic layer-by-layer self-assembly (LBL) techniques were applied to achieve composite mats with enhanced physical and biological properties. Electrospun silk fibroin (SF) was selected as the substrate, and chitosan (CS) and rectorite (REC) were assembled on the surface of the substrate as positively and negatively charged layers via electrostatic LBL. The morphology, composition and structure of the mats were examined, and the results suggested that LBL modification was successful. In addition, the variation of the bilayer numbers and the component of the outmost layer could affect the morphology and the physical and biological properties of LBL mats. Additionally, the morphology and the water contact angle investigation results of the as-prepared mats indicated that the surface features were changed through the LBL process, resulting in a rougher surface than in pure SF mats. Moreover, the mechanical properties of the SF mats were improved after the LBL process. Furthermore, the antibacterial activity of the LBL self-assembled SF mats against E. coli and S. aureus with a concentration of 106 CFU/mL were 84 and 92%, respectively. The cell-culture experiments demonstrated that the mats maintained superior biocompatibility after the introduction of CS and REC. PMID- 29625324 TI - Lesbian, gay, and bisexual (LGB) youth within in welfare: Prevalence, risk and outcomes. AB - The purpose of this study was to estimate the population of sexual minority or LGB (lesbian, gay and bisexual) children and youth involved with the child welfare system, and to compare their health, mental health, placement and permanency outcomes to those of non-LGB youth. Data were drawn from the Second National Survey of Child and Adolescent Well-Being (NSCAW-II), a nationally representative sample of children who were referred to child welfare due to a report of abuse or neglect over a fifteen month period. This sample included youth ages eleven and older who self-identified their sexual orientation (n = 1095). Results indicate that approximately 15.5% of all system involved youth identified as lesbian, gay or bisexual, and that lesbian and bisexual females, and LGB youth of color are both overrepresented within child welfare systems. Although no substantive difference in risk factors, permanency and placement were found between LGB and Non-LGB youth, LGB youth were significantly more likely to meet the criteria for adverse mental health outcomes. Implications for child welfare practice and policy are presented, along with recommendations for future research in this area. PMID- 29625325 TI - Tailoring health-related messages for young adults with adverse childhood experiences (ACEs). AB - The goal was to identify factors that might affect likelihood of seeking health related interventions for young adults with adverse childhood experiences (ACEs). We tested whether ACEs were associated with (1) regulatory focus (tendency toward promoting good outcomes versus preventing bad outcomes), and (2) patient activation (the intention to take active charge of one's health). We further tested whether promotion and prevention and patient activation were associated with each other and with health. Students at a public university (N = 321) completed online questionnaires assessing ACEs, regulatory focus, patient activation, and health. Greater childhood adversity showed small but significant associations with being a less activated patient and being less focused on promoting good outcomes. In contrast, greater childhood adversity had a much stronger association with focusing on preventing negative outcomes. Students with a more significant mental health history were more likely to have been exposed to childhood adversity, to be less activated patients, and to focus more on prevention. Results suggest that using a prevention focus may be effective in health messages aimed to reach individuals with high levels of ACEs. Furthermore, individuals with high levels of ACEs may benefit from interventions aimed at increasing patient activation. PMID- 29625326 TI - Progression, maintenance, and feedback of online child sexual grooming: A qualitative analysis of online predators. AB - The limited literature on online child grooming has focused mainly on studying the characteristics of perpetrators and victims that facilitate the sexual abuse of minors. Little attention has been given to the perceptions of the perpetrators about the abuse process and the strategies used to sustain it over time. In the present study, after identifying a sample of 12 men convicted of online grooming, we used qualitative grounded theory through in-depth interviews and comparisons with the proven facts of their convictions. The results show how aggressors actively study the structural environment, the needs and vulnerabilities of the minors). In this way, the aggressors adapt by using most effective strategies of persuasion at all times, so that the child feels like an active part of the plot. This allows the aggressors to have sexual interactions with minors either online or offline and in a sporadic or sustained manner. This process is maintained with some distorted perceptions about minors and the abuse process, which seem to feed back to the beginning of the cycle with other potential victims. The interaction between the persuasive processes and the distorted perceptions of the aggressor leads to a potential work focus for treatment as well as detection and prevention. Trying to visualize the complexity of the phenomenon could also help researchers to understand processes from this approach that may be applied with other types of vulnerable populations. PMID- 29625327 TI - Ultrasensitive competitive method-based electrochemiluminescence immunosensor for diethylstilbestrol detection based on Ru(bpy)32+ as luminophor encapsulated in metal-organic frameworks UiO-67. AB - In this work, Ru(bpy)32+ encapsulated in metal-organic frameworks (MOFs) UiO-67 (Ru(bpy)32+/UiO-67) as luminophor was easily prepared and firstly applied in constructing an electrochemiluminescence (ECL) immunosensor to efficiently estimate diethylstilbestrol (DES). The competitive method-based ECL immunosensor platform was fabricated by amino-silicon dioxide which possesses large surface area. The poriness of UiO-67 was splendid so that Ru(bpy)32+ could be easily encapsulated. Ru(bpy)32+/UiO-67 with excellent ECL luminescence signal existed large specific surface area for easily labeled with antibodies. DES competed with bovine serum albumin-diethylstilbestrol (BSA-DES) for binding to antibody specific sites in the constructed immunosensor. However DES was micromolecule, which was easier to bond to antibodies than BSA-DES. The ECL signal was gradually decreases with the increase of the concentration of DES. Under optimal conditions, the proposed immunosensor exhibited a wide linear range from 0.01 pg mL-1 to 50 ng mL-1 with a low detetion limit of 3.27 fg mL-1 (S/N = 3). The novel fabricated immunosensor with interference immunity and high stability may cause an attractive approach for the other targets determination. PMID- 29625328 TI - Isothermal exponential amplification techniques: From basic principles to applications in electrochemical biosensors. AB - As a conventional amplification technique, polymerase chain reaction (PCR) has been widely applied to detect a variety of analytes with exponential amplification efficiency. However, the requirement of thermocycling procedures largely limits the application of PCR-based methods. Alternatively, several isothermal amplification techniques have been developed since the early 1990s. In particular, according to the reaction kinetics, isothermal exponential amplification techniques possess higher amplification efficiency and detection sensitivity. The isothermal exponential amplification techniques can be mainly divided into two categories: enzyme-based isothermal exponential amplification and enzyme-free isothermal exponential amplification. Considering the advantages of high sensitivity and selectivity, high signal-to-noise ratio, low cost and rapid response time, exponential amplification electrochemical biosensors have attracted considerable attention. In this review, we introduce the basic principles of isothermal exponential amplification techniques and summarize their applications in electrochemical biosensors during the past five years. We also highlighted the present challenges and further perspectives of isothermal exponential amplification-based electrochemical biosensors. PMID- 29625329 TI - Multiporous molybdenum carbide nanosphere as a new charming electrode material for highly sensitive simultaneous detection of guanine and adenine. AB - By introduction of Mo metal species (molybdenum-based polyoxometalates) into the Cu-MOF as co-precursor, molybdenum carbide nanosphere (MoxC@C) was prepared via a simple calcining routine and a further etching the metallic Cu process. The obtained MoxC@C showed a unique structure where well-dispersed MoxC nanoparticles (NPs) were encapsulated in porous carbon matrix. As-fabricated novel 3D porous architecture MoxC@C nanosphere exhibited a potent and persistent electro oxidation behavior followed by well-separated oxidation peaks (peak to peak voltage is about 350 mV) toward adenine (A) and guanine (G) by differential pulse voltammetry (DPV). This excellent electrochemical performance can be attributed to the unique structure and composition of 3D MoxC@C. Furthermore, 3D MoxC@C also revealed high selectivity and sensitivity, good reproducibility, excellent stability and anti-interference ability. The calibration curves for quantitive analysis of G and A were obtained: 0.03-122 uM, and 0.02-122 uM, respectively, the detection limits were 0.0085 uM, 0.008 uM, respectively. The proposed procedure was successfully applied to detect G and A in human urine and serum samples with satisfactory recovery, which manifests its viability application for practical analysis. PMID- 29625330 TI - Use of torsional resonators to monitor electroactive biofilms. AB - Whereas the study of interfaces and thin films with the quartz crystal microbalance (QCM) is well established, biofilms have proven to be a difficult subject for the QCM. The main problem is that the shear wave emanating from the resonator surface does not usually reach to the top of the sample. This problem can be solved with torsional resonators. These have a resonance frequency in the range of tens of kHz, which is much below the frequency of the thickness-shear QCMs. The depth of penetration of the shear wave is correspondingly larger. Data acquisition and data analysis can proceed in analogy to the conventional thickness-shear QCM. Torsional resonators may also be operated as electrochemical QCMs (EQCMs), meaning that a DC electrical potential may be applied to the active electrode and that shifts of frequency and bandwidth may be acquired in parallel to the electrical current. Here we report on the formation of mixed-culture biofilms dominated by the microorganism Geobacter anodireducens. The viscoelastic analysis evidences an increase in rigidity as the films grows. Potential sweeps on electroactive biofilms reveal a softening under negative potentials, that is, under conditions, where the layer's metabolism was slowed down by insufficient oxidative activity of the substrate. For comparison, biofilms were monitored in parallel with a conventional thickness-shear QCM. PMID- 29625331 TI - Real-time monitoring of immune responses under pathogen invasion and drug interference by integrated microfluidic device coupled with worm-based biosensor. AB - Immune response to environmental pathogen invasion is a complex process to prevent host from further damage. For quantitatively understanding immune responses and revealing the pathogenic environmental information, real-time monitoring of such a whole dynamic process with single-animal resolution in well defined environments is highly desired. In this work, an integrated microfluidic device coupled with worm-based biosensor was proposed for in vivo studies of dynamic immune responses and antibiotics interference in infected C. elegans. Individual worms housed in chambers were exposed to the various pathogens and discontinuously manipulated for imaging with limited influence on physiological activities. The expression of immune responses gene (irg-1) was time-lapse measured in intact worms during pathogen infection. Results demonstrated that irg 1 gene could be induced in the presence of P. aeruginosa strain PA14 in a dose dependent manner, and the survival of infected worm could be rescued under gentamicin or erythromycin treatments. We expect it to be a versatile platform to facilitate future studies on pathogenesis researches and rapid drug screen using C. elegans disease model. PMID- 29625333 TI - Stem cell-based therapeutic strategies for cartilage defects and osteoarthritis. AB - The gold standard cell therapy for repair of articular cartilage defects is autologous chondrocyte implantation, with good outcomes long-term. Mesenchymal stromal/stem cells (MSCs) from bone marrow or connective tissues such as fat are being pursued as alternatives for cartilage repair, and are trialled via intra articular administration in patients with knee osteoarthritis. Early-phase clinical studies concur on safety and provide some promising insight into efficacy, but the mechanism of action remains unclear. Recent studies implicate extracellular vesicles as important mediators of MSC action, offering exciting therapeutic prospects. Our increasing understanding of the mechanisms underlying intrinsic articular cartilage maintenance and repair fosters hope that novel/repurposed therapeutics could elicit repair through activation of endogenous stem/progenitor cells to maintain healthy joints and prevent osteoarthritis. PMID- 29625332 TI - Intra-articular drug delivery systems for joint diseases. AB - Intra-articular (IA) injections directly deliver high concentrations of therapeutics to the joint space and are routinely used in various musculoskeletal conditions such as osteoarthritis (OA) and rheumatoid arthritis (RA). However, current IA-injected drugs are rapidly cleared and do not significantly affect the course of joint disease. In this review, we highlight recent developments in IA therapy, with a special emphasis on current and emerging therapeutic carriers and their potential to deliver disease-modifying treatment modalities for arthritis. Recent IA approaches concentrate on platforms that are safe with efficient tissue penetration, and readily translatable for controlled and sustained delivery of therapeutic agents. Gene therapy delivered by viral or non-viral vectors and cell based therapy for cartilage preservation and regeneration are being intensively explored. PMID- 29625334 TI - Efficacy and safety of interscalene block combined with general anesthesia for arthroscopic shoulder surgery: A meta-analysis. AB - STUDY OBJECTIVE: There is controversy regarding the efficacy and safety of using interscalene block (ISB) combined with general anesthesia (GA) for arthroscopic shoulder surgery. Our meta-analysis was undertaken to evaluate the utility of this approach. MEASUREMENTS: We searched the PubMed, Cochrane Library, EMBASE, CNKI, VIP and ClinicalTrials.gov databases for randomized controlled trials. The primary endpoint was extubation time. Secondary endpoints included intraoperative heart rate, pain scores on the day of and 1 day after the operation, intraoperative systolic blood pressure and adverse events. MAIN RESULTS: Ten RCTs involving 746 patients undergoing arthroscopic shoulder surgery met inclusion criteria. Compared with GA alone, ISB + GA was associated with a shorter extubation time(WMD = -6.13; 95% CI = -8.68 to -3.57; P < 0.00001; I2 = 94%), a lower pain score on the day of the operation (WMD = -2.46; 95% CI = -4.53 to 0.40; P = 0.02; I2 = 97%), a lower pain score 1 day after the operation (WMD = 1.49; 95% CI = -2.46 to -0.52; P = 0.003; I2 = 88%), a lower intraoperative systolic blood pressure (WMD = -12.64; 95% CI = -20.90 to -4.39; P = 0.003; I2 = 95%), a lower heart rate (WMD = -8.81; 95% CI = -15.34 to -2.28; P = 0.008; I2 = 95%) and a lower incidence of adverse events (RR = 0.31; 95% CI = 0.15-0.66; P = 0.002; I2 = 32%). CONCLUSIONS: In patients undergoing arthroscopic shoulder surgery, ISB + GA is associated with a lower heart rate, lower pain scores on the day of and 1 day after the operation, a lower intraoperative systolic blood pressure, a shorter extubation time and a lower incidence of adverse events compared with GA alone. PMID- 29625335 TI - Cerebrospinal fluid IL-10 as an early stage discriminative marker between multiple sclerosis and neuro-Behcet disease. AB - Multiple Sclerosis (MS) and Neuro-Behcet's Disease (NBD) are two recurrent disorders affecting the central nervous system (CNS) by causing inflammation and irreversible damage. Inaugural clinical symptoms for both diseases might be very similar and definitive diagnosis could be delayed. The present study aimed to find out possible differences at early stages in the transcription factors/cytokines expression profiles in blood and cerebrospinal fluid (CSF) of MS and NBD patients which could be useful discriminative markers. Cytokines and transcription factors related to Th1, Th2, Th17 and T regulatory populations were studied by quantitative RT-PCR simultaneously in PBMCs and CSF, from 40 patients presenting a first episode of clinical features related to CNS inflammation and 22 controls with non inflammatory neurological diseases enrolled mainly for severe headache. The follow up of 12 months did allow a definitive diagnosis of remitting relapsing MS (RRMS) in 21 patients and of NBD in the other 19 among those with CNS inflammation compared to controls. In initial blood samples, T-bet was significantly increased in NBD patients only while IFN-gamma was elevated in patients who evolved into RRMS or NBD. IL-17a, GATA-3 and IL-4 were significantly lower in RRMS patients than in the NBD group. In initial CSF samples, ROR-gammat, IL-17a and IFN-gamma were significantly elevated in patients compared to controls. The most striking finding was the significant increase of CSF IL-10 that we did observe in NBD patients only. Thus, we propose CSF IL-10 as a predictive marker to help clinicians discriminating between these two neurological disorders. PMID- 29625336 TI - Clinical significance of serum soluble TNF receptor II level and soluble TNF receptor II/I ratio as indicators of coronary artery lesion development in Kawasaki disease. AB - To investigate the clinical significance of serum soluble tumor necrosis factor receptor (sTNFR) II level and sTNFR II/I ratio as indicators of the development of coronary artery lesions (CALs) in Kawasaki disease (KD), we measured levels of serum sTNFR I and II, interleukin (IL)-6, IL-18, and neopterin in 63 patients with KD, including nine patients with CALs and 20 healthy controls. At the time of diagnosis of KD before intravenous immunoglobulin (IVIG) treatment, serum sTNFR I and II levels were found to be significantly higher in non-responders to IVIG treatment than in responders. On the contrary, serum sTNFR II levels and sTNFR II/I ratio were significantly higher in patients with KD having CALs than in those without CALs. Longitudinal observation in a patient with KD who is unresponsive to IVIG revealed sustained elevation of serum sTNFR II level, and elevated sTNFR II/I ratio was linked to the CALs development. Increase in serum sTNFR II level and elevated sTNFR II/I ratio may be promising indicators of the development of CALs in KD. PMID- 29625337 TI - Domain swapping between FabGs deciphers the structural determinant for in solution oligomerization and substrate binding. PMID- 29625338 TI - On the retrieval of crystallographic information from atom probe microscopy data via signal mapping from the detector coordinate space. AB - Atom probe tomography is a powerful microscopy technique capable of reconstructing the 3D position and chemical identity of millions of atoms within engineering materials, at the atomic level. Crystallographic information contained within the data is particularly valuable for the purposes of reconstruction calibration and grain boundary analysis. Typically, analysing this data is a manual, time-consuming and error prone process. In many cases, the crystallographic signal is so weak that it is difficult to detect at all. In this study, a new automated signal processing methodology is demonstrated. We use the affine properties of the detector coordinate space, or the 'detector stack', as the basis for our calculations. The methodological framework and the visualisation tools are shown to be superior to the standard method of crystallographic pole visualisation directly from field evaporation images and there is no requirement for iterations between a full real-space initial tomographic reconstruction and the detector stack. The mapping approaches are demonstrated for aluminium, tungsten, magnesium and molybdenum. Implications for reconstruction calibration, accuracy of crystallographic measurements, reliability and repeatability are discussed. PMID- 29625339 TI - Comparison of the clinical efficacy of craniotomy and craniopuncture therapy for the early stage of moderate volume spontaneous intracerebral haemorrhage in basal ganglia: Using the CTA spot sign as an entry criterion. AB - OBJECTIVES: Surgical treatment is widely used for haematoma removal in spontaneous intracerebral haemorrhage (ICH) patients, but there is controversy about the selection of surgical methods. The CT angiography (CTA) spot sign has been proven to be a promising factor predicting haematoma expansion and is recommended as an entry criterion for haemostatic therapy in patients with ICH. This trial was designed to evaluate the clinical efficacy of two surgical methods (haematoma removal by craniotomy and craniopuncture combined with urokinase infusion) for patients in the early stage (<=6h from symptom onset) of spontaneous ICH with a moderate haematoma volume (30 ml - 60 ml). PATIENTS AND METHODS: From January 2012 to July 2017, 196 eligible patients treated in our institution were enrolled according to the inclusion criteria. The patients were divided into the CTA spot sign positive type and CTA spot sign negative type according to the presence or absence of the CTA spot sign. For each type, the patients were randomly assigned to two groups, i.e., the craniotomy group, in which patients underwent craniotomy with haematoma removal, and the craniopuncture group, in which patients underwent minimally invasive craniopuncture combined with urokinase infusion therapy. Neurological function was evaluated with the Scandinavian Stroke Scale (SSS) at day 14. The disability level and the activities of daily living were assessed using a modified Rankin Scale (mRS) and Barthel Index (BI) at day 90. Case fatalities were recorded at day 14 and 90. Complications were recorded during hospitalization. RESULTS: For the CTA spot sign positive type, the craniotomy group had a higher SSS than that in the craniopuncture group (P < 0.05) at day 14. The rebleeding rate was higher in the craniopuncture group than that in the craniotomy group (P < 0.05) during hospitalization. The craniotomy group had a lower mRS than that in the craniopuncture group (P < 0.01) and had a higher BI than that in the craniopuncture group (P < 0.05) at day 90. There was no statistically significant difference in the fatality rate between the two groups. For the CTA spot sign negative type, there were no significant differences in the SSS, mRS, BI, fatality rate and complication rate between the two groups. CONCLUSION: ICH can be divided into the CTA spot sign positive and negative type according to the presence or absence of the CTA spot sign. For the CTA spot sign positive type, patients can benefit from craniotomy with haematoma removal, which can reduce the postoperative rebleeding rate and improve the prognosis. For the CTA spot sign negative type, both craniotomy and craniopuncture are applicable. Considering simple procedure and minor surgical injury, craniopuncture can be a more reasonable choice. PMID- 29625340 TI - Environmental surveillance and in vitro activity of antimicrobial agents against Legionella pneumophila isolated from hospital water systems in Campania, South Italy: a 5-year study. AB - BACKGROUND: Legionellosis' treatment failures have been recently reported showing the possibility of resistance development to traditional therapy, especially in healthcare related disease cases. Environmental impact of antibiotic residues, especially in hospital waters, may act on the resistome of Legionella resulting in developing resistance mechanisms. OBJECTIVES: In this study we investigate the antibiotic susceptibility of environmental Legionella pneumophila (Lpn) strains isolated from hospital water systems in Campania, a region located in Southwest Italy. METHODS: 5321 hospital water samples were investigated for the presence of Lpn. Among positive samples, antibiotic susceptibility was tested for a random subset of 125 Lpn strains (25 Lpn isolates from each of the following serogroups: 1, 3, 5, 6, 8). Susceptibility testing was performed, using the E-test on buffered charcoal yeast extract agar supplemented with alpha-ketoglutarate, for 10 antimicrobial drugs: azithromycin, cefotaxime, clarithromycin, doxycycline, erythromycin, rifampicin, tigecycline, ciprofloxacin, levofloxacin and moxifloxacin. Non parametric tests were used to determine and assess the significant differences in susceptibility to the different antimicrobics between the serogroups. RESULTS: Among the isolated strains, none showed resistance to the antibiotics tested. Rifampicin was the most active antibiotic against overall Legionella strains, followed by levofloxacin. Between the macrolides the clarithromycin was overall the most active drug, instead the azithromycin was the less active. Analyzing the different serogroups a significant difference was found between serogroup 1 and non-1 serogroup isolates for doxycycline and tigecycline. CONCLUSIONS: Antibiotic susceptibility of environmental isolates of Legionella spp. might be useful for the early detection of resistance to antibiotics that directly impacts on mortality and length of hospital stay. PMID- 29625341 TI - Medications as a potential source of exposure to parabens in the U.S. population. AB - INTRODUCTION: Use of paraben-containing medications has been shown to be associated with urinary paraben concentrations among couples undergoing fertility treatment, but it is unknown whether this association is also present among the general population. METHODS: A list of prescription medications of interest was developed based on their likelihood of containing parabens and the ability to identify users in the National Health and Nutrition Examination Survey (NHANES); alendronate, escitalopram oxalate, fluoxetine, and olanzapine were chosen. Participants reported whether they had used each medication in the past month. Linear regression models were used to compare model-based mean urinary concentrations of each paraben among users and non-users of these four medications. RESULTS: A total of 10,302 respondents were included in the analysis, 265 (2.6%) of whom had reported using a paraben-containing prescription medication in the previous month. Users of alendronate had mean concentrations of ethyl paraben that were approximately three-fold higher than non-users (p >= 0.001 in unadjusted and adjusted models), which was likely due to three participants with very high concentrations. No other differences in paraben concentrations were found for any of the medications of interest (all p >= 0.13). Compared to non-users, a significantly greater proportion of alendronate users had butyl and ethyl paraben concentrations above the 95th percentile (17.8% and 12.3%, respectively) compared to non-users (5.0% and 5.0%, respectively; both p <= 0.01), despite ethyl paraben not being an expected ingredient in the brand name formulation of alendronate. CONCLUSION: Despite previous work showing that medications can be an important source of paraben exposure, there was no clear overall evidence of associations between the use of paraben-containing medications and increases in urinary paraben concentrations among participants in NHANES 2005-2012. These results highlight the difficulties inherent in proper assessment of exposures with short half-lives based on a single cross-sectional biologic sample. PMID- 29625342 TI - Phantom somatosensory evoked potentials following selective intraneural electrical stimulation in two amputees. AB - OBJECTIVE: The aim of the paper is to objectively demonstrate that amputees implanted with intraneural interfaces are truly able to feel a sensation in the phantom hand by recording "phantom" somatosensory evoked potentials from the corresponding brain areas. METHODS: We implanted four transverse intrafascicular multichannel electrodes, available with percutaneous connections to a multichannel electrical stimulator, in the median and ulnar nerves of two left trans-radial amputees. Two channels of the implants that were able to elicit sensations during intraneural nerve stimulation were chosen, in both patients, for recording somatosensory evoked potentials. RESULTS: We recorded reproducible evoked responses by stimulating the median and the ulnar nerves in both cases. Latencies were in accordance with the arrival of somatosensory information to the primary somatosensory cortex. CONCLUSION: Our results provide evidence that sensations generated by intraneural stimulation are truly perceived by amputees and located in the phantom hand. Moreover, our results strongly suggest that sensations perceived in different parts of the phantom hand result in different evoked responses. SIGNIFICANCE: Somatosensory evoked potentials obtained by selective intraneural electrical stimulation in amputee patients are a useful tool to provide an objective demonstration of somatosensory feedback in new generation bidirectional prostheses. PMID- 29625343 TI - Rapid exhaustion of auditory neural conduction in a prototypical mitochondrial disease, Friedreich ataxia. AB - OBJECTIVES: In patients with Friedreich ataxia (FRDA), mitochondrial failure leads to impaired cellular energetics. Since many FRDA patients have impaired hearing in noise, we investigated the objective consequences on standard auditory brainstem-evoked responses (ABRs). METHODS: In 37 FRDA patients, among whom 34 with abnormal standard ABRs, hearing sensitivity, speech-in-noise intelligibility and otoacoustic emissions were controlled. ABR recordings were split into four consecutive segments of the total time frame used for data collection, thus allowing the dynamics of ABR averaging to be observed. RESULTS: Most ears showed features of an auditory neuropathy spectrum disorder with flattened ABRs and impaired speech-in-noise intelligibility contrasting with near-normal hearing sensitivity and normal preneural responses. Yet split-ABRs revealed short-lived wave patterns in 26 out of 68 ears with flattened standard ABRs (38%). While averaging went on, the pattern of waves shifted so that interwave latencies increased by 35% on average. CONCLUSIONS: In FRDA, the assumption of stationarity used for extracting standard ABRs is invalid. The preservation of early split ABRs indicates no short-term dyssynchrony of action potentials. A large decrease in conduction velocity along auditory neurons occurs within seconds, attributed to fast energetic failure. SIGNIFICANCE: This model of metabolic sensory neuropathy warns against exposure of metabolically-impaired patients to sustained auditory stimulation. PMID- 29625344 TI - Response of antioxidant enzymes to Cd and Pb exposure in water flea Daphnia magna: Differential metal and age - Specific patterns. AB - To investigate oxidative stress responses to cadmium and lead, the freshwater water flea Daphnia magna was exposed to Cd and Pb for 48 h. Following treatment with sub-lethal concentrations, intracellular reactive oxygen species (ROS) levels, as well as modulation of multiple biomarker, such as superoxide dismutase (SOD) activity, glutathione (GSH) contents, glutathione S-transferase (GST) activity, antioxidant enzyme - coding genes (three GST isoforms, glutaredoxin [GRx], glutathione peroxidase [GPx], and thioredoxin [TRx]), and stress-response proteins (heat shock protein 70 [Hsp70] and Hsp90) were examined. The results showed that intracellular ROS level was not changed at 24 h, but reduced at 48 h. Levels of total GSH content were reduced by Cd, but highly induced by Pb. SOD and GST activities were stimulated 48 h after exposure to Cd and Pb. A significant modulation of oxidative stress marker genes was observed after exposure to each element with different expression patterns depending on the metal and developmental stages. In particular, the expression levels of GST-sigma, HSP70, and HSP90 genes were enhanced in Cd - and Pb - exposed neonates. These findings imply that oxidative stress markers appear to be actively involved in cellular protection against metal-induced oxidative stress in D. magna. This study would facilitate the understanding of the molecular response to Cd and Pb exposure in water fleas. PMID- 29625345 TI - Toward an adverse outcome pathway for impaired growth: Mitochondrial dysfunction impairs growth in early life stages of the fathead minnow (Pimephales promelas). AB - Chemical contaminants present in the environment can affect mitochondrial bioenergetics in aquatic organisms and can have substantial effects on individual fitness. As early life stages of fish are particularly vulnerable to environmental contaminants, they are ideal models for examining the relationship between impaired mitochondrial bioenergetics (ATP-dependent respiration, basal oxidative respiration) and apical endpoints such as growth. Here, early life stages of the fathead minnow (Pimephales promelas), an ecologically relevant North American species, were used to investigate the relationship between mitochondrial bioenergetics and growth following perturbation with model mitochondrial toxicants 2,4-dinitrophenol and octylamine. Fathead minnows were exposed to 2,4-dinitrophenol and octylamine at 3 concentrations for 24 h and endpoints related to mitochondrial bioenergetics were measured with the Agilent Seahorse XFe24 Bioanalyzer. In order to link changes in mitochondrial bioenergetics to growth, fathead minnows were exposed to the same chemical contaminants for 7-14 days and growth was measured by measuring total length on a weekly basis. There was a significant correlation between decrease in average length at 14 days and basal respiration (r = 0.997, p = 0.050, n = 3), as well as maximal respiration (r = 0.998, p-value = 0.043, n = 3) for embryos exposed to 2,4 dinitrophenol. For octylamine, ATP production was highly correlated with average length at 7 days (p-value = 0.1) and spare respiratory capacity and average length at 14 days were highly correlated (p-value = 0.1). These data improve understanding of how mitochondrial toxicants impair growth in fish larvae and may be useful for developing an adverse outcome pathway for growth. PMID- 29625346 TI - A laboratory information management system for the analysis of tritium (3H) in environmental waters. AB - Accurate and precise measurements of low levels of tritium (3H) in environmental waters are difficult to attain due to complex steps of sample preparation, electrolytic enrichment, liquid scintillation decay counting, and extensive data processing. We present a Microsoft AccessTM relational database application, TRIMS (Tritium Information Management System) to assist with sample and data processing of tritium analysis by managing the processes from sample registration and analysis to reporting and archiving. A complete uncertainty propagation algorithm ensures tritium results are reported with robust uncertainty metrics. TRIMS will help to increase laboratory productivity and improve the accuracy and precision of 3H assays. The software supports several enrichment protocols and LSC counter types. TRIMS is available for download at no cost from the IAEA at www.iaea.org/water. PMID- 29625347 TI - Improved freeze-dried kit for the preparation of 188ReN-DEDC/lipiodol for the therapy of unresectable hepatocellular carcinoma. AB - Rhenium-188-N-(DEDC)2/lipiodol (abbreviated as 188ReN-DEDC, where DEDC = monoanionic diethyldithiocarbamate) is a clinically proven radiopharmaceutical for the therapy of unresectable hepatocellular carcinoma (HCC) through trans arterial radioembolization (TARE). A two-vial freeze-dried kit for the preparation of [188ReN(DEDC)2] complex using sodium perrhenate (Na188ReO4) obtained from a commercial Tungsten-188/Rhenium-188 generator had been reported earlier. This method required addition of stipulated volume of glacial acetic acid into vial 1 by the user for efficient preparation of [188ReN]2+ intermediate. An error in this step can result in low radiochemical yield of [188ReN]2+ intermediate as well as sub-optimal pH of the reaction mixture for the second step, leading to poor radiochemical purity of 188ReN-DEDC complex. In the present work, a solution to this problem was found by including an oxalate buffer of pH = 3 in vial 1, eliminating the need for the addition of glacial acetic acid by the user. This modification not only made the kits more user-friendly, it resulted in significant improvement in the kinetics of formation of [188ReN]2+ intermediate, wherein > 95% radiochemical purity could be achieved within 5 min incubation at ambient temperature. Moreover, the novel route for the preparation of [188ReN]2+ intermediate may be applied to any radiopharmaceutical based on 188ReN-core. PMID- 29625348 TI - Role of dietary alpha- and gamma-tocopherol from Rosa mosqueta oil in the prevention of alterations induced by high-fat diet in a murine model. AB - OBJECTIVE: The aim of this study was to evaluate the contribution of tocopherols present in Rosa mosqueta oil (RM) in the prevention of high-fat diet (HFD) induced alterations. METHODS: Male C57 BL/6 J mice (n = 9/group) were fed for 12 wk and divided into four groups: control (CD; 10% kcal fat, 20% kcal protein, 70% kcal carbohydrates); HFD (60% as fat, 20% kcal protein, 20% kcal carbohydrates); HFD + RM (0.01 mL/g body weight/d); and HFD + RM- without tocopherols (0.01 mL/g body weight/d). Parameters of obesity, liver steatosis (histology, triacylglycerols content), inflammation (adipose NLRP3 inflammasome, tumor necrosis factor-alpha and interleukin-1 beta expression, hepatic nuclear factor kappaB) and oxidative stress (hepatic Nrf2 activation, carbonylated proteins) were evaluated. RESULTS: Liver steatosis, inflammatory, and oxidative stress parameters were significantly (P < 0.05) increased in the HFD + RM- compared with the HFD + RM, with no differences between HFD and HFD + RM-. CONCLUSION: The present study suggests that alpha- and gamma-tocopherols from RM may have an important role in the prevention of alterations induced by HFD. PMID- 29625349 TI - Dietary correlates of chronic widespread pain in Meru, Kenya. AB - OBJECTIVE: To gather preliminary data examining whether dehydration and/or exposure to monosodium glutamate (MSG) may influence pain in Meru, Kenya. METHODS: Two small pilot studies were conducted in Meru, Kenya after community report of high chronic pain in the region. First, a prevalence estimate was conducted among 89 participants from random households. Second, widespread chronic pain participants, recruited from the community, completed a demographic questionnaire, pain impact questionnaire, and 1-wk food/symptom diary. Those who returned the food/symptom diary 1 wk later were assigned to a treatment group based on their report of water/tea intake per day (<2 L versus >=2 L) and reported use of mixed spices with MSG (yes/no). Groups received 1) water, 2) alternative spices without MSG, 3) water and alternative spices, or 4) acetaminophen (1000 mg twice daily) for those with neither exposure. Improvement was defined as >=30% reduction in pain impact score. RESULTS: Prevalence of chronic pain among 89 participants surveyed was 60%. Thirty participants were recruited for the intervention (90% female; average age 56 [ +/- 18] y). The water and alternative spices and acetaminophen groups both experienced significant reductions in pain after 2 wk, with the greatest percentage of participants improving in the water and alternative spices group. CONCLUSION: This pilot data suggests an abnormally high prevalence of pain in Meru, Kenya, and that MSG intake, combined with dehydration, may be contributing to chronic widespread pain in this region. Future research should include a formal pain prevalence estimate and a randomized controlled trial to further test this dietary intervention. PMID- 29625350 TI - Victims of Chinese famine in early life have increased risk of metabolic syndrome in adulthood. AB - OBJECTIVES: To investigate the association of exposure to the Chinese famine during early life with metabolic syndrome risk in adults. METHODS: There were 7,915 participants from Dongfeng-Tongji cohort were included in the present study. Participants were classified as non-exposed group, fetal exposed group, early childhood-, mid childhood-, and late childhood-exposed groups, respectively. Metabolic syndrome was defined according to International Diabetes Foundation criteria (2005). Logistic regression model was used to explore the association between famine exposure in early life and metabolic syndrome risk in adults. RESULTS: The metabolic syndrome prevalence in non-, fetal-, early childhood-, mid childhood-, and late childhood- exposed groups were 25.2%, 26.9%, 30.3%, 32.7%, and 32.7%, respectively. Compared with non-exposed group, participants exposed to famine in the fetal (0.96, 95% CI: 0.77-1.20), early childhood (1.24, 95% CI: 1.01-1.52), mid childhood (1.39, 95% CI: 1.13-1.72), and late childhood (1.33, 95% CI: 1.08-1.63) had higher metabolic syndrome prevalence risk in adults after adjustment for potential confounders (P for trend < 0.0001). In gender-specific analyses, women exposed to famine in early childhood (1.26, 95% CI: 1.02-1.56), mid childhood (1.43, 95% CI: 1.14-1.78), and late childhood (1.47, 95% CI: 1.18-1.84) had higher metabolic syndrome prevalence risk than non exposed women (P for trend < 0.0001). There was a famine-gender interaction on metabolic syndrome prevalence risk (P for interaction = 0.0001). CONCLUSION: Results in the present study indicated that exposure to famine in early life increases the risk of metabolic syndrome in adulthood, particularly in women. PMID- 29625351 TI - Influence of tube potential on CT body composition analysis. AB - OBJECTIVES: Our purpose was to investigate whether tube potential in contrast enhanced computed tomography (CT) affects body composition analysis. METHODS: Images from dual-source, dual-energy CT from the abdomen with intravenous contrast media administration were used. A total of 17 patients (11 women, mean age 52) with a mean body mass index of 20.8 kg/cm2 were included. Simultaneously acquired images with a tube voltage of 80 kV and 140 kV were compared. Body composition was analyzed on a single slice at the L3 level. Parameters evaluated included muscle and fat attenuation (Hounsfield units [HU]), skeletal muscle index (cm2/m2), muscle area (cm2), and steatotic muscle area (cm2). Significant differences between 80 kV and 140 kV series were compared using the paired Student's t test. RESULTS: Tube potential affected muscle attenuation with an average difference of 17% between 80 kV and 140 kV series (48 HU versus 41 HU, P < 0.01), fat attenuation (-84 HU versus -69 HU, P < 0.01), skeletal muscle index of 5.2% (40.1 cm2/m2 versus 42.2 cm2/m2, P < 0.01), muscle area of 5.1% (117 cm2 versus 123 cm2, P < 0.01), and steatotic muscle area of 12.9% (31 cm2 versus 35 cm2, P < 0.01). CONCLUSION: Tube potential significantly affects body segmentation in contrast-enhanced CT. PMID- 29625352 TI - Beyond Low-Rank Representations: Orthogonal clustering basis reconstruction with optimized graph structure for multi-view spectral clustering. AB - Low-Rank Representation (LRR) is arguably one of the most powerful paradigms for Multi-view spectral clustering, which elegantly encodes the multi-view local graph/manifold structures into an intrinsic low-rank self-expressive data similarity embedded in high-dimensional space, to yield a better graph partition than their single-view counterparts. In this paper we revisit it with a fundamentally different perspective by discovering LRR as essentially a latent clustered orthogonal projection based representation winged with an optimized local graph structure for spectral clustering; each column of the representation is fundamentally a cluster basis orthogonal to others to indicate its members, which intuitively projects the view-specific feature representation to be the one spanned by all orthogonal basis to characterize the cluster structures. Upon this finding, we propose our technique with the following: (1) We decompose LRR into latent clustered orthogonal representation via low-rank matrix factorization, to encode the more flexible cluster structures than LRR over primal data objects; (2) We convert the problem of LRR into that of simultaneously learning orthogonal clustered representation and optimized local graph structure for each view; (3) The learned orthogonal clustered representations and local graph structures enjoy the same magnitude for multi-view, so that the ideal multi-view consensus can be readily achieved. The experiments over multi-view datasets validate its superiority, especially over recent state-of-the-art LRR models. PMID- 29625353 TI - The convergence analysis of SpikeProp algorithm with smoothing L1/2 regularization. AB - Unlike the first and the second generation artificial neural networks, spiking neural networks (SNNs) model the human brain by incorporating not only synaptic state but also a temporal component into their operating model. However, their intrinsic properties require expensive computation during training. This paper presents a novel algorithm to SpikeProp for SNN by introducing smoothing L1/2 regularization term into the error function. This algorithm makes the network structure sparse, with some smaller weights that can be eventually removed. Meanwhile, the convergence of this algorithm is proved under some reasonable conditions. The proposed algorithms have been tested for the convergence speed, the convergence rate and the generalization on the classical XOR-problem, Iris problem and Wisconsin Breast Cancer classification. PMID- 29625354 TI - Multilayer bootstrap networks. AB - Multilayer bootstrap network builds a gradually narrowed multilayer nonlinear network from bottom up for unsupervised nonlinear dimensionality reduction. Each layer of the network is a nonparametric density estimator. It consists of a group of k-centroids clusterings. Each clustering randomly selects data points with randomly selected features as its centroids, and learns a one-hot encoder by one nearest-neighbor optimization. Geometrically, the nonparametric density estimator at each layer projects the input data space to a uniformly-distributed discrete feature space, where the similarity of two data points in the discrete feature space is measured by the number of the nearest centroids they share in common. The multilayer network gradually reduces the nonlinear variations of data from bottom up by building a vast number of hierarchical trees implicitly on the original data space. Theoretically, the estimation error caused by the nonparametric density estimator is proportional to the correlation between the clusterings, both of which are reduced by the randomization steps. PMID- 29625355 TI - Learning from label proportions on high-dimensional data. AB - Learning from label proportions (LLP), in which the training data is in the form of bags and only the proportion of each class in each bag is available, has attracted wide interest in machine learning. However, how to solve high dimensional LLP problem is still a challenging task. In this paper, we propose a novel algorithm called learning from label proportions based on random forests (LLP-RF), which has the advantage of dealing with high-dimensional LLP problem. First, by defining the hidden class labels inside target bags as random variables, we formulate a robust loss function based on random forests and take the corresponding proportion information into LLP-RF by penalizing the difference between the ground truth and estimated label proportion. Second, a simple but efficient alternating annealing method is employed to solve the corresponding optimization model. At last, various experiments demonstrate that our algorithm can obtain the best accuracies on high-dimensional data compared with several recently developed methods. PMID- 29625356 TI - Continuous hyperpolarization with parahydrogen in a membrane reactor. AB - Hyperpolarization methods entail a high potential to boost the sensitivity of NMR. Even though the "Signal Amplification by Reversible Exchange" (SABRE) approach uses para-enriched hydrogen, p-H2, to repeatedly achieve high polarization levels on target molecules without altering their chemical structure, such studies are often limited to batch experiments in NMR tubes. Alternatively, this work introduces a continuous flow setup including a membrane reactor for the p-H2, supply and consecutive detection in a 1 T NMR spectrometer. Two SABRE substrates pyridine and nicotinamide were hyperpolarized, and more than 1000-fold signal enhancement was found. Our strategy combines low-field NMR spectrometry and a membrane flow reactor. This enables precise control of the experimental conditions such as liquid and gas pressures, and volume flow for ensuring repeatable maximum polarization. PMID- 29625357 TI - Influence of soft tissue in the assessment of the primary fixation of acetabular cup implants using impact analyses. AB - BACKGROUND: The acetabular cup (AC) implant primary stability is an important determinant for the success of cementless hip surgery but it remains difficult to assess the AC implant fixation in the clinic. A method based on the analysis of the impact produced by an instrumented hammer on the ancillary has been developed by our group (Michel et al., 2016a). However, the soft tissue thickness present around the acetabulum may affect the impact response, which may hamper the robustness of the method. The aim of this study is to evaluate the influence of the soft tissue thickness (STT) on the acetabular cup implant primary fixation evaluation using impact analyses. METHODS: To do so, different AC implants were inserted in five bovine bone samples. For each sample, different stability conditions were obtained by changing the cavity diameter. For each configuration, the AC implant was impacted 25 times with 10 and 30 mm of soft tissues positioned underneath the sample. The averaged indicator Im was determined based on the amplitude of the signal for each configuration and each STT and the pull-out force was measured. FINDINGS: The results show that the resonance frequency of the system increases when the value of the soft tissue thickness decreases. Moreover, an ANOVA analysis shows that there was no significant effect of the value of soft tissue thickness on the values of the indicator Im (F = 2.33; p value = 0.13). INTERPRETATION: This study shows that soft tissue thickness does not appear to alter the prediction of the acetabular cup implant primary fixation obtained using the impact analysis approach, opening the path towards future clinical trials. PMID- 29625359 TI - Multilayered structures using thin plates of LiTaO3 for acoustic wave resonators with high quality factor. AB - Multilayered substrates, including thin plates of LiTaO3 (LT) bonded to silicon (Si) or glass wafers either directly or via intermediate layers, were numerically investigated as potential materials for surface acoustic wave (SAW) resonators with high quality (Q)-factor required for the next generation of mobile communication systems. The propagation velocities and electromechanical coupling coefficients of shear horizontally (SH) polarized acoustic waves were estimated as functions of LT orientation and thicknesses of all layers in LT/Si, LT/SiO2/Si, LT/glass, LT/AlN/glass and structures with several pairs of SiO2/AlN layers between LT and the glass wafer. Optimal combinations of cut angle, LT and electrode thicknesses, as well as the number and thicknesses of intermediate layers, required for the construction of resonators with improved performance were observed for each analyzed structure. In the resonators employing LT/Si and LT/SiO2/Si structures with 30 degrees YX - 48 degrees YX LT cuts, high electromechanical coupling k2, reaching 11.6%, can be combined with high velocities up to 4000 m/s, zero TCF at the resonant frequency and Q-factors that are considerably higher than in the LSAW filters using regular LT substrates. To understand the loss mechanisms that limit resonator Q-factors in LT/glass, mechanical displacements that accompany wave propagation in multilayered structures were visualized. Investigation of the nature of acoustic modes and their transformations with number and thicknesses of the layers revealed that the low-velocity glass wafer can be used as a supporting substrate if an intermediate AlN layer or alternating pairs of low- and high-velocity layers, for example SiO2/AlN, are introduced between LT and the glass wafer. PMID- 29625358 TI - The role of travel distance and price promotions in tobacco product purchase quantity. AB - INTRODUCTION: Rural Americans are particularly vulnerable to tobacco price reducing promotions are known to be directed to and used by vulnerable populations. Tobacco purchasing decisions, such as unit quantity purchased, may vary by rurality, by price promotion use, and possibly by the interaction between the two. Purchase decisions are likely to affect tobacco use behavior. Therefore, explanation of variation in tobacco purchase quantity by factors associated with rural vulnerability and factors that fall under the regulatory scope of the Tobacco Control Act (TCA) of 2009 could be of value to regulatory proposals intended to equitably benefit public health. METHODS: Our sample included 54 combustible tobacco users (298 purchase events) and 27 smokeless tobacco users (112 purchase events), who were asked to report all tobacco purchases on a smartphone application. We used an ecological momentary assessment methodology to collect data about tobacco users' purchasing patterns, including products, quantity purchased, and use of price promotions. A parent cohort study provided relevant data for home-outlet distance calculation and covariates. Our analysis examined associations between our outcome-purchase quantity per purchase event and distance from participant's home to the nearest outlet, whether a price reducing promotion was used, and the interaction of these two factors. RESULTS: Combustible users showed an increased cigarette pack purchase quantity if they lived further from an outlet and used a price promotion (i.e., an interaction effect; RR = 1.70, 95% CI [1.11, 2.62]). Smokeless users purchased more units of snuff when they used price promotions (RR = 1.81, 95% CI [1.02, 3.20]). CONCLUSIONS: Regulatory action that imposes restrictions on the availability or use of price promotions could alter the purchasing behavior of rural Americans in such a way that makes it easier to reduce tobacco use or quit. Such action would also restrict flexibility in the price of tobacco products, which is known as a powerful tobacco control lever. PMID- 29625360 TI - Correlation between quadriceps and hamstrings inter-limb strength asymmetry with change of direction and sprint in U21 elite soccer-players. AB - The aim of this study was to investigate the relationship between in quadriceps and hamstrings inter-limb strength asymmetry and change of direction, sprinting and jumping abilities in U21 elite soccer players. Twenty-seven soccer players volunteered for this study. Isokinetic quadriceps and hamstrings peak torque was measured at high and low angular velocities, both in concentric and eccentric modalities. Performance in agility T-test, 20 + 20 m shuttle-test, 10 m and 30 m sprint, squat jump (SJ) and counter-movement jump (CMJ), were measured. Overall, time on agility T-test and 20 + 20 m shuttle-test was moderately and positively correlated with the quadriceps and hamstrings inter-limb eccentric peak torque asymmetry, both at high and low angular velocities. In addition, time on 10 m and 30 m sprints was moderately and positively correlated with the hamstrings inter limb high-velocity concentric peak torque asymmetry. SJ and CMJ showed trivial to small correlations with hamstrings and quadriceps inter-limb peak torque asymmetry. The present results provide further information insight the role of lower-limb muscle strength balance in COD, sprinting and jumping performance. PMID- 29625361 TI - Quadriceps concentric-eccentric force and muscle architecture in COPD patients vs healthy men. AB - The aim of this study was to compare quadriceps concentric and eccentric strength and muscle architecture in chronic obstructive pulmonary disease (COPD) patients vs healthy men. Thirty-five COPD patients (age = 65 +/- 4 yrs, forced expiratory volume (FEV1) = 63 +/- 10%; FEV1/forced vital capacity (FVC)=57 +/- 13% of predicted) and 25 age-matched healthy men (age = 65 +/- 4 yrs, FEV1=114 +/- 17%; FEV1/FVC = 101 +/- 6% of predicted) (CON) participated in the present cross sectional study. Concentric and eccentric isokinetic peak-torque was measured at low and high angular-velocity. Vastus lateralis pennation angle, fascicle length and muscle thickness were recorded using ultrasound device. Similar eccentric peak-torque was found in COPD and CON at low (2.57 +/- 0.55 and 2.80 +/- 0.60 N?m?kg-1, p = 0.128 respectively) and high (2.44 +/- 0.51 and 2.58 +/- 0.46 N?m?kg-1, p = 0.259) angular-velocity. Lower concentric peak-torque was found in COPD than in CON (p < 0.05). Smaller pennation angle (13.8 +/- 3.4 vs 16.2 +/- 3.9 degrees ) and muscle thickness (17.1 +/- 2.8 vs 20.3 +/- 3.0 mm) were found in COPD patients vs healthy men, with no difference in fascicle length. In COPD patients only, FEV1 and FEV1/FVC were negatively correlated with the eccentric-to concentric peak-torque ratio (r = -0.465 and r = -0.414, respectively); irrespective of the testing-modality, FEV1 and FEV1/FVC were moderately correlated with peak-torque (p < 0.05). The preserved eccentric strength in COPD patients could be accounted for both mechanical and neural adaptations caused by the disease severity. PMID- 29625363 TI - Off-label use and manipulations of antiepileptic drugs in children: Analysis of the outpatient prescriptions in a tertiary center. AB - OBJECTIVES: Little is known about off-label use and manipulations to achieve the prescribed dose of antiepileptic drugs (AEDs) in outpatient prescriptions. This study aimed to evaluate this practice in a tertiary center for child epilepsy. METHODS: We reviewed off-label use and manipulations of AEDs delivered to the outpatient's epilepsy clinic. Multivariate logistic regressions were used to determine the factors associated with off-label and manipulated uses. RESULTS: Five hundred eleven consultations generated 897 AED deliveries (1.75/consultation). Off-label use involved 182 (20.3%) of prescribed AEDs. Factors associated with off-label use were polytherapy and new AEDs while increase of age and nondevelopmental and structural-metabolic etiologies have a protective effect. Among the 1725 doses of AEDs prescribed per day, 33.5% generated manipulations (n=582): 40% inadequate (n=237) and 60% adequate (203 syrups, 112 scored tablets, 30 drops medicine). Polytherapy (p<10-4) and the absence of market authorization significantly favored manipulations whereas the increase in age restricted them. CONCLUSION: Off-label use and manipulations of AEDs remain an important problem in home care of children with epilepsy. This is mainly a concern for the most vulnerable groups, i.e., young patients, patients undergoing polytherapy, and patients with developmental and epileptic encephalopathy (DEE). International initiatives have been launched to improve the availability of labeled and adapted drugs in this population. PMID- 29625362 TI - Epilepsy-related concerns among patients with epilepsy in West China. AB - PURPOSE: In the present study, we aimed to investigate patient-derived epilepsy related concerns among Chinese individuals with epilepsy and the impact of seizure control on patient concerns. METHODS: All adult patients with epilepsy who had visited the outpatient clinic at West China Hospital between July 2014 and June 2016 were invited to participate in the study. All patients were given a blank sheet of paper and asked to list any concerns they had regarding their disease in order of importance. Demographic and clinical characteristics were also evaluated while regression models were used to examine the impact of seizure control on patient concerns. RESULTS: A total of 1040 patients reported 2202 concerns across 25 distinct categories. The most frequently listed concerns were worries about seizures (55.4%), maintaining a job (17.4%), and the heritability of epilepsy (16.0%). The legal right to drive was listed by only 3.5% of patients who took the survey while seizure recurrence was described by participants as the most important concern (379, 36.4%). Compared with the group with uncontrolled seizures, the group with controlled seizures reported less frequently about "holding down a job" (odds ratio (OR): 0.333 (0.187-0.591)), "fear of being injured during a seizure" (OR: 0.353 (0.183-0.682)), and "leading a normal life" (OR: 0.452 (0.234-0.871)), but they reported more frequently about "having another seizure" (OR: 2.447 (1.614-3.710)), "problems with medication side effects" (OR: 1.733 (1.148-2.616)), and their "legal right or ability to drive" (OR: 2.360 (1.094-5.092)). CONCLUSION: Our findings indicated that Chinese adults with epilepsy had various concerns, some of which differed from those observed in Western populations. Concerns about heritability of seizures, marriage, and pregnancy were of greater concern to Chinese patients compared with Western patients while the legal right to drive appeared to be less of a concern to Chinese patients. Patients with controlled seizures may still have many concerns. Chinese physicians should monitor patient concerns even among those whose seizures remain controlled to meet their needs. More time and attention should be given to address these issues in clinical practice in the context of Chinese culture. PMID- 29625364 TI - Usage of EpiFinder clinical decision support in the assessment of epilepsy. AB - BACKGROUND: The diagnosis of epilepsy is at times elusive for both neurologists and nonneurologists, resulting in delays in diagnosis and therapy. The development of screening methods has been identified as a priority in response to this diagnostic and therapeutic gap. EpiFinder is a novel clinical decision support tool designed to enhance the process of information gathering and integration of patient/proxy respondent data. It is designed specifically to take key terms from a patient's history and incorporate them into a heuristic algorithm that dynamically produces differential diagnoses of epilepsy syndromes. OBJECTIVE: The objective of this study was to test the usability and diagnostic accuracy of the clinical decision support application EpiFinder in an adult population. METHODS: Fifty-seven patients were prospectively identified upon admission to the Epilepsy Monitoring Unit (EMU) for episode classification from January through June of 2017. Based on semiologic input, the application generates a list of epilepsy syndromes. The EpiFinder-generated diagnosis for each subject was compared to the final diagnosis obtained via continuous video electroencephalogram (cVEEG) monitoring. RESULTS: Fifty-three patients had habitual events recorded during their EMU stay. A diagnosis of epilepsy was confirmed (with cVEEG monitoring) in 26 patients while 27 patients were found to have a diagnosis other than epilepsy. The algorithm appropriately predicted differentiation between the presence of an epilepsy syndrome and an alternative diagnosis with 86.8% (46/53 participants) accuracy. EpiFinder correctly identified the presence of epilepsy with a sensitivity of 86.4% (95% confidence interval [CI]: 65.0-97.1) and specificity of 85.1% (95% CI: 70.2-96.4). CONCLUSION: The initial testing of the EpiFinder algorithm suggests possible utility in differentiating between an epilepsy syndrome and an alternative diagnosis in adult patients. PMID- 29625365 TI - Morphometric MRI features and surgical outcome in patients with epilepsy related to hippocampal sclerosis and low intellectual quotient. AB - OBJECTIVE: The objectives of this study were to verify in a series of patients with mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) if those with low intellectual quotient (IQ) levels have more extended areas of atrophy compared with those with higher IQ levels and to analyze whether IQ could be a variable implicated on a surgical outcome. MATERIAL AND METHODS: Patients (n=106) with refractory MTLE-HS submitted to corticoamygdalohippocampectomy (CAH) (57 left mesial temporal lobe epilepsy (MTLE); 45 males) were enrolled. To determine if the IQ was a predictor of seizure outcome, totally seizure-free (SF) versus nonseizure-free (NSF) patients were evaluated. FreeSurfer was used for cortical thickness and volume estimation, comparing groups with lower (<80) and higher IQ (90-109) levels. RESULTS: In the whole series, 42.45% of patients were SF (Engel Class 1a; n=45), and 57.54% were NSF (n=61). Total cortical volume was significantly reduced in the group with lower IQ (p=0.01). Significant reductions in the left hemisphere included the following: rostral middle frontal (p=0.001), insula (p=0.002), superior temporal gyrus (p=0.003), thalamus (p=0.004), and precentral gyrus (p=0.02); and those in the right hemisphere included the following: rostral middle frontal (p=0.003), pars orbitalis (p=0.01), and insula (p=0.02). Cortical thickness analysis also showed reductions in the right superior parietal gyrus in patients with lower IQ. No significant relationship between IQ and seizure outcome was found. CONCLUSIONS: This is the first study of a series of patients with pure MTLE-HS, including those with low IQ and their morphometric magnetic resonance imaging (MRI) features using FreeSurfer. Although patients with lower intellectual scores presented more areas of brain atrophy, IQ was not a predictor of surgical outcome. Therefore, when evaluating seizure follow-up, low IQ in patients with MTLE-HS might not contraindicate resective surgery. PMID- 29625366 TI - Serial changes in the paroxysmal discharges in rolandic epilepsy may predict seizure recurrence: A retrospective 3-year follow-up study. AB - OBJECTIVE: The aim of this study was to assess the electrographic criteria related to seizure recurrence and determine age-related seizure recurrence in children with rolandic epilepsy under long-term follow-up. METHODS: We retrospectively analyzed the data belonging to 109 patients with rolandic epilepsy with sufficient information regarding disease course and follow-up duration longer than 3years. Patients were divided into two categories: Group A (n: 75), comprised of "patients having fewer than four seizures", and Group B (n: 34), the "recurrence group comprised of patients having more than four seizures in the first three months". The number of spikes per minute during both wakefulness and sleep, the localization of spikes other than centrotemporal region, and the duration of spike-wave activity were evaluated longitudinally, with repeated electroencephalogram (EEG) recordings every 6months. RESULTS: The appearance of rolandic spikes in awake EEGs tended to be more prevalent in Group B than Group A. In Group B, spike rates significantly increased in the 12 and 18months after onset whereas spike rates increased significantly only 6months after onset in Group A. Seizure recurrence is mostly seen at 6-8years, and improvement becomes evident by age 12. The mean number of paroxysmal rolandic discharges during sleep was significantly higher in the younger age groups (3-5, 6-8), and the mean number of spikes per minute significantly decreased at ages 9 11 and over 12. CONCLUSION: Our study demonstrates that extended periods of high frequency of paroxysmal discharges, initial frontal EEG focus, and persistence of awake interictal abnormalities are highly effective in predicting seizure recurrence in patients with rolandic epilepsy (RE). PMID- 29625367 TI - Support values through the eyes of the patient: An exploratory study into long term support of persons with refractory epilepsy. AB - A significant group of persons affected by refractory epilepsy require a wide range of long-term support from professionals as well as informal support givers. To enhance person-centeredness, it is important to know which patient values are associated with long-term support. An Internet survey produced a total of 1176 statements from 289 persons with epilepsy for analysis. Statements were expressed in the respondent's own words and were related to positive experiences (704) as well as possible areas of improvement (472) regarding the support received in the past six months. Thematic summaries of the survey results were presented to four focus groups of persons with epilepsy and proxies with a request to formulate the most important patient values which should be observed in long-term support. In iterative sessions with a panel of epilepsy experts, a framework of twelve value domains was formulated, organized in four major value clusters. An example of how these value domains can be operationalized for use in practice is next presented as a checklist to help evaluate the support patients with long-term support needs actually receive. Correspondingly, two sets of reflective questions were formulated for informal and professional support givers for the purpose of evaluating and improving person-centeredness in their support practices. PMID- 29625368 TI - Reconfiguring the violent encounter? Preloading, security staff and breathalyser use in the night-time economy. AB - BACKGROUND: In a culture of preloading and late-night licenses, alcohol-related violence remains a persistent problem for police and public health. Understood as a ritualized 'micro-social' interaction (Collins 2009a, 2009b), entry into bars and clubs is a particular flashpoint for violence between bouncers/door staff and customers. METHODS: A police-led initiative to deter excessive drunkenness and preloading using hand-held breathalysers (the #RU2Drunk scheme) was investigated from the perspective of security and bar staff using the devices. Interviews (n = 18 + 12), a focus group with security staff (n = 22) and a focus group with a security company (n = 3) were conducted in two seaside towns in the South-West of England, UK. A qualitative thematic analysis was conducted. FINDINGS: Door staff emphasised the normality of 'determined drunkenness' and associated violence in their working lives. Breathalyser use appeared to disrupt the 'ritual' of the violent encounter by reconfiguring it into an interaction between customer and technology. This depersonalized the judgement about who was 'too drunk' to enter the venue, with the more discretionary nature of who to breathalyse hidden from customers. Other door staff found it less useful and saw it as a challenge to their authority and expertise. At a managerial level there was concern about the transfer of responsibility for policing the night time economy (NTE). CONCLUSION: There is potential to reconfigure the violent encounter for door staff using breathalyser devices. However, this is more likely to succeed where other structural limits (e.g. restrictions on late licenses) are in place, and as part of wider policy initiatives to reconfigure the alcohol-saturated NTE leisure scene. PMID- 29625370 TI - Radon-222 related influence on ambient gamma dose. AB - Ambient gamma dose, radon, and rainfall have been monitored in southern Bucharest, Romania, from 2010 to 2016. The seasonal cycle of background ambient gamma dose peaked between July and October (100-105 nSv h-1), with minimum values in February (75-80 nSv h-1), the time of maximum snow cover. Based on 10 m a.g.l. radon concentrations, the ambient gamma dose increased by around 1 nSv h-1 for every 5 Bq m-3 increase in radon. Radon variability attributable to diurnal changes in atmospheric mixing contributed less than 15 nSv h-1 to the overall variability in ambient gamma dose, a factor of 4 more than synoptic timescale changes in air mass fetch. By contrast, precipitation-related enhancements of the ambient gamma dose were 15-80 nSv h-1. To facilitate routine analysis, and account in part for occasional equipment failure, an automated method for identifying precipitation spikes in the ambient gamma dose was developed. Lastly, a simple model for predicting rainfall-related enhancement of the ambient gamma dose is tested against rainfall observations from events of contrasting duration and intensity. Results are also compared with those from previously published models of simple and complex formulation. Generally, the model performed very well. When simulations underestimated observations the absolute difference was typically less than the natural variability in ambient gamma dose arising from atmospheric mixing influences. Consequently, combined use of the automated event detection method and the simple model of this study could enable the ambient gamma dose "attention limit" (which indicates a potential radiological emergency) to be reduced from 200 to 400% above background to 25-50%. PMID- 29625369 TI - Maternal mental health during the neonatal period: Relationships to the occupation of parenting. AB - PURPOSE: To (1) examine the extent of a range of early mental health challenges in mothers with a very preterm infant hospitalized in the NICU and mothers of full-term infants, (2) identify family social background and infant medical factors associated with higher levels of maternal psychological distress, and (3) assess the relationship between maternal psychological distress and maternal perceptions of the parenting role, parenting confidence and NICU engagement. METHODS: At hospital discharge 37 mothers of very preterm infants (<=32 weeks gestation) and 47 mothers of full-term infants (>=37 weeks gestation) completed structured assessments of their psychological wellbeing and transition to parenting. Mothers of very preterm infants were also questioned about their NICU visitation and involvement in infant care. RESULTS: Sixty-four percent (n = 54) of mothers experienced psychological distress (n = 26, 70% of preterm; n = 28, 60% of full-term). Lower infant birthweight was associated with maternal psychological distress (p = .03). Mothers of very preterm infants had significantly more psychological distress related to having a Cesarean section delivery (p = .02). Higher levels of psychological distress were associated with lower levels of parenting confidence in mothers of both very preterm and full term infants (p < .02). CONCLUSION: Although parents of very preterm infants have higher rates of maternal mental health challenges, mothers of full-term infants at high social risk are also impacted. PMID- 29625371 TI - Purification of human erythropoietin by affinity chromatography using cyclic peptide ligands. AB - Prior work described the identification and characterization of erythropoietin binding cyclic peptides SLFFLH, VVFFVH, FSLLHH and FSLLSH (all of the form cyclo[(Nalpha-Ac)Dap(A)-X1-X6-AE], wherein X1-X6 is the listed sequences). In this work, the peptide ligands were synthesized on Toyopearl chromatographic resins and utilized for purifying recombinant human erythropoietin (rHuEPO) from complex sources. Elution buffer pH and composition were optimized to maximize the recovery of standard rHuEPO from the peptide resins. The peptide-based adsorbents were employed for separating rHuEPO from a mixture of albumin, myoglobin, and IgG to examine their selectivity. When using FSLLHH, the inclusion of low amounts of surfactants in the wash and elution buffers facilitated the recovery of rHuEPO with high yield and purity. Specifically, FSLLSH and VVFFVH afforded the most efficient separation of rHuEPO, with yield and purity of 85% and 95-97%, respectively. The affinity resins were also utilized to purify rHuEPO from spiked CHO cell culture fluid. In particular, FSLLSH provided the most successful separation from CHO, with yield and purity above 90%, and 1.0 log10 reduction of host cell proteins. The influence of conductivity and pH in the CHO-rHuEPO load was investigated. Finally, FSLLSH-based resins were used to purify rHuEPO spiked into a Pichia pastoris cell culture fluid, resulting in product yield and purity of 96% and 84%, respectively, and 1.3 log10 reduction of host DNA. These results compare well with values obtained using wheat germ agglutinin agarose and clearly indicate the potential of the cyclic peptide resins as a viable tool for rHuEPO purification. PMID- 29625372 TI - Mechanisms for rhamnolipids-mediated biodegradation of hydrophobic organic compounds. AB - The widespread existence of hydrophobic organic compounds (HOCs) in soil and water poses a potential health hazard to human, such as skin diseases, heart diseases, carcinogenesis, etc. Surfactant-enhanced bioremediation has been regarded as one of the most viable technologies to treat HOCs contaminated soil and groundwater. As a biosurfactant that has been intensively studied, rhamnolipids have shown to enhance biodegradation of HOCs in the environment, however, the underlying mechanisms are not fully disclosed. In this paper, properties and production of rhamnolipids are summarized. Then effects of rhamnolipids on the biodegradation of HOCs, including solubilization, altering cell affinity to HOCs, and facilitating microbial uptake are reviewed in detail. Special attention is paid to how rhamnolipids change the bioavailability of HOCs, which are crucial for understanding the mechanism of rhamnolipids-mediated biodegradation. The biodegradation and toxicity of rhamnolipids are also discussed. Finally, perspectives and future research directions are proposed. This review adds insight to rhamnolipids-enhanced biodegradation process, and helps in application of rhamnolipids in bioremediation. PMID- 29625373 TI - Leptin/Adiponectin ratio as a potential biomarker for metabolic syndrome in patients with schizophrenia. AB - OBJECTIVE: Leptin and adiponectin are adipokines which have opposing roles in the development of insulin resistance and metabolic syndrome (MetS). Leptin/adiponectin ratio (L/A ratio) has been proposed as a good biomarker for MetS in general population. This study aimed to compare the strength of association between MetS and leptin, adiponectin and L/A ratio, as well as to assess their performance to diagnose MetS in patients with schizophrenia. METHODS: Patients diagnosed with DSM-IV schizophrenia and under clozapine or olanzapine monotherapy for at least six months were recruited. We used the modified ATP III criteria for Asians to evaluate subjects for a diagnosis of MetS. RESULTS: We recruited 262 study subjects with schizophrenia, and classified them into those with MetS (n = 87) and those without MetS (n = 175). Leptin level was positively correlated with BMI, waist circumference, and insulin level. Adiponectin level was negatively correlated with most metabolic parameters, except glucose level. L/A ratio was positively correlated with most metabolic parameters, except levels of glucose and HDL-C. Significant gender differences existed in leptin levels, adiponectin levels, and L/A ratio. Without and with adjustment of age and gender, binary logistic regression analysis showed that leptin level, adiponectin level, and L/A ratio were significantly associated with MetS. The area under curve (AUC) of L/A ratio and leptin level for MetS was 0.744 (95% CI = 0.685-0.802) and 0.666 (95% CI = 0.601-0.731). The AUC of adiponectin level for the absence of MetS was 0.717 (95% CI = 0.655-0.780). The discriminative strength of L/A ratio for MetS was better in men than in women. CONCLUSIONS: The present study results suggest that L/A ratio may be a preferential marker of metabolic syndrome in patients with schizophrenia compared to leptin or adiponectin alone. PMID- 29625374 TI - Psychosocial stress affects the acquisition of cerebellar-dependent sensorimotor adaptation. AB - Despite being overlooked in theoretical models of stress-related disorders, differences in cerebellar structure and function are consistently reported in studies of individuals exposed to current and early-life stressors. However, the mediating processes through which stress impacts upon cerebellar function are currently unknown. The aim of the current experiment was to test the effects of experimentally-induced acute stress on cerebellar functioning, using a classic, forward saccadic adaptation paradigm in healthy, young men and women. Stress induction was achieved by employing the Montreal Imaging Stress Task (MIST), a task employing mental arithmetic and negative social feedback to generate significant physiological and endocrine stress responses. Saccadic adaptation was elicited using the double-step target paradigm. In the experiment, 48 participants matched for gender and age were exposed to either a stress (n = 25) or a control (n = 23) condition. Saliva for cortisol analysis was collected before, immediately after, and 10, and 30 min after the MIST. Saccadic adaptation was assessed approximately 10 min after stress induction, when cortisol levels peaked. Participants in the stress group reported significantly more stress symptoms and exhibited greater total cortisol output compared to controls. The stress manipulation was associated with slower learning rates in the stress group, while control participants acquired adaptation faster. Learning rates were negatively associated with cortisol output and mood disturbance. Results suggest that experimentally-induced stress slowed acquisition of cerebellar-dependent saccadic adaptation, related to increases in cortisol output. These 'proof-of principle' data demonstrate that stress modulates cerebellar-related functions. PMID- 29625375 TI - The first (6-4) photolyase with DNA damage repair activity from the Antarctic microalga Chlamydomonas sp. ICE-L. AB - The psychrophilic microalga, Chlamydomonas sp. ICE-L, isolated from floating ice in the Antarctic, one of the most highly UV exposed ecosystems on Earth, displays an efficient DNA photorepair capacity. Here, the first known (6-4) photolyase gene (6-4CiPhr) from C. sp. ICE-L was identified. The 6-4CiPhr encoded 559-amino acid polypeptide with a pI of 8.86, and had a predicted Mw of 64.2 kDa. Real-time PCR was carried out to investigate the response of 6-4CiPhr to UVB exposure. The transcription of 6-4CiPhr was up-regulated continuously within 6 h, achieving a maximum of 62.7-fold at 6 h. Expressing 6-4CiPhr in a photolyase-deficient Escherichia coli strain improved survival rate of the strain. In vitro activity assays of purified protein demonstrated that 6-4CiPhr was a photolyase with 6-4PP repair activity. These findings improve understanding of photoreactivation mechanisms of (6-4) photolyase. PMID- 29625377 TI - Clinical characteristics associated with paedophilia and child sex offending - Differentiating sexual preference from offence status. AB - Contrary to public perception, child sex offending (CSO) and paedophilia are not the same. Only half of all cases of CSO are motivated by paedophilic preference, and a paedophilic preference does not necessarily lead to CSO. However, studies that investigated clinical factors accompanying and contributing to paedophilia so far mainly relied on paedophiles with a history of CSO. The aim of this study was to distinguish between factors associated with sexual preference (paedophile versus non-paedophile) and offender status (with versus without CSO). Accordingly, a 2 (sexual preference) * 2 (offender status) factorial design was used for a comprehensive clinical assessment of paedophiles with and without a history of CSO (n = 83, n = 79 respectively), child sex offenders without paedophilia (n = 32) and healthy controls (n = 148). Results indicated that psychiatric comorbidities, sexual dysfunctions and adverse childhood experiences were more common among paedophiles and child sex offenders than controls. Offenders and non-offenders differed in age, intelligence, educational level and experience of childhood sexual abuse, whereas paedophiles and non-paedophiles mainly differed in sexual characteristics (e.g., additional paraphilias, onset and current level of sexual activity). Regression analyses were more powerful in segregating offender status than sexual preference (mean classification accuracy: 76% versus 68%). In differentiating between offence- and preference-related factors this study improves clinical understanding of both phenomena and may be used to develop scientifically grounded CSO prevention and treatment programmes. It also highlights that some deviations are not traceable to just one of these two factors, thus raising the issue of the mechanism underlying both phenomena. PMID- 29625378 TI - Impulsivity profiles in pathological slot machine gamblers. AB - INTRODUCTION: In gambling disorder (GD), impulsivity has been related with severity, treatment outcome and a greater dropout rate. The aim of the study is to obtain an empirical classification of GD patients based on their impulsivity and compare the resulting groups in terms of sociodemographic, clinical and gambling behavior variables. METHODS: 126 patients with slot machine GD attending the Pathological Gambling Unit between 2013 and 2016 were included. The UPPS-P Impulsive Behavior Scale was used to assess impulsivity, and the severity of past year gambling behavior was established with the Screen for Gambling problems questionnaire (NODS). Depression and anxiety symptoms and executive function were also assessed. A two-step cluster analysis was carried out to determine impulsivity profiles. RESULTS: According to the UPPS-P data, two clusters were generated. Cluster 1 showed the highest scores on all the UPPS-P subscales, whereas patients from cluster 2 exhibited only high scores on two UPPS-P subscales: Negative Urgency and Lack of premeditation. Additionally, patients on cluster 1 were younger and showed significantly higher scores on the Beck Depression Inventory and on the State-Trait Anxiety Inventory questionnaires, worse emotional regulation and executive functioning, and reported more psychiatric comorbidity compared to patients in cluster 2. With regard to gambling behavior, cluster 1 patients had significantly higher NODS scores and a higher percentage presented active gambling behavior at treatment start than in cluster 2. CONCLUSIONS: We found two impulsivity subtypes of slot machine gamblers. Patients with high impulsivity showed more severe gambling behavior, more clinical psychopathology and worse emotional regulation and executive functioning than those with lower levels of impulsivity. These two different clinical profiles may require different therapeutic approaches. PMID- 29625379 TI - Broadening emission band of Ba2B2O5: Dy3+ by codoping Ce3+ as sensitizer and its application to white LEDs. AB - In order to achieve broad-band white emitting phosphor, Ce3+/Dy3+ codoped Ba2B2O5 were synthesized by a solid-state method, and the luminescence property and energy transfer were discussed in detail. Dy3+ doped Ba2B2O5 shows white emission, and the two narrow peaks which are assigned to the 4F9/2->6H15/2 and 4F9/2->6H13/2 transitions of Dy3+ ions, respectively. When codoped Ce3+ as sensitizer, the broad-band white emission can be obtained by the energy transfer from Ce3+ to Dy3+ ions in Ba2B2O5, and the mechanism is the dipole-dipole interaction. And the CIE coordinates can be tuned from (0.2501, 0.2323) to (0.3422, 0.3799) by increase Dy3+ content. The emission peak blue-shift of Ce3+ ions in Ba2B2O5:Ce3+, Dy3+ was observed from the thermal spectra, and the mechanism was analyzed. A white light emitting diodes (LEDs) can be fabricated Ba2B2O5:Ce3+, Dy3+ with 380nm chip, and the results show that the phosphor may be a potential application in this field. PMID- 29625380 TI - Interactions of tetracationic porphyrins with DNA and their effects on DNA cleavage. AB - The interaction of tetracationic porphyrins with DNA was studied using UV-Vis absorption, fluorescence spectroscopy and viscometry, and the particle sizes were determined. As cationic porphyrins, two isomer porphyrins, 3,3',3",3''' (5,10,15,20-Porphyrintetrayl)tetrakis(1-methylpyridinium) (TMPyP3) and 4,4',4",4'''-(5,10,15,20-Porphyrintetrayl)tetrakis(1-methylpyridinium) (TMPyP4), were studied. They differ in the position of NCH3+ group in phenyl ring of the porphyrins and hence, in degree of freedom of rotation of the phenyl rings about the central macrocycle. It was found that intercalated complexes are formed at DNA/porphyrin molar ratios (R) of 2.2 and 3.9 for TMPyP3 i TMPyP4, respectively. Decreasing R up to 0.4 and 0.8 for TMPyP3 i TMPyP4, respectively, leads mainly to formation of outside complexes due to pi-pi stacking between the porphyrin chromophores interacting electrostatically with phosphate framework of DNA. Each type of the obtained complexes was characterized using Scatchard approach. It was ascertained that the affinity of TMPyP4 to DNA is stronger than TMPyP3, meanwhile the wedge effect of the latter is higher. The differences between the porphyrin isomers become more evident at irradiation of their complexes with DNA. It was established that irradiation of the intercalated complexes results in DNA fragmentation. In the case of TMPyP4, DNA fragments of different size are formed. The irradiation of the outside DNA/porphyrin complexes leads to cleavage of DNA (TMPyP3 and TMPyP4) and partial destruction of the complex due to photolysis of the porphyrin (TMPyP3). PMID- 29625381 TI - Transcriptomics provides mechanistic indicators of mixture toxicology for IMX-101 and IMX-104 formulations in fathead minnows (Pimephales promelas). AB - Within the US military, new insensitive munitions (IMs) are rapidly replacing conventional munitions improving safety from unintended detonation. Toxicity data for IM chemicals are expanding rapidly, however IM constituents are typically deployed in mixture formulations, and very little is known about their mixture toxicology. In the present study we sought to characterize the mixture effects and toxicology of the two predominant IM formulations IMX-101 and IMX-104 in acute (48 h) larval fathead minnow (Pimephales promelas) exposures. IMX-101 consists of a mixture of 2,4-dinitroanisole (DNAN), 3-nitro-1,2,4-triazol-5-one (NTO), and nitroguanidine (NQ) while IMX-104 is composed of DNAN, NTO, and hexahydro-1,3,5-trinitro-1,3,5-triazine (RDX). DNAN was the most potent constituent in IMX-101 eliciting an LC50 of 36.1 mg/L, whereas NTO and NQ did not elicit significant mortality in exposures up to 1040 and 2640 mg/L, respectively. Toxic unit calculations indicated that IMX-101 elicited toxicity representative of the component concentration of DNAN within the mixture. Toxicogenomic responses for the individual constituents of IMX-101 indicated unique transcriptional expression and functional responses characteristic of: oxidative stress, impaired energy metabolism, tissue damage and inflammatory responses in DNAN exposures; impaired steroid biosynthesis and developmental cell-signaling in NQ exposures; and altered mitogen-activated protein kinase signaling in NTO exposures. Transcriptional responses to the IMX-101 mixture were driven by the effects of DNAN where expression and functional responses were nearly identical comparing DNAN alone versus the fractional equivalent of DNAN within IMX-101. Given that each individual constituent of the IMX-101 mixture elicited unique functional responses, and NTO and NQ did not interact with DNAN within the IMX 101 mixture exposure, the overall toxicity and toxicogenomic responses within acute exposures to the IMX-101 formulation are indicative of "independent" mixture toxicology. Alternatively, in the IMX-104 exposure both DNAN and RDX were each present at concentrations sufficient to elicit lethality (RDX LC50 = 28.9 mg/L). Toxic-unit calculations for IMX-104 mixture formulation exposures indicated slight synergistic toxicity (SigmaTU LC50 = 0.82, 95% confidence interval = 0.73-0.90). Unique functional responses relative to DNAN were observed in the IMX-104 exposure including responses characteristic of RDX exposure. Based on previous transcriptomics responses to acute RDX exposures in fathead minnow larvae, we hypothesize that the potentially synergistic responses within the IMX 104 mixture are related to interactive effects of each DNAN and RDX on oxidative stress mitigation pathways. PMID- 29625382 TI - Phthalimide conjugations for the degradation of oncogenic PI3K. AB - PI3K/Akt/mTOR pathway is crucial for carcinogenesis and its inhibitors have made a great progress in cancer treatment. However, there is still a great developing space for PI3K inhibitors as the acquired drug resistance hindered their application in clinical. Proteolysis-targeting chimeras (PROTACs) with the potential to handle the challenges faced in drug development could be an alternative therapeutic strategy. Moreover, the past two years have witnessed remarkable advances in the development of phthalimide conjugation as a strategy for the degradation instead of inhibition of the targets, including BET family proteins, Sirtuin 2, CDK 9, Smad 3, and BCR-ABL proteins. Here, we designed and synthesized a series of potential small molecular PROTACs for the degradation of PI3K. Four compounds induced remarkable PI3K degradation and down-regulated the phosphorylation of Akt, S6K and GSK-3beta in liver cancer cells HepG2. Furthermore, the representative compound D proved to inhibit tumor cells proliferation by the induction of autophagy instead of apoptosis or cell cycle arrest. PMID- 29625383 TI - Architecture and activation of phosphatidylinositol 3-kinase related kinases. AB - The phosphatidylinositol 3-kinase related protein kinases (PIKKs) are key to the regulation of a variety of eukaryotic cellular processes including DNA repair and growth regulation. While these massive proteins had long resisted structural analysis, recent advances in electron cryo-microscopy have now facilitated structural analysis of the major examples of PIKKs, including mTOR, DNA-PK, ATM, ATR and TRAPP/Tra1. In these PIKKs, the carboxy-terminal kinase domains and their proximal regions are structurally conserved. The structural organization of their extensive amino-terminal repeat regions, however, as well as their oligomeric organization and their interactions with accessory proteins, differ markedly amongst PIKKs. This architectural divergence provides the structural basis for the complex regulatory roles and functional diversity of PIKKs. PMID- 29625384 TI - Cancer: a CINful evolution. AB - Pioneering studies described cancer as an evolutionary process and detailed its intratumor heterogeneity in patients' specimens. The development of unbiased single-cell sequencing technologies confirmed these early observations and neoplasms are now widely recognized as populations of genetically, chromosomally and epigenetically distinct cells in which clones carrying beneficial traits expand in presence of selection factors like chemotherapy treatment. In support of this view, intratumor heterogeneity, by providing a large pool of phenotypically distinct clones, was shown to correlate with poor prognosis, therapy failure and metastasis. While most research has been focused on the role of nucleotide sequence variation, in recent years an increasing body of evidence suggests that aneuploidy and chromosome instability (CIN) contribute to tumor evolution. Here, we review recent advances in our understanding of the causes of aneuploidy and CIN and detail how they provide phenotypic variation at the cellular level. Moreover, we discuss evidences that aneuploidy and CIN kickstart a vicious loop generating genetic and karyotypic instability and provide clinical and experimental observations linking them to cancer progression. Finally, we suggest that aneuploidy and CIN contribute to tumor evolution by generating genome instability and intratumor heterogeneity. PMID- 29625385 TI - Targeting macrophage immunometabolism: Dawn in the darkness of sepsis. AB - Sepsis is known since the time (470 BC) of great Greek physician, Hippocrates. Advancement in modern medicine and establishment of separate branches of medical science dealing with sepsis research have improved its outcome. However, mortality associated with sepsis still remains higher (25-30%) that further increases to 40-50% in the presence of septic shock. For example, sepsis associated deaths account more in comparison to deaths-associated with myocardial infarction and certain cancers (i.e. breast and colorectal cancer). However, it is now well established that profound activation of innate immune cells including macrophages play a very important role in the immunopathogenesis of sepsis. Macrophages are sentinel cells of the innate immune system with their location varying from peripheral blood to various target organs including lungs, liver, brain, kidneys, skin, testes, vascular endothelium etc. Thus, profound and dysregulated activation of these cells during sepsis can directly impact the outcome of sepsis. However, the emergence of the concept of immunometabolism as a major controller of immune response has raised a new hope for identifying new targets for immunomodulatory therapeutic approaches. Thus this present review starts with an introduction of sepsis as a major medical problem worldwide and signifies the role of dysregulated innate immune response including macrophages in its immunopathogenesis. Thereafter, subsequent sections describe changes in immunometabolic stage of macrophages (both M1 and M2) during sepsis. The article ends with the discussion of novel macrophage-specific therapeutic targets targeting their immunometabolism during sepsis and epigenetic regulation of macrophage immunometabolism and vice versa. PMID- 29625386 TI - Sounds from seeing silent motion: Who hears them, and what looks loudest? AB - Some people hear what they see: car indicator lights, flashing neon shop signs, and people's movements as they walk may all trigger an auditory sensation, which we call the visual-evoked auditory response (vEAR or 'visual ear'). We have conducted the first large-scale online survey (N > 4000) of this little-known phenomenon. We analysed the prevalence of vEAR, what induces it, and what other traits are associated with it. We assessed prevalence by asking whether respondents had previously experienced vEAR. Participants then rated silent videos for vividness of evoked auditory sensations, and answered additional trait questions. Prevalence appeared higher relative to other typical synaesthesias. Prior awareness and video ratings were associated with greater frequency of other synaesthesias, including flashes evoked by sounds, and musical imagery. Higher rated videos often depicted meaningful events that predicted sounds (e.g., collisions). However, even videos containing abstract flickering or moving patterns could also elicit higher ratings, despite having no predictable association with sounds. Such videos had higher levels of raw 'motion energy' (ME), which we quantified using a simple computational model of motion processing in early visual cortex. Critically, only respondents reporting prior awareness of vEAR tended to show a positive correlation between video ratings and ME. This specific sensitivity to ME suggests that in vEAR, signals from visual motion processing may affect audition relatively directly without requiring higher-level interpretative processes. Our other findings challenge the popular assumption that individuals with synaesthesia are rare and have ideosyncratic patterns of brain hyper-connectivity. Instead, our findings of apparently high prevalence and broad associations with other synaesthesias and traits are jointly consistent with a common dependence on normal variations in physiological mechanisms of disinhibition or excitability of sensory brain areas and their functional connectivity. The prevalence of vEAR makes it easier to test such hypotheses further, and makes the results more relevant to understanding not only synaesthetic anomalies but also normal perception. PMID- 29625387 TI - Urinary phthalate metabolite concentrations in girls with premature thelarche. AB - In girls, breast development before eight years of age is called "premature thelarche (PT)". There are few studies in literature that show the interaction between PT and phthalate exposure. The aim of this study was to determine the urinary levels of di-(2-ethylhexyl) phthalate (DEHP) metabolites and other phthalate metabolites in girls with PT. PT group consisted of 29 newly diagnosed subjects. Control group comprised of healthy age-matched girls (n = 25). Urinary phthalate metabolite concentrations were measured by liquid chromatography/tandem mass spectroscopy (LC-MS/MS). The urinary concentrations of mono-(2-ethyl hexyl)phthalate (MEHP) in the PT group (33.96 +/- 6.88 MUg/g creatinine) were found to be significantly higher compared to control group (11.54 +/- 1.39 MUg/g creatinine, p = 0.002). In PT group, %MEHP was also markedly higher vs. control (17.84 +/- 3.31 vs. 6.44 +/- 1.13, p = 0.001). Our results suggest that DEHP is more efficiently converted to MEHP in girls with PT, the importance of which needs to be further elucidated. PMID- 29625388 TI - Crocin reverses unilateral renal ischemia reperfusion injury-induced augmentation of oxidative stress and toll like receptor-4 activity. AB - Renal Ischemia (RI) usually develops as a secondary manifestation of hypertension, various cardiovascular disorders and renal transplantation. It exerts hypoxic oxidative stress to kidneys, together with stimulation of several immune-mediated inflammatory cascades. Such events eventually damage renal tubules and glomeruli, driving acute kidney injury (AKI) and ultimately, renal failure. Crocin; the main bioactive constituent of Crocus sativus extract has been reported to demonstrate numerous pharmacological merits. In the current study, unilateral renal ischemia reperfusion injury (URIRI) was induced in rats by unilateral clamping of the left renal pedicle for 45 min followed by 24 h of reperfusion. Daily pre-treatment with crocin (20 mg/kg, orally) for 7 days, significantly improved all signs of renal injury. Biochemically, kidney functions; including serum creatinine (Sr Cr), blood urea nitrogen (BUN), proteinuria and creatinine clearance (Cr Cl) significantly improved. Inflammatory biomarkers; serum lactate dehydrogenase (LDH) and kidney nitric oxide (Nos) contents significantly declined. Oxidant/antioxidant balance was significantly restored; manifested in recovery of renal superoxide dismutase (SOD) activity, glutathione (GSH) concentration, malondialdehyde (MDA) content and restoration of serum catalase activity. Kidney contents of inflammatory cytokine interleukin-6 (IL6) and toll-like receptors 4 (TLR4) significantly declined as well. Histopathologically, crocin pretreatment resulted in signs of improvement with minimal renal lesions with significant decrease in renal inflammatory cells count. In conclusion, crocin induced restoration of normal kidney functions is mediated through multiple mechanisms including mainly attenuation of oxidative stress and inflammation via down-regulation of renal TLR4 and IL6 expression. PMID- 29625389 TI - High molecular weight hyaluronan attenuates fine particulate matter-induced acute lung injury through inhibition of ROS-ASK1-p38/JNK-mediated epithelial apoptosis. AB - Inhalation of fine particulate matter (PM2.5) is asscoiated with lung injury. High molecular weight hyaluronan (HMW-HA) is an essential constituent of extracellular matrix (ECM), exhibiting anti-oxidative and anti-inflammatory properties when administered by injection, inhalation, nebulization or gene delivery of HA synthases. The aim of the present study is to determine whether HMW-HA alleviates PM2.5-induced acute lung injury (ALI) and investigate the underlying mechanisms. We observed that HMW-HA suppressed pathological injury, inflammation, oxidative stress, edema and epithelial damage caused by PM2.5 in the lungs of the rats. The protective mechanism of HMW-HA was further explored in vitro. The results elucidated that reactive oxygen species (ROS) was involved in PM2.5-induced cell apoptosis, and HMW-HA mitigated the oxidative potential of PM2.5, subsequently inhibiting phosphorylation of ASK1 at Thr845, downstream phosphorylation of p38 and JNK, and eventual apoptosis. Our study indicates that HMW-HA is a promising strategy in the prevention of PM2.5-induced pulmonary damage. PMID- 29625390 TI - Dysfunction of regulatory T cells in patients with ankylosing spondylitis is associated with a loss of Tim-3. AB - An expansion of regulatory T cells (Tregs) in ankylosing spondylitis (AS) was observed. However, AS patients continue to exhibit aberrant inflammation. In this study, we collected PBMCs from 26 AS patients and 26 healthy controls, and investigated the functional capacity of Treg cells from these subjects. In AS patients, the frequency of CD4+CD25+Foxp3+CD127- Treg cells was slightly increased compared to healthy controls, but the level of Foxp3 MFI in AS patient CD4+CD25+Foxp3+CD127- Treg cells was significantly lower than that in healthy control CD4+CD25+Foxp3+CD127- Treg cells. Tim-3+ Treg cells were previously shown to present stronger suppressive capacity than Tim-3- Treg cells. Here, we discovered that the Tim-3+ cell frequency in CD4+CD25+Foxp3+CD127- Treg cells was significantly lower in AS patients. In both healthy volunteers and AS patients, Tim-3+ Treg cells demonstrated higher transcription of Foxp3, IL-10 and TGF-beta, higher secretion of IL-10 and TGF-beta, and stronger inhibition of conventional T cell inflammation, than Tim-3- Treg cells. In some but not all functional aspects, the Tim-3+ Treg cells from healthy controls were more potent than the Tim-3+ Treg cells from AS patients. Collectively, these results demonstrated two Treg-related impairments in AS patients. First, the frequency of the more potent Tim-3+ Treg cells was lower in AS patients, and second, some of Tim-3+ Treg mediated functions were less potent in AS patients. Interestingly, the ratio of Tim-3-/Tim-3+ Treg cells in AS patients was directly correlated with the Bath ankylosing spondylitis disease activity index (BASDAI) score, the C-reactive protein (CRP) level, and the erythrocyte sedimentation rate (ESR). Given the fact that Tim-3+ Treg cells presented potent suppressive functions, Tim-3+ Treg cells and Tim-3+ Treg-mediated mechanisms might be potential candidates for immunotherapies in AS patients. PMID- 29625391 TI - Imaging thrombosis with 99mTc-labeled RAM.1-antibody in vivo. AB - INTRODUCTION: Platelets play a major role in thrombo-embolic diseases, notably by forming a thrombus that can ultimately occlude a vessel. This may provoke ischemic pathologies such as myocardial infarction, stroke or peripheral artery diseases, which represent the major causes of death worldwide. The aim of this study was to evaluate the specificity of radiolabeled Rat-Anti-Mouse antibody (RAM.1). METHODS: We describe a method to detect platelets by using a RAM.1 coupled with the chelating agent hydrazinonicotinic acid (HYNIC) conjugated to 99mTc, for Single Photon Emission Computed Tomography (SPECT). To induce platelet accumulation at a site of interest, we used a mouse model of FeCl3 induced injury of the carotid artery. 90 min after i.v. injection of [99mTc][Tc(HYNIC)-RAM.1], biodistribution of the radiolabeled RAM.1 was assessed, SPECT imaging and histological analysis were performed on the mice that underwent FeCl3-induced vessel damage. RESULTS: We demonstrated a quick and strong affinity of the radiolabeled RAM.1 for the platelet thrombus. Results clearly demonstrated the ability of this radioimmunoconjugate for detecting thrombi from 10 min post injection with an exceptional thrombi uptake. Using FeCl3, the median ratio between the thrombus and the background was 12.4 (range 9.3-42.3) as compared to 1.0 (range: 0.86-2.7) p < 0.05 when using 0.9% NaCl. CONCLUSION: Thanks to the high sensitivity of SPECT, we provided evidence that [99mTc][Tc(HYNIC)-RAM.1] represents a powerful tool to detect localized platelet thrombi which could potentially be used in humans. Because of the relative low cost and high sensitivity, these results encourage further study like the detection of non induced thrombus and further developments toward clinical application. This is further supported by the fact that RAM.1 recognizes human platelets. PMID- 29625393 TI - Effect of aluminum (Al) speciation on erythrocytic antioxidant defense process: Correlations between lipid membrane peroxidation and morphological characteristics. AB - Al contamination becomes a growing problem in human society. Accumulation of Al in blood could destroy the structure and disorder function of erythrocyte, and finally cause blood diseases. In the present study, AlCl3 and Al(malt)3 are respectively used in the erythrocyte system, in order to investigate the comparative toxic effect on erythrocyte fragility, the influence on cellular biochemical components and lipid peroxidation level. We find that the osmotic fragility, the number of Heinz bodies, the content of MDA and advanced oxidation protein product of the AlCl3 treated erythrocytes were higher than the Al(malt)3 treated erythrocytes at the same concentrations of Al(III). The morphological and membrane protein changes of the AlCl3 treated group show superior to the Al(malt)3 treated group. In summary, we conclude that the comparative effect on the erythrocyte between organic aluminum and inorganic aluminum is significantly different, and the prime comparative difference between the toxic effects of both the compounds is oxidative stress. Further research should focus on in vivo experiments to confirm the differential toxicity and to elucidate the molecular mechanisms underlying Al-induced erythrocyte toxicity in order to prevent hematological disorders. PMID- 29625392 TI - The current landscape of nucleic acid tests for filovirus detection. AB - Nucleic acid testing (NAT) for pathogenic filoviruses plays a key role in surveillance and to control the spread of infection. As they share clinical features with other pathogens, the initial spread of these viruses can be misdiagnosed. Tests that can identify a pathogen in the initial stages of infection are essential to control outbreaks. Since the Ebola virus disease (EVD) outbreak in 2014-2016 several tests have been developed that are faster than previous tests and more suited for field use. Furthermore, the ability to test for a range of pathogens simultaneously has been expanded to improve clinical pathway management of febrile syndromes. This review provides an overview of these novel diagnostic tests. PMID- 29625394 TI - Sulfur dioxide derivatives alleviate cadmium toxicity by enhancing antioxidant defence and reducing Cd2+ uptake and translocation in foxtail millet seedlings. AB - Sulfur dioxide (SO2) was recently proposed as a novel bio-regulator in mammals. However, the possible advantageous effects of SO2 in plant adaptation to heavy metal-contaminated environments are largely unknown. In the present study, using Na2SO3/NaHSO3 derivatives as SO2 donors, we investigated the possible roles and regulation mechanisms of SO2 in alleviating Cd2+ toxicity in foxtail millet seedlings. Exogenous SO2 derivatives (0.5 mM) application significantly reduced the seedling growth inhibition caused by Cd2+ stress. Cd2+-induced oxidative damage was also alleviated by SO2 derivatives, which was supported by the decreased malondialdehyde (MDA) level in the leaves of seedlings pretreated with SO2 derivatives. These responses were related to the enhanced activities of representative antioxidant enzymes, including catalase and superoxide dismutase, as well as the up-regulation of ascorbate-glutathione cycle, which contributed to the scavenging of Cd2+-elicited O2*- and H2O2 within the leaves of foxtail millet seedlings. Also, SO2 derivative application promoted sulfur assimilation and increased the content of glutathione and phytochelatins, which may help to enhance Cd2+ detoxification capacity in foxtail millet seedlings. Moreover, application of SO2 derivatives caused down-regulation of the transcript expression levels of several genes involved in Cd2+ uptake and translocation, such as NRAMP1, NRAMP6, IRT1, IRT2, HMA2, and HMA4, thus resulting in reduced Cd2+ accumulation in the shoots and roots of Cd2+-stressed seedlings. Collectively, these results suggest that exogenous SO2 derivative application can alleviate oxidative damage and restrict Cd2+ buildup, thereby reducing Cd2+ induced growth inhibition in foxtail millet seedlings upon Cd2+ exposure. This novel finding indicates that the usage of SO2 derivatives may be an effective approach for enhancing Cd2+ tolerance in foxtail millet and other crops. PMID- 29625395 TI - Heavy metal bioaccumulation and cation release by growing Bacillus cereus RC-1 under culture conditions. AB - In an effort to explore the detoxifying mechanisms of B. cereus RC-1 under heavy metal stress, the bioaccumulation by growing cells under varying range of pH, culture time and initial metal concentration were investigated from a perspective of cation release. The maximum removal efficiencies were 16.7%, 38.3%, 81.4% and 40.3% for Cu2+, Zn2+, Cd2+ and Pb2+, respectively, with initial concentrations of 10 mg/L at pH 7.0. In presence of Cu2+ or Zn2+, large quantities of cations were released into the medium in descending order of Na+>K+>Ca2+>Mg2+, while bioremoval of the two essential metals Cd2+ and Pb2+ was accompanied with cellular Na+ and Mg2+ uptake from the medium, respectively. The relative mean contributions of intracellular accumulation to the total removal were approximately 19.6% for Cu2+, 12.8% for Zn2+, 51.1% for Cd2+, and only 4.6% for Pb2+. Following exposure at high concentration, B. cereus RC-1 could keep intracellular Cd2+ concentrations constant, possibly by means of a Cd-efflux system whose activity coincided with uptake of Na+, and reduce intracellular Pb2+ concentration due to the effect of Mg2+ on limiting Pb2+ access to the cells. Cellular morphology, surface functional groups and intracellular trace elements were further investigated by SEM-EDX, TEM-EDX, FTIR and ICP-MS analysis. The phenomena that removal of Cd2+ and Pb2+ coincided with uptake of Na+ and Mg2+, respectively, inspires a novel research perspective towards the study of protective mechanism of bacterial cells against the toxicity of heavy metals. PMID- 29625397 TI - Arbuscular mycorrhizal fungi alleviate arsenic toxicity to Medicago sativa by influencing arsenic speciation and partitioning. AB - In a pot experiment, Medicago sativa inoculated with/without arbuscular mycorrhizal (AM) fungus Rhizophagus irregularis were grown in four levels (0, 10, 25, and 75 mg/kg) of arsenic (As)-polluted soil to investigate the influences of AM symbiosis on plant As tolerance. The results showed that mycorrhizal inoculation significantly increased plant biomass, while As addition decreased mycorrhizal colonization and hyphal length density. Mycorrhizal inoculation dramatically improved plant phosphorus (P) nutrition, restricted As uptake and retained more As in roots by upregulating the expression of the AM-induced P transporter gene MsPT4 and the metallothionein gene MsMT2. High soil As content downregulated MsPT4 expression. Dimethylarsenic acid (DMA) was detected only in the shoots of mycorrhizal plants, indicating that AM fungi likely play an essential role in As detoxification by biological methylation. The present investigation allowed deeper insights into the As detoxification mechanisms of AM associations and demonstrated the important role of AM fungi in plant resistance under As-contaminated conditions. PMID- 29625396 TI - Tolerance of Ulothrix sp. LAFIC 010 (Chlorophyta) against high concentration of metals from acid mine drainage. AB - The production of acid mine drainage of (AMD) is one of the main phenomena responsible for much of the degradation of water and soil resources. Organisms present at sites contaminated by AMD can have the potential to bioaccumulate heavy metals, stimulating their application in bioremediation processes. Ulothrix sp. LAFIC 010 was identified among the species of algae isolated from water contaminated by AMD in the region of Sideropolis (Brazil). The present study evaluated its tolerance and bioaccumulation potential related to zinc, manganese and nickel. Experiments were performed to see the effects of different concentrations of Zn, Mn and Ni (individually and in combination) on the physiological performance of the alga. The results showed that only the cultures submitted to concentrations above 0.55 mM Zn showed a decrease in growth rate and damage to physiological processes. There was no observed effect of Mn and Ni on Ulothrix sp. LAFIC 010 physiology, even with an 8-fold increase in concentrations of these metals in the medium. In cultures with combined metals, only the treatments with the highest concentrations of Zn presented reduced growth, regardless of the presence of other metals. Additionally, we observed that Mn and Ni did not decrease the toxic effect of Zn. Mn accumulation was indicated in the cell wall and Ni in the vacuole. Our results suggest that the distribution of this alga in contaminated medium is not affected by the concentration of Ni and Mn, at least under the pH that was evaluated. We conclude that Ulothrix sp. LAFIC 010 tolerates and grows under conditions with higher metal concentrations than previously reported for AMD. PMID- 29625398 TI - Estradiol shapes mutualistic behaviour of female cleaner fish (Labroides dimidiatus - Valenciennes, 1839): Potential implications of environmental disturbance. AB - The presence of endocrine-derived compounds in the environment occurs due to a myriad of human or industrial activity and can disrupt the endocrine system of animals, including fish. One important group of endocrine disruptors are the estrogens, such as 17-beta estradiol (E2, estradiol). Estrogens are gonadal steroid hormones, able to be influential even in small concentrations. Here, we demonstrate that E2 is linked to female' decisions made by an important coral reef species, the cleaner fish Labroides dimidiatus, during interactions with other reef fishes (known as clients). E2 treatment in natural conditions interfered directly in the cooperative relationships, by increasing cleaners' willingness to interact with clients, providing greater amounts of physical contact to their fish partners. We discuss the meaning of the observed behavioural disruption produced by E2, which by affecting a key species (cleaners) may produce a cascade impact in the aquatic ecosystem. PMID- 29625399 TI - Optimization of lactic acid fermentation for pathogen inactivation in fecal sludge. AB - The efficiency of lactic acid fermentation (LAF) as a pretreatment for human feces was investigated in laboratory-scale experiments that lasted for 3 weeks. The sanitization effect of LAF on fecal sludge (FS) was conducted in triplicate. This study used three materials, namely, lactobacillus of lactic acid bacteria, fermented cassava flour, and fermented rice flour, which were known to enhance the production of lactic acid. Each material was mixed in three different reactors at equal ratio with raw FS (i.e., 1:1 v/w, w/w, and w/w). The pH decline rate, lactic acid production rate, and fecal coliform suppression degree were monitored over the period of the treatment process as parameters to evaluate the efficiency of various LAF for pathogen inactivation in FS. Results showed that only fermented rice flour was able to completely inactivate the indicator organism (fecal coliform) at the end of fermentation. Final plate counts of 8.6 * 108 CFU/100 mL, 2.4 * 108 CFU/100 mL, and zero (0) were achieved from lactobacillus, fermented cassava flour, and fermented rice flour treatment processes, respectively. The final pH from the reactors that contained lactobacillus and FS, cassava flour and FS, and fermented rice flour and FS were 5.5, 8, and 3.9, respectively. This study revealed that not all LAF materials can effectively suppress pathogens in FS. The results serve as the foundation in developing an effective, cheap, and easy to use LAF on FS pretreatment for pathogen inactivation. PMID- 29625400 TI - Spirulina platensis attenuates the associated neurobehavioral and inflammatory response impairments in rats exposed to lead acetate. AB - Heavy metals are well known as environmental pollutants with hazardous impacts on human and animal health because of their wide industrial usage. In the present study, the role of Spirulina platensis in reversing the oxidative stress-mediated brain injury elicited by lead acetate exposure was evaluated. In order to accomplish this aim, rats were orally administered with 300 mg/kg bw Spirulina for 15 d, before and simultaneously with an intraperitoneal injection of 50 mg/kg bw lead acetate [6 injections through the two weeks]. As a result, the co administration of Spirulina with lead acetate reversed the most impaired open field behavioral indices; however, this did not happen for swimming performance, inclined plane, and grip strength tests. In addition, it was observed that Spirulina diminished the lead content that accumulated in both the blood and the brain tissue of the exposed rats, and reduced the elevated levels of oxidative damage indices, and brain proinflammatory markers. Also, because of the Spirulina administration, the levels of the depleted biomarkers of antioxidant status and interleukin-10 in the lead-exposed rats were improved. Moreover, Spirulina protected the brain tissue (cerebrum and cerebellum) against the changes elicited by lead exposure, and also decreased the reactivity of HSP70 and Caspase-3 in both cerebrum and cerebellum tissues. Collectively, our findings demonstrate that Spirulina has a potential use as a food supplement in the regions highly polluted with heavy metals. PMID- 29625401 TI - Protective effect of Chitosan nanoparticles against the inhibitory effect of linoleic acid supplementation on maturation and developmental competence of bovine oocytes. AB - The current study was conducted to investigate the effect of linoleic acid treated oocytes during in vitro maturation (IVM) on cumulus cell expansion, oocyte nuclear maturation, blastocyst development and DNA damage of cumulus cells and how its effects were alleviated by supplementation of the maturation medium with Chitosan nanoparticles (CSNPs). Inhibitory effects of LA at a concentration (100 MUM/ml) or more significantly decreased the percentage of oocytes reaching metaphase II stage, the rate of fully expanded cumulus cells 24 h after IVM and the percentage of blastocyst rate compared with the control (p < 0.05). These inhibitory effects were associated with an increased in DNA damage of cumulus cells compared with controls. However, 10 MUg/mL CSNPs completely alleviated the inhibitory effects of LA on nuclear maturation of oocytes, cumulus cell expansion, and blastocyst rate but failed to do so for cleavage rate. The current study concluded that low concentration of LA used for maturation had no inhibitory effect on developmental competence of bovine oocytes compared to the high concentration of LA. Moreover, CSNPs with 10 MUg/mL concentration may provide protection to most of the detrimental effects of LA during IVM. Furthermore, supplementation of in vitro maturation media with a higher concentration of CSNPs was of no significance. PMID- 29625402 TI - Effect of tropical thermal stress on peri-implantation immune responses in cows. AB - Pregnancy losses during the peri-implantation period cause a negative impact on the reproductive and economic performance of dairy herds. In this study, we investigated the possible immunological factors which may contribute to pregnancy loss during the peri-implantation period under different seasons of tropical conditions. Eighteen Karan Fries cows, six cows in each season (W: winter; HH: hot-humid; HD: hot-dry) were selected. These cows exhibited heat and were brought for artificial insemination (AI; day 0). Blood was collected on days 0, 10, 14, 16, 18, 21 and 28 post-AI. Pregnancy was confirmed by non-return to heat, progesterone assay and ultrasonography. Blood neutrophils were isolated and tested for their number, myeloperoxidase (MPO) concentrations and expression of cell adhesion molecules (CD11b, CD14, CD25, CD47), interferon tau stimulated genes (ISG15, MX1, OAS1) and chemokine receptors (CXCR1, CCL2). Plasma cortisol, progesterone, IL-2 and IL-10 were also estimated. Neutrophil number, MPO levels, the relative expression of various neutrophil receptors and plasma IL-2 were low between days 14-21 post-AI in all seasons. However, plasma cortisol and IL-10 were higher during the same period. The inflammatory activity of neutrophils, plasma IL-2 and cortisol were highest in HH, intermediate in HD and lowest in W season. However, plasma progesterone and IL-10 were highest in W season and lowest in HH season. Our results show that blood neutrophils sense the implanting embryo and downregulate their activity to ensure successful implantation; however, under harsh environmental conditions, it is a great challenge for the immune system to maintain such balance and thus it may negatively affect the outcome of pregnancy. PMID- 29625404 TI - Dual Insect specific virus infection limits Arbovirus replication in Aedes mosquito cells. AB - Aedes mosquitoes are vectors for many pathogenic viruses. Cell culture systems facilitate the investigation of virus growth in the mosquito vector. We found Zika virus (ZIKV) growth to be consistent in A. albopictus cells but hypervariable in A. aegypti cell lines. As a potential explanation of this variability, we tested the hypothesis that our cells harbored opportunistic viruses. We screened Aedes cell lines for the presence of insect specific viruses (ISVs), Cell-fusing agent virus (CFAV) and Phasi charoen-like virus (PCLV). PCLV was present in the ZIKV-growth-variable A. aegypti cell lines but absent in A. albopictus lines, suggesting that these ISVs may interfere with ZIKV growth. In support of this hypothesis, PCLV infection of CFAV-positive A. albopictus cells inhibited the growth of ZIKV, dengue virus and La Crosse virus. These data suggest ISV infection of cell lines can impact arbovirus growth leading to significant changes in cell permissivity to arbovirus infection. PMID- 29625403 TI - Inhibition of vaccinia virus replication by nitazoxanide. AB - Nitazoxanide (NTZ) is an FDA-approved anti-protozoal drug that inhibits several bacteria and viruses as well. However, its effect on poxviruses is unknown. Therefore, we investigated the impact of NTZ on vaccinia virus (VACV). We found that NTZ inhibits VACV production with an EC50 of ~2 MUM, a potency comparable to that reported for several other viruses. The inhibitory block occurs early during the viral life cycle, prior to viral DNA replication. The mechanism of viral inhibition is likely not due to activation of intracellular innate immune pathways, such as protein kinase R (PKR) or interferon signaling, contrary to what has been suggested to mediate the effects of NTZ against some other viruses. Rather, our finding that addition of exogenous palmitate partially rescues VACV production from the inhibitory effect of NTZ suggests that NTZ impedes adaptations in cellular metabolism that are needed for efficient completion of the VACV replication cycle. PMID- 29625405 TI - Recycling of drinking water treatment residue as an additional medium in columns for effective P removal from eutrophic surface water. AB - This study assesses the feasibility of recycling drinking water treatment residue (DWTR) to treat eutrophic surface water in a one-year continuous flow column test. Heat-treated DWTR was used as an additional medium (2%-4%) in columns in case excessive organic matter and N were released from the DWTR to surface water. The results indicated that with minimal undesirable effects on other water properties, DWTR addition substantially enhanced P removal, rendering P concentrations in treated water oligotrophic and treated water unsuitable for Microcystis aeruginosa breeding. Long-term stable P removal by DWTR-column treatment was mainly attributed to the relatively low P levels in raw water (<0.108 mg L-1) and high P adsorption capability of DWTR, as confirmed by increases in amorphous Al/Fe in DWTR after the tests and low adsorption of P in the mobile forms. The major components of DWTR showed minimal changes, and potential metal pollution from DWTR was not a factor to consider during recycling. DWTR also enriched functional bacterial genera that benefitted biogeochemical cycles and multiple pollution control (e.g., Dechloromonas, Geobacter, Leucobacter, Nitrospira, Rhodoplanes, and Sulfuritalea); an apparent decrease in Mycobacterium with potential pathogenicity was observed in DWTR columns. Regardless, limited denitrification of DWTR-columns was observed as a result of low bioavailability of C in surface water. This finding indicates that DWTR can be used with other methods to ensure denitrification for enhanced treatment effects. Overall, the use of DWTR as an additional medium in column systems can potentially treat eutrophic surface water. PMID- 29625406 TI - Biomass-derived carbon composites for enrichment of dilute methane from underground coal mines. AB - Ventilation air methane (VAM), which is the main source of greenhouse gas emissions from coal mines, has been a great challenge to deal with due to its huge flow rates and dilute methane levels (typically 0.3-1.0 vol%) with almost 100% humidity. As part of our continuous endeavor to further improve the methane adsorption capacity of carbon composites, this paper presents new carbon composites derived from macadamia nut shells (MNSs) and incorporated with carbon nanotubes (CNTs). These new carbon composites were fabricated in a honeycomb monolithic structure to tolerate dusty environment and to minimize pressure drop. This paper demonstrates the importance of biomass particle size distributions when formed in a composite and methane adsorption capacities at low pressures relevant to VAM levels. The selectivity of methane over nitrogen was about 10.4 at each relevant partial pressure, which was much greater than that (6.5) obtained conventionally (at very low pressures), suggesting that capturing methane in the presence of pre-adsorbed nitrogen would be a practical option. The equilibrium and dynamic performance of biomass-derived carbon composites were enhanced by 30 and 84%, respectively, compared to those of our previous carbon fiber composites. In addition, the presence of moisture in ventilation air resulted in a negligible effect on the dynamic VAM capture performance of the carbon composites, suggesting that our carbon composites have a great potential for site applications at coal mines because the cost and performance of solid adsorbents are critical factors to consider. PMID- 29625407 TI - Camelia oil and soybean-camelia oil blend enhance antioxidant activity and cardiovascular protection in hamsters. AB - OBJECTIVES: The aim of this study was to examine the effects of several vegetable oils and blended oil composed of soybean and camellia oils on blood lipid reduction and antioxidative activity. METHODS: Forty male hamsters were fed an AIN-93 G diet for 1 wk, followed by dividing into five groups: control group-1 was fed a low-fat diet containing 5% oil for 6 wk, and the other four groups were fed high-fat diets with group-2 containing 14% palm oil, group-3 containing 14% camellia oil, group-4 containing 14% soybean oil, and group-5 containing 14% blended oil (8.4% soybean oil and 5.6% camellia oil) along with 0.2% cholesterol and 0.1% bile acid. RESULTS: High-fat diets raised serum triacylglycerol, total cholesterol, and aspartate aminotransferase in hamsters without affecting alanine aminotransferase. Compared with palm oil-containing diet, the other three high fat diets reduced serum total cholesterol, low-density lipoprotein cholesterol, and the ratio of low-density lipoprotein to high-density lipoprotein cholesterol with an opposite trend for liver total cholesterol. However, compared with the control group, the serum high-density lipoprotein cholesterol level was raised for all four high-fat diets. The higher the degree of oil unsaturation, the higher the serum thiobarbituric acid reactive substances and the lower the liver triacylglycerol level and activities of fatty acid synthase, glucose 6-phosphate dehydrogenase, and malic enzymes. Both soybean and blended oils lowered the antioxidative activity of liver. CONCLUSION: Camellia and blended oils were more efficient than soybean oil in elevating serum high-density lipoprotein cholesterol and decreasing the ratio of low-density lipoprotein to high-density lipoprotein cholesterol in hamsters. PMID- 29625408 TI - Nutritional intervention in head and neck cancer patients during chemo radiotherapy. AB - OBJECTIVE: Head and neck cancer patients experience unintentional weight loss and malnutrition at diagnosis, during oncologic treatment, and after the end of therapy because of reduction of eating ability. The aim of the present study was to assess nutrition intervention efficacy in maintaining basal nutritional conditions. METHODS: Head and neck cancer patient candidates for chemoradiotherapy and requiring enteral nutrition (EN) support through gastrostomy, according to international guidelines, were included in the study. Nutritional intervention aimed to reach 30 kcal/kg/d, considering both EN and oral intake. Adjustments were made during and after treatment, aiming to maintain stable or improving nutritional indicators. Anthropometry, body composition measured by bioelectrical impedance vector analysis, and oral and EN intake were monitored at baseline (before chemoradiotherapy) and at 1, 3, and 6 mo. RESULTS: A total of 54 patients were evaluated; 35 patients completed follow-up at 6 mo and were included in the analysis. At baseline, mean weight loss in the last 6 mo was 12 +/- 7.9%; mean body mass index and phase angle were 20.6 +/- 3.9 kg/m2 and 4.8 +/- 1.2 degrees . Before chemoradiotherapy 21 patients (60%) were able to eat; the percentage decreased during and after treatment to 34.3% (P = 0.026) at 1 and 3 mo and at 51.4% at 6 mo. From the analysis, a mean daily energy intake of 35 +/- 10 kcal/kg was needed to maintain stable body weight and phase angle during and after treatment. CONCLUSION: To preserve body weight and composition, we identified an energy requirement greater than expected both during and after chemoradiotherapy. PMID- 29625409 TI - Relationship of nutritional status and inflammation with survival in patients with advanced cancer in palliative care. AB - OBJECTIVE: This study aimed to evaluate the prognostic value of nutritional and inflammatory status in patients with advanced cancer receiving palliative care. METHODS: The systemic inflammatory response was assessed using the modified Glasgow Prognostic Score (mGPS), and nutritional status was evaluated according to the Patient-Generated Subjective Global Assessment (PG-SGA) in 172 patients evaluated on their first visit in the Palliative Care Unit at the National Cancer Institute in Brazil. The receiver operating characteristic (ROC) curve was used to define the best cutoff point for the death-related PG-SGA score in 90 d. Kaplan-Meier curves were conducted for survival analyses, and logistic regression analyses were performed using the Cox proportional hazards model. RESULTS: According to the PG-SGA, 83.6% of the patients (n = 143) were malnourished (B + C) and 34.8% (n = 53) had mGPS >=1. The best cutoff of the PG-SGA score for death was >=19 points (area under the curve, 0.69; P = 0.041). Patients with scores >=19, mGPS >=1, albumin <3.5 g/dL, and C-reactive protein >=10 mg/L had a significantly lower overall survival. According to the multivariate analysis, albumin <3.5 g/dL (hazard ratio [HR], 2.04; 95% confidence interval [CI], 1.16 3.58), mGPS >=1 (HR, 1.46; 95% CI, 1.09-2.22), and PG-SGA score >=19 (HR, 1.66; 95% CI, 1.08-2.55) were independent prognostic factors for overall survival. CONCLUSION: The severity of the systemic inflammation and the poor nutritional status predict survival and were considered independent prognostic factors. Thus they can be useful tools for nutritional evaluation in palliative care. PMID- 29625410 TI - Exploring the influence of Diels-Alder linker length on photothermal molecule release from gold nanorods. AB - We studied the photothermal release of carboxyfluorescein (CF) linked to the gold surface of gold nanorods (GNRs) by two Diels-Alder adducts of different lengths (n = 4 and n = 9). The functionalized GNRs were irradiated with infrared light to produce photothermal release of CF by a retro-Diels-Alder reaction. The adducts were chemisorbed on the GNRs and the functionalized nanoparticles were characterized by UV-vis, DLS, zeta potential and Raman and surface-enhanced Raman spectroscopy (SERS). On the basis of the degree of nanoparticle functionalization and the SERS results, we inferred the orientation of CF on the surface of the gold nanoparticle. Moreover, we determined the photothermal release profiles of CF from the gold surface by laser irradiation. The release was faster for the longer linker (n = 9). SERS revealed that, for the shorter linker (n = 4), molecules are oriented perpendicularly with respect to the gold surface, thereby maintaining the CF far from the surface. In contrast, the longer linker was observed to be tilted, thus maintaining CF close to the gold surface and therefore potentially favoring the photothermal transfer of energy. These results are relevant for the future development of the spatial and temporal controlled release of drugs by means of gold nanoparticles. PMID- 29625411 TI - Joint moment strategies during stair descent in patients with peripheral arterial disease and intermittent claudication. AB - OBJECTIVE: To determine the lower limb joint kinetic strategies during stair descent in claudicants with peripheral arterial disease (PAD-IC). DESIGN: Cross sectional observation study. SETTING: University laboratory. PARTICIPANTS: A total of 22 participants; 10 healthy controls and 12 patients diagnosed with PAD IC. MAIN OUTCOME MEASURES: Between-group comparisons of ground reaction force (GRF) and, hip, knee and ankle kinetics during steady-state stair descent. RESULTS: The claudicating-limb group demonstrated reduced vertical and posterior GRF compared to healthy controls (ES = -1.46 [-2.32,-0.69] and ES = -1.08 [-0.42, 0.26]) as well as demonstrating an greater contribution to support moment from the ankle and trends towards a smaller hip contribution (42 +/- 14% vs 28 +/- 7%, P = .005 and Hip 16 +/- 8% vs 21 +/- 11%, P = .056, respectively). A unique sub group was identified within the PAD-IC cohort demonstrating different hip moment strategies during weight acceptance: a novel hip extensor group (PAD-IC HExt) and stereotypical hip flexor group (PAD-IC HFlex). Compared to both healthy controls and the PAD-IC HFlex groups, the PAD-IC HExt group demonstrated increased hip extensor moment (ES = 3.05 [1.67,4.42] and ES = 3.62 [1.89,5.35]) and reduced knee extensor moment (ES = -2.00 [-3.15,-0.85] and ES = -1.36 [-2.60,-0.11] respectively) during weight acceptance. CONCLUSIONS: A novel hip extensor strategy was identified in a sub-group of claudicants which acts to reduce the demand on the knee extensors, but not the plantarflexors. Weakness in the knee extensors may prevent redistribution of the task demand, typically seen in older adults in stair descent, away from the functionally limited plantarflexor muscle group. Further investigation into multi-level joint strength and the relationship to functional tasks is warranted to inform targeted intervention programmes. PMID- 29625412 TI - Which is the best predictor of excessive hip internal rotation in women with patellofemoral pain: Rearfoot eversion or hip muscle strength? Exploring subgroups. AB - BACKGROUND: Patellofemoral pain (PFP) has been linked to increased patellofemoral joint stress as a result of excessive hip internal rotation. Lower hip strength and/or excessive rearfoot eversion have been used to explain such altered movement pattern; however, it is unknown which one is the best predictor of excessive hip internal rotation. RESEARCH QUESTION: To investigate if peak rearfoot eversion and/or peak concentric hip abductor strength can predict peak hip internal rotation during stair ascent in women with PFP. METHODS: This cross sectional study included thirty-seven women with PFP which underwent three dimensional kinematic analysis during stair ascent and hip abductor strength analysis in an isokinetic dynamometer. A forced entry linear regression model analysis was carried out to determine which independent variables present the best capability to predict the hip internal rotation. RESULTS: Peak concentric hip abductor strength significantly predicted peak hip internal rotation during stair ascent (R2 = 0.27, p = 0.001). Peak rearfoot eversion did not predict peak hip internal rotation during stair ascent (R2 < 0.01, p = 0.62). A Post-hoc analysis was conducted to explore if a subgroup with excessive rearfoot eversion would predict hip internal rotation. Based on a previous reported cut-off point, 48.6% of the participants were classified as excessive rearfoot eversion. For the subgroup with excessive rearfoot eversion, peak concentric hip abductor strength and peak rearfoot eversion significantly predicted peak hip internal rotation during stair ascent (R2 = 0.26, p = 0.02; R2 = 0.42, p = 0.003, respectively). For non-excessive rearfoot eversion subgroup, peak concentric hip abductor strength significantly predicted peak hip internal rotation during stair ascent (R2 = 0.53; p < 0.001); and peak rearfoot eversion did not (R2 = 0.01; p = 0.65). SIGNIFICANCE: Findings indicate that hip muscle strength seems to be related with hip internal rotation in all women with PFP. Rearfoot eversion seems to be related with hip internal rotation only in a subgroup with excessive rearfoot eversion. PMID- 29625413 TI - A novel approach for the detection and exploration of joint coupling patterns in the lower limb kinetic chain. AB - BACKGROUND: A comprehensive perspective on foot and lower limb joint coupling is lacking since previous studies did not consider the multi-articular nature of the foot and lower limb neither accounted for biomechanical heterogeneity. RESEARCH QUESTION: The current manuscript describes a novel methodological process for detection and exploration of joint coupling patterns in the lower limb kinetic chain. METHODS: The first stage of the methodological process encompasses the measurement of 3D joint kinematics of the foot and lower limb kinetic chain during dynamic activities. The second stage consists of selecting the kinematic waveforms of interest. In the third stage, cross-correlation coefficients are calculated across the selected one-dimensional continua of each subject. In the fourth stage, all cross-correlation coefficients per subject are used as input variable in a cluster algorithm. Algorithm specific qualitative metrics are subsequently considered to determine the most robust clustering. Finally, in the fifth stage the process of biomechanical interpretation is initiated and further exploration is recommended by triangulating with other biomechanical variables. RESULTS: A first clinical illustration of the novel method was provided using data of fourteen young elite athletes. Cross-correlation coefficients for each leg were calculated across continua of the pelvis, hip, knee, rear foot and midfoot. A hierarchical clustering approach stratified the coefficients into two distinct clusters which was mainly guided by the frontal plane knee kinematics. Both clustered differed significantly from each other with respect to their frontal plane ankle, knee and hip kinetics. SIGNIFICANCE: The presented method seems to provide a valuable approach to gain insight into foot and lower joint coupling. PMID- 29625414 TI - Regulation of quasi-joint stiffness by combination of activation of ankle muscles in midstances during gait in patients with hemiparesis. AB - BACKGROUND: The regulation of ankle joint stiffness by combination of activation of plantarflexor and dorsiflexor during gait has not been investigated in patients with hemiparesis. The objective of the present study was to examine the relationship between combination of activation of ankle muscles and quasi-joint stiffness (QJS) during the stance phase of gait. METHODS: The activation of the medial head of the gastrocnemius (MG), soleus, and tibialis anterior, gait parameters were collected from 19 patients with hemiparesis due to stroke and from 12 healthy controls using a three-dimensional motion analysis system. The indexes of reciprocal activation and coactivation were calculated from the ratio of plantarflexor to dorsiflexor activation and magnitude of coactivation (MC), which is computed by multiplying an index of simultaneous activation of ankle muscles by plantarflexor activation. RESULTS: QJS was significantly correlated with MC of MG on the paretic side, whereas it correlated with the ratio of MG (r = 0.63, p < 0.05) in healthy controls and the ratio of MG (r = 0.67, p < 0.05) and soleus (r = 0.61, p < 0.05) on the non-paretic side in midstance. Furthermore, QJS on the paretic side was lower than that on the non-paretic side and in healthy controls (p < 0.05). SIGNIFICANCE: Our findings support that the regulation of QJS in midstance by reciprocal activation is altered on the paretic side, whereas it may be regulated by reciprocal activation and enhanced by relatively high activity of plantarflexor on the non-paretic side and in healthy controls. PMID- 29625415 TI - Heritability estimates of meat sensory characteristics are a function of the number of panellists and their inter-correlations. AB - The objective of the present study was to quantify, using simulated data, the impact on estimated heritability of varying the number of panellists and their inter-correlations using meat sensory tenderness in cattle as an example. Estimated parameters from actual sensory-based tenderness scores from 9 individual panellists on 1252 beef cattle were used to parameterise the simulation. A single "tenderness score" for each of 10 panellists was simulated for 15,000 cattle. Heritability estimates were calculated for each of the 10 panellists individually as well as the mean score per animal for all n combinations of panellists. Heritability estimates improved with increasing number of panellists in line with expectations from a deterministic equation. The increase in heritability was due to a reduction in the residual variance, albeit the rate of reduction in residual variance declined with each additional panellist included in the calculated mean tenderness score. Results highlight the importance of reporting the number of panellist scores per animal as well as their inter-correlations in sensory-based studies. PMID- 29625416 TI - Molecular dynamics and ligand docking of a hinge region variant of South African HIV-1 subtype C protease. AB - HIV-1 protease is an important antiretroviral drug target due to its key role in viral maturation. Computational models have been successfully used in the past to understand the dynamics of HIV-1 protease variants. We performed molecular dynamics simulations and induced fit docking on a wild-type South African HIV-1 subtype C protease and an N37T?V hinge region variant. The simulations were initiated in a cubic cell universe and run in explicit solvent, with the wild type and variant proteases in the fully closed conformation and under periodic boundary conditions. The trajectory for each simulation totalled 20 ns. The results indicate that the N37T?V hinge region mutation and insertion alter the molecular dynamics of the flap and hinge regions when compared to the wild-type protease. Specifically, the destabilisation of the hinge region allowed a larger and protracted opening of the flap region due to the formation of two key hinge/cantilever salt-bridges, which are absent in the wild-type protease. Domain domain anti-correlation was observed between the flap and hinge region for both models. However, the N37T?V variant protease displayed a lower degree of anti correlation. The mutations affected the thermodynamic landscape of inhibitor binding as there were fewer observable chemical contacts between the N37T?V variant protease and lopinavir, atazanavir and darunavir, respectively. These data elucidate the biophysical basis for the selection of hinge region insertion mutations by the HI virus. PMID- 29625417 TI - The role of conserved QXG and binding affinity of S23G & S26G receptors on avian H5, swine H1 and human H1 of influenza A virus hemagglutinin. AB - Outbreaks of avian, human and swine influenza are a serious concern for public health. In the reproductive cycle of the influenza virus, hemagglutinin (HA) is the primary protein responsible for binding to glycan receptor sites on the host cell surface. MD simulations of avian H5, swine H1 and human H1 complexed with S23G and S26G receptors were performed to study the role of key residues on the receptor conformational behaviors, hydrogen bond formation, binding free energy and residue-wise energy contribution. The obtained results indicated that the relative energies of swH1_S23G and swH1_S26G were found to be close to each other (3.1 kcal/mol) while the relative energies of AvH5 and HuH1 were found to be significantly different (11.1 +/- 6.8 and 29.0 +/- 8.2 kcal/mol for AvH5 and HuH1, respectively). PMID- 29625418 TI - Gold nanoparticles induce a reactive oxygen species-independent apoptotic pathway in Escherichia coli. AB - Gold nanoparticles (AuNPs) are a promising material for use in biological and biotechnological applications. While applications such as drug delivery, sensory probe, and organic photovoltaics have been widely evaluated, studies of the antimicrobial activity of AuNPs in therapeutic agents are lacking. In this study, the antibacterial activity and mode of action of AuNPs on Escherichia coli was focused. The membrane-impermeable dye SYTOX green was not taken up and membrane potential was depolarized by AuNPs. This demonstrated that AuNPs inhibit cell growth without directly causing membrane damage. Depolarization of membrane potential results in calcium uptake and processes such as bacterial apoptotic like cell death. We confirmed that AuNPs induced DNA fragmentation resulting in apoptosis-like cell death in a TUNEL assay. FITC-VAD-FMK showed that caspase-like protein(s) such as RecA were activated, induced, and overexpressed. Additionally, elevated levels of intracellular reactive oxygen species (ROS) and decreased reduced glutathione were observed. In AuNP-treated cells, ROS elevation was not confirmed; however, glutathione was decreased. Based on these observations, AuNPs induce apoptotic-like death by severely damaging DNA and this was independent of ROS in E. coli. PMID- 29625419 TI - Plant virus nanoparticles: Novel and robust nanocarriers for drug delivery and imaging. AB - Nanoparticles have been gained much attention for biomedical applications. A promising type of nanocarriers is viral nanoparticles (VNPs) which are natural bio-nanomaterials derived from different type of viruses. Amongst VNPs, plant VNPs present several pros over general nanoparticles such as liposomes, dendrimers or quantum dots. Some of these advantages include: degradability, safety for human, known structures to atomic level, possibility of attaching ligand with vigorous control on structure, availability for genetic and chemical manipulations and very flexible methods to prepare them. Variety of plant viruses have been modified by chemical and genetic modification of their inner cavities and their outer-surfaces. These modifications provide suitable sites for attachment of markers and drug molecules for vascular imaging and tumor targeting. In this review a brief description of plant virus nanoparticles and their biomedical applications especially in drug delivery is provided. The methods of loading cargos in these VNPs and their final biofate are also reviewed. PMID- 29625420 TI - A facile method to prepare a versatile surface coating with fibrinolytic activity, vascular cell selectivity and antibacterial properties. AB - Clot and thrombus formation on surfaces that come into contact with blood is still the most serious problem for blood contacting devices. Despite many years of continuous efforts in developing hemocompatible materials, it is still of great interest to develop multifunctional materials to enable vascular cell selectivity (to favor rapid endothelialization while inhibiting smooth muscle cell proliferation) and improve hemocompatibility. In addition, biomaterial associated infections also cause the failure of biomedical implants and devices. However, it remains a challenging task to design materials that are multifunctional, since one of their functions will usually be compromised by the introduction of another function. In the present work, the gold substrate was first layer-by-layer (LbL) deposited with a multilayered polyelectrolyte film containing chitosan (positively charged) and a copolymer of sodium 4 vinylbenzenesulfonate (SS) and the "guest" adamantane monomer 1-adamantan-1 ylmethyl methacrylate (P(SS-co-Ada), negatively charged) via electro-static interactions, referred to as Au-LbL. The chitosan and P(SS-co-Ada) were intended to provide, respectively, resistance to bacteria and heparin-like properties. Then, "host" beta-cyclodextrin derivatives bearing seven lysine ligands (CD-L) were immobilized on the Au-LbL surface by host-guest interactions between adamantane residues and CD-L, referred to as Au-LbL/CD-L. Finally, a versatile surface coating with fibrinolytic activity (lysis of nascent clots), vascular cell selectivity and antibacterial properties was developed. PMID- 29625421 TI - Protein adsorption behaviors onto Mn(II)-doped calcium hydroxyapatite particles with different morphologies. AB - Fundamental experiments on the adsorption behaviors of proteins onto plate-like and rod-like manganese-doped calcium hydroxyapatite particle (abbreviated as MnHAp) were examined. All of the obtained adsorption isotherms of bovine serum albumin (BSA) and lysozyme (LSZ) in a 1 * 10-4 mol/dm3 KCl solution were of the Langmuirian type. We found that the saturated amounts of the adsorbed BSA (nsBSA) increased with the increase in Mn/(Ca + Mn) atomic ratio (abbreviated as XMn) of the plate-like MnHAp, while the saturated amounts of adsorbed LSZ (nsLCZ) decreased. This result is explained by plate shape of the particles; the large fraction of positively charged adsorbing sites produced on the ac and bc faces (C sites) of these particles is advantageous to the adsorption of negatively charged BSA. In this case, however, the fraction of negatively charged adsorbing sites produced on the ab faces (P sites) decreased, and the (nsLCZ) values therefore decreased. In the case of the rod-like MnHAp, (nsBSA) decreased until XMn = 0.08, while the (nsLCZ) values were almost constant (ca. 0.2 mg/m2) over the whole range of XMn. This decrease in (nsBSA) values is explained by the increase in the specific surface area of rod-like particles as XMn increased. However, since the fraction of P sites on the ab faces does not depend on the particle length, the (nsLCZ) values were nearly constant. The binding effect of the Mn2+ and Ca2+ ions dissolved from rod-like particles caused the increase in (nsBSA) at XMn >= 0.1. The adsorption behavior of proteins onto MnHAp is therefore strongly dependent on the morphology of these particles. PMID- 29625422 TI - Paclitaxel and di-fluorinated curcumin loaded in albumin nanoparticles for targeted synergistic combination therapy of ovarian and cervical cancers. AB - Paclitaxel (PTX) encapsulated in albumin (Abraxane(r)) is an FDA approved frontline nano-formulation for treating advance metastatic pancreatic, lung and breast cancers. Currently in clinic, Abraxane(r) is being used as a one of the components of combination therapy regimens. On the other hand, difluorinated curcumin (CDF) is a novel and potent synthetic curcumin analogue that is being evaluated for several malignancies including pancreatic, liver, ovarian and breast cancers. To improve the bioavailability and targeting ability of hydrophobic PTX and CDF, we have encapsulated them in folic acid decorated bovine serum albumin nanoparticles, namely FA-BSA-PTX and FA-BSA-CDF, respectively. Both the formulations yielded uniform nano-sized particles with smooth surface morphology, negative surface potential and high drug loading efficiency. Due to heterogeneity and complexity of several cancers, combination regimens are becoming standard arsenals against several deadly cancers. To evaluate the synergistic anti-cancer effect of PTX and CDF, we assessed the combination therapy using intravenously administrable folate decorated albumin bio-conjugate nanoparticles against folate overexpressing ovarian and cervical cancers. Our results demonstrate that combination of FA-BSA-CDF with FA-BSA-PTX produced synergistic anticancer effect, augmented due to folate receptor mediated targeted uptake as well as induction of apoptosis. In conclusion, our preliminary studies show a promising nanomedicine platform for combination therapy for leading gynecological tumor, such as ovarian and cervical cancer. PMID- 29625423 TI - Elucidation of the intra- and inter-molecular electron transfer pathways of glucoside 3-dehydrogenase. AB - Glucoside 3-dehydrogenase (G3DH) is a flavin adenine dinucleotide (FAD) containing oxidoreductase that catalyzes the oxidation of the hydroxy group on the C-3 position of pyranose and shows broad substrate specificity by oxidizing many saccharides. Due to unique site specificity and wide substrate specificity, G3DHs can be used for synthesis of sugar derivatives, anodic catalysis in biofuel cells, multi-sugar analysis using enzyme electrode, and for enzymatic detection of 1,5-anhydro-d-glucitol, a clinical marker for diabetes. However, few studies have focused on the fundamental biochemical properties of G3DH, including its electron transfer pathway. In this study, we isolated the G3DH gene from Rhizobium radiobacter, a homologue of marine bacterial G3DH, and reported that the isolated gene fragment contains the genes encoding the G3DH catalytic subunit (subunit I), G3DH hitch-hiker subunit (subunit II), and cytochrome c-like molecule (CYTc). Furthermore, we report the recombinant expression of G3DH from R. radiobacter in Escherichia coli, the characterization of recombinant G3DH and the investigation of the molecular electron pathway of G3DH. We first prepared the G3DH subunit I-II complex using a co-expression vector for both subunits. The G3DH subunit I-II complex showed dye-mediated G3DH activity toward methyl-alpha-d glucoside (MalphaG). Electron paramagnetic resonance (EPR) and inductively coupled plasma optical emission spectroscopy (ICP-OES) analyses revealed that subunit I contains an iron-sulfur cluster. We, then, prepared recombinant CYTc and revealed that it is capable of accepting electrons from the catalytic subunit of G3DH by absorption spectrum analysis. These results suggested that R. radiobacter G3DH possesses an iron-sulfur cluster that may play an important role in the electron transfer from FAD to cytochrome c like molecule, which is an external electron acceptor of G3DH. Furthermore, we demonstrated that CYTc mediate the electron transfer from G3DH to electrode without the artificial electron mediator. PMID- 29625424 TI - mGlu receptors in the treatment of Parkinson's disease and L-DOPA-induced dyskinesia. AB - Parkinson's disease (PD) is a neurodegenerative disorder characterized by typical motor features that result from dopamine (DA) depletion in the striatum. DA replacement therapy with L-DOPA is the most efficacious symptomatic treatment, but causes complications that limit its utility, in particular, L-DOPA-induced dyskinesia (LID). LID is primarily caused by pre-synaptic and post-synaptic changes in DA neurotransmission, although it also depends on altered glutamatergic transmission at several nodes of the cortico-basal ganglia thalamocortical network. The important functional interplay between dopaminergic and glutamatergic systems has stimulated an interest in metabotropic glutamate receptors (mGluRs) as potential therapeutic targets in PD and LID. We here review the antiparkinsonian and antidyskinetic potential of modulating group I, II, and III mGluRs in several preclinical models of PD. We also provide an update on clinical trials evaluating mGluR5 or mGluR4 ligands in PD. PMID- 29625425 TI - School-Based Speech-Language Pathologists' Perspectives on Diagnostic Decision Making. AB - Purpose: This study used a structured open interview approach to elicit information from school-based speech-language pathologists (SLPs) regarding their assessment practices for children with suspected language impairment. Method: Phone interviews were conducted with 39 school-based SLPs who were employed across the United States. The interviews explored assessment topics related to assessment tool selection and rationale and the integration of assessment data to determine treatment eligibility. Results: The results of this study suggest that SLPs use both standardized testing and informal testing for their diagnostic procedures. Standardized testing appears to be the tool that drives diagnostic decisions regarding eligibility and severity. Informal measures, such as parent/teacher interviews and language sampling, were used by school-based SLPs to gather information regarding naturalistic language use; however, they seem less important in the diagnostic decision-making process. Also, SLPs reported completing language sample transcription and analysis in real time while interacting with a child. Conclusions: School-based SLPs appear to rely on the results from standardized testing when determining treatment eligibility for children with language impairment. The reliance on standardized testing appears to be driven by institutional policies. We discuss the potential impact of federal/state/district guidelines on diagnostic decisions and consider the research-to-practice gap. PMID- 29625426 TI - Using Language-Specific and Bilingual Measures to Explore Lexical-Grammatical Links in Young Latino Dual-Language Learners. AB - Purpose: This study examined the nature of the relation between language-specific vocabulary and conceptual lexical-semantic skills with grammatical abilities within and across languages in preschool Latino dual language learners (DLLs). Method: Sixty-one typically developing, Spanish-English speaking DLLs from preschools serving low-income families participated in the study. Lexical, semantic, and grammar skills were assessed toward the end of the fall in both Spanish and English using normative and researcher-developed assessment instruments. Hierarchical linear regressions using baseline cross-sectional data were completed to determine the association of language-specific vocabulary and bilingual lexical and semantic abilities to grammatical skills measured by sentence repetition tasks in Spanish and English both within and across languages. Results: Results from the study revealed that a considerable percentage of the variance in the grammatical ability of these Latino DLL preschoolers in both Spanish and English was explained by lexical variables in the same language (54% in English and 16% in Spanish). In the strong language (Spanish), bilingual semantic skills also played a role, explaining an additional 8% of the variance. Conceptual vocabulary was a significant predictor of English grammar in the model that excluded the language-specific vocabulary measures. Conclusions: These findings suggest that grammatical skills in the Latino preschoolers examined in the study are strongly related to language-specific measures of vocabulary. In contrast, no evidence supporting the relation between vocabulary and grammar skills across languages was observed. Findings from this study provide insight into the impact of bilingual lexical-semantic knowledge on the grammatical skills of dual-language preschool children developing language abilities in their 2 languages. Clinical implications are also discussed. PMID- 29625427 TI - Comprehension of Degraded Speech Matures During Adolescence. AB - Purpose: The aim of the study was to compare comprehension of spectrally degraded (noise-vocoded [NV]) speech and perceptual learning of NV speech between adolescents and young adults and examine the role of phonological processing and executive functions in this perception. Method: Sixteen younger adolescents (11 13 years), 16 older adolescents (14-16 years), and 16 young adults (18-22 years) listened to 40 NV sentences and repeated back what they heard. They also completed tests assessing phonological processing and a variety of executive functions. Results: Word-report scores were generally poorer for younger adolescents than for the older age groups. Phonological processing also predicted initial word-report scores. Learning (i.e., improvement across training times) did not differ with age. Starting performance and processing speed predicted learning, with greater learning for those who started with the lowest scores and those with faster processing speed. Conclusions: Degraded (NV) speech comprehension is not mature even by early adolescence; however, like adults, adolescents are able to improve their comprehension of degraded speech with training. Thus, although adolescents may have initial difficulty in understanding degraded speech or speech as presented through hearing aids or cochlear implants, they are able to improve their perception with experience. Processing speed and phonological processing may play a role in degraded speech comprehension in these age groups. PMID- 29625428 TI - Illustrating a Supports-Based Approach Toward Friendship With Autistic Students. AB - Purpose: The present clinical focus article describes and illustrates 3 key elements of a supports-based approach to enhancing friendship with autistic students. Method: In comparison to the predominant skills-based approach, we highlight 3 key elements of a supports-based approach to social interaction for autistic children and youth. We then offer descriptive details of the activity based music program as an illustrative example of a program that integrated all 3 elements of a supports-based approach. Specifically, we designed an activity based music program to enhance social interaction among a 7-year-old autistic student and 4 of his nonautistic peers. Results: We focused on 3 key elements of a supports-based approach for enhancing peer interaction: (a) focusing on participation in a shared activity, (b) encouraging flexible use of multiple communicative resources, and (c) supporting egalitarian interaction. Conclusion: A supports-based approach presents a theoretically distinct and viable alternative to a skills-based approach in the design of social supports for autistic students and their peers. PMID- 29625430 TI - Grammatical Abilities in Young Cochlear Implant Recipients and Children With Normal Hearing Matched by Vocabulary Size. AB - Purpose: This study sought to expand understanding of the impact of cochlear implantation on grammatical acquisition by comparing young children who have vocabularies of comparable size. Two research questions were investigated: (a) Do young cochlear implant (CI) recipients have grammatical skills comparable to those of children with normal hearing (NH) matched by spoken vocabulary size? (b) Do these groups show associations between vocabulary size and grammatical measures? Method: The participants included 13 CI recipients at 24 months postactivation (chronological ages = 33-60 months; M = 44.62) and 13 children with NH between 27 and 30 months old (M = 20.69). The 2 groups were matched by their vocabulary size. Four grammatical outcomes were analyzed from the MacArthur Communicative Development Inventory (Fenson, Marchman, Thal, Dale, & Reznick, 2007) and 20-min language samples: (a) grammatical complexity, (b) mean length of utterances, (c) tense marker total, and (d) productivity scores. Results: The 2 groups showed comparable grammatical skills across the 4 measures. Consistently significant associations between vocabulary size and grammatical outcomes were found in the CI group, with fewer associations in the NH group. Conclusions: The 2 groups showed similar grammatical abilities. The young CI recipients appeared to be following a typical pattern of linguistic development. PMID- 29625431 TI - The Risks to Patient Safety From Health System Expansions. PMID- 29625432 TI - Treating Childhood Apraxia of Speech With the Kaufman Speech to Language Protocol: A Phase I Pilot Study. AB - Purpose: A Phase I pilot study was designed to collect preliminary evidence on the use of the Kaufman Speech to Language Protocol (K-SLP; Kaufman, 2014) to treat children with childhood apraxia of speech. We hypothesized that the K-SLP approach would result in more accurate speech production in targeted words, whereas untrained (control) words and speech sounds would remain unchanged. Method: A single-case multiple-baseline across behaviors experimental design was used to see if experimental feasibility could be demonstrated. Two children each received a total of 12 1-hr treatment sessions over 3 weeks. The children's response to treatment and experimental control was measured by administering baseline, treatment, and posttreatment probes. Results: Both children showed some response to treatment, as measured by percent phonemes correct; however, the response to treatment varied. In general, for the treated words that improved with therapy, accuracy was maintained above baseline level during the maintenance phase. Minimal generalization was observed for this study, with only 1 participant generalizing treatment gains to 2 sets of untrained (similar) words. Conclusion: This Phase I pilot study provides limited preliminary evidence for the effectiveness of the K-SLP approach in treating childhood apraxia of speech in some children under the conditions specified in this study. Replication of these results in well-controlled studies is needed before this structured and operationalized version of the K-SLP approach can be recommended for clinical use. PMID- 29625429 TI - A Latent Variable Approach to Differentiating Neural Mechanisms of Irritability and Anxiety in Youth. AB - Importance: Comorbidity is ubiquitous in psychiatry, but it is unclear how to differentiate neural mechanisms of co-occurring symptoms. Pediatric irritability and anxiety symptoms are prevalent and frequently co-occur. Threat orienting is pertinent to both phenotypes and is an ideal context in which to examine their unique and common neural mechanisms. Objectives: To decompose the unique and shared variances of pediatric irritability and anxiety symptoms and to determine neural correlates of these differentiated phenotypes during threat orienting. Design, Setting, and Participants: This investigation was a cross-sectional functional magnetic resonance imaging study. The setting was a research clinic at the National Institute of Mental Health. Participants were youth aged 8 to 18 years spanning multiple diagnostic categories (141 youth with disruptive mood dysregulation disorder, anxiety disorder, and/or attention-deficit/hyperactivity disorder and 56 healthy youth). This combination provided wide variation in levels of irritability and anxiety symptoms. Data were acquired between June 30, 2012, and June 28, 2016. Main Outcomes and Measures: Participants and parents rated youth's irritability on the Affective Reactivity Index and anxiety on the Screen for Child Anxiety Related Emotional Disorders. Bifactor analysis decomposed the unique and shared variances. A functional magnetic resonance imaging dot-probe task assessed attention orienting to angry (ie, threat) vs neutral faces. Whole-brain analyses examined associations between the bifactor derived phenotypes and both neural activity and amygdala functional connectivity. Results: Among 197 participants included in the final analysis, the mean (SD) age was 13.1 (2.7) years, and 91 (46.2%) were female. The best-fit bifactor model (Comparative Fit Index, 0.959; Root Mean Square Error of Approximation, 0.066) included unique factors of parent-reported irritability, youth-reported irritability, and anxiety, as well as a common factor of negative affectivity. When the task required attention away from threat, higher parent-reported irritability was associated with increased activity in the insula, caudate, dorsolateral and ventrolateral prefrontal cortex, and inferior parietal lobule (t189>=4.15 for all, P < .001 for all). In contrast, higher anxiety was associated with decreased amygdala connectivity to the cingulate, thalamus, and precentral gyrus (t189<=-4.19 for all, P < .001 for all). These distinctive neural correlates did not emerge using a diagnostic approach. Conclusions and Relevance: A latent variable approach to parsing co-occurring symptom dimensions revealed a novel double dissociation. During orientation away from threat, only irritability was associated with neural activity, whereas only anxiety was associated with amygdala connectivity. Despite the challenges of symptom co occurrence for clinical neuroscience, data-driven phenotyping may facilitate a path forward. PMID- 29625433 TI - A Preliminary Examination of Concussion Knowledge by Collegiate Athletes and Non Athletes. AB - Purpose: Concussions affect various populations, including collegiate athletes and non-athletes. The purpose of this study was to compare collegiate varsity athletes, recreational athletes, and non-athletes' knowledge of concussion definition, symptoms, and support services available following injury. Preferred method of concussion education delivery was also examined. Method: We surveyed 306 current college students using an online survey system. The survey included free recall and forced-choice question formats. Quantitative analyses were used to analyze results and compare responses among groups. Results: Collegiate athletes and non-athletes demonstrate incomplete knowledge of concussion definition, related symptoms, and professionals involved in postinjury management. Varsity athletes rated self-knowledge of concussion parameters significantly higher than the other groups (p < .001), though few significant differences in actual knowledge levels were observed. Overall, respondents reported having the highest preference for concussion education delivered by medical professionals. Conclusion: Knowledge concerning concussion is incomplete in the collegiate population. Varsity athletes' exposure to formal education did not result in higher knowledge levels compared with other groups. Further examination of concussion educational delivery models' effect on change in concussion-related behavior in this population is warranted. PMID- 29625434 TI - Readability of Patient-Reported Outcome Measures in Adult Audiologic Rehabilitation. AB - Purpose: The purpose of this study was to examine the readability of published patient-reported outcome measures (PROMs) designed for use in adult audiologic rehabilitation. The readability results were compared with the readability levels recommended for health information by health literacy experts. Method: Reading grade levels were calculated using the Flesch-Kincaid Grade Level Formula (Flesch, 1948), Gunning Fog Index (Gunning, 1952), Simple Measure of Gobbledygook (McLaughlin, 1969), and FORCAST (Caylor, Sticht, Fox, & Ford, 1973) readability formulas for 10 published PROMs. Descriptive statistics were computed across the different PROM sections: instructions, items, response scale, and overall contents of the measure directed toward respondents. Results: The majority of the PROM sections exceeded the 6th grade reading level recommended by health literacy experts, regardless of the formula applied. All PROM sections exceeded the 6th grade reading level when calculated according to the FORCAST formula, the most appropriate readability formula for use with a nonnarrative text format, such as PROMs. Conclusions: When developing or reevaluating PROMs designed for use in adult audiologic rehabilitation, researchers should consider ways to improve the readability of their measure, as poor readability may affect the validity of the empirical data collected using the PROM. Additionally, the adequate readability of audiologic PROMs is required if patient/family-centered care values are to be adhered to within the field of adult audiologic rehabilitation. PMID- 29625435 TI - The Impact of Individual Differences on a Bilingual Vocabulary Approach for Latino Preschoolers. AB - Purpose: The purpose of this study was twofold: First, we replicated in a new sample our previous findings that a culturally and linguistically responsive (CLR) bilingual approach for English vocabulary instruction for preschool Latino dual language learners was effective. Subsequently, we investigated whether the positive effect of CLR instruction varies as a function of individual child characteristics, including baseline vocabulary levels and gender. Method: Using a randomized pretest-posttest follow-up group design, we first replicated our previous study (N = 42) with a new sample by randomly assigning 35 Spanish speaking Latino preschoolers to a CLR bilingual group or an English-only group. The preschoolers received small-group evidence-informed shared readings targeting 30 English words 3 times a week for 5 weeks in their preschools. Vocabulary outcomes were measured using both standardized and researcher-developed measures. We subsequently conducted further studies with the combined sample size of 77 children to examine the variability in intervention effects related to child gender and baseline vocabulary levels. Results: The direct replication study confirmed findings of our earlier work suggesting that the CLR bilingual approach promoted greater gains in L1 and L2 vocabulary than in an English-only approach. The extension studies revealed that the effect of the CLR bilingual vocabulary approach on English and Spanish vocabulary outcomes was not impacted by gender or vocabulary status at baseline. Conclusion: This study provides additional evidence of the benefits of strategically combining L1 and L2 for vocabulary instruction over an English-only approach. Our findings also suggest that preschool Latino dual language learners can benefit from a bilingual vocabulary instructional approach regardless of gender or baseline vocabulary levels in L1. PMID- 29625436 TI - Incorrect Address and Reference. PMID- 29625437 TI - Metalloproteinase Adamts16 Is Required for Proper Closure of the Optic Fissure. AB - Purpose: Coloboma is a sight-threatening congenital eye disease caused by a failure in optic fissure (OF) closure. The aim of this study was to investigate the role of Adamts16, a metalloproteinase, in OF closure. Methods: RNA in situ hybridization was used to examine the expression of Adamts16 in developing mouse and zebrafish eyes. Morpholino knockdowns were performed to study adamts16 function during zebrafish eye development. Additionally, immunofluorescent staining, RNA in situ hybridization, bromodeoxyuridine (BrdU) labeling, TUNEL assays, and high-throughput sequencing were used to examine altered cellular and molecular events in adamts16-morphant optic cups (OCs). Results: Adamts16 is expressed at the edges of the closing OF in both mice and zebrafish eyes. Zebrafish adamts16 knockdown resulted in coloboma formation. In adamts16-morphant eyes, the basement membrane failed to disassemble at the closing OF edges, OC cells exhibited decreased proliferation and increased apoptosis, and fibroblast growth factor 8 (fgf8) was ectopically upregulated in the OC. Conclusions: adamts16 is required for proper OF closure in zebrafish eyes. adamts16 controls OF closure possibly through the combined functions of degrading the basement membrane at the closing OF edges, promoting cell proliferation and survival, and restricting fgf8 expression. Our study linked a metalloproteinase to OF closure, which may facilitate future etiologic studies on human coloboma cases. PMID- 29625438 TI - Changes in Myosin Heavy Chain Isoforms Along the Length of Orbital Fibers in Rabbit Extraocular Muscle. AB - Purpose: Extraocular muscles express 10 myosin heavy chain (MyHC) isoforms that cater for a wide range of contractile speeds. We aim to characterize the variations in MyHC expression along the length of singly (SIFs) and multiply innervated fibers (MIFs) in the orbital layer of rabbit superior rectus muscle. Methods: Monospecific antibodies to nine MyHCs, including an anti-slow-tonic antibody characterized here were used to immunohistochemically map variations in MyHC distribution in serial sections along the muscle's full length. Results: The fastest MyHC, EO, is expressed at the endplate zone (EPZ) of SIFs, flanked proximally and distally by segments expressing the slower 2A, with or without embryonic MyHC. MIFs with constant diameter express alpha-cardiac MyHC at the EPZ, flanked by segments co-expressing alpha-cardiac/embryonic and possibly slow tonic MyHCs. MIFs with varying diameter also express alpha-cardiac MyHC at the EPZ in their thin, central region, flanked by thin segments co-expressing alpha cardiac/embryonic MyHCs, with long proximal and distal extensions of larger diameter that co-express embryonic/slow-tonic and alpha-cardiac or beta/slow MyHCs. Conclusions: Orbital fiber types express multiple MyHCs, with faster ones in SIFs, slower ones in MIFs, but all have fast EPZs and slower end segments. We hypothesize that these unique MyHC distributions enable these fibers to relax in two kinetically distinct phases while acting in an antagonistic manner during a saccade: the fast phases facilitate acceleration of eyeball rotation during agonist contraction, while the slow phases help its deceleration toward the visual target, thereby linearizing the saccade. These properties also facilitate pulley movements to implement Listing's law. PMID- 29625439 TI - Mesenchymal Stromal Cells Inhibit Neutrophil Effector Functions in a Murine Model of Ocular Inflammation. AB - Purpose: Neutrophil-secreted effector molecules are one of the primary causes of tissue damage during corneal inflammation. In the present study, we have investigated the effect of stromal cells in regulating neutrophil expression of tissue-damaging enzymes, myeloperoxidase (MPO), and N-elastase (ELANE). Methods: Bone marrow-purified nonhematopoietic mesenchymal stromal cells and formyl methionyl-leucyl-phenylalanine-activated neutrophils were cocultured in the presence or absence of Transwell inserts for 1 hour. Neutrophil effector molecules, MPO and ELANE, were quantified using ELISA. In mice, corneal injury was created by mechanical removal of the corneal epithelium and anterior stroma approximating one third of total corneal thickness, and mesenchymal stromal cells were then intravenously injected 1 hour post injury. Corneas were harvested to evaluate MPO expression and infiltration of CD11b+Ly6G+ neutrophils. Results: Activated neutrophils cocultured with mesenchymal stromal cells showed a significant 2-fold decrease in secretion of MPO and ELANE compared to neutrophils activated alone (P < 0.05). This suppressive effect was cell-cell contact dependent, as stromal cells cocultured with neutrophils in the presence of Transwell failed to suppress the secretion of neutrophil effector molecules. Following corneal injury, stromal cell-treated mice showed a significant 40% decrease in MPO expression by neutrophils and lower neutrophil frequencies compared to untreated injured controls (P < 0.05). Reduced MPO expression by neutrophils was also accompanied by normalization of corneal tissue structure following stromal cell treatment. Conclusions: Mesenchymal stromal cells inhibit neutrophil effector functions via direct cell-cell contact interaction during inflammation. The current findings could have implications for the treatment of inflammatory ocular disorders caused by excessive neutrophil activation. PMID- 29625440 TI - Changes in Blood Pressure and Urine Albumin-Creatinine Ratio in a Randomized Clinical Trial Comparing Aflibercept, Bevacizumab, and Ranibizumab for Diabetic Macular Edema. AB - Purpose: To compare blood pressure and urine albumin-creatinine ratio over time for participants receiving aflibercept, bevacizumab, or ranibizumab. Methods: Preplanned secondary analyses from a randomized trial comparing aflibercept, bevacizumab, and ranibizumab for diabetic macular edema (DME). The Diabetic Retinopathy Clinical Research Network (DRCR.net) enrolled 660 participants with DME and visual acuity 20/32 or worse in at least one eye. Eyes received intravitreous injections of 2.0 mg aflibercept, 1.25 mg bevacizumab, or 0.3 mg ranibizumab based on a structured retreatment protocol over 2 years. Main outcome measures were (1) a change in blood pressure at 2 years, and (2) a change in urine albumin-creatinine ratio (UACR) at 1 year. Results: At baseline, 95 participants (14%) had normal blood pressure, 220 (33%) had borderline blood pressure elevation, 206 (31%) had mild blood pressure elevation, and 139 (21%) had moderate blood pressure elevation. Average change in mean arterial pressure from baseline to 2 years was -1.2 +/- 15, -1.8 +/- 13.5, -2.6 +/- 14.4 mm Hg in the aflibercept, bevacizumab, and ranibizumab groups, respectively (global P = 0.69). At baseline 247 participants (38%) had no albuminuria (<30 mg/g), 195 (30%) had microalbuminuria (30-300 mg/g), and 212 (32%) had macroalbuminuria (>300 mg/g). Changes in UACR category were not different among treatment groups at the 52-week visit (global P = 0.29). Conclusions: There do not appear to be treatment group differences for changes in blood pressure or UACR as a reflection of kidney function in patients with DME treated with aflibercept, bevacizumab, or ranibizumab. PMID- 29625441 TI - Comparison of Choroidal Vascularity Markers on Optical Coherence Tomography Using Two-Image Binarization Techniques. AB - Purpose: To compare the agreement between optical coherence tomography (OCT) based choroidal vascularity markers measured by two previously reported image binarization techniques. Methods: Spectral-domain OCT using enhanced-depth imaging was performed in 100 eyes from 52 normal subjects. Choroidal images were binarized to luminal area and stromal area using two different algorithms. Choroidal vascularity marker was defined as the ratio of luminal area to total choroidal area and they were termed "luminal/choroidal area ratio (L/C ratio)" and "choroidal vascularity index (CVI)" per the algorithm. The agreement between choroidal vascularity markers measured by the two techniques was compared using intraclass correlation coefficient (ICC) and Bland-Altman analysis. Results: The mean values of choroidal vascularity markers were 70.12% (range, 56.76%-78.55%) for CVI and 67.44% (range, 51.09%-81.31%) for L/C ratio. Low level of absolute agreement between the two binarization techniques was reflected by an adjusted ICC of 0.353 using linear mixed model with age, sex, and spherical equivalent as covariates. Conclusions: There was discrepancy between measurements of choroidal vascularity using two commonly adopted image binarization techniques. It remained unclear what was the true choroidal vascularity and which binarization algorithm was more accurate. Future studies with enhanced image quality and improved image analysis algorithm are required to decipher the ground truth for choroidal vascularity. PMID- 29625443 TI - Comprehensive Molecular Screening in Chinese Usher Syndrome Patients. AB - Purpose: Usher syndrome (USH) refers to a group of autosomal recessive disorders causing deafness and blindness. The objectives of this study were to determine the mutation spectrum in a cohort of Chinese patients with USH and to describe the clinical features of the patients with mutations. Methods: A total of 119 probands who were clinically diagnosed with USH were recruited for genetic analysis. All probands underwent ophthalmic examinations. A combination of molecular screening methods, including targeted next-generation sequencing, Sanger-DNA sequencing, and multiplex ligation probe amplification assay, was used to detect mutations. Results: We found biallelic mutations in 92 probands (77.3%), monoallelic mutations in 5 patients (4.2%), and 1 hemizygous mutation in 1 patient (0.8%), resulting in an overall mutation detection rate of 78.2%. Overall, 132 distinct disease-causing mutations involving seven USH (ABHD12, CDH23, GPR98, MYO7A, PCDH15, USH1C, and USH2A) genes; 5 other retinal degeneration genes (CHM, CNGA1, EYS, PDE6B, and TULP1); and 1 nonsyndromic hearing loss gene (MYO15A) were identified, and 78 were novel. Mutations of MYOA7 were responsible for 60% of USH1 families, followed by PCDH15 (20%) and USH1C (10%). Mutations of USH2A accounted for 67.7% of USH2 families, and mutation c.8559-2A>G was the most frequent one, accounting for 19.1% of the identified USH2A alleles. Conclusions: Our results confirm that the mutation spectrum for each USH gene in Chinese patients differs from those of other populations. The formation of the mutation profile for the Chinese population will enable a precise genetic diagnosis for USH patients in the future. PMID- 29625442 TI - Improved Binocular Outcomes Following Binocular Treatment for Childhood Amblyopia. AB - Purpose: Childhood amblyopia can be treated with binocular games or movies that rebalance contrast between the eyes, which is thought to reduce depth of interocular suppression so the child can experience binocular vision. While visual acuity gains have been reported following binocular treatment, studies rarely report gains in binocular outcomes (i.e., stereoacuity, suppression) in amblyopic children. Here, we evaluated binocular outcomes in children who had received binocular treatment for childhood amblyopia. Methods: Data for amblyopic children enrolled in two ongoing studies were pooled. The sample included 41 amblyopic children (6 strabismic, 21 anisometropic, 14 combined; age 4-10 years; <=4 prism diopters [PD]) who received binocular treatment (20 game, 21 movies; prescribed 9-10 hours treatment). Amblyopic eye visual acuity and binocular outcomes (Randot Preschool Stereoacuity, extent of suppression, and depth of suppression) were assessed at baseline and at 2 weeks. Results: Mean amblyopic eye visual acuity (P < 0.001) and mean stereoacuity improved (P = 0.045), and mean extent (P = 0.005) and depth of suppression (P = 0.003) were reduced from baseline at the 2-week visit (87% game adherence, 100% movie adherence). Depth of suppression was reduced more in children aged <8 years than in those aged >=8 years (P = 0.004). Worse baseline depth of suppression was correlated with a larger depth of suppression reduction at 2 weeks (P = 0.001). Conclusions: After 2 weeks, binocular treatment in amblyopic children improved visual acuity and binocular outcomes, reducing the extent and depth of suppression and improving stereoacuity. Binocular treatments that rebalance contrast to overcome suppression are a promising additional option for treating amblyopia. PMID- 29625445 TI - Erratum. PMID- 29625444 TI - Predictive Mathematical Models for the Spread and Treatment of Hyperoxia-induced Photoreceptor Degeneration in Retinitis Pigmentosa. AB - Purpose: To determine whether the oxygen toxicity hypothesis can explain the distinctive spatio-temporal patterns of retinal degeneration associated with human retinitis pigmentosa (RP) and to predict the effects of antioxidant and trophic factor treatments under this hypothesis. Methods: Three mathematical models were derived to describe the evolution of the retinal oxygen concentration and photoreceptor density over time. The first model considers only hyperoxia induced degeneration, while the second and third models include mutation-induced rod and cone loss respectively. The models were formulated as systems of partial differential equations, defined on a two-dimensional domain spanning the region between the foveal center and the ora serrata, and were solved numerically using the finite element method. Results: The mathematical models recapitulate patterns of retinal degeneration which involve preferential loss of photoreceptors in the parafoveal/perifoveal and far-peripheral retina, while those which involve a preferential loss of midperipheral photoreceptors cannot be reproduced. Treatment with antioxidants or trophic factors is predicted to delay, halt, or partially reverse retinal degeneration, depending upon the strength and timing of treatment and disease severity. Conclusions: The model simulations indicate that while the oxygen toxicity hypothesis is sufficient to explain some of the patterns of retinal degeneration observed in human RP, additional mechanisms are necessary to explain the full range of behaviors. The models further suggest that antioxidant and trophic factor treatments have the potential to reduce hyperoxia-induced disease severity and that, where possible, these treatments should be targeted at retinal regions with low photoreceptor density to maximize their efficacy. PMID- 29625446 TI - Quantitative Evaluation of Vascular Microcirculation Using Contrast-Enhanced Ultrasound Imaging In Rabbit Models of Choroidal Melanoma. AB - Purpose: We investigated the application of contrast-enhanced ultrasound (CEUS) to quantify vascular perfusion in two animal models of choroidal melanoma. Methods: B16F10 and choroidal melanoma cell line (OCM1) melanoma xenografts were implanted into the cyclodialysis cleft of rabbits' right eyes. Fundus photography, indocyanine green angiography (ICGA), B-mode ultrasound, and CEUS were used to examine the tumors. Standard vascular parameters of CEUS imaging were evaluated, including the area under the receiver operating characteristic curve (AUC), peak intensity (IMAX), mean transit time (mTT), rise time, and time to peak. Kruskal-Wallis tests followed by Nemenyi tests and Bonferroni corrections were used to analyze the findings. Results: OCM1 and B16F10 animal models of choroidal melanoma were established. Tumor size was larger in the animals receiving B16F10 xenografts compared with the OCM1. Choroidal melanoma received a more abundant blood supply and had higher blood flow velocities than normal eye tissue. The animals receiving B16F10 xenografts had larger blood volume but smaller blood flow velocity compared with the OCM1 models. Vascular mimicry was present in seven of eight OCM1 tumors (87.5%). Growth and blood circulation patterns differed between OCM1 and B16F10 melanomas. Conclusions: CEUS could be used to noninvasively dynamically, and safely detect the microcirculation patterns, quantify blood circulation volume, and velocity in ocular melanoma in animal models. The blood circulation patterns of two models were different in both qualitatively and quantitative analysis under CEUS and ICGA. PMID- 29625447 TI - Imaging of Corneal Neovascularization: Optical Coherence Tomography Angiography and Fluorescence Angiography. AB - Purpose: The purpose of this study was to compare optical coherence tomography angiography (OCTA) and indocyanine green angiography (ICGA) for the assessment of corneal neovascularization (CoNV). Methods: Patients with CoNV extending at least 3 mm into the cornea were included. All patients underwent corneal imaging at the same visit. Images were recorded using the AngioVue OCTA system (Optovue, Inc.) with the long corneal adaptor module (CAM-L). ICGA images were recorded with fluorescent filters using the Heidelberg system (HRA2 Scanning Laser Ophthalmoscope; Heidelberg Engineering). Images were graded for quality by two independent observers. Vessel parameters: area, number, diameter, branch and end points, and tortuosity, were compared between devices. Bland-Altman plots were used to assess differences between parameters. Results: Fifteen patients with CoNV predominantly associated with microbial keratitis were included. Mean subjective image quality score was better for ICGA (3.3 +/- 0.9) than for OCTA (2.1 +/- 1.2, P = 0.002), with almost perfect interobserver agreement for ICGA images (kappa = 0.83) and substantial agreement for OCTA images (kappa = 0.69). Agreement of grading of all investigated vessel parameters between ICGA and OCT images was slight to moderate, with significant differences found for vessel diameter (-8.98 MUm, P = 0.01, 95% limits of agreement [LOA]: -15.89 to -2.07), number of branch (25.93, P = 0.09, 95% LOA: -4.31 to 56.17), and terminal points (49, P = 0.05, 95% LOA: 0.78 to 97.22). Conclusion: Compared with ICGA, current OCTA systems are less precise in capturing small vessels in CoNV complexes, and validation studies are needed for OCTA segmentation software. OCTA, however, complements ICGA by providing evidence of red blood cell flow, which together with depth information, may be helpful when planning treatment of CoNV. PMID- 29625449 TI - Erratum. PMID- 29625448 TI - Anterior Choroidal Thickness Increased in Primary Open-Angle Glaucoma and Primary Angle-Closure Disease Eyes Evidenced by Ultrasound Biomicroscopy and SS-OCT. AB - Purpose: To compare the anterior and posterior choroid thickness (ACT and PCT, respectively) in primary open-angle glaucoma (POAG), primary angle-closure disease (PACD), and healthy control subjects. Methods: A total of 29 POAG patients (56 eyes), 37 PACD patients (64 eyes), and 34 healthy volunteers (68 eyes) were enrolled in this study; 50 POAG eyes were divided into 25 early/moderate-stage and 25 advanced-stage eyes by visual field loss, while 64 PACD eyes were classified as primary angle-closure suspect (PACS), 8 eyes; primary angle closure (PAC), 18 eyes; and primary angle-closure glaucoma (PACG), 38 eyes. Ultrasound biomicroscopy (UBM) was used to measure the ACT at a distance of 4 mm from the root of iris in all participants. ACT and PCT were measured using UBM and swept-source optical coherence tomography (SS-OCT), respectively. A 4-mm distance from the iris root was self-defined as the anterior choroid that well matched the real anterior choroid. Results: The mean ACT measured by UBM was 0.45 +/- 0.057 mm in POAG eyes, 0.38 +/- 0.050 mm in PACD eyes, and 0.30 +/- 0.050 mm in healthy eyes. Both the POAG and PACD eyes had a thicker anterior choroid than healthy eyes (P < 0.01). Compared to early/moderate-stage eyes of POAG, advanced-stage eyes had similar ACT (P > 0.05). PACG eyes had a thinner anterior choroid than PAC/PACS eyes (P < 0.05). However, no statistically significant difference was noted for POAG, PACD, and normal control eyes' PCT using SS-OCT (P > 0.05). Conclusions: POAG/PACD eyes had a thicker anterior choroid than the controls. However, there was no significant difference in the PCT among the groups. The anterior choroid might play a role in the pathogenesis of glaucoma, warranting further investigation. PMID- 29625450 TI - Asymmetric Patterns of Visual Field Defect in Primary Open-Angle and Primary Angle-Closure Glaucoma. AB - Purpose: To compare the hemifield asymmetry of visual field (VF) loss in primary open-angle glaucoma (POAG) and primary angle-closure glaucoma (PACG) across all severity levels. Methods: A total of 522 eyes of 327 patients with POAG (mean age +/- SD, 54.1 +/- 12.4 years) and 375 eyes of 204 patients with PACG (67.3 +/- 8.9 years) were included. Subjects meeting the definitions of POAG or PACG were included. Means of the total deviation (TD) values (Humphrey 24-2 VF) in the Glaucoma Hemifield Test (GHT) regions were calculated in early (>= -6 dB), moderate (< -6 dB and >= -12 dB), and advanced (< -12 dB) stages of POAG and PACG eyes. Then the differences of the TD values between superior and inferior hemifield GHT regions of POAG and PACG eyes were calculated. Also, the relationship between the values of pattern SD (PSD) and mean TD (mTD) was compared between POAG and PACG. Results: In POAG eyes in the early stage, three regions (central, paracentral, and peripheral) in the superior hemifield had greater loss than their inferior counterparts; in moderate and advanced stages, all GHT regions in the superior hemifield had greater loss than their inferior counterparts. In PACG eyes, siginificantly fewer regions in the superior hemifield were significantly worse than their inferior counterpart, compared with POAG: one region (central) in early stage, two regions (central and peripheral) in moderate stage, and one region (central) in advanced stage. POAG eyes had greater PSD values than PACG eyes for given mean of TD values. Conclusions: In both POAG and PACG eyes, VF damage was more pronounced in superior hemifield than inferior hemifield; however, this tendency was more obvious in POAG eyes than in PACG eyes. PMID- 29625451 TI - A Robust Optomotor Assay for Assessing the Efficacy of Optogenetic Tools for Vision Restoration. AB - Purpose: To develop an animal behavioral assay for the quantitative assessment of the functional efficacy of optogenetic therapies. Methods: A triple-knockout (TKO) mouse line, Gnat1-/-Cnga3-/-Opn4-/-, and a double-knockout mouse line, Gnat1-/-Cnga3-/-, were employed. The expression of channelrhodopsin-2 (ChR2) and its three more light-sensitive mutants, ChR2-L132C, ChR2-L132C/T159C, and ChR2 132C/T159S, in inner retinal neurons was achieved using rAAV2 vectors via intravitreal delivery. Pupillary constriction was assessed by measuring the pupil diameter. The optomotor response (OMR) was examined using a homemade optomotor system equipped with light-emitting diodes as light stimulation. Results: A robust OMR was restored in the ChR2-mutant-expressing TKO mice; however, significant pupillary constriction was observed only for the ChR2-L132C/T159S mutant. The ability to evoke an OMR was dependent on both the light intensity and grating frequency. The most light-sensitive frequency for the three ChR2 mutants was approximately 0.042 cycles per degree. Among the three ChR2 mutants, ChR2 L132C/T159S was the most light sensitive, followed by ChR2-L132C/T159C and ChR2 L132C. Melanopsin-mediated pupillary constriction resulted in a substantial reduction in the light sensitivity of the ChR2-mediated OMR. Conclusions: The OMR assay using TKO mice enabled the quantitative assessment of the efficacy of different optogenetic tools and the properties of optogenetically restored vision. Thus, the assay can serve as a valuable tool for developing effective optogenetic therapies. PMID- 29625452 TI - Inner Retinal Microvasculature Damage Correlates With Outer Retinal Disruption During Remission in Behcet's Posterior Uveitis by Optical Coherence Tomography Angiography. AB - Purpose: To quantify the inner retinal vascular changes that occur in the superficial and deep layers in patients with Behcet's disease (BD) in remission using optical coherence tomography angiography (OCTA) and to evaluate the associations with outer retinal structure. Methods: Nineteen eyes from 19 patients with BD in remission were enrolled, including 10 eyes with less than five ocular attacks (n < 5) and nine eyes with five or more attacks (n >= 5). The foveal avascular zone (FAZ) and global and regional vessel density (VD) in both layers were compared between BD eyes and normal eyes. Their outer retinal structure, including integrity of the ellipsoid zone (EZ), interdigitation zone (IZ), and outer retinal layer thickness were evaluated. Associations between the inner retinal vasculature and outer retinal disruption were sought. Results: Compared to normal eyes, except for the nasal region, all deep capillary VD values were lower in the BD groups, especially in the inferior region. In the superficial layer, the VD differences between groups were larger in capillaries than in small vessels. The FAZ in the n >= 5 group was larger than that in normal and the n < 5 groups in the deep layer. Greater disruption of EZ and IZ was correlated with decreasing global and regional deep capillary VD. Conclusions: BD Patients in remission had significant changes in the inner retinal vasculature that corresponded to the outer retinal disruption. Quantitative measurement by OCTA and algorithm might be useful for evaluation of the vasculature and pathologic changes in BD. PMID- 29625453 TI - Substance P Modulation of Human and Murine Corneal Neovascularization. AB - Purpose: The purpose of this study was to investigate the role of substance P (SP) in patients affected with corneal neovascularization (CNV) and in three different Tac1-knockout (KO) murine models of CNV. Methods: SP levels in tears were measured with a multiplex bead assay. The extent of human CNV was quantified as number of affected corneal quadrants. Murine CNV was induced in both strains by means of total disepithelization, alkali burn, and intrastromal sutures. After death, CNV (blood and lymphatic) and leukocyte infiltration were quantified by CD31, LYVE1, and CD45 immunofluorescence, respectively. Trigeminal ganglions were collected for quantitatitive PCR IL1beta quantification. Hematoxylin-eosin corneal cross sections and whole-mounted beta-3-tubulin nerve staining were used to compare anatomy and nerve density of wild-type (WT) versus Tac1-KO normal mice. Results: SP tear levels correlate positively with CNV extension in patients (r = 0.49, P = 0.03). After disepithelization, Tac1-KO corneas showed reduced blood and lymphatic vascularization (-34% and -51% respectively) compared with the WT counterpart. CD45+ leukocytes infiltrating the cornea were reduced in Tac1 KO mice as opposed to WT in the disepithelization (P = 0.0001), alkali burn (P = 0.0258), and suture (P = 0.0149) models. Tac1-KO mice showed reduced IL1beta expression in the trigeminal ganglion. Normal WT and Tac1-KO corneas did not show significant differences in transparency, thickness, and nerve density. Conclusions: Our results suggest (1) the involvement of SP in human CNV; (2) the key role of SP in promoting inflammatory CNV in three different mouse models; and (3) that absence of SP is not associated with obvious ocular surface pathology in a KO model. PMID- 29625454 TI - White Matter Abnormalities and Correlation With Severity in Normal Tension Glaucoma: A Whole Brain Atlas-Based Diffusion Tensor Study. AB - Purpose: To detect injury of whole brain white matter (WM) in normal tension glaucoma (NTG) patients by using diffusion tensor imaging (DTI) and to analyze the correlations between DTI parameters and glaucoma indices. Methods: Twenty mild, 17 moderate, and 18 severe NTG patients as well as 25 normal subjects were enrolled in this study. Atlas-based diffusion tensor analysis was performed to measure the fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD), and radial diffusivity (RD). One-way analyses of variance were used for comparisons of DTI parameters between NTG subgroups and normal control (NC) group. The relationships between DTI parameters and glaucoma indices were also assessed by Pearson's correlation and "broken-stick" analyses. Results: As compared with NC subjects, significantly decreased FA and AD and increased MD and RD were observed in the bilateral posterior thalamic radiation, bilateral sagittal stratum, bilateral cingulum-hippocampus, and bilateral fornix/stria terminalis in NTG patients. The DTI parameters of these WM regions correlated with the mean deviation of visual field (MDVF) and retinal nerve fiber layer (RNFL) thickness. Additionally, there was a tipping point between MDVF and DTI parameters as well as between MDVF and RNFL thickness. Conclusions: Atlas-based DTI analysis was capable of indicating WM damage in the four regions associated with visual and visual-related functions in NTG patients, and it could also be used for investigating disease progression and pathologic changes. In addition, WM impairment and RNFL thinning occurred before patients showed detectable visual field loss. PMID- 29625455 TI - Release of Different Cell Mediators During Retinal Pigment Epithelium Regeneration Following Selective Retina Therapy. AB - Purpose: To investigate the effect of selective retina therapy (SRT) on the release of AMD-relevant cell mediators, such as matrix metalloproteinases (MMPs), VEGF, and pigment epithelium derived factor (PEDF) using different laser spot sizes and densities. Methods: Porcine RPE-choroid explants were treated with a pulsed 532 nm Nd:YAG laser using (1) large spot sizes, (2) small spot sizes with a high-density (hd) treatment, and (3) small spot sizes with a low-density (ld) treatment. Explants were cultivated in modified Ussing chambers. RPE regeneration and RPE cell death were investigated by calcein-AM staining and immunofluorescence. The MMP release was examined via zymography and immunofluorescence. VEGF and PEDF secretion was analyzed by ELISA. Results: During pigment epithelium regeneration (PER), mitosis and RPE cell migration were observed. Four days after SRT (large spot size) the content of active MMP2 increased significantly (P < 0.01). Hd treatment with small spot sizes resulted also in an increase of active MMP2 (P < 0.05). In immunofluorescence explants showed a localized expression of MMP2 within the healing lesions after irradiation. The PEDF level increased significantly (P = 0.01) after SRT with large spot sizes. VEGF secretion decreased significantly (P < 0.05) following SRT with large spot sizes and with hd treatment of small spot sizes. Conclusions: SRT induces a cytokine profile, which may improve the flux across Bruch's membrane, slows down progression of early AMD by RPE regeneration, and inhibits the formation of choroidal neovascularization. The cytokine release depends on the size and density of applied laser spots. PMID- 29625457 TI - Differentiation Patterns of Immortalized Human Meibomian Gland Epithelial Cells in Three-Dimensional Culture. AB - Purpose: To establish a simplified three-dimensional (3D) meibomian gland culture model using a meibomian gland epithelial cell (HMGEC) line that might be a useful tool to gain deeper insights into meibomian gland dysfunction. For this purpose, 3D differentiation patterns and growth characteristics of HMGECs were studied on various membranes/scaffolds as well as in hanging drops. Methods: Several types of inserts consisting of different materials (Millicell-HA, Millicell-PCF, ThinCert, and Alvetex) as well as hanging drop culture were analyzed. Culture conditions were optimized employing exposure to air (air-lift) and different cell culture media for a maximum of 28 days. To characterize cell differentiation in the developed 3D model, the expression pattern of cytokeratins was investigated by immunohistochemistry. Sudan III staining was performed for detection of lipid formation and transmission electron microscopy (TEM) was used for ultrastructural analysis. Results: Only Alvetex scaffolds and the hanging drop method revealed satisfactory results with regard to 3D culture. Continuous use of proliferation medium (serum-free keratinocyte medium containing epidermal growth factor and bovine pituitary extract) and air-lift were important steps for HMGEC differentiation in 3D culture. However, HMGECs only reached a differentiating state and never became mature or hypermature. When cultured in hanging drops, HMGECs showed serum-induced keratinization processes. Conclusions: HMGECs have the capability to differentiate in a long-term 3D culture, especially when adapted to an air-rich environment. However, even in the 3D format, HMGECs only reach a state of differentiating meibocytes. PMID- 29625456 TI - Local S100A8 Levels Correlate With Recurrence of Experimental Autoimmune Uveitis and Promote Pathogenic T Cell Activity. AB - Purpose: To investigate the role of damage-associated molecular patterns (DAMPs) in recurrent experimental autoimmune uveitis (EAU). Methods: Recurrent EAU was induced in Lewis rats by interphotoreceptor retinoid-binding protein (IRBP) R16 peptide specific T cells (tEAU). Aqueous humor and serum samples were kinetically collected and DAMPs examined by quantitative proteomics, Western blot analysis, and ELISA. tEAU rats were treated with S100 inhibitor paquinimod followed by disease evaluation. The functions of T effector cells and T regulatory cells (Tregs) were compared between treated and nontreated groups. The expression of costimulatory molecules on antigen-presenting cells was examined by flow cytometry. Results: S100A8, but not high mobility group box 1 (HMGB1), in the eye was found to be correlated with intraocular inflammatory episodes. Administration of paquinimod significantly protected tEAU rats from recurrence. Treated tEAU rats had fewer R16-specific Th1 and Th17 cells, but increased numbers of Tregs. R16-specific T cells from treated tEAU rats into naive recipients prevented induction of tEAU by R16-specific T cells from nontreated tEAU rats. Moreover, APCs from treated tEAU rats expressed higher levels of a negative costimulatory molecule, CD200R, and lower levels of CD80, CD86, and MHC class II molecules compared to APCs from nontreated tEAU rats. An opposite pattern of expression of these molecules was observed on APCs incubated in vitro with recombinant S100A8. Conclusions: Our data demonstrate a link between local expression of DAMPs and autoimmune responses, and suggest that complete S100A8/A9 blockade may be a new therapeutic target in recurrent autoimmune uveitis. PMID- 29625458 TI - What Are the Characteristics of Primary Angle Closure With Longer Axial Length? AB - Purpose: To compare biometric parameters between primary angle closure with longer axial length (AL) and those with medium or shorter AL. Methods: We prospectively recruited 138 primary angle-closure patients. Low-coherence interferometry and ultrasound biomicroscopy examinations were performed before laser peripheral iridotomy and pilocarpine treatment. AL was categorized as shorter (<22.5 mm), medium (>=22.5 to <23.5 mm), or longer (>=23.5 mm). Anterior chamber depth and width (ACD and ACW), lens vault (LV), anterior vault (AV), relative AV (AV/AL), relative lens position (RLP, [ACD + 1/2 lens thickness]/AL), trabecular-ciliary angle (TCA), keratometry, and other biometric parameters were compared among different AL groups. Results: Among 138 angle-closure patients, 15 (10.9%) patients had longer ALs, of which 11 (73.3%) were male. These angle closure eyes with longer AL had flatter cornea (P = 0.006 and 0.022 for flat and steep keratometry) and larger ACW (P = 0.006), but smaller RLP (P = 0.019) than those with medium AL; similarly, they had flatter cornea (P < 0.001 for both flat and steep keratometry), and larger ACW (P < 0.001), AV (P = 0.004), and TCA (P = 0.024), but smaller relative AV (P = 0.040) and RLP (P = 0.005) than those with shorter AL. No significant differences were found in the other parameters. Conclusions: Primary angle closure with longer AL was uncommon. Causes of angle closure in these atypical patients were manifold. These patients were predominantly male; they had smaller relative dimension of the anterior segment, flatter cornea, and more anterior RLP and less anteriorly rotated ciliary body compared with those angle-closure patients with relatively shorter AL. PMID- 29625459 TI - Beyond Hyperglycemia, Evidence for Retinal Neurodegeneration in Metabolic Syndrome. AB - Purpose: We evaluated the retinal effects of systemic metabolic changes clustered under the umbrella of metabolic syndrome (MetS) in comparison with age-matched healthy subjects. Methods: Spectral-domain optical coherence tomography (OCT) retinal segmentation analysis of 29 patients with MetS and 36 control subjects was performed. Patients with diabetes mellitus (DM), uncontrolled hypertension, retinopathy, high myopia or hyperopia, and posterior segment surgery, were excluded from analysis. The control group (CG) was selected from age- and sex matched healthy lean subjects. Mean thickness values of individual retinal layers in nine macular early treatment of diabetic retinopathy study (ETDRS) subfields were determined. Results: The MetS group had a significantly thinner ganglion cell layer in two (MetS, 52.4 +/- 5.1 MUm; CG, 54.8 +/- 3.8 MUm; P = 0.030), thinner inner plexiform layer in three (MetS, 39.8 +/- 4.4 MUm; CG, 43.0 +/- 3.5 MUm; P = 0.003), thinner photoreceptor layer in seven (MetS, 79.4 +/- 2.9 MUm; CG, 81.1 +/- 2.9 MUm; P = 0.009) of nine ETDRS subfields. No difference was found in nerve fiber, inner nuclear, outer plexiform, and outer nuclear layers. Conclusions: The patients with MetS had thinner inner retinal layers and photoreceptor layer in OCT segmentation analysis, which suggests that inherent factors of MetS, such as insulin resistance and adipose tissue-derived inflammation, might have a neurodegenerative effect independent of the hyperglycemic levels associated with DM. Therefore, beyond glycemic control measures, weight reduction also might be advised to overweight patients with type 2 DM and MetS to prevent the occurrence of retinal neurodegeneration. PMID- 29625460 TI - Macrophage-Associated Gelatinase Degrades Basement Membrane at the Optic Fissure Margins During Normal Ocular Development in Mice. AB - Purpose: Basement membrane degradation and macrophage aggregation at the optic fissure margins are crucial to optic fissure closure during normal murine eye development. Basement membrane degradation is also an essential step in cancer development, and matrix metalloproteinases (MMPs) play an important role. In this study, we investigated MMP alteration at the degrading basement membrane of optic fissure margins in mice and attempted to clarify the relationship between MMP activity and macrophages. Methods: Serial coronal frozen sections of eyes from BALB/c fetuses were prepared and gelatinase activity was examined using in situ zymography techniques. The frozen sections were immunohistochemically stained with anti-F4/80, anti-MMP 2, and anti-MMP 9 antibodies. Serial coronal paraffin sections were also immunohistochemically stained with anti-type IV collagen and anti-F4/80, and basement membrane disintegration and macrophage aggregation at the optic fissure margins were examined. Results: The basement membrane of optic fissure margins was rapidly degraded during gestational days (GDs) 12.0 to 12.5. Meanwhile, gelatinase activity at F4/80-positive macrophages significantly increased during GDs 11.5 to 12.0 and declined thereafter; some of those were also positive for MMP2. The number of macrophages was also increased and decreased at nearly the same time. Conclusions: Intramacrophage MMPs may be responsible for basement membrane degradation at the optic fissure margins during normal eye development in mice. PMID- 29625461 TI - Allogeneic iPSC-Derived RPE Cell Graft Failure Following Transplantation Into the Subretinal Space in Nonhuman Primates. AB - Purpose: To characterize the intraocular immune response following transplantation of iPS-derived allogeneic RPE cells into the subretinal space of non-immune-suppressed rhesus macaques. Methods: GFP-labeled allogeneic iPS derived RPE cells were transplanted into the subretinal space of one eye (n = 6), and into the contralateral eye 1 day to 4 weeks later, using a two-stage transretinal and transscleral approach. Retinas were examined pre- and post surgery by color fundus photography, fundus autofluorescence, and optical coherence tomography (OCT) imaging. Animals were euthanized between 2 hours and 7 weeks following transplantation. T-cell (CD3), B-cell (CD20), and microglial (Iba1) responses were assessed immunohistochemically. Results: Cells were delivered into the subretinal space in all eyes without leakage into the vitreous. Transplanted RPE cells were clearly visible at 4 days after surgery but were no longer detectable by 3 weeks. In localized areas within the bleb containing transplanted cells, T- and B-cell infiltrates and microglia were observed in the subretinal space and underlying choroid. A T-cell response predominated at 4 days, but converted to a B-cell response at 3 weeks. By 7 weeks, few infiltrates or microglia remained. Host RPE and choroid were disrupted in the immediate vicinity of the graft, with fibrosis in the subretinal space. Conclusions: Engraftment of allogeneic RPE cells failed following transplantation into the subretinal space of rhesus macaques, likely due to rejection by the immune system. These data underscore the need for autologous cell sources and/or confirmation of adequate immune suppression to ensure survival of transplanted RPE cells. PMID- 29625462 TI - Retinal Pigment Epithelial Cells Control Early Mycobacterium tuberculosis Infection via Interferon Signaling. AB - Purpose: Mycobacterium tuberculosis (Mtb) bacilli have been found in retinal pigment epithelial (RPE) cells from uveitis patients without signs of systemic tuberculosis (TB) infection. RPE cells are important for ocular immune privilege and uveitis development. Methods: To address a potential role for Mtb-infected RPE cells in the development of uveitis, we delineated the response to Mtb infection in human RPE cells and primary human macrophages, the main target cell of Mtb. Primary human RPE cells, the human RPE cell line ARPE-19, and monocyte derived proinflammatory M1 and anti-inflammatory M2 macrophages were infected with DsRed-expressing Mtb strain H37Rv. Infection rates and clearance were addressed along with RNA sequencing analysis, a confirmation analysis by dual color reverse-transcriptase multiplex ligation-dependent probe amplification (dcRT-MLPA) and cytokine secretion. Results: RPE cells robustly controlled intracellular outgrowth of Mtb early after infection. The response in RPE cells to control Mtb survival was dominated by interferon (IFN) signaling and further characterized by prominent regulation of cell death/survival-associated genes and low-level production of Th1-associated cytokines. In contrast, macrophages engaged a plethora of responses including IFN signaling and communication between innate and adaptive immune cells to induce granuloma formation. Conclusions: Together, our data demonstrate that RPE cells display a strong response to Mtb infection that appears, however, incomplete in comparison to the macrophage response to Mtb. The RPE response might reflect a balance between mechanisms aimed at Mtb eradication and mechanisms that limit retinal inflammation. PMID- 29625463 TI - Taurine Depletion Causes ipRGC Loss and Increases Light-Induced Photoreceptor Degeneration. AB - Purpose: To examine if light exposure exacerbates retinal neuronal loss induced by taurine depletion. Methods: Albino rats received beta-alanine in the drinking water to induce taurine depletion. One month later, half of the animals were exposed to white light (3000 lux) continuously for 48 hours and the rest remained in normal environmental conditions. A control group of animals nontreated with beta-alanine also was prepared, and half of them were exposed to light using the same protocol. All the animals were processed 2 months after the beginning of the experiment. Retinas were dissected as wholemounts and immunodetected with antibodies against Brn3a, melanopsin, S-opsin, and L-opsin to label different retinal populations: Brn3a+ retinal ganglion cells (RGCs) (image-forming RGCs), m+RGCs (non-image-forming RGCs), and S- and L/M-cones, respectively. Results: Light exposure did not affect the numbers of Brn3a+RGCs or m+RGCs but diminished the numbers of S- and L/M-cones and caused the appearance of rings devoid of cones, mainly in an "arciform" area in the superotemporal retina. Taurine depletion caused a diminution of all the studied populations, with m+RGCs the most affected, followed by S-cones. Light exposure under taurine depletion increased photoreceptor degeneration but did not seem to increase Brn3a+RGCs or m+RGCs loss. Conclusions: Our results document that taurine is necessary for cell survival in the rat retina and even more under light-induced photoreceptor degeneration. Thus, taurine supplementation may help to prevent retinal degenerations, especially those that commence with S-cone degeneration or in which light may be an etiologic factor, such as inherited retinal degenerations, AMD, or glaucoma. PMID- 29625465 TI - Gene Expression and Pathways Underlying Form Deprivation Myopia in the Guinea Pig Sclera. AB - Purpose: Posterior scleral remodeling accompanies myopia. In guinea pigs developing myopia, the region around the optic nerve (peripapillary zone, PPZ) rapidly expands followed by inhibition in eye size in the periphery. We studied the differential gene expression in the sclera that accompanies these changes. Methods: Guinea pigs were form-deprived (FD) for 2 weeks to induce myopia, while the fellow eye served as a control. After 2 weeks, the PPZ and the peripheral temporal sclera were isolated in representative animals to extract the RNA. RNA sequencing was undertaken using an Illumina HiSeq 2000, with differential expression analyzed using Voom and pathways analyzed using the Ingenuity Pathway Analysis tool. RNA from additional PPZ and peripheral temporal sclera in FD and fellow eyes was used for validation of gene expression using quantitative real time PCR (qRT-PCR). Results: In myopic sclera, 348 genes were differentially expressed between PPZ and the peripheral temporal region (corrected P < 0.05), of which 61 were differentially expressed in the PPZ between myopic and control eyes. Pathway analyses of these gene sets showed the involvement of Galphai signaling along with previously reported gamma-aminobutyric acid (GABA) and glutamate receptors among numerous novel pathways. The expression pattern of three novel genes and two myopia-related genes was validated using qRT-PCR. Conclusions: Gene expression changes are associated with the rapid elongation that occurs around the optic nerve region during the development of myopia. A prominent change in Galphai signaling, which affects cAMP synthesis and thus collagen levels, may be critical in mediating the regional changes in myopic sclera. PMID- 29625464 TI - Safety Studies for a 44-Channel Suprachoroidal Retinal Prosthesis: A Chronic Passive Study. AB - Purpose: Following successful clinical outcomes of the prototype suprachoroidal retinal prosthesis, Bionic Vision Australia has developed an upgraded 44-channel suprachoroidal retinal prosthesis to provide a wider field of view and more phosphenes. The aim was to evaluate the preclinical passive safety characteristics of the upgraded electrode array. Methods: Ten normal-sighted felines were unilaterally implanted with an array containing platinum electrodes (44 stimulating and 2 returns) on a silicone carrier near the area centralis. Clinical assessments (color fundus photos, optical coherence tomography, full field electroretinography, intraocular pressure) were performed under anesthesia prior to surgery, and longitudinally for up to 20 weeks. Histopathology grading of fibrosis and inflammation was performed in two animals at 13 to 15 weeks. Results: Eight animals showed safe electrode array insertion (good retinal health) and good conformability of the array to the retinal curvature. Eight animals demonstrated good mechanical stability of the array with only minor (<2 disc diameters) lateral movement. Four cases of surgical or stability complications occurred due to (1) bulged choroid during surgery, (2) hemorrhage from a systemic bleeding disorder, (3) infection, and (4) partial erosion of thin posterior sclera. There was no change in retinal structure or function (other than that seen at surgery) at endpoint. Histopathology showed a mild foreign body response. Electrodes were intact on electrode array removal. Conclusions: The 44 channel suprachoroidal electrode array has an acceptable passive safety profile to proceed to clinical trial. The safety profile is expected to improve in human studies, as the complications seen are specific to limitations (anatomic differences) with the feline model. PMID- 29625466 TI - Narrow Spectrum Kinase Inhibitors Demonstrate Promise for the Treatment of Dry Eye Disease and Other Ocular Inflammatory Disorders. AB - Purpose: The purpose of this study is to determine the potential of narrow spectrum kinase inhibitors (NSKIs) to treat inflammatory eye disorders. Methods: Human conjunctival epithelial (HCE) cells were retrieved from subjects via impression cytology. Real-time quantitative PCR (qPCR) was performed on HCE cells to determine gene expression of NSKI kinase targets and proinflammatory cytokines in dry eye disease (DED) patients versus healthy controls. qPCR also assessed p38alpha expression in hyperosmolar-treated Chang conjunctival epithelial cells. Interaction of NSKI TOP1362 with the kinases was evaluated in ATP-dependent Z LYTE and competition binding assays. Anti-inflammatory activity was assessed in human peripheral blood mononuclear cells and primary macrophages. In an endotoxin induced uveitis (EIU) study, lipopolysaccharide (LPS) was administered intravitreally to Lewis rats. TOP1362, dexamethasone, or vehicle was administered topically, and inflammatory cytokine levels were measured 6 hours after LPS injection. Results: HCE cells from DED patients showed significantly increased expression of p38alpha, spleen tyrosine kinase (Syk), Src, lymphocyte-specific protein tyrosine kinase (Lck), interleukin one beta (IL-1beta), interleukin eight (IL-8), monocyte chemotactic protein-1 (MCP-1), and matrix metalloproteinase-9 (MMP-9). TOP1362 strongly inhibited the kinase targets p38alpha, Syk, Src, and Lck, blocked the rise in p38alpha expression in hyperosmolar Chang cells, and potently reduced inflammatory cytokine release in cellular models of innate and adaptive immunities. In the EIU model, TOP1362 dose-dependently attenuated the LPS-induced rise in inflammatory cell infiltration and ocular cytokine levels with efficacy comparable to that of dexamethasone. Conclusions: TOP1362 is a potent inhibitor of kinases upregulated in DED and markedly attenuates proinflammatory cytokine release in vitro and in vivo, highlighting the therapeutic potential of NSKIs for treating ocular inflammation, such as that observed in DED. PMID- 29625467 TI - Detection of Amblyopia Using Sweep VEP Vernier and Grating Acuity. AB - Purpose: Vernier and grating acuity can be measured with swept-parameter visual evoked potentials (sVEP). However, whether sVEP Vernier and grating acuities are comparable in predicting letter acuity has not been systematically evaluated. This study evaluated the validity and reliability of sVEP Vernier and grating acuity for the detection of amblyopia in adults. Methods: Three types of acuity were measured in 36 adults with amblyopia and 36 age-matched normal-vision controls. Letter acuity was measured with a logMAR chart. Both Vernier and grating acuity were estimated by sVEP and psychophysics for the same stimuli. Regression analyses were performed between the perceptual and electrophysiologic acuity measurements. Results: SVEP Vernier and grating acuities were significantly correlated with their corresponding psychophysical acuities (P < 0.001). Both the sVEP Vernier (P < 0.0001) and grating (P < 0.01) acuities were also significantly correlated with letter acuity. However, Vernier acuity more precisely reflected the magnitude of the letter acuity loss than did grating acuity for both sVEP and psychophysical measures. Repeating sVEP grating acuity tests with different temporal frequencies and modulation types indicated good reliability of sVEP acuity measures. Conclusions: SVEP Vernier acuity has a 1:1 relationship with letter acuity, but sVEP grating acuity does not. SVEP Vernier acuity thus provides a better characterization of the magnitude of the amblyopic acuity loss than does sVEP grating acuity. Nonetheless, each of the sVEP measurements can be used to predict letter acuity and because they can be made without a behavioral response, they may be useful measures of visual function in pre- and nonverbal patients. PMID- 29625469 TI - A Novel Visual Psychometric Test for Light-Induced Discomfort Using Red and Blue Light Stimuli Under Binocular and Monocular Viewing Conditions. AB - Purpose: To develop an objective psychophysical method to quantify light-induced visual discomfort, and to measure the effects of viewing condition and stimulus wavelength. Methods: Eleven visually normal subjects participated in the study. Their pupils were dilated (2.5% phenylephrine) before the experiment. A Ganzfeld system presented either red (1.5, 19.1, 38.2, 57.3, 76.3, 152.7, 305.3 cd/m2) or blue (1.4, 7.1, 14.3, 28.6, 42.9, 57.1, 71.4 cd/m2) randomized light intensities (1 s each) in four blocks. Constant white-light stimuli (3 cd/m2, 4 s duration) were interleaved with the chromatic trials. Participants reported each stimulus as either "uncomfortably bright" or "not uncomfortably bright." The experiment was done binocularly and monocularly in separate sessions, and the order of color/viewing condition sequence was randomized across participants. The proportion of "uncomfortable" responses was used to generate individual psychometric functions, from which 50% discomfort thresholds were calculated. Results: Light-induced discomfort was higher under blue compared with red light stimulation, both during binocular (t(10) = 3.58, P < 0.01) and monocular viewing (t(10) = 3.15, P = 0.01). There was also a significant difference in discomfort between viewing conditions, with binocular viewing inducing more discomfort than monocular viewing for blue (P < 0.001), but not for red light stimulation. Conclusions: The light-induced discomfort characteristics reported here are consistent with features of the melanopsin-containing intrinsically photosensitive retinal ganglion cell light irradiance pathway, which may mediate photophobia, a prominent feature in many clinical disorders. This is the first psychometric assessment designed around melanopsin spectral properties that can be customized further to assess photophobia in different clinical populations. PMID- 29625468 TI - The Role of Wnt/beta-Catenin Signaling and K-Cadherin in the Regulation of Intraocular Pressure. AB - Purpose: Wnt/beta-catenin signaling in the trabecular meshwork (TM) is required for maintaining normal intraocular pressure (IOP), although the mechanism(s) behind this are unknown. We hypothesize that Wnt/beta-catenin signaling regulates IOP via beta-catenin's effects on cadherin junctions. Methods: Nonglaucomatous primary human TM (NTM) cells were treated with or without 100 ng/ml Wnt3a, 1 MUg/ml sFRP1, or both for 4 to 48 hours. Cells were immunostained for beta catenin, total cadherins, or cadherin isoforms. Membrane proteins or whole-cell lysates were isolated for Western immunoblotting and probed for cadherin isoforms. RNA was extracted for cDNA synthesis and qPCR analysis of cadherin expression. Some NTM cells were cultured on electric plates for cell impedance assays. Ad5.CMV recombinant adenoviruses encoding K-cadherin, and/or sFRP1 were injected into eyes of 4- to 6-month-old female BALB/cJ mice (n = 8-10). Conscious IOPs were assessed for 35 days. Results: Upon Wnt3a treatment, total cadherin expression increased and beta-catenin accumulated at the TM cell membrane and on processes formed between TM cells. qPCR showed that Wnt3a significantly increased K-cadherin expression in NTM cells (P < 0.01, n = 3), and Western immunoblotting showed that Wnt3a increased K-cadherin in NTM cells, which was inhibited by the addition of sFRP1. Cell impedance assays showed that Wnt3a treatment increased transcellular resistance and anti-K-cadherin siRNA decreased transcellular resistance (P < 0.001, n = 4-6). Our in vivo study showed that K-cadherin significantly decreased sFRP1-induced ocular hypertension (P < 0.05, n = 6). Western immunoblotting also showed that K-cadherin alleviated sFRP1-induced beta catenin decrease in mouse anterior segments. Conclusions: Our results suggest that cadherins play important roles in the regulation of TM homeostasis and IOP via the Wnt/beta-catenin pathway. PMID- 29625470 TI - Human Conjunctival Epithelial Sheets Grown on Poly(Lactic-Co-Glycolic) Acid Membranes and Cocultured With Human Tenon's Fibroblasts for Corneal Repair. AB - Purpose: We determine the feasibility of human conjunctival epithelial cells (hCjECs) on poly(lactic-co-glycolic) acid (PLGA) membranes for corneal epithelium regeneration. hCjECs on PLGA or polyester (PET) membranes with or without coculture of human Tenon's fibroblasts (hTFs) were compared in vitro, and to determine whether epithelial sheets grown on PLGA membranes can repair injured rabbit corneal epithelium by transplantation for 2 weeks in vivo. Methods: Primary hCjECs were cultured on PLGA or the original PET membrane-based transwell inserts with or without coculture of hTFs on the floor of the culture plate. Cell behaviors, such as proliferation and differentiation, were compared. For in vivo assessment, the corneas of rabbits were burned, and PLGA-based epithelial sheets then were transplanted for 2 weeks before histologic staining was conducted and analyzed to determine the effectiveness of the repair. Results: Primary human epithelial cells on the PLGA membrane showed an increased proliferation when cocultured with fibroblasts, which was confirmed by CCK-8 analysis, and upregulation of Ki67, with the expression of the epithelial marker CK19. The stratified squamous cell marker MUC1 and conjunctival cell marker MUC5AC also were expressed in the epithelial sheet. The epithelial defect in the burned corneas was decreased in the PLGA-based epithelial sheet treatment group (6.1% +/ 1.6% of the area) compared to that in the no-treatment group (30.5% +/- 6.3%) 2 weeks postoperatively. Conclusions: We developed a coculture system using a human feeder cell layer and PLGA membrane-based transwell inserts to create human conjunctival epithelial sheets. This system represents a promising strategy to regenerate corneal epithelium by transplantation. PMID- 29625471 TI - An Anatomic Characterization of the Midbrain Near Response Neurons in the Macaque Monkey. AB - Purpose: These experiments were designed to reveal the location of the premotor neurons that have previously been designated physiologically as the midbrain near response cells controlling vergence, lens accommodation, and pupillary constriction in response to target distance. Methods: To identify this population, the fixed N2c strain of rabies virus was injected into the ciliary body of seven Macaca fascicularis monkeys. The virus was trans-synaptically transported to the brain. Following a 58- to 76-hour survival, animals were perfused with formalin fixative. After frozen sectioning, tissue was reacted to reveal the location of the infected populations by use of a monoclonal anti rabies antibody. Another series of sections was processed to determine which of the rabies-positive cells were cholinergic motoneurons by use of an antibody to choline acetyl transferase. Results: At earlier time points, only cholinergic cells in the preganglionic Edinger-Westphal nucleus ipsilateral to the injection were labeled. At later time points, an additional population of noncholinergic, premotor cells was present. These were most numerous at the caudal end of the supraoculomotor area, where they formed a bilateral band, oriented mediolaterally immediately above the oculomotor nucleus. Rostral to this, a smaller bilateral population was located near the midline within the supraoculomotor area. Conclusions: Most lens preganglionic motoneurons are multipolar cells making up a continuous column within the Edinger-Westphal nucleus. A population of premotor cells that likely represents the midbrain near response cells is located in the supraoculomotor area. These cells are bilaterally distributed relative to the eye they control, and are most numerous caudally. PMID- 29625472 TI - Visual Cortex Activation in Patients With Stargardt Disease. AB - Purpose: Primary visual cortex (PVC) contains a retinotopic map in which the central visual field (CVF) is highly magnified compared to the peripheral field. Several studies have used functional magnetic resonance imaging (fMRI) in patients with macular degeneration to assess the reorganization of visual processing in relationship with the development of extrafoveal preferred retinal locus (PRL). We evaluated the functional response in PVC and its correlation with retinal parameters in patients with Stargardt disease due to ABCA4 mutations (STGD1). Methods: Twenty-four STGD1 patients underwent best-corrected visual acuity, full-field standard electroretinogram (ERG), optical coherence tomography, and microperimetry. Furthermore, patients underwent fMRI to assess cerebral activation during visual stimulation by a flickering checkerboard in four PVC subdivisions, corresponding to 0 degrees to 5 degrees (V1), 5 degrees to 10 degrees (V2), 10 degrees to 15 degrees (V3), and 15 degrees to 40 degrees (V4) of CVF. Results: Higher ERG responses were significantly (P < 0.0125) associated with larger functional cerebral response in V1, V2, and V3 subdivisions. Moreover, larger retinal pigment epithelium atrophy area was significantly (P < 0.0125) associated with smaller PVC activation in V2 and V3 subdivisions. Larger activation in V1 subdivision was significantly (P = 0.001) associated with higher mean macular sensitivity and smaller dense scotoma size. Finally, our results showed reduced activation in V2 and V3 with increased PRL eccentricity. Conclusions: Our study, for the first time in the literature, showed stronger PVC activation in STGD1 patients with a more preserved retinal function and macular structure. Furthermore, our study data strongly suggest that the evaluation of neuronal reorganization could be performed by considering only retinal parameters, particularly ERG responses. PMID- 29625474 TI - Gut Microbiota Composition and Fecal Metabolic Phenotype in Patients With Acute Anterior Uveitis. AB - Purpose: To investigate gut microbiota composition and fecal metabolic phenotype in patients with acute anterior uveitis. Methods: Fecal DNA was extracted from 78 fecal samples (38 acute anterior uveitis (AAU) patients and 40 family members of patients or sex- and age-matched healthy controls) and then sequenced by high throughput 16S rDNA analysis. Gas chromatographic mass spectrometry (GC-MS) based metabolomics was performed on 60 fecal samples (30 AAU patients and 30 healthy controls). Results: A significant difference was observed in beta diversity between AAU patients and healthy controls. Eight genera including Roseburia were reduced in AAU patients, and Veillonella was increased in AAU patients as compared with healthy controls. Significance was however lost after false discovery rate (FDR) correction. The expression of seven fecal metabolites including 6-deoxy-D-glucose 1, linoleic acid, N-Acetyl-beta-D-mannosamine 3, shikimic acid, azelaic acid, isomaltose 1 and palmitoleic acid was increased in AAU patients. Linoleic acid showed a significant correlation with Roseburia and Veillonella according to Spearman correlation analysis. Conclusions: Our results did not reveal a difference in gut microbiota composition, but did show that the fecal metabolic phenotype in AAU patients was significantly different from healthy controls. PMID- 29625473 TI - Corneal Epithelial Cells Exhibit Myeloid Characteristics and Present Antigen via MHC Class II. AB - Purpose: To explore the impact of ocular surface insults on the immunomodulatory capacity and phenotype of corneal epithelial cells (CECs) with a focus on epithelial-mesenchymal transition (EMT). Methods: Corneas were harvested from mice 6 days following scratch injury, ragweed pollen-induced allergy, or herpes simplex virus type 1 (HSV-1) infection and compared to healthy tissue controls. Corneas were enzymatically digested and CECs phenotypically characterized using flow cytometry. CECs were defined as epithelial cell adhesion molecule (EpCAM) positive CD45-negative cells. CECs were assessed by PCR to evaluate EMT associated transcripts. Recombinant HSV-1 and transgenic mice were utilized to investigate the role of vascular endothelial growth factor A (VEGFA) on the phenotype observed. The immunomodulatory potential of CECs was assessed in coculture assays with ovalbumin-specific CD4 T cells. Results: Ectopic expression of classic "myeloid" antigens Ly6G, CCR2, and CX3CR1 was identified in CEC subsets from all groups with evidence supporting an underlying partial EMT event resulting from loss of cell-cell contacts. Corneal HSV-1 infection induced Ly6C expression and major histocompatibility complex (MHC)-II upregulation in CECs through a VEGFA-linked mechanism. These Ly6C+ MHC-II+ CECs were found to function as amateur antigen-presenting cells and induced CD4 T cell proliferation in vitro. Conclusions: This study characterizes a novel immunomodulatory CEC phenotype with possible implications for immune privilege, chronic inflammation, and tissue fibrosis. Moreover, the identification of CECs masquerading with multiple "myeloid" antigens warrants careful evaluation of flow cytometry data involving corneal digests. PMID- 29625475 TI - Diagnostic Performance and Repeatability of a Novel Game-Based Visual Field Test for Children. AB - Purpose: To demonstrate utility of a game-based test ("Caspar's Castle") for the detection of visual field defects in children. Methods: A validity and reliability study was carried out at Manchester Royal Eye Hospital Pediatric Ophthalmology Outpatients Department. We recruited 108 children with no eye pathology (aged 4-12 years) and examined a single eye with the Caspar's Castle system using either normal thresholds or thresholds artificially adapted to recreate defects to assess diagnostic utility. Number of peripheral stimuli missed was used to determine sensitivity and specificity of artificial defect detection and to plot receiver-operator characteristic curves. A further 21 children (aged 4-16 years) with pathology were recruited and Caspar's fields compared qualitatively with established field testing. A total of 106 of the Caspar's Castle examinations were able to be performed twice and repeatability was determined through coefficient of repeatability and Bland-Altman chart. Results: In diagnostic testing using children with no eye pathology, 45 children completed a test using normal thresholds and 43 with tests using artificial defects. Area under receiver-operator characteristic curves for artificial defect detection was 0.895. Of the 21 children with pathology, seven had completed standard Humphreys field testing and Caspar's Castle fields corresponded with each of these by expert opinion. Coefficient of repeatability for number of points missed across all cohorts of children (106 patients) was 6.9 (95% confidence interval: 6.16-8.07). Conclusions: The Caspar's Castle system of assessing visual fields using novel game-based strategies demonstrates encouraging levels of sensitivity, specificity, and reliability. It could help address current difficulties in perimetry in young children. PMID- 29625478 TI - Genetic Risk Factors for Radiation Vasculopathy. AB - Purpose: The purpose of this study was to perform a genome-wide scan for polymorphisms associated with risk of vision loss from radiation complications in patients treated with proton beam irradiation for choroidal melanoma. Methods: We identified a cohort of 126 patients at high risk of radiation complications due to tumor location within 2 disc diameters of the optic nerve and/or fovea who provided a blood sample to the Massachusetts Eye and Ear Uveal Melanoma Repository. Controls (n = 76) were defined as patients with visual acuity 20/40 or better 3 years after treatment. Cases (n = 50) were selected as patients with visual acuity 20/200 or worse due to radiation damage 3 years after treatment. Genotyping of these samples was performed using the Omni 2.5 chip (Illumina, Inc.). Results: Hypertension (odds ratio [OR] = 3.749, P = 0.0009), visual acuity at diagnosis of choroidal melanoma (OR = 1.031, P = 0.002), tumor distance to fovea (OR = 0.341, P = 6.52E-05), tumor distance to optic disc (OR = 0.481, P = 5.41E-05), and height of tumor (OR = 1.704, P = 0.0069) were associated with poor vision (20/200 or worse). Individual single nucleotide polymorphism (SNP) analysis was performed controlling for the risk factors identified using stepwise regression and the first principal component. Although this analysis determined that there were 74,529 nominally significant SNPs (P < 0.05), there were no SNPs that reached genome-wide significance (P < 5E-08). The SNP reaching the highest significance level (P < 1E-04) was rs11678387, located on chromosome 2, intergenic between EPB41L5/RALB (P = 4.43E-05). Conclusions: Visual loss from radiation vasculopathy after treatment for choroidal melanoma is not only related to tumor location but may be influenced by hypertension and possibly genetic factors. PMID- 29625480 TI - Microvascular Density Is Associated With Retinal Ganglion Cell Axonal Volume in the Laminar Compartments of the Human Optic Nerve Head. AB - Purpose: To quantify associations between microvascular density and retinal ganglion cell (RGC) axonal volume in the laminar compartments of the human optic nerve head (ONH). Methods: Eleven normal human ONHs were evaluated. Antibodies were used to label the vascular endothelium (factor VIII-related antigen/von Willebrand factor antibody) and RGC axons (neurofilament heavy antibody). Three dimensional analysis of confocal scanning laser microscope images was used to study microvascular density and RGC axonal volume in the prelaminar, anterior lamina cribrosa, posterior lamina cribrosa, and retrolaminar compartments. Results: Microvascular volume was significantly different between laminar compartments (P < 0.0083) and was greatest in the prelaminar region, occupying 11.7% of tissue volume. Microvascular volume per RGC axonal volume and cumulative capillary length per RGC axonal volume were significantly different between laminar compartments (all P < 0.0083). Both were significantly greater in the posterior laminar cribrosa (27.4% and 2.28 * 10-3 MUm/MUm3, respectively). Conclusions: Microvascular density is closely coupled to RGC axonal volume in the ONH. The posterior laminar cribrosa is a site of high blood supply as evidenced by a greater ratio of microvascular density to RGC axonal volume. The greater percentage of tissue volume occupied by microvasculature in the prelaminar region may implicate it as a site where significant connections between the central retinal artery and short posterior ciliary arteries occur. PMID- 29625479 TI - Agreement of Anterior Segment Parameters Obtained From Swept-Source Fourier Domain and Time-Domain Anterior Segment Optical Coherence Tomography. AB - Purpose: To assess the interdevice agreement between swept-source Fourier-domain and time-domain anterior segment optical coherence tomography (AS-OCT). Methods: Fifty-three eyes from 41 subjects underwent CASIA2 and Visante OCT imaging. One hundred eighty-degree axis images were measured with the built-in two-dimensional analysis software for the swept-source Fourier-domain AS-OCT (CASIA2) and a customized program for the time-domain AS-OCT (Visante OCT). In both devices, we examined the angle opening distance (AOD), trabecular iris space area (TISA), angle recess area (ARA), anterior chamber depth (ACD), anterior chamber width (ACW), and lens vault (LV). Bland-Altman plots and intraclass correlation (ICC) were performed. Orthogonal linear regression assessed any proportional bias. Results: ICC showed strong correlation for LV (0.925) and ACD (0.992) and moderate agreement for ACW (0.801). ICC suggested good agreement for all angle parameters (0.771-0.878) except temporal AOD500 (0.743) and ARA750 (nasal 0.481; temporal 0.481). There was a proportional bias in nasal ARA750 (slope 2.44, 95% confidence interval [CI]: 1.95-3.18), temporal ARA750 (slope 2.57, 95% CI: 2.04 3.40), and nasal TISA500 (slope 1.30, 95% CI: 1.12-1.54). Bland-Altman plots demonstrated in all measured parameters a minimal mean difference between the two devices (-0.089 to 0.063); however, evidence of constant bias was found in nasal AOD250, nasal AOD500, nasal AOD750, nasal ARA750, temporal AOD500, temporal AOD750, temporal ARA750, and ACD. Among the parameters with constant biases, CASIA2 tends to give the larger numbers. Conclusions: Both devices had generally good agreement. However, there were proportional and constant biases in most angle parameters. Thus, it is not recommended that values be used interchangeably. PMID- 29625481 TI - Induced Pluripotent Stem Cells Promote Retinal Ganglion Cell Survival After Transplant. AB - Purpose: The purpose of this study was to characterize whether induced pluripotent stem cells (iPSCs) affect survival of grafted retinal ganglion cells (RGCs) after transplantation. Methods: For in vitro studies, human iPSCs were either directly cocultured with mouse RGCs or plated in hanging inserts in RGC cultures for 1 week. For ex vivo studies, RGCs and iPSCs were seeded onto the inner surface of an adult rat retina explant and cultured for 1 week. For in vivo studies, RGCs and iPSCs were intravitreally coinjected into an adult rat eye 1 week before examining retinas by explant and immunostaining. Results: A dose dependent increase in RGC survival was observed in RGC-iPSC direct cocultures, and RGC-iPSC indirect cocultures showed a similar RGC protective effect, but to a lesser extent than in direct coculture. Enhanced RGC survival was also identified in RGC-iPSC cotransplantations to adult retinas ex vivo and in vivo. In addition, RGCs with iPSC cotransplantation extended significantly longer neurites than RGC only transplants. Conclusions: Human iPSCs promote transplanted RGC survival and neurite extension. This effect may be mediated at least partially through secretion of diffusible neuroprotective factors. PMID- 29625482 TI - Distribution Pattern of Choroidal Thickness at the Posterior Pole in Chinese Children With Myopia. AB - Purpose: To determine the relationship between choroidal thickness (ChT) at the posterior pole and refractive error and to explore the difference between the macular and peripapillary regions in children with myopia. Methods: A total of 340 healthy Chinese children underwent a series of comprehensive ocular examinations including cycloplegic refraction. Swept-source optical coherence tomography was used to measure the ChT in the macular and peripapillary regions. The Early Treatment of Diabetic Retinopathy Study grid was applied to define the sectors. Results: The mean spherical equivalent (SE) of the participants was 1.71 +/- 2.22 diopter (D; range from -7.63 to 4.25 D). The mean ChT in the central foveal, parafoveal, and perifoveal regions were 229 +/- 65 MUm, 227 +/- 60 MUm, and 215 +/- 50 MUm, respectively, and the mean global peripapillary choroidal thickness (PPCT) was 136 +/- 33 MUm. The choroid in the macular region and the global PPCT was thinner in myopes compared to hyperopes. The area between the central fovea and the optic disc underwent the largest change as myopia worsened. SE, uncorrected visual acuity, cornea curvature radius (CR), retinal thickness (RT), and retinal nerve fiber layer thickness (RNFLT, except for the central fovea) were the independent factors of ChT in the macular region. SE, CR, RT, and RNFLT were the independent factors of PPCT temporally, inferiorly, and globally, while only CR, RT, and RNFLT were independently associated with PPCT superiorly and nasally. Conclusions: Choroidal thinning might be uneven during the development of myopia. SE only influenced the macular area and sectors temporal and inferior to the optic disc. PMID- 29625483 TI - Tear Levels of 8-hydroxy-2'-deoxyguanosine. PMID- 29625484 TI - Author Response: Tear Levels of 8-hydroxy-2'-deoxyguanosine. PMID- 29625486 TI - Structure-Function Analysis in Patients With Intermediate Age-Related Macular Degeneration. AB - Purpose: To examine the topographic correlation between retinal morphology and retinal sensitivity by mesopic and scotopic fundus-controlled perimetry (FCP) in eyes with intermediate AMD. Methods: Thirty-five eyes from 32 patients (mean age 70.9 years) and 29 age-matched controls prospectively underwent spectral-domain optical coherence tomography (SD-OCT) imaging. Mesopic (Goldman III, 200 ms, 4-2 strategy) and scotopic (Goldman V, 200 ms, 4-2 strategy) FCP with a 56-stimulus point grid was performed in AMD patients with the MP-1S. Thickness values of different retinal layers were measured at each stimulus point and compared, topographically corresponding to values in controls of similar age for pointwise structural-functional analysis. Results: The overall mean sensitivity in patients was 16.9 +/- 3.0 dB for mesopic and 14.0 +/- 3.7 dB for scotopic testing. Within the central 4 degrees of the macula, reduced mesopic and scotopic sensitivity values were found (P < 0.0001). These findings correlated to central increasing retinal pigment epithelium-drusen complex (RPEDC) thickness and central decreasing outer nuclear layer (ONL) and photoreceptor (PR)-segments thickness (P < 0.0001, respectively). Structure-function correlations revealed that a reduction of mesopic and scotopic sensitivity was associated with increasing thickness of the total retina and the RPEDC and a decrease of the ONL and the PR segments (P < 0.001, respectively). Conclusions: Accumulation of sub-RPE material in patients with intermediate AMD is spatially associated to quantifiable structural alterations in various retinal layers and to corresponding retinal dysfunction. The topographic analysis of retinal thickness and retinal sensitivity will be helpful for a better understanding of the disease process and for the evaluation of new interventional approaches. PMID- 29625485 TI - Atovaquone Impairs Growth of Aspergillus and Fusarium Keratitis Isolates by Modulating Mitochondrial Function and Zinc Homeostasis. AB - Purpose: Aspergillus and Fusarium molds cause blinding corneal infections as a consequence of ocular trauma and in association with contact lens wear. As these fungi require zinc for fungal growth, we examined the effect of atovaquone, a ubiquinone analog that disrupts zinc homeostasis, on fungal growth in vitro and in vivo. Methods: In vitro: Aspergillus and Fusarium germinating conidia were incubated overnight with atovaquone, and hyphal growth was measured by fluorimetry. In vivo: C57BL/6 mouse corneas were infected with Aspergillus or Fusarium conidia. Atovaquone was added topically and corneal opacification and fungal growth were quantified. Results: Atovaquone has antifungal activity against Aspergillus and Fusarium clinical isolates, with Fusarium species being more sensitive to atovaquone than Aspergillus species. Atovaquone also reduced labile intracellular zinc levels and increased the sensitivity of Aspergillus to metal shock. Atovaquone reduced vacuolar acidification, which regulates storage of intracellular free zinc, and also acted synergistically with voriconazole and itraconazole to kill hyphae. Furthermore, mitochondrial potential and ATP production were reduced in both Aspergillus and Fusarium following atovaquone treatment. Finally, topical application of atovaquone to the ocular surface significantly inhibited fungal growth and corneal opacification in murine models of fungal keratitis. Conclusions: These studies demonstrate that atovaquone has pronounced in vitro and in vivo antifungal activity against filamentous fungi by disrupting both metal homeostasis and mitochondrial function, and therefore has potential as a novel antifungal agent. PMID- 29625487 TI - Parapapillary Gamma Zone and Progression of Myopia in School Children: The Beijing Children Eye Study. AB - Purpose: To assess the development and enlargement of the parapapillary gamma zone in school children. Methods: This school-based prospective longitudinal study included Chinese children attending grade 1 in 2011 and returning for yearly follow-up examinations until 2016. These examinations consisted of a comprehensive ocular examination with biometry and color fundus photographs. The parents underwent a standardized interview. The parapapillary gamma zone was defined as the area with visible sclera at the temporal optic disc margin, and the optic disc itself was measured on fundus photographs. Results: The study included 294 children (mean age in 2016, 11.4 +/- 0.5 years [range, 10-13 years]; mean axial length, 24.1 +/- 1.1 mm [range, 21.13-27.29 mm]). In multivariate analysis, larger increases in the gamma zone area during the study period were correlated (coefficient of determination for bivariate analysis [r2], r2 = 0.69) with larger increases in the vertical-to-horizontal disc diameter ratios (P < 0.001; standardized regression coefficient beta [beta], 0.53; nonstandardized regression coefficient B [B], 4.05; 95% confidence intervals [CI], 3.37-4.73), larger axial elongation (P < 0.001; beta, 0.32; B, 0.37; 95% CI, 0.26-0.47), a larger vertical disc diameter at baseline (P < 0.001; beta, 0.22; B, 0.98; 95% CI, 0.62-1.33), a larger gamma zone area at baseline (P < 0.001; beta, 0.14; B, 0.41; 95% CI, 0.17-0.64), and more time spent indoors studying (P = 0.015; beta, 0.10; B, 0.09; 95% CI, 0.02-0.17). Conclusions: The development and enlargement of the gamma zone in the temporal parapapillary region were associated with an optic disc rotation around the vertical disc axis as indicated by an increasing vertical-to-horizontal disc diameter ratio. These morphologic findings fit with the notion of a backward pull of the temporal peripapillary sclera through the optic nerve dura mater in axially elongated eyes. PMID- 29625489 TI - Visualizing the Fate of Transplanted K14-Confetti Corneal Epithelia in a Mouse Model of Limbal Stem Cell Deficiency. AB - Purpose: Therapies for limbal stem cell deficiency (LSCD) include stem cell (SC) grafts that regenerate the damaged ocular surface. However, the fate of transplanted cells is ill-defined. We addressed this limitation using primary corneal epithelial cells from K14-Confetti mice. Methods: Cultures of primary corneo-limbal epithelia were generated from K14-Confetti (n = 6) and wild-type (WT) (n = 3) mice. Cell phenotype and function was ascertained by immunofluorescence, flow cytometry, quantitative PCR and colony formation. K14 Confetti cells were nurtured on fibrin and transferred onto WT mice with experimentally induced LSCD (n = 16) to determine the site of implantation, longevity, and phenotype. Results: Transgenic and WT cells derived from explanted corneal tissue displayed no phenotypic or functional differences. K14-Confetti corneo-limbal epithelia that engrafted in recipient LSCD WT mice formed 107 +/- 36 fluorescent clones at 2 weeks postprocedure, which decreased to 70.0 +/- 5.5 by 6 weeks (P = 0.15). Furthermore, cells commonly implanted in the periphery (P < 0.05) and some generated clones that migrated centripetally. However, a normal corneal epithelial phenotype was not restored. We speculate this is due to insufficient SCs being seeded within grafts, and shows evidence of both cell loss from the implants and transdifferentiation into K8+-conjunctival and K10+ cutaneous epithelia after transplantation. Conclusions: This study successfully tracked the fate of transplanted corneo-limbal epithelia in a mouse model of LSCD by intravital microscopy. Our data shed new light into how donor cells behave, the positions they take, how long they survive, and potential mechanisms of loss from the ocular surface. This information is important for improving future animal models, to render them clinically relevant. PMID- 29625488 TI - A Cell Culture Approach to Optimized Human Corneal Endothelial Cell Function. AB - Purpose: Cell-based therapies to replace corneal endothelium depend on culture methods to optimize human corneal endothelial cell (HCEC) function and minimize endothelial-mesenchymal transition (EnMT). Here we explore contribution of low mitogenic media on stabilization of phenotypes in vitro that mimic those of HCECs in vivo. Methods: HCECs were isolated from cadaveric donor corneas and expanded in vitro, comparing continuous presence of exogenous growth factors ("proliferative media") to media without those factors ("stabilizing media"). Identity based on canonical morphology and expression of surface marker CD56, and function based on formation of tight junction barriers measured by trans endothelial electrical resistance assays (TEER) were assessed. Results: Primary HCECs cultured in proliferative media underwent EnMT after three to four passages, becoming increasingly fibroblastic. Stabilizing the cells before each passage by switching them to a media low in mitogenic growth factors and serum preserved canonical morphology and yielded a higher number of cells. HCECs cultured in stabilizing media increased both expression of the identity marker CD56 and also tight junction monolayer integrity compared to cells cultured without stabilization. Conclusions: HCECs isolated from donor corneas and expanded in vitro with a low-mitogenic media stabilizing step before each passage demonstrate more canonical structural and functional features and defer EnMT, increasing the number of passages and total canonical cell yield. This approach may facilitate development of HCEC-based cell therapies. PMID- 29625491 TI - Wide Corneal Epithelial Mapping Using an Optical Coherence Tomography. AB - Purpose: To map the corneal epithelium using a map measuring 9 mm in diameter and view the effects of age, sex, and axial length. Additionally, we wanted to demonstrate the reproducibility of this technique. Methods: We calculated the epithelial thickness in 220 individuals using an SD-OCT machine with the newly released commercially available algorithm. We included normal eyes with refractive errors between +5 and -6 diopters (D). We excluded patients with an intraocular pressure of >22 mm Hg, history of cataract, previous ocular surgery, or disease and those with corneal pathology. Additionally, we excluded patients with evidence of systemic disease or pregnancy. Lastly, reproducibility was measured in 50 individuals. Results: We found the center of the corneal epithelium to be thicker than the peripheral in all zones except the nasal (P = 0.124). The superior quadrant was found to be the thinnest while the inferior was the thickest. Males had a thicker epithelium in all locations except the superior outer section (P = 0.123). Three zones had a weak correlation with age: outer superior (P = 0.039, R = -0.152); outer temporal (P = 0.042, R = -0.150); and outer superior temporal (P = 0.011, R = -0.187). There was no significant relationship with the axial length. We found good to excellent reproducibility when using this technique in the central as well as the peripheral cornea. Conclusions: We provide a comprehensive study in healthy, normal eyes using a novel algorithm to map the corneal epithelium with a wide diameter. This study can be used as a reference for future research. PMID- 29625490 TI - Keratan Sulfate Phenotype in the beta-1,3-N-Acetylglucosaminyltransferase-7-Null Mouse Cornea. AB - Purpose: Synthesis of keratan sulfate (KS) relies on coordinated action of multiple enzymes, including the N-acetylglucosamine-transferring enzyme, beta-1,3 N-acetylglucosaminyltransferase-7 (beta3GnT7). A mouse model deficient in beta3GnT7 was developed to explore structural changes in KS and the extracellular matrix (ECM; i.e., the corneal stroma), elucidate the KS biosynthesis mechanism, and understand its role in corneal organization. Methods: A knockout vector for the beta3GnT7-encoding gene, B3gnt7, was created to develop heterozygous- (htz) and homozygous-null (null) knockouts. Epithelial, stromal, and whole cornea thicknesses were measured from each group. Proteoglycans were stained with cupromeronic blue for visualization by electron microscopy, and Western blot analyses were conducted on the KS core protein, lumican. Corneal sections were labelled fluorescently for KS and chondroitin sulfate/dermatan sulfate (CS/DS) using monoclonal antibodies 1B4 or 2B6, respectively. Results: Wild-type (WT) and htz corneas were of similar stromal thickness, whereas null specimens measured relatively thin. Electron micrographs revealed that WT and htz samples contained comparable levels of KS- and CS/DS-PGs. Null corneas, however, lacked detectable KS and featured uncharacteristically elongated electron dense PG filaments, which were susceptible to chondroitinase ABC digestion. Western blotting revealed lumican in the null corneas was substituted with low-molecular-weight KS, relative to WT or htz tissue. KS was not immunohistochemically detectable in the null cornea, whereas CS/DS content appeared increased. Conclusions: Addition of N acetylglucosamine via beta3GnT7 to KS glycosaminoglycans is necessary for their biosynthesis. Without beta3GnT7, murine corneal stromas lack KS and appear to compensate for this loss with upregulation of chondroitinase ABC-sensitive PGs. PMID- 29625492 TI - Dark Rearing Does Not Prevent Rod Oxidative Stress In Vivo in Pde6brd10 Mice. AB - Purpose: In cyclic light-reared Pde6brd10 mice, rod cell oxidative stress contributes to the degenerative phenotype. Dark rearing Pde6brd10 mice slows but does not prevent atrophy. This suggests that outer retinal oxidative stress occurs in Pde6brd10 mice independent of light exposure, a hypothesis tested in this study. Methods: Mouse strains Pde6brd10 and C57Bl/6 (wild type) were dark reared until postnatal day (P) 23 (P23) or P30. In subgroups of dark-reared mice, (1) layer-specific excessive free radical production (i.e., an oxidative stress biomarker) in vivo via QUEnch-assiSTed magnetic resonance imaging (QUEST MRI) was indicated by a significant reduction in the greater-than-normal spin-lattice relaxation rate R1 (1/T1) with methylene blue, (2) superoxide production was measured ex vivo in whole retina (lucigenin), and (3) retinal layer spacing and thickness were assessed in vivo (optical coherence tomography, MRI). Results: In P23 male Pde6brd10 mice, only the outer superior retina showed oxidative stress in vivo, as measured by QUEST MRI; a lucigenin assay confirmed supernormal superoxide production. In contrast, at P30, no evidence for retinal oxidative stress was observed. In P23 female Pde6brd10 mice, no retinal oxidative stress was apparent; however, at P30, oxidative stress was observed in superior inner and outer nuclear layers. Male and female Pde6brd10 mice at P23 had normal retinal thicknesses, whereas at P30, modest thinning was noted in inferior and superior retina. Conclusions: We confirmed that outer retinal oxidative stress occurs in male and female dark-reared Pde6brd10 mice. Male and female Pde6brd10 mice demonstrated similar degrees of retinal thinning, but with unexpectedly distinct spatial and temporal retinal oxidative stress patterns. PMID- 29625493 TI - Characterization of a Spontaneously Immortalized Murine Muller Glial Cell Line QMMuC-1. AB - Purpose: Muller glia are critical for the survival of retinal neurons and the integrity of retinal blood vessels. Muller glial cultures are important tools for investigating Muller glial pathophysiology. Here, we report a spontaneously immortalized Muller glial cell line originally cultured and subsequently cloned from mouse pups. The cell line, Queen's University Murine Muller glia Clone-1 (QMMuC-1), has been cultured for over 60 passages, has morphologic features like primary Muller cell (PMC) cultures and remains stable. Methods: QMMuC-1 and PMC cells were processed for immunohistochemistry, quantitative RT-PCR, Western blotting, whole cell voltage-clamping, and bioenergetic profiling. Results: Immunocytochemistry showed that QMMuC-1 express known Muller glial markers, including glutamine synthetase, glial fibrillary acidic protein (GFAP), alpha smooth muscle actin (alpha-SMA), Aquaporin 4, Kir4.1, interleukin 33 (IL-33), and sex determining region Y (SRY)-box2 (Sox2), but not Cone arrestin, Calbindin 1, CD68, and ionized calcium-binding adapter molecule 1 (Iba1). Compared with PMC, QMMuC-1 express higher levels of chemokine (C-C motif) ligand 2 (Ccl2), VEGFA, and glutamate aspartate transporter (GLAST), but lower levels of interleukin 6 (IL-6), brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1 (IGF1), and neurotrophin 3 (NTF3). Whole-cell patch clamp recordings demonstrated characteristic inward currents in response to L-glutamate and L-trans-pyrrolidine 2,4-dicarboxylic acid (PDC) by QMMuC-1 cells. The L-glutamate-induced current was significantly higher in QMMuC-1 cells compared with PMC. Bioenergetic profiling studies revealed similar levels of glycolysis and basal mitochondrial respiration between QMMuC-1 and PMC. However, mitochondrial spare capacity was significantly lower in QMMuC-1 compared with PMC. Conclusions: Our results suggest that the QMMuC-1 Muller glial cell line retains key characteristics of PMC with its unique profiles in cytokine/neurotrophic factor expression and mitochondrial respiration. QMMuC-1 has utility as an invaluable tool for understanding the role of Muller glia in physiological and pathological conditions. PMID- 29625494 TI - The Role of 2% Rebamipide Eye Drops Related to Conjunctival Differentiation in Superoxide Dismutase-1 (Sod1) Knockout Mice. AB - Purpose: The superoxide dismutase-1 knockout (Sod1-/-) mouse is an age-related dry eye mouse model. We evaluated the role of 2% rebamipide ophthalmic solution on the conjunctiva and ocular surface alterations in Sod1-/- mice. Methods: Rebamipide eye drops (2%) were instilled in six 50-week-old male Sod1-/- mice and six C57BL/6 strain wild-type (WT) male mice four times a day for 2 weeks. Aqueous tear secretion quantity and tear film breakup time measurements as well as vital stainings were performed. Immunohistochemistry staining of the conjunctiva was performed using SAM pointed domain-containing ETS transcription factor (SPDEF), transglutaminase-1, and involucrin antibodies. Quantitative RT-PCR was carried out to study mRNA expression of the same markers. Results: The mean tear quantities showed no significant changes in both mice strains after treatment (P = 0.24). The mean tear film breakup time (P = 0.003) and vital staining scores significantly improved in the Sod1-/- mice after treatment. Treatment with 2% rebamipide eye drops significantly decreased the corneal fluorescein (P = 0.0093) and Rose Bengal (P = 0.002) staining scores in the Sod1-/- mice. We showed a notable increase in SPDEF and a marked decrease in transglutaminase-1 and involucrin immunohistochemistry stainings, together with a significant increase in SPDEF (P = 0.0003) and a significant decline in transglutaminase-1 (P = 0.0072) and involucrin (P = 0.009) mRNA expression after treatment in the Sod1-/- mice. Conclusions: Topical use of 2% rebamipide drops was observed to improve conjunctival epithelial differentiation and suppress keratinization in the Sod1-/ mice. PMID- 29625495 TI - Bevacizumab Promotes T-Cell-Mediated Collagen Deposition in the Mouse Model of Conjunctival Scarring. AB - Purpose: We determine the effects of bevacizumab on collagen production in a mouse model of conjunctival scarring. Methods: Experimental surgery was performed as described for the mouse model of conjunctival scarring, and bevacizumab was introduced by conjunctival injection. The capacity of bevacizumab to recognize conjunctival VEGF-A was determined by ELISA. Col1a1 was measured by real-time PCR and immunoblotting. T cells and collagen were visualized by immunofluorescence and picrosirius red staining of bleb cryosections. Conjunctival CD4+ or CD8a+ T cells were counted by flow cytometry. Mouse splenic T cells were cultured with bevacizumab/IgG and their numbers, cell cycle, and collagen production were measured using a cell counter, flow cytometry, and sircol soluble collagen assay, respectively. Reconstitution experiments in severe combined immunodeficiency (SCID) mice were performed by injection of freshly isolated T cells on day 2 postoperatively. Results: Bevacizumab recognized approximately 20% of endogenous murine VEGF-A. Injection of bevacizumab raised Col1a1 expression in the blebs at mRNA and protein levels. Bevacizumab did not induce collagen in conjunctival fibroblasts, but increased CD4+ and CD8a+ cell numbers as well as collagen production by these cells. Collagen appeared to accumulate in the vicinity of T cells in the bevacizumab-treated blebs. While SCID blebs did not show elevated collagen levels, reconstitution with CD4+ or CD8a+ cells resulted in increased Col1a1 expression at mRNA and protein levels. Conclusions: Bevacizumab increased collagen production in the mouse model of conjunctival scarring. This collagen induction was mediated by T cells that were also stimulated by bevacizumab to increase in numbers. PMID- 29625496 TI - The Evolving Pharmaceutical Benefits Market. PMID- 29625498 TI - Platelet Inhibition and Bleeding in Patients Undergoing Non-Cardiac Surgery-The BIANCA Observational Study. AB - Nearly 20% of patients will need non-cardiac surgery within 1 year of coronary stenting and their management is complicated by concomitant antiplatelet therapy. Platelet function testing may optimize the timing of surgery in these patients. In this prospective observational study, we explored the association between platelet reactivity and bleeding in patients undergoing non-cardiac surgery treated with clopidogrel with or without aspirin within 7 days before surgery. The timing of surgery was at the surgeon's discretion. Blood was drawn at induction of anaesthesia and platelet reactivity assessed by light transmittance aggregometry (LTA), vasodilator stimulated phosphoprotein (VASP) assay, Multiplate Analyzer and Innovance PFA-200. The primary endpoint was surgery related thrombolysis in myocardial infarction (TIMI) bleeding. Among 197 patients enrolled, 72 and 12% underwent surgery within 24 and 48 hours of the last dose of clopidogrel, respectively. The median (interquartile range [IQR]) for pre operative maximal adenosine diphosphate (ADP)-induced aggregation was 33.0% (21.0 57.5%), for VASP-platelet reactivity index was 61.5% (40.1-75.4%), for Multiplate was 22.0 (14.5-36.0) U*min and for Innovance PFA-200 was 224 (101.0-300.0) seconds. TIMI bleeding, observed in 25% of patients, decreased with increasing tertiles of platelet reactivity to ADP assessed by LTA (p = 0.031). Additionally, in a multivariable logistic regression analysis, platelet reactivity to ADP assessed by LTA was significantly associated with TIMI bleeding, as were age and urgency of surgery. These results demonstrate that in clopidogrel-treated patients, pre-operative platelet reactivity to ADP is associated with surgical bleeding risk. An objective assessment of pre-operative platelet function may optimize the timing of non-cardiac surgery in these patients. PMID- 29625497 TI - Impact of the Canonical Wnt Pathway Activation on the Pathogenesis and Prognosis of Adamantinomatous Craniopharyngiomas. AB - CTNNB1 mutations and abnormal beta-catenin distribution are associated with the pathogenesis of adamantinomatous craniopharyngioma (aCP). We evaluated the expression of the canonical Wnt pathway components in aCPs and its association with CTNNB1 mutations and tumor progression. Tumor samples from 14 aCP patients and normal anterior pituitary samples from eight individuals without pituitary disease were studied. Gene expression of Wnt pathway activator (WNT4), inhibitors (SFRP1, DKK3, AXIN1, and APC), transcriptional activator (TCF7), target genes (MYC, WISP2, and, CDH1), and Wnt modulator (TP53) was evaluated by qPCR. beta Catenin, MYC, and WISP2 expression was determined by immunohistochemistry (IHC). The transcription levels of all genes studied, except APC, were higher in aCPs as compared to controls and TCF7 mRNA levels correlated with CTNNB1 mutation. CDH1 mRNA was overexpressed in tumor samples of patients with disease progression in comparison to those with stable disease. beta-Catenin was positive and aberrantly distributed in 11 out of 14 tumor samples. Stronger beta-catenin immunostaining associated positively with tumor progression. MYC positive staining was found in 10 out of 14 cases, whereas all aCPs were negative for WISP2. Wnt pathway genes were overexpressed in aCPs harboring CTNNB1 mutations and in patients with progressive disease. Recurrence was associated with stronger staining for beta catenin. These data suggest that Wnt pathway activation contributes to the pathogenesis and prognosis of aCPs. PMID- 29625499 TI - Optimizing Vitamin K Antagonist Treatment in Patients with Mechanical Heart Valve Prosthesis. PMID- 29625500 TI - The da Vinci Xi Robotic Four-Arm Approach for Robotic-Assisted Minimally Invasive Esophagectomy. AB - Robotic surgery is gaining importance in complex thoracoscopic surgery, such as robotic-assisted minimally invasive esophagectomy (RAMIE). The RAMIE procedure was designed using the first generation of the robotic system. The latest da Vinci Xi system has substantially increased the dexterity, especially designed for multiquadrant surgery. The original three-arm RAMIE approach was modified including the robotic four-arm use for the thoracoscopic and laparoscopic part of the operation. This extended approach (four-arm RAMIE approach) provides more flexibility and raises the independence of the surgeon. PMID- 29625501 TI - A Contemporary Meta-Analysis of Antegrade versus Retrograde Cerebral Perfusion for Thoracic Aortic Surgery. AB - OBJECTIVE: To determine which of antegrade and retrograde cerebral perfusion (ACP and RCP) surpasses for a reduction in postoperative incidence of neurological dysfunction and all-cause death in thoracic aortic surgery, we performed a meta-analysis of contemporary comparative studies. METHODS: MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched from January 2010 to June 2017. For each study, data regarding the endpoints in both the ACP and RCP groups were used to generate odds ratios (ORs) and 95% confidence intervals (CIs). Study-specific estimates were combined using inverse variance weighted averages of logarithmic ORs in the fixed-effect model. RESULTS: We identified and included 19 eligible studies with a total of 15,365 patients undergoing thoracic aortic surgery by means of ACP (a total of 7,675 patients) or RCP (a total of 7,690 patients). Pooled analysis demonstrated no statistically significant differences in postoperative incidence of stoke (17 studies enrolling a total of 9,421 patients; OR, 0.92; 95% CI, 0.79-1.08; p = 0.32) and mortality (16 studies including a total of 14,452 patients; OR, 1.07; 95% CI, 0.90-1.26; p = 0.46) between ACP and RCP, whereas a trend toward a significant reduction in incidence of temporary neurological dysfunction (TND) for ACP (12 studies enrolling a total of 7922 patients; OR, 0.85; 95% CI, 0.69-1.04; p = 0.12) was found. CONCLUSION: In thoracic aortic surgery, postoperative incidence of stroke and mortality was similar between ACP and RCP, whereas a trend toward a reduction of TND incidence existed in ACP. PMID- 29625502 TI - Effectiveness of Robotic Lobectomy-Outcome and Learning Curve in a High Volume Center. AB - BACKGROUND: Robotic surgery has been developed as a sophisticated tool to expand possibilities in minimal invasive surgery. The learning curve for this method is short in various surgical fields; however, limited data exist on the learning curve in robotic thoracic surgery. METHODS: This study analyzes a single center experience of robotic lobectomies using a prospectively kept database. Perioperative data and outcome of patients during the learning curve were compared with patients operated with increased institutional experience. The learning curve was defined as the initial 20 lobectomies. RESULTS: Sixty-four robotic lobectomies were performed between January 2014 and February 2017. Indications, preoperative lung functions, comorbidities, patient age, and tumor stage were comparable between patients operated during the learning curve and thereafter. The mean operative time could be significantly reduced after the learning curve (286 +/- 86 vs. 211 +/- 62 minutes; p = 0.0003). The conversion rate dropped from 4 of 20 (20%) during the learning curve to 2 of 44 (4.5%, p = 0.07) thereafter. Chest tube duration (4.3 +/- 2.9 vs. 3.8 +/- 2.1 days) and hospital stay (8.3 +/- 3.4 vs. 7.9 +/- 4.5 days) were not different in the two phases. The number of resected lymph nodes increased from 11.2 +/- 6.8 to 13.9 +/ 6.5 (p = 0.0797). Lymph node upstaging was achieved in 8 (12.9%) cases. Ninety day mortality was 0%, and 2-year overall survival was 83%. CONCLUSIONS: Robotic thoracic surgery can be safely performed and trained with low complication rates and contributes to the extension of minimal invasive thoracic surgery. The initial learning curve in our experience is overcome after 20 cases. However, to become proficient in more advanced procedures and to further reduce operative time, additional training is required. Prospective studies are required to clearly determine the role of robotic surgery in comparison to the video-assisted thoracoscopic surgery (VATS) procedures. PMID- 29625503 TI - "Free or Perforator-Pedicled Propeller Flaps in Lower Extremity Reconstruction: Defining the Coverage Failure": Response. PMID- 29625504 TI - Sternal Reconstruction with the Omental Flap-Acute and Late Complications, Predictors of Mortality, and Quality of Life. AB - BACKGROUND: The omental flap is a reliable flap for the coverage of sternal defects. However, little is known about the predictors of mortality and the long term outcome in such patients. METHODS: We, therefore, performed a retrospective study from 2002 to 2013, including all patients who underwent sternal reconstruction with the omental flap. RESULTS: A total of 50 patients were identified and mean follow-up was 3.8 years. Patient data was collected from the charts and 14 patients were available for telephone interviews. The majority of patients suffered from deep sternal wound infections. There was no complete flap loss and an overall success rate was 96%. In-hospital mortality was 14% and overall survival over follow-up was 50%. Significant predictors of mortality were age > 65, American Society of Anesthesiologists' status, defect size, prolonged ventilation, and the need for tracheotomy. Postoperative quality of life was reduced compared with other cohorts, especially with regard to bodily function. Pain was also a major problem for most patients along with herniation. CONCLUSION: The omental flap is a safe option even in patients with severe comorbidities. However, based on the data in this study, we would recommend the omental flap as a reserve option rather than first-line treatment for sternal defects. PMID- 29625505 TI - Proximal versus Distal Recipient Vessels in Lower Extremity Reconstruction: A Retrospective Series and Systematic Review. AB - BACKGROUND: Recipient vessels proximal to the zone of injury have traditionally been preferred for lower extremity reconstruction. However, more recent data have shown mixed outcomes when performing anastomoses distal to the zone of injury. We investigated the impact of recipient vessel location on free flap outcomes. METHODS: Retrospective review (1979-2016); 312 soft tissue free flaps for open tibia fractures met inclusion criteria. Flap characteristics and perioperative outcomes were examined. Systematic review identified articles evaluating anastomosis location and flap outcomes; pooled data analysis was performed. RESULTS: More anastomoses were performed proximal to the zone of injury (80.7%) than distal (19.3%). Distal anastomoses were not associated with increased take back rates (19.6%) compared with proximal (23.8%) anastomoses (p = 0.356). Regression analysis comparing proximal and distal anastomoses found no difference in partial flap failures (7.4% vs 11.9%; p = 0.978) or total flap failures (9.3% vs 9.3%; p = 0.815) when controlling for the presence of arterial injury, flap type, and time from injury to coverage. Systematic review yielded 11 articles with 1,245 proximal and 127 distal anastomoses for comparison. Pooled analysis (p = 0.58) and weighted comparative analysis (p = 0.39) found no difference in flap failure rates between proximal and distal groups. CONCLUSION: Our results are congruent with the current lower extremity literature and demonstrate no difference in perioperative complication rates between anastomoses performed proximal or distal to the zone of injury. These findings suggest that anastomotic location choice should be based primarily on recipient vessel quality/flow and ease of access/exposure rather than orientation relative to the zone of injury. PMID- 29625506 TI - Factors associated with delayed bleeding after resection of large nonpedunculated colorectal polyps. AB - BACKGROUND: Delayed bleeding is the most common significant complication after piecemeal endoscopic mucosal resection (p-EMR) of large nonpedunculated colorectal polyps (NPCPs). Risk factors for delayed bleeding are incompletely defined. We aimed to determine risk factors for delayed bleeding following p-EMR. METHODS: Data were analyzed from a prospective tertiary center audit of patients with NPCPs >= 20 mm who underwent p-EMR between 2010 and 2012. Patient, polyp, and procedure-related data were collected. Four post p-EMR defect factors were evaluated for interobserver agreement and included in analysis. Delayed bleeding severity was reported in accordance with guidelines. Predictors of bleeding were identified. RESULTS: Delayed bleeding requiring hospitalization occurred after 22 of 330 procedures (6.7 %). A total of 11 patients required blood transfusion; of these, 4 underwent urgent colonoscopy, 1 underwent radiological embolization, and 1 required surgery. Interobserver agreement for identification of the four post p-EMR defect factors was moderate (kappa range 0.52 - 0.57). Factors associated with delayed bleeding were visible muscle fibers (P = 0.03) and the presence of a "cherry red spot" (P = 0.05) in the post p-EMR defect. Factors not associated with delayed bleeding were American Association of Anesthesiologists class, aspirin use, polyp size, site, and use of argon plasma coagulation. CONCLUSIONS: Visible muscle fibers and the presence of a "cherry red spot" in the resection defect were associated with delayed bleeding after p-EMR. These findings suggest evaluation and photodocumentation of the post p-EMR defect is important and, when considered alongside other patient and procedural factors, may help to reduce the incidence and severity of delayed bleeding. PMID- 29625507 TI - Efficacy of transoral incisionless fundoplication for refractory gastroesophageal reflux disease: a systematic review and meta-analysis. AB - BACKGROUND: Given poor symptomatic response rates and rising awareness of the adverse events associated with the long-term use of proton pump inhibitors (PPIs), endoscopic modalities for treatment of refractory gastroesophageal reflux disease (GERD) have become more prominent. The aim of this study was to perform a systematic review and meta-analysis to evaluate feasibility, efficacy, and tolerability of transoral incisionless fundoplication (TIF) for the treatment of refractory GERD. METHODS: Searches of PubMed, EMBASE, Web of Science, and Cochrane Library databases were performed to March 2017. Measured outcomes included immediate technical success rate and serious adverse events. Symptomatic improvement was measured using GERD Health-related Quality of Life (HRQL), Gastroesophageal Reflux Symptom Score (GERSS), and Reflux Symptom Index (RSI). Objective success was determined by hiatal hernia reduction and pH monitoring. RESULTS: 32 studies (1475 patients; 48.2 % male) met inclusion criteria. TIF success rate was 99 % (95 % confidence interval [CI] 97 to 100; P < 0.001), with an adverse event rate of 2 % (95 %CI 1 to 3; P < 0.001). GERD HRQL, GERSS, and RSI improved significantly post-TIF (mean difference 17.72, 95 %CI 17.31 to 18.14; mean difference 23.78, 95 %CI 22.96 to 24.60; mean difference 14.28, 95 %CI 13.56 to 15.01; all P < 0.001, respectively). Hernia reduction occurred in 91 % of patients (95 %CI 83 to 98; P < 0.001). DeMeester scores improved significantly (mean difference 10.22, 95 %CI 8.38 to 12.12; P < 0.001). PPI therapy was discontinued post-procedure in 89 % of patients (95 %CI 82 to 95; P < 0.001). CONCLUSIONS: TIF appears to be a safe and effective endoscopic procedure for patients with refractory GERD. Future controlled trials are needed to directly compare efficacy, long-term durability, and safety between TIF and Nissen fundoplication. PMID- 29625508 TI - Automated Office Blood Pressure Measurement. AB - Manual blood pressure (BP) recorded in routine clinical practice is relatively inaccurate and associated with higher readings compared to BP measured in research studies in accordance with standardized measurement guidelines. The increase in routine office BP is the result of several factors, especially the presence of office staff, which tends to make patients nervous and also allows for conversation to occur. With the disappearance of the mercury sphygmomanometer because of environmental concerns, there is greater use of oscillometric BP recorders, both in the office setting and elsewhere. Although oscillometric devices may reduce some aspects of observer BP measurement error in the clinical setting, they are still associated with higher BP readings, known as white coat hypertension (for diagnosis) or white coat effect (with treated hypertension). Now that fully automated sphygmomanometers are available which are capable of recording several readings with the patient resting quietly, there is no longer any need to have office staff present when BP is being recorded. Such readings are called automated office blood pressure (AOBP) and they are both more accurate than conventional manual office BP and not associated with the white coat phenomena. AOBP readings are also similar to the awake ambulatory BP and home BP, both of which are relatively good predictors of cardiovascular risk. The available evidence suggests that AOBP should now replace manual or electronic office BP readings when screening patients for hypertension and also after antihypertensive drug therapy is initiated. PMID- 29625509 TI - Adult Congenital Heart Disease with Pregnancy. AB - The number of women with congenital heart disease (CHD) at risk of pregnancy is growing because over 90% of them are grown-up into adulthood. The outcome of pregnancy and delivery is favorable in most of them provided that functional class and systemic ventricular function are good. Women with CHD such as pulmonary hypertension (Eisenmenger syndrome), severe left ventricular outflow stenosis, cyanotic CHD, aortopathy, Fontan procedure and systemic right ventricle (complete transposition of the great arteries [TGA] after atrial switch, congenitally corrected TGA) carry a high-risk. Most frequent complications during pregnancy and delivery are heart failure, arrhythmias, bleeding or thrombosis, and rarely maternal death. Complications of fetus are prematurity, low birth weight, abortion, and stillbirth. Risk stratification of pregnancy and delivery relates to functional status of the patient and is lesion specific. Medication during pregnancy and post-delivery (breast feeding) is a big concern. Especially prescribing medication with teratogenicity should be avoidable. Adequate care during pregnancy, delivery, and the postpartum period requires a multidisciplinary team approach with cardiologists, obstetricians, anesthesiologists, neonatologists, nurses and other related disciplines. Caring for a baby is an important issue due to temporarily pregnancy-induced cardiac dysfunction, and therefore familial support is mandatory especially during peripartum and after delivery. Timely pre-pregnancy counseling should be offered to all women with CHD to prevent avoidable pregnancy-related risks. Successful pregnancy is feasible for most women with CHD at relatively low risk when appropriate counseling and optimal care are provided. PMID- 29625510 TI - Interventional Management of "Balloon-Uncrossable" Coronary Chronic Total Occlusion: Is There Any Way Out? AB - It has been estimated that coronary chronic total occlusion (CTO) is encountered in 15 to 20% patients referred for coronary angiography (CAG). The success of percutaneous coronary intervention (PCI) of CTO can be attributed to the vast array of hardware that has now become available and also to the vastly enhanced operator expertise. It is however realistic to state that despite the tremendous increase in the rate of success, there then comes a subset of CTO where PCI attempts fail. The reason for such failures given that other variables remain constant is the inability to cross the CTO lesion. This can be due to a failure to cross the lesion with a guide wire (despite guide wire escalation). The second cause of failure is the inability to cross the lesion with a balloon (balloon uncrossable [BU] CTO). This can occur despite the successful placement of a guidewire in the distal true lumen. The BU lesions contribute 2% to 10% of CTO PCI failure cases. The author attempts to present a creative solution to assist crossing such lesions. PMID- 29625511 TI - Laboratory Markers in Incomplete Kawasaki Disease according to Coronary Artery Outcome. AB - BACKGROUND AND OBJECTIVES: We defined laboratory marker profiles typical of incomplete Kawasaki disease (iKD) during illness, especially with respect to the presence of a coronary artery abnormality such as coronary artery dilation or aneurysm. METHODS: This retrospective study examined the clinical and laboratory markers of patients with iKD over time, along with those of patients with complete KD (cKD) and febrile controls. RESULTS: Of 795 patients, 178 had iKD, 504 had cKD and 113 were febrile controls. During the transition from the acute to subacute phase, the age-adjusted hemoglobin levels and platelet counts were significantly lower and higher, respectively, in the subacute phase than in the acute phase in both iKD and cKD patients, which differed from those of febrile controls. Lower levels of acute and subacute age-adjusted hemoglobin levels in iKD patients (odds ratio [OR], 0.538 and 0.583; p=0.006 and 0.018, respectively) and higher subacute platelet counts in cKD patients (OR, 1.004; p=0.014) were correlated with the risk of coronary dilation. A higher acute neutrophil-to lymphocyte ratio was associated with aneurysm only in cKD patients (OR, 1.059; p=0.044). CONCLUSIONS: The iKD patients share KD-specific laboratory marker profiles in terms of complete blood cell counts and acute phase reactant levels with cKD patients. However, the factors predicting coronary dilation differ according to the phenotype; lower acute and subacute age-adjusted hemoglobin levels predict coronary dilation only in iKD patients. PMID- 29625512 TI - beta-arrestin2 Affects Cardiac Progenitor Cell Survival through Cell Mobility and Tube Formation in Severe Hypoxia. AB - BACKGROUND AND OBJECTIVES: beta-arrestin2 (beta-arr2) basically regulates multiple signaling pathways in mammalian cells by desensitization and internalization of G-protein coupled receptors (GPCRs). We investigated impacts of beta-arr2 on survival, mobility, and tube formation of cardiac progenitor cells (CPCs) obtained from wild-type (WT) mouse (CPC-WT), and beta-arr2 knock-out (KO) mouse (CPC-KO) cultured in presence or absence of serum and oxygen as non canonical roles in GPCR system. METHODS: CPCs were cultured in Dulbecco's Modified Eagle Medium/Nutrient Mixture F-12 -based media containing fetal bovine serum and growth factors. Survival of 2 types of CPCs in hypoxia and/or serum deprivation was measured by fluorescence-activated cell sorting. Wound healing ability, and tube formation ability on Matrigel of 2 kinds of CPCs were compared in normoxic and hypoxic cultures. Protein expression related to survival and mobility were measured with the Western blot for each culture conditions. RESULT: CPC-KO showed significantly worse mobility in the wound healing assay and in tube formation on Matrigel especially in hypoxic culture than did the CPC-WT. Also, CPC-KO showed significantly higher apoptosis fraction in both normoxic and hypoxic cultures than did the CPC-WT. Expression of proteins associated with cell survival and mobility, e.g., protein kinase B (Akt), beta-catenin, and glycogen synthase kinase-3beta (GSK-3beta) was significantly worse in CPC-KO. CONCLUSIONS: The CPC-KO had significantly worse cell mobility, tube formation ability, and survival than the CPC-WT, especially in the hypoxic cultures. Apparently, beta arr2 is important on CPC survival by means of mobility and tube formation in myocardial ischemia. PMID- 29625513 TI - Trends, Characteristics, and Clinical Outcomes of Patients Undergoing Percutaneous Coronary Intervention in Korea between 2011 and 2015. AB - BACKGROUND AND OBJECTIVES: We sought to evaluate nationwide trends, characteristics, and clinical outcomes in patients undergoing percutaneous coronary intervention (PCI) in Korea. METHODS: From National Health Insurance claims data in Korea, 81,115 patients, who underwent PCI for the first episode of coronary artery disease between 2011 and 2015, were enrolled. Patients were categorized into angina (n=49,288) or acute myocardial infarction (AMI, n=31,887) groups and analyzed. RESULTS: The mean age of patients was 64.4+/-12.2 years and 56,576 (69.7%) were men. Diabetes, hyperlipidemia, and hypertension were observed in 27,086 (33.4%), 30,675 (37.8%), and 45,389 (56.0%) patients, respectively. There was a 10% increase in the number of patients undergoing PCI for angina between 2011-2012 and 2014-2015 (11,105 vs. 13,261; p=0.021). However, the number of patients undergoing PCI for AMI marginally decreased between 2011-2012 and 2014-2015 (8,068 vs. 7,823; p=0.052). In procedures, drug-eluting stent was the most frequently used device (93.2%), followed by balloon angioplasty (5.5%) and bare metal stents (1.3%). The mean number of stents per patient was 1.39+/-0.64. At discharge, dual-anti platelet therapy, statin, beta-blockers, and angiotensin converting enzyme inhibitor or angiotensin receptor blocker were provided to 76,292 (94.1%), 71,411 (88.0%), 57,429 (70.8%), and 54,418 (67.1%) patients, respectively. The mean in-hospital and 1-year total medical costs were 8,628,768+/-4,832,075 and 13,128,158+/-9,758,753 Korean Won, respectively. In hospital mortality occurred in 2,094 patients (2.6%). CONCLUSIONS: Appropriate healthcare strategies reflecting trends, characteristics, and clinical outcomes of PCI are needed in Korea. PMID- 29625514 TI - Current Practices of Percutaneous Coronary Intervention in Korea between 2011 and 2015. PMID- 29625515 TI - You're Not under Arrest: Worry-free with beta-arrestin. PMID- 29625516 TI - Risk Factors Related to Coronary Artery Outcome in Kawasaki Disease. PMID- 29625517 TI - Atypical Annulus Rupture after Transcatheter Aortic Valve Implantation. PMID- 29625518 TI - Intermittent Claudication due to Cystic Adventitial Disease of the Popliteal Artery: Importance of Multiple Imaging Modalities. PMID- 29625519 TI - Effect of Precursors on the Synthesis of CuO Nanoparticles Under Microwave for Photocatalytic Activity Towards Methylene Blue and Rhodamine B Dyes. AB - Copper oxide nanoparticles have been successfully synthesized by microwave assisted precipitation method. Different precursors like copper chloride, copper nitrate and copper sulphate were used for synthesis of CuO nanoparticles with different shape, size and catalytic activity. Sodium hydroxide acts as a capping agent and ethanol as solvent for the synthesis. The XRD study was conducted to confirm the single phase monoclinic structure of as-synthesized and annealed CuO nano particles. The morphology of the as-synthesized and annealed CuO samples was analyzed by high resolution field emission scanning electron microscope. Fourier transform infrared spectroscopy was done for all the synthesized CuO nanoparticles for functional group characterization. The wide band gap and photocatalytic activity were studied by UV-Visible spectroscopy. The photocatalytic degradation of Methylene blue (MB) and Rhodamine B (RhB) dyes in aqueous solution were investigated under UV light (254 nm). In all the cases annealed samples showed good catalytic activity compared to as-synthesized CuO nanoparticles. The CuO nanoparticles from CuCl2 precursor act as excellent photocatalyst for both MB and RhB compared to CuNO3 and CuSO4. PMID- 29625520 TI - Gold Nanoparticle-Based Probe for Colorimetric Detection of Copper Ions. AB - A new ligand 10-mercaptodecyl-1-iminodiacetic acid (MDIA) was synthesized and used to modify gold nanoparticles to provide a simple assay to repeatedly sense Cu2+ in the solution at room temperature. This functionalized gold nanosensor was applied for the detection of Cu2+ in water samples with sensitivity and simplicity. The chelation/aggregation process is reversible via addition of a strong metal ion chelator such as EDTA. This simple and fast colorimetric sensor is important in the application of copper ion detection in water quality during the emergency and early warning monitoring. PMID- 29625521 TI - Preparation and Electrochemical Properties of Mesoporous Manganese Dioxide-Based Composite Electrode for Supercapacitor. AB - The mesoporous manganese dioxide with high specific surface area was obtained through a one-pot prepare procedure at ambient temperature under acidic conditions. And the graphene/mesoporous manganese dioxide composite was synthesized by a simple hydrothermal approach. As a comparison, silver nanowires also as a conductor was added to the mesoporous manganese dioxide. Both of the graphene and silver nanowires can increase the capacitance of the mesoporous manganese dioxide-based composite electrode materials. Compared with the graphene/mesoporous manganese dioxide composite, the silver nanowires/mesoporous manganese dioxide mixture has a better electrochemical performance, the specific capacitance and energy density is almost 2.2 times larger than that of the composites. The morphology and detail structure were investigated by the Scanning electron microscopy, X-ray diffraction, Raman spectra, Fourier transform infrared spectrometry and Nitrogen adsorption-desorption isotherms. The electrochemical performance was assessed by the cyclic voltammograms, galvanostatic charge/discharge and electrochemical impedance spectroscopy. PMID- 29625522 TI - Solvothermal Preparation of Zinc Oxide/Reduced Graphene Oxide Composites for Rapid Removal of Methylene Blue. AB - Zinc oxide/reduced graphene oxide composites with various morphologies and properties were prepared via a one-step solvothermal process. The formation of zinc oxide and reduction of graphene oxide were simultaneously accomplished. These as-obtained samples showed high performance in removing methylene blue from aqueous solution. Solvent could play an important role in tuning the morphologies of the zinc oxide and the efficiency of the final composites. Composites prepared in acetone showed the highest removal efficiency, compared with those prepared in water and ethanol. Loading content of the reduced graphene oxide could affect the performance as well. With the increase in the content of the reduced graphene oxide, the as-prepared samples showed enhanced performance gradually. The as prepared composite showed certain stability, with a maximum recyclability of 5 times for efficient removal. The effective removal of target dye turned out to be the result of the combination of physical adsorption and photo-catalysis. PMID- 29625523 TI - Pemetrexed degradation by photocatalytic process: Kinetics, identification of transformation products and estimation of toxicity. AB - This study employed a UV-A/visible/TiO2 system to investigate the degradation of pemetrexed, an antifolate agent used in chemotherapy. The laboratory-scale method employed a photostability chamber that could be used to study multiple samples. Reversed-phase HPLC coupled with high-resolution ESI-LTQ-Orbitrap mass spectrometry was used to determine the transformation products (TPs) of PEME. Based on the identified TPs and existing chemical knowledge, the mechanism of degradation of the target compound was proposed. Concentrations were monitored as a function of time, and the degradation kinetics were compared. The structures of seven TPs, four of which have not been described to date, were proposed. Most of the TPs stemmed from OH radical additions to the dihydropyrrole moiety and oxidative decarboxylation of the glutamate residue. Based on the elucidated structures, a computational toxicity assessment was performed, showing that the TPs with higher log D values than the parent compound are more toxic than the PEME itself. To support these findings, the toxicities of irradiated samples on Vibrio fischeri were monitored over time. The experimental results corresponded well with the results of previous computational studies. PMID- 29625524 TI - Effective removal of the antibiotic Nafcillin from water by combining the Photoelectro-Fenton process and Anaerobic Biological Digestion. AB - The elimination of the antibiotic Nafcillin (NAF), which is usually used in hospitals and veterinary clinics around the world, was assessed through a combination of three advanced electrochemical oxidation processes followed by anaerobic digestion process. In the first stage different electrochemical advanced oxidation processes (EAOPs) were used: electro-oxidation with hydrogen peroxide (EO-H2O2), electro-Fenton (EF) and Photo electro-Fenton (PEF). After PEF, almost complete and highly efficient degradation and elimination of NAF was achieved, with the concomitant elimination of the associated antimicrobial activity. The fast degradation rate produced by PEF is explained by the oxidative action of hydroxyl radicals (*OH) together with the direct UV photolysis of complexes formed between Fe3+ and some organic intermediates. Total removal of NAF occurs after 90min of electrolysis by PEF, with the generation of organic intermediates that remain in solution. However, when this post PEF process solution was treated with an anaerobic biological process, the intermediates generated in the electrochemical degradation of NAF were completely eliminated after 24h. The kinetic degradation of NAF as well as the identification/quantification of products and intermediates formed during the degradation of antibiotic, such as inorganic ions, carboxylic acids and aromatic compounds, were determined by chromatographic and photometric methods. Finally, an oxidation pathway is proposed for the complete conversion to CO2. PMID- 29625525 TI - Remediation of arsenic in mung bean (Vigna radiata) with growth enhancement by unique arsenic-resistant bacterium Acinetobacter lwoffii. AB - Arsenic, a carcinogenic and toxic contaminant of soil and water, affects human health adversely. During last few decades, it has been an important global environmental issue. Among several arsenic detoxification methods remediation using arsenic resistant microbes is proved to be environment-friendly and cost effective. This study aimed to test the effects of arsenic utilizing bacterial strain Acinetobacter lwoffii (RJB-2) on arsenic uptake and growth of mung bean plants (Vigna radiata). RJB-2 exhibited tolerance up to 125mM of arsenic (V) and 50mM of arsenic (III). RJB-2 produced plant growth promoting substances e.g. indole acetic acid (IAA), siderophores, exopolysaccharide (EPS) and phosphate solubilization in the absence and in presence of arsenic. Pot experiments were used to scrutinize the role of RJB-2 on arsenic uptake and growth of mung bean plants grown in soil amended with 22.5mgkg-1 of sodium arsenate (Na2HAsO4.7H2O). RJB-2 could arrest arsenic uptake in just 7days and increase plant growth, number of plants per pot, chlorophyll and carotenoid content of the mung bean plants. RJB-2 formed biofilm and its root-association helped to abate arsenic uptake in mung bean. Confocal and light microscopic studies also revealed the abatement of arsenic uptake and increase in chlorophyll content in mung bean plants in presence of RJB-2. RJB-2 was also responsible for less production of reactive oxygen species (ROS) in mung bean plants reducing the oxidative damage caused by arsenic. The lower percentage of electrolytic leakage (EL) in RJB-2 inoculated mung bean plants proved arsenic abatement. The study also reported the distribution of arsenic in various parts of mung bean plant. RJB-2 owing to its intrinsic abilities of plant growth promotion even in presence of high concentrations of arsenic could inhibit arsenic uptake completely and therefore it could be used in large-scale cultivation for phytostabilization of plants. PMID- 29625526 TI - Incineration and pyrolysis vs. steam gasification of electronic waste. AB - Constructional complexity of items and their integration are the most distinctive features of electronic wastes. These wastes consist of mineral and polymeric materials and have high content of valuable metals that could be recovered. Elimination of polymeric components (especially epoxy resins) while leaving non volatile mineral and metallic phases is the purpose of thermal treatment of electronic wastes. In the case of gasification, gaseous product of the process may be, after cleaning, used for energy recovery or chemical synthesis. If not melted, metals from solid products of thermal treatment of electronic waste could be recovered by hydrometallurgical processing. Three basic, high temperature ways of electronic waste processing, i.e. smelting/incineration, pyrolysis and steam gasification were shortly discussed in the paper, giving a special attention to gasification under steam, illustrated by laboratory experiments. PMID- 29625527 TI - Soil and land management in a circular economy. AB - This article elaborates the role of soil and land management in a circular economy. The circular economy is highly dependent on the functioning of soils and land for the production of food and other biomass; the storage, filtration and transformation of many substances including water, carbon, and nitrogen; the provision of fresh mineral resources and fossil fuels; and the use of their functions as the platform for nature and human activities. Resource demand is increasing as a result of the growing human population. In addition to the shrinking availability of resources resulting from their unsustainable use in the past, our planet's diminishing potential for resource production, due to a range of reasons, is leading to resource scarcity, especially in the case of depletable resources. As an economic system that focuses on maximizing the reuse of resources and products and minimizing their depreciation, the circular economy greatly influences, and depends on, soil and land management. The concise management of the resources, land and soil is thus necessary, to make a circular economy successful. PMID- 29625528 TI - Down-regulation of LGR6 promotes bone fracture recovery using bone marrow stromal cells. AB - OBJECTIVE: The Leucine-rich repeat-containing G-protein coupled receptor 6 (LGR6) is a well-known marker of stem cells. In present study, we aimed to further explore the effects of LGR6 on promoting osteogenic differentiation of bone marrow stromal cells (BMSCs) and bone healing. METHODS: Flow cytometry assay was used to determine the expression of BMSCs surface markers, and western blot was performed to detect the LGR6 protein expression. The osteogenic differentiation of BMSCs was qualified using ALP and ARS staining. Protein expression of osteogenic genes (ALP, Collagen I, Runx2 and OCN) were evaluated using western blot. In vivo, BMSCs transfected with sh-LGR6 or LGR6 cDNA were injected into the fracture site to establish rat fracture healing model. X-ray system and hematoxylin-eosin (HE) staining were conducted to observe the fracture recovery. Biomechanical test was performed to detect the changes of maximum load, elastic modules and bone mineral density. RESULTS: In BMSCS, CD90 and CD44 were positively expressed, while CD11b was negatively expressed. Expression level of LGR6 gradually decreased with the osteogenic differentiation of BMSCs. The osteogenic genes expression level during the osteogenic differentiation significantly increased with the down-regulation of LGR6. In vivo, 8 weeks after injection, rats treated with LGR6 knocked-down BMSCs showed increased number of fibroblasts. Maximum load, elastic modulus and the bone mineral density were enhanced with the knocking-down of LGR6. CONCLUSION: Inhibition of LGR6 promoted the osteogenic differentiation of BMSCs in vitro. Moreover, transplantation of LGR6-knockout BMSCs in rat models contributes to a better recovery after the fracture. PMID- 29625529 TI - Quantifying patient centered outcomes associated with the use of bilateral endobronchial coil treatment in patients with severe emphysema. AB - OBJECTIVE: To determine the impact of endobronchial coils on health-related quality-of-life (HRQoL). This paper utilizes trial data to identify the predictors of HRQoL in patients with severe emphysema, and subsequently estimates the impact of a new treatment on HRQoL (measured by utilities). These utility estimates are used to generate indicative long-term QALY estimates for a range of clinically plausible scenarios as a precursor to cost-effectiveness analyses. METHODS: Patient level HRQoL data from RENEW and the National Emphysema Treatment Trial (NETT) were combined and mapped to generic EuroQol 5-dimension health utility questionnaire (EQ-5D) values using a published algorithm. Multilevel statistical models were developed using treatment, time, response, and baseline characteristics (EQ-5D, age, gender, FEV1, lung RV) to predict EQ-5D over time. Lifetime QALY estimates were generated using published survival data from NETT (assuming no impact of treatment on mortality) and four clinically plausible response profiles. Each response profile was combined with assumptions around treatment impact (constant or time varying). RESULTS: After controlling for baseline characteristics, both treatment and response had a statistically significant impact (p < .001) on utility (+0.101 and +0.061, respectively). When combined with selected baseline characteristics and time, Coils and Standard of Care (SoC) generated more QALYs than SoC alone in all scenarios, with incremental lifetime benefit ranging from 0.29-0.55 QALYs. CONCLUSIONS: Coils and SoC resulted in statistically significant improvements in HRQoL compared to SoC alone in patients with severe emphysema. PMID- 29625530 TI - Epicardial adipose tissue and atrial fibrillation: pathophysiological mechanisms, clinical implications, and potential therapies. AB - BACKGROUND: Atrial fibrillation (AF) is the most common arrhythmia in clinical practice and is associated with increased cardiovascular morbidity and mortality. Epicardial adipose tissue (EAT) serves as a biologically active organ with important endocrine and inflammatory function. Review An accumulating body of evidence suggests that EAT is associated with the initiation, perpetuation, and recurrence of AF, but the precise role of EAT in AF pathogenesis is not completely elucidated. Pathophysiological mechanisms involve adipocyte infiltration, profibrotic and pro-inflammatory paracrine effects, oxidative stress, neural mechanisms, and genetic factors. CONCLUSIONS: Notably, EAT accumulation seems to be associated with stroke and adverse cardiovascular outcomes in AF. Weight loss, specific medications and ablation of ganglionated plexi (GP) seem to be potential therapies in this setting. PMID- 29625531 TI - The burden of AIDS: a time series analysis of thirty-five years of the epidemic in Brazil. AB - Although traditional epidemiological information, such as mortality rate and prevalence or incidence rates, is relevant to the understanding of AIDS epidemiology in Brazil, a more complete indicator would be recommended. The aim of this study was to estimate the burden of AIDS and its trends in Brazil from 1980 to 2015. An ecological study using secondary data on mortality, morbidity and demography was carried out. Data were collected from official health information sources. Disability-adjusted life years (DALY) index was estimated by year. Trend analysis of the rates were performed using a segmented linear regression method. There were 826,452 confirmed HIV/AIDS cases and 302,614 deaths from AIDS-related causes in the studied period. The greatest burden occurred between 1994 and 1996, with a significant increase in the burden of AIDS for both sexes. The burden of AIDS in Brazil remains high, with a tendency to increase significantly the DALY rates in the study period. However, trend reversals in the DALY rates and in the mortality component, with a consequent increase in the morbidity component, were identified from 1995 onwards. PMID- 29625532 TI - Non-invasive patient-controlled analgesia in the management of acute postoperative pain in the hospital setting. AB - OBJECTIVE: Acute postoperative pain is experienced by the majority of hospitalized patients undergoing surgical procedures, with many reporting inadequate pain relief and/or high levels of dissatisfaction with their pain management. Patient-controlled analgesia (PCA) ensures patient involvement in acute pain control, a key component for implementing a quality management system. This narrative article overviews the clinical evidence for conventional PCA and briefly discusses new, non-invasive PCA systems, namely the sufentanil sublingual tablet system (SSTS) and the fentanyl iontophoretic transdermal system (FITS). METHODS: A Medline literature search ("patient-controlled analgesia" and "acute postoperative pain") was conducted to 1 April 2017; results from the main clinical trials are discussed. Additional literature was identified from the reference lists of cited publications. RESULTS: Moderate to low quality evidence supports opioid-based intravenous PCA as an efficacious alternative to non patient-controlled systemic analgesia for postoperative pain. However, despite the benefits of PCA, conventional intravenous PCA is limited by system-, drug- and human-related issues. The non-invasive SSTS and FITS have demonstrated good efficacy and safety in placebo- and intravenous morphine PCA-controlled trials, and are associated with high patient/healthcare practitioner satisfaction/ease of care ratings and offer early patient mobilization. CONCLUSIONS: Evidence-based guidelines for acute postoperative pain management support the use of multimodal regimens in many situations. As effective and safe alternatives to conventional PCA, and with the added benefits of being non-invasive, easy to use and allowing early patient mobilization, the newer PCA systems may complement multimodal approaches, or potentially replace certain regimens, in hospitalized patients with acute postoperative pain. PMID- 29625533 TI - Cross-cultural Adaptation and Validation of the Nepali Translation of the Patient Specific Functional Scale. AB - Background The Patient-Specific Functional Scale (PSFS) is among the most commonly used measures to assess physical function. Objectives We aimed to translate and cross-culturally validate the PSFS to Nepali and further assess its psychometric properties. Methods This longitudinal, single-arm cohort study translated and cross-culturally adapted the PSFS to Nepali (PSFS-NP) following recommended guidelines. A sample of 104 Nepalese with musculoskeletal pain was recruited to evaluate the psychometric properties of the PSFS-NP. We assessed the internal consistency (Cronbach alpha), 2-week test-retest reliability (intraclass correlation coefficient [ICC3,2]), the smallest detectable change at the 90% confidence interval (CI), and construct validity. Concurrent validity was assessed against the Nepali versions of the Oswestry Disability Index, global rating of change, and numeric pain-rating scale. Receiver operating characteristic curves were plotted to measure responsiveness and area under the curve, and the minimum important change (MIC) was estimated. Results The PSFS-NP showed good reliability, with a Cronbach alpha of .75, an ICC of 0.89 (95% CI: 0.78, 0.94), and a smallest detectable change at the 90% CI of 1.46. It demonstrated significant correlations with the Nepali versions of the Oswestry Disability Index (r = -0.47, P = .001), global rating of change (r = 0.71, P<.001), and numeric pain-rating scale (r = -0.32 and -0.55, P<.001). Areas under the curve ranged from 0.72 to 0.99. The MIC was 2.00 in the main analysis. Secondary analyses revealed MICs of 0.50, 0.66, and 2.00 for small, medium, and large improvement, respectively. Conclusion The PSFS-NP is a reliable, valid, and responsive measure. It can be used in clinical practice and research in Nepalese with musculoskeletal pain. J Orthop Sports Phys Ther 2018;48(8):659-664. Epub 6 Apr 2018. doi:10.2519/jospt.2018.7925. PMID- 29625534 TI - Burden of illness of chemotherapy in castration-resistant prostate cancer patients in Japan: a retrospective database analysis. AB - OBJECTIVE: The objective was to assess the burden of chemotherapy for castration resistant prostate cancer (CRPC) in Japan. METHODS: Utilizing a large administrative hospital database we compared a set of outcome measures 12 months before and after initiation of chemotherapy, namely total medical costs, number of outpatient visits, number of hospital admissions and number of days spent in hospital. RESULTS: A total of 598 CRPC patients were identified in the database. Total healthcare costs increased from 143,578 Japanese Yen (JPY) per patient per month (PPPM), before chemotherapy, to 333,628 JPY after start of chemotherapy. The number of hospital admissions increased by 280%, and the number of days spent in hospital by 380%. CONCLUSIONS: The overall costs of chemotherapy for patients diagnosed with castration-resistant prostate cancer in Japan are high. Our findings can serve as a basis for health economic evaluations. PMID- 29625535 TI - Dietary astaxanthin can accumulate in the brain of rats. AB - We evaluated the distribution of astaxanthin in rat brains after a single dose administration and after feeding 0.1% astaxanthin diet for 5 days. Astaxanthin was detected in the hippocampus and cerebral cortex 4 and 8 h after a single dose. Astaxanthin concentration in rat brains was higher after consumption of astaxanthin diet for 5 days than after a single dose. PMID- 29625536 TI - Weight change and risk of uterine leiomyomas: Korea Nurses' Health Study. AB - OBJECTIVE: This study examined the associations between anthropometric measures and uterine leiomyomas. METHODS: This study included a total of 5,062 women (median age of 35.5 years) who had experienced pregnancy and, of these women, 210 reported a diagnosis of uterine leiomyomas within the past 2 years prior to baseline in the Korea Nurses' Health Study. Participants were asked about their anthropometric factors. The odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using logistic regression models. RESULTS: Mean body mass index (BMI) was 21.8 kg/m2 among non-cases. An increase in weight from the age of 18 years to the present was associated with increased risk of uterine leiomyomas (p for trend = .002); compared to women whose weight remained stable, the multivariate ORs (95% CIs) were 1.84 (1.22-2.76) for weight gain of 5-10 kg and 2.00 (1.25-3.20) for weight gain of more than 10 kg since age 18. A similar pattern was observed when the analysis was limited to women with a BMI of 18.5-25 kg/m2. Current weight was associated with higher odds of uterine leiomyomas. No associations were found for body size in childhood or in adolescence, weight at age 18, current BMI, or current body size. CONCLUSIONS: Weight gain in adulthood was associated with increased risk of uterine leiomyomas in Korean women, even in those with normal weight. PMID- 29625537 TI - Evaluation of dystonia in children and adolescents treated with atomoxetine within the Truven MarketScan database: a retrospective cohort study. AB - OBJECTIVE: Atomoxetine is a non-stimulant drug indicated for the treatment of attention-deficit/hyperactivity disorder in children aged >=6 years, adolescents, and adults. In this retrospective cohort study, the incidence and risk of dystonia in children and adolescents treated with atomoxetine was compared to a propensity score-matched cohort of stimulant users. METHODS: Data between 1 January 2006 and 31 December 2014 from patients aged 6-17 years in the Truven Health Analytics MarketScan database were used to generate two cohorts of patients: (1) atomoxetine users and (2) stimulant (methylphenidates or amphetamines) users. A Cox proportional hazards regression model was used to compare incidence of dystonia across propensity score-matched cohorts. RESULTS: Of the 70,657 atomoxetine users, 70,655 users were propensity score-matched to a stimulant user. In the atomoxetine- and stimulant-treated cohorts, the crude incidence rates of dystonia were 54.9 (95% CI: 27.1-82.7) and 77.9 (95% CI: 49.1 106.8) per 100,000 person-years, respectively. The hazard ratio for occurrence of dystonia with atomoxetine use relative to stimulant use was 0.68 (95% CI: 0.36 - 1.28; P = 0.23). CONCLUSION: In this large retrospective cohort study, there was no significant difference in incidence or risk of dystonia among patients treated with atomoxetine compared to stimulants. PMID- 29625538 TI - Hospitalization risk in bipolar disorder patients treated with lurasidone versus other atypical antipsychotics. AB - OBJECTIVE: This observational study compared the risk of hospitalization for patients with bipolar disorder when treated with lurasidone versus other oral atypical antipsychotics. METHODS: This US commercial claims analysis (4 April 2010 through 24 September 2014) used the Optum Research Database to identify adult patients with bipolar disorder treated with oral atypical antipsychotics (N = 11,132). The first claim for an atypical antipsychotic defined the index date, with pre-index and post-index periods of 180 and 360 days, respectively. Every month of the post-index period was categorized as monotherapy treatment with lurasidone, aripiprazole, olanzapine, quetiapine, risperidone, ziprasidone, no/minimal treatment or other. Starting with the initial month of treatment, the risk of psychiatric or all-cause hospitalization in the subsequent month was examined based on treatment in the current month and pre-index covariates (age, gender, hospitalizations, emergency room visits, diagnoses for anxiety, alcohol abuse, substance abuse, hypertension, type 2 diabetes and obesity) and time varying versions of the pre-index covariates using a marginal structural model. RESULTS: After controlling for covariates, relative to lurasidone, the odds of psychiatric and all-cause hospitalization, respectively, were 2-3 times higher for olanzapine (odds ratio [OR] = 2.78, CI 1.09, 7.08, p = .032; OR = 3.20, CI 1.24, 8.26, p = .016), quetiapine (OR = 2.80, CI 1.13, 6.95, p = .026; OR = 3.23, CI 1.29, 8.11, p = .013), risperidone (OR = 2.50, CI 1.01, 6.21, p = .048; OR = 2.79, CI 1.11, 7.02, p = .029), aripiprazole (OR = 2.13, CI 0.87, 5.20, p = .097; OR = 2.57, CI 1.04, 6.37, p = .041) and ziprasidone (OR =2.31, CI 0.91, 5.85, p = .079; OR = 2.49, CI 0.97, 6.40, p = .058). CONCLUSIONS: In this claims database analysis, lurasidone-treated patients with bipolar disorder had a significantly lower risk of psychiatric hospitalization compared to quetiapine, olanzapine and risperidone, but not aripiprazole or ziprasidone. Lurasidone-treated patients had a significantly lower risk of all-cause hospitalization compared to quetiapine, olanzapine, risperidone and aripiprazole, but not ziprasidone. PMID- 29625540 TI - The Role of Transposable Elements in Emergence of Metazoa. AB - Systems initially emerged for protecting genomes against insertions of transposable elements and represented by mechanisms of splicing regulation, RNA interference, and epigenetic factors have played a key role in the evolution of animals. Many studies have shown inherited transpositions of mobile elements in embryogenesis and preservation of their activities in certain tissues of adult organisms. It was supposed that on the emergence of Metazoa the self-regulation mechanisms of transposons related with the gene networks controlling their activity could be involved in intercellular cell coordination in the cascade of successive divisions with differentiated gene expression for generation of tissues and organs. It was supposed that during evolution species-specific features of transposons in the genomes of eukaryotes could form the basis for creation of dynamically related complexes of systems for epigenetic regulation of gene expression. These complexes could be produced due to the influence of noncoding transposon-derived RNAs on DNA methylation, histone modifications, and processing of alternative splicing variants, whereas the mobile elements themselves could be directly involved in the regulation of gene expression in cis and in trans. Transposons are widely distributed in the genomes of eukaryotes; therefore, their activation can change the expression of specific genes. In turn, this can play an important role in cell differentiation during ontogenesis. It is supposed that transposons can form a species-specific pattern for control of gene expression, and that some variants of this pattern can be favorable for adaptation. The presented data indicate the possible influence of transposons in karyotype formation. It is supposed that transposon localization relative to one another and to protein-coding genes can influence the species-specific epigenetic regulation of ontogenesis. PMID- 29625541 TI - Plasticity of Human THP-1 Cell Phagocytic Activity during Macrophagic Differentiation. AB - Studies of the role of macrophages in phagocytosis are of great theoretical and practical importance for understanding how these cells are involved in the organism's defense response and in the development of various pathologies. Here we investigated phagocytic plasticity of THP-1 (acute monocytic human leukemia) cells at different stages (days 1, 3, and 7) of phorbol ester (PMA)-induced macrophage differentiation. Analysis of cytokine profiles showed that PMA at a concentration of 100 nM induced development of the proinflammatory macrophage population. The functional activity of macrophages was assessed on days 3 and 7 of differentiation using unlabeled latex beads and latex beads conjugated with ligands (gelatin, mannan, and IgG Fc fragment) that bind to the corresponding specific receptors. The general phagocytic activity increased significantly (1.5 2.0-fold) in the course of differentiation; phagocytosis occurred mostly through the Fc receptors, as shown previously for M1 macrophages. On day 7, the levels of phagocytosis of gelatin- and Fc-covered beads were high; however, the intensity of ingestion of mannan-conjugated beads via mannose receptors increased 2.5-3.0 fold as well, which indicated formation of cells with an alternative phenotype similar to that of M2 macrophages. Thus, the type and the plasticity of phagocytic activity at certain stages of macrophage differentiation can be associated with the formation of functionally mature morphological phenotype. This allows macrophages to exhibit their phagocytic potential in response to specific ligands. These data are of fundamental importance and can be used to develop therapeutic methods for correcting the M1/M2 macrophage ratio in an organism. PMID- 29625542 TI - Main Strategies of Plant Expression System Glycoengineering for Producing Humanized Recombinant Pharmaceutical Proteins. AB - Most the pharmaceutical proteins are derived not from their natural sources, rather their recombinant analogs are synthesized in various expression systems. Plant expression systems, unlike mammalian cell cultures, combine simplicity and low cost of procaryotic systems and the ability for posttranslational modifications inherent in eucaryotes. More than 50% of all human proteins and more than 40% of the currently used pharmaceutical proteins are glycosylated, that is, they are glycoproteins, and their biological activity, pharmacodynamics, and immunogenicity depend on the correct glycosylation pattern. This review examines in detail the similarities and differences between N- and O glycosylation in plant and mammalian cells, as well as the effect of plant glycans on the activity, pharmacokinetics, immunity, and intensity of biosynthesis of pharmaceutical proteins. The main current strategies of glycoengineering of plant expression systems aimed at obtaining fully humanized proteins for pharmaceutical application are summarized. PMID- 29625543 TI - Mechanisms of Mitochondrial DNA Repair in Mammals. AB - Accumulation of mutations in mitochondrial DNA leads to the development of severe, currently untreatable diseases. The contribution of these mutations to aging and progress of neurodegenerative diseases is actively studied. Elucidation of DNA repair mechanisms in mitochondria is necessary for both developing approaches to the therapy of diseases caused by mitochondrial mutations and understanding specific features of mitochondrial genome functioning. Mitochondrial DNA repair systems have become a subject of extensive studies only in the last decade due to development of molecular biology methods. DNA repair systems of mammalian mitochondria appear to be more diverse and effective than it had been thought earlier. Even now, one may speak about the existence of mitochondrial mechanisms for the repair of single- and double-stranded DNA lesions. Homologous recombination also takes place in mammalian mitochondria, although its functional significance and molecular mechanisms remain obscure. In this review, I describe DNA repair systems in mammalian mitochondria, such as base excision repair (BER) and microhomology-mediated end joining (MMEJ) and discuss a possibility of existence of mitochondrial DNA repair mechanisms otherwise typical for the nuclear DNA, e.g., nucleotide excision repair (NER), mismatch repair (MMR), homologous recombination, and classical non-homologous end joining (NHEJ). I also present data on the mechanisms for coordination of the nuclear and mitochondrial DNA repair systems that have been actively studied recently. PMID- 29625544 TI - Identification of Single Amino Acid Substitutions in Proteogenomics. AB - An important aim of proteogenomics, which combines data of high throughput nucleic acid and protein analysis, is to reliably identify single amino acid substitutions representing a main type of coding genome variants. Exact knowledge of deviations from the consensus genome can be utilized in several biomedical fields, such as studies of expression of mutated proteins in cancer, deciphering heterozygosity mechanisms, identification of neoantigens in anticancer vaccine production, search for RNA editing sites at the level of the proteome, etc. Generation of this new knowledge requires processing of large data arrays from high-resolution mass spectrometry, where information on single-point protein variation is often difficult to extract. Accordingly, a significant problem in proteogenomic analysis is the presence of high levels of false positive results for variant-containing peptides in the produced results. Here we review recently suggested approaches of high quality proteomics data processing that may provide more reliable identification of single amino acid substitutions, especially contrary to residue modifications occurring in vitro and in vivo. Optimized methods for assessment of false discovery rate save instrumental and computational time spent for validation of interesting findings of amino acid polymorphism by orthogonal methods. PMID- 29625545 TI - Expression of Soluble Active Interferon alphaA in Escherichia coli Periplasm by Fusion with Thermostable Lichenase Using the Domain Insertion Approach. AB - A recombinant DNA in which the interferon alphaA (IFN-alphaA) gene sequence is integrated into a loop region of the gene coding thermostable lichenase was constructed. This approach of insertion fusion with thermostable lichenase is advantageous in terms of increasing the solubility, stability, and production of the fusion partner in soluble form in general and in the periplasm of bacterial cells in particular. Thus, the insertion of IFN-alphaA into the loop (53 a.a.) of thermostable lichenase from Clostridium thermocellum resulted in effective expression of the soluble form of the recombinant protein in the periplasm of Escherichia coli without any compromise in biological activity of IFN-alphaA, while the thermostable lichenase retained its ability for functional folding without dramatic loss of its basic activity and thermostability. PMID- 29625546 TI - Possible Role of Escherichia coli Protein YbgI. AB - Proteins containing the NIF3 domain are highly conserved and are found in bacteria, eukaryotes, and archaea. YbgI is an Escherichia coli protein whose gene is conserved among bacteria. The structure of YbgI is known; however, the function of this protein in cells remains obscure. Our studies of E. coli cells with deleted ybgI gene suggest that YbgI is involved in formation of the bacterial cell wall. PMID- 29625547 TI - Endonuclease Activity of MutL Protein of the Rhodobacter sphaeroides Mismatch Repair System. AB - We have purified the MutL protein from Rhodobacter sphaeroides mismatch repair system (rsMutL) for the first time. rsMutL demonstrated endonuclease activity in vitro, as predicted by bioinformatics analysis. Based on the alignment of 1483 sequences of bacterial MutL homologs with presumed endonuclease activity, conserved functional motifs and amino acid residues in the rsMutL sequence were identified: five motifs comprising the catalytic site responsible for DNA cleavage were found in the C-terminal domain; seven conserved motifs involved in ATP binding and hydrolysis and specific to the GHKL family of ATPases were found in the N-terminal domain. rsMutL demonstrated the highest activity in the presence of Mn2+. The extent of plasmid DNA hydrolysis declined in the row Mn2+ > Co2+ > Mg2+ > Cd2+; Ni2+ and Ca2+ did not activate rsMutL. Divalent zinc ions inhibited rsMutL endonuclease activity in the presence of Mn2+ excess. ATP also suppressed plasmid DNA hydrolysis by rsMutL. Analysis of amino acid sequences and biochemical properties of five studied bacterial MutL homologs with endonuclease activity revealed that rsMutL resembles the MutL proteins from Neisseria gonorrhoeae and Pseudomonas aeruginosa. PMID- 29625548 TI - Glutamic Acid Signal Synchronizes Protein Synthesis Kinetics in Hepatocytes from Old Rats for the Following Several Days. Cell Metabolism Memory. AB - The kinetics of protein synthesis was investigated in primary cultures of hepatocytes from old rats in serum-free medium. The rats were fed mixed fodder supplemented with glutamic acid and then transferred to a regular mixed fodder. The amplitude of protein synthesis rhythm in hepatocytes isolated from these rats increased on average 2-fold in comparison with the rats not receiving glutamic acid supplement. Based on this indicator reflecting the degree of cell-cell interactions, the cells from old rats were not different from those of young rats. The effect was preserved for 3-4 days. These results are discussed in connection with our previous data on preservation of the effect of single administration of gangliosides, noradrenaline, serotonin, and other synchronizers on various cell populations. In contrast to the other investigated factors, glutamic acid is capable of penetrating the blood-brain barrier, which makes its effect possible not only in the case of hepatocytes and other non-brain cells, but also in neurons. PMID- 29625549 TI - Genomic evaluation of feed efficiency component traits in Duroc pigs using 80K, 650K and whole-genome sequence variants. AB - BACKGROUND: Increasing marker density was proposed to have potential to improve the accuracy of genomic prediction for quantitative traits; whole-sequence data is expected to give the best accuracy of prediction, since all causal mutations that underlie a trait are expected to be included. However, in cattle and chicken, this assumption is not supported by empirical studies. Our objective was to compare the accuracy of genomic prediction of feed efficiency component traits in Duroc pigs using single nucleotide polymorphism (SNP) panels of 80K, imputed 650K, and whole-genome sequence variants using GBLUP, BayesB and BayesRC methods, with the ultimate purpose to determine the optimal method to increase genetic gain for feed efficiency in pigs. RESULTS: Phenotypes of average daily feed intake (ADFI), average daily gain (ADG), ultrasound backfat depth (FAT), and loin muscle depth (LMD) were available for 1363 Duroc boars from a commercial breeding program. Genotype imputation accuracies reached 92.1% from 80K to 650K and 85.6% from 650K to whole-genome sequence variants. Average accuracies across methods and marker densities of genomic prediction of ADFI, FAT, LMD and ADG were 0.40, 0.65, 0.30 and 0.15, respectively. For ADFI and FAT, BayesB outperformed GBLUP, but increasing marker density had little advantage for genomic prediction. For ADG and LMD, GBLUP outperformed BayesB, while BayesRC based on whole-genome sequence data gave the best accuracies and reached up to 0.35 for LMD and 0.25 for ADG. CONCLUSIONS: Use of genomic information was beneficial for prediction of ADFI and FAT but not for that of ADG and LMD compared to pedigree-based estimates. BayesB based on 80K SNPs gave the best genomic prediction accuracy for ADFI and FAT, while BayesRC based on whole-genome sequence data performed best for ADG and LMD. We suggest that these differences between traits in the effect of marker density and method on accuracy of genomic prediction are mainly due to the underlying genetic architecture of the traits. PMID- 29625550 TI - Classification and phylogenetic analyses of the Arabidopsis and tomato G-type lectin receptor kinases. AB - BACKGROUND: Pathogen perception by plants is mediated by plasma membrane localized immune receptors that have varied extracellular domains. Lectin receptor kinases (LecRKs) are among these receptors and are subdivided into 3 classes, C-type LecRKs (C-LecRKs), L-type LecRKs (L-LecRKs) and G-type LecRKs (G LecRKs). While C-LecRKs are represented by one or two members in all plant species investigated and have unknown functions, L-LecRKs have been characterized in a few plant species and have been shown to play roles in plant defense against pathogens. Whereas Arabidopsis G-LecRKs have been characterized, this family of LecRKs has not been studied in tomato. RESULTS: This investigation updates the current characterization of Arabidopsis G-LecRKs and characterizes the tomato G LecRKs, using LecRKs from the monocot rice and the basal eudicot columbine to establish a basis for comparisons between the two core eudicots. Additionally, revisiting parameters established for Arabidopsis nomenclature for LecRKs is suggested for both Arabidopsis and tomato. Moreover, using phylogenetic analysis, we show the relationship among and between members of G-LecRKs from all three eudicot plant species. Furthermore, investigating presence of motifs in G-LecRKs we identified conserved motifs among members of G-LecRKs in tomato and Arabidopsis, with five present in at least 30 of the 38 Arabidopsis members and in at least 45 of the 73 tomato members. CONCLUSIONS: This work characterized tomato G-LecRKs and added members to the currently characterized Arabidopsis G LecRKs. Additionally, protein sequence analysis showed an expansion of this family in tomato as compared to Arabidopsis, and the existence of conserved common motifs in the two plant species as well as conserved species-specific motifs. PMID- 29625551 TI - Foreskin-derived mesenchymal stromal cells with aldehyde dehydrogenase activity: isolation and gene profiling. AB - BACKGROUND: Mesenchymal stromal cells (MSCs) become an attractive research topic because of their crucial roles in tissue repair and regenerative medicine. Foreskin is considered as a valuable tissue source containing immunotherapeutic MSCs (FSK-MSCs). RESULTS: In this work, we used aldehyde dehydrogenase activity (ALDH) assay (ALDEFLUORTM) to isolate and therefore characterize subsets of FSK MSCs. According to their ALDH activity, we were able to distinguish and sort by fluorescence activated cell sorting (FACS) two subsets of FSK-MSCs (referred as ALDH+ and ALDH-). Consequently, these subsets were characterized by profiling the gene expression related to the main properties of MSCs (proliferation, response to hypoxia, angiogenesis, phenotype, stemness, multilineage, hematopoiesis and immunomodulation). We thus demonstrated by Real Time PCR several relevant differences in gene expression based on their ALDH activity. CONCLUSION: Taken together, this preliminary study suggests that distinct subsets of FSK-MSCs with differential gene expression profiles depending of ALDH activity could be identified. These populations could differ in terms of biological functionalities involving the selection by ALDH activity as useful tool for potent therapeutic applications. However, functional studies should be conducted to confirm their therapeutic relevance. PMID- 29625552 TI - Low pyrrolizidine alkaloid levels in perennial ryegrass is associated with the absence of a homospermidine synthase gene. AB - BACKGROUND: Pyrrolizidine alkaloids (PAs) are a class of secondary metabolites that function as feeding deterrents in a range of different plant species. In perennial ryegrass (Lolium perenne L.) the only PAs that have been identified are the thesinine-rhamnoside group, which displays significant genetic variation. Homospermidine synthase (HSS) has evolved from deoxyhypusine synthase (DHS) and catalyses the first step in the PA pathway, making it a key candidate for the investigation of genes influencing observed PA trait variation. RESULTS: During PCR amplification and sequence analysis of DHS we identified two putative HSS genes in perennial ryegrass. One of the genes (LpHSS1) was absent in some perennial ryegrass plants. Thesinine-rhamnoside levels were measured using liquid chromatography coupled with mass spectrometry in a diverse association mapping population, consisting of 693 plants free of fungal endophytic symbionts. Association tests that accounted for population structure identified a significant association of absence of the LpHSS1 gene with lower levels of thesinine-rhamnoside PAs. HSS-like gene sequences were identified for other grass species of the Poaceae, including tall fescue, wheat, maize and sorghum. CONCLUSION: HSS is situated at the crucial first step in the PA pathway making it an important candidate gene for investigation of involvement in PA phenotypic variation. In this study, PA level in perennial ryegrass was strongly associated with the presence or absence of the LpHSS1 gene. A genetic marker, developed for the presence/absence of LpHSS1, may be used for marker-assisted breeding to either lower or increase PAs in breeding populations of perennial or Italian ryegrass to investigate a potential role in the deterrence of herbivore pests. The presence of HSS-like genes in several other Poaceae species suggests that PA biosynthesis may occur in plant family members beyond perennial ryegrass and tall fescue and identifies a potential route for manipulating PA levels. PMID- 29625553 TI - A nutrient-dependent division antagonist is regulated post-translationally by the Clp proteases in Bacillus subtilis. AB - BACKGROUND: Changes in nutrient availability have dramatic and well-defined impacts on both transcription and translation in bacterial cells. At the same time, the role of post-translational control in adaptation to nutrient-poor environments is poorly understood. Previous studies demonstrate the ability of the glucosyltransferase UgtP to influence cell size in response to nutrient availability. Under nutrient-rich medium, interactions with its substrate UDP glucose promote interactions between UgtP and the tubulin-like cell division protein FtsZ in Bacillus subtilis, inhibiting maturation of the cytokinetic ring and increasing cell size. In nutrient-poor medium, reductions in UDP-glucose availability favor UgtP oligomerization, sequestering it from FtsZ and allowing division to occur at a smaller cell mass. RESULTS: Intriguingly, in nutrient-poor conditions UgtP levels are reduced ~ 3-fold independent of UDP-glucose. B. subtilis cells cultured under different nutrient conditions indicate that UgtP accumulation is controlled through a nutrient-dependent post-translational mechanism dependent on the Clp proteases. Notably, all three B. subtilis Clp chaperones appeared able to target UgtP for degradation during growth in nutrient poor conditions. CONCLUSIONS: Together these findings highlight conditional proteolysis as a mechanism for bacterial adaptation to a rapidly changing nutritional landscape. PMID- 29625554 TI - Antiepileptic drug exposure in pregnancy and pregnancy outcome from national drug usage data. AB - BACKGROUND: Antiepileptic drugs (AEDs) are used by pregnant women to manage conditions such as epilepsy and bipolar disorder even though they pose a risk to the developing foetus. This study aimed to determine the overall use of AEDs by women during their childbearing years and women who are pregnant and the association between AED use and rates of pregnancy termination and spontaneous abortion. METHODS: Retrospective population based cohort study using administrative databases in New Zealand between 2008 and 2014. Women who had been pregnant were identified by the National Minimum Dataset and were linked to the Pharmaceutical Collection to obtain information on use of AEDs. Women aged between 15 and 45 years dispensed AEDs were identified in the Pharmaceutical Collection. RESULTS: There was an increase in the number of women of child bearing potential prescribed AEDs, from 9 women per 1000 women in 2008 to 11.4 women per 1000 women in 2014. Women who had been dispensed an AED had an increased rate of spontaneous abortion 8.97 spontaneous abortions per 100 pregnancies, compared with, 6.31 per 100 pregnancies (risk ratio 1.42, 95% CI 1.40 to 1.44), and a decreased rate of pregnancy termination, 18.51 terminations per 100 pregnancies compared with 19.58 per 100 pregnancies (risk ratio 1.95, 95% CI 0.94-0.96). CONCLUSION: Use of newer AEDs is increasing in women of child bearing potential in New Zealand leading to an overall increase in AED use in this group despite a fall in the use of older AEDs. AED use is this study was associated with an increased risk of spontaneous abortion and decreased rate of pregnancy termination, however confounding by indication could not be excluded. PMID- 29625555 TI - Subarachnoid hemorrhage after transient global amnesia caused by cerebral venous congestion: case report. AB - BACKGROUND: Transient global amnesia is reported to be caused by cerebral venous congestion. Internal jugular venous flow reversal in particular with the Valsalva maneuver leads to cerebral venous congestion. In addition, Valsalva maneuver can also induce subarachnoid hemorrhage. Transient global amnesia and subarachnoid hemorrhage might have common a pathophysiology in cerebral venous congestion. CASE PRESENTATION: We report here the case of a 57-year-old woman who twice experienced convexal subarachnoid hemorrhage just after straining at stool following an episode of transient global amnesia. Digital subtraction angiography showed left temporal congestion. Left jugular vein ultrasonography revealed reflux with the Valsalva maneuver only in acute phase, indicating transient cerebral venous congestion. CONCLUSIONS: Subarachnoid hemorrhage followed by transient global amnesia indicates a common factor between them. Transient venous congestion is discussed in order to explain this rare phenomenon. PMID- 29625556 TI - Targeted next generation sequencing with an extended gene panel does not impact variant detection in mitochondrial diseases. AB - BACKGROUND: Since the advent of next generation sequencing (NGS), several studies have tried to evaluate the relevance of targeted gene panel sequencing and whole exome sequencing for molecular diagnosis of mitochondrial diseases. The comparison between these different strategies is extremely difficult. A recent study analysed a cohort of patients affected by a mitochondrial disease using a NGS approach based on a targeted gene panel including 132 genes. This strategy led to identify the causative mutations in 15.2% of cases. The number of novel genes responsible for respiratory chain deficiency increases very rapidly. METHODS: In order to determine the impact of larger panels used as a first screening strategy on molecular diagnosis success, we analysed a cohort of 80 patients affected by a mitochondrial disease with a first mitochondrial DNA (mtDNA) NGS screening and secondarily a targeted mitochondrial panel of 281 nuclear genes. RESULTS: Pathogenic mtDNA abnormalities were identified in 4.1% (1/24) of children and 25% (14/56) of adult patients. The remaining 65 patients were analysed with our targeted mitochondrial panel and this approach enabled us to achieve an identification rate of 21.7% (5/23) in children versus 7.1% (3/42) in adults. CONCLUSIONS: Our results confirm that larger gene panels do not improve diagnostic yield of mitochondrial diseases due to (i) their very high genetic heterogeneity, (ii) the ongoing discovery of novel genes and (iii) mutations in genes apparently not related to mitochondrial function that lead to secondary respiratory chain deficiency. PMID- 29625557 TI - Case report: lactic acidosis and rhabdomyolysis during telbivudine and tenofovir treatment for chronic hepatitis B. AB - BACKGROUND: Current treatment options for chronic hepatitis B (CHB) are pegylated interferon alpha and nucleoside analogues (NAs). NAs have relatively fewer side effects than interferon alpha, and generally well tolerated. Previously 12.9% of patients on telbivudine treatment were reported to develop severe elevation of serum creatine phosphokinase (CPK) levels, but related clinical disease, like lactic acidosis (LA) and rhabdomyolysis (RM) were rare. The pathophysiology may be mitochondrial toxicity, for the NAs inhibit not only hepatitis B virus (HBV) polymerase, but also the host mitochondrial DNA polymerase gamma. As mitochondria are the main sites of oxidative phosphorylation, there will be an increase of pyruvate reduction to lactic acid and insufficient adenosine triphosphate. The accumulation of lactic acid causes LA, while lack of energy leads to cell dysfunction and mitochondria-associated disease, including RM. All five NAs, except tenofovir, have been reported causing LA and RM. Here we report the first case of CHB patients developing fatal LA and RM during telbivudine and tenofovir treatment. CASE PRESENTATION: The patient is a 51-year-old man who was hospitalized in November 2015. He had taken telbivudine regularly because of CHB. Later, tenofovir was added to antiviral treatment because of HBV resistance. Then he had myalgia, chest tightness and anorexia. The blood lactate was 12.7 mmol/L. The arterial blood gas analysis showed pH 7.25, base excess 21.1 mmol/L. CPK was 991 U/L, myoglobin was 1745 ng/ml and creatine was 83 MUmol/L. Abdomen magnetic resonance revealed cirrhosis. Muscle biopsy revealed myogenic lesion with abnormality of mitochondria and fat metabolism. The patient was diagnosed with Hepatitis B envelope Antigen positive CHB, cirrhosis, LA and RM characterized by myalgia and elevated myoglobin. He was given tenofovir alone as antiviral treatment instead. After hemodialysis and 4 weeks' treatment of corticosteroids, his symptoms recovered, and blood lactate gradually returned to a normal range. CONCLUSIONS: This case shows that tenofovir may trigger muscle damage and fatal RM in combination with telbivudine treatment in CHB patients. Thus, patients receiving tenofovir and telbivudine should be closely monitored for muscular abnormalities, blood lactate level and other mitochondrial toxicity associated side effects. PMID- 29625558 TI - Predominant but silent C1q deposits in mesangium on transplanted kidneys - long term observational study. AB - BACKGROUND: C1q nephropathy (C1qN) was first described as glomerular disease characterized by predominant meangial C1q deposits in patients with proteinuria and no evidence of systemic lupus erythematosus. Several studies, however, revealed the clinical heterogeneity of C1qN, showing some cases with normal urinalysis. To confirm the existence of cases with predominant mesangial C1q deposits and negative or mild proteinuria and/or hematuria, we investigated renal graft biopsy specimens showing negative to mild proteinuria (less than or equal to 1+ by dip stick test) and/or hematuria. METHODS: Eligible participants were kidney transplant cases who corresponded to the criteria for C1qN and were followed more than 10 years. Their medical records were reviewed to determine the age at detection of predominant mesangial C1q deposits, gender, original renal disease and reason for renal graft biopsy, blood pressure, degree of proteinuria and hematuria, and serum creatinine levels. RESULTS: From 414 cases in adults and children, five pediatric patients (the male to female ratio, 1:1.5) were eligible. At the time when predominant mesangial C1q deposits were detected, 2 cases presented with mild proteinuria without hematuria, but the other 3 cases showed normal urinalysis. Light microscopy revealed minor glomerular abnormality in all the cases. Immunofluorescent study showed predominant mesangial C1q deposits with IgG, IgM and C3 in all cases. All selected specimens presented electron dense-depos in the mesangium. Ten years later from the detection, 2 cases continued to be normal urinalysis and 3 cases had mild proteinuria without hematuria. During this follow-up period, no cases presented with persistent proteinuria and/or hematuria greater than or equal to 2+ by dip stick test. And no cases developed systemic lupus erythematosus. Follow-up renal graft biopsies were performed once in 2 cases 8 years later from the detection. They showed minor glomerular abnormalities. C1q deposit disappeared in one case. In another case, immunofluorescent study was not examined. CONCLUSIONS: This long-term observational study on transplanted kidneys confirms the existence of cases with predominant but silent C1q deposits in the mesangium who have negative or mild proteinuria. PMID- 29625559 TI - Dynamic imaging and pathological changes in pig liver after MR-guided microwave ablation. AB - BACKGROUND: Magnetic resonance (MR)-guided microwave ablation is a well-developed technique for the treatment of tumors, especially hepatic carcinomas. However, there are no detailed reports on the changes in the MR images and histology observed after the ablation. This study aimed to dynamically map the pathological changes after ablation and the changes occurring on MR images. METHODS: We performed MR-guided microwave ablation in 10 Wuzhishan pigs and obtained an MR scan immediately after ablation (0 weeks) and at 1, 2, 3, and 4 weeks after ablation. We compared the ablation assessed on MR images to tissue specimens obtained during follow-up. RESULTS: We found no significant difference in the ablation size between MR images and tissue specimens; the mean length and width of the ablated zone were 4.27 cm and 2.42 cm, respectively, on MR images and 4.26 cm and 2.45 cm, respectively, on specimens (P > 0.05). Immediately after ablation, carbonization and cavities were observed in the center of the ablation zone. Surrounding layer cells were necrotic but maintained their original shapes. The outermost layer was inflamed, but gradually showed fibrotic characteristics. The MR images accurately reflected the exact histological tissue changes after the ablation procedure. CONCLUSION: The dynamic imaging and pathological features of liver ablation outlined in this study will provide a useful reference for patient follow-up after MR-guided microwave ablation. PMID- 29625560 TI - Resolution of maternal Mirror syndrome after succesful fetal intrauterine therapy: a case series. AB - BACKGROUND: Mirror syndrome (MS) is a rare obstetric condition usually defined as the development of maternal edema in association with fetal hydrops. The pathogenesis of MS remains unclear and may be misdiagnosed as pre-eclampsia. CASE PRESENTATION: We report a case series of MS in which fetal therapy (intrauterine blood transfusion and pleuroamniotic shunt) resulted in fetal as well as maternal favourable course with complete resolution of the condition in both mother and fetus. CONCLUSIONS: Our case series add new evidence to support that early diagnosis of MS followed by fetal therapy and clinical maternal support are critical for a good outcome. PMID- 29625561 TI - COZOID: contact zone identifier for visual analysis of protein-protein interactions. AB - BACKGROUND: Studying the patterns of protein-protein interactions (PPIs) is fundamental for understanding the structure and function of protein complexes. The exploration of the vast space of possible mutual configurations of interacting proteins and their contact zones is very time consuming and requires the proteomic expert knowledge. RESULTS: In this paper, we propose a novel tool containing a set of visual abstraction techniques for the guided exploration of PPI configuration space. It helps proteomic experts to select the most relevant configurations and explore their contact zones at different levels of detail. The system integrates a set of methods that follow and support the workflow of proteomics experts. The first visual abstraction method, the Matrix view, is based on customized interactive heat maps and provides the users with an overview of all possible residue-residue contacts in all PPI configurations and their interactive filtering. In this step, the user can traverse all input PPI configurations and obtain an overview of their interacting amino acids. Then, the models containing a particular pair of interacting amino acids can be selectively picked and traversed. Detailed information on the individual amino acids in the contact zones and their properties is presented in the Contact-Zone list-view. The list-view provides a comparative tool to rank the best models based on the similarity of their contacts to the template-structure contacts. All these techniques are interactively linked with other proposed methods, the Exploded view and the Open-Book view, which represent individual configurations in three dimensional space. These representations solve the high overlap problem associated with many configurations. Using these views, the structural alignment of the best models can also be visually confirmed. CONCLUSIONS: We developed a system for the exploration of large sets of protein-protein complexes in a fast and intuitive way. The usefulness of our system has been tested and verified on several docking structures covering the three major types of PPIs, including coiled-coil, pocket-string, and surface-surface interactions. Our case studies prove that our tool helps to analyse and filter protein-protein complexes in a fraction of the time compared to using previously available techniques. PMID- 29625562 TI - Development and testing of an online community care platform for frail older adults in the Netherlands: a user-centred design. AB - BACKGROUND: Recent transitions in long-term care in the Netherlands have major consequences for community-dwelling older adults. A new paradigm expects them to manage and arrange their own care and support as much as possible. Technology can support this shift. A study has been conducted to explore the needs of community dwelling frail older adults with regard to an online platform. An existing platform was subsequently modified, based upon these needs, resulting in an online community care platform (OCC-platform) comprising of care, health, and communication functions. The purpose of this platform was to support frail older adults in their independence and functioning, by stimulating self-care and providing reliable information, products and services. METHODS: The study used a User-Centred Design. The development processes involved the following steps: Step 1) Identification of the User Requirements. To assess the user requirements, direct observations (N = 3) and interviews (N = 14) were performed. Step 2) Modification of an Existing Online Platform. Based upon Step 1, available online platforms were explored to determine whether an existing useful product was available. Two companies collaborated in modifying such a platform; Step 3) Testing the Modified Platform. A total of 73 older adults were invited to test a prototype of the OCC-platform during 6 months, which comprised of two phases: (1) a training phase; and (2) a testing phase. RESULTS: An iterative process of modifications resulted in an interactive software concept on a Standard PC, containing 11 Functions. The Functions of 'contacts', 'services' and 'messaging', were by far, the most frequently used. The use was at its highest during the first 2 weeks of the testing and then its use steadily declined. The vast majority of the subjects (94%) were positive about the usability of the platform. Only a minority of the subjects (27%) indicated that the platform had added value for them. CONCLUSION: The overall prospect was that an OCC-platform can contribute to the social participation and the self-management competencies of frail older adults, together with their social cohesion in the community. In order to validate these prospects, further research is needed on the characteristics and the impact of online platforms. PMID- 29625563 TI - Design and Implementation of a postgraduate curriculum to support Ethiopia's first emergency medicine residency training program: the Toronto Addis Ababa Academic Collaboration in Emergency Medicine (TAAAC-EM). AB - BACKGROUND: To design and implement an emergency medicine (EM) postgraduate training curriculum to support the establishment of the first EM residency program at Addis Ababa University (AAU). METHODS: In response to the Ethiopian Federal Ministry of Health mandate to develop EM services in Ethiopia, University of Toronto EM faculty were invited to develop and deliver EM content and expertise for the first EM postgraduate residency training program at AAU. The Toronto Addis Ababa Academic Collaboration-EM (TAAAC-EM) used five steps of a six step approach to guide curriculum development and implementation: 1. Problem identification and general needs assessment, 2. Targeted needs assessment using indirect methods (interviews and site visits of the learners and learning environment), 3. Defining goals and objectives, 4. Choosing educational strategies and curriculum map development and 5. IMPLEMENTATION: RESULTS: The needs assessment identified a learning environment with appropriate, though limited, resources for the implementation of an EM residency program. A lack of educational activities geared towards EM practice was identified, specifically of active learning techniques (ALTs) such as bedside teaching, simulation and procedural teaching. A curriculum map was devised to supplement the AAU EM residency program curriculum. The TAAAC-EM curriculum was divided into three distinct streams: clinical, clinical epidemiology and EM administration. The clinical sessions were divided into didactic and ALTs including practical/procedural and simulation sessions, and bedside teaching was given a strong emphasis. Implementation is currently in its seventh year, with continuous monitoring and revisions of the curriculum to meet evolving needs. CONCLUSION: We have outlined the design and implementation of the TAAAC-EM curriculum; an evaluation of this curriculum is currently underway. As EM spreads as a specialty throughout Africa and other resource-limited regions, this model can serve as a working guide for similar bi-institutional educational partnerships seeking to develop novel EM postgraduate training programs. PMID- 29625564 TI - Urinary proteomics for prediction of mortality in patients with type 2 diabetes and microalbuminuria. AB - BACKGROUND: The urinary proteomic classifier CKD273 has shown promise for prediction of progressive diabetic nephropathy (DN). Whether it is also a determinant of mortality and cardiovascular disease in patients with microalbuminuria (MA) is unknown. METHODS: Urine samples were obtained from 155 patients with type 2 diabetes and confirmed microalbuminuria. Proteomic analysis was undertaken using capillary electrophoresis coupled to mass spectrometry to determine the CKD273 classifier score. A previously defined CKD273 threshold of 0.343 for identification of DN was used to categorise the cohort in Kaplan-Meier and Cox regression models with all-cause mortality as the primary endpoint. Outcomes were traced through national health registers after 6 years. RESULTS: CKD273 correlated with urine albumin excretion rate (UAER) (r = 0.481, p = <0.001), age (r = 0.238, p = 0.003), coronary artery calcium (CAC) score (r = 0.236, p = 0.003), N-terminal pro-brain natriuretic peptide (NT-proBNP) (r = 0.190, p = 0.018) and estimated glomerular filtration rate (eGFR) (r = 0.265, p = 0.001). On multivariate analysis only UAER (beta = 0.402, p < 0.001) and eGFR (beta = - 0.184, p = 0.039) were statistically significant determinants of CKD273. Twenty participants died during follow-up. CKD273 was a determinant of mortality (log rank [Mantel-Cox] p = 0.004), and retained significance (p = 0.048) after adjustment for age, sex, blood pressure, NT-proBNP and CAC score in a Cox regression model. CONCLUSION: A multidimensional biomarker can provide information on outcomes associated with its primary diagnostic purpose. Here we demonstrate that the urinary proteomic classifier CKD273 is associated with mortality in individuals with type 2 diabetes and MA even when adjusted for other established cardiovascular and renal biomarkers. PMID- 29625565 TI - SALL1 functions as a tumor suppressor in breast cancer by regulating cancer cell senescence and metastasis through the NuRD complex. AB - BACKGROUND: SALL1 is a multi-zinc finger transcription factor that regulates organogenesis and stem cell development, but the role of SALL1 in tumor biology and tumorigenesis remains largely unknown. METHODS: We analyzed SALL1 expression levels in human and murine breast cancer cells as well as cancer tissues from different types of breast cancer patients. Using both in vitro co-culture system and in vivo breast tumor models, we investigated how SALL1 expression in breast cancer cells affects tumor cell growth and proliferation, metastasis, and cell fate. Using the gain-of function and loss-of-function strategies, we dissected the molecular mechanism responsible for SALL1 tumor suppressor functions. RESULTS: We demonstrated that SALL1 functions as a tumor suppressor in breast cancer, which is significantly down-regulated in the basal like breast cancer and in estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor 2 (HER2) triple negative breast cancer patients. SALL1 expression in human and murine breast cancer cells inhibited cancer cell growth and proliferation, metastasis, and promoted cell cycle arrest. Knockdown of SALL1 in breast cancer cells promoted cancer cell growth, proliferation, and colony formation. Our studies revealed that tumor suppression was mediated by recruitment of the Nucleosome Remodeling and Deacetylase (NuRD) complex by SALL1, which promoted cancer cell senescence. We further demonstrated that the mechanism of inhibition of breast cancer cell growth and invasion by SALL1-NuRD depends on the p38 MAPK, ERK1/2, and mTOR signaling pathways. CONCLUSION: Our studies indicate that the developmental control gene SALL1 plays a critical role in tumor suppression by recruiting the NuRD complex and thereby inducing cell senescence in breast cancer cells. PMID- 29625566 TI - Passing MRCP (UK) PACES: a cross-sectional study examining the performance of doctors by sex and country. AB - BACKGROUND: There is much discussion about the sex differences that exist in medical education. Research from the United Kingdom (UK) and United States has found female doctors earn less, and are less likely to be senior authors on academic papers, but female doctors are also less likely to be sanctioned, and have been found to perform better academically and clinically. It is also known that international medical graduates tend to perform more poorly academically compared to home-trained graduates in the UK, US, and Canada. It is uncertain whether the magnitude and direction of sex differences in doctors' performance is variable by country. We explored the association between doctors' sex and their performance at a large international high-stakes clinical examination: the Membership of the Royal Colleges of Physicians (UK) Practical Assessment of Clinical Examination Skills (PACES). We examined how sex differences varied by the country in which the doctor received their primary medical qualification, the country in which they took the PACES examination, and by the country in which they are registered to practise. METHODS: Seven thousand six hundred seventy-one doctors attempted PACES between October 2010 and May 2013. We analysed sex differences in first time pass rates, controlling for ethnicity, in three groups: (i) UK medical graduates (N = 3574); (ii) non-UK medical graduates registered with the UK medical regulator, the General Medical Council (GMC), and thus likely to be working in the UK (N = 1067); and (iii) non-UK medical graduates without GMC registration and so legally unable to work or train in the UK (N = 2179). RESULTS: Female doctors were statistically significantly more likely to pass at their first attempt in all three groups, with the greatest sex effect seen in non UK medical graduates without GMC registration (OR = 1.99; 95% CI = 1.65-2.39; P < 0.0001) and the smallest in the UK graduates (OR = 1.18; 95% CI = 1.03-1.35; P = 0.02). CONCLUSIONS: As found in a previous format of this examination and in other clinical examinations, female doctors outperformed male doctors. Further work is required to explore why sex differences were greater in non-UK graduates, especially those without GMC registration, and to consider how examination performance may relate to performance in practice. PMID- 29625567 TI - Geographic variations in involuntary care and associations with the supply of health and social care: results from a nationwide study. AB - BACKGROUND: Involuntary psychiatric care remains controversial. Geographic disparities in its use can challenge the appropriateness of the care provided when they do not result from different health needs of the population. These disparities should be reduced through dedicated health policies. However, their association with the supply of health and social care, which could be targeted by such policies, has been insufficiently studied. Our objectives were therefore to describe geographic variations in involuntary admission rates across France and to identify the characteristics of the supply of care which were associated with these variations. METHODS: Involuntary admission rate per 100,000 adult inhabitants was calculated in French psychiatric sectors' catchment areas using 2012 data from the national psychiatric discharge database. Its variations were first described numerically and graphically. Several factors potentially associated with these variations were then considered in a negative binomial regression with an offset term accounting for the size of catchment areas. They included characteristics of the supply of care (public and private care, health and social care, hospital and community-based care, specialised and non specialised care) as well as adjustment factors related to epidemiological characteristics of the population of each sector's catchment area and its level of urbanization. Such variables were extracted from complementary administrative databases. Supply characteristics associated with geographic variations were identified using a significance level of 0.05. RESULTS: Significant variations in involuntary admission rates were observed between psychiatric sectors' catchment areas with a coefficient of variation close to 80%. These variations were associated with some characteristics of the supply of health and social care in the sectors' catchment areas. Notably, an increase in the availability of community-based private psychiatrists and the capacity of housing institutions for disabled individuals was associated with a decrease in involuntary admission rates while an increase in the availability of general practitioners was associated with an increase in those rates. CONCLUSIONS: There is evidence of considerable variations in involuntary admission rates between psychiatric sectors' catchment areas. Our results provide lines of thoughts to reduce such variations, in particular by supporting an increase in the availability of upstream and downstream care in the community. PMID- 29625569 TI - Community-based directly observed treatment for TB patients to improve HIV services: a cross-sectional study in a South African province. AB - BACKGROUND: There is uncertainty about how directly observed treatment (DOT) support for tuberculosis (TB) can be delivered most effectively and how DOT support can simultaneously be used to strengthen human immunodeficiency virus (HIV) prevention and control among TB patients. This study describes how DOT support by community health workers (CHWs) was used in four municipalities in the Free State province - a high TB/HIV burden, poorly-resourced setting - to provide HIV outreach, referrals, and health education for TB patients. METHODS: The study was part of a larger cross-sectional study of HIV counselling and testing (HCT) among 1101 randomly-selected TB patients registered at 40 primary health care (PHC) facilities (clinics and community health centres) across small town/rural and large town/urban settings. Univariate analysis of percentages, chi-square tests and t-tests for difference in means were used to describe differences between the types of TB treatment support and patient characteristics, as well as the types of - and patient satisfaction with - HIV information and referrals received from various types of treatment supporters including home-based DOT supporters, clinic-based DOT supporters or support from family/friends/employers. Multivariate logistic regression was used to predict the likelihood of not having receiving home-based DOT and of never having received HIV counselling. The independent variables include poverty-related health and socio-economic risk factors for poor outcomes. Statistical significance is shown using a 95% confidence interval and a 0.05 p-value. RESULTS: Despite the fact that DOT support for all TB patients was the goal of South African health policy at the time (2012), most TB patients were not receiving formal DOT support. Only 155 (14.1%) were receiving home-based DOT, while 114 (10.4%) received clinic-based DOT. TB patients receiving home-based DOT reported higher rates of HIV counselling than other patients. CONCLUSIONS: Public health providers should train DOT supporters to provide HIV prevention and target DOT to those at greatest risk of HIV, particularly those at greatest socio-economic risk. PMID- 29625568 TI - Consensus clinical management guidelines for Niemann-Pick disease type C. AB - Niemann-Pick Type C (NPC) is a progressive and life limiting autosomal recessive disorder caused by mutations in either the NPC1 or NPC2 gene. Mutations in these genes are associated with abnormal endosomal-lysosomal trafficking, resulting in the accumulation of multiple tissue specific lipids in the lysosomes. The clinical spectrum of NPC disease ranges from a neonatal rapidly progressive fatal disorder to an adult-onset chronic neurodegenerative disease. The age of onset of the first (beyond 3 months of life) neurological symptom may predict the severity of the disease and determines life expectancy.NPC has an estimated incidence of ~ 1: 100,000 and the rarity of the disease translate into misdiagnosis, delayed diagnosis and barriers to good care. For these reasons, we have developed clinical guidelines that define standard of care for NPC patients, foster shared care arrangements between expert centres and family physicians, and empower patients. The information contained in these guidelines was obtained through a systematic review of the literature and the experiences of the authors in their care of patients with NPC. We adopted the Appraisal of Guidelines for Research & Evaluation (AGREE II) system as method of choice for the guideline development process. We made a series of conclusive statements and scored them according to level of evidence, strengths of recommendations and expert opinions. These guidelines can inform care providers, care funders, patients and their carers of best practice of care for patients with NPC. In addition, these guidelines have identified gaps in the knowledge that must be filled by future research. It is anticipated that the implementation of these guidelines will lead to a step change in the quality of care for patients with NPC irrespective of their geographical location. PMID- 29625570 TI - The inhibition of human lung fibroblast proliferation and differentiation by Gs coupled receptors is not predicted by the magnitude of cAMP response. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a chronic and progressive fibrotic lung disease for which there is no cure. Current therapeutics are only able to slow disease progression, therefore there is a need to explore alternative, novel treatment options. There is increasing evidence that the 3', 5' cyclic adenosine monophosphate (cAMP) pathway is an important modulator in the development of fibrosis, with increasing levels of cAMP able to inhibit cellular processes associated with IPF. In this study we investigate the expression of Gs coupled G protein-coupled receptors (GPCR) on human lung fibroblasts (HLF), and explore which can increase cAMP levels, and are most efficacious at inhibiting proliferation and differentiation. METHODS: Using TaqMan arrays we determined that fibroblasts express a range of Gs-coupled GPCR. The function of selected agonists at expressed receptors was then tested in a cAMP assay, and for their ability to inhibit fibroblast proliferation and differentiation. RESULTS: Expression analysis of GPCR showed that the prostacyclin, prostaglandin E2 (PGE2) receptor 2 and 4, melanocortin-1, beta2 adrenoceptor, adenosine 2B, dopamine-1, and adenosine 2A receptors were expressed in HLF. Measuring cAMP accumulation in the presence of selected Gs-coupled receptor ligands as well as an adenylyl cyclase activator and inhibitors of phosphodiesterase showed formoterol, PGE2, treprostinil and forskolin elicited maximal cAMP responses. The agonists that fully inhibited both fibroblast proliferation and differentiation, BAY60-6583 and MRE-269, were partial agonists in the cAMP accumulation assay. CONCLUSIONS: In this study we identified a number of ligands that act at a range of GPCR that increase cAMP and inhibit fibroblast proliferation and differentiation, suggesting that they may provide novel targets to develop new IPF treatments. From these results it appears that although the cAMP response is important in driving the anti-fibrotic effects we have observed, the magnitude of the acute cAMP response is not a good predictor of the extent of the inhibitory effect. This highlights the importance of monitoring the kinetics and localisation of intracellular signals, as well as multiple pathways when profiling novel compounds, as population second messenger assays may not always predict phenotypic outcomes. PMID- 29625572 TI - Standardized patients in psychiatry - the best way to learn clinical skills? AB - BACKGROUND: Standardized patients (SP) have been successfully utilized in medical education to train students' communication skills. At the Medical University of Vienna communication training with SPs in psychiatry is a mandatory part of the curriculum. In the training, the SP plays the role of four different patients suffering from depression/suicidal tendencies, somatoform disorder, anxiety disorder, or borderline disorder while the student attempts to gather the patient's medical history. Both the instructor and SP then give the student constructive feedback afterwards. METHOD: The aim of the study was to evaluate the quality of the SP's roleplay and feedback, using a self-created questionnaire. Additionally, we wanted to gauge the differences between the students' and teachers' evaluations of the SP's role playing performance and feedback. RESULTS: The questionnaire was completed by 529 students and 29 teachers who attended the training. Overall, both students and teachers evaluated the SPs' performance and feedback very well. In comparison to the responses given by the teachers, more students reported that the "SP overacted" while fewer students believed that the "SP could be a real patient". The feedback given by the SP was evaluated similarly by students and teachers, suggesting that students are able to recognize the quality of constructive feedback. Furthermore, the SP's quality of roleplaying was evaluated as the poorest while playing the psychiatric disorder "depression/suicidal tendencies." CONCLUSIONS: Our study showed that students and teachers appreciate SPs' competence of role play and of giving feedback. However, further studies should be performed to figure out why both students and teachers alike evaluated the played psychiatric disorder "depression/suicidal tendencies" to be the worst. PMID- 29625571 TI - Language-concordant automated telephone queries to assess medication adherence in a diverse population: a cross-sectional analysis of convergent validity with pharmacy claims. AB - BACKGROUND: Clinicians have difficulty accurately assessing medication non adherence within chronic disease care settings. Health information technology (HIT) could offer novel tools to assess medication adherence in diverse populations outside of usual health care settings. In a multilingual urban safety net population, we examined the validity of assessing adherence using automated telephone self-management (ATSM) queries, when compared with non-adherence using continuous medication gap (CMG) on pharmacy claims. We hypothesized that patients reporting greater days of missed pills to ATSM queries would have higher rates of non-adherence as measured by CMG, and that ATSM adherence assessments would perform as well as structured interview assessments. METHODS: As part of an ATSM facilitated diabetes self-management program, low-income health plan members typed numeric responses to rotating weekly ATSM queries: "In the last 7 days, how many days did you MISS taking your ..." diabetes, blood pressure, or cholesterol pill. Research assistants asked similar questions in computer-assisted structured telephone interviews. We measured continuous medication gap (CMG) by claims over 12 preceding months. To evaluate convergent validity, we compared rates of optimal adherence (CMG <= 20%) across respondents reporting 0, 1, and >= 2 missed pill days on ATSM and on structured interview. RESULTS: Among 210 participants, 46% had limited health literacy, 57% spoke Cantonese, and 19% Spanish. ATSM respondents reported >=1 missed day for diabetes (33%), blood pressure (19%), and cholesterol (36%) pills. Interview respondents reported >=1 missed day for diabetes (28%), blood pressure (21%), and cholesterol (26%) pills. Optimal adherence rates by CMG were lower among ATSM respondents reporting more missed days for blood pressure (p = 0.02) and cholesterol (p < 0.01); by interview, differences were significant for cholesterol (p = 0.01). CONCLUSIONS: Language concordant ATSM demonstrated modest potential for assessing adherence. Studies should evaluate HIT assessments of medication beliefs and concerns in diverse populations. TRIAL REGISTRATION: NCT00683020 , registered May 21, 2008. PMID- 29625573 TI - Long term consistency and location specificity of equine gluteus medius muscle activity during locomotion on the treadmill. AB - BACKGROUND: The equine m. gluteus medius (GM) is the largest muscle of the horse, its main movement function is the extension of the hip joint. The objective of the present study was to measure equine GM activity in three adjacent locations on GM during walk and trot on a treadmill, in order to document potential differences. Fourteen Haflinger mares were measured using surface electromyography and kinematic markers to identify the motion cycles on three occasions over 16 weeks. The electrodes were placed on left and right gluteus medius muscle over the middle of its widest part and 5 cm lateral and medial of it. For data processing, electrical activity was normalised to its maximum value and timing was normalised to the motion cycle. A Gaussian distribution approach was used to determine up to 10 modes of focussed activity, and results were analysed separately for stance and swing phase of the ipsilateral hindlimb. RESULTS: Fair reliability was found for mean mode values (Cronbach's alpha = 0.66) and good reliability was found for mean mode locations (Cronbach's alpha = 0.71) over the three data collection days. The magnitude of muscle activity identified as mean mode value was much larger at trot than at walk, and mean mode value was significantly different between stance phases of walk and trot for all electrode positions (p < 0.01). The pattern of muscle activity identified as mean mode location was significantly different for walk and trot at all electrode positions, both during stance and swing phases (p < 0.001). This indicates the different timing pattern between the gaits. Results of the three electrode positions on the same muscle during each gait were not significantly different when comparing the same measurement. CONCLUSIONS: The middle of the equine GM does not show any indication of functional differentiation during walk and trot on a treadmill; this might be due to lack of segmentation as such, or due to lack of need for segmented use for these very basic main tasks of the muscle. The reliability of the sEMG measurements over several weeks was fair to good, an indication for the robustness of the methodology. PMID- 29625574 TI - Challenges of DHS and MIS to capture the entire pattern of malaria parasite risk and intervention effects in countries with different ecological zones: the case of Cameroon. AB - BACKGROUND: In 2011, the demographic and health survey (DHS) in Cameroon was combined with the multiple indicator cluster survey. Malaria parasitological data were collected, but the survey period did not overlap with the high malaria transmission season. A malaria indicator survey (MIS) was also conducted during the same year, within the malaria peak transmission season. This study compares estimates of the geographical distribution of malaria parasite risk and of the effects of interventions obtained from the DHS and MIS survey data. METHODS: Bayesian geostatistical models were applied on DHS and MIS data to obtain georeferenced estimates of the malaria parasite prevalence and to assess the effects of interventions. Climatic predictors were retrieved from satellite sources. Geostatistical variable selection was used to identify the most important climatic predictors and indicators of malaria interventions. RESULTS: The overall observed malaria parasite risk among children was 33 and 30% in the DHS and MIS data, respectively. Both datasets identified the Normalized Difference Vegetation Index and the altitude as important predictors of the geographical distribution of the disease. However, MIS selected additional climatic factors as important disease predictors. The magnitude of the estimated malaria parasite risk at national level was similar in both surveys. Nevertheless, DHS estimates lower risk in the North and Coastal areas. MIS did not find any important intervention effects, although DHS revealed that the proportion of population with an insecticide-treated nets access in their household was statistically important. An important negative relationship between malaria parasitaemia and socioeconomic factors, such as the level of mother's education, place of residence and the household welfare were captured by both surveys. CONCLUSION: Timing of the malaria survey influences estimates of the geographical distribution of disease risk, especially in settings with seasonal transmission. In countries with different ecological zones and thus different seasonal patterns, a single survey may not be able to identify all high risk areas. A continuous MIS or a combination of MIS, health information system data and data from sentinel sites may be able to capture the disease risk distribution in space across different seasons. PMID- 29625575 TI - Targeted genome engineering in human induced pluripotent stem cells from patients with hemophilia B using the CRISPR-Cas9 system. AB - BACKGROUND: Replacement therapy for hemophilia remains a lifelong treatment. Only gene therapy can cure hemophilia at a fundamental level. The clustered regularly interspaced short palindromic repeats-CRISPR associated nuclease 9 (CRISPR-Cas9) system is a versatile and convenient genome editing tool which can be applied to gene therapy for hemophilia. METHODS: A patient's induced pluripotent stem cells (iPSCs) were generated from their peripheral blood mononuclear cells (PBMNCs) using episomal vectors. The AAVS1-Cas9-sgRNA plasmid which targets the AAVS1 locus and the AAVS1-EF1alpha-F9 cDNA-puromycin donor plasmid were constructed, and they were electroporated into the iPSCs. When insertion of F9 cDNA into the AAVS1 locus was confirmed, whole genome sequencing (WGS) was carried out to detect the off-target issue. The iPSCs were then differentiated into hepatocytes, and human factor IX (hFIX) antigen and activity were measured in the culture supernatant. Finally, the hepatocytes were transplanted into non-obese diabetic/severe combined immunodeficiency disease (NOD/SCID) mice through splenic injection. RESULTS: The patient's iPSCs were generated from PBMNCs. Human full length F9 cDNA was inserted into the AAVS1 locus of iPSCs of a hemophilia B patient using the CRISPR-Cas9 system. No off-target mutations were detected by WGS. The hepatocytes differentiated from the inserted iPSCs could secrete hFIX stably and had the ability to be transplanted into the NOD/SCID mice in the short term. CONCLUSIONS: PBMNCs are good somatic cell choices for generating iPSCs from hemophilia patients. The iPSC technique is a good tool for genetic therapy for human hereditary diseases. CRISPR-Cas9 is versatile, convenient, and safe to be used in iPSCs with low off-target effects. Our research offers new approaches for clinical gene therapy for hemophilia. PMID- 29625576 TI - Skeletal, cardiac, and respiratory muscle function and histopathology in the P448Lneo- mouse model of FKRP-deficient muscular dystrophy. AB - BACKGROUND: Fukutin-related protein (FKRP) mutations are the most common cause of dystroglycanopathies known to cause both limb girdle and congenital muscular dystrophy. The P448Lneo- mouse model has a knock-in mutation in the FKRP gene and develops skeletal, respiratory, and cardiac muscle disease. METHODS: We studied the natural history of the P448Lneo- mouse model over 9 months and the effects of twice weekly treadmill running. Forelimb and hindlimb grip strength (Columbus Instruments) and overall activity (Omnitech Electronics) assessed skeletal muscle function. Echocardiography was performed using VisualSonics Vevo 770 (FujiFilm VisualSonics). Plethysmography was performed using whole body system (ADInstruments). Histological evaluations included quantification of inflammation, fibrosis, central nucleation, and fiber size variation. RESULTS: P448Lneo- mice had significantly increased normalized tissue weights compared to controls at 9 months of age for the heart, gastrocnemius, soleus, tibialis anterior, quadriceps, and triceps. There were no significant differences seen in forelimb or hindlimb grip strength or activity monitoring in P448Lneo- mice with or without exercise compared to controls. Skeletal muscles demonstrated increased inflammation, fibrosis, central nucleation, and variation in fiber size compared to controls (p < 0.05) and worsened with exercise. Plethysmography showed significant differences in respiratory rates and decreased tidal and minute volumes in P448Lneo- mice (p < 0.01). There was increased fibrosis in the diaphragm compared to controls (p < 0.01). Echocardiography demonstrated decreased systolic function in 9-month-old mutant mice (p < 0.01). There was increased myocardial wall thickness and mass (p < 0.001) with increased fibrosis in 9-month-old P448Lneo- mice compared to controls (p < 0.05). mRNA expression for natriuretic peptide type A (Nppa) was significantly increased in P448Lneo- mice compared to controls at 6 months (p < 0.05) and for natriuretic peptide type B (Nppb) at 6 and 9 months of age (p < 0.05). CONCLUSIONS: FKRP-deficient P448Lneo- mice demonstrate significant deficits in cardiac and respiratory functions compared to control mice, and this is associated with increased inflammation and fibrosis. This study provides new functional outcome measures for preclinical trials of FKRP-related muscular dystrophies. PMID- 29625577 TI - Gene therapy in rare diseases: the benefits and challenges of developing a patient-centric registry for Strimvelis in ADA-SCID. AB - BACKGROUND: Strimvelis (autologous CD34+ cells transduced to express adenosine deaminase [ADA]) is the first ex vivo stem cell gene therapy approved by the European Medicines Agency (EMA), indicated as a single treatment for patients with ADA-severe combined immunodeficiency (ADA-SCID) who lack a suitable matched related bone marrow donor. Existing primary immunodeficiency registries are tailored to transplantation outcomes and do not capture the breadth of safety and efficacy endpoints required by the EMA for the long-term monitoring of gene therapies. Furthermore, for extended monitoring of Strimvelis, the young age of children treated, small patient numbers, and broad geographic distribution of patients all increase the risk of loss to follow-up before sufficient data have been collected. Establishing individual investigator sites would be impractical and uneconomical owing to the small number of patients from each location receiving Strimvelis. RESULTS: An observational registry has been established to monitor the safety and effectiveness of Strimvelis in up to 50 patients over a minimum of 15 years. To address the potential challenges highlighted above, data will be collected by a single investigator site at Ospedale San Raffaele (OSR), Milan, Italy, and entered into the registry via a central electronic platform. Patients/families and the patient's local physician will also be able to submit healthcare information directly to the registry using a uniquely designed electronic platform. Data entry will be monitored by a Gene Therapy Registry Centre (funded by GlaxoSmithKline) who will ensure that necessary information is collected and flows between OSR, the patient/family and the patient's local healthcare provider. CONCLUSION: The Strimvelis registry sets a precedent for the safety monitoring of future gene therapies. A unique, patient-focused design has been implemented to address the challenges of long-term follow-up of patients treated with gene therapy for a rare disease. Strategies to ensure data completeness and patient retention in the registry will help fulfil pharmacovigilance requirements. Collaboration with partners is being sought to expand from a treatment registry into a disease registry. Using practical and cost-efficient approaches, the Strimvelis registry is hoped to encourage further innovation in registry design within orphan drug development. PMID- 29625578 TI - Congenital hypopituitarism: how to select the patients for genetic analyses. PMID- 29625579 TI - Is treatment outcome improved if patients match themselves to treatment options? Study protocol for a randomized controlled trial. AB - BACKGROUND: Research on matching patients to treatment has shown that matching grounded in expert views is little better than allocating patients by chance. Furthermore, there is growing emphasis on involving patients in their own treatment as a key to health behavior change. Research on the benefit of having patients choose their treatment from among options, in contrast to being assigned to a treatment by experts, has been limited. Consequently, we designed a rigorous test of patient self-matching to determine whether it does improve retention, adherence, and outcome in alcoholism treatment. METHODS/DESIGN: The present study is being conducted as a randomized controlled trial. Four hundred consecutive patients aged 18 years or older will be enrolled and randomized to either self matching or expert-matching to one of five different treatment approaches. All patients entering the alcohol outpatient clinic in Odense are offered the opportunity to participate in the study. Exclusion criteria are cognitive dysfunction as measured with the Mini Mental State Examination, and non-Danish- or non-English-speaking individuals. The following instruments will be administered at intake to provide standardized measures of alcohol problems: the Addiction Severity Index, Timeline Followback, the World Health Organization quality of life questionnaire, the NEO Five-Factor Inventory 3, and the Personal Happiness Form. For each outcome measure, two analyses will be conducted. Intention-to-treat analyses (ITT) will be carried out with all patients, regardless of whether they complete the interventions or are reinterviewed. Regarding incomplete data, multiple imputations will be used together with ITT analysis. Completer analyses will also be carried out with patients who complete their respective interventions. The primary outcome is decrease in number of monthly excessive drinking days 6 months after initiation of treatment. Secondary outcomes are compliance and 2 quality of life. The influence of personality traits on outcome will also be examined in both groups. DISCUSSION: The debate on matching patients to treatment has been going on for decades. This study will cast light on this issue by focusing on patients' choice and thereby clarifying if patients' perceived autonomy yields better outcomes. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03278821 . Registered on 12 September 2017. PMID- 29625580 TI - Expression levels of long non-coding RNAs are prognostic for AML outcome. AB - BACKGROUND: Long non-coding RNA (lncRNA) expression has been implicated in a range of molecular mechanisms that are central in cancer. However, lncRNA expression has not yet been comprehensively characterized in acute myeloid leukemia (AML). Here, we assess to what extent lncRNA expression is prognostic of AML patient overall survival (OS) and determine if there are indications of lncRNA-based molecular subtypes of AML. METHODS: We performed RNA sequencing of 274 intensively treated AML patients in a Swedish cohort and quantified lncRNA expression. Univariate and multivariate time-to-event analysis was applied to determine association between individual lncRNAs with OS. Unsupervised statistical learning was applied to ascertain if lncRNA-based molecular subtypes exist and are prognostic. RESULTS: Thirty-three individual lncRNAs were found to be associated with OS (adjusted p value < 0.05). We established four distinct molecular subtypes based on lncRNA expression using a consensus clustering approach. LncRNA-based subtypes were found to stratify patients into groups with prognostic information (p value < 0.05). Subsequently, lncRNA expression-based subtypes were validated in an independent patient cohort (TCGA-AML). LncRNA subtypes could not be directly explained by any of the recurrent cytogenetic or mutational aberrations, although associations with some of the established genetic and clinical factors were found, including mutations in NPM1, TP53, and FLT3. CONCLUSION: LncRNA expression-based four subtypes, discovered in this study, are reproducible and can effectively stratify AML patients. LncRNA expression profiling can provide valuable information for improved risk stratification of AML patients. PMID- 29625581 TI - Evaluation of the effects of ascorbic acid on metabolism of human mesenchymal stem cells. AB - BACKGROUND: Mesenchymal stem cells (MSCs) are multipotent cells holding much promise for applications in regenerative medicine. However, with problems such as aging, increases in heteroploid cells, genomic instability, and reduced maintenance of stemness, more stable culturing methods and the production of MSCs with an improved therapeutic effect are desired. Ascorbic acid (AsA), which is a cofactor for a variety of enzymes and has an antioxidant effect, cannot be synthesized by certain animals, including humans. Nevertheless, little attention has been paid to AsA when culturing MSCs. METHODS: We analyzed the effect of adding AsA to the culture medium on the proliferation and metabolism of human MSCs by serial analysis of gene expression and metabolome analysis. RESULTS: We found that AsA promotes MSC proliferation, and is particularly useful when expanding MSCs isolated from bone marrow. Serial analysis of gene expression and metabolome analysis suggested that, due to HIF1alpha accumulation caused by decreased activity of the enzymes that use AsA as a coenzyme in cultures without AsA, genes downstream of HIF1alpha are expressed and there is a conversion to a hypoxia-mimetic metabolism. AsA promotes HIF1alpha breakdown and activates mitochondria, affecting cell proliferation and metabolism. Comprehensive evaluation of the effects of AsA on various metabolic products in MSCs revealed that AsA increases HIF1alpha hydroxylase activity, suppressing HIF1a transcription and leading to mitochondrial activation. CONCLUSIONS: Adding AsA during MSC expansion leads to more efficient preparation of cells. These are expected to be important findings for the future application of MSCs in regenerative medicine. PMID- 29625582 TI - TSG-6 released from intraperitoneally injected canine adipose tissue-derived mesenchymal stem cells ameliorate inflammatory bowel disease by inducing M2 macrophage switch in mice. AB - BACKGROUND: Inflammatory bowel disease (IBD) is an intractable autoimmune disorder that markedly deteriorates one's quality of life. Mesenchymal stem cells (MSCs) alleviate inflammation by modulating inflammatory cytokines in inflamed tissues, and have been suggested as a promising alternative for IBD treatment in human and veterinary cases. Furthermore, tumor necrosis factor-alpha-induced gene/protein 6 (TSG-6) is a key factor influencing MSC immunomodulatory properties; however, the precise mechanism of TSG-6 release from canine MSCs in IBD remains unclear. This study aimed to assess the therapeutic effects of canine adipose tissue-derived (cAT)-MSC-produced TSG-6 in an IBD mouse model and to explore the mechanisms underlying the immunomodulatory properties. METHODS: Mice with dextran sulfate sodium-induced colitis were administered cAT-MSCs intraperitoneally; colon tissues were collected on day 10 for histopathological, quantitative real-time polymerase chain reaction, and immunofluorescence analyses. RESULTS: cAT-MSC-secreted TSG-6 ameliorated IBD and regulated colonic expression of pro- and anti-inflammatory cytokines such as tumor necrosis factor alpha, interleukin-6, and interleukin-10. To investigate the effect of cAT-MSC secreted TSG-6 on activated macrophages in vitro, a transwell coculture system was used; TSG-6 released by cAT-MSCs induced a macrophage phenotypic switch from M1 to M2. The cAT-MSC-secreted TSG-6 increased M2 macrophages in the inflamed colon in vivo. CONCLUSIONS: TSG-6 released from cAT-MSCs can alleviate dextran sulfate sodium-induced colitis by inducing a macrophage phenotypic switch to M2 in mice. PMID- 29625584 TI - Temporomandibular joint regeneration: proposal of a novel treatment for condylar resorption after orthognathic surgery using transplantation of autologous nasal septum chondrocytes, and the first human case report. AB - BACKGROUND: Upon orthognathic mandibular advancement surgery the adjacent soft tissues can displace the distal bone segment and increase the load on the temporomandibular joint causing loss of its integrity. Remodeling of the condyle and temporal fossa with destruction of condylar cartilage and subchondral bone leads to postsurgical condylar resorption, with arthralgia and functional limitations. Patients with severe lesions are refractory to conservative treatments, leading to more invasive therapies that range from simple arthrocentesis to open surgery and prosthesis. Although aggressive and with a high risk for the patient, surgical invasive treatments are not always efficient in managing the degenerative lesions. METHODS: We propose a regenerative medicine approach using in-vitro expanded autologous cells from nasal septum applied to the first proof-of-concept patient. After the required quality controls, the cells were injected into each joint by arthrocentesis. Results were monitored by functional assays and image analysis using computed tomography. RESULTS: The cell injection fully reverted the condylar resorption, leading to functional and structural regeneration after 6 months. Computed tomography images showed new cortical bone formation filling the former cavity space, and a partial recovery of condylar and temporal bones. The superposition of the condyle models showed the regeneration of the bone defect, reconstructing the condyle original form. CONCLUSIONS: We propose a new treatment of condylar resorption subsequent to orthognathic surgery, presently treated only by alloplastic total joint replacement. We propose an intra-articular injection of autologous in-vitro expanded cells from the nasal septum. The proof-of-concept treatment of a selected patient that had no alternative therapeutic proposal has given promising results, reaching full regeneration of both the condylar cartilage and bone at 6 months after the therapy, which was fully maintained after 1 year. This first case is being followed by inclusion of new patients with a similar pathological profile to complete an ongoing stage I/II study. TRIAL REGISTRATION: This clinical trial is approved by the National Commission of Ethics in Medical Research (CONEP), Brazil, CAAE 12484813.0.0000.5245, and retrospectively registered in the Brazilian National Clinical Trials Registry and in the USA Clinical Trials Registry under the Universal Trial Number (UTN) U1111-1194-6997 . PMID- 29625585 TI - Insecticide resistance status of the malaria mosquitoes: Anopheles gambiae and Anopheles funestus in eastern and northern Uganda. AB - BACKGROUND: Uganda's malaria burden includes the sixth highest number of annual deaths in Africa (10,500) with approximately 16 million cases (2013) and the entire population at risk. The President's Malaria Initiative has been supporting the malaria control interventions of indoor residual spraying (IRS) and distribution of long-lasting insecticidal nets (LLIN) in Uganda since 2007. These interventions are threatened by emerging and spreading insecticide resistance, known to exist in Ugandan malaria vectors. Pyrethroid insecticides have been used in agriculture since the early 1990s and in IRS programmes from the mid-2000s until 2010. A universal LLIN coverage campaign was executed in 2013-2014, distributing pyrethroid-treated LLINs throughout the country. This study investigated insecticide susceptibility, intensity, and oxidase detoxification in Anopheles gambiae sensu lato and Anopheles funestus to permethrin and deltamethrin in four eastern Ugandan sites. METHODS: The susceptibility status of An. gambiae and An. funestus to bendiocarb, permethrin and deltamethrin was determined using the CDC (Centers for Disease Control and Prevention) bottle bioassay. Presence of oxidative enzyme detoxification mechanisms were determined by pre-exposing mosquitoes to piperonyl butoxide followed with exposure to discriminating doses of deltamethrin- and permethrin-coated CDC bottles. Resistance intensity was investigated using serial dosages of 1*, 2*, 5* and 10* the diagnostic dose and scored at 30 min to determine the magnitude of resistance to both of these LLIN pyrethroids. Testing occurred in the Northern and Eastern Regions of Uganda. RESULTS: Anopheles gambiae and An. funestus were fully susceptible to bendiocarb where tested. Anopheles gambiae resistance to deltamethrin and permethrin was observed in all four study sites. Anopheles funestus was resistant to deltamethrin and permethrin in Soroti. Oxidative resistance mechanisms were found in An. gambiae conferring pyrethroid resistance in Lira and Apac. 14.3% of An. gambiae from Tororo survived exposure of 10* concentrations of permethrin. CONCLUSIONS: Both An. gambiae and An. funestus are resistant to pyrethroids but fully susceptible to bendiocarb at all sites. Susceptibility monitoring guided the Ministry of Health's decision to rotate between IRS insecticide classes. Intensity bioassay results may indicate encroaching control failure of pyrethroid-treated LLINs and should inform decision-makers when choosing LLINs for the country. PMID- 29625583 TI - Structural and mechanistic aspects influencing the ADAM10-mediated shedding of the prion protein. AB - Background: Proteolytic processing of the prion protein (PrPC) by endogenous proteases generates bioactive membrane-bound and soluble fragments which may help to explain the pleiotropic roles of this protein in the nervous system and in brain diseases. Shedding of almost full-length PrPC into the extracellular space by the metalloprotease ADAM10 is of peculiar relevance since soluble PrP stimulates axonal outgrowth and is protective in neurodegenerative conditions such as Alzheimer's and prion disease. However, molecular determinates and mechanisms regulating the shedding of PrP are entirely unknown. Methods: We produced an antibody recognizing the neo-epitope of shed PrP generated by ADAM10 in biological samples and used it to study structural and mechanistic aspects affecting the shedding. For this, we investigated genetically modified cellular and murine models by biochemical and morphological approaches. Results: We show that the novel antibody specifically detects shed PrP in cell culture supernatants and murine brain. We demonstrate that ADAM10 is the exclusive sheddase of PrPC in the nervous system and reveal that the glycosylation state and type of membrane-anchorage of PrPC severely affect its shedding. Furthermore, we provide evidence that PrP shedding can be modulated by pharmacological inhibition and stimulation and present data suggesting that shedding is a relevant part of a compensatory network ensuring PrPC homeostasis of the cell. Conclusions: With the new antibody, our study introduces a new tool to reliably investigate PrP-shedding. In addition, this study provides novel and important insight into the regulation of this cleavage event, which is likely to be relevant for diagnostic and therapeutic approaches even beyond neurodegeneration. PMID- 29625586 TI - A 17-year trend analysis of malaria at Adi Arkay, north Gondar zone, Northwest Ethiopia. AB - BACKGROUND: Malaria is one of the leading causes of death worldwide. This study aimed to determine the trend of malaria among febrile patients seeking treatment over 17 year (1997-2013) at Adi Arkay, Northwest Ethiopia. METHODS: A 17-year malaria microscopy data were extracted retrospectively at Adi Arkay health centre. Time series and curve estimation analysis were used to evaluate trends in the data. Pearson's Chi square test was also used to describe associations of variables. RESULTS: Over 17 years, 20,483 blood films were requested for malaria diagnosis at the health centre. Out of this, 7428 (36.1%) were microscopically confirmed malaria cases. Plasmodium falciparum, Plasmodium vivax, and their mixed infection accounted for 68.85, 28.79, and 2.34% of all malaria cases, respectively. There was a remarkable reduction of overall malaria during the 17 years. Malaria was reported in all age groups of both sexes, but its positivity rate was significantly higher in males and in the 15-24 years than their counterparts. CONCLUSION: In relative terms, the overall positivity rate of malaria in the area over 17 years showed a significant reduction, but its magnitude as a public health problem is still alarming. Plasmodium falciparum played a significant role in the remarkable drop of overall malaria in the area, whereas vivax malaria remained unchanged. Therefore, control measures should continue to strengthen targeting both predominant malaria parasites in the area. PMID- 29625587 TI - The Norwegian National Summary Care Record: a qualitative analysis of doctors' use of and trust in shared patient information. AB - BACKGROUND: This paper explores Norwegian doctors' use of and experiences with a national tool for sharing core patient health information. The summary care record (SCR; the Kjernejournal in Norwegian) is the first national system for sharing patient information among the various levels and institutions of health care throughout the country. The health authorities have invested heavily in the development, implementation and deployment of this tool, and as of 2017 all Norwegian citizens have a personalised SCR. However, as there remains limited knowledge about health professionals' use of, experiences with and opinions regarding this new tool, the purpose of this study was to explore doctors' direct SCR experiences. METHODS: We conducted 25 in-depth interviews with 10 doctors from an emergency ward, 5 doctors from an emergency clinic and 10 doctors from 5 general practitioner offices. We then transcribed, thematically coded and analysed the interviews utilising a grounded theory approach. RESULTS: The SCRs contain several features for providing core patient information that is particularly relevant in acute or emergency situations; nonetheless, we found that the doctors generally used only one of the tool's six functions, namely, the pharmaceutical summary. In addition, they primarily used this summary for a few subgroups of patients, including in the emergency ward for unconscious patients, for elderly patients with multiple prescriptions and for patients with substance abuse conditions. The primary difference of the pharmaceutical summary compared with the other functions of the tool is that patient information is automatically updated from a national pharmaceutical server, while other clinically relevant functions, like the critical information category, require manual updates by the health professionals themselves, thereby potentially causing variations in the accuracy, completeness and trustworthiness of the data. CONCLUSION: Therefore, we can assume that the popularity of the pharmaceutical summary among doctors is based on their preference to place their trust in - and therefore more often utilise - automatically updated information. In addition, the doctors' lack of trust in manually updated information might have severe implications for the future success of the SCR and for similar digital tools for sharing patient information. PMID- 29625588 TI - Rapid detection of three rabbit pathogens by use of the Luminex x-TAG assay. AB - BACKGROUND: Domestic rabbits especially New Zealand white rabbits play an important role in biological research. The disease surveillance and quality control are essential to guarantee the results of animal experiments performed on rabbits. Rabbit hemorrhagic disease virus, rabbit rotavirus and Sendai virus are the important pathogens that needed to be eliminated. Rapid and sensitive method focus on these three viruses should be established for routine monitoring. The Luminex x-TAG assay based on multiplex PCR and fluorescent microsphere is a fast developing technology applied in high throughput detection. Specific primers modified with oligonucleotide sequence/biotin were used to amplify target fragments. The conjugation between oligonucleotide sequence of the PCR products and the MagPlex-TAG microspheres was specific without any cross-reaction, and the hybridization products could be analyzed using the Luminex 200 analyzer instrument. Recombinant plasmids were constructed to estimate the detection limit of the viruses. Furthermore, 40 clinical samples were used to evaluate the efficiency of this multiplex PCR based Luminex x-TAG assay. RESULTS: According to the results, this new method showed high specificity and good stability. Assessed by the recombinant plasmids, the detection limit of three viruses was 100copies/MUl. Among 40 clinical specimens, 18 specimens were found positive, which was completely concordant with the conventional PCR method. CONCLUSIONS: The new developed Luminex x-TAG assay is an accurate, high throughput method for rapid detection of three important viruses of rabbits. PMID- 29625589 TI - Intramuscular transplantation of bone marrow cells prolongs the lifespan of SOD1G93A mice and modulates expression of prognosis biomarkers of the disease. AB - BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by progressive muscle weakness, paralysis and death. There is no effective treatment for ALS and stem cell therapy has arisen as a potential therapeutic approach. METHODS: SOD1 mutant mice were used to study the potential neurotrophic effect of bone marrow cells grafted into quadriceps femoris muscle. RESULTS: Bone marrow intramuscular transplants resulted in increased longevity with improved motor function and decreased motoneuron degeneration in the spinal cord. Moreover, the increment of the glial-derived neurotrophic factor and neurotrophin 4 observed in the grafted muscles suggests that this partial neuroprotective effect is mediated by neurotrophic factor release at the neuromuscular junction level. Finally, certain neurodegeneration and muscle disease-specific markers, which are altered in the SOD1G93A mutant mouse and may serve as molecular biomarkers for the early detection of ALS in patients, have been studied with encouraging results. CONCLUSIONS: This work demonstrates that stem cell transplantation in the muscle prolonged the lifespan, increased motoneuron survival and slowed disease progression, which was also assessed by genetic expression analysis. PMID- 29625591 TI - Neurodevelopmental assessment of HIV-exposed uninfected and early-treated HIV infected children: study protocol. AB - OBJECTIVE: Sub-Saharan Africa has the highest prevalence of children at risk of not achieving their developmental potential, attributable largely to the human immunodeficiency virus (HIV) pandemic coupled with negative environmental factors. Childhood developmental stimulation programmes can mitigate adverse outcomes. METHODS: Neonates testing HIV positive at birth will be initiated on antiretroviral treatment (ART) and receive an age-appropriate stimulation program, updated at 3 monthly intervals through the first year of life. Neurodevelopment at 12 months of age will be assessed using the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III). Outcomes will be compared with HIV-infected and HIV-exposed uninfected children (HEU) not having received the stimulatory intervention. Associations between neurodevelopmental outcomes, environmental factors, and parental stress will be investigated. The study will take place at a single site in Johannesburg, South Africa. This non randomised controlled intervention study, with a single non-blinded comparative intervention group, aims to investigate whether an early childhood stimulation programme used in conjunction with ART initiated at birth can positively impact neurodevelopmental outcomes at 1 year of age in children infected with HIV. Trial registration 15 January 2018, Pan African Clinical Trial Registry PACTR201801002967587. PMID- 29625590 TI - Guideline on management of the acute asthma attack in children by Italian Society of Pediatrics. AB - BACKGROUND: Acute asthma attack is a frequent condition in children. It is one of the most common reasons for emergency department (ED) visit and hospitalization. Appropriate care is fundamental, considering both the high prevalence of asthma in children, and its life-threatening risks. Italian Society of Pediatrics recently issued a guideline on the management of acute asthma attack in children over age 2, in ambulatory and emergency department settings. METHODS: The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology was adopted. A literature search was performed using the Cochrane Library and Medline/PubMed databases, retrieving studies in English or Italian and including children over age 2 year. RESULTS: Inhaled beta2 agonists are the first line drugs for acute asthma attack in children. Ipratropium bromide should be added in moderate/severe attacks. Early use of systemic steroids is associated with reduced risk of ED visits and hospitalization. High doses of inhaled steroids should not replace systemic steroids. Aminophylline use should be avoided in mild/moderate attacks. Weak evidence supports its use in life-threatening attacks. Epinephrine should not be used in the treatment of acute asthma for its lower cost / benefit ratio, compared to beta2 agonists. Intravenous magnesium solphate could be used in children with severe attacks and/or forced expiratory volume1 (FEV1) lower than 60% predicted, unresponsive to initial inhaled therapy. Heliox could be administered in life-threatening attacks. Leukotriene receptor antagonists are not recommended. CONCLUSIONS: This Guideline is expected to be a useful resource in managing acute asthma attacks in children over age 2. PMID- 29625592 TI - Orphan receptor GPR37L1 contributes to the sexual dimorphism of central cardiovascular control. AB - BACKGROUND: Over 100 mammalian G protein-coupled receptors are yet to be matched with endogenous ligands; these so-called orphans are prospective drug targets for the treatment of disease. GPR37L1 is one such orphan, abundant in the brain and detectable as mRNA in the heart and kidney. GPR37L1 ablation was reported to cause hypertension and left ventricular hypertrophy, and thus, we sought to further define the role of GPR37L1 in blood pressure homeostasis. METHODS: We investigated the cardiovascular effects of GPR37L1 using wild-type (GPR37L1wt/wt) and null (GPR37L1KO/KO) mice established on a C57BL/6J background, both under baseline conditions and during AngII infusion. We profiled GPR37L1 tissue expression, examining the endogenous receptor by immunoblotting and a beta galactosidase reporter mouse by immunohistochemistry. RESULTS: GPR37L1 protein was abundant in the brain but not detectable in the heart and kidney. We measured blood pressure in GPR37L1wt/wt and GPR37L1KO/KO mice and found that deletion of GPR37L1 causes a female-specific increase in systolic, diastolic, and mean arterial pressures. When challenged with short-term AngII infusion, only male GPR37L1KO/KO mice developed exacerbated left ventricular hypertrophy and evidence of heart failure, while the female GPR37L1KO/KO mice were protected from cardiac fibrosis. CONCLUSIONS: Despite its absence in the heart and kidney, GPR37L1 regulates baseline blood pressure in female mice and is crucial for cardiovascular compensatory responses in males. The expression of GPR37L1 in the brain, yet absence from peripheral cardiovascular tissues, suggests this orphan receptor is a hitherto unknown contributor to central cardiovascular control. PMID- 29625593 TI - Radiotherapy-induced anti-tumor immune response and immune-related adverse events in a case of recurrent nasopharyngeal carcinoma undergoing anti-PD-1 immunotherapy. AB - BACKGROUND: Treatment of recurrent nasopharyngeal carcinoma is a challenging clinical problem. We report the case of a 46 year old male showing excellent response and signs of immunostimulation following re-re-irradiation for recurrent nasopharyngeal carcinoma under systemic treatment with pembrolizumab. CASE PRESENTATION: Patient was first diagnosed with locoregionally advanced, non keratinizing nasopharyngeal carcinoma in 2010. After achieving complete remission following induction chemotherapy and concurrent curative chemoradiation, the patient subsequently developed distant and locoregionally recurrent disease. He received various treatments (neck dissection, radiotherapy to a bony metastasis, palliative chemotherapy, stereotactic re-irradiation of local recurrence) before initiation of anti- PD-1 immunotherapy with pembrolizumab in January of 2016. Following marked local progression 6 months thereafter, we performed re-re irradiation of the recurrent tumor after careful evaluation and treatment planning. While treatment was well tolerated, the patient subsequently developed marked clinical and radiological signs of immunostimulation with mucosal irritation and swelling of lacrimal and salivary glands as described in the report. Immunotherapy with pembrolizumab was reinitiated, with re- staging showing excellent response with regression of all tumorous lesions. At the time of this report, following near complete recovery of inflammatory symptoms, the patient remains in excellent condition and free from recurrence under treatment with pembrolizumab. CONCLUSIONS: To our knowledge, we report the first observation of a combined effect of immunotherapy and radiotherapy in a patient with recurrent nasopharyngeal carcinoma. Demonstrating distinct signs of immunostimulation as well as excellent tumor response in a heavily pretreated patient progressing under anti-PD-1 immunotherapy, the case adds to the rising paradigm of an immunostimulatory effect of radiotherapy in patients undergoing treatment with immune checkpoint inhibitors. PMID- 29625594 TI - The first case of SMARCB1 (INI1) - deficient squamous cell carcinoma of the pleura: a case report. AB - BACKGROUND: SMARCB1 (INI1) is a tumor-suppressor gene located at 22q11.2. Loss of SMARCB1 protein expression has been reported to be associated with atypical teratoid/rhabdoid tumors and malignant rhabdoid tumors of the kidney and extrarenal tissues. To date, however, SMARCB1-deficient carcinoma of the pleura has not been reported. We report the first case of SMARCB1- deficient squamous cell carcinoma of the pleura. CASE PRESENTATION: The case was a 33-year-old female. She was diagnosed squamous cell carcinoma of the pleura by thoracoscopy. The tumor cells were completely negative for SMARCB1 protein expression by immunohistochemistry. She received six cycles of cisplatin plus gemcitabine therapy and TS-1 monotherapy, however, her disease progressed rapidly with worsening chest pain and dyspnea, and she died at 10 months after diagnosis. CONCLUSIONS: This is the first report of SMARCB1-deficient squamous cell carcinoma of pleura. The tumor was highly aggressive and carried a poor prognosis with short survival. The clinical features and treatments of this tumor are not clear, and additional cases will assist the establishment of treatments. PMID- 29625595 TI - Psychometric properties of the Arabic version of the confusion assessment method for the intensive care unit (CAM-ICU). AB - BACKGROUND: It is recommended that critically ill patients undergo routine delirium monitoring with a valid and reliable tool such as the Confusion Assessment Method for the Intensive Care Unit (CAM-ICU). However, the validity and reliability of the Arabic version of the CAM-ICU has not been investigated. Here, we test the validity and reliability of the Arabic CAM-ICU. METHODS: We conducted a psychometric study at ICUs in a tertiary-care hospital in Saudi Arabia. We recruited consecutive adult Arabic-speaking patients, who had stayed in the ICU for at least 24 hours, and had a Richmond Agitation-Sedation Scale (RASS) score >= - 2 at examination. Two well-trained examiners (ICU nurse and intensivist) independently assessed delirium in eligible patients with the Arabic CAM-ICU. Evaluations by the two examiners were compared with psychiatrist blind clinical assessment of delirium according to the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5). Subgroup analyses were conducted for age, invasive mechanical ventilation, and gender. RESULTS: We included 108 patients (mean age: 62.6 +/- 17.6; male: 51.9%), of whom 37% were on invasive mechanical ventilation. Delirium was diagnosed in 63% of enrolled patients as per the psychiatrist clinical assessment. The Arabic CAM-ICU sensitivity was 74% (95% confidence interval [CI] = 0.63-0.84) and 56% (95%CI = 0.44-0.68) for the ICU nurse and intensivist, respectively. Specificity was 98% (95%CI = 0.93-1.0) and 92% (95%CI = 0.84-1.0), respectively. Sensitivity was greater for mechanically-ventilated patients, women, and those aged >=65 years. Specificity was greater for those aged < 65 years, non-mechanically-ventilated patients and men. The median duration to complete the Arabic CAM-ICU was 2 min (interquartile range, 2-3) and 4.5 min (IQR, 3-5) for the ICU nurse and intensivist, respectively. Inter-rater reliability (kappa) was 0.66. CONCLUSIONS: The Arabic CAM-ICU demonstrated acceptable reliability and validity to assess delirium in Arabic-speaking ICU patients. PMID- 29625596 TI - Comparative bench study evaluation of different infant interfaces for non invasive ventilation. AB - BACKGROUND: To compare, in terms of patient-ventilator interaction and performance, a new nasal mask (Respireo, AirLiquide, FR) with the Endotracheal tube (ET) and a commonly used nasal mask (FPM, Fisher and Paykel, NZ) for delivering Pressure Support Ventilation (PSV) in an infant model of Acute Respiratory Failure (ARF). METHODS: An active test lung (ASL 5000) connected to an infant mannequin through 3 different interfaces (Respireo, ET and FPM), was ventilated with a standard ICU ventilator set in PSV. The test lung was set to simulate a 5.5 kg infant with ARF, breathing at 50 and 60 breaths/min). Non invasive ventilation (NIV) mode was not used and the leaks were nearly zero. RESULTS: The ET showed the shortest inspiratory trigger delay and pressurization time compared to FPM and Respireo (p < 0.01). At each respiratory rate tested, the FPM showed the shortest Expiratory trigger delay compared to ET and Respireo (p < 0.01). The Respireo presented a lower value of Inspiratory pressure-time product and trigger pressure drop than ET (p < 0.01), while no significant difference was found in terms of pressure-time product at 300 and 500 ms. During all tests, compared with the FPM, ET showed a significantly higher tidal volume (VT) delivered (p < 0.01), while Respireo showed a trend toward an increase of tidal volume delivered compared with FPM. CONCLUSIONS: The ET showed a better patient-ventilator interaction and performance compared to both the nasal masks. Despite the higher internal volume, Respireo showed a trend toward an increase of the delivered tidal volume; globally, its efficiency in terms of patient ventilator interaction was comparable to the FPM, which is the infant NIV mask characterized by the smaller internal volume among the (few) models on the market. PMID- 29625597 TI - How do we incorporate patient views into the design of healthcare services for older people: a discussion paper. AB - BACKGROUND: Across the European Union costs for the treatment of oral disease is expected to rise to ?93 Billion by 2020 and be higher than those for stroke and dementia combined. A significant proportion of these costs will relate to the provision of care for older people. Dental caries severity and experience is now a major public health issue in older people and periodontal disease disproportionately affects older adults. Poor oral health impacts on older people's quality of life, their self-esteem, general health and diet. Oral health care service provision for older people is often unavailable or poor, as is the standard of knowledge amongst formal and informal carers. The aim of this discussion paper is to explore some of the approaches that could be taken to improve the level of co-production in the design of healthcare services for older people. MAIN TEXT: People's emotional and practical response to challenges in health and well-being and the responsiveness of systems to their needs is crucial to improve the quality of service provision. This is a particularly important aspect of care for older people as felt, expressed and normative needs may be fundamentally different and vary as they become increasingly dependent. Co production shifts the design process away from the traditional 'top-down' medical model, where needs assessments are undertaken by someone external to a community and strategies are devised that encourage these communities to become passive recipients of services. Instead, an inductive paradigm of partnership working and shared leadership is actively encouraged to set priorities and ultimately helps improve the translational gap between research, health policy and health-service provision. DISCUSSION: The four methodological approaches discussed in this paper (Priority Setting Partnerships, Discrete Choice Experiments, Core Outcome Sets and Experience Based Co-Design) represent an approach that seeks to better engage with older people and ensure an inductive, co-produced process to the research and design of healthcare services of the future. These methods facilitate partnerships between researchers, healthcare professionals and patients to produce more responsive and appropriate public services for older people. PMID- 29625598 TI - Community readiness and momentum: identifying and including community-driven variables in a mixed-method rural palliative care service siting model. AB - BACKGROUND: Health service administrators make decisions regarding how to best use limited resources to have the most significant impact. Service siting models are tools that can help in this capacity. Here we build on our own mixed-method service siting model focused on identifying rural Canadian communities most in need of and ready for palliative care service enhancement through incorporating new community-driven insights. METHODS: We conducted 40 semi-structured interviews with formal and informal palliative care providers from four purposefully selected rural communities across Canada. Communities were selected by running our siting model, which incorporated GIS methods, and then identifying locations suitable as qualitative case studies. Participants were identified using multiple recruitment methods. Interviews were transcribed verbatim and the transcripts were reviewed to identify emerging themes and were coded accordingly. Thematic analysis then ensued. RESULTS: We previously introduced the inclusion of a 'community readiness' arm in the siting model. This arm is based on five community-driven indicators of palliative care service enhancement readiness and need. The findings from the current analysis underscore the importance of this arm of the model. However, the data also revealed the need to subjectively assess the presence or absence of community awareness and momentum indicators. The interviews point to factors such as educational tools, volunteers, and local acknowledgement of palliative care priorities as reflecting the presence of community awareness and factors such as new employment and volunteer positions, new care spaces, and new projects and programs as reflecting momentum. The diversity of factors found to illustrate these indicators between our pilot study and current national study demonstrate the need for those using our service siting model to look for contextually-relevant signs of their presence. CONCLUSION: Although the science behind siting model development is established, few researchers have developed such models in an open way (e.g., documenting every stage of model development, engaging with community members). This mixed method study has addressed this notable knowledge gap. While we have focused on rural palliative care in Canada, the process by which we have developed and refined our siting model is transferrable and can be applied to address other siting problems. PMID- 29625599 TI - A Healthy School Start Plus for prevention of childhood overweight and obesity in disadvantaged areas through parental support in the school setting - study protocol for a parallel group cluster randomised trial. AB - BACKGROUND: Systematic reviews conclude that interventions to prevent overweight and obesity in children obtain stronger effects when parents are involved. Parenting practices and parent-child interactions shape children's health-related behaviours. The Healthy School Start Plus intervention aims to promote healthy dietary habits and physical activity and prevent obesity in children through parental support in disadvantaged areas with increased health needs, delivered by teachers and school nurses. This protocol describes the design, outcome and process evaluation of the study. METHODS: Effectiveness of the intervention is compared to standard care within school health services. The 6-month programme, based on Social Cognitive Theory, consists of four components: 1) Health information to parents regarding the child; 2) Motivational Interviewing with the parents by the school nurse concerning the child; 3) classroom activities for the children by teachers; and 4) a web-based self-test of type-2 diabetes risk by parents. Effects will be studied in a cluster randomised trial including 17 schools and 352 six-year old children. The primary outcome is dietary intake of indicator foods, and secondary outcomes are physical activity, sedentary behaviour and BMI. Outcomes will be measured at baseline, at 6 months directly after the intervention, and at follow-up 18 months post baseline. Statistical analysis will be by mixed-effect regression analysis according to intention to treat and per protocol. Mediation analysis will be performed with parental self efficacy and parenting practices. Quantitative and qualitative methods will be used to study implementation in terms of dose, fidelity, feasibility and acceptability. The hypothesis is that the programme will be more effective than standard care and feasible to perform in the school context. DISCUSSION: The programme is in line with the cumulated evidence regarding the prevention of childhood obesity: That schools should be a focal point of prevention efforts, interventions should involve multiple components, and include the home environment. If effective, it will fill a knowledge gap concerning evidence-based health promotion practice within school health services to prevent obesity, and in the long term reduce social inequalities in health. TRIAL REGISTRATION: The trial was retrospectively registered on January 4, 2018 and available online at ClinicalTrials.gov : No. NCT03390725 . PMID- 29625600 TI - Implementing paediatric early warning scores systems in the Netherlands: future implications. AB - BACKGROUND: Paediatric Early Warning Scores (PEWS) are increasingly being used for early identification and management of clinical deterioration in paediatric patients. A PEWS system includes scores, cut-off points and appropriate early intervention. In 2011, The Dutch Ministry of Health advised hospitals to implement a PEWS system in order to improve patient safety in paediatric wards. The objective of this study was to examine the results of implementation of PEWS systems and to gain insight into the attitudes of professionals towards using a PEWS system in Dutch non-university hospitals. METHODS: Quantitative data were gathered at start, midway and at the end of the implementation period through retrospective patient record review (n = 554). Semi-structured interviews with professionals (n = 8) were used to gain insight in the implementation process and experiences. The interviews were transcribed and analysed using an inductive approach. RESULTS: Looking at PEWS systems of the five participating hospitals, different parameters and policies were found. While all hospitals included heart rate and respiratory rate, other variables differed among hospitals. At baseline, none of the hospitals used a PEWS system. After 1 year, PEWS were recorded in 69.2% of the patient records and elevated PEWS resulted in appropriate action in 49.1%. Three themes emerged from the interviews: 1) while the importance of using a PEWS system was acknowledged, professionals voiced some doubts about the effectiveness and validity of their PEWS system 2) registering PEWS required little extra effort and was facilitated by PEWS being integrated into the electronic patient record 3) Without a national PEWS system or guidelines, hospitals found it difficult to identify a suitable PEWS system for their setting. Existing systems were not always considered applicable in a non university setting. CONCLUSIONS: After 1 year, hospitals showed improvements in the use of their PEWS system, although some were decidedly more successful than others. Doubts among staff about validity, effectiveness and communication with other hospitals during transfer to higher level care hospital might hinder sustainable implementation. For these purposes the development of a national PEWS system is recommended, consisting of a "core set" of PEWS, cut-off points and associated early intervention. PMID- 29625601 TI - Connecting the dots between breast cancer, obesity and alcohol consumption in middle-aged women: ecological and case control studies. AB - BACKGROUND: Breast cancer (BC) incidence in Australian women aged 45 to 64 years ('middle-aged') has tripled in the past 50 years, along with increasing alcohol consumption and obesity in middle-age women. Alcohol and obesity have been individually associated with BC but little is known about how these factors might interact. Chronic psychological stress has been associated with, but not causally linked to, BC. Here, alcohol could represent the 'missing link' - reflecting self medication. Using an exploratory cross-sectional design, we investigated inter correlations of alcohol intake and overweight/obesity and their association with BC incidence in middle-aged women. We also explored the role of stress and various lifestyle factors in these relationships. METHODS: We analysed population data on BC incidence, alcohol consumption, overweight/obesity, and psychological stress. A case control study was conducted using an online survey. Cases (n = 80) were diagnosed with BC and controls (n = 235) were women in the same age range with no BC history. Participants reported lifestyle data (including alcohol consumption, weight history) over consecutive 10-year life periods. Data were analysed using a range of bivariate and multivariate techniques including correlation matrices, multivariate binomial regressions and multilevel logistic regression. RESULTS: Ecological inter-correlations were found between BC and alcohol consumption and between BC and obesity but not between other variables in the matrix. Strong pairwise correlations were found between stress and alcohol and between stress and obesity. BMI tended to be higher in cases relative to controls across reported life history. Alcohol consumption was not associated with case-control status. Few correlations were found between lifestyle factors and stress, although smoking and alcohol consumption were correlated in some periods. Obesity occurring during the ages of 31 to 40 years emerged as an independent predictor of BC (OR 3.5 95% CI: 1.3-9.4). CONCLUSIONS: This study provides ecological evidence correlating obesity and alcohol consumption with BC incidence. Case-control findings suggest lifetime BMI may be important with particular risk associated with obesity prior to 40 years of age. Stress was ecologically linked to alcohol and obesity but not to BC incidence and was differentially correlated with alcohol and smoking among cases and controls. Our findings support prevention efforts targeting weight in women below 40 years of age and, potentially, lifelong alcohol consumption to reduce BC risk in middle aged women. PMID- 29625602 TI - Aggressive primary treatments with favourable 5-year survival for screen-interval breast cancers. AB - BACKGROUND: To assess the impact of the participation in screening programme according to the mode of detection on the early diagnosis, treatment, and specific survival outcomes in women with breast cancer. METHODS: Women diagnosed with invasive breast cancer in Poitou-Charentes region (France) between 2008 and 2009 were classified into three groups, using data linkage of cancer registry, vital statistics and French organized screening programme: the screening programme (SP), interval cancer (IC), and non-screening programme detected cancer (NSP) groups. Specific survival rates were analysed using the Kaplan-Meier method and Cox proportional hazard models. RESULTS: Among 1613 patients, 65.7% (n = 1059) participated in a screening programme. The interval cancer rate was 17.1% (n = 181). Tumours in the IC group were diagnosed at a more advanced stage, i.e. with further regional lymph node metastasis or local spread, than those in the SP group (p < 0.001), but with significantly fewer metastases at diagnosis than in the NSP group (p < 0.001). ICs underwent more aggressive primary treatments than the two other groups, with 28% of radical mastectomy and 67% undergoing chemotherapy. The five-year survival rate for IC group were 92.0% (95% CI, 89.9 94.0%). CONCLUSIONS: Interval cancers had more aggressive features than screen detected cancers but were diagnosed at a less advanced stage compared to non screen detected cancers. Despite having cancers missed by the screening programme, women who participate in the screening process seem to benefit from early treatment. These results must be confirmed with long-term follow-up. PMID- 29625603 TI - Postural awareness and its relation to pain: validation of an innovative instrument measuring awareness of body posture in patients with chronic pain. AB - BACKGROUND: Habitual postural patterns are associated with musculoskeletal pain, and improving a maladaptive posture requires postural awareness in order to lead to clinical improvements. This study aimed to develop and evaluate the psychometric properties of an innovative postural awareness scale. METHODS: A 12 item Postural Awareness Scale (PAS) was developed and administered to 512 chronic pain patients (50.3 +/- 11.4 years, 91.6% female, 37.1% spinal/shoulder pain) to assess its factor structure and reliability. To determine convergent validity, measures of body awareness, body responsiveness, body image, and mindfulness were correlated with the PAS, as were clinical measures of pain intensity, disability, and mental health. Sensitivity to change was assessed in 202 outpatients participating in a 10-week multimodal mind-body program. RESULTS: Factor analysis revealed two factors (Ease/Familiarity with Postural Awareness and Need for Attention Regulation with Postural Awareness) that explained 50.8% of the variance. Cronbach's alpha for the complete scale was 0.80; Spearman-Brown coefficient of split-half reliability was 0.67; and intra-class correlation was ICC2,1 = 0.75 (95% confidence interval = 0.71, 0.78). Significant positive correlations were found for body awareness (r = 0.23), body responsiveness (r = 0.41), body image (r = 0.22-0.32), and mindfulness (r = 0.38); negative correlations for pain intensity (r = - 0.14), disability (r = - 0.12), depression (r = - 0.23), and stress (r = - 0.29). Postural awareness scores increased with a mind-body program (p < 0.001); changes in the PAS were negatively correlated with changes in pain intensity (r = - 0.35) in patients with spinal/shoulder pain. CONCLUSION: Self-reported postural awareness is associated with clinical symptoms in chronic pain patients; improvements in postural awareness are longitudinally associated with reduced pain in patients with spinal/shoulder pain. PMID- 29625604 TI - Apatinib for advanced sarcoma: results from multiple institutions' off-label use in China. AB - BACKGROUND: Anti-angiogenesis Tyrosine kinase inhibitors (TKIs) have been proved to show promising effects on prolonging progression-free survival (PFS) for advanced sarcoma after failure of standard multimodal Therapy. Methylsulfonic apatinib is one of those TKIs which specifically inhibits VEGFR-2. This paper summarizes the experience of three Peking University affiliated hospitals in off label use of apatinib in the treatment of extensively pre-treated sarcoma. METHODS: We retrospectively analysed files of patients with advanced sarcoma not amenable to curative treatment, who were receiving an apatinib-containing regimen between June 1, 2015 and December 1, 2016. Fifty-six patients were included: 22 osteosarcoma, 10 Ewing's sarcoma, 3 chondrosarcoma and 21 soft tissue sarcoma. RESULTS: With median follow-up time of 6 months (range, 0.7-18.0 m), thirty-five (62.5%) patients had partial response, and disease was stable in 11 (19.6%). The 4-month and 6-month progression-free survival rates were 46.3 and 36.5%, respectively. The median duration of response was 3.8 months (95% CI 1.9-5.6 m), with much variability among disease subtypes. The median overall survival was 9.9 months (95% CI 7.6-12.2 m). Grade 3 and 4 toxicities were observed in 8 (14.3%) patients, the most common being hypertension, pneumothorax, wound-healing problems, anorexia, and rash or desquamation. CONCLUSIONS: Apatinib might be effective, with a high objective response rate, in an off-label study of sarcoma patients with advanced, previously treated disease. The duration of response was consistent with reports in different subtypes of sarcomas. Prospective trials of apatinib in the treatment of selected subtypes of sarcomas are needed. TRIAL REGISTRATION: Retrospectively registered in the Medical Ethics Committee of Peking University People's Hospital, Peking University Shougang Hospital and Peking University International Hospital. The trial registration number is 2017PHB176-03 and the date of registration is January 20th 2017. PMID- 29625605 TI - What is the influence of tonsillectomy on the level of periodontal pathogens on the tongue dorsum and in periodontal pockets. AB - BACKGROUND: For periodontal treatment, the full mouth disinfection approach suggests disinfection of oral soft tissues, such as tongue and tonsils concomitant to scaling and root planning since patients might benefit from treatment of these oral niches either. Periodontopathogenes in tonsillar tissue support this hypothesis. This prospective controlled clinical study investigated the change in the oral flora of patients who underwent tonsillectomy. Pockets were tested for eleven bacterial species before and six weeks after the surgical intervention. METHODS: Fifty generally healthy adults were included in this study. The test group consisted of 25 patients with tonsillectomy. The control group included 25 patients with otorhinolarynologic surgery without involvement of the oral cavity. Clinical parameters such as probing pocket depth, bleeding-on probing index and plaque index were registered the evening before surgery. Also bacterial samples from the gingival sulcus and dorsum linguae were taken, and an additional sample from the removed tonsils in the test group. Six weeks after the intervention microbial samples of pockets and tongue were taken again. Data were tested for significant differences using Wilcoxon rank and Whitney-u-test. RESULTS: No relevant intra- or intergroup differences were found for the change of the eleven investigated species. CONCLUSION: Based on the results of the present study, tonsillectomy does not seem to have an immediate relevant effect on the bacterial flora of tongue or periodontium. This study design was approved by the ethical committee of Zurich (KEK-ZH-Nr.2013-0419). TRIAL REGISTRATION: The trial was retrospectively registered in the German Clinical Trials Register ( DRK00014077 ) on February 20, 2018. PMID- 29625606 TI - What is the impact of rerouting a cancer diagnosis from emergency presentation to GP referral on resource use and survival? Evidence from a population-based study. AB - BACKGROUND: Studies on alternative routes to diagnosis stimulated successful policy interventions reducing the number of emergency diagnoses and associated mortality risk. A dearth of evidence on the costs of such interventions might prevent new policies from achieving more ambitious targets. METHODS: We conducted a retrospective cohort study on the population of colorectal (88,051), breast (90,387), prostate (96,219), and lung (97,696) cancer patients diagnosed after a GP referral or an emergency presentation and reported in the Cancer Registry of England. Resource use and survival were compared 1 year before and 5 years after diagnosis (3 years for lung), including the costs of GP referrals not converted into a positive diagnosis. Risk-adjusted statistical models were used to calculate the effect of rerouting patient' diagnoses from emergency presentation to GP referral. RESULTS: Rerouting a cancer diagnosis results in a relatively small additional costs to the National Health System against additional years of life saved to the patient. The cost per year of life saved is L6456 in colorectal, L1057 in breast, -L662 in prostate (savings), and L819 in lung cancer. Reducing the overall prevalence of emergency presentations to the level achieved by the 20% of Clinical Commissioning Groups with the lowest prevalence would result in L11,481,948 against 1863 years of life saved for Colorectal, L847,750 against 889 years for breast, -L943,434 (cost savings) against 1195 years for prostate, and L609,938 against 1011 years for lung cancer. CONCLUSION: Redirecting diagnoses from emergency presentation to GP referral appears an achievable target that can produce large benefits to patients against modest additional costs to the National Health System. PMID- 29625607 TI - Asparagus cochinchinensis stimulates release of nerve growth factor and abrogates oxidative stress in the Tg2576 model for Alzheimer's disease. AB - BACKGROUD: Use of multifunctional drugs with neurotrophic supporting and oxidative stress suppressing activity may be considered a therapeutic strategy to protect or repair cellular damage caused during the progression of Alzheimer's disease (AD). In this study, we investigated the therapeutic effects of aqueous extract of A. cochinchinesis root (AEAC), particularly its role as a nerve growth factor (NGF) stimulator and anti-oxidant in Tg2576 mice showing AD phenotypes of human. METHODS: Tg2576 mice were received 100 mg/kg/day AEAC via oral administration, while mice in the Vehicle treated group received dH2O for 4 weeks. Non-Tg littermates were used as a control group. Following AEAC treatment for 4 weeks, NGF function, anti-oxidantive status, Abeta-42 peptide level, gamma secretase expression and neuronal cell functions were analyzed in the brain of Tg2576 mice. RESULTS: AEAC containing flavonoids, phenols, saponins and protodioscin induced enhancement of NGF secretion and decreased intracellular ROS in the neuronal and microglial cell line. These effects as well as enhanced SOD levels were also detected in AEAC treated Tg2576 mice. The expression of p-Akt among downstream effectors of the high affinity NGF receptor was dramatically recovered in AEAC treated Tg2576 mice, while the expression of p75NTR was slightly recovered in the same group. Significant recovery on the level of Abeta 42 peptides and the expression of gamma-secretase members including PS-2, APH-1 and NCT were detected in AEAC treated Tg2576 mice. Furthermore, AEAC treated Tg2576 mice showed decreased numbers of dead cells and suppressed acetyl choline esterase (AChE) activity. CONCLUSIONS: These results suggest that AEAC contribute to improving the deposition of Abeta-42 peptides and neuronal cell injuries during the pathological progression stage of AD in the brain of Tg2576 mice through increased NGF secretion and suppressed oxidative stress. PMID- 29625608 TI - The obesogenic environment around elementary schools: food and beverage marketing to children in two Mexican cities. AB - BACKGROUND: Unhealthy environments and food advertisements are major determinants of childhood obesity. Recent regulation has banned unhealthy foods from schools in Mexico. However, currently there is no regulation limiting exposure to food marketing around schools. Thus, our objective was to analyze the characteristics of food advertising practices around 60 elementary schools in two cities and to evaluate compliance with the Pan American Health Organization (PAHO) recommendations and the local food industry self-regulatory marketing code. METHODS: Data were collected during the period of October 2012 to March 2013. A random sample of elementary schools was selected from two Mexican cities. Using geographic information systems, we drew a 100-m-diameter buffer around each school. Trained personnel obtained photographs to assess the locations and types of food advertisements. Our results were stratified by school type and by indicators of compliance with the PAHO and industry recommendations. We developed a multivariate negative binomial regression model to determine factors predicting the number of advertisements around schools. RESULTS: The number of advertisements was significantly higher around public schools than around private schools (6.5 +/- 5.6 vs. 2.4 +/- 3.5, p < 0.05). Printed posters were the most common type of marketing medium (97%), showing mostly sugar-sweetened beverages, sweet breads, candies, and bottled water. Promotions, such as special prices or gifts, were included on 30% of printed posters. Food advertising practices were often in compliance with industry recommendations (83%) but not with those from the PAHO (32%) (p < 0.001). CONCLUSION: Our results support the importance of monitoring the obesogenic environment and identifying policy tools to protect children from food marketing not only inside schools but also around them, particularly in lower income communities. PMID- 29625609 TI - Lay responder naloxone access and Good Samaritan law compliance: postcard survey results from 20 Indiana counties. AB - BACKGROUND: To reduce fatal drug overdoses, two approaches many states have followed is to pass laws expanding naloxone access and Good Samaritan protections for lay persons with high likelihood to respond to an opioid overdose. Most prior research has examined attitudes and knowledge among lay responders in large metropolitan areas who actively use illicit substances. The present study addresses current gaps in knowledge related to this issue through an analysis of data collected from a broader group of lay responders who received naloxone kits from 20 local health departments across Indiana. METHODS: Postcard surveys were included inside naloxone kits distributed in 20 Indiana counties, for which 217 returned cards indicated the person completing it was a lay responder. The survey captured demographic information and experiences with overdose, including the use of 911 and knowledge about Good Samaritan protections. RESULTS: Few respondents had administered naloxone before, but approximately one third had witnessed a prior overdose and the majority knew someone who had died from one. Those who knew someone who had overdosed were more likely to have obtained naloxone for someone other than themselves. Also, persons with knowledge of Good Samaritan protections or who had previously used naloxone were significantly more likely to have indicated calling 911 at the scene of a previously witnessed overdose. Primary reasons for not calling 911 included fear of the police and the person who overdosed waking up on their own. CONCLUSIONS: Knowing someone who has had a fatal or non-fatal overdose appears to be a strong motivating factor for obtaining naloxone. Clarifying and strengthening Good Samaritan protections, educating lay persons about these protections, and working to improve police interactions with the public when they are called to an overdose scene are likely to improve implementation and outcomes of naloxone distribution and opioid related Good Samaritan laws. PMID- 29625610 TI - A novel interaction between CX3CR1 and CCR2 signalling in monocytes constitutes an underlying mechanism for persistent vincristine-induced pain. AB - BACKGROUND: A dose-limiting side effect of chemotherapeutic agents such as vincristine (VCR) is neuropathic pain, which is poorly managed at present. Chemokine-mediated immune cell/neuron communication in preclinical VCR-induced pain forms an intriguing basis for the development of analgesics. In a murine VCR model, CX3CR1 receptor-mediated signalling in monocytes/macrophages in the sciatic nerve orchestrates the development of mechanical hypersensitivity (allodynia). CX3CR1-deficient mice however still develop allodynia, albeit delayed; thus, additional underlying mechanisms emerge as VCR accumulates. Whilst both patrolling and inflammatory monocytes express CX3CR1, only inflammatory monocytes express CCR2 receptors. We therefore assessed the role of CCR2 in monocytes in later stages of VCR-induced allodynia. METHODS: Mechanically evoked hypersensitivity was assessed in VCR-treated CCR2- or CX3CR1-deficient mice. In CX3CR1-deficient mice, the CCR2 antagonist, RS-102895, was also administered. Immunohistochemistry and Western blot analysis were employed to determine monocyte/macrophage infiltration into the sciatic nerve as well as neuronal activation in lumbar DRG, whilst flow cytometry was used to characterise monocytes in CX3CR1-deficient mice. In addition, THP-1 cells were used to assess CX3CR1-CCR2 receptor interactions in vitro, with Western blot analysis and ELISA being used to assess expression of CCR2 and proinflammatory cytokines. RESULTS: We show that CCR2 signalling plays a mechanistic role in allodynia that develops in CX3CR1-deficient mice with increasing VCR exposure. Indeed, the CCR2 antagonist, RS-102895, proves ineffective in mice possessing functional CX3CR1 receptors but reduces VCR-induced allodynia in CX3CR1-deficient mice, in which CCR2+ monocytes are elevated by VCR. We suggest that a novel interaction between CX3CR1 and CCR2 receptors in monocytes accounts for the therapeutic effect of RS 102895 in CX3CR1-deficient mice. Indeed, we observe that CCR2, along with its ligand, CCL2, is elevated in the sciatic nerve in CX3CR1-deficient mice, whilst in THP-1 cells (human monocytes), downregulating CX3CR1 upregulates CCR2 expression via p38 MAP kinase signalling. We also show that the CX3CR1-CCR2 interaction in vitro regulates the release of pronociceptive cytokines TNF-alpha and IL1beta. CONCLUSIONS: Our data suggests that CCL2/CCR2 signalling plays a crucial role in VCR-induced allodynia in CX3CR1-deficient mice, which arises as a result of an interaction between CX3CR1 and CCR2 in monocytes. PMID- 29625611 TI - Serological evidence of rift valley fever Phlebovirus and Crimean-Congo hemorrhagic fever orthonairovirus infections among pygmies in the east region of Cameroon. AB - BACKGROUND: Rift Valley Fever Phlebovirus (RVFV) and Crimean-Congo Hemorrhagic Fever Orthonairovirus (CCHFV) specific antibodies had been documented among humans in urban settings of the southwestern and northern Cameroon in the late 1980s. Recently, evidence for enzootic circulation of RVFV was reported among livestock in both rural and urban settings in Cameroon. However, current estimates of human exposure to RVFV and CCHFV are still to be documented in Cameroon, especially in rural areas. The aim of this study was to assess the seroprevalence of RVFV and CCHFV in rural settings in the Southeastern rain forest of Cameroon. RESULTS: Using Enzyme-linked Immunosorbent Assays, the presence of RVFV and CCHFV Immunoglobulin G antibodies was investigated in plasma samples originating from 137 Pygmies from four villages of the East region of Cameroon. The studied population was found to be 12.4% (17/137) and 4.4% (6/137) seropositive for RVFV and CCHFV, respectively. The rates of RVFV IgG were comparable between the age groups and sex. Conversely, the rate of CCHFV IgG was significantly higher among the 41-60 years old participants (p = 0.02). CONCLUSIONS: This study provides a substantial evidence of the circulation of RVFV and CCHFV among rural inhabitants of the East region of Cameroon. PMID- 29625612 TI - Interaction between human osteosarcoma and mesenchymal stem cells via an interleukin-8 signaling loop in the tumor microenvironment. AB - BACKGROUND: Osteosarcoma (OS) is the representative primary malignant bone tumor with the highest incidence. It is known that malignant phenotypes of OS, such as proliferation, invasion, and metastasis, are significantly influenced not only by characteristics of the tumor itself, but also by the surrounding microenvironment. In other words, OS is considered to utilize cells in the vicinity of the tumor by changing the characteristics of these cells. Direct intercellular contact is believed to be important for this phenomenon. In the present study, we hypothesized that an interaction mediated by a humoral factor, requiring no cellular contact, might play a significant role in the progression of OS. METHODS: We developed a new co-culture model, using OS cells and mesenchymal stem cells (MSCs) without cellular contact, and found that both cell types expressed IL-8 at a high level, and FAK in OS cells was phosphorylated leading to an increase in the metastatic potential of the tumor in the co-culture condition. RESULTS: It was revealed that OS cells formed a loop of signal cross talk in which they released IL-8 as a paracrine factor, stimulating MSCs to express IL-8, and received IL-8 released by MSCs to accelerate IL-8 expression in OS cells. Administration of anti-IL-8 antibody resulted in the inhibition of FAK expression, its downstream signaling, and the invasive potential of the OS cells, resulting in decrease in metastatic lesions. CONCLUSION: The present study might lead not only to the clarification of a new molecular mechanism of invasion and metastasis of OS, but also to the development of a new therapeutic strategy of blocking IL-8 in OS. PMID- 29625613 TI - CD109 and squamous cell carcinoma. AB - Squamous cell carcinoma (SCC) is well-known for its high rate of metastasis with poor prognosis. CD109 is a glycosylphosphatidylinositol-anchored cell-surface glycoprotein. Recently, CD109 emerges as a potential biomarker and a therapeutic target for SCCs. Accumulating studies have reported that CD109 is highly expressed in human SCCs of multiple organs, and may contribute to the progression of SCCs. In this review, we summarized the findings on expression pattern of CD109 in SCCs, and discussed the molecular mechanisms underlying the roles of CD109 in pathogenesis of SCCs. PMID- 29625614 TI - A novel implant removal technique by endoscopy. AB - BACKGROUND: Routine implant removal after fracture healing remains controversial. However, it has been suggested that implant removal should be performed in cases of joint impingement, painful scar adhesion, and implant malposition. Entrance selection is relatively critical in patients with poor soft tissue conditions or sloughing coverage. We propose an innovative technique using endoscopy. METHODS: Consecutive surgeries of endoscopic implant removal performed between 2005 and 2016 by a single experienced arthroscopic surgeon were included. Overall, 73 patients were enrolled; 44 were not eligible for inclusion and were excluded from the study. RESULTS: Twenty-nine patients, including 32 surgical sites, were included. Twenty-four plates and 166 screws were removed using this technique. There were five complications during the follow-up period (range, 0.5 to 104 months; mean, 8.8), including one broken screw, one persistent knee joint contracture, and three wound dehiscence. There were no infections or neurovascular injuries. CONCLUSION: Implant removal using endoscopy is a minimally invasive surgery that ensures that the screw axis does not strip, and treats the intra-articular pathology concomitantly. This innovative technique may be considered as an alternative to the traditional open method in cases with good surgical indications. PMID- 29625615 TI - To fill or not to fill: a qualitative cross-country study on dentists' decisions in managing non-cavitated proximal caries lesions. AB - BACKGROUND: This study aimed to identify barriers and enablers for dentists managing non-cavitated proximal caries lesions using non- or micro-invasive (NI/MI) approaches rather than invasive and restorative methods in New Zealand, Germany and the USA. METHODS: Semi-structured interviews were conducted, focusing on non-cavitated proximal caries lesions (radiographically confined to enamel or the outer dentine). Twelve dentists from New Zealand, 12 from Germany and 20 from the state of Michigan (USA) were interviewed. Convenience and snowball sampling were used for participant recruitment. A diverse sample of dentists was recruited. Interviews were conducted by telephone, using an interview schedule based on the Theoretical Domains Framework (TDF). RESULTS: The following barriers to managing lesions non- or micro-invasively were identified: patients' lacking adherence to oral hygiene instructions or high-caries risk, financial pressures and a lack of reimbursement for NI/MI, unsupportive colleagues and practice leaders, not undertaking professional development and basing treatment on what had been learned during training, and a sense of anticipated regret (anxiety about not restoring a proximal lesion in its early stages before it progressed). The following enablers were identified: the professional belief that remineralisation can occur in early non-cavitated proximal lesions and that these lesions can be arrested, the understanding that placing restorations weakens the tooth and inflicts a cycle of re-restoration, having up-to-date information and supportive colleagues and work environments, working as part of a team of competent and skilled dental practitioners who perform NI/MI (such as cleaning or scaling), having the necessary resources, undertaking ongoing professional development and continued education, maintaining membership of professional groups and a sense of professional and personal satisfaction from working in the patient's best interest. Financial aspects were more commonly mentioned by the German and American participants, while continuing education was more of a focus for the New Zealand participants. CONCLUSIONS: Decisions on managing non cavitated proximal lesions were influenced by numerous factors, some of which could be targeted by interventions for implementing evidence-based management strategies in practice. PMID- 29625616 TI - The role of ethnic tourism in the food knowledge tradition of Tyrolean migrants in Treze Tilias, SC, Brazil. AB - BACKGROUND: Food knowledge and consumption in the context of migration is an important topic in ethnobiological research. Little research is done on the process of how external factors impact food knowledge amongst migrants. Taking into account social organisation and power relations of food knowledge transmission and distribution of food knowledge, this study sheds light on how the accessibility of resources, the predominant cuisine in the host country and ethnic tourism influences the food knowledge tradition of Tyrolean migrants and their descendants in Treze Tilias. METHODS: Field research was conducted in Austria and Brazil in 2008-2009, using free-listing, social network analysis and participatory observation. The collected data was analysed by calculating Smith's Salience index, visualising personal and social networks and qualitative text analysis. RESULTS: Tyroleans in Austria had a different perception and a higher agreement of what Tyrolean food comprises than Tyroleans in Brazil, indicating different developments: Tyrolean migrants adapted their food habits according to available resources and over time in Brazil. Later, ethnic tourism had a strong impact: In Treze Tilias, dishes with the highest Smith's Salience index-forming the core of cultural food knowledge-strongly coincided with Tyrolean food served in ethnic restaurants, whose staff were perceived to be experts in Tyrolean food. CONCLUSION: Despite most food knowledge in Treze Tilias was transmitted within families, ethnic food prepared in restaurants and hotels determined the shared perception of what Tyrolean food comprises. Perceived as experts, the staff in ethnic restaurants were in a powerful position to transform cultural food knowledge by providing institutionalised and standardised knowledge about Tyrolean food. PMID- 29625617 TI - Analysis of prognostic factors for survival in patients with primary spinal chordoma using the SEER Registry from 1973 to 2014. AB - BACKGROUND: Spinal chordomas are rare primary osseous tumors that arise from the remnants of the notochord. They are commonly considered slow-growing, locally invasive neoplasms with little tendency to metastasize, but the high recurrent rate of spinal chordomas may seriously affect the survival rate and quality of life of patients. The aim of the study is to describe the epidemiological data and determine the prognostic factors for decreased survival in patients with primary spinal chordoma. METHODS: The Surveillance, Epidemiology, and End Results (SEER) Registry database, a US population-based cancer registry database, was used to identify all patients diagnosed with primary spinal chordoma from 1973 to 2014. We utilized Kaplan-Meier method and Cox proportional hazards regression analysis to evaluate the association between patients overall survival and relevant characteristics, including age, gender, race, disease stage, treatment methods, primary tumor site, marital status, and urban county background. RESULTS: In the data set between 1973 and 2014, a total of 808 patients were identified with primary spinal chordoma. The overall rate of distant metastatic cases in our cohort was only 7.7%. Spinal chordoma was more common occurred in men (62.6%) than women (37.3%). Majority of neoplasms were found in the White (87.9%), while the incidence of the Black is relatively infrequent (3.3%). Three hundred fifty-seven spinal chordomas (44.2%) were located in the vertebral column, while 451 patients' tumor (55.8%) was located in the sacrum or pelvis. Age >= 60 years (HR = 2.72; 95%CI, 1.71 to 2.89), distant metastasis (HR = 2.16; 95%CI, 1.54 to 3.02), and non-surgical therapy (HR = 2.14; 95%CI, 1.72 to 2.69) were independent risk factors for survival reduction in analysis. Survival did not significantly differ as a factor of tumor site (vertebrae vs sacrum/pelvis) for primary spinal chordoma (HR = 0.93, P = 0.16). Race (P = 0.52), gender (P = 0.11), marital status (P = 0.94), and urban background (P = 0.72) were not main factors which affected overall survival rate. CONCLUSION: There was no significant difference in overall survival rate between chordomas located in the sacrum and vertebral column. Spinal chordoma patients with an elderly age (age >= 60), performing non-surgical therapy, and distant metastasis were associated with worse overall survival. Performing surgery was an effective and reliable treatment method for patients with spinal chordoma, and public health efforts should pay more attention to the elderly patients with spinal chordoma prior to distant metastasis. PMID- 29625619 TI - Mapping the lack of public initiative against female genital mutilation in Denmark. AB - BACKGROUND: Female genital mutilation (FGM) is a harmful practice prevalent in 35 countries, mainly in Africa, as well as in some Middle Eastern countries and a few Asian countries. FGM comprises all procedures that involve partial or complete resection of, or other injury to, external female genitalia for non medical reasons. The practice of FGM has spread to Western countries due to migration. The European Institute for Gender Equality recommend that FGM be combatted by nationally coordinated efforts through implementation of national action plans, guidelines for professionals as well as comprehensive research in the field. FGM was outlawed in Denmark 2003, but no national actions plan has been implemented. Instead, the task of combatting FGM is currently under the responsibility of local governments in the form of the 98 municipalities. The aim of this study is to investigate the Danish municipalities' efforts to prevent FGM on the local level, and whether these initiatives are in accordance with international recommendations and standards. METHODS: All 98 Danish municipalities were invited to respond to a questionnaire regarding FGM in their respective municipalities. The inclusion process and questionnaire was designed after a pilot study, which included 29 municipalities. The questionnaire consisted of four overall areas of focus: "action plan", "registration", "information material" and "preventive initiatives". Demographic data were gathered from the 2017 census by Statistics Denmark. Risk countries were defined as countries with a tradition for FGM, identified from the 2016 UNICEF definition. RESULTS: A total of 67 municipalities participated in the study. At the time of census, 1.8% of the Danish population was immigrants with origins in risk countries. A total of 10.4% of the responding municipalities indicated to have implemented a specific action plan against FGM. A total of 7,5% had implemented specific preventive initiatives against FGM. Registration of reported FGM cases were indicated to be performed in 73.1% of the responding municipalities; however, only 17.9% stated to perform registration of FGM specifically as such, and not as general child abuse. CONCLUSIONS: Our study shows that the current situation of FGM registration and prevention being under local administrative responsibility in the 98 Danish municipalities has led to a severe lack of coordinated public initiative against FGM. PMID- 29625618 TI - Exposure to radial extracorporeal shock waves modulates viability and gene expression of human skeletal muscle cells: a controlled in vitro study. AB - BACKGROUND: Recent clinical and animal studies have shown that extracorporeal shock wave therapy has a promoting influence on the healing process of musculoskeletal disorders. However, the underlying biological effects of extracorporeal shock wave therapy on human skeletal muscle cells have not yet been investigated. METHODS: In this study, we investigated human skeletal muscle cells after exposure to radial extracorporeal shock waves in a standardized in vitro setup. Cells were isolated from muscle specimens taken from adult patients undergoing spine surgery. Primary muscle cells were exposed once or twice to radial extracorporeal shock waves in vitro with different energy flux densities. Cell viability and gene expression of the paired box protein 7 (Pax7), neural cell adhesion molecule (NCAM), and myogenic factor 5 (Myf5) and MyoD as muscle cell markers were compared to non-treated muscle cells that served as controls. RESULTS: Isolated muscle cells were positive for the hallmark protein of satellite cells, Pax7, as well as for the muscle cell markers NCAM, MyoD, and Myf5. Exposure to radial extracorporeal shock waves at low energy flux densities enhanced cell viability, whereas higher energy flux densities had no further significant impact. Gene expression analyses of muscle specific genes (Pax7, NCAM, Myf5, and MyoD) demonstrated a significant increase after single exposure to the highest EFD (4 bar, 0.19 mJ/mm2) and after double exposure with the medium EFDs (2 and 3 bar; 0.09 and 0.14 mJ/mm2, respectively). Double exposure of the highest EFD, however, results in a significant down-regulation when compared to single exposure with this EFD. CONCLUSIONS: This is the first study demonstrating that radial extracorporal shock wave therapy has the potential to modulate the biological function of human skeletal muscle cells. Based on our experimental findings, we hypothesize that radial extracorporal shock wave therapy could be a promising therapeutic modality to improve the healing process of sports-related structural muscle injuries. PMID- 29625621 TI - Expanding harm reduction to include fentanyl urine testing: results from a pilot in rural British Columbia. AB - BACKGROUND: Harm reduction has been at the forefront of the response to the opioid overdose public health emergency in British Columbia (BC). The unprecedented number of opioid overdose deaths in the province calls for an expansion of harm reduction services. The purpose of this study was to determine the acceptability of a fentanyl urine drug test among people who use drugs (PWUD) and explore whether testing introduced any changes in participants' attitudes and behaviors towards their drug use. METHODS: A pilot of fentanyl urine testing was implemented in partnership with an outreach harm reduction program in rural BC. Participants were PWUD who had consumed within the last 3 days prior to the test. Participants filled out a semi-structured questionnaire at the time of the test and were invited for a follow-up interview 2 to 4 weeks after the test. Urine samples were tested with BNTX Rapid ResponseTM fentanyl urine strip test at a detection level of 20 ng/ml norfentanyl. RESULTS: Of the 24 participants who completed the urine test and first interview, 4 had a positive fentanyl urine test. Fifteen clients completed the second questionnaire, 10 of whom reported introducing a behavior change after testing and the remaining 5 indicated being already engaged in harm reduction practices. All four clients who tested positive completed the second questionnaire; all but one indicated adopting behaviors towards overdose prevention. DISCUSSION: Fentanyl urine testing appealed to illicit opioid users and may have contributed to adopting behaviors towards safer drug use. A relationship of trust between tester and client seemed important for clients who expressed concerns with privacy of the urine test results. Post consumption urine testing could complement the use of pre-consumption drug checking in the context of harm reduction services. PMID- 29625620 TI - Identification and genetic analysis of Kadipiro virus isolated in Shandong province, China. AB - BACKGROUND: Kadipiro virus (KDV) belongs to the Reoviridae family, which consists of segmented, non-enveloped, double-stranded RNA viruses. It has previously been isolated from Culex, Anopheles, Armigeres and Aedes mosquitoes in Indonesia and China. Here, we describe the isolation and characterization of SDKL1625 from Anopheles sinensis mosquitoes in Shandong province, China. METHODS: In this study, we isolated Kadipiro virus in Aedes albopictus C6/36 cell culture and the complete genome sequencing was made by next generation sequencing. RESULTS: We isolated and characterized a Kadipiro virus from Anopheles sinensis mosquitoes in 2016 in Shandong province, China. Nucleotide and amino acid homology analysis of SDKL1625 showed higher levels of sequence identity with QTM27331 (Odonata, China, 2016) than with JKT-7075 (Culex fuscocephalus, Indonesia, 1981). The SDKL1625 has 86-97% amino acid identity with the JKT-7075, 88-99% amino acid identity with the QTM27331. Among the 12 fragments, VP1, VP2, VP4, VP6, VP7, VP9 and VP12 showed high amino acid identity (> 90%) and VP5 showed the lowest identity (86% and 88%). CONCLUSIONS: This is the first identification of KDV from mosquito in China. Virus morphology and genome organization were also determined, which will further enrich our understanding of the molecular biological characteristics of KDV and seadornaviruses. PMID- 29625622 TI - Effect of exercise on pain and functional capacity in breast cancer patients. AB - PURPOSE: To assess the influence of combined training on pain, fatigue, maximal oxygen uptake (VO2 max), body mass index (BMI), flexibility, and strength in patients with breast cancer. METHODS: A controlled pilot study with 28 patients undergoing chemotherapy, radiation therapy, and clinical observation in a renowned cancer treatment center; the patients were aged from 30 to 59 years old and were not engaged in physical training for three months previously. The Study Group (SG) underwent 12 weeks of training, including three 60-min sessions of aerobic exercise and resistance training, and two sessions of flexibility training per week; each flexibility exercise lasted 20 s and was performed in sets of three repetitions. The Control Group (CG) received only the standard hospital treatment. Participants were evaluated at the beginning of the study to establish a baseline and reevaluated at the end of 12 weeks. RESULTS: Patients in the SG showed a significant decrease in total pain points (p = 0.0047), pain intensity (p = 0.0082), and the extent to which pain interfered with their daily life (p = 0.0047). There was an increase in maximum oxygen uptake (p = 0.0001), flexibility (p = 0.0001), and strength on both sides (right p = 0.0001 and left p = 0.0008). No significant differences were observed in fatigue (p = 0.0953) or BMI (p = 0.6088). CONCLUSION: Combined training was effective in decreasing pain and increasing VO2 max, flexibility and static strength in patients with breast cancer. TRIAL REGISTRATION: NCT03061773 . Registered on February 19, 2017, 'retrospectively registered'. PMID- 29625623 TI - Facilitators and barriers to the delivery of school-based smoking prevention interventions for children and young people: a protocol for a systematic review of qualitative studies. AB - BACKGROUND: Despite a decline in child and adult smoking prevalence, young people who smoke (even occasionally) can rapidly become addicted to nicotine, with most adult smokers initiating smoking before they are 18. Schools have long been a popular setting to deliver youth smoking prevention interventions, but evidence of the effectiveness of school-based prevention programmes is mixed, and outcomes vary by the type of programme delivered. Existing systematic reviews that explore the factors contributing to the success or failure of school-based smoking prevention programmes often exclude qualitative studies, due to a focus on intervention effectiveness which qualitative research cannot answer. Instead, qualitative research is focussed on the experiences and perceptions of those involved in the programmes. This systematic review will address this gap by updating a 2009 review to examine qualitative studies. The aim is to generate deeper insight to help target resources which have the potential to save lives by preventing smoking initiation among children and young people. METHODS: This systematic review will be searching the following databases: the Cochrane Library, MEDLINE, EMBASE, PsycINFO, HMIC, ERIC, ASSIA, Web of Science and CINAHL. In order to identify additional references, we will consult the reference lists of a sample of systematic reviews and search relevant organizational websites in order to identify appropriate grey literature. The search strategy will include key words and database-specific subject headings relating to smoking, children and young people, health promotion and school. Authors will independently screen, assess data quality and extract data for synthesis. Study findings will be synthesised thematically using 'best-fit framework syntheses'. This allows for an existing set of themes to be used as a starting point to map or code included studies. These themes are then adapted as coding takes place to accommodate new emerging themes. DISCUSSION: This review will focus on qualitative studies that seek to examine the barriers and facilitators to the delivery of school-based smoking prevention programmes in order to inform the design of future theory based interventions in schools to prevent children and young people from smoking. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42014015483. PMID- 29625624 TI - An RNAi based screen in Drosophila larvae identifies fascin as a regulator of myoblast fusion and myotendinous junction structure. AB - BACKGROUND: A strength of Drosophila as a model system is its utility as a tool to screen for novel regulators of various functional and developmental processes. However, the utility of Drosophila as a screening tool is dependent on the speed and simplicity of the assay used. METHODS: Here, we use larval locomotion as an assay to identify novel regulators of skeletal muscle function. We combined this assay with muscle-specific depletion of 82 genes to identify genes that impact muscle function by their expression in muscle cells. The data from the screen were supported with characterization of the muscle pattern in embryos and larvae that had disrupted expression of the strongest hit from the screen. RESULTS: With this assay, we showed that 12/82 tested genes regulate muscle function. Intriguingly, the disruption of five genes caused an increase in muscle function, illustrating that mechanisms that reduce muscle function exist and that the larval locomotion assay is sufficiently quantitative to identify conditions that both increase and decrease muscle function. We extended the data from this screen and tested the mechanism by which the strongest hit, fascin, impacted muscle function. Compared to controls, animals in which fascin expression was disrupted with either a mutant allele or muscle-specific expression of RNAi had fewer muscles, smaller muscles, muscles with fewer nuclei, and muscles with disrupted myotendinous junctions. However, expression of RNAi against fascin only after the muscle had finished embryonic development did not recapitulate any of these phenotypes. CONCLUSIONS: These data suggest that muscle function is reduced due to impaired myoblast fusion, muscle growth, and muscle attachment. Together, these data demonstrate the utility of Drosophila larval locomotion as an assay for the identification of novel regulators of muscle development and implicate fascin as necessary for embryonic muscle development. PMID- 29625625 TI - Association of EGLN1 genetic polymorphisms with SpO2 responses to acute hypobaric hypoxia in a Japanese cohort. AB - BACKGROUND: Recent studies have explored various genetic and physiological factors related to high-altitude adaptation in highlander populations. However, the effects of single nucleotide polymorphisms (SNPs), influencing such adaptation, on physiological responses to hypobaric hypoxia have not been examined in lowlanders with lowlander ancestry. Thus, we aimed to investigate the association between SNPs around the EGLN1 genomic region, possibly involved in high-altitude adaptation, and physiological changes to hypobaric hypoxia exposure in a cohort of Japanese lowlanders. METHODS: Physiological data were obtained from 46 healthy Japanese male students under different atmospheric pressure conditions (equivalent to sea level and altitudes of 2500 and 4000 m). Genotypes of seven SNPs around EGLN1 were determined in all subjects by PCR-direct sequencing or TaqMan SNP genotyping assay. RESULTS: Results of the association study suggest that percutaneous arterial oxygen saturation (SpO2) responses of individuals with rs12097901 and rs2790859 alleles, whose frequencies are high in highlander populations (HL alleles), may be susceptible to acute hypobaric hypoxia. SpO2 levels of individuals with HL alleles were lower than those of individuals with non-HL alleles. At the same time, the subjects with HL alleles did not appear to have any remarkable hematological or pulmonary features that may counteract the low levels of SpO2. One may hypothesize that the low SpO2 levels in HL allele carriers could be a risk factor for acute mountain sickness in Japanese population. CONCLUSIONS: Our findings suggest that rs12097901 and rs2790859 genotypes affect SpO2 responses and may be associated with the susceptibility to acute hypobaric hypoxia in Japanese population. PMID- 29625626 TI - Characteristics and status of Korean medicine use in whiplash-associated disorder patients. AB - BACKGROUND: Patients are free to choose conventional or Korean medicine treatment under the dual medical system in Korea, and the prevalence of patients who choose Korean medicine treatment for whiplash-associated disorders (WADs) is high. This study analyzed the sociodemographic characteristics and medical service use in this population to provide healthcare providers with basic usage information of complementary and alternative medicine for WAD. METHODS: A total of 8291 outpatients who registered under automobile insurance coverage and visited the main branch of Jaseng Hospital of Korean Medicine from April 1, 2014 to August 10, 2016 were included. Data on sociodemographic characteristics, symptoms, and accident and treatment-related details were collected from electronic medical records. Univariate and multivariate regression analyses were performed to identify baseline factors predictive of total treatment duration. RESULTS: The most prevalent demographic of patients who chose Korean medicine for WAD treatment was males in their thirties whose initial visit to the hospital was 16.1 +/- 94.1 days from the accident. Neck pain accompanied by low back pain (57.0%) was the most common complaint, and for singular pain, neck pain (13.5%) was the most prevalent. Baseline numeric rating scale (NRS) pain levels were generally moderate (4-6) regardless of area. Patients received 7.2 +/- 10.2 sessions of treatment for 32.6 +/- 55.3 days. The most commonly prescribed treatment modalities in order of highest frequency were acupuncture, cupping, pharmacopuncture, and herbal medicine, which collectively accounted for > 90% of treatments. Acupuncture was administered 29.0 +/- 40.8 times, and cupping 14.0 +/ 18.7 times as the two highest frequency treatments. In multivariate regression analysis, longer treatment periods were found to be associated with higher NRS, older age, and delayed initial visits at baseline. CONCLUSIONS: This study highlights the characteristics and Korean medicine use of WAD patients. These results are particularly relevant and informative for consideration of personal preferences and effective prioritization in further insurance coverage. PMID- 29625627 TI - A pilot screening of high-risk Gaucher disease children using dried blood spot methods in Shandong province of China. AB - BACKGROUND: The study aim was to verify the feasibility of a diagnostic algorithm with the evaluation of beta glucocerebrosidase (GBA) activity on dried blood spots (DBS) in screening high-risk Gaucher disease (GD) children in China, and to investigate the GD prevalence in this selected population. METHODS: Children were recruited from 20 departments of pediatrics or children's hospitals in Shandong Province, China, due to splenomegaly and/or thrombocytopenia associated with one or more of the following creteria: anemia, history of bone pain, monoclonal gammopathy of unknown significance (MGUS), polyclonal gammopathy and splenectomy. GBA activity on DBS was tested, and patients with DBS GBA activity under 30 nmol/h.ml were recalled to assess enzyme assay with gold standard and molecular GBA gene analysis on leukocytes. RESULTS: A total of 73 children (47 boys and 26 girls) were enrolled in this study. GBA activity DBS < 30 nmol/h.ml was found in 18 (23.7%) children among which four (three boys and one girl) were diagnosed as GD with a median age 1.5 years, and the prevalence in this pediatric population was 5.5% (1.5%~ 13.4%). Three new mutations of GBA found in the four GD patients, L264I, A100Cfs*7 and D399E, have not been reported before. CONCLUSIONS: With evaluation of GBA activity on DBS as a preliminary screening method, the diagnostic algorithm used in this study is appropriate to make early diagnosis for GD patients with mild symptoms or atypical symptoms and avoid diagnosis delay. TRIAL REGISTRATION: Not applicable. PMID- 29625629 TI - Using PCD's First-Ever External Review to Enhance the Journal's Worldwide Usefulness to Researchers, Practitioners, and Policy Makers. PMID- 29625630 TI - Public Awareness of Health-Related Risks From Uncontrolled Hypertension. AB - Uncontrolled hypertension, a common disorder, is associated with increased long term risk of several serious conditions. Awareness of the health risks of uncontrolled hypertension is not well understood. We used data from a nationwide panel survey to assess the awareness of risk associated with uncontrolled hypertension, stratified by cardiovascular disease risk factors. Awareness of increased risk from uncontrolled hypertension was high for some outcomes (heart attack, heart failure, stroke), and low for others (kidney disease, dementia). Several disparities in awareness were found. Complementary clinical and public health interventions could be instituted to increase awareness and target people who are high risk. PMID- 29625631 TI - Operationalizing Surveillance of Chronic Disease Self-Management and Self Management Support. AB - Sixty percent of US adults have at least one chronic condition, and more than 40% have multiple conditions. Self-management (SM) by the individual, along with self management support (SMS) by others, are nonpharmacological interventions with few side effects that are critical to optimal chronic disease control. Ruiz and colleagues laid the conceptual groundwork for surveillance of SM/SMS at 5 socio ecological levels (individual, health system, community, policy, and media). We extend that work by proposing operationalized indicators at each socio-ecologic level and suggest that the indicators be embedded in existing surveillance systems at national, state, and local levels. Without a robust measurement system at the population level, we will not know how far we have to go or how far we have come in making SM and SMS a reality. The data can also be used to facilitate planning and service delivery strategies, monitor temporal changes, and stimulate SM/SMS-related research. PMID- 29625632 TI - Anatomy and Biomechanics of the Finger Proximal Interphalangeal Joint. AB - A complete understanding of the normal anatomy and biomechanics of the proximal interphalangeal joint is critical when treating pathology of the joint as well as in the design of new reconstructive treatments. The osseous anatomy dictates the principles of motion at the proximal interphalangeal joint. Subsequently, the joint is stabilized throughout its motion by the surrounding proximal collateral ligament, accessory collateral ligament, and volar plate. The goal of this article is to review the normal anatomy and biomechanics of the proximal interphalangeal joint and its associated structures, most importantly the proper collateral ligament, accessory collateral ligament, and volar plate. PMID- 29625633 TI - Surgical Exposure of the Proximal Interphalangeal Joint. AB - There are 3 main surgical approaches to the proximal interphalangeal (PIP) joint; dorsal, volar, and lateral and several described modifications to these main approaches. Historically, the dorsal approach has been the standard for the most common procedures of the PIP joint. The volar approach is advantageous for surgical interventions requiring access to the volar plate. It spares the central slip insertion from possible disruption, as does the lateral approach. This article describes the surgical approaches to the PIP joint, explains the rationale for choosing each approach, and discusses some of the most common complications. PMID- 29625634 TI - Treating Proximal Interphalangeal Joint Dislocations. AB - Proximal interphalangeal (PIP) joint dislocation a common injury. Usually, concentric stable reduction can be achieved with closed reduction. Occasionally, PIP joint dislocations are irreducible and open reduction is necessary. Complications include prolonged splinting and delay in presentation with subluxation or persistent dislocation. Surgery is often recommended for contracture or joint reduction. Surgical techniques focus on contracture release, joint reduction, and range of motion. Techniques have evolved from primary repair to tenodesis and suture anchor reconstruction. Most studies on PIP joint dislocations are retrospective case reports with good outcomes but chronic mild contracture and deformity are consistent in the literature. PMID- 29625628 TI - Advanced Robotic Therapy Integrated Centers (ARTIC): an international collaboration facilitating the application of rehabilitation technologies. AB - BACKGROUND: The application of rehabilitation robots has grown during the last decade. While meta-analyses have shown beneficial effects of robotic interventions for some patient groups, the evidence is less in others. We established the Advanced Robotic Therapy Integrated Centers (ARTIC) network with the goal of advancing the science and clinical practice of rehabilitation robotics. The investigators hope to exploit variations in practice to learn about current clinical application and outcomes. The aim of this paper is to introduce the ARTIC network to the clinical and research community, present the initial data set and its characteristics and compare the outcome data collected so far with data from prior studies. METHODS: ARTIC is a pragmatic observational study of clinical care. The database includes patients with various neurological and gait deficits who used the driven gait orthosis Lokomat(r) as part of their treatment. Patient characteristics, diagnosis-specific information, and indicators of impairment severity are collected. Core clinical assessments include the 10-Meter Walk Test and the Goal Attainment Scaling. Data from each Lokomat(r) training session are automatically collected. RESULTS: At time of analysis, the database contained data collected from 595 patients (cerebral palsy: n = 208; stroke: n = 129; spinal cord injury: n = 93; traumatic brain injury: n = 39; and various other diagnoses: n = 126). At onset, average walking speeds were slow. The training intensity increased from the first to the final therapy session and most patients achieved their goals. CONCLUSIONS: The characteristics of the patients matched epidemiological data for the target populations. When patient characteristics differed from epidemiological data, this was mainly due to the selection criteria used to assess eligibility for Lokomat(r) training. While patients included in randomized controlled interventional trials have to fulfill many inclusion and exclusion criteria, the only selection criteria applying to patients in the ARTIC database are those required for use of the Lokomat(r). We suggest that the ARTIC network offers an opportunity to investigate the clinical application and effectiveness of rehabilitation technologies for various diagnoses. Due to the standardization of assessments and the use of a common technology, this network could serve as a basis for researchers interested in specific interventional studies expanding beyond the Lokomat(r). PMID- 29625635 TI - Management of Proximal Interphalangeal Joint Fracture Dislocations. AB - Fracture dislocations of the proximal interphalangeal (PIP) joint of the finger are often caused by axial load applied to a flexed joint. The most common injury pattern is a dorsal fracture dislocation with a volar lip fracture of the middle phalanx. Damage to the soft-tissue stabilizers of the PIP joint contributes to the deformity seen with these fracture patterns. Unfortunately, these injuries are commonly written off and left untreated. A late-presenting PIP joint fracture dislocation has a poor chance of regaining normal range of motion. The provider must be suspicious of these injuries. Treatment options and algorithm are reviewed. PMID- 29625636 TI - Treating the Proximal Interphalangeal Joint in Swan Neck and Boutonniere Deformities. AB - Swan neck and boutonniere deformities of the proximal interphalangeal (PIP) joint are challenging to treat. In a swan neck deformity, the PIP joint is hyperextended with flexion at the distal interphalangeal (DIP) joint. In a boutonniere deformity, there is flexion the PIP joint with hyperextension of the DIP joint. When the deformities are flexible, treatment begins with splinting. However, when the deformity is fixed, serial casting or surgery is often necessary to restore joint motion before surgical correction. Many surgical techniques have been described to treat both conditions. Unfortunately, incomplete correction and deformity recurrence are common. PMID- 29625637 TI - Proximal Interphalangeal Joint Fusion: Indications and Techniques. AB - This article is an in-depth analysis of proximal interphalangeal joint arthrodesis indications and surgical techniques. There are a wide variety of indications for proximal interphalangeal joint arthrodesis with relatively few contraindications. Moreover, although there is a limited surgical approach, there is a wide breadth of modalities in which to obtain the arthrodesis, of which several are listed here. Proximal interphalangeal joint arthrodesis has been shown to have excellent outcomes and a high success rate. PMID- 29625639 TI - Implant Arthroplasty: Selection of Exposure and Implant. AB - This review analyzes various surgical exposures and implant designs for proximal interphalangeal (PIP) joint pathology. Our literature review found that silicone implants using a volar approach had the best arc of motion, least extension lag, and lowest complication rates compared with all the other implant designs and approaches. Surface replacement arthroplasties had more frequent surgical revisions compared with silicone implants. Continued efforts toward the development of improved PIP joint implants are necessary. PMID- 29625638 TI - Advances in Proximal Interphalangeal Joint Arthroplasty: Biomechanics and Biomaterials. AB - Proximal interphalangeal (PIP) joint arthritis is a debilitating condition. The complexity of the joint makes management particularly challenging. Treatment of PIP arthritis requires an understanding of the biomechanics of the joint. PIP joint arthroplasty is one treatment option that has evolved over time. Advances in biomaterials have improved and expanded arthroplasty design. This article reviews biomechanics and arthroplasty design of the PIP joint. PMID- 29625640 TI - Microvascular Toe Joint for Proximal Interphalangeal Joint Replacement: Indications, Technique, and Outcomes. AB - Microvascular toe interphalangeal joint transfer can serve as a means of autogenous digit proximal interphalangeal joint (PIPJ) arthroplasty. Among surgical options for treating dysfunctional, absent, or destroyed PIPJs, free toe joint transfer is the most technically challenging and carries the greatest donor site cost to patients. Despite drawbacks, free toe joint transfer is a valuable tool with considerable advantages over conventional arthroplasty in the appropriate clinical setting. Particular advantages include lifelong durability, coronal plane stability, low infection risk, and growth potential in skeletally immature patients. This technique requires a balanced assessment of the risk-to benefit ratio for each patient. PMID- 29625641 TI - Salvaging a Failed Proximal Interphalangeal Joint Implant. AB - Salvaging a failed proximal interphalangeal (PIP) joint implant arthroplasty remains a considerable technical and rehabilitation challenge. Experienced arthroplasty surgeons have reported 70% survival of revision PIP implants at 10 years with 25% of patients requiring subsequent revision surgery. At this time, there is no consensus surgical approach or implant proven superior for revision implant arthroplasty of the PIP joint. Secondary arthrodesis or amputation may be required to salvage the failed PIP implant arthroplasty with compromised bone stock or soft tissue envelopes that are inadequate for implant arthroplasty. PMID- 29625642 TI - Treatment of Proximal Interphalangeal Joint Contracture. AB - Proximal interphalangeal joint (PIPJ) flexion contracture is a challenging and often frustrating problem. Treatment of PIPJ contracture begins with conservative measures. With good compliance and prolonged use, favorable results can be achieved using these modalities. For contractures that fail to respond to conservative treatment, surgical intervention can be considered. The affected structures that can be released during surgery include the accessory collateral ligaments, volar plate, checkrein ligaments, retinacular ligaments, and the flexor and extensor tendons. A stepwise approach to release is typically favored in which active motion is tested after each release to determine the need for subsequent releases. PMID- 29625643 TI - Treating Congenital Proximal Interphalangeal Joint Contracture. AB - The management of congenital proximal interphalangeal joint deformity, also known as camptodactyly, is challenging. There are numerous theories on the cause of this abnormal finger posture, leading to variations in classification, definition, and treatment approaches. This article assesses the previous literature and provides clarity and guidance for the practical treatment of camptodactyly. PMID- 29625644 TI - Management of Flexor Pulley Injuries with Proximal Interphalangeal Joint Contracture. AB - Flexor pulley ruptures with severe proximal interphalangeal (PIP) joint contracture present a complex challenge for the hand surgeon. Four patients were treated with a delayed presentation of pulley rupture and fixed PIP flexion contracture with a technique of external extension torque application followed by splinting without pulley reconstruction. Using this technique, the PIP joint contractures improved from an average of 66 degrees to an average of 19 degrees , patient satisfaction was high, and the pulley injuries were managed with splinting alone without open pulley reconstruction. PMID- 29625646 TI - Therapy Concepts for the Proximal Interphalangeal Joint. AB - The principles of hand therapy for proximal interphalangeal joint disorders include protecting injured structures, minimizing patient discomfort, and optimizing patient recovery. Comprehension of hand anatomy, the nature of the injury being treated, and the phases of healing are critical when designing a safe and effective hand therapy program. Hand therapists use a combination of orthoses, guided exercises, and modalities to improve edema, sensitivity, range of motion, and function. PMID- 29625647 TI - Current Concepts in the Management of Proximal Interphalangeal Joint Disorders. PMID- 29625645 TI - Complications of Proximal Interphalangeal Joint Injuries: Prevention and Treatment. AB - Proximal interphalangeal joint injuries are one of the most common injuries of the hand. The severity of injury can vary from a minor sprain to a complex intra articular fracture. Because of the complex anatomy of the joint, complications may occur even after an appropriate treatment. This article provides a comprehensive review on existing techniques to manage complications and imparts practical points to help prevent further complications after proximal interphalangeal joint injury. PMID- 29625648 TI - Role of Echocardiography in Transcatheter Mitral Valve Replacement in Native Mitral Valves and Mitral Rings. AB - Adaptation and evolution of transcatheter aortic valve replacement (TAVR) technologies has led to approval of TAVR for consideration in patients at intermediate risk for surgical aortic valve intervention. As TAVR becomes more mainstream, attention is shifting toward percutaneous mitral valve (MV) repair and transcatheter MV replacement (TMVR) techniques. Transcatheter heart valves (both purpose-built and off-label-use TAVR valves) are being implanted during TMVR procedures to treat clinically significant MV disease (native disease, degenerated bioprosthetic valves, and dysfunctional surgical MV annuloplasty repairs) when the risk of open heart MV surgery is prohibitive. The success of these high-risk procedures is directly related to accurate periprocedural imaging with echocardiography and other modalities. Although a multidisciplinary heart valve team approach is necessary for optimal patient selection, a multimodality team-based imaging approach and comprehensive understanding of the MV are required for safe procedural planning. Collaboration between noninvasive cardiac imagers and the intraprocedural interventional imaging team and translation of the periprocedural imaging to the implanting team are crucial to the success of TMVR technology. Currently, the TMVR procedures discussed here are conducted either as part of clinical research or off label. The US Food and Drug Administration-approved mitral valve-in-valve procedures for the treatment of degenerated mitral bioprosthetic valves are not discussed here. PMID- 29625650 TI - Nashville, Here We Come! PMID- 29625651 TI - Nashville and SS. A Combination Better than Chocolate and Peanut Butter. PMID- 29625649 TI - Validation of a Novel Software Tool for Automatic Aortic Annular Sizing in Three Dimensional Transesophageal Echocardiographic Images. AB - BACKGROUND: Accurate aortic annulus (AoA) sizing is crucial for transcatheter aortic valve implantation planning. Three-dimensional (3D) transesophageal echocardiography (TEE) is a viable alternative to the standard multidetector row computed tomography (MDCT) for such assessment, with few automatic software solutions available. The aim of this study was to present and evaluate a novel software tool for automatic AoA sizing by 3D TEE. METHODS: One hundred one patients who underwent both preoperative MDCT and 3D TEE were retrospectively analyzed using the software. The automatic software measurements' accuracy was compared against values obtained using standard manual MDCT, as well as against those obtained using manual 3D TEE, and intraobserver, interobserver, and test retest reproducibility was assessed. Because the software can be used as a fully automatic or as an interactive tool, both options were addressed and contrasted. The impact of these measures on the recommended prosthesis size was then evaluated to assess if the software's automated sizes were concordant with those obtained using an MDCT- or a TEE-based manual sizing strategy. RESULTS: The software showed very good agreement with manual values obtained using MDCT and 3D TEE, with the interactive approach having slightly narrower limits of agreement. The latter also had excellent intra- and interobserver variability. Both fully automatic and interactive analyses showed excellent test-retest reproducibility, with the first having a faster analysis time. Finally, either approach led to good sizing agreement against the true implanted sizes (>77%) and against MDCT based sizes (>88%). CONCLUSIONS: Given the automated, reproducible, and fast nature of its analyses, the novel software tool presented here may potentially facilitate and thus increase the use of 3D TEE for preoperative transcatheter aortic valve implantation sizing. PMID- 29625652 TI - The Sound and Science of Perioperative Echocardiography. PMID- 29625653 TI - The role of efflux pumps in Bacteroides fragilis resistance to antibiotics. AB - The resistance of Bacteroides fragilis to the most antimicrobial agents has been reported in the world. Identification of the microbial resistance mechanisms can play an important role in controlling these resistances. Currently, B. fragilis is resistant to most antibiotics. The multi-drug efflux pumps have been shown to underlie the antimicrobial resistance in B. fragilis strains. Two types of these efflux pumps including RND and MATE can be regarded as main structures responsible for antibiotic resistance. Therefore, the strategy for suppressing of this efflux system may be useful in the treatment and control of the multidrug resistant B. fragilis. The purpose of this study is to review the B. fragilis efflux pumps and their functions in the resistance to antibiotics. PMID- 29625654 TI - Characterization of Cd-resistant Klebsiella michiganensis MCC3089 and its potential for rice seedling growth promotion under Cd stress. AB - Application of heavy metal resistant plant growth promoting rhizobacteria has an important role as they help to evade metal-induced toxicity in plants on one hand and enhance plant growth on the other. The present study is therefore focused on the characterization of a cadmium resistant bacterial strain isolated from heavy metal contaminated rhizospheric soil designated as S8. This S8 strain was selected in terms of cadmium resistance and plant growth promoting traits. Moreover, it also showed resistance to lead and arsenic to a considerable extent. The selected strain S8 was identified as Klebsiella michiganensis by modern approaches of bacterial taxonomy. The plant growth promoting traits exhibited by the strain include 1-aminocyclopropane-1-carboxylic acid deaminase activity (58.33 ng alpha-keto butyrate/mg protein/h), Indole-3-acetic acid production (671 MUg/ml), phosphate solubilization (71.98 ppm), nitrogen fixation (3.72 MUg of nitrogen fixed/h/mg protein) etc. Besides, the strain also exhibited high cadmium removal efficiency (73-97%) from the medium and intracellular accumulation as well. Its efficiency to alleviate cadmium-induced toxicity was determined against a rice cultivar in terms of morphological and biochemical changes. Enhanced growth and reduced oxidative stress were detected in presence of the bacterium. On the basis of these results, it can be concluded that K. michiganensis strain S8 is cadmium accumulating plant growth promoting rhizobacterium that can be applied in cadmium contaminated agricultural soil to achieve better productivity of rice. PMID- 29625655 TI - Identification and characterization of a new Bacillus atrophaeus strain B5 as biocontrol agent of postharvest anthracnose disease in soursop (Annona muricata) and avocado (Persea americana). AB - Anthracnose is a fungal disease caused by Colletotrichum species that is detrimental to numerous fruit, including soursop and avocado. The use of fungicides to maintain the high quality of fruit creates a potential health risk. One alternative to this problem is the biological control, which has been applied successfully during postharvest. The Bacillus species are one of the most studied biological agents against postharvest pathogens because accomplish their biocontrol performance by producing a variety of metabolites. In this study, we evaluated the activity of metabolites contained in the cell free supernatant, obtained from Bacillus strain B5 culture, against micelial growth and spore germination of two virulent strains of C. gloeosporioides isolated from soursop and avocado. On the basis of 16S rDNA gene sequence analysis, this strain was identified as Bacillus atrophaeus. A preventive treatment using cell free supernatant, reduced severity and incidence of anthracnose disease on harvested soursop and avocado fruit. B. atrophaeus strain B5 harbors genes involved in the production of antibiotics such as surfactin, bacillomycin and iturin, which could be contributing to the efficiency of the preventive treatment during postharvest. The antagonistic role of metabolites contained in the cell free supernatant against anthracnose disease, provide a new approach by which to attack this problem and can help reduce the use of chemical pesticides, environmental pollution, leading to the safer fruit preservation. PMID- 29625656 TI - Roles of phospholipid methyltransferases in pycnidia development, stress tolerance and secondary metabolism in the taxol-producing fungus Pestalotiopsis microspore. AB - Phosphatidylcholine (PC) is an important membrane component of the eukaryotic cell. In yeast fungi, two phospholipid methyltransferases catalyze consecutive steps of methylation in the formation of phosphatidylcholine from phosphatidylethanolamine. However, roles of phospholipid methyltransferases in filamentous fungi remains less investigated. We report here the characterization of two genes, choA and choC, that putatively encoded phospholipid methyltransferases in the taxol-producing fungus Pestalotiopsis microspora. Deletion of choC resulted in defects in PC production, vegetative growth and development of asexual structure. The mutant strains exhibited multiple morphological abnormalities, e.g. swollen hyphal tips and enhanced hyphal branching, and even mycelial autolysis. Some novel roles for the genes were also revealed, for instance, the deletion of either choC or choA impaired the development of pycnidia and conidia, the cell wall integrity. The mutant strains displayed a hypersensitivity to stress conditions, e.g. osmotic stress, cold and metal ions. The osmotic hypersensitivity indicates a crosstalk of PC pathways to other signaling pathways, such as the HOG pathway. Still more, choA, but not choC, was required for the production of secondary metabolites, e.g. pestalotiollide B, suggesting distinct roles of the two genes. This work would contribute to better understanding the function of phospholipid methyltransferases in fungi. PMID- 29625657 TI - Multicellular behavior of environmental Escherichia coli isolates grown under nutrient-poor and low-temperature conditions. AB - The multicellular behavior designated "red dry and rough" (rdar) morphotype characterized by production of extracellular matrix mainly comprising curli fimbriae and cellulose-is a potential survival strategy of Escherichia coli outside the host. This study documents the ability of Escherichia cryptic clades, which have recently been recognized as new lineages genetically divergent from E. coli, to grow in unfavorable conditions through expression of distinct phenotypes. Growth under low-temperature and nutrient-poor conditions induced the rdar morphotype in all cryptic clade strains tested, especially after preincubation in broth supplemented with uracil. Such phenotypic response to harsh growth conditions was clearly detected by transmission and scanning electron microscopy, which showed that bacteria were encased in a fibrous matrix. Conversely, cells incubated in rich medium at 37 degrees C showed no matrix. Uracil enhanced the biosynthesis of matrix components, fostering biofilm production and strain adhesion to abiotic surfaces, as demonstrated by the increase of strong biofilm producers in biofilm assays. Harsh growth conditions also induced catalase activity, resulting in clade strain resistance to hydrogen peroxide oxidative stress. The present findings further support the 'environmental hypothesis' whereby cryptic clades would be able to persist in natural habitats outside the host through the expression of distinct survival phenotypes. PMID- 29625658 TI - Quorum sensing: A less known mode of communication among fungi. AB - Quorum sensing (QS), a density-dependent signaling mechanism of microbial cells, involves an exchange and sense of low molecular weight signaling compounds called autoinducers. With the increase in population density, the autoinducers accumulate in the extracellular environment and once their concentration reaches a threshold, many genes are either expressed or repressed. This cell density dependent signaling mechanism enables single cells to behave as multicellular organisms and regulates different microbial behaviors like morphogenesis, pathogenesis, competence, biofilm formation, bioluminescence, etc guided by environmental cues. Initially, QS was regarded to be a specialized system of certain bacteria. The discovery of filamentation control in pathogenic polymorphic fungus Candida albicans by farnesol revealed the phenomenon of QS in fungi as well. Pathogenic microorganisms primarily regulate the expression of virulence genes using QS systems. The indirect role of QS in the emergence of multiple drug resistance (MDR) in microbial pathogens necessitates the finding of alternative antimicrobial therapies that target QS and inhibit the same. A related phenomenon of quorum sensing inhibition (QSI) performed by small inhibitor molecules called quorum sensing inhibitors (QSIs) has an ability for efficient reduction of gene expression regulated by quorum sensing. In the present review, recent advancements in the study of different fungal quorum sensing molecules (QSMs) and quorum sensing inhibitors (QSIs) of fungal origin along with their mechanism of action and/or role/s are discussed. PMID- 29625659 TI - Inhibition of coxsackievirus B4 by Lactobacillus plantarum. AB - The enterovirus Coxsackievirus B4 (CV-B4) can infect different human tissues and provoke abnormal function or destruction of various organs and cells. Moreover, its infections have been linked to the onset of type 1 diabetes. Coxsackievirus B4 is classified as a "challenging virus", due to the intense yet vain efforts to find effective prevention and therapeutic agents, especially within biological compounds. Lactobacillus plantarum is a lactic acid bacterium that is endowed with probiotic properties, and holds great potential for applications in medical and food industry sectors. Several compounds produced by this microorganism have been associated with various benefits including antimicrobial activity. In this work, we investigated the possible antiviral abilities of two Lb. plantarum strains and their derivatives against CV-B4. The different assays carried out (e.g. pre-incubation, competition and post-infection, using HEp-2 cells as human cell model) suggest that the tested microorganisms and their derivatives have an in vitro inhibiting activity against CV-B4. This is the first report showing the anti-CVB4 activity of Lb. plantarum strains and their derivatives. PMID- 29625660 TI - The transcription factor-encoding gene crtf is involved in Clonostachys chloroleuca mycoparasitism on Sclerotinia sclerotiorum. AB - Clonostachys chloroleuca 67-1 (formerly C. rosea 67-1) is a potential biocontrol fungus active against various fungal plant pathogens. From transcriptome sequencing of 67-1 parasitizing sclerotia of Sclerotinia sclerotiorum, we identified the transcription factor-encoding gene crtf that is significantly up regulated during mycoparasitism. Transcription factors are widely distributed in fungi and involved in multiple biological processes. However, their role and regulatory mechanisms in mycoparasitism remain poorly understood. In this study, the function of crtf during 67-1 mycoparasitism was verified through gene knockout and complementation. The results showed that deletion of crtf did not influence fungal morphological characteristics, but the ability of the Deltacrtf mutant to parasitize sclerotia and suppress soybean Sclerotinia white mold in the greenhouse was markedly diminished compared with the wild type strain. The biocontrol activity of Deltacrtf recovered wild type levels when complemented with a plasmid expressing the crtf gene. These findings suggest that crtf plays a crucial role in C. chloroleuca mycoparasitism and provide insight into the molecular mechanisms underlying C. chloroleuca mycoparasitism on plant pathogenic fungi. PMID- 29625662 TI - Choosing wisely in the era of biologics for asthma. PMID- 29625661 TI - Antibiotic-producing Pseudomonas fluorescens mediates rhizome rot disease resistance and promotes plant growth in turmeric plants. AB - Rhizome rot of turmeric caused by Pythium aphanidermatum is a major threat to turmeric-cultivating areas of India. This study intends to evaluate the performance of fluorescent pseudomonads against Rhizome rot disease and understand the resistance mechanism in Turmeric plants. Fluorescent pseudomonads were screened against Pythium aphanidermatum using dual culture. Selected strains were evaluated for the performance of growth promoting attributes and the presence of antibiotic genes through PCR analysis. Strain FP7 recorded the maximum percent inhibition of P. aphanidermatum under in vitro conditions. Strains FP7 and TPF54 both increased plant growth in turmeric plants in vitro. Strain FP7 alone contained all the evaluated antibiotic biosynthetic genes. Talc and liquid-based formulations were prepared with effective strain and tested for its biocontrol activities under both glasshouse and field conditions. Enzymatic activities of the induced defense enzymes such as PO, PPO, PAL, CAT and SOD were estimated and subjected to spectrophotometric analysis. A combination of rhizome dip and soil drench of FP7 liquid formulation treatment remarkably recorded the minimum disease incidence, higher defense enzymes, maximum plant growth and yield under glasshouse and field conditions. Application of strain FP7 increased the defense molecules, plant growth and yield in turmeric plants thereby reducing the incidence of rhizome rot disease. Moreover, this study has a potential to be adopted for sustainable and eco-friendly turmeric production. PMID- 29625663 TI - Biologics. PMID- 29625664 TI - Challenges in the treatment of asthma in children and adolescents. AB - OBJECTIVE: Despite the availability of effective treatments, asthma control in children and adolescents remains inadequate and rates of health care use are high. This follow-up to a recent review (O'Byrne et al, Eur Respir J. 2017;50[3]) examines a number of challenges in current pediatric asthma management compared with that of an adult perspective and discusses possible alternative strategies that might improve pediatric asthma management and control. DATA SOURCES: The evidence base for this review is limited because, historically, much of the research has been performed in adults. STUDY SELECTIONS: Not applicable. RESULTS: Pediatric asthma management is complicated by variability in asthma severity and control and difficulty in measuring pulmonary function and airway inflammation. Current challenges in pediatric asthma management include the recommended initial therapy treating only the symptoms rather than the underlying inflammation and switching to controller therapy only when asthma subsequently worsens. CONCLUSION: Alternative strategies that might improve pediatric asthma management and control include replacement of short-acting beta2-agonist relievers by an inhaled corticosteroid plus a fast-acting beta2-agonist (short-acting beta2 agonist or fast- and long-acting beta2-agonist) combination at Global Initiative for Asthma step 1 or 2 to ensure that patients receive an inhaled corticosteroid whenever they feel the need for symptomatic relief. Such an approach could eliminate the problem of learned overuse or over-reliance on short-acting beta2 agonist reliever medication and address the other challenges in current pediatric asthma management. Clinical studies in pediatric patients or large studies involving a proportion of pediatric patients are required to provide the supporting evidence needed to help advance such new approaches and improve asthma control from a pediatric perspective. PMID- 29625665 TI - Subcutaneous venom immunotherapy in children: Efficacy and safety. AB - BACKGROUND: Venom immunotherapy (VIT) is safe in children, although adverse effects can occur. OBJECTIVE: To document adverse effects and to determine re sting reactions and the efficacy of VIT in childhood. METHODS: We retrospectively analyzed data from children who had taken VIT from 2002 through 2015. These patients were queried by telephone to determine reactions after re-stings during or after VIT. RESULTS: In total 107 children with a systemic reaction after Hymenoptera sting and with proved immunoglobulin E-mediated sensitization were enrolled. Participants had a median age of 10.0 years (7.2-12.4 years) at the beginning of immunotherapy. Fifty-two participants had allergic reactions during VIT; 40 of these reactions were local (37.4%), 5 were large local (4.7%), and 7 were systemic (6.5%). Of the 52 patients with adverse reactions, most reactions were local (n = 40, 89%) and were observed mainly in dose-increase periods (n = 25, 60%; P < .001). Although local reactions were more frequently seen with Vespula treatment (P = .047), systemic reactions were common with Apis treatment (P = .031). Sixty-eight patients (63.5%) were queried for re-sting, 33 (48.5%) had a re-sting and 24 (72.7%) of these 33 patients developed allergic reactions. The reactions were local (n = 19), large local (n = 1), and systemic (n = 4). Risk analysis for local and systemic reactions during VIT showed pre-existing asthma as an independent risk factor (odds ratio 4.1, 95% confidence interval 1.3 12.7, P = .016). CONCLUSION: In children, VIT appears to be safe and protective against severe reactions after re-sting. However, pre-existing asthma was identified as a risk factor for systemic and large local reactions during VIT in children. PMID- 29625667 TI - Skin testing and desensitization outcomes among platinum-sensitive oncology patients. PMID- 29625666 TI - Late presentation of subtotal C6 deficiency in a patient with recurrent Neisseria meningitides infections. PMID- 29625668 TI - Is there a link between nasal polyposis and increased risk for sinonasal malignancy? PMID- 29625669 TI - Outpatient penicillin skin testing has greater value in targeted patient populations. PMID- 29625670 TI - Anaphylaxis and severe immune hemolytic anemia during the course of desensitization with carboplatin. PMID- 29625671 TI - Selective IgM deficiency associated with adult-onset Still disease. PMID- 29625672 TI - Food allergy management and anaphylaxis preparedness in a suburban school district varies by school level. PMID- 29625673 TI - Commitment needed from South Africa's new president. PMID- 29625674 TI - PepsNMR for 1H NMR metabolomic data pre-processing. AB - In the analysis of biological samples, control over experimental design and data acquisition procedures alone cannot ensure well-conditioned 1H NMR spectra with maximal information recovery for data analysis. A third major element affects the accuracy and robustness of results: the data pre-processing/pre-treatment for which not enough attention is usually devoted, in particular in metabolomic studies. The usual approach is to use proprietary software provided by the analytical instruments' manufacturers to conduct the entire pre-processing strategy. This widespread practice has a number of advantages such as a user friendly interface with graphical facilities, but it involves non-negligible drawbacks: a lack of methodological information and automation, a dependency of subjective human choices, only standard processing possibilities and an absence of objective quality criteria to evaluate pre-processing quality. This paper introduces PepsNMR to meet these needs, an R package dedicated to the whole processing chain prior to multivariate data analysis, including, among other tools, solvent signal suppression, internal calibration, phase, baseline and misalignment corrections, bucketing and normalisation. Methodological aspects are discussed and the package is compared to the gold standard procedure with two metabolomic case studies. The use of PepsNMR on these data shows better information recovery and predictive power based on objective and quantitative quality criteria. Other key assets of the package are workflow processing speed, reproducibility, reporting and flexibility, graphical outputs and documented routines. PMID- 29625675 TI - A high-performance electrochemical sensor for biologically meaningful l-cysteine based on a new nanostructured l-cysteine electrocatalyst. AB - As a new class of l-cysteine electrocatalyst explored in this study, Au/CeO2 composite nanofibers (CNFs) were employed to modify the screen printed carbon electrode (SPCE) to fabricate a novel l-cysteine (CySH) electrochemical sensor with high performance. Its electrochemical behavior and the roles of Au and CeO2 in the composite toward electro-oxidation of CySH were elucidated and demonstrated using cyclic voltammetry and amperometry techniques for the first time through the comparison with pure CeO2 NFs. More specifically, the Au/CeO2 CNFs modified SPCE possessed greatly enhanced electrocatalytic activity toward CySH oxidation. An ultra high sensitivity of 321 MUA mM-1cm-2 was obtained, which is almost 2.7 times higher than that of pure CeO2 NFs, revealing that the presence of Au imposed an important influence on the electrocatalytic activity toward CySH. The detailed reasons on such high performance were also discussed. In addition, the as-prepared sensor showed a low detection limit of 10 nM (signal to noise ratio of 3), a wide linear range up to 200 MUM for the determination of CySH, an outstanding reproducibility and good long-term stability, as well as an excellent selectivity against common interferents such as tryptophan, tyrosine, methionine, ascorbic acid and uric acid. All these features indicate that the Au/CeO2 composite nanofiber is a promising candidate as a new class of l-cysteine electrocatalyst in the development of highly sensitive and selective CySH electrochemical sensor. PMID- 29625676 TI - Rapid and low-cost strategy for detecting genome-editing induced deletion: A single-copy case. AB - Genome editing techniques have been implemented in human daily lives, which has created a high demand for the development of new gene-edited product analysis methods. Conventional assays are time-consuming, labor-intensive, and costly. This paper proposes a rapid and low-cost strategy for detecting genome-editing induced deletion which works by integrating rapid-multiplex ligation-dependent probe amplification (MLPA) with a dual-lateral flow nucleic acid biosensor (LFNAB) cascade in a single-copy case. A rapid-MLPA was first introduced to the LFNAB system as a replacement for the conventional PCR for enhanced specificity and accuracy. A dual-LFNAB was applied for the detection of genome-editing induced deletion without any additional instrumentation or complex operation. After optimization, we achieved the specific detection of wildtype alleles and deletion alleles in spiked samples with a detection limit of 0.4 fM, which is comparable to that of electrophoresis-based detection assays and fluorescent biosensors. To confirm the validity and feasibility of our strategy, we assayed two pork samples from two WUZHISHAN pigs successfully. By comparing the detection results from next-generation sequencing analysis, we found that the proposed cascade demonstrates at least 20-fold shorter assay time and at least 100-fold less assay cost. To this effect, the proposed method is a rapid and low-cost solution to sample-to-answer detection of genome-editing induced deletion and shows remarkable potential in regards to international trade, transparency, and freedom of choice. PMID- 29625677 TI - Magnetically controlled fluorescence aptasensor for simultaneous determination of ochratoxin A and aflatoxin B1. AB - Development of an efficient method for the simultaneous detection of two highly concerning mycotoxins, ochratoxin A (OTA) and aflatoxin B1 (AFB1), is of great significance on food safety monitoring. Herein, a magnetically controlled fluorescence aptasensor for simultaneous determination of OTA and AFB1 has been successfully developed. The working principle of the aptasensor is based on the specific aptamer-mycotoxin recognition and further leads to the partial release of two distinguishable fluorescence labels from the magnetic carriers. Through the magnetic separation, the reporter probes in the supernatant solution can be collected and converted into a sensitive fluorescence signal with dual emission peaks. This aptasensor provided a wide detection range of 2 pg mL-1 - 5 ng mL-1 for OTA and 5 pg mL-1 - 10 ng mL-1 for AFB1. The new easy-to-wash and simple-to use approach offers a simultaneous and high selective detection with high sensitivity (limits of detection of 0.67 and 1.70 pg mL-1 for OTA and AFB1, respectively). Remarkable accuracy (relative standard deviation < 5.6%) during the mycotoxins determination as well as excellent quantitative recoveries (95 108%) during the analysis of the spiked corn samples were also achieved. This simple aptasensing scheme provides a new avenue for high throughput screen of dual mycotoxins due to its simple manipulation, short assay times, high selectivity and sensitivity. PMID- 29625678 TI - Ethane-bridged hybrid monoliths with well-defined mesoporosity and great stability for high-performance peptide separation. AB - A novel kind of hybrid monolith with well-defined mesopore structure was prepared based on sol-gel condensation of 1, 2-bis(trimethoxysilyl)ethane (BTME) and tetramethoxysilane. Compared with terminal organosiloxanes used for preparation of conventional hybrid monoliths, BTME, as an ethane-bridged alkoxysilane precursor, could not only maintain the uniformity of pore size distribution, but also improve the chemical stability of the monolith via Si-C bonds in the framework. Owing to the controllable mesoporous structure and good stability, the monolithic column was used for the separation of peptides with half peak width less than 6 s and the run-to-run and column-to-column relative standard deviations (RSD) for the retention time of five standard peptides less than 2.5%, showing narrow peak width and good reproducibility. Moreover, the separation performance could be well maintained even after washed by the mobile phase with pH 11.0 at 50 degrees C. Furthermore, 100 cm-length monolithic column was prepared and successfully used for nanoRPLC-ESI-MS/MS analysis of HeLa cell lysate digests, and 5670 proteins corresponding to 37574 peptides were identified from 750 ng of the sample, showing great promising of "single-shot" large-scale in-depth proteomic research. PMID- 29625679 TI - Recognition mechanism of aromatic derivatives resolved by argentation chromatography: The driving role played by substituent groups. AB - Argentation chromatography is widely used nowadays as a powerful tool to separate complex mixtures of analytes containing unsaturated and/or aromatic fragments. Here we present the results of chromatographic and computational studies on a silver-thiolate stationary phase, in which the silver metal is covalently bonded to mercaptopropyl silica particles. The exceptionally high selectivity displayed by this organometallic moiety prompted us to deeply investigate its molecular recognition properties. The interactions of the silver atom with a series of benzene derivatives was investigated to gain information on the mechanism by which the different ring substituents modulate retention factors and selectivity. The experimental trend was fully rationalized by means of quantum-mechanical Density Functional Theory (DFT) calculations, which allowed us to elucidate the chromatographic results in the light of unusual and unexpected substituent effects. PMID- 29625680 TI - Microstructured optical fiber-based luminescent biosensing: Is there any light at the end of the tunnel? - A review. AB - This review covers the current state of the art of luminescent biosensors based on various types of microstructured optical fiber. The unique optical and structural properties of this type of optical fiber make them one of the most promising integrated platforms for bioassays. The individual sections of this review are devoted to a) classification of microstructured optical fibers, b) microstructured optical fiber materials, c) aspects of biosensing based on the biomolecules incorporated into the microstructured optical fibers, and d) development of models for prediction of the efficiency of luminescent signal processing. The authors' views on current trends and limitations of microstructured optical fibers for biosensing as well as the most promising areas and technologies for application in analytical practice are presented. PMID- 29625681 TI - Corrigendum to "New look inside human breast ducts with Raman imaging. Raman candidates as diagnostic markers for breast cancer prognosis: Mammaglobin, palmitic acid and sphingomyelin" [ACA 909, (2016) 91-100]. PMID- 29625682 TI - Recent trends in atomic fluorescence spectrometry towards miniaturized instrumentation-A review. AB - Atomic fluorescence spectrometry (AFS), as one of the common atomic spectrometric techniques with high sensitivity, simple instrumentation, and low acquisition and running cost, has been widely used in various fields for trace elemental analysis, notably the determination of hydride-forming elements by hydride generation atomic fluorescence spectrometry (HG-AFS). In recent years, the soaring demand of field analysis has significantly promoted the miniaturization of analytical atomic spectrometers or at least instrumental components. Various techniques have also been developed to approach the goal of portable/miniaturized AFS instrumentation for field analysis. In this review, potentially portable/miniaturized AFS techniques, primarily involving advanced instrumental components and whole instrumentation with references since 2000, are summarized and discussed. The discussion mainly includes five aspects: radiation source, atomizer, detector, sample introduction, and miniaturized atomic fluorescence spectrometer/system. PMID- 29625683 TI - Evaluation of batch effect elimination using quality control replicates in LC-MS metabolite profiling. AB - Systematic variation of the instrument's response both within- and between batches is frequently observed in untarget LC-MS metabolomics involving the analysis of a large number of samples. The so-called batch effect decreases the statistical power and has a negative impact on repeatability and reproducibility of the results. As there is no standard way of assessing or correcting LC-MS batch effects and there is no single method providing optimal results in all situations, the selection of the optimal approach is not trivial. This work explores the effectiveness of a set of tools for batch effect assessment. Qualitative tools include the monitoring of spiked internal standards, principal component analysis and hierarchical cluster analysis. Quantitative tools comprise the distribution of RSDQC values, the median Pearson correlation coefficient in QCs, the ratio of random features in QCs using the runs test, as well as multivariate tools such as the delta-statistic, Silhouette plots, Principal Variance Component Analysis and the expected technical variation in the prediction. Results show that qualitative and quantitative approaches are complementary and that by limiting the analysis to QCs the power to detect and evaluate both within and between batch effects is increased. Besides, the graphical integration of outputs from multiple quantitative tools facilitates the evaluation of batch effects and it is proposed as a straightforward way for comparing and tailoring batch effect elimination approaches. PMID- 29625684 TI - Multivariate estimation of the limit of detection by orthogonal partial least squares in temperature-modulated MOX sensors. AB - Metal oxide semiconductor (MOX) sensors are usually temperature-modulated and calibrated with multivariate models such as partial least squares (PLS) to increase the inherent low selectivity of this technology. The multivariate sensor response patterns exhibit heteroscedastic and correlated noise, which suggests that maximum likelihood methods should outperform PLS. One contribution of this paper is the comparison between PLS and maximum likelihood principal components regression (MLPCR) in MOX sensors. PLS is often criticized by the lack of interpretability when the model complexity increases beyond the chemical rank of the problem. This happens in MOX sensors due to cross-sensitivities to interferences, such as temperature or humidity and non-linearity. Additionally, the estimation of fundamental figures of merit, such as the limit of detection (LOD), is still not standardized in multivariate models. Orthogonalization methods, such as orthogonal projection to latent structures (O-PLS), have been successfully applied in other fields to reduce the complexity of PLS models. In this work, we propose a LOD estimation method based on applying the well-accepted univariate LOD formulas to the scores of the first component of an orthogonal PLS model. The resulting LOD is compared to the multivariate LOD range derived from error-propagation. The methodology is applied to data extracted from temperature modulated MOX sensors (FIS SB-500-12 and Figaro TGS 3870-A04), aiming at the detection of low concentrations of carbon monoxide in the presence of uncontrolled humidity (chemical noise). We found that PLS models were simpler and more accurate than MLPCR models. Average LOD values of 0.79 ppm (FIS) and 1.06 ppm (Figaro) were found using the approach described in this paper. These values were contained within the LOD ranges obtained with the error-propagation approach. The mean LOD increased to 1.13 ppm (FIS) and 1.59 ppm (Figaro) when considering validation samples collected two weeks after calibration, which represents a 43% and 46% degradation, respectively. The orthogonal score-plot was a very convenient tool to visualize MOX sensor data and to validate the LOD estimates. PMID- 29625685 TI - Molecularly imprinted mesoporous silica nanoparticles for specific extraction and efficient identification of Amadori compounds. AB - Amadori compounds are an important family of chemical species with high values in the quality control and research of food and tobacco products as well as disease diagnosis. Since they are present in a large population with close structure and nature, recognition of specific Amadori compounds from complex sample matrices presents a challenging task. Particularly, few reagents or materials that can recognize specific Amadori compounds have been reported. In this study, we synthesized molecularly imprinted mesoporous silica nanoparticles (MIMSNs) that can highly specifically recognize and efficiently extract an Amadori compound of interest from complex samples. N-(1-deoxy-d-glucose-1-yl)tryptophan (Glc-Trp), a typical Amadori compound, was used as the template and target compound. The prepared MIMSNs exhibited excellent binding properties. The cross-reactivity was only 2.9-4.8% towards interfering analogs. The binding constant and binding capacity towards the target were 66 MUM and 45 MUmol/g, respectively. The imprinting approach showed outstanding imprinting effect, giving an imprinting factor of 119.4. Through combining MIMSNs-based extraction with electrospray ionization-mass spectrometry (ESI-MS) and capillary electrography (CE), a targeted analysis approach was established and demonstrated to be an efficient platform for identification and determination of Glc-Trp from cigarette sample. PMID- 29625686 TI - Automated bundled hollow fiber array-liquid-phase microextraction with liquid chromatography tandem mass spectrometric analysis of perfluorinated compounds in aqueous media. AB - An automated bundled hollow fiber array (BHF)-liquid-phase microextraction (LPME) methodology in combination with ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) has been developed for the determination of perfluorinated compounds (PFCs) in environmental aqueous matrices. Eight PFCs were considered, including perfluoroheptanoic acid, perfluorooctanoic acid, perfluorononanoic acid, perfluorodecanoic acid, perfluoroundecanoic acid, perfluorododecanoic acid, perfluorotridecanoic acid, perfluorotetradecanoic acid. Experimental parameters influencing extraction efficiency, such as number of hollow fibers in the BHF extraction device, type of extraction and desorption solvent, extraction conditions (stirring rate, temperature and duration), elution conditions and the salting out effect were examined. Under the most favourable conditions, enrichment factors of between 9 and 40 were achieved for the target compounds when extracting from 10 mL of sample. Good intra and inter-day precision were obtained with relative standard deviations of less than 12%. The linearity range investigated was between 5 and 10,000 ng L-1, with coefficients of determination (r2) >= 0.991. The developed method was applied for the UHPLC MS/MS determination of environmental PFCs in industrial water discharge samples. The automation of BHF-LPME together with UHPLC-MS/MS rendered the method efficient, rapid and sensitive to determine PFCs, with the possibility of on-site real-time monitoring of contaminants in environmental waters. PMID- 29625687 TI - Ultra-sensitive, stable isotope assisted quantification of multiple urinary mycotoxin exposure biomarkers. AB - There is a critical need to better understand the patterns, levels and combinatory effects of exposures we are facing through our diet and environment. Mycotoxin mixtures are of particular concern due to chronic low dose exposures caused by naturally contaminated food. To facilitate new insights into their role in chronic disease, mycotoxins and their metabolites are quantified in bio-fluids as biomarkers of exposure. Here, we describe a highly sensitive urinary assay based on ultra-high performance liquid chromatography - tandem mass spectrometer (UHPLC-MS/MS) and 13C-labelled or deuterated internal standards covering the most relevant regulated and emerging mycotoxins. Utilizing enzymatic pre-treatment, solid phase extraction and UHPLC separation, the sensitivity of the method was significantly higher (10-160x lower LODs) than in a previously described method used for comparison purpose, and stable isotopes provided compensation for challenging matrix effects. This method was in-house validated and applied to re assess mycotoxin exposure in urine samples obtained from Nigerian children, adolescent and adults, naturally exposed through their regular diet. Owing to the methods high sensitivity, biomarkers were detected in all samples. The mycoestrogen zearalenone was the most frequently detected contaminant (82%) but also ochratoxin A (76%), aflatoxin M1 (73%) and fumonisin B1 (71%) were quantified in a large share of urines. Overall, 57% of 120 urines were contaminated with both, aflatoxin M1 and fumonisin B1, and other co-exposures were frequent. These results clearly demonstrate the advanced performance of the method to assess lowest background exposures (pg mL-1 range) using a single, highly robust assay that will allow for the systematic investigation of low dose effects on human health. PMID- 29625688 TI - Development of a general method for quantifying IgG-based therapeutic monoclonal antibodies in human plasma using protein G purification coupled with a two internal standard calibration strategy using LC-MS/MS. AB - Monoclonal antibody (mAb) drugs have generated much interest in recent years for treating various diseases. Immunoglobulin G (IgG) represents a high percentage of mAb drugs that have been approved by the Food and Drug Administration (FDA). To facilitate therapeutic drug monitoring and pharmacokinetic/pharmacodynamic studies, we developed a general liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantify the concentration of IgG-based mAbs in human plasma. Three IgG-based drugs (bevacizumab, nivolumab and pembrolizumab) were selected to demonstrate our method. Protein G beads were used for sample pretreatment due to their universal ability to trap IgG-based drugs. Surrogate peptides that were obtained after trypsin digestion were quantified by using LC MS/MS. To calibrate sample preparation errors and matrix effects that occur during LC-MS/MS analysis, we used two internal standards (IS) method that include the IgG-based drug-IS tocilizumab and post-column infused IS. Using two internal standards was found to effectively improve quantification accuracy, which was within 15% for all mAb drugs that were tested at three different concentrations. This general method was validated in term of its precision, accuracy, linearity and sensitivity for 3 demonstration mAb drugs. The successful application of the method to clinical samples demonstrated its' applicability in clinical analysis. It is anticipated that this general method could be applied to other mAb-based drugs for use in precision medicine and clinical studies. PMID- 29625689 TI - Spinopelvic injuries. Facts and controversies. AB - Spinopelvic injuries result from high energy trauma with overloading through the sacrum. These lesions can accomplish either bone fractures, ligament injuries or, most commonly, both. They may be accompanied with other associated life threatening injuries and cause biomechanical instability with potential fracture non-union, mal-union and subsequent lifetime pain and disability. Surgical stabilization of spinopelvic injuries requires planning in order to apply the appropriate osteosynthesis principles (compression; neutralization; buttressing and tension band). In general terms simple sacral fractures can be treated under compression by iliosacral screws. However, as more complex ones cannot be compressed, they need vertical support and neutralization of shearing forces (neutralization and buttressing principles). For that purpose, spinopelvic instrumentations appear to be the current appropriate technique of stabilization. In the herein paper the general principles of sacral fracture osteosynthesis are discussed, as well as its application to spinopelvic injuries. Controversies on positioning, surgical approach, per-operative traction, sacral laminectomy, type of biomechanical construct, length of fixation, screws length, mode of weight bearing, and osteosynthesis hardware removal are discussed. PMID- 29625690 TI - Discussion of "Use of integrative services is associated with maintenance of work schedule during and after cancer treatment". PMID- 29625691 TI - The relation between working conditions, aberrant driving behaviour and crash propensity among taxi drivers in China. AB - Although the taxi industry is playing an important role in Chinese everyday life, little attention has been posed towards occupational health issues concerning the taxi drivers' working conditions, driving behaviour and road safety. A cross sectional survey was administered to 1021 taxi drivers from 21 companies in four Chinese cities and collected information about (i) sociodemographic characteristics, (ii) working conditions, (iii) frequency of daily aberrant driving behaviour, and (iv) involvement in property-damage-only (PDO) and personal injury (PI) crashes over the past two years. A hybrid bivariate model of crash involvement was specified: (i) the hybrid part concerned a latent variable model capturing unobserved traits of the taxi drivers; (ii) the bivariate part modelled jointly both types of crashes while capturing unobserved correlation between error terms. The survey answers paint a gloomy picture in terms of workload, as taxi drivers reported averages of 9.4 working hours per day and 6.7 working days per week that amount on average to about 63.0 working hours per week. Moreover, the estimates of the hybrid bivariate model reveal that increasing levels of fatigue, reckless behaviour and aggressive behaviour are positively related to a higher propensity of crash involvement. Lastly, the heavy workload is also positively correlated with the higher propensity of crashing, not only directly as a predictor of crash involvement, but also indirectly as a covariate of fatigue and aberrant driving behaviour. The findings from this study provide insights into potential strategies for preventive education and taxi industry management to improve the working conditions and hence reduce fatigue and road risk for the taxi drivers. PMID- 29625692 TI - Young drivers' perception of adult and child pedestrians in potential street crossing situations. AB - Despite overall improvements in road traffic safety, pedestrian accidents continue to be a serious public health problem. Due to lack of experience, limited cognitive and motoric skills, and smaller size, children have a higher injury risk as pedestrians than adults. To what extent drivers adjust their driving behaviour to children's higher vulnerability is largely unknown. To determine whether young male drivers' behaviour and scanning pattern differs when approaching a child and an adult pedestrian in a potential street-crossing situation, sixty-five young (18-24) male drivers' speed, lateral position and eye movements were recorded in a driving simulator. Results showed that fewer drivers responded by slowing down and that drivers had a higher driving speed when approaching a child pedestrian, although the time of the first fixation on both types of pedestrians was the same. However, drivers drove farther away from a child than an adult pedestrian. Additionally, fewer drivers who did not slow down fixated on the speedometer while approaching the child pedestrian. The results show that young drivers behave differently when approaching a child and an adult pedestrian, though not in a way that appropriately accounts for the limitations of a child pedestrian. A better understanding of how drivers respond to different types of pedestrians and why could contribute to the development of pedestrian detection and emergency braking systems. PMID- 29625694 TI - Low-quality evidence suggests that powered toothbrushing may promote better gingival health than manual toothbrushing in patients with fixed orthodontic appliances. PMID- 29625693 TI - [Implementation and assessment of anticancer drugs batch preparation circuit in a teaching hospital]. AB - INTRODUCTION: In 2011, the anticancer preparation unit in a teaching hospital implemented a circuit for batch preparation of anticancer drugs. In this circuit, a manual and a semi-automatic production process coexist. The aim of the study is to describe the circuit in 2016 and to assess the impact of batch preparation in a anticancer preparation unit. MATERIAL AND METHODS: Eligible anticancer drugs for batch preparation satisfy two conditions: solution stability up to 28 days, prescription frequency up to one every two days. Batch worksheets are standardized. The pharmaceutical validation relies on the conformity of microbiological, analytical, gravimetric and visual controls of infusion bags. The duration of manual and semi-automatic batch preparation process and the time availability of an infusion bag were assessed. RESULTS: In 2016, eleven anticancer drugs (33 dosages) were eligible for batch preparation: it represents 22% of total production. In total, 70% was semi-automatic. The mean batch sizes were 27+/-9 (semi-automatic) and 14+/-1 (manual). The mean duration of production process was respectively 78min and 113min for semi-automatic and manual batch preparation. The mean time availability of an infusion bag was 32min+/-17. DISCUSSION AND CONCLUSION: Our process is secure. Batch preparation of anticancer drugs contributes to smooth production and spare nurses from preparing infusion bags outside opening hours of the anticancer preparation unit. Eligible anticancer drugs and batches size change constantly according to the evolution of prescription frequencies and anticancer drugs public tenders. PMID- 29625695 TI - Uncertainty about the benefits of dental extractions in the esthetic outcomes of patients undergoing orthodontic treatment owing to important limitations in a study addressing this question. PMID- 29625696 TI - Walking bleach technique for endodontically treated teeth with 35% hydrogen peroxide and 37% carbamide peroxide may result in similar improvements in tooth color and patient satisfaction. PMID- 29625697 TI - Although silver diamine fluoride arrested caries sooner than fluoride varnish, the overall proportion of arrested caries was not importantly different after 30 months. PMID- 29625698 TI - Evaluating the Usefulness of MP-3 Microperimetry in Glaucoma Patients. PMID- 29625699 TI - Reply. PMID- 29625700 TI - Quality of Life in Cushing's disease: A long term issue? AB - The purpose of this review is to describe how quality of life (QoL) is impaired in patients with hypercortisolism due to Cushing's syndrome of any aetiology, including pituitary-dependent Cushing's disease. It is worse in active disease, but improvement after successful therapy is often incomplete, due to persistent physical and psychological co-morbidities, even years after endocrine "cure". Physical symptoms like extreme fatigability, central obesity with limb atrophy, hypertension, fractures, and different skin abnormalities severely impair the affected patients' everyday life. Psychological and cognitive problems like bad memory, difficulties to concentrate and emotional distress, often associated with anxiety and depression, make it difficult for many patients to overcome the aftermath of treated Cushing's syndrome. Recent studies have shown diffuse structural abnormalities in the central nervous system during active hypercortisolism, thought to be related to the wide distribution of glucocorticoid receptors throughout the brain. Even though they improve after treatment, normalization is often not complete. Shortening the exposure to active Cushing's syndrome by reducing the often long delay to diagnosis and promptly receiving effective treatment is highly desirable, together with preparing the patient for the difficult periods, especially after surgery. In this way they are prepared for the impairments they perceive in every day life, and live with the hope of later improvement, which can be therapeutic in many instances. PMID- 29625701 TI - What's your number? The effects of trial order on the one-target advantage. AB - When moving our upper-limb towards a single target, movement times are typically shorter than when movement to a second target is required. This is known as the one-target advantage. Most studies that have demonstrated the one-target advantage have employed separate trial blocks for the one- and two-segment movements. To test if the presence of the one-target advantage depends on advance knowledge of the number of segments, the present study investigated whether the one-target advantage would emerge under different trial orders/sequences. One- and two-segment responses were organized in blocked (i.e., 1-1-1, 2-2-2), alternating (i.e., 1-2-1-2-1-2), and random (i.e., 1-1-2-1-2-2) trial sequences. Similar to previous studies, where only blocked schedules have typically been utilized, the one-target advantage emerged during the blocked and alternate conditions, but not in the random condition. This finding indicates that the one target advantage is contingent on participants knowing the number of movement segments prior to stimulus onset. PMID- 29625702 TI - Comparison of Long-Term Survival Benefits With Cardiac Resynchronization Therapy in Patients With Mild Heart Failure With Versus Without Diabetes Mellitus (from the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy [MADIT-CRT]). AB - We have previously shown a reduction in HF events with cardiac resynchronization therapy with defibrillator (CRT-D) in patients with mild heart failure (HF) and diabetes mellitus (DM). It remains unknown whether HF remission in DM patients with CRT-D translates into reduced mortality. The effects of CRT-D versus an implantable cardioverter-defibrillator (ICD) alone to reduce long-term mortality were assessed in patients with left bundle branch block with DM (n = 386) and without DM (n = 982), enrolled in the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT). We further subdivided DM patients by insulin and noninsulin therapy. Kaplan-Meier survival analyses and multivariate cox proportional hazards regression models were utilized. At the 7-year follow-up, CRT-D was associated with a lower mortality in DM patients compared with ICD alone (21% vs 42%, p = 0.02), similar to non-DM patients (16 vs 24%, p = 0.014). CRT-D was associated with a 41% reduction in the risk of long-term all-cause mortality in DM patients (hazard ratio [HR] 0.59, 95% confidence interval 0.36 to 0.96, p = 0.033) and a similar reduction in non-DM patients (HR 0.69, 95% confidence interval 0.48 to 0.99, p = 0.045, treatment diabetes interaction p = 0.611). Among DM patients, mortality benefit was evident in insulin-treated patients only (HR 0.40, p = 0.030). Reductions in HF events were present in all groups. In the MADIT-CRT, patients with mild HF with DM derive significant long-term survival benefit from CRT-D, similar to those without DM. The mortality benefit from CRT-D within the DM subgroup seems to be confined to patients with insulin treated diabetes. PMID- 29625703 TI - Treatment of a Refractory Venous Ulcer With Terminal Interruption of the Reflux Source. PMID- 29625704 TI - The Keystone Flap in Dermatology: Clinical Experience with 18 Patients. AB - INTRODUCTION AND OBJECTIVES: The keystone flap is a fasciocutaneous flap supplied by perforating arteries. It is used in dermatology to repair surgical defects in areas with low skin extensibility (the upper and lower limbs and the back). We review the clinical experience gained with keystone flap reconstruction at our hospital and report on the surgical outcomes. MATERIAL AND METHODS: Descriptive retrospective study of patients with malignant skin tumors on the lower limbs who underwent keystone flap reconstruction. RESULTS: Eighteen patients (mean age, 77.83 years) underwent keystone flap reconstruction using the Behan technique in 17 cases and the modified Moncrieff technique in one. Basal cell carcinomas accounted for 38.8% of the tumors excised, squamous cell carcinomas 33.3%, and malignant pigmented tumors 27.7%. Cardiovascular risk factors were observed in 72.2% of patients. Minor complications occurred in 38.8% of patients, and there were no cases of partial or total flap necrosis. CONCLUSIONS: We consider the keystone flap to be a good alternative to other flaps and grafts for the surgical reconstruction of lower limb defects. The success rate was high, and the cosmetic and functional outcomes were good. PMID- 29625705 TI - Mycobacterium tuberculosis protein Rv2220 induces maturation and activation of dendritic cells. AB - Tuberculosis remains a serious health problem worldwide. Characterization of the dendritic cell (DC)-activating mycobacterial proteins has driven the development of effective TB vaccine candidates besides improving the understanding of immune responses. Some studies have emphasized the essential role of protein Rv2220 from M. tuberculosis in mycobacterial growth. Nonetheless, little is known about cellular immune responses to Rv2220. In this study, our aim was to test whether protein Rv2220 induces maturation and activation of DCs. Rv2220-activated DCs appeared to be in a mature state with elevated expression of relevant surface molecules and proinflammatory cytokines. DC maturation caused by Rv2220 was mediated by MAPK and NF-kappaB signaling pathways. Specifically, Rv2220-matured DCs induced the expansion of memory CD62LlowCD44highCD4+ T cells in the spleen of mycobacteria-infected mice. Our results suggest that Rv2220 regulates host immune responses through maturation of DCs, a finding that points to a new vaccine candidate against tuberculosis. PMID- 29625706 TI - Pharmaceutical cognitive doping in students: A chimeric way to get-a-head? AB - For students, the pressing demands for memorization, top-level performance, and peer competition create an environment favorable for pharmaceutical cognitive doping behavior. We aimed to describe recent practices and the benefit/risk ratio of such behavior and to discuss the issues at stake. The prevalence of pharmaceutical cognitive doping among students has been reported from 1.3% to 33% across studies, with variations depending on country and definition of pharmaceutical cognitive doping. The therapeutic classes most frequently cited as being diverted for doping purposes are psychostimulants and nootropics (methylphenidate, modafinil, piracetam), corticosteroids, sedative drugs and beta blockers. Some illegal substances such as cannabis, amphetamines and cocaine are also consumed in order to boost mental function. Finally, over-the-counter products, such as caffeine-based tablets or energy drinks, or alcohol, are also widely used by students whose motivations involve enhanced performance, concentration, memory, and staying awake during the revision and exam period. However, the expected (often fantasized) effectiveness of these products does not correspond to the reality of a modest controversial impact on cognitive performance. There appears to be an emerging profile of the student more inclined to doping behavior. Cognitive doping thus raises the question of its regulation, opening a debate opposing, on one hand, individual freedom and supposed collective benefits and, on the other hand, health consequences, educational (in)equality, and the risk of tarnished academic success. Strengthening school and university medicine, through prevention campaigns and the identification of subjects at risk, is essential to limit the extent, risk, and damages associated with such practices. PMID- 29625707 TI - [Atropinic burden and anticholinergic drugs: Interest and application in clinical practice in the elderly]. AB - Anticholinergic drugs (also called antimuscarinics or atropinics) increase the risk of falls, cognitive impairment and/or mortality in older patients. These drugs belong to the lists of potentially inappropriate medications in the elderly. The aim of this review was to present and discuss the different tools available to measure the atropinic risk in drug exposure of older patients. Several scales, developed from biological and/or clinical criteria, allow to classify anticholinergic drugs according to their atropinic potency and to assign to them an atropinic burden. Total atropinic burden of patient drug exposure can be calculated as the sum of atropinic score of each drug. Other tools include drug daily doses to better estimate the atropinic risk. These different methods are a precious help to decrease atropinic exposure in the elderly. Nevertheless, they have to be considered as upgradable and it is necessary to adapt them regularly according to the introduction of new drugs in clinical practice. PMID- 29625709 TI - Digital pathology: quo vadis? PMID- 29625708 TI - Is video observation as effective as live observation in improving teamwork in the operating room? AB - BACKGROUND: Teamwork in the operating room decreases the risk of preventable patient harm. Observation in the operating room allows for evaluation of compliance with best-practice surgical guidelines. This study examines the relative ability of video and live observation to promote operating room teamwork. METHODS: Video and audio cameras were installed in 2014 into all operating rooms at an 875-bed, urban teaching hospital. Recordings were chosen at random for review by an internal quality improvement team. Concurrently, live observers were deployed into a random selection of operations. A customized tool was used to evaluate compliance to TeamSTEPPS skills during surgical briefs and debriefs. RESULTS: A total of 1,410 briefs were evaluated: 325 (23%) through live observation and 1,085 (77%) through video; 1,398 debriefs were evaluated: 166 (12%) live and 1,232 (88%) video. For briefs, greater compliance was observed under live observation compared to video for recognition of team membership (87% vs 44%, P<.001), anticipation of complex procedural events (61% vs 45%, P<.001), and monitoring of resources (58% vs 42%, P<.001). For debriefs, greater compliance was observed under live observation for determination of team structure (90% vs 60%, P<.001), establishment of a leader (70% vs 51%, P<.001), postoperative planning (77% vs 48%, P<.001), case review and feedback (49% vs 33%, P<.001), team engagement (64% vs 41%, P<.001), and check back (61% vs 46%, P<.001) compared to video. CONCLUSION: Video observations may not be as effective as evaluating live performance in promoting teamwork in the OR. Live observation enables immediate feedback, which may improve behavior and decrease barriers to compliance with surgical safety practices. PMID- 29625710 TI - Inexpensive Research in the Golden Open-Access Era. AB - The financial pressure that publishers impose on libraries is a worldwide concern. Gold open-access publishing with an expensive article-processing charge paid by the authors is often presented as an ideal solution to this problem. However, such a system threatens less-funded departments and even article quality. PMID- 29625711 TI - [A survey on geriatric consultation activity in Spanish hospitals]. PMID- 29625712 TI - Contaminants of emerging concern: Nicotine in wastewater as a public health analysis tool. PMID- 29625713 TI - Are There Differences Between the Available Treatments for Emphysema Associated with Alpha-1 Antitrypsin Deficiency? PMID- 29625714 TI - [An update on the opioid crisis]. PMID- 29625715 TI - [Enforcement of a new data protection law in Europe: A threat and an opportunity for registries and cohorts in the field of rare diseases]. PMID- 29625716 TI - [Ocular manifestations in Behcet's disease]. AB - Ocular disease in Behcet's disease is frequent and may be associated with a poor functional prognosis. Uveitis is the most common ocular manifestation in Behcet's disease and represents a diagnostic criterion of the disease. The ocular involvement is inaugural of the disease in 20% of the cases or may develop 2 to 3 years after the beginning of the extraocular signs. The risk of blindness at 5 years is in the order of 15 to 25%, mainly due to macular involvement or retinal vasculitis. Uveitis may be anterior, intermediate, posterior or panuveitis. Anterior uveitis is rarely isolated and is frequently accompanied by posterior involvement. Anterior uveitis is always non granulomatous, sometimes associated with hypopion. Posterior involvement may include the presence of hyalitis, retinal vasculitis, mainly venous and often occlusive, macular edema, and/or foci of necrotizing retinitis. Behcet's disease is a chronic disorder, characterized by a relapsing and remitting course. Male patients with younger age at onset and severe lesions at presentation are at higher risk of severe visual loss over time. The main goals in the management of patients with Behcet's disease associated uveitis are rapid suppression of intraocular inflammation, preservation of vision, and prevention of recurrences. The treatment is based on the use of systemic glucocorticosteroids and immunosuppressive agents. Posterior segment involvement requires the use of corticosteroids and immunosuppressants, primarily azathioprine. This treatment does not appear to be sufficient for severe uveitis with reduced visual acuity or retinal vasculitis that requires anti-TNF alpha or interferon alpha. Therapeutic strategies such as TNF-alpha blockers have dramatically improved the visual prognosis of patients with intraocular inflammation related to this chronic and potentially blinding condition. PMID- 29625718 TI - Septal anchoring suture: a key suture to improve the nasolabial symmetry in unilateral cheiloplasty. AB - Since 2008, a septal anchoring suture has been used in unilateral cleft lip repair at Chang Gung Memorial Hospital in order to stabilize the lateral lip centrally. This study compared the symmetry of two groups of patients: those treated with and without an anchoring suture. Multiple standardized direct and photographic facial measurements were performed on the faces of all patients pre cheiloplasty and at 5 years post-cheiloplasty. The degree of nasolabial symmetry was evaluated by comparing the ratios of measurements of the cleft vs. non-cleft sides. The ratio of change in these measurements was also compared postoperatively. The vertical lip length ratio approached 1 in the septal anchoring suture group, which differed significantly from the group without the suture (0.968 vs. 0.873, P<0.001). As expected, the horizontal lip length and central lip height ratios showed no statistically significant change. The ratio of change from pre- to postoperative also showed a significant improvement (P=0.028) in the vertical lip length of the group with the septal anchoring suture compared to the one without. The septal anchoring suture is a useful method to correct the tendency of the lip to shift to the cleft side. PMID- 29625717 TI - Prospective observational study in elderly patients with non-valvular atrial fibrillation: Rationale and design of the All Nippon AF In the Elderly (ANAFIE) Registry. AB - BACKGROUND: Although anticoagulation effectively prevents stroke in patients with atrial fibrillation (AF), it has been underused in elderly AF patients for many reasons, mainly because of knowledge gaps regarding cardiovascular treatment of these populations with multiple comorbidities and poor prognosis. The objectives of the All Nippon AF In the Elderly (ANAFIE) Registry are to collect real-world information about the clinical status of patients with non-valvular AF (NVAF) aged >=75 years, current status of anticoagulant therapy, and prognosis with/without anticoagulation to establish a database for this specific patient population that is increasing remarkably worldwide. METHODS AND DESIGN: The ANAFIE Registry is an observational, multicenter, prospective study of Japanese patients with NVAF aged >=75 years that will include 30,000 patients and have the primary endpoint of composite of stroke and systemic embolism over a 2-year follow-up period. In parallel with the main study, seven sub-cohort studies will be conducted with assessments including coagulation-fibrinolysis markers, echocardiography, heart rate, hypertension, cognitive function, frailty, and medication adherence. Subgroup analyses will be performed, and stratified by renal function, HbA1c, and maximum number of drugs used. The study was started in October 2016, with a planned 2-year recruitment period. As of January 31, 2018, 33,213 patients were enrolled; the recruitment was therefore ended 8 months earlier than the original plan. CONCLUSIONS: The ANAFIE Registry will provide a valuable database for the clinical status, management, and outcomes of mortality, stroke, systemic embolism, and hemorrhagic events with/without anticoagulation in the increasing population of elderly NVAF patients, and will identify risk factors associated with these clinical events. PMID- 29625719 TI - Endocytoscopy for in situ real-time histology of oral mucosal lesions. AB - This study investigated the utility of endocytoscopy, a novel emerging endoscopic system, for in situ real-time histology of oral mucosal lesions. Endocytoscopy involves the use of a contact light microscopy system with 380-fold magnification. With the development of endoscopic instruments, it has become possible to observe the abnormal microvascular and capillary patterns of tumour cells. The resolution of the endoscopic image is improved in situ, and a more detailed diagnosis is possible. In this study, endocytoscopy along with other diagnostic modalities was used in nine patients. Normal mucous membranes and oral malignant lesions were observed. Endocytoscopy enabled the pathological diagnosis of oral malignancies in situ and the observation of both structural and cytological atypia. In the future, it is expected that pathological diagnoses will be made in situ by direct viewing of living cells. This technique has the potential to allow an 'optical biopsy'. PMID- 29625720 TI - A Computerized Tomography Study of Vocal Tract Setting in Hyperfunctional Dysphonia and in Belting. AB - BACKGROUND: Vocal tract setting in hyperfunctional patients is characterized by a high larynx and narrowing of the epilaryngeal and pharyngeal region. Similar observations have been made for various singing styles, eg, belting. The voice quality in belting has been described to be loud, speech like, and high pitched. It is also often described as sounding "pressed" or "tense". The above mentioned has led to the hypothesis that belting may be strenuous to the vocal folds. However, singers and teachers of belting do not regard belting as particularly strenuous. PURPOSE: This study investigates possible similarities and differences between hyperfunctional voice production and belting. This study concerns vocal tract setting. METHODS: Four male patients with hyperfunctional dysphonia and one male contemporary commercial music singer were registered with computerized tomography while phonating on [a:] in their habitual speaking pitch. Additionally, the singer used the pitch G4 in belting. The scannings were studied in sagittal and transversal dimensions by measuring lengths, widths, and areas. RESULTS: Various similarities were found between belting and hyperfunction: high vertical larynx position, small hypopharyngeal width, and epilaryngeal outlet. On the other hand, belting differed from dysphonia (in addition to higher pitch) by a wider lip and jaw opening, and larger volumes of the oral cavity. CONCLUSIONS: Belting takes advantage of "megaphone shape" of the vocal tract. Future studies should focus on modeling and simulation to address sound energy transfer. Also, they should consider aerodynamic variables and vocal fold vibration to evaluate the "price of decibels" in these phonation types. PMID- 29625721 TI - Agerarin inhibits alpha-MSH-induced TYR gene transcription via STAT3 suppression independent of CREB-MITF pathway. PMID- 29625722 TI - An inexplicable upsurge: The rise in type 1 diabetes. PMID- 29625723 TI - Infectious complications in head and neck surgery: Porto Oncology Centre retrospective analysis. AB - OBJECTIVE: To analyze the impact of infectious complications and microbiology in the postoperative period after major oncologic neck surgeries. METHODS: A retrospective study conducted in an oncology center, including all the consecutive patients who developed infectious complications after major neck cancer surgery, from October 2012 to May 2016 (44 months). Among other data, we collected TNM stage, ASA score, body mass index, comorbidities and habits, pre and postoperative hemoglobin levels, albumin serum levels, pre-surgical treatments, length of inpatient stay, isolated microbiological agents and the recorded complications and mortality rate. RESULTS: In the studied period, 761 major neck surgeries were performed. Of these, 96 patients had complications (12.6%). Pharyngocutaneous fistula (PCF) was the most frequent complication (56%) and nosocomial pneumonia was the most common systemic complication (23%). Pseudomonas aeruginosa was the principal microorganism of the 26 species isolated (15%). 12 deaths were registered. Using multiple linear regression we concluded that flap/cutaneous necrosis and PCF were complications with statistical significance that prolonged inpatient stay. The same complications had significant relative risk for more than 30 days of hospitalization. CONCLUSION: The postoperative period is critical for the successful treatment of head and neck oncology patients. PCF and flap/cutaneous necrosis were the principal complications which worsened the outcomes during this critical period. The early recognition and treatment of these complications is crucial. PMID- 29625724 TI - Salvage surgery in the treatment of local recurrences of nasopharyngeal carcinomas. AB - INTRODUCTION AND OBJECTIVES: Chemoradiotherapy is the treatment of choice for nasopharyngeal carcinoma. Local recurrences are one of the leading causes of death in these patients, and surgical salvage the treatment of choice. Our goal was to evaluate and compare the results of salvage surgery in the treatment of local recurrence of nasopharyngeal carcinomas comparing endoscopic to open approaches. METHODS: Twenty patients with local recurrence of nasopharyngeal carcinomas underwent surgery: 12 patients underwent open surgery and 8 endoscopic endonasal transpterygoid nasopharyngectomy. One patient was classified as rT1; 3 as rT2;2 as rT3; and 6 as rT4 in the group of open approaches; in the endoscopic series, 2 patients were rT1, 5 rT2 and one rT3. RESULTS: In 3 patients (25%) operated by an open approach (one rT4, one rT3 and one rT2) a complete gross resection was not achieved. Gross total resection was achieved in patients operated by endoscopic surgery. The complication rate in the group operated by an open approach was 92% (5 minor complications, 5 moderate complications, and one serious complication) and in the group that underwent endoscopic surgery all patients had some complication (7 had minor complications and one patient developed a severe complication). Survival at 3 and 5 years was 53% and 42% with the open approach and 100% and 50% with the endoscopic approach, respectively. CONCLUSIONS: Endoscopic approaches decrease the morbidity associated with open approaches and allow for favourable oncological control. PMID- 29625725 TI - Intervertebral vacuum phenomenon: A cause of bulging of the pharyngeal wall. PMID- 29625726 TI - Multiple sclerosis: Left advantage for auditory laterality in dichotic tests of central auditory processing and relationship of psychoacoustic tests with the Multiple Sclerosis Disability Scale-EDSS. AB - OBJECTIVE: To evaluate the central auditory processing disorders in patients with multiple sclerosis, emphasizing auditory laterality by applying psychoacoustic tests and to identify their relationship with the Multiple Sclerosis Disability Scale (EDSS) functions. METHOD: Depression scales (HADS), EDSS, and 9 psychoacoustic tests to study CAPD were applied to 26 individuals with multiple sclerosis and 26 controls. Correlation tests were performed between the EDSS and psychoacoustic tests. RESULTS: Seven out of 9 psychoacoustic tests were significantly different (P<.05); right or left (14/19 explorations) with respect to control. In dichotic digits there was a left-ear advantage compared to the usual predominance of RDD. There was significant correlation in five psychoacoustic tests and the specific functions of EDSS. CONCLUSION: The left-ear advantage detected and interpreted as an expression of deficient influences of the corpus callosum and attention in multiple sclerosis should be investigated. There was a correlation between psychoacoustic tests and specific EDSS functions. PMID- 29625727 TI - Effectiveness of Screening Postmenopausal Women for Cardiovascular Diseases: A Population Based, Prospective Parallel Cohort Study. AB - OBJECTIVES: To investigate the effectiveness of systematic screening for multifaceted cardiovascular disease (CVD) in postmenopausal women on all cause mortality and, secondarily, on CVD morbidity. Effectiveness was also evaluated across age strata. METHODS: This was a population based, prospective, parallel cohort study. In total, 107,491 women born in 1936-1951 living in the Central Denmark region were identified in the Danish Civil Registration System. From this population, all women born in 1936, 1941, 1946, and 1951 (n = 1984) living in the Viborg municipality were invited to attend screening. Of those invited to the screening, 1474 (74.3%) attended. The control group included all women from the general population born in 1936-1951 and living in the Central Denmark Region, excluding those invited for the screening. Information on medication and comorbidities prior to inclusion and study outcomes were retrieved from national registries for both groups. The screening included examination for abdominal aortic aneurysm (AAA), peripheral arterial disease (PAD), carotid plaque (CP), potential hypertension (HT), atrial fibrillation (AF), diabetes mellitus (DM), and dyslipidaemia. The adjusted Cox proportional hazards model with the intention to screen principle was used to assess effectiveness for the total population and across age groups. RESULTS: During follow up (median 3.3 years, IQR 2.9-3.9), the adjusted hazard ratios (HRs) for invited versus controls were the following: all cause mortality, 0.89 (95% CI 0.71-1.12); myocardial infarction (MI), 1.26 (95% CI 0.52-3.07); ischaemic heart disease (IHD), 0.72 (95% CI 0.49-1.05); PAD, 1.07 (95% CI 0.49-2.31); and ischaemic stroke, 1.20 (95% CI 0.78-1.85). A substantial number of women with AAA, PAD, and/or CP declined prophylactic therapy: 45% for antiplatelet and 35% for cholesterol lowering agents. CONCLUSIONS: This multifaceted screening offer to a general population sample of postmenopausal women had no effects on all cause mortality or hospital admission for MI, IHD, PAD, and stroke within a short-term follow up period. PMID- 29625728 TI - Long-term Changes in Depressive Symptoms and Estimated Cardiorespiratory Fitness and Risk of All-Cause Mortality: The Nord-Trondelag Health Study. AB - OBJECTIVE: To assess the independent and combined associations of long-term changes in depressive symptoms (DSs) and estimated cardiorespiratory fitness (eCRF) with all-cause mortality. PARTICIPANTS AND METHODS: This is a longitudinal cohort study of 15,217 middle-aged and older individuals attending both the second (from August 15, 1995, through June 18, 1997) and third (from October 3, 2006, through June 25, 2008) health surveys of the Nord-Trondelag Health Study, Norway, and followed until December 31, 2014. Depressive symptoms were estimated using the validated Hospital Anxiety and Depression Scale, and a validated nonexercise model estimated eCRF. Hazard ratios (HRs) were computed using Cox regression. All-cause mortality was ascertained using the Norwegian Cause of Death Registry. RESULTS: The mean age was 63.3+/-8.9 years, and 7932 (52.1%) were women. During the follow-up period of 7.1+/-1.1 years, 1157 participants (7.6%) died. Multivariable-adjusted analyses revealed that persistently low DSs were independently associated with a 28% risk reduction of all-cause mortality (HR, 0.72; 95% CI, 0.56-0.92; P=.008) as compared with persistently high DSs. Persistently high eCRF independently predicted a 26% lower risk of death (HR, 0.76; 95% CI, 0.66-0.88; P<.001) relative to low eCRF. Analyses of changes in DSs and eCRF revealed that persistently high eCRF combined with decreased or persistently low DSs decreased mortality risk by 49% (HR, 0.51; 95% CI, 0.28 0.91; P=.02) and 47% (HR, 0.53; 95% CI, 0.37-0.76, P=.001), respectively. CONCLUSION: Maintaining low DSs and high eCRF was independently associated with a lower risk of all-cause mortality. The lowest mortality risk was observed for persistently high eCRF combined with decreased or persistently low DSs. These results emphasize the effect of preventing DSs and maintaining high CRF on long term mortality risk, which is potentially important for long-term population health. PMID- 29625729 TI - Corrigendum to "Elevated 20-HETE in metabolic syndrome regulates arterial stiffness and systolic hypertension via MMP12 activation" [J. Mol. Cell. Cardiol. 117 (2018) 88-99]. PMID- 29625730 TI - Natural History of Postnatal Cardiopulmonary Adaptation in Infants Born Extremely Preterm and Risk for Death or Bronchopulmonary Dysplasia. AB - OBJECTIVE: To study the natural history of postnatal cardiopulmonary adaptation in infants born extremely preterm and establish its association with death or bronchopulmonary dysplasia (BPD). STUDY DESIGN: This was a prospective, observational, cohort study of infants born extremely preterm (<29 weeks). Initial echocardiogram was performed at <48 hours of life, followed by serial echocardiograms every 24-48 hours until 14 days of life. Resolution or no resolution of pulmonary hypertension (PH) at 72-96 hours was considered normal or delayed postnatal cardiopulmonary adaptation, respectively. PH between 96 hours and 14 days was defined as subsequent PH. Elevated pulmonary artery pressure throughout the 14 days of life was considered persistent PH. BPD was assessed at 36 weeks of postmenstrual age. RESULTS: Sixty infants were enrolled; 2 died before a sequential echocardiogram could be done at 72-96 hours. Normal and delayed cardiopulmonary adaptation were noted in 26 (45%) and 32 (55%) infants, respectively. Five patterns of postnatal cardiopulmonary adaptation were recognized: normal without subsequent PH (n = 20), normal with subsequent PH (n = 6), delayed adaptation without subsequent PH (n = 6), delayed adaptation with subsequent PH (n = 16), and persistent PH (n = 10). Infants with delayed cardiopulmonary adaptation were of lower gestation and birth weight and required prolonged ventilation and supplemental oxygen (P < .05). On multivariate analysis, the incidence of death or BPD was significantly greater among infants with delayed adaptation (P < .001). CONCLUSION: Infants born extremely preterm have normal or delayed postnatal cardiopulmonary adaptation that can be complicated by subsequent or persistent PH. Delayed cardiopulmonary adaptation is associated independently with death or BPD. PMID- 29625732 TI - Healthcare Use Patterns and Economic Burden of Chronic Musculoskeletal Pain in Children before Diagnosis. AB - OBJECTIVES: To evaluate the healthcare use and costs of amplified musculoskeletal pain syndrome (AMPS) in children before diagnosis. STUDY DESIGN: We performed a retrospective study in children with AMPS at a pediatric rheumatology clinic between 2010 and 2014. Data were abstracted on 80 patients after primary rheumatic diseases were excluded. Healthcare visits, medications and diagnostic testing that occurred in the years before diagnosis were collected. The Medical Expenditure Panel Survey was used to estimate visit costs. RESULTS: Patients were adolescent females (89%) and white (86%). The median time to diagnosis was 10.2 months. The median pain score was 6.5 and the median Childhood Health Assessment Questionnaire score was 1.1. In this cohort, 29% had at least 1 ED visit and 5% were hospitalized. All patients saw a rheumatologist and 41% had visited another specialist, typically orthopedics and sports medicine. More than one-half had at least 1 radiographic study and 21% had at least 1 magnetic resonance imaging. The total cost for office, emergency department, and hospital visits for AMPS in all 80 patients was $152 853. The mean cost per patient over the entire study period (2008-2014) was $1911 +/- $3808, and 43% of costs were outpatient visits. CONCLUSIONS: Children with AMPS have high levels of disability and take a long time to be diagnosed. As a result, even before diagnosis, they have high levels of healthcare use, diagnostic testing, and medical costs. Early recognition of disability and quicker referral to trained subspecialists may improve the prognosis, reduce unnecessary testing, and reduce the overall costs of healthcare. PMID- 29625734 TI - The significance of digital citizenship in the well-being of older migrants. AB - OBJECTIVES: To understand the increasingly important role of digital citizenship (the ability to participate in society online) in supporting the well-being of ageing migrants. STUDY DESIGN: Participant observation, social network mapping, ethnographic and life-history interviews. METHODS: Fifteen in-depth case studies examined the role of online participation in fostering the well-being and care of older migrants in Perth, Western Australia. Participants are members of an 'internet cafe' that facilitates their shared development of Internet skills. The case studies are derived from ethnographic research conducted between July and October 2016. RESULTS: Older peoples' maintenance of support networks and social engagement, and their access to healthcare services, can be enhanced when they are motivated to increase their digital literacy (the ability to use the Internet for information and communication) through appropriate educational, technological, infrastructure and social support. This support is likely to be more effective when developed through social learning systems that create communities of practice. Improving digital literacy has special implications for the well-being of older migrants because it can enhance their ability to exchange emotional support across distance. CONCLUSIONS: Digital literacy for older migrants can dramatically increase their ability to maintain and expand dispersed networks of support. Effective implementation of affordable and age-inclusive information and communication technology (ITC) infrastructure requires integrated support that connects individuals and their homes with social learning systems to ensure that participation continues as mobility declines. As health information and social engagement are increasingly delivered through online platforms, supporting the digital citizenship of older people is becoming an important equity issue. PMID- 29625735 TI - Peas and carrots, apples and oranges: Not all malperfusion is the same. PMID- 29625733 TI - Evidence of Echocardiographic Markers of Pulmonary Vascular Disease in Asymptomatic Infants Born Preterm at One Year of Age. AB - OBJECTIVE: To test the hypothesis that echocardiographic markers of pulmonary vascular disease (PVD) exist in asymptomatic infants born preterm at 1-year corrected age. STUDY DESIGN: We conducted a prospective cohort study of 80 infants born preterm (<29 weeks of gestation) and 100 age- and weight-matched infants born at term and compared broad-based conventional and quantitative echocardiographic measures of pulmonary hemodynamics at 1-year corrected age. Pulmonary artery acceleration time (PAAT), a validated index of pulmonary vascular resistance, arterial pressure, and compliance, was used to assess pulmonary hemodynamics. Lower PAAT is indicative of PVD. Subanalyses were performed in infants with bronchopulmonary dysplasia (BPD, n = 48, 59%) and/or late-onset pulmonary hypertension (n = 12, 15%). RESULTS: At 1 year, there were no differences between conventional measures of pulmonary hypertension in the infants born at term and preterm. All infants born preterm had significantly lower values of PAAT than infants born at term (73 +/- 8 milliseconds vs 98 +/- 5 milliseconds, P < .001). Infants born preterm with BPD had even lower PAAT than those without BPD (69 +/- 5 milliseconds vs 79 +/- 4 milliseconds, P < .01). The degree of PVD at 1-year corrected age was inversely related to gestation in all infants born preterm. Data analysis included adjustment for ventricular function and other confounding factors. CONCLUSIONS: In comparison with infants born at term, infants born preterm exhibit abnormal PAAT at 1-year corrected age irrespective of neonatal lung disease status, suggesting the existence of PVD beyond infancy. PAAT measurements offer a reliable, noninvasive tool for screening and longitudinal monitoring of pulmonary hemodynamics in infants. PMID- 29625736 TI - A center of excellence displays its wares: How does your mitral practice stack up? PMID- 29625737 TI - HeartMate 3: Bridging from clinical trial experience to real-world use. PMID- 29625731 TI - Cost Analysis of Treating Neonatal Hypoglycemia with Dextrose Gel. AB - OBJECTIVE: To evaluate the costs of using dextrose gel as a primary treatment for neonatal hypoglycemia in the first 48 hours after birth compared with standard care. STUDY DESIGN: We used a decision tree to model overall costs, including those specific to hypoglycemia monitoring and treatment and those related to the infant's length of stay in the postnatal ward or neonatal intensive care unit, comparing the use of dextrose gel for treatment of neonatal hypoglycemia with placebo, using data from the Sugar Babies randomized trial. Sensitivity analyses assessed the impact of dextrose gel cost, neonatal intensive care cost, cesarean delivery rate, and costs of glucose monitoring. RESULTS: In the primary analysis, treating neonatal hypoglycemia using dextrose gel had an overall cost of NZ$6863.81 and standard care (placebo) cost NZ$8178.25; a saving of NZ$1314.44 per infant treated. Sensitivity analyses showed that dextrose gel remained cost saving with wide variations in dextrose gel costs, neonatal intensive care unit costs, cesarean delivery rates, and costs of monitoring. CONCLUSIONS: Use of buccal dextrose gel reduces hospital costs for management of neonatal hypoglycemia. Because it is also noninvasive, well tolerated, safe, and associated with improved breastfeeding, buccal dextrose gel should be routinely used for initial treatment of neonatal hypoglycemia. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry: ACTRN12608000623392. PMID- 29625738 TI - What lies beneath (the mitral annulus): The geometric implications of restrictive annuloplasty. PMID- 29625739 TI - Roll up your sleeves, roll up your retractor, and repair the mitral valve. PMID- 29625740 TI - The craftsman's toolbox: Stents, coils, glue, and sometimes a scalpel. PMID- 29625741 TI - Ghosts in the machines. PMID- 29625742 TI - Appropriate use criteria for aortic stenosis: Guidelines or opinion? PMID- 29625743 TI - High diagnostic accuracy of white blood cell scintigraphy for fracture related infections: Results of a large retrospective single-center study. AB - INTRODUCTION: White blood cell (WBC) scintigraphy for diagnosing fracture-related infections (FRIs) has only been investigated in small patient series. Aims of this study were (1) to establish the accuracy of WBC scintigraphy for diagnosing FRIs, and (2) to investigate whether the duration of the time interval between surgery and WBC scintigraphy influences its accuracy. PATIENTS AND METHODS: 192 consecutive WBC scintigraphies with 99mTc-HMPAO-labelled autologous leucocytes performed for suspected peripheral FRI were included. The golden standard was based on the outcome of microbiological investigation in case of surgery, or - when these were not available - on clinical follow-up of at least six months. The discriminative ability of the imaging modalities was quantified by several measures of diagnostic accuracy. A multivariable logistic regression analysis was performed to identify predictive variables of a false-positive or false-negative WBC scintigraphy test result. RESULTS: WBC scintigraphy had a sensitivity of 0.79, a specificity of 0.97, a positive predicting value of 0.91, a negative predicting value of 0.93 and a diagnostic accuracy of 0.92 for detecting an FRI in the peripheral skeleton. The duration of the interval between surgery and the WBC scintigraphy did not influence its diagnostic accuracy; neither did concomitant use of antibiotics or NSAIDs. There were 11 patients with a false negative (FN) WBC scintigraphy, the majority of these patients (n = 9, 82%) suffered from an infected nonunion. Four patients had a false-positive (FP) WBC scintigraphy. CONCLUSIONS: WBC scintigraphy showed a high diagnostic accuracy (0.92) for detecting FRIs in the peripheral skeleton. Duration of the time interval between surgery for the initial injury and the WBC did not influence the results which indicate that WBC scintigraphy is accurate shortly after surgery. PMID- 29625745 TI - Evaluation of a single-pass with biphasic intravenous contrast medium injection CT protocol for the assessment of complications post-simultaneous pancreas-kidney transplant. AB - AIM: To evaluate the use of a single-pass with biphasic intravenous contrast medium injection computed tomography (CT) protocol to provide diagnostic quality CT studies for the assessment of complications post-simultaneous pancreas-kidney transplant (SPK). MATERIALS AND METHODS: This was an audit of practice and the need for informed consent was waived. The protocol was used in consecutive patients undergoing CT to exclude intra-abdominal sepsis post-SPK between June and December 2015. Single CT acquisition of the abdomen and pelvis was initiated 70 seconds after the start of biphasic contrast medium injection (66 ml at 1.2 ml/s, followed by 34 ml at 2.4 ml/s, 370 mg iodine/ml). The named transplant pancreas vessels were identified and the attenuation values of the blood within were measured. Diagnostic quality was confirmed if values were >211 HU and >80 HU in the arteries and veins, respectively. RESULTS: Thirteen CT studies were performed in 10 patients. CT studies were excluded due to complete pancreatic necrosis, and transplant superior mesenteric artery (SMA) thrombus with pancreatic head ischaemia causing effacement of the transplant superior mesenteric vein (SMV). Diagnostic quality of the analysed CT studies were confirmed with mean attenuation value of blood >211 HU in the transplant pancreatic arteries (SMA=259.0+/-51.4 HU, splenic artery=245.3+/-37.5 HU), and >80 HU in the pancreatic veins (SMV=195.4+/-36.2 HU, splenic vein=185.1+/-54.2 HU). CONCLUSION: Diagnostic quality CT studies were obtained using the single pass CT protocol. Radiation exposure to patients may be reduced with this protocol, while permitting simultaneous assessment of parenchymal and vascular complications post-SPK. PMID- 29625744 TI - Long term (7 or more years) outcomes of the sleeve gastrectomy: a meta-analysis. AB - BACKGROUND: The laparoscopic sleeve gastrectomy is now the most common bariatric operation in the United States and has become an established procedure in the armamentarium of the bariatric surgeon. However, this has happened without the strong support of long-term outcomes data, namely the rate of revision and durability of the weight loss. Newly published data from around the world are starting to show alarming trends in these 2 areas. This paper will examine the published and presented data with at least a 7-year follow-up. OBJECTIVES: This is a meta-analysis on published data with at least 7 years of follow-up from the laparoscopic sleeve gastrectomy. SETTING: Online published articles. METHODS: We performed a meta-analysis of publications with at least 7 years of follow-up with the keywords "laparoscopic, bariatric, sleeve gastrectomy, sleeve, long-term, long, term, results, follow-up, follow up, conversion, 7 years, 8 years, 9 years, 10 years, 11 years." We queried the PubMed, MEDLINE, and ClinicalKey search engines, which included abstracts as well. The I2 statistic was used to determine the heterogeneity across the studies. In presence of heterogeneity, a random effect model using the Dersimonian and Laird method was used to estimate the pooled estimates. The results were summarized using effect size along with a 95% confidence interval (CI). Meta-regression was also used to assess the effect of body mass index and follow-up years on the incidence of recidivism at >=7 years. RESULTS: Nine cohort studies met the inclusion criteria, with a total of 2280 patients included initially. Only 652 patients had completed >=7 years of follow up. At >=7 years, the long-term weight recidivism rate was estimated to be 27.8% (I2 = .60%; 95% CI: 22.8%-32.7%) with a range of 14% to 37%. The overall revision rate was estimated to be 19.9% (I2 = 93.8%; 95% CI: 11.3%-28.5%). This was broken down into 13.1% (I2 = 93.8%; 95% CI: 5.6%-20.6%) due to weight regain (5 studies) and 2.9% (I2 = 60.8%; 95% CI: 1%-4.9%) due to gastroesophageal reflux disease (5 studies). CONCLUSIONS: Based on available data up to the beginning of 2017, bariatric surgeons should be aware of the long-term outcomes of the sleeve gastrectomy, especially regarding revisions and weight regain. It is incumbent on the surgeon to make sure that bariatric patients are truly informed regarding the long-term results of the sleeve gastrectomy. PMID- 29625746 TI - Preoperative CT texture analysis of gastric cancer: correlations with postoperative TNM staging. AB - AIM: To explore the role of computed tomography (CT) texture analysis in predicting pathologic stage of gastric cancers. MATERIALS AND METHODS: Preoperative enhanced CT images of 153 patients (112 men, 41 women) with gastric cancers were reviewed retrospectively. Regions of interest (ROIs) were manually drawn along the margin of the lesion on the section where it appeared largest on the arterial and venous CT images, which yielded texture parameters, including mean, maximum frequency, mode, skewness, kurtosis, and entropy. Correlations between texture parameters and pathological stage were analysed with Spearman's correlation test. The diagnostic performance of CT texture parameters in differentiating different stages was evaluated using receiver operating characteristic (ROC) analysis. RESULTS: Maximum frequency in the arterial phase and mean, maximum frequency, mode in the venous phase correlated positively with T stage, N stage, and overall stage (all p<0.05) of gastric cancer. Entropy in the venous phase also correlated positively with N stage (p=0.009) and overall stage (p=0.032). Skewness in the arterial phase had the highest area under the ROC curve (AUC) of 0.822 in identifying early from advanced gastric cancers. Multivariate analysis identified four parameters, including maximum frequency, skewness, entropy in the venous phase, and differentiation degree from biopsy, for predicting lymph node metastasis of gastric cancer. The multivariate model could distinguish gastric cancers with and without lymph node metastasis with an AUC of 0.892. CONCLUSION: Multiple CT texture parameters, especially those in the venous phase, correlated well with pathological stage and hold great potential in predicting lymph node metastasis of gastric cancers. PMID- 29625747 TI - Brain tissue strains vary with head impact location: A possible explanation for increased concussion risk in struck versus striking football players. AB - BACKGROUND: On-field football helmet impacts over a large range of severities have caused concussions in some players but not in other players. One possible explanation for this variability is the struck player's helmet impact location. METHODS: We examined the effect of impact location on regional brain tissue strain when input energy was held constant. Laboratory impacts were performed at 12 locations distributed over the helmet and the resulting head kinematics were simulated in two finite element models of the brain: the Simulated Injury Monitor and the Global Human Body Model Consortium brain model. FINDINGS: Peak kinematics, injury metrics and brain strain varied significantly with impact location. Differences in impact location explained 33 to 37% of the total variance in brain strain for the whole brain and cerebrum, considerably more than the variance explained by impact location for the peak resultant head kinematics (8 to 23%) and slightly more than half of the variance explained by the difference in closing speed (57 to 61%). Both finite element models generated similar strain results, with minor variations for impacts that generated multi axial rotations, larger variations in brainstem strains for some impact locations and a small bias for the cerebellum. INTERPRETATION: Based on this experimental and computational simulation study, impact location on the football helmet has a large effect on regional brain tissue strain. We also found that the lowest strains consistently occurred in impacts to the crown and forehead, helmet locations commonly associated with the striking player. PMID- 29625748 TI - Engineering approaches to understanding mechanisms of spinal column injury leading to spinal cord injury. AB - BACKGROUND: The mechanical interactions occurring between the spinal column and spinal cord during an injury event are complex and variable, and likely have implications for the clinical presentation and prognosis of the individual. METHODS: The engineering approaches that have been developed to better understand spinal column and cord interactions during an injury event are discussed. These include injury models utilising human and animal cadaveric specimens, in vivo anaesthetised animals, finite element models, inanimate physical systems and combinations thereof. FINDINGS: The paper describes the development of these modelling approaches, discusses the advantages and disadvantages of the various models, and the major outcomes that have had implications for spinal cord injury research and clinical practice. INTERPRETATION: The contribution of these four engineering approaches to understanding the interaction between the biomechanics and biology of spinal cord injury is substantial; they have improved our understanding of the factors contributing to the spinal column disruption, the degree of spinal cord deformation or motion, and the resultant neurological deficit and imaging features. Models of the injury event are challenging to produce, but technological advances are likely to improve these models and, consequently, our understanding of the mechanical context in which the biological injury occurs. PMID- 29625749 TI - Real-time coordination of visual and linguistic processes in novice readers. AB - Skilled reading requires coordinating real-time visual fixations, orthographic analyses, and phonological encoding across multiple words in sentences. These procedures are well studied in experienced readers, but less is known about their status during development. To investigate how visual properties influence the origins of coordinated processing, the current study combined rapid automatized naming (RAN) with an eye-tracking paradigm and compared the timing of fixations and vocalizations in typically developing adults and 6-year-old children. Within RAN displays, sequences varied visual features of items (i.e., similar such as p q vs. dissimilar such as p-t) and their locations in rows (i.e., row-initial vs. row-medial positions). Adults and children accessed parafoveal preview of subsequent items when fixating on current items, leading to longer latency to speak for similar items compared with dissimilar ones. Both groups also vocalized previous items while fixating on current items, leading to longer eye-voice overlap for row-medial items compared with row-initial ones. Yet, relative to adults, children exhibited exaggerated delays in latency to speak from parafoveal preview and reduced eye-voice overlap due to row transitions. Together, this suggests that coordinated processing is present at the earliest points of development but that greater inexperience increases susceptibility to momentary visual hurdles. Relationships to previous work on real-time RAN performance in dyslexic adults and children are discussed. PMID- 29625750 TI - Comment on: "Synchronizing biological cycles as key to survival under a scenario of global change: The Common quail (Coturnix coturnix) strategy" by Nadal, J., Ponz, C., Margalida, A. AB - Nadal et al. (2018) recently reported on changes in the phenology of the Common quail (Coturnix coturnix) in seven cloudy regions of Spain in relation to climate change. The authors used a long-term ringing database (1961-2014) and calculated the mean date for three biological stages: arrival at the breeding areas, stay and autumn departure. They observed that some of these phenological variables were associated with the climate variables of temperature and rainfall (Figs. 4 and 6 of their article). They also analysed the yearly variation in temperature and rainfall over the last 86years, reporting an increase in temperature and a decrease in rainfall (Figs. 3 and 5 of their article). Based on these results, the authors suggested that the Common quail phenology has varied as a response to climate change in Spain, thus concluding that "quail movements and breeding attempts are eco-synchronized sequentially in cloudy regions. Our results suggest that quails attempt to overcome the negative impacts of climate change and agricultural intensification by searching for alternative high-quality habitats". We disagree with two methodological aspects of the article by Nadal et al. (2018): (1) the estimation of the mean date of arrival, stay and departure in the different regions studied; and (2) the analyses carried out to correlate the phenology of the species with the changes in climate variables. PMID- 29625751 TI - Naloxone formulation for overdose reversal preference among patients receiving opioids for pain management. AB - BACKGROUND: Opioid-related overdose has increased 137% in the past decade. Training nonmedical bystanders to administer naloxone (NarcanTM) is a widely researched intervention that has been associated with decreases in overdose rates in the communities in which it has been implemented. A recent review advocated for noninjectable formulations of naloxone, however patient preference for naloxone formulations has not yet been examined (Strang et al., 2016). METHODS: Two cohorts of respondents (N1 = 501, N2 = 172) who reported currently being prescribed an opioid for pain management were recruited through the crowd sourcing program Amazon Mechanical Turk (MTurk) to assess their preference for naloxone formulations. All respondents were provided a description of different formulations and asked to indicate all formulations they would be willing to administer for overdose reversal and to then rank formulations in order of preference. RESULTS: Results were remarkably similar across both cohorts. Specifically, respondents preferred noninjectable formulations (intranasal, sublingual, buccal) over injectable (intravenous, intramuscular) formulations. A small percent (8.9%-9.8%) said they would never be willing to administer naloxone. An identical percent of respondents in both cohorts (44.9%) rated intranasal as their most preferred formulation. CONCLUSIONS: Two independent cohorts of respondents who were receiving opioid medications for pain management reported a preference for noninjectable over injectable formulations of naloxone to reverse an opioid overdose. Though initial preference is only one of many factors that impacts ultimate public acceptance and uptake of a new product, these results support the additional research and development of noninjectable naloxone formulations. PMID- 29625752 TI - Linear magnetic clutch to automatically control torque output. AB - A novel eddy-current Magnetic Clutch (MC) unit with its torque-adjustable mechanism is proposed by this research. As to mechanical structure, the MC unit is mainly constituted by a squirrel-cage inner rotor and a magnet-embedded outer rotor. The transmitted output torque can be adjusted by either the Overlapped Length (OL) or the relative angular velocity between outer rotor and inner rotor. Firstly, the mathematical model of the MC system is developed. Secondly, the features and characterization of the MC unit are explored by intensive experiments under various overlapped length and relative rotational speed between inner rotor and outer rotor. The major novelties of the MC system unit include: (i). being very handy to operate even for non-professional users, (ii). the output torque of the proposed MC can be adjusted automatically, and (iii). the proposed MC can be easily incorporated to any torque control system. To examine the validity of the MC unit, two control strategies, i.e., PID action and pole placement method are presented and compared for the performance of the closed loop feedback systems. In addition, the locations of system roots are found to ensure the stability of the torque control loops. At last, several experiments are undertaken, including constant torque control and variable torque control. Particularly, an experiment of screw-driven into a wooden board is conducted to illustrate the drilling quality much upgraded by the proposed torque control device. Besides, a couple of torque-tracking experiments realistically manifest the quick response and high precision of the MC unit. In summary, either for stability or performance, the proposed MC feedback system is eligible to execute superior torque tracking or torque regulation. PMID- 29625753 TI - Corrigendum to "Robust inertia-free attitude takeover control of postcapture combined spacecraft with guaranteed prescribed performance" [ISA Trans 74 (2018) 28-44]. PMID- 29625754 TI - Re: Focal Therapy in Primary Localised Prostate Cancer: The European Association of Urology Position in 2018. PMID- 29625755 TI - 99mTechnetium-based Prostate-specific Membrane Antigen-radioguided Surgery in Recurrent Prostate Cancer. AB - BACKGROUND: Prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) can visualize metastatic lesions in recurrent prostate cancer (PC). However, reliable identification of small and/or atypically localized lesions during salvage surgery procedures is challenging. OBJECTIVE: To describe the technique, feasibility, and short-term outcomes of 99mTechnetium (99mTc) based PSMA-radioguided surgery (99mTc-PSMA-RGS) for removal of recurrent PC lesions. DESIGN, SETTING, AND PARTICIPANTS: Thirty-one consecutive patients with evidence of recurrent PC on 68Ga-PSMA N,N'-bis[2-hydroxy-5-(carboxyethyl)benzyl] ethylenediamine-N,N'-diacetic acid (68Ga-PSMA-11) PET after radical prostatectomy undergoing 99mTc-PSMA-RGS were retrospectively analyzed. SURGICAL PROCEDURE: Salvage surgery with intraoperative radioguidance using a gamma probe was performed after intravenous application of 99mTc-PSMA investigation and surgery (mean activity 571 MBq, mean time to surgery 19.7h). MEASUREMENTS: Radioactive rating (positive vs negative) of resected tissue was compared with the findings of postoperative histopathological analysis. Best prostate-specific antigen (PSA) response without additional treatment was determined after 8-16 wk postoperatively. Biochemical recurrence- and treatment-free survival was evaluated. RESULTS AND LIMITATIONS: In total, 132 tissue specimens were removed, of which 58 showed metastatic involvement on histological analysis. On a specimen basis, radioactive rating yielded a sensitivity of 83.6% (confidence interval [CI]: 70.9-91.5%), a specificity of 100%, and an accuracy of 93.0% (CI: 85.5 96.7%). With 99mTc-PSMA-RGS, all lesions visualized on preoperative 68Ga-PSMA-11 PET could be removed. Moreover, 99mTc-PSMA-RGS detected additional metastases as small as 3mm in two patients. Thirteen patients suffered from complications related to surgery (Clavien-Dindo grade 1: 12 patients; grade 3a: one patient). A PSA reduction below 0.2 ng/ml was observed in 20 patients. Thirteen patients remained biochemical recurrence free after a median follow-up of 13.8 (range: 4.6 18.3) mo. Twenty patients continued to be treatment free after a median follow-up of 12.2 (range: 5.5-18.3) mo. CONCLUSIONS: As a new technique for surgical guidance, 99mTc-PSMA-RGS is feasible, and has been proved to be of high value for successful intraoperative detection and removal of metastatic lesions in PC patients scheduled for salvage surgery. Its long-term impact on outcome has to be evaluated. PATIENT SUMMARY: In this report, we evaluated a novel technique to identify metastatic lesions intraoperatively in patients with recurrent prostate cancer to facilitate surgical removal. After intravenous injection of radioactive molecules that specifically bind to prostate cancer cells that show increased expression of the prostate-specific membrane antigen, we were able to detect and remove these metastatic lesions during surgery. Following salvage surgery, 41.9% of patients remained biochemical recurrence free (median follow-up of 13.8 mo) and 64.5% continued to be treatment free (median follow-up of 12.2 mo). PMID- 29625756 TI - Active Surveillance for Localized Renal Masses: Tumor Growth, Delayed Intervention Rates, and >5-yr Clinical Outcomes. AB - BACKGROUND: Active surveillance (AS) has gained acceptance as a management strategy for localized renal masses. OBJECTIVE: To review our large single-center experience with AS. DESIGN, SETTING, AND PARTICIPANTS: From 2000 to 2016, we identified 457 patients with 544 lesions managed with AS from our prospectively maintained kidney cancer database. A subset analysis was performed for patients with >=5-yr follow-up without delayed intervention (DI). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Linear growth rates (LGRs) were estimated using linear regression for the initial LGR (iLGR) AS interval and the entire AS period. Overall survival (OS) and cumulative incidence of DI were estimated with Kaplan Meier methods utilizing iLGR groups, adjusting for covariates. DI was evaluated for association with OS in Cox models. RESULTS AND LIMITATIONS: Median follow-up was 67 mo (interquartile range [IQR] 41-94 mo) for surviving patients. Cumulative incidence of DI (n=153) after 1, 2, 3, 4, and 5 yr was 9%, 22%, 29%, 35%, and 42%, respectively. Median initial maximum tumor dimension was 2.1cm (IQR 1.5 3.1cm). Median iLGR and overall LGR were 1.9 (IQR 0-7) and 1.9 (IQR 0.3-4.2) mm/yr, respectively. Compared with the no growth group, low iLGR (hazard ratio [HR] 1.25, 95% cumulative incidence [CI] 0.82-1.91), moderate iLGR (HR 2.1, 95% CI 1.31-3.36), and high iLGR (HR 1.87, 95% CI 1.23-2.84) were associated with DI (p=0.003). The iLGR was not associated with OS (p=0.8). DI was not associated with OS (HR 1.34, 95% CI 0.79-2.29, p=0.3). Five-year cancer-specific mortality (CSM) was 1.2% (95% CI 0.4-2.8%). Of 99 patients on AS without DI for >5 yr, one patient metastasized. CONCLUSIONS: At >5 yr, AS+/-DI is a successful strategy in carefully managed patients. DI often occurs in the first 2-3 yr, becoming less likely over time. Rare metastasis and low CSM rates should reassure physicians that AS is safe in the intermediate to long term. PATIENT SUMMARY: In this report, we looked at the outcomes of patients with kidney masses who elected to enroll in active surveillance rather than immediate surgery. We found that patients who need surgery are often identified early and those who remain on active surveillance become less likely to need surgery over time. We concluded that active surveillance with or without delayed surgery is a safe practice and that, when properly managed and followed, patients are unlikely to metastasize or die from kidney cancer. PMID- 29625757 TI - Will Image-guided Metastasis-directed Therapy Change the Treatment Paradigm of Oligorecurrent Prostate Cancer? AB - Although recent studies support the role of image-guided metastasis-directed therapies in the oligo-recurrent setting, several issues including the risk of possible underestimation of the true tumor burden at imaging, patient selection and the lack of studies comparing different approaches limit their implementation in the clinical practice. As such, metastasis-directed therapies should still be considered as investigational treatment options in oligo-recurrent prostate cancer patients. PMID- 29625758 TI - A Larger Perspective Study is Needed When Judging Robotic Radical Nephrectomy. PMID- 29625759 TI - Re: Who Should be Investigated for Hematuria? Results of a Contemporary Prospective Observational Study of 3556 Patients. PMID- 29625760 TI - [Nipple-areola complexity]. PMID- 29625761 TI - [Recurrent nevus: Case-report about a pagetoid form occurring from a congenital nevus in infancy]. AB - INTRODUCTION: Recurrent nevus (RN) is a cutaneous benign tumour with similarities with malignant lesions. Typically, it occurs after a partial resection of commun acquired nevus. Its incidence varies from 0.3 to 27% according to the studies. We present here a pediatric case of a pagetoid form of a recurrent nevus occurring from a congenital nevus. CASE REPORT: A congenital nevus was removed from a 9 month-old girl. Pathologists concluded to a commun-acquired nevus of complete exeresis. Two other cutaneous lesions appeared and we decided to realise a total removal. Analysis showed a recurrent nevus with some atypical histological features. No recurrence has occurred during the three post-operative of follow up. DISCUSSION: It is an interesting case because of the occurrence of a RN after the removal of a congenital nevus in a child. Furthermore, it displayed some atypical histological features. Practicians, such as surgeons, dermatologists or pathologists, have to be aware of the risk of misdiagnosis with this lesion, which presents some similarities with SSM melanoma. It would be interesting to determinate some markers to statuate about its benign feature. There is no management recommendation about this lesion but it seems to be necessary to remove it to eliminate a malignant tumour. PMID- 29625762 TI - Effectiveness of preventive cognitive therapy while tapering antidepressants versus maintenance antidepressant treatment versus their combination in prevention of depressive relapse or recurrence (DRD study): a three-group, multicentre, randomised controlled trial. AB - BACKGROUND: Keeping individuals on antidepressants after remission or recovery of major depressive disorder is a common strategy to prevent relapse or recurrence. Preventive cognitive therapy (PCT) has been proposed as an alternative to maintenance antidepressant treatment, but whether its addition would allow tapering of antidepressants or enhance the efficacy of maintenance antidepressant treatment is unclear. We aimed to compare the effectiveness of antidepressants alone, with PCT while tapering off antidepressants, or PCT added to antidepressants in the prevention of relapse and recurrence. METHODS: In this single-blind, multicentre, parallel, three-group, randomised controlled trial, individuals recruited by general practitioners, pharmacists, secondary mental health care, or media were randomly assigned (10:10:8) to PCT and antidepressants, antidepressants alone, or PCT with tapering of antidepressants, using computer-generated randomised allocation stratified for number of previous depressive episodes and type of care. Eligible participants had previously experienced at least two depressive episodes and were in remission or recovery on antidepressants, which they had been receiving for at least the past 6 months. Exclusion criteria were current mania or hypomania, a history of bipolar disorder, any history of psychosis, current alcohol or drug abuse, an anxiety disorder that requires treatment, psychological treatment more than twice a month, and a diagnosis of organic brain damage. The primary outcome was time related proportion of individuals with depressive relapse or recurrence in the intention-to-treat population, assessed four times in 24 months. Assessors were masked to treatment allocation, whereas physicians and participants could not be masked. This trial is registered with the Netherlands Trial Register, number NTR1907. FINDINGS: Between July 14, 2009, and April 30, 2015, 2486 participants were assessed for eligibility and 289 were randomly assigned to PCT and antidepressant (n=104), antidepressant alone (n=100), or PCT with tapering of antidepressant (n=85). The overall log-rank test was significant (p=0.014). Antidepressants alone were not superior to PCT while tapering off antidepressants in terms of the risk of relapse or recurrence (hazard ratio [HR] 0.86, 95% CI 0.56-1.32; p=0.502). Adding PCT to antidepressant treatment resulted in a 41% relative risk reduction compared with antidepressants alone (0.59, 0.38-0.94; p=0.026). There were two suicide attempts (one in the antidepressants alone group and one in the PCT with tapering of antidepressants group) and one death (in the PCT and antidepressants group) not related to the interventions during the 24 months' follow-up. INTERPRETATION: Maintenance antidepressant treatment is not superior to PCT after recovery, whereas adding PCT to antidepressant treatment after recovery is superior to antidepressants alone. PCT should be offered to recurrently depressed individuals on antidepressants and to individuals who wish to stop antidepressants after recovery. FUNDING: The Netherlands Organisation for Health Research and Development. PMID- 29625763 TI - Time to rethink the approach to recurrent depression. PMID- 29625764 TI - Systematic review of cost-effectiveness studies of human papillomavirus (HPV) vaccination: 9-Valent vaccine, gender-neutral and multiple age cohort vaccination. AB - BACKGROUND: The success of human papillomavirus (HPV) national immunization program depends on effective strategies in optimizing the uptake of HPV vaccine. Given the increasing number of economic evaluations, this review was conducted to update the economic evidence on HPV vaccination, by focusing on: (i) 9-valent vaccine compared to bi- or quadrivalent vaccine; (ii) gender-neutral vaccination compared to female only vaccination; and (iii) multiple age cohort immunization compared to single age cohort immunization. METHODS: Searches were performed until June 2016 using 4 databases: PubMed; Embase; Cochrane Library; and LILACS. The combined WHO, Drummond and CHEERS checklist were used to evaluate the quality of included studies. RESULTS: Thirty-four studies were included in the review and most of them were conducted in high-income countries. The inclusion of adolescent boys in vaccination program was found to be cost-effective if vaccine price and coverage was low. When coverage for female was above 75%, gender-neutral vaccination was less cost-effective than when targeting only girls aged 9-18 years. Current evidence does not show conclusive proof of greater cost effectiveness of 9-valent vaccine compared to the older HPV vaccines as the price for 9-valent vaccine was still uncertain. Multicohort immunization strategy was cost-effective in the age range 9-14 years but the upper age limit at which vaccination was no longer cost-effective needs to be further investigated. Key influential parameters identified were duration of vaccine protection, vaccine price, coverage, and discounting rates. CONCLUSIONS: These findings are expected to support policy-makers in making recommendations for HPV immunization programs on either switching to the 9-valent vaccine or inclusion of adolescent boys' vaccination or extending the age of vaccination. PMID- 29625765 TI - LemA and Erp Y-like recombinant proteins from Leptospira interrogans protect hamsters from challenge using AddaVaxTM as adjuvant. AB - BACKGROUND: Recombinant subunit vaccines have been extensively evaluated as promising alternatives against leptospirosis. Here, we evaluated two proteins in formulations containing the adjuvant AddaVaxTM as vaccine candidates for prevention and control of leptospirosis. METHODS: Recombinant proteins rErp Y like and rLemA were characterized by ELISA to assess their ability to bind extracellular matrix (ECM) components and fibrinogen. Groups of eight hamsters were immunized intramuscularly with rErp Y-like or rLemA mixed with a squalene based adjuvant (AddaVax), and then vaccine efficacy was determined in terms of protection against a lethal challenge. The humoral immune response was determined by ELISA, and the evidence of sub-lethal infection was evaluated by histopathology and kidney culture. RESULTS: rLemA protein binds laminin, fibrinogen, and collagen type IV, while rErp Y-like interacts with fibrinogen. Significant protection was achieved for rLemA and rErp Y-like vaccines, which showed 87.5% and 62.5% survivals, respectively. On day 28, the humoral immune response was significantly greater in the vaccine groups as compared to that in the control group, and the response was predominantly based on IgG2/3. The surviving animals showed negative results in culture isolation but presented with tissue lesions in the lungs and kidneys. CONCLUSION: Cumulatively, our findings suggest that LemA and Erp Y-like proteins act as adhesins and are able to protect against mortality, but not against tissue lesions. Moreover, AddaVax is a novel adjuvant with potential for improving the immunogenicity of leptospiral vaccines. PMID- 29625766 TI - A follow-up comparative safety analysis of pandemic H1N1 vaccination during pregnancy and risk of infant birth defects among U.S. military mothers. AB - OBJECTIVE: To update a previous assessment of birth defects among infants born to active duty U.S. military mothers who received the 2009-2010 pandemic H1N1 vaccine, in comparison to the 2008-2009 seasonal influenza vaccine, during pregnancy. Here, we updated the previous comparative analyses with a more refined definition for birth defects using an additional year of follow-up data from both inpatient and outpatient medical encounters. METHODS: The study population included 15,510 live born infants born to active duty mothers vaccinated during pregnancy with either the 2009-2010 pandemic H1N1 vaccine (n = 9033) or the 2008 2009 seasonal influenza vaccine (n = 6477). Birth defect cases were defined as those infants who received a birth defect diagnosis on one inpatient record or two outpatient records on different days within the first year of life. Multivariable logistic regression models were conducted to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) for the association between birth defects and maternal vaccination during pregnancy with pandemic H1N1 vaccine versus seasonal influenza vaccine. RESULTS: Infants born to mothers vaccinated during pregnancy with the pandemic H1N1 vaccine, versus the seasonal influenza vaccine, were not at increased odds of birth defects in univariable (OR: 1.13, 95% CI: 0.95-1.34) or multivariable (OR: 1.14, 95% CI: 0.96-1.35) models. Findings were not significant when further limited to first trimester exposure. Multivariable models were adjusted for infant sex and plurality; maternal age, race/ethnicity, marital status, service branch, military rank, and occupation; timing of vaccination; and receipt of vaccination(s) not routinely recommended during pregnancy. CONCLUSION: Comparable to our previous analyses assessing birth defects diagnosed at birth, no significant association was found between the pandemic H1N1 vaccination during pregnancy and birth defects, versus the seasonal influenza vaccine. These findings are reassuring and provide additional support for H1N1-containing seasonal influenza vaccination during pregnancy. PMID- 29625767 TI - Review of mathematical models of HSV-2 vaccination: Implications for vaccine development. AB - Development of a vaccine against herpes simplex virus type 2 (HSV-2), a life-long sexually-transmitted infection (STI), would be a major step forward in improving global sexual and reproductive health. In this review, we identified published literature of dynamic mathematical models assessing the impact of either prophylactic or therapeutic HSV-2 vaccination at the population level. We compared each study's model structure and assumptions as well as predicted vaccination impact. We examined possible causes of heterogeneity across model predictions, key gaps, and the implications of these findings for future modelling efforts. Only eight modelling studies have assessed the potential public health impact of HSV-2 vaccination, with the majority focusing on impact of prophylactic vaccines. The studies showed that even an imperfect prophylactic HSV-2 vaccine could have an important public health impact on HSV-2 incidence, and could also impact HIV indirectly in high HIV prevalence settings. Therapeutic vaccines also may provide public health benefits, though they have been explored less extensively. However, there was substantial variation in predicted population-level impact for both types of vaccine, reflecting differences in assumptions between model scenarios. Importantly, many models did not account for heterogeneity in infection rates such as by age, sex and sexual activity. Future modelling work to inform decisions on HSV vaccine development and implementation should consider cost-effectiveness, account for additional HSV-2 sequelae such as neonatal transmission, and model greater heterogeneity in infection rates between individuals, more realistic vaccine deployment, and more thorough sensitivity and uncertainty analyses. PMID- 29625768 TI - Human papillomavirus vaccine acceptability and decision-making among adolescent boys and parents: A meta-ethnography of qualitative studies. AB - OBJECTIVE: Genital warts and human papillomavirus (HPV)-associated cancers in men can be substantially reduced through HPV vaccination; yet, globally, HPV vaccine uptake among boys remains low. This meta-ethnography synthesizes qualitative studies to understand, in-depth, HPV vaccine acceptability and decision-making among adolescent boys and/or their parents. METHODS: A systematic search identified qualitative studies examining HPV vaccines from the perspectives of boys and/or boys' parents. The Consolidated Criteria for Reporting Qualitative Research (COREQ) 32-item checklist was used to assess quality of reporting. Using meta-ethnographic techniques, we conducted a structured and iterative process of data analysis, coded original studies, and then developed descriptive and analytic themes to synthesize the findings. RESULTS: Review of 15 eligible studies (n = 3362 parents, n = 39 boys) revealed multilevel factors that influence HPV vaccine acceptability and decision-making among adolescent boys and their parents: (1) individual, e.g., low HPV vaccine knowledge/awareness, (2) interpersonal, e.g., key relationships between parents, sons, and healthcare providers (HCP), (3) community/societal, e.g., parental duty to protect, and (4) systemic, e.g., HPV vaccine messaging. Parents generally accepted adolescent boys' sexuality and the need for vaccination, motivated by wanting to protect their sons from HPV and HPV-associated cancers, and valued HCP-initiated discussion and recommendation. Acceptability was mitigated by low awareness/knowledge of HPV vaccines and low perceived benefits for boys, lack of HCP-initiated discussion, out-of-pocket costs, multiple doses, stigma, and mixed messages about HPV. CONCLUSIONS: Multilevel factors influence HPV vaccine acceptability and decision-making among parents and their adolescent sons. Providing clear and unambiguous messages about HPV vaccines-for whom (boys and girls), for what (genital warts and cancers in men), and when (before sexual debut)-through increased HCP-initiated discussion and targeted public health campaigns may support HPV vaccine uptake among boys. Future research should consistently disaggregate findings by sex of child and parent, and explore effective messaging tailored for boys and parents. PMID- 29625770 TI - Temperature dependence of antibody adsorption in protein A affinity chromatography. AB - Staphylococcal protein A affinity chromatography is a well-established platform for purification of clinical-grade antibodies. The wild type ligand has been mutated to improve caustic stability, elution behavior, and/or to increase binding capacity. Several modified protein A ligands are nowadays commercially available, one of them being the thermosensitive chromatography medium Byzen Pro from Nomadic Bioscience Co., Ltd. According to the manufacturer, Byzen Pro has the ability to release IgG upon a change in temperature. It is based on a thermosensitive mutant of protein A which should allow elution at neutral pH by changing the temperature from binding at 5 degrees C to elution conditions at 40 degrees C. We determined equilibrium binding capacities of the thermosensitive protein A medium (Byzen Pro), MabSelect SuRe (GE Healthcare), and TOYOPEARL AF rProtein A HC-650F (Tosoh Bioscience LLC) for antibodies of the subclass IgG1 and IgG2 at five different temperatures from 4 degrees C to 40 degrees C to elucidate the temperature effect. We also observed a temperature dependence of the dynamic binding capacities which were determined for the subclass IgG2 at three temperatures from 4 degrees C to 40 degrees C. However, for Byzen Pro, the temperature dependence was only present at a low flow rate and vanished at high flow rates indicating that pore diffusion is the rate-limiting step. Binding of the antibody to MabSelect SuRe and TOYOPEARL AF-rProtein A HC-650F stabilized the conformations as shown by an increase in melting temperature in differential scanning calorimetry measurements. The antibody conformation was slightly destabilized upon binding to the thermosensitive ligand. The conformation change upon binding was fully reversible as shown by circular dichroism, differential scanning calorimetry and size exclusion chromatography. Isothermal titration calorimetry was used to measure the raw heat of adsorption for the IgG2 molecule. The thermosensitive ligand can also be used for antibodies with low stability, because elution can also be effected by salt. PMID- 29625771 TI - Ion exchange column capacities. Predicting retention behavior of open tubular columns coated with the same phase. AB - We discuss the reported capacities of available packed ion exchange columns and the different methods used for their measurement. We outline basic considerations related to both packed and open tubular columns based on ion exchange latex particles. There is a large body of information covering the retention behavior of packed ion exchange columns based on ion exchange latex particles. We propose a parameter gammaiex, which is the ion exchange capacity of a column (packed or open tubular) per unit liquid volume present in the column (including accessible volume within pores) and show that the retention factor for any given ion is directly related to gammaiex. On this basis, if based on the same type of latex, the behavior of one type of column can be reasonably predicted from the known behavior of the other, even when the absolute capacities differ by more than 5 orders of magnitude. PMID- 29625769 TI - Correlation between body mass index and obstructive sleep apnea severity indexes A retrospective study. AB - PURPOSE: To evaluate if Body Mass Index (BMI) is correlated to Apnea-Hypopnea Index (AHI), mean arterial oxygen saturation (SaO2) and Nadir SaO2, which are all indexes defining the severity of the respiratory stress associated with Obstructive Sleep Apnea (OSA). MATERIALS AND METHODS: Seventy-five adult patients (mean age 51.4) referred for polysomnography were retrospectively recruited. BMI was calculated for each patient, as well as AHI, SaO2, and Nadir SaO2 recorded during polysomnography. Spearman's Rho test was used to evaluate if OSA severity was correlated to BMI values. First type error was set as p < 0.025. RESULTS: No correlation was observed between BMI and AHI, and between BMI and SaO2. A statistically significant negative correlation (r2 = 0.424; p < 0.001) was found between the BMI index and the Nadir SaO2. CONCLUSIONS: Higher BMI values were correlated with lower Nadir SaO2 during overnight polysomnography. Since hypoxia stress is a risk factor for cardiovascular diseases and alters the lipid metabolism, dietary consulting should be recommended in association with other treatment modalities for OSA. PMID- 29625772 TI - Pulmonary sarcoidosis. AB - Sarcoidosis is a granulomatous disease of unknown cause, occurs worldwide and has a highly variable prevalence. The disease is typically dominant in the lungs, although it can affect virtually any organ and is unpredictable in its clinical course. The severity of pulmonary sarcoidosis ranges from incidentally discovered radiographic abnormalities in asymptomatic patients to a chronic progressive disease that is refractory to treatment. Mortality from sarcoidosis appears to have increased in the past three decades, with respiratory failure being the most common cause of sarcoidosis-related death. Pulmonary fibrosis, extensive disease on high-resolution chest CT, impaired lung function, and pulmonary hypertension are well established predictors of poor clinical outcomes. In patients who need systemic therapy to control their disease, corticosteroids are the most commonly used first-line treatment, with antimetabolites generally representing an alternative for patients who are unresponsive to corticosteroids or who cannot tolerate them. Indeed, corticosteroid therapy is associated with toxic effects that correlate with both the cumulative dose and duration of treatment. The scarcity of truly effective therapies and shortage of reliable predictors of the unpredictable development of disease in individual patients greatly contribute to making sarcoidosis such a difficult disease to manage. PMID- 29625773 TI - Asthma in the USA: the good, the bad, and the disparity. PMID- 29625774 TI - 'Surface Transplantation' for Nerve Injury and Repair: The Quest for Minimally Invasive Cell Delivery. AB - Cell transplantation is an ambitious, but arguably realistic, therapy for repair of the nervous system. Cell delivery is a major challenge for clinical translation, especially given the apparently inhibitory astrogliotic environment in degenerated tissue. However, astrogliotic tissue also contains endogenous structural and biochemical cues that can be harnessed for functional repair. Minimizing damage to these cues during cell delivery could enhance cell integration. This theory is supported by studies with an auditory astrocyte scar model, in which cells delivered onto the surface of the damaged nerve were more successfully integrated in the host than those injected into the tissue. We consider the application of this less invasive approach for nerve injury and its potential application to some neurodegenerative disorders. PMID- 29625775 TI - Wall shear stress fixed points in cardiovascular fluid mechanics. AB - Complex blood flow in large arteries creates rich wall shear stress (WSS) vectorial features. WSS acts as a link between blood flow dynamics and the biology of various cardiovascular diseases. WSS has been of great interest in a wide range of studies and has been the most popular measure to correlate blood flow to cardiovascular disease. Recent studies have emphasized different vectorial features of WSS. However, fixed points in the WSS vector field have not received much attention. A WSS fixed point is a point on the vessel wall where the WSS vector vanishes. In this article, WSS fixed points are classified and the aspects by which they could influence cardiovascular disease are reviewed. First, the connection between WSS fixed points and the flow topology away from the vessel wall is discussed. Second, the potential role of time-averaged WSS fixed points in biochemical mass transport is demonstrated using the recent concept of Lagrangian WSS structures. Finally, simple measures are proposed to quantify the exposure of the endothelial cells to WSS fixed points. Examples from various arterial flow applications are demonstrated. PMID- 29625776 TI - Agreement between diseases-centered and multidimensional models of care in disadvantaged settings. PMID- 29625777 TI - Tai Chi and Pulmonary Rehabilitation Compared for Treatment-Naive Patients With COPD: A Randomized Controlled Trial. AB - BACKGROUND: In COPD, functional status is improved by pulmonary rehabilitation (PR) but requires specific facilities. Tai Chi, which combines psychological treatment and physical exercise and requires no special equipment, is widely practiced in China and is becoming increasingly popular in the rest of the world. We hypothesized that Tai Chi is equivalent (ie, difference less than +/-4 St. George's Respiratory Questionnaire [SGRQ] points) to PR. METHODS: A total of 120 patients (mean FEV1, 1.11 +/- 0.42 L; 43.6% predicted) bronchodilator-naive patients were studied. Two weeks after starting indacaterol 150 MUg once daily, they randomly received either standard PR thrice weekly or group Tai Chi five times weekly, for 12 weeks. The primary end point was change in SGRQ prior to and following the exercise intervention; measurements were also made 12 weeks after the end of the intervention. RESULTS: The between-group difference for SGRQ at the end of the exercise interventions was -0.48 (95% CI PR vs Tai Chi, -3.6 to 2.6; P = .76), excluding a difference exceeding the minimal clinically important difference. Twelve weeks later, the between-group difference for SGRQ was 4.5 (95% CI, 1.9 to 7.0; P < .001), favoring Tai Chi. Similar trends were observed for 6-min walk distance; no change in FEV1 was observed. CONCLUSIONS: Tai Chi is equivalent to PR for improving SGRQ in COPD. Twelve weeks after exercise cessation, a clinically significant difference in SGRQ emerged favoring Tai Chi. Tai Chi is an appropriate substitute for PR. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02665130; URL: www.clinicaltrials.gov. PMID- 29625778 TI - [The epidermal barrier]. AB - The skin acts as an interface between the body and its surrounding environment. The epidermis, the surface layer of the skin, is chiefly responsible for this interactive protective function. The epidermal barrier may be subdivided into three defensive systems: the photoprotective barrier, the immune barrier, and the physical and chemical barrier of the stratum corneum or horny layer. To protect against harmful ultraviolet radiation, the epidermis has absorption factors such as melanin, produced by melanocytes, and urocanic acid, which is a degradation product of filaggrin. The epidermal immune defence system comprises an innate component, which is rapid but non-specific, together with adaptive response, which is systemic and antigen-specific, initiated by Langerhans cells. The stratum corneum, derived from terminal differentiation of epidermal keratinocytes, plays a key role as a physical and chemical permeability barrier. This horny layer is made up of corneocytes, covered with horny envelopes and linked to one another by corneodesmosomes and by extracellular matrix sheets. The epidermal barrier, which is constantly being renewed, is characterised by its extremely great capacity of adaptation to changing conditions in the environment. PMID- 29625779 TI - B-type natriuretic peptide may predict prognosis in older adults admitted with a diagnosis other than heart failure. AB - BACKGROUND AND AIMS: The diagnosis of heart failure (HF) in elderly patients is often difficult, due to overlap of typical signs and symptoms with those of comorbidities. B-type Natriuretic Peptide (BNP) predicts diagnosis and prognosis of HF, but little is known on its predictive role of short-term prognosis when admission diagnosis is other than HF. METHODS AND RESULTS: We prospectively recruited 404 consecutive patients (aged>=65 years) hospitalized in the Unit of Internal Medicine, University of Catania, Catania, Italy, with an admission diagnosis other than HF. Clinical examination, laboratory data and BNP were evaluated at the admission. The predictive value of BNP and other variables for in-hospital mortality, thirty-day mortality and three month re-hospitalization was assessed. During hospitalization 48 (12%) patients died; by logistic regression analysis, in-hospital mortality was not predicted by BNP>600 pg/ml (OR = 1.36; CI 95% = 0.60-2.80; p = 0.4), while it was by chronic kidney disease (CKD, p < 0.001), WBC count (p < 0.001), immobilization syndrome (p < 0.008) and age (p = 0.012). After discharge, 54 patients (15%) died within 30 days; in these patients thirty-day mortality was significantly predicted by BNP>600 pg/ml (OR = 2.70; CI 95% = 1.40-5.00; p = 0.001), CKD (p < 0.001), malnutrition (p = 0.029) and age (p = 0.033). Re-hospitalized patients were 97 (32%); three month re hospitalization was predicted by BNP>600 pg/ml (OR = 12.28; CI 95% = 6.00-24.90; p < 0.001) and anamnestic HF (p = 0.002). CONCLUSIONS: Our study shows that BNP>600 pg/ml, CKD, malnutrition and age predict thirty-day mortality after discharge in elderly patients with an admission diagnosis other than HF, while CKD, WBC count, immobilization syndrome and age predict in-hospital mortality. Three-month re-hospitalization was predicted by BNP>600 pg/ml and anamnestic HF. PMID- 29625780 TI - Pharmacovigilance of sodium-glucose co-transporter-2 inhibitors: What a clinician should know on disproportionality analysis of spontaneous reporting systems. AB - Sodium-glucose co-transporter-2 inhibitors (SGLT2-Is) have consistently demonstrated a clinically significant reduction of cardiovascular mortality. However, their safety in clinical practice is still incompletely characterized, and post-marketing monitoring is required considering the expected increase in clinical use. Different analyses of international spontaneous reporting systems, known as disproportionality analyses (DAs), have highlighted the occurrence of ketoacidosis, amputations, acute renal failure and skin toxicity. In this viewpoint, we critically appraise these pharmacovigilance data on SGLT2-Is, with the aim of supporting clinicians in proper interpretation of these studies, and discussing their risk-benefit profile. To this aim, we offer a broad perspective on basic technical aspects subtending DAs of spontaneous reporting databases (describing peculiarities of the Food and Drug Administration Adverse Event Reporting System), their common and evolving uses, key pitfalls in presenting study results (in terms of "risk" or "association") and relevant strategies to account for major confounders. This will also facilitate reviewers and editors in proper evaluation of DAs, and prompt pharmacovigilance experts in converging towards a set of minimum requirements in standardization of design, performance and reporting of DAs. A consensus on quality assessment of DAs will finally establish their transferability to clinical practice. It is anticipated that DAs cannot be used per se as a standalone approach to assess a drug-related risk and cannot replace clinical judgment in the individual patient. PMID- 29625781 TI - Human exposure to trace elements via consumption of mussels Mytilus galloprovincialis from Boka Kotorska Bay, Montenegro. AB - In order to assess human health risks via consumption of potentially toxic mussels, the concentrations of Al, Ba, Cd, Co, Cr, Cu, Fe, Li, Mn, Ni, Pb, Sr, Zn and Hg were studied in Mytilus galloprovincialis collected from the coastal area of Montenegro. By two approaches for the human health risk assessment (HHRA), considering oral reference doses by the United States Environmental Protection Agency (US EPA) and provisional tolerable intakes by the Joint FAO/WHO Expert Committee on Food Additives (JECFA), it has been revealed that despite the fact that trace element levels do not exceed the defined limits for mussels, they can be limiting factors for the mussel consumption. Specifically, it was noticed that the levels of Co, Pb, Cd and Li could be the limiting factors for the consumption of mussels from this coastal area. Al and Li data obtained in this study are especially important since these two elements have not been previously studied in M. galloprovincialis. Furthermore, taking into account the significant differences in concentrations of elements in different seasons, the study confirmed the starting assumption that in the calculations for the HHRA the average concentrations of elements in samples taken in different seasons during a longer period should be used. PMID- 29625783 TI - Unexpected breast metastasis from cutaneous melanoma on 18F-FDG PET/CT. PMID- 29625782 TI - Lymph node yield during radical prostatectomy does not impact rate of biochemical recurrence in patients with seminal vesicle invasion and node-negative disease. AB - OBJECTIVES: Seminal vesicle invasion (SVI) is a risk factor for poor oncologic outcome in patients with prostate cancer. Modifications to the pelvic lymph node dissection (PLND) during radical prostatectomy (RP) have been reported to have a therapeutic benefit. The present study is the first to determine if lymph node yield (LNY) is associated with a lower risk of biochemical recurrence (BCR) for men with SVI. METHODS: A total of 220 patients from 2 high-volume institutions who underwent RP without adjuvant treatment between 1990 and 2015 and had prostate cancer with SVI (i.e., pT3b) were identified, and 21 patients did not undergo lymph node dissection. BCR was defined as a postoperative PSA>0.2ng/mL, or use of salvage androgen deprivation therapy (ADT) or radiation. Multivariable Cox proportional hazards models were used to determine whether LNY was predictive of BCR, controlling for PSA, pathologic Gleason Score, pathologic lymph node status, NCCN risk category, etc. The Kaplan-Meier method was used to determine 3 year freedom from BCR. RESULTS: Median number of lymph nodes sampled were 7 (IQR: 3-12; range: 0-35) and 90.5% underwent PLND. The estimated 3-year BCR rate was 43.9%. Results from multivariable analysis demonstrated that LNY was not significantly associated with risk of BCR overall (HR = 1.00, 95% CI: 0.98-1.03; P = 0.848) for pN0 (HR = 0.99, 95% CI: 0.97-1.03; P = 0.916) or pN1 patients (HR = 0.96, 95% CI: 0.88-1.06; P = 0.468). Overall, PSA (HR = 1.02, P<0.001) and biopsy Gleason sum >= 8 (HR = 1.81, P = 0.001) were associated with an increased risk of BCR, and increasing LNY increased the likelihood of detecting>2 positive lymph nodes (OR = 1.27, 95% CI: 1.06-1.65, P = 0.023). CONCLUSION: Seminal vesicle invasion is associated with an increased risk of BCR at 3 years, primarily due to pathologic Gleason score and PSA. Although greater lymph node yield is diagnostic and facilitates more accurate pathologic staging, our data do not show a therapeutic benefit in reducing BCR. PMID- 29625784 TI - Impact of the burden of hospitalisation for pneumonia. PMID- 29625785 TI - The role of infectious disease impact in informing decision-making for animal health management in aquaculture systems in Bangladesh. AB - The aquaculture sector in Bangladesh is an important employer and a significant source of foreign exchange. In addition, it contributes significantly to food security due to the role of fish in peoples' diets, the most important source of protein and micronutrients. However, infectious diseases represent an important barrier to sector development due to economic losses and vulnerability of smallholders. The aim of this study was to gain an overview of the impact of infectious diseases in the aquaculture sector, and to assess the usefulness and use of impact studies in decision making for animal health management and biosecurity governance in Bangladesh. A review of scientific and grey literature on infectious disease impact in different aquaculture systems was conducted and their methodologies and findings summarised. Subsequently, interviews with 28 stakeholders from the private and public sector were conducted to enquire about decision-making structures in animal health management. The data were analysed using the framework method to allow the development of themes, by using the information, experiences and opinions inductively obtained from interviewees, deductively through the reviewed literature. Results showed a substantial socio economic impact of infectious diseases. The numerous stakeholders involved in the decision-making process explained that key barriers to effective aquaculture health management were insufficient resources to investigate and tackle infectious aquatic animal diseases, a dearth of legislation and capacity for disease surveillance, a reliance on reactive response, and a lack of impact and evidence-based approaches for prioritising problem-solving, commonly based on anecdotal evidence. Furthermore, communication among the multiple stakeholders involved was reported to be weak. This complex situation requires a multi-level response, which should span from strengthening the knowledge of farmers and professionals in the field to the improvement of surveillance and diagnostic systems. Improved systems along with evidence on disease impact could inform the prioritisation of diseases and resource allocation for disease control in Bangladesh. Further, this evidence needs to be used to advise decisions to have a true value, for which establishing and strengthening communication pathways and processes is critical to make systematic use of the information and improve animal health management. In the light of future threats to Bangladesh such as climate change, increasing population density and demand for animal source foods, it is crucial to strengthen animal health management systems to reduce livelihoods vulnerability, food insecurity and the likelihood of disease emergence. PMID- 29625787 TI - Tropical diseases in the ICU: A syndromic approach to diagnosis and treatment. AB - Tropical infections form 20-30% of ICU admissions in tropical countries. Diarrheal diseases, malaria, dengue, typhoid, rickettsial diseases and leptospirosis are common causes of critical illness. Overlapping clinical features makes initial diagnosis challenging. A systematic approach involving (1) history of specific continent or country of travel, (2) exposure to specific environments (forests or farms, water sports, consumption of exotic foods), (3) incubation period, and (4) pattern of organ involvement and subtle differences in manifestations help in differential diagnosis and choice of initial empiric therapy. Fever, rash, hypotension, thrombocytopenia and mild derangement of liver function tests is seen in a majority of patients. Organ failure may lead to shock, respiratory distress, renal failure, hepatitis, coma, seizures, cardiac arrhythmias or hemorrhage. Diagnosis in some conditions is made by peripheral blood smear examination, antigen detection or detection of microbial nucleic acid by PCR. Tests that detect specific IgM antibody become positive only in the second week of illness. Initial therapy is often empiric; a combination of intravenous artesunate, ceftriaxone and either doxycycline or azithromycin would cover a majority of the treatable syndromes. Additional antiviral or antiprotozoal medications are required for some specific syndromes. Involving a physician specializing in tropical or travel medicine is helpful. PMID- 29625786 TI - Development and public release of a computerized adaptive (CAT) version of the Schizotypal Personality Questionnaire. AB - One of the most widely used measures of psychosis-related symptoms and characteristics is the 74-item Schizotypal Personality Questionnaire (SPQ). Using multidimensional Item Response Theory (bifactor 2-parameter model), we calibrated SPQ items in a sample of 375 youths aged 9-24 years and constructed a fully functional computerized adaptive form of the SPQ on an open-source platform for public use. To assess validity, we used the above parameters to simulate CAT sessions in a separate validation sample (N = 100) using three test-length-based stopping rules: 8 items, 16 items, and 32 items. Those scores were then compared to full-form and SPQ-Brief scores on their abilities to predict psychosis or clinical risk status. Areas under the receiver operating characteristic curves indicated mediocre predictive ability, but did not differ among any of the forms, even when only eight adaptive items were administered. The Youden index for the 16-item adaptive version was higher than that for the 22-item SPQ-Brief. Classification accuracy for the full SPQ was 73% compared to 66% for the both the SPQ-Brief and adaptive versions (average of three stopping rules). The SPQ-CAT shows promise as a much shorter but valid assessment of schizotypy which can save time with minimal loss of information. PMID- 29625789 TI - Cidaroids spines facing ocean acidification. AB - When facing seawater undersaturated towards calcium carbonates, spines of classical sea urchins (euechinoids) show traces of corrosion although they are covered by an epidermis. Cidaroids (a sister clade of euechinoids) are provided with mature spines devoid of epidermis, which makes them, at first sight, more sensitive to dissolution when facing undersaturated seawater. A recent study showed that spines of a tropical cidaroid are resistant to dissolution due to the high density and the low magnesium concentration of the peculiar external spine layer, the cortex. The biofilm and epibionts covering the spines was also suggested to take part in the spine protection. Here, we investigate the protective role of these factors in different cidaroid species from a broad range of latitude, temperature and depth. The high density of the cortical layer and the cover of biofilm and epibionts were confirmed as key protection against dissolution. The low magnesium concentration of cidaroid spines compared to that of euechinoid ones makes them less soluble in general. PMID- 29625788 TI - Clinicopathological and predictive significance of SIRT1 and peroxisome proliferator-activated receptor gamma in esophageal squamous cell carcinoma: The correlation with EGFR and Survivin. AB - SIRT1 (silent mating type information regulation 2 homolog 1) is an enzyme that deacetylates proteins that contributes to cell survival and angiogenesis. Peroxisome proliferator-activated receptor Y (PPAR Y) is a member of the nuclear steroid hormone receptor superfamily and regulates cell apoptosis and proliferation. The functional roles of SIRT1 and PPAR Y in tumor progression remain controversy. This study aims to investigate the roles of SIRT1 and PPAR Y in esophageal squamous cell carcinoma (ESCC), as well as correlation with expression of EGFR and Survivin. Here, we analyzed the protein expression of SIRT1 and PPAR Y in tumor microarray with ESCC and its associations with clinicopathological parameters and overall survival. Both SIRT1 and PPAR Y were highly expressed in tumor tissues comparing with non-cancerous epithelium. High expression of SIRT1 was positively correlated with advanced TNM stage and poor outcome, while high expression of PPAR Y was positively related with tumor grading, not with patients' prognosis. In addition, the high expression of SIRT1 was positively correlated with overexpression of EGFR, not related with PPAR Y or Survivin expression status. These data suggests SIRT1 may serve as a predictor of poor prognosis in ESCC, and its mediated tumor-promoting role might be associated with the overexpression of EGFR protein in ESCC. PMID- 29625791 TI - Celebrating donors and the World Blood Donor Day 2018. PMID- 29625790 TI - Transfusion-associated hazards: A revisit of their presentation. AB - As a therapy or a support to other therapies, despite being largely beneficial to patients in general, transfusion it is not devoid of some risks. In a moderate number of cases, patients may manifest adverse reactions, otherwise referred to as transfusion-associated hazards (TAHs). The latest French 2016 haemovigilance report indicates that 93% of TAHs are minor (grade 1), 5.5% are moderate (grade 2) and 1.6% are severe (grade 3), with only five deaths (grade 4) being attributed to transfusion with relative certainty (imputability of level [or grade] 1 to 3). Health-care providers need to be well aware of the benefits and potential risks (to best evaluate and discuss the benefit-risk ratio), how to prevent TAHs, the overall costs and the availability of alternative therapeutic options. In high-income countries, most blood establishments (BEs) and hospital blood banks (HBBs) have developed tools for reporting and analysing at least severe transfusion reactions. With nearly two decades of haemovigilance, transfusion reaction databases should be quite informative, though there are four main caveats that prevent it from being fully efficient: (ai) reporting is mainly declarative and is thus barely exhaustive even in countries where it is mandatory by law; (aii) it is often difficult to differentiate between the different complications related to transfusion, diseases, comorbidities and other types of therapies in patients suffering from debilitating conditions; (aiii) there is a lack of consistency in the definitions used to describe and report some transfusion reactions, their severity and their likelihood of being related to transfusion; and (aiv) it is difficult to assess the imputability of a particular BC given to a patient who has previously received many BCs over a relatively short period of time. When compiling all available information published so far, it appears that TAHs can be analysed using different approaches: (bi) their pathophysiological nature; (bii) their severity; (biii) the onset scheme; (biv) a quality assessment (preventable or non-preventable); (bv) their impact on ongoing therapy. Moreover, TAHs can be reported either in a non-integrative or in an integrative way; in the latter case, presentation may also differ when issued by a blood establishment or a treating ward. At some point, a recapitulative document would be useful to gain a better understanding of TAHs in order to decrease their occurrence and severity and allow decision makers to determine action plans: this is what this review attempts to make. This review attempts to merge the different aspects, with a focus on the hospital side, i.e., how the most frequent TAHs can be avoided or mitigated. PMID- 29625792 TI - Gray matter differences between affective and non-affective first episode psychosis: A review of Magnetic Resonance Imaging studies: Special Section on "Translational and Neuroscience Studies in Affective Disorders" Section Editor, Maria Nobile MD, PhD. This Section of JAD focuses on the relevance of translational and neuroscience studies in providing a better understanding of the neural basis of affective disorders. The main aim is to briefly summaries relevant research findings in clinical neuroscience with particular regards to specific innovative topics in mood and anxiety disorders. AB - BACKGROUND: Non-affective and affective psychoses are very common mental disorders. However, their neurobiological underpinnings are still poorly understood. Therefore, the goal of the present review was to evaluate structural Magnetic Resonance Imaging (MRI) studies exploring brain deficits in both non affective (NA-FEP) and affective first episode psychosis (A-FEP). METHODS: A bibliographic search on PUBMED of all MRI studies exploring gray matter (GM) differences between NA-FEP and A-FEP was conducted. RESULTS: Overall, the results from the available evidence showed that the two diagnostic groups share common GM alterations in fronto-temporal regions and anterior cingulate cortex. In contrast, unique GM deficits have also been observed, with reductions in amygdala for A-FEP and in hippocampus and insula for NA-FEP. LIMITATIONS: Few small MRI studies with heterogeneous methodology. CONCLUSIONS: Although the evidences are far to be conclusive, they suggest the presence of common and distinct pattern of GM alterations in NA-FEP and A-FEP. Future larger longitudinal studies are needed to further characterize specific neural biomarkers in homogenous NA-FEP and A-FEP samples. PMID- 29625793 TI - [Restriction fragment length polymorphism of ITS1-ITS2 region to identify Candida auris]. PMID- 29625794 TI - The role of epigenetic therapies in colorectal cancer. AB - Although developments in the diagnosis and therapy of colorectal cancer (CRC) have been made in the last decade, much work remains to be done as it remains the second leading cause of cancer death. It is now well established that epigenetic events, together with genetic alterations, are key events in initiation and progression of CRC. Epigenetics refers to heritable alterations in gene expression that do not involve changes in the DNA sequence. These alterations include DNA methylation, histone alterations, chromatin remodelers, and noncoding RNAs. In CRC, aberrations in epigenome may also involve in the development of drug resistance to conventional drugs such as 5-fluorouracil, oxaliplatin, and irinotecan. Thus, it has been suggested that combined therapies with epigenetic agents may reverse drug resistance. In this regard, DNA methyltransferase inhibitors and histone deacetylase inhibitors have been extensively investigated in CRC. The aim of this review is to provide a brief overview of the preclinical data that represent a proof of principle for the employment of epigenetic agents in CRC with a focus on the advantages of combinatorial therapy over single-drug treatment. We will also critically discuss the results and limitations of initial clinical experiences of epigenetic-based therapy in CRC and summarize ongoing clinical trials. Nevertheless, since recent translational research suggest that epigenetic modulators play a key role in augmenting immunogenicity of the tumor microenvironment and in restoring immune recognition, we will also highlight the recent developments of combinations strategies of immunotherapies and epigenetic therapies in CRC, summarizing preclinical, and clinical data to signify this evolving and promising field for CRC treatment. PMID- 29625795 TI - The venous patterns of the cubital fossa in subjects from Brazil. AB - Venous punctures are among the most common procedures performed by healthcare professionals. In particular, the cubital fossa is the site where the venous accesses are frequently made due to the number of superficial veins and the numerous anastomoses in this region. The arrangement of these venous connections is of particular interest for clinical application in several areas, thus, the healthcare professional must possess knowledge about these vessels and their anatomical relationships. The present study aims to analyze the venous pattern of the cubital fossa among individuals from Brazil. This study was approved by a Research Ethics Committee. The sample had 100 healthy individuals (50 men and 50 women). The superficial veins of the cubital fossa were analyzed with the aid of a sphygmomanometer. When inflated, the pressure in the forearm increased and the veins became prominent. It was observed that in the selected sample the types with the highest prevalence were the Type I and Type VII, both with 22% in 200 limbs studied. The chi2 test showed a significant statistical difference between the anastomosis pattern and the sex of the studied sample. The anastomotic pattern of the superficial veins of the studies sample is similar to African, European and Asian populations. The study of these variations is necessary to provide scientific basis for the healthcare professional during a venipuncture in order to avoid iatrogenic errors and damages in cutaneous nerves or neighboring arteries. PMID- 29625796 TI - Sexualised drug use in the United Kingdom (UK): A review of the literature. AB - BACKGROUND: Sexualised drug use (SDU) refers to the use of drugs in a sexual context. This includes 'Chemsex'- the use of drugs (specifically crystal methamphetamine, GHB/GBL and mephedrone) before or during planned sexual activity to sustain, enhance, disinhibit or facilitate the experience. Here we aimed to synthesise available UK prevalence data for Chemsex, SDU and the use of Chemsex drugs in an undefined context (CDU) in men who have sex with men (MSM). METHODS: Papers published between January 2007 and August 2017 reporting Chemsex, SDU and/or Chemsex drug use (CDU) prevalence in MSM were identified through PubMed. Citations were searched for further eligible publications. We also conducted a review of national surveillance data, extracting prevalence data for Chemsex, SDU or CDU. Synthesized data were then assessed to determine the time at which these drugs were taken, in this case just prior to or during sexual activity (event level). RESULTS: Our search identified 136 publications, of which 28 were included in the final data synthesis. Three of the four surveillance systems assessed provided SDU or CDU data in MSM. Few publications included event-level data for Chemsex (n = 4), with prevalence estimates ranging from 17% among MSM attending sexual health clinics (SHC) to 31% in HIV-positive MSM inpatients. Prevalence estimates for SDU (n = 7 publications) also varied considerably between 4% in MSM receiving HIV care to 41% among MSM attending SHC for HIV post exposure prophylaxis (PEP). Eighteen publications provided data for CDU. CONCLUSION: Prevalence estimates varied considerably due to differences in the definition used and population assessed. Standardised definitions and studies with representative national samples of MSM are required to improve our understanding of the extent of Chemsex and its associated risks. Longitudinal event-level data for SDU and Chemsex are needed to monitor impact of interventions. PMID- 29625797 TI - Corrigendum to "Systemic and airway oxidative stress in competitive swimmers" [Respiratory Medicine 137 (2018) 129-133]. PMID- 29625798 TI - Avascular Necrosis of the Metacarpal Head: A Review of 4 Cases. AB - PURPOSE: To report on 4 cases of avascular necrosis of the metacarpal head. METHODS: We retrospectively reviewed 4 patients who received a diagnosis of avascular necrosis of the metacarpal head and were treated from 2000 to 2016. RESULTS: All patients were males with involvement of the dominant hand. Three patients had a history of trauma and/or fractures in another finger and one had a history of fracture in the same finger. The diagnosis was confirmed on regular x rays and magnetic resonance imaging. Nonsurgical management was offered to all patients (rest, placement of an orthosis, and nonsteroidal anti-inflammatory drugs) for 3 to 6 months. Two patients responded well to nonsurgical management and improved in their symptoms. One patient refused surgical intervention and continued to have persistent pain. The other patient was treated with curettage and bone graft and had total resolution of pain symptoms with full active range of motion. CONCLUSIONS: A high index of suspicion is required to diagnose and treat avascular necrosis of the metacarpal head correctly. Treatment options are numerous and require further studies to investigate their effectiveness in the treatment of this rare disease. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic V. PMID- 29625799 TI - Impact of Stroke Call on the Stroke Neurology Workforce in the United States: Possible Challenges and Opportunities. AB - BACKGROUND: The Stroke & Vascular Neurology Section of the American Academy of Neurology was charged to identify challenges to the recruitment and retention of stroke neurologists and to make recommendations to address any identified problems. The Section initiated this effort by determining the impact of stroke on-call requirements as a barrier to the recruitment and retention of vascular neurologists. METHODS: This is a cross-sectional survey of a sample of US Neurologists providing acute stroke care. RESULTS: Of the 900 neurologists who were sent surveys, 313 (35%) responded. Of respondents from institutions providing stroke coverage, 71% indicated that general neurologists and 45% indicated that vascular neurologists provided that service. Of those taking stroke call, 36% agreed with the statement, "I spent too much time on stroke call," a perception that was less common among those who took less than 12-hour shifts (P < .0001); 21% who participated in stroke call were dissatisfied with their current job. Forty-six percent indicated that their stroke call duties contributed to their personal feeling of "burnout." CONCLUSIONS: Although the reasons are likely multifactorial, our survey of neurologists providing stroke care suggests that over-burdensome on-call responsibilities may be contributing to the vascular neurology workforce burnout and could be affecting recruitment and retention of vascular neurologists. Strategies to reduce the lifestyle impact of stroke call may help address this problem. PMID- 29625800 TI - Reaction Time and Brake Pedal Depression Following Arthroscopic Hip Surgery: A Prospective Case-Control Study. AB - PURPOSE: The purpose of this study was to determine whether patients diagnosed with femoroacetabular impingement (FAI) syndrome have prolonged braking times compared with age- and gender-matched controls and how long after surgery braking times return to preoperative baseline. METHODS: Fifty-nine patients undergoing arthroscopic hip surgery for FAI and 59 age- and gender-matched controls without FAI were enrolled in a prospective comparative study between September 2015 and October 2016. Total brake reaction time (BRT) and brake pedal depression (BPD) were measured for study patients preoperatively, and at 2, 4, and 6 weeks postoperatively. BRT and BPD were compared between study and control patients and between preoperative and postoperative time periods, using mixed effects models. RESULTS: Patients with FAI had significantly prolonged BRT (but not BPD) prior to surgery compared with controls (568 vs 520 msec, P = .002). For study patients undergoing left hip surgery, there was no difference in BRT or BPD between preoperative measurements and any postoperative time point, including the first postoperative appointment at 2 weeks (563 vs 566 msec, P = .89). Patients undergoing right hip surgery had significantly prolonged BRT at 2 weeks postoperatively compared with their preoperative baseline (688 vs 573 msec, P < .001). By 4 weeks postoperatively, study patients undergoing right hip surgery had returned to their preoperative baseline (573 vs 594 msec, P = .28). No significant effect was seen based on visual analog scale pain score, opiate usage, or patient-reported outcome scores. CONCLUSIONS: Patients undergoing arthroscopic surgery of the right hip show significantly prolonged BRT until 4 weeks after surgery, while patients undergoing surgery of the left hip show no postoperative impairment in either BRT or BPD. The clinical relevance of this measured difference (an increase in 10 feet of stopping distance at 60 miles per hour) remains an open question. LEVEL OF EVIDENCE: Level II, diagnostic, prospective. PMID- 29625801 TI - Alveolar soft part sarcoma: Clinical presentation, treatment, and outcome in a series of 13 patients. AB - BACKGROUND: Alveolar soft part sarcoma (ASPS) is a rare soft tissue tumor that typically affects young patients. Similar to other soft tissue sarcomas, it has high pulmonary metastasis ability, whereas compared with other soft tissue sarcomas, it has high brain metastasis ability. Because of the rarity of the disease, most studies on ASPS have been case reports and small series studies. METHOD: We performed a retrospective study to evaluate the clinical and pathological features and oncological results in a consecutive series of patients with localized or metastatic ASPS treated at our institute between 1994 and 2014. Demographics, location, severity of disease, treatment provided, progression-free survival, and overall survival were evaluated. RESULTS: A total of 13 patients were investigated. The most common locations of primary tumor were the thigh (n = 6, 47%), followed by the flank (n = 3, 23%), forearm (n = 2, 15%), and calf (n = 2, 15%). Three patients were initially diagnosed as having hemangiomas elsewhere. These patients received unplanned intralesional excision. All the patients received wide tumor resection at our institute. Over the average follow-up period of 80.5 months (range: 36-133 months), the 5-year overall survival rate was 67.5%. Four patients were continuously disease free (31%), six were living with disease (46%), and three died of disease (23%). Of nine patients who presented with distant pulmonary metastasis, two had bony and brain metastases. The 5-year survival rate was 66.7% in patients who received chemotherapy and those who did not (p = 0.941). CONCLUSION: The treatment strategy for ASPS is wide resection, and postoperative chemotherapy may be crucial for long-term survival. In addition, this type of tumor has a high distant metastasis rate at the time of diagnosis, particularly in the lungs and brain. PMID- 29625802 TI - Cryosurvival of rabbit embryos obtained after superovulation with corifollitropin alfa with or without LH. AB - The efficiency of an embryo bank depends on provision of optimal conditions for recovery, cryopreservation and transfer to a breed or strain. In this sense, increasing the number of embryos available using superovulation should improve the cryobank efficiency. However, vagueness of response to conventional protocols to control or increase ovarian response and the quality of oocytes and embryos and their cryotolerance remain a challenge. The aim of our study was to evaluate the effect of corifollitropin alpha (CTP) and a recombinant human FSH (rhFSH), alone or supplemented with rhLH, on embryo cryosurvival by in vitro development and OCT4 and NANOG mRNA abundance at blastocyst stage and offspring rate. In vitro development of vitrified embryos was not significantly affected by superstimulation with or without rhLH supplementation, resulting in similar development rates to those of the control groups (fresh and vitrified embryos from non-superstimulated donor does). Blastocysts developed from vitrified embryos showed higher levels of OCT4 transcript abundance than fresh control, while NANOG transcript abundance was only higher in the blastocysts developed from vitrified embryos after superstimulation treatment in comparison with control groups. The implantation and offspring rates at birth were negatively affected by supplementation with rhLH. Both rhFSH or CTP vitrified embryo groups showed an implantation rate similar to those of the control groups, but an offspring rate lower than control. In conclusion, embryos produced using corifollitropin alpha did not compromise the cryosurvival of vitrified embryos in the rabbit. In addition, this study points out the negative effect of rhLH supplementation in terms of offspring rate on embryo vitrification. PMID- 29625803 TI - Using Patient Portals to Increase Engagement in Patients with Cancer. AB - OBJECTIVES: To review patient portals which serve as a tool for patient engagement by increasing access to electronic health care information and expanding ways to communicate with health care providers. DATA SOURCES: Reviews of the literature and first-hand experience. CONCLUSION: Meaningful Use requirements propelled the design and development of patient portals in recent years. Patient engagement in oncology can improve quality of life and outcomes. IMPLICATIONS FOR NURSING PRACTICE: Oncology nurses facilitate patient adoption of patient portals and support usage. Patient education helps manage communication expectations and understanding of online medical information. PMID- 29625804 TI - [Use of the 2D:4D digit ratio as a biological marker of specific language disorders]. AB - INTRODUCTION: The finding of biological markers of specific language impairment would facilitate their detection and early intervention. In this sense, the 2D:4D finger ratio is considered an indirect indicator of prenatal exposure to testosterone. Previous studies have related it to linguistic competence and aggressive behaviour, and could be a candidate for a biological marker of language impairment. The aim was to compare the value of the 2D:4D ratio in children with Specific Language Impairment (SLI) with those of children with typical language development, as well as to establish to what extent this biological index correlates with the behaviour (linguistic, cognitive, social,...) in both groups. SUBJECTS AND METHODS: 2D:4D ratio, language, cognition and social behaviour were compared in a group of children with SLI (n=15), with a group of children without language difficulties (n=16) of the same age (between 5-8 years), gender (male), and socio-cultural level. RESULTS: Children with SLI showed significantly higher values of 2D:4D ratio of the right hand, and a negative correlation between this ratio and their linguistic competence. Although the children with SLI showed impaired adaptive abilities, but not more aggressive behaviour, these measurements did not correlate with the 2D:4D index. Nevertheless, social behaviour correlated with language and cognition competence. CONCLUSIONS: A higher value of the biological 2D:4D ration (lower intrauterine exposure to testosterone) seems to be associated with language difficulties in boys with SLI, but not with their behavioural difficulties. Their behavioural difficulties seem to be a consequence of their linguistic difficulties and their level of cognition. PMID- 29625805 TI - [Kaposiform haemangioendothelioma with Kasabach-Merritt phenomenon]. PMID- 29625806 TI - [Respiratory co-infections between influenza viruses and respiratory syncytial virus (2014-2017)]. PMID- 29625807 TI - [Meconium periorchitis in the diagnosis of scrotal mass]. PMID- 29625808 TI - High dose rate brachytherapy for prostate cancer: A prospective toxicity evaluation of a one day schedule including two 13.5 Gy fractions. AB - BACKGROUND AND PURPOSE: High dose-rate (HDR) brachytherapy (BT) provides a highly conformal method of dose delivery to the prostate. The purpose of this study is to prospectively determine the toxicity of the treatment protocol of 13.5 Gy * 2 fractions. MATERIALS AND METHODS: From 2010 through 2017, 119 patients with low (71%) or intermediate-risk prostate cancer were prospectively treated in a single institute with HDR-BT at 13.5 Gy * 2 fractions within one day. Median follow-up time was 4.4 years. RESULTS: Actuarial rates of no biochemical evidence of disease, overall survival and metastasis-free survival for all patients were 96%,98% and 98%, respectively. The cumulative incidence of acute grade 2 and 3 genitourinary (GU) toxicity was 9% and 2%, respectively. The corresponding incidences of late GU toxicity were 18% and 1%. No grade >=4 of either type of toxicity was detected. Multivariate analysis showed that having higher international prostate symptom score (IPSS; P = 0.041) or higher V200 (P = 0.013) was associated with a higher risk of experiencing any grade of acute GU toxicity. In addition, patients having a higher IPSS (P = 0.019) or a higher V150 (P = 0.033) were associated with a higher grade >1 acute GU toxicity. CONCLUSIONS: The findings of this study show that HDR-BT 13.5 Gy * 2 as monotherapy was safe and effective for prostate cancer patients with low-intermediate risk. PMID- 29625809 TI - PROGRAD - An observational study of the prognosis of inpatients evaluated for palliative radiotherapy. AB - BACKGROUND AND PURPOSE: Low-and-middle-income countries have resource constraints and waiting lists for radiotherapy (RT). In this context, we sought to determine the survival of inpatients evaluated for palliative RT in a large referral cancer center in Brazil. MATERIAL AND METHODS: From November 2014 through December 2015, we enrolled 333 inpatients with palliative RT evaluation requests in this prospective observational study. We applied Palliative Prognostic Index (PPI) and Survival Prediction Score using Number of Risk Factors (NRF). Primary endpoint was overall survival. Secondary endpoints were survival by PPI and NRF. (ClinicalTrials.gov number, NCT02312791). RESULTS: Median survival (MS) for the entire cohort was 73 days. PPI <=2 had MS of 120 days; PPI 2.5-4 had MS of 55 days (HR 1.84; 95% CI, 1.07-3.16); PPI >4 had MS of 39 days (HR 3.45; 95% CI, 2.07-5.74) (p < .0001). NRF 0-1 had MS of 129 days; NRF 2 had MS of 73 days (HR 1.74; 95% CI 0.89-3.38); NRF 3 had MS of 40 days (HR 2.95; 95% CI, 1.50-5.78) (p < .0001). CONCLUSION: Inpatients with palliative RT requests seem to have an overall poor survival. PPI and NRF can define subgroups with different prognosis. This could help hospitals and healthcare systems to standardize criteria for prioritization and contribute for fairness. PMID- 29625810 TI - ENLIGHT: European network for Light ion hadron therapy. AB - The European Network for Light Ion Hadron Therapy (ENLIGHT) was established in 2002 following various European particle therapy network initiatives during the 1980s and 1990s (e.g. EORTC task group, EULIMA/PIMMS accelerator design). ENLIGHT started its work on major topics related to hadron therapy (HT), such as patient selection, clinical trials, technology, radiobiology, imaging and health economics. It was initiated through CERN and ESTRO and dealt with various disciplines such as (medical) physics and engineering, radiation biology and radiation oncology. ENLIGHT was funded until 2005 through the EC FP5 programme. A regular annual meeting structure was started in 2002 and continues until today bringing together the various disciplines and projects and institutions in the field of HT at different European places for regular exchange of information on best practices and research and development. Starting in 2006 ENLIGHT coordination was continued through CERN in collaboration with ESTRO and other partners involved in HT. Major projects within the EC FP7 programme (2008-2014) were launched for R&D and transnational access (ULICE, ENVISION) and education and training networks (Marie Curie ITNs: PARTNER, ENTERVISION). These projects were instrumental for the strengthening of the field of hadron therapy. With the start of 4 European carbon ion and proton centres and the upcoming numerous European proton therapy centres, the future scope of ENLIGHT will focus on strengthening current and developing European particle therapy research, multidisciplinary education and training and general R&D in technology and biology with annual meetings and a continuously strong CERN support. Collaboration with the European Particle Therapy Network (EPTN) and other similar networks will be pursued. PMID- 29625811 TI - Further characterization of CAPOS/CAOS syndrome with the Glu818Lys mutation in the ATP1A3 gene: A case report. AB - A 38-year-old female patient experienced recurrent episodes of neurological deterioration during febrile illness at the age of 7 and 8 months, and 2, 4, and 37 years. Acute symptoms comprised unconsciousness, headache, abnormal ocular movements, flaccid paralysis with areflexia, ataxia, dysphagia, and movement disorders. Each episode of neurological deterioration was followed by partial recovery with residual symptoms of progressive disturbance of visual acuity with optic atrophy and hearing loss, moderate intellectual disability, strabismus, ophthalmoplegia, as well as fluctuating degree of gait ataxia, chorea, tremor, and myoclonus. In addition, electrocardiography revealed incomplete right bundle branch block. The genetic testing revealed a de novo heterozygous mutation of c.2452G > A (p.Glu818Lys) in the ATP1A3 gene, which was compatible with the clinical phenotype of CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy, and sensorineural hearing loss)/CAOS syndrome. Here we discuss the significance of clinical features of a patient, overlapping with those of alternating hemiplegia of childhood, along with a literature review. PMID- 29625812 TI - SCN2A mutation in an infant presenting with migrating focal seizures and infantile spasm responsive to a ketogenic diet. AB - SCN2A mutations have been identified in various encephalopathy phenotypes, ranging from benign familial neonatal-infantile seizure (BFNIS) to more severe forms of epileptic encephalopathy such as Ohtahara syndrome or epilepsy of infancy with migrating focal seizure (EIMFS). Thus far, no particularly effective treatment is available for severe epileptic encephalopathy caused by SCN2A mutations in children. We present the case of a boy who developed seizures on the third day of life and received a diagnosis of EIMFS based on his clinical presentations and electroencephalography reports. Antiepileptic drugs, namely oxcarbazepine, phenytoin, valproate, levetiracetam, and clonazepam, as well as adrenocorticotropic hormone therapy failed to reduce the severity of the seizures. Seizure pattern changed to infantile spasm with extensor thrust since 5 months of age. A ketogenic diet consisting of a medium-chain triglyceride recipe was introduced at 8 months of age and the seizures were resolved in the following 10 months. A de novo mutation in SCN2A (c.573G > T; p.W191C) was proven through next-generation sequencing. PMID- 29625813 TI - Sidus Stem-Free Shoulder System for primary osteoarthritis: short-term results of a multicenter study. AB - BACKGROUND: The aim of this prospective multicenter study was to evaluate clinical and radiologic results of a new metaphyseal anchored system. This system features a different anchor geometry that potentially leads to better bony integration and less loosening. METHODS: From November 2012 until December 2015, 148 patients (151 shoulders) were treated with the Sidus Stem-Free Shoulder System at 9 centers in Europe. The main indication was primary osteoarthritis (80.1%). This analysis only includes patients diagnosed with primary osteoarthritis (n = 121). A clinical evaluation was performed using the Constant Murley score, Subjective Shoulder Value, American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form, and range of motion. Radiologic assessment was based on the occurrence of radiolucent lines and signs of implant migration, osteolysis, loosening, and heterotopic ossification. RESULTS: We evaluated 105 patients after a follow-up period of 2 years. There were 53 women and 52 men. The average age was 64 years. Total shoulder arthroplasty was performed in 73 cases and hemiarthroplasty in 32. The Constant-Murley score improved from 26 points preoperatively to 70 points at 2 years' follow-up (P < .001). The Subjective Shoulder Value increased from 34% to 84% (P < .001), and the American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form increased from 34 points to 86 points (P < .001). Radiologically, neither migration nor loosening was found. However, radiolucent lines of 2 mm or greater could be detected around the glenoid in 2 cases, but none of them have had clinical relevance yet. The overall complication rate was 6.7%, and the revision rate was 0%. CONCLUSION: Patients with the Sidus Stem-Free Shoulder System achieve good clinical and radiologic short-term results that are comparable with the results of other stem-free shoulder implants. PMID- 29625814 TI - Firearm mortality in California, 2000-2015: the epidemiologic importance of within-state variation. AB - PURPOSE: Firearm mortality is a significant problem in the United States. Previous studies have largely focused on firearm mortality at the national or state level, leaving open the question of within-state variation. This study examined firearm mortality within California. METHODS: We used Multiple Cause of Death data files to identify all firearm fatalities in California from 2000 to 2015. We described firearm mortality rates and counts over time, by age and county, stratifying by intent, gender, and race/ethnicity. County-level rates were smoothed with empirical Bayes estimates from random-effect Poisson models. RESULTS: From 2000 to 2015, there were 24,922 firearm homicides and 23,682 firearm suicides in California. Rates of firearm homicide decreased 30% and suicide rates increased 1% since the mid-2000s, but these trends varied substantially by county. Due to a decline in firearm homicides in metropolitan areas, there was no significant difference in these rates between urban and rural counties by 2015. Non-Hispanic black men had the highest rate of firearm homicide, but Hispanic men had the greatest number of deaths. CONCLUSIONS: We found considerable intrastate variation in firearm mortality in California. Our results will be of interest to researchers, policymakers, and public health practitioners. Similar epidemiologic profiles of firearm mortality are warranted for other states. PMID- 29625815 TI - Cutaneous lupus erythematosus, morphea profunda and psoriasis: A case report. AB - Psoriasis is a common inflammatory dermatosis that may be associated with a number of diseases. Recent studies provide evidence that there is a greater frequency of autoimmune diseases, but association with autoimmune connective tissue diseases is uncommon. The coexistence of psoriasis and lupus erythematosus is rare. Besides, the occurrence of morphea has rarely been reported in patients with lupus or psoriasis. We report a woman with cutaneous lupus and morphea profunda associated with psoriasis, with an excellent response to methotrexate, and review the literature. PMID- 29625816 TI - IgG4-related orbital pseudotumor. PMID- 29625817 TI - Re: "A Miss Is Still a Miss". PMID- 29625818 TI - Re: "Social Media and the 21st-Century Scholar: How You Can Harness Social Media to Amplify Your Career". PMID- 29625819 TI - A Miss Is Still a Miss. PMID- 29625820 TI - Re: "Social Media and the 21st-Century Scholar: How You Can Harness Social Media to Amplify Your Career". PMID- 29625821 TI - Improving Breast MR Wait Times: A Model for Transitioning Newly Implemented Diagnostic Imaging Procedures into Routine Clinical Operation. AB - PURPOSE: The purpose of this quality improvement (QI) initiative was to increase patient access to breast MR while maintaining diagnostic image quality. METHODS: Institutional review board approval was waived for this HIPAA-compliant QI initiative, which was conducted from December 2014 through March 2016. Breast MR wait times, scheduling grids, and staffing models were reviewed to identify root causes of elevated wait times. Breast MR wait times were tracked on a biweekly basis as root causes were identified and action plans were implemented. Patient recall rates for repeat MR imaging were tracked. A retrospective analysis of image quality was performed in a randomly selected sample (20 per month; total: 320 examinations). Wait time and image quality data were analyzed with statistical process control charts and logistic regression. RESULTS: In all, 798 breast MR examinations were performed during the study period. Monthly volume increased from 23 in December 2014 to 50 in March 2016 (range: 23-64). Wait time for a routine breast MRI fell from 101 days before implementation to 5 days at study completion. The technical recall rate was 0.5% (4 of 798); no recall was performed for a technologist-related error or scan quality concern. The proportion of examinations with minor (31% [99 of 320]) or major (3% [9 of 320]) image quality impairments did not significantly change during the study period (P = .69-.70). CONCLUSION: A specialized MR examination was transitioned into routine clinical operation while maintaining image quality. This model may be useful for transitioning other specialized diagnostic imaging examinations into routine clinical practice. PMID- 29625822 TI - Comparing 36.5 degrees C with 37 degrees C for human embryo culture: a prospective randomized controlled trial. AB - This prospective, double-blind, randomized controlled trial was designed to evaluate the efficacy of a culture temperature of 36.5 degrees C versus 37 degrees C on human embryo development in vitro. A total of 412 women undergoing IVF were randomized to two groups: the oocytes and embryos of the intervention group were cultured at 36.5 degrees C; those of the control group were cultured at 37 degrees C. Although no significant effect of culture temperature was observed on pregnancy or implantation rates, differences were found in embryo development. Embryo culture at 36.5 degrees C was associated with a significantly higher cleavage rate (OR 1.6, 95% CI 1.03 to 2.51), but a lower fertilization rate, fewer high-quality embryos on day 3, a lower blastocyst formation rate on day 5, and fewer high-quality and cryopreserved blastocysts (OR 0.87, 95% CI 0.78 to 0.98), (OR 0.60, 95% CI 0.53 to 0.69), (OR 0.85, 95% CI 0.75 to 0.97), (OR 0.5, 95% CI 0.44 to 0.56) and (OR 0.77, 95% CI 0.68 to 0.88), respectively, compared with 37 degrees C. On the basis of these results, and in the absence of data on the optimal temperature for each stage of embryo development in vitro, we recommend continuation of the use of 37 degrees C for human embryo culture. PMID- 29625823 TI - Secoiridoid analogues from the fruits of Ligustrum lucidum and their inhibitory activities against influenza A virus. AB - A phytochemical study focusing on the secoiridoid components in the fruits of Ligustrum lucidum was carried out, which finally led to the isolation of nine secoiridoid glycosides (1-9) together with two secoiridoids (10, 11). The structures of all compounds were established mainly by NMR and MS experiments as well as the necessary chemical evidence, of which 1, 2, 4 (ligulucisides A-C), 10 and 11 (liguluciridoids A and B) were identified as new secoiridoid analogues. An in vitro antiviral bioassay indicated that 1, 4, 6, and 10 displayed the inhibitory activities against influenza A virus with the IC50 values of 16.5, 12.5, 13.1, and 18.5 MUM, respectively, which were better than the positive control Ribavirin (IC50 22.6 MUM). . PMID- 29625824 TI - The genetic incorporation of p-azidomethyl-l-phenylalanine into proteins in yeast. AB - The noncanonical amino acid p-azidomethyl-l-phenylalanine can be genetically incorporated into proteins in bacteria, and has been used both as a spectroscopic probe and for the selective modification of proteins by alkynes using click chemistry. Here we report identification of Escherichia coli tyrosyl tRNA synthetase mutants that allow incorporation of p-azidomethyl-l-phenylalanine into proteins in yeast. When expressed together with the cognate E. coli tRNACUATyr, the new mutant tyrosyl tRNA synthetases directed robust incorporation of p azidomethyl-l-phenylalanine into a model protein, human superoxide dismutase, in response to the UAG amber nonsense codon. Mass spectrometry analysis of purified superoxide dismutase proteins confirmed the efficient site-specific incorporation of p-azidomethyl-l-phenylalanine. This work provides an additional tool for the selective modification of proteins in eukaryotic cells. PMID- 29625825 TI - C21 steroidal glycosides with cytotoxic activities from Cynanchum otophyllum. AB - Eight new C21 steroidal glycosides, namely cynanotins A-H (1-8), together with fifteen known analogues, were isolated from the roots of Cynanchum otophyllum. Their structures were elucidated by spectroscopic analysis and chemical methods. In this study, all of isolates were tested for their vitro inhibitory activities against five human tumor cell lines (HL-60, SMMC-7721, A-549, MCF-7 and SW480). Compounds 3-15 showed moderate cytotoxic activities against HL-60 cell lines with IC50 values ranging from 11.4 to 37.9 uM. Compounds 5, 9, and 10 showed marked or moderate cytotoxic activities against five human tumor cell lines with IC50 values ranging from 11.4 to 36.7 uM. Compound 11 displayed moderate cytotoxic activities against HL-60, SMMC-7721, MCF-7 and SW480 cell lines with IC50 values of 12.2-30.8 uM. Compared to the positive control (IC50: 35.0 uM), compounds 5, 9 11 exhibited more potential inhibitory activity against MCF-7 cells (IC50: 16.1 25.6 uM). PMID- 29625826 TI - Obesity and Inflammation: One Size Never Fits All. PMID- 29625827 TI - A sofosbuvir-based quadruple regimen is highly effective in HCV type 4-infected Egyptian patients with DAA treatment failure. PMID- 29625828 TI - Reply to: "May sarcopenia and/or hepatic encephalopathy improve the predictivity of model for end-stage liver disease?" and "Has the time come for using MELD Sarcopenia score?" PMID- 29625829 TI - Has the time come for using MELD-Sarcopenia score? PMID- 29625830 TI - The important role of the peer reviewer. PMID- 29625831 TI - Insights into cytokine release syndrome and neurotoxicity after CD19-specific CAR T cell therapy. AB - T-cells engineered to express CD19-specific chimeric antigen receptors (CD19 CAR T cells) can achieve high response rates in patients with refractory/relapsed (R/R) CD19+ hematologic malignancies. Nonetheless, the efficacy of CD19-specific CAR-T cell therapy can be offset by significant toxicities, such as cytokine release syndrome (CRS) and neurotoxicity. In this report of our presentation at the 2018 Second French International Symposium on CAR-T cells (CAR-T day), we describe the clinical presentations of CRS and neurotoxicity in a cohort of 133 adults treated with CD19 CAR-T cells at the Fred Hutchinson Cancer Research Center, and provide insights into the mechanisms contributing to these toxicities. PMID- 29625832 TI - Considerations pertaining to cell collection and administration of industry manufactured autologous CAR-T cells, in relation to French healthcare organization and regulations. AB - Access to treatment with CAR-T Cells at European hospitals in general and at French hospitals in particular remains limited, when compared with the situation that prevails in the USA or in certain Asian countries. Multiple reasons explain why European investigators lag behind their US or Chinese colleagues in this clinical research area. Some of these reasons are related to the European and French regulatory landscapes that hamper the design and rapid implementation of organizational solutions needed for safe and efficient administration of CAR-T Cells. We here identify some of these pressing issues and propose some possible paths to move forward. PMID- 29625833 TI - Celyad's novel CAR T-cell therapy for solid malignancies. AB - Celyad recently initiated several clinical trials with the CYAD-01 product, a natural killer group 2D (NKG2D)-based chimeric antigen receptor (CAR), in both solid and hematologic tumor types. This review discusses the unique properties of CYAD-01, expecting to provide a new paradigm to fight against solid tumors. PMID- 29625834 TI - Internet-based treatment for panic disorder: A three-arm randomized controlled trial comparing guided (via real-time video sessions) with unguided self-help treatment and a waitlist control. PAXPD study results. AB - A growing body of evidence suggests that Internet-based cognitive behavioral treatments (ICBT) are effective to treat anxiety disorders. However, the effect of therapist guidance in ICBT is still under debate and guided ICBT offered in a real-time audio-video communication format has not yet been systematically investigated. This three-arm RCT compared the efficacy of guided with unguided ICBT (12 weeks intervention) and a waitlist (WL). A total of 111 individuals meeting the diagnostic criteria for panic disorder (PD) were randomly assigned to one of three conditions. Primary outcomes were the severity of self-report panic symptoms and diagnostic status. Secondary outcomes were symptoms of depression, functional impairment, catastrophic cognitions, fear of sensations and body vigilance. At post-treatment, both active conditions showed superior outcomes regarding PD and associated symptoms (guided ICBT vs. WL: d = 1.04-1.36; unguided ICBT vs. WL: d = 0.70-1.06). At post-treatment, the two active conditions did not differ significantly in self-reported symptom reduction (d = 0.21-0.54, all ps > 0.05), but the guided treatment was superior to the unguided treatment in terms of diagnostic status (chi2 (1) = 13.15, p < 0.01). Treatment gains were maintained at successive follow-ups and the guided treatment became superior to the unguided treatment at 6 months follow-up (d = 0.72-1.05, all ps < 0.05). PMID- 29625835 TI - A MYH3 mutation identified for the first time in a Chinese family with Sheldon Hall syndrome (DA2B). AB - Sheldon-Hall syndrome is the most common type of distal arthrogryposis syndromes, also known as distal arthrogryposis 2B (DA2B). Sheldon-Hall syndrome is caused by mutations in the TPM2, TNNI2, TNNT3 or MYH3 gene and characterized by ulnar deviation, camptodactyly, overlapping fingers and scoliosis from birth. We investigated a Chinese family with multiple members who clinically presented with distal arthrogryposis of the hands. In total, 261 subjects including one proband and ten family members from the non-consanguineous Chinese family and 250 healthy volunteers were included and had their genomic DNA extracted. A novel missense mutation in exon 13 of the MYH3 gene, c.1160A > G (p.Tyr387Cys), was identified in the proband and his father through whole-exome sequencing. The proband and six affected family members were confirmed to carry this mutation by Sanger sequencing, although the mutation was not detected in the four unaffected individuals or 250 volunteers. This is the first report of a novel MYH3 mutation being identified as the cause of DA2B in a Chinese family. Our findings confirm that MYH3 gene mutations can be a pathogenic cause of DA2B in Asian patients. This study increases the mutational spectrum in MYH3 and aids genetic counseling and prenatal diagnosis. PMID- 29625836 TI - Restoration of common bile duct diameter within 2 weeks after endoscopic stone retraction is a preventive factor for stone recurrence. AB - BACKGROUND: Little information is available about the relationship between restoration of common bile duct (CBD) diameter after endoscopic stone retraction and recurrence of CBD stones in elderly patients. The present study was to determine whether restoration of CBD diameter is a preventive factor for CBD stone recurrence in elderly patients who underwent endoscopic retrograde cholangiopancreatography (ERCP). METHODS: From January 2006 to December 2010, 238 patients underwent the first and the second session of ERCP for the removal of CBD stones. Among them, 173 were over 65 years old. These patients were divided into recurrent group and non-recurrent group. Restoration of CBD diameter and patients' characteristics were compared. RESULTS: There was no statistical difference in patients' characteristics, associated diseases, or ERCP-related complications between the two groups. Reduction of CBD diameter was significantly larger in the non-recurrent group (2.7 +/- 1.7 mm) compared to that in the recurrent group (1.4 +/- 2.3 mm, P = 0.002). The proportion of patients with restoration of CBD diameter were significantly lower in the recurrent group (6/42, 14.3%) compared with that in the non-recurrent group (67/131, 51.1%) (P < 0.01). CONCLUSIONS: There is an inverse relationship between restoration of CBD diameter and CBD stone recurrence. Therefore, patients without restoration of CBD diameter within 2 weeks after endoscopic stone removal should be monitored more frequently. PMID- 29625837 TI - HBsAg stimulates NKG2D receptor expression on natural killer cells and inhibits hepatitis C virus replication. AB - BACKGROUND: Higher hepatitis B surface antigen (HBsAg) facilitates hepatitis C virus (HCV) clearance in patients with hepatitis B virus (HBV)/HCV co-infection. We investigated the effect of exogenous HBsAg on the inhibition of HCV replication mediated by natural killer (NK) cells. METHODS: After isolated from peripheral blood of 42 chronic hepatitis B (CHB) patients and 16 healthy individuals, NK cells were co-cultured with HCV-infected Huh7 cells, respectively, with or without HBsAg. Three days later, the co-cultured supernatants were collected and HCV RNA levels were measured by real-time quantitative PCR. NKG2D, NKp46 and NKG2A expression levels were measured by flow cytometry. NKG2D on NK cells from CHB responsive subgroup was blocked and HCV RNA levels were examined again. RESULTS: HCV RNA levels in the co-cultured system were significantly reduced by NK cells isolated from healthy donors (P < 0.01) but not from CHB patients. However, HCV RNA levels in CHB cultures were significantly decreased following HBsAg addition (P < 0.05), whereas no such effect was seen in control cultures. No significant difference was observed in basic NKG2D expression between the CHB patients and healthy donors. On NK cells from CHB patients, the expression of NKG2D was increased significantly by HBsAg stimulation (P < 0.01), and higher than that from healthy controls (P < 0.05). HCV RNA levels were increased significantly after the blockage of NKG2D on NK cells from responsive CHB patients in the co-cultured system (P < 0.05). CONCLUSION: Exogenous HBsAg stimulated NKG2D expression on NK cells from CHB patients which inhibit HCV replication, suggesting that HBsAg may facilitate the clearance of HCV in patients with HBV/HCV co-infection. PMID- 29625838 TI - Suppression of Melatonin Secretion in Totally Visually Blind People by Ocular Exposure to White Light: Clinical Characteristics. AB - PURPOSE: Although most totally visually blind individuals exhibit nonentrained circadian rhythms due to an inability of light to entrain the circadian pacemaker, a small proportion retain photic circadian entrainment, melatonin suppression, and other nonimage-forming responses to light. It is thought that these responses to light persist because of the survival of melanospin-containing intrinsically photosensitive retinal ganglion cells (ipRGCs), which project primarily to the circadian pacemaker and are functionally distinct from the rod and cone photoreceptors that mediate vision. We aimed to assess the integrity of nonimage-forming photoreception in totally visually blind patients with a range of ocular disorders. DESIGN: Within-subject, dark-controlled design. PARTICIPANTS: A total of 18 totally visually blind individuals (7 females; mean age +/- standard deviation = 49.8+/-11.0 years) with various causes of blindness, including 3 bilaterally enucleated controls. METHODS: Melatonin concentrations were compared during exposure to a 6.5-hour bright white light (~7000 lux) with melatonin concentrations measured 24 hours earlier at the corresponding clock times under dim-light (4 lux) conditions. MAIN OUTCOME MEASURES: Area under the curve (AUC) for melatonin concentration. RESULTS: Melatonin concentrations were significantly suppressed (defined as >=33% suppression) during the bright-light condition compared with the dim-light condition in 5 of 15 participants with eyes (retinitis pigmentosa, n = 2; retinopathy of prematurity [ROP], n = 2; bilateral retinal detachments, n = 1). Melatonin concentrations remained unchanged in response to light in the remaining 10 participants with eyes (ROP, n = 3; optic neuritis/neuropathy, n = 2; retinopathy unknown, n = 2; congenital glaucoma, n = 1; congenital rubella syndrome, n = 1; measles retinopathy, n = 1) and in all 3 bilaterally enucleated participants. CONCLUSIONS: These data confirm that light induced suppression of melatonin remains functionally intact in a minority of totally visually blind individuals with eyes. None of the bilaterally enucleated individuals or those with phthisis bulbi was responsive to light; of the remainder, half were responsive to light. Although inner retinal damage is associated with a high likelihood that nonimage-forming photoreception is absent, the impact of outer retinal damage is more ambiguous, and therefore the assessment of the presence, attenuation, or absence of nonimage-forming light responses in totally blind patients requires careful individual confirmation and cannot simply be assumed from the type of blindness. PMID- 29625839 TI - Choroidal and Sub-Retinal Pigment Epithelium Caverns: Multimodal Imaging and Correspondence with Friedman Lipid Globules. AB - PURPOSE: To survey Friedman lipid globules by high-resolution histologic examination and to compare with multimodal imaging of hyporeflective caverns in eyes with geographic atrophy (GA) secondary to age-related macular (AMD) and other retinal diseases. DESIGN: Histologic survey of donor eyes with and without AMD. Clinical case series with multimodal imaging analysis. PARTICIPANTS: Donor eyes (n = 139; 26 with early AMD, 13 with GA, 40 with nAMD, 52 with a healthy macula, and 8 with other or unknown characteristics) and 41 eyes of 28 participants with GA (n = 16), nAMD (n = 8), Stargardt disease (n = 4), cone dystrophy (n = 2), pachychoroid spectrum (n = 6), choroidal hemangioma (n = 1), and healthy eyes (n = 4). METHODS: Donor eyes were prepared for macula-wide epoxy resin sections through the foveal and perifoveal area. In patients, caverns were identified as nonreflective spaces on OCT images. Multimodal imaging included color and red-free fundus photography; fundus autofluorescence; fluorescein and, indocyanine green angiography; OCT angiography; near-infrared reflectance; and confocal multispectral (MultiColor [Spectralis, Heidelberg Engineering, Germany]) imaging. MAIN OUTCOME MEASURES: Presence and morphologic features of globules, and presence and appearance of caverns on multimodal imaging. RESULTS: Globules were found primarily in the inner choroidal stroma (91.0%), but also localized to the sclera (4.9%) and neovascular membranes (2.1%). Mean diameters of solitary and multilobular globules were 58.9+/-37.8 MUm and 65.4+/-27.9 MUm, respectively. Globules showed morphologic signs of dynamism including pitting, dispersion, disintegration, and crystal formation. Evidence for inflammation in the surrounding tissue was absent. En face OCT rendered sharply delimited hyporeflective areas as large as choroidal vessels, frequently grouped around choroid vessels or in the neovascular tissue. Cross-sectional OCT revealed a characteristic posterior hypertransmission. OCT angiography showed absence of flow signal within caverns. CONCLUSIONS: Based on prior literature documenting OCT signatures of tissue lipid in atheroma and nAMD, we speculate that caverns are lipid rich. Globules, with similar sizes and tissue locations in AMD and healthy persons, are candidates for histologic correlates of caverns. The role of globules in chorioretinal physiologic features, perhaps as a lipid depot for photoreceptor metabolism, is approachable through clinical imaging. PMID- 29625840 TI - Measuring Patient Loyalty in Ophthalmology: A Nationally Representative Study. PMID- 29625842 TI - Shifting the treatment model for resectable pancreatic cancer. PMID- 29625841 TI - Safety and efficacy of preoperative or postoperative chemotherapy for resectable pancreatic adenocarcinoma (PACT-15): a randomised, open-label, phase 2-3 trial. AB - BACKGROUND: Pancreatic ductal adenocarcinoma are known to metastasise early and a rationale exists for the investigation of preoperative chemotherapy in patients with resectable disease. We aimed to assess the role of combination chemotherapy in this setting in the PACT-15 trial. METHODS: We did this randomised, open label, phase 2-3 trial in ten hospitals in Italy. We report the phase 2 part here. Patients aged 18-75 years who were previously untreated for pancreatic ductal adenocarcinoma, with Karnofsky performance status of more than 60, and pathologically confirmed stage I-II resectable disease were enrolled. Patients were randomly assigned (1:1:1), with a minimisation algorithm that stratified treatment allocation by centre and concentrations of carbohydrate antigen 19-9 (CA19-9 <=5 * upper limit of normal [ULN] vs >5 * ULN), to receive surgery followed by adjuvant gemcitabine 1000 mg/m2 on days 1, 8, 15 every 4 weeks for six cycles (arm A), surgery followed by six cycles of adjuvant PEXG (cisplatin 30 mg/m2, epirubicin 30 mg/m2, and gemcitabine 800 mg/m2 on days 1 and 15 every 4 weeks and capecitabine 1250 mg/m2 on days 1-28; arm B), or three cycles of PEXG before and three cycles after surgery (arm C). Patients and investigators who gave treatments or assessed outcomes were not masked to treatment allocation. The primary endpoint was the proportion of patients who were event-free at 1 year. The primary endpoint was analysed in the per-protocol population. Safety analysis was done for all patients receiving at least one dose of study treatment. The trial is registered with ClinicalTrials.gov, number NCT01150630. FINDINGS: Between Oct 5, 2010, and May 30, 2015, 93 patients were randomly allocated to treatment. One centre was found to be non-compliant with the protocol, and all five patients at this centre were excluded from the study. Thus, 88 patients were included in the final study population: 26 in group A, 30 in group B, and 32 in group C. In the per-protocol population, six (23%, 95% CI 7-39) of 30 patients in group A were event-free at 1 year, as were 15 (50%, 32-68) of 30 in group B and 19 (66%, 49-83) of 29 in group C. The main grade 3 toxicities were neutropenia (five [28%] of 18 in group A, eight [38%] of 21 in group B, eight [28%] of 29 in group C before surgery, and ten [48%] of 21 in group C after surgery), anaemia (one [6%] in group A, four [19%] in group B, eight [28%] in group C before surgery, and five [24%] in group C after surgery), and fatigue (one [6%] in group A, three [14%] in group B, two [7%] in group C before surgery, and one [5%] in group C after surgery). The main grade 4 toxicity reported was neutropenia (two [11%] in group A, four [19%] in group B, none in group C). Febrile neutropenia was observed in one patient (3%) before surgery in group C. No treatment-related deaths were observed. INTERPRETATION: Our results provide evidence of the efficacy of neoadjuvant chemotherapy in resectable pancreatic ductal adenocarcinoma. Since the trial began, the standard of care for adjuvant therapy has altered, and other chemotherapy regimens developed. Thus, we decided to not continue with the phase 3 part of the PACT-15. We are planning a phase 3 trial of this approach with different chemotherapy regimens. FUNDING: PERLAVITA ONLUS and MyEverest ONLUS. PMID- 29625843 TI - Role of genetic variations on MHC class I antigen-processing genes in human cancer and viral-mediated diseases. AB - Cytotoxic T lymphocytes constantly monitor peptide-MHC class I complexes on the cell surface to eliminate transformed and virally infected cells expressing peptides derived from abnormal proteins. The generation of antigenic peptides and their loading on MHC class I molecules is a multistep process involving different molecules that constitute the so-called antigen processing and presentation machinery (APM). To avoid immune-mediated elimination, human tumors and pathogens have adopted different strategies including loss of MHC class I expression and dysregulation of APM genes and proteins. Here, we summarize recent knowledge on genetic variations in APM genes and their association with cancer development and viral-mediated diseases. PMID- 29625845 TI - Current status and outlook on the development of traditional Chinese medicine in Taiwan. PMID- 29625846 TI - Maturational Changes of Gamma-Aminobutyric Acid A Receptors Measured With Benzodiazepine Binding of Iodine 123 Iomazenil Single-Photon Emission Computed Tomography. AB - BACKGROUND: Iodine 123 (I-123) iomazenil is a specific ligand of the central benzodiazepine receptor, which is a part of the postsynaptic gamma-aminobutyric acid A receptor complex. We performed statistical image processing of I-123 iomazenil single-photon emission computed tomography to elucidate maturational changes in the GABAergic system. METHODS: Thirty patients (18 boys and 12 girls, aged 17 days to 14 years) with cryptogenic focal epilepsy were enrolled and underwent I-123 iomazenil single-photon emission computed tomography. We used a semiquantitative analytical method consisting of brain surface extraction, anatomic normalization, and a three-parameter exponential model. We then assessed developmental changes in benzodiazepine receptor binding activity in 18 regions of interest in both hemispheres. RESULTS: The highest benzodiazepine receptor binding activity was observed during early infancy in all regions of interest. Benzodiazepine receptor binding activity then decreased exponentially across development. Benzodiazepine receptor binding in the primary sensorimotor cortex, primary visual cortex, cerebellar vermis, and striatum declined more rapidly than that in the cerebellar hemispheres and the frontal cortex. The pons and the thalamus had the lowest benzodiazepine receptor binding activities during the neonatal period, and benzodiazepine receptor binding in these areas declined gradually after infancy toward adolescence. There were no differences in adjusted benzodiazepine receptor binding activity according to laterality or sex. CONCLUSIONS: Benzodiazepine receptor binding activity decreased exponentially during infancy in all regions of interest. Binding activity in the primary somatosensory and motor cortices (M1 and S1), the primary and association visual areas, the cerebellar vermis, and the striatum (caudate nucleus and putamen) tended to decline more rapidly than that in the cerebellar hemisphere and the frontal association cortex. PMID- 29625844 TI - WHO/IUIS Allergen Nomenclature: Providing a common language. AB - A systematic nomenclature for allergens originated in the early 1980s, when few protein allergens had been described. A group of scientists led by Dr. David G. Marsh developed a nomenclature based on the Linnaean taxonomy, and further established the World Health Organization/International Union of Immunological Societies (WHO/IUIS) Allergen Nomenclature Sub-Committee in 1986. Its stated aim was to standardize the names given to the antigens (allergens) that caused IgE mediated allergies in humans. The Sub-Committee first published a revised list of allergen names in 1986, which continued to grow with rare publications until 1994. Between 1994 and 2007 the database was a text table online, then converted to a more readily updated website. The allergen list became the Allergen Nomenclature database (www.allergen.org), which currently includes approximately 880 proteins from a wide variety of sources. The Sub-Committee includes experts on clinical and molecular allergology. They review submissions of allergen candidates, using evidence-based criteria developed by the Sub-Committee. The review process assesses the biochemical analysis and the proof of allergenicity submitted, and aims to assign allergen names prior to publication. The Sub Committee maintains and revises the database, and addresses continuous challenges as new "omics" technologies provide increasing data about potential new allergens. Most journals publishing information on new allergens require an official allergen name, which involves submission of confidential data to the WHO/IUIS Allergen Nomenclature Sub-Committee, sufficient to demonstrate binding of IgE from allergic subjects to the purified protein. PMID- 29625847 TI - A Rare Syndrome With Eye, Skin, and Brain Abnormalities. PMID- 29625848 TI - Seizure Severity Is Correlated With Severity of Hypoxic-Ischemic Injury in Abusive Head Trauma. AB - BACKGROUND: The objective of this study was to characterize hypoxic-ischemic injury and seizures in abusive head trauma. METHODS: We studied 58 children with moderate or severe traumatic brain injury due to abusive head trauma. Continuous electroencephalograms and magnetic resonance images were scored. RESULTS: Electrographic seizures (51.2%) and hypoxic-ischemic injury (77.4%) were common in our cohort. Younger age was associated with electrographic seizures (no seizures: median age 13.5 months, interquartile range five to 25 months, versus seizures: 4.5 months, interquartile range 3 to 9.5 months; P = 0.001). Severity of hypoxic-ischemic injury was also associated with seizures (no seizures: median injury score 1.0, interquartile range 0 to 3, versus seizures: 4.5, interquartile range 3 to 8; P = 0.01), but traumatic injury severity was not associated with seizures (no seizures: mean injury score 3.78 +/- 1.68 versus seizures: mean injury score 3.83 +/- 0.95, P = 0.89). There was a correlation between hypoxic ischemic injury severity and seizure burden when controlling for patient age (rs=0.61, P < 0.001). The ratio of restricted diffusion volume to total brain volume (restricted diffusion ratio) was smaller on magnetic resonance imaging done early (median restricted diffusion ratio 0.03, interquartile range 0 to 0.23 on magnetic resonance imaging done within two days versus median restricted diffusion ratio 0.13, interquartile range 0.01 to 0.43 on magnetic resonance imaging done after two days, P = 0.03). CONCLUSIONS: Electrographic seizures are common in children with moderate to severe traumatic brain injury from abusive head trauma, and therefore children with suspected abusive head trauma should be monitored with continuous electroencephalogram. Severity of hypoxic-ischemic brain injury is correlated with severity of seizures, and evidence of hypoxic ischemic injury on magnetic resonance imaging may evolve over time. Therefore children with a high seizure burden should be reimaged to evaluate for evolving hypoxic-ischemic injury. PMID- 29625849 TI - AbobotulinumtoxinA Efficacy and Safety in Children With Equinus Foot Previously Treated With Botulinum Toxin. AB - BACKGROUND: The effects of botulinum toxin are transient, and repeat injections are required in children with lower-limb spasticity. However, the efficacy of botulinum toxin in patients who have received previous injections has remained largely unexplored. METHODS: We present subgroup analyses of a phase III study conducted in ambulatory children (aged two to 17) with spastic equinus foot. Patients were randomized to single doses of abobotulinumtoxinA 10 U/kg/leg, 15 U/kg/leg, or placebo injected into the gastrocnemius-soleus complex (one or both legs). The first analysis was prespecified to review the effect of abobotulinumtoxinA in children previously treated with botulinum toxin versus those children new to the treatment; a second post hoc analysis evaluated the effect of abobotulinumtoxinA in children who changed botulinum toxin formulation. RESULTS: Of the 241 randomized patients, 113 had previously received botulinum toxin, including 86 who had been treated with another formulation. In both analyses, muscle tone (Modified Ashworth Scale) and the Physicians Global Assessment, at week 4, improved with abobotulinumtoxinA treatment versus placebo, regardless of baseline botulinum toxin status. Placebo responses in patients new to treatment were consistently higher than in the previously treated group. CONCLUSIONS: These results demonstrate similar abobotulinumtoxinA efficacy and safety profiles in children with spasticity who are new to botulinum toxin treatment and those children who were previously treated. The efficacy and safety of abobotulinumtoxinA treatment in these previously treated patients were comparable with the overall trial population, indicating that doses of 10 and 15 U/kg/leg are suitable starting doses for children with spasticity regardless of the previous botulinum toxin preparation used. PMID- 29625850 TI - The Neural Representations Underlying Human Episodic Memory. AB - A fundamental question of human episodic memory concerns the cognitive and neural representations and processes that give rise to the neural signals of memory. By integrating behavioral tests, formal computational models, and neural measures of brain activity patterns, recent studies suggest that memory signals not only depend on the neural processes and representations during encoding and retrieval, but also on the interaction between encoding and retrieval (e.g., transfer appropriate processing), as well as on the interaction between the tested events and all other events in the episodic memory space (e.g., global matching). In addition, memory signals are also influenced by the compatibility of the event with the existing long-term knowledge (e.g., schema matching). These studies highlight the interactive nature of human episodic memory. PMID- 29625851 TI - Photosynthetic Energy Transfer at the Quantum/Classical Border. AB - Quantum mechanics diverges from the classical description of our world when very small scales or very fast processes are involved. Unlike classical mechanics, quantum effects cannot be easily related to our everyday experience and are often counterintuitive to us. Nevertheless, the dimensions and time scales of the photosynthetic energy transfer processes puts them close to the quantum/classical border, bringing them into the range of measurable quantum effects. Here we review recent advances in the field and suggest that photosynthetic processes can take advantage of the sensitivity of quantum effects to the environmental 'noise' as means of tuning exciton energy transfer efficiency. If true, this design principle could be a base for 'nontrivial' coherent wave property nano-devices. PMID- 29625852 TI - Double-blind evaluation of homeopathy on cocaine craving: a randomized controlled pilot study. AB - BACKGROUND: Brazil is among the nations with the greatest rates of annual cocaine usage. Pharmacological treatment of cocaine addiction is still limited, opening space for nonconventional interventions. Homeopathic Q-potencies of opium and Erythroxylum coca have been tested in the integrative treatment of cocaine craving among homeless addicts, but this setting had not proven feasible, due to insufficient recruitment. OBJECTIVE: This study investigates the effectiveness and tolerability of homeopathic Q-potencies of opium and E. coca in the integrative treatment of cocaine craving in a community-based psychosocial rehabilitation setting. DESIGN, SETTING, PARTICIPANTS, AND INTERVENTIONS: A randomized, double-blind, placebo-controlled, parallel-group, eight-week pilot trial was performed at the Psychosocial Attention Center for Alcohol and Other Drugs (CAPS-AD), Sao Carlos/SP, Brazil. Eligible subjects included CAPS-AD patients between 18 and 65 years of age, with an International Classification of Diseases-10 diagnosis of cocaine dependence (F14.2). The patients were randomly assigned to two treatment groups: psychosocial rehabilitation plus homeopathic Q potencies of opium and E. coca (homeopathy group), and psychosocial rehabilitation plus indistinguishable placebo (placebo group). MAIN OUTCOME MEASURES: The main outcome measure was the percentage of cocaine-using days. Secondary measures were the Minnesota Cocaine Craving Scale and 12-Item Short Form Health Survey scores. Adverse events were reported in both groups. RESULTS: The study population comprised 54 patients who attended at least one post baseline assessment, out of the 104 subjects initially enrolled. The mean percentage of cocaine-using days in the homeopathy group was 18.1% (standard deviation (SD): 22.3%), compared to 29.8% (SD: 30.6%) in the placebo group (P < 0.01). Analysis of the Minnesota Cocaine Craving Scale scores showed no between group differences in the intensity of cravings, but results significantly favored homeopathy over placebo in the proportion of weeks without craving episodes and the patients' appraisal of treatment efficacy for reduction of cravings. Analysis of 12-Item Short-Form Health Survey scores found no significant differences. Few adverse events were reported: 0.57 adverse events/patient in the homeopathy group compared to 0.69 adverse events/patient in the placebo group (P = 0.41). CONCLUSIONS: A psychosocial rehabilitation setting improved recruitment but was not sufficient to decrease dropout frequency among Brazilian cocaine treatment seekers. Psychosocial rehabilitation plus homeopathic Q-potencies of opium and E. coca were more effective than psychosocial rehabilitation alone in reducing cocaine cravings. Due to high dropout rate and risk of bias, further research is required to confirm our findings, with specific focus on strategies to increase patient retention. TRIAL REGISTRATION: RBR-2xzcwz (http://www.ensaiosclinicos.gov.br). PMID- 29625853 TI - Symptomatic delayed coil migration after balloon assisted embolization: An underreported adverse event? AB - Microsurgical clipping is still regarded as the gold-standard treatment for broad neck intracranial aneurysms. New endovascular techniques like balloon or stent assisted coiling are quickly rising to the challenge and showing promising outcomes. As a result, broad-neck aneurysms are increasingly addressed by these techniques despite they have not been tested against clipping in a randomized controlled trial and long-term complications might be unknown yet. Intraprocedural coil migration has been well documented in the literature, but the same complication in a delayed fashion is scarcely reported. We present a case of delayed coil migration occurring after a balloon-assisted embolization of a wide-necked intracranial aneurysm and we perform a literature review for similar cases. We discuss how, despite seeming an extremely rare complication, with new endovascular techniques increasingly perceived as the safer option in any aneurysm, potential adverse events may become more frequent. Strategies proposed to address this developing scenario are also reviewed. PMID- 29625854 TI - Relevance of insulin immunoassay characteristics in factitious hypoglycemia. PMID- 29625855 TI - Fentanyl-associated illness among substance users - Fulton County, Georgia, 2015. PMID- 29625856 TI - Characteristics and outcomes of reversed patients admitted to an emergency department for VKA-related intramuscular hematoma. AB - BACKGROUND: According to the International Society on Thrombosis and Haemostasis (ISTH), intramuscular hematoma without other severity criteria is not considered a major bleeding. OBJECTIVES: In a large cohort of reversed vitamin K antagonist (VKA) patients admitted to the emergency unit for muscular hematoma, we assess frequency, severity, and anticoagulation management based on whether ISTH criteria were met or not. MATERIALS AND METHODS: We performed a retrospective single-center study involving patients admitted to an emergency unit for VKA induced intramuscular hematoma whose bleeding was reversed with prothrombin complex concentrates. RESULTS: During the study period, 631 VKA-induced bleeding events occurred in our emergency unit, of which 73 (11.6%) were intramuscular hematomas and half met ISTH criteria. The mean age was 75.5years (95% CI=72.6 78.3). Admission blood tests showed that patients with ISTH criteria had higher international normalized ratio (7.0+/-4.6 vs. 4.1+/-3.0, p=0.002) and lower hemoglobin (8.1+/-1.8 vs. 11.9+/-2.2, p<0.001) than those without. Patients with ISTH criteria were more likely to have intramuscular hematoma in the iliopsoas, gluteal, and pectoral muscles than those without. Interestingly, two-thirds of rectus sheath hematomas involved patients without ISTH criteria. However, patients with or without ISTH criteria exhibited a similar hospitalization duration and rate of re-bleeding. CONCLUSION: We showed that half of the patients admitted with intramuscular hematoma could not be qualified as having ISTH criteria major bleeding. Interestingly, these patients displayed a similar hospitalization duration and rate of re-bleeding to those with ISTH-criteria major bleeding. PMID- 29625857 TI - Decrease of premature mothers' stress levels in the intensive care unit. AB - OBJECTIVE: To determine the effectiveness of the 'Creating Opportunities for Parent Empowerment' (COPE) programme in reducing stress levels in mothers of preterm infants in the neonatal intensive care unit (NICU). METHODS: Clinical trial performed in Colombia, including mothers of infants younger than 34 weeks of gestation, hospitalized, without a history of premature delivery. The mothers with psychiatric illnesses, language disorders, history of use of psychoactive substances and whose newborns had a congenital malformation were excluded. A group intervened with the COPE programme and a control group with the usual institutional management were formed. Block randomization and masking was used for mothers and evaluators. The Parental Stress Scale was applied: NICU; Shapiro Wilk normality test, Wilcoxon test and covariance analysis (ANCOVA) with a significance level of p<.05, 95% CI. RESULTS: 66 mothers were enrolled. The two groups were similar in their demographic characteristics and in the initial stress level score. The control group increased the final stress score in two categories and the intervention group decreased final values in all categories. The initial and final scores of the overall general stress level showed a significant decrease (p<.01), but when comparing with the ANCOVA analysis there was no significant difference (p=.4). CONCLUSIONS: The COPE programme reduces the level of maternal stress, strengthening aspects during hospitalization, such as: emotional support, strengthening their role as caregivers and interaction with their babies and the development of a friendly environment in the NICU. PMID- 29625858 TI - M2 polarization of macrophages by Oncostatin M in hypoxic tumor microenvironment is mediated by mTORC2 and promotes tumor growth and metastasis. AB - Oncostatin M (OSM), an inflammatory cytokine belonging to the interleukin-6 (IL 6) superfamily, plays a vital role in multitude of physiological and pathological processes. Its role in breast tumor progression and metastasis to distant organs is well documented. Recent reports implicate OSM in macrophage M2 polarization, a key pro-tumoral phenomenon. M2 polarization of macrophages is believed to promote tumor progression by potentiating metastasis and angiogenesis. In the current study, we delineated the mechanism underlying OSM induced macrophage M2 polarization. The findings revealed that OSM skews macrophages towards an M2 polarized phenotype via mTOR signaling complex 2 (mTORC2). mTORC2 relays signals through two effector kinases i.e. PKC-alpha and Akt. Our results indicated that mTORC2 mediated M2 polarization of macrophages is not dependent on PKC-alpha and is primarily affected via Akt, particularly Akt1. In vivo studies conducted on 4T1/BALB/c mouse orthotropic model of breast cancer further corroborated these observations wherein i.v. reintroduction of mTORC2 abrogated monocytes into orthotropic mouse model resulted in diminished acquisition of M2 specific attributes by tumor associated macrophages. Metastasis to distant organs like lung, liver and bone was reduced as evident by decrease in formation of focal metastatic lesions in mTORC2 abrogated monocytes mice. Our study pinpoints key role of mTORC2-Akt1 axis in OSM induced macrophage polarization and suggests for possible usage of Oncostatin-M blockade and/or selective mTORC2 inhibition as a potential anti-cancer strategy particularly with reference to metastasis of breast cancer to distant organs such as lung, liver and bone. PMID- 29625859 TI - Unconscious retinotopic motion processing affects non-retinotopic motion perception. AB - Unconscious visual stimuli can affect conscious perception: For example, an invisible prime can affect responses to a subsequent target. The invisible interpretation of an ambiguous figure can have similar effects. Invisibility in these situations is typically explained by stimulus-suppression in early, retinotopic brain areas. We have previously argued that invisibility is closely linked to Gestalt ("object") organization principles. For example, motion is typically perceived in non-retinotopic, object-centered, and not in retinotopic coordinates. Such is the case for a bicycle-reflector that is perceived as circling, although its retinotopic trajectory is cycloidal. Here, we used a modified Ternus-Pikler display in which, just as in everyday vision, the retinotopic motion is invisible and the non-retinotopic motion is perceived. Nevertheless, the invisible retinotopic motion, can strongly degrade the conscious non-retinotopic motion percept. This effect cannot be explained by inhibition at a retinotopic processing stage. PMID- 29625860 TI - [The Confusion Assessment Method: Transcultural adaptation of a French version]. AB - INTRODUCTION: The Confusion Assessment Method (CAM) is a validated key tool in clinical practice and research programs to diagnose delirium and assess its severity. There is no validated French version of the CAM training manual and coding guide (Inouye SK). The aim of this study was to establish a consensual French version of the CAM and its manual. METHODS: Cross-cultural adaptation to achieve equivalence between the original version and a French adapted version of the CAM manual. RESULTS: A rigorous process was conducted including control of cultural adequacy of the tool's components, double forward and back translations, reconciliation, expert committee review (including bilingual translators with different nationalities, a linguist, highly qualified clinicians, methodologists) and pretesting. A consensual French version of the CAM was achieved. CONCLUSION: Implementation of the CAM French version in daily clinical practice will enable optimal diagnosis of delirium diagnosis and enhance communication between health professionals in French speaking countries. Validity and psychometric properties are being tested in a French multicenter cohort, opening up new perspectives for improved quality of care and research programs in French speaking countries. PMID- 29625861 TI - [Targeted newborn screening for sickle-cell anemia: Sickling test (Emmel test) boundaries in the prenatal assessment in West African area]. AB - BACKGROUND: Newborn screening for sickle cell anemia is necessary in Africa where the disease is more frequent. Hemoglobin electrophoresis is used for screening, but is limited by a high cost and difficult access. Sickling test (Emmel test), which is more affordable and technically more accessible, is often requested for prenatal assessment of pregnant women in West African areas to reserve screening for newborns from mothers in whom the positive sickling test attests the presence of hemoglobin S. This study aims to evaluate the number of undetected sickle cell anemia newborns by a screening policy targeting only newborns from mothers in whom a sickling test would have been positive. METHODS: From 2010 to 2012, in Bamako, Mali, West Africa, 2489 newborns were routinely screened for sickle cell anemia at the umbilical cord or heel by isoelectrofocusing and, if necessary, by high-performance liquid chromatography. These newborns were born from 2420 mothers whose hemoglobin was studied by isoelectrofocusing. The data was recorded and processed using Excel software version 14.0.0. We calculated the frequency of the sickle cell gene in mothers and newborns as well as the number of SCA newborns from heterozygous or C homozygous mothers. RESULTS: Of the 2489 newborns, 16 had sickle cell anemia (6 SS and 10 SC); 198 had the sickle cell trait; 139 were AC and 1 was CC. Of the 10 newborns with SC profile, 3 were born from mothers not carrying the S gene but the C gene of hemoglobin and in which an Emmel test would have been negative. CONCLUSION: Targeted newborn screening, based on the results of sickling test in pregnant women, would misdiagnose more than one of six sickle cell anemia newborns who would not benefit from early care. Cost-effectiveness studies of routine newborn screening for sickle cell anemia should lead to a better screening strategy in contexts where hemoglobin S and other hemoglobin defect genes coexist. PMID- 29625862 TI - Intramural Hematoma. PMID- 29625863 TI - Circulating cell-free DNA for non-invasive cancer management. AB - Cell-free DNA (cfDNA) was first identified in human plasma in 1948 and is thought to be released from cells throughout the body into the circulatory system. In cancer, a portion of the cfDNA originates from tumour cells, referred to as circulating-tumour DNA (ctDNA), and can contain mutations corresponding to the patient's tumour, for instance specific TP53 alleles. Profiling of cfDNA has recently become an area of increasing clinical relevance in oncology, in particular due to advances in the sensitivity of molecular biology techniques and development of next generation sequencing technologies, as this allows tumour mutations to be identified and tracked non-invasively. This has opened up new possibilities for monitoring tumour evolution and acquisition of resistance, as well as for guiding treatment decisions when tumour biopsy tissue is insufficient or unavailable. In this review, we will discuss the biology of cell-free nucleic acids, methods of analysis, and the potential clinical uses of these techniques, as well as the on-going clinical development of ctDNA assays. PMID- 29625864 TI - Dietary Intakes of Branched-Chained Amino Acid and Risk for Type 2 Diabetes in Adults: The Harbin Cohort Study on Diet, Nutrition and Chronic Non-Communicable Diseases Study. AB - OBJECTIVES: To assess the association between branched-chain amino acid (BCAA) intakes and risk for type 2 diabetes. METHODS: Dietary intakes were assessed in 1,804 people with type 2 diabetes and 7,020 controls with information on nutrient intakes, including BCAAs derived from Chinese food composition tables. Principal component analysis was used to identify dietary patterns (DPs) and multivariable adjusted odds ratios (ORs) of type 2 diabetes, and 95% confidence intervals (CIs) by quartiles of BCAAs were estimated using logistic regression with 2-sided p<0.05. RESULTS: Multivariable-adjusted ORs and 95% CI were 1.00, 1.297 (1.087 to 1.548), 1.380 (1.153 to 1.652) and 1.561 (1.291 to 1.888), p<0.0001, across energy-adjusted quartiles of total BCAA intakes. We identified 6 DPs: wheaten foods; vegetables, fruit and milk; beverages and snacks; potatoes, soybean and egg; meat; and fish. Multivariable-adjusted ORs and 95% CI across quartiles of total BCAA intakes for people with type 2 diabetes within the 4th quartile of DPs were 1.00, 1.337 (0.940 to 1.903); 1.579 (1.065 to 2.343); 2.412 (1.474 to 3.947); Pfor trend=0.001 for vegetables, fruit and milk, 1.00, 1.309 (0.930 to 1.842), 1.328 (0.888 to 1.985), 2.044 (1.179 to 3.544); Pfor trend=0.028 for meat and 1.00, 1.043 (0.720 to 1.509), 1.497 (0.969 to 2.312), 1.896 (1.067 to 3.367); Pfor trend=0.017 for fish. CONCLUSIONS: BCAA intakes and type 2 diabetes risk depend on the context of DPs, not exclusively on BCAA intake. PMID- 29625865 TI - Corrigendum to "Disinfection and healing effects of 222-nm UVC light on methicillin-resistant Staphylococcus aureus infection in mouse wounds" [J. Photochem. Photobiol. B Biol. 178 (January 2018) 10-18]. PMID- 29625866 TI - Mixed facial reanimation technique to treat paralysis in medium-term cases. AB - Recent facial paralyses, in which fibrillations of the mimetic muscles are still detectable by electromyography (EMG), allow facial reanimation based on giving new neural stimuli to musculature. However, if more time has elapsed, mimetic muscles can undergo irreversible atrophy, and providing a new neural stimulus is simply not effective. In these cases function is provided by transferring free flaps into the face or transposing masticatory muscles to reinstitute major movements, such as eyelid closure and smiling. In a small number of cases, patients affected by paralysis are referred late - more than 18 months after onset. In these cases, reinnervating the musculature carries a high risk of failure because some or all of the mimetic muscles may atrophy irreversibly while axonal ingrowth is taking place. A mixed reanimation technique to address this involves a neurorrhaphy between the masseteric nerve and a facial nerve branch for the orbicularis oculi, to ensure a stronger innervation to that muscle, associated with the transposition of the temporalis muscle to the nasiolabial sulcus. This gives good symmetry in the rest of the midface, while smiling movement is achievable, but not guaranteed. This one-time facial reanimation is particularly indicated for those who refuse major free-flap surgery or when that may be risky, as in previously operated and irradiated fields. More extensive procedures based on utilizing a free flap to recover smiling, while adding a cross-face nerve graft to restore blinking, may be proposed for motivated patients. Between 2010 and 2015, five patients affected by complete unilateral facial palsy underwent this technique in the Maxillofacial Surgery Department, San Paolo Hospital (Milan, Italy). Symmetry of the middle-third of the face at rest and recovery of smiling was quite good. Complete voluntary eyelid closure was obtained in all cases. Combining temporalis flap rotation and a masseteric-to orbicularis-oculi-facial-nerve branch neurorrhaphy seems to be a valid solution for those medium-term referred patients. PMID- 29625867 TI - Balloon Aortic Valvuloplasty for Congenital Aortic Stenosis: A 14-Year Single Centre Review. AB - BACKGROUND: The approach to intervention for congenital aortic valve stenosis (AS) differs depending upon centre bias toward a primary catheter or surgical approach. We therefore investigated associations with freedom from re intervention (FFI) in the cohort of children who underwent primary balloon aortic valvuloplasty (BAV) for congenital AS in our centre. METHODS: All patients who underwent BAV as a primary procedure in the period between 2001 and 2015 in a single service were included. Echocardiographic parameters before and after catheterisation and procedural data was collected on all patients. RESULTS: Sixty four patients underwent BAV as the primary intervention during the study period. Follow-up data was available for 60 of these. Balloon aortic valvuloplasty was performed at a median age of 143 days (range 2 days-18.8 years). Freedom from re intervention was observed in 75% of patients with a median follow-up of 6.8 years and a mean follow-up of 3 years. Catheter-based peak-to-peak aortic valve gradients decreased from 58+/-15.9mmHg to 22.9+/-13.1mmHg. There was no short- or long-term mortality. FFI was predicted by aortic valve morphology (p<0.01), post BAV mean echo gradient (p=0.03) and post-BAV regurgitation (p<0.01). No patient had re-intervention for restenosis with post-BAV mean echo gradient <30mmHg. Catheter gradients before and after BAV approached significance for predicting FFI (p=0.06 and p=0.09 respectively). Fifteen patients were neonates with significantly lower aortic valve (AoV) Z-scores (mean 0.63 vs 1.76, p=0.002) and no difference in FFI (p=0.19). Annulus size, balloon/annulus ratio (within the range utilised) and pre-BAV echo findings were not predictive for re intervention. CONCLUSIONS: Balloon aortic valvuloplasty is an effective primary approach to congenital valvular AS with the potential of avoiding surgical intervention in the majority of patients at all ages. Freedom from re intervention in our cohort was associated with valve morphology and the degree of stenosis and regurgitation immediately post BAV. PMID- 29625868 TI - Combined use of flexible ureteroscopic lithotripsy with micro-percutaneous nephrolithotomy in pediatric multiple kidney stones. AB - BACKGROUND: We investigated the clinical value of treating pediatric multiple kidney stones with extensive distribution using flexible ureteroscopic lithotripsy (FUL) combined with micro-percutaneous nephrolithotomy (micro-PNL). PATIENTS AND METHODS: In total, 21 pediatric patients with multiple renal calculi between May 2016 and June 2017 received FUL combined with micro-PNL. The group included 13 boys and eight girls; the patients' mean age was 3.8 years (range 1-8 years). The maximum stone diameter ranged from 1.0 to 1.5 cm. FUL was first performed in the lithotomy position to fragment stones that were located in the renal pelvis, and upper and mid-renal calyx. Patients were then moved to a prone position, and micro-PNL was performed to treat lower pole stones that could not be reached by the flexible ureteroscope during FUL. Percutaneous renal access to the lower calyx was achieved using a 4.8F "all-seeing needle" with ultrasound guidance, and stone fragmentation was performed with a 200-MUm holmium laser at different settings to disintegrate 1- to 2-mm fragments. RESULTS: All 21 pediatric patients with multiple kidney stones underwent combined FUL and micro PNL. The stone free rate (SFR) was 85.7% (18/21). The mean surgical time was 45 min (range 30-70 min). The mean volume of irrigation fluid used was 480 mL (range 300-1200 mL). The mean surgical time for FUL and micro-PNL was 31 min and 14 min, respectively, and the mean volume of fluid used for FUL and micro-PNL was 360 mL and 120 mL, respectively. According to the modified Clavien classification, grade 1 and 2 postoperative complications occurred in five and one patients, respectively. The mean decrease in the level of hemoglobin was 0.4 g/dL (0-0.7 g/dL), and no patients required a transfusion. The average hospital stay was 3 days (range 2-5 days). CONCLUSION: Combined FUL and micro-PNL is a safe, effective, and minimally invasive operation to remove multiple renal calculi with extensive distribution in children in selected cases. PMID- 29625869 TI - The effect of provision of information on serum cortisol in patients transferred from the coronary care unit to the general ward: A randomised controlled trial. AB - BACKGROUND AND AIM: Patients' transfer from coronary care units to general wards is a main source of anxiety for patients. Transfer anxiety is due to either lack of patients' knowledge or inadequacy of transfer-related information to patients. This study aimed to evaluate the effect of provision of information on the serum cortisol level, as an indicator of anxiety, in patients transferred from the coronary care unit to the general ward. METHODS: This pretest-posttest randomised clinical trial was conducted on fifty patients transferred from coronary care units to general wards. Patients were selected using a purposeful sampling method and randomly were allocated to control and intervention groups. After taking blood samples for a baseline cortisol measurement, the patients in the control group received routine verbal transfer-related information. The patients in the intervention group were provided with an educational pamphlet consisting of textual and visual data about patients' transfer, continuity of care and the target general ward. The second and the third blood samples were taken for a cortisol measurement half an hour after informing the patients about the transfer order and half an hour after entrance to the general ward, respectively. Descriptive and inferential statistics via the SPSS software v. 21 was used for data analysis. RESULTS: No statistically significant differences were reported between the groups in terms of demographic characteristics (p > 0.05). The serum levels of cortisol in the intervention group decreased from 40.16 (microgram per decilitre) at the baseline to 36.52 and 34.34 at the second and the third measurement time points, respectively. Conversely, the serum levels of cortisol in the control group increased from 37.48 at the baseline to 40.52 and 41.52 at the second- and the third-time points, respectively. While no statistically significant difference was reported between the groups in the baseline serum level of cortisol, between-group differences were statistically significant at the second- and the third-time points (p < 0.05). CONCLUSION: Provision of transfer-related information can reduce transfer anxiety among patients, that should be transferred from coronary care units to general wards. PMID- 29625870 TI - The association between spiritual well-being and burnout in intensive care unit nurses: A descriptive study. AB - OBJECTIVES: To describe the spiritual well-being and burnout of intensive care unit nurses and examine the relationship between these factors. RESEARCH METHODOLOGY: This was a cross-sectional descriptive study. The participants were 318 intensive care unit recruited from three university hospitals in South Korea. The survey questionnaire included demographic information, work-related characteristics and end-of-life care experience, along with the Spiritual Well Being Scale and Burnout Questionnaire. The data were analysed using descriptive statistics, t-tests, ANOVA with Scheffe test and a multiple regression analysis. RESULTS: The burnout level among intensive care unit nurses was 3.15 out of 5. A higher level of burnout was significantly associated with younger age, lower education level, single marital status, having no religion, less work experience and previous end-of-life care experience. Higher levels of spiritual well-being were associated with lower levels of burnout, even after controlling for the general characteristics in the regression model. CONCLUSION: Intensive care unit nurses experience a high level of burnout in general. Increased spiritual well being might reduce burnout among intensive care unit nurses. Younger and less experienced nurses should receive more attention as a vulnerable group with lower spirituality and greater burnout in intensive care unit settings. PMID- 29625871 TI - NGS-based likelihood ratio for identifying contributors in two- and three-person DNA mixtures. AB - DNA fingerprinting, also known as DNA profiling, serves as a standard procedure in forensics to identify a person by the short tandem repeat (STR) loci in their DNA. By comparing the STR loci between DNA samples, practitioners can calculate a probability of match to identity the contributors of a DNA mixture. Most existing methods are based on 13 core STR loci which were identified by the Federal Bureau of Investigation (FBI). Analyses based on these loci of DNA mixture for forensic purposes are highly variable in procedures, and suffer from subjectivity as well as bias in complex mixture interpretation. With the emergence of next-generation sequencing (NGS) technologies, the sequencing of billions of DNA molecules can be parallelized, thus greatly increasing throughput and reducing the associated costs. This allows the creation of new techniques that incorporate more loci to enable complex mixture interpretation. In this paper, we propose a computation for likelihood ratio that uses NGS (next generation sequencing) data for DNA testing on mixed samples. We have applied the method to 4480 simulated DNA mixtures, which consist of various mixture proportions of 8 unrelated whole genome sequencing data. The results confirm the feasibility of utilizing NGS data in DNA mixture interpretations. We observed an average likelihood ratio as high as 285,978 for two-person mixtures. Using our method, all 224 identity tests for two-person mixtures and three-person mixtures were correctly identified. PMID- 29625872 TI - Construction of scaffolds composed of acellular cardiac extracellular matrix for myocardial tissue engineering. AB - High rates of mortality and morbidity stemming from cardiovascular diseases unveil extreme limitations in current therapies despite enormous advances in medical and pharmaceutical sciences. Following myocardial infarction (MI), parts of myocardium undergo irreversible remodeling and is substituted by a scar tissue which eventually leads to heart failure (HF). To address this issue, cardiac patches have been utilized to initiate myocardial regeneration. In this study, a porous cardiac patch is fabricated using a mixture of decellularized myocardium extracellular matrix (ECM) and chitosan (CS). Results of rheological measurements, SEM, biodegradation test, and MTT assay showed that the scaffold composed of 3.5% (w/w) CS and 0.5% ECM has the best potential in providing cardiac progenitor cells (CPCs) with a suitable microenvironmental condition for both attachment and growth. This study demonstrates that the fabricated scaffold is capable of transmitting both mechanical and chemical cues that is native to myocardial tissue and supports efficient growth of the CPCs. PMID- 29625873 TI - [Lower Uterine Segment Trial: A pragmatic open multicenter randomized trial]. AB - BACKGROUND: The data from literature show that trial of labor and elective repeat cesarean delivery after a prior cesarean delivery both present significant risks and benefits, and these risks and benefits differ for the woman and her fetus. The benefits to the woman can be at the expense of her fetus and vice-versa. This uncertainty is compounded by the scarcity of high-level evidence that preclude accurate quantification of the risks and benefits that could help provide a fair counseling about a trial of labor and elective repeat cesarean delivery. An interesting way of research is to evaluate the potential benefits of a decision rule associated to the ultrasound measurement of the lower uterine segment (LUS). Indeed, ultrasonography may be helpful in determining a specific risk for a given patient by measuring the thickness of the LUS, i,e, the thickness of the cesarean delivery scar area. Although only small and often methodologically biased data have been published, they look promising as their results are concordant: ultrasonographic measurements of the LUS thickness is highly correlated with the intraoperative findings at cesarean delivery. Furthermore, the thinner the LUS becomes on ultrasound, the higher the likelihood of a defect in the LUS. Finally, ultrasound assessment of LUS has an excellent negative predictive value for the risk of uterine defect. Therefore, this exam associated with a rule of decision could help to reduce the rate of elective repeat cesarean delivery and especially to reduce the fetal and maternal mortality and morbidity related to trial of labor after a prior cesarean delivery. METHODS/DESIGN: This is a pragmatic open multicenter randomized trial with two parallel arms. Randomization will be centralized and computerized. Since blindness is impossible, an adjudication committee will evaluate the components of the primary composite outcome in order to avoid evaluation bias. An interim analysis will be planned mid-strength of the trial. Ultrasound will be performed by expert sonographers after certification by the main investigator. Women aged 18 years or older are eligible for this trial if they have a singleton pregnancy in cephalic presentation at a gestational age from 36 to 38 weeks, a previous low transverse cesarean delivery and sign the informed consent sheet. Women will be asked to participate in this study when they reach a term of 36 to 38 weeks of gestation. After agreement, women will be randomized into two groups: in the study group, they will have the LUS measured by ultrasound and the patient will be informed that, based on a threshold value of 3.5mm for the ultrasound measurement of the LUS thickness, the patient with a higher measurement will be considered at low risk and will be encouraged to choose a trial of labor whereas the patient with a measurement is equal to or less than this threshold will be considered at risk and encouraged to choose an elective repeat cesarean; in the control group, ultrasound LUS measurement will not be performed. The mode of delivery will be decided according to standard practice at the center. The primary composite outcome will include: uterine rupture, uterine dehiscence, hysterectomy, thromboembolic complications, transfusion, endometritis, maternal mortality, fetal prenatal and intrapartum mortality, hypoxic-ischemic encephalopathy and neonatal mortality. DISCUSSION: This trial assesses the efficacy of ultrasound measurement of the lower uterine segment in women with a prior cesarean delivery in reducing fetal and maternal morbidity and mortality and it will provide evidence in order to establish clinical recommendations. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01916044 (date of registration: 5 August 2013). PMID- 29625874 TI - Peripheral neuropathy is associated with more frequent falls in Parkinson's disease. AB - INTRODUCTION: Peripheral neuropathy is a common condition in the elderly that can affect balance and gait. Postural imbalance and gait difficulties in Parkinson's disease (PD), therefore, may stem not only from the primary neurodegenerative process but also from age-related medical comorbidities. Elucidation of the effects of peripheral neuropathy on these difficulties in PD is important to provide more targeted and effective therapy. The purpose of this study was to investigate the association between lower-limb peripheral neuropathy and falls and gait performance in PD while accounting for disease-specific factors. METHODS: From a total of 140 individuals with PD, 14 male participants met the criteria for peripheral neuropathy and were matched 1:1 for Hoehn & Yahr stage and duration of disease with 14 male participants without peripheral neuropathy. All participants underwent fall (retrospectively) and gait assessment, a clinical evaluation, and [11C]dihydrotetrabenazine and [11C]methylpiperidin-4-yl propionate PET imaging to assess dopaminergic and cholinergic denervation, respectively. RESULTS: The presence of peripheral neuropathy was significantly associated with more falls (50% vs. 14%, p = 0.043), as well as a shorter stride length (p = 0.011) and greater stride length variability (p = 0.004), which resulted in slower gait speed (p = 0.016) during level walking. There was no significant difference in nigrostriatal dopaminergic denervation, cortical and thalamic cholinergic denervation, and MDS-UPDRS motor examination scores between groups. CONCLUSION: Lower-limb peripheral neuropathy is significantly associated with more falls and gait difficulties in PD. Thus, treating such neuropathy may reduce falls and/or improve gait performance in PD. PMID- 29625876 TI - Recycling of polyurethanes from laboratory to industry, a journey towards the sustainability. AB - The recycling of any kind of plastic to convert it in valuable products is one of the main challenges of today's society. Besides, if the recycling process is itself green, then it would be a great achievement. This paper reviews the way covered from the first attempts of reusing the polyurethane (PU) scraps as a filler for cushions to the last chemical routes employing green recycling agents. Polyurethane is the 6th most used polymer all over the world with a production of 18 millions tons per year, which means a daily production of PU specialties greater than 1 million of cubic meters, equivalent to the volume of the Empire State Building. The thermostable nature of the majority of the polyurethanes specialties has made that the preferred solution for their recycling are the chemical recycling processes. Among them, glycolysis is the one that receives a greater attention from an industrial point of view, so this review puts the spotlight on it. However, the existing reviews in literature do not paid a special attention on glycolysis and only give a superficial description of the process. Nevertheless, in the present review, the scientific literature relative to glycolysis is completely reviewed, updated and ordered according the type of PU specialty recycled. Additionally, the other main chemical recycling processes are also revisited in a more extended and deeper way than in the previous approaches to this topic. Moreover, it is crucial to take into account that some of these technologies, which were described in the literature as promising technologies at laboratory scale are now commercial processes running at industrial scale. For that reason, it is essential to remark that the present review comprises not only a detailed state of art of the scientific literature on the subject, also includes a detailed revision of the past and running on pilot plants and industrial facilities, including several patents, which has never been covered in the current literature. Moreover, this review also describes the most recent studies employing crude glycerol (biodiesel subproduct) as an economic, sustainable and environmental friendly cleavage agent, which should lead the way to the industrial implantation of split-phase glycolysis in a near future, providing high quality recovered products, susceptible of replacing raw ones in the synthesis of new PU specialties. What is more, this review intends that any reader could know and understand the reactions involved in the polyurethane chemistry and recycling, the main polyurethanes types and the fundamentals of the recycling strategies in order to comprehend what are the advantages and drawbacks of each recycling process as starting point for looking for new advantageous alternatives from an environmental, technical and economic point of view. Broader context. This paper reviews the main advances in the polyurethane (PU) recycling field, from laboratory and academia processes to pilot plant and industrial scale ones, including the most relevant patents in the subject. Opposite to other common used plastics, PUs are not polymerization but condensation polymers, synthesized from polyols and isocyanates. The wide diversity of polyols and isocyanates allows the synthesis of numerous different compounds covering a huge range of applications. As a direct consequence of their commercial success, an increasing quantity of PU waste is being disposed by landfilling in the last decades. Such waste comprises not only post-consumer products but also scrap from slabstock manufacturing, which can reach the 10% of the total foam production. However, the massive enforcement of the environmental laws is pointing out a new route in the polymer waste removal sector based in the polymer recycling, and this fact has placed the research in waste treatment as one of the most prolific topics nowadays. In fact, polymer recycling processes have experienced a growing attention from the research and industrial worlds as a direct result of the enforcement of the environmental legislations. Hence, it is essential to develop new environmental sustainable recycling processes with the aim of conserving the natural resources, reducing the amount of waste disposed in landfills and enhancing the sustainability for forthcoming generation. PMID- 29625875 TI - Relationship between the MDS-UPDRS and Quality of Life: A large multicenter study of 3206 patients. AB - BACKGROUND: The relationship between Health-Related Quality of Life (HRQoL) and MDS-UPDRS has not been fully studied so far. The aim of this study was to evaluate the relationship between all MDS-UPDRS components and HRQoL in a representative international cohort of PD patients. METHODS: We collected demographic and disease-related data as well as MDS-UPDRS and PDQ8 scales. Data were analyzed using correlations between PDQ8 and all MDS-UPDRS items, subsequently two hierarchical multiple regressions were performed, first between the scores of the MDS-UPDRS Parts and PDQ8 and second between individual items from those Parts demonstrating significant relationship to PDQ8 scores in the first regression. LASSO regression analyses were performed to evaluate the relationship between PDQ8 and all individual MDS-UPDRS items. RESULTS: A total of 3206 PD patients were included in the study. In the first regression analysis, PDQ8 was significantly related to MDS-UPDRS parts I and II, but not to III and IV. In the second regression model, significant contributions to PDQ8 were found for Part I items Fatigue, Pain, Depressed mood, Apathy; and Part II items Dressing, Doing hobbies, Freezing, Speech and Tremor. In the LASSO analysis, six Part I, seven Part II, three Part III and one Part IV items contributed to PDQ8 scores. The five items most significantly related to the model were Depressed mood, Dressing, Apathy, Pain and Fatigue. CONCLUSIONS: This is so far the largest study related to HRQoL issues in PD. Restrictions in activities of daily living and non-motor symptoms significantly contribute to HRQoL in PD. PMID- 29625877 TI - Bioethanol from sugarcane bagasse: Focused on optimum of lignin content and reduction of enzyme addition. AB - To investigate the effect of delignification on enzymatic saccharification and ethanol fermentation of sugarcane bagasse (SCB), NaClO, NaOH, and Na2CO3 were used to prepare SCB with different lignin contents. We found that a lignin content of approximately 11% was sufficient for enzymatic saccharification and fermentation. Based on this result, an economical delignification pretreatment method using a combination of acid and alkali (CAA) was applied. Lignin content of 11.7% was obtained after CAA pretreatment with 0.5% w/v H2SO4 at 140 degrees C for 10 min and 1.0% w/v NaOH at 90 degrees C for 60 min. Presaccharification simultaneous saccharification and fermentation (P-SSF) of the CAA-pretreated SCB resulted in an ethanol concentration of 43.8 g/L and an ethanol yield of 81.7%, with an enzyme loading of 15 FPU/g-CAA-pretreated SCB. Enzyme activities (filter paper, carboxymethyl cellulase, and beta-glucosidase activities) were determined in liquid phase during P-SSF, indicating that the residual cellulase activity could be further used. Thus, fed-batch P-SSF was carried out, and an ethanol concentration of 43.1 g/L and an ethanol yield of 80.4% were obtained with an enzyme loading of 10 FPU/g-CAA-pretreated SCB. Fed-batch P-SSF was found to be effective to reduce enzyme loading. PMID- 29625878 TI - Evaluation of biodegradation feasibility through rotary drum composting recalcitrant primary paper mill sludge. AB - Primary paper mill sludge (PPMS) is the major waste expelled from the pulp and paper industries contributing soil and water pollution through the recalcitrant organic and inorganic constituents. These pollutants can, however, be transformed into a high-value soil ameliorating material with nominal investment and time. Current study therefore evaluated the potential of rotary drum composting PPMS for 20 days to delineate an environmentally sustainable option. Five trials with proportions of PPMS, cow dung and saw dust: Trial 1 (10:0:0), Trial 2 (8:1:1), Trial 3 (7:2:1), Trial 4 (6:3:1) and Trial 5 (5:4:1) were performed for evaluation of degrading and nutritive ability along with the fate of pollutants for total mass of 150 kg. Trial 4 exhibited highest metabolic activity contributing higher temperature evolution and longer thermophilic phase (10 days) owing to optimum addition of innoculum and nitrogen through the cattle manure. Moreover, degradation of 16.8% organic matter was also best achieved in Trial 4 following up first-order kinetics. Furthermore, BOD, COD and C/N ratio also explains degradation to be maximum in trial 4 (6:3:1) with reduction of 59.3%, 60.1% and C/N ratio from 55.1 to 18 respectively, proving to be the essential determining factors. Phosphorus availability increased by around 67% in trial 4. PPMS can be thus transformed into a potential valued added product and safe for subsequent land application. PMID- 29625880 TI - Tivantinib for advanced hepatocellular carcinoma: is MET still a viable target? PMID- 29625881 TI - Reply to "high abnormal rate in the repetitive nerve stimulation test in acute onset myasthenia gravis". PMID- 29625879 TI - Tivantinib for second-line treatment of MET-high, advanced hepatocellular carcinoma (METIV-HCC): a final analysis of a phase 3, randomised, placebo controlled study. AB - BACKGROUND: Tivantinib (ARQ 197), a selective, oral MET inhibitor, improved overall survival and progression-free survival compared with placebo in a randomised phase 2 study in patients with high MET expression (MET-high) hepatocellular carcinoma previously treated with sorafenib. The aim of this phase 3 study was to confirm the results of the phase 2 trial. METHODS: We did a phase 3, randomised, double-blind, placebo-controlled study in 90 centres in Australia, the Americas, Europe, and New Zealand. Eligible patients were 18 years or older and had unresectable, histologically confirmed, hepatocellular carcinoma, an Eastern Cooperative Oncology Group performance status of 0-1, high MET expression (MET-high; staining intensity score >=2 in >=50% of tumour cells), Child-Pugh A cirrhosis, and radiographically-confirmed disease progression after receiving sorafenib-containing systemic therapy. We randomly assigned patients (2:1) in block sizes of three using a computer-generated randomisation sequence to receive oral tivantinib (120 mg twice daily) or placebo (twice daily); patients were stratified by vascular invasion, extrahepatic spread, and alpha-fetoprotein concentrations (<=200 ng/mL or >200 ng/mL). The primary endpoint was overall survival in the intention-to-treat population. Efficacy analyses were by intention to treat and safety analyses were done in all patients who received any amount of study drug. This study is registered with ClinicalTrials.gov, number NCT01755767. FINDINGS: Between Dec 27, 2012, and Dec 10, 2015, 340 patients were randomly assigned to receive tivantinib (n=226) or placebo (n=114). At a median follow-up of 18.1 months (IQR 14.1-23.1), median overall survival was 8.4 months (95% CI 6.8-10.0) in the tivantinib group and 9.1 months (7.3-10.4) in the placebo group (hazard ratio 0.97; 95% CI 0.75-1.25; p=0.81). Grade 3 or worse treatment-emergent adverse events occurred in 125 (56%) of 225 patients in the tivantinib group and in 63 (55%) of 114 patients in the placebo group, with the most common being ascites (16 [7%] patients]), anaemia (11 [5%] patients), abdominal pain (nine [4%] patients), and neutropenia (nine [4%] patients) in the tivantinib group. 50 (22%) of 226 patients in the tivantinib group and 18 (16%) of 114 patients in the placebo group died within 30 days of the last dose of study medication, and general deterioration (eight [4%] patients) and hepatic failure (four [2%] patients) were the most common causes of death in the tivantinib group. Three (1%) of 225 patients in the tivantinib group died from a treatment-related adverse event (one sepsis, one anaemia and acute renal failure, and one acute coronary syndrome). INTERPRETATION: Tivantinib did not improve overall survival compared with placebo in patients with MET-high advanced hepatocellular carcinoma previously treated with sorafenib. Although this METIV HCC trial was negative, the study shows the feasibility of doing integral tissue biomarker studies in patients with advanced hepatocellular carcinoma. Additional randomised studies are needed to establish whether MET inhibition could be a potential therapy for some subsets of patients with advanced hepatocellular carcinoma. FUNDING: ArQule Inc and Daiichi Sankyo (Daiichi Sankyo Group). PMID- 29625882 TI - A new method for monitoring abnormal muscle response in hemifacial spasm: A prospective study. AB - OBJECTIVE: To examine a new abnormal muscle response (AMR) monitoring method during microvascular decompression (MVD) for hemifacial spasm. METHODS: 486 patients with hemifacial spasm were monitored for an AMR during MVD with a new method involving preoperative mapping and intraoperative centrifugal stimulation of the facial nerve. For the last 62 patients, we performed the AMR monitoring using both, the new and conventional methods simultaneously. RESULTS: Preoperative facial nerve mapping showed that the maximal AMR was detected most frequently (66.9%) at the "F" location (the direction towards the frontalis muscle). An intraoperative AMR was observed in 86.2% of the patients, which disappeared after MVD in 96.4% of the patients. A comparison of the new and conventional methods respectively showed that AMR disappearance after MVD was observed in 98.2% and 61.8% of the patients, no AMR in 0% and 9.1%, and persistent AMR after MVD in 1.8% and 29.1%. CONCLUSIONS: The new AMR monitoring method demonstrated greater AMR monitoring efficacy and supports the finding that disappearance of an AMR is a good indicator of effective decompression during MVD surgery. SIGNIFICANCE: Preoperative mapping and intraoperative centrifugal stimulation of the facial nerve during MVD surgery in HFS patients showed greater efficacy of AMR monitoring. PMID- 29625883 TI - Intestinal perforation secondary to strangulated internal hernia after Roux-en-Y gastric bypass. PMID- 29625884 TI - Integration of Wall Motion, Coronary Flow Velocity, and Left Ventricular Contractile Reserve in a Single Test: Prognostic Value of Vasodilator Stress Echocardiography in Patients with Diabetes. AB - BACKGROUND: Coronary flow velocity reserve (CFVR) and left ventricular contractile reserve (LVCR) have demonstrated prognostic importance in patients with diabetes. The aim of this study was to investigate the prognostic contribution of combined evaluation of CFVR and LVCR in patients with diabetes with nonischemic stress echocardiography. METHODS: Three hundred seventy-five patients with diabetes (mean age, 68 +/- 9 years) with nonischemic dipyridamole stress echocardiography underwent assessment of CFVR of the left anterior descending coronary artery (prospectively) and LVCR with left ventricular force (retrospectively) in a multicenter study. RESULTS: On receiver operating characteristic analysis, LVCR <= 1.1 was the best prognostic predictor and was considered an abnormal value. CFVR was abnormal (<=2) in 139 patients (37%), LVCR in 156 (42%), neither in 157 (42%), and both in 77 (21%). During a median follow up period of 16 months, 86 major adverse cardiac events occurred: 16 deaths, 13 myocardial infarctions, and 57 revascularizations. Multivariate prognostic indicators were CFVR <= 2 (P < .0001), age (P = .03), and LVCR <= 1.1 (P = .04). The 3-year rate of major adverse cardiac events was 63% in patients with both abnormal CFVR and LVCR, 42% in those with abnormal CFVR only, 19% in those with abnormal LVCR only, and 10% in patients with both normal CFVR and LVCR. The 3 year hard event rate was 3% in patients with both normal CFVR and LVCR, fivefold higher in patients with abnormal CFVR or LVCR only, and ninefold higher in patients with both abnormal CFVR and LVCR. CONCLUSIONS: Patients with diabetes with nonischemic dipyridamole stress echocardiography may still have significant risk in presence of abnormal CFVR and/or LVCR, which assess the underlying, largely unrelated, microvascular and myocardial components of coronary circulation. PMID- 29625886 TI - Evaluation of Staff Radiation Exposure during Transthoracic Echocardiography Close to Myocardial Perfusion Imaging. AB - BACKGROUND: Transthoracic echocardiography (TTE) and myocardial perfusion imaging (MPI) are used in cardiac patients. In this study the radiation exposure of sonographers performing TTE following MPI was evaluated. METHODS: Of 40 study patients, 30 underwent same-day 99mTc sestamibi MPI and TTE, while another 10 underwent only TTE. Patients who underwent both studies were divided into three groups: right-handed TTE performed by an echocardiographer and right- and left handed TTE performed by a cardiac sonographer. Seven thermoluminescent radiation dosimeter badges monitored the forehead, wrists, anterolateral right and left chest, sternal notch, and umbilical region of each examiner. Group characteristics were compared. Radiation exposures were deemed positive if >0.1 mSv. RESULTS: There were no statistical differences in patient weight and body mass index. The left-handed approach group had higher residual radioactivity (979 +/- 73 vs 884 +/- 73 MBq [P < .01] and 906 +/- 81 MBq [P < .04]), but no statistical difference in duration of TTE, compared with the other two MPI groups. Radiation exposure was positive in the right anterolateral chest and hand (0.45 and 1 mSv, respectively) for the echocardiographer, the right anterolateral chest and wrist and umbilical region (0.59, 1.06, and 0.15 mSv, respectively) for the right-handed sonographer, and the left chest and hand (0.12 and 0.34 mSv, respectively) for the left-handed sonographer. Dosimeters indicated no radiation exposure in the TTE-only group. CONCLUSIONS: Staff members performing TTE after MPI are exposed to radiation that might warrant monitoring. Altering study sequence, adopting a left-handed approach, and using other radiation-reducing techniques can minimize the degree of exposure. PMID- 29625885 TI - Prognostic Value of Transthoracic Doppler Echocardiography Coronary Flow Velocity Reserve in Patients with Nonculprit Stenosis of Intermediate Severity Early after Primary Percutaneous Coronary Intervention. AB - BACKGROUND: Treatment of nonculprit coronary stenosis during primary percutaneous coronary intervention in patients with ST-segment elevation myocardial infarction may be beneficial, but the mode and timing of the intervention are still controversial. The aim of this study was to examine the significance and prognostic value of preserved coronary flow velocity reserve (CFVR) in patients with nonculprit intermediate stenosis early after primary percutaneous coronary intervention. METHODS: Two hundred thirty patients with remaining intermediate (50%-70%) stenosis of non-infarct-related arteries, in whom CFVR was performed within 7 days after primary percutaneous coronary intervention, were prospectively enrolled. Twenty patients with reduced CFVR and positive results on stress echocardiography or impaired fractional flow reserve underwent revascularization and were not included in further analysis. The final study population of 210 patients (mean age, 58 +/- 10 years; 162 men) was divided into two groups on the basis of CFVR: group 1, CFVR > 2 (n = 174), and group 2, CFVR <= 2 (n = 36). Cardiac death, nonfatal myocardial infarction, and revascularization of the evaluated vessel were considered adverse events. RESULTS: Mean follow-up duration was 47 +/- 16 months. Mean CFVR for the whole group was 2.36 +/- 0.40. There were six adverse events (3.4%) related to the nonculprit coronary artery in group 1, including one cardiac death, one ST segment elevation myocardial infarction, and four revascularizations. In group 2, there were 30 adverse events (83.3%, P < .001 vs group 1), including two cardiac deaths, two ST-segment elevation myocardial infarctions, and 26 revascularizations. CONCLUSIONS: In patients with CFVR > 2 of the intermediate nonculprit coronary lesion, deferral of revascularization is safe and associated with excellent long-term clinical outcomes. PMID- 29625887 TI - Clearly, with Regard to Transesophageal Echocardiography, "Need Is the Mother of Invention". PMID- 29625888 TI - Tear film secretion and stability in welders. AB - PURPOSE: Welders are prone to ocular injuries and ocular surface problems due to exposure to ultraviolet light. The aim of this study was to evaluate the tear film comprehensively and assess objective and subjective indices of dry eye in welders. METHODS: In this historical cohort, welders with at least 5 years of experience were compared with controls. A complete evaluation of ocular health was done for all participants. The Schirmer test (invasive and non-invasive) and Invasive Tear Break-Up Time (ITBUT) were applied for objective evaluation and the Ocular Surface Disease Index (OSDI) was used for subjective assessment of the tear film status. The results were compared between the two groups using the SPSS software. RESULTS: The results of 140 welders (mean age: 46.66 +/- 13.01 years) and 172 controls (mean age: 45.05 +/- 12.61) were analyzed. The values of the Schirmer test and ITBUT were significantly lower in welders than controls; the difference was more prominent for the Schirmer test as compared to TBUT (Schirmer difference = 4.98 mm, ITBUT difference = 2.23 s). OSDI values were also significantly lower in welders than controls (P < 0.001). Considering a cut-off point of 12, 81.2% of welders had degrees of dry eye which was severe in 46.2% while 35.5% of controls had dry eye. CONCLUSION: The results indicate that the percentage of dry eye and tear problems is far higher in welders than non welders. Most of the affected welders have severe dry eye. It seems that the main reason for dry eye in these people is aqueous deficiency. PMID- 29625889 TI - Involuntary outpatient treatment: A proposal of regulation. PMID- 29625890 TI - What most influent psychiatry journals do not show. PMID- 29625891 TI - How to improve the integrity of clinical trial articles. PMID- 29625892 TI - Enantiomorphism and rule similarity in the astigmatism axes of fellow eyes: A population-based study. AB - PURPOSE: To evaluate the relationship patterns between astigmatism axes of fellow eyes (rule similarity and symmetry) and to determine the prevalence of each pattern in the studied population. METHODS: This population-based study was conducted in 2015 in Iran. All participants had tests for visual acuity, objective refraction, subjective refraction (if cooperative), and assessment of eye health at the slit-lamp. Axis symmetry was based on two different patterns: direct (equal axes) and mirror (mirror image symmetry) or enantiomorphism. Bilateral astigmatism was classified as isorule if fellow eyes had the same orientation (e.g. both eyes were with-the-rule) and as anisorule if otherwise. RESULTS: Of the total cases of bilateral astigmatism, 80% were isorule, and in the studied population, the prevalence of isorule and anisorule astigmatism was 14.89% and 3.53%, respectively. The prevalence of isorule increased with age (p<0.001). The prevalence of both isorule and anisorule increased at higher degrees of spherical ametropia (p<0.001). Median inter-ocular axis difference was 10 degrees in mirror symmetry and 20 degrees in direct symmetry with no significant difference between two genders (p>0.288). Both symmetry patterns reduced with age (p<0.001). Among cases of bilateral astigmatism, 15.5% and 19.8% had exact direct and mirror symmetry, respectively. CONCLUSION: Bilateral astigmatism is mainly isorule in the population and anisorule astigmatism is rare. The enantiomorphism is the most common pattern in the population of bilateral astigmatism. PMID- 29625894 TI - Toll-like Receptor 9 Contains Two DNA Binding Sites that Function Cooperatively to Promote Receptor Dimerization and Activation. AB - Toll-like receptor 9 (TLR9) recognizes DNA containing CpG motifs derived from bacteria and viruses and activates the innate immune response to eliminate them. TLR9 is known to bind to CpG DNA, and here, we identified another DNA binding site in TLR9 that binds DNA containing cytosine at the second position from the 5' end (5'-xCx DNA). 5'-xCx DNAs bound to TLR9 in the presence of CpG DNA and cooperatively promoted dimerization and activation of TLR9. Binding at both sites was important for efficient activation of TLR9. The 5'-xCx DNA bound the site corresponding to the nucleoside binding site in TLR7 and TLR8 as revealed by the structural analysis. This study revealed that TLR9 recognizes two types of DNA through its two binding sites for efficient activation. This information may contribute to the development of drugs that control the activity of TLR9. PMID- 29625893 TI - Interleukin-15 Complex Treatment Protects Mice from Cerebral Malaria by Inducing Interleukin-10-Producing Natural Killer Cells. AB - Cerebral malaria is a deadly complication of Plasmodium infection and involves blood brain barrier (BBB) disruption following infiltration of white blood cells. During experimental cerebral malaria (ECM), mice inoculated with Plasmodium berghei ANKA-infected red blood cells develop a fatal CM-like disease caused by CD8+ T cell-mediated pathology. We found that treatment with interleukin-15 complex (IL-15C) prevented ECM, whereas IL-2C treatment had no effect. IL-15C expanded natural killer (NK) cells were necessary and sufficient for protection against ECM. IL-15C treatment also decreased CD8+ T cell activation in the brain and prevented BBB breakdown without influencing parasite load. IL-15C induced NK cells to express IL-10, which was required for IL-15C-mediated protection against ECM. Finally, we show that ALT-803, a modified human IL-15C, mediates similar induction of IL-10 in NK cells and protection against ECM. These data identify a regulatory role for cytokine-stimulated NK cells in the prevention of a pathogenic immune response. PMID- 29625895 TI - KLRG1+ Effector CD8+ T Cells Lose KLRG1, Differentiate into All Memory T Cell Lineages, and Convey Enhanced Protective Immunity. AB - Protective immunity against pathogens depends on the efficient generation of functionally diverse effector and memory T lymphocytes. However, whether plasticity during effector-to-memory CD8+ T cell differentiation affects memory lineage specification and functional versatility remains unclear. Using genetic fate mapping analysis of highly cytotoxic KLRG1+ effector CD8+ T cells, we demonstrated that KLRG1+ cells receiving intermediate amounts of activating and inflammatory signals downregulated KLRG1 during the contraction phase in a Bach2 dependent manner and differentiated into all memory T cell linages, including CX3CR1int peripheral memory cells and tissue-resident memory cells. "ExKLRG1" memory cells retained high cytotoxic and proliferative capacity distinct from other populations, which contributed to effective anti-influenza and anti-tumor immunity. Our work demonstrates that developmental plasticity of KLRG1+ effector CD8+ T cells is important in promoting functionally versatile memory cells and long-term protective immunity. PMID- 29625896 TI - Co-inhibitory Molecule B7 Superfamily Member 1 Expressed by Tumor-Infiltrating Myeloid Cells Induces Dysfunction of Anti-tumor CD8+ T Cells. AB - The molecular mechanisms whereby CD8+ T cells become "exhausted" in the tumor microenvironment remain unclear. Programmed death ligand-1 (PD-L1) is upregulated on tumor cells and PD-1-PD-L1 blockade has significant efficacy in human tumors; however, most patients do not respond, suggesting additional mechanisms underlying T cell exhaustion. B7 superfamily member 1 (B7S1), also called B7-H4, B7x, or VTCN1, negatively regulates T cell activation. Here we show increased B7S1 expression on myeloid cells from human hepatocellular carcinoma correlated with CD8+ T cell dysfunction. B7S1 inhibition suppressed development of murine tumors. Putative B7S1 receptor was co-expressed with PD-1 but not T cell immunoglobulin and mucin-domain containing-3 (Tim-3) at an activated state of early tumor-infiltrating CD8+ T cells, and B7S1 promoted T cell exhaustion, possibly through Eomes overexpression. Combinatorial blockade of B7S1 and PD-1 synergistically enhanced anti-tumor immune responses. Collectively, B7S1 initiates dysfunction of tumor-infiltrating CD8+ T cells and may be targeted for cancer immunotherapy. PMID- 29625897 TI - A Circular RNA Protects Dormant Hematopoietic Stem Cells from DNA Sensor cGAS Mediated Exhaustion. AB - Disrupting the balance between self-renewal and differentiation of hematopoietic stem cells (HSCs) leads to bone marrow failure or hematologic malignancy. However, how HSCs sustain their quiescent state and avoid type I interferon (IFN) mediated exhaustion remains elusive. Here we defined a circular RNA that we named cia-cGAS that was highly expressed in the nucleus of long-term (LT)-HSCs. Cia cGAS deficiency in mice caused elevated expression of type I IFNs in bone marrow and led to decreased numbers of dormant LT-HSCs. Under homeostatic conditions, cia-cGAS bound DNA sensor cGAS in the nucleus to block its synthase activity, thereby protecting dormant LT-HSCs from cGAS-mediated exhaustion. Moreover, cia cGAS harbored a stronger binding affinity to cGAS than self-DNA did and consequently suppressed cGAS-mediated production of type I IFNs in LT-HSCs. Our findings reveal a mechanism by which cia-cGAS inhibits nuclear cGAS by blocking its enzymatic activity and preventing cGAS from recognizing self-DNA to maintain host homeostasis. PMID- 29625898 TI - Palliative thoracic radiation therapy for non-small cell lung cancer: 2018 Update of an American Society for Radiation Oncology (ASTRO) Evidence-Based Guideline. AB - PURPOSE: To revise the recommendation on the use of concurrent chemotherapy (CC) with palliative thoracic external beam radiation therapy (EBRT) made in the original 2011 American Society for Radiation Oncology guideline on palliative thoracic radiation for lung cancer. METHODS AND MATERIALS: Based on a systematic PubMed search showing new evidence for this key question, the task force felt an update was merited. Guideline recommendations were created using a predefined consensus-building methodology supported by American Society for Radiation Oncology-approved tools for grading evidence quality and recommendation strength. RESULTS: Although few randomized clinical trials address the question of CC combined with palliative thoracic EBRT for non-small cell lung cancer (NSCLC), a strong consensus was reached among the task force on recommendations for incurable stage III and IV NSCLC. For patients with stage III NSCLC deemed unsuitable for curative therapy but who are (1) candidates for chemotherapy, (2) have an Eastern Cooperative Oncology Group PS of 0 to 2, and (3) have a life expectancy of at least 3 months, administration of a platinum-containing chemotherapy doublet concurrently with moderately hypofractionated palliative thoracic radiation therapy is recommended over treatment with either modality alone. For patients with stage IV NSCLC, routine use of concurrent thoracic chemoradiation is not recommended. CONCLUSIONS: Optimal palliation of patients with incurable NSCLC requires coordinated interdisciplinary care. Recent data establish a rationale for CC with palliative thoracic EBRT for a well-defined subset of patients with incurable stage III NSCLC. For all other patients with incurable NSCLC, data remain insufficient to support this treatment approach. PMID- 29625899 TI - Safety and feasibility of elective liver resection in adult Jehovah's Witnesses: the Henri Mondor Hospital experience. AB - BACKGROUND: Elective liver resection (LR) in Jehovah's Witness (JW) patients, for whom transfusion is not an option, involves complex ethical and medical issues and surgical difficulties. METHODS: Consecutive data from a LR program for liver tumors in JWs performed between 2014 and 2017 were retrospectively reviewed. A systematic review of the literature with a pooled analysis was performed. RESULTS: Ten patients were included (median age = 61 years). None needed preoperative erythropoietin. Tumor biopsy was not performed. Major hepatectomy was performed in 4 patients. The median estimated blood loss was 200 mL. A cell saver was installed in 2 patients, none received saved blood. The median hemoglobin values before and at the end of surgery were 13.4 g/dL and 12.6 g/dL, respectively (p = 0.04). Nine complications occurred in 4 patients, but no postoperative hemorrhage occurred. In-hospital mortality was nil. Nine studies including 35 patients were identified in the literature; there was reported no mortality and low morbidity. None of the patients were transfused. CONCLUSIONS: By using a variety of blood conservation techniques, the risk/benefit ratio of elective liver resection for liver was maintained in selected adult JW patients. JW faith should not constitute an absolute exclusion from hepatectomy. PMID- 29625900 TI - ADAR1 and PKR, interferon stimulated genes with clashing effects on HIV-1 replication. AB - The induction of hundreds of Interferon Stimulated Genes (ISGs) subsequent to virus infection generates an antiviral state that functions to restrict virus growth at multiple steps of their replication cycles. In the context of Human Immunodeficiency Virus-1 (HIV-1), ISGs also possess antiviral functions, but some ISGs show proapoptotic or proviral activity. One of the most studied ISGs, the RNA activated Protein Kinase (PKR), shuts down the viral protein synthesis upon activation. HIV-1 has evolved to evade its inhibition by PKR through viral and cellular mechanisms. One of the cellular mechanisms is the induction of another ISG, the Adenosine Deaminase acting on RNA 1 (ADAR1). ADAR1 promotes viral replication by acting as an RNA sensing inhibitor, by editing viral RNA and by inhibiting PKR. This review challenges the orthodox dogma of ISGs as antiviral proteins, by demonstrating that two ISGs have opposing and clashing effects on viral replication. PMID- 29625901 TI - Megalopyge opercularis Caterpillar Stings Reported to Texas Poison Centers. AB - INTRODUCTION: The Megalopyge opercularis caterpillar is covered with spines that break off and release venom on contact, resulting in severe pain, erythema, rash, and other adverse effects. In Texas, these caterpillars are abundant and of potential health threat. This study describes M opercularis caterpillar stings reported to Texas poison centers. METHODS: Cases were M opercularis caterpillar stings reported to Texas poison centers during 2000-2016. The distribution of stings was determined related to exposure circumstances and management. RESULTS: There were 3484 M opercularis caterpillar stings reported during 2000-2016. The annual number of stings did not consistently change over the 17-year time period. The monthly number of stings was highest in July (12%) and October to November (59%). The patients were female in 53% of cases and aged 20 years or more in 56%. The sting occurred at the patient's own residence in 91% of cases. The patients were managed outside of a healthcare facility in 89% of cases; 93% of the patients were known or expected to have no or at most minor clinical effects. Dermal clinical effects were reported in 90% of cases, the most common being irritation/pain (84%), puncture/wound (45%), erythema/flushed (29%), and edema (15%). CONCLUSIONS: M opercularis caterpillar stings reported to Texas poison centers were more frequently reported in July and October to November. Most of the patients were adults. The majority of patients were managed outside of healthcare facilities and did not have serious outcomes. Most of the adverse clinical effects were dermal in nature. PMID- 29625902 TI - Anthropometrics in preoperative prediction of resection weight in reduction mammaplasty: Is it really accurate? PMID- 29625903 TI - Should microsurgery move away from our binary measures of success and is it time to embrace reconstructive failure as a true measure of our patient outcomes? PMID- 29625904 TI - The forgotten aspects of the quality of life of significant others of patients with a peripheral facial palsy. PMID- 29625905 TI - Myogenic oxidative imbalance interferes with antral motility in obese subjects. AB - BACKGROUND: Obesity is characterized by a systemic low-grade chronic inflammatory oxidative condition that affects vascular and cardiac smooth muscle relaxation. In human antrum, relaxation is mediated by vasoactive intestinal peptide (VIP) through cAMP and cGMP signaling pathways. A genome-wide association study has demonstrated an association between VIP and obesity. AIM: To evaluate smooth muscle activity in human obese antrum, both in in vitro preparations as well as in vivo. METHODS: Antral muscle strips and cells were isolated from surgical gastric samples from obese and normal weight subjects. Muscle contraction and relaxation, myogenic oxidative stress and inflammatory status were analyzed in vitro. Distal antral motility was evaluated in vivo by magnetic resonance imaging. RESULTS: Obese antral muscle cells showed an oxidative-inflammatory imbalance with overexpression of NLRP3 inflammasome, increased IL-1beta secretion and caspase1-activation, and reduced antioxidant capacity associated with a myogenic motor impairment of VIP-induced relaxation. The intracellular alterations were characterized by a decreased activation of the cAMP-signaling pathway and a decreased expression of eNOS. These in vitro alterations coincided with the hindering of antral motor activity observed in vivo. Apocynin treatment, counteracting oxidative stress, reverted alterations observed in obese antral muscle. CONCLUSION: Antral myogenic activity of obese subjects can be impaired by alterations of signaling pathways induced by oxidative stress. PMID- 29625906 TI - Tenofovir disoproxil fumarate-induced severe liver injury in a patient with chronic hepatitis B virus infection. PMID- 29625907 TI - Adalimumab treatment of anti-TNF-naive patients with ulcerative colitis: Deep remission and response factors. AB - BACKGROUND: Adalimumab is the second tumour necrosis factor antagonist (anti-TNF) adopted for the treatment of ulcerative colitis. Clinical data from naive patients are scarce. AIM: Examine the response to adalimumab in TNF-antagonist naive patients. METHODS: This multicentre, observational, prospective study was conducted using a cohort of consecutive patients with ulcerative colitis. Clinical remission, mucosal healing and deep remission were examined employing the Mayo Score and Mayo Endoscopic Score. Clinical response was assessed using the Partial Mayo Score. RESULTS: Of 53 individuals included in this study, 49.1% of patients were in clinical remission at week 8 and 60.3%, at week 52. Clinical response was observed in 84.9% and 69.8%, respectively. Mucosal healing was found in 62.3% and 67.9% of the patients, and 43.4% and 58.4% showed deep remission at week 8 and 52, respectively. After a year, 71.7% of the patients continued the adalimumab treatment. Adverse effects were observed in 28.3% of patients. Multivariate analysis showed that the long-term factor predictive of response at week 52 was the response in week 8 (expressed as Mayo Score; OR 0.66; 95% IC 0.1 0.67, p < 0.006). CONCLUSIONS: Adalimumab treatment of ulcerative colitis is effective; the results are better in clinical practice and in patients naive to anti-TNF. PMID- 29625908 TI - Sprue-like enteropathy, do not forget olmesartan! PMID- 29625909 TI - An unusual primary hepatic lymphoma. PMID- 29625910 TI - Corrigendum to "Differences in liver stiffness values obtained with new ultrasound elastography machines and fibroscan: A comparative study" [Dig. Liver Dis. 49 (2017) 802-808]. PMID- 29625911 TI - Specialized Second Opinion Interpretations of Breast Imaging: Impact on Additional Workup and Management. AB - BACKGROUND: Women with breast imaging often seek second opinions at tertiary care centers. Our study measures the frequency of discrepancy between initial and second opinion breast imaging recommendations and evaluates the impact on patient management. MATERIALS AND METHODS: A retrospective chart review was conducted on 504 consecutive patients with second opinion breast radiology interpretations performed by 6 sub-specialized breast radiologists at a dedicated cancer center from January 1, 2014 through September 1, 2014. Outside imaging reports were compared with second opinion reports to categorize discrepancies. Interpretations were considered discrepant in cases with Breast Imaging Reporting and Data System (BI-RADS) category changes, recommendation for additional imaging, or identification of previously undiagnosed additional extent of disease greater than 5 cm. The frequencies of discrepancy, alterations in surgical management, and incremental cancer detection were measured. Statistical analysis of associated factors was performed with the Fisher exact test, with a P-value < .05 considered significant. RESULTS: Second opinion evaluation discrepancies were seen in 287 (57%) patients and resulted in percutaneous image-guided biopsies in 92 (18%). Forty-five additional sites of cancer were biopsy-detected in 41 (8%) patients, including 20 breast malignancies and 25 axillary metastases. Another 9 biopsies yielded high-risk pathology. Second opinion interpretations altered surgical management in 66 (13%) patients. Factors associated with increased discrepancy frequency were cancer diagnosis at presentation (P = .004), dense breasts (P = .005), and the absence of prior studies for comparison (P = .007). CONCLUSION: Although additional imaging and resources are required, second opinion radiology review by subspecialized breast radiologists increases cancer detection and results in clinically relevant changes in patient management. PMID- 29625912 TI - Integrating a health information exchange into a community pharmacy transitions of care service. AB - OBJECTIVE: To describe the incorporation of a state health information exchange (HIE) into a community pharmacy transitions of care (TOC) service and to assess its impact on 30-day readmission rates. SETTING: Three suburban community pharmacies in Olathe, Kansas. PRACTICE DESCRIPTION: Balls Food Stores is a grocery store chain which operates 21 supermarket community pharmacies in the Kansas City metropolitan area. PRACTICE INNOVATION: Balls Food Stores launched a pharmacist-led self-referral TOC study in which a state HIE was utilized to collect discharge information from patients' electronic medical records (EMRs) to facilitate TOC comprehensive medication reviews (CMRs). EVALUATION: Descriptive statistics were used to assess types and outcomes of identified drug therapy problems and the ability to access Kansas Health Information Network EMRs. A chi square test was used to assess 30-day readmissions between patients who accepted and declined the service. RESULTS: Forty patients were identified for inclusion and 18 elected to participate in the service. The majority of participants were white females with a median age of 64.5 years. Out of 40 study patients, 85% had an EMR available; 12.5% of patients had a medication list included in their EMR hospitalization documentation. Participants who underwent the service had a statistically significantly lower rate of overall 30-day hospital readmission than those who declined (11.1% vs 36.4%, P = 0.032). Among the 18 TOC CMRs performed, 90 drug therapy problems were identified and 77 were resolved in collaboration with a patient, caregiver, or physician. CONCLUSION: Incorporation of a state HIE into a community pharmacist-led TOC service is a novel strategy for collecting patient data. During the study, no TOC participants were readmitted within 30 days. However, pharmacists found HIE data alone was insufficient to perform TOC CMRs for the majority of participants. In order to expand state HIE utilization, more health systems will need to upload a minimum standard data set to help facilitate care. PMID- 29625913 TI - What is the association between social capital and diabetes mellitus? A systematic review. AB - Social capital has been included as an element that could influence the self perception of health, mortality and mental diseases. We systematically reviewed papers that studied the influence of social capital in the control of diabetes mellitus (DM). We included studies published up to Feb. 16, 2017, without restriction of time or year of publication. Quantitative studies were included since they presented one well-defined parameter to evaluate DM and specifically measured social capital. We used the PRISMA and STROBE guidelines to perform this review and to evaluate the quality of papers. Only three papers met the inclusion criteria. All studies adopted cross-sectional design. The population, the instruments used to measure social capital, and the statistical analysis were different among the papers. In conclusion, although social capital seems to be related to DM, more studies are necessary to understand which dimensions are more important in this association, if the association is the same at the individual or neighborhood level, and what kind of population in terms of education, poverty and culture would be more influenced by social capital in DM control. PMID- 29625914 TI - Maternal Food-Related Practices, Quality of Diet, and Well-Being: Profiles of Chilean Mother-Adolescent Dyads. AB - OBJECTIVE: To identify mother-adolescent dyad profiles according to food-related parenting practices and to determine differences in diet quality, family meal frequency, life satisfaction, and sociodemographic characteristics. DESIGN: Cross sectional study. SETTING: Mothers and children were surveyed in their homes or at schools in Temuco, Chile. PARTICIPANTS: A total of 300 mothers (average age, 41.6 years) and their adolescent children (average age, 13.2 years; 48.7% female). MAIN OUTCOME MEASURES: Maternal feeding practices using the abbreviated Family Food Behavior Survey (AFFBS), life satisfaction, food-related and family life satisfaction, diet quality, and eating habits. ANALYSIS: Principal component factor analysis and confirmatory factor analysis were used to verify Family Food Behavior Survey components in mother and adolescent subsamples. Hierarchical cluster analysis was used to identify profiles. RESULTS: Three AFFBS components were detected: maternal control of child snacking behavior, maternal presence during eating, and child involvement in food consumption. Cluster analysis identified 3 mother-adolescent dyad profiles with different food-related parenting practices (P <= .001), mother (P <= .05) and child (P <= .001) diet quality, frequency of shared family meals (P <= .001), and mother (P <= .001) and child (P <= .05) life satisfaction levels. CONCLUSIONS AND IMPLICATIONS: Results indicated that maternal well-being increased with an increased frequency of shared mealtime. Significantly, in contrast to the findings of previous studies, greater control over child eating habits was shown to affect adolescent well being positively. These findings, among others, may contribute to the development of strategies for improving diet quality, overall well-being, and well-being in the food and family domains for all family members. PMID- 29625915 TI - Healthy Choices for Every Body Adult Curriculum Improves Participants' Food Resource Management Skills and Food Safety Practices. AB - OBJECTIVE: To evaluate the impact of the University of Kentucky's Healthy Choices for Every Body (HCEB) adult nutrition education curriculum on participants' food resource management (FRM) skills and food safety practices. METHODS: A quasi experimental design was employed using propensity score matching to pair 8 intervention counties with 8 comparison counties. Independent-samples t tests and ANCOVA models compared gains in FRM skills and food safety practices between the intervention and comparison groups (n = 413 and 113, respectively). RESULTS: Propensity score matching analysis showed a statistical balance and similarities between the comparison and intervention groups. Food resource management and food safety gain scores were statistically significantly higher for the intervention group (P < .001), with large effect sizes (d = 0.9) for both variables. The group differences persisted even after controlling for race and age in the ANCOVA models. CONCLUSIONS AND IMPLICATIONS: The HCEB curriculum was effective in improving the FRM skills and food safety practices of participants. PMID- 29625916 TI - Agreement between invasive blood pressures measured in three peripheral arteries in anaesthetized horses under clinical conditions. AB - OBJECTIVE: To determine agreement between invasive blood pressures measured in three peripheral arteries in anaesthetized horses undergoing elective surgery. STUDY DESIGN: Prospective balanced incomplete block design. ANIMALS: A total of 18 client-owned horses. METHODS: Invasive blood pressure (IBP) was measured simultaneously in one of the following three combinations: 1) transverse facial and facial artery; 2) transverse facial and metatarsal artery; and 3) facial and metatarsal artery. The agreement in blood pressure measured for each combination was performed in six horses. At each sample time, systolic (SAP), mean (MAP) and diastolic (DAP) arterial pressures were measured concurrently in each artery, and the mean of three consecutive measurements was recorded. The position of horse, heart rate and use of dobutamine were also recorded. Bland-Altman analysis was used to assess agreement between sites. RESULTS: A total of 54 paired measurements were obtained, with 18 paired measurements from each combination. All paired measurements showed poor and haphazard (nonsystematic) agreement. The widest limit of agreement was 51 mmHg for SAP measured in the facial artery and metatarsal artery, with a bias of -11 mmHg. The smallest limit of agreement was 16 mmHg for MAP measured in the transverse facial and metatarsal artery, with a bias of 1 mmHg. CONCLUSIONS AND CLINICAL RELEVANCE: There was poor and haphazard agreement for SAP, MAP and DAP measured in each pair of peripheral arteries in this study. These results show that blood pressure measured in different peripheral arteries cannot be used interchangeably. This has implications for studies that use IBP as an outcome variable and studies determining agreement between noninvasive blood pressure and IBP measurements in horses under general anaesthesia. PMID- 29625917 TI - Alfaxalone anaesthesia in Lemur catta following dexmedetomidine-butorphanol midazolam sedation. AB - OBJECTIVE: To evaluate the clinical effects and quality of sedation, induction, maintenance and recovery in Lemur catta after dexmedetomidine-butorphanol midazolam sedation and alfaxalone anaesthesia. STUDY DESIGN: Prospective, observational study. ANIMALS: Six male L. catta weighing 3.0 +/- 0.6 kg undergoing surgical castration. METHODS: Lemurs were sedated with intramuscular dexmedetomidine (0.015 mg kg-1), butorphanol (0.2 mg kg-1) and midazolam (0.2 mg kg-1). Anaesthesia was induced with intravenous alfaxalone 0.5 mg kg-1 over 60 seconds; further boluses were administered until tracheal intubation was feasible and final dose recorded. Alfaxalone continuous infusion was used to maintain anaesthesia. Atipamezole (0.15 mg kg-1) was administered during recovery. The quality of sedation, induction, intubation, maintenance and recovery was assessed using a scoring system. Physiological parameters were recorded during sedation, maintenance and recovery. RESULTS: Sedation was achieved in 13.6 +/- 5.6 minutes and no reactions were observed during handling or venepuncture. The mean dose of alfaxalone required for induction and maintenance was 2.09 +/- 0.65 and 0.08 +/- 0.02 mg kg-1 minute-1, respectively. Quality of induction, intubation and maintenance was good in almost all animals. Mild self-limiting muscle twitching was observed after alfaxalone administration in three animals. Cardiorespiratory function was stable in all animals but one. One lemur showed respiratory depression and required oxygen administration and manual ventilation. The mean maintenance time was 29.2 +/- 7.4 minutes. The mean times from the end of alfaxalone administration to extubation, atipamezole administration and full recovery were: 15.3 +/- 8.0, 22.2 +/- 4.6 and 60.0 +/- 8.4 minutes, respectively. Recovery was considered good in all animals. CONCLUSIONS AND CLINICAL RELEVANCE: Dexmedetomidine-butorphanol-midazolam combination provided reliable sedation and adequate muscle relaxation in L. catta. Alfaxalone proved to be a useful drug for induction and maintenance of anaesthesia and might be considered an option for injectable anaesthesia in lemurs. PMID- 29625918 TI - In response to 'Stress-related biomarkers in dogs administered regional anaesthesia or fentanyl for analgesia during stifle surgery': A comment. PMID- 29625919 TI - Ultrasound-guided lateral and subcostal transversus abdominis plane block in calves: a cadaveric study. AB - OBJECTIVE: To describe and assess the ultrasound-guided transversus abdominis plane (TAP) block feasibility in calf cadavers, to compare two injection volumes and to evaluate possible undesired solution spreads. STUDY DESIGN: Prospective, descriptive, anatomic study. ANIMALS: A group of 15 bovine cadavers weighing 47+/ 11 kg (mean+/-standard deviation). METHODS: Lateral (n = 24) and subcostal (n = 12) TAP block approaches were assessed. For each approach, two volumes (0.2 or 0.4 mL kg-1) of toluidine blue and contrast medium were injected using both sides of the animals. Nerve staining was assessed by anatomical dissection and spread of injectate by contrast-enhanced computed tomography. Objective and subjective technique feasibility was evaluated by a specific score (poor, good, excellent). RESULTS: Using the lateral approach, 58%, 92% and 25% and 75%, 83% and 25% of the thirteenth thoracic, first and second lumbar nerves were stained by 0.2 and 0.4 mL kg-1, respectively. Craniocaudal and dorsoventral solution spread and number of blocks that adequately stained an individual nerve were not significantly different between the volumes. Using the subcostal approach, 67%, 83%, 67%, 67% and 50%, and 83%, 100%, 83%, 83% and 50% of the eighth, ninth, tenth, eleventh, twelfth thoracic nerves were stained by 0.2 and 0.4 mL kg-1, respectively. With both techniques, no intraspinal and one intraperitoneal spread were observed. Objective and subjective feasibility score was excellent for both approaches in the majority of the cases. CONCLUSIONS AND CLINICAL RELEVANCE: TAP injections were easy to perform with both techniques in calf cadavers. The volume of injectate did not influence spread. The authors conclude that a combination of the two approaches is necessary, but perhaps not sufficient, to stain all of the nerves innervating the ventral abdominal wall. Further studies are required to refine the technique and evaluate its efficacy in preventing nociception in calves. PMID- 29625920 TI - Simultaneous detection of Theileria annulata and Theileria orientalis infections using recombinase polymerase amplification. AB - Theileriosis is a disease of domesticated animals in tropical and subtropical countries and causes significant reductions in livestock productivity. The arid region of Punjab in Pakistan is notorious for the presence of the vector tick (Acari: Ixodidae) and tick-borne diseases, such as theileriosis and babesiosis. The distribution of Theileria annulata and T. orientalis in the Chakwal district of Punjab was determined by developing a multiplex recombinase polymerase amplification (RPA) assay as a scientific basis for formulating control strategies for bovine theileriosis. Specificity was evaluated using DNA from related piroplasm species, while analytical sensitivity was calculated using a long fragment of the enolase gene. A total of 188 blood samples were collected on FTA cards (Whatman(r)) from tick-infested asymptomatic breeds of cattle (Bos indicus, Bos taurus, and Bos indicus * Bos taurus) in the study district. Finally, infections with of T. annulata and T. orientalis were detected using the multiplex RPA and compared with the conventional multiplex polymerase chain reaction (PCR). The multiplex RPA specifically amplified 282-bp and 229-bp fragments of the enolase gene from T. annulata and T. orientalis and had no cross reaction with other piroplasm species. It was determined that 45 (23.9%) and 5 (2.6%) out of 188 blood samples were positive for T. annulata and T. orientalis, respectively, when examined using RPA. Multiplex PCR detection indicated that 32 (17.0%) and 3 (1.6%) blood samples were positive for T. annulata and T. orientalis, respectively. In the present study, a specific RPA method was developed for simultaneous differentiation and detection of T. annulata and T. orientalis infections and used for the first time for the detection of the two bovine Theileria infections. PMID- 29625921 TI - Integrative taxonomy of Afrotropical Ornithodoros (Ornithodoros) (Acari: Ixodida: Argasidae). AB - Afrotropical Ornithodoros (Ornithodoros) ticks are revised based on qualitative morphology of females and nymphs, as well as tarsus I shape outlines of females measured in a geometric morphometric framework. These lines of evidence corroborate lineages based on 16S rRNA nucleotide sequence data. Four previously unrecognized species are described, along with a revived nomen nudum that was previously considered a synonym. Afrotropical Ornithodoros (Ornithodoros) now comprise ten species. Ornithodoros moubata and Ornithodoros porcinus are separated from three other species in southern Africa (Ornithodoros compactus, Ornithodoros phacochoerusn. sp., Ornithodoros waterbergensisn. sp.), with O. porcinus restricted to central east Africa. Known species boundaries for Ornithodoros apertus and O. compactus are supported. Ornithodoros savignyi are separated from three other species in South Africa and Namibia, with O. savignyi restricted to north Africa. Neumann's Ornithodoros pavimentosusnom. rev. are resurrected from synonymy as a species that occur in Bushmanland, Namaqualand and Namibia, while Ornithodoros kalahariensisn. sp. occur in Kalahari thornveld, and Ornithodoros noorsveldensisn. sp. occur in Noorsveld thicket of South Africa. Detailed descriptions are given for each species along with high resolution images and point map distributions. Support is provided for speciation driven by riverine barriers, Pliocene uplift and differential arid tolerance. Exaggerated tarsus I shape in the O. savignyi group suggests adaptation to fossorial habits and soil type. Conversely, reduced tarsus I shape in the O. moubata group is suggested as an evolutionary consequence of the life history change from soil to warthog burrows. This study represents an integrative (iterative) approach to delimiting Afrotropical Ornithodoros (Ornithodoros) species, and provides the first application of tarsus I shape outlines in a geometric morphometric framework for testing species boundaries. PMID- 29625922 TI - New records of tick-associated spotted fever group Rickettsia in an Amazon Savannah ecotone, Brazil. AB - Human rickettsiosis has been recorded in the Amazon Biome. However, the epidemiological cycle of causative rickettsiae has not been fully accounted for in the Amazon region. This study investigates the presence of spotted fever group (SFG) Rickettsia spp. in free-living unfed ticks of the Amblyomma genus. The study was conducted in seven municipalities in Rondonia State, Brazil, where the main biomes are Amazon forest, Brazilian Savannah and their ecotones (areas of ecological tension between open ombrophilous forest and savannah). The following tick species were collected: Amblyomma cajennense (sensu lato) s.l., A. cajennense (sensu stricto) s.s., A. coelebs, A. naponense, A. oblongoguttatum, A. romitii, A. scalpturatum and A. sculptum. A total of 167 adults, 248 nymphs and 1004 larvae were subjected to DNA extraction and polymerase chain reaction (PCR) to determine the presence of SFG Rickettsia spp. PCR-positive samples included: one A. cajennense s.s. female and one A. cajennense s.l. male from a rural area in Vilhena Municipality; 10 nymphs and a sample of larvae of A. cajennense s.l. from a peri-urban area in Cacoal Municipality; and an A. oblongoguttatum adult male from a rural area of Pimenta Bueno Municipality. All sequences obtained exhibited 100% identity with Rickettsia amblyommatis sequences. This is the first confirmation of SFG Rickettsia in an A. oblongoguttatum tick. Furthermore, this is the first record of SFG Rickettsia in the municipalities targeted by this study. These results warn that SFG Rickettsia circulation poses a threat in Rondonia State (among Amazon-Savannah ecotones), and that this threat is increased by the fact that SFG Rickettsia infect a human-biting tick species hitherto unconfirmed as a vector. PMID- 29625923 TI - Wilson's disease: A 2017 update. AB - Wilson's disease (WD) is characterised by a deleterious accumulation of copper in the liver and brain. It is one of those rare genetic disorders that benefits from effective and lifelong treatments that have dramatically transformed the prognosis of the disease. In Europe, its clinical prevalence is estimated at between 1.2 and 2/100,000 but the genetic prevalence is higher, at around 1/7000. Incomplete penetrance of the gene or the presence of modifier genes may account for the difference between the calculated genetic prevalence and the number of patients diagnosed with WD. The clinical spectrum of WD is broader as expected with mild clinical presentations and late onset of the disease after the age of 40 in 6% of patients. WD is usually suspected when ceruloplasmin and serum copper levels are low and 24h urinary copper excretion is elevated. Recently, a major diagnostic advance was achieved with implementation of the direct assay of "free copper", or exchangeable copper (CuEXC). The relative exchangeable copper (REC) that corresponds to the ratio between CuEXC and total serum copper enables a diagnosis of WD with high sensitivity and specificity when REC>18.5%. Moreover, CuEXC values at diagnosis are a marker of extrahepatic involvement and its severity. A value of >2.08MUmol/L is suggestive of corneal and brain involvement (Se=86%, Sp=94%), and the disease will be more clinically and radiologically severe as values rise. The use of FibroScan(r) is becoming more widespread to assess liver stiffness measurements in WD patients. 6.6kPa is considered to be a threshold value between mild and moderate fibrosis, whereas a value higher than 8.4 is indicative of severe fibrosis. More studies are now necessary to confirm the usefulness of Fibroscan(r) in managing chronic therapy for WD patients. Treatment of this disease is based on an initial active and prolonged chelating phase (with D-Penicillamine or Trientine) followed by maintenance with Trientine or zinc salt. The two major problems that may be encountered are neurological worsening during the initial phase and non-compliance with treatment during maintenance therapy. Liver transplantation is the recommended therapeutic option in WD with acute liver failure or end-stage liver cirrhosis; its indication should be considered when neurological status deteriorates rapidly despite effective chelation. Regular clinical, biological and liver ultrasound follow-up is essential to evaluate efficacy, tolerance and treatment compliance, but also to detect the onset of hepatocellular carcinoma on a cirrhotic liver. There are hopes in the near future with the introduction of a new chelator and inhibitor of copper absorption, tetrathiomolybdate (TTM) and the development of gene therapy. PMID- 29625924 TI - Crohn's disease treatment practices in France in1999-2013: A prospective survey in non-academic hospitals. AB - AIMS: To describe the characteristics of patients with Crohn's disease (CD) in non-academic hospitals in France and to evaluate how therapeutic practices changed between 1999 and 2013. METHODS: During 2 weeks in September 2013, we solicited disease and treatment information for CD patients seen by gastroenterologists in 57 French non-academic hospitals. In four groups of patients defined according to the date of CD diagnosis (<1999, 1999-2003, 2004 2008, and 2009-2013), the use of immunosuppressor (IS) and anti-TNF treatments during the first 5 years following diagnosis of CD was compared using the Kaplan Meier method. RESULTS: 739 consecutive CD patients (median age at diagnosis 25.4 years) were included in the survey. CD location was ileal for 31%, colonic for 21%, and ileocolonic for 45%. CD phenotypes were non-penetrating/non-stricturing (58.7%), stricturing (26.9%), and penetrating (12.7%), with perianal lesions in 26.1%. The proportions of patients who began IS or anti-TNF treatment within 5 years of diagnosis increased significantly from 18% and 0%, respectively, in <1999 (n=170) to 52% and 23% in 1999-2003 (n=120), 66% and 70% in 2004-2008 (n=155), and 75% and 100% in 2009-2013 (n=294; P<0.0001). CONCLUSIONS: In this French non-academic hospital cohort of CD patients, the proportions of patients being treated with anti-TNF or IS therapy in the first 5 years after diagnosis both increased sharply since 1999. PMID- 29625925 TI - Pancreatic and gastric heterotopic tissue presenting as a symptomatic gallbladder mass: A case report and literature review. AB - Pancreatic and gastric heterotopia is an uncommon congenital anomaly in which gastric and/or pancreatic tissue is found outside of its anatomic location. In the majority of patients, lesions are found incidentally because they tend to be asymptomatic. However, lesions may become symptomatic when inflammation, obstruction, and bleeding occurs. Depending on tissue size and location they can harvest a landscape of nonspecific symptoms, causing a delay in diagnosis. Heterotopic tissue of either gastric or pancreatic origin have been reported in literature, however the presence of combined gastric and pancreatic heterotopic tissue is exceedingly rare. We report a case of an 18-year-old female with polypoid gastric and pancreatic heterotopia and focal intestinal metaplasia of the gallbladder with clinical findings of acute cholecystitis. In this literature review, we synthesize the clinical significance, histopathological features, diagnosis and management of pancreatic and gastric heterotopic tissue. PMID- 29625926 TI - Oral Pharmacologic Management of Overactive Bladder Syndrome: Where Do We Stand? AB - Overactive bladder syndrome (OAB) is a prevalent disorder with a significant impact on quality of life. Despite this high prevalence, there is significant underdiagnosis and undertreatment due to several barriers, including embarrassment, poor communication and low patient adherence. Currently, various antimuscarinic are available in the treatment of OAB. The introduction of mirabegron has broadened the therapeutic approach and combination therapy of both agents can be valuable in clinical practice. Yet, patient adherence to most drugs for OAB is still relatively poor. Healthcare providers need to identify and utilise strategies to improve treatment adherence by defining clear treatment goals, implement educational methods and frequently communicate with patients to identify problems with adherence. The elderly population form need special attention as in these patients, anticholinergics should be prescribed with care and adequate knowledge regarding pharmacokinetics and drug interactions in essential. Furthermore, patient expectations should be clearly discussed. In this narrative review, the current advances in oral pharmacotherapy are evaluated and the most important factors involved in the management of OAB are discussed. PMID- 29625928 TI - Serum Free Light Chain Difference and beta2 Microglobulin Levels Are Risk Factors for Thromboembolic Events in Patients With AL Amyloidosis. AB - BACKGROUND: AL amyloidosis might increase the risk of thromboembolism and other plasma cell dyscrasias; however, only a few reports have described the clinical features of thromboembolism. The present study aimed to elucidate the clinical features of thromboembolic events and to identify the risk factors for these events. MATERIALS AND METHODS: The medical records were retrospectively reviewed to define the clinically significant thromboembolic events. RESULTS: A total of 106 patients with biopsy-proven AL amyloidosis were included. During a median follow-up of 18.1 months (range, 0.4-166.9 months), 13 thromboembolism events were identified in 13 patients. Of the 13 patients, 9 (8.5%) experienced acute cerebral infarction, 2 (1.9%) experienced pulmonary embolism, and 2 (1.9%) experienced deep vein thrombosis. Patients with a higher serum free light chain (FLC) difference (>= 172.4 mg/L) or beta2-microglobulin (beta2MG) levels (>= 2.78 mg/L) experienced significantly more thromboembolic events compared with those with a lower value according to multivariable analysis (for FLC difference: hazard ratio, 4.309; 95% confidence interval, 1.158-16.032; P = .029; for beta2MG: hazard ratio, 9.739; 95% confidence interval, 1.127-84.174; P = .039). Most thromboembolic events (11 of 13; 84.6%) occurred within the first year after the AL amyloidosis diagnosis. CONCLUSION: The incidence of thromboembolism was substantial in those with AL amyloidosis. A greater FLC difference and for beta2MG levels were risk factors for thromboembolic events. PMID- 29625927 TI - Tolerance, Kinetics, and Depth of Response for Subcutaneous Versus Intravenous Administration of Bortezomib Combination in Chinese Patients With Newly Diagnosed Multiple Myeloma. AB - BACKGROUND: Peripheral neuropathy (PN) is an important toxicity that limits the use of bortezomib (Btz). Attempts to reduce PN have included its subcutaneous (SC) administration. PATIENTS AND METHODS: We retrospectively analyzed 307 patients with newly diagnosed multiple myeloma from a single Chinese center, receiving Btz-based regimens administered either via SC injection (SC group, n = 167) or intravenous (IV) infusion (IV group, n = 140). The efficacy and safety of Btz administration via SC and IV were then compared. RESULTS: Most baseline characteristics were similar between these 2 groups. A lower frequency of adverse events, especially grade >= 3 PN (P = .002), was observed in the SC group compared with the IV group. The estimated median Btz dosage when PN developed was higher (20.8 mg/m2 vs. 15.6 mg/m2), and fewer patients reduced or discontinued Btz owing to adverse events in the SC group compared with the IV group. The overall response rate (>= partial response [PR]) was comparable (94.8% vs. 96.2%). However, patients in the IV group required fewer cycles to achieve PR, whereas a larger proportion of patients in the IV group achieved >= very good PR. After a median follow-up of 23 months (range, 1-84 months), no significant difference in median progression-free survival (not arrived vs. 33.0 +/- 2.735 months) and overall survival (not arrived vs. 56.0 months) was noted. CONCLUSION: SC Btz is associated with better tolerance; however, IV administration achieves a faster and deeper response in Chinese patients with newly-diagnosed multiple myeloma. PMID- 29625929 TI - Thiotepa 10 mg/kg Treatment Regimen Is Superior to Thiotepa 5 mg/kg in TBF Conditioning in Patients Undergoing Allogeneic Stem-Cell Transplantation. AB - INTRODUCTION: The optimal intensity of myeloablation with a reduced-toxicity conditioning regimen to decrease relapse rate after allogeneic stem-cell transplantation without increasing transplant-related mortality (TRM) has not been well established. MATERIALS AND METHODS: We compared outcomes between 5 mg/kg (T5) and 10 mg/kg (T10) thiotepa-based conditioning regimens in 29 adults who underwent allogeneic stem-cell transplantation for hematologic malignancies. RESULTS: After a median follow-up of 11 months, TRM was 0% and 14% at 100 days and 1 year, respectively, with TRM observed only in the T5 group (P = .016). The relapse incidence at 1 year was 20%. No patient had disease in first complete remission at the time of transplantation. At 1 year, progression-free and overall survival were 30% versus 87% (P = .012) and 46% versus 87% (P = .008) in the T5 and T10 groups, respectively. In univariate and multivariate analysis, only age at transplantation and total dose of thiotepa had a significant impact on TRM, overall, and progression-free survival. CONCLUSION: Patients deemed fit to receive T10-based conditioning for allogeneic stem-cell transplantation to treat high-risk hematologic malignancies had better overall and progression-free survival than those who received T5 with no additional toxicities. Patients should be stratified before conditioning, and those judged fit should receive T10, while the others should consider alternative reduced-intensity conditioning regimens. PMID- 29625930 TI - Cloning, expression and characterization of the maltooligosyl trehalose synthase from the archaeon Sulfolobus tokodaii. AB - The maltooligosyl trehalose synthase gene from the hyperthermophilic archaeon Sulfolobus tokodaii strain 7 was cloned and the recombinant peotein was expressed in E. coli. The protein was purified to homogeneity by nickel column chromatography. The archaeal enzyme could catalyze an intramolecular transglycosylation reaction and convert the glycosidic bond at the reducing end of dextrins from alpha-1, 4 (reducing end) into alpha-1, 1 (non-reducing end). The most suitable temperature was 75 degrees C and the optimal pH was 5. Substrate specificity investigation revealed that maltodextrin and maltooligosaccharide were used as substrates by the enzyme but maltose, chitooligosaccharide, sucrose and beta-cyclodextrin weren't used. PMID- 29625931 TI - Development and validation of a stability-indicating RP-HPLC-FLD method for determination of 5-[(4-chlorophenoxy) methyl]-1, 3, 4-oxadiazole-2-thiol; A novel drug candidate. AB - The present study describes the development and validation of a simple high performance liquid chromatographic method for the determination of a novel drug candidate, 5-[(4-chlorophenoxy) methyl]-1, 3, 4-oxadiazole-2-thiol. The stability indicating capacity of the method was evaluated by subjecting the compound's solution to hydrolytic, oxidative, photolytic, transition metal- and thermal- stress. The chromatographic separation was achieved over a C18 column (Promosil, 5 um, 4.60 * 250 mm), maintained at 25 degrees C, using an isocratic mobile phase comprising a mixture of acetonitrile and acidified water of pH 2.67 (1:1, v/v), at a flow rate of 1.00 mL/min and detection using a fluorescent light detector (excitation at 250 nm and emission at 410 nm). The Beer's law was followed over the concentration range 2.50-50.00 MUg/ml. The recovery (98.56-100.19%, SD <5%), intraday accuracy and precision (97.31-100.81%, RSD <5%), inter-day accuracy and precision (97.50-100.75%, RSD <5%) and intermediate accuracy and precision (98.10 99.91%, RSD <5%) indicated that the method was reliable, repeatable, reproducible and rugged. The resolution and selectivity factors of the compound's peak from the nearest resolving peak, particularly in case of dry heat and copper metal stress, were found to be greater than 2 and 1, respectively, which indicated specificity and selectivity. The compound was extensively decomposed in alkaline hydrolytic, oxidative, metal- and dry heat- stress. However, the compound in acidic and neutral conditions was resistant to photolysis. The results of the present study indicate that the developed method is specific, selective, sensitive and suitable, hence, may be used for quality control, stability testing and preformulation studies. PMID- 29625932 TI - Effect of caffeine on anti-clotting activity of warfarin in healthy male albino rabbits. AB - Drug-drug interactions are most commonly occurring phenomenon in clinical practice. Many physicians are afraid of being involved in an allegation of malpractices due to the occurrence of any severe interaction. These interactions not only occur between drugs but also between any kind of food, tobacco smoke, caffeine and alcohol etc. Therefore, the present study was directed to inspect the effect of caffeine on the anticoagulation activity of warfarin in healthy adult male albino rabbits. Blank blood samples were collected from each rabbit. Rabbits were given warfarin (0.5mg kg-1) orally via stomach tube and blood samples were collected in PT/INR vials at various intervals. After a washout period of 14 days, warfarin was orally administrated at same dose rate along with caffeine (5 mg kg-1 every twelve hours for three days) and same sampling schedule was repeated. Prothrombin time (PT) and the international normalized ratio (INR) of blood samples were determined to estimate changes in the anticoagulation activity of warfarin after its concurrent administration with caffeine. The PT data revealed that Rmax and AUC increased significantly (P<0.05) from 1991.6 and 60.5 to 2124.8 and 67.5, respectively, before and after co-administration. Similarly, a significant (P<0.05) increase was observed in Rmax and AUC of INR from 6.42 and 153.7 to 7.4 and 167.5, respectively, alone and along with caffeine. However, no change was observed in Tmax associated with PT and INR either the drug was administered alone or in combination with caffeine. It was concluded that caffeine has the capacity to inhibit the metabolism of warfarin and enhance its plasma concentration and hence anticoagulant effects. Thus, patients should be advised to limit the frequent use of caffeine-rich products i.e. tea and coffee during warfarin therapy. PMID- 29625933 TI - Prevalence of statin induced myopathy in Lahore, Pakistan. AB - Cardiovascular diseases are considered to be the leading cause of disability and deaths in the whole world. The major cause behind this disease is the formation of lipid plagues in the form of thrombus. The statins (HMG-CoA reductase inhibitors) are used for the treatment and prevention of hyperlipidemia. Myopathy is the major side effect caused by statins. The purpose of this study was to determine the prevalence of statin induced myopathy. A cross-sectional study design was adopted using convenient random sampling technique at Punjab Institute of Cardiology, Lahore Pakistan from November 2016 to February 2017. A total of 300 male and female patients were included having age range of 40-80 years. Data was collected directly from the patients and prevalence of myalgia was determined by the symptoms of the patients. Creatine Phospho Kinase levels were obtained of those patients showing symptoms. Data was analyzed by using SPSS version 21. The results showed that 51% patients were myalgic with mean+/-SEM, 1.49+/-0.29. Myalgia was more prevalent in age range 40-50, with females 57% and males 47%. Significant relation was found between myalgia and type of statin (p=0.05), duration of use of statin (p=0.036) and dose of statin (p=0.031). The study concludes that the prevalence of myalgia was not significant but females were more prone to myalgic symptoms as compared to males. It was further concluded that myalgic symptoms were directly related to dose and duration & type of statin use. PMID- 29625934 TI - Comparative antioxidant and antidiabetic effects of Syzygium polyanthumleaf and Momordica charantia fruit extracts. AB - The study was aimed to perform aqueous extraction of two plants using different extraction methods, and evaluate their antioxidant and antidiabetic potential. Plant materials were extracted by maceration, soxhlet, sonication and fresh juice methods to produce aqueous extracts. In vitro antioxidant DPPH (1,1-diphenyl-2- picrylhydrazyl) and FRAP (Ferric reducing antioxidant power), antidiabetic alpha amylase and alpha-glucosidase enzyme inhibitory assays were carried out on the extracts. Extracts of Syzygium polyanthum demonstrated better free radical scavenging and antidiabetic activity than Momordica charantia. It was observed that the % inhibition of DPPH by fresh juice of S. polyanthum was 64.93 similar to quercetin 69.21 (p>0.05). Its FRAP value (69.05) was significantly (p<0.05) higher than Quercetin (63.27). Its fresh juice alsodemonstrated significant inhibitory actions (p<0.05) against alpha-amylase (92.21%) and alpha-glucosidase (96.06%) than acarbose. It is concluded that extracts had varied results due to differences in their chemical composition as noticed in LC-MS. The fresh juice of S. polyanthum has superior in vitro antioxidant and antidiabetic activities. Therefore, intake of exogenous antioxidants in the form of fresh juices of someherbs can help the body toscavenge free radicals and exert hyperglycaemic control in post prandial hyperglycaemia. PMID- 29625935 TI - Antihyperglycemic effect of Conocarpus erectus leaf extract in alloxan-induced diabetic mice. AB - Synthetic drugs have widely been helpful in management of diabetes mellitus type 2. However, side effects associated with synthetic drugs serve as an impetus to explore plants as alternate mode of treatment. The hydroethanolic leaf extracts of Conocarpus erectus were evaluated for phenolic contents, flavonoid distribution, antioxidant activity and antidiabetic potential. The maximum extract yield, total phenolic and flavonoid contents were exposed by 60% ethanolic extract. The Antioxidant and anti alpha-glucosidase tendency of 60% ethanolic extract was the most promising and complemented by in-vivo antihyperglycemic impact on mice. The findings were substantial regarding suppression of blood glucose levels in alloxan induced diabetic mice establishing the Conocarpus erectus as proficient pool of nutraceuticals for diabetes mellitus type 2 management. PMID- 29625936 TI - Effects of superdisintegrants in oral dissolving formulation of cinitapride tablets. AB - The initiation of newer techniques and development of mouth dissolving (MD) products has created new avenues of higher patients' compliance. MD formulations are actually lessen the difficulties associated with solid swallowing with better bioavailability of especially poorly soluble drugs. In the current study mouth dissolving tablet (MDT) formulations of cinitapride (1 mg) were prepared by direct compression method using various proportion and combination of superdisintegrants. Nine formulations in three batches were compressed by incorporating low (2%), intermediate (6%) and higher (10%) levels of crospovidone, croscarmellose sodium, sodium starch glycolate. Micromeritic assessment of the powder blends were carried out and were found within the acceptable official limits. All newly developed trial formulations were exposed to different pharmacopoeial and non-pharmacopoeial testing. It was found that FC2 trial tablets containing polyplasdone XL(r) (crospovidone) at level of 6% (4.5 mg) presented the best physico-chemical attributes deemed to be desirable for the ODT products. Disintegration and wetting time of optimized FC2 was computed between 15-17 and 12-15 seconds respectively. The assay and content uniformity of FC2 were estimated to be 100.02+/-0.36 and 99.66+/-1.70 percent correspondingly. On the basis of the findings it was concluded that MDT could be successfully developed by incorporating appropriate concentration of superdisintegrant and their combinations. PMID- 29625937 TI - Prevention and treatment of osteoporosis caused by oestrogen shortage in rats. AB - Through castrated rats osteoporosis models, this study aims to explore whether the intraperitoneal injection of Scutellaria baicalensis extract could prevent the occurrence of osteoporosis and slow down/reverse osteoporosis or not, and further explore the influence on BMMSCs extracted by Scutellaria baicalensis extract. Scutellaria baicalensis extracts on the prevention and treatment of oestrogen shortage and osteoporosis. After the screening of appropriate concentration, in the model of castrated female rats with osteoporosis, rats in prevent group were given intraperitoneal injection of Scutellaria baicalensis extract within 1 week after the castration, and the rats in treatment group were injected Scutellaria baicalensis extract at the abdominal cavity in two months of castration. It required 2 times per week, 12 weeks in total, Micro CT scanning was performed respectively at 6th and 12th week on one side of the femur to compare the differences in bone mass and bone trabecular quantity, in order to evaluate the prevention and treatment of Scutellaria baicalensis extract in osteoporosis. After intraperitoneal injection of Scutellaria baicalensis extract, Micro CT results showed the animal bone mass and bone trabecular quantity in prevention and treatment group were increased compared to control group, while, it only reduced bone loss and restored bone mass to a certain extent. In this study, the small molecular compound with higher content of flavonoids through leaching, extraction, enrichment method from Traditional Chinese medicine radix scutellariae and could be utilized on the prevention and treatment of osteoporosis caused by rats castration. PMID- 29625938 TI - Evaluation of antibiotic resistant bacteria in underground drinking water and transfer of their resistant character to normal flora of the body. AB - The untreated surface water for drinking and domestic use is an alarming situation to public health especially in prevalence of antibiotics resistant bacteria. This investigation aimed to isolate and identify the antibiotic resistance bacteria in underground water samples in district Dera Ismail Khan, Pakistan. The underground water samples were collected from four different places using hand pumps (Khyber town, riverside, Gomal University and united town). Cultured on nutrient agar media, identified by Gam staining and biochemical tests. There after antibiotic resistance assay were performed by measuring zone of inhibition of different antibiotics by disc diffusion method. Six different bacterial colonies were isolated and identified as Enterobacteriaceae, Serriata specie, Proteues, Pseudomonas, all these bacterial colonies were 33% resistant to chloramphenicol with and 100% resistant to amoxicillin. Some colonies were also considered as resistant, according to the criteria of National Committee for Clinical Records (NCCL) that less than 10mm zone of inhibition are considered as resistant. Subsequently, the chloramphenicol resistance bacteria were analyzed for their ability to transfer resistant gene to sensitive bacteria. In in-vitro method, an isolate M1b (resistant) was found capable to transfer resistance gene to M1a isolate (sensitive) in nutrient rich environment. It was concluded that antibiotics resistance bacteria found in underground water, moreover capable of transferring the antibiotic resistant character to suitable recipient i.e. normal flora of the body or to other pathogens by conjugation. PMID- 29625939 TI - Ameliorative effect of hydro-methanolic extract from roots of Rauwolfia serpentina on some biochemical parameters of type 1 diabetic mice. AB - Present work seeks to investigate the biochemical parameters in terms of hypoglycemic and hypolipidemic effects of hydro-methanolic roots extract (HyMREt) of Rauwolfia serpentina in type 1 (alloxan induced) diabetic mice. Animals were divided into seven groups, four control groups, and three were test groups (HyMREt at 50, 100, & 150mg/kg). Each treatment was repeated for 14 days regularly in all seven respective groups and afterwards the body weights, fasting blood glucose (FBG), insulin, and serum lipid levels were determined. Total body weights of diabetic mice treated with HyMREt extract were dose dependently (p<0.05) improved. FBG of test groups were significantly (p<0.0001) reduced in comparison with diabetic controls which displayed elevated fasting blood glucose level. The insulin levels of HyMREt treated groups were significantly (p<0.0001) higher than those of diabetic controls. Lower triglyceride (TG), total cholesterol (TC), low density lipoprotein cholesterol (LDL-c) and very low density lipoprotein cholesterol (VLDL-c) whereas elevated level of high density lipoprotein cholesterol (HDL-c) were observed in test dose treated groups. In comparison with diabetic controls, the converse levels of serum lipid were observed. Significant improvement in cardio-protective indices and coronary risk index was also observed. Findings of present study support the hypoglycemic and hypolipidemic potential of HyMREt of R. serpentina. PMID- 29625940 TI - Incidence of drug interactions in intensive care units in tertiary care settings: Classification, facts and measures. AB - Drug-drug interactions (DDIs) are extremely significant concern, particularly in sensitive population including pediatric and geriatric. Propensity for the development of DDIs is high in patients admitted at intensive care units (ICU). This study was conducted to evaluate the DDIs incidence, facts and measures in ICU. From a total of 150 cases studied for ICU patients, with the mean age of 56.37+/-12.45 years, 55.33% were male and the rest were female 44.66%. The demographic information like age, gender and main diagnosis details of study participants that were extracted from the patients' clinical record. A statistically significant association between the drug interaction and the number of drugs prescribed per prescription was observed (p<0.0001). Concerning the onset of outcome, 52% of DDIs distinguished as delayed onset of effect (past 24 hours) and 35% were categorized as rapid onset (within 24 hours). Despite the facts regarding patient safety and minimizing DIs error, polypharmacy is still frequent in critically ill patients admitted in ICU attributed high risk of adverse reactions due to use of multiple interventions to treat severity of disease condition. Such studies may be used to develop an effective tool for the diagnosis and management of DDIs. PMID- 29625941 TI - Antioxidant capacity and polyphenolic content of the Echinocystis lobata (Michx.) Torr. et A.Gray flowers. AB - Echinocystis lobata (Michx.) Torr. et A.Gray is a spontaneous species in the Romanian flora, lesser studied by scientific literature, but which has proved significant activities in traditional medicine. The present study is aimed to provide data on the polyphenolic compounds in the composition of the flowers of this species and to test their biological potential. Polyphenols were identified and quantified using an HPLC-MS method. Tested biological activities were the cytotoxic, anti-plasmodial and antioxidant ones. Methods used for testing the antioxidant activity were the DPPH, CUPRAC, FRAP, TEAC, EPR and SNPAC assays. Cytotoxic activity was tested on cancerous and healthy cell lines and anti plasmodial activity was assesed on two strains of Plasmodium falciparum. Ethanolic extracts of the flowers of E. lobata proved to contain isoquercitrin, rutin, quercitrin, kaempferol, p-coumaric and ferulic acid. No cytotoxic and anti plasmodial activity was found, but antioxidant assays showed an important antioxidant capacity. The obtained results show that flowers of E. lobata are important sources of antioxidant compounds. It is the first approach of the kind on the flowers of this species and it offers a new perspective on possible sources of antioxidant compounds. PMID- 29625942 TI - Lethal toxic Dose (i.p LD50), total protein contents and comparative hemolytic potential of (99mTc labeled & non-labeled) Naja naja karachiensis venom. AB - Recent recognition about snake bite envenomation on June, 2017 as neglected tropical disease under category-A by World Health Organization advocated again its undeniable importance. Present circumstances reasoned to work on a neglected subspecies of Naja naja, i.e., Naja naja karachiensis (N. n. karachensis) has been documented for frequent deaths in Pakistan. In this study median lethal toxic dose (LD50) was determined intraperitoneally in Swiss albino mice and was found to be 2.0ug/g (2.0mg/kg) equal in potency to Naja pallida (red spitting African cobra). Total protein contents (188+/-0.011ug / 200ug of dry weight) were high enough (94%) to represent an arsenal of proteins. Furthermore, 99mTc was labeled 99.9% with venom and didn't find to alter hemolytic activity of venom in dose dependent manner at 125MUg/ml (p>0.5), 250 MUg/ml (p>0.1) and 500 MUg/ml (p>0.1) when compared with its crude form. Present work will pave the way for proteomics study in effective production of antidote against specific species of snakes as dare demand of it has been felt since long period of time in Pakistan. PMID- 29625943 TI - Drug utilization and prescribing pattern of antibiotics in a tertiary care setups; trends and practices. AB - Irrational, over and misuse of antibiotics arise as global concern in both hospital and community settings and lead to adverse events including antimicrobial resistance, associated health problems, amplified hospitalization stay and cost. Hence, Drug Utilization Evaluation (DUE) studies are designed to evaluate and improve the prescribing, administration and the rational use of medications. The present study was designed to assess the pattern of antimicrobial drug utilization in in-patients cohort of tertiary care setup in Karachi, Pakistan. This cross sectional observational study was conducted in retrospective manner. World health organization (WHO) guidelines and criteria are considered to evaluate the appropriateness of drug use in various disease conditions. ATC/DDD system was applied to determine the study outcome. High frequency of antibiotics utilization found in respiratory tract infections of both lower (LRTI) 16.8% (n=42) and upper (UTI) 13.2% (n=33). The estimated total number of drug units administered per month was greater with cefixime (46) and ciprofloxacin (45) both. DDD/100 bed days drug utilization of antibiotics was higher with ciprofloxacin, cefexime and meropenem (47, 46 and 29.25) correspondingly. In conclusion, the current investigation signifies extensive scope for progress in prescribing trend. Drug adherence to customary guidelines of disease management and constraint policies to endorse judicious drug use may be considered vital in healthcare setup. PMID- 29625944 TI - Prophylactic mechanisms of Cucumis melo var. flexuosus and Phoenix dactylifera fruit extracts against diabetic cardiomyopathy in streptozotocin induced diabetic rats. AB - The aim of this investigation was to study the antidiabetic impact of Cucumis melo var. flexuosus and/or Phoenix dactylifera fruit aqueous extracts and their mechanisms in repressing diabetes induced cardio-myopathy in diabetic rats. Type 2 diabetes was promoted in rats by a single intraperitoneal injection of streptozotocin (30mg/kg body wight). C. flexuosus and P. dactylifera extracts (200mg/kg body weight, each) were ingested to diabetic rats daily for a month. The results showed that ingestion of either plant extract or their combination to diabetic rats significantly diminished the glucose level and boosted the insulin concentration in the blood. The plant extracts markedly ameliorated the serum inflammatory molecules, tumor necrosis factor (TNF-alpha) and C -reactive protein (CRP), as well as the alteration in the cardiac malondialdehyde (MDA) and glutathione peroxidase (GPx). The extracts attenuated the increase in cardiac apoptosis enzyme (caspase -3) and the oxidative DNA fragmentation. Treating diabetic rats with plant extracts also scaled down the serum cardiac function enzyme, creatine phosphokinase-MB (CPK-MB). The biochemical results were confirmed by histopathological examination. This study has proven that both the plant extracts particularly their combination have potential hypoglycemic effect and could attenuate cardiomyopathy in diabetic rats. PMID- 29625945 TI - Structural and functional annotation of citrate synthase from Aspergillus niger ANJ-120. AB - Citrate synthase (CS) is involved in citric acid biosynthesis which is a well established metabolic pathway. The condensation of acetyl-CoA with oxaloacetate is catalyzed by CS. Citric acid (CA) has a number of applications in pharmaceutical industry. CA in combination with bicarbonates is used as an effervescent in the preparations of tablets and powders. It has also been used as an anticoagulant and acidulant to form mild astringent. In current study, detailed structural and functional analyses of CS protein were carried out using various bioinformatics tools. Structural modeling was also done by building 3D model of CS from Aspergillus niger ANJ-120 using Modeller 9.16 software. The 3D Model was then evaluated using different online approaches. Furthermore, superimposition of query and template structures, Root Mean Squared Deviation and visualization of generated model were done through UCSF Chimera 1.5.3. Even though various roles of CS protein were already known and verified experimentally, here we presented a structural analysis of CS protein. The structural investigation of CS protein will be helpful for protein engineering strategies and understanding the interactions among proteins. Due to large number of applications, the production of citric acid by A. niger and its bioinformatics studies will offer substantial improvement in commercial scale intensification of this useful product. PMID- 29625946 TI - Homeostasis model assessment of insulin resistance in non-diabetic heart failure patients: A case-control investigation at tertiary care Hospitals of Karachi. AB - eart failure is a progressive, chronic disorder. Insulin resistance (IR) has been more and more involved as a preliminary metabolic perturbance predisposing to hyperglycemia, hyperlipidemia and atherosclerosis with others heart diseases. To investigate the relation of insulin resistance (IR) in non-diabetic heart failure patients this case-control study was carried out to ascertain the presence of IR with the aid of Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) in non-diabetic heart failure patients (NDHF patients) compared with healthy controls. The sample size was calculated for both, cases (NDHF patients) and control (healthy subjects), which was initially consisted of 113 respondents each. The study consisted of two phase duration. In Phase I, NDHF patients were approached initially; only 80 patients with NDHF completed the study procedure. In Phase II, 80 healthy subjects were targeted and matched. Fasting blood glucose level (FBGL) and serum insulin was estimated. Mathematical model to quantify beta cell function and insulin resistance was also computed through Homeostasis Model Assessment of Insulin Resistance (HOMA-IR) in both groups. Data was analyzed on SPSS version 16. Mean values with +/- standard deviation (SD) of insulin (10.2+/ 4.36) and HOMA-IR (2.52+/-1.15) were significantly (p<0.05) higher in NDHF patients as compared to control subject (6.4+/-3.39, 1.45+/-0.80). Average insulin to glucose ratio was 0.10+/-0.044 in NDHF patients which was significantly (p<0.0001) lowered in controls i.e., 0.073+/-0.039. Marginal and matrix plot analysis revealed that a higher patients count have had the HOMA-IR values <1.5 units while opposite scenario was observed in control group. Regression analyses of HOMA-IR with FBGL (as independent indicator) also authenticate the similar pattern. The present study concludes that insulin resistance (decreased insulin sensitivity) is a characteristic finding in Pakistani population of heart failure as compared to matched healthy controls. PMID- 29625947 TI - Interaction of palladium inorganic salt and organic complex with glutathione content of liver homogenate. AB - Glutathione is an essential antioxidant of living organism that provides a primary protection against metals toxicity. A significant amount of glutathione is present in blood erythrocytes, plasma and liver hepatocytes to protect them from oxidative damage from both external and internal oxidants. Metalo-element palladium has numerous pharmacological, clinical and toxicological compensations, like palladium is used as anti-viral, anti-bacterial, neuro-protective and anti tumor agent. However studies have also indicated some mild to serious toxic effects of palladium metallo-elements. In the presence study the interaction of palladium inorganic salt and organic complex with glutathione (GSH) content of liver homogenate was examined spectro-photometrically. 20% (w/v) liver homogenate was prepared of the collected liver of rabbit in 5% TCA (tri-chloro-acetic acid) solution and 1mm EDTA, using a potter-eveljhem homogenizer with motor driven Teflon pestle. The GSH content quantification was carried out by Elman's method. Our finding showed that there was a depletion of GSH content by both palladium inorganic salts and organic complexes, concentrations wise as well as with time elapse as level of GSH content decrease from (43.6% to 72.62%) with Palladium Nitrate and from (24.09 to 59.5%) with Bis-benzonitrile Palladium II Chloride as compared to control, and further dropped with time incubation from 0-90 minutes from (49.7 to 87.1%), with Palladium Nitrate and from (29.3% to 67.6%) respectively. The result showed that the effect of both inorganic salt of palladium was more enhanced as compare to its organic complex. It was suggested from our finding that the depletion in the glutathione content of liver homogenate may be due to oxidation of glutathione or due to glutathione metal abduct formation by both inorganic salt and organic complex of palladium. This study in situ is a model of in vivo. PMID- 29625948 TI - Comparing the Diagnostic Accuracy of Simple Tests to Screen for Diabetic Peripheral Neuropathy: Protocol for a Cross-Sectional Study. AB - BACKGROUND: Various tests are used to detect diabetic peripheral neuropathy by assessing sense perception in the feet. Tests vary in terms of time and resources required. Simple tests are those that can be conducted quickly and easily in primary care without laboratory equipment. There are some limitations to these simple tests, an example being the variable amplitude of the 128 Hz tuning fork. A new test, VibraTip (McCallan Medical, UK), might be a valuable alternative as it emits a consistent amplitude and may offer improved diagnostic accuracy. OBJECTIVE: The aims of this study are to estimate the diagnostic accuracy of the VibraTip device for diabetic peripheral neuropathy against the reference standard of sural nerve conduction velocity measurement, and to assess whether the VibraTip offers superior diagnostic accuracy to other routine tests based on vibration or touch. METHODS: The study will prospectively recruit adults with type 2 diabetes who are due to attend a routine follow-up clinic. A cross sectional study design will be employed to assess the diagnostic accuracy of 5 standard index tests for peripheral neuropathy, including VibraTip. The reference test will be sural nerve conduction velocity measurement. RESULTS: Funding is being sought to conduct this research. The outcomes assessed will be the diagnostic accuracy of the 5 index tests against sural nerve conduction velocity measurement, including sensitivity, specificity, positive predictive value, negative predictive value, positive likelihood ratio, and negative likelihood ratio. Receiver operating characteristic curves will be constructed and compared for each test. CONCLUSIONS: This study will be the first within-study comparison of 5 simple tests for screening diabetic peripheral neuropathy and will address uncertainties in the potential benefits of using VibraTip in comparison with the other tests. PMID- 29625949 TI - Optimizing Electronic Consultation Between Primary Care Providers and Psychiatrists: Mixed-Methods Study. AB - BACKGROUND: The use of electronic consultation (e-consult) between primary care providers (PCPs) and psychiatrists has potential, given the high prevalence of mental health issues in primary care and problematic access to specialist care. Utilization and uptake, however, appears to be lower than would be expected. OBJECTIVE: This study aimed to examine actual utilization of e-consult between PCPs and psychiatrists and investigate the perceptions of PCPs about this form of psychiatric advice to inform how to optimize the utility and thereby the uptake of this service. METHODS: In this mixed-methods study, we conducted a chart review of psychiatry e-consults (N=37) over 2 platforms during early implementation in Ontario, Canada, as well as 3 group interviews and 1 individual interview with PCPs (N=10) with variable experience levels and from a range of practice settings. The chart review assessed response times and referral content including the type of request, referral attachments, and consultant responses. Interviews explored the perceptions of the PCPs about the uses and barriers of psychiatry e-consult. Thematic content analysis of interview data identified common themes as well as themes unique to different provider profiles (eg, experienced PCPs vs new PCPs and rural vs urban practice). On the basis of interpretation of the quantitative and qualitative findings, we developed recommendations for the optimization of psychiatry e-consultation services. RESULTS: During the study period, psychiatry e-consults comprised 3.66% (49/1339) of all e-consults submitted on the studied platforms. Among the e-consults reviewed, different psychiatric diagnoses were represented: 70% of requests (26/37) queried about medication safety or side effects, whereas 59% (22/37) asked about psychiatric symptom management. Moreover, 81% (30/37) of e-consults were answered within 24 hours, and 65% (24/37) were addressed in a single exchange. Themes from the interview data included psychiatry having a complexity that differentiates it from other specialties and may limit the utility of e consult, other than for psychopharmacology advice. Variability in awareness exists in the way e-consultation could be used in psychiatry, with new PCPs feeling unsure about the appropriateness of a question. In general, new PCPs and PCPs practicing in rural areas were more receptive to psychiatry e-consult. PCPs viewed e-consult as an opportunity to collaborate and desired that it be integrated with other available services. Recommendations include the need for appropriate specialist staffing to address a wide range of requests, adequate education to referrers regarding the use of psychiatry e-consult, and the need to integrate psychiatry e-consult with other geographically relevant services, given the complexity of psychiatric issues. CONCLUSIONS: E-consult is a viable and timely way for PCPs to get much-needed psychiatric advice. For optimizing its utility and uptake, e-consult needs to be integrated into reliable care pathways with adequate referrer and consultant preparation. PMID- 29625950 TI - Understanding Older People's Readiness for Receiving Telehealth: Mixed-Method Study. AB - BACKGROUND: The Dutch Ministry of Health has formulated ambitious goals concerning the use of telehealth, leading to subsequent changes compared with the current health care situation, in which 93% of care is delivered face-to-face. Since most care is delivered to older people, the prospect of telehealth raises the question of whether this population is ready for this new way of receiving care. To study this, we created a theoretical framework consisting of 6 factors associated with older people's intention to use technology. OBJECTIVE: The objective of this study was to understand community-dwelling older people's readiness for receiving telehealth by studying their intention to use videoconferencing and capacities for using digital technology in daily life as indicators. METHODS: A mixed-method triangulation design was used. First, a cross sectional survey study was performed to investigate older people's intention to use videoconferencing, by testing our theoretical framework with a multilevel path analysis (phase 1). Second, for deeper understanding of older people's actual use of digital technology, qualitative observations of older people executing technological tasks (eg, on a computer, cell phone) were conducted at their homes (phase 2). RESULTS: In phase 1, a total of 256 people aged 65 years or older participated in the survey study (50.0% male; median age, 70 years; Q1 Q3: 67-76). Using a significance level of .05, we found seven significant associations regarding older people's perception of videoconferencing. Older people's (1) intention to use videoconferencing was predicted by their performance expectancy (odds ratio [OR] 1.26, 95% CI 1.13-1.39), effort expectancy (OR 1.23, 95% CI 1.07-1.39), and perceived privacy and security (OR 1.30, 95% CI 1.17-1.43); (2) their performance expectancy was predicted by their effort expectancy (OR 1.38, 95% CI 1.24-1.52); and (3) their effort expectancy was predicted by their self-efficacy (OR 1.55, 95% CI 1.42-1.68). In phase 2, a total of 6 men and 9 women aged between 65 and 87 years participated in the qualitative observation study. Of the primary themes, 5 themes were identified that could provide greater understanding of older people's capacities and incapacities in using digital technology: (1) "self-efficacy and digital literacy," (2) "obstacles to using technology," (3) "prior experience and frequency of use," (4) "sources of support and facilitating conditions," and (5) "performance expectancy." These 5 themes recurred in all 15 observations. CONCLUSIONS: Performance expectancy, effort expectancy, and perceived privacy and security are direct predictors of older people's intention to use videoconferencing. Self-efficacy appeared to play a role in both older people's intention to use, as well as their actual use of technology. The path analysis revealed that self-efficacy was significantly associated with older people's effort expectancy. Furthermore, self-efficacy and digital literacy appeared to play a major role in older people's capacities to make use of digital technology. PMID- 29625951 TI - Perceptions of Adolescents With Cancer Related to a Pain Management App and Its Evaluation: Qualitative Study Nested Within a Multicenter Pilot Feasibility Study. AB - BACKGROUND: Pain in adolescents with cancer is common and negatively impacts health-related quality of life. The Pain Squad+ smartphone app, capable of providing adolescents with real-time pain management support, was developed to enhance pain management using a phased approach (ie, systematic review, consensus conference and vetting, iterative usability testing cycles). A 28-day Pain Squad+ pilot was conducted with 40 adolescents with cancer to evaluate the feasibility of implementing the app in a future clinical trial and to obtain estimates of treatment effect. OBJECTIVE: The objective of our nested qualitative study was to elucidate the perceptions of adolescents with cancer to determine the acceptability and perceived helpfulness of Pain Squad+, suggestions for app improvement, and satisfaction with the pilot study protocol. METHODS: Post pilot study participation, telephone-based, semistructured, and audio-recorded exit interviews were conducted with 20 adolescents with cancer (12-18 years). All interviews were transcribed and independently coded by 2 study team members. Content analysis was conducted to identify data categories and overarching themes. RESULTS: Five major themes comprising multiple categories and codes emerged. These themes focused on the acceptability of the intervention, acceptability of the study, the perceived active ingredients of the intervention, the suitability of the intervention to adolescents' lives, and recommendations for intervention improvement. CONCLUSIONS: Overall, Pain Squad+ and the pilot study protocol were acceptable to adolescents with cancer. Suggestions for intervention and study improvements will be incorporated into the design of a future randomized clinical trial (RCT) aimed at assessing the effectiveness of Pain Squad+ on adolescents with cancer health outcomes. PMID- 29625952 TI - Effects of Dietary Inorganic Nitrate Supplementation on Exercise Performance in Patients With Heart Failure: Protocol for a Randomized, Placebo-Controlled, Cross Over Trial. AB - BACKGROUND: Chronic heart failure is characterized by an inability of the heart to pump enough blood to meet the demands of the body, resulting in the hallmark symptom of exercise intolerance. Chronic underperfusion of the peripheral tissues and impaired nitric oxide bioavailability have been implicated as contributors to the decrease in exercise capacity in these patients. nitric oxide bioavailability has been identified as an important mediator of exercise tolerance in healthy individuals, but there are limited studies examining the effects in patients with chronic heart failure. OBJECTIVE: The proposed trial is designed to determine the effects of chronic inorganic nitrate supplementation on exercise tolerance in both patients with heart failure preserved ejection fraction (HFpEF) and heart failure reduced ejection fraction (HFrEF) and to determine whether there are any differential responses between the 2 cohorts. A secondary objective is to provide mechanistic insights into the 2 heart failure groups' exercise responses to the nitrate supplementation. METHODS: Patients with chronic heart failure (15=HFpEF and 15=HFrEF) aged 40 to 85 years will be recruited. Following an initial screen cardiopulmonary exercise test, participants will be randomly allocated in a double-blind fashion to consume either a nitrate-rich beetroot juice (16 mmol nitrate/day) or a nitrate-depleted placebo (for 5 days). Participants will continue daily dosing until the completion of the 4 testing visits (maximal cardiopulmonary exercise test, submaximal exercise test with echocardiography, vascular function assessment, and vastus lateralis muscle biopsy). There will then be a 2-week washout period after which the participants will cross over to the other treatment and complete the same 4 testing visits. RESULTS: This study is funded by National Heart Foundation of Australia and Victoria University. Enrolment has commenced and the data collection is expected to be completed in mid 2018. The initial results are expected to be submitted for publication by the end of 2018. CONCLUSIONS: If inorganic nitrate supplementation can improve exercise tolerance in patients with chronic heart failure, it has the potential to aid in further refining the treatment of patients in this population. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12615000906550; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=368912 (Archived by WebCite at http://www.webcitation.org/6xymLMiFK). PMID- 29625954 TI - Youth Mental Health Services Utilization Rates After a Large-Scale Social Media Campaign: Population-Based Interrupted Time-Series Analysis. AB - BACKGROUND: Despite the uptake of mass media campaigns, their overall impact remains unclear. Since 2011, a Canadian telecommunications company has operated an annual, large-scale mental health advocacy campaign (Bell Let's Talk) focused on mental health awareness and stigma reduction. In February 2012, the campaign began to explicitly leverage the social media platform Twitter and incented participation from the public by promising donations of Can $0.05 for each interaction with a campaign-specific username (@Bell_LetsTalk). OBJECTIVE: The intent of the study was to examine the impact of this 2012 campaign on youth outpatient mental health services in the province of Ontario, Canada. METHODS: Monthly outpatient mental health visits (primary health care and psychiatric services) were obtained for the Ontario youth aged 10 to 24 years (approximately 5.66 million visits) from January 1, 2006 to December 31, 2015. Interrupted time series, autoregressive integrated moving average modeling was implemented to evaluate the impact of the campaign on rates of monthly outpatient mental health visits. A lagged intervention date of April 1, 2012 was selected to account for the delay required for a patient to schedule and attend a mental health-related physician visit. RESULTS: The inclusion of Twitter into the 2012 Bell Let's Talk campaign was temporally associated with an increase in outpatient mental health utilization for both males and females. Within primary health care environments, female adolescents aged 10 to 17 years experienced a monthly increase in the mental health visit rate from 10.2/1000 in April 2006 to 14.1/1000 in April 2015 (slope change of 0.094 following campaign, P<.001), whereas males of the same age cohort experienced a monthly increase from 9.7/1000 to 9.8/1000 (slope change of 0.052 following campaign, P<.001). Outpatient psychiatric services visit rates also increased for both male and female adolescents aged 10 to 17 years post campaign (slope change of 0.005, P=.02; slope change of 0.003, P=.005, respectively). For young adults aged 18 to 24 years, females who used primary health care experienced the most significant increases in mental health visit rates from 26.5/1000 in April 2006 to 29.2/1000 in April 2015 (slope change of 0.17 following campaign, P<.001). CONCLUSIONS: The 2012 Bell Let's Talk campaign was temporally associated with an increase in the rate of mental health visits among Ontarian youth. Furthermore, there appears to be an upward trend of youth mental health utilization in the province of Ontario, especially noticeable in females who accessed primary health care services. PMID- 29625953 TI - Predictors of Facebook User Engagement With Health-Related Content for Gay, Bisexual, and Other Men Who Have Sex With Men: Content Analysis. AB - BACKGROUND: Social media is used by community-based organizations (CBOs) to promote the well-being of gay and bisexual men (GBM). However, few studies have quantified which factors facilitate the diffusion of health content tailored for sexual minorities. OBJECTIVE: The aim of this study was to identify post characteristics that can be leveraged to optimize the health promotion efforts of CBOs on Facebook. METHODS: The Facebook application programming interface was used to collect 5 years' of posts shared across 10 Facebook pages administered by Vancouver-based CBOs promoting GBM health. Network analysis assessed basic indicators of network structure. Content analyses were conducted using informatics-based approaches. Hierarchical negative binomial regression of post engagement data was used to identify meaningful covariates of engagement. RESULTS: In total, 14,071 posts were shared and 21,537 users engaged with these posts. Most users (n=13,315) engaged only once. There was moderate correlation between the number of posts and the number of CBOs users engaged with (r=.53, P<.001). Higher user engagement was positively associated with positive sentiment, sharing multimedia, and posting about pre-exposure prophylaxis, stigma, and mental health. Engagement was negatively associated with asking questions, posting about dating, and sharing posts during or after work (versus before). CONCLUSIONS: Results highlight the existence of a core group of Facebook users who facilitate diffusion. Factors associated with greater user engagement present CBOs with a number of strategies for improving the diffusion of health content. PMID- 29625955 TI - Patient-Physician Communication in the Era of Mobile Phones and Social Media Apps: Cross-Sectional Observational Study on Lebanese Physicians' Perceptions and Attitudes. AB - BACKGROUND: The increased prevalence of virtual communication technology, particularly social media, has shifted the physician-patient relationship away from the well-established face-to-face interaction. The views and habits of physicians in Lebanon toward the use of online apps and social media as forms of patient communication have not been previously described. OBJECTIVE: The aim of this study is to describe the views of Lebanese physicians toward the use of social media and other online apps as means of patient communication. METHODS: This was a cross-sectional observational study using an online survey that addressed physicians' perceptions on the use of virtual communication in their clinical practice. The study took place between April and June 2016, and was directed toward physicians at the American University of Beirut Medical Center. RESULTS: A total of 834 doctors received the online survey, with 238 physicians completing the survey. Most of the participants were from medical specialties. Most responders were attending physicians. Less than half of the respondents believed that Web-based apps and social media could be a useful tool for communicating with patients. Email was the most common form of professional online app, followed by WhatsApp (an instant messaging service). The majority of participants felt that this mode of communication can result in medicolegal issues and that it was a breach of privacy. Participants strictly against the use of virtual forms of communication made up 47.5% (113/238) of the study sample. CONCLUSIONS: The majority of physicians at the American University of Beirut Medical Center are reluctant to use virtual communication technology as a form of patient communication. Appropriate policy making and strategies can allow both physicians and patients to communicate virtually in a more secure setting without fear of breaching privacy and confidentiality. PMID- 29625956 TI - Real-World Implementation of Video Outpatient Consultations at Macro, Meso, and Micro Levels: Mixed-Method Study. AB - BACKGROUND: There is much interest in virtual consultations using video technology. Randomized controlled trials have shown video consultations to be acceptable, safe, and effective in selected conditions and circumstances. However, this model has rarely been mainstreamed and sustained in real-world settings. OBJECTIVE: The study sought to (1) define good practice and inform implementation of video outpatient consultations and (2) generate transferable knowledge about challenges to scaling up and routinizing this service model. METHODS: A multilevel, mixed-method study of Skype video consultations (micro level) was embedded in an organizational case study (meso level), taking account of national context and wider influences (macro level). The study followed the introduction of video outpatient consultations in three clinical services (diabetes, diabetes antenatal, and cancer surgery) in a National Health Service trust (covering three hospitals) in London, United Kingdom. Data sources included 36 national-level stakeholders (exploratory and semistructured interviews), longitudinal organizational ethnography (300 hours of observations; 24 staff interviews), 30 videotaped remote consultations, 17 audiotaped face-to-face consultations, and national and local documents. Qualitative data, analyzed using sociotechnical change theories, addressed staff and patient experience and organizational and system drivers. Quantitative data, analyzed via descriptive statistics, included uptake of video consultations by staff and patients and microcategorization of different kinds of talk (using the Roter interaction analysis system). RESULTS: When clinical, technical, and practical preconditions were met, video consultations appeared safe and were popular with some patients and staff. Compared with face-to-face consultations for similar conditions, video consultations were very slightly shorter, patients did slightly more talking, and both parties sometimes needed to make explicit things that typically remained implicit in a traditional encounter. Video consultations appeared to work better when the clinician and patient already knew and trusted each other. Some clinicians used Skype adaptively to respond to patient requests for ad hoc encounters in a way that appeared to strengthen supported self-management. The reality of establishing video outpatient services in a busy and financially stretched acute hospital setting proved more complex and time-consuming than originally anticipated. By the end of this study, between 2% and 22% of consultations were being undertaken remotely by participating clinicians. In the remainder, clinicians chose not to participate, or video consultations were considered impractical, technically unachievable, or clinically inadvisable. Technical challenges were typically minor but potentially prohibitive. CONCLUSIONS: Video outpatient consultations appear safe, effective, and convenient for patients in situations where participating clinicians judge them clinically appropriate, but such situations are a fraction of the overall clinic workload. As with other technological innovations, some clinicians will adopt readily, whereas others will need incentives and support. There are complex challenges to embedding video consultation services within routine practice in organizations that are hesitant to change, especially in times of austerity. PMID- 29625957 TI - Development and Feasibility Testing of Internet-Delivered Acceptance and Commitment Therapy for Severe Health Anxiety: Pilot Study. AB - BACKGROUND: Severe health anxiety (hypochondriasis), or illness anxiety disorder according to the Diagnostic and Statistical Manual of Mental Disorders, 5th edition, is characterized by preoccupation with fear of suffering from a serious illness in spite of medical reassurance. It is a debilitating, prevalent disorder associated with increased health care utilization. Still, there is a lack of easily accessible specialized treatment for severe health anxiety. OBJECTIVE: The aims of this paper were to (1) describe the development and setup of a new internet-delivered acceptance and commitment therapy (iACT) program for patients with severe health anxiety using self-referral and a video-based assessment; and (2) examine the feasibility and potential clinical efficacy of iACT for severe health anxiety. METHODS: Self-referred patients (N=15) with severe health anxiety were diagnostically assessed by a video-based interview. They received 7 sessions of clinician-supported iACT comprising self-help texts, video clips, audio files, and worksheets over 12 weeks. Self-report questionnaires were obtained at baseline, post-treatment, and at 3-month follow-up. The primary outcome was Whiteley-7 Index (WI-7) measuring health anxiety severity. Depressive symptoms, health-related quality of life (HRQoL), life satisfaction, and psychological flexibility were also assessed. A within-group design was employed. Means, standard deviations, and effect sizes using the standardized response mean (SRM) were estimated. Post-treatment interviews were conducted to evaluate the patient experience of the usability and acceptability of the treatment setup and program. RESULTS: The self-referral and video-based assessments were well received. Most patients (12/15, 80%) completed the treatment, and only 1 (1/15, 7%) dropped out. Post-treatment (14/15, 93%) and 3-month follow-up (12/15, 80%) data were available for almost all patients. Paired t tests showed significant improvements on all outcome measures both at post-treatment and 3-month follow-up, except on one physical component subscale of HRQoL. Health anxiety symptoms decreased with 33.9 points at 3-month follow-up (95% CI 13.6-54.3, t11= 3.66, P=.004) with a large within-group effect size of 1.06 as measured by the SRM. CONCLUSIONS: Treatment adherence and potential efficacy suggest that iACT may be a feasible treatment for health anxiety. The uncontrolled design and small sample size of the study limited the robustness of the findings. Therefore, the findings should be replicated in a randomized controlled trial. Potentially, iACT may increase availability and accessibility of specialized treatment for health anxiety. TRIAL REGISTRATION: Danish Data Protection Agency, Central Denmark Region: 1-16-02-427 14; https://www.rm.dk/sundhed/faginfo/forskning/datatilsynet/ (Archived by Webcite at http://www.webcitation.org/6yDA7WovM). PMID- 29625959 TI - Personalising care with a Year of Care approach makes the most of appointment day. PMID- 29625958 TI - Economic Recession and Obesity-Related Internet Search Behavior in Taiwan: Analysis of Google Trends Data. AB - BACKGROUND: Obesity is highly correlated with the development of chronic diseases and has become a critical public health issue that must be countered by aggressive action. This study determined whether data from Google Trends could provide insight into trends in obesity-related search behaviors in Taiwan. OBJECTIVE: Using Google Trends, we examined how changes in economic conditions using business cycle indicators as a proxy-were associated with people's internet search behaviors related to obesity awareness, health behaviors, and fast food restaurants. METHODS: Monthly business cycle indicators were obtained from the Taiwan National Development Council. Weekly Taiwan Stock Exchange (TWSE) weighted index data were accessed and downloaded from Yahoo Finance. The weekly relative search volumes (RSV) of obesity-related terms were downloaded from Google Trends. RSVs of obesity-related terms and the TWSE from January 2007 to December 2011 (60 months) were analyzed using correlation analysis. RESULTS: During an economic recession, the RSV of obesity awareness and health behaviors declined (r=.441, P<.001; r=.593, P<.001, respectively); however, the RSV for fast food restaurants increased (r=-.437, P<.001). Findings indicated that when the economy was faltering, people tended to be less likely to search for information related to health behaviors and obesity awareness; moreover, they were more likely to search for fast food restaurants. CONCLUSIONS: Macroeconomic conditions can have an impact on people's health-related internet searches. PMID- 29625960 TI - Folic acid and vitamin B12 fortification of food for preventing neural tube defects in Europe. PMID- 29625961 TI - Break pay is deducted for locum shift work covering rota gaps every six hours regardless. PMID- 29625963 TI - Can public health strategies tackle London's rise in fatal violence? PMID- 29625962 TI - How serious are global health leaders about gender equality? PMID- 29625964 TI - Real world evidence: experience and lessons from China. PMID- 29625965 TI - Hospital doctors face unfair disciplinary procedures, says defence organisation. PMID- 29625966 TI - Identification of ST3AGL4, MFHAS1, CSNK2A2 and CD226 as loci associated with systemic lupus erythematosus (SLE) and evaluation of SLE genetics in drug repositioning. AB - OBJECTIVES: Systemic lupus erythematosus (SLE) is a prototype autoimmune disease with a strong genetic component in its pathogenesis. Through genome-wide association studies (GWAS), we recently identified 10 novel loci associated with SLE and uncovered a number of suggestive loci requiring further validation. This study aimed to validate those loci in independent cohorts and evaluate the role of SLE genetics in drug repositioning. METHODS: We conducted GWAS and replication studies involving 12 280 SLE cases and 18 828 controls, and performed fine mapping analyses to identify likely causal variants within the newly identified loci. We further scanned drug target databases to evaluate the role of SLE genetics in drug repositioning. RESULTS: We identified three novel loci that surpassed genome-wide significance, including ST3AGL4 (rs13238909, pmeta=4.40E 08), MFHAS1 (rs2428, pmeta=1.17E-08) and CSNK2A2 (rs2731783, pmeta=1.08E-09). We also confirmed the association of CD226 locus with SLE (rs763361, pmeta=2.45E 08). Fine-mapping and functional analyses indicated that the putative causal variants in CSNK2A2 locus reside in an enhancer and are associated with expression of CSNK2A2 in B-lymphocytes, suggesting a potential mechanism of association. In addition, we demonstrated that SLE risk genes were more likely to be interacting proteins with targets of approved SLE drugs (OR=2.41, p=1.50E-03) which supports the role of genetic studies to repurpose drugs approved for other diseases for the treatment of SLE. CONCLUSION: This study identified three novel loci associated with SLE and demonstrated the role of SLE GWAS findings in drug repositioning. PMID- 29625967 TI - Determinants of happiness and quality of life in patients with rheumatoid arthritis: a structural equation modelling approach. AB - OBJECTIVES: Besides increasing longevity, the ultimate goal of medical care is to improve patients' enjoyment of life, a concept akin to happiness. This study examined the determinants of happiness and quality of life (QoL) in patients with rheumatoid arthritis (RA). METHODS: In this observational, cross-sectional study, patients were assessed on disease activity, disease impact, personality, QoL and happiness. Structural equation modelling estimation was used to analyse the associations between these dimensions, pursuing three hypotheses: H1-disease activity and perceived impact of disease are negatively associated with overall QoL and happiness in patients with RA; H2-'positive' personality traits are related to happiness both directly and indirectly through perceived disease impact; H3-happiness has a mediating effect in the relation between impact of disease and QoL. RESULTS: Data from 213 patients were analysed. Results supported all driving hypotheses. Happiness was positively related to 'positive' personality and, to a lesser extent, negatively related to impact of disease. Impact of disease, in turn, was positively related to disease activity and mitigated by 'positive' personality traits. Impact of disease had a much stronger relation with QoL than with happiness. Happiness mitigated the negative effect of disease impact on QoL. CONCLUSION: Optimisation of QoL and happiness of people with RA requires effective control of the disease process and also improvement of the disease impact domains. Personality seems to play a pivotal mediating role in these relations. PMID- 29625968 TI - 2018 update of the EULAR recommendations for the management of Behcet's syndrome. AB - Several new treatment modalities with different mechanisms of action have been studied in patients with Behcet's syndrome (BS). The aim of the current effort was to update the recommendations in the light of these new data under the auspices of the European League Against Rheumatism (EULAR) Standing Committee for Clinical Affairs. A task force was formed that included BS experts from different specialties including internal medicine, rheumatology, ophthalmology, dermatology, neurology, gastroenterology, oral health medicine and vascular surgery, along with a methodologist, a health professional, two patients and two fellows in charge of the systematic literature search. Research questions were determined using a Delphi approach. EULAR standardised operating procedures was used as the framework. Results of the systematic literature review were presented to the task force during a meeting. The former recommendations were modified or new recommendations were formed after thorough discussions followed by voting. The recommendations on the medical management of mucocutaneous, joint, eye, vascular, neurological and gastrointestinal involvement of BS were modified; five overarching principles and a new recommendation about the surgical management of vascular involvement were added. These updated, evidence-based recommendations are intended to help physicians caring for patients with BS. They also attempt to highlight the shortcomings of the available clinical research with the aim of proposing an agenda for further research priorities. PMID- 29625970 TI - Clinical Course and Quality of Life in High-Risk Patients With Hypertrophic Cardiomyopathy and Implantable Cardioverter-Defibrillators. AB - BACKGROUND: High-risk patients with hypertrophic cardiomyopathy (HCM) are identified by contemporary risk stratification and effectively treated with implantable cardioverter-defibrillators (ICDs). However, long-term HCM clinical course after ICD therapy for ventricular tachyarrhythmias is incompletely understood. METHODS AND RESULTS: Cohort of 486 high-risk HCM patients with ICDs was assembled from 8 international centers. Clinical course and device interventions were addressed, and survey questionnaires assessed patient anxiety level and psychological well-being related to ICD therapy. Of 486 patients, 94 (19%) experienced appropriate ICD interventions terminating ventricular tachycardia/ventricular fibrillation, 3.7% per year for primary prevention, over 6.4+/-4.7 years. Of 94 patients, 87 were asymptomatic or only mildly symptomatic at the time of appropriate ICD interventions; 74 of these 87 (85%) remained in classes I/II without significant change in clinical status over the subsequent 5.9+/-4.9 years (up to 22). Among the 94 patients, there was one sudden death (caused by device failure; 1.1%); 3 patients died from other HCM-related processes unrelated to arrhythmic risk (eg, end-stage heart failure). Post-ICD intervention, freedom from HCM mortality was 100%, 97%, and 92% at 1, 5, and 10 years, distinctly lower than in ischemic or nonischemic cardiomyopathy ICD trials. HCM patients with ICD interventions reported heightened anxiety in expectation of future shocks, but with intact general psychological well-being and quality of life. CONCLUSIONS: In HCM, unlike ischemic heart disease, prevention of sudden death with ICD therapy is unassociated with significant increase in cardiovascular morbidity or mortality, or transformation to heart failure deterioration. ICD therapy does not substantially impair overall psychological and physical well-being. PMID- 29625971 TI - Is Acupuncture in Medicine a fake medical journal? PMID- 29625972 TI - Long-term electroacupuncture stimulation prevents osteoporosis in ovariectomised osteopaenic rats through multiple signalling pathways. AB - BACKGROUND: The pathogenic mechanisms of postmenopausal osteoporosis (PMOP) development are complex and are related to multiple cellular signalling transduction pathways. The aim of this study was to compare the effects of electroacupuncture (EA) at GV4/GV6 versus BL20/BL23 on the bones in ovariectomised (OVX) rats to explore the pathways that mediate the effects of EA on bone. METHODS: Forty female Sprague-Dawley rats were allocated to one of four groups (n=10 rats each) that received sham surgery (Sham group), OVX surgery only (OVX group), OVX surgery plus EA at GV4/GV6 (GV group) and OVX surgery plus EA at BL20/BL23 (BL group). Bone turnover markers osteocalcin (OC) and tartrate resistant acid phosphatase 5b (TRACP 5b) were measured in serum, and bone mineral density (BMD) of the lumbar vertebrae and histomorphology of the femur were evaluated. Moreover, the expression of osteoprotegerin (OPG) and receptor activator of nuclear factor-kappaB ligand (RANKL) was detected by ELISA. The expression of lipoprotein receptor-related protein (LRP) 5, beta-catenin, runt related transcription factor (Runx) 2 involving Wnt/beta-catenin signalling and p38, c-Jun N-terminal kinase (JNK) and extracellular regulated protein kinases 1/2 involving mitogen-activated protein kinase signalling were determined by Western blotting. RESULTS: The two EA-treated groups demonstrated increased levels of OC and the BMD of lumbar vertebrae, decreased levels of TRACP 5b and improved bone microstructure in the femur, compared with the untreated OVX group (P<0.05). Histomorphology analysis showed that EA treatment significantly increased the values of the trabeculae (um), trabecular area (%) and trabecular bone number (per mm) and reduced trabecular separation (mm), compared with the OVX group. In addition, the ratio of OPG to RANKL and LRP5, beta-catenin and Runx2 expression were significantly upregulated, while the expression of phosphorylated (p)-p38 and p-JNK were downregulated in EA-treated groups compared with the OVX group. CONCLUSION: EA attenuates PMOP and it appears that the mechanism involves the regulation of multiple targets and pathways. PMID- 29625973 TI - Commissioners are warned not to spend too little on mental health. PMID- 29625974 TI - The Geographic Structure of Viruses in the Cuatro Cienegas Basin, a Unique Oasis in Northern Mexico, Reveals a Highly Diverse Population on a Small Geographic Scale. AB - The Cuatro Cienegas Basin (CCB) is located in the Chihuahuan desert in the Mexican state of Coahuila; it has been characterized as a site with high biological diversity despite its extreme oligotrophic conditions. It has the greatest number of endemic species in North America, containing abundant living microbialites (including stromatolites and microbial mats) and diverse microbial communities. With the hypothesis that this high biodiversity and the geographic structure should be reflected in the virome, the viral communities in 11 different locations of three drainage systems, Churince, La Becerra, and Pozas Rojas, and in the intestinal contents of 3 different fish species, were analyzed for both eukaryotic and prokaryotic RNA and DNA viruses using next-generation sequencing methods. Double-stranded DNA (dsDNA) virus families were the most abundant (72.5% of reads), followed by single-stranded DNA (ssDNA) viruses (2.9%) and ssRNA and dsRNA virus families (0.5%). Thirteen families had dsDNA genomes, five had ssDNA, three had dsRNA, and 16 had ssRNA. A highly diverse viral community was found, with an ample range of hosts and a strong geographical structure, with very even distributions and signals of endemicity in the phylogenetic trees from several different virus families. The majority of viruses found were bacteriophages but eukaryotic viruses were also frequent, and the large diversity of viruses related to algae were a surprise, since algae are not evident in the previously analyzed aquatic systems of this ecosystem. Animal viruses were also frequently found, showing the large diversity of aquatic animals in this oasis, where plants, protozoa, and archaea are rare.IMPORTANCE In this study, we tested whether the high biodiversity and geographic structure of CCB is reflected in its virome. CCB is an extraordinarily biodiverse oasis in the Chihuahuan desert, where a previous virome study suggested that viruses had followed the marine ancestry of the marine bacteria and, as a result of their long isolation, became endemic to the site. In this study, which includes a larger sequencing coverage and water samples from other sites within the valley, we confirmed the high virus biodiversity and uniqueness as well as the strong biogeographical diversification of the CCB. In addition, we also analyzed fish intestinal contents, finding that each fish species eats different prey and, as a result, presents different viral compositions even if they coexist in the same pond. These facts highlight the high and novel virus diversity of CCB and its "lost world" status. PMID- 29625975 TI - Development of new application for comprehensive viability analysis based on microbiome analysis by next-generation sequencing: insights into staphylococcal carriage in human nasal cavities. AB - The nasal carriage rate of Staphylococcus aureus in human is 25--30% and S. aureus sporadically causes severe infections. However, mechanisms underlying staphylococcal carriage remain largely unknown. In the present study, we constructed an rpoB-based microbiome method for staphylococcal species discrimination. Based on a microbiome scheme targeting viable cell DNA using PMA dye (PMA microbiome), we also developed a new method to allow the comprehensive viability analysis of any bacterial taxon. To clarify the ecological distribution of staphylococci in the nasal microbiota, we applied these methods in 46 nasal specimens from healthy adults. PMA microbiome results showed that Staphylococcaceae and Corynebacteriaceae were the most predominant viable taxa (average relative abundance: 0.435262 and 0.375195, respectively), and S. epidermidis exhibited the highest viability in the nasal microbiota. S. aureus detection rates from nasal specimens by rpoB-based conventional and PMA microbiome were 84.8% (39 of 46) and 69.5% (32 of 46), respectively, which substantially exceeded the values by a culture method using identical specimens (36.9%). Our results suggests that Staphylococcaceae especially S. epidermidis adapted most successfully to human nasal cavity. High detection of S. aureus DNA by microbiome methods suggests that almost all healthy adults are consistently exposed to S. aureus in everyday life. Furthermore, the large difference in S. aureus detection rates between culture and microbiome methods suggests that S. aureus cells frequently exist under the viable but non-culturable state in nasal cavities. Our method and findings will contribute to a better understanding of the mechanisms underlying carriage of indigenous bacteria.Importance Metagenomic analyses, such as 16S rRNA microbiome, have provided new insight in various research fields. However, conventional 16S rRNA microbiome dose not permit taxonomic analysis of only viable bacteria, and has poor resolving power below the genus level. Our new schemes allowed for viabile cell specific analysis and species discrimination, nasal microbiome data using these methods provided some interesting findings regarding staphylococcal nasal carriage. According to our comprehensive viability analysis, high viability of Staphylococcus genus, especialy S. epidermidis in human nasal carriage suggests that this taxon has adapted most successfully to human nasal tissue. And also, higher detection of S. aureus DNA by microbiome methods (84.8%) than that by a culture method (36.9%) suggests that almost all healthy adults are consistently exposed to S. aureus in the medium- and long-term. Our findings will contribute to a better understanding of the mechanisms underlying carriage of indigenous bacteria. PMID- 29625976 TI - Sesquiterpene Synthase-3-Hydroxy-3-Methylglutaryl Coenzyme A Synthase Fusion Protein Responsible for Hirsutene Biosynthesis in Stereum hirsutum. AB - The wood-rotting mushroom Stereum hirsutum is a known producer of a large number of namesake hirsutenoids, many with important bioactivities. Hirsutenoids form a structurally diverse and distinct class of sesquiterpenoids. No genes involved in hirsutenoid biosynthesis have yet been identified or their enzymes characterized. Here, we describe the cloning and functional characterization of a hirsutene synthase as an unexpected fusion protein of a sesquiterpene synthase (STS) with a C-terminal 3-hydroxy-3-methylglutaryl-coenzyme A (3-hydroxy-3-methylglutaryl-CoA) synthase (HMGS) domain. Both the full-length fusion protein and truncated STS domain are highly product-specific 1,11-cyclizing STS enzymes with kinetic properties typical of STSs. Complementation studies in Saccharomyces cerevisiae confirmed that the HMGS domain is also functional in vivo Phylogenetic analysis shows that the hirsutene synthase domain does not form a clade with other previously characterized sesquiterpene synthases from Basidiomycota. Comparative gene structure analysis of this hirsutene synthase with characterized fungal enzymes reveals a significantly higher intron density, suggesting that this enzyme may be acquired by horizontal gene transfer. In contrast, the HMGS domain is clearly related to other fungal homologs. This STS-HMGS fusion protein is part of a biosynthetic gene cluster that includes P450s and oxidases that are expressed and could be cloned from cDNA. Finally, this unusual fusion of a terpene synthase to an HMGS domain, which is not generally recognized as a key regulatory enzyme of the mevalonate isoprenoid precursor pathway, led to the identification of additional HMGS duplications in many fungal genomes, including the localization of HMGSs in other predicted sesquiterpenoid biosynthetic gene clusters.IMPORTANCE Hirsutenoids represent a structurally diverse class of bioactive sesquiterpenoids isolated from fungi. Identification of their biosynthetic pathways will provide access to this chemodiversity for the discovery and synthesis of molecules with new bioactivities. The identification and successful cloning of the previously elusive hirsutene synthase from the S. hirsutum provide important insights and strategies for biosynthetic gene discovery in Basidiomycota. The finding of a terpene synthase-HMGS fusion, the discovery of other sesquiterpenoid biosynthetic gene clusters with dedicated HMGS genes, and HMGS gene duplications in fungal genomes give new importance to the role of HMGS as a key regulatory enzyme in isoprenoid and sterol biosynthesis that should be exploited for metabolic engineering. PMID- 29625977 TI - Spatiotemporal Dynamics of Vibrio cholerae in Turbid Alkaline Lakes as Determined by Quantitative PCR. AB - In recent years, global warming has led to a growing number of Vibrio cholerae infections in bathing water users in regions formerly unaffected by this pathogen. It is therefore of high importance to monitor V. cholerae in aquatic environments and to elucidate the main factors governing its prevalence and abundance. For this purpose, rapid and standardizable methods that can be performed by routine water laboratories are prerequisite. In this study, we applied a recently developed multiplex quantitative PCR (qPCR) strategy (i) to monitor the spatiotemporal variability of V. cholerae abundance in two small soda pools and a large lake that is intensively used for recreation and (ii) to elucidate the main factors driving V. cholerae dynamics in these environments. V. cholerae was detected with qPCR at high concentrations of up to 970,000 genomic units 100 ml-1 during the warm season, up to 2 orders of magnitude higher than values obtained by cultivation. An independent cytometric approach led to results comparable to qPCR data but with significantly more positive samples due to problems with DNA recovery for qPCR. Not a single sample was positive for toxigenic V. cholerae, indicating that only nontoxigenic V. cholerae (NTVC) was present. Temperature was the main predictor of NTVC abundance, but the quality and quantity of dissolved organic matter were also important environmental correlates. Based on this study, we recommend using the developed qPCR strategy for quantification of toxigenic and nontoxigenic V. cholerae in bathing waters with the need for improvements in DNA recovery.IMPORTANCE There is a definitive need for rapid and standardizable methods to quantify waterborne bacterial pathogens. Such methods have to be thoroughly tested for their applicability to environmental samples. In this study, we critically tested a recently developed multiplex qPCR strategy for its applicability to determine the spatiotemporal variability of V. cholerae abundance in lakes with a challenging water matrix. Several qPCR protocols for V. cholerae detection have been developed in the laboratory, but comprehensive studies on the application to environmental samples are extremely scarce. In our study, we demonstrate that our developed qPCR approach is a valuable tool but that there is a need for improvement in DNA recovery for complex water matrices. Furthermore, we found that nontoxigenic V. cholerae is present in very high numbers in the investigated ecosystems, while toxigenic V. cholerae is apparently absent. Such information is of importance for public health. PMID- 29625978 TI - Subgroup characteristics of marine methane-oxidizing ANME-2 archaea and their syntrophic partners revealed by integrated multimodal analytical microscopy. AB - Phylogenetically diverse environmental ANME archaea and sulfate-reducing bacteria cooperatively catalyze the anaerobic oxidation of methane oxidation (AOM) in multi-celled consortia within methane seep environments. To better understand these cells and their symbiotic associations, we applied a suite of electron microscopy approaches including correlative fluorescence in situhybridization - electron microscopy (FISH-EM), transmission electron microscopy (TEM), and serial block face scanning electron microscopy 3D reconstructions (SBEM). FISH-EM of methane seep derived consortia revealed phylogenetic variability in terms of cell morphology, ultrastructure, and storage granules. Representatives of the ANME-2b clade, but not other ANME-2 groups, contained polyphosphate-like granules, while some bacteria associated with ANME-2a/2c contained two distinct phases of iron mineral chains resembling magnetosomes. 3D segmentation of two ANME-2 consortia types revealed cellular volumes of ANME and their symbiotic partners which were larger than previous estimates based on light microscopy. Phosphorous granule containing ANME (tentatively ANME-2b) were larger than both ANME with no granules and partner bacteria. This cell type was observed with up to 4 granules per cell and the volume of the cell was larger in proportion to the number of granules inside it, but the percent of the cell occupied by these granules did not vary with granule number. These results illuminate distinctions between ANME-2 archaeal lineages and partnering bacterial populations that are apparently unified in their capability of performing anaerobic methane oxidation.Importance Methane oxidation in anaerobic environments can be accomplished by a number of archaeal groups, some of which live in syntrophic relationships with bacteria in structured consortia. Little is known as to the distinguishing characteristics of these groups. Here we applied imaging approaches to better understand the properties of these cells. We found unexpected morphological, structural, and volume variability of these uncultured groups by correlating fluorescence labeling of cells with electron microscopy observables. PMID- 29625979 TI - Soft Rot Enterobacteriaceae Are Carried by a Large Range of Insect Species in Potato Fields. AB - Pathogenic soft rot Enterobacteriaceae (SRE) belonging to the genera Pectobacterium and Dickeya cause diseases in potato and numerous other crops. Seed potatoes are the most important source of infection, but how pathogen-free tubers initially become infected remains an enigma. Since the 1920s, insects have been hypothesized to contribute to SRE transmission. To validate this hypothesis and to map the insect species potentially involved in SRE dispersal, we have analyzed the occurrence of SRE in insects recovered from potato fields over a period of 2 years. Twenty-eight yellow sticky traps were set up in 10 potato fields throughout Norway to attract and trap insects. Total DNA recovered from over 2,000 randomly chosen trapped insects was tested for SRE, using a specific quantitative PCR (qPCR) TaqMan assay, and insects that tested positive were identified by DNA barcoding. Although the occurrence of SRE-carrying insects varied, they were found in all the tested fields. While Delia species were dominant among the insects that carried the largest amount of SRE, more than 80 other SRE-carrying insect species were identified, and they had different levels of abundance. Additionally, the occurrence of SRE in three laboratory-reared insect species was analyzed, and this suggested that SRE are natural members of some insect microbiomes, with herbivorous Delia floralis carrying more SRE than the cabbage moth (Plutella xylostella) and carnivorous green lacewing larvae (Chrysoperla carnea). In summary, the high proportion, variety, and ubiquity of insects that carried SRE show the need to address this source of the pathogens to reduce the initial infection of seed material.IMPORTANCE Soft rot Enterobacteriaceae are among the most important pathogens of a wide range of vegetables and fruits. The bacteria cause severe rots in the field and in storage, leading to considerable harvest losses. In potato, efforts to understand how soft rot bacteria infect and spread between healthy plants have been made for over a century. Early on, fly larvae were implicated in the transmission of these bacteria. This work aimed at investigating the occurrence of soft rot bacteria in insects present in potato fields and at identifying the species of these insects to better understand the potential of this suspected source of transmission. In all tested potato fields, a large proportion of insects were found to carry soft rot bacteria. This suggests a need to give more weight to the role of insects in soft rot ecology and epidemiology to design more effective pest management strategies that integrate this factor. PMID- 29625980 TI - Mechanisms of Mineral Substrate Acquisition in a Thermoacidophile. AB - The thermoacidophile Acidianus is widely distributed in Yellowstone National Park hot springs that span large gradients in pH (1.60 to 4.84), temperature (42 to 90 degrees C), and mineralogical composition. To characterize the potential role of flexibility in mineral-dependent energy metabolism in contributing to the widespread ecological distribution of this organism, we characterized the spectrum of minerals capable of supporting metabolism and the mechanisms that it uses to access these minerals. The energy metabolism of Acidianus strain DS80 was supported by elemental sulfur (S0), a variety of iron (hydr)oxides, and arsenic sulfide. Strain DS80 reduced, oxidized, and disproportionated S0 Cells growing via S0 reduction and disproportionation did not require direct access to the mineral to reduce it, whereas cells growing via S0 oxidation did require direct access, observations that are attributable to the role of H2S produced by S0 reduction/disproportionation in solubilizing and increasing the bioavailability of S0 Cells growing via iron (hydr)oxide reduction did not require access to the mineral, suggesting that the cells reduce Fe(III) that is being leached by the acidic growth medium. Cells growing via oxidation of arsenic sulfide with Fe(III) did not require access to the mineral to grow. The stoichiometry of reactants to products indicates that cells oxidize soluble As(III) released from oxidation of arsenic sulfide by aqueous Fe(III). Taken together, these observations underscore the importance of feedbacks between abiotic and biotic reactions in influencing the bioavailability of mineral substrates and defining ecological niches capable of supporting microbial metabolism.IMPORTANCE Mineral sources of electron donor and acceptor that support microbial metabolism are abundant in the natural environment. However, the spectrum of minerals capable of supporting a given microbial strain and the mechanisms that are used to access these minerals in support of microbial energy metabolism are often unknown, in particular among thermoacidophiles. Here, we show that the thermoacidophile Acidianus strain DS80 is adapted to use a variety of iron (hydro)oxide minerals, elemental sulfur, and arsenic sulfide to support growth. Cells rely on a complex interplay of abiologically and biologically catalyzed reactions that increase the solubility or bioavailability of minerals, thereby enabling their use in microbial metabolism. PMID- 29625981 TI - A Consistent and Predictable Commercial Broiler Chicken Bacterial Microbiota in Antibiotic-Free Production Displays Strong Correlations with Performance. AB - Defining the baseline bacterial microbiome is critical to understanding its relationship with health and disease. In broiler chickens, the core microbiome and its possible relationships with health and disease have been difficult to define, due to high variability between birds and flocks. Presented here are data from a large, comprehensive microbiota-based study in commercial broilers. The primary goals of this study included understanding what constitutes the core bacterial microbiota in the broiler gastrointestinal, respiratory, and barn environments; how these core players change across age, geography, and time; and which bacterial taxa correlate with enhanced bird performance in antibiotic-free flocks. Using 2,309 samples from 37 different commercial flocks within a vertically integrated broiler system and metadata from these and an additional 512 flocks within that system, the baseline bacterial microbiota was defined using 16S rRNA gene sequencing. The effects of age, sample type, flock, and successive flock cycles were compared, and results indicate a consistent, predictable, age-dependent bacterial microbiota, irrespective of flock. The tracheal bacterial microbiota of broilers was comprehensively defined, and Lactobacillus was the dominant bacterial taxon in the trachea. Numerous bacterial taxa were identified, which were strongly correlated with broiler chicken performance across multiple tissues. While many positively correlated taxa were identified, negatively associated potential pathogens were also identified in the absence of clinical disease, indicating that subclinical dynamics occur that impact performance. Overall, this work provides necessary baseline data for the development of effective antibiotic alternatives, such as probiotics, for sustainable poultry production.IMPORTANCE Multidrug-resistant bacterial pathogens are perhaps the greatest medical challenge we will face in the 21st century and beyond. Antibiotics are necessary in animal production to treat disease. As such, animal production is a contributor to the problem of antibiotic resistance. Efforts are underway to reduce antibiotic use in animal production. However, we are also challenged to feed the world's increasing population, and sustainable meat production is paramount to providing a safe and quality protein source for human consumption. In the absence of antibiotics, alternative approaches are needed to maintain health and prevent disease, and probiotics have great promise as one such approach. This work paves the way for the development of alternative approaches to raising poultry by increasing our understandings of what defines the poultry microbiome and of how it can potentially be modulated to improve animal health and performance. PMID- 29625982 TI - The Protease ClpXP and the PAS Domain Protein DivL Regulate CtrA and Gene Transfer Agent Production in Rhodobacter capsulatus. AB - Several members of the Rhodobacterales (Alphaproteobacteria) produce a conserved horizontal gene transfer vector, called the gene transfer agent (GTA), that appears to have evolved from a bacteriophage. The model system used to study GTA biology is the Rhodobacter capsulatus GTA (RcGTA), a small, tailed bacteriophage like particle produced by a subset of the cells in a culture. The response regulator CtrA is conserved in the Alphaproteobacteria and is an essential regulator of RcGTA production: it controls the production and maturation of the RcGTA particle and RcGTA release from cells. CtrA also controls the natural transformation-like system required for cells to receive RcGTA-donated DNA. Here, we report that dysregulation of the CckA-ChpT-CtrA phosphorelay either by the loss of the PAS domain protein DivL or by substitution of the autophosphorylation residue of the hybrid histidine kinase CckA decreased CtrA phosphorylation and greatly increased RcGTA protein production in R. capsulatus We show that the loss of the ClpXP protease or the three C-terminal residues of CtrA results in increased CtrA levels in R. capsulatus and identify ClpX(P) to be essential for the maturation of RcGTA particles. Furthermore, we show that CtrA phosphorylation is important for head spike production. Our results provide novel insight into the regulation of CtrA and GTAs in the RhodobacteralesIMPORTANCE Members of the Rhodobacterales are abundant in ocean and freshwater environments. The conserved GTA produced by many Rhodobacterales may have an important role in horizontal gene transfer (HGT) in aquatic environments and provide a significant contribution to their adaptation. GTA production is controlled by bacterial regulatory systems, including the conserved CckA-ChpT-CtrA phosphorelay; however, several questions about GTA regulation remain. Our identification that a short DivL homologue and ClpXP regulate CtrA in R. capsulatus extends the model of CtrA regulation from Caulobacter crescentus to a member of the Rhodobacterales We found that the magnitude of RcGTA production greatly depends on DivL and CckA kinase activity, adding yet another layer of regulatory complexity to RcGTA. RcGTA is known to undergo CckA-dependent maturation, and we extend the understanding of this process by showing that the ClpX chaperone is required for formation of tailed, DNA-containing particles. PMID- 29625983 TI - Tissue Distribution and Visualization of Internalized Human Norovirus in Leafy Greens. AB - Lettuce has been implicated in human norovirus (HuNoV) outbreaks. The virus is stable on the leaf surface for at least 2 weeks; however, the dynamics of virus internalization has not been fully investigated. The purpose of this study was to assess the internalization and distribution of HuNoV and two surrogate viruses, porcine sapovirus SaV and Tulane virus (TV), in lettuce and spinach. Viral inoculations through the roots of seedlings and the petiole of leaves from mature plants were performed and the viruses were tracked on day 1 and 6 post-root inoculation and on 16h and 72h post petiole-inoculation. Confocal Microscopy was used to visualize root-internalized HuNoV. In both lettuce and spinach: (i) HuNoV internalized to roots and leaves at similar RNA titers, whereas surrogate viruses were more restricted to the roots; (ii) all three viruses were stable inside the roots and leaves for at least 6 days; and (iii) HuNoV disseminated similarly inside the central veins and leaf lamina, whereas surrogate viruses were more restricted to the central veins. Infectious TV, but not SaV, was detectable in all tissues, suggesting a higher stability of TV compared with SaV. HuNoV was visualized inside the roots vascular bundle and the leaf mesophyll of both plants. In conclusion, using surrogate viruses may underestimate the level of HuNoV internalization into edible leaves. The internalization of HuNoV through roots and cut leaves and the dissemination into various spinach and lettuce tissues raise concerns of internal contamination through irrigation and/or wash water.Importance Human noroviruses are the leading cause of foodborne outbreaks, with lettuce being implicated in the majority of outbreaks. The virus causes acute gastroenteritis in all age groups with more severe symptoms in children, elderly and immune-compromised patients contributing to over 200,000 deaths worldwide annually. The majority of deaths due to HuNoV occur in the developing world where limited sanitation exists along with poor wastewater treatment facilities, resulting in contamination of water resources that are often used for irrigation. Our study confirms the ability of lettuce and spinach to internalize HuNoV from contaminated water through the roots into the edible leaves. Since these leafy greens are consumed with minimal processing that only targets surface pathogens, the internalized HuNoV presents an added risk to consumers. Thus, preventive measures should be in place to limit contamination of irrigation water. In addition, better processing technologies are needed to inactivate internalized viral pathogens. PMID- 29625984 TI - Increasing the Antimicrobial Activity of Nisin-Based Lantibiotics against Gram Negative Pathogens. AB - Lantibiotics are ribosomally synthesized and posttranslationally modified antimicrobial compounds containing lanthionine and methyl-lanthionine residues. Nisin, one of the most extensively studied and used lantibiotics, has been shown to display very potent activity against Gram-positive bacteria, and stable resistance is rarely observed. By binding to lipid II and forming pores in the membrane, nisin can cause the efflux of cellular constituents and inhibit cell wall biosynthesis. However, the activity of nisin against Gram-negative bacteria is much lower than that against Gram-positive bacteria, mainly because lipid II is located at the inner membrane, and the rather impermeable outer membrane in Gram-negative bacteria prevents nisin from reaching lipid II. Thus, if the outer membrane-traversing efficiency of nisin could be increased, the activity against Gram-negative bacteria could, in principle, be enhanced. In this work, several relatively short peptides with activity against Gram-negative bacteria were selected from literature data to be fused as tails to the C terminus of either full or truncated nisin species. Among these, we found that one of three tails (tail 2 [T2; DKYLPRPRPV], T6 [NGVQPKY], and T8 [KIAKVALKAL]) attached to a part of nisin displayed improved activity against Gram-negative microorganisms. Next, we rationally designed and reengineered the most promising fusion peptides. Several mutants whose activity significantly outperformed that of nisin against Gram-negative pathogens were obtained. The activity of the tail 16 mutant 2 (T16m2) construct against several important Gram-negative pathogens (i.e., Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter aerogenes) was increased 4- to 12-fold compared to that of nisin. This study indicates that the rational design of nisin can selectively and significantly improve its outer membrane-permeating capacity as well as its activity against Gram-negative pathogens.IMPORTANCE Lantibiotics are antimicrobial peptides that are highly active against Gram-positive bacteria but that have relatively poor activity against most Gram-negative bacteria. Here, we modified the model lantibiotic nisin by fusing parts of it to antimicrobial peptides with known activity against Gram-negative bacteria. The appropriate selection of peptidic moieties that could be attached to (parts of) nisin could lead to a significant increase in its inhibitory activity against Gram-negative bacteria. Using this strategy, hybrids that outperformed nisin by displaying 4- to 12-fold higher levels of activity against relevant Gram-negative bacterial species were produced. This study shows the power of modified peptide engineering to alter target specificity in a desired direction. PMID- 29625985 TI - Importance of Proteasome Gene Expression during Model Dough Fermentation after Preservation of Baker's Yeast Cells by Freezing. AB - Freeze-thaw stress causes various types of cellular damage, survival and/or proliferation defects, and metabolic alterations. However, the mechanisms underlying how cells cope with freeze-thaw stress are poorly understood. Here, model dough fermentations using two baker's yeast strains, 45 and YF, of Saccharomyces cerevisiae were compared after 2 weeks of cell preservation in a refrigerator or freezer. YF exhibited slow fermentation after exposure to freeze thaw stress due to low cell viability. A DNA microarray analysis of the YF cells during fermentation revealed that the genes involved in oxidative phosphorylation were relatively strongly expressed, suggesting a decrease in the glycolytic capacity. Furthermore, we found that mRNA levels of the genes that encode the components of the proteasome complex were commonly low, and ubiquitinated proteins were accumulated by freeze-thaw stress in the YF strain. In the cells with a laboratory strain background, treatment with the proteasome inhibitor MG132 or the deletion of each transcriptional activator gene for the proteasome genes (RPN4, PDR1, or PDR3) led to marked impairment of model dough fermentation using the frozen cells. Based on these data, proteasomal degradation of freeze thaw-damaged proteins may guarantee high cell viability and fermentation performance. We also found that the freeze-thaw stress-sensitive YF strain was heterozygous at the PDR3 locus, and one of the alleles (A148T/A229V/H336R/L541P) was shown to possess a dominant negative phenotype of slow fermentation. Removal of such responsible mutations could improve the freeze-thaw stress tolerance and the fermentation performance of baker's yeast strains, as well as other industrial S. cerevisiae strains.IMPORTANCE The development of freezing technology has enabled the long-term preservation and long-distance transport of foods and other agricultural products. Fresh yeast, however, is usually not frozen because the fermentation performance and/or the viability of individual cells is severely affected after thawing. Here, we demonstrate that proteasomal degradation of ubiquitinated proteins is an essential process in the freeze-thaw stress responses of S. cerevisiae Upstream transcriptional activator genes for the proteasome components are responsible for the fermentation performance after freezing preservation. Thus, this study provides a potential linkage between freeze-thaw stress inputs and the transcriptional regulatory network that might be functionally conserved in higher eukaryotes. Elucidation of the molecular targets of freeze-thaw stress will contribute to advances in cryobiology, such as freezing preservation of human cells, tissues, and embryos for medical purposes and breeding of industrial microorganisms and agricultural crops that adapt well to low temperatures. PMID- 29625986 TI - Survival of the Enveloped Virus Phi6 in Droplets as a Function of Relative Humidity, Absolute Humidity, and Temperature. AB - Infectious diseases caused by enveloped viruses, such as influenza, severe acute respiratory syndrome (SARS), and Middle East respiratory syndrome (MERS), cause thousands of deaths and billions of dollars of economic losses per year. Studies have found a relationship among temperature, humidity, and influenza virus incidence, transmission, or survival; however, there are contradictory claims about whether absolute humidity (AH) or relative humidity (RH) is most important in mediating virus infectivity. Using the enveloped bacteriophage Phi6, which has been suggested as a surrogate for influenza viruses and coronaviruses, we designed a study to discern whether AH, RH, or temperature is a better predictor of virus survival in droplets. Our results show that Phi6 survived best at high (>85%) and low (<60%) RHs, with a significant decrease in infectivity at mid range RHs (~60 to 85%). At an AH of less than 22 g . m-3, the loss in infectivity was less than 2 orders of magnitude; however, when the AH was greater than 22 g . m-3, the loss in infectivity was typically greater than 6 orders of magnitude. At a fixed RH of 75%, infectivity was very sensitive to temperature, decreasing two orders of magnitude between 19 degrees C and 25 degrees C. We used random forest modeling to identify the best environmental predictors for modulating virus infectivity. The model explained 83% of variation in Phi6 infectivity and suggested that RH is the most important factor in controlling virus infectivity in droplets. This research provides novel information about the complex interplay between temperature, humidity, and the survival of viruses in droplets.IMPORTANCE Enveloped viruses are responsible for a number of infectious diseases resulting in thousands of deaths and billions of dollars of economic losses per year in the United States. There has been a lively debate in the literature over whether absolute humidity (AH) or relative humidity (RH) modulates virus infectivity. We designed a controlled study and used advanced statistical modeling techniques specifically to address this question. By providing an improved understanding of the relationship between environmental conditions and virus infectivity, our work will ultimately lead to improved strategies for predicting and controlling disease transmission. PMID- 29625987 TI - Efficacy of Silver Dihydrogen Citrate and Steam Vapor against a Human Norovirus Surrogate, Feline Calicivirus, in Suspension, on Glass, and on Carpet. AB - Carpets and other soft surfaces have been associated with prolonged and reoccurring human norovirus (HuNoV) outbreaks. Environmental hygiene programs are important to prevent and control HuNoV outbreaks. Despite our knowledge of HuNoV transmission via soft surfaces, no commercially available disinfectants have been evaluated on carpets. Our aim was to adapt a current standardized method for virucidal testing by assessing two disinfection technologies, silver dihydrogen citrate (SDC) and steam vapor, against one HuNoV surrogate, feline calicivirus (FCV), on wool and nylon carpets. First, we evaluated the effect of both technologies on the appearance of carpet. Next, we evaluated the efficacy of SDC in suspension and the efficacy of SDC and steam vapor against FCV on a glass surface, each with and without serum. Lastly, we tested both technologies on two types of carpet, wool and nylon. Both carpets exhibited no obvious color changes; however, SDC treatments left a residue while steam vapor left minor abrasions to fibers. SDC in suspension and on glass reduced FCV by 4.65 log10 and >4.66 log10 PFU, respectively, but demonstrated reduced efficacy in the presence of serum. However, SDC was only efficacious against FCV on nylon (3.62-log10 PFU reduction) and not wool (1.82-log10 PFU reduction). Steam vapor reduced FCV by >4.93 log10 PFU on glass in 10 s and >3.68 log10 PFU on wool and nylon carpet carriers in 90 s. There was a limited reduction of FCV RNA under both treatments compared to that of infectivity assays, but RNA reductions were higher in samples that contained serum.IMPORTANCE Human noroviruses (HuNoV) account for ca. 20% of all diarrheal cases worldwide. Disease symptoms may include diarrhea and vomit, with both known to contribute to transmission. The prevention and control of HuNoV are difficult because they are environmentally resilient and resistant to many disinfectants. Several field studies have linked both hard and soft surfaces to HuNoV outbreaks. However, many disinfectants efficacious against HuNoV surrogates are recommended for hard surfaces, but no commercially available products have demonstrated efficacy against these surrogates on soft surfaces. Our research objectives were to evaluate liquid and steam-based technologies in suspension and on hard surface carriers in addition to adapting and testing a protocol for assessing the virucidal effects of disinfection technologies on carpet carriers. These results will inform both the government and industry regarding a standard method for evaluating the virucidal effects of disinfectants on carpet while demonstrating their efficacy relative to suspension and hard-surface tests. PMID- 29625988 TI - Microbial dynamics during industrial rearing, processing, and storage of the tropical house cricket (Gryllodes sigillatus) for human consumption. AB - In this study, the microbiota during industrial rearing, processing, and storage of the edible tropical house cricket, Gryllodes sigillatus, was investigated. To this end, samples were analyzed of the cricket feed, before feeding as well as taken from the cages, and the crickets during rearing, after harvest, and after processing into frozen, oven-dried, and smoked and subsequently oven-dried end products. Although the feed contained lower microbial numbers than the crickets, both were dominated by the same species-level operational taxonomic units as determined by Illumina Miseq sequencing. They corresponded, among others, to members of Porphyromonadaceae, Fusobacterium, Parabacteroides and Erwinia The harvested crickets contained high microbial numbers, but none of the investigated food pathogens Salmonella spp., Listeria monocytogenes, Bacillus cereus, and coagulase-positive staphylococci. However, some possible mycotoxin-producing fungi were isolated from the crickets. A post-harvest heat treatment, shortly boiling the crickets, reduced microbial numbers, but an endospore load of 2.4 log cfu/g remained. After processing, an increase in microbial counts was observed for dried and smoked plus dried crickets. Additionally, in the smoked plus dried crickets, a high abundance of a Bacillus sp. was observed. Considering the possible occurrence of food-pathogenic species from this genus, it is advised to apply a heat treatment which is sufficient to eliminate spores. Nevertheless, the microbial numbers remained constant over a six-month storage period, frozen (frozen end product) or at ambient temperature (oven-dried and smoked plus dried end products).Importance. The need for sustainable protein sources has led to the emergence of a new food sector, producing and processing edible insects into foods. However, insight into the microbial quality of this new food and into the microbial dynamics during rearing, processing and storage of edible insects is still limited. Samples monitored for their microbiota were obtained in this study from an industrial rearing and processing cycle. The results lead in the first place to the identification of process steps which are critical for microbial food safety. Secondly, they can be used in the construction of a HACCP plan and of a Novel Food dossier which is required in Europe for edible insects. Finally, they confirm the shelf life period which was determined by the rearer. PMID- 29625989 TI - A Phage Lysin Fused to a Cell-Penetrating Peptide Kills Intracellular Methicillin Resistant Staphylococcus aureus in Keratinocytes and Has Potential as a Treatment for Skin Infections in Mice. AB - Staphylococcus aureus is the main pathogen that causes skin and skin structure infections and is able to survive and persist in keratinocytes of the epidermis. Since the evolution of multidrug-resistant bacteria, the use of phages and their lysins has presented a promising alternative approach to treatment. In this study, a cell wall hydrolase (also called lysin) derived from Staphylococcus phage JD007 (JDlys) was identified. JDlys showed strong lytic activity against methicillin-resistant Staphylococcus aureus (MRSA) strains from different sources and of different multilocus sequence typing (MLST) types. Furthermore, a fusion protein consisting of a cell-penetrating peptide derived from the trans activating transcription (Tat) factor fused to JDlys (CPPTat-JDlys) was used to kill MRSA bacteria causing intracellular infections. CPPTat-JDlys, in which the fusion of CPPTat to JDlys had almost no effect on the bacteriolytic activity of JDlys, was able to effectively eliminate intracellular MRSA bacteria and alleviate the inflammatory response and cell damage caused by MRSA. Specifically, CPPTat-JDlys was able to combat MRSA-induced murine skin infections and, consequently, expedite the healing of cutaneous abscesses. These data suggest that the novel antimicrobial CPP-JDlys may be a worthwhile candidate as a treatment for skin and skin structure infections caused by MRSA.IMPORTANCES. aureus is the main cause of skin and skin structure infections due to its ability to invade and survive in the epithelial barrier. Due to the overuse of antibiotics in humans and animals, S. aureus has shown a high capacity for acquiring and accumulating mechanisms of resistance to antibiotics. Moreover, most antibiotics are usually limited in their ability to overcome the intracellular persistence of bacteria causing skin and skin structure infections. So, it is critical to seek a novel antimicrobial agent to eradicate intracellular S. aureus In this study, a cell-penetrating peptide fused to lysin (CPP-JDlys) was engineered. Our results show that CPP-JDlys can enter keratinocytes and effectively eliminate intracellular MRSA. Meanwhile, experiments with mice revealed that CPP-JDlys efficiently inhibits the proliferation of MRSA in murine skin and thus shortens the course of wound healing. Our results indicate that the CPP-fused lysin has potential for use for the treatment of skin infections caused by MRSA. PMID- 29625990 TI - VqsA, a Novel LysR-Type Transcriptional Regulator, Coordinates Quorum Sensing (QS) and Is Controlled by QS To Regulate Virulence in the Pathogen Vibrio alginolyticus. AB - The quorum sensing (QS) system controls bacterial group behaviors in response to cell density. In vibrios, LuxR and AphA are two master QS regulators (MQSRs) controlling gene expression in response to high or low cell density. Other regulators involved in the regulation of these two MQSRs and QS pathways remain to be determined. Here, we performed bacterial one-hybrid (B1H)-assay-based screens of transcriptional factors (TFs) to identify TFs that can directly regulate the expression of luxR and aphA from a library of 285 TFs encoded by the fish pathogen Vibrio alginolyticus A total of 7 TFs were identified to bind to the promoters of both luxR and aphA Among these TFs, the novel LysR-type transcriptional regulator (LTTR) VqsA could activate LuxR and repress AphA transcription. Meanwhile, LuxR and AphA exerted feedback inhibition and activation of vqsA expression, respectively, indicating that VqsA coordinates QS and is also regulated by QS. In addition, VqsA inhibited its own expression by directly binding to its own promoter region. The VqsA-binding sites in the promoter regions of luxR and aphA as well as the binding sites of LuxR, AphA, and VqsA in the vqsA gene were uncovered by electrophoretic mobility shift assays (EMSAs) and DNase I footprinting analysis. Finally, VqsA was verified to play essential roles in QS-regulated phenotypes, i.e., type VI secretion system 2 (T6SS2)-dependent interbacterial competition, biofilm formation, exotoxin production, and in vivo virulence of V. alginolyticus Collectively, our data showed that VqsA is an important QS regulator in V. alginolyticusIMPORTANCE Investigation of the mechanism of regulation of quorum sensing (QS) systems will facilitate an understanding of bacterial pathogenesis and the identification of effective QS interference (QSI) targets. Here, we systematically screened transcriptional factors (TFs) that modulate the expression of the master QS regulators (MQSRs) LuxR and AphA, and a novel LysR-type transcriptional regulator, VqsA, was identified. Our data illuminated the mechanisms mediating the interaction among LuxR, AphA, and VqsA as well as the effects of these regulators on the expression and output of QS. The impaired expression of virulence genes as a result of vqsA disruption demonstrated that VqsA is an important player in QS regulation and pathogenesis and may be the third MQSR involved in sensing environmental signals by vibrios to coordinate QS responses. This study will facilitate the development of strategies to interfere with QS and effectively control this pathogen that plagues the aquaculture industry. PMID- 29625992 TI - What is the greatest achievement of the NHS? PMID- 29625991 TI - T3 Induces Both Markers of Maturation and Aging in Pancreatic beta-Cells. AB - Previously, we showed that thyroid hormone (TH) triiodothyronine (T3) enhanced beta-cell functional maturation through induction of Mafa High levels of T3 have been linked to decreased life span in mammals and low levels to lengthened life span, suggesting a relationship between TH and aging. Here, we show that T3 increased p16Ink4a (a beta-cell senescence marker and effector) mRNA in rodent and human beta-cells. The kinetics of Mafa and p16Ink4a induction suggested both genes as targets of TH via TH receptors (THRs) binding to specific response elements. Using specific agonists CO23 and GC1, we showed that p16Ink4a expression was controlled by THRA and Mafa by THRB. Using chromatin immunoprecipitation and a transient transfection yielding biotinylated THRB1 or THRA isoforms to achieve specificity, we determined that THRA isoform bound to p16Ink4a , whereas THRB1 bound to Mafa but not to p16Ink4a On a cellular level, T3 treatment accelerated cell senescence as shown by increased number of beta cells with acidic beta-galactosidase activity. Our data show that T3 can simultaneously induce both maturation (Mafa) and aging (p16Ink4a ) effectors and that these dichotomous effects are mediated through different THR isoforms. These findings may be important for further improving stem cell differentiation protocols to produce functional beta-cells for replacement therapies in diabetes. PMID- 29625993 TI - An Observational Study of the Association of Video- Versus Text-Based Informed Consent With Multicenter Trial Enrollment: Lessons From the PALM Study (Patient and Provider Assessment of Lipid Management). AB - BACKGROUND: Patient participation in clinical research is low, in part because of the length and complexity of the informed consent process. Video informed consent may enhance the appeal of research and help break down barriers to participation. METHODS AND RESULTS: The PALM study (Patient and Provider Assessment of Lipid Management) enrolled 7904 patients at cardiology, endocrinology, and primary care clinics across the United States to evaluate cholesterol management practices. Of 153 participating clinics, 67 (43.8%) secured institutional review board approval to use a tablet-based video informed consent tool that patients could select to navigate through the informed consent process instead of traditional text-based informed consent. At sites without institutional review board approval of video consent, all patients read a text-based informed consent document. Site activation times and enrollment volumes, as well as characteristics of enrolled patients, were compared between sites with and without video consent capability. Sites with video consent capability more often used a central institutional review board (89.6% versus 73.3%), were more often rural (16.7% versus 3.8%), and tended to have fewer providers. Compared with sites without video consent capability, sites with video consent capability had shorter times from site approach to first patient enrollment (median 178 versus 207 days; P=0.02). Sites with video consent capability enrolled similar numbers of patients as sites without video consent capability (P=0.48) but enrolled a greater proportion of patients who were >=75 years old (27.5% versus 23.6%; P<0.001) and nonwhite (17.7% versus 14.2%; P<0.001). CONCLUSIONS: In this observational study of recruitment in a multicenter registry, sites approved for video consent use enrolled the same number of patients as sites with only traditional text-based informed consent but had faster speed to first patient enrolled and more often enrolled older and nonwhite patients. Future randomized trials are needed to assess the impact of video consent on enrollment mechanics and demographics. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02341664. PMID- 29625995 TI - New medication review method cuts veterans' Rx load, saves millions. PMID- 29625996 TI - Hospitals get serious about pharmacy technician training. PMID- 29625994 TI - A High-Resolution Map of Meiotic Recombination in Cryptococcus deneoformans Demonstrates Decreased Recombination in Unisexual Reproduction. AB - Multiple species within the basidiomycete genus Cryptococcus cause cryptococcal disease. These species are estimated to affect nearly a quarter of a million people leading to ~180,000 mortalities, annually. Sexual reproduction, which can occur between haploid yeasts of the same or opposite mating type, is a potentially important contributor to pathogenesis as recombination can generate novel genotypes and transgressive phenotypes. However, our quantitative understanding of recombination in this clinically important yeast is limited. Here, we describe genome-wide estimates of recombination rates in Cryptococcus deneoformans and compare recombination between progeny from alpha-alpha unisexual and a-alpha bisexual crosses. We find that offspring from bisexual crosses have modestly higher average rates of recombination than those derived from unisexual crosses. Recombination hot and cold spots across the C. deneoformans genome are also identified and are associated with increased GC content. Finally, we observed regions genome-wide with allele frequencies deviating from the expected parental ratio. These findings and observations advance our quantitative understanding of the genetic events that occur during sexual reproduction in C. deneoformans, and the impact that different forms of sexual reproduction are likely to have on genetic diversity in this important fungal pathogen. PMID- 29625997 TI - Correction. PMID- 29625998 TI - FDA approves novel biologic for resistant HIV infection. PMID- 29625999 TI - Value proposition for psychiatric pharmacy. PMID- 29626000 TI - Physical compatibility of levetiracetam injection with heparin, dobutamine, and dopamine. PMID- 29626001 TI - Description of a tall-man lettering program for look-alike and sound-alike antineoplastic agents. PMID- 29626002 TI - Evaluating off-label uses of acetazolamide. AB - PURPOSE: Current off-label uses of acetazolamide in hospitalized patients are reviewed. SUMMARY: Acetazolamide is a carbonic anhydrase inhibitor typically used for indications including epilepsy, glaucoma, edema, and altitude sickness but it may be prescribed in hospitalized patients for off-label indications. It inhibits carbonic anhydrase, which leads to reduced hydrogen ion secretion in the proximal renal tubule, resulting in increased bicarbonate and cation excretion and causing urinary alkalization and diuresis. In addition, acetazolamide decreases the production of cerebrospinal fluid (CSF) and aqueous humor, reducing intracranial pressure (ICP) and intraocular pressure. This allows acetazolamide to be used for treatment of idiopathic intracranial hypertension and elevated ICP due to CSF leaks to avoid invasive procedures. It is a sulfonamide derivative, with dosages ranging from 250 to 4,000 mg daily divided every 6-12 hours. The plasma half-life is 4-8 hours, though the pharmacologic effects of acetazolamide last longer. Acetazolamide is highly protein bound and primarily eliminated by the kidneys, so administration should not be more frequent than every 12 hours if creatinine clearance is less than 50 mL/min. Limited literature exists describing the optimal patients to receive acetazolamide therapy. CONCLUSION: The potential benefits of acetazolamide include ventilator weaning for chronic obstructive pulmonary disease patients, avoidance of invasive procedures in patients with a CSF leak or elevated ICP, and prevention of high-dose methotrexate toxicity and contrast-induced nephropathy. Uncertainty remains regarding the selection of patients who would best benefit from acetazolamide use. PMID- 29626003 TI - Probable fidaxomicin-induced pancytopenia. AB - PURPOSE: A case of pancytopenia in a patient receiving treatment with fidaxomicin for Clostridium difficile infection (CDI) is described. SUMMARY: A 33-year-old Caucasian woman was admitted to the hospital with a chief complaint of loose stools occurring approximately 7 times a day; she also reported fever, nausea, diffuse abdominal pain, and fatigue. The patient had a history of recurrent CDI, recurrent urinary tract infections, nephrolithiasis, chronic hepatitis C, and endometriosis. Her previous therapies for CDI included metronidazole, vancomycin, rifaximin, and fecal microbiota transplantation. On admission, she had a platelet count of 172,000 platelets/mm3, hemoglobin concentration of 11.1 g/dL, and white blood cell (WBC) count of 3,100 cells/mm3. Within 24 hours of the first dose of fidaxomicin and before the second dose, the patient's platelet count fell to 156,000 platelets/mm3, her hemoglobin concentration decreased to 9.9 g/dL, and her WBC count fell to 2,600 cells/mm3. Values for all 3 tests continued to decrease during the first few days of fidaxomicin therapy. One dose of filgrastim 300 MUg was administered subcutaneously on day 6 in response to the pancytopenia, after which the platelet, hemoglobin, and WBC values stabilized for a day and then generally declined. Platelet, hemoglobin, and WBC values returned to normal within 3 days of the patient's last dose of fidaxomicin. Use of the Naranjo et al. adverse drug reaction probability scale indicated a probable association (score of 6) between fidaxomicin and the patient's pancytopenia. CONCLUSION: A 33 year-old woman developed pancytopenia during a course of fidaxomicin therapy for CDI. Platelet, hemoglobin, and WBC values returned to normal within 3 days of the final fidaxomicin dose. PMID- 29626004 TI - Pharmacy staffing, workload, and productivity benchmarks in state psychiatric hospitals. AB - PURPOSE: Current benchmark statistics on staffing, workload, and productivity in hospital pharmacy departments of state psychiatric hospitals are described and assessed by hospital size. METHODS: An electronic survey of state psychiatric hospitals was conducted. Hospitals were categorized based on number of occupied beds. Descriptive statistics using Student's t tests, Pearson's chi-square tests, and Pearson's correlation coefficients were used to characterize the data and compare productivity by hospital size. RESULTS: Responses were received from 41 of 116 hospitals, yielding a response rate of 35.3%. Respondent hospitals did not differ from nonrespondents based on demographic data. Average inpatient census, patient days per year, expenditures, and workload were found to correlate positively with hospital size (r = 0.381-0.991, p < 0.05). Over 30% of hospitals reported using no indicators to monitor pharmacy productivity. Productivity ratios differed between very small-small and medium-large hospital groups: mean pharmaceutical expenditures per 100 occupied beds and per 1,000 patient days (p = 0.017 and 0.05, respectively), mean full-time equivalents (FTEs) per 1,000 doses dispensed or administered per month and per 100 occupied beds (p = 0.042 and 0.026, respectively), and mean pharmacist and technician FTEs per 100 occupied beds (p = 0.012 and 0.019, respectively). CONCLUSION: A survey of pharmacies in state psychiatric hospitals provided metrics data on staffing, workload, and productivity that may be used as benchmarks in efforts to improve workforce efficiency, pharmaceutical care services, and financial performance. PMID- 29626005 TI - Contemporary challenges and novel strategies for health-system formulary management. PMID- 29626006 TI - ASHP Guidelines for the Management of Investigational Drug Products. PMID- 29626007 TI - ASHP professional policy recommendations-Invitation to comment. PMID- 29626008 TI - Differences between ATA, AACE/ACE/AME and ACR TI-RADS ultrasound classifications performance in identifying cytological high-risk thyroid nodules. AB - OBJECTIVE: Thyroid ultrasound is crucial for clinical decision in the management of thyroid nodules. In this study, we aimed to estimate and compare the performance of ATA, AACE/ACE/AME and ACR TI-RADS ultrasound classifications in discriminating nodules with high-risk cytology. DESIGN: Cross-sectional study. METHODS: 1077 thyroid nodules undergoing fine-needle aspiration were classified according to ATA, AACE/ACE/AME and ACR TI-RADS ultrasound classifications by an automated algorithm. Odds ratios (ORs) and receiver operating characteristic (ROC) curves for high-risk cytology categories (TIR3b, TIR4 and TIR5) were calculated for the different US categories and compared. RESULTS: Cytological categories of risk increased together with all US classifications' sonographic patterns (P < 0.001). The diagnostic performance (C-index) of ACR TI-RADS and AACE/ACE/AME significantly improved when adding clinical data as gender and age in the regression model (P < 0.001). A significant difference in the final model C-index between the three US classification systems was found (P < 0.029), with the ACR TI-RADS showing the highest nominal C-index value, significantly superior to ATA (P = 0.008), but similar to AACE/ACE/AME (P = 0.287). ATA classification was not able to classify 54 nodules, which showed a significant 7 times higher risk of high-risk cytology than the 'very low suspicion' nodules (OR: 7.20 (95% confidence interval: 2.44-21.24), P < 0.001). CONCLUSIONS: The ACR TI-RADS classification system has the highest area under the ROC curve for the identification of cytological high-risk nodules. ATA classification leaves 'unclassified' nodules at relatively high risk of malignancy. PMID- 29626009 TI - The Nurr1 Ligand,1,1-bis(3'-Indolyl)-1-(p-Chlorophenyl)Methane, Modulates Glial Reactivity and Is Neuroprotective in MPTP-Induced Parkinsonism. AB - The orphan nuclear receptor Nurr1 (also called nuclear receptor-4A2) regulates inflammatory gene expression in glial cells, as well as genes associated with homeostatic and trophic function in dopaminergic neurons. Despite these known functions of Nurr1, an endogenous ligand has not been discovered. We postulated that the activation of Nurr1 would suppress the activation of glia and thereby protect against loss of dopamine (DA) neurons after subacute lesioning with 1 methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Our previous studies have shown that a synthetic Nurr1 ligand, 1,1-bis(3'-indolyl)-1-(p chlorophenyl)methane (C-DIM12), suppresses inflammatory gene expression in primary astrocytes and induces a dopaminergic phenotype in neurons. Pharmacokinetic analysis of C-DIM12 in mice by liquid chromatography-mass spectrometry demonstrated that approximately three times more compound concentrated in the brain than in plasma. Mice treated with four doses of MPTP + probenecid over 14 days were monitored for neurobehavioral function, loss of dopaminergic neurons, and glial activation. C-DIM12 protected against the loss of DA neurons in the substantia nigra pars compacta and DA terminals in the striatum, maintained a ramified phenotype in microglia, and suppressed activation of astrocytes. In vitro reporter assays demonstrated that C-DIM12 was an effective activator of Nurr1 transcription in neuronal cell lines. Computational modeling of C-DIM12 binding to the three-dimensional structure of human Nurr1 identified a high-affinity binding interaction with Nurr1 at the coactivator domain. Taken together, these data suggest that C-DIM12 is an activator of Nurr1 that suppresses glial activation and neuronal loss in vivo after treatment with MPTP, and that this receptor could be an efficacious target for disease modification in individuals with Parkinson's disease and related disorders. PMID- 29626010 TI - Comparison of Empiric Antibiotics for Acute Osteomyelitis in Children. AB - OBJECTIVES: Broad-spectrum antibiotics are commonly used for the empiric treatment of acute hematogenous osteomyelitis and often target methicillin resistant Staphylococcus aureus (MRSA) with medication-associated risk and unknown treatment benefit. We aimed to compare clinical outcomes among patients with osteomyelitis who did and did not receive initial antibiotics used to target MRSA. METHODS: A retrospective cohort study of 974 hospitalized children 2 to 18 years old using the Pediatric Health Information System database, augmented with clinical data. Rates of hospital readmission, repeat MRI and 72-hour improvement in inflammatory markers were compared between treatment groups. RESULTS: Repeat MRI within 7 and 180 days was more frequent among patients who received initial MRSA coverage versus methicillin-sensitive S aureus (MSSA)-only coverage (8.6% vs 4.1% within 7 days [P = .02] and 12% vs 5.8% within 180 days [P < .01], respectively). Ninety- and 180-day hospital readmission rates were similar between coverage groups (9.0% vs 8.7% [P = .87] and 10.9% vs 11.2% [P = .92], respectively). Patients with MRSA- and MSSA-only coverage had similar rates of 72 hour improvement in C-reactive protein values, but patients with MRSA coverage had a lower rate of 72-hour white blood cell count normalization compared with patients with MSSA-only coverage (4.2% vs 16.4%; P = .02). CONCLUSIONS: In this study of children hospitalized with acute hematogenous osteomyelitis, early antibiotic treatment used to target MRSA was associated with a higher rate of repeat MRI compared with early antibiotic treatment used to target MSSA but not MRSA. Hospital readmission rates were similar for both treatment groups. PMID- 29626012 TI - Maintaining optimism in adversity: physicians leading innovation, education and responsible care delivery. PMID- 29626013 TI - Diabetes remission: a realistic goal? PMID- 29626014 TI - Glasgow Blatchford Score and risk stratifications in acute upper gastrointestinal bleed: can we extend this to 2 for urgent outpatient management? AB - Upper gastrointestinal (GI) bleeds are a common presentation to emergency departments in the UK. The Glasgow Blatchford score (GBS) predicts the outcome of patients at presentation. Current UK and European guidelines recommend outpatient management for a GBS of 0. In the current study, our aim was to assess whether extending the GBS allows for early discharge while maintaining patient safety. We also analysed whether pathologies could be missed by discharging patients too early. Data were retrospectively collected on patients admitted with symptoms of an upper GI bleed between 1 October 2013 and 10 June 2016. The GBS was calculated and gastroscopy reports were obtained for each patient. In total, 399 patients were identified, 63 of whom required therapy. The negative predictive value (NPV) for excluding the need for endoscopic intervention with a GBS score up to 1 was 100%. Extending the score to 2 and 3 reduced the NPV to 98.53% and 98.77%, respectively. The NPV of GBS in excluding any diagnosis at 0 was 43.55%. Two patients died as a result of GI bleeding, with a GBS score of 3. Therefore, we can conclude that, for non-variceal bleeds, the GBS can be extended to 2 for safe outpatient management, thereby reducing the number of bed days and pressure for urgent endoscopies. PMID- 29626011 TI - Centromere transcription allows CENP-A to transit from chromatin association to stable incorporation. AB - Centromeres are essential for chromosome segregation and are specified epigenetically by the presence of the histone H3 variant CENP-A. In flies and humans, replenishment of the centromeric mark is uncoupled from DNA replication and requires the removal of H3 "placeholder" nucleosomes. Although transcription at centromeres has been previously linked to the loading of new CENP-A, the underlying molecular mechanism remains poorly understood. Here, we used Drosophila melanogaster tissue culture cells to show that centromeric presence of actively transcribing RNA polymerase II temporally coincides with de novo deposition of dCENP-A. Using a newly developed dCENP-A loading system that is independent of acute transcription, we found that short inhibition of transcription impaired dCENP-A incorporation into chromatin. Interestingly, initial targeting of dCENP-A to centromeres was unaffected, revealing two stability states of newly loaded dCENP-A: a salt-sensitive association with the centromere and a salt-resistant chromatin-incorporated form. This suggests that transcription-mediated chromatin remodeling is required for the transition of dCENP-A to fully incorporated nucleosomes at the centromere. PMID- 29626015 TI - The prediction of in-hospital mortality by mid-upper arm circumference: a prospective observational study of the association between mid-upper arm circumference and the outcome of acutely ill medical patients admitted to a resource-poor hospital in sub-Saharan Africa. AB - There are few reports of the association of nutritional status with in-hospital mortality of acutely ill medical patients in sub-Saharan Africa. This is a prospective observational study comparing the predictive value of mid-upper arm circumference (MUAC) of 899 acutely ill medical patients admitted to a resource poor sub-Saharan hospital with mental alertness, mobility and vital signs. Mid upper arm circumference ranged from 15 cm to 42 cm, and 12 (24%) of the 50 patients with a MUAC less than 20 cm died (OR 4.84, 95% CI 2.23-10.37). Of the 237 patients with a MUAC more than 28 cm only six (2.5%) died (OR 0.27, 95% CI 0.10-0.67). On logistic regression, the National Early Warning Score (NEWS), alertness, mobility and MUAC were independent predictors of in-hospital mortality. Mid-upper arm circumference is an independent predictor of the in hospital mortality of acutely ill medical patients in a resource-poor hospital in sub-Saharan Africa. PMID- 29626016 TI - One year's activity and outcome data from an ambulatory cardiology unit. AB - In 2015, the Belfast Trust piloted an ambulatory cardiology unit (ACU). The ethos of the ACU was to reduce pressure on the Emergency Department by providing a unit where rapid evaluation, treatment and follow-up could be provided by the cardiology team and, at the same time, reduce inpatient admissions to cardiology beds. The service proved effective in reducing admissions to cardiology beds by 13.5% over a 1-year period, while patient outcomes at 30 days and 6 months demonstrated that the service is safe, with only 1.7% of patients readmitted at 30 days and 6 months with the same or a related complaint. The principles of ACU could be adopted by many other specialities. PMID- 29626017 TI - Systemic inflammatory disorders in patients admitted for aseptic meningitis. AB - Acute meningitis can be the first manifestation of an underlying systemic inflammatory disorder (SID). In the current study, we aimed to identify clinical indicators for SIDs in patients admitted for acute aseptic meningitis. All patients hospitalised for acute aseptic meningitis over a 4-year period in a department of internal medicine were included retrospectively. Patients with neoplastic meningitis were excluded. Extraneurological signs were recorded using a systematic panel. Systemic inflammatory disorder diagnosis was made according to current international criteria. Forty-three (average age 46 years [range 19-82 years], 60% females) consecutive patients were analysed retrospectively. Of these, 23 patients had an SID (mostly sarcoidosis and Behcet's disease). Multiple logistic regression analysis showed that the probability of an SID was 93.7% in patients with both neurological and extraneurological signs, but 14.9% in patients with neither neurological nor extraneurological signs. In conclusion, clinical sorting according to both neurological and extraneurological signs could help to identify patients with acute aseptic meningitis caused by an SID. PMID- 29626018 TI - Drug therapies in chronic heart failure: a focus on reduced ejection fraction. AB - There are multiple evidence-based drug treatments for chronic heart failure (HF), both disease-modifying agents and those for symptom control. The majority of the evidence base supports drugs used in HF with reduced left ventricular ejection fraction. The mainstay of disease modification involves manipulation of neurohormonal activation that occurs in HF. In addition to established angiotensin-converting enzyme inhibitors, beta blockers and mineralocorticoid receptor antagonists (MRAs), newer agents are now available such as the angiotensin receptor neprilysin inhibitors. Achieving the optimal drug regimen is complex and best performed by a specialist heart failure team. We aim to provide a comprehensive overview of contemporary drug therapies in chronic heart failure, as well as practical guidance for their use. There is a focus on treating patients with challenging comorbidities such as hypotension and chronic kidney disease (CKD), where a thorough understanding of drug therapy is essential. Multiple trials assessing the benefits of new therapies in HF, such as intravenous iron, are also ongoing. PMID- 29626019 TI - Diagnosis and management of sepsis. AB - Sepsis is a common condition with high morbidity and mortality. Although many patients may require critical care, this article considers the features of sepsis that are of most relevance to acute general physicians. Recently updated definitions of sepsis and septic shock have been proposed which better identify patients who are likely to have a poor outcome, and therefore give an opportunity to escalate care. Despite these advances, there is still no molecular signature able to diagnose sepsis. Pathogenesis is complex, with many immune and non-immune mediators involved. Four key areas are endothelial dysfunction, coagulation abnormalities, alterations in cell function and dysregulated cardiovascular responses. No specific therapy targeting the mediators of sepsis has yet proven effective. Prompt administration of appropriate antibiotics is of benefit, together with fluid resuscitation and oxygen. PMID- 29626020 TI - Bone and joint infection. AB - Bone and joint infections include septic arthritis, prosthetic joint infections, osteomyelitis, spinal infections (discitis, vertebral osteomyelitis and epidural abscess) and diabetic foot osteomyelitis. All of these may present through the acute medical take. This article discusses the pathogenesis of infection and highlights the importance of taking a careful history and fully examining the patient. It also emphasises the importance of early surgical intervention in many cases. Consideration of alternative diagnoses, appropriate imaging and high quality microbiological sampling is important to allow appropriate and targeted antimicrobial therapy. This article makes some suggestions as to empiric antibiotic choice; however, therapy should be guided by local antimicrobial policies and infection specialists. Involvement of a multidisciplinary team is essential for optimal outcomes. PMID- 29626021 TI - Acute encephalitis - diagnosis and management. AB - Encephalitis, inflammation of the brain, is most commonly caused by a viral infection (especially herpes simplex virus [HSV] type 1 in the UK) although autoimmune causes, such as N-methyl D-aspartate receptor (NMDAR) antibody encephalitis, are increasingly recognised. Most patients present with a change in consciousness level and may have fever, seizures, movement disorder or focal neurological deficits. Diagnosis hinges crucially on lumbar puncture and cerebrospinal fluid (CSF) examination, but imaging and electroencephalography (EEG) may also be helpful. Treatment of HSV encephalitis with aciclovir dramatically improves outcome, but the optimal management of autoimmune encephalitis is still uncertain. Many patients with encephalitis are left with residual physical or neuropsychological deficits which require long-term multidisciplinary management. Here we review assessment of patients with suspected encephalitis, general aspects of management and areas of ongoing research. PMID- 29626022 TI - Diagnosis and management of cellulitis. AB - Cellulitis is a frequently encountered condition, but remains a challenging clinical entity. Under and overtreatment with antimicrobials frequently occurs and mimics cloud the diagnosis. Typical presentation, microbiology and management approaches are discussed. PMID- 29626023 TI - Management of acute meningitis. AB - Acute meningitis remains a devastating disease. Clinicians need a low threshold for suspecting meningitis, to undertake appropriate investigations and provide treatment in a timely manner, to minimise the risk of poor outcome in bacterial disease, while limiting unnecessary treatment in viral meningitis. PMID- 29626024 TI - Pyrexia of unknown origin. AB - The syndrome of pyrexia of unknown origin (PUO) was first defined in 1961 but remains a clinical challenge for many physicians. Different subgroups with PUO have been suggested, each requiring different investigative strategies: classical, nosocomial, neutropenic and HIV-related. This could be expanded to include the elderly as a fifth group. The causes are broadly divided into four groups: infective, inflammatory, neoplastic and miscellaneous. Increasing early use of positron emission tomography-computed tomography (PET-CT) and the development of new molecular and serological tests for infection have improved diagnostic capability, but up to 50% of patients still have no cause found despite adequate investigations. Reassuringly, the cohort of undiagnosed patients has a good prognosis. In this article we review the possible aetiologies of PUO and present a systematic clinical approach to investigation and management of patients, recommending potential second-line investigations when the aetiology is unclear. PMID- 29626025 TI - CME Infectious diseases (113044) self-assessment questionnaire. PMID- 29626026 TI - Dilated cardiomyopathy as the first presentation of coeliac disease: association or causation? AB - Global ventricular impairment is a frequent presentation in clinical practice, but dissection of causative mechanisms from clinical associations is challenging. We present the case of a 19-year-old man who presented with dilated cardiomyopathy as the first presentation of coeliac disease. The manifestation of iron deficiency anaemia prompted gastroenterology input and enabled accurate diagnosis. It is unclear whether coeliac disease was simply coexistent or directly implicated in pathophysiology. Mechanisms may relate to nutritional deficiencies or autoimmune myocarditis arising from cross-reactivity. We advocate early multidisciplinary involvement in such contexts to aid with management strategy. Despite adherence to a gluten-free diet, ventricular dysfunction persisted and he has been referred to a cardiac transplant centre. PMID- 29626027 TI - Lesson of the month 1: Massive spontaneous haematomas in an elderly man. AB - A 73-year-old man presented with bilateral leg pain and swelling, and no history of trauma or bleeding disorders. Clinical examination, biochemistry and magnetic resonance imaging of the thighs were suggestive of muscle haematomas. These progressed significantly during the admission, requiring blood transfusion. Normal vascular anatomy on computed tomography, renal and liver function, and absence of infection made a bleeding diathesis more likely. This may be caused by coagulation defects, platelet disorders and vascular fragility. An undetectable serum ascorbic acid level confirmed the clinical suspicion of scurvy, and administration of vitamin C resulted in rapid improvement. Our case provides a structured approach to the diagnosis of bleeding disorders and scurvy, a treatable and potentially fatal disease which is often forgotten. PMID- 29626028 TI - Lesson of the month 2: A rare presentation of stroke: diagnosis made on magnetic resonance imaging. AB - Bilateral thalamic infarcts are uncommon posterior circulation strokes. The artery of Percheron (AOP) is a rare anatomical variant involving a singular arterial supply to both thalami and occlusion leads to bilateral thalamic infarction.We report the case of a 71-year-old man who presented with decreased consciousness (fluctuating Glasgow Coma Scale score of 5-7). He had a background of atrial fibrillation and was anticoagulated with dabigatran, a novel oral anticoagulant. Computed tomography (CT) scan showed a mildly reduced attenuation in the region of the left thamalus.Subsequent diffusion-weighted magnetic resonance imaging (MRI) showed acute brainstem infarction, extending into the thalamus bilaterally, likely due to AOP occlusion. Bilateral thalamic infarcts due to AOP occlusion may not be recognised on initial CT scan and are more readily seen using diffusion-weighted MRI, which is the most beneficial imaging modality to aid in early diagnosis and treatment. PMID- 29626029 TI - Respiratory symptoms in a patient with inflammatory bowel disease. PMID- 29626030 TI - Recognised training routes are needed to sustain new maternal medicine networks. PMID- 29626031 TI - Collaborative research has direct patient benefit and merits recognition. PMID- 29626032 TI - Response. PMID- 29626033 TI - The hazards of neglecting the skin. PMID- 29626034 TI - A 68-year-old with cranial nerve neuropathies and a troponin rise. PMID- 29626035 TI - Varicella zoster encephalitis, cranial nerve neuropathies, and takotsubo syndrome: delving further into the pathogenesis. PMID- 29626036 TI - Consultant recognition for accepting work experience students. PMID- 29626037 TI - Response. PMID- 29626038 TI - Not only what investigations? When, why, at what cost, whose choice? PMID- 29626039 TI - Response. PMID- 29626040 TI - Editorial note. PMID- 29626041 TI - Atom-by-atom tuning of the electrostatic potassium-channel modulator dehydroabietic acid. AB - Dehydroabietic acid (DHAA) is a naturally occurring component of pine resin that was recently shown to open voltage-gated potassium (KV) channels. The hydrophobic part of DHAA anchors the compound near the channel's positively charged voltage sensor in a pocket between the channel and the lipid membrane. The negatively charged carboxyl group exerts an electrostatic effect on the channel's voltage sensor, leading to the channel opening. In this study, we show that the channel opening effect increases as the length of the carboxyl-group stalk is extended until a critical length of three atoms is reached. Longer stalks render the compounds noneffective. This critical distance is consistent with a simple electrostatic model in which the charge location depends on the stalk length. By combining an effective anchor with the optimal stalk length, we create a compound that opens the human KV7.2/7.3 (M type) potassium channel at a concentration of 1 uM. These results suggest that a stalk between the anchor and the effector group is a powerful way of increasing the potency of a channel-opening drug. PMID- 29626042 TI - Incidence and risk factors of first-line antiretroviral treatment failure among human immunodeficiency virus-infected children in Amhara regional state, Ethiopia: a retrospective follow-up study. AB - OBJECTIVE: This study aimed to assess the incidence and risk factors of treatment failure among HIV/AIDS-infected children who were on antiretroviral therapy (ART) in Amhara National Regional State, Ethiopia. METHODS: A retrospective follow-up study was conducted from January 2010 to March 2016. A total of 824 children under the age of 15 who had started ART were included in the study. Data were collected from children's medical charts and ART registration logbook using a standard checklist. A Weibull regression model was used to identify the risk factors of treatment failure. Adjusted HRs (AHRs) with 95% CIs were used to declare statistical significance. RESULTS: The mean (+/-SD) age of the children was 6.4+/-3.6 years, with a median (IQR) follow-up of 30.5 (14.6-51.4) months. Sixty-three children (7.7%, 95% CI 5.8 to 9.5) developed treatment failure, 17 (27.0%) of whom were immunological and 46 (73.0%) were clinical failures. The incidence rate of treatment failure was 22.1/10 000 person-months. The cumulative probability of failure was 0.4, with 28 562.5 person-month observations. Lack of disclosure (AHR=4. 4, 95% CI 1.8 to 11.3), opportunistic infections during initiation of ART (AHR=2.3, 95% CI 1.3 to 4.1) and prolonged follow-up (AHR=0.06, 95% CI 0.02 to 0.18) were the main predictors of treatment failure. CONCLUSION: This study revealed that the incidence of treatment failure remains a significant public health concern in Ethiopia. Undisclosed HIV status to children, the presence of opportunistic infections during initiation of ART and prolonged follow-up were found to be the main predictors of treatment failure. Hence, early detection of treatment failure and further studies on viral monitoring need to be considered. PMID- 29626043 TI - HIV-1 disease progression in immune-competent HIV-1-infected and breastfeeding mothers participating in the ANRS 12174 clinical trial in Burkina Faso, South Africa, Uganda and Zambia: a cohort study. AB - OBJECTIVE: We have assessed HIV-1 disease progression among HIV-1-positive mothers in relation to duration of any or exclusive breast feeding in the context of ANRS 12174 trial. METHODS: The analysis was completed on 203, 212, 272 and 529 HIV-1-positive and lactating mothers with CD4 count >350 cells/uL from Burkina Faso, South Africa, Uganda and Zambia, respectively. The trial compared lamivudine and lopinavir/ritonavir as a peri-exposure prophylaxis during a 50 week follow-up time. A multiple logistic regression model was run with the mothers' weight, CD4 count and HIV-1 viral load as separate dependent variables, then combined into a dependent composite endpoint called HIV-1 disease progression where HIV-1 viral load was replaced by the HIV-1 clinical stage. Exclusive or predominant breast feeding (EPBF) and any breastfeeding duration were the key explanatory variables. RESULTS: In the adjusted model, the associations between EPBF duration and weight change, CD4 cell count and the HIV 1 viral load were consistently insignificant. The CD4 cell count was associated with a significantly higher mothers' body mass index (BMI; a mean increase of 4.9 (95% CI 2.1 to 7.7) CD4 cells/uL per each additional kilogram per square metre of BMI) and haemoglobin concentration (19.4 (95% CI 11.4 to 27.4) CD4 cells/uL per each additional gram per decilitre of haemoglobin concentration). There was no significant association between EPBF duration and HIV-1 disease progression. A higher education level was a factor associated with a slower HIV-1 disease progression. CONCLUSION: Breast feeding was not a risk factor for a faster progression of HIV-1 disease in mothers of this cohort with a baseline CD4 cell count >350 cells/uL. TRIAL REGISTRATION NUMBER: NCT0064026; Post-results. PMID- 29626044 TI - Efficacy of iron supplementation on fatigue and physical capacity in non-anaemic iron-deficient adults: a systematic review of randomised controlled trials. AB - OBJECTIVE: Iron supplementation in iron-deficiency anaemia is standard practice, but the benefits of iron supplementation in iron-deficient non-anaemic (IDNA) individuals remains controversial. Our objective is to identify the effects of iron therapy on fatigue and physical capacity in IDNA adults. DESIGN: Systematic review and meta-analysis of randomised controlled trials (RCTs). SETTING: Primary care. PARTICIPANTS: Adults (>=18 years) who were iron deficient but non-anaemic. INTERVENTIONS: Oral, intramuscular or intravenous iron supplementation; all therapy doses, frequencies and durations were included. COMPARATORS: Placebo or active therapy. RESULTS: We identified RCTs in Medline, Embase, Cochrane Central Register of Controlled Trials, Cumulative Index of Nursing and Allied Health, SportDiscus and CAB Abstracts from inception to 31 October 2016. We searched the WHO's International Clinical Trials Registry Platform for relevant ongoing trials and performed forward searches of included trials and relevant reviews in Web of Science. We assessed internal validity of included trials using the Cochrane Risk of Bias tool and the external validity using the Grading of Recommendations Assessment, Development and Evaluation methodology. From 11 580 citations, we included 18 unique trials and 2 companion papers enrolling 1170 patients. Using a Mantel-Haenszel random-effects model, iron supplementation was associated with reduced self-reported fatigue (standardised mean difference (SMD) -0.38; 95% CI 0.52 to -0.23; I2 0%; 4 trials; 714 participants) but was not associated with differences in objective measures of physical capacity, including maximal oxygen consumption (SMD 0.11; 95% CI -0.15 to 0.37; I2 0%; 9 trials; 235 participants) and timed methods of exercise testing. Iron supplementation significantly increased serum haemoglobin concentration (MD 4.01 g/L; 95% CI 1.22 to 6.81; I2 48%; 12 trials; 298 participants) and serum ferritin (MD 9.23 umol/L; 95% CI 6.48 to 11.97; I2 58%; 14 trials; 616 participants). CONCLUSION: In IDNA adults, iron supplementation is associated with reduced subjective measures of fatigue but not with objective improvements in physical capacity. Given the global prevalence of both iron deficiency and fatigue, patients and practitioners could consider consumption of iron-rich foods or iron supplementation to improve symptoms of fatigue in the absence of documented anaemia. PROSPERO REGISTRATION NUMBER: CRD42014007085. PMID- 29626045 TI - Effect of emotional content on online video sharing among health care professionals and researchers (DIFFUSION): results and lessons learnt from a randomised controlled trial. AB - OBJECTIVES: We assessed the effect of emotional content on the extent to which online videos are shared among health professionals. SETTING: We conducted a two arm randomised controlled trial. We sent a link to one of two videos by email to participants asking them to watch the video and forward it to their colleagues. PARTICIPANTS: Health professionals and researchers (obstetrics, gynaecology and midwifery) with an email address apart from those in countries where access to YouTube is banned. We estimated that 7000 participants were required. INTERVENTIONS: We compared two online videos providing background information about the WOMAN trial. The videos were the same length and had the same content. However, the intervention video had more emotional impact than the control video. OUTCOME MEASURES: The primary outcome was video sharing and the secondary outcome was views generated by participants. We conducted a chi2 test for the primary outcome and t-test for the secondary outcome. RESULTS: We randomly allocated 8353 email addresses, 4178 to the intervention video and 4175 to the control. Of these, 221 (5.3%) watched the intervention video and 215 (5.1%) watched the control. In the intervention group, 44 (1.1%) forwarded the video compared with 37 (0.9%) in the control group (risk ratio 1.2 [95% CI 0.8 to 1.8], p=0.44). Mean number of views generated by participants allocated to the intervention video was 0.04 and the control video was 0.03 (mean difference 0.01 [95% CI -0.02 to 0.04], p=0.53). CONCLUSIONS: We found no evidence that emotional content increased forwarding. The trial had low power due to the low video watching rate and the small number of outcome events. A key challenge for online dissemination is ensuring recipients watch the video. TRIAL REGISTRATION NUMBER: NCT02109159; Results. PMID- 29626046 TI - Using the Oxford Foot Model to determine the association between objective measures of foot function and results of the AOFAS Ankle-Hindfoot Scale and the Foot Function Index: a prospective gait analysis study in Germany. AB - OBJECTIVE: After cross-cultural adaption for the German translation of the Ankle Hindfoot Scale of the American Orthopaedic Foot and Ankle Society (AOFAS-AHS) and agreement analysis with the Foot Function Index (FFI-D), the following gait analysis study using the Oxford Foot Model (OFM) was carried out to show which of the two scores better correlates with objective gait dysfunction. DESIGN AND PARTICIPANTS: Results of the AOFAS-AHS and FFI-D, as well as data from three dimensional gait analysis were collected from 20 patients with mild to severe ankle and hindfoot pathologies.Kinematic and kinetic gait data were correlated with the results of the total AOFAS scale and FFI-D as well as the results of those items representing hindfoot function in the AOFAS-AHS assessment. With respect to the foot disorders in our patients (osteoarthritis and prearthritic conditions), we correlated the total range of motion (ROM) in the ankle and subtalar joints as identified by the OFM with values identified during clinical examination 'translated' into score values. Furthermore, reduced walking speed, reduced step length and reduced maximum ankle power generation during push-off were taken into account and correlated to gait abnormalities described in the scores. An analysis of correlations with CIs between the FFI-D and the AOFAS-AHS items and the gait parameters was performed by means of the Jonckheere-Terpstra test; furthermore, exploratory factor analysis was applied to identify common information structures and thereby redundancy in the FFI-D and the AOFAS-AHS items. RESULTS: Objective findings for hindfoot disorders, namely a reduced ROM, in the ankle and subtalar joints, respectively, as well as reduced ankle power generation during push-off, showed a better correlation with the AOFAS-AHS total score-as well as AOFAS-AHS items representing ROM in the ankle, subtalar joints and gait function-compared with the FFI-D score.Factor analysis, however, could not identify FFI-D items consistently related to these three indicator parameters (pain, disability and function) found in the AOFAS-AHS. Furthermore, factor analysis did not support stratification of the FFI-D into two subscales. CONCLUSIONS: The AOFAS-AHS showed a good agreement with objective gait parameters and is therefore better suited to evaluate disability and functional limitations of patients suffering from foot and ankle pathologies compared with the FFI-D. PMID- 29626048 TI - Dabigatran persistence and adherence in New Zealand: a nationwide retrospective observational study. AB - OBJECTIVE: To determine the effect of age and gender on persistence and adherence in patients taking dabigatran for atrial fibrillation. DESIGN: A retrospective observational study over 4 years using refill prescription data from the National Pharmaceutical Database. SETTING: All patients in New Zealand who received dabigatran from July 2011 to September 2015. POPULATION: 43 339 people filled at least one prescription of dabigatran. MAIN OUTCOME MEASURES: The proportion of patients with good adherence (treatment available at least 80% of the time), and the proportion at risk of thrombosis (a break in treatment of more than 2 days) measured 6-monthly for 3 years. Medication persistence recorded over 3 years. RESULTS: Persistence was highest in older patients and showed a significant correlation with age (p<0.001); 24% over 70 years had discontinued treatment by 6 months compared with 50% under 50 years. Adherence was highest in the elderly (p<0.001) with 90% of patients over 80 years with good adherence at 12 months compared with 70% in patients aged 50-60 years and less than 60% in those under 50 years. The time at risk of thrombosis showed a similar pattern with 25% below 60 years with inadequate anticoagulation more than 20% of the time. Adherence dropped during the first 18 months of treatment with the most marked fall in those under 50 years. Adherence shows that breaks in treatment are common with 30% of men under 60 years with a break in treatment of at least 28 days during the first 12 months. CONCLUSION: Adherence and persistence correlate with the patient's age. Those over 70 years have high adherence consistent over time whereas younger patients have significantly worse adherence which declines over the first 18 months, with the lowest rate in those under 50 years. Adherence in our study is lower than reported in clinical trials, therefore the benefit of dabigatran in stroke prevention may not be realised in clinical practice especially in younger patients. PMID- 29626047 TI - Risk factors and biomarkers of non-alcoholic fatty liver disease: an observational cross-sectional population survey. AB - OBJECTIVE: Non-alcoholic fatty liver disease (NAFLD) is a major public health burden in China, and its prevalence is increasing. This study aimed to determine the risk factors and biomarkers of NAFLD. DESIGN: An observational cross sectional primary survey. SETTING: Central China. PARTICIPANTS: The study included 1479 participants aged over 18 and below 80 years, not currently being treated for cancer or infectious disease or no surgery in the previous year, and no history of cancer or an infectious disease. Participants underwent clinical examination, metabolomic assay and anthropometric assessment. Univariate and logistic regression analyses were used to evaluate associations between covariates and NAFLD. MAIN OUTCOME MEASURES: Risk factors and metabolic biomarkers including sex, body mass index, hypertension, body fat ratio, blood triglycerides, blood fasting glucose, liver enzyme elevation, uric acid and oleic acid-hydroxy oleic acid (OAHOA). RESULTS: Data from the 447 participants (mean age 44.3+/-11.9 years) were analysed, and the prevalence of NAFLD was 24.7%. Male sex (OR 3.484, 95% CI 2.028 to 5.988), body mass index >=24 kg/m2 (OR 8.494, 95% CI 5.581 to 12.928), body fat ratio (>=25 for women, >=20 for men) (OR 1.833, 95% CI 1.286 to 2.756), triglycerides >=1.7 mmol/L (OR 1.340, 95% CI 1.006 to 1.785), fasting glucose >=6.1 mmol/L (OR 3.324, 95% CI 1.888 to 5.850), blood pressure >=140/90 mm Hg or antihypertensive drug treatment (OR 1.451, 95% CI 1.069 to 1.970), uric acid (>=357 MUmol/L for women, >=416 MUmol/L for men) (OR 2.755, 95% CI 2.009 to 3.778) and OAHOA (<5 nmol/L) (OR 1.340, 95% CI 1.006 to 1.785) were independent predictors of NAFLD (all P<0.05). These results were verified by all 1479 participants. CONCLUSIONS: NAFLD was common among the study participants. In particular, NAFLD was correlated with uric acid. We identified OAHOA as a novel marker of NAFLD prevalence. It provides a reference on the prevention of NAFLD and related metabolic diseases with the rapid urbanisation, technological advancement and population ageing in China over the recent decades. PMID- 29626049 TI - Impact of workplace incivility against new nurses on job burn-out: a cross sectional study in China. AB - : This study had three objectives: (1) to investigate the impact of workplace incivility on job burn-out of new nursing staff, (2) to verify the partial mediating role of anxiety in the relationship between workplace incivility and job burn-out, (3) to examine the resilience moderating the relations between workplace incivility and job burn-out. DESIGN: A cross-sectional online survey was conducted in May 2016 in China. SETTING: The survey was conducted in 54 cities across 29 provinces of China. PARTICIPANTS: A total of 903 participants were invited. Ultimately, 696 new nurses (<3 service years) completed valid questionnaires. The effective response rate was 77.1%. Entry criteria: voluntary participation, having less than three service years and being a registered nurse. EXCLUSION CRITERIA: being an irregular nurse, having more than three service years and refusing to participate in this work. OUTCOME MEASURES: An anonymous questionnaire was distributed among new nurses. The relationships and mechanism among the variables were explored using descriptive statistical analysis, Pearson's correlation coefficient and multiple linear regression analysis. RESULTS: The findings showed that workplace incivility was positively correlated with anxiety (r=0.371, p<0.01) and job burn-out (r=0.238, p<0.01) of new nurses. The positive relation between anxiety (beta=0.364, p<0.01) and job burn-out (beta=0.240, p<0.01) was also significant. Moreover, anxiety partially mediated (z=7.807, p<0.01) and resilience moderated (beta=-0.564, p<0.01) the association between workplace incivility and job burn-out. CONCLUSION: Experience of workplace incivility by new nurses would likely generate anxiety in the victims. Further, the increased anxiety state could elevate their level of job burn-out. New nurses with high levels of resilience could buffer the negative influence of workplace incivility by using a positive coping style. PMID- 29626050 TI - Impact of multimorbidity count on all-cause mortality and glycaemic outcomes in people with type 2 diabetes: a systematic review protocol. AB - INTRODUCTION: Type 2 diabetes (T2D) is a leading health priority worldwide. Multimorbidity (MM) is a term describing the co-occurrence of two or more chronic diseases or conditions. The majority of people living with T2D have MM. The relationship between MM and mortality and glycaemia in people with T2D is not clear. METHODS AND ANALYSIS: Medline, Embase, Cumulative Index of Nursing and Allied Health Complete, The Cochrane Library, and SCOPUS will be searched with a prespecified search strategy. The searches will be limited to quantitative empirical studies in English with no restriction on publication date. One reviewer will perform title screening and two review authors will independently screen the abstract and full texts using Covidence software, with disagreements adjudicated by a third reviewer. Data will be extracted using a using a Population, Exposure, Comparator and Outcomes framework. Two reviewers will independently extract data and undertake the risk of bias (quality) assessment. Disagreements will be resolved by consensus. A narrative synthesis of the results will be conducted and meta-analysis considered if appropriate. Quality appraisal will be undertaken using the Newcastle-Ottawa quality assessment scale and the quality of the cumulative evidence of the included studies will be assessed using the Grading of Recommendations, Assessment, Development and Evaluation approach. This protocol was prepared in adherence to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols guidelines to ensure the quality of our review. ETHICS AND DISSEMINATION: This review will synthesise the existing evidence about the impact of MM on mortality and glycaemic outcomes in people living with T2D and increase our understanding of this subject and will inform future practice and policy. Findings will be disseminated via conference presentations, social media and peer-reviewed publication. PROSPERO REGISTRATION NUMBER: CRD42017079500. PMID- 29626051 TI - Access to palliative care by disease trajectory: a population-based cohort of Ontario decedents. AB - OBJECTIVES: To examine access to palliative care between different disease trajectories and compare to other geographic areas. DESIGN: A retrospective population-based decedent cohort study using linked administrative data. SETTING: Ontario, Canada. PARTICIPANTS: Ontario decedents between 1 April 2010 and 31 December 2012. Patients were categorised into disease trajectories: terminal illness (eg, cancer), organ failure (eg, chronic heart failure), frailty (eg, dementia), sudden death or other. INTERVENTIONS: Receipt of palliative care services from institutional and community settings, derived from a validated list of palliative care codes from multiple administrate databases. OUTCOME MEASURES: Receiving any palliative care services in the last year of life (yes/no), intensity (total days) and time of initiation of palliative care, in hospital and community sectors. Multivariable analysis examined the association between disease trajectory and the receipt of palliative care in the last year of life. RESULTS: We identified 235 159 decedents in Ontario. In the last year of life, 88% of terminal illness, 44% of organ failure and 32% of frailty decedents accessed at least one palliative care service. Most care was provided during an inpatient hospitalisation. Terminal illness decedents received twice as many palliative care days (mean of 49 days) compared with organ failure and frailty decedents. Patients with terminal illness initiated palliative care median of 107 days before death compared with median of 19 days among those using the US Medicare hospice benefit. CONCLUSIONS: Terminal illness decedents are more likely to receive any palliative care, with increased intensity and earlier before death than organ failure or frailty decedents. These data serve as a useful comparison for other countries with similar and different healthcare systems and eligibility criteria. PMID- 29626052 TI - Association between serum lipids concentration and patients with age-related cataract in China: a cross-sectional, case-control study. AB - OBJECTIVE: Obesity and a high-fat diet have been found to be associated with an increased risk of age-related cataract (ARC). Thus, this study aimed to investigate whether serum lipid levels are associated with the incidence of ARC. DESIGN: Cross-sectional, case-control study. SETTING: EyeandENT Hospital of Fudan University, Shanghai, China. PARTICIPANTS: A total of 219 ARC (male=94, female=125) subjects and 218 (male=110, female=118) normal control subjects were recruited in this study. OUTCOME MEASURES: A detailed eye and systematic examination was performed. Serum high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG) and cholesterol (CHO) levels were measured by enzymatic colorimetry, and serum apolipoprotein A (APOA) and apoB (APOB) levels were measured by immunoturbidimetry. The subgroups were classified according to gender and types of disease (cortical, nuclear and posterior subcapsular cataract). Logistic regression analyses were performed to identify the association between serum lipid levels and ARC. RESULTS: The serum LDL-C, TG, CHO and APOA levels were significantly higher (p<0.05) in the ARC group than in the control group. A similar result was observed when the serum lipid concentrations were compared between the ARC and control groups both in male and female subgroups. A higher proportion of individuals in the ARC group had higher LDL-C, TG, CHO and APOA levels (fold=3.45, 17.37, 3.27 and11.91, respectively; p<0.0001 in all cases) than in the control group. Results of the logistic regression analyses revealed that high LDL-C (ORs=1.897, 95% CI 0.960 to 3.678) and TG (OR=1.854, 95% CI 1.232 to 2.791) were the independent risk factors for ARC. CONCLUSION: The serum LDL-C and TG levels were demonstrated to be independent risk factors for ARC. PMID- 29626054 TI - Sports medicine highlights from other journals. PMID- 29626055 TI - Internal workload and non-contact injury: a one-season study of five teams from the UEFA Elite Club Injury Study. AB - BACKGROUND: Internal workload (ie, from training and matches) is considered one of the most important injury risk factors for elite European football teams, however there is little published evidence to support this belief. OBJECTIVE: We examined the association and predictive power of internal workload and non contact injuries. METHODS: Five elite European teams, 171 players (age: 25.1+/ 4.9 years; height: 181.6+/-6.7 cm; body mass: 77.5+/-7.2 kg) participated over one full competitive season. Using the session-rating of perceived exertion (s RPE) method player's internal workloads were calculated for acute week, week-to week changes, cumulated weeks, chronic weeks and acute:chronic ratios and analysed for association with non-contact injury (using generalised estimating equations (GEE)). Associated variables from GEE analysis were categorised into very low to very high workload zones and checked for increased relative risks (RRs). Associated workload variables were also analysed for predictive power (receiver operating characteristics). RESULTS: Acute:chronic workload ratios at 1:3 and 1:4 weeks were associated with non-contact injury (P<0.05). Specifically, a greater risk of injury was found for players with an acute:chronic workload at 1:4 weeks of 0.97 to 1.38 (RR 1.68; 95% CI 1.02 to 2.78, likely harmful) and >1.38 (RR 2.13; 95% CI 1.21 to 3.77, very likely harmful) compared with players whose acute:chronic workload was 0.60 to 0.97. An acute:chronic workload 1:3 of >1.42 compared with 0.59 to 0.97 displayed a 1.94 times higher risk of injury (RR 1.90; 95% CI 1.08 to 3.36, very likely harmful). Importantly, acute:chronic workload at both 1:4 and 1:3 showed poor predictive power (area under the curve 0.53 to 0.58) despite previous reports and beliefs that it can predict injury. CONCLUSIONS: This study provides evidence for the acute:chronic internal workload (measured using s-RPE) as a risk factor for non-contact injury in elite European footballers. However the acute:chronic workload, in isolation, should not be used to predict non-contact injury. PMID- 29626057 TI - Acute tubulointerstitial nephritis following hymenopteran stings. PMID- 29626056 TI - Methylindoles and Methoxyindoles are Agonists and Antagonists of Human Aryl Hydrocarbon Receptor. AB - Novel methylindoles were identified as endobiotic and xenobiotic ligands of the human aryl hydrocarbon receptor (AhR). We examined the effects of 22 methylated and methoxylated indoles on the transcriptional activity of AhRs. Employing reporter gene assays in AZ-AHR transgenic cells, we determined full agonist, partial agonist, or antagonist activities of tested compounds, having substantially variable EC50, IC50, and relative efficacies. The most effective agonists (EMAX relative to 5 nM dioxin) of the AhR were 4-Me-indole (134%), 6-Me indole (91%), and 7-MeO-indole (80%), respectively. The most effective antagonists of the AhR included 3-Me-indole (IC50; 19 MUM), 2,3-diMe-indole (IC50; 11 MUM), and 2,3,7-triMe-indole (IC50; 12 MUM). Reverse transcription polymerase chain reaction analyses of CYP1A1 mRNA in LS180 cells confirmed the data from gene reporter assays. The compound leads, 4-Me-indole and 7-MeO-indole, induced substantial nuclear translocation of the AhR and enriched binding of the AhR to the CYP1A1 promoter, as observed using fluorescent immunohistochemistry and chromatin immunoprecipitation assays, respectively. Molecular modeling and docking studies suggest the agonists and antagonists likely share the same binding pocket but have unique binding modes that code for their affinity. Binding pocket analysis further revealed that 4-methylindole and 7-methoxyindole can simultaneously bind to the pocket and produce synergistic interactions. Together, these data show a dependence on subtle and specific chemical indole structures as AhR modulators and furthermore underscore the importance of complete evaluation of indole compounds as nuclear receptor ligands. PMID- 29626058 TI - Protean manifestations of Proteus syndrome. PMID- 29626060 TI - Blocking MICA/MICB Shedding Reactivates Antitumor Immunity. AB - Inhibition of protease-driven MICA and MICB shedding enhances NK cell-mediated tumor immunity. PMID- 29626059 TI - Evaluation of lipid profile and its relationship with blood pressure in patients with Cushing's disease. AB - INTRODUCTION: The purpose of the study was to describe lipid profile and explore pathogenetic role of LDL-c on hypertension in patients with Cushing's disease (CD). Hypertension is a common feature in patients with CD. Previous study found low-density lipoprotein cholesterol (LDL-c) uptake in vascular cells might be involved in vascular remodeling in patients with CD. Therefore, we evaluated the relationship between lipid profile and the blood pressure in patients with CD. METHODS: This retrospective study included 84 patients referred to Huashan Hospital for the evaluation and diagnosis of CD from January 2012 to December 2013. All subjects had detailed clinical evaluation by the same group of endocrinology specialists to avoid subjective influences. RESULTS: We found that high LDL-c patients had significant higher body mass index (BMI), systolic blood pressure (SBP), cholesterol (CHO), triglyceride (TG), and apolipoproteinB (apoB) (P < 0.05). An association was detected between SBP values and lipids profile including CHO, TG, LDL-c, apolipoproteinA (apoA), apoB and lipoprotein(a) (LP(a)). After adjustment for all covariates, the LDL-c remained positively associated with SBP. In patients with or without taking statins, patients with LDL-c >=3.37 mmol/L had higher SBP than patients with LDL-c <3.37 mmol/L. Then, LDL-c was coded using restricted cubic splines (RCS) function with three knots located at the 5th, 50th and 95th percentiles of the distribution of LDL-c. Compared to individuals with 3.215 mmol/L of LDL-c, individuals with 4.0, 4.5 and 5.0 mmol/L of LDL-c had differences of 3.86, 8.53 and 14.11 mmHg in SBP, respectively. CONCLUSIONS: An independent association between LDL-c and SBP was found in patients with CD. We speculate that LDL-c may be a pathogenic factor for hypertension in those patients. PMID- 29626053 TI - Insulin-like growth factors: actions on the skeleton. AB - The discovery of the growth hormone (GH)-mediated somatic factors (somatomedins), insulin-like growth factor (IGF)-I and -II, has elicited an enormous interest primarily among endocrinologists who study growth and metabolism. The advancement of molecular endocrinology over the past four decades enables investigators to re examine and refine the established somatomedin hypothesis. Specifically, gene deletions, transgene overexpression or more recently, cell-specific gene ablations, have enabled investigators to study the effects of the Igf1 and Igf2 genes in temporal and spatial manners. The GH/IGF axis, acting in an endocrine and autocrine/paracrine fashion, is the major axis controlling skeletal growth. Studies in rodents have clearly shown that IGFs regulate bone length of the appendicular skeleton evidenced by changes in chondrocytes of the proliferative and hypertrophic zones of the growth plate. IGFs affect radial bone growth and regulate cortical and trabecular bone properties via their effects on osteoblast, osteocyte and osteoclast function. Interactions of the IGFs with sex steroid hormones and the parathyroid hormone demonstrate the significance and complexity of the IGF axis in the skeleton. Finally, IGFs have been implicated in skeletal aging. Decreases in serum IGFs during aging have been correlated with reductions in bone mineral density and increased fracture risk. This review highlights many of the most relevant studies in the IGF research landscape, focusing in particular on IGFs effects on the skeleton. PMID- 29626061 TI - The Structure of GATOR1-Rag GTPases Reveal Modes of Regulation. AB - A Rag GTPases-DEPDC5 inhibitory interaction mode suppresses GATOR1 GAP activity. PMID- 29626062 TI - Trastuzumab Extends Progression-Free Survival in HER2/neu+ Uterine Tumors. AB - Adding trastuzumab to carboplatin-paclitaxel is well tolerated in patients with uterine serous carcinoma. PMID- 29626064 TI - Immune Checkpoint Blockade Is Active in Melanoma Brain Metastases. AB - Treatment with nivolumab alone or nivolumab plus ipilimumab achieves intracranial responses. PMID- 29626063 TI - Ibrutinib plus Venetoclax May Be Effective in Mantle-Cell Lymphoma. AB - Ibrutinib plus venetoclax is superior to monotherapy in patients with mantle-cell lymphoma. PMID- 29626067 TI - Endothelial C-Type Natriuretic Peptide Acts on Pericytes to Regulate Microcirculatory Flow and Blood Pressure. AB - Background -Peripheral vascular resistance has a major impact on arterial blood pressure levels. Endothelial C-type natriuretic peptide (CNP) participates in the local regulation of vascular tone but the target cells remain controversial. The cGMP-producing guanylyl cyclase-B (GC-B) receptor for CNP is expressed in vascular smooth muscle cells (VSMC). However, whereas endothelial cell-specific CNP knockout mice are hypertensive, mice with deletion of GC-B in VSMC have unaltered blood pressure. Methods -We analyzed whether the vasodilating response to CNP changes along the vascular tree, i.e. whether the GC-B receptor is expressed in microvascular types of cells. Mice with a floxed GC-B (Npr2) gene were interbred with Tie2-Cre or PDGF-Rbeta-CreERT2 lines to develop mice lacking GC-B in endothelial cells or in precapillary arteriolar SMC and capillary pericytes. Intravital microscopy, (non)invasive hemodynamics, fluorescence energy transfer studies of pericyte's cAMP levels in situ and renal physiology were combined to dissect whether and how CNP/GC-B/cGMP signaling modulates microcirculatory tone and blood pressure. Results -Intravital microscopy studies revealed that the vasodilatatory effect of CNP increases towards small-diameter arterioles and capillaries. Consistently, CNP did not prevent endothelin-1 induced acute constrictions of proximal arterioles but fully reversed endothelin effects in precapillary arterioles and capillaries. Here, the GC-B receptor is expressed both in endothelial and mural cells, i.e. in pericytes. Notably, the vasodilatatory effects of CNP were preserved in mice with endothelial GC-B deletion but abolished in mice lacking GC-B in microcirculatory SMC and pericytes. CNP, via GC-B/cGMP signaling modulates two signaling cascades in pericytes: it activates cGMP-dependent protein kinase I to phosphorylate downstream targets such as the cytoskeleton-associated vasodilator activated phosphoprotein; and it inhibits phosphodiesterase 3A, thereby enhancing pericyte's cAMP levels. Ultimately these pathways prevent endothelin-induced increases of pericyte calcium levels and pericyte contraction. Mice with deletion of GC-B in microcirculatory SMC and pericytes have elevated peripheral resistance and chronic arterial hypertension without a change in renal function. Conclusions -Our studies indicate that endothelial CNP regulates distal arteriolar and capillary blood flow. CNP-induced GC-B/cGMP signaling in microvascular SMC and pericytes is essential for the maintenance of normal microvascular resistance and blood pressure. PMID- 29626068 TI - Clinical Benefit of Evolocumab by Severity and Extent of Coronary Artery Disease. AB - BACKGROUND: The FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk) recently showed that the PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitor evolocumab significantly reduced major vascular events in patients with stable atherosclerotic cardiovascular disease, including patients with prior myocardial infarction (MI). Within the broad group of patients with prior MI, we hypothesized that readily ascertainable features would identify subsets who derive greater clinical risk reduction with evolocumab. METHODS: The 22 351 patients with a prior MI were characterized on the basis of time from most recent MI, number of prior MIs, and presence of residual multivessel coronary artery disease (>=40% stenosis in >=2 large vessels). The relative and absolute risk reductions in major vascular events, including the primary end point (cardiovascular death, MI, stroke, hospitalization for unstable angina, or coronary revascularization) and the key secondary end point (cardiovascular death, MI, or stroke), with evolocumab in these subgroups were compared. RESULTS: A total of 8402 patients (38%) were within 2 years of their most recent MI; 5285 patients (24%) had >=2 prior MIs; and 5618 patients (25%) had residual multivessel coronary artery disease. In a multivariable-adjusted model that simultaneously included all 3 high-risk features and other baseline covariates, more recent MI, multiple prior MIs, and residual multivessel coronary disease remained independent predictors of cardiovascular outcomes, with adjusted hazard ratios (HRs) for the primary end point of 1.37 (95% confidence interval [CI],1.22 1.53), 1.78 (95% CI, 1.59-1.99), and 1.39 (95% CI, 1.24-1.56; all P<0.001). The relative risk reductions with evolocumab for the primary end point tended to be greater in the high-risk subgroups and were 20% (HR, 0.80; 95% CI, 0.71-0.91), 18% (HR, 0.82; 95% CI, 0.72-0.93), and 21% (HR, 0.79; 95% CI, 0.69-0.91) for those with more recent MI, multiple prior MIs, and residual multivessel coronary artery disease, whereas they were 5% (HR, 0.95; 95% CI, 0.85-1.05), 8% (HR, 0.92; 95% CI, 0.84-1.02), and 7% (HR, 0.93; 95% CI, 0.85-1.02) in those without, respectively. Given the higher baseline risk, the respective absolute risk reductions at 3 years exceeded 3% in the high-risk groups (3.4%, 3.7%, and 3.6%) versus ~1% in the low-risk groups (0.8%, 1.3%, and 1.2%). CONCLUSIONS: Patients closer to their most recent MI, with multiple prior MIs, or with residual multivessel coronary artery disease are at high risk for major vascular events and experience substantial risk reductions with low-density lipoprotein cholesterol lowering with evolocumab. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT01764633. PMID- 29626070 TI - Shy Girl Gives Kiwifruit Male Flowers. PMID- 29626069 TI - A Y-Encoded Suppressor of Feminization Arose via Lineage-Specific Duplication of a Cytokinin Response Regulator in Kiwifruit. AB - Dioecy, the presence of male and female flowers on distinct individuals, has evolved independently in multiple plant lineages, and the genes involved in this differential development are just starting to be uncovered in a few species. Here, we used genomic approaches to investigate this pathway in kiwifruits (genus Actinidia). Genome-wide cataloging of male-specific subsequences, combined with transcriptome analysis, led to the identification of a type-C cytokinin response regulator as a potential sex determinant gene in this genus. Functional transgenic analyses in two model systems, Arabidopsis thaliana and Nicotiana tabacum, indicated that this gene acts as a dominant suppressor of carpel development, prompting us to name it Shy Girl (SyGI). Evolutionary analyses in a panel of Actinidia species revealed that SyGI is located in the Y-specific region of the genome and probably arose from a lineage-specific gene duplication. Comparisons with the duplicated autosomal counterpart, and with orthologs from other angiosperms, suggest that the SyGI-specific duplication and subsequent evolution of cis-elements may have played a key role in the acquisition of separate sexes in this species. PMID- 29626071 TI - Postnatal steroids: still a dilemma for neonatologists and parents? PMID- 29626072 TI - Improving endotracheal tube placement in neonates. PMID- 29626073 TI - Risk of Incident Heart Failure in Patients With Diabetes and Asymptomatic Left Ventricular Systolic Dysfunction. AB - OBJECTIVE: Although diabetes is well known to be common in prevalent heart failure (HF) and portends a poor prognosis, the role of diabetes in the development of incident HF is less well understood. We studied the role of diabetes in the transition from asymptomatic left ventricular systolic dysfunction (ALVSD) to overt HF in the prevention arm of the Studies of Left Ventricular Dysfunction (SOLVD-P). RESEARCH DESIGN AND METHODS: We examined the development of symptomatic HF, HF hospitalization, and cardiovascular death according to diabetes status at baseline in patients in SOLVD-P. These outcomes were analyzed by using cumulative incidence curves and Cox regression models adjusted for age, sex, and other prognostic factors, including randomized treatment, HF severity, and comorbidity. RESULTS: Of the 4,223 eligible participants, 647 (15%) had diabetes at baseline. Patients with diabetes were older and had a higher average weight, systolic blood pressure, and heart rate. During the median follow-up of 36 months, 861 of the 3,576 patients without diabetes (24%) developed HF compared with 214 of the 647 patients with diabetes (33%). In unadjusted analyses, patients with diabetes had a higher risk of development of HF (hazard ratio 1.53 [95% CI 1.32-1.78]; P < 0.001), HF hospitalization (2.04 [1.65-2.52]; P < 0.0001), and the composite outcome of development of HF or cardiovascular death (1.48 [1.30-1.69]; P < 0.001). The effect of enalapril on outcomes was not modified by diabetes status. CONCLUSIONS: In patients with ALVSD, diabetes is associated with an increased risk of developing HF. Development of HF is associated with an increased risk of death irrespective of diabetes status. PMID- 29626075 TI - Sulfotransferase 4A1 Increases Its Expression in Mouse Neurons as They Mature. AB - Cytosolic sulfotransferases (SULTs) catalyze sulfation and play essential roles in detoxification of xenobiotics as well as inactivation of endobiotics. SULT4A1, which was originally isolated as a brain-specific sulfotransferase, is the most highly conserved isoform among SULTs in vertebrates. Here, expression of SULT4A1 was examined neuron enriched and neuron-glia mixed cells derived from mouse embryo brains at day 14 gestation and mixed glia from 2-day-old neonate brains. Western blots showed an increase of SULT4A1 expression as neurons maturated. Reverse-transcription polymerase chain reaction and agarose gel analysis found two different forms (variant and wild type) of SULT4A1 mRNA in neurons; the level of wild type correlated with the protein level of SULT4A1. SULT1E1 was not expressed in mouse brains, neuron-enriched cells, or mixed glia cells. SULT1A1 protein was only detected in adult brains. Immunofluorescence staining of neuron glia mixed cells confirmed selective expression of SULT4A1 in neurons, including dopaminergic neurons, but not in either astrocytes or microglia. Thus, SULT4A1 is a neuron-specific sulfotransferase and may play a role in neuronal development. PMID- 29626076 TI - Predicting opioid use disorder in patients with chronic pain who present to the emergency department. AB - BACKGROUND: Emergency department (ED) patients with chronic pain challenge providers to make quick and accurate assessments without an in-depth pain management consultation. Emergency physicians need reliable means to determine which patients may receive opioid therapy without exacerbating opioid use disorder (OUD). METHODS: Eighty-nine ED patients with a chief complaint of chronic pain were enrolled. Researchers administered questionnaires and reviewed medical and state prescription monitoring database information. Participants were classified as either OUD or non-OUD. Statistical analysis included a bivariate analysis comparing differences between groups and multivariate logistic regression evaluating ORs. RESULTS: The 45 participants categorised as OUD had a higher proportion of documented or reported psychiatric diagnoses (p=0.049), preference of opioid treatment (p=0.005), current oxycodone prescription (p=0.043), borrowed pain medicine (p=0.004) and non-authorised dose increase (p<0.001). The state prescription monitoring database revealed the OUD group to have an increased number of opioid prescriptions (p=0.005) and pills (p=0.010). Participants who borrowed pain medicine and engaged in non-authorised dose increase were 5.2 (p=0.025, 95% CI 1.24 to 21.9) and 6.1 times (p=0.001, 95% CI 1.55 to 24.1) more likely to have OUD, respectively. LIMITATIONS: Major limitations of our study include a small sample size, self-reported measures and convenience sample which may introduce selection bias. CONCLUSION: Patients with chronic pain with OUD have distinguishable characteristics. Emergency physicians should consider such evidence-based variables prior to opioid therapy to ameliorate the opioid crisis and limit implicit bias. PMID- 29626074 TI - Intensive Treat-to-Target Statin Therapy in High-Risk Japanese Patients With Hypercholesterolemia and Diabetic Retinopathy: Report of a Randomized Study. AB - OBJECTIVE: Diabetes is associated with high risk of cardiovascular (CV) events, particularly in patients with dyslipidemia and diabetic complications. We investigated the incidence of CV events with intensive or standard lipid-lowering therapy in patients with hypercholesterolemia, diabetic retinopathy, and no history of coronary artery disease (treat-to-target approach). RESEARCH DESIGN AND METHODS: In this multicenter, prospective, randomized, open-label, blinded end point study, eligible patients were randomly assigned (1:1) to intensive statin therapy targeting LDL cholesterol (LDL-C) <70 mg/dL (n = 2,518) or standard statin therapy targeting LDL-C 100-120 mg/dL (n = 2,524). RESULTS: Mean follow-up was 37 +/- 13 months. LDL-C at 36 months was 76.5 +/- 21.6 mg/dL in the intensive group and 104.1 +/- 22.1 mg/dL in the standard group (P < 0.001). The primary end point events occurred in 129 intensive group patients and 153 standard group patients (hazard ratio [HR] 0.84 [95% CI 0.67-1.07]; P = 0.15). The relationship between the LDL-C difference in the two groups and the event reduction rate was consistent with primary prevention studies in patients with diabetes. Exploratory findings showed significantly fewer cerebral events in the intensive group (HR 0.52 [95% CI 0.31-0.88]; P = 0.01). Safety did not differ significantly between the two groups. CONCLUSIONS: We found no significant decrease in CV events or CV-associated deaths with intensive therapy, possibly because our between-group difference of LDL-C was lower than expected (27.7 mg/dL at 36 months of treatment). The potential benefit of achieving LDL-C <70 mg/dL in a treat-to-target strategy in high-risk patients deserves further investigation. PMID- 29626077 TI - New York City's window guard policy: four decades of success. AB - BACKGROUND: Preventing child falls from windows is easily accomplished by installing inexpensive window-limiting devices but window falls remain a common cause of child injuries. This article describes the history and evolution of the New York City (NYC) window guard rule,which requires building owners to install window guards in apartments housing children aged <=10 years. The NYC window guard rule was the first directive of its kind in the USA when it was adopted in 1976, and it has led to a dramatic and long-lasting reduction in child window fall-related injuries and deaths. METHODS: Data about the history of the window guard rule were obtained by reviewing programmatic records, correspondence, legal decisions and the published literature. In addition, key informant interviews were conducted with programme staff. RESULTS AND DISCUSSION: This article describes each stage of policy development, starting with epidemiological studies defining the scope of the problem in the 1960s and pilot-testing of the window guard intervention. We describe the adoption, implementation and enforcement of the rule. In addition, we show how the rule was modified over time and document the rule's impact on window fall incidence in NYC. We describe litigation that challenged the rule's constitutionality and discuss the legal arguments used by opponents of the rule. Finally, we discuss criminal and tort liability as drivers of compliance and summarise lessons learnt. PMID- 29626078 TI - Early Cardiac Involvement Affects Left Ventricular Longitudinal Function in Females Carrying alpha-Galactosidase A Mutation: Role of Hybrid Positron Emission Tomography and Magnetic Resonance Imaging and Speckle-Tracking Echocardiography. AB - BACKGROUND: Hybrid 18F-fluorodeoxyglucose (FDG) positron emission tomography and magnetic resonance imaging may differentiate mature fibrosis or scar from fibrosis associated to active inflammation in patients with Anderson-Fabry disease, even in nonhypertrophic stage. This study was designed to compare the results of positron emission tomography and magnetic resonance cardiac imaging with those of speckle-tracking echocardiography in heterozygous Anderson-Fabry disease females. METHODS AND RESULTS: Twenty-four heterozygous females carrying alpha-galactosidase A mutation and without left ventricular hypertrophy underwent cardiac positron emission tomography and magnetic resonance using 18F-FDG for glucose uptake and 2-dimensional strain echocardiography. 18F-FDG myocardial uptake was quantified by measuring the coefficient of variation (COV) of the standardized uptake value using a 17-segment model. Focal 18F-FDG uptake with COV >0.17 was detected in 13 patients, including 2 patients with late gadolinium enhancement at magnetic resonance. COV was 0.30+/-0.14 in patients with focal 18F FDG uptake and 0.12+/-0.03 in those without (P<0.001). Strain echocardiography revealed worse global longitudinal systolic strain in patients with COV >0.17 compared with those with COV <=0.17 (-18.5+/-2.7% versus -22.2+/-1.8%; P=0.024). For predicting COV >0.17, a global longitudinal strain >-19.8% had 77% sensitivity and 91% specificity and a value >2 dysfunctional segments 92% sensitivity and 100% specificity. CONCLUSIONS: In females carrying alpha galactosidase A mutation, focal 18F-FDG uptake represents an early sign of disease-related myocardial damage and is associated with impaired left ventricular longitudinal function. These findings support the hypothesis that inflammation plays an important role in glycosphingolipids storage disorders. PMID- 29626079 TI - Acute Versus Chronic Ischemic Mitral Regurgitation: An Echocardiographic Study of Anatomy and Physiology. AB - BACKGROUND: Little is known on the mechanism of acute ischemic mitral regurgitation (IMR) caused by sudden-onset left ventricular dysfunction in acute myocardial infarction (MI). We sought to investigate the mitral valve (MV) complex geometry in acute IMR in comparison with chronic IMR by 2-dimensional and 3-dimensional transthoracic echocardiography. METHODS AND RESULTS: Forty-four first-onset acute MI and 36 previous MI with >=moderate IMR were examined by 2 dimensional/3-dimensional transthoracic echocardiography. MV morphology was quantitatively analyzed and compared between the 2 groups. Left ventricular end diastolic volume and left ventricular end-systolic volume were significantly smaller in acute IMR than in chronic IMR (40.8 [33.1-48.3] versus 88.8 [66.5 108.8] mL/m2; P<0.001, 17.8 [17.0-30.1] versus 49.5 [34.2-73.7] mL/m2; P<0.001). MV tenting volume and annular area were significantly smaller in acute IMR compared with chronic IMR (0.98 [0.66-1.68] versus 1.88 [1.16-2.65] cm3/m2; P=0.008, 5.17 [4.80-5.86] versus 5.81 [5.47-8.22] cm2/m2; P=0.008). Leaflet surface area was significantly smaller in acute IMR than in chronic IMR (5.78 [5.16-6.32] versus 7.56 [6.89-11.32] cm2/m2; P<0.001). The ratio of MV leaflet surface area and MV annular area was significantly smaller in acute IMR than in chronic IMR (1.08 [1.01-1.14] versus 1.28 [1.24-1.37]; P=0.001). CONCLUSIONS: Sudden-onset left ventricular dysfunction in acute MI may cause loss of coaptation of the MV even with a relatively mild degree of valve tethering. Compared with previously studied chronic IMR, a smaller leaflet area without leaflet adaptation and a larger hemodynamic burden at the acute onset of MI could result in clinically significant IMR despite relatively small leaflet tethering. PMID- 29626080 TI - Mitral Valve Adaptation: Can We Win the Race? PMID- 29626082 TI - diploS/HIC: An Updated Approach to Classifying Selective Sweeps. AB - Identifying selective sweeps in populations that have complex demographic histories remains a difficult problem in population genetics. We previously introduced a supervised machine learning approach, S/HIC, for finding both hard and soft selective sweeps in genomes on the basis of patterns of genetic variation surrounding a window of the genome. While S/HIC was shown to be both powerful and precise, the utility of S/HIC was limited by the use of phased genomic data as input. In this report we describe a deep learning variant of our method, diploS/HIC, that uses unphased genotypes to accurately classify genomic windows. diploS/HIC is shown to be quite powerful even at moderate to small sample sizes. PMID- 29626085 TI - Correction: Metabolic biomarker signature to differentiate pancreatic ductal adenocarcinoma from chronic pancreatitis. PMID- 29626081 TI - Recognition of the polycistronic nature of human genes is critical to understanding the genotype-phenotype relationship. AB - Technological advances promise unprecedented opportunities for whole exome sequencing and proteomic analyses of populations. Currently, data from genome and exome sequencing or proteomic studies are searched against reference genome annotations. This provides the foundation for research and clinical screening for genetic causes of pathologies. However, current genome annotations substantially underestimate the proteomic information encoded within a gene. Numerous studies have now demonstrated the expression and function of alternative (mainly small, sometimes overlapping) ORFs within mature gene transcripts. This has important consequences for the correlation of phenotypes and genotypes. Most alternative ORFs are not yet annotated because of a lack of evidence, and this absence from databases precludes their detection by standard proteomic methods, such as mass spectrometry. Here, we demonstrate how current approaches tend to overlook alternative ORFs, hindering the discovery of new genetic drivers and fundamental research. We discuss available tools and techniques to improve identification of proteins from alternative ORFs and finally suggest a novel annotation system to permit a more complete representation of the transcriptomic and proteomic information contained within a gene. Given the crucial challenge of distinguishing functional ORFs from random ones, the suggested pipeline emphasizes both experimental data and conservation signatures. The addition of alternative ORFs in databases will render identification less serendipitous and advance the pace of research and genomic knowledge. This review highlights the urgent medical and research need to incorporate alternative ORFs in current genome annotations and thus permit their inclusion in hypotheses and models, which relate phenotypes and genotypes. PMID- 29626083 TI - The Pseudokinase Domain of Saccharomyces cerevisiae Tra1 Is Required for Nuclear Localization and Incorporation into the SAGA and NuA4 Complexes. AB - Tra1 is an essential component of the SAGA/SLIK and NuA4 complexes in S. cerevisiae, recruiting these co-activator complexes to specific promoters. As a PIKK family member, Tra1 is characterized by a C-terminal phosphoinositide 3 kinase (PI3K) domain. Unlike other PIKK family members (e.g., Tor1, Tor2, Mec1, Tel1), Tra1 has no demonstrable kinase activity. We identified three conserved arginine residues in Tra1 that reside proximal or within the cleft between the N- and C-terminal subdomains of the PI3K domain. To establish a function for Tra1's PI3K domain and specifically the cleft region, we characterized a tra1 allele where these three arginine residues are mutated to glutamine. The half-life of the Tra1[Formula: see text] protein is reduced but its steady state level is maintained at near wild-type levels by a transcriptional feedback mechanism. The tra1[Formula: see text] allele results in slow growth under stress and alters the expression of genes also regulated by other components of the SAGA complex. Tra1[Formula: see text] is less efficiently transported to the nucleus than the wild-type protein. Likely related to this, Tra1[Formula: see text] associates poorly with SAGA/SLIK and NuA4. The ratio of Spt7SLIK to Spt7SAGA increases in the tra1[Formula: see text] strain and truncated forms of Spt20 become apparent upon isolation of SAGA/SLIK. Intragenic suppressor mutations of tra1[Formula: see text] map to the cleft region further emphasizing its importance. We propose that the PI3K domain of Tra1 is directly or indirectly important for incorporating Tra1 into SAGA and NuA4 and thus the biosynthesis and/or stability of the intact complexes. PMID- 29626086 TI - Former ASHP VP Dwight R. Tousignaut dies at 84. PMID- 29626084 TI - Genetic Loci Governing Androgenic Capacity in Perennial Ryegrass (Lolium perenne L.). AB - Immature pollen can be induced to switch developmental pathways from gametogenesis to embryogenesis and subsequently regenerate into homozygous, diploid plants. Such androgenic production of doubled haploids is particularly useful for species where inbreeding is hampered by effective self-incompatibility systems. Therefore, increasing the generally low androgenic capacity of perennial ryegrass (Lolium perenne L.) germplasm would enable the efficient production of homozygous plant material, so that a more effective exploitation of heterosis through hybrid breeding schemes can be realized. Here, we present the results of a genome-wide association study in a heterozygous, multiparental population of perennial ryegrass (n = 391) segregating for androgenic capacity. Genotyping-by sequencing was used to interrogate gene- dense genomic regions and revealed over 1,100 polymorphic sites. Between one and 10 quantitative trait loci (QTL) were identified for anther response, embryo and total plant production, green and albino plant production and regeneration. Most traits were under polygenic control, although a major QTL on linkage group 5 was associated with green plant regeneration. Distinct genetic factors seem to affect green and albino plant recovery. Two intriguing candidate genes, encoding chromatin binding domains of the developmental phase transition regulator, Polycomb Repressive Complex 2, were identified. Our results shed the first light on the molecular mechanisms behind perennial ryegrass microspore embryogenesis and enable marker-assisted introgression of androgenic capacity into recalcitrant germplasm of this forage crop of global significance. PMID- 29626088 TI - Granulocytes Are Unresponsive to IL-6 Due to an Absence of gp130. AB - IL-6 mediates broad physiological and pathological effects through its receptor signal transducing unit gp130. Due to the reportedly wide cellular expression of gp130, IL-6 is thought to signal ubiquitously via gp130 complex formation with membrane-bound IL-6Ralpha or soluble IL-6Ralpha. gp130 signaling primarily induces p-STAT3 and p-STAT1. In contrast to the previous dogma, we show in this article that circulating mouse and human granulocytes are unable to induce p STAT3 or p-STAT1 after stimulation with IL-6 or an IL-6/soluble IL-6R complex. Furthermore, we demonstrate that this is due to a lack of gp130 expression on mouse and human granulocytes, despite their expression of membrane-bound IL-6R. Importantly, the absence of gp130 is not only a feature of mature granulocytes in healthy individuals, it is also observed after allogeneic stem cell transplantation. Moreover, granulocyte gp130 expression is lost during maturation, because granulocyte-monocyte progenitor cells express gp130 and respond to IL-6. Given that granulocytes constitute 50-70% of circulating leukocytes, this indicates a significantly smaller scope of IL-6 signaling than previously anticipated and has important implications for therapeutic IL-6 inhibition and the mechanisms of action thereof. PMID- 29626087 TI - Human IgG Increases Virulence of Streptococcus pyogenes through Complement Evasion. AB - Streptococcus pyogenes is an exclusively human pathogen that can provoke mild skin and throat infections but can also cause fatal septicemia. This gram positive bacterium has developed several strategies to evade the human immune system, enabling S. pyogenes to survive in the host. These strategies include recruiting several human plasma proteins, such as the complement inhibitor, C4b binding protein (C4BP), and human (hu)-IgG through its Fc region to the bacterial surface to evade immune recognition. We identified a novel virulence mechanism whereby IgG-enhanced binding of C4BP to five of 12 tested S. pyogenes strains expressed diverse M proteins that are important surface-expressed virulence factors. Importantly, all strains that bound C4BP in the absence of IgG bound more C4BP when IgG was present. Further studies with an M1 strain that additionally expressed protein H, also a member of the M protein family, revealed that binding of hu-IgG Fc to protein H increased the affinity of protein H for C4BP. Increased C4BP binding accentuated complement downregulation, resulting in diminished bacterial killing. Accordingly, mortality from S. pyogenes infection in hu-C4BP transgenic mice was increased when hu-IgG or its Fc portion alone was administered concomitantly. Electron microscopy analysis of human tissue samples with necrotizing fasciitis confirmed increased C4BP binding to S. pyogenes when IgG was present. Our findings provide evidence of a paradoxical function of hu IgG bound through Fc to diverse S. pyogenes isolates that increases their virulence and may counteract the beneficial effects of IgG opsonization. PMID- 29626089 TI - Stearic Acid Induces CD11c Expression in Proinflammatory Macrophages via Epidermal Fatty Acid Binding Protein. AB - Obesity is associated with elevated levels of free fatty acids (FAs) and proinflammatory CD11c+ macrophages. However, whether and how free FAs contribute to CD11c+ macrophage differentiation and proinflammatory functions remain unclear. Here we report that dietary saturated FAs, but not unsaturated FAs, promoted the differentiation and function of CD11c+ macrophages. Specifically, we demonstrated that stearic acid (SA) significantly induced CD11c expression in monocytes through activation of the nuclear retinoid acid receptor. More importantly, cytosolic expression of epidermal FA binding protein (E-FABP) in monocytes/macrophages was shown to be critical to the mediation of the SA-induced effect. Depletion of E-FABP not only inhibited SA-induced CD11c upregulation in macrophages in vitro but also abrogated high-saturated-fat diet-induced skin lesions in obese mouse models in vivo. Altogether, our data demonstrate a novel mechanism by which saturated FAs promote obesity-associated inflammation through inducing E-FABP/retinoid acid receptor-mediated differentiation of CD11c+ macrophages. PMID- 29626091 TI - The ubiquitin-specific protease USP8 deubiquitinates and stabilizes Cx43. AB - Connexin-43 (Cx43, also known as GJA1) is the most ubiquitously expressed connexin isoform in mammalian tissues. It forms intercellular gap junction (GJ) channels, enabling adjacent cells to communicate both electrically and metabolically. Cx43 is a short-lived protein which can be quickly degraded by the ubiquitin-dependent proteasomal, endolysosomal, and autophagosomal pathways. Here, we report that the ubiquitin-specific peptidase 8 (USP8) interacts with and deubiquitinates Cx43. USP8 reduces both multiple monoubiquitination and polyubiquitination of Cx43 to prevent autophagy-mediated degradation. Consistently, knockdown of USP8 results in decreased Cx43 protein levels in cultured cells and suppresses intercellular communication, revealed by the dye transfer assay. In human breast cancer specimens, the expression levels of USP8 and Cx43 proteins are positively correlated. Taken together, these results identified USP8 as a crucial and bona fide deubiquitinating enzyme involved in autophagy-mediated degradation of Cx43. PMID- 29626090 TI - A GTPase-activating protein-binding protein (G3BP1)/antiviral protein relay conveys arteriosclerotic Wnt signals in aortic smooth muscle cells. AB - In aortic vascular smooth muscle (VSM), the canonical Wnt receptor LRP6 inhibits protein arginine (Arg) methylation, a new component of noncanonical Wnt signaling that stimulates nuclear factor of activated T cells (viz NFATc4). To better understand how methylation mediates these actions, MS was performed on VSM cell extracts from control and LRP6-deficient mice. LRP6-dependent Arg methylation was regulated on >500 proteins; only 21 exhibited increased monomethylation (MMA) with concomitant reductions in dimethylation. G3BP1, a known regulator of arteriosclerosis, exhibited a >30-fold increase in MMA in its C-terminal domain. Co-transfection studies confirm that G3BP1 (G3BP is Ras-GAP SH3 domain-binding protein) methylation is inhibited by LRP6 and that G3BP1 stimulates NFATc4 transcription. NFATc4 association with VSM osteopontin (OPN) and alkaline phosphatase (TNAP) chromatin was increased with LRP6 deficiency and reduced with G3BP1 deficiency. G3BP1 activation of NFATc4 mapped to G3BP1 domains supporting interactions with RIG-I (retinoic acid inducible gene I), a stimulus for mitochondrial antiviral signaling (MAVS) that drives cardiovascular calcification in humans when mutated in Singleton-Merten syndrome (SGMRT2). Gain-of-function SGMRT2/RIG-I mutants increased G3BP1 methylation and synergized with osteogenic transcription factors (Runx2 and NFATc4). A chemical antagonist of G3BP, C108 (C108 is 2-hydroxybenzoic acid, 2-[1-(2-hydroxyphenyl)ethylidene]hydrazide CAS 15533-09-2), down-regulated RIG-I-stimulated G3BP1 methylation, Wnt/NFAT signaling, VSM TNAP activity, and calcification. G3BP1 deficiency reduced RIG-I protein levels and VSM osteogenic programs. Like G3BP1 and RIG-I deficiency, MAVS deficiency reduced VSM osteogenic signals, including TNAP activity and Wnt5 dependent nuclear NFATc4 levels. Aortic calcium accumulation is decreased in MAVS deficient LDLR-/- mice fed arteriosclerotic diets. The G3BP1/RIG-I/MAVS relay is a component of Wnt signaling. Targeting this relay may help mitigate arteriosclerosis. PMID- 29626092 TI - Identification of a metabolic disposal route for the oncometabolite S-(2 succino)cysteine in Bacillus subtilis. AB - Cellular thiols such as cysteine spontaneously and readily react with the respiratory intermediate fumarate, resulting in the formation of stable S-(2 succino)-adducts. Fumarate-mediated succination of thiols increases in certain tumors and in response to glucotoxicity associated with diabetes. Therefore, S-(2 succino)-adducts such as S-(2-succino)cysteine (2SC) are considered oncometabolites and biomarkers for human disease. No disposal routes for S-(2 succino)-compounds have been reported prior to this study. Here, we show that Bacillus subtilis metabolizes 2SC to cysteine using a pathway encoded by the yxe operon. The first step is N-acetylation of 2SC followed by an oxygenation that we propose results in the release of oxaloacetate and N-acetylcysteine, which is deacetylated to give cysteine. Knockouts of the genes predicted to mediate each step in the pathway lose the ability to grow on 2SC as the sulfur source and accumulate the expected upstream metabolite(s). We further show that N acetylation of 2SC relieves toxicity. This is the first demonstration of a metabolic disposal route for any S-(2-succino)-compound, paving the way toward the identification of corresponding pathways in other species. PMID- 29626093 TI - Restoring mitochondrial calcium uniporter expression in diabetic mouse heart improves mitochondrial calcium handling and cardiac function. AB - Diabetes mellitus is a growing health care problem, resulting in significant cardiovascular morbidity and mortality. Diabetes also increases the risk for heart failure (HF) and decreased cardiac myocyte function, which are linked to changes in cardiac mitochondrial energy metabolism. The free mitochondrial calcium level ([Ca2+] m ) is fundamental in activating the mitochondrial respiratory chain complexes and ATP production and is also known to regulate pyruvate dehydrogenase complex (PDC) activity. The mitochondrial calcium uniporter (MCU) complex (MCUC) plays a major role in mediating mitochondrial Ca2+ import, and its expression and function therefore have a marked impact on cardiac myocyte metabolism and function. Here, we investigated MCU's role in mitochondrial Ca2+ handling, mitochondrial function, glucose oxidation, and cardiac function in the heart of diabetic mice. We found that diabetic mouse hearts exhibit altered expression of MCU and MCUC members and a resulting decrease in [Ca2+] m , mitochondrial Ca2+ uptake, mitochondrial energetic function, and cardiac function. Adeno-associated virus-based normalization of MCU levels in these hearts restored mitochondrial Ca2+ handling, reduced PDC phosphorylation levels, and increased PDC activity. These changes were associated with cardiac metabolic reprogramming toward normal physiological glucose oxidation. This reprogramming likely contributed to the restoration of both cardiac myocyte and heart function to nondiabetic levels without any observed detrimental effects. These findings support the hypothesis that abnormal mitochondrial Ca2+ handling and its negative consequences can be ameliorated in diabetes by restoring MCU levels via adeno-associated virus-based MCU transgene expression. PMID- 29626094 TI - The substrate-binding cap of the UDP-diacylglucosamine pyrophosphatase LpxH is highly flexible, enabling facile substrate binding and product release. AB - Gram-negative bacteria are surrounded by a secondary membrane of which the outer leaflet is composed of the glycolipid lipopolysaccharide (LPS), which guards against hydrophobic toxins, including many antibiotics. Therefore, LPS synthesis in bacteria is an attractive target for antibiotic development. LpxH is a pyrophosphatase involved in LPS synthesis, and previous structures revealed that LpxH has a helical cap that binds its lipid substrates. Here, crystallography and hydrogen-deuterium exchange MS provided evidence for a highly flexible substrate binding cap in LpxH. Furthermore, molecular dynamics simulations disclosed how the helices of the cap may open to allow substrate entry. The predicted opening mechanism was supported by activity assays of LpxH variants. Finally, we confirmed biochemically that LpxH is inhibited by a previously identified antibacterial compound, determined the potency of this inhibitor, and modeled its binding mode in the LpxH active site. In summary, our work provides evidence that the substrate-binding cap of LpxH is highly dynamic, thus allowing for facile substrate binding and product release between the capping helices. Our results also pave the way for the rational design of more potent LpxH inhibitors. PMID- 29626096 TI - The mitochondrial ribosomal protein L13 is critical for the structural and functional integrity of the mitochondrion in Plasmodium falciparum. AB - The phylum Apicomplexa contains a group of protozoa causing diseases in humans and livestock. Plasmodium spp., the causative agent of malaria, contains a mitochondrion that is very divergent from that of their hosts. The malarial mitochondrion is a clinically validated target for the antimalarial drug atovaquone, which specifically blocks the electron transfer activity of the bc1 complex of the mitochondrial electron transport chain (mtETC). Most mtETC proteins are nuclear-encoded and imported from the cytosol, but three key protein subunits are encoded in the Plasmodium mitochondrial genome: cyt b, COXI, and COXIII. They are translated inside the mitochondrion by mitochondrial ribosomes (mitoribosomes). Here, we characterize the function of one large mitoribosomal protein in Plasmodium falciparum, PfmRPL13. We found that PfmRPL13 localizes to the parasite mitochondrion and is refractory to genetic knockout. Ablation of PfmRPL13 using a conditional knockdown system (TetR-DOZI-aptamer) caused a series of adverse events in the parasite, including mtETC deficiency, loss of mitochondrial membrane potential (Deltapsim), and death. The PfmRPL13 knockdown parasite also became hypersensitive to proguanil, a drug proposed to target an alternative process for maintaining Deltapsim Surprisingly, transmission EM revealed that PfmRPL13 disruption also resulted in an unusually elongated and branched mitochondrion. The growth arrest of the knockdown parasite could be rescued with a second copy of PfmRPL13, but not by supplementation with decylubiquinone or addition of a yeast dihydroorotate dehydrogenase gene. In summary, we provide first and direct evidence that mitoribosomes are essential for malaria parasites to maintain the structural and functional integrity of the mitochondrion. PMID- 29626095 TI - The ErpA/NfuA complex builds an oxidation-resistant Fe-S cluster delivery pathway. AB - Fe-S cluster-containing proteins occur in most organisms, wherein they assist in myriad processes from metabolism to DNA repair via gene expression and bioenergetic processes. Here, we used both in vitro and in vivo methods to investigate the capacity of the four Fe-S carriers, NfuA, SufA, ErpA, and IscA, to fulfill their targeting role under oxidative stress. Likewise, Fe-S clusters exhibited varying half-lives, depending on the carriers they were bound to; an NfuA-bound Fe-S cluster was more stable (t1/2 = 100 min) than those bound to SufA (t1/2 = 55 min), ErpA (t1/2 = 54 min), or IscA (t1/2 = 45 min). Surprisingly, the presence of NfuA further enhanced stability of the ErpA-bound cluster to t1/2 = 90 min. Using genetic and plasmon surface resonance analyses, we showed that NfuA and ErpA interacted directly with client proteins, whereas IscA or SufA did not. Moreover, NfuA and ErpA interacted with one another. Given all of these observations, we propose an architecture of the Fe-S delivery network in which ErpA is the last factor that delivers cluster directly to most if not all client proteins. NfuA is proposed to assist ErpA under severely unfavorable conditions. A comparison with the strategy employed in yeast and eukaryotes is discussed. PMID- 29626098 TI - Medical students report the effect of tuition fees. PMID- 29626097 TI - Oxidative stress alters mitochondrial bioenergetics and modifies pancreatic cell death independently of cyclophilin D, resulting in an apoptosis-to-necrosis shift. AB - Mitochondrial dysfunction lies at the core of acute pancreatitis (AP). Diverse AP stimuli induce Ca2+-dependent formation of the mitochondrial permeability transition pore (MPTP), a solute channel modulated by cyclophilin D (CypD), the formation of which causes ATP depletion and necrosis. Oxidative stress reportedly triggers MPTP formation and is elevated in clinical AP, but how reactive oxygen species influence cell death is unclear. Here, we assessed potential MPTP involvement in oxidant-induced effects on pancreatic acinar cell bioenergetics and fate. H2O2 application promoted acinar cell apoptosis at low concentrations (1-10 MUm), whereas higher levels (0.5-1 mm) elicited rapid necrosis. H2O2 also decreased the mitochondrial NADH/FAD+ redox ratio and DeltaPsim in a concentration-dependent manner (10 MUm to 1 mm H2O2), with maximal effects at 500 MUm H2O2 H2O2 decreased the basal O2 consumption rate of acinar cells, with no alteration of ATP turnover at <50 MUm H2O2 However, higher H2O2 levels (>=50 MUm) diminished spare respiratory capacity and ATP turnover, and bioenergetic collapse, ATP depletion, and cell death ensued. Menadione exerted detrimental bioenergetic effects similar to those of H2O2, which were inhibited by the antioxidant N-acetylcysteine. Oxidant-induced bioenergetic changes, loss of DeltaPsim, and cell death were not ameliorated by genetic deletion of CypD or by its acute inhibition with cyclosporine A. These results indicate that oxidative stress alters mitochondrial bioenergetics and modifies pancreatic acinar cell death. A shift from apoptosis to necrosis appears to be associated with decreased mitochondrial spare respiratory capacity and ATP production, effects that are independent of CypD-sensitive MPTP formation. PMID- 29626099 TI - Incidence, Risk Factors, and Clinical Characteristics of Peripartum Cardiomyopathy in South Korea. AB - BACKGROUND: Peripartum cardiomyopathy (PPCM) is a rare disorder associated with pregnancy that can lead to life-threatening conditions. The incidence and clinical characteristics of this condition remain poorly understood. METHODS AND RESULTS: We aimed to perform the first population-based study of PPCM in South Korea, using the Korea National Health Insurance Claims Database of the Health Insurance Review and Assessment Service. Patients who fulfilled predefined diagnostic criteria for PPCM from January 1, 2010, to December 31, 2012, were identified from International Classification of Diseases, Tenth Revision, Clinical Modification codes. To discriminate PPCM from other causes of heart failure, we excluded subjects who already had heart failure-related International Classification of Diseases, Tenth Revision, Clinical Modification codes at least 1 year before delivery. During the study period, there were 1 404 551 deliveries in South Korea, and we excluded 20 159 patients who already had heart failure. In those, a total of 795 cases were identified as PPCM. Patients with PPCM were older, had a higher prevalence of preeclampsia and gestational diabetes mellitus, and were more likely to be primiparous and have multiple pregnancies. Moreover, cesarean section and pregnancy-related complications and in-hospital death were also more common in patients with PPCM. Intriguingly, a considerable number of heart failure cases (n=64; 8.1% of total PPCM) were noted between 5 and 12 months after delivery. CONCLUSIONS: The incidence of PPCM was 1 in 1741 deliveries in South Korea. Patients with PPCM were older, were more associated with primiparity and multiple pregnancy, had more pregnancy-related complications, and revealed higher in-hospital mortality than controls. The number of cases diagnosed as PPCM were decreased over time after delivery; however, a large number of patients were still noted through 12 months after delivery. PMID- 29626100 TI - Devil in Disguise: Hints and Pitfalls in Diagnosis of Peripartum Cardiomyopathy. PMID- 29626101 TI - Advanced Dilated Cardiomyopathy in a Patient With Hutterite Limb-Girdle Muscular Dystrophy: Use of a Left Ventricular Assist Device. PMID- 29626102 TI - Identification of unusual oxysterols and bile acids with 7-oxo or 3beta,5alpha,6beta-trihydroxy functions in human plasma by charge-tagging mass spectrometry with multistage fragmentation. AB - 7-Oxocholesterol (7-OC), 5,6-epoxycholesterol (5,6-EC), and its hydrolysis product cholestane-3beta,5alpha,6beta-triol (3beta,5alpha,6beta-triol) are normally minor oxysterols in human samples; however, in disease, their levels may be greatly elevated. This is the case in plasma from patients suffering from some lysosomal storage disorders, e.g., Niemann-Pick disease type C, or the inborn errors of sterol metabolism, e.g., Smith-Lemli-Opitz syndrome and cerebrotendinous xanthomatosis. A complication in the analysis of 7-OC and 5,6-EC is that they can also be formed ex vivo from cholesterol during sample handling in air, causing confusion with molecules formed in vivo. When formed endogenously, 7-OC, 5,6-EC, and 3beta,5alpha,6beta-triol can be converted to bile acids. Here, we describe methodology based on chemical derivatization and LC/MS with multistage fragmentation (MSn) to identify the necessary intermediates in the conversion of 7-OC to 3beta-hydroxy-7-oxochol-5-enoic acid and 5,6-EC and 3beta,5alpha,6beta-triol to 3beta,5alpha,6beta-trihydroxycholanoic acid. Identification of intermediate metabolites is facilitated by their unusual MSn fragmentation patterns. Semiquantitative measurements are possible, but absolute values await the synthesis of isotope-labeled standards. PMID- 29626103 TI - Role of RAB5A in FSHR-mediated signal transduction in human granulosa cells. AB - Polycystic ovary syndrome, a common condition characterized by endocrine dysfunction, menstrual irregularity, anovulation and polycystic ovaries, affects 5-7% of reproductive-age women. RAB5B, which is identified by a genome-wide association study as a risk locus for this syndrome, encodes a small GTPase involved in control of receptor internalization and early endosome fusion. We found that RAB5A mRNA levels in luteinized granulosa cells of obese patients with polycystic ovary syndrome were lower than in those of obese women without the syndrome. RAB5A regulated follicle-stimulating hormone (FSH)-mediated translocation of the FSH receptor (FSHR) from the membrane to the cytoplasm and the subsequent FSH-FSHR signaling pathway. We showed that RAB5A negatively regulated aromatase expression and estradiol synthesis in human granulosa cells in association with changes in FSHR levels by way of the cAMP/PKA/CREB pathway. The regulation of FSHR by RAB5A may have been associated with two transcription factors, USF1 and USF2. In conclusion, RAB5A gene was abnormally expressed in luteinized granulosa cells of obese patients with polycystic ovary syndrome, which may help explain high FSHR levels found in this syndrome. PMID- 29626104 TI - Activation of lysosomal cathepsins in pregnant bovine leukocytes. AB - In ruminants, interferon-tau (IFNT)-mediated expression of interferon-stimulated genes in peripheral blood leukocytes (PBLs) can indicate pregnancy. Recently, type 1 IFN-mediated activation of lysosomes and lysosomal cathepsins (CTSs) was observed in immune cells. This study investigated the status of lysosomal CTSs and lysosomes in PBLs collected from pregnant (P) and non-pregnant (NP) dairy cows, and conducted in vitro IFNT stimulation of NP blood leukocytes. Blood samples were collected 0, 7, 14 and 18 days post-artificial insemination, and the peripheral blood mononuclear cells (PBMCs) and polymorphonuclear granulocytes (PMNs) separated. The fluorescent activity of CTSB and CTSK in PMNs significantly increased with the progress of pregnancy, especially on day 18. In vitro supplementation of IFNT significantly increased the activities of CTSB and CTSK in NP PBMCs and PMNs. CTSB expression was significantly higher in PBMCs and PMNs collected from P day-18 cows than from NP cows, whereas there was no difference in CTSK expression. IFNT increased CTSB expression but did not affect CTSK expression. Immunodetection showed an increase of CTSB in P day-18 PBMCs and PMNs. In vitro stimulation of IFNT increased CTSB in NP PBMCs and PMNs. Lysosomal acidification showed a significant increase in P day-18 PBMCs and PMNs. IFNT also stimulated lysosomal acidification. Expressions of lysosome-associated membrane protein (LAMP) 1 and LAMP2 were significantly higher in P day-18 PBMCs and PMNs. The results suggest that pregnancy-specific activation of lysosomal functions by CTS activation in blood leukocytes is highly associated with IFNT during maternal and fetal recognition of pregnancy. PMID- 29626105 TI - Murine sperm capacitation, oocyte penetration and decondensation following moderate alcohol intake. AB - Male chronic alcohol abuse causes testicular failure and infertility. We analyzed the effects of moderate sub-chronic alcohol intake on sperm morphology, capacitation, fertilization and sperm head decondensation. CF-1 male mice were administered 15% ethanol in drinking water for 15 days; control mice received ethanol-free water. Similar patterns of tyrosine phosphorylation were observed in capacitated spermatozoa of control and treated males. Percentage of hyperactivation (H) and spontaneous (SAR) and progesterone-induced (IAR) acrosome reaction significantly decreased at 120 and 150 min of capacitation in treated males compared to controls (H: 14.1 +/- 2.5 vs 23.7 +/- 2.6, P < 0.05; SAR-T120 min: 17.9 +/- 2.5 vs 32.9 +/- 4.1, P < 0.01; IAR-150 min: 43.3 +/- 3.5 vs 73.1 +/ 1.1, P < 0.001, n = 6). During in vitro fertilization (2.5, 3.5 and 4.5 h post insemination), there was an increased percentage of fertilized oocytes (with a decondensed sperm head and one or two pronuclei) in treated males (P < 0.001, n = 7). After 60 min of in vitro decondensation with glutathione plus heparin, the percentage of decondensed sperm heads was significantly higher in treated males than in controls (mean +/- s.d.: 57.1 +/- 5.6 vs 48.3 +/- 4.5, P < 0.05, n = 5). The percentage of morphologically normal sperm heads was significantly decreased in treated males with respect to controls (P < 0.001, n = 9). These results show that short-term moderate alcohol consumption in outbred mice affect sperm morphology, hyperactivation, acrosomal exocytosis, and the dynamics of in vitro fertilization and in vitro sperm nuclear decondensation. PMID- 29626106 TI - Comment on the calculations in protein thermodynamics. PMID- 29626107 TI - Reply to Kang and Brooks: Comment on the calculations in protein thermodynamics. PMID- 29626108 TI - Carb loading takes proteins on a ride. AB - Cytoplasmic protein O-glycosylation in bacteria is often required for protein maturation, but the dependence of protein export on carbohydrate modifications is less understood. In the current issue of JBC, Chen et al. describe the mechanism for posttranslational modification of a Streptococcus gordonii adhesin and its delivery to the membrane, leading to the first comprehensive model featuring the interplay of glycosyltransferases and the translocation system. PMID- 29626109 TI - Structures of exopolysaccharides involved in receptor-mediated perception of Mesorhizobium loti by Lotus japonicas. PMID- 29626110 TI - Impaired endocrine-metabolic homeostasis: underlying mechanism of its induction by unbalanced diet. AB - To characterize the intrinsic mechanism by which sucrose induces beta-cell dysfunction. Normal rats received for 3 weeks a standard diet supplemented with 10% sucrose in the drinking water (high sucrose (HS)) with/out an antioxidant agent (R/S alpha-lipoic acid). We measured plasma glucose, insulin, triglyceride, leptin, and lipid peroxidation levels; homeostasis model assessment (HOMA) insulin resistance (HOMA-IR) and HOMA for beta-cell function (HOMA-beta) indexes were also determined. Insulin secretion, beta-cell apoptosis, intracellular insulin and leptin mediators, and oxidative stress (OS) markers were also measured in islets isolated from each experimental group. HS rats had increased plasma triglyceride, insulin, leptin, and lipid peroxidation (OS marker) levels associated with an insulin-resistant state. Their islets developed an initial compensatory increase in glucose-induced insulin secretion and mRNA and protein levels of beta-cell apoptotic markers. They also showed a significant decrease in mRNA and protein levels of insulin and leptin signaling pathway mediators. Uncoupling protein 2 (UCP2), peroxisome proliferator-activated receptor (PPAR) alpha and -delta mRNA and protein levels were increased whereas mRNA levels of Sirtuin-1 (Sirt-1), glutathione peroxidase, and catalase were significantly lower in these animals. Development of all these endocrine-metabolic abnormalities was prevented by co-administration of R/S alpha-lipoic acid together with sucrose. OS may be actively involved in the mechanism by which unbalanced/unhealthy diet induces beta-cell dysfunction. Since metabolic-endocrine dysfunctions recorded in HS rats resembled those measured in human pre-diabetes, knowledge of its molecular mechanism could help to develop appropriate strategies to prevent the progression of this metabolic state toward type 2 diabetes (T2D). PMID- 29626111 TI - Characterization of the novel mitochondrial genome replication factor MiRF172 in Trypanosoma brucei. AB - The unicellular parasite Trypanosoma brucei harbors one mitochondrial organelle with a singular genome called the kinetoplast DNA (kDNA). The kDNA consists of a network of concatenated minicircles and a few maxicircles that form the kDNA disc. More than 30 proteins involved in kDNA replication have been described. However, several mechanistic questions are only poorly understood. Here, we describe and characterize minicircle replication factor 172 (MiRF172), a novel mitochondrial genome replication factor that is essential for cell growth and kDNA maintenance. By performing super-resolution microscopy, we show that MiRF172 is localized to the kDNA disc, facing the region between the genome and the mitochondrial membranes. We demonstrate that depletion of MiRF172 leads to a loss of minicircles and maxicircles. Detailed analysis suggests that MiRF172 is involved in the reattachment of replicated minicircles to the kDNA disc. Furthermore, we provide evidence that the localization of the replication factor MiRF172 not only depends on the kDNA itself, but also on the mitochondrial genome segregation machinery, suggesting an interaction between the two essential entities.This article has an associated First Person interview with the first author of the paper. PMID- 29626112 TI - Amyloid blood biomarker detects Alzheimer's disease. AB - Alzheimer's disease (AD) is currently incurable, but there is general agreement that a minimally invasive blood biomarker for screening in preclinical stages would be crucial for future therapy. Diagnostic tools for detection of AD are either invasive like cerebrospinal fluid (CSF) biomarkers or expensive such as positron emission tomography (PET) scanning. Here, we determine the secondary structure change of amyloid-beta (Abeta) in human blood. This change used as blood amyloid biomarker indicates prodromal AD and correlates with CSF AD biomarkers and amyloid PET imaging in the cross-sectional BioFINDER cohort. In a further population-based longitudinal cohort (ESTHER), the blood biomarker detected AD several years before clinical diagnosis in baseline samples with a positive likelihood ratio of 7.9; that is, those who were diagnosed with AD over the years were 7.9 times more likely to test positive. This assay may open avenues for blood screening of early AD stages as a funnel for further more invasive and expensive tests. PMID- 29626113 TI - Low--resolution vision in a velvet worm (Onychophora). AB - Onychophorans, also known as velvet worms, possess a pair of simple lateral eyes, and are a key lineage with regard to the evolution of vision. They resemble ancient Cambrian forms, and are closely related to arthropods, which boast an unrivalled diversity of eye designs. Nonetheless, the visual capabilities of onychophorans have not been well explored. Here, we assessed the spatial resolution of the onychophoran Euperipatoides rowelli using behavioural experiments, three-dimensional reconstruction, anatomical and optical examinations, and modelling. Exploiting their spontaneous attraction towards dark objects, we found that E. rowelli can resolve stimuli that have the same average luminance as the background. Depending on the assumed contrast sensitivity of the animals, we estimate the spatial resolution to be in the range 15-40 deg. This results from an arrangement where the cornea and lens project the image largely behind the retina. The peculiar ellipsoid shape of the eye in combination with the asymmetric position and tilted orientation of the lens may improve spatial resolution in the forward direction. Nonetheless, the unordered network of interdigitating photoreceptors, which fills the whole eye chamber, precludes high acuity vision. Our findings suggest that adult specimens of E. rowelli cannot spot or visually identify prey or conspecifics beyond a few centimetres from the eye, but the coarse spatial resolution that the animals exhibited in our experiments is likely to be sufficient to find shelter and suitable microhabitats from further away. To our knowledge, this is the first evidence of resolving vision in an onychophoran. PMID- 29626116 TI - A new research paradigm for bivariate allometry: combining ANOVA and non-linear regression. AB - A novel statistical routine is presented here for exploring and comparing patterns of allometric variation in two or more groups of subjects. The routine combines elements of the analysis of variance (ANOVA) with non-linear regression to achieve the equivalent of an analysis of covariance (ANCOVA) on curvilinear data. The starting point is a three-parameter power equation to which a categorical variable has been added to identify membership by each subject in a specific group or treatment. The protocol differs from earlier ones in that different assumptions can be made about the form for random error in the full statistical model (i.e. normal and homoscedastic, normal and heteroscedastic, lognormal and heteroscedastic). The general equation and several modifications thereof were used to study allometric variation in field metabolic rates of marsupial and placental mammals. The allometric equations for both marsupials and placentals have an explicit, non-zero intercept, but the allometric exponent is higher in the equation for placentals than in that for marsupials. The approach followed here is extraordinarily versatile, and it has wider application in allometry than standard ANCOVA performed on logarithmic transformations. PMID- 29626117 TI - Correction: Are we what we eat? Changes to the feed fatty acid composition of farmed salmon and its effects through the food chain (doi: 10.1242/jeb.161521). PMID- 29626114 TI - Combination anti-Abeta treatment maximizes cognitive recovery and rebalances mTOR signaling in APP mice. AB - Drug development for Alzheimer's disease has endeavored to lower amyloid beta (Abeta) by either blocking production or promoting clearance. The benefit of combining these approaches has been examined in mouse models and shown to improve pathological measures of disease over single treatment; however, the impact on cellular and cognitive functions affected by Abeta has not been tested. We used a controllable APP transgenic mouse model to test whether combining genetic suppression of Abeta production with passive anti-Abeta immunization improved functional outcomes over either treatment alone. Compared with behavior before treatment, arresting further Abeta production (but not passive immunization) was sufficient to stop further decline in spatial learning, working memory, and associative memory, whereas combination treatment reversed each of these impairments. Cognitive improvement coincided with resolution of neuritic dystrophy, restoration of synaptic density surrounding deposits, and reduction of hyperactive mammalian target of rapamycin signaling. Computational modeling corroborated by in vivo microdialysis pointed to the reduction of soluble/exchangeable Abeta as the primary driver of cognitive recovery. PMID- 29626118 TI - Does PET Reconstruction Method Affect Deauville Scoring in Lymphoma Patients? PMID- 29626115 TI - Macrophage/microglial Ezh2 facilitates autoimmune inflammation through inhibition of Socs3. AB - Histone 3 Lys27 (H3K27) trimethyltransferase Ezh2 is implicated in the pathogenesis of autoimmune inflammation. Nevertheless, the role of Ezh2 in macrophage/microglial activation remains to be defined. In this study, we identified that macrophage/microglial H3K27me3 or Ezh2, rather than functioning as a repressor, mediates toll-like receptor (TLR)-induced proinflammatory gene expression, and therefore Ezh2 depletion diminishes macrophage/microglial activation and attenuates the autoimmune inflammation in dextran sulfate sodium induced colitis and experimental autoimmune encephalomyelitis. Mechanistic characterizations indicated that Ezh2 deficiency directly stimulates suppressor of cytokine signaling 3 (Socs3) expression and therefore enhances the Lys48 linked ubiquitination and degradation of tumor necrosis factor receptor associated factor 6. As a consequence, TLR-induced MyD88-dependent nuclear factor kappaB activation and the expression of proinflammatory genes in macrophages/microglia are compromised in the absence of Ezh2. The functional dependence of Ezh2 for Socs3 is further illustrated by the rescue experiments in which silencing of Socs3 restores macrophage activation and rescues autoimmune inflammation in macrophage/microglial Ezh2-deficient mice. Together, these findings establish Ezh2 as a macrophage lineage-specific mediator of autoimmune inflammation and highlight a previously unknown mechanism of Ezh2 function. PMID- 29626119 TI - Development of Quinoline-Based Theranostic Ligands for the Targeting of Fibroblast Activation Protein. AB - Fibroblast activation protein (FAP) is overexpressed in cancer-associated fibroblasts and is involved in a variety of tumor-promoting activities such as matrix remodeling, angiogenesis, chemotherapy resistance, and immunosuppression. Because FAP shows low expression in most normal organs, it presents an interesting target for imaging and endoradiotherapy. In this investigation, FAP inhibitors (FAPIs) were modified and optimized for use as theranostic tracers. Methods: FAPIs based on a quinoline structure were synthesized and characterized with respect to binding, internalization, and efflux in cells expressing human and murine FAP as well as CD26. Preclinical pharmacokinetics were determined in tumor-bearing animals with biodistribution experiments and small-animal PET. Finally, a proof-of-concept approach toward imaging and therapy was chosen for 2 patients with metastasized breast cancer. Results: Of 15 synthesized FAPIs, FAPI 04 was identified as the most promising tracer for clinical application. Compared with the previously published ligand, FAPI-02, FAPI-04 showed excellent stability in human serum, higher affinity for FAP as opposed to CD26, and slower excretion in vitro. In vivo, a higher SUV was reached in tumor-bearing animals, leading to larger areas under the curve as calculated from biodistribution experiments. Finally, PET/CT scans with 68Ga-FAPI-04 in 2 patients with metastasized breast cancer revealed high tracer uptake in metastases and a reduction in pain symptoms after therapy with a considerably low dose of 90Y-FAPI-04. Conclusion: FAPI-04 represents a promising tracer for both diagnostic imaging and, possibly, targeted therapy of malignant tumors with a high content of activated fibroblasts, such as breast cancer. PMID- 29626120 TI - A Tumor-Imaging Method Targeting Cancer-Associated Fibroblasts. AB - The tumor stroma, which accounts for a large part of the tumor mass, represents an attractive target for the delivery of diagnostic and therapeutic compounds. Here, the focus is notably on a subpopulation of stromal cells, known as cancer associated fibroblasts, which are present in more than 90% of epithelial carcinomas, including pancreatic, colon, and breast cancer. Cancer-associated fibroblasts feature high expression of fibroblast activation protein (FAP), which is not detectable in adult normal tissue but is associated with a poor prognosis in cancer patients. Methods: We developed an iodinated and a DOTA-coupled radiotracer based on a FAP-specific enzyme inhibitor (FAPI) and evaluated them in vitro using uptake, competition, and efflux studies as well as confocal microscopy of a fluorescence-labeled variant. Furthermore, we performed imaging and biodistribution studies on tumor-bearing animals. Finally, proof of concept was realized by imaging patients with 68Ga-labeled FAPI. Results: Both FAPIs showed high specificity, affinity, and rapid internalization into FAP-expressing cells in vitro and in vivo. Biodistribution studies on tumor-bearing mice and on the first cancer patients demonstrated high intratumoral uptake of the tracer and fast body clearance, resulting in high-contrast images and negligible exposure of healthy tissue to radiation. A comparison with the commonly used radiotracer 18F FDG in a patient with locally advanced lung adenocarcinoma revealed that the new FAP ligand was clearly superior. Conclusion: Radiolabeled FAPIs allow fast imaging with very high contrast in tumors having a high stromal content and may therefore serve as pantumor agents. Coupling of these molecules to DOTA or other chelators allows labeling not only with 68Ga but also with therapeutic isotopes such as 177Lu or 90Y. PMID- 29626122 TI - Age-Specific 18F-FDG Image Processing Pipelines and Analysis Are Essential for Individual Mapping of Seizure Foci in Pediatric Patients with Intractable Epilepsy. AB - 18F-FDG PET is an important tool for the presurgical assessment of children with drug-resistant epilepsy. Standard assessment is performed visually and is often subjective and highly user-dependent. Voxelwise statistics can be used to remove user-dependent biases by automatically identifying areas of significant hypo- or hypermetabolism associated with the epileptogenic area. In the clinical setting, this analysis is performed using commercially available software. These software packages suffer from two main limitations when applied to pediatric PET data: pediatric scans are spatially normalized to an adult standard template, and statistical comparisons use an adult control dataset. The aim of this work was to provide a reliable observer-independent pipeline for the analysis of pediatric 18F-FDG PET scans, as part of presurgical planning in epilepsy. Methods: A pseudocontrol dataset (19 subjects 6-9 y old, and 93 subjects 10-20 y old) was used to create two age-specific 18F-FDG PET pediatric templates in standard pediatric space. The 18F-FDG PET scans of 46 epilepsy patients (16 patients 6-9 y old, and 30 patients 10-17 y old) were retrospectively collated and analyzed using voxelwise statistics. This procedure was implemented with the standard pipeline available in the commercial software Scenium and an in-house Statistical Parametric Mapping, version 8 (SPM8), pipeline (including age-specific pediatric templates and reference database). A kappa-test was used to assess the level of agreement between the findings of voxelwise analyses and the clinical diagnosis of each patient. The SPM8 pipeline was further validated using postsurgical seizure-free patients. Results: Improved agreement with the clinical diagnosis was reported using SPM8, in terms of focus localization, especially for the younger patient group: kappa = 0.489 for Scenium versus 0.826 for SPM. The proposed pipeline also showed a sensitivity of about 70% in both age ranges for the localization of hypometabolic areas on pediatric 18F-FDG PET scans in postsurgical seizure-free patients. Conclusion: We showed that by creating age specific templates and using pediatric control databases, our pipeline provides an accurate and sensitive semiquantitative method for assessing the 18F-FDG PET scans of patients under 18 y old. PMID- 29626121 TI - Reproducibility and Repeatability of Semiquantitative 18F Fluorodihydrotestosterone Uptake Metrics in Castration-Resistant Prostate Cancer Metastases: A Prospective Multicenter Study. AB - 18F-fluorodihydrotestosterone (18F-FDHT) is a radiolabeled analog of the androgen receptor's primary ligand that is currently being credentialed as a biomarker for prognosis, response, and pharmacodynamic effects of new therapeutics. As part of the biomarker qualification process, we prospectively assessed its reproducibility and repeatability in men with metastatic castration-resistant prostate cancer. Methods: We conducted a prospective multiinstitutional study of metastatic castration-resistant prostate cancer patients undergoing 2 (test/retest) 18F-FDHT PET/CT scans on 2 consecutive days. Two independent readers evaluated all examinations and recorded SUVs, androgen receptor-positive tumor volumes, and total lesion uptake for the most avid lesion detected in each of 32 predefined anatomic regions. The relative absolute difference and reproducibility coefficient (RC) of each metric were calculated between the test and retest scans. Linear regression analyses, intraclass correlation coefficients (ICCs), and Bland-Altman plots were used to evaluate repeatability of 18F-FDHT metrics. The coefficient of variation and ICC were used to assess interobserver reproducibility. Results: Twenty-seven patients with 140 18F-FDHT-avid regions were included. The best repeatability among 18F-FDHT uptake metrics was found for SUV metrics (SUVmax, SUVmean, and SUVpeak), with no significant differences in repeatability among them. Correlations between the test and retest scans were strong for all SUV metrics (R 2 >= 0.92; ICC >= 0.97). The RCs of the SUV metrics ranged from 21.3% (SUVpeak) to 24.6% (SUVmax). The test and retest androgen receptor-positive tumor volumes and TLU, respectively, were highly correlated (R 2 and ICC >= 0.97), although variability was significantly higher than that for SUV (RCs > 46.4%). The prostate-specific antigen levels, Gleason score, weight, and age did not affect repeatability, nor did total injected activity, uptake measurement time, or differences in uptake time between the 2 scans. Including the most avid lesion per patient, the 5 most avid lesions per patient, only lesions 4.2 mL or more, only lesions with an SUV of 4 g/mL or more, or normalizing of SUV to area under the parent plasma activity concentration-time curve did not significantly affect repeatability. All metrics showed high interobserver reproducibility (ICC > 0.98; coefficient of variation < 0.2% 10.8%). Conclusion: Uptake metrics derived from 18F-FDHT PET/CT show high repeatability and interobserver reproducibility. PMID- 29626123 TI - 11C-Choline Pharmacokinetics in Recurrent Prostate Cancer. AB - The aim of this study was to investigate the value of pharmacokinetic modeling for quantifying 11C-choline uptake in patients with recurrent prostate cancer. Methods: In total, 194 patients with clinically suspected recurrence of prostate cancer underwent 11C-choline dynamic PET over the pelvic region (0-8 min), followed by a 6-min static acquisition at about 25 min after injection. Regions of interest were drawn over sites of disease identified by a radiologist with experience in nuclear medicine. 11C-choline uptake and pharmacokinetics were evaluated by SUV, graphical analysis (Patlak plot; K i P), and 1- and 2 compartment pharmacokinetic models (K 1, K 1/k 2, k 3, k 4, and the macro parameter K i C). Twenty-four local recurrences, 65 metastatic lymph nodes, 19 osseous metastases, and 60 inflammatory lymph nodes were included in the analysis, which was subsequently repeated for regions of interest placed over the gluteus maximus muscle and adipose tissue as a control. Results: SUVmean and K i P were 3.60 +/- 2.16 and 0.28 +/- 0.22 min-1 in lesions, compared with 2.11 +/- 1.33 and 0.15 +/- 0.10 min-1 in muscle and 0.26 +/- 0.07 and 0.02 +/- 0.01 min-1 in adipose tissue. According to the Akaike information criterion, the 2 compartment irreversible model was most appropriate in 85% of lesions and resulted in a K 1 of 0.79 +/- 0.98 min-1 (range, 0.11-7.17 min-1), a K 1/k 2 of 2.92 +/- 3.52 (range, 0.31-20.00), a k 3 of 0.36 +/- 0.30 min-1 (range, 0.00-1.00 min-1) and a K i C of 0.28 +/- 0.22 min-1 (range, 0.00-1.33 min-1). The Spearman rho between SUV and K i P, between SUV and K i C, and between K i P and K i C was 0.94, 0.91, and 0.97, respectively, and that between SUV and K 1, between SUV and K 1/k 2, and between SUV and k 3 was 0.70, 0.44, and 0.33, respectively. Malignant lymph nodes exhibited a higher SUV, K i P, and K i C than benign lymph nodes. Conclusion: Although 11C-choline pharmacokinetic modeling has potential to uncouple the contributions of different processes leading to intracellular entrapment of 11C-choline, the high correlation between SUV and both K i P and K i C supports the use of simpler SUV methods to evaluate changes in 11C-choline uptake and metabolism for treatment monitoring. PMID- 29626124 TI - In Vivo Characterization of 4 68Ga-Labeled Multimeric RGD Peptides to Image alphavbeta3 Integrin Expression in 2 Human Tumor Xenograft Mouse Models. AB - alphavbeta3 integrins play an important role in angiogenesis and cell migration in cancer and are highly expressed on the activated endothelial cells of newly formed blood vessels. Here, we compare the targeting characteristics of 4 68Ga labeled multimeric cyclic arginine-glycine-aspartate (RGD)-based tracers in an alphavbeta3 integrin-expressing tumor model and a tumor model in which alphavbeta3 integrin is expressed solely on the neovasculature. Methods: Female BALB/c nude mice were subcutaneously injected with SK-RC-52 (alphavbeta3 integrin positive) or FaDu (alphavbeta3 integrin-negative) tumor cells. 68Ga-labeled DOTA (RGD)2, TRAP-(RGD)3, FSC-(RGD)3, or THP-(RGD)3 was intravenously administered to the mice (0.5 nmol per mouse, 10-20 MBq), followed by small-animal PET/CT imaging and ex vivo biodistribution studies 1 h after injection. Nonspecific uptake of the tracers in both models was determined by coinjecting an excess of unlabeled DOTA-(RGD)2 (50 nmol) along with the radiolabeled tracers. Results: Imaging and biodistribution data showed specific uptake in the tumors for each tracer in both models. Tumor uptake of 68Ga-FSC-(RGD)3 was significantly higher than that of 68Ga-DOTA-(RGD)2, 68Ga-TRAP-(RGD)3, or 68Ga-THP-(RGD)3 in the SK-RC-52 model but not in the FaDu model, in which 68Ga-FSC-(RGD)3 showed significantly higher tumor uptake than 68Ga-TRAP-(RGD)3 Most importantly, differences were also observed in normal tissues and in tumor-to-blood ratios. Conclusion: All tracers showed sufficient targeting of alphavbeta3 integrin expression to allow for tumor detection. Although the highest tumor uptake was found for 68Ga-FSC-(RGD)3 and 68Ga-THP-(RGD)3 in the SK-RC-52 and FaDu models, respectively, selection of the optimal tracer for specific diagnostic applications also depends on tumor-to blood ratio and uptake in normal tissues; these factors should therefore also be considered. PMID- 29626126 TI - APTO-253 Is a New Addition to the Repertoire of Drugs that Can Exploit DNA BRCA1/2 Deficiency. AB - APTO-253 is a small molecule with antiproliferative activity against cell lines derived from a wide range of human malignancies. We sought to determine the mechanisms of action and basis for resistance to APTO-253 so as to identify synthetic lethal interactions that can guide combination studies. The cellular pharmacology of APTO-253 was analyzed in Raji lymphoma cells and a subline selected for resistance (Raji/253R). Using LC/MS/ESI analysis, APTO-253 was found to convert intracellularly to a complex containing one molecule of iron and three molecules of APTO-253 [Fe(253)3]. The intracellular content of Fe(253)3 exceeded that of the native drug by approximately 18-fold, and Fe(253)3 appears to be the most active form. Treatment of cells with APTO-253 caused DNA damage, which led us to ask whether cells deficient in homologous recombination (i.e., loss of BRCA1/2 function) were hypersensitive to this drug. It was found that loss of either BRCA1 or BRCA2 function in multiple isogenic paired cell lines resulted in hypersensitivity to APTO-253 of a magnitude similar to the effects of PARP inhibitors, olaparib. Raji cells selected for 16-fold acquired resistance had 16 fold reduced accumulation of Fe(253)3 RNA-seq analysis revealed that overexpression of the ABCG2 drug efflux pump is a key mechanism of resistance. ABCG2-overexpressed HEK-293 cells were resistant to APTO-253, and inhibition of ABCG2 reversed resistance to APTO-253 in Raji/253R. APTO-253 joins the limited repertoire of drugs that can exploit defects in homologous recombination and is of particular interest because it does not produce myelosuppression. Mol Cancer Ther; 17(6); 1167-76. (c)2018 AACR. PMID- 29626125 TI - Age-Related Change in 5-HT6 Receptor Availability in Healthy Male Volunteers Measured with 11C-GSK215083 PET. AB - Serotonin receptor 6 (5-hydroxytrypamine-6, or 5-HT6) is a potential therapeutic target given its distribution in brain regions that are important in depression, anxiety, and cognition. This study sought to investigate the effects of age on 5 HT6 receptor availability using 11C-GSK215083, a PET ligand with affinity for 5 HT6 in the striatum and 5-HT2A in the cortex. Methods: Twenty-eight healthy male volunteers (age range, 23-52 y) were scanned with 11C-GSK215083 PET. Time activity curves in regions of interest were fitted using a multilinear analysis method. Nondisplaceable binding potential (BPND) was calculated using the cerebellum as the reference region and corrected for partial-volume effects. Results: In 5-HT6-rich areas, regional 11C-GSK215083 showed a negative correlation between BPND and age in the caudate (r = -0.41, P = 0.03) (14% change per decade) and putamen (r = -0.30, P = 0.04) (11% change per decade) but not in the ventral striatum or pallidum. A negative correlation with age was also seen in cortical regions (r = -0.41, P = 0.03) (7% change per decade), consistent with the literature on 5-HT2A availability. Conclusion: To our knowledge, this was the first in vivo study on humans to examine the effect of age on 5-HT6 receptor availability. The study demonstrated a significant age-related decline in 5-HT6 availability (BPND) in the caudate and putamen. PMID- 29626127 TI - APTO-253 Stabilizes G-quadruplex DNA, Inhibits MYC Expression, and Induces DNA Damage in Acute Myeloid Leukemia Cells. AB - APTO-253 is a phase I clinical stage small molecule that selectively induces CDKN1A (p21), promotes G0-G1 cell-cycle arrest, and triggers apoptosis in acute myeloid leukemia (AML) cells without producing myelosuppression in various animal species and humans. Differential gene expression analysis identified a pharmacodynamic effect on MYC expression, as well as induction of DNA repair and stress response pathways. APTO-253 was found to elicit a concentration- and time dependent reduction in MYC mRNA expression and protein levels. Gene ontogeny and structural informatic analyses suggested a mechanism involving G-quadruplex (G4) stabilization. Intracellular pharmacokinetic studies in AML cells revealed that APTO-253 is converted intracellularly from a monomer to a ferrous complex [Fe(253)3]. FRET assays demonstrated that both monomeric APTO-253 and Fe(253)3 stabilize G4 structures from telomeres, MYC, and KIT promoters but do not bind to non-G4 double-stranded DNA. Although APTO-253 exerts a host of mechanistic sequelae, the effect of APTO-253 on MYC expression and its downstream target genes, on cell-cycle arrest, DNA damage, and stress responses can be explained by the action of Fe(253)3 and APTO-253 on G-quadruplex DNA motifs. Mol Cancer Ther; 17(6); 1177-86. (c)2018 AACR. PMID- 29626128 TI - BRAF Gene Copy Number and Mutant Allele Frequency Correlate with Time to Progression in Metastatic Melanoma Patients Treated with MAPK Inhibitors. AB - Metastatic melanoma is characterized by complex genomic alterations, including a high rate of mutations in driver genes and widespread deletions and amplifications encompassing various chromosome regions. Among them, chromosome 7 is frequently gained in BRAF-mutant melanoma, inducing a mutant allele-specific imbalance. Although BRAF amplification is a known mechanism of acquired resistance to therapy with MAPK inhibitors, it is still unclear if BRAF copy number variation and BRAF mutant allele imbalance at baseline can be associated with response to treatment. In this study, we used a multimodal approach to assess BRAF copy number and mutant allele frequency in pretreatment melanoma samples from 46 patients who received MAPK inhibitor-based therapy, and we analyzed the association with progression-free survival. We found that 65% patients displayed BRAF gains, often supported by chromosome 7 polysomy. In addition, we observed that 64% patients had a balanced BRAF-mutant/wild-type allele ratio, whereas 14% and 23% patients had low and high BRAF mutant allele frequency, respectively. Notably, a significantly higher risk of progression was observed in patients with a diploid BRAF status versus those with BRAF gains [HR, 2.86; 95% confidence interval (CI), 1.29-6.35; P = 0.01] and in patients with low percentage versus those with a balanced BRAF mutant allele percentage (HR, 4.54; 95% CI, 1.33-15.53; P = 0.016). Our data suggest that quantitative analysis of the BRAF gene could be useful to select the melanoma patients who are most likely to benefit from therapy with MAPK inhibitors. Mol Cancer Ther; 17(6); 1332-40. (c)2018 AACR. PMID- 29626129 TI - Light-activated helical inversion in cholesteric liquid crystal microdroplets. AB - Cholesteric liquid crystal (CLC) droplets exhibit nontrivial topological features, which are controlled by the ratio between the cholesteric pitch and the droplet radius. The radial spherical structure (RSS) is of particular interest, as it reveals an onion-like concentric organization of the cholesteric helices, leading to the expression of spherical Bragg microcavities. Using an overcrowded alkene-based unidirectional molecular motor as a dopant, we show that the topological defect structure in the droplet can be activated by illumination. By using appropriate molecular motor concentrations, light can either break the symmetry of topological defects (as observed for the bent-twisted bipolar structure), or it can induce inversion of handedness in an onion-like organization (in the case of RSS). This latter feature may pave the way toward alternative activation modes of lasers based on cholesteric droplets. By also studying CLC droplets once they have reached full photoconversion at photostationary state (PSS), we highlight that the strong influence of confinement on the droplets structure occurs to the same extent after the helix inversion event. Our results are interpreted in terms of numerical simulations of the droplets' structure, which shed light on the major role played by curvature close to the droplets' center, this latter one becoming dominant when the droplet radius is small. PMID- 29626130 TI - The gene regulatory program of Acrobeloides nanus reveals conservation of phylum specific expression. AB - The evolution of development has been studied through the lens of gene regulation by examining either closely related species or extremely distant animals of different phyla. In nematodes, detailed cell- and stage-specific expression analyses are focused on the model Caenorhabditis elegans, in part leading to the view that the developmental expression of gene cascades in this species is archetypic for the phylum. Here, we compared two species of an intermediate evolutionary distance: the nematodes C. elegans (clade V) and Acrobeloides nanus (clade IV). To examine A. nanus molecularly, we sequenced its genome and identified the expression profiles of all genes throughout embryogenesis. In comparison with C. elegans, A. nanus exhibits a much slower embryonic development and has a capacity for regulative compensation of missing early cells. We detected conserved stages between these species at the transcriptome level, as well as a prominent middevelopmental transition, at which point the two species converge in terms of their gene expression. Interestingly, we found that genes originating at the dawn of the Ecdysozoa supergroup show the least expression divergence between these two species. This led us to detect a correlation between the time of expression of a gene and its phylogenetic age: evolutionarily ancient and young genes are enriched for expression in early and late embryogenesis, respectively, whereas Ecdysozoa-specific genes are enriched for expression during the middevelopmental transition. Our results characterize the developmental constraints operating on each individual embryo in terms of developmental stages and genetic evolutionary history. PMID- 29626131 TI - Pervasive contingency and entrenchment in a billion years of Hsp90 evolution. AB - Interactions among mutations within a protein have the potential to make molecular evolution contingent and irreversible, but the extent to which epistasis actually shaped historical evolutionary trajectories is unclear. To address this question, we experimentally measured how the fitness effects of historical sequence substitutions changed during the billion-year evolutionary history of the heat shock protein 90 (Hsp90) ATPase domain beginning from a deep eukaryotic ancestor to modern Saccharomyces cerevisiae We found a pervasive influence of epistasis. Of 98 derived amino acid states that evolved along this lineage, about half compromise fitness when introduced into the reconstructed ancestral Hsp90. And the vast majority of ancestral states reduce fitness when introduced into the extant S. cerevisiae Hsp90. Overall, more than 75% of historical substitutions were contingent on permissive substitutions that rendered the derived state nondeleterious, became entrenched by subsequent restrictive substitutions that made the ancestral state deleterious, or both. This epistasis was primarily caused by specific interactions among sites rather than a general effect on the protein's tolerance to mutation. Our results show that epistasis continually opened and closed windows of mutational opportunity over evolutionary timescales, producing histories and biological states that reflect the transient internal constraints imposed by the protein's fleeting sequence states. PMID- 29626133 TI - Long-Term Risk of Hemorrhagic Stroke in Young Patients With Congenital Heart Disease. AB - BACKGROUND AND PURPOSE: The risk of ischemic stroke is increased in patients with congenital heart disease (CHD); however, data on the risk of hemorrhagic stroke, including intracerebral hemorrhage (ICH) and subarachnoid hemorrhage (SAH), are lacking. METHODS: The Swedish Patient Register was used to identify all patients who were born with a diagnosis of CHD between 1970 and 1993. Each patient was compared with 10 randomly selected controls from the general population, matched for age, sex, and county. Follow-up data were collected until December 2011 for both cases and controls. RESULTS: Of 21 982 patients with CHD, 70 developed ICH and 57 developed SAH up to the age of 42 years. CHD patients had more than an 8* higher risk (incidence rate ratio, 8.23; 95% confidence interval, 6-11.2) of developing ICH and almost an 8* higher risk of developing SAH (incidence rate ratio, 7.64; 95% confidence interval, 5.41-10.7) compared with controls. The absolute risk of ICH and SAH was low, with incidence rates of 1.18 and 0.96 cases per 10 000 person-years, respectively. Patients with severe nonconotruncal defects (incidence rate ratio, 16.5; 95% confidence interval, 5.63-51.2) or coarctation of the aorta (incidence rate ratio, 17.3; 95% confidence interval, 6.63-51.8) had the highest relative risk of developing hemorrhagic stroke, with incidence rates of 3.22 and 2.79 cases per 10 000 person-years, respectively. CONCLUSIONS: The relative risk of hemorrhagic stroke among children and young adults with CHD was almost 8* higher than that of matched controls from the general population, although the absolute risk was low. The highest risk of ICH and SAH occurred in patients with severe nonconotruncal defects and coarctation of the aorta. PMID- 29626132 TI - Shortwave infrared fluorescence imaging with the clinically approved near infrared dye indocyanine green. AB - Fluorescence imaging is a method of real-time molecular tracking in vivo that has enabled many clinical technologies. Imaging in the shortwave IR (SWIR; 1,000 2,000 nm) promises higher contrast, sensitivity, and penetration depths compared with conventional visible and near-IR (NIR) fluorescence imaging. However, adoption of SWIR imaging in clinical settings has been limited, partially due to the absence of US Food and Drug Administration (FDA)-approved fluorophores with peak emission in the SWIR. Here, we show that commercially available NIR dyes, including the FDA-approved contrast agent indocyanine green (ICG), exhibit optical properties suitable for in vivo SWIR fluorescence imaging. Even though their emission spectra peak in the NIR, these dyes outperform commercial SWIR fluorophores and can be imaged in the SWIR, even beyond 1,500 nm. We show real time fluorescence imaging using ICG at clinically relevant doses, including intravital microscopy, noninvasive imaging in blood and lymph vessels, and imaging of hepatobiliary clearance, and show increased contrast compared with NIR fluorescence imaging. Furthermore, we show tumor-targeted SWIR imaging with IRDye 800CW-labeled trastuzumab, an NIR dye being tested in multiple clinical trials. Our findings suggest that high-contrast SWIR fluorescence imaging can be implemented alongside existing imaging modalities by switching the detection of conventional NIR fluorescence systems from silicon-based NIR cameras to emerging indium gallium arsenide-based SWIR cameras. Using ICG in particular opens the possibility of translating SWIR fluorescence imaging to human clinical applications. Indeed, our findings suggest that emerging SWIR-fluorescent in vivo contrast agents should be benchmarked against the SWIR emission of ICG in blood. PMID- 29626134 TI - Modified Thrombolysis in Cerebral Infarction 2C/Thrombolysis in Cerebral Infarction 3 Reperfusion Should Be the Aim of Mechanical Thrombectomy: Insights From the ASTER Trial (Contact Aspiration Versus Stent Retriever for Successful Revascularization). AB - BACKGROUND AND PURPOSE: Although successful reperfusion is usually defined as a modified Thrombolysis in Cerebral Infarction (mTICI) 2B or 3 at the end of the procedure, studies have shown that mTICI 2B patients had poorer functional outcomes than TICI 3 patients. An mTICI 2C category has been recently introduced for patients with near-complete perfusion except for slow flow in a few distal cortical vessels or presence of small distal cortical emboli after mechanical thrombectomy. The purpose of this study was to evaluate the difference in functional outcome between patients achieving successful reperfusion (ie, mTICI 2B, mTICI 2C, and TICI 3 scores). METHODS: Ancillary study from the ASTER (Contact Aspiration Versus Stent Retriever for Successful Revascularization) prospective multicenter blinded end point trial. Reperfusion results are reported as the mTICI score, including the mTICI 2C grade. Primary outcome was the percentage of patients with favorable outcome defined as a 90-day modified Rankin Scale score of 0 to 2. RESULTS: Two hundred ninety patients with successful reperfusion (mTICI >=2B), harboring ischemic stroke secondary to occlusion of the anterior circulation within 6 hours of onset of symptoms, undergoing mechanical thrombectomy by contact aspiration or stent retriever were included. Favorable outcome (pre-specified as primary outcome of this ancillary study) did not differ significantly between the 3 reperfusion grades, with a similar positive effect of 2C (odds ratio, 1.71; 95% confidence interval, 0.98-3.00) and 3 (odds ratio, 1.73; 95% confidence interval, 0.88-3.41) grades compared with 2B grade. After combining grades 2C and 3, patients had a significantly higher rate of favorable outcome than patients with 2B (odds ratio, 1.72; 95% confidence interval, 1.01 2.90; P=0.043). Favorable outcome rate decreased with increasing onset-to reperfusion time, with no significant interaction between mTICI 2C/3 grade and onset-to-reperfusion time on favorable outcome. CONCLUSIONS: Combining mTICI 2C and TICI 3 grades helps to determine a subgroup of patients achieving better functional outcomes than mTICI 2B patients. Achieving mTICI 2C/3 reperfusion should be the new aim of mechanical thrombectomy for anterior circulation LVO. PMID- 29626135 TI - Feasibility of Multiple Burr Hole With Erythropoietin in Acute Moyamoya Patients. AB - BACKGROUND AND PURPOSE: In patients with acute symptomatic moyamoya (<2 weeks), the feasibility of a combination therapy of multiple burr hole procedure under local anesthesia and intravenous erythropoietin pretreatment was assessed. We also identified the factors associated with transdural revascularization. METHODS: In this prospective single-arm study, perfusion-impaired patients presenting with transient ischemic attack or acute cerebral infarction were assessed. Combination therapy was performed to patients lacking transdural collaterals. Primary outcomes were evaluated clinically with modified Rankin Scale scores and radiologically with revascularization success (transhemispheric, trans-burr hole, and sufficient revascularizations [filling >=33% of ipsilateral supratentorium]) at 6 months. Treatment-related adverse events were analyzed in 3 phases: pre burr hole, post burr hole, and after-discharge as secondary outcome. Factors associated with sufficient revascularization were investigated. RESULTS: Fifty hemispheres from 37 patients were included. Compared with discharge, modified Rankin Scale score at 6 months significantly improved (2.0 [0.0-5.0] versus 1.0 [0.0-4.0]; P<0.001). Majority had successful revascularization: trans burr hole arteriogenesis (89.5%), transhemispheric arteriogenesis (98.0%), and sufficient revascularization (52.0%). There was no significant pre burr hole or post burr hole complication. Two (5.4%) transient ischemic attack and 1 (2.7%) cerebral infarction occurred after discharge. Presentation with acute infarction (odds ratio, 4.8; 95% confidence interval, 1.1-21.4), ipsilateral basal moyamoya vessels (odds ratio, 13.9; 95% confidence interval, 1.3-144.2), and delayed mean transit time (odds ratio, 3.9; 95% confidence interval, 1.3-12.2) predicted sufficient revascularization. CONCLUSIONS: Combination therapy allows safe and effective revascularization in moyamoya patients with acute ischemic presentation. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03162588. PMID- 29626136 TI - Evolution of a US County System for Acute Comprehensive Stroke Care. AB - BACKGROUND AND PURPOSE: In Orange County, California, patients with suspected acute stroke are taken to stroke neurology receiving centers that are designated by County Emergency Medical Services authorities as either hubs or spokes based on endovascular treatment capability. We examined relationships between stroke details, reperfusion therapies, hospital transfers, and their change over time. METHODS: All patients from January 1, 2013, to December 31, 2015, for whom 911 was called within 7 hours of onset in whom Emergency Medical Services personnel suspected acute stroke were evaluated. RESULTS: Among 6132 patients, 3924 (64%) had confirmed diagnosis of stroke (74% ischemic/26% hemorrhagic), yielding diagnostic precision of 64% in the field. Of the 2892 patients with acute ischemic stroke, acute reperfusion therapy was given to 29.2% (21.7% intravenous tPA [tissue-type plasminogen activator] only and 7.5% endovascular treatment). Rates of endovascular treatment of patients with ischemic stroke increased over time, more than doubling from 5.6% in 2013 to 12.5% (odds ratio per 3-month quarter=1.09; 95% confidence interval, 1.04-1.14; P<0.0001). Only 3.4% of patients with acute ischemic stroke were transferred from a spoke to a hub hospital; transfer rates were inversely related to age (P<0.0001), and reperfusion therapy rates did not vary according to transfer status. CONCLUSIONS: Favorable features of this acute stroke care system include reperfusion therapy in 29.2% of patients with ischemic stroke and substantial increases in endovascular treatment rates over time. Continued efforts to optimize acute stroke systems of care can be directed toward improving access to best acute stroke therapies. PMID- 29626137 TI - Snakebites in Africa and Europe: a military perspective and update for contemporary operations. AB - Snakebite envenoming is rare among military patients, with few cases reported in recent years. Increasingly, however, military operations are taking place in remote parts of Africa, which are inhabited by numerous species of venomous snake, and in Europe, where dangerous species exist but are less common. Bites from a venomous snake may prove fatal, and therefore military medics must be adequately prepared to manage them. This paper reviews the most medically significant species of venomous snake present in Africa and Europe, before suggesting an evidence-based approach to snakebite prevention and management, including possible changes to the UK's Clinical Guidelines for Operations. PMID- 29626138 TI - How a major incident plan can be used in an acute healthcare setting. AB - All NHS Trusts face a diverse range of potential threats and disruptions that can overwhelm the delivery of their routine healthcare services. Major incidents range from significant infrastructure failure to responding to significant casualty numbers from natural disasters and malicious incidents. Major incident plans are one of the body of documents that support trusts and in this instance acute NHS trusts in emergency preparedness. Major incident plans can be used as a reference point for staff of all disciplines, that is, clinical and non-clinical. Major incident plans incorporate the requirements of the Civil Contingencies Act 2004 for NHS-funded providers to ensure trusts conduct risk assessments, emergency planning, cooperating with other organisations, and internal and external communication. This paper summarises some of the key aspects in the construction and the use of major incident plans in acute care trusts. PMID- 29626139 TI - Manchester Arena bombing: lessons learnt from a mass casualty incident. AB - On 22 May 2017 Salman Abedi detonated an improvised explosive device in the Manchester Arena resulting in 23 deaths (including the attacker). This was the deadliest terrorist attack on UK soil since the 2005 London bombings, but was only one of five mass casualty terrorist attacks in the UK in 2017. Preparation for mass casualty incidents (MCI) is obligatory, involving such methods as multiagency tabletop exercises, mock hospital exercises, as well as simulation and training for clinicians in managing the injuries that would be anticipated in such an event. Even in the best prepared units, such an incident will pose significant challenges due to the unpredictable nature of these events with respect to timing and number of casualties. Following an MCI, local and national reviews are undertaken to assess the effectiveness of the response, but also to identify areas where lessons can be learnt and to disseminate these to allow inclusion in future planning. We present the experience following a mass casualty terrorist incident along with a number of lessons learnt from this event. PMID- 29626140 TI - Military application of mechanical CPR devices: a pressing requirement? AB - Maintaining high-quality chest compressions during cardiopulmonary resuscitation following cardiac arrest presents a challenge. The currently available mechanical CPR (mCPR) devices are described in this review, coupled with an analysis of the evidence pertaining to their efficacy. Overall, mCPR appears to be at least equivalent to high-quality manual CPR in large trials. There is potential utility for mCPR devices in the military context to ensure uninterrupted quality CPR following a medical cardiac arrest. Particular utility may be in a prohibitive operational environment, where manpower is limited or where timelines to definitive care are stretched resulting in a requirement for prolonged resuscitation. mCPR can also act as a bridge to advanced endovascular resuscitation techniques should they become more mainstream therapy. PMID- 29626141 TI - Novel use for the abdominal tourniquet in the management of postpartum haemorrhage. PMID- 29626142 TI - Collection and sharing of medical information and medical intelligence (M2I) in NATO: a transversal survey. AB - INTRODUCTION: There is a requirement for adequate medical expertise to be available throughout the range of potential future operations involving members of the North Atlantic Treaty Organization (NATO). The aim of this study was to assess the collection and sharing of medical intelligence and medical information (M2I) by NATO Nations, Partner Nations and NATO Command Structure and NATO Force Structure Headquarters (NCS/NFS HQs). MATERIALS AND METHODS: A transversal survey was conducted between December 2014 and March 2015 using a survey form on M2I sent to NATO Nations and Partnership for Peace (PfP) Nations as well as NCS/NFS HQs. RESULTS: Correctly completed responses were received from 15/40 (37.5%) of the possible NATO and PfP Nations (37.5%) and 7/8 (87.5%) of the NCS/NFS HQs (100.0%). Deficiencies in the collection of M2I data were found due to lack of specific doctrines, networks, tools, structures and organisation. CONCLUSIONS: The survey provided an indication even though the participation rate was low for Nations. Part of the problem is thought to be that medical information and medical intelligence often lie in different chains of command. Future directions for this research could include studying the possibilities of a new specific information technology (IT) system to collect and to share M2I. Collection and sharing of M2I within the NATO/PfP community requires facilitation in order to strengthen the basis for decision-making and force health protection. The development of a dedicated NATO IT system may be a precondition for the implementation of an efficient M2I network. PMID- 29626143 TI - Opioid analgesia on the battlefield: a retrospective review of data from Operation HERRICK. AB - BACKGROUND: Acute pain secondary to trauma is commonly encountered on the battlefield. The use of morphine to manage pain during combat has been well established since the 19th century. Despite this, there is relatively little research on analgesia use in this environment. This study aims to review the use and complications of morphine and other opioids during Operation HERRICK. METHODS: A database search of the Joint Theatre Trauma Registry was completed looking for all incidences of morphine, fentanyl or naloxone use from February 2007 to September 2014. Microsoft Excel was used to analyse the results. RESULTS: Opioid analgesia was administered to 5801 casualties. Morphine was administered 6742 times to 3808 patients. Fentanyl was administered 9672 times to 4318 patients. Naloxone was used 18 times on 14 patients, giving a complication rate of 0.24%. Opioid doses prior to naloxone administration range from 0 to 72 mg of morphine and from 0 to 100 mcg of fentanyl. Four casualties (two local civilians and two coalition forces) received naloxone despite no recorded opioids being administered. Opium abuse was prevalent among the local population in Afghanistan, and this could explain the rationale behind two local national casualties receiving naloxone without any documented opioids being given. CONCLUSION: The use of opioids in a battlefield environment is extremely safe. Complication rates are similar to previously published data which is reassuring. The efficacy of different opioids was not covered by this study, and further analysis is required, particularly following the introduction of oral transmucosal fentanyl citrate and the availability of novel non-opioid analgesics. PMID- 29626144 TI - Safest light in a combat area while performing intravenous access in the dark. AB - INTRODUCTION: Cannulation for the administration of intravenous fluids is integral to the prehospital management of injured military patients. However, this may be technically challenging to undertake during night-time conditions where the use of light to aid cannulation may give the tactical situation away to opponents. The aim of this study was to investigate the success and tactical safety of venepuncture under battlefield conditions with different colour light sources. METHOD: The procedure was carried out with naked eye in a bright room in the absence of a separate light source, with a naked eye in a dark room under red, white, blue and green light sources and under an infrared light source while wearing night vision goggles (NVGs). The success, safety, degree of difficulty and completion time for each procedure were then explored. RESULTS: All interventions made in daylight and in a dark room were found to be 100% successful. Interventions performed under infrared light while wearing NVGs took longer than under other light sources or in daylight. Interventions performed under blue light were tactically safer when compared with interventions performed under different light sources. CONCLUSION: Blue light offered the best tactical safety during intravenous cannulation under night-time conditions and is recommended for future use in tactical casualty care. The use of NVGs using infrared light cannot be recommended if there is the possibility of opponents having access to the technology. PMID- 29626145 TI - Risk factors for lower limb injuries during initial naval training: a prospective study. AB - INTRODUCTION: This study aimed to identify risk factors associated with the development of common lower limb injuries during initial defence training in naval recruits who were enrolled in a randomised trial. METHODS: Three-hundred and six naval recruits were randomly allocated flat insoles (n=153) or foot orthoses (n=153) while undertaking 11 weeks of initial training. Participant characteristics (including anthropometrics, general health, physical activity, fitness and foot characteristics) were collected at the baseline assessment and injuries were documented prospectively. Injury was defined as the combined incidence of participants with medial tibial stress syndrome, patellofemoral pain, Achilles tendinopathy and plantar fasciitis/plantar heel pain throughout the 11 weeks of training. A discriminant function analysis was used to explore the ability of baseline measures to predict injury. RESULTS: Overall, 67 (21.9%) participants developed an injury. Discriminant function analysis revealed that participants who sustained an injury were slightly younger (mean 21.4+/-SD 4.1 vs 22.5+/-5.0 years) and were less likely to be allocated to the foot orthosis group (40% vs 53%) compared with those who remained uninjured. The accuracy of these baseline variables to predict injury was moderate (78.1%). CONCLUSIONS: Lower limb injury was not accurately predicted from health questionnaires, fitness results and clinical assessments in naval recruits undertaking initial defence training. However, although not reaching statistical significance, the use of foot orthoses may be protective against common lower limb injuries. TRIAL REGISTRATION NUMBER: ACTRN12615000024549; Post-results. PMID- 29626146 TI - Exploring the combinatorial space of complete pathways to chemicals. AB - Computational pathway design tools often face the challenges of balancing the stoichiometry of co-metabolites and cofactors, and dealing with reaction rule utilization in a single workflow. To this end, we provide an overview of two complementary stoichiometry-based pathway design tools optStoic and novoStoic developed in our group to tackle these challenges. optStoic is designed to determine the stoichiometry of overall conversion first which optimizes a performance criterion (e.g. high carbon/energy efficiency) and ensures a comprehensive search of co-metabolites and cofactors. The procedure then identifies the minimum number of intervening reactions to connect the source and sink metabolites. We also further the pathway design procedure by expanding the search space to include both known and hypothetical reactions, represented by reaction rules, in a new tool termed novoStoic. Reaction rules are derived based on a mixed-integer linear programming (MILP) compatible reaction operator, which allow us to explore natural promiscuous enzymes, engineer candidate enzymes that are not already promiscuous as well as design de novo enzymes. The identified biochemical reaction rules then guide novoStoic to design routes that expand the currently known biotransformation space using a single MILP modeling procedure. We demonstrate the use of the two computational tools in pathway elucidation by designing novel synthetic routes for isobutanol. PMID- 29626147 TI - Nucleosome-level 3D organization of the genome. AB - Nucleosomes are the unitary structures of chromosome folding, and their arrangements are intimately coupled to the regulation of genome activities. Conventionally, structural analyses using electron microscopy and X-ray crystallography have been used to study such spatial nucleosome arrangements. In contrast, recent improvements in the resolution of sequencing-based methods allowed investigation of nucleosome arrangements separately at each genomic locus, enabling exploration of gene-dependent regulation mechanisms. Here, we review recent studies on nucleosome folding in chromosomes from these two methodological perspectives: conventional structural analyses and DNA sequencing, and discuss their implications for future research. PMID- 29626149 TI - Translational science in albuminuria: a new view of de novo albuminuria under chronic RAS suppression. AB - The development of de novo albuminuria during chronic renin-angiotensin system (RAS) suppression is a clinical entity that remains poorly recognized in the biomedical literature. It represents a clear increment in global cardiovascular (CV) and renal risk that cannot be counteracted by RAS suppression. Although not specifically considered, it is clear that this entity is present in most published and ongoing trials dealing with the different forms of CV and renal disease. In this review, we focus on the mechanisms promoting albuminuria, and the predictors and new markers of de novo albuminuria, as well as the potential treatment options to counteract the excretion of albumin. The increase in risk that accompanies de novo albuminuria supports the search for early markers and predictors that will allow practising physicians to assess and prevent the development of de novo albuminuria in their patients. PMID- 29626148 TI - New insights into the interplay between the translation machinery and nonsense mediated mRNA decay factors. AB - Faulty mRNAs with a premature stop codon (PTC) are recognized and degraded by nonsense-mediated mRNA decay (NMD). Recognition of a nonsense mRNA depends on translation and on the presence of NMD-enhancing or the absence of NMD-inhibiting factors in the 3'-untranslated region. Our review summarizes our current understanding of the molecular function of the conserved NMD factors UPF3B and UPF1, and of the anti-NMD factor Poly(A)-binding protein, and their interactions with ribosomes translating PTC-containing mRNAs. Our recent discovery that UPF3B interferes with human translation termination and enhances ribosome dissociation in vitro, whereas UPF1 is inactive in these assays, suggests a re-interpretation of previous experiments and modification of prevalent NMD models. Moreover, we discuss recent work suggesting new functions of the key NMD factor UPF1 in ribosome recycling, inhibition of translation re-initiation and nascent chain ubiquitylation. These new findings suggest that the interplay of UPF proteins with the translation machinery is more intricate than previously appreciated, and that this interplay quality-controls the efficiency of termination, ribosome recycling and translation re-initiation. PMID- 29626150 TI - Rac1 Modulates Endothelial Function and Platelet Aggregation in Diabetes Mellitus. AB - BACKGROUND: Vascular complications and abnormal platelet function contribute to morbidity and mortality in diabetes mellitus. We hypothesized that the Rho related GTPase protein, Rac1, can influence both endothelial and platelet function and might represent a potential novel therapeutic target in diabetes mellitus. METHODS AND RESULTS: We used both in vitro and ex vivo approaches to test the effects of pharmacological inhibition of Rac1 during hyperglycemic condition. We evaluated the effect of NSC23766, a pharmacological inhibitor of Rac1, on vascular function in diabetic mice and platelet aggregation in diabetic subjects. We demonstrated that the administration of NSC23766 protects from hyperglycemia-induced endothelial dysfunction, restoring NO levels, and reduces oxidative stress generated by nicotinamide adenine dinucleotide phosphate oxidase. Mechanistically, we identified Rho-associated coiled-coil serine/threonine kinase-1 as a downstream target of Rac1. Moreover, we reported that during hyperglycemic conditions, human platelets showed hyperactivation of Rac1 and impaired NO release, which were both partially restored after NSC23766 treatment. Finally, we characterized the antiplatelet effect of NSC23766 during hyperglycemic conditions, demonstrating the additional role of Rac1 inhibition in reducing platelet aggregation in diabetic patients treated with common antiplatelet drugs. CONCLUSIONS: Our data suggest that the pharmacological inhibition of Rac1 could represent a novel therapeutic strategy to reduce endothelial dysfunction and platelet hyperaggregation in diabetes mellitus. PMID- 29626151 TI - Metabolomic Profiling in Acute ST-Segment-Elevation Myocardial Infarction Identifies Succinate as an Early Marker of Human Ischemia-Reperfusion Injury. AB - BACKGROUND: Ischemia-reperfusion injury following ST-segment-elevation myocardial infarction (STEMI) is a leading determinant of clinical outcome. In experimental models of myocardial ischemia, succinate accumulation leading to mitochondrial dysfunction is a major cause of ischemia-reperfusion injury; however, the potential importance and specificity of myocardial succinate accumulation in human STEMI is unknown. We sought to identify the metabolites released from the heart in patients undergoing primary percutaneous coronary intervention for emergency treatment of STEMI. METHODS AND RESULTS: Blood samples were obtained from the coronary artery, coronary sinus, and peripheral vein in patients undergoing primary percutaneous coronary intervention for acute STEMI and in control patients undergoing nonemergency coronary angiography or percutaneous coronary intervention for stable angina or non-STEMI. Plasma metabolites were analyzed by targeted liquid chromatography and mass spectrometry. Metabolite levels for coronary artery, coronary sinus, and peripheral vein were compared to derive cardiac and systemic release ratios. In STEMI patients, cardiac magnetic resonance imaging was performed 2 days and 6 months after primary percutaneous coronary intervention to quantify acute myocardial edema and final infarct size, respectively. In total, 115 patients undergoing acute STEMI and 26 control patients were included. Succinate was the only metabolite significantly increased in coronary sinus blood compared with venous blood in STEMI patients, indicating cardiac release of succinate. STEMI patients had higher succinate concentrations in arterial, coronary sinus, and peripheral venous blood than patients with non STEMI or stable angina. Furthermore, cardiac succinate release in STEMI correlated with the extent of acute myocardial injury, quantified by cardiac magnetic resonance imaging. CONCLUSION: Succinate release by the myocardium correlates with the extent of ischemia. PMID- 29626152 TI - "Summer Shift": A Potential Effect of Sunshine on the Time Onset of ST-Elevation Acute Myocardial Infarction. AB - BACKGROUND: ST-elevation acute myocardial infarction (STEMI) represents one of the leading causes of death. The time of STEMI onset has a circadian rhythm with a peak during diurnal hours, and the occurrence of STEMI follows a seasonal pattern with a salient peak of cases in the winter months and a marked reduction of cases in the summer months. Scholars investigated the reason behind the winter peak, suggesting that environmental and climatic factors concur in STEMI pathogenesis, but no studies have investigated whether the circadian rhythm is modified with the seasonal pattern, in particular during the summer reduction in STEMI occurrence. METHODS AND RESULTS: Here, we provide a multiethnic and multination epidemiological study (from both hemispheres at different latitudes, n=2270 cases) that investigates whether the circadian variation of STEMI onset is altered in the summer season. The main finding is that the difference between numbers of diurnal (6:00 to 18:00) and nocturnal (18:00 to 6:00) STEMI is markedly decreased in the summer season, and this is a prodrome of a complex mechanism according to which the circadian rhythm of STEMI time onset seems season dependent. CONCLUSIONS: The "summer shift" of STEMI to the nocturnal interval is consistent across different populations, and the sunshine duration (a measure related to cloudiness and solar irradiance) underpins this season dependent circadian perturbation. Vitamin D, which in our results seems correlated with this summer shift, is also primarily regulated by the sunshine duration, and future studies should investigate their joint role in the mechanisms of STEMI etiogenesis. PMID- 29626153 TI - Sex and Racial Disparities in Cardiac Rehabilitation Referral at Hospital Discharge and Gaps in Long-Term Mortality. AB - BACKGROUND: Cardiac rehabilitation (CR) referral is recommended for eligible patients, regardless of sex or race. It is unclear whether inequality in CR referral practices was associated with patients' long-term survival. METHODS AND RESULTS: We linked the American Heart Association Get With The Guidelines Coronary Artery Disease registry with Medicare claims data for 48 993 coronary artery disease patients from 365 hospitals across the United States between 2003 and 2009. We used generalized estimation equations to estimate the association between CR referral and mortality accounting for clustering within hospitals. Between 2003 and 2009, only 40% of eligible patients received CR referrals. Females were 12% less likely to receive CR referral compared with males. Black, Hispanic, and Asian patients were 20%, 36%, and 50% less likely, respectively, to receive CR referral than white patients. CR referral was associated with 40% lower 3-year all-cause mortality. Women and minorities who received CR referral at hospital discharge had significantly lower mortality compared with those who did not (odds ratios=0.61 [95% confidence interval, 0.56-0.66] for women, 0.75 [95% confidence interval, 0.63-0.88] for black, 0.62 [95% confidence interval, 0.50-0.79] for Hispanic, and 0.63 [95% confidence interval, 0.46-0.85] for Asian patients). Seven percent of the black versus white mortality gap could potentially be reduced by equitable CR referral. CONCLUSIONS: CR referral rates at hospital discharge remained low. Gaps in receiving CR referral at hospital discharge were large for women and minorities, and the mortality gap could potentially be reduced through elimination of inequality in CR referral. PMID- 29626154 TI - Biological role of site-specific O-glycosylation in cell adhesion activity and phosphorylation of osteopontin. AB - Osteopontin (OPN) is an extracellular glycosylated phosphoprotein that promotes cell adhesion by interacting with several integrin receptors. We previously reported that an OPN mutant lacking five O-glycosylation sites (Thr134/Thr138/Thr143/Thr147/Thr152) in the threonine/proline-rich region increased cell adhesion activity and phosphorylation compared with the wild type. However, the role of O-glycosylation in cell adhesion activity and phosphorylation of OPN remains to be clarified. Here, we show that site-specific O-glycosylation in the threonine/proline-rich region of OPN affects its cell adhesion activity and phosphorylation independently and/or synergistically. Using site-directed mutagenesis, we found that OPN mutants with substitution sets of Thr134/Thr138 or Thr143/Thr147/Thr152 had decreased and increased cell adhesion activity, respectively. In contrast, the introduction of a single mutation into the O-glycosylation sites had no effect on OPN cell adhesion activity. An adhesion assay using function-blocking antibodies against alphavbeta3 and beta1 integrins, as well as alphavbeta3 integrin-overexpressing A549 cells, revealed that site-specific O-glycosylation affected the association of OPN with the two integrins. Phosphorylation analyses using phos-tag and LC-MS/MS indicated that phosphorylation levels and sites were influenced by the O-glycosylation status, although the number of O-glycosylation sites was not correlated with the phosphorylation level in OPN. Furthermore, a correlation analysis between phosphorylation level and cell adhesion activity in OPN mutants with the site specific O-glycosylation showed that they were not always correlated. These results provide conclusive evidence of a novel regulatory mechanism of cell adhesion activity and phosphorylation of OPN by site-specific O-glycosylation. PMID- 29626156 TI - The Gcn2-eIF2alpha pathway connects iron and amino acid homeostasis in Saccharomyces cerevisiae. AB - In eukaryotic cells, amino acid biosynthesis is feedback-inhibited by amino acids through inhibition of the conserved protein kinase Gcn2. This decreases phosphorylation of initiation factor eIF2alpha, resulting in general activation of translation but inhibition of translation of mRNA for transcription factor (TF) Gcn4 in yeast or ATF4 in mammals. These TFs are positive regulators of amino acid biosynthetic genes. As several enzymes of amino acid biosynthesis contain iron-sulfur clusters (ISCs) and iron excess is toxic, iron and amino acid homeostasis should be co-ordinated. Working with the yeast Saccharomyces cerevisiae, we found that amino acid supplementation down-regulates expression of genes for iron uptake and decreases intracellular iron content. This cross regulation requires Aft1, the major TF activated by iron scarcity, as well as Gcn2 and phosphorylatable eIF2alpha but not Gcn4. A mutant with constitutive activity of Gcn2 (GCN2c ) shows less repression of iron transport genes by amino acids and increased nuclear localization of Aft1 in an iron-poor medium, and increases iron content in this medium. As Aft1 is activated by depletion of mitochondrial ISCs, it is plausible that the Gcn2-eIF2alpha pathway inhibits the formation of these complexes. Accordingly, the GCN2c mutant has strongly reduced activity of succinate dehydrogenase, an iron-sulfur mitochondrial enzyme, and is unable to grow in media with very low iron or with galactose instead of glucose, conditions where formation of ISCs is specially needed. This mechanism adjusts the uptake of iron to the needs of amino acid biosynthesis and expands the list of Gcn4-independent activities of the Gcn2-eIF2alpha regulatory system. PMID- 29626155 TI - Protein CoAlation and antioxidant function of coenzyme A in prokaryotic cells. AB - In all living organisms, coenzyme A (CoA) is an essential cofactor with a unique design allowing it to function as an acyl group carrier and a carbonyl-activating group in diverse biochemical reactions. It is synthesized in a highly conserved process in prokaryotes and eukaryotes that requires pantothenic acid (vitamin B5), cysteine and ATP. CoA and its thioester derivatives are involved in major metabolic pathways, allosteric interactions and the regulation of gene expression. A novel unconventional function of CoA in redox regulation has been recently discovered in mammalian cells and termed protein CoAlation. Here, we report for the first time that protein CoAlation occurs at a background level in exponentially growing bacteria and is strongly induced in response to oxidizing agents and metabolic stress. Over 12% of Staphylococcus aureus gene products were shown to be CoAlated in response to diamide-induced stress. In vitro CoAlation of S. aureus glyceraldehyde-3-phosphate dehydrogenase was found to inhibit its enzymatic activity and to protect the catalytic cysteine 151 from overoxidation by hydrogen peroxide. These findings suggest that in exponentially growing bacteria, CoA functions to generate metabolically active thioesters, while it also has the potential to act as a low-molecular-weight antioxidant in response to oxidative and metabolic stress. PMID- 29626157 TI - A plasmid borne, functionally novel glycoside hydrolase family 30 subfamily 8 endoxylanase from solventogenic Clostridium. AB - Glycoside hydrolase family 30 subfamily 8 (GH30-8) beta-1,4-endoxylanases are known for their appendage-dependent function requiring recognition of an alpha 1,2-linked glucuronic acid (GlcA) common to glucuronoxylans for hydrolysis. Structural studies have indicated that the GlcA moiety of glucuronoxylans is coordinated through six hydrogen bonds and a salt bridge. These GlcA-dependent endoxylanases do not have significant activity on xylans that do not bear GlcA substitutions such as unsubstituted linear xylooligosaccharides or cereal bran arabinoxylans. In the present study, we present the structural and biochemical characteristics of xylanase 30A from Clostridium acetobutylicum (CaXyn30A) which was originally selected for study due to predicted structural differences within the GlcA coordination loops. Amino acid sequence comparisons indicated that this Gram-positive-derived GH30-8 more closely resembles Gram-negative derived forms of these endoxylanases: a hypothesis borne out in the developed crystallographic structure model of the CaXyn30A catalytic domain (CaXyn30A-CD). CaXyn30A-CD hydrolyzes xylans to linear and substituted oligoxylosides showing the greatest rate with the highly arabinofuranose (Araf)-substituted cereal arabinoxylans. CaXyn30A-CD hydrolyzes xylooligosaccharides larger than xylotriose and shows an increased relative rate of hydrolysis for xylooligosaccharides containing alpha 1,2-linked arabinofuranose substitutions. Biochemical analysis confirms that CaXyn30A benefits from five xylose-binding subsites which extend from the -3 subsite to the +2 subsite of the binding cleft. These studies indicate that CaXyn30A is a GlcA-independent endoxylanase that may have evolved for the preferential recognition of alpha-1,2-Araf substitutions on xylan chains. PMID- 29626158 TI - Deubiquitinating enzyme USP9X regulates cellular clock function by modulating the ubiquitination and degradation of a core circadian protein BMAL1. AB - Living organisms on the earth maintain a roughly 24 h circadian rhythm, which is regulated by circadian clock genes and their protein products. Post-translational modifications of core clock proteins could affect the circadian behavior. Although ubiquitination of core clock proteins was studied extensively, the reverse process, deubiquitination, has only begun to unfold and the role of this regulation on circadian function is not completely understood. Here, we use affinity purification and mass spectrometry analysis to identify probable ubiquitin carboxyl-terminal hydrolase FAF-X (USP9X) as an interacting protein of the core clock protein aryl hydrocarbon receptor nuclear translocator-like protein 1 (ARNTL or BMAL1). Through biochemical experiments, we discover that USP9X reduces BMAL1 ubiquitination, enhances its stability, and increases its protein level, leading to the elevated transcriptional activity. Bioluminescence measurement reveals that USP9X knockdown decreases the amplitude of the cellular circadian rhythm but the period and phase are not affected. Our experiments find a new regulator for circadian clock at the post-translational level and demonstrate a different regulatory function for the circadian clock through the deubiquitination and the up-regulation of the core clock protein BMAL1 in the positive limb of the transcription-translation feedback loop. PMID- 29626159 TI - Structural insights into the nanomolar affinity of RING E3 ligase ZNRF1 for Ube2N and its functional implications. AB - RING (Really Interesting New Gene) domains in ubiquitin RING E3 ligases exclusively engage ubiquitin (Ub)-loaded E2s to facilitate ubiquitination of their substrates. Despite such specificity, all RINGs characterized till date bind unloaded E2s with dissociation constants (Kds) in the micromolar to the sub millimolar range. Here, we show that the RING domain of E3 ligase ZNRF1, an essential E3 ligase implicated in diverse cellular pathways, binds Ube2N with a Kd of ~50 nM. This high-affinity interaction is exclusive for Ube2N as ZNRF1 interacts with Ube2D2 with a Kd of ~1 uM, alike few other E3s. The crystal structure of ZNRF1 C-terminal domain in complex with Ube2N coupled with mutational analyses reveals the molecular basis of this unusual affinity. We further demonstrate that the ubiquitination efficiency of ZNRF1 : E2 pairs correlates with their affinity. Intriguingly, as a consequence of its high E2 affinity, an excess of ZNRF1 inhibits Ube2N-mediated ubiquitination at concentrations >=500 nM instead of showing enhanced ubiquitination. This suggests a novel mode of activity regulation of E3 ligases and emphasizes the importance of E3-E2 balance for the optimum activity. Based on our results, we propose that overexpression-based functional analyses on E3 ligases such as ZNRF1 must be approached with caution as enhanced cellular levels might result in aberrant modification activity. PMID- 29626160 TI - NLRP3 regulates macrophage M2 polarization through up-regulation of IL-4 in asthma. AB - Activation of nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) inflammasome received substantial attention recently in inflammatory diseases. Macrophages contribute to allergic inflammation in asthma. The present study was aimed to investigate the effect of NLRP3 inflammasome on the polarization of macrophages. We utilized human primary monocytes and monocyte derived macrophages to study the expression of NLRP3 inflammasome components (NLRP3, apoptosis-associated specklike protein, and caspase-1) and its downstream cytokine interleukin-1beta (IL-1beta). By gain- or loss-of-function assays, we next explored the effects of NLRP3 inflammasome on M1/M2 polarization and secretion of IL-4, interferon-gamma, tumor necrosis factor-alpha, and IL-1beta. The results showed increased numbers of M2 cells in asthma. And NLRP3 inflammasome was activated and involved in the inflammation of asthma. Furthermore, silence of NLRP3 down-regulated IL-4 secretion and up-regulated M1/M2. In contrast, overexpression of NLRP3 increased IL-4 and decreased M1/M2. As expected, IL-4 was involved in NLRP3-mediated down-regulation of Ml/M2 ratio. Moreover, NLRP3 interacted with IRF4 and was required for optimal IRF4-dependent IL-4 transcription. Subsequently, deficiency of NLRP3 in ovalbumin-induced allergic asthmatic mice impaired lung inflammation and up-regulated M1/M2, and diminished IL-4 in bronchoalveolar lavage fluid. Collectively, we demonstrated here that activation of NLRP3 was engaged in the promotion of asthma. NLRP3, but not the inflammasome adaptor ASC or caspase-1, promoted the polarization of M2 macrophages through up-regulating the expression of IL-4, thereby contributing to its regulation of asthma. PMID- 29626161 TI - Extracellular ATP activates hyaluronan synthase 2 (HAS2) in epidermal keratinocytes via P2Y2, Ca2+ signaling, and MAPK pathways. AB - Extracellular nucleotides are used as signaling molecules by several cell types. In epidermis, their release is triggered by insults such as ultraviolet radiation, barrier disruption, and tissue wounding, and by specific nerve terminals firing. Increased synthesis of hyaluronan, a ubiquitous extracellular matrix glycosaminoglycan, also occurs in response to stress, leading to the attractive hypothesis that nucleotide signaling and hyaluronan synthesis could also be linked. In HaCaT keratinocytes, ATP caused a rapid and strong but transient activation of hyaluronan synthase 2 (HAS2) expression via protein kinase C-, Ca2+/calmodulin-dependent protein kinase II-, mitogen-activated protein kinase-, and calcium response element-binding protein-dependent pathways by activating the purinergic P2Y2 receptor. Smaller but more persistent up regulation of HAS3 and CD44, and delayed up-regulation of HAS1 were also observed. Accumulation of peri- and extracellular hyaluronan followed 4-6 h after stimulation, an effect further enhanced by the hyaluronan precursor glucosamine. AMP and adenosine, the degradation products of ATP, markedly inhibited HAS2 expression and, despite concomitant up-regulation of HAS1 and HAS3, inhibited hyaluronan synthesis. Functionally, ATP moderately increased cell migration, whereas AMP and adenosine had no effect. Our data highlight the strong influence of adenosinergic signaling on hyaluronan metabolism in human keratinocytes. Epidermal insults are associated with extracellular ATP release, as well as rapid up-regulation of HAS2/3, CD44, and hyaluronan synthesis, and we show here that the two phenomena are linked. Furthermore, as ATP is rapidly degraded, the opposite effects of its less phosphorylated derivatives facilitate a rapid shut off of the hyaluronan response, providing a feedback mechanism to prevent excessive reactions when more persistent signals are absent. PMID- 29626162 TI - Biotin Attachment Domain-Containing Proteins Irreversibly Inhibit Acetyl CoA Carboxylase. AB - The first committed step in fatty acid synthesis is mediated by acetyl-CoA carboxylase (ACCase), a biotin-dependent enzyme that carboxylates acetyl-CoA to produce malonyl-CoA. ACCase can be feedback regulated by short-term or long-term exposure to fatty acids in the form of Tween 80 (predominantly containing oleic acid), which results in reversible or irreversible ACCase inhibition, respectively. Biotin attachment domain-containing (BADC) proteins are inactive analogs of biotin carboxyl transfer proteins that lack biotin, and their incorporation into ACCase down-regulates its activity by displacing active (biotin-containing) biotin carboxyltransferase protein subunits. Arabidopsis (Arabidopsis thaliana) lines containing T-DNA insertions in BADC1, BADC2, and BADC3 were used to generate badc1 badc2 and badc1 badc3 double mutants. The badc1 badc3 mutant exhibited normal growth and development; however, ACCase activity was 26% higher in badc1 badc3 and its seeds contained 30.1% more fatty acids and 32.6% more triacylgycerol relative to wild-type plants. To assess whether BADC contributes to the irreversible phase of ACCase inhibition, cell suspension cultures were generated from the leaves of badc1 badc3 and wild-type plants and treated with 10 mm Tween 80. Reversible ACCase inhibition was similar in badc1 badc3 and wild-type cultures after 2 d of Tween 80 treatment, but irreversible inhibition was reduced by 50% in badc1 badc3 relative to wild-type plants following 4 d of Tween 80 treatment. In this study, we present evidence for two important homeostatic roles for BADC proteins in down-regulating ACCase activity: by acting during normal growth and development and by contributing to its long term irreversible feedback inhibition resulting from the oversupply of fatty acids. PMID- 29626163 TI - Should a Teenager Be Allowed to Leave the Hospital AMA to Attend His Father's Funeral? AB - What should physicians do when an adolescent wishes to risk his physical health and leave the hospital to attend the funeral of his late father? What if the young man's mother, and only remaining guardian, both supports and encourages such a decision? In this Ethics Rounds discussion, we examine the legality, morality, and safety of discharging a minor under such conditions. PMID- 29626164 TI - Neighborhood Child Opportunity and Individual-Level Pediatric Acute Care Use and Diagnoses. AB - : : media-1vid110.1542/5751513300001PEDS-VA_2017-2309Video Abstract OBJECTIVES: Although health care providers and systems are increasingly interested in patients' nonmedical needs as a means to improve health, little is known about neighborhood conditions that contribute to child health problems. We sought to determine if a novel, publicly available measure of neighborhood context, the Child Opportunity Index, was associated with pediatric acute care visit frequency and diagnoses. METHODS: This cross-sectional study included San Francisco residents <18 years of age with an emergency department and/or urgent care visit to any of 3 medical systems (N = 47 175) between 2007 and 2011. Hot-spot analysis was used to compare the spatial distribution of neighborhood child opportunity and income. Generalized estimating equation logistic regression models were used to examine independent associations between neighborhood child opportunity and frequent acute care use (>=4 visits per year) and diagnosis group after adjusting for neighborhood income and patient age, sex, race and/or ethnicity, payer, and health system. RESULTS: Neighborhood child opportunity and income had distinct spatial distributions, and we identified different clusters of high- and low-risk neighborhoods. Children living in the lowest opportunity neighborhoods had significantly greater odds of >=4 acute care visits per year (odds ratio 1.33; 95% confidence interval 1.03-1.73) compared with those in the highest opportunity neighborhoods. Neighborhood child opportunity was negatively associated with visits for respiratory conditions, asthma, assault, and ambulatory care-sensitive conditions but positively associated with injury-related visits. CONCLUSIONS: The Child Opportunity Index could be an effective tool for identifying neighborhood factors beyond income related to child health. PMID- 29626165 TI - Collagen XIII Is Required for Neuromuscular Synapse Regeneration and Functional Recovery after Peripheral Nerve Injury. AB - Collagen XIII occurs as both a transmembrane-bound and a shed extracellular protein and is able to regulate the formation and function of neuromuscular synapses. Its absence results in myasthenia: presynaptic and postsynaptic defects at the neuromuscular junction (NMJ), leading to destabilization of the motor nerves, muscle regeneration and atrophy. Mutations in COL13A1 have recently been found to cause congenital myasthenic syndrome, characterized by fatigue and chronic muscle weakness, which may be lethal. We show here that muscle defects in collagen XIII-deficient mice stabilize in adulthood, so that the disease is not progressive until very late. Sciatic nerve crush was performed to examine how the lack of collagen XIII or forced expression of its transmembrane form affects the neuromuscular synapse regeneration and functional recovery following injury. We show that collagen XIII-deficient male mice are unable to achieve complete NMJ regeneration and functional recovery. This is mainly attributable to presynaptic defects that already existed in the absence of collagen XIII before injury. Shedding of the ectodomain is not required, as the transmembrane form of collagen XIII alone fully rescues the phenotype. Thus, collagen XIII could serve as a therapeutic agent in cases of injury-induced PNS regeneration and functional recovery. We conclude that intrinsic alterations at the NMJ in Col13a1-/- mice contribute to impaired and incomplete NMJ regeneration and functional recovery after peripheral nerve injury. However, such alterations do not progress once they have stabilized in early adulthood, emphasizing the role of collagen XIII in NMJ maturation.SIGNIFICANCE STATEMENT Collagen XIII is required for gaining and maintaining the normal size, complexity, and functional capacity of neuromuscular synapses. Loss-of-function mutations in COL13A1 cause congenital myasthenic syndrome 19, characterized by postnatally progressive muscle fatigue, which compromises patients' functional capacity. We show here in collagen XIII deficient mice that the disease stabilizes in adulthood once the NMJs have matured. This study also describes a relevant contribution of the altered NMJ morphology and function to neuromuscular synapses, and PNS regeneration and functional recovery in collagen XIII-deficient mice after peripheral nerve injury. Correlating the animal model data on collagen XIII-associated congenital myasthenic syndrome, it can be speculated that neuromuscular connections in congenital myasthenic syndrome patients are not able to fully regenerate and restore normal functionality if exposed to peripheral nerve injury. PMID- 29626168 TI - The Magnitude, But Not the Sign, of MT Single-Trial Spike-Time Correlations Predicts Motion Detection Performance. AB - Spike-time correlations capture the short timescale covariance between the activity of neurons on a single trial. These correlations can significantly vary in magnitude and sign from trial to trial, and have been proposed to contribute to information encoding in visual cortex. While monkeys performed a motion-pulse detection task, we examined the behavioral impact of both the magnitude and sign of single-trial spike-time correlations between two nonoverlapping pools of middle temporal (MT) neurons. We applied three single-trial measures of spike time correlation between our multiunit MT spike trains (Pearson's, absolute value of Pearson's, and mutual information), and examined the degree to which they predicted a subject's performance on a trial-by-trial basis. We found that on each trial, positive and negative spike-time correlations were almost equally likely, and, once the correlational sign was accounted for, all three measures were similarly predictive of behavior. Importantly, just before the behaviorally relevant motion pulse occurred, single-trial spike-time correlations were as predictive of the performance of the animal as single-trial firing rates. While firing rates were positively associated with behavioral outcomes, the presence of either strong positive or negative correlations had a detrimental effect on behavior. These correlations occurred on short timescales, and the strongest positive and negative correlations modulated behavioral performance by ~9%, compared with trials with no correlations. We suggest a model where spike-time correlations are associated with a common noise source for the two MT pools, which in turn decreases the signal-to-noise ratio of the integrated signals that drive motion detection.SIGNIFICANCE STATEMENT Previous work has shown that spike time correlations occurring on short timescales can affect the encoding of visual inputs. Although spike-time correlations significantly vary in both magnitude and sign across trials, their impact on trial-by-trial behavior is not fully understood. Using neural recordings from area MT (middle temporal) in monkeys performing a motion-detection task using a brief stimulus, we found that both positive and negative spike-time correlations predicted behavioral responses as well as firing rate on a trial-by-trial basis. We propose that strong positive and negative spike-time correlations decreased behavioral performance by reducing the signal-to-noise ratio of integrated MT neural signals. PMID- 29626166 TI - Cascades of Homeostatic Dysregulation Promote Incubation of Cocaine Craving. AB - In human drug users, cue-induced drug craving progressively intensifies after drug abstinence, promoting drug relapse. This time-dependent progression of drug craving is recapitulated in rodent models, in which rats exhibit progressive intensification of cue-induced drug seeking after withdrawal from drug self administration, a phenomenon termed incubation of drug craving. Although recent results suggest that functional alterations of the nucleus accumbens (NAc) contribute to incubation of drug craving, it remains poorly understood how NAc function evolves after drug withdrawal to progressively intensify drug seeking. The functional output of NAc relies on how the membrane excitability of its principal medium spiny neurons (MSNs) translates excitatory synaptic inputs into action potential firing. Here, we report a synapse-membrane homeostatic crosstalk (SMHC) in male rats, through which an increase or decrease in the excitatory synaptic strength induces a homeostatic decrease or increase in the intrinsic membrane excitability of NAc MSNs, and vice versa. After short-term withdrawal from cocaine self-administration, despite no actual change in the AMPA receptor mediated excitatory synaptic strength, GluN2B NMDA receptors, the SMHC sensors of synaptic strength, are upregulated. This may create false SMHC signals, leading to a decrease in the membrane excitability of NAc MSNs. The decreased membrane excitability subsequently induces another round of SMHC, leading to synaptic accumulation of calcium-permeable AMPA receptors and upregulation of excitatory synaptic strength after long-term withdrawal from cocaine. Disrupting SMHC-based dysregulation cascades after cocaine exposure prevents incubation of cocaine craving. Thus, cocaine triggers cascades of SMHC-based dysregulation in NAc MSNs, promoting incubated cocaine seeking after drug withdrawal.SIGNIFICANCE STATEMENT Here, we report a bidirectional homeostatic plasticity between the excitatory synaptic input and membrane excitability of nucleus accumbens (NAc) medium spiny neurons (MSNs), through which an increase or decrease in the excitatory synaptic strength induces a homeostatic decrease or increase in the membrane excitability, and vice versa. Cocaine self-administration creates a false homeostatic signal that engages this synapse-membrane homeostatic crosstalk mechanism, and produces cascades of alterations in excitatory synapses and membrane properties of NAc MSNs after withdrawal from cocaine. Experimentally preventing this homeostatic dysregulation cascade prevents the progressive intensification of cocaine seeking after drug withdrawal. These results provide a novel mechanism through which drug induced homeostatic dysregulation cascades progressively alter the functional output of NAc MSNs and promote drug relapse. PMID- 29626167 TI - Intracranial Electrophysiology Reveals Reproducible Intrinsic Functional Connectivity within Human Brain Networks. AB - Evidence for intrinsic functional connectivity (FC) within the human brain is largely from neuroimaging studies of hemodynamic activity. Data are lacking from anatomically precise electrophysiological recordings in the most widely studied nodes of human brain networks. Here we used a combination of fMRI and electrocorticography (ECoG) in five human neurosurgical patients with electrodes in the canonical "default" (medial prefrontal and posteromedial cortex), "dorsal attention" (frontal eye fields and superior parietal lobule), and "frontoparietal control" (inferior parietal lobule and dorsolateral prefrontal cortex) networks. In this unique cohort, simultaneous intracranial recordings within these networks were anatomically matched across different individuals. Within each network and for each individual, we found a positive, and reproducible, spatial correlation for FC measures obtained from resting-state fMRI and separately recorded ECoG in the same brains. This relationship was reliably identified for electrophysiological FC based on slow (<1 Hz) fluctuations of high-frequency broadband (70-170 Hz) power, both during wakeful rest and sleep. A similar FC organization was often recovered when using lower-frequency (1-70 Hz) power, but anatomical specificity and consistency were greatest for the high-frequency broadband range. An interfrequency comparison of fluctuations in FC revealed that high and low-frequency ranges often temporally diverged from one another, suggesting that multiple neurophysiological sources may underlie variations in FC. Together, our work offers a generalizable electrophysiological basis for intrinsic FC and its dynamics across individuals, brain networks, and behavioral states.SIGNIFICANCE STATEMENT The study of human brain networks during wakeful "rest", largely with fMRI, is now a major focus in both cognitive and clinical neuroscience. However, little is known about the neurophysiology of these networks and their dynamics. We studied neural activity during wakeful rest and sleep within neurosurgical patients with directly implanted electrodes. We found that network activity patterns showed striking similarities between fMRI and direct recordings in the same brains. With improved resolution of direct recordings, we also found that networks were best characterized with specific activity frequencies and that different frequencies show different profiles of within-network activity over time. Our work clarifies how networks spontaneously organize themselves across individuals, brain networks, and behavioral states. PMID- 29626169 TI - On the Flexibility of Basic Risk Attitudes in Monkeys. AB - Monkeys and other animals appear to share with humans two risk attitudes predicted by prospect theory: an inverse-S-shaped probability-weighting (PW) function and a steeper utility curve for losses than for gains. These findings suggest that such preferences are stable traits with common neural substrates. We hypothesized instead that animals tailor their preferences to subtle changes in task contexts, making risk attitudes flexible. Previous studies used a limited number of outcomes, trial types, and contexts. To gain a broader perspective, we examined two large datasets of male macaques' risky choices: one from a task with real (juice) gains and another from a token task with gains and losses. In contrast to previous findings, monkeys were risk seeking for both gains and losses (i.e., lacked a reflection effect) and showed steeper gain than loss curves (loss seeking). Utility curves for gains were substantially different in the two tasks. Monkeys showed nearly linear PWs in one task and S-shaped ones in the other; neither task produced a consistent inverse-S-shaped curve. To account for these observations, we developed and tested various computational models of the processes involved in the construction of reward value. We found that adaptive differential weighting of prospective gamble outcomes could partially account for the observed differences in the utility functions across the two experiments and thus provide a plausible mechanism underlying flexible risk attitudes. Together, our results support the idea that risky choices are constructed flexibly at the time of elicitation and place important constraints on neural models of economic choice.SIGNIFICANCE STATEMENT We respond in reliable ways to risk, but are our risk preferences stable traits or ephemeral states? Using various computational models, we examined two large datasets of macaque risky choices in two different tasks. We observed several deviations from "classic" risk preferences seen in humans and monkeys: no reflection effect, loss seeking as opposed to loss aversion, and linear and S-shaped, as opposed to inverse-S-shaped, probability distortion. These results challenge the idea that our risk attitudes are evolved traits shared with the last common ancestor of macaques and humans, suggesting instead that behavioral flexibility is the hallmark of risky choice in primates. We show how this flexibility can emerge partly as a result of interactions between attentional and reward systems. PMID- 29626171 TI - Charting new horizons for Science Immunology. AB - Charting new horizons for Science Immunology. PMID- 29626172 TI - "That's not helping-T follicular helper cells drive skin fibrosis". AB - T follicular helper-like cells and IL-21 are drivers of skin fibrosis in systemic sclerosis. PMID- 29626170 TI - The receptor repertoire and functional profile of follicular T cells in HIV infected lymph nodes. AB - Follicular helper CD4+ T cells (TFH) play an integral role in promoting B cell differentiation and affinity maturation. Whereas TFH cell frequencies are increased in lymph nodes (LNs) from individuals infected with HIV, humoral immunity remains impaired during chronic HIV infection. Whether HIV inhibits TFH responses in LNs remains unclear. Advances in this area have been limited by the difficulty of accessing human lymphoid tissues. Here, we combined high dimensional mass cytometry with T cell receptor repertoire sequencing to interrogate the composition of TFH cells in primary human LNs. We found evidence for intact antigen-driven clonal expansion of TFH cells and selective utilization of specific complementarity-determining region 3 (CDR3) motifs during chronic HIV infection, but the resulting TFH cells acquired an activation-related TFH cell signature characterized by interleukin-21 (IL-21) dominance. These IL-21+ TFH cells contained an oligoclonal HIV-reactive population that preferentially accumulated in patients with severe HIV infection and was associated with aberrant B cell distribution in the same LN. These data indicate that TFH cells remain capable of responding to HIV antigens during chronic HIV infection but become functionally skewed and oligoclonally restricted under persistent antigen stimulation. PMID- 29626173 TI - The right angle on IL-2 therapy. AB - Engineered cytokines are able to improve immunotherapy in mouse tumor models. PMID- 29626174 TI - Acceptability and effectiveness of using mobile applications to promote HIV and other STI testing among men who have sex with men in Barcelona, Spain. AB - OBJECTIVE: To evaluate the acceptability and effectiveness of a pilot intervention programme using gay geosocial mobile applications (apps) to offer rapid HIV and other STI tests to men who have sex with men (MSM) in Barcelona between December 2015 and March 2016. METHODOLOGY: We offered rapid HIV, syphilis and hepatitis C testing by sending private messages on apps for sexual and social encounters. Acceptance was defined as the proportion of users who favourably responded to the message and effectiveness was defined as the proportion of users who attended our facilities among those who were interested in attending. To identify variables associated with the response to the messages, multivariate logistic regression was used. Adjusted OR (ORa) and 95% CIs were calculated. We collected information on sociodemographics, sexual behaviours and app usage from the contacted user profiles and from users who attended our facilities. A descriptive analysis was carried out. RESULTS: 2656 individual messages were sent. Overall, a 38.4% response rate was obtained, 83.0% of them found it acceptable to receive the unsolicited message, and 73.2% effectiveness was obtained. Responders had higher odds of being 45 years or older (ORa=1.48; 95% CI 1.06 to 2.08), being connected at the moment the message was sent or during the previous hour (ORa=1.92; 95% CI 1.38 to 2.68), having a profile photo not exposing bare chest or abdomen (ORa=1.44; 95% CI 1.07 to 1.92) and using the Grindr app (ORa=1.39; 95% CI 1.12 to 1.73). Of those who were tested and took the survey (n=77), 45.5% had not taken an HIV test in over a year, 24.7% had had a previous STI diagnosis, 51.4% had reported anal sex without condom and 52% had consumed alcohol or drugs for sex. CONCLUSIONS: The response rate, acceptance and effectiveness observed in this study indicate that this strategy could be a useful tool for promoting STI testing among high-risk MSM population. PMID- 29626175 TI - Diabetes and Parkinson disease: A sweet spot? PMID- 29626176 TI - Preventive Antibiotics in Stroke Study (PASS): A cost-effectiveness study. AB - OBJECTIVE: To evaluate the cost-effectiveness of preventive ceftriaxone vs standard stroke unit care without preventive antimicrobial therapy in acute stroke patients. METHODS: In this multicenter, randomized, open-label trial with masked endpoint assessment, 2,550 patients with acute stroke were included between 2010 and 2014. Economic evaluation was performed from a societal perspective with a time horizon of 3 months. Volumes and costs of direct, indirect, medical, and nonmedical care were assessed. Primary outcome was cost per unit of the modified Rankin Scale (mRS) and per quality-adjusted life year (QALY) for cost-effectiveness and cost-utility analysis. Incremental cost effectiveness analyses were performed. RESULTS: A total of 2,538 patients were available for the intention-to-treat analysis. For the cost-effectiveness analysis, 2,538 patients were available for in-hospital resource use and 1,453 for other resource use. Use of institutional care resources, out-of-pocket expenses, and productivity losses was comparable between treatment groups. The mean score on mRS was 2.38 (95% confidence interval [CI] 2.31-2.44) vs 2.44 (95% CI 2.37-2.51) in the ceftriaxone vs control group, the decrease by 0.06 (95% CI 0.04 to 0.16) in favor of ceftriaxone treatment being nonsignificant. However, the number of QALYs was 0.163 (95% CI 0.159-0.166) vs 0.155 (95% CI 0.152-0.158) in the ceftriaxone vs control group, with the difference of 0.008 (95% CI 0.003 0.012) in favor of ceftriaxone (p = 0.006) at 3 months. The probability of ceftriaxone being cost-effective ranged between 0.67 and 0.89. Probability of 0.75 was attained at a willing-to-pay level of ?2,290 per unit decrease in the mRS score and of ?12,200 per QALY. CONCLUSIONS: Preventive ceftriaxone has a probability of 0.7 of being less costly than standard treatment per unit decrease in mRS and per QALY gained. PMID- 29626177 TI - Diabetes mellitus and Parkinson disease. AB - OBJECTIVE: To investigate whether diabetes mellitus is associated with Parkinson like pathology in people without Parkinson disease and to evaluate the effect of diabetes mellitus on markers of Parkinson pathology and clinical progression in drug-naive patients with early-stage Parkinson disease. METHODS: We compared 25 patients with Parkinson disease and diabetes mellitus to 25 without diabetes mellitus, and 14 patients with diabetes mellitus and no Parkinson disease to 14 healthy controls (people with no diabetes mellitus or Parkinson disease). The clinical diagnosis of diabetes mellitus was confirmed by 2 consecutive fasting measurements of serum glucose levels >126 mL/dL. Over a 36-month follow-up period, we then investigated in the population with Parkinson disease whether the presence of diabetes mellitus was associated with faster motor progression or cognitive decline. RESULTS: The presence of diabetes mellitus was associated with higher motor scores (p < 0.01), lower striatal dopamine transporter binding (p < 0.05), and higher tau CSF levels (p < 0.05) in patients with Parkinson disease. In patients with diabetes but without Parkinson disease, the presence of diabetes mellitus was associated with lower striatal dopamine transporter binding (p < 0.05) and higher tau (p < 0.05) and alpha-synuclein (p < 0.05) CSF levels compared to healthy controls. At the Cox survival analysis in the population of patients with Parkinson disease, the presence of diabetes mellitus was associated with faster motor progression (hazard ratio = 4.521, 95% confidence interval = 1.468-13.926; p < 0.01) and cognitive decline (hazard ratio = 9.314, 95% confidence interval = 1.164-74.519; p < 0.05). CONCLUSIONS: Diabetes mellitus may predispose toward a Parkinson-like pathology, and when present in patients with Parkinson disease, can induce a more aggressive phenotype. PMID- 29626178 TI - Unique clinical and neurophysiologic profile of a cohort of children with CMTX3. AB - OBJECTIVE: To describe in detail the clinical profile of Charcot-Marie-Tooth disease subtype 3 (CMTX3) to aid appropriate genetic testing and rehabilitative therapy. METHODS: We reviewed the clinical and neurophysiologic profile and CMT Pediatric Scale (CMTPedS) assessments of 11 children with CMTX3. RESULTS: Compared with the more common forms of CMT, CMT1A and CMTX, CMTX3 was characterized by early onset with early and progressive hand weakness. Most affected children were symptomatic within the first 2 years of life. The most common presentation was foot deformity in the first year of life. CMTPedS analysis in these children revealed that CMTX3 progressed more rapidly (4.3 +/- 4.1 points over 2 years, n = 7) than CMT1A and CMTX1. Grip strength in affected boys was 2 SDs below age- and sex-matched normative reference values (z score 2.05 +/- 1.32) in the second decade of life. The most severely affected individual was wheelchair bound at 14 years of age, and 2 individuals had no movement in the small muscles of the hand in the second decade of life. Nerve conduction studies showed a demyelinating sensorimotor neuropathy with motor conduction velocity <=23 m/s. CONCLUSIONS: CMTX3 had an earlier onset, severe hand weakness, and more rapidly progressive disability compared to the more common forms of CMT. Understanding the unique phenotype of CMTX3 is essential for directing genetic testing because the CMTX3 insertion will not be seen on a routine microarray or neuromuscular gene panel. Early diagnosis will enable rehabilitation to be started early in this rapidly progressive neuropathy. PMID- 29626179 TI - Reversible vestibular neuropathy in adult Refsum disease. PMID- 29626180 TI - Telemedicine in a pediatric headache clinic: A prospective survey. AB - OBJECTIVE: The aim of this prospective study was to survey our patients about their experience with our clinic's telemedicine program to better understand telemedicine's utility for families, and to improve patient satisfaction and ultimately patient care. METHODS: This was a prospective survey study of patients and their families who had a routine telemedicine follow-up visit with the University of California San Francisco Pediatric Headache Program. The survey was administered to patients and a parent(s) following their telemedicine visit. RESULTS: Fifty-one of 69 surveys (74%) were completed. All (51/51) patients and families thought that (1) telemedicine was more convenient compared to a clinic visit, (2) telemedicine caused less disruption of their daily routine, and (3) they would choose to do telemedicine again. The mean round-trip travel time from home to clinic was 6.8 hours (SD +/- 8.6 hours). All participants thought telemedicine was more cost-effective than a clinic visit. Parents estimated that participating in a telemedicine visit instead of a clinic appointment saved them on average $486. CONCLUSION: This prospective, pediatric headache telemedicine study shows that telemedicine is convenient, perceived to be cost-effective, and patient-centered. Providing the option of telemedicine for routine pediatric headache follow-up visits results in high patient and family satisfaction. PMID- 29626181 TI - Disability in adults with arthrogryposis is severe, partly invisible, and varies by genotype. AB - OBJECTIVE: To understand the disability of adults with arthrogryposis multiplex congenita (AMC), a rare disease spectrum characterized by at least 2 joint contractures at birth in different body areas. METHODS: This is a retrospective analysis of data for unselected persons with AMC referred to the French center for adults with AMC from 2010 to 2016. All underwent a pluriprofessional systematic and comprehensive investigation of deficits, activity limitation, and participation restriction according to the International Classification of Functioning, Disability and Health and genetic analysis when indicated. Participants were divided by amyoplasia and other AMC types. RESULTS: Mean (SD) age of the 43 participants (27 female) was 33.2 (13.4) years; 28 had amyoplasia and 15 other types of AMC. Beyond joint stiffness, deformities, and muscle weakness, the well-known core symptoms that we quantified and for which first line treatment involved technical aids, other less visible disorders that could contribute to severe participation restriction were particularly pain and psychological problems including anxiety, fatigue, difficulty in sexual life, altered self-esteem, and feelings of solitude. Severe respiratory disorders were infrequent and were linked to PIEZO2 mutations. Gait disorders were not due to respiratory impairment but to skeletal problems and were always associated with amyoplasia when severe. Functional independence was worse but respiratory and swallowing capacities were better with amyoplasia than other AMC types. CONCLUSION: This study describes disability patterns of a cohort of adults with AMC by genotype. The disability of adults with AMC is influenced by genotype, with important invisible disability. PMID- 29626182 TI - Primary acquired Grynfeltt Hernia: two new cases and literature review. AB - AIM: We report two cases of the very rare Primary Acquired Grynfeltt Hernia. The related abdominal wall defects were repaired, by open surgery, placing a partially absorbable plug and mesh. The observation and management of these two new cases prompted us to review the literature with the purpose of suggesting the most appropriate surgical approach and technique. MATHERIAL OF STUDY: A 60 years old female patient showing a swelling at the left lumbar region, and a 76 years old male patient showing evidence of a tumefaction located at the right lumbar region, were diagnosed at our department with Primary Acquired Grynfeltt Hernia. RESULTS: Postoperative courses were uneventful and the patients were discharged from hospital respectively on the third and second postoperative day. Follow-up at thirty days, six months, two and three years showed no signs of recurrence. DISCUSSION: Primary Acquired Grynfeltt Hernia is one of the rarest abdominal hernias. In literature there are no comparative studies showing which type of surgical approach should be preferred for this specific abdominal wall defect. In our department, open surgery was successfully performed for the treatment of two new cases of Primary Acquired Grynfeltt Hernias and, second time in literature, partially absorbable plug and mesh were placed in order to repair the causative abdominal wall defect. CONCLUSION: Based on our experience and literature review, we consider open hernia repair with partially absorbable plug and mesh as an appropriate and advisable surgical approach for not complicated cases of Primary Acquired Grynfeltt Hernia. Surgery is performed rapidly, effortlessly and securely if the patient is under general anesthesia, in lateral decubitus position with the operating table flexed at the level of the iliac crest. KEY WORDS: Primary Acquired Grynfeltt Hernia, Lumbar Hernia. PMID- 29626183 TI - Primary basosquamous carcinoma of the lower eyelid with ocular invasion A case report. AB - INTRODUCTION: Ocular invasion is extremely rare for a primary eyelid Basosquamous Carcinoma (BSC). It can however occur in neglected cases if the clinical signs are overseen and the BSC is misdiagnosed for a less aggressive skin carcinoma. MATERIALS AND METHODS: A 58-year-old man suffering from an inferior eyelid BSC that had been neglected for 7 years was referred to our clinic. A local infiltration of the maxillary sinus and the contents of the orbit by the tumor was discovered, and he was managed with a left orbital exenteration and resection of the involved orbital bone. A follow up was established. DISCUSSION: BSC is a rare type of skin malignancy which as an entity rests between Basal Cell Carcinoma (BCC) and Squamous Cell Carcinoma (SCC), and its aggressive nature is often greater than that of the BCC and the SCC. Having no specific clinical features differentiating it from other BCC types, it can only be diagnosed by an adequate biopsy. Its early diagnosis is crucial in diminishing it's recurrence rate and it's metastatic potential. The standard therapeutical approach is the complete excision of the tumor, best performed by Mohs micrographic surgery. In cases of ocular infiltration, orbital exenteration is also usually necessary. CONCLUSIONS: Suspect, rapidly growing skin lesions should alert clinicians and an adequate biopsy should be performed. Regarding BSC, prompt and complete excision along with systemic exclusion of metastases and a close follow up are necessary. Adjuvant radiotherapy and chemotherapy could be beneficial to the patients. KEY WORDS: Basosquamous carcinoma (BSC), Basal cell carcinoma (BCC), Eyelid tumor, Ocular tissue invasion, Imiquimod, Maxillectomy, Metatypical basal cell carcinoma, Mohs micrographic surgery, Orbital exenteration, Orbit invasion, Squamous cell carcinoma (SCC), Vismodegib. PMID- 29626184 TI - Tachyphylaxis to the Sedative Action of Mirtazapine. AB - BACKGROUND The pharmacological term tachyphylaxis is used to describe rapidly occurring response desensitization, a situation where the biological response to a given drug dose diminishes when it is given continuously. This pharmacological phenomenon is well observed in some drug categories such as ephedrine, nitrates, beta blockers and H2 antagonists. Mirtazapine is a widely-used antidepressant with a multimodal mechanism of action. CASE REPORT In the present case, we report rapid onset and consistent tachyphylaxis regarding the sedative action of mirtazapine in a 30-year-old female. CONCLUSIONS To our knowledge this is the first reported case of rapid onset and consistent tachyphylaxis to the sedative effect of mirtazapine confirming the complexity of the pharmacological profile of the drug. PMID- 29626185 TI - Relationship Between INPP5E Gene Expression and Embryonic Neural Development in a Mouse Model of Neural Tube Defect. AB - BACKGROUND The INPP5E gene encodes for the inositol polyphosphate-5-phosphatase (INPP5E) 72 kDa protein that regulates the phosphoinositide signaling pathway and other cellular activities, but the functional role of this gene in embryonic neurodevelopment and neural tube defect (NTD) remains unclear. The aim of this study was to use a mouse model of NTD to investigate the expression levels of the INPP5E gene during neural development and the occurrence of NTD. MATERIAL AND METHODS In an established NTD mouse model, stereoscopy was used to look for morphological defects. Transcription and expression levels of the INPP5E gene in neural tissues were detected using real-time fluorescence quantitative polymerase chain reaction (PCR) and Western blotting in the NTD mouse embryos and compared with control mouse embryos. RESULTS The expression levels of the INPP5E gene decreased as embryonic development progressed in the neural tissue of control mice embryos, but showed no obvious trend in the neural tissues of the NTD mouse embryos. The expression levels of the INPP5E gene in NTD mouse embryos were significantly lower compared with control embryos, at the time of neural tube closure (gestational day 11.5). CONCLUSIONS The INPP5E gene regulates the process of embryonic neural development. Abnormal levels of expression of the INPP5E gene may contribute to NTDs. Increased knowledge of the expression pattern of the INPP5E gene may lead to an advanced understanding of the molecular mechanism of embryonic neurodevelopment and identify more specific directions to explore potential treatments for NTDs associated with abnormalities in INPP5E gene expression levels. PMID- 29626186 TI - De novo reconstruction of human adipose transcriptome reveals conserved lncRNAs as regulators of brown adipogenesis. AB - Obesity has emerged as an alarming health crisis due to its association with metabolic risk factors such as diabetes, dyslipidemia, and hypertension. Recent work has demonstrated the multifaceted roles of lncRNAs in regulating mouse adipose development, but their implication in human adipocytes remains largely unknown. Here we present a catalog of 3149 adipose active lncRNAs, of which 909 are specifically detected in brown adipose tissue (BAT) by performing deep RNA seq on adult subcutaneous, omental white adipose tissue and fetal BATs. A total of 169 conserved human lncRNAs show positive correlation with their nearby mRNAs, and knockdown assay supports a role of lncRNAs in regulating their nearby mRNAs. The knockdown of one of those, lnc-dPrdm16, impairs brown adipocyte differentiation in vitro and a significant reduction of BAT-selective markers in in vivo. Together, our work provides a comprehensive human adipose catalog built from diverse fat depots and establishes a roadmap to facilitate the discovery of functional lncRNAs in adipocyte development. PMID- 29626187 TI - Control of laser plasma accelerated electrons for light sources. AB - With gigaelectron-volts per centimetre energy gains and femtosecond electron beams, laser wakefield acceleration (LWFA) is a promising candidate for applications, such as ultrafast electron diffraction, multistaged colliders and radiation sources (betatron, compton, undulator, free electron laser). However, for some of these applications, the beam performance, for example, energy spread, divergence and shot-to-shot fluctuations, need a drastic improvement. Here, we show that, using a dedicated transport line, we can mitigate these initial weaknesses. We demonstrate that we can manipulate the beam longitudinal and transverse phase-space of the presently available LWFA beams. Indeed, we separately correct orbit mis-steerings and minimise dispersion thanks to specially designed variable strength quadrupoles, and select the useful energy range passing through a slit in a magnetic chicane. Therefore, this matched electron beam leads to the successful observation of undulator synchrotron radiation after an 8 m transport path. These results pave the way to applications demanding in terms of beam quality. PMID- 29626188 TI - Structural rearrangements of the histone octamer translocate DNA. AB - Nucleosomes, the basic unit of chromatin, package and regulate expression of eukaryotic genomes. Nucleosomes are highly dynamic and are remodeled with the help of ATP-dependent remodeling factors. Yet, the mechanism of DNA translocation around the histone octamer is poorly understood. In this study, we present several nucleosome structures showing histone proteins and DNA in different organizational states. We observe that the histone octamer undergoes conformational changes that distort the overall nucleosome structure. As such, rearrangements in the histone core alpha-helices and DNA induce strain that distorts and moves DNA at SHL 2. Distortion of the nucleosome structure detaches histone alpha-helices from the DNA, leading to their rearrangement and DNA translocation. Biochemical assays show that cross-linked histone octamers are immobilized on DNA, indicating that structural changes in the octamer move DNA. This intrinsic plasticity of the nucleosome is exploited by chromatin remodelers and might be used by other chromatin machineries. PMID- 29626189 TI - Origin of large plasticity and multiscale effects in iron-based metallic glasses. AB - The large plasticity observed in newly developed monolithic bulk metallic glasses under quasi-static compression raises a question about the contribution of atomic scale effects. Here, nanocrystals on the order of 1-1.5 nm in size are observed within an Fe-based bulk metallic glass using aberration-corrected high-resolution transmission electron microscopy (HRTEM). The accumulation of nanocrystals is linked to the presence of hard and soft zones, which is connected to the micro scale hardness and elastic modulus confirmed by nanoindentation. Furthermore, we performed systematic simulations of HRTEM images at varying sample thicknesses, and established a theoretical model for the estimation of the shear transformation zone size. The findings suggest that the main mechanism behind the formation of softer regions are the homogenously dispersed nanocrystals, which are responsible for the start and stop mechanism of shear transformation zones and hence, play a key role in the enhancement of mechanical properties. PMID- 29626190 TI - A crossroad for validating digital tools in schizophrenia and mental health. PMID- 29626192 TI - Optimal diversification strategies in the networks of related products and of related research areas. AB - Countries and cities are likely to enter economic activities that are related to those that are already present in them. Yet, while these path dependencies are universally acknowledged, we lack an understanding of the diversification strategies that can optimally balance the development of related and unrelated activities. Here, we develop algorithms to identify the activities that are optimal to target at each time step. We find that the strategies that minimize the total time needed to diversify an economy target highly connected activities during a narrow and specific time window. We compare the strategies suggested by our model with the strategies followed by countries in the diversification of their exports and research activities, finding that countries follow strategies that are close to the ones suggested by the model. These findings add to our understanding of economic diversification and also to our general understanding of diffusion in networks. PMID- 29626191 TI - Lipid binding promotes the open conformation and tumor-suppressive activity of neurofibromin 2. AB - Neurofibromatosis type 2 (NF2) is a tumor-forming disease of the nervous system caused by deletion or by loss-of-function mutations in NF2, encoding the tumor suppressing protein neurofibromin 2 (also known as schwannomin or merlin). Neurofibromin 2 is a member of the ezrin, radixin, moesin (ERM) family of proteins regulating the cytoskeleton and cell signaling. The correlation of the tumor-suppressive function and conformation (open or closed) of neurofibromin 2 has been subject to much speculation, often based on extrapolation from other ERM proteins, and controversy. Here we show that lipid binding results in the open conformation of neurofibromin 2 and that lipid binding is necessary for inhibiting cell proliferation. Collectively, our results provide a mechanism in which the open conformation is unambiguously correlated with lipid binding and localization to the membrane, which are critical for the tumor-suppressive function of neurofibromin 2, thus finally reconciling the long-standing conformation and function debate. PMID- 29626194 TI - A giant amphipathic helix from a perilipin that is adapted for coating lipid droplets. AB - How proteins are targeted to lipid droplets (LDs) and distinguish the LD surface from the surfaces of other organelles is poorly understood, but many contain predicted amphipathic helices (AHs) that are involved in targeting. We have focused on human perilipin 4 (Plin4), which contains an AH that is exceptional in terms of length and repetitiveness. Using model cellular systems, we show that AH length, hydrophobicity, and charge are important for AH targeting to LDs and that these properties can compensate for one another, albeit at a loss of targeting specificity. Using synthetic lipids, we show that purified Plin4 AH binds poorly to lipid bilayers but strongly interacts with pure triglycerides, acting as a coat and forming small oil droplets. Because Plin4 overexpression alleviates LD instability under conditions where their coverage by phospholipids is limiting, we propose that the Plin4 AH replaces the LD lipid monolayer, for example during LD growth. PMID- 29626195 TI - In situ X-ray scattering observation of two-dimensional interfacial colloidal crystallization. AB - Charged colloids at interfaces hold such a simple configuration that their interactions are supposed to be fully elucidated in the framework of classical electrostatics, yet the mysterious existence of attractive forces between these like-charged particles has puzzled the scientific community for decades. Here, we perform the in situ grazing-incidence small-angle X-ray scattering study of the dynamic self-assembling process of two-dimensional interfacial colloids. This approach allows simultaneous monitoring of the in-plane structure and ordering and the out-of-plane immersion depth variation. Upon compression, the system undergoes multiple metastable intermediate states before the stable hexagonal close-packed monolayer forms under van der Waals attraction. Remarkably, the immersion depth of colloidal particles is found to increase as the interparticle distance decreases. Numerical simulations demonstrate the interface around a colloid is deformed by the electrostatic force from its neighboring particles, which induces the long-range capillary attraction. PMID- 29626193 TI - Evaluation of the graded redefined assessment of strength, sensibility and prehension (GRASSP) in children with tetraplegia. AB - STUDY DESIGN: Psychometric study. OBJECTIVE: To validate the GRASSP in pediatric SCI populations and establish the lower age of test administration. SETTING: United States: Pennsylvania, Maryland, Illinois, Michigan, California, Texas. METHODS: Mean, SD and range of scores were calculated and examined for known group differences. Test-retest reliability was measured by the intra-class correlation, concurrent validity of the GRASSP against the SCIM, SCIM-SS, and the CUE-Q was measured by the Spearman correlation. RESULTS: GRASSP scores differed between participants with motor complete and incomplete injuries (p = <0.0001 0.036). Test-retest reliability was strong (ICC = 0.99). Weak correlation with the total SCIM (r = 0.33-0.66), and moderate to strong correlation with the SCIM SC (r = 37-0.70) and CUE-Q (r = 0.40-0.84). CONCLUSION: Results support the validity of the GRASSP and provide evidence that the scores are reliable when administered to children. The GRASSP sensory and strength subtests are recommended for children beginning at 6 years of age, and the GRASSP prehension performance/ability subtest for children beginning at 8 years of age. Normative data are needed for the performance components of the GRASSP. PMID- 29626197 TI - Proteomic and genomic integration identifies kinase and differentiation determinants of kinase inhibitor sensitivity in leukemia cells. PMID- 29626196 TI - Mutation, methylation, and gene expression profiles in dup(1q)-positive pediatric B-cell precursor acute lymphoblastic leukemia. AB - High-throughput sequencing was applied to investigate the mutation/methylation patterns on 1q and gene expression profiles in pediatric B-cell precursor acute lymphoblastic leukemia (BCP ALL) with/without (w/wo) dup(1q). Sequencing of the breakpoint regions and all exons on 1q in seven dup(1q)-positive cases revealed non-synonymous somatic single nucleotide variants (SNVs) in BLZF1, FMN2, KCNT2, LCE1C, NES, and PARP1. Deep sequencing of these in a validation cohort w (n = 17)/wo (n = 94) dup(1q) revealed similar SNV frequencies in the two groups (47% vs. 35%; P = 0.42). Only 0.6% of the 36,259 CpGs on 1q were differentially methylated between cases w (n = 14)/wo (n = 13) dup(1q). RNA sequencing of high hyperdiploid (HeH) and t(1;19)(q23;p13)-positive cases w (n = 14)/wo (n = 52) dup(1q) identified 252 and 424 differentially expressed genes, respectively; only seven overlapped. Of the overexpressed genes in the HeH and t(1;19) groups, 23 and 31%, respectively, mapped to 1q; 60-80% of these encode nucleic acid/protein binding factors or proteins with catalytic activity. We conclude that the pathogenetically important consequence of dup(1q) in BCP ALL is a gene-dosage effect, with the deregulated genes differing between genetic subtypes, but involving similar molecular functions, biological processes, and protein classes. PMID- 29626198 TI - Aryl hydrocarbon receptor and intestinal immunity. AB - Aryl hydrocarbon receptor (AhR) is a member of the basic helix-loop-helix-(bHLH) superfamily of transcription factors, which are associated with cellular responses to environmental stimuli, such as xenobiotics and oxygen levels. Unlike other members of bHLH, AhR is the only bHLH transcription factor that is known to be ligand activated. Early AhR studies focused on understanding the role of AhR in mediating the toxicity and carcinogenesis properties of the prototypic ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In recent years, however, it has become apparent that, in addition to its toxicological involvement, AhR is highly receptive to a wide array of endogenous and exogenous ligands, and that its activation leads to a myriad of key host physiological functions. In this study, we review the current understanding of the functions of AhR in the mucosal immune system with a focus on its role in intestinal barrier function and intestinal immune cells, as well as in intestinal homeostasis. PMID- 29626200 TI - Improved pain management. PMID- 29626201 TI - Obesity associated with resistance to anti-angiogenic therapy. PMID- 29626202 TI - Endocrine disruptors - putting the mechanistic cart before the phenomenological horse. PMID- 29626203 TI - IBD - a potential adverse effect of DDP4 inhibitors in T2DM. PMID- 29626199 TI - Advances in predictive in vitro models of drug-induced nephrotoxicity. AB - In vitro screens for nephrotoxicity are currently poorly predictive of toxicity in humans. Although the functional proteins that are expressed by nephron tubules and mediate drug susceptibility are well known, current in vitro cellular models poorly replicate both the morphology and the function of kidney tubules and therefore fail to demonstrate injury responses to drugs that would be nephrotoxic in vivo. Advances in protocols to enable the directed differentiation of pluripotent stem cells into multiple renal cell types and the development of microfluidic and 3D culture systems have opened a range of potential new platforms for evaluating drug nephrotoxicity. Many of the new in vitro culture systems have been characterized by the expression and function of transporters, enzymes, and other functional proteins that are expressed by the kidney and have been implicated in drug-induced renal injury. In vitro platforms that express these proteins and exhibit molecular biomarkers that have been used as readouts of injury demonstrate improved functional maturity compared with static 2D cultures and represent an opportunity to model injury to renal cell types that have hitherto received little attention. As nephrotoxicity screening platforms become more physiologically relevant, they will facilitate the development of safer drugs and improved clinical management of nephrotoxicants. PMID- 29626204 TI - Does lower limb amputation concern all SGLT2 inhibitors? PMID- 29626205 TI - Origin of vertical orientation in two-dimensional metal halide perovskites and its effect on photovoltaic performance. AB - Thin films based on two-dimensional metal halide perovskites have achieved exceptional performance and stability in numerous optoelectronic device applications. Simple solution processing of the 2D perovskite provides opportunities for manufacturing devices at drastically lower cost compared to current commercial technologies. A key to high device performance is to align the 2D perovskite layers, during the solution processing, vertical to the electrodes to achieve efficient charge transport. However, it is yet to be understood how the counter-intuitive vertical orientations of 2D perovskite layers on substrates can be obtained. Here we report a formation mechanism of such vertically orientated 2D perovskite in which the nucleation and growth arise from the liquid air interface. As a consequence, choice of substrates can be liberal from polymers to metal oxides depending on targeted application. We also demonstrate control over the degree of preferential orientation of the 2D perovskite layers and its drastic impact on device performance. PMID- 29626206 TI - High-throughput mouse phenomics for characterizing mammalian gene function. AB - We are entering a new era of mouse phenomics, driven by large-scale and economical generation of mouse mutants coupled with increasingly sophisticated and comprehensive phenotyping. These studies are generating large, multidimensional gene-phenotype data sets, which are shedding new light on the mammalian genome landscape and revealing many hitherto unknown features of mammalian gene function. Moreover, these phenome resources provide a wealth of disease models and can be integrated with human genomics data as a powerful approach for the interpretation of human genetic variation and its relationship to disease. In the future, the development of novel phenotyping platforms allied to improved computational approaches, including machine learning, for the analysis of phenotype data will continue to enhance our ability to develop a comprehensive and powerful model of mammalian gene-phenotype space. PMID- 29626208 TI - Publisher Correction: ERK-mediated phosphorylation regulates SOX10 sumoylation and targets expression in mutant BRAF melanoma. AB - In the original version of this Article, financial support was not fully acknowledged. The PDF and HTML versions of the Article have now been corrected to include the following: The National Basic Research Program (2015CB553602 to J.L.), the National Natural Science Foundation of China (31570777, 91649106, 31770917 to J.L.) and Tianjin Applied Basic and Frontier Tech Major Project (12JCZDJC34400 to J.L.) and Tianjin Higher Education Sci-Tech Development Project (20112D05 to J.L.). PMID- 29626207 TI - Genetic basis to hybrid inviability is more complex than hybrid male sterility in Caenorhabditis nematodes. AB - Hybrid male sterility often evolves before female sterility or inviability of hybrids, implying that the accumulation of divergence between separated lineages should lead hybrid male sterility to have a more polygenic basis. However, experimental evidence is mixed. Here, we use the nematodes Caenorhabditis remanei and C. latens to characterize the underlying genetic basis of asymmetric hybrid male sterility and hybrid inviability. We demonstrate that hybrid male sterility is consistent with a simple genetic basis, involving a single X-autosome incompatibility. We also show that hybrid inviability involves more genomic compartments, involving diverse nuclear-nuclear incompatibilities, a mito-nuclear incompatibility, and maternal effects. These findings demonstrate that male sensitivity to genetic perturbation may be genetically simple compared to hybrid inviability in Caenorhabditis and motivates tests of generality for the genetic architecture of hybrid incompatibility across the breadth of phylogeny. PMID- 29626210 TI - The life cycle of non-polio enteroviruses and how to target it. AB - The genus Enterovirus (EV) of the family Picornaviridae includes poliovirus, coxsackieviruses, echoviruses, numbered enteroviruses and rhinoviruses. These diverse viruses cause a variety of diseases, including non-specific febrile illness, hand-foot-and-mouth disease, neonatal sepsis-like disease, encephalitis, paralysis and respiratory diseases. In recent years, several non-polio enteroviruses (NPEVs) have emerged as serious public health concerns. These include EV-A71, which has caused epidemics of hand-foot-and-mouth disease in Southeast Asia, and EV-D68, which recently caused a large outbreak of severe lower respiratory tract disease in North America. Infections with these viruses are associated with severe neurological complications. For decades, most research has focused on poliovirus, but in recent years, our knowledge of NPEVs has increased considerably. In this Review, we summarize recent insights from enterovirus research with a special emphasis on NPEVs. We discuss virion structures, host-receptor interactions, viral uncoating and the recent discovery of a universal enterovirus host factor that is involved in viral genome release. Moreover, we briefly explain the mechanisms of viral genome replication, virion assembly and virion release, and describe potential targets for antiviral therapy. We reflect on how these recent discoveries may help the development of antiviral therapies and vaccines. PMID- 29626209 TI - XRCC3 polymorphism is associated with hypertension-induced left ventricular hypertrophy. AB - Deficiency of X-ray repair cross-complementing protein 3 (XRCC3), a DNA-damage repair molecule, and the 241Met variant of XRCC3 have been reported to increase endoreduplication, which induces polyploidy. The aims of this study were to determine the impact of the XRCC3 polymorphism on the incidence of hypertension induced left ventricular hypertrophy (LVH) and to investigate the mechanisms underlying any potential relationship. Patients undergoing chronic hemodialysis (n = 77) were genotyped to assess for the XRCC3 Thr241Met polymorphism. The XRCC3 241Thr/Met genotype was more frequent in the LVH (+) group than in the LVH (-) group (42.3 vs. 13.7%, chi2 = 7.85, p = 0.0051). To investigate possible mechanisms underlying these observations, human XRCC3 cDNA of 241Thr or that of 241Met was introduced into cultured CHO cells. The surface area of CHO cells expressing XRCC3 241Met was larger than that expressing 241Thr. Spontaneous DNA double-strand breaks accumulated to a greater degree in NIH3T3 cells expressing 241Met (3T3-241Met) than in those expressing 241Thr (3T3-241Thr). DNA damage caused by radiation induced cell senescence more frequently in 3T3-241Met. The levels of basal and TNF-alpha-stimulated MCP-1 mRNA and protein secretion were higher in 3T3-241Met. Finally, FACS analysis revealed that the cell percentage in G2/M phase including polyploidy was significantly higher in 3T3-241Met than in 3T3-241Thr. Furthermore, the basal level of MCP-1 mRNA positively correlated with the cell percentage in G2/M phase and polyploidy. These data suggest that the XRCC3 241Met increases the risk of LVH via accumulation of DNA damage, thereby altering cell cycle progression and inducing cell senescence and a proinflammatory phenotype. PMID- 29626211 TI - Targeting cytokines to treat asthma and chronic obstructive pulmonary disease. AB - Cytokines play a key role in orchestrating and perpetuating the chronic airway inflammation in asthma and chronic obstructive pulmonary disease (COPD), making them attractive targets for treating these disorders. Asthma and some cases of COPD are mainly driven by type 2 immune responses, which comprise increased airway eosinophils, T helper 2 (TH2) cells and group 2 innate lymphoid cells (ILC2s) and the secretion of IL-4, IL-5 and IL-13. Clinical trials of antibodies that block these interleukins have shown reduced acute exacerbations and oral corticosteroid use and improvements in lung function and symptoms in selected patients. More recent approaches that block upstream cytokines, such as thymic stromal lymphopoietin (TSLP), show promise in improving patient outcome. Importantly, the clinical trials in cytokine blockade have highlighted the crucial importance of patient selection for the successful use of these expensive therapies and the need for biomarkers to better predict drug responses. PMID- 29626212 TI - Palmitic Acid Induces Muller Cell Inflammation that is Potentiated by Co treatment with Glucose. AB - Chronic hyperglycemia is thought to be the major stimulator of retinal dysfunction in diabetic retinopathy (DR). Thus, many diabetes-related systemic factors have been overlooked as inducers of DR pathology. Cell culture models of retinal cell types are frequently used to mechanistically study DR, but appropriate stimulators of DR-like factors are difficult to identify. Furthermore, elevated glucose, a gold standard for cell culture treatments, yields little to no response from many primary human retinal cells. Thus, the goal of this project was to demonstrate the effectiveness of the free fatty acid, palmitic acid and compare its use alone and in combination with elevated glucose as a stimulus for human Muller cells, a retinal glial cell type that is activated early in DR pathogenesis and uniquely responsive to fatty acids. Using RNA sequencing, we identified a variety of DR-relevant pathways, including NFkappaB signaling and inflammation, intracellular lipid signaling, angiogenesis, and MAPK signaling, that were stimulated by palmitic acid, while elevated glucose alone did not significantly alter any diabetes-relevant pathways. Co-treatment of high glucose with palmitic acid potentiated the expression of several DR-relevant angiogenic and inflammatory targets, including PTGS2 (COX-2) and CXCL8 (IL-8). PMID- 29626213 TI - On-chip temporal focusing of elastic waves in a phononic crystal waveguide. AB - The ability to manipulate acoustic and elastic waveforms in continuous media has attracted significant research interest and is crucial for practical applications ranging from biological imaging to material characterization. Although several spatial focusing techniques have been developed, these systems require sophisticated resonant structures with narrow bandwidth, which limit their practical applications. Here we demonstrate temporal pulse manipulation in a dispersive one-dimensional phononic crystal waveguide, which enables the temporal control of ultrasonic wave propagation. On-chip pulse focusing is realized at a desired time and position with chirped input pulses that agree perfectly with the theoretical prediction. Moreover, traveling four-wave mixing experiments are implemented, providing a platform on which to realize novel nonlinear phenomena in the system. Incorporating this dispersive pulse engineering scheme into nonlinear phononic crystal architecture opens up the possibility of investigating novel phenomena such as phononic solitons. PMID- 29626215 TI - The coming of age of chaperone-mediated autophagy. AB - Chaperone-mediated autophagy (CMA) was the first studied process that indicated that degradation of intracellular components by the lysosome can be selective - a concept that is now well accepted for other forms of autophagy. Lysosomes can degrade cellular cytosol in a nonspecific manner but can also discriminate what to target for degradation with the involvement of a degradation tag, a chaperone and a sophisticated mechanism to make the selected proteins cross the lysosomal membrane through a dedicated translocation complex. Recent studies modulating CMA activity in vivo using transgenic mouse models have demonstrated that selectivity confers on CMA the ability to participate in the regulation of multiple cellular functions. Timely degradation of specific cellular proteins by CMA modulates, for example, glucose and lipid metabolism, DNA repair, cellular reprograming and the cellular response to stress. These findings expand the physiological relevance of CMA beyond its originally identified role in protein quality control and reveal that CMA failure with age may aggravate diseases, such as ageing-associated neurodegeneration and cancer. PMID- 29626216 TI - Minimized approaches to the posterolateral chest wall in the fixation of rib fracture. PMID- 29626214 TI - Cryptic glucocorticoid receptor-binding sites pervade genomic NF-kappaB response elements. AB - Glucocorticoids (GCs) are potent repressors of NF-kappaB activity, making them a preferred choice for treatment of inflammation-driven conditions. Despite the widespread use of GCs in the clinic, current models are inadequate to explain the role of the glucocorticoid receptor (GR) within this critical signaling pathway. GR binding directly to NF-kappaB itself-tethering in a DNA binding-independent manner-represents the standing model of how GCs inhibit NF-kappaB-driven transcription. We demonstrate that direct binding of GR to genomic NF-kappaB response elements (kappaBREs) mediates GR-driven repression of inflammatory gene expression. We report five crystal structures and solution NMR data of GR DBD kappaBRE complexes, which reveal that GR recognizes a cryptic response element between the binding footprints of NF-kappaB subunits within kappaBREs. These cryptic sequences exhibit high sequence and functional conservation, suggesting that GR binding to kappaBREs is an evolutionarily conserved mechanism of controlling the inflammatory response. PMID- 29626217 TI - Axillary Accessory Breast: Optimal Time for Operation. AB - BACKGROUND: Accessory breasts are usually located in the axilla. Symptoms associated with an axillary accessory breast (AAB) may newly develop or worsen after pregnancy. After childbirth, AAB engorgement and hyperplasia may occur due to milk formation. We evaluated the optimal time for AAB excision and assessed variations in clinical presentations and surgical outcomes associated with pregnancy. METHODS: In total, 540 women whose symptoms began from puberty and underwent AAB excision were retrospectively analyzed. Group 1 comprised 416 patients who underwent operations before pregnancy, and Group 2 comprised 124 patients who underwent operations after childbirth. AABs were classified according to the Damsoyu-Lee (DL) classification. Satisfaction was measured by pain and cosmesis 3 months postoperatively. RESULTS: Group 2 had more patients with severe symptoms [DL class II (n = 8, 6.5%) and III (n = 15, 12.1%)] than Group 1 (p = 0.049). The specimen weight and liposuction volume were greater in Group 2. The reoperation rate was also higher in Group 2 [loosening skin excision (n = 4, 3.2%) and remnant gland excision (n = 3, 2.4%)] (p = 0.032). In Group 2, 31 (25%) patients had AAB engorgement after childbirth and 7 (5.6%) had milk secretion from the accessory nipple after childbirth. The overall satisfaction score was lower in Group 2 than 1. CONCLUSIONS: Pregnancy may cause accessory breast gland hyperplasia. After childbirth, symptoms such as AAB engorgement and milk secretion from the accessory nipple may occur. The optimal timing for operation for AAB appears to be before the onset of pregnancy because of lower reoperation rates and greater patient satisfaction. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 29626218 TI - Letter to the Editor Regarding: Fleming D, Stone J, Tansley P. Spontaneous Regression and Resolution of Breast Implant-Associated Anaplastic Large Cell Lymphoma: Implications for Research, Diagnosis and Clinical Management. Aesth Plast Surg, 2018. PMID- 29626219 TI - Smoking and the intestinal microbiome. AB - Studies are emerging alluding to the role of intestinal microbiome in the pathogenesis of diseases. Intestinal microbiome is susceptible to the influence of environmental factors such as smoking, and recent studies have indicated microbiome alterations in smokers. The aim of the study was to review the literature regarding the impact of smoking on the intestinal microbiome. A literature review of publications in PUBMED was performed using combinations of the terms "Intestinal/Gut/Gastrointestinal/Colonic" with "Microbiome/Microbiota/Microbial/Flora" and "Smoking/Smoker/Tobacco". We selected studies that were published between the years 2000 and 2016 as our inclusion criteria. Observational and interventional studies suggest that the composition of intestinal microbiome is altered due to smoking. In these studies, Proteobacteria and Bacteroidetes phyla were increased, as well as the genera of Clostridium, Bacteroides and Prevotella. On the other hand, Actinobacteria and Firmicutes phyla as well as the genera Bifidobacteria and Lactococcus were decreased. Smoking also decreased the diversity of the intestinal microbiome. Mechanisms that have been suggested to explain the effect of smoking on intestinal microbiome include: oxidative stress enhancement, alterations of intestinal tight junctions and intestinal mucin composition, and changes in acid base balance. Interestingly, some smoking-induced alterations of intestinal microbiome resemble those demonstrated in conditions such as inflammatory bowel disease and obesity. Further studies should be performed to investigate this connection. Smoking has an effect on intestinal microbiome and is suggested to alter its composition. This interaction may contribute to the development of intestinal and systemic diseases, particularly inflammatory bowel diseases. PMID- 29626220 TI - Metabolomics insights into early type 2 diabetes pathogenesis and detection in individuals with normal fasting glucose. AB - AIMS/HYPOTHESIS: Identifying the metabolite profile of individuals with normal fasting glucose (NFG [<5.55 mmol/l]) who progressed to type 2 diabetes may give novel insights into early type 2 diabetes disease interception and detection. METHODS: We conducted a population-based prospective study among 1150 Framingham Heart Study Offspring cohort participants, age 40-65 years, with NFG. Plasma metabolites were profiled by LC-MS/MS. Penalised regression models were used to select measured metabolites for type 2 diabetes incidence classification (training dataset) and to internally validate the discriminatory capability of selected metabolites beyond conventional type 2 diabetes risk factors (testing dataset). RESULTS: Over a follow-up period of 20 years, 95 individuals with NFG developed type 2 diabetes. Nineteen metabolites were selected repeatedly in the training dataset for type 2 diabetes incidence classification and were found to improve type 2 diabetes risk prediction beyond conventional type 2 diabetes risk factors (AUC was 0.81 for risk factors vs 0.90 for risk factors + metabolites, p = 1.1 * 10-4). Using pathway enrichment analysis, the nitrogen metabolism pathway, which includes three prioritised metabolites (glycine, taurine and phenylalanine), was significantly enriched for association with type 2 diabetes risk at the false discovery rate of 5% (p = 0.047). In adjusted Cox proportional hazard models, the type 2 diabetes risk per 1 SD increase in glycine, taurine and phenylalanine was 0.65 (95% CI 0.54, 0.78), 0.73 (95% CI 0.59, 0.9) and 1.35 (95% CI 1.11, 1.65), respectively. Mendelian randomisation demonstrated a similar relationship for type 2 diabetes risk per 1 SD genetically increased glycine (OR 0.89 [95% CI 0.8, 0.99]) and phenylalanine (OR 1.6 [95% CI 1.08, 2.4]). CONCLUSIONS/INTERPRETATION: In individuals with NFG, information from a discrete set of 19 metabolites improved prediction of type 2 diabetes beyond conventional risk factors. In addition, the nitrogen metabolism pathway and its components emerged as a potential effector of earliest stages of type 2 diabetes pathophysiology. PMID- 29626221 TI - Marker-free genetic manipulations in yeast using CRISPR/CAS9 system. AB - The budding yeast is currently one of the major model organisms for the study of a wide variety of biological processes. Genetic manipulation of yeast involves the extensive usage of selectable markers that can lead to undesired effects. Thus, marker-free genetic manipulation in yeast is highly desirable for gene/promoter replacement and various other applications. Here we combine the power of selectable markers followed by CRISPR/CAS9 genome editing for common genetic manipulations in yeast in a marker-free manner. We demonstrate our approach for whole gene and promoter replacements and for high-efficiency operator array integration. Our approach allows the utilization of many thousands of existing strains including library strains for the generation of significant genetic changes in yeast in a marker-free and cloning-free fashion. PMID- 29626222 TI - Measuring hand grip strength in rheumatoid arthritis. AB - Rheumatoid arthritis (RA) is a systemic inflammatory disease with a particular predilection for causing pain, deformity and functional limitation affecting the hands. Measures of the severity of RA, such as the disease activity score with 28 joint count may not fully reflect the regional impact of RA on the hands. Hand grip strength measurements are a form of objective assessment that focuses specifically on the hands in RA. This review explores what is currently known about the assessment of hand grip strength; what it may indicate, how it is measured, some of the practical aspects and challenges associated with performing these tests, and how this information can be applied in a clinical setting. It summarises the role that grip strength has in assessing patients with RA and finishes with some recommendations for how to use grip strength measurements in clinical practice, and what direction future research might take. PMID- 29626223 TI - Effect of temperature and vector nutrition on the development and multiplication of Trypanosoma rangeli in Rhodnius prolixus. AB - Trypanosoma rangeli is a protozoan parasite that infects mammals and triatomines, causing different levels of pathogenicity in its invertebrate vectors, particularly those from the genus Rhodnius. We have recently shown that temperature can modulate T. rangeli growth during in vitro culture, as well as its in vivo pathogenicity to R. prolixus. In the present study, we investigated colonization of R. prolixus by T. rangeli and assessed the role of temperature and vector nutrition on parasite development and multiplication. We infected nymphs and either assessed parasite density in the first hours after the ingestion of the infected blood or maintained the nymphs for up to 60 days at different temperatures (21, 24, 27, and 30 degrees C) and under different blood feeding schedules (either every 15 days, or on day 30 post infection only), with parasite development and multiplication measured on days 15, 30, and 60 post infection. In the first hours after ingesting infected blood, epimastigogenesis not only occurred in the anterior midgut, but a stable parasite population also established in this intestinal region. T. rangeli subsequently colonized all intestinal regions examined, but with fewer parasites being found in the rectum. The number of parasites was only affected by higher temperatures (27 and 30 degrees C) during the beginning of the infection (15 days post infection). Nutritional status of the vector also had a significant effect on parasite development, as reduced blood-feeding decreased infection rates by approximately 30%. PMID- 29626224 TI - Who Wants to Save the Forest? Characterizing Community-Led Monitoring in Prey Lang, Cambodia. AB - Community monitoring is believed to be successful only where there is sustained funding, legislation for communities to enforce rules, clear tenure rights, and an enabling environment created by the state. Against this backdrop, we present the case of an autonomous grassroots-monitoring network that took the initiative to protect their forest, in a context, where no external incentives and rule enforcement power were provided. The aim was to analyze the socio-demographic and economic backgrounds, motivations and achievements of forest monitors, compared to non-monitors in the same communities. A total of 137 interviews were conducted in four villages bordering Prey Lang forest in Cambodia. We used binary logit models to identify the factors that influenced the likelihood of being a monitor. Results show that there were few (22%, n = 30) active monitors. Active monitors were intrinsically motivated forest-users, and not specifically associated with a particular gender, ethnicity, or residence-time in that area. The most common interventions were with illegal loggers, and the monitors had a general feeling of success in stopping the illegal activities. Most (73%, n = 22) of them had been threatened by higher authorities and loggers. Our results show that despite the lack of power to enforce rules, absence of external funding and land ownership rights, and enduring threats of violence and conflicts, autonomous community monitoring may take place when community members are sufficiently motivated by the risk of losing their resources. PMID- 29626225 TI - Symptoms in individuals with adult-onset ADHD are masked during childhood. PMID- 29626226 TI - Transcranial direct current stimulation (tDCS) for treatment of phobic postural vertigo: an open label pilot study. PMID- 29626229 TI - Left ventricular hypertrabeculation/noncompaction, cardiac phenotype, and neuromuscular disorders. AB - BACKGROUND: The prognosis of patients with left ventricular hypertrabeculation/noncompaction (LVHT) and its association with neuromuscular disorders (NMDs) is a controversial topic. The aim of this study was to assess whether the prognosis of LVHT patients is dependent on cardiac phenotype and the presence of NMDs. METHODS: Consecutive patients who were diagnosed with LVHT between 1995 and 2016 were included in the study. Cardiac phenotype was classified according to the recommendations of the European Society of Cardiology as: "dilated" if the left ventricular end-diastolic diameter (LVEDD) was >57 mm and left ventricular fractional shortening (FS) was <=25%; "hypertrophic" if LVEDD was <=57 mm, FS > 25%, and left ventricular posterior wall (LVPWT) and interventricular septal thickness (IVST) were both >13 mm; "intermediate" if LVEDD was >57 mm and FS > 25% or if LVEDD was <=57 mm and FS <= 25%; and "normal" if LVEDD was <=57 mm, FS > 25%, and IVST and LVPWT <= 13 mm. Therapy was carried out by the treating physicians. RESULTS: LVHT was diagnosed in 273 patients (80 females, 53 +/- 16 years). The phenotype was assessed as dilated in 46%, hypertrophic in 8%, intermediate in 17%, and normal in 29% of the patients. Of these patients, 72% underwent neurological examinations, and an NMD was found in 76%. Over a period of 7.4 years (+/-5.7), 84 patients died and six underwent cardiac transplantation. The highest mortality rate was observed in the dilated and the lowest in the hypertrophic cardiac phenotype groups. Among the dilated phenotype, mortality was higher in patients with than without NMDs. CONCLUSION: Patients with LVHT and dilated cardiac phenotype have a worse prognosis than patients with a hypertrophic or intermediate/normal cardiac phenotype, especially if they suffer from NMDs. PMID- 29626228 TI - Venous beading in two or more quadrants might not be a sensitive grading criterion for severe nonproliferative diabetic retinopathy. AB - PURPOSE: To determine whether venous beading (VB) in two or more quadrants is an appropriate grading criterion for severe nonproliferative diabetic retinopathy (NPDR). METHODS: A hospital-based, retrospective, cross-sectional study. A total of 806 patients admitted with diabetic retinopathy (DR) from January 2014 to April 2017 were included in this study. DR severity was graded by the international grading criterion. The status of VB, intraretinal microvascular abnormalities (IRMA), capillary nonperfusion, arteriovenous nicking, and diabetic macular edema was evaluated based on fundus fluorescein angiography. RESULTS: The prevalence of VB in eyes with proliferative diabetic retinopathy (PDR), severe NPDR, and moderate NPDR was 41.3% (327/791), 5.9% (31/526), and 0% (0/295), respectively (p < 0.001). Moreover, the proportion of VB in two or more quadrants was even lower (27.1% for PDR and 2.1% for severe NPDR, p < 0.001), and among the total of 225 eyes with VB in two or more quadrants, 214 eyes (95.1%) were graded as PDR. Furthermore, VB formation was significantly correlated with capillary nonperfusion, duration of diabetes (both p < 0.001), and smoking (p < 0.05). After adjusting for age, sex, and other possible factors, VB (OR = 7.479, p < 0.001) and IRMA (OR = 2.433, p < 0.001) were determined as independent risk factors for developing PDR. CONCLUSIONS: Our study suggested that VB in two or more quadrants might not be a sensitive grading criterion for severe NPDR among a Chinese population with type 2 diabetes. Nevertheless, VB has a great specificity to define an advanced form of DR. PMID- 29626230 TI - Multiple filters affect tree species assembly in mid-latitude forest communities. AB - Species assembly patterns of local communities are shaped by the balance between multiple abiotic/biotic filters and dispersal that both select individuals from species pools at the regional scale. Knowledge regarding functional assembly can provide insight into the relative importance of the deterministic and stochastic processes that shape species assembly. We evaluated the hierarchical roles of the alpha niche and beta niches by analyzing the influence of environmental filtering relative to functional traits on geographical patterns of tree species assembly in mid-latitude forests. Using forest plot datasets, we examined the alpha niche traits (leaf and wood traits) and beta niche properties (cold/drought tolerance) of tree species, and tested non-randomness (clustering/over-dispersion) of trait assembly based on null models that assumed two types of species pools related to biogeographical regions. For most plots, species assembly patterns fell within the range of random expectation. However, particularly for cold/drought tolerance related beta niche properties, deviation from randomness was frequently found; non-random clustering was predominant in higher latitudes with harsh climates. Our findings demonstrate that both randomness and non-randomness in trait assembly emerged as a result of the alpha and beta niches, although we suggest the potential role of dispersal processes and/or species equalization through trait similarities in generating the prevalence of randomness. Clustering of beta niche traits along latitudinal climatic gradients provides clear evidence of species sorting by filtering particular traits. Our results reveal that multiple filters through functional niches and stochastic processes jointly shape geographical patterns of species assembly across mid-latitude forests. PMID- 29626227 TI - Effect of internal contamination with tritiated water on the neoplastic colonies in the lungs, innate anti-tumour reactions, cytokine profile, and haematopoietic system in radioresistant and radiosensitive mice. AB - Tritium is a potentially significant source of internal radiation exposure which, at high levels, can be carcinogenic. We evaluated whether single intraperitoneal injection of BALB/c and C57BL/6 mice with tritiated water (HTO) leading to exposure to low (0.01 or 0.1 Gy) and intermediate (1.0 Gy) cumulative whole-body doses of beta radiation is immunosuppressive, as judged by enhancement of artificial tumour metastases, functioning of NK lymphocytes and macrophages, circulating cytokine's levels, and numbers of bone marrow, spleen, and peripheral blood cells. We demonstrate that internal contamination of radiosensitive BALB/c and radioresistant C57BL/6 mice with HTO at all the absorbed doses tested did not affect the development of neoplastic colonies in the lungs caused by intravenous injection of syngeneic cancer cells. However, internal exposure of BALB/c and C57BL/6 mice to 0.1 and 0.01 Gy of beta radiation, respectively, up-regulated cytotoxic activity of and IFN-gamma synthesis in NK lymphocytes and boosted macrophage secretion of nitric oxide. Internal contamination with HTO did not affect the serum levels of pro- (IL-1beta, IL-2, IL-6, TNF-alpha,) and anti inflammatory (IL-1Ra, IL-4, IL-10) cytokines. In addition, exposure of mice of both strains to low and intermediate doses from the tritium-emitted beta particles did not result in any significant changes in the numbers of bone marrow, spleen, and peripheral blood cells. Overall, our data indicate that internal tritium contamination of both radiosensitive and radioresistant mice leading to low and intermediate absorbed beta-radiation doses is not immunosuppressive but may enhance some but not all components of anticancer immunity. PMID- 29626231 TI - The effect of Guarana (Paullinia cupana) on metabolic and inflammatory parameters in adult male mice programmed by maternal obesity. AB - PURPOSE: Maternal obesity can program the offspring, increasing the risk of overweight and obesity in adult life. Guarana (Paullinia cupana) is a Brazilian plant that has weight-reducing effects. Thus, this study aimed to evaluate the effects of Guarana on metabolic and inflammatory parameters in mice programmed by maternal obesity. METHODS: Swiss female mice were divided into two groups: control and high fat (HF), who received a standard diet or a high-fat diet (HFD), respectively, for 8 weeks prior to mating, gestation, and lactation. After post natal day (PN) 21, the offspring of the HF group were subdivided into three groups: HF without treatment; HF early treatment, offspring treated with Guarana (1 g/kg bodyweight) in PN25-PN30; HF late treatment, offspring treated with Guarana (1 g/kg bodyweight) in PN65-PN75. Basal energy expenditure, the lipid profile and fasting glucose levels were determined. Body composition was evaluated by dissecting adipose tissue depots. Gene expression was analyzed using real-time PCR. RESULTS: During mating, the weight of HF females increased; after lactation, their adipose tissue depots and fasting glycemic levels also increased. The offspring of the HF group showed an increased body weight at PN21. At PN80, in the mice treated with Guarana (with both treatments), VO2 and energy expenditure increased, adipose tissue depots decreased, and the expression of leptin, IL-6, TNF-alpha, and MCP-1 decreased compared with that in the HF group. CONCLUSIONS: Guarana treatment at both stages of life reversed some of the alterations developed by the offspring of HF animals in adult life. PMID- 29626232 TI - A pre-meal of whey proteins induces differential effects on glucose and lipid metabolism in subjects with the metabolic syndrome: a randomised cross-over trial. AB - PURPOSE: Postprandial lipaemia (PPL), an independent risk factor for cardiovascular disease, is affected by composition and timing of meals. We evaluated if whey proteins (WP) consumed as a pre-meal before a fat-rich meal reduce postprandial triglyceride (TG) and apolipoprotein B-48 (ApoB-48) responses in subjects with the metabolic syndrome (MeS). METHODS: An acute, randomised, cross-over trial was conducted. 20 subjects with MeS consumed a pre-meal of 0, 10 or 20 g WP 15 min prior to a fat-rich meal. The responses of TG and ApoB-48 were assessed. We also analysed postprandial responses of free fatty acids (FFA), glucose, insulin, glucagon, glucagon-like peptide 1 (GLP-1), glucose-dependent insulinotropic peptide (GIP) and paracetamol (reflecting gastric emptying rates). RESULTS: WP pre-meal did not alter the TG or ApoB-48 responses. In contrast, the insulin response was more pronounced after a pre-meal of 20 g WP than with 10 g WP (P = 0.0005) and placebo (P < 0.0001). Likewise, the postprandial glucagon response was greater with a pre-meal of 20 g WP than with 10 g WP (P < 0.0001) and 0 g WP (P < 0.0001). A pre-meal with 20 g of WP generated lower glucose (P = 0.0148) and S-paracetamol responses (P = 0.0003) and a higher GLP-1 response (P = 0.0086) than placebo. However, the pre-meal did not influence responses of GIP, FFA or appetite assessed by a Visual Analog Scale. CONCLUSIONS: Consumption of a WP pre-meal prior to a fat-rich meal did not affect TG and chylomicron responses. In contrast, the WP pre-meal stimulates insulin and glucagon secretion and reduces blood glucose as expected, and delays gastric emptying. Consequently, our study points to a differential impact of a WP pre-meal on lipid and glucose metabolism to a fat-rich meal in subjects with MeS. PMID- 29626233 TI - The effect of intrauterine human chorionic gonadotropin flushing on live birth rate after vitrified-warmed embryo transfer in programmed cycles: a randomized clinical trial. AB - PURPOSE: To assess the influence of intrauterine human chorionic gonadotropin (hCG) before embryo transfer on the clinical pregnancy and live birth rates after vitrified-warmed embryo transfer (ET) in programmed cycles. METHODS: This study was a single-blind randomized clinical trial for eligible patients underwent frozen ET cycles with long-term hormonal GnRH agonist protocol for endometrial preparation. Immediately prior to ET, the women were randomly divided into three groups. In the experimental group, 7-10 min before embryo transfer, 500 IU of hCG with a 40 MUL of culture medium was injected into the uterus. In the first control (sham) group, 7-10 min before ET just 40 MUL of culture medium intrauterine was infused. In the second control group, no intervention was done. The pregnancy outcomes were compared in the three groups using appropriate statistical tests. RESULTS: Finally, 180 patients allocated into three groups. There was no significant difference in terms of patients 'characteristics among three groups. No significant difference was found in terms of clinical pregnancy among three groups. The miscarriage rate in control group (0%) was significantly lower than those of in the sham and hCG groups (9.8% and P = 0.01, 6.6% and P = 0.04, respectively). In addition, live birth rate (39.3%) in control group was significantly higher than those of in the sham and hCG groups (16.4% and P = 0.005, 23% and P = 0.051, respectively). CONCLUSION(S): It was found that intrauterine injection of 500 IU hCG before vitrified-warmed ET at cleavage stage has no beneficial effect on pregnancy outcome and is not suggested. NCT02355925. PMID- 29626234 TI - ? PMID- 29626236 TI - Prospective study of comminuted articular distal radius fractures stabilized by volar plating in the elderly. AB - PURPOSE: The objective was to assess the ability of the volar locking plate to maintain the radiographic parameters over the time in elderly patients with complex intra-articular distal radius fractures. METHODS: Prospective cohort of 66 consecutive patients with mean age of 68 (range 60-81) years and AO type C fractures treated with volar locking plate. Radiographic measurements were performed pre and post-operatively at each follow-up. Clinical assessment was made by Patient-Rated Wrist Evaluation scores, Disabilities of the Arm, Shoulder and Hand score, range of motion, and grip strength. RESULTS: The mean post operative follow-up was 31 (range, 24-47) months. The most difficult parameters to restore intra-operatively were volar tilt and radial height, while radial inclination and ulnar variance were restored in a high rate of patients. There was significant loss of reduction within four post-operative months in volar tilt (p = 0.001) and radial height (p = 0.029). Mean radiographic parameters had no changes from four months to final evaluation. At final follow-up, 50.1% of the patients had all radiographic parameters restored in comparison with the noninvolved wrist, but 83.3% had all radiographic parameters within a functional range (p = 0.001). No significant relationship between radiographic and functional outcomes was found (p = 0.474). CONCLUSIONS: This study found that volar locking plate fixation for displaced intra-articular distal radius fractures in elderly patients was an effective procedure to obtain success functional outcomes. Although reduction loss in volar tilt and radial height occurred within four first months, volar plate was able to maintain fracture stabilization with radiographic parameters within functional range over the time in most patients of these elderly patients. PMID- 29626235 TI - The CRISPR/Cas9 system sheds new lights on the biology of protozoan parasites. AB - The CRISPR/Cas9 system, a natural defence system of bacterial organisms, has recently been used to modify genomes of the most important protozoa parasites. Successful genome manipulations with the CRISPR/Cas9 system are changing the present view of genetics in parasitology. The application of this system offers a major chance to overcome the current restriction in culturing, maintaining and analysing protozoan parasites, and allows dynamic analysis of parasite genes functions, leading to a better understanding of pathogenesis. CRISPR/Cas9 system will have a significant influence on the process of developing novel drugs and treatment strategies against protozoa parasites. PMID- 29626237 TI - The utility of outpatient commitment: acute medical care access and protecting health. AB - OBJECTIVES: This study considers whether, in an easy access single-payer health care system, patients placed on outpatient commitment-community treatment orders (CTOs) in Victoria Australia-are more likely to access acute medical care addressing physical illness than voluntary patients with and without severe mental illness. METHOD: For years 2000 to 2010, the study compared acute medical care access of 27,585 severely mentally ill psychiatrically hospitalized patients (11,424 with and 16,161 without CTO exposure) and 12,229 never psychiatrically hospitalized outpatients (individuals with less morbidity risk as they were not considered to have severe mental illness). Logistic regression was used to determine the influence of the CTO on the likelihood of receiving a diagnosis of physical illness requiring acute care. RESULTS: Validating their shared and elevated morbidity risk, 53% of each hospitalized cohort accessed acute care compared to 32% of outpatients during the decade. While not under mental health system supervision, however, the likelihood that a CTO patient would receive a physical illness diagnosis was 31% lower than for non-CTO patients, and no different from lower morbidity-risk outpatients without severe mental illness. While, under mental health system supervision, the likelihood that CTO patients would receive a physical illness diagnosis was 40% greater than non-CTO patients and 5.02 times more likely than outpatients were. Each CTO episode was associated with a 4.6% increase in the likelihood of a member of the CTO group receiving a diagnosis. CONCLUSION: Mental health system involvement and CTO supervision appeared to facilitate access to physical health care in acute care settings for patients with severe mental illness, a group that has, in the past, been subject to excess morbidity and mortality. PMID- 29626238 TI - Primary central nervous system lymphoma and atypical glioblastoma: Differentiation using radiomics approach. AB - OBJECTIVES: To evaluate the diagnostic performance of magnetic resonance (MR) radiomics-based machine-learning algorithms in differentiating primary central nervous system lymphoma (PCNSL) from non-necrotic atypical glioblastoma (GBM). METHODS: Seventy-seven patients (54 individuals with PCNSL and 23 with non necrotic atypical GBM), diagnosed from January 2009 to April 2017, were enrolled in this retrospective study. A total of 6,366 radiomics features, including shape, volume, first-order, texture, and wavelet-transformed features, were extracted from multi-parametric (post-contrast T1- and T2-weighted, and fluid attenuation inversion recovery images) and multiregional (enhanced and non enhanced) tumour volumes. These features were subjected to recursive feature elimination and random forest (RF) analysis with nested cross-validation. The diagnostic abilities of a radiomics machine-learning classifier, apparent diffusion coefficient (ADC), and three readers, who independently classified the tumours based on conventional MR sequences, were evaluated using receiver operating characteristic (ROC) analysis. Areas under the ROC curves (AUC) of the radiomics classifier, ADC value, and the radiologists were compared. RESULTS: The mean AUC of the radiomics classifier was 0.921 (95 % CI 0.825-0.990). The AUCs of the three readers and ADC were 0.707 (95 % CI 0.622-0.793), 0.759 (95 %CI 0.656 0.861), 0.695 (95 % CI 0.590-0.800) and 0.684 (95 % CI0.560-0.809), respectively. The AUC of the radiomics-based classifier was significantly higher than those of the three readers and ADC (p< 0.001 for all). CONCLUSIONS: Large-scale radiomics with a machine-learning algorithm can be useful for differentiating PCNSL from atypical GBM, and yields a better diagnostic performance than human radiologists and ADC values. KEY POINTS: * Machine-learning algorithm radiomics can help to differentiate primary central PCNSL from GBM. * This approach yields a higher diagnostic accuracy than visual analysis by radiologists. * Radiomics can strengthen radiologists' diagnostic decisions whenever conventional MRI sequences are available. PMID- 29626239 TI - High spatial resolution free-breathing 3D late gadolinium enhancement cardiac magnetic resonance imaging in ischaemic and non-ischaemic cardiomyopathy: quantitative assessment of scar mass and image quality. AB - PURPOSE: To compare breath-hold (BH) with navigated free-breathing (FB) 3D late gadolinium enhancement cardiac MRI (LGE-CMR) MATERIALS AND METHODS: Fifty-one patients were retrospectively included (34 ischaemic cardiomyopathy, 14 non ischaemic cardiomyopathy, three discarded). BH and FB 3D phase sensitive inversion recovery sequences were performed at 3T. FB datasets were reformatted into normal resolution (FB-NR, 1.46x1.46x10mm) and high resolution (FB-HR, isotropic 0.91-mm voxels). Scar mass, scar edge sharpness (SES), SNR and CNR were compared using paired-samples t-test, Pearson correlation and Bland-Altman analysis. RESULTS: Scar mass was similar in BH and FB-NR (mean +/- SD: 15.5+/ 18.0 g vs. 15.5+/-16.9 g, p=0.997), with good correlation (r=0.953), and no bias (mean difference +/- SD: 0.00+/-5.47 g). FB-NR significantly overestimated scar mass compared with FB-HR (15.5+/-16.9 g vs 14.4+/-15.6 g; p=0.007). FB-NR and FB HR correlated well (r=0.988), but Bland-Altman demonstrated systematic bias (1.15+/-2.84 g). SES was similar in BH and FB-NR (p=0.947), but significantly higher in FB-HR than FB-NR (p<0.01). SNR and CNR were lower in BH than FB-NR (p<0.01), and lower in FB-HR than FB-NR (p<0.01). CONCLUSION: Navigated free breathing 3D LGE-CMR allows reliable scar mass quantification comparable to breath-hold. During free-breathing, spatial resolution can be increased resulting in improved sharpness and reduced scar mass. KEY POINTS: * Navigated free breathing 3D late gadolinium enhancement is reliable for myocardial scar quantification. * High-resolution 3D late gadolinium enhancement increases scar sharpness * Ischaemic and non-ischaemic cardiomyopathy patients can be imaged using free-breathing LGE CMR. PMID- 29626241 TI - Infectious disease risks in pediatric renal transplantation. AB - Renal transplantation is a vital treatment option in children with ESRD with more than 10,000 pediatric kidney transplants and survival rates of greater than 80% at 10 years post-transplant in the USA alone. Despite these advances, infection remains a significant cause of morbidity in pediatric recipients. Screening potential organ donors and recipients is imperative to identify and mitigate infectious risks in the transplant patient. Despite the unique risks of each patient, the timing of many infections post-transplant is predictable. In early post-transplant infections (within 30 days), bacterial and fungal pathogens predominate with donor-derived events and nosocomial infections. In the intermediate period (31-180 days after transplant), latent infections from donor organs, such as EBV and CMV, develop. Late infections occurring > 180 days after the transplant can be due to latent pathogens or community-acquired organisms. Approaching an infectious evaluation in a pediatric kidney recipient requires finesse to diagnose and treat this vulnerable population in a timely manner. The following article highlights the most relevant and common infections including clinical manifestations, risk factors, diagnostic techniques, and treatment options. PMID- 29626240 TI - Mammographic density changes following discontinuation of tamoxifen in premenopausal women with oestrogen receptor-positive breast cancer. AB - OBJECTIVES: To evaluate the changes in mammographic density after tamoxifen discontinuation in premenopausal women with oestrogen receptor-positive breast cancers and the underlying factors METHODS: A total of 213 consecutive premenopausal women with breast cancer who received tamoxifen treatment after curative surgery and underwent three mammograms (baseline, after tamoxifen treatment, after tamoxifen discontinuation) were included. Changes in mammographic density after tamoxifen discontinuation were assessed qualitatively (decrease, no change, or increase) by two readers and measured quantitatively by semi-automated software. The association between % density change and clinicopathological factors was evaluated using univariate and multivariate regression analyses. RESULTS: After tamoxifen discontinuation, a mammographic density increase was observed in 31.9% (68/213, reader 1) to 22.1% (47/213, reader 2) by qualitative assessment, with a mean density increase of 1.8% by quantitative assessment compared to density before tamoxifen discontinuation. In multivariate analysis, younger age (<= 39 years) and greater % density decline after tamoxifen treatment (>= 17.0%) were independent factors associated with density change after tamoxifen discontinuation (p < .001 and p = .003, respectively). CONCLUSIONS: Tamoxifen discontinuation was associated with mammographic density change with a mean density increase of 1.8%, which was associated with younger age and greater density change after tamoxifen treatment. KEY POINTS: * Increased mammographic density after tamoxifen discontinuation can occur in premenopausal women. * Mean density increase after tamoxifen discontinuation was 1.8%. * Density increase is associated with age and density decrease after tamoxifen. PMID- 29626242 TI - Incidence of kidney stone disease in Icelandic children and adolescents from 1985 to 2013: results of a nationwide study. AB - BACKGROUND: An increase in the incidence of kidney stone disease has been reported for all age groups worldwide. To examine this trend, we conducted a nationwide study of the epidemiology of kidney stones in Icelandic children and adolescents over a 30-year period. METHODS: Computerized databases of all major hospitals and medical imaging centers in Iceland were searched for International Classification of Diseases and radiologic and surgical procedure codes indicative of kidney stones in patients aged < 18 years, followed by a thorough medical record review. Age-adjusted incidence was calculated for the time intervals 1985 1989, 1990-1994, 1995-1999, 2000-2004, 2005-2009, and 2010-2013. Time trends in stone incidence were assessed by Poisson regression. The prevalence of stone disease for the years 1999-2013 was also determined. RESULTS: Almost all the 190 patients (97%) that we identified had symptomatic stones, and acute flank or abdominal pain and hematuria were the most common presenting features. The total annual incidence of kidney stones increased from 3.7/100,000 in the first 5-year interval to 11.0/100,000 during the years 1995-2004 (p < 0.001) and decreased thereafter to 8.7/100,000 in 2010-2013 (p = 0.63). The incidence rise was highest in girls aged 13-17 years, in whom it rose from 9.8/100,000 in 1985-1989 to 39.2/100,000 in 2010-2013 (p < 0.001), resulting in an overall female predominance in this age group. The mean annual prevalence of stone disease in 1999-2013 was 48/100,000 for boys and 52/100,000 for girls. CONCLUSION: We found a significant increase in the incidence of childhood kidney stone disease, driven by a dramatic increase of stone frequency in teenage females which is poorly understood and warrants further study. PMID- 29626243 TI - Postnatal imaging of prenatally detected hydronephrosis-when is voiding cystourethrogram necessary? AB - OBJECTIVE: To evaluate whether grade 4-5 vesicoureteral reflux (VUR) can be predicted from renal ultrasound (RUS) findings and perform voiding cystourethrograms (VCUGs) only on high-risk patients. METHODS: The RUS and VCUG images of infants with prenatally detected hydronephrosis admitted to our institution between 2003 and 2013 were re-evaluated. The UTI episodes were collected retrospectively from patient journals. Patients with complex urinary tract anomalies were excluded. RESULTS: One hundred eighty, 44 female and 136 male, patients (352 renal units (RU)), 23 (30 RU) of them having grade 4-5 VUR, were included. The median age of the patients at the time of the RUS was 1.3 (0.1 3.0) months and the median follow-up time was 2.0 (0.1-11.2) years. In multivariate analysis, a visible ureter (OR 12.72; CI 5.33-32.04, p < 0.001) and shorter renal length (OR 2.67; CR 1.50-4.86, p < 0.001) in RUS predicted grade 4 5 VUR while a visible ureter predicted UTIs (OR 5.75; CI 2.59-12.66, p < 0.001). A three-grade risk score for high-grade VUR was developed based on the RUS findings and the patients were categorized into low-, intermediate-, and high risk groups. The incidence of grade 4-5 VUR was 2.9% in the low-risk, 12.2% in the intermediate-risk, and 52.2% in the high-risk group. The sensitivity and specificity for detecting grade 4-5 VUR were 79 and 82%, respectively. CONCLUSIONS: In patients with antenatally detected hydronephrosis, a visible ureter and reduced renal length in RUS are significant risk factors for high grade VUR. A RUS-based risk scoring would probably reduce the proportion of unnecessary VCUGs. PMID- 29626244 TI - Weekend vs. weekday appendectomy for complicated appendicitis, effects on outcomes and operative approach. AB - PURPOSE: We hypothesized that laparoscopic (LA) or open appendectomy (OA) outcomes in complicated appendicitis are associated with weekend vs. weekday procedure date. METHODS: We queried the Kids' Inpatient Database (1997-2012) for complicated (540.0, 540.1) appendicitis treated with LA or OA. Propensity score (PS)-matched analysis compared outcomes associated with weekend vs. weekday LA and OA. RESULTS: Overall, 103,501 cases of complicated appendicitis were identified. On 1:1 PS-matched analyses of complicated appendicitis, weekday OA had increased wound infection rates (odds ratio: 1.3) vs. weekend OA, p < 0.001. Weekend OA had higher pneumonia rates (1.4) and longer length of stay, but lower home healthcare requirement following discharge vs. weekday OA, p < 0.05. Weekend and weekday LA had no significant outcome differences. CONCLUSION: On a PS matched comparison of appendectomies performed for complicated appendicitis on weekends and weekdays, procedure day is associated with different complication rates and resource utilization for OA. For LA, no weekend effect was noted for complicated appendicitis. To ensure the optimal patient care, prospective studies should be sought to identify causes of complications dependent on the day of procedure. PMID- 29626245 TI - A New Method for Surgical Abdominal Mass Closure After Abdominal Fascial Dehiscence Using Nasogastric Tube and Hemovac Perforator: A Case-Series Study. AB - BACKGROUND: As the challenge for finding the best abdominal incision closure technique continues, surgeons are aiming to minimize postoperative wound complications such as wound dehiscence and hernia as an acute or late manifestation. In order to achieve this goal, several abdominal opening and closure techniques have been tried. In this article, we describe a method in which we used a nasogastric tube (NGT) in mass closure for patients with fascial dehiscence. METHODS: In this case-series study, a total number of 25 patients participated. All of the patients had abdominal dehiscence after a surgery and had to undergo for another. An NGT was used for abdominal closure. The patients were followed for a month and were examined for any signs and symptoms of fever, infection, pain, material expenses, closing time, and laboratory data. The data were analyzed using SPSS software V.22. Mean +/- SD and frequencies were used for describing the variables. RESULTS: The mean NGT mass closure material expenses for each patient were 8400.00 +/- 0.00 IRR (around 0.25 US dollars). The mean closure time after the operation was 13.08 +/- 3.09 min. There was no evidence of infection among the patients as well as no other complications after the surgery in the 1-month study period. CONCLUSION: Abdominal mass closure with NG tube suturing technique is associated with reduced time required for closure of the incision, incidence of wound dehiscence, and the incidence of incisional hernia as well as infection, with a considerable low cost. PMID- 29626246 TI - Gallstone Pancreatitis and Choledocholithiasis: Using Imaging and Laboratory Trends to Predict the Likelihood of Persistent Stones at Cholangiography. AB - BACKGROUND: Patients with gallstone pancreatitis (GP) or choledocholithiasis (CDL) may have common bile duct (CBD) stones that persist until cholangiography. The aim of this study is to evaluate pre-cholangiogram factors that predict persistent CBD stones. METHODS: Multiple logistic regression analyses were performed to identify demographic, laboratory, and radiologic predictors of persistent CBD stones and non-therapeutic cholangiography among adults with GP or CDL. RESULTS: In 152 patients from 2010 to 2015, preoperative diagnosis, presence of a CBD stone on US, and age >= 60 years were associated with persistent CBD stones. Two risk factors alone had a PPV of 88% and the absence of all risk factors had a NPV of 94%. Age < 60 years and the absence of a CBD stone on US were most predictive of non-therapeutic cholangiography. CONCLUSION: Age, LFTs, and US help predict persistent CBD stones in patients initially presenting with GP or CDL and help minimize non-therapeutic preoperative cholangiography. PMID- 29626247 TI - Commentary on 'A Consensus-Based Criterion Standard for the Requirement of a Trauma Team:' Low-Resource Setting Considerations. PMID- 29626248 TI - A New Approach of Rpf Addition to Explore Bacterial Consortium for Enhanced Phenol Degradation Under High Salinity Conditions. AB - Only a small fraction of salt-tolerant phenol-degrading bacteria can be isolated by conventional plate separation methods, because most bacteria in nature are in a viable but non-culturable (VBNC) state. The aims of this study were to screen out more effective functional bacteria using resuscitation-promoting factor (Rpf), and to determine whether a mixed bacterial consortium possesses better phenol-degrading capabilities under high salinity conditions. The results indicated that three strains unique to treatment group with Rpf addition were obtained. A mixed bacterial consortium consisting of two high-efficient strains which belonged to genera Bacillus and Corynebacterium was capable of utilizing phenol as a sole source of carbon at high salinity. Complete degradation of 100 mg/L phenol at 2% NaCl concentration was achieved within 8 h. This study provides new insights into resuscitation of VBNC bacteria for enhanced treatment of phenol laden saline wastewater. PMID- 29626250 TI - Effect of voice therapy on vocal fold polyp treatment. AB - PURPOSE: To investigate the role of voice therapy (VT) and factors that may affect the response to VT in the treatment of vocal fold polyps, especially as a complement to phonosurgery. METHODS: Retrospective review of patients with vocal fold polyp undergoing surgery and/or VT in a tertiary medical center. The demographic data, phoniatric history, videolaryngostroboscopic findings, polyp characteristics, VHI-10 and GRB scores, and voice analysis data were recorded before and after the treatment. The patients were grouped as those who had undergone endolaryngeal microsurgery only (Group S), those who had first received VT then undergone surgery due to inadequate VT outcome (Group VTpS), and those who had only undergone VT with a follow-up plan (Group VT). RESULTS: Data were reviewed from 211 (108 M, 103 F) patients with a mean age of 41.3 +/- 11 years. The improvement in all voice-related variables observed in the S and VTpS groups was significantly greater compared to the VT group despite the degree of improvement achieved in this group. At the end of the treatment period, improvements in G-R-B, VHI-10 and stroboscopy scores were significantly greater in the VTpS group than in the S and VT groups. CONCLUSION: Voice therapy can improve voice quality to some extent during the treatment of vocal fold polyps. However, VT alone is unsatisfactory compared to surgery alone. Pre-surgical VT can enhance the ultimate success of treatment. A young age, small polyps, and short duration of dysphonia may increase the possibility of benefiting from VT. PMID- 29626251 TI - [Radiological imaging of inflammatory diseases of the gastrointestinal tract]. PMID- 29626249 TI - Molecular markers in well-differentiated thyroid cancer. AB - PURPOSE: Thyroid nodules are of common occurrence in the general population. About a fourth of these nodules are indeterminate on aspiration cytology placing many a patient at risk of unwanted surgery. The purpose of this review is to discuss various molecular markers described to date and place their role in proper perspective. This review covers the fundamental role of the signaling pathways and genetic changes involved in thyroid carcinogenesis. The current literature on the prognostic significance of these markers is also described. METHODS: PubMed was used to search relevant articles. The key terms "thyroid nodules", "thyroid cancer papillary", "carcinoma papillary follicular", "carcinoma papillary", "adenocarcinoma follicular" were searched in MeSH, and "molecular markers", "molecular testing", mutation, BRAF, RAS, RET/PTC, PAX 8, miRNA, NIFTP in title and abstract fields. Multiple combinations were done and a group of experts in the subject from the International Head and Neck Scientific Group extracted the relevant articles and formulated the review. RESULTS: There has been considerable progress in the understanding of thyroid carcinogenesis and the emergence of numerous molecular markers in the recent years with potential to be used in the diagnostic algorithm of these nodules. However, their precise role in routine clinical practice continues to be a contentious issue. Majority of the studies in this context are retrospective and impact of these mutations is not independent of other prognostic factors making the interpretation difficult. CONCLUSION: The prevalence of these mutations in thyroid nodule is high and it is a continuously evolving field. Clinicians should stay informed as recommendation on the use of these markers is expected to evolve. PMID- 29626253 TI - Interobserver variability in the H&E-based assessment of tumor budding in pT3/4 colon cancer: does it affect the prognostic relevance? AB - Tumor budding is a mostly accepted adverse prognostic factor in colorectal carcinoma. It is on the cusp of a widespread use after agreement was reached recently on uniform assessment criteria. We investigated whether the interobserver variability has a direct influence on the prognostic relevance in pT3/4 colon cancer in the background of different levels of experience of the investigators. In total, six investigators with different levels of experience evaluated tumor budding on H&E slides in 244 cases with primary diagnosed (2002 2011) colon carcinoma (pT3/4, N+/-, M0). High-grade tumor budding/budding grade 3 (defined as majority assessment among the investigators) was significantly associated with an adverse outcome (overall survival p = 0.03, cancer-specific survival p = 0.08) and the occurrence of distant metastasis (p = 0.009). However, a detailed analysis of the rating results of the individual investigators revealed that only ratings of one investigator (advanced resident) were associated with an adverse outcome (p = 0.01 cancer-specific survival, overall survival p = 0.09, distant metastasis p = 0.002). The results of another investigator (consultant) were significantly associated with distant metastasis (p = 0.007). The kappa values among the investigators have a range between 0.077 and 0.357 (median 0.166). Total agreement of all investigators existed in 109 cases (44.7%). Our results demonstrate that the evaluation of tumor budding on H&E slides in pT3/4 colon cancer goes along with a considerable interobserver variability among investigators of different levels of experience. Furthermore, our results reveal that these findings directly influence the prognostic value. PMID- 29626254 TI - CUL4B promotes the pathology of adjuvant-induced arthritis in rats through the canonical Wnt signaling. AB - : This work aims to discuss the possibility that disordered CUL4B was involved in the pathogenesis of adjuvant-induced arthritis (AIA) in rats. Synovium and FLS from AIA rats both showed increased CUL4B and beta-catenin, and up-regulated CUL4B enhanced the canonical Wnt signaling by targeting the GSK3beta. Increased CUL4B promoted the FLS abnormal proliferation, activated the secretion of IL 1beta and IL-8, and promoted the production of AIA pathology gene MMP3 and fibronectin. Furthermore, miR-101-3p was significantly down-regulated in AIA rats compared with controls, and transfection of AIA FLS with miR-101-3p mimics significantly down-regulated the CUL4B expression, whereas transfection with miR 101-3p inhibitors resulted in an opposite observation. The dual-luciferase reporter assay confirmed that the CUL4B was a direct target of miR-101-3p, and further analysis suggested that lowly expressed miR-101-3p contributed to disordered CUL4B activating the canonical Wnt signaling pathway and further promoting the development of AIA rats. Thus clarification of the CUL4B roles in the pathogenesis of AIA rats and corresponding mechanisms will contribute to the disease diagnosis and treatment for rheumatoid arthritis (RA) patients. KEY MESSAGES: CUL4B expression is up-regulated in synovium and FLS from AIA rats. Increased CUL4B promotes the canonical Wnt signaling. Increased CUL4B promotes the pathogenesis of AIA rats. Decreased miR-101-3p contributes to disordered CUL4B. PMID- 29626255 TI - The effect of geographical and climatic properties on grass pollen and Phl p 5 allergen release. AB - The Poaceae family, including grasses, comprises several cosmopolitan and allergenic species. The aim of this study was to determine the correlations between Poaceae pollen and Phl p 5 allergen concentrations in two cities with different geographical and climatic properties in Turkey. Pollen were collected from Burkard traps in Ankara and Zonguldak. Phl p 5 sampling was carried out between March and October in both 2015 and 2016 using a BGI900 Cascade High Volume Air Sampler (900 L/min.). The concentrations of Phl p 5 were measured by the enzyme-linked immunosorbent assay (ELISA) technique. The annual sum of Poaceae pollen (pollen index) during 2015-2016 was 5454 in Ankara and 4142 in Zonguldak. The total Phl p 5 concentration was 1309 pg/m3 in Zonguldak, whereas it was 8181 pg/m3 in Ankara over 2 years. About 90% of the allergen was found in the fraction with particulate matter (PM) > 10 MUm in both cities. It was found that the main meteorological parameter which affected pollen and Phl p 5 was temperature in both stations. Rainfall was also found to be important for Zonguldak, due to its climatic and geographic properties. Lastly, we suggest that the primary wind direction, which is from the south of Zonguldak, could have a 'drift effect' for allergens because of the airborne pollen concentrations and the dates on which the allergen is released into the atmosphere. The wind direction may be an important factor in the distribution of allergen and pollen grains in stations, especially those with a hilly topography. PMID- 29626256 TI - Dual-layer spectral detector CT: non-inferiority assessment compared to dual source dual-energy CT in discriminating uric acid from non-uric acid renal stones ex vivo. AB - PURPOSE: To assess the non-inferiority of dual-layer spectral detector CT (SDCT) compared to dual-source dual-energy CT (dsDECT) in discriminating uric acid (UA) from non-UA stones. METHODS: Fifty-seven extracted urinary calculi were placed in a cylindrical phantom in a water bath and scanned on a SDCT scanner (IQon, Philips Healthcare) and second- and third-generation dsDECT scanners (Somatom Flash and Force, Siemens Healthcare) under matched scan parameters. For SDCT data, conventional images and virtual monoenergetic reconstructions were created. A customized 3D growing region segmentation tool was used to segment each stone on a pixel-by-pixel basis for statistical analysis. Median virtual monoenergetic ratios (VMRs) of 40/200, 62/92, and 62/100 for each stone were recorded. For dsDECT data, dual-energy ratio (DER) for each stone was recorded from vendor specific postprocessing software (Syngo Via) using the Kidney Stones Application. The clinical reference standard of X-ray diffraction analysis was used to assess non-inferiority. Area under the receiver-operating characteristic curve (AUC) was used to assess diagnostic performance of detecting UA stones. RESULTS: Six pure UA, 47 pure calcium-based, 1 pure cystine, and 3 mixed struvite stones were scanned. All pure UA stones were correctly separated from non-UA stones using SDCT and dsDECT (AUC = 1). For UA stones, median VMR was 0.95-0.99 and DER 1.00 1.02. For non-UA stones, median VMR was 1.4-4.1 and DER 1.39-1.69. CONCLUSION: SDCT spectral reconstructions demonstrate similar performance to those of dsDECT in discriminating UA from non-UA stones in a phantom model. PMID- 29626257 TI - String sign of Kantor. PMID- 29626258 TI - MR elastography in primary sclerosing cholangitis: correlating liver stiffness with bile duct strictures and parenchymal changes. AB - AIM: To determine correlation of liver stiffness measured by MR Elastography (MRE) with biliary abnormalities on MR Cholangiopancreatography (MRCP) and MRI parenchymal features in patients with primary sclerosing cholangitis (PSC). METHODS: Fifty-five patients with PSC who underwent MRI of the liver with MRCP and MRE were retrospectively evaluated. Two board-certified abdominal radiologists in agreement reviewed the MRI, MRCP, and MRE images. The biliary tree was evaluated for stricture, dilatation, wall enhancement, and thickening at segmental duct, right main duct, left main duct, and common bile duct levels. Liver parenchyma features including signal intensity on T2W and DWI, and hyperenhancement in arterial, portal venous, and delayed phase were evaluated in nine Couinaud liver segments. Atrophy or hypertrophy of segments, cirrhotic morphology, varices, and splenomegaly were scored as present or absent. Regions of interest were placed in each of the nine segments on stiffness maps wherever available and liver stiffness (LS) was recorded. Mean segmental LS, right lobar (V-VIII), left lobar (I-III, and IVA, IVB), and global LS (average of all segments) were calculated. Spearman rank correlation analysis was performed for significant correlation. Features with significant correlation were then analyzed for significant differences in mean LS. Multiple regression analysis of MRI and MRCP features was performed for significant correlation with elevated LS. RESULTS: A total of 439/495 segments were evaluated and 56 segments not included in MRE slices were excluded for correlation analysis. Mean segmental LS correlated with the presence of strictures (r = 0.18, p < 0.001), T2W hyperintensity (r = 0.38, p < 0.001), DWI hyperintensity (r = 0.30, p < 0.001), and hyperenhancement of segment in all three phases. Mean LS of atrophic and hypertrophic segments were significantly higher than normal segments (7.07 +/- 3.6 and 6.67 +/- 3.26 vs. 5.1 +/- 3.6 kPa, p < 0.001). In multiple regression analysis, only the presence of segmental strictures (p < 0.001), T2W hyperintensity (p = 0.01), and segmental hypertrophy (p < 0.001) were significantly associated with elevated segmental LS. Only left ductal stricture correlated with left lobe LS (r = 0.41, p = 0.018). Global LS correlated significantly with CBD stricture (r = 0.31, p = 0.02), number of segmental strictures (r = 0.28, p = 0.04), splenomegaly (r = 0.56, p < 0.001), and varices (r = 0.58, p < 0.001). CONCLUSION: In PSC, there is low but positive correlation between segmental LS and segmental duct strictures. Segments with increased LS show T2 hyperintensity, DWI hyperintensity, and post-contrast hyperenhancement. Global liver stiffness shows a moderate correlation with number of segmental strictures and significantly correlates with spleen stiffness, splenomegaly, and varices. PMID- 29626259 TI - Hypoxia upregulates the expression of the pluripotency markers in the stem cells from human deciduous teeth. AB - OBJECTIVES: Cultivation under hypoxia promotes different responses in the mesenchymal stem cells and it has been producing promising results for clinical applications. Pulp tissue from deciduous teeth is a source of stem cells which has a high proliferative potential but this is usually discarded. This study has evaluated the effects of hypoxia on proliferation, apoptosis, and the expression of the pluripotency-related genes of the stem cells from human exfoliated deciduous teeth (SHED). MATERIALS AND METHODS: The cells were isolated from dental pulp (n = 5) and characterized as mesenchymal stem cells, in accordance with the International Society for Cell Therapy. The cells were cultivated under hypoxia (3% oxygen) and compared to the normoxia cells (21% oxygen). The proliferation rate was evaluated by the Ki67 antibody for up to 7 days, while the metabolic activity was measured by the wst-8 assay for up to 14 days. The apoptotic cells were analyzed by Annexin V and propidium iodide staining at 24 h and 4 and 7 days. The expression of the pluripotent genes (OCT4, SOX2, and NANOG) was quantified by qPCR after 24 h, or 7 days, when cultivated under hypoxia or normoxia. RESULTS: No differences in the metabolic activity, the proliferation rate, and the apoptosis of SHED when cultivated under hypoxia or normoxia (p > 0.05) were observed. The expression of the pluripotent genes was significantly higher after 24 h and 7 days of the cells that were exposed to hypoxia (p < 0.01). CONCLUSION: These findings have indicated an increase of the pluripotency related genes within 7 days as being the main advantage of SHED culture under hypoxia. CLINICAL RELEVANCE: Hypoxia culture may help maintain the quiescent state of the SHED, which could be advantageous for their future clinical applications. PMID- 29626260 TI - Clinical utility of pharmacogenetic testing in children and adolescents with severe mental disorders. AB - This is a retrospective cohort study of 20 children and adolescents to evaluate the clinical utility of a pharmacogenetic decision support tool. Twenty children and adolescents underwent pharmacogenetic testing between June 2014 and May 2017. All children and adolescents were evaluated at Puerta de Hierro University Hospital-Majadahonda (Madrid, Spain). We report the proportion of patients achieving clinical improvement, amelioration of side effects, and changes in number of drugs. Data normality was assessed with the Shapiro-Wilk test, and changes of pre- and post-pharmacogenetic testing were analyzed with the Wilcoxon test for paired samples. A two-sided p value threshold of 0.05 was considered for significance. Pharmacogenetic testing helped to improve the clinical outcome as measured by the Clinical Global Impressions (CGI) Scale in virtually all children (95%; 19 out of 20 children). The CGI improvement (CGI-I) was 2 (0.79) (range 1 4), 2.1 (0.56) (range 1-3), and 1.9 (0.99) (range 1-4) in foster and non-foster care children, respectively. Pharmacogenetic testing also helped to reduce the number of children using polypharmacy (from 65 to 45%), the mean number of drugs per children (from 3.3 to 2.4 drugs, p = 0.017), and self-reported relevant side effects (p = 0.006). Pharmacogenetic testing helped to improve the clinical outcome, and to reduce polypharmacy and the number of drugs used in children and adolescents with severe mental disorders. More evidence using robust (i.e., clinical trials) independent studies is required to properly determine the clinical utility and cost-effectiveness of pharmacogenetic testing tools in children and adolescents with mental disorders. PMID- 29626261 TI - Changes in Borg scale for resistance training and test of exercise tolerance in patients undergoing allogeneic hematopoietic stem cell transplantation. AB - PURPOSE: We aimed to investigate the relationship between Borg scale and intensity of resistance training in patients who had undergone allogeneic hematopoietic stem cell transplantation (allo-HSCT). Furthermore, the relationship between Borg scale, heart rate (HR), and intensity of exercise tolerance test was also studied. METHODS: The study included 28 patients (19 men and 9 women) who had undergone allo-HSCT between June 2015 and February 2017. Their knee extension strengths and exercise tolerances were evaluated. Patients were asked to grade between 0 and 10 on Borg scale based on the level of difficulty experienced during exercising, after 10 repetitions in randomized 20, 40, and 60% resistance training for knee extension. Additionally, we evaluated Borg scale, HR, and load intensity during exercise tolerance test, every minute of the exercise for 2 weeks before and 3 weeks after HSCT. RESULTS: Knee extension strength and exercise tolerance were significantly decreased 3 weeks after HSCT from those before HSCT (p < 0.01). Additionally, rise in Borg scale with increase in load intensity during knee extension resistance training, both before and after HSCT (p < 0.01), was noted. Furthermore, Borg scale was found to be associated with HR and load intensity during exercise tolerance test in patients both before and after HSCT (p < 0.01). CONCLUSIONS: A correlation was found between Borg scale with intensity of resistance training and exercise tolerance in patients who had undergone allo-HSCT. Therefore, Borg scale could be useful to determine the intensity of physical exercise in patients who have undergone allo-HSCT. PMID- 29626262 TI - Functional status of patients with metastatic spinal cord compression. AB - PURPOSE: This prospective study was conducted to evaluate the functional status and clinical features of inpatients with metastatic spinal cord compression and to explore possible associated factors and the correlation with neurological deficits. METHODS: Cases were identified through an active search in the hospital units of the National Cancer Institute. For 47 patients, clinical and demographic characteristics were collected; functional status was measured by the Functional Independence Measure; modified Tokuhashi score was used to predict survival time; neurological deficits were measured using the American Spinal Injury Association Impairment Scale; and general condition was evaluated using the Karnofsky Performance Status Scale. The correlation between the level of neurological deficits and functional status was calculated using the Spearman correlation test. The difference in the functional independence score according to neurological status was assessed with the Kruskall-Wallis test. RESULTS: The degree of functional status was associated with Karnofsky Performance Status, level of neurological deficits, ability to walk, survival time, and skin color (p < 0.05). There was difference in the functional status (p = 0.004) and in the motor domain (p = 0.001) according to the level of neurological deficits. The correlation of the Functional Independence Measure with level of neurological deficits and with Karnofsky Performance Status was moderate (r = 0.46, p < 0.02). CONCLUSION: The Functional Independence Measure was adequate for evaluating the functional status of patients with metastatic spinal cord compression. Palliative rehabilitation should be integrated early and strategies should be linked to the prognosis of survival. PMID- 29626264 TI - Active particle condensation by non-reciprocal and time-delayed interactions. AB - We consider the flocking of self-propelling agents in two dimensions, each of which communicates with its neighbors within a limited vision-cone. Also, the communication occurs with some time-delay. The communication among the agents are modeled by Vicsek rules. In this study we explore the combined effect of non reciprocal interaction (induced by limited vision-cone) among the agents and the presence of delay in the interactions on the dynamical pattern formation within the flock. We find that under these two influences, without any position-based attractive interactions or confining boundaries, the agents can spontaneously condense into "drops". Though the agents are in motion within the drop, the drop as a whole is pinned in space. We find that this novel state of the flock has a well-defined order and it is stabilized by the noise present in the system. PMID- 29626263 TI - Investigation of the Pharmaceutical Care in One Elderly Parkinson's Disease Patient with Psychotic Symptoms. AB - A 66-year-old male patient with a 10-year course of Parkinson's disease (PD) was admitted for hallucination lasting a half a month. After treatment with levodopa/carbidopa, selegiline, and piribedil, the patient's motor symptoms were improved while no significant effects were observed on psychotic symptoms. A clinical pharmacist analyzed the pharmacologic and pharmacokinetic characteristics of selegiline and piribedil, summarized the scheme of PD with psychotic symptoms in the literature, and discovered that selegiline might potentiate psychotic side effects of piribedil, while the use of levodopa/carbidopa cannot be ruled out either. Finally, the clinical pharmacist proposed to reduce the dosage of levodopa/carbidopa, increase the dosage of selegiline and quetiapine, and discontinue piribedil. The clinician accepted this suggestion. After the adjustment of medication, the patient's motor symptoms were absolutely improved and the psychotic symptoms were notably improved. This case study suggests that long-term treatment with levodopa/carbidopa and piribedil, along with the progression of the disease itself, could contribute to the emergence of psychotic symptoms in PD. Additionally, selegiline could potentiate psychotic side effects of piribedil. Neurology clinical pharmacists should work alongside neurology clinicians at the bedside to optimize pharmacotherapy, improve patient safety, and contribute to scholarly efforts. PMID- 29626265 TI - Addressing the immediate need for emergency providers in resource-limited settings: the model of a six-month emergency medicine curriculum in Haiti. AB - BACKGROUND: In many resource-limited settings, emergency medicine (EM) is underdeveloped and formal EM training limited. Residencies and fellowships are an ideal long-term solution but cannot meet immediate needs for emergency providers, while short-term programs are often too limited in content. We describe a third method successfully implemented in Haiti: a medium-duration certificate program to meet the immediate need for emergency specialists. METHODS: In conjunction with the Haitian Ministry of Health and National Medical School, we developed and implemented a novel, 6-month EM certificate program to build human resources for health and emergency care capacity. The program consisted of didactic and supervised clinical components, covering core content in EM. Didactics included lectures, simulations, hands-on skill-sessions, and journal clubs. Supervised clinical time reinforced concepts and taught an EM approach to patient care. RESULTS: Fourteen physicians from around Haiti successfully completed the program; all improved from their pre-test to post-test. At the end of the program and 9-month post-program evaluations, participants rated the program highly, and most felt they used their new knowledge daily. Participants found clinical supervision and simulation particularly useful. Key components to our program's success included collaboration with the Ministry of Health and National Medical School, supervised clinical time, and the continual presence of a course director. The program could be improved by a more flexible curriculum and by grouping participants by baseline knowledge levels. CONCLUSION: Medium-duration certificate programs offer a viable option for addressing immediate human resource gaps in emergency care, and our program offers a model for implementation in resource-limited settings. Similar options should be considered for other emerging specialties in resource-limited settings. PMID- 29626266 TI - Preferences for home- and community-based long-term care services in Germany: a discrete choice experiment. AB - BACKGROUND: Most people prefer to "age in place" and to remain in their homes for as long as possible even in case they require long-term care. While informal care is projected to decrease in Germany, the use of home- and community-based services (HCBS) can be expected to increase in the future. Preference-based data on aspects of HCBS is needed to optimize person-centered care. OBJECTIVE: To investigate preferences for home- and community-based long-term care services packages. DESIGN: Discrete choice experiment conducted in mailed survey. SETTING AND PARTICIPANTS: Randomly selected sample of the general population aged 45-64 years in Germany (n = 1.209). MAIN VARIABLES STUDIED: Preferences and marginal willingness to pay (WTP) for HCBS were assessed with respect to five HCBS attributes (with 2-4 levels): care time per day, service level of the HCBS provider, quality of care, number of different caregivers per month, co-payment. RESULTS: Quality of care was the most important attribute to respondents and small teams of regular caregivers (1-2) were preferred over larger teams. Yet, an extended range of services of the HCBS provider was not preferred over a more narrow range. WTP per hour of HCBS was ?8.98. CONCLUSIONS: Our findings on preferences for HCBS in the general population in Germany add to the growing international evidence of preferences for LTC. In light of the great importance of high care quality to respondents, reimbursement for services by HCBS providers could be more strongly linked to the quality of services. PMID- 29626267 TI - Different ventilation techniques and hemodynamic optimization to maintain regional cerebral oxygen saturation (rScO2) during laparoscopic bariatric surgery: a prospective randomized interventional study. AB - PURPOSE: The purpose of this study was to assess the changes in regional cerebral oxygen saturation (rScO2) in response to different ventilation strategies: inspired oxygen concentration (FiO2), end-tidal carbon dioxide (EtCO2), and positive end expiratory pressure (PEEP) in addition to optimizing mean arterial pressure (MAP) in obese patients subjected to laparoscopic bariatric surgery in the reverse trendelenburg position. METHODS: 50 obese patients were randomly assigned into one of two groups. Each group is 25 patients. Control patients subjected to a ventilation strategy aimed to maintain FiO2 0.4 and EtCO2 30 mmHg without PEEP. Study patients were assigned to specific protocol; T0, baseline rScO2; T1, 5 min following induction; T2, PP/RTP (10 min after pneumoperitoneum and reverse trendelenburg position); T3, PEEP 10 cmH2O; T4, FiO2 1.0; T5, EtCO2 40 mmHg and T6, MAP/BL; MAP back to baseline in both groups. MAIN RESULTS: 10 min after PP/RTP, there was a significant decrease in rScO2 in both groups. At T4, with FiO2 1.0, there was significant improvement in rScO2 when compared to T2. At T5, with EtCO2 40 mmHg, rScO2 significantly enhanced when compared to EtCO2 30 mmHg. At T4 and T5, we observed highly significance difference between both groups. At the end of the procedure and when MAP increased back to baseline (T6) in both groups, rScO2 statistically increased in both groups when compared to T2. CONCLUSION: In obese patients, subjected to laparoscopic bariatric surgery in reverse trendelenburg position, adjustment of ventilation strategies and hemodynamic optimization succeeded to improve rScO2. PMID- 29626268 TI - Intervertebral disc status is associated with vertebral marrow adipose tissue and muscular endurance. AB - PURPOSE: Low back pain is a major public health issue. Identifying factors associated with better intervertebral disc (IVD) characteristics gives insight into IVD metabolism and highlights intervention targets for improvement of IVD health. This cross-sectional study investigates whether IVD T2-relaxation time on magnetic resonance imaging (MRI) is associated with vertebral fat fraction (VFF; to quantify marrow adipose tissue), trunk muscle cross-sectional area (CSA), muscle function and physical activity (PA). METHODS: Seventy-nine healthy subjects (35 males, 44 females) without history of spinal disease were included. Lumbar IVDs T2-relaxation time, lumbar VFF and CSA of multifidus, erector spinae, quadratus lumborum, and psoas muscles were quantified via MRI. Isometric trunk flexion and extension endurance times as well as habitual PA levels and exposure to occupational spine risk factors were documented. Pearson-partial correlations adjusted for anthropometric differences by controlling for vertebral body height. RESULTS: Higher IVD T2-time correlated with: (a) lower VFF (r = - 0.27, p < 0.05), (b) greater trunk extensor muscle endurance (r = 0.37, p < 0.01), and (c) greater trunk flexor muscle endurance (r = 0.30, p < 0.01) but not with muscle CSA. Lower VFF also correlated with greater extensor muscle endurance (r = - 0.26, p < 0.05) and habitual PA (MET-mins per week) (r = - 0.24, p < 0.05). CONCLUSION: This is the first study to show that better IVD hydration is associated with lower VFF and that greater physical activity is associated with favourable levels of vertebral marrow adipose tissue in young healthy individuals. Reduced vertebral marrow adipose tissue may specifically improve IVD hydration via improved nutrient supply. These slides can be retrieved under Electronic Supplementary Material. PMID- 29626270 TI - Recent therapeutic strategies for metastatic melanoma: introduction to invited articles. PMID- 29626269 TI - Analysis of PD-1 and Tim-3 expression on CD4+ T cells of patients with rheumatoid arthritis; negative association with DAS28. AB - Expression of T cell immunoglobulin and mucin-domain containing-3 (Tim-3) and programmed cell death-1 (PD-1) was studied on CD4+ T cells of patients with rheumatoid arthritis (RA). Association of Tim-3 and PD-1 expression with disease activity of RA patients was also addressed. A total of 37 RA patients and 31 sex- and age-matched healthy controls were included in this study. Disease activity of RA patients was determined by Disease Activity Score of 28 joints scoring system (DAS28). A three-color flow cytometry method was applied to determine the frequency of Tim-3+/PD-1+/CD4+ T cells. To measure the cytokine production, peripheral blood mononuclear cells (PBMCs) were stimulated with PMA/ionomycin. Concentrations of IL-17, IL-10, IFN-gamma, and TNF-alpha were measured in culture supernatants by ELISA. The frequency of PD-1+/CD4+ and Tim-3+/PD-1+/CD4+ T cells was significantly higher in patients with RA compared to that in controls (p = 0.0013 and p = 0.050, respectively). The percentage of Tim-3+/CD4+ T cells was similar in patients and controls (p = 0.4498). The RA patients have produced significant higher levels of TNF-alpha, IL-17, and IFN-gamma than those of healthy controls (p = 0.0121, p = 0.0417, and p = 0.0478, respectively). Interestingly, an inverse correlation was found between the frequency of Tim 3+/CD4+ cells and DAS28 of RA patients (r = - 0.4696, p = 0.0493). Similarly, the percentage of Tim-3+/PD-1+/CD4+ T cells was also revealed an inverse correlation with DAS28 (r = - 0.5268, p = 0.0493). Moreover, significant positive correlations were detected between the concentrations of TNF-alpha (r = 0.6418, p = 0.0023) and IL-17 (r = 0.4683, p = 0.0373) with disease activity of RA patients. Our results indicate that Tim-3 and PD-1 are involved in immune dysregulation mechanisms of rheumatoid arthritis and could be considered as useful biomarkers for determination of disease activity and progression. PMID- 29626271 TI - Bursal immunopathology responses of specific-pathogen-free chickens and red jungle fowl infected with very virulent infectious bursal disease virus. AB - Very virulent infectious bursal disease virus (vvIBDV) targets B lymphocytes in the bursa of Fabricius (BF), causing immunosuppression and increased mortality rates in young birds. There have been few studies on the host immune response following vvIBDV infection at different inoculum doses in chickens with different genetic backgrounds. In this study, we characterized the immune responses of specific-pathogen-free (SPF) chickens and Malaysian red jungle fowl following infection with vvIBDV strain UPM0081 at 103.8 and 106.8 times the 50% embryo infectious dose (EID50). The viral burden, histopathological changes, immune cell populations, and expression of immune-related genes were measured and compared between infected and uninfected bursa at specific intervals. The populations of KUL1+, CD3+CD4+ and CD3+CD8+ cells were significantly increased in both types of chickens at 3 dpi, and there was significant early depletion of IgM+ B cells at 1 dpi in the red jungle fowl. vvIBDV infection also induced differential expression of genes that are involved in Th1 and pro-inflammatory responses, with groups receiving the higher dose (106.8 EID50) showing earlier expression of IFNG, IL12B, IL15, IL6, CXCLi2, IL28B, and TLR3 at 1 dpi. Although both chicken types showed equal susceptibility to infection, the red jungle fowl were clinically healthier than the SPF chickens despite showing more depletion of IgM+ B cells and failure to induce IFNB activation. In conclusion, high-dose vvIBDV infection caused an intense early host immune response in the infected bursa, with depletion of IgM+ B cells, bursal lesions, and cytokine expression as a response to mitigate the severity of the infection. PMID- 29626272 TI - A Semi-passive Planar Manipulandum for Upper-Extremity Rehabilitation. AB - Robotic rehabilitation is a promising approach to treat individuals with neurological or orthopedic disorders. However, despite significant advancements in the field of rehabilitation robotics, this technology has found limited traction in clinical practice. A key reason for this issue is that most robots are expensive, bulky, and not scalable for in-home rehabilitation. Here, we introduce a semi-passive rehabilitation robot (SepaRRo) that uses controllable passive actuators (i.e., brakes) to provide controllable resistances at the end effector over a large workspace in a manner that is cost-effective and safe for in-home use. We also validated the device through theoretical analyses, hardware experiments, and human subject experiments. We found that by including kinematic redundancies in the robot's linkages, the device was able to provide controllable resistances to purely resist the movement of the end-effector, or to gently steer (i.e., perturb) its motion away from the intended path. When testing these capabilities on human subjects, we found that many of the upper-extremity muscles could be selectively targeted based on the forcefield prescribed to the user. These results indicate that SepaRRo could serve as a low-cost therapeutic tool for upper-extremity rehabilitation; however, further testing is required to evaluate its therapeutic benefits in patient population. PMID- 29626273 TI - Hyperelastic Mechanical Properties of Ex Vivo Normal and Intrauterine Growth Restricted Placenta. AB - Intrauterine Growth Restriction (IUGR) is a serious and prevalent pregnancy complication that is due to placental insufficiency and IUGR babies suffer significantly higher risks of mortality and morbidity. Current detection rate for IUGR is generally poor and thus an alternative diagnostic tool is needed to improve the IUGR detection. Elastography, a non-invasive method that measures the tissue stiffness, has been proposed as one such technique. However, to date, we have limited information on the mechanical properties of IUGR placenta. In this study, we investigated the mechanical properties of normal and IUGR placentae and prescribed a suitable hyperelastic model to describe their mechanical behaviors. A total of 46 normal and 43 IUGR placenta samples were investigated. Results showed that placenta samples were isotropic, but had a high spatial variability of stiffness. The samples also had significant viscoelasticity. IUGR placenta was observed to be slightly stiffer than normal placenta but the difference was significant only at compression rate of 0.25 Hz and with 20% compression depth. Three simple hyperelastic models-Yeoh, Ogden and Fung models, were found to be able to fit the experimentally measured mechanical behaviors, and Fung model performed slightly better. These results may be useful for optimizing placenta elastography for the detection of IUGR. PMID- 29626274 TI - Predictors of surgical outcome and early criteria of remission in acromegaly. AB - BACKGROUND: Transsphenoidal surgery (TSS) is the cornerstone of acromegaly treatment, however there are no robust predictors of surgical outcome and remission can only be defined three months after surgery. PURPOSE: To analyze if biochemical, demographical, radiological, and immunohistochemical characteristics are predictors of surgical remission and investigate if immediate postoperative GH and IGF-I levels can help defining remission earlier. METHODS: Consecutive acromegaly patients submitted to TSS between 2013-2016 were evaluated. Remission criteria was defined as normal IGF-I and GH <1 mcg/L three months after surgery. Data of age, sex, GH and IGF-I levels, tumor volume, cavernous sinus invasion, T2 weighted signal, Ki-67, and granulation pattern were correlated with remission status. GH and IGF-I levels at 24, 48 h, and one week postoperative were evaluated as early criteria of remission. RESULTS: Sixty-nine patients were included (84% macroadenomas) and surgical remission was achieved in 45%. No difference between cured and not cured patients concerning age, gender, preoperative GH or IGF-I levels, tumor volume, T2-weighted signal, Ki-67 and tumor granularity was observed. Remission was obtained in 20 of 36 (56%) of the non-invasive tumors, and in 3 of 16 (19%) of the invasive tumors (p = 0.017). A GH <1.57 mcg/L 48 h after surgery was able to predict remission with 93% sensitivity and 86% specificity and an IGF-I < 231% ULNR one week after surgery predicted remission with 86% sensitivity and 93% specificity. CONCLUSION: Cavernous sinus invasion is the only preoperative predictor of surgical remission. GH at 48 h and IGF-I one week after surgery can define earlier not cured patients. PMID- 29626275 TI - Antenatal Management for Women with Inflammatory Bowel Disease: Experience from Our 'IBD MOM' Clinic. AB - BACKGROUND: Inflammatory bowel disease affects women during their reproductive years and thus pregnancy outcomes. IBD MOM is a multidisciplinary, single-center clinic established to benefit women with IBD and their neonates. AIM: The aim of this study was to evaluate the perinatal outcomes of the IBD MOM clinic patients compared to patients who attended antenatal and gastrointestinal disease community clinics (IBD CC). METHODS: This single-center, prospective study was conducted from 2011 to 2015. The primary outcome was cesarean delivery; secondary was adverse perinatal outcomes. In parallel, a new pregnancy-oriented, disease severity score was evaluated for its association with perinatal risk (score low = 0 to severe = 5). RESULTS: We identified 90 women in the IBD MOM clinic and 206 in the IBD CC. Maternal age, smoking habits, pregnancy complications, and type of IBD (CD/UC) were similar between groups. Rates of labor induction and birth weight were also similar between IBD MOM and IBD GI. The IBD MOM overall preterm delivery (PTD) rate (< 37 weeks) was significantly higher 18.9 versus 9.7% (P = 0.028). The IBD MOM group had a significantly higher IBD MOM disease severity score that correlated with a higher rate of PTD. The overall IBD MOM score and scores > 3 were significantly associated with PTD risk in both groups (P = 0.013 and P = 0.004, respectively). CONCLUSION: Women with moderate and severe IBD who attended a multidisciplinary clinic may benefit from this unique center. Healthcare planning policies can assume that costly, multidisciplinary clinics for women with IBD should be reserved for those with moderate and severe disease. PMID- 29626277 TI - Evaluation of Fecal M2PK as a Diagnostic Marker in Colorectal Cancer. AB - BACKGROUND: Invasive colonoscopy is the gold standard for patients at risk for colorectal cancer. However, the need for non-invasive and specific markers is required. OBJECTIVE: To evaluate the sensitivity of the glycolytic pyruvate kinase isoenzyme type M2 dimer (M2PK) as a diagnostic biomarker for colorectal cancer (CRC) and adenomatous colorectal polyps (CRP) screening. DESIGN: Case control. PATIENTS: Twenty patients with CRC, 20 patients with CRP (lack criteria for colonic cancer by biopsy), and 20 normal subjects. OUTCOME: Complete blood count (CBC), erythrocyte sedimentation rate (ESR), tumor markers: carcino embryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9), fecal occult blood test (FOBT), and fecal M2PK. Pelvic and abdominal ultrasound (US), colonoscopy, and a histopathological examination. RESULTS: Only weight loss and cachexia were significantly associated with CRC than CRP or control groups. M2PK was the most sensitive and specific test in differentiating CRC from CRP and the control subjects (sensitivity = 75%, specificity = 100%). LIMITATIONS: (1) The selection of cases for three well-matched groups, as to perform colonoscopy in well-prepared cases and conditions. (2) Replicates in more than 20 cases for confirmation at the expense of enrolling new patients. (3) The cost associated with tumor markers analysis. CONCLUSION: Fecal M2PK can be used as a precolonoscopy screening test for CRC patients, and is superior to other tumor markers, and in indicating the progress of colorectal adenomas > 1 cm. Thus being cost-effective and easy-to-perform test, it is a feasible tool to preselect patients who require colonoscopy. PMID- 29626276 TI - Immunohistochemistry in Diagnostic Parathyroid Pathology. AB - Pathologists are usually readily able to diagnose parathyroid tissues and diseases, particularly when they have knowledge of the clinical information, laboratory findings, and radiographic imaging studies. However, the identification of parathyroid tissue or lesions can be difficult in small biopsies, ectopic locations, supranumerary glands, and in some oxyphil/oncocytic lesions. Widely available immunohistochemical studies such as chromogranin-A, synaptophysin, keratin, parathyroid hormone, thyroglobulin, and thyroid transcription factor-1 can help in difficult cases. One of the most difficult diagnostic aspects faced by the pathologist in evaluating parathyroid is distinguishing between parathyroid adenoma, particularly atypical adenoma, and parathyroid carcinoma. Many markers have and continue to be evaluated for diagnostic utility, and are even beginning to be studied for prognostic utility. Single immunohistochemical markers such as parafibromin and Ki-67 are among the most studied and most utilized, but many additional markers have and continue to be evaluated such as galectin-3, PGP9.5, Rb, bcl2, p27, hTERT, mdm2, and APC. Although not widely available in many laboratories, a panel of immunohistochemical markers may prove most useful as an adjunct in the evaluation of challenging parathyroid tumors. PMID- 29626278 TI - Establishment and proteomic characterization of a novel synovial sarcoma cell line, NCC-SS2-C1. AB - Synovial sarcoma is an aggressive mesenchymal tumor, characterized by the presence of unique transfusion gene, SS18-SSX. Cell lines enable researchers to investigate the molecular backgrounds of disease and the significance of SS18-SSX in relevant cellular contexts. We report the establishment and proteomic characterization of a novel synovial sarcoma cell line. Primary tissue culture was performed using tumor tissue of synovial sarcoma. The established cell line was authenticated by assessing its DNA microsatellite short tandem repeat analysis and characterized by in vitro assay. Proteomic study was achieved by mass spectrometry, and the results were analyzed by treemap. The cell line NCC SS2-C1 was established from a primary tumor tissue of a synovial sarcoma patient. The cell line has grown well for 11 mo and has been subcultured more than 15 times. The established cells were authenticated by assessing their short tandem repeat pattern comparing with that of original tumor tissue. The cells showed polygonal in shape and formed spheroid when seeded on the low-attachment dish. Proteomic analysis revealed the molecular pathways which are unique to the original tumor tissue or the established cell line. In conclusion, a novel synovial sarcoma cell line NCC-SS2-C1 was successfully established from the primary tumor tissue. The cell line has characteristic transfusion SS18-SSX and poses aggressive in vitro growth and capability of spheroid formation. Thus, NCC SS2-C1 cell line will be a useful tool for investigation of the mechanisms of disease and the biological role of fusion gene. PMID- 29626279 TI - Activation of adenosine A2b receptor attenuates high glucose-induced apoptosis in H9C2 cells via PI3K/Akt signaling. AB - High glucose plays a vital role in apoptosis in H9C2 cells. However, the exact molecular mechanism remains unclear. In this study, we aimed to evaluate the cardio-protective role of A2b receptor in high glucose-induced cardiomyocyte apoptosis via PI3K/Akt pathway. Adenosine A2b receptor agonist (Bay506583), antagonist (MRS1754), and Akt inhibitor (LY294002) were applied respectively to H9C2 cells before exposed to high glucose for 12 h. Apoptosis of H9C2 cells was determined by TUNEL assay and the apoptosis rate by flow cytometry. The protein level of adenosine A2b receptor, p-Akt, total Akt, cleaved capase-3, cleaved capase-9, bax, and bcl-2 was measured by western blotting. The results demonstrated that apoptosis of H9C2 cardiomyocytes triggered by high-glucose treatment was time-dependent. The protein level of A2b receptor and activated Akt was both decreased in cardiomyocyte with high-glucose treatment. Moreover, we found that high glucose-induced apoptosis in H9C2 cells could be attenuated by administration of adenosine A2b receptor agonist Bay606583. This effect could be reversed by Akt inhibitor LY294002. In conclusion, activation of A2b receptor could prevent high glucose-induced apoptosis of H9C2 cells in vitro to a certain extent by activating PI3K/Akt signaling. In conclusion, these results suggested that activation of A2b receptor could be a novel therapeutic approach to high glucose-induced cardiomyocyte injury. PMID- 29626280 TI - Automated muscle segmentation from CT images of the hip and thigh using a hierarchical multi-atlas method. AB - PURPOSE: Patient-specific quantitative assessments of muscle mass and biomechanical musculoskeletal simulations require segmentation of the muscles from medical images. The objective of this work is to automate muscle segmentation from CT data of the hip and thigh. METHOD: We propose a hierarchical multi-atlas method in which each hierarchy includes spatial normalization using simpler pre-segmented structures in order to reduce the inter-patient variability of more complex target structures. RESULTS: The proposed hierarchical method was evaluated with 19 muscles from 20 CT images of the hip and thigh using the manual segmentation by expert orthopedic surgeons as ground truth. The average symmetric surface distance was significantly reduced in the proposed method (1.53 mm) in comparison with the conventional method (2.65 mm). CONCLUSION: We demonstrated that the proposed hierarchical multi-atlas method improved the accuracy of muscle segmentation from CT images, in which large inter-patient variability and insufficient contrast were involved. PMID- 29626282 TI - Development and Validation of the Pediatric Diabetes Routines Questionnaire for Adolescents. AB - This study describes the development and psychometric evaluation of an adolescent self-report version of the Pediatric Diabetes Routines Questionnaire (PDRQ:A), a measure of diabetes-specific routines for youth with type 1 diabetes, and further validation of the parent-version (PDRQ:P) in an adolescent sample. Participants included 120 parent-adolescent dyads (ages 12-17) and an additional 24 parents who completed measures of diabetes-specific adolescent routines, general adolescent routines, diabetes self-care, and family support of youth diabetes care. The PDRQ:P/A demonstrated good internal consistency, test-retest reliability, and parent-child agreement, and adequate validity coefficients. Confirmatory factor analysis supported a one-factor model. Promising results were obtained. The PDRQ:P/A is a clinically feasible parent- and self-report measure that can provide valuable information regarding how frequently adolescents engage in their diabetes management tasks in a consistent manner. Addition of an adolescent report format will enhance the utility of the measure for clinical and research use. PMID- 29626281 TI - Hospital length of stay in patients initiated on direct oral anticoagulants versus warfarin for venous thromboembolism: a real-world single-center study. AB - This study was conducted to describe the real-world hospital length of stay in patients treated with all of the U.S. Food and Drug Administration approved direct oral anticoagulants (DOACs) versus warfarin for new-onset venous thromboembolism (VTE) at a large, tertiary, academic medical center. A retrospective cohort analysis of all adult patients diagnosed with acute onset VTE was conducted. Of the 441 patients included, 261 (57%) patients received DOACs versus 180 (41%) patients received warfarin. In the DOAC group, a total of 92 (35%) patients received rivaroxaban, followed by 83 (32%) patients received apixaban, 50 (19%) patients received dabigatran, and 36 (14%) patients received edoxaban. Patients initiated on DOACs had a statistically significant shorter hospital length of stay compared to patients initiated on warfarin (median 3 days, [IQR 0-5] vs. 8 days [IQR 5-11], P < 0.05). Despite the shorter hospital length of stay in patients receiving DOACs, the overall reported differences between the DOACs group and the warfarin group in terms of recurrent VTE, major bleeding, intracranial bleeding, and gastrointestinal bleeding at 3 and 6 months were deemed to be statistically insignificant. PMID- 29626283 TI - Left ventricular energy loss and wall shear stress assessed by vector flow mapping in patients with hypertrophic cardiomyopathy. AB - The aim of this study was to assess left ventricular (LV) summation of energy loss (EL-SUM), average energy loss (EL-AVE) and wall shear stress (WSS) using vector flow mapping (VFM) in patients with hypertrophic cardiomyopathy (HCM). Forty HCM patients, and 40 controls were evaluated by transthoracic echocardiography. Conventional echocardiographic parameters, summation and average of energy loss (EL-total, EL-base, EL-mid and EL-apex), and WSS in each segment were calculated at different phases. Compared with controls, conventional diastolic measurements were impaired in HCM patients. HCM patients also showed increased EL-SUM-total and EL-AVE-total at the peak of LV rapid ejection period as well as decreased EL-SUM-total and EL-AVE-total at the end of early diastole. In controls, EL-SUM and EL-AVE showed a gradual decrease from the basal segment to the apex, this regularity was not observed in HCM patients. Compared with controls, HCM patients showed increased WSS at the peak of the LV rapid ejection period and the atrial contraction period as well as decreased WSS at the end of early diastole (all p < 0.05). WSS was increased slightly at the peak of the LV rapid filling period in HCM patients (p = 0.055). EL and WSS values derived from VFM are novel flow dynamic parameters that can effectively evaluate systolic and diastolic hemodynamic function in HCM patients. PMID- 29626284 TI - A parent-centered approach to autism diagnosis in early childhood. PMID- 29626285 TI - Image-guided minimally invasive treatment for small renal cell carcinoma. AB - : Surgical partial nephrectomy is still considered as the "gold standard" for the definitive management of small malignant renal masses, whereas treatment with image-guided percutaneous ablation is still mainly reserved for those patients who cannot undergo nephron-sparing surgical resection due to advanced age, underlying comorbidities or compromised renal function. Nonetheless, the recent evidence that underlines the long-term oncological equipoise of percutaneous ablation methods with surgical resection in combination with the reduced complication rate and cost supports the use of an image-guided minimally invasive approach as a first-line treatment. The purpose of this review is to offer an overview of the most widely used percutaneous renal ablation treatments (radiofrequency, microwave and cryoablation) with a focus on their main technical aspects and application techniques for curative ablation of small renal cell carcinoma (stage cT1a). The authors also provide a critical narrative of the relevant medical literature with an emphasis on outcomes of comparative effectiveness research, and appraise the percutaneous methods compared to surgery in the context of evidence-based practice and future research studies. TEACHING POINTS: * RCC is a common cancer and is increasingly detected incidentally at early stages. * There is long-term oncological equipoise of percutaneous ablation compared to surgical resection. * Large-scale trials are required to produce Level 1a evidence. PMID- 29626286 TI - Multidetector CT of expected findings and complications after hysterectomy. AB - : Indicated to manage a variety of disorders affecting the female genital tract, hysterectomy represents the second most common gynaecological operation after caesarean section. Performed via an open, laparoscopic or vaginal approach, hysterectomy is associated with non-negligible morbidity and occasional mortality. Iatrogenic complications represent a growing concern for gynaecologists and may result in prolonged hospitalisation, need for interventional procedures or repeated surgery, renal impairment and malpractice claims. As a result, radiologists are increasingly requested to investigate patients with suspected complications after hysterectomy. In the vast majority of early postoperative situations, multidetector CT represents the ideal modality to comprehensively visualise the surgically altered pelvic anatomy and to consistently triage the varied spectrum of possible injuries. This pictorial review provides an overview of current indications and surgical techniques, illustrates the expected CT appearances after recent hysterectomy, the clinical and imaging features of specific complications such as lymphoceles, surgical site infections, haemorrhages, urinary tract lesions and fistulas, bowel injury and obstruction. Our aim is to increase radiologists' familiarity with normal post hysterectomy findings and with post-surgical complications, which is crucial for an appropriate choice between conservative, interventional and surgical management. TEACHING POINTS: * Hysterectomy via open, laparoscopic or vaginal route is associated with non-negligible morbidity. * Multiplanar CT imaging optimally visualises the surgically altered pelvic anatomy. * Familiarity with early post-hysterectomy CT and expected findings is warranted. * Complications encompass surgical site infections, haemorrhages, bowel injury and obstruction. * Urological complications include ureteral leakage, bladder injury, urinomas and urinary fistulas. PMID- 29626287 TI - Suppressive effect of pitavastatin on aortic arch dilatation in acute stanford type B aortic dissection: analysis of STANP trial. AB - OBJECTIVES: Medical therapy for patients with uncomplicated acute type B aortic dissection (ABAD) is essentially accepted for its excellent early outcome; however, long-term outcomes have not been satisfactory due to aorta-related complications. This trial was performed to investigate the efficacy of a statin as an additive that may enhance the effectiveness of conventional medical treatment in patients with ABAD. METHODS: This was a multi-center, prospective, and randomized comparative investigation of patients with uncomplicated ABAD. Fifty patients with ABAD compatible with inclusion criteria were randomly assigned to two groups and then received administration of pitavastatin (group P) or not (group C). We followed up the patients for 1 year from study onset. RESULTS: Two patients demised during the follow-up period (both were in group C). In addition, aorta-related interventions were performed in two patients (entry closure for aortic dissection by endovascular repair in one patient in each group). Aortic arch diameters at 1 year in group P tended to be smaller than in group C (P = 0.17), and the rate of change of the aortic arch diameters from onset to 1 year was significantly lower in group P (P = 0.046). Multivariate analysis identified patency of the false lumen was detected as a risk factor for aortic arch dilatation (P = 0.02), and pitavastatin intake was a negative risk factor (P = 0.03). CONCLUSIONS: Pitavastatin treatment, in addition to the standard antihypertensive therapy, may have a suppressive effect on aortic arch dilatation in patients with ABAD. PMID- 29626288 TI - Evidence for intrathecal sodium butyrate as a novel option for leptomeningeal metastasis. AB - INTRODUCTION: The prognosis for leptomeningeal metastasis (LM) remains extremely poor regardless of intrathecal chemotherapy with various drugs, and thus, new treatments are necessary. Butyrate is an endogenous 4-carbon saturated fatty acid, has been investigated as an anti-tumor agent because of its multiple suppressive effects on several tumors. In this study, we investigated the cellular basis of sodium butyrate (SB), a sodium salt compound of butyrate, in vitro and evaluated the clinical potential of intrathecal SB administration for LM in vivo. METHODS: We examined SB's effects on Walker 256 rat mammary tumor cells with regard to cytotoxicity, cell morphology, colony formation, migration, and invasion. We also examined SB's neurotoxicity for primary neurons and primary astrocytes. We finally evaluated the potency of continuous intrathecal SB administration in rats with intrathecally transplanted breast tumors as an LM model. RESULTS: Physiological SB concentrations (2-4 mM) induced growth suppression, morphological changes, and inhibition of migration and invasion, but did not exhibit neurotoxic effects on primary neurons and astrocytes. Continuous intrathecal SB administration in a rat LM model significantly increased survival periods with little neurotoxicity. CONCLUSIONS: Continuous intrathecal SB administration significantly improved prognoses in a rat LM model, which suggests that SB is a promising therapy for LM. PMID- 29626289 TI - Dosimetric changes with computed tomography automatic tube-current modulation techniques. AB - The study is aimed at a verification of dose changes for a computed tomography automatic tube-current modulation (ATCM) technique. For this purpose, anthropomorphic phantom and Gafchromic(r) XR-QA2 films were used. Radiochromic films were cut according to the shape of two thorax regions. The ATCM algorithm is based on noise index (NI) and three exam protocols with different NI were chosen, of which one was a reference. Results were compared with dose values displayed by the console and with Poisson statistics. The information obtained with radiochromic films has been normalized with respect to the NI reference value to compare dose percentage variations. Results showed that, on average, the information reported by the CT console and calculated values coincide with measurements. The study allowed verification of the dose information reported by the CT console for an ATCM technique. Although this evaluation represents an estimate, the method can be a starting point for further studies. PMID- 29626291 TI - Comparing the performance of meta-classifiers-a case study on selected imbalanced data sets relevant for prediction of liver toxicity. AB - Cheminformatics datasets used in classification problems, especially those related to biological or physicochemical properties, are often imbalanced. This presents a major challenge in development of in silico prediction models, as the traditional machine learning algorithms are known to work best on balanced datasets. The class imbalance introduces a bias in the performance of these algorithms due to their preference towards the majority class. Here, we present a comparison of the performance of seven different meta-classifiers for their ability to handle imbalanced datasets, whereby Random Forest is used as base classifier. Four different datasets that are directly (cholestasis) or indirectly (via inhibition of organic anion transporting polypeptide 1B1 and 1B3) related to liver toxicity were chosen for this purpose. The imbalance ratio in these datasets ranges between 4:1 and 20:1 for negative and positive classes, respectively. Three different sets of molecular descriptors for model development were used, and their performance was assessed in 10-fold cross-validation and on an independent validation set. Stratified bagging, MetaCost and CostSensitiveClassifier were found to be the best performing among all the methods. While MetaCost and CostSensitiveClassifier provided better sensitivity values, Stratified Bagging resulted in high balanced accuracies. PMID- 29626292 TI - Faculty Development for Teaching Faculty in Psychiatry: Where We Are and What We Need. AB - OBJECTIVE: A Faculty Development Task Force surveyed the American Association of Directors of Psychiatric Residency Training membership to assess faculty development for graduate medical education faculty in psychiatry departments and barriers to seeking graduate medical education careers. METHODS: An anonymous Survey Monkey survey was emailed to 722 American Association of Directors of Psychiatric Residency Training members. The survey included questions about demographics, the current state of faculty development offerings within the respondent's psychiatry department and institution, and potential American Association of Directors of Psychiatric Residency Training faculty development programming. Two open-response questions targeted unmet faculty development needs and barriers to seeking a career in graduate medical education. Results were analyzed as frequencies and open-ended questions were coded by two independent coders. We limited our analysis to general psychiatry program director responses for questions regarding faculty development activities in an attempt to avoid multiple responses from a single department. RESULTS: Response rates were 21.0% overall and 30.4% for general program directors. General program directors reported that the most common existing departmental faculty development activities were educational grand rounds (58.7%), teaching workshops (55.6%), and funding for external conference attendance (52.4%). Of all survey respondents, 48.1% expressed the need for more protected time, 37.5% teaching skills workshops, and 16.3% mentorship. Lack of funding (56.9%) and time (53.9%) as well as excessive clinical demands (28.4%) were identified as the main barriers to seeking a career in graduate medical education. CONCLUSIONS: Despite increasing faculty development efforts in psychiatry departments and institutions, real and significant unmet faculty development needs remain. Protected time remains a significant unmet need of teaching faculty which requires careful attention by departmental leadership. PMID- 29626294 TI - Routine immunohistochemical staining in membranous nephropathy: in situ detection of phospholipase A2 receptor and thrombospondin type 1 containing 7A domain. AB - BACKGROUND: Membranous nephropathy (MN) can be idiopathic (iMN) or manifest as a result of systemic underlying conditions as a secondary epiphenomenon. For the prognostic and predictive consequences of this discrimination, the routine use of reliable markers is crucial. This large MN series aimed to evaluate the routine and standardized immunohistochemical (IHC) employment of a panel of 3 biomarkers phospholipase A2 receptor (PLA2R), thrombospondin type-1 domain-containing 7A (THSD7A), and immunoglobulin (Ig)G4-in the differential diagnosis of MN forms, contributing to the validation of the technique and the correct interpretation of reproducible patterns of reactivity. METHODS: We classified 95 patients with a biopsy proven diagnosis of MN as primary (n = 72) or secondary (n = 23) cases based on clinical data. After performing an IHC assay directed against PLA2R, THSD7A and IgG4 antigens, samples were interpreted by three different nephropathologists to assess the positivity/negativity of the staining according to new interpretation criteria. RESULTS: Useful interpretation criteria were introduced to exclude false positive patterns of reactivity and to identify only true granular membranous or mesangial deposits in MN. The IHC directed against PLA2R resulted positive in 51 iMN cases and negative in 21, while 4/23 secondary forms were considered positive. Based on these data the technique showed a sensitivity of 71% and specificity of 83%. On the other hand, the IHC analysis for IgG4 resulted positive in 44 cases of iMN and negative in 28 cases, while only 4/23 secondary forms were positive (same cases positive to PLA2R). Finally, THSD7A was found to be positive only in 1 case, which was negative to PLA2R and IgG4. The combination of the results allowed a classification of the series into two major groups: "double-positive" (PLA2R+/IgG4+/THSD7A-) and "triple-negative" (PLA2R-/IgG4-/THSD7A-) cases. CONCLUSIONS: Based on these data, the diagnostic performance of the three biomarkers used in a "tandem fashion" can reach 79% sensitivity and 83% specificity, significantly reducing the risk of a false positive or false-negative result and improving the routine characterization of this frequent glomerulonephritis. PMID- 29626295 TI - UV-POSIT: Web-Based Tools for Rapid and Facile Structural Interpretation of Ultraviolet Photodissociation (UVPD) Mass Spectra. AB - UV-POSIT (Ultraviolet Photodissociation Online Structure Interrogation Tools) is a suite of web-based tools designed to facilitate the rapid interpretation of data from native mass spectrometry experiments making use of 193 nm ultraviolet photodissociation (UVPD). The suite includes four separate utilities which assist in the calculation of fragment ion abundances as a function of backbone cleavage sites and sequence position; the localization of charge sites in intact proteins; the calculation of hydrogen elimination propensity for a-type fragment ions; and mass-offset searching of UVPD spectra to identify unknown modifications and assess false positive fragment identifications. UV-POSIT is implemented as a Python/Flask web application hosted at http://uv-posit.cm.utexas.edu . UV-POSIT is available under the MIT license, and the source code is available at https://github.com/jarosenb/UV_POSIT . Graphical Abstract. PMID- 29626296 TI - Real-world efficacy and safety of ledipasvir and sofosbuvir in patients with hepatitis C virus genotype 1 infection: a nationwide multicenter study by the Japanese Red Cross Liver Study Group. AB - BACKGROUND: We aimed to describe the real-world efficacy and safety of combination therapy with ledipasvir and sofosbuvir (LDV/SOF) for chronic hepatitis C virus (HCV) genotype 1 (GT1) infection. METHODS: This retrospective analysis of a prospective, nationwide, multicenter registry included GT1-infected patients treated with LDV/SOF for 12 weeks. We assessed the rate of sustained virological response at 12 weeks post-treatment (SVR12), incidence of adverse events, and serum markers of hepatocellular carcinoma (HCC). RESULTS: Among the 1461 patients included (mean age, 69 years; 29.5% aged > 75 years; cirrhosis, 23.8%; history of treatment for HCC, 10.9%), the overall SVR12 rate was 98.4% (1438/1461). Factors associated with treatment failure were cirrhosis (odds ratio, 4.19; p = 0.014) and resistance-associated substitutions (RASs) in NS5A at baseline (odds ratio, 7.78; p = 0.0004). The SVR12 rate in patients with cirrhosis and NS5A RASs was 93.0% compared to 100% in patients without cirrhosis or NS5A RASs. In patients with SVR, the levels of alpha-fetoprotein (AFP), AFP L3, and Mac-2 binding protein glycosylation isomer (M2BPGi) decreased from baseline to end of treatment (from 13.4 +/- 37.6 to 6.0 +/- 10.6 ng/mL, p < 0.0001; from 2.2 +/- 4.9 to 1.5 +/- 6.3%, p < 0.005; and from 3.6 +/- 3.7 to 2.0 +/- 3.5 cut-off index, p < 0.0001; respectively). Adverse events were rare and not associated with age. No decrease in estimated glomerular filtration rate was observed in patients with baseline chronic kidney disease stage 3. CONCLUSIONS: LDV/SOF therapy is highly effective and safe in elderly Japanese patients with HCV GT1, even in the presence of cirrhosis or NS5A RASs. Patients with SVR may have a lower risk of HCC. PMID- 29626297 TI - Effects of feedback reliability on feedback-related brain activity: A feedback valuation account. AB - Adaptive decision making relies on learning from feedback. Because feedback sometimes can be misleading, optimal learning requires that knowledge about the feedback's reliability be utilized to adjust feedback processing. Although previous research has shown that feedback reliability indeed influences feedback processing, the underlying mechanisms through which this is accomplished remain unclear. Here we propose that feedback processing is adjusted by the adaptive, top-down valuation of feedback. We assume that unreliable feedback is devalued relative to reliable feedback, thus reducing the reward prediction errors that underlie feedback-related brain activity and learning. A crucial prediction of this account is that the effects of feedback reliability are susceptible to contrast effects. That is, the effects of feedback reliability should be enhanced when both reliable and unreliable feedback are experienced within the same context, as compared to when only one level of feedback reliability is experienced. To evaluate this prediction, we measured the event-related potentials elicited by feedback in two experiments in which feedback reliability was varied either within or between blocks. We found that the fronto-central valence effect, a correlate of reward prediction errors during reinforcement learning, was reduced for unreliable feedback. But this result was obtained only when feedback reliability was varied within blocks, thus indicating a contrast effect. This suggests that the adaptive valuation of feedback is one mechanism underlying the effects of feedback reliability on feedback processing. PMID- 29626298 TI - L-Cysteine in vitro can restore cellular glutathione and inhibits the expression of cell adhesion molecules in G6PD-deficient monocytes. AB - L-Cysteine is a precursor of glutathione (GSH), a potent physiological antioxidant. Excess glucose-6-phosphate dehydrogenase (G6PD) deficiency in African Americans and low levels of L-cysteine diet in Hispanics can contributes to GSH deficiency and oxidative stress. Oxidative stress and monocyte adhesion was considered to be an initial event in the progression of vascular dysfunction and atherosclerosis. However, no previous study has investigated the contribution of GSH/G6PD deficiency to the expression of monocyte adhesion molecules. Using human U937 monocytes, this study examined the effect of GSH/G6PD deficiency and L cysteine supplementation on monocyte adhesion molecules. G6PD/GSH deficiency induced by either siRNA or inhibitors (6AN/BSO, respectively) significantly (p < 0.005) increased the levels of cell adhesion molecules (ICAM-1, VCAM-1, SELL, ITGB1 and 2); NADPH oxidase (NOX), reactive oxygen species (ROS) and MCP-1 were upregulated, and decreases in levels of GSH, and nitric oxide were observed. The expression of ICAM-1 and VCAM-1 mRNA levels increased in high glucose, MCP-1 or TNF-alpha-treated G6PD-deficient compared to G6PD-normal cells. L-Cysteine treatment significantly (p < 0.005) increased G6PD activity and levels of GSH, and decreased NOX, ROS, and adhesion molecules. Thus, GSH/G6PD deficiency increases susceptibility to monocyte adhesion processes, whereas L-cysteine supplementation can restore cellular GSH/G6PD and attenuates NOX activity and expression of cell adhesion molecules. PMID- 29626299 TI - Short-chain consensus alpha-neurotoxin: a synthetic 60-mer peptide with generic traits and enhanced immunogenic properties. AB - The three-fingered toxin family and more precisely short-chain alpha-neurotoxins (also known as Type I alpha-neurotoxins) are crucial in defining the elapid envenomation process, but paradoxically, they are barely neutralized by current elapid snake antivenoms. This work has been focused on the primary structural identity among Type I neurotoxins in order to create a consensus short-chain alpha-neurotoxin with conserved characteristics. A multiple sequence alignment considering the twelve most toxic short-chain alpha-neurotoxins reported from the venoms of the elapid genera Acanthophis, Oxyuranus, Walterinnesia, Naja, Dendroaspis and Micrurus led us to propose a short-chain consensus alpha neurotoxin, here named ScNtx. The synthetic ScNtx gene was de novo constructed and cloned into the expression vector pQE30 containing a 6His-Tag and an FXa proteolytic cleavage region. Escherichia coli Origami cells transfected with the pQE30/ScNtx vector expressed the recombinant consensus neurotoxin in a soluble form with a yield of 1.5 mg/L of culture medium. The 60-amino acid residue ScNtx contains canonical structural motifs similar to alpha-neurotoxins from African elapids and its LD50 of 3.8 ug/mice is similar to the most toxic short-chain alpha-neurotoxins reported from elapid venoms. Furthermore, ScNtx was also able to antagonize muscular, but not neuronal, nicotinic acetylcholine receptors (nAChR). Rabbits immunized with ScNtx were able to immune-recognize short-chain alpha-neurotoxins within whole elapid venoms. Type I neurotoxins are difficult to isolate and purify from natural sources; therefore, the heterologous expression of molecules such ScNtx, bearing crucial motifs and key amino acids, is a step forward to create common immunogens for developing cost-effective antivenoms with a wider spectrum of efficacy, quality and strong therapeutic value. PMID- 29626300 TI - Taurine prevents ethanol-induced apoptosis mediated by mitochondrial or death receptor pathways in liver cells. AB - One pathogenic mechanism of ethanol-induced liver injury is the excessive production of reactive oxygen species (ROS), which may result in alcoholic liver disease (ALD) characterized by cell death due to necrosis and apoptosis. Taurine was proved to protect against liver damage. However, whether taurine attenuates ethanol-induced hepatic apoptosis remains unknown. The present study aims to elucidate this effect and its underlying mechanism. Taurine was administered to ALD rats and an in vitro experiment in which taurine was added to primary rat hepatocytes cultured with ethanol was conducted. Mitochondrial function and anti oxidative capacity of the liver were tested. TUNEL and AO-EB double staining were conducted to detect apoptosis of liver cells. Expressions of factors and proteins involved in mitochondrial and death receptor pathways were detected by RT-PCR and Western-blot. The results showed that taurine inhibited the decline of cell functions and apoptosis in hepatocytes cultured with ethanol. Furthermore, increased malondialdehyde (MDA) and reduced superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), total antioxidant capacity (T-AOC), cytochrome c oxidase (COX) and NADH dehydrogenase (ND) in ALD rats were mediated by taurine. RT-PCR and western-blot results revealed that taurine down-regulated expression of Bax, Fas, Fas ligand (FasL), caspase 3 and caspase 9 while up-regulating the expression of Bcl-2 in ethanol-cultured hepatocytes. In summary, taurine inhibit ethanol-induced hepatic apoptosis by regulating mitochondrial or death receptor pathways. PMID- 29626302 TI - 2018 Presidential Address-Society of Surgical Oncology: The Fundamental Difference Between Cancer Treatment and Patient Care. PMID- 29626301 TI - Nucleoprotein from the unique human infecting Orthobunyavirus of Simbu serogroup (Oropouche virus) forms higher order oligomers in complex with nucleic acids in vitro. AB - Oropouche virus (OROV) is the unique known human pathogen belonging to serogroup Simbu of Orthobunyavirus genus and Bunyaviridae family. OROV is transmitted by wild mosquitoes species to sloths, rodents, monkeys and birds in sylvatic environment, and by midges (Culicoides paraensis and Culex quinquefasciatus) to man causing explosive outbreaks in urban locations. OROV infection causes dengue fever-like symptoms and in few cases, can cause clinical symptoms of aseptic meningitis. OROV contains a tripartite negative RNA genome encapsidated by the viral nucleocapsid protein (NP), which is essential for viral genome encapsidation, transcription and replication. Here, we reported the first study on the structural properties of a recombinant NP from human pathogen Oropouche virus (OROV-rNP). OROV-rNP was successfully expressed in E. coli in soluble form and purified using affinity and size-exclusion chromatographies. Purified OROV rNP was analyzed using a series of biophysical tools and molecular modeling. The results showed that OROV-rNP formed stable oligomers in solution coupled with endogenous E. coli nucleic acids (RNA) of different sizes. Finally, electron microscopy revealed a total of eleven OROV-rNP oligomer classes with tetramers (42%) and pentamers (43%) the two main populations and minor amounts of other bigger oligomeric states, such as hexamers, heptamers or octamers. The different RNA sizes and nucleotide composition may explain the diversity of oligomer classes observed. Besides, structural differences among bunyaviruses NP can be used to help in the development of tools for specific diagnosis and epidemiological studies of this group of viruses. PMID- 29626303 TI - Axillary Surgery for Early-Stage, Node-Positive Mastectomy Patients and the Use of Postmastectomy Chest Wall Radiation Therapy. AB - BACKGROUND: We examined axillary surgery in mastectomy patients with tumor positive nodes and how the type of axillary surgery impacted use of postmastectomy chest wall radiation therapy (PMRT). METHODS: Using the National Cancer Data Base, we selected patients with AJCC cT1/T2c N0 breast cancer with one to three tumor-positive lymph nodes treated between 2013 and 2014. Type of axillary surgery was analyzed using the FORDS scope of regional lymph node surgery variable. Multivariable logistic regression modeling was used to identify independent predictors associated with SNB alone and the use of PMRT. RESULTS: Of 8089 patients, 2482 (30.7%) underwent SNB alone, 1339 (16.6%) underwent axillary dissection (ALND) alone, and 4268 (52.7%) underwent SNB followed by ALND. Fifty seven percent of patients with micrometastases underwent SNB alone compared with 22.6% of patients with macrometastases. Independent predictors of SNB alone for patients with micrometastases were African American race, number of nodes positive, and PMRT. For patients with macrometastases, age, facility type and location, and PMRT were independent predictors for SNB alone. Of 2449 patients who underwent SNB alone, 1538 (62.8%) had no PMRT, 261 (10.7%) had PMRT alone, and 650 (26.5%) had PMRT with regional nodal irradiation. Patients undergoing SNB alone were 1.70 times [96% confidence interval (CI) 1.45-2.00] more likely to undergo PMRT than upfront ALND and 1.51 times (96% CI 1.34-1.71) more likely than SNB followed by ALND. CONCLUSIONS: Surgeons are omitting completion ALND in a third of early-stage, node-positive mastectomy patients. SNB alone patients are more likely to undergo PMRT than patients undergoing ALND. PMID- 29626304 TI - Efficacy of the Gallbladder Cancer Predictive Risk Score Based on Pathological Findings: A Propensity Score-Matched Analysis. AB - BACKGROUND: The optimal prognostic predictive system for gallbladder carcinoma (GBC) has not been established. The gallbladder cancer predictive risk score (GBRS) based on pathological findings identifies incidental GBC patients at risk of recurrence. OBJECTIVE: We aimed to validate the prognostic ability of the GBRS in all GBC patients following curative surgery. METHODS: Fifty-six patients with GBC who underwent curative surgery between 1996 and 2016 were included in this study. Univariate and multivariate analyses were performed to determine prognostic factors associated with overall and recurrence-free survival, and propensity score-matched analysis was performed. RESULTS: The median patient age was 71.9 years, and 39.3% of patients were males. All patients underwent curative surgery (33.9%, simple cholecystectomy; 66.1%, more advanced procedures, such as hepatectomy; and 32.1%, bile duct reconstruction). On univariate analysis, preoperative carbohydrate antigen 19-9 (CA19-9) >= 37 U/mL (p = 0.042), postoperative complications (p = 0.043), and a high GBRS (p < 0.001) were prognostic factors for worse overall survival. On multivariate analysis, CA19-9 >= 37 U/mL (p = 0.039 and p = 0.043, respectively) and a high GBRS (p = 0.001 and p = 0.010, respectively) were independent risk factors for poor overall and recurrence-free survival. After propensity score-matched analysis, the GBRS precisely predicted prognosis of patients with GBC. CONCLUSIONS: The GBRS is an easy and novel prognostic predicting score. Our validation revealed good discrimination, suggesting its clinical utility to improve individualized prediction of survival for patients undergoing resection of GBC. PMID- 29626305 TI - Prevalence and Predictors of Preoperative Venous Thromboembolism in Asymptomatic Patients Undergoing Major Oncologic Surgery. AB - BACKGROUND: Postoperative venous thromboembolism (VTE) is a leading cause of in hospital mortality for cancer patients; however, the prevalence of preoperative VTE remains unclear. OBJECTIVE: The aim of this study was to evaluate the prevalence and risk factors associated with preoperative VTE in asymptomatic patients undergoing major oncologic surgery. METHODS: Retrospective analysis of 346 patients identified from our prospectively maintained database of patients undergoing abdominopelvic oncologic surgery from 2009 to 2016. RESULTS: The prevalence of preoperative VTE found on screening venous duplex scan was 10.1%. Patients with a history of prior VTE were more likely to have a preoperative deep vein thrombosis (DVT) versus those with no prior VTE (42.9% vs. 4.5%, p < 0.01). Relative risk for prior VTE was 8.2 [95% confidence interval (CI) 4.7-14.3]. Older age was also associated with preoperative VTE. Regression modeling determined that patients were 1.24-fold as likely to have a preoperative DVT for every 5-year increase in age (relative risk 1.24, 95% CI 1.09-1.42). Patients with preoperative DVT were more likely to have been diagnosed with sepsis 1 month prior to surgery (8.6% vs. 1.6%, p = 0.04). There were no postoperative pulmonary emboli. The overall postoperative complication rate was higher in those with a preoperative DVT (25.7% vs. 13.2%, p = 0.071). CONCLUSION: Asymptomatic patients undergoing major oncologic surgery have a 10.1% prevalence of preoperative DVT. Increasing age, recent diagnosis of sepsis, and a history of prior VTE are significantly associated with preoperative DVTs. This suggests high-risk oncologic patients may benefit from screening lower extremity venous duplex ultrasound prior to Surgery. PMID- 29626306 TI - Value of Preoperative PET-CT in the Prediction of Pathological Stage of Gastric Cancer. AB - BACKGROUND: Preoperative precise staging is essential for the treatment of gastric cancer (GC); however, the diagnostic accuracy of conventional modalities needs to be increased. The present study investigated the clinical value of positron emission tomography-computed tomography (PET-CT) for the staging of GC. METHODS: This was a retrospective study of 117 patients with a clinical diagnosis of advanced GC who underwent PET-CT followed by gastrectomy. The incidence of FDG uptake in the primary tumor or lymph nodes and its relationship with clinicopathological factors, particularly pathological stage (pStage) III/IV, were examined. RESULTS: FDG uptake in the primary tumor was noted in 83 patients (70.9%). FDG uptake in the lymph nodes was detected in 21 patients (17.9%), and its sensitivity and specificity for lymph node metastasis were 22.7 and 90.5%, respectively. Multiple logistic regression analyses showed that FDG uptake in the primary tumor (odds ratio (OR) 2.764; 95% confidence interval (CI) 1.104-7.459, p = 0.029) and that in the lymph nodes (OR 4.660; 95% CI 1.675-13.84, p = 0.003) were factors independently associated with pStage III/IV. FDG uptake in the primary tumor detected pStage III/IV with higher sensitivity (80.4%) and that in lymph nodes found pStage III/IV with higher specificity (88.7%) than those of upper endoscopy plus CT (60.9 and 67.6%, respectively). CONCLUSIONS: PET-CT appears to be a useful complementary modality in the assessment of pStage III/IV because of the high sensitivity of FDG uptake in the primary tumor and the high specificity of FDG uptake in the lymph nodes. PMID- 29626307 TI - Preoperative Fluorouracil, Doxorubicin, and Streptozocin for the Treatment of Pancreatic Neuroendocrine Liver Metastases. AB - INTRODUCTION: While preoperative chemotherapy is frequently utilized before resection of non-neuroendocrine liver metastases, patients with resectable neuroendocrine liver metastases typically undergo surgery first. FAS is a cytotoxic chemotherapy regimen that is associated with substantial response rates in locally advanced and metastatic pancreatic neuroendocrine tumors. METHODS: All patients who underwent R0/R1 resection of pancreatic neuroendocrine liver metastases at a single institution between 1998 and 2015 were included. The outcomes of patients treated with preoperative FAS were compared with those of patients who were not. RESULTS: Of the 67 patients included, 27 (40.3%) received preoperative FAS, whereas 40 (59.7%) did not. Despite being associated with higher rates of synchronous disease, lymph node metastases, and larger tumor size, patients who received preoperative FAS had similar overall survival [overall survival (OS), 108.2 months (95% confidence interval (CI) 78.0-136.0) vs. 107.0 months (95% CI 78.0-136.0), p = 0.64] and recurrence-free survival [RFS, 25.1 months (95% CI 23.2-27.0) vs. 18.0 months (95% CI 13.8-22.2), p = 0.16] as patients who did not. Among patients who presented with synchronous liver metastases (n = 46), the median OS [97.3 months (95% CI 65.9-128.6) vs. 65.0 months (95% CI 28.1-101.9), p = 0.001] and RFS [24.8 months (95% CI 22.6 26.9) vs. 12.1 months (2.2-22.0), p = 0.003] were significantly greater among patients who received preoperative FAS compared with those who did not. CONCLUSIONS: The use of FAS before liver resection is associated with improved OS compared with surgery alone among patients with advanced synchronous pancreatic neuroendocrine liver metastases. PMID- 29626308 TI - Patterns of Treatment Failure in Patients with Sinonasal Mucosal Melanoma. AB - BACKGROUND: Head and neck mucosal melanoma is a locally aggressive tumor with a high recurrence rate. The paranasal sinuses and nasal cavity are the most common primary tumor sites. OBJECTIVE: The purpose of this retrospective study was to identify independent predictors of outcome in sinonasal mucosal melanoma (SNMM) and characterize the patterns of treatment failure. METHODS: This study included 198 patients with SNMM who had been treated at The University of Texas MD Anderson Cancer Center from 1 January 1991 through 31 December 2016. The survival outcomes included overall survival (OS), disease-specific survival (DSS), disease free survival (DFS), local recurrence-free survival, and distant metastasis-free survival. A stepwise regression analysis was used to assess associations in the multivariate models. RESULTS: The 5-year OS, DSS, and DFS rates were 38, 58, and 27%, respectively. Independent predictors of poor OS and DSS were the paranasal sinuses as the primary tumor site [hazard ratio (HR) 1.73, 95% confidence interval (CI) 1.11-2.66; and HR 2.12, 95% CI 1.21-3.74, respectively] and the presence of distant metastases at presentation (HR 4.53, 95% CI 2.24-7.83; and HR 3.6, 95% CI 1.12-7.1). Recurrence occurred in 96 patients (48%). The most common cause of treatment failure was distant metastasis in 69 of 198 patients (35%), followed by local [36 (18%)] and regional [22 (11%)] recurrence. CONCLUSION: The most common cause of treatment failure in SNMM is distant metastasis. The tumor site and the presence of metastatic disease at presentation were the only independent predictors of survival. These data can be used to inform quality improvement efforts and the counseling of high-risk SNMM patients. PMID- 29626309 TI - Application of Serum Annexin A3 in Diagnosis, Outcome Prediction and Therapeutic Response Evaluation for Patients with Hepatocellular Carcinoma. AB - PURPOSE: Annexin A3 (ANXA3) could induce progression of hepatocellular carcinoma (HCC) via promoting stem cell traits of CD133-positive cells. Moreover, serum ANXA3 showed preliminary diagnostic potential, however further validation was required. Meanwhile, the prognostic value of ANXA3 remained elusive. The present study aimed to validate diagnostic performance and further systematically investigate the prognostic value of serum ANXA3. METHODS: Serum ANXA3 of 368 HCC patients was determined by enzyme-linked immunosorbent assay (ELISA); 295 of these patients underwent resection and 73 underwent transcatheter arterial chemoembolization (TACE). Diagnostic performance of ANXA3 was evaluated by receiver operating characteristic (ROC) analysis, and the prognostic value was evaluated by Cox regression and Kaplan-Meier analysis. To evaluate the relationship between serum ANXA3 and circulating CD133 mRNA-positive tumor cells (CD133mRNA+ CTCs), real-time polymerase chain reaction was conducted in 69 patients who underwent resection. RESULTS: Serum ANXA3 provided greater diagnostic performance than alpha-fetoprotein (area under the curve [AUC] 0.869 vs. 0.782), especially in early diagnosis (AUC 0.852 vs. 0.757) and discriminating HCC from patients at risk (0.832 vs. 0.736). Pretreatment ANXA3 was an independent predictor of tumor recurrence (hazard ratio [HR] 1.87, 95% confidence interval [CI] 1.26-2.76, p = 0.002)/progression (HR 1.88, 95% CI 1.04 3.43, p = 0.038) and survival (resectable: HR 2.26, 95% CI 1.44-3.56, p = 0.001; unresectable: HR 2.08, 95% CI 1.10-4.05, p = 0.025), and retained its performance in low-recurrence-risk subgroups. Specifically, dynamic changes of ANXA3-positive status was associated with worse prognosis. ANXA3 was positively correlated with CD133mRNA+ CTCs (r = 0.601, p < 0.001). In patients with detectable CD133mRNA+ CTC, high ANXA3 was positively associated with a higher risk of recurrence and shorter overall survival. CONCLUSIONS: Serum ANXA3 shows promise as a biomarker for diagnosis, outcome prediction, and therapeutic response evaluation in patients with HCC. PMID- 29626310 TI - GA3 application in grapes (Vitis vinifera L.) modulates different sets of genes at cluster emergence, full bloom, and berry stage as revealed by RNA sequence based transcriptome analysis. AB - In grapes (Vitis vinifera L.), exogenous gibberellic acid (GA3) is applied at different stages of bunch development to achieve desirable bunch shape and berry size in seedless grapes used for table purpose. RNA sequence-based transcriptome analysis was used to understand the mechanism of GA3 action at cluster emergence, full bloom, and berry stage in table grape variety Thompson Seedless. At cluster emergence, rachis samples were collected at 6 and 24 h after application of GA3, whereas flower clusters and berry samples were collected at 6, 24, and 48 h after application at full bloom and 3-4 mm berry stages. Seven hundred thirty-three genes were differentially expressed in GA3-treated samples. At rachis and flower cluster stage respectively, 126 and 264 genes were found to be significantly differentially expressed within 6 h of GA3 application. The number of DEG reduced considerably at 24 h. However, at berry stage, major changes occurred even at 24 h and a number of DEGs at 6 and 24 h were 174 and 191, respectively. As compared to upregulated genes, larger numbers of genes were downregulated. Stage-specific response to the GA3 application was observed as evident from the unique set of DEGs at each stage and only a few common genes among three stages. Among the DEGs, 67 were transcription factors. Functional categorization and enrichment analysis revealed that several transcripts involved in sucrose and hexose metabolism, hormone and secondary metabolism, and abiotic and biotic stimuli were enriched in response to application of GA3. A high correlation was recorded for real-time PCR and transcriptome data for selected DEGs, thus indicating the robustness of transcriptome data obtained in this study for understanding the GA3 response at different stages of berry development in grape. Chromosomal localization of DEGs and identification of polymorphic microsatellite markers in selected genes have potential for their use in breeding for varieties with improved bunch architecture. PMID- 29626312 TI - Experiences of stigma and health care engagement among Black MSM newly diagnosed with HIV/STI. AB - Rates of HIV/STI transmission among Black men who have sex with men (BMSM) are alarmingly high and demand urgent public health attention. Stigma related concerns are a key barrier to accessing health care and prevention tools, yet limited research has been focused in this area. Experiences of stigma related to health care were evaluated among 151 BMSM residing in the Atlanta, GA area, both prior to and post HIV or STI diagnosis in a longitudinal study (data collected from 2014 to 2016). Findings demonstrated that inadequate health care engagement is associated with post-diagnosis anticipated stigma (b = - 0.38, SE = 0.17 p <= .05). Pre-diagnosis prejudice is a predictor of post-diagnosis enacted (b = 0.39, SE = 0.14, p < .01), anticipated (b = .28, SE = 0.14, p < .05), and internalized (b = .22, SE = 0.06, p < .001) stigmas. This study is the first of its kind to assess experiences of stigma among BMSM during a critical time (i.e., before and after diagnosis) for HIV/STI prevention and treatment. Results provide a novel understanding of how stigma unfolds over-time and provide direction for stigma intervention development. PMID- 29626311 TI - Exploration of miRNAs and target genes of cytoplasmic male sterility line in cotton during flower bud development. AB - Cytoplasmic male sterility (CMS) lines provide crucial material to harness heterosis for crop plants, which serves as an important strategy for hybrid seed production. However, the molecular mechanism remains obscure. Although microRNAs (miRNAs) play important roles in vegetative growth and reproductive growth, there are few reports on miRNAs regulating the development of male sterility in Upland cotton. In present study, 12 small RNA libraries were constructed and sequenced for two development stages of flower buds from a CMS line and its maintainer line. Based on the results, 256 novel miRNAs were allocated to 141 new miRNA families, and 77 known miRNAs belonging to 54 conserved miRNA families were identified as well. Comparative analysis revealed that 61 novel and 10 conserved miRNAs were differentially expressed. Further transcriptome analysis identified 232 target genes for these miRNAs, which participated in cellular developmental process, cell death, pollen germination, and sexual reproduction. In addition, expression patterns of typical miRNA and the negatively regulated target genes, such as PPR, ARF, AP2, and AFB, were verified by qRT-PCR in cotton flower buds. These targets were previously reported to be related to reproduction development and male sterility, suggesting that miRNAs might act as regulators of CMS occurrence. Some miRNAs displayed specific expression profiles in special developmental stages of CMS line and its fertile hybrid (F1). Present study offers new information on miRNAs and their related target genes in exploiting CMS mechanism, and revealing the miRNA regulatory networks in Upland cotton. PMID- 29626314 TI - Necrotising fasciitis: a fatal case of sepsis and a diagnostic challenge - case report and review of literature. AB - BACKGROUND: Necrotising fasciitis (NF) is a severe, devastating soft tissue infection characterised by rapidly progressing tissue necrosis. This rare condition has a high mortality rate and poses diagnostic and management challenges to the clinician. There is usually a history of trauma, which maybe trivial. Some of the premorbid conditions associated with NF are diabetes and or immunocompromised state. It requires prompt recognition and early treatment with intravenous antibiotics and extensive surgical debridement. CASE PRESENTATION: We describe a 74-year-old lady who presented to our emergency department following 3 days' history of watery diarrhoea and feeling generally unwell. She had signs of severe sepsis and was started on broad-spectrum intravenous antibiotics and fluids for sepsis with unknown source. She was found to have an area of blackish discolouration on her thigh which was suspected as necrotising fasciitis (NF) and referred to the surgeons. She had no history of trauma or significant comorbidity. She underwent surgical exploration and debridement within few hours of arrival into the emergency department and subsequent further debridement with above-knee amputation of the affected limb. She eventually died after about 48 h of hospital stay despite an early diagnosis and prompt surgical debridement and a multidisciplinary approach. CONCLUSIONS: Necrotising fasciitis has been previously reported in literature but we would like to highlight through this case the importance of looking for the source of sepsis by thorough clinical examination and the need to have a high threshold of suspicion for this rare condition and urgent involvement of a surgical team for debridement. PMID- 29626313 TI - Evidence for mood-dependent attentional processing in asthma: attentional bias towards health-threat in depressive mood and attentional avoidance in neutral mood. AB - Attentional biases have been observed in populations with psychological disorders, but have been under-investigated in populations with physical illnesses. This study investigated potential attentional biases in asthma as a function of mood. Asthma (N = 45), and healthy (N = 39) participants were randomly allocated to a depressed or a neutral mood state induction. They completed a visual probe task that measured participants' reaction times to health-threat and neutral pictures and words. Compared to the healthy controls, the asthma group showed attentional bias towards health-threat pictures in depressed mood, and avoidance of health-threat pictures in neutral mood. Attentional biases were found in a group with a physical illness as a function of induced mood. It is suggested that attentional processes in people with physical illness may be important in relation to symptom perception and illness management. PMID- 29626316 TI - Comparative in silico profiling of epigenetic modifiers in human tissues. AB - The technology of tissue differentiation from human pluripotent stem cells has attracted attention as a useful resource for regenerative medicine, disease modeling and drug development. Recent studies have suggested various key factors and specific culture methods to improve the successful tissue differentiation and efficient generation of human induced pluripotent stem cells. Among these methods, epigenetic regulation and epigenetic signatures are regarded as an important hurdle to overcome during reprogramming and differentiation. Thus, in this study, we developed an in silico epigenetic panel and performed a comparative analysis of epigenetic modifiers in the RNA-seq results of 32 human tissues. We demonstrated that an in silico epigenetic panel can identify epigenetic modifiers in order to overcome epigenetic barriers to tissue-specific differentiation. PMID- 29626315 TI - New views and possibilities of antidiabetic drugs in treating and/or preventing mild cognitive impairment and Alzheimer's Disease. AB - Mounting evidence suggests that diabetes mellitus (DM) is associated with mild cognitive impairment (MCI), vascular dementia and Alzheimer's disease (AD). Biological, clinical and epidemiological data support a close link between DM and AD. Increasingly, studies have found that several antidiabetic agents can promote neurogenesis, and clinically ameliorate cognitive and memory impairments in different clinical settings. Data has shown that these antidiabetic drugs positively affect mitochondrial and synaptic function, neuroinflammation, and brain metabolism. Evidence to date strongly suggests that these antidiabetic drugs could be developed as disease-modifying therapies for MCI and AD in patients with and without diabetes. PMID- 29626317 TI - Mining and comparative survey of EST-SSR markers among members of Euphorbiaceae family. AB - Euphorbiaceae represents flowering plants family of tropical and sub-tropical region rich in secondary metabolites of economic importance. To understand and assess the genetic makeup among the members, this study was undertaken to characterize and compare SSR markers from publicly available ESTs and GSSs of nine selected species of the family. Mining of SSRs was performed by MISA, primer designing by Primer3, while functional annotation, gene ontology (GO) and enrichment analysis were performed by Blast2GO. A total 12,878 number of SSRs were detected from 101,701 number of EST sequences. SSR density ranged from 1 SSR/3.22 kb to 1 SSR/15.65 kb. A total of 1873 primer pairs were designed for the annotated SSR-Contigs. About 77.07% SSR-ESTs could be assigned a significant match to the protein database. 3037 unique SSR-FDM were assigned and IPR003657 (WRKY Domain) was found to be the most dominant FDM among the members. 1810 unique GO terms obtained were further subjected to enrichment analysis to obtain 513 statistically significant GO terms mapped to the SSR containing ESTs. Most frequent enriched GO terms were, GO:0003824 for molecular function, GO:0006350 for biological process and GO:0005886 for cellular component, justifying the richness of defensive secondary metabolites and phytomedicine within the family. The results from this study provides tangible insight to genetic make-up and distribution of SSRs. Functional annotation corresponded many genes of unknown functions which may be considered as novel genes or genes responsible for stress specific secondary metabolites. Further studies are required to understand stress specific genes accountable for leveraging the synthesis of secondary metabolites. PMID- 29626318 TI - Thermal stability and conformation of DNA and proteins under the confined condition in the matrix of hydrogels. AB - Spatially confined environments are seen in biological systems and in the fields of biotechnology and nanotechnology. The confinement restricts the conformational space of polymeric molecules and increasing the degree of molecular crowding. Here, we developed preparation methods for agarose and polyacrylamide gels applicable to UV spectroscopy that can evaluate the confinement effects on DNA and protein structures. Measurements of UV absorbance and CD spectra showed no significant effect of the confinement in the porous media of agarose gels on the base-pair stability of DNA polynucleotides [poly(dA)/poly(dT)] and oligonucleotides (hairpin, duplex, and triplex structures). On the other hand, a highly confined environment created by polyacrylamide gels at high concentrations increased the stability of polynucleotides while leaving that of oligonucleotides unaffected. The changes in the base-pair stability of the polynucleotides were accompanied by the perturbation of the helical conformation. The polyacrylamide gels prepared in this study were also used for the studies on proteins (lysozyme, bovine serum albumin, and myoglobin). The effects on the proteins were different from the effects on DNA structures, suggesting different nature of interactions within the gel. The experimental methods and results are useful to understand the physical properties of nucleic acids and proteins under confined conditions. PMID- 29626320 TI - Uric acid levels are associated with endothelial dysfunction and severity of coronary atherosclerosis during a first episode of acute coronary syndrome. AB - The role of serum uric acid in coronary artery disease has been extensively investigated. It was suggested that serum uric acid level (SUA) is an independent predictor of endothelial dysfunction and related to coronary artery lesions. However, the relationship between SUA and severity of coronary atherosclerosis evaluated via endothelial dysfunction using peripheral arterial tone (PAT) and the reactive hyperhemia index (RHI) has not been investigated during a first episode of acute coronary syndrome (ACS). The aim of our study was to address this point. We prospectively enrolled 80 patients with a first episode of ACS in a single-center observational study. All patients underwent coronary angiography, evaluation of endothelial function via the RHI, and SUA measurement. The severity of the coronary artery lesion was assessed angiographically, and patients were classified in three groups based on the extent of disease and Gensini and SYNTAX scores. Endothelial function was considered abnormal if RHI < 1.67. We identified a linear correlation between SUA and RHI (R2 = 0.66 P < 0.001). In multivariable analyses, SUA remained associated with RHI, even after adjustment for traditional cardiovascular risk factors and renal function. SUA was associated with severity of coronary artery disease. SUA is associated with severity of coronary atherosclerosis in patients with asymptomatic hyperuricemia. This inexpensive, readily measured biological parameter may be useful to monitor ACS patients. PMID- 29626321 TI - LncRNA PlncRNA-1 overexpression inhibits the growth of breast cancer by upregulating TGF-beta1 and downregulating PHGDH. AB - OBJECTIVE: To investigate the role of lncRNA PlncRNA-1 in the pathogenesis of breast cancer. METHODS: A total of 78 patients with breast cancer as well as 48 healthy females were included in this study. Expression in tumor tissues and adjacent healthy tissues of breast cancer patients, as well as in breast tissues and serum of both patients and healthy control was detected by qRT-PCR. Cell proliferation was detected by CCK-8 assay, and cell apoptosis was tested by MTT assay. PlncRNA-1 overexpression cell lines were constructed and the effects on TGF-beta1 as well as phosphoglycerate dehydrogenase (PHGDH) were explored by western blot. RESULTS: Expression levels of PlncRNA-1 were significantly lower in tumor tissues than those in adjacent healthy tissues. Significantly lower expression levels of PlncRNA-1 were also found in breast cancer patients than those in healthy controls in both breast tissue and serum. Upregulation of PlncRNA-1 promoted the expression of TGF-beta1, but inhibited the expression of PHGDH. LncRNA PlncRNA-1 overexpression reduced the proliferation rate, but increased the apoptosis rate of breast cancer cells, while treatment with TGF beta inhibitor reduced those effects of PlncRNA-1 overexpression. CONCLUSION: LncRNA PlncRNA-1 overexpression inhibits the growth of breast cancer by upregulating TGF-beta1 and downregulating PHGDH. PMID- 29626323 TI - The Case for a Private Healthcare Insurance Monopoly. AB - This article advocates for a regulated private monopoly as an audacious solution to replace Obamacare, help manage Medicare and Medicaid and reform the US healthcare insurance industry. Contemporary economics vilifies monopolies and praises the 'magic wand' of perfect competition without much debate on the merits of these assumptions. The problems with the perfect competition model as applied to healthcare insurance are well established, but exploration of other possible economic models (i.e. monopoly and oligopoly) as a replacement for Obamacare is non-existent. New thinking about the role of monopolies may help achieve public policy goals and make health insurance available to the largest number of people at a reasonable premium while containing medical costs. PMID- 29626324 TI - Apalutamide: First Global Approval. AB - Apalutamide (ErleadaTM) is a next-generation oral androgen receptor (AR) inhibitor that is being developed by Janssen for the treatment of prostate cancer (PC). It binds directly to the ligand-binding domain of the AR and blocks the effects of androgens. In February 2018, apalutamide received its first global approval in the USA for the treatment of non-metastatic castration-resistant PC (nmCRPC). Apalutamide is undergoing phase III investigation in chemotherapy-naive patients with metastatic CRPC (in combination with abiraterone acetate plus prednisone), patients with high-risk localized or locally advanced PC receiving primary radiation therapy, and in patients with metastatic hormone-sensitive PC and biochemically-relapsed PC. This article summarizes the milestones in the development of apalutamide leading to this first approval in nmCRPC. PMID- 29626322 TI - A Scoping Review Protocol to Explore the Use of Interleukin-1-Targeting Drugs for the Treatment of Dermatological Diseases: Indications, Mechanism of Action, Efficacy, and Safety. AB - INTRODUCTION: The interleukin (IL)-1 pathway has been identified as being involved in inflammatory and neoplastic skin diseases such as psoriasis, atopic dermatitis, neutrophilic dermatosis, melanoma, and squamous cell carcinoma. Drugs developed to target the IL-1 pathway are currently used to treat these pathologies, and although they are becoming more selective, they are not exempt from adverse events and high costs. Integrating the best research evidence with clinical experience and patient needs has been shown to improve care, health, and cost outcomes. This is because evidence-based guidelines rank interventions according to cost-effectiveness. However, evidence on this topic is scarce for several reasons. First, although randomized clinical trials currently provide the best evidence, they are not always available. Second, there are no secondary scientific studies that summarize the use of IL-1-targeting agents in dermatology. We therefore sought to develop an a priori protocol for broadly reviewing the available evidence on the use of IL-1-targeting drugs in the treatment of dermatological diseases. METHODS: We used the latest methodology to perform a scoping review as described in the Joanna Briggs Institute manual. RESULTS/DISCUSSION: Developing and applying a methodology for evidence synthesis promotes reproducibility and increases the validity of secondary scientific investigations, making it the optimal strategy for scientifically synthesizing a broad field such as the indications for and the mechanisms of action, efficacies, safety, and costs of IL-1-targeting drugs in the treatment of dermatological diseases. Quantitative synthesis facilitates the detection of knowledge gaps and the identification of new questions that can be addressed through systematic reviews. We present an a priori protocol for exploring the available evidence on this topic. PMID- 29626319 TI - Clearance of Amyloid Beta and Tau in Alzheimer's Disease: from Mechanisms to Therapy. AB - Alzheimer's disease (AD) is the most common neurodegenerative disease. Pathological proteins of AD mainly contain amyloid-beta (Abeta) and tau. Their deposition will lead to neuron damage by a series of pathways, and then induce memory and cognitive impairment. Thus, it is pivotal to understand the clearance pathways of Abeta and tau in order to delay or even halt AD. Abeta clearance mechanisms include ubiquitin-proteasome system, autophagy-lysosome, proteases, microglial phagocytosis, and transport from the brain to the blood via the blood brain barrier (BBB), arachnoid villi and blood-CSF barrier, which can be named blood circulatory clearance. Recently, lymphatic clearance has been demonstrated to play a key role in transport of Abeta into cervical lymph nodes. The discovery of meningeal lymphatic vessels is another direct evidence for lymphatic clearance in the brain. Furthermore, periphery clearance also contributes to Abeta clearance. Tau clearance is almost the same as Abeta clearance. In this review, we will mainly introduce the clearance mechanisms of Abeta and tau proteins, and summarize corresponding targeted drug therapies for AD. PMID- 29626325 TI - What to Do with a Second Chance in Life? Long-Term Experiences of Non-carriers of Huntington's Disease. AB - Little is known about how people's lives are influenced when going from a 50% risk status of Huntington's disease (HD) to no risk after performing predictive testing. In this study, 20 interviews were conducted to explore the long-term (> 5 years) experiences after receiving predictive test results as a non-carrier of HD. The results showed a broad variety of both positive and negative reactions. The most prominent positive reaction reported was feelings of relief and gratitude, of not carrying the HD mutation for themselves and for their children. Also, the non-carrier status promoted in some individuals' significant life changes such as a wishing to have (more) children, pursuing a career or breaking up from an unhappy relationship. However, negative reactions on their psychological well-being were also described. Some had experienced psychological pressure of needing to do something extraordinary in their lives; others expressed feelings of guilt towards affected or untested siblings, resulting in sadness or clinical depression. The new genetic risk status could generate a need of re-orientation, a process that for some persons took several years to accomplish. The results of the present study show the importance of offering long term post-result counselling for non-carriers in order to deal with the psychological consequences that may follow predictive testing. PMID- 29626326 TI - Development of a Physiologically Based Pharmacokinetic Model for Sinogliatin, a First-in-Class Glucokinase Activator, by Integrating Allometric Scaling, In Vitro to In Vivo Exploration and Steady-State Concentration-Mean Residence Time Methods: Mechanistic Understanding of its Pharmacokinetics. AB - AIM: The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model for sinogliatin (HMS-5552, dorzagliatin) by integrating allometric scaling (AS), in vitro to in vivo exploration (IVIVE), and steady-state concentration-mean residence time (Css-MRT) methods and to provide mechanistic insight into its pharmacokinetic properties in humans. METHODS: Human major pharmacokinetic parameters were analyzed using AS, IVIVE, and Css-MRT methods with available preclinical in vitro and in vivo data to understand sinogliatin drug metabolism and pharmacokinetic (DMPK) characteristics and underlying mechanisms. On this basis, an initial mechanistic PBPK model of sinogliatin was developed. The initial PBPK model was verified using observed data from a single ascending dose (SAD) study and further optimized with various strategies. The final model was validated by simulating sinogliatin pharmacokinetics under a fed condition. The validated model was applied to support a clinical drug-drug interaction (DDI) study design and to evaluate the effects of intrinsic (hepatic cirrhosis, genetic) factors on drug exposure. RESULTS: The two-species scaling method using rat and dog data (TS-rat,dog) was the best AS method in predicting human systemic clearance in the central compartment (CL). The IVIVE method confirmed that sinogliatin was predominantly metabolized by cytochrome P450 (CYP) 3A4. The Css-MRT method suggested dog pharmacokinetic profiles were more similar to human pharmacokinetic profiles. The estimated CL using the AS and IVIVE approaches was within 1.5-fold of that observed. The Css-MRT method in dogs also provided acceptable prediction of human pharmacokinetic characteristics. For the PBPK approach, the 90% confidence intervals (CIs) of the simulated maximum concentration (Cmax), CL, and area under the plasma concentration-time curve (AUC) of sinogliatin were within those observed and the 90% CI of simulated time to Cmax (tmax) was closed to that observed for a dose range of 5-50 mg in the SAD study. The final PBPK model was validated by simulating sinogliatin pharmacokinetics with food. The 90% CIs of the simulated Cmax, CL, and AUC values for sinogliatin were within those observed and the 90% CI of the simulated tmax was partially within that observed for the dose range of 25-200 mg in the multiple ascending dose (MAD) study. This PBPK model selected a final clinical DDI study design with itraconazole from four potential designs and also evaluated the effects of intrinsic (hepatic cirrhosis, genetic) factors on drug exposure. CONCLUSIONS: Sinogliatin pharmacokinetic properties were mechanistically understood by integrating all four methods and a mechanistic PBPK model was successfully developed and validated using clinical data. This PBPK model was applied to support the development of sinogliatin. PMID- 29626327 TI - Community response to a sustainable restoration plan for a superfund site. AB - Large-scale copper (Cu) mining activities in Michigan's Upper Peninsula produced millions of metric tons of mining wastes also known as stamp sands. The stamp sands containing high concentrations of Cu were disposed of into several lakes connected to the Lake Superior. Eventually, as aquatic organisms in these lakes started to exhibit toxicity symptoms, the stamp sands were dredged and discarded on the lake shores. Consequently, these areas turned into degraded, marginal lands and were collectively classified as a Torch Lake Superfund site by the US EPA. Due to the lack of vegetative cover, the Cu-rich stamp sands eroded into the lakes, affecting the aquatic life. To alleviate this issue, a sustainable restoration plan (SRP) was developed and tested in a greenhouse environment prior to field implementation. Cold-tolerant oilseed crops, camelina (Camelina sativa) and field pennycress (Thlaspi arvense), were grown on compost-fertilized stamp sands, which reduced soil erosion by acting as a vegetative cap. Oilseed plants produced normal yield, demonstrating their potential utilization as biofuel feedstock. Prior to implementing the SRP in field-scale in the Torch Lake Superfund site, a public opinion survey of the local community was conducted to understand the views of residents. Door-to-door survey was performed in July August 2015, which yielded a response rate of 68.1%. Results showed that residents were generally concerned with stamp sand erosion into the Torch Lake and were overwhelmingly supportive of the SRP, which would not only provide environmental benefits but could boost the local economy via biofuel production. To gauge the general environmental awareness of the respondents, the survey included questions on climate change. Most of the respondents acknowledged that climate change is real and anthropogenically mediated. Having college education and a relatively high annual household income showed a positive and significant correlation with climate change awareness. PMID- 29626328 TI - Techno-economic and environmental assessment of biogas production from banana peel (Musa paradisiaca) in a biorefinery concept. AB - Two scenarios for the biogas production using Banana Peel as raw material were evaluated. The first scenario involves the stand-alone production of biogas and the second scenario includes the biogas production together with other products under biorefinery concept. In both scenarios, the influence of the production scale on the process economy was assessed and feasibility limits were defined. For this purpose, the mass and energy balances were established using the software Aspen Plus along with kinetic models reported in the literature. The economic and environmental analysis of the process was performed considering Colombian economic conditions. As a result, it was found that different process scales showed great potential for biogas production. Thus, plants with greater capacity have a greater economic benefit than those with lower capacity. However, this benefit leads to high-energy consumption and greater environmental impact. PMID- 29626329 TI - Assessment of toxicity of heavy metal-contaminated soils toward Collembola in the paddy fields supported by laboratory tests. AB - Effects on soil Collembola of Cu, Zn, Pb, and Cd pollution from Cu smelters over 40 years were investigated in paddy fields from an area of Eastern China. We compared the field effects to those observed in single-species laboratory tests employing the hemiedaphic collembolan Folsomia candida and the epedaphic Sinella curviseta obtained from laboratory cultures and exposed to field-collected polluted soil. The results indicated that different collembolan species responded differently to the pollution in the fields and could be divided into sensitive, indifferent, and tolerant types accordingly. The abundance of sensitive species decreased as the pollution increased, but this was not the same for indifferent and tolerant species. The dominant species changed from sensitive to tolerant species as the pollution increased. The reproduction of F. candida and S. curviseta was most sensitive to the contaminated soil compared to growth and survival; the sensitivity of the two species was similar. The growth was more sensitive than the survival for F. candida but not for S. curviseta. The growth and survival of F. candida were much more sensitive than those of S. curviseta. Sensitivity of field populations of F. candida (EC10 31 [15-46]) and hemiedaphic species Folsomia quadrioculata (EC10 52 [0.7-102]) were comparable with sensitivity of the reproduction of F. candida in the single-species tests (EC10 21 [14-27]), suggesting that single-species test based on laboratory cultures and field soil could be used to link laboratory and field data and then reflect the field situation. S. curviseta could be used as an epedaphic species in single species tests and F. quadrioculata as an indicator species for assessment of field effect. PMID- 29626331 TI - In silico design of polycationic antimicrobial peptides active against Pseudomonas aeruginosa and Staphylococcus aureus. AB - Antimicrobial peptides (AMPs) have the potential to become valuable antimicrobial drugs in the coming years, since they offer wide spectrum of action, rapid bactericidal activity, and low probability for resistance development in comparison with traditional antibiotics. The search and improvement of methodologies for discovering new AMPs to treat resistant bacteria such as Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii and Pseudomonas aeruginosa are needed for further development of antimicrobial products. In this work, the software Peptide ID 1.0(r) was used to find new antimicrobial peptide candidates encrypted in proteins, considering the physicochemical parameters characteristics of AMPs such as positive net charge, hydrophobicity, and sequence length, among others. From the selected protein fragments, new AMPs were designed after conservative and semi-conservative modifications and amidation of the C-terminal region. In vitro studies of the antimicrobial activity of the newly designed peptides showed that two peptides, P3-B and P3-C, were active against P. aeruginosa Escherichia coli and A. baumannii with low minimum inhibitory concentrations. Peptide P3-C was also active against K. pneumoniae and S. aureus. Furthermore, bactericidal activity and information on the possible mechanisms of action are described according to the scanning electron microscopy studies. PMID- 29626330 TI - Distribution of greenhouse gases in hyper-arid and arid areas of northern Chile and the contribution of the high altitude wetland microbiome (Salar de Huasco, Chile). AB - Northern Chile harbors different bioclimatic zones including hyper-arid and arid ecosystems and hotspots of microbial life, such as high altitude wetlands, which may contribute differentially to greenhouse gases (GHG) such as carbon dioxide (CO2), methane (CH4) and nitrous oxide (N2O). In this study, we explored ground level GHG distribution and the potential role of a wetland situated at 3800 m.a.s.l, and characterized by high solar radiation < 1600 W m-2, extreme temperature ranges (-12 to 24 degrees C) and wind stress (< 17 m s-1). The water source of the wetland is mainly groundwater springs, which generates streams and ponds surrounded by peatlands. These sites support a rich microbial aquatic life including diverse bacteria and archaea communities, which transiently form more complex structures, such as microbial mats. In this study, GHG were measured in the water and above ground level air at the wetland site and along an elevation gradient in different bioclimatic areas from arid to hyper-arid zones. The microbiome from the water and sediments was described by high-throughput sequencing 16S rRNA and rDNA genes. The results indicate that GHG at ground level were variable along the elevation gradient potentially associated with different bioclimatic zones, reaching high values at the high Andean steppe and variable but lower values in the Atacama Desert and at the wetland. The water areas of the wetland presented high concentrations of CH4 and CO2, particularly at the spring areas and in air bubbles below microbial mats. The microbial community was rich (> 40 phyla), including archaea and bacteria potentially active in the different matrices studied (water, sediments and mats). Functional microbial groups associated with GHG recycling were detected at low frequency, i.e., < 2.5% of total sequences. Our results indicate that hyper-arid and arid areas of northern Chile are sites of GHG exchange associated with various bioclimatic zones and particularly in aquatic areas of the wetland where this ecosystem could represent a net sink of N2O and a source for CH4 and CO2. PMID- 29626332 TI - Benzalkonium chloride tolerance of Listeria monocytogenes strains isolated from a meat processing facility is related to presence of plasmid-borne bcrABC cassette. AB - Listeria monocytogenes is a serious foodborne pathogen capable of persisting in food processing environments. Tolerance to disinfectants used in industrial settings constitutes an important factor of Listeria survival. In the present study, the mechanism of tolerance to benzalkonium chloride (BAC) was investigated in 77 L. monocytogenes isolates from a meat facility. By PCR approach, the mdrL and lde chromosomal efflux pump genes were detected in all isolates. No isolate was positive for qacH and emrE genes. However, the bcrABC cassette was present in 17 isolates of serogroup IIa possessing the same AscI/ApaI pulsotype, the operon being localized on a plasmid. The significant relation of BAC tolerance with bcrABC presence was confirmed as all bcrABC positive isolates showed the highest minimal inhibitory concentration (MIC) values for BAC and increased sensitivity to BAC was observed after plasmid curing. No effect of the efflux pump inhibitor reserpine on BAC tolerance in bcrABC positive strains was observed in contrast to all bcrABC negative strains. Lower ethidium bromide efflux in bcrABC positive isolates compared to bcrABC negative and plasmid-cured L. monocytogenes isolates was observed. The expression of bcrABC genes was BAC-induced. The confirmed effect of bcrABC to increased BAC tolerance, coupled with its plasmid location, may be an important factor in potential dissemination of the biocide resistance among Listeria species. The understanding of molecular mechanisms of biocide tolerance should help to improve control measures to prevent further spread of L. monocytogenes in food production environments with frequent use of BAC. PMID- 29626333 TI - Cross-Sectional Associations of Reallocating Time Between Sedentary and Active Behaviours on Cardiometabolic Risk Factors in Young People: An International Children's Accelerometry Database (ICAD) Analysis. AB - INTRODUCTION: Sedentary time and time spent in various intensity-specific physical activity are co-dependent, and increasing time spent in one behaviour requires decreased time in another. OBJECTIVE: The aim of the present study was to examine the theoretical associations with reallocating time between categories of intensities and cardiometabolic risk factors in a large and heterogeneous sample of children and adolescents. METHODS: We analysed pooled data from 13 studies comprising 18,200 children and adolescents aged 4-18 years from the International Children's Accelerometry Database (ICAD). Waist-mounted accelerometers measured sedentary time, light physical activity (LPA) and moderate-to-vigorous physical activity (MVPA). Cardiometabolic risk factors included waist circumference (WC), systolic blood pressure (SBP), fasting high- and low-density lipoprotein cholesterol (HDL-C and LDL-C), triglycerides, insulin, and glucose. Associations of reallocating time between the various intensity categories with cardiometabolic risk factors were explored using isotemporal substitution modelling. RESULTS: Replacing 10 min of sedentary time with 10 min of MVPA showed favourable associations with WC, SBP, LDL-C, insulin, triglycerides, and glucose; the greatest magnitude was observed for insulin (reduction of 2-4%), WC (reduction of 0.5-1%), and triglycerides (1-2%). In addition, replacing 10 min of sedentary time with an equal amount of LPA showed beneficial associations with WC, although only in adolescents. CONCLUSIONS: Replacing sedentary time and/or LPA with MVPA in children and adolescents is favourably associated with most markers of cardiometabolic risk. Efforts aimed at replacing sedentary time with active behaviours, particularly those of at least moderate intensity, appear to be an effective strategy to reduce cardiometabolic risk in young people. PMID- 29626334 TI - A Meta-Analysis of Resistance Training in Female Youth: Its Effect on Muscular Strength, and Shortcomings in the Literature. AB - BACKGROUND: Resistance training is an effective way to enhance strength in female youth but, to date, no researcher has meta-analysed its effect on muscular strength in that population. OBJECTIVES: This meta-analysis characterised female youths' adaptability to resistance training (RT). A second objective was to highlight the limitations of the body of literature with a view to informing future research. DATA SOURCES: Google Scholar, PubMed, Web of Science. STUDY ELIGIBILITY CRITERIA: Resistance training interventions in healthy females with a mean age between 8 and 18 years. Programmes of between 4 and 16 weeks' duration that included a control group. STUDY APPRAISAL AND SYNTHESIS METHODS: The inverse variance random effects model for meta-analyses was used because it allocates a proportionate weight to trials based on the size of their individual standard errors and facilitates analysis whilst accounting for heterogeneity across studies. Effect sizes, calculated from a measure of muscular strength, are represented by the standardised mean difference and are presented alongside 95% confidence intervals. RESULTS: The magnitude of the main effect was 'small' (0.54, 95% confidence interval: 0.23-0.85). Effect sizes were larger in older (> 15 years; ES = 0.72 [0.23-1.21] vs. 0.38 [- 0.02-0.79]), taller (> 163 cm; ES = 0.67 [0.20-1.13] vs. 0.55 [0.08-1.02]) and heavier (< 54 kg; ES = 0.67 [0.30 1.03] vs. 0.53 [- 0.00-1.06]) participants. CONCLUSIONS AND IMPLICATIONS OF KEY FINDINGS: Resistance training is effective in female youth. These findings can be used to inform the prescription of RT in female youth. PMID- 29626336 TI - Immunological Processes in Schizophrenia Pathology: Potential Biomarkers? AB - Accumulating evidence suggests that the pathophysiology or schizophrenia involves alterations in immune functions, both peripherally and centrally. Immunopsychiatric research has provided a number of candidate biomarkers that could aid estimating the risk of developing schizophrenia and/or predicting its clinical course or outcomes. This chapter summarizes the findings of immune dysfunctions along the clinical course of schizophrenia and discusses their potential value as predictive, trait or state biomarkers. Given the convergence of findings deriving from immunology, epidemiology, and genetics, the possibility of identifying immune-based biomarkers of schizophrenia seems realistic. Despite these promises, however, the field has realized that immune dysfunctions in schizophrenia may be as heterogeneous as the disorder itself. While challenging for psychiatric nosology, this heterogeneity offers the opportunity to define patient subgroups based on the presence or absence of distinct immune dysfunctions. This stratification may be clinically relevant for schizophrenic patients as it may help establishing personalized add-on therapies or preventive interventions with immunomodulating drugs. PMID- 29626335 TI - Release pattern of dexamethasone after administration through an implant-mediated drug delivery device with an active plunger of super absorbent polymer. AB - The implant-mediated drug delivery system (IMDDS) is a novel, innovative device that allows drug delivery through bone marrow. The purpose of this study was to investigate the effect of an active plunger component made of super absorbent polymer (SAP) on the plasma concentration of dexamethasone released from the IMDDS. The IMDDSs were installed in a total of 18 rabbits. After complete healing, dexamethasone was loaded with the SAP active plunger and with water to cause expansion in the test group (n = 9), while only the drug was loaded in the control group, as per the original protocol (n = 9). The release patterns of each group were monitored for 2 weeks by measuring the plasma concentration of the drug. Both groups showed sustained release of drug. However, the test groups showed more rapid increase in plasma concentration and higher area under the curve (AUC) throughout the observation period. The incorporation of a SAP active plunger component in the IMDDS resulted in an increase in initial release of drug and higher bioavailability within the observation period of 2 weeks after dexamethasone administration. PMID- 29626337 TI - Network Neuroscience: A Framework for Developing Biomarkers in Psychiatry. AB - Psychiatric disorders are disturbances of cognitive and behavioral processes mediated by the brain. Emerging evidence suggests that accurate biomarkers for psychiatric disorders might benefit from incorporating information regarding multiple brain regions and their interactions with one another, rather than considering local perturbations in brain structure and function alone. Recent advances in the field of applied mathematics generally - and network science specifically - provide a language to capture the complexity of interacting brain regions, and the application of this language to fundamental questions in neuroscience forms the emerging field of network neuroscience. This chapter provides an overview of the use and utility of network neuroscience for building biomarkers in psychiatry. The chapter begins with an overview of the theoretical frameworks and tools that encompass network neuroscience before describing applications of network neuroscience to the study of schizophrenia and major depressive disorder. With reference to work on genetic, molecular, and environmental correlates of network neuroscience features, the promises and challenges of network neuroscience for providing tools that aid in the diagnosis and the evaluation of treatment response in psychiatric disorders are discussed. PMID- 29626338 TI - Imaging and Genetic Biomarkers Predicting Transition to Psychosis. AB - The search for diagnostic and prognostic biomarkers in schizophrenia care and treatment is the focus of many within the research community. Longitudinal cohorts of patients presenting at elevated genetic and clinical risk have provided a wealth of data that has informed our understanding of the development of schizophrenia and related psychotic disorders.Imaging follow-up of high-risk cohorts has demonstrated changes in cerebral grey matter of those that eventually transition to schizophrenia that predate the onset of symptoms and evolve over the course of illness. Longitudinal follow-up studies demonstrate that observed grey matter changes can be employed to differentiate those who will transition to schizophrenia from those who will not prior to the onset of the disorder.In recent years our understanding of the genetic makeup of schizophrenia has advanced significantly. The development of modern analysis techniques offers researchers the ability to objectively quantify genetic risk; these have been successfully applied within a high-risk paradigm to assist in differentiating between high-risk individuals who will subsequently become unwell and those who will not.This chapter will discuss the application of imaging and genetic biomarkers within high-risk groups to predict future transition to schizophrenia and related psychotic disorders. We aim to provide an overview of current approaches focussing on grey matter changes that are predictive of future transition to illness, the developing field of genetic risk scores and other methods being developed to aid clinicians in diagnosis and prognosis. PMID- 29626339 TI - Using Pattern Classification to Identify Brain Imaging Markers in Autism Spectrum Disorder. AB - Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social interaction and communication, as well as repetitive and restrictive behaviours. The etiological and phenotypic complexity of ASD has so far hindered the development of clinically useful biomarkers for the condition. Neuroimaging studies have been valuable in establishing a biological basis for ASD. Increasingly, neuroimaging has been combined with 'machine learning'-based pattern classification methods to make individual diagnostic predictions. Moving forward, the hope is that these techniques may not only facilitate the diagnostic process but may also aid in fractionating the ASD phenotype into more biologically homogeneous sub-groups, with defined pathophysiology, predictable outcomes and/or responses to targeted treatments and/or interventions. This review chapter will first introduce 'machine learning' and pattern recognition methods in general, with a focus on their application to diagnostic classification. It will highlight why such approaches to biomarker discovery may have advantages over more conventional analytical methods. Magnetic resonance imaging (MRI) findings of atypical brain structure, function and connectivity in ASD will be briefly reviewed before we describe how pattern recognition has been applied to generate predictive models for ASD. Last, we will discuss some limitations and pitfalls of pattern recognition analyses in ASD and consider how the field can advance beyond the prediction of binary outcomes. PMID- 29626340 TI - Neuroimmune Biomarkers in Mental Illness. AB - Exploration of neuroimmune mechanisms is vital to the understanding of the pathogenesis and pathophysiology of mental disorders. Inflammatory and immune mechanisms are increasingly understood to underpin a number of neuropsychiatric disorders, with an ever-expanding evidence base drawn from basic science to large scale epidemiological data. Unravelling of these mechanisms should lead to biomarker discovery and potential new avenues for therapeutics that modulate immunological mechanisms. Identification of neuroimmune biomarkers is vital to improving diagnosis, stratification and treatment of mental disorders. There is an urgent clinical need for new therapeutic approaches with poor treatment response and treatment resistance a major problem for many psychiatric disorders including depression and schizophrenia. Neurodegenerative psychiatric disorders such as Alzheimer's also have clear neuroimmune underpinnings and manifest an urgent clinical need for improvements in diagnosis and research towards transformative disease-modifying treatments. This chapter provides some background on the role of the neuroimmune system in mental illness, exploring the role for biomarkers, in addition to reviewing the current state of knowledge in this exciting field. We also reflect on the inherent challenges and methodological pitfalls faced by research in this field, including the complexity of conceptualising multidimensional mental disorders and the dynamic shifting sands of the immune system. PMID- 29626341 TI - Toward understanding the relationship between personality and well-being states and traits. AB - OBJECTIVE: Although there is a robust connection between dispositional personality traits and well-being, relatively little research has comprehensively examined the ways in which all Big Five personality states are associated with short-term experiences of well-being within individuals. We address three central questions about the nature of the relationship between personality and well-being states: First, to what extent do personality and well-being states covary within individuals? Second, to what extent do personality and well-being states influence one another within individuals? Finally, are these within-person relationships moderated by dispositional personality traits and well-being? METHOD: Two experience sampling studies (N = 161 and N = 146) were conducted over 2 weeks. RESULTS: Across both studies, all Big Five personality states were correlated with short-term experiences of well-being within individuals. Individuals were more extraverted, emotionally stable, conscientious, agreeable, and open in moments when they experienced higher well-being (greater self-esteem, life satisfaction and positive affect, and less negative affect). Moreover, personality and well-being states dynamically influenced one another over time within individuals, and these associations were not generally moderated by dispositional traits or well-being. CONCLUSIONS: Behavior and well-being are interconnected within the context of the Big Five model of personality. PMID- 29626342 TI - A neuroscientific perspective on basic psychological needs. AB - OBJECTIVE: Self-determination theory's (SDT) most basic propositions are, first, that all people possess an inherent set of psychological needs and, second, that autonomy, competence, and relatedness are the three critical psychological satisfactions needed to maintain and promote personal growth and well-being. In this article, we identify the neural basis of the psychological needs and, in doing so, seek to advance the integration of SDT and neuroscience. METHOD: We examine the neural underpinnings of SDT-based motivational states and traits for autonomy, competence, and relatedness. To study motivational states, participants are exposed to situational conditions known to affect their psychological needs, and neuroscience methods (e.g., fMRI) are used to examine changes in their brain activity. To study motivational traits, participants complete self-report trait measures that are then correlated with their brain activity observed during need satisfying activities. RESULTS: For both motivational states and traits and across all three needs, intrinsic satisfaction is associated with striatum-based reward processing, anterior insula-based subjective feelings, and the integration of these subjective feelings with reward-based processing. CONCLUSIONS: Psychological need satisfaction is associated with striatum activity, anterior insula activity, and the functional coactivation between these two brain areas. Given these findings, it is now clear that several opportunities exist to integrate SDT motivational constructs with neuroscientific study, so we suggest eight new questions for future research. PMID- 29626343 TI - A neural correlate for common trait dissociation: Decreased EEG connectivity is related to dissociative absorption. AB - OBJECTIVE: Dissociation refers to a disintegration between psychological elements; common manifestations are embodied in "absorption and imaginative involvement," a propensity for being immersed in a stimulus while oblivious to the environment, and acting without awareness. Trait dissociation was hypothesized to relate to lower EEG signal connectivity, but studies on healthy populations are scarce. The present study set out to examine whether dissociative absorption in a nonclinical sample would be associated with decreased intrahemispheric coherence. METHOD: In 84 healthy Israeli soldiers (49% females; Mage = 22.24, SD = 2.64), resting-state electroencephalography (rsEEG) was recorded for a period of 3 min with eyes closed and 3 min with eyes open. RESULTS: Decreased coherence was related to high dissociative absorption in the long (frontal-occipital) range, and in one of the pairs of the short range (central-parietal). The effects emerged mostly in the left hemisphere, in both eyes-open and eyes-closed conditions, and for a range of spectral bands, although long-range effects were more pronounced in slow-wave bands (theta and delta). CONCLUSIONS: Dissociative absorption is manifested in segregated cortical activity, supporting the notion that it may represent less integrated mental functioning. The findings contribute to our understanding of the neural correlates of consciousness and personality. PMID- 29626344 TI - Racialised prescribing: enacting race/ethnicity in clinical practice guidelines and in accounts of clinical practice. AB - This article examines the articulation and enactment of racialised classifications in clinical practice guidelines and in accounts of clinical practice. It contributes to debates about racialisation in medicine and its consequences. The research centred on the case study of prescribing guidelines for hypertension in England and Wales, drawing on documentary sources and semi structured expert interviews. We found that conceptual and socio-political uncertainties existed about how to interpret the designation 'Black patients' and about the practices for identifying patients' race/ethnicity. To 'close' uncertainties, and thus produce the guidelines and treat patients, respondents drew authority from disparate elements of the 'topologies of race'. This has implications for understanding processes of racialisation and for the future use of racialised clinical practice guidelines. We argue that clinical practice guidelines play a 'nodal' role in racialisation by forming an authoritative material connection that creates a path for translating racialised research into racialised healthcare practice, and that they carry with them implicit conceptual and socio-political uncertainties that are liable to create inconsistencies in healthcare practice. PMID- 29626345 TI - The personalities of Danish MPs: Trait- and aspect-level differences. AB - OBJECTIVE: We study personality traits of Danish parliamentarians (MPs) and examine elite-voter congruence and elite differentiation. Whereas previous political elite studies have focused only on the Big Five level, we include aspect-level differences. METHOD: In a highly representative survey of Danish MPs (N = 81; response rate = 46.3%) and a representative study of Danish voters (N = 3,612), we used the 60-item NEO-PI-R short version to examine personality differences on the Big Five level and, based on the NEO-BFAS, the aspect level. RESULTS: MPs were more extraverted, conscientious, and open than the average voter. On the elite level, liberal MPs were more agreeable and, on the aspect level, more compassionate but not more polite than conservative MPs. MPs in center parties had stronger power aspirations and were less agreeable and more extraverted than MPs in peripheral parties. On the aspect level, MPs in center parties were more assertive and enthusiastic and less polite. Conscientiousness and Agreeableness were associated with power aspiration, but Extraversion was not because the assertiveness effect was suppressed by a non-effect for enthusiasm. CONCLUSIONS: The inclusion of the aspect level explains null findings at the Big Five level and adds important nuances to the personality portrait of political elites. PMID- 29626346 TI - Propofol for implantable cardioverter defibrillator implantation in patients with Brugada syndrome. AB - AIMS: Avoiding propofol in patients with Brugada syndrome has been suggested because of the theoretical risk of provoking ventricular arrhythmias, although propofol may be selected for conscious sedation during electrophysiological procedures in catheterization laboratories. This study aimed to document periprocedural electrocardiographic changes and adverse events in patients with Brugada syndrome undergoing implantable cardioverter defibrillator (ICD) implantation using propofol sedation. METHODS: We reviewed the clinical data of 53 consecutive patients who underwent ICD implantation during 1998-2011. Sedation was achieved by combining propofol with either midazolam or fentanyl, and a bolus propofol dose (0.5-1 mg/kg) was administered to induce deep sedation. Periprocedural events, including arrhythmias, defibrillations, and hyperthermia episodes, were evaluated, and electrocardiogram (ECG) variables were measured. The need for emergency anesthetic support/intubation and incidence of perioperative complications or mortality were analyzed. RESULTS: Procedure time and cumulative propofol dose for each patient was 125.2 (42.8) min and 204.6 (212.7) mg, respectively. During deep sedation, blood pressure, heart rate, and oxygen saturation were significantly decreased (P < 0.001) such that eight (15.1%) patients required manual ventilation and one (1.9%) needed atropine injection. No significant ECG changes were observed. Only two (3.7%) patients showed newly developed ST elevation in the anterior precordial lead, whereas three (5.6%) had isolated premature ventricular contractions. CONCLUSION: ICD implantation without significant ECG changes or adverse outcomes is feasible under propofol sedation in patients with Brugada syndrome. However, because of significant hemodynamic changes and respiratory compromise, close monitoring and meticulous propofol dose titration is warranted. PMID- 29626347 TI - Detecting local diversity-dependence in diversification. AB - Whether there are ecological limits to species diversification is a hotly debated topic. Molecular phylogenies show slowdowns in lineage accumulation, suggesting that speciation rates decline with increasing diversity. A maximum-likelihood (ML) method to detect diversity-dependent (DD) diversification from phylogenetic branching times exists, but it assumes that diversity-dependence is a global phenomenon and therefore ignores that the underlying species interactions are mostly local, and not all species in the phylogeny co-occur locally. Here, we explore whether this ML method based on the nonspatial diversity-dependence model can detect local diversity-dependence, by applying it to phylogenies, simulated with a spatial stochastic model of local DD speciation, extinction, and dispersal between two local communities. We find that type I errors (falsely detecting diversity-dependence) are low, and the power to detect diversity-dependence is high when dispersal rates are not too low. Interestingly, when dispersal is high the power to detect diversity-dependence is even higher than in the nonspatial model. Moreover, estimates of intrinsic speciation rate, extinction rate, and ecological limit strongly depend on dispersal rate. We conclude that the nonspatial DD approach can be used to detect diversity-dependence in clades of species that live in not too disconnected areas, but parameter estimates must be interpreted cautiously. PMID- 29626348 TI - Clinical outcomes after colopexy through left ventral paramedian incision in 156 thoroughbred broodmares with large colon disorders (1999-2015). AB - OBJECTIVE: To describe a technique for colopexy via a left ventral paramedian incision and report postoperative clinical outcomes. STUDY DESIGN: Retrospective case series. ANIMALS: One hundred fifty-six thoroughbred broodmares treated with a colopexy through a left ventral paramedian incision between 1999 and 2015. METHODS: Medical records were reviewed for postoperative complications and survival to discharge. The survival rate at 1 year after surgery was based on the medical record, progeny record, or client telephone conversation. Progeny records were reviewed to assess reproductive performance. T tests, chi2 tests, logistic regression, and Kaplan-Meier survival curves were used to identify prognostic factors. RESULTS: The rates of postoperative recurrence of large colon volvulus and colon rupture were 1.2% and 3%, respectively. Ninety-three percent of mares that were treated were discharged alive from the hospital, and 78% were alive 1 year after surgery. The diagnosis of 1 of the following complications increased the risk of death within 1 year: systemic inflammatory response syndrome (SIRS), diarrhea, and/or thrombophlebitis (odds ratio [OR] 4.76). Sixty-six percent of mares that were pregnant at the time of colopexy and discharged alive from the hospital produced a live foal. The percentage of live foals produced each year that the mare was bred after colopexy was 67%. CONCLUSION: Thoroughbred mares treated with colopexy via a left paramedian incision had a good prognosis for survival and continued use as a broodmare. SIRS, diarrhea, or jugular thrombophlebitis affected long-term survival in this population. CLINICAL SIGNIFICANCE: Colopexy via a left paramedian incision is a suitable alternative to colopexies requiring a second incision or creating adhesions between the colon and the linea alba in thoroughbred mares. PMID- 29626349 TI - Phosphoproteome profiling provides insight into the mechanism of action for carvedilol-mediated cancer prevention. AB - Recent studies suggest that the beta-blocker drug carvedilol prevents skin carcinogenesis but the mechanism is unknown. Carvedilol is one of a few beta blockers identified as biased agonist based on an ability to promote beta arrestin-mediated processes such as ERK phosphorylation. To understand the role of phosphoproteomic signaling in carvedilol's anticancer activity, the mouse epidermal JB6 P+ cells treated with EGF, carvedilol, or their combination were analyzed using the Phospho Explorer Antibody Array containing 1318 site-specific and phospho-specific antibodies of over 30 signaling pathways. The array data indicated that both EGF and carvedilol increased phosphorylation of ERK's cytosolic target P70S6 K while its nuclear target ELK-1 were activated only by EGF; Furthermore, EGF-induced phosphorylation of ELK-1 and c-Jun was attenuated by carvedilol. Subcellular fractionation analysis indicated that ERK nuclear translocation induced by EGF was blocked by co-treatment with carvedilol. Western blot and luciferase reporter assays confirmed that the biased beta-blockers carvedilol and alprenolol blocked EGF-induced phosphorylation and activation of c Jun/AP-1 and ELK-1. Consistently, both carvedilol and alprenolol strongly prevented EGF-induced neoplastic transformation of JB6 P+ cells. Remarkably, oral carvedilol treatment significantly inhibited the growth of A375 melanoma xenograft in SCID mice. As nuclear translocation of ERK is a key step in carcinogenesis, inhibition of this event is proposed as a novel anticancer mechanism for biased beta-blockers such as carvedilol. PMID- 29626351 TI - Parathyroid hormone-induced down-regulation of miR-532-5p for matrix metalloproteinase-13 expression in rat osteoblasts. AB - Parathyroid hormone (PTH) acts on osteoblasts and functions as an essential regulator of calcium homeostasis and as a mediator of bone remodeling. We previously reported that PTH stimulates the expression of matrix metalloproteinase-13 (MMP-13) in rat osteoblasts and that MMP-13 plays a key role in bone remodeling, endochondral bone formation, and bone repair. Recent evidence indicated that microRNAs (miRNAs) have regulatory functions in bone metabolism. In this study, we hypothesized that the down-regulation of miRNAs that target MMP 13 by PTH leads to the stimulation of MMP-13 expression in osteoblasts. We used various bioinformatic tools to identify miRNAs that putatively target rat MMP-13. Among these miRNAs, the expression of miR-532-5p in rat osteoblasts decreased at 4 h of PTH-treatment, whereas MMP-13 mRNA expression was maximal at the same time point. When an miR-532-5p mimic was transiently transfected into UMR-106-01 cells, MMP-13 mRNA and protein expression decreased. Using a luciferase reporter assay system, we also identified that miR-532-5p directly targeted the 3' UTRs of MMP-13 gene. Based on these results, we suggest that PTH-induced down-regulation of miR-532-5p resulted in the stimulation of MMP-13 expression in rat osteoblasts. This study identified a significant role of miRNA in controlling bone remodeling via PTH-stimulated MMP-13 expression. This finding enhances our understanding of bone metabolism and bone-related diseases and it could provide information regarding the usage of miRNAs as therapeutic agents or biomarkers. PMID- 29626350 TI - Correlates of suicidal ideation in college women with eating disorders. AB - OBJECTIVE: To identify the correlates of suicidal ideation (SI) in a large sample of college women with eating disorders (EDs). METHOD: A total of 690 female college students from 28 US colleges who screened positive for an ED, with the exception of anorexia nervosa, were assessed for SI. Univariate logistic regression analyses were performed to determine independent correlates of SI. Measures included: ED psychopathology, ED behaviors (i.e., binge eating, vomiting, laxatives, compulsive exercise), current co-morbid psychopathology (i.e., depression, anxiety, insomnia), weight/shape concerns, ED-related clinical impairment, and body mass index (BMI). All significant variables were included in a backward binary multivariate logistic regression model to determine which variables were most strongly associated with SI. RESULTS: A total of 25.6% of the sample reported SI. All variables examined were significantly independently associated with SI, with the exception of compulsive exercise. Depression, anxiety, and vomiting remained as significant correlates of SI in the multivariate logistic regression model. DISCUSSION: ED screening on college campuses should assess for suicidality, and prevention and treatment efforts should target vomiting and co-morbid depression and anxiety symptoms to reduce risk of SI for high-risk individuals. PMID- 29626352 TI - Drought induced tree mortality - a tree-ring isotope based conceptual model to assess mechanisms and predispositions. PMID- 29626353 TI - Ecological momentary assessment of maladaptive eating in children and adolescents with overweight or obesity. AB - OBJECTIVES: Contextual factors related to maladaptive eating behavior in youth with overweight/obesity are poorly understood. This pilot study sought to elucidate immediate internal and external cues related to perceptions of overeating and loss of control (LOC) over eating in a heterogeneous sample of children and adolescents with overweight/obesity assessed in their natural environments. METHOD: Community-based youth [N = 40; 55% female (n = 22)], aged 8 14 y (M age = 11.2 +/- 1.9 y), with overweight/obesity (M z-BMI = 2.07 +/- 0.49) reported on all eating episodes and their physiological, environmental, affective, and interpersonal antecedents and correlates via ecological momentary assessment over a 2-week period. Generalized estimating equations were used to assess the relationship between contextual variables and degree of overeating and LOC. RESULTS: Eating occasions involving greater food hedonics (i.e., perceived palatability of food being consumed) were associated with greater LOC severity (within-subjects effect: B = 0.01, p = .015), although youth with lower overall levels of food hedonics reported higher LOC severity ratings on average (between subjects effect: B = -0.04, p = .005). Youth reporting higher overall cravings reported higher average ratings of LOC severity (between-subjects effect: B = 0.20, p = .001). Finally, youth reporting greater overall influence of others on eating behavior evidenced greater average levels of overeating severity (between subjects effect: B = 0.17, p < .001). DISCUSSION: Eating-related factors appear to be most strongly associated with LOC severity, while environmental factors were most associated with overeating severity. Interventions targeting maladaptive eating in youth with overweight/obesity may benefit from helping youth incorporate palatable foods and satisfy cravings in a planned and controlled manner, and enhancing awareness of social-contextual effects on eating. PMID- 29626354 TI - Second regional plasmapheresis conference and workshop for Southeast Asia (SEA) on the immunomodulatory role of plasma exchange in central and peripheral nervous system disorders, Kuala Lumpur, Malaysia, 9th December 2017. AB - In December 2017, 79 delegates attended the 2nd regional plasmapheresis conference and workshop for Southeast Asia (SEA) on the immunomodulatory role of plasma exchange in central and peripheral nervous system disorders in Kuala Lumpur, Malaysia. This meeting featured 6 plenary lectures, interactive sessions dedicated for experience sharing, case presentations, and a practical session for paramedics. Clinical experts and researchers from 7 SEA countries and India shared experience and challenges in treating autoimmune neurological disorders. While the spectrum of diseases and neurology practice remained largely similar, there was great disparities in accessibility of therapeutic plasma exchange (TPE) within SEA countries and between urban or rural settings. Costs, human resources, and healthcare policies are common challenges in providing sustainable TPE services. Novel techniques and innovative ideas in performing TPE were explored. A working consortium comprising of key opinion leaders was proposed to improve standards of TPE and enhance future research. PMID- 29626355 TI - Formation of Polymeric Particles by Direct Polymerization on the Surface of a Supramolecular Template. AB - Formation of polymeric materials on the surface of supramolecular assemblies is rather challenging because of the often weak noncovalent interactions between the self-assembled template and the monomers before polymerization. We herein show that the introduction of a supramolecular anion recognition motif, the guanidiniocarbonyl pyrrole cation (GCP), into a short Fmoc-dipeptide 1 leads to self-assembled spherical nanoparticles in aqueous solution. Negatively charged diacetylene monomers can be attached onto the surface of these nanoparticles, which, after UV polymerization, leads to the formation of a polymer shell around the self-assembled template. The hybrid supramolecular and polymeric nanoparticles demonstrate intriguing thermal hysteresis phenomena. The template nanoparticles could be disassembled upon treatment with organic base, which cleaved the Fmoc moiety on 1. This strategy thus showed that a supramolecular anion recognition motif allows the post-assembly formation of polymeric nanomaterials from anionic monomers around a cationic self-assembled template. PMID- 29626356 TI - Fit to father? Online accounts of lifestyle changes and help-seeking on a male infertility board. AB - The reproductive realm is routinely viewed as a feminised space requiring women's commitment and labour. By contrast, men's procreative contributions and 'reproductive masculinity' is represented as unproblematic, with men assumed to be fertile across the lifespan. Recent scientific research has, however, cast doubt over these longstanding assumptions, suggesting that a link does exist between 'lifestyle' factors and male fertility. The notion that fertility can be improved with effort (for both women and men) can be located within wider cultural and political shifts which construct individuals as increasingly responsible for acting on health messages and engaging in self-disciplining body projects. Through an exploration of 'lifestyle changes' within a men's online infertility discussion forum board, this paper examines how discourses of individualisation healthism and masculinity are reproduced and interlinked. Our thematic analysis indicates that 'lifestyle work' is construed as crucial for achieving conception - and as a means to demonstrate men's commitment to the dyadic goal of parenthood, which in turn may challenge and extend previous notions of 'reproductive masculinity'. PMID- 29626357 TI - Aberrant expression of LncRNA-MIR31HG regulates cell migration and proliferation by affecting miR-31 and miR-31* in Hirschsprung's disease. AB - Hirschsprung's disease (HSCR) is a birth defect that causes a failure of the enteric nervous system to cover the distal gut during early embryonic development. Evidence shows that long non-coding RNAs (lncRNA) play important roles in HSCR. The MIR31 host gene (MIR31HG), also known as Loc554202, is a long non-coding RNA (lncRNA), which acts as the host gene of (microRNA) miR-31 and miR 31*. There have been no studies regarding its function in early developmental defects during pregnancy, and its downstream genetic receptors. We report that downregulation of MIR31HG inhibited migration and proliferation in 293T and SH SY5Y cell lines, by suppressing miR-31 and miR-31*. Moreover, the downregulation of miR-31 and miR-31* enhanced inter-alpha-trypsin inhibitor heavy chain 5 (ITIH5) and the phosphatidylinositol-4, 5-bisphosphate 3-kinase catalytic gamma subunit (PIK3CG), respectively with reductions of cell migration and proliferation in 293T and SH-SY5Y cell lines. In addition, synergistic actions were observed between miR-31 and miR-31* in cell migration and proliferation. Our results demonstrated that the MIR31HG-miR-31/31*-ITIH5/PIK3CG pathway plays a role in the pathogenesis of HSCR. PMID- 29626358 TI - Mother-Stepfather Coparenting in Stepfamilies as Predictor of Child Adjustment. AB - Coparenting between biological parents is a strong predictor of child adjustment. To date, however, little is known about the coparenting dynamics between parent and stepparent in stepfamilies. This study aimed at exploring the links between coparenting in the mother-stepfather dyad and child behavior in stepfamilies compared with the links between mother-father coparenting and child behavior in first-marriage families. Two modes of coparenting were assessed: overt coparenting, that is, coparental behaviors in the presence of the child, and covert coparenting, that is, the way each parent speaks of the other parent to the child. The sample (N = 80) comprised 48 stepfamilies and 32 first-marriage families with a child between 7 and 13 years old. Overt coparenting was assessed through direct observation in the standardized situation of the PicNic Game. Covert coparenting and child behavior were assessed through mother-reported questionnaires. Results showed (a) more covert coparenting behaviors in first marriage families, (b) no differences in overt coparenting, (c) more child difficulties reported in stepfamilies, (d) less optimal overt coparenting being linked with more difficulties in children in both family structures, and (e) an interaction effect between family structure and coparenting, showing that overt coparenting is linked with child behavior mainly in stepfamilies. PMID- 29626360 TI - An Ambient Temperature Electrolyte with Superior Lithium Ion Conductivity based on a Self-Assembled Block Copolymer. AB - In searching for polymer-based electrolytes with improved performance for lithium ion and lithium metal batteries, we studied block copolymer electrolytes with high amounts of bis(trifluoromethane)sulfonimide lithium obtained by macromolecular co-assembly of a poly(isoprene)-block-poly(styrene)-block poly(ethylene oxide) and the salt from tetrahydrofuran. Particularly, an ultra short poly(ethylene oxide) block of 2100 g mol-1 was applied, giving rise to 2D continuous lamellar microstructures. The macroscopic stability was ensured with major blocks from poly(isoprene) and poly(styrene), which separated the ionic conductive PEO/salt lamellae. Thermal annealing led to high ionic conductivities of 1.4 mS cm-1 at 20 degrees C with low activation energy and a superior lithium ion transference number of 0.7, accompanied by an improved mechanical stability (storage modulus of up to 107 Pa). With high Li:O ratios >1, we show a viable concept to achieve fast Li+ transport in block copolymers (BCP), decoupled from slow polymer relaxation. PMID- 29626361 TI - A dicistronic precursor encoding miR398 and the legume-specific miR2119 coregulates CSD1 and ADH1 mRNAs in response to water deficit. AB - Plant microRNAs are commonly encoded in transcripts containing a single microRNA precursor. Processing by DICER-LIKE 1 and associated factors results in the production of a small RNA, followed by its incorporation into an AGO-containing protein complex to guide silencing of an mRNA possessing a complementary target sequence. Certain microRNA loci contain more than one precursor stem-loop structure, thus encoding more than one microRNA in the same transcript. Here, we describe a unique case where the evolutionary conserved miR398a is encoded in the same transcript as the legume-specific miR2119. The dicistronic arrangement found in common bean was also observed in other legumes. In Phaseolus vulgaris, mature miR398 and miR2119 are repressed in response to water deficit, and we demonstrate that both are functional as they target the mRNAs for CSD1 and ADH1, respectively. Our results indicate that the repression of miR398 and miR2119 leads to coordinated up-regulation of CSD1 and ADH1 mRNAs in response to water deficit in common bean and possibly in other legumes. Furthermore, we show that miRNA directed CSD1 and ADH1 mRNAs up-regulation also occurs when common bean plants are exposed to flooding, suggesting that plant redox status and fermentation metabolism must be closely coordinated under different adverse conditions. PMID- 29626359 TI - Simultaneous pH-sensitive and oxygen-sensitive MRI of human gliomas at 3 T using multi-echo amine proton chemical exchange saturation transfer spin-and-gradient echo echo-planar imaging (CEST-SAGE-EPI). AB - PURPOSE: To introduce a new pH-sensitive and oxygen-sensitive MRI technique using amine proton CEST echo spin-and-gradient echo (SAGE) EPI (CEST-SAGE-EPI). METHODS: pH-weighting was obtained using CEST estimations of magnetization transfer ratio asymmetry (MTRasym ) at 3 ppm, and oxygen-weighting was obtained using R2' measurements. Glutamine concentration, pH, and relaxation rates were varied in phantoms to validate simulations and estimate relaxation rates. The values of MTRasym and R2' in normal-appearing white matter, T2 hyperintensity, contrast enhancement, and macroscopic necrosis were measured in 47 gliomas. RESULTS: Simulation and phantom results confirmed an increase in MTRasym with decreasing pH. The CEST-SAGE-EPI estimates of R2 , R2*, and R2' varied linearly with gadolinium diethylenetriamine penta-acetic acid concentration (R2 = 6.2 mM 1 .sec-1 and R2* = 6.9 mM-1 .sec-1 ). The CEST-SAGE-EPI and Carr-Purcell-Meiboom Gill estimates of R2 (R2 = 0.9943) and multi-echo gradient-echo estimates of R2* (R2 = 0.9727) were highly correlated. T2 lesions had lower R2' and higher MTRasym compared with normal-appearing white matter, suggesting lower hypoxia and high acidity, whereas contrast-enhancement tumor regions had elevated R2' and MTRasym , indicating high hypoxia and acidity. CONCLUSION: The CEST-SAGE-EPI technique provides simultaneous pH-sensitive and oxygen-sensitive image contrasts for evaluation of the brain tumor microenvironment. Advantages include fast whole brain acquisition, in-line B0 correction, and simultaneous estimation of CEST effects, R2 , R2*, and R2' at 3 T. PMID- 29626362 TI - Clinical outcome of dental procedures among renal transplant recipients. AB - AIMS: To compare outcomes of dental procedures among a group of renal transplant recipients who had received antibiotic prophylaxis (AP) before the procedure and another group that had not received AP. METHODS AND RESULTS: The records of all renal transplant patients treated at the Special Care Dentistry Center (SCDC) were assessed. Dental procedures documented in the records were classified as invasive or noninvasive. All dental procedures performed were compiled, and the prescription or nonprescription of prophylactic antibiotics, and the incidence and description of postoperative complications after invasive procedures were recorded. Eighty-seven records were evaluated. Out of 190 invasive procedures all were simple dental extractions, 107 (56.3%) were preceded by AP; out of 242 noninvasive procedures, 14 (5.7%) were preceded by AP. A lack of uniformity on the type and dose of the antibiotic prescribed was observed. Four postoperative complications after invasive procedures (dental extraction) were noted and in 2 cases the procedures were preceded by AP. CONCLUSION: This retrospective study showed no difference in postextraction outcomes between renal transplant recipients who received and who did not receive AP before dental extractions. PMID- 29626363 TI - Smartphone addiction risk and daytime sleepiness in Korean adolescents. AB - AIM: Smartphone overuse can cause not only mobility problems in the wrists, fingers and neck but also interference with sleep habits. However, research on smartphone addiction and sleep disturbances is scarce. Therefore, we aimed to investigate daytime sleepiness in association with smartphone addiction risk in Korean adolescents. METHODS: A cross-sectional survey method was used in this study. The Pediatric Daytime Sleepiness Scale was used to assess daytime sleepiness, and the Korean Smartphone Addiction Proneness Scale index was used to evaluate the degree of risk for smartphone addiction. RESULTS: The analyses were performed in 1796 adolescents using smartphones, including 820 boys and 976 girls. The at-risk smartphone users made up 15.1% of boys and 23.9% of girls. Our multivariate analyses demonstrated that students who were female, consumed alcohol, had lower academic performance, did not feel refreshed in the morning and initiated sleep after 12 am were at a significantly higher risk of smartphone addiction. The at-risk smartphone user group was independently associated with the upper quartile Pediatric Daytime Sleepiness Scale score in students with the following factors: Female gender, alcohol consumption, poor self-perceived health level, initiating sleep after 12 am, longer time taken to fall asleep and duration of night sleep less than 6 h. CONCLUSIONS: The quality of sleep in adolescence affects growth, emotional stability and learning skills. Therefore, the management of smartphone addiction seems to be essential for proper sleeping habits. There is a critical need to develop a means of preventing smartphone addiction on a social level. PMID- 29626364 TI - Elevated expression of keratin 17 in oropharyngeal squamous cell carcinoma is associated with decreased survival. AB - BACKGROUND: Overexpression of keratin 17 (K17) is highly associated with poor prognosis in squamous cell carcinoma (SCC) of the cervix. This study was performed to (1) determine whether K17 may be a prognostic biomarker in head and neck squamous cell carcinoma (HNSCC) and (2) to establish if K17 expression is associated with human papillomavirus (HPV) status. METHODS: Immunohistochemical staining was performed for K17 of oral, oropharyngeal, and laryngeal SCCs, and normal oropharyngeal mucosa. The HPV status was determined using polymerase chain reaction (PCR). RESULTS: Elevated K17 expression was significantly associated with an overall decreased patient survival (P = .02) and, more specifically, in patients with oropharyngeal SCC (P = .01). When controlling for HPV status and tumor location K17 was still a significant predictor of survival (P = .01). CONCLUSION: Therefore, K17 is a novel prognostic biomarker of poor survival for patients with HNSCCs, controlling for anatomic site and HPV status. PMID- 29626365 TI - Tongue cancer epidemiology in Brazil: incidence, morbidity and mortality. AB - BACKGROUND: The purpose of this current research was to clarify for the scientific community the trends of tongue cancer epidemiology in Brazil. METHODS: The data came from Population Based Cancer Registries, Hospital Cancer Registries, and Mortality Information System from 2000 to 2014. RESULTS: The age adjusted incidence rate are increasing in both men and women for base of tongue cancer and for other and unspecified parts of the tongue in women, and decreasing in men for other and unspecified parts of the tongue. The majority of cases were diagnosed at clinical stages III and IV. The mortality rate remained relatively stable in both men and women in the period studied. CONCLUSION: The increase in age-adjusted incidence rate for tongue cancers (except for other and unspecified parts of the tongue in men), with most patients over 50 years of age, with low education levels, and advanced disease reinforces the need for interventions that address access to health promotion resources and medical care in Brazil. PMID- 29626367 TI - Management of leaking tracheoesophageal puncture with hyaluronic acid injection. AB - BACKGROUND: Tracheoesophageal puncture (TEP) with voice prosthesis is a widely used technique for voice restoration in laryngectomy and pharyngolaryngectomy patients. Complications include leakage around the prosthesis or a persistent TEP postremoval of the prosthesis. METHODS: We describe a method for managing leakage around voice prosthesis or persistent TEP using hyaluronic acid injection. We also present a retrospective audit of our practice. RESULTS: This study had 8 patients who were treated over a 32-month period. All cases had immediate cessation of salivary leak. Duration of efficacy was variable. Five of the 8 cases had permanent resolution of their symptoms after multiple injections. Two cases of persistent TEP were treated surgically after multiple injections. One patient with peripheral leakage continues to have regular injections. CONCLUSION: Hyaluronic acid injection in the treatment of persistent TEP or peripheral leak around a voice prosthesis is a useful treatment option to provide immediate and occasionally long-lasting relief from symptoms. PMID- 29626366 TI - Six-year follow-up of the initial Dutch subcutaneous implantable cardioverter defibrillator cohort: Long-term complications, replacements, and battery longevity. AB - INTRODUCTION: Experience with the subcutaneous implantable cardioverter defibrillator (S-ICD) is expanding rapidly. However, data on long-term performance or complications related to elective generator replacement are lacking. METHODS: Follow-up (FU) data of all patients implanted between December 2008 and April 2011 were collected. Complications were defined as those requiring surgical intervention. Kaplan-Meier estimates for complication and shock rates, with corresponding 95% confidence intervals (CI), were calculated. RESULTS: One hundred and eighteen patients were included. Median FU was 6.1 years (IQR 5.6-6.5 years). Short-term complication rate (0-30 days) was 3% (CI 0-6%). Long-term complication rate at 6 years was 19% (CI 12-26%), corresponding with an annual complication rate of 3%. One patient in this cohort developed a need for a transvenous ICD (TV-ICD) in order to provide pacing for bradycardia (1%). Six patients were implanted with a TV-ICD after experiencing an S-ICD complication for which extraction was necessary. In total, 10 S-ICDs were extracted; none resulted in a complication. Eight patients had a nonsystemic ICD-related infection and no lead failures were observed. The majority, 68 (58%) patients, received an elective generator replacement. Two patients had a complication related to generator replacement (3%). Battery longevity was 5.6 years (IQR 5.2 6.1). Appropriate and inappropriate shock rates of 6-year estimates were 17% (CI 9-25%) and 21% (CI 15-27%), respectively. CONCLUSIONS: This cohort represents the longest follow-up to date and shows a low annual complication rate without lead failures or systemic infections. Battery longevity of the first S-ICD generation results in relative early generator replacement procedures. PMID- 29626368 TI - Patient-centred value framework for haemophilia. AB - INTRODUCTION: Growing budgetary demands have led to increased scrutiny of healthcare spending for rare diseases, leading to a unified goal within the haemophilia community to define objectively patient-centred value in haemophilia care. AIM: To develop a patient-centred outcomes framework with global applicability for assessing value in haemophilia healthcare. METHODS: An international, multidisciplinary panel of experts convened to identify the range of patient impacts of haemophilia health care and organize these into a three tiered, patient-centred outcomes framework based on Porter's model for assessing value. RESULTS: In addition to measures common to other chronic diseases (eg survival and quality of life), Tier 1, health status achieved or retained, includes haemophilia-specific outcomes of bleeding frequency, musculoskeletal complications and life-threatening bleeds, as well as measures of function or activity. Tier 2, process of recovery, includes such outcomes as time to initial treatment, time to recovery and time missed at education/work; also included are disutility of care, measured by inhibitor development, pathogen transmission/infections, orthopaedic intervention and difficult venous access. Tier 3, sustainability of health, is measured by bleed avoidance, maintenance of productive lives and good health over time; potential long-term negative consequences include insufficient or inappropriate therapy and age-related complications. The applicability of the outcomes framework for different types of haemophilia healthcare interventions is described. CONCLUSION: Haemophilia health care can affect multiple patient-centred outcomes across diverse patient types and healthcare systems. This framework organizes those outcomes for informing value-based decision making by multiple stakeholders and provides the basis for further refinement and development of a standardized outcomes set. PMID- 29626369 TI - Pilot study of acupuncture to treat anxiety in children and adolescents. AB - AIM: This pilot study investigated the use of acupuncture in the treatment of paediatric anxiety. METHODS: Children with anxiety, aged 8-16, were randomised to either the acupuncture or waitlist control groups. Anxiety was measured using the Hamilton Anxiety Rating Scale (HAM-A) for children and adolescents with generalised anxiety disorder and Multidimensional Anxiety Scale for Children 2nd Edition (MASC-2) self-rated and parent-rated forms. RESULTS: Twenty participants were enrolled in the study and 19 completed all the questionnaires to be included in the analysis. There were no differences in socio-demographic characteristics at baseline between the two groups. At the second assessment, the mean MASC parent score for the acupuncture group was significantly lower than the waitlist group (65.6 (SD 15.0) compared to 81.0 (SD 11.9), P = 0.025) with an effect size = 1.13. The pre- and post-treatment comparisons were also significantly lower for both groups in the anxiety measures. In the acupuncture group, MASC-parent (P = 0.008, effect size 0.75) and the HAM-A (P < 0.001, effect size 1.4). In the waitlist group, MASC-self (P = 0.022; effect size 0.4), MASC-parent (P = 0.048; effect size 0.75) and HAM-A (P = 0.007; effect size 1.21). CONCLUSIONS: This study provided promising results on the potential use of acupuncture to treat children and adolescents with general anxiety. Future research using a randomised control trial with a sufficient sample size to control for confounders and sham (placebo) comparators is warranted. PMID- 29626370 TI - Environmental microbiology: Too much food for thought? - An argument for reductionism. PMID- 29626371 TI - Phosphodiesterase PdeD, dynacortin, and a Kelch repeat-containing protein are direct GSK3 substrates in Dictyostelium that contribute to chemotaxis towards cAMP. AB - The migration of cells according to a diffusible chemical signal in their environment is called chemotaxis, and the slime mold Dictyostelium discoideum is widely used for the study of eukaryotic chemotaxis. Dictyostelium must sense chemicals, such as cAMP, secreted during starvation to move towards the sources of the signal. Previous work demonstrated that the gskA gene encodes the Dictyostelium homologue of glycogen synthase kinase 3 (GSK3), a highly conserved serine/threonine kinase, which plays a major role in the regulation of Dictyostelium chemotaxis. Cells lacking the GskA substrates Daydreamer and GflB exhibited chemotaxis defects less severe than those exhibited by gskA- (GskA null) cells, suggesting that additional GskA substrates might be involved in chemotaxis. Using phosphoproteomics we identify the GskA substrates PdeD, dynacortin and SogA and characterize the phenotypes of their respective null cells in response to the chemoattractant cAMP. All three chemotaxis phenotypes are defective, and in addition, we determine that carboxylesterase D2 is a common downstream effector of GskA, its direct substrates PdeD, GflB and the kinases GlkA and YakA, and that it also contributes to cell migration. Our findings identify new GskA substrates in cAMP signalling and break down the essential role of GskA in myosin II regulation. PMID- 29626372 TI - Bleeding-related hospitalization in patients with von Willebrand disease and the impact of prophylaxis: Results from national registers in Sweden compared with normal controls and participants in the von Willebrand Disease Prophylaxis Network. AB - INTRODUCTION: Patients suffering from von Willebrand disease (VWD) have a variety of bleeding symptoms and require both outpatient care for treatment and, in more severe cases, hospitalization. AIM: To investigate the impact of having VWD on frequency of hospitalization compared to a control group and to evaluate whether regular replacement therapy (prophylaxis) is associated with reduction in the number of hospitalizations. METHODS: Linkage of national population-based registries was used in the Congenital Bleeding Disorders study in Sweden (CBDS). Data were from the von Willebrand Disease Prophylaxis Network (VWD PN). RESULTS: The national registries contained 2790 subjects with a diagnosis of VWD between 1987 and 2009. A total of 13 920 age- and gender-matched controls were identified. There were 2.0 times (range 1.5-2.5) as many inpatient hospitalizations among subjects with VWD compared to controls. The most common causes of hospitalization were gastrointestinal (GI) bleeding (n = 232 as primary diagnosis), menorrhagia (n = 198) and epistaxis (n = 192). Outpatient visits per year were also twice as common among those with VWD. From the VWD PN, 105 subjects were included (VWD type 3, 52.4%; type2A, 22.9%; type 1, 12.4% and other types, 3.9%). A total of 122 hospitalizations due to bleeding episodes, dominated by GI bleeds, were analysed. Significantly fewer hospitalizations occurred after initiation of prophylaxis (75 prior to and 45 after, P = .006). CONCLUSION: Our study indicates that subjects with VWD have a considerably higher consumption of healthcare resources compared to controls and that initiation of prophylaxis may reduce the number of hospitalizations due to bleeding. PMID- 29626373 TI - Sexual dimorphism of substrate utilization: Differences in skeletal muscle mitochondrial volume density and function. AB - NEW FINDINGS: What is the central question of this study? Females rely to a greater extent than males on fat oxidation during exercise. Whether any difference in skeletal muscle mitochondrial phenotype and oxidative capacity contributes to this sexual dimorphism remains incompletely explored. What is the main finding and its importance? Female prioritization of fat during exercise occurs in parallel to augmented mitochondrial volume density and intrinsic fatty acid and lactate oxidation in skeletal muscle fibres compared with males, independently of aerobic exercise capacity. The enlarged metabolic machinery in skeletal muscle of females is associated with lower body size and leg mass. ABSTRACT: Fat oxidation during exercise is greater in females than in males. We sought to determine whether sex differences in substrate metabolism are paralleled by distinct skeletal muscle mitochondrial volume density and oxidative capacity. Whole-body substrate (fat and carbohydrate) utilization during submaximal treadmill running was assessed, and skeletal muscle biopsies were taken to determine mitochondrial volume density and function in healthy young females (n = 12) and males (n = 12) matched by aerobic exercise capacity and exercise performance. Females presented a lower respiratory exchange ratio (0.87 +/- 0.04 versus 0.91 +/- 0.04, P = 0.023) and whole-body carbohydrate oxidation (27.8 +/- 8.3 versus 35.8 +/- 6.5 mg kg-1 min-1 , P = 0.027), whereas fat oxidation was higher (8.7 +/- 2.8 versus 5.9 +/- 2.6 mg kg-1 min-1 , P = 0.034) during submaximal exercise compared with males. In skeletal muscle biopsies, females demonstrated augmented mitochondrial volume density (7.51 +/- 1.77 versus 5.90 +/- 1.72%, P = 0.035) and oxidative capacity for fatty acid [36.6 +/- 12.8 versus 24.5 +/- 7.3 pmol O2 s-1 (mg wet weight)-1 , P = 0.009] and lactate [71.1 +/- 24.4 versus 53.2 +/- 14.6 pmol O2 s-1 (mg wet weight)-1 , P = 0.040]. No sex differences in respiratory exchange ratio, whole-body fat oxidation and skeletal muscle variables were detected when adjusted for anthropometric variables including body mass or leg mass, which were lower in females. In conclusion, female prioritization of fat over carbohydrate oxidation during exercise is underpinned by augmented body size-related mitochondrial volume density, fatty acid and lactate oxidative capacity in skeletal muscle fibres. PMID- 29626374 TI - Cleaved caspase-3 expression is a potential prognostic factor for endometrial cancer with positive peritoneal cytology. AB - INTRODUCTION: Positive peritoneal cytology (PPC) in endometrial cancer remains a controversial topic. Cleaved caspase-3 (CC3) and Ki-67 are excellent markers of apoptotic and proliferating cells, respectively. The objective of this study was to determine the significance of CC3 and Ki-67 expression in peritoneal cytology samples as prognostic factors for endometrial cancer with PPC. METHODS: Sixty endometrial cancer specimens with PPC alone were divided into 51 endometrioid tumours (43 endometrioid carcinomas and eight carcinomas with squamous differentiation) and nine non-endometrioid tumours (two serous carcinomas, three clear cell carcinomas and four carcinosarcomas). CC3 and Ki-67 expression in peritoneal cytology samples were immunocytochemically assessed and correlated with disease-free survival (DFS) and overall survival (OS). RESULTS: Expression levels of CC3 and Ki-67 were not associated with any clinicopathological parameter. Patients with non-endometrioid tumours had significantly shorter DFS (P = .001) and OS (P = .001). Low CC3 expression (CC3Low ) was significantly associated with shorter OS (P = .02), but not DFS (P = .13). Multivariate analysis showed that non-endometrioid histology and CC3Low were independent prognostic factors. However, Ki-67 expression was not associated with survival. When endometrioid and non-endometrioid tumours were assessed separately, CC3Low was significantly associated with shorter DFS (P = .002) and OS (P = .002) in patients with non-endometrioid tumours. CONCLUSIONS: Our results suggest that CC3Low in peritoneal cytology samples is a poor prognostic factor in patients with endometrial cancers, especially non-endometrioid tumours. Immunocytochemical analysis of CC3 expression could potentially facilitate identification of patients with high-risk endometrial cancer with PPC. PMID- 29626375 TI - The link between intrauterine adhesions and induced termination of pregnancy remains a challenge. PMID- 29626376 TI - LI-RADS 2017: An update. AB - : The computed tomography / magnetic resonance imaging (CT/MRI) Liver Imaging Reporting & Data System (LI-RADS) is a standardized system for diagnostic imaging terminology, technique, interpretation, and reporting in patients with or at risk for developing hepatocellular carcinoma (HCC). Using diagnostic algorithms and tables, the system assigns to liver observations category codes reflecting the relative probability of HCC or other malignancies. This review article provides an overview of the 2017 version of CT/MRI LI-RADS with a focus on MRI. The main LI-RADS categories and their application will be described. Changes and updates introduced in this version of LI-RADS will be highlighted, including modifications to the diagnostic algorithm and to the optional application of ancillary features. Comparisons to other major diagnostic systems for HCC will be made, emphasizing key similarities, differences, strengths, and limitations. In addition, this review presents the new Treatment Response algorithm, while introducing the concepts of MRI nonviability and viability. Finally, planned future directions for LI-RADS will be outlined. LEVEL OF EVIDENCE: 5 Technical Efficacy: Stage 5 J. Magn. Reson. Imaging 2018;47:1459-1474. PMID- 29626377 TI - Classic paper: Are the chickenpox virus and the zoster virus identical?: HELMUT RUSKA. AB - As early as 1943, the German physician Helmut Ruska visualized the virus of varicella and zoster (at that time, he was not completely certain whether the virus was the same) by the newly developed electron microscope; he is regarded as the discoverer of this virus. Here, we present a translation of his classical paper into the English language. In our introduction and commentary to his paper, we discuss the significance of Helmut Ruska's work for the development of virology, his distinction between the varicella, zoster, and herpes virus group on one hand and poxviruses on the other, as well as the development of imaging techniques which have refined or substituted for electron microscopy of viruses and virus-infected cells. PMID- 29626378 TI - Physiological and psychological effects of gardening activity in older adults. AB - AIM: Gardening has long been one of most enjoyable pastimes among older adults. Whether gardening activities contribute to the well-being of older adults is a major question. Therefore, the aim of the present study was to clarify the psychophysiological relaxing effects of gardening activities on older adults living in modern institutional care. METHODS: The study participants were 40 older women aged 79.5 +/- 8.09 years (mean +/- SD). A cross-over study design was used to investigate the physiological and psychological responses to environments with and without plants. Physiological evaluation was carried out using blood pressure and electroencephalography, and psychological evaluation was carried out using the State-Trait Anxiety Inventory and Semantic Differential method. RESULTS: Blood pressure was significantly lower, and changes in brainwaves were observed. Psychological responses showed that participants were more "comfortable and relaxed" after the plant task than after the control task. In addition, total anxiety levels were significantly lower after carrying out the plant task than after the control task. CONCLUSIONS: Our research suggests that gardening activities might enhance physiological and psychological relaxation in older adults. Geriatr Gerontol Int 2018; 18: 1147-1152. PMID- 29626379 TI - Patterns of thaumarchaeal gene expression in culture and diverse marine environments. AB - Thaumarchaea are ubiquitous in marine habitats where they participate in carbon and nitrogen cycling. Although metatranscriptomes suggest thaumarchaea are active microbes in marine waters, we understand little about how thaumarchaeal gene expression patterns relate to substrate utilization and activity. Here, we report the global transcriptional response of the marine ammonia-oxidizing thaumarchaeon 'Candidatus Nitrosopelagicus brevis' str. CN25 to ammonia limitation using RNA Seq. We further describe the genome and transcriptome of Ca. N. brevis str. U25, a new strain capable of urea utilization. Ammonia limitation in CN25 resulted in reduced expression of transcripts coding for ammonia oxidation proteins, and increased expression of a gene coding an Hsp20-like chaperone. Despite significantly different transcript abundances across treatments, two ammonia monooxygenase subunits (amoAB), a nitrite reductase (nirK) and both ammonium transporter genes were always among the most abundant transcripts, regardless of growth state. Ca. N. brevis str. U25 cells expressed a urea transporter 139-fold more than the urease catalytic subunit ureC. Gene coexpression networks derived from culture transcriptomes and 10 thaumarchaea-enriched metatranscriptomes revealed a high degree of correlated gene expression across disparate environmental conditions and identified a module of coexpressed genes, including amoABC and nirK, that we hypothesize to represent the core ammonia oxidation machinery. PMID- 29626380 TI - The arbuscular mycorrhizal fungus Rhizophagus irregularis uses a reductive iron assimilation pathway for high-affinity iron uptake. AB - Arbuscular mycorrhizal (AM) fungi can improve iron (Fe) acquisition of their host plants. Here, we report a characterization of two components of the high-affinity reductive Fe uptake system of Rhizophagus irregularis, the ferric reductase (RiFRE1) and the high affinity Fe permeases (RiFTR1-2). In the extraradical mycelia (ERM), Fe deficiency induced activation of a plasma membrane-localized ferric reductase, an enzyme that reduces Fe(III) sources to the more soluble Fe(II). Yeast mutant complementation assays showed that RiFRE1 encodes a functional ferric reductase and RiFTR1 an iron permease. In the heterologous system, RiFTR1 was expressed in the plasma membrane while RiFTR2 was expressed in the endomembranes. In the ERM, the highest expression levels of RiFTR1 were found in mycelia grown in media with 0.045 mM Fe, while RiFTR2 was upregulated under Fe deficient conditions. RiFTR2 expression also increased in the intraradical mycelia (IRM) of maize plants grown without Fe. These data indicate that the Fe permease RiFTR1 plays a key role in Fe acquisition and that RiFTR2 is involved in Fe homeostasis under Fe-limiting conditions. RiFTR1 was highly expressed in the (IRM), which suggests that the maintenance of Fe homeostasis in the IRM might be essential for a successful symbiosis. PMID- 29626381 TI - Real life experiences of a PK dosing study-Challenges and lessons learned. PMID- 29626382 TI - Discriminating gastric cancer and gastric ulcer using human plasma amino acid metabolic profile. AB - Patients with gastric ulcer (GU) have a significantly higher risk of developing gastric cancer (GC), especially within 2 years after diagnosis. The main way to improve the prognosis of GC is to predict the tumorigenesis and metastasis in the early stage. The objective of this study was to demonstrate the ability of human plasma amino acid metabolic profile for discriminating GC and GU. In this study, we first used liquid chromatography-tandem mass spectrometry technique to characterize the plasma amino acid metabolism in GC and GU patients. Plasma samples were collected from 84 GC patients and 82 GU patients, and 22 amino acids were detected in each patient. Partial least squares-discriminant analysis model was performed to analyze the data of these amino acids. We observed seven differential amino acids between GC and GU. A regression analysis model was established using these seven amino acids. Finally, a panel of five differential amino acids, including glutamine, ornithine, histidine, arginine and tryptophan, was identified for discriminating GC and GU with good specificity and sensitivity. The receiver operating characteristic curve was used to evaluate diagnostic ability of the regression model and area under the curve was 0.922. In conclusion, this study demonstrated the potential values of plasma amino acid metabolic profile and metabolomic analysis technique in assisting diagnosis of GC. More studies are needed to highlight the theoretical strengths of metabolomics to understand the potential metabolic mechanisms in GC. (c) 2018 IUBMB Life, 70(6):553-562, 2018. PMID- 29626383 TI - MicroRNP-mediated translational activation of nonadenylated mRNAs in a mammalian cell-free system. AB - MicroRNAs are small noncoding RNAs that regulate translation and mRNA stability by binding target mRNAs in complex with Argonaute (AGO) proteins. AGO interacts with a member of the TNRC6 family proteins to form a microRNP complex, which recruits the CCR4-NOT complex to accelerate deadenylation and inhibits translation. MicroRNAs primarily repress translation of target mRNAs but have been shown to enhance translation of a specific type of target reporter mRNAs in various experimental systems: G0 quiescent mammalian cells, Xenopus laevis oocytes, Drosophila embryo extracts, and HeLa cells. In all of the cases mentioned, a common feature of the activated target mRNAs is the lack of a poly(A) tail. Here, we show let-7-microRNP-mediated translational activation of nonadenylated target mRNAs in a mammalian cell-free system, which contains over expressed AGO2, TNRC6B, and PAPD7 (TUTase5, TRF4-1). Importantly, translation of nonadenylated mRNAs was activated also by tethered TNRC6B silencing domain (SD), in the presence of PAPD7. Deletion of the poly(A)-binding protein (PABP) interacting motif (PAM2) from the TNRC6B-SD abolished the translational activation, suggesting the involvement of PABP in the process. Similar results were also obtained in cultured HEK293T cells. This work may provide novel insights into microRNP-mediated mRNA regulation. PMID- 29626384 TI - Parent-child genetic testing for familial hypercholesterolaemia in an Australian context. AB - AIM: The aim of this study was to evaluate the clinical outcome of parent-child testing for familial hypercholesterolaemia (FH) employing genetic testing and the likely additional cost of treating each child. METHODS: Parent-child testing for gene variants causative of FH was carried out according to Australian guidelines. The number of new cases detected, the low-density lipoprotein (LDL)-cholesterol that best predicted a mutation and the proportional reduction in LDL-cholesterol following statin treatment was evaluated. Treatment costs were calculated as the cost per mmol/L reduction in LDL-cholesterol. RESULTS: A total of 126 adult patients, known to have a pathogenic mutation causative of FH, and their children were studied. From 244 children identified, 148 (60.7%) were genetically screened; 84 children were identified as mutative positive (M+) and 64 as mutative negative. Six of the M+ children were already on statin treatment; 40 were subsequently treated with low-dose statins, with LDL-cholesterol falling significantly by 38% (P < 0.001). The estimated cost per mmol/L reduction of LDL cholesterol of a child receiving statins from ages 10 to 18 years is AU$1361, which can potentially be cost-effective. An LDL-cholesterol threshold of 3.5 mmol/L had a sensitivity of 92.8% and specificity of 96.6% for the detection of a mutation. CONCLUSION: Genetic testing of children of affected parents with FH is an effective means of detecting new cases of FH. Cascade testing can enable early statin therapy with significant reductions in LDL-cholesterol concentration. PMID- 29626385 TI - Microbial conservation in the Anthropocene. PMID- 29626386 TI - Effectiveness of weekend physical rehabilitation for functional recovery in geriatric patients with hip fracture. AB - AIM: To test the hypothesis that the functional outcome of hip fracture patients who receive weekend rehabilitation is better than that of similar patients who undergo non-weekend rehabilitation. METHODS: The present retrospective observational study used data from the Japan Rehabilitation Database spanning 2005-2015. We identified in-hospital hip fracture patients admitted to acute hospitals. After applying exclusion criteria, 469 patients were eligible. The primary outcome was motor Functional Independence Measure (FIM) efficiency. RESULTS: Of the patients with hip fracture, 68.0% received weekend rehabilitation. The patients who received weekend rehabilitation had significantly higher scores in motor FIM efficiency (mean 1.08 vs 0.73, P < 0.001), FIM efficiency (mean 1.12 vs 0.79, P = 0.001) and shorter length of stay (mean 32 vs 54, P < 0.001) than the patients without weekend rehabilitation. Multivariate linear regression analysis identified the weekend rehabilitation as a significant factor in motor FIM efficiency (coefficient 0.237, 95% confidence interval 0.074-0.400, P = 0.004), FIM efficiency (coefficient 0.235, 95% confidence interval 0.079-0.391, P = 0.003) and length of stay (coefficient 9.649, 95% confidence interval -18.194 to -1.104, P = 0.027). CONCLUSIONS: The present cohort analysis showed that weekend rehabilitation for hip fracture patients can lead to functional recovery and reduce the length of stay. Geriatr Gerontol Int 2018; 18: 1143-1146. PMID- 29626387 TI - Goal Attainment Scaling for haemophilia (GAS-Hem): testing the feasibility of a new patient-centric outcome measure in people with haemophilia. AB - INTRODUCTION: To address the need for a patient-reported outcome that can measure clinically and personally meaningful change in people with haemophilia (PwH) on prophylaxis, an approach based on Goal Attainment Scaling (GAS) was developed: the GAS-Hem. AIM: To establish real-world feasibility of GAS-Hem in PwH. METHODS: Patients aged 5-65 years were enroled from four North American centres for a 12 week study. The primary outcome was the proportion of participants who completed GAS-Hem interviews at baseline, 6 and 12 weeks. GAS-Hem scores were obtained by subject- and clinician-rated goal attainment at Weeks 6 and 12, and compared with quality of life (QoL) measures and annualized bleed rate (ABR) for construct validity. Goals were evaluated qualitatively for content validity. Responsiveness was calculated using standardized response means (SRM). RESULTS: Forty-two participants set 63 goals. Participants preferred to define (37/63) their own goals or further individualize (23/63) from the GAS-Hem menu. Thirty of the 37 self-defined goals were matched to goals on the GAS-Hem menu. The most common goal areas were: weight, exercise and nutrition (n = 17); leisure activities (n = 8); and joint problems (n = 7). Both participant- and clinician-rated GAS-Hem scores at 6 weeks (n = 40) and 12 weeks (n = 41) demonstrated satisfactory goal attainment (SRM [subject-rated] at 12 weeks for adult and paediatric groups was 1.25 and 1.16, respectively). Correlations of GAS-Hem scores with QoL measures and ABR were uniformly small. CONCLUSION: GAS-Hem was feasible and tapped constructs not captured by ABR or QoL measures. PMID- 29626389 TI - Efficient and Stable Inverted Planar Perovskite Solar Cells Using a Triphenylamine Hole-Transporting Material. AB - Inverted perovskite solar cells (PSCs) with a p-i-n structure have attracted great attention. Normally, inorganic p-type metal oxides or polymers are used as the hole-transport material (HTM), a vital component in the inverted PSCs. However, this type of HTM often requires high processing temperatures and/or high costs. On the other hand, a commonly used organic HTM, poly(3,4 ethylenedioxythiophene polystyrene sulfonate (PEDOT:PSS), is sensitive to humidity and thus affects the stability of the PSCs. Herein, we employ a small molecule, 4,4',4''-tris(N-3-methylphenyl-N-phenylamino) triphenylamine (m-MTDATA) to replace PEDOT:PSS as a new HTM for inverted PSCs. Compared to a PEDOT:PSS based device, m-MTDATA-based PSCs exhibit enhanced performance. The highest power conversion efficiency (PCE) was notably improved from 13.44 % (PEDOT:PSS) to 18.12 % (m-MTDATA), suggesting that m-MTDATA could be an efficient HTM to achieve high performance inverted PSCs. Furthermore, the m-MTDATA-based device demonstrated improved stability (retaining 90 % PCE) under ambient conditions over 1000 h compared with the PEDOT:PSS-based devices (retaining 40 % PCE). PMID- 29626388 TI - Prevalence and Determinants of Engagement with Obesity Care in the United States. AB - OBJECTIVE: Medical management of obesity can result in significant weight loss and reduce the burden of obesity-related complications. This report employs a new conceptual model to quantify engagement with obesity care and associated determinants in the US adult population. METHODS: Engagement with obesity care was conceptualized as a cascade comprising 5 successive steps: perceiving oneself as overweight, desiring to lose weight, attempting weight loss, seeking care from a health care professional for obesity, and seeking care from a physician specifically. RESULTS: Among adults with obesity, 7.3% did not perceive themselves as overweight, 1.5% perceived themselves as overweight but had no desire to lose weight, 29.9% wanted to lose weight but did not try in the last year, 51.3% tried to lose weight but did not consult a health professional, and 6.4% sought help for weight loss from a health professional but not a physician, implying that 96.4% of the population with obesity had an unmet need for obesity care. CONCLUSIONS: This analysis provides new insight into the most common points along the cascade at which disengagement occurs and can inform efforts to improve uptake of obesity-related health care services. PMID- 29626390 TI - Whole-field macro- and micro-deformation characteristic of unbound water-loss in dentin hard tissue. AB - High-resolution deformation measurements in a functionally graded hard tissue such as human dentin are essential to understand the unbound water-loss mediated changes and their role in its mechanical integrity. Yet a whole-field, 3 dimensional (3D) measurement and characterization of fully hydrated dentin in both macro- and micro-scales remain to be a challenge. This study was conducted in 2 stages. In stage-1, a stereo-digital image correlation approach was utilized to determine the water-loss and load-induced 3D deformations of teeth in a sagittal section over consecutively acquired frames, from a fully hydrated state to nonhydrated conditions for a period up to 2 hours. The macroscale analysis revealed concentrated residual deformations at the dentin-enamel-junction and the apical regions of root in the direction perpendicular to the dentinal tubules. Significant difference in the localized deformation characteristics was observed between the inner and outer aspects of the root dentin. During quasi-static loadings, further increase in the residual deformation was observed in the dentin. In stage-2, dentin microstructural variations induced by dynamic water loss were assessed with environmental scanning electron microscopy and atomic force microscopy (AFM), showing that the dynamic water-loss induced distention of dentinal tubules with concave tubular edges, and concurrent contraction of intertubular dentin with convex profile. The findings from the current macro- and micro-scale analysis provided insight on the free-water-loss induced regional deformations and ultrastructural changes in human dentin. PMID- 29626391 TI - Pregnancy after liver transplantation: Can renal function quell the fear? PMID- 29626392 TI - Exercise and exercise training-induced increase in autophagy markers in human skeletal muscle. AB - Moderately trained male subjects (mean age 25 years; range 19-33 years) completed an 8-week exercise training intervention consisting of continuous moderate cycling at 157 +/- 20 W for 60 min (MOD; n = 6) or continuous moderate cycling (157 +/- 20 W) interspersed by 30-sec sprints (473 +/- 79 W) every 10 min (SPRINT; n = 6) 3 days per week. Sprints were followed by 3:24 min at 102 +/- 17 W to match the total work between protocols. A muscle biopsy was obtained before, immediately and 2 h after the first training session as well as at rest after the training session. In both MOD and SPRINT, skeletal muscle AMPKThr172 and ULKSer317 phosphorylation was elevated immediately after exercise, whereas mTORSer2448 and ULKSer757 phosphorylation was unchanged. Two hours after exercise LC3I, LC3II and BNIP3 protein content was overall higher than before exercise with no change in p62 protein. In MOD, Beclin1 protein content was higher immediately and 2 h after exercise than before exercise, while there were no differences within SPRINT. Oxphos complex I, LC3I, BNIP3 and Parkin protein content was higher after the training intervention than before in both groups, while there was no difference in LC3II and p62 protein. Beclin1 protein content was higher after the exercise training intervention only in MOD. Together this suggests that exercise increases markers of autophagy in human skeletal muscle within the first 2 h of recovery and 8 weeks of exercise training increases the capacity for autophagy and mitophagy regulation. Hence, the present findings provide evidence that exercise and exercise training regulate autophagy in human skeletal muscle and that this in general was unaffected by interspersed sprint bouts. PMID- 29626393 TI - Cyto-morphologic spectrum of thyroid lesions in children. AB - INTRODUCTION: Fine needle aspiration (FNA) is routinely used in triaging thyroid lesions in adults. However, role of FNA in pediatric thyroid lesions is less studied. AIM AND OBJECTIVE: To study the cyto-morphologic spectrum of thyroid lesions in pediatric population. MATERIALS AND METHODS: A retrospective analysis (duration-6 years) of thyroid FNA for patients who were 18 years or younger was conducted. The aspirates were classified according to the Bethesda System for Reporting Cytopathology. RESULTS: A total of 2716 thyroid aspirates were reviewed, out of which 327 (12%) were pediatric thyroid FNAs performed on 301 patients. Of these 256 (85%) were females and 45 (15%) were male patients. Aspirates were classified as follows: Nondiagnostic-30 (10%), Benign-260 (86%), Atypia of undetermined significance-6 (2%), Suspicious of follicular neoplasm-0 (0%), Suspicious of malignancy-0 (0%), Malignant-5 (2%). Out of the 253 benign lesions, 153 (58%) were spectrum of colloid goitre, 106 (42%) were Lymphocytic thyroiditis and 1(0.5%) was granulomatous thyroiditis (0.5%). CONCLUSION: Thyroid disorders are fairly common in children. Majority of these are benign in nature of which most common are spectrum of colloid goitre. With the benefits of being a noninvasive procedure and cost effective, FNA is a reliable method for screening and diagnosis of thyroid lesions in pediatric population. PMID- 29626394 TI - Microbiome and Health: Ramifications of Intelligent Deception. AB - Ten thousand years ago, the foundation for agricultural development and animal domestication was laid. Neolithic founder crops were carbohydrate-laden cereal grasses that facilitated transformation of hunter-gather societies into ancient civilizations with realistic capabilities for population expansion. In the last 3 4 decades, however, debilitating medical consequences of a progressively narrowed high caloric diet incorporating processed carbohydrates, animal protein, saturated fat and cholesterol, are translated into a global epidemic of obesity linked to metabolic and endocrine disorders, which, in part, emerged from the enhancement of our longevity. The initiation and progression of pathophysiological processes associated with this restrictive diet may well reside in the gastrointestinal tract. The critical role of human gut microbiome in facilitating normal gut physiology and linkages to other physiological systems points to its significance in comorbid pathologies when its diversity is compromised. Cortical desensitization to the potentially damaging effects of intentionally restricted high carbohydrate diets is progressively enhanced by compromised metabolic activities and widespread pro-inflammatory processes within all organ systems. Our cognitive ability must overcome the desire for comfort foods. The solution is simple: minimize "processed" foods and those of similar commercial origin in our diet, restoring a more diverse gut microbiome. Initially the solution may be costly, however, within the scope of sustained healthy longevity it will "payoff". PMID- 29626395 TI - Achieving Integrated Care for Older People: Shuffling the Deckchairs or Making the System Watertight For the Future? AB - Integrated care has been recognised as a key initiative to resolve the issues surrounding care for older people living with multi-morbidity. Multiple strategies and policies have been implemented to increase coordination of care globally however, evidence of effectiveness remains mixed. The reasons for this are complex and multifactorial, yet many strategies deal with parts of the problem rather than taking a whole systems view with the older person clearly at the centre. This approach of fixing parts of the system may be akin to shuffling the deckchairson the Titanic, rather than dealing with the fundamental reasons why the ship is sinking. Attempts to make the ship more watertight need to be firmly centred on the older person, pay close attention to implementation and embrace approaches that promote collaborative working between all the stakeholders involved. PMID- 29626396 TI - Settling Ulysses: An Adapted Research Agenda for Refugee Mental Health. AB - Refugees and asylum seekers arriving in Europe during the 2015/2016 wave of migration have been exposed to war conditions in their country of origin, survived a dangerous journey, and often struggled with negative reception in transit and host countries. The mental health consequence of such forced migration experiences is named the Ulysses syndrome. Policies regarding the right to residency can play an important role in reducing mental health symptoms. We propose that facilitating a sense of belonging should be seen as one important preventive mental healthcare intervention. A refugee mental health agenda needs to take into account the interplay between refugees' and asylum seekers' mental health, feeling of belonging, and access to healthcare. We urge for policies to restore individuals' dignity, and recognize the right for homecoming to parallel the mythology of Ulysses. PMID- 29626397 TI - An Analysis of the Extent of Social Inclusion and Equity Consideration in Malawi's National HIV and AIDS Policy Review Process. AB - BACKGROUND: Equity and social inclusion for vulnerable groups in policy development processes and resulting documents remain a challenge globally. Most often, the marginalization of vulnerable groups is overlooked in both the planning and practice of health service delivery. Such marginalization may occur because authorities deem the targeting of those who already have better access to healthcare a cheaper and easier way to achieve short-term health gains. The Government of Malawi wishes to achieve an equitable and inclusive HIV and AIDS Policy. The aim of this study is to assess the extent to which the Malawi Policy review process addressed regional and international health priorities of equity and social inclusion for vulnerable groups in the policy content and policy revision process. METHODS: This research design comprised two phases. First, the content of the Malawi HIV and AIDS Policy was assessed using EquiFrame regarding its coverage of 21 Core Concepts of human rights and inclusion of 12 Vulnerable Groups. Second, the engagement of vulnerable groups in the policy process was assessed using the EquIPP matrix. For the latter, 10 interviews were conducted with a purposive sample of representatives of public sector, civil society organizations and development partners who participated in the policy revision process. Data was also collected from documented information of the policy processes. RESULTS: Our analyses indicated that the Malawi HIV and AIDS Policy had a relatively high coverage of Core Concepts of human rights and Vulnerable Groups; although with some notable omissions. The analyses also found that reasonable steps were taken to engage and promote participation of vulnerable groups in the planning, development, implementation, monitoring and evaluation processes of the HIV and AIDS Policy, although again, with some notable exceptions. This is the first study to use both EquiFrame and EquIPP as complimentary tools to assess the content and process of policy. CONCLUSION: While the findings indicate inclusive processes, commitment to Core Concepts of human rights and inclusion of Vulnerable Groups in relation to the Malawi HIV and AIDS Policy, the results also point to areas in which social inclusion and equity could be further strengthened. PMID- 29626398 TI - Measuring Hospital Performance Using Mortality Rates: An Alternative to the RAMR. AB - BACKGROUND: The risk-adjusted mortality rate (RAMR) is used widely by healthcare agencies to evaluate hospital performance. The RAMR is insensitive to case volume and requires a confidence interval for proper interpretation, which results in a hypothesis testing framework. Unfamiliarity with hypothesis testing can lead to erroneous interpretations by the public and other stakeholders. We argue that screening, rather than hypothesis testing, is more defensible. We propose an alternative to the RAMR that is based on sound statistical methodology, easier to understand and can be used in large-scale screening with no additional data requirements. METHODS: We use an upper-tail probability to screen for hospitals performing poorly and a lower-tail probability to screen for hospitals performing well. Confidence intervals and hypothesis tests are not needed to compute or interpret our measures. Moreover, unlike the RAMR, our measures are sensitive to the number of cases treated. RESULTS: To demonstrate our proposed methodology, we obtained data from the New York State Department of Health for 10 Inpatient Quality Indicators (IQIs) for the years 2009-2013. We find strong agreement between the upper tail probability (UTP) and the RAMR, supporting our contention that the UTP is a viable alternative to the RAMR. CONCLUSION: We show that our method is simpler to implement than the RAMR and, with no need for a confidence interval, it is easier to interpret. Moreover, it will be available for all hospitals and all diseases/conditions regardless of patient volume. PMID- 29626399 TI - Empirical Study of Nova Scotia Nurses' Adoption of Healthcare Information Systems: Implications for Management and Policy-Making. AB - BACKGROUND: This paper used the Theory of Planned Behavior (TPB), which was extended, to investigate nurses' adoption of healthcare information systems (HIS) in Nova Scotia, Canada. METHODS: Data was collected from 197 nurses in a survey and data analysis was carried out using the partial least squares (PLS) technique. RESULTS: In contrast to findings in prior studies that used TPB to investigate clinicians' adoption of technologies in Canada and elsewhere, this study found no statistical significance for the relationships between attitude and subjective norm in relation to nurses' intention to use HIS. Rather, facilitating organizational conditions was the only TPB variable that explained sampled nurses' intention to use HIS at work. In particular, effects of computer habit and computer anxiety among older nurses were signified. CONCLUSION: To encourage nurses' adoption of HIS, healthcare administrators need to pay attention to facilitating organization conditions at work. Enhancing computer knowledge or competence is important for acceptance. Information presented in the study can be used by administrators of healthcare facilities in the research location and comparable parts of the world to further improve HIS adoption among nurses. The management of nursing professionals, especially in certain contexts (eg, prevalence of older nursing professionals), can make use of this study's insights. PMID- 29626400 TI - Assessing and Improving Performance: A Longitudinal Evaluation of Priority Setting and Resource Allocation in a Canadian Health Region. AB - BACKGROUND: In order to meet the challenges presented by increasing demand and scarcity of resources, healthcare organizations are faced with difficult decisions related to resource allocation. Tools to facilitate evaluation and improvement of these processes could enable greater transparency and more optimal distribution of resources. METHODS: The Resource Allocation Performance Assessment Tool (RAPAT) was implemented in a healthcare organization in British Columbia, Canada. Recommendations for improvement were delivered, and a follow up evaluation exercise was conducted to assess the trajectory of the organization's priority setting and resource allocation (PSRA) process 2 years post the original evaluation. RESULTS: Implementation of RAPAT in the pilot organization identified strengths and weaknesses of the organization's PSRA process at the time of the original evaluation. Strengths included the use of criteria and evidence, an ability to reallocate resources, and the involvement of frontline staff in the process. Weaknesses included training, communication, and lack of program budgeting. Although the follow up revealed a regression from a more formal PSRA process, a legacy of explicit resource allocation was reported to be providing ongoing benefit for the organization. CONCLUSION: While past studies have taken a cross-sectional approach, this paper introduces the first longitudinal evaluation of PSRA in a healthcare organization. By including the strengths, weaknesses, and evolution of one organization's journey, the authors' intend that this paper will assist other healthcare leaders in meeting the challenges of allocating scarce resources. PMID- 29626401 TI - Improving the Distribution of Rural Health Houses Using Elicitation and GIS in Khuzestan Province (the Southwest of Iran). AB - BACKGROUND: Rural health houses constitute a major provider of some primary health services in the villages of Iran. Given the challenges of providing health services in rural areas, health houses should be established based on the criteria of health network systems (HNSs). The value of these criteria and their precedence over others have not yet been thoroughly investigated. The present study was conducted to propose a model for improving the distribution of rural health houses in HNSs. METHODS: The present applied study was conducted in Khuzestan province in the southwest of Iran in 2014-2016. First, the descriptive and spatial data required were collected and entered into ArcGIS after modifications, and the Geodatabase was then created. Based on the criteria of the HNS and according to experts' opinions, the main criteria and the sub-criteria for an optimal site selection were determined. To determine the criteria's coefficient of importance (ie, their weight), the main criteria and the sub criteria were compared in pairs according to experts' opinions. The results of the pairwise comparisons were entered into Expert Choice and the weight of the main criteria and the sub-criteria were determined using the analytic hierarchy process (AHP). The application layers were then formed in geographic information system (GIS). A model was ultimately proposed in the GIS for the optimal distribution of rural health houses by overlaying the weighting layers and the other layers related to villages and rural health houses. RESULTS: Based on the experts' opinions, six criteria were determined as the main criteria for an optimal site selection for rural health houses, including welfare infrastructures, population, dispersion, accessibility, corresponding routes, distance to the rural health center and the absence of natural barriers to accessibility. Of the main criteria proposed, the highest weight was given to "population" (0.506). The priorities suggested in the proposed model for establishing rural health houses are presented within five zoning levels -from excellent to very poor. CONCLUSION: The results of the study showed that the proposed model can help provide a better picture of the distribution of rural health houses. The GIS is recommended to be used as a means of making the HNS more efficient. PMID- 29626402 TI - The No-Destination Ship of Priority-Setting in Healthcare: A Call for More Democracy. AB - In dealing with scarcity of resources within healthcare systems, decision-makers inevitably have to make choices about which services to fund. Setting priorities represents a challenging task that requires systematic, explicit and transparent methodologies with focus on economic efficiency. In addition, the engagement of the general public in the process of decision-making has been regarded as one of the most important aspects of the management of publicly-funded health systems in liberal democracies. In the current essay, we aim to discuss the problematics of public engagement in the process of resource allocation and priority-setting within the context of publiclyfunded health systems. Our central argument is that although there may be a conflict between democratic mechanisms of citizen participation and economic efficiency, in the extra-welfarist sense, expected for/from the system, the solution for this tension does not seem to rely on more or novel authoritative technocratic approaches, but rather on the deepening and betterment of democratic participation. PMID- 29626403 TI - Providers and Patients Caught Between Standardization and Individualization: Individualized Standardization as a Solution Comment on "(Re) Making the Procrustean Bed? Standardization and Customization as Competing Logics in Healthcare". AB - In their 2017 article, Mannion and Exworthy provide a thoughtful and theory-based analysis of two parallel trends in modern healthcare systems and their competing and conflicting logics: standardization and customization. This commentary further discusses the challenge of treatment decision-making in times of evidence based medicine (EBM), shared decision-making and personalized medicine. From the perspective of systems theory, we propose the concept of individualized standardization as a solution to the problem. According to this concept, standardization is conceptualized as a guiding framework leaving room for individualization in the patient physician interaction. The theoretical background is the concept of context management according to systems theory. Moreover, the comment suggests multidisciplinary teams as a possible solution for the integration of standardization and individualization, using the example of multidisciplinary tumor conferences and highlighting its limitations. The comment also supports the authors' statement of the patient as co-producer and introduces the idea that the competing logics of standardization and individualization are a matter of perspective on macro, meso and micro levels. PMID- 29626404 TI - Making Research Matter Comment on "Public Spending on Health Service and Policy Research in Canada, the United Kingdom, and the United States: A Modest Proposal". AB - We offer a UK-based commentary on the recent "Perspective" published in IJHPM by Thakkar and Sullivan. We are sympathetic to the authors' call for increased funding for health service and policy research (HSPR). However, we point out that increasing that investment - in any of the three countries they compare: Canada, the United States and the United Kingdom- will ipso facto not necessarily lead to any better use of research by health system decision-makers in these settings. We cite previous authors' descriptions of the many factors that tend to make the worlds of researchers and decision-makers into "two solitudes." And we call for changes in the structure and funding of HSPR, particularly the incentives now in place for purely academic publishing, to tackle a widespread reality: most published research in HSPR, as in other applied fields of science, is never read or used by the vast majority of decision-makers, working out in the "real world. PMID- 29626405 TI - Best of Both Worlds Comment on "(Re) Making the Procrustean Bed? Standardization and Customization as Competing Logics in Healthcare". AB - This article builds on Mannion and Exworthy's account of the tensions between standardization and customization within health services to explore why these tensions exist. It highlights the limitations of explanations which root them in an expression of managerialism versus professionalism and suggests that each logic is embedded in a set of ontological, epistemological and moral commitments which are held in tension. At the front line of care delivery, people cannot resolve these tensions but must navigate and negotiate them. The legitimacy of a health system depends on its ability to deliver the 'best of both worlds' to citizens, offering the reassurance of sameness and the dignity of difference. PMID- 29626406 TI - Competing Logics and Healthcare Comment on "(Re) Making the Procrustean Bed? Standardization and Customization as Competing Logics in Healthcare". AB - This paper offers a short commentary on the editorial by Mannion and Exworthy. The paper highlights the positive insights offered by their analysis into the tensions between the competing institutional logics of standardization and customization in healthcare, in part manifested in the conflict between managers and professionals, and endorses the plea of the authors for further research in this field. However, the editorial is criticized for its lack of a strong societal reference point, the comparative absence of focus on hybridization, and its failure to highlight structural factors impinging on the opposing logics in a broader neo-institutional framework. With reference to the Procrustean metaphor, it is argued that greater stress should be placed on the healthcare user in future health policy. Finally, the case of complementary and alternative medicine is set out which - while not explicitly mentioned in the editorial - most effectively concretizes the tensions at the heart of this analysis of healthcare. PMID- 29626407 TI - Additional Insights Into Problem Definition and Positioning From Social Science Comment on "Four Challenges That Global Health Networks Face". AB - Commenting on a recent editorial in this journal which presented four challenges global health networks will have to tackle to be effective, this essay discusses why this type of analysis is important for global health scholars and practitioners, and why it is worth understanding and critically engaging with the complexities behind these challenges. Focusing on the topics of problem definition and positioning, I outline additional insights from social science theory to demonstrate how networks and network researchers can evaluate these processes, and how these processes contribute to better organizing, advocacy, and public health outcomes. This essay also raises multiple questions regarding these processes for future research. PMID- 29626408 TI - The Politics and Power of Populism: A Response to the Recent Commentaries. PMID- 29626409 TI - Wind of Change: Brexit and European Rehabilitation. PMID- 29626410 TI - Comparison of five cell-free DNA isolation methods to detect the EGFR T790M mutation in plasma samples of patients with lung cancer. PMID- 29626411 TI - The curious case of postprandial glucose less than fasting glucose: little things that matter much. PMID- 29626412 TI - Standardization of autoimmune testing - is it feasible? PMID- 29626413 TI - Early adjustment of antimicrobial therapy after PCR/electrospray ionization mass spectrometry-based pathogen detection in critically ill patients with suspected sepsis. PMID- 29626414 TI - Can we use a point-of-care blood gas analyzer to measure the lactate concentration in cerebrospinal fluid of patients with suspected meningitis? PMID- 29626415 TI - Effects of common hemoglobin variants on HbA1c measurements in China: results for alpha- and beta-globin variants measured by six methods. AB - BACKGROUND: HbA1c is a widely used biomarker for diabetes mellitus management. Here, we evaluated the accuracy of six methods for determining HbA1c values in Chinese patients with common alpha- and beta-globin chains variants in China. METHODS: Blood samples from normal subjects and individuals exhibiting hemoglobin variants were analyzed for HbA1c, using Sebia Capillarys 2 Flex Piercing (C2FP), Bio-Rad Variant II Turbo 2.0, Tosoh HLC-723 G8 (ver. 5.24), Arkray ADAMS A1c HA 8180V fast mode, Cobas c501 and Trinity Ultra2 systems. RESULTS: DNA sequencing revealed five common beta-globin chain variants and three common alpha-globin chain variants. The most common variant was Hb E, followed by Hb New York, Hb J Bangkok, Hb G-Coushatta, Hb Q-Thailand, Hb G-Honolulu, Hb Ube-2 and Hb G-Taipei. Variant II Turbo 2.0, Ultra2 and Cobas c501 showed good agreement with C2FP for most samples with variants. HLC-723 G8 yielded no HbA1c values for Hb J-Bangkok, Hb Q-Thailand and Hb G-Honolulu. Samples with Hb E, Hb G-Coushatta, Hb G-Taipei and Hb Ube-2 produced significant negative biases for HLC-723 G8. HA-8180V showed statistically significant differences for Hb E, Hb G-Coushatta, Hb G-Taipei, Hb Q Thailand and Hb G-Honolulu. HA-8180V yielded no HbA1c values for Hb J-Bangkok. All methods showed good agreement for samples with Hb New York. CONCLUSIONS: Some common hemoglobin variants can interfere with HbA1c determination by the most popular methods in China. PMID- 29626416 TI - Effects of Increased Frequency, High Dose, and Pulsatile Oxytocin Regimens on Abnormal Labor Delivery. AB - BACKGROUND The current guideline for oxytocin regimens in the abnormal labor of delivery is continuous infusion. The objective of the present study was to compare effects and safety measures of various available regimens of oxytocin in abnormal labor delivery. MATERIAL AND METHODS In this clinical experimental study, a total of 900 pregnant women admitted for delivery were randomized into 5 group with 162 each. Pregnant women received oxytocin as continuous administration of 16 mU/min (Group I), 1 mU/min (group II), 4 mU/min (group III), 5 mU/min quarter-hourly (group IV), and through a syringe pump (group V). Measurement of the expense of delivery, the ratio of the instrumental delivery, and the other secondary outcome measures was performed to find the best regimen of oxytocin. The 2-tailed paired t test and Mann-Whitney U test following Dunnett's multiple comparison tests were used at 95% confidence level. RESULTS Pulsatile delivery had least risk of instrumental delivery as compared to continuous infusion (p<0.0001, q=6.663) and normal-frequency low-dose (p<0.0001, q=5.638) of oxytocin. The time required from infusion to delivery was longer for group II (p=0.001, q=2.925), group IV (p<0.0001, q=4.829), and group V (p<0.0001, q=41.456) than for group I. The expense of delivery was: group I < group II < group IV < group III < group V. CONCLUSIONS High-dose and pulsatile preparation of oxytocin had reduced risks of operative delivery vs. continuous administration. PMID- 29626417 TI - Morphology, compressibility and viscoelasticity of the mixed lipid monolayers in the presence of beta-carotene. AB - The aim of the present study was to investigate the interfacial behaviour of model biomembranes in the presence of beta-carotene (betaC). The Langmuir monolayer technique was used to form the mixed lipid film at the air/water interface. Using the surface pressure-area isotherms, the surface potential-area curves and the Brewster angle microscopy the nature of interactions between carotenoid and lipid components of the monolayers was investigated. The results were obtained for complex models of the lipid bilayer composed of 1,2-dipalmitoyl sn-glycero-3-phosphocholine (DPPC) and cholesterol (CHOL). It was found that beta carotene affected the membrane stability, fluidity and rigidity, however this influence varied with the DPPC/CHOL ratio. The membrane permeability which is significant for biological functions was found to be affected by the presence of beta-carotene in the membrane. The morphology of mixed films visualized by Brewster angle microscopy was similar for DPPC/CHOL and DPPC/CHOL/betaC films indicating incorporation of carotenoid into the film. In contrary to previous reports for individual lipids, we did not observed the aggregation of betaC in the mixed lipid monolayer. Moreover, from dilatational rheology experiment we concluded about the significant role of beta-carotene in modulation of the elastic behaviour of the membrane, especially in physiologically significant surface pressure, i.e. at pi = 30 mN/m. PMID- 29626418 TI - Bergamot natural products eradicate cancer stem cells (CSCs) by targeting mevalonate, Rho-GDI-signalling and mitochondrial metabolism. AB - Here, we show that a 2:1 mixture of Brutieridin and Melitidin, termed "BMF", has a statin-like properties, which blocks the action of the rate-limiting enzyme for mevalonate biosynthesis, namely HMGR (3-hydroxy-3-methylglutaryl-CoA-reductase). Moreover, our results indicate that BMF functionally inhibits several key characteristics of CSCs. More specifically, BMF effectively i) reduced ALDH activity, ii) blocked mammosphere formation and iii) inhibited the activation of CSC-associated signalling pathways (STAT1/3, Notch and Wnt/beta-catenin) targeting Rho-GDI-signalling. In addition, BMF metabolically inhibited mitochondrial respiration (OXPHOS) and fatty acid oxidation (FAO). Importantly, BMF did not show the same toxic side-effects in normal fibroblasts that were observed with statins. Lastly, we show that high expression of the mRNA species encoding HMGR is associated with poor clinical outcome in breast cancer patients, providing a potential companion diagnostic for BMF-directed personalized therapy. PMID- 29626420 TI - Corrigendum to "Nicotinic Activity Depresses Synaptic Potentiation in Layer V Pyramidal Neurons of Mouse Insular Cortex" [Neuroscience 358C (2017) 13-27]. PMID- 29626419 TI - The K-path entrance in cytochrome c oxidase is defined by mutation of E101 and controlled by an adjacent ligand binding domain. AB - Three mutant forms of Rhodobacter sphaeroides cytochrome c oxidase (RsCcO) were created to test for multiple K-path entry sites (E101W), the existence of an "upper ligand site" (M350 W), and the nature and binding specificity of the "lower ligand site" (P315W/E101A) in the region of a crystallographically-defined deoxycholate at the K-path entrance. The effects of inhibitory and stimulatory detergents (dodecyl maltoside and Tween20) on these mutants are presented, as well as competition with other ligands, including the potentially physiologically relevant ligands cholesterol and retinoic acid. Ligands are shown to be able to compete with natural lipids to affect the activity of membrane-bound RsCcO. Results point to a single K-path entrance site at E101, with a single ligand binding pocket proximal to the entrance. The affinity of this pocket for amphipathic ligands is enhanced by removal of the E101 carboxyl and blocked by substituting a tryptophan in this area. A new crystal structure of the E101A mutant of RsCcO is presented that illustrates the structural basis of these results, showing that the loss of the E101 carboxyl creates a more hydrophobic groove consistent with altered ligand affinities. PMID- 29626421 TI - Characterisation of peroxidasin activity in isolated extracellular matrix and direct detection of hypobromous acid formation. AB - Peroxidasin is a heme peroxidase that catalyses the oxidation of bromide by hydrogen peroxide to form an essential sulfilimine cross-link between methionine and hydroxylysine residues in collagen IV. We investigated cross-linking by peroxidasin embedded in extracellular matrix isolated from cultured epithelial cells and its sensitivity to alternative substrates and peroxidase inhibitors. Peroxidasin showed peroxidase activity as measured with hydrogen peroxide and Amplex red. Using a specific mass spectrometry assay that measures NADH bromohydrin, we showed definitively that the enzyme releases hypobromous acid (HOBr). Less than 1 MUM of the added hydrogen peroxide was used by peroxidasin. The remainder was consumed by catalase activity that was associated with the matrix. Results from NADH bromohydrin measurements indicates that low micromolar HOBr generated by peroxidasin was sufficient for maximum sulfilimine cross linking, whereas 100 MUM reagent HOBr or taurine bromamine was less efficient. This implies selectivity for the enzymatic process. Physiological concentrations of thiocyanate and urate partially inhibited cross-link formation. 4-Aminobenzoic acid hydrazide, a commonly used myeloperoxidase inhibitor, also inhibited peroxidasin, whereas acetaminophen and a 2-thioxanthine were much less effective. In conclusion, HOBr is produced by peroxidasin in the extracellular matrix. It appears to be directed at the site of collagen IV sulfilimine formation but the released HOBr may also undergo other reactions. PMID- 29626422 TI - HCM and DCM cardiomyopathy-linked alpha-tropomyosin mutations influence off-state stability and crossbridge interaction on thin filaments. AB - Calcium regulation of cardiac muscle contraction is controlled by the thin filament proteins troponin and tropomyosin bound to actin. In the absence of calcium, troponin-tropomyosin inhibits myosin-interactions on actin and induces muscle relaxation, whereas the addition of calcium relieves the inhibitory constraint to initiate contraction. Many mutations in thin filament proteins linked to cardiomyopathy appear to disrupt this regulatory switching. Here, we tested perturbations caused by mutant tropomyosins (E40K, DCM; and E62Q, HCM) on intra-filament interactions affecting acto-myosin interactions including those induced further by myosin association. Comparison of wild-type and mutant human alpha-tropomyosin (Tpm1.1) behavior was carried out using in vitro motility assays and molecular dynamics simulations. Our results show that E62Q tropomyosin destabilizes thin filament off-state function by increasing calcium-sensitivity, but without apparent affect on global tropomyosin structure by modifying coiled coil rigidity. In contrast, the E40K mutant tropomyosin appears to stabilize the off-state, demonstrates increased tropomyosin flexibility, while also decreasing calcium-sensitivity. In addition, the E40K mutation reduces thin filament velocity at low myosin concentration while the E62Q mutant tropomyosin increases velocity. Corresponding molecular dynamics simulations indicate specific residue interactions that are likely to redefine underlying molecular regulatory mechanisms, which we propose explain the altered contractility evoked by the disease-causing mutations. PMID- 29626423 TI - Immuno-efficacy of DNA vaccines encoding PLP1 and ROP18 against experimental Toxoplasma gondii infection in mice. AB - We constructed a new plasmid pIRESneo/ROP18/PLP1 that was injected intramuscularly into Kunming mice to evaluate its immune efficacy. The immunized mice exhibited significantly increased serum IgG2a levels, lymphocyte counts and Th1-type cytokine (IL-2, IL-12 and IFN-gamma) levels. Moreover, the immunized mice exhibited longer survival times (44.7 +/- 2.1 days for ROP18/PLP1 and 47.2 +/- 2.9 days for ROP18/PLP1 + IL-18) and lower brain cyst burden (68.9% for ROP18/PLP1 and 72.4% for ROP18/PLP1 + IL-18) than control mice after T. gondii challenge. Our results demonstrate that the multiple-gene DNA vaccine including both ROP18 and PLP1 elicits greater protection against T. gondii challenge and stronger immunogenicity than single-gene vaccines. PMID- 29626424 TI - Multifocal nitrous oxide cryoballoon ablation with or without EMR for treatment of neoplastic Barrett's esophagus (with video). AB - BACKGROUND AND AIMS: Endoscopic cryotherapy can eradicate neoplastic Barrett's esophagus (BE). A new contact cryoballoon focal ablation system (CbFAS)) freezes esophageal mucosa with nitrous oxide. We studied the safety and efficacy of CbFAS for complete eradication of neoplastic Barrett's esophagus. METHODS: In a prospective clinical trial, consecutive BE patients with confirmed neoplasia (low grade dysplasia [LGD], high-grade dysplasia [HGD], and/or intramucosal adenocarcinoma [ImCA]), at least 1 cm of BE, with or without prior ablation, were treated with a dose 10 seconds of spray per site. EMR was performed for nodular lesions. Treatments were repeated every 10 to 12 weeks until complete eradication, with a maximum of 5 treatments. Primary outcomes were complete eradication of all dysplasia (CE-D) and complete eradication of intestinal metaplasia (CE-IM) at 1 year (intention-to-treat analysis). RESULTS: Forty-one assessable patients (22 treatment naive, 19 previously ablated) with LGD (n = 13), HGD (n = 23), or ImCA (n = 5) were treated. The median procedure time was 30 minutes. The median number of ablation procedures for CE-IM was 3 (interquartile range, 2-4). Overall 1-year CE-D and CE-IM rates were 95% and 88%, respectively. CE-D rate was significantly lower (67%) in those with ultra-long BE compared with those with <8 cm (100%, P = .02). Median pain scores were zero at day 1. Four patients (9.7%) developed mild dysphagia from stenoses requiring dilation. One patient on aspirin developed upper GI bleeding that did not require therapy. CONCLUSIONS: Multifocal nitrous oxide cryotherapy using CbFAS is a promising, highly effective, and safe endoscopic treatment for primary or rescue therapy of BE-associated neoplasia and IM. (Clinical trial registration number: NCT02534233.). PMID- 29626425 TI - Salidroside improves brain ischemic injury by activating PI3K/Akt pathway and reduces complications induced by delayed tPA treatment. AB - Cerebral ischemia causes blood-brain barrier (BBB) injury and thus increases the risk of complications secondary to thrombolysis, which limited its clinical application. This study aims to clarify the role and mechanism of salidroside (SALD) in alleviating brain ischemic injury and whether pretreatment of it could improve prognosis of delayed treatment of tissue plasminogen activator (t-PA). Rats were subjected to 3 h of middle cerebral artery occlusion (MCAO) and were intraperitoneally administered with 10, 20 or 40 mg/kg SALD before ischemia. 1.5% 5-triphenyl-2H-tetrazolium chloride (TTC) staining and neurological studies were performed to observe the effectiveness of SALD. The expressions and the distribution of phosphoinositide-3-kinase/protein kinase B (PI3K/Akt) signaling were analyzed. Experiments were further conducted in isolated microvessels and human brain microvascular endothelial cells (HBMECs) to explore the protective mechanism of SALD. Finally, rats were subjected to 6 h of MCAO and 24 h of reperfusion. tPA was given with or without the pretreatment of SALD. Various approaches including gelatin zymography, western blot and immunofluorescence were used to evaluate the effect of this combination therapy. SALD could reduce cerebral ischemic injury and enhance HBMECs viability subjected to OGD. In vivo and in vitro studies showed the mechanism might be related to the activation of PI3K/Akt signaling by phosphorylating Akt on Ser473. Pretreatment of SALD could alleviate BBB injury and improve the outcome of delayed treatment of tPA. These results provide evidence that SALD might be an effective adjuvant to reduce the complications induced by delayed tPA treatment for brain ischemia. PMID- 29626427 TI - Engineering Improved Balance Confidence in Older Adults With Complex Health Care Needs: Learning From the Muscling Up Against Disability Study. AB - OBJECTIVE: To investigate the associations of balance confidence with physical and cognitive markers of well-being in older adults receiving government-funded aged care services and whether progressive resistance plus balance training could positively influence change. DESIGN: Intervention study. SETTING: Community-based older adult-specific exercise clinic. PARTICIPANTS: Older adults (N=245) with complex care needs who were receiving government-funded aged care support. INTERVENTIONS: Twenty-four weeks of twice weekly progressive resistance plus balance training carried out under the supervision of accredited exercise physiologists. MAIN OUTCOME MEASURES: The primary measure was the Activity specific Balance Confidence Scale. Secondary measures included the Short Physical Performance Battery; fall history gathered as part of the health history questionnaire; hierarchical timed balance tests; Geriatric Anxiety Index; Geriatric Depression Scale; Fatigue, Resistance, Ambulation, Illness, Loss of Weight scale; and EuroQoL-5 dimension 3 level. RESULTS: At baseline, better physical performance (r=.54; P<.01) and quality of life (r=.52; P<.01) predicted better balance confidence. In contrast, at baseline, higher levels of frailty predicted worse balance confidence (r=-.55; P<.01). Change in balance confidence after the exercise intervention was accompanied by improved physical performance (+12%) and reduced frailty (-11%). Baseline balance confidence was identified as the most consistent negative predictor of change scores across the intervention. CONCLUSIONS: This study shows that reduced physical performance and quality of life and increased frailty are predictive of worse balance confidence in older adults with aged care needs. However, when a targeted intervention of resistance and balance exercise is implemented that reduces frailty and improves physical performance, balance confidence will also improve. Given the influence of balance confidence on a raft of well-being determinants, including the capacity for positive physical and cognitive change, this study offers important insight to those looking to reduce falls in older adults. PMID- 29626426 TI - Plasma phospho-tau181 increases with Alzheimer's disease clinical severity and is associated with tau- and amyloid-positron emission tomography. AB - INTRODUCTION: We examined and compared plasma phospho-tau181 (pTau181) and total tau: (1) across the Alzheimer's disease (AD) clinical spectrum; (2) in relation to brain amyloid beta (Abeta) positron emission tomography (PET), tau PET, and cortical thickness; and (3) as a screening tool for elevated brain Abeta. METHODS: Participants included 172 cognitively unimpaired, 57 mild cognitively impaired, and 40 AD dementia patients with concurrent Abeta PET (Pittsburgh compound B), tau PET (AV1451), magnetic resonance imaging, plasma total tau, and pTau181. RESULTS: Plasma total tau and pTau181 levels were higher in AD dementia patients than those in cognitively unimpaired. Plasma pTau181 was more strongly associated with both Abeta and tau PET. Plasma pTau181 was a more sensitive and specific predictor of elevated brain Abeta than total tau and was as good as, or better than, the combination of age and apolipoprotein E (APOE). DISCUSSION: Plasma pTau181 may have utility as a biomarker of AD pathophysiology and as a noninvasive screener for elevated brain Abeta. PMID- 29626428 TI - Effectiveness of Oral Pain Medication and Corticosteroid Injections for Carpal Tunnel Syndrome: A Systematic Review. AB - OBJECTIVE: To present an evidence-based overview of the effectiveness of oral pain medication and corticosteroid injections to treat carpal tunnel syndrome (CTS). DATA SOURCES: The Cochrane Library, PubMed, Embase, CINAHL, and Physiotherapy Evidence Database were searched for relevant systematic reviews and randomized controlled trials (RCTs). STUDY SELECTION: Two reviewers independently applied the inclusion criteria to select potential studies. DATA EXTRACTION: Two reviewers independently extracted the data on pain (visual analog scale), function or recovery, and assessed the methodologic quality. DATA SYNTHESIS: A best-evidence synthesis was performed to summarize the results of the included studies. Four reviews and 9 RCTs were included. For oral pain medication, strong and moderate evidence was found for the effectiveness of oral steroids versus placebo in the short term. Moderate evidence was found in favor of oral steroids versus splinting in the short term. No evidence was found for the effectiveness of oral steroids in the long term. For corticosteroid injections, strong evidence was found in favor of a corticosteroid injection versus a placebo injection and moderate evidence was found in favor of corticosteroid injection versus oral steroids in the short term. Also, in the short term, moderate evidence was found in favor of a local versus a systematic corticosteroid injection. Higher doses of corticosteroid injections seem to be more effective in the midterm; however, the benefits of corticosteroid injections were not maintained in the long term. CONCLUSIONS: The reviewed evidence supports that oral steroids and corticosteroid injections benefit patient with CTS particularly in the short term. Although a higher dose of steroid injections seems to be more effective in the midterm, the benefits of oral pain medication and corticosteroid injections were not maintained in the long term. PMID- 29626429 TI - Is Frailty a Predictor of Outcomes in Elderly Inpatients with Acute Kidney Injury? A Prospective Cohort Study. AB - BACKGROUND: Frailty and acute kidney injury are independently associated with an increased risk of morbidity and mortality. The degree of frailty can be assessed by the Clinical Frailty Score (CFS). This study assessed whether an individual's CFS was associated with acute kidney injury in acute elderly medical admissions and recorded the short-term outcomes. METHODS: This was a single-center prospective observational cohort study. All patients aged >=65 years admitted under an acute medical take over 12 nonconsecutive days were included. Patient demographics, comorbidities, baseline CFS, and renal status on admission were recorded. Outcomes of death, length of stay, and hospital re-attendance were assessed 2 weeks following admission. RESULTS: Of 164 patients (77 males), 19% had acute kidney injury on admission and 22% were considered severely frail. Severe frailty was associated with acute kidney injury (P = .01) and death within 2 weeks (P = .01). Two-week mortality was highest among patients with both (36%). CONCLUSION: The incidence of acute kidney injury in "severely frail" acutely unwell elderly patients is significantly higher and associated with an increased short-term mortality. The CFS may be useful in acute illness to guide clinical decisions in elderly patients. PMID- 29626430 TI - 2017 Is Banner Year for Drug Approvals by the Food and Drug Administration. AB - In 2017, the US Food and Drug Administration approved 46 novel drugs, and 29 drugs received newly approved indications. This record setting year was due in part to the new expedited review pathways. A review of these drugs is summarized. PMID- 29626431 TI - Twenty Children, Six Teachers, Two Sets of Eyes, a Dog, and a Transformation. PMID- 29626432 TI - Newcastle disease virus strain AF2240 as an oncolytic virus: A review. AB - The discovery of tumour selective virus-mediated apoptosis marked the birth of an alternative cancer treatment in the form of oncolytic viruses. Even though, its oncolytic efficiency was demonstrated more than 50 years ago, safety concerns which resulted from mild to lethal side effects hampered the progress of oncolytic virus research. Since the classical oncolytic virus studies rely heavily on its natural oncolytic ability, virus manipulation was limited, thereby, restricted efforts to improve its safety. In order to circumvent such restriction, experiments involving non-human viruses such as the avian Newcastle disease virus (NDV) was conducted using cultured cells, animal models and human subjects. The corresponding reports on its significant tumour cytotoxicity along with impressive safety profile initiated immense research interest in the field of oncolytic NDV. The varying degree of oncolytic efficiency and virulency among NDV strains encouraged researchers from all around the world to experiment with their respective local NDV isolates in order to develop an oncolytic virus with desirable characteristics. Such desirable features include high tumour-killing ability, selectivity and low systemic cytotoxicity. The Malaysian field outbreak isolate, NDV strain AF2240, also currently, receives significant research attention. Apart from its high cytotoxicity against tumour cells, this strain also provided fundamental insight into NDV-mediated apoptosis mechanism which involves Bax protein recruitment as well as death receptor engagement. Studies on its ability to selectively induce apoptosis in tumour cells also resulted in a proposed p38 MAPK/NF-kappaB/IkappaBalpha pathway. The immunogenicity of AF2240 was also investigated through PBMC stimulation and macrophage infection. In addition, the enhanced oncolytic ability of this strain under hypoxic condition signifies its dynamic tumour tropism. This review is aimed to introduce and discuss the aforementioned details of the oncolytic AF2240 strain along with its current challenges which outlines the future research direction of this virus. PMID- 29626433 TI - Plasmodium falciparum merozoite protein-1 genetic diversity and multiplicity of infection in isolates from Congolese children consulting in a pediatric hospital in Brazzaville. AB - As in many sub-Saharan African countries, the burden of malaria has been reduced in the Republic of Congo as a result of massive deployment of insecticide treated nets and availability of artemisinin-combinations therapies (ACTs). High to moderate genetic diversity of msp-1 gene of Plasmodium falciparum (P. falciparum) has been reported from different parts of the world but limited data are available from Central Africa including the Republic of Congo. For this reason, the aim of study was to investigate the P. falciparum genetic diversity and to determine the multiplicity of infection in P. falciparum isolates from Congolese children in order to dispose of an additional parameter to measure the impact malaria control intervention. A total of 229 blood samples were collected from September 2014 to February 2015 in children aged from one to ten years presenting a paediatric hospital Marien NGOUABI located in Northern part of Brazzaville. Inclusion criterion was fever (axillary temperature >= 37.5 degrees C) or history of fever in the preceding 48 h before inclusion in this study. Then thick and thin blood smears were done to detect malaria parasites, to determine parasite density and to identify plasmodial species. Sub-microscopic infection was detected by PCR using the P. falciparum msp-1 gene as molecular marker. The prevalence of microscopic and sub-microscopic infection in this cohort was 10% and 27.5%, respectively. The K1 allelic family was predominant (45% of isolates) whereas the RO33 and MAD20 represented 35% and 20%, respectively of isolates. In this study 48% (38/79) of isolates harbored more than one parasite clone. Overall the multiplicity of infection (MOI) was 1.7. According to type of infection, the MOI was significantly higher in children with microscopic infection (2.5 vs 1.4 for submicroscopic infection, P = .001). When considering age, hemoglobin genotype (AA or AS) and level and parasite density, no association was observed with the MOI. This study reveals that the P. falciparum genetic diversity in isolates from Congolese children is high but with low multiplicity of infection. PMID- 29626434 TI - Socio-economic burden of parasitic infections in yaks from 1984 to 2017 on Qinghai Tibetan Plateau of China-A review. AB - Yak is an important animal for the Tibetans at Qinghai-Tibetan Plateau of China. The burden of parasitic diseases has been a major threat to the health of yaks at this region presenting a considerable socio-economic losses and impact to yak production and local nomads. Keeping in view, we collected the published papers from 1984 to 2017 on major parasitic infections in yaks by electronic literature search from five databases including CNKI, Google, PubMed, Science Direct and Web of Science. The prevalence of Eimeria, Babesia, Theileria, Hypodermosis, Cystic echinococcosis, Alveolar echinococcosis, Toxoplasma gondii, Neospora caninum, Cryptosporidium, Giardia duodenalis, Enterocytozoon bieneusi, Toxocara vitulorum, and Fascioliasis infection in yaks was found to be 48.02%, 13.06%, 36.11%, 59.85%, 16.93%, 0.99%, 20.50%, 5.14%, 10.00%, 3.68%, 4.07%, 22.23% and 28.7% respectively. Data presented are contemplated to enhance our current understanding on the major parasitic diseases of yaks at Qinghai Tibetan plateau, China. The main aim of this effort is to ameliorate the effects of the parasitic burden in this specie; so that, the attempts are made to minimize the incidence of these infections in future to raise the socio-economic levels of local community. PMID- 29626435 TI - Experimental porcine cysticercosis using infected beetles with Taenia solium eggs. AB - Beetles are intermediate hosts for human and animal parasites, and several beetle species have been shown to carry Taenia eggs. An experimental porcine cysticercosis infection model was developed using beetles (Ammophorus rubripes) infected with Taenia solium eggs and then using these beetles for oral pig challenge. A total of 18 three months-old Landrace pigs were divided in four groups. Pigs from groups 1, 2, and 3 (n = 6 pigs per group) were challenged with one, three, and six beetles infected with T. solium eggs, containing approximately 52, 156 or 312 eggs respectively. Pigs were necropsied 12 weeks after infection to assess the presence of T. solium metacestode. Porcine cysticercosis by T. solium was produced in 17 out of 18 pigs (94.4%) challenged with infected beetles, all infected pigs had viable cysts. Only one pig from group 1 was negative to the presence of cysts. The median number of metacestodes per pig in groups 1, 2, and 3 were 2 (range 0-71), 26 (range 5-33) and 40 cysts (range 4-111), respectively. Experimental porcine cysticercosis infection is consistently obtained using beetles as mechanical vectors for T. solium eggs. PMID- 29626436 TI - Remnant-like particles and coronary artery disease in familial hypercholesterolemia. AB - BACKGROUND: Although remnant-like particle cholesterol (RLP-C) has been associated with coronary artery disease (CAD) in the general population, few data exist regarding this issue in patients with familial hypercholesterolemia (FH). The aim of our study was to investigate the association between RLP-C and the presence of CAD in patients with FH. METHODS: We examined 282 patients with FH (144 males, mean age, 41 +/- 17 years) whose RLP-C levels were measured. We assessed the baseline characteristics, including lipid levels, other conventional risk factors for cardiovascular events, the presence of CAD, and the serum RLP-C levels. RESULTS: Serum RLP-C levels significantly correlated with serum triglyceride (TG) levels (Pearson's r = 0.631, p < 0.001). We observed that a larger proportion of individuals in the higher tertiles of serum RLP-C had a larger number of diseased coronary arteries (p < 0.001 for the trend of multi vessel disease). Logistic regression analysis, after adjusting for age, sex, hypertension, diabetes, smoking, high-density lipoprotein cholesterol, low density lipoprotein cholesterol, and lipoprotein (a) [Lp(a)], revealed that RLP-C was significantly associated with CAD [odds ratio (OR): 1.08, 95% confidence interval (CI): 1.00-1.16, p = 0.046]; however, adding serum TG levels into the logistic regression model nullified this association (OR: 1.07, 95% CI: 0.98 1.17, p = 0.141), whereas Lp(a) was independently associated with CAD (OR: 1.02, 95% CI: 1.00-1.03, p = 0.015). CONCLUSIONS: Serum RLP-C levels were significantly associated with the presence and severity of CAD in patients with FH. However, the clinical usefulness of measuring RLP-C levels beyond that of measuring TG levels should be further assessed. PMID- 29626437 TI - Dynamic reference intervals for coagulation parameters from infancy to adolescence. AB - INTRODUCTION: Practical and ethical challenges as well as time and costs have restricted the generation of pediatric reference intervals. Therefore, pediatric reference intervals on coagulation parameters based on solid evidence are still scarce. Furthermore, reference intervals by age-group cannot reflect the dynamics of age and sex specific coagulation values during childhood. This study is the first to close this gap and provide continuous age and sex dependent reference intervals during childhood in hemostasis. METHODS: We used an innovative indirect method for providing continuous reference intervals for five common coagulation parameters: Activated partial thromboplastin time (aPTT), prothrombin time (PT), thrombin clotting time (TT), fibrinogen (FIB) and antithrombin (AT). Calculations were performed using retrospective laboratory data from pediatric patients between 2005 and 2015 of two major Austrian hospitals, resulting in a total of 195.360 measurements (aPTT: 55,100; PT: 35,492; TT: 35,295; FIB: 49,789; AT: 19,684). RESULTS: This multicenter study provides calculations of continuous reference intervals for five common coagulation parameters in a large pediatric cohort, accounting for age and gender. CONCLUSION: To the best of our knowledge, this is the first multicenter study, determining continuous pediatric coagulation reference intervals based on a large retrospective dataset. PMID- 29626438 TI - Aquaporin 1 gene deletion affects the amniotic fluid volume and composition as well as the expression of other aquaporin water channels in placenta and fetal membranes. AB - OBJECTIVE: To explore the role of aquaporin 1 (AQP1) in regulation of amniotic fluid volume and composition. To investigate the effects of AQP1 gene knockout on expression of other aquaporin water channels (AQP3, AQP8 and AQP9) in placentas and fetal membranes. METHODS: Mice were sacrificed at 9.5, 13.5 and 16.5 gestational day (GD). Amniotic fluid volume, osmolality and composition, fetal membranes, placental and fetal weights as well as placenta areas were recorded in Aqp1 homozygote conceptus group, heterozygote conceptus group and wild-type group, respectively. The expression of AQP1, AQP3, AQP8 and AQP9 mRNA and protein in placenta and fetal membranes were examined by quantitative Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and Western blotting. RESULTS: Aqp1 homozygote conceptus had a greater volume of amniotic fluid, lower osmolality and calcium concentration than their wild-type counterparts at 16.5 GD. There was no significant difference in expression of AQP1, AQP3, AQP8 and AQP9 in placentas among three groups. While expression of AQP8 was increased at 13.5 and 16.5 GD in fetal membranes, the expression of AQP9 was significantly decreased in fetal membranes in Aqp1 homozygote group compared with Aqp1 heterozygote and wild-type groups. CONCLUSION: AQP1 may play an important role in the homeostasis of maternal-fetal fluid at late gestation days. The mechanism of mutual compensation among AQPs gene needs further investigation. PMID- 29626439 TI - Regulation of dichloroacetate biotransformation in rat liver and extrahepatic tissues by GSTZ1 expression and chloride concentration. AB - Biotransformation of dichloroacetate (DCA) to glyoxylate by hepatic glutathione transferase zeta 1 (GSTZ1) is considered the principal determinant of the rate of plasma clearance of the drug. However, several other organismal and subcellular factors are also known to influence DCA metabolism. We utilized a female rat model to study these poorly understood processes. Rats aged 4 weeks (young) and 42-52 weeks (adult) were used to model children and adults, respectively. Hepatic chloride concentrations, which influence the rate of GSTZ1 inactivation by DCA, were lower in rat than in human tissues and rats did not show the age dependence previously seen in humans. We found GSTZ1 expression and activity in rat brain, heart, and kidney cell-free homogenates that were age-dependent. GSTZ1 expression in brain was higher in young rats than adult rats, whereas cardiac and renal GSTZ1 expression levels were higher in adult than young rats. GSTZ1 activity with DCA could not be measured accurately in kidney cell-free homogenates due to rapid depletion of glutathione by gamma-glutamyl transpeptidase. Following oral administration of DCA, 100 mg/kg, to rats, GSTZ1 expression and activity were reduced in all rat tissues, but chloride concentrations were not affected. Together, these data extend our understanding of factors that determine the in vivo kinetics of DCA. PMID- 29626440 TI - In vivo and in vitro diclofenac 5-hydroxylation mediated primarily by cytochrome P450 3A enzymes in common marmoset livers genotyped for P450 2C19 variants. AB - Common marmosets (Callithrix jacchus) are potentially useful nonhuman primate models for preclinical studies. An anti-inflammatory drug, diclofenac is reportedly metabolized mainly by human cytochrome P450 (P450) 2C9 to 4' hydroxydiclofenac and minorly by P450 3A4 to 5-hydroxydiclofenac that leads to reactive intermediates. In this study, in vivo pharmacokinetics in six marmosets and in vitro metabolism in nine marmoset liver microsomes were analyzed using diclofenac to evaluate marmosets as preclinical drug metabolism models. In wild type marmosets genotyped for P450 2C19 p.[(Phe7Leu; Ser254Leu; Ile469Thr)], plasma levels of 5-hydroxydiclofenac and 4'-hydroxydiclofenac were roughly similar, but the homozygotes showed approximately three-times higher plasma levels of 5-hydroxydiclofenac than those of 4'-hydroxydiclofenac after oral administrations of diclofenac (50 mg/kg). Nine marmoset liver microsomes catalyzed mainly diclofenac 5-hydroxylation with no significant effects of the the P450 2C19 genotype, and partly diclofenac 4'-hydroxylation that depended on the P450 2C19 genotype, at substrate concentrations of 10 uM and 100 uM. Both Michaels-Menten constant Km values for diclofenac 4'-hydroxylation in human and marmoset liver microsomes were ~30 MUM and those for diclofenac 5-hydroxylation were ~120 MUM. Ketoconazole significantly suppressed only diclofenac 5 hydroxylation in marmoset or human liver microsomes at 0.030 MUM, indicating main contribution of P450 3A enzymes, which were found to be P450 3A5/90 using recombinant marmoset P450 3A enzymes. These results suggest that marmosets would be a functional animal model for in vivo and in vitro metabolites likely generated via arene oxide intermediates of diclofenac by P450 3A enzymes in humans, primarily because marmosets lack the ortholog of human P450 2C9. PMID- 29626441 TI - Physiologically-relevant levels of sphingomyelin, but not GM1, induces a beta sheet-rich structure in the amyloid-beta(1-42) monomer. AB - To resolve the contribution of ceramide-containing lipids to the aggregation of the amyloid-beta protein into beta-sheet rich toxic oligomers, we employed molecular dynamics simulations to study the effect of cholesterol-containing bilayers comprised of POPC (70% POPC, and 30% cholesterol) and physiologically relevant concentrations of sphingomyelin (SM) (30% SM, 40% POPC, and 30% cholesterol), and the GM1 ganglioside (5% GM1, 70% POPC, and 25% cholesterol). The increased bilayer rigidity provided by SM (and to a lesser degree, GM1) reduced the interactions between the SM-enriched bilayer and the N-terminus of Abeta42 (and also residues Ser26, Asn27, and Lys28), which facilitated the formation of a beta-sheet in the normally disordered N-terminal region. Abeta42 remained anchored to the SM-enriched bilayer through hydrogen bonds with the side chain of Arg5. With beta-sheets in the at the N and C termini, the structure of Abeta42 in the sphingomyelin-enriched bilayer most resembles beta-sheet-rich structures found in higher-ordered Abeta fibrils. Conversely, when bound to a bilayer comprised of 5% GM1, the conformation remained similar to that observed in the absence of GM1, with Abeta42 only making contact with one or two GM1 molecules. This article is part of a Special Issue entitled: Protein Aggregation and Misfolding at the Cell Membrane Interface edited by Ayyalusamy Ramamoorthy. PMID- 29626442 TI - Aggregation-induced conformation changes dictate islet amyloid polypeptide (IAPP) membrane affinity. AB - Islet amyloid polypeptide (IAPP) is a 37 residue intrinsically disordered protein whose aggregation is associated with Type II diabetes. Like most amyloids, it appears that the intermediate aggregates ("oligomers") of IAPP are more toxic than the mature fibrils, and interaction with the cell membrane is likely to be an integral component of the toxicity. Here we probe the membrane affinity and the conformation of the peptide as a function of its aggregation state. We find that the affinity of the peptide for artificial lipid bilayers is more than 15 times higher in the small oligomeric state (hydrodynamic radius ~ 1.6 nm) compared to the monomeric state (hydrodynamic radius ~ 0.7 nm). Binding with RIN m5F cell membranes also shows qualitatively similar behavior. The monomeric state, as determined by Forster Resonance Energy Transfer, has a much larger end to end distance than the oligomeric state, suggesting conformational change between the monomers and the oligomers. Raman and Infrared spectroscopic measurements show the presence of considerable alpha helical content in the oligomers, whereas the larger aggregates have largely beta sheet character. Therefore, the conformation of the small oligomers is distinct from both the smaller monomers and the larger oligomers, and this is associated with an enhanced membrane affinity. This provides a possible structural basis for the enhanced toxicity of amyloid oligomers. Such change is also reminiscent of amyloid beta, another aggregation prone amyloidogenic peptide, though the nature of the conformational change is quite different in the two cases. We infer that conformational change underlying oligomer formation is a key factor in determining the enhanced membrane affinity of disease causing oligomers, but the toxic "oligomer fold" may not be universal. PMID- 29626445 TI - Editorial Comment. PMID- 29626444 TI - Calcium accelerates SNARE-mediated lipid mixing through modulating alpha synuclein membrane interaction. AB - alpha-Synuclein is involved in Parkinson's disease, and its interaction with cell membrane is vital to its pathological and physiological functions. We have shown that Ca2+ can regulate alpha-synuclein membrane interaction, but the physiological role of Ca2+ in modulating alpha-synuclein membrane interaction is still unexplored. Based on the previous findings that alpha-synuclein inhibits membrane fusion and its inhibitory effect is highly related to its membrane binding, here we employed solution state Nuclear Magnetic Resonance (NMR) spectroscopy and the ensemble fluorescence fusion assay to show that Ca2+ can modulate the inhibitory effect of alpha-synuclein on SNARE-mediated membrane fusion through disrupting alpha-synuclein membrane interaction, resulting in acceleration of SNARE-mediated membrane fusion. These results suggest a modulatory effect of Ca2+ on membrane mediated normal function of alpha synuclein, which of importance for the study of the Parkinson's disease. PMID- 29626446 TI - Editorial Comment. PMID- 29626443 TI - Effect of dietary docosahexaenoic acid on rhodopsin content and packing in photoreceptor cell membranes. AB - Docosahexaenoic acid (DHA) is enriched in photoreceptor cell membranes. DHA deficiency impairs vision due to photoreceptor cell dysfunction, which is caused, at least in part, by reduced activity of rhodopsin, the light receptor that initiates phototransduction. It is unclear how the depletion of membrane DHA impacts the structural properties of rhodopsin and, in turn, its activity. Atomic force microscopy (AFM) was used to assess the impact of DHA deficiency on membrane structure and rhodopsin organization. AFM revealed that signaling impairment in photoreceptor cells is independent of the oligomeric status of rhodopsin and causes adaptations in photoreceptor cells where the content and density of rhodopsin in the membrane is increased. Functional and structural changes caused by DHA deficiency were reversible. PMID- 29626447 TI - Hemimandibular Hyperplasia Correction by Simultaneous Orthognathic Surgery and Condylectomy Under Digital Guidance. AB - PURPOSE: Orthognathic surgery with simultaneous condylectomy under digital guidance has been proved to be a feasible method to treat hemimandibular hyperplasia (HH). The objective of this study was to evaluate the effects and precision of correction of HH by use of this method. PATIENTS AND METHODS: This was a case-series study. Fourteen patients with HH who had undergone simultaneous bimaxillary orthognathic surgery and condylectomy from January 2016 to April 2017 were included in this study. Presurgical virtual treatment planning was performed, transferred to the operation room, and realized with the assistance of surgical navigation and 3-dimensionally printed occlusion splints. Postoperative computed tomography data were used to analyze improvement in facial symmetry and verify the accuracy of the surgical procedure. RESULTS: All patients exhibited satisfactory clinical effects; facial asymmetry was corrected as expected. Postoperative validation showed that the presurgical planning had been achieved more precisely on the unaffected side than on the affected side. Moreover, bilateral mandibular proximal segments showed a tendency for outward rotation compared with the presurgical planning model. Furthermore, when we assessed facial symmetry compared with the presurgical model, deviation of all midline landmarks was less than 2 mm, occlusal-plane inclination was less than 1 mm, and the asymmetry index of paired landmarks was remarkably decreased after surgery (P < .01). CONCLUSIONS: Orthognathic surgery with simultaneous condylectomy under digital guidance is a realistic and precise method for treatment of HH. Surgical results can be validated during surgery by virtual navigation. However, movement of each bone segment cannot be accurately controlled as planned before surgery. PMID- 29626448 TI - Zoledronic Acid Induces Site-Specific Structural Changes and Decreases Vascular Area in the Alveolar Bone. AB - PURPOSE: The aim was to assess the effect of a relevant regimen of zoledronic acid (ZA) treatment for the study of bisphosphonate-related osteonecrosis of the jaw on alveolar bone microstructure and vasculature. A sub-objective was to use 3 dimensional imaging to describe site-specific changes induced by ZA in the alveolar bone. MATERIALS AND METHODS: Five Wistar rats received ZA (0.6 mg/kg) and five (controls) received saline solution in the same volume. The compounds were administered intraperitoneally in 5 doses every 28 days. The rats were euthanized 150 days after therapy onset. The mandibles were scanned using high resolution (14-MUm) micro-computed tomography (micro-CT), decalcified, cut into slices for histologic analysis (5 MUm), and stained with hematoxylin-eosin. Bone quality parameters were calculated using CT-Analyser software (Bruker, Kontich, Belgium) in 2 different volumes of interest (VOIs): the region between the first molar roots (VOI-1) and the periapical region under the first and second molars' apex (VOI-2). Blood vessel density and bone histomorphometric parameters were calculated only for the region between the roots of the first molar using AxioVision Imaging software (version 4.8; Carl Zeiss, Gottingen, Germany). RESULTS: ZA-treated rats showed a significant increase in percentage of bone volume and density (P < .05), with thicker and more connected trabeculae. Furthermore, the ZA group showed a significant decrease in the size of the marrow spaces and nutritive canals and in blood vessel density (P < .05). In the micro CT evaluation, VOI-2 showed better outcomes in measuring the effect of ZA on alveolar bone. CONCLUSIONS: ZA treatment induced bone corticalization and decreased alveolar bone vascularization. VOI-2 should be preferred for micro-CT evaluation of the effect of bisphosphonates on alveolar bone. This analysis allowed the effect of ZA on alveolar bone and its vascularization to be characterized. The results of this analysis may add further knowledge to the understanding of the physiopathology of osteonecrosis of the jaw. PMID- 29626449 TI - Vascular endothelial growth factor (VEGF-A) and fibroblast growth factor (FGF-2) as potential regulators of seasonal reproductive processes in male European bison (Bison bonasus, Linnaeus 1758). AB - Growth factors: vascular endothelial growth factor A (VEGF-A) and fibroblast growth factor (FGF-2) were reported to affect normal physiological reproductive processes in human, domestic and free living animals. Moreover, some reports suggest that VEGF-A and FGF-2 may be directly involved in the control of the annual reproductive cycle of seasonally breeding animals but detailed knowledge is still missing. Our study aimed to demonstrate the expression of mRNA and protein for both factors in the tissues of testis and epididymis (caput, corpus, cauda) at different periods of the year (March, June, November, December) in European bison as a model of seasonally breeding animal. Results suggest, that VEGF-A expression was more pronounced in testis than in epididymis and the highest expression was noted in December and June. Surprisingly, the highest protein accumulation was observed in June at the same level in all tissues analyzed. On the other hand, the highest FGF-2 mRNA expression was noted in testis in June and in epididymis in March. However, no differences in protein expression of FGF-2 were found between analyzed groups. The results indicate that both factors are necessary for proper functioning of the reproductive system and their levels differ seasonally. Perhaps, it is linked to increased need of these factors in the testis as well as epididymis during preparation for the reproductive functions. Moreover, VEGF-A and FGF-2 not only may regulate reproductive functions by affecting vascularization and cell nutrition, but it also may be possible that they possess protective functions by stabilizing the reproductive cells. Therefore, obtained results provide new insight into mechanisms underlying seasonal breeding of the male European bison. PMID- 29626451 TI - Effectiveness of Colorectal Cancer Screening in Detecting Earlier-Stage Disease-A Nationwide Cohort Study in Denmark. AB - BACKGROUND & AIMS: Most studies of the effectiveness of screening for colorectal cancer (CRC) using the fecal occult blood test tested the guaiac fecal occult blood test. However, the fecal immunochemical test (FIT) is now commonly used in screening. We aimed to evaluate the effectiveness of FIT-based screening for CRC on the number of incident CRC diagnoses and stage at diagnosis for individuals in Denmark who were invited for screening vs not yet invited. METHODS: We collected data for this register-based retrospective cohort study during the first 16 months of the prevalence round of a FIT-based CRC screening program (March 1, 2014 through June 30, 2015). A total of 402,826 residents of Denmark (50-72 years old) were randomly invited to undergo CRC screening within the study period, and 956,514 were invited thereafter. We obtained information on CRC diagnosis, date, and stage at diagnosis from the Danish Colorectal Cancer Group database. Cancer incidence per 100,000 invited/not yet invited individuals was calculated, along with the relative risk (RR) of CRC among invited compared with not yet invited individuals. RESULTS: CRC incidence during the study period was 339.4/100,000 invited individuals and 169.6/100,000 not yet invited individuals. CRC incidence increased with age among invited and not yet invited individuals. For invited women compared with not yet invited women, the RR of being diagnosed with stage I CRC was 3.39 (95% CI, 2.61-4.39), with stage II CRC was 2.16 (95% CI, 1.71-2.72), with stage III CRC was 1.37 (95% CI, 1.08-1.75), and with stage IV CRC was 0.92 (95% CI, 0.68-1.23). For invited men compared with not yet invited men, the RR of being diagnosed with stage I CRC was 3.71 (95% CI, 2.97-4.64); with stage II CRC was 2.26 (95% CI, 1.84-2.77), with stage III CRC was 1.88 (95% CI, 1.53-2.30), and with stage IV CRC was 1.20 (95% CI, 0.95-1.52). CONCLUSIONS: In analyzing data from a register-based cohort study in Denmark, we found that inviting individuals to undergo FIT-based CRC screening led to detection of almost 2-fold more cases of CRC than not inviting participants. The significant increase of CRC incidence among those invited for screening indicates a need for awareness of treatment capacity in countries introducing FIT-based CRC screening. PMID- 29626452 TI - Peripheral Distribution of Thrombus Does Not Affect Outcomes After Surgical Pulmonary Embolectomy. AB - BACKGROUND: Thrombus located distal to the main or primary pulmonary arteries has been previously viewed as a relative contraindication to surgical pulmonary embolectomy. We compared outcomes for surgical pulmonary embolectomy for submassive and massive pulmonary embolism (PE) in patients with central vs peripheral thrombus burden. METHODS: All consecutive patients (2011 to 2016) undergoing surgical pulmonary embolectomy at a single center were retrospectively reviewed. Computed tomography angiography of each patient was used to define central PE as any thrombus originating within the lateral pericardial borders (main or right/left pulmonary arteries). Peripheral PE was defined as thrombus exclusively beyond the lateral pericardial borders, involving the lobar pulmonary arteries or distal. The primary outcome was in-hospital and 90-day survival. RESULTS: We identified 70 patients: 52 (74%) with central PE and 18 (26%) with peripheral PE. Preoperative vital signs and right ventricular dysfunction were similar between the two groups. Compared with the central PE cohort, operative time was significantly longer in the peripheral PE group (191 vs 210 minutes, p < 0.005). Median right ventricular dysfunction decreased from moderate dysfunction preoperatively to no dysfunction at discharge in both groups. Overall 90-day survival was 94%, with 100% survival in patients with submassive PE in both cohorts. CONCLUSIONS: This single-center experience demonstrates excellent overall outcomes for surgical pulmonary embolectomy, with resolution of right ventricular dysfunction and comparable morbidity and mortality for central and peripheral PE. In an experienced center and when physiologically warranted, surgical pulmonary embolectomy for peripheral distribution of thrombus is technically feasible and effective. PMID- 29626453 TI - Model of End-Stage Liver Disease-eXcluding International Normalized Ratio (MELD XI) Scoring System to Predict Outcomes in Patients Who Undergo Left Ventricular Assist Device Implantation. AB - BACKGROUND: The use of continuous-flow left ventricular assist devices (CF-LVADs) to treat advanced heart failure is increasing. Although risk scores, such as Model for End-Stage Liver Disease and the HeartMate II Risk Score, require the use of the international normalized ratio, many patients are on anticoagulation before CF-LVAD implantation. This study evaluated the ability of the Model of End Stage Liver Disease-eXcluding International Normalized Ratio (MELD-XI) scoring system to predict clinical outcomes in patients with advanced heart failure who undergo CF-LVAD implantation. METHODS: A single-center retrospective review was performed of 524 patients who were implanted with the HeartMate II LVAD (Thoratec Corporation, Pleasanton, CA) or the HeartWare HVAD (HeartWare International Inc, Framingham, MA) between 2004 and 2016. Patients were stratified into two cohorts: those with a MELD-XI score of less than 14 (n = 301) and 14 or higher (n = 223). RESULTS: Patients with the higher-risk MELD-XI score of 14 or higher demonstrated lower survival rates at 1, 3, 6, 12, and 24 months (p < 0.001 for all) and increased risk of early right heart failure and infections compared with patients with MELD-XI score of less than 14. MELD-XI was not significantly inferior at predicting 90-day mortality compared with the HeartMate II Risk Score (p = 0.92). Patients with elevated MELD-XI scores at follow-up demonstrated higher rates of mortality. CONCLUSIONS: These findings suggest that a MELD-XI score of 14 or higher was associated with a higher postoperative mortality rate than that seen in patients with a lower MELD-XI score. The MELD-XI scoring system can be used to predict outcomes in patients with advanced heart failure who undergo CF-LVAD implantation. PMID- 29626450 TI - Female-Specific Association Between Variants on Chromosome 9 and Self-Reported Diagnosis of Irritable Bowel Syndrome. AB - BACKGROUND & AIMS: Genetic factors are believed to affect risk for irritable bowel syndrome (IBS), but there have been no sufficiently powered and adequately sized studies. To identify DNA variants associated with IBS risk, we performed a genome-wide association study (GWAS) of the large UK Biobank population-based cohort, which includes genotype and health data from 500,000 participants. METHODS: We studied 7,287,191 high-quality single nucleotide polymorphisms in individuals who self-reported a doctor's diagnosis of IBS (cases; n = 9576) compared to the remainder of the cohort (controls; n = 336,499) (mean age of study subjects, 40-69 years). Genome-wide significant findings were further investigated in 2045 patients with IBS from tertiary centers and 7955 population controls from Europe and the United States, and a small general population sample from Sweden (n = 249). Functional annotation of GWAS results was carried out by integrating data from multiple biorepositories to obtain biological insights from the observed associations. RESULTS: We identified a genome-wide significant association on chromosome 9q31.2 (single nucleotide polymorphism rs10512344; P = 3.57 * 10-8) in a region previously linked to age at menarche, and 13 additional loci of suggestive significance (P < 5.0*10-6). Sex-stratified analyses revealed that the variants at 9q31.2 affect risk of IBS in women only (P = 4.29 * 10-10 in UK Biobank) and also associate with constipation-predominant IBS in women (P = .015 in the tertiary cohort) and harder stools in women (P = .0012 in the population-based sample). Functional annotation of the 9q31.2 locus identified 8 candidate genes, including the elongator complex protein 1 gene (ELP1 or IKBKAP), which is mutated in patients with familial dysautonomia. CONCLUSIONS: In a sufficiently powered GWAS of IBS, we associated variants at the locus 9q31.2 with risk of IBS in women. This observation may provide additional rationale for investigating the role of sex hormones and autonomic dysfunction in IBS. PMID- 29626454 TI - "Twin Icicle" Calcifications Cause Aortic Annular Rupture. AB - Aortic annular rupture is a potentially fatal complication after transcatheter aortic valve implantation with high mortality. Although it is quite rare and difficult to identify the mechanisms and predictors, prosthesis oversizing and massive calcification of the aortic annulus are thought to be a potential risk of this complication. A case presented here is an aortic annular rupture after transcatheter aortic valve implantation. Although the valve was not oversized, there were 2 severe calcifications of aortic annulus at nearby areas like "twin icicles," thought to be a trigger of this potentially fatal complication. PMID- 29626455 TI - Septal Leaflet Versus Chordal Detachment in Closure of Hard-to-Expose Ventricular Septal Defects. AB - BACKGROUND: Different techniques have been used for exposure of ventricular septal defect (VSD) margins when there is crowding of the VSD anatomy by tricuspid valve subvalvar apparatus. This study compared surgical outcomes for the two techniques of tricuspid valve leaflet detachment and the rarely described tricuspid valve chordal detachment for hard-to-expose VSDs. METHODS: Patients undergoing transatrial VSD repair were identified from our institutional database. Follow-up echocardiography and patient data were obtained from medical records. Between January 2005 and August 2016, 130 isolated conoventricular VSDs were repaired. Among these, 26 patients underwent leaflet detachment, 15 underwent chordal detachment, and 89 underwent regular VSD repair (reference group). RESULTS: The groups did not differ significantly in age, weight, postoperative length of stay, genetic/syndromic abnormalities, time to extubation, and left and right ventricular systolic function. The cardiopulmonary bypass and cross-clamp time were significantly longer in the leaflet detachment group than in the reference group (118 +/- 28 vs 102 +/- 32 minutes [p = 0.02] and 73 +/- 20 vs 61 +/- 23 minutes [p = 0.01], respectively). Echocardiographic follow-up was available for 87 patients at a mean of 2.6 years (range, 1 month to 11 years). Tricuspid regurgitation was rated as none or trivial in 66 (76%), mild in 20 (23%), and moderate in 1 reference group patient. There was no difference in presence of residual VSD or degree of tricuspid regurgitation among the three groups. There was no reoperation for tricuspid regurgitation. CONCLUSIONS: Tricuspid valve leaflet and chordal detachment techniques provide an equally viable and safe alternative to closure of hard-to-expose VSDs while maintaining appropriate tricuspid valve function. Their use in our series did not lead to increased tricuspid valve dysfunction at early-to-midterm echocardiographic assessment. PMID- 29626456 TI - Reply. PMID- 29626457 TI - Reply. PMID- 29626458 TI - Reexpansion Pulmonary Edema After Atrial Septal Defect Closure Through Right Sided Minithoracotomy. AB - We describe a patient with reexpanded pulmonary edema after atrial septal defect closure through a right-sided minithoracotomy. After reexpansion of the right lung after weaning from cardiopulmonary bypass, a large amount of serous slight hemorrhagic bronchial secretions spilled out from the right bronchus. Positive pressure ventilation and differential ventilation were used. We found no bleeding and decreased secretions 24 hours after the onset of reexpanded pulmonary edema. The patient was extubated 42 hours after the operation. To the best of our knowledge, this is the first case report of the development of reexpansion pulmonary edema during a routine minimally invasive operation for atrial septal defect. PMID- 29626459 TI - An Unusual Invasive Ectopic Thymoma in the Thyroid and Anterior Mediastinum. AB - An 81-year-old woman with a 2-year history of dysphagia detected a cervical mass. Computed tomography showed a thyroid tumor extending through the superior and anterior mediastinum. Analysis of an incisional biopsy specimen revealed a thymoma. Total resection of the thyroid and mediastinal tumor was performed. The thymoma invaded the anterior tracheal wall and left brachiocephalic vein. Pathologic examination revealed thymoma type B1 concomitant with B2 and B3 (World Health Organization classification), Masaoka IVb, and T3 N2 M0-IVb, with cervical lymph node metastasis. Clinicians must be cautious during radical operations for invasive ectopic thymomas. PMID- 29626460 TI - Venous Malformation of the Esophagus. AB - Venous malformations are an extremely infrequent condition in the gastrointestinal tract, particularly in the esophagus. We report a rare case of an adult with an asymptomatic mass located in the mediastinum and in whom the diagnosis and treatment of a venous malformation of the esophagus was performed through a thoracoscopic approach. When dealing with a hypervascularized submucosal esophageal tumor, venous malformations can be among the differential diagnoses. PMID- 29626462 TI - Is Post-Operative Lung Ultrasonography Effective in Lung Abnormalities Analysis? PMID- 29626461 TI - Enoxaparin 40 mg per Day Is Inadequate for Venous Thromboembolism Prophylaxis After Thoracic Surgical Procedure. AB - BACKGROUND: Many patients undergoing thoracic surgical procedures have venous thromboembolism (VTE) events despite the receipt of chemical prophylaxis. Enoxaparin's pharmacologic impact can be quantified by using anti-Factor Xa (aFXa) levels. We hypothesized that enoxaparin 40 mg once daily would be inadequate for most inpatients undergoing thoracic surgical procedures and that a real-time dose adjustment algorithm would be effective. METHODS: This prospective clinical trial enrolled inpatients who were to undergo a thoracic surgical procedure and placed on enoxaparin 40 mg once daily for VTE prophylaxis after surgical procedures. aFXa levels were used to measure the anticoagulant effect of enoxaparin once steady state had been reached. Patients whose aFXa levels were out of range received real-time enoxaparin dose adjustment and had repeat aFXa levels drawn. RESULTS: Ninety-three inpatients undergoing thoracic surgical procedures were prospectively enrolled. The majority of patients (67.4%) had low peak aFXa levels (<0.3 IU/mL), indicative of inadequate enoxaparin prophylaxis, and 30.3% of patients had in-range aFXa levels (0.3 to 0.5 IU/mL). Patient weight had a moderate correlation (r2 0.38) with peak aFXa level. Patient weight, female sex, and preoperative creatinine were independent predictors of peak aFXa in a linear regression model. Real-time, protocol-driven enoxaparin dose adjustment allowed a significantly increased proportion of patients to achieve in-range aFXa levels (30.3% vs 97.6%, p < 0.001). CONCLUSIONS: Enoxaparin 40 mg once daily is inadequate for most inpatients undergoing thoracic surgical procedures, based on a pharmacodynamic study of aFXa levels. Future research should examine the impact of weight-based once daily enoxaparin dosing versus twice daily enoxaparin dosing on prophylaxis adequacy. PMID- 29626463 TI - Cryopreservation of cultured mantle cells of Paphia malabarica for perennial availability. AB - Laboratory friendly, cryopreservation procedures with respect to cryopreservation formulations and cryopreservation temperatures were attempted, in the present study to ensure perennial availability of cultured mantle cells of bivalve (Paphia malabarica). Screening of cryopreservative formulations with different concentrations of DMSO, Propylene glycol and Glycerol was carried out for cryopreservation of freshly dissociated cells of Paphia malabarica. Out of these cryopreservative formulations, 10% DMSO, 10% Propylene glycol and 15% Glycerol were selected for cryopreservation of the mantle cells pooled from 1-day old primary culture and cell line after 3 passages at the end of different cryopreservation periods. Cryopreservative formulation with 15% glycerol, served as a best cryoprotectant for the cryopreservation of cells sourced from freshly dissociated cells as well as from primary cultures and cell cultures after three passages of mantle cells of Paphia malabarica, retaining metabolic activity of resurrected cells. Both, cell cultures established from uncryopreserved cells as well as cryopreserved cells showed similar alkaline phosphatase and carbonic anhydrase activities thus indicating retention of their biomineralization capacity even after cryopreservation at low and ultralow temperatures. PMID- 29626464 TI - Impact of l-carnitine on lipid content and post thaw survivability of buffalo embryos produced in vitro. AB - The aim of the present study was to see the impact of L-Carnitine (LC) on lipid biosynthesis and metabolism of buffalo embryos, and post thaw blastocyst survivability. In vitro fertilized (IVF) embryos were derived from slaughterhouse derived COCs and cultured in different doses of LC i.e. 0, 1 mM, 1.5 mM, 2 mM starting at 48 h post IVF. Blastocyst rate was significantly (p < 0.05) higher in 1.5 mM group than control and 1.0 mM group. Lipid content was measured indirectly by fluorescent intensity of lipid droplets after Nile red staining, and it was lower (p < 0.05) in treated than control groups. CPT1B, DGAT2 and DGAT1 mRNA expression was up regulated (p < 0.05) while AMPKg1 expression was down regulated in 1.5 mM and 2 mM groups compared to other groups (p < 0.05). mRNA expression of GLUT1, OCT4 and IFN-tau was higher (P < 0.05) in 1.5 mM group than the control group. Expression of BAX was down regulated at 1.5 mM LC. Blastocyts were vitrified by a modified OPS method and post thaw survivability of blastocysts was higher (P < 0.05) in 1.5 mM LC than other groups. In post thaw blastocysts, mRNA expression of GLUT1, OCT4 and IFN-tau was higher (P < 0.05) in 1.5 mM than other groups. Thus, it can be concluded that supplementation of l-carnitine (1.5 mM) in embryo culture media improved the quality of buffalo embryo production and post thaw blastocysts survivability by reducing fatty acid synthesis, enhancing fatty acid metabolism, and reducing lipid droplet formation. PMID- 29626465 TI - Adjuvant androgen-deprivation therapy following prostate total cryoablation in high-risk localized prostate cancer patients - Open-labeled randomized clinical trial. AB - PURPOSE: To investigate the efficacy and safety profile of 12-month adjuvant androgen-deprivation therapy (ADT) following total-gland cryoablation (TGC) in patients with high-risk localized prostate cancer (HRLPC). MATERIALS AND METHODS: This open-label randomized trial included 38 HRLPC patients who received TGC between July 2011 and March 2013. Within 4 weeks after TGC, subjects were randomly assigned (1:1) to either the 12-month adjuvant ADT or non-adjuvant ADT group. The primary outcome was biochemical failure measured by the Phoenix definition. Adverse events were measured at month 1, 2, 3, 6, 9 and 12. In addition, a cohort of 145 HRLPC patients was selected retrospectively for outcome validation. RESULTS: The adjuvant ADT and non-adjuvant ADT groups did't differ in peri-operative characters, such as age, preoperative PSA, tumor stages, Gleason score, prostate size and cryoprobe number. Four patients with adjuvant ADT withdrew from this trial for personal reasons (N = 2), elevated liver function (N = 1) and poorly controlled hyperglycemia (N = 1). In contrast, none in non adjuvant ADT group experienced adverse events. Biochemical failures were identified in 5 (26%) patients in each group during a median follow-up duration of 45 months. The median times to biochemical failure were 25 and 5.5 months for adjuvant ADT and non-adjuvant ADT groups, respectively. Biochemical-failure survival curves converged 24 months after TGC. Univariable and multivariable analyses revealed adjuvant ADT was not associated with biochemical recurrences in the validation cohort. CONCLUSIONS: Adjuvant ADT does not reduce biochemical failure for HRPLC patients undergoing TGC. It should be further confirmed by a larger cohort. PMID- 29626466 TI - Substance P preserves pancreatic beta-cells in type 1 and type 2 diabetic mice. AB - Preservation of pancreatic beta-cells is required for the development of therapies for type 1 and type 2 diabetes (T1D and T2D, respectively). Our previous study demonstrated that substance P (SP) preserves beta-cell populations in mice with streptozotocin-induced T1D. Here, we demonstrated that chronic systemic treatment with SP restored the mass of beta-cells both in nonobese diabetic (NOD) mice with T1D or db/db mice with T2D. SP delayed the onset of T1D in NOD mice via immune modulation. SP inhibited immune infiltration into islets and the salivary glands of NOD mice. In db/db mice, SP treatment rescued glucose intolerance. Moreover, SP inhibited apoptosis, as well as the activation of pancreatic stellate cells in pancreatic islets of db/db mice. SP downregulated the number of alpha-smooth muscle actin (alpha-SMA) expressing cells in db/db pancreatic islets. Cleaved-caspase-3 expression was reduced in islets of SP treated db/db mice compared to that in the control. Therefore, these results suggested that SP may preserve pancreatic beta-cells through immune modulation and protection from the stimulated activation of pancreatic stellate cells and apoptosis in T1D and T2D, respectively. PMID- 29626467 TI - Cooperation of Rho family proteins Rac1 and Cdc42 in cartilage development and calcified tissue formation. AB - Rac1 and Cdc42, Rho family low molecular weight G proteins, are intracellular signaling factors that transmit various information from outside to inside cells. Primarily, they are known to control various biological activities mediated by actin cytoskeleton reorganization, such as cell proliferation, differentiation, and apoptosis. In order to investigate the functions of Rac1 and Cdc42 in bone formation, we prepared cartilage-specific double conditional knockout mice, Rac1fl/fl; Cdc42fl/fl; Col2-Cre (Rac1: Cdc42 dcKO mice), which died just after birth, similar to Cdc42fl/fl; Col2-Cre mice (Cdc42 cKO mice). Our findings showed that the long tubule bone in Rac1: Cdc42 dcKO mice was shorter than that in Rac1fl/fl; Col2-Cre mice (Rac1 cKO mice) and Cdc42 cKO mice. Abnormal skeleton formation was also observed and disordered columnar formation in the growth plate of the Rac1: Cdc42 dcKO mice was more severe as compared to the Rac1 cKO and Cdc42 cKO mice. Together, these results suggest that Rac1 and Cdc42 have cooperating roles in regulation of bone development. PMID- 29626468 TI - Comparative metabolomic analysis of Crypthecodinium cohnii in response to different dissolved oxygen levels during docosahexaenoic acid fermentation. AB - Oxygen supply is an important factor during Crypthecodinium cohnii fermentation for docosahexaenoic acid (DHA) production. However, few studies about the intrinsic correlation between dissolved oxygen (DO) and cellular metabolism have been reported. In this study, the responses of C. cohnii to different DO levels were evaluated. The results showed the growth and glucose consumption rates of C. cohnii were much higher under high oxygen supply condition. Furthermore, GC-MS based comparative metabolomic analysis was employed to discriminate the responsive metabolites associated with varying DO levels. The results showed the intermediates involved in glycolytic pathway and TCA cycle were up-regulated under high DO levels at exponential phase. At stationary phase, under high DO levels, metabolites involved in triacylglycerol metabolism were up-regulated, while the OPP pathway intermediate product ribose 5-phosphate was down-regulated. Together, these results provide useful insights into the functional metabolic relationship between DO levels and DHA production in C. cohnii. PMID- 29626469 TI - Decursin and decursinol angelate improve wound healing by upregulating transcription of genes encoding extracellular matrix remodeling proteins, inflammatory cytokines, and growth factors in human keratinocytes. AB - The coumarins decursin and decursinol angelate, which are found in Angelica gigas Nakai, have a variety of biological functions. Here, we show that treatment with these compounds improves wound healing by HaCaT human keratinocytes. Wound healing was increased by treatment with up to a threshold concentration of decursin, decursinol angelate, a mixture of both, and a nano-emulsion of these compounds, but inhibited by treatment with higher concentrations. Immunoblotting and fluorescence imaging of cells expressing an epidermal growth factor receptor (EGFR) biosensor demonstrated that these compounds did not stimulate wound healing by inducing EGFR phosphorylation. Rather, transcriptional analysis revealed that decursin and decursinol angelate improved wound healing by upregulating the expression of genes encoding extracellular matrix remodeling proteins, inflammatory cytokines, and growth factors. PMID- 29626470 TI - Exosomal miR-675 from metastatic osteosarcoma promotes cell migration and invasion by targeting CALN1. AB - Exosomal microRNAs(miRNAs) transfer from tumor to stromal cells is reportedly associated with cancer progression and metastasis in various epithelial cancers. However, the role of exosomal miRNA in the metastasis of osteosarcoma(OS) -the most common bone malignancy-still largely remains unknown. In this study, we purified exosomes with a median size close to 100 nm from cell culture media as well as patient serum, and proved that exosomes derived from the metastatic, but not the non-metastatic OS cells increase the migration and invasion of non malignant fibroblast cells (hFOB1.19) in vitro. Furthermore, the differential miRNA cargo between metastatic and non-metastatic OS is identified by small RNA sequencing and RT-PCR validation, we found a highly expression of exosomal, but not cellular miR-675 level in the metastatic OS cell-lines compared with non metastatic counterparts. Meanwhile, we also found that exosomal miR-675 could down-regulate CALN1 expression in recipient cell, which may influence the invasion and migration of hFOB1.19. Finally, the up regulation serum exosomal miR 675 and down regulation of CALN1 in tumor specimen was also found to be associated with the metastatic phenotype in OS patients. Our findings indicate that the exosomal miR-675 is a gene associated with OS and serum exosomal miR-675 expression may serve as a novel biomarker for the metastasis of OS. PMID- 29626471 TI - PMN inhibits colorectal cancer cells through inducing mitotic arrest and p53 dependent apoptosis via the inhibition of tubulin polymerization. AB - Colorectal cancer (CRC) is the third most prevalent malignancy worldwide. New understandings about this disease are urgently required to guide clinical therapies. In this study, we focused on the effects of the small molecule PMN on CRC cells. PMN dose-dependently inhibited CRC cell proliferation through inducing mitotic arrest and apoptosis. PMN induced mitotic arrest via the disruption of spindle apparatus by inhibiting microtubule polymerization. PMN-induced mitotic arrest resulted in apoptosis and p53 upregulation. Furthermore, p53 upregulation sensitized PMN-induced mitotic cells to apoptosis. This study deepens the understanding of the effects of p53 on the response of CRC cells to PMN, providing the basis for the potential development of PMN as a lead compound of microtubule-destabilizers for p53-positive CRC treatment. PMID- 29626472 TI - Tyrosine kinase activity of EphA2 promotes its S897 phosphorylation and glioblastoma cell proliferation. AB - EphA2, a member of the Eph family of receptor tyrosine kinases, has been reported to promote tumor malignancy through phosphorylation of serine 897 (S897). Here, we found that overexpression of wild-type EphA2 induced S897 phosphorylation through ERK activation without growth factors or cytokines and promoted glioblastoma cell proliferation. However, overexpression of a kinase-inactive mutant of EphA2 failed to induce ERK activation, S897 phosphorylation, and promotion of glioblastoma cell proliferation. These data suggest that when overexpressed, EphA2 induces ERK activation through its tyrosine kinase activity, leading to S897 phosphorylation and promotion of glioblastoma cell proliferation. Our findings provide a new insight into how EphA2 mediates glioblastoma progression. PMID- 29626473 TI - Effect of GAPDS overexpression on high glucose-induced oxidative damage. AB - The occurrence of infertility in diabetic patients is attributed to oxidative damage of peroxidized products. High glucose-induced mitochondrial oxidative stress and glycolytic enzyme inactivation is considered to be an important mediator for sperm dysfunction. In this study, we successfully constructed TM3 GAPDS stable strain and investigated the role of sperm specific glyceraldehyde-3 phosphate dehydrogenase (GAPDS) on high glucose-induced apoptosis in TM3 cells. High glucose decreased the protein expression of SOD2 and catalase, while the level of intracellular ROS and the apoptosis - related protein increased in TM3 cells. Furthermore, high glucose-induced oxidative stress and apoptosis were reversed by GAPDS overexpression or antioxidant treatment. In conclusion, our data suggest that GAPDS overexpression antagonize high glucose-induced apoptosis by controlling ROS accumulation in TM3 cells. PMID- 29626474 TI - Canstatin modulates L-type calcium channel activity in rat ventricular cardiomyocytes. AB - Excessive increase of cytosolic Ca2+ through the activation of L-type Ca2+ channels (LTCCs) via beta adrenergic receptor induces apoptosis of cardiomyocytes. Canstatin, a cleaved fragment of collagen type IV alpha2 chain, is abundantly expressed in normal heart tissue. We previously reported that canstatin inhibits beta adrenergic receptor-stimulated apoptosis in cardiomyoblasts. Here, we tested the hypothesis that canstatin regulates LTCCs activity in ventricular cardiomyocytes. Collagen type IV alpha2 chain (COL4A2) small interfering (si) RNA (for canstatin suppression) or control siRNA was injected via jugular vein in Wistar rats. Two days after the injection, electrocardiogram (ECG) was recorded and the left ventricular tissue was isolated using Langendorff apparatus. Immunofluorescence staining was performed to clarify the distribution of canstatin in cardiomyocytes. The knockdown efficiency was confirmed by Western blotting. The L-type Ca2+ channel current (ICaL) of ventricular cardiomyocyte was measured by a whole-cell patch clamp technique. In immunofluorescence staining, colocalization of canstatin and alphav integrin was observed in the isolated ventricular cardiomyocytes. The ICaL of ventricular cardiomyocyte isolated from COL4A2 siRNA-injected rats was significantly enhanced compared with control siRNA-injected rats. Recombinant canstatin (250 ng/ml) significantly reversed it. ECG analysis showed that QT interval tended to be shortened and amplitude of T wave was significantly increased in the COL4A2 siRNA injected rats. In summary, we for the first time clarified that suppressing canstatin expression increases the basal ICaL in ventricular cardiomyocytes. It is proposed that canstatin might play a role in the stabilization of cardiac function through the modulation of LTCC activity in cardiomyocytes. PMID- 29626475 TI - FGF8 and FGFR3 are up-regulated in hypertrophic chondrocytes: Association with chondrocyte death in deep zone of Kashin-Beck disease. AB - OBJECTIVE: The aim of this study was to investigate FGF8 and FGFR3 expression in clinical samples of Kashin-Beck disease (KBD), an endemic osteochondropathy found in China, as well as in pre-clinical models of this disease. METHOD: Cartilage was collected from the hand phalanges of five patients with KBD and from five healthy children. Sprague-Dawley rats were administered a selenium-deficient diet for four weeks prior to exposure to the T-2 toxin. ATDC5 cells were differentiated into hypertrophic chondrocytes for twenty-one days, and then treated with 3-morpholinosydnonimine (SIN-1) (0, 1, 3, or 5 mM) for 24 h. FGF8 and FGFR3 were visualized using immunohistochemistry; protein levels were assessed by western blotting, and mRNA levels were determined by real-time RT PCR. RESULTS: Increased staining of FGF8 and FGFR3 was observed in the cartilage of children with KBD compared to normal children. Both increased FGF8 and FGFR3 staining, as well as protein levels, were also observed in the cartilage of rats fed normal or Se-deficient diets plus T-2 toxin exposure, compared to those in rats fed with normal or Se-deficient diets alone. SIN-1 treatment of hypertrophic chondrocytes (ATCD5 cells) increased FGF8 and FGFR3 protein and mRNA levels in a dose-dependent manner. CONCLUSION: Our data indicate that SIN-1 induces FGF8 and FGFR3 overexpression and this is involved in the abnormal terminal differentiation and degradation of the ECM in cartilage. FGF8 and FGFR3 may therefore play an important role in the onset of deep zone necrosis and pathogenesis in KBD in adolescent children. PMID- 29626476 TI - Long non-coding RNA THOR promotes human osteosarcoma cell growth in vitro and in vivo. AB - Long non-coding RNA (LncRNA) dysregulation is associated with human osteosarcoma (OS) cell progression. Recent studies have characterized a novel but ultra conserved LncRNA THOR ("Lnc-THOR") as a cancer-specific LncRNA, mediating cell growth. In the current study, we show that Lnc-THOR is expressed in established and primary human OS cells. It is also detected in human OS tissues, but not in the surrounding normal bone tissues. siRNA-induced knockdown or CRSIPR/Cas9 mediated knockout Lnc-THOR significantly inhibited human OS cell survival and proliferation. Insulin-like growth factor 2 mRNA-binding protein 1 (IGF2BP1) target mRNAs, including IGF2, GLI1 and CD44, were downregulated in Lnc-THOR silenced OS cells as well. Conversely, forced over-expression of Lnc-THOR enhanced IGF2BP1 target mRNA expression, promoting OS cell survival and proliferation. In vivo, xenograft tumors of Lnc-THOR-knockout U2OS cells grew significantly slower than the control U2OS tumors. Together, these results show that Lnc-THOR expression is essential for human OS cell growth. Lnc-THOR could be a novel therapeutic target and/or diagnosis marker for human OS. PMID- 29626477 TI - Chronic cold exposure results in subcutaneous adipose tissue browning and altered global metabolism in Qinghai-Tibetan plateau pika (Ochotona curzoniae). AB - The plateau pika (Ochotona curzoniae), one of the indigenous animals of the Qinghai-Tibet Plateau, is adapted to life in a cold and hypoxic environment. We conducted a series of genomic, proteomic and morphological studies to investigate whether changes in energy metabolism contribute to adaptation of the plateau pika to cold stress by analyzing summer and winter cohorts. The winter group showed strong morphological and histological features of brown adipose tissue (BAT) in subcutaneous white adipose tissue (sWAT). To obtain molecular evidence of browning of sWAT, we performed reverse transcription and quantitative real-time PCR, which revealed that BAT-specific genes, including uncoupling protein 1 (UCP 1) and PPAR-gamma coactivator 1alpha (PGC-1alpha), were highly expressed in sWAT from the winter group. Compared with the summer group, Western blot analysis also confirmed that UCP-1, PGC-1alpha and Cox4 protein levels were significantly increased in sWAT from the winter group. Increased BAT mass in the inter-scapular region of the winter group was also observed. These results suggest that the plateau pika adapts to cold by browning sWAT and increasing BAT in order to increase thermogenesis. These changes are distinct from the previously reported adaptation of highland deer mice. Understanding the regulatory mechanisms underlying this adaptation may lead to novel therapeutic strategies for treating obesity and metabolic disorders. PMID- 29626478 TI - Knockout of NCOA5 impairs proliferation and migration of hepatocellular carcinoma cells by suppressing epithelial-to-mesenchymal transition. AB - Nuclear receptor coactivator 5 (NCOA5) plays important roles in the development of a variety of malignancies. However, the underlying mechanisms remain obscure. In this study, we successfully generated the NCOA5 knockout hepatocellular carcinoma (HCC) cells by CRISPR/Cas9 - mediated genome editing and found that knockout of NCOA5 inhibited the proliferation and tumor microsphere formation of HCC cells significantly. Moreover, the migration ability of NCOA5 knockout HCC cells declined. Mechanistic analyses indicated that knockout of NCOA5 can suppress the epithelial - mesenchymal transition (EMT) in HCC cells. In conclusion, our findings provide a mechanistic insight into the role of NCOA5 in HCC progression. PMID- 29626479 TI - Protein ISGylation and free ISG15 levels are increased by interferon gamma in breast cancer cells. AB - The induction of ISG15 by interferon (IFN)-alpha/beta and subsequent protein ISGylation has been demonstrated in several cell types. However, regulation of free ISG15 levels and ISGylation by other IFNs and its implications in some carcinomas have not yet been completely evaluated. Here, we demonstrated that free ISG15 and ISGylation levels are enhanced by IFN-gamma treatment in the estrogen receptor-alpha-positive and -negative breast cancer cells, MCF-7 and MDA MB-231, respectively. Specifically, IFN-gamma increases free ISG15 levels in the cytoplasm and ISGylation in the nucleus and cytoplasm, but in a manner distinct between MCF-7 and MDA-MB-231 cells. Therefore, free ISG15 and ISGylation may play central roles in mammary tumors by differentially modulating certain tumorigenic characteristics of estrogen receptor-alpha-positive and -negative breast cancer cells. PMID- 29626480 TI - TSPA as a novel ATF6alpha translocation inducer efficiently ameliorates insulin sensitivity restoration and glucose homeostasis in db/db mice. AB - Activating transcription factor 6alpha (ATF6alpha) as a transducer in unfolded protein response (UPR), plays an important role in liver glucose metabolism and insulin resistance. Thus, targeting ATF6alpha activation has been proposed to be a potential strategy for anti-T2DM drug discovery. Here, we determined that small molecule 2-[5-[1-(4-chlorophenoxy)ethyl]-4-phenyl-4H-1,2,4-triazol-3-yl]sulfanyl N-(1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazol-4-yl)acetamide (TSPA) functioned as an ATF6alpha translocation inducer effectively promoting ATF6alpha translocation into nucleus and ameliorating glucose homeostasis on db/db mice. TSPA promoted ATF6alpha translocation into nucleus without incresing C/EBP homologous protein (CHOP) expression. TSPA restored the tunicamycin (TM) stimulated insulin receptor (IR) desensitization through ATF6alpha activation, inhibited gluconeogenesis and efficiently improved glucose homeostasis on db/db mice. Furthermore, TSPA protected insulin pathway involving p38/X-box binding protein 1s (Xbp1s)/ER chaperones signaling pathway. Our current study has determined that ATF6alpha was a promising therapeutic target and also highlighted the potential of TSPA in the treatment of type 2 diabetes mellitus (T2DM). PMID- 29626481 TI - Nicotine induces aberrant hypermethylation of tumor suppressor genes in pancreatic epithelial ductal cells. AB - Tobacco smoking is an independent risk factor for the initiation of pancreatic cancer (PC). Hypermethylation of tumor suppressor genes has been demonstrated to be associated with smoking. This study aimed to find the relationship between nicotine exposure and hypermethylation of tumor suppressor genes in normal pancreatic epithelial cells. Human pancreatic epithelial cells ware cultured exposing to nicotine and the methylation status of tumor suppressor genes were detected. Proenkephalin (PENK) was chosen as the target gene and methylation level of PENK promoter region was measured. Expression of DNA methyltransferase (DNMT), nicotine acetylcholine receptor (alpha7nAChR) and signaling pathway downstream were analyzed. Nicotine induces overexpression of DNMT3A and 3B, and methylated-inactivation of PENK gene in normal pancreatic epithelial cells. An activation of alpha7nAChR and MAPK signaling pathway has been detected in the nicotine-treated group. Demethylated drug, antagonist of alpha7nAChR and inhibitor of p38 MAPK is verified to attenuate the overexpression of DNMTs stimulated by nicotine as well as inhibit aberrant hypermethylation-related silence of PENK gene. Nicotine stimulation can induce aberrant hypermethylation of tumor suppressor genes by alpha7nAChR and MAPK signaling pathway-mediated up regulation of DNMTs in pancreatic epithelial cells, thus we can provide epigenetic evidence of the mechanisms by which smoking causes pancreatic cancer and find new therapeutic target. PMID- 29626482 TI - Binding orientation and interaction of bile salt in its ternary complex with pancreatic lipase-colipase system. AB - The interfacial activity of pancreatic lipases (PL) depends on the presence of colipase and bile salt. The activity of PL is inhibited by micellar concentrations of bile salt which can be restored by the addition of colipase. Though the formation of 1:1:1 tertiary complex by lipase-colipase-bile salt micelle is well accepted, the residue-level interactions between lipase-colipase and bile salt are yet to be clearly understood. Molecular dynamic simulations of lipase-colipase complex, lipase and colipase were performed in the presence of a model bile salt, sodium taurocholate (NaTC), at its near-CMC and supra-micellar concentrations. From the interactions obtained from the molecular dynamic simulations, the ternary complex was modelled and compared with earlier reports. The analysis suggested that a micelle of NaTC consisting of nine monomers was formed at the concave groove between lipase and colipase chain and it mainly interacted with the fourth finger of colipase. This complex was mainly stabilized by van der Waals interactions. Interestingly, the C-terminal domain of lipase which holds the colipase did not show any significant role in formation or stabilization of NaTC micelle. PMID- 29626483 TI - SlyD-deficient Escherichia coli strains: A highway to contaminant-free protein extraction. AB - Binding of native bacterial protein SlyD to metal affinity matrices remains a major problem in affinity purification of His-tagged recombinant proteins from Escherichia coli cells. In this study, four novel E. coli strains that lack the expression of SlyD/SlyX, were engineered using lambda-red mediated chromosomal deletion. The resultant mutant E. coli strains allow us to obtain SlyD-free proteins immediately after metal affinity chromatography, and eliminate additional purification processes. As a model protein, bispecific antibodies composed of anti-F4/80 VHH module and anti-TNF VHH module (MYSTI-2) were used. Using this protein we have shown that the SlyD/SlyX-deficient E. coli strains allow us to obtain a fully functional protein. PMID- 29626484 TI - Neuroestradiol in regulation of GnRH release. AB - Contribution to Special Issue on Fast effects of steroids. The concept that the positive feedback effect of ovarian estradiol (E2) results in GnRH and gonadotropin surges is a well-established principle. However, a series of studies investigating the rapid action of E2 in female rhesus monkeys has led to a new concept that neuroestradiol, synthesized and released in the hypothalamus, also contributes to regulation of the preovulatory GnRH surge. This unexpected finding started from our surprising observation that E2 induces rapid stimulatory action in GnRH neurons in vitro. Subsequently, we confirmed that a similar rapid stimulatory action of E2 occurs in vivo. Unlike subcutaneous injection of E2 benzoate (EB), a brief (10-20 min), direct infusion of EB into the median eminence in ovariectomized (OVX) female monkeys rapidly stimulates release of GnRH and E2 in a pulsatile manner, and the EB-induced GnRH and E2 release is blocked by simultaneous infusion of the aromatase inhibitor, letrozole. This suggests that stimulated release of E2 is of hypothalamic origin. To further determine the role of neuroestradiol we examined the effects of letrozole on EB induced GnRH and LH surges in OVX females. Results indicate that letrozole treatment greatly attenuated the EB-induced GnRH and LH surges. Collectively, neuroestradiol released from the hypothalamus appears to be necessary for the positive feedback effect of E2 on the GnRH/LH surge. PMID- 29626487 TI - Testing for developmental neurotoxicity using a battery of in vitro assays for key cellular events in neurodevelopment. AB - Medium- to high-throughput in vitro assays that recapitulate the critical processes of nervous system development have been proposed as a means to facilitate rapid testing and identification of chemicals which may affect brain development. In vivo neurodevelopment is a complex progression of distinct cellular processes. Therefore, batteries of in vitro assays that model and quantify effects on a variety of neurodevelopmental processes have the potential to identify chemicals which may affect brain development at different developmental stages. In the present study, the results of concentration-response screening of 67 reference chemicals in a battery of high content imaging and microplate reader-based assays that evaluate neural progenitor cell proliferation, neural proginitor cell apoptosis, neurite initiation/outgrowth, neurite maturation and synaptogenesis are summarized and compared. The assay battery had a high degree of combined sensitivity (87%) for categorizing chemicals known to affect neurodevelopment as active and a moderate degree of combined specificity (71%) for categorizing chemicals not associated with affects on neurodevelopment as inactive. The combined sensitivity of the assay battery was higher compared to any individual assay while the combined specificity of the assay battery was lower compared to any individual assay. When selectivity of effects for a neurodevelopmental endpoint as compared to general cytotoxicity was taken into account, the combined sensitivity of the assay battery decreased (68%) while the combined specificity increased (93%). The identity and potency of chemicals identified as active varied across the assay battery, underscoring the need for use of a combination of diverse in vitro models to comprehensively screen chemicals and identify those which potentially affect neurodevelopment. Overall, these data indicate that a battery of assays which address many different processes in nervous system development may be used to identify potential developmental neurotoxicants and to distinguish specific from generalized cytotoxic effects with a high degree of success. PMID- 29626485 TI - Rapid effects of ovarian hormones in dorsal striatum and nucleus accumbens. AB - Contribution to Special Issue on Fast effects of steroids. Estradiol and progesterone rapidly induce changes in dopaminergic signaling within the dorsal striatum and nucleus accumbens of female rats. In ovariectomized females, estradiol rapidly enhances dopamine release and modulates binding of dopamine receptors. Progesterone further potentiates the effect of estradiol on dopamine release. The effects of both estradiol and progesterone are time course dependent, with increases in dopamine release immediately after acute hormone administration followed by later inhibition of dopamine release. Importantly, these changes are also seen in naturally cycling females, indicating their importance for normal physiological states and relevant reproductive behaviors. Here, we summarize the literature establishing the rapid effects of estradiol and progesterone on dopamine release and receptor expression in dorsal striatum and nucleus accumbens of both males and females. Integrating this literature with the larger body of work focusing on dopamine regulated behaviors, we propose hypotheses for adaptive reasons (i.e., ultimate causes) as to why changes in ovarian hormones modulate dopamine release. Finally, we note the importance of these studies for understanding sex differences in vulnerability to drug addiction. Research on how dopaminergic systems regulate behavior in both males and females is crucial for developing a full appreciation of dopamine's role in both natural and drug-induced behaviors. PMID- 29626488 TI - Berberine induced modulation of PHLPP2-Akt-MST1 kinase signaling is coupled with mitochondrial impairment and hepatoma cell death. AB - Pleckstrin homology domain leucine-rich repeat protein phosphatase 2 (PHLPP2) has been known to exert tumor suppressive activity for long without much knowledge about its regulation and implications. Protein kinase B (Akt), Protein kinase C (PKC) and Ribosomal protein S6 Kinase (S6K) are known downtargets of PHLPP2, regulating a plethora of life processes viz. cell growth, survival and evasion from apoptosis. Present study decoded the crucial role of PHLPP2 in inducing apoptosis by its interaction with the newly found binding partner Mammalian sterile 20-like kinase 1 (Mst1) in berberine (BBR)-treated human hepatoma cells. HepG2 cells were exposed to (50 MUM, 100 MUM) berberine for different time intervals (18 h, 24 h). The results showed enhanced expression of PHLPP2 at transcriptional (2.13 fold, P < 0.01) and translational level (4 fold, P < 0.001), but not of PHLPP1, in berberine-treated HepG2 cells. Elevated expression of PHLPP2 was reported to inactivate Akt by dephosphorylating it on Ser473 (P < 0.001). As Akt is known to inhibit apoptotic effect of Mst1, we found that PHLPP2 mediated inactivation of Akt releases its repression from Mst1 leading to heightened phosphorylation of Mst1 on its activating site Thr183 (1.5 fold, P < 0.001). Consequently, coordination between PHLPP2, Akt and Mst1 stimulated downstream targets c-jun N-terminal kinase (JNK), Bim and Bak which are direct activators of pro-apoptotic proteins leading to cell death. Further, PHLPP2/Mst1 knock-down efficiently curtailed anti-proliferative effect of berberine by restoring the basal level of downstream anti-apoptotic proteins. In addition, pre treatment of NAC (5 mM) showed that ROS generation was a primitive event to initiate activation of stress kinases. Thus, our findings suggest that PHLPP2, Akt and Mst1 constitute an autoinhibitory triangle which may be partly responsible for antiproliferative effect of berberine. PMID- 29626489 TI - MicroRNA repertoire and comparative analysis of Andrias davidianus infected with ranavirus using deep sequencing. AB - Andrias davidianus is a large and economically important amphibian in China. Ranavirus infection causes serious losses in A. davidianus farming industry. MicroRNA mediated host-pathogen interactions are important in antiviral defense. In this study, five small-RNA libraries from ranavirus infected and non-infected A. davidianus spleens were sequenced using high throughput sequencing. The miRNA expression pattern, potential functions, and target genes were investigated. In total, 1356 known and 431 novel miRNAs were discovered. GO and KEGG analysis revealed that certain miRNA target genes are associated with apoptotic, signal pathway, and immune response categories. Analysis identified 82 downregulated and 9 upregulated differentially expressed miRNAs, whose putative target genes are involved in pattern-recognition receptor signaling pathways and immune response. These findings suggested miRNAs play key roles in A. davidianus's response to ranavirus and could provide a reference for further miRNA functional identification, leading to novel approaches to improve A. davidianus ranavirus resistance. PMID- 29626490 TI - Beyond good and evil: A putative continuum-sorting hypothesis for the functional role of proBDNF/BDNF-propeptide/mBDNF in antidepressant treatment. AB - Depression and posttraumatic stress disorder are assumed to be maladaptive responses to stress and antidepressants are thought to counteract such responses by increasing BDNF (brain-derived neurotrophic factor) levels. BDNF acts through TrkB (tropomyosin-related receptor kinase B) and plays a central role in neuroplasticity. In contrast, both precursor proBDNF and BDNF propeptide (another metabolic product from proBDNF cleavage) have a high affinity to p75 receptor (p75R) and usually convey apoptosis and neuronal shrinkage. Although BDNF and proBDNF/propeptide apparently act in opposite ways, neuronal turnover and remodeling might be a final common way that both act to promote more effective neuronal networking, avoiding neuronal redundancy and the misleading effects of environmental contingencies. This review aims to provide a brief overview about the BDNF functional role in antidepressant action and about p75R and TrkB signaling to introduce the "continuum-sorting hypothesis." The resulting hypothesis suggests that both BDNF/proBDNF and BDNF/propeptide act as protagonists to fine-tune antidepressant-dependent neuroplasticity in crucial brain structures to modulate behavioral responses to stress. PMID- 29626486 TI - Diverse actions of estradiol on anorexigenic and orexigenic hypothalamic arcuate neurons. AB - Contribution to Special Issue on Fast effects of steroids. There is now compelling evidence for membrane-associated estrogen receptors in hypothalamic neurons that are critical for the hypothalamic control of homeostatic functions. It has been known for some time that estradiol (E2) can rapidly alter hypothalamic neuronal activity within seconds, indicating that some cellular effects can occur via membrane initiated events. However, our understanding of how E2 signals via membrane-associated receptors and how these signals impact physiological functions is only just emerging. Thus, E2 can affect second messenger systems including calcium mobilization and a plethora of kinases to alter cell excitability and even gene transcription in hypothalamic neurons. One population of hypothalamic neurons, the anorexigenic proopiomelanocortin (POMC) neurons, has long been considered to be a target of E2's actions based on gene (Pomc) expression studies. However, we now know that E2 can rapidly alter POMC neuronal activity within seconds and activate several intracellular signaling cascades that ultimately affect gene expression, actions which are critical for maintaining sensitivity to insulin in metabolically stressed states. E2 also affects the orexigenic Neuropeptide Y/Agouti-related Peptide (NPY/AgRP) neurons in similarly rapid but antagonistic manner. Therefore, this review will summarize our current state of knowledge of how E2 signals via rapid membrane-initiated and intracellular signaling cascades in POMC and NPY/AgRP neurons to regulate energy homeostasis. PMID- 29626491 TI - A tetravalent vaccine comprising hexon-chimeric adenoviruses elicits balanced protective immunity against human adenovirus types 3, 7, 14 and 55. AB - Human adenovirus (Ad) species B contains several of the most important types associated with acute respiratory diseases, Ad3, -7, -14 and -55, which often lead to severe lower respiratory tract diseases and epidemic outbreaks. However, there is currently no Ad vaccine approved for general use. The major capsid protein, hexon, is the primary determinant recognized by neutralizing antibodies (NAbs). In this study, four recombinant Ads that have the same genome sequence as Ad3 with the exception of the hexon genes, rAd3EGFP, rAd3H7, rAd3H14 and rAd3H55, were combined as a tetravalent Ad candidate vaccine against Ad3, -7, -14 and -55. The replication efficiencies of chimeric rAd3H14, rAd3H7 and rAd3H55 were similar to that of rAd3EGFP. Recombinant rAd3EGFP, rAd3H7, rAd3H14 and rAd3H55 induced high titers of NAbs against Ad3, -7, -14 and -55, respectively, which were comparable to those induced by wild-type Ads. The mixture of the four recombinant Ads in equal proportions, rAdMix, or rAdMix inactivated by beta-propiolactone, induced balanced NAb responses against Ad3, -7, -14 and -55 in mice without reciprocal immunological interference. In co-culture the four recombinant Ads replicated with a similar efficiency without reciprocal inhibition, and the progeny virions may be chimeric. Purified co-culture, rAdMix-C, also elicited balanced immune responses, suggesting a simple method for multivalent vaccine production. These results indicate the possible advantage of the four Ads as a live combined vaccine. Importantly, pre-immunization with rAdMix conferred protection against Ad3, -7, -14 or -55 challenge in mice in vivo. Thus, this research provides a novel tetravalent Ad vaccine candidate against Ad3, -7, -14 and -55. PMID- 29626492 TI - Environmental enrichment reduces cocaine neurotoxicity during cocaine-conditioned place preference in male rats. AB - Environmental enrichment (EE) has a neuroprotective role and prevents the development of cocaine addiction behavior in rats. Studies showing the role of EE in cocaine toxicity are nonexistent. We hypothesized that rats exposed to EE are protected from cocaine-induced changes in the redox profile and DNA damage after undergoing conditioned place preference (CPP). Ten male Wistar rats were placed in EE cages equipped with toys, a ladder and tunnels, and ten were provided clean, standard laboratory housing (non-EE). EE and non-EE rats were randomly allocated to the classical CPP cocaine vs. saline (COC/Saline) group, where cocaine (15 mg/kg; i.p.) was tested alternately with saline. Afterwards, intracellular reactive species and antioxidant enzymes were evaluated and the comet essay was performed in the prefrontal cortex and hippocampus of rats. As expected, EE rats spent less time in the cocaine-paired chamber, and as a new result, less cocaine-induced DNA damage was observed in the two brain structures. Altogether, our results demonstrate that EE decreases neurotoxicity in brain regions linked to cocaine addiction but does not extinguish it completely. PMID- 29626493 TI - Profiling calcium signals of in vitro polarized human effector CD4+ T cells. AB - Differentiation of naive CD4+ T cells into effector subtypes with distinct cytokine profiles and physiological roles is a tightly regulated process, the imbalance of which can lead to an inadequate immune response or autoimmune disease. The crucial role of Ca2+ signals, mainly mediated by the store operated Ca2+ entry (SOCE) in shaping the immune response is well described. However, it is unclear if human effector CD4+ T cell subsets show differential Ca2+ signatures in response to different stimulation methods. Herein, we provide optimized in vitro culture conditions for polarization of human CD4+ effector T cells and characterize their SOCE following both pharmacological store depletion and direct T-cell receptor (TCR) activation. Moreover, we measured whole cell Ca2+ release activated Ca2+ currents (ICRAC) and investigated whether the observed differences correlate to the expression of CRAC genes. Our results show that Ca2+ profiles of helper CD4+ Th1, Th2 and Th17 are distinct and in part shaped by the intensity of stimulation. Regulatory T cells (Treg) are unique being the subtype with the most prominent SOCE response. Analysis of in vivo differentiated Treg unraveled the role of differential expression of ORAI2 in fine-tuning signals in Treg vs. conventional CD4+ T cells. PMID- 29626495 TI - Correction. PMID- 29626494 TI - Ammonia: This is not the end but rather the end of the beginning. PMID- 29626496 TI - Coaching positively influences the effects of working memory training on visual working memory as well as mathematical ability. AB - The goal of the present study was to test whether the amount of coaching influenced the results of working memory training on both visual and verbal working memory. Additionally, the effects of the working memory training on the amount of progress after specific training in mathematics were evaluated. In this study, 23 children between 9 and 12 years of age with both attentional and mathematical difficulties participated in a working memory training program with a high amount of coaching, while another 25 children received no working memory training. Results of these groups were compared to 21 children who completed the training with a lower amount of coaching. The quality of working memory, as well as mathematic skills, were measured three times using untrained transfer tasks. Bayesian statistics were used to test informative hypotheses. After receiving working memory training, the highly coached group performed better than the group that received less coaching on visual working memory and mathematics, but not on verbal working memory. The highly coached group retained their advantage in mathematics, even though the effect on visual working memory decreased. However, no added effect of working memory training was found on the learning curve during mathematical training. Moreover, the less-coached group was outperformed by the group that did not receive working memory training, both in visual working memory and mathematics. These results suggest that motivation and proper coaching might be crucial for ensuring compliance and effects of working memory training, and that far transfer might be possible. PMID- 29626497 TI - Time course of influence on the allocation of attentional resources caused by unconscious fearful faces. AB - Emotionally affective stimuli have priority in our visual processing even in the absence of conscious processing. However, the influence of unconscious emotional stimuli on our attentional resources remains unclear. Using the continuous flash suppression (CFS) paradigm, we concurrently recorded and analyzed visual event related potential (ERP) components evoked by the images of suppressed fearful and neutral faces, and the steady-state visual evoked potential (SSVEP) elicited by dynamic Mondrian pictures. Fearful faces, relative to neutral faces, elicited larger late ERP components on parietal electrodes, indicating emotional expression processing without consciousness. More importantly, the presentation of a suppressed fearful face in the CFS resulted in a significantly greater decrease in SSVEP amplitude which started about 1-1.2 s after the face images first appeared. This suggests that the time course of the attentional bias occurs at about 1 s after the appearance of the fearful face and demonstrates that unconscious fearful faces may influence attentional resource allocation. Moreover, we proposed a new method that could eliminate the interaction of ERPs and SSVEPs when recorded concurrently. PMID- 29626498 TI - Interaction of fluorescently labeled pyrrole-imidazole polyamide probes with fixed and living murine and human cells. AB - Pericentromeric heterochromatin plays important roles in controlling gene expression and cellular differentiation. Fluorescent pyrrole-imidazole polyamides targeting murine pericentromeric DNA (major satellites) can be used for the visualization of pericentromeric heterochromatin foci in live mouse cells. New derivatives targeting human repeated DNA sequences (alpha-satellites) were synthesized and their interaction with target DNA was characterized. The possibility to use major satellite and alpha -satellite binding polyamides as tools for staining pericentromeric heterochromatin was further investigated in fixed and living mouse and human cells. The staining that was previously observed using the mouse model was further characterized and optimized, but remained limited regarding the fluorophores that can be used. The promising results regarding the staining in the mouse model could not be extended to the human model. Experiments performed in human cells showed chromosomal DNA staining without selectivity. Factors limiting the use of fluorescent polyamides, in particular probe aggregation in the cytoplasm, were investigated. Results are discussed with regards to structure and affinity of probes, density of target sites and chromatin accessibility in both models. PMID- 29626499 TI - Effects of advanced maternal age on cognitive and emotional development in offspring rats. AB - Due to socio-economic development, an increasing number of women delay childbirth to their late 30 s and older. However, this delay brings a series of health problems to pregnant women and their offspring. The few studies on the effects of advanced maternal age (AMA) on offspring development, especially regarding neurocognitive and emotional development, reported mixed results. We examined the relationship between AMA and the performance of immature offspring of 3- versus 12-month-old Sprague-Dawley rat females on neurocognitive development tests and the possible mechanism of this relationship; the rats were individually housed with a randomly selected 3-month-old male, and the cognitive development of the offspring was evaluated by behavior tests including the Morris water maze, elevated plus maze, forced swimming and 3-chambered social behavior tests. Moreover, hematoxylin-eosin (HE) staining and Nissl staining were conducted to detect differences in the hippocampal morphology of the offspring, and Western blot analysis was conducted to detect the protein expression of brain-derived neurotrophic factor (BDNF), cAMP response element binding protein (CREB) and phosphorylated CREB (pCREB). The behavior tests detected defects in the AMA rats compared with the control group. The HE and Nissl staining results showed no significant difference. However, the expression of BDNF, CREB and pCREB was reduced in the immature offspring of AMA rats compared with that in control rats. Based on our results, CREB-dependent expression of BDNF may be responsible for the damage to cognitive and emotional development in offspring caused by delayed motherhood. PMID- 29626501 TI - Birth weight predicts aging trajectory: A hypothesis. AB - Increasing evidence suggests that risk for age-related disease and longevity can be programmed early in life. In human populations, convincing evidence has been accumulated indicating that intrauterine growth restriction (IUGR) resulting in low birth weight (<2.5 kg) followed by postnatal catch-up growth is associated with various aspects of metabolic syndrome, type 2 diabetes and cardiovascular disease in adulthood. Fetal macrosomia (birth weight > 4.5 kg), by contrast, is associated with high risk of non-diabetic obesity and cancers in later life. Developmental modification of epigenetic patterns is considered to be a central mechanism in determining such developmentally programmed phenotypes. Growth hormone/insulin-like growth factor (GH/IGF) axis is likely a key driver of these processes. In this review, evidence is discussed that suggests that different aging trajectories can be realized depending on developmentally programmed life course dynamics of IGF-1. In this hypothetical scenario, IUGR-induced deficit of IGF-1 causes "diabetic" aging trajectory associated with various metabolic disorders in adulthood, while fetal macrosomia-induced excessive levels of IGF-1 lead to "cancerous" aging trajectory. If the above reasoning is correct, then both low and high birth weights are predictors of short life expectancy, while the normal birth weight is a predictor of "normal" aging and maximum longevity. PMID- 29626502 TI - Sustained release of anti-PD-1 peptide for perdurable immunotherapy together with photothermal ablation against primary and distant tumors. AB - Immune checkpoint PD-1/PD-L1 blockade has emerged as a successful immunotherapy strategy for treating several types of malignant tumors. A constant and proper drug concentration during the treatment is important because the long-term activation of the immune system is urgently needed to perdurably recognize and attack cancer cells for a better therapeutic effect with minimum side effects. However, practically few related studies have been reported to date. In this study, we constructed a therapeutic strategy combining PD-1 blocking with photothermal ablation for malignant tumors by co-encapsulating anti-PD-1 peptide (APP) and hollow gold nanoshell (HAuNS) into biodegradable Poly (d, l-lactic-co glycolide) nanoparticles (APP- and HAuNS-loaded PLGA nanoparticles, AA@PN). Slow and continuous release of APP from AA@PN could be obtained from 0 to 40 days, and this release was easily accelerated by illumination with a near-infrared (NIR) laser. A clear killing effect on distant tumor cells was observed after treatment of the co-culture system of PMBCs and tumor cells with AA@PN plus an NIR laser, reflecting the activated immune response. AA@PN followed by multiple irradiations with an NIR laser showed the strongest antitumor effect, with the elimination of most primary tumors compared with other treatments, and significantly inhibited the growth of the distant uninjected primary tumors, similarly to free APP with frequent injections, which induced the longest survival time for the mice in this group. PMID- 29626503 TI - HSF1 deficiency accelerates the transition from pressure overload-induced cardiac hypertrophy to heart failure through endothelial miR-195a-3p-mediated impairment of cardiac angiogenesis. AB - Heat shock transcription factor 1 (HSF1) deficiency aggravates cardiac remodeling under pressure overload. However, the mechanism is still unknown. Here we employed microRNA array analysis of the heart tissue of HSF1-knockout (KO) mice to investigate the potential roles of microRNAs in pressure overload-induced cardiac remodeling under HSF-1 deficiency, and the profiles of 478 microRNAs expressed in the heart tissues of adult HSF1-KO mice were determined. We found that the expression of 5 microRNAs was over 2-fold higher expressed in heart tissues of HSF1-KO mice than in those of wild-type (WT) control mice. Of the overexpressed microRNAs, miR-195a-3p had the highest expression level in HSF1 null endothelial cells (ECs). Induction with miR-195a-3p in ECs significantly suppressed CD31 and VEGF, promoted AngII-induced EC apoptosis, and impaired capillary-like tube formation. In vivo, the upregulation of miR-195a-3p accentuated cardiac hypertrophy, increased the expression of beta-MHC and ANP, and compromised systolic function in mice under pressure overload induced by transverse aortic constriction (TAC). By contrast, antagonism of miR-195a-3p had the opposite effect on HSF1-KO mice. Further experiments confirmed that AMPKalpha2 was the direct target of miR-195a-3p. AMPKalpha2 overexpression rescued the reduction of eNOS and VEGF, and the impairment of angiogenesis that was induced by miR-195a-3p. In addition, upregulation of AMPKalpha2 in the myocardium of HSF1-null mice by adenovirus-mediated gene delivery enhanced CD31, eNOS and VEGF, reduced beta-MHC and ANP, alleviated pressure overload-mediated cardiac hypertrophy and restored cardiac function. Our findings revealed that the upregulation of miR-195a-3p due to HSF1 deficiency impaired cardiac angiogenesis by regulating AMPKalpha2/VEGF signaling, which disrupted the coordination between the myocardial blood supply and the adaptive hypertrophic response and accelerated the transition from cardiac hypertrophy to heart failure in response to pressure overload. PMID- 29626504 TI - Social aggravation: Understanding the complex role of social relationships on stress and health-relevant physiology. AB - There is a rich literature on social support and physical health, but research has focused primarily on the protective effects of social relationship. The stress buffering model asserts that relationships may be protective by being a source of support when coping with stress, thereby blunting health relevant physiological responses. Research also indicates relationships can be a source of stress, also influencing health. In other words, the social buffering influence may have a counterpart, a social aggravating influence that has an opposite or opposing effect. Drawing upon existing conceptual models, we expand these to delineate how social relationships may influence stress processes and ultimately health. This review summarizes the existing literature that points to the potential deleterious physiological effects of our relationships when they are sources of stress or exacerbate stress. PMID- 29626500 TI - The role of the cell-matrix interface in aging and its interaction with the renin angiotensin system in the aged vasculature. AB - The extracellular matrix (ECM) is an intricate network that provides structural and anchoring support to cells in order to stabilize cell morphology and tissue architecture. The ECM also controls many aspects of the cell's dynamic behavior and fate through its ongoing, bidirectional interaction with cells. These interactions between the cell and components of the surrounding ECM are implicated in several biological processes, including development and adult tissue repair in response to injury, throughout the lifespan of multiple species. The present review gives an overview of the growing evidence that cell-matrix interactions play a pivotal role in the aging process. The focus of the first part of the article is on recent studies using cell-derived decellularized ECM, which strongly suggest that age-related changes in the ECM induce cellular senescence, a well-recognized hallmark of aging. This is followed by a review of findings from genetic studies indicating that changes in genes involved in cell ECM adhesion and matrix-mediated intracellular signaling cascades affect longevity. Finally, mention is made of novel data proposing an intricate interplay between cell-matrix interactions and the renin-angiotensin system that may have a significant impact on mammalian arterial stiffness with age. PMID- 29626505 TI - Impact of consumer trends on feeding and eating behaviors in babies and toddlers. PMID- 29626506 TI - Hippocampal glial cells modulate morphine-induced behavioral responses. AB - Drugs of abuse cause persistent alterations in synaptic plasticity that is thought to underlie addictive-like behaviors. Although, the perisynaptic glial cells are implicated in metabolic maintenance and support of the nervous systems, accumulating evidence suggests that glial cells exert a modulatory action on synaptic functions and participate in synaptic plasticity. However, it is well documented that glial cells are associated with the acquisition of rewarding effects of abused drugs. The role of hippocampal glial cells in addictive-like behaviors remains poorly understood. In this study, we investigated the role of hippocampal glial cells in morphine-induced behavioral responses including morphine dependence, tolerance to the antinociceptive properties of morphine, and conditioned place preference (CPP). Male rats received subcutaneous (s.c.) morphine sulfate (10 mg/kg) at an interval of 12 h for 9 days. To suppress glial cells activity, the animals received microinjection of fluorocitrate (FC, a metabolic inhibitor of glial cells) into the CA1 region before each morphine administration. The animals were assessed for morphine dependence by monitoring naloxone hydrochloride-induced precipitation of somatic signs of morphine withdrawal. The tolerance to the antinociceptive effects of morphine and morphine induced CPP were measured in a separate set of experimental groups. We found animals receiving FC before morphine injection demonstrated a significant reduction in several signs of morphine withdrawal such as freezing, defecation, chewing, explosive running, ptosis, activity, scratching, wet dog shake, and writhing. Inhibition of glial cells caused a significant reduction of tolerance to the antinociceptive effect of morphine. Finally, intra-CA1 administration of FC decreased morphine-induced CPP. Our findings suggest that hippocampal glial cells may be involved in morphine-induced behavioral responses. PMID- 29626507 TI - Laccase 1 gene from Plutella xylostella (PxLac1) and its functions in humoral immune response. AB - Laccase (EC 1.10.3.2) is a phenoloxidase found in many insect species. The Laccase 1 gene from Plutella xylostella (PxLac1) was cloned, and its expression patterns and functions were determined using qPCR and RNAi methods. The results showed that the expression levels of PxLac1 were consistently high in all larval stages, and the most abundant was in the midgut during the 4th instar stage. Moreover, the expression of PxLac1 was up-regulated in response to bacterial infection, and decreased 24 h after being parasitized by Cotesia vestalis. Further analyses indicated that the effect of parasitization on PxLac1 was induced by active C. vestalis Bracovirus (CvBV). Haemocyte-free hemolymph phenoloxidase (PO) activity was suppressed when PxLac1 was treated with RNAi. Our results provide evidence for a connection between the Laccase 1 gene and insect immunity, and revealed that parasitoid polydnavirus suppresses host PO activity via PxLac1 regulation. PMID- 29626508 TI - Minimally Invasive SAPIEN in Mitral Annular Calcification Following Transcatheter Aortic Valve Replacement: Feasibility and Lessons Learned. PMID- 29626509 TI - Manipulation of spray-drying conditions to develop dry powder particles with surfaces enriched in hydrophobic material to achieve high aerosolization of a hygroscopic drug. AB - This study aimed to develop dry powder particles with surfaces enriched in hydrophobic material by manipulation of spray-drying conditions and to investigate the effect of hydrophobic surface enrichment on aerosolization of hygroscopic drug. The composite dry powder formulations of kanamycin (hygroscopic drug) and rifampicin (hydrophobic drug) were produced by systematically (23 full factorial design) varying the drug ratio, co-solvent composition and inlet temperature using Buchi B-290 Mini Spray-Dryer. All the composite powder particles were inhalable in size (3.1-3.9 um), wrinkled, flake-shaped and amorphous. X-ray photoelectron spectroscopy and time-of-flight secondary ion mass spectrometry showed that hydrophobic surface enrichment was significantly affected by co-solvent composition. Complete hydrophobic surface enrichment was achieved in one formulation (F7). The aerosolization efficiency by next generation impactor (NGI) showed that the composite formulations had higher fine particle fraction (FPF: >48.0%) than kanamycin-only formulation (FPF: 27.6%). Increase in hydrophobic surface enrichment (from 80.8 to 100%) decreased the powder density and increased FPF (from 48.0 to 77.2%). This is the first systematic study reporting the manipulation of spray-drying conditions for hydrophobic surface enrichment in composite dry powder particles and its effect on aerosolization. The high aerosolization efficiency of the combination formulations may be useful to deliver high doses of these drugs to treat lung infections. PMID- 29626510 TI - Vacuum Induced Surface Freezing as an effective method for improved inter- and intra-vial product homogeneity. AB - The stochastic nature of nucleation makes it difficult to control batch homogeneity in conventional freezing, and this lack of control is in contrast with the current emphasis on Quality by Design. Among the techniques which have been developed to overcome this problem, Vacuum Induced Surface Freezing is probably the most promising for application in manufacturing, because it does not require additional equipment and can be scaled-up more easily than other proposed approaches. In this work, we summarize the impact of Vacuum Induced Surface Freezing on product morphology, and the efficiency of the subsequent drying steps as well. We will show that this controlled freezing approach is extremely beneficial for both the efficiency of the freeze-drying process, and the quality and homogeneity of the final product. The hope is that this work could contribute to the commercial implementation of controlled nucleation technology, overcoming the final resistance to its widespread use. It is our opinion that this would be a substantial improvement, beneficial for both the pharmaceutical industry and the end users. PMID- 29626511 TI - RNA sequencing analysis of salt tolerance in soybean (Glycine max). AB - Salt stress causes foliar chlorosis and scorch, plant stunting, and eventually yield reduction in soybean. There are differential responses, namely tolerance (excluder) and intolerance (includer), among soybean germplasm. However, the genetic and physiological mechanisms for salt tolerance is complex and not clear yet. Based on the results from the screening of the RA-452 x Osage mapping population, two F4:6 lines with extreme responses, most tolerant and most sensitive, were selected for a time-course gene expression study in which the 250 mM NaCl treatment was initially imposed at the V1 stage and continued for 24 h (hrs). Total RNA was isolated from the leaves harvested at 0, 6, 12, 24 h after the initiation of salt treatment, respectively. The RNA-Seq analysis was conducted to compare the salt tolerant genotype with salt sensitive genotype at each time point using RNA-Seq pipeline method. A total of 2374, 998, 1746, and 630 differentially expressed genes (DEGs) between salt-tolerant line and salt sensitive line, were found at 0, 6, 12, and 24 h, respectively. The expression patterns of 154 common DEGs among all the time points were investigated, of which, six common DEGs were upregulated and seven common DEGs were downregulated in salt-tolerant line. Moreover, 13 common DEGs were dramatically expressed at all the time points. Based on Log2 (fold change) of expression level of salt tolerant line to salt-sensitive line and gene annotation, Glyma.02G228100, Glyma.03G226000, Glyma.03G031000, Glyma.03G031400, Glyma.04G180300, Glyma.04G180400, Glyma.05 g204600, Glyma.08G189600, Glyma.13G042200, and Glyma.17G173200, were considered to be the key potential genes involving in the salt-tolerance mechanism in the soybean salt-tolerant line. PMID- 29626512 TI - Substrate-bound structures of a ketoreductase from amphotericin modular polyketide synthase. AB - Ketoreductase (KR) domains of modular polyketide synthases (PKSs) control the stereochemistry of C2 methyl and C3 hydroxyl substituents of polyketide intermediates. To understand the molecular basis of stereocontrol exerted by KRs, the crystal structure of a KR from the second module of the amphotericin PKS (AmpKR2) complexed with NADP+ and 2-methyl-3-oxopentanoyl-pantetheine was solved. This first ternary structure provides direct evidence to the hypothesis that a substrate enters into the active site of an A-type KR from the side opposite the coenzyme to generate an L-hydroxyl substituent. A comparison with the ternary complex of a G355T/Q364H mutant sheds light on the structural basis for stereospecificity toward the substrate C2 methyl substituent. Functional assays suggest the pantetheine handle shows obvious influence on the catalytic efficiency and the stereochemical outcome. Together, these findings extend our current understanding of the stereochemical control of PKS KR domains. PMID- 29626513 TI - Effects of exercise training on adipose tissue apelin expression in streptozotocin-nicotinamide induced diabetic rats. AB - Apelin is an adipocyte-derived peptide that plays an important role in regulation of energy homoeostasis and decrease of insulin resistance. We investigated the effects of exercise training on adipose tissue apelin expression in streptozotocin-nicotinamide induced diabetic rats. In this experimental study, 38 male Wistar rats were assigned to 4 groups: sedentary non-diabetic, trained non diabetic, sedentary diabetic and trained diabetic. Type 2 diabetes mellitus (T2DM) was induced by intraperitoneal injection of streptozotocin and nicotinamide in adult rats. The trained groups ran 8-week on treadmill progressively for 45 min at a speed of 24 m/min and a 5% grade. After the training period, an intraperitoneal glucose tolerance test was performed in addition to the measurement of blood lipids and plasma apelin levels. Apelin mRNA levels in visceral adipose tissue were also analyzed. Two-way repeated measures analysis of variance (ANOVA) and Pearson correlation coefficient was used for analyzing data. P < 0.05 was considered to be statistically significant. Results indicated a significant decrease of insulin resistance followed by a significant increase of plasma levels and mRNA expression of apelin in trained diabetic compared with sedentary diabetic rats. Furthermore, apelin levels did not correlate significantly with body weight and epididymal fat weight in trained diabetic rats. In conclusion, the findings revealed that chronic exercise training, independently of body weight and fat pad weight by decrease of insulin resistance can increase apelin levels in visceral adipose tissue, thereby attenuating the progression of diabetes and decreasing insulin resistance in T2DM rats. PMID- 29626514 TI - Control of Cytomegalovirus Viremia after Allogeneic Stem Cell Transplantation: A Review on CMV-Specific T Cell Reconstitution. AB - Recipients of allogeneic stem cell transplantation (alloSCT) are at risk for reactivation of endogenous herpesviruses due to profound and prolonged T cell deficiency following conditions such as graft-versus-host disease, immunosuppression, and/or T cell depletion. Reactivation of endogenous cytomegalovirus (CMV) is the most frequently occurring herpesvirus reactivation following alloSCT. Antiviral medication is often used in pre-emptive treatment strategies initiated when increases in CMV viral loads are detected as a result of active reactivation of the virus. Despite pre-emptive antiviral treatment, the incidence of CMV disease in CMV-seropositive alloSCT patients is still 10% at 1 year following alloSCT. This illustrates the necessity for adequate CMV-specific T cell immunity for long-term control of CMV and prevention of CMV disease. In this review, we analyzed the available studies on the influence of donor CMV status on CMV-specific T cell reconstitution and CMV disease. Furthermore, we reviewed the available studies on the safety and efficacy of adoptive transfer of donor CMV-specific T cells for the prevention and treatment of CMV disease following alloSCT, including studies on adoptive transfer of third-party CMV specific T cells as a possible alternative when donor T cells are not available. PMID- 29626515 TI - Health-Related Quality of Life after Autologous Stem Cell Transplantation for Multiple Myeloma. AB - Autologous stem cell transplantation (ASCT) is an integral part of the frontline therapy in eligible multiple myeloma (MM) patients. The impact of ASCT on health related quality of life (HRQoL) in myeloma has not been well described. We performed a systematic literature search to identify studies evaluating the impact of ASCT on HRQoL. Our search retrieved 12 relevant studies: 10 manuscripts and 2 conference abstracts. There was a widespread heterogeneity across studies in instruments used to measure HRQoL, time points of measurement, and statistical analysis. Only 1 study was a randomized controlled trial with HRQoL as a prespecified secondary endpoint. The common theme that emerged from most studies is that ASCT leads to an immediate deterioration in HRQoL and increase in symptom burden. However, baseline HRQoL and symptom scores are regained as early as 1 to 2 months post-transplantation. Furthermore, an improvement in HRQoL and pain on long-term follow-up was noted in some studies. We describe opportunities for further research in this area, including routine incorporation of HRQoL as an endpoint in transplant-related clinical trials and need for trials investigating interventions that may improve short and long-term HRQoL in myeloma ASCT recipients. PMID- 29626516 TI - National Trends and Outcomes of Endomyocardial Biopsy for Patients With Myocarditis: From the National Inpatient Sample Database. AB - BACKGROUND: The utility of endomyocardial biopsy (EMB) in the management of myocarditis in the era of advanced cardiac imaging has been challenged. METHODS AND RESULTS: The Nationwide Inpatient Sample Database (years 1998-2013) was queried to identify hospitalization records with a primary diagnosis of myocarditis, and underwent EMB procedure. We identified 22,299 hospitalization records with a diagnosis of myocarditis during the study period. Of those, 798 (3.6%) underwent EMB procedures. There was an average decrease in the incidence of EMB for myocarditis by 0.15% (P < .01) over the study period. Younger patients, women, and those with chronic kidney disease were more likely to undergo EMB. On multivariate analysis, patients with myocarditis who underwent EMB had higher in-hospital mortality (hazard ratio [HR] 1.97, 95% confidence interval [CI] 1.41-2.74) and longer median hospital stay (9 days vs 3 days; P < .001). EMB was associated with a higher incidence of cardiac tamponade (odds ratio [OR] 5.21, 95% CI 2.76-9.82), cardiogenic shock (OR 4.66, 95% CI 3.75 5.78), need for intra-aortic balloon pump (OR 3.52, 95% CI 2.49-4.97), and need for extracorporeal membrane oxygenation (OR 4.26, 95% CI 2.78-6.53). CONCLUSIONS: The use of EMB in hospitalizations with myocarditis has decreased over time. The use of EMB was associated with a higher likelihood of in-hospital mortality and morbidity. Whether these findings represent a causative association from the procedure or a consequence of more severe disease in this group could not be confirmed in this study. PMID- 29626517 TI - eIRIS: Eigen-analysis approach for improved spine multi-shot diffusion MRI. AB - Image reconstruction using image-space sampling function (IRIS) corrects motion induced inter-shot phase variations using phase maps from navigator-echo for multi-shot diffusion MRI. However, the bandwidth along the phase-encoding direction of navigator-echo is usually lower than that of image-echo, and thus their geometric distortions may be different. This geometric mismatch is corrected in IRIS by using the B0 map from an additional scan. In this paper, we present an enhanced IRIS (eIRIS) method that remove the requirement of B0 map. eIRIS treats shots as virtual coils, and then uses an eigen-analysis-based approach, which is insensitive to geometric mismatch, to estimates coil sensitivity maps containing the inter-shot phase variations. The final image is reconstructed under the framework of SENSE. Simulation, phantom, and cervical spine experiments were performed to evaluate the eIRIS method. The images generated by IRIS without B0 correction contain severe artifacts. eIRIS obtains results without noticeable artifacts and comparable to those of IRIS with B0 correction and GRAPPA with a compact kernel (GRAPPA-CK) method. eIRIS slightly outperforms GRAPPA-CK in the terms of normalized root-mean-square error and signal-to-noise ratio. eIRIS has the potential to obtain high-quality diffusion weighted images and will benefit the research and clinical diagnosis of spinal cord. PMID- 29626518 TI - Effect of cardiac-related translational motion in diffusion MRI of the spinal cord. AB - Cardiac-related spinal cord motion affects diffusion-weighted (DWI) signal. The goal of this study was to further quantify the specific detrimental effect of cord translational motion on the DWI signal in order to make better informed decisions about the cost-benefit of cardiac gating. We designed an MRI-compatible phantom mimicking the spinal cord translational motion. Cardiac-gated DWI data were acquired by varying the trigger delay and the b-values. Evaluation of the effect of motion on the DWI signal was done by computing the apparent diffusion coefficient (ADC) along (z-direction) and orthogonal (y- and x-directions) to the phantom. The computed ADCs of the phantom moving along Z were similar for the three orthogonal diffusion-encoding directions, with an average value of 1.65.10 9 , 1.66.10-9 and 1.65.10-9 m2/s along X, Y and Z respectively. DW phase images on the other hand showed the expected linear relationship with phantom velocity. Pure translational motion has minor effect on the diffusion-weighted magnitude signal. The sudden signal drop typically observed in in vivo spinal cord DWI is likely not caused by translational motion of the spinal cord, and possibly originates from non-rigid compression/stretching of the cord and/or from intra voxel incoherent motion (IVIM). PMID- 29626519 TI - Polycomb complex protein BMI1 confers resistance to tamoxifen in estrogen receptor positive breast cancer. AB - We report that BMI1 promotes tamoxifen resistance in estrogen receptor (ER) positive breast cancer (BC). BMI1 overexpression conferred MCF7 and TD47 cells resistance to tamoxifen; BMI1 knockdown sensitized the process. In MCF7-derived tamoxifen resistant cells, BMI1 expression was upregulated and BMI1 knockdown reduced the resistance. BMI1 is an oncogene; its oncogenic activity is attributed to BMI1-stimulated E3 ubiquitin ligase activity, a process that requires BMI1's ring finger (RF) domain. However, a BMI1 mutant without RF conferred tamoxifen resistance. Tamoxifen significantly reduced the growth of xenografts derived from MCF7 cells, but accelerated the growth of tumors produced by BMI1 overexpressing MCF7 cells. BMI1 enhances the pathways that promote resistance to endocrine therapy, including ER, androgen receptor, and MUC1. In patients with ER + BCs (n = 177), BMI1 expression was associated with BC recurrence. In the Curtis dataset consisting of ER + BCs (n = 1506) and ER- BCs (n = 474; cBioPortal), upregulations in BMI1 mRNA expression were correlated with ER + BCs; the upregulation was associated with a set of differentially expressed genes (DEGs). These DEGs were enriched with reductions in immunological processes, indicating a role of BMI1 in downregulation of the immune surveillance. PMID- 29626520 TI - Efficient protease based purification of recombinant matrix metalloprotease-1 in E. coli. AB - MMP1 is an essential enzyme for tissue remodeling both in normal and pathological states. We report a method of purifying activated human MMP1 in E. coli without using urea or 4-Aminophenylmercuric acetate (APMA). Instead, a non-ionic detergent, Triton X-100, was used in the lysis buffer to solubilize MMP1 followed by the protease activities of both trypsin and MMP1 to digest E. coli proteins and activate pro-MMP1. Identity of activated MMP1 was confirmed by Western blot using anti-human MMP1 antibodies, whereas the mass was determined to be 43 kD using matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI TOF-MS). Collagen and gelatin degradation by purified MMP1 were confirmed by sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS PAGE) of degraded FITC-labeled type-1 collagen and gelatin zymogram. Broad spectrum protease activity of purified MMP1 was also confirmed by lysis of native E. coli proteins. Inexpensive high throughput purification of recombinant human MMP1 in E. coli will enable easier MMP1 production for diverse applications. PMID- 29626521 TI - Wnt/beta-catenin modulates chronic tobacco smoke exposure-induced acquisition of pulmonary cancer stem cell properties and diallyl trisulfide intervention. AB - Lung cancer is the leading cause of cancer-related death worldwide; tobacco smoke (TS) constitutes the main causes of lung cancer. Acquisition of cancer stem cells (CSCs)-like properties is the essential progression for the initiation of lung cancer. However, the mechanisms for tobacco smoke-induced lung carcinogenesis remain elusive. In the present study, we demonstrated that long-term exposure of human bronchial epithelial (HBE) cells to TS resulted in malignant transformation and acquisition of CSC-like properties. Moreover, Wnt/beta-catenin pathway was involved in acquisition of the CSC-like phenotype during neoplastic transformation of HBE cells induced by TS. Downregulation of beta-catenin reduced the tumorsphere and decreased the protein expression of lung CSCs markers in TS transformated HBE sphere-forming cells. Furthermore, Diallyl trisulfide (DATS) inhibited the CSCs activity of TS-transformed HBE cells, as well as Wnt/beta catenin suppression. Activation of Wnt/beta-catenin diminished the inhibitory effects of DATS on TS-induced stemness of HBE cells. Together, the present investigation elucidates the modulation of Wnt/beta-catenin in chronic TS exposure-triggered pulmonary acquisition of CSCs properties and DATS intervention, which may provide new insights into the interventional strategies against lung CSCs. PMID- 29626523 TI - Expression of genes in primo vasculature floating in lymphatic endothelium under lipopolysaccharide and acupuncture electric stimulation. AB - It is known that the existence of primo vascular system (PVS) including the primo nodes and vessels. However, it is poorly understood the relevant genes in the PVS system both patho- and physiologic condition. Here, we first examined the gene expression in primo vessels (PV) floating in lymphatic endothelium by isolation of PVS and lymphatic vessels (LV) containing PVS. To investigate therapeutic effects, both PV and LV containing PVS were isolated after lipopolysaccharides (LPS) injection and acupuncture electric stimulation (AES) at two acupoints of Joksamni (ST36) and Hapgok (LI04) following LPS. We used reverse transcriptase polymerase chain reaction (RT-PCR) to examine expression of lymphatic endothelial cell (LEC) markers and inflammatory related genes. We found that LEC markers such as Flt4, Lyve-1, Prox-1, and Pdpn were highly expressed in PV, compared to that of lymphatic endothelium, suggesting pivotal roles of PV in LV under inflammation. Furthermore, lymphatic related genes including Mtf2, Hif1a, Agtr1, and Agtr2 were also overall increased in PV and remarkably increased and these genes except Pparg after AES in two acupoints, implying central role of PV by gene activation. PMID- 29626522 TI - The acute effects of citrus flavanones on the metabolism of glycogen and monosaccharides in the isolated perfused rat liver. AB - Citrus flavanones are often linked to their antihyperglycemic properties. This effect may be in part due to the inhibition of hepatic gluconeogenesis through different mechanisms. One of the possible mechanisms appears to be impairment of oxidative phosphorylation, which may also interfere with glycogen metabolism. Based on these facts, the purpose of the present study was to investigate the effects of three citrus flavanones on glycogenolysis in the isolated perfused rat liver. Hesperidin, hesperetin, and naringenin stimulated glycogenolysis and glycolysis from glycogen with concomitant changes in oxygen uptake. At higher concentrations (300 MUM), hesperetin and naringenin clearly altered fructose and glucose metabolism, whereas hesperidin exerted little to no effects. In subcellular fractions hesperetin and naringenin inhibited the activity of glucose 6-phosphatase and glucokinase and the mitochondrial respiration linked to ADP phosphorylation. Hesperetin and naringenin also inhibited the transport of glucose into the cell. At a concentration of 300 MUM, the glucose influx rate inhibition was 83% and 43% for hesperetin and naringenin, respectively. Hesperidin was the less active among the assayed citrus flavanones, indicating that the rutinoside moiety noticeably decrease the activity of these compounds. The effects on glycogenolysis and fructolysis were mainly consequence of an impairment on mitochondrial energy metabolism. The increased glucose release, due to the higher glycogenolysis, together with glucose transport inhibition is the opposite of what is expected for antihyperglycemic agents. PMID- 29626524 TI - Intratumoral evaluation of 3D microvasculature and nanoparticle distribution using a gadolinium-dendron modified nano-liposomal contrast agent with magnetic resonance micro-imaging. AB - The enhanced permeability and retention (EPR) effect is variable depending on nanoparticle properties and tumor/vessel conditions. Thus, intratumoral evaluations of the vasculature and nanoparticle distribution are important for predicting the therapeutic efficacy and the intractability of tumors. We aimed to develop a tumor vasculature evaluation method and high-resolution nanoparticle delivery imaging using magnetic resonance (MR) micro-imaging technology with a gadolinium (Gd)-dendron assembled liposomal contrast agent. Using the Gd-liposome and a cryogenic receiving coil, we achieved 50-MUm isotropic MR angiography with clear visualization of tumor micro-vessel structure. The Gd-liposome-enhanced MR micro-imaging revealed differences in the vascular structures between Colon26- and SU-DHL6-grafted mice models. The vessel volumes and diameters measured for both tumors were significantly correlated with histological observations. The MR micro-imaging methods facilitate the evaluation of intratumoral vascularization patterns, the quantitative assessment of vascular-properties that alter tumor malignancy, particle retentivity, and the effects of treatment. PMID- 29626525 TI - Whole genome sequence of an MCR-1-carrying, extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli ST746 isolate recovered from a community acquired urinary tract infection. AB - OBJECTIVES: Colistin is regarded as one of the last-resort antimicrobials for severe infections. Isolates carrying the plasmid-borne mobile colistin resistance gene mcr-1 were rarely reported in community-acquired infections. Here we report the draft genome sequence of an MCR-1-carrying, extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli isolate from community-acquired urinary tract infection. METHODS: Antimicrobial susceptibility testing (AST) was performed by the broth microdilution method. Transferability of the mcr-bearing plasmid was determined by filter mating using E. coli EC600 as recipient strain. Multilocus sequence typing (MLST) was undertaken using the E. coli MLST database. The draft genome sequence of isolate LX13 was obtained using an Illumina HiSeq X-Ten platform. The genome was assembled using SOAPdenovo. Acquired antimicrobial resistance genes were identified using ResFinder 2.1. RESULTS: AST showed that LX13 was resistant to ampicillin, amoxicillin/clavulanic acid, piperacillin/tazobactam, cefazolin, cefepime and polymyxins. MLST showed that isolate LX13 belongs to ST746. The MCR-1-producing plasmid was conjugative and conferred increased resistance to colistin the transconjugant. The draft genome of E. coli LX13 was 4914035bp in size. In silico analysis revealed the presence of eight putative acquired resistance genes, including blaCTX-M-14, blaTEM-1B, aadA5, mcr-1, dfrA17, sul2, tet34 and tetA. plasmidSPAdes revealed that the mcr-1 gene was harboured by a plasmid of replicon type IncI2. CONCLUSIONS: This study highlights the potential risk of spread of MCR-1-carrying, ESBL-producing E. coli in the community. The genome sequence of E. coli LX13 will facilitate the understanding of colistin resistance mechanisms and genomic features of clinically isolated colistin-resistant E. coli. PMID- 29626526 TI - Differential modulation of white adipose tissue endocannabinoid levels by n-3 fatty acids in obese mice and type 2 diabetic patients. AB - n-3 polyunsaturated fatty acids (n-3 PUFA) might regulate metabolism by lowering endocannabinoid levels. We examined time-dependent changes in adipose tissue levels of endocannabinoids as well as in parameters of glucose homeostasis induced by n-3 PUFA in dietary-obese mice, and compared these results with the effect of n-3 PUFA intervention in type 2 diabetic (T2DM) subjects. Male C57BL/6J mice were fed for 8, 16 or 24 weeks a high-fat diet alone (cHF) or supplemented with n-3 PUFA (cHF + F). Overweight/obese, T2DM patients on metformin therapy were given for 24 weeks corn oil (Placebo; 5 g/day) or n-3 PUFA concentrate as above (Omega-3; 5 g/day). Endocannabinoids were measured by liquid chromatography tandem mass-spectrometry. Compared to cHF-fed controls, the cHF + F mice consistently reduced 2-arachidonoylglycerol (up to ~2-fold at week 24) and anandamide (~2-fold) in adipose tissue, while the levels of endocannabinoid related anti-inflammatory molecules N-eicosapentaenoyl ethanolamine (EPEA) and N docosahexaenoyl ethanolamine (DHEA) increased more than ~10-fold and ~8-fold, respectively. At week 24, the cHF + F mice improved glucose tolerance and fasting blood glucose, the latter being positively correlated with adipose 2 arachidonoylglycerol levels only in obese cHF-fed controls, like fasting insulin and HOMA-IR. In the patients, n-3 PUFA failed to reduce 2-arachidonoylglycerol and anandamide levels in adipose tissue and serum, but they increased both adipose tissue and serum levels of EPEA and DHEA. In conclusion, the inability of n-3 PUFA to reduce adipose tissue and serum levels of classical endocannabinoids might contribute to a lack of beneficial effects of these lipids on glucose homeostasis in T2DM patients. PMID- 29626528 TI - Growth-inhibition of S180 residual-tumor by combination of cyclophosphamide and chitosan oligosaccharides in vivo. AB - Chitosan oligosaccharides (COS), hydrolyzed products of chitosan, have recently been reported to have various biological activities. Herein, the present study was undertaken to assess the ability of COS to potentiate the antitumor effect of cyclophosphamide (CTX) as well as alleviating the CTX-associated toxicities in vivo, in a residual-tumor; a model which is closer to clinical surgery. Sarcoma 180 (S180) residual-tumor mice were divided into 6 groups (n = 6); including control, CTX, COS 40 mg/kg, COS 80 mg/kg, and combination groups (CTX + COS 40, CTX + COS 80). Animals were killed 18 days post-intraperitoneal administration and the tumors were weighed. The spleens were harvested to determine lymphocytes proliferation and NK cell activities; blood cells were evaluated by flow cytometry, and the expression levels of TNF-alpha were measured using ELISA. Notably, the combined therapy (CTX + COS80) showed the most effective reduction of the tumor weight, the highest inhibition of tumor growth, and proliferation, when compared with control as well single CTX group. Additionally, COS was able to recover the CTX-induced decreases in the lymphocyte proliferation, splenocyte NK cell activity, TNF-alpha concentration, and abnormal CD4+/CD8+ T lymphocyte subset. The increase in infiltrating T cells and macrophages best explain the immunostimulatory effect of COS. Results herein highlighted the therapeutic potential of COS as adjuvant treatment during tumor chemotherapy. PMID- 29626527 TI - In vitro photodynamic inactivation effects of benzylidene cyclopentanone photosensitizers on clinical fluconazole-resistant Candida albicans. AB - BACKGROUND: The incidence of Candida infections has increased for various reasons, including, the more frequent use of immunosuppresants or broad-spectrum antibiotics. Photodynamic inactivation (PDI) is a promising approach for treating localized Candida infections. METHODS: The PDI efficacies of three benzylidene cyclopentanone-based (BCB) photosensitizers (PSs: P1, P2 and Y1) against three fluconazole-resistant C. albicans (cal-1, cal-2, and cal-3) and one control C. albicans (ATCC 90028), respectively, were evaluated using an established plate dilution method. The binding of PSs to C. albicans was determined by fluorescence spectroscopy. The mechanism of antifungal PDI was investigated using confocal laser scanning microscopy (CLSM) and transmission electron microscopy (TEM). RESULTS: Three BCB PSs all bound rapidly to C. albicans. After incubation with PSs for 30 min and irradiation with a 532 nm laser for 10 min (40 mW cm-2, 24 J cm-2), the fungicidal activity was achieved as 7.5 MUM for P1 and P2, and 25 MUM for Y1. CLSM confirmed that P1 and Y1 were located in intracellular components, including mitochondria, while P2 bound to the protoplast exterior and failed to enter the cells. TEM revealed the damage of mitochondria ultrastructures after P1 or Y1-mediated PDI, consistenting with the CLSM results. However, most cells became edematous, enlarged or deformation after P2-mediated PDI. CONCLUSIONS: The three BCB PSs all have remarkable PDI effects on C. albicans. The best effect is obtained by P1, which has one cationic charge with a proper lipophilicity. The respective subcellular localization of the three PSs led to different PDI mechanisms. PMID- 29626529 TI - Pre- vs. post-treatment with melatonin in CCl4-induced liver damage: Oxidative stress inferred from biochemical and pathohistological studies. AB - AIMS: The present study was designed to compare the ameliorating potential of pre and post-treatments with melatonin, a potent natural antioxidant, in the carbon tetrachloride-induced rat liver damage model by tracking changes in enzymatic and non-enzymatic liver tissue defense parameters, as well as in the occurring pathohistological changes. MAIN METHODS: Rats from two experimental groups were treated with melatonin before and after CCl4 administration, while the controls, negative and positive, received vehicle/melatonin and CCl4, respectively. Serum levels of transaminases, alkaline phosphates, gamma-GT, bilirubin, and albumin, as well as a wide panel of oxidative stress-related parameters in liver tissue, were determined in all experimental animals. Liver tissue specimens were stained with hematoxylin and eosin and further evaluated for morphological changes. KEY FINDINGS: Both pre- and post-treatment with melatonin prevented a CCl4-induced increase in serum (ALT, AST, and gamma-GT) and tissue (MDA and XO) liver damage markers and a decrease in the tissue total antioxidant capacity, in both enzymatic and non-enzymatic systems. The intensity of pathological changes, hepatocyte vacuolar degeneration, necrosis and inflammatory cell infiltration, was suppressed by the treatment with melatonin. SIGNIFICANCE: In conclusion, melatonin, especially as a post-intoxication treatment, attenuated CCl4-induced liver oxidative damage, increased liver antioxidant capacities and improved liver microscopic appearance. The results are of interest due to the great protective potential of melatonin that was even demonstrated to be stronger if applied after the tissue damage. PMID- 29626530 TI - High-fat diet affects gut nutrients transporters in hypo and hyperthyroid mice by PPAR-a independent mechanism. AB - AIMS: High fat diet consumes and thyroid hormones (THs) disorders may affect nutrients metabolism, but their impact on the absorptive epithelium, the first place of nutrients access, remains unknown. Our aim was to evaluate the intestinal morphology and nutrients transporters content in mice fed standard (LFD) or high fat (HFD) diets in hypo or hyperthyroidism-induced condition. MATERIAL AND METHODS: C57BL/6 male mice fed LFD or HFD diets for 12 weeks, followed by saline, PTU (antithyroid drug) or T3 treatment up to 30 days. The mice were euthanized and proximal intestine was removed to study GLUT2, GLUT5, PEPT1, FAT-CD36, FATP4, NPC1L1 and NHE3 distribution by Western blotting. Since PPAR-a is activated by fatty acids, which is abundant in the HFD, we also evaluated whether PPAR-a affects nutrients transporters. Thus, mice were treated with fenofibrate, a PPAR-a agonist. KEY FINDINGS: HFD decreased GLUT2, PEPT1, FAT CD6 and NPC1L1, but increased NHE3, while GLUT5 and FATP4 remained unaltered. THs did not alter distribution of nutrients transporters neither in LFD nor in HFD groups, but they increased villi length and depth crypt in LFD and HFD, respectively. Fenofibrate did not affect content of nutrients transporters, excluding PPAR-a involvement on the HFD-induced changes. SIGNIFICANCE: We assume that chronic HFD consumption reduced most of the nutrients transporters content in the small intestine of mice, which might limit the entrance of nutrients and gain weight. Since NHE3 promotes sodium absorption, and it was increased in HFD group, this finding could contribute to explain the hypertension observed in obesity. PMID- 29626531 TI - Zafirlukast and vincamine ameliorate tamoxifen-induced oxidative stress and inflammation: Role of the JNK/ERK pathway. AB - AIMS: This study investigated the hepatoprotective effects of both zafirlukast and vincamine and their possible role in the treatment of tamoxifen-induced liver injury in rats. MATERIALS AND METHODS: Female Wistar rats were divided into five groups (10 rats each). Groups I and II received 1% Tween 80 and served as normal and tamoxifen controls, respectively. Groups III, IV and V were treated with zafirlukast (80 mg/kg), vincamine (10 mg/kg) and a combination of zafirlukast (80 mg/kg) and vincamine (10 mg/kg), respectively for 10 successive days. Tamoxifen was given orally to all groups, except for 1st group, in the dose of 45 mg/kg for 10 days to induce liver injury. Subsequently, rats were sacrificed for biochemical, histopathological, Immunohistochemistry, PCR and western blot assessment. KEY FINDINGS: Tamoxifen-induced liver injury was reflected by alterations in estimated biochemical parameters, activation of JNK/ERK pathway, increased expression of NF-kappaB, liver oxidative stress and inflammatory markers parallel to histopathological changes in liver tissue. Treatment of rats with zafirlukast and vincamine ameliorated tamoxifen induced hepatic cell injury via suppressing oxidative stress, inflammatory markers, caspases-3, p-JNK/p-ERK and NF-kappaB pathways. SIGNIFICANCE: Zafirlukast and vincamine may be regarded as potential therapeutic strategies with antioxidant and anti-inflammatory activities against tamoxifen-induced oxidative damage in rat liver. PMID- 29626532 TI - Container Closure Integrity Testing of Prefilled Syringes. AB - Prefilled syringes (PFSs) are increasingly preferred over vials as container closure systems (CCSs) for injectable drug products when facilitated or self administration is required. However, PFSs are more complex compared to CCSs consisting of vial, rubber stopper, and crimp cap. Container closure integrity (CCI) assurance and verification has been a specific challenge for PFSs as they feature several sealing areas. A comprehensive understanding of the CCS is necessary for an appropriate CCI assessment as well as for packaging development and qualification. A comprehensive CCI assessment of 6 different PFSs from 3 different manufacturers (including 1 polymeric PFS) was conducted using helium leak testing. PFS components were manipulated to systematically assess the contribution of the different sealing areas to CCI, namely rigid needle shield (RNS)/needle, RNS/tip cone, and the individual ribs of a syringe plunger. The polymeric PFS required an equilibrium measurement for accurate container closure integrity testing. The different sealing areas and a single plunger rib were shown to provide adequate CCI. Acceptable tip cap movement until the point of CCI failure was estimated. The assessment of acceptable tip cap movement demonstrated the importance of considering the RNS/tip cone seal design to ensure CCI of the PFS upon post assembly possesses and shipment. PMID- 29626533 TI - The Repurposing of Ivermectin for Malaria: A Prospective Pharmacokinetics-Based Virtual Clinical Trials Assessment of Dosing Regimen Options. AB - Ivermectin has demonstrated many successes in the treatment of a range of nematode infections. Considering the increase in malaria resistance, attention has turned toward ivermectin as a candidate for repurposing for malaria. This study developed and validated an ivermectin physiology-based pharmacokinetic model in healthy adults (20-50 years), pediatric (3-5 years/15-25 kg) subjects, and a representative adult malaria population group (Thailand). Dosing optimization demonstrating a twice-daily dose for 3- or 5-day regimens would provide a time above the LC50 of more than 7 days for adult and pediatric subjects. Furthermore, to address the occurrence of CYP450 induction that is often encountered with antiretroviral agents, simulated drug-drug interaction studies with efavirenz highlighted that a 1-mg/kg once-daily dose for 5 days would counteract the increased ivermectin hepatic clearance and enable a time above LC50 of 138.8 h in adults and 141.2 h in pediatric subjects. It was also demonstrated that dosage regimen design would require consideration of the age weight geographical relationship of the subjects, with a dosage regimen for a representative Thailand population group requiring at least a single daily dose for 5 days to maintain ivermectin plasma concentrations and a time above LC50 similar to that in healthy adults. PMID- 29626534 TI - Nonlinear Protein Binding: Not What You Think. AB - Nonlinear protein binding is traditionally thought of as an increasing fraction unbound with increasing total drug concentration. In the past several years, research into the protein binding of several tetracyclines has shown that an unexpected and counterintuitive phenomenon has been observed, specifically that of decreasing unbound drug fraction with increasing total concentrations of drug over certain concentration ranges. Although several studies of tigecycline have shown the importance calcium and its chelation may play in the protein-drug interaction, the potential clinical implications and relevance have not been explored. Here, we define typical and atypical nonlinear protein binding, overview protein binding theory, and discuss theoretical implications on pharmacokinetics. Using tigecycline as an example, in silico simulations and calculations show how when atypical nonlinear protein binding is not accounted for free drug exposure, and drug tissue penetration may be overestimated. It is important to revisit the impacts of nonlinearity in protein binding on clinical pharmacokinetics and pharmacodynamics, and ultimately, clinical efficacy. Although this phenomenon could potentially warrant clinical dose adjustment for certain compounds, it also presents a potential opportunity to exploit underlying mechanisms to develop new therapies and better understand molecular interactions of xenobiotics within the physiological system. PMID- 29626535 TI - Biophysical Properties and Heating-Induced Aggregation of Lysine-Conjugated Antibody-Drug Conjugates. AB - The commercially available antibody-drug conjugate (ADC) product, Kadcyla(r) is synthesized using a 2-step reaction, wherein the linker is conjugated to native lysines on the mAb in step 1, followed by drug conjugation to the linker-modified antibody in step 2. In our study, we synthesized a lysine-conjugated ADC (Syn ADC) on the same trastuzumab scaffold as Kadcyla(r) using a 1-step reaction. Mass spectrometry of both products revealed a subpopulation of Kadcyla(r) containing free linkers conjugated to the mAb, but not conjugated to the drug, which were absent in the 1-step reaction ADC product. Differential scanning calorimetry thermograms showed that the drug and linker conjugation significantly reduced the thermal stability and energies of activation for the denaturation of the CH2 domain of the ADCs. The heating induced aggregation events started as early as ~57 degrees C and ~45 degrees C for Kadcyla(r) and Syn-ADC, respectively, compared with 71 degrees C for Herceptin(r). The colloidal stability measurements clearly showed that the hydrophobic drug payload on ADCs significantly reduced the repulsive interprotein interactions when compared to the unconjugated antibody under formulation buffer conditions (pH 6.0). Attaching hydrophobic drug and linker moieties onto the antibody lowered the thermal and colloidal stabilities and increased the aggregation propensity of the ADCs. PMID- 29626536 TI - Mechanism and Structural Factors of Lipid and Surfactant in the Formation of Self Emulsified Nanoemulsion. AB - The study aims to elucidate the mechanism and the role of the molecular structure of surfactants and lipids in the formation of oil-in-water (o/w) self-emulsified nanoemulsions (SENs). The hypothesis is that the overall change of Gibb's free energy (DeltaGf) during the mixing of the lipid and surfactant, the formation of the interface between the lipid nanodroplets and water, and the dispersion of the lipid nanodroplets into the water are the determinants of the formation of SEN, which are the result of the intermolecular interactions between the excipients involved. Various lipids and surfactants of different structures were studied for the possible formation of SEN. The results demonstrate that the formation of SEN requires (1) enough hydrophobic attractions between the surfactant molecule and the lipid molecule, which can break up the lipid-lipid and surfactant-surfactant intermolecular binding forces and (2) the surfactant to be able to associate with enough water molecules which can effectively cover the lipid droplets' surface to prevent coalescence. PMID- 29626537 TI - Intrinsically Disordered Proteins Link Alternative Splicing and Post translational Modifications to Complex Cell Signaling and Regulation. AB - Intrinsically disordered proteins and regions (IDPs and IDRs) lack well-defined tertiary structures, yet carry out various important cellular functions, especially those associated with cell signaling and regulation. In eukaryotes, IDPs and IDRs contain the preferred loci for both alternative splicing (AS) and many post-translational modifications (PTMs). Furthermore, AS and/or PTMs at these loci generally alter the signaling outcomes associated with these IDPs or IDRs, where the functional cooperation of these three features is named the IDP AS-PTM toolkit. However, the prevalence of such functional modulations remains unknown. Also, the signal-altering mechanisms by which AS, and PTMs modulate function and the extent to which AS and PTMs collaborate in their signaling modulations have not been well defined for particular protein examples. Here we focus on three important signaling and regulatory IDR-containing protein families in humans, namely, G protein-coupled receptors (GPCRs), which are transmembrane proteins; the nuclear factors of activated T cells (NFATs), which are transcription factors; and the Src family kinases (SFKs), which are signaling enzymes. The goals here are to determine how AS and PTMs individually alter the outcomes of the signaling carried out by the various IDRs and to determine whether AS and PTMs work together to bring about differential cellular responses. We also present data indicating that a wide range of other signaling IDPs or IDRs undergo both AS- and PTM-based modifications, suggesting that they, too, likely take advantage of signal outcome modulations that result from collaboration between these two events. Hence, we propose that the widespread cooperation of IDPs, AS and/or PTMs provides an IDP-AS-PTM toolkit and substantially contributes to the vast complexity of eukaryotic cell signaling systems. PMID- 29626538 TI - ClusPro FMFT-SAXS: Ultra-fast Filtering Using Small-Angle X-ray Scattering Data in Protein Docking. AB - We have recently demonstrated that incorporation of small-angle X-ray scattering (SAXS)-based filtering in our heavily used docking server ClusPro improves docking results. However, the filtering step is time consuming, since ~105 conformations have to be sequentially processed. At the same time, we have demonstrated the possibility of ultra-fast systematic energy evaluation for all rigid body orientations of two proteins, by sampling using Fast Manifold Fourier Transform (FMFT), if energies are represented as a combination of convolution like expressions. Here we present a novel FMFT-based algorithm FMFT-SAXS for massive SAXS computation on multiple conformations of a protein complex. This algorithm exploits the convolutional form of SAXS calculation function. FMFT-SAXS allows computation of SAXS profiles for millions of conformations in a matter of minutes, providing an opportunity to explore the whole conformational space of two interacting proteins. We demonstrate the application of the new FMFT-SAXS approach to significantly speed up SAXS filtering step in our current docking protocol (1 to 2 orders of magnitude faster, running in several minutes on a modern 16-core CPU) without loss of accuracy. This is demonstrated on the benchmark set as well as on the experimental data. The new approach is available as a part of ClusPro server (https://beta.cluspro.org) and as an open source C library (https://bitbucket.org/abc-group/libfmftsaxs). PMID- 29626539 TI - Rationalizing Drug Response in Cancer Cell Lines. AB - Cancer cell lines (CCLs) play an important role in the initial stages of drug discovery allowing, among others, for the screening of drug candidates. As CCL panels continue to grow in size and diversity, many polymorphisms in genes encoding drug-metabolizing enzymes, transporters and drug targets, as well as disease-related genes have been linked to altered drug sensitivity. However, identifying the correlation between this variability and pharmacological responses remains challenging due to the heterogeneity of cancer biology and the intricate interplay between cell lines and drug molecules. Here, we propose a network-based strategy that exploits information on gene expression and somatic mutations of CCLs to group cells according to their molecular similarity. We then identify genes that are characteristic of each cluster and correlate their status with drug response. We find that CCLs with similar characteristic active network regions present specific responses to certain drugs, and identify a limited set of genes that might be directly involved in drug sensitivity or resistance. PMID- 29626540 TI - Supramolecular Assembly of Human Pulmonary Surfactant Protein SP-D. AB - Pulmonary surfactant protein D (SP-D) is a glycoprotein from the collectin family that is a component of the lung surfactant system. It exhibits host defense and immune regulatory functions in addition to contributing to the homeostasis of the surfactant pool within the alveolar airspaces. It is known that the SP-D monomer forms trimers, which further associate into higher-order oligomers. However, the pathway and the interactions involved in the assembly of SP-D oligomers are not clearly understood. In the current study, a recombinant form of full-length human SP-D (rhSP-D) has been qualitatively and quantitatively studied by atomic force microscopy (AFM) and electrophoresis, with the aim to understand the conformational diversity and the determinants defining the oligomerization of the protein. The rhSP-D preparation studied is a mixture of trimers, hexamers, dodecamers and higher-order oligomeric species, with dodecamers accounting for more than 50% of the protein by mass. Similar structures were also found in hSP-D obtained from proteinosis patients, with the largest fuzzy-ball-like oligomers being more abundant in these samples. The proportion of dodecamer is increased under acidic conditions, accompanied by a conformational change into more compact configurations. Two hexamers appear to be the minimal necessary unit for dodecamer formation, with stabilization of the dodecamer occurring via non covalent, ionic, and hydrophobic interactions between the individual N-terminal domains and the proximal area of the SP-D collagen stems. PMID- 29626542 TI - NO-GC in cells 'off the beaten track'. AB - Nitric oxide-sensitive guanylyl cyclase (NO-GC) has been shown to regulate a plethora of different functions in the body. These include, among many others, the fine-tuning of vascular tone, platelet reactivity and gastrointestinal motility. Evidence for the participation of NO-GC in these functions has been obtained from various species including humans, rodents, as well as insects. Clearly, individual cell types that express NO-GC contribute differentially to organ-specific NO/cGMP signaling in the body. Hence, identification of NO-GC expressing cells and their individual involvement in NO/cGMP signaling constituted the focus of many studies over the last 40 years. Probably most information has been obtained from vascular smooth muscle cells and platelets, in which NO-GC is known to induce relaxation and inhibition of aggregation, respectively. Many other cell types that express the enzyme have been linked to certain functions, e.g. cardiomyocyte/inotropy or gastrointestinal smooth muscle cells/motility. However, in some cell types, e.g. myofibroblasts or pericytes, NO GC expression is evident but individual functions of NO/cGMP signaling have yet to be assigned, whereas in other cell types, e.g. in erythrocytes, expression and role of NO-GC is still a matter of debate. This review discusses the current knowledge on 'less popular' cell types that express NO-GC (pericytes, myofibroblasts, cardiomyocytes, adipocytes, interstitial cells of Cajal, fibroblast-like cells and blood cells) and outlines possible further functions in cell types that have not gained strong attention so far. PMID- 29626543 TI - Exploring rainfall impacts on the crash risk on Texas roadways: A crash-based matched-pairs analysis approach. AB - Interaction between adverse weather conditions and motor vehicle crashes is an important topic for traffic engineers and hydrometeorologists. With the recent availability of high resolution precipitation products (hourly, 4 * 4 km), it is possible to evaluate crash risk during rainfall events more accurately. Texas, the second largest state in the U.S., with a relatively high population density in its eastern part that receives significant rainfall from tropical events, experiences many hazardous traffic conditions every year. This study investigates temporal and spatial variability of the Relative Accident Risk (RAR) due to rainy conditions across Texas during the year 2015 using a Crash-Based Matched Pairs Analysis (CB-MPA) approach for every 4 * 4 km grid using an hourly time scale. The overall findings show that rainfall increases crash risk across the state by about 57%, while seasonal-based analysis confirms the role of precipitation patterns on crash rates. Although eastern and central counties (wetter and more urbanized) have remarkably higher rates of crash occurrence, the western counties (mainly rural and dry) show higher RAR values. Moreover, higher rainfall intensity can increase RAR up to three-fold while directly having an adverse effect on crash injury type. There is a relatively high correlation between rainfall intensity and RAR values (R2 = 0.76). The analysis also shows higher RAR values on high-speed interstate highways and tollways compared to urban local streets. RAR values also vary according to the gender and age of drivers. The study findings shed light on future paths toward more detailed applications of high-resolution environmental data in crash risk analysis. PMID- 29626545 TI - Hypoxia-selective allosteric destabilization of activin receptor-like kinases: A potential therapeutic avenue for prophylaxis of heterotopic ossification. AB - Heterotopic ossification (HO), the pathological extraskeletal formation of bone, can arise from blast injuries, severe burns, orthopedic procedures and gain-of function mutations in a component of the bone morphogenetic protein (BMP) signaling pathway, the ACVR1/ALK2 receptor serine-threonine (protein) kinase, causative of Fibrodysplasia Ossificans Progressiva (FOP). All three ALKs (-2, -3, -6) that play roles in bone morphogenesis contribute to trauma-induced HO, hence are well-validated pharmacological targets. That said, development of inhibitors, typically competitors of ATP binding, is inherently difficult due to the conserved nature of the active site of the 500+ human protein kinases. Since these enzymes are regulated via inherent plasticity, pharmacological chaperone like drugs binding to another (allosteric) site could hypothetically modulate kinase conformation and activity. To test for such a mechanism, a surface pocket of ALK2 kinase formed largely by a key allosteric substructure was targeted by supercomputer docking of drug-like compounds from a virtual library. Subsequently, the effects of docked hits were further screened in vitro with purified recombinant kinase protein. A family of compounds with terminal hydrogen bonding acceptor groups was identified that significantly destabilized the protein, inhibiting activity. Destabilization was pH-dependent, putatively mediated by ionization of a histidine within the allosteric substructure with decreasing pH. In vivo, nonnative proteins are degraded by proteolysis in the proteasome complex, or cellular trashcan, allowing for the emergence of therapeutics that inhibit through degradation of over-active proteins implicated in the pathology of diseases and disorders. Because HO is triggered by soft tissue trauma and ensuing hypoxia, dependency of ALK destabilization on hypoxic pH imparts selective efficacy on the allosteric inhibitors, providing potential for safe prophylactic use. PMID- 29626544 TI - The YAP/TAZ transcriptional co-activators have opposing effects at different stages of osteoblast differentiation. AB - The related transcriptional co-factors YAP (Yes-associated protein) and TAZ (transcriptional co-activator with PDZ-binding motif) have been proposed to either promote or inhibit osteoblast differentiation. Here we investigated the skeletal consequences of deleting YAP and TAZ at different stages of the osteoblast lineage using Prx1-Cre, Osx1-Cre, and Dmp1-Cre transgenic mice. Prx1 Cre-mediated deletion resulted in embryonic lethality. Mice lacking both copies of TAZ and one copy of YAP in cells targeted by Prx1-Cre were viable and displayed elevated bone mass associated increased bone formation. Deletion of YAP and TAZ using Osx1-Cre mice led to perinatal lethality. Suppression of Osx1-Cre activity until 21 days of age permitted postnatal deletion of YAP and TAZ, which resulted in increased osteoblast number at 12 weeks of age but no change in bone mass. Mechanistic studies revealed that YAP and TAZ suppress canonical Wnt signaling and Runx2 activity in osteoblast progenitors. Consistent with this, deletion of YAP and TAZ from osteoprogenitor cells increased osteoblast differentiation in vitro. Deletion of YAP and TAZ from mature osteoblasts and osteocytes using Dmp1-Cre mice led to reduced osteoblast number and bone formation, as well as increased osteoclast number, but no changes in known regulators of bone turnover such as RANKL, OPG, and Sost. Together these results suggest that YAP and TAZ in osteoblast progenitors oppose differentiation towards the osteoblast lineage but in mature osteoblasts and osteocytes, they promote bone formation and inhibit bone resorption. PMID- 29626546 TI - Aptamer chemistry. AB - Aptamers are single-stranded DNA or RNA molecules capable of tightly binding to specific targets. These functional nucleic acids are obtained by an in vitro Darwinian evolution method coined SELEX (Systematic Evolution of Ligands by EXponential enrichment). Compared to their proteinaceous counterparts, aptamers offer a number of advantages including a low immunogenicity, a relative ease of large-scale synthesis at affordable costs with little or no batch-to-batch variation, physical stability, and facile chemical modification. These alluring properties have propelled aptamers into the forefront of numerous practical applications such as the development of therapeutic and diagnostic agents as well as the construction of biosensing platforms. However, commercial success of aptamers still proceeds at a weak pace. The main factors responsible for this delay are the susceptibility of aptamers to degradation by nucleases, their rapid renal filtration, suboptimal thermal stability, and the lack of functional group diversity. Here, we describe the different chemical methods available to mitigate these shortcomings. Particularly, we describe the chemical post-SELEX processing of aptamers to include functional groups as well as the inclusion of modified nucleoside triphosphates into the SELEX protocol. These methods will be illustrated with successful examples of chemically modified aptamers used as drug delivery systems, in therapeutic applications, and as biosensing devices. PMID- 29626541 TI - Use the Protonmotive Force: Mitochondrial Uncoupling and Reactive Oxygen Species. AB - Mitochondrial respiration results in an electrochemical proton gradient, or protonmotive force (pmf), across the mitochondrial inner membrane. The pmf is a form of potential energy consisting of charge (?psim) and chemical (?pH) components, that together drive ATP production. In a process called uncoupling, proton leak into the mitochondrial matrix independent of ATP production dissipates the pmf and energy is lost as heat. Other events can directly dissipate the pmf independent of ATP production as well, such as chemical exposure or mechanisms involving regulated mitochondrial membrane electrolyte transport. Uncoupling has defined roles in metabolic plasticity and can be linked through signal transduction to physiologic events. In the latter case, the pmf impacts mitochondrial reactive oxygen species (ROS) production. Although capable of molecular damage, ROS also have signaling properties that depend on the timing, location, and quantity of their production. In this review, we provide a general overview of mitochondrial ROS production, mechanisms of uncoupling, and how these work in tandem to affect physiology and pathologies, including obesity, cardiovascular disease, and immunity. Overall, we highlight that isolated bioenergetic models-mitochondria and cells-only partially recapitulate the complex link between the pmf and ROS signaling that occurs in vivo. PMID- 29626547 TI - Repurposing excipients as active inhalation agents: The mannitol story. AB - The story of how we came to use inhaled mannitol to diagnose asthma and to treat cystic fibrosis began when we were looking for a surrogate for exercise as a stimulus to identify asthma. We had proposed that exercise-induced asthma was caused by an increase in osmolarity of the periciliary fluid. We found hypertonic saline to be a surrogate for exercise but an ultrasonic nebuliser was required. We produced a dry powder of sodium chloride but it proved unstable. We developed a spray dried preparation of mannitol and found that bronchial responsiveness to inhaling mannitol identified people with currently active asthma. We reasoned that mannitol had potential to replace the 'osmotic' benefits of exercise and could be used as a treatment to enhance mucociliary clearance in patients with cystic fibrosis. These discoveries were the start of a journey to develop several registered products that are in clinical use globally today. PMID- 29626548 TI - Clinical indications for, and the future of, circulating tumor cells. AB - Circulating tumor cells (CTCs) are cells that have detached from the primary tumor and entered circulation with potential to initiate a site of metastasis. Currently, CTC detection using CellSearch is cleared by the Food and Drug Administration for monitoring metastatic breast, prostate, and colorectal cancers as a prognostic biomarker for progression-free and overall survival. Accumulating evidence suggests CTCs have similar prognostic value in other metastatic and non metastatic settings. Current research efforts are focused on extending the utility of CTCs beyond a prognostic biomarker to help guide clinical decision making. These include using CTCs as a screening tool for diagnosis, liquid biopsy for molecular profiling, predictive biomarker to specific therapies, and monitoring tool to assess response and guide changes to treatment. CTCs have unique advantages vs circulating tumor DNA in this endeavor. Indications for CTCs in daily practice will expand as isolation techniques improve and clinical studies validating their utility continue to grow. PMID- 29626549 TI - Transforming nanomedicine manufacturing toward Quality by Design and microfluidics. AB - Nanopharmaceuticals aim at translating the unique features of nano-scale materials into therapeutic products and consequently their development relies critically on the progression in manufacturing technology to allow scalable processes complying with process economy and quality assurance. The relatively high failure rate in translational nanopharmaceutical research and development, with respect to new products on the market, is at least partly due to immature bottom-up manufacturing development and resulting sub-optimal control of quality attributes in nanopharmaceuticals. Recently, quality-oriented manufacturing of pharmaceuticals has undergone an unprecedented change toward process and product development interaction. In this context, Quality by Design (QbD) aims to integrate product and process development resulting in an increased number of product applications to regulatory agencies and stronger proprietary defense strategies of process-based products. Although QbD can be applied to essentially any production approach, microfluidic production offers particular opportunities for QbD-based manufacturing of nanopharmaceuticals. Microfluidics provides unique design flexibility, process control and parameter predictability, and also offers ample opportunities for modular production setups, allowing process feedback for continuously operating production and process control. The present review aims at outlining emerging opportunities in the synergistic implementation of QbD strategies and microfluidic production in contemporary development and manufacturing of nanopharmaceuticals. In doing so, aspects of design and development, but also technology management, are reviewed, as is the strategic role of these tools for aligning nanopharmaceutical innovation, development, and advanced industrialization in the broader pharmaceutical field. PMID- 29626551 TI - Microfluidics in nanoparticle drug delivery; From synthesis to pre-clinical screening. AB - Microfluidic technologies employ nano and microscale fabrication techniques to develop highly controllable and reproducible fluidic microenvironments. Utilizing microfluidics, lead compounds can be produced with the controlled physicochemical properties, characterized in a high-throughput fashion, and evaluated in in vitro biomimetic models of human organs; organ-on-a-chip. As a step forward from conventional in vitro culture methods, microfluidics shows promise in effective preclinical testing of nanoparticle-based drug delivery. This review presents a curated selection of state-of-the-art microfluidic platforms focusing on the fabrication, characterization, and assessment of nanoparticles for drug delivery applications. We also discuss the current challenges and future prospects of nanoparticle drug delivery development using microfluidics. PMID- 29626552 TI - Smoking cessation intervention delivered by social service organisations for a diverse population of Australian disadvantaged smokers: A pragmatic randomised controlled trial. AB - OBJECTIVES: There remains a need to identify effective smoking cessation interventions in severely disadvantaged populations. This trial aimed to examine the effectiveness of an intervention (Call it Quits) developed to promote smoking cessation and delivered by community social service case-workers. METHODS: Call it Quits was a pragmatic, parallel randomised trial of a case-worker delivered smoking cessation intervention conducted in a non-government community social service organisation in New South Wales (NSW), Australia. Adult smokers requiring financial assistance were randomly assigned to the five-session Call it Quits intervention or usual care control group. Of the 618 eligible individuals, 300 were randomised to the intervention group, of whom 187 (62%) consented and 318 were randomised to the control group, of whom 244 (77%) consented, resulting in 431 participants. The primary outcome measure was self-reported continuous abstinence up to 6-month follow-up with biochemical verification. Primary analysis was performed using all the available data from participants under the assumption the data is missing completely at random, followed by sensitivity analyses. RESULTS: No statistically significant differences in the primary outcome were found (1.4% in the control group versus 1.0% in the intervention group, OR = 0.77, p = 0.828). CONCLUSIONS: A multi-component smoking cessation intervention delivering motivational interviewing-based counselling and free NRT by a trained case-worker within a community social service setting was not effective at achieving abstinence in a highly disadvantaged sample of smokers but increased attempts to stop and led to a reduction in number of cigarettes smoked daily. PMID- 29626553 TI - Development of a risk score for the prediction of incident dementia in older adults using a frailty index and health checkup data: The JAGES longitudinal study. AB - In Japan, the prevalence of dementia is expected to reach 4.7 million by 2025. This study aimed to develop a risk score for the prediction of incident dementia in community-dwelling older adults. In this longitudinal observational study, we used data from the Japan Gerontological Evaluation Study (JAGES) conducted in K City. We performed Cox regression analyses to develop three risk score models for the prediction of incident dementia in older adults using a frailty index and health checkup data. Analyses of the area under the receiver operating characteristic curve were conducted to compare the models' predictive abilities. We identified 6656 (9.2%) individuals who developed incident dementia during the observation period. The C-statistics of the risk scores ranged from 0.733 to 0.790. The risk score models were able to predict incident dementia in older adults and may help non-medical professionals detect dementia risk at an early stage. PMID- 29626554 TI - Physical activity and dual disease burden among South African primary schoolchildren from disadvantaged neighbourhoods. AB - People from low- and middle-income countries still face challenges stemming from parasitic infections. Additionally, non-communicable diseases (NCDs) and their risk factors are rapidly increasing, which puts South African children at an elevated risk of a dual disease burden, with negative consequences for child development and wellbeing. Contrastingly, regular physical activity (PA) is associated with decreased cardiovascular disease (CVD) risk. Therefore, the objective of this study was to examine whether PA is associated with the double infection-CVD phenotype burden in South African schoolchildren. 801 children (402 boys, 399 girls; mean age 9.5 years) from eight schools from disadvantaged neighbourhoods were included. Data assessment took place between February and March 2015 in Port Elizabeth, South Africa. Children who achieved PA recommendations (physically active on 6-7 days/week for at least 60 min), who were active, but below recommended standards (2-5 physically active days/week), or who were insufficiently active on almost all days (0-1 physically active days/week) were compared with regard to systolic and diastolic blood pressure, body mass index (BMI), percent body fat, and infection with soil-transmitted helminths. Moderate and high self-reported PA levels were associated with lower BMI, lower body fat, and lower risk of being hypertensive. Conversely, children with high self-reported PA were more likely to be infected with soil-transmitted helminths than peers with low PA levels. Promoting PA in disadvantaged areas is worthwhile to prevent NCD later in life, but should be combined with regular anthelminthic treatment to comprehensively improve children's health and wellbeing. PMID- 29626550 TI - Drug delivery systems and materials for wound healing applications. AB - Chronic, non-healing wounds place a significant burden on patients and healthcare systems, resulting in impaired mobility, limb amputation, or even death. Chronic wounds result from a disruption in the highly orchestrated cascade of events involved in wound closure. Significant advances in our understanding of the pathophysiology of chronic wounds have resulted in the development of drugs designed to target different aspects of the impaired processes. However, the hostility of the wound environment rich in degradative enzymes and its elevated pH, combined with differences in the time scales of different physiological processes involved in tissue regeneration require the use of effective drug delivery systems. In this review, we will first discuss the pathophysiology of chronic wounds and then the materials used for engineering drug delivery systems. Different passive and active drug delivery systems used in wound care will be reviewed. In addition, the architecture of the delivery platform and its ability to modulate drug delivery are discussed. Emerging technologies and the opportunities for engineering more effective wound care devices are also highlighted. PMID- 29626555 TI - Behavioral economics and diabetic eye exams. AB - Diabetic retinopathy is a common microvascular complication of diabetes mellitus and is the leading cause of new blindness among working-age adults in the United States. Timely intervention to prevent vision loss is possible with early detection by regular eye examinations. Unfortunately, adherence to recommended annual diabetic eye exams is poor. Public health interventions have targeted traditional barriers to care, such as cost and transportation, with limited success. Behavioral economics provides an additional framework of concepts and tools to understand low screening rates and to promote regular diabetic eye exams for populations at risk. In particular, behavioral economics outlines biases and heuristics that affect decision-making and underlie pervasive barriers to care, such as not viewing diabetic eye exams as a priority or perceiving oneself as too healthy to need an examination. In this review, we examine the literature on the use of behavioral economics interventions to promote regular diabetic eye exams. From the results of the included studies, we outline how concepts from behavioral economics can improve eye examination rates. In particular, the default bias, present bias, and self-serving bias play a significant role in precluding regular diabetic eye examinations. Potential tools to mitigate these biases include leveraging default options, using reminder messages, providing behavioral coaching, applying commitment contracts, offering financial incentives, and personalizing health messages. When combined with traditional public health campaigns, insights from behavioral economics can improve understanding of pervasive barriers to care and offer additional strategies to promote regular preventive eye care for patients with diabetes. PMID- 29626556 TI - Estimation of compliance with exclusive smoking of very low nicotine content cigarettes using plasma cotinine. AB - Regulations requiring a reduction of the nicotine content in cigarettes to minimally addictive levels could significantly reduce the public health impact of cigarette smoking. Clinical trials evaluating this strategy are ongoing and methods have been developed to use nicotine biomarkers to estimate compliance with use of very low nicotine content cigarettes (VLNCs). To date, these methods have not considered the potential contribution of nicotine absorption from environmental tobacco smoke (ETS) among research participants. This study used data from 100 randomly selected study completers in ongoing clinical trials of VLNCs (50 randomized to Usual Nicotine Content Cigarettes (UNCs) and 50 to VLNCs) to assess the use of plasma cotinine to estimate compliance. Plasma cotinine and smoking behavior were recorded at baseline after 2 weeks smoking UNC cigarettes, and then after 18 weeks of either continuing smoking UNCs or reducing the nicotine content such that the last 6 weeks comprised smoking VLNCs. Plasma cotinine remained stable (267 ng/ml) in the UNC group but reduced to 93 ng/ml in the VLNC group (p < 0.01). Compliance with smoking VLNCs was first estimated by comparing the cotinine per cigarette on VLNCs with UNCs after allowing for potential compensatory smoking. We found that 29 (58%) of the VLNC group were compliant. Adjusting for potential ETS exposure estimated 32 (64%) to be compliant. This latter group (n = 32) had a mean plasma cotinine on VLNCs of 7 ng/ml (range = 3-16.4 ng/ml). Adjusting for potential ETS exposure may improve identification of participants who plausibly complied with exclusive VLNC use. PMID- 29626557 TI - Response to reduced nicotine content cigarettes among smokers differing in tobacco dependence severity. AB - This study examines whether tobacco dependence severity moderates the acute effects of reducing nicotine content in cigarettes on the addiction potential of smoking, craving/withdrawal, or smoking topography. Participants (N = 169) were daily smokers with mild, moderate, or high tobacco-dependence severity using the Heaviness of Smoking Index. Following brief abstinence, participants smoked research cigarettes varying in nicotine content (0.4, 2.4, 5.2, 15.8 mg nicotine/g tobacco) in a within-subject design. Results were analyzed using repeated measures analysis of co-variance. No main effects of dependence severity or interactions with nicotine dose were noted in relative reinforcing effects in concurrent choice testing or subjective effects on the modified Cigarette Evaluation Questionnaire. Demand for smoking in the Cigarette Purchase Task was greater among more dependent smokers, but reducing nicotine content decreased demand independent of dependence severity. Dependence severity did not significantly alter response to reduced nicotine content cigarettes on the Minnesota Tobacco Withdrawal Scale nor Questionnaire of Smoking Urges-brief (QSU) Factor-2 scale; dependence severity and dose interacted significantly on the QSU brief Factor-1 scale, with reductions dependent on dose among highly but not mildly or moderately dependent smokers. Dependence severity and dose interacted significantly on only one of six measures of smoking topography (i.e., maximum flow rate), which increased as dose increased among mildly and moderately but not highly dependent smokers. These results suggest that dependence severity has no moderating influence on the ability of reduced nicotine content cigarettes to lower the addiction potential of smoking, and minimal effects on relief from craving/withdrawal or smoking topography. PMID- 29626558 TI - Ensuring childhood vaccination among slums dwellers under the National Immunization Program in India - Challenges and opportunities. AB - AIMS: Almost, one third of the world's urban population resides in slums and the number would double by 2030. Slums denotes collection of people from various communities having a meagre income and living in unhygienic conditions thus making themselves most vulnerable for outbreaks of communicable diseases. India contributes substantially to the global disease burden and under-five mortality rates i.e. 20% attributable to vaccine preventable diseases. Immunization plays a crucial role in combating high childhood mortality rates attributable to vaccine preventable diseases across the globe. This systematic review, provides insights on immunization status in slums, identifies various factors influencing it thus, exploring opportunities that may be available to improve vaccination coverage under the National Immunization Program. METHODS: Taking into account the above aspects, a review of literature was undertaken in various databases that included studies published between 2006 and 2017. RESULTS: In India, ~33% of the urban population lives in slums with suboptimal vaccination coverage ranging from 14% to upto 90%. Few of the important causes for low coverage included socioeconomic factors such as poor community participation, lack of awareness, frequent migration, and loss of daily income. Hence, mere presence of vaccines in the National Immunization Program doesn't do the job, there is a definite unmet need to emphasize upon the importance of immunization among slums dwellers and take necessary steps. For instance, delivering immunization services at the doorstep (e.g. pulse polio program), community-based education, text messaging as reminders and incentivized immunization services are some of the opportunities that can be explored and implemented to improve immunization status in the slums. CONCLUSION: Thus, in addition to inclusion of more and more vaccines in the National Immunization Program, there is a definite need to focus on people living in high risk areas in order to improve coverage and healthcare indicators. PMID- 29626559 TI - A truly safer alternative? Sunless tanning products and the unknown. PMID- 29626560 TI - Bioelectrical control of positional information in development and regeneration: A review of conceptual and computational advances. AB - Positional information describes pre-patterns of morphogenetic substances that alter spatio-temporal gene expression to instruct development of growth and form. A wealth of recent data indicate bioelectrical properties, such as the transmembrane potential (Vmem), are involved as instructive signals in the spatiotemporal regulation of morphogenesis. However, the mechanistic relationships between Vmem and molecular positional information are only beginning to be understood. Recent advances in computational modeling are assisting in the development of comprehensive frameworks for mechanistically understanding how endogenous bioelectricity can guide anatomy in a broad range of systems. Vmem represents an extraordinarily strong electric field (~1.0 * 106 V/m) active over the thin expanse of the plasma membrane, with the capacity to influence a variety of downstream molecular signaling cascades. Moreover, in multicellular networks, intercellular coupling facilitated by gap junction channels may induce directed, electrodiffusive transport of charged molecules between cells of the network to generate new positional information patterning possibilities and characteristics. Given the demonstrated role of Vmem in morphogenesis, here we review current understanding of how Vmem can integrate with molecular regulatory networks to control single cell state, and the unique properties bioelectricity adds to transport phenomena in gap junction-coupled cell networks to facilitate self-assembly of morphogen gradients and other patterns. Understanding how Vmem integrates with biochemical regulatory networks at the level of a single cell, and mechanisms through which Vmem shapes molecular positional information in multicellular networks, are essential for a deep understanding of body plan control in development, regeneration and disease. PMID- 29626561 TI - Saline extract of Pilosocereus gounellei stem has antinociceptive effect in mice without showing acute toxicity and altering motor coordination. AB - People broadly use medicinal plants although their safety and efficacy are often neglected. Several Cactaceae plants are used for medicinal purposes, but Pilosocereus gounellei (xique-xique) has been little studied for their pharmacological properties. In this study, a saline extract from Pilosocereus gounellei stem was evaluated for acute toxicity, effects on motor function, and antinociceptive activity in mice. Thin-layer chromatography and high-performance liquid chromatography revealed the presence of flavonoids and reducing sugars. No death of mice was noted with oral treatments at 2000 and 5000 mg/kg. Body weight gain, food intake, and water consumption were not affected with treatment at 2000 mg/kg. The number of segmented leukocytes was higher in the treated mice than in control, and reduced serum levels of cholesterol and triglycerides were detected after both extract treatments. No histological alterations in the liver, heart, lung, kidney, and spleen were detected. Open field and rotarod tests showed that the extract did not affect motor function and exploratory activity. Antinociceptive activity was detected in acetic acid-induced writhing, tail immersion, and formalin tests, indicating interference with both non-inflammatory and inflammatory pain. In conclusion, the P. gounellei extract has antinociceptive activity in mice without showing toxicity and altering motor coordination. PMID- 29626562 TI - A human relevance investigation of PPARalpha-mediated key events in the hepatocarcinogenic mode of action of propaquizafop in rats. AB - Propaquizafop is an herbicide with demonstrated hepatocarcinogenic activity in rodents. A rodent-specific mode of action (MOA) in the liver via activation of peroxisome proliferator-activated receptor alpha (PPARalpha) has been postulated based on existing data. Experience with PPARalpha-inducing pharmaceuticals indicates a lack of human relevance of this MOA. The objective of the present investigation was to evaluate the dependency of early key events leading to liver tumors on PPARalpha activation in wildtype (WT) compared to PPARalpha-knockout (KO) rats following 2 weeks exposure to 75, 500 and 1000 ppm propaquizafop in the diet. In WT rats, both WY-14643 (50 mg/kg bw/day) and propaquizafop (dose dependently) induced marked increases in liver weights, correlating with liver enlargement and hepatocellular hypertrophy, along with increased CYP4A and acyl CoA oxidase mRNA expression and enzyme activities versus controls, while in KO rats liver weight was mildly increased only at the high dose with minimal microscopic correlates and without any changes in liver peroxisomal or CYP4A activities. In addition, BrdU labeling resulted in higher numbers and density of positive hepatocytes versus controls in WT but not in KO rats, indicating increased mitotic activity and cell proliferation only in WT rats, thus confirming the PPARalpha-dependency of the biochemical and histological changes in the liver. Based on an assessment of the results of this investigation, together with existing propaquizafop data according to the MOA-Human Relevance Framework, we conclude that liver tumors observed in rodents after dietary administration of propaquizafop do not pose a relevant health risk to humans. PMID- 29626563 TI - Combined effect of Benzophenone-2 and ultraviolet radiation promote photogenotoxicity and photocytotoxicity in human keratinocytes. AB - Benzophenone-2 (BP2), a common ingredient of sunscreens formulation is widely used as UV filter. We have assessed the photogenotoxic and photocytotoxic potential of BP2. Photostability test showed that BP2 is unstable under UV exposure. Cell proliferation assay revealed that viability of HaCaT cells significantly reduced under UVA, UVB and sunlight exposure. DCF fluorescence intensity proved intracellular ROS generation capacity of BP2 under sunlight, UVA and UVB irradiation. Photodynamic degradation of guanine base of DNA is promoted by BP2 under UV treatment. Genotoxicity assessed by comet assay, showed that photosensitized BP2 enhanced DNA damage, which is measured in term of % tail DNA and olive tail moment. Genotoxic potential of BP2 was further validated with photomicronuclei assay. Photogenotoxicity of BP2 was lastly confirmed by formation of CPDs (Cyclo butane pyrimidine dimmers). DNA damage induced by BP2 was irreversible and extended incubation periods (6-12 h) not favored the recovery from damaged DNA. JC 1 staining showed significant reduction in mitochondrial membrane potential. Membrane integrity compromisation of HaCaT cells was established by AO (Acridine orange), EtBr (Ethidium bromide) staining and confirmed with sub G1 population of cell cycle. Thus, results suggest that BP2 should be avoided in topical application for safe sunscreen practices. PMID- 29626565 TI - Antidepressant-like actions by silencing of neuronal ELAV-like RNA-binding proteins HuB and HuC in a model of depression in male mice. AB - Currently available antidepressant drugs often fail to achieve full remission and patients might evolve to treatment resistance, showing the need to achieve a better therapy of depressive disorders. Increasing evidence supports that post transcriptional regulation of gene expression is important in neuronal development and survival and a relevant role is played by RNA binding proteins (RBP). To explore new therapeutic strategies, we investigated the role of the neuron-specific ELAV-like RBP (HuB, HuC, HuD) in a mouse model of depression. In this study, a 4-week unpredictable chronic mild stress (UCMS) protocol was applied to mice to induce a depressive-like phenotype. In the last 2 weeks of the UCMS regimen, silencing of HuB, HuC or HuD was performed by using specific antisense oligonucleotides (aODN). Treatment of UCMS-exposed mice with anti-HuB and anti-HuC aODN improved both anhedonia and behavioural despair, used as measures of depressive-like behaviour, without modifying the response of stressed mice to an anxiety-inducing environment. On the contrary, HuD silencing promoted an anxiolytic-like behaviour in UCMS-exposed mice without improving depressive like behaviours. The antidepressant-like phenotype of anti-HuB and anti-HuC mice was not shown concurrently with the promotion of adult hippocampal neurogenesis in the dentate gyrus, and no increase in the BDNF and CREB content was detected. Conversely, in the CA3 hippocampal region, projection area of newly born neurons, HuB and HuC silencing increased the number of BrdU/NeuN positive cells. These results give the first indication of a role of nELAV in the modulation of emotional states in a mouse model of depression. PMID- 29626564 TI - Dorsal CA1 interneurons contribute to acute stress-induced spatial memory deficits. AB - Exposure to severely stressful experiences disrupts the activity of neuronal circuits and impairs declarative memory. GABAergic interneurons coordinate neuronal network activity, but their involvement in stress-evoked memory loss remains to be elucidated. Here, we provide evidence that interneurons in area CA1 of the dorsal hippocampus partially modulate acute stress-induced memory deficits. In adult male mice, both acute forced swim stress and restraint stress impaired hippocampus-dependent spatial memory and increased the density of c-fos positive interneurons in the dorsal CA1. Selective activation of dorsal CA1 interneurons by chemogenetics disrupted memory performance in the spatial object recognition task. In comparison, anxiety-related behavior, spatial working memory and novel object recognition memory remained intact when dorsal CA1 interneurons were overactivated. Moreover, chemogenetic activation of dorsal CA1 interneurons suppressed the activity of adjacent pyramidal neurons, whereas a single exposure to forced swim stress but not restraint stress increased the activity of CA1 pyramidal neurons. However, chemogenetic inhibition of dorsal CA1 interneurons led to spatial memory impairments and failed to attenuate acute stress-induced memory loss. These findings suggest that acute stress may overactivate interneurons in the dorsal CA1, which reduces the activity of pyramidal neurons and in turn disrupts long-term memory. PMID- 29626566 TI - Antidepressant-like effects of a novel curcumin derivative J147: Involvement of 5 HT1A receptor. AB - Depression is a dysthymia disorder characterized by a pervasive or persistent mental disorder that causes mood, cognitive and memory deficits. J147, a curcumin analogue, increases brain derived neurotrophic factor (BDNF) levels and facilitates memory in animals. Because curcumin has the antidepressant-like activity, the present study investigated the potential antidepressant-like effects of J147 in the forced swimming test (FST) and tail suspension tests (TST) and the involvement of 5-HT receptors related to cAMP signaling. The results suggested that acute treatment of J147 at doses of 5 and 10 mg/kg via gavage markedly reduced the duration of immobility in both TST and FST, either 1 h or 3 h after treatment, respectively. It did not alter locomotor activity but influence the immobile response. The molecular biological assays showed that 5 HT1A receptor expression was significantly increased at 1 h after treatment with J147 at a dose of 10 mg/kg. In addition, pre-treatment of mice with WAY-100635 blocked the J147's effect in the FST. 5-HT1B receptor expression was not significantly increased with increasing doses of J147. The 5-HT1B receptors antagonist isamoltan partially prevented J147's effect in the FST. The levels of downstream molecular targets, cAMP, PKA, pCREB and BDNF were significantly increased 1 h after treatment with J147 at doses of 5 and 10 mg/kg. The up regulated pCREB and BDNF levels lasted for 3 h after 10 mg/kg of J147. These findings demonstrated that J147 has antidepressant-like effects that are mediated, at least in part, by activating the 5-HT1A/cAMP/PKA/CREB/BDNF-signaling pathway. PMID- 29626567 TI - Evaluation of the intracellular activity of drugs against Mycobacterium abscessus using a THP-1 macrophage model. AB - We evaluated the antimicrobial effectiveness against M. abscessus in a THP-1 cell line model. No intracellular activity was observed when using amikacin or imipenem. A bacteriostatic effect was observed for cefoxitin, clarithromycin and azithromycin. Tigecycline showed the best antibacterial effect by decreasing the intracellular growth up to bactericidal level. PMID- 29626568 TI - Urinary Tract Infections After Urinary Diversion-Different Occurrence Patterns in Patients With Ileal Conduit and Orthotopic Neobladder. AB - OBJECTIVE: To compare the incidence rate of urinary tract infections (UTIs) and associated pathogens between patients with ileal conduit and patients with orthotopic neobladder urinary diversion. PATIENTS AND METHODS: The medical records of 179 patients treated with radical cystectomy between 2006 and 2011 were reviewed and data pertaining to postoperative UTI were collected. UTI incidence was reported at 3 months' intervals and compared by diversion type. Preoperative predictors of UTI were evaluated with Cox regression analyses. RESULTS: The study cohort included 130 patients with ileal conduit and 49 patients with orthotopic neobladder. Patients with a neobladder were younger (P <.001). Median follow-up was 38 months (IQR [interquartile range], 11-63). Median time from surgery to first infection was 1.5 months (IQR, 1-12.5) for patients with a neobladder and 11 months (IQR, 2.5-27) for patients with a conduit (P = .04). During the first 3 months after surgery, 29% of the patients with a neobladder and 8% of the patients with ileal conduit had a UTI episode (P = .001). Rates of UTI did not differ during subsequent follow-up. Diversion type was not associated with UTI on multivariable analysis. Escherichia coli was the most common pathogen in patients with a conduit (58%), and Klebsiella spp. in patients with a neobladder (29%). CONCLUSION: The risk of UTI is significantly higher in patients with a neobladder during the first 3 months after surgery and comparable to patients with ileal conduit during subsequent follow-up. These findings may facilitate preoperative counseling regarding the expected risk of UTI after urinary diversion. PMID- 29626569 TI - A Voice From the Past: Rediscovering the Virchow Node With Prostate-specific Membrane Antigen-targeted 18F-DCFPyL Positron Emission Tomography Imaging. PMID- 29626570 TI - What Is the Role of alpha-Blockers for Medical Expulsive Therapy? Results From a Meta-analysis of 60 Randomized Trials and Over 9500 Patients. AB - Use of alpha-blockers for medical expulsive therapy (MET) has been the subject of huge debate in urology. Moreover, there have been a number of randomized controlled trials with differing results. We conducted a systematic review and meta-analysis of randomized controlled trials investigating the efficacy of alpha blockers for MET. This review confirms there is a role for alpha-blockers in MET for ureteric stones specifically in stones >5 mm and distal ureteric stones, which is associated with improved stone expulsion. However, there is a slight increase in risk of nonsignificant side effects. PMID- 29626571 TI - Prepubertal Malignant Large Cell Calcifying Sertoli Cell Tumor of the Testis. AB - An otherwise healthy 7-year-old boy was diagnosed with malignant large cell calcifying Sertoli cell tumor (LCCSCT) of the testis. He underwent attempted partial orchiectomy with conversion to radical orchiectomy due to suspected malignancy on intraoperative frozen section. There was no lymph node or visceral metastases. To our knowledge, this is the first report of malignant LCCSCT in the prepubertal population. LCCSCT of the testis is an extremely rare neoplasm, with low malignant potential. Malignant cases are exclusively reported previously in the adult population. We report the first case of malignant LCCSCT in a pediatric patient. We review the literatures and discuss the clinical, pathologic features and treatments of malignant LCCSCT. PMID- 29626572 TI - TH1/TH17 cell recognition of desmoglein 3 and bullous pemphigoid antigen 180 in patients with lichen planus. PMID- 29626573 TI - Correlation of allergen-specific T follicular helper cell counts with specific IgE levels and efficacy of allergen immunotherapy. PMID- 29626574 TI - Assessing the effects of silver nanoparticles on monolayers of differentiated Caco-2 cells, as a model of intestinal barrier. AB - Since ingestion is one of the main routes of entry of nanoparticles (NPs) in our organism, simple and fast in vitro models of the intestinal barrier can be helpful to evaluate NPs risk. The human colon adenocarcinoma Caco-2 cell line has been extensively used due to its ability to differentiate, forming a well structured cell monolayer. In this study, we have used these differentiated cells as a model of intestinal barrier to evaluate a wide set of effects caused by exposure to silver nanoparticles (AgNPs) with an average size of 7.74 nm. Different parameters such as toxicity, monolayer integrity and permeability (assessed by changes in cells' morphology and gene expression pattern), internalization (uptake), translocation, and induction of DNA damage (DNA breaks and oxidative DNA damage) were evaluated. No significant effects were observed on the monolayer's integrity/permeability after exposure to silver nanoparticles, although cellular uptake was demonstrated by using confocal microscopy. Despite the observed uptake, no translocation of AgNPs to the basolateral chamber was demonstrated with any of the different experimental approaches used. The genotoxic effects evaluated using the comet assay indicate that, although AgNPs were not able to induce direct DNA breaks, its exposure induced a significant increase in the oxidative DNA damage levels, at non-toxic concentrations. PMID- 29626575 TI - RIFM fragrance ingredient safety assessment beta-Patchoulene, CAS Registry Number 514-51-2. PMID- 29626576 TI - 2',4'-Dihydroxy-6'-methoxy-3',5'-dimethylchalcone, a potent Nrf2/ARE pathway inhibitor, reverses drug resistance by decreasing glutathione synthesis and drug efflux in BEL-7402/5-FU cells. AB - 2',4'-Dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC) is a major active constituent of the buds of Cleistocalyx operculatus (Roxb.) Merr. et Perry (Myrtaceae), a main ingredient of herbal tea in tropical zones. DMC has been reported to significantly reverse drug resistance in BEL-7402/5-FU cells. Glutathione (GSH) and glutathione S-transferase (GST) play important roles in an efflux system that protects the cells from anticancer drugs. In this study, DMC remarkably decreased the intracellular GSH content and GST activity. Furthermore, DMC suppressed the expression of factor erythroid 2-related factor 2 (Nrf2), prevented Nrf2 nuclear translocation, and inhibited the binding of Nrf2 to the antioxidant response element (ARE). The glutamate-cysteine ligase catalytic subunit (GCLC) and glutamate-cysteine ligase modifier subunit (GCLM) were down regulated by inhibiting Nrf2 with DMC treatment. These results suggested that DMC reduced drug efflux to reverse drug resistance by suppressing the Nrf2/ARE signaling pathway in human hepatocellular carcinoma BEL-7402/5-FU cells. PMID- 29626577 TI - Intake of arsenic and mercury from fish and seafood in a Northern Italy community. AB - Regular consumption of fish is generally recommended by authorities because fish is an important source of essential nutrients. However, the presence of potentially toxic contaminants in fish has raised many concerns about the food's safety for human health. In the present study, we used a validated semi quantitative food frequency questionnaire to assess the dietary habits of a representative sample of 719 individuals (319 males and 400 females) aged 18-87 years residing in Northern Italy. We estimated weekly dietary intakes of Arsenic (As) and Mercury (Hg), and we compared them with safety standards set by the European Food Safety Authority. In this population, fish was the main contributor to As and Hg intake. The highest levels of As were in sardine, sole/flounder and cephalopods, and of Hg in the biggest, predatory fish. About the other foods, cereals were the second contributor to the intake of these elements, especially rice for As and bread for Hg, and high levels of As and Hg were also found in mushrooms, coffee and wine. Average weekly intake of both contaminants was below recommended safety limits. PMID- 29626578 TI - Stability of dietary polyphenols: It's never too late to mend? AB - We have comprehensively investigated the structure-stability relationship of natural polyphenols in DMEM medium without cells. Polyphenols with catechol or pyrogallol structure were evidently instable in DMEM medium without cells. Herein, we further investigate stability of polyphenols when incubated with cancer cells and its related mechanism. After incubated with SK-28 cells and A549 cells at 37 degrees C in 5% CO2 for 72 h, the new products of quercetin and 5,7,3',4'-tetrahydroxyflavone were found to quite different from different cells. It is time to investigate what really happened for polyphenols and the new products of polyphenols in cancer cells, as well as the related mechanism. It is very important to further check the bioactivity of these new products, which will avoid erroneous conclusions for what's the really bioactive compounds. PMID- 29626580 TI - A risk perception gap? Comparing expert, producer and consumer prioritization of food hazard controls. AB - Using a survey approach, the study examined how experts (i.e. food control representatives), producers (i.e. food industry representatives) and consumers prioritized control activities for 28 hazards related to food and other everyday items. The investigated hazards encompassed a wide range of safety issues, including health risks, consumer deception and poor food hygiene behaviour. The participants included 41 experts, 138 producers and 243 consumers from the German and French-speaking parts of Switzerland. Based on detailed descriptions of the hazards, they were asked to rank these on a score sheet in terms of the perceived importance of monitoring by food control authorities. A between-group comparison of average rankings showed that consumers and experts differed significantly in relation to 17 of the 28 hazards. While the experts assigned higher priority to hazards related to everyday items such as nitrosamine in mascara and chromium VI in leather products, producers and consumers tended to prioritize products related to plant treatment and genetic modification of food and feeds. Producer and consumer rankings of the hazards were highly correlated (r = .96, p < .001). Rankings were also similar among participants from the two cultural regions (i.e. German and French-speaking parts of Switzerland). PMID- 29626581 TI - The use of plants containing genotoxic carcinogens as foods and medicine. AB - In many developing countries, populations rely on traditional medicine for primary health care, which have infiltrated commercial markets globally as natural remedies are generally regarded as safe. Traditional and natural remedies are adapted and expanded in commercial products and product ranges to provide alternatives for various diseases and illnesses. These products resemble very little of the traditional use and application and adverse effects are observed in several cases. Some of the herbs and botanical formulations therefore, are not as safe as are commonly contemplated. This paper discusses some plants that are used as food or medicine. These plants are known to contain chemical components that have been identified as genotoxic carcinogens. Often contradictory results are obtained with beneficial and adverse effects reported. The concentration, biotransformation and metabolism of these compounds, as well as the matrix effect, affect the outcome of these results, therefore not providing a clear picture of the risk associated with the use and consumption of these plants. This paper focuses on plants that are accepted as healthy, however contain compounds that are genotoxic and carcinogenic. We further highlight the risks in use of these plants where thorough studies have been conducted in various food and plant products. PMID- 29626579 TI - Naturally complex: Perspectives and challenges associated with Botanical Dietary Supplement Safety assessment. PMID- 29626582 TI - Prevalence, awareness, treatment and control of diabetes in Portugal: Results from the first National Health examination Survey (INSEF 2015). AB - AIMS: Diabetes Mellitus is a major public health threat worldwide and continues to increase in numbers and significance. Estimates of diabetes prevalence, awareness, treatment and control are essential to effectively monitor its trends, plan and evaluate interventions. METHODS: We conducted a nationwide health examination survey in the population residing in Portugal aged between 25 and 74 years old in 2015. It consisted in a cross sectional prevalence study which included the measurement of HbA1c, a physical examination and a general health interview of a probabilistic sample of 4911 individuals (Authorization n degrees 9348/2010 of the National Committee for Data Protection). RESULTS: The overall prevalence of diabetes was 9.9% (95%CI: 8.4; 11.5). It was higher in males than in females (12.1% vs 7.8%). Diabetes was more prevalent among individuals of lower education and without any professional activity. The majority of persons with diabetes was aware of their condition (87.1%) and was taking antidiabetic medication (79.7%). Of these, 63.2% had glycated hemoglobin levels lower than 7.0% (53 mmol/mol), but the majority failed to comply with the LDL and blood pressure recommended clinical targets (71.9% and 59.0%). Similarly, the prevalence of prediabetes was 16%, higher among women than men (17.5% vs 14.4%). CONCLUSION: The prevalence of diabetes and prediabetes remains higher than the global and European estimates, although there is increasing awareness of this disorder. PMID- 29626583 TI - Abnormalities in the relationship of paraoxonase 1 with HDL and apolipoprotein A1 and their possible connection to HDL dysfunctionality in type 2 diabetes. AB - AIMS: Lipid parameters, lipid risk indexes and lipid-related oxidative stress markers (paraoxonase 1 [PON1] and lipid peroxides [LPO]) reflect the actual status of lipid metabolism in type 2 diabetes (T2DM). We hypothesized that relationships of high-density lipoprotein cholesterol (HDL-c) with PON1 and apolipoprotein A1 (ApoA1) and/or PON1 with ApoA1 under conditions of hyperglycaemia and oxidative stress might reveal HDL functionality. We investigated relationships between PON1, LPO, and lipid risk markers in T2DM subjects and compared them with those in healthy subjects. METHODS: A total of 107 Caucasian subjects, 67 T2DM outpatients (mean age 52.2 +/- 6.9 years) and 40 healthy subjects (mean age 48.1 +/- 7.5 years) were included in the study. Serum levels of total cholesterol (CHOL-T), HDL-c, low-density lipoprotein cholesterol (LDL-c), triglycerides (TG), apolipoprotein B (ApoB), ApoA1, LPO, and PON1 activity were measured. Non-HDL-c, ApoB/ApoA1 and non-HDL/HDL (lipid risk indexes) were calculated. RESULTS: Higher levels of TG, LPO (P < 0.0001), nonHDL/HDL and ApoB/ApoA1 (P < 0.001, 0.05, respectively), and lower levels of HDL-c, ApoA1, and PON1 (P < 0.0001) were observed in T2DM subjects than in controls. There is a lack of relationship among PON1, HDL-c, and ApoA1 in T2DM patients. PON1 activity positively correlated with these parameters (P < 0.0001) in controls. Strong correlations between non-HDL-c and ApoB (r = 0.956 vs. 0.756; P < 0.0001), LPO and TG (r = 0.831 vs. 0.739; P < 0.0001) were recorded in both study groups (P < 0.0001). CONCLUSIONS: Impaired anti-oxidant and anti atherogenic HDL properties associated with weakened PON1 function and lipid peroxidation may contribute to the development of atherosclerosis-related diseases in T2DM. PMID- 29626584 TI - Maternal gestational diabetes and long-term respiratory related hospitalizations of the offspring. AB - AIMS: To assess the implications of gestational diabetes mellitus (GDM) on long term respiratory related hospitalizations of the offspring. METHODS: A population based cohort analysis including singleton pregnancies delivered between the years 1991 to 2014 in a tertiary referral hospital was conducted. Incidence of hospitalizations (up to age 18 years) due to various respiratory diseases was compared between offspring of GDM-complicated pregnancies and normoglycemic pregnancies. Kaplan-Meyer curves were used to assess cumulative hospitalization incidence. Cox proportional hazards model was used to control for baseline selected confounders. RESULTS: During the study period 216,197 deliveries met the inclusion criteria. Of those, 4.7% (n = 10,184) were complicated by GDM. In most of the investigated respiratory diseases, no significant differences were found between offspring of both groups. Nonetheless, obstructive sleep apnea-related hospitalization rate was higher among the GDM group, an association which proved to be independent of potential confounders with an adjusted hazard ratio of 1.26 (95% CI 1.02-1.55; p = 0.036). CONCLUSION: Gestational diabetes mellitus does not appear to be associated with long-term respiratory hospitalizations of the offspring other than obstructive sleep apnea-related hospitalizations. PMID- 29626585 TI - The Better Diabetes Diagnosis (BDD) study - A review of a nationwide prospective cohort study in Sweden. AB - The incidence of type 1 diabetes (T1D) in Sweden is one of the highest in the world. However, the possibility of other types of diabetes must also be considered. In addition, individuals with T1D constitute a heterogeneous group. A precise classification of diabetes is a prerequisite for optimal outcome. For precise classification, knowledge on the distribution of genetic factors, biochemical markers and clinical features in individuals with new onset of diabetes is needed. The Better Diabetes Diagnosis (BDD), is a nationwide study in Sweden with the primary aim to facilitate a more precise classification and diagnosis of diabetes in order to enable the most adequate treatment for each patient. Secondary aims include identification of risk factors for diabetes related co-morbidities. Since 2005, data on almost all children and adolescents with newly diagnosed diabetes in Sweden are prospectively collected and including heredity of diabetes, clinical symptoms, levels of C peptide, genetic analyses and detection of autoantibodies. Since 2011, analyses of HLA profile, autoantibodies and C peptide levels are part of clinical routine in Sweden for all pediatric patients with suspected diagnosis of diabetes. In this review, we present the methods and main results of the BDD study so far and discuss future aspects. PMID- 29626586 TI - Outcomes of integrated management versus specialized care for patients with type 2 diabetes: An observational study. AB - AIMS: To compare type 2 diabetes (T2D) patients included in a Diabetes Integrated Management (DIM) program with those followed in Diabetes Specialized Care (DSC), investigating differences in general characteristics, changes in clinical outcomes, and factors related with the inclusion in the DIM program. METHODS: T2D patients living in the ASLTO3 district and included into the DIM program, a shared disease management between general practitioners and diabetes specialists, from 2008 to 2014 were compared with T2D patients living in the same district and in charge of the local DSC. Demographic, anthropometric and clinical data for both groups of patients were obtained from the electronic records of DSC. RESULTS: 1326 DIM patients were compared with 3494 DSC patients. A higher proportion of females was observed among DIM patients than among DSC patients. DIM patients were older, more frequently in therapy with diet only or with oral hypoglycemic, and had HbA1c and creatinine lower than DSC patients. The analyses of changes in clinical parameters during the study period showed a good and statistically significant improvement of most parameters, independently of the inclusion in DIM or DSC, with the exception of creatinine level. CONCLUSIONS: Integrated Management is an efficient and effective way to achieve good long-term clinical outcomes for patients with diabetes. PMID- 29626587 TI - Metabolite changes in risk of type 2 diabetes mellitus in cohort studies: A systematic review and meta-analysis. AB - AIMS: Fasting plasma glucose, oral glucose tolerance test, and glycated hemoglobin are diagnostic markers for type 2 diabetes mellitus (T2DM). However, it is necessary to detect physiological changes in T2DM rapidly and stratify diabetic stage using other biomarkers. We performed a systematic review and meta analysis to contribute to the development of objective and sensitive diagnostic indicators by integrating metabolite biomarkers derived from large-scale cohort studies. METHODS: We searched for metabolomics studies of T2DM cohort in PubMed, Scopus, and Web of Science for studies published within the last 10 years from January 2008 to February 2017. The concentrations of metabolites and odds ratios (ORs) were integrated and risk ratio (RR) values were estimated to distinguish subjects with T2DM and normal participants. RESULTS: Fourteen cohort studies were investigated in this meta-analysis. There were 4592 patients in the case group and 11,492 participants in the control group. We noted a 1.89-, 1.63-, and 1.87 fold higher risk of T2DM associated with leucine (RR 1.89 [95% CI 1.57-2.29]), alanine (RR 1.63 [95% CI 1.48-1.79]), and oleic acid (RR 1.87 [95% CI 1.62 2.17]), respectively. Lysophosphatidylcholine C18:0 (RR 0.80 [95% CI 0.72-0.90]) and creatinine (RR 0.63 [95% CI 0.53-0.74]) were associated with 20% and 37% decreased T2DM risks, respectively. CONCLUSIONS: Most amino acids in patients were positively related to diabetes, while creatinine and some lysophosphatidylcholines showed a negative relationship. This suggests that diabetic risk prediction using metabolites that sensitively reflect changes in the body will improve individual diagnosis and personalize medicine. PMID- 29626588 TI - Risk of gestational diabetes mellitus in relation to plasma concentrations of amino acids and acylcarnitines: A nested case-control study. AB - AIMS: Gestational diabetes mellitus (GDM) affects between 5 and 10% of all pregnancies in Canada and can lead to adverse health outcomes in both the mother and fetus. Amino acids (AA) and acylcarnitines (AC) have been identified as early biomarkers of type 2 diabetes but their usefulness in screening for GDM has yet to be demonstrated. METHODS: We conducted a nested case-control study involving 50 controls and 50 GDM cases diagnosed between the 24th and 28th week of gestation. Heparinized plasma samples were obtained during the first and early second trimester of pregnancy. Case and controls were matched according to date of recruitment, maternal age, gestational age at blood sampling as well as pre pregnancy body mass index. Eight AA and eight AC were quantified using an ultra high pressure liquid-chromatography quadrupole time-of-flight mass spectrometry platform. Conditional regression analyses adjusted for matching factors and smoking habits during pregnancy were performed to identify plasma metabolites associated with GDM risk. RESULTS: Odds ratio (OR) and 95% confidence interval (CI) for the prediction of GDM per one standard deviation increase of AA or AC in plasma levels were 0.25 (0.08-0.79) for butyrylcarnitine, 0.31 (0.12-0.79) for glutamic acid, 2.5 (1.2-5.3) for acetylcarnitine, 2.9 (1.3-6.8) for isobutyrylcarnitine and 5.3 (1.7-17.0) for leucine. These five metabolites were selected by stepwise conditional logistic regression to create a predictive model with an OR of 2.7 (1.5-4.9). CONCLUSION: Whether the identified metabolites can predict the risk of developing GDM requires additional studies in a larger sample of pregnant women. PMID- 29626589 TI - Red onion scales ameliorated streptozotocin-induced diabetes and diabetic nephropathy in Wistar rats in relation to their metabolite fingerprint. AB - AIM: The present study was designed to investigate the effect of red onion scales extract (ROS) against diabetic nephropathy, in relation to its metabolic profiling. METHODS: Four groups of male Wistar rats were assigned as follows; 1st untreated group, 2nd group (animals with diabetes) treated with streptozotocin (STZ, 50 mg/kg) IP, 3rd group co-treated with ROS (150 mg/kg + STZ, 50 mg/kg) and 4th group co-treated with ROS by a dose (300 mg/kg + STZ, 50 mg/kg) daily. After four weeks, random and fasting blood glucose (FBG) levels, serum insulin, advanced glycation end products (AGEs), urea, uric acid and inflammatory and fibrotic gene expression were evaluated. Moreover, histopathological examination of the renal tissues was performed. In addition, the metabolic profiling of ROS was performed via RP-HPLC-DAD-QTOF-MS and -MS/MS. RESULTS: The metabolic profiling of ROS revealed that protocatechuic acid and cyanidin-3-O-glucoside were the predominant compounds among 32 metabolites identified in the extract. ROS treated groups showed improvement of FBG and AGEs levels, whereas serum insulin level showed significant elevation. In addition, down-regulation of inflammatory mRNA expression associated with the hyperglycemic condition and amelioration in histopathological alterations in kidney tissues were observed. CONCLUSION: This study displayed the presence of 32 phenolic compounds in the ethanolic extract of ROS, a common by-product of the industrial production of onion in Egypt. This study proved the therapeutic potential of ROS as antidiabetic agent and its preventive effect against diabetic nephropathy. Therefore, this study represents a perspective of the utilization of food waste products. PMID- 29626590 TI - Altered expression of WFS1 and NOTCH2 genes associated with diabetic nephropathy in T2DM patients. AB - AIM: The increased incidence of type 2 diabetes mellitus (T2DM) and the importance of early identification and management of its complications, especially diabetic nephropathy (DN), have spotted the light on genetic factors that increase risk of T2DM and its related nephropathy. The present study aimed at investigating expression of (KCNJ11, ABCC8, JAZF1, WFS1, PPARG, NOTCH2 and EXOSC4) genes in peripheral blood of T2DM patients. METHOD: The study included 30 non-complicated T2DM patients, 30 patients with DN and 40 healthy controls. Quantitative Real Time PCR Array was used to study gene expression. RESULTS: NOTCH2 showed higher expression while KCNJ11, JAZF1, WFS1 and PPARG genes showed lower expression in DN patients compared to non-complicated patients. KCNJ11, JAZF1, WFS1, PPARG, and EXOSC4 expression showed significant negative correlation with microalbumin, while NOTCH2 expression was significantly positively correlated with microalbumin. AS regard HbA1c and studied genes expression, there was significant negative correlation between WFS1 expression and HbA1c, while NOTCH2, KCNJ11, JAZF1, PPARG, EXOSC4 expression didn't show significant correlation with HbA1c. Risk ratio of studied genes expression showed that WFS1 and NOTCH2 had highest risk ratio (30) and highest sensitivity and specificity, in relation to DN and they were the best predictors in the group of studied genes at cut off value of <=0.861 for WFS1 and >=0.678 for NOTCH2. CONCLUSION: Altered expression of WFS1 and NOTCH2 genes may play a role in pathogenesis and development of DN in patients with T2DM. These results may contribute in early identification and management of DN. PMID- 29626591 TI - Impact of the Canadian Diabetes Association guideline dissemination strategy on clinician knowledge and behaviour change outcomes. AB - AIM: Implementation of clinical practice guideline (CPG) into clinical practice remains limited. Using the Knowledge-To-Action framework, a guideline dissemination and implementation strategy for the Canadian Diabetes Association's 2013 CPG was developed and launched to clinicians and people with diabetes. METHODS: The RE-AIM framework guided evaluation of this strategy clinician; we report here one aspect of the effectiveness dimension using mixed methods. We measured impact of the strategy on clinican knowledge and behaviour change constructs using evaluation forms, national online survey and individual interviews. RESULTS: After attending a lecture, clinician confidence (n = 915) increased (3.7(SD 0.7) to 4.5 (SD 0.6) on a 5-point scale (p < 0.001)), with 55% (n = 505) intending to make a practice change (e.g. clinical management regarding glycemic control). Ninety-four percent of survey respondents (n = 907) were aware of the guidelines, attributed to communications from professional associations, continuing professional development events, and colleagues. Forty to 98% of respondents (total n 462-485) were correct in their interpretation of CPG messages, and 33-65%(total n 351-651) reported that they had made changes to their practice. Interviews with 28 clinicians revealed that organizational credibility, online access to tools, clarity of tool content, and education sessions facilitated uptake; lack of time, team-based consensus, and seamless integration into care and patient complexity were barriers. CONCLUSION: The complexity of diabetes care requires systemic adoption of organization of care interventions, including interprofessional collaboration and consensus. Augmenting our strategy to include scalable models for professional development, integration of guidelines into electronic medical records, and expansion of our target audience to include health care teams and patients, may optimize guideline uptake. PMID- 29626592 TI - Differences in fundamental and functional properties of HPMC co-processed fillers prepared by fluid-bed coating and spray drying. AB - This study aimed to develop novel co-processed tablet fillers based on the principle of particle engineering for direct compaction and to compare the characteristics of co-processed products obtained by fluid-bed coating and co spray drying, respectively. Water-soluble mannitol and water-insoluble calcium carbonate were selected as representative fillers for this study. Hydroxypropyl methylcellulose (HPMC), serving as a surface property modifier, was distributed on the surface of primary filler particles via the two co-processing methods. Both fundamental and functional properties of the products were comparatively investigated. The results showed that functional properties of the fillers, like flowability, compactibility, and drug-loading capacity, were effectively improved by both co-processing methods. However, fluid-bed coating showed greater advantages over co-spray drying in some aspects, which was mainly attributed to the remarkable differences in some fundamental properties of co-processed powders, like particle size, surface topology, and particle structure. For example, the more irregular surface and porous structure induced by fluid-bed coating could contribute to better compaction properties and lower lubricant sensitivity due to the increasing contact area and mechanical interlocking between particles under pressure. More effective surface distribution of HPMC during fluid-bed coating was also a contributor. In addition, such a porous agglomerate structure could also reduce the separation of drug and excipients after mixing, resulting in the improvement in drug loading capacity and tablet uniformity. In summary, fluid-bed coating appears to be more promising for co processing than spray drying in some aspects, and co-processed excipients produced by it have a great prospect for further investigations and development. PMID- 29626593 TI - Use of microreactors and freeze-drying in the manufacturing process of chitosan coated PCL nanoparticles. AB - This paper is focused on the synthesis of chitosan-coated polycaprolactone nanoparticles in microreactors and on the freeze-drying of the nanosuspension, to separate the particles from the liquid phase. Nanoparticles were produced in the confined impinging jets mixer (CIJM) and in the multi-inlet vortex mixer (MIVM), using the solvent displacement method, with acetone or tert-butanol (TBA) as polymer solvent. The study was initially carried out considering a feed flow rate of 80 ml min-1: using acetone, the mean particle size was lower (163 +/- 7 nm) and the Zeta potential was higher (31.4 +/- 37 mV) with the MIVM, with respect to the CIJM (265 +/- 31 nm and 9.8 +/- 2.4 mV, respectively). Slightly larger particles were obtained using TBA in the MIVM (mean diameter: 221 +/- 44 nm): in this case it is no longer required removing the solvent before the freeze-drying stage. The effect of the liquid flow rate was then investigated, confirming that the best results were obtained at 80 ml min-1. With respect to the freeze-drying process, the effect of lyoprotectants and of steric stabilizers on particle stability was investigated. Best results were obtained with 5% sucrose and 2.5% Poloxamer 388 (mean diameter: 306 +/- 8 nm); in all cases Zeta potential remained positive and larger than +30 mV. Preliminary results about the encapsulation of a test drug, ciprofloxacin, are also shown and discussed. PMID- 29626594 TI - Population pharmacokinetics of oxaliplatin after intraperitoneal administration with hyperthermia in Wistar rats. AB - BACKGROUND: The evaluation of the efficacy and toxicity of hyperthermic intraoperative peritoneal chemotherapy presents some difficulties, due in part to the lack of information about the pharmacokinetic behavior of the drugs administered in this procedure. The aim of this study was to characterize the population pharmacokinetics of hyperthermic intraoperative peritoneal oxaliplatin in Wistar rats and to evaluate the effect of treatment-related covariates dose, instillation time and temperature on the pharmacokinetic parameters. METHODS: Oxaliplatin peritoneal and plasma concentrations from 37 rats treated by either intravenous or intraperitoneal oxaliplatin administrations under different instillation times, temperatures and doses were analyzed according to a population pharmacokinetic approach using the software NONMEM V7.3(r). RESULTS: Intraperitoneal (n = 115) and plasma (n = 263) concentrations were successfully described according to a two-compartment model with first order absorption. No significant effect of dose, temperature and instillation time on pharmacokinetic parameters was found. However, an abrupt decrease in the elimination process was observed, reflected in the structural pharmacokinetic model through a modification in clearance. The typical parameters values and the interindividual variability (CV %) in clearance, central and peripheral volume of distribution were 3.25 mL/min (39.1%), 53.6 mL (37.8%) and 54.1 mL (77.3%), respectively. Clearance decreased to 0.151 mL/min (39.1%) when the instillation was still ongoing, at 31.4 min. One of the possible reasons behind the clearance decrease would be an alteration of renal function due to surgery and/or hyperthermia. CONCLUSIONS: This study described the deterioration of the drug elimination process due to the procedure, and estimated the time at which this deterioration is most likely to occur. In addition, dose, instillation time and temperature had no influence in the PK parameters. PMID- 29626595 TI - pH-sensitive release of insulin-loaded mesoporous silica particles and its coordination mechanism. AB - In this work, we investigated the feasibility of employing metal ion that coordinated with amino group grafted mesoporous silica as a pH-sensitive release carrier of insulin. Mesoporous silica particles were firstly grafted with amino groups. After coordination of metal ions onto the surface of mesoporous pore, insulin was loaded onto mesoporous silica particles through coordination bonds with metal ions. Insulin-loaded mesoporous silica particle with an acid sensitivity between the pH range of physiological environment (pH 7.4) and diabetic acidosis (pH 7.0) and with an insulin encapsulation rate of 74.50% was identified by investigating the influence factors of pH response value. The morphology of particles was confirmed by different analytical methods, indicating that insulin-loaded mesoporous silica particles maintained the rod-like and orderly hexagonal phase mesoporous structure. The coordination mechanism results showed that half of the amino groups on the carrier were coordinated with Cu2+, and insulin was successfully coordinated with Cu2+ without any damage on the secondary structure. The amount of insulin coordination with Cu2+ was positively correlated with the pH of the reaction solution. The cytotoxicity result shows that SBA15-NH2-Cu2+-Ins was biocompatible with cells in the concentration ranging from 25 to 100 MUg.mL-1. In vivo study preformed on rats showed that the insulin loaded particles elicited a period hypoglycemic response. Furthermore, fluorescence and UV methods revealed that insulin-loaded mesoporous silica particles had no significant effect on the secondary structure of serum albumin. PMID- 29626596 TI - Renal histology in a patient with TAFRO Syndrome: A case report. AB - An 84-year-old Japanese man was admitted due to anasarca, thrombocytopenia, systemic inflammation, and progressive renal insufficiency, resistant to diuretics, glucocorticoid therapy and plasma exchange. Renal biopsy showed diffuse endocapillary proliferation and mesangiolysis without any immune deposits. Tocilizumab suppressed systemic inflammation, resulting in improvement of anasarca and renal dysfunction, but thrombocytopenia persisted and platelet associated IgG antibody was elevated. Though romiplostim was effective for thrombocytopenia, the patient died of aspiration pneumonia after cerebral hemorrhage. Autopsy showed the hyaline vascular type Castleman's disease-like lymphadenopathy and reticulin myelofibrosis with an increase of megakaryocytes. Renal finding showed that endocapillary injury improved, and collapsed glomeruli was noted. This patient fitted the criteria of TAFRO (thrombocytopenia (T), anasarca (A), fever (F), reticulin myelofibrosis (R), and organomegaly (O)) syndrome. The clinical course suggests that two factors, including overproduction of interleukin-6 and autoimmune-mediated thrombocytopenia via thrombopoietin receptor, may have contributed to the pathogenesis of TAFRO syndrome in this patient. PMID- 29626597 TI - Placentas from women with pregnancy-associated venous insufficiency show villi damage with evidence of hypoxic cellular stress. AB - Lower extremity venous insufficiency (VI) is a complication of pregnancy. The potential association of this venous disease with structural damage of the placenta has not been described. We analyzed the pattern of histopathologic lesions and the gene and protein expression of HIF1-alpha and apoptosis regulatory proteins. A prospective study was carried out on placenta samples from 43 women with pregnancy-associated VI and 24 age-matched pregnant healthy controls (HCs). Women with VI showed a significant increase in the number of villi (150.77 +/- 42.55 VI versus 122.13 +/- 27.74 HC) and in syncytial knots compared with those found in the placentas from HCs (67.15 +/- 31.08 VI versus 42.49 +/- 17.36 HC), and an increase in the number of bridges (32.40 +/- 2.67 VI versus 22.73 +/- 2.37 HC; P < .05). The mean number of syncytial nodes per villus is 1.37 +/- 0.90 in the VI group and 0.49 +/- 0.58 in the HC group (P < .001). Significant increases in the expression of Bax and caspase-3 and caspase-9 in the placentas from women with VI were observed compared with those found in HC. The expression of HIF-1alpha at both the messenger RNA and protein levels was also significantly increased in the placentas from women with VI. Our study demonstrates that placentas from women with pregnancy-associated VI show structural remodeling, with an increase in the number of villi and syncytial knots and enhanced apoptotic cellular death. Interestingly, this placental damage is associated with an increased expression of hypoxia-triggered molecular pathways, such as HIF-1alpha. PMID- 29626598 TI - EWSR1-NFATC2 gene fusion in a soft tissue tumor with epithelioid round cell morphology and abundant stroma: a case report and review of the literature. AB - Mesenchymal round cell tumors are a diverse group of neoplasms defined by primitive, often high-grade cytomorphology. The most common molecular alterations detected in these tumors are gene rearrangements involving EWSR1 to one of many fusion partners. Rare EWSR1-NFATC2 gene rearrangements, corresponding to a t(20;22) gene translocation, have been described in mesenchymal tumors with clear round cell morphology and a predilection for the skeleton. We present a case of a tumor harboring the EWSR1-NFATC2 gene fusion arising in the subcutaneous tissue of a young woman. The tumor exhibited corded and trabecular architecture of epithelioid cells within abundant myxoid and fibrous stroma. The cells showed strong immunoreactivity for NKX2.2, variable CD99, keratin, and epithelial membrane antigen, but were negative for S100 and myoepithelial markers. Importantly, similar to previously reported cases, the clinical course was more indolent than that of Ewing sarcoma. This case highlights the distinctive clinicopathological characteristics of EWSR1-NFATC2 gene fusion-associated neoplasms that distinguish them from Ewing sarcoma. PMID- 29626599 TI - Expanding the Histomorphologic Spectrum of TFE3 Rearranged PEComas. AB - Perivascular epithelioid tumors (PEComas) are a family of mesenchymal neoplasms that have smooth muscle and melanocytic differentiation. They can be sporadic or associated with Tuberous Sclerosis Complex and commonly present in the kidney as angiomyolipoma or in the lung as pulmonary clear cell sugar tumors or lymphangioleiomyomatosis. However, they can present at any visceral or soft tissue site. They usually have a benign clinical course, but rarely can behave in a malignant fashion. Most PEComas demonstrate abnormalities of TSC2, but a recently described subset harbor TFE3 rearrangements that appear to be mutually exclusive of TSC2 alterations. TFE3 rearranged PEComas demonstrate a distinct alveolar morphology that lacks spindle cells and smooth muscle differentiation. Distinction between these may have important therapeutic consequences. Herein, we present a case of a TFE3 rearranged PEComa without the customary morphology that required ancillary investigation with TFE3 immunohistochemistry and break-apart fluorescence in-situ hybridization (FISH) for proper categorization. PMID- 29626600 TI - Oxime-functionalized cryogel disks for catalase immobilization. AB - Catalase is a protective enzyme against oxidative stress and converts hydrogen peroxide into water and molecular oxygen. In the current study, catalase immobilization was applied onto the oxime-functionalized cryogel disks. Cryogel disks were produced by free radical polymerization. After cutting as circular disks, oxime ligand (4-biphenylchloroglyoxime, BPCGO) was attached and oxime functionalized cryogel disks were obtained. After optimization of several immobilization parameters such as pH, initial catalase concentration, temperature and ionic strength, maximum catalase load was detected as 261.7 +/- 11.2mg/g for cryogel disk at pH5.0. Activity studies indicated that immobilization enhanced the enzyme activity in basic pH region, the temperature range of 15-35 degrees C and at ionic strengths between 0.2 and 1.0M NaCl. Km was detected as 9.9 and 11.0mM and Vmax was 357.1 and 769.2MUmol min-1 for free and immobilized catalase, respectively. kcat and Km/kcat values showed that immobilization enhanced the catalytic efficiency. Storage stability experiments demonstrated that immobilization increased the usability period. Furthermore, catalase desorption was achieved by 1.0M NaSCN at pH8.0 successfully and catalase adsorption capacity of oxime-functionalized cryogel disk was decreased by 9.9% at the end of 5 adsorption-desorption cycle. PMID- 29626601 TI - A new purified Lawsoniaside remodels amyloid-beta42 fibrillation into a less toxic and non-amyloidogenic pathway. AB - Mounting evidence indicates soluble Abeta42 oligomers as the most toxic species causing neuronal death which leads to the onset and progression of Alzheimer disease (AD). Recently, it has been found that neurotoxic Abeta42 oligomers grow from monomeric species or arise following secondary nucleation by preformed mature fibrils. Thus, the use of natural compounds such as polyphenols to hinder the growth or to remodel Abeta42 fibrils is one of the most promising strategies for AD treatment. In our previous study, we showed that 1, 2, 4 trihydroxynaphthalene-2-O-beta-d-glucopyranoside (THNG) inhibits Abeta42 aggregation during the early steps of the aggregation process, inhibits its conformational change to a beta-sheet-rich structure, decreases its polymerization, inhibits its fibrillogenisis and reduces oxidative stress and aggregate cytotoxicity. Here, we used different spectroscopic and cell culture methods to check the effect of THNG on fibrils disaggregation. We showed that THNG binds to mature Abeta42 fibrils, rearrange their secondary structure, and remodels them into non-amyloid, less toxic, species by inhibiting their interaction with the plasma membrane. Our findings reveal that THNG is a good agent to remodel amyloid fibrils and could be used as a starting molecular scaffold to design new anti-AD drugs. PMID- 29626602 TI - Protective properties of combined fungal polysaccharides from Cordyceps sinensis and Ganoderma atrum on colon immune dysfunction. AB - In vivo an ecological network of polysaccharides utilization by gut microbiota is not only an intense competition but also an impressive cooperation pattern. The present study evaluated the in vivo protective effect of combined fungal polysaccharides (CFP) from Cordyceps sinensis and Ganoderma atrum on colon immune dysfunction, induced by 150mg/kg cyclophosphamide (CP). The results showed that C. sinensis polysaccharides (CSP) significantly promoted microbial-derived butyrate to improve histone h3 acetylation mediating regulatory T (Treg) cell specific Foxp3, as well as significantly restored CP-induced elevation of interleukin (IL)-17 and IL-21. Additionally, G. atrum polysaccharides (PSG) significantly down-regulated MyD88, as well as significantly increased IL-10 and TGF-beta3. Furthermore, CFP balanced the disequilibrium of cytokines secretion and Foxp3/RORgammat ratio related Treg/T helper 17 (Th17) balance, as well as down-regulated the TLR-mediated inflammatory signaling pathway and promoted secretory immunoglobulin A (sIgA) secretion to suppress colonic inflammation. Therefore, our results typically contribute to understand the in vivo immunoregulatory function of fungal polysaccharides compounds, involving microbial-associated inflammatory signals and specific metabolic products. PMID- 29626603 TI - Peroxidase from jackfruit: Purification, characterization and thermal inactivation. AB - Peroxidase (POD) from jackfruit bulb was purified using ammonium sulfate precipitation, hydrophobic interaction and gel filtration columns. The POD was a dimer with a molecular weight of 104kDa. The Km and Vmax values for guaiacol, gallic acid and o-phenylenediamine (OPD) were estimated. OPD was the most suitable substrate. The enzyme showed its maximum activity at pH5.5 and 55-60 degrees C. The activation energy (Ea) of heat inactivation was estimated to be 206.40kJ/mol. The enthalpy, free energy and entropy values for the thermal inactivation were also determined. The POD activity was enhanced by K+, Zn2+, Ba2+, citric acid, malic acid, benzoic acid and EDTA.Na2, but inhibited by Cu2+, Ca2+, glutathione, cysteine and ascorbic acid. Chemical modification indicated a histidine residue was located in the enzyme active site. The POD activity in fruit extracts significantly decreased when heated at 80 degrees C and 90 degrees C. The ferric-reducing antioxidant power, ABTS radical scavenging activity and total phenolics decreased with increasing heating temperature and time. PMID- 29626604 TI - Transgenerational effects of paternal dietary Astragalus polysaccharides on spleen immunity of broilers. AB - Our previous study indicated that paternal dietary Astragalus polysaccharides (APS) could induce endotoxin tolerance-like response in jejunum of offspring chickens. There exist positive interaction between intestinal mucosal immunity and systemic immunity. So we studied the transgenerational effect and nutri epigenetic role of paternal dietary APS on spleen immunity. 64 one-day-old Avein breeder cocks were used in a single-factor design with 0 and 10g/kg APS, respectively, 4 replicated cages each group, and 8 birds each cage. When the breeder cocks at 40-week-age, semen of cocks was collected and used for hatching experiment to get broiler chickens. The paternal dietary APS could transgenerational up-regulated the serum type-I-interferon level of offspring chickens. In spleen of breeder cocks, the dietary APS didn't have any systematic effect on genes transcription. Whereas, the paternal dietary APS supplementation could induce endotoxin tolerance-like immune response (TLR4 pathway) in spleen of broiler chickens. But the APS had no significant effect on transcription of ET related regulators and promotor methylation of core regulators (TRIF, MyD88, and SOCS1). This means that the paternal dietary APS can transgenerational induce endotoxin tolerance-like immune response in spleen, and the fundamental cause of the this response might lies on its effect on intestinal mucosal immunity. PMID- 29626605 TI - Mechanisms of selenium hyperaccumulation in plants: A survey of molecular, biochemical and ecological cues. AB - BACKGROUND: Selenium (Se) is a micronutrient required for many life forms, but toxic at higher concentration. Plants do not have a Se requirement, but can benefit from Se via enhanced antioxidant activity. Some plant species can accumulate Se to concentrations above 0.1% of dry weight and seem to possess mechanisms that distinguish Se from its analog sulfur (S). Research on these so called Se hyperaccumulators aims to identify key genes for this remarkable trait and to understand ecological implications. SCOPE OF REVIEW: This review gives a broad overview of the current knowledge about Se uptake and metabolism in plants, with a special emphasis on hypothesized mechanisms of Se hyperaccumulation. The role of Se in plant defense responses and the associated ecological implications are discussed. MAJOR CONCLUSIONS: Hyperaccumulators have enhanced expression of S transport and assimilation genes, and may possess transporters with higher specificity for selenate over sulfate. Genes involved in antioxidant reactions and biotic stress resistance are also upregulated. Key regulators in these processes appear to be the growth regulators jasmonic acid, salicylic acid and ethylene. Hyperaccumulation may have evolved owing to associated ecological benefits, particularly protection against pathogens and herbivores, and as a form of elemental allelopathy. GENERAL SIGNIFICANCE: Understanding plant Se uptake and metabolism in hyperaccumulators has broad relevance for the environment, agriculture and human and animal nutrition and may help generate crops with selenate-specific uptake and high capacity to convert selenate to less toxic, anticarcinogenic, organic Se compounds. PMID- 29626606 TI - Curcumin provides neuroprotection in model of traumatic brain injury via the Nrf2 ARE signaling pathway. AB - Curcumin has been found to play the protective role in many neurological disorders, however, its roles and the underlying molecular mechanisms in traumatic brain injury (TBI) are not fully understood. The aim of this study was to investigate the potential neuroprotection of curcumin and the possible role of Nrf2-ARE pathway in the weight-drop model of TBI. The administration of curcumin (100 mg/kg, i.p.) significantly ameliorated secondary brain injury induced by TBI, such as brain water content, oxidative stress, neurological severity score, and neuronal apoptosis. Curcumin possessed anti-apoptotic character evidenced by elevating Bcl-2 content and reducing that of cleaved caspase-3. Moreover, curcumin markedly enhanced the translocation of Nrf2 from the cytoplasm to the nucleus, proved by the results of western blot and immunofluorescence, subsequently increased the expression of downstream factors such as heme oxygenase 1 (HO1) and NAD(P)H: quinone oxidoreductase 1 (NQO1) and prevented the decline of antioxidant enzyme activities. In conclusion, curcumin could increase the activities of antioxidant enzymes and attenuate brain injury in the model of TBI, possibly via the activation of the Nrf2-ARE pathway. PMID- 29626607 TI - Prevalence, clinical characteristics and long-term outcomes of classical 11 beta hydroxylase deficiency (11BOHD) in Turkish population and novel mutations in CYP11B1 gene. AB - : Congenital adrenal hyperplasia (CAH) due to 11beta-hydroxylase deficiency (11BOHD) is a rare autosomal recessive disorder and the second most common form of CAH. AIM: To investigate genotype-phenotype correlation and to evaluate clinical characteristics and long-term outcomes of patients with 11BOHD. METHODS: A total of 28 patients (n = 14, 46,XX; n = 14, 46,XY) with classical 11BOHD from 25 unrelated families were included in this study. Screening of CYP11B1 is performed by Sanger sequencing. Pathogenic features of novel variants are investigated by the use of multiple in silico prediction tools and with family based co-segregation studies. Protein simulations were investigated for two novel coding region alterations. RESULTS: The age at diagnosis ranged from 6 days to 12.5 years. Male patients received diagnose at older ages than female patients. The rate of consanguinity was high (71.4%). Five out of nine 46,XX patients were diagnosed late (age 2-8.7 years) and were assigned as male due to severe masculinization. Twenty one patients have reached adult height and sixteen were ultimately short due to delayed diagnosis. Two male patients had testicular microlithiasis and 5 (35.7%) patients had testicular adrenal rest tumor during follow up. Four patients (28.6%) had gynecomastia. Mutation analyses in 25 index patients revealed thirteen different mutations in CYP11B1 gene, 4 of which were novel (c.393 + 3A > G, c.428G > C, c.1398 + 2T > A, c.1449_1451delGGT). The most frequent mutations were c.896T > C with 32%, c.954G > A with 16% and c.1179_1180dupGA with 12% in frequency. There was not a good correlation between genotype and phenotype; phenotypic variability was observed among the patients with same mutation. CONCLUSION: This study presents the high allelic heterogeneity of CYP11B1 mutations in CAH patients from Turkey. Three dimensional protein simulations may provide additional support for the pathogenicity of the genetic alterations. Our results provide reliable information for genetic counseling, preventive and therapeutic strategies for the families. PMID- 29626608 TI - Regulation and function of runt-related transcription factors (RUNX1 and RUNX2) in goat granulosa cells. AB - Transcription factors, runt-related transcription factor 1 (RUNX1) and 2 (RUNX2), belong to the runt-related (RUNX) gene family and play critical roles in mammalian reproduction processes. However, the regulatory mechanisms of RUNX1 and RUNX2 expression or their functions in goat follicles remain largely unknown. Herein, RUNX1 and RUNX2 proteins were detected in the oocytes and granulosa cells of preantral and antral follicles, as well as corpus luteum by immunohistochemistry. Treatments with human chorionic gonadotropin (hCG) or with the agonists and inhibitors of hCG-induced intracellular signaling pathways in granulosa cells in vitro, we found that hCG increased RUNX1 expression by activating PKC and PI3K signaling molecules, and increased RUNX2 expression by activating adenylate cyclase, PKC, and PI3K signaling molecules. We also demonstrated that miR-181b expression is dependent on the hCG-induced activation of PKC and PKA, and miR-222 expression is dependent on the hCG-induced activation of PI3K and PKC in cultured granulosa cells. Meanwhile, miR-181b and miR-222 suppressed RUNX1 and RUNX2 expression by targeting RUNX1 and RUNX2 3' untranslated regions (3'UTRs) with or without hCG, respectively. These results suggested that hCG-mediated miR-181b and miR-222 expression are important for the regulation of RUNX1 and RUNX2 expression levels in granulosa cells. To explore the specific functions of RUNX1 and RUNX2, we transfected RUNX1 and RUNX2 small interfering RNAs into primary cultured granulosa cells. Knockdown of RUNX1 and RUNX2 significantly decreased progesterone productions and the mRNA abundance of key steroidogenic enzymes (StAR, CYP11A1 and HSD3B) after hCG treatment. But only miR-222 increased estradiol secretion in goat granulosa cells. In addition, knockdown of RUNX1 and RUNX2 also promoted granulosa cell proliferation. The hormonally regulated expression of RUNX1 and RUNX2 in granulosa cells, their involvement in progesterone production, and promoted granulosa cell proliferation suggest important roles of RUNX1 and RUNX2 in follicular development and luteinization. PMID- 29626609 TI - Homozygous LAMC3 mutation links to structural and functional changes in visual attention networks. AB - The occipital lobe contains a substantial part of the neural machinery involved in visual perception. Mutations in the LAMC3 gene have recently been shown to cause complex bilateral occipital cortical gyration abnormalities. However, to what extent these structural changes impact visual behavior is not known. We recorded responses for two screening test batteries targeting visual function (Leuven - Perceptual Organization Screening Test, Cortical Vision Screening Test) and measured eye fixation performance in a visual attention experiment from a patient with homozygous LAMC3 gene mutation. Using voxel-based morphometry (VBM) we quantitatively assessed the extent of structural changes brought on by the genetic mutation by comparing mean cortical curvature, cortical thickness, and gray matter volume in 34 cortical areas between patient and an age-, sex-, and education-matched control group. Anatomical connectivity between these cortical areas was investigated by a structural covariance analysis. Visual screening-, and behavioral results revealed that the patient's impairments were predominantly in visuo-spatial attention. Consistent with this, VBM and structural connectivity results revealed significant structural changes in cortical regions subserving attentional functions. We conclude that the LAMC3 gene mutation affects cortical areas beyond the occipital lobe and primarily those visual functions that involve heavily distributed networks - such as visuo-spatial attention. PMID- 29626610 TI - Health related quality of life after extracorporeal cardiopulmonary resuscitation in refractory cardiac arrest. AB - BACKGROUND: Recent data identifies extracorporeal cardio-pulmonary resuscitation (eCPR) as a potential addendum of conventional cardiopulmonary-resuscitation (cCPR) in highly specified circumstances and selected patients. However, consented criteria indicating eCPR are lacking. Therefore we provide first insights into the health-related quality of life (HRQoL) outcomes of patients treated with eCPR in a real world setting. METHODS: Retrospective single-center experience of 60 consecutive patients treated with eCPR between 01/2014 and 06/2016 providing 1-year survival- and HRQoL data obtained through the Short-Form 36 Survey (SF-36) after refractory out-of-hospital- (OHCA) and in-hospital cardiac arrest (IHCA) of presumed cardiac etiology. RESULTS: Resuscitation efforts until initiation of eCPR averaged 66 +/- 35 min and 63.3% of the patients suffered from OHCA. Fifty-five (91.7%) of the overall events were witnessed and bystander-CPR was performed in 73.3% (n = 44) of cases. Cause of arrest was dominated by acute myocardial infarction (AMI, 66.7%) and initial rhythm slightly outbalanced by ventricular fibrillation/tachycardia (VF/VT 53.3%). 12-month survival was 31%. Survivors experienced more often bystander-CPR (p = .001) and a shorter duration of cCPR (p = .002). While mid-term survivors' perceived HRQoL was compromised compared to controls (p ? .0001 for PF, RP, RE and BP; p = .007 for GH; p = .016 for SF; p = .030 for MH; p = .108 for VT), scores however resembled HRQoL of subjects on hemodialysis, following cardiogenic shock or pulmonary failure treated with extracorporeal membrane oxygenation (ECMO). CONCLUSIONS: While HRQoL scores of our survivors ranged markedly below controls, compared to patients on chronic hemodialysis, following ECMO for cardiogenic shock or pulmonary failure most of the discrepancies ameliorated. Thus, successfull eCPR in properly selected patients does translate into an encouraging HRQoL approximating chronic renal failure. PMID- 29626612 TI - Genicular Radiofrequency Ablation for the Treatment of Post-traumatic Knee Pain: A Case Presentation. AB - This is the first reported case presentation utilizing cooled genicular radiofrequency ablation (C-RFA) for the treatment of post-traumatic knee pain. The patient is a 29-year-old man who sustained open right femoral and tibial fractures following 2 motor vehicle collisions. He was deemed too young to undergo total knee arthroplasty by orthopedic surgery. It was recommended he trial diagnostic genicular nerve blocks followed by C-RFA. The procedure provided a >50% reduction in average pain with an increase in activity tolerance lasting 9 months. In this case, C-RFA of the genicular nerves was a safe, effective, and durable treatment modality for post-traumatic knee pain. LEVEL OF EVIDENCE: V. PMID- 29626611 TI - Preliminary observations in systemic oxygen consumption during targeted temperature management after cardiac arrest. AB - AIM: Limited data suggests low oxygen consumption (VO2), driven by mitochondrial injury, is associated with mortality after cardiac arrest. Due to the challenges of measurement in the critically ill, post-arrest metabolism remains poorly characterized. We monitored VO2, carbon dioxide production (VCO2) and the respiratory quotient (RQ) in post-arrest patients and explored associations with outcome. METHODS: Using a gas exchange monitor, we measured continuous VO2 and VCO2 in post- arrest patients treated with targeted temperature management. We used area under the curve and medians over time to evaluate the association between VO2, VCO2, RQ and the VO2:lactate ratio with survival. RESULTS: In 17 patients, VO2 in the first 12 h after return of spontaneous circulation (ROSC) was associated with survival (median in survivors 3.35 mL/kg/min [2.98,3.88] vs. non-survivors 2.61 mL/kg/min [2.21,2.94], p = .039). This did not persist over 24 h. The VO2:lactate ratio was associated with survival (median in survivors 1.4 [IQR: 1.1,1.7] vs. non-survivors 0.8 [IQR: 0.6,1.2] p < 0.001). Median RQ was 0.66 (IQR 0.63,0.70) and 71% of RQ measurements were <0.7. Patients with initial RQ < 0.7 had 17% survival versus 64% with initial RQ > 0.7 (p = .131). VCO2 was not associated with survival. CONCLUSIONS: There was a significant association between VO2 and mortality in the first 12 h after ROSC, but not over 24 h. Lower VO2: lactate ratio was associated with mortality. A large percentage of patients had RQs below physiologic norms. Further research is needed to explore whether these parameters could have true prognostic value or be a potential treatment target. PMID- 29626613 TI - Comparing the Effects of Dual-Task Gait Testing in New and Established Ambulators With Lower Extremity Amputations. AB - BACKGROUND: Gait is a complex process that involves coordinating motor and sensory systems through higher-order cognitive processes. Walking with a prosthesis after lower extremity amputation challenges these processes. However, the factors that influence the cognitive-motor interaction in gait among lower extremity amputees has not been evaluated. To assess the interaction of cognition and mobility, individuals must be evaluated using the dual-task paradigm. OBJECTIVE: To investigate the effect of etiology and time with prosthesis on dual task performance in those with lower extremity amputations. DESIGN: Cross sectional study. SETTING: Outpatient and inpatient amputee clinics at an academic rehabilitation hospital. PARTICIPANTS: Sixty-four individuals (aged 58.20+/-12.27 years; 74.5% male) were stratified into 3 groups; 1 group of new prosthetic ambulators with transtibial amputations (NewPA) and 2 groups of established ambulators: transtibial amputations of vascular etiology (TTA-vas), transtibial amputations of nonvascular etiology (TTA-nonvas). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Time to complete the L Test measured functional mobility under single and dual-task conditions. A serial arithmetic task (subtraction by 3s) was paired with the L Test to create the dual-task test condition. Single task performance on the cognitive arithmetic task was also recorded. Dual-task costs (DTCs) were calculated for performance on the cognitive and gait tasks. Analysis of variance determined differences between groups. A performance resource operating characteristic (POC) graph was used to graphically display DTCs. RESULTS: Gait performance was worse under dual-task conditions for all groups. Gait was significantly slower under dual-task conditions for the TTA-vas (P < .001), TTA-nonvas (P < .001), and NewPA groups (P < .001). However, there was no between-group difference for gait DTC. The 3 groups tested did not differ in the amount of cognitive DTC (DTCcog). Dual-task conditions also had a negative impact on cognitive task performance for the TTA-nonvas (P = .02) and NewPA groups (P < .001). The TTA-vas group had a slight improvement during dual-task conditions and has a positive DTCcog as a result (P = .04). However, no between group differences were seen for DTCcog. The POC graph demonstrated that many individuals had a decrease in performance on both tasks; however, the gait task was prioritized for the majority (56.2%) of participants. CONCLUSIONS: Cognitive distractions while walking pose challenges to individuals regardless of etiology, level of amputation, or time with the prosthesis. These findings highlight that individuals are at risk for adverse events when performing multiple tasks while walking. LEVEL OF EVIDENCE: II. PMID- 29626614 TI - Effects of Whole Body Vibration on Tibia Strength and Structure of Competitive Adolescent Swimmers: A Randomized Controlled Trial. AB - BACKGROUND: Swimming has no effect on bone mass or structure. Therefore, adolescent swimmers present similar bone strength values when compared to normo active controls, and lower values when compared to weight-bearing athletes. It thus seems necessary to try to improve bone structure and strength of adolescent swimmers through a weight-bearing intervention in order to reduce the risk of suffering osteoporosis later in life. OBJECTIVE: To evaluate the effects of a 6 month whole body vibration (WBV) intervention on bone strength and structure of adolescent swimmers. DESIGN: Randomized controlled trial. SETTING: Research center. PARTICIPANTS: A total of 51 swimmers (14.4 +/- 2.0 years) participated in the study. METHODS: Swimmers were randomly allocated into 2 groups: 20 swimmers (9 females) who only performed their swimming training, and 31 swimmers (15 females) who performed their swimming training and received a WBV intervention (3.6-11.6 g) 3 times per week during 6 months (VIB). OUTCOME MEASUREMENTS: Peripheral quantitative computed tomography was performed in the nondominant tibia of all swimmers at 4%, 38%, and 66% of the tibia length before and after the intervention. RESULTS: No differences between groups in any bone structure variable were found at pre- or postintervention. Both groups presented similar improvements in time, and no group by time interactions were found, suggesting that the WBV intervention was not intense enough to achieve positive changes in bone strength or structure. CONCLUSION: WBV, at the chosen intensities and durations, had no effect on adolescent swimmers' bone strength or structure. Future studies should test other weight-bearing interventions aiming to improve bone strength and structure of adolescent swimmers. LEVEL OF EVIDENCE: II. PMID- 29626615 TI - Comparative Sonographic and Magnetic Resonance Images of an Acute Pronator Teres Full-Thickness Tear. PMID- 29626616 TI - Benefits of Hippotherapy and Horse Riding Simulation Exercise on Healthy Older Adults: A Systematic Review. AB - OBJECTIVE: To provide an up-to-date research analysis on equine-assisted therapies and horse riding simulation exercise in older adults, and to suggest future directions in clinical practice and research. TYPE: Systematic review. LITERATURE SURVEY: A comprehensive search of studies was performed in 4 electronic databases (Cochrane, PubMed, PEDro, and Web of Science) regarding the effects of equine-assisted therapies and horse riding simulation exercise in older adults. Eight articles were selected, 5 of them focused on hippotherapy, 2 on horse riding simulation, and a single article that used the 2 types of therapy. METHODOLOGY: PRISMA guidelines were followed for the data extraction process. SYNTHESIS: The studies were all randomized controlled trials, but not double-blind, so they were classified as level of evidence B. Duration of hippotherapy programs ranged from 8-12 weeks. Sessions lasted between 15 and 60 minutes and were performed 2-5 times per week. Interventions using a horse simulator spanned 8 weeks and were conducted for 20 minutes 5 times per week. CONCLUSIONS: Results indicate that hippotherapy might improve balance, mobility, gait ability, and muscle strength, as well as could induce hormonal and cerebral activity changes in healthy older adults. Benefits of horse riding simulation could be limited to physical fitness and muscular activity. LEVEL OF EVIDENCE: I. PMID- 29626617 TI - Dynamic Sonographic Visualization of an Occult Posterior Lateral Meniscocapsular Separation: A Case Report. AB - Meniscocapsular separation describes detachment of the meniscus from the knee joint capsule. Diagnosis is challenging with conventional examination and imaging methods. We report a case of an 18-year-old female softball catcher with unrevealing magnetic resonance imaging despite continued left knee locking and discomfort with deep squatting. Meniscocapsular separation was revealed only on dynamic sonographic examination, where knee flexion revealed a 3.1-mm gap that developed between the capsule and peripheral meniscus. Arthroscopy confirmed the sonographic findings, and repair resulted in complete resolution of symptoms. This case highlights the utility of dynamic diagnostic sonography in a rare case of posterior lateral meniscocapsular separation. LEVEL OF EVIDENCE: V. PMID- 29626618 TI - Comparative activity of silver-based antimicrobial composites for urinary catheters. AB - Biomedical polymers are an integral component in a wide range of medical devices because of their many desirable properties. However, extensive use of polymer materials in medical devices has been associated with an increasing incidence of patient infections. Efforts to address this issue have included incorporating antimicrobial additives to develop novel antimicrobial polymeric materials. Silver, with its high toxicity towards bacteria, oligodynamic effect and good thermal stability, has been employed as an additive for polymeric medical devices. In the present study, commercially available elemental (Biogate) and ionic (Ultrafresh 16) silver additives were incorporated into a Polyamide 11 (PA 11) matrix using a compression press. These polymer composites were evaluated for their antimicrobial and ion-release properties. Elemental silver composites were shown to retain their antimicrobial properties for extended periods and actively released silver ions for 84 days; whereas ionic silver composites lost their ion release activity and, therefore, their antibacterial activity after 56 days. Bacterial log reduction units of 3.87 for ionic silver and 2.41 for elemental silver were identified within 24 h, when tested in accordance with the ISO 22196 test standard; this indicates that ionic silver is more efficient for short-term applications than elemental silver. PMID- 29626619 TI - Localization of Pulmonary Ground-Glass Opacities with Folate Receptor-Targeted Intraoperative Molecular Imaging. AB - PURPOSE: Intraoperative localization and resection of ill-defined pulmonary ground-glass opacities (GGOs) during minimally invasive pulmonary resection is technically challenging. Current preoperative techniques to facilitate localization of GGOs include microcoil and hook wire placement, both of which have logistic limitations, carry safety concerns, and do not help with margin assessment. In this clinical trial, we explored an alternative method involving near-infrared molecular imaging with a folate receptor-targeted agent, OTL38, to improve localization of GGOs and confirmation of resection margins. METHODS: In a human trial, 20 subjects with pulmonary GGOs who were eligible for video-assisted thoracoscopic surgery (VATS) resection received 0.025 mg/kg of OTL38 before the resection. The primary objectives were to (1) determine whether use of OTL38 allows safe localization of GGOs and assessment of margins during VATS and (2) determine patient, radiographic, and histopathologic variables that predict the amount of fluorescence during near-infrared imaging. RESULTS: We observed no toxicity. Of the 21 GGOs, 20 accumulated OTL38 and displayed fluorescence upon in situ or back table evaluation. Intraoperatively, near-infrared imaging localized 15 of 21 lesions whereas VATS alone localized 10 of 21 (p = 0.05). The addition of molecular imaging affected care of nine of 21 subjects by improving intraoperative localization (n = 6) and identifying close margins (n = 3). This approach was most effective for subpleural lesions measuring less than 2 cm. For lesions deeper than 1.5 cm from the pleural surface, intraoperative localization using fluorescent feedback was limited. CONCLUSIONS: This approach provides a safe alternative for intraoperative localization of small, peripherally located pulmonary lesions. In contrast to alternative localization techniques, use of OTL38 also allows confirmation of adequate margins. Future studies will compare this approach to alternative localization techniques in a clinical trial. PMID- 29626620 TI - Genetic Contribution to Nonsquamous, Non-Small Cell Lung Cancer in Nonsmokers. AB - INTRODUCTION: Lung carcinogenesis is strongly influenced by environmental and heritable factors. The genetic contribution to the different histologic subtypes is unknown. METHODS: A population-based computerized genealogy resource linked to a statewide cancer registry of lung cancer cases (N = 5408) was analyzed to evaluate the heritable contribution to lung cancer histologic subtype in smokers (n = 1751) and nonsmokers (n = 818). Statistical methods were used to test for significant excess relatedness of lung cancer cases. RESULTS: Significant excess distant relatedness was observed for all lung cancer histologic subgroups analyzed except for the SCLC subset (p = 0.213). When histologic subsets of smokers and nonsmokers with lung cancer were considered, excess relatedness was observed only in nonsmokers with NSCLC (n = 653 [p = 0.026]) and, in particular, in those nonsmokers with the nonsquamous histologic subtype (n = 561 [p = 0.036]). A total of 61 pedigrees demonstrating a significant excess risk of nonsquamous lung cancer in nonsmokers were identified, and an excess of cases in females was observed among the individuals with these high-risk pedigrees. CONCLUSIONS: This analysis supports a genetic predisposition to lung cancer carcinogenesis in nonsmokers with nonsquamous NSCLC. PMID- 29626621 TI - First-in-Human Phase I Study of AC0010, a Mutant-Selective EGFR Inhibitor in Non Small Cell Lung Cancer: Safety, Efficacy, and Potential Mechanism of Resistance. AB - INTRODUCTION: AC0010 is a mutation-selective, third-generation EGFR tyrosine kinase inhibitor (TKI). This aim of this first-in-human phase I trial was to determine the maximum tolerated dose, recommended phase II dose, schedule, safety, pharmacokinetics, pharmacodynamics, and antitumor activity of AC0010 in patients with advanced or recurrent NSCLC and acquired resistance to a first generation EGFR TKI. METHODS: Patients received escalating daily doses of AC0010 (50-600 mg) throughout 28-day cycles. A modified three-plus-three design was applied. Patients with EGFR T790M mutation were selected by dose expansion. Next generation sequencing of plasma cell-free DNA was performed before and after treatment to determine mechanisms of anticancer activity and underlying acquired resistance. RESULTS: Data from 52 patients were reported. Common treatment emergent adverse events were diarrhea (75%), skin rash (48%), and increased alanine transaminase level (44%); adverse events of grade 3 or higher were seen for increased transaminase level (12%) and skin rash (4%). The maximum tolerated dose was not reached. When all evaluated doses and patients negative for T790M were included, the overall response rate was 36.5%. At daily doses of 350 mg or higher, the overall response rate was 50.0% and the median progression-free survival estimated by the Kaplan-Meier method ranged from 14.0 to 35.6 weeks across a daily dose level from 350 mg to 600 mg. On the basis of pharmacokinetics data analysis, twice-daily administration is recommended and 300 mg twice daily is suggested as the recommended phase II dose. The cell-free DNA sequencing results from 17 patients indicate that T790M allele frequency decreased significantly after treatment with AC0010 (from 2.24 at baseline to 0 with a partial response or stable disease [p < .001]). In patients with development of resistance to AC0010, BRAF V600E mutation, ROS1 fusion, MNNG HOS Transforming gene (c-Met), and erb-b2 receptor tyrosine kinase 2 gene (ERBB2) amplification were detected but EGFR C797S mutation was not detected. CONCLUSIONS: AC0010 had a well-tolerated safety profile and promising antitumor activity in patients with NSCLC with acquired resistance to a first-generation EGFR TKI, supporting its continued development. PMID- 29626622 TI - Bacteroides fragilis: A whole MALDI-based workflow from identification to confirmation of carbapenemase production for routine laboratories. AB - Bacteroides fragilis is a frequent anaerobic pathogen and can cause severe infections. Resistance to carbapenems, associated with the cfiA gene encoded carbapenemase, represents an emerging problem. To date, no rapid methods are available to detect and confirm this resistance mechanism in routine laboratories, and the missed recognition of carbapenemase-producing strains can lead to therapeutic failures. In this study we have investigated a whole MALDI TOF MS-based workflow to detect carbapenemase-producing B. fragilis, using the largest set of B. fragilis clinical isolates ever tested. The presence of the cfiA gene was predicted by MALDI subtyping into Division I (cfiA-negative) or Division II (cfiA-positive). The carbapenemase activity in cfiA-positive strains was confirmed by a MALDI-TOF MS imipenem hydrolysis assay (MBT STAR-Carba, Bruker Daltonik, Germany), that was further used for a characterization of the strains in terms of cfiA expression level. The validity of MALDI subtyping was verified by PCR for the cfiA gene, while results of MALDI hydrolysis assay were compared to conventional methods for susceptibility testing and carbapenemase detection (Carba-NP and disk diffusion synergy test). A genetic analysis of the IS elements upstream cfiA was performed, for the evaluations regarding the expression level of cfiA. A total of 5300 B. fragilis isolates (406 from Bologna, Italy, and 4894 from Dortmund, Germany) were identified and subtyped by MALDI-TOF MS, yielding 41/406 (10.1%) strains from Bologna and 374/4894 (7.6%) from Dortmund to belong to Division II. Molecular verification by PCR for the cfiA gene on a subset of strains confirmed the MALDI typing results in all cases (sensitivity and specificity of 100%). MBT STAR-Carba assay detected the carbapenemase activity in all of the 70 cfiA-carrying strains tested. Moreover, it allowed distinct separation into slow (59) and fast (11) imipenem hydrolyzers corresponding to cfiA expression levels as well as to low or high MICs for carbapenems, respectively. Among the 11 cfiA-positive strains with high carbapenem MIC, only 7 harboured IS elements upstream the carbapenemase gene showing low expression level as well. The MALDI-TOF MS-based workflow was superior to the currently available phenotypic methods for carbapenemase detection as it proved to be more sensitive and accurate than Carba NP and disk diffusion synergy test. The whole MALDI-TOF MS-based workflow allows an accurate identification of B. fragilis clinical strains with reliable classification into Division I/II, and confirmation of the carbapenemase-production, together with estimation of carbapenemase activity, within less than 2 h. This may be of particular interest for early therapeutical decisions in life-threatening infections. PMID- 29626623 TI - MALDI-TOF MS in Anaerobiospirillum succiniciproducens bacteremia: A report of 4 cases in different hosts. AB - Anaerobiospirillum succiniciproducens is known as an uncommon cause of diarrhea and bacteremia in humans, usually in immunocompromised hosts. We report four cases of A. succiniciproducens bloodstream infection in different hosts, including a previously healthy man. We describe clinical features, antibiotics susceptibility profile, treatment and outcomes. Strains were identified by 16S rRNA gene sequences which contributed to the extension of our MALDI-TOF MS database. PMID- 29626624 TI - Trichodermadiones A and B from the solid culture of Trichoderma atroviride S361, an endophytic fungus in Cephalotaxus fortunei. AB - Chemical investigation on the solid rice culture of Trichoderma atroviride S361, an endophyte isolated from Cephalotaxus fortunei, has afforded a pair of novel N furanone amide enantiomers, (-)-trichodermadione A (1a) and (+)-trichodermadione A (1b), and a new cyclohexenone sesquiterpenoid, trichodermadione B (2), together with six known secondary metabolites. Chiral separation of compound 1 was successfully performed on a Lux Cellulose-2 column. Their structures were elucidated by detailed spectroscopic analyses on the basis of NMR, HRMS, and ECD data, and the absolute configurations of the new compounds were determined by computational analyses of their electronic circular dichroism (ECD) spectra and Snatzke's method. Compounds 1a, 1b and 2 were also evaluated for their cytotoxicity against DU145 and PC3 cell lines, as well as inhibitory effects against the production of NO in LPS-stimulated RAW264.7 cells. PMID- 29626625 TI - Informed consent to research trials on Alzheimer's disease: How to foster research without infringing upon the patient's right to self-determination. PMID- 29626626 TI - Proteomics study of silver nanoparticles on Caco-2 cells. AB - Silver nanoparticles (AgNPs) have been incorporated into several consumer products. While these advances in technology are promising and exciting, the effects of these nanoparticles have not equally been studied. Due to the size, AgNPs can penetrate the body through oral exposure and reach the gastrointestinal tract. The present study was designed as a comparative proteomic analysis of Caco 2 cells, used as an in vitro model of the small intestine, exposed to 30 nm citrate stabilized-silver nanoparticles (AgNPs) for 24 or 72 h. Using two complementary proteomic approaches, 2D gel-based and label-free mass spectrometry, we present insight into the effects of AgNPs at proteins level. Exposure of 1 or 10 MUg/mL AgNPs to Caco-2 cells resulted in 56 and 88 altered proteins at 24 h and 72 h respectively, by 2D gel-based technique. Ten of these proteins were found to be common between the two time-points. Using label-free mass spectrometry technique, 291 and 179 altered proteins were found at 24 h and 72 h, of which 24 were in common. Analysis of the proteomes showed several major biological processes altered, from which, cell cycle, cell morphology, cellular function and maintenance were the most affected. PMID- 29626627 TI - Tangeretin inhibits the proliferation of human breast cancer cells via CYP1A1/CYP1B1 enzyme induction and CYP1A1/CYP1B1-mediated metabolism to the product 4' hydroxy tangeretin. AB - Tangeretin is a polymethoxylated flavone with multifaceted anticancer activity. In the present study, the metabolism of tangeretin was evaluated in the CYP1 expressing human breast cancer cell lines MCF7 and MDA-MB-468 and in the normal breast cell line MCF10A. Tangeretin was converted to 4' OH tangeretin by recombinant CYP1 enzymes and by CYP1 enzymes expressed in MCF7 and MDA-MB-468 cells. This metabolite was absent in MCF10A cells that did not express CYP1 enzymes. Tangeretin exhibited submicromolar IC50 (0.25 +/- 0.15 MUM) in MDA-MB 468 cells, whereas it was less active in MCF7 cells (39.3 +/- 1.5 MUM) and completely inactive in MCF10A cells (>100 MUM). In MDA-MB-468 cells that were coincubated with the CYP1 inhibitor acacetin, an approximately 70-fold increase was noted in the IC50 (18 +/- 1.6 MUM) of tangeretin. In the presence of the CYP1 inhibitor acacetin, the conversion of tangeretin to 4' OH tangeretin was significantly reduced in MDA-MB-468 cells (2.55 +/- 0.19 MUM vs. 6.33 +/- 0.12 MUM). The mechanism of antiproliferative action involved cell cycle arrest at the G1 phase for MCF7 and MDA-MB-468 cells. Tangeretin was further shown to induce CYP1 enzyme activity and CYP1A1/CYP1B1 protein expression in MCF7 and MDA-MB-468 cells. These results suggest that tangeretin inhibits the proliferation of breast cancer cells via CYP1A1/CYP1B1-mediated metabolism to the product 4' hydroxy tangeretin. PMID- 29626628 TI - Hepatocyte-specific deletion of LASS2 protects against diet-induced hepatic steatosis and insulin resistance. AB - Homo sapienslongevity assurance homolog 2 of yeast LAG1 (LASS2) is expressed mostly in human liver. Here, we explored roles of LASS2 in pathogenesis of hepatic steatosis. Hepatocyte-specific LASS2 knockout (LASS2-/-) mice were generated using Cre-LoxP system. LASS2-/- and wild-type (WT) mice were fed with chow or high-fat diet (HFD). We found LASS2-/- mice were resistant to HFD-induced hepatic steatosis and insulin resistance. In HFD-fed mice, LASS2 deficiency significantly inhibited p38 MAPK and ERK1/ERK2 signaling in mouse liver. This effect was mediated by a significant increase of V-ATPase activity and a decrease of ROS level. We also observed that elevated expression of LASS2 in mouse hepatocyte cell line AML12 obviously decreased V-ATPase activity and increased ROS level by activation of p38 MAPK and ERK1/ERK2 signaling. Our findings indicate that LASS2 plays an important role in the pathogenesis of diet-induced hepatic steatosis and is a potential novel target for prevention and intervention of liver diseases. PMID- 29626629 TI - The burden of allergic rhinitis and allergic rhinoconjunctivitis on adolescents: A literature review. AB - OBJECTIVE: To evaluate the literature regarding the burden of allergic rhinitis (AR) and allergic rhinoconjunctivitis (ARC) in adolescents (aged 10-19 years). DATA SOURCES: Searches were performed in MEDLINE, Embase, Health Technology Assessment Database, and National Health Service Economic Evaluation Database for studies that evaluated concepts of symptoms, quality of life (QOL), daily activities, sleep, examination performance, school absenteeism and presenteeism, and treatment burden in adolescents with AR or ARC. STUDY SELECTIONS: English language journal articles indexed in the last 15 years describing noninterventional, population-based studies. Records were assessed by 2 independent reviewers. RESULTS: A total of 27 articles were identified; outcomes evaluated were symptoms (n = 6 studies), QOL (n = 9), daily activities (n = 5), emotional aspects (n = 3), sleep (n = 6), education (n = 7), and treatment burden (n = 2). AR symptoms rated most bothersome were rhinorrhea, nasal congestion, and itchy eyes. QOL was worse in adolescents with AR vs controls regardless of QOL instrument used. Nasal symptoms and nasal obstruction were more likely to be associated with poor QOL in adolescents than in adults or younger children, respectively. Daily functioning and sleep were also negatively affected by AR. In addition, a detrimental effect on absenteeism, school productivity, and academic performance was reported. CONCLUSION: Although AR and ARC are sometimes perceived as trivial conditions, this review indicates that their effect on adolescent life is negative and far-reaching. It is critical that clinicians gain a greater understanding of the unique burden of AR and ARC in adolescents to ensure they receive prompt and appropriate care and treatment to improve clinical and academic outcomes. PMID- 29626630 TI - Reefer madness or much ado about nothing? Cannabis legalization outcomes among young adults in the United States. AB - In 2012, Colorado became one of the first two U.S. States to legalize cannabis for recreational use for adults 21 and older. Given that cannabis use holds potential physical and mental health risks, particularly among adolescent users, concerns have grown regarding changes in use following this change in policy. Studies examining medical cannabis legalization have found inconsistent changes in cannabis use and prevalence of dependence following medical implementation. However, recreational legalization holds potential unique changes, such as increased availability and social acceptance, as well as decreased price and perceived harm of use. There also may be increased interest in moving to Colorado related to the changes in cannabis laws. Based on past literature, two hypotheses were made for this study. First, college student cannabis use would increase after recreational legalization, however just for those 21 years old and older. Second, there would be a positive relation between the influence of cannabis legislation on out-of-State student's decision to attend a Colorado university and their cannabis use. Data from 5241 undergraduate students was available to test study hypotheses using Pearson's Chi-square, negative binomial regressions, and path analysis. Results indicated that cannabis use increased since recreational legalization for all students, but more so for those over 21 years. No differences in past month use frequency were found between pre- and post legalization. Influence of cannabis laws on non-resident student's decision to attend a Colorado college predicted lifetime and past 30-day use. Additionally, out-of-State students reported higher past 30-day use than in-State students. These findings may help inform other States considering recreational legalization of potential outcomes, as well as potential interventions. PMID- 29626632 TI - NGS combined with phylogenetic analysis to detect HIV-1 dual infection in Romanian people who inject drugs. AB - Dual HIV infections are possible and likely in people who inject drugs (PWID). Thirty-eight newly diagnosed patients, 19 PWID and 19 heterosexually HIV infected were analyzed. V2V3 loop of HIV-1 env gene was sequenced on the NGS platform 454 GSJunior (Roche). HIV-1 dual/multiple infections were identified in five PWID. For three of these patients, the reconstructed variants belonged to pure F1 subtype and CRF14_BG strains according to phylogenetic analysis. New recombinant forms between these parental strains were identified in two PWID samples. NGS data can provide, with the help of phylogenetic analysis, important insights about the intra-host sub-population structure. PMID- 29626633 TI - Serum lipoproteins are not associated with the severity of asthma. AB - BACKGROUND: Asthma is a chronic inflammatory disorder of the bronchi with a complicated and largely unknown pathogenesis. In this context, an emerging role is attributed to the apolipoproteins which serve as structural components of plasma lipoproteins. Low density lipoproteins (LDL) may be involved in the inflammatory pathways of the asthmatic airways; in particular, small dense LDL (sdLDL) particles were associated with increased oxidative susceptibility compared to medium and large sized LDL. In our previous study, we found a positive correlation between forced expiratory volume 1 s (FEV1) % predicted and larger LDL particles (LDL-1), and an inverse correlation between FEV1% predicted and sdLDL (LDL-3) in mild, untreated asthmatics. Although LDL appear to be important modulators of inflammation, data on their clinical implications are still lacking. OBJECTIVE: The aim of the study is to investigate whether LDL subclasses correlate with the severity of asthma, assuming that the atherogenic and most pro-inflammatory LDL contribute to ignite and perpetuate the airway inflammatory processes. METHODS: The study was conducted in one visit, and included clinical and lung functional assessments, as well as measurements of serum concentrations of the LDL subclasses. Non-denaturing, linear polyacrylamide gel electrophoresis was used to separate and measure LDL subclasses, with the LipoPrint(c) System (Quantimetrix Corporation, Redondo Beach, CA, USA). LDL subclasses were distributed as seven bands (LDL-1 to LDL-7), LDL-1 and -2 being defined as large LDL (least pro-inflammatory), and LDL-3 to 7 defined as sdLDL (most pro-inflammatory). RESULTS: 70 asthmatics under inhaled treatment (M/F: 35/35) were enrolled; 10 healthy subjects (M/F: 3/7) served as controls. In the asthmatic group, FEV1% predicted was 81 +/- 22% (mean +/- SD), vital capacity (VC) % predicted was 97 +/- 18%, and FEV1/FVC was 0.68 +/- 0.1. The mean asthma control test (ACT) score was 18 +/- 5. LDL-1 were significantly lower in asthmatics as compared to controls (18 +/- 4% vs. 22 +/- 4%, p = 0.008). On the contrary, LDL-2 (12 +/- 4% vs. 12 +/- 5%) and LDL-3 (3 +/- 3% vs. 2 +/- 2%) were not statistically different between the two groups; smaller subclasses were undetectable. To comply with the design of the study, subjects were classified according to their degree of severity into the 5 Global Initiative for Asthma (GINA) steps: Step 1 (M/F: 4/3, 44 +/- 12 yrs), Step 2 (M/F: 1/2, 37 +/- 11 yrs), Step 3 (M/F: 12/7, 47 +/- 12 yrs), Step 4 (M/F: 8/15, 54 +/- 12 yrs), and Step 5 (M/F: 7/9, 56 +/- 9 yrs). None of the LDL subclasses showed significant differences between classes of severity: LDL-1 were 16.1 +/- 5.6% in Step 1, 18 +/- 2.8% in Step 2, 16.7 +/- 3.7% in Step 3, 18 +/- 3.3% in Step 4, and 19.5 +/- 3.2% in Step 5 (p = NS); LDL2 were 14 +/- 3.6%, 15 +/- 3.4%, 12.4 +/- 5.3%, 12.7 +/- 4.4% and 11.3 +/- 4.2%, respectively (p = NS); LDL3 were 5 +/- 5.2%, 4.4 +/- 2.6%, 3.3 +/- 3.6%, 3.2 +/- 2.6% and 2.4 +/- 1.8%, p = NS. Finally, no relationship was detected between LDL subclasses and lung function parameters as well as the ACT scores. CONCLUSIONS: The current findings confirm a role of LDL as a potential biomarker in the diagnostic process for asthma, and suggest that LDL cannot be used as marker of severity of the disease. PMID- 29626634 TI - Evidence for local adaptation and pleiotropic effects associated with melanization in a plant pathogenic fungus. AB - We combined a common garden experimental design with digital image analysis to determine how melanization responds to temperature and fungicide stress in 126 strains of Rhynchosporium commune sampled from nine global field populations. We found that different temperatures and fungicide stress significantly affected the degree of melanization. The nine field populations showed similar patterns in response to the different temperatures. Significant correlations were found between the degree of melanization and the local environment, including mean annual temperature, latitude, and relative humidity, suggesting that melanization is a locally adaptive trait. We also found that melanization is positively correlated with both virulence and fungicide resistance. These findings suggest that melanization has pleiotropic effects in Rhynchosporium commune. PMID- 29626631 TI - Ift25 is not a cystic kidney disease gene but is required for early steps of kidney development. AB - Eukaryotic cilia are assembled by intraflagellar transport (IFT) where large protein complexes called IFT particles move ciliary components from the cell body to the cilium. Defects in most IFT particle proteins disrupt ciliary assembly and cause mid gestational lethality in the mouse. IFT25 and IFT27 are unusual components of IFT-B in that they are not required for ciliary assembly and mutant mice survive to term. The mutants die shortly after birth with numerous organ defects including duplex kidneys. Completely duplex kidneys result from defects in ureteric bud formation at the earliest steps of metanephric kidney development. Ureteric bud initiation is a highly regulated process involving reciprocal signaling between the ureteric epithelium and the overlying metanephric mesenchyme with regulation by the peri-Wolffian duct stroma. The finding of duplex kidney in Ift25 and Ift27 mutants suggests functions for these genes in regulation of ureteric bud initiation. Typically the deletion of IFT genes in the kidney causes rapid cyst growth in the early postnatal period. In contrast, the loss of Ift25 results in smaller kidneys, which show only mild tubule dilations that become apparent in adulthood. The smaller kidneys appear to result from reduced branching in the developing metanephric kidney. This work indicates that IFT25 and IFT27 are important players in the early development of the kidney and suggest that duplex kidney is part of the ciliopathy spectrum. PMID- 29626635 TI - On the origin of vanillyl alcohol oxidases. AB - Vanillyl alcohol oxidase (VAO) is a fungal flavoenzyme that converts a wide range of para-substituted phenols. The products of these conversions, e.g. vanillin, coniferyl alcohol and chiral aryl alcohols, are of interest for several industries. VAO is the only known fungal member of the 4-phenol oxidising (4PO) subgroup of the VAO/PCMH flavoprotein family. While the enzyme has been biochemically characterised in great detail, little is known about its physiological role and distribution in fungi. We have identified and analysed novel, fungal candidate VAOs and found them to be mostly present in Pezizomycotina and Agaricomycotina. The VAOs group into three clades, of which two clades do not have any characterised member. Interestingly, bacterial relatives of VAO do not form a single outgroup, but rather split up into two separate clades. We have analysed the distribution of candidate VAOs in fungi, as well as their genomic environment. VAOs are present in low frequency in species of varying degrees of relatedness and in regions of low synteny. These findings suggest that fungal VAOs may have originated from bacterial ancestors, obtained by fungi through horizontal gene transfer. Because the overall conservation of fungal VAOs varies between 60 and 30% sequence identity, we argue for a more reliable functional prediction using critical amino acid residues. We have defined a sequence motif P-x-x-x-x-S-x-G-[RK]-N-x-G-Y-G-[GS] that specifically recognizes 4PO enzymes of the VAO/PCMH family, as well as additional motifs that can help to further narrow down putative functions. We also provide an overview of fingerprint residues that are specific to VAOs. PMID- 29626637 TI - Intraoperative anaphylaxis secondary to systemic cooling in a pediatric patient with cold-induced urticaria. PMID- 29626636 TI - Occupational exposures and asthma prevalence among US farmworkers: National Agricultural Workers Survey, 2003-2014. PMID- 29626638 TI - Synthesis and molecular docking study of piperazine derivatives as potent inhibitor of thymidine phosphorylase. AB - Thymidine phosphorylase triggers the phosphorylation of pyrimidine base to thymine and 2-deoxyribose 1-phosphate which undergoes dephosphorylation to 2 deoxyribose. It plays a role in tumor angiogenesis which is referred to the development of blood vessels during tumor growth and therefore is an attractive drug target. Keeping in view the greater importance of its inhibition, here in this study we have synthesized piperazine analogs (1-18) and evaluated for thymidine phosphorylase inhibitory activity. All analogs showed potent inhibitory potential with IC50 values ranging between 0.2 +/- 0.01 and 42.20 +/- 0.70 uM when compared with standard 7-Deazaxanthine (IC50 value of 38.68 +/- 1.12 uM). Structure activity relationship has been also established for all newly synthesized compounds. Molecular docking studies revealed that these compounds established stronger hydrogen bonding networks with active site residues of enzyme. PMID- 29626639 TI - Assessing the real-time activation of the cannabinoid CB1 receptor and the associated structural changes using a FRET biosensor. AB - The cannabinoid receptor 1 (CB1) is mainly expressed in the nervous system and regulates learning, memory processes, pain and energy metabolism. However, there is no way to directly measure its activation. In this study, we constructed a CB1 intramolecular fluorescence resonance energy transfer (FRET) sensor, which could measure CB1 activation by monitoring structural changes between the third intracellular loop and the C-terminal tail. CB1 agonists induced a time- and concentration-dependent increase in the FRET signal, corresponding to a reduction in the distance between the third intracellular loop and the C-terminal tail. This, in turn, mobilized intracellular Ca2+, inhibited cAMP accumulation, and increased phosphorylation of the ERK1/2 MAP kinases. The activation kinetics detected using this method were consistent with those from previous reports. Moreover, the increased FRET signal was markedly inhibited by the CB1 antagonist rimonabant, which also reduced phosphorylation of the ERK1/2 MAP kinases. We mutated a single cysteine residue in the sensor (at position 257 or 264) to alanine. Both mutation reduced the agonist-induced increase in FRET signal and structural changes in the CB1 receptor, which attenuated phosphorylation of the ERK1/2 MAP kinases. In summary, our sensor directly assesses the kinetics of CB1 activation in real-time and can be used to monitor CB1 structure and function. PMID- 29626640 TI - Differential responses to Cd stress induced by exogenous application of Cu, Zn or Ca in the medicinal plant Catharanthus roseus. AB - Cd(II) is one of the most widespread and toxic heavy metals and seriously threatens plant growth, furthermore negatively affecting human health. For survival from this metal stress, plants always fight with Cd(II) toxicity by themselves or using other external factors. The effects of second metals copper (Cu(II)), zinc (Zn(II)) and calcium (Ca(II)) on the Cd(II)-affected root morphology, Cd(II) translocation and metabolic responses in Catharanthus roseus were investigated under hydroponic conditions. We found that the Cd-stressed plants displayed the browning and rot root symptom, excess H2O2 content, lipid peroxidation and Cd(II) accumulation in plants. However, the supplement with second metals largely alleviated Cd-induced toxicity, including browning and rot roots, oxidative stress and internal Cd(II) accumulation. The amended effects at metabolic and transcriptional levels involved in different second metals share either common or divergent strategies. They commonly repressed Cd uptake and promoted Cd(II) translocation from roots to shoots with divergent mechanisms. High Zn(II) could activate MTs expression in roots, while Cu(II) or Ca(II) did not under Cd(II) stress condition. The presence of Ca(II) under Cd stress condition largely initiated occurrence of lateral roots. We then grouped a metabolic diagram integrating terpenoid indole alkaloid (TIA) accumulation and TIA pathway gene expression to elucidate the metabolic response of C. roseus to Cd(II) alone or combined with second metals. The treatment with 100 Cd(II) alone largely promoted accumulation of vinblastine, vindoline, catharanthine and loganin, whereas depressed or little changed the expression levels of genes detected here, compared to 0 Cd(II) control. In the presence of Cd(II), the supplement with second metals displayed specific effect on different alkaloid. Among them, the metal Ca(II) is especially beneficial for serpentine accumulation, Zn(II) mainly promoted tabersonine production. However, the addition of Cu(II) commonly depressed accumulation of most alkaloids detected here. Generally, we presented different mechanisms by which the second metals used to alleviate Cd (II) toxicity. This plant has potential application in phytoremediation of Cd(II), due to relatively substantial accumulation of biomass, as well as secondary metabolites TIAs used as pharmaceutical materials when facing Cd stress. PMID- 29626641 TI - Platelet rich plasma versus hyaluronic acid in patients with hip osteoarthritis: A meta-analysis of randomized controlled trials. AB - BACKGROUND: This study aims to compare the efficacy of intra-articular injection of hyaluronic acid (HA) and platelet-rich plasma (PRP) for treating hip osteoarthritis (OA). METHODS: We performed systematic searches in PubMed, EmBase, ScienceDirect Web of science and the Cochrane Library for relevant literature published in or before February 2018. Only randomized controlled trials (RCTs) were included. The risk of bias assessment was performed using the tool recommended in the Cochrane Handbook for Systematic Reviews of Interventions (version 5.1.0). We used STATA 14.0 (College Station, TX, USA) to analyze the data. RESULTS: A total of 287 records were identified by the initial database search. Finally, 4 RCTs were included in our study. The present meta-analysis indicated that PRP was associated with a significant reduction of VAS score at 2 months compared with HA. However, it did not show significantly better outcomes at 6 and 12 months. There was no significant difference regarding the WOMAC and HHS at a 12-month follow up. No increased risk of adverse effects were observed. CONCLUSION: Intra-articular injection of PRP was associated with a significant reduction of VAS at 2 months. Both of them showed comparable results in terms of functional recovery. Further studies were still necessary. PMID- 29626642 TI - Haemostatic effects of latex from Croton sparsiflorus Morang, in vitro, in vivo, in silico approaches. AB - The present investigations are phytochemical screening of Latex aqueous (Laq) extract of C. sparsiflorus and study its role in homeostasis. It is being traditionally used for fresh cuts to stop bleeding immediately. To know the contents of extract, the quantitative phytochemical analysis were performed it showed the contents such as saponins (15.2%), alkaloids (7.61%), phenols (0.62%), tannins (1.1%), and flavonoids (0.224%). The in vitro and in vivo blood clotting mechanism was observed in Wister albino rats to understand the blood clotting activity. The in vitro cytotoxicity assay was performed by 3T3L1 cell lines evaluated by Laq extract of C. sparsiflorus to determine the toxic effects of the extract. The gas chromatographic and liquid chromatographic mass spectra (GCMS and LCMS) were observed there were three compounds obtained namely, 1) methyl hexafuranoside, 2) cumarandione, and 3) crotonosine, in addition to that the NMR (1H and 13C) elemental analysis, FT-IR (4000-400 cm-1) and UV-vis (800-200 nm) spectra were also recorded in aqueous solution. The molecular docking studies performed, in which the blood clotting factors have a potential interaction with crotonosine. This in-silico study demonstrates the interactions of active components of C. sparsiflorus with blood clotting factors. Furthermore, since the crotonosine compound has more blood clotting factor the molecular structure was treated with density functional theory calculation (DFT) to understand the optimized geometry, vibrational behaviour and electronic excitation states. PMID- 29626644 TI - Mitochondrial haplotypes are not associated with mice selectively bred for high voluntary wheel running. AB - Mitochondrial haplotypes have been associated with human and rodent phenotypes, including nonshivering thermogenesis capacity, learning capability, and disease risk. Although the mammalian mitochondrial D-loop is highly polymorphic, D-loops in laboratory mice are identical, and variation occurs elsewhere mainly between nucleotides 9820 and 9830. Part of this region codes for the tRNAArg gene and is associated with mitochondrial densities and number of mtDNA copies. We hypothesized that the capacity for high levels of voluntary wheel-running behavior would be associated with mitochondrial haplotype. Here, we analyzed the mtDNA polymorphic region in mice from each of four replicate lines selectively bred for 54 generations for high voluntary wheel running (HR) and from four control lines (Control) randomly bred for 54 generations. Sequencing the polymorphic region revealed a variable number of adenine repeats. Single nucleotide polymorphisms (SNPs) varied from 2 to 3 adenine insertions, resulting in three haplotypes. We found significant genetic differentiations between the HR and Control groups (Fst = 0.779, p <= 0.0001), as well as among the replicate lines of mice within groups (Fsc = 0.757, p <= 0.0001). Haplotypes, however, were not strongly associated with voluntary wheel running (revolutions run per day), nor with either body mass or litter size. This system provides a useful experimental model to dissect the physiological processes linking mitochondrial, genomic SNPs, epigenetics, or nuclear-mitochondrial cross-talk to exercise activity. PMID- 29626643 TI - Patterns of repeated anal cytology results among HIV-positive and HIV-negative men who have sex with men. AB - BACKGROUND: Men who have sex with men (MSM) are at increased risk for anal cancer. In cervical cancer screening, patterns of repeated cytology results are used to identify low- and high-risk women, but little is known about these patterns for anal cytology among MSM. METHODS: We analyzed Multicenter AIDS Cohort Study (MACS) data for MSM who were offered anal cytology testing annually (HIV-positive) or every 2 years (HIV-negative) for 4 years. RESULTS: Following an initial negative (normal) cytology, the frequency of a second negative cytology was lower among HIV-positive MSM with CD4 >= 500 (74%) or CD4 < 500 (68%) than HIV-negative MSM (83%) (p < 0.001). After an initial abnormal cytology, the frequency of a second abnormal cytology was highest among HIV-positive MSM with CD4 < 500 (70%) compared to CD4 >= 500 (53%) or HIV-negative MSM (46%) (p = 0.003). Among HIV-positive MSM with at least three results, 37% had 3 consecutive negative results; 3 consecutive abnormal results were more frequent among CD4 < 500 (22%) than CD4 >= 500 (10%) (p = 0.008). CONCLUSIONS: More than one-third of HIV-positive MSM have consistently negative anal cytology over three years. Following abnormal anal cytology, a repeated cytology is commonly negative in HIV negative or immunocompetent HIV-positive men, while persistent cytological abnormality is more likely among HIV-positive men with CD4 < 500. PMID- 29626646 TI - Cirrhosis induced by bile duct ligation alleviates acetic acid intestinal damages in rats: Involvements of nitrergic and opioidergic systems. AB - BACKGROUND: Colitis, a colonic inflammatory condition, showed a linkage with hepatobiliary disorders such as cirrhosis. It has been reported that both endogenous opioids and nitric oxide (NO) play critical roles in colitis pathogenesis. Moreover, opioid and NO levels showed elevation in patients with cirrhosis. The aim of this study was to evaluate the effect of cirrhosis on the experimental model of colitis and the possible involvement of opioidergic/nitrergic systems in rats. METHODS: Colitis was induced by acetic acid 28days after bile duct ligation (BDL). L-NAME, as an inhibitor of NO synthase and naltrexone, as an antagonist of opioid receptors were administered intraperitoneally to animals during 3days after induction of colitis. Macroscopic colitis lesion area, inflammatory mediators change, NO metabolite levels, and colon microscopic injuries were assessed 3days after induction. RESULTS: Cirrhosis significantly reduced the severity of damages to the colon. Administration of L-NAME (10mg/kg), naltrexone (10mg/kg) and co-administration of L-NAME (1mg/kg) and naltrexone (5mg/kg) significantly decreased the protective effect of BDL on colitis. Nitrite elevated levels in BDL rats were significantly diminished in L-NAME- and naltrexone-treated animals. Histopathology parameters and cytokines level alterations in the colon of acetic acid-treated animals after BDL was reversed after injection of L-NAME, naltrexone, and co-administration of L-NAME (1mg/kg) + naltrexone (5mg/kg). CONCLUSION: Cirrhosis improved the intestinal damages induced by acetic acid in rats which may be mediated through interaction of nitrergic and opioidergic systems. PMID- 29626645 TI - Chitosan (CMD)-mediated co-delivery of SN38 and Snail-specific siRNA as a useful anticancer approach against prostate cancer. AB - BACKGROUND: Prostate cancer is known as the most common malignancy in men. Chitosan has generated great interest as a useful biopolymer for the encapsulation of small interfering RNA (siRNA). Due to cationic nature, chitosan is able to efficiently encapsulate siRNA molecules and form nanoparticles. Furthermore, the biocompatible and biodegradable attributes of chitosan have paved the way for its potential application in the in vivo delivery of therapeutic siRNAs. In this study, we aimed to design chitosan/CMD nanoparticles for the efficient encapsulation of the anti-cancer drugs SN38 and Snail-specific siRNA. METHODS: Physicochemical characteristics, growth inhibitory properties, and anti-migratory capacities of the dual delivery of SN38-Snail siRNA CMD chitosan nanoparticles were investigated in prostate cancer cells. RESULTS: Our findings provided evidence for the suggestion that, ChNP-CMD-SN38-siRNA treated cells, the mRNA level of snail decreased from 1.00 to 0.30 (+/-0.14) and 0.09 (+/ 0.04) after 24h and 48h, respectively. Additionally, the fold induction of E cadherin and Claudin-1 increased from 1.00 to now 3.12 (+/-0.62), 3.02 (+/-0.28) after 24h and 5.6 (+/-0.91), 4.42 (+/-0.51) after 48h, respectively. Also, co delivery of SN38 and Snail-specific siRNA by an appropriate nanocerrier (chitosan nanoparticles) could reduce the viability, proliferation, and migration of PC-3 cells. CONCLUSIONS: In conclusion, ChNPs encapsulating SN38 and Snail-specific siRNA may represent huge potential as an effective anti-cancer drug delivery system for the treatment of prostate cancer. PMID- 29626647 TI - Multiple pathways for mitophagy: A neurodegenerative conundrum for Parkinson's disease. AB - It has been nearly a decade since the first landmark studies implicating familial recessive Parkinson's disease genes in the regulation of selective mitochondrial autophagy. The PTEN-induced kinase 1 (PINK1) and the E3 ubiquitin ligase Parkin (encoded by the PARK2 gene) act together to mark depolarized mitochondria for degradation. There is now an extensive body of literature detailing key mediators and steps in this pathway, based mostly on work in transformed cell lines. However, the degree to which PINK1-triggered mitophagy contributes to mitochondrial quality control in the mammalian brain, and the extent to which its disruption contributes to Parkinson's disease pathogenesis remain uncertain. In recent years, it has become clear that there are multiple, potentially redundant, pathways of cargo specification for mitophagy. Important mitophagy-independent functions of PINK1 and Parkin are also emerging. This review summarizes key features of three major mitophagy cargo recognition systems: receptor-mediated, ubiquitin-mediated and cardiolipin-mediated. New animal models that may be useful for tracking the delivery of mitochondria into lysosomes in different neuronal populations will be highlighted. Combining these research tools with methods to selectively disrupt specific mitophagy pathways may lead to a better understanding of the potential role of mitophagy in modulating neuronal vulnerability in Parkinson's spectrum (PD/PDD/DLB) and other neurodegenerative diseases. PMID- 29626648 TI - Abnormal circadian locomotor rhythms and Per gene expression in six-month-old triple transgenic mice model of Alzheimer's disease. AB - Circadian rhythm disturbance (CRD) is one of the iconic manifestations in Alzheimer's disease (AD), a disease tightly associated with age, but the characteristics and gender difference of CRD occurred in AD have not been well demonstrated. Using 6-month-old triple transgenic AD mouse model (3xTg-AD) without obvious brain pathological changes, we demonstrated the gender difference of CRD at this age. We further showed abnormal Per gene expression in the central clock suprachiasmatic nucleus (SCN) of the 3xTg-AD mice. Specifically, compared with the wide type (WT) mice, the 3xTg-AD mice showed disrupted circadian locomotor rhythms both at LD (light-dark 12 h:12 h) and DD (constant dark) conditions, such as increased activities in the resting phase, decreased and scattered activities in the active phase, decreased overall activity intensities, amplitude, robustness, and increased intradaily variability. We further observed that 3xTg-AD female mice showed obviously less CRD compared with the 3xTg-AD male mice, and female mice of both WT and 3xTg-AD were more active in locomotor activity. Accordingly, 3xTg-AD mice showed a phase delay in the expression of Per1 and Per2 mRNA in the SCN, with the levels of Per1 and Per2 mRNA were significantly lower than that of WT mice at specific time points. We conclude that 3xTg-AD mice exhibit behavioral CRD at the age of six months with male gender preference, and these phenomena are at least partly associated with the alteration of Per1 and Per2 transcription patterns in the SCN. PMID- 29626649 TI - Random forest based classification of alcohol dependence patients and healthy controls using resting state MRI. AB - Currently, classification of alcohol use disorder (AUD) is made on clinical grounds; however, robust evidence shows that chronic alcohol use leads to neurochemical and neurocircuitry adaptations. Identifications of the neuronal networks that are affected by alcohol would provide a more systematic way of diagnosis and provide novel insights into the pathophysiology of AUD. In this study, we identified network-level brain features of AUD, and further quantified resting-state within-network, and between-network connectivity features in a multivariate fashion that are classifying AUD, thus providing additional information about how each network contributes to alcoholism. Resting-state fMRI were collected from 92 individuals (46 controls and 46 AUDs). Probabilistic Independent Component Analysis (PICA) was used to extract brain functional networks and their corresponding time-course for AUD and controls. Both within network connectivity for each network and between-network connectivity for each pair of networks were used as features. Random forest was applied for pattern classification. The results showed that within-networks features were able to identify AUD and control with 87.0% accuracy and 90.5% precision, respectively. Networks that were most informative included Executive Control Networks (ECN), and Reward Network (RN). The between-network features achieved 67.4% accuracy and 70.0% precision. The between-network connectivity between RN-Default Mode Network (DMN) and RN-ECN contribute the most to the prediction. In conclusion, within network functional connectivity offered maximal information for AUD classification, when compared with between-network connectivity. Further, our results suggest that connectivity within the ECN and RN are informative in classifying AUD. Our findings suggest that machine-learning algorithms provide an alternative technique to quantify large-scale network differences and offer new insights into the identification of potential biomarkers for the clinical diagnosis of AUD. PMID- 29626650 TI - Rewarding and reinforcing effects of 4-chloro-2,5-dimethoxyamphetamine and AH 7921 in rodents. AB - New psychoactive substances (NPSs), i.e., newly designed substances with chemical residues that are slightly different from those of known psychoactive substances, have been emerging since the late 2000s, and social problems related to the use of these substances are increasing globally. Two such NPSs are 4-chloro-2,5 dimethoxyamphetamine (DOC), a psychedelic substance that is structurally related to amphetamine, and AH-7921, an opioid analgesic that is used for recreational purposes and has a potency similar to that of morphine. Currently, scientific evidence for the dependence liability or toxicity of NPSs is lacking. Therefore, in this study, we performed animal behavioral tests to evaluate the dependence liability of DOC and AH-7921. The rewarding and reinforcing effects of DOC and AH 7921 were evaluated using the conditioned place preference (CPP) paradigm in mice and the self-administration (SA) procedure in rats. Both DOC and AH-7921 increased the preference for the drug-paired compartment in the CPP test at a dose of 0.3 mg/kg and increased the number of responses to the active lever in the SA test at 0.01 mg/(kg.infusion). Collectively, the data suggest that DOC and AH-7921 may have both rewarding and reinforcing effects. Further studies are needed to confirm the reinforcing effects in broader dose ranges with various schedules. PMID- 29626652 TI - Participation of satellite glial cells of the dorsal root ganglia in acute nociception. AB - At dorsal root ganglia, neurons and satellite glial cells (SGC) can communicate through ATP release and P2X7 receptor activation. SGCs are also interconnected by gap junctions and have been previously implicated in modulating inflammatory and chronic pain.We now present evidence that SGCs are also involved in processing acute nociception in rat dorsal root ganglia. Using primary dorsal root ganglia cultures we observed that calcium transients induced in neurons by capsaicin administration were followed by satellite glial cells activation. Only satellite glial cells response was reduced by administration of the P2X7 receptor antagonist A740003. In vivo, acute nociception induced by intraplantar injection of capsaicin in rats was inhibited by A740003 or by the gap junction blocker carbenoxolone administered at the dorsal root ganglia (L5 level). Both drugs also reduced the second phase of the formalin test. These results suggest that communication between neurons and satellite glial cells is not only involved in inflammatory or pathological pain, but also in the transmission of the nociceptive signal, possibly in situations involving C-fiber activation. PMID- 29626654 TI - Geniposide improves repeated restraint stress-induced depression-like behavior in mice by ameliorating neuronal apoptosis via regulating GLP-1R/AKT signaling pathway. AB - Geniposide (GP), a bioactive iridoid glycoside isolated from Gardenia jasminoides Ellis, as well as an agonist of Glucagon-like peptide-1 receptor (GLP-1R), has been reported to exhibit antidepressant-like effects in several rodent models. However, the underlying mechanisms remain obscure. In this study, we mainly investigated the antidepressant-like effects of GP and explored the possible mechanisms associated with GLP-1R signaling by using the repeated restraint stress (RRS)-induced depression model of mice. We found that GP treatment significantly ameliorated depression-like behaviors induced by RRS, such as decreased sucrose preference (SP) in sucrose preference test (SPT), reduced locomotor activity in open field test (OFT) and extended immobility time in tail suspension test (TST) and forced swimming test (FST). In addition, GP suppressed the neuronal apoptosis as well as reduced pro-inflammatory cytokines levels including Interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF alpha) in the hippocampus of RRS-induced mice. Moreover, GP restored the expression of GLP-1R/protein kinase B (AKT) signaling-related protein. Importantly, these effects were blocked by an antagonist of GLP-1R, Exendin(9-39) (Ex(9-39)), indicating that GLP-1R signaling pathway might be involved in the neuroprotective and antidepressant-like effecacy of GP. In conclusion, GP exerted promising antidepressant-like effects in RRS mice, and the antidepressant-like action of GP might be closely relevant to GLP-1R/AKT signaling. PMID- 29626655 TI - Complications and cost of single-stage vs. two-stage bilateral unicompartmental knee arthroplasty: A case-control study. AB - BACKGROUND: Single-stage bilateral knee arthroplasty, even when unicompartmental, remains controversial, chiefly due to the risk of peri-operative complications. The primary objective of this study was to compare the short-term complication rate and cost of single- vs. two-stage bilateral unicompartmental knee arthroplasty (UCA). The secondary objective was to compare total hospital stay lengths and motion-range recovery. HYPOTHESIS: Single-stage bilateral UCA is a cost-saving alternative that is not associated with higher complication rates compared to two-stage bilateral UCA. MATERIAL AND METHOD: This single-centre retrospective comparative study included 70 patients of any age managed between 2010 and 2016. Among them, 44 (88 UKAs) had single-stage surgery (1S group) and 26 (52 UCAs) two-stage surgery (2S group). The two groups were comparable for age, body mass index, gender distribution, compartment replaced, ASA score, and Charlson comorbidity index. The following were evaluated: operative time, haemoglobin level before and after surgery, major and minor complication rates, motion-range recovery, and the radiographic hip-knee-ankle (HKA) angle. Costs were estimated based on the standard codes assigned to the procedures by the national statutory health insurance system (GHM 08C24 for knee arthroplasty to treat knee osteoarthritis and NFKA006 for unicompartmental tibio-femoral or femoro-patellar arthroplasty), modulated according to the concomitant diagnoses. RESULTS: No differences were found for the haemoglobin level change, time to motion-range recovery, or HKA angle. The complication rates per patient were not significantly different between the groups: major complications, 9.1% (n=4) in the 1S group and 15.4% (n=4) in the 2S group (p=1.00); minor complications, 4.5% (n=2) in the 1S group and 3.8% (n=1) in the 2S group (p=1.00). Cost of the total hospital stay was significantly higher in the 2S group than in the 1S group (11,766.7?) and 5626.4?, respectively; p<0.001). Mean total hospital stay duration per patient was 6.7 days with single-stage surgery and 13.4 days with two-stage surgery. DISCUSSION: Single-stage bilateral UCA is not associated with a higher rate of peri-operative complications compared to the two-stage alternative and is substantially less costly. Financial incentives from the healthcare authorities are warranted to increase the use of the single-stage procedure. LEVEL OF EVIDENCE: III, case-control study. PMID- 29626653 TI - Neuronal lysosomes. AB - Lysosomes support diverse cellular functions by acting as sites of macromolecule degradation and nutrient recycling. The degradative abilities of lysosomes are conferred by a lumen that is characterized by an acidic pH and which contains numerous hydrolases that support the breakdown of major cellular macromolecules to yield cellular building blocks (amino acids, nucleic acids, sugars, lipids and metals) that are transported into the cytoplasm for their re-use. In addition to these important hydrolytic and recycling functions, lysosomes also serve as a signaling platform that integrates nutrient and metabolic cues to control signaling via the mTORC1 pathway. Due to their extreme longevity, polarity, demands of neurotransmission and metabolic activity, neurons are particularly sensitive to perturbations in lysosome function. The dependence of neurons on optimal lysosome function is highlighted by insights from human genetics that link lysosome dysfunction to a wide range of both rare and common neurological diseases. How then is lysosome function adapted to the unique demands of neurons? This review will focus on the roles played by lysosomes in distinct neuronal sub compartments, the regulation of neuronal lysosome sub-cellular localization and the implications of such neuronal lysosome regulation for both physiology and disease. PMID- 29626656 TI - Equine Granulocytic Anaplasmosis 28 years later. AB - Equine granulocytic anaplasmosis (EGA) is an important tick borne disease of equines that is caused by Anaplasma phagocytophilum (A. phagocytophilum). The etiological agent has veterinary as well as public health importance because of its zoonotic nature. A. phagocytophilum causes an acute illness in equines with loss of appetite, lethargy, hemorrhages and lameness. Clinically, EGA is diagnosed upon examination of morulae within neutrophils especially granulocytes in the blood. The best diagnostic tool for the detection of EGA is Polymerase chain reaction (PCR). Previous studies suggested that EGA is a self-limiting disease and tetracycline therapy is considered as a best treatment regimen. There is no comprehensive summary on the occurrence and distribution of the infection at global level. Therefore, we intended to provide a comprehensive summary on the prevalence and epidemiology of EGA in different areas of the world. It includes mapping the global distribution of EGA in different areas of the world to identify the endemic regions which may be a source of potential disease outbreak. For this purpose, the published data from 1990 to 2018 on EGA was reviewed and collected by electronic literature search of five databases including Google, Google Scholar, Science Direct, PubMed and Web of Science. PMID- 29626651 TI - Autophagy as a common pathway in amyotrophic lateral sclerosis. AB - Age-dependent neurodegenerative diseases are associated with a decline in protein quality control systems including autophagy. Amyotrophic lateral sclerosis (ALS) is a motor neuron degenerative disease of complex etiology with increasing connections to other neurodegenerative conditions such as frontotemporal dementia. Among the diverse genetic causes for ALS, a striking feature is the common connection to autophagy and its associated pathways. There is a recurring theme of protein misfolding as in other neurodegenerative diseases, but importantly there is a distinct common thread among ALS genes that connects them to the cascade of autophagy. However, the roles of autophagy in ALS remain enigmatic and it is still unclear whether activation or inhibition of autophagy would be a reliable avenue to ameliorate the disease. The main evidence that links autophagy to different genetic forms of ALS is discussed. PMID- 29626657 TI - Transcriptome analysis of gene expression profiling of infected macrophages between Brucella suis 1330 and live attenuated vaccine strain S2 displays mechanistic implication for regulation of virulence. AB - Brucellosis is one of the most common zoonotic epidemics worldwide. Vaccination against brucellosis is an important control strategy to prevent the disease in many high-prevalence regions. At present, Brucella vaccine strain S2 is the most widely used vaccine in China. To uncover the mechanisms underlying virulence attenuation of S2, in this study we characterized the transcriptional profile of S2 and 1330 infected macrophages by transcriptome analysis. The results revealed that expressions of 440 genes were significantly different between macrophages infected by 1330 and S2. Data analysis showed that in the gene ontology term, the different expressed genes involved in innate immune response, phagoctyosis, recognition, and inflammatory response were significantly enriched. Pathway enrichment analysis indicated that the genes involved in transcriptional misregulation in cancer, staphylococcus aureus infection pathways and NF-kappa B signaling pathway were significantly affected. To reveal the molecular mechanisms related to different expression profiles of infected macrophages, the transcription levels of the different genes between the two bacterial genomes were detected. In total, the transcription of 29 different genes was significantly changed in either culture medium or infected microphages. The results of this study can be conducive to the promotion of better understanding of the related mechanisms underlying virulence attenuation of S2 and interactions between host cells and Brucella strains. PMID- 29626658 TI - Immunization with the outer membrane proteins OmpK17 and OmpK36 elicits protection against Klebsiella pneumoniae in the murine infection model. AB - Klebsiella pneumoniae is a Gram-negative bacterium that is increasingly reported as a serious nosocomial and community-acquired pathogen. In the current study, two K. pneumoniae antigens, OmpK17 and OmpK36, as well as their fusion protein cognate F36/17 were investigated as potential vaccine candidates in a murine infection model. Three immunoadjuvants, namely the Gram-positive Enhancer Matrix (GEM) adjuvant, synthetic hemozoin (Hz) adjuvant and incomplete Freund's adjuvant (IFA) were evaluated. Genes of OmpK17 and OmpK36 antigens as well as their fusion protein were cloned in Escherichia coli for recombinant expression. Mice were immunized thrice with the individual recombinant purified antigens adjuvanted with one of the three adjuvants. Two weeks after the last booster, animals were challenged with a lethal dose of K. pneumoniae and immune protection parameters were assessed. Animals immunized with GEM- or Hz-adjuvanted K. pneumoniae antigens did not show significant protection upon bacterial challenge. Animals immunized with subcutaneous IFA-adjuvanted antigens showed the best results with survival percentages of 50, 60 and 50% for groups immunized with OmpK17, OmpK36 and F36/17, respectively. Serum IgG1, rather than IgG2a, antibodies were the most prevalent following vaccination indicating bias towards T helper type 2 (Th2) immune response. Opsonophagocytic assays demonstrated significant percentage killing in case of animals immunized with IFA-adjuvanted antigens. Overall, OmpK17 and OmpK36 are promising vaccine antigens which are worthy of further optimization of the immunization conditions, particularly the used immunoadjuvants, in order to achieve full protection against K. pneumoniae. PMID- 29626660 TI - Venom-derived peptide Mastoparan-1 eradicates planktonic and biofilm-embedded methicillin-resistant Staphylococcus aureus isolates. AB - During the past decade, cationic antimicrobial peptides (CAPs) have gained particular interest among researchers, since they often display broad-spectrum antimicrobial activity and low possibility of resistance emergence. This study aimed to investigate in vitro effectiveness of Mastoparan-1 (MP-1), a tetradecapeptide CAP from hornet venom, against methicillin-resistant Staphylococcus aureus (MRSA) isolates. MP-1 had a high propensity to form alpha helix based on structural predictions. MP-1 was found to possess strong antimicrobial activities and weak cytotoxic effects. Multiple treatments of MRSA with MP-1 at sub-lethal dose did not induce resistance. At 4 * minimum bactericidal concentration (MBC), MP-1 eradicated bacteria within 60 min, whereas vancomycin was unable to eradicate MRSA even after 480 min of exposure, highlighting rapid bactericidal kinetics of MP-1. Treatment of bacteria with 2 * MBC of MP-1 caused a time-dependent increase in orange/red fluorescence intensity. Compared with vancomycin, MP-1 significantly reduced biofilm formation and diminished both biofilm biomass and viability of biofilm-embedded bacteria in a concentration-dependent manner. Taken together, the current data reveal not only that MP-1 is a potent bactericidal and antibiofilm agent, but also that it is less likely to invoke antimicrobial resistance, reinforcing further studies concerning the therapeutic applications of MP-1. PMID- 29626661 TI - Patterns of frailty in non-adults from medieval London. AB - Famine has the potential to target frail individuals who are at greater risk of mortality than their peers. Although children have been at elevated risk of mortality during recent famines, little is known about the risks posed to children during the medieval period. This study uses burials from the St. Mary Spital cemetery (SRP98), London (c. 1120-1540) to examine the relationships among non-adult age at death, burial type (attritional or famine), and four skeletal lesions (porotic hyperostosis, cribra orbitalia, linear enamel hypoplasia [LEH], and periosteal new bone formation). Hierarchical log-linear analysis reveals significant associations between famine burials and LEH, independent of age. Significant associations also exist between age and the presence of cribra orbitalia, porotic hyperostosis, and periosteal lesions, with all three lesions present in greater frequencies among older children and adolescents, independent of burial type. The LEH results suggest that early exposure to stressors increased frailty among non-adults in the context of famine. The associations between age and the other skeletal indicators suggest that, in both famine and non-famine conditions, frailer individuals died at younger ages and before skeletal lesions could manifest, while their less frail peers survived multiple physiological insults before succumbing to death at older ages. PMID- 29626659 TI - Modeling-based optimization approaches for the development of Anti-Agrobacterium tumefaciens activity using Streptomyces sp TN71. AB - A new aerobic bacterium TN71 was isolated from Tunisian Saharan soil and has been selected for its antimicrobial activity against phytopathogenic bacteria. Based on cellular morphology, physiological characterization and phylogenetic analysis, this isolate has been assigned as Streptomyces sp. TN71 strain. In an attempt to increase its anti-Agrobacterium tumefaciens activity, GYM + S (glucose, yeast extract, malt extract and starch) medium was selected out of five different production media and the medium composition was optimized. Plackett-Burman design (PBD) was used to select starch, malt extract and glucose as parameters having significant effects on antibacterial activity and a Box-Behnken design was applied for further optimization. The analysis revealed that the optimum concentrations for anti-A. tumefaciens activity of the tested variables were 19.49 g/L for starch, 5.06 g/L for malt extract and 2.07 g/L for glucose. Several Artificial Neural Networks (ANN): the Multilayer perceptron (MLP) and the Radial basis function (RBF) were also constructed to predict anti-A. tumefaciens activity. The comparison between experimental with predicted outputs from ANN and Response Surface Methodology (RSM) were studied. ANN model presents an improvement of 12.36% in terms of determination coefficients of anti A. tumefaciens activity. To our knowledge, this is the first work reporting the statistical versus artificial intelligence based modeling for optimization of bioactive molecules against phytopathogens. PMID- 29626662 TI - Can early-life growth disruptions predict longevity? Testing the association between vertebral neural canal (VNC) size and age-at-death. AB - This study tests the association of vertebral neural canal (VNC) size and age-at death in a Portuguese skeletal collection from the 19th-20th century. If the plasticity and constraint model best explains this association, VNC size would be negatively related to mortality risk. If the predictive adaptive response (PAR) model is a better fit, no association can be inferred between VNC size and age-at death. Ninety individuals were used in this study. The anteroposterior and transverse diameters of all vertebrae were measured. A Cox regression analysis was performed by sex to assess the effect of VNC size on age-at-death, after adjusting for the effects of year of birth and cause of death. Several measurements of VNC diameters have a statistically significant effect on age-at death, but when the covariates were considered, this association became non significant. The PAR model seems the best fit to explain the relation between VNC and age-at-death. Individuals who went through stressful events early in life were prepared to face a stressful environment later in life, allowing them to cope with adversity without affecting longevity. However, developmental plasticity may be buffered by maternal capital accumulated over several generations, and health hazards encountered throughout life can contribute to health outcomes and longevity. PMID- 29626663 TI - A case of Graves' ophthalmopathy associated with pembrolizumab (Keytruda) therapy. AB - We present the first reported case of Graves' orbitopathy induced by pembrolizumab, a new FDA-approved drug used for the treatment of multiple refractory solid tumors and classic Hodgkin lymphoma. Pembrolizumab elicits T lymphocyte proliferation; we suspect that thyroid eye disease may result in some cases. PMID- 29626664 TI - Misperceptions of reactive attachment disorder persist: Poor methods and unsupported conclusions. AB - Reactive Attachment Disorder (RAD) is an often discussed, but misunderstood, diagnostic presentation. A growing body of well-designed prospective studies is providing a wealth of information about the condition; however, misconceptions of RAD abound in both clinical and research arenas. As such, it can be difficult for reviewers to critically evaluate papers pertaining to RAD that are submitted to academic journals and even more difficult for practicing clinicians operating under the time constraints of community-based practice. Papers continue to appear that promote RAD as a form of conduct disorder (CD) or callous/unemotional (CU) presentation among maltreated children, although this conceptualization is directly at odds with the diagnostic criteria found in the DSM-5 and ICD-10 as well as a significant body of well-conducted research. Studies attempting to promote this understanding of RAD typically suffer from significant and multiple methodological flaws. This paper reviews these concerns and provides 5 questions that must be sufficiently answered when evaluating a paper purportedly examining RAD. A recently published paper promoting the CD/CU-conceptualization of RAD is critiqued as an exemplar of applying these 5 questions. PMID- 29626665 TI - Ethiopian highlands as a cradle of the African fossorial root-rats (genus Tachyoryctes), the genetic evidence. AB - Root-rats of the genus Tachyoryctes (Spalacidae) are subterranean herbivores occupying open humid habitats in the highlands of Eastern Africa. There is strong disagreement about species diversity of the genus, because some authors accept two species, while others more than ten. Species with relatively high surface activity, the giant root-rat Tachyoryctes macrocephalus, which is by far largest member of the genus, and the more fossorial African root-rat Tachyoryctes splendens, which eventually has been divided up to 12-13 species, represent two major morphological forms within the genus. In our study, we carried out a multilocus analysis of root-rats' genetic diversity based on samples from 41 localities representing most of Tachyoryctes geographic distribution. Using two mitochondrial and three nuclear genes, we found six main genetic clades possibly representing separate species. These clades were organised into three basal groups whose branching is not well resolved, probably due to fast radiation in the late Pliocene and early Pleistocene. Climatic changes in that time, i.e. fast and repeated changes between extremely dry and humid conditions, which both limited root-rat dispersal, probably stimulated their initial genetic diversification. Contrary to expectation based on the largest root-rat diversity in Kenya (up to eight species by some authors), we found the highest diversity in the Ethiopian highlands, because all but one putative species occur there. All individuals outside of Ethiopia belong to a single recently diverged and expanded clade. This species should bear the name T. annectens (Thomas, 1891), and all other names of taxa described from outside of Ethiopia should be considered its junior synonyms. However, to solve taxonomic issues, future detailed morphological analyses should be conducted on all main clades together with genetic analysis of material from areas of their supposed contact. One of the most interesting findings of the study is the internal position of T. macrocephalus in T. splendens sensu lato. This demonstrates the intriguing phenomenon of accelerated morphological evolution of rodents occupying the Afroalpine zone in Ethiopia. Finally, we discuss how the distribution of Tachyoryctes is influenced by competition with another group of subterranean herbivores on the continent, the African mole-rats. We assume that both groups do not compete directly as previously expected, but specialisation to different subterranean niches is the main factor responsible for their spatial segregation. PMID- 29626666 TI - Filtering nucleotide sites by phylogenetic signal to noise ratio increases confidence in the Neoaves phylogeny generated from ultraconserved elements. AB - Despite genome scale analyses, high-level relationships among Neoaves birds remain contentious. The placements of the Neoaves superorders are notoriously difficult to resolve because they involve deep splits followed by short internodes. Using our approach, we investigate whether filtering UCE loci on their phylogenetic signal to noise ratio helps to resolve key nodes in the Neoaves tree of life. We find that our analysis of data sets filtered for high signal to noise ratio results in topologies that are inconsistent with unfiltered results but that are congruent with whole-genome analyses. These relationships include the Columbea + Passerea sister relationship and the Phaethontimorphae + Aequornithia sister relationship. We also find increased statistical support for more recent nodes (i.e. the Pelecanidae + Ardeidae sister relationship, the Eucavitaves clade, and the Otidiformes + Musophagiformes sister relationship). We also find instances where support is reduced for well-established clades, possibly due to the removal of sites with moderate signal-to-noise ratio. Our results suggest that filtering on the basis of signal to noise ratio is a useful tool for resolving problematic splits in phylogenomic data sets. PMID- 29626667 TI - The effects of IL-1beta, IL-8, G-CSF and TNF-alpha as molecular adjuvant on the immune response to an E. tarda subunit vaccine in flounder (Paralichthys olivaceus). AB - Cytokines play vital roles in mounting immune responses and activating host defense network. In this study, the expression plasmid pcDNA3.1 (pcN3) encoding four flounder (Paralichthys olivaceus) cytokines including IL-1beta, TNF-alpha, IL-8 or G-CSF (pcIL-1beta, pcTNF-alpha, pcIL-8 and pcG-CSF) were successfully constructed, and their adjuvant potential on an Edwardsiella tarda (E. tarda) subunit vaccine OmpV (rOmpV) were comparatively analyzed in vaccinated flounder model. Results revealed that flounder vaccinated with rOmpV plus pcIL-1beta, pcIL 8 or pcG-CSF produced the relative percent survivals (RPS) of 71%, 65% and 49% respectively, which were higher than that in flounder vaccinated with rOmpV plus pcTNF-alpha (39%) or pcN3 (36%, the control group). Immunological analysis showed that: (1) except pcTNF-alpha, higher levels of anti-E. tarda serum antibodies and sIg + lymphocytes in spleen, head kidney and peripheral blood were significantly enhanced by pcIL-1beta, pcIL-8 or pcG-CSF, however, pcIL-8 and pcIL-1beta enhanced higher levels of sIg + lymphocytes and anti-E. tarda antibodies than pcG CSF; (2) pcTNF-alpha could promote the up-regulation of genes participated in cellular immunity (MHCIalpha, IFN-gamma, CD8alpha and CD8beta), pcIL-1beta could enhance the expression of genes related to humoral immunity (CD4-1, CD4-2, MHCIIalpha and IgM), and all the detected genes were augmented by pcIL-8 and pcG CSF; Among the four cytokines, pcIL-8 and pcIL-1beta could strengthen the highest levels of genes participated in cellular immunity and humoral immunity, respectively. These results demonstrated that pcIL-8 and pcIL-1beta could enhance stronger cellular and/or humoral immunity induced by rOmpV than pcG-CSF and pcTNF alpha, and evoked higher RPS against E. tarda challenge in flounder, which indicated that pcIL-8 and pcIL-1beta are promising adjuvants of vaccines in controlling E. tarda infection. PMID- 29626668 TI - Influences of Chlorella vulgaris dietary supplementation on growth performance, hematology, immune response and disease resistance in Oreochromis niloticus exposed to sub-lethal concentrations of penoxsulam herbicide. AB - Little is known regarding the impact of penoxsulam, a fluorinated benzenesulfonamid rice herbicide, on Oreochromis niloticus (O. niloticus). Therefore, the current study was undertaken to highlight the effects of penoxsulam exposure on O. niloticus and to evaluate the advantages of Chlorella vulgaris (CV) dietary supplementation against the induced effects. The 96-h lethal concentration 50 (LC50) penoxsulam value for O. niloticus was estimated at 8.948 mg/L by probit analysis in a static bioassay experiment. Next, 360 healthy fish were randomly allocated into 6 treatment groups. The T1 group served as the negative control and was fed a basal diet. The T2 group served as the positive control and was fed a basal diet supplemented with 10% CV. The fish in the T3 and T4 groups were exposed to 1/10 the 96-h LC50 of penoxsulam (0.8948 mg/L) and were fed the basal diet alone or the basal diet supplemented with 10% CV, respectively. The fish in the T5 and T6 groups were exposed to 1/5 the 96-h LC50 of penoxsulam (1.7896 mg/L) and fed the basal diet alone or the basal diet supplemented with 10% CV, respectively. Sub-acute penoxsulam exposure significantly altered hematological indices, as well as compromised the fish's immune defense mechanisms, including the phagocytic percentage, phagocytic index, nitric oxide production, immunoglobulin M levels and lysozyme, anti-trypsin and bactericidal activities subsequently decreasing O. niloticus's resistance to the Aeromonus sobria challenge and increasing disease symptoms and the mortality rate. Furthermore, sub-chronic penoxsulam exposure markedly altered growth performance, oxidant/antioxidant status and liver status and down-regulated the expression of interleukin-1beta (IL-1beta) and tumor necrosis-alpha (TNF-alpha). Interestingly, incorporating 10% CV into the diet protects fish against sub-acute penoxsulam-induced immunotoxicity via improvement of immune responses that increases the resistance against bacterial infection. Further, it improved the growth performance, oxidant/antioxidant status, liver status and markedly up regulated immune-related gene expression, IL-1beta and TNF-alpha, in the spleens of fish sub-chronically exposed to penoxsulam. These outcomes showed that dietary CV supplementation can protect the commercially valuable freshwater fish O. niloticus against penoxsulam toxicity and may be a potential feed supplement for Nile tilapia in aquaculture. PMID- 29626669 TI - The effects of feeding Lactobacillus pentosus on growth, immunity, and disease resistance in Haliotis discus hannai Ino. AB - To study the effects of probiotic-added food on the survival and growth of abalone (Haliotis discus hannai Ino), the expression levels of nonspecific immune genes and the anti-Vibrio parahaemolyticus infection were examined. During an 8 week culturing experiment in an indoor aquarium and a 2-week V. parahaemolyticus artificial infection experiment, the control group was fed with untreated food once a day, while the experimental groups (L1, L2 and L3) were fed with Lactobacillus pentosus added food. The concentration of probiotics in the experimental food was 103 cfu/g (L1), 105 cfu/g (L2) and 107 cfu/g (L3), respectively. The results showed that the survival rate, shell length-specific growth rate, and the food conversion rate (FCR) of abalones in L1 and L2 were significantly higher than the control group. The food intake of abalones in L3 was significantly lower than that in L1, L2 and the control group, but there was no significant difference in FCR identified between L1, L2 and L3. In the L. pentosus-added groups, the total number of blood lymphocytes, lysozyme activity, acid phosphatase, superoxide dismutase, and expression levels of Mn-superoxide dismutase (Mn-SOD) and thioredoxin peroxidase (TPx) were significantly higher than the control group, while the malondialdehyde (MDA) content was significantly lower than the control group. The phagocytic activity of blood lymphocytes, catalase activity and the expression levels of heat shock protein 70 (HSP70) of abalones in the control group were significantly lower than that in L1 and L2, but there was no significant difference when compared with L3. The levels of O2-, NO produced by respiratory burst of blood lymphocytes and the expression levels of catalase (CAT) in L1 and L2 were significantly higher than both L3 and the control group. Seven days after infection with V. parahaemolyticus, all abalones in the control group were dead. After 14 days the cumulative mortality rate of abalones in the L. pentosus-added groups was significantly lower than that in the control group. Therefore, the 103 cfu/g and 105 cfu/g L. pentosus-added food not only promoted food intake and growth of abalones, but also improved their non specific immunity and reduced V. parahaemolyticus infection, indicating that this strain is a good potential candidate for probiotic added food in the aquaculture industry. PMID- 29626670 TI - Dietary effects of succinic acid on the growth, digestive enzymes, immune response and resistance to ammonia stress of Litopenaeus vannamei. AB - Organic acids acts as an growth promoter and antimicrobial agent in aquaculture. The present study investigated the effects of a natural organic acid - succinic acid (SA) on the growth, digestive enzymes, immune response and resistance to ammonia stress of Litopenaeus vannamei. The shrimps were firstly fed with diets containing different levels of SA: 0% (Control), 0.25% (SA1), 0.50% (SA2), and 1.0% (SA3) (w/w) for 56 days, followed by an acute ammonia stress for 48 h. The results indicated that dietary of SA improved the growth of shrimp, and increased the survival rate of shrimp after ammonia stress for 48 h. The amylase, lipase and pepsin activity increased in hepatopancreas in three SA group, while trypsin activity was only increased in the SA1 and SA2 groups. At 56 d, T-NOS activity, proPO and HSP70 gene expression level increased in the three SA group, PO activity increased in the SA1 and SA2 groups, T-AOC content and Toll gene expression level increased in the SA2 and SA3 groups, Trx and SOD gene expression level increased in the SA2 group, while Imd, GS and GDH gene expression level was no changes. After exposure to ammonia stress for 48 h, immune biochemical parameters (T-AOC and PO) and genes (proPO, HSP70, Trx and GDH) expression level increased in the three SA group, T-NOS activity, Toll, Imd and GS gene expression level increased in the SA2 and SA3 groups, while SOD gene expression level increased in the SA1 and SA2 groups. These results indicated that SA improved growth, enhanced digestive and immune capacities of L. vannamei against ammonia stress, and may be a potential feed additive for shrimp. The optimal dietary supplementation dosage is 0.50% (w/w) in diet. PMID- 29626671 TI - Bioactivities of decoctions from Plectranthus species related to their traditional use on the treatment of digestive problems and alcohol intoxication. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Decoctions of Plectranthus species are traditionally ingested after large meals for treatment of food digestion and alcohol abuse. AIM OF THE STUDY: This study aims at associating the digestion related ethno-uses of Plectranthus species decoctions to molecular mechanism that might explain them: easing digestion (AChE inhibition) and treating hangover (ADH inhibition) MATERIAL AND METHODS: Decoctions from Plectranthus species were analysed for their alcohol dehydrogenase (ADH) inhibition and acetylcholinesterase (AChE) inhibition, related with alcohol metabolism and intestinal motility, respectively. Identification of the active components was carried out by LC-MS/MS and the docking studies were performed with AChE and the bioactive molecules detected. RESULTS: All decoctions inhibited ADH activity. This inhibition was correlated with their rosmarinic acid (RA) content, which showed an IC50 value of 19 MUg/mL, similar to the reference inhibitor CuCl2. The presence of RA also leads to most decoctions showing AChE inhibiting capacity. P. zuluensis decoction with an IC50 of 80 MUg/mL presented also medioresinol, an even better inhibitor of AChE, as indicated by molecular docking studies. Furthermore, all decoctions tested showed no toxicity towards two human cell lines, and a high capacity to quench free radicals (DPPH), which also play a helpful in the digestive process, related with their RA content. CONCLUSIONS: All activities presented by the RA-rich Plectranthus decoctions support their use in treating digestion disorders and P. barbatus could explain its use also for alleviating hangover symptoms. Medioresinol, which is present in P. zuluensis, exhibited a significant AChE inhibition and may provide, in the future, a new lead for bioactive compounds. PMID- 29626672 TI - Suppressive effects of Vochysia divergens aqueous leaf extract and its 5 methoxyflavone on murine macrophages and lymphocytes. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Vochysia divergens Pohl (Vochysiaceae), popularly known as "Cambara", is a tree that is resistant to the seasonal floods in the Pantanal, and usually found in monodominant stands called "Cambarazal". The inhabitants of the Pantanal exploit this tree for medicinal uses. Infusions and decoctions of its leaves are taken as teas, particularly for the treatment of asthma, flu and diarrhea, according to the local tradition transmitted empirically through the generations. AIM OF THE STUDY: To evaluate the beneficial health effects related to the ethnomedicinal uses of V. divergens (Vd) by using biomonitored fractionation of an aqueous leaf extract. MATERIALS AND METHODS: The aqueous leaf extract was obtained by decoction, and then the extract was fractionated by a combination of separation techniques including precipitation, organic partition and chromatography. Chromatographic analyses of the active samples were carried out using HPLC-DAD-MS. Flavonoid 1 was isolated from the n BuOH fraction through classic chromatographic techniques. The inhibitory effects and cytotoxicity of the Vd extract, fractions and flavonoid 1 on NO and TNF-alpha production were assessed in LPS-stimulated RAW 264.7 macrophage cultures. Additionally, suppression on the proliferation of BALB/c lymphocytes was estimated by [3H] thymidine incorporation. The antioxidant activity of the samples was verified by SNP and DPPH assays and the suppression of the iNOS protein expression was evaluated through Western blotting. RESULTS: The HPLC-DAD MS analysis of the Vd extract led to the identification of 5-methoxyluteolin-7-O beta-glucopyranoside (2), rutin (4) and the tannin galloyl-HHDP-glucopyranoside (3), besides the main flavonoid 3',5-dimethoxyluteolin-7-O-beta-glucopyranoside (1), which was biologically evaluated in comparison with luteolin aglycone. The Vd extract, n-BuOH fraction and flavonoid 1 inhibited NO and TNF-alpha production by LPS-stimulated macrophages. The reduction of NO levels was mediated mainly by suppression of the iNOS expression. In addition, both the Vd extract (IC50 13.6 ug/mL) and flavonoid 1 (IC50 19.8 ug/mL; 41.6 uM) strongly inhibited stimulated lymphocyte proliferation when compared to the immunosuppressive agent cyclosporin A (IC50 43.8 ug/mL; 36.4 uM). The Vd extract also showed a scavenging activity toward DPPH and NO free radicals. This is the first report describing the immunomodulatory potential of V. divergens and its major flavonoid (1). CONCLUSION: Our findings showed that the aqueous leaf extract of V. divergens and its flavonoid reduced the production of excessive pro-inflammatory markers, collaborating with the Pantanal folk medicinal tradition that recommends the tea of cambara leaves for both asthma and flu. In addition, this study contributes to the knowledge of the pharmacological properties of 5-methoxy flavones, a poorly investigated subclass of flavonoids. PMID- 29626673 TI - Assessment of gonadotropins and testosterone hormone levels in regular Mitragyna speciosa (Korth.) users. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Mitragyna speciosa (Korth.) also known as kratom, is a native medicinal plant of Southeast Asia with opioid-like effects. Kratom tea/juice have been traditionally used as a folk remedy and for controlling opiate withdrawal in Malaysia. Long-term opioid use is associated with depletion in testosterone levels. AIM OF THE STUDY: Since kratom is reported to deform sperm morphology and reduce sperm motility, we aimed to clinically investigate the testosterone levels following long-term kratom tea/juice use in regular kratom users. METHODS: A total of 19 regular kratom users were recruited for this cross-sectional study. A full-blood test was conducted including determination of testosterone level, follicle stimulating hormone (FSH) and luteinizing hormone (LH) profile, as well as hematological and biochemical parameters of participants. RESULTS: We found long-term kratom tea/juice consumption with a daily mitragynine dose of 76.23-94.15 mg did not impair testosterone levels, or gonadotrophins, hematological and biochemical parameters in regular kratom users. CONCLUSION: Regular kratom tea/juice consumption over prolonged periods (>2 years) was not associated with testosterone impairing effects in humans. PMID- 29626674 TI - Pharmacological activity of Curarea toxicofera in combination with classical antimalarial treatments. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In the Leticia-Amazonas area, Uitoto indigenous people use a preparation of Curarea toxicofera (Wedd) Barneby & Krukoff (Menispermaceae) alone or combined with prescribed medications to prevent and treat malaria. AIM OF STUDY: To determine the in vitro and in vivo antiplasmodial activity of traditional preparations of Curarea toxicofera alone and in combination with classical antimalarials. MATERIAL AND METHODS: The traditional preparation was evaluated in vitro against P. falciparum FCR3 CQ resistant strain, alone and combined. The preparation was further administered orally alone or combined with chloroquine and artesunate in mice infected with Plasmodium berghei ANKA strain on the four-day antimalarial test model. RESULTS: The herbal remedy used alone was able to significantly decrease the parasitemia both in vitro (IC50 7.3 ug/ml) and in vivo (ED50 328 mg/Kg) but it was less active than chloroquine (IC50 0.29 ug/ml in vitro and ED50 2.3 mg/Kg/day in vivo), and than artesunate (IC50 0.002 ug/ml and ED50 3.7 mg/Kg/day). Interestingly it presented synergism with chloroquine in vitro (Combination Index: 0.39) and in vivo; and was additive with artesunate in vitro (Combination Index: 0.94) and in vivo. CONCLUSION: The traditional preparation showed potential as an antimalarial and, when used in combination, does not negatively affect the efficacy of the drugs evaluated. Pre-clinical studies should be conducted with a standardized preparation to confirm its efficacy and safety alone and in combination with chloroquine and artesunate. PMID- 29626675 TI - Is the activity of CGRP and Adrenomedullin regulated by RAMP (-2) and (-3) in Trypanosomatidae? An in-silico approach. AB - The Calcitonin-Like Receptor (CLR) belongs to the classical seven-transmembrane segment molecules coupled to heterotrimeric G proteins. Its pharmacology depends on the simultaneous expression of the so-called Receptor Activity Modifier Proteins (RAMP-) -1, -2 and -3. RAMP-associated proteins modulate glycosylation and cellular traffic of CLR, therefore determining its pharmacodynamics. In higher eukaryotes, the complex formed by CLR and RAMP-1 is more akin to bind Calcitonin Gene-Related Peptide (CGRP), whereas those formed by CLR and RAMP-2 or RAMP-3, bind preferentially Adrenomedullin (AM). In lower eukaryotes, RAMPs, or any homologous protein, have not been identified until now. Herein we demonstrated a negative chemotactic response elicited by CGRP (10-9 and 10-8 M) and AM (10-9 to 10-5 M). Whether or not this response is receptor mediated should be verified, as well as the expression of a 24 kDa band in Leishmania, recognized by western blot analysis by the use of (human-)-RAMP-2 antibodies as detection probes. Queries with human RAMP-2 and RAMP-3 protein sequences in blastp against Leishmania (Viannia) braziliensis predicted proteome, allowed us to detect two sequence alignments in the parasite: A RAMP-2-aligned sequence corresponding to Leishmania folylpolyglutamate synthase (FPGS), and a RAMP-3 aligned protein, a hypothetical Leishmania protein with yet unknown function. The presence of homologous of these proteins was described in-silico in other members of the Trypanosomatidae. These preliminary and not yet complete data suggest the feasibility that both CGRP and Adrenomedullin activities may be regulated by homologs of RAMP- (-2) and (-3) in these parasites. PMID- 29626676 TI - Current epidemiology, genetic evolution and clinical impact of extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella pneumoniae. AB - The worldwide spread of extended-spectrum beta-lactamase (ESBL)-producing bacteria, particularly Escherichia coli and Klebsiella pneumoniae, is a critical concern for the development of therapies against multidrug-resistant bacteria. Since the 2000s, detection rates of CTX-M types ESBL-producing E. coli in the community have been high, possibly contributing to their nosocomial detection. Various factors, such as environmental sources, food animals, and international travel, accelerate the global ESBL spread in the community. The dramatic dissemination of ESBLs in the community is associated with the relatively recent emergence of CTX-M-15-producing ST131 E. coli clones, which often carry many other antibiotic resistance genes (including quinolone). The usefulness of beta lactam/beta-lactamase inhibitor, particularly, piperacillin/tazobactam, has been considered as a carbapenem-sparing regimen for ESBL infections, although the global trend of AmpC beta-lactamase-producing bacteria should be monitored carefully. Careful therapeutic selection and continued surveillance for the detection of multidrug-resistant bacteria are required. PMID- 29626677 TI - Regarding "Cyst of Nuck: A Disregarded Pathology". PMID- 29626678 TI - Ulipristal Acetate Improves Clinical Symptoms in Women with Adenomyosis and Uterine Myomas. AB - STUDY OBJECTIVE: To study the effects of ulipristal acetate (UPA) on adenomyosis associated clinical symptoms. DESIGN: A retrospective, single-center observational study (Canadian Task Force classification II-2). SETTING: A university tertiary referral center. PATIENTS: Premenopausal women (163) with adenomyosis and symptomatic uterine myomas (41 patients, A + F group) versus a control group with only myomas (122 patients, F group) treated with the first course of UPA. INTERVENTIONS: This was a retrospective study to assess the effects of a 12-week course of UPA (5 mg/d). MEASUREMENTS AND MAIN RESULTS: Clinical symptoms including bleeding control, amenorrhea, pain outcomes, and self perceived severity of the disease and quality of life. Amenorrhea was present in 90.4% of the A + F group compared with 77.6% in the F group (p = .0017). Optimal bleeding control was significantly higher in the adenomyosis group (pictorial blood loss assessment chart < 75) than in the F group (90.2% vs 73.8%, p = .028). At the end of the first UPA course, the self-reported visual analog scale scores in the A + F group were significantly higher than in the F group (p = .017), reflecting greater improvement in pain outcomes for women with adenomyosis. UPA treatment improved the quality of life in both study groups. Most of the women rated their global health status as "better" after the first UPA course than before the treatment (A + F group: 67.00% and F group: 80.50%, p = .223). CONCLUSION: Treatment with UPA led to a significant reduction in the clinical symptoms of adenomyosis (bleeding and pain) and achieved a high rate of amenorrhea in a cohort of women with concomitant uterine myomas. Despite the limitations of the study, our results showed that UPA might be a good alternative treatment for adenomyosis. PMID- 29626679 TI - Gamma Knife Radiosurgery for Trigeminal Neuralgia Associated with Osteogenesis Imperfecta. AB - BACKGROUND: Trigeminal neuralgia is a rare feature of basilar impression, a complication of osteochondrodysplasic disorders. Microvascular decompression is difficult in medically refractory cases. Gamma knife radiosurgery (GKS) is effective for classical trigeminal neuralgia, and we first applied this GKS for a patient suffering from trigeminal neuralgia with basilar impression complicated by osteogenesis imperfecta. CASE DESCRIPTION: An 18-year-old man with type I osteogenesis imperfecta presented with a 2-year history of typical left trigeminal neuralgia affecting the ophthalmic, maxillary, and mandibular nerves. His condition was poorly controlled by carbamazepine and pregabalin. Magnetic resonance imaging confirmed severe basilar impression and an elongated cisternal portion of the left trigeminal nerve. GKS was performed under local anesthesia. The middle part of the cisternal portion of the left trigeminal nerve was chosen as the radiosurgical target, despite the lack of neurovascular compression. The maximum radiosurgical dose was 85 Gy, using a single 4-mm collimator. The patient's trigeminal neuralgia improved by 1 month after GKS, and at 21 months after GKS he remained free of pain and medications. CONCLUSIONS: We report a case of trigeminal neuralgia resulting from severe basilar impression. Conventional microvascular decompression would not have been an appropriate treatment for this patient, so GKS was used. GKS is a simple and effective option even in cases with severe cranial deformity. PMID- 29626680 TI - Intraoperative Computed Tomography Navigational Assistance for Transforaminal Endoscopic Decompression of Heterotopic Foraminal Bone Formation After Oblique Lumbar Interbody Fusion. AB - Transforaminal endoscopic spine surgery is an emerging technique in spine surgery, but it offers 2 distinct challenges to spine surgeons looking to adopt it: 1) targeting spine pathology and 2) understanding the endoscopic anatomy visualized through the endoscope. Intraoperative computed tomography (CT)-guided navigation is also an emerging technique in spine surgery that is becoming widely adopted for its benefits in assisting surgeons in localizing pathology and guided spine instrumentation placement. In this technical note, we describe a technique that uses intraoperative CT-guided navigation concomitantly with a transforaminal endoscopic approach to decompress a L4-L5 foraminal heterotopic bone formation after an oblique lumbar interbody fusion. The addition of intraoperative CT guided navigation proved beneficial in targeting the pathology during the procedure and ensuring that the pathology was resolved by offering postoperative CT visualization of the decompressed neural foramen. PMID- 29626681 TI - Preliminary Results of Emergency Computed Tomography-Guided Ventricular Drain Placement-Precision for the Most Difficult Cases. AB - BACKGROUND: External ventricular drainage (EVD) catheter placement is one of the most commonly performed neurosurgical procedures. The study's objective was to compare a computed tomography (CT) bolt scan-guided approach for the placement of EVDs with conventional landmark-based insertion. METHODS: In this retrospective case-control study, we analyzed patients undergoing bolt-kit EVD catheter placement, either CT-guided or landmark-based, between 2013 and 2016. The CT bolt scan-guided approach was based on a dose-reduced CT scan after bolt fixation with immediate image reconstruction along the axis of the bolt to evaluate the putative insertion axis. If needed, angulation of the bolt was corrected and the procedure repeated before the catheter was inserted. Primary endpoint was the accuracy of insertion. Secondary endpoints were the overall number of attempts, duration of intervention, complication rates, and cumulative radiation dose. RESULTS: In total, 34 patients were included in the final analysis. In the group undergoing CT-guided placement, the average ventricle width was significantly smaller (P = 0.04) and average midline shift significantly more pronounced (P = 0.01). CT-guided placement resulted in correct positioning of the catheter in the ipsilateral frontal horn in all 100% of the cases compared with landmark-guided insertion (63%; P = 0.01). Application of the CT-guided approach increased the number of total CT scans (3.6 +/- 1.9) and the overall radiation dose (3.34 +/- 1.61 mSv) compared with the freehand insertion group (1.84 +/- 2.0 mSv and 1.55 +/- 1.66 mSv). No differences were found for the other secondary outcome parameters. CONCLUSIONS: CT-guided bolt-kit EVD catheter placement is feasible and accurate in the most difficult cases. PMID- 29626682 TI - Patterns, Predictors, and Outcomes of Postprocedure Delayed Hemorrhage Following Flow Diversion for Intracranial Aneurysm Treatment. AB - OBJECTIVE: To evaluate patterns, predictors, and outcomes of postprocedure delayed hemorrhage (PPDH) following flow diversion therapy for intracranial aneurysm treatment. METHODS: From 2012 to 2016, 50 patients with 52 aneurysms were treated with the Pipeline embolization device. Device placement was performed as a standalone therapy or with adjunctive coil embolization. Patients underwent dual antiplatelet therapy for 6 months after treatment. Medical comorbidities; aneurysm traits; and treatment factors, including platelet function testing, were studied. Statistical analysis was performed using cross tabulation. RESULTS: Six PPDHs (12%) occurred 2-16 days (mean 6.8 days) after Pipeline placement, manifesting as 1 of 2 distinct patterns: convexity subarachnoid hemorrhage (cSAH) (n = 4) or lobar intraparenchymal hemorrhage (IPH) (n = 2). All PPDHs occurred ipsilateral to the device; 1 IPH occurred ipsilateral but in a different arterial territory. PPDH occurred in both treated anterior communicating artery aneurysms. Cases of PPDH demonstrated on average lower P2Y12 reaction unit values at the time of treatment. Platelet function testing at the time of hemorrhage was consistently hypertherapeutic. Patients with cSAH had only minimal worsening of modified Rankin Scale score at the time of discharge, whereas the 2 patients with IPH experienced significant deterioration. CONCLUSIONS: PPDH is a poorly understood complication following flow diversion therapy that can result in significant morbidity. In our experience, nonaneurysmal cSAH does not result in poor clinical outcomes, whereas IPH leads to long-term deficits or death. As previously suggested, there appears to be a correlation between low P2Y12 reaction unit values and PPDH. PMID- 29626683 TI - Assessment of Hemodynamic Changes and Hyperperfusion Risk After Extracranial-to Intracranial Bypass Surgery Using Intraoperative Indocyanine Green-Based Flow Analysis. AB - BACKGROUND: Intraoperative blood flow assessments during cerebral bypass would ideally assess vessel patency, downstream perfusion, and risk of postoperative hyperperfusion syndrome (HPS). Previous studies using indocyanine green-based flow analyses (ICG-BFA) have identified multiple parameters that can intraoperatively track bypass-related changes in cerebral perfusion and potentially predict postoperative risk of HPS. Herein, we determine the most robust parameter and anatomic location for intraoperative ICG-BFA assessment of bypass-related perfusion changes and prediction of postoperative risk of HPS. METHODS: Retrospective analysis of an institutional review board-approved prospective database identified patients undergoing superficial temporal artery to-middle cerebral artery bypass. Demographic and clinical information, as well as manually calculated and automated pre- and postbypass intraoperative ICG-BFA data from cortical, arterial, and venous regions of interest were recorded and analyzed. RESULTS: Seven patients underwent superficial temporal artery-to-middle cerebral artery bypass (4 Moyamoya, 3 carotid occlusions). Average age was 48.2 +/- 13.9 years (3 female, 4 male). Although all parameters measured showed trends toward improvement postbypass, only changes in arterial and venous automated ICG BFA slope (also known as blood flow index [maximum intensity/rise time]) reached significance. None of the patients experienced symptomatic HPS, despite 5 of 7 (71.4%) having an increased HPS risk based on previously published ICG-BFA data. CONCLUSIONS: ICG-BFA has utility for the intraoperative assessment of bypass related changes in cerebral perfusion, with automated blood flow index being the most robustly affected parameter. Although previously published ICG-BFA indices did not predict the development of symptomatic postoperative HPS, larger-scale studies correlating observed ICG-BFA changes with risk of HPS are warranted. PMID- 29626685 TI - Discrepancy Between Neurosurgery Morbidity and Mortality Conference Discussions and Hospital Quality Metric Standards. AB - OBJECTIVE: Medical institutions use quality metrics to track complications seen in hospital admissions. Similarly, morbidity and mortality (M&M) conferences are held to peer review complications. The purpose of this study was to compare the complications identified in a cohort of patients within 30 days of neurosurgical intervention with those captured in a cohort of M&M conferences. METHODS: All complications that occurred within 30 days of surgery were obtained for patients admitted to the neurosurgical service between May and September 2013. All patients discussed in M&M conference between August 2012 and February 2015 were included in a second data set. Complications were subdivided into 4 categories and compared between the 2 cohorts. RESULTS: A total of 749 postoperative complications were identified, including 52 urinary tract infections, 52 pneumonias, 15 deep vein thromboses, 19 strokes, 75 seizures, 25 wound infections, 6 cardiac arrests, and 162 reoperations. Eighty-five M&M cases were reviewed, identifying 9 strokes, 3 seizures, 8 wound infections, 13 hematomas, 7 intraoperative errors, and 11 postoperative deaths. The M&M cohort showed higher rates of neurologic complications (P < 0.0001) and surgical complications (P < 0.0001). The neurosurgical admission cohort showed higher rates of general medical adverse events (P = 0.0118) and infectious complications (not surgical wound related, P = 0.0002). CONCLUSIONS: Both neurosurgical service inpatient complications and complications discussed in M&M provide valuable opportunities for identifying areas in need of quality improvement. As the United States moves toward an outcomes reimbursement model, neurosurgical programs should adjust M&M conferences to reflect both technical operative complications as well as more common complications. PMID- 29626684 TI - Clinical and Radiographic Results of a Minimally Invasive Lateral Transpsoas Approach for Treatment of Septic Spondylodiscitis of the Thoracolumbar and Lumbar Spine. AB - BACKGROUND: The minimally invasive lateral transpsoas approach allows retroperitoneal access for discectomy and graft placement. However, the procedure has rarely been used for the treatment of septic spondylodiscitis. The purposes of this study were to evaluate the clinical and radiographic outcomes from this minimally invasive procedure for septic spondylodiscitis. METHODS: Thirty-one consecutive patients (17 males and 14 females) were included in this study from July 2013 to January 2016. Clinical outcomes were assessed by Oswestry Disability Index, visual analog scale, modified Macnab criteria, and inflammatory parameters. Radiographic results were analyzed by studying the changes in diseased disc height, lordosis, and fusion status. RESULTS: The Oswestry Disability Index and visual analog scale score improved by 58% and 69% at the last follow-up. The modified Macnab criteria were found to be excellent in 21 patients (68%) and good in 10 (32%). Inflammatory parameters normalized over the average 24 months follow-up. There were no major complications that might have influenced the outcomes in this cohort. A complete fusion after 12 months was achieved in 87% of patients. A mean 7.5 mm restoration in disc height and 6.4 degrees restoration in lumbar lordosis were observed in all patients, whereas an average 4.5 mm loss in restored height resulting from graft subsidence was observed in 24 patients during the follow-up. However, graft subsidence did not influence clinical outcomes significantly. CONCLUSIONS: A minimally invasive lateral transpsoas approach in combination with instrumentation provides a novel treatment for patients with septic spondylodiscitis without severe kyphosis and neurologic impairment. PMID- 29626686 TI - Does Preoperative Degenerative Spondylolisthesis Influence Outcome in Degenerative Lumbar Spinal Stenosis? Three-Year Results of a Swiss Prospective Multicenter Cohort Study. AB - BACKGROUND: Decompression alone to treat degenerative lumbar stenosis with and without concomitant degenerative spondylolisthesis (DS; non-DS) has shown ambiguous results in the literature. OBJECTIVE: The aim is to compare clinical outcomes in DS and non-DS patients with lumbar stenosis who underwent decompression alone surgery without fusion on 1-3 adjacent levels after 6-month, 12-month, 24-month, and 36-month follow-up. METHODS: We conducted a prospective cohort study at 8 medical centers. The main outcomes of this study are changes in Spinal Stenosis Measure (SSM) symptoms score, SSM function score, and quality of life (EQ-5D-3L sum score) over time. Propensity score matching for DS versus non DS was applied. RESULTS: One hundred seventy-seven patients met the inclusion criteria, 68 of whom had DS. In the matched cohort (n = 136), the estimated difference in SSM symptoms score of DS versus non-DS for changes from baseline to 36 months was 0.21 (95% CI, -0.15 to 0.57). For SSM function score, the estimated difference from baseline to 36 months was 0.05 (-0.21 to 0.31). Differences in changes between groups in EQ-5D-3L sum score were estimated to be -3.66 (-10.63 to 3.31) from baseline to 36 months. None of the group differences between the non-DS and the DS group was statistically significant. All matched patients improved over time in all additional outcomes. CONCLUSIONS: Even after 3 years of follow-up, we show that among patients with degenerative lumbar spinal stenosis, both groups (DS and non-DS) distinctively take advantage of decompression alone without fusion. PMID- 29626687 TI - Aseptic Bone Flap Resorption after Cranioplasty with Autologous Bone: Incidence, Risk Factors, and Clinical Implications. AB - OBJECTIVES: Aseptic bone flap resorption (ABFR) is a known complication of cranioplasty (CP) with an autologous bone flap. The incidence of ABFR has been reported to be as high as 34.2% in the literature; however, it is underestimated in clinical fields. We retrospectively reviewed 13 years of clinical cases of patients who underwent CP after decompressive craniectomy (DC) to investigate the incidence and risk factors of ABFR. METHODS: Ninety-one patients who underwent DC and CP in Guro Hospital, Korea University Medical Center, were enrolled. ABFR was defined using serial brain computed tomography. To identify possible risk factors for ABFR, univariate and multivariate Cox regression and receiver operating characteristic curve analyses were performed. RESULTS: Of the 91 patients enrolled, ABFR was diagnosed in 32 patients (35.1%). Bone flap size, existence of a shunting system, and the DC-CP interval were significant in the univariate analysis. Bone flap size was statistically significant in the multivariate analysis (P = 0.0189). The cutoff points of the DC-CP interval and bone flap size were 44 days and 110 cm2, respectively. CONCLUSIONS: The incidence of ABFR was remarkably high. Bone flap size, the existence of a shunting system, and the DC CP interval were shown to be potential risk factors of ABFR after CP. PMID- 29626688 TI - Houdini Tumor: Case Report and Literature Review of Pregnancy-Associated Meningioma. AB - BACKGROUND: Meningiomas are common intracranial neoplasms of undetermined etiology. Accelerated growth during episodes of elevated serum estrogen and progesterone have been demonstrated in pregnant patients, as exhibited by an overexpression of estrogen or progesterone on immunohistochemical analysis. This case report and literature review describe a case of complete meningioma regression in a postpartum patient. CASE DESCRIPTION: A 23-year-old female presented at 37 weeks of pregnancy with 1-month history of fluctuating severe left-sided headaches, periodic blurry vision, nausea, and vomiting. She had 2 previous pregnancies without complication. Magnetic resonance imaging revealed a dural-based, heterogeneously enhancing mass along the left tentorium, just posterior to the transverse sinus, with supratentorial extension and surrounding edema. Differential diagnoses included meningioma versus hemangioma versus hemangiopericytoma. The patient followed up with neurosurgery 1 month after delivery. She had continued left-sided headaches but no longer complained of visual changes. A postpartum surgical resection via left occipital and suboccipital craniotomy was planned. Approximately 1 month later (now about 3 months after delivery) a repeat magnetic resonance imaging demonstrated a marked decrease in meningioma size, and the previously seen edema had resolved. In light of the sudden disappearance of the meningioma, no further surgical intervention was pursued. CONCLUSIONS: Because meningioma shrinkage or disappearance may occur after pregnancy, repeat imaging is advised as part of a preoperative evaluation. In addition, it is possible that an undetermined amount of meningioma removal surgeries may be avoided with further research into monitoring hormone levels connected to meningioma growth. PMID- 29626689 TI - Petrous Face Meningiomas: Classification, Clinical Syndromes, and Surgical Outcomes. AB - BACKGROUND: Petrous face meningiomas (PFMs) are challenging tumors because of their proximity to the cranial nerves, brainstem, and critical vasculature. The objective of this study is to present surgical outcomes and support an anatomic classification for PFM based on clinical presentation. METHODS: A retrospective chart review was performed, and 51 PFMs were identified. Tumors were classified by location along the petrous face into anterior, middle, and posterior. Presentation and outcomes were analyzed with logistic regression. RESULTS: The median follow-up was 31.6 months. Tumors were World Health Organization grade I (n = 50), with 1 World Health Organization grade II tumor. Location was anterior (22%), middle (14%), posterior (53%), and overlapping (12%). Median tumor diameter was 3.0 cm (range, 0.8-6.2 cm). Anterior location was associated with facial pain/numbness on presentation (P < 0.0001), middle location with hearing loss/vestibular dysfunction (P = 0.0035), and posterior with hydrocephalus (P = 0.0190), headache (P = 0.0039), and vertigo (P = 0.0265). Extent of resection was gross total (63%), near total (14%), and subtotal (25%). The observed radiographic recurrence rate was 15%. Mean progression-free survival after diagnosis was 9.1 years with 2-year, 5-year, and 10-year progression-free survival of 91.8%, 78.6%, and 62.9%, respectively. The complication rate was 27%. Age, location, and approach were not associated with complications. CONCLUSIONS: PFMs present with distinct clinical syndromes based on their location along the petrous face: anterior with trigeminal symptoms, middle with auditory/vestibular symptoms, and posterior with symptoms of mass effect/hydrocephalous. Surgical resection is associated with excellent long-term survival and a low rate of recurrence, which can be managed with radiotherapy. PMID- 29626690 TI - Traumatic Posterolateral C1-C2 Dislocation Complicated with Locked Lateral Mass and Type II Odontoid Fracture-5-Year Follow-up. AB - OBJECTIVE: We sought to document our experience in managing a rare complex of traumatic posterolateral atlantoaxial dislocation combined with locked lateral mass and type II odontoid fracture. METHOD: A 30-year-old male patient was referred to the author's department. He complained of a decrease in neck range of motion following a traffic accident. Neurologic examination was normal. Computed tomography and open-mouth radiographs showed a type II odontoid fracture and a posterolateral dislocation with a laterally locked left lateral mass at the C1-C2 level. Considering the difficulty and risk in reduction, due to this rare instability and dislocation, a 2-staged treatment was performed. With up to 11 kg skull traction for 7 days before surgery, the locked lateral mass and the lateral dislocation was finally reduced without any neurologic deficit. And once closed reduction was confirmed by open-mouth and lateral X-ray views in the cervical spine, a second staged C1-C2 surgical fixation and fusion with iliac bone graft was performed to achieve a normal anatomic alignment with a better stability. RESULT: The patient showed significant amelioration of neck symptoms postoperatively, and a successful reduction and fixation of the C1-C2 articulation was achieved. At the 5-year follow-up, solid bone fusion was evident on the computed tomography scan. CONCLUSION: For traumatic posterolateral atlantoaxial dislocation complicated with type II odontoid fracture, a closed reduction of the lateral dislocation before operation is both useful and safe because surgeons do not need to reduce the extremely rare lateral dislocation during the operation. Posterior atlantoaxial stabilization and fusion, rather than the occipitocervical fusion as reported previously, is biomechanically stable enough to achieve solid fusion in this rare trauma while not sacrificing the occipitoatlantal joint. PMID- 29626691 TI - Spinal Concussion in Adults: Transient Neuropraxia of Spinal Cord Exposed to Vertical Forces. AB - OBJECTIVE: The aim of the study is to discuss along with literature knowledge the post-traumatic clinical progression of cases with symptoms of transient spinal cord impact and cases of spinal concussion following exposure of the vertebral column to vertical forces. MATERIALS AND METHODS: A total of 43 cases, all falls from height, were diagnosed with spinal concussion. It was determined that the vertebral column had been exposed to the effects of vertical forces, and the spinal cord had been affected by vertical forces. In all cases, spinal magnetic resonance imaging and dynamic X-ray examinations were performed at the time of admission. Clinical symptoms of the cases were recorded by scoring based on the Torg Grading System. RESULTS: Cases were started on conservative treatment because radiologic symptoms that would explain the clinical symptoms could not be detected. Most frequently encountered were the neurologic symptoms related to the upper thoracic and lower cervical segments being affected. In 7 cases, urinary incontinence was also detected. Symptoms related to the spinal cord being affected were completely recovered in 1-3 days in all cases. CONCLUSION: As a result of the vertebral column being affected by vertical forces, the most frequently affected are the thoracic segments of the spinal cord. These cases show similarities to real spinal cord injury without radiographic abnormality cases when evaluated along with clinical and radiologic symptoms. Absolute differential diagnosis from real spinal cord injury without radiographic abnormality cases cannot be made until total neurologic recovery takes place. PMID- 29626692 TI - Global and gene-specific DNA methylation effects of different asbestos fibres on human bronchial epithelial cells. AB - Inhalation exposure to asbestos is associated with lung and pleural diseases in humans and remains a major public health issue worldwide. Human bronchial epithelial cells (16HBE) were exposed to UICC amosite, crocidolite and chrysotile. Cytotoxicity, genotoxicity, global DNA methylation on cytosine residues (using LC-MS/MS) were investigated at different doses (2.5-100 MUg/ml). Gene-specific DNA methylation alterations at the whole genome were investigated using a microarray that interrogates >450 thousand CpG sites. Subsequently, gene functional analyses (KEGG pathway, Gene Ontology and functional classification) were performed on genes with differentially methylated gene promoters. At non cytotoxic doses, global DNA methylation was altered after 24 h exposure to amosite and crocidolite (>2.5 MUg/ml). Exposure to amosite and crocidolite (amphibole type asbestos) induced both hypomethylation and hypermethylation at single CpG site and gene promoter levels whereas exposure to chrysotile (serpentine type asbestos) induced hypomethylation at the gene promoter level. Gene functional classification analyses revealed that all types of asbestos fibres induce alterations on GO-clusters i.e. on regulation of Rho-protein signal transduction, nucleus, (e.g. homeobox genes), ATP-binding function and extracellular region (e.g. WNT-group of genes). These differentially methylated genes might contribute to asbestos-related diseases in bronchial cells. PMID- 29626694 TI - Temporal and seasonal variations of mortality burden associated with hourly temperature variability: A nationwide investigation in England and Wales. AB - BACKGROUND: Sudden temperature change may elevate short-term mortality and remains an important global health threat in the context of climate change. To date, however, little available temperature-mortality evidence has taken into account both intra- and inter-day temperature variability (TV), thus largely limiting the comprehensive understanding of mortality burden due to unstable weather. Moreover, seasonal and temporal patterns in TV-mortality associations were sparsely discussed, nationally and regionally. OBJECTIVES: We aimed to assess the nationwide association of all-cause mortality with hourly temperature variability (HTV), quantify HTV-attributable mortality, and further explore the temporal and seasonal variations of mortality burden due to HTV in United Kingdom. METHODS: Fourteen-year time-series data on temperature and mortality were collected from 10 regions in England and Wales during 1993-2006, totally including 7,573,716 all-cause deaths. HTV was calculated from the standard deviation of hourly temperature records within two neighboring days. A three stage analytic approach was adopted to assess HTV-associated mortality burden. We first applied a time-series quasi-Poisson regression to estimate region-specific HTV-mortality associations, then pooled these associations at the national level using a multivariate meta-analysis, and finally estimated the HTV-attributable mortality fraction and illustrated its seasonal and temporal variations by conducting season- and period-specific analyses based on time-varying distributed lag models. RESULTS: We found strong evidence that large HTV exposure elevated short-term mortality risk in England and Wales, with a pooled estimate of 1.13% (95% confidence interval (CI): 0.88, 1.39) associated with a 1- degrees C increase in HTV. During the whole study period, HTV accounted for a national average attributable fraction of 2.52% (95% empirical confidence interval (eCI): 2.27, 2.76) of the total deaths. This HTV-attributable mortality estimate showed a significant temporal decrease (p < 0.001) from 2.72% (95% eCI: 2.58, 2.87) in 1993-99 to 2.28% (95% eCI: 2.13, 2.43) in 2000-06. Additionally, clear seasonal variations were observed for HTV-attributable mortality burden, with the largest estimate of 3.08% (95% eCI: 2.80, 3.38) in summer, followed by 2.71% (95% eCI: 2.44, 2.98) in spring, 2.40% (95% eCI: 2.16, 2.63) in autumn, and 2.00% (95% eCI: 1.81, 2.20) in winter. CONCLUSIONS: Despite clear evidence observed for the reduction, mortality burden caused by temperature variability remained a great public health threat, especially in warm seasons. It highlighted the importance of specific interventions targeted to unstable weather as well as temperature extremes, so as to reduce climate-related mortality burden. PMID- 29626693 TI - Antibiotic resistance in wastewater treatment plants: Tackling the black box. AB - Wastewater is among the most important reservoirs of antibiotic resistance in urban environments. The abundance of carbon sources and other nutrients, a variety of possible electron acceptors such as oxygen or nitrate, the presence of particles onto which bacteria can adsorb, or a fairly stable pH and temperature are examples of conditions favouring the remarkable diversity of microorganisms in this peculiar habitat. The wastewater microbiome brings together bacteria of environmental, human and animal origins, many harbouring antibiotic resistance genes (ARGs). Although numerous factors contribute, mostly in a complex interplay, for shaping this microbiome, the effect of specific potential selective pressures such as antimicrobial residues or metals, is supposedly determinant to dictate the fate of antibiotic resistant bacteria (ARB) and ARGs during wastewater treatment. This paper aims to enrich the discussion on the ecology of ARB&ARGs in urban wastewater treatment plants (UWTPs), intending to serve as a guide for wastewater engineers or other professionals, who may be interested in studying or optimizing the wastewater treatment for the removal of ARB&ARGs. Fitting this aim, the paper overviews and discusses: i) aspects of the complexity of the wastewater system and/or treatment that may affect the fate of ARB&ARGs; ii) methods that can be used to explore the resistome, meaning the whole ARB&ARGs, in wastewater habitats; and iii) some frequently asked questions for which are proposed addressing modes. The paper aims at contributing to explore how ARB&ARGs behave in UWTPs having in mind that each plant is a unique system that will probably need a specific procedure to maximize ARB&ARGs removal. PMID- 29626695 TI - Multi-functional electrospun antibacterial core-shell nanofibrous membranes for prolonged prevention of post-surgical tendon adhesion and inflammation. AB - : The possibility of endowing an electrospun anti-adhesive barrier membrane with multi-functionality, such as lubrication, prevention of fibroblast attachment and anti-infection and anti-inflammation properties, is highly desirable for the management of post-surgical tendon adhesion. To this end, we fabricated core shell nanofibrous membranes (CSNMs) with embedded silver nanoparticles (Ag NPs) in the poly(ethylene glycol) (PEG)/poly(caprolactone) (PCL) shell and hyaluronic acid (HA)/ibuprofen in the core. HA imparted a lubrication effect for smooth tendon gliding and reduced fibroblast attachment, while Ag NPs and ibuprofen functioned as anti-infection and anti-inflammation agents, respectively. CSNMs with a PEG/PCL/Ag shell (PPA) and HA core containing 0% (H/PPA), 10% (HI10/PPA), 30% (HI30/PPA) and 50% (HI50/PPA) ibuprofen were fabricated through co-axial electrospinning and assessed through microscopic, spectroscopic, thermal, mechanical and drug release analyses. Considering nutrient passage through the barrier, the microporous CSNMs exerted the same barrier effect but drastically increased the mass transfer coefficients of bovine serum albumin compared with the commercial anti-adhesive membrane SurgiWrap(r). Cell attachment/focal adhesion formation of fibroblasts revealed effective reduction of initial cell attachment on the CSNM surface with minimum cytotoxicity (except HI50/PPA). The anti-bacterial effect against both Gram-negative and Gram-positive bacteria was verified to be due to the Ag NPs in the membranes. In vivo studies using H/PPA and HI30/PPA CSNMs and SurgiWrap(r) in a rabbit flexor tendon rupture model demonstrated the improved efficacy of HI30/PPA CSNMs in reducing inflammation and tendon adhesion formation based on gross observation, histological analysis and functional assays. We conclude that HI30/PPA CSNMs can act as a multifunctional barrier membrane to prevent peritendinous adhesion after tendon surgery. STATEMENT OF SIGNIFICANCE: A multi-functional anti-adhesion barrier membrane that could reduce fibroblasts attachment and penetration while simultaneously prevent post-surgical infection and inflammation is urgently needed. To this end, we prepared electrospun core-shell hyaluronic acid + ibuprofen/polyethylene glycol + polycaprolactone + Ag nanoparticles nanofibrous membranes by co-axial electrospinning as an ideal anti-adhesive membrane. The core-shell structure could meet the need of a desirable anti-adhesion barrier through release of ibuprofen and Ag nanoparticles to reduce infection and inflammation while hyaluronic acid can reduce fibroblasts adhesion. The superior performance of this multi-functional core-shell nanofibrous membrane in preventing peritendinous adhesion and post-surgical inflammation was demonstrated in a rabbit flexor tendon rupture model. PMID- 29626696 TI - Fine-tuning pro-angiogenic effects of cobalt for simultaneous enhancement of vascular endothelial growth factor secretion and implant neovascularization. AB - : Rapid neovascularization of a tissue-engineered (TE) construct by the host vasculature is quintessential to warrant effective bone regeneration. This process can be promoted through active induction of angiogenic growth factor secretion or by implementation of in vitro pre-vascularization strategies. In this study, we aimed at optimizing the pro-angiogenic effect of Cobalt (Co2+) to enhance vascular endothelial growth factor (VEGF) expression by human periosteum derived mesenchymal stem cells (hPDCs). Simultaneously we set out to promote microvascular network formation by co-culturing with human umbilical vein endothelial cells (HUVECs). The results showed that Co2+ treatments (at 50, 100 or 150 uM) significantly upregulated in vitro VEGF expression, but inhibited hPDCs growth and HUVECs network formation in co-cultures. These inhibitory effects were mitigated at lower Co2+ concentrations (at 5, 10 or 25 uM) while VEGF expression remained significantly upregulated and further augmented in the presence of Ascorbic Acid and Dexamethasone possibly through Runx2 upregulation. The supplements also facilitated HUVECs network formation, which was dependent on the quantity and spatial distribution of collagen type-1 matrix deposited by the hPDCs. When applied to hPDCs seeded onto calcium phosphate scaffolds, the supplements significantly induced VEGF secretion in vitro, and promoted higher vascularization upon ectopic implantation in nude mice shown by an increase of CD31 positive blood vessels within the scaffolds. Our findings provided novel insights into the pleotropic effects of Co2+ on angiogenesis (i.e. promoted VEGF secretion and inhibited endothelial network formation), and showed potential to pre-condition TE constructs under one culture regime for improved implant neovascularization in vivo. STATEMENT OF SIGNIFICANT: Cobalt (Co2+) is known to upregulate vascular endothelial growth factor (VEGF) secretion, however it also inhibits in vitro angiogenesis through unknown Co2+-induced events. This limits the potential of Co2+ for pro-angiogenesis of tissue engineered (TE) implants. We showed that Co2+ upregulated VEGF expression by human periosteum-derived cells (hPDCs) but reduced the cell growth, and endothelial network formation due to reduction of col-1 matrix deposition. Supplementation with Ascorbic acid and Dexamethasone concurrently improved hPDCs growth, endothelial network formation, and upregulated VEGF secretion. In vitro pre-conditioning of hPDC-seeded TE constructs with this fine-tuned medium enhanced VEGF secretion and implant neovascularization. Our study provided novel insights into the pleotropic effects of Co2+ on angiogenesis and formed the basis for improving implant neovascularization. PMID- 29626697 TI - Hyperspectral chemical imaging reveals spatially varied degradation of polycarbonate urethane (PCU) biomaterials. AB - : Hyperspectral chemical imaging (HCI) is an emerging technique which combines spectroscopy with imaging. Unlike traditional point spectroscopy, which is used in the majority of polymer biomaterial degradation studies, HCI enables the acquisition of spatially localised spectra across the surface of a material in an objective manner. Here, we demonstrate that attenuated total reflectance Fourier transform infra-red (ATR-FTIR) HCI reveals spatial variation in the degradation of implantable polycarbonate urethane (PCU) biomaterials. It is also shown that HCI can detect possible defects in biomaterial formulation or specimen production; these spatially resolved images reveal regional or scattered spatial heterogeneity. Further, we demonstrate a map sampling method, which can be used in time-sensitive scenarios, allowing for the investigation of degradation across a larger component or component area. Unlike imaging, mapping does not produce a contiguous image, yet grants an insight into the spatial heterogeneity of the biomaterial across a larger area. These novel applications of HCI demonstrate its ability to assist in the detection of defective manufacturing components and lead to a deeper understanding of how a biomaterial's chemical structure changes due to implantation. STATEMENT OF SIGNIFICANCE: The human body is an aggressive environment for implantable devices and their biomaterial components. Polycarbonate urethane (PCU) biomaterials in particular were investigated in this study. Traditionally one or a few points on the PCU surface are analysed using ATR-FTIR spectroscopy. However the selection of acquisition points is susceptible to operator bias and critical information can be lost. This study utilises hyperspectral chemical imaging (HCI) to demonstrate that the degradation of a biomaterial varies spatially. Further, HCI revealed spatial variations of biomaterials that were not subjected to oxidative degradation leading to the possibility of HCI being used in the assessment of biomaterial formulation and/or component production. PMID- 29626698 TI - In vitro evaluation of MgSr and MgCaSr alloys via direct culture with bone marrow derived mesenchymal stem cells. AB - : Magnesium (Mg) and its alloys have been widely investigated as the most promising biodegradable metals to replace conventional non-degradable metals for temporary medical implant applications. New Mg alloys have been developed for medical applications in recent years; and the concept of alloying Mg with less toxic elements have aroused tremendous interests due to the promise to address the problems associated with rapid degradation of Mg without compromising its cytocompatibility and biocompatibility. Of particular interests for orthopedic/spinal implant applications are the additions of calcium (Ca) and strontium (Sr) into Mg matrix because of their beneficial properties for bone regeneration. In this study, degradation and cytocompatibility of four binary MgSr alloys (Mg-xSr, x = 0.2, 0.5, 1 and 2 wt%) and four ternary MgCaSr alloys (Mg-1Ca-xSr, x = 0.2, 0.5, 1 and 2 wt%) were investigated and compared via direct culture with bone marrow-derived mesenchymal stem cells (BMSCs). The influence of the alloy composition on the degradation rates were studied and compared. Moreover, the cellular responses to the binary MgSr alloys and the ternary MgCaSr alloys were comparatively evaluated; and the critical factors influencing BMSC behaviors were discussed. This study screened the degradability and in vitro cytocompatibility of the binary MgSr alloys and the ternary MgCaSr alloys. Mg 1Sr, Mg-1Ca-0.5Sr and Mg-1Ca-1Sr alloys are recommended for further in vivo studies toward clinical translation due to their best overall performances in terms of degradation and cytocompatibility among all the alloys studied in the present work. STATEMENT OF SIGNIFICANCE: Traditional Mg alloys with slower degradation often contain aluminum or rare earth elements as alloying components, which raised safety and regulatory concerns. To circumvent unsafe elements, nutrient elements such as calcium (Ca) and strontium (Sr) were selected to create Mg-Sr binary alloys and Mg-Ca-Sr ternary alloys to improve the safety and biocompatibility of bioresorbable Mg alloys for medical implant applications. In this study, in vitro degradation and cellular responses to four binary Mg-xSr alloys and four ternary Mg-1Ca-xSr alloys with increasing Sr content (up to 2 wt%) were evaluated in direct culture with bone marrow derived mesenchymal stem cells (BMSCs). The roles of Sr and Ca in tuning the alloy microstructure, degradation behaviors, and BMSC responses were collectively compared in the BMSC direct culture system for the first time. The most promising alloys were identified and recommended for further in vivo studies toward clinical translation. PMID- 29626699 TI - Therapeutics incorporating blood constituents. AB - : Blood deficiency and dysfunctionality can result in adverse events, which can primarily be treated by transfusion of blood or the re-introduction of properly functioning sub-components. Blood constituents can be engineered on the sub cellular (i.e., DNA recombinant technology) and cellular level (i.e., cellular hitchhiking for drug delivery) for supplementing and enhancing therapeutic efficacy, in addition to rectifying dysfunctioning mechanisms (i.e., clotting). Herein, we report the progress of blood-based therapeutics, with an emphasis on recent applications of blood transfusion, blood cell-based therapies and biomimetic carriers. Clinically translated technologies and commercial products of blood-based therapeutics are subsequently highlighted and perspectives on challenges and future prospects are discussed. STATEMENT OF SIGNIFICANCE: Blood based therapeutics is a burgeoning field and has advanced considerably in recent years. Blood and its constituents, with and without modification (i.e., combinatorial), have been utilized in a broad spectrum of pre-clinical and clinically-translated treatments. This review article summarizes the most up-to date progress of blood-based therapeutics in the following contexts: synthetic blood substitutes, acellular/non-recombinant therapies, cell-based therapies, and therapeutic sub-components. The article subsequently discusses clinically translated technologies and future prospects thereof. PMID- 29626700 TI - Combinatory approach for developing silk fibroin scaffolds for cartilage regeneration. AB - : Several processing technologies and engineering strategies have been combined to create scaffolds with superior performance for efficient tissue regeneration. Cartilage tissue is a good example of that, presenting limited self-healing capacity together with a high elasticity and load-bearing properties. In this work, novel porous silk fibroin (SF) scaffolds derived from horseradish peroxidase (HRP)-mediated crosslinking of highly concentrated aqueous SF solution (16 wt%) in combination with salt-leaching and freeze-drying methodologies were developed for articular cartilage tissue engineering (TE) applications. The HRP crosslinked SF scaffolds presented high porosity (89.3 +/- 0.6%), wide pore distribution and high interconnectivity (95.9 +/- 0.8%). Moreover, a large swelling capacity and favorable degradation rate were observed up to 30 days, maintaining the porous-like structure and beta-sheet conformational integrity obtained with salt-leaching and freeze-drying processing. The in vitro studies supported human adipose-derived stem cells (hASCs) adhesion, proliferation, and high glycosaminoglycans (GAGs) synthesis under chondrogenic culture conditions. Furthermore, the chondrogenic differentiation of hASCs was assessed by the expression of chondrogenic-related markers (collagen type II, Sox-9 and Aggrecan) and deposition of cartilage-specific extracellular matrix for up to 28 days. The cartilage engineered constructs also presented structural integrity as their mechanical properties were improved after chondrogenic culturing. Subcutaneous implantation of the scaffolds in CD-1 mice demonstrated no necrosis or calcification, and deeply tissue ingrowth. Collectively, the structural properties and biological performance of these porous HRP-crosslinked SF scaffolds make them promising candidates for cartilage regeneration. STATEMENT OF SIGNIFICANCE: In cartilage tissue engineering (TE), several processing technologies have been combined to create scaffolds for efficient tissue repair. In our study, we propose novel silk fibroin (SF) scaffolds derived from enzymatically crosslinked SF hydrogels processed by salt-leaching and freeze drying technologies, for articular cartilage applications. Though these scaffolds, we were able to combine the elastic properties of hydrogel-based systems, with the stability, resilience and controlled porosity of scaffolds processed via salt-leaching and freeze-drying technologies. SF protein has been extensively explored for TE applications, as a result of its mechanical strength, elasticity, biocompatibility, and biodegradability. Thus, the structural, mechanical and biological performance of the proposed scaffolds potentiates their use as three-dimensional matrices for cartilage regeneration. PMID- 29626701 TI - Barriers and facilitators to preventing pressure ulcers in nursing home residents: A qualitative analysis informed by the Theoretical Domains Framework. AB - BACKGROUND: Pressure ulcers are areas of localised damage to the skin and underlying tissue; and can cause pain, immobility, and delay recovery, impacting on health-related quality of life. The individuals who are most at risk of developing a pressure ulcer are those who are seriously ill, elderly, have impaired mobility and/or poor nutrition; thus, many nursing home residents are at risk. OBJECTIVES: To understand the context of pressure ulcer prevention in nursing homes and to explore the potential barriers and facilitators to evidence informed practices. METHODS: Semi-structured interviews were conducted with nursing home nurses, healthcare assistants and managers, National Health Service community-based wound specialist nurses (known in the UK as tissue viability nurses) and a nurse manager in the North West of England. The interview guide was developed using the Theoretical Domains Framework to explore the barriers and facilitators to pressure ulcer prevention in nursing home residents. Data were analysed using a framework analysis and domains were identified as salient based on their frequency and the potential strength of their impact. FINDINGS: 25 participants (nursing home: 2 managers, 7 healthcare assistants, 11 qualified nurses; National Health Service community services: 4 tissue viability nurses, 1 manager) were interviewed. Depending upon the behaviours reported and the context, the same domain could be classified as both a barrier and a facilitator. We identified seven domains as relevant in the prevention of pressure ulcers in nursing home residents mapping to four "barrier" domains and six "facilitator" domains. The four "barrier" domains were knowledge, physical skills, social influences and environmental context and resources and the six "facilitator" domains were interpersonal skills, environmental context and resources, social influences, beliefs about capabilities, beliefs about consequences and social/professional role and identity). Knowledge and insight into these barriers and facilitators provide a theoretical understanding of the complexities in preventing pressure ulcers with reference to the staff capabilities, opportunities and motivation related to pressure ulcer prevention. CONCLUSION: Pressure ulcer prevention in nursing home residents is complex and is influenced by several factors. The findings will inform a theory and evidence-based intervention to aid the prevention of pressure ulcers in nursing home settings. PMID- 29626702 TI - Risk factors associated with dehydration in older people living in nursing homes: Scoping review. AB - BACKGROUND: Dehydration in the older people is a prevalent problem that is often associated with physiological changes, physical limitations and environmental conditions. OBJECTIVES: The scoping review was carried out to identify risk factors associated with dehydration in older people living in nursing homes. DESIGN: The revised scoping methodology framework of Arksey and O'Malley (2005) was applied. Study selection was carried out in accordance with Davis et al. (2009) and focused on the inclusion criteria (people over 65 years old and living in nursing homes). Risk factors were classified using the geriatric assessment. DATA SOURCES: An electronic database search was performed in PubMed, Scopus and CINAHL. The literature search was carried out between October 2016 and January 2017. REVIEW METHODS: Thematic reporting was performed and study findings were validated through interdisciplinary meetings of experts. The quality of the papers consulted was also evaluated using the Newcastle-Ottawa Scale adapted for cross-sectional, cohort and case-control studies. RESULTS: In all, 16 papers were analysed, all of which were observational studies. The risk of bias ranged from very low (n = 1), to medium (n = 13) and high (n = 2). The risk factors were classified in line with the different components of the geriatric assessment. In the socio-demographic characteristics age and gender were identified. In the clinical component, infections, renal and cardiovascular diseases and end-of-life situations were the most common factors highlighted in the papers analysed. With reference to the functional component, its limitation was associated with dehydration, while for factors of mental origin, it was related to dementia and behavioural disorders. Finally, the factors relating to the social component were institutionalisation, requiring a skilled level of care and it being winter. CONCLUSIONS: The most commonly repeated factors highlighted in the review were age, gender, infections, end of life and dementia, with it being important to highlight the large number of factors in the clinical component. Even so, the great majority of the factors were unmodifiable conditions associated typically associated with the physiology of ageing. PMID- 29626703 TI - Work schedule flexibility is associated with emotional exhaustion among registered nurses in Swiss hospitals: A cross-sectional study. AB - BACKGROUND: Emotional exhaustion among healthcare workers is a widely investigated, well-recognized problem, the incidence of which has recently been linked to work environment factors, particularly work/family conflict. However, another environmental feature that may be equally influential, but that is more amenable to nurse manager action, remains less recognized: shift schedule flexibility. OBJECTIVES: This study's main purposes were to assess variations in work schedule flexibility between Swiss acute care hospital units, and to investigate associations between psychosocial work environment (e.g. work schedule flexibility) and self-reported emotional exhaustion among registered nurses. METHODS: This is a secondary analysis of data collected for the multi center observational cross-sectional MatchRN study, which included a national sample of 23 hospitals and 1833 registered nurses across Switzerland. RESULTS: Overall, self-reported work schedule flexibility among registered nurses was limited: 32% of participants reported little or no influence in planning their own shifts. Work schedule flexibility (beta -0.11; CI -0.16; -0.06) and perceived nurse manager ability (beta -0.30; CI -0.49; -0.10) were negatively related to self-reported emotional exhaustion. Work-family conflict (beta 0.39; CI 0.33; 0.45) was positively correlated to emotional exhaustion. CONCLUSIONS: The study results indicate that managerial efforts to improve working environments, including special efforts to improve work schedule flexibility, might play an important role in promoting nurses' emotional health. PMID- 29626704 TI - Serum cortisol levels in asphyxiated infants with hypotension. PMID- 29626705 TI - Biosynthetic pathways of glycinebetaine in Thalassiosira pseudonana; functional characterization of enzyme catalyzing three-step methylation of glycine. AB - Betaine (trimethylglycine) is an important compatible solute that accumulates in response to abiotic stresses such as drought and salinity. Biosynthetic pathways of betaine have been extensively studied, but it remains to be clarified on algae. A diatom Thalassiosira pseudonana CCMP1335 is an important component of marine ecosystems. Here we show that the genome sequence of Thalassiosira suggests the presence of two biosynthetic pathways for betaine, via three step methylation of glycine and via two step oxidation of choline. The choline oxidation via choline dehydrogenase was suggested and its sequential characteristics were analyzed. A candidate gene TpORF1 for glycine methylation encodes a protein consisted of 574 amino acids with two putative tandem repeat methyltransferase domains. The TpORF1 was expressed in E. coli, and the purified protein was shown to synthesize betaine via three step methylation of glycine and designated as TpGSDMT. The proteins containing C-terminal half or N-terminal half were expressed in E. coli and exhibited the methyl transferase activities with different substrate specificity for glycine, sarcosine and dimethylglycine. Upregulation of TpGSDMT transcription and betaine levels were observed at high salinity, suggesting the importance of TpGSDMT for salt tolerance in T. pseudonana cells. PMID- 29626706 TI - Cost-Effectiveness Analysis of Pneumococcal and Influenza Vaccines Administered to Children Less Than 5 Years of Age in a Low-Income District of Bogota, Colombia. AB - BACKGROUND: The Colombian health authorities introduced the pneumococcal conjugated vaccine and the seasonal influenza vaccine into the national immunization schedule for children in 2009 and 2007, respectively. Despite this, the health authorities continue to be concerned about the high economic and disease burden among children from low-income households caused by these vaccine preventable diseases. OBJECTIVES: 1) To evaluate the potential health outcomes of four vaccination strategies for subsidized children younger than 5 years in a low income district in Colombia from a public, direct medical health care perspective. 2) To perform univariate, multivariate, and probabilistic sensitivity analysis to evaluate the robustness of these results. METHODS: We built a Markov deterministic cohort model to evaluate five consecutive cohorts across four alternative situations: 1) no vaccination; 2) vaccination with the 10 valent pneumococcal conjugate vaccine (PCV10 vaccine); 3) vaccination with the trivalent inactivated vaccine (TIV) annually; and 4) combined vaccination with PCV10 vaccine and TIV. RESULTS: The introduction of PCV10 vaccine and TIV and their combined use in particular would be highly cost-effective in comparison to no vaccination. For the combined vaccination with PCV10 vaccine and TIV, the incremental cost-effectiveness ratio would be $1,280 per disability-adjusted life year (DALY) averted, the total incremental cost of the vaccination program would be $776,800, and it would avert four deaths and 332 DALYs for the five cohorts. CONCLUSIONS: The introduction of PCV10 vaccine and TIV would be highly cost effective from a public, direct medical health care perspective. Despite these results, we have not observed decreases in severity or hospitalizations. Our findings highlight the need for further studies of the immunization campaign indicators and socioeconomic indicators for this low-income community. PMID- 29626707 TI - Longitudinal association between psychosocial stress and retinal microvasculature in children and adolescents. AB - BACKGROUND: Retinal microvessels provides a window to assess the microcirculation of heart and brain, and might reflect cardio- or cerebrovascular disease risk. Limited information exist on the relation between psychosocial stress and the microcirculation, even though psychosocial stress might trigger vascular diseases. This study investigates whether childhood psychosocial stress is a predictor of retinal microvasculature. METHODS: We followed-up 182 Belgian children, aged 5.7-11.3 years at baseline (53.3% boys). Information about psychosocial stress was obtained using emotional, behavioral and negative life events questionnaires and hair cortisol, an objective stress marker. Retinal photographs were used to calculate vessel diameters, bifurcation angles and optimality deviation with semiautomated software. Cross-sectional and longitudinal associations were explored using multivariable regression analysis with retinal parameters in 2015 as outcome, while adjusting for age, sex, socioeconomic status, cardiovascular parameters and lifestyle factors. RESULTS: Feelings of happiness, sadness and negative life events were associated with retinal vascular diameter, but behavior and hair cortisol were not. High stress levels over a 4-year time period (less happy, sadder and higher total negative emotions) were associated with larger venules (beta = 0.21-0.43) and children who experienced more negative life events had smaller arterioles (beta = -0.15). No consistent patterns were seen with bifurcation angles and optimality deviation. CONCLUSION: Based on the results, we conclude that high levels of childhood psychosocial stress unfavorably affect the retinal vascular diameters, potentially reflecting the microvasculature of the heart and brain. It seems this might even be independent of lifestyle and BMI, but further research on mechanisms is necessary. PMID- 29626708 TI - Ureteral injuries during different types of hysterecomy: A 7-year series at a single university center. AB - OBJECTIVES: Accidental ureteral injury with gynaecologic surgery, especially hysterectomy, represents a high risk of patient morbidity. The incidence may vary from centre to centre. As the introduction of new minimally invasive surgical techniques and instruments may have affected the incidence of ureteral injury, we de novo analysed the incidence data for the last seven years. STUDY DESIGN: Incidence of ureteral injury was analysed stratifying the data according to the type of hysterectomy (n = 3071). The incidence rate was reported as a confidence interval (CI). Ureteral injuries were classified as direct or indirect. RESULTS: Fifteen ureteral injuries were registered. The highest incidence was evidenced for radical hysterectomy (CI: 0.82-3.99), followed by laparoscopic radical hysterectomy (CI: 0-11.9). The incidence of direct ureteral injury was 26.6%, half of which were identified during the operative procedure. In 26.7% of the operations resulting in ureteral injury, heat-generating instruments were used. CONCLUSIONS: The incidence of ureteral injury during different types of hysterectomy was low. The majority of injuries were indirect. These were injuries which resulted from a micro-trauma, and developed due to the delayed necrosis of the ureteral wall. Laparoscopic approach to radical and simple hysterectomy didn't substantially raise the incidence of ureteral injury. PMID- 29626709 TI - Impact of the mode of delivery on maternal and neonatal outcome in spontaneous onset breech labor at 32+0-36+6 weeks of gestation: A retrospective cohort study. AB - OBJECTIVE: To compare neonatal and maternal outcomes in spontaneously onset preterm breech deliveries after trial of labor (BTOL) and intended cesarean section (BCS), and between BTOL and vertex control deliveries, in singleton fetuses at 32+0-36+6 weeks of gestation. STUDY DESIGN: Retrospective single center cohort study in a Finnish University Hospital including all spontaneous onset preterm breech deliveries with 32 completed gestational weeks in 2003-2015. The study population comprised a total of 176 preterm breech and 103 vertex control deliveries, matched by gestational age and whether the mother had given birth vaginally before or not. Infants with severe malformations and antepartum fetal distress were excluded. Subgroup analyses were made in two cohorts according to gestational age. Main outcome measures were maternal and neonatal mortality and morbidity, low cord pH and Apgar score. RESULTS: No mortality was observed, and severe morbidity was rare. No difference in incidence of low cord pH or five-minute Apgar score was observed between the groups. Apgar scores at the age of one minute were comparable in the breech groups but more often low in the BTOL group compared to the vertex control group. 16.5% of neonates in the BTOL group, 23.3% in the BCS group and 7.8% in the vertex group needed intensive care. In logistic regression analysis, lower gestational age and being small for gestational age were associated with the need for neonatal intensive care. Being allowed a trial of labor was not associated with the need for neonatal intensive care. Maternal morbidity was similar across the groups, but median blood loss was more pronounced in the BCS group compared to the BTOL group. CONCLUSION: In breech deliveries at 32+0-36+6 gestational weeks, trial of labor did not increase neonatal morbidity compared to intended cesarean delivery. Infants born after a trial of labor in breech presentation display low one-minute Apgar score and need intensive care more often compared to vertex controls. PMID- 29626711 TI - Non invasive prenatal diagnosis of fetal aneuploidy using cell free fetal DNA. AB - The discovery of cell free fetal DNA in maternal plasma has stimulated a rapid development of non-invasive prenatal testing. The recent advent of massively parallel sequencing has allowed the analysis of circulating cell-free fetal DNA to be performed with unprecedented sensitivity and precision. It is thus expected that plasma DNA-based non invasive prenatal testing will play an increasingly important role in the future of obstetric care. The present review summarizes recent advances in non invasive prenatal testing using cell free fetal DNA. The importance of genetic counseling, the current guidelines for the use of cffDNA screening in pregnancy, as well as specific maternal conditions that can affect the performance of non invasive prenatal testing are also discussed in this review. PMID- 29626710 TI - Prenatal diagnosis of Wolf-Hirschhorn syndrome: Ultrasonography and molecular karyotyping results. AB - OBJECTIVE: To present the experience on prenatal diagnosis of Wolf-Hirschhorn syndrome (WHS) to further delineate the fetal presentation of this syndrome. STUDY DESIGN: This was a retrospective analysis of ten pregnancies with fetal WHS identified by chromosomal microarray (CMA). Clinical data were reviewed for these cases, including maternal demographics, indications for invasive testing, sonographic findings, CMA results and pregnancy outcomes. RESULTS: Three cases were diagnosed at the first trimester because of an increased NT or cystic hygroma. The remaining seven cases were identified at late gestation for abnormal ultrasound findings. CMA revealed 4p deletions to be terminal in all of the ten cases. Deletion sizes ranged from 2.05 to 19.02 Mb. CONCLUSION: Prenatal findings such as increased NT, severe and early onset intrauterine growth retardation, and renal dysplasia or oligohydramnios should warrant the diagnosis of WHS and invasive testing using CMA. PMID- 29626712 TI - Treatment of twin reversed arterial perfusion sequence with radiofrequency ablation and expectant management: A single center study in China. AB - OBJECTIVE: To evaluate the treatment of pregnancies in different stages complicated by TRAP sequence at a single medical center in China. STUDY DESIGN: A retrospective study evaluating 25 pregnancies with TRAP sequence was performed at Shengjing Hospital in Shenyang, Liaoning between 2012 and 2016. Patients were diagnosed by ultrasound and categorized into three groups (Ia, IIa and IIb) and were expectantly managed or performed RFA (radiofrequency ablation) according to their stage of TRAP sequence. Perinatal outcomes and survival rates were analyzed. RESULTS: There were four cases in stage Ia, 19 cases in stage IIa, and two cases in stage IIb. Cases in stage Ia were expectantly managed. Among cases in stage IIa, we performed RFA (radiofrequency ablation) in 10 cases and expectant management in 6 cases, with the remainder of the patients refusing intrauterine treatment. We applied RFA to treat one case in stage IIb and the other was managed expectantly. For expectant management group and the RFA group, the survival rates were both 64%(7/11). All pump twins in stage Ia survived and the average gestational age at delivery was 37.9 weeks. In stage IIa, the overall survival rate of the pump twin was 70% (7/10) and the average gestational age at delivery was 35.8 weeks in cases treated by RFA. The survival rate was 50% (3/6) and the average gestational age at delivery was 32.8 weeks in expectantly managed cases in stage IIa. No pump twin survived in stage IIa without treatment (3 cases refused any therapy who were excluded) or in stage IIb. CONCLUSION: Expectant management is effective for treatment of TRAP sequence in stage Ia. In stage IIa, RFA improves the prognosis of pump twins. PMID- 29626714 TI - Nuclear receptors as potential drug targets in osteoarthritis. AB - Osteoarthritis is amongst the major causes of disability worldwide, but no medications that can slow or stop progression of this disorder have been identified. Recent evidence suggests roles for a variety of members of the nuclear receptor family of ligand-activated transcription factors in various forms of osteoarthritis. Since nuclear receptors are amongst the major classes of drug targets, these studies suggest that modulators of nuclear receptor activity might provide novel strategies to treat osteoarthritis. This review focuses on recent advances in our understanding of the role of nuclear receptors in osteoarthritis onset and progression, as well as their therapeutic implications. Future studies should continue to examine the possible roles of additional nuclear receptors in the pathophysiology of different types of osteoarthritis. PMID- 29626715 TI - Targeting therapeutics to bone by conjugation with bisphosphonates. AB - Bisphosphonates target and bind avidly to the mineral (hydroxyapatite) found in bone. This targeting ability has been exploited to design and prepare bisphosphonate conjugate prodrugs to deliver a wide variety of drug molecules selectively to bones. It is important that conjugates be stable in the blood stream and that conjugate that is not taken up by bone is eliminated rapidly. The prodrugs should release active drug at a rate appropriate so as to provide efficacy. Radiolabelling is the best method to quantify and evaluate pharmacokinetics, tissue distribution, bone uptake and release of the active drug(s). Recent reports have described bisphosphonate conjugates derived from the antiresorptive drug, alendronic acid and anabolic prostanoid drugs that effectively deliver prostaglandins and prostaglandin EP4 receptor agonists to bone and show enhanced anabolic efficacy and tolerability compared to the drugs alone. These conjugate drugs can be dosed infrequently (weekly or bimonthly) whereas the free drugs must be dosed daily. PMID- 29626713 TI - Differentiation of hepatocyte-like cells from human pluripotent stem cells using small molecules. AB - A variety of approaches have been developed for the derivation of hepatocyte-like cells from pluripotent stem cells. Currently, most of these strategies employ step-wise differentiation approaches with recombinant growth-factors or small molecule analogs to recapitulate developmental signaling pathways. Here, we tested the efficacy of a small-molecule based differentiation protocol for the generation of hepatocyte-like cells from human pluripotent stem cells. Quantitative gene-expression, immunohistochemical, and western blot analyses for SOX17, FOXA2, CXCR4, HNF4A, AFP, indicated the stage-specific differentiation into definitive endoderm, hepatoblast and hepatocyte-like derivatives. Furthermore, hepatocyte-like cells displayed morphological and functional features characteristic of primary hepatocytes, as indicated by the production of ALB (albumin) and alpha-1-antitrypsin (A1AT), as well as glycogen storage capacity by periodic acid-Schiff staining. Together, these data support that the small-molecule based hepatic differentiation protocol is a simple, reproducible, and inexpensive method to efficiently drive the differentiation of human pluripotent stem cells towards a hepatocyte-like phenotype, for downstream pharmacogenomic and regenerative medicine applications. PMID- 29626716 TI - Pharmacological mechanisms leading to synergy in fixed-dose dual bronchodilator therapy. AB - Long-acting beta2 adrenoceptor agonists (LABAs) in combination with long-acting muscarinic antagonists (LAMAs) can elicit functional and clinical benefits in chronic obstructive pulmonary disease (COPD). LABA/LAMA combinations synergistically relax human isolated airways at the level of the medium and small bronchi. LABAs and LAMAs both modulate the bronchial tone via different pathways localized at the level of presynaptic parasympathetic fibers and airway smooth muscle cells. The exact nature of the interactions between these pathways is not completely understood, but there is cross-talk at many levels in airway smooth muscle cells that is also regulated by the activity of calcium-activated potassium channels and protein tyrosine kinases. While the synergy between LABAs and LAMAs is a class effect, some of the currently available fixed-dose combinations (FDCs) do not induce synergistic interaction because the individual components are not appropriately balanced in the combination. Concerns remain on the cardiovascular safety profile of LABA/LAMA FDCs. PMID- 29626718 TI - Does the ethno-religious diversity of a neighbourhood affect the perceived health of its residents? AB - Concerns about the diversification of Britain, and its impact on social capital and health are widely debated. The literature has however produced a fuzzy discourse, full of assumptions and claims that are rarely tested. We attempt to disentangle some of these assumptions by providing empirical evidence on the mediating and moderating influence of inter-ethnic conflict and contact, and examine whether they underlie the erosion of health among minorities and white British respondents residing in diverse local areas. Analyses were conducted using multilevel models that relied on geocoded data from a random stratified sample of adults 16-75 years collected in the 2009-2011 Citizenship Survey merged to small area aggregated statistics from the 2011 UK census. The final sample comprised of minorities (n = 13,236) and white British (n = 15,021) residing in England. We find that local area deprivation matters much more for the health of minorities and whites than diversity. Yet, residing in diverse areas can be problematic for whites if it is accompanied by high levels of social distance measured by negative attitudes towards immigrants. Greater contact among minorities and whites, residing in more diverse areas appears to have no significant effect on health. Overall, the findings supported our hypothesis that residing in areas of greater diversity has a differential impact on minorities when compared to whites. In particular, diversity appear to be more beneficial for minorities, especially newly arriving migrants. The effect of contact as measured by social capital is dwarfed in comparison to the effect of deprivation, underlying the importance for policy makers to tackle structural inequalities. PMID- 29626717 TI - Trace determination of mutagenic alkyl toluenesulfonate impurities via derivatization headspace-GC/MS in an active pharmaceutical ingredient of a candidate drug. AB - This study aims to optimize sodium iodide (NaI) derivatization headspace-GC/MS described in European Pharmacopoeia by using vitamin C as an alternative antioxidant for the determination of mutagenic alkyl toluenesulfonate impurities in an active pharmaceutical ingredient (API) of a candidate drug with an artemisinin derivative. Alkyl toluenesulfonates are transformed into their corresponding alkyl iodides (methyl iodide, ethyl iodide, propyl iodide, and isopropyl iodide) by utilizing the derivatization reagent NaI. Results show that the MS response of methyl iodide is a critical indicator of method robustness because of the deteriorating effects of methyl iodide on stability when sodium thiosulfate is used as an antioxidant originally described in the pharmacopoeia. With vitamin C as a newly developed antioxidant, the robustness of this method is improved significantly. The optimized method is further validated and applied successfully for the quality control and safety of the API of an artemisinin derivative. PMID- 29626719 TI - Adhesive interactions between milk fat globule membrane and Lactobacillus rhamnosus GG inhibit bacterial attachment to Caco-2 TC7 intestinal cell. AB - Milk is the most popular matrix for the delivery of lactic acid bacteria, but little is known about how milk impacts bacterial functionality. Here, the adhesion mechanisms of Lactobacillus rhamnosus GG (LGG) surface mutants to a milk component, the milk fat globule membrane (MFGM), were compared using atomic force microscopy (AFM). AFM results revealed the key adhesive role of the LGG SpaCBA pilus in relation to MFGM. A LGG mutant without exopolysaccharides but with highly exposed pili improved the number of adhesive events between LGG and MFGM compared to LGG wild type (WT). In contrast, the number of adhesive events decreased significantly for a LGG mutant without SpaCBA pili. Moreover, the presence of MFGM in the dairy matrix was found to decrease significantly the bacterial attachment ability to Caco-2 TC7 cells. This work thus demonstrated a possible competition between LGG adhesion to MFGM and to epithelial intestinal cells. This competition could negatively impact the adhesion capacity of LGG to intestinal cells in vivo, but requires further substantiation. PMID- 29626720 TI - Potential fluorescence and magnetic resonance imaging modality using mixed lanthanide oxide nanoparticles. AB - Imaging is a very important technique in the diagnosis and treatment of cancer diseases. This study developed a dual modality (fluorescence/MR) imaging technique for cancer cell lines (HeLa) and T2-weighted phantom imaging by using a mixed lanthanide (Dy/Er/Tb) oxide nanoparticles. To further enhance the solubility, stability and biocompatibility of mixed lanthanide oxide, the nanoparticles were coated with folic acid as well as G4.5 PAMAM dendrimer. The coated nanoparticles were then compared, the later with results demonstrating pronounced effects in both T2 weighted phantom MR and fluorescence imaging of the cancer cell lines. Imaging enhancement was attributed to a synergistic effect of the fluorescent properties and higher water solubility of the PAMAM dendrimer when compared to the folic acid. Besides, mixed lanthanides of Dy and Tb were used for T2 weighted MR imaging, while mixed lanthanides of Er and Tb were used for fluorescence imaging in the near infrared and visible regions, and were synthesized in the facile composition control. Hence, the mixed lanthanide oxides are packed together, and stable, which is used to facilitate biomedical imaging in vitro. To conclude, the G4.5 PAMAM dendrimer coated mixed lanthanide oxide nanoparticles will be used for dual-modality (fluorescence/MR imaging) cancer cell line detection in both in vitro and in vivo study. PMID- 29626721 TI - Curcumin-loaded ultradeformable nanovesicles as a potential delivery system for breast cancer therapy. AB - In the current study, the transdermal route has been investigated to deliver the poorly bioavailable drug; curcumin into the systemic circulation, aiming to target both superficial and subcutaneous tumors such as the breast tumors. Accordingly, different colloidal carriers viz. ultradeformable nanovesicles comprising various penetration enhancers were exploited. Curcumin-loaded deformable vesicles were prepared by the thin film hydration method followed by extrusion. Sodium cholate and Tween 80 were set as standard edge activators and Labrasol, Transcutol, limonene and oleic acid were the penetration enhancers that were evaluated for their efficacy in skin permeation. The particle size and zeta potential of the prepared vesicles were significantly affected by the type of surfactant/penetration enhancer. The polydispersity measurements showed uniform particle size distribution indicating the sufficiency of the extrusion cycles performed. Curcumin, as a hydrophobic molecule, was well accommodated within the lipid bilayers of the prepared vesicles with entrapment efficiency (EE%) percentages and drug loading percentages (DL%) as high as 93.91% and 7.04%, respectively. The ex-vivo permeation studies were performed on male albino mice skin mounted on Franz diffusion cells. Oleic acid and Transcutol exhibited comparable fluxes to sodium cholate and Tween 80 (~16 MUg cm-2 h-1), whereas the fluxes of Labrasol and limonene were significantly lower. Cytotoxicity studies were performed using MTT assay on human breast cancer cell lines (MCF-7 cells). The results of the MTT assay demonstrated that oleic acid ultradeformable nanovesicles scored an IC50 of 20 MUg/ml which introduce these new curcumin loaded nanovesicles as a successful delivery system for breast cancer therapy. PMID- 29626722 TI - A qualitative study of nulliparous women's decision making on mode of delivery under China's two-child policy. AB - OBJECTIVE: To explore nulliparous women's perceptions of decision making regarding mode of delivery under China's two-child policy. DESIGN: Qualitative descriptive design with in-depth semi-structured interviews. SETTING: Postnatal wards at a tertiary specialized women's hospital in Shanghai, China. PARTICIPANTS: 21 nulliparous women 2-3 days postpartum were purposively sampled until data saturation. METHODS: In-depth semi-structured interviews were conducted between October 8th, 2015 and January 31st, 2016. RESULTS: Two overarching descriptive categories were identified: (1) women's decision-making process: stability versus variability, and (2) factors affecting decision making: variety versus interactivity. Four key themes emerged from each category: (1) initial decision making with certainty: anticipated trial of labour, failed trial of labour, 'shy away' and compromise, anticipated caesarean delivery; (2) initial decision making with uncertainty: anticipated trial of labour, failed trial of labour, 'shy away' and compromise; (3) internal factors affecting decision making: knowledge and attitude, and childbirth self-efficacy; and (4) external factors affecting decision making: social support, and the situational environment. CONCLUSION AND IMPLICATIONS FOR PRACTICE: At the initial period of China's two-child policy, nulliparous women have perceived their decision-making process regarding mode of delivery as one with complexity and uncertainty, influenced by both internal and external factors. This may have implications for the obstetric setting to develop a well-designed decision support system for pregnant women during the entire pregnancy periods. And it is recommended that care providers should assess women's preferences for mode of delivery from early pregnancy and provide adequate perinatal support and continuity of care for them. PMID- 29626723 TI - On the relation between outdoor 222Rn and atmospheric stability determined by a modified Turner method. AB - In practice, information about atmospheric stability is often obtained from discrete stability classes determined from routine meteorological observations. However, changing concentrations of the radioactive gas 222Rn present in the atmosphere are also considered a good indicator of vertical dispersion and atmospheric stability. A complex, in-depth analysis between these different approaches of atmospheric stability assessment has not been performed so far, and was the main motivation behind this study. The study presents atmospheric radon data measured in Bratislava (Slovakia) and stability indexes (SI) calculated according to a modified Turner method during a period of one year. Basic features of the diurnal and seasonal variations of these variables are discussed. It was found that the time series of radon activity concentration (RAC) lags approximately 5 h behind that of the Turner stability classes adjusted for temperate climate regions. Various time lags were also identified between RAC and meteorological variables used to determine the stability classes. Evaluation of seasonal trends revealed a low variability of mean monthly values of stability classes compared to the variability of mean monthly values of RAC. Another notable difference between RAC and stability indexes was found - while the stability index can both increase and decrease with wind speed, concentration of outdoor radon was never observed to increase with increasing wind speed. In spite of the mentioned discrepancies, the time series of RAC and SI are generally in a good agreement. This is especially true if one compares the deviations of RAC and SI from their mean daily values, when the differences in their seasonal variability are eliminated. Deviations of RAC can be used to calculate diurnal variations of stability indexes. Analysis of a complete year of data also revealed a roughly linear relationship between average values of RAC and calculated stability indexes, because in large datasets random processes tend to cancel each other out. PMID- 29626724 TI - Radiocaesium derived from the TEPCO Fukushima accident in the North Pacific Ocean: Surface transport processes until 2017. AB - We report temporal variations of 137Cs activity concentrations in surface waters of six regions of the western and central North Pacific Ocean during 2011-2017 using a combination of 1264 previously published data and 42 new data. In the western and central North Pacific Ocean at latitudes of 30-42 degrees N and longitudes of 140 degrees E to 160 degrees W, eastward transport of radiocaesium was clearly apparent. 137Cs activity concentrations in surface water decreased rapidly to ~2-3 Bq m-3 in 2015/2016, still a bit higher than 137Cs activity concentrations before the FNPP1 accident (1.5-2 Bq m-3). 134Cs/137Cs activity ratios decay-corrected to 11 March 2011 were ~0.5-0.8. To the south of 30 degrees N and between 130 degrees E and 160 degrees W in the western and central Pacific Ocean, 137Cs activity concentrations were around 1-7 Bq m-3 in 2011/2012 but then stabilized at a few Bq m-3 up to 2017.134Cs activity concentrations were detected at levels of 0.1-0.9 Bq m-3, and 134Cs/137Cs activity ratios decay-corrected to 11 March 2011 were ~0.3-0.5. Temporal variations of model-simulated 137Cs activity concentrations in surface water in the region of interest showed good agreement with observations, except in the southwestern North Pacific Ocean. PMID- 29626725 TI - iTRAQ-based quantitative proteomic analysis of the androgenic glands of the oriental river prawn, Macrobrachium nipponense, during nonreproductive and reproductive seasons. AB - The androgenic gland produces hormones that play crucial roles in driving male sexual development. In this study, we investigated the regulatory proteins and pathways affecting male sexual development of M. nipponense, by analyzing the proteomes of their androgenic glands during their reproductive and nonreproductive seasons using isobaric tags for relative and absolute quantitation (iTRAQ). A total of 13 sex-related protein homologs out of 999 total proteins were identified in the proteome of M. nipponense based on comparisons with the published literature. A total of 32 proteins were differentially expressed in the androgenic gland between the reproductive and nonreproductive seasons of M. nipponense. However, only 10 differentially expressed proteins (DEPs) were annotated in the Nr, COG, GO, and KEGG databases. Other non-annotated DEPs may also play vital roles in the male sexual development of M. nipponense. The qPCR analysis indicated that the mRNA expression patterns of the 10 annotated DEPs were consistent with that determined by iTRAQ analysis. Additional qPCR analysis of the 10 DEPs in testes, ovaries, and androgenic glands showed that Gem, Ferritin, and Rev3 were highly expressed in the androgenic gland, implying importance in male sexual development, given the important role of the androgenic gland in male differentiation and development in many crustacean species. Our study provided valuable information about DEPs in androgenic glands between reproductive and nonreproductive seasons for M. nipponense and identified their potential roles in male sexual development, which will improve our understanding of the development process in both M. nipponense and other crustaceans. PMID- 29626726 TI - Identification and evolution of olfactory genes in the small poplar longhorn beetle Saperda populnea. AB - Saperda populnea is a serious pest of poplar and willow trees in the Palaearctic region, causing extensive damage to forests and the lumber industry. Until recently, there is no safe and effective chemical method to control this pest due to the lack of sufficient knowledge on the molecular basis of its olfactory genes, moreover, the evolutionary history of the olfactory gene family in subfamily Lamiinae is still fully unknown. Our RNA sequencing of the antennae of S. populnea identified 43 odorant binding proteins (OBPs), 15 chemosensory proteins (CSPs), 56 odorant receptors (ORs) and 24 inotropic receptors (IRs) in S. populnea. The RT-PCR results showed several genes were expressed in a sex specific manner, suggesting that these genes might play key role in their olfactory-sensing and sex-related behaviors. Further evolutionary studies were performed on these olfactory genes, overall comparison of the Ka/Ks values of orthologous genes in S. populnea and two other Lamiinae species showed three main conclusions: 1. olfactory genes have evolved more rapidly than the non-olfactory genes in the tested long horn beetles; 2. the IR gene family are under a strong purifying selection; 3. the OBPs of Monochamus alternatus evolved more rapidly than the other two species, which is speculated to be correlated with differentiation of selective pressure in different geographic origins. Detailed evolutionary studies on each olfactory genes showed that several OBPs and ORs are under significantly purifying/relaxed selective pressure, and several positive selection sites were also detected, modeling of SpopOR14 and SpopOBP4/5 showed that most of the positive selection sites were distributed at the N-terminus of SpopOR14, while the positive selection sites in SpopOBP4/5 were located in H-bond donors, results suggest that these sites are more likely to be linked with the selectivity of modeled olfactory genes. The research provided a better understanding of the molecular basis and evolutionary history of the olfactory genes in Lamiinae, through elaborating the mechanism whereby amino structural evolution affects specific variants in OBPs and ORs. PMID- 29626727 TI - The phantom midge menace: Migratory Chaoborus larvae maintain poor ecosystem state in eutrophic inland waters. AB - Chaoborus spp. (phantom midge) are prevalent in eutrophic inland waters. In Lake Soppen, Switzerland, C. flavicans larvae diurnally migrate between the methane rich, oxygen-depleted hypolimnion and sediments, and the methane-poor, oxygen rich epilimnion. Using a combination of experiments and system modelling, this study demonstrated that the larvae's burrowing activities in and out of the sediment perturbed the sediment and re-introduced sequestered phosphorus into the overlying water at a rate of 0.022 MUg P ind-1 d-1, thereby exacerbating internal nutrient loading in the water column. Fluxes of sediment methane and other reduced solutes enhanced by the larval bioturbation would consume oxygen and sustain the hypoxic/anoxic condition below the thermocline. In addition to increasing diffusive fluxes, migrating larvae also directly transported methane in their gas vesicles from the deep water and release it in the surface water at a rate of 0.99 nmol CH4 ind-1 d-1, potentially contributing to methane emission to air. As nutrient pollution and climate warming persist or worsen in the coming decades, proliferation of Chaoborus could intensify this positive feedback loop and delay lake recovery. PMID- 29626728 TI - Using models of farmer behavior to inform eutrophication policy in the Great Lakes. AB - To address the management of eutrophication in aquatic systems, the behavioral mechanisms that drive change at the individual level must be considered when designing policy interventions. This analysis identifies the beliefs that are critical to behavioral change, and explores the likelihood that farmers will adopt two management practices believed to be critical to reducing nutrient loading to recommended levels in Lake Erie. We find that there is potential for farmers to adopt key infield practices needed to reduce nutrient inputs. And further, that increased adoption of such practices is possible by increasing the perceived efficacy of the majority of farmers who are motivated to take action. Integrating these findings with physical models of nutrient movement indicates that adoption of these practices in combination with edge of field practices can attain phosphorus reduction targets for the lake. Future research should focus on measuring the effectiveness of education and outreach programs aimed at engaging farmers and promoting adoption of recommended practices. Such programs may only be effective if they are successfully building farmer confidence in their ability to implement the practices (i.e., perceived self efficacy) and increasing farmer's belief in the effectiveness of the practices at reducing nutrient loss and improving local water quality (i.e., perceived response efficacy). PMID- 29626729 TI - CFD simulation of fluid dynamic and biokinetic processes within activated sludge reactors under intermittent aeration regime. AB - Due to the aeration system, biological reactors are the most energy-consuming facilities of convectional WWTPs. Many biological reactors work under intermittent aeration regime; the optimization of the aeration process (air diffuser layout, air flow rate per diffuser, aeration length ...) is necessary to ensure an efficient performance; satisfying the effluent requirements with the minimum energy consumption. This work develops a CFD modelling of an activated sludge reactor (ASR) which works under intermittent aeration regime. The model considers the fluid dynamic and biological processes within the ASR. The biological simulation, which is transient, takes into account the intermittent aeration regime. The CFD modelling is employed for the selection of the aeration system of an ASR. Two different aeration configurations are simulated. The model evaluates the aeration power consumption necessary to satisfy the effluent requirements. An improvement of 2.8% in terms of energy consumption is achieved by modifying the air diffuser layout. An analysis of the influence of the air flow rate per diffuser on the ASR performance is carried out. The results show a reduction of 14.5% in the energy consumption of the aeration system when the air flow rate per diffuser is reduced. The model provides an insight into the aeration inefficiencies produced within ASRs. PMID- 29626730 TI - A microbial electro-fenton cell for removing carbamazepine in wastewater with electricity output. AB - High electrical energy is required for the electro-Fenton process to remove pharmaceuticals and personal care products (PPCPs) in wastewater. The aim of this study was to develop a novel and more cost-effective process, specifically a microbial electro-Fenton cell (MeFC), for treating PPCPs in wastewater. Acetylene black was selected as the catalyst for H2O2 electrogeneration and Fe-Mn binary oxide for hydroxyl radical production. In addition to lowering energy needs, the MeFC produced a maximum power density of 112 +/- 11 mW/m2 with 1 g/L acetate as a representative substrate and 10 mg/L carbamazepine (CBZ) as a typical PPCP. Comparing with electro-Fenton process, the CBZ removal in the MeFC was 38% higher within 24 h operation (90% vs. 62%). Furthermore, the CBZ removal rate in the MeFC was 10-100 times faster than that in other biological treatment processes. Such enhanced degradation of CBZ in the MeFC was attributed to the synergistic reactions between radical oxidation of CBZ and biodegradation of degradative intermediates. The MeFC provides a promising method to remove PPCPs from wastewater coupling with efficient removal of other biodegradable organics. PMID- 29626731 TI - Microbial composition of spoiled industrial-scale Sichuan paocai and characteristics of the microorganisms responsible for paocai spoilage. AB - The microorganisms of spoiled industrial-scale Sichuan paocai (ISSP) were isolated using six types of media, and 16S rRNA and 26S rRNA gene sequence analyses were used to identify the isolates. Meanwhile, the microbial composition was investigated using a culture-independent method through 16S rRNA and ITS sequencing on an Illumina MiSeq platform. The results obtained by these two methods were compared. Furthermore, characteristics of the isolated microorganisms responsible for ISSP spoilage were studied. Sixty-two strains belonging to twenty-three species, including three ammonia-producing genera, two gas-producing genera, two pectinase-producing genera, two cellulase-producing genera, three film-producing genera and one slime-producing genus, were isolated. Lactobacillus, Bacillus, Debaryomyces and Kazachstania were the dominant genera as confirmed through both culture-dependent and culture-independent methods. Bacillus, Paenibacillus, Pichia and Debaryomyces could be the main microorganisms responsible for ISSP spoilage. Bac. licheniformis was closely correlated with the off-flavour of ISSP. Pae. peoriae, Bac. stratosphericus, Bac. toyonensis and Bac. cereus were responsible for tissue softening, and Bac. subtilis, Bac. methylotrophicus, Pic. membranifaciens and Deb. hansenii caused film formation. PMID- 29626732 TI - A multivariate additive noise model for complete causal discovery. AB - Explaining causal reasoning in the form of directed acyclic graphs (DAGs) yields nodal structures with multivariate relationships. In real-world phenomena, these effects can be seen as multiple feature dependency with unmeasured external influences or noises. The bivariate models for causal discovery simply miss to find the multiple feature dependency criteria in the causal models. Here, we propose a multivariate additive noise model (MANM) to solve these issues while analyzing and presenting a multi-nodal causal structure. We introduce new criteria of causal independence for qualitative analysis of causal models and causal influence factor (CIF) for the successful discovery of causal directions in the multivariate system. The scores of CIF provide the information for the goodness of casual inference. The identifiability of the proposed model to discover linear, non-linear causal relations is verified in simulated, real-world datasets and the ability to construct the complete causal model. In comparison test, MANM has out performed Independent Component Analysis based Linear Non Gaussian Acyclic Model (ICA-LiNGAM), Greedy DAG Search (GDS) and Regression with Sub-sequent Independent Test (RESIT), and performed better for Gaussian and non Gaussian mixture models with both correlated and uncorrelated feature relations. In performance test, different model fitting errors which occur during causal model construction are discussed and the performance of MANM in comparison to ICA LiNGAM, GDS and RESIT is provided. Results show that MANM has better causal model construction ability, producing few extra sets of direction with no missing or wrong directions and can estimate every possible causal direction in complex feature sets. PMID- 29626733 TI - Boundedness and global robust stability analysis of delayed complex-valued neural networks with interval parameter uncertainties. AB - In this paper, the boundedness and robust stability for a class of delayed complex-valued neural networks with interval parameter uncertainties are investigated. By using Homomorphic mapping theorem, Lyapunov method and inequality techniques, sufficient condition to guarantee the boundedness of networks and the existence, uniqueness and global robust stability of equilibrium point is derived for the considered uncertain neural networks. The obtained robust stability criterion is expressed in complex-valued LMI, which can be calculated numerically using YALMIP with solver of SDPT3 in MATLAB. An example with simulations is supplied to show the applicability and advantages of the acquired result. PMID- 29626734 TI - A survey on Barrett's esophagus analysis using machine learning. AB - This work presents a systematic review concerning recent studies and technologies of machine learning for Barrett's esophagus (BE) diagnosis and treatment. The use of artificial intelligence is a brand new and promising way to evaluate such disease. We compile some works published at some well-established databases, such as Science Direct, IEEEXplore, PubMed, Plos One, Multidisciplinary Digital Publishing Institute (MDPI), Association for Computing Machinery (ACM), Springer, and Hindawi Publishing Corporation. Each selected work has been analyzed to present its objective, methodology, and results. The BE progression to dysplasia or adenocarcinoma shows a complex pattern to be detected during endoscopic surveillance. Therefore, it is valuable to assist its diagnosis and automatic identification using computer analysis. The evaluation of the BE dysplasia can be performed through manual or automated segmentation through machine learning techniques. Finally, in this survey, we reviewed recent studies focused on the automatic detection of the neoplastic region for classification purposes using machine learning methods. PMID- 29626735 TI - Using optimal control methods with constraints to generate singlet states in NMR. AB - A method is proposed for optimizing the performance of the APSOC (Adiabatic Passage Spin Order Conversion) technique, which can be exploited in NMR experiments with singlet spin states. In this technique magnetization-to-singlet conversion (and singlet-to-magnetization conversion) is performed by using adiabatically ramped RF-fields. Optimization utilizes the GRAPE (Gradient Ascent Pulse Engineering) approach, in which for a fixed search area we assume monotonicity to the envelope of the RF-field. Such an approach allows one to achieve much better performance for APSOC; consequently, the efficiency of magnetization-to-singlet conversion is greatly improved as compared to simple model RF-ramps, e.g., linear ramps. We also demonstrate that the optimization method is reasonably robust to possible inaccuracies in determining NMR parameters of the spin system under study and also in setting the RF-field parameters. The present approach can be exploited in other NMR and EPR applications using adiabatic switching of spin Hamiltonians. PMID- 29626736 TI - Innovations in CRISPR technology. AB - CRISPR-Cas9 is a versatile tool for genome engineering that has revolutionized biotechnology and is poised to impact medicine. Recent advances in the identification of unique CRISPR systems, as well as the re-engineering of the Cas9 protein for expanded function, has enabled the diversification of the CRISPR genome engineering toolbox. In this review, we highlight these innovations and discuss how advances in CRISPR technology can lead to breakthroughs in the field of gene therapy. PMID- 29626737 TI - Treatment Satisfaction Questionnaire for Medication: Validation of the Translated Arabic Version among Patients Undergoing Warfarin Therapy in Saudi Arabia. AB - OBJECTIVES: To validate the psychometric properties of the translated Arabic version of the Treatment Satisfaction Questionnaire for Medication (TSQM 1.4) for patients on warfarin therapy in Saudi anticoagulation clinics (ACCs). METHODS: A cross-sectional survey was conducted at the Security Forces Hospital ACC in Riyadh, Saudi Arabia. It involved administering questionnaires related to patients' satisfaction and assessing adherence through interviews. The quality of the international normalized ratio control was assessed using the Rosendaal method. A psychometric evaluation of TSQM 1.4 was carried out, addressing internal consistency and known-groups and convergent validity. RESULTS: A total of 101 patients completed the questionnaire with an 80% response rate. The independent Cronbach alpha values for the effectiveness, side effects, and global satisfaction domains were consistently higher than 0.75, demonstrating good internal consistency and suitability of these domains for application in the current patients' setting. When these domains were used together in a multivariable logistic regression model of adherence, the only domain that remained significant was TSQM effectiveness (P = 0.017). Interestingly, a higher likelihood of moderate to optimal international normalized ratio control was significantly and independently associated with increased satisfaction scores in the effectiveness and convenience domains, but not in the side effects and global satisfaction domains. CONCLUSIONS: This study provides evidence in favor of the reliability and validity of the Arabic version of TSQM 1.4 as a useful measure of satisfaction with anticoagulant therapy in patients visiting ACCs. The TSQM subscales in this patient setting seem to detect a clinically meaningful change over time, enhancing the potential of their use in routine practice. PMID- 29626738 TI - Return on Investment Analysis of Breast Cancer Screening and Downstaging in Egypt: Implications for Developing Countries. AB - OBJECTIVE: The aim of this study was to perform a return-on-investment (ROI) analysis of a breast cancer screening program in Egypt by comparing net profit in treatment costs saved to program cost investment. METHODS: The breast cancer downstaging program targeted women living in an Egyptian slum, where residents have low access to health care. Program costs were estimated by using data from interviews with program administrative staff. Screening and treatment costs were estimated by using Ministry of Health medical reimbursement data. Estimates for expected rates of downstaging were modeled on the basis of data from a previous study. ROI, or relative cost savings, was calculated by comparing treatment cost savings to costs for the screening program. A baseline ROI for facility-based screening was calculated, followed by ROIs for different scenarios. RESULTS: Average per-person treatment cost for screened and unscreened patients was estimated to be $28,632 and $58,170, respectively, with a cumulative lifetime risk of 6.36%. Total screening program cost per person was $112.10. The study estimated an expected decrease in late-stage breast cancer diagnosis by 13.7% as a result of the screening program, saving $4,049 in treatment costs per individual diagnosed. The analysis resulted in a positive ROI of 133% for facility-based screening. CONCLUSIONS: Breast cancer represents an increasing burden on health care in Egypt and other developing countries. This study concludes that a community-based downstaging program resulted in a positive ROI, or overall cost-savings. The findings inform that policymakers in low-income and middle-income countries may consider implementing community-based downstaging programs for breast cancer. PMID- 29626739 TI - Hormonal strategy to reduce suckled beef cow handling for timed artificial insemination with sex-sorted semen. AB - Two experiments were conducted to assess a hormonal strategy developed to reduce animal handling for timed artificial insemination (TAI) with sex-sorted semen. Four-hundred ninety-one (491) suckled beef cows received a progesterone (P4) intravaginal device and 2 mg intramuscular (im) injection of estradiol benzoate (EB) on a randomly chosen day of the estrus cycle (Day 0) in Experiment 1. Cows were treated with 500 MUg of sodic cloprostenol (PGF2alpha) and with 300 IU of eCG at P4 device removal (Day 8); these cows were also randomly assigned to receive 1 mg of estradiol cypionate (EC) administered at P4 device removal (treatment EC-0h) or 1 mg of EB 24 h after P4 device removal (treatment EB-24h). Both treatments were timed inseminated (TAI) with sex-sorted semen 60 h after P4 device removal. Cows treated with EC-0h presented higher pregnancy rate per AI (P/AI) [45.0% (113/251)] than the ones treated with EB-24h [35.4% (85/240); P = 0.03)]. A subset of cows (n = 26) were subjected to ultrasound examination every 12 h after P4 device removal for 96 h in the row in order to determine the time of ovulation. Similar interval between device removal and ovulation was recorded for EB-24h = 70.0 +/- 2.9 h vs. EC-0h = 66.0 +/- 2.8 h (P = 0.52). Five-hundred ninety-one (591) cows were subjected to the same synchronization protocols and treatments (EC-0h or EB-24h). In addition, they were randomly assigned to a 2 * 2 factorial arrangement aiming at determining the effects of treatment with estradiol (EC-0h vs. EB-24h) and of semen type (Sex-sorted vs. Non-sex-sorted semen). All animals were timed inseminated 60 h after P4 device removal. There was no interaction (P = 0.07) between the ovulation inducer and semen type. The EC protocol led to greater P/AI than EB (P = 0.03). Greater (P = 0.01) P/AI was achieved through treatments with non-sex-sorted semen rather than with sex-sorted semen [sex-sorted (EB-24h = 49.0%; EC-0h = 51.0%) vs. non-sex-sorted semen (EB 24h = 52.4%; EC-0h = 68.2%)]. Therefore, EC administered at P4 device removal resulted in greater P/AI. Furthermore, the EC-0h protocol allowed reducing suckled beef cow handing for timed artificial insemination with sex-sorted semen. PMID- 29626740 TI - The relationship between impulsivity and methamphetamine use severity in a community sample. AB - BACKGROUND: Abuse of psychostimulants, including methamphetamine (MA), has been linked to heightened impulsivity. While previous research has demonstrated differences in impulsivity between MA users and non-substance users, less is known about variability in impulsivity within MA users and whether the severity of MA use related problems predicts impulsivity within individuals who regularly use MA. This study aims to elucidate the relationship between impulsivity and MA use severity. METHOD: Non-treatment seeking individuals who reported regular MA use (n = 177) completed an impulsivity battery comprising self-report and behavioral measures. A structural equation modeling (SEM) approach was used to test the relationship between the MA use related problem severity and measures of impulsivity. RESULTS: The final SEM model of impulsivity and MA use related problems (CFI = 0.897, RMSEA = 0.059, S-B scaled chi2 [260,n = 103] = 406.86) revealed that greater MA use severity was associated with greater self-reported impulsiveness, but no relationship was found between MA use severity and behavioral measures of impulsivity. CONCLUSIONS: The current findings extend previous research by providing additional evidence that MA use is associated with increased self-reported impulsivity and highlights the importance of evaluating impulsivity as a multidimensional construct. PMID- 29626741 TI - Prescription opioid misusing chronic pain patients exhibit dysregulated context dependent associations: Investigating associative learning in addiction with the cue-primed reactivity task. AB - BACKGROUND: Associative learning undergirds the development of addiction, such that drug-related cues serve as conditioned stimuli to elicit drug-seeking responses. Plausibly, among opioid misusing chronic pain patients, pain-related information may serve as a conditioned stimulus to magnify opioid cue-elicited autonomic and craving responses through a process of second-order conditioning. METHODS: We utilized a novel psychophysiological probe of pain-opioid conditioned associations, the Cue-Primed Reactivity (CPR) task. In this task, participants were presented with images as primes (200 ms) and cues (6000 ms) in pairs organized in four task blocks: "control-opioid," "pain-opioid," "control-pain," and "opioid-pain." Opioid-treated chronic pain patients (N = 30) recruited from an Army base in the Western United States were classified as opioid misusers (n = 17) or non-misusers (n = 13) via a validated cutpoint on the Prescription Drug Use Questionnaire (PDUQ; Compton et al., 2008). Opioid misuse status was examined as a predictor of HRV, craving, and mood responses on the CPR task. RESULTS: HRV increased to a greater extent during the pain-opioid block compared to the control-opioid block for non-misusers compared to misusers (p = .003, eta2partial = 0.27). In contrast, craving increased to a greater extent from baseline to the pain-opioid block for misusers than for non-misusers (p = .03, eta2partial = .16). CONCLUSIONS: Findings suggest that opioid-treated chronic pain patients exhibit Pavlovian conditioned responses to opioid cues strengthened by an associative learning process of second-order conditioning when primed by pain related images. This pain-opioid contingency appears to become disrupted among individuals who engage in opioid misuse, such that opioid-related stimuli elicit motivational responses irrespective of pain-related contextual stimuli. PMID- 29626742 TI - Dissatisfaction with opioid maintenance treatment partly explains reported side effects of medications. AB - BACKGROUND: Drop-out is a core problem in opioid maintenance treatment (OMT), but patients' reactions to and acceptance of the various OMT medications are insufficiently investigated. In Norway, there has been vocal patient resistance to the newest medication, buprenorphine-naloxone (BNX), and complaints have focused on the side effect profile. There has been no comparison of patient satisfaction and side effects of the three most common OMT medications. AIM: To compare patient satisfaction with OMT and side effects of BNX, buprenorphine monopreparate (BUP), and methadone (MET) as reported by patients. METHODS: Data were drawn from a national peer-to-peer survey developed by a patient advocacy group. The survey engaged more than 1000 OMT patients, corresponding to one seventh of OMT patients in Norway. The associations between side effects, treatment satisfaction, and patient characteristics were tested in multinomial logistic regressions. RESULTS: High patient satisfaction with OMT overall was reported despite lower satisfaction with medication itself and widely prevalent side effects. Among each medication group, dissatisfaction with medications or OMT in general along with poor health status increased the relative risk ratio of reporting the heaviest side effect burden. MET users reported the highest side effect burden and BNX users the lightest, but BNX users were more dissatisfied with their medication. CONCLUSIONS: Side effects are a concern for nearly all OMT patients, and they do not appear to accumulate with age or length of treatment. BNX users' dissatisfaction with their medication is of particular concern, and expectations and preferences of medication may be influencing their dissatisfaction. PMID- 29626744 TI - Opioids in oral fluid of Spanish drivers. AB - BACKGROUND: Driving under the influence of certain drugs is not allowed, and roadside drug testing is being considered an important tool for deterring driving under the influence of them. This study aimed to assess the presence and concentration of opioids, as well as their combined use with other drugs (laboratory confirmation after the on-road screening) in Spanish drivers between 2011 and 2016. METHODS: In Spain, mandatory roadside breath alcohol and oral fluid drug testing (screening) are carried out by the Traffic Police using Drager Alcotest(r) 6810 device, and Drager DrugTest(r) 5000, DrugWipe(r), or AlereTM DDS(r)2 Mobile Test System. For positive cases in the period covered, 65,244, confirmation analysis and quantification using chromatographic techniques were performed. RESULTS: Opioids were confirmed in 8.6% of positive cases, being 7.2% positives to 6-acetylmorphine (6-AM), 6.5% to morphine, 5.4% to codeine, and 4.1% to methadone. The majority of the confirmed tests for morphine (96.5%), codeine (88.4%) and methadone (81.9) were also positive for 6-AM. The presence of other drugs, particularly cocaine and cannabis, was very common. Concentration values reached important levels. Positive results for morphine (0.1%), codeine (0.6%) or methadone (0.4%) alone were very infrequent. CONCLUSIONS: Drivers with a confirmed positive roadside test for morphine, codeine, and methadone had also consumed heroin and/or other illicit drugs, such as cocaine and/or THC, and at relevant concentrations. Improving interventions to combat the problem of driving under the influence of driving-impairing substances is a priority. PMID- 29626745 TI - Influence of comorbid alcohol use disorders on the clinical patterns of major depressive disorder: A general population-based study. AB - BACKGROUND: To compare the symptom patterns of major depressive disorder (MDD) among subjects with MDD and 1) no alcohol use disorder (AUD), 2) alcohol abuse and 3) alcohol dependence, respectively. METHODS: In a general population survey of 38,694 French individuals, MDD and AUDs were assessed using the Mini International Neuropsychiatric Interview 5.0.0 (MINI). A total of 4339 subjects (11.2%) in the sample met the criteria for MDD. Among them, 413 (9.5%) AUD subjects were identified: 138 (3.2%) for alcohol abuse and 275 (6.3%) for alcohol dependence. The associations of each of the ten MDD criteria of the MINI and psychiatric clinical features were compared among the three groups. The relative profiles of 'MDD + AUD' vs. 'MDD alone' were determined using a multivariable stepwise regression model. RESULTS: With the noAUD group as the reference, sadness (OR = 0.46; 95%CI, 0.29-0.74) and anhedonia (OR = 1.66; 95%CI, 1.06-2.73) were only associated with alcohol abuse. Sleep disorders (OR = 2.07; 95%CI, 1.51 2.88), feelings of guilt (OR = 1.41; 95%CI, 1.05-1.90), diminished concentration/indecisiveness (OR = 1.52; 95%CI, 1.12-2.07) and thoughts of death (OR = 1.95; 95%CI 1.49-2.55) were only associated with alcohol dependence. Weight or appetite variations were both associated with alcohol abuse (OR = 1.7; 95%CI, 1.15-2.53) and dependence (OR = 1.41; 95%CI, 1.06-1.88). Bipolar disorder and PTSD were only associated with alcohol dependence. Psychotic features, previous suicide attempts, and panic disorder were more frequent in the MDD-AUD group. CONCLUSION: MDD-AUD subjects displayed a more severe profile with specific symptomatology and comorbidity profiles compared to MDD-only subjects. PMID- 29626746 TI - Experiences with skin and soft tissue infections among people who inject drugs in Philadelphia: A qualitative study. AB - OBJECTIVES: To understand how people who inject drugs (PWID) experience skin and soft tissue infections (SSTI) and make decisions to seek or delay medical treatment. METHODS: We conducted semi-structured, in-depth interviews in 2015 with 19 PWID at a syringe exchange program in Philadelphia. We analyzed the data using standard qualitative techniques. RESULTS: PWID described adequate knowledge about SSTI, although they could not always implement knowledge about SSTI prevention due to environmental constraints. Participants reported different experiences with incident SSTI. Some sought immediate medical care at initial presentation. Most, however, waited to seek care. Previous positive and negative healthcare experiences, both in general -including stigma and withdrawal- and specific to SSTI, influenced this decision. Among those who delayed medical care, some reported self-treatment, including increased drug use for pain control, and lancing and draining their own wounds. CONCLUSION: Reducing the incidence of SSTI and promoting earlier treatment are important public health priorities. Both require ongoing attention and improvements to the environments in which PWID inject and receive care. PMID- 29626743 TI - Examining racial/ethnic differences in patterns of benzodiazepine prescription and misuse. AB - BACKGROUND: Benzodiazepines (BZDs) are widely prescribed during psychiatric treatment. Unfortunately, their misuse has led to recent surges in overdose emergency visits and drug-related deaths. METHODS: Electronic health record data from a large healthcare system were used to describe racial/ethnic, sex, and age differences in BZD use and dependence. Among patients with a BZD prescription, we assessed differences in the likelihood of subsequently receiving a BZD dependence diagnosis, number of BZD prescriptions, receiving only one BZD prescription, and receiving 18 or more BZD prescriptions. We also estimated multivariate hazard models and generalized linear models, assessing racial/ethnic differences after adjustment for covariates. RESULTS: In both unadjusted and adjusted analyses, Whites were more likely than Blacks, Hispanics, and Asians to have a BZD dependence diagnosis and to receive a BZD prescription. Racial/ethnic minority groups received fewer BZD prescriptions, were more likely to have only one BZD prescription, and were less likely to have 18 or more BZD prescriptions. We identified greater BZD misuse among older patients but no sex differences. CONCLUSIONS: Findings from this study add to the emerging evidence of high relative rates of prescription drug abuse among Whites. There is a concern, given their greater likelihood of having only one BZD prescription, that Blacks, Hispanics, and Asians may be discontinuing BZDs before their clinical need is resolved. Research is needed on provider readiness to offer racial/ethnic minorities BZDs when indicated, patient preferences for BZDs, and whether lower prescription rates among racial/ethnic minorities offer protection against the progression from prescription to addiction. PMID- 29626747 TI - Non-invasive prenatal paternity testing using cell-free fetal DNA from maternal plasma: DNA isolation and genetic marker studies. AB - Invasive prenatal paternity tests can result in miscarriage and congenital malformations; therefore, a non-invasive method of testing is preferable. However, little progress could be made in this field until the introduction of cell-free fetal DNA (cffDNA) in 2009. In this review, two aspects regarding the history and development of non-invasive prenatal paternity testing (NIPAT) are summarized: (1) extraction and enrichment of cffDNA and (2) genetic marker-based studies. Although column-based kits are used widely for NIPAT, some researchers have suggested that an automated method, such as magnetic extraction, generally has a higher cffDNA yield than that of manual column-based extraction; therefore, its popularity might increase in the near future. In addition, size- and methylation-based enrichment methods are expected to perform better than formaldehyde-based methods. On the other hand, single nucleotide polymorphism based techniques have contributed to NIPAT, whereas the application of short tandem repeat testing has so far been restricted to pregnant women bearing male fetuses only. Additional methods and techniques are expected to be innovated to facilitate the forensic practice of NIPAT. PMID- 29626749 TI - The effects of prebiotic, probiotic, and synbiotic supplementation on blood parameters of renal function: A systematic review and meta-analysis of clinical trials. AB - OBJECTIVES: Recent studies have demonstrated promising results regarding possible improvements in renal function after prebiotic, probiotic, and synbiotic supplementation. The aim of this review was to demonstrate whether such supplementation will improve renal profile indexes including glomerular filtration rate (GFR), creatinine, blood urea nitrogen (BUN), uric acid (UA), and urea. METHOD: The meta-analysis included all studies that examined the effect of prebiotic, probiotic, and synbiotic supplements on one or more renal function parameters and had a control group. We searched July 1967 through to March 2016 MEDLINE, Scopus, and Google Scholar databases. RESULTS: Of 437 studies, 13 were eligible for inclusion in the meta-analysis. GFR levels tended to be reduced; whereas creatinine levels increased in the intervention group compared with the placebo group, both in a non-significant manner. The pooled effect on BUN demonstrated a significant decline compared with the placebo group (MD, -1.72 mmol/L; 95% confidence interval [CI], -2.93 to -0.51; P = 0.005). Urea significantly decreased after intervention (-0.46 mmol/L; 95% CI, -0.60 to -0.32; P <0.0001). The UA levels significantly increased in the intervention group compared with the placebo group (12.28 umol/L; 95% CI, 0.85-23.71; P = 0.035). CONCLUSION: This study showed a significant increase in UA and a decrease in urea and BUN. The use of prebiotic, probiotic, and synbiotic supplements among those with compromised renal function or those at risk for renal failure should be limited until large-scale, well-designed randomized controlled trials prove the safety and efficacy of these supplements in improving renal function. PMID- 29626748 TI - pUL34 binding near the human cytomegalovirus origin of lytic replication enhances DNA replication and viral growth. AB - The human cytomegalovirus (HCMV) UL34 gene encodes sequence-specific DNA-binding proteins (pUL34) which are required for viral replication. Interactions of pUL34 with DNA binding sites represses transcription of two viral immune evasion genes, US3 and US9. 12 additional predicted pUL34-binding sites are present in the HCMV genome (strain AD169) with three binding sites concentrated near the HCMV origin of lytic replication (oriLyt). We used ChIP-seq analysis of pUL34-DNA interactions to confirm that pUL34 binds to the oriLyt region during infection. Mutagenesis of the UL34-binding sites in an oriLyt-containing plasmid significantly reduced viral-mediated oriLyt-dependent DNA replication. Mutagenesis of these sites in the HCMV genome reduced the replication efficiencies of the resulting viruses. Protein-protein interaction analyses demonstrated that pUL34 interacts with the viral proteins IE2, UL44, and UL84, that are essential for viral DNA replication, suggesting that pUL34-DNA interactions in the oriLyt region are involved in the DNA replication cascade. PMID- 29626750 TI - Novel Regulatory Roles of Wnt1 in Infection-Associated Colorectal Cancer. AB - Salmonella infection is a major public health concern, and colonization in humans can be chronic and increases the risk of cancers. Wnt signaling is a key pathway for intestinal renewal and development, inflammation, and tumorigenesis. In the current study, we report a novel role of Wnt1 in infection and colon cancer using cell culture models, a Salmonella-colitis colon cancer model, and human samples. In contrast to the bacteria-induced increases in Wnt2 and Wnt11, Salmonella colonization significantly reduced the level of Wnt1 in intestinal epithelial cells in vivo and in vitro. The bacterial AvrA protein is known to activate the canonical Wnt pathway. Wnt1 expression level was downregulated by AvrA-expressing Salmonella but stabilized by AvrA-deficient Salmonella in the intestine of Salmonella-colitis mice. In a chronic Salmonella-infected cancer model, the Wnt1 protein level was decreased in the AvrA+ infected group. Thus, we further assessed the functional role of Wnt1 downregulation in the inflammatory response and colorectal cancer (CRC) progression. Moreover, downregulation of Wnt1 by the Crispr-Cas9 method affected cancer cell invasion and migration. Interestingly, we found that Wnt1 was downregulated in human CRC tissue, and Wnt1 downregulation may be correlated with cancer progression. Our study provides insights into mechanisms by which enteric bacteria regulate Wnt1 expression and potentially contribute to infection-associated colon cancer. PMID- 29626752 TI - Efficacy of ONC201 in Desmoplastic Small Round Cell Tumor. AB - Desmoplastic Small Round Cell Tumor (DSRCT) is a rare sarcoma tumor of adolescence and young adulthood, which harbors a recurrent chromosomal translocation between the Ewing's sarcoma gene (EWSR1) and the Wilms' tumor suppressor gene (WT1). Patients usually develop multiple abdominal tumors with liver and lymph node metastasis developing later. Survival is poor using a multimodal therapy that includes chemotherapy, radiation and surgical resection, new therapies are needed for better management of DSRCT. Triggering cell apoptosis is the scientific rationale of many cancer therapies. Here, we characterized for the first time the expression of pro-apoptotic receptors, tumor necrosis-related apoptosis-inducing ligand receptors (TRAILR1-4) within an established human DSRCT cell line and clinical samples. The molecular induction of TRAIL-mediated apoptosis using agonistic small molecule, ONC201 in vitro cell based proliferation assay and in vivo novel orthotopic xenograft animal models of DSRCT, was able to inhibit cell proliferation that was associated with caspase activation, and tumor growth, indicating that a cell-based delivery of an apoptosis-inducing factor could be relevant therapeutic agent to control DSRCT. PMID- 29626753 TI - A psychometric evaluation of the Concise Health Risk Tracking Self-Report (CHRT SR)- a measure of suicidality-in patients with stimulant use disorder. AB - Stimulant use disorders are both common and associated with suicidal ideation and attempts. The psychometric properties of the 12-item Concise Health Risk Tracking Scale Self-Report (CHRT-SR), a measure that was created to assess suicidal thinking and several factors associated with a propensity to act, has been established in persons with mood disorders. This is a secondary analysis to assess the CHRT-SR in 302 stimulant abusing patients that had participated in a clinical trial. A confirmatory factor analysis (CFA) was conducted to assess the factor validity of the 12-item CHRT-SR model with a second-order Propensity factor. The CHRT-SR total score and 2 factor scores (Propensity and Suicidal Thoughts) demonstrated acceptable internal consistency and test-retest reliabilities. These two subscales and the total score were modestly but significantly associated with measures of depression and life satisfaction, demonstrating construct validity. Two additional items assessing Impulsivity were also analyzed, and demonstrated acceptable internal consistency, test-retest reliability, and construct validity. The CHRT-SR appears to be a reliable and valid tool to assess suicidality in persons with stimulant use disorder. PMID- 29626754 TI - Comparison of penumbra regions produced by ancient Gamma knife model C and Gamma ART 6000 using Monte Carlo MCNP6 simulation. AB - The accuracy of penumbral measurements in radiotherapy is pivotal because dose planning computers require accurate data to adequately modeling the beams, which in turn are used to calculate patient dose distributions. Gamma knife is a non invasive intracranial technique based on principles of the Leksell stereotactic system for open deep brain surgeries, invented and developed by Professor Lars Leksell. The aim of this study is to compare the penumbra widths of Leksell Gamma Knife model C and Gamma ART 6000. Initially, the structure of both systems were simulated by using Monte Carlo MCNP6 code and after validating the accuracy of simulation, beam profiles of different collimators were plotted. MCNP6 beam profile calculations showed that the penumbra values of Leksell Gamma knife model C and Gamma ART 6000 for 18, 14, 8 and 4 mm collimators are 9.7, 7.9, 4.3, 2.6 and 8.2, 6.9, 3.6, 2.4, respectively. The results of this study showed that since Gamma ART 6000 has larger solid angle in comparison with Gamma Knife model C, it produces better beam profile penumbras than Gamma Knife model C in the direct plane. PMID- 29626755 TI - Infants use linguistic group distinctions to chunk items in memory. AB - Although the capacity of infants' working memory is highly constrained, infants can overcome this limit via chunking; for example, they can use spatial cues to group individual objects into sets, thereby increasing memory efficiency. Here we investigated the use of abstract social knowledge as a basis for chunking. In four experiments, we asked whether 16-month-olds can use their sensitivity to distinctions between languages to efficiently chunk an array. Infants saw four identical dolls hidden in a box. Without chunking cues, infants in previous experiments fail to remember this number of items in such arrays. In Experiment 1, infants saw two of the four dolls each produce an utterance in a familiar language (English) prior to hiding and saw the other two dolls each produce an unfamiliar language (German or Mandarin). Infants successfully remembered all four dolls. Next we asked whether infants could chunk using linguistic group distinctions even when all dolls spoke unfamiliar languages. Infants failed to chunk speakers of unfamiliar languages when each doll within a pair produced a unique utterance (Experiment 2), but they succeeded when each doll within a pair produced the same utterance (Experiment 3). Infants' performance was not driven by low-level acoustical cues in the utterances given that infants failed to chunk when the dolls' speech was played backward (Experiment 4). Together, these results suggest that infants can leverage their early sensitivities to linguistic distinctions to hierarchically reorganize their memory representations, thereby overcoming working memory limits. PMID- 29626756 TI - Beat gestures help preschoolers recall and comprehend discourse information. AB - Although the positive effects of iconic gestures on word recall and comprehension by children have been clearly established, less is known about the benefits of beat gestures (rhythmic hand/arm movements produced together with prominent prosody). This study investigated (a) whether beat gestures combined with prosodic information help children recall contrastively focused words as well as information related to those words in a child-directed discourse (Experiment 1) and (b) whether the presence of beat gestures helps children comprehend a narrative discourse (Experiment 2). In Experiment 1, 51 4-year-olds were exposed to a total of three short stories with contrastive words presented in three conditions, namely with prominence in both speech and gesture, prominence in speech only, and nonprominent speech. Results of a recall task showed that (a) children remembered more words when exposed to prominence in both speech and gesture than in either of the other two conditions and that (b) children were more likely to remember information related to those words when the words were associated with beat gestures. In Experiment 2, 55 5- and 6-year-olds were presented with six narratives with target items either produced with prosodic prominence but no beat gestures or produced with both prosodic prominence and beat gestures. Results of a comprehension task demonstrated that stories told with beat gestures were comprehended better by children. Together, these results constitute evidence that beat gestures help preschoolers not only to recall discourse information but also to comprehend it. PMID- 29626751 TI - Role of Mitochondria-Associated ER Membranes in Calcium Regulation in Cancer Specific Settings. AB - Mitochondria-associated endoplasmic reticulum (ER) membranes (MAMs) are highly specialized subcellular compartments that are shaped by ER subdomains juxtaposed to mitochondria but are biochemically distinct from pure ER and pure mitochondria. MAMs are enriched in enzymes involved in lipid synthesis and transport, channels for calcium transfer, and proteins with oncogenic/oncosuppressive functions that modulate cell signaling pathways involved in physiological and pathophysiological processes. The term "cancer" denotes a group of disorders that result from uncontrolled cell growth driven by a mixture of genetic and environmental components. Alterations in MAMs are thought to account for the onset as well as the progression and metastasis of cancer and have been a focus of investigation in recent years. In this review, we present the current state of the art regarding MAM-resident proteins and their relevance, alterations, and deregulating functions in different types of cancer from a cell biology and clinical perspective. PMID- 29626757 TI - NmtA, a novel metallothionein of Anabaena sp. strain PCC 7120 imparts protection against cadmium stress but not oxidative stress. AB - Metallothioneins (MTs) are low molecular weight, sulfhydryl-containing, cysteine rich, metal-binding proteins. Eukaryotes have multiple metallothionein genes; however, there is dearth of reports on prokaryotic metallothioneins. Bacterial MTs with SmtA from Synechococcus PCC 7942 as prototype have been studied in the context of cadmium detoxification. In this study, a smtA related ORF, namely nmtA, was identified in the heterocystous, nitrogen-fixing cyanobacterium, Anabaena PCC 7120. A recombinant N-terminal histidine-tagged Anabaena NmtA protein was overexpressed in Escherichia coli and purified. The protein was identified by peptide mass fingerprinting using MALDI-TOF Mass Spectrometry as putative metallothionein of Anabaena PCC 7120 with a calculated mass of ~6.1 kDa. While the native metallated NmtA exhibited resistance against proteolysis, metal free apo-NmtA resulting from acid and dithiothreitol (DTT) treatment could be digested by proteinase K revealing a metal dependent proteolytic protection of NmtA. Expression of nmtA in Anabaena PCC 7120 was induced evidently by cadmium, zinc and copper but not by uranium or hydrogen peroxide. Recombinant Anabaena PCC 7120 overexpressing NmtA protein revealed superior cadmium tolerance but showed limited influence against oxidative stress tolerance as compared with the strain carrying vector alone. In contrast, a mutant of Synechococcus PCC 7942 deficient in MT locus was found to be highly susceptible to H2O2 indicating a likely involvement of cyanobacterial MT in protection against oxidative damage. Overall, the study improved our understanding of metal tolerance mechanisms in Anabaena PCC 7120 by demonstrating a key role of NmtA in cadmium tolerance. PMID- 29626758 TI - Use of risk assessment instruments to predict violence in forensic psychiatric hospitals: a systematic review and meta-analysis. AB - BACKGROUND AND AIMS: Violent behaviour by forensic psychiatric inpatients is common. We aimed to systematically review the performance of structured risk assessment tools for violence in these settings. METHODS: The nine most commonly used violence risk assessment instruments used in psychiatric hospitals were examined. A systematic search of five databases (CINAHL, Embase, Global Health, PsycINFO and PubMed) was conducted to identify studies examining the predictive accuracy of these tools in forensic psychiatric inpatient settings. Risk assessment instruments were separated into those designed for imminent (within 24 hours) violence prediction and those designed for longer-term prediction. A range of accuracy measures and descriptive variables were extracted. A quality assessment was performed for each eligible study using the QUADAS-2. Summary performance measures (sensitivity, specificity, positive and negative predictive values, diagnostic odds ratio, and area under the curve value) and HSROC curves were produced. In addition, meta-regression analyses investigated study and sample effects on tool performance. RESULTS: Fifty-two eligible publications were identified, of which 43 provided information on tool accuracy in the form of AUC statistics. These provided data on 78 individual samples, with information on 6,840 patients. Of these, 35 samples (3,306 patients from 19 publications) provided data on all performance measures. The median AUC value for the wider group of 78 samples was higher for imminent tools (AUC 0.83; IQR: 0.71-0.85) compared with longer-term tools (AUC 0.68; IQR: 0.62-0.75). Other performance measures indicated variable accuracy for imminent and longer-term tools. Meta regression indicated that no study or sample-related characteristics were associated with between-study differences in AUCs. INTERPRETATION: The performance of current tools in predicting risk of violence beyond the first few days is variable, and the selection of which tool to use in clinical practice should consider accuracy estimates. For more imminent violence, however, there is evidence in support of brief scalable assessment tools. PMID- 29626759 TI - Hierarchical assembly of urchin-like alpha-iron oxide hollow microspheres and molybdenum disulphide nanosheets for ethanol gas sensing. AB - In this paper, we fabricated a high-performance ethanol sensor using layer-by layer self-assembled urchin-like alpha-iron oxide (alpha-Fe2O3) hollow microspheres/molybdenum disulphide (MoS2) nanosheets heterostructure as sensitive materials. The nanostructural, morphological, and compositional properties of the as-prepared alpha-Fe2O3/MoS2 heterostructure were characterized by X-ray diffraction (XRD), energy dispersive spectrometer (EDS), scanning electron microscopy (SEM), transmission electron microscope (TEM) and X-ray photoelectron spectroscopy (XPS), which confirmed its successful preparation and rationality. The alpha-Fe2O3/MoS2 nanocomposite sensor shows good selectivity, excellent reproducibility, fast response/recovery time and low detection limit towards ethanol gas at room temperature, which is superior to the single component of alpha-Fe2O3 hollow microspheres and MoS2 nanosheets. Furthermore, the response of the alpha-Fe2O3/MoS2 nanocomposite sensor as a function of ethanol gas concentration was also demonstrated. The enhanced ethanol sensing properties of the alpha-Fe2O3/MoS2 nanocomposite sensor were ascribed to the synergistic effect and heterojunction between the urchin-Like alpha-Fe2O3 hollow microspheres and MoS2 nanosheets. This work verifies that the hierarchical alpha-Fe2O3/MoS2 nanoheterostructure is a potential candidate for fabricating room-temperature ethanol gas sensor. PMID- 29626760 TI - Hybrids of carbon dots with subunit B of ricin toxin for enhanced immunomodulatory activity. AB - Although Ricin toxin binding subunit B (RTB) can promote the activation of macrophages and modulate the cell-mediated immunity, its applications are severely limited due to the intrinsic properties of proteins, like poor stability and low efficacy of cellular uptake. In this work, the stable nanoparticles were prepared by supramolecular assembling of carbon dots (CDs) and RTB. The formed CDs-RTB possesses robust stability and can protect RTB against enzymatic hydrolysis. More importantly, CDs-RTB can promote macrophages proliferation, improve the generation of NO, IL-6 and TNF-alpha in RAW264.7 cells and increase the expression of mRNA, indicating the enhanced immunomodulatory activity of CDs RTB. This work highlights the potential of using CDs as a simple and stable platform to assemble RTB and effectively promotes the application of RTB as the immunostimulant. PMID- 29626761 TI - Controlled release of bupivacaine using hybrid thermoresponsive nanoparticles activated via photothermal heating. AB - Near-infrared (NIR) responsive nanoparticles are of great interest in the biomedical field as antennas for photothermal therapy and also as triggers for on demand drug delivery. The present work reports the preparation of hollow gold nanoparticles (HGNPs) with plasmonic absorption in the NIR region covalently bound to a thermoresponsive polymeric shell that can be used as an on-demand drug delivery system for the release of analgesic drugs. The photothermal heating induced by the nanoparticles is able to produce the collapse of the polymeric shell thus generating the release of the local anesthetic bupivacaine in a spatiotemporally controlled way. Those HGNPs contain a 10 wt.% of polymer and present excellent reversible heating under NIR light excitation. Bupivacaine released at physiological temperature (37 degrees C) showed a pseudo-zero order release that could be spatiotemporally modified on-demand after applying several pulses of light/temperature above and below the lower critical solution temperature (LCST) of the polymeric shell. Furthermore, the nanomaterials obtained did not displayed detrimental effects on four mammalian cell lines at doses up to 0.2 mg/mL. From the results obtained it can be concluded than this type of hybrid thermoresponsive nanoparticle can be used as an externally activated on-demand drug delivery system. PMID- 29626762 TI - Self-powered highly enhanced broad wavelength (UV to visible) photoresponse of ZnO@ZnO1-xSx@ZnS core-shell heterostructures. AB - In the present scenario of energy crisis, it is inevitable to focus on the low powered or self-powered devices. Multi-spectral photoresponse is an additional advantage to the above feature. We have developed an efficient self-powered photodetector with broad wavelength detection range based on heterostructures of two wide band-gap materials ZnO and ZnS. More than two orders higher responsivity and 'ON/OFF' ratio has been observed in case of heterostructure sample as compared to pristine ZnO. On the basis of the controlled experimental results, it has been established that the interfacial surface engineering, can be useful to improve the visible response and a significant photovoltaic performance under visible light illumination can be achieved. Unlike the other recent reports on self-powered UV-visible photodetector, we have achieved two order higher visible response without compromising the UV photoresponse. Unprecedented broad wavelength photodetection in self-powered mode in the present study highlights the uniqueness and advantage of an interface in a core-shell heterostructure for photodetection applications. PMID- 29626764 TI - Effect of alkali-treatment on the characteristics of natural zeolites with different compositions. AB - A series of natural zeolites with different compositions were modified by post synthesis modification with sodium hydroxide (NaOH) solution. Natural and modified zeolites were characterized by XRD, SEM, nitrogen adsorption, FTIR, zeta potential and temperature programmed desorption of ammonia (NH3-TPD). The adsorption capacities of these samples were evaluated by the adsorption of manganese from aqueous solution. The treatment with NaOH led to a decrease in the surface area and microporosity of all natural zeolites as well as partly damage of the zeolite structure depending on zeolite composition. In addition, the amount of weak, medium and strong acid sites in the zeolites was changed significantly by NaOH treatment depending on zeolite composition. The NaOH treatment resulted in a four-fold improvement in adsorption capacity of natural zeolite originated from Bigadic and a twofold decrease in that of the natural zeolite originated from Manisa-Gordes. Although the improved adsorption capacity might be mainly due to modification of porosity in the zeolites and formation of hydroxysodalite, the reduced adsorption capacity of the zeolite might be mainly due to a significant deformation of the zeolite structure. The pseudo-second order kinetic model for the adsorption of manganese on all natural and modified zeolites fits well. PMID- 29626763 TI - Bacteriophage-based strategies for biofouling control in ultrafiltration: In situ biofouling mitigation, biocidal additives and biofilm cleanser. AB - The ability of bacteriophages to infect and destroy specific bacteria makes them promising antimicrobial agents in industrial processes. In this study, potential strategies of bacteriophage-facilitated biofouling control during membrane ultrafiltration (UF) were investigated through use of the model T4 bacteriophage and the model host bacterium, Escherichia coli. In the dead-end filtration mode, phages were immobilized on the membrane surface to serve as biocidal agents and inhibit the propagation of bacteria in situ. After 6 h of filtration, a 36% flux reduction was observed for the T4-functionalized membrane in comparison to 71% for the non-functionalized membrane. Surface modification of the membrane using O2 plasma treatment resulted in increased numbers of bound phage and enhanced biofouling resistance of the membrane. Introducing the phage into the feed of a cross-flow filtration system effectively mitigated the water flux reduction of the membrane caused by bacterial growth. By modifying the concentration of phage additives, the growth of bacteria was delayed, inhibited, or eliminated. Phage treatment changed the structure of biofilms on the membrane surface and facilitated in situ biofilm cleaning. A 20% greater recovery in water flux was observed for the biofilm-contaminated membrane following phage-assisted cleaning when compared to the membrane cleaned via a physical washing process. Taken together, these results show that bacteriophage assisted anti-biofouling strategies have the potential to mitigate biofouling in membrane processes in an environmentally friendly manner. PMID- 29626765 TI - Oxidatively-induced DNA damage and base excision repair in euthymic patients with bipolar disorder. AB - Oxidatively-induced DNA damage has previously been associated with bipolar disorder. More recently, impairments in DNA repair mechanisms have also been reported. We aimed to investigate oxidatively-induced DNA lesions and expression of DNA glycosylases involved in base excision repair in euthymic patients with bipolar disorder compared to healthy individuals. DNA base lesions including both base and nucleoside modifications were measured using gas chromatography-tandem mass spectrometry and liquid chromatography-tandem mass spectrometry with isotope dilution in DNA samples isolated from leukocytes of euthymic patients with bipolar disorder (n = 32) and healthy individuals (n = 51). The expression of DNA repair enzymes OGG1 and NEIL1 were measured using quantitative real-time polymerase chain reaction. The levels of malondialdehyde were measured using high performance liquid chromatography. Seven DNA base lesions in DNA of leukocytes of patients and healthy individuals were identified and quantified. Three of them had significantly elevated levels in bipolar patients when compared to healthy individuals. No elevation of lipid peroxidation marker malondialdehyde was observed. The level of OGG1 expression was significantly reduced in bipolar patients compared to healthy individuals, whereas the two groups exhibited similar levels of NEIL1 expression. Our results suggest that oxidatively-induced DNA damage occurs and base excision repair capacity may be decreased in bipolar patients when compared to healthy individuals. Measurement of oxidatively-induced DNA base lesions and the expression of DNA repair enzymes may be of great importance for large scale basic research and clinical studies of bipolar disorder. PMID- 29626766 TI - Posterior assessment of reference gages for water resources management using instantaneous flow measurements. AB - Reference stream gages are commonly used for a variety of hydrologic studies and water resources management purposes. Reference gage selection methods have been extensively investigated in literature. However, the posterior assessment of reference gages is a long-standing challenge faced by water resources managers. This study aims to evaluate the accuracy of using reference gages in estimating low flow conditions at ungaged sites. The proposed assessment method is comprised of three fundamental components including: (1) a field campaign to obtain instantaneous flow measurements at ungaged sites during baseflow conditions; (2) streamflow correlation and streamflow ratio analyses using field measured values at ungaged sites and concurrent reference gage data; and (3) map correlation analysis to identify alternative reference gages for ungaged sites with undesirable flow correlation and flow ratio values. The method was tested using 18 systematically selected reference gages used by the Susquehanna River Basin Commission for regulating water withdrawals and ensuring compliance with passby flow requirements. Streamflow monitoring during baseflow conditions over the course of four consecutive low flow seasons resulted in the collection of ten streamflow measurements for each ungaged site. The streamflow correlation coefficients between streamflow measurements at ungaged sites and concurrent reference gage streamflow data were found to be greater than 0.7 for 17 of the 18 sites. Map correlation analysis was conducted to identify alternative reference gages for three ungaged sites which exhibited high prediction errors or low streamflow correlation. The case study demonstrates that proposed posterior assessment method for evaluating reference gage performance is easy to use with reasonable cost. PMID- 29626767 TI - Environmental contaminant mixtures modulate in vitro influenza infection. AB - Environmental chemicals, particularly organochlorinated contaminants (OCs), are associated with a ranged of adverse health effects, including impairment of the immune system and antiviral immunity. Influenza A virus (IAV) is an infectious disease of major global public health concern and exposure to OCs can increase the susceptibility, morbidity, and mortality to disease. It is however unclear how pollutants are interacting and affecting the outcome of viral infections at the cellular level. In this study, we investigated the effects of a mixture of environmentally relevant OCs on IAV infectivity upon in vitro exposure in Madin Darby Canine Kidney (MDCK) cells and human lung epithelial cells (A549). Exposure to OCs reduced IAV infectivity in MDCK and A549 cells during both short (18-24h) and long-term (72h) infections at 0.05 and 0.5ppm, and effects were more pronounced in cells co-treated with OCs and IAV than pre-treated with OCs prior to IAV (p<0.001). Pre-treatment of host cells with OCs did not affect IAV cell surface attachment or entry. Visualization of IAV by transmission electron microscopy revealed increased envelope deformations and fewer intact virions during OC exposure. Taken together, our results suggest that disruption of IAV infection upon in vitro exposure to OCs was not due to host-cell effects influencing viral attachment and entry, but perhaps mediated by direct effects on viral particles or cellular processes involved in host-virus interactions. In vitro infectivity studies such as ours can shed light on the complex processes underlying host-pathogen-pollutant interactions. PMID- 29626768 TI - Seasonal characterization of sugarcane vinasse: Assessing environmental impacts from fertirrigation and the bioenergy recovery potential through biodigestion. AB - Sugarcane vinasse has been widely used as a soil fertilizer in the Brazilian sucro-alcohol industry for recycling potassium and water. However, the potential negative effects from long-term soil fertirrigation represent a major drawback regarding this practice, whereas the application of biodigestion represents an efficient method for reducing the polluting organic load and recovering bioenergy from vinasse. Regardless of the predicted use for vinasse, an understanding of the potential of each option is imperative, as the seasonal alterations in the inorganic/organic fractions of vinasse directly affect its management. In this context, this study presents a detailed compositional characterization of sugarcane vinasse from a large-scale Brazilian biorefinery throughout the 2014/2015 harvest to assess the environmental effects (due to fertirrigation) and to estimate the biogas energetic potential. Calculated inputs of organic matter into soils due to vinasse land application were equivalent to the polluting load of populations (117-257inhabha-1) at least 2-fold greater than the largest Brazilian capital cities (78-70inhabha-1). Two-phase biodigestion could efficiently reduce the polluting load of vinasse (23-52inhabha-1) and eliminate the negative effects from direct sulfide emissions in the environment. However, a high risk of soil sodification could result from using high doses of Na-based alkalizing compounds in biodigestion plants. Finally, the optimized recovery of bioenergy through biogas (13.3-26.7MW as electricity) could supply populations as large as 305 thousand inhabitants, so that over 30% of the surplus electricity produced by the studied biorefinery could be obtained from biogas. Overall, applying biodigestion in the treatment of vinasse provides important environmental and energetic gains. However, the benefits of reducing the polluting organic load of vinasse through bioenergy recovery may lose their effect depending on the alkalizing strategy, indicating that the proper use of chemicals in full-scale biodigestion plants is imperative to attain process sustainability. PMID- 29626770 TI - Estimating environmental fate of tricyclic antidepressants in wastewater treatment plant. AB - TCAs are known to be toxicants and endocrine disrupting agents. Generally, after being used, TCAs are passed through wastewater treatment plants (WWTPs) to be treated. However, still trace amounts (ng/L to MUg/L) of TCAs have been founded even in the treated water. Therefore, the aim of this study is to elucidate the environmental behaviors of TCAs in the sewage water from WWTPs (Jeonju, Korea). For the experiments, seven TCAs (amitriptyline, imipramine, clomipramine, desipramine, protriptyline, nortriptyline, and doxepin) were selected. Hydrolysibility, biodegradability, and adsorbability of the selected seven TCAs were evaluated. Based on the results, it was concluded that TCAs are not readily hydrolyzed in water and also not biodegraded by aerobic sludge. The 60% to 85% of TCAs were adsorbed immediately onto the activated sludge within 1 s via electrostatic and hydrophobic interactions. It was clearly observed that adsorption affinities were dependent on the types of activated sludge (i.e. anaerobic and aerobic sludge). The affinities of aerobic and anaerobic sludge towards the TCAs at trace concentrations e.g., 1 to 10 MUg/L, were estimated to be in the range from 0.021 +/- 0.000 to 0.087 +/- 0.000 L/MUg and from 0.001 +/- 0.000 to 0.108 +/- 0.001 L/MUg, respectively. PMID- 29626769 TI - Chemical profiling of PM10 from urban road dust. AB - Road dust resuspension is one of the main sources of particulate matter with impacts on air quality, health and climate. With the aim of characterising the thoracic fraction, a portable resuspension chamber was used to collect road dust from five main roads in Oporto and an urban tunnel in Braga, north of Portugal. The PM10 samples were analysed for: i) carbonates by acidification and quantification of the evolved CO2, ii) carbonaceous content (OC and EC) by a thermo-optical technique, iii) elemental composition by ICP-MS and ICP-AES after acid digestion, and iv) organic speciation by GC-MS. Dust loadings of 0.48+/ 0.39mgPM10m-2 were obtained for asphalt paved roads. A much higher mean value was achieved in a cobbled pavement (50mgPM10m-2). In general, carbonates were not detected in PM10. OC and EC accounted for PM10 mass fractions up to 11% and 5%, respectively. Metal oxides accounted for 29+/-7.5% of the PM10 mass from the asphalt paved roads and 73% in samples from the cobbled street. Crustal and anthropogenic elements, associated with tyre and brake wear, dominated the inorganic fraction. PM10 comprised hundreds of organic constituents, including hopanoids, n-alkanes and other aliphatics, polycyclic aromatic hydrocarbons (PAH), alcohols, sterols, various types of acids, glycerol derivatives, lactones, sugars and derivatives, phenolic compounds and plasticizers. In samples from the cobbled street, these organic classes represented only 439MUgg-1PM10, while for other pavements mass fractions up to 65mgg-1PM10 were obtained. Except for the cobbled street, on average, about 40% of the analysed organic fraction was composed of plasticizers. Although the risk via inhalation of PAH was found to be insignificant, the PM10 from some roads can contribute to an estimated excess of 332 to 2183 per million new cancer cases in adults exposed via ingestion and dermal contact. PMID- 29626771 TI - Emission quantification using the tracer gas dispersion method: The influence of instrument, tracer gas species and source simulation. AB - The tracer gas dispersion method (TDM) is a remote sensing method used for quantifying fugitive emissions by relying on the controlled release of a tracer gas at the source, combined with concentration measurements of the tracer and target gas plumes. The TDM was tested at a wastewater treatment plant for plant integrated methane emission quantification, using four analytical instruments simultaneously and four different tracer gases. Measurements performed using a combination of an analytical instrument and a tracer gas, with a high ratio between the tracer gas release rate and instrument precision (a high release precision ratio), resulted in well-defined plumes with a high signal-to-noise ratio and a high methane-to-tracer gas correlation factor. Measured methane emission rates differed by up to 18% from the mean value when measurements were performed using seven different instrument and tracer gas combinations. Analytical instruments with a high detection frequency and good precision were established as the most suitable for successful TDM application. The application of an instrument with a poor precision could only to some extent be overcome by applying a higher tracer gas release rate. A sideward misplacement of the tracer gas release point of about 250m resulted in an emission rate comparable to those obtained using a tracer gas correctly simulating the methane emission. Conversely, an upwind misplacement of about 150m resulted in an emission rate overestimation of almost 50%, showing the importance of proper emission source simulation when applying the TDM. PMID- 29626772 TI - Annual input and output fluxes of heavy metals to paddy fields in four types of contaminated areas in Hunan Province, China. AB - This study focused on the heavy metal concentrations in the soil and their representative input and output fluxes to paddy fields in four types of contaminated areas in Changzhutan urban agglomerations, Hunan, China. Four types of contaminated areas (mining area, livestock breeding area, suburb area and control area) were chosen for monitoring. Three input pathways and three output pathways were considered so as to figure out the heavy metal balance throughout the topsoil. In all study areas, the input fluxes of atmospheric deposition, accounting for 51.21%-94.74% of the total input fluxes, were significantly higher than those of fertilizer and irrigation water. Nevertheless, the manure fertilizer contributes nearly the same proportion as atmospheric deposition in livestock breeding area. In suburb area, only the flux of atmospheric deposition was higher than that in control area, and other input fluxes showed no significant difference. Crop removal, especially straw removal, was the primary output pathway of soil elements, contributing 60.19%-89.37% of the total output fluxes. Annual balance demonstrated that Cd was the metal of the primary concern in study areas. Furthermore, obvious differences were observed among the distribution of heavy metals (Cd, Pb and As) fractions in four types of contaminated areas. In general, the available content was the primary portion of the total contents, mostly up to about 51.70%-87.76%. The information obtained in this paper provides a more comprehensive understanding of the differences in the net inputs of heavy metals among four types of contaminated areas and emphasizes the significance of straw removal for Hunan agricultural soil. PMID- 29626773 TI - Development of land-use regression models for fine particles and black carbon in peri-urban South India. AB - Land-use regression (LUR) has been used to model local spatial variability of particulate matter in cities of high-income countries. Performance of LUR models is unknown in less urbanized areas of low-/middle-income countries (LMICs) experiencing complex sources of ambient air pollution and which typically have limited land use data. To address these concerns, we developed LUR models using satellite imagery (e.g., vegetation, urbanicity) and manually-collected data from a comprehensive built-environment survey (e.g., roads, industries, non residential places) for a peri-urban area outside Hyderabad, India. As part of the CHAI (Cardiovascular Health effects of Air pollution in Telangana, India) project, concentrations of fine particulate matter (PM2.5) and black carbon were measured over two seasons at 23 sites. Annual mean (sd) was 34.1 (3.2) MUg/m3 for PM2.5 and 2.7 (0.5) MUg/m3 for black carbon. The LUR model for annual black carbon explained 78% of total variance and included both local-scale (energy supply places) and regional-scale (roads) predictors. Explained variance was 58% for annual PM2.5 and the included predictors were only regional (urbanicity, vegetation). During leave-one-out cross-validation and cross-holdout validation, only the black carbon model showed consistent performance. The LUR model for black carbon explained a substantial proportion of the spatial variability that could not be captured by simpler interpolation technique (ordinary kriging). This is the first study to develop a LUR model for ambient concentrations of PM2.5 and black carbon in a non-urban area of LMICs, supporting the applicability of the LUR approach in such settings. Our results provide insights on the added value of manually-collected built-environment data to improve the performance of LUR models in settings with limited data availability. For both pollutants, LUR models predicted substantial within-village variability, an important feature for future epidemiological studies. PMID- 29626774 TI - Will temperature and salinity changes exacerbate the effects of seawater acidification on the marine microalga Phaeodactylum tricornutum? AB - To evaluate the effects related to the combination of potential future changes in pH, temperature and salinity on microalgae, a laboratory experiment was performed using the marine diatom Phaeodactylum tricornutum. Populations of this species were exposed during 48h to a three-factor experimental design (3*2*2) with two artificial pH values (6, 7.4), two levels of temperature (23 degrees C, 28 degrees C), two levels of salinity (34psu, 40psu) and a control (pH8, Temp 23 degrees C, Sal 34psu). The effects on growth, cell viability, metabolic activity, and inherent cell properties (size, complexity and autofluorescence) of P. tricornutum were studied using flow cytometry. The results showed adverse effects on cultures exposed to pH6 and high temperature and salinity, being the inherent cell properties the most sensitive response. Also, linked effects of these parameters resulted on cell viability and cell size decrease and an increase of cell autofluorescence. The conclusions obtained from this work are useful to address the potential effects of climate change (in terms of changes on pH, salinity and temperature) in microalgae. PMID- 29626775 TI - Climate change and associated spatial heterogeneity of Pakistan: Empirical evidence using multidisciplinary approach. AB - Climate change is a multidimensional phenomenon, which has various implications for the environment and socio-economic conditions of the people. Its effects are deeper in an agrarian economy which is susceptible to the vagaries of nature. Therefore, climate change directly impacts the society in different ways, and society must pay the cost. Focusing on this truth, the main objective of this research was to investigate the empirical changes and spatial heterogeneity in the climate of Pakistan in real terms using time series data. Climate change and variability in Pakistan, over time, were estimated from 1961 to 2014 using all the climate variables for the very first time. Several studies were available on climate change impacts, mitigation, and adaptation; however, it was difficult to observe exactly how much change occurred in which province and when. A multidisciplinary approach was utilized to estimate the absolute change through a combination of environmental, econometric, and remote sensing methods. Moreover, the Autoregressive Distributed Lag (ARDL) model was used to ascertain the extent of variability in climate change and information was digitalized through ground truthing. Results showed that the average temperature of Pakistan increased by 2 degrees C between 1960 and 1987 and 4 degrees C between 1988 and 2014, and R2 was 0.978. The rate of temperature increased 0.09 degrees C between 1960 and 2014. The mean annual precipitation of Pakistan increased by 478mm, and its R2 were 0.34-0.64. The mean annual humidity of Pakistan increased by 2.94%, and the rate of humidity has been increased by 0.97% from 1988 to 2014. Notably, Sindh and Balochistan provinces have shown a significant spatial heterogeneity regarding the increase in precipitation. Statistically all variables are significant. This would serve as a baseline information for climate change-related studies in Pakistan and its application in different sectors. This would also serve the plant breeders and policymakers of the country. PMID- 29626777 TI - The source and diversion of pharmaceutical drugs for non-medical use: A systematic review and meta-analysis. AB - BACKGROUND: The non-medical use (NMU) of pharmaceutical drugs is an increasing public health concern. This systematic review consolidates current knowledge about how pharmaceutical drugs are obtained for NMU and the processes and people involved in diversion. METHODS: Peer-reviewed and grey literature databases were searched for empirical studies published between 1996 and 2017 that examined the source or diversion of pharmaceutical opioids, sedatives or stimulants for NMU in countries with reported misuse problems. Pooled prevalence meta-analyses using random effects models were used to estimate the prevalence of medical and non medical sourcing reported by end-users, and gifting, selling and trading by various populations. RESULTS: This review synthesizes the findings of 54 cross sectional studies via meta-analyses, with a remaining 95 studies examined through narrative review. Pharmaceutical drugs are primarily sourced for NMU from friends and family (57%, 95% CI 53%-62%, I2 = 98.5, n = 30) and despite perceptions of healthcare professionals to the contrary, illegitimate practices such as doctor shopping are uncommon (7%, 95% CI 6%-10%, I2 = 97.4, n = 29). Those at risk of diversion include patients displaying aberrant medication behaviors, people with substance use issues and students in fraternity/sorority environments. Sourcing via dealers is also common (32%, 95% CI 23%-41%, I2 = 99.8, n = 25) and particularly so among people who use illicit drugs (47%, 95% CI 35%-60%, I2 = 99.1, n = 15). There is little to no organized criminal involvement in the pharmaceutical black market. CONCLUSION: Pharmaceutical drugs for NMU are primarily sourced by end-users through social networks. Future research should examine how dealers source pharmaceutical drugs. PMID- 29626776 TI - A fMRI study on the impact of advertising for flavored e-cigarettes on susceptible young adults. AB - BACKGROUND: E-cigarettes are sold in flavors such as "skittles," "strawberrylicious," and "juicy fruit," and no restrictions are in place on marketing e-cigarettes to youth. Sweets/fruits depicted in e-cigarette advertisements may increase their appeal to youth and interfere with health warnings. This study tested a brain biomarker of product preference for sweet/fruit versus tobacco flavor e-cigarettes, and whether advertising for flavors interfered with warning labels. METHODS: Participants (N = 26) were college-age young adults who had tried an e-cigarette and were susceptible to future e-cigarette use. They viewed advertisements in fMRI for sweet/fruit and tobacco flavor e-cigarettes, menthol and regular cigarettes, and control images of sweets/fruits/mints with no tobacco product. Cue-reactivity was measured in the nucleus accumbens, a brain biomarker of product preference. Advertisements randomly contained warning labels, and recognition of health warnings was tested post-scan. Visual attention was measured using eye-tracking. RESULTS: There was a significant effect of e-cigarette condition (sweet/tobacco/control) on nucleus accumbens activity, that was not found for cigarette condition (menthol/regular/control). Nucleus accumbens activity was greater for sweet/fruit versus tobacco flavor e-cigarette advertisements and did not differ compared with control images of sweets and fruits. Greater nucleus accumbens activity was correlated with poorer memory for health warnings. CONCLUSIONS: These and exploratory eye-tracking findings suggest that advertising for sweet/fruit flavors may increase positive associations with e-cigarettes and/or override negative associations with tobacco, and interfere with health warnings, suggesting that one way to reduce the appeal of e-cigarettes to youth and educate youth about e-cigarette health risks is to regulate advertising for flavors. PMID- 29626779 TI - Hydrothermal synthesis of hierarchically structured birnessite-type MnO2/biochar composites for the adsorptive removal of Cu(II) from aqueous media. AB - In this study, hierarchical birnessite-type MnO2/biochar composites (delta MnO2/BCs) were synthesized by a hydrothermal technique, and their Cu(II) removal performance was examined in aqueous solution. Morphological characterization confirmed that a three-dimensional flower-like structure of delta-MnO2 was formed, which results in effective adsorption affinity towards Cu(II). The effects of solution pH, adsorbent dosage, and ionic strength on the adsorption behavior of the prepared materials were systemically investigated. The adsorption kinetics indicated that Cu(II) adsorption onto delta-MnO2/BCs follows a pseudo second-order model. Analysis of possible adsorption/diffusion mechanisms suggested that the adsorption process is controlled by both film and pore diffusion. The adsorption isotherms fit closely to the Sips isotherm model, and the theoretical maximum adsorption capacities of Cu(II) on the synthesized delta MnO2/BCs are approximately 124, 154, 199, and 230 mg/g at 15, 25, 35, and 45 degrees C, respectively. Adsorption-desorption studies demonstrated the recyclability of the delta-MnO2/BCs for the removal of Cu(II) from aqueous solutions. PMID- 29626780 TI - Performance of pilot scale anaerobic biofilm digester (ABD) for the treatment of leachate from a municipal waste transfer station. AB - The anaerobic treatment of leachate from a municipal waste transfer station in Malaysia was tested using a pilot scale anaerobic biofilm digester system that was operated under HRT sequence of 30-day, 25-day, 20-day and 10-day for 163 days under mesophilic conditions. Despite the leachate's complex characteristics, the system showed great performance given its maximum COD, BOD5 and total phosphorus removal efficiencies of 98 +/- 1%, 99 +/- 1% and 92 +/- 9% respectively. The system was stable throughout its operation and showed optimal average values for the monitored parameters such as pH (7.53 +/- 0.14), total VFA (79 +/- 66 mg HOAc/L), alkalinity (10,919 +/- 1556 mg CaCO3/L) and a non-toxic value for accumulated ammonia (960 +/- 106 mg NH3-N/L). Measurement of the average daily biogas production yielded a value of 25 +/- 1 m3/day throughout the system's operation with a composition of 57 +/- 12% methane and 26 +/- 6% carbon dioxide. PMID- 29626781 TI - Assessing the integration of forward osmosis and anaerobic digestion for simultaneous wastewater treatment and resource recovery. AB - This study assessed the performance and key challenges associated with the integration of forward osmosis (FO) and anaerobic digestion for wastewater treatment and resource recovery. Using a thin film composite polyamide FO membrane, maximising the pre-concentration factor (i.e. system water recovery) resulted in the enrichment of organics and salinity in wastewater. Biomethane potential evaluation indicated that methane production increased correspondingly with the FO pre-concentration factor due to the organic retention in the feed solution. At 90% water recovery, about 10% more methane was produced when using NaOAc compared with NaCl because of the contribution of biodegradable reverse NaOAc flux. No negative impact on anaerobic digestion was observed when wastewater was pre-concentrated ten-fold (90% water recovery) for both draw solutes. Interestingly, the unit cost of methane production using NaOAc was slightly lower than NaCl due to the lower reverse solute flux of NaOAc, although NaCl is a much cheaper chemical. PMID- 29626778 TI - A longitudinal study of risk perceptions and e-cigarette initiation among college students: Interactions with smoking status. AB - BACKGROUND: Recent data suggest that lower perceived risks of e-cigarettes are associated with e-cigarette use in young adults; however, the temporality of this relationship is not well-understood. We explore how perceptions of harmfulness and addictiveness of e-cigarettes influence e-cigarette initiation, and specifically whether this association varies by cigarette smoking status, in a longitudinal study of tobacco use on college campuses. METHODS: Data are from a 5 wave 24-college study in Texas. Only students who reported never using e cigarettes at wave 1 were included (n = 2565). Multilevel discrete-time hazard models, accounting for school clustering, were used. The dependent variable, ever e-cigarette use, was assessed at each wave. Both time-varying (e-cigarette perceptions of harmfulness and addictiveness, age, use of cigarettes, use of other tobacco products, and use of other substances) and time-invariant demographic covariates were included. Two-way interactions between each e cigarette perception variable and current conventional cigarette use were tested to determine if the hypothesized relationship differed among smokers and non smokers. RESULTS: 21% of all never e-cigarette users at baseline had initiated e cigarette ever use by wave 5. Significant two-way interactions qualified the relationship between risk perceptions and e-cigarette initiation. Specifically, perceptions of a lower degree of harmfulness (OR = 1.13, p = .047) and addictiveness (OR = 1.34, p < .001) of e-cigarettes predicted initiation among non-smokers, but not among current smokers. CONCLUSION: Perceiving a lower degree of risk of e-cigarettes contributes to subsequent e-cigarette initiation among non-smokers, but not among current smokers. FINDINGS: have implications for prevention campaigns focusing on the potential harm of e-cigarettes for non smoking college students. PMID- 29626782 TI - Induced bioelectrochemical metabolism for bioremediation of petroleum refinery wastewater: Optimization of applied potential and flow of wastewater. AB - Hybrid based bioelectrochemical system (BES) configured with embedded anode and cathode electrodes in soil was tested for the bioelectrochemical degradation of petroleum refinery wastewater (PRW). Four applied potentials were studied to optimize under batch mode operation, among which 2 V resulted in higher COD degradation (69.2%) and power density (725 mW/m2) during 7 days of operation. Further studies with continuous mode of operation at optimized potential (2 V) showed that hydraulic retention time (HRT) of 19 h achieved the highest COD removal (37%) and highest power density (561 mW/m2). BES function with respect to treatment efficiencies of other pollutants of PRW was also identified with respect to oil and grease (batch mode, 91%; continuous mode, 34%), total dissolved salts (batch mode, 53%; continuous mode, 24%) and sulfates (batch mode, 59%; continuous mode, 42%). Soil microenvironment in association with BES forms complex processes, providing suitable conditions for efficient treatment of PRW. PMID- 29626783 TI - Utilization of agro-industrial waste for biosurfactant production under submerged fermentation and its application in oil recovery from sand matrix. AB - This study reports biosurfactant production by Pseudomonas azotoformans AJ15 under submerged fermentation via utilizing the agro-industrial wastes (bagasse and potato peels). The extracted biosurfactant was characterized for its classification (nature, group, and class) and stability against environmental stresses. Further, the biosurfactant was employed to explore its oil recovery efficiency from the sand matrix with 2000 ppm salt concentration. Results revealed that substrates developed by mixing both the agro-industrial wastes account for high yield of biosurfactant. The subsequent experimental studies demonstrated that the biosurfactant might belong to glycolipid group and rhamnolipid class. Moreover, the biosurfactant was stable at a high temperature of 90 degrees C and enable to persist its activity in the high salt concentration of 6% and varying pH. The biosurfactant was found to be effective in recovering up to 36.56% of trapped oil under saline condition. PMID- 29626785 TI - Men's experiences of early life trauma and pathways into long-term homelessness. AB - Previous studies that have explored the association between childhood trauma and homelessness indicate that traumatic events can lead to survivor distrust of interpersonal relationships and institutions, prolonged homelessness and poor health and social outcomes. The majority of this literature relies on quantitative data and fails to investigate the personal experiences of childhood trauma that are found to impact housing status later in life. Semi-structured, qualitative interviews were conducted with 25 men living in an urban area in Ontario who had spent more than 30 consecutive nights in an emergency shelter over the course of their housing histories. During data analysis, it was observed that all of the men had experienced some form of trauma or neglect in childhood which contributed to their entries into homelessness. Using a case study approach, three entry pathways into long term homelessness are described: 1) youth; 2) emerging or early adulthood; and 3) middle adulthood. Participants are classified into the pathways by the developmental period at which they first entered homelessness. These findings have implications for policy makers and service providers, as key intervention points are identified. Establishing effective interventions that address crises experienced at these points could assist with homelessness prevention across the life course. PMID- 29626784 TI - Racemic & quasi-racemic protein crystallography enabled by chemical protein synthesis. AB - A racemic protein mixture can be used to form centrosymmetric crystals for structure determination by X-ray diffraction. Both the unnatural d-protein and the corresponding natural l-protein are made by total chemical synthesis based on native chemical ligation-chemoselective condensation of unprotected synthetic peptide segments. Racemic protein crystallography is important for structure determination of the many natural protein molecules that are refractory to crystallization. Racemic mixtures facilitate the crystallization of recalcitrant proteins, and give diffraction-quality crystals. Quasi-racemic crystallization, using a single d-protein molecule, can facilitate the determination of the structures of a series of l-protein analog molecules. PMID- 29626786 TI - Dynamics of dual-fluorescent polymersomes with durable integrity in living cancer cells and zebrafish embryos. AB - The long-term fate of biomedical nanoparticles after endocytosis is often only sparsely addressed in vitro and in vivo, while this is a crucial parameter to conclude on their utility. In this study, dual-fluorescent polyisobutylene polyethylene glycol (PiB-PEG) polymersomes were studied for several days in vitro and in vivo. In order to optically track the vesicles' integrity, one fluorescent probe was located in the membrane and the other in the aqueous interior compartment. These non-toxic nanovesicles were quickly endocytosed in living A549 lung carcinoma cells but unusually slowly transported to perinuclear lysosomal compartments, where they remained intact and luminescent for at least 90 h without being exocytosed. Fluorescence-assisted flow cytometry indicated that after endocytosis, the nanovesicles were eventually degraded within 7-11 days. In zebrafish embryos, the polymersomes caused no lethality and were quickly taken up by the endothelial cells, where they remained fully intact for as long as 96 h post-injection. This work represents a novel case-study of the remarkable potential of PiB-PEG polymersomes as an in vivo bio-imaging and slow drug delivery platform. PMID- 29626787 TI - Enzyme-triggered size shrink and laser-enhanced NO release nanoparticles for deep tumor penetration and combination therapy. AB - Chemotherapy remains restricted by poor drug delivery efficacy due to the heterogenous nature of tumor. Herein, we presented a novel nanoparticle that could not only response to the tumor microenvironment but also modulate it for deep tumor penetration and combination therapy. The intelligent nanoparticle (IDDHN) was engineered by hyaluronidase (HAase)-triggered size shrinkable hyaluronic acid shells, which were modified with NIR laser sensitive nitric oxide donor (HN), small-sized dendrimeric prodrug (IDD) of doxorubicin (DOX) as chemotherapy agent and indocyanine green (ICG) as photothermal agent into a single nanoparticle. IDDHN displayed synergistic deep penetration both in vitro and in vivo, owing to the enzymatically degradable HN shell mediated by HAase and laser-enhanced NO release triggered deep penetration upon strong hyperthermia effect of ICG under the NIR laser irradiation. The therapeutic effect of IDDHN was verified in 4T1 xenograft tumor model, and IDDHN showed a much better antitumor efficiency with few side effects upon NIR laser irradiation. Therefore, the valid of this study might provide a novel tactic for engineering nanoparticles both response to and modulate the tumor microenvironment for improving penetration and heterogeneity distribution of therapeutic agents in tumor. PMID- 29626789 TI - Determination of plasma Levetiracetam level by Liquid Chromatography-Tandem Mass Spectrometry (LC-MS-MS) and its application in pharmacokinetics studies in neonates. AB - BACKGROUND: Levetiracetam (LEV) is an antiepileptic drug which has good safety and efficacy in neonatal seizure (NS), a common incident in neonates with weight <1500 g. The pharmacokinetics for LEV in neonatal populations is yet to be clearly understood. In this study, we developed and validated a method for determination of LEV in plasma by liquid chromatography tandem mass spectrometry for the purpose of pharmacokinetic study. METHODS: Plasma LEV was spiked with Lamivudine as internal standard before extraction by C18 solid-phase extraction (SPE) cartridge. Chromatography was performed using isocratic elution with mobile phase A: B (10: 90) for 2.0 min with flow rate 0.4 mL/min. The mobile phase was composed of 0.1% formic acid in 10.0 mM ammonium acetate (A) and 100% methanol (B). The injection volume was 1.0 MUL and the total run time was 2.0 min. Multiple reaction monitoring (MRM) with electro spray in positive mode was used. The mass transition for LEV was 171.2/126.0 and 230.0/112.0 for IS with retention time of 0.73 and 0.72 min, respectively. RESULTS: A calibration curve range from 0.50-80.0 MUg/mL was obtained with a correlation coefficient >0.99 in the quadratic model. Precision and accuracy was within the acceptable range and the intra- and inter-day %CV for three concentrations of QCs were <10%. CONCLUSION: This method was reliable, accurate and applicable for LEV pharmacokinetic study in neonates with seizure. PMID- 29626788 TI - Decrease in the prevalence of extended-spectrum cephalosporin-resistant Salmonella following cessation of ceftiofur use by the Japanese poultry industry. AB - Extended-spectrum cephalosporin (ESC)-resistant Salmonella in chicken meat is a significant food safety concern. We previously reported that the prevalence of ESC-resistant Salmonella in chicken meat, giblets, and processed chicken (chicken meat products) increased in Japan between 2005 and 2010, with 27.9% (17/61) of Salmonella isolated from chicken meat products in 2010 showing resistance to ESC. The aims of the present study were to clarify trends in the prevalence of ESC resistant Salmonella in chicken meat products in Japan between 2011 and 2015, and to determine the genetic profiles of bla-harboring plasmids, including replicon types, using next-generation sequencing. Our results showed that the prevalence of ESC-resistant Salmonella, mainly consisting of AmpC beta-lactamase CMY-2 producing isolates, in chicken meat products had increased to 45.5% (10/22) by 2011. However, following the voluntary cessation of ceftiofur use by the Japanese poultry industry in 2012, the prevalence of ESC-resistant Salmonella steadily decreased each year, to 29.2% (7/24), 18.2% (4/22), 10.5% (2/19), and 10.5% (2/19) in 2012, 2013, 2014, and 2015, respectively. Furthermore, no AmpC beta lactamase CMY-2-producing isolates were identified in 2014 and 2015. However, the prevalence of Salmonella enterica subspecies enterica serovar Manhattan isolates harboring a blaTEM-52-carrying IncX1 plasmid remained steady even after the cessation of ceftiofur use. Therefore, continuous monitoring of ESC resistance amongst Salmonella isolates from chicken meat products is required for food safety. PMID- 29626790 TI - pH gradient-liquid chromatography tandem mass spectrometric assay for determination of underivatized polyamines in cancer cells. AB - Altered levels of polyamines in biological specimens have been suggested as potential biomarkers for cancer. Difluoromethylornithine (DFMO, an irreversible inhibitor of ornithine decarboxylase) is reported to modulate polyamines to potentially attenuate proliferation of neuroblastoma cells. A clinical trial is being conducted to evaluate DFMO in various cancers. To determine the pharmacodynamics effect of DFMO, an analytical assay is needed to accurately measure the changes in polyamines in cancer cells. In this study, a novel pH gradient LC-ESI-MS/MS method was developed and validated for the quantitation of polyamines (putrescine, spermidine and spermine) in cancer cells. To separate polar and basic polyamines, a multi-mode column composed of ODS and weak ionic ligands was used. The pH gradient was generated from pH 5.3 to pH 2.7 with 2 mM ammonium acetate and 0.4% acetic acid in 10% acetonitrile as mobile phase. The detection of polyamines was performed utilizing multiple reaction monitoring on electrospray ionization mass spectrometry operated in positive ion mode. A pH gradient method increased resolution and decreased peak width of conventional analytical assays, resulting in 10-250-fold higher detection limits. Mobile phases without ion-pairing reagents were LC-MS compatible and eliminated possible signal suppression and MS contamination. The developed method was successfully applied to the analysis of polyamines in neuroblastoma and leukemia cells treated with DFMO. Putrescine levels were significantly (p < 0.001) decreased in CCRF-CEM (3.68 vs 1.23 ng/mg protein), SK-N-BE(2) (1.98 vs 1.31 ng/mg protein) and CHLA-20 (2.06 vs 0.90 ng/mg protein) cells treated with DFMO relative to vehicle control. The assay will provide a useful tool in determining the pharmacodynamic effect of DFMO in cancer clinical trials. PMID- 29626791 TI - Biotransformation and oxidative stress responses in rat hepatic cell-line (H4IIE) exposed to racemic ketoprofen (RS-KP) and its enantiomer, dexketoprofen (S(+) KP). AB - Pharmaceuticals such as racemate ketoprofen (RS-KP) and its enantiomer, dexketoprofen (S(+)-KP) are highly detectable non-steroidal anti-inflammatory drugs (NSAIDs) in the aquatic environment and therefore are designated as one of the most emerging groups of pollutants that can affect environmental and human health. The potential impact of these pharmaceuticals was assessed for the first time in vitro using a rat hepatocellular carcinoma cell line (H4IIE). Cells were exposed to low and high concentrations of these drugs. Cytotoxicity was determined by MTT reduction assay; CYP1A1 transcriptional and enzymatic levels together with canonical oxidative stress responsive markers (GPx, GR, GST and CAT) were also investigated. Cells exposed to RS-KP and S(+)-KP did not show cytotoxicity effect at the concentrations tested. However, this study highlighted differences between RS-KP and S(+)-KP in most of the evaluated markers, showing compound-, concentration- and time-specific effect patterns which suggest a potential stereo-selective toxicity of these drugs. PMID- 29626792 TI - Mindfulness buffers the effects of cue-induced craving on alcohol demand in college drinkers. AB - Alcohol consumption among young adult college students represents a significant public health problem. The presence of alcohol-related cues in drinkers' environments can trigger powerful alcohol cravings, which may influence drinking outcomes. Less is known about how this cue-induced craving influences behavioral economic demand for alcohol. In addition, research has suggested that trait mindfulness may be an important buffer of the effects of internal states of craving on drinking decisions. Based on this literature, we hypothesized that cue induced cravings would be associated with increased alcohol demand, an effect that would be attenuated among drinkers who have higher levels of mindfulness. Young adult college student drinkers (n = 69) completed a laboratory-based cue induced craving assessment, a self-report assessment of trait mindfulness, and an alcohol purchase task. Findings revealed that cue-induced craving was related to higher alcohol demand. Consistent with the study hypothesis, acceptance, a component of mindfulness, buffered the effects of cue-induced craving on alcohol demand. Results raise the possibility that mindfulness-based interventions may be useful in helping disrupt the link between internal states of craving and drinking decisions in young adult college student drinkers. PMID- 29626794 TI - The paca that roared: Immediate cumulative semantic interference among newly acquired words. AB - With 40,000 words in the average vocabulary, how can speakers find the specific words that they want so quickly and easily? Cumulative semantic interference in language production provides a clue: when naming a large series of pictures, with a few mammals sprinkled about, naming each subsequent mammal becomes slower and more error-prone. Such interference mirrors predictions from an incremental learning algorithm applied to meaning-driven retrieval from an established vocabulary, suggesting retrieval benefits from a constant, implicit, re optimization process (Oppenheim et al., 2010). But how quickly would a new mammal (e.g. paca) engage in this re-optimization? In this experiment, 18 participants studied 3 novel and 3 familiar exemplars from each of six semantic categories, and immediately performed a timed picture-naming task. Consistent with the learning model's predictions, naming latencies revealed immediate cumulative semantic interference in all directions: from new words to new words, from new words to old words, from old words to new words, and from old words to old words. Repeating the procedure several days later produced similar-magnitude effects, demonstrating that newly acquired words can be immediately semantically integrated, at least to the extent necessary to produce typical cumulative semantic interference. These findings extend the Dark Side model's scope to include novel word production, and are considered in terms of mechanisms for lexical selection. PMID- 29626793 TI - Infants' prosocial behavior is governed by cost-benefit analyses. AB - Cost-benefit analyses are central to mature decision-making and behavior across a range of contexts. Given debates regarding the nature of infants' prosociality, we investigated whether 18-month-old infants' (N = 160) prosocial behavior is impacted by anticipated costs and benefits. Infants participated in a helping task in which they could carry either a heavy or light block across a room to help an experimenter. Infants' helping behavior was attenuated when the anticipated physical costs were high versus low (Experiment 1), and high-cost helping was enhanced under conditions of increased intrinsic motivational benefits (Experiments 2 and 3). High-cost helping was further predicted by infants' months of walking experience, presumably because carrying a heavy block across a room is more effortful for less experienced walkers than for more experienced walkers demonstrating that infants subjectively calibrate costs. Thus, infants' prosocial responding may be guided by a rational decision-making process that weighs and integrates costs and benefits. PMID- 29626795 TI - Growth hormone facilitates 5'-azacytidine-induced myogenic but inhibits 5' azacytidine-induced adipogenic commitment in C3H10T1/2 mesenchymal stem cells. AB - The C3H10T1/2 cells are considered mesenchymal stem cells (MSCs) because they can be induced to become the progenitor cells for myocytes, adipocytes, osteoblasts, and chondrocytes by the DNA methyltransferase inhibitor 5'-azacytidine. In this study, we determined the effect of growth hormone (GH) on the myogenic and adipogenic lineage commitment in C3H10T1/2 cells. The C3H10T1/2 cells were treated with recombinant bovine GH in the presence or absence of 5'-azacytidine for 4 days. The myogenic commitment in C3H10T1/2 cells was assessed by immunostaining them for MyoD, the marker for myoblasts, and by determining their capacity to differentiate into the multinucleated myotubes. The adipogenic commitment in C3H10T1/2 cells was assessed by determining their ability to differentiate into adipocytes. Myotubes and adipocyteswere identified by immunocytochemistry and Oil Red O staining, respectively. C3H10T1/2 cells treated with 5'-azacytidine and GH for 4 days contained a greater percentage of MyoD positive cells than those treated with 5'-axacytidine alone (P < 0.05). The former generated more myotubes than the latter upon induced myoblast differentiation (P < 0.05). However, C3H10T1/2 cells treated with GH alone did not form any myotubes. C3H10T1/2 cells treated with 5'-azacytidine formed adipocytes upon adipocyte differentiation induction, whereas C3H10T1/2 cells treated with GH alone did not form any adipocytes. C3H10T1/2 cells treated with both 5'-azacytidine and GH formed fewer adipocytes than those treated with 5' azacytidine alone (P < 0.05). Both GHR and IGF-I mRNA expression in C3H10T1/2 cells were increased by 5'-azacytidine (P < 0.05), but neither was affected by GH. Overall, this study showed that GH enhanced 5'-azacytidine-induced commitment in C3H10T1/2 cells to myoblasts but inhibited 5'-azacytidine-induced commitment to preadipocytes. These results support the possibility that GH stimulates skeletal muscle growth and inhibits adipose tissue growth in part by stimulating the myogenic commitment and inhibiting the adipogenic commitment, respectively, in mesenchymal stem cells. PMID- 29626796 TI - Structural insights into the evolution feature of a bony fish CD8alphaalpha homodimer. AB - The CD8alphaalpha homodimer structures of endotherms demonstrate that despite distinct diversity at the amino acid sequence level, a few conserved key amino acids ensure common structural features. The structure of CD8alphaalpha in ancient ectotherms, such as lower bony fish, remains unclear. In this study, the high-resolution structure of the grass carp (Ctenopharyngodon idella) CD8alphaalpha (Ctid-CD8alphaalpha) homodimer was determined using the single wavelength anomalous diffraction (SAD) method. The structure of Ctid CD8alphaalpha shows distinct differences from the known CD8alphaalpha structures of endotherms, including a distinct topological structure with shorter back beta sheets. The configuration and distribution of the hydrophobic core are different from those in endotherms. Interestingly, mutation of the key amino acid F32S, which is very common in fish and lies in the CDR loop region, leads to the absence of the typical cavity that binds to an epitope-MHC I (p/MHC I) in endotherms, yet Ctid-CD8alphaalpha can still specifically bind the grass carp peptide-Ctid-UAA-beta2m (p/UAA-beta2m). Our results indicate that during the evolutionary process, CD8alphaalpha has undergone dramatic changes that affect its dimeric structure and may use a new strategy to interact with p/MHC I. PMID- 29626797 TI - Synthesis, molecular modeling studies and evaluation of antifungal activity of a novel series of thiazole derivatives. AB - In the search for new antifungal agents, a novel series of fifteen hydrazine thiazole derivatives was synthesized and assayed in vitro against six clinically important Candida and Cryptococcus species and Paracoccidioides brasiliensis. Eight compounds showed promising antifungal activity with minimum inhibitory concentration (MIC) values ranging from 0.45 to 31.2 MUM, some of them being equally or more active than the drug fluconazole and amphotericin B. Active compounds were additionally tested for toxicity against human embryonic kidney (HEK-293) cells and none of them exhibited significant cytotoxicity, indicating high selectivity. Molecular modeling studies results corroborated experimental SAR results, suggesting their use in the design of new antifungal agents. PMID- 29626798 TI - Synthesis and biological evaluation of clovamide analogues as potent anti neuroinflammatory agents in vitro and in vivo. AB - A series of clovamide analogues, namely, 1a-13a and 1b-13b, was synthesized and evaluated for their anti-neuroinflammatory activities using BV-2 microglia cells. Among these compounds, six (1b, 4b-8b) showed NO inhibition with no or weak cytotoxicity (CC50 > 100 MUM), especially 4b, and showed an IC50 value of 2.67 MUM. Enzyme activity and docking assay revealed that the six compounds, especially 4b, target inducible NO synthase (iNOS) and exhibit potent inhibitory effects on iNOS with IC50 values ranging from 1.01 MUM to 29.23 MUM 4b significantly suppressed the expression of pro-inflammatory cytokines in lipopolysaccharide-stimulated cells. Notably, the oral administration of 4b remarkably improved dyskinesia, reduced the expression of glial fibrillary acidic protein (GFAP)-a marker of neuroinflammation, and increased tyrosine hydroxylase positive cells in 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine-induced Parkinson's disease (PD) mouse models. These observations demonstrated that 4b is an effective and promising candidate for PD therapy. PMID- 29626800 TI - Corrigendum to "Methyleugenol and selected oxidative metabolites affect DNA Damage signalling pathways and induce apoptosis in human colon tumour HT29 cells" [ Food Chem. Toxicol. 108 (2017) 267-275]. PMID- 29626799 TI - Lipid reducing activity and toxicity profiles of a library of polyphenol derivatives. AB - Obesity is an increasing epidemic worldwide and novel treatments are urgently needed. Polyphenols are natural compounds derived from plants, which are known in particular for their antioxidant properties. However, some polyphenols were described to possess anti-obesity activities in vitro and in vivo. In this study, we aimed to screen a library of 85 polyphenol derivatives for their lipid reducing activity and toxicity. Compounds were analyzed at 5 MUM with the zebrafish Nile red fluorescence fat metabolism assay and for general toxicity in vivo. To improve the safety profile, compounds were screened at 50 MUM in murine preadipocytes in vitro for cytotoxicity. Obtained activity data were used to create a 2D-QSAR (quantitative structure activity relationship) model. 38 polyphenols showed strong lipid reducing activity. Toxicity analysis revealed that 18 of them did not show any toxicity in vitro or in vivo. QSAR analysis revealed the importance of the number of rings, fractional partial positively charged surface area, relative positive charge, relative number of oxygen atoms, and partial negative surface area for lipid-reducing activity. The five most potent compounds with EC50 values in the nanomolar range for lipid reducing activity and without any toxic effects are strong candidates for future research and development into anti-obesity drugs. Molecular profiling for fasn, sirt1, mtp and ppary revealed one compound that reduced significantly fasn mRNA expression. PMID- 29626801 TI - Study protocol: A Montessori approach to dementia-related, non-residential respite services in Australia. AB - Given the social burden and significant cost of dementia care in Australia, finding evidence-based approaches that improve outcomes, maintain independence, and reduce the impact on patients and families is essential. Finding effective ways to train and assist the healthcare staff who support these individuals is also critical, as they are considered to be at risk of workplace stress, burnout, and other psychological disturbances which negatively affects standards of care. The current paper describes a protocol for evaluating the effects of a Montessori based approach to dementia care, in non-residential respite centres. An 18 month prospective observational, cohort controlled design is suggested that will compare participants from a community respite service that has undergone a Montessori-based workplace culture change and those from a service that provides a person-centred 'care as usual' approach. To achieve this, the protocol includes the assessment of participants across multiple variables on a monthly basis including the cognitive, behavioural, and emotional functioning of clients with dementia, levels of caregiver burden experienced by informal carers, and burnout, compassion satisfaction and workplace engagement among respite staff. The protocol also employs a qualitative evaluation of program fidelity. This approach will provide further insight into the potential benefits of early intervention with Montessori approaches for persons living with dementia in the community, their caregivers, and the staff and volunteers who assist them. PMID- 29626803 TI - Response to letter to the editors. PMID- 29626802 TI - Laparoscopic excision of a retroperitoneal completely isolated enteric duplication cyst in an adult male: A case report and review of literature. AB - INTRODUCTION: Duplication cysts are very rare congenital malformations in adults. They are lined by gastrointestinal mucosa, connect to the digestive tract, and share smooth muscular layers and a common blood supply. In rare cases, duplication cysts are completely isolated from the digestive tract and have a proper blood supply. Completely isolated duplication cysts in the retroperitoneum are unusual so it is hard to diagnose them without a surgical resection. PRESENTATION OF CASE: A 19-year-old male presented at our emergency department with sharp abdominal pain. Contrast-enhanced computed tomography detected a 5-cm multilocular cystic mass located in the retroperitoneum, caudal to the pancreatic body. The cystic mass was safely resected with laparoscopic surgery without any complication. The final pathological diagnosis was an epithelium-lined duplication cyst in the retroperitoneal space. There was no evidence of malignancy in the duplication cyst. Intracystic bleeding was assumed to be the cause of the abdominal pain. DISCUSSION: The most common differential diagnoses of retroperitoneal cystic masses are pseudocysts related to pancreatitis, cysts from surrounding structures, and neoplasms. In this case, the cystic mass was diagnosed as completely isolated duplication cyst after surgical resection. It is very rarely observed in adults, but it should be listed on differential diagnoses because it has some possibility of malignancy. CONCLUSION: A completely isolated duplication cyst is very rare but noteworthy because there is some possibility of malignancy, ulcerative bleeding, and perforation. A surgical resection is recommended for diagnostic treatment. Laparoscopic surgery is favorable for intraoperative inspection and it is minimally invasive. PMID- 29626804 TI - The role of folic acid-conjugated polyglycerol coated iron oxide nanoparticles on radiosensitivity with clinical electron beam (6 MeV) on human cervical carcinoma cell line: In vitro study. AB - BACKGROUND AND PURPOSE: The objective of this study was to investigate the therapeutic effect of Folic Acid-Conjugated polyglycerol coated iron oxide nanoparticles on the radiosensitivity of HeLa cells when irradiated with 6 MeV electron beams. MATERIALS AND METHODS: Different concentrations of iron oxide nanoparticles (PG-SPIONs and FA-PG-SPIONs (25, 50, 100, 200 MUg ml-1)) were synthesized by the thermal decomposition technique. The effect of PG-SPIONs and FA-PG-SPIONs in combination with radiation (2, 4, 6 Gy) on the viability of cells and cell survival were estimated using the trypan blue dye exclusion test and MTT assay immediately and 48 h after irradiations, respectively. RESULTS: It was observed that the penetration rate of uptake for cells treated with >50 MUg ml-1 FA-PG-SPIONs was more than that of non-targeted nanoparticles. The data obtained by trypan blue dye exclusion test showed no significant reduction in cell viability for all groups in comparison with control group. The results revealed that increasing the radiation doses in the presence of the concentrations of the nanoparticles increased the value of radiosensitivity. The most radiosensitivity was obtained at the highest concentration of FA-PG-SPIONs (200 MUg ml-1) as well as the longest radiation doses. CONCLUSION: It was revealed that higher concentrations of the FA-PG-SPIONs in combination with 6 MeV electron beams could enhance radiosensitization of HeLa cells. PMID- 29626805 TI - Evaluation of the precision ID whole MtDNA genome panel for forensic analyses. AB - Mitochondrial DNA (mtDNA) amplification and Massively Parallel Sequencing (MPS) using an early access version of the Precision ID Whole MtDNA Genome Panel (Thermo Fisher Scientific) and the Ion Personal Genome Machine (PGM) were evaluated using 15 forensically relevant samples. Samples were selected to represent typical forensic specimens for mtDNA analysis including hairs, hair shafts, swabs and ancient solid tissue samples (bones and teeth) that were stored in the freezer for up to several years after having been typed with conventional Sanger-type Sequencing and Capillary Electrophoresis. The MPS haplotypes confirmed the earlier results in all samples and provided additional sequence information that improved discrimination power and haplogroup estimation. The results raised the appetite for further experiments to validate and apply the new technology in forensic practice. PMID- 29626806 TI - Ultrasonic suction pump at vapour pressure for condensate return in a vibrating heat pipe. AB - An ultrasonic suction pump for condensate return is characterized and successfully applied to a heat pipe cooled ultrasonic horn operating at 20 kHz. The suction pump is tested at atmospheric and for the first time at heat pipe conditions, i.e. near vapour pressure. Pump characteristic near vapour pressure differs remarkably from that observed under atmospheric conditions. The optimal gap size between pipe and vibrating surface is bigger at vapour pressure and it is less sensitive to gap size adjustments. PMID- 29626807 TI - Wavenumber domain analysis of surface acoustic wave scattering from localized gratings on layered piezoelectric substrate. AB - This paper proposes a general finite element method (FEM)-based wavenumber domain analysis (WDA) to calculate scattering characteristics of surface acoustic wave (SAW) on arbitrary piezoelectric substrates. We add a damping loss mechanism (DLM) to the SAW injection port to avoid interferences from the incident and backscattered modes. After checking the validity of the proposed method, we calculate and study Sezawa mode scattering using a small number of electrodes on the ScAlN/3CSiC structure for demonstration. The frequency dependences of reflection and transmission coefficients and that of the power dissipation ratio for different termination conditions and electrode thicknesses are calculated. Also, the influence of base substrate materials and that of gratings on scattering parameters are explored. Investigation results demonstrate that high reflectivity with suppressed mode conversion can be obtained for the ScAlN-based layer structure if a base substrate with an extremely large velocity is used and if proper grating design is applied. PMID- 29626808 TI - Oxidative stress responses of two different ecophysiological species of earthworms (Eutyphoeus waltoni and Eisenia fetida) exposed to Cd-contaminated soil. AB - The aim of this study was to assess the biomarkers of oxidative stress [reduced glutathione (GSH), glutathione-S-transferase (GST), superoxide dismutase (SOD), glutathione peroxidase (GPx), catalase (CAT), glutathione reductase (GR), aldehyde dehydrogenase (ALDH) and lipid peroxidation (LPO)] in earthworms of different ecological categories [epigeic Eisenia fetida (E. fetida) and anecic Eutyphoeus waltoni (E. waltoni)] exposed to cadmium (Cd)-polluted soil (30, 60 and 120 mg kg-1) for 28 days. Cd accumulation in earthworms increased significantly with increasing exposure dose and duration. However, E. fetida showed a relatively higher level of Cd accumulation until day 21; thereafter, depletion in the Cd level was recorded for the highest exposure dose. In E. waltoni, the detoxification enzymes and GSH level increased significantly with increasing exposure dose and Cd accumulation for 14 days (acute phase). In contrast, in E. fetida, acute exposure to Cd increased detoxification enzymes with decrease in GSH levels. For both species, sub-chronic exposures (28 days) increased lipid peroxidation with decrease in detoxification enzymes. GPx and ALDH responses of Cd-exposed earthworms showed a similar trend. Thus, these enzymes can be used as general biomarkers in these two species. The consistent variations in GST, GPx and ALDH activities suggest that E. waltoni may be used as a bioindicator species; this further signifies the use of endemic earthworms as a bioindicator to assess the risk of soil contamination. The present investigation indicates that Cd accumulation and biomarker responses in earthworms depend on dose and duration of exposure and on the concerned species. PMID- 29626809 TI - Cypermethrin, chlorpyrifos, deltamethrin, and imidacloprid exposure up-regulates the mRNA and protein levels of bdnf and c-fos in the brain of adult zebrafish (Danio rerio). AB - The aim of the present study is to investigate the toxicity effects of frequently used pesticides, involving cypermethrin, deltamethrin, chlorpyrifos and imidacloprid, on the expression of bdnf and c-fos genes in zebrafish brain tissues. Therefore, brain tissues exposed to intoxication was primarily analyzed by indirect immunofluorescence assay. Afterwards, the mRNA transcription levels of BNDF and c-fos genes and the protein levels were measured by qRT-PCR and Western blotting, respectively. The data of the immunofluorescence assay revealed intensive immunopositivity for bdnf and c-fos genes in the tissues exposed to pesticide intoxication in comparison to the control group (p<0.05). Moreover, the transcription levels of BNDF and c-fos genes, and protein levels were elevated following the intoxication (p<0.05, p<0.01, and p<0.001, respectively). These results showed that the exposure to the acute cypermethrin, deltamethrin, chlorpyrifos and imidacloprid intoxication disrupted the normal neuronal activity, resulting in neurotoxic effect, also DNA-binding Increasing c-fos activation, an oncoprotein from the family of the Nuclear Proteins, is also true of the knowledge that these chemicals are oncogenic in zebrafish brain tissues. Thus, the use of these pesticides poses a potential neuronal and oncogenic risk to the non-target organisms. PMID- 29626810 TI - Generation of nanobubbles by ceramic membrane filters: The dependence of bubble size and zeta potential on surface coating, pore size and injected gas pressure. AB - Generation of gaseous nanobubbles (NBs) by simple, efficient, and scalable methods is critical for industrialization and applications of nanobubbles. Traditional generation methods mainly rely on hydrodynamic, acoustic, particle, and optical cavitation. These generation processes render issues such as high energy consumption, non-flexibility, and complexity. This research investigated the use of tubular ceramic nanofiltration membranes to generate NBs in water with air, nitrogen and oxygen gases. This system injects pressurized gases through a tubular ceramic membrane with nanopores to create NBs. The effects of membrane pores size, surface energy, and the injected gas pressures on the bubble size and zeta potential were examined. The results show that the gas injection pressure had considerable effects on the bubble size, zeta potential, pH, and dissolved oxygen of the produced NBs. For example, increasing the injection air pressure from 69 kPa to 414 kPa, the air bubble size was reduced from 600 to 340 nm respectively. Membrane pores size and surface energy also had significant effects on sizes and zeta potentials of NBs. The results presented here aim to fill out the gaps of fundamental knowledge about NBs and development of efficient generation methods. PMID- 29626811 TI - Fate and impact of phthalates in activated sludge treated municipal wastewater on the water bodies in the Eastern Cape, South Africa. AB - The concentration and fates of six priority phthalate esters (PAEs); dimethyl phthalate (DMP), diethyl phthalate (DEP), di-n-butyl phthalate (DBP), benzyl butyl phthalate (BBP), di (2-ethyl hexyl) phthalate (DEHP), and di-n-octyl phthalate (DOP) in wastewaters from the wastewater treatment plants (WWTPs) which adopted the activated sludge technology in the Amathole Municipality, Eastern Cape, South Africa were investigated. The six PAEs were detected in all the influents and in almost all the WWTP effluent of which DBP was the most abundant in the influent followed by DEHP. Influent concentration of DBP in the three WWTPs ranged between 2.7 and 2488 MUgL-1 and the average effluent concentration was 4.90-8.88 MUgL-1. On average, the concentration of PAEs in WWTP effluents were higher than PAEs in the upstream and downstream of the discharging point suggesting PAE impact on the receiving water. The concentrations detected in the sludge of which DEHP and DBP were more pervasive ranged between 130 and 1094 MUg/g dry weight. The average removal capacity; 27.3-99.5% suggested more adsorption on settling particles and sludge than biodegradation as high significant correlation was found between PAEs removal, total suspended solid and turbidity. Removal of high molecular weight and high octanol-water partition coefficient (logKow) PAEs through adsorption was found to be significantly high. It could be concluded that the release of PAEs into the sludge, and the amount in the final effluent which were found to exceed the acceptable levels allowed internationally, raises safety concern for both aquatic and human's health. PMID- 29626812 TI - Natural organic matter undergoes different molecular sieving by adsorption on activated carbon and carbon nanotubes. AB - We have comprehensively compared the molecular sieving of natural organic matter (NOM) by adsorption on activated carbon (AC) and multi-walled carbon nanotubes (CNT) using different types of NOM. All water samples were characterized using UV visible and fluorescence spectroscopies as well as high-performance size exclusion chromatography (HPSEC) before and after adsorption. Adsorption isotherm results fitted well with Freundlich model (R2 = 0.95-0.99) and the model parameters indicated higher adsorption of NOM on CNT than AC. Fluorescence index (FI) and freshness index (BIX) showed preferential adsorption of microbial derived and fresh NOM on AC, whereas, terrestrial derived and decomposed NOM were preferentially adsorbed on CNT. Further, HPSEC revealed that AC adsorbed NOM fractions with small molecular weight (MW) (<0.4 kDa) faster than the fractions with higher MW. In contrast, CNT adsorbed NOM fractions characterized by high MW (>1 kDa) while the smallest fraction (<0.4 kDa) was not adsorbed, possibly due to its hydrophilic character. Our results also demonstrated a good correlation between FI and average MW of NOM (R2 > 0.93). These findings illustrate the influence of the adsorbent's type and characteristics (i.e., porosity and pore size distribution) on the preferential adsorption of different NOM fractions. PMID- 29626814 TI - Effect of nitrogen plasma afterglow on the surface charge effect resulted during XPS surface analysis of amorphous carbon nitride thin films. AB - The aim of this paper is to investigate the relationship between the micro structure and the surface charge effect resulted during XPS surface analysis of amorphous carbon nitride thin films prepared by laser ablation method. The study results show that the charge effect coefficient (E) is not just a correction factor. We found that the changes in this coefficient value due to incorporation of nitrogen atoms into the carbon network are related to the spatial configurations of the sp2 bonded carbon atoms, order degree and sp2 clusters size. In addition, results show that the curve E vs. C(sp3)-N is a characteristic curve of the micro structure. This means that using this curve makes it easy to sorting the samples according to the micro structure (hexagonal rings or chains). PMID- 29626813 TI - Elevated CO2 induces a global metabolic change in basil (Ocimum basilicum L.) and peppermint (Mentha piperita L.) and improves their biological activity. AB - Many studies have discussed the influence of elevated carbon dioxide (eCO2) on modeling and crop plants. However, much less effort has been dedicated to herbal plants. In this study, a robust monitoring for the levels of 94 primary and secondary metabolites and minerals in two medicinal herbs, basil (Ocimum basilicum L.) and peppermint (Mentha piperita L.), grwon under both ambient (aCO2, 360 ppm) and eCO2 (620 ppm) was performed. We also assessed how the changes in herbal tissue chemistry affected their biological activity. Elevated CO2 significantly increased herbal biomass, improved the rates of photosynthesis and dark respiration, and altered the tissue chemistry. Principal Component Analysis of the full data set revealed that eCO2 induced a global change in the metabolomes of the two plants. Moreover, Hierarchical Clustering Analyses showed quantitative differences in the metabolic profiles of the two plants and in their responsiveness to eCO2. Out of 94 metabolites, 38 and 31 significantly increased in basil and peppermint, respectively, as affected by eCO2. Regardless of the plant species, the levels of non-structural carbohydrates, fumarate, glutamine, glutathione, ascorbate, phylloquinone (vitamin K1), anthocyanins and a majority of flavonoids and minerals were significantly improved by eCO2. However, some metabolites tended to show species specificity. Interestingly, eCO2 caused enhancement in antioxidant, antiprotozoal, anti-bacterial and anticancer (against urinary bladder carcinoma; T24P) activities in both plants, which was consequent with improvement in the levels of antioxidant metabolites such as glutathione, ascorbate and flavonoids. Therefore, this study suggests that the metabolic changes triggered by eCO2 in the target herbal plants improved their biological activities. PMID- 29626815 TI - Spectroscopic and photoacoustic characterization of encapsulated iron oxide super paramagnetic nanoparticles as a new multiplatform contrast agent. AB - Recently, a number of photoacoustic (PA) agents with increased tissue penetration and fine spatial resolution have been developed for molecular imaging and mapping of pathophysiological features at the molecular level. Here, we present bio conjugated near-infrared light-absorbing magnetic nanoparticles as a new agent for PA imaging. These nanoparticles exhibit suitable absorption in the near infrared region, with good photoacoustic signal generation efficiency and high photo-stability. Furthermore, these encapsulated iron oxide nanoparticles exhibit strong super-paramagnetic behavior and nuclear relaxivities that make them useful as magnetic resonance imaging (MRI) contrast media as well. Their simple bio conjugation strategy, optical and chemical stability, and straightforward manipulation could enable the development of a PA probe with magnetic and spectroscopic properties suitable for in vitro and in vivo real-time imaging of relevant biological targets. PMID- 29626816 TI - Construction of an efficient two-photon fluorescent probe for imaging nitroreductase in live cells and tissues. AB - Compared with traditional confocal microscopy, two-photon fluorescence microscopy (TPFM), which excites a two-photon (TP) fluorophore by near-infrared light, provides improved three-dimensional image resolution with increased tissue-image depth (>500MUm) and an extended observation time. Therefore, the development of novel functional TP fluorophores has attracted great attention in recent years. Herein, a novel TP fluorophore CM-NH2, which have the donor-pi-acceptor (D-pi-A) structure, was designed and synthesized. We further used this dye developed a new type of TP fluorescent probe CM-NO2 for detecting nitroreductase (NTR). Upon incubated with NTR for 15min, CM-NO2 displayed a ~90-fold fluorescence enhancement at 505nm and the maximal TP action cross-section value after reaction was detected and calculated to be 200 GM at 760nm. The probe exhibited excellent properties such as high sensitivity, high selectivity, low cytotoxicity, and high photostability. Moreover, the probe was utilized to image the tumor hypoxia in live HeLa cells. Finally, using the CM-NO2 to image NTR in tissues was demonstrated. PMID- 29626817 TI - Influences of donor/acceptor ratio on the optical and electrical properties of the D/A alternating model oligomers: A density functional theory study. AB - We adopted an ingenious method that cut out the DA alternating oligomers from the corresponding DA alternating copolymers. From analyzing the orbital compositions of the HOMOs and LUMOs as well as the reorganization energies, we found the level of charge transfer is increased with the increasing of D/A ratio, but ionization potentials and electron affinities show a contrary trend. Moreover, with the greater ratio, the trend in the nearness of two transitions results in broadening the absorption band in the visible range. That is why experimentally improving the ratio is beneficial for the copolymers used as the p-type materials in the BHJ solar cells. This method is impossible to take the real copolymer system, however, it could provide a strategy to avoid the limitation of the theory level and perform reliable result to study the intrinsic properties of DA alternating copolymers, which can provide a guidance to experimental works. PMID- 29626818 TI - Rapid authentication and identification of different types of A. roxburghii by Tri-step FT-IR spectroscopy. AB - Anoectochilus roxburghii (Wall.) Lindl. (Orchidaceae) is a precious traditional Chinese medicinal herb and has been perennially used to treat various illness. However, there were unethical sellers who adulterated wild A. roxburghii with tissue cultured and cultivated ones. Therefore, there is an urgent need for an effective authentication method to differentiate between these different types of A. roxburghii. In this research, the infrared spectroscopic tri-step identification approach including Fourier transform infrared spectroscopy (FT IR), Second derivative infrared spectra (SD-IR) and two-dimensional correlation infrared spectra (2D-IR) was used to develop a simple and rapid method to discriminate between wild, cultivated and tissue cultivated A. roxburghii plant. Through this study, all three types of A. roxburghii plant were successfully identified and discriminated through the infrared spectroscopic tri-step identification method. Besides that, all the samples of wild, cultivated and tissue cultivated A. roxburghii plant were analysed with the Soft Independent Modelling of Class Analogy (SIMCA) pattern recognition technique to test and verify the experimental results. The results showed that the three types of A. roxburghii can be discriminated clearly as the recognition rate was 100% for all three types and the rejection rate was more than 60%. 70% of the validated samples were also identified correctly by the SIMCA model. The SIMCA model was also validated by comparing 70 standard herbs to the model. As a result, it was demonstrated that the macroscopic IR fingerprint method and the classification analysis could discriminate not only between the A. roxburghi samples and the standard herbs, it could also distinguish between the three different types of A. roxburghi plant in a direct, rapid and holistic manner. PMID- 29626819 TI - Cyclist exposure to black carbon, ultrafine particles and heavy metals: An experimental study along two commuting routes near Antwerp, Belgium. AB - Urban environments typically exhibit large atmospheric pollution variation, in both space and time. In contrast to traditional monitoring networks suffering from a limited spatial coverage, mobile platforms enable personalized high resolution monitoring, providing valuable insights into personal atmospheric pollution exposure, and the identification of potential pollution hotspots. This study evaluated personal cyclist exposure to UFPs, BC and heavy metals whilst commuting near Antwerp, Belgium, by performing mobile measurements with wearable black carbon (BC) and ultrafine particle (UFP) instruments. Loaded micro aethalometer filterstrips were chemically analysed and the inhaled pollutant dose determined from the exhibited heart rate. Considerable spatial pollutant variation was observed along the travelled routes, with distinct contributions from spatial factors (e.g. traffic intersections, urban park and market) and temporary events. On average 300% higher BC, 20% higher UFP and changing elemental concentrations are observed along the road traffic route (RT), when compared to the bicycle highway route (BH). Although the overall background pollution determines a large portion of the experienced personal exposure (in this case 53% for BC and 40% for UFP), cyclists can influence their personal atmospheric pollution exposure, by selecting less exposed commuting routes. Our results, hereby, strengthen the body of evidence in favour of further policy investments in isolated bicycle infrastructure. PMID- 29626820 TI - Lung cancer and particulate pollution: A critical review of spatial and temporal analysis evidence. AB - BACKGROUND: Particulate matter (PM) has been recognized as one of the key risk factors of lung cancer. However, spatial and temporal patterns of this association remain unclear. Spatiotemporal analyses incorporate the spatial and temporal structure of the data within random effects models, generating more accurate evaluations of PM-lung cancer associations at a scale that can better inform lung cancer prevention programs. METHODS: We conducted a critical review of spatial and temporal analyses of PM and lung cancer. The databases of PubMed, Web of Science and Scopus were searched for potential articles published until September 30, 2017. We included studies that applied spatial and temporal analyses to evaluate the associations of PM2.5 (inhalable particles with diameters that are 2.5 um and smaller) and PM10 (inhalable particles with diameters that are 10 um and smaller) with lung cancer. RESULTS: We identified 17 articles eligible for the review. Of these, 11 focused on PM2.5, five on PM10, and one on both. These studies suggested a significant positive association between PM2.5 exposure and the risk of lung cancer. Relative risks of lung cancer mortality ranged from 1.08 (95% confidence interval (CI): 1.07-1.09) to 1.60 (95%CI: 1.09-2.33) for 10 ug/m3 increase in PM2.5 exposure. The association between PM10 and lung cancer had been less well researched and the results were not consistent. In terms of the analysis methods, 16 papers undertook spatial analysis and one paper employed temporal analysis. No paper included spatial and temporal analyses simultaneously and considered spatiotemporal uncertainty into model predictions. Among the 16 papers with spatial analyses, thirteen studies presented maps, while only five and 11 studies utilized spatial exploration and modeling methods, respectively. CONCLUSIONS: Advanced spatial and temporal epidemiological methods were seldom applied to PM-lung cancer associations. Further research is urgently needed to develop and employ robust and comprehensive spatiotemporal analysis methods for the evaluation of PM-lung cancer associations and the support of lung cancer prevention strategies. PMID- 29626821 TI - Biomarkers of exposure in environment-wide association studies - Opportunities to decode the exposome using human biomonitoring data. AB - BACKGROUND: The European Union's 7th Framework Programme (EU's FP7) project HEALS - Health and Environment-wide Associations based on Large Population Surveys - aims a refinement of the methodology to elucidate the human exposome. Human biomonitoring (HBM) provides a valuable tool for understanding the magnitude of human exposure from all pathways and sources. However, availability of specific biomarkers of exposure (BoE) is limited. OBJECTIVES: The objective was to summarize the availability of BoEs for a broad range of environmental stressors and exposure determinants and corresponding reference and exposure limit values and biomonitoring equivalents useful for unraveling the exposome using the framework of environment-wide association studies (EWAS). METHODS: In a face-to face group discussion, scope, content, and structure of the HEALS deliverable "Guidelines for appropriate BoE selection for EWAS studies" were determined. An expert-driven, distributed, narrative review process involving around 30 individuals of the HEALS consortium made it possible to include extensive information targeted towards the specific characteristics of various environmental stressors and exposure determinants. From the resulting 265 page report, targeted information about BoE, corresponding reference values (e.g., 95th percentile or measures of central tendency), exposure limit values (e.g., the German HBM I and II values) and biomonitoring equivalents (BEs) were summarized and updated. RESULTS: 64 individual biological, chemical, physical, psychological and social environmental stressors or exposure determinants were included to fulfil the requirements of EWAS. The list of available BoEs is extensive with a number of 135; however, 12 of the stressors and exposure determinants considered do not leave any measurable specific substance in accessible body specimens. Opportunities to estimate the internal exposure stressors not (yet) detectable in human specimens were discussed. CONCLUSIONS: Data about internal exposures are useful to decode the exposome. The paper provides extensive information for EWAS. Information included serves as a guideline - snapshot in time without any claim to comprehensiveness - to interpret HBM data and offers opportunities to collect information about the internal exposure of stressors if no specific BoE is available. PMID- 29626823 TI - Microcystin-leucine arginine (MC-LR) induces bone loss and impairs bone micro architecture by modulating host immunity in mice: Implications for bone health. AB - Osteoporosis or enhanced bone loss is one of the most commonly occurring bone conditions in the world, responsible for higher incidence of fractures leading to increased morbidity and mortality in adults. Bone loss is affected by various environmental factors including diet, age, drugs, toxins etc. Microcystins are toxins produced by cyanobacteria with microcystin-LR being the most abundantly found around the world effecting both human and animal health. The present study demonstrates that MC-LR treatment induces bone loss and impairs both trabecular and cortical bone microarchitecture along with decreasing the mineral density and heterogeneity of bones in mice. This effect of MC-LR was found due to its immunomodulatory effects on the host immune system, wherein MC-LR skews both T cell (CD4+ and CD8+ T cells) and B cell populations in various lymphoid tissues. MC-LR further was found to significantly enhance the levels of osteoclastogenic cytokines (IL-6, IL-17 and TNF-alpha) along with simultaneously decreasing the levels of anti-osteoclastogenic cytokines (IL-10 and IFN-gamma). Taken together, our study for the first time establishes a direct link between MC-LR intake and enhanced bone loss thereby giving a strong impetus to the naive field of "osteo toxicology", to delineate the effects of various toxins (including cyanotoxins) on bone health. PMID- 29626822 TI - Biodegradation of nonylphenol during aerobic composting of sewage sludge under two intermittent aeration treatments in a full-scale plant. AB - The urbanization and industrialization of cities around the coastal region of the Bohai Sea have produced large amounts of sewage sludge from sewage treatment plants. Research on the biodegradation of nonylphenol (NP) and the influencing factors of such biodegradation during sewage sludge composting is important to control pollution caused by land application of sewage sludge. The present study investigated the effect of aeration on NP biodegradation and the microbe community during aerobic composting under two intermittent aeration treatments in a full-scale plant of sewage sludge, sawdust, and returned compost at a ratio of 6:3:1. The results showed that 65% of NP was biodegraded and that Bacillus was the dominant bacterial species in the mesophilic phase. The amount of NP biodegraded in the mesophilic phase was 68.3%, which accounted for 64.6% of the total amount of biodegraded NP. The amount of NP biodegraded under high-volume aeration was 19.6% higher than that under low-volume aeration. Bacillus was dominant for 60.9% of the composting period under high-volume aeration, compared to 22.7% dominance under low-volume aeration. In the thermophilic phase, high volume aeration promoted the biodegradation of NP and Bacillus remained the dominant bacterial species. In the cooling and stable phases, the contents of NP underwent insignificant change while different dominant bacteria were observed in the two treatments. NP was mostly biodegraded by Bacillus, and the rate of biodegradation was significantly correlated with the abundance of Bacillus (r = 0.63, p < 0.05). Under aeration, Bacillus remained the dominant bacteria, especially in the thermal phase; this phenomenon possibly increased the biodegradation efficiency of NP. High-volume aeration accelerated the activity and prolonged the survival of Bacillus. The risk of organic pollution could be decreased prior to sewage sludge reuse in soil by adjusting the ventilation strategies of aerobic compost measurements. PMID- 29626824 TI - Reduction of clog matter in constructed wetlands by metabolism of Eisenia foetida: Process and modeling. AB - Introducing of earthworms to constructed wetlands (CWs) has been considered as a new approach to solve the clogging problems in the long-established systems. Despite its potential advantage, the correlational researches are still in the stage of preliminary observation and speculation. This paper presents a comprehensive and in-depth research about the positive effects of earthworms (Eisenia foetida) on clog matter (CM) reduction through different pathways, including in vivo metabolism and uptake, conversion, transport, and promotion of microorganism quantities. The results showed that the metabolism and uptake by Eisenia foetida could effectively reduce the CM content at an average removal rate of 0.155 mg g-1 d-1, which was obviously higher than the rate of CM decomposition by microorganisms alone. Through the metabolism of earthworms, the amounts of proteins and polysaccharides in CM were decreased, while the amounts of humin and nucleic acids were increased. Simultaneously, the viscosity of CM was reduced by 0.0082 mPa s g-1 d-1, and the quantity of microorganisms was increased by 0.0109 mg g-1 d-1, which finally made the treated CM can be easily washed away and decomposed. Furthermore, earthworms could reduce the CM content in the clogging layer by transporting the metabolic products out. A regression model was further performed for describing the interaction between earthworm and CM. The simulated value of porosity fitted well with the measured one, suggesting that the earthworms can increase the substrate porosity at a rate of 0.33 mL g-1 d-1. This study quantitively depicted the mechanisms of earthworms on the decrement of CM content in CWs, which is of great benefit for the engineering management of constructed wetlands in the future. We also proposed that the density of introduced earthworms should exceed a certain threshold for effectively increasing the substrate porosity and solving the clogging problems. PMID- 29626825 TI - Emotional eating and temperamental traits in Eating Disorders: A dimensional approach. AB - Growing evidence shows that temperamental features and emotional dysregulation are linked to Eating Disorders (EDs). Aim of this study was to explore the possible relationship between temperament and emotional eating (EE) from a dimensional standpoint, and the association of specific temperamental dimensions with overeating triggered by specific emotions. We enrolled 253 women with Anorexia Nervosa, Bulimia Nervosa and Binge Eating Disorder. Of those, 189 (74.7%), 73 (28.8%), and 80 (31.6%) reported binge eating, purging, or restrictive behaviors, respectively (the categories are not mutually exclusive). Participants completed the Emotional Eating Scale (EES), the Temperament and Character Inventory, the Eating Disorder Examination Questionnaire (EDE-Q) and the Symptom Checklist 90-Revised (SCL-90-R). Higher Persistence scores were found in the Restriction group, while the Binge group reported lower Persistence and higher Novelty Seeking scores. The Purge group showed lower Reward Dependence, Self Directedness and Cooperativeness scores. Patients with Purge also reported lower BMI and higher scores on EDE-Q restriction and eating concern subscales as well as higher scores for all SCL 90-R subscales. Patterns of association between temperamental traits and specific emotions were found in each group. Therefore, some temperamental features could be considered predictors of specific associations between emotions and the tendency to eat. PMID- 29626826 TI - Measures of morally injurious experiences: A quantitative comparison. AB - A recent body of literature has examined the psychological effects of perpetrating or failing to prevent acts that violate one's sense of right and wrong. The objective of this study was to examine and compare correlations between the two most widely used instruments measuring this construct in a sample of military veterans and relevant psychosocial variables. Individuals (N = 182) who reported military combat experience completed the Moral Injury Events Scale and the Moral Injury Questionnaire-Military Version, along with measures of combat exposure, depression, posttraumatic stress disorder, alcohol concerns, anger, guilt, and shame. Results indicate similar correlations between the morally injurious experiences instruments and negative psychosocial variables, but different correlations with combat exposure. Implications for further research in the conceptualization and treatment of morally injurious experiences are discussed. PMID- 29626827 TI - Nightmares and suicide risk in psychiatric patients: The roles of hopelessness and male depressive symptoms. AB - Although nightmares have been shown to increase the risk for suicide, less is known about the mechanisms underlying this relationship. In order to address this gap and guided by the hopelessness theory of suicide risk, we examined hopelessness and male depressive symptoms as risk factors for suicide while considering the frequency of and impairment due to nightmares. Data were collected from 172 psychiatrically hospitalized, adult patients (91 women, 81 men) with an average age of 39.15 (SD = 13.48) years. Patients were administered self-report measures of nightmare frequency/impairment, hopelessness, and male depressive symptoms, as well as undergoing a fully structured diagnostic clinical interview to determine diagnoses and suicide risk. Compared to patients with yearly or no nightmares, those with monthly or weekly nightmares reported nightmares reported higher levels of hopelessness, male depressive symptoms, and suicide risk. Male depressive symptoms significantly mediated the relation between hopelessness and suicide risk in patients who reported monthly to weekly nightmares, but not in those who reported yearly or no nightmares. Moreover, impairment due to nightmares was significantly and positively associated with male depression, but not hopelessness or suicide risk. The results also provide evidence and further understanding about possible mechanisms of emerging suicide. PMID- 29626828 TI - Higher concentration of interleukin 6 - A possible link between major depressive disorder and childhood abuse. AB - Little is known about the correlation between IL-6 and childhood abuse and neglect which may be risk factors for the development of affective disorders in adulthood. The aim of this study was to analyze differences in serum concentrations of IL-6 between patients with major depressive disorder and healthy controls, and to investigate possible correlations with adverse childhood experiences. Peripheral venous blood samples were obtained from 64 patients who fulfilled DSM-IV-R criteria for a current major depressive episode without psychotic symptoms (MDD) and 53 healthy controls, matched for age and gender. Participants were assessed by the Beck Depression Inventory (BDI), Childhood Trauma Questionnaire (CTQ), Hamilton Depression Rating Scale (HDRS) and Hamilton Anxiety Rating Scale (HARS). The concentration of IL-6 was significantly higher in patients with major depressive disorder compared to healthy controls. The total score of childhood trauma questionnaire highly statistically significantly correlated with IL-6 levels in patient group. Persons who were physically abused, physically neglected and emotionally abused had higher levels of IL-6. Interleukin 6 as a pro-inflammatory immune marker could be an important developmental mediator linking physical and emotional abuse in early life with the development of depressive disorder in adulthood. PMID- 29626829 TI - The effects of adiposity and alcohol use disorder on adipokines and biomarkers of inflammation in depressed patients. AB - Patients with depression and alcohol use disorder frequently present with elevated markers of inflammation. Adipose tissue may function as a source for inflammation, yet the interplay between adiposity, alcohol use and depression has remained unknown. We examined 242 patients, referred to treatment for depressive symptoms, and followed for a period of 6 months. The assessments included screening for alcohol use and measurements of body mass index, serum adiponectin, leptin, resistin, progranulin, hs-CRP, IL-6 and MCP-1 at baseline and after 6 months of treatment. During follow-up, mean MADRS and AUDIT scores decreased significantly, whereas BMI increased. The changes in the levels of cytokines and adipokines were influenced by alcohol consumption and adiposity in a gender dependent manner. The presence of AUD seemed to particularly influence the levels of cytokines. The levels of IL-6, hs-CRP, progranulin, and leptin differed between AUD and non-AUD groups at baseline, but no longer at 6 months. Baseline levels of leptin and resistin were higher in women and changes occurring in leptin, progranulin, and adiponectin were more notable in women. The data indicates significant gender-dependent interactions between depression, alcohol and mediators of inflammation, which should be considered in studies on the pathogenesis of depression and its comorbidities. PMID- 29626830 TI - Mediation effect of beliefs about pleasure and emotional experience between social anhedonia and prediction of pleasant events. AB - Few studies have examined whether there is a relationship between social anhedonia and prediction of future events and the role of beliefs about pleasure and emotional experience. In this study, 513 college students were recruited to complete a set of self-reported questionnaires, including the Revised Social Anhedonia Scale (CSAS), the Temporal Experience of Pleasure Scale (TEPS), the Belief about Pleasure Scale (BAPS) and the Beck Depression Inventory. Moreover, a checklist of 100 daily life events was also administrated to all participants. Mediation analysis found that social anhedonia had a direct impact on prediction of pleasant events. Emotional experience partly mediated the relationship between social anhedonia and subjective prediction of pleasant events. However, beliefs about pleasure had no significant mediation effect between social anhedonia and prediction of pleasant events, but were shown to influence the subjective prediction of pleasant events completely through emotional experience. These findings suggest that beliefs about pleasure and emotional experience may be considered promising factors for interventions in individuals with anhedonia. PMID- 29626831 TI - Neuroticism and anxious attachment as potential vulnerability factors of repeat suicide attempts. AB - The recurrence risk of suicide attempts can reach 50% in the first year, each attempt increasing suicide-risk by 32%. No screening tool efficiently identifies potential repeat suicide attempters who are too often regarded as borderline personality. Our aim was to identify individual and interpersonal psychopathological dimensions that could represent a vulnerability to repeat suicide attempts. Sixty first-time and repeat suicide attempters consecutively admitted in emergency rooms were compared for fundamental dimensions of personality, patterns of attachment, personality and mental disorders using standardized questionnaires. Confounding and significantly different factors were evaluated using univariate and multivariate logistic regressions. Repeat suicide attempters differed from first-attempters by higher neuroticism and anxious attachment. Combined in an 11-item measure, these two parameters identified a 3.99 times higher risk of repeat suicide attempt. These traits associated with the other two best predictors (non-suicidal self-injury history, current psychotropic drugs) provide a vulnerability model with better screening performance compared to each factor individually. Repeat suicide attempters have more psychological features impairing emotional stability and social interactions than first attempters. Cross-sectional study design, sample size, lack of independent sample and of fearful-avoidant attachment evaluation are the main limitations. The model needs to be validated in a prospective and controlled study. PMID- 29626832 TI - Impaired orienting in youth with Internet Addiction: Evidence from the Attention Network Task (ANT). AB - BACKGROUND AND AIMS: An important theory of attention suggests that there are three separate networks that execute discrete cognitive functions: alerting, orienting and conflict networks. Recent studies showed that there was a dysfunction of attention in Internet Addiction. In order to investigate the underlying mechanism of attention dysfunction in Internet Addiction, we recorded performance related to the Attentional Network Test (ANT) in youth. METHODS: The ANT, a behavioral assay of the functional integrity of attention networks, was used to examine the performance in Internet Addiction and healthy controls. RESULTS: Performance on the ANT clearly differentiated the participants with and without Internet Addiction in terms of mean reaction times (RTs). Compared with control group, the Internet Addiction group detected targets more slowly and this effect was evident only for spatial cue condition. The Internet Addiction group demonstrated deficits in the orienting network in terms of slower RT. There was no demonstration of a deficit in both the alerting and conflict network in Internet Addiction on this task. CONCLUSIONS: The youth with Internet Addiction demonstrated deficits in the orienting network but normal functioning of the alerting and conflict attention networks. PMID- 29626833 TI - Enablers to seeking professional help for psychological distress-a study on Chinese primary care attenders. AB - This study investigated enablers to seeking professional help for psychological distress among Chinese primary care attenders in Hong Kong. Nine focus groups and six individual interviews were conducted among adult patients with/without known distress, significant others of the distressed, and the general public. The identified potential enablers were further investigated in a questionnaire survey with data from 1626 patients. Survey respondents who had sought professional help for distress (n = 231) and those without this experience (n = 1395) showed similar attitudes to the enabler items. However, the first group had more "strongly agree" responses and their top five enablers were: crisis caused by distress, distress affecting daily life, wanting to treat associated physical symptoms, having trust in doctor, and encouragement by family/friends to seek help. Qualitative interviews found that the patients often somatised distress and they felt comfortable to consult for somatic symptoms. There was strong family involvement in help-seeking whereas the doctors were the authoritative figures to convince the patients for treatment. The findings, in line with Western literature, indicate that crisis and interference in daily life due to distress are the top enablers to seeking professional help. The other three key enablers are likely to be influenced by Chinese culture. PMID- 29626834 TI - Advanced concentration analysis of atom probe tomography data: Local proximity histograms and pseudo-2D concentration maps. AB - Analysing the distribution of selected chemical elements with respect to interfaces is one of the most common tasks in data mining in atom probe tomography. This can be represented by 1D concentration profiles, 2D concentration maps or proximity histograms, which represent concentration, density etc. of selected species as a function of the distance from a reference surface/interface. These are some of the most useful tools for the analysis of solute distributions in atom probe data. In this paper, we present extensions to the proximity histogram in the form of 'local' proximity histograms, calculated for selected parts of a surface, and pseudo-2D concentration maps, which are 2D concentration maps calculated on non-flat surfaces. This way, local concentration changes at interfaces or and other structures can be assessed more effectively. PMID- 29626835 TI - Exploring possibilities of band gap measurement with off-axis EELS in TEM. AB - A technique to measure the band gap of dielectric materials with high refractive index by means of energy electron loss spectroscopy (EELS) is presented. The technique relies on the use of a circular (Bessel) aperture and suppresses Cherenkov losses and surface-guided light modes by enforcing a momentum transfer selection. The technique also strongly suppresses the elastic zero loss peak, making the acquisition, interpretation and signal to noise ratio of low loss spectra considerably better, especially for excitations in the first few eV of the EELS spectrum. Simulations of the low loss inelastic electron scattering probabilities demonstrate the beneficial influence of the Bessel aperture in this setup even for high accelerating voltages. The importance of selecting the optimal experimental convergence and collection angles is highlighted. The effect of the created off-axis acquisition conditions on the selection of the transitions from valence to conduction bands is discussed in detail on a simplified isotropic two band model. This opens the opportunity for deliberately selecting certain transitions by carefully tuning the microscope parameters. The suggested approach is experimentally demonstrated and provides good signal to noise ratio and interpretable band gap signals on reference samples of diamond, GaN and AlN while offering spatial resolution in the nm range. PMID- 29626836 TI - Optimal sampling and reconstruction of undersampled atomic force microscope images using compressive sensing. AB - Atomic force microscope (AFM) is an analytical instrument which is used to study the surface structure and morphology of materials. The AFM can measure and observe samples either in air or liquid environment. However, the standard AFM requires a long time to acquire accurate images and data. In our work, the compressive sensing (CS) was applied in order to reduce the imaging time, lower the interactions between the probe and the sample, finally avoid sample damage in AFM. Three samples (PAA film, TGG1 grating and BOPP film) were used as the testing samples. Different image reconstruction algorithms (l1-ls, TVAL3, GPSR and IHT) were employed to reconstruct AFM image with different sampling rate. And various sampling patterns (Random Scan, Row Scan, SRM, Spiral Scan and Square shape Scan) were used to obtain the undersampling data. A large number of experiments show that the choice of sampling pattern and image reconstruction algorithm has significant impact on the quality of the reconstructed images in AFM. Subsequently the reconstruction results of sample topographic images were analyzed and evaluated by the image quality indicators (PSNR and SSIM). The CS method can be used to obtain accurate images by reducing measurement data. It finally improves the measurement speed of AFM without cutting down the quality of AFM image. PMID- 29626837 TI - Accurate interpolation of 3D fields in charged particle optics. AB - Standard 3D interpolation polynomials often suffer from numerical errors of the calculated field and lack of node points in the 3D solution. We introduce a novel method for accurate and smooth interpolation of arbitrary electromagnetic fields in the vicinity of the optical axis valid up to 90% of the bore radius. Our method combines Fourier analysis and Gaussian wavelet interpolation and provides the axial multipole field functions and their derivatives analytically. The results are accurate and noiseless, usually up to the 5th derivative. This is very advantageous for further applications, such as accurate particle tracing, and evaluation of aberration coefficients and other optical properties. The proposed method also enables studying the strength and orientation of all multipole field components. To illustrate the capabilities of the proposed algorithm, we present three examples: a magnetic lens with a hole in the polepiece, a saturated magnetic lens with an elliptic polepiece, and an electrostatic 8-electrode multipole. PMID- 29626838 TI - Integrated computer-aided forensic case analysis, presentation, and documentation based on multimodal 3D data. AB - Three-dimensional (3D) crime scene documentation using 3D scanners and medical imaging modalities like computed tomography (CT) and magnetic resonance imaging (MRI) are increasingly applied in forensic casework. Together with digital photography, these modalities enable comprehensive and non-invasive recording of forensically relevant information regarding injuries/pathologies inside the body and on its surface. Furthermore, it is possible to capture traces and items at crime scenes. Such digitally secured evidence has the potential to similarly increase case understanding by forensic experts and non-experts in court. Unlike photographs and 3D surface models, images from CT and MRI are not self explanatory. Their interpretation and understanding requires radiological knowledge. Findings in tomography data must not only be revealed, but should also be jointly studied with all the 2D and 3D data available in order to clarify spatial interrelations and to optimally exploit the data at hand. This is technically challenging due to the heterogeneous data representations including volumetric data, polygonal 3D models, and images. This paper presents a novel computer-aided forensic toolbox providing tools to support the analysis, documentation, annotation, and illustration of forensic cases using heterogeneous digital data. Conjoint visualization of data from different modalities in their native form and efficient tools to visually extract and emphasize findings help experts to reveal unrecognized correlations and thereby enhance their case understanding. Moreover, the 3D case illustrations created for case analysis represent an efficient means to convey the insights gained from case analysis to forensic non-experts involved in court proceedings like jurists and laymen. The capability of the presented approach in the context of case analysis, its potential to speed up legal procedures and to ultimately enhance legal certainty is demonstrated by introducing a number of representative forensic cases. PMID- 29626839 TI - Image re-sampling detection through a novel interpolation kernel. AB - Image re-sampling involved in re-size and rotation transformations is an essential element block in a typical digital image alteration. Fortunately, traces left from such processes are detectable, proving that the image has gone a re-sampling transformation. Within this context, we present in this paper two original contributions. First, we propose a new re-sampling interpolation kernel. It depends on five independent parameters that controls its amplitude, angular frequency, standard deviation, and duration. Then, we demonstrate its capacity to imitate the same behavior of the most frequent interpolation kernels used in digital image re-sampling applications. Secondly, the proposed model is used to characterize and detect the correlation coefficients involved in re-sampling transformations. The involved process includes a minimization of an error function using the gradient method. The proposed method is assessed over a large database of 11,000 re-sampled images. Additionally, it is implemented within an algorithm in order to assess images that had undergone complex transformations. Obtained results demonstrate better performance and reduced processing time when compared to a reference method validating the suitability of the proposed approaches. PMID- 29626840 TI - Treadmill walking reduces pre-frontal activation in patients with Parkinson's disease. AB - BACKGROUND: Among patients with Parkinson's disease (PD), gait is typically disturbed and less automatic. These gait changes are associated with impaired rhythmicity and increased prefrontal activation, presumably in an attempt to compensate for reduced automaticity. RESEARCH QUESTION: We investigated whether during treadmill walking, when the pace is determined and fixed, prefrontal activation in patients with PD is lower, as compared to over-ground walking. METHODS: Twenty patients with PD (age: 69.8 +/- 6.5 yrs.; MoCA: 26.9 +/- 2.4; disease duration: 7.9 +/- 4.2 yrs) walked at a self-selected walking speed over ground and on a treadmill. A wireless functional near infrared spectroscopy (fNIRS) system measured prefrontal lobe activation, i.e., oxygenated hemoglobin (Hb02) in the pre-frontal area. Gait was evaluated using 3D-accelerometers attached to the lower back and ankles (OpalTM, APDM). Dynamic gait stability was assessed using the maximum Lyapunov exponent to investigate automaticity of the walking pattern. RESULTS: Hb02 was lower during treadmill walking than during over-ground walking (p = 0.001). Gait stability was greater on the treadmill, compared to over-ground walking, in both the anteroposterior and medio-lateral axes (p < 0.001). SIGNIFICANCE: These findings support the notion that when gait is externally paced, prefrontal lobe activation is reduced in patients with PD, perhaps reflecting a reduced need for compensatory cognitive mechanisms. PMID- 29626841 TI - Compatibilization of HIPS/ABS blends from WEEE by using Styrene-Butadiene Rubber (SBR). AB - The aim of this work is to develop compatibilization strategies for High Impact Polystyrene (HIPS)/ Acrylonitrile-Butadiene-Styrene (ABS) blends from WEEE in order to add value to these recycled plastics by improving their mechanical performance. Results from a screening study of HIPS/ABS blends compatibilization by the addition of Styrene-Butadiene Rubber (SBR) are presented. Two different weight proportion of HIPS/ABS physical blends were analyzed, 80/20 and 20/80, with three different concentration of SBR: 2, 10 and 20 wt%. Compatibilization efficiency was analyzed from an accurate thermal and mechanical analysis, by comparing each physical blend and corresponding compatibilized blends with SBR. Results were discussed relating glass transition changes with mechanical performance, both aspects were interpreted in terms of blend morphology. Phase and fillers dispersion and distribution as well as SBR amount and its interaction with each phase were accurate analyzed. Compatibilization of HIPS/ABS blends from WEEE with the addition of SBR is effective in blends with HIPS as main component. With the addition of 2 wt% of SBR, strength and toughness have notably increased respect to the corresponding physical blend, 244% and 186% respectively. From this screening study is possible to infer that SBR is a sustainable and efficient compatibilizer of HIPS rich blends allowing to obtain a final blend that can be used as a replacement material of separated resins from WEEE. PMID- 29626842 TI - Quantification of dissolved organic carbon (DOC) storage in lakes and reservoirs of mainland China. AB - As a major fraction of carbon in inland waters, dissolved organic carbon (DOC) plays a crucial role in carbon cycling on a global scale. However, the quantity of DOC stored in lakes and reservoirs was not clear to date. In an attempt to examine the factors that determine the DOC storage in lakes and reservoirs across China, we assembled a large database (measured 367 lakes, and meta-analyzed 102 lakes from five limnetic regions; measured 144 reservoirs, and meta-analyzed 272 reservoirs from 31 provincial units) of DOC concentrations and water storages for lakes and reservoirs that are used to determine DOC storage in static inland waters. We found that DOC concentrations in saline waters (Mean/median +/- S.D: 50.5/30.0 +/- 55.97 mg/L) are much higher than those in fresh waters (8.1/5.9 +/- 6.8 mg/L), while lake DOC concentrations (25.9/11.5 +/- 42.04 mg/L) are much higher than those in reservoirs (5.0/3.8 +/- 4.5 mg/L). In terms of lake water volume and DOC storage, the Tibet-Qinghai lake region has the largest water volume (552.8 km3), 92% of which is saline waters, thus the largest DOC (13.39 Tg) is stored in these alpine lake region; followed by the Mengxin lake region, having a water volume of 99.4 km3 in which 1.75 Tg DOC was stored. Compared to Mengxin lake region, almost the same amount of water was stored in East China lake region (91.9 km3), however, much less DOC was stored in this region (0.43 Tg) due to the lower DOC concentration (Ave: 3.45 +/- 2.68 mg/L). According to our investigation, Yungui and Northeast lake regions had water storages of 32.14 km3 and 19.44 km3 respectively, but relatively less DOC was stored in Yungui (0.13 Tg) than in Northeast lake region (0.19 Tg). Due to low DOC concentration in reservoirs, especially these large reservoirs having lower DOC concentration (V > 1.0 km3: 2.31 +/- 1.48 mg/L), only 1.54 Tg was stored in a 485.1 km3 volume of water contained in reservoirs across the entire country. PMID- 29626843 TI - Evaluation of strategies for mitigating risks associated with metals in pyrite ash. AB - The main objective was to evaluate and optimise strategies for the immobilisation or mobilisation of Cd, Cu, Cr, Ni, Pb, and Zn from pyrite ash. Alkaline amendments were used for the immobilisation test: cement, sandstone, marl, marble waste and calcareous crust. The amendments were mixed with pyrite ash at a 1:2 rate, incubated for 28 days, and leachates analysed at the beginning of the experiment (day 0) and after 2, 7, 14 and 28 days. The mobilisation experiment tested metal release from pyrite ash by four concentrations of H2SO4 (0.25 M, 0.5 M, 1 M and 2 M) and contact times (60, 120, 180 and 240 min). Results for the immobilisation/mobilisation tests for Cr and Ni are not presented due to the low concentration in pyrite ash. In the immobilisation test, optimum results across metals and amendments were obtained after two days with percentages of retention being about 90% compared to leachates from pyrite ash only. The release success (in % of total content) using sulphuric acid followed the order: Cd (75%) > Zn (62%) > Cu (37%) > Pb (7%). The concentration of acid was more important than contact time (release enhanced at higher concentrations) except for Zn. The two strategies tested were successful to reduce the risk posed by metals. In terms of optimization, all alkaline materials showed high efficiency for metal retention after a short contact time; for mobilisation, treatment with sulphuric acid at high concentration (up to 2 M tested) resulted to be the optimum with contact time having limited influence. PMID- 29626844 TI - Self-reported anxiety and depression unchanged after endoscopic sinus surgery for chronic rhinosinusitis. AB - BACKGROUND: Prior research has established that anxiety and depression, as measured by the Hospital Anxiety Depression Score (HADS), are strongly correlated with disease-specific quality of life (Rhinosinusitis Disability Index - RSDI) in chronic rhinosinusitis (CRS). We hypothesized that anxiety and depression would decrease after functional endoscopic sinus surgery (FESS), and furthermore that HADS would predict improvement in RSDI following surgery. METHODOLOGY: The study cohort from 2014 consisted of 99 CRS patients who underwent nasal endoscopy, RSDI, and HADS evaluation. The cohort was segregated by whether or not they underwent FESS and an updated HADS was administered. For 44 surgical patients, pre- and post-operative RSDI (n=38), Lund-Kennedy (LK) (n=34) and HADS (n=18) scores were compared. Delta RSDI was compared between patients with varying levels of anxiety and depression. RESULTS: Lund-Kennedy scores improved from 5.8 +/- 4.1 to 3.2 +/- 2.6 following surgery, as did total RSDI (39.3 +/- 26.8 to 24.6 +/- 29.2). Total HADS (9.8 +/- 6.4 to 11.3 +/- 7.4) and depression and anxiety subscores were unchanged. Linear regression did not reveal a correlation between HADS and change in RSDI following FESS. Delta RSDI was not significantly different between patients with varying levels of anxiety and depression. CONCLUSIONS: Despite improvements in objective evidence of sinonasal inflammation (LK) and disease-specific quality of life (RSDI), neither depression nor anxiety improved after FESS, nor did the magnitude of psychological comorbidity predict post-operative improvement in quality of life. Improvement in RSDI was not different among patients with varying levels of anxiety and depression. Levels of depression and anxiety may be hard-wired, and therefore not influenced by changes in objective or perceived sinonasal disease burden. PMID- 29626845 TI - Adjuvant radiation with androgen-deprivation therapy for men with lymph node metastases after radical prostatectomy: identifying men who benefit. AB - OBJECTIVES: To perform a comparative analysis of three current management strategies for patients with lymph node metastases (LNM; pN1) following radical prostatectomy (RP): observation, androgen-deprivation therapy (ADT), and external beam radiation therapy (EBRT) + ADT. PATIENTS AND METHODS: Patients with LNM after RP were identified using the National Cancer Database (2004-2013). Exclusion criteria included any use of radiation therapy or ADT before RP, clinical M1 disease, or incomplete follow-up data. Patients were categorised according to postoperative management strategy. The primary outcome was overall survival (OS). Kaplan-Meier curves and adjusted multivariable Cox proportional hazards models were employed. Sub-analyses further evaluated patient risk stratification and time to receipt of adjuvant therapy. RESULTS: A total of 8 074 patients met the inclusion criteria. Postoperatively, 4 489 (55.6%) received observation, 2 065 (25.6%) ADT, and 1 520 (18.8%) ADT + EBRT. The mean (median; interquartile range) follow-up was 52.3 (48.0; 28.5-73.5) months. Patients receiving ADT or ADT + EBRT had higher pathological Gleason scores, T-stage, positive surgical margin rates, and nodal burden. Adjusted multivariable Cox models showed improved OS for ADT + EBRT vs observation (hazard ratio [HR] 0.77, 95% confidence interval [CI] 0.64-0.94; P = 0.008) and vs ADT (HR 0.76, 95% CI: 0.63-0.93; P = 0.007). There was no difference in OS for ADT vs observation (HR 1.01, 95% CI: 0.87-1.18; P = 0.88). Findings were similar when restricting adjuvant cohorts for timing of adjuvant therapy. There was no difference in OS between groups for up to 2 549 (31.6%) patients lacking any of the following adverse features: >=pT3b disease, Gleason score >=9, three or more positive nodes, or positive surgical margin. CONCLUSIONS: For patients with LNM after RP, the use of adjuvant ADT + EBRT improved OS in the majority of patients, especially those with adverse pathological features. Conversely, adjuvant therapy did not confer significant OS benefit in up to 30% of patients without high-risk features, who may be managed with observation and forego the morbidity associated with immediate ADT or radiation. PMID- 29626846 TI - The evolution of eccrine sweat gland research towards developing a model for human sweat gland function. AB - For several decades now, researchers, professional bodies, governments, and journals such as the journal of Experimental Dermatology have worked to reduce the number of animals used in experimentation. This review centres on investigations into how human sweat glands produce sweat and how that research has evolved over the years. It is hoped that this review will show that as methodologies advanced, sweat gland research has come to rely less and less on a variety of animal models as investigative tools and information is being primarily obtained through human and mouse material, with a view to further reductions in using animal models. PMID- 29626847 TI - Crystal structures of amyloidogenic segments of human transthyretin. AB - Amyloid diseases are characterized by the deposition of proteins in the form of amyloid fibrils, in organs that eventually fail. The development of effective drug candidates follows from the understanding of the molecular processes that lead to protein aggregation. Here, we study amyloidogenic segments of transthyretin (TTR). TTR is a transporter of thyroxine and retinol in the blood and cerebrospinal fluid. When mutated and/or as a result of aging, TTR aggregates into amyloid fibrils that accumulate in organs such as the heart. Recently, we reported two amyloidogenic segments that drive amyloid aggregation. Here, we report the crystal structure of another six amyloidogenic segments of TTR. We found that the segments from the C-terminal region of TTR form in-register steric zippers with highly-interdigitated, wet interfaces, whereas the beta-strand B from the N-terminal region of TTR forms an out-of-register assembly, previously associated with oligomeric formation. Our results contribute fundamental information for understanding the mechanism of aggregation of TTR. PMID- 29626848 TI - Hippocampal and amygdalar cell-specific translation is similar soon after stress but diverge over time. AB - Stress is known to cause contrasting patterns of morphological and physiological plasticity in the hippocampus and amygdala. An obligatory cellular process underlying such neural changes is de novo translation and alterations in protein expression. Yet the nature of the translational response to stress in neurons remains largely unexplored. Even less is known about how glia are affected. Using a click-chemistry-based method to label the de novo proteome in live brain slices, we monitored translation in neurons and astrocytes of the basolateral amygdala (BLA) and dorsal hippocampal area CA3 (dCA3) in rats at different time points after a single 2-hr exposure to immobilization stress. We observed enhancements in neuronal translation in both brain regions 1 hour after stress. This initial increase persisted in the BLA up to 10 days afterwards. In contrast, dCA3 neuronal translation gradually decreased to below control levels 10 days later. Translation profiles of dCA3 astrocytes followed timelines similar to neurons, but in BLA astrocytes translation peaked 1 day later and remained elevated 10 days later. Together our results demonstrate that stress causes an immediate upregulation of protein synthesis in both amygdalar and hippocampal neurons and astrocytes. However, these two areas eventually exhibit opposite temporal profiles of protein expression well after the end of stress. These findings identify new metrics of stress-induced plasticity at the level of cell type specific proteomic landscape that may provide important insights into the molecular basis of the divergent temporal effects of stress across brain regions and biological scales. PMID- 29626850 TI - Diagnostic and therapeutic implications of novel peptides in hepatocellular carcinoma. PMID- 29626851 TI - Antibody-mediated rejection induced cardiogenic shock: Too late for conventional therapy. AB - BACKGROUND: Data are scarce on the prognosis of heart allograft antibody-mediated rejection (AMR) with cardiogenic shock (CS). METHODS: We performed a retrospective, single center, observational study. We included patients with biopsy-proven AMR and CS. We aimed to analyze the characteristics, treatment, and prognosis of patients treated for CS due to AMR. Patients alive after AMR were followed to analyze recurrences of AMR, graft function, and cardiac allograft vasculopathy (CAV). RESULTS: Seventeen patients met the inclusion criteria. Patients were mostly males (70%). Median age at diagnosis was 56 years, and median time between heart transplantation and AMR was 21 months. AMR was mostly due to high-level de novo class II DSA. Only 2 patients had past history of biopsy-proven AMR. Despite aggressive immunosuppressive therapies, in-hospital and 1-year mortality were as high as 76% and 82%, respectively. Four patients were discharged from hospital. Two of them were diagnosed with recurrent subclinical AMR: one died suddenly and the other presented rapidly progressive CAV. CONCLUSION: CS due to AMR occurred mostly in patients without history of AMR who developed de novo class II DSA. Despite aggressive conventional immunosuppressive therapies, prognosis after CS due to AMR was poor. PMID- 29626849 TI - The ED95 of Nalbuphine in Outpatient-Induced Abortion Compared to Equivalent Sufentanil. AB - This prospective study evaluated the 95% effective dose (ED95 ) of nalbuphine in inhibiting body movement during outpatient-induced abortion and its clinical efficacy versus the equivalent of sufentanil. The study was divided into two parts. For the first part, voluntary first-trimester patients who needed induced abortions were recruited to measure the ED95 of nalbuphine in inhibiting body movement during induced abortion using the sequential method (the Dixon up-and down method). In the second part, this was a double-blind, randomized study. Sixty cases of first-trimester patients were recruited and were randomly divided into two groups (n = 30), including group N (nalbuphine at the ED95 dose) and group S (sufentanil at an equivalent dose). Propofol was given to both groups as the sedative. The circulation, respiration and body movement of the two groups in surgery were observed. The amount of propofol, the awakening time, the time to leave the hospital and the analgesic effect were recorded. The ED95 of nalbuphine in inhibiting body movement during painless surgical abortion was 0.128 mg/kg (95% confidence intervals 0.098-0.483 mg/kg). Both nalbuphine and the equivalent dose of sufentanil provided a good intraoperative and post-operative analgesic effect in outpatient-induced abortion. However, the post-operative morbidity of dizziness for nalbuphine was less than for sufentanil (p < 0.05), and the awakening time and the time to leave the hospital were significantly shorter than those of sufentanil (p < 0.05). Nalbuphine at 0.128 mg/kg was used in outpatient induced abortion as an intraoperative and post-operative analgesic and showed a better effect compared with sufentanil. PMID- 29626852 TI - Alkyl hydrogen atom abstraction reactions of the CN radical with ethanol. AB - We present a study of the abstraction of alkyl hydrogen atoms from the beta and alpha positions of ethanol by the CN radical in solution using the Empirical Valence Bond (EVB) method. We have built separate 2 * 2 EVB models for the Hbeta and Halpha reactions, where the atom transfer is parameterized using ab initio calculations. The intra- and intermolecular potentials of the reactant and product molecules were modelled with the General AMBER Force Field, with some modifications. We have carried out the dynamics in water and chloroform, which are solvents of contrasting polarity. We have computed the potential of mean force for both abstractions in each of the solvents. They are found to have a small and early barrier along the reaction coordinate with a large energy release. Analyzing the solvent structure around the reaction system, we have found two solvents to have little effect on either reaction. Simulating the dynamics from the transition state, we also study the fate of the energies in the HCN vibrational modes. The HCN molecule is born vibrationally hot in the CH stretch in both reactions and additionally in the HCN bends for the Halpha abstraction reaction. In the early stage of the dynamics, we find that the CN stretch mode gains energy at the expense of the energy in CH stretch mode. PMID- 29626853 TI - Fluctuating chemohydrodynamics and the stochastic motion of self-diffusiophoretic particles. AB - The propulsion of active particles by self-diffusiophoresis is driven by asymmetric catalytic reactions on the particle surface that generate a mechanochemical coupling between the fluid velocity and the concentration fields of fuel and product in the surrounding solution. Because of thermal and molecular fluctuations in the solution, the motion of micrometric or submicrometric active particles is stochastic. Coupled Langevin equations describing the translation, rotation, and reaction of such active particles are deduced from fluctuating chemohydrodynamics and fluctuating boundary conditions at the interface between the fluid and the particle. These equations are consistent with microreversibility and the Onsager-Casimir reciprocal relations between affinities and currents and provide a thermodynamically consistent basis for the investigation of the dynamics of active particles propelled by diffusiophoretic mechanisms. PMID- 29626854 TI - Time-resolved stimulated emission depletion and energy transfer dynamics in two photon excited EGFP. AB - Time and polarization-resolved stimulated emission depletion (STED) measurements are used to investigate excited state evolution following the two-photon excitation of enhanced green fluorescent protein (EGFP). We employ a new approach for the accurate STED measurement of the hitherto unmeasured degree of hexadecapolar transition dipole moment alignment alpha40 present at a given excitation-depletion (pump-dump) pulse separation. Time-resolved polarized fluorescence measurements as a function of pump-dump delay reveal the time evolution of alpha40 to be considerably more rapid than predicted for isotropic rotational diffusion in EGFP. Additional depolarization by homo-Forster resonance energy transfer is investigated for both alpha20 (quadrupolar) and alpha40 transition dipole alignments. These results point to the utility of higher order dipole correlation measurements in the investigation of resonance energy transfer processes. PMID- 29626856 TI - Nonlinear dielectric spectroscopy of propylene carbonate derivatives. AB - Nonlinear dielectric measurements were carried out on two strongly polar liquids, 4-vinyl-1,3-dioxolan-2-one (VPC) and 4-ethyl-1,3-dioxolan-2-one (EPC), having chemical structures differing from propylene carbonate (PC) only by the presence of a pendant group. Despite their polarity, the compounds are all non-associated, "simple" liquids. From the linear component of the dielectric response, the alpha relaxation peak breadth was found to be invariant at a fixed value of the relaxation time, taualpha. From spectra from the nonlinear component, the number of dynamically correlated molecules was determined; it was also constant at fixed taualpha. Thus, two manifestations of dynamic heterogeneity depend only on the time constant for structural reorientation. More broadly, the cooperativity of molecular motions for non-associated glass-forming materials is connected to (i.e., reciprocally governs) the time scale. The equation of state for the two liquids was also obtained from density measurements made over a broad range of pressures and temperatures. Using these data, it was determined that the relaxation times of both liquids conform to density scaling. The effect of density, relative to thermal effects, on the alpha relaxation increases going from PC < VPC < EPC. PMID- 29626855 TI - Dynamic stability of nano-fibers self-assembled from short amphiphilic A6D peptides. AB - Self-assembly of A6D amphiphilic peptides in explicit water is studied by using coarse-grained molecular dynamics simulations. It is observed that the self assembly of randomly distributed A6D peptides leads to the formation of a network of nano-fibers. Two other simulations with cylindrical nano-fibers as the initial configuration show the dynamic stability of the self-assembled nano-fibers. As a striking feature, notable fluctuations occur along the axes of the nano-fibers. Depending on the number of peptides per unit length of the nano-fiber, flat shaped bulges or spiral shapes along the nano-fiber axis are observed at the fluctuations. Analysis of the particle distribution around the nano-fiber indicates that the hydrophobic core and the hydrophilic shell of the nano structure are preserved in both simulations. The size of the deformations and their correlation times are different in the two simulations. This study gives new insights into the dynamics of the self-assembled nano-structures of short amphiphilic peptides. PMID- 29626857 TI - Combination of large and small basis sets in electronic structure calculations on large systems. AB - Two basis sets-a large and a small one-are associated with each nucleus of the system. Each atom has its own separate one-electron basis comprising the large basis set of the atom in question and the small basis sets for the partner atoms in the complex. The perturbed atoms in molecules and solids model is at core of the approach since it allows for the definition of perturbed atoms in a system. It is argued that this basis set approach should be particularly useful for periodic systems. Test calculations are performed on one-dimensional arrays of H and Li atoms. The ground-state energy per atom in the linear H array is determined versus bond length. PMID- 29626858 TI - Effect of wetting on nucleation and growth of D2 in confinement. AB - We have performed a computational study to determine how the wetting of liquid deuterium to the walls of the material influences nucleation. We present the development of a pair-wise interatomic potential that includes zero-point motion of molecular deuterium. Deuterium is used in this study because of its importance to inertial confinement fusion and the potential to generate a superfluid state if the solidification can be suppressed. Our simulations show that wetting dominates undercooling compared to the pore geometries. We observe a transition from heterogeneous nucleation at the confining wall to homogeneous nucleation at the bulk of the liquid (and intermediate cases) as the interaction with the confining wall changes from perfect wetting to non-wetting. When nucleation is heterogeneous, the temperature needed for solidification changes by 4 K with decreasing deuterium-wall interaction, but it remains independent (and equal to the one from bulk samples) when homogeneous nucleation dominates. We find that growth and quality of the resulting microstructure also depends on the magnitude of liquid deuterium-wall interaction strength. PMID- 29626859 TI - Lessons on electronic decoherence in molecules from exact modeling. AB - Electronic decoherence processes in molecules and materials are usually thought and modeled via schemes for the system-bath evolution in which the bath is treated either implicitly or approximately. Here we present computations of the electronic decoherence dynamics of a model many-body molecular system described by the Su-Schrieffer-Heeger Hamiltonian with Hubbard electron-electron interactions using an exact method in which both electronic and nuclear degrees of freedom are taken into account explicitly and fully quantum mechanically. To represent the electron-nuclear Hamiltonian in matrix form and propagate the dynamics, the computations employ the Jordan-Wigner transformation for the fermionic creation/annihilation operators and the discrete variable representation for the nuclear operators. The simulations offer a standard for electronic decoherence that can be used to test approximations. They also provide a useful platform to answer fundamental questions about electronic decoherence that cannot be addressed through approximate or implicit schemes. Specifically, through simulations, we isolate basic mechanisms for electronic coherence loss and demonstrate that electronic decoherence is possible even for one-dimensional nuclear bath. Furthermore, we show that (i) decreasing the mass of the bath generally leads to faster electronic decoherence; (ii) electron-electron interactions strongly affect the electronic decoherence when the electron-nuclear dynamics is not pure-dephasing; (iii) classical bath models with initial conditions sampled from the Wigner distribution accurately capture the short-time electronic decoherence dynamics; (iv) model separable initial superpositions often used to understand decoherence after photoexcitation are only relevant in experiments that employ delta-like laser pulses to initiate the dynamics. These insights can be employed to interpret and properly model coherence phenomena in molecules. PMID- 29626860 TI - Flexible scheme to truncate the hierarchy of pure states. AB - The hierarchy of pure states (HOPS) is a wavefunction-based method that can be used for numerically modeling open quantum systems. Formally, HOPS recovers the exact system dynamics for an infinite depth of the hierarchy. However, truncation of the hierarchy is required to numerically implement HOPS. We want to choose a "good" truncation method, where by "good" we mean that it is numerically feasible to check convergence of the results. For the truncation approximation used in previous applications of HOPS, convergence checks are numerically challenging. In this work, we demonstrate the application of the "n-particle approximation" to HOPS. We also introduce a new approximation, which we call the "n-mode approximation." We then explore the convergence of these truncation approximations with respect to the number of equations required in the hierarchy in two exemplary problems: absorption and energy transfer of molecular aggregates. PMID- 29626861 TI - Note: Formation of the nematic splay-bend in two-dimensional systems of bow shaped particles. PMID- 29626862 TI - Transient isomers in the photodissociation of bromoiodomethane. AB - The photochemistry of halomethanes is fascinating for the complex cascade reactions toward either the parent or newly synthesized molecules. Here, we address the structural rearrangement of photodissociated CH2IBr in methanol and cyclohexane, probed by time-resolved X-ray scattering in liquid solution. Upon selective laser cleavage of the C-I bond, we follow the reaction cascade of the two geminate geometrical isomers, CH2I-Br and CH2Br-I. Both meta-stable isomers decay on different time scales, mediated by solvent interaction, toward the original parent molecule. We observe the internal rearrangement of CH2Br-I to CH2I-Br in cyclohexane by extending the time window up to 3 MUs. We track the photoproduct kinetics of CH2Br-I in methanol solution where only one isomer is observed. The effect of the polarity of solvent on the geminate recombination pathways is discussed. PMID- 29626863 TI - Intermolecular dissociation energies of dispersively bound complexes of aromatics with noble gases and nitrogen. AB - We measured accurate intermolecular dissociation energies D0 of the supersonic jet-cooled complexes of 1-naphthol (1NpOH) with the noble gases Ne, Ar, Kr, and Xe and with N2, using the stimulated-emission pumping resonant two-photon ionization method. The ground-state values D0(S0) for the 1NpOH?S complexes with S= Ar, Kr, Xe, and N2 were bracketed to be within +/-3.5%; they are 5.67 +/- 0.05 kJ/mol for S = Ar, 7.34 +/- 0.07 kJ/mol for S = Kr, 10.8 +/- 0.28 kJ/mol for S = Xe, 6.67 +/- 0.08 kJ/mol for isomer 1 of the 1NpOH?N2 complex, and 6.62 +/- 0.22 kJ/mol for the corresponding isomer 2. For S = Ne, the upper limit is D0 < 3.36 kJ/mol. The dissociation energies increase by 1%-5% upon S0 -> S1 excitation of the complexes. Three dispersion-corrected density functional theory (DFT-D) methods (B97-D3, B3LYP-D3, and omegaB97X-D) predict that the most stable form of these complexes involves dispersive binding to the naphthalene "face." A more weakly bound edge isomer is predicted in which the S moiety is H-bonded to the OH group of 1NpOH; however, no edge isomers were observed experimentally. The B97-D3 calculated dissociation energies D0(S0) of the face complexes with Ar, Kr, and N2 agree with the experimental values within <5%, but the D0(S0) for Xe is 12% too low. The B3LYP-D3 and omegaB97X-D calculated D0(S0) values exhibit larger deviations to both larger and smaller dissociation energies. For comparison to 1 naphthol, we calculated the D0(S0) of the carbazole complexes with S = Ne, Ar, Kr, Xe, and N2 using the same DFT-D methods. The respective experimental values have been previously determined to be within <2%. Again, the B97-D3 results are in the best overall agreement with experiment. PMID- 29626864 TI - Polarized two-photon photoselection in EGFP: Theory and experiment. AB - In this work, we present a complete theoretical description of the excited state order created by two-photon photoselection from an isotropic ground state; this encompasses both the conventionally measured quadrupolar (K = 2) and the "hidden" degree of hexadecapolar (K = 4) transition dipole alignment, their dependence on the two-photon transition tensor and emission transition dipole moment orientation. Linearly and circularly polarized two-photon absorption (TPA) and time-resolved single- and two-photon fluorescence anisotropy measurements are used to determine the structure of the transition tensor in the deprotonated form of enhanced green fluorescent protein. For excitation wavelengths between 800 nm and 900 nm, TPA is best described by a single element, almost completely diagonal, two-dimensional (planar) transition tensor whose principal axis is collinear to that of the single-photon S0 -> S1 transition moment. These observations are in accordance with assignments of the near-infrared two-photon absorption band in fluorescent proteins to a vibronically enhanced S0 -> S1 transition. PMID- 29626865 TI - Translocation of a vesicle through a narrow hole across a membrane. AB - We study the translocation process of a vesicle through a hole in a solid membrane separating two chambers by using the Onsager principle. By considering the stretching energy of the vesicle and the driving force due to pressure difference, we derive a free energy that shows clearly a decrease in the energy barrier as the pressure difference between two sides of the membrane increases. The difference between the reaction path obtained from the string method and the actual kinetic paths obtained from the Onsager principle is discussed when the friction parameter changes. The translocation time decreases as the pressure difference increases or the initial size of the vesicle decreases. PMID- 29626866 TI - How do glycerol and dimethyl sulphoxide affect local tetrahedral structure of water around a nonpolar solute at low temperature? Importance of preferential interaction. AB - Glycerol and dimethyl sulphoxide (DMSO) have vital roles in cryoprotection of living cells, tissues, etc. The above action has been directly linked with disruption of hydrogen (H-) bond structure and dynamics of water by these cosolvents at bulk region and around various complex units, such as peptide, amino acid, protein, and lipid membrane. However, the disruption of the local structure of the water solvent around a purely hydrophobic solute is still not studied extensively. The latter is also important in the context of stabilization of protein from cold denaturation. Through all-atom molecular dynamics simulation, we have investigated the comparative effect of glycerol and DMSO on the orientational order of water around a nonpolar solute at -5 degrees C. A steady reduction of the tetrahedral order of water is observed at bulk (>10 A distance from the solute) and solute interface (<5.5 A distance from the solute) with increasing the cosolvent concentration. Contrasting roles of glycerol and DMSO have been evidenced. While DMSO affects the H-bond structure of the interfacial water more than that of the bulk water, glycerol affects the water structure almost uniformly at all regions around the solute. Furthermore, while glycerol helps to retain water molecules at the interface, DMSO significantly reduces the water content in that region. We have put forward a plausible mechanism for these contrasting roles of these cosolvents. The solute-cosolvent hydrophobic-interaction-induced orientational alignment of an interfacial cosolvent molecule determines whether the involvement of the cosolvent molecules in H-bonding with solvent water in the interface is akin to the bulk region or not. PMID- 29626867 TI - The vertical growth of MoS2 layers at the initial stage of CVD from first principles. AB - Chemical vapor deposition (CVD) is the highly preferred method for mass production of transition metal dichalcogenide (TMD) layers, yet the atomic-scale knowledge is still lacking about the nucleation and growth. In this study, by using first-principles calculations, we show that, on Au(111) surface, one dimensional (1D) MoxSy chains are first formed by coalescing of smaller feeding species and are energetically favored at the early stage of nucleation. Two dimensional (2D) layers can be stabilized only after the number of Mo atoms exceeds ~12. A vertical growth mode is revealed which accomplishes the structural transformation from the 1D chains to the 2D layers for the clusters while growing. The competition between intralayer and interlayer interactions is the key. These findings serve as new insights for better understanding the atomistic mechanism of the nucleation and growth of TMDs on the surface. PMID- 29626868 TI - A simple and effective solution to the constrained QM/MM simulations. AB - It is a promising extension of the quantum mechanical/molecular mechanical (QM/MM) approach to incorporate the solvent molecules surrounding the QM solute into the QM region to ensure the adequate description of the electronic polarization of the solute. However, the solvent molecules in the QM region inevitably diffuse into the MM bulk during the QM/MM simulation. In this article, we developed a simple and efficient method, referred to as the "boundary constraint with correction (BCC)," to prevent the diffusion of the solvent water molecules by means of a constraint potential. The point of the BCC method is to compensate the error in a statistical property due to the bias potential by adding a correction term obtained through a set of QM/MM simulations. The BCC method is designed so that the effect of the bias potential completely vanishes when the QM solvent is identical with the MM solvent. Furthermore, the desirable conditions, that is, the continuities of energy and force and the conservations of energy and momentum, are fulfilled in principle. We applied the QM/MM-BCC method to a hydronium ion(H3O+) in aqueous solution to construct the radial distribution function (RDF) of the solvent around the solute. It was demonstrated that the correction term fairly compensated the error and led the RDF in good agreement with the result given by an ab initio molecular dynamics simulation. PMID- 29626869 TI - Theoretical characterization on the size-dependent electron and hole trapping activity of chloride-passivated CdSe nanoclusters. AB - Ligand passivation is often used to suppress the surface trap states of semiconductor quantum dots (QDs) for their continuous photoluminescence output. The suppression process is related to the electrophilic/nucleophilic activity of surface atoms that varies with the structure and size of QD and the electron donating/accepting nature of ligand. Based on first-principles-based descriptors and cluster models, the electrophilic/nucleophilic activities of bare and chloride-coated CdSe clusters were studied to reveal the suppression mechanism of Cl-passivated QDs and compared to experimental observations. The surface atoms of bare clusters have higher activity than inner atoms and their activity decreases with cluster size. In the ligand-coated clusters, the Cd atom remains as the electrophilic site, while the nucleophilic site of Se atoms is replaced by Cl atoms. The activities of Cd and Cl atoms in the coated clusters are, however, remarkably weaker than those in bare clusters. Cluster size, dangling atoms, ligand coverage, electronegativity of ligand atoms, and solvent (water) were found to have considerable influence on the activity of surface atoms. The suppression of surface trap states in Cl-passivated QDs was attributed to the reduction of electrophilic/nucleophilic activity of Cd/Se/Cl atoms. Both saturation to under-coordinated surface atoms and proper selection for the electron donating/accepting strength of ligands are crucial for eliminating the charge carrier traps. Our calculations predicted a similar suppressing effect of chloride ligands with experiments and provided a simple but effective approach to assess the charge carrier trapping behaviors of semiconductor QDs. PMID- 29626870 TI - Effect of tacticity on the structure and glass transition temperature of polystyrene adsorbed onto solid surfaces. AB - We have carried out atomistic (all-atom) molecular dynamics simulations to investigate the effect of tacticity on the structure and glass transition temperature (Tg) of polystyrene (PS) thin films adsorbed on two distinct types of solid substrates. The systems consist of thin films made of atactic, isotactic, and syndiotactic PS chains supported by graphite or hydroxylated alpha-quartz substrates, which are known to be atomically flat but chemically and structurally different. We have observed a marked dependence of the film structure on substrate type as well as on tacticity. For instance, rings' orientation near substrate surfaces depends on substrate type for atactic PS and isotactic PS films, while no such dependence is observed for syndiotactic PS films whose interfacial structure seems to result from their propensity to adopt the trans conformation rather than their specific interaction with the substrates. Moreover, our results indicate that glass transition temperatures of substrate supported polystyrene films are higher compared to those of the corresponding free-standing films. More specifically, PS films on graphite exhibit larger Tg values than those on alpha-quartz, and we have noticed that syndiotactic PS has the largest Tg irrespective of the substrate type. Furthermore, the local Tg in the region of the film in contact with the substrates shows a strong tacticity and substrate dependence, whereas no dependencies were found for the local Tg in the middle of the film. Substrate-film interaction energy and chains' dynamics near substrate-film interfaces were subsequently investigated in order to substantiate the obtained Tgs, and it was found that films with higher Tgs are strongly adsorbed on the substrates and/or exhibit smaller interfacial chains' dynamics essentially due to steric hindrance. PMID- 29626871 TI - What is measured by hyper-Rayleigh scattering from a liquid? AB - Polarization and angle dependence of hyper-Rayleigh scattering (HRS) measured for liquid acetonitrile and dimethyl sulfoxide (DMSO) is analyzed in terms of contributions from randomly oriented molecules and additional contributions produced during intermolecular collisions and induced by the electric field of dissolved ions. All three contributions show the effect of long-range correlation, and the correlation functions are determined using the HRS observations combined with the results of molecular dynamics simulations. HRS from acetonitrile is polarized transverse to the scattering vector. This is due to long-range molecular orientation correlation produced by the dipole-dipole interaction, and correlation at distances r > 100 nm must be included to account for the HRS observations. Analysis of the HRS measurements for acetonitrile determines the length scale a = 0.185 nm for the long-range longitudinal and transverse orientation correlation functions BL=-2BT=a3/r3. Transverse polarized collision-induced HRS is also observed for acetonitrile, indicating long-range correlation of intermolecular modes. Strong longitudinal HRS is induced by the radial electric field of dissolved ions in acetonitrile. For DMSO, the angle between the molecular dipole and the vector part of the first hyperpolarizability tensor is about 100 degrees . As a result, HRS from the randomly oriented molecules in DMSO is nearly unaffected by dipole correlation, and ion-induced HRS is weak. The strong longitudinal polarized HRS observed for DMSO is due to the collision-induced contribution, indicating long-range correlation of intermolecular modes. The HRS observations require correlation that has r-3 long range asymptotic form, for molecular orientation and for intermolecular vibration and libration, for both acetonitrile and DMSO. PMID- 29626872 TI - Stratification of mixtures in evaporating liquid films occurs only for a range of volume fractions of the smaller component. AB - I model the drying of a liquid film containing small and big colloid particles. Fortini et al. [Phys. Rev. Lett. 116, 118301 (2016)] studied these films with both computer simulation and experiment. They found that at the end of drying, the mixture had stratified with a layer of the smaller particles on top of the big particles. I develop a simple model for this process. The model has two ingredients: arrest of the diffusion of the particles at high density and diffusiophoretic motion of the big particles due to gradients in the volume fraction of the small particles. The model predicts that stratification only occurs over a range of initial volume fractions of the smaller colloidal species. Above and below this range, the downward diffusiophoretic motion of the big particles is too slow to remove the big particles from the top of the film, and so there is no stratification. In agreement with earlier work, the model also predicts that large Peclet numbers for drying are needed to see stratification. PMID- 29626873 TI - Current density tensors. AB - It is shown that nonsymmetric second-rank current density tensors, related to the current densities induced by magnetic fields and nuclear magnetic dipole moments, are fundamental properties of a molecule. Together with magnetizability, nuclear magnetic shielding, and nuclear spin-spin coupling, they completely characterize its response to magnetic perturbations. Gauge invariance, resolution into isotropic, deviatoric, and antisymmetric parts, and contributions of current density tensors to magnetic properties are discussed. The components of the second-rank tensor properties are rationalized via relationships explicitly connecting them to the direction of the induced current density vectors and to the components of the current density tensors. The contribution of the deviatoric part to the average value of magnetizability, nuclear shielding, and nuclear spin spin coupling, uniquely determined by the antisymmetric part of current density tensors, vanishes identically. The physical meaning of isotropic and anisotropic invariants of current density tensors has been investigated, and the connection between anisotropy magnitude and electron delocalization has been discussed. PMID- 29626874 TI - Potential energy landscape of TIP4P/2005 water. AB - We report a numerical study of the statistical properties of the potential energy landscape of TIP4P/2005, one of the most accurate rigid water models. We show that, in the region where equilibrated configurations can be generated, a Gaussian landscape description is able to properly describe the model properties. We also find that the volume dependence of the landscape properties is consistent with the existence of a locus of density maxima in the phase diagram. The landscape-based equation of state accurately reproduces the TIP4P/2005 pressure vs-volume curves, providing a sound extrapolation of the free-energy at low T. A positive-pressure liquid-liquid critical point is predicted by the resulting free energy. PMID- 29626875 TI - Adaptive enhanced sampling by force-biasing using neural networks. AB - A machine learning assisted method is presented for molecular simulation of systems with rugged free energy landscapes. The method is general and can be combined with other advanced sampling techniques. In the particular implementation proposed here, it is illustrated in the context of an adaptive biasing force approach where, rather than relying on discrete force estimates, one can resort to a self-regularizing artificial neural network to generate continuous, estimated generalized forces. By doing so, the proposed approach addresses several shortcomings common to adaptive biasing force and other algorithms. Specifically, the neural network enables (1) smooth estimates of generalized forces in sparsely sampled regions, (2) force estimates in previously unexplored regions, and (3) continuous force estimates with which to bias the simulation, as opposed to biases generated at specific points of a discrete grid. The usefulness of the method is illustrated with three different examples, chosen to highlight the wide range of applicability of the underlying concepts. In all three cases, the new method is found to enhance considerably the underlying traditional adaptive biasing force approach. The method is also found to provide improvements over previous implementations of neural network assisted algorithms. PMID- 29626876 TI - Molecular dynamics simulations of polyethers and a quaternary ammonium ionic liquid as CO2 absorbers. AB - The properties of mixtures of butyltrimethylammonium bis(trifluoromethylsulfonyl)imide, [N4111][NTf2], with poly(ethyleneglycol) dimethyl ether, PEO, were described as a function of PEO chain size by molecular dynamics simulations. Both PEO chain size and mixture composition revealed to play a significant role in determining the structure and the dynamics of the fluids. The remarkably higher viscosity observed for mixtures composed by 0.25 mole fraction of PEO was attributed to the increase in the gauche population of OCCO dihedral of the polyether of longer chains. The negative solvation enthalpy (DeltasolH < 0) and entropy (DeltasolS < 0) revealed a favorable CO2 absorption by the neat and mixture systems. The CO2 absorption was higher in neat PEO, particularly considering longer chains. The gas solubility in the mixtures presented intermediate values in comparison to the neat PEO and neat ionic liquid. The CO2 solutions had their structures discussed in the light of the calculated radial and spatial distribution functions. PMID- 29626877 TI - Comment on "The putative liquid-liquid transition is a liquid-solid transition in atomistic models of water" [I and II: J. Chem. Phys. 135, 134503 (2011); J. Chem. Phys. 138, 214504 (2013)]. PMID- 29626879 TI - Effective diffusion coefficient including the Marangoni effect. AB - Surface-active molecules supplied from a particle fixed at the water surface create a spatial gradient of the molecule concentration, resulting in Marangoni convection. Convective flow transports the molecules far from the particle, enhancing diffusion. We analytically derive the effective diffusion coefficient associated with the Marangoni convection rolls. The resulting estimated effective diffusion coefficient is consistent with our numerical results and the apparent diffusion coefficient measured in experiments. PMID- 29626878 TI - Energy transfer mechanisms in layered 2D perovskites. AB - Two-dimensional (2D) perovskite quantum wells are generating broad scientific interest because of their potential for use in optoelectronic devices. Recently, it has been shown that layers of 2D perovskites can be grown in which the average thicknesses of the quantum wells increase from the back to the front of the film. This geometry carries implications for light harvesting applications because the bandgap of a quantum well decreases as its thickness increases. The general structural formula for the 2D perovskite systems under investigation in this work is (PEA)2(MA)n-1[PbnI3n+1] (PEA = phenethyl ammonium, MA = methyl ammonium). Here, we examine two layered 2D perovskites with different distributions of quantum well thicknesses. Spectroscopic measurements and model calculations suggest that both systems funnel electronic excitations from the back to the front of the film through energy transfer mechanisms on the time scales of 100's of ps (i.e., energy transfer from thinner to thicker quantum wells). In addition, the model calculations demonstrate that the transient absorption spectra are composed of a progression of single exciton and biexciton resonances associated with the individual quantum wells. We find that exciton dissociation and/or charge transport dynamics make only minor contributions to the transient absorption spectra within the first 1 ns after photo-excitation. An analysis of the energy transfer kinetics indicates that the transitions occur primarily between quantum wells with values of n that differ by 1 because of the spectral overlap factor that governs the energy transfer rate. Two-dimensional transient absorption spectra reveal a pattern of resonances consistent with the dominance of sequential energy transfer dynamics. PMID- 29626880 TI - Inhomogeneity induced and appropriately parameterized semilocal exchange and correlation energy functionals in two-dimensions. AB - The construction of meta generalized gradient approximations based on the density matrix expansion (DME) is considered as one of the most accurate techniques to design semilocal exchange energy functionals in two-dimensional density functional formalism. The exchange holes modeled using DME possess unique features that make it a superior entity. Parameterized semilocal exchange energy functionals based on the DME are proposed. The use of different forms of the momentum and flexible parameters is to subsume the non-uniform effects of the density in the newly constructed semilocal functionals. In addition to the exchange functionals, a suitable correlation functional is also constructed by working upon the local correlation functional developed for 2D homogeneous electron gas. The non-local effects are induced into the correlation functional by a parametric form of one of the newly constructed exchange energy functionals. The proposed functionals are applied to the parabolic quantum dots with a varying number of confined electrons and the confinement strength. The results obtained with the aforementioned functionals are quite satisfactory, which indicates why these are suitable for two-dimensional quantum systems. PMID- 29626881 TI - Ground states of linear rotor chains via the density matrix renormalization group. AB - In recent years, experimental techniques have enabled the creation of ultracold optical lattices of molecules and endofullerene peapod nanomolecular assemblies. It was previously suggested that the rotor model resulting from the placement of dipolar linear rotors in one-dimensional lattices at low temperature has a transition between ordered and disordered phases. We use the density matrix renormalization group (DMRG) to compute ground states of chains of up to 100 rotors and provide further evidence of the phase transition in the form of a diverging entanglement entropy. We also propose two methods and present some first steps toward rotational spectra of such molecular assemblies using DMRG. The present work showcases the power of DMRG in this new context of interacting molecular rotors and opens the door to the study of fundamental questions regarding criticality in systems with continuous degrees of freedom. PMID- 29626882 TI - Swimming trajectories of a three-sphere microswimmer near a wall. AB - The hydrodynamic flow field generated by self-propelled active particles and swimming microorganisms is strongly altered by the presence of nearby boundaries in a viscous flow. Using a simple model three-linked sphere swimmer, we show that the swimming trajectories near a no-slip wall reveal various scenarios of motion depending on the initial orientation and the distance separating the swimmer from the wall. We find that the swimmer can either be trapped by the wall, completely escape, or perform an oscillatory gliding motion at a constant mean height above the wall. Using a far-field approximation, we find that, at leading order, the wall-induced correction has a source-dipolar or quadrupolar flow structure where the translational and angular velocities of the swimmer decay as inverse third and fourth powers with distance from the wall, respectively. The resulting equations of motion for the trajectories and the relevant order parameters fully characterize the transition between the states and allow for an accurate description of the swimming behavior near a wall. We demonstrate that the transition between the trapping and oscillatory gliding states is first order discontinuous, whereas the transition between the trapping and escaping states is continuous, characterized by non-trivial scaling exponents of the order parameters. In order to model the circular motion of flagellated bacteria near solid interfaces, we further assume that the spheres can undergo rotational motion around the swimming axis. We show that the general three-dimensional motion can be mapped onto a quasi-two-dimensional representational model by an appropriate redefinition of the order parameters governing the transition between the swimming states. PMID- 29626883 TI - Nonlinear optical response of a gold surface in the visible range: A study by two color sum-frequency generation spectroscopy. I. Experimental determination. AB - We experimentally determine the effective nonlinear second-order susceptibility of gold over the visible spectral range. To reach that goal, we probe by vibrational two-color sum-frequency generation spectroscopy the methyl stretching region of a dodecanethiol self-assembled monolayer adsorbed on a gold film. The sum-frequency generation spectra show a remarkable shape reversal when the visible probe wavelength is tuned from 435 to 705 nm. After correcting from Fresnel effects, the methyl stretching vibrations serve as an internal reference, allowing to extract the dispersion of the absolute phase and relative amplitude of the effective nonlinear optical response of gold in the visible range. PMID- 29626884 TI - Fate of the open-shell singlet ground state in the experimentally accessible acenes: A quantum Monte Carlo study. AB - By means of the Jastrow correlated antisymmetrized geminal power (JAGP) wave function and quantum Monte Carlo (QMC) methods, we study the ground state properties of the oligoacene series, up to the nonacene. The JAGP is the accurate variational realization of the resonating-valence-bond (RVB) ansatz proposed by Pauling and Wheland to describe aromatic compounds. We show that the long-ranged RVB correlations built in the acenes' ground state are detrimental for the occurrence of open-shell diradical or polyradical instabilities, previously found by lower-level theories. We substantiate our outcome by a direct comparison with another wave function, tailored to be an open-shell singlet (OSS) for long-enough acenes. By comparing on the same footing the RVB and OSS wave functions, both optimized at a variational QMC level and further projected by the lattice regularized diffusion Monte Carlo method, we prove that the RVB wave function has always a lower variational energy and better nodes than the OSS, for all molecular species considered in this work. The entangled multi-reference RVB state acts against the electron edge localization implied by the OSS wave function and weakens the diradical tendency for higher oligoacenes. These properties are reflected by several descriptors, including wave function parameters, bond length alternation, aromatic indices, and spin-spin correlation functions. In this context, we propose a new aromatic index estimator suitable for geminal wave functions. For the largest acenes taken into account, the long range decay of the charge-charge correlation functions is compatible with a quasi metallic behavior. PMID- 29626885 TI - Dissociation dynamics of 3- and 4-nitrotoluene radical cations: Coherently driven C-NO2 bond homolysis. AB - Monosubstituted nitrotoluenes serve as important model compounds for nitroaromatic energetic molecules such as trinitrotoluene. This work investigates the ultrafast nuclear dynamics of 3- and 4-nitrotoluene radical cations using femtosecond pump-probe measurements and the results of density functional theory calculations. Strong-field adiabatic ionization of 3- and 4-nitrotoluene using 1500 nm, 18 fs pulses produces radical cations in the ground electronic state with distinct coherent vibrational excitations. In both nitrotoluene isomers, a one-photon excitation with the probe pulse results in NO2 loss to form C7H7+, which exhibits out-of-phase oscillations in yield with the parent molecular ion. The oscillations in 4-nitrotoluene with a period of 470 fs are attributed to the torsional motion of the NO2 group based on theoretical results showing that the dominant relaxation pathway in 4-nitrotoluene radical cations involves the rotation of the NO2 group away from the planar geometry. The distinctly faster oscillation period of 216 fs in 3-nitrotoluene is attributed to an in-plane bending motion of the NO2 and CH3 moieties based on analysis of the normal modes. These results demonstrate that coherent nuclear motions determine the probability of C-NO2 homolysis in the nitrotoluene radical cations upon optical excitation within several hundred femtoseconds of the initial ionization event. PMID- 29626886 TI - Committor of elementary reactions on multistate systems. AB - In our study, we extend the committor concept on multi-minima systems, where more than one reaction may proceed, but the feasible data evaluation needs the projection onto partial reactions. The elementary reaction committor and the corresponding probability density of the reactive trajectories are defined and calculated on a three-hole two-dimensional model system explored by single particle Langevin dynamics. We propose a method to visualize more elementary reaction committor functions or probability densities of reactive trajectories on a single plot that helps to identify the most important reaction channels and the nonreactive domains simultaneously. We suggest a weighting for the energy committor plots that correctly shows the limits of both the minimal energy path and the average energy concepts. The methods also performed well on the analysis of molecular dynamics trajectories of 2-chlorobutane, where an elementary reaction committor, the probability densities, the potential energy/committor, and the free-energy/committor curves are presented. PMID- 29626887 TI - Vibrational tug-of-war: The pKA dependence of the broad vibrational features of strongly hydrogen-bonded carboxylic acids. AB - Medium and strong hydrogen bonds give rise to broad vibrational features frequently spanning several hundred wavenumbers and oftentimes exhibiting unusual substructures. These broad vibrational features can be modeled from first principles, in a reduced dimensional calculation, that adiabatically separates low-frequency modes, which modulate the hydrogen bond length, from high-frequency OH stretch and bend modes that contribute to the vibrational structure. Previously this method was used to investigate the origin of an unusual vibrational feature frequently found in the spectra of dimers between carboxylic acids and nitrogen-containing aromatic bases that spans over 900 cm-1 and contains two broad peaks. It was found that the width of this feature largely originates from low-frequency modes modulating the hydrogen bond length and that the structure results from Fermi resonance interactions. In this report, we examine how these features change with the relative acid and base strength of the components as reflected by their aqueous pKA values. Dimers with large pKA differences are found to have features that can extend to frequencies below 1000 cm-1. The relationships between mean OH/NH frequency, aqueous pKA, and O-N distance are examined in order to obtain a more rigorous understanding of the origin and shape of the vibrational features. The mean OH/NH frequencies are found to correlate well with O-N distances. The lowest OH stretch frequencies are found in dimer geometries with O-N distances between 2.5 and 2.6 A. At larger O-N distances, the hydrogen bonding interaction is not as strong, resulting in higher OH stretch frequencies. When the O-N distance is smaller than 2.5 A, the limited space between the O and N determines the OH stretch frequency, which gives rise to frequencies that decrease with O-N distances. These two effects place a lower limit on the OH stretch frequency which is calculated to be near 700 cm-1. Understanding how the vibrational features of strongly hydrogen-bonded structures depend on the relative pKA and other structural parameters will guide studies of biological structures and analysis of proton transfer studies using photoacids. PMID- 29626888 TI - Transient dynamics of a quantum-dot: From Kondo regime to mixed valence and to empty orbital regimes. AB - Based on the hierarchical equations of motion approach, we study the time dependent transport properties of a strongly correlated quantum dot system in the Kondo regime (KR), mixed valence regime (MVR), and empty orbital regime (EOR). We find that the transient current in KR shows the strongest nonlinear response and the most distinct oscillation behaviors. Both behaviors become weaker in MVR and diminish in EOR. To understand the physical insight, we examine also the corresponding dot occupancies and the spectral functions, with their dependence on the Coulomb interaction, temperature, and applied step bias voltage. The above nonlinear and oscillation behaviors could be understood as the interplay between dynamical Kondo resonance and single electron resonant-tunneling. PMID- 29626889 TI - Molecular dynamics analysis of the influence of Coulomb and van der Waals interactions on the work of adhesion at the solid-liquid interface. AB - We investigated the solid-liquid work of adhesion of water on a model silica surface by molecular dynamics simulations, where a methodology previously developed to determine the work of adhesion through thermodynamic integration was extended to a system with long-range electrostatic interactions between solid and liquid. In agreement with previous studies, the work of adhesion increased when the magnitude of the surface polarity was increased. On the other hand, we found that when comparing two systems with and without solid-liquid electrostatic interactions, which were set to have approximately the same total solid-liquid interfacial energy, former had a significantly smaller work of adhesion and a broader distribution in the interfacial energies, which has not been previously reported in detail. This was explained by the entropy contribution to the adhesion free energy; i.e., the former with a broader energy distribution had a larger interfacial entropy than the latter. While the entropy contribution to the work of adhesion has already been known, as a work of adhesion itself is free energy, these results indicate that, contrary to common belief, wetting behavior such as the contact angle is not only governed by the interfacial energy but also significantly affected by the interfacial entropy. Finally, a new interpretation of interfacial entropy in the context of solid-liquid energy variance was offered, from which a fast way to qualitatively estimate the work of adhesion was also presented. PMID- 29626890 TI - Electron transfer driven decomposition of adenine and selected analogs as probed by experimental and theoretical methods. AB - We report on a combined experimental and theoretical study of electron-transfer induced decomposition of adenine (Ad) and a selection of analog molecules in collisions with potassium (K) atoms. Time-of-flight negative ion mass spectra have been obtained in a wide collision energy range (6-68 eV in the centre-of mass frame), providing a comprehensive investigation of the fragmentation patterns of purine (Pu), adenine (Ad), 9-methyl adenine (9-mAd), 6-dimethyl adenine (6-dimAd), and 2-D adenine (2-DAd). Following our recent communication about selective hydrogen loss from the transient negative ions (TNIs) produced in these collisions [T. Cunha et al., J. Chem. Phys. 148, 021101 (2018)], this work focuses on the production of smaller fragment anions. In the low-energy part of the present range, several dissociation channels that are accessible in free electron attachment experiments are absent from the present mass spectra, notably NH2 loss from adenine and 9-methyl adenine. This can be understood in terms of a relatively long transit time of the K+ cation in the vicinity of the TNI tending to enhance the likelihood of intramolecular electron transfer. In this case, the excess energy can be redistributed through the available degrees of freedom inhibiting fragmentation pathways. Ab initio theoretical calculations were performed for 9-methyl adenine (9-mAd) and adenine (Ad) in the presence of a potassium atom and provided a strong basis for the assignment of the lowest unoccupied molecular orbitals accessed in the collision process. PMID- 29626891 TI - Dynamic signatures of the transition from stacking disordered to hexagonal ice: Dielectric and nuclear magnetic resonance studies. AB - Using various temperature-cycling protocols, the dynamics of ice I were studied via dielectric spectroscopy and nuclear magnetic resonance relaxometry on protonated and deuterated samples obtained by heating high-density amorphous ices as well as crystalline ice XII. Previous structural studies of ice I established that at temperatures of about 230 K, the stacking disorder of the cubic/hexagonal oxygen lattice vanishes. The present dielectric and nuclear magnetic resonance investigations of spectral changes disclose that the memory of the existence of a precursor phase is preserved in the hydrogen matrix up to 270 K. This finding of hydrogen mobility lower than that of the undoped hexagonal ice near the melting point highlights the importance of dynamical investigations of the transitions between various ice phases and sheds new light on the dynamics in ice I in general. PMID- 29626892 TI - A pair natural orbital based implementation of CCSD excitation energies within the framework of linear response theory. AB - We present a pair natural orbital (PNO)-based implementation of coupled cluster singles and doubles (CCSD) excitation energies that builds upon the previously proposed state-specific PNO approach to the excited state eigenvalue problem. We construct the excited state PNOs for each state separately in a truncated orbital specific virtual basis and use a local density-fitting approximation to achieve an at most quadratic scaling of the computational costs for the PNO construction. The earlier reported excited state PNO construction is generalized such that a smooth convergence of the results for charge transfer states is ensured for general coupled cluster methods. We investigate the accuracy of our implementation by applying it to a large and diverse test set comprising 153 singlet excitations in organic molecules. Already moderate PNO thresholds yield mean absolute errors below 0.01 eV. The performance of the implementation is investigated through the calculations on alkene chains and reveals an at most cubic cost-scaling for the CCSD iterations with the system size. PMID- 29626893 TI - Multi-scale coarse-graining for the study of assembly pathways in DNA-brick self assembly. AB - Inspired by recent successes using single-stranded DNA tiles to produce complex structures, we develop a two-step coarse-graining approach that uses detailed thermodynamic calculations with oxDNA, a nucleotide-based model of DNA, to parametrize a coarser kinetic model that can reach the time and length scales needed to study the assembly mechanisms of these structures. We test the model by performing a detailed study of the assembly pathways for a two-dimensional target structure made up of 334 unique strands each of which are 42 nucleotides long. Without adjustable parameters, the model reproduces a critical temperature for the formation of the assembly that is close to the temperature at which assembly first occurs in experiments. Furthermore, the model allows us to investigate in detail the nucleation barriers and the distribution of critical nucleus shapes for the assembly of a single target structure. The assembly intermediates are compact and highly connected (although not maximally so), and classical nucleation theory provides a good fit to the height and shape of the nucleation barrier at temperatures close to where assembly first occurs. PMID- 29626894 TI - Time-resolved photoion imaging spectroscopy: Determining energy distribution in multiphoton absorption experiments. AB - We propose an approach to determine the excitation energy distribution due to multiphoton absorption in the case of excited systems following decays to produce different ion species. This approach is based on the measurement of the time resolved photoion position spectrum by using velocity map imaging spectrometry and an unfocused laser beam with a low fluence and homogeneous profile. Such a measurement allows us to identify the species and the origin of each ion detected and to depict the energy distribution using a pure Poisson's equation involving only one variable which is proportional to the absolute photon absorption cross section. A cascade decay model is used to build direct connections between the energy distribution and the probability to detect each ionic species. Comparison between experiments and simulations permits the energy distribution and accordingly the absolute photon absorption cross section to be determined. This approach is illustrated using C60 as an example. It may therefore be extended to a wide variety of molecules and clusters having decay mechanisms similar to those of fullerene molecules. PMID- 29626895 TI - MCTDH on-the-fly: Efficient grid-based quantum dynamics without pre-computed potential energy surfaces. AB - We present significant algorithmic improvements to a recently proposed direct quantum dynamics method, based upon combining well established grid-based quantum dynamics approaches and expansions of the potential energy operator in terms of a weighted sum of Gaussian functions. Specifically, using a sum of low-dimensional Gaussian functions to represent the potential energy surface (PES), combined with a secondary fitting of the PES using singular value decomposition, we show how standard grid-based quantum dynamics methods can be dramatically accelerated without loss of accuracy. This is demonstrated by on-the-fly simulations (using both standard grid-based methods and multi-configuration time-dependent Hartree) of both proton transfer on the electronic ground state of salicylaldimine and the non-adiabatic dynamics of pyrazine. PMID- 29626896 TI - A walk through the approximations of ab initio multiple spawning. AB - Full multiple spawning offers an in principle exact framework for excited-state dynamics, where nuclear wavefunctions in different electronic states are represented by a set of coupled trajectory basis functions that follow classical trajectories. The couplings between trajectory basis functions can be approximated to treat molecular systems, leading to the ab initio multiple spawning method which has been successfully employed to study the photochemistry and photophysics of several molecules. However, a detailed investigation of its approximations and their consequences is currently missing in the literature. In this work, we simulate the explicit photoexcitation and subsequent excited-state dynamics of a simple system, LiH, and we analyze (i) the effect of the ab initio multiple spawning approximations on different observables and (ii) the convergence of the ab initio multiple spawning results towards numerically exact quantum dynamics upon a progressive relaxation of these approximations. We show that, despite the crude character of the approximations underlying ab initio multiple spawning for this low-dimensional system, the qualitative excited-state dynamics is adequately captured, and affordable corrections can further be applied to ameliorate the coupling between trajectory basis functions. PMID- 29626897 TI - Effects of dielectric inhomogeneity on electrostatic twist rigidity of a helical biomolecule in Debye-Huckel regime. AB - The electrostatic interactions play a crucial role in biological systems. Here we consider an impermeable dielectric molecule in the solvent with a different dielectric constant. The electrostatic free energy in the problem is studied in the Debye-Huckel regime using the analytical Green function that is calculated in the paper. Using this electrostatic free energy, we study the electrostatic contribution to the twist rigidity of a double stranded helical molecule such as a DNA and an actin filament. The dependence of the electrostatic twist rigidity of the molecule to the dielectric inhomogeneity, structural parameters, and the salt concentration is studied. It is shown that, depending on the parameters, the electrostatic twist rigidity could be positive or negative. PMID- 29626898 TI - Rotaxane liquid crystals with variable length: The effect of switching efficiency on the isotropic-nematic transition. AB - We examine a solution of non-adaptive two-state rotaxane molecules which can switch from a short state of length L to a long state of length qL, using statistical thermodynamics. This molecular switching is externally driven and can result in an isotropic-nematic phase transition without altering temperature and concentration. Here we concentrate on the limitation imposed by switching inefficiency, i.e., on the case where molecular switching is not quantitative, leading to a solution of rotaxanes in different states. We present switching diagrams that can guide in the design of rotaxanes which affect a macroscopic phase change. PMID- 29626899 TI - Bizarre behavior of heat capacity in crystals due to interplay between two types of anharmonicities. AB - The heat capacity of classical crystals is determined by the Dulong-Petit value CV ? D (where D is the spatial dimension) for softly interacting particles and has the gas-like value CV ? D/2 in the hard-sphere limit, while deviations are governed by the effects of anharmonicity. Soft- and hard-sphere interactions, which are associated with the enthalpy and entropy of crystals, are specifically anharmonic owing to violation of a linear relation between particle displacements and corresponding restoring forces. Here, we show that the interplay between these two types of anharmonicities unexpectedly induces two possible types of heat capacity anomalies. We studied thermodynamics, pair correlations, and collective excitations in 2D and 3D crystals of particles with a limited range of soft repulsions to prove the effect of interplay between the enthalpy and entropy types of anharmonicities. The observed anomalies are triggered by the density of the crystal, changing the interaction regime in the zero-temperature limit, and can provide about 10% excess of the heat capacity above the Dulong-Petit value. Our results facilitate understanding effects of complex anharmonicity in molecular and complex crystals and demonstrate the possibility of new effects due to the interplay between different types of anharmonicities. PMID- 29626900 TI - Linear response coupled cluster theory with the polarizable continuum model within the singles approximation for the solvent response. AB - We report the theory and the implementation of the linear response function of the coupled cluster (CC) with the single and double excitations method combined with the polarizable continuum model of solvation, where the correlation solvent response is approximated with the perturbation theory with energy and singles density (PTES) scheme. The singles name is derived from retaining only the contribution of the CC single excitation amplitudes to the correlation density. We compare the PTES working equations with those of the full-density (PTED) method. We then test the PTES scheme on the evaluation of excitation energies and transition dipoles of solvated molecules, as well as of the isotropic polarizability and specific rotation. Our results show a negligible difference between the PTED and PTES schemes, while the latter affords a significantly reduced computational cost. This scheme is general and can be applied to any solvation model that includes mutual solute-solvent polarization, including explicit models. Therefore, the PTES scheme is a competitive approach to compute response properties of solvated systems using CC methods. PMID- 29626901 TI - Transformation of hydrazinium azide to molecular N8 at 40 GPa. AB - Hydrazinium azide (HA) has been investigated at high pressures to 68 GPa using confocal micro-Raman spectroscopy and synchrotron powder x-ray diffraction. The results show that HA undergoes structural phase transitions from solid HA-I to HA II at 13 GPa, associated with the strengthening of hydrogen bonding, and then to N8 at 40 GPa. The transformation of HA to recently predicted N8 (N=N+-N--N=N--N +N=N) is evident by the emergence of new peaks at 2384 cm-1, 1665 cm-1, and 1165 cm-1, arising from the terminal N=N stretching, the central N=N stretching, and the N-N stretching, respectively. However, upon decompression, N8 decomposes to epsilon-N2 below 25 GPa, but the remnant can be seen as low as 3 GPa. PMID- 29626902 TI - On the solvation of the phosphocholine headgroup in an aqueous propylene glycol solution. AB - The atomic-scale structure of the phosphocholine (PC) headgroup in 30 mol. % propylene glycol (PG) in an aqueous solution has been investigated using a combination of neutron diffraction with isotopic substitution experiments and computer simulation techniques-molecular dynamics and empirical potential structure refinement. Here, the hydration of the PC headgroup remains largely intact compared with the hydration of this group in a bilayer and in a bulk water solution, with the PG molecules showing limited interactions with the headgroup. When direct PG interactions with PC do occur, they are most likely to coordinate to the N(CH3)3+ motifs. Further, PG does not affect the bulk water structure and the addition of PC does not perturb the PG-solvent interactions. This suggests that the reason why PG is able to penetrate into membranes easily is that it does not form strong-hydrogen bonding or electrostatic interactions with the headgroup allowing it to easily move across the membrane barrier. PMID- 29626903 TI - Computational prediction of muon stopping sites using ab initio random structure searching (AIRSS). AB - The stopping site of the muon in a muon-spin relaxation experiment is in general unknown. There are some techniques that can be used to guess the muon stopping site, but they often rely on approximations and are not generally applicable to all cases. In this work, we propose a purely theoretical method to predict muon stopping sites in crystalline materials from first principles. The method is based on a combination of ab initio calculations, random structure searching, and machine learning, and it has successfully predicted the MuT and MuBC stopping sites of muonium in Si, diamond, and Ge, as well as the muonium stopping site in LiF, without any recourse to experimental results. The method makes use of Soprano, a Python library developed to aid ab initio computational crystallography, that was publicly released and contains all the software tools necessary to reproduce our analysis. PMID- 29626904 TI - Anomalous van der Waals-Casimir interactions on graphene: A concerted effect of temperature, retardation, and non-locality. AB - Dispersion forces play a major role in graphene, largely influencing adhesion of adsorbate moieties and stabilization of functional multilayered structures. However, the reliable prediction of dispersion interactions on graphene up to the relevant ~10 nm scale is an extremely challenging task: in fact, electromagnetic retardation effects and the highly non-local character of pi electrons can imply sizeable qualitative variations of the interaction with respect to known pairwise approaches. Here we address both issues, determining the finite-temperature van der Waals (vdW)-Casimir interaction for point-like and extended adsorbates on graphene, explicitly accounting for the non-local dielectric permittivity. We find that temperature, retardation, and non-locality play a crucial role in determining the actual vdW scaling laws and the stability of both atomic and larger molecular adsorbates. Our results highlight the importance of these effects for a proper description of systems of current high interest, such as graphene interacting with biomolecules, and self-assembly of complex nanoscale structures. Due to the generality of our approach and the observed non-locality of other 2D materials, our results suggest non-trivial vdW interactions from hexagonal mono-layered materials from group 14 of the periodic table, to transition metal dichalcogenides. PMID- 29626905 TI - Communication: Fast dynamics perspective on the breakdown of the Stokes-Einstein law in fragile glassformers. AB - The breakdown of the Stokes-Einstein (SE) law in fragile glassformers is examined by Molecular-Dynamics simulations of atomic liquids and polymers and consideration of the experimental data concerning the archetypical ortho terphenyl glassformer. All the four systems comply with the universal scaling between the viscosity (or the structural relaxation) and the Debye-Waller factor ?u2?, the mean square amplitude of the particle rattling in the cage formed by the surrounding neighbors. It is found that the SE breakdown is scaled in a master curve by a reduced ?u2?. Two approximated expressions of the latter, with no and one adjustable parameter, respectively, are derived. PMID- 29626906 TI - Lipid-protein interaction induced domains: Kinetics and conformational changes in multicomponent vesicles. AB - The spatio-temporal organization of proteins and the associated morphological changes in membranes are of importance in cell signaling. Several mechanisms that promote the aggregation of proteins at low cell surface concentrations have been investigated in the past. We show, using Monte Carlo simulations, that the affinity of proteins for specific lipids can hasten their aggregation kinetics. The lipid membrane is modeled as a dynamically triangulated surface with the proteins defined as in-plane fields at the vertices. We show that, even at low protein concentrations, strong lipid-protein interactions can result in large protein clusters indicating a route to lipid mediated signal amplification. At high protein concentrations, the domains form buds similar to that seen in lipid lipid interaction induced phase separation. Protein interaction induced domain budding is suppressed when proteins act as anisotropic inclusions and exhibit nematic orientational order. The kinetics of protein clustering and resulting conformational changes are shown to be significantly different for the isotropic and anisotropic curvature inducing proteins. PMID- 29626907 TI - QED effects on individual atomic orbital energies. AB - Several issues, concerning QED corrections, that are important in precise atomic calculations are presented. The leading QED corrections, self-energy and vacuum polarization, to the orbital energy for selected atoms with 30 <= Z <= 118 have been calculated. The sum of QED and Breit contributions to the orbital energy is analyzed. It has been found that for ns subshells the Breit and QED contributions are of comparative size, but for np and nd subshells the Breit contribution takes a major part of the QED+Breit sum. It has also, been found that the Breit to leading QED contributions ratio for ns subshells is almost independent of Z. The Z-dependence of QED and Breit+QED contributions per subshell is shown. The fitting coefficients may be used to estimate QED effects on inner molecular orbitals. We present results of our calculations for QED contributions to orbital energy of valence ns-subshell for group 1 and 11 atoms and discuss about the reliability of these numbers by comparing them with experimental first ionization potential data. PMID- 29626908 TI - Assessment of interaction-strength interpolation formulas for gold and silver clusters. AB - The performance of functionals based on the idea of interpolating between the weak- and the strong-interaction limits the global adiabatic-connection integrand is carefully studied for the challenging case of noble-metal clusters. Different interpolation formulas are considered and various features of this approach are analyzed. It is found that these functionals, when used as a correlation correction to Hartree-Fock, are quite robust for the description of atomization energies, while performing less well for ionization potentials. Future directions that can be envisaged from this study and a previous one on main group chemistry are discussed. PMID- 29626909 TI - Probing the CZTS/CdS heterojunction utilizing photoelectrochemistry and x-ray absorption spectroscopy. AB - The importance of renewable resources is becoming more and more influential on research due to the depletion of fossil fuels. Cost-effective ways of harvesting solar energy should also be at the forefront of these investigations. Cu2ZnSnS4 (CZTS) solar cells are well within the frame of these goals, and a thorough understanding of how they are made and processed synthetically is crucial. The CZTS/CdS heterojunction was examined using photoelectrochemistry and synchrotron radiation (SR) spectroscopy. These tools provided physical insights into this interface that was formed by the electrophoretic deposition of CZTS nanocrystals and chemical bath deposition (CBD) of CdS for the respective films. It was discovered that CBD induced a change in the local and long range environment of the Zn in the CZTS lattice, which was detrimental to the photoresponse. X-ray absorption near-edge structures and extended X-ray absorption fine structures (EXAFSs) of the junction showed that this change was at an atomic level and was associated with the coordination of oxygen to zinc. This was confirmed through FEFF fitting of the EXAFS and through IR spectroscopy. It was found that this change in both photoresponse and the Zn coordination can be reversed with the use of low temperature annealing. Investigating CZTS through SR techniques provides detailed structural information of minor changes from the zinc perspective. PMID- 29626910 TI - Short- and long-time diffusion and dynamic scaling in suspensions of charged colloidal particles. AB - We report on a comprehensive theory-simulation-experimental study of collective and self-diffusion in concentrated suspensions of charge-stabilized colloidal spheres. In theory and simulation, the spheres are assumed to interact directly by a hard-core plus screened Coulomb effective pair potential. The intermediate scattering function, fc(q, t), is calculated by elaborate accelerated Stokesian dynamics (ASD) simulations for Brownian systems where many-particle hydrodynamic interactions (HIs) are fully accounted for, using a novel extrapolation scheme to a macroscopically large system size valid for all correlation times. The study spans the correlation time range from the colloidal short-time to the long-time regime. Additionally, Brownian Dynamics (BD) simulation and mode-coupling theory (MCT) results of fc(q, t) are generated where HIs are neglected. Using these results, the influence of HIs on collective and self-diffusion and the accuracy of the MCT method are quantified. It is shown that HIs enhance collective and self-diffusion at intermediate and long times. At short times self-diffusion, and for wavenumbers outside the structure factor peak region also collective diffusion, are slowed down by HIs. MCT significantly overestimates the slowing influence of dynamic particle caging. The dynamic scattering functions obtained in the ASD simulations are in overall good agreement with our dynamic light scattering (DLS) results for a concentration series of charged silica spheres in an organic solvent mixture, in the experimental time window and wavenumber range. From the simulation data for the time derivative of the width function associated with fc(q, t), there is indication of long-time exponential decay of fc(q, t), for wavenumbers around the location of the static structure factor principal peak. The experimental scattering functions in the probed time range are consistent with a time-wavenumber factorization scaling behavior of fc(q, t) that was first reported by Segre and Pusey [Phys. Rev. Lett. 77, 771 (1996)] for suspensions of hard spheres. Our BD simulation and MCT results predict a significant violation of exact factorization scaling which, however, is approximately restored according to the ASD results when HIs are accounted for, consistent with the experimental findings for fc(q, t). Our study of collective diffusion is amended by simulation and theoretical results for the self intermediate scattering function, fs(q, t), and its non-Gaussian parameter alpha2(t) and for the particle mean squared displacement W(t) and its time derivative. Since self-diffusion properties are not assessed in standard DLS measurements, a method to deduce W(t) approximately from fc(q, t) is theoretically validated. PMID- 29626912 TI - Expanding the calculation of activation volumes: Self-diffusion in liquid water. AB - A general method for calculating the dependence of dynamical time scales on macroscopic thermodynamic variables from a single set of simulations is presented. The approach is applied to the pressure dependence of the self diffusion coefficient of liquid water as a particularly useful illustration. It is shown how the activation volume associated with diffusion can be obtained directly from simulations at a single pressure, avoiding approximations that are typically invoked. PMID- 29626911 TI - Structure and dynamics of propylammonium nitrate-acetonitrile mixtures: An intricate multi-scale system probed with experimental and theoretical techniques. AB - In this article, we report the study of structural and dynamical properties for a series of acetonitrile/propylammonium nitrate mixtures as a function of their composition. These systems display an unusual increase in intensity in their X ray diffraction patterns in the low-q regime, and their 1H-NMR diffusion-ordered NMR spectroscopy (DOSY) spectra display unusual diffusivities. However, the magnitude of both phenomena for mixtures of propylammonium nitrate is smaller than those observed for ethylammonium nitrate mixtures with the same cosolvent, suggesting that the cation alkyl tail plays an important role in these observations. The experimental X-ray scattering data are compared with the results of molecular dynamics simulations, including both ab initio studies used to interpret short-range interactions and classical simulations to describe longer range interactions. The higher level calculations highlight the presence of a strong hydrogen bond network within the ionic liquid, only slightly perturbed even at high acetonitrile concentration. These strong interactions lead to the symmetry breaking of the NO3- vibrations, with a splitting of about 88 cm 1 in the nu3 antisymmetric stretch. The classical force field simulations use a greater number of ion pairs, but are not capable of fully describing the longest range interactions, although they do successfully account for the observed concentration trend, and the analysis of the models confirms the nano inhomogeneity of these kinds of samples. PMID- 29626913 TI - Communication: Probing the interaction of infrared antenna arrays and molecular films with ultrafast quantum dynamics. AB - Narrowband vibrational molecular transitions interacting with the broadband resonance of infrared plasmonic antennas lead to Fano lineshapes observed in linear (FTIR) and third-order (transient absorption and 2DIR) spectroscopic experiments. Both molecular and plasmonic components are inherently dissipative, and the effects associated with their coupling can be observed, in principle, when measuring the corresponding ultrafast quantum dynamics. We used 2DIR spectroscopy to study the waiting time evolution of quantum coherence excited in the carbonyl stretching modes of rhodium (acetylacetonato) dicarbonyl molecules, which were embedded in an 80 nm-thick polymer film spin-coated on an array of infrared half-wavelength gold antennas. Despite the pronounced Fano lineshapes obtained for the molecular transitions, and up to a four order of magnitude enhancement of the third-order signals, which taken together, indicate the coupling between the plasmonic and molecular transitions, the dynamics of the quantum coherence were identical to that obtained with 3 MUm-thick film without the interaction with the plamson mode. This suggests that the coupling rate between the molecular and plasmonic excitations is significantly smaller than the relaxation rates of the molecular excitations monitored in the experiment. Here, the Fano lineshape, observed at the frequency of the molecular transition, can result from the mutual radiation damping of the molecular and plasmon modes. PMID- 29626914 TI - Active and passive transport of cargo in a corrugated channel: A lattice model study. AB - Inside cells, cargos such as vesicles and organelles are transported by molecular motors to their correct locations via active motion on cytoskeletal tracks and passive, Brownian diffusion. During the transportation of cargos, motor-cargo complexes (MCCs) navigate the confining and crowded environment of the cytoskeletal network and other macromolecules. Motivated by this, we study a minimal two-state model of motor-driven cargo transport in confinement and predict transport properties that can be tested in experiments. We assume that the motion of the MCC is directly affected by the entropic barrier due to confinement if it is in the passive, unbound state but not in the active, bound state where it moves with a constant bound velocity. We construct a lattice model based on a Fokker Planck description of the two-state system, study it using a kinetic Monte Carlo method and compare our numerical results with analytical expressions for a mean field limit. We find that the effect of confinement strongly depends on the bound velocity and the binding kinetics of the MCC. Confinement effectively reduces the effective diffusivity and average velocity, except when it results in an enhanced average binding rate and thereby leads to a larger average velocity than when unconfined. PMID- 29626916 TI - Solitonic natural orbitals. AB - The dependence of the natural amplitudes of the harmonium atom in its ground state on the confinement strength omega is thoroughly investigated. A combination of rigorous analysis and extensive, highly accurate numerical calculations reveals the presence of only one positive-valued natural amplitude ("the normal sign pattern") for all omega>=12. More importantly, it is shown that unusual, weakly occupied natural orbitals (NOs) corresponding to additional positive valued natural amplitudes emerge upon sufficient weakening of the confinement. These solitonic NOs, whose shapes remain almost invariant as their radial positions drift toward infinity upon the critical values of omega being approached from below, exhibit strong radial localization. Their asymptotic properties are extracted from the numerical data and their relevance to calculations on fully Coulombic systems is discussed. PMID- 29626915 TI - New investigation of the nu3 C-H stretching region of 12CH4 through the analysis of high temperature infrared emission spectra. AB - The nu3 C-H stretching region of methane was reinvestigated in this work using high temperature (620-1715 K) emission spectra recorded in Rennes at Doppler limited resolution. This work follows our recent global analysis of the Dyad system Deltan = +/-1 (1000-1500 cm-1), with n being the polyad number [B. Amyay et al., J. Chem. Phys. 144, 24312 (2016)]. Thanks to the high temperature, new assignments of vibration-rotation methane line positions have been achieved successfully in the Pentad system and some associated hot bands (Deltan = +/-2) observed in the spectral region 2600-3300 cm-1. In particular, rotational assignments in the cold band [Pentad-ground state (GS)] and in the first related hot band (Octad-Dyad) were extended up to J = 30 and 27, respectively. In addition, 1525 new transitions belonging to the Tetradecad-Pentad hot band system were assigned for the first time, up to J = 20. The effective global model used to deal with the new assignments was developed to the 6th order for the first three polyads (Monad, Dyad, and Pentad), and to the 5th order for both the Octad and the Tetradecad. 1306 effective parameters were fitted with a dimensionless standard deviation sigma = 2.64. The root mean square deviations dRMS obtained are 4.18 * 10-3 cm-1 for the Pentad-GS cold band, 2.48 * 10-3 cm-1 for the Octad Dyad, and 1.43 * 10-3 cm-1 for the Tetradecad-Pentad hot bands. PMID- 29626917 TI - Structural-Functional Organization of the Eukaryotic Cell Nucleus and Transcription Regulation: Introduction to This Special Issue of Biochemistry (Moscow). AB - This issue of Biochemistry (Moscow) is devoted to the cell nucleus and mechanisms of transcription regulation. Over the years, biochemical processes in the cell nucleus have been studied in isolation, outside the context of their spatial organization. Now it is clear that segregation of functional processes within a compartmentalized cell nucleus is very important for the implementation of basic genetic processes. The functional compartmentalization of the cell nucleus is closely related to the spatial organization of the genome, which in turn plays a key role in the operation of epigenetic mechanisms. In this issue of Biochemistry (Moscow), we present a selection of review articles covering the functional architecture of the eukaryotic cell nucleus, the mechanisms of genome folding, the role of stochastic processes in establishing 3D architecture of the genome, and the impact of genome spatial organization on transcription regulation. PMID- 29626918 TI - Structural-Functional Domains of the Eukaryotic Genome. AB - It is well known that DNA folding in the eukaryotic cell nucleus is tightly coupled with the operation of epigenetic mechanisms defining the repertoires of the genes expressed in different types of cells. To understand these mechanisms, it is important to know how DNA is packaged in chromatin. About 30 years ago a hypothesis was formulated, according to which epigenetic mechanisms operate not at the level of individual genes, but rather groups of genes localized in structurally and functionally isolated genomic segments that were called structural and functional domains. The question of what exactly these domains constitute has been re-examined multiple times as our knowledge of principles of chromatin folding has changed. In this review, we discuss structural and functional genomic domains in light of the current model of interphase chromosome organization based on the results of analysis of spatial proximity between remote genomic elements. PMID- 29626919 TI - The 4D Nucleome: Genome Compartmentalization in an Evolutionary Context. AB - 4D nucleome research aims to understand the impact of nuclear organization in space and time on nuclear functions, such as gene expression patterns, chromatin replication, and the maintenance of genome integrity. In this review we describe evidence that the origin of 4D genome compartmentalization can be traced back to the prokaryotic world. In cell nuclei of animals and plants chromosomes occupy distinct territories, built up from ~1 Mb chromatin domains, which in turn are composed of smaller chromatin subdomains and also form larger chromatin domain clusters. Microscopic evidence for this higher order chromatin landscape was strengthened by chromosome conformation capture studies, in particular Hi-C. This approach demonstrated ~1 Mb sized, topologically associating domains in mammalian cell nuclei separated by boundaries. Mutations, which destroy boundaries, can result in developmental disorders and cancer. Nucleosomes appeared first as tetramers in the Archaea kingdom and later evolved to octamers built up each from two H2A, two H2B, two H3, and two H4 proteins. Notably, nucleosomes were lost during the evolution of the Dinoflagellata phylum. Dinoflagellate chromosomes remain condensed during the entire cell cycle, but their chromosome architecture differs radically from the architecture of other eukaryotes. In summary, the conservation of fundamental features of higher order chromatin arrangements throughout the evolution of metazoan animals suggests the existence of conserved, but still unknown mechanism(s) controlling this architecture. Notwithstanding this conservation, a comparison of metazoans and protists also demonstrates species-specific structural and functional features of nuclear organization. PMID- 29626920 TI - Crowding, Entropic Forces, and Confinement: Crucial Factors for Structures and Functions in the Cell Nucleus. AB - The view of the cell nucleus as a crowded system of colloid particles and that chromosomes are giant self-avoiding polymers is stimulating rapid advances in our understanding of its structure and activities, thanks to concepts and experimental methods from colloid, polymer, soft matter, and nano sciences and to increased computational power for simulating macromolecules and polymers. This review summarizes current understanding of some characteristics of the molecular environment in the nucleus, of how intranuclear compartments are formed, and of how the genome is highly but precisely compacted, and underlines the crucial, subtle, and sometimes unintuitive effects on structures and reactions of entropic forces caused by the high concentration of macromolecules in the nucleus. PMID- 29626921 TI - Banding Pattern of Polytene Chromosomes as a Representation of Universal Principles of Chromatin Organization into Topological Domains. AB - Drosophila polytene chromosomes are widely used as a model of eukaryotic interphase chromosomes. The most noticeable feature of polytene chromosome is transverse banding associated with alternation of dense stripes (dark or black bands) and light diffuse areas that encompass alternating less compact gray bands and interbands visible with an electron microscope. In recent years, several approaches have been developed to predict location of morphological structures of polytene chromosomes based on the distribution of proteins on the molecular map of Drosophila genome. Comparison of these structures with the results of analysis of the three-dimensional chromatin organization by the Hi-C method indicates that the morphology of polytene chromosomes represents direct visualization of the interphase nucleus spatial organization into topological domains. Compact black bands correspond to the extended topological domains of inactive chromatin, while interbands are the barriers between the adjacent domains. Here, we discuss the prospects of using polytene chromosomes to study mechanisms of spatial organization of interphase chromosomes, as well as their dynamics and evolution. PMID- 29626922 TI - The Role of Chromosome-Nuclear Envelope Attachments in 3D Genome Organization. AB - Chromosomes are intricately folded and packaged in the cell nucleus and interact with the nuclear envelope. This complex nuclear architecture has a profound effect on how the genome works and how the cells function. The main goal of review is to highlight recent studies on the effect of chromosome-nuclear envelope interactions on chromatin folding and function in the nucleus. The data obtained suggest that chromosome-nuclear envelope attachments are important for the organization of nuclear architecture in various organisms. A combination of experimental cell biology methods with computational modeling offers a unique opportunity to explore the fundamental relationships between different aspects of 3D genome organization in greater details. This powerful interdisciplinary approach could reveal how the organization and function of the genome in the nuclear space is affected by the chromosome-nuclear envelope attachments and will enable the development of novel approaches to regulate gene expression. PMID- 29626923 TI - Role of Nuclear Lamina in Gene Repression and Maintenance of Chromosome Architecture in the Nucleus. AB - Nuclear lamina is a protein meshwork composed of lamins and lamin-associated proteins that lines the nuclear envelope from the inside and forms repressive transcription compartment. The review presents current data on the contribution of nuclear lamina to the repression of genes located in this compartment and on the mechanisms of chromatin attachment to the nuclear envelope. PMID- 29626924 TI - Unsolvable Problems of Biology: It Is Impossible to Create Two Identical Organisms, to Defeat Cancer, or to Map Organisms onto Their Genomes. AB - The review is devoted to unsolvable problems of biology. 1) Problems unsolvable due to stochastic mutations occurring during DNA replication that make it impossible to create two identical organisms or even two identical complex cells (Sverdlov, E. D. (2009) Biochemistry (Moscow), 74, 939-944) and to "defeat" cancer. 2) Problems unsolvable due to multiple interactions in complex systems leading to the appearance of unpredictable emergent properties that prevent establishment of unambiguous relationships between the genetic architecture and phenotypic manifestation of the genome and make impossible to predict with certainty responses of the organism, its parts, or pathological processes to external factors. 3) Problems unsolvable because of the uncertainty principle and observer effect in biology, due to which it is impossible to obtain adequate information about cells in their tissue microenvironment by isolating and analyzing individual cells. In particular, we cannot draw conclusions on the properties of stem cells in their niches based on the properties of stem cell cultures. A strategy is proposed for constructing the pattern most closely approximated to the relationship of genotypes with their phenotypes by designing networks of intermediate phenotypes (endophenotypes). PMID- 29626925 TI - Genetic and Epigenetic Mechanisms of beta-Globin Gene Switching. AB - Vertebrates have multiple forms of hemoglobin that differ in the composition of their polypeptide chains. During ontogenesis, the composition of these subunits changes. Genes encoding different alpha- and beta-polypeptide chains are located in two multigene clusters on different chromosomes. Each cluster contains several genes that are expressed at different stages of ontogenesis. The phenomenon of stage-specific transcription of globin genes is referred to as globin gene switching. Mechanisms of expression switching, stage-specific activation, and repression of transcription of alpha- and beta-globin genes are of interest from both theoretical and practical points of view. Alteration of balanced expression of globin genes, which usually occurs due to damage to adult beta-globin genes, leads to development of severe diseases - hemoglobinopathies. In most cases, reactivation of the fetal hemoglobin gene in patients with beta-thalassemia and sickle cell disease can reduce negative consequences of irreversible alterations of expression of the beta-globin genes. This review focuses on the current state of research on genetic and epigenetic mechanisms underlying stage-specific switching of beta-globin genes. PMID- 29626926 TI - Interpreting Chromosomal Rearrangements in the Context of 3-Dimentional Genome Organization: A Practical Guide for Medical Genetics. AB - In this exciting era of "next-gen cytogenetics", the use of novel molecular methods such as comparative genome hybridization and whole genome and whole exome sequencing becomes more and more common in clinics. This results in generation of large amounts of high-resolution patient-specific data and challenges the development of new approaches for interpretation of obtained information. Usually, interpretation of chromosomal rearrangements is focused on alterations of linear genome sequence, underestimating the role of spatial chromatin organization. In this article, we describe the main features of 3-dimentional genome organization, emphasizing their role in normal and pathological development. We highlight some tips to help physicians estimating the impact of chromosomal rearrangements on the patient phenotype. A separate section describes available tools that can be used to visualize and analyze human genome architecture. PMID- 29626927 TI - Effect of Environmental Factors on Nuclear Organization and Transformation of Human B Lymphocytes. AB - Chromosomal translocations have long been known for their association with malignant transformation, particularly in hematopoietic disorders such as B-cell lymphomas. In addition to the physiological process of maturation, which creates double strand breaks in immunoglobulin gene loci, environmental factors including the Epstein-Barr and human immunodeficiency viruses, malaria-causing parasites (Plasmodium falciparum), and plant components (Euphorbia tirucalli latex) can trigger a reorganization of the nuclear architecture and DNA damage that together will facilitate the occurrence of deleterious chromosomal rearrangements. PMID- 29626928 TI - Protein-Protein Interactions in DNA Base Excision Repair. AB - The system of base excision repair (BER) ensures correction of the most abundant DNA damages in mammalian cells and plays an important role in maintaining genome stability. Enzymes and protein factors participate in the multistage BER in a coordinated fashion, which ensures repair efficiency. The suggested coordination mechanisms are based on formation of protein complexes stabilized via either direct or indirect DNA-mediated interactions. The results of investigation of direct interactions of the proteins participating in BER with each other and with other proteins are outlined in this review. The known protein partners and sites responsible for their interaction are presented for the main participants as well as quantitative characteristics of their affinity. Information on the mechanisms of regulation of protein-protein interactions mediated by DNA intermediates and posttranslational modification is presented. It can be suggested based on all available data that the multiprotein complexes are formed on chromatin independent of the DNA damage with the help of key regulators of the BER process scaffold protein XRCC1 and poly(ADP-ribose) polymerase 1. The composition of multiprotein complexes changes dynamically depending on the DNA damage and the stage of BER process. PMID- 29626929 TI - Structure and Functions of the Mediator Complex. AB - Mediator is a key factor in the regulation of expression of RNA polymerase II transcribed genes. Recent studies have shown that Mediator acts as a coordinator of transcription activation and participates in maintaining chromatin architecture in the cell nucleus. In this review, we present current concepts on the structure and functions of Mediator. PMID- 29626930 TI - Link Between Double-Strand DNA Break Hotspots and Transcription Regulation: Forum Domains - 50-250 kb Chromosome Regions Containing Coordinately Expressed Genes. AB - The data on forum domains formed by DNA double-strand break (DSB) hotspots are reviewed including forum domain identification by pulsed-field gel electrophoresis, whole genome mapping of these domains using deep sequencing strategies, analysis of gene expression in forum domains, and binding of nuclear proteins to their boundaries. Earlier unpublished data by the authors are presented. The "piano playing" hypothesis is suggested based on coordinated active transcription in some of the forum domains and coordinated silencing in the majority of them. The data on the DSB hotspots in human ribosomal DNA gene clusters and their possible association with chromosomal translocations are presented. These clusters are the most actively transcribed DNA regions in cells, as well as the most fragile sites in human chromosomes. The need to revise the available data on DNase I-hypersensitive sites in various genomes, including endogenous DNA breaks of different nature, is discussed. PMID- 29626931 TI - Who Needs This Junk, or Genomic Dark Matter. AB - Centromeres (CEN), pericentromeric regions (periCEN), and subtelomeric regions (subTel) comprise the areas of constitutive heterochromatin (HChr). Tandem repeats (TRs or satellite DNA) are the main components of HChr forming no less than 10% of the mouse and human genome. HChr is assembled within distinct structures in the interphase nuclei of many species - chromocenters. In this review, the main classes of HChr repeat sequences are considered in the order of their number increase in the sequencing reads of the mouse chromocenters (ChrmC). TRs comprise ~70% of ChrmC occupying the first place. Non-LTR (-long terminal repeat) retroposons (mainly LINE, long interspersed nuclear element) are the next (~11%), and endogenous retroviruses (ERV; LTR-containing) are in the third position (~9%). HChr is not enriched with ERV in comparison with the whole genome, but there are differences in distribution of certain elements: while MaLR like elements (ERV3) are dominant in the whole genome, intracisternal A-particles and corresponding LTR (ERV2) are prevalent in HChr. Most of LINE in ChrmC is represented by the 2-kb fragment at the end of the 2nd open reading frame and its flanking regions. Almost all tandem repeats classified as CEN or periCEN are contained in ChrmC. Our previous classification revealed 60 new mouse TR families with 29 of them being absent in ChrmC, which indicates their location on chromosome arms. TR transcription is necessary for maintenance of heterochromatic status of the HChr genome part. A burst of TR transcription is especially important in embryogenesis and other cases of radical changes in the cell program, including carcinogenesis. The recently discovered mechanism of epigenetic regulation with noncoding sequences transcripts, long noncoding RNA, and its role in embryogenesis and pluripotency maintenance is discussed. PMID- 29626932 TI - Examining the challenges posed to parents by the contemporary screen environments of children: a qualitative investigation. AB - BACKGROUND: The ubiquity of technology in modern society has led to the American Academy of Pediatrics adapting their screen-viewing (SV) recommendations for children. The revised guidelines encourage families to identify an appropriate balance between SV and other activities. The aims of this study were to explore parents' views of their child's SV time and how important it is for families to achieve a 'digital balance'. METHODS: Semi-structured telephone interviews were conducted with 51 parents of 8-9-year-old children, between July and October 2016. Inductive and deductive content analyses were used to explore parents' perceptions of their child's level of SV (low, medium, high), how parents feel about child SV, and the importance placed on achieving a digital balance. Parent report of child SV behaviours on weekdays and weekend days were assessed via questionnaire. RESULTS: Interview data revealed that because SV is considered the 'norm', parents struggle to limit it, partly because they want their children to be equipped for the modern technological world. While most parents believe SV to have negative effects on children, parents also report advantages to SV. Many parents feel that not all SV is equal, with tablets considered worse than television because of the isolated nature of activities, and educational SV considered more beneficial than non-educational SV. Most parents feel it is important for their family to achieve a digital balance, primarily to spend more quality family time together. Large variation was observed in parents' descriptions of child SV time on weekdays and weekend days. CONCLUSIONS: Parents recognise the importance of digital balance but want their children to fit into the ever-advancing digital world. Parents do not treat all SV equally. Watching television and engaging in educational SV may be encouraged, while 'playing' on tablets is discouraged. These findings highlight the challenge faced by researchers and policy makers to help families achieve a digital balance, and strategies are needed to support parents to plan child SV time. PMID- 29626933 TI - Effects of nutrition therapy on HbA1c and cardiovascular disease risk factors in overweight and obese patients with type 2 diabetes. AB - BACKGROUND: Nutrition Therapy (NT) is essential in type 2 diabetes (T2D) management. Standards of care recommend that each patient engages with a nutritionist (RDN) to develop an individualized eating plan. However, it is unclear if it is the most efficient method of NT. This study evaluates the effects of three different methods of NT on HbA1c and cardiovascular disease risk factors in overweight and obese patients with T2D. METHODS: We randomized 108 overweight and obese patients with T2D (46 M/62F; age 60 +/- 10 years; HbA1c 8.07 +/- 1.05%; weight 101.4 +/- 21.1 kg and BMI 35.2 +/- 7.7 kg/m2) into three groups. Group A met with RDN to develop an individualized eating plan. Group B met with RDN and followed a structured meal plan. Group C did similar to group B and received weekly phone support by RDN. RESULTS: After 16 weeks, all three groups had a significant reduction of their energy intake compared to baseline. HbA1c did not change from baseline in group A, but decreased significantly in groups B (- 0.66%, 95% CI -1.03 to - 0.30) and C (- 0.61%, 95% CI -1.0 to - 0.23) (p value for difference among groups over time < 0.001). Groups B and C also had significant reductions in body weight, body fat percentage and waist circumference. CONCLUSION: Structured NT alone improves glycemia in comparison to individualized eating plans in overweight and obese patients with T2D. It also reduces other important cardiovascular disease risk factors like body fat percentage and waist circumference. TRIAL REGISTRATION: The trial was retrospectively registered at clinicaltrials.gov( NCT02520050 ). PMID- 29626934 TI - Positive in vitro wound healing effects of functional inclusion bodies of a lipoxygenase from the Mexican axolotl. AB - BACKGROUND: AmbLOXe is a lipoxygenase, which is up-regulated during limb redevelopment in the Mexican axolotl, Ambystoma mexicanum, an animal with remarkable regeneration capacity. Previous studies have shown that mammalian cells transformed with the gene of this epidermal lipoxygenase display faster migration and wound closure rate during in vitro wound healing experiments. RESULTS: In this study, the gene of AmbLOXe was codon-optimized for expression in Escherichia coli and was produced in the insoluble fraction as protein aggregates. These inclusion bodies or nanopills were shown to be reservoirs containing functional protein during in vitro wound healing assays. For this purpose, functional inclusion bodies were used to coat cell culture surfaces prior cell seeding or were added directly to the medium after cells reached confluence. In both scenarios, AmbLOXe inclusion bodies led to faster migration rate and wound closure, in comparison to controls containing either no AmbLOXe or GFP inclusion bodies. CONCLUSIONS: Our results demonstrate that AmbLOXe inclusion bodies are functional and may serve as stable reservoirs of this enzyme. Nevertheless, further studies with soluble enzyme are also necessary in order to start elucidating the exact molecular substrates of AmbLOXe and the biochemical pathways involved in the wound healing effect. PMID- 29626937 TI - Letter from the Editors-May 2018 Issue. PMID- 29626936 TI - The effect of change in fasting glucose on the risk of myocardial infarction, stroke, and all-cause mortality: a nationwide cohort study. AB - BACKGROUND: The effect of change in blood glucose levels on the risk of cardiovascular disease among individuals without diabetes is currently unclear. We aimed to examine the association of change in fasting serum glucose with incident cardiovascular disease and all-cause mortality among representative large population. METHODS: We analyzed the data from retrospective cohort of Korean National Health Insurance Service. In total, 260,487 Korean adults aged over 40 years, without diabetes mellitus and cardiovascular disease at baseline measured change in fasting serum glucose according to the criteria of impaired and diabetic fasting glucose status: normal fasting glucose (NFG, fasting glucose: < 100 mg/dL), impaired fasting glucose (IFG, fasting glucose: 100.0 125.9 mg/dL), and diabetic fasting glucose (DFG, fasting glucose: >= 126.0 mg/dL). Compared to the persistently unchanged group (i.e. NFG to NFG or IFG to IFG), Cox proportional hazards regression analyses were performed in the changed group to obtain the hazards ratio (HR) with 95% confidence interval (CI) for the subsequent median 8-year myocardial infarction, stroke, and all-cause mortality. RESULTS: Compared to individuals with persistent NFG (i.e., NFG to NFG), individuals who shifted from NFG to DFG had an increased risk of stroke (HR [95% CI]: 1.19 [1.02-1.38]) and individuals who shifted from NFG to IFG or DFG had increased risks of all-cause mortality (HR [95% CI]: 1.08 [1.02-1.14] for NFG to IFG and 1.56 [1.39-1.75] for NFG to DFG). Compared to individuals with persistent IFG, individuals who shifted from IFG to DFG had an increased risk of MI and all cause mortality (HR [95% CI]: 1.65 [1.20-2.27] and 1.16 [1.02-1.33], respectively). CONCLUSIONS: Increasing fasting glucose in non-diabetic population is associated with risks of the MI, stroke, and all-cause mortality, which is more rapid, more severe. PMID- 29626938 TI - Guest Editorial on Molecular Imaging of Infection and Inflammation. PMID- 29626935 TI - Circular RNAs function as ceRNAs to regulate and control human cancer progression. AB - Circular RNAs (circRNAs) are connected at the 3' and 5' ends by exon or intron cyclization, forming a complete ring structure. circRNA is more stable and conservative than linear RNA and abounds in various organisms. In recent years, increasing numbers of reports have found that circRNA plays a major role in the biological functions of a network of competing endogenous RNA (ceRNA). circRNAs can compete together with microRNAs (miRNAs) to influence the stability of target RNAs or their translation, thus, regulating gene expression at the transcriptional level. circRNAs are involved in biological processes such as tumor cell proliferation, apoptosis, invasion, and migration as ceRNAs. circRNAs, therefore, represent promising candidates for clinical diagnosis and treatment. Here, we review the progress in studying the role of circRNAs as ceRNAs in tumors and highlight the participation of circRNAs in signal transduction pathways to regulate cellular functions. PMID- 29626939 TI - The "3M" Approach to Cardiovascular Infections: Multimodality, Multitracers, and Multidisciplinary. AB - Cardiovascular infections are associated with high morbidity and mortality. Early diagnosis is crucial for adequate patient management, as early treatment improves the prognosis. The diagnosis cannot be made on the basis of a single symptom, sign, or diagnostic test. Rather, the diagnosis requires a multidisciplinary discussion in addition to the integration of clinical signs, microbiology data, and imaging data. The application of multimodality imaging, including molecular imaging techniques, has improved the sensitivity to detect infections involving heart valves and vessels and implanted cardiovascular devices while also allowing for early detection of septic emboli and metastatic infections before these become clinically apparent. In this review, we describe data supporting the use of a Multimodality, Multitracer, and Multidisciplinary approach (the 3M approach) to cardiovascular infections. In particular, the role of white blood cell SPECT/CT and [18F]FDG PET/CT in most prevalent and clinically relevant cardiovascular infections will be discussed. In addition, the needs of advanced hybrid equipment, dedicated imaging acquisition protocols, specific expertise for image reading, and interpretation in this field are discussed, emphasizing the need for a specific reference framework within a Cardiovascular Multidisciplinary Team Approach to select the best test or combination of tests for each specific clinical situation. PMID- 29626940 TI - PET/MRI in Infection and Inflammation. AB - Hybrid positron emission tomography/magnetic resonance imaging (PET/MR) systems are now more and more available for clinical use. PET/MR combines the unique features of MR including excellent soft tissue contrast, diffusion-weighted imaging, dynamic contrast-enhanced imaging, fMRI and other specialized sequences as well as MR spectroscopy with the quantitative physiologic information that is provided by PET. Most of the evidence of the potential clinical utility of PET/MRI is available for neuroimaging. Other areas, where PET/MR can play a larger role include head and neck, upper abdominal, and pelvic tumours. Although the role of PET/MR in infection and inflammation of the cardiovascular system and in musculoskeletal applications are promising, these areas of clinical investigation are still in the early phase and it may be a little longer before these areas reach their full potential in clinical practice. In this review, we outline the potential of hybrid PET/MR for imaging infection and inflammation. A background to the main radiopharmaceuticals and some technical considerations are also included. PMID- 29626941 TI - Imaging Macrophage-associated Inflammation. AB - Macrophages belong to the mononuclear phagocyte system comprising closely related cells of bone marrow origin. Activated macrophages are critical in several diseases such as tuberculosis, sarcoidosis, Crohn's disease, and atherosclerosis. Noninvasive imaging techniques that can specifically image activated macrophages could therefore help in differentiating various forms of inflammatory diseases and to monitor therapeutic responses. PMID- 29626942 TI - Nuclear Imaging in Sarcoidosis. AB - Sarcoidosis is a multisystem granulomatosis which may result in a wide variety of clinical and biological presentations. Symptoms are often nonspecific, and incidental abnormal findings on chest radiography is rather common. Although sarcoidosis resolves favorably in most cases, some localizations can provoke functional impairment or even impact on patients' prognosis. The diagnosis is based on a pathological hallmark which is the non-necrotizing epithelioid-cell rich granuloma. Owing to the ability to detect inflammation throughout the body with a high sensibility, FDG-PET/CT gained a central role in sarcoidosis because it can suggest the diagnosis in certain clinical context, guide biopsy, evaluate the extent of the disease, help assess the prognosis, and monitor immunosuppressive therapy. This review will briefly describe clinical and typical findings of conventional imaging according to organ involvement, in order to highlight the additional information provided by nuclear imaging. In the future, we can expect to further improve diagnostic performance of imaging in some indications through the availability of more specific radiopharmaceuticals and the wider use of combined PET/MRI. PMID- 29626943 TI - New SPECT and PET Radiopharmaceuticals for Imaging Inflammatory Diseases: A Meta analysis of the Last 10 Years. AB - Modern molecular nuclear medicine is rapidly developing in the field of imaging of chronic inflammatory diseases, and many new radiopharmaceuticals have been recently described and tested in animals and man. These can detect early pathophysiological changes before the development of anatomical changes and, often, before clinical onset of symptoms. This field includes new radiopharmaceuticals for SPECT and PET use to define new strategies for imaging immune cells as well as tissue modifications induced by the inflammatory process. In this review, we present the results of a meta-analysis based on radiopharmaceuticals (for SPECT or PET) that are not commercially available and that have been used, at least once, in humans in the last 10 years. PMID- 29626945 TI - Molecular Imaging of Vulnerable Plaque. AB - Molecular imaging provides multiple imaging techniques to identify characteristics of vulnerable plaque including I) Inflammatory cells (the presence and metabolic activity of macrophages), II) synthesis of lipid and fatty acid in the plaque, III) the presence of hypoxia in severely inflamed lesions, IV) expression of factors stimulating angiogenesis, V) expression of protease enzymes in the lesion, VI) development of microthrombi in late-phase lesions, VII) apoptosis, and VIII) microcalcification. PMID- 29626944 TI - Molecular Imaging of Inflammatory Arthritis and Related Disorders. AB - Rheumatic disorders comprise a number of diseases that range from benign, mildly symptomatic degenerative disease to severe systemic disorders such as giant-cell vasculitis with dramatic consequences such as acute blindness. The former is relatively common, whereas the latter is rare. In between, commonly encountered disorders such as rheumatoid arthritis and the various spondyloarthritides, with or without peripheral enthesitis, are daily challenges for the caring physician. Clinical evaluation is of utmost importance and is constantly described under the form of specialist guidelines in all parts of the world. Objective assessment of inflammatory arthritis and related disorders is of interest both for the care of the individual patient and for the assessment of the effects of the many novel experimental therapies proposed in this field, most of them being very expensive. High-resolution ultrasound, CT and spectral CT, MRI using various sequences, and molecular imaging using either gamma camera imaging (including SPECT-CT) or PET CT are all proposed for a better assessment of these diseases. This review focuses on the several nuclear medicine techniques that are or may become useful to helping provide better patient care in this field and is mainly oriented to inflammatory rheumatic disorders, excluding mechanical degenerative diseases. PMID- 29626947 TI - Microchamber arrays for controlled NIR laser mediated drug delivery to single cells. PMID- 29626946 TI - Implementation of Quality Systems in Nuclear Medicine: Why It Matters. An Outcome Analysis (Quality Management Audits in Nuclear Medicine Part III). AB - The International Atomic Energy Agency (IAEA) developed a comprehensive program Quality Management Audits in Nuclear Medicine (QUANUM). This program covers all aspects of nuclear medicine practices including, but not limited to, clinical practice, management, operations, and services. The QUANUM program, which includes quality standards detailed in relevant checklists, aims at introducing a culture of comprehensive quality audit processes that are patient oriented, systematic, and outcome based. This paper will focus on the impact of the implementation of QUANUM on daily routine practices in audited centers. Thirty seven centers, which had been externally audited by experts under IAEA auspices at least 1 year earlier, were invited to run an internal audit using the QUANUM checklists. The external audits also served as training in quality management and the use of QUANUM for the local teams, which were responsible of conducting the internal audits. Twenty-five out of the 37 centers provided their internal audit report, which was compared with the previous external audit. The program requires that auditors score each requirement within the QUANUM checklists on a scale of 0 4, where 0-2 means nonconformance and 3-4 means conformance to international regulations and standards on which QUANUM is based. Our analysis covering both general and clinical areas assessed changes on the conformance status on a binary manner and the level of conformance scores. Statistical analysis was performed using nonparametric statistical tests. The evaluation of the general checklists showed a global improvement on both the status and the levels of conformances (P < 0.01). The evaluation of the requirements by checklist also showed a significant improvement in all, with the exception of Hormones and Tumor marker determinations, where changes were not significant. Of the 25 evaluated institutions, 88% (22 of 25) and 92% (23 of 25) improved their status and levels of conformance, respectively. Fifty-five requirements, on average, increased from nonconformance to conformance status. In 8 key areas, the number of improved requirements was well above the average: Administration & Management (checklist 2); Radiation Protection & Safety (checklist 4); General Quality Assurance system (checklist 6); Imaging Equipment Quality Assurance or Quality Control (checklist 7); General Diagnostic (checklist 9); General Therapeutic (checklist 12); Radiopharmacy Level 1 (checklist 14); and Radiopharmacy Level 2 (checklist 15). Analysis of results related to clinical activities showed an overall positive impact on both the status and the level of conformance to international standards. Similar results were obtained for the most frequently performed clinical imaging and therapeutic procedures. Our study shows that the implementation of a comprehensive quality management system through the IAEA QUANUM program has a positive impact on nuclear medicine practices. PMID- 29626949 TI - After School Anatomy Lesson. PMID- 29626948 TI - Marbles. PMID- 29626950 TI - Apnea in the Nonobese: A Need for Awareness. PMID- 29626951 TI - Reclassification of Bronchodilator Reversibility in the U-BIOPRED Adult Asthma Cohort Using z Scores. PMID- 29626952 TI - Sarcoidosis in World Trade Center-Exposed Firefighters. PMID- 29626953 TI - Adoption Rate of Video-Assisted Thoracic Surgery for Lung Cancer Varies Widely in China. PMID- 29626954 TI - Pre-intubation Checklist: Need of the Hour. PMID- 29626955 TI - Response. PMID- 29626956 TI - Response. PMID- 29626957 TI - Could Aspiration Pepsin Be Used as a Marker of Gastric Reflux? PMID- 29626958 TI - Not So Fast With the Foley Catheter: In Response to Intensive Monitoring of Urine Output in the Critically Ill. PMID- 29626959 TI - Response. PMID- 29626960 TI - Response. PMID- 29626961 TI - The Best Approach for Detecting B-Lines: Transparietal or Subcostal Ultrasound Views? PMID- 29626962 TI - Learning Through Teaching. PMID- 29626964 TI - Correction to Additional Information in: Giants in Chest Medicine: Professor Nan shan Zhong, MD. PMID- 29626963 TI - Response. PMID- 29626965 TI - Statin Effect on Sepsis Mortality: Can We Close the Book? PMID- 29626966 TI - Do Not Throw the Intubation Checklist Out With the Bath Water! PMID- 29626967 TI - Sealing the Leak: A Step Forward in Improving CPAP Adherence. PMID- 29626968 TI - Giants in Chest Medicine: Professor Emeritus Elizabeth F. Juniper, MCSP, MSc. PMID- 29626969 TI - A 54-Year-Old Man With Neck Swelling, Respiratory Distress, and Hoarseness. PMID- 29626970 TI - A 59-Year-Old Man With ARDS Receiving "Protective" Ventilation. PMID- 29626971 TI - Likely False-Positive Pneumococcal Antigen Test BinaxNOW Due to Parvimonas micra: A Four-Case Series. AB - We retrospectively report four cases from two hospitals of nonpneumococcal pleural empyema with a likely false-positive result on the pneumococcal antigen test BinaxNOW (PATB) (Alere) performed in pleural fluid samples in patients with aspiration pneumonia risk factors. To determine whether the positive reaction was due to cross-reactivity, we separately tested the isolates from the pleural fluid samples, along with collection and reference strains. All patients had polymicrobial aerobic and anaerobic positive cultures, including Parvimonas micra in every case. In all cases, 16S rDNA polymerase chain reaction sequencing yielded Fusobacterium nucleatum. Samples for culture and specific polymerase chain reaction were negative for Streptococcus pneumoniae. We found that the false-positive PATB finding was likely due to P micra, a previously unknown cross reactivity. In case of aspiration pneumonia risk factors, a positive PATB result must be interpreted with caution because there can be a false positivity due to anaerobic infection or co-infection. PMID- 29626972 TI - Two Siblings With Interstitial Lung Disease. AB - A 52-year-old white woman and her 61-year-old white brother separately presented with gradually worsening dyspnea on exertion and cough, and evidence of interstitial lung disease on chest imaging. PMID- 29626973 TI - A 64-Year-Old Woman With an Incidental Pulmonary Nodule. AB - CASE PRESENTATION: A 64-year-old Latin American woman was referred for evaluation of an incidental pulmonary nodule. She had originally presented to her primary care physician with complaints of abdominal pain warranting a CT scan of the abdomen, which revealed a right lower lobe pulmonary nodule. She denied any complaints of shortness of breath or cough. Review of systems was unremarkable and medical history was significant for hypertension only. She also denied primary or secondary tobacco exposure or any recreational drug abuse. Patient denied any recent travels and resided in Houston, Texas. There was no family history of malignancy or lung disease. PMID- 29626974 TI - A Young Man With Hemoptysis and Cavitary Lung Lesions. AB - CASE PRESENTATION: A man in his 20s presented with 2 months of mild fatigue and intermittent hemoptysis of less than a tablespoon per episode. He was previously healthy and was on no medications. He denied fevers, night sweats, weight loss, wheezing, dyspnea, musculoskeletal symptoms, and rashes. He had emigrated from a South American country to the United States 3 years earlier. He worked as a groundskeeper but had no exposures to animals, mold, or dusts. He reported rare prior cigarette smoking with no history of alcohol or drug use. He was unsure whether he had received the Bacillus Calmette-Guerin vaccine. PMID- 29626975 TI - A 77-Year-Old Woman With Acute Shortness of Breath and Chest Pain. AB - CASE PRESENTATION: A 77-year-old woman presented to the hospital with symptoms of progressive shortness of breath with associated right-sided pleuritic pain. The patient had begun noting dyspnea on exertion, limiting her ability to go on hikes over the few days prior to admission. Her medical history is significant for carcinoid tumor status postresection in 2012 without recurrence. She has no history of thromboembolism or clotting disorders, and she has no history of smoking or drug abuse. Current medications include amlodipine, celecoxib, hydrochlorothiazide, and rosuvastatin. PMID- 29626976 TI - Chronic histiocytic intervillositis - Clinical, biochemical and radiological findings: An observational study. AB - INTRODUCTION: Chronic histiocytic intervillositis (CHI) of the placenta although rare, has a high recurrence rate, is associated with serious adverse pregnancy outcomes and has no available treatment. This study aims to determine clinical, biochemical and radiological factors associated with CHI, to guide management of subsequent pregnancies. METHODS: This retrospective observational study included consecutive cases with a histopathologic diagnosis of CHI after 18 weeks of gestation, between 2001 and 2014, and no controls. Clinical (maternal, fetal and delivery outcomes), biochemical (first- and second-trimester biomarkers for fetal aneuploidy and serum alkaline phosphatase) and radiological (second- and third trimester fetal, placental and Doppler ultrasound) factors associated with a histopathological diagnosis of CHI were identified and results presented as percentages. Outcomes of subsequent pregnancies were described. RESULTS: Of 231 identified cases of 'intervillositis', 33 were confirmed to have CHI, of which only 4/33 (12.1%) had prior uncomplicated term deliveries. During pregnancy, 10/18 (55.5%) had abnormal first-trimester screening, 4/16 (25%) had abnormal second-trimester screening, 6/19 (31.6%) had at least one elevated alkaline phosphatase level, and 15/20 (75%) had at least one abnormal feature on mid trimester placental ultrasound. In subsequent pregnancies that were closely followed with a combination of biochemical and radiologic tests, there were no cases of fetal loss, and lower incidence of fetal growth restriction and preterm birth. DISCUSSION: No clinical, biochemical or radiological finding is consistently associated with CHI and adverse outcomes thereof. Whether the incorporation of these tests in individualized care-plans could improve outcomes in subsequent pregnancies needs to be studied further. PMID- 29626977 TI - IFNtau mediates chemotaxis, motility, metabolism and CK18 downregulation in bovine trophoblast cells in vitro via STAT1 and MAPK42/44 signaling. AB - INTRODUCTION: IFNtau is the ruminant pregnancy recognition signal. In the study we investigated the autocrine influence of IFNtau on bovine F3 trophoblast cells. In detail chemotaxis, motility, metabolism, cell polarisation (CK18; ezrin) and the underlying classical (STAT1) and non-classical (MAPK42/44) signaling pathways were examined. METHODS: Cellular signaling was analysed by densitometric Western blot (STAT1, MAPK42/44, proteinkinase B) and RT-PCR (IFNAR1, -2). Cellular assays were carried out for chemotaxis (agarose spot assay), cell motility (live cell imaging), metabolism (MTT) and cell polarisation (CK18; ezrin). In vivo-produced conceptuses of gestational days (GD) 20-39 underwent immunohistochemistry (CK18; ezrin) to set the in vitro findings (cell polarisation) in proportion to the in vivo situation. RESULTS: IFNtau (10-1000 ng/ml) mediated dose-dependent effects. 10 ng/ml IFNtau induced chemotaxis and motility, whilst 1000 ng/ml led to reduced chemotaxis, motility and a 92-fold activation of MAPK44. Stimulation of cells with 10-1000 ng/ml IFNtau promoted metabolism (1.4-fold), increased the gene expression of IFNAR1/2 (24 h) and downregulated CK18 but not ezrin. All described in vitro effects were significant. Signaling, motility and metabolism could be blocked by specific inhibitors (PD98059, LY294002). CK18 and ezrin expression patterns in the trophoblast of in vivo conceptuses differed depending on GD. DISCUSSION: IFNtau is a major factor for bovine F3 trophoblast cells and mediates a variety of cellular actions ranging from chemotaxis to polarisation. IFNtau exerts its effects via classical (STAT1) and non-classical (MAPK42/44) signaling pathways in a dose-dependent way. We hypothesize that (dose-dependent) IFNtau regulation of the cellular effects could also be essential for bovine elongation and implantation. PMID- 29626978 TI - A novel scoring system for predicting adherent placenta in women with placenta previa. AB - INTRODUCTION: Placenta previa (PP) is one of the most significant risk factors for adherent placenta (AP). The aim of this study was to evaluate the diagnostic efficacy of a novel scoring system for predicting AP in pregnant women with PP. METHODS: This prospective cohort study enrolled 175 women with PP. The placenta previa with adherent placenta score (PPAP score) is composed of 2 categories: (1) past history of cesarean section (CS), surgical abortion, and/or uterine surgery; and (2) ultrasonography and magnetic resonance imaging findings. Each category is graded as 0, 1, 2, or 4 points, yielding a total score between 0 and 24. When women with PP had PPAP score >=8, they were considered to be at a high risk for AP and received placement of preoperative internal iliac artery occlusion balloon catheters. If they were found to have AP during CS, they underwent hysterectomy or placenta removal using advanced bipolar with balloon catheter occlusion. The predictive accuracy of PPAP score was evaluated. RESULTS: In total, 23 of the 175 women with PP were diagnosed as having AP, histopathologically or clinically. Twenty-one of 24 women with PPAP score >=8 had AP, whereas two of 151 women with PPAP score <8 had AP. The scoring system yielded 91.3% sensitivity, 98.0% specificity, 87.5% positive predictive value, and 98.7% negative predictive value for predicting AP in women with PP. DISCUSSION: This prospective study demonstrated that PPAP scoring system may be useful for predicting AP in women with PP. PMID- 29626979 TI - Placental exosomes profile in maternal and fetal circulation in intrauterine growth restriction - Liquid biopsies to monitoring fetal growth. AB - INTRODUCTION: Placenta-derived exosomes may represent an additional pathway by which the placenta communicates with the maternal system to induce maternal vascular adaptations to pregnancy and it may be affected during Fetal growth restriction (FGR). The objective of this study was to quantify the concentration of total and placenta-derived exosomes in maternal and fetal circulation in small fetuses classified as FGR or small for gestational age (SGA). METHODS: Prospective cohort study in singleton term gestations including 10 normally grown fetuses and 20 small fetuses, sub-classified into SGA and FGR accordingly to birth weight (BW) percentile and fetoplacental Doppler. Exosomes were isolated from maternal and fetal plasma and characterized by morphology, enrichment of exosomal proteins, and size distribution by electron microscopy, western blot, and nanoparticle tracking analysis, respectively. Total and specific placenta derived exosomes were determined using quantum dots coupled with CD63+ve and placental-type alkaline phosphatase (PLAP)+ve antibodies, respectively. RESULTS: Maternal concentrations of CD63+ve and PLAP+ve exosomes were similar between the groups (all p > 0.05). However, there was a significant positive correlation between the ratio of placental-derived to total exosomes (PLAP+ve ratio) and BW percentile, [rho = 0.77 (95% CI: 0.57 to 0.89); p = 0.0001]. The contribution of placental exosomes to the total exosome concentration in maternal and fetal circulation showed a significant decrease among cases, with lower PLAP+ve ratios in FGR compared to controls and SGA cases. DISCUSSION: Quantification of placental exosomes in maternal plasma reflects fetal growth and it may be a useful indicator of placental function. PMID- 29626980 TI - Placental function and structure at term is altered in broodmares fed with cereals from mid-gestation. AB - INTRODUCTION: Feeding pregnant broodmares with cereal concentrates has been shown to increase maternal insulin resistance and affect foal metabolism in the short and long-term. These effects are likely to be mediated by the placenta. Here, we investigated feto-placental biometry and placental structure and function at term in mares fed with or without cereals concentrates. MATERIAL AND METHODS: From 7 months of gestation, 22 multiparous mares were fed forage only (group F (n = 12)) or received forage and cracked barley (group B (n = 10)) until foaling. Foals and placentas were weighed and placental samples were collected above the umbilical cord insertion at birth. Placental histological structure was studied by stereology. A RNAseq analysis was performed on 9 placentas of each group. Enrichment of gene sets was analysed using the Gene Set Enrichment Analysis (GSEA) software using the KEGG and GO databases. RESULTS: No difference in feto placental biometry was observed between groups. The volume of microcotyledonary vessels was decreased in B placentas and the vascular wall of allantoic arterioles was thickened. Gene sets involved in neutral amino acids, folate and anions transport and fatty acids, cholesterol and folate degradation were down regulated while gene sets involved in RNA expression, inflammation and vascularisation were up-regulated in B placentas. CONCLUSION: Feeding pregnant mares with concentrates from mid-gestation alters the placental function and structure as observed in other species in cases of maternal insulin resistance. PMID- 29626981 TI - Placental lipoprotein lipase activity is positively associated with newborn adiposity. AB - INTRODUCTION: Recent data suggest that in addition to glucose, fetal growth is related to maternal triglycerides (TG). To reach the fetus, TG must be hydrolyzed to free fatty acids (FFA) and transported across the placenta, but regulation is uncertain. Placental lipoprotein lipase (pLPL) hydrolyzes TG, both dietary chylomicron TG (CM-TG) and very-low density lipoprotein TG (VLDL-TG), to FFA. This may promote fetal fat accretion by increasing the available FFA pool for placental uptake. We tested the novel hypothesis that pLPL activity, but not maternal adipose tissue LPL activity, is associated with newborn adiposity and higher maternal TG. METHODS: Twenty mothers (n = 13 normal-weight; n = 7 obese) were prospectively recruited. Maternal glucose, insulin, TG (total, CM-TG, VLDL TG), and FFA were measured at 14-16, 26-28, and 36-37 weeks, and adipose tissue LPL was measured at 26-28 weeks. At term delivery, placental villous biopsies were immediately analyzed for pLPL enzymatic activity. Newborn percent body fat (newborn %fat) was assessed by skinfolds. RESULTS: Placental LPL activity was positively correlated with birthweight (r = 0.48;P = 0.03) and newborn %fat (r = 0.59;P = 0.006), further strengthened by correcting for gestational age at delivery (r = 0.75;P = 0.0001), but adipose tissue LPL was not. Maternal TG and BMI were not correlated with pLPL activity. Additionally, pLPL gene expression, while modestly correlated with enzymatic activity (r = 0.53;P < 0.05), was not correlated with newborn adiposity. DISCUSSION: This is the first study to show a positive correlation between pLPL activity and newborn %fat. Placental lipase regulation and the role of pLPL in pregnancies characterized by nutrient excess and fetal overgrowth warrant further investigation. PMID- 29626982 TI - Genetic and microscopic assessment of the human chemotherapy-exposed placenta reveals possible pathways contributive to fetal growth restriction. AB - INTRODUCTION: Fetal growth restriction (FGR) carries an increased risk of perinatal mortality and morbidity. A major cause of FGR is placental insufficiency. After in utero chemotherapy-exposure, an increased incidence of FGR has been reported. In a prospective cohort study we aimed to explore which pathways may contribute to chemotherapy-associated FGR. METHODS: Placental biopsies were collected from 25 cancer patients treated with chemotherapy during pregnancy, and from 66 control patients. Differentially expressed pathways between chemotherapy-exposed patients and controls were examined by whole transcriptome shotgun sequencing (WTSS) and Ingenuity Pathway Analysis (IPA). Immunohistochemical studies for 8-OHdG and eNOS (oxidative DNA damage), proliferation (PCNA) and apoptosis (Cleaved Caspase 3) were performed. The expression level of eNOS, PCNA and IGFBP6 was verified by real-time quantitative Reverse Transcription Polymerase Chain Reaction (RT-qPCR). RESULTS: Most differential expressed genes between chemotherapy-exposed patients and controls were related to growth, developmental processes, and radical scavenging networks. The duration of chemotherapy exposure had an additional impact on the expression of genes related to the superoxide radicals degeneration network. Immunohistochemical analyses showed a significantly increased expression of 8 OHdG (P = 0.003) and a decreased expression of eNOS (P=0.015) in the syncytiotrophoblast of the placenta of cancer patients. A decreased expression of PCNA was detected by immunohistochemistry as RT-qPCR (NS). CONCLUSION: Chemotherapy exposure during pregnancy results in an increase of oxidative DNA damage and might impact the placental cellular growth and development, resulting in an increased incidence of FGR in this specific population. Further large prospective cohort studies and longitudinal statistical analyses are needed. PMID- 29626983 TI - Hematopoietic changes in the offspring induced by maternal overweight: Effect on placenta and fetal liver populations. AB - INTRODUCTION: Bone marrow cells (BMC) from obese adult mice display an increased apoptosis rate over proliferation. Hematopoietic stem cells (HSC) form all blood cells and are important BMC used in cell therapy. Because it is known that prenatal development can be affected by adverse metabolic epigenetic programming from the maternal organism, this work aimed to investigate the effects of maternal overweight on placenta and fetal liver hematopoietic niches. METHODS: Overweight was induced in female mice by overfeeding during lactation. After Swiss females were mated with healthy males, fetuses at 19 dpc (day post conception) and placentas were analyzed. Maternal biometric parameters were compared, and hematopoiesis in the dissociated placenta and fetal liver cells was analyzed by flow cytometry. Placenta morphology and protein content were also studied. RESULTS: The model induced accumulation of adipose tissue, weight gain, and maternal hyperglycemia. Placentas from the overfed group (OG) displayed altered morphology, higher carbohydrate and lipid deposition, and increased protein content of fibronectin and PGC-1alpha. Cytometric analysis showed that placentas from OG presented a higher percentage of circulating macrophages, endothelial progenitor cells, HSC, and progenitor cells. No difference was detected in the percentage of neutrophil granulocytes and total leukocytes or in the proliferation of total cells, HSC, or total leukocytes. With regard to liver analysis of the OG group, there was a significant increase in circulating macrophages, primitive HSC, and oval cells but no difference in hematopoietic progenitor cells, total leukocytes, or leukocyte or total cell proliferation. CONCLUSION: Unregulated maternal metabolism can affect hematopoietic populations within the placenta and fetal liver. PMID- 29626985 TI - Asthma-chronic obstructive pulmonary disease overlap (ACO): An emerging entity in allergic respiratory diseases. PMID- 29626984 TI - The proteome of fetal fluids in mares with experimentally-induced placentitis. AB - INTRODUCTION: Placental inflammation (placentitis) is one of the leading causes of late-term abortion in mares. Although prognosis is good assuming early diagnosis and treatment, diagnostics are limited. METHODS: To better characterize the disease and identify potential biomarkers, we analyzed the proteome of fetal fluids (amniotic and allantoic) in both control mares (n = 5) and mares with experimentally-induced placentitis (n = 5) using LTQ-Orbitrap mass-spectrometry. Placentitis was induced via trans-cervical inoculation of Streptococcus equi ssp. zooepidemicus. RESULTS: In total, 130 proteins were identified in either amniotic fluid, allantoic fluid, or both, with amniotic proteins being more prevalent and better conserved across samples. A total of 18 proteins were up-regulated in amniotic fluid during placentitis, including haptoglobin, plasminogen isoform X2 and plasminogen-like isoform X1 which were found exclusively in samples from mares with placentitis. Five allantoic proteins were up-regulated, of which four were also found to be up-regulated in amniotic fluid, including alpha-1 antiproteinase and transferrin family members. A total of 19 proteins were down regulated in amniotic fluid, with none decreasing significantly in allantoic fluid. DISCUSSION: We have performed the first proteomic analysis of amniotic and allantoic fluid during placental infection in any domestic livestock species. We identified a number of proteins with significantly altered expression, primarily those related to immune function. These findings provide information on the physiology of placentitis as well as identify potential biomarkers for future diagnostic work. PMID- 29626986 TI - Molecular characterization and expression profiling of ryanodine receptor gene in the pink stem borer, Sesamia inferens (Walker). AB - The susceptibilities of three field populations of pink stem borer (PSB), Sesamia inferens (walker) to diamide insecticides, chlorantraniliprole and flubendiamide, were evaluated in this study. The results showed that these PSB field populations were still sensitive to the two diamide insecticides after many years of exposure. To further understand PSB and diamide insecticide, the full-length ryanodine receptor (RyR) cDNA (named as SiRyR), the molecular target of diamide insecticides was cloned from PSB and characterized. The SiRyR gene contains an open reading frame of 15,420 nucleotides, encoding 5140 amino acid residues, which shares 77% to 98% sequence identity with RyR homologous of other insects. All hallmarks of RyR proteins are conserved in the SiRyR protein, including the conserved C-terminal domain with the consensus calcium-biding EF-hands (calcium binding motif), the six transmembrane domains, as well as mannosyltransferase, IP3R and RyR (pfam02815) (MIR) domains. Real-time qPCR analysis revealed that the highest mRNA expression levels of SiRyR were observed in pupa and adults, especially in males. SiRyR was expressed at the highest level in thorax, and the lowest level in wing. The full genetic characterization of SiRyR could provide useful information for future functional expression studies and for discovery of new insecticides with selective insecticidal activity. PMID- 29626987 TI - Munronin O, a potential activator for plant resistance. AB - A series of limonoids (1-8) were isolated from the whole plant of Munronia henryi and antiviral activities of the compounds were evaluated. The bioassay results demonstrated that Munronin O (1) showed remarkable protective activity and compounds 7 and 8 showed significant inactivating, protective, and curative activities against tobacco mosaic virus (TMV). With a 50% effective concentration (EC50) value of 91.5 MUg/mL, compound 1 exhibited the best protective activity compared with ningnanmycin (192.3 MUg/mL). The potential for these compound of inducing systemic acquired resistance (SAR) was also evaluated, and compound 1 showed excellent induction activities. Furthermore, it was found that potentiation of defense-related enzyme activity and the contents of SA was increased. Compound 1 could also inhibit the expression of TMV CP and up-regulate the expression of defense-related genes. This work revealed that compound 1 can induce resistance and enhance plant tolerance to TMV infection. Hence, compound 1 can be considered as a potential activator for inducing plant resistance. PMID- 29626988 TI - Thrombin generation test: A reliable tool to evaluate the pharmacodynamics of vitamin K antagonist rodenticides in rats. AB - Vitamin K antagonist rodenticide pharmacodynamics (PD) is studied in rodents with traditional laboratory tests. We wondered if thrombin generation test (TGT) could add value. Difethialone (10 mg/kg) was administered per os to 97 OFA-Sprague Dawley rats. PD was studied over a 72 h-period using the Calibrated Automated Thrombogram on platelet poor plasma before and after intoxication (3 female and 3 male rats for each 13 time points) and TGT parameters were compared with the prothrombin time (PT) and vitamin K dependent factor activities previously reported. Following intoxication, preliminary tests evidenced rapid and full inhibition of thrombin generation triggered with 5 or 20 pM human recombinant tissue factor. To study the evolution of TGT parameters following difethialone intake, we adapted the test by complementing intoxicated rat samples with pooled normal rat plasma (3/1, v/v). Adapted TGT confirmed the known higher procoagulant basal level in females compared to males through higher endogenous thrombin potential (ETP) and peak height (PH) (p < 0.0001 and p = 0.0003, respectively). An exponential model fitted well the PH and ETP decay after intoxication. In contrast to PT, the decreases were observed immediately following VKA intake and had comparable time to halving values: 10.5 h (95% CI [8.2; 13.6]) for ETP and 10.4 h (95% CI [7.8; 14.1]) for PH. The decrease of FVII and FX preceded that of PH, ETP and FII while FIX decreased later on, contributing to the severe hypo coagulability. We demonstrated that TGT performed in samples of intoxicated rats complemented with normal plasma is a reliable tool for evaluation of VKA rodenticide PD in rats. PMID- 29626989 TI - Quinclorac resistance induced by the suppression of the expression of 1 aminocyclopropane-1-carboxylic acid (ACC) synthase and ACC oxidase genes in Echinochloa crus-galli var. zelayensis. AB - We previously reported that the mechanism of quinclorac resistance in Echinochloa crus-galli var. zelayensis may be closely related to ethylene biosynthesis and the detoxification of cyanide. Differences in EcCAS gene sequences and expression levels may result in higher capacity to detoxify cyanide in resistant biotypes, which may avoid cyanide accumulation and avoid more ethylene and cyanide production and then avoid damage. In the present study, we focused on the mechanism of resistance related to ethylene biosynthesis in E. crus-galli var. zelayensis. The fresh weight of susceptible and moderately resistant biotypes were significantly reduced after treatment with quinclorac. However, AOA, an ethylene biosynthesis inhibitor, reduced the impact of quinclorac. On pretreatment with AOA, ethylene production was significantly reduced in the three biotypes. The highly resistant biotype produced less ethylene compared to the other two biotypes. Three ACS and seven ACO genes, which are the key genes in ethylene biosynthesis, were obtained. The expression levels of EcACS-like, EcACS7, and EcACO1 varied in the three biotypes upon treatment with quinclorac, which could be manipulated by AOA. In summary, it is inferred that the expression of EcACS-like, EcACS7, and EcACO1 can be stimulated to varying extent after quinclorac treatment in three E. crus-galli var. zelayensis biotypes, which consequently results in varying levels of ethylene production. Lower expression of these three genes results in more resistance to quinclorac, which may also be related to quinclorac resistance in E. crus-galli var. zelayensis. PMID- 29626990 TI - Evaluation of antifungal metabolites activity from bacillus licheniformis OE-04 against Colletotrichum gossypii. AB - Anthracnose disease in the cotton plant caused by fungal pathogen Colletotrichum gossypii. It is supposed to be most critical diseases in the cotton crop as it causes infection and leads to complete damaging of the cotton crop by infecting the leaves, stems, and bolls in the field. The disease control is challenging due to the absence of an effective fungicide without damaging the farmer health and environment. So the series of experiments were designed to assess the antagonistic activity of biosurfactant released by strain Bacillus licheniformis OE-04 against the anthracnose causing agent in cotton and this strain was screened out from forty eight strain of rhizobacteria. We also estimated the heat stability and pH range and toxicity of biosurfactant produced by strain 0E-04. The results showed that biosurfactant has maximum antifungal activity against C. gossypii. In vitro study concluded that the biosurfactant can reduce fungal activity by inhibiting the spore germination of C. gossypii. Moreover, the biosurfactant also has wide pH and temperature range. We observed Antifungal activity of biosurfactant at 5 to 10 pH range and temperature range was also wide from room temperature to 100 degrees C. We also observed the toxicity of biosurfactant produced by Bacillus licheniformis against zebra fish (Danio rerio). We were noticed that biosurfactant have least harmful effect with maximum concentration. The study confirmed that biosurfactant of Bacillus licheniformis have high pH and heat stability range with least harmful effects so it can be a good replacement of chemical pesticides for cotton anthracnose control. PMID- 29626991 TI - Binding properties of four antennae-expressed chemosensory proteins (CSPs) with insecticides indicates the adaption of Spodoptera litura to environment. AB - Insects receive a variety of chemical signals from the environment. Chemosensory protein (CSP) is one of the olfactory proteins that can accommodate a variety of small molecules and have the ability to bind to lipophilic compounds, transmitting nonvolatile odor molecules and chemical stimuli to target cells. To understand the correlation between the insect olfactory system and environment, we identified four antennae-expressed SlituCSP genes and investigated their expression profiles after treatment with different temperatures, starvation and three commonly used pesticides: chlorpyrifos, emamectin benzoate and fipronil. The transcriptions of four SlituCSP genes are affected by pesticide treatment and less affected by starvation and different temperatures. To further understand the molecular function of CSPs and their correlation with pesticides, we expressed and purified four SlituCSPs and assayed their binding ability with pesticides. The binding of four SlituCSPs with three pesticides were determined using a fluorescence competitive binding assay. We found direct binding between CSPs and pesticides, especially between SlituCSP18 and chlorpyrifos/fipronil and between SlituCSP6 and all three pesticides. The high binding affinity with pesticides and the significant down-regulation of SlituCSP18 by chlorpyrifos suggests that SlituCSP18 is more sensitive to pesticide treatment and may play an important role in mediating the interaction of the olfactory system and the pesticide. This study can help us understand the role of CSP proteins in the adaption of S. litura to the environment. PMID- 29626992 TI - Target-site mutations (AChE and kdr), and PSMO activity in codling moth (Cydia pomonella (L.) (Lepidoptera: Tortricidae)) populations from Spain. PMID- 29626993 TI - Jack bean urease modulates neurotransmitter release at insect neuromuscular junctions. AB - BACKGROUND: Plants have developed a vast range of mechanisms to compete with phytophagous insects, including entomotoxic proteins such as ureases. The legume Canavalia ensiformis produces several urease isoforms, of which the more abundant is called Jack Bean Urease (JBU). Previews work has demonstrated the potential insecticidal effects of JBU, by mechanisms so far not entirely elucidated. In this work, we investigated the mechanisms involved in the JBU-induced activity upon neurotransmitter release on insect neuromuscular junctions. METHODS: Electrophysiological recordings of nerve and muscle action potentials, and calcium imaging bioassays were employed. RESULTS AND CONCLUSION: JBU (0.28 mg/animal/day) in Locusta migratoria 2nd instar through feeding and injection did not induce lethality, although it did result in a reduction of 20% in the weight gain at the end of 168 h (n = 9, p <= 0.05). JBU (0.014 and 0.14 mg) injected direct into the locust hind leg induced a dose and time-dependent decrease in the amplitude of muscle action potentials, with a maximum decrease of 70% in the amplitude at the highest dose (n = 5, p <= 0.05). At the same doses JBU did not alter the amplitude of action potentials evoked from motor neurons. Using Drosophila 3rd instar larvae neuromuscular preparations, JBU (10-7 M) increased the occurrence of miniature Excitatory Junctional Potentials (mEJPs) in the presence of 1 mM CaCl2 (n = 5, p <= 0.05). In low calcium (0.4 mM) assays, JBU (10-7 M) was not able to modulate the occurrence of the events. In Ca2+-free conditions, with EGTA or CoCl2, JBU induced a significant decrease in the occurrence of mEPJs (n = 5, p <= 0.05). Injected into the 3rd abdominal ganglion of Nauphoeta cinerea cockroaches, JBU (1 MUM) induced a significant increase in Ca2+ influx (n = 7, p <= 0.01), similar to that seen for high KCl (35 mM) condition. Taken together the results confirm a direct action of JBU upon insect neuromuscular junctions and possibly central synapses, probably by disrupting the calcium machinery in the pre-synaptic region of the neurons. PMID- 29626994 TI - Investigation of glyphosate resistance levels and target-site based resistance (TSR) mechanisms in Conyza canadensis (L.) from apple orchards around areas of Bohai seas and Loess Plateau in China. AB - The resistance levels to glyphosate and target-site based resistance mechanisms in susceptible (S) and resistant (R) Conyza canadensis (L.) populations, which were collected from apple orchards around areas of Bohai seas and Loess Plateau in China, were investigated. Among forty C. canadensis populations, eighteen populations (45%) were still susceptible; fourteen populations (35%) evolved low resistance levels resistance to glyphosate with resistance index (RI) of 2.02 to 3.90. In contrast, eight populations (20%) evolved medium resistance levels with RI of 4.35 to 8.38. The shikimic acid concentrations in R populations were highly negative relative with the glyphosate resistance levels in C. canadensis, the Pearson correlation coefficient was -0.82 treated by glyphosate at 1.8mg/L. Three 5-enoylpyruvylshikimate 3'-phosphate synthase genes (EPSPS1, EPSPS2 and EPSPS3) were cloned in all S and glyphosate-resistant C. canadensis populations. No amino acid substitution was identified at site of 102 and 106 in three EPSPS genes, which were reported to confer glyphosate resistance in other weed species. The relative expression level of EPSPS mRNA in R populations (SD07, LN05, SHX06 and SD09) was 4.5 to 13.2 times higher than in S biotype. The Pearson correlation coefficient between EPSPS expression levels and RI was 0.79, which indicated the over expression of EPSPS mRNA may cause these R populations evolve higher resistance level to glyphosate. PMID- 29626995 TI - Monitoring and biochemical characterization of beta-cypermethrin resistance in Spodoptera exigua (Lepidoptera: Noctuidae) in Sichuan Province, China. AB - The beet armyworm Spodoptera exigua, a major pest affecting numerous cultivated crops in China, has developed a serious resistance to many traditional chemical insecticides. The resistance levels of the field-collected populations from different districts in Sichuan Province, China, to nine insecticides were detected with a diet-incorporation bioassay. Compared to the Lab-ZN strain, five (in 2014) and three (in 2016) field populations displayed either high or extremely high levels of resistance to beta-cypermethrin. All the field populations collected in 2014 were susceptible to emamectin benzoate, hexaflumuron, methoxyfenozide, chlorantraniliprole, cyantraniliprole and indoxacarb but exhibited low or moderate levels of resistance to abamectin. The resistances of field populations collected in 2016 were significantly higher than two years earlier, especial for chlorantraniliprole and cyantraniliprole with RRs rising from 173.4- to 582.6-fold and 175.3- to 287.6-fold, respectively, even though the field populations had retained moderate or low levels of resistance to chlorpyrifos and hexaflumuron. The synergism experiment revealed that the resistance of the LS16 population to beta-cypermethrin may be mainly related to cytochrome P450 monooxygenases (P450s), which was responsible for the highest increase ratio of 37.97-fold, for piperonyl butoxide, rather than either carboxylesterase (CarE) or glutathione S-transferase (GST). The cytochrome P450 ethoxycoumarin O-deethylase activity of the LS16 population was also the strongest among the treatments (P < 0.05). Non-denaturing polyacrylamide gel electrophoresis (native PAGE) indicated that enhanced E11, E13 and E15-E16 bands in the LS16 population likely contribute to the development of resistance to beta cypermethrin. PMID- 29626996 TI - Molecular and biological characterization of Sclerotinia sclerotiorum resistant to the anilinopyrimidine fungicide cyprodinil. AB - Cyprodinil belongs to the chemical class of anilinopyrimidines fungicides. In this study, baseline sensitivity of Sclerotinia sclerotiorum (Lib.) de Bary to cyprodinil was determined using 100 strains collected from the fields in Jiangsu Province of China. The EC50 (50% effective concentration) values ranged from 0.0636-0.8163 MUg/ml with a mean value of 0.1869 (+/-0.1118) ug/ml for mycelial growth. Nine cyprodinil-resistant mutants (Range of resistance factor: 20.22 271.59) were obtained from sensitive strains exposed on PDA medium amended with cyprodinil and the resistance was stable after their ten transfers on PDA without the fungicide or stored at 4 degrees C for two months. There was positive cross resistance between cyprodinil and pyrimethanil but not to fludioxonil, dimetachlone, procymidone, carbendazim and boscalid in S. sclerotiorum. Compared with the parental strains, all of the nine cyprodinil-resistant mutants decreased in sclerotial production. The dry weight of mycelia, pathogenicity and cell membrane permeability of most resistant mutants decreased. The mycelial growth, oxalic acid content, and the response to various stress for resistant mutants were almost the same as the sensitive parental strains. Sequencing alignment results showed that there was no alteration of amino acid in cystathionine gamma synthase (MetB) and cystathionine beta-lyase (MetC) between cyprodinil-resistant mutants and their sensitive parental strains, which indicated that MetB or MetC was not the molecular target of cyprodinil in S. sclerotiorum. The addition of amino acids L-methionine, L-cystine or L-cysteine decreased the inhibition of cyprodinil against mycelial growth of S. sclerotiorum, which indicated that cyprodinil could not only inhibited methionine biosynthesis but also suppressed cystine and cysteine biosynthesis. These results will contribute to evaluating the resistance risk of cyprodinil for management of the plant diseases of Sclerotinia stem rot caused by S. sclerotiorum and further increase our understanding about the mode of action of cyprodinil. PMID- 29626997 TI - Interacting effect of diclofop-methyl on the rice rhizosphere microbiome and denitrification. AB - A better knowledge of the intertwined effects of herbicides on plant physiology and microbiome as well as nutrient biogeochemical cycles are needed for environmental management. Here we studied the influence of herbicide diclofop methyl (DM) on the rice root microbiome and its relationship with N cycle. To do so, we exposed rice seedlings to 100 MUg/L DM and studied rhizosphere microbiota using MiSeq-pyrosequencing, root exudation by GC-MS, and denitrification activity by 15N isotope-tracing and qRT-PCR. The richness and diversity of rhizosphere microorganisms, significantly increased after DM exposure combined with an increase in root exudation of amino acids, sugars, and fatty acids. Transcription of denitrification-related gene and denitrification rate increased significantly in the rice rhizosphere. Our results suggest that DM strongly influenced the root exudation of bacteria nutrients, which affected root microbiome community and potentially influenced N cycle in rice rhizosphere. PMID- 29626998 TI - First report of target site insensitivity to pyrethroids in human flea, Pulex irritans (Siphonaptera: Pulicidae). AB - The human flea, Pulex irritans, is the most important ectoparasite of humans. Intensive use of pyrethroids for its control has led to insecticide resistance. Monitoring pyrethroid resistance and its underlying mechanisms is essential for flea control. The aims of this study were to identify the susceptibility status of human flea to permethrin and to detect the presence of knockdown resistance (kdr) mutation and its frequency in populations of P. irritans. Adults of P. irritans were collected from Zanjan Province, northwest of Iran, during 2013 2017. Different populations of this flea were exposed to permethrin 0.75% for one and 8 h and then the mortality rate, as well as KD50 and KD95 times were calculated. Total RNA and gDNA of samples were extracted, and the fragments of cDNA encoding the partial voltage-gated sodium channel (VGSC) peptides were amplified using degenerated primers. Specific PCR and TaqMan real-time assays were conducted to characterize the vgsc gene and to detect the presence of mutation and genotyping of the populations. Mortality rates were in the range from 32% to 67% for one-hour and 73% to 90% for eight-hour exposure to permethrin 0.75%. KD50 and KD95 times varied in a range from 46 to 241 and 177 to 899 min, respectively. Sequencing of 70 amplified fragments of gDNA resulted in a 578-bp product. These fragments contained two introns (92 and 63 bp) and three exons (141, 189, and 92 bp) encoding 138 amino acids that encompassed IIS4-IIS6 and the partial linker between domains II and III of VGSC. All the studied populations showed L1014F mutation, substitution of CTT for TTT at the 1014 allele. The result of TaqMan assay for 624 samples showed 96.6% homogenous and 3.36% heterozygous mutant. The development of permethrin resistance and the presence of the L1014F mutation at high frequency in flea populations indicate that pyrethroids are likely ineffective in controlling human flea. Therefore, novel alternative control methods are needed to combat this human ectoparasite. PMID- 29626999 TI - Disappearance of MRI imaging signals in a patient with neuronal intranuclear inclusion disease. PMID- 29627000 TI - Excessively increased CSF glutamate levels in GABAB-receptor antibody associated encephalitis: A case report. PMID- 29627001 TI - Sex differences in neuropathic pain intensity in diabetes. AB - INTRODUCTION: Sex and gender play roles in the pain experience, such that pain is more frequent in women. Explanations for this observation range from factors related to biological sex to those related to psychosocial gender. OBJECTIVES: To explore neuropathic pain characteristics in females with diabetes with and without established polyneuropathy. METHODS: We compared the presence and intensity of pain in males and females in 2 separate cohorts of patients with type II diabetes, with and without established diabetic polyneuropathy. Cohort #1 was recruited prospectively, while cohort #2 was studied retrospectively. RESULTS: Cohort #1 of 223 patients with diabetes with a relatively broad spectrum of nerve injury, showed more frequent pain in females (68% versus 53% in males), a higher frequency of additional neuropathic symptoms, and evidence of milder nerve injury. Cohort #2 of 128 patients with established diabetic polyneuropathy, showed a similar frequency of pain and additional neuropathic symptoms in both sexes. In both cohorts, females reported greater pain intensity (7.9-8.5 versus 6.8-6.9 in males, on visual analog scale). DISCUSSION: Though nerve injury and polyneuropathy are more common in males, females with diabetes report a higher frequency and intensity of pain despite milder polyneuropathy. Prospective epidemiological studies are required in order to confirm these findings in the community setting. PMID- 29627002 TI - Muscle, cardiac, and cerebral manifestations in female carriers of dystrophin variants. PMID- 29627003 TI - Using real-time fMRI brain-computer interfacing to treat eating disorders. AB - Real-time functional magnetic resonance imaging based brain-computer interfacing (fMRI neurofeedback) has shown encouraging outcomes in the treatment of psychiatric and behavioural disorders. However, its use in the treatment of eating disorders is very limited. Here, we give a brief overview of how to design and implement fMRI neurofeedback intervention for the treatment of eating disorders, considering the basic and essential components. We also attempt to develop potential adaptations of fMRI neurofeedback intervention for the treatment of anorexia nervosa, bulimia nervosa and binge eating disorder. PMID- 29627004 TI - Brain connectivity and cognitive processing speed in multiple sclerosis: A systematic review. AB - BACKGROUND: Processing speed (PS) decline is the most commonly observed cognitive deficit in people with multiple sclerosis (MS) resulting in a significant impact on quality of life. Despite its importance, knowledge of the underlying neural substrates is lacking. OBJECTIVE: As MS is increasingly recognised as a disconnection syndrome, our aim was to carry out a systematic literature review to clarify the relationship between PS performance and MRI measures of structural and functional brain connectivity in people with MS. SEARCH METHODS: A literature search was carried out on PubMed and Web of Science that included publications predating September 2017. Additional articles were added after inspection of the reference lists of all selected papers. DATA EXTRACTION: All selected papers were categorised in three sections according to the MRI measures investigated, independently or both. Quality assessment was carried out using a customised set of criteria. RESULTS: Thirty-two articles met the inclusion criteria and were included in the review. Microstructural integrity of the anterior corpus callosum and functional connectivity of frontal areas were more consistently found to correlate with PS performance, though high variability of findings was observed across studies. Several methodological flaws emerged from the reviewed literature. CONCLUSIONS: Despite the observed trends, no definite conclusions can be drawn on the relationship between brain connectivity and PS decline in MS given the limitations of the current literature. Future investigations may benefit from theoretical and methodological advances to clarify how MS-related brain damage affects patients' cognition. PMID- 29627005 TI - Natural history of benign multiple sclerosis: Clinical and HLA correlates in a Western Australian cohort. AB - BACKGROUND: Benign multiple sclerosis (BMS) is a controversial term that has been used for MS patients with minimal disability decades after disease onset. Herein, we evaluated disease status after 20 years in a Western Australian cohort defined as BMS based on an Expanded Disability Status Scale (EDSS) score <= 3.0 at 10 years from onset. METHODS: MS patients with an EDSS score <= 3.0 at 10 years from onset and minimum of 20 years follow up were included in the study. The 20-year EDSS score was considered the primary outcome. Associations with demographic and clinical characteristics and HLA-DRB1 genotype were investigated. RESULTS: Among 120 patients with a benign course at 10 years, 78 (65%) remained benign at the 20 year follow up, but patients with an EDSS >= 2.5 were more likely to go on to develop more severe disability in the next decade. When considering factors associated with an increase in EDSS score <= 1 from 10 to 20 years, indicating limited progression, apart from the EDSS score at 10 years, poly-symptomatic presentation (p = 0.004) and cerebellar/brainstem mono-symptomatic presentation (p = 0.016) were independently associated with more rapid progression compared with other mono-symptomatic presentations. Carriage of the high risk HLA DRB1*1501 allele was marginally associated with slower progression. CONCLUSIONS: In this geographically isolated MS cohort of predominantly Anglo-Celtic origin clinical progression in the benign MS group was similar to that in other published series from Western countries. These results are in keeping with the view that patients labeled as benign MS are part of a heterogeneous continuum of disease progression and do not possess unique clinical characteristics. Possible genetic determinants of a benign course warrant further investigation. PMID- 29627006 TI - Predictors of cognitive impairment in multiple system atrophy. AB - OBJECTIVE: To determine predictors of cognitive impairment and frontal dysfunction in patients with multiple system atrophy (MSA). METHODS: We recruited 59 patients with MSA and determined the predictors of a decline in the Mini Mental State Examination (MMSE) and Frontal Assessment Battery (FAB) scores. RESULTS: The MMSE scores negatively correlated with disease duration, Unified MSA Rating Scale (UMSARS) part 1 and 4 scores, and residual urine volume, and positively correlated with the coefficient of variation of electrocardiographic RR intervals. The FAB scores negatively correlated with the UMSARS part 2 score, periventricular hyperintensity grade, and deep white matter hyperintense signal grade. A significant predictor of rapidly progressive cognitive impairment was a high residual urine volume. CONCLUSIONS: Impairment of global cognitive function correlates with the long-term disease duration, global disability due to the disease, and autonomic dysfunction, whereas frontal dysfunction correlates with motor function and degeneration of cerebral white matter. PMID- 29627007 TI - Mutation of the cellular adhesion molecule NECL2 is associated with neuromyelitis optica spectrum disorder. AB - AIMS: To investigate the association of the Nectin/Necl family genes with the risk of developing NMOSD. METHODS: Whole-exome sequencing was performed on two familial NMOSD cases and two unaffected family members. Additionally, 106 patients with sporadic NMOSD and 212 healthy controls (HCs) underwent screening for mutant Necl2. Finally, the molecular weight and cellular localization of mutant NECL2 was examined in transfected HeLa cells. RESULTS: We identified a novel deletion mutation in Necl2 (c.1052_1060delCCACCACCA; p. Thr351_Thr353del), which was associated with disease manifestation in the NMOSD familial cases. The frequency at which the mutation occurred in patients with sporadic NMOSD was significantly higher than for HCs (5.7% and 0, respectively; p<0.01). The mutation was located in the extracellular domain close to the transmembrane region, at a point in the protein sequence characterized by threonine enrichment. The mutant NECL2 had a lower molecular weight and exhibited defective trafficking to the cell surface. CONCLUSIONS: Our results suggest that the Necl2 mutation identified herein may be associated with the risk of developing NMOSD. Furthermore, mutated NECL2 may play a role in the pathogenesis of the disease, potentially through its roles in axonal regeneration and/or via neuron-glia interactions that are relevant to myelination. PMID- 29627008 TI - Levodopa-induced dystonia in a patient with possible progressive supranuclear palsy with progressive gait freezing. PMID- 29627010 TI - Improvement of distal acquired demyelinating symmetric (DADS) neuropathy after exposure to factor Xa inhibitor. PMID- 29627009 TI - The combined effects of cardiovascular disease related SNPs on ischemic stroke. AB - PURPOSE: Previous studies have revealed multiple common variants associated with known risk factors for cardiovascular disease (CVD). Ischemic stroke (IS) and CVD share several risk factors with each having substantial heritability. We aimed to generate a multi-locus genetic risk score (GRS) for IS based on CVD related SNPs to evaluate their combined effects on IS. METHODS: A total of 851 patients and 977 controls were selected from Beijing, Tianjin, Shandong, Shanxi, Shaanxi and Heilongjiang communities. The candidate genes were genotyped by PCR hybridization. Information about demographic factors, history of disease (such as hypertension), and lifestyle was obtained using structured questionnaires. A GRS model weighted by the absolute value of regression coefficient beta was established to comprehensively assess the association between candidate SNPs and IS. Using the area under the receiver operating characteristic curve (AUC) to evaluate the value of GRS on predicting IS. RESULTS: The GRS of cases was 2.87 +/ 0.28, which was significantly higher than controls' GRS (2.78 +/- 0.30) (P < 0.000). With the increase of the GRS, the risk of IS became higher (Ptrend < 0.000). Subjects in the top quartile of the GRS had about 1.9-fold increased risk of IS compared with subjects in the lowest quartile (OR adjusted = 1.880, 95%CI = 1.442-2.452, P < 0.000). The AUC = 0.580, P < 0.000. CONCLUSION: 13 CVD related SNPs had combined effects on IS. The GRS of cases was significantly higher than controls' GRS. As the GRS increased, the risk of IS increased. The GRS model has some value for the prediction of IS. PMID- 29627011 TI - Inorganic phosphorus (Pi) in CSF is a biomarker for SLC20A2-associated idiopathic basal ganglia calcification (IBGC1). AB - INTRODUCTION: Idiopathic basal ganglia calcification (IBGC), also called Fahr's disease or recently primary familial brain calcification (PFBC), is characterized by abnormal deposits of minerals including calcium mainly and phosphate in the brain. Mutations in SLC20A2 (IBGC1 (merged with former IBGC2 and IBGC3)), which encodes PiT-2, a phosphate transporter, is the major cause of IBGC. Recently, Slc20a2-KO mice have been showed to have elevated levels of inorganic phosphorus (Pi) in cerebrospinal fluid (CSF); however, CSF Pi levels in patients with IBGC have not been fully examined. METHODS: We investigated the cases of 29 patients with IBGC including six patients with SLC20A2 mutation and three patients with PDGFB mutation, and 13 controls. The levels of sodium (Na), potassium (K), chloride (Cl), calcium (Ca), and Pi in sera and CSF were determined by potentiometry and colorimetry. Moreover, clinical manifestations were investigated in the IBGC patients with high Pi levels in CSF. RESULTS: The study revealed that the average level of Pi in the CSF of the total group of patients with IBGC is significantly higher than that of the control group, and the levels of Pi in CSF of the IBGC patients with SLC20A2 mutations are significantly higher than those of the IBGC patients with PDGFB mutations, the other IBGC patients and controls. CONCLUSION: Results of this study suggest that the levels of CSF Pi will be a good biomarker for IBGC1. PMID- 29627012 TI - Idarucizumab-facilitated intravenous thrombolysis in acute stroke with dabigatran: Two cases with hemorrhagic transformation. PMID- 29627013 TI - Intrafamilial variability in a polish family harbouring a frameshift THAP1 mutation. PMID- 29627014 TI - Bilateral subthalamic nucleus stimulation in refractory status dystonicus. PMID- 29627015 TI - Spinal cord infarction: Clinical and imaging insights from the periprocedural setting. AB - OBJECTIVE: Describe the range of procedures associated with spinal cord infarction (SCI) as a complication of a medical/surgical procedure and define clinical and imaging characteristics that could be applied to help diagnose spontaneous SCI, where the diagnosis is often less secure. METHODS: We used an institution-based search tool to identify patients evaluated at Mayo Clinic, Rochester, MN from 1997 to 2016 with a periprocedural SCI. We performed a descriptive analysis of clinical features, MRI and other laboratory findings, and outcome. RESULTS: Seventy-five patients were identified with SCI related to an invasive or non-invasive surgery including: aortic aneurysm repair (49%); other aortic surgery (15%); and a variety of other procedures (e.g., cardiac surgery, spinal decompression, epidural injection, angiography, nerve block, embolization, other vascular surgery, thoracic surgery) (36%). Deficits were severe (66% para/quadriplegia) and maximal at first post-procedural evaluation in 61 patients (81%). Impaired dorsal column function was common on initial examination. Imaging features included classic findings of owl eyes or anterior pencil sign on MRI (70%), but several other T2-hyperintensity patterns were also seen. Gadolinium enhancement of the SCI and/or cauda equina was also common when assessed. Six patients (10%) had an initial normal MRI despite a severe deficit. CONCLUSIONS: Procedures associated with SCI are many, and this complication does not exclusively occur following aortic surgery. The clinical and radiologic findings that we describe with periprocedural SCI may be used in future studies to help distinguish spontaneous SCI from alternate causes of acute myelopathy. PMID- 29627016 TI - Real-world persistence with fingolimod for the treatment of multiple sclerosis: A systematic review and meta-analysis. AB - OBJECTIVE: To systematically review reports of fingolimod persistence in the treatment of relapsing-remitting multiple sclerosis (RRMS) across data sources and practice settings, and to develop a consensus estimate of the 1-year real world persistence rate. METHODS: A systematic literature review was conducted (MEDLINE, EMBASE, and abstracts from selected conferences [2013-2015]) to identify observational studies reporting 1-year fingolimod persistence among adult patients with RRMS (sample size >=50). A random-effects meta-analysis was performed to estimate a synthesized 1-year persistence rate and to assess heterogeneity across studies. RESULTS: Of 527 publications identified, 25 real world studies reporting 1-year fingolimod persistence rates were included. The studies included patients from different data sources (e.g., administrative claims, electronic medical records, or registries), used different definitions of persistence (e.g., based on prescriptions refills, patient report, or prescription orders), and spanned multiple geographic regions. Reported 1-year persistence rates ranged from 72%-100%, and exhibited statistical evidence of heterogeneity (I2 = 93% of the variability due to heterogeneity across studies). The consensus estimate of the 1-year persistence rate was 82% (95% confidence interval: 79%-85%). CONCLUSIONS: Across heterogeneous study designs and patient populations found in real-world studies, the consensus 1-year fingolimod persistence rate exceeded 80%, consistent with persistence rates identified in the recently-completed trial, PREFERMS. PMID- 29627018 TI - Bilateral wallerian degeneration of the middle cerebellar peduncles secondary to pontine infarction: A case series. AB - OBJECTIVE: Wallerian degeneration (WD) of middle cerebellar peduncles (MCPs) secondary to pontine infarction is rarely reported in the literature. Our aim in this study is to characterize its clinical and neuroradiological features. METHODS: A retrospective review of 7 patients from a single institution was conducted. Only patients with pontine infarction and subsequent degeneration of the MCPs were included in the analysis. The features of clinical presentation and neuroimaging finding were summarized by our experienced neurologists. RESULTS: Seven patients (5 male, 2 female), ranging in age from 50 to 77 years, satisfied the inclusion criteria. All patients had cardiovascular risk factors and hypertension was the most common one. Almost all of the patients had hemiparesis and dysarthria, and could achieved good clinical outcome. On the initial scan, hyperintense on T2- and diffusion-weighted images suggested the acute pontine infarction. On the follow-up scan, however, hyperintensities of bilateral MCPs on T2-weight and FLAIR images were apparently demonstrated in all patients. The specific lesions in the MCPs were attributed to bilateral WD of the pontocerebellar fibres secondary to pontine infarction. CONCLUSION: WD should be taken into account when patients are initially diagnosed with paramedian pontine infarction and follow-up MRI manifest as symmetrical hyperintense in the MCPs. PMID- 29627017 TI - Effect of teriflunomide on gray and white matter brain pathology in multiple sclerosis using volumetric and diffusion-tensor imaging MRI measures. AB - OBJECTIVES: To investigate the effect of teriflunomide on microstructural pathology in the gray matter (GM) and white matter (WM), as measured by changes in brain volume and diffusion-tensor imaging (DTI) in patients with multiple sclerosis (MS). METHODS: 30 relapsing MS patients and 20 healthy controls (HCs) were enrolled in the study and followed prospectively for 12 months with clinical and 3T MRI examinations. Of those, 26 MS patients and 18 HCs completed the 6 month and 22 MS and 16 HCs patients the 12-month follow-up. Whole brain, GM, WM and thalamus volumes, and global and tract-based spatial statistics (TBSS) DTI measures of fractional anisotropy, mean, axial and radial diffusivity were obtained in the thalamus and normal appearing WM (NAWM). MRI differences between the groups were compared using non-parametric statistical methods due to sample size limitations, followed by post-hoc covariate-adjusted models. RESULTS: At baseline, MS patients showed more severe brain volume and DTI measures compared to HCs (p < .05). At follow-up, no significant differences for brain volume and global and TBSS DTI measures between MS patients and HCs were found. No clinical progression or serious adverse events occurred in MS patients over the follow-up. CONCLUSIONS: MS patients did not significantly deteriorate over the follow-up in brain volume or thalamus/NAWM global or TBSS DTI measures, compared to HCs. This suggests that treatment with teriflunomide could potentially slow down accumulation of microstructural tissue damage in the GM and NAWM. PMID- 29627019 TI - Intercepting Parkinson disease non-motor subtypes: A proof-of-principle study in a clinical setting. AB - The construct of non-motor symptoms (NMS) subtyping in Parkinson Disease (PD) is emerging as a line of research in the light of its potential role in etiopathological interpretation of PD heterogeneity. Different approaches of NMS subtyping have been proposed: an anatomical model suggests that NMS aggregate according to the underpinning pathology; other researchers find aggregation of NMS according to the motor phenotype; the contribution of genetic background to NMS has also been assessed, primarily focusing on cognitive impairment. We have analyzed NMS burden assessed through an extensive clinical and neuropsychological battery in 137 consecutive non-demented PD patients genotyped for MAPT haplotypes (H1/H1 vs H2 carriers) in order to explore the applicability of the "anatomo clinical", "motor" or "genetic" models for subtyping PD in a clinical setting; a subsequent independent analysis was conducted to verify a possible cluster distribution of NMS. No clear-cut NMS profiles according to the previously described models emerged: in our population, the autonomic dysfunctions and depressive symptoms represent the leading determinant of NMS clusters, which seems to better fit with the hypothesis of a "neurotransmitter-based" model. Selective preferential neurotransmitter network dysfunctions may account for heterogeneity of PD and could address translational research. PMID- 29627020 TI - Cerebral small vessel disease caused by a novel heterozygous mutation in HTRA1. PMID- 29627021 TI - The incidental finding of elevated anti GQ1B antibodies in a patient with selective small fiber neuropathy. AB - Small fiber neuropathy (SFN) selectively affects small diameter sensory and/or autonomic axons. Pain and autonomic dysfunctions are the most common symptoms. SFN occurs in several autoimmune diseases and autoantibodies against neuronal proteins may play a role in SFN pathophysiology. Anti-GQ1b antibody has been associated with Miller Fisher syndrome, Bickerstaff's brainstem encephalitis, acute ophthalmoplegia, pharyngeal-cervical-brachial weakness and peripheral neuropathy involving large fibers. Isolated SFN associated with anti-GQ1b antibodies has not been previously reported. Here we report a 45-year-old woman presenting with highly positive anti-GQ1b titer and selective SFN without central nervous system or peripheral large nerve involvement. She improved upon administration of adalizumab. Further studies will clarify a possible pathogenetic role of antiganglioside antibodies in SFN. Moreover, the recognition of antiganglioside antibodies in SFN may have therapeutic consequences with patients who would benefit from immunotherapy. PMID- 29627022 TI - Hyperglycemia predicts unfavorable outcomes in acute ischemic stroke patients treated with intravenous thrombolysis among a Chinese population: A prospective cohort study. AB - BACKGROUND AND PURPOSE: Poorly controlled blood glucose was reported to cause deterioration of acute ischemic stroke. In this study, we investigated whether an elevated admission serum glucose level in the 3-h time window of intravenous thrombolysis for acute ischemic stroke determined poor functional outcomes among Chinese population. METHODS: This was a prospective cohort study. From December 1, 2004 to December 31, 2016, a total of 2370 patients were enrolled and categorized into two cohorts by blood glucose levels of >=200 and <200 mg/dl in the 3 h after stroke onset. The primary objective was to determine whether admission hyperglycemia increased major disability and death at 30 and 90 days, which was defined by a modified Rankin Scale of 3-6. The secondary objective was to determine whether admission hyperglycemia increased the symptomatic intracranial hemorrhage (SICH) at 90 days. The number needed to harm (NNH) and patient expected event rate (PEER) were evaluated for both the primary and secondary objectives. RESULTS: The primary outcome occurred in 216 of 305 patients (70.8%) in the blood glucose >=200 mg/dl cohort and in 951 of 1587 patients (59.9%) in the blood glucose <200 mg/dl cohort at 30 days, and in 191 of 287 patients (66.6%) in the blood glucose >=200 mg/dl cohort and in 827 of 1517 patients (54.5%) in the blood glucose <200 mg/dl cohort at 90 days. Patients with admission hyperglycemia had significantly increased major disability and death at 30 (adjusted relative risk (RR): 1.194 [1.073-1.329], p = 0.0012) and 90 days (adjusted RR: 1.203 [1.079-1.340], p = 0.0008). Admission hyperglycemia increased the risk of the occurrence of SICH by nearly 2-fold (adjusted RR: 1.891 [0.977 3.657], p = 0.0585 with the SITS-MOST criteria and adjusted RR: 1.884 [1.138 3.121], p = 0.0139 with the NINDS criteria). NNH values of admission hyperglycemia in major disability and death at 30 and 90 days were 9 and 10, and NNH values of SICH by the SITS-MOST NINDS criteria were 44 and 34, respectively. CONCLUSIONS: The study evidenced the association and temporal relationship of admission hyperglycemia causing deterioration of functional outcomes and increased SICH among Chinese population with acute ischemic stroke treated with intravenous thrombolysis. PMID- 29627024 TI - The Glasgow Outcome Scale Extended-Revised (GOSE-R) to include minimally conscious state in the vegetative state category. PMID- 29627023 TI - Motor and non-motor features of Parkinson's disease in LRRK2 G2019S carriers versus matched controls. AB - INTRODUCTION: LRRK2 G2019S mutation carriers with Parkinson's disease (PD) have been generally indistinguishable from those with idiopathic PD, with the exception of variable differences in some motor and non-motor domains, including cognition, gait, and balance. LRRK2 G2019S is amongst the most common genetic etiologies for PD, particularly in Ashkenazi Jewish (AJ) populations. METHODS: This cross-sectional data collection study sought to clarify the phenotype of LRRK2 G2019S mutation carriers with PD. Primary endpoints were the Movement Disorder Society Unified Parkinson Disease Rating Scale (MDS-UPDRS) and Montreal Cognitive Assessment (MoCA). Other motor and non-motor data were also assessed. The Mann-Whitney U Test was utilized to compare LRRK2 G2019S carriers with PD (LRRK2+) with non-carrier PD controls who were matched for age, gender, education, and PD duration. Survival analyses and log rank tests were utilized to compare interval from onset of PD to development of motor and non-motor complications. RESULTS: We screened 251 subjects and 231 completed the study, of whom 9 were LRRK2+, including 7 AJ subjects. 22.73% of AJ subjects with a family history of PD (FH) and 12.96% of AJ subjects without a FH were LRRK2+. There were no significant differences between the 9 LRRK2+ subjects and 19 matched PD controls in MDS-UPDRS, MoCA, or other motor and non-motor endpoints. CONCLUSION: Prevalence of the LRRK2 G2019S mutation in AJ and non-AJ subjects in our study population in Cleveland, Ohio was comparable to other clinical studies. There were no significant motor or non-motor differences between LRRK2+ PD and matched PD controls. PMID- 29627025 TI - Cerebrovascular imaging of cerebral ischemia in acute type A aortic dissection. AB - BACKGROUND AND PURPOSE: Stanford type A aortic dissection (AAD) sometimes causes acute ischemic stroke (AIS) or transient ischemic attack (TIA). There is little understanding of cerebrovascular imaging of AIS or TIA in patients with AAD. METHODS: Consecutive AIS/TIA patients with AAD who were admitted within 4.5 h of onset were reviewed. We compared findings of MRI/MRA between these and consecutive AIS/TIA patients without AAD within 4.5 h of onset. RESULTS: Seventeen AAD and 249 non-AAD patients were identified. Compared to non-AAD patients, AAD patients had infarcts more frequently in the right anterior cerebral artery (ACA) territory (18% vs. 2%, P = 0.007) and the right middle cerebral artery (MCA) territory (71% vs. 29%, P < 0.001). There was no difference between the groups regarding whether it was perforator or cortical infarct, single or multiple infarcts, unilateral or bilateral infarcts, or ischemic change extension. On the MRA imaging, the AAD patients more frequently had poor visualization of the right internal carotid artery (ICA) (47% vs. 6%, P < 0.001). After adjustment for sex, age and confounding factors, the right ACA territory infarct [odds ratio (OR), 12.2; 95% confidence interval (CI), 1.4-119.4], the MCA territory infarct (OR, 4.9; 95% CI, 1.0-25.0) and poor visualization of the right ICA (OR, 18.1; 95% CI, 4.0-101.9) were independently associated with AAD. CONCLUSION: In emergency AIS/TIA patients, right anterior circulation infarct and poor visualization of the right ICA on cerebrovascular imaging are potential imaging markers of AAD. PMID- 29627026 TI - Ganciclovir and foscarnet dual-therapy for cytomegalovirus encephalitis: A case report and review of the literature. AB - Cytomegalovirus (CMV) is a ubiquitous herpesvirus which establishes lifelong latency following primary infection. It is then capable of reactivating in the face of immunosuppression. Encephalitis is a less common, but particularly devastating syndrome associated with CMV. Here, we describe a case of CMV encephalitis in an allogeneic hematopoietic stem cell transplant recipient who received dual antiviral therapy with ganciclovir and foscarnet. The case presentation is followed by a summary of cases reported in the last ten years, with the goal of describing vulnerable patient populations, treatment courses, and outcomes. Finally, the discussion includes a review of the literature, with a focus on diagnostic criteria and the role for dual antiviral therapy in CMV encephalitis. PMID- 29627027 TI - Paroxysmal painful spasms associated with central pontine myelinolisis in the context of nonketotic hyperglycemia. PMID- 29627028 TI - Juvenile-onset neuronal ceroid lipofuscinosis (CLN1) disease with a novel deletion and duplication in the PPT1 gene. PMID- 29627029 TI - Reported concussion incidence in youth community Rugby Union and parental assessment of post head injury cognitive recovery using the King-Devick test. AB - AIM: To assess the frequency of reported head injuries in youth community Rugby Union and determine whether the King-Devick (K-D) test could be used by parents as a means to chart cognitive recovery following head injury. METHODS: A prospective cohort study of 489 junior players (U9-U18) conducted at a community level Rugby Union club over four seasons. All players undertook a baseline K-D test at the start of each season. Players identified with suspected concussion performed the K-D test post injury and results were compared to their most recent baseline assessment. Parent/Guardians of the player then oversaw repeated daily testing until baseline scores were surpassed. RESULTS: 49 players were sent for assessment after suspected head injury. 46 parents oversaw daily repeated K-D testing (93.8% engagement). The median reduction in K-D test performance speed post-injury from baseline was 7.32 s (IQR 2.46 - 7.98). A median of 5.1 days/tests were taken for players to surpass baseline performance. No correlation was found between initial post-injury test and cognitive recovery time. 38 head injuries were reported from match play with an incidence rate of 12.7 per 1000 match hours (95% CI 9.2-17.5). CONCLUSION: The K-D test is a practical tool for baseline, post injury and parentally supervised repeated testing within youth community Rugby Union. Incidence of reported head injuries following match play is higher than previously reported. Parental engagement was high. Post-Injury K-D test performance should not be used as a means to predict symptom recovery. PMID- 29627030 TI - Potential therapeutic effect of repetitive transcranial magnetic stimulation for tremor in Minamata disease: A case report. PMID- 29627031 TI - Pregnancy outcomes in women with spinal muscular atrophy: A review. AB - Spinal muscular atrophy (SMA) is an autosomal recessive disease characterized by muscle weakness and atrophy resulting from progressive degeneration and loss of the anterior horn cells in the spinal cord and brain stem nuclei. The onset of weakness ranges from prenatal age to young adulthood. Thus, many female patients reach fertile age and may consider getting pregnant. However, only little information is available about outcomes and complications of pregnancy in women with SMA. In this review, we compared different studies on the subject, then we analyzed outcomes in the different stages of the pregnancy (preconceptional period, embryonal period, fetal period, delivery and post partum), with a special focus on maternal and fetal complications, prematurity, mode of delivery, anesthesiological risk, respiratory function and influence of pregnancy on the disease course. This is the first review focused exclusively on pregnancy in women affected by SMA. Our aim is to help clinicians who wish to understand the risks connected with pregnancy in SMA patients and to manage pregnancy course and delivery in an evidence-based and patient-oriented manner. PMID- 29627033 TI - A mild myopathy with anti-SRP plus anti-PL-12 antibodies successfully treated by oral steroid monotherapy. PMID- 29627032 TI - Factors associated with distal symmetric polyneuropathies in adult Zambians: A cross-sectional, observational study of the role of HIV, non-antiretroviral medication exposures, and nutrition. AB - BACKGROUND: Non-antiretroviral (ART) drug exposures and poor nutrition may be important modifiable risk factors for distal symmetric polyneuropathies (DSP) in sub-Saharan Africa. METHODS: We conducted a cross-sectional study of DSP prevalence and factors associated with DSP among clinic attendees in urban and rural Zambia. All participants underwent neurologist-performed examination. Laboratory investigations seeking comorbid risk factors for DSP were performed for DSP cases. RESULTS: We identified 31/137 (22.6%) HIV+ and 21/177 (11.9%) HIV- DSP cases. DSP prevalence did not differ by urbanicity, although rural participants were significantly more likely to have one asymptomatic DSP sign. Low dietary diversity, history of syphilis, history of tuberculosis, and prior metronidazole and ciprofloxacin use were associated with DSP amongst HIV+ cases, while age and education were associated with DSP in HIV- participants (all p values < 0.05). In a multivariate logistic regression model, HIV (p = 0.0001) and age (p < 0.0001), and ciprofloxacin exposure (p = 0.01) remained independently associated with DSP. While diabetes was rare, supoptimal micronutrients levels were common among DSP cases regardless of HIV status. CONCLUSIONS: While HIV infection is strongly associated with DSP in Zambia, history of non-ART drug exposures and low dietary diversity are also important determinants of DSP in HIV+ individuals. Treatable micronutrient deficiencies were common. PMID- 29627034 TI - Comparison of the abbreviated minimal assessment of cognitive function in multiple sclerosis (aMACFIMS) and the brief international cognitive assessment for multiple sclerosis (BICAMS). AB - BACKGROUND: Cognitive impairment is a prevalent and often intrusive problem among persons with multiple sclerosis (PwMS). Valid and reliable assessments, including quick screening measures, are crucial. The Brief International Cognitive Assessment for MS (BICAMS) was developed for this reason. While it lends itself to use in locations where formal neuropsychological resources might be limited, it does not include measures of verbal fluency or executive functioning, domains assessed as part of the Minimal Assessment of Cognitive Function in MS (MACFIMS). OBJECTIVE: Given previous evidence that shortened MACFIMS measures have strong criterion validity, this study aimed to determine which of these should be included in the abbreviated MACFIMS (aMACFIMS), and how the aMACFIMS compares to the BICAMS. METHODS: One hundred forty-seven PwMS were included in the analyses. A stepwise logistic regression was used to determine the measures in the aMACFIMS. Receiver-operating-characteristic (ROC) curves assessed the classification accuracy, sensitivity, and specificity. The batteries' sensitivity, specificity, and predictive values were then compared. RESULTS: Compared to the BICAMS, the final aMACFIMS had higher specificity (87% versus 72%) and positive predictive value (86% versus 77%), but lower sensitivity (71% versus 81%). CONCLUSION: The aMACFIMS has several benefits, including reduced administration time and the addition of a verbal fluency/executive functioning measure. PMID- 29627035 TI - Acute and reversible crying following deep brain stimulation targeting the globus pallidus interna in dystonia. PMID- 29627036 TI - Nocebo in chronic inflammatory demyelinating polyneuropathy; a systematic review and meta-analysis of placebo-controlled clinical trials. AB - INTRODUCTION: Nocebo is very prevalent among neurological disorders, resulting in low adherence and treatment outcome. We sought to examine the adverse events (AE) following placebo administration in placebo-controlled randomized clinical trials (RCTs) for chronic inflammatory demyelinating polyneuropathy (CIDP). METHODS: After a systematic literature search for RCTs for CIDP pharmacotherapy treatments, we assessed the number of AE in the placebo groups and the number discontinuations because of placebo intolerance. RESULTS: Our literature search strategy revealed 82 papers. Data were extracted from three RCTs fulfilling our inclusion criteria. Approximately two in five placebo-treated patients (42.0%) reported at least one AE and approximately one in fifty placebo-treated patients discontinued placebo treatment because of AEs (2.1%). All patients participating in the CIDP trials reported similar AEs independently of the study arm they belonged. CONCLUSION: Compared to other neurological diseases the nocebo effect in CIDP is significantly smaller. PMID- 29627037 TI - Neuronal intranuclear hyaline inclusion disease presenting with childhood-onset night blindness associated with progressive retinal dystrophy. PMID- 29627038 TI - Combining clinical and magnetic resonance imaging markers enhances prediction of 12-year employment status in multiple sclerosis patients. AB - BACKGROUND: Multiple sclerosis (MS) is frequently diagnosed in the most productive years of adulthood and is often associated with worsening employment status. However, reliable predictors of employment status change are lacking. OBJECTIVE: To identify early clinical and brain magnetic resonance imaging (MRI) markers of employment status worsening in MS patients at 12-year follow-up. METHODS: A total of 145 patients with early relapsing-remitting MS from the original Avonex-Steroids-Azathioprine (ASA) study were included in this prospective, longitudinal, observational cohort study. Cox models were conducted to identify MRI and clinical predictors (at baseline and during the first 12 months) of worsening employment status (patients either (1) working full-time or part-time with no limitations due to MS and retaining this status during the course of the study, or (2) patients working full-time or part-time with no limitations due to MS and switching to being unemployed or working part-time due to MS). RESULTS: In univariate analysis, brain parenchymal fraction, T1 and T2 lesion volume were the best MRI predictors of worsening employment status over the 12-year follow-up period. MS duration at baseline (hazard ratio (HR) = 1.10, 95% confidence interval (CI) 1.03-1.18; p = 0.040) was the only significant clinical predictor. Having one extra milliliter of T1 lesion volume was associated with a 53% greater risk of worsening employment status (HR = 1.53, 95% CI 1.16-2.02; p = 0.018). A brain parenchymal fraction decrease of 1% increased the risk of worsening employment status by 22% (HR = 0.78, 95% CI 0.65-0.95; p = 0.034). CONCLUSION: Brain atrophy and lesion load were significant predictors of worsening employment status in MS patients. Using a combination of clinical and MRI markers may improve the early prediction of an employment status change over long-term follow-up. PMID- 29627039 TI - Peripheral nervous system involvement in Leber's hereditary optic neuropathy. PMID- 29627040 TI - Insulin resistance and cognitive test performance in elderly adults: National health and nutrition examination survey (NHANES). AB - OBJECTIVES: To examine the relationship between homeostatic model of insulin resistance (HOMA-IR) and cognitive test performance among population>=60years in a national database. HYPOTHESIS: Higher insulin resistance is associated with lower cognitive test performance score in the population>=60years. PARTICIPANTS: We analyzed data from the National Health and Nutrition Examination Survey (NHANES) 1999-2000 and 2001-2002. MEASUREMENTS: Cognitive test performance was measured by the Digit Symbol Substitution (DSS) exercise score. The main independent variable was the homeostasis model assessment of insulin resistance (HOMA-IR). We used bivariate analysis and generalized linear model adjusting for age, gender, race, education, body mass index, and systolic and diastolic blood pressures; total cholesterol, low density lipoprotein (LDL), high density lipoprotein (HDL) and triglyceride levels; and physical activity, diabetes mellitus, stroke, and congestive heart failure. STATA 14 was used to analyze the data taking into consideration the design, strata and weight. RESULTS: Of the 1028 participants, 44% were male and 85% were white. The mean age was 70.0+/-0.28 (SE) years. Their average HOMA-IR was 3.6+/-0.14 and they had a mean of 49.2+/ 0.8 correct DSS score in the cognitive test. Adjusting for the confounding variables, HOMA-IR was associated with decline in DSS score (B=-0.30, 95% confidence interval=-0.54 and -0.05, p=0.01). The model explained 44% of the variability of the DSS score (R2=0.44). Significant predictors of decline in DSS score were age, gender, race, and education (p=0.01). CONCLUSION: Insulin resistance as measured by HOMA-IR was independently associated with lower cognitive test performance score among elderly participants aged >=60years. Longitudinal studies are needed to test the mechanism and the causal relationship. PMID- 29627044 TI - Fundamental and Practical Aspects of Airway Anatomy: From Glottis to Segmental Bronchus. AB - The surgical anatomy of the airways from the glottis to segmental bronchi is reviewed with a focused review on pertinent anatomic findings surrounding common surgical procedures. The knowledge of the anatomy of the trachea while performing tracheostomy, tracheal and sleeve carinal resection, and bronchoplastic procedures is addressed. Pertinent anatomic relationships as evident on common computed tomographic imagery are emphasized. PMID- 29627043 TI - Birth of Airway Surgery and Evolution over the Past Fifty Years. AB - Significant developments in airway surgery occurred following the introduction of mechanical ventilators and intubation with cuffed endotracheal tubes during the poliomyelitis epidemic of the 1950s. The resulting plethora of postintubation injuries provided extensive experience with resection and reconstruction of stenotic tracheal lesions. In the early 1960s, it was thought that no more 2 cm of trachea could be removed. By the late 1960s, this was challenged owing to better knowledge of airway anatomy and blood supply, tension-releasing maneuvers, and improved anesthetic techniques. Currently, about half of the tracheal length can be safely removed and continuity restored by primary anastomosis. PMID- 29627045 TI - Advanced Technologies for Imaging and Visualization of the Tracheobronchial Tree: From Computed Tomography and MRI to Virtual Endoscopy. AB - Advanced imaging plays an increasingly important role in the evaluation of the trachea. The use of computed tomography (CT) has evolved to include multi-planar reconstructions and 3-dimensional reconstructions for the evaluation of benign and malignant disease of the trachea. Advanced applications of CT include dynamic expiratory imaging for the diagnosis of tracheomalacia and virtual endoscopy as a complementary or alternative examination to flexible bronchoscopy. MRI of the trachea has limited applications but may see increased use in the future. PMID- 29627041 TI - Obesity and asthma. AB - Obesity is a vast public health problem and both a major risk factor and disease modifier for asthma in children and adults. Obese subjects have increased asthma risk, and obese asthmatic patients have more symptoms, more frequent and severe exacerbations, reduced response to several asthma medications, and decreased quality of life. Obese asthma is a complex syndrome, including different phenotypes of disease that are just beginning to be understood. We examine the epidemiology and characteristics of this syndrome in children and adults, as well as the changes in lung function seen in each age group. We then discuss the better recognized factors and mechanisms involved in disease pathogenesis, focusing particularly on diet and nutrients, the microbiome, inflammatory and metabolic dysregulation, and the genetics/genomics of obese asthma. Finally, we describe current evidence on the effect of weight loss and mention some important future directions for research in the field. PMID- 29627047 TI - Biology of Adenoid Cystic Carcinoma of the Tracheobronchial Tree and Principles of Management. AB - Adenoid cystic carcinoma of the trachea is a rare tumor. The mainstay of treatment remains surgical resection, even in the presence of positive margins or metastatic disease. Perineural involvement commonly causes positive margins and should not deter from resection. Knowledge of releasing maneuvers is essential for surgical success. Long-term follow-up is required with patients presenting late and surviving with recurrent disease for years. PMID- 29627046 TI - Tracheal Injuries Complicating Prolonged Intubation and Tracheostomy. AB - Respiratory care advances such as the introduction of ventilatory assistance have been associated with postintubation airway stenosis resulting from tracheal injury at the site of the inflatable cuff on endotracheal or tracheostomy tubes. Low-pressure cuffs have significantly reduced this occurrence. Loss of airway stability at the site of a tracheostomy stoma may result in tracheal stenosis. Subglottic stenosis may result from a high tracheostomy site at, or just inferior to, the cricoid arch, or to malposition of an endotracheal tube cuff. Awareness of these complications and their causes is essential to prevent their occurrence. PMID- 29627048 TI - Pathology of Primary Tracheobronchial Malignancies Other than Adenoid Cystic Carcinomas. AB - Most primary tracheal tumors are malignant. Malignancy of larynx and bronchi are much more likely than trachea. Tracheal tumors are most likely due to direct extension for surrounding tumors. Squamous cell carcinoma and adenoid cystic carcinoma make up about two-thirds of adult primary tracheal tumors. Because of their predominantly local growth pattern, malignant salivary gland-type tumors show a better outcome than other histologic types. PMID- 29627049 TI - Tuberculosis and Other Granulomatous Diseases of the Airway. AB - Granulomatous diseases of the airway are challenging lesions to diagnose and effectively manage not only because they are uncommon but also because they can occur in different forms, each with unique clinical and radiological characteristics. Most such lesions can be effectively managed conservatively with repeated airway dilatation, use of intraluminal stents, and specific antimicrobial treatment. The only exception is those lesions presenting with localized airway obstruction wherein surgical resection may be indicated and beneficial. PMID- 29627050 TI - Tracheobronchomalacia and Expiratory Collapse of Central Airways. AB - Tracheobronchomalacia is an uncommon acquired disorder of the central airways. Common symptoms include dyspnea, constant coughing, inability to raise secretions, and recurrent respiratory infections. Evaluation includes an inspiratory-expiratory chest CT (dynamic CT), an awake functional bronchoscopy, and pulmonary function studies. Patients with significant associated symptoms and severe collapse on CT and bronchoscopy are offered membranous wall plication. Tracheobronchoplasty is performed through a right thoracotomy. The posterior airway is exposed after the azygous vein is ligated. Patients report generally good results with improvement of their symptoms. Quality of life is usually improved, whereas pulmonary function tests usually are not improved. PMID- 29627052 TI - Partial Cricotracheal Resection and Extended Cricotracheal Resection for Pediatric Laryngotracheal Stenosis. AB - The management of pediatric laryngotracheal stenosis remains a challenging problem for the surgeon. The complexity of the various preoperative situations implies that no single treatment modality can solve the problem. This article focuses on the yield of partial cricotracheal resection and extended cricotracheal resection for the most severe grades of stenosis. Overall decannulation rates of 95% and 100% can be expected for isolated subglottic stenosis in patients with and without comorbidities but only 68% and 90% for patients with glotto-subglottic stenosis, respectively. Predictors of less favorable outcomes are severity of the stenosis, glottic involvement, and presence of comorbidities. PMID- 29627051 TI - Contemporary Management of Idiopathic Laryngotracheal Stenosis. AB - Idiopathic laryngotracheal stenosis is a rare but well-described indication for subglottic tracheal resection. Initially described by Pearson in 1975, the 1 stage subglottic tracheal resection with reconstruction of the airway ensures preservation of the recurrent laryngeal nerves while resulting in an effective and durable repair of the stenosis. PMID- 29627053 TI - Laryngeal Split and Rib Cartilage Interpositional Grafting: Treatment Option for Glottic and Subglottic Stenosis in Adults. AB - Optimal management of tracheal stenosis depends on identifying causative factors. Risk factors include high tracheostomy, cricothyroidotomy, prolonged intubation, and proximal migration of an endotracheal tube cuff. Management ranges from conservative observation to endoscopic procedures or open surgical resections. The goal of surgical repair is an adequate airway, decannulation, and normal laryngeal function. For early stage disease, management of refractory conditions is via endoscopic procedures. An understanding of the respiratory function of the glottis and subglottis is essential when an optimum functional reconstruction of the glottic/subglottic area is considered. In this article we discuss different airway assessments and surgical management techniques. PMID- 29627054 TI - Distal Tracheal Resection and Reconstruction: State of the Art and Lessons Learned. AB - Tracheal disease is an infrequent problem requiring surgery. A high index of suspicion is necessary to correctly diagnose the problems. Primary concerns are safe control and assessment of the airway, familiarity with the principles of airway surgery, preserving tracheal blood supply, and avoiding anastomotic tension. A precise reproducible anastomotic technique must be mastered. Operation requires close cooperation with a knowledgeable anesthesia team. The surgeon must understand how to achieve the least tension on the anastomosis to avoid. It is advisable to examine the airway before discharge to check for normal healing and airway patency. PMID- 29627055 TI - Factors Favoring and Impairing Healing of Tracheal Anastomosis. AB - The factors governing successful healing of and impairing of tracheal and bronchial anastomosis are best understood by reviewing the normal histologic changes accompanying healing, governing factors, and biochemical advances made in the last 5 decades. Normal wound healing factors, also relevant to tracheal and bronchial reconstruction, rely on precise handling of tissues without interfering with tissue perfusion, careful selection and placement of sutures, and steps to minimize tension. Impairments of satisfactory healing are well recognized in gastrointestinal surgery and apply to tracheal and carinal resection, and sleeve bronchial resection. PMID- 29627056 TI - Airway Management Following Tracheal Surgery. AB - The ability to remove longer segments of airway and to extend resections into the larynx proper has managed to create novel situations that will require attention to postoperative management. This article deals with prophylactic measures to prevent the requirement of assisted ventilation. It, however, also emphasizes various bronchoscopic and intubation techniques, which if required, will help to avoid trauma to the airway anastomosis. In addition, a variety of ventilator modalities are discussed that were developed by the author over many years at the Toronto General Hospital. PMID- 29627058 TI - Nonoperative Endoscopic Management of Benign Tracheobronchial Disorders. AB - Modern thoracic surgery requires knowledge and skill in advanced bronchoscopic techniques. Rigid bronchoscopy remains a workhorse for the management of central airway obstruction. Dilation of tracheal strictures is now much simpler with the advent of the balloon dilator, which can be passed through a therapeutic bronchoscope. Numerous adjuncts, such as laser, argon beam coagulation, electrocautery, and cryotherapy, can be used to improve airway patency. There are now numerous stenting options for strictures that require stenting to maintain airway patency. PMID- 29627057 TI - Prophylaxis and Treatment of Complications After Tracheal Resection. AB - Tracheal resections are major surgical procedures with a complication rate as high as 44%. Early detection of complications followed by a structured and expedited course of action is critical for achieving a successful outcome. The prevention of complications after tracheal resection starts with a correct indication for resection. A thorough preoperative evaluation, meticulous surgical technique, and good postoperative care in a center that performs airway surgery routinely are important factors for achieving good results. PMID- 29627060 TI - Tribute to Frederick Griffith Pearson (1926-2016). PMID- 29627059 TI - Fundamentals of Airway Surgery, Part I. PMID- 29627061 TI - Causal evidence in risk and policy perceptions: Applying the covariation/mechanism framework. AB - Today's information-rich society demands constant evaluation of cause-effect relationships; behaviors and attitudes ranging from medical choices to voting decisions to policy preferences typically entail some form of causal inference ("Will this policy reduce crime?", "Will this activity improve my health?"). Cause-effect relationships such as these can be thought of as depending on two qualitatively distinct forms of evidence: covariation-based evidence (e.g., "states with this policy have fewer homicides") or mechanism-based (e.g., "this policy will reduce crime by discouraging repeat offenses"). Some psychological work has examined how people process these two forms of causal evidence in instances of "everyday" causality (e.g., assessing why a car will not start), but it is not known how these two forms of evidence contribute to causal judgments in matters of public risk or policy. Three studies (n = 715) investigated whether judgments of risk and policy scenarios would be affected by covariation and mechanism evidence and whether the evidence types interacted with one another (as suggested by past studies). Results showed that causal judgments varied linearly with mechanism strength and logarithmically with covariation strength, and that the evidence types produced only additive effects (but no interaction). We discuss the results' implications for risk communication and policy information dissemination. PMID- 29627062 TI - Immune active cells with 4-1BB signal enhancement inhibit hepatitis B virus replication in noncytolytic manner. AB - Immune active cells (IACs) have been shown to be an alternative immunotherapy for CHB patients. However, there is a practical problem of different expansion rate and function of HBV inhibition as individual variability exists. Our previous studies have confirmed that the proliferation and cytolysis of IACs were significantly up-regulated by engineered cells for costimulatory enhancement (ECCE) delivering a 4-1BBzeta activating signal. In this study, we aimed to investigate the contribution of ECCE to IACs from CHB patients. We found that ECCE could enhance larger-scale expansion of IACs and the levels of HBV-markers were reduced prominently with minimal cytolysis, in the indirect system which separated ECCE-IACs and HepG2.2.15 by a 0.4-MUm membrane. Furthermore, ECCE-IACs produced a lot of IFN-gamma and TNF-alpha. Blockading them, the inhibition was abrogated. These results provide direct evidence that ECCE-IACs efficiently control HBV replication in a noncytolytic manner, and this effect is mediated by IFN-gamma and TNF-alpha. PMID- 29627063 TI - High fiber dietary and sodium butyrate attenuate experimental autoimmune hepatitis through regulation of immune regulatory cells and intestinal barrier. AB - Autoimmune hepatitis (AIH) is chronic autoimmune liver disease accompanied with the imbalance of Treg/Th17 and increased intestinal permeability. We investigated the effects of a high fiber diet and sodium butyrate on the Treg/Th17 and intestinal barrier function in an experimental autoimmune hepatitis. Intraperitoneal injection of hepatic antigen (S100) was used to induce experimental autoimmune hepatitis mice model and mice were divided into normal control, S100 model control, S100 plus high fiber diet and S100 plus sodium butyrate. Serum aminotransferases and liver histology were examined. Short chain fatty acids in feces were determined by HPLC. The ratio of CD4 + C25 + Foxp3+ Treg and CD4 + IL-17 + Th17 were evaluated by flow cytometry. Tight junction proteins Zonula ocluden, Occludin and Claudin-1 were used to assess intestinal barrier function, so does Escherichia coli protein in the liver. Mice fed with either high fiber diet or sodium butyrate showed significantly lower levers of serum aminotransferases and minor liver injury compared to that of model control. Moreover, the ratio of Treg/Th17 was significantly higher in high fiber diet and sodium butyrate fed mice than that in model control. Furthermore, high fiber diet and sodium butyrate significantly increased intestinal tight junction proteins and decreased Escherichia Coli protein in the liver. In conclusion, high fiber diet and sodium butyrate can attenuate development of autoimmune hepatitis through regulation of immune regulatory cells and intestinal barrier function. PMID- 29627064 TI - Reply. PMID- 29627065 TI - WITHDRAWN: After a motor vehicle accident is it neurogenic thoracic outlet syndrome or ulnar entrapment syndrome? How to make the correct diagnosis. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at https://www.elsevier.com/about/our business/policies/article-withdrawal. PMID- 29627066 TI - Treatment of hepatocellular carcinoma in the caudate lobe: US-guided percutaneous radiofrequency ablation combined with ethanol ablation. AB - AIM: To evaluate the technical feasibility and treatment results of ultrasound (US)-guided percutaneous radiofrequency ablation (RFA) combined with ethanol ablation (EA) for hepatocellular carcinoma (HCC) in the caudate lobe. MATERIALS AND METHODS: The institutional review board approved this retrospective study and the requirement for informed consent was waived. From October 2009 to June 2016, there were 49 patients with HCC in the caudate lobe underwent ablation. Among them, 14 patients (12 men and two women, mean age: 49.9+/-14.9 years) with 16 caudate lobe HCCs (mean size: 3+/-1.1 cm) who underwent US-guided RFA-EA were identified. These patients were compared with patients who underwent RFA alone (n=17) and EA alone (n=18). RESULTS: HCCs in the RFA-EA group were larger than those in the EA-alone group (3+/-1.1 versus 2.1+/-0.7 cm, p=0.028). In the RFA-EA group, all the patients achieved treatment success (14/14) and entered follow-up. After a follow-up period of 17.1+/-10.6 months (range, 5-36 months), local tumour progression (LTP) was detected in four tumours. The 1- and 2-year LTP rates after RFA-EA were 18.8% and 27.8%, respectively. The 1- and 2-year disease-free survival (DFS) rates were 35.7% and 13.4%. Six patients died, with the 1-, 2-, and 3-year overall survival (OS) rates of 85.1%, 63.1%, and 21%, respectively. There were no significant differences in the LTP, DFS, and OS rates between the RFA-EA group and RFA-alone or EA groups (p=0.363-0.733). CONCLUSION: US-guided percutaneous RFA-EA appears to be a feasible and effective treatment for HCC in the caudate lobe. PMID- 29627067 TI - Novel developments in non-invasive imaging of peripheral arterial disease with CT: experience with state-of-the-art, ultra-high-resolution CT and subtraction imaging. AB - Despite advances, challenges remain for less invasive imaging of peripheral arterial occlusive disease (PAOD) using computed tomography (CT) angiography. The application of dual-energy imaging to PAOD has been reported to improve the diagnostic accuracy of this application; however, severe arteriosclerosis with heavy arterial wall calcification still hampers definitive lesion characterisation, especially in distal and smaller arteries. Recently an ultra high resolution scanner has been introduced. In combination with advances in post processing, such as subtraction techniques, these developments may overcome some of the current challenges and allow far more detailed characterisation of PAOD non-invasively. The aim of this review is to describe our current experience with ultra-high resolution CT in combination with subtraction and discuss the potential advantages of their application for peripheral angiography. PMID- 29627068 TI - Role of Fish Oil in Post-Cardiotomy Bleeding: A Summary of the Basic Science and Clinical Trials. AB - BACKGROUND: Omega-3 fatty acids are widely used. This article reviews the coagulopathic effects of fish oil. METHODS: A review was performed of all English articles that addressed the topic from 1980 to 2017. RESULTS: Fish oil induces an in vitro coagulopathy in humans due to inhibitory effects in platelet-to-platelet adhesion and platelet-stimulated thrombin generation. The effect from fish oil alone is weak, but it is enhanced and may become clinically noticeable in patients taking antiplatelet therapy, and, to a lesser extent, in patients on factor Xa inhibitors and warfarin. In the absence of other anticoagulants, fish oil alone is not capable of producing a clinically significant coagulopathy that would induce or contribute to surgical bleeding. CONCLUSIONS: Patients who are taking fish oil without other anticoagulants do not have an increased risk of bleeding surgical complications. Because of the highly variable amounts of actual eicosapentaenoic acid and docosahexaenoic acid in commercially available supplements, thromboelastography with platelet mapping would allow a surgeon to know if a coagulopathic effect is present in a patient taking fish oil, especially if the patient was also taking other anticoagulants. PMID- 29627069 TI - Immunoglobulin G particles manufacturing by spray drying process for pressurised metered dose inhaler formulations. AB - OBJECTIVE: The objective of this work is to show the feasibility of manufacturing from a spray drying process particles containing immunoglobulin G capable of being administered by inhalation via a pressurized metered dose inhaler. METHODS: Spray drying were made from aqueous solutions containing IgG and two types of excipients, mannitol and trehalose, with two ratios: 25% w/w and 75%w/w. The physicochemical and aerodynamic properties of the powders obtained were characterized just after manufacturing and after 1 month of storage at 40 degrees C/75% RH according to criteria defined as needed to satisfy an inhaled formulation with a pressurized metered dose inhaler. Maintain of the biological activity and the structure of IgG after atomization was also tested by slot blot and circular dichroism. RESULTS: All spray-dried powders presented a median diameter lower than 5MUm. The powders atomized with trehalose showed a solid state more stable than those atomized with mannitol. All atomized powders were in the form of wrinkled particles regardless the nature and the ratios of excipients. The results showed that the aerosolisation properties were compliant with the target, independently of the excipient used at a ratio of 25% w/w IgG excipient. Moreover, the addition of excipient during the atomization process the denaturation of IgG was limited. CONCLUSION: This study showed that the use of trehalose as excipient could satisfy the requirements of an inhaled formulation with a pressurized metered dose inhaler. PMID- 29627070 TI - The emerging importance of ultradian glucocorticoid rhythms within metabolic pathology. AB - Glucocorticoid (GC) hormones play significant roles within homeostasis and the chrono-dynamics of their regulatory role has become increasingly recognised within dysregulated GC pathology, particularly with metabolic phenotypes. Within this article, we will discuss the relevance of the ultradian homeostatic rhythm, how its dysregulation effects glucocorticoid receptor and RNA polymeraseII recruitment and may play a significant role within aberrant metabolic action. PMID- 29627071 TI - Ultrasound versus anatomical landmarks: Immediate complications in the central venous catheterization in children under 18 years of age. AB - INTRODUCTION: The insertion of a central venous line in children and adolescents is technically more difficult, due to the smaller size of the structures. This can lead to an increase in immediate complications, which can be reduced when using ultrasound. In our institution, the percentage of these complications and the use of ultrasound are unknown. OBJECTIVE: To describe the frequency of immediate complications of central venous catheterisation guided by the ultrasound in a general university hospital, compared to the anatomical landmarks technique in children less than 18years of age. MATERIALS AND METHODS: Observational, retrospective, and analytical study, comparing the frequency of complications with two central venous catheterisation techniques: anatomical landmarks and ultrasound, according to the clinical records of procedures performed from June to November 2016. RESULTS: A total of 201 procedural records were analysed, of which 71% were with landmarks, and 29% with ultrasound. The overall incidence of immediate complications was 18.4%, with 12% using ultrasound and 21% using landmarks (OR: 0.5; 95%CI: 0.2-1.2). Children under 5years of age presented with 90% of the complications, the most frequent being the impossibility of passing the guide (29.7%) and multiple punctures (24.3%). There was no arterial puncture with use of ultrasound. Ultrasound was used by 13.4% of paediatric surgeons, by 32.4% of paediatricians, and 46.4% of anaesthetists, with complications of 25%, 19%, and 7%, respectively. The main indication for catheterisation was the need for vasoactive agents (74%), with the procedure being more complicated in patients with no peripheral venous accesses (46%). The success rate with anatomical landmarks was 77.6%, compared to 91.4% with ultrasound. CONCLUSION: Central venous catheterisation with ultrasound guidance in children under 18 reduces immediate complications by 42.8% and improves the success rate by 13.8%. PMID- 29627072 TI - Burden, resilience and coping in caregivers of patients with interstitial lung disease. AB - RATIONALE: Prior work has described the experience of caregiving in idiopathic pulmonary fibrosis, but the effect on caregivers in interstitial lung disease (ILD) has not been explored. OBJECTIVES: Describe the burden, resilience, and health related quality of life (HRQoL) of caregivers of people with ILD. METHODS: In a mixed methods study, ILD caregivers completed questionnaires and participated in focus groups. A qualitative thematic analysis of the focus group transcripts was conducted. RESULTS: Thirty seven caregivers completed the survey, and 15 participated in the focus groups. 65% were female; the average age was 66 (SD = 13). The mean Short Form-36 role emotional and mental health scores were 18 (SD = 4) and 46 (SD = 7). The focus groups identified 4 major themes: emotional burden, changes in relationship, coping strategies, and unmet needs of caregivers. CONCLUSIONS: Caregiving for patients with ILD significantly impairs HRQoL, particularly, emotional health. Increasing resources could improve the caregiving experience in ILD. PMID- 29627074 TI - Risk profile of myocardial infarction in young versus older adults. AB - BACKGROUND: In developing countries, the number of adults who develop myocardial infarction (MI) at a young age is high. The popularity of waterpipe smoking (WPS) has increased among the same age group. It is unknown if WPS contributes to the incidence of early-onset MI. OBJECTIVE: To study the association of WPS with early-onset MI, which is defined as first MI occurring in individuals 18 >= age <= 45 years compared to those older than 45 years. METHODS: This was a cross sectional study. The association of WPS with first-time MI was compared between younger and older adults (N = 225). RESULTS: Twenty-five percent of all participants developed an acute MI before the age of 46 years. Both cigarette and WPS were more common among younger first-time MI patients than older first-time MI patients. CONCLUSIONS: WPS is one risk factor that distinguishes the risk profile of young adults with early-onset MI. PMID- 29627073 TI - Stress, cognitive appraisal, coping, and event free survival in patients with heart failure. AB - OBJECTIVES: To describe self-reported stress level, cognitive appraisal and coping among patients with heart failure (HF), and to examine the association of cognitive appraisal and coping strategies with event-free survival. METHODS: This was a prospective, longitudinal, descriptive study of patients with chronic HF. Assessment of stress, cognitive appraisal, and coping was performed using Perceived Stress Scale, Cognitive Appraisal Health Scale, and Brief COPE scale, respectively. The event-free survival was defined as cardiac rehospitalization and all-cause death. RESULTS: A total of 88 HF patients (mean age 58 +/- 13 years and 53.4% male) participated. Linear and cox regression showed that harm/loss cognitive appraisal was associated with avoidant emotional coping (beta = -0.28; 95% CI: -0.21 - 0.02; p = 0.02) and event free survival (HR = 0.53; 95% CI: 0.28 1.02; p = 0.05). CONCLUSIONS: The cognitive appraisal of the stressors related to HF may lead to negative coping strategies that are associated with worse event free survival. PMID- 29627076 TI - Tackling obesity seriously: the time has come. PMID- 29627075 TI - Congenital syphilis. AB - Congenital syphilis remains a major public health problem worldwide, and its incidence is increasing in the United States. This review highlights the ongoing problem of this preventable infection, and discusses vertical transmission and clinical manifestations while providing a practical algorithm for the evaluation and management of infants born to mothers with reactive serologic tests for syphilis. Every case of congenital syphilis must be seen as a failure of our public health system to provide optimal prenatal care to pregnant women, as congenital syphilis can be prevented by early and repeated prenatal serologic screening of mothers and penicillin treatment of infected women, their sexual partners, and their newborn infants. PMID- 29627077 TI - Poor qualitative analysis of Naled necessarily leads to incorrect quantitative analysis. AB - This correspondence is in regards to a published article, titled "Prenatal Naled and Chlorpyrifos Exposure is Associated with Deficits in Infant Motor Function in a Cohort of Chinese Infants" Silver et al., Environ Int., 2017 Sep; 106:248-256. Upon careful review of this work we identified some significant issues in the mass spectral analysis of naled, specifically its identification and quantification. In this communication we address these issues and provide analytical data and rationale to support our criticism of the reported work. We collected mass spectral data for naled (analytical standard grade) under a variety of mass spectrometric conditions in an attempt to obtain a fragmentation pattern similar to what was reported in Silver et al., 2017. We however, could not reproduce a similar fragmentation pattern under any of the tested experimental conditions. Our results however were in excellent agreement with the National Institute of Standards and Technology (NIST) database, which is a very well established and widely accepted resource for such compounds. This leads us to conclude that naled was in all probability misidentified in the reported (Silver et al., 2017) study which consequently raises serious questions regarding the quantification of naled in the blood samples thus placing the whole statistical correlation of naled as a contributor to impairment of motor function in infants in question. PMID- 29627078 TI - The roles of JAK2 in DNA damage and repair in the myeloproliferative neoplasms: Opportunities for targeted therapy. AB - The JAK2V617F-positive myeloproliferative neoplasms (MPN) serve as an excellent model for the study of genomic instability accumulation during cancer progression. Recent studies highlight the implication of JAK2 activating mutations in the development of DNA damage via reactive oxygen species (ROS) production, replication stress induction and the accumulation of genomic instability via the increased degradation of p53 and acquisition of a "mutagenic" phenotype. The accumulation of genomic instability and acquisition of mutations in critical DNA damage repair (DDR) mediators appears to be implicated in the progression of JAK2V617F-positive MPN. On the other hand, JAK2 signaling normally induces DDR through activation of repair mediators such as Chk1, RAD51 and RECQL5. These opposing effects on DNA integrity in the setting of JAK2V617F have significant clinical implications and have led to the introduction of novel combinational therapies for these diseases. The inhibition of MDM2 with Nutlin-3 improves the efficacy of IFN-alpha via decreased p53 degradation, the combination of hydroxyurea with Ruxolitinib, and their combination with PARP inhibitors have significant anti-tumor effects. A better understanding of the implication of JAK2 in the development and repair of DNA damage can improve our understanding of the biology of these neoplasms, meliorate the risk stratification of our patients and enrich our therapeutic armamentarium. PMID- 29627079 TI - Wear measurement of dental tissues and materials in clinical studies: A systematic review. AB - OBJECTIVES: This study aims to systematically review the different methods used for wear measurement of dental tissues and materials in clinical studies, their relevance and reliability in terms of accuracy and precision, and the performance of the different steps of the workflow taken independently. METHODS: An exhaustive search of clinical studies related to wear of dental tissues and materials reporting a quantitative measurement method was conducted. MedLine, Embase, Scopus, Cochrane Library and Web of Science databases were used. Prospective studies, pilot studies and case series (>10 patients), as long as they contained a description of wear measurement methodology. Only studies published after 1995 were considered. RESULTS: After duplicates' removal, 495 studies were identified, and 41 remained for quantitative analysis. Thirty-four described wear-measurement protocols, using digital profilometry and superimposition, whereas 7 used alternative protocols. A specific form was designed to analyze the risk of bias. The methods were described in terms of material analyzed; study design; device used for surface acquisition; matching software details and settings; type of analysis (vertical height-loss measurement vs volume loss measurement); type of area investigated (entire occlusal area or selective areas); and results. SINIFICANCE: There is a need of standardization of clinical wear measurement. Current methods exhibit accuracy, which is not sufficient to monitor wear of restorative materials and tooth tissues. Their performance could be improved, notably limiting the use of replicas, using standardized calibration procedures and positive controls, optimizing the settings of scanners and matching softwares, and taking into account unusable data. PMID- 29627080 TI - Assessment and management of diarrhea following VEGF receptor TKI treatment in patients with ovarian cancer. AB - Angiogenesis is a proven clinical target for the treatment of advanced epithelial ovarian cancer. Vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs) offer patients potential new treatment regimens as they can be given as monotherapy, in combination with poly(ADP-ribose) polymerase (PARP) inhibitors, or with and following cytotoxic chemotherapy. If VEGFR-TKIs are licensed for use in ovarian cancer, patients will require prompt and effective management of adverse events, including diarrhea, to optimize compliance and benefit. As diarrhea is one of the most prevalent toxicities of this class of drug, it is important to consider the potential causes, be they disease related (bowel obstruction), treatment related (VEGFR-TKI-related or infective/neutropenic septic diarrhea when patients are receiving cytotoxic chemotherapy combined with VEGFR inhibitor treatment), or incurred through diet. Here, we provide an overview of the possible mechanisms responsible for VEGFR-TKI induced diarrhea. We review potential interventions that can help in the management of diarrhea induced by VEGFR-TKIs, when used in combination or as single agents, and we provide a diarrhea treatment algorithm to serve as a clinical reference point for the management of diarrhea in patients with ovarian cancer treated with a VEGFR-TKI in combination with chemotherapy or PARP inhibitors, or as monotherapy. PMID- 29627081 TI - Vaccination against IL-31 for the treatment of atopic dermatitis in dogs. PMID- 29627082 TI - Treating insect-bite hypersensitivity in horses with active vaccination against IL-5. AB - BACKGROUND: Insect-bite hypersensitivity is the most common allergic dermatitis in horses. Excoriated skin lesions are typical symptoms of this seasonal and refractory chronic disease. On a cellular level, the skin lesions are characterized by massive eosinophil infiltration caused by an underlying allergic response. OBJECTIVE: To target these cells and treat disease, we developed a therapeutic vaccine against equine IL-5 (eIL-5), the master regulator of eosinophils. METHODS: The vaccine consisted of eIL-5 covalently linked to a virus like particle derived from cucumber mosaic virus containing the tetanus toxoid universal T-cell epitope tt830-843 (CMVTT). Thirty-four Icelandic horses were recruited and immunized with 400 MUg of eIL-5-CMVTT formulated in PBS without adjuvant (19 horses) or PBS alone (15 horses). RESULTS: The vaccine was well tolerated and did not reveal any safety concerns but was able to induce anti-eIL 5 autoantibody titers in 17 of 19 horses. This resulted in a statistically significant reduction in clinical lesion scores when compared with previous season levels, as well as levels in placebo-treated horses. Protection required a minimal threshold of anti-eIL-5 antibodies. Clinical improvement by disease scoring showed that 47% and 21% of vaccinated horses reached 50% and 75% improvement, respectively. In the placebo group no horse reached 75% improvement, and only 13% reached 50% improvement. CONCLUSION: Our therapeutic vaccine inducing autoantibodies against self IL-5 brings biologics to horses, is the first successful immunotherapeutic approach targeting a chronic disease in horses, and might facilitate development of a similar vaccine against IL-5 in human subjects. PMID- 29627083 TI - High-Frequency Quantitative Ultrasound for Imaging Prostate Cancer Using a Novel Micro-Ultrasound Scanner. AB - Currently, biopsies guided by transrectal ultrasound (TRUS) are the only method for definitive diagnosis of prostate cancer. Studies by our group suggest that quantitative ultrasound (QUS) could provide a more sensitive means of targeting biopsies and directing focal treatments to cancer-suspicious regions in the prostate. Previous studies have utilized ultrasound signals at typical clinical frequencies, i.e., in the 6-MHz range. In the present study, a 29-MHz, TRUS, micro-ultrasound system and transducer (ExactVu micro-ultrasound, Exact Imaging, Markham, Canada) was used to acquire radio frequency data from 163 patients immediately before 12-core biopsy procedures, comprising 1956 cores. These retrospective data are a subset of data acquired in an ongoing, multisite, 2000 patient, randomized, clinical trial (clinicaltrials.gov NCT02079025). Spectrum based QUS estimates of effective scatter diameter (ESD), effective acoustic concentration (EAC), midband (M), intercept (I) and slope (S) as well as envelope statistics employing a Nakagami distribution were used to train linear discriminant classifiers (LDCs) and support vector machines (SVMs). Classifier performance was assessed using area-under-the-curve (AUC) values obtained from receiver operating characteristic (ROC) analyses with 10-fold cross validation. A combination of ESD and EAC parameters resulted in an AUC value of 0.77 using a LDC. When Nakagami-u or prostate-specific antigen (PSA) values were added as features, the AUC value increased to 0.79. SVM produced an AUC value of 0.77, using a combination of envelope and spectral QUS estimates. The best classification produced an AUC value of 0.81 using an LDC when combining envelope statistics, PSA, ESD and EAC. In a previous study, B-mode-based scoring and evaluation using the PRI-MUS protocol produced a maximal AUC value of 0.74 for higher Gleason-score values (GS >7) when read by an expert. Our initial results with AUC values of 0.81 are very encouraging for developing a new, predominantly user-independent, prostate-cancer, risk-assessing tool. PMID- 29627084 TI - One-Lung Flooding Enables Ultrasound-Guided Transthoracic Needle Biopsy of Pulmonary Nodules with High Sensitivity. AB - Ultrasound-guided transthoracic needle biopsy (USgTTNB) can only be used for peripheral tumours that contact the pleura. Sonographic accessibility of the entire lung can be achieved using one-lung flooding. In this study, feasibility, sensitivity and complication rate of USgTTNB of lung nodules after one-lung flooding in an ex vivo and in vivo lung tumour model were assessed. USgTTNB was performed ex vivo after one-lung flooding in 10 resected human lung lobes containing carcinoma or metastasis. USgTTNB after one-lung flooding and simulation of a lung nodule was conducted in vivo in 5 animals. Transthoracic sonography and chest X-ray were obtained 30 min after reventilation. The lungs were examined macroscopically and histopathologically. The pathologic diagnosis was confirmed in 85.7% and 100% of tumours after first and second puncture attempts, respectively. The successful puncture rate in vivo was 90%. Neither pneumothorax nor bleeding was observed. One-lung flooding enables USgTTNB of lung nodules with a high sensitivity and minimal risk of complications in a pre clinical model. PMID- 29627085 TI - Illness Among Paralympic Athletes: Epidemiology, Risk Markers, and Preventative Strategies. AB - Paralympic athletes have unique preexisting medical conditions that predispose them to increased risk of illness, but data are limited to studies conducted during the last 3 Paralympic Games. This article reviews the epidemiology of illness (risk, patterns, and predictors) in Paralympic athletes and provides practical guidelines for illness prevention. The incidence rate of illness (per 1000 athlete-days) in Paralympic athletes is high in Summer (10.0-13.2) and Winter (18.7) Paralympic Games. The authors propose general and specific guidelines on preventative strategies regarding illness in these athletes. PMID- 29627086 TI - Acute and Chronic Musculoskeletal Injury in Para Sport: A Critical Review. AB - Sport-related injury patterns among Para athletes have been described with increasing frequency. This review summarizes musculoskeletal injuries in Para athletes. Seated Para athletes sustain upper extremity injuries more commonly; ambulant Para athletes frequently sustain lower extremity injuries. The upper extremity is the most commonly injured anatomic area in all Para athletes, unlike able-bodied athletes. Advanced age and spinal cord injury may increase the risk of upper extremity injury. Injury data for recreational and youth Para athletes are sparse. Summarizing current injury epidemiology data may help to accelerate the development of injury prevention strategies and lifetime injury models for Para athletes. PMID- 29627087 TI - Autonomic Nervous System in Paralympic Athletes with Spinal Cord Injury. AB - Individuals sustaining a spinal cord injury (SCI) frequently suffer from sensorimotor and autonomic impairment. Damage to the autonomic nervous system results in cardiovascular, respiratory, bladder, bowel, and sexual dysfunctions, as well as temperature dysregulation. These complications not only impede quality of life, but also affect athletic performance of individuals with SCI. This article summarizes existing evidence on how damage to the spinal cord affects the autonomic nervous system and impacts the performance in athletes with SCI. Also discussed are frequently used performance-enhancing strategies, with a special focus on their legal aspect and implication on the athletes' health. PMID- 29627088 TI - Athletes with Brain Injury: Pathophysiologic and Medical Challenges. AB - Participation in elite sporting activities is becoming increasingly popular for individuals with brain injury. This article outlines the types of brain injury and the associated movement dysfunctions. In addition, specific pathophysiologic and medical challenges facing athletes with brain injury are discussed. Further research conducted using athletes with brain injury will add to the existing literature indicating the benefits of athletic training in this population. Increased scientific study within this area stands to further improve understanding of the complex interaction between neuromuscular impairment and athletic performance. PMID- 29627089 TI - Key Nutritional Strategies to Optimize Performance in Para Athletes. AB - Para athletes are a high-risk population for inadequate dietary intake leading to insufficiencies in nutrients important to athletic performance. This is partly due to minimal support and resources, especially in sport nutrition education, combined with limited prior nutrition knowledge and risks associated with different impairment types. Inadequate energy, carbohydrate, protein, iron, and vitamin D status are of particular concern in Para athletes. Assessment of these key nutrients, along with sport nutrition education, is needed to empower Para athletes with the knowledge to understand their individual nutrition needs and maximize athletic performance. PMID- 29627090 TI - Concussion in Para Sport. AB - Although Para athletes (the International Paralympic Committee term for sportspeople with a disability) are exposed to a risk of concussion just like their able-bodied counterparts, there has been little research into the incidence of concussion in para sport. Existing assessment and management guidelines and tools have been developed for the general sport population but may not be appropriate for use in some para-athletes. This review examines what is currently known about concussion in para sport and identifies challenges and opportunities in moving knowledge on this topic forward. PMID- 29627091 TI - Applying Scientific Principles to Enhance Paralympic Classification Now and in the Future: A Research Primer for Rehabilitation Specialists. AB - Para-sport classification systems define eligibility for Para sport and provide a competition structure that controls for the impact of impairment on the outcome of competition. This article focuses on the classification of para athletes with physical impairments. Development of classification systems based on scientific evidence has only recently been made possible by adoption of a statement of the purpose of classification by the International Paralympic Committee and its member organizations. Rigorous descriptive science can improve extant systems of classification and a recently published study described a data-driven classification structure with validity superior to that of the extant system. PMID- 29627092 TI - Performance Characteristics of Para Swimmers: How Effective Is the Swimming Classification System? AB - Swimming is one of the inaugural sports within the Olympic and Paralympic Games, the key difference between the Olympic and Paralympic games being the classification system. The aim of this study was to investigate how effective the current classification system creates clearly differentiated Paralympic competition classes, based on performance time for all swimming strokes and events. Based on the performance characteristics of swimmers within the current classification system, the relationship between impairment and swimming performance is inconsistent, potentially disadvantaging some athletes. Appropriate sports medicine tests are required for the development of an evidence based swimming classification system. PMID- 29627093 TI - Engineering and Technology in Wheelchair Sport. AB - Technologies capable of projecting injury and performance metrics to athletes and coaches are being developed. Wheelchair athletes must be cognizant of their upper limb health; therefore, systems must be designed to promote efficient transfer of energy to the handrims and evaluated for simultaneous effects on the upper limbs. This article is brief review of resources that help wheelchair users increase physiologic response to exercise, develop ideas for adaptive workout routines, locate accessible facilities and outdoor areas, and develop wheelchair sports specific skills. PMID- 29627094 TI - Sport-Specific Limb Prostheses in Para Sport. AB - Prostheses form an essential part of participation in sport and physical activity for athletes with lower or upper limb amputation. These prostheses come in the form of everyday nonsport-specific prostheses, as well as sport-specific prostheses designed to enable participation in specific sports. Sport-specific prostheses are designed to the requirements of the sport to facilitate the achievement of peak performance without causing significant risk of injury. This article addresses the various factors associated with participation in sport and physical activity for individuals with amputation, including the various prostheses for upper and lower limbs and prostheses for different sports. PMID- 29627095 TI - Para Sport Athletic Identity from Competition to Retirement: A Brief Review and Future Research Directions. AB - The primary purpose of this article is to review the literature on para sport athletic identity and provide avenues for future research direction. First, the authors briefly describe the existing quantitative and qualitative research on para sport athletic identity and, thereby, illustrate the complexities para sport athletes experience regarding the way they describe their participation in competitive sport. Next, the authors describe how para sport athletes with acquired permanent disabilities and congenital disabilities face similar, yet unique, identity-related challenges. Finally, the authors argue that future researchers should consider examining para sport athletes' identity through narrative identity. PMID- 29627096 TI - The Social Empowerment of Difference: The Potential Influence of Para sport. AB - This article explores the significance of parasport culture in highlighting an emancipatory understanding of difference and enhancing social empowerment. Disability studies are used to illuminate the influence of ableist ideology on people with impairments. Rather than being suppressed, difference should be recognized and valued in parasport practices and ideologies, leading to a pluralist culture, in which farther and wider social emancipation can be grounded. Acceptance of difference is an absolute and essential precondition for parasport cultures to promote positive social change for people with disabilities. PMID- 29627097 TI - Social Inclusion Through Para sport: A Critical Reflection on the Current State of Play. AB - Medicine has played an integral role in both the inception and development of the Paralympic Games. Sports physicians are well positioned to continue to influence the development of the paralympic movement and to help focus the movement on its agenda to promote social inclusion. This article looks critically at some of the key challenges that the paralympic movement faces in its quest to promote social inclusion, and considers the role of sports medicine in this process. PMID- 29627098 TI - Paralympic Games: History and Legacy of a Global Movement. AB - The Paralympic Games have an interesting history that began after World War II. The Games and movement have been impacted by and have had an impact on society and the larger able-bodied sport system. The future of the Games and movement is also further impacted by larger cultural shifts, and the Games themselves have potentially left lasting legacies for the host cities and persons with impairment worldwide. PMID- 29627099 TI - Maximizing One's Potential. PMID- 29627100 TI - Contemporary Medical, Scientific & Social Perspectives on Para Sport. PMID- 29627101 TI - Bioaccumulation and physiological effects of copepods sp. (Eucyclop sp.) fed Chlorella ellipsoides exposed to titanium dioxide (TiO2) nanoparticles and lead (Pb2+). AB - The demand for manufactured products and the derivatives of nanomaterials and non essential metals continue to increase, and as a consequence their presence in fisheries and aquaculture has therefore become a major concern for the risks to which our environment is exposed. The bioaccumulation profile of binary compounds (Titanium dioxide nanoparticles and lead) and their effects on the feeding behaviour of copepods were assessed in a simplified food chain including, the freshwater alga Chlorella ellipsoides and the cyclopoids copepods sp. Our results indicated that Pb and TiO2 NPs individually and mixed can be transferred from alga to copepods via dietary pathway. The highest bioconcentration factor (748.5) was recorded for Pb in the combined compounds (Pb15 + Ti16.5) MUg L-1 and the highest BCF (5.57) recorded for TiO2 NPs was found in TiO2 NPs (16.5) alone. Ingestion and filtration rate decreased significantly (p < 0.05) in all treatments. Analysis of variance (ANOVA) showed that the combination of these metals significantly (p < 0.05) decreased ingestion and filtration rate. In addition, the individual compounds and their combinations significantly (p < 0.05) increased carbohydrate and total lipid content. The antioxidant activities showed significant (p < 0.05) effect of Glutathione peroxidase (GPx), Glutathione reductase (GR), catalase (CAT) however, SOD and MDA were not significant (p > 0.05) in both single and binary treatments. The results demonstrate that the co exposure of TiO2 NPs and Pb inhibit the ingestion and filtration of microalgae by cyclopoid copepods sp. and also induce increase of carbohydrate, lipid; GPx, GR and CAT due to stress. PMID- 29627102 TI - Hypertension Control in Africa: A Call to Action. PMID- 29627103 TI - The Journey From Research Discovery to Optimal Heart Health for All. PMID- 29627104 TI - A systematic review of social stress and mental health among transgender and gender non-conforming people in the United States. AB - Transgender and gender non-conforming (TGNC) populations, including those who do not identify with gender binary constructs (man or woman) are increasingly recognized in health care settings. Research on the health of TGNC people is growing, and disparities are often noted. In this review, we examine 77 studies published between January 1, 1997 and March 22, 2017 which reported mental health outcomes in TGNC populations to (a) characterize what is known about mental health outcomes and (b) describe what gaps persist in this literature. In general, depressive symptoms, suicidality, interpersonal trauma exposure, substance use disorders, anxiety, and general distress have been consistently elevated among TGNC adults. We also used the minority stress model as a framework for summarizing existing literature. While no studies included all elements of the Minority Stress Model, this summary gives an overview of which studies have looked at each element. Findings suggest that TGNC people are exposed to a variety of social stressors, including stigma, discrimination, and bias events that contribute to mental health problems. Social support, community connectedness, and effective coping strategies appear beneficial. We argue that routine collection of gender identity data could advance our understanding mental health risk and resilience factors among TGNC populations. PMID- 29627105 TI - Utilization, In-Hospital Mortality, and 30-Day Readmission After Percutaneous Mitral Valve Repair in the United States Shortly After Device Approval. AB - The MitraClip device for percutaneous mitral valve repair was approved by the Food and Drug Administration in the United States in October 2013. Few studies have evaluated national outcomes after this procedure in routine clinical practice. We identified adults aged >=18 years who received percutaneous mitral valve repair from November 2013 to December 2014 in the Nationwide Readmissions Database, a publicly available administrative claims database. Procedural volumes, number of performing hospitals, individual hospital volumes, in-hospital mortality rate, and 30-day hospital readmission rate were determined. Patient demographics, clinical comorbidities, and hospital characteristics were analyzed using logistic regression to determine risk factors for in-hospital death and 30 day readmission. We identified 879 cases performed in the first 14 months after device approval (mean age +/- SD, 75.0 +/- 13.1 years; 45% women). The number of performing hospitals increased by 5.7-fold (23 to 132), although mean individual hospital volumes remained small (6.2 +/- 10.4 cases per hospital). In-hospital all-cause mortality was 3.3% and was associated with higher number of clinical comorbidities. The rate of 30-day readmission was 14.6%, and 6.6% of patients died during rehospitalization. Increased procedural experience was associated with a nonsignificant trend toward reduced hospital readmission after multivariable adjustment (p = 0.08). In conclusion, use of percutaneous mitral valve repair in the United States early after approval increased steadily over time, although individual hospital volumes remained low. More than 1 in 7 patients who underwent this procedure are readmitted within 30 days of discharge. PMID- 29627107 TI - Out-of-Hospital Cardiac Arrests During the Japanese Professional Baseball Championship Series. AB - Because the Japan Professional Baseball Championship Series (Japan Series) is a stressful sports event, it is possible that watching Japan Series matches may increase the risk of cardiovascular events. Therefore, we investigated the potential association between the Japan Series and the incidence of out-of hospital cardiac arrest (OHCA) events. National registry data for all cases of OHCA between 2005 and 2014 from 47 prefectures of Japan were obtained. We used a time-stratified case-crossover design with a conditional Poisson regression model to compare OHCA events during the Japan Series with those events that occurred during the periods except for dates of the Japan Series. The estimated associations for each prefecture were pooled at the nationwide level using a random-effects meta-analysis. In total, 666,020 OHCAs of presumed cardiac origin were reported during the study period. On days of Japan Series matches, the pooled relative risk of OHCA was 1.033 (95% confidence interval 1.012 to 1.055; p = 0.002; I2 = 3.5%, P for heterogeneity = 0.405). Stratified analyses by gender revealed that the substantial increase in OHCA during the events was observed for men, whereas we found no significant increase for women. We also found a considerable rise in OHCA among patients aged >=65 years; however, there was no significant evidence of increased risk in those aged 18 to 64 years. In conclusion, stressful baseball match is associated with an increased risk of OHCA. Prevention measures for severe emotional stress-related OHCA should be implemented, particularly for elderly men. PMID- 29627106 TI - Clinical Features Associated With Nascent Left Ventricular Diastolic Dysfunction in a Population Aged 40 to 55 Years. AB - Diastolic dysfunction (DD), an abnormality in cardiac left ventricular (LV) chamber compliance, is associated with increased morbidity and mortality. Although DD has been extensively studied in older populations, co-morbidity patterns are less well characterized in middle-aged subjects. We screened 156,434 subjects with transthoracic echocardiogram reports available through Vanderbilt's electronic heath record and identified 6,612 subjects 40 to 55 years old with an LV ejection fraction >=50% and diastolic function staging. We tested 452 incident and prevalent clinical diagnoses for associations with early-stage DD (n = 1,676) versus normal function. There were 44 co-morbid diagnoses associated with grade 1 DD including hypertension (odds ratio [OR] = 2.02, 95% confidence interval [CI] 1.78 to 2.28, p <5.3 * 10-29), type 2 diabetes (OR 1.96, 95% CI 1.68 to 2.29, p = 2.1 * 10-17), tachycardia (OR 1.38, 95% CI 0.53 to 2.19, p = 2.9 * 10-6), obesity (OR 1.76, 95% CI 1.51 to 2.06, p = 1.7 * 10-12), and clinical end points, including end-stage renal disease (OR 3.29, 95% CI 2.19 to 4.96, p = 1.2 * 10-8) and stroke (OR 1.5, 95% CI 1.12 to 2.02, p = 6.9 * 10-3). Among the 60 incident diagnoses associated with DD, heart failure with preserved ejection fraction (OR 4.63, 95% CI 3.39 to 6.32, p = 6.3 * 10-22) had the most significant association. Among subjects with normal diastolic function and blood pressure at baseline, a blood pressure measurement in the hypertensive range at the time of the second echocardiogram was associated with progression to stage 1 DD (p = 0.04). In conclusion, DD was common among subjects 40 to 55 years old and was associated with a heavy burden of co-morbid disease. PMID- 29627108 TI - Effect of Grand-Aides Nurse Extenders on Readmissions and Emergency Department Visits in Medicare Patients With Heart Failure. AB - Numerous procedures have been tested to reduce hospital readmissions with varying success. The objective of this study was to evaluate all-cause readmissions and emergency department (ED) visits 30 days and 6 months after discharge with Grand Aides (GAs): nurse extenders making frequent home visits under video direction by a nurse supervisor. Medicare patients with primary diagnosis of heart failure at the University of Virginia discharged January 1, 2013 to January 1, 2015 were included. A GA visited the patient's home within 24 to 48 hours with supervisor on video for medication reconciliation. Every visit, a GA completed a questionnaire for a supervisor who then had brief video conversation with the patient, reinforced adherence with medical regimen and danger signs, making 3 visits in the first week, 2 visits each in weeks 2 and 3, 1 visit in week 4, then a monthly visit supplemented by telephone. Outcomes were recorded for 108 GA and 854 controls. Statistical adjustment was performed through inverse probability of treatment weighting, with the distribution of covariates resembling a propensity score-matched cohort. Patients with GA had 2.8% 30-day all-cause readmissions versus 15.8% controls-82% reduction-(adjusted odds ratio [aOR] = 0.17; p = 0.0060); 6-month all-cause readmissions 13.0% versus 44.7% (aOR = 0.19; p <0.0001); ED 30-days 2.8% versus 45.1% (aOR = 0.03; p <0.0001); ED 6-months 12.0% versus 51.5% (aOR = 0.09; p <0.0001); and 6-month mortality 6.5% versus 8.8% (aOR = 0.73; p = 0.4698). At 30 days, 92% had "substantial medication adherence." Savings per $562,097, 7* return on investment. In conclusion, the GA approach to population health compares favorably in outcomes and expense 30 days and 6 months after discharge. PMID- 29627109 TI - Myocardial Infarction Subtypes in Patients With Type 2 Diabetes Mellitus and the Effect of Liraglutide Therapy (from the LEADER Trial). AB - Diabetes mellitus (DM) is a known risk factor for myocardial infarction (MI); however, data regarding MI subtypes in people with diabetes are limited. In the Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial (n = 9,340), liraglutide significantly reduced the risk of major adverse cardiovascular (CV) events (composite of CV death, nonfatal MI, or nonfatal stroke) versus placebo in patients with type 2 DM and high CV risk. Liraglutide also reduced risk of first MI (292 events with liraglutide vs 339 with placebo). This post hoc analysis characterized MIs (first and recurrent) occurring in LEADER, by treatment arm and regarding incidence, outcome, subtype, and troponin levels. A total of 780 MIs (first and recurrent) were reported, with fewer in the liraglutide-treatment group than in the placebo-treatment group (359 vs 421, p = 0.022). Numerically fewer MIs were associated with CV death with liraglutide than with placebo (17 vs 28 fatal MIs, p = 0.28). Symptomatic MIs in both arms were mainly non-ST-segment elevation MI (555/641) and spontaneous MI (518/641). Numerically greater proportions of symptomatic MIs were associated with troponin levels <=5* or <=10* the upper reference limit with liraglutide versus placebo (p = 0.16 and p = 0.42, respectively). At baseline, more liraglutide-treated patients than placebo-treated patients with MI during the trial had a history of coronary artery bypass graft (p = 0.008), and fewer had peripheral arterial disease in the lower extremities (p = 0.005) and >50% stenosis of the coronary artery, the carotid artery, or other arteries (p = 0.044). In conclusion, this analysis showed that liraglutide reduces the incidence of MIs in patients with type 2 DM at high CV risk and may impact the clinical outcomes of MI. PMID- 29627110 TI - Comparison of Outcomes of Transfemoral Aortic Valve Implantation in Patients <90 With Those >90 Years of Age. AB - In patients who underwent transcatheter aortic valve implantation (TAVI), postoperative mortality risk is commonly assessed with risk scores such as the Society of Thoracic Surgeons-Postoperative Risk of Mortality (STS-PROM) and EuroSCORE II, in which age plays a dominant role. However, we reason that in the naturally selected oldest-old patients (nonagenarians), this may not be completely justified and that therefore age should play a minor role in decision making. The objective of this study was to compare procedural outcome and mid term mortality of transfemoral (TF)-TAVI patients aged >=90 years with patients aged <90 years. In this single-center analysis of 599 prospectively acquired consecutive TF-TAVI patients between 2009 and 2017, we compared patients aged >=90 (i.e., nonagenarians, n = 47) with patients aged <90 years (n = 552), using Kaplan-Meyer analysis and multivariate logistic regression. In the nonagenarians, we found more aortic regurgitation, moderate to severe paravalvular leakage, strokes and vascular complications, and less device success and bleeding complications compared with patients <90 years. Both groups showed similar symptomatic improvement. The predicted (STS-PROM) and actual procedural mortality were 8.033% and 2.1% (3.8*) and 4.868% and 1.8% (2.7*) for the nonagenarians and controls, respectively. Survival was not statistically different at the 1-, 2-, 3 , 4-, and 5-year mark. In conclusion, nonagenarians had similar symptomatic improvement and acceptable procedural outcome and mid-term survival to TF-TAVI patients aged <90 years. Thus, age is not a risk factor in predicting postoperative outcome and mortality and therefore should not be a reason to deny the oldest-old patient transfemoral TAVI. PMID- 29627111 TI - In-Stent Restenosis of Drug-Eluting Stents Compared With a Matched Group of Patients With De Novo Coronary Artery Stenosis. AB - Drug-eluting stents (DES) significantly reduced the incidence of in-stent restenosis (ISR). However, ISR still exists in the contemporary DES era. Previously deemed to be a benign process, ISR leads to complex presentation and intervention. This study aimed to compare the presentation and outcome of DES-ISR versus de novo lesions. We performed a retrospective analysis of 11,666 patients receiving percutaneous coronary intervention from 2003 to 2017 and divided them into 2 groups by de novo stenosis and ISR. They were matched based on common cardiovascular risk factors at a 4:1 ratio, respectively. After matching, a total of 1,888 patients with 3,126 de novo lesions and 472 patients with 508 ISR lesions were analyzed. Patients with ISR presented more often with unstable angina (61% vs 45%, p <0.001) and less often with myocardial infarction (6% vs 14%, p <0.001). One-year composite major adverse cardiovascular event, defined as death, Q-wave myocardial infarction, and target vessel revascularization, was 10% in the de novo group and 17% in the ISR group (hazard ratio 1.98, 95% confidential interval 1.58 to 2.46, p <0.001). After adjusting for myocardial infarction presentation, hazard ratio of major adverse cardiovascular events was still higher for the ISR group at 1 year (2.03, 95% confidential interval 1.62 to 2.55, p <0.001). ISR of DES remains a therapeutic challenge and leads to complex presentation and worse outcomes compared with matched de novo patients. These data show that DES-ISR demands better appreciation and prevention with more precise stent technique and should motivate the continued development of fully bioresorbable scaffolds. PMID- 29627112 TI - Impact of Chronic Kidney Disease on Outcomes After Percutaneous Coronary Intervention for Chronic Total Occlusions (from the Japanese Multicenter Registry). AB - The impact of chronic kidney disease (CKD) and potential pharmacologic intervention on clinical outcomes after percutaneous coronary intervention (PCI) for chronic total occlusions (CTOs) remains unknown. A total of 1,463 patients underwent successful CTO-PCI between August 2004 and December 2014. Major adverse cardiovascular events (MACE) defined as the composite of all-cause death, myocardial infarction and target lesion revascularization, cardiac death, and stent thrombosis were compared between patients with and without CKD (555 and 908 patients, respectively). The results demonstrated higher risks of MACE (log-rank p = 0.015), all-cause death (log-rank p <0.001), and cardiac death (log-rank p <0.001) in the CKD group compared with the non-CKD group. Multivariable analyses demonstrated that CKD was an independent predictor for MACE (hazard ratio 1.23, 95% confidence interval 1.02 to 1.47, p = 0.03). With regard to pharmacotherapy, statin use was associated with significantly lower rates of MACE in the CKD group (log-rank p = 0.003). In conclusion, the presence of CKD would be an important predictor of long-term clinical outcomes in patients who underwent CTO-PCI, and use of statin may influence in reducing the adverse clinical outcomes. PMID- 29627113 TI - Do invasive corals alter coral reef processes? An empirical approach evaluating reef fish trophic interactions. AB - Understanding how invasive species affect key ecological interactions and ecosystem processes is imperative for the management of invasions. We evaluated the effects of invasive corals (Tubastraea spp.) on fish trophic interactions in an Atlantic coral reef. Remote underwater video cameras were used to examine fish foraging activity (bite rates and food preferences) on invasive cover levels. Using a model selection approach, we found that fish feeding rates declined with increased invasive cover. For Roving Herbivores (RH) and Sessile Invertivores (SI), an abrupt reduction of fish feeding rates corresponded with higher invasive cover, while feeding rates of Territorial Herbivores (TH) and Mobile Invertivores (MI) decreased linearly with cover increase. Additionally, some fish trophic groups, such as RH, SI and Omnivores (OM), had lower densities in reef sections with high invasive cover. These findings demonstrate that invasive corals negatively impact fish-benthic interactions, and could potentially alter existing trophic relationships in reef ecosystems. PMID- 29627114 TI - Partial medial second toe pulp free flap and dermal substitute with skin graft for salvage reconstruction of a complete skin envelope degloving of the small finger. AB - Skin envelope degloving of fingers are rare injuries that require rapid care and surgical treatment. Mostly caused by ring finger injuries, these traumas include bone, tendon and neurovascular pedicle damage. The authors present an unusual case of finger degloving limited exclusively to the skin envelope, without skeletal, tendinous or vascular lesion. This rare case of skin envelope degloving rendered microsurgical revascularization impossible. The authors report the results at 12 months following salvage reconstruction combining a partial second toe pulp free flap for the volar side and a dermal substitute with a thin skin graft for the dorsum. PMID- 29627115 TI - Migrant children within Europe: a systematic review of children's perspectives on their health experiences. AB - OBJECTIVES: To review the extant literature to explore what is known about children's own perspectives on their health experiences, focussing on children and young people who have migrated into, and within, Europe. STUDY DESIGN: A systematic review with narrative synthesis. METHODS: A review of English language articles was performed in June 2016 using the following databases: MEDLINE, CINAHL, Cochrane and Web of Science. Included articles had to report data generated directly with children, up to 18 years of age, who had migrated across national borders into, or within, Europe during their own lifetimes. Extraction from articles was undertaken by all authors, and quality assessment of included reviews was performed using the Mixed Methods Appraisal Tool. RESULTS: The articles in the final data set included research based on four broad areas: alcohol, smoking and substance use; diet, eating disorders and overweight; emotional, psychological and mental health issues; and children's views and experiences of health and health services. Most studies were cross-sectional analytic or incidence or prevalence studies. CONCLUSION: There is a general lack of clarity in the literature regarding the reporting of children's own migration status. Children's voices are often subsumed within those of their adult parents or carers. There is a need to promote more child-focussed research which gives voice to migrant children to better understand the complex and multidimensional factors that contribute to their (ill)health. PMID- 29627116 TI - Association between maternal depression and risk of infant diarrhea: a systematic review and meta-analysis. AB - OBJECTIVE: To systematically review the evidence for an association between maternal depression and the risk of diarrheal illness in infants. STUDY DESIGN: This study is a meta-analysis. METHODS: Nine databases were searched systematically for studies that investigated the risk of diarrheal illness in infants born to mothers with depression. RESULTS: Our search strategy yielded 10 studies of the association between maternal depression and the risk of diarrheal illness in infants: eight studies of postnatal depression, two studies of antenatal depression, and one study of perinatal depression. Our meta-analysis showed that infants born to mothers with postnatal depression were more likely to develop diarrheal illness (odds ratio [OR] = 1.902, 95% confidence interval [95% CI] = 1.385-2.612, P < 0.001, n = 18,585). A similar trend was noted for antenatal depression (OR = 2.703, 95% CI = 0.920-7.942, P = 0.071, n = 583). Only one study reported an association between perinatal depression and risk of diarrhea in infants (OR = 1.848, log OR = 0.614, standard error = 0.093, n = 107,587). CONCLUSIONS: Only a few studies so far have identified an association between maternal depression and risk of diarrhea in infants. The evidence available to date suggests that infants born to mothers with depression are more likely to develop diarrhea than infants whose mothers do not have depression. PMID- 29627117 TI - [Caregiver's health: adaption and validation in a Spanish population of the Experience of Caregiving Inventory (ECI)]. AB - OBJECTIVE: To adapt and to validate the Experience of Caregiving Inventory (ECI) in a Spanish population, providing empirical evidence of its internal consistency, internal structure and validity. METHOD: Psychometric validation of the adapted version of the ECI. One hundred and seventy-two caregivers (69.2% women), mean age 57.51 years (range: 21-89) participated. Demographic and clinical data, standardized measures (ECI, suffering scale of SCL-90-R, Zarit burden scale) were used. The two scales of negative evaluation of the ECI most related to serious mental disorders (disruptive behaviours [DB] and negative symptoms [NS]) and the two scales of positive appreciation (positive personal experiences [PPE], and good aspects of the relationship [GAR]) were analyzed. Exploratory structural equation modelling was used to analyze the internal structure. The relationship between the ECI scales and the SCL-90-R and Zarit scores was also studied. RESULTS: The four-factor model presented a good fit. Cronbach's alpha (DB: 0.873; NS: 0.825; PPE: 0.720; GAR: 0.578) showed a higher homogeneity in the negative scales. The SCL-90-R scores correlated with the negative ECI scales, and none of the ECI scales correlated with the Zarit scale. CONCLUSIONS: The Spanish version of the ECI can be considered a valid, reliable, understandable and feasible self-report measure for its administration in the health and community context. PMID- 29627118 TI - Alveolar and Bronchial Nitric Oxide in Chronic Obstructive Pulmonary Disease and Asthma-COPD Overlap. AB - INTRODUCTION: Exhaled nitric oxide (FENO) measurements differentiate COPD phenotypes from asthma-COPD overlap (ACO). To date, no study has been conducted to determine whether alveolar and bronchial components differ in this group of patients. METHODS: This was an observational cross-sectional study recruiting ambulatory COPD patients. FENO was measured, differentiating alveolar (CANO) from bronchial (JawNO) components using a multiple-flow technique. CANO and JawNO values were compared between eosinophilic COPD patients (defined as >= 300 eosinophils/MUL in peripheral blood test, or >= 2% eosinophils or >= 3% eosinophils), and a linear regression analysis was performed to determine clinical and biological variables related to these measurements. RESULTS: 73 COPD patients were included in the study. Eosinophil counts were associated with increased values of CANO and JawNO (for the latter only the association with >= 300 or >= 3% eosinophils was significant). CANO was also associated with CRP, and JawNO with smoking. CONCLUSIONS: Patients with COPD and ACO characteristics show increased inflammation in the large and small airways. CANO and JawNO are associated with clinical and biological variables. PMID- 29627119 TI - Creating a list of low-value health care interventions according to medical students perspective. PMID- 29627120 TI - Attending Diabetes Clinics is associated with a lower all-cause mortality. A meta analysis of observational studies performed in Italy. AB - OBJECTIVE: The epidemiological explosion of diabetes is a challenge for Health Systems and the identification of the most appropriate models of care are warranted. The inclusion of primary care physicians in the models is unquestioned whereas the role played by secondary and tertiary care (Diabetes Clinic) is often debated. However, studies focusing on hard endpoints and comparing Diabetes Clinic attendance vs. no attendance are scant. RESEARCH DESIGN AND METHODS: A meta-analysis was performed including all observational cohort studies performed in Italy, reporting crude and/or adjusted estimates of all-cause mortality in patients with diabetes attending or not attending Diabetes Clinics. Attendance was defined by prescriptions and reimbursement of specialist visits by the National Health System. RESULTS: Three studies enrolling 191,847 subjects with diabetes were included in the analysis, and about half of them had at least one visit in the Diabetes Clinic per year. During the follow-up, ranging 1-11 years, 9653 subjects died. Mortality was remarkably lower in subjects attending Diabetes Clinic (MH-OR 0.70, 95% CI 0.55-0.88, p = 0.002). Results were confirmed after adjusting for confounders (MH-OR 0.81, 95% CI 0.69-0.95, p = 0.009). CONCLUSIONS: The results of the present study suggest that attending Diabetes Clinics is associated with a lower all-cause mortality. This finding might be instrumental to implement the best models of care for persons with diabetes. PMID- 29627121 TI - Coffee consumption and risk of aortic valve stenosis: A prospective study. AB - BACKGROUND AND AIMS: Coffee contains many biologically active compounds with potential adverse or beneficial effects on the cardiovascular system. Whether coffee consumption is associated with the risk of aortic valve stenosis (AVS) is unknown. The purpose of this study was therefore to examine the association between coffee consumption and AVS incidence. METHODS AND RESULTS: This prospective study included 71 178 men and women who provided information on their coffee consumption through a questionnaire at baseline. Incident cases of AVS were identified through linkage with the Swedish National Patient and Cause of Death Registers. During a mean follow-up of 15.2 years, 1295 participants (777 men and 518 women) were diagnosed with AVS. Coffee consumption was positively associated with risk of AVS in a dose-response manner after adjustment for age, sex, smoking, and other risk factors (P-trend = 0.005). The multivariable hazard ratios were was 1.11 (95% confidence interval 1.04-1.19) per 2 cups/day increase of coffee consumption and 1.65 (95% confidence interval 1.10-2.48) when comparing the highest (>=6 cups/day) with the lowest (<0.5 cup/day) category of coffee consumption. The association was not modified by other risk factors. CONCLUSIONS: This study provides novel evidence that high coffee consumption is associated with an increased risk of AVS. PMID- 29627122 TI - Radiofrequency-thermoablation: General principle, historical overview and modern applications for epilepsy. AB - Stereotactically guided radiofrequency thermoablation (RFTA) for epilepsy has been frequently applied over the last 40 years. Radiofrequency electrodes with temperature control function generate a coagulation lesion with clearly defined borders. In combination with high-resolution MRI imaging, this technique allows minimally-invasive ablation of periventricular nodular heterotopias, small focal type II dysplasias, and hypothalamic hamartomas. This review summarises the literature addressing this topic mainly regarding technical aspects. In essence, RFTA is a safe treatment option for patients suffering from epileptogenic pathologies visible on MRI-images. PMID- 29627123 TI - Key features of radiology reports in oncology. AB - In oncology, the radiology report is a fundamental tool for communication between the radiologist, clinician, and patient. The radiology report is a document that integrates the final outcome of the radiologist's contribution to the care of the oncologic patient; therefore, the information it contains must be accurate and clear. The report must be understandable for both the patient and the clinician, so that they can use it to make the right decisions. To be effective, the information in the report must be structured, concise, accurate, and relevant. This article describes a systematic method for elaborating quality oncologic reports that are complete and useful for both clinicians and patients. PMID- 29627124 TI - Report of a case of delayed hypoxic leukoencephalopathy: A peculiar image. PMID- 29627125 TI - Hydrophobicity-driven unfolding of Trp-cage encapsulated between graphene sheets. AB - Understanding the interaction between proteins and graphene not only helps elucidate the behaviors of proteins in confined geometries, but is also imperative to the development of a plethora of graphene-based biotechnologies, such as the graphene liquid cell transmission electron microscopy. To discuss the overall geometrical-thermal effects on proteins, we performed molecular dynamics simulations of hydrated Trp-cage miniprotein sandwiched between two graphene sheets and in the bulk environment at the temperatures below and above its unfolding temperature. The structural fluctuations of Trp-cage were characterized using the backbone root mean square displacement and the radius of gyration, from which the free energy landscape of Trp-cage was further constructed. We observed that at both temperatures the confined protein became adsorbed to the graphene surfaces and exhibited unfolded structures. Residue-specific analyses clearly showed the preference for the graphene to interact with the hydrophobic regions of Trp-cage. These results suggested that the conformation space accessible to the protein results from the competition between the thermodynamic driving forces and the geometrical restraints. While confinement usually tends to restrict the conformation of proteins by volume exclusion, it may also induce the unfolding of proteins by hydrophobic interactions. PMID- 29627126 TI - Vaccination against tuberculosis. AB - BCG (Bacille Calmette-Guerin) vaccination is included in the immunization schedule for tuberculosis endemic countries with a global coverage at birth close to 90% worldwide. BCG was attenuated from Mycobacterium bovis almost a century ago, and provides a strong protection against disseminated forms of the disease, though very limited against pulmonary forms of tuberculosis, responsible for transmission. Novel prophylactic tuberculosis vaccines are in clinical development either to replace BCG or to improve its protection against respiratory forms of the disease. There are limitations understanding the immunological responses involved and the precise type of long-lived immunity that new vaccines need to induce. MTBVAC is the first and only tuberculosis vaccine candidate based on live-attenuated Mycobacterium tuberculosis in clinical evaluation. MTBVAC clinical development plans to target tuberculosis prevention in newborns, as a BCG replacement strategy, and as secondary objective to be tested in adolescents and adults previous vaccinated with BCG. PMID- 29627127 TI - The action of estrogens and progestogens in the young female breast. AB - Evidence from different sources sustains a pro-oncogenic role of hormones, estrogens and progestogens, on the breast. The issue is of interest for young women, who are exposed to the hormonal changes imposed by the ovarian cycle and, often, take hormones with contraceptive purposes. Experimental and clinical studies show that both estrogens and progesterone are involved in mammary development during puberty and lactation, the changes being observed across mammalian species, including humans. Estrogen receptors, and more particularly the alpha isoform, participate in molecular processes of stem cells differentiation and epithelial proliferation through paracrine actions implicating growth factors. Progesterone also contributes through paracrine mechanisms involving one member of the tumor necrosis factor (TNF) family, the receptor activator of nuclear factor kappaB ligand (RANKL) and its receptor (RANK). Epidemiological studies have found that the length of the exposure to endogenous hormones, as determined by an early menarche or a late menopause, is a risk factor for breast cancer. Additional evidence has derived from studies with compounds modulating the estrogen or the progesterone receptors. Selective estrogen receptor modulators (SERM), like tamoxifen, have been shown to decrease the risk of breast cancer in both pre- and post-menopausal women. Aromatase inhibitors, which drastically reduce the levels of circulating estrogens, have reproduced the findings. The selective progesterone receptor modulators (SPRM) have been less investigated and issues concerning safety have arisen. These observations have interest for young women. High-risk women may consider the use of SERMs, for example, to reduce their risk. Much more common is the case of women who take hormones for contraception. The goal of the present article is twofold: i) to summarize the actual knowledge of the mechanisms implicating estrogens and progestogens on the risk for breast cancer and ii) to provide rationality for the debate about potential cancer risk of hormonal contraceptives, frequently used by premenopausal women. PMID- 29627128 TI - Performance of the modified TRISS for evaluating trauma care in subpopulations: A cohort study. AB - INTRODUCTION: Previous research showed that there is no agreement on a practically applicable model to use in the evaluation of trauma care. A modification of the Trauma and Injury Severity Score (modified TRISS) is used to evaluate trauma care in the Netherlands. The aim of this study was to evaluate the prognostic ability of the modified TRISS and to determine where this model needs improvement for better survival predictions. METHODS: Patients were included if they were registered in the Brabant Trauma Registry from 2010 through 2015. Missing values were imputed according to multiple imputation. Subsets were created based on age, length of stay, type of injury and injury severity. Probability of survival was calculated with the modified TRISS. Discrimination was assessed with the Area Under the Receiver Operating Curve (AUROC). Calibration was studied graphically. RESULTS: The AUROC was 0.84 (95% CI: 0.83, 0.85) for the total cohort (N = 69 747) but only 0.53 (95% CI: 0.51, 0.56) for elderly patients with hip fracture. Overall, calibration of the modified TRISS was adequate for the total cohort, with an overestimation for elderly patients and an underestimation for patients without brain injury. CONCLUSIONS: Outcome comparison conducted with TRISS-based predictions should be interpreted with care. If possible, future research should develop a simple prediction model that has accurate survival prediction in the aging overall trauma population (preferable with patients with hip fracture), with readily available predictors. PMID- 29627129 TI - [New nosological and therapeutic perspectives in syndromic vascular malformations with a vein-lymphatic component]. AB - Vascular malformations are poorly recognized constitutional anomalies which arises during early childhood. Several classifications tried to draw a distinction across the different entities. Recent advances in molecular biology have contributed to the update of their nosology. Syndromic vascular malformations are an example: while Klippel-Trenaunay syndrome, Proteus or CLOVES syndrome share many common features, understanding of pathological mechanism and specially the role of the PIK3/AKT/mTOR pathway enables us to rethink their classification. Then, some syndromes associated with overgrowth and vascular malformation have been grouped under a single term: "PIK3CA-related overgrowth spectrum" (PROS), and this group continues to grow. This new approach suggests new treatment options. Rapamycin, a PIK3/AKT/mTOR pathway inhibitor, demonstrated its efficiency for some forms of PROS. Targeted therapies such as PIK3 or mTOR selective inhibitor are still in a developmental phase and results are encouraging. This is an example of personalized medicine with significant therapeutic benefit for some patients. However, genotype relation with therapeutic efficiency must be clarified and physicians should pay attention to possible negative effects of these drugs, especially for young patients. PMID- 29627130 TI - Patient satisfaction after fractional ablation of burn scar with 2940nm wavelength Erbium-Yag laser. AB - OBJECTIVE: Fractional laser therapy is a new treatment with potential benefit in the treatment of burn scars. We sought to determine patient satisfaction after burn scar treatment with the Erbium-Yag laser. METHODS: We performed a telephone survey of all patients who underwent fractional resurfacing of burn scars with the Erbium-Yag 2940 wavelength laser at Parkland Hospital from 01/01/2016 to 05/01/2017. Subjects were asked to rate their satisfaction with their scars' after treatment characteristics on a scale from 1 (completely unsatisfied) to 10 (completely satisfied). Subjects were also asked to assess their treatment response using the UNC 4P Scar Scale before and after treatment. RESULTS: Sixty four patients underwent 156 treatments. A survey response rate of 77% (49/64) was seen (age: 36.8+21 years; surface area treated=435+326cm2; 35% of burn scars were >2 years old; mean scar age of 1.02+0.4 years). Overall, 46/49 (94%) of patients reported some degree of scar improvement after treatment. Patient satisfaction scores were 8.3+2.3. Number of laser treatments included: 1 (31%), 2 (33%), 3 (18%), 4(10%), >5 (8%). Treatment depth, scar age, and number of laser procedures were not significant predictors of satisfaction or UNC 4P Scar scores. The paired t-test showed a significant reduction on each of the UNC 4P Scar scale items (pain, pruritus, pliability, paresthesia). One subject reported that she felt that the laser treatment made her scar worse (2%). CONCLUSION: Burn patients treated with the Erbium-Yag laser are highly satisfied with changes in their burn scars. PMID- 29627131 TI - Treatment of toxic epidermal necrolysis by a multidisciplinary team. A review of literature and treatment results. AB - BACKGROUND: Stevens-Johnson Syndrome (SJS) and Toxic Epidermal Necrolysis (TEN) are mucocutaneous hypersensitivity reactions, usually to drugs or their metabolites. TEN is the most severe involving greater than 30% of the total body surface area (TBSA). Management of these patients usually benefits from a large multidisciplinary team for both wound and medical management. Treatment of these patients varies between centers and physicians and there is lack of a standardized treatment protocol in the medical literature. OBJECTIVES: To review the literature and complete a retrospective review of patients treated at Vancouver General Hospital over a 11-year period. METHODS: A retrospective chart review of all patients diagnosed with SJS/TEN and treated at Vancouver General Hospital from 2001 to 2011 was completed. Data collected include patient demographics, time to transfer to a burn center, SCORTEN calculation, suspected cause of TEN, %TBSA involved, length of stay in hospital and ICU, medications, dressings, infections/cultures, fluids, mucosal involvement, teams involved, associated complications, morbidity and mortality. Data is reported quantitatively. RESULTS: A total of 67 patients were identified (28 SJS, 21 SJS/TEN overlap, 18 TEN). In SJS/TEN overlap and TEN patients, oral mucosa and trunk were the primary sites involved. SCORTEN calculations were highest in the TEN group. Plastic surgery was consulted in 53% of TEN cases, 52% of SJS/TEN cases and 25% of SJS cases. Patients were admitted to a burn unit in 74% of TEN cases, 57% of TEN/SJS cases and 21% of SJS cases. Time from symptoms to diagnosis and transfer to a burn unit was highest for TEN patients. Time from presentation to diagnosis was highest in SJS/TEN overlap. Triggers were identified in 67-82% of cases. Treatment varied widely. Patients were treated conservatively, with steroids, IVIg, and cyclosporine alone or in combination. Observed mortality was higher than predicted by SCORTEN for patients treated with IVIg and lower for those treated with Cyclosporin. Dressings varied greatly and were often changed throughout a patients stay. Total mortality was 20.9% being the highest in the TEN group (35%). CONCLUSIONS: SJS and TEN are a spectrum of severe mucocutaneous reactions that have unclear treatment recommendations within the literature and within our Level 1 hospital. Information gleaned from this research will help educate physicians involved in the treatment and management of patients with these diagnoses and has resulted in development of treatment guidelines in our hospital. PMID- 29627132 TI - An image processing approach for investigation on transport of iron oxide nanoparticles (FE3O4) stabilized with poly acrylic acid in two-dimensional porous media. AB - Iron oxide nanoparticles were stabilized using poly acrylic acid (PAA) to yield stabilized slurry of Iron oxide nanoparticles. A two-dimensional physical model filled by glass beads was used to study the fate and transport of the iron oxide nanoparticles stabilized with PAA in porous media under saturated, steady-state flow conditions. Transport data for a nonreactive tracer, slurry of iron oxide nanoparticles stabilized with PAA were collected under similar flow conditions. The results show that low concentration slurry of iron oxide nanoparticles stabilized with PAA can be transported like a tracer without significant retardation. The image processing technique was employed to measure the tracer/nanoparticle concentration inside the 2-D model filled with glass beads. The groundwater flow model, Visual MODFLOW, was used to model the observed transport patterns through MT3DMS module. Finally, it was demonstrated that the numerical model MODFLOW can be used to predict the fate and transport characteristics of nanoparticles stabilized with PAA in groundwater aquifers. PMID- 29627133 TI - Quantitative evaluation of facet deflection, stiffness, strain and failure load during simulated cervical spine trauma. AB - Traumatic cervical facet dislocation (CFD) is often associated with devastating spinal cord injury. Facet fractures commonly occur during CFD, yet quantitative measures of facet deflection, strain, stiffness and failure load have not been reported. The aim of this study was to determine the mechanical response of the subaxial cervical facets when loaded in directions thought to be associated with traumatic bilateral CFD - anterior shear and flexion. Thirty-one functional spinal units (6 * C2/3, C3/4, C4/5, and C6/7, 7 * C5/6) were dissected from fourteen human cadaver cervical spines (mean donor age 69 years, range 48-92; eight male). Loading was applied to the inferior facets of the inferior vertebra to simulate the in vivo inter-facet loading experienced during supraphysiologic anterior shear and flexion motion. Specimens were subjected to three cycles of sub-failure loading (10-100 N, 1 mm/s) in each direction, before being failed in a randomly assigned direction (10 mm/s). Facet deflection, surface strains, stiffness, and failure load were measured. Linear mixed-effects models (alpha = 0.05; random effect of cadaver) accounted for variations in specimen geometry and bone density. Specimen-specific parameters were significantly associated with most outcome measures. Facet stiffness and failure load were significantly greater in the simulated flexion loading direction, and deflection and surface strains were higher in anterior shear at the non-destructive analysis point (47 N applied load). The sub-failure strains and stiffness responses differed between the upper and lower subaxial cervical regions. Failure occurred through the facet tip during anterior shear loading, while failure through the pedicles was most common in flexion. PMID- 29627134 TI - Delivering a "New Deal" of Kidney Health Opportunities to Improve Outcomes Within the Veterans Health Administration. AB - Just as the "New Deal" aimed to elevate the "forgotten man" of the Great Depression through governmental relief and reform, so does the Department of Veterans Affairs (VA) health care system aim to improve the health of veterans with the invisible illness of chronic kidney disease through a concerted series of health care delivery reforms. Augmenting its primary care platform with advances in informatics and health service delivery initiatives targeting kidney disease, the VA is changing how nephrology care is provided to veterans with the goal of optimized population kidney health. As the largest provider of kidney health services in the country, the VA offers an instructive case study of the value of comprehensive health care coverage for people with chronic kidney disease. Recent reports of kidney health outcomes among veterans support the benefit of the VA's integrated health care delivery system. Suggestions to optimize veterans' kidney health further may be equally applicable to other health systems caring for people afflicted with kidney disease. PMID- 29627135 TI - Plantar Fascia Release Through a Single Lateral Incision in the Operative Management of a Cavovarus Foot: A Cadaver Model Analysis of the Operative Technique. AB - Plantar fascia release and calcaneal slide osteotomy are often components of the surgical management for cavovarus deformities of the foot. In this setting, plantar fascia release has traditionally been performed through an incision over the medial calcaneal tuberosity, and the calcaneal osteotomy through a lateral incision. Two separate incisions can potentially increase the operative time and morbidity. The purpose of the present study was threefold: to describe the operative technique, use cadaveric dissection to analyze whether a full release of the plantar fascia was possible through the lateral incision, and examine the proximity of the medial neurovascular structures to both the plantar fascia release and calcaneal slide osteotomy when performed together. In our cadaveric dissections, we found that full release of the plantar fascia is possible through the lateral incision with no obvious damage to the medial neurovascular structures. We also found that the calcaneal branch of the tibial nerve reliably crossed the osteotomy in all specimens. We have concluded that both the plantar fascia release and the calcaneal osteotomy can be safely performed through a lateral incision, if care is taken when completing the calcaneal osteotomy to ensure that the medial neurovascular structures remain uninjured. PMID- 29627136 TI - TEIPP antigens for T-cell based immunotherapy of immune-edited HLA class Ilow cancers. AB - T-cell based immunotherapies through checkpoint blockade or adoptive transfer are effective treatments for a wide range of cancers like melanomas and lung carcinomas that harbor a high mutational load. The HLA class I and class II (HLA I and HLA-II) presented neoantigens arise from genetic mutations in the cancerous cells and are ideal non-self targets for the T cell-based treatments. Although some cancer patients responded with complete regression, many others are irresponsive to checkpoint blockade treatments, or relapse after initial success. One of the mechanisms by which tumors evade T cell recognition is by acquiring deficiencies in the HLA-I antigen-processing pathway, leading to downregulation of HLA-I molecules at the cell surface and thereby creating an 'invisible' tumor phenotype. Interestingly, an alternative antigen repertoire arises on these HLA Ilow cancer cells. We refer to this alternative antigen repertoire as TEIPP: T cell epitopes associated with impaired peptide processing. TEIPP antigens are curious non-mutated peptides from housekeeping proteins that are not presented in homeostasis. In this review, for the first time we recapitulate all our published work on TEIPP antigens, including our recent understanding of the CD8 T cell repertoire. We are convinced that TEIPP-directed T cells will be valuable resources to target immune-edited tumors that have acquired resistance to checkpoint blockade therapy. PMID- 29627137 TI - Fatigue, insomnia and hot flashes after definitive radiochemotherapy and image guided adaptive brachytherapy for locally advanced cervical cancer: An analysis from the EMBRACE study. AB - OBJECTIVE: To evaluate the pattern of manifestation of fatigue, insomnia and hot flashes within the prospective, observational, multi-center EMBRACE study. METHODS: Morbidity was prospectively assessed according to CTCAE v.3 and patient reported outcome with EORTC QLQ-C30/CX24 at baseline and regular follow-up. Analyses of crude incidence, prevalence rates and actuarial estimates were performed. RESULTS: A total of 1176 patients were analyzed with a median follow up of 27 months. At baseline, CTCAE G1/G2 prevalence rates for fatigue were 29%/6.2%, for insomnia 18%/3.1% and for hot flashes 7.9%/1.6% with respective 3 year prevalence rates of 29%/6.8%, 17%/4.4% and 19%/5.9%. Similar patterns of manifestation were seen in patient-reported EORTC outcomes. The 3-year actuarial estimates for G >= 3 CTCAE fatigue, insomnia and hot flashes were 5.5%, 4.7% and 1.9%. Younger age was associated with significantly higher risk for fatigue, insomnia and hot flashes. CONCLUSION: Fatigue, insomnia and hot flashes occurred mainly in the mild to moderate range. Fatigue and insomnia were already present before treatment and showed minor fluctuations or recovery during follow-up, whereas hot flashes showed a considerable increase after treatment. More research is needed to evaluate contributing risk factors in order to define intervention strategies. PMID- 29627138 TI - Longitudinal Changes in Right Ventricular Function in Tetralogy of Fallot in the Initial Years after Surgical Repair. AB - BACKGROUND: Right ventricular (RV) dysfunction is associated with adverse long term outcomes in patients with tetralogy of Fallot. Little is known about RV function in the first years after surgical repair. The aim of this study was to investigate perioperative changes in myocardial deformation using global longitudinal strain. METHODS: A retrospective analysis of patients with surgically repaired tetralogy of Fallot was performed. Global longitudinal peak systolic RV strain was measured on early postoperative echocardiograms, two subsequent postoperative echocardiograms through 2 years postoperatively, and preoperative echocardiograms, when available. Preoperative and late follow-up strain was compared with strain in 0- to 8-month-old and 1- to 4-year-old control subjects, respectively. RESULTS: Forty-seven patients were included. Compared with postoperative strain (7 +/- 7 days postoperatively), strain at follow-up 1 (8.3 +/- 4 months postoperatively) was significantly improved (-12.3 +/- 3.3% vs 18.8 +/- 2.5%, P < .001), with no additional improvement 23.2 +/- 6 months postoperatively (-18.8 +/- 2.5% vs -19.8 +/- 3.1%, P = .12). Postoperative strain was worse than preoperative strain (n = 25, -12.5 +/- 3.6% vs -18.4 +/- 2.9%, P < .001). Compared with control subjects, preoperative strain was similar (-19.3 +/- 3.8% vs -18.4 +/- 2.9%, P = .30), though late follow-up strain was significantly worse (-27.7 +/- 2.8% vs -19.8 +/- 3.1%, P < .001). CONCLUSIONS: RV global longitudinal strain worsens in the early postoperative period following surgical repair of tetralogy of Fallot but recovers through 2 postoperative years. Despite recovery to preoperative values, the presence of RV dysfunction compared with control subjects suggests that long-term dysfunction may begin early. The trajectory of RV dysfunction through the later years needs further study. PMID- 29627139 TI - Structured Reporting of CT Angiography Runoff Examinations of the Lower Extremities. AB - OBJECTIVES: The aim was to evaluate the effect of structured reporting of computed tomography angiography (CTA) runoff studies on clarity, completeness, clinical relevance, usefulness of the radiology reports, further testing, and therapy in patients with known or suspected peripheral arterial disease. METHODS: Conventional reports (CRs) and structured reports (SRs) were generated for 52 patients who had been examined with a CTA runoff examination of the lower extremities. The sample size was based on power calculations with a power of 95% and a significance level of .007 (adjusted for multiple testing). CRs were dictated in a free text form; SRs contained a consistent ordering of observations with standardised subheadings. CRs were compared with SRs. Two vascular medicine specialists and two vascular surgeons rated the reports regarding their satisfaction with clarity, completeness, clinical relevance, and usefulness as well as overall satisfaction. Additionally, they made hypothetical decisions on further testing and therapy. Median ratings were compared using the Wilcoxon signed rank test and generalised linear mixed effects models. RESULTS: SRs received higher ratings for satisfaction with clarity (median rating 9.0 vs. 7.0, p < .0001) and completeness (median rating 9.0 vs. 7.5, p < .0001) and were judged to be of greater clinical relevance (median rating 9.0 vs. 8.0, p < .0001) and usefulness (median rating 9.0 vs. 8.0, p < .0001). Overall satisfaction was also higher for SRs (median rating 9.0 vs. 7.0, p < .0001) than CRs. There were no significant differences in further testing or therapy. CONCLUSION: Referring clinicians perceive SRs of CTA runoff examinations of the lower extremities as offering superior clarity, completeness, clinical relevance, and usefulness than CRs. Structured reporting does not appear to alter further testing or therapy in patients with known or suspected peripheral arterial disease. PMID- 29627140 TI - Difference in the fusion rate and bone formation between artificial bone and iliac autograft inside an inter-body fusion cage - A comparison between porous hydroxyapatite/type 1 collagen composite and autologous iliac bone. AB - BACKGROUND: Lateral inter-body fusion (LIF) using cages with a large bone grafting space can lead to a shortage of autologous grafting materials. The use of artificial bone is an option to increase the volume of grafting materials. However, the rate of bony fusion for these materials compared to that of autologous bone is unclear. METHODS: The bone fusion rate for artificial bone (HAp/Col) and autologous iliac bone (IBG) graft among 23 patients who had undergone LIF (total 66 disc levels) combined with multilevel posterior corrective fusion for the treatment of adult spinal deformity was retrospectively evaluated. To allow comparison, one of the two separate bone grafting holes in each LIF cage was filled with HAp/Col and the other, with IBG. The change in Hounsfield units (HU) inside the implanted holes at 1-year post surgery (PO1Y) from baseline and immediately after surgery and bony fusion between adjacent vertebrae, defined by the extent of trabecular continuity at PO1Y, were evaluated using computed tomography. Differences between the convex and concave sides as well as effects of the side of approach were investigated. RESULTS: HU values increased significantly for IBG, from 228.9 at baseline to 286.1 at PO1Y (p < 0.001), with no change for HAp/Col. The fusion rate was higher for IBG (71.2%) than for HAp/Col (19.7%; p < 0.001). A significant effect of the location of the holes on fusion rate was identified for HAp/Col but not IBG. No effects of the side of approach were identified. CONCLUSIONS: A higher rate of fusion in LIF cages was obtained with IBG than with HAp/Col, with no effect of location of implantation (convex or concave) for IBG. Therefore, exclusive use of artificial bone, particularly on the convex side, should be avoided during LIF. PMID- 29627141 TI - Corrigendum to ''An automated blastomere identification method for the evaluation of day 2 embryos during IVF/ICSI treatments'' [Computer Methods and Programs in Biomedicine, 156 (2018) pp. 53-59]. PMID- 29627142 TI - Double jeopardy: Competing arrhythmias in heterotopic heart transplants. PMID- 29627143 TI - Telehealth, Mobile Applications, and Wearable Devices are Expanding Cancer Care Beyond Walls. AB - OBJECTIVES: To review telehealth solutions, mobile applications, and wearable devices that are currently impacting patients, caregivers, and providers who work in the oncology setting. DATA SOURCES: A literature search was conducted using the terms (Telehealth, Mobile Health, mHealth, Wearable Devices) + (Oncology, Cancer Care). CONCLUSION: There are many current applications of telehealth and mobile health in the oncology setting. IMPLICATIONS FOR NURSING PRACTICE: Nurses who care for patients with cancer should be aware of the pervasiveness and impact of telehealth and mobile health to this unique population. PMID- 29627144 TI - [Assessing bioethics education: Teaching to be virtuous doctors or just doctors with practical ethical skills]. AB - OBJECTIVE: In the last decades, bioethics has been incorporated into the academic training of the Medical Schools. Some studies analyze the ethical-moral development of medical students and the effect of ethical education in other countries. This evaluation is done by measuring Kohlberg's moral reasoning (virtuous doctors), or ethical sensitivity to resolve clinical cases (physicians with ethical skills). The following study is proposed to assess the impact of bioethics training on these two variables, in Spanish medical students. DESIGN: Observational cross-sectional study. SITE: Faculty of Medicine, University of Lleida. PARTICIPANTS: 175 students from third year of medicine (78 before bioethics and 97 after bioethics, in different courses) were conducted. INTERVENTION: Bioethics course. MAIN MEASUREMENTS: A socio-demographic questionnaire, the Rest Defining Issue test scale, and Problem Identification Test with clinical vignettes were administered. RESULTS: A consistent and significant correlation has been found between moral reasoning and ethical sensitivity. Women presented greater post-conventional reasoning. There were no changes in Kohlberg's stage of global moral reasoning with ethical training. There were changes in ethical sensitivity with bioethical training, with a significantly and globally improvement. CONCLUSION: In our study, training in bioethics does not improve moral development but rather the ethical problem solving skills. It is asked if this improvement is enough to train doctors prepared for the new challenges. PMID- 29627145 TI - Influence of hypoxia induced by sleep disordered breathing in case of hypertension and atrial fibrillation. AB - Sleep disordered breathing (SDB) has been recognized as one of the important causes or factors of worsening for various cerebro- and cardiovascular diseases. On the other hand, a recent large randomized study and meta-analysis about the effect of continuous positive airway pressure (CPAP) indicated no or only minor effects to improve the outcome of SDB patients. Accumulating evidence has indicated that the key factor of the link between SDB and cardiovascular diseases might be hypoxia caused during repetitive long apneic episodes. Hypertension and atrial fibrillation (AF) are two important cardiovascular diseases that relate to SDB and the therapeutic consequences by CPAP treatment have been studied. As for the mechanism that elevates blood pressure during night, stimulation of chemoreceptors by hypoxia and the resultant increase in sympathetic nervous activity is the first step and repetitive hypoxic stimulation changes the characteristics of chemoreceptors and baroreceptors resulting in daytime hypertension. Pathological changes in the atrial muscle in SDB patients might be a result of repetitive hypoxia and atrial expansion. As for triggering AF, several animal studies revealed that the changes in autonomic nervous system caused by hypoxia and negative intra-thoracic pressure might be crucial. However, a recent observational study could not show the relation between SDB and AF. The difference between the previous studies and this negative study seems to exist in the difference of the severity of SDB or the degree of hypoxia. Such a difference might be also one of the reasons why a recent randomized trial to prove the effect of CPAP in cardio- or cerebrovascular patients failed to improve the patient prognosis. Hence, in this review, the relationship between hypoxia and onset or continuation of hypertension and AF will be reconsidered to understand the fundamental and robust relationship between SDB and these cardiovascular diseases. PMID- 29627146 TI - Ebola virus vaccination and the longevity of total versus neutralising antibody response-is it enough? PMID- 29627148 TI - [Synthesis and regulation of flavor compounds derived from brewing yeast: Esters]. AB - During brewing process yeast produce more than 500 chemical compounds that can negatively and positively impact beer at the organoleptic level. In recent years, and particularly thanks to the advancement of molecular biology and genomics, there has been considerable progress in our understanding about the molecular and cellular basis of the synthesis and regulation of many of these flavor compounds. This article focuses on esters, responsible for the floral and fruity beer flavor. Its formation depends on various enzymes and factors such as the concentration of wort nutrients, the amount of dissolved oxygen and carbon dioxide, fermentation temperature and mainly the genetics of the yeast used. We provide information about how the esters originate and how is the impact of different fermentative parameters on the final concentrations of these compounds and the quality of the end product. PMID- 29627149 TI - Combined bilobed trapezius myocutaneous and scapula osteomyocutaneous flaps for the restoration of through-and-through defects of the mandible following salvage surgery for recurrent head and neck tumours. AB - This study was performed to evaluate the outcomes of combined bilobed trapezius myocutaneous and scapula osteomyocutaneous flaps for the restoration of through and-through defects of the mandible. The subjects were six patients with recurrent malignant tumours who underwent salvage surgeries and reconstruction with combined flaps based on the transverse cervical vessels (TCVs). All patients had combined bone (four type H, one type LCL, and one type C) and extensive soft tissue defects (through-and-through defects) following salvage surgery. All tumours were removed and the complex defects restored successfully. Two patients experienced minor complications: one minor intraoral flap failure and one case of wound dehiscence at the donor site. The appearance of the face and neck was satisfactory or acceptable in all patients. No patient showed severely limited range of motion of the upper limb. The patients were followed up for 10 to 18months. One patient was living with no evidence of disease. The use of combined bilobed trapezius myocutaneous and scapula osteomyocutaneous flaps based on the TCVs may be an effective approach for the restoration of through-and-through defects of the mandible and may provide satisfactory or acceptable functional and aesthetic outcomes following salvage surgery for advanced head and neck tumours. PMID- 29627147 TI - Determinants of antibody persistence across doses and continents after single dose rVSV-ZEBOV vaccination for Ebola virus disease: an observational cohort study. AB - BACKGROUND: The recombinant vesicular stomatitis virus (rVSV) vaccine expressing the Zaire Ebola virus (ZEBOV) glycoprotein is efficacious in the weeks following single-dose injection, but duration of immunity is unknown. We aimed to assess antibody persistence at 1 and 2 years in volunteers who received single-dose rVSV ZEBOV in three previous trials. METHODS: In this observational cohort study, we prospectively followed-up participants from the African and European phase 1 rVSV ZEBOV trials, who were vaccinated once in 2014-15 with 300 000 (low dose) or 10 50 million (high dose) plaque-forming units (pfu) of rVSV-ZEBOV vaccine to assess ZEBOV glycoprotein (IgG) antibody persistence. The primary outcome was ZEBOV glycoprotein-specific IgG geometric mean concentrations (GMCs) measured yearly by ELISA compared with 1 month (ie, 28 days) after immunisation. We report GMCs up to 2 years (Geneva, Switzerland, including neutralising antibodies up to 6 months) and 1 year (Lambarene, Gabon; Kilifi, Kenya) after vaccination and factors associated with higher antibody persistence beyond 6 months, according to multivariable analyses. Trials and the observational study were registered at ClinicalTrials.gov (Geneva: NCT02287480 and NCT02933931; Kilifi: NCT02296983) and the Pan-African Clinical Trials Registry (Lambarene PACTR201411000919191). FINDINGS: Of 217 vaccinees from the original studies (102 from the Geneva study, 75 from the Lambarene study, and 40 from the Kilifi study), 197 returned and provided samples at 1 year (95 from the Geneva study, 63 from the Lambarene, and 39 from the Kilifi study) and 90 at 2 years (all from the Geneva study). In the Geneva group, 44 (100%) of 44 participants who had been given a high dose (ie, 10 50 million pfu) of vaccine and who were seropositive at day 28 remained seropositive at 2 years, whereas 33 (89%) of 37 who had been given the low dose (ie, 300 000 pfu) remained seropositive for 2 years (p=0.042). In participants who had received a high dose, ZEBOV glycoprotein IgG GMCs decreased significantly between their peak (at 1-3 months) and month 6 after vaccination in Geneva (p<0.0001) and Lambarene (p=0.0298) but not in Kilifi (p=0.5833) and subsequently remained stable at all sites apart from Geneva, where GMC in those given a high dose of vaccine increased significantly between 6 months and 1 year (p=0.0264). Antibody persistence was similar at 1 year and at 6 months in those who had received a low dose of vaccine, with lower titres among participants from the Geneva study at 2 years than at 1 year after vaccination (GMC ratio 0.61, 95% CI 0.49-0.77; p<0.0001). In multivariable analyses, predictors of increased IgG GMCs beyond 6 months included high-dose versus low-dose vaccination (Geneva p=0.0133; Lambarene p=0.008) and vaccine-related arthritis (p=0.0176), but not sex, age, or baseline seropositivity (all p>0.05). Neutralising antibodies seem to be less durable, with seropositivity dropping from 64-71% at 28 days to 27-31% at 6 months in participants from the Geneva study. INTERPRETATION: Antibody responses to single-dose rVSV-ZEBOV vaccination are sustained across dose ranges and settings, a key criterion in countries where booster vaccinations would be impractical. FUNDING: The Wellcome Trust and Innovative Medicines Initiative 2 Joint Undertaking. PMID- 29627150 TI - Postoperative bleeding risk of direct oral anticoagulants after oral surgery procedures: a systematic review and meta-analysis. AB - Direct oral anticoagulants (dabigatran, rivaroxaban, apixaban and edoxaban; DOACs) have been introduced to improve safety and superior therapeutic value compared to their predecessors such as warfarin or enoxaparin. The aim of this systematic review and meta-analysis was to assess the postoperative bleeding risk of DOACs during oral surgery procedures. Systematic searches were performed in electronic databases including PubMed, Scopus, Web of Science and Cochrane Library. Thirteen studies were included in the qualitative synthesis: two retrospective case-control studies, five prospective case-control studies, three cross-sectional studies, two case series and a case report; while only six studies were statistically analysed. The risk ratio of postoperative bleeding in DOACs patients was significantly greater than in healthy patients (3.04; 95% confidence interval (CI)=1.31-7.04). This is especially true for rivaroxaban (4.13; 95% CI=1.25-13.69), and less so for dabigatran which presented a risk ratio similar to that of healthy patients (1.00; 95% CI=0.21-4.82). However, further research is required to support these results. Both apixaban and edoxaban were excluded from statistical analysis due to the lack of clinical studies. PMID- 29627151 TI - Warthin's tumour in oral and maxillofacial regions: an 18-year retrospective study of 1084 cases in an eastern-Chinese population. AB - There is little information in the English-language literature regarding Warthin's tumour (WT) in the eastern-Chinese population. A large retrospective study (1084 primary tumours over a period of 18years) was carried out to investigate the clinicopathological features (patients' gender, age and tumour location) of these tumours in this population. A total of 994 (91.7%) patients were male and 90 (8.3%) were female, with a male/female ratio of 11:1. The mean age was 56.48years (range 20-89years), with a peak incidence in the fifth to seventh decade (82.1%). The favorite primary site of the tumour was the parotid gland (n=1055), followed by intra-/peri-parotid lymph nodes (n=13), upper neck (n=10), submandibular gland (n=4) and upper lip (n=1). Multifocal WTs arose in 9.5% (103 patients) of cases whereas bilateral multifocal WTs were found in 0.65% (seven patients). In 24 (2.2%) patients, WT were found to coexist with other different types of neoplasm synchronously. The most common subtype of metaplasia was the squamous metaplasia (166/250, 66.4%). The usual treatment measure is (bilateral) superficial parotidectomy and the patients should be followed long term, in view of possible metachronous WT, even after prolonged time intervals. PMID- 29627152 TI - Three-dimensional radiographic evaluation of root migration patterns 4-8.5 years after lower third molar coronectomy: a cone beam computed tomography study. AB - This prospective study in patients with a follow-up of 4-8.5years aimed to describe the long-term, three-dimensional changes of coronectomized lower third molar roots. Pre- and postoperative cone beam computed tomography (CBCT) scans were compared. The distance of root migration, the direction of root translation and rotation, and the amount of bone regeneration at the adjacent second molar and superficially to the third molar root were recorded. Age, gender, time elapsed following surgery, the status of the retained root including, impaction pattern and depth of impaction were tested to check if they were influencing factors for the above outcomes. A total of 57 coronectomized third molars from 44 patients were included. The distance of the mean root migration was 2.82mm, and they predominantly translated mesially (76.8%). Age negatively correlated with the distance of migration. Root remnants with a soft tissue coverage had less bone regenerated at the adjacent second molar (1.27mm vs. 2.95mm) in comparison to their impacted counterparts. Based on the present radiographic results and the absence of any pathological findings, coronectomy can be recommended for selected cases of third molar removal as a safe procedure with favourable long-term outcomes. PMID- 29627153 TI - Commentary to "Hypospadias repair with the glanular frenular collar (GFC) technique". PMID- 29627154 TI - How to close classic bladder exstrophy: Are subspecialty training and technique important? AB - INTRODUCTION: Successful primary closure is one of the main factors for achieving continence in a classic bladder exstrophy (CBE) patient. Even with contemporary management, patients still have failed primary closures. We sought to understand the role of training, surgical technique, and their impacts on outcomes of CBE closure. MATERIALS AND METHODS: A retrospective cohort study from the largest single-institution database of primary and re-closure CBE patients in the world was performed. Failed closure was defined as developing bladder outlet obstruction, wound dehiscence, bladder prolapse, or any need for a re-closure operation. Patient demographics and surgical factors were abstracted and analyzed. Multivariable analysis was performed to test for associations with successful exstrophy closure. RESULTS: Data from 722 patients were analyzed. On bivariate analysis, successful closure was associated with gestational age at presentation, time of closure, location of closure, credential of surgeon performing the closure, closure type, concomitant osteotomy, and type of immobilization. Multivariable analysis, adjusting for patient comorbidity and location of closure, demonstrated increased odds of failure for closure by pediatric surgeon compared with pediatric urologist (OR 4.32, 95% CI 1.98-9.43; p = 0.0002), closure by unknown credentialed surgeon (OR 1.86, 95% CI 1.15-2.99; p = 0.011), Complete Primary Repair of Exstrophy (CPRE) closure compared with Modern Staged Repair of Exstrophy (OR 2.05, 95% CI 1.29-2.99; p = 0.0024), and unknown closure type (OR 4.81, 95% CI 2.94-7.86; p < 0.0001) (Table). DISCUSSION: Many factors associated with failure on bivariate analysis can be explained by these patients presenting to a center of excellence or the selection bias of this cohort stemming from a single center database that have been previously published. However, the finding on adjusted multivariable logistic regression analysis that closure by a pediatric surgeon is associated with higher odds of failure is novel. The additional finding that CPRE closure is associated with failure is most likely secondary to these patients being referred to our institution after having been closed with CPRE which falsely increases its impact on closure failure. Nevertheless, as a center with a large exstrophy volume, this study draws from a cohort that is larger than any other. CONCLUSION: Classic bladder exstrophy closure should be performed at a center with pediatric urologists to ensure the best chance of a successful primary closure. PMID- 29627155 TI - Alendronate and FTI-277 combination as a possible therapeutic approach for hepatocellular carcinoma: An in vitro study. AB - BACKGROUND: An important product of mevalonate pathway is downstream synthesis of isoprenoid units that has long been implicated in development and progression of tumor. It has been speculated that inhibition of protein prenylation might be therapeutically beneficial. The objective of current study was to evaluate antitumor potential of a novel therapeutic combination of mevalonate pathway inhibitors, FTI-277 and alendronate. We also examined differentially expressed proteins in response to treatment using proteomics approach. METHODS: Huh-7 cells were incubated with different concentrations of FTI-277 alone and in combination with alendronate. Differential protein and gene expression was examined through two dimensional gel electrophoresis and real-time quantitative polymerase chain reaction (qPCR), respectively. Proteins were identified using tandem mass spectrometry analysis. RESULTS: Treatment of hepatocellular carcinoma (HCC) cell line with FTI-277 alone showed cell death in a time and dose dependent manner while in combination with alendronate, a synergistic apoptotic effect at 24 h was observed. Proteomic studies on the 20 umol/L FTI-277 and 5 umol/L alendronate +20 umol/L FTI-277 treated cells revealed altered expression of different proteins including peroxiredoxin 2 (Prx2), glutathione S transferase 1 (GSTP1), Rho GTPase activating protein (RhoGAP), triosephosphate isomerase (TPI), and heat shock protein 60 (HSP60). Down-regulated expression of Prx2 and GSTP1 in treated cells was also confirmed by real-time qPCR analysis. CONCLUSIONS: Combined treatment of FTI-277 and alendronate on Huh-7 HCC cells showed cell death suggesting their anticancer potential. Such treatment approaches are likely to offer new therapeutic strategies. PMID- 29627156 TI - Various approaches of laparoscopic common bile duct exploration plus primary duct closure for choledocholithiasis: A systematic review and meta-analysis. AB - BACKGROUND: Common bile duct (CBD) stones may occur in up to 3%-14.7% of all patients with cholecystectomy. Various approaches of laparoscopic CBD exploration plus primary duct closure (PDC) are the most commonly used and the best methods to treat CBD stone. This systematic review was to compare the effectiveness and safety of the various approaches of laparoscopic CBD exploration plus PDC for choledocholithiasis. DATA SOURCES: Randomized controlled trials (RCTs) and non randomized controlled trials (NRCTs) (case-control studies or cohort studies) were searched from Cochrane library (until Issue 2, 2015), Web of Science (1980 January 2016), PubMed (1966-January 2016), and Baidu search engine. After independent quality assessment and data extraction, meta-analysis was conducted using RevMan 5.1 software. RESULTS: Four RCTs and 18 NRCTs were included. When compared with choledochotomy exploration (CE) plus T-tube drainage (TTD) (CE + TTD), CE plus PDC (CE + PDC) and CE + PDC with biliary drainage (BD) (CE + PDC + BD) had a lower rate of postoperative biliary peritonitis (OR = 0.22; 95% CI: 0.06, 0.88; P < 0.05; OR = 0.27; 95% CI: 0.08, 0.84; P < 0.05; respectively) where T-tubes were removed more than 3 weeks. The operative time of CE + PDC was significantly shorter (WMD = -24.82; 95% CI: -27.48, -22.16; P < 0.01) than that of CE + TTD in RCTs. Cystic duct exploration (CDE) plus PDC (CDE + PDC) has a lower rate of postoperative complications (OR = 0.39; 95% CI: 0.23, 0.67; P < 0.01) when compared with CE + PDC. Confluence part micro-incision exploration (CME) plus PDC (CME + PDC) has a lower rate of postoperative bile leakage (OR = 0.17; 95% CI: 0.04, 0.74; P < 0.05) when compared with CE + PDC. CONCLUSION: PDC with other various approaches are better than TTD in the treatment of choledocholithiasis. PMID- 29627157 TI - TGFB1 modulates in vitro secretory activity and viability of equine luteal cells. AB - In the present report we describe the involvement of transforming growth factor B1 (TGF) in functional regression and structural luteolysis in the mare. Firstly, TGF and its receptors activin-like kinase (ALK) 5 and TGF receptor 2 were identified in corpus luteum (CL) steroidogenic, endothelial and fibroblast-like cells. Also, TGF and ALK5 protein expression were shown to be increased in Mid-, and Late-CL (p < 0.05). Subsequently, using an in vitro model with Mid-CL cells, we studied the role of TGF on secretory activity and cell viability. Cell treatment with TGF decreased progesterone (P4) and prostaglandin (PG) E2 concentrations in culture media (p < 0.05), and downregulated mRNA and protein of StAR, CYP11A1, cPGES and mPGES1 (p < 0.05). Conversely, TGF augmented PGF2a concentration in culture media, through PTGS2 and PGFS gene expression activation (p < 0.05). When cells were incubated with PGF2a, both TGF and ALK5 were upregulated (p < 0.05). Additionally, treatment with the pharmacological inhibitor of ALK5, ALK4 and ALK7 - SB431542 (SB) attenuated PGF2a functional and structural luteolytic actions. Indeed, SB blocked: (i) PGF2a inhibitory effect on StAR, CYP11A1, 3BHSD and mPGES1; (ii) PGF2a auto-amplification signal via PTGS2 and PGFS expression (p < 0.05); (iii) the PGF2a-induced BAX and FASL expression (p < 0.05). Finally, TGF decreased cell viability (p < 0.05) and promoted caspase 3 activity (p = 0.08) and the expression of pro-apoptotic FASL and BAX (p < 0.05). Our results suggest that TGF supports functional regression and structural luteolysis, and also confirm the importance of ALK5, ALK4 and ALK7 activation during PGF2a mediated luteolysis in mares. PMID- 29627158 TI - Kinetics of endocan in patients undergoing cardiac surgery with and without cardiopulmonary bypass. AB - BACKGROUND: Endocan plays an important role in the processes of inflammation and infection. The use of cardiopulmonary bypass (CPB) during cardiac surgery can induce an inflammatory response. We aimed to describe the kinetics of endocan in patients undergoing cardiac surgery with and without the use of CPB. METHODS: Single-centre, observational study with retrospective analysis of prospectively collected data, to compare the kinetics of endocan in patients undergoing isolated coronary artery bypass graft (CABG) surgery. Endocan was measured at induction of general anesthesia (baseline), and at 6, 24, 48 and 72 h after the end of surgery. Patients were classified into two groups, namely those undergoing CPB (CPB group) and those without CPB (off-pump group). RESULTS: In total, 91 patients were included in this analysis: 61 patients in the CPB group and 30 in the off-pump group. There were no major significant differences between groups. Patients with CPB had a significantly higher level of endocan at 6 h (9.7 +/- 6.7 ng/ml vs 6.9 +/- 3.3 ng/ml, p = 0.03), but the difference was no longer statistically significant at subsequent timepoints. Endocan values were not significantly correlated with the duration of CPB (p = 0.53). CONCLUSION: Endocan levels in patients undergoing isolated CABG surgery with CPB are significantly higher at 6 h than in patients with off-pump surgery, and peaks earlier in those with CPB (6 h) than in those undergoing off-pump surgery (24 h). PMID- 29627159 TI - Investing in non-communicable diseases: an estimation of the return on investment for prevention and treatment services. AB - The global burden of non-communicable diseases (NCDs) is growing, and there is an urgent need to estimate the costs and benefits of an investment strategy to prevent and control NCDs. Results from an investment-case analysis can provide important new evidence to inform decision making by governments and donors. We propose a methodology for calculating the economic benefits of investing in NCDs during the Sustainable Development Goals (SDGs) era, and we applied this methodology to cardiovascular disease prevention in 20 countries with the highest NCD burden. For a limited set of prevention interventions, we estimated that US$120 billion must be invested in these countries between 2015 and 2030. This investment represents an additional $1.50 per capita per year and would avert 15 million deaths, 8 million incidents of ischaemic heart disease, and 13 million incidents of stroke in the 20 countries. Benefit-cost ratios varied between interventions and country-income levels, with an average ratio of 5.6 for economic returns but a ratio of 10.9 if social returns are included. Investing in cardiovascular disease prevention is integral to achieving SDG target 3.4 (reducing premature mortality from NCDs by a third) and to progress towards SDG target 3.8 (the realisation of universal health coverage). Many countries have implemented cost-effective interventions at low levels, so the potential to achieve these targets and strengthen national income by scaling up these interventions is enormous. PMID- 29627160 TI - Tackling socioeconomic inequalities and non-communicable diseases in low-income and middle-income countries under the Sustainable Development agenda. AB - Five Sustainable Development Goals (SDGs) set targets that relate to the reduction of health inequalities nationally and worldwide. These targets are poverty reduction, health and wellbeing for all, equitable education, gender equality, and reduction of inequalities within and between countries. The interaction between inequalities and health is complex: better economic and educational outcomes for households enhance health, low socioeconomic status leads to chronic ill health, and non-communicable diseases (NCDs) reduce income status of households. NCDs account for most causes of early death and disability worldwide, so it is alarming that strong scientific evidence suggests an increase in the clustering of non-communicable conditions with low socioeconomic status in low-income and middle-income countries since 2000, as previously seen in high income settings. These conditions include tobacco use, obesity, hypertension, cancer, and diabetes. Strong evidence from 283 studies overwhelmingly supports a positive association between low-income, low socioeconomic status, or low educational status and NCDs. The associations have been differentiated by sex in only four studies. Health is a key driver in the SDGs, and reduction of health inequalities and NCDs should become key in the promotion of the overall SDG agenda. A sustained reduction of general inequalities in income status, education, and gender within and between countries would enhance worldwide equality in health. To end poverty through elimination of its causes, NCD programmes should be included in the development agenda. National programmes should mitigate social and health shocks to protect the poor from events that worsen their frail socioeconomic condition and health status. Programmes related to universal health coverage of NCDs should specifically target susceptible populations, such as elderly people, who are most at risk. Growing inequalities in access to resources for prevention and treatment need to be addressed through improved international regulations across jurisdictions that eliminate the legal and practical barriers in the implementation of non-communicable disease control. PMID- 29627161 TI - Action to address the household economic burden of non-communicable diseases. AB - The economic burden on households of non-communicable diseases (NCDs), including cardiovascular diseases, cancer, respiratory diseases, and diabetes, poses major challenges to global poverty alleviation efforts. For patients with NCDs, being uninsured is associated with 2-7-fold higher odds of catastrophic levels of out of-pocket costs; however, the protection offered by health insurance is often incomplete. To enable coverage of the predictable and long-term costs of treatment, national programmes to extend financial protection should be based on schemes that entail compulsory enrolment or be financed through taxation. Priority should be given to eliminating financial barriers to the uptake of and adherence to interventions that are cost-effective and are designed to help the poor. In concert with programmes to strengthen national health systems and governance arrangements, comprehensive financial protection against the growing burden of NCDs is crucial in meeting the UN's Sustainable Development Goals. PMID- 29627162 TI - Taxes for health: evidence clears the air. PMID- 29627163 TI - 2018 must be the year for action against NCDs. PMID- 29627164 TI - Rachel Nugent: global health economist making NCDs count. PMID- 29627165 TI - Acting on NCDs: counting the cost. PMID- 29627166 TI - Equity impacts of price policies to promote healthy behaviours. AB - Governments can use fiscal policies to regulate the prices and consumption of potentially unhealthy products. However, policies aimed at reducing consumption by increasing prices, for example by taxation, might impose an unfair financial burden on low-income households. We used data from household expenditure surveys to estimate patterns of expenditure on potentially unhealthy products by socioeconomic status, with a primary focus on low-income and middle-income countries. Price policies affect the consumption and expenditure of a larger number of high-income households than low-income households, and any resulting price increases tend to be financed disproportionately by high-income households. As a share of all household consumption, however, price increases are often a larger financial burden for low-income households than for high-income households, most consistently in the case of tobacco, depending on how much consumption decreases in response to increased prices. Large health benefits often accrue to individual low-income consumers because of their strong response to price changes. The potentially larger financial burden on low-income households created by taxation could be mitigated by a pro-poor use of the generated tax revenues. PMID- 29627167 TI - Investing in non-communicable disease prevention and management to advance the Sustainable Development Goals. AB - Reduction of the non-communicable disease (NCD) burden is a global development imperative. Sustainable Development Goal (SDG) 3 includes target 3.4 to reduce premature NCD mortality by a third by 2030. Progress on SDG target 3.4 will have a central role in determining the success of at least nine SDGs. A strengthened effort across multiple sectors with effective economic tools, such as price policies and insurance, is necessary. NCDs are heavily clustered in people with low socioeconomic status and are an important cause of medical impoverishment. They thereby exacerbate economic inequities within societies. As such, NCDs are a barrier to achieving SDG 1, SDG 2, SDG 4, SDG 5, and SDG 10. Productivity gains from preventing and managing NCDs will contribute to SDG 8. SDG 11 and SDG 12 offer clear opportunities to reduce the NCD burden and to create sustainable and healthy cities. PMID- 29627168 TI - Cystic fibrosis papers of the year 2017. AB - The number of published articles on Cystic Fibrosis (CF) continues to increase year on year. The evidence base for small molecule therapies in CF has continued to expand, with evidence for lumacaftor/ivacaftor in younger patients and longer term evidence in adults, and pivotal studies on tezacaftor/ivacaftor. There were reports on emerging CFTR mutation agnostic therapies, and new evidence for long standing therapies. PMID- 29627169 TI - Side effects of medications used to treat childhood interstitial lung disease. AB - Interstitial lung disease in children (chILD) comprises a range of different rare diseases. There is limited evidence for the treatment of chILD and no randomised clinical trials of treatment have been undertaken. Most treatments are therefore prescribed off-label based on expert opinion. The off-label nature of prescription of drugs for chILD highlights the importance of a solid understanding of the side effects to facilitate risk-benefit assessment. The European Respiratory Society chILD guidelines recommend the use of systemic glucocorticosteroids, hydroxychloroquine and azithromycin. Side effects of these drugs will be discussed followed by consideration of other drugs used for the treatment of chILD. PMID- 29627170 TI - Spontaneous Micro-Aggregation of Platelets Predicts Clinical Outcome in Acute Ischemic Stroke. AB - BACKGROUNDS: Spontaneous micro-aggregation of platelets (SMAP) is frequently observed in stroke patients and is a trigger for the additional development of larger thrombi. We tested the hypothesis that SMAP may predict clinical outcome in acute ischemic stroke patients. METHODS AND RESULTS: Consecutive acute ischemic stroke patients (n = 358) who were transferred to our hospital within 24 hours after its onset were enrolled. Peripheral venous blood was sampled to measure various parameters when they arrived. SMAP was correlated with plasma brain natriuretic peptide and diastolic blood pressure positively, and with serum albumin and body weight negatively. Multivariable Cox regression analysis showed that only serum albumin was an independent predictor of the SMAP (P = .0023). The proportion of patients who were functionally independent (score 0-2 on the modified Rankin Scales) at discharge was lower in the third tertile of SMAP (higher level) as compared with the first and the second tertiles in ischemic stroke (odds ratio [OR], 5.76; 95 % confidence interval [CI], 3.31-10.05; P < .0001) and atherothrombotic stroke (P = .02 by chi-square test). The lower proportion of patients achieving independence was found in the first tertile of serum albumin (lower level) as compared with the second and third tertiles in ischemic (OR, 4.60; 95% CI, 2.66-7.95; P < .0001), atherothrombotic, and cardioembolic stroke (P = .004 and P < .0001 by chi-square test). On logistic regression analysis, SMAP and serum albumin remained independent predictors of poor outcome in ischemic stroke. CONCLUSIONS: SMAP within 24 hours after stroke onset is a novel independent predictor of clinical outcome in acute ischemic stroke patients. PMID- 29627171 TI - Comparison of Nicardipine with Clevidipine in the Management of Hypertension in Acute Cerebrovascular Diseases. AB - BACKGROUND AND PURPOSE: In acute stroke, hypertension worsens outcomes. Guidelines do not mention a preferred antihypertensive agent. This present study aimed to compare the efficacy and safety of nicardipine and clevidipine in acute stroke. METHODS: This retrospective review compared nicardipine with clevidipine for hypertension in acute stroke patients from March 17, 2015 to December 23, 2016. Ischemic and hemorrhagic stroke types were evaluated. Patients were excluded if under 18 years, had traumatic brain injury, had intracranial neoplasm, were on dialysis, had both study drugs during the stroke admission, or the study drug was infused for less than 1 hour. Efficacy outcomes were: time to goal blood pressure, percent time in goal, blood pressure range, and need for additional antihypertensive agents during the infusion. A composite of in hospital death, 30-day readmission, rebleeding, ischemic to hemorrhagic conversion, and hematoma expansion were compared. Other clinical outcomes included length of intensive care unit and hospital stay, hypotension, bradycardia, tachycardia, onset of atrial fibrillation, and acute kidney injury. RESULTS: Mean time to goal blood pressure was 65.5 minutes and 65.8 minutes in the nicardipine and clevidipine group, respectively (P = .83). No efficacy outcome was significantly different between 2 groups after multivariate analysis. CONCLUSIONS: Both nicardipine and clevidipine are reasonable antihypertensive agents in stroke, although cost and volume restriction could differentiate preference. PMID- 29627172 TI - Cerebrospinal fluid levels of sphingolipids associate with disease severity in first episode psychosis patients. PMID- 29627173 TI - Room to move: Plasticity in early auditory information processing and auditory learning in schizophrenia revealed by acute pharmacological challenge. AB - Many patients with chronic psychotic disorders including schizophrenia (SZ) maintain meaningful levels of plasticity (i.e., capacity for change) within neurocognition-relevant brain mechanisms, as evidenced by gains in neurocognition and function after interventions such as targeted cognitive training. However, like many clinical features of these disorders, therapeutic responses in SZ are heterogeneous, and prospectively identifying treatment-sensitive individuals and individualized treatment modalities remains an unmet challenge. We propose that available plasticity in neurocognition-relevant brain mechanisms in individual SZ patients can be detected by gains in laboratory measures of early auditory information processing (EAIP) and auditory learning after a single challenge-dose of a pharmacologic agent; here, we present supportive data for this strategy with the non-competitive NMDA antagonist, memantine, and the psychostimulant, amphetamine. We describe a novel therapeutic model where this "challenge dose" strategy is used to prospectively identify a sensitive cohort of patients, and in these patients, a therapeutic response is elicited by pairing drug-enhanced EAIP and auditory learning with auditory-based targeted cognitive training. PMID- 29627174 TI - Short-term outcomes in children undergoing restorative proctocolectomy with ileal pouch anal anastomosis. AB - INTRODUCTION: Patients with familial adenomatous polyposis (FAP) and ulcerative colitis (UC) commonly undergo restorative proctocolectomy with ileal-pouch anal anastomosis (RP-IPAA). We sought to describe patient characteristics and postoperative outcomes in this patient population. METHODS: Using the National Surgical Quality Improvement Program-Pediatric Participant Use Files from 2012 to 2015, children who were 6-18years old who underwent RP-IPAA for FAP or UC were identified. Postoperative morbidity, including reoperation and readmission were quantified. Associations between preoperative characteristics and postoperative outcomes were analyzed. RESULTS: A total of 260 children met the inclusion criteria, of which 56.2% had UC. Most cases were performed laparoscopically (58.1%), and the operative time was longer with a laparoscopic versus open approach (326 [257-408] versus 281 [216-391] minutes, p=0.02). The overall morbidity was 11.5%, and there were high reoperation and readmission rates (12.7% and 21.5%, respectively). On bivariate analysis, preoperative steroid use was associated with reoperation (22.5% versus 10.9%, p=0.04). On multivariable regression analysis, obesity was independently associated with reoperation (odds ratio: 3.34 [95% confidence intervals: 1.08-10.38], p=0.04). CONCLUSIONS: Children who undergo RP-IPAA have high rates of overall morbidity, reoperation, and readmission. Obesity was independently associated with reoperation. This data can be used by practitioners in the preoperative setting to better counsel families and establish expectations for the postoperative setting. TYPE OF STUDY: Retrospective Comparative Study. LEVEL OF EVIDENCE: Level III. PMID- 29627176 TI - 2017 AAP National Conference & Exhibition-Section on Surgery Annual Meeting. PMID- 29627175 TI - Multivariate analysis of risk factors for Nuss bar infections: A single center study. AB - BACKGROUND/PURPOSE: Our previously published data suggested several risk factors for infection after the Nuss procedure. We aimed to further elucidate these findings. METHODS: An IRB-approved (14-03-WC-0034), single institution, retrospective review was performed to evaluate the incidence of postoperative Nuss bar infections associated with seven variables. These were subjected to bivariate and multivariable analyses. A broad definition of infection was used including cellulitis, superficial infection with drainage, or deep infection occurring at any time postoperatively. RESULTS: Over 7years (4/1/2009-7/31/2016), 25 (3.2%) of 781 patients developed a postoperative infection after primary Nuss repair. Multivariable analyses demonstrated an increased risk of infection with perioperative clindamycin versus cefazolin for all infections (AOR 3.72, p=.017), and specifically deep infections (AOR 5.72, p=.004). The risk of a superficial infection was increased when antibiotic infusion completed >60min prior to incision (AOR 10.4, p=.044) and with the use of peri-incisional subcutaneous catheters (OR 8.98, p=.008). CONCLUSION: Following primary Nuss repair, the rate of deep bar infection increased with the use of perioperative clindamycin rather than cefazolin. The rate of superficial infection increased when perioperative antibiotic infusion was completed more than 60min prior to incision and with the use of peri-incisional subcutaneous catheters. Further studies are needed to better understand these findings. TYPE OF STUDY: Retrospective chart review. LEVEL OF EVIDENCE: Level III treatment study. PMID- 29627177 TI - The evolutionary saga of circumcision from a religious perspective. AB - Circumcision is the oldest surgical operation known to mankind. It probably originated as a less radical form of genital mutilation inflicted on prisoners of war. Over time it was adopted by the Egyptian priesthood and nobility, perhaps inspired by the mythology of Osiris. In turn, circumcision became part of the Jewish and Muslim religious cultures. In contrast, ancient Greeks valued an intact prepuce, as evident from the nude figures of Renaissance art. In the 19th century, circumcision was touted as a treatment for excessive masturbation, seizures, epilepsy, and paraplegia. Adoption of the procedure by medical science was almost akin to a religious belief. By the mid-20th century, it was widely performed on male infants on the pretext of phimosis when the prepuce was not retractable. In 1949, Gairdner documented that the tight prepuce of infants gradually becomes retractile as childhood progresses. Thus, childhood circumcision solely for non-retractile prepuce is unnecessary, which is the foundation for modern anti-circumcision movements. PMID- 29627178 TI - Growth morbidity in extremely low birth weight survivors of necrotizing enterocolitis at discharge and two-year follow-up. AB - PURPOSE: The purpose of this study was to examine postnatal growth outcomes and predictors of growth failure at 18-24months corrected age among extremely low birth weight (ELBW) survivors of necrotizing enterocolitis (NEC) compared to survivors without NEC. METHODS: Data were collected prospectively on ELBW (22 27weeks gestation or 401-1000g birth weight) infants born 2000-2013 at 46 centers participating in the Vermont Oxford Network follow-up project. Severe growth failure was defined as <3rd percentile weight-for-age. RESULTS: There were 9171 evaluated infants without NEC, 416 with medical NEC, and 462 with surgical NEC. Rates of severe growth failure at discharge were higher among infants with medical NEC (56%) and surgical NEC (61%), compared to those without NEC (36%). At 18-24months follow-up, rates of severe growth failure decreased and were similar between without NEC (24%), medical NEC (24%), and surgical NEC (28%). On multivariable analysis, small for gestational age, chronic lung disease, severe intraventricular hemorrhage or cystic periventricular leukomalacia, severe growth failure at discharge, and postdischarge tube feeding predicted <3rd percentile weight-for-age at follow-up. CONCLUSIONS: ELBW survivors of NEC have higher rates of severe growth failure at discharge. While NEC is not associated with severe growth failure at follow-up, one quarter of ELBW infants have severe growth failure at 18-24months. TYPE OF STUDY: Prognosis study. LEVEL OF EVIDENCE: II. PMID- 29627179 TI - A prostacyclin agonist and an omental flap increased myocardial blood flow in a porcine chronic ischemia model. AB - OBJECTIVE: We hypothesized that therapeutic efficacy may be augmented by a combination of placing a sheet immersed in ONO-1301SR, a slow-release synthetic prostacyclin agonist-inducing multiproangiogenic cytokines, over the left ventricle and a pedicled omental flap in a chronic myocardial infarct heart. METHODS: A minipig chronic myocardial infarction was generated by placing an ameroid constrictor ring around the left anterior descending artery for 4 weeks. The minipigs were then assigned into 4 groups of 6 each: sham, omental flap only, ONO-1301SR only, and ONO-1301SR combined with an omental flap (combined). Four weeks after treatment, therapeutic efficacy was evaluated histologically and via several modalities used in the clinical setting. RESULTS: In an angiogram and pressure wire study, the combined group induced development of collateral arteries to decrease the resistance and increase the flow reserve of microvasculature in the left circumflex territory. In a 13N-ammonia positron emission tomography study, the combined group displayed a prominent increase in myocardial blood flow and myocardial flow reserve in the left circumflex territory, particularly at the infarct-border region. Consequently, the combined group showed greater regional cardiac function in the left circumflex territory particularly at the infarct-border region, contributing to a greater global ejection fraction with a smaller left ventricular endosystolic volume. Pathologically, attenuated fibrosis, nonswollen myocytes, and upgraded capillary density and proangiogenic cytokines were prominent in the combined group. CONCLUSIONS: ONO-1301SR combined with a pedicled omental flap synergistically promoted myocardial angiogenesis, leading to function recovery in a porcine chronic myocardial infarction model. PMID- 29627181 TI - Less is sometimes less. PMID- 29627180 TI - Transatrial implantation of a transcatheter heart valve for severe mitral annular calcification. AB - OBJECTIVE: To assess the outcomes of transatrial implantation of a transcatheter heart valve (THV) for the treatment of mitral valve disease with severe mitral annular calcification (MAC). METHODS: Implantation of a balloon-expandable THV was performed on cardiopulmonary bypass via left atrial exposure in patients considered at risk for left ventricular outflow tract obstruction. The anterior mitral valve leaflet was systematically resected and pledgeted sutures were placed to enhance stability and reduce paravalvular leak. RESULTS: Twenty-six consecutive symptomatic patients with severe MAC (mean age, 78 +/- 7 years; 92% female; mean Society of Thoracic Surgeons score, 9.4 +/- 4.8) were included at 6 different centers. Two patients (8%) received an Edwards Sapien XT (Edwards Lifesciences, Irvine, Calif), and 24 (92%) an Edwards Sapien 3 bioprosthesis (Edwards Lifesciences). Concomitant aortic valve replacement was performed in 11 patients. Technical success according to the criteria of the Mitral Valve Academic Research Consortium was achieved in all patients. The mean transmitral gradient decreased from 10 +/- 5 to 4 +/- 2 mm Hg (P < .001) with trace or mild regurgitation in all patients. An elevated mean transaortic gradient (30 mm Hg) was observed in 1 patient (4%). Five patients died during hospital stay (19%) and 2 additional between discharge and 30 days (30-day mortality: 27%). Sustained functional improvement was observed in the remaining patients. CONCLUSIONS: Transatrial implantation of a THV for the treatment of MAC is associated with high technical success despite unfavorable anatomy. In this early experience of very high surgical risk patients, 30-day all-cause mortality was high. Patients at particular risk appear to be those with chronic kidney disease requiring multiple valve surgery. PMID- 29627182 TI - Transesophageal echocardiographic strain imaging predicts aortic biomechanics: Beyond diameter. AB - BACKGROUND: Clinical guidelines recommend resection of ascending aortic aneurysms at diameters 5.5 cm or greater to prevent rupture or dissection. However, approximately 40% of all ascending aortic dissections occur below this threshold. We propose new transesophageal echocardiography strain-imaging moduli coupled with blood pressure measurements to predict aortic dysfunction below the surgical threshold. METHODS: A total of 21 patients undergoing aortic resection were recruited to participate in this study. Transesophageal echocardiography imaging of the aortic short-axis and invasive radial blood pressure traces were taken for 3 cardiac cycles. By using EchoPAC (GE Healthcare, Madison, Wis) and postprocessing in MATLAB (MathWorks, Natick, Mass), circumferential stretch profiles were generated and combined with the blood pressure traces. From these data, 2 in vivo stiffness moduli were calculated: the Cardiac Cycle Pressure Modulus and Cardiac Cycle Stress Modulus. From the resected aortic ring, testing squares were isolated for ex vivo mechanical analysis and histopathology. Each square underwent equibiaxial tensile testing to generate stress-stretch profiles for each patient. Two ex vivo indices were calculated from these profiles (energy loss and incremental stiffness) for comparison with the Cardiac Cycle Pressure Modulus and Cardiac Cycle Stress Modulus. RESULTS: The echo-derived stiffness moduli demonstrate positive significant covariance with ex vivo tensile biomechanical indices: energy loss (vs Cardiac Cycle Pressure Modulus: R2 = 0.5873, P < .0001; vs Cardiac Cycle Stress Modulus: R2 = 0.6401, P < .0001) and apparent stiffness (vs Cardiac Cycle Pressure Modulus: R2 = 0.2079, P = .0378; vs Cardiac Cycle Stress Modulus: R2 = 0.3575, P = .0042). Likewise, these transesophageal echocardiography-derived moduli are highly predictive of the histopathologic composition of collagen and elastin (collagen/elastin ratio vs Cardiac Cycle Pressure Modulus: R2 = 0.6165, P < .0001; vs Cardiac Cycle Stress Modulus: R2 = 0.6037, P < .0001). CONCLUSIONS: Transesophageal echocardiography derived stiffness moduli correlate strongly with aortic wall biomechanics and histopathology, which demonstrates the added benefit of using simple echocardiography-derived biomechanics to stratify patient populations. PMID- 29627183 TI - Value of routine timed barium esophagram follow-up in achalasia after myotomy. AB - OBJECTIVES: The value of routine timed barium esophagram (TBE) in longitudinal follow-up of achalasia after Heller myotomy is unknown. We prospectively prescribed a yearly follow-up TBE. Purposes were to characterize esophageal emptying over time after myotomy, identify preoperative TBE measures associated with follow-up TBE, and characterize follow-up TBE over time in relationship to reintervention. METHODS: From March 1995 to April 2013, 635 patients underwent Heller myotomy for achalasia; 559 had at least 1 follow-up TBE. Temporal trends of 1335 follow-up TBEs in all nonreintervention and reintervention patients were assessed. Multivariable longitudinal analysis identified preoperative TBE measures associated with follow-up TBE. RESULTS: On average, TBE height and width at 1 and 5 minutes decreased approximately 50% and 60%, respectively, at first postoperative follow-up, and remained stable or slightly decreased for up to 5 years. Wider TBE width at 5 minutes was associated with greater follow-up TBE height and width at 1 minute. Of 118 patients undergoing reintervention, 64 (57%) had only 1 reintervention, with follow-up TBE returning to that of nonreintervention patients. Patients whose follow-up TBE remained abnormal underwent a further reintervention, some normalizing on subsequent TBE, and some not. CONCLUSIONS: Follow-up TBE is valuable postmyotomy, particularly if there is substantial esophageal dilatation preoperatively. Follow-up TBE reassures patients with stable or decreasing TBE measures, permitting decreased follow-up intensity. Reintervention should not be considered a myotomy failure, because a successful, single, nonsurgical reintervention often results in long-term successful palliation. More than 1 reintervention requires intensification of TBE follow-up, facilitating treatment planning. PMID- 29627184 TI - Short- and long-term cause of death in patients undergoing isolated coronary artery bypass grafting: A nationwide cohort study. AB - OBJECTIVES: Knowledge of the association between time and causes of death after coronary artery bypass grafting is sparse. We examined short- and long-term mortality and cause of death in patients undergoing coronary artery bypass grafting. METHODS: With the use of Danish nationwide registries, we identified all patients undergoing isolated coronary artery bypass grafting from 1998 to 2014. Cause of death was classified as cardiovascular or noncardiovascular according to death certificates. Landmark analyses of the cumulative incidences of cardiovascular and noncardiovascular mortality after 1, 3, and 5 years after coronary artery bypass grafting were performed. Multivariable cause-specific Cox regression models were used to evaluate changes over time in the risk of all cause, cardiovascular, and noncardiovascular mortality after 1 and 7 years after coronary artery bypass grafting, respectively. RESULTS: Among 37,495 included patients, 12,230 (32.6%) died during a median follow-up of 7.4 years. Causes of death were classified as cardiovascular in 6459 patients (52.8%) and noncardiovascular in 5771 patients (47.2%). Within the first year, the incidence of cardiovascular death was higher compared with noncardiovascular death (3.9% vs 1.1%, P < .001). The cumulative incidences of cardiovascular and noncardiovascular were deaths similar in the periods 1 to 3 years (2.3% vs 2.6%, P = .004), 3 to 5 years (3.1% vs 3.2%, P = .75), and 5 to 7 years postsurgery (3.7% vs 4.0%, P = .07). The crude rates and adjusted risks of short- and long term all-cause and cardiovascular mortality decreased during the study period despite an increase in age and burden of comorbidities. CONCLUSIONS: In patients undergoing coronary artery bypass grafting, cardiovascular causes were responsible for the majority of deaths within the first year. Deaths due to noncardiovascular causes gained importance over time elapsed since coronary artery bypass grafting. PMID- 29627185 TI - The convergence on extremes. PMID- 29627186 TI - Perforation of Meckel's diverticulum by a foreign body. PMID- 29627187 TI - Severe Cardiac Involvement Is Rare in Patients with Late-Onset Pompe Disease and the Common c.-32-13T>G Variant: Implications for Newborn Screening. AB - Based on a review of a large patient cohort, published literature, and 3 newborn screening cohorts, we concluded that children diagnosed through newborn screening with late-onset Pompe disease and the common heterozygous c.-32-13T>G variant require frequent cardiac follow-up with electrocardiography for arrhythmias. However, there is limited evidence for performing repeated echocardiography for cardiomyopathy. PMID- 29627189 TI - Variations in Mechanisms of Injury for Children with Concussion. AB - OBJECTIVES: To assess the distribution of injury mechanisms and activities among children with concussions in a large pediatric healthcare system. STUDY DESIGN: All patients, age 0-17 years, who had at least 1 clinical encounter with an International Classification of Diseases, Ninth Revision, Clinical Modification diagnosis of concussion in the Children's Hospital of Philadelphia's electronic health record system from July 1, 2012 to June 30, 2014, were selected (N = 8233) and their initial concussion-related visit identified. Approximately, 20% of the patients (n = 1625) were randomly selected for manual record review to examine injury mechanisms and activities. RESULTS: Overall, 70% of concussions were sports related; however, this proportion varied by age. Only 18% of concussions sustained by children aged 0-4 were sports related, compared with greater proportions for older children (67% for age 5-11, 77% for age 12-14, and 73% for age 15-17). When the concussion was not sports related, the primary mechanisms of injury were struck by an object (30%) and falls (30%). CONCLUSIONS: Sports related injuries in children older than 6 years of age contributed to the majority of concussions in this cohort; however, it is important to note that approximately one-third of concussions were from non-sports-related activities. Although there is increased participation in community and organized sports activities among children, a focus on prevention efforts in other activities where concussions occur is needed. PMID- 29627191 TI - Moving the Dementia-Related Stigma Dial among Chinese Americans. PMID- 29627190 TI - Associations of Early to Mid-Childhood Adiposity with Elevated Mid-Childhood Alanine Aminotransferase Levels in the Project Viva Cohort. AB - OBJECTIVES: To examine the longitudinal relationship of early to mid-childhood adiposity measures with mid-childhood alanine aminotransferase (ALT) levels. STUDY DESIGN: We studied 635 children in the Project Viva cohort. Research staff measured weight, height, skinfolds thicknesses, and waist and hip circumferences at early (median 3.2 years) and mid-childhood (median 7.7 years) visits. At mid childhood, we collected blood for ALT analysis. We used established sex-specific ALT cut-offs to define elevated ALT. In multivariable linear and logistic regression models, we assessed the association of adiposity measures from early to mid-childhood with mid-childhood ALT level, adjusting for confounders. RESULTS: Children were 48% female, 59% white, 21% black, 6% Hispanic/Latino, and 3% Asian. At early childhood, 29% had overweight/obesity and mean waist circumference was 51.5 (SD 3.8) cm. At mid-childhood, mean ALT was 20.3 (SD 7.3) units/L, and 23% had an elevated ALT. In multivariable-adjusted regression models, each additional 10-cm greater waist circumference at early childhood was associated with 1.99 (95% CI 1.19-3.33) greater odds of elevated ALT at mid childhood. Greater increases from early to mid-childhood in body mass index z score, sum of subscapular and triceps skinfold thicknesses, waist circumference, and hip circumference were associated with greater ALT at mid-childhood. CONCLUSIONS: In this prospective cohort, greater waist circumference at early childhood and greater increases in adiposity measures from early to mid-childhood were associated with greater ALT levels at mid-childhood. PMID- 29627192 TI - Why Do the Very Old Self-Harm? A Qualitative Study. AB - OBJECTIVES: To examine the perspectives of people aged 80 years or older who self harmed regarding their reasons for self-harm and its consequences, and their perceptions of care. DESIGN: A qualitative study using in-depth interviews. SETTING: Participants were recruited from two teaching hospitals and associated community services. PARTICIPANTS: People aged 80 years or older who had self harmed within the previous month. METHODS: Structured psychiatric assessment including cognitive testing, DSM-5 diagnosis, and an in-depth qualitative interview focusing upon the reasons for and consequences of self-harm. Narrative enquiry was used to guide the discussion. All interviews were undertaken by a geriatric psychiatrist, audio recorded, transcribed verbatim, and subjected to thematic analysis using N-VIVO. RESULTS: Themes that emerged for the reasons for self-harm included "enough is enough"; "loneliness"; "disintegration of self"; "being a burden"; "cumulative adversity"; "hopelessness and endless suffering"; "helplessness with rejection"; and "the untenable situation". Themes for the consequences of self-harm were "becoming engaged with or distanced from family"; "the problem was solved"; "gaining control"; "I"m worse off now"; "rejection by health professionals"; and "tension in the role of the inpatient clinical environment". CONCLUSIONS: Self-harm may communicate a need that cannot otherwise be expressed. An individualized person-centered approach is required to respond to self-harm, including a combination of practical, medical, and psychological approaches as indicated. Involvement of families in the process of understanding the meaning of and responding to self-harm through education and family therapy, as well as education of healthcare professionals beyond risk factor notation may be indicated. PMID- 29627193 TI - Kinase-catalyzed biotinylation of DNA. AB - Prior work documented use of gamma-phosphate modified ATP analogs to label DNA using T4 polynucleotide kinases (T4PNK), although applications have been limited. To fully characterize kinase-catalyzed labeling of nucleic acids, we explored use of ATP-biotin as a cosubstrate with T4PNK. T4PNK accepted ATP-biotin to 5'-label single stranded DNA. However, T4PNK-mediated labeling of double stranded substrates was low yielding. In addition, the phosphoramidate bond connecting the biotin group to the DNA was unstable. These results suggest that kinase-catalyzed biotinylation will be useful with single stranded DNA substrates and mild reaction conditions. By revealing the scope and limitations of kinase-catalyzed biotinylation, these studies provide a foundation for future development and application of kinase-catalyzed labeling to DNA-based biological studies. PMID- 29627188 TI - Maternal Black Race and Persistent Wheezing Illness in Former Extremely Low Gestational Age Newborns: Secondary Analysis of a Randomized Trial. AB - OBJECTIVE: To evaluate the relationship between maternal self-reported race/ethnicity and persistent wheezing illness in former high-risk, extremely low gestational age newborns, and to quantify the contribution of socioeconomic, environmental, and biological factors on this relationship. STUDY DESIGN: We assessed persistent wheezing illness determined at 18-24 months corrected (for prematurity) age in survivors of a randomized trial. Parents/caregivers were surveyed for wheeze and inhaled asthma medication use quarterly to 12 months, and at 18 and 24 months. We used multivariable analysis to evaluate the relationship of maternal race to persistent wheezing illness, and identified mediators for this relationship via formal mediation analysis. RESULTS: Of 420 infants (25.2 +/ 1.2 weeks of gestation and 714 +/- 166 g at birth, 57% male, 34% maternal black race), 189 (45%) had persistent wheezing illness. After adjustment for gestational age, birth weight, and sex, infants of black mothers had increased odds of persistent wheeze compared with infants of nonblack mothers (OR = 2.9, 95% CI 1.9, 4.5). Only bronchopulmonary dysplasia, breast milk diet, and public insurance status were identified as mediators. In this model, the direct effect of race accounted for 69% of the relationship between maternal race and persistent wheeze, whereas breast milk diet, public insurance status, and bronchopulmonary dysplasia accounted for 8%, 12%, and 10%, respectively. CONCLUSIONS: Among former high-risk extremely low gestational age newborns, infants of black mothers have increased odds of developing persistent wheeze. A substantial proportion of this effect is directly accounted for by race, which may reflect unmeasured environmental influences, and acquired and innate biological differences. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01022580. PMID- 29627194 TI - The association between blood eosinophils and risk and treatment outcome in COPD is not dichotomised. PMID- 29627195 TI - Blood eosinophils as a marker of eosinophilic exacerbations in COPD. PMID- 29627196 TI - Non-molecular Methods to Detect Bacteriuria Prior to Urological Interventions: A Diagnostic Accuracy Systematic Review. AB - Urine culture still has to be considered as the gold standard to rule out bacteriuria and should, therefore, be obtained prior to invasive endoscopic or open urological procedures to minimize the risk of severe infectious complications. PMID- 29627197 TI - Time-to-event Outcomes in Men with Nonmetastatic Castrate-resistant Prostate Cancer-A Systematic Literature Review and Pooling of Individual Participant Data. AB - CONTEXT: Until recently, there has been a lack of evidence-based treatment alternatives in men with nonmetastatic castrate-resistant prostate cancer (NM CRPC). However, new evidence-based treatment alternatives are emerging. OBJECTIVE: We aimed to describe time-to-event outcomes in NM-CRPC patients based on evidence from both prospective and retrospective studies. Second, we aimed to describe predictors of these outcomes in the same patient population. EVIDENCE ACQUISITION: A systematic review was conducted to identify clinical studies (both prospective and retrospective) in NM-CRPC patients. All published Kaplan-Meier curves were digitized, and individual participant data were extracted using a published and validated R code. The following outcomes were considered: overall survival (OS), bone metastasis-free survival (BMFS), time to bone metastasis (TTBM), metastasis-free survival, time to metastasis, time to progression (TTP), progression-free survival, and time to prostate-specific antigen (PSA) progression. Second, we described all predictor/outcome relationships. EVIDENCE SYNTHESIS: Median survival times, in months, for OS, BMFS, TTBM, and TTP in placebo arms of randomized clinical trials are 45.3 (95% confidence interval [CI]: 43.5-46.8), 31.5 (95% CI: 28-33.4), 28.8 (95% CI: 25.2-31.6), and 22.2 (95% CI: 19.3-24.8), respectively. In general, reported outcomes in retrospective studies seemed to be longer than those reported in clinical trials. Baseline PSA nadir levels, PSA doubling time, PSA velocity, and alkaline phosphatase velocity are reliable predictors of time-to-event outcomes in NM-CRPC patients, whereas Gleason score is not. CONCLUSIONS: NM-CRPC is a long-standing condition where effective treatments to slow down disease progression historically have been lacking. Compared with prospective studies, retrospective studies have had limited ability to correctly identify NM-CRPC patients and estimate time to different outcomes in NM-CRPC patients. PATIENT SUMMARY: For patients with nonmetastatic castration-resistant prostate cancer (NM-CRPC), currently no effective treatments resulting in longer survival compared with watchful waiting are available. On average, without additional treatment, half of these patients survive <45 mo after NM-CRPC diagnosis. PMID- 29627198 TI - The opioid epidemic and injection drug use: MIPIE and health harms related to the injection of prescription opioids. PMID- 29627199 TI - Mixed and inhomogeneous expression profile of Th1/Th2 related cytokines detected by cytometric bead array in the saliva of patients with oral lichen planus. AB - OBJECTIVE: The aim of this study was to measure T helper (Th) 1/Th2-related cytokine expression in saliva from patients with oral lichen planus (OLP), compared with healthy controls (HC group) and controls with recurrent aphthous ulcers (RAU group). STUDY DESIGN: Saliva was collected from 41 patients with OLP, 14 HCs, and 14 controls with RAU for Th1/Th2-related cytokines analysis with cytometric bead array. Disease activity in OLP was recorded by reticulation/keratosis, erythema, and ulceration scores. RESULTS: Interleukin (IL)-6, IL-10, interferon-gamma (IFN-gamma), and IFN-gamma/IL-4 in saliva were significantly higher in the OLP group than in the HC group. A positive and significant correlation among IL-6, IL-10, and reticulation/keratosis, erythema, and ulceration scores in the OLP group was revealed. Significantly increased IL 4, IL-5, IL-6, IL-10, tumor necrosis factor-alpha and IFN-gamma/IL-4 were found in the RAU group. CONCLUSIONS: Salivary cytokine profiles analyzed by cytometric bead array may provide a convenient research approach to OLP. Data indicated complicated Th1/Th2-related cytokine profile changes, rather than simple dominance model, in OLP. IL-10 and especially IL-6 may provide a surrogate endpoint for monitoring OLP. PMID- 29627200 TI - Computer-assisted resection and reconstruction of bilateral osteoradionecrosis of the mandible using 2 separate flaps prepared from a single fibula. AB - OBJECTIVES: Osteoradionecrosis of the mandible is a late radiation-induced complication, which is a major concern in survivors of head and neck cancer. STUDY DESIGN: In this study, we present a case of a patient with nasopharyngeal carcinoma who developed extensive bilateral osteoradionecrosis of the ascending ramus of the mandible. After preoperative virtual surgical planning, the obtained data were used to fabricate patient-specific cutting templates. The bilateral mandibular defects were reconstructed using 2 separate flaps prepared from a single fibula. RESULTS: Both defects were successfully reconstructed, and satisfactory aesthetic and functional results were achieved. CONCLUSIONS: Bilateral mandibular osteoradionecrosis can be managed with virtual surgical planning, and the defects can be reconstructed using 2 separate flaps prepared from a single fibula. PMID- 29627201 TI - Perioperative analgesic effects of an ultrasound-guided transversus abdominis plane block with a mixture of bupivacaine and lidocaine in cats undergoing ovariectomy. AB - OBJECTIVE: To evaluate the perioperative analgesic effects of a transversus abdominis plane (TAP) block with a mixture of lidocaine and bupivacaine administered to cats undergoing ovariectomy. STUDY DESIGN: Controlled, randomized, prospective, blinded clinical study. ANIMALS: A group of 20 healthy cats. METHODS: Robenacoxib (2 mg kg-1) was administered subcutaneously 0.5 hour before intramuscular (IM) administration of ketamine (5 mg kg-1), methadone (0.1 mg kg-1) and dexmedetomidine (0.01 mg kg-1). General anesthesia was induced with intravenous (IV) propofol and maintained with isoflurane. An ultrasound-guided TAP block was performed by injecting 0.5% bupivacaine (0.2 mL kg-1) diluted in a total volume of 1.5 mL 2% lidocaine bilaterally (TAP group, n = 10) or the same volume of saline solution bilaterally in controls (CTR group, n = 10). During surgery, a 20% increase in heart rate and respiratory frequency was treated with IV fentanyl (0.001 mg kg-1). Before premedication and at 1, 2, 3, 4, 6, 8, 12, 16, 20 and 24 hours after extubation, pain was assessed with a simple descriptive pain scale, that ranged from 0 (no pain) to 4 (intense pain). For pain scores >=3, IM methadone (0.1 mg kg-1) was administered. Data were analyzed with the Friedman or the analysis of variance (anova) test, and p < 0.05 was considered statistically significant. RESULTS: Only two cats in the CTR group were administered one dose of fentanyl during surgery. At 2, 6, 8, 12, 16, 20 and 24 hours after surgery, the pain score was higher in the CTR group. A mean dose of 0.5 +/- 0.2 mg kg-1 methadone was administered to all cats in the CTR groups within 24 hours. Methadone was not administered to the TAP group (pain score < 3). CONCLUSIONS AND CLINICAL RELEVANCE: Ultrasound-guided TAP block can be a reliable adjunctive technique, providing analgesia for up to 24 hours in cats undergoing ovariectomy. PMID- 29627202 TI - Critical incident technique analysis applied to perianesthetic cardiac arrests at a university teaching hospital. AB - OBJECTIVE: To apply the critical incident technique (CIT) methodology to a series of perianesthetic cardiac arrest events at a university teaching hospital to describe the factors that contributed to cardiac arrest. STUDY DESIGN: CIT qualitative analysis of a case series. ANIMALS: A group of 16 dogs and cats that suffered a perioperative cardiac arrest between November 2013 and November 2016. METHODS: If an arrest occurred, the event was discussed among the anesthesiologists. The discussion included a description of the case, a description of the sequence of events leading up to the arrest and a discussion of what could have been done to affect the outcome. A written description of the case and the event including animal signalment and a timeline of events was provided by the supervising anesthesiologist following discussion among the anesthesiologists. Only dogs or cats were included. After the data collection period, information from the medical record was collected. A qualitative document analysis was performed on the summaries provided about each case by the supervising anesthesiologist, the medical record and any supporting documents. Each case was then classified into one or more of the following: animal, human, equipment, drug and procedural factors for cardiac arrest. RESULTS: The most common factor was animal (n=14), followed by human (n=12), procedural (n=4), drugs (n=1) and equipment (n=1). The majority (n=11) of animals had multiple factors identified. CONCLUSIONS AND CLINICAL RELEVANCE: Cardiac arrests during anesthesia at a referral teaching hospital were primarily a result of animal and human factors. Arrests because of procedural, drug and equipment factors were uncommon. Most animals experienced more than one factor and two animals arrested after a change in recumbency. Future work should focus on root cause analysis and interventions designed to minimize all factors, particularly human ones. PMID- 29627203 TI - Re-wilding Collective Behaviour: An Ecological Perspective. AB - The earliest studies of collective animal behaviour were inspired by and conducted in the wild. Over the past decades much of the research in this field has shifted to the laboratory, combining high-resolution tracking of individuals with mathematical simulations or agent-based models. Today we are beginning to see a 're-wilding' of collective behaviour thanks to technological advances, providing researchers with the opportunity to quantify and model the heterogeneity that exists within the social groupings they study and within the environments in which these groups live. The perspective we present here aims to inspire and steer this research toward answering fundamental and outstanding behavioural and ecological questions, while also tackling pertinent conservation challenges. PMID- 29627204 TI - Global development of various emerged substrates utilized in constructed wetlands. AB - Substrate selection is one of the key technical issues for constructed wetlands (CWs), which works for wastewater treatment based mainly on the biofilm principle. In recent years, many alternative substrates have been studied and applied in CWs, and a review is conducive to providing updated information on CW R&D. Based on the intensive research work especially over the last 10 years on the development of emerged substrates (except for the three conventional substrates of soil, sand, and gravel) in CWs, this review was made. The substrates are categorized depending on their main roles in pollutant removal as ion-exchange substrates, P-sorption substrates, and electron donor substrates. Among these, reuse of various waste products as substrates was suggested due to their competitive pollutant removal efficiency and minimized waste disposal. Regarding substrate development, future research on avoiding substrate clogging to extend their lifetime in CWs is needed. PMID- 29627205 TI - Color stability of nonpigmented and pigmented maxillofacial silicone elastomer exposed to 3 different environments. AB - STATEMENT OF PROBLEM: The color degradation of maxillofacial prostheses in clinical service requires their frequent renewal. How different materials compare is unclear. PURPOSE: The purpose of this in vitro study was to investigate the color stability of a nonpigmented and pigmented maxillofacial silicone when stored in darkness and exposed to accelerated aging in a weathering chamber and natural outdoor weathering. MATERIAL AND METHODS: M511 elastomer was colored with Spectromatch Pro colorants, stored in darkness, and exposed to accelerated aging and natural outdoor weathering for 1500 hours. Test groups included nonpigmented specimens (n=18), individually pigmented specimens (n=90), and Caucasian skin tone-colored specimens (n=18). The CIELab values of the test specimens were measured using the CM-2600d spectrophotometer (Konica Minolta Sensing) at base line (0 hours) and then every 100 hours up to 1500 hours of aging. Color changes (DeltaE) were calculated based on the recorded CIELab values. All data were analyzed by using linear mixed models and the Sidak multiple comparison of means test (alpha=.05). RESULTS: A significant effect of time was found on the DeltaE of all test specimens in all environments (P=.001). All pigmented M511 specimens demonstrated good color stability with maximum DeltaE below the acceptability threshold of 2 DeltaE when stored in darkness and exposed to outdoor weathering. However, nonpigmented specimens crossed this acceptability threshold when exposed to outdoor weathering with maximum DeltaE values of 3.65. The greatest color changes were observed for all specimens when exposed to accelerated aging and most exceeded the acceptability threshold. Nonpigmented (DeltaE, 4.86) and Indian yellow (DeltaE, 5.20) demonstrated the highest color changes after 1500 hours. CONCLUSIONS: All environments resulted in visible color changes of nonpigmented and pigmented M511 elastomer. The lowest DeltaE values were observed for specimens stored in darkness and the greatest for specimens exposed to accelerated aging. The organic pigment Logwood maroon demonstrated the best color stability with maximum DeltaE values below the perceptibility threshold (PT) of 1 DeltaE. PMID- 29627206 TI - Comparative analysis of the microstructures and mechanical properties of Co-Cr dental alloys fabricated by different methods. AB - STATEMENT OF PROBLEM: Limited information is available regarding the microstructures and mechanical properties of Co-Cr dental alloys prepared using conventional casting (CAST), computer numerical control (CNC) milling, and selective laser melting (SLM). PURPOSE: The purpose of this in vitro study was to evaluate the mechanical properties and microstructures of Co-Cr dental alloys fabricated using conventional casting, computer numerical control milling, and selective laser melting and to estimate the potential of applying the SLM technique in prosthetic dentistry. MATERIAL AND METHODS: Each group (n=6) of 50 mm-long Co-Cr alloy, dumbbell-shaped specimens was fabricated using the CAST, CNC, and SLM techniques. For each technique, the corresponding commercial alloy material was used. The mechanical properties were evaluated using a tensile test according to International Organization for Standardization (ISO) standard 6892, including 0.2% yield strength, ultimate tensile strength, elongation, and fracture analysis. The microstructures of the specimens were evaluated by using metallurgical microscopy, X-ray diffraction (XRD), and scanning electron microscopy. The Tukey honest significant difference test (alpha=.05) was used to statistically analyze the 0.2% yield strength, ultimate tensile strength, and microhardness values. RESULTS: The microstructures of the SLM specimens exhibited homogeneously distributed fine grains, dispersed second-phase particles, and few defects, and the XRD results showed the alpha-Co phase predominated, with minimal epsilon-Co phase and no harmful needle sigma phase in the SLM group. The mean +/ standard deviation of the 0.2% yield strength of the SLM specimens was 790 +/-11 MPa, and the ultimate tensile strength was 1072 +/-18 MPa. These values exceeded those of the CAST and CNC specimens by approximately 50% (P<.05). The SLM group showed the highest microhardness (475.3 +/-10.2 HV10), followed by the CNC (325.2 +/-17.8 HV10) and CAST group (323.7 +/-27.2 HV10). Additionally, the ductility and toughness of the SLM specimens were also better than those of the other 2 groups. No significant differences were found in the mechanical performance between the CNC and CAST specimens (P>.05). CONCLUSIONS: The microstructures and mechanical properties of Co-Cr dental alloys were dependent on the fabrication techniques. The SLM specimens exhibited better microstructures and mechanical properties than those fabricated with CNC or CAST. PMID- 29627207 TI - Comparison of clinical and electromyographic rest vertical dimensions in dolichofacial and brachyfacial young adults: A cross-sectional study. AB - STATEMENT OF PROBLEM: Therapeutic procedures that increase occlusal vertical dimension (OVD) may have different responses in patients with different craniofacial vertical patterns. The effect on these patients of increasing their OVD is not well understood. PURPOSE: The purpose of this clinical study was to compare measurements of vertical jaw separation (VJS) in patients with brachyfacial and dolichofacial craniofacial patterns in 2 vertical dimensions: the clinical rest/postural vertical dimension (CR/PVD) and electromyographic rest vertical dimension (EMGRVD). MATERIAL AND METHODS: Sixty healthy dental students were selected at random after a lateral skull radiograph was made. The Ricketts (VERT index) analysis was used to determine 30 brachyfacial (G1) and 30 dolichofacial (G2) types. The VJS was measured for G1 and G2 types in the 2 rest vertical dimensions specified. CR/PVD was recorded using 2 methods: swallowing (CR/PVD-P1) and the phonetic breathing method (CR/PVD-P2). The Shapiro-Wilk test was used for data distribution, and the Mann-Whitney U test was used to accept or reject the null hypothesis (alpha=.05). RESULTS: Mean VJS in CR/PVD-P1 was 1.92 +/-1.14 mm for the brachyfacial and 1.36 +/-0.58 mm for the dolichofacial facial group (P=.05). The mean VJS in CR/PVD-P2 was 1.89 +/-1.17 mm for the brachyfacial and 1.31 +/-0.58 mm for the dolichofacial group (P=.03). The mean VJS in EMGRVD was 8.23 +/-2.21 mm for the brachyfacial and 16.55 +/-4.29 mm the dolichofacial group (P<.001). CONCLUSIONS: CR/PVD measurements in dolichofacial individuals were lower than those in brachyfacial individuals. EMGRVD measurements were higher in dolichofacial individuals than those in brachyfacial individuals. Biomechanical, physiological, and behavioral reasons might explain such diversity. PMID- 29627208 TI - Influence of repeated firings on marginal, axial, axio-occlusal, and occlusal fit of metal-ceramic restorations fabricated with different techniques. AB - STATEMENT OF PROBLEM: Ill-fitting restorations can jeopardize dental, periodontal, and systemic health. Repeated ceramic firing may influence the fitting accuracy of restorations, but scientific information regarding this issue is lacking. PURPOSE: The purpose of this in vitro study was to assess and compare the influence of repeated firings on the marginal, axial, axio-occlusal, and occlusal fit of metal-ceramic 3-unit fixed partial dentures (FPDs) manufactured with different framework methods, including casting, fully sintered hard alloy milling (FHAM), presintered soft alloy milling (PSAM), and selective laser sintering (SLS). MATERIAL AND METHODS: A total of 60 Co-Cr metal frameworks for 3 unit FPDs were fabricated with 3 different computer-aided design and computer aided manufacturing (CAD-CAM) techniques and conventional casting for a typodont model. The discrepancy values for premolar and molar abutments were measured by using the silicone replica technique after fabrication of the framework, second firing, fourth firing, and seventh firing. The replicas were separated into mesiodistal and buccolingual cross-sections, and digital images of the cross sections were obtained with a stereomicroscope at *80 magnification. The measurement points were examined to record the discrepancy values (MUm) with in built measuring software. The recorded data were subjected to repeated-measures 4 way ANOVA and the Bonferroni post hoc test (alpha=.05). RESULTS: For all measurement periods, the marginal, axial, axio-occlusal, and occlusal discrepancy values differed significantly among the manufacturing groups (P<.001). Moreover, the repeated firings had a statistically significant influence on the discrepancy values of PSAM, FHAM, and SLS groups (P<.05). The cast group was not significantly affected by repeated firings (P>.05). The PSAM group revealed the lowest discrepancy values at all measurement periods (P<.05), except after the second firing in the marginal and axial locations. CONCLUSIONS: The PSAM fabricated restorations demonstrated superior fitting accuracy. All manufacturing groups were influenced by repeated firings, except the cast group. The marginal discrepancy values of all manufacturing groups were within the range of clinical acceptability (<120 MUm). PMID- 29627209 TI - Digital evaluation of absolute marginal discrepancy: A comparison of ceramic crowns fabricated with conventional and digital techniques. AB - STATEMENT OF PROBLEM: Marginal discrepancy is key to evaluating the accuracy of fixed dental prostheses. An improved method of evaluating marginal discrepancy is needed. PURPOSE: The purpose of this in vitro study was to evaluate the absolute marginal discrepancy of ceramic crowns fabricated using conventional and digital methods with a digital method for the quantitative evaluation of absolute marginal discrepancy. The novel method was based on 3-dimensional scanning, iterative closest point registration techniques, and reverse engineering theory. MATERIAL AND METHODS: Six standard tooth preparations for the right maxillary central incisor, right maxillary second premolar, right maxillary second molar, left mandibular lateral incisor, left mandibular first premolar, and left mandibular first molar were selected. Ten conventional ceramic crowns and 10 CEREC crowns were fabricated for each tooth preparation. A dental cast scanner was used to obtain 3-dimensional data of the preparations and ceramic crowns, and the data were compared with the "virtual seating" iterative closest point technique. Reverse engineering software used edge sharpening and other functional modules to extract the margins of the preparations and crowns. Finally, quantitative evaluation of the absolute marginal discrepancy of the ceramic crowns was obtained from the 2-dimensional cross-sectional straight-line distance between points on the margin of the ceramic crowns and the standard preparations based on the circumferential function module along the long axis. RESULTS: The absolute marginal discrepancy of the ceramic crowns fabricated using conventional methods was 115 +/-15.2 MUm, and 110 +/-14.3 MUm for those fabricated using the digital technique was. ANOVA showed no statistical difference between the 2 methods or among ceramic crowns for different teeth (P>.05). CONCLUSIONS: The digital quantitative evaluation method for the absolute marginal discrepancy of ceramic crowns was established. The evaluations determined that the absolute marginal discrepancies were within a clinically acceptable range. This method is acceptable for the digital evaluation of the accuracy of complete crowns. PMID- 29627210 TI - Retention of zirconia on titanium in two-piece abutments with self-adhesive resin cements. AB - STATEMENT OF PROBLEM: Two-piece abutments consisting of a prefabricated titanium luting base and a zirconia abutment are used widely in implant restorations. Straightforward and reliable procedures for bonding titanium and zirconia are necessary for ensuring low failure rates in such restorations. PURPOSE: The purpose of this in vitro study was to evaluate the tensile load of zirconia copings on prefabricated titanium abutments using 4 different self-adhesive resin cements. MATERIAL AND METHODS: A total of 128 industrially manufactured partially yttria-stabilized zirconia ceramic copings were bonded to titanium abutments with a luting space of about 60 MUm or 100 MUm. The bonding surfaces were airborne particle abraded with 50 MUm alumina and cleaned ultrasonically. The zirconia copings were bonded with Panavia SA Cement Automix (SA), RelyX Unicem 2 Automix (RU), MaxCem Elite (ME), or SmartCem 2 (SC). Specimens from each cement group were randomly assigned to be stored either in distilled water (37 degrees C) for 3 days or subjected to 37 500 thermocycles over 150 days. After debonding in tension, failure modes (adhesive or cohesive) were analyzed, and basic fuchsin dye penetration tests were performed using optical microscopy and scanning electron microscopy. Three-way ANOVA and Tukey HSD tests were used for statistical analysis (alpha=.05). RESULTS: Three-way ANOVA results determined that the luting resin used and the luting space had a significant effect (P<=.002), while the storage time did not have an overall effect (P>.05). The interaction between the luting resin used and storage time was significant (P<.001). After storage for 3 days, the retentive force of SA (1002 N) was highest, followed by that for RU (614 N), ME (550 N), and SC (346 N) (P<=.05); the forces for RU and ME were not significantly different (P>.05). However, after thermocycling, RU had the highest retentive force (848 N), followed by SA (646 N), ME (475 N), and SC (364 N) (P<=.05). Retentive forces for ME and SC were not significantly different (P>.05). The failure modes of the zirconia abutment surfaces were predominantly adhesive, while those of the titanium surfaces were mainly cohesive. The SA specimens showed the lowest dye penetration, followed by the RU, ME, and SC specimens. CONCLUSIONS: The greatest mean retention was found with Panavia SA Cement Automix and RelyX Unicem 2 Automix with a luting space of 60 MUm when bonding zirconia copings to titanium. PMID- 29627211 TI - Intraoral scan bodies in implant dentistry: A systematic review. AB - STATEMENT OF PROBLEM: Intraoral scan body (ISB) design is highly variable and its role in the digital workflow and accuracy of digital scans is not well understood. PURPOSE: The purpose of this systematic review was to determine the relevant reports pertaining to ISBs with regard to design and accuracy and to describe their evolution and role in the digital dentistry workflow. Special attention was placed on their key features in relation to intraoral scanning technology and the digitization process. MATERIALS AND METHODS: A MEDLINE/PubMed search was performed to identify relevant reports pertaining to ISB usage in dentistry. This search included but was not limited to scan body features and design, scan body accuracy, and scan body techniques and the role of ISBs in computer-aided design and computer-aided manufacturing (CAD-CAM) processes. Commercially available scan bodies were examined, and a patient situation was shown highlighting the use of ISBs in the digital workflow. RESULTS: Deficiencies in the reports were found regarding various scan body topics, including ISB features/design, accuracy, and the role of ISBs in CAD-CAM processes. CONCLUSIONS: ISBs are complex implant-positioning-transfer devices that play an essential role in the digital workflow and fabrication of accurately fitting implant-supported restorations. With scanner technology rapidly evolving and becoming more widespread, future studies are needed and should be directed toward all parts of the digital workflow when using ISBs. By understanding the basic components of ISBs and how they relate to digital scanning and CAD-CAM technology, more emphasis may be placed on their importance and usage in the digital workflow to ensure accurate transfer of implant position to the virtual and analog definitive cast. Efforts should be made by clinicians to identify an optimal ISB design in relation to the specific intraoral scanning technology being used. PMID- 29627212 TI - Does veneering technique affect the flexural strength or load-to-failure of bilayer Y-TZP? A systematic review and meta-analysis. AB - STATEMENT OF PROBLEM: Causes of failures of bilayer yttria-stabilized tetragonal zirconia polycrystal (Y-TZP) restorations include the processing technique and the properties of the veneer ceramic. The effect of the veneering method on the mechanical behavior of veneered Y-TZP remains unclear. PURPOSE: The purpose of this systematic review was to assess the effect of the veneering method on the flexural strength and failure load of bilayer Y-TZP. MATERIAL AND METHODS: This study followed the Preferred Reporting Items for the Systematic Reviews and Meta Analyses (PRISMA) statement. Searches were performed through August 2017 in PubMed/MEDLINE, Web of Science (Core Collection), Scopus, and Embase, with no year or language limit, targeting in vitro studies evaluating the effect of the veneering technique on the flexural strength and load-to-failure of bilayer Y-TZP immediately or after aging. Statistical analyses were conducted using an appropriate software. Comparisons were drawn with random effect models (alpha=.05). RESULTS: From 3242 identified studies, 241 were selected for full text analysis; from these, 33 studies were included. Manual searching yielded no additional papers. The meta-analysis consisted of 32 studies. Meta-analysis was performed separately for flexural strength and failure load data to compare the hand-layered method (control) with pressed, fused, and cemented veneering techniques. The cemented and fused methods were analyzed using subgroups depending on the veneering material being examined (predominantly glass-ceramics and particle-filled glass-ceramics), and the results were compared with those of the hand-layered method. The pressed group presented flexural strength (7 studies) (P=.150) and failure load (19 studies) (P=.140) values that were similar to those of the hand-layered group. Subgroup analysis revealed that the fused group with particle-filled glass-ceramics (7 studies) produced higher load-to failure (P=.006) values than the hand-layered group. Subgroup analyses showed a statistical difference that favored the hand-layered over the cemented method, with predominantly glass-ceramic materials (5 studies) (P=.002). CONCLUSIONS: The fused technique with particle-filled glass-ceramics seems more appropriate for the veneering of Y-TZP, with improved failure load, than the hand-layered method with predominantly glass-ceramic materials. The use of predominantly glass ceramics for the cemented method is not recommended as failure load was lower than for the hand-layered group. Pressed veneers showed failure load and flexural strength values similar to those of the the hand-layered technique. PMID- 29627213 TI - Macro- and microtopographical examination and quantification of CAD-CAM composite resin 2- and 3-body wear. AB - STATEMENT OF PROBLEM: The selection of an appropriate restorative material based on wear behavior is important for the long-term success of a dental restoration. For computer-aided design and computer-aided manufacturing (CAD-CAM) composite resins, information about their wear resistance and wear mechanism is scarce. PURPOSE: The purpose of this in vitro study was to compare the 2- and 3-body wear of CAD-CAM composite resins with that of lithium disilicate ceramic and to develop analysis software. MATERIAL AND METHODS: Flat specimens were prepared from the following CAD-CAM composite resins: Cerasmart (CS), SHOFU Block HC (SH), Katana Avencia (KA), Brilliant Crios (BC), an experimental composite resin (EXP), and lithium disilicate ceramic IPS e.max CAD (REF). The specimens underwent 2 body wear (50 N, 5/55 degrees C, 400 000 cycles) opposed by human enamel antagonists. Specimen wheels were prepared with each material on each wheel for 3 body wear with a millet slurry (15 N, 15% slip, 200 000 cycles). All specimens were digitized by using a dedicated laser scanner. Analysis software was developed to calculate macrotopographical examination of volume loss. The microtopography of the surfaces was examined by using scanning electron microscopy. For data analysis, the Kruskal-Wallis test with the Tukey-Kramer post hoc test and the 1-sample Wilcoxon test were used (alpha=.05). RESULTS: After 2 body wear simulation, SH and KA presented higher volume loss than the other CAD CAM materials. For 3-body wear, REF had lower volume loss than CS, SH, or BC. In addition, BC led to higher volume loss than EXP. The patterns of 2- and 3-body wear were different. CONCLUSIONS: The ceramic showed good global wear resistance. The volume loss of the CAD-CAM composite resins differed and depended on the material. The 2- and 3-body wear test methods tended to differ with regard to volume loss. Examination of the worn surfaces revealed different mechanisms acting in 2- and 3-body wear test. PMID- 29627214 TI - Digital technology for performing a nasopalatine and greater palatine nerve block with a modified implant surgical guide: A technique article. AB - This article describes a computer-aided design and computer-aided manufacturing (CAD-CAM) technique to perform a precise nerve block of the nasopalatine and greater palatine nerves by using an implant surgical guide. The technique uses additional guide anchor pins planned and positioned for specific anatomic landmarks during guided implant surgical guide planning. A relief modification virtually designed on the intaglio surface of the surgical guide allows for palatal soft tissue distension following administration of local anesthetic. This information is then transferred to the guide manufacturer to order the modified guided implant surgical guide. The purpose of this procedure is to provide precise delivery of local anesthetic and to prevent any discrepancy in surgical guide seating following injection. PMID- 29627215 TI - Thermal cracks of implant-based zirconia four-unit restorations: A fractographic analysis of two restorations fractured during production. AB - Two zirconia-based 4-unit restorations intended for the same patient fractured during the veneering process even though the prolonged cooling protocol recommended by the manufacturers was used. Fractographic analyses revealed that both restorations fractured as a result of thermal shock, but at different times during production. Further investigation is necessary to optimize the firing protocols for large zirconia-based restorations and avoid fracture due to thermal shock. PMID- 29627216 TI - A safe holder for adjusting indirect prostheses: The silicone cube technique. PMID- 29627217 TI - Replicating a discolored tooth preparation: A technique for effective laboratory communication. AB - Fabricating a ceramic restoration for a discolored anterior tooth presents a clinical challenge. The dental technician is often hampered by being unaware of the shade of the discolored tooth preparation, which influences the color of the overlying ceramic restoration. A definitive cast that replicates the shade of the prepared tooth helps the ceramist to fabricate a restoration that masks the discoloration appropriately and still achieves the desired optical properties. This report demonstrates the use of a technique of recording and communicating the shade of a prepared tooth to the dental laboratory technician. PMID- 29627218 TI - Effect of chemical surface treatment of titanium on its bond with dental ceramics. AB - STATEMENT OF PROBLEM: Airborne-particle abrasion of titanium is a clinically accepted method of surface preparation. As a side effect of airborne-particle abrasion, particles of the abrasive material get embedded into the surface. How particle presence or removal from the titanium surface affects the strength of the titanium-ceramic bond is unclear. PURPOSE: The purpose of this in vitro study was to determine the effect of removing Al2O3 particles embedded into the surface by means of chemical surface treatment on the strength of the titanium-ceramic bond. MATERIAL AND METHODS: Titanium (TritanCpTi 1, Dentaurum, 99.5% Ti) disks were airborne-particle abraded with 110 MUm Al2O3 at a pressure of 0.4 MPa and an angle of approximately 45 degrees. The surface was etched chemically using 1 of 8 reagents, and the veneering ceramic applied and fired. The strength of the metal ceramic bond was determined using the shear strength test. Further, the effect of thermal fatigue on the bond strength was evaluated. The results were analyzed with 2-way ANOVA and the Tukey honest significant difference (HSD) test (alpha=.05). Fractographic investigations and microscopic tests were also performed to determine the quality of the titanium-ceramic bond. RESULTS: Effective etching of the titanium surface and removal of Al2O3 particles included a 30% water solution of HNO3 + 3% HF, a mixture of HNO3 + HF + glycerin, a 4% solution of HF in H2O2, and a 4% solution of HF in H2O. A statistically significant difference (of about 50%) in bond strength was found between the groups subjected to chemical etching and the control group (P<.05). Additionally, a statistically significant difference (about 25%) was found after thermocycling (P<.05). CONCLUSIONS: Removing the Al2O3 particles embedded into the titanium surface after airborne-particle abrasion lowers the strength of the titanium ceramic bond (P<.05). Thermocycling also weakens the strength of the titanium ceramic bond, regardless of the surface preparation (P<.05). PMID- 29627219 TI - Incorporation of TiO2 nanotubes in a polycrystalline zirconia: Synthesis of nanotubes, surface characterization, and bond strength. AB - STATEMENT OF PROBLEM: Despite numerous advantages such as high strength, the bond of yttria-stabilized tetragonal zirconia polycrystal (Y-TZP) to tooth structure requires improvement. PURPOSE: The purpose of this in vitro study was to evaluate the incorporation of TiO2 nanotubes into zirconia surfaces and the bond strength of resin cement to the modified ceramic. MATERIAL AND METHODS: TiO2 nanotubes were produced by alkaline synthesis, mixed with isopropyl alcohol (50 wt%) and applied on presintered zirconia disks. The ceramics were sintered, and the surfaces were characterized by confocal laser microscopy, scanning electron microscopy (SEM), and energy-dispersive X-ray spectroscopy (EDS) analysis. For bond strength, the following 6 groups (n=16) were evaluated: without TiO2 and Single Bond Universal; with TiO2 nanotubes and Single Bond Universal; without TiO2 nanotubes and Z-prime; with TiO2 nanotubes and Z-prime; without TiO2 and Signum Zirconia Bond; with TiO2 and Signum Zirconia Bond. After sintering, resin cement cylinders, diameter of 1.40 mm and 1 mm in height, were prepared and polymerized for 20 seconds. Specimens were stored in water at 37 degrees C for 30 days and submitted to a shear test. Data were analyzed by 2-way ANOVA and Tukey honest significant difference (alpha=.05) tests. RESULTS: EDS analysis confirmed that nanoagglomerates were composed of TiO2. The shear bond strength showed statistically significant differences among bonding agents (P<.001). No significant differences were found with the application of nanotubes, regardless of the group analyzed (P=.682). The interaction among the bonding agent factors and addition of nanotubes was significant (P=.025). CONCLUSIONS: Nanotubes can be incorporated into zirconia surfaces. However, this incorporation did not improve bond strength. PMID- 29627220 TI - Correlations of pri-Let-7 gene polymorphisms with the recurrence and metastasis of primary liver cancer after transcatheter arterial chemoembolization. AB - BACKGROUND AND AIM: Single nucleotide polymorphisms (SNPs) within miRNAs could change their production or affinity with target genes, thus leading to malignant diseases. This study aims to explore correlations of pri-let-7 gene polymorphisms with the recurrence and metastasis of primary liver cancer (PLC) after a transcatheter arterial chemoembolization (TACE) surgical procedure. MATERIALS AND METHODS: A total of 302 PLC patients treated with hepatoprotective therapies after TACE were selected to and assigned into recurrent and non-recurrent groups. Genotypes of pri-let-7a-1 rs1073997 and pri-let-7a-2 rs629367 were analyzed by Taqman assay. The relationship between PLC with the mutation of each SNP was determined by a multivariate logistic regression analyses. Moreover, the association between survival and pri-let-7 gene polymorphisms was analyzed by the Kaplan-Meier method. The Progress Free Survival (PFS) curve, correlation of pri let-7a-1 rs629367 with alcohol, HBsAg-positive and TNM III/IV were analyzed by a stratified analysis. Additionally, the risk factors for the recurrence of PLC were analyzed by a multivariate logistic regression analyses. RESULTS: Results showed that the allelic frequency of the pri-let-7a-2 rs629367 SNP in the recurrent group was higher than that of the non-recurrent group. The distribution of CC genotype was significantly higher than non-CC genotype in the recurrent group. Alcohol consumption, positive expression of hepatitis B surface antigen (HBsAg), AC + CC genotype of rs629367 and TNM III/IV were determined to be the risk factors for the recurrence and metastasis of PLC after TACE. We found a positive correlation between pri-let-7a-2 rs629367 with alcohol consumption, HBsAg-positive and TNM III/IV. The median PFS of HBsAg-positive and TNM III/IV patients with the AC + CC genotype of rs629367 was shorter than those with non-AC + CC genotype. CONCLUSION: Our findings provide evidence that patients with PLC that carry the AC + CC genotype of pri-let-7a-2 rs629367 after TACE have a worse prognosis than those who carry the AA genotype. We speculate that the pri-let-7 rs629367 SNP could be used as a predictor of recurrence and metastasis after TACE for patients with PLC. PMID- 29627221 TI - Fluorescence microscopy of H&E stained cervical biopsies to assist the diagnosis and grading of CIN. AB - BACKGROUND: Prevention of cervical cancer is based upon the accurate diagnosis and grading of cervical lesions identified during screening. The pathological classification of cervical intraepithelial neoplasia (CIN) is problematic, as it relies on subjective criteria and is known to have high interobserver variability and low reproducibility. These limitations can result in either over or under treatment of patients. Biomarkers to improve CIN diagnosis have not overcome all these challenges. MAIN BODY: Here we review the use of a promising optical imaging method using eosin-based fluorescence spectroscopy. This technique is able to perform fluorescent analysis of cervical biopsies directly from hematoxylin and eosin (H&E) stained tissues. Eosin is a brominated derivative of fluorescein. Fluorescence characteristics of protein-eosin complexes can demonstrate tissue changes associated with dysplasia and cancer. In this article we review the progress made towards developing eosin-based fluorescence spectroscopy. We describe the various morphologies seen among the CIN grades with this optical method and highlight the progress made to quantitate the spectral image characteristics. CONCLUSION: Eosin-based fluorescence spectroscopy can be used to directly examine H&E stained tissue slides. Relevant areas can be imaged and spectral analysis done to obtain objective data to identify and grade cervical lesions. PMID- 29627222 TI - Lower expression of bone marrow miR-122 is an independent risk factor for overall survival in cytogenetically normal acute myeloid leukemia. AB - BACKGROUND: The liver-enriched microRNA-122 (miR-122) plays a crucial role in pathogenesis of hepatocellular carcinoma (HCC) with prognostic value. Recently, miR-122 was also found to be related to many other cancers besides HCC. However, less study determined miR-122 expression and its clinical significance in acute myeloid leukemia (AML). METHODS: Real-time quantitative PCR was performed to detect the level of bone marrow (BM) miR-122 in de novo AML patients. The clinical significance of miR-122 expression in AML was further investigated. RESULTS: Among whole-cohort AML, lower expression of BM miR-122 was associated with male patients, higher hemoglobin and favorable-karyotypes (P = 0.038, 0.006, and 0.038, respectively). Among cytogenetically normal AML (CN-AML), lower expression of BM miR-122 was correlated with DNMT3A wild type (P = 0.043). Moreover, patients with lower expression of BM miR-122 presented lower complete remission (CR) rate and shorter overall survival (OS) than those with higher expression of BM miR-122 in CN-AML (P = 0.025 and 0.013, respectively). Cox regression analyses further confirmed the prognostic value of BM miR-122 expression in CN-AML (P = 0.024). In follow-up patients, BM miR-122 expression level in CR time was increased compared to diagnosis time, and was returned to primary level when in relapse time again (P = 0.062 and 0.049, respectively). CONCLUSIONS: Our findings indicated that lower expression of BM miR-122 acted as an independent risk factor for OS in CN-AML. PMID- 29627223 TI - May sarcopenia and/or hepatic encephalopathy improve the predictivity of model for end-stage liver disease? PMID- 29627224 TI - Primed for the spotlight: Transplantation for alcohol-associated liver disease. PMID- 29627225 TI - Response to the letter from Dr. Kim and colleagues. PMID- 29627226 TI - Does preimplantation genetic diagnosis improve reproductive outcome in couples with recurrent pregnancy loss owing to structural chromosomal rearrangement? A systematic review. AB - Recurrent pregnancy loss (RPL) is a common, yet elusive, complication of pregnancy. Among couples at high risk of RPL, such as those carrying a structural chromosomal rearrangement, preimplantation genetic diagnosis (PGD) has been proposed as a tool to improve live birth rates and reduce the incidence of miscarriage; however, no clear consensus has been reached on its benefits in this population. This systematic review summarizes existing published research on the effect of PGD on pregnancy outcomes among carriers of chromosomal abnormalities with RPL. A comprehensive search of common databases was conducted, which yielded 20 studies. Meta-analysis was precluded owing to significant heterogeneity between studies. The primary outcome of interest was live birth rate (LBR), and a pooled total of 847 couples who conceived naturally had a LBR ranging from 25-71% compared with 26.7-87% among 562 couples who underwent IVF and PGD. Limitations of the study include lack of large comparative or randomized control studies. Patients experiencing RPL with structural chromosomal rearrangement should be counselled that good reproductive outcomes can be achieved through natural conception, and that IVF-PGD should not be offered first-line, given the unproven benefits, additional cost and potential complications associated with assisted reproductive technology. PMID- 29627227 TI - Effects of moxifloxacin on the proarrhythmic surrogate markers in healthy Filipino subjects: Exposure-response modeling using ECG data of thorough QT/QTc study. AB - Effects of moxifloxacin on QTc as well as proarrhythmic surrogate markers including J-Tpeakc, Tpeak-Tend and short-term variability (STV) of repolarization were examined by using both standard E14 time-based evaluation and exposure response modeling. The study was conducted with a single-blind, randomized, single-dose, placebo-controlled and two-period cross-over design in healthy Filipino subjects. QT interval was corrected by Fridericia's formula (QTcF). In the E14 time-based evaluation of ECG data, the largest DeltaDeltaQTcF with 90% confidence interval was 14.1 ms (11.2-16.9) with Cmax of 3.39 MUg/mL at 3 h post dose (n = 69; male: 35, female: 34), indicating a positive effect on the QTcF. Moxifloxacin significantly increased the DeltaDeltaJ-Tpeakc and DeltaDeltaTpeak Tend, whereas the DeltaDeltaSTV was not altered. Meanwhile in the exposure response modeling of the same ECG data, the slope of moxifloxacin plasma concentration-DeltaDeltaQTcF relationship was 4.84 ms per MUg/mL and the predicted DeltaDeltaQTcF with 90% confidence interval was 13.8 ms (13.1-15.1) at Cmax, also indicating a positive effect on the QTcF. Importantly, results in each proarrhythmic surrogate marker obtained by the exposure-response modeling also showed high similarity to those obtained by the E14 statistical evaluation. Thus, these results of moxifloxacin may become a guide to estimate proarrhythmic potential of new chemical entities. PMID- 29627228 TI - Establishment of an abnormal vascular patterning model in the mouse retina. AB - Abnormalities in retinal blood vessels and neuronal function persist in eyes undergoing retinopathy of prematurity. In this study, we examined morphological and functional changes in retinal blood vessels and neurons in mice that had undergone short-term interruption of retinal vascular development through inhibition of vascular endothelial growth factor (VEGF) signaling. In mice treated with the VEGF receptor tyrosine kinase inhibitor KRN633 on postnatal day (P) 0 and 1, the vascular density in the retinal surface increased by P12, but development of deep retinal vascular plexus and choroidal vasculature was delayed until P14. Overall retinal morphology was mostly normal in KRN633-treated mice during the observation period (~P28), with the exception of P8 and P14. On P28, abnormalities in retinal vascular patterns were evident, but electroretinogram and retinal blood perfusion were within the normal range. Abnormal architecture of retinal vasculature disturbs retinal hemodynamics; therefore, mice treated postnatally with VEGF receptor inhibitors could serve as an animal model for studying the regulatory mechanism of local retinal blood flow and the effect of persistent abnormal retinal vascular patterns on the risk of onset of retinal ischemia. PMID- 29627229 TI - The use of cell cycle arrest biomarkers in the early detection of acute kidney injury. Is this the new renal troponin? AB - Acute kidney injury (AKI) has a high prevalence in critical care patients. Early detection might prevent patients from developing chronic kidney disease and requirement for renal replacement therapy. If we compare AKI with acute coronary syndrome, in which an increase in cardiac troponin may trigger early diagnosis and therapeutic intervention, we could extrapolate a similar technique in patients with early AKI without changes in urinary frequency or serum creatinine. The objective is to identify biomarker-positive, creatinine-negative patients that would allow therapeutic interventions to be initiated before finding changes in serum creatinine, preventing kidney damage. Tissue inhibitor of metalloproteinase 2 and insulin-like growth factor binding protein 7 are cell cycle arrest biomarkers that have demonstrated, in recent clinical trials, to have good sensitivity and specificity for early detection of AKI. Other recent studies have shown that the joint use of these biomarkers with serum creatinine and urine production could improve the prognosis of AKI in critical patients. The application of these biomarkers in clinical practice would enable the early identification of patients at risk of AKI, establishing interventions that would improve the survival of renal function. PMID- 29627230 TI - Analysis of adenovirus-induced immunity to infection with Listeria monocytogenes: Fading protection coincides with declining CD8 T cell numbers and phenotypic changes. AB - Defining correlates of T cell mediated protection is important in order to accelerate the development of efficient T cell based vaccines conferring long term immunity. Extensive studies have provided important insight regarding the characteristics and functional properties of the effector and memory CD8 T cells induced by viral vector based vaccines. However, long-term protection has been difficult to achieve with T cell inducing vaccines, and the determinants underlying this loss in protection over time are still not fully defined. In this study we analyzed different parameters of the CD8 T cell response as a function of time after vaccination with a human serotype 5 adenovector expressing the glycoprotein (GP) of LCMV tethered to the MHC class II-associated invariant chain. Using this vector we have previously found that CD8 T cells mediate protection from challenge with GP-expressing Listeria monocytogenes at 60 days post vaccination, but only little protection after further 60 days, and we now confirm this observation. A comparison of vaccine-primed CD8 T cells early and late after vaccination revealed a minor decline in the overall numbers of antigen specific memory CD8 T cells during this interval. More importantly, we also observed phenotypic changes over time with a distinct decline in the frequency and number of KLRG1+ CD8 T cells, and, notably, adoptive transfer studies confirmed that memory CD8 T cells expressing KLRG1 are central to protection from systemic L. monocytogenes infection. Together these findings imply that multiple factors including changes in memory T cell numbers and phenotypic composition over time influence the longevity of CD8 T-cell mediated protection. PMID- 29627231 TI - Status of vaccine research and development for Helicobacter pylori. AB - Gastric adenocarcinoma is globally the third leading cause of death due to malignancy, with the bulk of this disease burden being suffered by low and middle income countries (LMIC), especially in Asia. The majority of these cancers develop as a result of a chronic gastritis that arises in response to infection with the stomach-dwelling bacterium, Helicobacter pylori. A vaccine against this pathogen would therefore be a powerful tool for preventing gastric adenocarcinoma. However, notwithstanding a proof-of-concept that vaccination can protect children from acquisition of H. pylori infection, there are currently no advanced vaccine candidates with only a single vaccine in Phase I clinical trial. Further, the development of a vaccine against H. pylori is not a current strategic priority of major pharmaceutical companies despite the large global disease burden. Given the involvement of such companies is likely to be critical for late stage development, there is therefore a need for an increased appreciation of the burden of this disease in LMIC and more investment to reinvigorate research in H. pylori vaccine Research and Development. PMID- 29627232 TI - Protective efficacy of recombinant BCG over-expressing protective, stage-specific antigens of Mycobacterium tuberculosis. AB - Tuberculosis (TB) remains a major cause of mortality and morbidity worldwide, yet current control strategies, including the existing BCG vaccine, have had little impact on disease control. CysVac2, a fusion protein comprising stage-specific Mycobacterium tuberculosis antigens, provided superior protective efficacy against chronic M. tuberculosis infection in mice, compared to BCG. To determine if the delivery of CysVac2 in the context of BCG could improve BCG-induced immunity and protection, we generated a recombinant strain of BCG overexpressing CysVac2 (rBCG:CysVac2). Expression of CysVac2 in BCG was facilitated by the M. tuberculosis hspX promoter, which is highly induced inside phagocytic cells and induces strong cellular immune responses to antigens expressed under its regulation. Intradermal vaccination with rBCG:CysVac2 resulted in increased monocyte/macrophage recruitment and enhanced antigen-specific CD4+ T cell priming compared to parental BCG, indicating CysVac2 overexpression had a marked effect on rBCG induced-immunity. Further, rBCG:CysVac2 was a more potent inducer of antigen-specific multifunctional CD4+ T cells (CD4+IFN-gamma+TNF+IL-2+) than BCG after vaccination of mice. This improved immunogenicity however did not influence protective efficacy, with both BCG and rBCG:CysVac2 affording comparable level of protection aerosol infection with M. tuberculosis. Boosting either BCG or rBCG:CysVac2 with the CysVac2 fusion protein resulted in a similar improvement in protective efficacy. These results demonstrate that the expression of protective antigens in BCG can augment antigen-specific immunity after vaccination but does not alter protection against infection, further highlighting the challenge of developing effective vaccines to control TB. PMID- 29627233 TI - Effectiveness of a 3 + 0 pneumococcal conjugate vaccine schedule against invasive pneumococcal disease among a birth cohort of 1.4 million children in Australia. AB - BACKGROUND: Most studies use indirect cohort or case-control methods to estimate vaccine effectiveness (VE) of 7- and 13-valent pneumococcal conjugate vaccines (PCV7 and PCV13) against invasive pneumococcal disease (IPD). Neither method can measure the benefit vaccination programs afford the unvaccinated and many studies were unable to estimate dose-specific VE. We linked Australia's national immunisation register with health data from two states to calculate IPD incidence by vaccination status and VE for a 3 + 0 PCV schedule (doses at 2, 4, 6 months, no booster) among a cohort of 1.4 million births. METHODS: Births records for 2001-2012 were probabilistically linked to IPD notifications, hospitalisations, deaths, and vaccination history (available until December 2013). IPD rates in vaccinated and unvaccinated children <2 years old were compared using Cox proportional hazards models (adjusting for potential confounders), with VE = (1 - adjusted hazard ratio) * 100. Separate models were performed for all-cause, PCV7, PCV13 and PCV13-non-PCV7 serotype-specific IPD, and for Aboriginal and non Aboriginal children. RESULTS: Following introduction of universal PCV7 in 2005, rates of PCV7 serotype and all-cause IPD in unvaccinated children declined 89.5% and 61.4%, respectively, to be similar to rates in vaccinated children. Among non Aboriginal children, VEs for 3 doses were 94.2% (95%CI: 81.9-98.1) for PCV7 serotype-specific IPD, 85.6% (95%CI: 60.5-94.8) for PCV13-non-PCV7 serotype specific IPD and 80.1% (95%CI: 59.4-90.3) for all-cause IPD. There were no statistically significant differences between the VEs for 3 doses and for 1 or 2 doses against PCV13 and PCV13-non-PCV7 serotype-specific IPD, or between Aboriginal and non-Aboriginal children. CONCLUSION: Our population-based cohort study demonstrates that >90% coverage in the first year of a universal 3 + 0 PCV program provided high population-level protection, predominantly attributable to strong herd effects. The size of the cohort enabled calculation of robust dose specific VE estimates for important population sub-groups relevant to vaccination policies internationally. PMID- 29627234 TI - Nasal vaccination with r4M2e.HSP70c antigen encapsulated into N-trimethyl chitosan (TMC) nanoparticulate systems: Preparation and immunogenicity in a mouse model. AB - In this study, the potential of N-trimethyl chitosan (TMC) nanoparticles as a carrier system for the nasal delivery of the r4M2e.HSP70c, as an M2e-based universal recombinant influenza virus vaccine candidate, was investigated in mice. The anti-M2e specific cellular and humoral immune responses were assessed and the protective efficacy against a 90% lethal dose (LD90) of influenza A/PR/8/34 (H1N1) in a mice model was evaluated. Our results showed that the intranasal immunization of mice with r4M2e.HSP70c+TMC rather than the control groups, r4M2e+TMC, r4M2e and PBS (Phosphate buffer saline), significantly elevated both longevity and serum level of the total M2e-specific IgG antibody with a significant shift in the IgG2a/IgG1 ratio toward IgG2a, induced a Th1 skewed humoral and cellular immune responses, increased IFN-gamma, IgG, and IgA in the bronchoalveolar lavage fluid (BALF), and promoted the proliferation of peripheral blood lymphocytes with lower morbidity and mortality rate against viral challenge. In conclusion, based on evidence to our finding, nasal vaccination with r4M2e.HSP70c antigen encapsulated into N-Trimethyl Chitosan (TMC) nanoparticulate system showed to induce a long lasting M2e-specific humoral and cellular immune responses and also provided full protection against a 90% lethal dose (LD90) of the influenza virus A/PR/8/34 (H1N1). It seems, protective immunity following intranasal administration of r4M2e could be resulted by the cooperation of both adjuvants, TMC and HSP70c. PMID- 29627235 TI - Affinity chromatography for vaccines manufacturing: Finally ready for prime time? AB - Affinity chromatography is among the most powerful separation techniques, achieving the finest separation with high yields even in the most challenging feed streams. Incorporating affinity chromatography in vaccine purification has long been attempted by researchers to improve unit yield and purity with the secondary goal of reducing the number of downstream process operations. Despite the success in laboratory-scale proof of concept, implementation of this technique in pilot or cGMP manufacturing has rarely been realised due to technical and economic challenges in design and manufacturing of ideal ligands as well as availability of high-productivity chromatography media. This paper reviews evolving technologies in engineered ligands and chromatography media that are encouraging companies to re-visit the possible use of affinity chromatography in larger scale vaccine purification. It is postulated that commercial-scale implementation of high throughput single-use affinity chromatography can significantly simplify process architecture, improve productivity and flexibility, and reduce cost of goods. PMID- 29627236 TI - Associations between parents' satisfaction with provider communication and HPV vaccination behaviors. AB - BACKGROUND: Despite increasing awareness of the importance of a provider recommendation for HPV vaccine, the U.S. has yet to achieve the Healthy people 2020 goal of 80% series completion among adolescents. This failure indicates a need for further examination of the modifiable influences on parents' decision making. Healthcare providers can influence parents' HPV vaccination decision making, but little is known about parents' perspectives on the counseling they receive. We sought to assess U.S. parents' satisfaction with provider communication about HPV vaccine and associations with vaccination behaviors. METHODS: Parents of 11-to-17-year-old adolescents who discussed HPV vaccination with a healthcare provider at least once (n = 795) completed our online survey in Fall 2016. We assessed their satisfaction with the discussion using the HPV Vaccine Communication Satisfaction Scale (alpha = 0.94). We examined associations between satisfaction (categorized as low, moderate, or high), and three vaccination behaviors: refusal/delay, series initiation (>=1 dose), and continuation (>=2 doses among initiators) using multivariable logistic regression. RESULTS: Most parents reported high (36%) or moderate (38%) satisfaction with provider communication about HPV vaccination; fewer reported low (26%) satisfaction. Moderately satisfied parents (vs. low) had lower odds of refusal/delay (aOR = 0.59, 95% CI: 0.38-0.89), and higher odds of initiation (aOR = 1.71, 95% CI:1.15-2.55) and continuation (aOR = 2.05, 95% CI: 1.24-3.40). The associations were stronger for highly satisfied parents (refusal/delay aOR = 0.45, 95% CI: 0.29-0.70, initiation aOR = 3.59, 95% CI: 2.23-5.78, and continuation aOR = 4.08, 95% CI: 2.38-7.01). CONCLUSIONS: Our study suggests that parent satisfaction with provider communication may play an important role in HPV vaccination decision-making. Yet, communication satisfaction has been largely unexamined in the HPV-vaccine literature to date. We introduce a brief, 7-item HPV Vaccine Communication Scale that can be used to assess parents' level of satisfaction with their provider's communication specific to HPV vaccine. We identify communication areas for providers to prioritize when discussing HPV vaccine with parents. PMID- 29627237 TI - Immunogenicity and protective capacity of EF-Tu and FtsZ of Streptococcus suis serotype 2 against lethal infection. AB - Vaccine development efforts against Streptococcus suis serotype 2 (S. suis 2) are often constrained by strain/serotype antigen variability. Bioinformatics analyses revealed two highly conserved S. suis 2 factors, EF-Tu and FtsZ. Murine immunization with recombinant proteins emulsified in white oil adjuvant or eukaryotic DNA vaccine vectors provided significant protection against lethal S. suis 2 challenge. Immune responses elicited by recombinant protein immunization revealed the robust generation of humoral immune responses, with a mixed induction of Th1-type and Th2-type responses. Furthermore, the antiserum from mice immunized with recombinant proteins significantly inhibited the growth of S. suis 2 in healthy pig whole blood, suggesting the triggering of a strong opsonizing response. Histological examination found that immunizing mice with purified recombinant proteins reduced neutrophil and macrophage accumulation in brain and lung tissues after challenge with virulent S. suis. Taken together, these findings reveal that EF-Tu and FtsZ may be promising targets for subunit and DNA vaccine candidates against S. suis 2 infection. PMID- 29627238 TI - Coverage of recommended vaccines during pregnancy in Flanders, Belgium. Fairly good but can we do better? AB - BACKGROUND: In Flanders, Belgium, pertussis vaccination is recommended since 2013 and available free-of-charge in every pregnancy between 24 and 32 weeks of gestation. Influenza vaccination is recommended for more than 10 years with a co payment system in the second or third trimester of pregnancy, when pregnancy coincides with the influenza season. This study aims to estimate the coverage of pertussis and influenza vaccination during pregnancy in 2016 and to determine predictors for missing vaccination. METHODS: Postpartum women were visited at home for a vaccination coverage survey using an Expanded Program on Immunization (EPI)-based two-stage cluster sampling design. Predictors for missed vaccination were identified using a multiple logistic regression model. RESULTS: Among 481 participating women, 69.3% were vaccinated against pertussis and 47.2% were vaccinated against influenza. Moreover, 65.3% of pertussis vaccine recipients and 96.9% of influenza vaccine recipients were vaccinated within the recommended gestational window. Surprisingly, among women who were completely informed (i.e. on disease-associated risks, maternal vaccination costs and recommendations), still 12.4% were unvaccinated against pertussis and 23.9% against influenza. In the final models, the only common predictor of missing maternal pertussis and influenza vaccination was multiparity. Significant predictors of maternal pertussis vaccination were family income (less likely if unknown or low (< ?3000) than if moderate (?3001-?4000)) and hospital of delivery (less likely if >800 annual deliveries than <800). Significant predictors of maternal influenza vaccination, though with less straight-forward associations, were maternal ethnicity and educational level, involvement of a gynaecologist in pregnancy follow-up, and characteristics of the hospital of delivery. CONCLUSION: In Flanders, more than two-third of pregnant women receives pertussis vaccination but less than half of them receives the influenza vaccine. Further improvement for both maternal vaccination programs can be achieved by targeting the underserved populations and diminishing vaccination hurdles. PMID- 29627239 TI - An observational cohort study on persistency of internal teat sealant residues in milk after calving in dairy cows. AB - Our objectives were to evaluate the prevalence of quarters with an observable internal teat sealant (ITS) plug at first milking following calving and investigate persistency of ITS residues in milk after calving. An observational cohort study was carried out on 557 quarters of 156 cows treated with ITS in 6 farms in Quebec, Canada. The presence of an ITS plug at first milking and ITS residues in milk at each milking were observed by producers. The effects of various factors on the odds of observing an ITS plug and persistency of ITS residues in milk were studied using generalized logistic mixed and generalized negative binomial mixed models, respectively. Milk samples were taken on the day before dry-off and on 2 occasions after calving for bacterial identification to detect intramammary infection (IMI) using bacteriological culture followed by MALDI-TOF identification. The association between the absence of an ITS plug and the presence of new IMI was assessed using a mixed logistic regression model. Internal teat sealant plugs after calving were more often observed in rear quarters and in quarters receiving ITS alone at drying-off versus antimicrobial and ITS. We observed an average (standard deviation) persistency of 4.0 d (2.3 d). When an ITS plug was still present at first milking (83% of quarters), the elimination of ITS residues in milk after calving was significantly longer (4.5 d, on average) compared with 1.2 d when an ITS plug was absent. In cows with an ITS plug at calving, we observed a higher number of days of excretion in older cows. When a plug could not be observed, rear quarters, older cows, and cows with a long dry period duration excreted ITS residues for a significantly longer period. The lack of a significant association between the absence of a plug and the odds of new IMI at calving suggests that despite the loss of the plug, cows were still protected against new IMI. Although we were able to highlight some statistically significant risk factors explaining persistency of ITS residues following calving, observed differences were often relatively small and, perhaps, not clinically relevant. In conclusion, an ITS plug was present until first milking after calving for 83% quarters, quarters without an ITS plug at first milking appeared to have been protected from new IMI, and ITS residues could be observed in milk up to 12 d in milk. PMID- 29627240 TI - Short communication: Temporal changes in the skin morphology of dairy cows during the periparturient period. AB - Management of dairy cow productivity requires monitoring of their nutritional status by visual observation. It has been suggested that changes in hair coat appearance are among the indicators of nutritional state in dairy cows. Temporal changes in the skin morphology in cows, however, have not been reported. In this study, we examined the changes in the skin of dairy cows that occur during the peripartum period. Seven pluriparous cows were used. Skin samples were collected at 28 d before the due date and 28 d and 56 d after calving for morphological examination. Hair follicle width was 108.8 +/- 5.9 um (+/-SD) in the dry period, 95.5 +/- 5.5 um at 28 d after calving, and 104.2 +/- 5.3 um at 56 d postpartum. The percentages of anagen hair follicles during these 3 periods were 41.4 +/- 3.4, 18.5 +/- 3.4, and 32.3 +/- 3.3%, respectively. The corresponding sebaceous gland sizes were 8,362.0 +/- 707.6, 7,800.0 +/- 831.4, and 9,186.8 +/- 962.6 um2, respectively. Hair follicle width was positively correlated with percentage of anagen hair follicles. The thickness of epidermal and proliferation rate of epidermal cell were also correlated. However, the hair follicle width, sebaceous gland size and cell proliferation rate, and thickness and proliferation rate of epidermal cells did not show any marked changes. PMID- 29627241 TI - Influence of adipocyte size and adipose depot on the number of adipose tissue macrophages and the expression of adipokines in dairy cows at the end of pregnancy. AB - The aim of this study was to determine the number of adipose tissue macrophages (ATM) and the mRNA expression of adipokines [adiponectin (ADIPOQ), leptin (LEP), interleukin 6 (IL6), tumor necrosis factor (TNF), and interleukin 10 (IL10)] in different adipose depots from cows with a variable body condition score (BCS) at the end of the dry period. We hypothesized that the number of ATM and the expression of these adipokines depend on adipocyte size and the anatomical location of the adipose depot. Subcutaneous, omental, mesenteric, perirenal, and intrapelvic adipose tissue samples were taken immediately after euthanasia of 10 Holstein Friesian dairy cows (upcoming parity 2 to 5, age 3.9 +/- 1.4 yr; mean +/ standard deviation) at the end of pregnancy (actual days of pregnancy at the moment of euthanasia: 269 +/- 5 d). During the dry period, all animals received similar diets to meet but not exceed requirements. Five animals were considered to have a normal BCS (2.5-3.5) and 5 animals were considered to be over conditioned (BCS = 3.75-5). Body weight of the animals at the moment of euthanasia was 717 +/- 77 kg. Expression of the different genes was determined by reverse transcription quantitative real-time PCR. Adipocyte size was determined by measuring the area of 100 adipocytes on histological sections. Average adipocyte area was 10,475 +/- 1,019, 8,500 +/- 780, 10,383 +/- 1,227, 11,466 +/- 1,039, and 11,087 +/- 1,632 um2 for the subcutaneous, mesenteric, omental, intrapelvic, and perirenal adipose depot, respectively. Immunohistochemistry using anti-bovine CD172a antibodies was performed to determine the proportion of ATM (the number of CD172a-positive cells per 100 adipocytes, given as a percentage). Expression of LEP, IL6, and TNF was positively associated with adipocyte size, whereas no association could be detected between ADIPOQ and IL10 with the size of the adipocytes. The omental adipose depot was especially infiltrated with ATM (1.92 +/- 0.55, 1.10 +/- 0.33, and 8.28 +/- 2.24% for the subcutaneous, mesenteric, and omental adipose depot, respectively). The proportion of ATM was positively associated with the size of the adipocytes in the omental and mesenteric adipose depot. Expression of ADIPOQ, LEP, IL6, TNF, and IL10 differed among depots, which suggests differences in inflammatory characteristics depending on the anatomical location of depots. In conclusion, the results of the present study confirm the adipose tissue as a potential source of inflammatory mediators and demonstrate ATM infiltration, especially in the omental adipose depot. PMID- 29627242 TI - Exopolysaccharide from Lactobacillus plantarum LRCC5310 offers protection against rotavirus-induced diarrhea and regulates inflammatory response. AB - We aimed to determine the effects of Lactobacillus strains against rotaviral infections. Rotaviruses are the major causative agent of acute gastroenteritis in infants and children worldwide. However, to date, no specific antiviral drugs for the treatment of rotavirus infection have been developed. We identified 263 Lactobacillus strains from 35 samples of the traditional Korean fermented vegetable food kimchi. Among them, Lactobacillus plantarum LRCC5310, more specifically the exopolysaccharides produced by these cells, were shown to have an antiviral effect against human rotavirus Wa strain in vitro. In vivo, the oral administration of exopolysaccharides for 2 d before and 5 d after mouse infection with the murine rotavirus epidemic diarrhea of infant mice strain led to a decrease in the duration of diarrhea and viral shedding and prevented the destruction of enteric epithelium integrity in the infected mice. We demonstrated here that the exopolysaccharides extracted from L. plantarum LRCC5310 can be used for the effective control of rotavirus infection. PMID- 29627243 TI - Effect of milk centrifugation and incorporation of high-heat-treated centrifugate on the composition, texture, and ripening characteristics of Maasdam cheese. AB - This study investigated the effect of centrifugation (9,000 * g, 50 degrees C, flow rate = 1,000 L/h), as well as the incorporation of high-heat-treated (HHT) centrifugate into cheese milk on the composition, texture, and ripening characteristics of Maasdam cheese. Neither centrifugation nor incorporation of HHT centrifugate into cheese milk had a pronounced effect on the compositional parameters of any experimental cheeses, except for moisture and moisture in nonfat substance (MNFS) levels. Incorporation of HHT centrifugate at a rate of 6 to 10% of the total milk weight into centrifuged milk increased the level of denatured whey protein in the cheese milk and also increased the level of MNFS in the resultant cheese compared with cheeses made from centrifuged milk and control cheeses; moreover, cheese made from centrifuged milk had ~3% higher moisture content on average than control cheeses. Centrifugation of cheese milk reduced the somatic cell count by ~95% relative to the somatic cell count in raw milk. Neither centrifugation nor incorporation of HHT centrifugate into cheese milk had a significant effect on age-related changes in pH, lactate content, and levels of primary and secondary proteolysis. However, the value for hardness was significantly lower for cheeses made from milk containing HHT centrifugate than for other experimental cheese types. Overall, centrifugation appeared to have little effect on composition, texture, and ripening characteristics of Maasdam cheese. However, care should be taken when incorporating HHT centrifugate into cheese milk, because such practices can influence the level of moisture, MNFS, and texture (particularly hardness) of resultant cheeses. Such differences may have the potential to influence subsequent eye development characteristic, although no definitive trends were observed in the present study and further research on this is recommended. PMID- 29627244 TI - Jugular arginine infusion relieves lipopolysaccharide-triggered inflammatory stress and improves immunity status of lactating dairy cows. AB - The objective of this study was to evaluate the effects of jugular l-Arg infusion on performance and immune function during lipopolysaccharide (LPS)-induced inflammation of lactating dairy cows. Eight Holstein cows (multiparous, 608.8 +/- 31.5 kg) at mid-lactation were randomly assigned to 5-d jugular infusions of control (saline), Arg (3 g/h), LPS (0.033 MUg/kg per h), and LPS + Arg (0.033 MUg/kg per h of LPS and 3 g/h of Arg) in a replicated 4 * 4 Latin square design with 4 infusion periods separated by 10-d noninfusion periods. Jugular solutions of saline, Arg, LPS, and LPS + Arg were continuously infused using peristaltic pumps for approximately 6 h/d during infusion periods. Milk yield was measured on each day of the infusion period. Milk samples were obtained on the last 2 d of each infusion period, and blood samples were obtained on the last day of each infusion period before infusion (0 h) and at 3 and 6 h. We found that the jugular LPS infusion significantly increased serum concentrations of IL-1beta, IL-6, tumor necrosis factor, inducible nitric oxide synthase, and lipopolysaccharide binding protein, whereas Arg attenuated the increase in IL-6 and inducible nitric oxide synthase levels and tended to decrease the lipopolysaccharide binding protein level. Arginine alleviated the decrease in dry matter intake and milk fat yield and the increase of somatic cell count induced by LPS. Total casein in milk was decreased during the LPS-induced inflammation period, and jugular Arg infusion significantly increased the content of total casein. In contrast, lactalbumin in milk increased during the LPS-induced inflammation period, whereas jugular Arg infusion significantly decreased the content of lactalbumin. The concentrations of plasma Gly, Thr, Ile, Leu, Arg, Phe, and total free AA were significantly decreased by LPS treatment, but Arg attenuated this tendency. These results indicated that jugular Arg infusion (18 g/d) has protective effects on relieving inflammatory stress and improving immunity status triggered by LPS. In conclusion, Arg could attenuate inflammatory stress and improve milk performance of lactating dairy cows. This protective effect may be due to the ability of Arg to suppress LPS effects and improve immunity status. PMID- 29627245 TI - Performance of human observers and an automatic 3-dimensional computer-vision based locomotion scoring method to detect lameness and hoof lesions in dairy cows. AB - The objective of this study was to determine if a 3-dimensional computer vision automatic locomotion scoring (3D-ALS) method was able to outperform human observers for classifying cows as lame or nonlame and for detecting cows affected and nonaffected by specific type(s) of hoof lesion. Data collection was carried out in 2 experimental sessions (5 mo apart). In every session all cows were assessed for (1) locomotion by 2 observers (Obs1 and Obs2) and by a 3D-ALS; and (2) identification of different types of hoof lesions during hoof trimming (i.e., skin and horn lesions and combinations of skin/horn lesions and skin/hyperplasia). Performances of observers and 3D-ALS for classifying cows as lame or nonlame and for detecting cows affected or nonaffected by types of lesion were estimated using the percentage of agreement (PA), kappa coefficient (kappa), sensitivity (SEN), and specificity (SPE). Observers and 3D-ALS showed similar SENlame values for classifying lame cows as lame (SENlame comparison Obs1-Obs2 = 74.2%; comparison observers-3D-ALS = 73.9-71.8%). Specificity values for classifying nonlame cows as nonlame were lower for 3D-ALS when compared with observers (SPEnonlame comparison Obs1-Obs2 = 88.5%; comparison observers-3D-ALS = 65.3-67.8%). Accordingly, overall performance of 3D-ALS for classifying cows as lame and nonlame was lower than observers (Obs1-Obs2 comparison PAlame/nonlame = 84.2% and kappalame/nonlame = 0.63; observers-3D-ALS comparisons PAlame/nonlame = 67.7-69.2% and kappalame/nonlame = 0.33-0.36). Similarly, observers and 3D-ALS had comparable and moderate SENlesion values for detecting horn (SENlesion Obs1 = 68.6%; Obs2 = 71.4%; 3D-ALS = 75.0%) and combinations of skin/horn lesions (SENlesion Obs1 = 51.1%; Obs2 = 64.5%; 3D-ALS = 53.3%). The SPEnonlesion values for detecting cows without lesions when classified as nonlame were lower for 3D ALS than for observers (SPEnonlesion Obs1 = 83.9%; Obs2 = 80.2%; 3D-ALS = 60.2%). This was translated into a poor overall performance of 3D-ALS for detecting cows affected and nonaffected by horn lesions (PAlesion/nonlesion Obs1 = 80.6%; Obs2 = 78.3%; 3D-ALS = 63.5% and kappalesion/nonlesion Obs1 = 0.48; Obs2 = 0.44; 3D-ALS = 0.25) and skin/horn lesions (PAlesion/nonlesion Obs1 = 75.1%; Obs2 = 75.9%; 3D ALS = 58.6% and kappalesion/nonlesion Obs1 = 0.35; Obs2 = 0.42; 3D-ALS = 0.10), when compared with observers. Performance of observers and 3D-ALS for detecting skin lesions was poor (SENlesion for Obs1, Obs2, and 3D-ALS <40%). Comparable SENlame and SENlesion values for observers and 3D-ALS are explained by an overestimation of lameness by 3D-ALS when compared with observers. Thus, comparable SENlame and SENlesion were reached at the expense high number of false positives and low SPEnonlame and SPEnonlesion. Considering that observers and 3D ALS showed similar performance for classifying cows as lame and for detecting horn and combinations of skin/horn lesions, the 3D-ALS could be a useful tool for supporting dairy farmers in their hoof health management. PMID- 29627246 TI - Robustness and sensitivity of a blueprint for on-farm estimation of dairy cow energy balance. AB - Excessive negative energy balance (EB) has been associated with decreased reproductive performance and increased risk of lameness and metabolic diseases. On-farm, automated EB estimates for individual cows would enable dairy farmers to detect excessive negative EB early and act to minimize its extent and duration by altering feeding. Previously, we have shown that EB can be estimated from frequent measurements of body weight (BW) and body condition score (BCS) changes, referred to as EBbody. In this study, we investigated the robustness and sensitivity of the EBbody method to assess its genericity and on-farm applicability. We used 5 data sets with BW of lactating cows (name of data set in parenthesis): 65 Holstein cows in a French feeding trial (INRA); 6 Holstein cows in a British feeding trial (Friggens); 31 Holstein cows and 17 Jersey cows in a Danish feeding trial (DCRC); 140 Holstein cows in a British feeding trial (Scotland's Rural College, SRUC); and 1,592 Holstein cows on 9 Danish farms with milking robots (automatic milking system). We used the INRA and Friggens data sets to develop a dynamic formula to correct BW for increasing residual gut-fill (RGF) during early lactation. With the DCRC data, we tested the effect of smoothing parameters and weighing frequency on EBbody. Also, 2 robustness tests were performed using the SRUC data to test the effect of diet change on BW and the automatic milking system data to test the effect of farm on BW variation. Finally, we combined the results into a blueprint describing different ways to calculate EBbody depending on the purpose and on the availability of BCS. The dynamic RGF adjustment resulted in a lower empty BW during early lactation than that obtained with the previously used constant RGF. The double-exponential smoothing method used to correct for meal-related gut-fill was robust to choice of smoothing parameters. Cows should be weighed at least once every 4 d during early lactation to capture the duration of negative EBbody. Our EBbody method proved robust to diet changes. Finally, although cow BW varied significantly between farms, the quantile regression smoothing of BW did not bias the estimation of weight differences between herds. In conclusion, these results validate the applicability of the EBbody method to estimate EB across a range of farm conditions, and we provided a blueprint that enables the estimation of EBbody for individual cows on-farm using only frequent BW, in combination with BCS when available. PMID- 29627247 TI - Use of on-farm emergency slaughter for dairy cows in British Columbia. AB - On-farm emergency slaughter (OFES), whereby inspection, stunning, and bleeding occur on the farm before the carcass is transported to a slaughterhouse, is permitted in some jurisdictions as a means to avoid inhumane transportation while salvaging meat from injured animals. However, OFES is controversial and its use for dairy cows has been little studied. Inspection documents for 812 dairy cows were examined to identify how OFES was used for dairy cows in British Columbia, Canada, over 16.5 mo. Producers used OFES for dairy cows aged 1 to 13 yr (median of 4 yr). Leg, hip, nerve, spinal, foot, and hind-end injuries or conditions (in that order) were the most common reasons for OFES, and some cases may have been a consequence of calving. Foot conditions were disproportionately common among cows 5 yr and older, and hind-end conditions were disproportionately common among cows 6 yr and older. Producers used OFES promptly after traumatic injury (within 1 d) for some cows, but OFES was delayed for others, sometimes until cows had been nonambulatory for 2 to 6 d. In some cases, OFES was used for nontraumatic chronic conditions, such as lameness and hind-end weakness, rather than traumatic injuries such as fractures and dislocated hips. Use of OFES appears to conform to the purpose of the program when used promptly after traumatic injuries, but clear guidelines are needed to avoid inappropriate use and delays that may prolong animal suffering. PMID- 29627248 TI - A canonical discriminant analysis to study the association between milk fatty acids of ruminal origin and milk fat depression in dairy cows. AB - Although milk fat depression (MFD) has been observed and described since the beginning of the last century, all the molecular and biochemical mechanisms involved are still not completely understood. Some fatty acids (FA) originating during rumen biohydrogenation have been proposed as causative elements of MFD. However, contradictory results were obtained when studying the effect of single FA on MFD. An alternative could be the simultaneous evaluation of the effect of many FA using a multivariate approach. The aim of this study was to evaluate the relationship between individual milk FA of ruminal origin and MFD using canonical discriminant analysis, a multivariate technique able to distinguish 2 or more groups on the basis of a pool of variables. In a commercial dairy herd, a diet containing 26% starch on a DM basis induced an unintentional MFD syndrome in 14 cows out of 40. Milk yielded by these 14 animals showed a fat content lower than 50% of the ordinary value, whereas milk production and protein content were normal. The remaining 26 cows secreted typical milk fat content and therefore were considered the control group, even though they ate the same diet. The stepwise discriminant analysis selected 14 milk FA of ruminal origin most able to distinguish the 2 groups. This restricted pool of FA was used, as variables, in a run of the canonical discriminant analysis that was able to significantly discriminate between the 2 groups. Out of the 14 FA, 5 conjugated linoleic acid isomers (C18:2 trans-10,trans-12, C18:2 trans-8,trans-10, C18:2 trans-11,cis-13, C18:2 cis-9,cis-11, C18:2 cis-10,cis-12) and C15:0 iso were more related to the control group, whereas C18:2 trans-10,cis-12, C16:1 trans-6-7, C16:1 trans-9, C18:1 trans-6-8, C18:1 trans-9, C18:1 trans-10, C18:1 cis-11, and C18:3n-3 were positively associated with the MFD group, allowing a complete discrimination. On the basis of these results, we can conclude that (1) the shift of ruminal biohydrogenation from C18:1 trans-11 to C18:1 trans-10 seemed to be strongly associated with MFD; (2) at the same time, other C18:1 trans isomers showed a similar association; (3) on the contrary, conjugated linoleic acid isomers other than C18:2 trans-10,cis-12 seemed to be associated with a normal fat secretion. Results confirmed that MFD is the consequence of a combined effect of the outflow of many ruminal FA, which collectively affect mammary fat synthesis. Because the animals of the 2 groups were fed the same diet, these results suggested that factors other than diet are involved in the MFD syndrome. Feeding behavior (i.e., ability to select dietary ingredients in a total mixed ration), rumen environment and the composition of ruminal bacteria are additional factors able to modify the products of rumen biohydrogenation. Results of the present work confirmed that the multivariate approach can be a useful tool to evaluate a metabolic pathway that involves several parameters, providing interesting suggestions about the role of some FA involved in MFD. However, results about the MFD syndrome obtained in the present research require a deep molecular investigation to be confirmed. PMID- 29627249 TI - On-farm deaths of dairy cows are associated with features of freestall barns. AB - On-farm death (OFD) of a dairy cow is always a financial loss for a farmer, and potentially a welfare issue that has to be addressed within the dairy industry. The aim of this study was to explore the associations between OFD of dairy cows, housing, and herd management in freestall barns. To achieve the goal, we followed 10,837 cows calving in 2011 in 82 herds. Data were gathered with observations and a structured interview during farm visits and from a national dairy herd improvement database. The hazard of OFD was modeled with a shared frailty survival model, with SAS 9.3 PHREG procedure (SAS Institute Inc., Cary, NC). The study population was 58% Ayrshire and 42% Holstein cows. The median herd size and mean milk yield in the study herds were 116 cows and 9,151 kg of milk per cow per year. The overall probability of OFD was 6.0%; 1.8% of the cows died unassisted and 4.2% were euthanized. Variation in OFD percentage between individual herds was large, from 0 to 16%, accounting for 0 to 58% of all removals in the herds. Keeping close-up dry cows in their own group was associated with higher hazard of OFD [hazard ratio (HR) = 1.37] compared with keeping them in the same pen with far-off dry cows. Higher hazard on OFD was observed when barns had only one kind of calving pen; single (HR = 2.09) or group pens (HR = 1.72), compared with having both of those types. The hazard of OFD was lower if the whole herd was housed in barns or pens that had only 1 type of feed barrier at the feed bunk, namely post-and-rail (HR = 0.51) or a type with barriers between the cow's heads (HR = 0.49), compared with having 2 types. Lower OFD hazard was observed with wider than 340 cm of walking alley next to the feeding table (HR = 0.75), and with housing a whole herd in pens with only 1 type of walking alley surface, specifically slatted (HR = 0.53) or solid (HR = 0.48), compared with having both types. The hazard of OFD was higher with stalls wider than 120 cm (HR = 1.38) compared with narrower stalls. The hazard of OFD was also associated with breed, parity, and calving season. This study identified many factors that contribute to the incidence of OFD of dairy cows. The solutions for reducing on-farm mortality include housing, management, and breeding choices that are most probably herd specific. PMID- 29627250 TI - Invited review: Current perspectives on eating and rumination activity in dairy cows. AB - Many early studies laid the foundation for our understanding of the mechanics of chewing, the physiological role of chewing for the cow, and how chewing behavior is affected by dietary characteristics. However, the dairy cow has changed significantly over the past decades, as have the types of diets fed and the production systems used. The plethora of literature published in recent years provides new insights on eating and ruminating activity of dairy cows. Lactating dairy cows spend about 4.5 h/d eating (range: 2.4-8.5 h/d) and 7 h/d ruminating (range: 2.5-10.5 h/d), with a maximum total chewing time of 16 h/d. Chewing time is affected by many factors, most importantly whether access to feed is restricted, intake of neutral detergent fiber from forages, and mean particle size of the diet. Feed restriction and long particles (>=19 mm) have a greater effect on eating time, whereas intake of forage neutral detergent fiber and medium particles (4-19 mm) affects rumination time. It is well entrenched in the literature that promoting chewing increases salivary secretion of dairy cows, which helps reduce the risk of acidosis. However, the net effect of a change in chewing time on rumen buffing is likely rather small; therefore, acidosis prevention strategies need to be broad. Damage to plant tissues during mastication creates sites that provide access to fungi, adhesion of bacteria, and formation of biofilms that progressively degrade carbohydrates. Rumination and eating are the main ways in which feed is reduced in particle size. Contractions of the rumen increase during eating and ruminating activity and help move small particles to the escapable pool and into the omasum. Use of recently developed low-cost sensors that monitor chewing activity of dairy cows in commercial facilities can provide information that is helpful in management decisions, especially when combined with other criteria. Although accuracy and precision can be somewhat variable depending on sensor and conditions of use, relative changes in cow behavior, such as a marked decrease in rumination time of a cow or sustained low rumination time compared with a contemporary group of cows, can be used to help detect estrus, parturition, and some illnesses. This review provides a comprehensive understanding of the dietary, animal, and management factors that affect eating and ruminating behavior in dairy cows and presents an overview of the physiological importance of chewing with emphasis on recent developments and practical implications for feeding and managing the modern housed dairy cow. PMID- 29627251 TI - A selective medium for the enumeration and differentiation of Lactobacillus delbrueckii ssp. bulgaricus. AB - Modified reinforced clostridial medium (mRCM) was developed and evaluated for the differential enumeration of Lactobacillus delbrueckii ssp. bulgaricus. Lactobacillus bulgaricus, an important species of lactic acid bacteria with health benefits, is used in the production of yogurt and other fermented foods. Our results showed that supplementing reinforced clostridial medium with 0.025% CaCl2, 0.01% uracil, and 0.2% Tween 80 (mRCM) significantly enhanced the growth rate of L. bulgaricus RR and ATCC 11842 strains as measured by the optical densities of these strains after 12 h of incubation at 42 degrees C. The bacterial populations (plate count) of the RR and ATCC 11842 strains were 0.76 and 0.77 log cfu/g higher in mRCM than in de Man, Rogosa, and Sharpe and reinforced clostridial medium media, respectively. Conversely, the population counts for other bacterial species (Bifidobacterium, Lactobacillus rhamnosus, and Lactobacillus reuteri) were significantly inhibited in the mRCM medium. The addition of aniline blue dye to mRCM (mRCM-blue) improved the selectivity of L. bulgaricus in mixed lactic bacterial cultures compared with de Man, Rogosa, and Sharpe medium and lactic agar with regard to colony appearance and morphology. The mRCM-blue performed better than the conventional medium in culturing, enumerating, and differentiating L. bulgaricus. Therefore, mRCM-blue could be used as a selective medium to enhance the growth and differentiation of L. bulgaricus in order to meet the increasing demand for this beneficial species of bacteria. PMID- 29627252 TI - Effects of rumen-undegradable protein on intake, performance, and mammary gland development in prepubertal and pubertal dairy heifers. AB - The objective of this study was to evaluate the influence of different amounts of rumen-undegradable protein (RUP) on intake, N balance, performance, mammary gland development, carcass traits, and hormonal status of Holstein heifers at different physiological stages (PS). Sixteen prepubertal (PRE) heifers (initial BW = 106 +/ 7.6 kg; age = 4.3 +/- 0.46 mo) and 16 pubertal (PUB) heifers (initial BW = 224 +/- 7.9 kg; age = 12.6 +/- 0.45 mo) were used in an experiment over a period of 84 d. Four diets with increasing RUP contents (38, 44, 51, and 57% of dietary crude protein) and heifers at 2 PS (PRE or PUB) were used in a 4 * 2 factorial arrangement of treatments in a completely randomized design. Throughout the experiment, 2 digestibility trials were performed over 5 consecutive days (starting at d 36 and 78) involving feed and ort sampling and spot collections of feces and urine. At d 0 and 83, body ultrasound images were obtained for real time carcass trait evaluation. The mammary gland was ultrasonically scanned at d 0 and every 3 wk during the experiment. Blood samples were taken at d 0 and 84 to determine serum concentrations of progesterone, estrogen, insulin-like growth factor I (IGF-I), and insulin. No interaction between PS and the level of RUP was found for any trait. Apparent digestibility of dry matter, organic matter, and neutral detergent fiber corrected for ash and protein was not affected by RUP level but was lower for PRE compared with PUB heifers. Sorting against neutral detergent fiber corrected for ash and protein (tendency only) and for crude protein was greater for PUB than PRE heifers. Pubertal heifers had greater average daily gain (905 vs. 505 g/d) and N retention (25.9 vs. 12.5 g/d) than PRE heifers. In addition, average daily gain and N retention were greatest at 51% RUP of dietary protein. Mammary ultrasonography indicated no effects of RUP amounts on mammary gland composition, whereas PRE heifers had greater pixel values than PUB, indicating higher contents of fat rather than protein in the mammary glands of PRE heifers. Serum progesterone and IGF-I concentration was affected only by PS, and PRE heifers had greater values of progesterone and IGF-I concentrations than PUB heifers. Serum insulin concentration was unaffected by PS but tended to be higher at 51% of RUP. In conclusion, an RUP level of 51% increases body weight, average daily gain, feed efficiency, and N retention in heifers regardless of the PS. In addition, PRE heifers have a lower sorting ability and reduced intake, total-tract digestibility, and N retention. They also have higher amounts of fat in their mammary glands, even at moderate growth rates. PMID- 29627253 TI - Yeast culture increased plasma niacin concentration, evaporative heat loss, and feed efficiency of dairy cows in a hot environment. AB - The supplementation of dairy cows with yeast culture may increase diet digestibility, plasma niacin concentration, heat dissipation, and lactation performance. Our objective was to evaluate the response of Holstein cows in late lactation (234 +/- 131 d in milk) to dead yeast culture (YC, 15 g/d, Factor SC, GRASP, Saccharomyces cerevisiae) during Brazilian summer (temperature-humidity index >68 for 92.2% of the time). Thirty-two cows were individually fed a standard total mixed ration for 14 d and control (CTL) or YC treatments for 35 d, in a covariate adjusted complete randomized block design. Response was evaluated in wk 5 or as repeated measures over time. Cows were milked 3 times per day and treatments (YC or placebo) were orally dosed to each cow before each milking. Plasma niacin was 1.50 for CTL and 1.66 ug/mL for YC. The YC reduced rectal temperature, respiration rate, and skin temperature, whereas it tended to increase sweating rate. The proportion of cows with rectal temperature >=39.2 degrees C on CTL and YC was, respectively, 8 and 0% at 0730 h, 52 and 25% at 1500 h, and 35 and 26% at 2200 h. Plasma glucose was increased by YC. The total-tract apparent digestibility of nutrients, plasma urea N concentration, molar proportion of ruminal VFA, and urinary allantoin excretion were not affected by YC. Cows fed YC were less selective against feed particles >19 mm in the morning, in the afternoon were more selective against long feed particles and in favor of particles <8 mm, and refused short particles at night. Milk yield was not different (30.5 kg/d for CTL and 30.2 kg/d for YC). Feeding YC reduced dry matter intake (20.3 vs. 19.4 kg/d) and the digestible organic matter intake (15.6 vs. 13.9 kg/d). The inclusion of YC increased the ratios of milk to dry matter intake (1.50 vs. 1.64) and energy-corrected milk to dry matter intake (1.81 vs. 1.98). The covariate adjusted body weight (648 kg) and body condition score (3.0) did not differ. Milk solids yields and concentrations, linear somatic cell count, and milk urea N were also similar. The supplementation of YC increased plasma niacin concentration, body heat loss, and feed efficiency of late lactation dairy cows by reducing intake at similar milk yield. PMID- 29627254 TI - Technical note: A simple rumen collection device for calves: An adaptation of a manual rumen drenching system. AB - A limited amount of research is available related to the rumen microbiota of calves, yet there has been a recent spike of interest in determining the diversity and development of calf rumen microbial populations. To study the microbial populations of a calf's rumen, a sample of the rumen fluid is needed. One way to take a rumen fluid sample from a calf is by fistulating the animal. This method requires surgery and can be very stressful on a young animal that is trying to adapt to a new environment and has a depressed immune system. Another method that can be used instead of fistulation surgery is a rumen pump. This method requires a tube to be inserted into the rumen through the calf's esophagus. Once inside the rumen, fluid can be pumped out and collected in a few minutes. This method is quick, inexpensive, and does not cause significant stress on the animal. This technical note presents the materials and methodology used to convert a drenching system into a rumen pump and its respective utilization in 2 experiments using dairy bull calves. PMID- 29627255 TI - Continuous 11-week feeding of reduced-fat distillers grains with and without monensin reduces lactation performance of dairy cows. AB - This study investigated the effects of continuous feeding of high inclusion of reduced-fat corn distillers grains with solubles with and without monensin on dry matter intake (DMI), production, milk fatty acid profile, and plasma AA profile in lactating cows. The experiment was conducted for 12 wk (1-wk covariate, 2-wk diet adaptation, and 9-wk experimental period of data collection) with 36 Holstein cows in a randomized complete block design. Cows were blocked by parity, days in milk, and milk yield and assigned to the following diets: (1) control (CON), (2) CON with reduced-fat corn distillers grains with solubles included at 28.8% (dry matter basis) replacing soybean meal, soyhulls, and supplemental fat (DG), and (3) DG with monensin (Rumensin; Elanco Animal Health, Greenfield, IN) supplemented at a rate of 20 mg/kg of DM offered (DGMon). Orthogonal contrasts were used to compare CON versus DG and DGMon and to compare DG versus DGMon. Milk yield was not affected (40.3 vs. 40.8 kg/d) by DG and DGMon compared with CON. However, for DG and DGMon compared with CON, decreased DMI (24.9 vs. 26.4 kg/d), milk fat yield (1.12 vs. 1.55 kg/d), milk protein yield (1.24 vs. 1.32 kg/d), and energy-corrected milk yield (37.7 vs. 43.5 kg/d) were observed. Feeding DGMon compared with DG did not affect DMI (24.4 vs. 25.4 kg/d) and milk yield (39.2 vs. 41.3 kg/d) but decreased milk fat yield (1.08 vs. 1.23 kg/d), milk protein yield (1.20 vs. 1.28 kg/d), and energy-corrected milk yield (36.0 vs. 39.4 kg/d). Interactions between treatment and week for DMI, milk fat yield, and energy corrected milk indicate that production responses to DG and DGMon versus CON were decreased over the experimental period. Cows fed DG and DGMon had increased milk fat concentration of trans-10,cis-12 18:2, trans-10 18:1, and long-chain (>16C) and polyunsaturated fatty acids and decreased short-chain (<16C) and odd- and branched-chain fatty acids compared with CON. No difference was observed between DG and DGMon in milk fatty acid profile. In the current study, feeding a high-DG diet did not sustain DMI and production, and supplementing monensin to a high-DG diet further decreased DMI and production. PMID- 29627256 TI - Patients With Poor Baseline Mental Health Undergoing Unicompartmental Knee Arthroplasty Have Poorer Outcomes. AB - BACKGROUND: The relationship between mental health and outcomes of unicompartmental knee arthroplasty (UKA) remains unclear. Poor preoperative mental health may be caused by pain and functional limitations associated with knee arthritis. We aimed at (1) investigating the effect of preoperative mental health on early outcomes and (2) assessing whether mental health improves after UKA. METHODS: Prospectively collected registry data of 1473 medial UKAs performed at a single institution in 2007-2014 were reviewed. Linear regression was used to determine improvement in mental health up to 2 years according to preoperative Short-Form 36 Mental Component Summary (MCS). Patients were stratified into low MCS (<50, n = 579) and high MCS (>=50, n = 894). The Knee Society Knee Score (KSKS), Function Score (KSFS), Oxford Knee Score (OKS), Short-Form 36, satisfaction, and expectation fulfilment were compared at 6 months and 2 years. RESULTS: The mean preoperative MCS was 41.2 in low MCS group and 58.6 in high MCS group (P < .001). The high MCS group had higher KSKS, KSFS, OKS, and Physical Component Summary, and a greater proportion of patients were satisfied and had expectations fulfilled at 6 months and 2 years (P < .05). However, the low MCS group demonstrated greater improvement in KSKS, KSFS, and OKS (P < .05). Lower preoperative MCS score was predictive of greater improvement in MCS (coefficient = -0.662, R = -0.602, P < .001). CONCLUSION: Patients with poor mental health benefit from greater improvements in their mental health and knee function after UKA, but also have a greater dissatisfaction. PMID- 29627257 TI - Robotic-Arm-Assisted vs Conventional Unicompartmental Knee Arthroplasty. The 2 Year Clinical Outcomes of a Randomized Controlled Trial. AB - BACKGROUND: Unicompartmental knee arthroplasty (UKA) for treatment of medial compartment osteoarthritis has potential benefits over total knee arthroplasty but UKA has a higher revision rate. Robotic-assisted UKA is increasingly common and offers more accurate implant positioning and limb alignment, lower early postoperative pain but evidence of functional outcome is lacking. The aim was to assess the clinical outcomes of a single-centre, prospective, randomised controlled trial, comparing robotic-arm-assisted UKA with conventional surgery. METHODS: A total of 139 participants were recruited and underwent robotic-arm assisted (fixed bearing) or conventional (mobile bearing) UKA. Fifty-eight patients in the robotic-arm-assisted group and 54 in the manual group at 2 years. The main outcome measures were the Oxford Knee Score, American Knee Society Score and revision rate. RESULTS: At 2 years, there were no significant differences for any of the outcome measures. Sub-group analysis (n = 35) of participants with a preoperative University of California Los Angeles Activity Scale >5 (more active) was performed. In this sub-group, the median Oxford Knee Score at 2 years was 46 (IQR 42.0-48.0) for robotic-arm-assisted and 41 (IQR 38.5-44.0) for the manual group (P = .036). The median American Knee Society Score was 193.5 (IQR 184.0 198.0) for the robotic-arm-assisted group and 174.0 (IQR 166.0-188.5) for the manual group (P = .017). Survivorship was 100% in robotic-arm-assisted group and 96.3% in the manual group. CONCLUSION: Overall, participants achieved an outcome equivalent to the most widely implanted UKA in the United Kingdom. Sub-group analysis suggests that more active patients may benefit from robotic-arm- assisted surgery. Long term follow-up is required to evaluate differences in survivorship. PMID- 29627258 TI - Does Prior Failed Debridement Compromise the Outcome of Subsequent Two-Stage Revision Done for Periprosthetic Joint Infection Following Total Knee Arthroplasty? AB - BACKGROUND: There has been a debate regarding the outcomes of 2-stage revision total knee arthroplasty (TKA) when debridement, antibiotics, irrigation, and implant retention (DAIR) had been carried out previously. The purpose of this study is to evaluate the influence of prior failed DAIR (F-DAIR) on the outcomes of 2-stage revision TKA done for periprosthetic joint infection (PJI). METHODS: This is a retrospective study of a consecutive series of 184 knees that completed 2-stage revision TKA for PJI, operated by a single surgeon between January 2000 and July 2011. The cohort was divided into 2 groups: (1) with previous F-DAIR (88 knees) and (2) direct 2-stage revision (96 knees). RESULTS: At an average follow up of 5.3 years, the failure rate was 23.86% (21/88 knees) in the F-DAIR group and 15.62% (15/96) in the direct 2-stage revision group. Prior F-DAIR procedure was associated with approximately twice the risk of failure compared to direct 2 stage surgery (hazards ratio 1.94, 95% confidence interval 1.01-3.714, P = .047). Excluding PJIs caused by methicillin-resistant Staphylococcus aureus, methicillin resistant Staphylococcus epidermidis, and Pseudomonas from analysis revealed similar failure rates between the 2 groups. The Knee Society Clinical Score, Knee Society Functional Score, and final range of motion at final follow-up were lower in the F-DAIR group. Incidence of culture negativity and infection with resistant organisms was higher in the F-DAIR group. The rates of eradication of methicillin resistant Staphylococcus aureus and Pseudomonas infection were much lower in the F-DAIR group. CONCLUSION: A failed prior DAIR results in higher failure rates, lower functional outcome, and increased risk of wound-related complications. PMID- 29627259 TI - Molecular and phylogenetic evidences of dispersion of human-infecting microsporidia to vegetable farms via irrigation with treated wastewater: One-year follow up. AB - BACKGROUND: Human-infecting microsporidia are a group of spore-forming eukaryotic microorganisms that can infect both animals and humans. Recent evidences indicate waterborne transmission of microsporidia spores to human via either drinking water or irrigation of vegetable farms with contaminated water resources. The current study aimed to evaluate the presence of human-infecting microsporidia in treated wastewater (TW) and vegetable farms irrigated with treated wastewater during a year. METHODS: Totally, twelve samples of each treated wastewater and vegetables were collected. In order to recover microsporidia spores, filtration using cellulose nitrate membrane (pore size 0.4 MUm) and sedimentation were employed. DNA extraction was performed for all samples and genus/species were characterized using specific primers. In order to characterize genotypes, ITS fragment of E. bieneusi was amplified, sequenced and compared in GenBank database. Phylogenetic tree was employed to analysis the probable correlation between obtained genotypes with those E. bieneusi genotypes, which were previously obtained from human and animals from same region. RESULTS: After nested PCR, expected fragments of E. bieneusi and Encephalitozoon spp were observed among 5/12 (41.7%) and 1/12 (8.33%) of vegetable samples, respectively. From total of 12 TW samples, expected fragments of E. bieneusi and Encephalitozoon spp were amplified among 7/12 (53.8%) and 1/12 (8.33%) of TW samples, respectively. Genotypes D and E were characterized from both TW and vegetables samples. Phylogenetic analysis showed close-relationship between E. bieneusi from TW and vegetable samples with E. bieneusi from animals and humans obtained from the same region. CONCLUSION: Our findings suggested the key role of animals in epidemiology of zoonotic transmission of E. bieneusi. Moreover, our findings revealed the occurrence of human-infecting microsporidia in treated wastewater because of either insufficiency of treatment process or distribution of microsporidia spores in wastewater treatment plant via animals. PMID- 29627260 TI - Design, synthesis and biological evaluation of seco-A-pentacyclic triterpenoids 3,4-lactone as potent non-nucleoside HBV inhibitors. AB - A series of seco-A-pentacyclic triterpenoids-3,4-lactone were synthesized and the anti-HBV activities were evaluated in vitro. Several compounds inhibited the secretion of HBV antigen and the replication of HBV DNA in micromolar level. Compounds D7 and D10, seco-A-oleanane-3,4-lactone, suppressed the HBeAg secretion with IC50 values of 0.14 MUM and 0.86 MUM respectively, and the inhibitory activities were also confirmed by detecting the fluorescence intensity of FITC labeled monoclonal mouse HBeAg antibody via flow cytometry. Compounds D7 and D10 as well as B4, ring-A cleaved 3,30-dioic acid, also displayed remarkable inhibition on both HBV DNA replication at the concentration of 25 MUM and HBV cccDNA (covalently closed circularDNA) replication with IC50 values of 33.5 MUM, 32.7 MUM and 12.3 MUM respectively. PMID- 29627261 TI - Development of novel pyridazinone-based adenosine receptor ligands. AB - With the aim of finding new adenosine receptor (AR) ligands, a preliminary investigation focusing on the thieno[2,3-d]pyridazin-5(4H)-one scaffold was undertaken. The synthesized compounds 1-11 were evaluated for their binding at hA1, hA2A and hA3 ARs and efficacy at hA2B subtype in order to determine the affinity at the human adenosine receptor subtypes. Small structural changes on this scaffold highly influenced affinity; compound 5 (5-ethyl-7-(thiazol-2 yl)thieno[2,3-d]pyridazin-4(5H)-one) emerged as the best of this series. The simplicity of the synthetic process, the capability of the scaffold to be easily decorated, together with the predicted ADME properties confirm the role of these compounds as promising hits. A molecular docking investigation at the hA1AR crystal structure was performed to rationalize the SARs of the herein reported thienopyridazinones. PMID- 29627262 TI - Structure-based design and discovery of potent and selective KDM5 inhibitors. AB - Histone lysine demethylases (KDMs) play a key role in epigenetic regulation and KDM5A and KDM5B have been identified as potential anti-cancer drug targets. Using structural information from known KDM4 and KDM5 inhibitors, a potent series of pyrazolylpyridines was designed. Structure-activity relationship (SAR) exploration resulted in the identification of compound 33, an orally available, potent inhibitor of KDM5A/5B with promising selectivity. Potent cellular inhibition as measured by levels of tri-methylated H3K4 was demonstrated with compound 33 in the breast cancer cell line ZR-75-1. PMID- 29627264 TI - Metapopulation model for rock-paper-scissors game: Mutation affects paradoxical impacts. AB - The rock-paper-scissors (RPS) game is known as one of the simplest cyclic dominance models. This game is key to understanding biodiversity. Three species, rock (R), paper (P) and scissors (S), can coexist in nature. In the present paper, we first present a metapopulation model for RPS game with mutation. Only mutation from R to S is allowed. The total population consists of spatially separated patches, and the mutation occurs in particular patches. We present reaction-diffusion equations which have two terms: reaction and migration terms. The former represents the RPS game with mutation, while the latter corresponds to random walk. The basic equations are solved analytically and numerically. It is found that the mutation induces one of three phases: the stable coexistence of three species, the stable phase of two species, and a single-species phase. The phase transitions among three phases occur by varying the mutation rate. We find the conditions for coexistence are largely changed depending on metapopulation models. We also find that the mutation induces different paradoxes in different patches. PMID- 29627263 TI - Utilizing a structure-based docking approach to develop potent G protein-coupled receptor kinase (GRK) 2 and 5 inhibitors. AB - G protein-coupled receptor (GPCR) kinases (GRKs) regulate the desensitization and internalization of GPCRs. Two of these, GRK2 and GRK5, are upregulated in heart failure and are promising targets for heart failure treatment. Although there have been several reports of potent and selective inhibitors of GRK2 there are few for GRK5. Herein, we describe a ligand docking approach utilizing the crystal structures of the GRK2-Gbetagamma.GSK180736A and GRK5.CCG215022 complexes to search for amide substituents predicted to confer GRK2 and/or GRK5 potency and selectivity. From this campaign, we successfully generated two new potent GRK5 inhibitors, although neither exhibited selectivity over GRK2. PMID- 29627265 TI - Rough set method accurately predicts unknown protein class/family of Leishmania donovani membrane proteome. AB - Leishmania donovani is the primary cause of a fatal disease visceral leishmaniasis (VL) in East Africa and in the Indian subcontinent. Human beings are the only known reservoir of L. donovani and due to the emergence and the spread of drug resistance control for this disease is become worse. Therefore, identification of novel drug target is very important to develop new drug and combat drug resistance issue. Experimental determination of target is costly and time-consuming, hence it is necessary to first identify the efficient target with the accurate mathematical method and then further go for in vitro/in vivo study. Earlier we have predicted the role of protein in term of the target with Naive Bayes probabilistic classifier on the proteins identified in our L. donovani membrane proteomics study. This time we have used alternative and the popular method named as a Rough Set method (an important part of soft computing method relevance in many real-world applications) and tried to re-visit/validate our earlier findings of L. donovani membrane proteomics and additionally decipher the unknown class/family of membrane proteins as known one. Comparing this result with other classifiers (NB, SVM, RF, C4.5 decision tree) Rough Set method has outperformed and we found the accuracy was 89.28%. This study further validates our previous finding strongly and predicts the class/family of unknown proteins which are very important for the identification and selection toward some novel drug target (still unexplored) and ultimately move in the direction of development of effective antileishmanials. PMID- 29627266 TI - Fast cheater migration stabilizes coexistence in a public goods dilemma on networks. AB - Through the lens of game theory, cooperation is frequently considered an unsustainable strategy: if an entire population is cooperating, each individual can increase its overall fitness by choosing not to cooperate, thereby still receiving all the benefit of its cooperating neighbors while no longer expending its own energy. Observable cooperation in naturally-occurring public goods games is consequently of great interest, as such systems offer insight into both the emergence and sustainability of cooperation. Here we consider a population that obeys a public goods game on a network of discrete regions (that we call colonies), between any two of which individuals are free to migrate. We construct a system of piecewise-smooth ordinary differential equations that couple the within-colony population dynamics and the between-colony migratory dynamics. Through a combination of analytical and numerical methods, we show that if the workers within the population migrate sufficiently fast relative to the cheaters, the network loses stability first through a Hopf bifurcation, then a torus bifurcation, after which one or more colonies collapse. Our results indicate that fast moving cheaters can act to stabilize worker-cheatercoexistence within network that would otherwise collapse. We end with a comparison of our results with the dynamics observed in colonies of the ant species Pristomyrmex punctatus, and argue that they qualitatively agree. PMID- 29627267 TI - Self-management education for rehabilitation inpatients: A cluster-randomized controlled trial. AB - OBJECTIVE: To evaluate generic self-management modules (SelMa) as an adjunct to disease-specific educational programs during inpatient medical rehabilitation. METHODS: A bi-center cluster-randomized controlled trial with 698 patients with coronary artery disease, metabolic syndrome, or inflammatory bowel disease was conducted. We compared two versions of SelMa, a group with 3 h or a lecture with 1 h, respectively, in addition to disease-related patient education, to usual care (only disease-related education). SelMa aims at providing skills that may help implementing health behavior. The primary outcomes were goal setting and behavior planning at discharge and goal attainment and health behavior at 6- and 12-months follow-up. Secondary outcomes included motivation, knowledge and self management competences. RESULTS: At discharge, SelMa group, but not SelMa lecture, proved superior to usual care regarding goal setting (p = 0.007, d = 0.26), but not behavior planning (p = 0.37, d = 0.09). Significant effects were also observed on several secondary outcomes. At later follow-up, however, no effects on primary outcomes emerged. Participants' satisfaction was higher in the group than the lecture format. CONCLUSIONS: These short modules did not succeed in improving self-management skills in the long-term. PRACTICE IMPLICATIONS: A self-management group may foster self-management skills in short term. Interventions should be developed to increase sustainability of effects. PMID- 29627268 TI - Findings from a feasibility study to improve GP elicitation of patient concerns in UK general practice consultations. AB - OBJECTIVES: To establish: a) feasibility of training GPs in a communication intervention to solicit additional patient concerns early in the consultation, using specific lexical formulations ("do you have 'any' vs. 'some' other concerns?") noting the impact on consultation length, and b) whether patients attend with multiple concerns and whether they voiced them in the consultation. METHODS: A mixed-methods three arm RCT feasibility study to assess the feasibility of the communication intervention. RESULTS: Intervention fidelity was high. GPs can be trained to solicit additional concerns early in the consultation (once patients have presented their first concern). Whilst feasible the particular lexical variation of 'any' vs 'some' seemed to have no bearing on the number of patient concerns elicited, on consultation length or on patient satisfaction. The level of missing questionnaire data was low, suggesting patients found completion of questionnaires acceptable. CONCLUSION: GPs can solicit for additional concerns without increasing consultation length, but the particular wording, specifically 'any' vs. 'some' may not be as important as the placement of the GP solicitation. PRACTICE IMPLICATIONS: GPs can solicit early for additional concerns and GPs can establish patients' additional concerns in the opening of the consultation, which can help to plan and prioritise patients multiple concerns. PMID- 29627269 TI - Diversity and Compatibility of Human Schistosomes and Their Intermediate Snail Hosts. AB - Human schistosomiasis is a major neglected tropical disease that remains endemic in numerous countries of the tropics and subtropics. Controlling the transmission of schistosomes in their intermediate snail hosts remains a key challenge in the fight against schistosomiasis. Divergence in species, biogeography, and genotype in schistosomes and their intermediate hosts has resulted in diverse parasite host interactions. This review focuses on recent insights in the biogeography and diversity of schistosome species and their snail hosts, and the molecular basis of compatibility polymorphism between them. PMID- 29627270 TI - Re-irradiation of the Brain. PMID- 29627271 TI - Biology is the King! PMID- 29627273 TI - Neural functional correlates of the impact of socio-emotional stimuli on performances on a flanker task in children aged 9-11 years. AB - Immature cognition is susceptible to interference from competing information, and particularly in affectively charged situations. Several studies have reported activation in the anterior cingulate cortex, prefrontal cortex and amygdala associated with emotional conflict processing in adults but literature is lacking regarding children. Moreover, studies in children and adolescents still disagree regarding the functional activation of amygdala related to facial stimuli. In the purpose of investigating both the effect of socio-emotional stimuli and its interaction with interference control, we designed a flanker task associated with an event-related fMRI paradigm in 30 healthy children ages 9-11. In addition to happy, angry and neutral faces, we presented scrambled stimuli to examine a potential effect of faces. Regarding both brain and behavior results, no effect of emotional valence was observed. However, both results evidenced an emotional effect of faces compared with scrambled stimuli. This was expressed by faster RTs associated with increased amygdala activity and activation of the ventral ACC, in congruent trials only. When scrambled were inversely compared to faces, increased activity was observed within the lateral prefrontal cortex. Regarding the amygdala, the results suggest that in late school age children, activity in the amygdala seemed to underlie the socio-emotional effect induced by faces but not the emotional conflict. Studying brain regions involved in emotion regulation is important to further understand neurodevelopmental disorders and psychopathologies, particularly in late childhood and adolescence. PMID- 29627272 TI - Multi-locus transcranial magnetic stimulation-theory and implementation. AB - BACKGROUND: Transcranial magnetic stimulation (TMS) is a non-invasive brain stimulation method: a magnetic field pulse from a TMS coil can excite neurons in a desired location of the cortex. Conventional TMS coils cause focal stimulation underneath the coil centre; to change the location of the stimulated spot, the coil must be moved over the new target. This physical movement is inherently slow, which limits, for example, feedback-controlled stimulation. OBJECTIVE: To overcome the limitations of physical TMS-coil movement by introducing electronic targeting. METHODS: We propose electronic stimulation targeting using a set of large overlapping coils and introduce a matrix-factorisation-based method to design such sets of coils. We built one such device and demonstrated the electronic stimulation targeting in vivo. RESULTS: The demonstrated two-coil transducer allows translating the stimulated spot along a 30-mm-long line segment in the cortex; with five coils, a target can be selected from within a region of the cortex and stimulated in any direction. Thus, far fewer coils are required by our approach than by previously suggested ones, none of which have resulted in practical devices. CONCLUSION: Already with two coils, we can adjust the location of the induced electric field maximum along one dimension, which is sufficient to study, for example, the primary motor cortex. PMID- 29627274 TI - How can familiar voice recognition be intact if unfamiliar voice discrimination is impaired? An introduction to this special section on familiar voice recognition. PMID- 29627276 TI - A review on drug-induced sedation endoscopy - Technique, grading systems and controversies. AB - Sleep disordered breathing (SDB) comprises a spectrum of disorders, ranging from simple snoring to severe obstructive sleep apnoea (OSA), with a significant burden to health care systems in high income countries. If left untreated, OSA has significant cumulative, long-term health consequences. In the 1990s drug induced sedation endoscopy (DISE) has been developed to become a primary tool in the diagnosis and management of OSA. It allows meticulous endoscopic evaluation of the airway and identifies areas of collapse, thereby informing both on the selection of surgical techniques, where efficacy depends entirely on success at relieving obstruction at a certain level and on the usefulness of conservative measures, such as mandibular advancement splints. This article provides a review of the literature on DISE, covering different grading systems and techniques, explaining different rationales and discussing controversies. PMID- 29627275 TI - Growth impairment in mucopolysaccharidoses. AB - Mucopolysaccharidoses (MPS) are a group of lysosomal storage disorders that affect regulation of glycosaminoglycan (GAG) processing. In MPS, the lysosomes cannot efficiently break down GAGs, and the specific GAGs accumulated depend on the type of MPS. The level of impairment of breakdown varies between patients, making this one of the many factors that lead to a range of clinical presentations even in the same type of MPS. These clinical presentations usually involve skeletal dysplasia, in which the most common feature is bone growth impairment and successive short stature. Growth impairment occurs due to the deposition and retention of GAGs in bone and cartilage. The accumulation of GAGs in these tissues leads to progressive damage in cartilage that in turn reduces bone growth by destruction of the growth plate, incomplete ossification, and imbalance of growth. Imbalance of growth leads to various skeletal abnormalities including disproportionate dwarfism with short neck and trunk, prominent forehead, rigidity of joints, tracheal obstruction, kyphoscoliosis, pectus carinatum, platyspondyly, round-shaped vertebral bodies or beaking sign, underdeveloped acetabula, wide flared iliac, coxa valgus, flattered capital femoral epiphyses, and genu valgum. If left untreated, skeletal abnormalities including growth impairment result in a significant impact on these patients' quality of life and activity of daily living, leading to high morbidity and severe handicap. This review focuses on growth impairment in untreated patients with MPS. We comprehensively describe the growth abnormalities through height, weight, growth velocity, and BMI in each type of MPS and compare the status of growth with healthy age-matched controls. The timing, the degree, and the difference in growth impairment of each MPS are highlighted to understand the natural course of growth and to evaluate future therapeutic efficacy. PMID- 29627277 TI - Vaccination in Heart Failure: An Approach to Improve Outcomes. PMID- 29627278 TI - Leaching kinetics of cobalt from the scraps of spent aerospace magnetic materials. AB - Based on physicochemical properties of the scraps of spent aerospace magnetic materials, a roasting - magnetic separation followed by sulfuric acid leaching process was proposed to extract cobalt. Roasting was performed at 500 degrees C to remove organic impurity. Non-magnetic impurities were reduced by magnetic separation and then the raw material was sieved into desired particle sizes. Acid leaching was carried out to extract cobalt from the scraps and experimental parameters included agitation speed, particle size, initial concentration of sulfuric acid and temperature. Agitation speed higher than 300 r/min had a relatively small impact on the cobalt extraction. As the particle size reduced, the content of cobalt in the raw material decreases and the extraction of cobalt by acid leaching increased at first and decreased afterwards. Raising the initial concentration of sulfuric acid and temperature contributed to improve the cobalt extraction and the influence of temperature was more remarkable. SEM image revealed that the spent aerospace magnetic materials mainly existed in the sliced strip flake with a loose surface and porous structure. Under the experimental condition, the leaching rate of cobalt from the scraps in sulfuric acid solution could be expressed as ln(-ln(1 - alpha)) = lnk + nlnt. The apparent activation energy was found to be 38.33 kJ/mol and it was mainly controlled by the surface chemical reaction. PMID- 29627279 TI - Understanding Patient Preferences in Proximal Interphalangeal Joint Surgery for Osteoarthritis: A Conjoint Analysis. AB - PURPOSE: We sought to compare preferences for arthroplasty versus arthrodesis among patients with proximal interphalangeal (PIP) joint osteoarthritis (OA) by quantifying the patient-assigned utility of each operation's attributes. METHODS: We undertook a multistep process to identify relevant surgical attributes, including a literature review, surgeon survey, and pretest patient pilot test to build a set of discrete choice experiments. Patients with PIP joint osteoarthritis were identified using a single university electronic medical record and were recruited via electronic message or postcard. Participants completed a demographic survey and 11 discrete choice experiments designed using Sawtooth Software's Discover tool. Utility and importance scores were generated for each attribute. RESULTS: Pretest analysis identified out-of-pocket cost, joint stiffness, need for future surgery, change in grip strength, and total recovery time as the most important surgical attributes. Initial response rate to the conjoint survey was 75% and survey completion rate was 61%. The study sample was predominantly white (91%) and female (72%), mean age 64.3 years (range, 34-90 years), and mean daily pain score was 4.32 (range, 0-10). Attribute importance scores demonstrated that joint stiffness (32%) and grip strength (29%) were most important to patients. Cost (17%) and need for future surgery (19%) were intermediate patient-preference drivers. Recovery time was the least important attribute (2%). CONCLUSIONS: In aggregate, patients prefer surgical attributes characteristic of arthroplasty (ability to preserve joint motion and grip strength) relative to those associated with arthrodesis (decreased need for reoperation, lower costs, and shorter reoperation times). TYPE OF STUDY/LEVEL OF EVIDENCE: Economic/Decision Analysis III. PMID- 29627280 TI - Bilateral Nonsynchronous Pacinian Corpuscle Neuroma. AB - Pacinian corpuscles are rapidly adapting mechanoreceptors distributed in the dermis of the fingers and palm of the hand. A neuroma of the pacinian corpuscle is rare and extremely painful, with only a few cases reported in the literature. A 71-year-old man with pain and swelling on his left index finger, initially diagnosed as tenosynovitis resistant to nonsurgical treatment, was referred to our center. During surgery, a cluster of spherical, gray lesions close to the digital nerve was found and excised. The pathological diagnosis was neuroma of the pacinian corpuscles. Two years later, he reported the same clinical findings on his right index finger with no improvement after nonsurgical treatment. During surgery, the same lesions were found and also identified as pacinian corpuscle neuromas. PMID- 29627281 TI - Colonic perforation associated with sodium polystyrene sulfonate (Kayexalate) use. PMID- 29627283 TI - Erratum in Wilderness Environ Med. 29/1. PMID- 29627282 TI - Effect of treatment of Bos indicus heifers with progesterone 0, 3 and 6 days after follicular aspiration on follicular dynamics and the timing of oestrus and ovulation. AB - Synchronisation of wave emergence is used to synchronise oestrus in cattle. The aim of this study was to determine if treatment with high concentrations of progesterone in Bos indicus heifers for 3 days would synchronise new wave emergence when treatment commenced at early, mid and late stages of follicular development. Heifers were treated with a sc silicone implant containing norgestomet from Days -7 to 9 and cloprostenol (IM) on Days -7 and -2. All follicles > 4 mm in diameter were removed by transvaginal follicular aspiration either on Days 0 (Experiment 1), 3 (Experiment 2) or 6 (Experiment 3). From Days 6 to 9 every heifer was treated with two intravaginal progesterone releasing inserts that each contained either no progesterone (Control, n = 8/experiment) or 3.12 g of progesterone (n = 8/experiment). Ovarian follicular development was monitored at least once daily following aspiration until oestrus and ovulation. In each experiment, treatment with progesterone significantly increased concentrations of progesterone in plasma from Days 6 to 9 compared to Control heifers. It also significantly delayed the day of emergence of the ovulatory follicle (1.6 +/- 0.6 vs 8.6 +/- 0.3; 4.1 +/- 0.1 vs 8.6 +/- 0.2; 7.0 +/- 0.0 vs 9.3 +/- 0.4, for Control vs progesterone treated heifers, respectively in Experiments 1 to 3) and the interval from implant removal to oestrus and ovulation. In conclusion, treatment with high concentrations of progesterone can synchronise wave emergence in Bos indicus heifers when administered at early, mid and late stages of follicular development. PMID- 29627284 TI - Blogs Written by Families During Their Child's Hospitalization: A Thematic Narrative Analysis. AB - PURPOSE: To identify stressors experienced by parents whose child is hospitalized in an intensive care unit, and identify coping mechanisms utilized to ameliorate those stressors. DESIGN AND METHODS: Using Lazarus and Folkman's Transactional Model of Stress and Coping as a framework, 20 publicly available blogs written by parents while their child was a patient in intensive care were analyzed using thematic analysis techniques. Stressors and coping techniques were identified, and grouped by theme for further analysis. RESULTS: The most frequently noted types of stressors were related to information; both knowing and not knowing information related to their child's condition was reported as stressful, as well as waiting for information and when the information was not what was expected. Reframing was the emotion-focused technique most often identified by the parents, and seeking support was the most frequently noted problem-focused coping mechanism. CONCLUSIONS: Illness blogs represent a rich source of information regarding the experiences of families with a child in the hospital. Parents transitioned from more emotion-focused coping strategies to problem-focused strategies during their child's hospital stay. PRACTICE IMPLICATIONS: When nurses give information to parents, they should be aware that knowing information can be stressful as well as not knowing, and care should be taken to provide support for parents after information is given. Nurses can also help parents identify sources of support. Writing about their experiences, either online or in a journal, may help parents cope in stressful situations. PMID- 29627285 TI - The Pediatric Inventory for Parents - Swedish Translation and Psychometric Testing. AB - : The Pediatric Inventory for Parents (PIP) measures parental stress related to caring for a child with an illness. However, no Swedish translation is available. PURPOSE: This study reports a Swedish translation of the PIP and psychometric properties of the instrument. DESIGN AND METHODS: This is a descriptive/methodological paper. The PIP was translated and culturally adapted to Swedish, and comprehensibility was tested. Data were collected twice from 48 parents of children with different illnesses, and initial psychometric properties of the instrument were examined. The IES-R (Impact of Event Scale-Revised) was used for concurrent validity. RESULTS: The Swedish version of the PIP demonstrated good correlations with the IES-R, and temporal changes were similar. Endorsement frequencies and test-retest were also satisfactory. When comparing groups of parents, the parents of children with cancer were statistically significantly more distressed, both on total score and for emotional distress and role function. Discriminative validity was demonstrated by comparing parents of children with cancer with parents of children with other diseases. CONCLUSIONS: The Swedish version of the PIP seems to be a valid and reliable instrument. However, as we used relatively small sample, for the future, we suggest further testing with larger samples. PRACTICE IMPLICATIONS: Clinicians and researchers seeking to measure parental distress in chronic illness could use the Swedish version of the PIP. PMID- 29627286 TI - Changing Faces of Cognitive Impairment in the U.S.: Detection Strategies for Underserved Communities. PMID- 29627287 TI - Corrections. PMID- 29627288 TI - Multiparametric Whole-body MRI with Diffusion-weighted Imaging and ADC Mapping for the Identification of Visceral and Osseous Metastases From Solid Tumors. AB - RATIONALE AND OBJECTIVES: The purpose of this study was to investigate the use of multiparametric, whole-body, diffusion-weighted imaging (WB-DWI) and apparent diffusion coefficient (ADC) maps with T2-weighted magnetic resonance imaging (MRI) at 3T for the detection and monitoring of metastatic disease in patients. MATERIALS AND METHODS: Fifty-four participants (32 healthy subjects and 22 patients) were scanned with WB-DWI methods using a 3T MRI scanner. Axial, sagittal, or coronal fat-suppressed T2-weighted (T2WI), T1-weighted (T1WI), and DWI images were acquired. Total MRI acquisition and set-up time was approximately 45 minutes. Metastatic disease on MRI was confirmed based on T2WI characteristics. The number of lesions was established on computed tomography (CT) or positron emission tomography (PET-CT). Whole-body ADC maps and T2WI were constructed, and region-of-interests were drawn in normal and abnormal-appearing tissue for quantitative analysis. Statistical analysis was performed using a paired t tests and P < .05 was considered statistically significant. RESULTS: There were 91 metastatic lesions detected from the CT or PET-CT with a missed recurrent lesion in the prostate. Multiparametric WB-MRI had excellent sensitivity (96%) for detection of metastatic lesions compared to CT. ADC map values and the ADC ratio in metastatic bone lesions were significantly increased (P < .05) compared to normal bone. In soft tissue, ADC map values and ratios in metastatic lesions were decreased compared to normal soft tissue. CONCLUSION: We have demonstrated that multiparametric WB-MRI is feasible for oncologic staging to identify bony and visceral metastasis in breast, prostate, pancreatic, and colorectal cancers. WB-MRI can be tailored to fit the patient, such that an "individualized patient sequence" can be developed for a comprehensive evaluation for staging and response during treatment. PMID- 29627290 TI - Delayed surgical site infection 2 years after cervical disk arthroplasty. Case report and literature review. AB - Anterior cervical discectomy has a low non-mechanical complication rate. In our literature review, we found 7 cases of delayed surgical site infection. We report a case of cervical prevertebral abscess due to Propionibacterium acnes 2 years after discectomy and arthroplasty, with a beta-2-transferrin false positive test as a complementary highlighted finding. We discuss the diagnosis and etiology of this rare delayed infectious complication. PMID- 29627289 TI - Mechanisms of neuropsychiatric lupus: The relative roles of the blood cerebrospinal fluid barrier versus blood-brain barrier. AB - The pathogenesis of neuropsychiatric lupus (NPSLE) is believed to include the entry of circulating neuropathic antibodies to the brain via a pathologically permeable blood-brain barrier (BBB). Nevertheless, direct evidence of BBB pathology or mechanisms underlying BBB dysfunction is missing. Here, we examined BBB integrity in an established NPSLE mouse model (MRL/faslpr/lpr). Surprisingly, challenging the barrier with various exogenous tracers demonstrated insignificant changes in BBB permeability. Furthermore, electron microscopy showed no ultrastructure changes supporting hyper-permeability. However, we found that abnormal function of the blood-cerebrospinal fluid barrier (BCSFB) in the choroid plexus underlies brain exposure to neuropathic antibodies. Considerable intrathecal lymphocyte infiltration likely occurs through the BCSFB, accompanied by epithelial hyper-permeability to antibodies. Our results challenge the commonly held view of BBB disruption in NPSLE, supporting a shift in focus to BCSFB dysfunction as a causative factor in the disease. PMID- 29627291 TI - Subdural hygroma secondary to rupture of an intracranial arachnoid cyst: description of 2cases and review of the literature. AB - The appearance of a subdural hygroma after the rupture of an arachnoid cyst wall is extremely rare, with very few cases described in the literature. Most cases are due to a traumatic cause. The therapeutic approach in symptomatic cases is controversial, with a current tendency toward conservative management initially. In those cases that require surgical treatment, multiple therapeutic options are available, with fenestration techniques being recommended as first-line treatment. We describe 2cases treated in our centre and review the literature. PMID- 29627292 TI - Altered Cellular Metabolism Drives Trained Immunity. AB - Exposing innate immune cells to an initial insult induces a long-term proinflammatory response due to metabolic and epigenetic alterations which encompass an emerging new concept called trained immunity. Recent studies provide novel insights into mechanisms centered on metabolic reprogramming which induce innate immune memory in hematopoietic stem cells and monocytes. PMID- 29627293 TI - [Tuberculous pseudotumour, a challenging diagnosis]. AB - INTRODUCTION: The pseudotumorous form of tuberculosis is a rare entity. Whatever its location, it can simulate neoplasia by its radiological and/or endoscopic appearances. We highlight the diagnostic difficulties associated with this type of presentation. METHODS: We performed a retrospective study of inpatient records from 2003 to 2016 in the pneumology department of La Rabta Hospital to identify cases of thoracic tuberculous pseudo-tumor. RESULTS: Seventeen patients were identified. The median age was 41 years and their symptomatology was dominated by cough and general debility. All had abnormal radiology with 10 cases of suspect lesions. Fibre-optic bronchoscopy revealed endobronchial abnormalities in 11 cases. The median overall diagnostic delay was 97 days. The diagnosis was confirmed bacteriologically in five cases, histologically in 14 cases and based on clinical presumption in one case. The progression was favourable: 13 patients have been declared cured and four patients are still undergoing treatment. CONCLUSION: Making a positive diagnosis of thoracic tuberculous pseudotumour can be difficult, as bacteriological samples are often negative. This can lead to a significant delay in diagnosis and treatment. PMID- 29627294 TI - beta-arrestin-biased agonism of beta-adrenergic receptor regulates Dicer-mediated microRNA maturation to promote cardioprotective signaling. AB - RATIONALE: MicroRNAs (miRs) are small, non-coding RNAs that function to post transcriptionally regulate target genes. First transcribed as primary miR transcripts (pri-miRs), they are enzymatically processed by Drosha into premature miRs (pre-miRs) and further cleaved by Dicer into mature miRs. Initially discovered to desensitize beta-adrenergic receptor (betaAR) signaling, beta arrestins are now well-appreciated to modulate multiple pathways independent of G protein signaling, a concept known as biased signaling. Using the beta-arrestin biased betaAR ligand carvedilol, we previously showed that beta-arrestin1 (not beta-arrestin2)-biased beta1AR (not beta2AR) cardioprotective signaling stimulates Drosha-mediated processing of six miRs by forming a multi-protein nuclear complex, which includes beta-arrestin1, the Drosha microprocessor complex and a single-stranded RNA binding protein hnRNPA1. OBJECTIVE: Here, we investigate whether beta-arrestin-mediated betaAR signaling induced by carvedilol could regulate Dicer-mediated miR maturation in the cytoplasm and whether this novel mechanism promotes cardioprotective signaling. METHODS AND RESULTS: In mouse hearts, carvedilol indeed upregulates three mature miRs, but not their pre miRs and pri-miRs, in a beta-arrestin 1- or 2-dependent manner. Interestingly, carvedilol-mediated activation of miR-466g or miR-532-5p, and miR-674 is dependent on beta2ARs and beta1ARs, respectively. Mechanistically, beta-arrestin 1 or 2 regulates maturation of three newly identified betaAR/beta-arrestin responsive miRs (beta-miRs) by associating with the Dicer maturation RNase III enzyme on three pre-miRs of beta-miRs. Myocardial cell approaches uncover that despite their distinct roles in different cell types, beta-miRs act as gatekeepers of cardiac cell functions by repressing deleterious targets. CONCLUSIONS: Our findings indicate a novel role for betaAR-mediated beta-arrestin signaling activated by carvedilol in Dicer-mediated miR maturation, which may be linked to its protective mechanisms. PMID- 29627296 TI - Relationship between lipoprotein subfraction cholesterol and residual risk for cardiovascular outcomes: A post hoc analysis of the AIM-HIGH trial. AB - BACKGROUND: The AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides and Impact on Global Health Outcomes) trial failed to demonstrate incremental clinical benefit of extended-release niacin (ERN) in 3414 statin-treated patients with established cardiovascular (CV) disease who had low baseline levels of high-density lipoprotein cholesterol (HDL C) as compared to placebo. A previous secondary analysis suggested that ERN provided outcome benefits in ERN-treated patients with high triglycerides (TGs; >200 mg/dL) and very low HDL-C (<32 mg/dL) at baseline. The current analysis sought to ascertain how changes in TG-enriched lipoproteins and HDL subfractions impact residual risk in the comparator treatment arms. OBJECTIVES: We evaluated the relationship between niacin treatment, lipoproteins and their subfractions, and CV outcomes in a non-prespecified, post hoc analysis of the AIM-HIGH trial. METHODS: Lipoprotein subfraction analysis was performed with zonal ultracentrifugation in 2457 AIM-HIGH participants at baseline and 1 year of treatment. Hazard ratios were estimated using Cox proportional hazards models for relationships between lipoproteins and the composite primary endpoint of CV death, myocardial infarction, acute coronary syndrome, ischemic stroke, or symptom-driven revascularization. Analyses were performed for the entire cohort and in participants with TGs > 200 mg/dL and HDL-C < 32 mg/dL. RESULTS: Apoprotein B-containing lipoproteins and their subfractions decreased significantly in both treatment arms but decreased more with ERN treatment. HDL-C and its subfractions increased significantly in both treatment groups, but more so in patients treated with ERN. For the entire study population, neither apoB- nor apoA1-containing lipoprotein subfractions predicted risk at baseline or at 1 year of follow-up. In the high TG and low HDL-C subgroup treated with placebo, changes at 1 year in HDL2-C, total cholesterol/HDL2-C, and non-HDL-C/HDL2-C may be associated with increased CV events, whereas in the ERN treatment arm, changes at 1 year in very low-density lipoprotein cholesterol and very low-density lipoprotein subfractions, total remnant lipoproteins, and various risk ratios may be associated with increased CV events, while HDL2-C may be associated with reduced risk. CONCLUSIONS: We provide hypothesis-generating findings that ERN may confer benefit in patients with coronary heart disease who have high TGs and low HDL by reducing serum levels of remnant lipoprotein cholesterol and increasing HDL2-C. PMID- 29627295 TI - Deficiency of aldose reductase exacerbates early pressure overload-induced cardiac dysfunction and autophagy in mice. AB - Pathological cardiac hypertrophy is associated with the accumulation of lipid peroxidation-derived aldehydes such as 4-hydroxy-trans-2-nonenal (HNE) and acrolein in the heart. These aldehydes are metabolized via several pathways, of which aldose reductase (AR) represents a broad-specificity route for their elimination. We tested the hypothesis that by preventing aldehyde removal, AR deficiency accentuates the pathological effects of transverse aortic constriction (TAC). We found that the levels of AR in the heart were increased in mice subjected to TAC for 2 weeks. In comparison with wild-type (WT), AR-null mice showed lower ejection fraction, which was exacerbated 2 weeks after TAC. Levels of atrial natriuretic peptide and myosin heavy chain were higher in AR-null than in WT TAC hearts. Deficiency of AR decreased urinary levels of the acrolein metabolite, 3-hydroxypropylmercapturic acid. Deletion of AR did not affect the levels of the other aldehyde-metabolizing enzyme - aldehyde dehydrogenase 2 in the heart, or its urinary product - (N-Acetyl-S-(2-carboxyethyl)-l-cystiene). AR null hearts subjected to TAC showed increased accumulation of HNE- and acrolein modified proteins, as well as increased AMPK phosphorylation and autophagy. Superfusion with HNE led to a greater increase in p62, LC3II formation, and GFP LC3-II punctae formation in AR-null than WT cardiac myocytes. Pharmacological inactivation of JNK decreased HNE-induced autophagy in AR-null cardiac myocytes. Collectively, these results suggest that during hypertrophy the accumulation of lipid peroxidation derived aldehydes promotes pathological remodeling via excessive autophagy, and that metabolic detoxification of these aldehydes by AR may be essential for maintaining cardiac function during early stages of pressure overload. PMID- 29627299 TI - Avoiding misinterpretations of Kappa angle for clinical research studies with Pentacam. PMID- 29627298 TI - Effect of distance vision and refractive error on the spontaneous eye blink activity in human subjects in primary eye gaze. AB - PURPOSE: To evaluate whether visual target character and visibility affects spontaneous eye blink rate (SEBR) in primary eye gaze and silence. METHODS: Video recordings were made of young healthy adults who were either emmetropic (n=32) or who wore spectacles for refractive error (range -4.75D and +4.50D (n=31). Emmetropes had 5min recordings made whilst seated and looking towards a distant whiteboard. For spectacle wearers, recordings were made whilst looking towards the whiteboard with a 35mm sized cross, and repeated after spectacle removal. The average number of eye blinks over 5min was assessed, and its intra-subject variability as the coefficient of variation (COV). RESULTS: Over 5min without a distance target, an average SEBR of 10.4blinks/min was observed in emmetropes with a of COV=38.1%, and a significant increase in SEBR over the 5th minute to 13.6blinks/min. Hyperopes being asked to look towards a distant target showed the essentially same blinking rate of 11.1/min with or without spectacle wear with the intra-subject variability (COV) being 21.3%. Myopic subjects showed a slightly higher SEBR if looking towards a target without their spectacles (12.4 vs. 11.0blinks/min), with the COV being 18.8%. CONCLUSIONS: The studies indicate that some form of visual target could be useful to promote constancy of spontaneous eye blink activity over time, but that a distance visual target (when provided) does not need to be seen clearly. PMID- 29627297 TI - Neuropharmacological effects of essential oil from the leaves of Croton conduplicatus Kunth and possible mechanisms of action involved. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Croton conduplicatus Kunth (Euphorbiaceae) is a Brazilian aromatic medicinal plant, widely known as "quebra-faca". In folk medicine, its leaves and stem-barks are used as a natural analgesic for the treatment of headaches. AIM OF THE STUDY: In this study, we describe for the first time the neuropharmacological potential of the essential oil obtained from the leaves of Croton conduplicatus (EO) in experimental models of pain, anxiety and insomnia. The mechanisms of action involved in these activities were also investigated. MATERIAL AND METHODS: Different experimental models were used to evaluate the antinociceptive (acetic acid, formalin-induced nociception and hot plate tests), anxiolytic (elevated plus maze and hole board tests) and sedative (thiopental-induced sleeping time) effects of EO in mice. EO was evaluated in three different doses (25, 50 and 100 mg/kg, i.p.) and compared with positive and negative controls in all experimental protocols. When appropriate, animals were pretreated with pharmacological antagonists (naloxone, atropine and flumazenil) in order to evaluate the mechanisms of action involved. A docking study also was performed to identify possible targets involved. RESULTS: EO (25, 50 and 100 mg/kg, i.p.) demonstrated a significant antinociceptive activity in all experimental models. Pretreatment with naloxone or atropine reversed the antinociceptive response (p < 0.05), suggesting the involvement of opioid and muscarinic receptors, respectively. A docking study was performed with the major components identified in EO (1,8 cineole - 21.42%, spathulenol - 15.47%, p-cymene - 12.41% and caryophyllene oxide - 12.15%), demonstrating favorable interaction profile with different subtypes of muscarinic (M2, M3 and M4) and opioids (delta and mu) receptors. EO also showed anxiolytic (mainly at doses of 25 and 50 mg/kg, i.p.) and sedative (only at the dose of 100 mg/kg, i.p.) effects in mice. These pharmacological responses were reversed by flumazenil (p < 0.05), indicating possible involvement of GABAA receptors. CONCLUSION: Our findings support the traditional use of this plant as a natural analgesic and suggest that EO is a multi-target natural product, presenting not only antinociceptive effect but also anxiolytic and sedative activities depending on the dose used. PMID- 29627300 TI - Influence of contrast polarity on the accommodative response. AB - PURPOSE: To assess the changes in the accommodative response of the eye while reading a text under different contrast polarity conditions: black letters on white background (BoW condition) and white letters on black background (WoB condition). METHODS: Eighteen subjects with ages ranging from 21 to 41 years participated in this experimental study. The accommodative response (AR) of the eye while reading a text with BoW or WoB contrast polarity was obtained objectively with an adaptive optics system that corrected all aberrations but subject's own. Two different letter sizes (visual acuity conditions), shown on a microdisplay, were tested. The AR of each eye was measured with its natural pupil diameter at 0-3D of accommodative demand from the far point of the eye, with a step of 0.5D. The slope of the stimulus-response curve was calculated for each subject and condition. RESULTS: The averaged maximum pupil size was bigger for reverse (WoB) than for normal (BoW) contrast with statistical significance. The slopes for the ARs of the four conditions were not significantly different from each other. CONCLUSIONS: Contrast polarity does not seem to influence the accommodative response when reading text from an electronic microdisplay. PMID- 29627301 TI - Effect of age in the ciliary muscle during accommodation: Sectorial analysis. AB - PURPOSE: To compare changes in the ciliary muscle area at different sectors between pre-presbyopic and presbyopic eyes during accommodation by means of an anterior segment optical coherence tomographer (OCT). METHODS: The anterior ciliary muscle area was measured in 20 healthy and phakic pre-presbyopic eyes, whose mean age was 23.3+/-4.4 years, and in 20 healthy and phakic presbyopic eyes, whose mean age was 46.5+/-5.2 years. The relative change in the cross sectional area of the ciliary muscle was measured at the nasal, inferior, and temporal sectors between 0 and -3 D of vergence, in -1 D step. A linear model was used to assess the correlation of each eye parameter with the accommodative demand. RESULTS: Each population group showed a significant increase in the anterior ciliary muscle area for each sector. The maximum increase in the ciliary muscle area within the pre-presbyopic group was about 30%, and for the presbyopic one was about 25%. At the same time, it was obtained that the larger the vergence, the larger the variability. Furthermore, the linear model showed a positive tendency between the change in the ciliary muscle area of each sector and the vergence for both population groups, which coefficient of determination was in all cases greater than 0.93. CONCLUSION: The anterior ciliary muscle area tends to increase with accommodation. The presbyopic nasal, inferior, and temporal ciliary muscle seem to have the same contractile capability as the young presbyopic ciliary muscle. These results might help to increase the evidences in the knowledge regarding the modern understanding of accommodation biometry and biomechanics. PMID- 29627302 TI - Inhibitive Effect of Resveratrol on the Inflammation in Cultured Astrocytes and Microglia Induced by Abeta1-42. AB - Astrocytes and microglia appear central to the initiation and progression of neuroinflammation in Alzheimer's disease (AD). In this study, inflammation was mimicked by Abeta1-42 treatment of rat astrocytes (RA) and N9 microglia cell lines. Inflammation induced by Abeta1-42 can be inhibited by pyrrolidine dithiocarbamic acid (PDTC), indicating that the NF-kappaB signal pathway is involved in inflammation. Then, the inhibitive effects of resveratrol (Res) on the inflammation in RA and N9 cells were assessed by observing the changes in inflammatory factors, chemokines, cell cycle and adhesion molecules on the cell surface. 17beta-Estradiol was used as an estrogen-positive control because Res is one of the selective estrogen receptor modulators. In RA cells, TNF-alpha, IL 1beta and MCP-1 in the supernatant and the proliferation index in the cell cycle were decreased by 5, 12.5, and 25 MUM Res and 20 nM 17beta-estradiol treatment 24 h before Abeta1-42. Similarly, in N9 microglial, the levels of IL-1beta, IL-6 and NO in the supernatant and CD40 and MHCII in the 10, 20, and 40 MUM Res and 20 nM 17beta-estradiol treatment groups decreased markedly compared with the Abeta1-42 treatment group. In addition, Res decreased the nuclear translocation of NF kappaB/p65 when checked by immunofluorescence. Furthermore, Res increased the expression of NF-kappaB/p65 and decreased the expression of p-IkappaB in the cytoplasm in both RA and N9 microglia. Taken together, the present data indicate that Res reduces inflammation in RA and N9 microglia, and the anti-NF-kappaB signal pathway may be one of the target mechanisms. PMID- 29627303 TI - Determining hemodynamic goals in neurocritically ill patients. PMID- 29627304 TI - Low fidelity model making activity by students: A novel way of learning concepts of neuroanatomy. AB - Teaching and learning anatomy has always been an integral part of medical education. Teaching neuroanatomy has always faced innate and contextual challenges therefore various innovative teaching-learning methods have been devised on the idea of engaging learners in meaningful learning activities through apt guidance, communication among peers and cluster activities. The present study aims at such an innovative method. The study was conducted in practical sessions of first year MBBS at the Institute during second semester. Neuroanatomy topic selected for present study was 'Neural Pathways/tracts'. Participants were divided into 8 groups and each was allotted a specific activity related to a particular cross-sectional level and allowed to build with the material provided by the department. Student feedback was taken through a structured questionnaire. 81 and 82.4% of students stated that the activity was clearly explained and should be offered more frequently in curriculum. The activity also developed a positive attitude and good coordination amongst peers with increase in communication skills (89.1%, 91.8%, 89% respectively). 87.8% of students agreed that small group learning is better than didactic lectures in neuroanatomy. In current medical scenario with reduced anatomy teaching hours and a continuous pressure on undergraduates, a low-cost learning intervention formulated to deliver a complex 3-D model of tracts passing through various parts of nervous system by simple materials would show better access and understanding of the tracts with improvement of 3D visualization skills. PMID- 29627305 TI - Starry Night on Liver MRI: An Unexpected Incidental Finding in a Healthy Recruit. PMID- 29627306 TI - Paraquat and MPTP induce alteration in the expression profile of long noncoding RNAs in the substantia nigra of mice: Role of the transcription factor Nrf2. AB - Parkinson's disease (PD) is a common age-related degenerative disease of the central nervous system caused mainly by hereditary, pesticides, metals, and polychlorinated biphenyls. Paraquat (PQ), a widely used herbicide, causes PD. Long noncoding RNAs (lncRNAs) are nonprotein-coding transcripts, expressed in the brain and play irreplaceable roles in neurodegenerative diseases. NF-E2-related factor-2 (Nrf2) is an important genetic transcription regulator in oxidative stress. We aimed to discover novel PQ or 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-Nrf2-related lncRNAs and explore their association with PD. 17157 lncRNAs and 13707 mRNAs (fold change >=2, P < 0.05) were identified by Microarray. And the expressions of six lncRNAs were confirmed by using qRT-PCR and two by FISH. Coding-noncoding analysis and qRT-PCR were applied to discover the functions of lncRNAs and predict the targeted genes. In mice, PQ and MPTP exposure caused alteration of the lncRNA expression profile, suggesting lncRNAs may be involved in PQ- and MPTP-induced neurotoxicity. The changes in their lncRNA expression were distinct but related. PQ caused lncRNA expression profiling alteration in the substantia nigra (SN) through an interaction with Nrf2, thus changing the NR_027648/Zc3h14/Cybb and NR_030777/Zfp326/Cpne5 mRNA pathways. Similarly, MPTP caused lncRNA expression profiling alteration in SN through an interaction with Nrf2. Nrf2 may be involved in the development of neurodegeneration induced by PQ and MPTP via interaction with lncRNAs as the molecular mechanism. Our findings indicate the potential roles of lncRNAs in the development of PD by PQ or MPTP and provide positive insights into future mechanism studies. PMID- 29627307 TI - Abnormal Myocardial Dietary Fatty Acid Metabolism and Diabetic Cardiomyopathy. AB - Patients with diabetes are at very high risk of hospitalization and death from heart failure. Increased prevalence of coronary heart disease, hypertension, autonomic neuropathy, and kidney failure all play a role in this increased risk. However, cardiac metabolic abnormalities are now recognized to play a role in this increased risk. Increased reliance on fatty acids to produce energy might predispose the diabetic heart to oxidative stress and ischemic damage. Intramyocellular accumulation of toxic lipid metabolites leads to a number of cellular abnormalities that might also contribute to cardiac remodelling and cardiac dysfunction. However, fatty acid availability from circulation and from intracellular lipid droplets to fuel the heart is critical to maintain its function. Fatty acids delivery to the heart is very complex and includes plasma nonesterified fatty acid flux as well as triglyceride-rich lipoprotein-mediated transport. Although many studies have shown a cross-sectional association between enhanced fatty acid delivery to the heart and reduction in left ventricular function in subjects with prediabetes and diabetes, these mechanisms change very rapidly during type 2 diabetes treatment. The present review focuses on the role of fatty acids in cardiac function, with particular emphasis on the possible role of early abnormalities of dietary fatty acid metabolism in the development of diabetic cardiomyopathy. PMID- 29627308 TI - Function in unaffected arms of children with obstetric brachial plexus palsy. AB - OBJECTIVE: The objective is to compare the fine and gross motor function of unaffected arms of children with obstetric brachial plexus palsy (OBBP) with typically developing children's dominant upper extremities. METHODS: Fifty-three patients with OBBP and fifty-one typically developing children between the age of 4 and 13 were included in the study. For gross motor function evaluation in the upper extremity box-block test (BBT), for fine motor skill nine-hole peg (9HP) test was used. For grasp and pinch strength measurements, a Jamar dynamometer is used. RESULTS: The patient group performed significantly worse in 9HP and BBT tests. When further divided into age groups, 4-8 age patient group performed significantly worse in 9HP and BBT tests, while there were no differences in children in the 9-13 age group. CONCLUSIONS: The fine and gross motor functions of the unaffected arms of children with OBPP are significantly worse in children between the ages of four and eight but this deficit improves with age, and possibly with ongoing therapy. PMID- 29627309 TI - Effect of Primary Tumor Location on Second- or Later-line Treatment Outcomes in Patients With RAS Wild-type Metastatic Colorectal Cancer and All Treatment Lines in Patients With RAS Mutations in Four Randomized Panitumumab Studies. AB - BACKGROUND: The primary tumor location has a prognostic impact in metastatic colorectal cancer (mCRC). We report the results from retrospective analyses assessing the effect of tumor location on prognosis and efficacy of second- and later-line panitumumab treatment in patients with RAS wild-type (WT) mCRC and on prognosis in all lines of treatment in patients with RAS mutant (MT) mCRC. PATIENTS AND METHODS: RAS WT data (n = 483) from 2 randomized phase III panitumumab trials (ClinicalTrials.gov identifiers, NCT00339183 and NCT00113763) were analyzed for treatment outcomes stratified by tumor location. The second analysis assessed the effect of tumor location in RAS MT patients (n = 1205) from 4 panitumumab studies (ClinicalTrials.gov identifiers, NCT00364013, NCT00819780, NCT00339183, and NCT00113763). Primary tumors located in the cecum to transverse colon were coded as right-sided; those located from the splenic flexure to the rectum were coded as left-sided. RESULTS: Of all patients, the tumor location was ascertained for 83% to 88%; 71% to 77% of patients had left-sided tumors. RAS WT patients with right-sided tumors did worse for all efficacy parameters compared with those with left-sided tumors. The patients with left-sided tumors had better outcomes with panitumumab than with the comparator treatment. Because of the low patient numbers, no conclusions could be drawn for right-sided mCRC. The prognostic effect of tumor location on survival was unclear for RAS MT patients. CONCLUSION: These retrospective analyses have confirmed that RAS WT right-sided mCRC is associated with a poor prognosis, regardless of the treatment. RAS WT patients with left-sided tumors benefitted from the addition of panitumumab in second or later treatment lines. Further research is warranted to determine the optimum management of right-sided mCRC and RAS MT tumors. PMID- 29627310 TI - Understanding antidepressant discontinuation syndrome (ADS) through preclinical experimental models. AB - Antidepressant drugs are currently one of the most prescribed medications. In addition to treatment resistance and side effects of antidepressants, their clinical use is further complicated by antidepressant discontinuation syndrome (ADS). ADS is a common problem in patients following the interruption, dose reduction, or discontinuation of antidepressant drugs. Clinically, ADS resembles a classical drug withdrawal syndrome, albeit differing from it because antidepressants generally do not induce addiction. The growing clinical importance and prevalence of ADS necessitate novel experimental (animal) models of this disorder. Currently available preclinical models of ADS are mainly rodent based, and study mostly serotonergic antidepressants and their combinations. Here, we systematically assess clinical ADS symptoms and discuss current trends and challenges in the field of experimental (animal) models of ADS. We also outline basic mechanisms underlying ADS pathobiology, evaluate its genetic, pharmacological and environmental determinants, and emphasize how using animal models may help generate important translational insights into human ADS condition, its prevention and therapy. PMID- 29627311 TI - Lysosomotropic cationic amphiphilic drugs inhibit adipocyte differentiation in 3T3-L1K cells via accumulation in cells and phospholipid membranes, and inhibition of autophagy. AB - Some cationic amphiphilic drugs (CADs) have been individually reported to interfere with the differentiation of immune system cells, such as macrophages and dendritic cells. To investigate the possible generic nature of this process, in this study we aimed to see whether these drugs are capable of interfering with the differentiation of adipocytes. Further, we investigated whether this feature might be connected to the lysosomotropic character of these drugs, and their disturbance of intracellular membrane trafficking rather than to the individual pharmacologic properties of each drug. Thus, for the selected set of compounds consisting of seven structurally and pharmacologically diverse CADs and three non CAD controls we have measured the impact on differentiation of 3T3-L1K murine preadipocytes to adipocytes. We conclude that CADs indeed inhibit adipocyte differentiation, as shown morphologically, at the level of lipid droplet formation and on the expression of genetic markers of adipocytes. Furthermore, the intensity of this inhibitory effect was found to strongly positively correlate with the extent of drug accumulation in adipocytes, with their affinity for phospholipid membranes, as well as with their ability to induce phospholipidosis and inhibit autophagy. PMID- 29627312 TI - [Does heliox administered by low-flow nasal cannula improve respiratory distress in infants with respiratory syncytial virus acute bronchiolitis? A randomized controlled trial]. AB - OBJECTIVES: The aim of our study is to evaluate whether the use of heliox (79:21) delivered through a low flow nasal cannula would improve respiratory distress in infants with acute bronchiolitis caused by respiratory syncytial virus. METHODS: We have conducted a prospective randomized controlled study. All patients fulfilled inclusion criteria were randomized to either heliox (79:21) or air via NC at 2 L/min for a continuous 24hours. Measurements were taken at baseline, after 2hours and at the end of the 24hours. RESULTS: We have included 104 patients into our study. The MCA-S did not show any significant difference between the two groups after 2hours 4.3 vs. 4.1 (P =.78), or at 24hours after 4.2 vs. 4.3 (P =.89). No difference was found in the proportion of participants progressed to MV, n-CPAP or oxygen via nasal cannula (RR 1.0, 0.86 and 0.89) (P= 1.0, .77 and .73). There was no notable reduction in length of treatment in Heliox group 2.42 days vs. 2.79 days in air group P =.65. The in oxygen saturation, PaO2, and PaCO2 did not to have any statistical difference between the two studied groups after 2hours and 24hours of treatment. CONCLUSION: Our data showed absence of any beneficial effect of heliox in a concentration (79:21) delivered through low flow nasal cannula in terms of respiratory distress improvement in infants with RSV acute bronchiolitis. PMID- 29627313 TI - [Arthroderma benhamiae in patients with guinea pigs]. PMID- 29627314 TI - Understanding contextual barriers and enablers to pressure injury prevention practice in an Australian intensive care unit: An exploratory study. AB - BACKGROUND: Skin integrity management is often a low clinical priority in the intensive care environment, possibly resulting in high pressure injury (PI) prevalence. This article reports the results of the first phase of a multiphased project, "Translating evidence-based pressure injury prevention strategies to the intensive care environment (SUSTAIN study)". The SUSTAIN study used a research translation framework to guide the assessment of research uptake, development, and monitoring of translational strategies to reduce PIs. OBJECTIVE: The objective was to assess the enablers and barriers to research translation of evidence-based skin integrity management in one Australian tertiary referral intensive care unit (ICU). METHODS: This exploratory study was conducted in an Australian metropolitan tertiary ICU on a sample of 204 registered nurses. Data were collected using (i) a descriptive cross-sectional cohort survey of barriers, enablers, and attitudes to PI prevention, (ii) a cross-sectional survey of PI knowledge, and (iii) focus groups to understand the local contextual factors impacting registered nurses' PI prevention practice. RESULTS: Participants reported a moderate to high ability to rise above barriers in PI prevention, a positive attitude towards PI prevention, and considered this a priority in their care of patients. High patient acuity emerged as a barrier to implementing timely PI prevention strategies. In the knowledge, test participants with postgraduate qualifications answered more statements correctly. Focus group data revealed four themes: (i) team ICU, (ii) processes of care, (iii) education for consistency, and (iv) the patient. CONCLUSIONS: It is essential that evidence-based PI prevention strategies are provided in the intensive care environment. Our findings indicate that despite positive attitudes and sound knowledge levels, high patient acuity is a significant barrier to evidence implementation. PMID- 29627315 TI - A Decade of Never-smokers Among Lung Cancer Patients-Increasing Trend and Improved Survival. AB - BACKGROUND: It is not known whether clinicopathologic characteristics, treatment, and survival of never-smokers among lung cancer incident cases have changed over time. We assessed the trend and overall survival (OS) of these patients within our institution during a 10-year period. PATIENTS AND METHODS: We reviewed 2 cohorts of non-small-cell lung cancer patients with a diagnosis from 1999 to 2002 and from 2008 to 2011. The patient characteristics and OS were compared by smoking status within each cohort and between the 2 cohorts over time. RESULTS: Of the 992 patients in the 1999-2002 cohort and the 1318 patients in the 2008 2011 cohort, 902 and 1272 had a known smoking status, respectively. The proportion of never-smokers increased from 31% in 1999-2002 to 48% in 2008-2011 (P < .001). Within both cohorts, the differences in characteristics among never-, former-, and current-smokers have remained largely constant over time. A greater proportion of never-smokers had Eastern Cooperative Oncology Group performance status 0 to 1 and adenocarcinoma. The median OS increased from 15.5 months in 1999-2002 to 24.9 months in 2008-2011 (P = .001) for never-smokers, 12.3 to 15.9 months (P = .150) for former-smokers, and 10.5 to 13.9 months (P = .011) for current-smokers. The larger survival improvement among never-smokers was likely accounted for by the larger increase in never-smokers who were treated with tyrosine kinase inhibitors and pemetrexed over time. CONCLUSION: We found an increasing trend of never-smokers among incident lung cancer cases and improved survival for these patients during a 10-year period. The documentation of smoking status in any national cancer registry is vital to estimate the true incidence of lung cancer among never-smokers over time. PMID- 29627316 TI - KMT2D Mutation Is Associated With Poor Prognosis in Non-Small-Cell Lung Cancer. AB - BACKGROUND: Mixed-lineage leukemia protein 2 (MLL2 or KMT2D) is a histone methyltransferase whose mutation has been associated with a poor prognosis in cancer. We compared the characteristics and significance of KMT2D alterations in non-small-cell lung cancer (NSCLC) with those in small cell lung cancer (SCLC). PATIENTS AND METHODS: Tumors from 194 NSCLC patients with locally advanced or advanced disease and 64 SCLC patients underwent targeted-exome sequencing. The association of KMT2D mutation with overall survival (OS) and progression-free survival (PFS) was measured using Kaplan-Meier methods and further evaluated using multivariable Cox proportional hazards regression model adjusting for known clinical prognostic features. RESULTS: The KMT2D mutation rate was 17.5% (34 of 194) in NSCLC. Patients with mutant KMT2D had significantly lower median OS (9.97 vs. 30.2 months; P < .0001) and median PFS (8.46 vs. 24.1 months; P = .0004) compared with patients with wild-type KMT2D. The KMT2D mutation was significantly more common in females (P = .017). Using a multivariate Cox regression model, KMT2D mutation was one of the most significant prognostic factors in NSCLC: hazard ratio (HR) for OS, 2.79 (95% confidence interval [CI], 1.8-4.33; P < .0001) and HR for PFS, 1.99 (95% CI, 1.32-3.01; P = .001). In contrast, the KMT2D mutation rate in SCLC was 32.8% (21 of 64) and showed no sex bias (P = .874). No significant change was found in survival in association with the KMT2D mutation in SCLC (OS, P = .952; PFS, P = .744). CONCLUSION: The KMT2D mutation was associated with reduced survival in NSCLC but not in SCLC. PMID- 29627317 TI - Intestinal CART is a regulator of GIP and GLP-1 secretion and expression. AB - Impaired incretin effect is a culprit in Type 2 Diabetes. Cocaine- and amphetamine-regulated transcript (CART) is a regulatory peptide controlling pancreatic islet hormone secretion and beta-cell survival. Here we studied the potential expression of CART in enteroendocrine cells and examined the role of CART as a regulator of incretin secretion and expression. CART expression was found in glucose-dependent insulinotropic polypeptide (GIP)-producing K-cells and glucagon-like peptide-1 (GLP-1)-producing L-cells in human duodenum and jejunum and circulating CART levels were increased 60 min after a meal in humans. CART expression was increased by fatty acids and GIP, but unaffected by glucose in GLUTag and STC-1 cells. Exogenous CART had no effect on GIP and GLP-1 expression and secretion in GLUTag or STC-1 cells, but siRNA-mediated silencing of CART reduced GLP-1 expression and secretion. Furthermore, acute intravenous administration of CART increased GIP and GLP-1 secretion during an oral glucose tolerance test in mice. We conclude that CART is a novel constituent of human K- and L-cells with stimulatory actions on incretin secretion and that interfering with the CART system may be a therapeutic avenue for T2D. PMID- 29627318 TI - Enzymatic properties and the gene structure of a cold-adapted laminarinase from Pseudoalteromonas species LA. AB - We isolated a laminarin-degrading cold-adapted bacterium strain LA from coastal seawater in Sagami Bay, Japan and identified it as a Pseudoalteromonas species. We named the extracellular laminarinase LA-Lam, and purified and characterized it. LA-Lam showed high degradation activity for Laminaria digitata laminarin in the ranges of 15-50 degrees C and pH 5.0-9.0. The major terminal products degraded from L. digitata laminarin with LA-Lam were glucose, laminaribiose, and laminaritriose. The degradation profile of laminarioligosaccharides with LA-Lam suggested that the enzyme has a high substrate binding ability toward tetrameric or larger saccharides. Our results of the gene sequence and the SDS-PAGE analyses revealed that the major part of mature LA-Lam is a catalytic domain that belongs to the GH16 family, although its precursor is composed of a signal peptide, the catalytic domain, and three-repeated unknown regions. PMID- 29627320 TI - TRIM24 promotes hepatocellular carcinoma progression via AMPK signaling. AB - Hepatocellular carcinoma (HCC) is one of the most common cancers diagnosed worldwide. However, the mechanism underlying HCC pathogenesis remains unknown. In the present study, TRIM24 was found increased in human HCC clinical samples and positively correlated with HCC tumor grade. Furthermore, TRIM24 knockdown inhibits proliferation and migration in a human HCC cell line in vitro while also inhibiting tumor growth in vivo. Mechanistically, TRIM24 appears to promote liver tumor development via AMPK signaling as AMPK knockdown alleviated the in vitro and in vivo effects of TRIM24 knockdown in a human HCC cell line. Taken together, these data enhance our understanding of HCC development in addition to highlighting TRIM24-regulated AMPK signaling as a potential therapeutic target for HCC treatment. PMID- 29627319 TI - Whole cell immobilization of refractory glucose isomerase using tris(hydroxymethyl)phosphine as crosslinker for preparation of high fructose corn syrup at elevated temperature. AB - Glucose isomerase (GI) responsible for catalyzing the isomerization from d glucose to d-fructose, was an important enzyme for producing high fructose corn syrup (HFCS). In a quest to prepare HFCS at elevated temperature and facilitate enzymatic recovery, an effective procedure for whole cell immobilization of refractory Thermus oshimai glucose isomerase (ToGI) onto Celite 545 using tris(hydroxymethyl)phosphine (THP) as crosslinker was established. The immobilized biocatalyst showed an activity of approximate 127.3 U/(g.immobilized product) via optimization in terms of cells loading, crosslinker concentration and crosslinking time. The pH optimum of the immobilized biocatalyst was displaced from pH 8.0 of native enzyme to neutral pH 7.0. Compared with conventional glutaraldehyde (GLU)-immobilized cells, it possessed the enhanced thermostability with 70.1% residual activity retaining after incubation at 90 degrees C for 72 h. Moreover, the THP-immobilized biocatalyst exhibited superior operational stability, in which it retained 85.8% of initial activity after 15 batches of bioconversion at 85 degrees C. This study paved a way for reducing catalysis cost for upscale preparation of HFCS with higher d-fructose concentration. PMID- 29627321 TI - Reduced substrate stiffness promotes M2-like macrophage activation and enhances peroxisome proliferator-activated receptor gamma expression. AB - The increased stiffness of the extracellular microenvironment observed in cancer and atherosclerosis is thought to regulate the activation of tissue-resident immune cells. However, it remains to be determined whether such substrate stiffness affects macrophage activation phenotypes. Here, we have studied the impact of substrate stiffness on in vitro activation phenotypes of the human monocyte cell line THP-1. THP-1 cells were activated while being cultured on 1%, 4%, 10% agarose gel (soft substrate) or on a plastic plate (stiff substrate). We have shown that a soft, versus a stiff, substrate attenuates the pro-inflammatory activity of M1 promoting-activated THP-1 cells. In addition, we have found that M1-related marker expression and phagocytic activity was lower in THP-1 cells activated on a soft substrate compared to cells on stiff substrates. THP-1 cells alternatively activated on soft substrates showed enhanced M2-like phenotypes. We have found that peroxisome proliferator-activated receptor gamma (PPARgamma) expression was up-regulated in THP-1 cells activated on a soft substrate. We have shown that the PPARgamma antagonist GW9662 partially suppresses M2-like activation of THP-1 cells activated on a soft substrate. Substrate stiffness is, therefore, an important factor in regulating the balance of the pro-inflammatory M1 and anti-inflammatory M2 activation phenotypes. PMID- 29627322 TI - Lipopeptide daptomycin: Interactions with bacterial and phospholipid membranes, stability of membrane aggregates and micellation in solution. AB - Daptomycin is a cyclic lipopeptide effective against multidrug Gram-positive bacteria. Despite having a net negative charge, it is selective against negatively charged bacterial membranes. It has been established that daptomycin's antibiotic activity is based on directly targeting the bacterial membranes and that this antibacterial activity depends on calcium ions. Importantly, however, both the precise role of ions and the physical mechanisms responsible for daptomycin's action remain poorly understood. We investigate these issues using three types of molecular dynamics simulations: umbrella sampling free energy calculations for a single daptomycin, unbiased simulations for daptomycin tetramers, and unbiased simulations of micellation of daptomycin both in the absence and presence of calcium ions. The simulations are in the excess of 4 MUs. As the most important finding, we establish that binding of the calcium ions on the aspartic acid residues is the key to stabilizing daptomycin tetramers inside the model material membrane. These complexes are vital for daptomycin's antibacterial activity. In the absence of binding, the tetramer is not stable and moves slowly out of the membrane. We also demonstrate that in solution, micellation of daptomycin occurs both in the presence and absence of calcium ions, and discuss the similarities between the behaviors of daptomycin and amyloid peptides in membranes. PMID- 29627324 TI - From excitation to intracellular Ca2+ movements in skeletal muscle: Basic aspects and related clinical disorders. AB - In skeletal muscle fiber, excitation-contraction coupling corresponds to the sequence of events occurring from action potential firing to initiation of contraction by an increase in cytosolic Ca2+. These events are elicited in response to excitation of the motor neuron which induces trains of action potentials in the muscle cell that spread along the sarcolemma and in depth along the T-tubule membrane. Depolarization of the T-tubule membrane induces a conformational change in a protein complex, called the dihydropyridine receptor, which opens a calcium channel anchored in the membrane of the sarcoplasmic reticulum, called the ryanodine receptor, in charge of release of Ca2+ ions that activate contractile proteins. Ryanodine receptors shut upon return of the T tubule membrane potential to its resting value and muscle cell relaxation results from the removal of cytosolic Ca2+ that is pumped back into the SR lumen through the sarcoplasmic reticulum Ca2+ ATPase. Mutations in genes encoding either plasma membrane ion channels, the main subunit of the dihydropyridine receptor, ryanodine receptor, sarcoplasmic reticulum Ca2+ ATPase or proteins interfering with trans-sarcolemmal Ca2+ influx or sarcoplasmic reticulum Ca2+ efflux lead to clinical disorders that manifest as myotonia, muscle weakness, paralysis or muscle wasting. PMID- 29627323 TI - Apoptosis signal regulating kinase-1 and NADPH oxidase mediate human amylin evoked redox stress and apoptosis in pancreatic beta-cells. AB - Misfolded toxic human islet amyloid polypeptide or amylin (hA) and plasma membrane-associated redox complex, NADPH oxidase (NOX), have been implicated in the islet beta-cell demise associated with type-2 diabetes mellitus (T2DM). Studies show that hA accumulation is stressful to beta-cells and that misfolding of human amylin evokes redox stress and activates mitogen activated protein (MAP) kinases, p38 MAPK and c-Jun N-terminal (JNK) kinase. However, the molecular link and causality between hA-evoked redox stress, NOX activity and MAP kinases signaling in pancreatic beta-cells is incompletely understood. Here, we show that in the process of activating JNK, aggregation prone hA also activates an upstream apoptosis signal regulating kinase-1 (ASK1) with concomitant decrease in intracellular levels of reduced glutathione. Inhibition of ASK1 kinase activity, either by specific ASK1 inhibitor, NQDI1 or by thiol antioxidants reduces human amylin-evoked ASK1 and JNK activation and consequently human amylin toxicity in rat insulinoma Rin-m5F cells and human islets. beta-cell specific overexpression of human amylin in mouse islets elicited ASK1 phosphorylation and activation in beta-cells but not in other rodent's islet or exocrine cells. This ASK1 activation strongly correlated with islet amyloidosis and diabetes progression. Cytotoxic human amylin additionally stimulated pro-oxidative activity and expressions of plasma membrane bound NADPH oxidase (NOX) and its regulatory subunits. siRNA mediated NOX1 knockdown and selective NOX inhibitors, ML171 and apocynin, significantly reduced hA-induced mitochondrial stress in insulinoma beta-cells. However, NOX inhibitors were largely ineffective against hA-evoked redox stress and activation of cytotoxic ASK1/JNK signaling complex. Thus, our studies suggest that NOX1 and ASK1 autonomously mediate human amylin-evoked redox and mitochondrial stress in pancreatic beta-cells. PMID- 29627325 TI - Shifts in the relationship between mRNA and protein abundance of gill ion transporters during smolt development and seawater acclimation in Atlantic salmon (Salmo salar). AB - Smolting Atlantic salmon exhibit a seasonal increase in seawater tolerance that is associated with changes in the abundance of major gill ion-transporter transcripts and proteins. In the present study, we investigate how the transcript and protein abundance of specific ion-transporter isoforms relate to each other during smolt development and seawater acclimation, and how each correlates to seawater tolerance. We show that during smolt development both mRNA and protein abundance of gill Na+/K+-ATPase alpha1a subunit (NKAalpha1a) decreased but the decrease in the mRNA was five-times greater than that of the protein. Gill NKAalpha1b mRNA levels increased only slightly (1.5-fold) throughout development whereas protein abundance increased 30-fold at its peak. Gill Na+/K+/2Cl- co transporter 1 (NKCC1) increased at the mRNA and protein level (5- and 12-fold) in smolts. The abundance of a gill ion-transporter's mRNA and protein changed in the same direction through development and after seawater transfer, but the changes were not always strongly correlated: NKAalpha1a (r = 0.768), NKAalpha1b (r = 0.40), and NKCC1 (r = 0.898). The maintenance of plasma chloride concentration correlated most strongly with the abundance of NKAalpha1a mRNA, and the ratio of NKAalpha1b to NKAalpha1a mRNA and protein. Growth performance after seawater transfer correlated most strongly with the abundance of NKAalpha1b protein and the ratio of NKAalpha1b to NKAalpha1a protein. Our results indicate that the abundance of ion-transporter mRNA and protein do not always correlate well and a decrease in the abundance of gill NKAalpha1a mRNA and increase in NKAalpha1b protein are strong predictors of seawater tolerance and growth performance after seawater transfer. PMID- 29627326 TI - One percent chlorhexidine-alcohol for preventing central venous catheter-related infection during intensive chemotherapy for patients with haematologic malignancies. AB - A central venous catheter (CVC) is a catheter placed into a large vein, and is used for chemotherapy administration. However, there is little confirmatory data on which antiseptic-such as chlorhexidine or povidone-iodine (PI) -is more protective against CVC-related infectious complications in patients receiving intensive chemotherapy. We aimed to compare the effectiveness of 1% chlorhexidine gluconate in 70% alcohol (CH) vs. PI for skin disinfection before CVC insertion in patients receiving intensive chemotherapy. Methods We used either CH or 10% PI as skin antiseptics before CVC insertion, and assessed which agent was more protective against CVC-related infection. The participants were 112 patients with haematologic malignancies who underwent chemotherapy; a total of 292 CVCs were inserted over this period. Blood cultures were obtained when febrile neutropenia occurred. The CVC was removed and the catheter-tip qualitatively cultured when catheter-related infection was suspected. The cumulative incidence of febrile neutropenia, microbial growth from blood or catheter-tip culture, and catheter related blood stream infection (CRBSI) was evaluated retrospectively. A univariate Cox proportional hazards model showed that CH significantly alleviated infectious complications. Notably, no case of CRBSI occurred in the CH group. Multivariate analysis, adjusted for prolonged neutropenia (>15 days) and older age (>52 years), also showed significant reduction in the cumulative incidence of microbial growth from catheter-tips in the CH group (hazard ratio = 0.146, 95% confidence interval: 0.023-0.502, p = 0.0008). Disinfection using CH, compared with PI, can potentially decrease catheter-related infection without causing adverse skin reactions in patients with haematologic malignancies. PMID- 29627327 TI - Macrolide and fluoroquinolone resistance is uncommon in clinical strains of Chlamydia trachomatis. AB - We analyzed the 23S rRNA, gyrA and parC genes of Chlamydia trachomatis DNAs from men with urethritis and determined microbiological outcomes of an extended release azithromycin (azithromycin-SR) regimen (2 g once daily for 1 day) and a sitafloxacin regimen (100 mg twice daily for 7 days) for chlamydial urethritis to clarify the macrolide and fluoroquinolone resistance status of clinical strains of C. trachomatis. We amplified the portions of 2 alleles of the 23S rRNA gene and the gyrA and parC genes from C. trachomatis DNAs in 284 first-voided urine specimens from men with chlamydial urethritis by PCR and sequenced their PCR products. We enrolled 369 men with chlamydial urethritis, comprising 314 and 55 treated with the azithromycin-SR regimen and the sitafloxacin regimen, respectively. Alleles 1 and/or 2 of the 23S rRNA gene were analyzed in 162 specimens. No mutations were found in the sequenced regions, including the central portion of domain V. The gyrA and parC genes were analyzed in 118 and 113 specimens, respectively. No amino acid changes were found within the quinolone resistance-determining region of the gyrA gene and in the sequenced region of the parC gene. The microbiological outcomes of the azithromycin-SR and sitafloxacin regimens were assessed in 176 and 30 men, respectively. The eradication rates were 96.0% (95% CI 93.1%-98.9%) for the azithromycin-SR regimen and 100% for the sitafloxacin regimen. Clinical strains of C. trachomatis with macrolide and/or fluoroquinolone resistance would be uncommon, and azithromycin or fluoroquinolone regimens could be recommended as treatments for chlamydial infections. PMID- 29627328 TI - Toxoplasma gondii as a possible causative pathogen of type-1 diabetes mellitus: Evidence from case-control and experimental studies. AB - Toxoplasma gondii is the causative parasite of an important worldwide disease. This obligate intracellular parasite can infect and replicate inside any nucleated cells including those of pancreas. Insulin is a hormone secreted by the pancreas and is responsible for controlling blood glucose concentration. Deficiency of insulin production accounts for the occurrence of type-1 diabetes mellitus (T1D). Thus, theoretically, toxoplasmosis could play a possible role in the development of T1D. However, the studies on this theory are still insufficient; therefore, this work was designed. Interestingly, in the case control study, seropositivity of anti-Toxoplasma IgG was significantly higher among T1D (86.37%) in comparison with T2D (66.67%) and the control group (60%). Moreover, the odd ratio of chronic toxoplasmosis was 4.2 folds higher among T1D patients than among controls. The experimental study included acute and chronic Me49 T. gondii infected mice groups in addition to a control group. Pathological examination revealed the presence of T. gondii zoites adjacent to the islets of Langerhans and in pancreatic parenchyma of acutely infected mice. With chronic infection, there was a significant reduction of islets number and sizes in association with grade-1 insulitis. Additionally, the immunohistochemical study showed significant infiltration of the islets of chronically infected mice by CD8+ and CD45+ immune cells. In contrary to the control group, the islets of the chronic group showed significantly higher expression of the apoptotic marker caspase-3 and a significantly lower expression of the proliferation marker Ki69. Finally, a significant reduction of insulin expression in the islets of chronic infection group was detected in association with a significant increase in serum glucose concentrations; however, the establishment of diabetes did not occur throughout this work. Thus, this study presents an evidence for the probable role of chronic toxoplasmosis in the development of T1D which should be considered in further studies. PMID- 29627329 TI - Molecular identification of Giardia intestinalis in two cities of the Colombian Caribbean Coast. AB - INTRODUCTION: Parasitoses are an important health problem and its post-infectious consequences can cause high morbidity and mortality, worldwide. Epidemiological data is scarce in our region. We aimed to obtain frequency and circulating genotypes of Giardia intestinalis in two cities of the Caribbean Coast. METHODS: To identify parasites in samples, a fecal concentration and microscopical examination were performed. For further identification and genotyping of G. intestinalis, molecular analyses were performed using specific available primers. RESULTS: Only 22.1% of participants had gastrointestinal symptoms (most frequently: abdominal pain and diarrhea). Microscopy examination was positive in 72.7% of the samples. The most frequent parasite was G. intestinalis (48.1%) and we found mixed parasitic infections in 46.7% of the participants. All the samples from Santa Marta were molecularly characterized as assemblage A of G. intestinalis, while in Cartagena we confirmed the presence of assemblages A and B. CONCLUSIONS: Molecular tools are important in the diagnosis of parasites and to increase comprehension of their distribution. In this study, a higher frequency of parasites, mostly protozoa, was observed. PMID- 29627330 TI - Traffic Light System Can Increase Healthfulness Perception: Implications for Policy Making. AB - OBJECTIVE: To evaluate how information about low nutrient content included in the traffic light labeling system influences consumers' perception of the healthfulness of products with high content of 1 key nutrient, and to compare the traffic light system with warnings in terms of the perception of healthfulness. DESIGN: Images of front-of-pack (FOP) nutrition labels (the traffic light labeling system with different numbers of nutrients with low content, and warnings) were evaluated in study 1, whereas product labels featuring the different FOP nutrition labels were evaluated in study 2. SETTING: Online studies conducted in Montevideo, Uruguay. PARTICIPANTS: A total of 1,228 Uruguayan Facebook users. MAIN OUTCOME MEASURES: Perception of healthfulness. ANALYSIS: The researchers used ANOVA to evaluate the influence of FOP nutrition labels on perceived healthfulness. RESULTS: The inclusion of information about low nutrient content in the traffic light system statistically significantly increased the perception of the healthfulness of products with high nutrient content. Nutritional warnings showed healthfulness ratings similar to those of the simplified version of the traffic light system. CONCLUSIONS AND IMPLICATIONS: Information about low nutrient content in the traffic light system might be used to infer health, and thus could raise the perception of healthfulness and decrease the traffic light system's efficacy in discouraging the consumption of unhealthful products. A simplified version of the traffic light highlighting only high-nutrient content or nutritional warnings seems to overcome this problem. PMID- 29627331 TI - A Community-Based Physical Activity Program May Increase Sustained Physical Activity at 2 Years and Reduce the Risk of Adverse Cardiovascular Events in Older Adults. PMID- 29627332 TI - Corrigendum to "Raman studies of nanocomposites catalysts: temperature and pressure effects of CeAl, CeMn and NiAl oxides" [Spectrochim. Acta A Mol. Biomol. Spectrosc. 198 (2018) 160-167]. PMID- 29627333 TI - Assessment of culture and environment in the Adolescent Brain and Cognitive Development Study: Rationale, description of measures, and early data. AB - Neurodevelopmental maturation takes place in a social environment in addition to a neurobiological one. Characterization of social environmental factors that influence this process is therefore an essential component in developing an accurate model of adolescent brain and neurocognitive development, as well as susceptibility to change with the use of marijuana and other drugs. The creation of the Culture and Environment (CE) measurement component of the ABCD protocol was guided by this understanding. Three areas were identified by the CE Work Group as central to this process: influences relating to CE Group membership, influences created by the proximal social environment, influences stemming from social interactions. Eleven measures assess these influences, and by time of publication, will have been administered to well over 7,000 9-10 year-old children and one of their parents. Our report presents baseline data on psychometric characteristics (mean, standard deviation, range, skewness, coefficient alpha) of all measures within the battery. Effectiveness of the battery in differentiating 9-10 year olds who were classified as at higher and lower risk for marijuana use in adolescence was also evaluated. Psychometric characteristics on all measures were good to excellent; higher vs. lower risk contrasts were significant in areas where risk differentiation would be anticipated. PMID- 29627334 TI - Preoperative Risk Score to Predict Occult Metastatic or Locally Advanced Disease in Patients with Resectable Perihilar Cholangiocarcinoma on Imaging. AB - BACKGROUND: Many patients with resectable perihilar cholangiocarcinoma (PHC) on imaging are diagnosed intraoperatively with occult metastatic or locally advanced disease, precluding a curative-intent resection. This study aimed to develop and validate a preoperative risk score. STUDY DESIGN: Patients with resectable PHC on imaging who underwent operations in 2 high-volume centers (US and Europe) between 2000 and 2015 were included. Multivariable logistic regression analysis was used to develop the risk score. Cross-validation was used to validate the score, alternating the 2 centers as "training" and "testing" datasets. RESULTS: Of 566 patients who underwent operations, 309 (55%) patients had a resection, and in 257 (45%) patients, a curative-intent resection was precluded due to distant metastasis (n = 151 [27%]) or locally advanced disease (n = 106 [19%]). Preoperative predictors included bilirubin >2 mg/dL, bile duct involvement on imaging, portal vein involvement on imaging (>=180 degrees), hepatic artery involvement on imaging (>=180 degrees), and suspicious lymph nodes on imaging. The new risk score (c-index 0.75 after cross-validation) provided significantly more accurate predictions than the Bismuth classification (c-index 0.62), Blumgart T-staging (c-index 0.67), and cTNM staging (c-index 0.68). The new risk score identified 4 risk groups for occult metastatic or locally advanced disease: low (14.7%), intermediate (29.5%), high (47.3%), and very high risk (81.3%). The preoperative score groups also predicted survival after operation, irrespective of intraoperative findings (p < 0.001). CONCLUSIONS: The validated risk score can predict occult distant metastatic or locally advanced PHC based on 5 preoperatively available factors. The score can be useful in preoperative shared decision making and selection of patients in neoadjuvant clinical trials. PMID- 29627335 TI - On-site detection of equid alphaherpesvirus 3 in perineal and genital swabs of mares and stallions. AB - Equine coital exanthema (ECE) is an infectious, venereally transmitted muco cutaneous disease affecting mares and stallions, caused by equid alphaherpesvirus 3 (EHV3). Diagnostic tools for rapid identification of EHV3 are of primary importance to diminish the risk of EHV3 dissemination at the time of breeding. In the last years, it has been shown that the performance of the insulated isothermal polymerase chain reaction (iiPCR) is comparable to virus isolation, nested PCR and real-time PCR (qPCR) in detecting pathogens of various animal species. Analytical sensitivity and specificity of the iiPCR were compared with a qPCR, using a plasmid containing the target region of the EHV3 glycoprotein G gene and an Argentinian EHV3 isolate (E/9283/07 C3A). In order to evaluate the diagnostic performance of the iiPCR, nucleic acids of 85 perineal and genital swabs (PGS) of mares and stallions were extracted by tacoTM mini and tested by both techniques. EHV3 was detected in 46 and 45 of the 85 PGS by the iiPCR and qPCR, respectively. There was almost perfect agreement between the two diagnostic methods (98.82%; 95% CI: 95.03-100%; kappa = 0.98). The iiPCR had a limit of detection of 95.00% at 6 genome equivalents per reaction and a detection endpoint for viral DNA comparable to that of the qPCR, and did not react with six non targeted equine pathogens. The iiPCR represents a sensitive and specific method for the rapid on-site diagnosis of EHV3 infection. Its routinely implementation in breeding facilities, and artificial insemination and embryo transfer centers, will contribute to prevent the dissemination of this venereal, highly contagious disease in horses. PMID- 29627336 TI - Real-time analysis of the cytopathic effect of African swine fever virus. AB - Conventional methods, which quantitatively assess virus replication, are based on direct examination of viral cytopathic effect (CPE), which is time consuming, tedious and based on endpoint reading. The Real-Time Cell Analysis (RTCA) xCELLigence(r) system offers an alternative approach to evaluate virus-induced CPE, and here was evaluated as a means to dynamically assess CPE caused by African swine fever virus (ASFV). RTCA was used to identify optimum time for ASFV infection based on cell index (CI) and to evaluate ASFV CPE kinetics in COS-1 cells. Data indicated that the RTCA has tremendous potential to methodologically and quantitatively improve assays used to study efficiency of ASFV drug inhibitors and neutralizing antibodies. PMID- 29627337 TI - Commentary: Moving beyond surveys to assess patient preferences. PMID- 29627338 TI - A comparative review on estrogen receptors in the reproductive male tract of non mammalian vertebrates. AB - Estrogen receptors alpha (ERalpha) and beta (ERbeta) are transcription factors known to be involved in the regulation of many complex physiological processes in mammals. They are expressed primarily in the reproductive tract of all vertebrates females, thus indicating important and conserved functions in female reproductive success. ERs are also present in physiological different tissues as bone, brain, liver, skin and adipose tissues, in both females and males. In the latter, ERs have been found also in the genital tract, supporting the findings of a complex role for estrogen in spermatogenesis and, more generally, in male reproduction. This review provides an overview and update on ERalpha and ERbeta expression and synthesis in male reproductive tract of non-mammalian vertebrates, with focus on their role in germ cells proliferation, maturation and survival. Data from studies on fish, amphibians, reptiles and birds were collated and common or species-specific distribution highlighted. The widespread distribution of estrogen receptors in testicular cells and ducts of all vertebrates so far investigated suggests that whatever are the roles that estrogens may exert on these structures, they are phylogenetically conserved and are possibly related to the physiological support given to achieve male reproductive success. PMID- 29627339 TI - [Results of anastomotic urethroplasty for male urethral stricture disease]. AB - OBJECTIVE: To report our experience with anastomotic uretroplasty (AU) due to male urethral stricture disease (USD) and to identify factors affecting the results. PATIENTS AND METHODS: We conducted a retrospective study over a period of 4 years and 6 months (July 2012 to December 2016). Any subsequent use of endoscopic urethrotomy or new urethroplasty was considered a failure. RESULTS: Forty-eight cases were included. The mean age of patients was 53.5+/-17.3 years (23-87 years). Urinary retention was the reason for consultation in 42 cases (87.5%). The most common localization of USD was the bulbar urethra (n=45). The mean length of USD was 1.23+/-0.62cm (0.5-3cm) with a median length of 1cm. The etiology was post-infectious in 56.3% of cases. More than half (58.3%) of patients had already undergone at least one urethral manipulation. After an average follow-up of 21.1+/-12.6 months (1 to 52 months), the overall success rate was 77.1%. In univariate analysis, length, cause and location of the stricture, age of patient, the presenting symptoms of the stricture, previous urethral manipulation and surgeon experience did not significantly impact on the success rate of anastomotic urethroplasty at one and two years follow-up. CONCLUSION: The AU had provided good results in our practice. The infectious origin of the stricture and previous urethral manipulation did not significantly impact the result of this surgical technique. LEVEL OF EVIDENCE: 4. PMID- 29627341 TI - Neonatal inflammation induces reorganization in dendritic morphology of retinal ganglion cells but not their retinogeniculate projection in mice. AB - Perinatal inflammatory insult in preterm babies is associated with vision impairment, but the underlying cellular mechanism is still unknown. In this study, we set out to explore whether systemic inflammatory stress affects the development of retinal ganglion cells (RGCs). Neonatal inflammation was induced by single and systemic injection of lipopolysaccharide (LPS, 1 mg/kg) at postnatal day 4 (P4). Morphological changes of RGCs were investigated by using 3D neuron reconstruction technique in Thy-1 YFPH transgenic mice at P21, of which a fraction of RGCs selectively expresses the yellow fluorescent protein (YFP). Three types (Type I, II, III) of RGCs were distinguished and classified according to the characteristic features in their dendritic field area and dendrite density. Neonatal exposure to LPS did not alter the composition of the three RGC types but induced a reorganization of dendritic architecture in the RGC Type I and II (but not Type III). The average diameter, surface area and volume of dendrites in both RGC Type I and II were increased after systemic inflammation compared with those in the control group. However, soma sizes of all three RGC types were not affected by neonatal inflammation. Meanwhile, using anterograde labeling of the retinal cells, we found that neonatal exposure to LPS also did not affect the pattern of RGC projections in the dorsal lateral geniculate nucleus of the thalamus (dLGN). These results indicate that RGC dendrite reorganization induced by neonatal inflammation may contribute to the retinal cell dysfunctions associated with systemic inflammation in premature babies. PMID- 29627340 TI - Deregulation of autophagy and vesicle trafficking in Parkinson's disease. AB - Parkinson's disease (PD) is a common neurodegenerative disease characterized pathologically by the selective loss of dopaminergic neurons in the substantia nigra and the intracellular accumulation of alpha-synuclein in the Lewy bodies. While the pathogenic mechanisms of PD are poorly understood, many lines of evidence point to a role of altered autophagy and membrane trafficking in the development of the disease. Emerging studies show that connections between the deregulation of autophagy and synaptic vesicle (SV) trafficking may contribute to PD. Here we review the evidence that many PD related-genes have roles in both autophagy and SV trafficking and examine how deregulation of these pathways contributes to PD pathogenesis. This review also discusses recent studies aimed at uncovering the role of PD-linked genes in autophagy-lysosome function. PMID- 29627342 TI - Blockade of alpha2-adrenergic or metabotropic glutamate receptors induces glutamate release in the locus coeruleus to activate descending inhibition in rats with chronic neuropathic hypersensitivity. AB - Locus coeruleus (LC)-spinal noradrenergic projections are important to endogenous analgesic mechanisms and can be activated by local glutamate signaling in the LC. The current study examined the local glutamatergic, GABAergic, and noradrenergic influences on glutamate release in the LC and noradrenergic descending inhibition in rats 6 weeks after spinal nerve ligation (SNL). Intra-LC injection of the alpha2 adrenoceptor antagonist idazoxan or the group 2 metabotropic glutamate receptor (mGluR) antagonist (RS)-alpha-Methyl-4-tetrazolylphenylglycine (MTPG) increased withdrawal thresholds in SNL animals and this was reversed by the blockade of alpha-amino-3-hydroxy-5-methyl- 4-isoxazolepropionic acid (AMPA) receptors in the LC or alpha2-adrenoceptors in the spinal cord, but not in normal animals. Neither blockade of GABA-A nor GABA-B receptors in the LC affected withdrawal thresholds in normal and SNL animals. Intra-LC perfusion of idazoxan increased extracellular glutamate in the LC in SNL animals but not in normal animals. Intra-LC perfusion of MTPG increased extracellular glutamate in the LC in both normal and SNL animals. These results suggest that local noradrenaline and glutamate tonically inhibit glutamate release in the LC after peripheral nerve injury and this may contribute to reduced descending inhibition in response to noxious input during chronic neuropathic pain. PMID- 29627345 TI - A spontaneous binge-like eating model in mice using unpredictable once weekly access to palatable diets. AB - Many pre-clinical models of binge-like eating involve predictable, scheduled, access to a palatable diet high in fat (HF), where access may be preceded by anticipatory behaviour. Here, to introduce spontaneity into the binge-type consumption of palatable diets, mice were allowed 2 h access on a random day once per week and at a random time within an 8 h window either side of the transition from dark phase to light phase. Despite normal intake of a stock diet prior to unpredictable access to HF diet, mice immediately initiated a substantial eating episode when presented with HF diet. Following this consumption, compensatory hypophagia was observed relative to stock diet-fed controls, and cumulative energy intakes converged. There were no effects of HF diet on body weight or body composition over a 12-week period. Binge-like consumption was also observed on unpredictable access to the complete liquid diet, chocolate Ensure, but not with a 10% sucrose solution. Binge-like responses to unpredictable access to HF diet or Ensure were similar in male and female mice, although there were effects of sex on caloric consumption from stock diet in the compensatory period following palatable diet intake, with higher intakes in females. The timing of the 2h access period relative to light phase transition affected intake of palatable diets, but less robustly than the equivalent effect on stock diet intake during the same timed periods - the diurnal patterning of energy intake was diet sensitive. The large spontaneous binge-like consumption on unpredictable access to either solid or liquid palatable diets in mice of either sex offers the potential to combine these attributes with other manipulations where a developing obesity is part of the binge-like eating phenotype. PMID- 29627344 TI - WITHDRAWN: Corrigendum to 'Development of an Italian RM Y-STR haplotype database: results of the 2013 GEFI collaborative exercise' [Forensic. Sci. Int. Genet. 15 (2015) 56-63]. PMID- 29627346 TI - The effect of sugar-sweetened beverage price increases and educational messages on beverage purchasing behavior among adults. AB - There is a paucity of evidence regarding the impact of sugar sweetened beverage (SSB) price increases on beverage consumption, using individual-level data, for the population overall and for different socioeconomic groups. This study aimed to predict the impact of altered beverage prices and educational messages on consumer purchasing behavior. 2020 adults representative of the Australian population by age, gender and income completed a discrete choice experiment online in 2016. Each subject completed 20 choice scenarios in a hypothetical convenience store setting where subjects chose between seven SSB and non-SSB beverage options or a no beverage option. Beverage prices and volumes varied between scenarios. Half of participants (n = 1012) were randomly exposed to an educational poster discouraging SSB consumption prior to completing choice scenarios. We used discrete choice models to predict purchases under several policy proposals, overall and for income and SSB consumption frequency sub groups. Compared to baseline prices, a 10% SSB price increase was predicted to reduce SSB purchases by 15.0% [95%CI -15.2, -14.7], and increase purchases of non SSBs by +11.0% [95%CI 10.8, 11.2] and no beverage by +15.5% [95%CI 15.1, 15.9]. Effects were greater with a 20% SSB price increase. Across all policy scenarios, the highest income quintile had a similar absolute and slightly greater relative decrease in SSB purchases compared to the lowest quintile. Educational poster exposure reduced SSB choice for all groups, with a greater reduction in the lower compared to higher income group, and additively increased response to price changes. Our results support the use of population-wide SSB pricing and educational interventions to reduce demand across all income groups. PMID- 29627348 TI - The Acute Treatment of Methemoglobinemia in Pregnancy. AB - BACKGROUND: Methemoglobinemia can be a potentially lethal condition due to the hypoxic stress placed on the body. In pregnancy, the deleterious effects can be even more catastrophic. The benefits of treatment in all patients, especially in those who are pregnant, must outweigh the inherent risks of the therapies used to treat methemoglobinemia. CASE REPORT: We present a case of a 26-year-old Hispanic pregnant female at 30 weeks gestation presenting to the emergency department for chest pain, hypoxia, and cyanosis. She was subsequently diagnosed with methemoglobinemia, treated with methylene blue, and admitted to the intensive care unit with toxicology and obstetrics consultations. As an outpatient, the patient underwent genetic testing and was diagnosed with homozygous cytochrome b5 reductase deficiency as the etiology of the methemoglobinemia. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Methemoglobinemia is a rare, potentially lethal, but treatable condition. In the setting of pregnancy, methemoglobinemia can pose a significant risk to the mother and fetus by causing acute hypoxia. Because methemoglobinemia can be acquired or congenital, treatments vary based on the etiology. Methylene blue is the mainstay treatment for symptomatic methemoglobinemia of levels > 20%. The teratogenic risks of methylene blue require risk-benefit analysis and discussion with the patient before utilization. Systemic maternal administration is theorized to be of lowest risk to the fetus. In this case, methylene blue was used safely as an emergent therapy for congenital methemoglobinemia during pregnancy. PMID- 29627349 TI - Recurrent Ethylene Glycol Poisoning with Elevated Lactate Levels to Obtain Opioid Medications. AB - BACKGROUND: Malingering is when a patient feigns illness for secondary gain. While most patients with malingering manufacture or exaggerate symptoms, some patients may induce illness. Previous reports of malingering patients inducing illness include sepsis, kidney pain, migraine, and chest pain. However, acute poisoning as a manifestation of malingering appears to be rare. CASE REPORT: We describe the case of a 39-year-old man who presented to the emergency department complaining of diffuse body pain. The patient reported multiple admission at outside hospitals for "lactate" and said, "it feels like it is happening again because of how my body feels." Laboratory findings were concerning for serum lactate of >20.0 mmol/L and ethylene glycol (EG) level of 19 mg/dL. A chart review found that the man had been admitted for elevated serum lactate 8 times to area hospitals in several years, often in the setting of EG poisoning. During these episodes he required intravenous fluids and frequent intravenous pain medications. When confronted about concern regarding the recurrent fallacious lactate levels in the setting of factitious EG ingestion, the patient often became combative and left against medical advice. The primary metabolite of EG, glycolic acid, can interfere with lactate assays, causing a false elevation. Our patient apparently recognized this and took advantage of it to be admitted and receive intravenous opioids. This is the only case known to us of malingering via EG ingestion. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians should be aware that metabolites of EG may interfere with serum lactate assay. In addition, they should be aware of possible malingering-related poisoning and plausible association with requests for intravenous opioid pain medications. This represents a risk to the patient and others if undiagnosed. PMID- 29627350 TI - Bedside Ultrasound Diagnosis of Complete Achilles Tendon Tear in a 25-Year-Old Man with Calf Injury. PMID- 29627347 TI - TRPA1 mediates the cardiac effects of acrolein through parasympathetic dominance but also sympathetic modulation in mice. AB - Numerous studies have demonstrated that short-term air pollution exposure causes cardiac autonomic imbalance as measured by heart rate variability (HRV). We previously showed that a single exposure to acrolein, a ubiquitous gaseous component of air pollution, not only causes autonomic imbalance, but also increases arrhythmia through transient receptor potential A1 (TRPA1) cation channels. Thus, the goal of this study was to characterize acrolein-induced autonomic changes in both normal and TRPA1-knockout mice (KO). Conscious, unrestrained C57BL/6 (WT) and KO mice were exposed to 3 ppm acrolein for 3 h. Separate groups were treated with either atenolol (sympathetic blocker), atropine (parasympathetic blocker) or hexamethonium (autonomic neurotransmission blocker), immediately before exposure. Electrocardiogram (ECG) and heart rate (HR) were recorded continuously before, during and after exposure. Exposure to acrolein produced significant increases in standard deviation of normal-to-normal R-R intervals (SDNN), Root Mean Square of the Successive Differences (RMSSD) and Low Frequency (LF), as well as an increase in arrhythmia in WT mice. Treatment with atenolol reduced this response while atropine enhanced it, and both drugs blocked the acrolein-induced increase in arrhythmia; hexamethonium had no effect. On the other hand, neither acrolein nor any drug had an effect in the KO mice. Thus, acrolein-induced HRV responses appear to be mediated by a combined parasympathetic and sympathetic modulation. KO mice did not demonstrate any increases in HRV with exposure to acrolein. These data demonstrate that the cardiac effects of irritant air pollutants likely involve disruption of homeostatic balance and altered regulation even in healthy animals. PMID- 29627343 TI - Omega-3 fatty acids, membrane remodeling and cancer prevention. AB - Proteins are often credited as the macromolecule responsible for performing critical cellular functions, however lipids have recently garnered more attention as our understanding of their role in cell function and human health becomes more apparent. Although cellular membranes are the lipid environment in which many proteins function, it is now apparent that protein and lipid assemblies can be organized to form distinct micro- or nanodomains that facilitate signaling events. Indeed, it is now appreciated that cellular function is partly regulated by the specific spatiotemporal lipid composition of the membrane, down to the nanosecond and nanometer scale. Furthermore, membrane composition is altered during human disease processes such as cancer and obesity. For example, an increased rate of lipid/cholesterol synthesis in cancerous tissues has long been recognized as an important aspect of the rewired metabolism of transformed cells. However, the contribution of lipids/cholesterol to cellular function in disease models is not yet fully understood. Furthermore, an important consideration in regard to human health is that diet is a major modulator of cell membrane composition. This can occur directly through incorporation of membrane substrates, such as fatty acids, e.g., n-3 polyunsaturated fatty acids (n-3 PUFA) and cholesterol. In this review, we describe scenarios in which changes in membrane composition impact human health. Particular focus is placed on the importance of intrinsic lipid/cholesterol biosynthesis and metabolism and extrinsic dietary modification in cancer and its effect on plasma membrane properties. PMID- 29627351 TI - Placental Growth Factor informed management of suspected pre-eclampsia or fetal growth restriction: The MAPPLE cohort study. AB - OBJECTIVES: Placental Growth Factor (PlGF) has been shown to be beneficial in diagnosing pre-eclampsia. We performed a prospective cohort study of revealed PlGF in standard clinical use in four teaching hospitals in UK, Germany, Austria and Australia. STUDY DESIGN: Clinical data from women with suspected pre eclampsia or fetal growth restriction <35 weeks' gestation with revealed PlGF measurement were collected (MAPPLE study). MAIN OUTCOME MEASURES: Data were compared to the PELICAN study (PlGF concealed). Pre-specified outcomes were compared using standard statistical tests (median difference or Risk Ratio). The results were further categorised by PlGF concentration: i) very low (<12 pg/ml), ii) low (12-100 pg/ml), iii) normal (>100 pg/ml). RESULTS: 396 women managed with revealed PlGF (MAPPLE) were compared with 287 women with concealed PlGF (PELICAN). Revealed PlGF led to delivery 1.4 weeks earlier (-2.0 to -0.9, 34.9 weeks vs 36.7 weeks). There were no significant differences in maternal adverse outcomes (11.9% vs 10.1%, Risk Ratio (RR) 1.17, 95% CI 0.76-1.82) or caesarean sections (73.8% vs 64.5%; RR 1.14, 95% CI 1.03-1.26). Revealed PlGF led to fewer perinatal deaths (2 vs 9; RR 0.16, 95% CI 0.03-0.74) and fewer babies with birthweight <3rd centile (28.9% vs 36.1%; RR 0.80, 0.65-0.99), but with more neonatal adverse outcomes (30.4% vs 17.1%; RR 1.78, 95% CI 1.32-2.41). CONCLUSIONS: Revealed PlGF may be associated with lower perinatal mortality and birthweight <3rd centile but appears to lead to earlier delivery with more neonatal respiratory morbidity. Randomised trials with adequate power for clinical outcomes are needed. FUNDING: Financial assistance was received from Alere to support the running of the MAPPLE database. Alere had no access to the information or control over the database itself. PMID- 29627352 TI - Viral exposure effects on life-history, flight-related traits, and wing melanisation in the Glanville fritillary butterfly. AB - Infections represent a constant threat for organisms and can lead to substantial fitness losses. Understanding how individuals, especially from natural populations, respond towards infections is thus of great importance. Little is known about immunity in the Glanville fritillary butterfly (Melitaea cinxia). As the larvae live gregariously in family groups, vertical and horizontal transmission of infections could have tremendous effects on individuals and consequently impact population dynamics in nature. We used the Alphabaculovirus type strain Autographa californica multiple nucleopolyhedrovirus (AcMNPV) and demonstrated that positive concentration-dependent baculovirus exposure leads to prolonged developmental time and decreased survival during larval and pupal development, with no sex specific differences. Viral exposure did not influence relative thorax mass or wing morphometric traits often related to flight ability, yet melanisation of the wings increased with viral exposure, potentially influencing disease resistance or flight capacity via thermal regulation. Further research is needed to explore effects under sub-optimal conditions, determine effects on fitness-related traits, and investigate a potential adaptive response of increased melanisation in the wings due to baculovirus exposure. PMID- 29627353 TI - Adipokinetic hormone and adenosine interfere with nematobacterial infection and locomotion in Drosophila melanogaster. AB - This study examined how adipokinetic hormone (AKH) and adenosine affect defense responses in Drosophila melanogaster larvae infected with entomopathogenic nematodes (EPN, Steinernema carpocapsae and Heterorhabditis bacteriophora). Three loss-of-function mutant larvae were tested: Akh1, AdoR1 (adenosine receptor), and Akh1 AdoR1. Mortality decreased in all mutants post-EPN infection compared with the control (w1118). Additionally, co-application of external AKH with EPN significantly increased mortality beyond rates observed in EPN-only treatment, while also elevating carbon dioxide production, a measure of metabolism. Furthermore trehalose levels increased in both w1118 and Akh1 larvae post-EPN infection, but the latter group exhibited a lower increase and total trehalose levels. Interestingly, baseline trehalose was relatively high in untreated AdoR1 and Akh1 AdoR1 mutants, with levels remaining unaffected by infection. Infection also elevated haemolymph lipid content overall, but the different mutations did not substantially influence this change. In contrast, haemolymph protein content dropped after EPN infection in all tested groups, but this decline was more intense among Akh1. In uninfected larvae mutations decreased antioxidative capacity in Akh1 and increased in AdoR1, however, its post-infection increases were similar in all mutants, suggesting that antioxidant response in Drosophila involves mechanisms also beyond AKH and adenosine. Furthermore, AKH application in w1118 larvae significantly increased movement distance and percentage of larval activity, but reduced velocity. Mutations of Akh and AdoR did not strongly affect locomotion. PMID- 29627354 TI - Distal intersection syndrome: An unusual cause of forearm pain. PMID- 29627355 TI - Atrial Fibrillation in the ICU. AB - Atrial fibrillation (AF) is the most common arrhythmia encountered in the ICU. Preexisting AF is highly prevalent among older patients with chronic conditions who are at risk for critical illness, whereas new-onset AF can be triggered by accelerated atrial remodeling and arrhythmogenic triggers encountered during critical illness. The acute loss of atrial systole and onset of rapid ventricular rates that characterize new-onset AF often lead to decreased cardiac output and hemodynamic compromise. Thus, new-onset AF is both a marker of disease severity as well as a likely contributor to poor outcomes, similar to other manifestations of organ dysfunction during critical illness. Evaluating immediate hemodynamic effects of new-onset AF during critical illness is an important component of rapid clinical assessment aimed at identifying patients in need of urgent direct current cardioversion, treatment of reversible inciting factors, and identification of patients who may benefit from pharmacologic rate or rhythm control. In addition to acute hemodynamic effects, new-onset AF during critical illness is associated with both short- and long-term increases in the risk of stroke, heart failure, and death, with AF recurrence rates of approximately 50% within 1 year following hospital discharge. In the absence of a strong evidence base, there is substantial practice variation in the choice of strategies for management of new-onset AF during critical illness. We describe acute and long term evaluation and management strategies based on current evidence and propose future avenues of investigation to fill large knowledge gaps in the management of patients with AF during critical illness. PMID- 29627356 TI - Sustained ophthalmic delivery of highly soluble drug using pH-triggered inner layer-embedded contact lens. AB - In the present work the feasibility of using inner layer-embedded contact lenses (CLs) to achieve sustained release of highly water soluble drug, betaxolol hydrochloride (BH) on the ocular surface was investigated. Blend film of cellulose acetate and Eudragit S100 was selected as the inner layer, while silicone hydrogel was used as outer layer to construct inner layer-embedded contact lenses. Influence of polymer ratio in the blend film on in vitro drug release behavior in phosphate buffered solution or simulated tear fluid was studied and drug-polymer interaction, erosion and swelling of the blend film were characterized to better understand drug-release mechanism. Storage stability of the inner layer-embedded contact lenses in phosphate buffer solution was also conducted, with ignorable drug loss and negligible change in drug release pattern within 30 days. In vivo pharmacokinetic study in rabbits showed sustained drug release for over 240 h in tear fluid, indicating prolonged drug precorneal residence time. In conclusion, cellulose acetate/Eudragit S100 inner layer embedded contact lenses are quite promising as controlled-release carrier of highly water soluble drug for ophthalmic delivery. PMID- 29627357 TI - Estimating the numbers of pregnant women infected with Zika virus and infants with congenital microcephaly in Colombia, 2015-2017. AB - BACKGROUND: Colombia experienced a Zika virus (ZIKV) outbreak in 2015-2016. To assist with planning for medical and supportive services for infants affected by prenatal ZIKV infection, we used a model to estimate the number of pregnant women infected with ZIKV and the number of infants with congenital microcephaly from August 2015 to August 2017. METHODS: We used nationally reported cases of symptomatic ZIKV disease among pregnant women and information from the literature on the percent of asymptomatic infections to estimate the number of pregnant women with ZIKV infection occurring August 2015-December 2016. We then estimated the number of infants with congenital microcephaly expected to occur August 2015 August 2017. To compare to the observed counts of infants with congenital microcephaly due to all causes reported through the national birth defects surveillance system, the model was time limited to produce estimates for February November 2016. FINDINGS: We estimated 1140-2160 (interquartile range [IQR]) infants with congenital microcephaly in Colombia, during August 2015-August 2017, whereas 340-540 infants with congenital microcephaly would be expected in the absence of ZIKV. Based on the time limited version of the model, for February November 2016, we estimated 650-1410 infants with congenital microcephaly in Colombia. The 95% uncertainty interval for the latter estimate encompasses the 476 infants with congenital microcephaly reported during that approximate time frame based on national birth defects surveillance. INTERPRETATION: Based on modeled estimates, ZIKV infection during pregnancy in Colombia could lead to 3-4 times as many infants with congenital microcephaly in 2015-2017 as would have been expected in the absence of the ZIKV outbreak. FUNDING: This publication was made possible through support provided by the Bureau for Global Health, U.S. Agency for International Development under the terms of an Interagency Agreement with Centers for Disease Control and Prevention. PMID- 29627359 TI - 3D structure determination of amyloid fibrils using solid-state NMR spectroscopy. AB - The amyloid fold is structurally characterized by a typical cross-beta architecture, which is under debate to represent an energy-favourable folding state that many globular or natively unfolded proteins can adopt. Being initially solely associated with amyloid fibrils observed in the propagation of several neurodegenerative disorders, the discovery of non-pathological (or "functional") amyloids in many native biological processes has recently further intensified the general interest invested in those cross-beta supramolecular assemblies. The insoluble and non-crystalline nature of amyloid fibrils and their usually inhomogeneous appearance on the mesoscopic level pose a challenge to biophysical techniques aiming at an atomic-level structural characterization. Solid-state NMR spectroscopy (SSNMR) has granted breakthroughs in structural investigations on amyloid fibrils ranging from the assessment of the impact of polymorphism in disease development to the 3D atomic structure determination of amyloid fibrils. First landmark studies towards the characterization of atomic structures and interactions involving functional amyloids have provided new impulses in the understanding of the role of the amyloid fold in native biological functions. Over the last decade many strategies have been developed in protein isotope labelling, NMR resonance assignment, distance restraint determination and 3D structure calculation of amyloid fibrils based on SSNMR approaches. We will here discuss the emerging concepts and state-of-the-art methods related to the assessment of amyloid structures and interactions involving amyloid entities by SSNMR. PMID- 29627358 TI - Hydrogen-deuterium exchange mass spectrometry reveals folding and allostery in protein-protein interactions. AB - Hydrogen-deuterium exchange mass spectrometry (HDXMS) has emerged as a powerful approach for revealing folding and allostery in protein-protein interactions. The advent of higher resolution mass spectrometers combined with ion mobility separation and ultra performance liquid chromatographic separations have allowed the complete coverage of large protein sequences and multi-protein complexes. Liquid-handling robots have improved the reproducibility and accurate temperature control of the sample preparation. Many researchers are also appreciating the power of combining biophysical approaches such as stopped-flow fluorescence, single molecule FRET, and molecular dynamics simulations with HDXMS. In this review, we focus on studies that have used a combination of approaches to reveal (re)folding of proteins as well as on long-distance allosteric changes upon interaction. PMID- 29627360 TI - The occult hemodynamically significant left main stenosis in the asymptomatic patient: Reconciling the visual-functional mismatch - A case report and review of screening appropriateness and assessment of left main in patient with multi vessel CAD. AB - We present a 40 year old asymptomatic man with mild left main artery narrowing who demonstrated extreme discordance between symptom presentation and ischemic burden i.e. visual (angiographic) and ischemic (functional) mismatch. The use of an appropriately selected screening stress test can lead to an appropriate decision for revascularization, supported by landmark risk assessment documents and revascularization trials. PMID- 29627361 TI - Successful percutaneous retrieval of a severely kinked and twisted femoral sheath under fluoroscopic guidance during Transcatheter Aortic Valve Implantation. PMID- 29627362 TI - Retrograde approach-related epicardial collateral channel perforation successfully treated with simultaneous bilateral coils embolization: A case illustration and review. PMID- 29627363 TI - Nesfatin-1 functions as a switch for phenotype transformation and proliferation of VSMCs in hypertensive vascular remodeling. AB - The phenotypic transformation from differentiated to dedifferentiated vascular smooth muscle cells (VSMCs) plays a crucial role in VSMC proliferation and vascular remodeling in many cardiovascular diseases including hypertension. Nesfatin-1, a multifunctional adipocytokine, is critically involved in the regulation of blood pressure. However, it is still largely unexplored whether nesfatin-1 is a potential candidate in VSMC phenotypic switch and proliferation in hypertension. Experiments were carried out in Wistar-Kyoto rats (WKY), spontaneously hypertensive rats (SHR), human VSMCs and primary rat aortic VSMCs. We showed that the expression of nesfatin-1 was upregulated in media layer of the aorta in SHR and SHR-derived VSMCs. Nesfatin-1 promoted VSMC phenotypic transformation, accelerated cell cycle progression and proliferation. Knockdown of nesfatin-1 inhibited the VSMC phenotype switch from a contractile to a synthetic state, attenuated cell cycle progression and retarded VSMC proliferation in SHR-derived VSMCs. Moreover, nesfatin-1-activated PI3K/Akt/mTOR signaling was abolished by JAK/STAT inhibitor WP1066, and the increased phosphorylation levels of JAK2/STAT3 in response to nesfatin-1 were suppressed by inhibition of PI3K/Akt/mTOR in VSMCs. Pharmacological blockade of the forming feedback loop between PI3K/Akt/mTOR and JAK2/STAT3 prevented the proliferation of nesfatin-1-incubated VSMCs and primary VSMCs from SHR. Chronic intraperitoneal injection of nesfatin-1 caused severe hypertension and cardiovascular remodeling in normal rats. In contrast, silencing of nesfatin-1 gene ameliorated hypertension, phenotype switching, and vascular remodeling in the aorta of SHR. Therefore, our data identified nesfatin-1 as a key modulator in hypertension and vascular remodeling by facilitating VSMC phenotypic switching and proliferation. PMID- 29627365 TI - Evolutionary conservation of a core fungal phosphate homeostasis pathway coupled to development in Blastocladiella emersonii. AB - The model yeast Saccharomyces cerevisiae elicits a transcriptional response to phosphate (Pi) depletion. To determine the origins of the phosphate response (PHO) system, we bioinformatically identified putative PHO components in the predicted proteomes of diverse fungi. Our results suggest that the PHO system is ancient; however, components have been expanded or lost in different fungal lineages. To show that a similar physiological response is present in deeply diverging fungi we examined the transcriptional and physiological response of PHO genes to Pi depletion in the blastocladiomycete Blastocladiella emersonii. Our physiological experiments indicate that B. emersonii relies solely on high affinity Na+-independent Pho84-like transporters. In response to Pi depletion, BePho84 paralogues were 4-8-fold transcriptionally upregulated, whereas several other PHO homologues like phosphatases and vacuolar transporter chaperone (VTC) complex components show 2-3-fold transcriptional upregulation. Since Pi has been shown to be important during the development of B. emersonii, we sought to determine if PHO genes are differentially regulated at different lifecycle stages. We demonstrate that a similar set of PHO transporters and phosphatases are upregulated at key points during B. emersonii development. Surprisingly, some genes upregulated during Pi depletion, including VTC components, are repressed at these key stages of development indicating that PHO genes are regulated by different pathways in different developmental and environmental situations. Overall, our findings indicate that a complex PHO network existed in the ancient branches of the fungi, persists in diverse extant fungi, and that this ancient network is likely to be involved in development and cell cycle regulation. PMID- 29627366 TI - A study on etiopathogenesis and clinical features of multi-headed (bifid and trifid) mandibular condyles and review of the literature. AB - PURPOSE: The formations of second or more condylar heads are considered as rare anomalies. Fourteen multi-headed condyles (MHC) were presented; 13 of these were bifid mandibular condyles (BMC), whereas one exceptionally rare case was a trifid mandibular condyle (TMC). The TMC presented in this paper is the eighth case reported in the literature. In this paper, etiopathogenesis, types, and treatments are discussed. MATERIALS AND METHODS: Patients were classified according to their status, etiologies, gender, functions of the mandible, interocclusal distances, pathological conditions, types, and treatment received. RESULTS: BMCs were classified into two groups: type I BMCs were nontraumatic, nonsymptomatic, mediolateral, presumably developmental, and characterized by shallow grooves. Type II BMCs were traumatic and may have two subgroups. The first group of type II BMCs were mediolateral and Y-shaped. The second group of type II BMCs were characterized by two separate and anteroposteriorly located condyles. CONCLUSION: Treatment depended on patients' complaints. In this study, asymptomatic patients did not receive therapy, whereas patients with temporomandibular join internal derangement received medical treatment, and patients with ankylosis had surgical treatment. PMID- 29627364 TI - Animal models of cholangiocarcinoma. AB - Cholangiocarcinoma (CCA) is an aggressive biliary tract malignancy with a poor overall prognosis. There is a critical need to develop effective targeted therapies for the treatment of this lethal disease. In an effort to address this challenge, preclinical in vivo studies have become paramount in understanding CCA carcinogenesis, progression, and therapy. Various CCA animal models exist including carcinogen-based models in which animals develop CCA after exposure to a carcinogen, genetically engineered mouse models in which genetic changes are induced in mice leading to CCA, murine syngeneic orthotopic models, as well as xenograft tumors derived from xenotransplantation of CCA cells, organoids, and patient-derived tissue. Each type has distinct advantages as well as shortcomings. In the ideal animal model of CCA, the tumor arises from the biliary tract in an immunocompetent host with a species-matched tumor microenvironment. Such a model would also be time-efficient, recapitulate the genetic and histopathological features of human CCA, and predict therapeutic response in humans. Recently developed biliary tract transduction and orthotopic syngeneic transplant mouse models encompass several of these elements. Herein, we review the different animal models of CCA, their advantages and deficiencies, as well as features which mimic human CCA. PMID- 29627367 TI - Development of a patient-specific temporomandibular joint prosthesis according to the Groningen principle through a cadaver test series. AB - OBJECTIVES: Patients suffering from osteoarthritis, ankylosis (e.g. post-trauma or tumour) in the temporomandibular joint (TMJ) can present with symptoms such as severely restricted mouth opening, pain or other dynamic restrictions of the mandible. To alleviate the symptoms, a total joint prosthesis can be indicated, such as the Groningen TMJ prosthesis. This was developed as a stock device with a lowered centre of rotation for improved translational and opening capacity. This study aimed to improve the design of the prosthesis, and produce a workflow for a customized Groningen TMJ prosthesis, in order to make it more accurate and predictable. METHODS: The fossa and mandibular components of the Groningen TMJ prosthesis were customized. A series of five human cadavers was operated and bilateral TMJ prostheses were placed using custom cutting and drilling guides. Placement accuracy was evaluated based on post-operative CT data. RESULTS: A total of N = 10 prostheses were placed and analysed. The average Euclidean distance deviation from planned to actual position was 0.81 mm (SD 0.21). All prostheses were placed according to the routine surgical approaches and had an excellent alignment with the bony structures. CONCLUSION: The newly developed custom Groningen TMJ prosthesis can be placed with great accuracy and is the first step for improving TMJ total joint replacement surgery. PMID- 29627368 TI - Supportive topical tranexamic acid application for hemostasis in oral bleeding events - Retrospective cohort study of 542 patients. AB - PURPOSE: Tranexamic acid (TXA) is widely used in the prevention of postsurgical oral bleeding. Tranexamic acid in addition to further surgical measures is widely utilized in prevention of post-surgical oral bleeding. The aim of the present study was to investigate: Can oral hemostasis be achieved by merely compression and topical application of tranexamic acid in different anticoagulant regimes among patients attending a general emergency department? Where are the limits to this procedure? Which has the greater impact on surgeons' choice for an invasive hemostatic approach-bleeding quality or oral anticoagulant therapy? MATERIALS AND METHODS: A retrospective cohort study of 542 patients who consecutively received treatment for oral bleeding was performed. We surveyed the values of the diverse hemostatic approaches. Special attention was granted to patient anticoagulant regimen and quality of the oral bleeding event. RESULTS: A total of 199 of 542 (36.7%) oral bleeding events were stopped by compression with a gauze or gauze soaked with TXA (4.8%). Stopping an oral bleeding event with wound compression can be improved by factor 1.6 if the gauze is soaked with tranexamic acid (4.8%), p <= 0.05. LMWH presented significantly more moderate bleeding than bloody oozing of the wound, p < 0.05. The quality of bleeding had a strong influence on oral surgeons' decisions to apply further surgical means. Sutures and native collagen fleeces were the favored methods to stop moderate and severe bleeding (p < 0.05). CONCLUSION: Topical application of TXA aids as a useful supportive tool to stop mild bleeding events such as the bloody oozing of an oral wound. The quality of an oral bleeding episode should be considered in the choice of hemostatic measure. Hemostatic approaches should begin with the least invasive procedure. TXA is a helpful tool. PMID- 29627370 TI - Aptamers as targeting ligands and therapeutic molecules for overcoming drug resistance in cancers. AB - Traditional anticancer therapies are often unable to completely eradicate the tumor bulk due to multi-drug resistance (MDR) of cancers. A number of mechanisms such as micro-environmental stress and overexpression of drug efflux pumps are involved in the MDR process. Hence, therapeutic strategies for overcoming MDR are urgently needed to improve cancer treatment efficacy. Aptamers are short single stranded oligonucleotides or peptides exhibiting unique three-dimensional structures and possess several unique advantages over conventional antibodies such as low immunogenicity and stronger tissue-penetration capacity. Aptamers targeting cancer-associated receptors have been explored to selectively deliver a therapeutic cargo (anticancer drugs, siRNAs, miRNAs and drug-carriers) to the intratumoral compartment where they can exert better tumor-killing effects. In this review, we summarize current knowledge of the multiple regulatory mechanisms of MDR, with a particular emphasis on aptamer-mediated novel therapeutic agents and strategies that seek to reversing MDR. The challenges associated with aptamer based agents and approaches are also discussed. PMID- 29627369 TI - Instructive microenvironments in skin wound healing: Biomaterials as signal releasing platforms. AB - Skin wound healing aims to repair and restore tissue through a multistage process that involves different cells and signalling molecules that regulate the cellular response and the dynamic remodelling of the extracellular matrix. Nowadays, several therapies that combine biomolecule signals (growth factors and cytokines) and cells are being proposed. However, a lack of reliable evidence of their efficacy, together with associated issues such as high costs, a lack of standardization, no scalable processes, and storage and regulatory issues, are hampering their application. In situ tissue regeneration appears to be a feasible strategy that uses the body's own capacity for regeneration by mobilizing host endogenous stem cells or tissue-specific progenitor cells to the wound site to promote repair and regeneration. The aim is to engineer instructive systems to regulate the spatio-temporal delivery of proper signalling based on the biological mechanisms of the different events that occur in the host microenvironment. This review describes the current state of the different signal cues used in wound healing and skin regeneration, and their combination with biomaterial supports to create instructive microenvironments for wound healing. PMID- 29627371 TI - The apparent competitive action of ECM proteases and cross-linking enzymes during fibrosis: Applications to drug discovery. AB - Progressive loss of organ function in most organs is associated with fibrosis, a tissue state associated with abnormal matrix buildup. If highly progressive, the fibrotic process eventually leads to organ failure and death. Fibrosis is a basic connective tissue lesion defined by the increase in the amount of fibrillar extracellular matrix (ECM) components in a tissue or organ. In addition, intrinsic changes in important structural cells can induce the fibrotic response by regulating the differentiation, recruitment, proliferation and activation of extracellular matrix-producing myofibroblasts. ECM enzymes belonging to the family of matrix metalloproteinases (MMPs) and lysyl oxidases (LOXs) play a crucial role in ECM remodeling and regeneration. MMPs have a catalytic role in degradation of ECM, whereas LOX/LOXLs mediate ECM, especially collagen, cross linking and stiffening. Importantly, enzymes from both families are elevated during the fibrotic response to tissue injury and its resolution. Yet, the apparent molecular competition or antagonistic activities of these enzyme families during the various stages of fibrosis is often overlooked. In this review, we discuss the diverse roles of MMPs and LOX/LOXL2 in chronic organ fibrosis. Finally, we review contemporary therapeutic strategies for fibrosis treatment, based on neutralization of MMP and LOX activity, as well as the development of novel drug delivery approaches. PMID- 29627373 TI - Potential mechanisms underlying differences in the effect of incretin-based antidiabetic drugs on the risk of major atherosclerotic ischemic events. PMID- 29627372 TI - Psoas and paraspinous muscle index as a predictor of mortality in African American men with type 2 diabetes mellitus. AB - AIM: Recent studies revealed a correlation between skeletal muscle mass index and density with longevity; these studies largely evaluated appendicular skeletal muscles in older Caucasians. This retrospective cohort study assessed the association between axial skeletal muscles size and density with survival in African Americans with type 2 diabetes mellitus. METHODS: Psoas and paraspinous muscle mass index (cross sectional area/height2) and radiographic density (in Hounsfield Units) were measured using computed tomography in African American Diabetes Heart Study participants, 314 women and 256 men, with median (25th, 75th quartile) age 55.0(48.0, 62.0) and 57.0(50.0, 64.0) years, respectively. Covariates in fully-adjusted model included age, sex, BMI, smoking, hormone replacement therapy (women), cardiovascular disease, hypertension, coronary artery calcified plaque mass, carotid artery calcified plaque mass, and African ancestry proportion. RESULTS: After median of 7.1(5.9, 8.2) years follow-up, 30(9.6%) of women and 49(19.1%) of men were deceased. In fully-adjusted models, psoas muscle mass index and paraspinous muscle mass index were inversely associated with mortality in men (psoas muscle mass index, hazard ratio [HR] = 0.61, P = 0.004; paraspinous muscle mass index, HR = 0.64, P = 0.004), but not in women. Psoas and paraspinous muscle densities did not associate with all-cause mortality. A penalized Cox regression that involved all covariates and predictors associated with mortality showed that only paraspinous muscle mass index remained a significant predictor of mortality (HR = 0.65, P = 0.02). CONCLUSION: Independent from established risk factors for mortality, higher psoas and paraspinous muscle index associate with reduced all-cause mortality in middle aged African American men with type 2 diabetes mellitus. PMID- 29627374 TI - Increased urinary albumin excretion in children with type 1 diabetes: is it a reason for concern? PMID- 29627375 TI - Longer diabetes duration reduces myocardial blood flow in remote myocardium assessed by dynamic myocardial CT perfusion. AB - AIMS: To investigate the relationship of type 2 diabetes duration and myocardial blood flow (MBF) assessed by myocardial CT perfusion. MATERIALS AND METHODS: We prospectively included 140 patients with type 2 diabetes who underwent dynamic myocardial CT perfusion exam. MBF of the remote myocardium was calculated using the deconvolution technique and the Voronoi method. The relationships of MBF and diabetic duration, diabetic complications, conventional risk factors, coronary calcium, and coronary stenosis were assessed by logistic regression analysis. RESULTS: A weak but significantly negative relationship was present between diabetes duration and MBF (R2 = 0.05, p < 0.01). The average MBF of patients with a duration of >8 years was 13% lower than that of the remaining patients (1.11 +/ 0.35 vs 1.28 +/- 0.27 ml min-1 g-1, p < 0.01). Duration of one year was associated with a 6% increased risk for low MBF (<1.18 ml min-1 g-1) (odds ratio 1.06, 95% confidence interval 1.01-1.12, p < 0.05). Calcium score was also a significant factor for low MBF (odds ratio 1.08 (per 100 Agatston units), 95% confidence interval 1.01-1.17, p < 0.05). CONCLUSION: Longer diabetes duration is associated with lower MBF independent of conventional cardiac risk factors or the presence of coronary stenosis. PMID- 29627376 TI - Taking adverse outcome pathways to the next level. PMID- 29627377 TI - FGF21, a liver hormone that inhibits alcohol intake in mice, increases in human circulation after acute alcohol ingestion and sustained binge drinking at Oktoberfest. AB - OBJECTIVE: Excessive alcohol consumption is a leading cause of global morbidity and mortality. However, knowledge of the biological factors that influence ad libitum alcohol intake may be incomplete. Two large studies recently linked variants in the KLB locus with levels of alcohol intake in humans. KLB encodes beta-klotho, co-receptor for the liver-derived hormone fibroblast growth factor 21 (FGF21). In mice, FGF21 reduces alcohol intake, and human Fgf21 variants are enriched among heavy drinkers. Thus, the liver may limit alcohol consumption by secreting FGF21. However, whether full-length, active plasma FGF21 (FGF21 (1 181)) levels in humans increase acutely or sub-chronically in response to alcohol ingestion is uncertain. METHODS: We recruited 10 healthy, fasted male subjects to receive an oral water or alcohol bolus with concurrent blood sampling for FGF21 (1-181) measurement in plasma. In addition, we measured circulating FGF21 (1-181) levels, liver stiffness, triglyceride, and other metabolic parameters in three healthy Danish men before and after consuming an average of 22.6 beers/person/day (4.4 g/kg/day of ethanol) for three days during Oktoberfest 2017 in Munich, Germany. We further correlated fasting FGF21 (1-181) levels in 49 healthy, non alcoholic subjects of mixed sex with self-reports of alcohol-related behaviors, emotional responses, and problems. Finally, we characterized the effect of recombinant human FGF21 injection on ad libitum alcohol intake in mice. RESULTS: We show that alcohol ingestion (25.3 g or ~2.5 standard drinks) acutely increases plasma levels of FGF21 (1-181) 3.4-fold in fasting humans. We also find that binge drinking for three days at Oktoberfest is associated with a 2.1-fold increase in baseline FGF21 (1-181) levels, in contrast to minor deteriorations in metabolic and hepatic biomarkers. However, basal FGF21 (1-181) levels were not correlated with differences in alcohol-related behaviors, emotional responses, or problems in our non-alcoholic subjects. Finally, we show that once-daily injection of recombinant human FGF21 reduces ad libitum alcohol intake by 21% in mice. CONCLUSIONS: FGF21 (1-181) is markedly increased in circulation by both acute and sub-chronic alcohol intake in humans, and reduces alcohol intake in mice. These observations are consistent with a role for FGF21 as an endocrine inhibitor of alcohol appetite in humans. PMID- 29627379 TI - The antipsychotic drug quetiapine stimulates oligodendrocyte differentiation by modulating the cell cycle. AB - Recent studies have revealed that oligodendrocyte differentiation deficits and de myelination occur in the brains of schizophrenic patients. Cell cycle proteins play a critical role in modulating oligodendrocyte proliferation and differentiation. In our previous studies, we found that cuprizone, a copper chelant, induces oligodendrocyte loss and demyelination, and this effect can be alleviated by using the atypical antipsychotic drug quetiapine. To explore the mechanisms of quetiapine in oligodendrocyte development, we examined the effects of quetiapine on cell cycle progression. Quetiapine promoted cell cycle exit and blocked the mitogenic effect of PDGF in cultured rat cortical oligodendrocyte progenitor cells (OPCs). Quetiapine accelerated OPC differentiation in vitro. Moreover, the systemic administration of quetiapine up-regulated p21 mRNA expression, a cyclin-dependent kinase inhibitor, in mice. Knocking down p21 expression by RNA interference enhanced proliferation and delayed differentiation. Our results suggest that cell cycle regulation may contribute to the differentiation-promoting effect of quetiapine. PMID- 29627378 TI - Brown adipose tissue derived ANGPTL4 controls glucose and lipid metabolism and regulates thermogenesis. AB - OBJECTIVES: Brown adipose tissue (BAT) controls triglyceride-rich lipoprotein (TRL) catabolism. This process is mediated by the lipoprotein lipase (LPL), an enzyme that catalyzed the hydrolysis of triglyceride (TAG) in glycerol and fatty acids (FA), which are burned to generate heat. LPL activity is regulated by angiopoietin-like 4 (ANGPTL4), a secretory protein produced in adipose tissues (AT), liver, kidney, and muscle. While the role of ANGPTL4 in regulating lipoprotein metabolism is well established, the specific contribution of BAT derived ANGPTL4 in controlling lipid and glucose homeostasis is not well understood. METHODS AND RESULTS: We generated a novel mouse model lacking ANGPTL4 specifically in brown adipose tissue (BAT-KO). Here, we report that specific deletion of ANGPTL4 in BAT results in enhanced LPL activity, circulating TAG clearance and thermogenesis. Absence of ANGPTL4 in BAT increased FA oxidation and reduced FA synthesis. Importantly, we observed that absence of ANGPTL4 in BAT leads to a remarkable improvement in glucose tolerance in short-term HFD feeding. CONCLUSION: Our findings demonstrate an important role of BAT derived ANGPTL4 in regulating lipoprotein metabolism, whole-body lipid and glucose metabolism, and thermogenesis during acute cold exposure. PMID- 29627380 TI - 12/15 lipoxygenase: A crucial enzyme in diverse types of cell death. AB - The 12/15-lipoxygenase (12/15-LOX) enzymes react with polyunsaturated fatty acids producing active lipid metabolites that are involved in plethora of human diseases including neurological disorders. A great many of elegant studies over the last decades have contributed to unraveling the mechanism how 12/15 lipoxygenase play a role in these diseases. And the way it works is mainly through apoptosis. However, recent years have found that the way 12/15 lipoxygenase works is also related to autophagy and ferroptosis, a newly defined type of cell death by Stockwell's lab in 2012. Figuring out how 12/15 lipoxygenase participate in these modes of cell death is of vital importance to understand its role in disease. The review aims to give a sight on our current knowledge on the role of this enzyme in apoptosis, autophagy and ferroptosis. And the relevant diseases that 12/15-lipoxygenase may be involved. PMID- 29627381 TI - Restorative effect of l-Dopa treatment against Ochratoxin A induced neurotoxicity. AB - The toxic effects of Ochratoxin A (OTA), a fungal secondary metabolite of the genera Aspergillus and Penicillium with 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP) a Parkinson inducing drug were investigated to evaluate the neurotoxic effects exerted by OTA. OTA is known to contaminate food and feedstuff leading to a wide range of toxicity like nephrotoxicity, hepatotoxicity, and immunotoxicity. However, due to the dearth of available information on the possible mechanisms of OTA neurotoxicity and neurodegeneration the current study was undertaken. Hence, in this study, we examined the neurotoxic effects and the possible mechanism of action of neurodegeneration by OTA toxicity on mice brain by conducting a battery of behavioural studies and reviewing neurotransmitter levels and neuronal apoptotic pathways. Further, they were treated with l-Dopa, a precursor of dopamine (DA) to explore its ameliorative effects against OTA. The results of behavioural studies like gait analysis, spontaneous activity, cylinder test and pole test showed that OTA exhibits Parkinsonian physiognomies which were stabilized with l-Dopa treatment. Also, OTA toxicity showed insults on neurotransmitter levels and general brain function parameters that were normalized with l-Dopa treatment. The results of the present study suggest that OTA promotes neurodegeneration by targeting neuronal pathway leading to the development of Parkinson's diseases. PMID- 29627382 TI - Identification of lipases with activity towards monoacylglycerol by criterion of conserved cap architectures. AB - Monoacylglycerol lipases (MGL) are a subclass of lipases that predominantly hydrolyze monoacylglycerol (MG) into glycerol and fatty acid. MGLs are ubiquitous enzymes across species and play a role in lipid metabolism, affecting energy homeostasis and signaling processes. Structurally, MGLs belong to the alpha/beta hydrolase fold family with a cap covering the substrate binding pocket. Analysis of the known 3D structures of human, yeast and bacterial MGLs revealed striking similarity of the cap architecture. Since MGLs from different organisms share very low sequence similarity, it is difficult to identify MGLs based on the amino acid sequence alone. Here, we investigated whether the cap architecture could be a characteristic feature of this subclass of lipases with activity towards MG and whether it is possible to identify MGLs based on the cap shape. Through database searches, we identified the structures of five different candidate alpha/beta hydrolase fold proteins with unknown or reported esterase activity. These proteins exhibit cap architecture similarities to known human, yeast and bacterial MGL structures. Out of these candidates we confirmed MGL activity for the protein LipS, which displayed the highest structural similarity to known MGLs. Two further enzymes, Avi_0199 and VC1974, displayed low level MGL activities. These findings corroborate our hypothesis that this conserved cap architecture can be used as criterion to identify lipases with activity towards MGs. PMID- 29627383 TI - Lpaatdelta/Agpat4 deficiency impairs maximal force contractility in soleus and alters fibre type in extensor digitorum longus muscle. AB - Lysophosphatidic acid acyltransferase (LPAAT) delta/acylglycerophosphate acyltransferase 4 is a mitochondrial enzyme and one of five homologues that catalyze the acyl-CoA-dependent synthesis of phosphatidic acid (PA) from lysophosphatidic acid. We studied skeletal muscle LPAATdelta and found highest levels in soleus, a red oxidative fibre-type that is rich in mitochondria, and lower levels in extensor digitorum longus (EDL) (white glycolytic) and gastrocnemius (mixed fibre-type). Using Lpaatdelta-deficient mice, we found no change in soleus or EDL mass, or in treadmill time-to-exhaustion compared to wildtype littermates. There was, however, a significant reduction in the proportion of type I and type IIA fibres in EDL but, surprisingly, not soleus, where these fibre-types predominate. Also unexpectedly, there was no impairment in force generation by EDL, but a significant reduction by soleus. Oxidative phosphorylation and activity of complexes I, I + II, III, and IV in soleus mitochondria was unchanged and therefore could not explain this effect. However, pyruvate dehydrogenase activity was significantly reduced in Lpaatdelta-/- soleus and EDL. Analysis of cellular lipids indicated no difference in soleus triacylglycerol, but specific elevations in soleus PA and phosphatidylethanolamine levels, likely due to a compensatory upregulation of Lpaatbeta and Lpaatepsilon in Lpaatdelta-/- mice. An anabolic effect for PA as an activator of skeletal muscle mTOR has been reported, but we found no change in serine 2448 phosphorylation, indicating reduced soleus force generation is unlikely due to the loss of mTOR activation by a specific pool of LPAATdelta derived PA. Our results identify an important role for LPAATdelta in soleus and EDL. PMID- 29627385 TI - Regulation of yeast fatty acid desaturase in response to iron deficiency. AB - Unsaturated fatty acids (UFA) are essential components of phospholipids that greatly contribute to the biophysical properties of cellular membranes. Biosynthesis of UFAs relies on a conserved family of iron-dependent fatty acid desaturases, whose representative in the model yeast Saccharomyces cerevisiae is Ole1. OLE1 expression is tightly regulated to adapt UFA biosynthesis and lipid bilayer properties to changes in temperature, and in UFA or oxygen availability. Despite iron deficiency being the most extended nutritional disorder worldwide, very little is known about the mechanisms and the biological relevance of fatty acid desaturases regulation in response to iron starvation. In this report, we show that endoplasmic reticulum-anchored transcription factor Mga2 activates OLE1 transcription in response to nutritional and genetic iron deficiencies. Cells lacking MGA2 display low UFA levels and do not grow under iron-limited conditions, unless UFAs are supplemented or OLE1 is overexpressed. The proteasome, E3 ubiquitin ligase Rsp5 and the Cdc48Npl4/Ufd1 complex are required for OLE1 activation during iron depletion. Interestingly, Mga2 also activates the transcription of its own mRNA in response to iron deficiency, hypoxia, low temperature and low UFAs. MGA2 up-regulation contributes to increase OLE1 expression in these situations. These results reveal the mechanism of OLE1 regulation when iron is scarce and identify the MGA2 auto-regulation as a potential activation strategy in multiple stresses. PMID- 29627386 TI - Long-Term Outcome After Pulmonary Artery Banding in Children With Atrioventricular Septal Defects. AB - BACKGROUND: Patients with atrioventricular septal defect (AVSD) may require pulmonary artery banding (PAB), either as a part of a staged univentricular palliation or to allow delayed biventricular repair in patients presenting with early heart failure. The long-term outcomes of PAB in children with AVSD have not been previously reported. METHODS: All children with AVSD who underwent PAB at a single institution were included in the study. Data were obtained from medical records and correspondence with general practitioners and cardiologists. RESULTS: A total of 68 patients with complete AVSD underwent PAB, of whom 58.8% of patients (40 of 68) had balanced AVSD (bAVSD) and underwent PAB with intent to subsequently perform biventricular repair. The remaining 41.2% of patients (28 of 68) had unbalanced AVSD (uAVSD) and underwent PAB as part of staged univentricular repair. PAB was not associated with a short-term increase in atrioventricular valve (AVV) regurgitation (p = 0.24). In patients with bAVSD, 83.8% (95% confidence interval [CI]: 67.4% to 92.4%) achieved biventricular repair. Survival was 73.4% (95% CI: 54.3% to 85.5%) and freedom from left AVV operation was 60.0% (95% CI: 36.1% to 77.4%) at 20 years of follow-up. In patients with uAVSD, 61.9% (95% CI: 40.5% to 77.5%) had achieved Fontan completion at 10 years of follow-up. Survival was 60.9% (95% CI: 36.2% to 78.5%) and freedom from AVV operation was 78.6% (95% CI: 55.5% to 90.6%) at 20 years. CONCLUSIONS: PAB can be used in patients with AVSD without compromising AVV function. Most patients with bAVSD progress to biventricular repair, albeit with a high rate of AVV reoperation. Patients with uAVSD who undergo PAB have similar outcomes to the overall uAVSD population. PMID- 29627384 TI - Can modulators of apolipoproteinB biogenesis serve as an alternate target for cholesterol-lowering drugs? AB - Understanding the molecular defects underlying cardiovascular disease is necessary for the development of therapeutics. The most common method to lower circulating lipids, which reduces the incidence of cardiovascular disease, is statins, but other drugs are now entering the clinic, some of which have been approved. Nevertheless, patients cannot tolerate some of these therapeutics, the drugs are costly, and/or the treatments are approved for only rare forms of disease. Efforts to find alternative treatments have focused on other factors, such as apolipoproteinB (apoB), which transports cholesterol in the blood stream. The levels of apoB are regulated by endoplasmic reticulum (ER) associated degradation as well as by a post ER degradation pathway in model systems, and we suggest that these events provide novel therapeutic targets. We discuss first how cardiovascular disease arises and how cholesterol is regulated, and then summarize the mechanisms of action of existing treatments for cardiovascular disease. We then review the apoB biosynthetic pathway, focusing on steps that might be amenable to therapeutic interventions. PMID- 29627387 TI - Predictors of Nodal Metastases for Clinical T2N0 Esophageal Adenocarcinoma. AB - BACKGROUND: Induction therapy has not been proven to be beneficial for patients with clinical T2N0 esophageal adenocarcinoma. Surgery alone is associated with disappointing survival for patients found to have nodal disease on final pathologic examination. The aim of this study was to identify factors that predict pathologic nodal involvement in patients with endoscopic ultrasound (EUS) proven T2N0 esophageal adenocarcinoma. METHODS: We retrospectively reviewed patients with EUS-staged T2N0 (uT2N0) esophageal adenocarcinoma treated with surgery alone. Final pathologic staging was compared with clinical staging. Demographic and clinicopathologic variables were evaluated as putative risk factors for nodal metastases. Logistic regression models were used to identify factors associated with nodal involvement. Kaplan-Meier analysis was performed to compare overall and recurrence-free survival between patients with (N+) and without (N-) nodal disease. RESULTS: We identified 80 patients with uT2N0 esophageal adenocarcinoma treated with surgery alone. Clinical staging with EUS was inaccurate for 73 patients (91%). Twenty-eight patients (35%) had pathologic N+ disease at resection. Five-year overall survival was 67% for N- patients and 41% for N+ patients (p = 0.006). Recurrence-free survival was 65% for N- patients and 32% for N+ patients (p = 0.0043). Univariable analysis identified vascular invasion and neural invasion as risk factors for nodal metastasis. Multivariable analysis identified vascular invasion as an independent predictor of pathologic nodal involvement. CONCLUSIONS: EUS is inaccurate for staging of T2N0 esophageal adenocarcinoma and often fails to identify nodal involvement. Identification of vascular invasion on preoperative biopsy should be explored as a prognostic marker to select patients for induction therapy. PMID- 29627388 TI - GABA Regulates Release of Inflammatory Cytokines From Peripheral Blood Mononuclear Cells and CD4+ T Cells and Is Immunosuppressive in Type 1 Diabetes. AB - The neurotransmitter gamma-aminobutyric acid (GABA) is an extracellular signaling molecule in the brain and in pancreatic islets. Here, we demonstrate that GABA regulates cytokine secretion from human peripheral blood mononuclear cells (PBMCs) and CD4+ T cells. In anti-CD3 stimulated PBMCs, GABA (100nM) inhibited release of 47 cytokines in cells from patients with type 1 diabetes (T1D), but only 16 cytokines in cells from nondiabetic (ND) individuals. CD4+ T cells from ND individuals were grouped into responder or non-responder T cells according to effects of GABA (100nM, 500nM) on the cell proliferation. In the responder T cells, GABA decreased proliferation, and inhibited secretion of 37 cytokines in a concentration-dependent manner. In the non-responder T cells, GABA modulated release of 8 cytokines. GABA concentrations in plasma from T1D patients and ND individuals were correlated with 10 cytokines where 7 were increased in plasma of T1D patients. GABA inhibited secretion of 5 of these cytokines from both T1D PBMCs and ND responder T cells. The results identify GABA as a potent regulator of both Th1- and Th2-type cytokine secretion from human PBMCs and CD4+ T cells where GABA generally decreases the secretion. PMID- 29627389 TI - Plasma mSEPT9: A Novel Circulating Cell-free DNA-Based Epigenetic Biomarker to Diagnose Hepatocellular Carcinoma. AB - BACKGROUND: Patients with cirrhosis are at high risk of hepatocellular carcinoma (HCC). The SEPT9 gene is a key regulator of cell division and tumor suppressor whose hypermethylation is associated with liver carcinogenesis. The primary aim of this study was to evaluate the diagnostic accuracy of a PCR-based assay for the analysis of SEPT9 promoter methylation in circulating cell-free DNA (mSEPT9) for diagnosing HCC among cirrhotic patients. METHODS: We report two phase II biomarker studies that included cirrhotic patients with or without HCC from France (initial study) and Germany (replication study). All patients received clinical and biological evaluations, and liver imaging according to current recommendations. The primary outcome was defined as the presence of HCC according to guidelines from the American Association for the Study of Liver Diseases. The diagnosis of HCC was confirmed by abdominal contrast-enhanced computed tomography scan and systematically discussed in a multidisciplinary consultation meeting. HCC-free cirrhotic patients were recruited if the screening abdominal ultrasound showed no evidence of HCC at the time of blood sampling for the mSEPT9 test and on the next visit six months later. The adjudicating physicians were blinded to patient results associated with the mSEPT9 test. FINDINGS: We included 289 patients with cirrhosis (initial: 186; replication: 103), among whom 98 had HCC (initial: 51; replication: 47). The mSEPT9 test exhibited high diagnostic accuracy for HCC diagnosis, with an area under the receiver operating characteristic curve (AUROC) of 0.944 (0.900-0.970, p<0.0001) in the initial study (replication: 0.930 [0.862-0.971, p<0.0001]; meta-analysis: AUROC=0.940 [0.910-0.970, p<0.0001], no heterogeneity: I2=0%, p=0.67; and no publication bias). In multivariate logistic regression analysis, the number of positive mSEPT9 triplicates was the only independent variable significantly associated with HCC diagnosis (initial: OR=6.30, for each mSEPT9 positive triplicate [2.92 13.61, p<0.0001]; replication: OR=6.07 [3.25-11.35, p<0.0001]; meta-analysis: OR=6.15 [2.93-9.38, p<0.0001], no heterogeneity: I2=0%, p=0.95; no publication bias). AUROC associated with the discrimination of the logistic regression models in initial and validation studies were 0.969 (0.930-0.989) and 0.942 (0.878 0.978), respectively, with a pooled AUROC of 0.962 ([0.937-0.987, p<0.0001], no heterogeneity: I2=0%, p=0.36; and no publication bias). INTERPRETATION: Among patients with cirrhosis, the mSEPT9 test constitutes a promising circulating epigenetic biomarker for HCC diagnosis at the individual patient level. Future prospective studies should assess the mSEPT9 test in the screening algorithm for cirrhotic patients to improve risk prediction and personalized therapeutic management of HCC. PMID- 29627391 TI - Chinese Expert Consensus on Enhanced Recovery After Hepatectomy (Version 2017). AB - Enhanced recovery after surgery (ERAS) is a series of perioperative optimized treatment measures based on evidence-based medicine which can control perioperative pathological and physiological responses, reduce surgical trauma and postoperative stress, and then achieve rapid recovery. This is a new concept in the 21st century, which is a revolution to the medical treatment and rehabilitation mode. Based on the clinical application study and expert experience in present ERAS in hepatectomy field at home and abroad, Chinese Expert Consensus on Enhanced Recovery After Hepatectomy (Version 2017) is established. The Chinese Expert consensus is the first guideline in the area of ERAS in hepatic surgery in China, which is drafted by the committee organized by Chinese Medical Association and China International Exchange and Promotive Association for Medical and Health Care. PMID- 29627390 TI - Sodium Butyrate Inhibits Inflammation and Maintains Epithelium Barrier Integrity in a TNBS-induced Inflammatory Bowel Disease Mice Model. AB - G Protein Coupled Receptor 109A (GPR109A), which belongs to the G protein coupled receptor family, can be activated by niacin, butyrate, and beta-hydroxybutyric acid. Here, we assessed the anti-inflammatory activity of sodium butyrate (SB) on 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis mice, an experimental model that resembles Crohn's disease, and explored the potential mechanism of SB in inflammatory bowel disease (IBD). In vivo, experimental GPR109a-/- and wild type (WT) mice were administered SB (5g/L) in their drinking water for 6weeks. The mice were then administered TNBS via rectal perfusion to imitate colitis. In vitro, RAW246.7 macrophages, Caco-2 cells, and primary peritoneal macrophages were used to investigate the protective roles of SB on lipopolysaccharide (LPS) induced inflammatory response and epithelium barrier dysfunction. In vivo, SB significantly ameliorated the inflammatory response and intestinal epithelium barrier dysfunction in TNBS-induced WT mice, but failed to provide a protective effect in TNBS-induced GPR109a-/- mice. In vitro, pre-treatment with SB dramatically inhibited the expression of TNF-alpha and IL-6 in LPS-induced RAW246.7 macrophages. SB inhibited the LPS-induced phosphorylation of the NF kappaB p65 and AKT signaling pathways, but failed to inhibit the phosphorylation of the MAPK signaling pathway. Our data indicated that SB ameliorated the TNBS induced inflammatory response and intestinal epithelium barrier dysfunction through activating GPR109A and inhibiting the AKT and NF-kappaB p65 signaling pathways. These findings therefore extend the understanding of GPR109A receptor function and provide a new theoretical basis for treatment of IBD. PMID- 29627392 TI - Recurrent intestinal stones in the Roux-en-Y limb after Kasai operation in an infant with biliary atresia. PMID- 29627393 TI - Highly efficient production of functional recombinant human fibroblast growth factor 22 in E. coli and its protective effects on H2O2-lesioned L02 cells. AB - In the 22 member mammalian FGF family, FGF22 belongs to FGF7 subfamily, and its effects are largely confined to the brain and skin. To explore the functions of FGF22 on other tissues and develop a large-scale production of recombinant human FGF22 (rhFGF22) without a fusion tag, a plasmid encoding human FGF22 (pET3a rhFGF22) was used to express rhFGF22 in E. coli BL21 (DE3) pLysS. A large amount of rhFGF22 inclusion body protein was obtained. A two-step denaturing method successfully solubilized rhFGF22, and it was refolded and then purified in one step via heparin affinity chromatography. A yield of 105 mg rhFGF22 with a purity of up to 95% was obtained from 100 g wet bacteria. It was found that the rhFGF22 had biological activity, since it effectively attenuated H2O2-induced human hepatic L02 cell death. Analysis by qRT-PCR and Western blot demonstrated that rhFGF22 protects L02 cells from H2O2-induced oxidative damage via suppression of mitochondrial apoptosis pathways. In conclusion, the strategy described in this paper may provide a novel means to solve the production of insoluble rhFGF22 and shine new light on its translational potential. PMID- 29627395 TI - Impact of the mother-nurse partnership programme on mother and infant outcomes in paediatric cardiac intensive care unit. AB - OBJECTIVES: To identify the effects of a mother-nurse partnership programme based on the core components of information sharing, negotiation and participation in care. Specifically, we examined the programme's effects on parental satisfaction, parental self-efficacy, perceived partnership and anxiety, as well as infants' time to reach full oral feeding and length of postoperative hospital stay, following cardiac surgery on infants at a paediatric intensive care unit with a restrictive visiting policy. RESEARCH METHODOLOGY/DESIGN: Quasi-experimental study. An analysis of covariance was used to investigate between-group differences while ensuring homogeneity. SETTING: A paediatric cardiac ICU. MAIN OUTCOME MEASURES: Parental satisfaction, parental self-efficacy, perceived partnership and anxiety. RESULTS: Data from 37 and 36 mothers in the control and experimental groups respectively, were analysed. Compared with controls, experimental group mothers reported significantly higher parental satisfaction (F = 39.29, p < .001), parental self-efficacy (F = 7.45, p = .008), perceived partnership (F = 62.30, p < .001) and lower anxiety (F = 12.93, p < .001), upon transfer to the ward. Infant outcomes did not differ between the groups. CONCLUSION: This programme appears to facilitate collaboration between nurses and mothers and positively influences mothers' emotional and cognitive outcomes following infants' cardiac surgery. PMID- 29627396 TI - Characterization of circulating steroid hormone profiles in the bottlenose dolphin (Tursiops truncatus) by liquid chromatography-tandem mass spectrometry (LC-MS/MS). AB - Systemic steroid hormone measurements are often used in the assessment of reproductive, developmental, and stress physiology in vertebrates. In protected wildlife, such as the common bottlenose dolphin (Tursiops truncatus), these measures can provide critical information about health and fitness to aid in effective conservation and management. Circulating steroid hormone concentrations are typically measured by immunoassays, which have imperfect specificity and are limited to the measurement of a single hormone per assay. Here we demonstrate that reverse phase solid phase extraction (SPE) coupled to liquid chromatography tandem mass spectrometry (LC-MS/MS) allows for the simultaneous, precise (<15% relative standard deviation), and accurate (between 70% and 120% recovery of spiked quantities) measurement of at least seven steroid hormones in dolphin plasma. These seven steroid hormones include three hormones that have been measured previously in bottlenose dolphin blood (progesterone, testosterone, and cortisol) and three hormones which have never been quantified in dolphin blood (17-hydroxyprogesterone, androstenedione, cortisone, and corticosterone). While 17beta-estradiol was not detected endogenously, we were able to accurately and precisely measure spiked quantities estradiol. Measures from plasma were more precise (i.e., lower RSD) than serum, and thus we recommend plasma as the preferred matrix for this analytical method. In order to facilitate comparison of current and future plasma-based studies to previous serum-based studies, we characterized the relationships between hormone measurements in matched plasma and serum, and found that measurements across matrices are significantly and positively correlated. Lastly, to demonstrate potential applications of this method, we examined how steroid hormone profiles vary by pregnancy, sexual maturity, and stress status - pregnancy was associated with elevated progesterone, adult males had higher testosterone, and capture stress was associated with elevated corticosteroids. Overall, we conclude that this method will enable investigators to more thoroughly and efficiently evaluate steroid hormone homeostasis in bottlenose dolphins compared to immunoassay methods. These methods can potentially be applied to the assessment of sexual maturity/seasonality, pregnancy status, and stress in free-ranging bottlenose dolphins as well as those maintained under human care, and potentially other marine mammals. PMID- 29627394 TI - Brucella melitensis and B. abortus in eggs, larvae and engorged females of Dermacentor marginatus. AB - Brucellosis is a relatively common zoonosis, particularly in the developing countries. Our aim was to cultivate the Brucella wild-type strain from eggs of Dermacentor marginatus, and to molecularly investigate the presence of Brucella DNA in different developmental stages. A total of 350 engorged adult female ticks were collected from sheep and cattle, and individually placed into a single clean breathable tube suitable for laying eggs and for the development of larvae. Detection of Brucella DNA was attempted in engorged female ticks and their offsprings based on the Brucella outer membrane protein gene 22 (omp22) and IS711 gene. Additionally, bacterial isolation in the culture medium of Brucella was performed. The eggs from the Brucella DNA-positive engorged female ticks were positive for Brucella omp22 (4.6%, 16/350). The prevalence was 40.9% (90/220) in larvae, which developed from the Brucella DNA-positive egg batch. Based on BLASTn analysis of IS711 gene, ten (4.1%, 10/242) PCR products were identified as Brucella melitensis in D. marginatus from sheep, while six (5.6%, 6/108) were identified as B. abortus in D. marginatus infesting cattle. B. melitensis biotype 3 was isolated from eggs of D. marginatus. This is the first study which demonstrates the transovarial transmission of Brucella in the D. marginatus. Furthermore, Brucella may be partially transmitted from D. marginatus eggs to larvae (40.9%) in D. marginatus. These findings extend our knowledge on the transmission of Brucella in D. marginatus offsprings. PMID- 29627397 TI - Correct AED electrode placement is rarely achieved by laypersons when attaching AED electrodes to a human thorax. PMID- 29627398 TI - Anatomical investigations on intraosseous access in stillborns - Comparison of different devices and techniques. AB - AIM: Intraosseous (IO)-access plays an alternative route during resuscitation. Our study was performed to investigate the successful rate of IO-access in preterm and term stillborns using different devices and techniques. METHODS: The cadavers used were legal donations. 16 stillborns, median: 29.2 weeks (IQR 27.2 38.4) were investigated. Two different needles (a: Butterfly needle, 21G, Venofix(r) Fa.Braun; b: Arrow(r)EZ-IO(r)15G, Teleflex, Dublin, Ireland) were used. Needles were inserted i: manually, using a Butterfly needle; ii: manually, using EZ-IO(r) needle or iii: using a battery-powered semi-automatic drill (Arrow(r)EZ-IO(r)). Spectral-CT's were performed. The diameter of the corticalis was determined from the CT-images. Successful hit rates with 95% confidence intervals (CI) and odds ratios between the three methods were estimated using a generalised linear mixed model (GLMM). RESULTS: Estimated success rate was 61.1% (95%CI:39.7%-78.9%) for the Butterfly needle, 43.0% (95%CI:23.4%-65.0%) for hand twisted EZ-IO(r) screwing and 39.7% (95%CI:24.1-57.7%) for the semi-automatic drill (Arrow(r)EZ-IO(r)), all referring to an average diameter of the corticalis of 1.2 mm. The odds of a correct position were 2.4 times higher (95%CI:0.8-7.6) when using the Butterfly needle than with the drill. In contrast, the odds of correct positioning when inserting the needle by hand were not significantly different from using the drill (odds ratio 1.1, 95%CI: 0.4-3.3). Neither of these effects nor the diameter of the corticalis with an odds ratio near one were significant in the model. Median diameter of the bone marrow cavity was 4.0 mm [IQR 3.3-4.7]. CONCLUSION: Intraosseous access for premature and neonatal infants could be best achieved by using a manually twisted Butterfly needle. PMID- 29627399 TI - p-Hacking - A call for ethics. PMID- 29627400 TI - Unusual diagnoses made by convex-probe endobronchial ultrasound-guided transbronchial needle aspiration. AB - Endobronchial ultrasound-guided transbronchial needle biopsy (EBUS-TBNA) has proven to be an effective and minimally invasive tool to diagnose and stage lung cancer. However, its use for the diagnosis of rare mediastinal and lung pathologies has been rarely described. Hereby we describe a retrospective chart review of our EBUS-TBNA database for unusual diagnosis made between July 2012 and October 2016. Those conditions considered unusual for EBUS-TBNA diagnosis were identified and their medical records reviewed. PMID- 29627401 TI - Endobronchial foreign bodies in adults - Flexible bronchoscopy as a first approach. PMID- 29627402 TI - Role of the impulse oscillometry in the evaluation of tracheal stenosis. AB - INTRODUCTION AND OBJECTIVES: Tracheal stenosis is a rare and challenging disease. Bronchoscopy is the gold standard for diagnosis and assessment but brings inherent risks. Spirometry is commonly used to access obstructions but is not always feasible due to patient related factors. We therefore considered impulse oscillometry (IOS) as a non-invasive method to quantify airway obstruction and its potential use for diagnosis and follow-up of tracheal stenosis. MATERIALS AND METHODS: Patients with confirmed tracheal stenosis were recruited between January 1st, 2015 and December 31st, 2016. Before bronchoscopy, all subjects underwent IOS and spirometry; for patients submitted to interventional bronchoscopy the same techniques were also performed after the procedure. We assessed the correlation between IOS measurements and airway narrowing as well as between IOS and spirometry values. RESULTS: Twenty-one patients were included. Tracheal narrowing was inversely correlated with X5% (r -0.442, p 0.045) and positively correlated with FEV1/PEF (r 0.467, p 0.033). The stenosis length was inversely correlated with PEF and PEF% (r -0.729, p=0.001 and r -0.707, p=0.002, respectively). There was a strong correlation between spirometric and IOS values. We did not find any significant differences between pre- and post-intervention IOS values for patients assessed after interventional bronchoscopy. CONCLUSIONS: Our study showed a weak correlation between X5% and tracheal narrowing making it unclear whether IOS can be used for physiological assessment of patients with tracheal stenosis. Stenosis length correlated with PEF making it a potential predictor of successful surgical approach. The correlation between IOS and spirometric values makes IOS a potential alternative in patients with suspected tracheal stenosis who are not able to perform spirometry. Larger scale studies should clarify the role of IOS in this pathology. PMID- 29627403 TI - Ventilatory practices in extremely low birth weight infants in a level III neonatal intensive care unit. AB - INTRODUCTION: Although non-invasive forms of ventilation have recently spread in neonatology, invasive ventilation still plays a key role in the support of extremely low birth weight (ELBW) infants. The purpose of this study was to assess changes in neonatal ventilation practices for ELBW infants and compare outcomes between two epochs (2005-2009 vs. 2010-2015) to analyze progression stemming from the implementation of newer clinical guidelines. MATERIALS AND METHODS: We conducted a retrospective study with data collection from all ELBW infants born between 2005 and 2015 in our center through their individual clinical records. The main outcome was the prevalence of bronchopulmonary dysplasia (BPD) in both periods. Assessment of other morbidities and survival were secondary outcomes. RESULTS: A hundred and thirty-one infants were included; median gestational age of 27 weeks (23-33) and mean birth weight of 794.58g (+/ 149.37). Invasive mechanical ventilation (IMV) was performed on 103 (78.6%) infants. Non-significant increases in the use of non-invasive mechanical ventilation (NIMV) were observed between epochs both exclusively and following IMV. In conventional ventilation there were significant variations between epochs, namely a decrease in synchronized intermittent mandatory ventilation (SIMV) and a major growth in the addition of volume guarantee (VG). Significant decreases in BPD (from 50.9% to 32.0%) and cystic periventricular leukomalacia (cPVL) (from 27.5% to 10.7%) were observed between epochs, with no major changes in other morbidities and survival. CONCLUSION: Changes in our neonatal intensive care unit's ventilatory practices according to the most up-to-date guidelines, have led to a decrease in BPD and cPVL, over an 11-year period. PMID- 29627404 TI - Development of spray-freeze-dried siRNA/PEI powder for inhalation with high aerosol performance and strong pulmonary gene silencing activity. AB - In the present study, a novel dry small interfering RNA (siRNA) powder for inhalation, containing polyethyleneimine (PEI) as a delivery vector, was produced by spray freeze drying (SFD). The powder had spherical and highly porous structure of approximately 10 MUm in diameter with high aerosol performance for emission and lung delivery. The reconstituted siRNA/PEI complex after dissolution of the powder had almost the same physicochemical properties and in vitro gene silencing activity as the original one constituted in the sample solution before SFD, showing that the integrity of the siRNA was maintained. In in vivo studies of intratracheal administration into lung metastasis mice and healthy mice, powder with a low dose of 3 MUg siRNA exhibited strong and specific gene silencing activity against tumors metastasized to the lungs, whereas it caused no significant histological changes, lactate dehydrogenase leakage, or inflammatory cytokine induction in the lungs. These results strongly indicated that inhalable dry siRNA/PEI powders can provide effective pulmonary gene silencing without severe lung injury and that SFD can be applied to the production of such powders. PMID- 29627406 TI - Post-9/11 drug- and alcohol- related hospitalizations among World Trade Center Health Registry enrollees, 2003-2010. AB - OBJECTIVE: To describe patterns of drug- and alcohol-related hospitalizations among persons exposed to the 2001 World Trade Center (WTC) terrorist attacks and to assess whether 9/11-related exposures or post-9/11 post-traumatic stress disorder (PTSD) were associated with increased odds of hospitalization. METHODS: Data for adult enrollees in the WTC Health Registry, a prospective cohort study, were linked to New York State (NYS) administrative hospitalization data to identify alcohol- and drug-related hospitalizations from enrollment to December 31, 2010. Logistic regression was used to analyze the associations between substance use-related hospitalization, 9/11-related exposure and PTSD. RESULTS: Of 41,176 NYS resident enrollees, we identified 626 (1.5%) who had at least one alcohol- or drug-related hospitalization; 53.4% (n = 591) of these hospitalizations were for alcohol only diagnoses and 46.6% (n = 515) were drug related. Witnessing >=3 traumatic events on 9/11 was significantly associated with having a drug-related hospitalization (AOR 1.4, 95% CI = [1.1, 1.9]). PTSD was significantly associated with both having a drug-related hospitalization as well as an alcohol only-related hospitalization. (AOR 2.6, 95% CI = [2.0, 3.3], AOR 1.8, 95% CI = [1.4, 2.3], respectively). CONCLUSIONS: Witnessing traumatic events and having PTSD were independently associated with substance use-related hospitalizations. Targeting people who witnessed traumatic events on 9/11 and/or who have PTSD for substance use- treatment could reduce alcohol and drug-related hospitalizations connected to 9/11. PMID- 29627405 TI - Prevalence and correlates of binge drinking among older adults with multimorbidity. AB - BACKGROUND: Binge drinking among older adults has increased in the past decade. Binge drinking is associated with unintentional injuries, medical conditions, and lower health-related quality of life. No studies have characterized multimorbidity among older binge drinkers. METHODS: We examined past 30-day binge alcohol use and lifetime medical conditions among adults age >=50 from the National Survey on Drug Use and Health from 2005 to 2014. Self-reported lifetime prevalence of 13 medical conditions and medical multimorbidity (>=2 diseases) among binge drinkers were compared to non-binge drinkers. Multivariable logistic regression models were used to examine correlates of binge alcohol use among older adults with medical multimorbidity. RESULTS: Among adults aged >=50, 14.4% reported past-month binge drinking. Estimated prevalence of medical multimorbidity was lower (21.4%) among binge drinkers than non-binge drinkers (28.3%; p < 0.01). Binge drinkers were more likely to use tobacco and illegal drugs than non-binge drinkers (ps < 0.001). In the adjusted model, among older adults with multimorbidity, higher income (AOR = 1.44, p < 0.05), past-month tobacco use (AOR = 2.55, p < 0.001) and substance use disorder for illegal drugs (AOR = 1.80, p < 0.05) was associated with increased odds of binge alcohol use. CONCLUSION: The prevalence of multimorbidity was lower among current binge drinkers compared to non-binge drinkers, possibly because older adults in good health are apt to drink more than adults in poorer health. Current use of tobacco and substance use disorder were associated with an increased risk for binge drinking among older adults with multimorbidity. Binge drinking by older adults with multimorbidity may pose significant health risks especially with the concurrent use of other substances. PMID- 29627407 TI - Long-term opioid use after inpatient surgery - A retrospective cohort study. AB - BACKGROUND: Knowledge of incidence and risk factors for long-term opioid prescribing is critical for surgical patients. In this retrospective cohort study, we linked information available at the time of surgery with prescription data to ascertain characteristics associated with prolonged opioid therapy. METHODS: Patients (n = 6003) with claims in the Colorado All Payer Claims Database (APCD) were matched with 20,501 encounters in a clinical database. Rates of prescription filling were defined by at least one monthly opioid claim relative to the date of surgery. Associations of variables with claims during months 2-6 post-operatively ("long-term prescription filling") were evaluated, and significant variables were jointly modeled using binomial regression. RESULTS: Rates of patients filling opioid prescriptions preoperatively [month (M) relative to date of surgery] were 22%(-3 M), 24%(-2 M), and 27%(-1 M); after surgery, opioid fill rates were 62%(1 M), 28%(2 M), 24%(3), 24%(4 M), 23%(5 M), and 22%(6 M). The majority, 71-76%, of patients filling prescriptions in months 2 6 after surgery had also filled before surgery. In the binomial regression model, long-term opioid use was associated with prior opioid use (p < 0.0001), age >=26 to <65 relative to age >= 65 (p < 0.0001), orthopedic surgery (p = 0.001), colorectal surgery (p = 0.003), multiple procedures (p < 0.0001), and worse physical status classification (p < 0.0001). CONCLUSIONS: Patients who had filled opioid prescriptions preoperatively comprised the majority of the group who filled long-term prescriptions. Surgical procedures were associated with discontinuation of previous opioid prescribing in some patients. For others, surgery marked the initiation of prolonged opioid therapy. Surgical encounters should include interventions aimed to reduce long-term opioid use. PMID- 29627408 TI - Validity of the PARADISE24 questionnaire in people with substance use disorders: A measure to assess psychosocial difficulties. AB - OBJECTIVES: Psychosocial difficulties (PSDs) are common in people with substance use disorders (SUDs). The PARADISE24 has been shown to be an adequate tool for measuring PSDs in inpatients with SUDs. The aim of this study is to evaluate the psychometric properties of the PARADISE24 in a sample of patients with SUDs. METHODS: 2637 participants with SUDs completed the PARADISE24 questionnaire during their treatment. The latent structure of the PARADISE24 questionnaire was analyzed in the outpatient sample by means of exploratory and confirmatory factor analysis (EFA and CFA). Metric invariance was then assessed in relation to the inpatient sample using multiple group CFA. Finally, evidences of known-groups validity were checked to test the ability of the questionnaire to differentiate between socio-demographic and clinical groups. RESULTS: The one-factor model presented an adequate fit in both the EFA (CFI = 0.98; TLI = 0.98; RMSEA = 0.07) and the CFA (CFI = 0.98; TLI = 0.98; RMSEA = 0.07) solutions. The reliability of the scale was found to be high (alpha = 0.93). Strict metric invariance between inpatients and outpatients was achieved (RMSEA = 0.063; TLI = 0.983; CFI = 0.981). The PARADISE24 was able to discriminate between the inpatients and outpatients at both latent (d = 0.98) and observed levels (d = 0.86). CONCLUSIONS: The PARADISE24 is a unidimensional tool that is reliable for assessing and comparing PSDs in both outpatients and inpatients with SUDs. Further research is required for evaluating the ability of the PARADISE24 to quantify longitudinal changes in PSDs. PMID- 29627409 TI - Marijuana use during and after pregnancy and association of prenatal use on birth outcomes: A population-based study. AB - BACKGROUND: We sought to describe the correlates of marijuana use during and after pregnancy, and to examine the independent relationship between prenatal marijuana use and infant outcomes. STUDY DESIGN: We used state-specific data from the Pregnancy Risk Assessment Monitoring System (N = 9013) to describe correlates of self-reported prenatal and postpartum marijuana use. We estimated differences in mean infant birth weight and gestational age among prenatal marijuana users and nonusers, controlling for relevant covariates (i.e., cigarette smoking). RESULTS: Respectively, 4.2% (95% CI: 3.8-4.7) and 6.8% (95% CI: 6.0-7.7) of women reported using marijuana during and after pregnancy. Compared to nonusers, prenatal marijuana users were more likely to be <=24 years; non-Hispanic white, not married, have <12 years of education, have Medicaid/IHS/Other insurance, be on WIC during pregnancy, have annual household income <$20,000, cigarette smokers, and alcohol drinkers during pregnancy (p-values < 0.05). After adjustment, no differences in gestational age or birthweight were observed. Postpartum users were more likely to smoke cigarettes (48.7% vs. 20.3%), experience postpartum depressive symptoms (14.0% vs. 9.0%), and breastfeed for <8 weeks (34.9% vs. 18.1%). CONCLUSION: Co-use of substances was common among prenatal and postpartum marijuana users. Prenatal marijuana use was not independently associated with lower average birthweight or gestational age. Postpartum marijuana use was associated with depressive symptoms and shorter breastfeeding duration. Surveillance of marijuana use among pregnant and postpartum women is critical to better understanding the relationship of marijuana use with birth outcomes, and postpartum experiences such as depression and breastfeeding. PMID- 29627410 TI - [Intrauterine device and pelvic inflammatory disease: Myth or reality?] AB - INTRODUCTION: Intrauterine device (IUD) is a reliable contraceptive method that is long term reversible, and well tolerated. Numerous studies prove its efficiency and report rare complications that are attributed to it. However, its use is limited due to fear that it can cause a pelvic inflammatory disease (PID). This is based on historical data on infections related to the "Dalkon Shield", which was removed from the market in 1974. METHOD: The analyzed articles were extracted from PUBMED database between 2000 and 2016. In total, 22 studies were retained. A meta-analysis was not possible due to the methodological diversity among the selected articles contributing to this narrative review of the literature. RESULTS: After analysis, the following factors influence the risk of PID linked to IUDs: an advanced age and sexually transmitted infections. CONCLUSION: The risk of PID linked to IUDs is lower than 1%. This is explained by new models of IUD, better screening tests, more frequent follow-up of the patients and the improvement of care PID patients. In the light of our results, the threat of pelvic inflammatory disease should not hinder the use of IUDs. PMID- 29627411 TI - Occurrence, sources and health risk of polycyclic aromatic hydrocarbons in soils around oil wells in the border regions between oil fields and suburbs. AB - The Yellow River Delta (YRD) is a typical region where oil fields generally overlap cities and towns, leading to complex soil contamination from both the oil fields and human activities. To clarify the distribution, speciation, potential sources and health risk of polycyclic aromatic hydrocarbons (PAHs) in soils of border regions between oil fields and suburbs of the YRD, 138 soil samples (0-20 cm) were collected among 12 sampling sites located around oil wells with different extraction histories. The 16 priority control PAHs (16PAHs), as selected by the United States Environmental Protection Agency (USEPA), were extracted via an accelerated solvent extraction and detected by GC-MS. The results showed that soils of the study area were generally polluted by the 16PAHs. Among these pollutions, chrysene and phenanthrene were the dominant components, and 4-ring PAHs were the most abundant. A typical temporal distribution pattern of the 16PAHs was revealed in soils from different sampling sites around oil wells with different exploitation histories. The concentrations of total 16PAHs and high-ring PAHs (HPAHs) both increased with the extraction time of the nearby oil wells. Individual PAH ratios and PCA method revealed that the 16PAHs in soil with newly developed oil wells were mainly from petroleum pollutants, whereas PAHs in soils around oil wells with a long exploitation history were probably from petroleum contamination; combustion of petroleum, fuel, and biomass; and degradation and migration of PAHs from petroleum. Monte Carlo simulation was used to evaluate the health risks of the 7 carcinogenic PAHs and 9 non-carcinogenic PAHs in the study area. The results indicated that ingestion and dermal contact were the predominant pathways of exposure to PAH residues in soils. Both the carcinogenic and non-carcinogenic burden of the 16PAHs in soils of the oil field increased significantly with exploitation time of nearby oil wells. PMID- 29627412 TI - Behavior of quizalofop-p and its commercial products in water by liquid chromatography coupled to high resolution mass spectrometry. AB - A degradation study of quizalofop-p and its commercial products (quizalofop-p ethyl, quizalofop-p-tefuryl and propaquizafop) in water samples has been performed using ultra high-performance liquid chromatography coupled to Orbitrap mass spectrometry (UHPLC-Orbitrap-MS). CHHQ (dihydroxychloroquinoxalin), CHQ (6 chloroquinoxalin-2-ol) and PPA ((R)-2-(4-hydroxyphenoxy)propionicacid) were the main metabolites of this active substance (quizalofop-p) in water. The degradation of the parent compound has been monitored in distilled water. Several commercial products (Panarex(r), Master-D(r) and Dixon(r)) were used to evaluate the degradation of the target compounds into their metabolites. The concentration of the main active substances (quizalofop-p-tefuryl, quizalofop-p-ethyl and propaquizafop) decreased during the degradation studies, whereas the concentration of quizalofop-p increased. DT50 of the main active substances ranged from 10 days to 70 days for most of the analytes, so it can be concluded that compounds are medium-high persistent in this matrix. Metabolites, such as PPA, CHHQ and CHQ, were detected in water samples after 7 days of the application of the commercial products at concentrations higher than their limits of quantification (> 0.1 ug/L). CHQ was detected at 1400 ug/L after 75 days of the application of quizalofop-p-ethyl commercial product. CHHQ and CHQ were found at the highest concentrations at 7-45 days after the application of quizalofop-p tefuryl, whereas PPA was detected at higher concentrations (up to 5.37 ug/L) in propaquizafop samples. PMID- 29627413 TI - Epithelial cell shape change of Drosophila as a biomonitoring model for the dose assessment of environmental radiation. AB - Inevitable exposure to ionizing radiation from natural and human-made sources has been increasing over time. After nuclear disasters, such as the Fukushima accident, the public concerns on health risk of radiation exposure because of radioactive contamination of the environment have increased. However, it is very difficult to assess the biological effects of exposure caused by environmental radiation. A reliable and rapid bioassay to monitor the physiological effects of radiation exposure is therefore needed. Here, we quantitatively analyzed the changes in cell shape in Drosophila epidermis after irradiation as a model for biomonitoring of radiation. Interestingly, the number of irregularly shaped epithelial cells was increased by irradiation in a dose-dependent manner. A dose response curve constructed with the obtained data suggests that the measurement of the number of irregular shaped cell in the epidermis is useful for the assessment of radiation dose. In addition, a comparison of the variation in the different samples and the data scored by different observers showed that our evaluation for cellular morphology was highly reliable and accurate and would, therefore, have immense practical application. Overall, our study suggests that detection of morphological changes in the epithelial cells is one of the efficient ways to quantify the levels of exposure to radioactive radiation from the environment. PMID- 29627414 TI - Removal of methylene blue from aqueous solution by modified bamboo hydrochar. AB - Four hydrochars (labeled as HC, AHC, MHC, and MAHC, respectively) were prepared by hydrothermal carbonization of bamboo with and without chlorane or followed by NaOH modification. Various techniques were adopted to characterize the physicochemical properties of hydrochars and the removal of methylene blue (MB) by these hydrochars from aqueous solution was investigated. The MB adsorption isotherm and kinetic onto MAHC and MHC can be preferably interpreted by Langmuir adsorption mode and the pseudo-second-order model, respectively. Thermodynamic parameters implied that adsorption was a spontaneous and exothermic process. The adsorption capacity of MAHC was 655.76 mg g-1, which was 2-3 times compared to that of MHC (268.93 mg g-1) at 303 K. The high adsorption capacity of MAHC for MB suggests that hydrothermal carbonization in acidic medium followed by alkaline treatment has the potential application to produce efficient MB adsorbents used in wastewater treatment. PMID- 29627415 TI - Biomarkers in tigerfish (Hydrocynus vittatus) as indicators of metal and organic pollution in ecologically sensitive subtropical rivers. AB - Studies have shown high levels of contamination of both metals and organochlorine pesticides (OCPs) in aquatic systems of the world renowned Kruger National Park, South Africa. With effects evident in top predators, including, unexplained Crocodylus niloticus deaths and organ level and histological changes in Hydrocynus vittatus. A suite of biomarkers reflecting exposure and were selected to evaluate biological responses of H. vittatus to anthropogenic stressors as well as to evaluate whether the chosen suite of biomarkers could successfully distinguish between the different pollution profiles present in the selected rivers. During this study a clear relationship was found between exposure to environmental contaminants and the concomitant responses of H. vittatus to these stressors. The ensuing biomarker responses indicated that there is a physiological attempt to deal with, and mitigate the deleterious effects that metals and OCPs may induce. In the Luvuvhu River there is a clear indication in H. vittatus of the stimulation of anti-oxidant protective mechanisms in response to internal OCP exposure. This is reflected by the increasing cytochrome P-450, superoxide dismutase, and more specifically reduced glutathione, which resulted in decreased lipid and protein breakdown (reflected in decreased lipid peroxidation and protein carbonyl levels). Consequently H. vittatus populations of the Luvuvhu River are under greater cumulative stress and this is reflected in the lower energy budgets. Our results further show the integrated application value of the current suite of biomarkers in assessing responses of subtropical fish to metal and OCP exposure as the entire suite of biomarkers when used in conjunction were able to explain 100% of the variation in the data. PMID- 29627416 TI - Dracaena sanderiana endophytic bacteria interactions: Effect of endophyte inoculation on bisphenol A removal. AB - Bisphenol A (BPA) is one of the most abundant endocrine-disrupting compounds which is found in the aquatic environment. However, actual knowledge regarding the effect of plant-bacteria interactions on enhancing BPA removal is still lacking. In the present study, Dracaena sanderiana endophytic bacteria interactions were investigated to evaluate the effect of bacterial inoculation on BPA removal under hydroponic conditions. Two plant growth-promoting (PGP) bacterial strains, Bacillus thuringiensis and Pantoea dispersa, which have high BPA tolerance and can utilize BPA for growth, were used as plant inocula. P. dispersa-inoculated plants showed the highest BPA removal efficiency at 92.32 +/- 1.23% compared to other inoculated and non-inoculated plants. This was due to a higher population of the endophytic inoculum within the plant tissues which resulted in maintained levels of indole-3-acetic acid (IAA) for the plant's physiological needs and lower levels of reactive oxygen species (ROS). In contrast, B. thuringiensis-inoculated plants had a lower BPA removal efficiency. However, individual B. thuringiensis possessed a significantly higher BPA removal efficiency compared to P. dispersa. This study provides convincing evidence that not all PGP endophytic bacteria-plant interactions could improve the BPA removal efficiency. Different inocula and inoculation times should be investigated before using plant inoculation to enhance phytoremediation. PMID- 29627417 TI - Biofilm development of Bacillus thuringiensis on MWCNT buckypaper: Adsorption synergic biodegradation of phenanthrene. AB - Adsorption-synergic biodegradation of a model PAH (phenanthrene, Phe) on MWCNT buckypaper surface with a potential PAH biodegrading bacterial strain Bacillus thuringiensis AT.ISM.11 has been studied in aqueous medium. Adsorption of Phe on buckypaper follows Dubinin-Ashtakhov model (R2 = 0.9895). MWCNT generally exerts toxicity to microbes but adsorbed layer of Phe prevents the direct contact between MWCNT and bacterial cell wall. FESEM study suggests that formation of biofilms occurred on buckypaper. Lower layer cells are disrupted and flattened as they are in direct contact with MWCNT but the upper layer cells of the developed biofilm are fully intact and functional. Force-distance curves of Bacillus thuringiensis AT.ISM.11 with buckypaper indicates adhesion forces varied from 10.3 to -15.6 nN with increasing contact time, which supports the phenomenon of biofilm formation. AFM surface statistical data of buckypaper suggests increase in bacterial cell count increases the Rms roughness (95.7242-632.565) while adhering to the buckypaper surface to form biofilm. We observed an enhanced Phe biodegradation of 93.81% from that of the 65.71% in 15 days' study period, using buckypaper as a bio-carrier or a matrix for the microbial growth. GC-MS study identified phthalic acid ester as metabolite, which is the evidence of protocatechuate pathway degradation of Phe. Current study enlightens the interaction between hydrocarbons and microbes in presence of MWCNT buckypaper matrix in aqueous system for the first time. An enhancement in biodegradation of Phe by 28.10% has also been reported which can be a basis for CNT aided enhanced biodegradation studies in future. PMID- 29627418 TI - Evaluation of a novel automated water analyzer for continuous monitoring of toxicity and chemical parameters in municipal water supply. AB - A novel tool, the DAMTA analyzer (Device for Analytical Monitoring and Toxicity Assessment), designed for fully automated toxicity measurements based on luminescent bacteria as well as for concomitant determination of chemical parameters, was developed and field-tested. The instrument is a robotic water analyzer equipped with a luminometer and a spectrophotometer, integrated on a thermostated reaction plate which contains a movable carousel with 80 cuvettes. Acute toxicity is measured on-line using a wild type Photobacterium phosphoreum strain with measurable bioluminescence and unaltered sensitivity to toxicants lasting up to ten days. The EC50 values of reference compounds tested were consistent with A. fischeri and P. phosphoreum international standards and comparable to previously published data. Concurrently, a laboratory trial demonstrated the feasibility of use of the analyzer for the determination of nutrients and metals in parallel to the toxicity measurements. In a prolonged test, the system was installed only in toxicity mode at the premises of the World Fair "Expo Milano-2015", a high security site to ensure the quality of the supplied drinking water. The monitoring program lasted for six months during which ca. 2400 toxicity tests were carried out; the results indicated a mean non toxic outcome of -5.5 +/- 6.2%. In order to warrant the system's robustness in detecting toxic substances, Zn was measured daily with highly reproducible inhibition results, 70.8 +/- 13.6%. These results assure that this novel toxicity monitor can be used as an early warning system for protection of drinking water sources from emergencies involving low probability/high impact contamination events in source water or treated water. PMID- 29627419 TI - Health risk assessment of heavy metals in freshwater fish in the central and eastern North China. AB - The distribution and potential health risks of eight heavy metals (Copper (Cu), Chromium (Cr), Zinc (Zn), Lead (Pb), Arsenic (As), Cadmium (Cd), Manganese (Mn), Nickel (Ni)) in 16 freshwater systems from central and eastern North China, were investigated. The fish were divided as wild fish, which grew naturally without artificially feeding, and farmed fish. The total concentrations of the eight heavy metals ranged from 82.9 to 226 MUg/L in the surface water samples and 3.32 27.6 mg/kg dw in the fish samples. There was no significant difference in the heavy metal concentrations between natural and farmed water systems. The concentrations of toxic metals, including Pb, As, Cd, Cr, are similar in all kinds of fish. However, the essential metals (Zn, Cu, Mn, Ni) in crucian carp (15.9 mg/kg) was much higher than other kinds of fish. Comparing the wild and farmed fish, the average concentrations of each heavy metal in wild crucian carp, bighead carp, grass carp were higher than those in farmed fish. The average log BCFs (bioconcentration factor) of Zn, Cr and Cu were the highest (2.14, 2.04, 2.00 L/kg) while that of Cd (0.65 L/kg) was the lowest. The non-carcinogenic and carcinogenic health risks to adults and children resulting from consuming the fish were assessed based on the target hazard quotients (THQ). The results indicated that the non-carcinogenic health risk to humans by consuming fish products, no matter wild or farmed fish, was relatively low. The carcinogenic risk of inorganic As was 5.11 * 10-6-1.95 * 10-4 for children and 2.71 * 10-6 1.04 * 10-4 for adult, which are within the acceptable range. The results indicated that the concentrations of heavy metals in the freshwater fish in central and eastern North China were relatively low, and did not cause considerable human health risks. PMID- 29627420 TI - Exercise training causes a partial improvement through increasing testosterone and eNOS for erectile function in middle-aged rats. AB - PURPOSE: Aging changes the balance of sex hormones and causes endothelial dysfunction in the penis, both of which are important determinants of erectile dysfunction (ED). The purpose of this study was to evaluate whether exercise training could protect against erectile dysfunction by increasing serum testosterone and penile eNOS levels in aging rats. METHODS: A total of 14 young (2-month-old) and 14 middle-aged (18-month-old) Sprague Dawley rats were randomly assigned to either untrained control (young control, [YC], middle-aged control, [MC]) or endurance exercise-trained (young exercise, [YE], middle-aged exercise, [ME]) groups with seven rats per group. The exercise groups trained with treadmill running for 6 weeks. Body composition parameters (body weight, heart mass, liver mass, and testicular mass), serum sex hormone levels (testosterone, luteinizing hormone, follicle-stimulating hormone, and prolactin), endothelial function-related parameters in the penis (endothelial nitric oxide synthase [eNOS], CD31, alpha smooth muscle actin [alpha-SMA]), and maximal intracavernous pressure measure (ICP) and total ICP were analyzed in middle-aged rats. RESULTS: The middle-aged groups showed increased body weight, as compared with the young groups, but exercise training attenuated the aging-induced increase in body weight. The middle-aged groups had lower testicular mass compared with the young groups, but exercise training attenuated aging-induced decreases in testicular mass. Exercise training increased serum testosterone levels in both the young and middle-aged groups. However, there were no changes in the levels of luteinizing hormone, follicle-stimulating hormone, and prolactin among the groups. MC group showed decreased protein levels of p-eNOS, as compared with the YC group. However, exercise training protected against aging-induced decrease in eNOS and p eNOS protein levels in the penis. Interestingly, exercise training also increased protein levels of alpha-SMA and maximal ICP in the middle-aged group. CONCLUSIONS: Exercise training has beneficial effects on erectile function in aged rats through increased testosterone production from the testis and strengthening of the cavernous endothelium with activation of eNOS. Therefore, exercise training may be a therapeutic modality for improving erectile dysfunction associated with aging. PMID- 29627421 TI - Depressive symptoms and muscle weakness: A two-way relation? AB - The potential association between depressive symptoms and dynapenia - i.e. muscle weakness - is limited to few, mainly cross-sectional, studies. We use SHARE (Survey on Health, Ageing and Retirement in Europe) panel data to investigate whether the onset of dynapenia at 4-year follow-up can be explained by pre existing (either at baseline, or at 2-year follow-up) depressive symptoms, or vice versa. Depressive symptoms were identified as a score of 4 or more on the 12 item EURO-D scale. Individuals were classified as affected by dynapenia if they had handgrip strength of <20 kg for women and 30 kg for men. We estimate whether being affected by symptoms of depression at baseline or becoming symptomatic between baseline and a 2-year follow-up increases the odds-ratio (OR) for dynapenia at a 4-year follow-up among individuals with no muscle strength impairment at baseline. We also carry out the reverse analysis, and study whether dynapenia at baseline or incident dynapenia between baseline and first follow-up increase the probability that individuals develop depressive symptoms by the second follow-up. The analysis was carried out using multivariate logistic regression. After adjusting for a full set of potential confounders, being symptomatic for depression at baseline did not increase the risk of dynapenia at the 4-year follow-up. Instead, individuals developing depressive symptoms between baseline and the 2-year follow-up had a 34% increased risk of developing dynapenia at the 4-year follow-up (OR 1.34, 95% CI 1.02 1.66). No significant association was detected between dynapenia at baseline or the onset of dynapenia between baseline and the 2-year follow-up and the incidence of depressive symptoms at the 4-year follow-up. In conclusion, our results support the effect of the onset of depressive symptoms on the onset of dynapenia, even after considering the role of confounding factors. PMID- 29627422 TI - Predictors of Failure in Infant Mandibular Distraction Osteogenesis. AB - PURPOSE: Mandibular distraction osteogenesis (MDO) has been shown to be successful in treating upper airway obstruction caused by micrognathia in pediatric patients. The purpose of this study was to assess the success rate of MDO and possible predictors of failure. PATIENTS AND METHODS: The records of all neonates and infants who underwent MDO from 2008 to 2015 were retrospectively reviewed. Procedural failure was defined as patient death or the need for tracheostomy postoperatively. Details of distraction, length of stay, and failures were captured and elucidated. RESULTS: Of the 82 patients, 47 (57.3%) were male; 46 (56.1%) had sporadic Pierre Robin sequence; 33 (40.3%) had syndromic Pierre Robin sequence; and 3 (3.7%) had micrognathia, not otherwise specified. The average distraction length was 27.5 mm (range, 15 to 30 mm; SD, 4.4 mm), the average age at operation was 63.3 days (range, 3 to 342 days; SD, 71.4 days), and the average length of post-MDO hospital stay was 43 days (range, 9 to 219 days; SD, 35 days) with an average follow-up period of 4.3 years (range, 1.1 to 9.6 years; SD, 2.6 years). There were 7 failures (8.5%) (5 tracheostomies and 2 deaths) resulting in a 91.5% success rate. Regression analysis showed that the predicted probability of the need for tracheostomy was 45% (P = .02) when the patient had a central nervous system (CNS) anomaly. The predicted probability of the need for tracheostomy and death combined was 99.6% when the patient had laryngomalacia and a CNS anomaly and was preoperatively intubated (P < .05). CONCLUSIONS: This review confirms that MDO is an effective method of treating the upper airway obstruction caused by micrognathia with a high success rate. In our sample the presence of CNS abnormalities, laryngomalacia, and preoperative intubation had a significant impact on the failure rate. PMID- 29627424 TI - Asthma across the lifespan: Time for a paradigm shift. AB - We have a unique opportunity to significantly reduce the worldwide burden of asthma in children and affect respiratory outcomes in adults. However, this will require a paradigm shift that is directed at altering the natural history of asthma, reducing asthma exacerbations, and preventing long-term adverse outcomes of childhood asthma. Attention should continue to be directed toward minimizing risk, as well as impairment, with a goal to achieve optimal control. Based on several National Institutes of Health studies conducted over the last 10 years, we now have the tools necessary to accomplish this goal. The tools include assessment of lung function over time or defining trajectories of lung growth, the Composite Asthma Severity Index score, a panel of useful biomarkers, the Seasonal Asthma Exacerbation Prediction Index score, and rapidly advancing technology that includes adherence monitoring. Future guideline revisions should consider incorporating recommendations to follow spirometry over time and defining trajectories of lung growth to assess risk for reduced lung growth and early decline, asthma burden by using biomarkers to select and monitor therapy, assessment of social determinants of health, evaluation of risk for seasonal exacerbations, and consideration of electronic adherence monitoring for difficult to-manage asthma. Guidelines should continue to include a core dedicated to the diagnosis and treatment of intermittent and mild and moderate persistent asthma and include additional sections dedicated to the management of severe asthma. PMID- 29627425 TI - Actinomycotic Hepatic Abscess Mimicking Liver Tumor. PMID- 29627423 TI - A Jagged 1-Notch 4 molecular switch mediates airway inflammation induced by ultrafine particles. AB - BACKGROUND: Exposure to traffic-related particulate matter promotes asthma and allergic diseases. However, the precise cellular and molecular mechanisms by which particulate matter exposure acts to mediate these effects remain unclear. OBJECTIVE: We sought to elucidate the cellular targets and signaling pathways critical for augmentation of allergic airway inflammation induced by ambient ultrafine particles (UFP). METHODS: We used in vitro cell-culture assays with lung-derived antigen-presenting cells and allergen-specific T cells and in vivo mouse models of allergic airway inflammation with myeloid lineage-specific gene deletions, cellular reconstitution approaches, and antibody inhibition studies. RESULTS: We identified lung alveolar macrophages (AM) as the key cellular target of UFP in promoting airway inflammation. Aryl hydrocarbon receptor-dependent induction of Jagged 1 (Jag1) expression in AM was necessary and sufficient for augmentation of allergic airway inflammation by UFP. UFP promoted TH2 and TH17 cell differentiation of allergen-specific T cells in a Jag1- and Notch 4 dependent manner. Treatment of mice with an anti-Notch 4 antibody abrogated exacerbation of allergic airway inflammation induced by UFP. CONCLUSION: UFP exacerbate allergic airway inflammation by promoting a Jag1-Notch 4-dependent interaction between AM and allergen-specific T cells, leading to augmented TH cell differentiation. PMID- 29627426 TI - Diffuse Esophageal Squamous Papillomatosis Covering the Entire Esophagus. PMID- 29627427 TI - Clinical and Endoscopic Remission in a Patient With Cronkhite-Canada Syndrome. PMID- 29627428 TI - Localized Gastrointestinal ALlambda Amyloidosis. PMID- 29627430 TI - Transverse subglottic diameter assessment in the third gestation trimester: Preeclampsia versus control. PMID- 29627429 TI - Gestational exposure to tetrabutyltin blocks rat fetal Leydig cell development. AB - Tetrabutyltin is a stable organotin and may exhibit endocrine disrupting properties. Herein, we investigated effects of tetrabutyltin on the development of rat fetal Leydig cells, which support differentiation of the male reproductive tract in late gestation. Female pregnant Sprague Dawley rats were gavaged with tetrabutyltin (0, 100, 200, and 500 mg/kg) from gestational day (GD) 12 to GD 21. Tetrabutyltin dose-dependently decreased testicular testosterone levels (0.756 +/ 0.208 and 0.813 +/- 0.277 ng/testis at the 200 and 500 mg/kg doses, respectively) compared to control (1.692 +/- 0.218 ng/testis) at GD 21. Furthermore, tetrabutyltin induced fetal Leydig cell aggregation, decreased fetal Leydig cell size and cytoplasmic size at the >=100 mg/kg doses, and downregulated the expression levels of Scarb1, Cyp17a1, and Insl3 at doses >=100 mg/kg and Star expression at 200 mg/kg. Taking together, the present results indicated that prenatal exposure of male rats to tetrabutyltin affected fetal Leydig cell development. PMID- 29627431 TI - The efficacy of ultrasound-guided type-I and type-II pectoral nerve blocks for postoperative analgesia after breast augmentation: A prospective, randomised study. AB - PURPOSE: The present study was planned to evaluate the efficacy and safety of ultrasound-guided Pecs I and II blocks for postoperative analgesia after sub pectoral breast augmentation. METHODS: Fifty-four adult female patients undergoing breast augmentation were randomly divided into two groups: the control group (Group C, n=27) who were not subjected to block treatment and Pecs group (Group P, n=27) who received Pecs I (bupivacain 0.25%, 10mL) and Pecs II (bupivacain 0.25%, 20mL) block. Patient-controlled fentanyl analgesia was used for postoperative pain relief in both groups, and the patients were observed for the presence of any block-related complications. RESULTS: The 24-h fentanyl consumption was smaller in Group P [mean+/-SD, 378.7+/-54.0MUg and 115.7+/ 98.1MUg, respectively; P<0.001]. VAS scores in Group P were significantly lower at the time of admission to the post-anaesthetic care unit and at 1, 2, 4, 8, 12, and 24h (P<0.001). The rates of nausea and vomiting were higher in Group C than in Group P (9 vs 2, P=0.018). Hospital stay duration was shorter in Group P than in Group C (24.4+/-1.2h vs 27.0+/-3.1h, P<0.001). No block-related complications were recorded. CONCLUSIONS: Combine used of Pecs I and II blocks provide superior postoperative analgesia in patients undergoing breast augmentation and shortens hospital stay. PMID- 29627432 TI - Influence of Parkinsonism on outcomes of elderly pneumonia patients. AB - INTRODUCTION: Pneumonia is one of the most frequent reasons for hospitalization in patients with Parkinson's disease. The present study aimed to evaluate the impact of Parkinsonism on the clinical courses of elderly patients hospitalized for pneumonia. METHODS: We conducted a retrospective cohort study of patients aged >=60 years who were hospitalized for pneumonia, using data from a national inpatient database in Japan. We performed one-to-four matching for age and sex between patients with and without Parkinsonism. Multivariable regression analyses were carried out for in-hospital mortality, length of stay, and discharge to home. RESULTS: Patients with Parkinsonism had significantly lower in-hospital mortality than those without Parkinsonism (odds ratio, 0.81; 95% confidence interval, 0.74-0.89). Length of stay was 8.1% longer in patients with Parkinsonism. Patients with Parkinsonism were less likely to be discharged to home (odds ratio, 0.62; 95% confidence interval, 0.58-0.67). CONCLUSION: Parkinsonism was not an independent predictor of in-hospital mortality, but was related to prolonged length of stay and discharge other than to home in patients with pneumonia. PMID- 29627434 TI - Biatrial tachycardia utilizing Bachmann bundle. PMID- 29627435 TI - Ventricular arrhythmias and sudden cardiac arrest in Takotsubo cardiomyopathy: Incidence, predictive factors, and clinical implications. AB - BACKGROUND: Takotsubo cardiomyopathy (TTC) is a stress-related transient cardiomyopathy. Life-threatening arrhythmias (LTA) can occur and worsen prognosis. OBJECTIVE: The purpose of this study was to assess the incidence and outcome of LTA in TTC, as well as its predictive factors and clinical implications. METHODS: We studied 214 consecutive cases of TTC over 8 years. The study cohort was divided into 2 groups: those with LTA (LTA group) and those without (non-LTA group). LTA was defined as ventricular tachycardia, ventricular fibrillation, or cardiac arrest. RESULTS: LTA occurred in 23 (10.7%) of patients mainly in the first 24 hours of hospitalization: ventricular tachycardia (n = 2), ventricular fibrillation (n = 11), cardiac arrest (n = 10: 5 asystole, 3 complete heart block, and 2 sinoatrial block). LTAs were associated with lower left ventricular ejection fraction (LVEF) and a high rate of conduction disturbances. In-hospital (39.1% vs 8.9%; P < .001) and 1-year mortality (47.8% vs 14.1%; P < .001) rates were significantly increased in the LTA group. LVEF and QRS duration >105 ms were independent predictors of LTA. In cases where a device was implanted, conduction disturbances persisted after the index event despite complete recovery of LVEF. There was no ventricular arrhythmia recurrence during follow-up. CONCLUSION: LTAs occur early in patients presenting with TTC and are associated with significantly worse short- and long-term prognosis. Left ventricular impairment and QRS duration >105 ms are independent predictors of LTA. Ventricular arrhythmias occurred in the acute phase without further recurrence recorded in hospital survivors, whereas severe conduction disorders persisted during long-term follow-up. These findings may have implications on the choice of device therapy for this specific patient subgroup. PMID- 29627433 TI - RNA Binding Proteins in Intestinal Epithelial Biology and Colorectal Cancer. AB - The intestinal epithelium is highly proliferative and consists of crypt invaginations that house stem cells and villus projections with differentiated cells. There exists a dynamic equilibrium between proliferation, migration, differentiation, and senescence that is regulated by several factors. Among these are RNA binding proteins (RBPs) that bind their targets in a both context dependent and independent manner. RBP-RNA complexes act as rheostats by regulating expression of RNAs both co- and post-transcriptionally. This is important, especially in response to intestinal injury, to fuel regeneration. The manner in which these RBPs function in the intestine and their interactions with other pivotal pathways in colorectal cancer may provide a framework for new insights and potential therapeutic applications. PMID- 29627436 TI - ALA-PDT as palliative care in a patient with secondary perineum EMPD. AB - Extramammary Paget's disease (EMPD) is a rare intraepithelial neoplasm arising in apocrine rich area of the skin. It is divided into primary and secondary EMPD based on whether there is an underlying malignancy, either local apocrine cancers or distant neoplasms. Therefore, all patients with EMPD should undergo an extensive and targeted cancer workup, depending on the histological staining pattern and the location. Surgical removal is considered the mainstay of treatment for patients with EMPD. Herein, we present a case of secondary EMPD where photodynamic therapy was effective in terms of improving symptoms and quality of life. Owing to preexisting comorbid conditions, large area of disease and risk of post-surgery mutilation and functional impairment, surgery could not be elected for this patient, necessitating nonsurgical approach. PMID- 29627437 TI - Feature selection for the classification of traced neurons. AB - BACKGROUND: The great availability of computational tools to calculate the properties of traced neurons leads to the existence of many descriptors which allow the automated classification of neurons from these reconstructions. This situation determines the necessity to eliminate irrelevant features as well as making a selection of the most appropriate among them, in order to improve the quality of the classification obtained. METHODS: The dataset used contains a total of 318 traced neurons, classified by human experts in 192 GABAergic interneurons and 126 pyramidal cells. The features were extracted by means of the L-measure software, which is one of the most used computational tools in neuroinformatics to quantify traced neurons. We review some current feature selection techniques as filter, wrapper, embedded and ensemble methods. The stability of the feature selection methods was measured. For the ensemble methods, several aggregation methods based on different metrics were applied to combine the subsets obtained during the feature selection process. RESULTS: The subsets obtained applying feature selection methods were evaluated using supervised classifiers, among which Random Forest, C4.5, SVM, Naive Bayes, Knn, Decision Table and the Logistic classifier were used as classification algorithms. COMPARISON WITH EXISTING METHODS: Feature selection methods of types filter, embedded, wrappers and ensembles were compared and the subsets returned were tested in classification tasks for different classification algorithms. CONCLUSIONS: L-measure features EucDistanceSD, PathDistanceSD, Branch_pathlengthAve, Branch_pathlengthSD and EucDistanceAve were present in more than 60% of the selected subsets which provides evidence about their importance in the classification of this neurons. PMID- 29627439 TI - MiR-155-5p inhibits PDK1 and promotes autophagy via the mTOR pathway in cervical cancer. AB - Cervical cancer is one of the most common malignant tumors and the leading cause of cancer-related mortality in women. Persistent cervical infection by high-risk human papillomavirus (hrHPV) is related to cervical cancer. MicroRNAs could regulate autophagy caused by viral infection. The aim of the present study was to investigate the regulation of autophagy by miR-155-5p in cervical cancer. In HPV+ human cervical lesion tissues, miR-155-5p expression was found to be markedly decreased. Compared to C33A cancer cells (HPV-), the miR-155-5p expression was significantly lower in Siha and HeLa cells (HPV+), which are both hrHPV positive. The level of autophagy was higher in C33A cells than in Siha and HeLa cells. In addition, in C33A, Siha and HeLa cervical cancer cells, miR-155-5p overexpression promoted autophagy, whereas miR-155-5p downregulation had the opposite effects. Furthermore, miR-155-5p downregulation suppressed LC3 and promoted P62 protein expression in C33A cells through promoting the PDK1/mTOR pathway, whereas miR-155 5p overexpression recovered LC3 and suppressed P62 protein expression by suppressing PDK1/mTOR signaling. Taken together, our results indicate the importance of miR-155-5p in cervical cancer cells and suggest a novel mechanism of hrHPV in promoting cervical lesions. PMID- 29627440 TI - Cyclic biaxial tensile strain promotes bone marrow-derived mesenchymal stem cells to differentiate into cardiomyocyte-like cells by miRNA-27a. AB - A physical stimuli, it has been reported that cyclic tensile strain can promote bone marrow-derived mesenchymal stem cells (BMSCs) to differentiate into cardiomyocytes, but the underlying mechanisms have been poorly elucidated so far. Here, we used a mimicking loading strain, cyclic biaxial tensile strain (CBTS), and found it can promote BMSCs to differentiate into cardiomyocytes. When the CBTS were loaded, the cells expressed cardiac-specific markers GATA4, TNNT2, MEF 2c, and Cx43, meanwhile we found miR-27a decreased and stem cell factor (SCF) increased. When we overexpressed miR-27a, the cardiac-specific markers were down regulated; we got the same results when SCF was knocked down by siRNA. Interestingly, we found SCF is a potential target of miR-27a by a bioinformatic analysis. So, we overexpressed miR-27a, and found SCF decreased both in mRNA and protein level. And, When miR-27a was co-transfected with SCF-3'UTR, it significantly reduced the luciferase activity, but not when co-transfected with SCF-3'UTR mutation plasmid. Furthermore, after transfected both miR-27a and SCF siRNA, and the protein expression of the markers were more down-regulated than that of single of them. Taken together, we found CBTS can promote BMSCs to differentiate into cardiomyocytes, and miR-27a functions as a mechano-sensitive miRNA in this process by targeting SCF. PMID- 29627441 TI - Amentoflavone-induced oxidative stress activates NF-E2-related factor 2 via the p38 MAP kinase-AKT pathway in human keratinocytes. AB - Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key transcription factor that responds to oxidative stress and xenobiotics. Multiple lines of evidence suggest that Nrf2 activation protects against aging, inflammation, and many diseases, including cancer. Nrf2 activators derived from natural sources have been widely studied. In this study, we investigated the effect of amentoflavone (AFN), a biflavonoid found in many plants, on Nrf2 signaling in human keratinocytes (HaCaT cells). AFN significantly increased ARE luciferase activity by Nrf2 accumulation in the nucleus. Subsequently, the levels of a Nrf2 target protein, NQO-1, were significantly increased by AFN in a dose- and time-dependent manner. To verify the mechanism of AFN-induced activation of Nrf2 signaling, we measured generation of reactive oxygen species (ROS). Interestingly AFN triggered mild ROS production. Additionally, AFN-induced Nrf2 activation was inhibited by N acetyl cysteine. Therefore, we studied the effect of ROS-related signaling on Nrf2 by measuring the activation of AKT and members of the mitogen-activated protein kinase family, such as extracellular signal-regulated kinase (ERK1/2) and p38. The results showed that the pharmacological inhibitor of PI3K/AKT (LY294002) or p38 (SB 203580), but not ERK1/2 (U0126), abrogated AFN-induced Nrf2 activation. Subsequently, we found that silencing or inhibition of p38 resulted in decrease of AKT phosphorylation as well as inhibition of Nrf2 accumulation. Furthermore, we found that AFN stabilized Nrf2 by inhibiting its ubiquitination. Taken together, our results suggest that AFN contributes to Nrf2 activation through ROS-mediated activation of the p38-AKT pathway in HaCaT cells. PMID- 29627438 TI - Perivascular cell alphav integrins as a target to treat skeletal muscle fibrosis. AB - Fibrosis following injury leads to aberrant regeneration and incomplete functional recovery of skeletal muscle, but the lack of detailed knowledge about the cellular and molecular mechanisms involved hampers the design of effective treatments. Using state-of-the-art technologies, Murray et al. (2017) found that perivascular PDGFRbeta-expressing cells generate fibrotic cells in the skeletal muscle. Strikingly, genetic deletion of alphav integrins from perivascular PDGFRbeta-expressing cells significantly inhibited skeletal muscle fibrosis without affecting muscle vascularization or regeneration. In addition, the authors showed that a small molecule inhibitor of alphav integrins, CWHM 12, attenuates skeletal muscle fibrosis. From a drug-development perspective, this study identifies a new cellular and molecular target to treat skeletal muscle fibrosis. PMID- 29627442 TI - A novel role of endocan in alleviating LPS-induced acute lung injury. AB - AIMS: Endotoxin induced acute lung injury (ALI) is a critical complication of some clinical illnesses. Endothelial cell dysfunction and excessive pro inflammation cytokine release are pivotal to the injury of alveolar-capillary membrane which is the typical characteristic of endotoxic lung injury. As a potential marker of endothelial cells, endocan plays an important role in many endothelial-dependent pathophysiological diseases. We speculated that endocan have anti-inflammatory property in ALI. Here, we investigated the role of endocan in LPS-induced ALI. MATERIALS AND METHODS: Mice were randomly divided into 4 groups. LPS were used to construct ALI mice model by aerosolization for 20 min. Endocan was intraperitoneal injected at 30 min before LPS exposure. Levels of TNF alpha, IFN-gamma, IL-1beta, IL-6 and MPO activities were detected by indicated ELISA. Cell apoptotic rate was determined by Annexin V/PI kit, ROS level and MPTP were detected by DCFH-DA and JC-1 kit, respectively. Seahorse XF96 was applied to evaluate the alteration of OCR and ECAR. Western blot and qRT-PCR were used to detect indicated molecules. KEY FINDINGS: Endocan effectively decreased TNF alpha, IFN-gamma, IL-1beta, and IL-6 levels as well as relieved pulmonary epithelium cell apoptosis caused by LPS exposure. Endocan significantly reversed LPS induced UPRmt and promoted cell metabolism reprogramming which were crucial for the protective characteristic of endocan in ALI mice model. SIGNIFICANCE: The above findings suggested endocan could significantly suppress inflammatory response in ALI model through attenuating UPRmt associated apoptosis and switch cellular bioenergetics, indicating endocan could be considered as a promising compound against LPS induced ALI. PMID- 29627443 TI - Breast milk microRNAs harsh journey towards potential effects in infant development and maturation. Lipid encapsulation can help. AB - The possibility that diet-derived miRNAs survive the gastrointestinal tract and exert biological effects in target cells is triggering considerable research in the potential abilities of alimentary preventive and therapeutic approaches. Many validation attempts have been carried out and investigators disagree on several issues. The barriers exogenous RNAs must surpass are harsh and adequate copies must reach target cells for biological actions to be carried out. This prospect opened a window for previously unlikely scenarios concerning exogenous non-coding RNAs, such as a potential role for breast milk microRNAs in infants' development and maturation. This review is focused on the thorny path breast milk miRNAs face towards confirmation as relevant role players in infants' development and maturation, taking into consideration the research carried out so far on the uptake, gastrointestinal barriers and potential biological effects of diet derived miRNAs. We also discuss the future pharmacological and pharma-nutritional consequences of appropriate miRNAs research. PMID- 29627444 TI - Inhalational anesthetics accelerate desensitization of acid-sensing ion channels. AB - Acid-sensing ion channels (ASICs) are neuronal Na+ channels that are activated by extracellular acidification. Inhibiting ASICs is neuroprotective in mouse models of ischemic stroke. As inhalational anesthetics interact with many ion channels and as some of them have neuroprotective effects, we hypothesized that inhalational anesthetics modulate ASICs. We expressed different homo- and heteromeric ASICs heterologously in Xenopus oocytes. We co-applied with acidic pH the halogenated inhalational anesthetics sevoflurane, desflurane, and isoflurane and the noble gases xenon and argon at concentrations that are roughly equivalent to their minimal alveolar concentrations and analyzed their effect on current kinetics and amplitude. Sevoflurane, desflurane, and isoflurane as well as xenon and argon accelerated by a factor of ~1.5 channel desensitization of the main ASICs of the central nervous system: homomeric ASIC1a and heteromeric ASIC1a/2a and ASIC1a/2b. Moreover, they decreased current amplitudes by ~25%. For example, isoflurane accelerated desensitization of homomeric ASIC1a from 1.0 +/- 0.4 s (mean +/- SD) to 0.6 +/- 0.2 s (n = 12; p = 0.0003) and decreased current amplitudes from 12.1 +/- 7.5 MUA to 9.3 +/- 5.6 MUA (n = 12; p = 0.0009). While inhalational anesthetics had similar effects on homomeric ASIC3, desensitization of ASIC1b was only accelerated by halogenated anesthetics but not noble gases; desensitization of homomeric ASIC2a was not modulated. In summary, we found a significant modulation of ASICs by different inhalational anesthetics. We conclude that ASICs should be considered as relevant targets of inhalation anesthetics. PMID- 29627445 TI - Response to the Letter to the Editor: 'Is a high tibial osteotomy superior to non surgical treatment in patients with varus malaligned medial knee osteoarthritis?' PMID- 29627446 TI - Is high tibial osteotomy superior to unloader brace treatment in patients with varus malaligned medial knee osteoarthritis? PMID- 29627447 TI - Gestational diabetes mellitus: Multi-disciplinary treatment approaches. AB - Gestational diabetes mellitus (GDM) is the most common metabolic disease of pregnancy, associated with several perinatal complications. Adequate glycemic control has been proved to decrease risk of GDM-related complications. Several studies have shown the beneficial effect of exercise and medical nutrition treatment on glycemic and weight control in GDM-affected women. Moreover, pharmacological agents, such as insulin and specific oral anti-diabetic agents can be prescribed safely during pregnancy, decreasing maternal blood glucose and, thus, perinatal adverse outcomes. Multi-disciplinary treatment approaches that include both lifestyle modifications (medical nutritional therapy and daily physical exercise) and pharmacological treatment, in cases of failure of the former, constitute the most effective approach. Insulin is the gold standard pharmacological agent for GDM treatment. Metformin and glyburide are two oral anti-diabetic agents that could serve as alternative, although not equal in terms of effectiveness and safety, treatment for GDM. As studies on short-term safety of metformin are reassuring, in some countries it is considered as first-line treatment for GDM management. More studies are needed to investigate the long term effects on offspring. As safety issues have been raised on the use of glyburide during pregnancy, it must be used only when benefits surpass possible risks. PMID- 29627448 TI - Maslinic acid protects against lipopolysaccharide/d-galactosamine-induced acute liver injury in mice. AB - Acute liver injury is a life-threatening syndrome that often caused by hepatocyte damage. In this study, we investigated the protective effects of maslinic acid (MA) on lipopolysaccharide (LPS)/d-galactosamine (D-gal)-induced acute liver injury and clarified its mechanism. Mice acute liver injury model was induced by given LPS and D-gal and MA was given intraperitoneally 1 h before LPS and D-gal. Our results showed that MA protected against liver injury by attenuating liver histopathologic changes, serum AST and ALT levels. The increased inflammatory cytokines TNF-alpha and IL-6 in serum and liver tissues were also inhibited by MA. The level of MDA and the activity of MPO in liver tissues were up-regulated by LPS/D-gal and dose-dependently inhibited by MA. Furthermore, MA attenuated hepatic NF-kappaB protein expression and increased hepatic Nrf2 and HO-1 protein expression. Taken together, MA offers a protective role against LPS/D-gal-induced liver injury through suppressing NF-kappaB and activating Nrf2 signaling pathways. PMID- 29627449 TI - Rutin inhibits quorum sensing, biofilm formation and virulence genes in avian pathogenic Escherichia coli. AB - The study aimed to investigate whether rutin affects the quorum sensing (QS) of avian pathogenic Escherichia coli (APEC). In this study, APEC-O78 was selected as the test strain. We mainly examined the effects of rutin on the AI-2 secretion by bioluminescence assay, biofilm formation through a crystal violet staining method, and expression of virulence genes of APEC by qRT-PCR. We found that rutin can significantly interfering with QS through reducing the secretion of AI-2, inhibited the biofilm formation, and reduced the expression of virulence genes of APEC. Moreover, rutin markedly decreased adhesion and damage of APEC to chicken type II pneumocytes. These results suggested rutin reduces cell damage of APEC infected chicken type II pneumocytes through interfering with QS via decreasing AI-2 production, biofilm formation, and the expression of virulence genes. This paper may provide a new evidence for colibacillosis prevention in chicken. PMID- 29627451 TI - Regulation and function of avian selenogenome. AB - BACKGROUND: Selenium (Se) is an essential micronutrient required by avian species. Dietary Se/vitamin E deficiency induces three classical diseases in chicks: exudative diathesis, nutritional pancreatic atrophy, and nutritional muscular dystrophy. SCOPE OF REVIEW: This review is to summarize and analyze the evolution, regulation, and function of avian selenogenome and selenoproteome and their relationship with the three classical Se/vitamin E deficiency diseases. MAJOR CONCLUSIONS: There are 24 selenoproteins confirmed in chicks, with two avian-specific members (SELENOU and SELENOP2) and two missing mammalian members (GPX6 and SELENOV). There are two forms of SELENOP containing 1 or 13 selenocysteine residues. In addition, a Gallus gallus gene was conjectured to be the counterpart of the human SEPHS2. Expression of selenoprotein genes in the liver, pancreas, and muscle of chicks seemed to be highly responsive to dietary Se changes. Pathogeneses of the Se/vitamin E deficient diseases in the chicks were likely produced by missing functions of selected selenoproteins in regulating cellular and tissue redox balance and inhibiting oxidative/reductive stress-induced cell death. GENERAL SIGNIFICANCE: Gene knockout models, similar to those of rodents, will help characterize the precise functions of avian selenoproteins and their comparisons with those of mammalian species. PMID- 29627450 TI - Combined thermodynamic and kinetic analysis of GroEL interacting with CXCR4 transmembrane peptides. AB - GroEL along with ATP and its co-chaperonin GroES has been demonstrated to significantly enhance the folding of newly translated G-protein-coupled receptors (GPCRs). This work extends the previous studies to explore the guest capture and release processes in GroEL-assisted folding of GPCRs, by the reduced approach of employing CXCR4 transmembrane peptides as model substrates. Each of the CXCR4 derived peptides exhibited high affinity for GroEL with a binding stoichiometry near seven. It is found that the peptides interact with the paired alpha helices in the apical domain of the chaperonin which are similar with the binding sites of SBP (strongly binding peptide: SWMTTPWGFLHP). Complementary binding study with a single-ring version of GroEL indicates that each of the two chaperonin rings is competent for accommodating all the seven CXCR4 peptides bound to GroEL under saturation condition. Meanwhile, the binding kinetics of CXCR4 peptides with GroEL was also examined; ATP alone, or in combination of GroES evidently promoted the release of the peptide substrates from the chaperonin. The results obtained would be beneficial to understand the thermodynamic and kinetic nature of GroEL GPCRs interaction which is the central molecular event in the assisted folding process. PMID- 29627452 TI - Fluorescent in vivo imaging of reactive oxygen species and redox potential in plants. AB - Reactive oxygen species (ROS) are by-products of aerobic metabolism, and excessive production can result in oxidative stress and cell damage. In addition, ROS function as cellular messengers, working as redox regulators in a multitude of biological processes. Understanding ROS signalling and stress responses requires methods for precise imaging and quantification to monitor local, subcellular and global ROS dynamics with high selectivity, sensitivity and spatiotemporal resolution. In this review, we summarize the present knowledge for in vivo plant ROS imaging and detection, using both chemical probes and fluorescent protein-based biosensors. Certain characteristics of plant tissues, for example high background autofluorescence in photosynthetic organs and the multitude of endogenous antioxidants, can interfere with ROS and redox potential detection, making imaging extra challenging. Novel methods and techniques to measure in vivo plant ROS and redox changes with better selectivity, accuracy, and spatiotemporal resolution are therefore desirable to fully acknowledge the remarkably complex plant ROS signalling networks. PMID- 29627453 TI - Role of circulating tumor DNA in the management of patients with colorectal cancer. AB - Colorectal cancer is a major health burden with a prognosis that has been improved with the progresses in diagnosis and the advance of chemotherapy and personalized medicine. However, because of intra-tumor heterogeneity, clonal evolution and selection, tumors often develop resistance to treatments. "Liquid biopsy" is a minimally invasive method, based on analysis of tumor-specific material in peripheral blood samples of patients. Analysis of tumor specific genetic or epigenetic alterations in cell-free circulating nucleic acids may reflect the molecular heterogeneity of the underlying disease process and serial testing could allow to monitor its temporal genomic changing without using re biopsy. In this review, we focused on the role of circulating tumor DNA (ctDNA) as a biomarker in the management of patients with colorectal cancer at early and advanced stages. Through recent studies, we described its promising clinical applications for diagnosis, detection of recurrence after surgery and monitoring for tumor response or therapeutic resistance in metastatic setting. Such recent developments offer new perspectives for personalized medicine in colorectal cancer but still needs some standardized detection methods and further studies to validate its use in clinical routine. PMID- 29627454 TI - Expression patterns of Yes-associated protein 1 in the developing mouse liver. AB - The Hippo signaling pathway regulates many cellular processes, but has been specifically associated with control organ size and tumor growth. Yes-associated protein 1 (YAP1) is a transcriptional cofactor, in the Hippo pathway, that regulates gene expression when localized in the nucleus. Elevated expression of YAP1 in adult mouse liver leads to hepatomegaly and can cause hepatocellular carcinoma; while the loss of function studies reveal its importance in regulating cholangiocyte development. Here, we report the expression of YAP1 in mouse embryonic and postnatal hepatic cells, using AFP-GFP transgenic mice to identify the hepatocyte lineage. At embryonic day (E) 8.5, YAP1 is highly expressed in the endoderm, but is not present in the nucleus. Between E9.5-12.5, hepatic cells display low levels of nuclear and non-nuclear YAP1. The nuclear expression of YAP1 is first detected in a small subset of hepatic cells starting at E13.5 when the hepatoblasts begin to differentiate into hepatocytes and cholangiocytes. At E18.5, nuclear YAP1 is nearly undetectable in hepatoblasts and hepatocytes, but enriched within the nuclei of cholangiocytes. These levels remain similar postnatally, consistent with the role of YAP1 in cholangiocyte specification and maintenance. PMID- 29627455 TI - The explanatory variable age is non-significant in diabetic nephropathy (DN) patients. PMID- 29627456 TI - Characterization of alphabeta and gammadelta T cell subsets expressing IL-17A in ruminants and swine. AB - As part of our ongoing program to expand immunological reagents available for research in cattle, we developed a monoclonal antibody (mAb) to bovine interleukin-17A (IL-17A), a multifunctional cytokine centrally involved in regulating innate and adaptive immune responses. Initial comparative studies demonstrated the mAb recognizes a conserved epitope expressed on orthologues of IL-17A in sheep, goats and pigs. Comparative flow cytometric analyses of lymphocyte subsets stimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin revealed differences in expression of IL-17A by CD4, CD8, and gammadelta T cells across ruminants and swine species. Results in cattle showed the largest proportion of IL-17A+ cells were CD4+ followed by gammadelta and CD8+ T cells. Further analysis revealed the IL-17A+ gammadelta T cell subset was comprised of WC1.1+, WC1.2+, and WC1- subsets. Analysis of the IL-17A+ CD8+ T cell subset revealed it was comprised of alphabeta and gammadelta T cell subsets. Results in sheep and goats revealed IL-17A is expressed mainly by CD4+ and CD8+ T cells, with little expression by gammadelta T cells. Analysis of IL-17A+ CD8+ T cells showed the majority were CD8+ alphabeta in sheep, whereas they were CD8+ gammadelta in goats. The majority of the sheep and goat IL-17A+ gammadelta T cells were WC1+. Results obtained in swine showed expression of IL-17A by CD4, CD8, and gammadelta T cell subsets were similar to results reported in other studies. Comparison of expression of IL-17A with IFN-gamma revealed subsets co expressed IL-17A and IFN-gamma in cattle, sheep, and goats. The new mAb expands opportunities for immunology research in ruminants and swine. PMID- 29627457 TI - Relationship of Inhaled Corticosteroid Adherence to Asthma Exacerbations in Patients with Moderate-to-Severe Asthma. AB - BACKGROUND: Patients with asthma and elevated blood eosinophils are at increased risk of severe exacerbations. Management of these patients should consider nonadherence to inhaled corticosteroid (ICS) therapy as a factor for increased exacerbation risk. OBJECTIVE: The objective of this study was to investigate whether poor adherence to ICS therapy explains the occurrence of asthma exacerbations in patients with elevated blood eosinophil levels. METHODS: This historical cohort study identified patients within the Optimum Patient Care Research Database, aged 18 years or more, at Global Initiative for Asthma step 3 or 4, with 2 or more ICS prescriptions during the year before the clinical review. Patient characteristics and adherence (based on prescription refills and patient self-report) for ICS therapy were analyzed for those with elevated (>400 cells/MUL) or normal (<=400 cells/MUL) blood eosinophils. RESULTS: We studied 7195 patients (66% female, mean age 60 years) with median eosinophil count of 200 cells/MUL and found 81% to be not fully adherent to ICS therapy. A total of 1031 patients (14%) had elevated blood eosinophil counts (58% female, mean age 60 years), 83% of whom were not fully adherent to ICS. An increased proportion of adherent patients in the elevated blood eosinophil group had 2 or more exacerbations (14.0% vs 7.2%; P = .003) and uncontrolled asthma (73% vs 60.8%; P = .004) as compared with non-fully adherent patients. CONCLUSIONS: Approximately 1 in 7 patients had elevated eosinophils. Adherence to ICS therapy was not associated with decreased exacerbations for these patients. Additional therapy should be considered for these patients, such as biologics, which have been previously shown to improve control in severe uncontrolled eosinophilic asthma. PMID- 29627458 TI - Synthetic fermentation of bioactive molecules. AB - The concept of synthetic fermentation is to 'grow' complex organic molecules in a controlled and predictable manner by combining small molecule building blocks in water-without the need for reagents, enzymes, or organisms. This approach mimics the production of small mixtures of structurally related natural products by living organisms, particularly microbes, under conditions compatible with direct screening of the cultures for biological activity. This review discusses the development and implementation of this concept, its use for the discovery of protease inhibitors, its basis as a chemistry outreach program allowing non specialists to make and discover new antibiotics, and highlights of related approaches. PMID- 29627459 TI - Tadpole-like Conformations of Huntingtin Exon 1 Are Characterized by Conformational Heterogeneity that Persists regardless of Polyglutamine Length. AB - Soluble huntingtin exon 1 (Httex1) with expanded polyglutamine (polyQ) engenders neurotoxicity in Huntington's disease. To uncover the physical basis of this toxicity, we performed structural studies of soluble Httex1 for wild-type and mutant polyQ lengths. Nuclear magnetic resonance experiments show evidence for conformational rigidity across the polyQ region. In contrast, hydrogen-deuterium exchange shows absence of backbone amide protection, suggesting negligible persistence of hydrogen bonds. The seemingly conflicting results are explained by all-atom simulations, which show that Httex1 adopts tadpole-like structures with a globular head encompassing the N-terminal amphipathic and polyQ regions and the tail encompassing the C-terminal proline-rich region. The surface area of the globular domain increases monotonically with polyQ length. This stimulates sharp increases in gain-of-function interactions in cells for expanded polyQ, and one of these interactions is with the stress-granule protein Fus. Our results highlight plausible connections between Httex1 structure and routes to neurotoxicity. PMID- 29627461 TI - Development of the SapI/AarI Incision Mediated Plasmid Editing Method. AB - Plasmid engineering and molecular cloning is a virtually ubiquitous tool in biology. Although various methods have been developed for ligating DNA molecules or targeted mutagenesis of plasmids, each has its limitations. Many of the commonly used laboratory strategies are inefficient, while commercially available kits are quite costly and often specialized for highly specific circumstances. Here, we describe the SapI/AarI incision mediated plasmid editing (SIMPLE) method, which allows users to perform site-directed mutagenesis, deletions, and even short insertions into any plasmid in a single PCR reaction, using just one restriction enzyme. In addition, the SIMPLE method can be adapted to insert any sized DNA fragment into a vector using a two-step PCR approach, and can be used to ligate any number of DNA fragments with non-compatible ends in the specific order desired. The SIMPLE method provides researches an efficient and powerful tool with a broad range of applications for molecular cloning. PMID- 29627462 TI - ProFUSO: Business process and ontology-based framework to develop ubiquitous computing support systems for chronic patients' management. AB - New advances in telemedicine, ubiquitous computing, and artificial intelligence have supported the emergence of more advanced applications and support systems for chronic patients. This trend addresses the important problem of chronic illnesses, highlighted by multiple international organizations as a core issue in future healthcare. Despite the myriad of exciting new developments, each application and system is designed and implemented for specific purposes and lacks the flexibility to support different healthcare concerns. Some of the known problems of such developments are the integration issues between applications and existing healthcare systems, the reusability of technical knowledge in the creation of new and more sophisticated systems and the usage of data gathered from multiple sources in the generation of new knowledge. This paper proposes a framework for the development of chronic disease support systems and applications as an answer to these shortcomings. Through this framework our pursuit is to create a common ground methodology upon which new developments can be created and easily integrated to provide better support to chronic patients, medical staff and other relevant participants. General requirements are inferred for any support system from the primary attention process of chronic patients by the Business Process Management Notation. Numerous technical approaches are proposed to design a general architecture that considers the medical organizational requirements in the treatment of a patient. A framework is presented for any application in support of chronic patients and evaluated by a case study to test the applicability and pertinence of the solution. PMID- 29627460 TI - Structure Versus Stochasticity-The Role of Molecular Crowding and Intrinsic Disorder in Membrane Fission. AB - Cellular membranes must undergo remodeling to facilitate critical functions including membrane trafficking, organelle biogenesis, and cell division. An essential step in membrane remodeling is membrane fission, in which an initially continuous membrane surface is divided into multiple, separate compartments. The established view has been that membrane fission requires proteins with conserved structural features such as helical scaffolds, hydrophobic insertions, and polymerized assemblies. In this review, we discuss these structure-based fission mechanisms and highlight recent findings from several groups that support an alternative, structure-independent mechanism of membrane fission. This mechanism relies on lateral collisions among crowded, membrane-bound proteins to generate sufficient steric pressure to drive membrane vesiculation. As a stochastic process, this mechanism contrasts with the paradigm that deterministic protein structures are required to drive fission, raising the prospect that many more proteins may participate in fission than previously thought. Paradoxically, our recent work suggests that intrinsically disordered domains may be among the most potent drivers of membrane fission, owing to their large hydrodynamic radii and substantial chain entropy. This stochastic view of fission also suggests new roles for the structure-based fission proteins. Specifically, we hypothesize that in addition to driving fission directly, the canonical fission machines may facilitate the enrichment and organization of bulky disordered protein domains in order to promote membrane fission by locally amplifying protein crowding. PMID- 29627463 TI - Recent advances on silver nanoparticle and biopolymer-based biomaterials for wound healing applications. AB - Silver nanoparticles (AgNPs) are classified as metal-based nanoparticles and have gained considerable attention amongst researchers in wound healing applications, owing to their physicochemical and biological properties. Biopolymers are abundantly available from natural sources and are used in numerous applications in pharmaceutical sciences and medicine. Silver nanoparticles and biopolymer based biomaterials (AgNP-BMs) are non-cytotoxic and safe for patients in wound care management. The unique intrinsic features of AgNP-BMs promote wound healing and effectively control the growth of microorganisms at the wound site, and this strategy plays an important role in the treatment of both acute and chronic wounds. In this review article, we focus on the advanced therapeutic approaches of AgNP-BMs and their potential role in wound healing applications, which includes multifunctional properties, antimicrobial activities and various forms of AgNP-BMs. Moreover, the review briefly recaps on recent progress made in biopolymers, silver, AgNPs and their potential role in clinical research and a commercial platform for the treatment of wounds. Silver nanoparticle and biopolymer-based biomaterial offers a high-degree of biocompatibility and biodegradability in physiological conditions and can be considered as an effective material for wound dressings in the treatment of different wounds. PMID- 29627464 TI - Letter to the Editor. AB - I read with great interest the paper by Dehvari and Ghahghaei (Dehvari and Ghahghaei, 2018 [1]). Their paper aimed to prove that biosynthesized AgNPs mediated by Pulicaria undulata L. has the capability in inhibiting amyloid fibril formation and thus could be considered as a therapeutic agent in the treatment of amyloidosis disorders. According to the literature (Jangholi et al., 2018 [2]), Thioflavin T (ThT) is a commonly used probe to monitor in vitro amyloid fibril formation. Also, since ThT fluorescence originates only from the bound population of the dye molecules, the several orders of magnitude increase in the fluorescence intensity makes ThT an unusually sensitive and efficient reporter. The authors used ThT to monitor in vitro amyloid fibril formation of alpha lactalbumin and fluorescence emission spectra were recorded upon titration of the indicated concentrations of nanoparticles or alpha-casein. They excited the assay solutions at 450nm and the emissions were measured over the range 460-600nm. Interestingly, upon binding to alpha-lactalbumin's amyloid fibrils, ThT displayed a (slight) relative increase of fluorescence signal at approximately ~530-540nm, when excited at 450nm with no background ThT fluorescence subtraction/reportage. Upon binding to amyloid fibrils, ThT generally exhibits a dramatic shift of the excitation maximum (from 385nm to 450nm) and the emission maximum from 445nm to the higher wavelengths, along with a strong fluorescence signal at ~482nm (Biancalana, 1804 [3]). Regarding the wavelength of ThT fluorescence maxima, the obtained results by Dehvari and Ghahghaei are inconsistent with what has yet been reported in the literature. Moreover, the respected authors, in the present work, have not tried to describe these unusual ThT results. However, I could not find evidence/fingerprint of "cotton effect" of ThT and/or absorption flattening within the results. PMID- 29627465 TI - Electrospun polyvinyl alcohol/gelatin/chondroitin sulfate nanofibrous scaffold: Fabrication and in vitro evaluation. AB - Electrospun nanofibers have attracted a lot of attention in recent years in tissue engineering applications. In this research, novel polyvinyl alcohol/gelatin/chondroitin sulfate (PVA/GE/Cs) nanofibrous scaffolds using non carcinogen solvent system via electrospinning technique was evaluated. A solvent system containing water and acetic acid was used as a safe solvent system to obtain a homogenous mixture with suitable solvent properties and finally non toxic nanofibrous scaffolds. The effect of water to the acetic acid ratio in the solvent system (7:3, 6:4, 5:5, 4:6, 3:7) and also polymer concentration (8, 9, 10w/v %) on nanofibers morphology was investigated. The appropriate flow rate and voltage ranges to obtain uniform and bead-free electrospun scaffold were investigated. Effect of different Cs ratio (0, 10, 15 and 20wt%) on solution properties was evaluated. Influence of Cs ratio on chemical, physical and thermal properties of the electrospun scaffolds was studied. The results of cell toxicity indicated that prepared PVA/GE/Cs scaffolds have no cell toxicity. SEM results demonstrated that L929 mouse fibroblast cells have suitable interaction with scaffold surface and also attached and proliferated well on the prepared substrate after 24 and 48h and also have a potential for using in tissue engineering. PMID- 29627466 TI - A polysaccharide from green tea (Camellia sinensis L.) protects human retinal endothelial cells against hydrogen peroxide-induced oxidative injury and apoptosis. AB - Oxidative damage of retinal pigment epithelium (RPE) cells is involved in the pathogenesis age related macular degeneration (AMD). The purpose of this study was to evaluate the potential protective effect of a purified green tea polysaccharide (GTWP) against hydrogen peroxide (H2O2) induced oxidative stress and apoptosis in human retinal pigment epithelial cells (ARPE-19 cells). Human ARPE-19 cells were treated with 1 h of 500 MUM H2O2 before incubation with GTWP for 24 h. Pretreatment of GTWP decreased H2O2-induced cell death and cell apoptosis, and efficiently suppressed the intracellular ROS production and malondialdehyde (MDA) generation induced by H2O2 treatment. Moreover, a loss of superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione (GSH) activities were restored to normal level in H2O2-induced ARPE 19 cells upon GTWP (100 MUg/ml) exposure. Also, the tendency of increased protein expression of Bax and cleaved-caspsae-3, as well as decrease of Bcl-2 protein in ARPE-19 cells challenged with H2O2 was changed to individual opposite way, thus inhibiting the apoptotic cell death. Our results demonstrated that GTWP protected RPE cells against oxidative injury through activation of anti-apoptotic and endogenous antioxidant enzymes signaling pathway, suggesting GTWP has attractive therapeutic potential to AMD. PMID- 29627467 TI - Synthesis of calcon-imprinted magnetic chitosan nanoparticles as a novel adsorbent and its application in selective removal of calcon dye from aqueous solutions. AB - Calcon-imprinted magnetic chitosan (CIMC) nanoparticles (NPs) were successfully synthesized as a novel adsorbent. Epichlorohydrin (ECH) and glutaraldehyde (GA) were used as cross-linkers to synthesize desired calcon-imprinted magnetic chitosan (ECH/CIMC and GA/CIMC) and non-imprinted magnetic chitosan (ECH/NIMC and GA/NIMC) NPs for adsorption and removal of calcon from polluted solutions. Fourier transform infrared spectroscopy (FT-IR) and scanning electron microscopy (SEM) techniques were employed to investigate the characteristics of ECH/CIMC and GA/CIMC. The effect of pH, temperature, adsorbent dosage and initial dye concentration was evaluated. The adsorption isotherm and kinetics were adequately described by Langmuir and pseudo second-order model, respectively. Maximum removal capacity by ECH/CIMC and GA/CIMC was computed as 51.71 and 39.23mg/g. Thermodynamic parameters were also estimated and results showed that the adsorption of calcon onto CIMC and NIMC was endothermic and that it is a spontaneous and favorable process. PMID- 29627468 TI - Cross-linking effect of polyphenolic extracts of Lepidium sativum seedcake on physicochemical properties of chitosan films. AB - Lepidium sativum seedcake phenolic extract (LSE), as compared to tannic acid (TA), was evaluated for its effect on film forming ability of chitosan. The films were investigated for their structural, mechanical, optical, thermal and in vitro antioxidant activity release profile. At 5% (v/v of film-forming solution), LSE led to improved 32.2% of tensile strength and 109% elongation, compared to the effect of TA in chitosan films. Moisture content, WVP, and crystallinity decreased with the increasing LSE concentration. Changes in absorbance intensity by FT-IR indicated structural modification. The DSC thermograph indicted a change in the melting point. SEM showed smooth and homogeneous surface cross-section composite film with LSE. The films exhibit dose-dependent and time-dependent release of total polyphenols and antioxidant activity in the water, 50% ethanol, and 95% ethanol. Hence, the current work help valorization of L. sativum seedcake after oil extraction for an alternative as novel active-packaging material for food and pharmaceutical application. PMID- 29627469 TI - Magnetic N-doped carbon aerogel from sodium carboxymethyl cellulose/collagen composite aerogel for dye adsorption and electrochemical supercapacitor. AB - Nitrogen-doped carbon aerogels derived from sodium carboxymethyl cellulose were prepared via a multistep approach involving sol-gel, freeze-drying, carbonization, and KOH activation processes; ferric trichloride and collagen were used as cross-linking agent and nitrogen source, respectively. The carbon aerogels exhibited well-developed porous three-dimensional morphologies, high specific surface areas, and excellent magnetic properties. When applied as electrode material, the CA-N0.5 showed a specific capacitance of 185.3F/g at the current density of 0.5A/g in a 6M KOH electrolyte. The specific capacitance retention was 90.2% after 5000 charge/discharge cycles, indicating excellent cycling stability. In addition, the carbon aerogels showed excellent adsorption capacities of 238.2 and 230.4mg/g for malachite green and methylene blue, respectively. These results suggest that N-doped carbon aerogels may be utilized as electrodes in supercapacitors as well as highly efficient contaminant adsorbents in aqueous solutions. PMID- 29627470 TI - Investigation of the physical properties, antioxidant and antimicrobial activity of ternary potato starch-furcellaran-gelatin films incorporated with lavender essential oil. AB - Lavender essential oil (OEL) was added to starch, furcellaran and gelatin (S/F/G) films in concentrations of 2%, 4% and 6%. The films were examined in terms of physical properties (thickness, density, water solubility, water absorption and degree of swelling) and mechanical properties (tensile strength, elongation at break). The test results show that the film thickness increased upon addition of OEL. The solubility, water absorption and degree of swelling of the film decreased with increasing concentration of oils. Tensile strength (TS) decreased considerably with increasing concentration of oil, which resulted in lower mechanical strength. Parameters of elongation at break (EAB) were not changed. The thermal behaviour of the film was affected by OEL. Possible interaction between film matrix and lavender oil was confirmed using FTIR. Antioxidant properties proved to be significantly enhanced with increasing OEL concentration. The microbiological analysis confirmed antimicrobial properties of S/F/G with OEL. S/F/G films with OEL can provide new formulation of active packaging with potential food-technology applications. PMID- 29627471 TI - Anti-colon-cancer effects of polysaccharides: A mini-review of the mechanisms. AB - Polysaccharides are an important class of functional phytochemicals, and various studies have demonstrated the beneficial pharmacological effects of polysaccharides, including against colorectal cancer and colitis. Numerous studies have shown that natural polysaccharides display anti-colon cancer activity through a variety of mechanisms. Our research group undertook a comprehensive review of the literature to summarize the studies reported in 2012 2017, and assessed the apoptogenic mechanisms of polysaccharide-rich extracts in colon cancer tumor cells. The relevant studies were identified with electronic searches of the Web of Science and Google Scholar. In total, different types of polysaccharides from 17 kinds of natural sources have shown anti-colon cancer activity. In vivo and in vitro experiments have demonstrated the ability of polysaccharide rich extracts to provide colon-protective effects by inducing the PI3K/AKT, NF-kappaB, and MAPK signaling pathways, the apoptosis of tumor cells, and the regulation of gut microflora. This mini-review extends our understanding of the colon-protective effects of polysaccharides and the relevant modulation of signaling pathways. It should be useful in designing more effective agents for the management of colon diseases. PMID- 29627472 TI - Antioxidant and antimicrobial activities of a purified polysaccharide from yerba mate (Ilex paraguariensis). PMID- 29627473 TI - Synthesis and characterization of chitosan modified polyurethane bio nanocomposites with biomedical potential. AB - A series of chitosan (CS) and montmorillonite (MMT) clay based polyurethane bio nanocomposites were synthesized by step growth polymerization; reacting hydroxyl terminated polybutadiene (HTPB) and toluene diisocyanate (TDI) to improve thermal and antibacterial properties of polyurethane (PU). Five different PU samples were prepared by varying mole ratio of CS and 1,4-butane diol (from 0 to 2 mol). Structural studies of PUs through FTIR and 1H NMR spectroscopy confirmed the incorporation of CS into the polymer matrix. The scanning electron microscope (SEM) analysis confirmed well dispersion of MMT clay into the PU matrix. Thermogravimetric analysis (TGA) of PUs indicated significant enhancement of thermal stability of PU with addition of CS. Antibacterial properties of PUs were measured by disc diffusion method; showed excellent potential against the selected strains. On the whole, CS showed potential to improve the antibacterial and structural properties of PU significantly; which might be precursor for biological applications. PMID- 29627474 TI - Effects of ascorbate and hydroxyl radical degradations on the structural, physicochemical, antioxidant and film forming properties of chitosan. AB - In this study, chitosan (CS) was degraded by ascorbate radical (Asc*-) and hydroxyl radical (*OH), respectively. The structural, physicochemical, antioxidant and film forming properties of Asc*- and *OH degraded CS were compared for the first time. Results showed the structure and physicochemical property of Asc*- degraded CS were significantly different from those of CS. Asc* had a deamination effect on CS with the formation of several unsaturated bonds. Accordingly, Asc*- degraded CS showed decreased crystallinity and thermal stability as well as a planar morphology. By contrast, OH degraded CS showed similar structure, crystallinity and thermal stability to CS. However, OH had an erosion effect on CS with the formation of many cavities inside. Antioxidant assay further demonstrated that the in vitro antioxidant activity of CS was improved by Asc*- and OH degradations. Moreover, film forming property of CS was also altered by Asc*- and OH degradations. Asc*- and OH degraded CS films showed higher thicknesses, UV-vis light barrier property and water vapor permeability than CS film. Besides, Asc*- degraded CS film had better mechanical properties than CS and OH degraded CS films. Therefore, Asc*- degradation could be a useful approach to improve the antioxidant and film forming properties of CS. PMID- 29627475 TI - Cytotoxic prenylated acylphloroglucinols from Hypericum annulatum. AB - A phytochemical investigation of the aerial parts of Hypericum annulatum Moris led to the isolation of five new prenylated acylphloroglucinol derivatives hyperannulatins A-E (1-3, 5 and 7) in addition to the known hypercalyxone A (4) and 3-geranyl-1-(2'-methylpropanoyl)phloroglucinol (6). The structures were determined by 1D and 2D NMR and MS spectroscopic techniques. Compounds 1 and 2 have in their structure evgenyl group, a rare hydrocarbon side chain. The cytotoxicity of isolated compounds was established on a panel of tumor cell lines (HL-60, HL-60/DOX, MDA-MB, SKW-3 and K-562) and was determined using MTT based assays. The compounds 1 and 2 showed to be the most potent cytotoxic agents, whose IC50 values against the chemosensitive cell lines ranged 3.42-5.87 MUM and 1.48-8.21 MUM, respectively. Noteworthy, albeit all tested compounds were less potent than podophyllotoxin their IC50 values were comparable to that of the other reference drug etoposide. In some of the cell lines compounds 1 and 2 even outclassed the cytotoxicity of etoposide. PMID- 29627476 TI - Infection of grass carp reovirus induced the expressional suppression of pro viral Fibulin-4 in host cells. AB - Fibulin-4 is not only involved in connective tissue development and elastic fiber formation, but also plays critical neoplastic roles in tumor growth by activating Wnt/beta-Catenin signaling in human. Recently, Fibulin-4 was shown to associate with grass carp reovirus (GCRV) outer capsid proteins and might relate to viral hemorrhagic disease in grass carp Ctenopharyngodon idella. Here, we monitored the expression pattern of Fibulin-4 during the infection course of GCRV at both translational and transcriptional levels, and found that Fibulin-4 was significantly suppressed upon the viral challenge in grass cap GCO cells. Over expression of Fibulin-4 was achieved by transduction of pEGFP-Fibulin-4 plasmids into GCO cells, which was confirmed by both Western blot and Real time RT-PCR analysis. In GCO cells with over-expression of Fibulin-4, significantly increase of viral protein synthesis and progeny virus production was detected. Our study indicated that Fibulin-4 displayed pro-viral function and was inhibited during viral challenge. Thus, repression of Fibulin-4 expression seemed to be involved in anti-viral response in grass carp Ctenopharyngodon idella. PMID- 29627477 TI - Distribution of mannose receptor in blunt snout bream (Megalobrama amblycephala) during the embryonic development and its immune response to the challenge of Aeromonas hydrophila. AB - The mannose receptor (MR) is a type I transmembrane protein. Its ectodomain has eight C-type lectin-like domains, which are able to recognize and mediate the phagocytosis of a wide range of pathogens. Comprehensive studies have revealed that mammalian MR is widely distributed in the mononuclear phagocyte system (MPS, previously known as the reticuloendothelial system) and play a key role both in the physiological clearance and cell activation. Hitherto, neither the MR distribution, nor the function of clearance and cell activation has been investigated in fish. In the previous study, we have reported the full-length cDNA of blunt snout bream MR, analyzed its structure and relative mRNA expression during embryogenesis and in the liver, head kidney, spleen and intestine of fish after stimulation with killed Aeromonas hydrophila. In the present study, we developed a rabbit polyclonal antibody against MR and undertook a systematic survey of the expression of MR at the protein level by immunohistochemistry. To get more information about MR function, the mRNA expression of MR, pro inflammatory factor TNF-alpha and anti-inflammatory factor ARG2 genes was measured by qRT-PCR in the liver, head kidney, and spleen after A. hydrophila challenge. We first observed MR expression in the yolk sac at the fertilized egg stage and possibly MR was expressed by early macrophages. We also showed the MR distribution in head kidney, body kidney, spleen, liver, intestine, muscle, brain, heart, and gills. Following A. hydrophila challenge the MR immunoreactive cells became more widespread in head kidney and spleen, which are the major reticuloendothelial systems of fish. The quantitative studies at mRNA levels showed that there exists a high correlation between MR expression and immune cytokine expressions after bacteria challenge. PMID- 29627479 TI - Classical swine fever virus induces pyroptosis in the peripheral lymphoid organs of infected pigs. AB - Classical swine fever virus (CSFV) causes a highly lethal disease in pigs, which is characterized by immunosuppression. Leukopenia is known to be a possible mechanism of immunosuppression during CSFV infection. As a new and specialized form of cell death, pyroptosis is the key response of the innate immune system to pathogens, and is widely involved in the occurrence and development of infectious diseases. However, the relationship between CSFV and pyroptosis has not been explored. In this study, we investigated the occurrence of pyroptosis in pigs following CSFV infection. According to qRT-PCR assay results, the prevalence of this virus in peripheral lymphoid organs (tonsils, lymph nodes, and spleen) was much higher than that in other organs. Severe bleeding, necrosis, and a significant reduction in lymphocytes were found in the peripheral lymphoid organs of CSFV-infected pigs based on histological examination. In-depth studies showed that an increased ratio of deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-positive cells were present in the peripheral lymphoid organs of the CSFV-infected group according to immunohistochemistry. Meanwhile, the p10 subunit and activity of caspase-1, which is a regulator of pyroptosis, the N terminal domain of gasdermin D, which is an executor of pyroptosis, and the cleavage and secretion of IL-1b, which is a product of pyroptosis were increased in the peripheral lymphoid organs of the CSFV-infected group. Together, these results demonstrated that pyroptosis is involved in CSFV-induced cell death in vivo, which provides a new understanding of the mechanism associated with lymphocyte depletion and immunosuppression in pigs infected with this virus. PMID- 29627480 TI - The effectiveness of progressive muscle relaxation on the postpartum quality of life. AB - PURPOSE: This study aimed to determine the effectiveness of progressive muscle relaxation (PMR) on the quality of life women during postpartum period. METHODS: A quasi-experimental design was used. The participants consisted of primiparous women who had experienced a vaginal birth in the obstetrics department of a hospital. Thirty women in the intervention group and 30 women in the control group were included. Data were collected by questionnaire and Maternal Postpartum Quality of Life Questionnaire (MAPP-QoL) between June 2016 and April 2017. Progressive muscle relaxation were applied to the intervention group. PMR were performed as contracting a muscle group, then relaxing it, moving (or progressing) from one muscle group to another. RESULTS: The mean pre-test and post-test scores of the MAPP-QoL in the intervention group were 24.43 +/- 4.58 and 26.07 +/- 4.58, respectively (t = -2.73, p < .05). The mean pre-test and post test scores of the MAPP-QoL in the control group were 23.29 +/- 4.37 and 21.99 +/ 5.58, respectively (t = 2.23, p < .05). The difference between the mean scores of the women in the intervention and control groups before PMR was not statistically significant (t = 0.99, p > .05), whereas the difference between the groups after PMR was found to be statistically significant (t = 3.09, p < .05. CONCLUSIONS: Postpartum quality of life of women was increased after PMR. Progressive muscle relaxation should be taught to women who are admitted to obstetrics and outpatient clinics, that home visits be completed in order to expand the use of PMR. PMID- 29627478 TI - A novel fucolectin from Apostichopus japonicus with broad PAMP recognition pattern. AB - F-type lectin (also known as fucolectin) is a newly identified family of fucose binding lectins with the sequence characters of a fucose binding motif and a unique lectin fold (the "F-type" fold). In the present study, a fucolectin was identified from sea cucumber Apostichopus japonicus (designated AjFL-1). The open reading frame (ORF) of AjFL-1 was of 546 bp, encoding a polypeptide of 181 amino acids with a predicted molecular mass of about 20 kDa. The deduced amino acid sequence of AjFL-1 shared 30%-40% similarity with the fucolectins from other animals. There were a typical F-type lectin domain (FLD) (residues 39-180) and a signal peptide (residues 1-24) in AjFL-1. The mRNA transcript of AjFL-1 could be detected by qRT-PCR in various tissues, such as intestinum, coelomocytes, respiratory tree, tentacle, and body wall, while undetectable in the gonads and longitudinal muscle. The mRNA expression level of AjFL-1 in coelomocytes was significantly up-regulated (47.06-fold to that in control group, p < 0.05) at 12 h after Vibrio splendidus challenge. Immunofluorescence assay showed that AjFL-1 protein was mainly distributed on the membrane, while few in cytoplasm of coelomocytes in sea cucumber. The recombinant AjFL-1 (rAjFL-1) could bind lipopolysaccharide (LPS), peptidoglycan (PGN), mannan (MAN) and fucose (FUC), and exhibited a broader binding activities towards Gram-negative bacterium Escherichia coli, Gram-positive bacterium Micrococcus luteus, as well fungus Pichia pastoris. In addition, rAjFL-1 could strongly promote the agglutination of fungus P. pastoris. These results indicated that AjFL-1 was a novel member of fucose-binding lectin family, which functioned as a pattern recognition receptor with broad spectrum of microbial recognition, and involved in innate immune response of sea cucumber. PMID- 29627482 TI - Assessment of statin-induced interstitial pneumonia in patients treated for hyperlipidemia using a health insurance claims database in Japan. AB - PURPOSE: This study aimed to determine the frequency and risk factors for statin induced interstitial pneumonia (IP). METHOD: We conducted a retrospective cohort study using a large Japanese health insurance claims database. We determined the statin-induced IP incidence in patients treated with statins for hyperlipidemia (n = 194,814) with 12-month screening and 3-month observation periods. Statin induced IP was defined as: (1) diagnosis with IP (ICD-10 codes: J70.2-J70.4, J84.1, and J84.9) within 3 months after starting statins; (2) steroid administration starts after starting statins; (3) undergoing laboratory tests for sialylated carbohydrate antigen Krebs von den Lungen-6 or pulmonary surfactant protein-D; and (4) undergoing high-resolution computed tomography (HRCT). Risk factors for IP were defined as presence of lung-related diseases including lung cancer and IP (ICD-10 codes: A15-16, J12-18, 43-46, 60-70, and 80-99) that were known to the risk factors inducing IP during the screening period. RESULTS: Cohort 1 had no IP-inducing risk factors; based on lung-related disease history, we identified 4 cases (male/female: 0/4, 61 +/- 2.5 years) and 46,574 controls (male/female: 29,677/16,897, 51.3 +/- 9.5 years). In cohort 1, all cases were female and average age was older than that of controls (p < 0.01). Cohort 2 had lung-related disease history that were known to the risk factors inducing IP; we identified 25 cases (male/female: 11/14, 52.8 +/- 11.3 years) and 4005 controls (male/female: 2305/1,700, 51.0 +/- 10.4 years). IP incidence was higher in cohort 2 than in cohort 1, who had no IP risk factors (0.6% vs. 0.009%, p < 0.01). The adjusted case/control odds ratio in cohort 2 was 3.8 (1.7-8.5) in patients who had taken atorvastatin and 2.5 (1.1 - 5.6) with diabetes mellitus. DISCUSSION: We clarified the incidence (0.009% and 0.6% in patients without and with lung related disease history that were known to the risk factors inducing IP, respectively) and risk factors for statin-induced IP (elderly females without lung-related disease history; atorvastatin administration in those with lung related disease history). Physicians and pharmacists should pay close attention to female patients starting atorvastatin, especially those with past histories of lung-related diseases that were known to the risk factors for IP. PMID- 29627481 TI - The redeployment of attention to the mouth of a talking face during the second year of life. AB - Previous studies have found that when monolingual infants are exposed to a talking face speaking in a native language, 8- and 10-month-olds attend more to the talker's mouth, whereas 12-month-olds no longer do so. It has been hypothesized that the attentional focus on the talker's mouth at 8 and 10 months of age reflects reliance on the highly salient audiovisual (AV) speech cues for the acquisition of basic speech forms and that the subsequent decline of attention to the mouth by 12 months of age reflects the emergence of basic native speech expertise. Here, we investigated whether infants may redeploy their attention to the mouth once they fully enter the word-learning phase. To test this possibility, we recorded eye gaze in monolingual English-learning 14- and 18 month-olds while they saw and heard a talker producing an English or Spanish utterance in either an infant-directed (ID) or adult-directed (AD) manner. Results indicated that the 14-month-olds attended more to the talker's mouth than to the eyes when exposed to the ID utterance and that the 18-month-olds attended more to the talker's mouth when exposed to the ID and the AD utterance. These results show that infants redeploy their attention to a talker's mouth when they enter the word acquisition phase and suggest that infants rely on the greater perceptual salience of redundant AV speech cues to acquire their lexicon. PMID- 29627483 TI - Effects of fluticasone propionate and budesonide on the expression of immune defense genes in bronchial epithelial cells. AB - BACKGROUND: COPD patients have increased risk of pneumonia when treated with fluticasone propionate (FP), whereas this is generally not the case with budesonide (BUD) treatment. We hypothesized that BUD and FP differentially affect the expression of immune defense genes. METHODS: Human bronchial epithelial 16HBE cells and air-liquid interface (ALI)-cultured primary bronchial epithelial cells (PBECs) were pre-treated with clinically equipotent concentrations of BUD or FP (0.16-16 nM BUD and 0.1-10 nM FP), and the expression of immune defense genes was studied at baseline and after exposure to rhinovirus (RV16). RESULTS: Using microfluidic cards, we observed that both BUD and FP significantly suppressed CXCL8, IFNB1 and S100A8 mRNA expression in unstimulated 16HBE cells. Interestingly, BUD, but not FP, significantly increased lactotransferrin (LTF) expression. The difference between the effect of BUD and FP on LTF expression was statistically significant and confirmed by qPCR and at the protein level by western blotting. RV16 infection of ALI-cultured PBECs significantly increased the expression of CCL20, IFNB1 and S100A8, but not of LTF or CAMP/LL-37. In these RV16-exposed cells, LTF expression was again significantly higher upon pre treatment with BUD than with FP. The same was observed for S100A8, but not for CCL20, IFNB1 or CAMP/LL-37 expression. CONCLUSIONS: Treatment of human bronchial epithelial cells with BUD results in significantly higher expression of specific immune defense genes than treatment with FP. The differential regulation of these immune defense genes may help to explain the clinical observation that BUD and FP treatment differ with respect to the risk of developing pneumonia in COPD. PMID- 29627484 TI - Subject preference emerges as cross-modal strategy for linguistic processing. AB - Research on spoken languages has identified a "subject preference" processing strategy for tackling input that is syntactically ambiguous as to whether a sentence-initial NP is a subject or object. The present study documents that the "subject preference" strategy is also seen in the processing of a sign language, supporting the hypothesis that the "subject"-first strategy is universal and not dependent on the language modality (spoken vs. signed). Deaf signers of Austrian Sign Language (OGS) were shown videos of locally ambiguous signed sentences in SOV and OSV word orders. Electroencephalogram (EEG) data indicated higher cognitive load in response to OSV stimuli (i.e. a negativity for OSV compared to SOV), indicative of syntactic reanalysis cost. A finding that is specific to the visual modality is that the ERP (event-related potential) effect reflecting linguistic reanalysis occurred earlier than might have been expected, that is, before the time point when the path movement of the disambiguating sign was visible. We suggest that in the visual modality, transitional movement of the articulators prior to the disambiguating verb position or co-occurring non-manual (face/body) markings were used in resolving the local ambiguity in OGS. Thus, whereas the processing strategy of "subject preference" is cross-modal at the linguistic level, the cues that enable the processor to apply that strategy differ in signing as compared to speech. PMID- 29627485 TI - Association and prognostic value of serum Cystatin C, IL-18 and Uric acid in urological patients with acute kidney injury. AB - PURPOSE: To assess the role of serum Cystatin C, IL-18 and Uric acid in acute kidney injury (AKI) in urological patients, along with their prognostic significance. MATERIALS AND METHODS: Prospective observational study included 61 cases, admitted in urology ward with baseline serum creatinine <=1.5 mg/dL. All patients had at least one or more predisposing factors for AKI. Daily urine output and creatinine level were checked. Serum levels of biomarkers were measured at baseline and postoperatively after 24 h. Development of AKI and its outcome were analysed. RESULTS: Thirty nine patients (63.9%) developed AKI in the study. Patients with AKI were found to have a greater percentage rise of Cystatin C (118.7% v/s 81.8%, p = 0.005), IL-18 (59.0% v/s 25.5%, p = 0.004) and Uric acid (34.3% v/s 19.2%, p = 0.008) after 24 h. Absolute Uric acid level at day 1 was also significantly associated with AKI (5.18 +/- 0.91 v/s 4.45 +/- 0.86, p = 0.003). Risk stratification of AKI was poor for all biomarkers. Area under curve for Cystatin C, IL-18 and Uric acid was 0.715, 0.696 and 0.734 respectively. Renal function after 3 months, had a positive correlation with baseline creatinine and baseline Cystatin C levels (r = 0.56 & 0.39). CONCLUSIONS: Postoperative serum Cystatin C, IL-18 and Uric acid after 24 h were significantly associated with AKI. Baseline Cystatin C had moderate capability to predict short term renal function. PMID- 29627486 TI - Association of red blood cell distribution width with severity of hepatitis B virus-related liver diseases. AB - BACKGROUND: Red blood cell distribution width (RDW) has been indicated to be an inflammatory indicator in a variety of diseases. However, no consistent conclusions regarding it's relevance to hepatitis B virus (HBV) -related liver diseases have been made. This meta-analysis was conducted to assess the significance of RDW in HBV-related liver diseases. METHODS: A comprehensive literature review was conducted using PubMed, Embase, and China National Knowledge Infrastructure (CNKI) through August 20, 2017 to identify studies that reported the association between RDW and HBV-related liver diseases. The standard mean difference (SMD) and corresponding 95% confidence interval (CI) were used to assess the associations. RESULTS: Twenty-four studies met the eligibility criteria were included in the meta-analysis. These studies included 3272 HBV infected patients and 2209 healthy controls. Chronic hepatitis B (CHB) patients had significantly increased RDW levels compared with healthy controls (SMD =1.399, 95% CI 0.971-1.827, p < 0.001]. Moreover, acute on chronic liver failure (ACLF) patients (SMD = 1.309, 95% CI 0.775-1.843, p < 0.001) and cirrhotic patients (SMD = 0.948, 95% CI 0.715-1.180, p < 0.001) had significantly elevated RDW levels compared with CHB patients. However, no statistical significance was obtained in RDW levels between cirrhosis and ACLF (SMD = 0.167, 95% CI -0.382 0.716, p = 0.051). CONCLUSION: RDW values were elevated in HBV-related liver diseases and correlated with the disease severity, suggesting that RDW levels may differentiate CHB from healthy controls and ACLF and cirrhosis from CHB but they appear to have no distinguishing characteristic between ACLF and cirrhosis. PMID- 29627487 TI - Meta-analysis of mitochondrial T16189C polymorphism for cancer and Type 2 diabetes risk. AB - AIM: Whereas many previous studies have revealed that mitochondrial DNA (mtDNA) polymorphism T16189C is associated with the risk of cancer and Type 2 diabetes mellitus (T2DM), there are others that have disputed the same. As a result, clarity on the role of mitochondrial T16189C in these disorders is missing. The aim of this study is to evaluate the association of T16189C polymorphism with the risk of cancer and T2DM development by pooling all case-control studies available. METHODS: Published studies till November 2017 were searched from PubMed, Google scholar, Google and EMBASE and isolated a total of 36 studies having 44,203 subjects (20,439 cases and 23,764 controls) based on strict inclusion and exclusion criteria. We used the statistical software "R" to calculate the Pooled Odds Ratios and 95% confidence intervals to evaluate the association of T16189C polymorphism with a possible risk towards cancer and T2DM development. RESULT: From the meta-analysis, we obtained Pooled Odds Ratios using Random effect model for cancer (OR: 1.20, 95% CI: 0.96-1.49, P = 0.104) and for T2DM (OR: 1.22, 95% CI: 1.09-1.36, P = 0.0004). In the subgroup analysis with Random effect model, we found that both Asians and Caucasians were at a statistically significant risk (OR: 1.25, P < 0.0001 and OR: 1.20, P < 0.0001, respectively) for the development of T2DM, whereas, a statistically non significant risk (OR: 1.28 P = 0.1965 and OR: 1.16, P = 0.1148) emerged for the development of cancer. There was no evidence of a significant publication bias (Egger's and Begg's test) in this meta-analysis. Further sensitivity analysis also demonstrated that our meta-analysis was relatively stable and credible. CONCLUSION: Individuals with 'C' allele at position 16,189 within the mitochondrial D-loop are seemingly at a higher risk of developing T2DM and cancer. However, before arriving at generalizations, it would be pertinent to conduct similar studies in different populations with larger numbers to corroborate these results, especially in cancer. PMID- 29627488 TI - Cell death after traumatic brain injury: Detrimental role of anoikis in healing. AB - Within the first few hours of a traumatic brain injury, the activity of extracellular matrix degradative enzymes increases. As a result, the blood brain barrier becomes disrupted as secondary white matter injury increases. Anoikis, a form of apoptosis, results from cells detaching from the extracellular matrix leading to cell death. This "homelessness" (anoikis) of cells hinders recovery progression, exacerbating brain injury while disrupting synaptic plasticity and other central nervous system functions. Here, we discuss the current knowledge of molecular pathways and proteins involved in both the activation and inhibition of anoikis. PMID- 29627489 TI - Practical laboratory-based clinical decision tools and associations with short term bleeding and mortality outcomes. AB - BACKGROUND: The red cell distribution width (RDW) predicts mortality in numerous populations. The Intermountain Risk Scores (IMRS) predict patient outcomes using laboratory measurements including RDW. Whether the RDW or IMRS predicts in hospital outcomes is unknown. METHODS: The predictive abilities of RDW and two IMRS formulations (the complete blood count [CBC] risk score [CBC-RS] or full IMRS using CBC plus the basic metabolic profile) were studied among percutaneous coronary intervention patients at Intermountain (males: N = 6007, females: N = 2165). Primary endpoints were a composite bleeding outcome and in-hospital mortality. RESULTS: IMRS predicted the composite bleeding endpoint (females: chi2 = 47.1, odds ratio [OR] = 1.13 per +1 score, p < 0.001; males: chi2 = 108.7, OR = 1.13 per +1 score, p < 0.001) more strongly than RDW (females: chi2 = 1.6, OR = 1.04 per +1%, p = 0.20; males: chi2 = 11.2, OR = 1.09 per +1%, p < 0.001). For in hospital mortality, RDW was predictive in females (chi2 = 4.3, OR = 1.13 per +1%, p = 0.037) and males (chi2 = 4.4, OR = 1.11 per +1%, p = 0.037), but IMRS was profoundly more predictive (females: chi2 = 35.5, OR = 1.36 per +1 score, p < 0.001; males: chi2 = 72.9, OR = 1.40 per+1 score, p < 0.001). CBC-RS was more predictive than RDW but not as powerful as IMRS. CONCLUSIONS: The IMRS, the CBC RS, and RDW predict in-hospital outcomes. Risk score-directed personalization of in-hospital clinical care should be studied. PMID- 29627491 TI - Colorectal malakoplakia in a patient with hypogammaglobulinemia. PMID- 29627490 TI - Genetically determined enlargement of carotid body evaluated using computed angiotomography. AB - It has recently been established that carotid bodies play a significant role in the regulation of activities of the cardiovascular system as well as in the pathogenesis of arterial hypertension, heart failure and diabetes. Aim of study was to determinate the influence of polymorphisms within genes of the renin angiotensin-aldosterone system (RAAS) on the volume of the carotid bodies (CB) in patients with hypertension (HTA). The study group consisted of 77 patients with HTA. All patients were genotyped for single-nucleotide polymorphisms of genes coding for: angiotensinogen: rs4762, rs5049, rs5051 and rs699; angiotensin converting enzyme: rs4343; angiotensin receptor type 1 gene (AGTR1): rs5182 and rs5186; and the aldosterone synthase: rs1799998. The estimation of volumes of CB (VrCB+lCB) was based on computed tomography angiography. Among individuals with essential hypertension certain relationships were documented between rs5182 and rs5186 polymorphisms of AGTR1 gene and rs1799998 polymorphism of CYP11B2 gene on one hand and the volume of carotid bodies on one other. Patients carrying the C alleles within the rs5182 and rs5186 of AGTR1 gene was associated with higher values of VrCB+lCB. The carriage of the T allele in the rs5182 locus of the AGTR1 gene determine lower values of VrCB+lCB. In summary, in patients with HTA a higher volume of CB may be resulted from the presence of specific genotypes in RAAS. PMID- 29627492 TI - Gastric adenomas in familial adenomatous polyposis: you only see them when you know what to look for. PMID- 29627493 TI - Gastric calcifying fibrous tumor mimicking GI stromal tumor. PMID- 29627494 TI - Metastatic rhabdomyosarcoma mimicking autoimmune pancreatitis diagnosed by EUS guided fine-needle biopsy. PMID- 29627495 TI - Superficial esophageal squamous cell carcinoma resembling epidermoid metaplasia of the esophagus. PMID- 29627496 TI - Simvastatin inhibits sonic hedgehog signaling and stemness features of pancreatic cancer. AB - Pancreatic ductal adenocarcinoma (PDA) has poor therapeutic options. Recent patient studies indicate that cholesterol-lowering statins have anti-tumor capacities. We examined several established and primary PDA and normal cell lines as well as PDA patient tissues (n = 68). We found that simvastatin inhibited viability, stemness, tumor growth and metastasis and that it enhanced the efficacy of gemcitabine. These changes were associated with modulation of Shh related gene expression. Overexpression of Shh prevented the anti-cancer effect of simvastatin, and inhibition of Shh mimicked the simvastatin effect. In PDA tissues, expression levels of Shh, downstream mediators of Shh and progression markers, namely, cMet, CxCR4 and Vimentin, were lower when patients were prescribed statin medication prior to surgery. These results suggested that statins are cost effective and well-tolerated drugs for prevention and co treatment of PDA. PMID- 29627497 TI - Osteoblast-secreted WISP-1 promotes adherence of prostate cancer cells to bone via the VCAM-1/integrin alpha4beta1 system. AB - Bone metastasis is a frequent occurrence in prostate cancer (PCa) that is associated with severe complications such as fracture, bone pain and hypercalcemia. The cross-talk between metastatic cancer cells and bone is critical to the development and progression of bone metastases. In our previous data, we have described how the involvement of the Wnt-induced secreted protein 1/vascular cell adhesion molecule-1 (WISP-1/VCAM-1) system in this tumor-bone interaction contributes to human PCa cell motility. In this study, we found that WISP-1 regulates bone mineralization by inducing bone morphogenetic protein-2 (BMP2), BMP4 and osteopontin (OPN) expression in osteoblasts. We also found that WISP-1 inhibited RANKL-dependent osteoclastogenesis. Moreover, osteoblast-derived WISP-1 enhanced VCAM-1 expression in PCa cells and subsequently promoted the adherence of cancer cells to osteoblasts. Furthermore, endothelin-1 (ET-1) expression in PCa cells was regulated by osteoblast-derived WISP-1, which promoted integrin alpha4beta1 expression in osteoblasts via the MAPK pathway. Pretreatment of PCa cells with VCAM-1 antibody or osteoblasts with integrin alpha4beta1 antibody attenuated the adherence of PCa cells to osteoblasts, suggesting that integrin alpha4beta1 serves as a ligand that captures VCAM-1+ metastatic tumor cells adhering to osteoblasts. Our findings reveal that osteoblast-derived WISP-1 plays a key role in regulating the adhesion of PCa cells to osteoblasts via the VCAM-1/integrin alpha4beta1 system. Osteoblast derived WISP-1 is a promising target for the prevention and inhibition of PCa bone interaction. PMID- 29627498 TI - Impact of motor fluctuations on real-life gait in Parkinson's patients. AB - BACKGROUND: People with PD (PWP) have an increased risk of becoming inactive. Wearable sensors can provide insights into daily physical activity and walking patterns. RESEARCH QUESTIONS: (1) Is the severity of motor fluctuations associated with sensor-derived average daily walking quantity? (2) Is the severity of motor fluctuations associated with the amount of change in sensor derived walking quantity after levodopa intake? METHODS: 304 Dutch PWP from the Parkinson@Home study were included. At baseline, all participants received a clinical examination. During the follow-up period (median: 97 days; 25 Interquartile range-IQR: 91 days, 75-IQR: 188 days), participants used the Fox Wearable Companion app and streamed smartwatch accelerometer data to a cloud platform. The first research question was assessed by linear regression on the sensor-derived mean time spent walking/day with the severity of fluctuations (MDS UPDRS item 4.4) as independent variable, controlled for age and MDS-UPDRS part III score. The second research question was assessed by linear regression on the sensor-derived mean post-levodopa walking quantity, with the sensor-derived mean pre-levodopa walking quantity and severity of fluctuations as independent variables, controlled for mean time spent walking per day, age and MDS-UPDRS part III score. RESULTS: PWP spent most time walking between 8am and 1pm, summing up to 72 +/- 39 (mean +/- standard deviation) minutes of walking/day. The severity of motor fluctuations did not influence the mean time spent walking (B = 2.4 +/- 1.9, p = 0.20), but higher age (B = -1.3 +/- 0.3, p = < 0.001) and greater severity of motor symptoms (B = -0.6 +/- 0.2, p < 0.001) was associated with less time spent walking (F(3216) = 14.6, p < .001, R2 = .17). The severity of fluctuations was not associated with the amount of change in time spent walking in relation to levodopa intake in any part of the day. SIGNIFICANCE: Analysis of sensor-derived gait quantity suggests that the severity of motor fluctuations is not associated with changes in real-life walking patterns in mildly to moderate affected PWP. PMID- 29627499 TI - Pelvic excursion during walking post-stroke: A novel classification system. AB - BACKGROUND: Researchers and clinicians often use gait speed to classify hemiparetic gait dysfunction because it offers clinical predictive capacity. However, gait speed fails to distinguish unique biomechanical characteristics that differentiate aspects of gait dysfunction. RESEARCH QUESTION: Here we describe a novel classification of hemiparetic gait dysfunction based on biomechanical traits of pelvic excursion. We hypothesize that individuals with greater deviation of pelvic excursion, relative to controls, demonstrate greater impairment in key gait characteristics. METHODS: We compared 41 participants (61.0 +/- 11.2yrs) with chronic post-stroke hemiparesis to 21 non-disabled controls (55.8 +/- 9.0yrs). Participants walked on an instrumented split-belt treadmill at self-selected walking speed. Pelvic excursion was quantified as the peak-to-peak magnitude of pelvic motion in three orthogonal planes (i.e., tilt, rotation, and obliquity). Raw values of pelvic excursion were compared against the distribution of control data to establish deviation scores which were assigned bilaterally for the three planes producing six values per individual. Deviation scores were then summed to produce a composite pelvic deviation score. Based on composite scores, participants were allocated to one of three categories of hemiparetic gait dysfunction with progressively increasing pelvic excursion deviation relative to controls: Type I (n = 15) - minimal pelvic excursion deviation; Type II (n = 20) - moderate pelvic excursion deviation; and Type III (n = 6) - marked pelvic excursion deviation. We assessed resulting groups for asymmetry in key gait parameters including: kinematics, joint powers temporally linked to the stance-to-swing transition, and timing of lower extremity muscle activity. RESULTS: All groups post-stroke walked at similar self-selected speeds; however, classification based on pelvic excursion deviation revealed progressive asymmetry in gait kinematics, kinetics and temporal patterns of muscle activity. SIGNIFICANCE: The progressive asymmetry revealed in multiple gait characteristics suggests exaggerated pelvic motion contributes to gait dysfunction post-stroke. PMID- 29627500 TI - Objective measures of unobstructed walking and obstacle avoidance in Parkinson's disease subtypes. AB - BACKGROUND: Objective measures of gait in Parkinson's disease (PD) patients according to motor subtypes are not yet fully understood. Although recent advances have been made for unobstructed walking, further work is required on locomotor tasks challenging postural stability, such as obstacle avoidance. RESEARCH QUESTION: This study aimed to investigate the influence of PD motor subtypes on objective measures of locomotion during unobstructed walking and obstacle avoidance. METHODS: Thirty-five PD patients classified as postural instability and gait disorder (PIGD) and 30 as tremor dominant (TD), as well as 45 healthy controls (CG) walked along an 8-m pathway under two conditions: (a) unobstructed walking and (b) obstacle avoidance. Outcome measures included spatiotemporal parameters recorded by an optoelectronic tridimensional system. RESULTS: During unobstructed walking, the PIGD group exhibited shorter stride length, slower velocity, and longer double support phase compared to the TD and CG groups. The TD group also presented slower stride velocity compared to the CG. The PIGD and TD groups presented shorter stride duration than the CG. Regarding obstacle avoidance, the PIGD group exhibited shorter distances for leading foot placement before obstacle, trailing foot placement after obstacle and trailing crossing step length compared to the TD and CG groups. The PIGD group exhibited wider leading crossing step width, lower trailing toe clearance, and slower leading and trailing velocity during obstacle avoidance compared to the CG. SIGNIFICANCE: PIGD subtype patients showed worse modifications in objective measures of unobstructed walking and obstacle avoidance. The observed modifications may contribute to increased fall occurrence in PIGD patients. PMID- 29627501 TI - Prenatal exposure to zearalenone disrupts reproductive potential and development via hormone-related genes in male rats. AB - The present study investigated the reproductive and developmental toxicity of male offspring induced by prenatal ZEN exposure and explored the possible mechanism. 64 pregnant rats were allocated into four groups and fed with ZEN contaminated (0, 5, 10 and 20 mg/kg) diet during the whole gestation period. The results showed that, F1 male foetal viability was not affected while newborn bodyweight (BW) was significantly decreased after prenatal exposure to ZEN. Decreased BW was found on postnatal day (PND) 21 but not on PND 63 in ZEN exposed male rats. Moreover, adult testis weight increased with seminiferous tubules atrophy as well as decreased spermatocytes and mature sperms (35% and 31%) in ZEN treated rats. Meanwhile, circulating levels of luteinizing hormone and testosterone decreased while estradiol increased in ZEN-treated rats. These impairments concurred with down-regulations of 3beta-HSD and StAR in both mRNA and protein levels in weaned and adult testis. Furthermore, gene and protein expressions of GnRHr and Esr1 were inhibited in the ZEN-treated foetal brain. These results suggested that prenatal ZEN exposure disrupted the system regulating the reproductive hormones and testis development through hormone related genes, which may result in a reproductive dysfunction in adult male offspring. PMID- 29627503 TI - Local traction force in the proximal leading process triggers nuclear translocation during neuronal migration. AB - Somal translocation in long bipolar neurons is regulated by actomyosin contractile forces, yet the precise spatiotemporal sites of force generation are unknown. Here we investigate the force dynamics generated during somal translocation using traction force microscopy. Neurons with a short leading process generated a traction force in the growth cone and counteracting forces in the leading and trailing processes. In contrast, neurons with a long leading process generated a force dipole with opposing traction forces in the proximal leading process during nuclear translocation. Transient accumulation of actin filaments was observed at the dipole center of the two opposing forces, which was abolished by inhibition of myosin II activity. A swelling in the leading process emerged and generated a traction force that pulled the nucleus when nuclear translocation was physically hampered. The traction force in the leading process swelling was uncoupled from somal translocation in neurons expressing a dominant negative mutant of the KASH protein, which disrupts the interaction between cytoskeletal components and the nuclear envelope. Our results suggest that the leading process is the site of generation of actomyosin-dependent traction force in long bipolar neurons, and that the traction force is transmitted to the nucleus via KASH proteins. PMID- 29627502 TI - Juglone induces apoptosis and autophagy via modulation of mitogen-activated protein kinase pathways in human hepatocellular carcinoma cells. AB - Juglone (JG), a naturally-occurring naphthoquinone of Manchurian walnut (Juglans mandshurica) was shown to inhibit proliferation in various tumor types. However, the molecular mechanisms of JG on the induction of apoptosis and autophagy in HepG2 cells have not been examined. Herein, we investigated that JG could inhibit cell proliferation by induction of G2/M phase arrest. Also, occurrence of apoptosis was closely related with loss of mitochondrial membrane potential, the changes of apoptosis-related proteins after treatment with JG. In addition, we found that JG caused autophagy, as evidenced by increased expressions of LC3-II and Beclin-1. Interestingly, inhibition of JG-induced autophagy by 3 methyladenine (3-MA) and wortmannin (WT) significantly decreased apoptosis, whereas the apoptosis inhibitor z-VAD-fmk slightly enhanced autophagy. Furthermore, the induction of autophagy and apoptosis was associated with activation of MAPK family members (p38 and JNK) and production of reactive oxygen species (ROS). Both JNK inhibitor (SP600125) and ROS scavenger (N-acetylcysteine, NAC) could attenuate JG-induced autophagy and apoptosis. However, the p38 specific inhibitor SB203580 enhanced autophagic and apoptotic death. Moreover, the ROS scavenger NAC prevented phosphorylation of both p38 and JNK. Collectively, our data revealed that JG induced G2/M phase arrest, apoptosis, and autophagy through the ROS-dependent signaling pathway. PMID- 29627504 TI - Prioritizing complex disease risk genes by integrating multiple data. AB - Complex diseases, such as obesity, type II diabetes and chronic obstructive pulmonary disease (COPD) as metabolic disorder-related diseases are major concern for worldwide public health in the 21st century. The identification of these disease risk genes has attracted increasing interest in computational systems biology. In this paper, a novel method was proposed to prioritize disease risk genes (PDRG) by integrating functional annotations, protein interactions and gene expression information to assess similarity between genes in a disease-related metabolic network. The gene prioritization method was successfully carried out for obesity and COPD, the effectiveness of which was superior to those of ToppGene and ToppNet in both literature validation and recall rate by LOOCV. Our method could be applied broadly to other metabolism-related diseases, helping to prioritize novel disease risk genes, and could shed light on diagnosis and effective therapies. PMID- 29627505 TI - Genome analysis of urease positive Serratia marcescens, co-producing SRT-2 and AAC(6')-Ic with multidrug efflux pumps for antimicrobial resistance. AB - In this study, we present the genome sequence of Serratia marcescens SM03, recovered from a human gut in India. The final assembly consists of 26 scaffolds (4620 coding DNA sequences, 5.08 Mb, 59.6% G + C ratio) and 79 tRNA genes. Analysis identified novel genes associated with lactose utilization, virulence, P loop GTPases involved in urease production, CFA/I fimbriae apparatus and Yersinia - type CRISPR proteins. Antibiotic susceptibility testing indicated drug tolerant phenotype and inhibition assays demonstrated involvement of extrusion in resistance. Presence of enzymes SRT-2, AAC(6')-Ic, with additional Ybh transporter and EamA-like efflux pumps signifies the genetic plasticity observed in S. marcescens SM03. PMID- 29627506 TI - Advances and prospects in metabolic engineering of Zymomonas mobilis. AB - Biorefinery of biomass-based biofuels and biochemicals by microorganisms is a competitive alternative of traditional petroleum refineries. Zymomonas mobilis is a natural ethanologen with many desirable characteristics, which makes it an ideal industrial microbial biocatalyst for commercial production of desirable bioproducts through metabolic engineering. In this review, we summarize the metabolic engineering progress achieved in Z. mobilis to expand its substrate and product ranges as well as to enhance its robustness against stressful conditions such as inhibitory compounds within the lignocellulosic hydrolysates and slurries. We also discuss a few metabolic engineering strategies that can be applied in Z. mobilis to further develop it as a robust workhorse for economic lignocellulosic bioproducts. In addition, we briefly review the progress of metabolic engineering in Z. mobilis related to the classical synthetic biology cycle of "Design-Build-Test-Learn", as well as the progress and potential to develop Z. mobilis as a model chassis for biorefinery practices in the synthetic biology era. PMID- 29627507 TI - MiYA, an efficient machine-learning workflow in conjunction with the YeastFab assembly strategy for combinatorial optimization of heterologous metabolic pathways in Saccharomyces cerevisiae. AB - Facing boosting ability to construct combinatorial metabolic pathways, how to search the metabolic sweet spot has become the rate-limiting step. We here reported an efficient Machine-learning workflow in conjunction with YeastFab Assembly strategy (MiYA) for combinatorial optimizing the large biosynthetic genotypic space of heterologous metabolic pathways in Saccharomyces cerevisiae. Using beta-carotene biosynthetic pathway as example, we first demonstrated that MiYA has the power to search only a small fraction (2-5%) of combinatorial space to precisely tune the expression level of each gene with a machine-learning algorithm of an artificial neural network (ANN) ensemble to avoid over-fitting problem when dealing with a small number of training samples. We then applied MiYA to improve the biosynthesis of violacein. Feed with initial data from a colorimetric plate-based, pre-screened pool of 24 strains producing violacein, MiYA successfully predicted, and verified experimentally, the existence of a strain that showed a 2.42-fold titer improvement in violacein production among 3125 possible designs. Furthermore, MiYA was able to largely avoid the branch pathway of violacein biosynthesis that makes deoxyviolacein, and produces very pure violacein. Together, MiYA combines the advantages of standardized building blocks and machine learning to accelerate the Design-Build-Test-Learn (DBTL) cycle for combinatorial optimization of metabolic pathways, which could significantly accelerate the development of microbial cell factories. PMID- 29627508 TI - The cerebellum in fear and anxiety-related disorders. AB - Fear and anxiety-related disorders are highly prevalent psychiatric conditions characterized by avoidant and fearful reactions towards specific stimuli or situations, which are disproportionate given the real threat such stimuli entail. These conditions comprise the most common mental disorder group. There are a high proportion of patients who fail to achieve remission and the presence of high relapse rates indicate the therapeutic options available are far from being fully efficient. Despite an increased understanding the neural circuits underlying fear and anxiety-related behaviors in the last decades, a factor that could be partially contributing to the lack of adequate therapies may be an insufficient understanding of the core features of the disorders and their associated neurobiology. Interestingly, the cerebellum shows connections with fear and anxiety-related brain areas and functional involvement in such processes, but explanations for its role in anxiety disorders are lacking. Therefore, the aims of this review are to provide an overview of the neural circuitry of fear and anxiety and its connections to the cerebellum, and of the animal studies that directly assess an involvement of the cerebellum in these processes. Then, the studies performed in patients suffering from anxiety disorders that explore the cerebellum will be discussed. Finally, we'll propose a function for the cerebellum in these disorders, which could guide future experimental approaches to the topic and lead to a better understanding of the neurobiology of anxiety related disorders, ultimately helping to develop more effective treatments for these conditions. PMID- 29627509 TI - Neuroimaging findings as predictors of treatment outcome of psychotherapy in anxiety disorders. AB - : Anxiety disorders are the largest group of mental disorders and a leading cause of impairment, implicating in high costs for health systems and society. Effective pharmacological and psychological treatments are available, but a significant fraction of these patients does not respond adequately to these treatments. The objective of this study is to identify neuroimaging findings that could predict response to psychotherapy in anxiety disorders. METHODS: The authors reviewed psychotherapy clinical trials with neuroimaging conducted with patients with anxiety disorders. A systematic review was performed in MEDLINE database through PubMed, the Cochrane Collaboration's Clinical Trials Register (CENTRAL), PsycINFO and Thomson Reuters's Web of Science. RESULTS: From the studies included in this review, 24 investigated anxiety disorder patients, and findings in the amygdala, dorsolateral prefrontal cortex (dlPFC), anterior cingulate cortex (ACC) and insula predicted response to psychotherapy in social anxiety disorder. Findings in ACC, hippocampus, insula, dlPFC, amygdala and inferior frontal gyrus (iFG) predicted response to psychotherapy in panic disorder and generalized anxiety disorder. LIMITATIONS: There was great heterogeneity between the included studies regarding neuroimaging techniques and the tasks performed during functional neuroimaging. CONCLUSION: Neuroimaging studies suggest that abnormalities in hippocampus, amygdala, iFG, uncus and areas linked with emotional regulation (dlPFC and ACC), predict a good outcome to psychotherapy in anxiety disorders. PMID- 29627510 TI - Occurrence of Clostridium difficile infections in Serbia and high proportion of PCR ribotype 027 strains in two hospitals in Belgrade. AB - BACKGROUND: The incidence of Clostridium difficile infections (CDI) in the Clinical Center of Serbia (CCS) and the entire Serbia has been constantly rising in the previous 5 years. We aimed to study C. difficile PCR-ribotypes isolated from patients hospitalized at two healthcare institutions: CCS and Specialized Hospital for Cerebrovascular Diseases "Sveti Sava" (SS), both of them from Belgrade, and to investigate the incidence rates of CDI in hospital settings in Serbia, from 2009 to 2013. METHODS: The Bacteriology laboratory database at Clinic for Infectious and Tropical Diseases of CCS was queried from January 1, 2009 to December 31, 2013 for all patients who underwent immunochromatographic toxin A and/or toxin B stool testing and C. difficile stool culture for suspected infection caused by this bacterium. Toxigenic culture was not performed. Ninety- six C. difficile isolates were then selected and characterized by PCR-ribotyping. These were obtained from 94 patients hospitalized in different clinics of CCS and SS from November 2011 to December 2013. RESULTS: Among 6164 stool samples sent to Bacteriology laboratory for culture of C. difficile and toxin detection during the study period, 1775 (28.8%) were positive, displaying linear trend of growth. From 96 isolates, typed by PCR-ribotyping, majority (85; 88.54%) belonged to PCR ribotype 027. The remaining 11 isolates belonged to PCR-ribotypes 014/020 (3 isolates), 015, SLO 191 (two isolates each), 017, 018, 070 and 001/072 (one isolate each). CONCLUSION: Our results demonstrated that C. difficile PCR ribotype 027 is by far predominant in two hospital settings in Belgrade, at least since 2011. PMID- 29627511 TI - Trend differences in men and women in rural and urban U.S. settings. AB - BACKGROUND: Smoking prevalence is declining at a slower rate in rural than urban settings in the United States (U.S.), and known predictors of smoking do not readily account for this trend difference. Given that socioeconomic and psychosocial determinants of health disparities accumulate in rural settings and that life-course disadvantages are often greater in women than men, we examined whether smoking trends are different for rural and urban men and women. METHOD: We used yearly cross-sectional data (n = 303,311) from the U.S. National Survey on Drug Use and Health (NSDUH) from 2007 through 2014 to compare cigarette smoking trends in men and women across rural and urban areas. Current smoking status was modelled using logistic regression controlling for confounding risk factors. RESULTS: Regression derived graphs predicting unadjusted prevalence estimates and 95% confidence bands revealed that whereas the smoking trends of rural men, urban men, and urban women significantly declined from 2007 to 2014, the trend for rural women was flat. Controlling for demographic, socioeconomic and psychosocial predictors of smoking did not explain rural women's significantly different trend from those of the other three groups. CONCLUSION: Rural women lag behind rural men, urban men and urban women in decreasing smoking, a health disparity finding that supports the need for tobacco control and regulatory policies and interventions that are more effective in reducing smoking among rural women. PMID- 29627512 TI - The carry-over effects of school gardens on fruit and vegetable availability at home: A randomized controlled trial with low-income elementary schools. AB - This group-randomized controlled trial examines the effects of a school garden intervention on availability of fruits and vegetables (FV) in elementary school children's homes. Within each region, low income U.S. schools in Arkansas, Iowa, New York, and Washington State were randomly assigned to intervention group (n = 24) or waitlist control group (n = 22). Children were in grades 2, 4, and 5 at baseline (n = 2768). The garden intervention consisted of both raised-bed garden kits and a series of grade-appropriate lessons. FV availability at home was measured with a modified version of the GEMS FJV Availability Questionnaire. The instrument was administered at baseline (Fall 2011) and throughout the intervention (Spring 2012, Fall 2012, Spring 2013). Analyses were completed using general linear mixed models. The garden intervention led to an overall increase in availability of low-fat vegetables at home. Among younger children (2nd grade at baseline), the garden intervention led to greater home availability of vegetables, especially, low-fat vegetables. Moreover, for the younger group, garden intervention fidelity (GIF) or robustness predicted home availability of fruit, vegetables, and low-fat vegetables. School gardens have potential to affect FV availability in the home environment. PMID- 29627514 TI - Combined effects of photobiomodulation and alendronate on viability of osteoporotic bone marrow-derived mesenchymal stem cells. AB - Osteoporotic bone marrow mesenchymal stem cells (BMMSCs) are involved in the pathogenesis of osteoporosis (OP). Photobiomodulation (PBM) has positive effects on healthy BMMSCs. The goal of current experiment was to evaluate the combined influence of photobiomodulation PBM and alendronate (ALN) incubation on ovariectomized induced osteoporosis(OVX)- BMMSC viability in vitro. 15 female adult Wistar rats were distributed into the 2 groups: (1) 3 healthy (sham)control rats, (2) 12 OVX- rats. All OVX rats underwent ovariectomy. After 3.5 months sham and OVX rats were euthanized and their MSC harvested and cultured in a complete osteogenic incubation medium (OM). As the next step, in sham and OVX groups flowcytometry and osteogenic differentiation assays were performed. OVX- rats were divided into (2) OVX-control, (3) OVX- PBM (HeNe laser, 623.8 nm, 1.2 J/cm2, one time), (4) OVX-ALN (10-8 M, three times incubations), and (5) OVX-PBM + ALN, Finally BMMSC viability of all five groups were evaluated using MTT (3-(4, 5 dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide) assay. Based on our observations, PBM significantly increased optical density of OVX-BMMSCs (2.15 +/- 0.11) compared to control -OVX-BMMSCs (1.55 +/- 0.10) and healthy -BMMSCs (1.65 +/- 0.10)(LSD test, both p < 0.05). Further, we found that both ALN, and ALN + PBM significantly increased optical densities of OVX-BMMSCs (24 h:2.40 +/- 0.03;48 h:2.06 +/- 0.00[ALN],both p < 0.01) and 1.88 +/- 0.05[ALN + PBM], p < 0.05 compared to control -OVX-BMMSCs (24 h: 1.46 +/- 0.01; 48 h: 1.83 +/- 0.00 and 1.57 +/- 0.08). It was concluded that PBM significantly increased cell viability of OVX-BMMSCs compared to control -OVX-BMMSCs and healthy -BMMSCs. PMID- 29627515 TI - A threshold dose distribution approach for the study of PDT resistance development: A threshold distribution approach for the study of PDT resistance. AB - Photodynamic therapy (PDT) is a technique with well-established principles that often demands repeated applications for sequential elimination of tumor cells. An important question concerns the way surviving cells from a treatment behave in the subsequent one. Threshold dose is a core concept in PDT dosimetry, as the minimum amount of energy to be delivered for cell destruction via PDT. Concepts of threshold distribution have shown to be an important tool for PDT results analysis in vitro. In this study, we used some of these concepts for demonstrating subsequent treatments with partial elimination of cells modify the distribution, which represents an increased resistance of the cells to the photodynamic action. HepG2 and HepaRG were used as models of tumor and normal liver cells and a protocol to induce resistance, consisted of repeated PDT sessions using Photogem(r) as a photosensitizer, was applied to the tumor ones. The response of these cells to PDT was assessed using a standard viability assay and the dose response curves were used for deriving the threshold distributions. The changes in the distribution revealed that the resistance protocol effectively eliminated the most sensitive cells. Nevertheless, HepaRG cell line was the most resistant one among the cells analyzed, which indicates a specificity in clinical applications that enables the use of high doses and drug concentrations with minimal damage to the surrounding normal tissue. PMID- 29627513 TI - High level efficacy of lufenuron against sea lice (Lepeophtheirus salmonis) linked to rapid impact on moulting processes. AB - Drug resistance in the salmon louse Lepeophtheirus salmonis is a global issue for Atlantic salmon aquaculture. Multiple resistance has been described across most available compound classes with the exception of the benzoylureas. To target this gap in effective management of L. salmonis and other species of sea lice (e.g. Caligus spp.), Elanco Animal Health is developing an in-feed treatment containing lufenuron (a benzoylurea) to be administered prior to seawater transfer of salmon smolts and to provide long-term protection of salmon against sea lice infestations. Benzoylureas disrupt chitin synthesis, formation, and deposition during all moulting events. However, the mechanism(s) of action are not yet fully understood and most research completed to date has focused on insects. We exposed the first parasitic stage of L. salmonis to 700 ppb lufenuron for three hours and observed over 90% reduction in survival to the chalimus II life stage on the host, as compared to vehicle controls. This agrees with a follow up in vivo administration study on the host, which showed >95% reduction by the chalimus I stage. Transcriptomic responses of salmon lice exposed to lufenuron included genes related to moulting, epithelial differentiation, solute transport, and general developmental processes. Global metabolite profiles also suggest that membrane stability and fluidity is impacted in treated lice. These molecular signals are likely the underpinnings of an abnormal moulting process and cuticle formation observed ultrastructurally using transmission electron microscopy. Treated nauplii-staged lice exhibited multiple abnormalities in the integument, suggesting that the coordinated assembly of the epi- and procuticle is impaired. In all cases, treatment with lufenuron had rapid impacts on L. salmonis development. We describe multiple experiments to characterize the efficacy of lufenuron on eggs, larvae, and parasitic stages of L. salmonis, and provide the most comprehensive assessment of the physiological responses of a marine arthropod to a benzoylurea chemical. PMID- 29627516 TI - Lighting up the brain: genetically encoded fluorescent sensors for imaging neurotransmitters and neuromodulators. AB - Measuring the precise dynamics of specific neurotransmitters and neuromodulators in the brain is essential for understanding how information is transmitted and processed. Thanks to the development and optimization of various genetically encoded sensors, we are approaching the stage in which a few key neurotransmitters/neuromodulators can be imaged with high cell specificity and good signal-to-noise ratio. Here, we summarize recent progress regarding these sensors, focusing on their design principles, properties, potential applications, and current limitations. We also highlight the G protein-coupled receptor (GPCR) scaffold as a promising platform that may enable the scalable development of the next generation of sensors, enabling the rapid, sensitive, and specific detection of a large repertoire of neurotransmitters/neuromodulators in vivo at cellular or even subcellular resolution. PMID- 29627517 TI - Molecular phylogeny of Galium L. of the tribe Rubieae (Rubiaceae) - Emphasis on Chinese species and recognition of a new genus Pseudogalium. AB - Galium L. is the largest genus in the tribe Rubieae, with about 667 species distributed worldwide. Previous researches mainly focused on species from the Americas and Europe. In the present paper, we greatly increased the number of samples examined from eastern Asia (especially China), representing the most comprehensive sampling of Galium to date. A total of 194 species and variations (subspecies) of Galium were sampled to determine phylogenetic relationships, using two nuclear and five chloroplast markers. Our data are largely consistent with all previous phylogenetic results and confirmed that Galium is non monophyletic, as are most of its sections. Most members of Galium, including the Chinese taxa, fall into three large clades mixed with other genera from the Galium s.l. group; the exception being the distinct Galium paradoxum Maxim., the first diverged lineage in the Galium s.l. group, which was treated as a new genus (Pseudogalium L.-E. Yang, Z.-L. Nie & H. Sun, gen. nov.). The Galium s.s is a well-supported clade comprised entirely of Galium species, usually with six or more leaves per whorl, mostly from the Old World. Samples from G. maximowiczii (Kom.) Pobed, G. sect. Depauperata and sect. Aparinoides, together with a few from Asperula sect. Glabella and Microphysa (Schrenk ex Fisch. & C.A. Mey.) Pobed., form the second clade. The third clade comprises taxa purely from Galium that usually have four leaves per whorl, from both the New and Old World. Our results also indicated that the monotypic genus Microphysa should be retained and clarified phylogenetic relationships of some specific confused taxa from China. Unlike prior inferences, the combination of opposite leaves associated with two stipules is proposed as the ancestral characteristic of the Galium s.l. group and even the tribe. In addition, the shapes of different corolla and inflorescence types are important for distinguishing some taxa within Rubieae. PMID- 29627518 TI - Nursing and midwifery students' perception of learning enablers and gains in the first semester of their BSc programmes: A cross sectional study. AB - BACKGROUND: The student experience in the first year of university is fundamental to successful adaption to the higher education environment and shapes student engagement with their chosen degree. Students' feedback on this experience is essential when designing or reviewing curricula. OBJECTIVES: The aim of this study was to explore students' perceptions of their learning gains to identify factors that support student learning and identify elements that need improvement if specific learning needs are to be met. DESIGN: A cross sectional descriptive study. SETTING: A large urban university in Ireland that provides undergraduate nursing and midwifery degree programmes. PARTICIPANTS AND METHODS: The study was conducted using the Student Assessment of Learning Gains (SALG) questionnaire. This instrument consists of a series of closed questions which explore perceived student gains in skills, cognitions and attitudes. The questionnaire was adapted for a semester rather than a module evaluation. The tool also includes a series of open questions inviting students to comment in each section. RESULTS: Students (n = 206) positively evaluated teaching and learning approaches used. The greatest enablers of learning were clinical skills laboratory small group teaching and support followed by online learning materials and multiple choice formative assessment questions. They reported gains in knowledge, generic skills development and an increase in confidence and enthusiasm for their chosen career. CONCLUSION: The feedback gained in this study provides valuable knowledge about the elements that support nursing and midwifery students learning and highlights areas that require attention. This is particularly useful for faculty who are involved in curriculum review and enhancement and in student engagement and retention. PMID- 29627519 TI - Significant upregulation of U1 and U4 spliceosomal snRNAs by ATP nanoliposomes explains acceleration of wound healing, due to increased pre-mRNA processing to functional mRNA. AB - Delayed wound healing is one of the hallmarks of diabetic complications and certain autoimmune inflammatory diseases. Extensive wound healing studies in rabbits have indicated that the delivery of ATP encapsulated in unilamellar nanoliposomes causes rapid cell proliferation and fast tracks the wound healing process. In the current study, we explored the possible molecular mechanism underlying this response by comparing gene expression in cultured rabbit kidney cells treated with either ATP nanoliposomes (containing 1 mg Mg-ATP/ml formulation) or control nanoliposomes (containing 1 mg/ml unmetabolisable gamma thio-ATP/ml formulation). High-quality total RNA was isolated 24 h from the cells and subjected to RNA seq technology, which revealed significant overexpression of specific noncoding RNAs. The U1 spliceosomal RNA, U1 snRNA, was upregulated more than 250-fold following treatment with ATP nanoliposomes. This multifunctional U1 spliceosomal RNA may function in transcription by speeding up the critical splicing step, thereby facilitating faster processing of pre-mRNA to translatable mRNA. PMID- 29627520 TI - Promoting neuroregeneration by applying dynamic magnetic fields to a novel nanomedicine: Superparamagnetic iron oxide (SPIO)-gold nanoparticles bounded with nerve growth factor (NGF). AB - Neuroregeneration imposes a significant challenge in neuroscience for treating neurodegenerative diseases. The objective of this study is to evaluate the hypothesis that the nerve growth factor (NGF) functionalized superparamagnetic iron oxide (SPIO)-gold (Au) nanomedicine can stimulate the neuron growth and differentiation under external magnetic fields (MFs), and dynamic MFs outperform their static counterparts. The SPIO-Au core-shell nanoparticles (NPs) (Diameter: 20.8 nm) possessed advantages such as uniform quasi-spherical shapes, narrow size distribution, excellent stabilities, and low toxicity (viability >96% for 5 days). NGF functionalization has enhanced the cellular uptake. The promotion of neuronal growth and orientation using NGF functionalized SPIO-Au NPs, driven by both the static and dynamic MFs, was revealed experimentally on PC-12 cells and theoretically on a cytoskeletal force model. More importantly, dynamic MFs via rotation performed better than the static ones, i.e., the cellular differentiation ratio increased 58%; the neurite length elongation increased 63%. PMID- 29627521 TI - Epidermolysis bullosa: Molecular pathology of connective tissue components in the cutaneous basement membrane zone. AB - Epidermolysis bullosa (EB), a group of heritable skin fragility disorders, is characterized by blistering, erosions and chronic ulcers in the skin and mucous membranes. In some forms, the blistering phenotype is associated with extensive mutilating scarring and development of aggressive squamous cell carcinomas. The skin findings can be associated with extracutaneous manifestations in the ocular as well as gastrointestinal and vesico-urinary tracts. The phenotypic heterogeneity reflects the presence of mutations in as many as 20 different genes expressed in the cutaneous basement membrane zone, and the types and combinations of the mutations and their consequences at the mRNA and protein levels contribute to the spectrum of severity encountered in different subtypes of EB. This overview highlights the molecular genetics of EB based on mutations in the genes encoding type VII and XVII collagens as well as laminin-332. The mutations identified in these protein components of the extracellular matrix attest to their critical importance in providing stability to the cutaneous basement membrane zone, with implications for heritable and acquired diseases. PMID- 29627522 TI - Association of SERPINE1 rs6092 with type 2 diabetes and related metabolic traits in a Chinese population. AB - BACKGROUND: Plasminogen activator inhibitor-1 (PAI-I), encoded by SERPINE1 gene, is a member of the serine protease inhibitor superfamily, and polymorphisms in SERPINE1 have been reported to be associated with type 2 diabetes (T2D). This study investigated whether the polymorphism in PAI-I contribute to the risk for T2D. METHODS: A 1:1 case-control study was conducted to investigate the association of rs6092 in SERPINE1 with T2D and diabetes-related metabolic traits, including body mass index, waist circumference (WC), triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol, low density lipoprotein cholesterol, fasting plasma glucose and glycosylated hemoglobin (HbA1c) in a Chinese population, with a total of 1572 subjects (786 T2D patients and 786 healthy controls). The polymorphism was genotyped based on MassARRAY genotyping system. RESULTS: The AA genotype and A allele of rs6092 exerted a protective effect on T2D risk (odds ratio (OR) = 0.431 and 0.630, respectively). In a recessive model, we also observed the protective association of rs6092 with T2D (OR = 0.195). The above associations were only observed in men. In female patients, there was a significant difference in HbA1c level between the AA homozygotes and GG homozygotes, as well as between the AA homozygotes and combined GG and GA genotypes. In male patients, the WC level in the subjects carrying AA genotype was lower than those in the subjects with GG genotype (P = 0.000), and the association was also significant in a recessive model (P = 0.000). Additionally, there was a significant difference in TG level between the AA homozygotes and GG homozygotes (P = 0.017), as well as the AA homozygotes and combined GG and GA genotypes (P = 0.032). CONCLUSIONS: Our study suggests that the A allele and AA genotype of rs6092 may protect against T2D, and have a protective effect on WC, but a negative effect on TG in men, while may contribute to a lower HbA1c level in women. PMID- 29627523 TI - mircoRNA-3162-3p is a potential biomarker to identify new infections in HIV-1 infected patients. AB - BACKGROUND: Identification of new HIV infections (HIV incidence) is critical for monitoring AIDS epidemic and assessing the effectiveness of intervention measures. However, current methods for distinguishing new infections from newly diagnosed HIV-1 patients are still imperfect. We explored utilizing miRNAs as biomarker to identify HIV new infections. METHODS: According to the HIV-1 status and the estimated duration of infection (EDI), we enrolled participants and divided them into three groups: healthy control, new infection (within 1 year), and old infection (longer than 1 year). Participants were assigned into screening set or validation set. miRNA microarray was performed in screening set and the differentially expressed miRNAs were screened out. The differentially expressed miRNAs were further confirmed in validation set and HIV-1 IIIB-MT2 cells infection system. RESULTS: In screening set, 5 miRNAs including miR-1291, miR 3609, miR-3162-3p, miR-874-5p and miR-4258 were screened out for their differential expression in plasma among three groups. In validation set, down- trend of miR-3162-3p was validated from healthy control, new infection to old infection groups. In HIV-1 IIIB-MT2 system, the levels of miR-3162-3p also decreased along with infection duration in vitro. Sensitivity and specificity for miR-3162-3p to distinguish new infection from old infection were 100.0% and 71.43%, respectively, with the cut-off value of 0.916. CONCLUSION: miR-3162-3p in plasma could be a potential microRNA biomarker to identify HIV new infections in HIV-1 infected patients. PMID- 29627524 TI - Molecular cloning and the expression pattern of AePOPB involved in the alpha amanitin biosynthesis in Amanita exitialis fruiting bodies. AB - Amanita exitialis Zhu L. Yang & T. H. Li is the species responsible for the largest number of mushroom-associated human poisonings and fatalities in South China due to its lethal cyclic peptide toxins. Prolyl oligopeptidase B (POPB) is considered a key enzyme in the production of the highly toxic cyclic peptide alpha-amanitin. However, the POPB gene of A. exitialis has not been studied. In the present study we cloned and sequenced the full-length A. exitialis POPB (AePOPB) gene. The aim was to verify the gene structure and functions of AePOPB. The full-length sequence of AePOPB is 3144 bp, including 18 exons encoding 730 aa, and the advanced structure is very similar to that of the previously reported POPB in Galerina marginata (GmPOPB). The amino acid sequence of AePOPB is highly homologous with those from other amanitin-producing lethal mushrooms, implying that AePOPB may have a similar role in the biosynthesis of cyclic peptide toxins. Expression levels of AePOPB were detectable in all parts and developmental stages of the fruiting bodies, and AePOPB was expressed more strongly at early development stages (early and late elongation stages). At early and late elongation stages, the expression peaks occurred in the stipe, whereas at early and late mature stages, the expression peaks occurred in the pileus. The expression patterns of AePOPB in different stages and different parts of the fruiting bodies were highly consistent with those of Aealpha-AMA, which is required for alpha-amanitin accumulation. These results indicate that AePOPB should be involved in the alpha-amanitin biosynthesis in A. exitialis. PMID- 29627525 TI - Adiponectin gene polymorphisms as a predictor for development of type 2 diabetes mellitus in Iraqi population. AB - BACKGROUND: Type 2 diabetes mellitus (T2DM) incidence is increasing globally and nationally. The etiology of the disease includes environmental and genetic factors. Polymorphism of adiponectin gene was found to be implicated in the pathogenesis of T2DM in numerous populations. METHODS: A case-control study was conducted to assess the association of rs2241766 and rs822395 SNPs of adiponectin gene (ADIPOQ) with T2DM in Iraqi population. The study included 400 patients with T2DM and 400 healthy individuals served as a control group. Serum lipid concentrations, insulin level and the index of insulin resistance (HOMA) were measured. The genotyping of ADIPOQ for rs2241766 and rs822395 SNPs was performed by PCR-RFLP. RESULTS: The genotype distribution of rs2241766 SNP indicated a significant increase of carriers of the homozygous GG (OR: 5.04, CI95%: 2.27 11.19, P: 0.0001) and heterozygous TG (OR: 1.7, CI95%: 1.22-2.39, P: 0.002) variants when compared with those of the wild type, suggesting a risk factor of 2 and 5 to develop the disease. The minor allele frequency (MAF) G was observed to be significantly (P: 0.0001) higher in patients (22%) when compared with the control group (11.74%). Results of rs822395 SNP failed to exhibit a significant difference. Changes of BMI, cholesterol, triglycerides, insulin and insulin resistance index values in the diabetic patients seemed to be parallel with the presence of MAF of rs2241766 SNP. CONCLUSION: The rs2241766T>G SNP of adiponectin gene is a risk factor for the development of T2DM in Iraqi population and directs the changes of serum lipid concentrations as well as insulin resistance. PMID- 29627526 TI - Role of AKR1C3 in renal injury and glibenclamide is anti-inflammatory in preeclamptic rats. AB - Proteinuria is a common adverse effect of renal injury in preeclampsia. To explore the effects of AKR1C3 in renal injury due to preeclampsia and to determine an optimal method to prevent proteinuria, glibenclamide treatment was used in unrestrained Wistar rats exposed to N-nitro-L-arginine methyl ester hydrochloride (L-NAME). Successful rat models for preeclampsia were confirmed based on mean arterial pressure, a 24-h protein urine test, and by observing the structure of the kidney by transmission electron microscopy (TEM). Forty Wistar rats were randomly divided into L-NAME-induced preeclampsia (pregnant and L NAME), treatment (pregnant, L-NAME, and glybenclamide), non-pregnant (L-NAME), and control (pregnant and 0.9% saline) groups. Rats that were 19 days into their pregnancies were then euthanized and their kidneys were collected. After exposure to L-NAME, the mean arterial pressure increased by ~25 mmHg, which was largely prevented by the co-administration of glibenclamide. At 24 h, protein levels in the urine of the L-NAME-induced preeclampsia group were higher than those of the control and treatment groups. AKR1C3 was downregulated in the kidney and podocytes, whereas glibenclamide increased the expression of AKR1C3. The generation of reactive oxygen species (ROS) detected by ELISA was decreased by the glibenclamide co-administration. Compared with that in the L-NAME-induced preeclampsia group, the expression levels of AKR1C3 protein and mRNA significantly increased in the treatment group ([0.48 +/- 0.09] vs.[1.05 +/- 0.20];[0.05 +/- 0.02] vs.[0.22 +/- 0.06]; both P < 0.05]). Therefore, AKR1C3 expression was decreased in the kidneys of L-NAME-induced preeclampsia rats, and glibenclamide may be useful for the treatment of preeclampsia by regulating the generation of ROS and preventing proteinuria. PMID- 29627527 TI - Insight into stem cell regulation from sub-lethally irradiated worms. AB - Despite the significant advances in the comprehension of stem cell control network, the nature of extrinsic signals regulating their dynamic remains to be understood. In this paper, we take advantage of the stem cell repopulation process that follows low-dose X-ray treatment in planarians to identify genes, preferentially enriched in differentiated cells, whose expression is activated during the process. Genetic silencing of some of them impaired the stem cell repopulation, suggesting a tight extrinsic control of stem cell activity. PMID- 29627528 TI - The association between donor genetic variations in one-carbon metabolism pathway genes and hepatitis B recurrence after liver transplantation. AB - BACKGROUNDS AND AIM: Hepatitis B recurrence adversely affects patients' survival after liver transplantation. This study aims to find association between donor gene variations of one carbon metabolism and post-transplant hepatitis B recurrence. METHODS: This study enrolled 196 patients undergoing liver transplantation for HBV related end-stage liver diseases. We detected 11 single nucleotide polymorphisms (SNP) of 7 one-carbon metabolism pathway genes (including MTHFR, MTR, MTRR, ALDH1L1, GART, SHMT1 and CBS) in donor livers and analyzed their association with HBV reinfection after liver transplantation. RESULTS: Hepatitis B recurrence was observed in 19 of the 196 patients (9.7%) undergoing liver transplantation. Hepatitis B recurrence significantly affected post-transplant survival in the 196 patients (p = 0.018), and correlate with tumor recurrence in the subgroup of HCC patients (n = 99, p = 0.006). Among the 11 SNPs, donor liver mutation in rs1979277 (G > A) was adversely associated with post-transplant hepatitis B recurrence (p = 0.042). In the subgroup of HCC patients, survival analysis showed donor liver mutations in rs1801133 (G > A) and rs1979277 (G > A) were risk factors for hepatitis B recurrence (p < 0.05). None of the 11 SNPs was related to hepatitis B recurrence in non-HCC patients (n = 97, p > 0.05). CONCLUSION: Hepatitis B recurrence impaired post-transplant survival. Donor liver genetic variations in one-carbon metabolism pathway genes were significantly associated with post-transplant hepatitis B recurrence. PMID- 29627529 TI - Comparative mitogenomic analysis reveals cryptic species in Reticunassa festiva (Neogastropoda: Nassariidae). AB - The mitochondrial genome provides sets of genome-level characteristics, which can be useful in resolving ancient relationships. The complete mitochondrial genomes of five Reticunassa and one Nassarius were sequenced, including Reticunassa hiradoensis, R. fratercula, R. festiva complex A, B and C and Nassarius variciferus, and compared with other two Nassariidae species (Tritia reticulatus and T. obsolete). Eight genomes show the same gene order as in other caenogastropods, containing 13 protein-coding genes, 2 ribosome RNA genes and 22 transfer RNA genes, except R. fratercula, which lacks the trnF. Three-nucleotide deletion in nad6 genes, truncated major non-coding regions are detected in all Reticunassa mitogenomes. The reconstructed phylogenetic trees show (Reticunassa + (Tritia + Nassarius)) at genus level and support the relationship between R. festiva-C and the clade formed by R. hiradoensis + R. fratercula and R. festiva-A + R. festiva-B within Reticunassa. The specific mitogenomic characters and phylogenetic analyses support the validity of genus Reticunassa. Pairwise genetic distances of protein-coding genes between R. festiva complex A, B and C range from 0.063 to 0.109, which are close to that of R. hiradoensis and R. fratercula (0.065), and higher than those of several closely related sister species of mollusks. These variation in mitochondrial genomes of Reticunassa indicate that R. festiva-A, R. festiva-B and R. festiva-C should be considered as separate species. PMID- 29627530 TI - An enriched environment restores hepatitis B vaccination-mediated impairments in synaptic function through IFN-gamma/Arginase1 signaling. AB - Activation of the neonatal immune system may contribute to deficits in neuronal plasticity. We have reported that neonatal vaccination with a hepatitis B vaccine (HBV) transiently impairs mood status and spatial memory involving a systemic T helper (Th) 2 bias and M1 microglial activation. Here, an EE induced microglial anti-inflammatory M2 polarization, as evidenced by selectively enhanced expression of the Arginase1 gene (Arg-1) in the hippocampus. Interestingly, knock down of the Arg-1 gene prevented the effects of EE on restoring the dendritic spine density. Moreover, levels of the Th1-derived cytokine IFN-gamma (IFN-gamma) were elevated in the choroid plexus (CP), which is the interface between the brain and the periphery. IFN-gamma-blocking antibodies blunted the protective effects of an EE on spine density and LTP. Furthermore, levels of complement proteins C1q and C3 were elevated, and this elevation was associated with synapse loss induced by the HBV, whereas an EE reversed the effects of the HBV. Similarly, blockade of C1q activation clearly prevented synaptic pruning by microglia, LTP inhibition and memory deficits in hepatitis B-vaccinated mice. Together, the EE-induced increase in IFN-gamma levels in the CP may disrupt systemic immunosuppression related to HBV via an IFN-gamma/Arg-1/complement dependent pathway. PMID- 29627531 TI - CRP genetic variants are associated with mortality and depressive symptoms in chronic heart failure patients. AB - OBJECTIVE: Heart failure (HF) is a complex medical condition with a multitude of genetic and other factors being involved in the pathogenesis. Emerging evidence points to an involvement of inflammatory mechanisms at least in subgroups of patients. The same is true for depression and depressive symptoms, which have a high prevalence in HF patients and are risk factors for the development and outcomes of cardiovascular disease. METHODS: In 936 patients of the Interdisciplinary Network Heart Failure (INH) program, CRP and IL-6 protein blood levels were measured and genetic variants (single nucleotide polymorphisms) of the CRP and IL6 gene analyzed regarding their influence on mortality. RESULTS: Less common recessive genotypes of two single nucleotide polymorphisms in the CRP gene (rs1800947 and rs11265263) were associated with significantly higher mortality risk (p < 0.006), higher CRP levels (p = 0.029, p = 0.006) and increased depressive symptoms in the PHQ-9 (p = 0.005, p = 0.003). Variants in the IL-6 gene were not associated with mortality. CONCLUSION: Our results hint towards an association of less common CRP genetic variants with increased mortality risk, depressive symptoms and peripheral CRP levels in this population of HF patients thereby suggesting a possible role of the inflammatory system as link between poor prognosis in HF and depressive symptoms. PMID- 29627532 TI - Effector/memory CD8+ T cells synergize with co-stimulation competent macrophages to trigger autoimmune peripheral neuropathy. AB - Autoimmune peripheral neuropathy (APN) such as Guillain Barre Syndrome (GBS) is a debilitating illness and sometimes life threatening. The molecular and cellular mechanisms remain elusive but exposure to environmental factors including viral/bacterial infection and injury is highly associated with disease incidence. We demonstrated previously that both male and female B7.2 (CD86) transgenic L31 and L31/CD4KO mice develop spontaneous APN. Here we further reveal that CD8+ T cells in these mice exhibit an effector/memory phenotype, which bears a resemblance to the CD8+ T cell response following persistent cytomegalovirus (CMV) infection in humans and mice, whilst CMV has been considered as one of the most relevant pathogens in APN development. These activated, peripheral myelin Ag specific CD8+ T cells are required for the disease initiation. While an injury to a peripheral nerve results in Wallerian degeneration in control littermates, the same injury accelerates the development of APN in other non-injured nerves of L31 mice which have a predisposed inflammatory background consisting of effector/memory CD8+ T (CD8+ TEM) cells. However, CD8+ TEM cells alone are not sufficient. A certain threshold of B7.2 expression on nerve macrophages is an additional requisite. Our findings reveal that indeed, the synergism between CD8+ TEM cells and co-stimulation competent macrophages is crucial in inducing autoimmune-mediated peripheral neuropathy. The identification of decisive molecular/cellular players connecting environmental triggers and the occurrence of APN provides opportunities to prevent disease onset, reduce relapses and develop new therapeutic strategies. PMID- 29627533 TI - Lead exposure in an urban, free-ranging parrot: Investigating prevalence, effect and source attribution using stable isotope analysis. AB - Anthropogenic lead use has resulted in widespread environmental lead contamination known to affect wildlife populations worldwide. Ecotoxicological investigations in wild birds have thus far prioritised waterfowl and raptor species and primarily addressed contamination in natural ecosystems. Urban areas are increasingly associated with high levels of heavy metal contamination, however the risk of lead exposure in urban wildlife is less well known. This study investigates lead exposure in an urban population of North Island Kaka (Nestor meridionalis septentrionalis), an endemic New Zealand parrot. The inquisitive nature of these birds, an expanding urban population and increased availability of food in the urban environment are the primary factors implicated in their dispersal into urban areas where there is increased exposure to anthropogenic sources of lead. Blood lead concentrations were assessed in free ranging birds to quantify the prevalence and magnitude of lead exposure. The impact of lead on physiological and neurological function was assessed using behavioural and clinical examinations. Finally, lead stable isotope analysis was employed to investigate lead in roofing material as a potential source of exposure in the urban environment. Results indicate a significant prevalence of lead exposure in this population (43.2%) with a maximum recorded plasma concentration of 50.7MUg/dL. Although no mortality was observed during this study, lead exposure was associated with reduced body condition in kaka. Behavioural changes were present in one individual with the highest recorded blood lead concentration. Lead isotope values of roof-collected rainwater overlapped with kaka blood lead isotope values, suggesting this to be an important source of exposure in this population. The prevalence of lead exposure observed in this study suggests that lead is a toxin of importance to kaka in this urban area. Wildlife intoxications largely result from anthropogenic lead sources and this study identifies a previously undescribed urban source of lead for wildlife. PMID- 29627534 TI - Assessment of the effects of discontinuous sources of contamination through biomarker analyses on caged mussels. AB - The present study analysed potential adverse effects of discontinuous sources of contamination, namely the discharge of a combined sewer overflow (CSO) and of runoff in an urban area, the Bay of Santander (North Iberian Peninsula). Water samples and caged mussels were used to analyse concentrations of contaminants and biological responses. Mussels (Mytilus galloprovincialis) were transplanted to a marina receiving runoff from a petrol station and to a CSO discharge site. Samples were collected in synchrony with heavy rains along 62days. Lysosomal membrane stability (LMS) and acyl-CoA oxidase (AOX) activity were measured as core biomarkers and were analysed at all sampling times. Histopathology of digestive gland and gonads, transcription levels of vitellogenin gene, volume density of black silver deposits and micronuclei formation were measured at initial and final stages of the transplant. Chemical analyses of metals, polycyclic aromatic hydrocarbons (PAHs) and endocrine disruptors were performed in water samples and mussel flesh. Mussels accumulated low concentrations of contaminants, which is in accordance with results obtained from exposure biomarkers. AOX activity decreased in all transplanted mussels after the first heavy rain, but this change seems to be related to the seasonal pattern of the enzyme activity. Mussels located close to the CSO discharge site showed a reduction in LMS after the first rain event, when compared to mussels before the transplant and to mussels from the reference location. However, this was attributable to natural environmental changes rather than to pollution. Values of the rest of analysed biomarkers were below threshold values reported for the study area. PMID- 29627535 TI - Environmental and sustainability evaluation of livestock waste management practices in Cyprus. AB - The aim of this study was to compare the environmental performance and sustainability of different management options for livestock waste in Cyprus. The two most common practices in the country, i.e. the use of anaerobic lagoons and conventional biogas plants, were compared with the innovative scheme developed in the LiveWaste project (LIFE12 ENV/CY/000544), which aims not only to produce bioenergy, but also to treat the digestate for nutrient recovery and water reuse. The Life Cycle Assessment (LCA) methodology was combined with the Analytic Hierarchy Process (AHP) to compare the performance of these alternatives. Four relevant indicators were selected for each dimension of sustainability (environmental, social and economic). The results of the evaluations showed that anaerobic lagoons are not an appropriate option for the sustainable management of livestock waste due to environmental (e.g. climate change, acidification and eutrophication) and social impacts (e.g. noise exposure, visual impact and risk perception for human health). The most important strengths and weaknesses of anaerobic treatment with and without digestate treatment were identified. Compared to conventional anaerobic digestion where digestate is directly applied as an organic fertiliser, the technology proposed in the project entails higher technological complexity due to nitrogen removal and phosphorus recovery. The rise in chemical and electricity requirements increased the impacts on some indicators, such as climate change and operational cost (emissions of greenhouse gases and operation costs were around 50% higher), while reduced impacts in others due to proper nutrient management, as acidification and eutrophication impacts (which were 10 and almost two times lower, respectively). For the specific Cypriot conditions, where the overapplication of nutrients leads to pollution of water bodies, the innovative treatment scheme with higher technological development presents an interesting approach. Nevertheless, the treatment of the digestate should be analysed taking into account the specific characteristics of each scenario. PMID- 29627536 TI - Monocyclic aromatic hydrocarbons production from catalytic cracking of pine wood derived pyrolytic vapors over Ce-Mo2N/HZSM-5 catalyst. AB - A series of Mo2N/HZSM-5 and transition metal modified Mo2N/HZSM-5 catalysts were prepared for the catalytic upgrading of pine wood-derived pyrolytic vapors for the selective production of monocyclic aromatic hydrocarbons (MAHs), while restraining the formation of polycyclic aromatic hydrocarbons (PAHs). Pyrolysis gas chromatography/mass spectrometry (Py-GC/MS) experiments were performed to determine the effects of several factors on selective MAHs production, including Mo2N loading on HZSM-5, transition metal (Fe, Ce, La, Cu, Cr) modification of Mo2N/HZSM-5, pyrolysis temperature, and catalyst-to-biomass ratio. In addition, quantitative experiments were conducted to determine the actual yields of major aromatic hydrocarbons and the source of aromatic hydrocarbons from basic biomass components. Results indicated that among the various catalysts, the Ce 10%Mo2N/HZSM-5 exhibited the best performance on promoting the formation of MAHs and restraining the generation of PAHs. Under the optimal conditions, the actual yields of MAHs and PAHs from Ce-10%Mo2N/HZSM-5 catalytic process were 99.8mg/g and 7.5mg/g, while those from HZSM catalyst were only 77.2mg/g and 23.7mg/g respectively. Furthermore, the possible catalytic mechanism of the Ce-Mo2N/HZSM-5 catalyst was proposed based on the catalyst characterization. PMID- 29627537 TI - Elevated temperature and CO2 affect responses of European aspen (Populus tremula) to soil pyrene contamination. AB - High northern latitudes are climatic sensitive areas, and are also regions to which polycyclic aromatic hydrocarbons (PAHs) easily transport and accumulate with potential risk to natural ecosystems. However, the effect of PAHs on northern woody plant growth and defense under climate change is very little studied. Here, we conducted a unique experiment in greenhouses to investigate sex related responses of the dioecious Populus tremula to pyrene (50mgkg-1) and residue of pyrene in soils under ambient and elevated temperature (+1.8 degrees C on average) and CO2 (740ppm). Pyrene decreased stem biomass and leaf area by 9% and 6%, respectively under ambient conditions, and the reduction of leaf area was more severe under elevated temperature (38%), elevated CO2 (37%), and combined T+CO2 (42%). Other growth parameters were unchanged by pyrene. Pyrene did not affect the concentration of leaf total phenolics under ambient conditions, but increased it by 16%, 1%, and 20% compared to controls under elevated temperature, elevated CO2, and T+CO2, respectively. Pyrene had only minor sex-specific effects on plant growth and phenolics. The concentration of residual pyrene in pyrene spiked soils was higher under elevated CO2 than under ambient, elevated temperature, and combined T+CO2. The results suggest that both sexes of P. tremula have the capacity to regulate growth and metabolism to adjust to the stress of the tested pyrene contamination under elevated temperature and CO2, but potential risk of pyrene to plants still exists in the future changing climate. PMID- 29627538 TI - Heavy metal pollution in reservoirs in the hilly area of southern China: Distribution, source apportionment and health risk assessment. AB - Reservoirs play more and more important role in providing potable water in many developing countries, including the China. In the present study, pollution characteristics, source and health risk of dissolved heavy metals in 19 representative reservoirs in the hilly area of southern China were investigated. The results presented great spatial heterogeneity in heavy metal concentrations among the studied reservoirs due to the disturbances by different anthropogenic activities. Several reservoirs had significantly higher concentrations of heavy metals compared with others, FengTan (FT) reservoir (0.34MUg/L in dry season), Cr in reservoirs of HuangShi (HS) and ZheLin (ZL) with values of 4.16MUg/L and 3.45MUg/L in dry season respectively, and Al in reservoirs of JiaoKou (JK), GuTian (GT) and DouShui (DS) with values of 1011MUg/L, 1036MUg/L and 1001MUg/L in wet season, respectively. Furthermore, there was a great difference in the seasonal variation of heavy metals, especially for Al and Pb in wet season characterized with relatively high values of 643MUg/L and 0.67MUg/L, respectively. Accordingly, Al was identified with a great health risk to living beings in view of its mean value in wet season, which greatly exceeded the criteria for drinking water of China, WHO and US EPA. Furthermore, As might be the greatest concern of health risk in this region considering its high carcinogenic risk to the local residents around the reservoirs of OuYangHai (OYH), DS, ZhiXi (ZX) and HS. Multivariate statistical analysis suggested that there was great heterogeneity in the sources of these heavy metals in the hilly area of southern China. Therefore, specific measures, such as controls on point source pollution control and tailings, should be taken for maintaining drinking water safety and aquatic ecosystem health. PMID- 29627539 TI - Drivers of the accumulation of mercury and organochlorine pollutants in Mediterranean lean fish and dietary significance. AB - An integrated assessment of lean fish of commercial value as Hg and organochlorine compound source into the population of the Balearic Islands were reported. Dependences between pollutant concentrations, trophic level, fish species, specimen weight and physical-chemical properties were evaluated. Hg and total DDTs showed highest variability between fish species whereas PCBs and HCB displayed more constant median values. The organochlorine compounds found in highest concentrations were those with highest hydrophobicity, consistently with their higher bioaccumulation potential. These pollutant concentrations were higher in Mediterranean than Atlantic fish. Higher median total DDT and PCBs concentrations were also observed in the third than the second trophic level species. The observed concentrations were below the threshold recommended by the EU for human consumption (75ng/g wet weight). The Hg concentrations were higher in Mediterranean than Atlantic fish, with average values of 1.5MUg/g ww and 0.43MUg/g ww, respectively. Forty-one percent of the specimens from the Mediterranean and 25% of dusky grouper specimens from the Atlantic Ocean showed Hg concentrations above the EU recommended limits for human consumption, either 0.5MUg/g ww or 1MUg/g ww. In the third trophic level, a significant dependence between median Hg concentrations and weight of each studied species was observed, which remained significant in specimen weight correlations. Independent species correlations of Hg concentrations vs individual weight generally showed higher concentrations at higher weight. Weight/size of the individuals was therefore an important factor for Hg accumulation but the trend was modulated by a species effect. Extrapolation of the observed Hg concentrations in Mediterranean fish to Provisional Tolerable Weekly Intakes (PTWIs) showed higher intakes than the thresholds recommended by EFSA for adults and children, 110% and 140%, respectively. The estimated PTWIs for MeHg corresponded to 310% and 400% of the recommended threshold values. The PTWI values for organochlorine compounds were lower than those recommended. PMID- 29627540 TI - Tetracycline resistance gene tet(M) of a marine bacterial strain is not accumulated in bivalves from seawater in clam tank experiment and mussel monitoring. AB - Antibiotic resistance genes (ARGs) are found in marine as well as terrestrial bacteria. Bivalves are known to accumulate chemical pollutants and pathogenic microbes, however, the fate of ARGs in bivalves after the intake of ARG possessing bacteria is not known. Here we show that the copy number of oxytetracycline resistance gene tet(M) increased rapidly in the clam digestive tract by filtering water, then remained constant over 96h in a tank experiment even with the addition of tet(M)-possessing bacteria every 24h. >99.9% of the added tet(M) was decomposed, reaching a balanced state. Environmental sampling of mussel digestive tract and seawater supported the hypothesis that tet(M) was decomposed in bivalves as tet(M) was present in seawater from April to October at a concentration of 10-5 to 10-6 copies/16S, whereas tet(M) in mussels was mostly below the detection limit. Two (April) and three (July and October) individual mussels were positive for tet(M) with a concentration equivalent to that of seawater. We therefore conclude that bivalves do not accumulate tet(M) from seawater. PMID- 29627541 TI - Sorption and desorption of Pb(II) to biochar as affected by oxidation and pH. AB - The use of biochar for the removal of heavy metals from water has environmental benefits. In order to elucidate the potential application of highly functionalized biochar for the removal of Pb(II) in aqueous solution, maple wood biochar was oxidized using hydrogen peroxide. The pH values of oxidized biochar ranged from 8.1 to 3.7, with one set being adjusted to a pH of 7 as a comparison. It was found that oxidizing the biochars increased their Pb(II) adsorption capacity if the pH remained below 6 (strong oxidation), but decreased their Pb(II) adsorption ability above pH6 (weak oxidation). After adjusting the pH of oxidized biochar to pH7, the Pb(II) adsorption capacity further increased two to sixfold for oxidized biochars originally at pH3.7-6. The adsorption characteristics of Pb(II) were well described by the Langmuir equation. Adsorption of Pb(II) was not fully reversible in water. Less than 6% of Pb(II) desorbed in water in two consecutive steps than was previously adsorbed, for biochars with a pH below 7, irrespective of oxidation. Recovery using an extraction with 0.1M NaNO3 increased from 0.7% to 32.7% of Pb(II) undesorbed by both preceding water extractions with increasing oxidation, for biochars with a pH below 7. Unextractable Pb(II) was lower at low oxidation but increased to 99.0% of initially adsorbed amounts at low pH, which indicated that the adsorption of Pb(II) on oxidized biochar is pH independent. PMID- 29627542 TI - Effect of different carbon sources on denitrification performance, microbial community structure and denitrification genes. AB - Solid and liquid organic substances as carbon sources for denitrification process were deeply explored. In this study, the effect of three carbon sources, referred to as poly (3-hydroxybutyrate-co-3-hydroxyvalerate)/poly (lactic acid) (PHBV/PLA) polymer, glucose and CH3COONa, on denitrification performance, microbial community and functional genes were investigated. It was found that maximum denitrification rates of 0.37, 0.46 and 0.39gN/(L.d) were achieved in PHBV/PLA, glucose and CH3COONa supported denitrification systems, respectively. Meanwhile, Illumina MiSeq sequencing revealed that three carbon sources led to different microbial community structures. It can be seen that Brevinema/Thauera/Dechloromonas, Tolumonas/Thauera/Dechloromonas, Thauera dominated in the PHBV/PLA, glucose and CH3COONa supported denitrification systems, respectively. Transcriptome-based analysis further indicated that the glucose supported denitrification system showed the highest FPKM values (the fragments per kilobase per million mapped reads) of the genes participating in the dissimilatory nitrate reduction process, corresponding to the greatest effluent NH4+-N concentration. A better knowledge of effect of different carbon sources on denitrification process will be significant for nitrate removal in practice. PMID- 29627543 TI - Stable isotopes in water indicate sources of nutrients that drive algal blooms in the tributary bay of a subtropical reservoir. AB - Eutrophication has become a severe environmental problem in some tributaries of the Three Gorges Reservoir (TGR) in China. A two-year field investigation of nutrients, oxygen stable isotopes (delta18O), and hydrogen stable isotopes (deltaD) was performed from January 2010 to December 2011 to determine the sources of nutrients in Xiangxi Bay (XXB). The results showed that nitrogen, phosphorus and silicon varied seasonally depending on hydrodynamic changes. The bottom-layer intrusive density current decreased nitrogen and silicon concentrations and increase phosphorus concentrations in XXB, while the middle layer intrusive density current increased nitrogen and silicon concentrations and decrease phosphorus concentrations. The differences in delta18O and deltaD among the Yangtze River (YR), XXB and the region upstream of XXB were significant, and according to the tracer method, the estimated contribution ratios of nitrogen, phosphorus and silicon from the YR to XXB were much larger than those from the region upstream of XXB. These findings suggest that water quality in the TGR can be improved by reducing the pollution load throughout the upstream basin of the YR but not through decentralized efforts in only one or two tributary basins. PMID- 29627544 TI - Framework for the use of odour wheels to manage odours throughout wastewater biosolids processing. AB - Odorous emissions from wastewater biosolids processing can cause nuisance impacts to the surrounding community. Odour Wheels are an effective tool for environmental odour management, but have yet to be provided for wastewater biosolids processing. Emissions throughout the biosolids processing from eight wastewater treatment plants, each with different unit operation configurations, were surveyed to identify odorants present and their olfactory properties. Chemical and olfactory methods identified a range of odorants and odours emitted throughout biosolids processing. Within the biosolids processing locations studied Sulfur type odours, described as rotten eggs or cabbage, were typically encountered. However, there was also a varying presence of Rancid/putrid and Faecal/manure type odours. Odour Wheels were generated to communicate both the olfactory and chemical components of emissions which were measured throughout biosolids processing. Examples based on the operation of the eight wastewater treatment plants were used to demonstrate how the Odour Wheels can be used as an onsite odour management aid. The paper demonstrates how Odour Wheels can be prepared using chemical and olfactory measurements and then used to communicate olfactory properties, as well as identify the causes of nuisance emissions throughout biosolids processing at wastewater treatment plants. The linking of odours and odorants to process conditions throughout biosolids processing facilitates effective abatement and management practices. PMID- 29627545 TI - Efficiency of surfactant-enhanced bioremediation of aged polycyclic aromatic hydrocarbon-contaminated soil: Link with bioavailability and the dynamics of the bacterial community. AB - Shifts in the bacterial-community dynamics, bioavailability, and biodegradation of polycyclic aromatic hydrocarbons (PAHs) of chronically contaminated soil were analyzed in Triton X-100-treated microcosms at the critical micelle concentration (T-CMC) and at two sub-CMC doses. Only the sub-CMC-dose microcosms reached sorbed PAH concentrations significantly lower than the control: 166+/-32 and 135+/-4mgkg 1 dry soil versus 266+/-51mgkg-1; consequently an increase in high- and low molecular-weight PAHs biodegradation was observed. After 63days of incubation pyrosequencing data evidenced differences in diversity and composition between the surfactant-modified microcosms and the control, with those with sub-CMC doses containing a predominance of the orders Sphingomonadales, Acidobacteriales, and Gemmatimonadales (groups of known PAHs-degrading capability). The T-CMC microcosm exhibited a lower richness and diversity index with a marked predominance of the order Xanthomonadales, mainly represented by the Stenotrophomonas genus, a PAHs- and Triton X-100-degrading bacterium. In the T-CMC microcosm, whereas the initial surface tension was 35mNm-1, after 63days of incubation an increase up to 40mNm-1 was registered. The previous observation and the gas-chromatography data indicated that the surfactant may have been degraded at the CMC by a highly selective bacterial community with a consequent negative impact on PAHs biodegradation. This work obtained strong evidence for the involvement of physicochemical and biologic influences determining the different behaviors of the studied microcosms. The results reported here contribute significantly to an optimization of, surfactant-enhanced bioremediation strategies for chronically contaminated soil since the application of doses below the CMC would reduce the overall costs. PMID- 29627546 TI - Differential contribution of animal and vegetable food items on persistent organic pollutant serum concentrations in Spanish adults. Data from BIOAMBIENT.ES project. AB - Diet is considered the main source of Persistent Organic Pollutant (POP) exposure in the general population, although there are still several gaps of knowledge regarding the differential contribution of main food groups. The aim of this study was to identify dietary patterns that contribute to human exposure to organochlorine pesticides (OCPs), polychlorinated biphenyls (PCBs), and Perfluoroalkyl Substances (PFASs). Study population (n=1880, 18-65years old) was recruited during 2009-2010 in all the main geographical areas of Spain. For this work, exposure was estimated by chemical analyses of serum levels of 6 PCBs (n=1880), 13 OCPs (n=934), and 6 (PFASs) in a subsample of 755 (n=755). Dietary habits and covariates were gathered via self-administered questionnaires. Data analyses were performed by means of multivariable linear regression and weighted quantile sum regression. Both the consumption of animal-based and plant-based food were positively associated with the individual concentrations of p,p'-DDE, hexachlorobenzene, and PCB-congeners -138, -153, and-180. The contribution of animal-based products was 2.1-4.0* stronger except in p,p'-DDE, to which both patterns had similar contributions. In PFASs only animal food was positively associated with the exposure levels. The main animal-based contributors to PCB exposure were fish (49-64%) and eggs (19-36%), while OCP concentrations were mainly influenced by dairy products (32-48%) and fish (47-48%). PFOA and PFHxS were mainly explained by cold-meat (34-37%), fish (25-26%), and eggs (19-21%), while PFOS and PFDA were primarily influenced by fish consumption (44-77%). In the case of plant-based items, fruits (25-82%) and vegetables (18-63%) accounted for the majority of the variability of PCB and OCP concentrations. Our results highlight the relevance of dietary POP exposure as well as the need for the consideration of nutritional interventions in public health programs aiming to reduce POP exposure in the general population. PMID- 29627547 TI - Implementation of UV-based advanced oxidation processes in algal medium recycling. AB - Algae show great potential as sustainable feedstock for numerous bioproducts. However, large volume of water consumption during algal biomass production makes that the culture media recycling is a necessity due to economic and environmental concern. To avoid the negative effect of enriched organic matters in the harvested culture media, pre-treatment prior to medium replenishment and reuse is required. In this study, degradation of algenitic organic matters (AOM) in the culture media by UV-based photolysis processes (i.e., direct UV, UV/peroxydisulfate (PDS), UV/H2O2, and UV/NH2Cl) was explored. The results showed that UV, UV/PDS, UV/H2O2 and UV/NH2Cl caused a decrease of SUVA for 29.9%, 35.4%, 40.45%, and 22.6%, respectively, though the organic matter was almost not mineralized. Fluorescence excitation-emission matrix combined with parallel factor analysis indicated that UV/PDS and UV/H2O2 degraded 47.26%-56.31% of the fulvic-like and humic-like fractions in AOM. Powder activated carbon absorption and growth evaluation for the AOPs-treated media indicated that UV/PDS and UV/H2O2 processes not only could remove the growth inhibitors in the media, but were also beneficial to the algae growth. These results suggested that UV/PDS and UV/H2O2 could effectively degrade the hydrophobic components in AOM and converted the growth inhibition fraction of AOM in the recycled media into nutrient source for algal growth. Different from the general application of UV-based AOP in the wastewater treatment, this study provided an innovative idea about how to pre treat AOM in the media recycling: utilization rather than removal, which was a more sustainable and environment-friendly technology. PMID- 29627548 TI - Occurrence, partitioning and bioaccumulation of emerging and legacy per- and polyfluoroalkyl substances in Taihu Lake, China. AB - There are many studies about the occurrence of legacy perfluoroalkyl acids (PFAAs) in fresh water ecosystem, but related information about emerging per- and polyfluoroalkyl substances (PFASs) is limited. In this study, along with ten legacy PFAAs, twelve non-PFAAs, including precursors of perfluorooctane sulfonic acid (PFOS) and emerging PFASs in the water, sediment and organisms in Taihu Lake, China, were investigated. As one replacement product of PFOS, perfluorohexane sulfonic acid (PFHxS) (mean: 69.3ng/L) was the predominant PFAA in the water samples. Perfluorooctanesulfonamide (PFOSA) (mean: 0.190ng/L) and 6:2 fluorotelomer phosphate diester (6:2 diPAP) (0.034ng/L) were detected in all the water samples. Other emerging PFASs, such as N-ethyl perfluorooctanesulfonamidoa-cetic acid (NEtFOSAA), bis(perfluorohexyl) phosphinic acid (6:6 PFPiA) were frequently detected in the sediment and/or organisms. The organic carbon normalized sediment-water distribution coefficients (KOC) and bioaccumulation factors (BAFs) of the PFASs generally increased with their log KOW values. However, PFOSA, NEtFOSAA, 6:2 diPAP and 6:6 PFPiA displayed lower log BAFs, and/or lower log KOC than expected, which may be due to biotransformation potentials and/or large molecular size. PFOSA was not biomagnified in the food web. For other emerging PFASs, the low detection frequencies in the organisms hampered us to evaluate their biomagnification potentials. The lower percentage of most of the branched PFOS isomers while higher percentage of 1m-PFOS in the organisms suggested that there was indirect source of PFOS in the organisms. Similar to PFOS and PFOA, linear PFHxS isomer was preferentially enriched in organisms relative to its branched isomers. PMID- 29627549 TI - Prolonged exposure of di(2-ethylhexyl) phthalate induces multigenerational toxic effects in Caenorhabditis elegans. AB - The plasticizer di(2-ethylhexyl) phthalate (DEHP) is an emerging organic contaminant that has represented a risk for organisms present in the environment. However, there is still limited information regarding DEHP-induced multigenerational toxicity and the underlying mechanisms. In this study we investigated the multigenerational toxic effects including locomotive behaviors and reproduction upon prolonged DEHP exposure (from larval L1 to adult) and the underlying mechanisms in the nematode Caenorhabditis elegans. The multigenerational effects were examined over 6 generations (F0-F5) with only parental C. elegans (F0) was exposed to DEHP from larval L1 to adults (72h), and the subsequent offsprings (F1-F5) were grown under DEHP-free conditions. The results showed that prolonged exposure (72h) to various concentrations of DEHP caused dose-dependent locomotive impairments and reproduction defects in C. elegans and that a concentration of 0.2mg/L DEHP was enough to cause such sublethal effects. The results showed that after prolonged exposure to DEHP in the F0 generation, abnormal locomotive behaviors such as reduced body bends and head thrashes were observed from generations F0 to F5. Additionally, prolonged exposure to DEHP (20mg/L) in F0 significantly reduced total brood size in F0, and this parental exposure was sufficient to cause multigenerational reproductive toxicity in the offspring generations (F1-F5) as well. Furthermore, the expressions of reproduction-related genes such as vit-2 and vit-6 were down regulated by about 20% until F3, and the expression of H3Kme2 demethylase, spr-5, was downregulated in F1 by about 40%. Results from this study demonstrate that prolonged exposure to DEHP only at F0 adversely affected reproduction and locomotive behaviors in C. elegans across generations and might be associated with inadequate vitellogenin production and malfunction of H3Kme2 demethylase. This study implies that parentally prolonged exposure to DEHP caused multigenerational defects in both reproduction and locomotive behaviors raising the potential health and ecological risk. PMID- 29627550 TI - Speciation of organic fractions does matter for aerosol source apportionment. Part 2: Intensive short-term campaign in the Paris area (France). AB - The present study aimed at performing PM10 source apportionment, using positive matrix factorization (PMF), based on filter samples collected every 4h at a sub urban station in the Paris region (France) during a PM pollution event in March 2015 (PM10>50MUgm-3 for several consecutive days). The PMF model allowed to deconvolve 11 source factors. The use of specific primary and secondary organic molecular markers favoured the determination of common sources such as biomass burning and primary traffic emissions, as well as 2 specific biogenic SOA (marine+isoprene) and 3 anthropogenic SOA (nitro-PAHs+oxy-PAHs+phenolic compounds oxidation) factors. This study is probably the first one to report the use of methylnitrocatechol isomers as well as 1-nitropyrene to apportion secondary OA linked to biomass burning emissions and primary traffic emissions, respectively. Secondary organic carbon (SOC) fractions were found to account for 47% of the total OC. The use of organic molecular markers allowed the identification of 41% of the total SOC composed of anthropogenic SOA (namely, oxy-PAHs, nitro-PAHs and phenolic compounds oxidation, representing 15%, 9%, 11% of the total OC, respectively) and biogenic SOA (marine+isoprene) (6% in total). Results obtained also showed that 35% of the total SOC originated from anthropogenic sources and especially PAH SOA (oxy-PAHs+nitro-PAHs), accounting for 24% of the total SOC, highlighting its significant contribution in urban influenced environments. Anthropogenic SOA related to nitro-PAHs and phenolic compounds exhibited a clear diurnal pattern with high concentrations during the night indicating the prominent role of night-time chemistry but with different chemical processes involved. PMID- 29627551 TI - Indonesia's globally significant seagrass meadows are under widespread threat. AB - Indonesia's marine ecosystems form a fundamental part of the world's natural heritage, representing a global maxima of marine biodiversity and supporting the world's second largest production of seafood. Seagrasses are a key part of that support. In the absence of empirical data we present evidence from expert opinions as to the state of Indonesia's seagrass ecosystems, their support for ecosystem services, with a focus on fisheries, and the damaging activities that threaten their existence. We further draw on expert opinion to elicit potential solutions to prevent further loss. Seagrasses and the ecosystem services they support across the Indonesian archipelago are in a critical state of decline. Declining seagrass health is the result of shifting environmental conditions due largely to coastal development, land reclamation, and deforestation, as well as seaweed farming, overfishing and garbage dumping. In particular, we also describe the declining state of the fisheries resources that seagrass meadows support. The perilous state of Indonesia's seagrasses will compromise their resilience to climate change and result in a loss of their high ecosystem service value. Community supported management initiatives provide one mechanism for seagrass protection. Exemplars highlight the need for increased local level autonomy for the management of marine resources, opening up opportunities for incentive type conservation schemes. PMID- 29627552 TI - Spatial heterogeneity of leaf area index in a temperate old-growth forest: Spatial autocorrelation dominates over biotic and abiotic factors. AB - Leaf area index (LAI) controls many eco-physiological processes and can be widely used to scale-up leaf processes to ecosystem, landscape and regional levels. However, the macro-scale spatial heterogeneity of LAI and its controlling factors are not fully understood. We estimated annual maximum LAI using an LAI-2200 plant canopy analyzer in a 9-ha, old-growth, mixed broadleaved-Korean pine (Pinus koraiensis) forest in China. We analyzed the spatial heterogeneity of LAI and mapped its distribution using geostatistical methods; then, through variance partitioning, we examined the influences of several biotic factors, abiotic factors and spatial autocorrelation on the LAI distribution. Variance partitioning showed that these factors altogether explained 59% of the variation in the distribution of LAI. Compared to biotic and abiotic factors, spatial autocorrelation controlled more spatial heterogeneity of LAI by explaining 51.4% of the total variation in LAI. For biotic and abiotic factors, the mean diameter at breast height (DBH) of large trees (DBH > 10 cm), elevation, soil temperature and soil mass moisture content significantly affected the LAI distribution (P < 0.01). Notably, spatial autocorrelation unexpectedly explained the most variation in the LAI values, and it also varies with cardinal direction and is a key descriptor of LAI spatial variability. These results suggest that the influence of spatial autocorrelation on LAI distribution should attract more attention and that both the relative importance of and interactions among different determining factors is helpful for better understanding the mechanistic determinants of LAI distributions in temperate mixed forests. PMID- 29627553 TI - Sulphate-reducing bacteria (SRB) in the Yangtze Estuary sediments: Abundance, distribution and implications for the bioavailibility of metals. AB - Ubiquitous in the aquatic environment, sulphate-reducing bacteria (SRB) are considered one of the dominant microorganisms involved in the degradation of sulphate. This study focused on the spatial and temporal distributions of SRB in the Scirpus triquter rhizosphere sediments with a comparison to non-rhizosphere sediments and evaluated the implication of SRB to the bioavailability of metals in the Yangtze Estuary. The results showed that taking dsrB as the target gene, SRB abundances in rhizosphere sediments were significantly higher than those in non-rhizosphere sediments (P<0.01). SRB abundances were relatively higher in April and January than other seasons. Moreover, redundancy discriminate analysis (RDA) results indicated that sulphate, pH and TOC were the major environmental factors affecting the SRB abundance in rhizosphere sediments. The concentrations of most metals were significantly related to SRB abundance, and sulphide concentrations showed a significantly positive correlation to metal concentrations, indicating metal sulphide/metal associated sulphide could be regulated by SRB. Furthermore, electron microscope analysis found that nano-sized metal sulphide particles were ubiquitous in rhizosphere sediments and could be further taken up by plants. This study provides new insights into the immobilization and removal of heavy metals and the ecological value of the sulphate-reducing bacteria in the Yangtze Estuary. PMID- 29627554 TI - Leaching of natural colloids from forest topsoils and their relevance for phosphorus mobility. AB - The leaching of P from the upper 20cm of forest topsoils influences nutrient (re )cycling and the redistribution of available phosphate and organic P forms. However, the effective leaching of colloids and associated P forms from forest topsoils was so far sparsely investigated. We demonstrated through irrigation experiments with undisturbed mesocosm soil columns, that significant proportions of P leached from acidic forest topsoils were associated with natural colloids. These colloids had a maximum size of 400nm. By means of Field-flow fractionation the leached soil colloids could be separated into three size fractions. The size and composition was comparable to colloids present in acidic forest streams known from literature. The composition of leached colloids of the three size classes was dominated by organic carbon. Furthermore, these colloids contained large concentrations of P which amounted between 12 and 91% of the totally leached P depending on the type of the forest soil. The fraction of other elements leached with colloids ranged between 1% and 25% (Fe: 1-25%; Corg: 3-17%; Al: <4%; Si, Ca, Mn: all <2%). The proportion of colloid-associated P decreased with increasing total P leaching. Leaching of total and colloid-associated P from the forest surface soil did not increase with increasing bulk soil P concentrations and were also not related to tree species. The present study highlighted that colloid facilitated P leaching can be of higher relevance for the P leaching from forest surface soils than dissolved P and should not be neglected in soil water flux studies. PMID- 29627555 TI - The impact of nanoplastics on marine dissolved organic matter assembly. AB - The environmental impact of nanoplastics (NPs) released into natural aquatic surroundings is an increasing concern. NPs are widely generated from our daily waste disposal and eventually reach the ocean, wherein consequent influences on aquatic environments remain unclear. In this regard, there are few studies investigating NP-related ecological impacts. Comprising one of Earth's major carbon pools, marine dissolved organic matter (DOM) serves an essential role in global carbon dynamics. The spontaneous assembly of DOM into particulate organic matter (POM) plays important roles in the marine carbon cycle, and is involved in hemostasis of various ecological communities. Here, we report that 10 ppb NPs (polystyrene/polymethyl methacrylate, 25 nm) appeared in a water column accelerate the kinetic assembly rate of DOM-POM transition. NPs with various characteristics show similar influences on DOM assembly, and seawater samples collected from disparate sites were used to further confirm this unanticipated phenomenon. In this study, we demonstrated that hydrophobic interactions contribute to the facilitation of NP-DOM aggregations. Our results illustrate that NPs alter DOM-POM assembly, which may potentiate unanticipated perturbation to the largest marine carbon pool. Such effects would warrant increased vigilance on current practices of plastic usage and disposal. PMID- 29627556 TI - Proper management of lead-contaminated agricultural lands against the exceedance of lead in agricultural produce: Derivation of local soil criteria. AB - The Measures for Management of Soil Environment in Agricultural Land (Trial, Nov. 01, 2017, China) recently came into effect and highlighted the proper management of contaminated croplands to lower risks of exceedances of contaminants, especially toxic trace metals in agricultural produce. We aimed to develop local soil criteria for lead (Pb) in Hezhang county of southwestern China by the inverse use of reliable models linking Pb contamination levels between soils and vegetables. Dilute nitric acid (0.43 M) extraction, a new ISO standard (ISO 17586:2016) for extracting the geochemically reactive Pb fraction (PbNA), and calcium chloride (0.01 M) extraction (ISO-14255: 1998) for estimating the plant available Pb (PbCC) were performed in fifty historically polluted and newly Pb spiked soils with differing soil types, properties (pH 4.1-8.0), and total soil Pb levels (PbT, 20-6153 mg kg-1). Greenhouse experiments for Brassica pekinensis L., and in-situ soil porewater measurement for Pb were conducted to investigate the mechanism of Pb uptake, and to establish reliable Pb soil-plant relationships. The results indicated that about 83% of the variation for Pb concentrations in vegetable (PbCL, 0.009-1.06 mg kg-1) was contributable to free Pb2+ activity in soil porewater, which was mainly influenced by pH and dissolved organic matter. PbCL was satisfactorily predicted using PbNA and key soil properties (adj. R2 0.852). Soil Pb criteria for PbT and PbNA are then derived based on food standard. The full implementation of criteria derived for PbNA (i.e., 27-127 mg kg-1, soil pH 5.5-8.0) can avoid the exceedance of Pb in 95% of cabbage samples in this study, 95% of cabbage cultivars by model extrapolation, and one widely cultivated root vegetable, radish, in the study region. We provide a successful case study that has effectively tackled the challenge for the complexity of the soil management in contaminated croplands. PMID- 29627557 TI - Investigating in-sewer transformation products formed from synthetic cathinones and phenethylamines using liquid chromatography coupled to quadrupole time-of flight mass spectrometry. AB - Recent studies have demonstrated the role of biofilms on the stability of drug residues in wastewater. These factors are pertinent in wastewater-based epidemiology (WBE) when estimating community-level drug use. However, there is scarce information on the biotransformation of drug residues in the presence of biofilms and the potential use of transformation products (TPs) as biomarkers in WBE. The purpose of this work was to investigate the formation of TPs in sewage reactors in the presence of biofilm mimicking conditions during in-sewer transport. Synthetic cathinones (methylenedioxypyrovalerone, methylone, mephedrone) and phenethylamines (4-methoxy-methamphetamine and 4 methoxyamphetamine) were incubated in individual reactors over a 24h period. Analysis of parent species and TPs was carried out using liquid chromatography coupled to quadrupole time-of-flight mass spectrometry (LC-QToFMS). Identification of TPs was done using suspect and non-target workflows. In total, 18 TPs were detected and identified with reduction of beta-keto group, demethylenation, demethylation, and hydroxylation reactions observed for the synthetic cathinones. For the phenethylamines, N- and O-demethylation reactions were identified. Overall, the experiments showed varying stability for the parent species in wastewater in the presence of biofilms. The newly identified isomeric forms of TPs particularly for methylone and mephedrone can be used as potential target biomarkers for WBE studies due to their specificity and detectability within a 24h residence time. PMID- 29627558 TI - Water use patterns of co-occurring C3 and C4 shrubs in the Gurbantonggut desert in northwestern China. AB - In water-limited ecosystems, spatial and temporal partitioning of water sources is an important mechanism that facilitates plant survival and lessens the competition intensity of co-existing plants. Insights into species-specific root functional plasticity and differences in the water sources of co-existing plants under changing water conditions can aid in accurate prediction of the response of desert ecosystems to future climate change. We used stable isotopes of soil water, groundwater and xylem water to determine the seasonal and inter- and intraspecific differences variations in the water sources of six C3 and C4 shrubs in the Gurbantonggut desert. We also measured the stem water potentials to determine the water stress levels of each species under varying water conditions. The studied shrubs exhibited similar seasonal water uptake patterns, i.e., all shrubs extracted shallow soil water recharged by snowmelt water during early spring and reverted to deeper water sources during dry summer periods, indicating that all of the studied shrubs have dimorphic root systems that enable them to obtain water sources that differ in space and time. Species in the C4 shrub community exhibited differences in seasonal water absorption and water status due to differences in topography and rooting depth, demonstrating divergent adaptations to water availability and water stress. Haloxylon ammodendron and T. ramosissima in the C3/C4 mixed community were similar in terms of seasonal water extraction but differed with respect to water potential, which indicated that plant water status is controlled by both root functioning and shoot eco physiological traits. The two Tamarix species in the C3 shrub community were similar in terms of water uptake and water status, which suggests functional convergence of the root system and physiological performance under same soil water conditions. In different communities, Haloxylon ammodendron differed in terms of summer water extraction, which suggests that this species exhibits plasticity with respect to rooting depth under different soil water conditions. Shrubs in the Gurbantonggut desert displayed varying adaptations across species and communities through divergent root functioning and shoot eco-physiological traits. PMID- 29627559 TI - Spring-fen habitat islands in a warming climate: Partitioning the effects of mesoclimate air and water temperature on aquatic and terrestrial biota. AB - Climate warming and associated environmental changes lead to compositional shifts and local extinctions in various ecosystems. Species closely associated with rare island-like habitats such as groundwater-dependent spring fens can be severely threatened by these changes due to a limited possibility to disperse. It is, however, largely unknown to what extent mesoclimate affects species composition in spring fens, where microclimate is buffered by groundwater supply. We assembled an original landscape-scale dataset on species composition of the most waterlogged parts of isolated temperate spring fens in the Western Carpathian Mountains along with continuously measured water temperature and hydrological, hydrochemical, and climatic conditions. We explored a set of hypotheses about the effects of mesoclimate air and local spring-water temperature on compositional variation of aquatic (macroinvertebrates), semi-terrestrial (plants) and terrestrial (land snails) components of spring-fen biota, categorized as habitat specialists and other species (i.e. matrix-derived). Water temperature did not show a high level of correlation with mesoclimate. For all components, fractions of compositional variation constrained to temperature were statistically significant and higher for habitat specialists than for other species. The importance of air temperature at the expense of water temperature and its fluctuation clearly increased with terrestriality, i.e. from aquatic macroinvertebrates via vegetation (bryophytes and vascular plants) to land snails, with January air temperature being the most important factor for land snails and plant specialists. Some calcareous-fen specialists with a clear distribution centre in temperate Europe showed a strong affinity to climatically cold sites in our study area and may hence be considered as threatened by climate warming. We conclude that prediction models solely based on air temperature may provide biased estimates of future changes in spring fen communities, because their aquatic and semiterrestrial components are largely affected by water temperature that is modified by local hydrological and landscape settings. PMID- 29627560 TI - Arsenic species in wheat, raw and cooked rice: Exposure and associated health implications. AB - Arsenic concentrations above 10MUgL-1 were previously found in 89% of ground water sources in six villages of Pakistan. The present study has ascertained the health risks associated with exposure to total arsenic (tAs) and its species in most frequently consumed foods. Inorganic arsenic (iAs) concentrations were found to be 92.5+/-41.88MUgkg-1, 79.21+/-76.42MUgkg-1, and 116.38+/-51.38MUgkg-1 for raw rice, cooked rice and wheat respectively. The mean tAs concentrations were 47.47+/-30.72MUgkg-1, 71.65+/-74.7MUgkg-1, 105+/-61.47MUgkg-1. Wheat is therefore demonstrated to be a significant source of arsenic exposure. Dimethylarsinic acid was the main organic species detected in rice, whilst monomethylarsonic acid was only found at trace levels. Total daily intake of iAs exceeded the provisional tolerable daily intake of 2.1MUgkg-1day-1 body weight in 74% of study participants due to concurrent intake from water (94%), wheat (5%) and raw rice (1%). A significant association between tAs in cooked rice and cooking water resulted in tAs intake 43% higher in cooked rice compared to raw rice. The study suggests that arsenic intake from food, particularly from wheat consumption, holds particular significance where iAs is relatively low in water. Chronic health risks were found to be significantly higher from wheat intake than rice, whilst the risk in terms of acute effects was below the USEPA's limit of 1.0. Children were at significantly higher health risk than adults due to iAs exposure from rice and/or wheat. The dietary exposure of participants to tAs was attributable to staple food intake with ground water iAs <10MUgL-1, however the preliminary advisory level (200MUgkg-1) was achievable with rice consumption of <=200gday-1 and compliance with <=10MUgL-1 iAs in drinking water. Although the daily iAs intake from food was lower than total water intake, the potential health risk from exposure to arsenic and its species still exists and requires exposure control measures. PMID- 29627561 TI - River recharge versus O2 supply from the unsaturated zone in shallow riparian groundwater: A case study from the Selke River (Germany). AB - Besides gas-water-exchange in surface waters, respiratory consumption of dissolved oxygen (DO) in adjacent riparian groundwater may trigger the addition of so far hardly explored sources from the unsaturated zone. These processes also systematically influence stable isotope ratios of DO and were investigated together with Cl- as a conservative tracer for water mixing in a near-river riparian groundwater system. The study focused on a losing stream section of the Selke River at the foot of the Harz Mountains (Germany). The study area exposed steep DO gradients between the stream water and riparian groundwater between April 2016 and May 2017. Our results indicated dominant influences of microbial community respiration with observed DO concentration gradients. These observations can be explained by DO from the river that is subject to fractionation by microbial respiration with a typical fractionation factor (alphar) of 0.982. However, with such respiration dominance, we expected a simultaneous enrichment of delta18ODO towards values that are more positive than the well-known atmospheric O2 signal of +23.90/00 versus the Vienna Standard Mean Ocean Water standard (VSMOW). Surprisingly, our measurements revealed much lower delta18ODO values between +220/00 and +180/00 in the near-river groundwater. Mass balance calculations revealed that the DO pool in the shallow and unconfined aquifer receives contributions of up to about 80% by diffusion of oxygen from the vadose zone with a distinctly lower isotope value than the one of the atmosphere. This finding about additional oxygen sources from the unsaturated zone has numerous ramifications for oxygen related processes in near-river environments including the oxidation of pollutants, nutrients and ecosystem health. PMID- 29627562 TI - Biodiversity responds to increasing climatic extremes in a biome-specific manner. AB - An unprecedented rate of global environmental change is predicted for the next century. The response to this change by ecosystems around the world is highly uncertain. To address this uncertainty, it is critical to understand the potential drivers and mechanisms of change in order to develop more reliable predictions. Australia's Long Term Ecological Research Network (LTERN) has brought together some of the longest running (10-60years) continuous environmental monitoring programs in the southern hemisphere. Here, we compare climatic variables recorded at five LTERN plot network sites during their period of operation and place them into the context of long-term climatic trends. Then, using our unique Australian long-term datasets (total 117 survey years across four biomes), we synthesize results from a series of case studies to test two hypotheses: 1) extreme weather events for each plot network have increased over the last decade, and; 2) trends in biodiversity will be associated with recent climate change, either directly or indirectly through climate-mediated disturbance (wildfire) responses. We examined the biodiversity responses to environmental change for evidence of non-linear behavior. In line with hypothesis 1), an increase in extreme climate events occurred within the last decade for each plot network. For hypothesis 2), climate, wildfire, or both were correlated with biodiversity responses at each plot network, but there was no evidence of non-linear change. However, the influence of climate or fire was context specific. Biodiversity responded to recent climate change either directly or indirectly as a consequence of changes in fire regimes or climate-mediated fire responses. A national long-term monitoring framework allowed us to find contrasting species abundance or community responses to climate and disturbance across four of the major biomes of Australia, highlighting the need to establish and resource long-term monitoring programs across representative ecosystem types, which are likely to show context-specific responses. PMID- 29627563 TI - Ecological and ecotoxicological responses in the assessment of the ecological status of freshwater systems: A case-study of the temporary stream Brejo of Cagarrao (South of Portugal). AB - The objective of the study was to assess the integrated use of macroinvertebrate indexes and ecotoxicological parameters in the evaluation of the ecological status of a temporary stream with a strong agricultural influence. Water quality was analysed at two sampling sites along the stream, considering: chemical supporting parameters; hazardous substances (pesticides); benthic macroinvertebrate communities, through quality (Iberian Biological Monitoring Working Party and Iberian Average Score Per Taxon) and multi-metric indices (Southern Portuguese Index of Invertebrates and Ecological Quality Ratio); and ecotoxicological responses using lethal and sub-lethal bioassays. The water chemical characterization showed high levels of organic matter and nutrients, mainly in the dry period ((biochemical oxygen demand (BOD5): 18.5-25.5mgL-1, chemical oxygen demand (COD): 60.8-193.7mgL-1; total phosphorus (TP): 0.17 0.33mgL-1)), which may compromise the support of biological life. In accordance with the physicochemical results, the stream had an ecological status less than good. Of the 25 pesticides analysed, only five, namely terbuthylazine, 2-methyl chlorophenoxyacetic acid, bentazone, mecoprop and metolachlor were quantified. In general, the concentrations of pesticides detected were low, except at the source of the stream in January 2012 (sum of pesticides 2.29MUgL-1), mainly due to the concentration of bentazone (1.77MUgL-1), both values surpassing the European Commission threshold values. The analysis of benthic macroinvertebrates showed low levels of abundance and family diversity, with communities dominated by resistant groups to organic pollution and pesticides, such as the Chironomidae family. In general, the reproduction ecotoxicological results showed a very marked decrease in the number of juveniles per female. The Spearman correlation identified pesticides, namely MCPA (R=-0.89; p<0.05), as the main responsible for the observed effect. The results showed the linearity and complementarity of the two groups of biological responses, allowing to cover the interactions between the ecosystem's species and the different types of pollutants. PMID- 29627564 TI - Promoting inclusive water governance and forecasting the structure of water consumption based on compositional data: A case study of Beijing. AB - Water is centrally important for agricultural security, environment, people's livelihoods, and socio-economic development, particularly in the face of extreme climate changes. Due to water shortages in many cities, the conflicts between various stakeholders and sectors over water use and allocation are becoming more common and intense. Effective inclusive governance of water use is critical for relieving water use conflicts. In addition, reliable forecasting of the structure of water usage among different sectors is a basic need for effective water governance planning. Although a large number of studies have attempted to forecast water use, little is known about the forecasted structure and trends of water use in the future. This paper aims to develop a forecasting model for the structure of water usage based on compositional data. Compositional data analysis is an effective approach for investigating the internal structure of a system. A host of data transformation methods and forecasting models were adopted and compared in order to derive the best-performing model. According to mean absolute percent error for compositional data (CoMAPE), a hyperspherical-transformation based vector autoregression model for compositional data (VAR-DRHT) is the best performing model. The proportions of the agricultural, industrial, domestic and environmental water will be 6.11%, 5.01%, 37.48% and 51.4% by 2020. Several recommendations for water inclusive development are provided to give a better account for the optimization of the water use structure, alleviation of water shortages, and improving stake holders' wellbeing. Overall, although we focus on groundwater, this study presents a powerful framework broadly applicable to resource management. PMID- 29627565 TI - Applying beta-cyclodextrin to amaranth inoculated with white-rot fungus for more efficient remediation of soil co-contaminated with Cd and BDE-209. AB - A pot experiment was conducted to investigate the effect of a series of beta cyclodextrin (beta-CD) concentrations on bioremediation of soil co-contaminated with Cd and BDE-209 using amaranth and the white-rot fungus Phanerochaete chrysosporium, with BDE-209 degrading ability. Results showed that the white-rot fungus was beneficial to the growth of amaranth, Cd uptake and BDE-209 degradation. Addition of beta-CD further increased biomass of both shoots and roots, shoot Cd concentrations and contents, chlorophyll concentrations and soil manganese peroxidase (MnP) activities. Furthermore, well-organized mesophyll cells were observed in beta-CD treatments, implying that the combination of white rot fungus and beta-CD can alleviate the stresses of Cd and BDE-209 to mesophyll cells. The BDE-209 degradation rate was positively correlated to beta-CD concentration and MnP activity in soil. Our results also revealed that RF+beta0.8 treatment possessed the greatest Cd removal efficiency due to its well-configured mesophyll cells and the highest shoot biomass, chlorophyll concentration, and shoot Cd concentration. Considering simultaneous removal of Cd and BDE-209 from soil, using 0.8% beta-CD to amaranth inoculated with white-rot fungus is a promising way forward for the phytoremediation of soil co-contaminated with Cd and BDE-209. A high percentage of mono-BDE was detected in inoculated amaranth, suggesting that BDE-209 was debrominated into low brominated PBDEs by the fungus in soil, which were then absorbed and further debrominated into mono-BDE in the plant. PMID- 29627566 TI - Validation of the Simplified Chinese Version of the Memorial Symptom Assessment Scale-Short Form Among Cancer Patients. AB - CONTEXT: Comprehensive symptom assessment is crucial for symptom management. The Memorial Symptom Assessment Scale-Short Form (MSAS-SF) has been validated for symptom assessment in cancer patients, but there is no simplified Chinese version. OBJECTIVES: To present the validation procedures and results for the simplified Chinese version of the Memorial Symptom Assessment Scale-Short Form (MSAS-SF-SC) among cancer patients in mainland China. METHODS: The MSAS-SF was translated and culturally adapted into simplified Chinese. About 359 cancer patients completed the MSAS-SF-SC, the Chinese Functional Assessment of Cancer Therapy-General, the Chinese Brief Fatigue Inventory, the Chinese Hospital Anxiety and Depression Scale, and the Chinese Medical Outcomes Study Social Support Survey. Reliability was assessed by internal consistency and test-retest coefficients. Convergent and divergent validity were analyzed by Pearson's correlation coefficients between MSAS-SF-SC subscales and the other instruments. Known-groups validity used Eastern Cooperative Oncology Group-Performance Status, hemoglobin level, and primary site. RESULTS: The MSAS-SF-SC was reliable with Cronbach's alpha coefficients for subscales ranging from 0.782 to 0.874 and test retest coefficients ranging from 0.819 to 0.872. MSAS-SF-SC subscales correlated with corresponding Chinese Functional Assessment of Cancer Therapy-General subscales (-0.557 to -0.680; P < 0.001), Chinese Brief Fatigue Inventory (0.620; P < 0.001), and Chinese Hospital Anxiety and Depression Scale (0.663; P < 0.001) indicating convergent validity. MSAS-SF-SC subscales showed low or no correlations with the Chinese Medical Outcomes Study Social Support Survey ( 0.146 to -0.165; P < 0.01), indicating divergent validity. MSAS-SF-SC subscales showed appropriate differences by Eastern Cooperative Oncology Group-Performance Status, hemoglobin level, and primary site. CONCLUSION: The MSAS-SF-SC demonstrated good psychometric properties and is culturally adapted. The instrument could be a valuable tool for Chinese health care professionals and researchers. PMID- 29627567 TI - CDCA3 promotes cell proliferation by activating the NF-kappaB/cyclin D1 signaling pathway in colorectal cancer. AB - Cell division cycle associated 3 (CDCA3) is required for mitotic entry, and mediates the degradation of the inhibitory kinase Wee1. New evidence suggests CDCA3 plays a role in tumor promotion. However, little is known about the relevance of CDCA3 in colorectal cancer(CRC), especially in the regulation of NF kappaB activity. In this study, we found that colorectal tumors significantly expressed more CDCA3 than non-cancer tissues. In addition, CDCA3 promoted CRC cell proliferation in vitro. Furthermore, downregulation of CDCA3 not only induced cell cycle arrest but also facilitated apoptosis. Mechanistically, CDCA3 activates the NF-kappaB signaling pathway by interacting with TRAF2 in CRC. Together, these results define a tumor-supportive role for CDCA3, which may also provide a new promising strategy for treating CRC. PMID- 29627568 TI - The role of XBP1s in the metastasis and prognosis of hepatocellular carcinoma. AB - Tumor metastasis and recurrence are the primary contributors to poor prognosis in patients with hepatocellular carcinoma (HCC). The epithelial-mesenchymal transition (EMT) of tumor cells is the predominant mechanism of HCC progression. XBP1s is a newly discovered molecule involved in the endoplasmic reticulum (ER) stressresponse, which is an adaptive response and defense mechanism in cells that enablessurvival under adverse conditions. Abnormally high XBP1sexpression has been found in tumor cells, but the role of XBP1sin HCC progression remains unclear. We found that the expression of XBP1s in HCC cell lines and tissuesamples was higher than that in control cells and tissuesamples. Clinicopathological analysis showed that the expression of XBP1s was closely correlated with distant metastasis and poor prognosis in HCC. In vivo and invitro experiments confirmed that the overexpression of XBP1s promoted EMT and metastasis in HCC cells. XBP1ssilencing attenuated cellular migration and development of the EMT phenotypein vitro. Through further study to elucidate the molecular mechanism underlying the promotion ofEMT by XBP1s in HCC cells, we confirmed that XBP1s could mediate the expression of Twist. In HCC cells, XBP1s enhanced the expression of Twist and Snail, resulting in a subsequent reduction in the expression of E-cadherin, a contributor to cell-cell adhesion. Overall, this study reveals a novel XBP1s/Twist/Snail axis that mediates EMT in HCC cells and the invasion and metastasis of HCC. PMID- 29627569 TI - TICAM-1 is dispensable in STING-mediated innate immune responses in myeloid immune cells. AB - Stimulator of interferon genes (STING) is an essential molecule for the production of type I interferon (IFN), and other inflammatory cytokines, in response to cytosolic DNA. STING contributes to host defense against infection and anti-tumor responses. Previous reports have demonstrated that STING signaling is required by the adaptor Toll-IL-1 receptor-containing adaptor molecule-1 (TICAM-1), which has been identified as a TLR3-adaptor molecule using mouse embryonic fibroblasts. Here, we demonstrate that TICAM-1 does not affect STING mediated innate immune responses, as increases in the mRNA expression levels of IFN-beta, IL-6, and CCL5 were observed in bone marrow-derived or splenic myeloid cells. Moreover, STING ligand-enhanced co-stimulatory molecule expression, including CD80, CD86, and CD40, was detected on splenic CD11c + DCs, even in Ticam-1-deficient mice. Our results suggest that STING-mediated innate immune responses and dendritic cell maturation do not require TICAM-1 in myeloid lineage immune cells. TICAM-1 is ubiquitously expressed, even in cell types which do not express TLR3. Therefore, TICAM-1 may possess different functions depending on cell type and signaling purposes. PMID- 29627570 TI - Circular RNA hsa_circ_0000673 promotes hepatocellular carcinoma malignance by decreasing miR-767-3p targeting SET. AB - The importance of circular RNAs (circRNAs) in human cancers has gradually been acknowledged. In hepatocellular carcinoma (HCC), several circRNAs have been reported to regulate tumor growth and metastasis. However, the role of hsa_circ_0000673 in HCC remains largely unknown. In this study, we found that hsa_circ_0000673 was significantly upregulated in HCC tissues compared to adjacent non-tumor tissues. Moreover, we found that hsa_circ_0000673 knockdown markedly inhibited the proliferation and invasion of HCC cells in vitro. Besides, hsa_circ_0000673 silence led to delayed tumor growth in vivo. In terms of mechanism, we showed that hsa_circ_0000673 directly associated with miR-767-3p in HCC cells. Via inhibiting miR-767-3p, hsa_circ_0000673 promoted HCC cell proliferation and invasion. Furthermore, we demonstrated that SET was a downstream effector of hsa_circ_0000673/miR-767-3p signaling. We showed that miR 767-3p could significantly promote SET expression by sponging miR-767-3p in HCC cells. Finally, rescue assays indicated that SET expression was essential for the effects of hsa_circ_0000673/miR-767-3p signaling on HCC cell proliferation and invasion. Taken together, our findings demonstrated that hsa_circ_0000673 promoted HCC malignant behaviors via regulating miR-767-3p/SET pathway. PMID- 29627571 TI - Arginase overexpression and NADPH oxidase stimulation underlie impaired vasodilation induced by advanced glycation end products. AB - BACKGROUND: Advanced glycation endproducts (AGEs) play a major role in the development of many vascular complications that are mediated by endothelial dysfunction. The present work aimed to investigate the mechanism by which AGEs impair vasodilation. METHODS: The effect of AGEs on vasodilation induced by acetylcholine or D NONOate was examined by incubating isolated rat aortae with different AGEs concentrations. ACh-induced nitric oxide generation was assessed using the fluorescent probe diaminofluorecein (DAF-FM). The effect of AGEs on expression of mRNA for arginase 2, NADPH oxidase and endothelial nitric oxide synthase (eNOS) were determined by real-time PCR. RESULTS: One-hour in vitro incubation of rat aortae with AGEs impaired endothelial-dependent vasodilation produced by ACh, while increasing D NONOate-induced vasodilation. Preincubation of aortae with l-ornithine, an arginase 2-inhibitor, prevented the impairment effect induced by AGEs on endothelial-dependent vasodilation. Superoxide scavenging by tempol or NADPH oxidase inhibition by apocynin also blocked the effect of AGEs. AGEs decreased ACh-induced NO production and this was inhibited by both l-ornithine and apocynin. Furthermore, AGEs exposure increased arginase mRNA expression but decreased mRNA expression for eNOS in isolated rat aortae. CONCLUSION: The present results indicate that AGEs impairs endothelial-dependent vasodilation, and this effect is mediated via arginase overexpression and NADPH oxidase stimulation. PMID- 29627572 TI - Lipidomic profiling of plasma samples from patients with mitochondrial disease. AB - Mitochondrial disease (MD) is a rare mitochondrial respiratory chain disorder with a high mortality and extremely challenging to treat. Although genomic, transcriptomic, and proteomic analyses have been performed to investigate the pathogenesis of MD, the role of metabolomics in MD, particularly of lipidomics remains unclear. This study was undertaken to identify potential lipid biomarkers of MD. An untargeted lipidomic approach was used to compare the plasma lipid metabolites in 20 MD patients and 20 controls through Liquid Chromatography coupled to Mass Spectrometry. Volcano plot analysis was performed to identify the different metabolites. Receiver operating characteristic (ROC) curves were constructed and the area under the ROC curves (AUC) was calculated to determine the potentially sensitive and specific biomarkers. A total of 41 lipids were significantly different in MD patients and controls. ROC curve analysis showed the top 5 AUC values of lipids (phosphatidylinositols 38:6, lysoPC 20:0, 19:0, 18:0, 17:0) are more than 0.99. Multivariate ROC curve based exploratory analysis showed the AUC of combination of top 5 lipids is 1, indicating they may be potentially sensitive and specific biomarkers for MD. We propose combination of these lipid species may be more valuable in predicting the development and progression of MD, and this will have important implications for the diagnosis and treatment of MD. PMID- 29627573 TI - Regulation of glucosylceramide synthesis by Golgi-localized phosphoinositide. AB - Phosphoinositides mediate a large number of signaling processes in mammalian cells. Here, we report that phophatidylinositol-4-phosphate (PtdIns(4)P) downregulates the cellular glucosylceramide (GlcCer) level by inhibiting the interaction between GlcCer synthase (UGCG) and UDP-glucose in the Golgi apparatus. In this study, we used two PH domain probes to bind phosphoinositides; one derived from FAPP1 for targeting to the Golgi PtdIns(4)P and the other from PLC delta for targeting to the plasma membrane PtdIns(4,5)P2. The levels of GlcCer and lactosylceramide, but not of sphingomyelin (SM), were increased following expression of the FAPP1 PH domain in cells, accompanied by an increase in UGCG activity. However, no elevated GlcCer level was observed after expression of the PLC delta PH domain. PtdIns(4)P inhibited UGCG activity, but not SMS activity, in a concentration-dependent manner, and UGCG activity was restored by the addition of UDP-glucose in the reaction mixture. These results indicate that PtdIns(4)P inhibits UGCG activity by competing with UDP-glucose. We conclude that the increase in UGCG activity due to the expression of the FAPP1 PH domain was caused by an attenuation of the inhibitory effect of PtdIns(4)P on UGCG. This study provides new insights into the regulation of GlcCer synthesis by PtdIns(4)P in the Golgi apparatus. PMID- 29627575 TI - The dual role of cGMP in oocyte maturation of zebrafish. AB - The roles of cyclic guanosine monophosphate (cGMP) signaling in oocyte maturation attracts much attention in mammals, but its roles in fish are still largely unknown. Using zebrafish as a model, we demonstrated for the first time in fish that cGMP is involved in oocyte maturation, and its functional model in oocyte maturation is different from that of mammals. The intracellular cGMP could be regulated by nitric oxide (NO), we found that all three NO synthase enzymes and four soluble guanylyl cyclases (sGC) are expressed in the zebrafish ovary. Intriguingly, either the activation or inhibition of the NO/sGC/cGMP pathway in fully grown follicles could lead to oocyte maturation. During oocyte maturation, cGMP levels increased in the follicular cell layer but decreased in oocytes, while NO levels increased in follicular cells but remained constant in oocytes. Based on these findings in zebrafish, we propose a hypothetical model on the dual role of cGMP in oocyte maturation: in follicular cells the LH signal could increase the level of NO and cGMP which induces oocyte maturation, while in the oocyte the decreased cGMP level can also induce oocyte maturation. These findings help us to understand the molecular mechanism of fish oocyte maturation. PMID- 29627574 TI - Exosomes secreted by placental stem cells selectively inhibit growth of aggressive prostate cancer cells. AB - The current paradigm in the development of new cancer therapies is the ability to target tumor cells while avoiding harm to noncancerous cells. Furthermore, there is a need to develop novel therapeutic options against drug-resistant cancer cells. Herein, we characterized the placental-derived stem cell (PLSC) exosomes (PLSCExo) and evaluated their anti-cancer efficacy in prostate cancer (PCa) cell lines. Nanoparticle tracking analyses revealed the size distribution (average size 131.4 +/- 0.9 nm) and concentration of exosomes (5.23 * 1010+/-1.99 * 109 per ml) secreted by PLSC. PLSCExo treatment strongly inhibited the viability of enzalutamide-sensitive and -resistant PCa cell lines (C4-2B, CWR-R1, and LNCaP cells). Interestingly, PLSCExo treatment had no effect on the viability of a non neoplastic human prostate cell line (PREC-1). Mass spectrometry (MS) analyses showed that PLSCExo are loaded with 241 proteins and mainly with saturated fatty acids. Further, Ingenuity Pathway Analysis analyses of proteins loaded in PLSCExo suggested the role of retinoic acid receptor/liver x receptor pathways in their biological effects. Together, these results suggest the novel selective anti cancer effects of PLSCExo against aggressive PCa cells. PMID- 29627576 TI - Magnolol abrogates chronic mild stress-induced depressive-like behaviors by inhibiting neuroinflammation and oxidative stress in the prefrontal cortex of mice. AB - Magnolol, the main constituent of Magnolia officinalis, has been shown to produce antidepressant-like effect in rodents. Growing evidence shows that neuroinflammation, oxidative stress and neuroendocrine contribute to the pathogenesis of major depression. Here, the aim of this present study was to determine whether magnolol affected these systems in mice exposed to chronic mild stress (CMS). The ameliorative effect of magnolol on depressive-like symptoms was investigated through behavioral tests, including the classical sucrose preference and forced swimming tests. The behavioral evaluation showed that magnolol reversed the depressive-like deficits both in sucrose preference test and forced swimming test. The elevation of prefrontal cortex pro-inflammatory cytokines such as interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) was decreased by magnolol. Consistently, the microglia activation by CMS was also alleviated by magnolol. In addition, the hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis induced by CMS was attenuated by magnolol. Moreover, the increased lipid peroxidation such as malonaldehyde (MDA) and decreased antioxidant defense enzymes including superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) induced by CMS were also reversed by magnolol. These findings suggest that administration of magnolol could alleviate depressive-like behaviors in CMS mice that are mediated by suppressing neuroinflammation and oxidative stress in the prefrontal cortex. PMID- 29627577 TI - Role of neopterin as a biochemical marker for peripheral neuropathy in pediatric patients with type 1 diabetes: Relation to nerve conduction studies. AB - BACKGROUND: Neopterin, a marker of inflammation and cellular immune response, is elevated in conditions of T-cell or macrophages activation. Diabetic peripheral neuropathy (DPN) is associated with inflammatory/immune processes and therefore, we hypothesized that neopterin could be used as a marker of neuropathy in type 1 diabetes mellitus (T1DM). AIM: To measure neopterin levels in children and adolescents with T1DM and assess its possible relation to DPN and nerve conduction studies (NCS). METHODS: Sixty patients aged <=18 years and >5 years disease duration were subjected to neurological assessment by neuropathy disability score (NDS) and NCS for median, ulnar, posterior tibial and common peroneal nerves. Mean fasting blood glucose, lipid profile, HbA1c, high sensitivity C-reactive protein (hs-CRP) and serum neopterin levels were assessed. Patients were compared with 30 age- and sex-matched healthy controls. RESULTS: The frequency of DPN according to NDS was 40 (66.7%) patients out of 60 while NCS confirmed that only 30 of those 40 patients had this complication (i.e. 50% out of the total studied patients). Neopterin levels were significantly higher in patients with DPN than those without (median [IQR], 53.5 [35-60] nmol/L versus 17 [13-32] nmol/L) and healthy controls (5.0 [3.2-7.0] nmol/L) (p < 0.001). Significant positive correlations were found between neopterin levels and HbA1c (r = 0.560, p = 0.005), serum creatinine (r = 0.376, p = 0.003), total cholesterol (r = 0.405, p = 0.026) and hs-CRP (r = 0.425, p = 0.012) among patients with DPN. Neopterin levels were positively correlated to motor latency of tibial and common peroneal nerves as well as motor and sensory latencies of median and ulnar nerves. Logistic regression analysis revealed that neopterin was a significant independent variable related to DPN (Odds ratio, 2.976). Neopterin cutoff value 32 nmol/L could differentiate patients with and without DPN with 100% sensitivity and 96.7% specificity. CONCLUSIONS: Neopterin could be used as an early reliable serum biomarker for DPN in pediatric patients with T1DM. PMID- 29627578 TI - Selective alteration of adult hippocampal neurogenesis and impaired spatial pattern separation performance in the RSK2-deficient mouse model of Coffin-Lowry syndrome. AB - Adult neurogenesis is involved in certain hippocampus-dependent cognitive functions and is linked to psychiatric diseases including intellectual disabilities. The Coffin-Lowry syndrome (CLS) is a developmental disorder caused by mutations in the Rsk2 gene and characterized by intellectual disabilities associated with growth retardation. How RSK2-deficiency leads to cognitive dysfunctions in CLS is however poorly understood. Here, using Rsk2 Knock-Out mice, we characterized the impact of RSK2 deficiency on adult hippocampal neurogenesis in vivo. We report that the absence of RSK2 does not affect basal proliferation, differentiation and survival of dentate gyrus adult-born neurons but alters the maturation progression of young immature newborn neurons. Moreover, when RSK2-deficient mice were submitted to spatial learning, in contrast to wild-type mice, proliferation of adult generated neurons was decreased and no pro-survival effect of learning was observed. Thus, learning failed to recruit a selective population of young newborn neurons in association with deficient long-term memory recall. Given the proposed role of the dentate gyrus and of adult-generated newborn neurons in hippocampal-dependent pattern separation function, we explored this function in a delayed non-matching to place task and in an object-place pattern separation task and report severe deficits in spatial pattern separation in Rsk2-KO mice. Together, this study reveals a previously unknown role for RSK2 in the early stages of maturation and learning dependent involvement of adult-born dentate gyrus neurons. These alterations associated with a deficit in the ability of RSK2-deficient mice to finely discriminate relatively similar spatial configurations, may contribute to cognitive dysfunction in CLS. PMID- 29627579 TI - Genetic detection of Sonic hedgehog (Shh) expression and cellular response in the progression of acute through chronic demyelination and remyelination. AB - Multiple sclerosis is a demyelinating disease in which neurological deficits result from damage to myelin, axons, and neuron cell bodies. Prolonged or repeated episodes of demyelination impair remyelination. We hypothesized that augmenting Sonic hedgehog (Shh) signaling in chronically demyelinated lesions could enhance oligodendrogenesis and remyelination. Shh regulates oligodendrocyte development during postnatal myelination, and maintains adult neural stem cells. We used genetic approaches to detect Shh expression and Shh responding cells in vivo. ShhCreERT2 or Gli1CreERT2 mice were crossed to reporter mice for genetic fate-labeling of cells actively transcribing Shh or Gli1, an effective readout of canonical Shh signaling. Tamoxifen induction enabled temporal control of recombination at distinct stages of acute and chronic cuprizone demyelination of the corpus callosum. Gli1 fate-labeled cells were rarely found in the corpus callosum with tamoxifen given during acute demyelination stages to examine activated microglia, reactive astrocytes, or remyelinating cells. Gli1 fate labeled cells, mainly reactive astrocytes, were observed in the corpus callosum with tamoxifen given after chronic demyelination. However, Shh expressing cells were not detected in the corpus callosum during acute or chronic demyelination. Finally, SAG, an agonist of both canonical and type II non-canonical Hedgehog signaling pathways, was microinjected into the corpus callosum after chronic demyelination. Significantly, SAG delivery increased proliferation and enhanced remyelination. SAG did not increase Gli1 fate-labeled cells in the corpus callosum, which may indicate signaling through the non-canonical Hedgehog pathway. These studies demonstrate that Hedgehog pathway interventions may have therapeutic potential to modulate astrogliosis and to promote remyelination after chronic demyelination. PMID- 29627581 TI - Extracapsular fracture of the femur in an elderly male from the Church of Nossa Senhora da Anunciada (Setubal, Portugal). AB - In modern populations, hip fractures in older people are associated with high morbidity and mortality. Their incidence is rising; notwithstanding, fractures of the proximal femur are still relatively uncommon in archeological contexts. This case study represents a well-healed hip fracture in an aged male skeleton from Church of Nossa Senhora da Anunciada (16th-19th centuries AD) in Setubal (Portugal). The individual was also diagnosed with diffuse idiopathic skeletal hyperostosis. Fractures of the proximal femur are usually associated with bone loss but in this case other causes are proposed, including the anatomy of the proximal femur, and the potential combined effect of diffuse idiopathic skeletal hyperostosis, cardiovascular disease, diabetes mellitus and falls. PMID- 29627580 TI - Poloxamer 188 decreases membrane toxicity of mutant SOD1 and ameliorates pathology observed in SOD1 mouse model for ALS. AB - Here we report a gain in function for mutant (mt) superoxide dismutase I (SOD1), a cause of familial amyotrophic lateral sclerosis (FALS), wherein small soluble oligomers of mtSOD1 acquire a membrane toxicity. Phosphatidylglycerol (PG) lipid domains are selectively targeted, which could result in membrane damage or "toxic channels" becoming active in the bilayer. This PG-selective SOD1-mediated membrane toxicity is largely reversible in vitro by a widely-available FDA approved surfactant and membrane-stabilizer P188. Treatment of G93ASOD1 transgenic mice with P188 significantly delayed symptoms onset, extended survival and decreased motoneuron death. The use of P188 or an analogue, which targets mtSOD1 misfolding-induced membrane toxicity, may provide a new direction for ALS treatment. PMID- 29627582 TI - Life on a Napoleonic battlefield: A bioarchaeological analysis of soldiers from the Battle of Aspern, Austria. AB - On the 21st-22nd of May 1809, French and Austrian soldiers engaged in battle near the village of Aspern on the outskirts of Vienna. This battle, the first defeat of Napoleon's army on land, was one of the largest and deadliest encounters during the Napoleonic Wars (1798-1815). Salvage excavations between 2009 and 2016 have revealed several battlefield burial sites in Aspern. The remains of 30 individuals were evaluated for a series of pathological conditions which develop during childhood and adulthood to elucidate the impact of Napoleonic military conditions on health. Statistical comparisons were conducted of stature estimates and frequencies of pathological conditions between the Aspern soldiers, several contemporaneous military, and two civilian samples of differing socioeconomic status. These data were compared to test the hypothesis that military conscripts had 'healthy' childhoods, but then experienced deteriorating health as a result of military conditions. The analysis revealed comparatively high mean stature, but also a high prevalence of enamel hypoplastic defects, indicating that the childhood health of the military recruits was more varied than was initially expected. High frequencies of carious lesions, dental calculus, active maxillary sinusitis and pleuritis and osteoarthritis were recorded, demonstrating the deleterious effects of military life on health. PMID- 29627583 TI - Hispanic ethnicity, stress psychophysiology and paradoxical health outcomes: A review with conceptual considerations and a call for research. AB - It is not wise to generalize psychophysiological findings from WEIRD (Western, Educated, Industrialized, Rich, Democratic) samples to all people and yet this occurs frequently in research. Case-in-point is our understanding of psychophysiological responses to stress which suggest universality despite our knowledge that these pathways are moderated by factors such as ethnicity and culture. Here we discuss the epidemiological phenomenon commonly referred to as the Hispanic health paradox to illustrate the importance of culture in understanding stress. We posit that despite high stress exposure, Hispanics may experience relatively low levels of stress contributing to their paradoxical health advantages. Building on our prior work, we present a new, culturally tailored stress theory model to illustrate how sociocultural factors may moderate the experience of stress (through appraisals) with downstream effects on psychophysiological mechanisms. We support the model with available data and end this paper with a call for research that more carefully considers cultural and ethnic factors in psychophysiological research. PMID- 29627584 TI - Motor facilitation during observation of implied motion: Evidence for a role of the left dorsolateral prefrontal cortex. AB - The phenomenon of motor resonance (the increase in motor cortex excitability during observation of actions) has been previously described. Transcranial magnetic stimulation (TMS) studies have demonstrated a similar effect during perception of implied motion (IM). The left dorsolateral prefrontal cortex (DLPFC) seems to be activated during action observation. Furthermore, the role of this brain area in motor resonance to IM is yet to be investigated. Fourteen healthy volunteers were enrolled into the study. We used transcranial direct current stimulation (tDCS) to stimulate DLPFC aiming to investigate whether stimulation with different polarities would affect the amplitude of motor evoked potential collected during observation of images with and without IM. The results of our experiment indicated that Cathodal tDCS over the left DLPFC prevented motor resonance during observation of IM. On the contrary, anodal and sham tDCS did not significantly modulate motor resonance to IM. The current study expands the understanding of the neural circuits engaged during observation of IM. Our results are consistent with the hypothesis that action understanding requires the interaction of large networks and that the left DLPFC plays a crucial role in generating motor resonance to IM. PMID- 29627585 TI - Cardiovascular correlates of emotional state, cognitive workload and time-on-task effect during a realistic flight simulation. AB - In aviation, emotion and cognitive workload can considerably increase the probability of human error. An accurate online physiological monitoring of pilot's mental state could prevent accidents. The heart rate (HR) and heart rate variability (HRV) of 21 private pilots were analysed during two realistic flight simulator scenarios. Emotion was manipulated by a social stressor and cognitive workload with the difficulty of a secondary task. Our results confirmed the sensitivity of the HR to cognitive demand and training effects, with increased HR when the task was more difficult and decreased HR with training (time-on-task). Training was also associated with an increased HRV, with increased values along the flight scenario time course. Finally, the social stressor seemed to provoke an emotional reaction that enhanced motivation and performance on the secondary task. However, this was not reflected by the cardiovascular activity. PMID- 29627586 TI - Novel orthohepeviruses in wild rodents from Sao Paulo State, Brazil. AB - The Hepeviridae comprise single-stranded positive-sense RNA viruses classified into two genera, Orthohepevirus and Piscihepevirus. Orthohepeviruses have a wide host range that includes rodents, but previous studies had been restricted to rodents of the Muridae family. In this study, we applied a high-throughput sequencing approach to examine the presence of orthohepeviruses in rodents from Sao Paulo State, Brazil. We also used RT-PCR to determine the frequency of orthohepeviruses in our sampled population. We identified novel orthohepeviruses in blood samples derived from Necromys lasiurus (1.19%) and Calomys tener (3.66%). Therefore, our results expand the host range and viral diversity of the Hepeviridae family. PMID- 29627587 TI - The 164 K, 165 K and 167 K residues in 160YPVVKKPKLTEE171 are required for the nuclear import of goose parvovirus VP1. AB - goose parvovirus (GPV) belongs to the Dependoparvovirus genus in Parvovirinae subfamily within Parvoviridae family, is the etiological agent of Derzsy's disease. Nuclear localization signal (NLS) is important for parvovirus lifecycle in the delivery of genomes and the structural protein of progeny virus into the nucleus. Here, NLS was first identified in GPV. By using the PSORT II program, a basic region (BR, 160YPVVKKPKLTEE171) in the N-terminus of VP1 was found, which predicted as putative NLS motif of goose parvovirus capsid. The GPV BR could transfer both small reporter proteins (EGFP) and large reporter protein (beta galactosidase) into the nucleus by Immunofluorescence assay. Furthermore, the K164A, or K165A, or K167A substitutions mutation of GPV VP1 did abolish its nuclear localization, suggesting that the 164 K, 165 K and 167 K residues in the 160YPVVKKPKLTEE171 are required for its for nuclear import. Our finding may help us to gain a better understand of GPV lifecycle. PMID- 29627589 TI - Gaussian process uncertainty in age estimation as a measure of brain abnormality. AB - Multivariate regression models for age estimation are a powerful tool for assessing abnormal brain morphology associated to neuropathology. Age prediction models are built on cohorts of healthy subjects and are built to reflect normal aging patterns. The application of these multivariate models to diseased subjects usually results in high prediction errors, under the hypothesis that neuropathology presents a similar degenerative pattern as that of accelerated aging. In this work, we propose an alternative to the idea that pathology follows a similar trajectory than normal aging. Instead, we propose the use of metrics which measure deviations from the mean aging trajectory. We propose to measure these deviations using two different metrics: uncertainty in a Gaussian process regression model and a newly proposed age weighted uncertainty measure. Consequently, our approach assumes that pathologic brain patterns are different to those of normal aging. We present results for subjects with autism, mild cognitive impairment and Alzheimer's disease to highlight the versatility of the approach to different diseases and age ranges. We evaluate volume, thickness, and VBM features for quantifying brain morphology. Our evaluations are performed on a large number of images obtained from a variety of publicly available neuroimaging databases. Across all features, our uncertainty based measurements yield a better separation between diseased subjects and healthy individuals than the prediction error. Finally, we illustrate differences in the disease pattern to normal aging, supporting the application of uncertainty as a measure of neuropathology. PMID- 29627588 TI - The multidimensional representational space of observed socio-affective touch experiences. AB - Observed touch interactions provide useful information on how others communicate with the external world. Previous studies revealed shared neural circuits between the direct experience and the passive observation of simple touch, such as being stroked/slapped. Here, we investigate the complexity of the neural representations underlying the understanding of others' socio-affective touch interactions. Importantly, we use a recently developed touch database that contains a larger range of more complex social and non-social touch interactions. Participants judged affective aspects of each touch event and were scanned while watching the same videos. Using correlational multivariate pattern analysis methods, we obtained neural similarity matrices in 18 regions of interest from five different networks: somatosensory, pain, the theory of mind, visual and motor regions. Among them, four networks except motor cortex represent the social nature of the touch, whereas fine-detailed affective information is reflected in more targeted areas such as social brain regions and somatosensory cortex. Lastly, individual social touch preference at the behavioral level was correlated with the involvement of somatosensory areas on representing affective information, suggesting that individuals with higher social touch preference exhibit stronger vicarious emotional responses to others' social touch experiences. Together, these results highlight the overall complexity and the individual modulation of the distributed neural representations underlying the processing of observed socio-affective touch. PMID- 29627590 TI - Exploring experimental autoimmune optic neuritis using multimodal imaging. AB - BACKGROUND: Neuro-axonal injury is a key contributor to non-reversible long-term disability in multiple sclerosis (MS). However, the underlying mechanisms are not yet fully understood. Visual impairment is common among MS patients, in which episodes of optic neuritis (ON) are often followed by structural retinal damage and sustained functional impairment. Alterations in the optic nerve and retina have also been described in experimental autoimmune encephalomyelitis (EAE), a rodent model of MS. Thus, investigating structural anterior visual pathway damage may constitute a unique model for assessing mechanisms and temporal sequence of neurodegeneration in MS. We used a multimodal imaging approach utilizing optical coherence tomography (OCT) and diffusion tensor imaging (DTI) to explore the mechanisms and temporal dynamics of visual pathway damage in the animal model of MS. METHODS: 7 EAE-MOG35-55 and 5 healthy female C57BL/6J mice were used in this study. Ganglion cell complex (GCC) thickness was derived from an OCT volume scan centred over the optic nerve head, while the structure of the optic nerve and tracts was assessed from DTI and co-registered T2-weighted sequences performed on a 7T MRI scanner. Data was acquired at baseline, disease onset, peak of disease and recovery. Linear mixed effect models were used to account for intra-subject, inter-eye dependencies, group and time point. Correlation analyses assessed the relationship between GCC thickness and DTI parameters. Immunofluorescence staining of retina and optic nerve sections was used to assess distribution of marker proteins for microglia and neurodegeneration (nerve filaments). RESULTS: In EAE mice, a significant increase in GCC thickness was observed at disease onset (p < 0.001) followed by a decrease at recovery (p < 0.001) compared to controls. The EAE group had significant GCC thinning at recovery compared to all other time points (p < 0.001 for each). Signal increase on T2-weighted images around the optic nerves indicative of inflammation was seen in most of the EAE mice but in none of the controls. A significant decrease in axial diffusivity (AD) and increase in radial diffusivity (RD) values in EAE optic nerves (AD: p = 0.02, RD: p = 0.01) and tract (AD: p = 0.02, RD: p = 0.006) was observed compared to controls. GCC at recovery was positively correlated with AD (optic nerve: rho = 0.74, p = 0.04, optic tract: rho = 0.74, p = 0.04) and negatively correlated with RD (optic nerve: rho = -0.80, p = 0.02, optic tract: rho = -0.75, p = 0.04). Immunofluorescence analysis indicated the presence of activated microglia in the retina and optic nerves in addition to astrocytosis and axonal degeneration in the optic nerve of EAE mice. CONCLUSION: OCT detected GCC changes in EAE may resemble what is observed in MS-related acute ON: an initial phase of swelling (indicative of inflammatory edema) followed by a decrease in thickness over time (representative of neuro-axonal degeneration). In line with OCT findings, DTI of the visual pathway identifies EAE induced pathology (decreased AD, and increased RD). Immunofluorescence analysis provides support for inflammatory pathology and axonal degeneration. OCT together with DTI can detect retinal and optic nerve damage and elucidate to the temporal sequence of neurodegeneration in this rodent model of MS in vivo. PMID- 29627591 TI - Organization of area hV5/MT+ in subjects with homonymous visual field defects. AB - Damage to the primary visual cortex (V1) leads to a visual field loss (scotoma) in the retinotopically corresponding part of the visual field. Nonetheless, a small amount of residual visual sensitivity persists within the blind field. This residual capacity has been linked to activity observed in the middle temporal area complex (V5/MT+). However, it remains unknown whether the organization of hV5/MT+ changes following early visual cortical lesions. We studied the organization of area hV5/MT+ of five patients with dense homonymous defects in a quadrant of the visual field as a result of partial V1+ or optic radiation lesions. To do so, we developed a new method, which models the boundaries of population receptive fields directly from the BOLD signal of each voxel in the visual cortex. We found responses in hV5/MT+ arising inside the scotoma for all patients and identified two possible sources of activation: 1) responses might originate from partially lesioned parts of area V1 corresponding to the scotoma, and 2) responses can also originate independent of area V1 input suggesting the existence of functional V1-bypassing pathways. Apparently, visually driven activity observed in hV5/MT+ is not sufficient to mediate conscious vision. More surprisingly, visually driven activity in corresponding regions of V1 and early extrastriate areas including hV5/MT+ did not guarantee visual perception in the group of patients with post-geniculate lesions that we examined. This suggests that the fine coordination of visual activity patterns across visual areas may be an important determinant of whether visual perception persists following visual cortical lesions. PMID- 29627592 TI - Alignment of alpha-band desynchronization with syntactic structure predicts successful sentence comprehension. AB - Sentence comprehension requires the encoding of phrases and their relationships into working memory. To date, despite the importance of neural oscillations in language comprehension, the neural-oscillatory dynamics of sentence encoding are only sparsely understood. Although oscillations in a wide range of frequency bands have been reported both for the encoding of unstructured word lists and for working-memory intensive sentences, it is unclear to what extent these frequency bands subserve processes specific to the working-memory component of sentence comprehension or to general verbal working memory. In our auditory electroencephalography study, we isolated the working-memory component of sentence comprehension by adapting a subsequent memory paradigm to sentence comprehension and assessing oscillatory power changes during successful sentence encoding. Time-frequency analyses and source reconstruction revealed alpha-power desynchronization in left-hemispheric language-relevant regions during successful sentence encoding. We further showed that sentence encoding was more successful when source-level alpha-band desynchronization aligned with computational measures of syntactic-compared to lexical-semantic-difficulty. Our results are a preliminary indication of a domain-general mechanism of cortical disinhibition via alpha-band desynchronization superimposed onto the language-relevant cortex, which is beneficial for encoding sentences into working memory. PMID- 29627593 TI - Quantification of receptor activation by oxytocin and vasopressin in endocytosis coupled bioluminescence reduction assay using nanoKAZ. AB - Oxytocin (OXT) and arginine vasopressin (AVP) are structurally similar neuropeptide hormones that function as neurotransmitters in the brain, and have opposite key roles in social behaviors. These peptides bind to their G protein coupled receptors (OXTR and AVPRs), inducing calcium ion-dependent signaling pathways and endocytosis of these receptors. Because selective agonists and antagonists for these receptors have been developed as therapeutic and diagnostic agents for diseases such as psychiatric disorders, facile methods are in demand for the evaluation of selectivity between these receptors. In this study, we developed a quantitative assay for OXT- and AVP-induced endocytosis of their receptors. The mutated Oplophorus luciferase, nanoKAZ, was fused to OXTR and AVPRs to enable rapid quantification of agonist-induced endocytosis by bioluminescence reduction. Agonist stimulation significantly decreases bioluminescence of nanoKAZ-fused receptors in living cells. Using this system, we evaluated clinically used OXTR antagonist atosiban and a reported pyrazinyltriazole derivative, hereby designated as PF13. Atosiban acted as an antagonist of AVPR1a, as well as an agonist for AVPR1b, whereas PF13 antagonized OXTR more selectively than atosiban, as reported previously. This paper shows a strategy for quantification of agonist-induced endocytosis of OXTR and AVPRs, and confirms its potent utility in the evaluation of agonists and antagonists. PMID- 29627594 TI - "You stop thinking about yourself as a woman". An interpretive phenomenological study of the meaning of sexuality for Icelandic women during pregnancy and after birth. AB - OBJECTIVE: There exists considerable evidence about reduced sexual desire and sexual disorders during pregnancy and after giving birth. More in-depth qualitative evidence is needed. The purpose of this study was to find out how Icelandic women experienced their sexuality during pregnancy and after giving birth. DESIGN/SETTING: An interpretive phenomenological study based on individual interviews with eight women was carried out at two time points, six and 12 months after giving birth, giving a total of 16 interviews. Women who had given birth at Landspitali - The National University Hospital of Iceland were selected for the study through purposeful sampling. The interviews were audio-recorded and transcribed verbatim. The text was analysed by using interpretive phenomenology. FINDINGS: Changes during pregnancy and the post-partum period affected how the women perceived themselves as sexual beings. They expressed a great need for physical and emotional intimacy during this time. Their needs for physical intimacy did not necessarily include the desire for sexual intercourse. How well their needs were met by their partner depended apparently on how intimate their relationship was. The relationship either tilted towards balance or imbalance, more towards balance when intimacy needs were taken care of. Communication, being emotionally close to the partner, and how the partner showed consideration played a great role in their sexual relationship. KEY CONCLUSIONS: During these transitional times women felt differently as sexual beings, they had great need for emotional and physical intimacy, and needed to share their thoughts, to be close and to be appreciated. IMPLICATIONS FOR PRACTICE: Health care professionals, especially midwives and nurses, could contribute to the balance in the relationship through the provision of evidence-based information about normal changes in sexual behaviour during the childbearing process and by discussing intimacy issues. The partner may need this information as much as the woman. PMID- 29627595 TI - Factors influencing first-time fathers' involvement in their wives' pregnancy and childbirth: A correlational study. AB - OBJECTIVE: To examine factors influencing first-time fathers' involvement in their wives' pregnancy and childbirth in Singapore. DESIGN AND SETTING: A cross sectional descriptive correlational study was conducted in a public tertiary hospital in Singapore. PARTICIPANTS: A total of 182 first-time fathers whose wives were hospitalized at four obstetric wards were recruited from November 2015 to January 2016. MEASUREMENTS: Data were collected by three newly developed and validated instruments, namely Father's Involvement in Pregnancy and Childbirth, Father's Informational and Sources of Support, and Father's Attitude Towards Involvement in Pregnancy and Childbirth, as well as the 16-item Couple Satisfaction Index and Family of Origin Questionnaire. FINDINGS: The participants were generally involved in their wives' pregnancy and childbirth, with 35.2% being highly involved. There was no significant difference in fathers' levels of involvement between or among any sociodemographic subgroups. Significant Spearman's correlations were found between fathers' levels of involvement and levels of informational support as well as fathers' attitudes towards involvement. However, the logistic regression showed the level of informational support was the only significant factor that influenced first-time fathers' high levels of involvement in their wives' pregnancy and childbirth. KEY CONCLUSION: The study revealed the importance of providing sufficient informational support to first-time fathers so that they can be highly involved in their wife's pregnancy and childbirth. Future studies can develop technology-based intervention programmes to improve fathers' involvement in their wife's pregnancy and childbirth. IMPLICATIONS FOR PRACTICE: Healthcare professionals should examine and improve the existing informational support for first-time fathers and ensure its relevance and convenient access. PMID- 29627596 TI - Omega-3 fatty acids for a better mental state in working populations - Happy Nurse Project: A 52-week randomized controlled trial. AB - The efficacy of omega-3 fatty acids for maintaining a better mental state has not been examined among working populations. We aimed to explore the effectiveness of omega-3 fatty acids for hospital nurses. In a multi-center randomized trial, 80 junior nurses were randomly allocated to either omega-3 fatty acids (1200 mg/day of eicosapentaenoic acid and 600 mg/day of docosahexaenoic acid) or identical placebo pills for 13 weeks. The primary outcome was the total score of the Hospital Anxiety and Depression Scale (HADS), determined by a blinded rater at week 26 from the study enrolment. Secondary outcomes included the total score of the HADS at 13 and 52 weeks; incidence of a major depressive episode; severity of depression, anxiety, insomnia, burnout, and presenteeism; utility scores; and adverse events at 13, 26 and 52 weeks. The mean HADS score at baseline was 7.2. At 26 weeks, adjusted mean scores on the HADS were 6.32 (95% CIs of standard errors: 5.13, 7.52) in the intervention and 6.81 (5.57, 8.05) in the placebo groups, respectively. The coefficient of the group by time interaction was not statistically significant at 0.58 (-1.35, 2.50; P = 0.557). Although the intervention group showed significant superiority on the HADS score at 52 weeks, depression severity at 52 weeks, insomnia severity at 13 weeks, and absolute presenteeism at 26 weeks, no significant superiority or inferiority was observed on the other outcomes. The additive value of omega-3 fatty acids was not confirmed regarding mental state and self-evaluated work efficiency. PMID- 29627597 TI - Genetic pathways to posttraumatic stress disorder and depression in children: Investigation of catechol-O-methyltransferase (COMT) Val158Met using different PTSD diagnostic models. AB - The catechol-O-methyltransferase (COMT) Val158Met polymorphism has been linked to PTSD, although findings have been inconsistent. Recently, different diagnostic criteria for PTSD have been introduced by ICD-11 and DSM-5, including separate criteria for adults and for young children (i.e., the preschool criteria). The preschool criteria may be applicable to older children as well. This study is the first to examine COMT associations with depression and PTSD, using new diagnostic models, in school-age children (7-11 years) exposed to a natural disaster. Children (n = 115) provided saliva samples for genotyping and completed measures assessing disaster exposure, posttraumatic stress, and depressive symptoms. COMT Met allele carriers were at risk for PTSD, but only when using ICD-11 (OR = 6.99) or the preschool criteria (OR = 4.77); there was a trend for DSM-IV and no association for DSM-5 (adult criteria). However, all children agreed upon as having PTSD by both DSM-5 and ICD-11 were Met allele carriers. The genetic association between the COMT Met allele and PTSD seemed primarily driven by arousal symptoms, as a significant relationship emerged only for the PTSD arousal symptom cluster. In contrast, COMT Val allele homozygosity was associated with depression (OR = 4.34). Thus, findings suggest that opposing COMT genotypes increased vulnerability to depressive versus arousal-based clinical presentations following trauma exposure. As a result, the heterogeneity of the DSM-5 PTSD criteria and its inclusion of depressive symptoms may mask COMT associations with DSM-5 PTSD. Future research should consider how the use of different diagnostic models of PTSD may influence genetic findings. PMID- 29627598 TI - Single-nucleotide polymorphisms and their role in coronary artery disease: Where do we stand now? PMID- 29627599 TI - Improving the practicality and safety of artificial corneas: Pre-assembly and gamma-rays sterilization of the Boston Keratoprosthesis. AB - PURPOSE: To make the Boston keratoprosthesis (B-KPro), together with its carrier corneal graft, more easily procured, transported and stored, as well as less expensive, easier for the surgeon to implant and safer for the patient, it is proposed that the B-KPro-graft combination be pre-assembled by an expert technician, followed by sterilization with gamma ray irradiation (GI) allowing long-term storage at room temperature. For this to be possible, it must be shown that the B-KPro itself (not only the graft) remains unharmed by the irradiation. METHODS: Polymethyl methacrylate (PMMA) discs and B-KPros were submitted to either ethylene oxide sterilization or different doses of GI. Cell biocompatibility, mechanical strength and optical quality were evaluated. The feasibility of assembling the B-KPro to a corneal graft, and gamma-radiate afterwards, was also assessed. RESULTS: There were no differences in cell biocompatibility between the samples. The optical evaluation showed high levels of transparency for all the groups. The absorbance of ultraviolet was higher for the groups treated with GI. The mechanical evaluation by nanoindentation showed no alterations of the PMMA discs after GI. The flexure test revealed a similar mechanical behavior. Technically, pre-assembly and GI of the B-KPro revealed no problems. CONCLUSIONS: Sterilization of B-KPro using GI has no detrimental influence on the device. The pre-assembly of B-KPro to a donor cornea, followed by gamma sterilization, emerges as an efficient and safe procedure. PMID- 29627600 TI - A single-step transconjugation system for gene deletion in Aggregatibacter actinomycetemcomitans. AB - Aggregatibacter (A.) actinomycetemcomitans is a periodontopathogenic bacterium causing aggressive periodontitis. Here we describe a single-step transconjugation system as novel and easily applicable protocol for site-specific genetic manipulation of A. actinomycetemcomitans. Deletion of PgaC, which is involved in the synthesis of biofilm matrix, led to a reduced biofilm formation. PMID- 29627601 TI - CYP1A1 gene polymorphisms modify the association between PM10 exposure and lung function. AB - Genetic epidemiological studies have provided evidence that several genes modify the link between air pollution and lung function. We assessed whether the adverse impacts of particulate matter with an aerodynamic diameter <=10 MUm (PM10) on lung function are modified by CYP1A1 gene polymorphisms in Korean adults. We used health check-up data from 1817 men, and the annual mean concentrations of ambient PM10 estimated from the ambient data. Three single nucleotide polymorphisms (SNPs) of CYP1A1 were selected for our study. We identified significant CYP1A1 SNPs-by-PM10 interactions for forced expiratory volume 1 s (FEV1) and forced vital capacity (FVC) (all pint < 0.05). Minor allele carriers of the SNPs were more susceptible to PM10-induced FEV1 and FVC reduction. The subgroup analysis of SNP genotypes showed that no significant association between PM10 and FEV1 or FVC was observed in homozygous reference genotype groups of all SNPs (all passoc > 0.05), whereas in heterozygous or homozygous alternate genotype groups, PM10 was significantly associated with decreased FEV1 (all passoc for FEV1 < 0.05). The association between persistent exposure to PM10 and lung function decline in Korean men may be determined in part by several functional variants of the CYP1A1 gene. PMID- 29627602 TI - Characterizing the binding interactions of PFOA and PFOS with catalase at the molecular level. AB - Perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) have effects on human health by inducing oxidative stress and catalase (CAT) is a vital enzyme involved in protection against oxidative damage. The interactions of PFOA and PFOS with CAT were investigated by using biophysical methods including spectroscopic techniques, molecular docking and enzyme activity measurements. UV visible, circular dichroism (CD) and resonance light scattering (RLS) spectroscopy results showed that the structure and conformation of CAT were changed by PFOA and PFOS. PFOA could loosen and unfold the skeleton of CAT but PFOS affected the microenvironment around the aromatic amino acid residues and heme groups. Both PFOA and PFOS altered the secondary structure of CAT by decreasing alpha-helix and increasing beta-sheet content. The size of CAT was smaller and CAT became dispersed when it was bound by perfluorinated compounds (PFCs). Furthermore, enzyme activity test showed that PFOS decreased the activity of CAT because the binding site of PFOS was close to the active center of CAT, but PFOA had little effect on the activity because PFOA bound at the surface of the enzyme. These results indicated that PFCs could damage the structures and conformations of CAT but the changes were not always related to the activity and function of CAT. PMID- 29627603 TI - Impact of biofilm formation and detachment on the transmission of bacterial antibiotic resistance in drinking water distribution systems. AB - There is growing awareness of the antibiotic-resistance crisis and its implications for public health among clinicians, researchers, politicians, and the public. We studied bacterial antibiotic resistance transition and the role of biofilms in a drinking water distribution system (DWDS). We tracked several different antibiotic resistant bacteria (ARB) with resistance to tetracycline, sulfamethoxazole, clindamycin, and norfloxacin for one year in a DWDS. The results indicated that the amount of ARB increased in tap water, presumably due to biofilm detachment. The effect of biofilm detachment on the transmission of antibiotic resistance from biofilms to tap water was explored by using a bacterial annular reactor. The percentage of ARB of inlet water, outlet water, and biofilms ranged from 0.26% to 9.85%, 1.08%-16.29%, and 0.52%-29.97%, respectively in a chlorinated system, and from 0.23% to 9.89%, 0.84%-16.84%, and 0.35%-17.77%, respectively, in a chloraminated system. The relative abundances of antibiotic resistance Acinetobacter, Sphingomonas, and Bradyrhizobium were higher in outlet water than in inlet water, as determined by high throughout sequencing. The amount of ARB percentage varied with the concentration of viable but non culturable (VBNC) cells (r = 0.21, n = 160, P < 0.05) in biofilm, suggesting a higher antibiotic resistance mutation rate in VBNC cells. Our results suggest that biofilm detachment was promoted by disinfectant and affected the overall bacterial antibiotic resistance of microbes in tap water. PMID- 29627604 TI - Exposed zebrafish (Danio rerio) to imidazolium-based ionic liquids with different anions and alkyl-chain lengths. AB - Ionic liquids (ILs) were considered new "green solvents" in consideration of the low volatility. Since their inception, ionic liquids (ILs) have attracted widespread attention. However, ILs were not safe enough as what we thought. The toxicity of 1-ethyl-3-methylimidazolium ILs ([C2mim]R, R = Cl-, Br-, BF4-) and 1 alkyl-3-methylimidazolium bromine ([Cnmim]Br, n = 2, 4, 8, 10, 12) using 50% lethal concentration (LC50) were studied in the present study to enrich the toxicological information. Besides the LC50 values, the sensitivity test using potassium dichromate (K2Cr2O7) and residue determinations of the tested ILs were also performed. The sensitivity and dynamic changes of IL doses both catered for the stipulation that declared the accuracy of the toxicological test results, which illustrated that the alkyl-chain lengths contributed more than anions to the toxicity of the ILs described above to zebrafish. Additionally, the present study also enriched the toxicological information on imidazolium-based ILs to aquatic systems. PMID- 29627605 TI - Evaluation of Bisphenol A influence on endocannabinoid system in pregnant women. AB - Bisphenol A (BPA) is a synthetic chemical widely used in the industry, which may potentially evoke negative effects on human health, especially on reproductive processes and fetal development. BPA has been reported to act on estrogen, estrogen-related, androgen, thyroid hormone, pregnane X, peroxisome proliferation activated, and aryl hydrocarbon receptors. However, other potential mechanisms of BPA action on pregnancy cannot be excluded. Comprehensive evaluation of BPA effect on pregnant women can be performed by use of metabolomics. In the present study LC-MS-based plasma metabolomics was performed in the group of pregnant women with known concentrations of free, conjugated and total BPA. Significant positive correlations were observed between several endocannabinoids (fatty acid amides) and free (r = 0.307-0.557, p-value = 0.05-0.00002) and total (r = 0.413 0.519, p-value = 0.008-0.00006) BPA concentrations. Palmitoleamide was positively correlated with conjugated (r = 0.348, p-value = 0.05) while lysophosphatidylethanolamine 18:0 with free (r = 0.519, p-value = 0.00006) BPA concentration. The docking calculations of BPA and fatty acid amide hydrolase (enzyme degrading endocannabinoids, FAAH) indicated that it can act as a competitive inhibitor by blocking FAAH catalytic residues. In vitro study showed that BPA moderately inhibits FAAH activity (15% decrease for 200 ng mL-1 and almost 50% for 200 MUg mL-1 of BPA). In the present study for the first time inhibitory potential of BPA on FAAH hydrolase is reported. Inhibition of FAAH may lead to a rise of plasma endocannabinoids level. BPA exposure and increased level of endocannabinoids are miscarriage risk factors. Based on obtained results it can be hypothesized that BPA may induce adverse pregnancy outcomes by acting on endocannabinoid system. PMID- 29627606 TI - Gestational exposure to ziram disrupts rat fetal Leydig cell development. AB - Ziram is an endocrine disruptor and may cause birth abnormality of the male reproductive system. However, the effects of ziram on fetal Leydig cell (FLC) development are still unknown. The objective of the present study was to determine the endocrine-disrupting effect of ziram on rat FLC development after gestational exposure. Pregnant Sprague Dawley dams were randomly divided into 5 groups and were gavaged with 0 (corn oil, the control), 1, 2, 4, or 8 mg/kg ziram from gestational day 12 (GD12) to GD21. FLC development was evaluated by measuring serum testosterone, FLC number and distribution, and the expression levels of Leydig and Sertoli cell genes. Ziram significantly increased serum testosterone level at 1 mg/kg (1.350 +/- 0.099 ng/ml vs. 0.989 +/- 0.106 ng/ml in the control), while it remarkably lowered it at 8 mg/kg (0.598 +/- 0.086 ng/ml). Quantitative immunohistochemical staining showed that ziram increased FLC number via stimulating cell proliferation at 1 mg/kg and lowered it via inhibiting its proliferation at 8 mg/kg without affecting Sertoli cell number. Further study demonstrated that the expression of Nr5a1, Lhcgr, Scarb1, Star, Cyp11a1, and Cyp17a1 genes and proteins in the testis was upregulated at 1 mg/kg and the expression of Leydig (Nr5a1, Lhcgr, Scarb1, Star, Cyp11a1, Cyp17a1, and Insl3) and Sertoli cell (Fshr, Hsd17b3, Dhh, Amh, and Sox9) genes and proteins was downregulated by ziram at 8 mg/kg. In conclusion, ziram had biphasic effects on FLC development with low dose to increase FLC number and function and high dose to decrease them. PMID- 29627607 TI - Metal-induced oxidative stress in terrestrial macrolichens. AB - Short-term (24 h) responses of Cladonia arbuscula subsp. mitis and Cladonia furcata to copper (CuII) or chromium (CrIII) excess (10 or 100 MUM) were compared. C. arbuscula accumulated more Cu and Cr at higher metal doses but both species revealed depletion of K and/or Ca amount. Not only Cu but also Cr typically elevated reactive oxygen species (ROS) formation (fluorescence microscopy detection of total ROS and hydrogen peroxide) and depleted nitric oxide (NO) signal, with Cu showing more negative impact on lipid peroxidation (BODIPY 581/591 C11 staining reagent). Metals and staining reagents also affected anatomical responses and photobiont/mycobiont visibility. Principally different impact of Cu and Cr was observed at antioxidative metabolites level, indicating various ways of metal-induced ROS removal and/or metal chelation: Cu strongly depleted glutathione (GSH) and stimulated phytochelatin 2 (PC2) content while ascorbic acid accumulation was depleted by Cu and stimulated by Cr. Subsequent experiment with GSH biosynthetic inhibitor (buthionine sulfoximine, BSO) revealed that 48 h of exposure is needed to deplete GSH and BSO-induced depletion of GSH and PC2 amounts under Cu or Cr excess elevated ROS but depleted NO. These data suggest close relations between thiols, NO and appearance of oxidative stress (ROS generation) under metallic stress also in lichens. PMID- 29627608 TI - Effect of Wheelchair Stroke Pattern on Upper Extremity Muscle Fatigue. AB - BACKGROUND: Shoulder dysfunction is common in persons with spinal cord injury (SCI) with an incidence of up to 63%. Dysfunction is a result of muscle imbalances, specifically denervated rotator cuff muscles that are repetitively used during manual wheelchair propulsion. OBJECTIVE: To determine which arm stroke technique, pump (P) or semicircular (SC), is most energy efficient for long periods of propulsion. DESIGN: A randomized study with repeated measures observations. SETTING: The study was performed at an institutional gait analysis laboratory. PARTICIPANTS: 18 able-bodied (AB) male participants were studied and randomized into one of 2 conditions, SC or P. METHODS: Shoulder muscle fatigue was measured by changes in Borg CR10 Rate of Perceived Exertion (Borg RPE) and upper extremity strength via a handheld dynamometer. Participants were studied and assigned into one of 2 conditions of wheelchair arm propulsion patterns, SC or P group, and propelled on a wheelchair treadmill for 10 minutes. MAIN OUTCOME MEASURES: The primary outcomes included recordings of Borg RPE scale during continuous wheelchair propulsion and pre- and post-test dynamometer testing means for bilateral elbow and shoulder extension. Analysis of covariance, t-tests, and Kruskal-Wallis tests were used in analyzing data. RESULTS: Although not significant (P = .23), the Borg RPE scores for the SC condition were consistently higher than the scores for the P condition. In addition, the dynamometer pre- and post-test readings demonstrated a larger decrease for the SC condition participants than for the P condition participants, but were not statistically significant. CONCLUSIONS: These data demonstrate that the SC wheelchair propulsion pattern appears to be more fatiguing to shoulder muscles than the P propulsion pattern. However, more data would need to be collected to find a significant difference. LEVEL OF EVIDENCE: II. PMID- 29627609 TI - Distinguishing allergens from non-allergenic homologues using Physical-Chemical Property (PCP) motifs. AB - Quantitative guidelines to distinguish allergenic proteins from related, but non allergenic ones are urgently needed for regulatory agencies, biotech companies and physicians. In a previous study, we found that allergenic proteins populate a relatively small number of protein families, as characterized by the Pfam database. However, these families also contain non-allergenic proteins, meaning that allergenic determinants must lie within more discrete regions of the sequence. Thus, new methods are needed to discriminate allergenic proteins within those families. Physical-Chemical Properties (PCP)-motifs specific for allergens within a Pfam class were determined for 17 highly populated protein domains. A novel scoring method based on PCP-motifs that characterize known allergenic proteins within these families was developed, and validated for those domains. The motif scores distinguished sequences of allergens from a large selection of 80,000 randomly selected non-allergenic sequences. The motif scores for the birch pollen allergen (Bet v 1) family, which also contains related fruit and nut allergens, correlated better than global sequence similarities with clinically observed cross-reactivities among those allergens. Further, we demonstrated that the average scores of allergen specific motifs for allergenic profilins are significantly different from the scores of non-allergenic profilins. Several of the selective motifs coincide with experimentally determined IgE epitopes of allergenic profilins. The motifs also discriminated allergenic pectate lyases, including Jun a 1 from mountain cedar pollen, from similar proteins in the human microbiome, which can be assumed to be non-allergens. The latter lacked key motifs characteristic of the known allergens, some of which correlate with known IgE binding sites. PMID- 29627610 TI - Three-dimensional CAD/CAM imaging of the maxillary sinus in ageing process. AB - OBJECTIVES: During the physiological ageing process atrophy of the alveolar bone appears in vertical direction. This bone resorption causes pushing the limits of the maxillary sinus at the expense of a degraded bone. The sinus volume increases due to the facial development in children and adolescents or during the ageing process due to the loss of teeth and bone mass. The main aim of this study is to determine the sinus shape and sinus floor morphology related to age. MATERIALS AND METHODS: Human adult male and female cadaveric heads (aged 37 to 83 years) with different dental status were used. The three-dimensional CAD/CAM software was used to scan the solid impressions of the maxillary sinus to visualize the real sinus shape and sinus floor. Subsequently, other findings are shown in tables and evaluated graphically. RESULTS: The maxillary sinus morphology, its relationship to the nasal cavity, the sub sinus alveolar bone height, displacement of the lowest and highest points of sinus, and the sinus relationship to the roots of the upper teeth were studied and evaluated. Some septa, crests, and the prominent infraorbital canal were also found in the area of the sinus floor. CONCLUSIONS: This paper provides a unique view on the maxillary sinus and its changes during the ageing process with preserved topographical relations in a representative sample of the Slovak population. The visualization of the maxillary sinus anatomy is necessary in the diagnosis and treatment plans for dental implants and during current surgical procedures. PMID- 29627611 TI - Phytosterols and their derivatives: Structural diversity, distribution, metabolism, analysis, and health-promoting uses. AB - Phytosterols (plant sterols) occur in the cells of all plants. They are important structural components that stabilize the biological membranes of plants. Sterols can occur in the "free" unbound form or they can be covalently bound via an ester or glycosidic bond. Since our previous 2002 review on phytosterols and phytosterol conjugates, phytosterol glucosides have been found to be important structural components in the lipid rafts of the plasma membrane of plant cells, where they are thought to be essential to the function of plasma membrane enzymes and perhaps other proteins. Phytosterols also serve as precursors in the synthesis of important bioactive compounds such as steroidal saponins, steroidal glycoalkaloids, phytoecdysteroids, and brassinosteroids. Methods for the analysis of phytosterols range from traditional gas chromatography of free phytosterols to modern sophisticated forms of mass spectrometry which have been used for the new field of sterol lipidomics, sometimes called "sterolomics." Phytosterol-enriched functional foods first appeared about twenty years ago and many clinical studies have confirmed the low density lipoprotein (LDL) cholesterol-lowering properties of various types of phytosterols. In recent years additional clinical studies and more than ten important meta-analyses have provided insights to better understand the cholesterol-lowering and other biological effects of plant sterols. PMID- 29627612 TI - Ag loading induced visible light photocatalytic activity for pervoskite SrTiO3 nanofibers. AB - The synthesis and photocatalytic activities of Ag-SrTiO3 nanofibers were reported in this work. The fabricated Ag-SrTiO3 nanofibers were characterized by TG-DSC, XRD, IR, XPS, SEM, TEM, DRS and ESR techniques. The XRD and IR results show that Ag-SrTiO3 nanofibers have a perovskite structure after the heat treatment at 700 degrees C. The XPS result shows that Ag element exists as Ag0 in the fabricated Ag-SrTiO3 nanofibers. The SEM and TEM images indicate the obtaining of nanofibers with porous structure. The photocatalytic activity of Ag-SrTiO3 nanofibers was evaluated by degrading RhB and MB under visible light irradiation. The Ag-SrTiO3 nanofibers show excellent photocatalytic activity under visible light irradiation because of the surface plasmon resonance effect of Ag0. In the photocatalysis process of RhB and MB, lots of hydroxyl radicals were generated, which plays the key role in the decomposition of organic pollutants. PMID- 29627613 TI - Synthesis, spectral, DFT modeling, cytotoxicity and microbial studies of novel Zr(IV), Ce(IV) and U(VI) piroxicam complexes. AB - The Zr(IV), Ce(IV) and U(VI) piroxicam anti-inflammatory drug complexes were prepared and characterized using elemental analyses, conductance, IR, UV-Vis, magnetic moment, IHNMR and thermal analysis. The ratio of metal: Pir is found to be 1:2 in all complexes estimated by using molar ratio method. The conductance data reveal that Zr(IV) and U(VI) chelates are non-electrolytes except Ce(IV) complex is electrolyte. Infrared spectroscopic confirm that the Pir behaves as a bidentate ligand co-ordinated to the metal ions via the oxygen and nitrogen atoms of nu(CO)carbonyl and nu(CN)pyridyl, respectively. The kinetic parameters of thermogravimetric and its differential, such as activation energy, entropy of activation, enthalpy of activation, and Gibbs free energy evaluated using Coats Redfern and Horowitz-Metzger equations for Pir and complexes. The geometry of the piroxicam drug in the Free State differs significantly from that in the metal complex. In the time of metal ion-drug bond formation the drug switches-on from the closed structure (equilibrium geometry) to the open one. The antimicrobial tests were assessed towards some types of bacteria and fungi. The in vitro cell cytotoxicity of the complexes in comparison with Pir against colon carcinoma (HCT 116) cell line was measured. PMID- 29627614 TI - Determination of mercury (II) ions based on silver-nanoparticles-assisted growth of gold nanostructures: UV-Vis and surface enhanced Raman scattering approaches. AB - Innovative dual detection methods for mercury(II) ions (Hg(II)) have been developed based on the formation of gold nanostructures (AuNSs) following the addition of mercury-containing solution to a mixture containing an optimized amount of Au(III), H2O2, HCl, and silver nanoparticles (AgNPs). In the absence of Hg(II), the addition of Au(III), H2O2, and HCl to the AgNP solution changes the solution's color from yellow to red, and the absorption peak shifts from 400 to 526nm, indicating the dissolution of AgNPs and the formation of gold nanoparticles (AuNPs). Because of the spontaneous redox reaction of Hg(II) toward AgNPs, the change in the amount of remaining AgNP seed facilitates the generation of irregular AuNSs, resulting in changes in absorption intensity and shifting the peak within the range from 526 to 562nm depending on the concentration of Hg(II). Under optimal conditions, the limit of detection (LOD) for Hg(II) at a signal-to noise ratio (S/N) of 3 was 0.3MUM. We further observed that AgNP-assisted catalytic formation of Au nanomaterials deposited on a surface enhanced Raman scattering active substrate significantly reduced the Raman signal of 4 mercaptobenzoic acid, dependent on the Hg(II) concentration. A linear relationship was observed in the range 0.1nM-100MUM with a LOD of 0.05nM (S/N 3.0). As a simple, accurate and precise method, this SERS-based assay has demonstrated its success in determining levels of Hg(II) in real water samples. PMID- 29627615 TI - A combined photophysical and computational study on the binding of mycophenolate mofetil and its major metabolite to transport proteins. AB - Binding of the immunosuppressive agent mycophenolate mofetil (MMP) and its pharmacologically active metabolite mycophenolic acid (MPA) to human serum albumin (HSA) and alpha1-acid glycoprotein (HAAG) has been investigated by means of an integrated approach involving selective excitation of the drug fluorophore, following their UV-A triggered fluorescence and docking studies. The formation of the protein/ligand complexes was evidenced by a dramatic enhancement of the fluorescence intensity and a hypsochromic shift of the emission band. In HSA, competitive studies using oleic acid as site I probe revealed site I as the main binding site of the ligands. Binding constants revealed that the affinity of the active metabolite by HSA is four-fold higher than its proactive form. Moreover, the affinity of MMP by HSA is three-fold higher than by HAAG. Docking studies revealed significant molecular binding differences in the binding of MMP and MPA to sub-domain IIA of HSA (site 1). For MPA, the aromatic moiety would be in close contact to Trp214 with the flexible chain pointing to the other end of the sub domain; on the contrary, for MMP, the carboxylate group of the chain would be fixed nearby Trp214 through electrostatic interactions with residues Arg218 and Arg222. PMID- 29627616 TI - Spectroscopic and structural investigation of interaction of 5-mercapto-3-phenyl 1,3,4-thiadiazole-2-thione potassium salt with molecular iodine. AB - The interest in the study of heteroaromatic thioamides which are known to exhibit antithyroid activity is stimulated by the variety and an unusual structure their complexes with molecular iodine. The directions of dithiones investigation are diversity enough, however a few works are devoted to the study them as the potential thyreostatics. The ability of 5-mercapto-3-phenyl-1,3,4-thiadiazole-2 thion potassium salt to form the outer-sphere charge-transfer complex in dilute chloroform solution, coordinating 2 iodine molecules has been studied by UV-vis spectroscopy (lgbeta=7.91). The compound of the 5,5'-disulfanediylbis(3-phenyl 1,3,4-thiadiazole-2(3H)-thione) - product of irreversible oxidation of 5-mercapto 3-phenyl-1,3,4-thiadiazole-2-thione potassium salt has been isolated and characterized by X-ray diffraction. Intermolecular interactions between sulfur atoms are observed with very short interatomic distance, shorter than sum of van der Waals radii. The contact between heterocyclic sulfur and heterocyclic nitrogen is also slightly short - 3.169A (0.053A less than vdW radii sum). This investigation constitutes a starting point for study of novel antithyroid drugs in future. PMID- 29627617 TI - Dopant induced local vibrational modes and Fano scattering in Ag doped ZnO microrods. AB - We discussed the influence of Ag doping on the crystallite size of ZnO and enhanced Raman spectroscopy properties. We reported optical and vibrational properties of Ag-doped ZnO microrods which have been prepared through reflux method. Dopant induced shift and asymmetric broadening of Raman modes have been discussed. In Raman spectra, silver doping induces a lower wavenumber shift in E2H mode. Moreover, the appearance of some additional peaks after Ag-doping were successfully studied and the doping is confirmed by the local vibration modes obtained at 230 and 390cm-1. Effect of doping is studied by calculating the crystallite size and we discussed the variations in full width half maximum (FWHM), phonon lifetime with respect to varying crystallite size. Phonon lifetime decreases with increasing Ag concentration. The asymmetric broadening in Raman modes E2H and E2L with the addition of Ag are analysed with Fano fitting. PMID- 29627618 TI - Chemometrics-assisted spectrophotometric green method for correcting interferences in biowaiver studies: Application to assay and dissolution profiling study of donepezil hydrochloride tablets. AB - A green, simple and cost effective chemometric UV-Vis spectrophotometric method has been developed and validated for correcting interferences that arise during conducting biowaiver studies. Chemometric manipulation has been done for enhancing the results of direct absorbance, resulting from very low concentrations (high incidence of background noise interference) of earlier points in the dissolution timing in case of dissolution profile using first and second derivative (D1 & D2) methods and their corresponding Fourier function convoluted methods (D1/FF& D2/FF). The method applied for biowaiver study of Donepezil Hydrochloride (DH) as a representative model was done by comparing two different dosage forms containing 5mg DH per tablet as an application of a developed chemometric method for correcting interferences as well as for the assay and dissolution testing in its tablet dosage form. The results showed that first derivative technique can be used for enhancement of the data in case of low concentration range of DH (1-8MUgmL-1) in the three different pH dissolution media which were used to estimate the low drug concentrations dissolved at the early points in the biowaiver study. Furthermore, the results showed similarity in phosphate buffer pH6.8 and dissimilarity in the other 2pH media. The method was validated according to ICH guidelines and USP monograph for both assays (HCl of pH1.2) and dissolution study in 3pH media (HCl of pH1.2, acetate buffer of pH4.5 and phosphate buffer of pH6.8). Finally, the assessment of the method greenness was done using two different assessment techniques: National Environmental Method Index label and Eco scale methods. Both techniques ascertained the greenness of the proposed method. PMID- 29627619 TI - Impact of prednisone in patients with repeated embryo implantation failures: Beneficial or deleterious? AB - INTRODUCTION: Corticotherapy is the leading medication worldwide for patients with history of repeated implantation failures (RIF) after IVF/ICSI. Nevertheless, we still do not know its local mechanism of action, hence its precise indication. Our objective is to document the impact of prednisone on the endometrial expression of immune biomarkers (CD56 cells count, IL-18/TWEAK, IL 15/Fn-14 mRNA ratio) at the time of uterine receptivity in a RIF population. MATERIALS AND METHOD: An endometrial biopsy was realized in the mid luteal phase for immune profiling: IL-15/Fn-14 and IL-18/TWEAK mRNA ratios were determined by quantitative RT-PCR and CD56 mobilization per IHC. Fifty-five patients with a RIF history were diagnosed to have local over-immune activation [high IL-18/TWEAK mRNA ratio, and/or high IL-15/Fn-14 mRNA ratio] likely to impair the implantation process. They underwent a second immune profiling with supplementation of prednisone. A paired comparison of the immune profile before and under prednisone was performed in the subset of patients subsequently pregnant under prednisone. FINDING: In 54.5% of the cases, both immune biomarkers were normalized and in 16.5%, only one was normalized under prednisone. In 29% we observed a paradoxical increase of both immune biomarkers. The IL-18/TWEAK mRNA ratio reflecting the Th 1/Th-2 local equilibrium was significantly reduced (0.29 versus 0.10, p = .004), through very significant increase of TWEAK expression, in patients who were subsequently pregnant under prednisone. CONCLUSION: Testing the response to prednisone in a RIF context may be very useful. Less than half of RIF patients with immune deregulation may be prednisone responders and would benefit from its administration. PMID- 29627620 TI - Efficacy, safety, and tolerability of lubiprostone for the treatment of non alcoholic fatty liver disease in adult patients with constipation: The LUBIPRONE, double-blind, randomised, placebo-controlled study design. AB - BACKGROUND: This paper reports the protocol of a randomised, double-blind, placebo-controlled study to test the efficacy, safety, and tolerability of lubiprostone (LUB) vs. placebo on suppressing gut permeability in non-alcoholic fatty liver disease (NAFLD) patients with constipation. NAFLD, including non alcoholic steatohepatitis (NASH), is a common chronic liver disorder. Progression is associated with increased gut permeability and gut-derived endotoxins. Most NAFLD/NASH clinical trial drugs aim to improve liver function or systemic metabolism. LUB is a type 2 chloride channel activator used as a laxative for the treatment of patients with constipation. LUB suppresses gut permeability induced by non-steroidal anti-inflammatory drugs in healthy volunteers and lowers blood endotoxin levels. There have been no clinical studies of LUB for NAFLD/NASH patients. METHODS: The study plans to enrol adult patients (20-85 years, planned enrolment, n = 150; planned sample size, n = 120) with NAFLD and constipation, alanine aminotransferase >=40 IU/L, equivalent steatosis grade >=1, and equivalent fibrosis stage <4 measured using non-invasive vibration-controlled transient elastography and magnetic resonance imaging. Participants will be randomly allocated into three groups: LUB 12 MUg, LUB 24 MUg, and a placebo group. RESULTS: The primary endpoint will be changes in alanine aminotransferase from baseline at 12 weeks. The main secondary endpoint will be changes in intestinal permeability from baseline at 12 weeks using the lactulose mannitol ratio. CONCLUSIONS: This study will determine whether LUB improves gut permeability in NAFLD patients with constipation. TRIAL REGISTRATION: This trial is registered in the University Hospital Medical Information Network (UMIN) Clinical Trials Registry (UMIN000026635). PMID- 29627621 TI - The OPTIMA study, buprenorphine/naloxone and methadone models of care for the treatment of prescription opioid use disorder: Study design and rationale. AB - BACKGROUND: Rates of non-medical use of opioids, and opioid use disorders (OUD) have been rising throughout North America. Methadone and buprenorphine/naloxone are the recommended first-line treatment options for OUD in Canada. Most studies to date have been conducted among heroin users, in controlled settings, and using similar strict dosing schedules (i.e., daily witnessed ingestion) despite buprenorphine/naloxone's superior safety profile, which allows a more flexible take-home dosing schedule. This study was designed to assess the relative effectiveness of buprenorphine/naloxone- and methadone-based models of opioid agonist therapy (OAT) for the treatment of prescription opioid use disorder (POUD) in routine clinical care. METHODS: OPTIMA is a multicenter, open-label, pragmatic, randomized, two-arm, non-inferiority, 24-week study comparing the relative effectiveness of buprenorphine/naloxone (provided via flexible take-home doses) to methadone (provided via daily witnessed ingestion) models of OAT for the treatment of POUD. Approximately 276 non-pregnant adults meeting DSM-5 criteria for OUD, currently not in OAT, will be randomized across 7 Canadian sites. The primary outcome is reduction of non-medical opioid use, measured by bi weekly urine drug screens during the 24-week study period. Secondary outcomes include treatment retention and satisfaction, safety, medication adherence, and patient engagement. DISCUSSION: The OPTIMA study is the first randomized clinical trial to compare the relative effectiveness of buprenorphine/naloxone (flexible take-home doses) versus methadone (daily witnessed ingestion) models of OAT for POUD in real-world clinical settings. This study will generate urgently needed evidence towards treatment options to guide the health system response to the ongoing opioid crisis. CLINICAL TRIAL REGISTRATION: NCT03033732. PMID- 29627622 TI - Investigating the role of ion-pair strategy in regulating nicotine release from patch: Mechanistic insights based on intermolecular interaction and mobility of pressure sensitive adhesive. AB - The aim of this study was to prepare a drug-in-adhesive patch of nicotine (NIC) and use ion-pair strategy to regulate drug delivery rate. Moreover, the mechanism of how ion-pair strategy regulated drug release was elucidated at molecular level. Formulation factors including pressure sensitive adhesives (PSAs), drug loading and counter ions (C4, C6, C8, C10, and C12) were screened. In vitro release experiment and in vitro transdermal experiment were conducted to determine the rate-limiting step in drug delivery process. FT-IR and molecular modeling were used to characterize the interaction between drug and PSA. Thermal analysis and rheology study were conducted to investigate the mobility variation of PSA. The optimized patch prepared with NIC-C8 had the transdermal profile fairly close to that of the commercial product (p > 0.05). The release rate constants (k) of NIC, NIC-C4 and NIC-C10 were 21.1, 14.4 and 32.4, respectively. Different release rates of NIC ion-pair complexes were attributed to the dual effect of ion-pair strategy on drug release. On one hand, ion-pair strategy enhanced the interaction between drug and PSA, which inhibited drug release. On the other hand, using ion-pair strategy improved the mobility of PSA, which facilitated drug release. Drug release behavior was determined by combined effect of two aspects above. These conclusions provided a new idea for us to regulate drug release behavior from patch. PMID- 29627623 TI - Encapsulation of trans-aconitic acid in mucoadhesive microspheres prolongs the anti-inflammatory effect in LPS-induced acute arthritis. AB - trans-Aconitic acid (TAA) is the main constituent of the leaves from the medicinal plant Echinodorus grandiflorus, used to treat different inflammatory diseases. TAA induces a potent but short-lasting biological response, credited to its high polarity and unfavorable pharmacokinetics. Here we developed, characterized and evaluated the anti-inflammatory activity of mucoadhesive microspheres loaded with TAA. Seven batches of mucoadhesive microspheres were prepared by the emulsification/solvent evaporation method, employing different proportions of TAA and Carbopol 934 or/and hydroxypropylmethylcellulose. All batches were characterized for their particle medium size, polydispersity index and entrapment percentage. The batch coded F3c showed highest entrapment percentage and was characterized by infrared spectroscopy (ATR-FTIR), scanning electron microscopy (SEM), differential scanning calorimetry (DSC), thermogravimetric analyses (TGA) and zeta potential. The anti-inflammatory activity of F3c was assessed in a model of acute arthritis induced by injection of LPS in the knee joint of Swiss mice. The granulometric analyses indicated heterogeneous size distribution for F3c. SEM characterization indicated microspheres with slightly irregular shape and rough surface. Results from ATR FTIR and thermal analyses (DSC and TGA) pointed out absence of incompatibility between the components of the formulation; thermal events related to the constituents were isolated and randomly located, suggesting amorphous distribution of TAA in the formulation matrix. The zeta potential of the formulations varied from -30 to -34 mV, which may contribute to good stability. When given orally to mice, F3c induced a prolonged anti-inflammatory response by reducing total cell count and neutrophilic accumulation in the joint cavity even when given 48 and 36 h before the stimulus, respectively, in comparison to free TAA (up to 24 and 6 h, respectively). Therefore, the encapsulation of TAA in mucoadhesive microspheres provided its sustained release, indicating that this drug delivery system is a potential agent to treat inflammatory diseases by regulating cell influx. PMID- 29627624 TI - Cryopreservation and egg yolk medium alter the proteome of ram spermatozoa. AB - : Cryopreservation causes significant lethal and sub-lethal damage to spermatozoa. In order to improve freezing outcomes, a comprehensive understanding of sub-lethal damage is required. Cryopreservation induced changes to sperm proteins have been investigated in several species, but few have employed currently available state of the art, data independent acquisition mass spectrometry (MS) methods. We used the SWATH LC-MS method to quantitatively profile proteomic changes to ram spermatozoa following exposure to egg yolk and cryopreservation. Egg yolk contributed 15 proteins to spermatozoa, including vitellogenins, apolipoproteins and complement component C3. Cryopreservation significantly altered the abundance of 51 proteins. Overall, 27 proteins increased (e.g. SERPINB1, FER) and 24 proteins decreased (e.g. CCT subunits, CSNK1G2, TOM1L1) in frozen thawed ram spermatozoa, compared to fresh spermatozoa. Chaperones constituted 20% of the proteins lost from spermatozoa following cryopreservation. These alterations may interfere with both normal cellular functioning and the ability of frozen thawed spermatozoa to appropriately respond to stress. This is the first study to apply SWATH mass spectrometry techniques to characterise proteins contributed by egg yolk based freezing media and to profile cryopreservation induced proteomic changes to ram spermatozoa. SIGNIFICANCE: This study profiles changes to the sperm proteome induced by exposure to egg yolk based media and the process of cryopreservation, and the biological consequences are discussed. PMID- 29627625 TI - The depressed central carbon and energy metabolisms is associated to the acquisition of levofloxacin resistance in Vibrio alginolyticus. AB - : The overuse and misuse of antibiotics lead to bacterial antibiotic resistance, challenging human health and intensive cultivation. It is especially required to understand for the mechanism of antibiotic resistance to control antibiotic resistant pathogens. The present study characterized the differential proteome of levofloxacin-resistant Vibrio alginolyticus with the most advanced iTRAQ quantitative proteomics technology. A total of 160 proteins of differential abundance were identified, where 70 were decreased and 90 were increased. Further analysis demonstrated that crucial metabolic pathways like TCA cycle were significantly down-regulated. qRT-PCR analysis demonstrated the decreased gene expression of glycolysis/gluconeogenesis, the TCA cycle, and fatty acid biosynthesis. Moreover, Na(+)-NQR complex gene expression, membrane potential and the adenylate energy charge ratio were decreased, indicating that the decreased central carbon metabolism is associated to the acquisition of levofloxacin resistance. Therefore, the reduced central carbon and energy metabolisms form a characteristic feature as fitness costs of V. alginolyticus in resistance to levofloxacin. BIOLOGICAL SIGNIFICANCE: The overuse and misuse of antibiotics lead to bacterial antibiotic resistance, challenging human health and intensive cultivation. Understanding for the antibiotic resistance mechanisms is especially required to control these antibiotic-resistant pathogens. The present study characterized the differential proteome of levofloxacin-resistant Vibrio alginolyticus using the most advanced iTRAQ quantitative proteomics technology. A total of 160 differential abundance of proteins were identified with 70 decreases and 90 increases by liquid chromatography matrix assisted laser desorption ionization mass spectrometry. Most interestingly, crucial metabolic pathways such as the TCA cycle sharply fluctuated. This is the first report that the reduced central carbon and energy metabolisms form a characteristic feature as a mechanism of V. alginolyticus in resistance to levofloxacin. PMID- 29627626 TI - The establishment of methods for free PAR generation and PAR reader detection. AB - Poly (ADP-ribose) polymerase 1 (PARP1) is a DNA damage sensor that catalyzes the poly (ADP-ribose) (PAR) onto a variety of target proteins, such as histones, DSB repair factors and PARP1 itself under consumption of NAD+. Besides, PARP1 can affect a variety of proteins in noncovalent modification manner to carry out specific cellular functions. Here, we established a method to generate non radiolabeled free PAR by PARG moderately cleaving PAR from autoPARylated PARP1, and utilized dot-blot assay to determine the interaction between free PAR and interested proteins. The methods to generate free PAR and detect the noncovalent interactions between proteins and free PAR are nonradioactive and convenient, which will facilitate the studies to explore the significance of PAR reading in various biological processes. PMID- 29627627 TI - Postoperative Posterior Ischemic Optic Neuropathy After Left Far-Lateral Craniectomy for Resection of Craniocervical Meningioma. AB - BACKGROUND: Postoperative posterior ischemic optic neuropathy (PION) is a rare cause of postoperative vision loss, most often seen when surgical patients are placed in the prone position for a prolonged period of time. We report a case of bilateral PION after far-lateral craniectomy in the lateral position. CASE DESCRIPTION: A 36-year-old man presented with a history of right extremity numbness, weakness, and muscle atrophy, and a craniocervical meningioma was diagnosed. Surgery in the lateral position lasted 9 hours, 52 minutes; the patient had 2 L of blood loss. On postoperative day 1, the patient had bilateral vision loss, which prompted further work-up. Diffusion-weighted imaging of the orbits demonstrated restricted diffusion within the bilateral optic nerves. The clinical presentation of painless vision loss after surgery with these imaging findings led to a diagnosis of PION. At the time of discharge, he had not recovered any visual function. CONCLUSIONS: This case suggests that PION can occur in the lateral position where there is no direct pressure on the orbits. PION is often not discussed as a potential complication during the preoperative consent process. This case suggests it may be prudent to discuss PION in similar neurosurgical cases. Intraoperative blood transfusion should be considered in prolonged surgeries in the lateral position, where slow blood loss over a long period could be a contributing factor to development of PION. PMID- 29627628 TI - Early Administration of Hypertonic-Hyperoncotic Hydroxyethyl Starch (HyperHES) Improves Cerebral Blood Flow and Outcome After Experimental Subarachnoid Hemorrhage in Rats. AB - OBJECTIVE: Early cytotoxic brain edema may be a decisive factor that maintains cerebral malperfusion after subarachnoid hemorrhage (SAH). In addition, endothelial cell swelling may be an independent factor restricting cerebral blood flow (CBF) in a very early stage after SAH. Immediate and aggressive treatment may be able to restore CBF in this critical period. METHODS: Male Sprague-Dawley rats were subjected to SAH by the endovascular filament model and treated by a bolus of hyperoncotic-hypertonic hydroxyethyl starch (4 mL/kg body weight) immediately after vessel perforation and 150 minutes later (n = 12) or by the same amount of normal saline (n = 9). Mean arterial blood pressure, intracranial pressure, and local CBF over both hemispheres were continuously measured by laser Doppler flowmetry. Neurologic assessment was performed 24 hours later. Hippocampal damage was assessed by hematoxylin-eosin and Caspase-3 staining. RESULTS: Arterial blood gases and mean arterial blood pressure were not significantly different between the 2 groups. Intracranial pressure was significantly reduced in the treatment group (P < 0.05). Local CBF was significantly improved in the treatment group over both hemispheres (P < 0.05; 180 minutes after treatment, P < 0.01). There was a trend to better neurologic performance in the treatment group. The rate of injured neurons was significantly reduced in animals of the treatment group compared with controls (P < 0.01). The number of Caspase-3-positive neurons in the hippocampal CA1 field was not reduced. CONCLUSIONS: In this study, the effects of very early and repeated treatment with a high-dose hyperoncotic-hypertonic hydroxyethyl starch were investigated. The results of this series show that this therapy can be highly effective to improve CBF and attenuate hippocampal cell damage in the early stage of SAH. Whether delayed cell death could be treated by longer therapy cannot be answered by this study. Because no differential diagnosis of the clinical suspicion of SAH prohibits the administration of hypertonic-hyperoncotic solutions, it may be useful as a first-tier preclinical therapy in suspected SAH and could even be used by emergency rescue services before the patient is admitted to a hospital. PMID- 29627629 TI - Hybrid Constructs for Performing Three-level Hybrid Surgery: A Finite Element Study. AB - OBJECTIVE: To systematically investigate the effect of 3-level hybrid constructs on the cervical spine biomechanics based on a validated model of the C3-C7 segments. METHODS: Three hybrid constructs with 2 U-shaped dynamic cervical implants and 1 cage were simulated. The 3 constructs were 1) Cage-U-U (cage implanted at the C3-C4 level and U-shaped dynamic cervical implants implanted at the C4-C5 and C5-C6 levels), 2) U-Cage-U, and 3) U-U-Cage. Biomechanical parameters including moments, cervical motions, and stresses in the facet and implants were analyzed in flexion and extension. RESULTS: The flexion and extension motions at artificial cervical disc replacement levels increased for all hybrid constructs when compared with those of intact model. However, the maximum increase was 52% with U-U-Cage model. At the unoperated adjacent level, the maximum motion increase in extension was 23% with the U-U-Cage model. Also, the U-U-Cage and U-Cage-U model generated more than 40% increase in terms of flexion motion at the adjacent level. The facet stress at the adjacent level increased by 28%, 20%, and 39% with the Cage-U-U, U-Cage-U, and U-U-Cage models, respectively. The moments required to reach the same motion as the intact model were significantly increased. CONCLUSIONS: The study showed that the U-U-Cage model lead to more compensation in terms of motion and facet stress. Furthermore, the present results imply that when conducting the hybrid surgery, the segmental motions should be taken into account. Performing anterior cervical discectomy and fusion at the level whose motion is relatively small may decrease the compensation required at the adjacent level. PMID- 29627630 TI - Awake Intradural Spinal Tumor Resection; Case Report and Literature Review. AB - BACKGROUND: Meningioma is a common slow-growing spinal tumor with a predilection for intradural occurrence. Patients usually present with pain followed by ataxia and sensory and sphincter problems. The gold standard treatment in these cases is gross total microsurgical resection under general anesthesia. However, there exist high-anesthetic-risk patients unsuitable for general anesthesia. Performing spinal surgeries under local anesthesia and sedation has been reported, albeit rarely for mostly minimally invasive procedures but not for open intradural pathologies. CASE DESCRIPTION: We report a 63-year-old woman with critical aortic stenosis, coronary artery disease, and severe chronic obstructive airways disease who presented with 10 months' history of worsening back pain and bilateral leg pain, ataxia, hyperreflexia in lower limbs, as well as altered lower limb sensation. Magnetic resonance imaging revealed a contrast-enhancing intradural lesion at T6/7 with severe spinal cord compression. However, the patient was American Society of Anesthesiologists class IV and her cardiac disease was not amenable to intervention. She underwent thoracic laminectomy and excision of the tumor under local anesthesia and sedation with no significant complications and clinical improvement. CONCLUSION: Our illustrative case and literature review suggest that using local anesthesia and sedation to perform spinal surgeries including intradural tumors is possible even in high-risk patients with good outcome. Our American Society of Anesthesiologists class IV patient tolerated the surgery well with gross total tumor resection and subsequent resolution of the symptoms. PMID- 29627631 TI - Lumbar Disc Herniations Causing Contralateral Radicular Symptoms: Can They Be Explained by Hypotenusal Theory? AB - OBJECTIVE: Cases presenting contralateral radicular symptoms are rarely encountered. It is difficult to decide on the correct side in cases where surgical intervention will be performed. The aim of the study is to explain the symptomatology in cases of lumbar disc herniations causing contralateral radicular symptoms by a hypotenusal effect. MATERIALS AND METHODS: In total, 27 cases were included in the study. Eight cases underwent surgical interventions performed on the side where disc herniation was radiologically detected. Nineteen cases were treated conservatively. Disc herniations were radiologically evaluated in 3 different groups, and the effect on the root on the symptomatic side was explained by a hypotenusal theory. Correlations among symptomatology, clinical findings, magnetic resonance imaging, and electromyography were discussed. RESULTS: Clinical improvement was observed in all cases that were operated on the side where disc herniation was detected radiologically. Neurologic examination findings in the postoperative period also revealed the correctness of the selected surgical approach. Electromyography is insufficient to explain clinical findings and to decide on the surgical side. CONCLUSION: Lumbar disc herniations, which lead to contralateral radicular symptoms, should be operated from the side where the disc is radiologically detected. The top of the disc is responsible for symptomatology. Surgical excision of the top of the disc removes the contralateral root traction and root compression on the same side. PMID- 29627632 TI - Giant Sacral Schwannoma Treated with a 360 Approach: A Rare Case and Systematic Review of the Literature. AB - BACKGROUND: Sacral schwannomas are very rare and typically have a benign nature. They occur in a permissive anatomical location leading to nonspecific symptoms that can result in them going unnoticed before reaching a considerable size. CASE DESCRIPTION: We report a rare case of a giant sacral schwannoma (130 * 110 * 90 mm) in a 38-year-old man originating from the S2 nerve root, encompassing the neural canal with sacral erosion and extension in to the pelvis. The patient presented with a history of abdominal pain associated with increased urinary frequency and a sensation of incomplete bladder emptying. Magnetic resonance imaging demonstrated a giant pelvic mass with sacral erosion and involvement of the nerve roots. Subsequently, he went on to have a 2-stage procedure in which complete resection of the schwannoma was achieved by both a posterior hemilaminectomy and laparotomy with the aid of neuromonitoring. The postoperative course was uneventful, with complete resolution of symptoms. CONCLUSIONS: We report one of the largest benign sacral schwannoma originating inside the spinal canal with pelvic extension to be resected without complications. We discuss our successful management and conduct a systematic review of the literature to provide the most up to date guidance on managing this tumor, including the application of neuromonitoring and a 360 approach in 2 stages. PMID- 29627633 TI - Development of fertility programs to achieve high 21-day pregnancy rates in high producing dairy cows. AB - Our objective is to overview the research that lead to the development of fertility programs for high-producing lactating dairy cows using only GnRH and Prostaglandin F2alpha (PGF2alpha), such as Ovsynch with a focus on the role of progesterone in fertility. A key factor affecting fertility to timed-AI is the response to each hormonal treatment of the Ovsynch protocol. Although not required for fertility, cows ovulating to the first GnRH treatment of the Ovsynch protocol (G1) have greater P/AI than cows failing to ovulate. The association between progesterone concentrations at each treatment during the Ovsynch protocol and fertility is reviewed, and data from 7792 cows from 14 studies are presented. Overall, medium P4 (between 0.5 and 6 ng/mL) at G1, high P4 concentrations (>1.0 ng/mL) at the PGF2alpha, and low P4 concentrations (<0.4 ng/mL) at final GnRH (G2) are associated with greater P/AI. The use of presynchronization treatments that increase the percentage of cows initiating the Ovsynch protocol during early diestrous increases the percentage of cows with medium P4 concentrations at G1 and with high P4 concentration at PGF2alpha. Some cows, however, fail to completely undergo luteal regression after a single PGF2alpha treatment, particularly cows that initiate the Ovsynch protocol in a low P4 environment and cows with a young (d 6) CL at the time of treatment with PGF2alpha. Addition of a second PGF2alpha treatment increased the percentage of cows with complete luteal regression and P/AI. The use of fertility programs that include the concepts described in this review have resulted in more P/AI than inseminating cows after an induced estrus at first insemination. In addition, extending these concepts to strategies for resynchronization of ovulation and the implementation of an aggressive reproductive management program for first and subsequent inseminations results in reproductive performance that is unprecedented for high-producing Holstein dairy cows. PMID- 29627634 TI - E-cigarette- specific symptoms of nicotine dependence among Texas adolescents. AB - INTRODUCTION: The potential of e-cigarettes to elicit symptoms of nicotine dependence has not been adequately studied, particularly in adolescent populations. The present study examined the prevalence of e-cigarette-specific symptoms of nicotine dependence ("symptoms of e-cigarette dependence") and the associations between these symptoms, e-cigarette usage group, and e-cigarette cessation-related items among Texas adolescents. METHODS: This study involved a cross-sectional analysis of adolescents from Wave 4 of the Texas Adolescent Tobacco and Marketing Surveillance System (TATAMS) (n = 2891/N = 461,069). Chi Square analyses examined differences in the prevalence of symptoms of dependence by e-cigarette usage group (exclusive versus dual users of e-cigarettes and combustible tobacco products) and demographic characteristics. Weighted multivariable logistic regression analyses examined the associations between symptoms of e-cigarette dependence, e-cigarette usage group, and e-cigarette cessation items. RESULTS: Exclusive e-cigarette users experienced symptoms of e cigarette dependence, although the prevalence of most of the symptoms was higher for dual users. Adolescents who reported more symptoms of dependence were less likely to report both wanting to quit e-cigarettes and a past-year quit attempt for e-cigarettes (adjusted odds ratio "AOR" = 0.61 (95% CI = 0.41, 0.92) and AOR = 0.52 (95% CI = 0.30, 0.92), respectively). CONCLUSIONS: This study is the first to demonstrate that adolescent e-cigarette users are experiencing symptoms of dependence specific to e-cigarettes. In addition, symptoms of dependence may be barriers to e-cigarette cessation. Future research is needed to determine if characteristics of e-cigarette use (e.g. frequency and intensity) are associated with dependence. PMID- 29627635 TI - The psychometric properties of the Persian version of the metacognitions about Smoking Questionnaire among smokers. AB - OBJECTIVES: It has been shown that smoking may be affected by metacognitions. This study aimed to evaluate the factor structure, reliability and validity of the Persian version of the Metacognitions about Smoking Questionnaire (MSQ) among a sample of Iranian male smokers. METHODS: When the English to Persian translation of the MSQ was performed, exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) were completed according to the four-factor solution of the original MSQ. Three hundred male treatment-seeking smokers (mean age = 41.37, SD = 15.90) filled out the Persian-translated version of the MSQ, the Smoking Effects Questionnaire (SEQ), and the Nicotine Dependence Syndrome Scale (NDSS). RESULTS: The results of EFA revealed that the Persian version of the MSQ had a four-factor structure named positive metacognitions about cognitive regulation (PM-CR), positive metacognitions about emotional regulation (PM-ER), negative metacognitions about uncontrollability (NM-U), and negative metacognitions about cognitive interference (NM-CI). The findings of CFA also indicated that the four-factor structure of the Persian version of the MSQ had appropriate fit. Validity and reliability of the Persian version of the MSQ were found to be good. Negative metacognitions about smoking predicted nicotine dependence over and above smoking outcome expectancies. Positive metacognitions about emotion regulation explained daily cigarette use independent of smoking outcome expectancies. CONCLUSIONS: The findings suggested that the Persian version of the MSQ had adequate psychometric properties among Iranian male treatment-seeking smokers. PMID- 29627636 TI - The association between e-cigarette use characteristics and combustible cigarette consumption and dependence symptoms: Results from a national longitudinal study. AB - BACKGROUND: Existing longitudinal surveys focused on the association between ever use of e-cigarettes and combustible cigarette consumption, making it difficult to infer what characteristics of e-cigarette use could potentially change combustible cigarette use behavior, which may have long-term health consequences. Although e-cigarettes' efficacy of alleviating dependence symptoms was supported by studies conducted in laboratory settings, whether the results can be translated into symptom reduction in the real world and over time is an open question. METHODS: This study conducted secondary analysis on the Waves 1-2 data of the Population Assessment of Tobacco and Health (PATH) Study to examine the association between e-cigarette use characteristics (frequency, flavoring, and voltage adjustment) and combustible cigarette use outcomes (frequency, quantity, and symptoms), using the Heckman 2-step selection procedure with the selection bias controlled. The inclusion criteria ensured that we followed an adult cohort of exclusive combustible cigarette users at Wave 1. RESULTS: The result shows that higher frequency of e-cigarette use was associated with lower combustible cigarette consumption and dependence symptoms, controlling for the corresponding baseline cigarette use variable and other confounders. Given the frequency of e cigarette use, the feature of voltage adjustment was not significantly associated with any of the cigarette use outcomes. Flavoring, on the other hand, was associated with lower quantity of cigarette use. CONCLUSIONS: Exclusive smokers who start using e-cigarettes do indeed change the frequency and quantity with which they smoke cigarettes. E-cigarette use may also help reduce dependence symptoms. PMID- 29627637 TI - Determination and pharmacokinetic study of guaiol in rat plasma by gas chromatography-mass spectrometry with selected ion monitoring. AB - Guaiol has been used for thousands of years as a traditional Uygur medicine and is the primary active component found in Ferula ferulaeoides (Steud.) Korov (F. ferulaeoides). In our present study, a rapid, selective, and sensitive method of monitoring selected ions was established based on gas chromatography-mass spectrometry. This method was optimized for the quantification and pharmacokinetic analysis of guaiol in rat plasma following oral administration of chloroform extract from Ferula ferulaeoides. Plasma was extracted using liquid liquid extraction with ethyl acetate and was analyzed on a HP-5MS column (30 m * 250 MUm * 0.25 MUm) with a mass selective detector. Detection was carried out under selected ion monitoring mode, and three selected ion monitoring ions (m/z 59.1, 107.1, and 161.1 for guaiol) were used for the quantitative determination of that under investigation. The assay demonstrated excellent linearity in the range of 1-200 ng/mL (r = 0.9993, n = 8) in the case of guaiol measured in rat plasma. The limit of detection and the limit of quantification for guaiol in rat plasma were found to be 0.25 ng/mL and 1 ng/mL, respectively. Intra-day and inter day precisions were expressed as the relative standard deviation for the method and were in the range of 97.49%-106.16% and 97.04%-105.91%, respectively. Extraction efficiencies were all determined to be >90%, and recoveries were ranged from 91.25% to 96.24%. This method has been successfully applied for the pharmacokinetic evaluation of chloroform extract isolated from F. ferulaeoides following a single oral administration dose (157.5 mg/kg) in rats. The guaiol pharmacokinetic study demonstrated that the half-life of guaiol was 9.18 +/- 3.75 h, the mean residence time was 9.07 +/- 3.86 h, the maximum guaiol concentration in the plasma was 28.63 +/- 6.82 ng/mL, and the maximum time guaiol was in the plasma was 0.50 h. PMID- 29627638 TI - The utility of ultra-high performance supercritical fluid chromatography-tandem mass spectrometry (UHPSFC-MS/MS) for clinically relevant steroid analysis. AB - Liquid chromatography tandem mass spectrometry (LC-MS/MS) assays are considered the reference standard for serum steroid hormone analyses, while full urinary steroid profiles are only achievable by gas chromatography (GC-MS). Both LC-MS/MS and GC-MS have well documented strengths and limitations. Recently, commercial ultra-high performance supercritical fluid chromatography-tandem mass spectrometry (UHPSFC-MS/MS) systems have been developed. These systems combine the resolution of GC with the high-throughput capabilities of UHPLC. Uptake of this new technology into research and clinical labs has been slow, possibly due to the perceived increase in complexity. Here we therefore present fundamental principles of UHPSFC-MS/MS and the likely applications for this technology in the clinical research setting, while commenting on potential hurdles based on our experience to date. PMID- 29627639 TI - Comment and correct to the paper "Arrival of carbapenem-hydrolyzing-oxacillinases in" Acinetobacter baumannii "in Bosnia and Herzegovina". PMID- 29627640 TI - Genetic variants, structural, and functional changes of Myelin Protein Zero and Mannose-Binding Lectin 2 protein involved in immune response and its allelic transmission in families of patients with leprosy in Colombia. AB - Leprosy is a chronic infectious disease caused by Mycobacterium leprae. Genetic factors associated with immune response contribute to infection development and disease. M. leprae has the capacity to invade Schwann cells in the peripheral nervous system and cause neuropathy. However, while the responsible molecular mechanisms remain to be fully unveiled, they have begun being elucidated. We studied genetic variants Myelin Protein Zero (MPZ), a major structural component of the myelin sheath, and Mannose Binding Lectin 2 (MBL2), a protein involved in immune response, in 112 family groups of 114 leprosy patients using PCR-RFLP, aiming to calculate the association and allelic transmission of variants associated in first, second and third-degree relatives. Polymorphisms found in MPZ and MBL2 showed association with leprosy. Different probabilities for allelic transmission were found for first and second-degree relatives, a fact that is important to take into account when evaluating risk in contacts of leprosy patients. Structural analysis allows the study of putative amino acids and their possible effect on protein structure and function, as well as on the assembly of a protein homotetramer. Our results suggest that the identified MPZ and MBL2 gene mutations are associated with leprosy in a Colombian population, which correlates with MPZ and MBL2 protein function, and increase the risk of M. leprae infection in leprosy-patients' family members. Additionally, structural analyses were carried out specifically for MPZ protein using information available in databases, and analyzing the substitutions in wildtype and mutant protein. The results show significant structural changes, which may be associated to infection and pathogenicity. PMID- 29627641 TI - Occiput-axis crossing translaminar screw fixation technique using offset connectors: An in vitro biomechanical study. AB - OBJECTIVE: Fixation with the axis vertebra (C2) using pedicle screws is commonly used to treat an unstable occipitocervical junction; however, it is accompanied by a risk of vertebral artery injury. The occiput-C2 (OC2) crossing translaminar screw fixation technique may avoid this risk, but rod implantation is difficult. Offset connectors can help facilitate this construct. This study aimed to evaluate the stability of a technique for OC2 crossing translaminar screw fixation using offset connectors (C2LAM + OF) in comparison with other methods. PATIENTS AND METHODS: Six fresh-frozen human cadaveric occipital-cervical spines were tested intact under flexion, extension, lateral bending, and axial rotation. These were then made into a type II odontoid fracture model, instrumented with an occipital plate, and tested in the following modes: C2 bilateral pedicle screws (C2P), a single C2 pedicle screw and bilateral C3 lateral mass screws (C2P + C3M), C2 crossing translaminar screws (C2LAM), and C2LAM + OF. The OC2 range of motion (ROM) for each construct was obtained and compared using a repeated measures analysis. RESULTS: The ROM of the C2LAM + OF construct was found not to be significantly different from that of the C2P and C2P + C3M fixations in every direction (p > 0.05). However, the C2LAM + OF construct was superior to the C2LAM construct in axial rotation (p < 0.05). CONCLUSIONS: OC2 crossing translaminar screw fixation using offset connectors offers similar stability to C2 pedicle screw fixation and is an effective alternative method for treating an unstable occipitocervical junction. PMID- 29627642 TI - A prognostic role for Low tri-iodothyronine syndrome in acute stroke patients: A systematic review and meta-analysis. AB - BACKGROUND: Low triiodothyronine (T3) syndrome could be a powerful prognostic factor for acute stroke; yet, a prognostic role for low T3 has not been given enough importance in stroke management. This meta-analysis aimed to evaluate whether low T3 among acute stroke patients could be used as a prognostic biomarker for stroke severity, functional outcome, and mortality. METHODS: Studies that investigated low T3 prognostic roles in acute stroke patients were sought from PubMed/Medline, Embase, and Cochrane databases through 11/23/2016. Pooled estimates of baseline stroke severity, mortality, and functional outcomes were assessed from fixed-effect (FE) and random-effects (RE) models. RESULTS: Eighteen studies met the inclusion criteria. Six studies (1,203 patients) provided data for low-T3 and normal-T3 patients and were meta-analyzed. Using the FE model, pooled results revealed low-T3 patients exhibited a significantly higher stroke severity, as assessed by the National Institutes of Health Stroke Scale (NIHSS) score at admission (mean difference = 3.18; 95%CI = 2.74, 3.63; I2 = 61.9%), had 57% higher risk of developing poor functional outcome (RR = 1.57; 95%CI = 1.33,1.8), and had 83% higher odds of mortality (Peto-OR = 1.83; 95%CI = 1.21, 1.99) compared to normal-T3 patients. In a univariate meta-regression analysis, the low-T3 and stroke severity association was reduced in studies with higher smokers% (slope = -0.11; P = 0.02), higher hypertension% (slope = -0.11; P = 0.047), older age (slope = -0.54; P = 0.02), or longer follow-up (slope = 0/17, P < 0.01). RE models yielded similar results. No significant publication bias was observed for either outcome using Begg's and Egger's tests. CONCLUSIONS: Low-T3 syndrome in acute stroke patients is an effective prognostic factor for predicting greater baseline stroke severity, poorer functional outcome, and higher overall mortality risk. PMID- 29627643 TI - Contribution of alcohol radicals to contaminant degradation in quenching studies of persulfate activation process. AB - Alcohols such as ethanol (EtOH) and tert-butanol (TBA) are frequently used as quenching agents to identify the primary radical species in the persulfate (PS) based oxidation processes. However, the contribution of alcohol radicals (ARs) to contaminant degradation in this process has rarely been assessed. In this study, trichloroacetic acid (TCA), phenol, and carbon tetrachloride were selected as probes to test the role of ARs in the thermally activated PS system. It was found that the degradation rates of these compounds were largely depended on their reactivities with ARs and the concentration of dissolved oxygen in the reaction system. In the PS/alcohol system, TCA was degraded efficiently under anaerobic conditions, while it was hardly degraded in the presence of oxygen. The results of electron paramagnetic resonance, reducing radical quenching studies, and the analysis of PS consumption suggested that ARs were the dominant reactive species contributing to TCA degradation in the PS/EtOH system under anaerobic conditions. Further studies indicated that ARs could significantly degrade CCl4 through dechlorination but not phenol. CCl4 was also degraded efficiently by ARs when oxygen in the reaction solution was completely consumed by ARs. This study highlights the important role of alcohol radicals in the degradation of contaminants during quenching studies in PS-activated processes. PMID- 29627644 TI - Characteristics of competitive uptake between Microcystin-LR and natural organic matter (NOM) fractions using strongly basic anion exchange resins. AB - Microcystins are the most commonly occurring cyanotoxins, and have been extensively studied across the globe. In the present study, a strongly basic anion exchange resin was employed to investigate the removal of Microcystin-LR (MCLR), one of the most toxic microcystin variants. Factors influencing the uptake behavior included the MCLR and resin concentrations, resin dosage, and natural organic matter (NOM) characteristics, specifically, the charge density and molecular weight distribution of source water NOM. Equivalent background concentration (EBC) was employed to evaluate the competitive uptake between NOM and MCLR. The experimental data were compared with different mathematical and physical models and pore diffusion was determined as the rate-limiting step. The resin dose/solute concentration ratio played a key role in the MCLR uptake process and MCLR removal was attributed primarily to electrostatic attractions. Charge density and molecular weight distribution of the background NOM fractions played a major role in MCLR removal at lower resin dosages (200 mg/L ~ 1 mL/L and below), where a competitive uptake was observed due to the limited exchange sites. Further, evidences of pore blockage and site reduction were also observed in the presence of humics and larger molecular weight organic fractions, where a four-fold reduction in the MCLR uptake was observed. Comparable results were obtained for laboratory studies on synthetic laboratory water and surface water under similar conditions. Given their excellent performance and low cost, anion exchange resins are expected to present promising potentials for applications involving the removal of removal of algal toxins and NOM from surface waters. PMID- 29627645 TI - Silver nanoclusters-assisted ion-exchange reaction with CdTe quantum dots for photoelectrochemical detection of adenosine by target-triggering multiple-cycle amplification strategy. AB - Herein, we successfully devised a novel photoelectrochemical (PEC) platform for ultrasensitive detection of adenosine by target-triggering cascade multiple cycle amplification based on the silver nanoparticles-assisted ion-exchange reaction with CdTe quantum dots (QDs). In the presence of target adenosine, DNA s1 is released from the aptamer and then hybridizes with hairpin DNA (HP1), which could initiate the cycling cleavage process under the reaction of nicking endonuclease. Then the product (DNA b) of cycle I could act as the "DNA trigger" of cycle II to further generate a large number of DNA s1, which again go back to cycle I, thus a cascade multiple DNA cycle amplification was carried out to produce abundant DNA c. These DNA c fragments with the cytosine (C)-rich loop were captured by magnetic beads, and numerous silver nanoclusters (Ag NCs) were synthesized by AgNO3 and sodium borohydride. The dissolved AgNCs released numerous silver ions which could induce ion exchange reaction with the CdTe QDs, thus resulting in greatly amplified change of photocurrent for target detection. The detection linear range for adenosine was 1.0 fM ~10 nM with the detection limit of 0.5 fM. The present PEC strategy combining cascade multiple DNA cycle amplification and AgNCs-induced ion-exchange reaction with QDs provides new insight into rapid, and ultrasensitive PEC detection of different biomolecules, which showed great potential for detecting trace amounts in bioanalysis and clinical biomedicine. PMID- 29627646 TI - Effective treatment of oily scum via catalytic wet persulfate oxidation process activated by Fe2. AB - Oily scum, a hazardous by-product of petroleum industry, need to be deposed urgently to reduce environmental risks. This paper introduces catalytic wet persulfate oxidation (CWPO) process in the treatment of oily scum to realize risk relief. Under the activation of heat and Fe2+, persulfate (PS) was decomposed into sulfate radicals and hydroxyl radicals, which played a major role on the degradation of petroleum hydrocarbons. The effects of wet air oxidation (WAO) and CWPO process on the degradation of oily scum were compared. In CWPO process, the total petroleum hydrocarbons (TPHs) content of oily scum was decreased from 92.63% to 16.75%, which was still up to 70.19% in WAO process. The degradation rate of TPHs in CWPO process was about 3.38 times higher than that in WAO process. The great performance of CWPO process was also confirmed by elemental analysis, which indicated that the C and H contents of oily scum were reduced significantly by CWPO process. These results indicated that CWPO process has high potential on the degradation of oily scum for environmental protection. PMID- 29627647 TI - Improving biogas production from anaerobic co-digestion of Thickened Waste Activated Sludge (TWAS) and fat, oil and grease (FOG) using a dual-stage hyper thermophilic/thermophilic semi-continuous reactor. AB - This paper investigates the feasibility and advantages of using a dual-stage hyper-thermophilic/thermophilic semi-continuous reactor system for the co digestion of Thickened Waste Activated Sludge (TWAS) and Fat, Oil and Grease (FOG) to produce biogas in high quantity and quality. The performance of the dual stage hyper-thermophilic (70 degrees C)/thermophilic (55 degrees C) anaerobic co digestion system is evaluated and compared to the performance of a single-stage thermophilic (55 degrees C) reactor that was used to co-digest the same FOG-TWAS mixtures. Both co-digestion reactors were compared to a control reactor (the control reactor was a single-stage thermophilic reactor that only digested TWAS). The effect of FOG% in the co-digestion mixture (based on total volatile solids) and the reactor hydraulic retention time (HRT) on the biogas/methane production and the reactors' performance were thoroughly investigated. The FOG% that led to the maximum methane yield with a stable reactor performance was determined for both reactors. The maximum FOG% obtained for the single-stage thermophilic reactor at 15 days HRT was found to be 65%. This 65% FOG resulted in 88.3% higher methane yield compared to the control reactor. However, the dual-stage hyper thermophilic/thermophilic co-digestion reactor proved to be more efficient than the single-stage thermophilic co-digestion reactor, as it was able to digest up to 70% FOG with a stable reactor performance. The 70% FOG in the co-digestion mixture resulted in 148.2% higher methane yield compared to the control at 15 days HRT. 70% FOG (based on total volatile solids) is so far the highest FOG% that has been proved to be useful and safe for semi-continuous reactor application in the open literature. Finally, the dual-stage hyper thermophilic/thermophilic co-digestion reactor also proved to be efficient and stable in co-digesting 40% FOG mixtures at lower HRTs (i.e., 9 and 12 days) and still produce high methane yields and Class A effluents. PMID- 29627648 TI - Questioning triple rice intensification on the Vietnamese mekong delta floodplains: An environmental and economic analysis of current land-use trends and alternatives. AB - Large areas of the Vietnamese Mekong Delta floodplains (VMDF) are protected by high dikes to facilitate three rice crops per year. While this has increased rice production, there is evidence that triple rice systems have negative long-term effects, both environmental and economic. Double rice cropping, or other alternatives, may be more advantageous. We analyzed the costs and benefits of intensive rice systems over time and compared these with alternatives farming systems, based on data collected via field surveys and interviews with farmers in two provinces in the VMDF. Results show that farmers in areas with dikes high enough for triple rice production incurred rising production costs over time. Production costs were 58%-91% higher in high-dike, triple crop areas, than in low dike double rice crop areas. Higher production costs are mainly the result of increased fertilizer and pesticide use. Profitability of triple rice farming systems was initially 57% more compared to double crop systems. After about 15 years, however, triple rice farmers earned only 6% more than double crop counterparts. Our results indicate that alternative farming systems, such as rice combined with vegetables, fisheries or other flood-based livelihood, could offer greater benefits than intensive rice monocultures. Importantly, these higher benefits can be obtained without the environmental costs and impact currently endured across the delta with triple rice cultivation in high dikes. PMID- 29627649 TI - Metal removal from solution using readily available inorganic reactive materials. AB - This research evaluated using inorganic adsorbents for removal of metals from solution. Batch experiments were carried out to determine the effects of adsorbent dosage, initial metal concentration and agitation time on metal removal. The results showed increasing metal ion removal with increasing adsorbent dosage, metal concentration and agitation time. Removal efficiencies of Al3+ and Mn2+ were reported at above 99% and 98%. Kinetic studies showed that the three adsorbents data on both Al3+ and Mn2+ removal were pertaining to pseudo first-order and second-order kinetics and had a good fit to Elovich indicating that the adsorption rate-limiting step could be inferred as chemical sorption. PMID- 29627650 TI - Performance of an under-loaded denitrifying bioreactor with biochar amendment. AB - Denitrifying bioreactors are recently-established agricultural best management practices with growing acceptance in the US Midwest but less studied in other agriculturally significant regions, such as the US Mid-Atlantic. A bioreactor was installed in the Virginia Coastal Plain to evaluate performance in this geographically novel region facing challenges managing nutrient pollution. The 25.3 m3 woodchip bed amended with 10% biochar (v/v) intercepted subsurface drainage from 6.5 ha cultivated in soy. Influent and effluent nitrate-nitrogen (NO3-N) and total phosphorus (TP) concentrations and flowrate were monitored intensively during the second year of operation. Bed surface fluxes of greenhouse gases (GHGs) nitrous oxide (N2O), methane (CH4), and carbon dioxide (CO2) were measured periodically with the closed dynamic chamber technique. The bioreactor did not have a statistically or environmentally significant effect on TP export. Cumulative NO3-N removal efficiency (9.5%) and average removal rate (0.56 +/- 0.25 g m-3 d-1) were low relative to Midwest tile bioreactors, but comparable to installations in the Maryland Coastal Plain. Underperformance was attributed mainly to low NO3-N loading (mean 9.4 +/- 4.4 kg ha-1 yr-1), although intermittent flow, periods of low HRT, and low pH (mean 5.3) also likely contributed. N removal rates were correlated with influent NO3-N concentration and temperature, but decreased with hydraulic residence time, indicating that removal was often N-limited. GHG emissions were similar to other bioreactors and constructed wetlands and not considered environmentally concerning. This study suggests that expectations of NO3-N removal efficiency developed from bioreactors receiving moderate to high NO3-N loading with influent concentrations exceeding 10-20 mg L-1 are unlikely to be met by systems where N-limitation becomes significant. PMID- 29627651 TI - Integral process assessment of sugarcane agricultural crop residues conversion to ethanol. AB - This work focuses a whole process assessment on post-harvesting sugarcane residues for 2G ethanol production by different saccharification-fermentation conditions at high solids loading, performed after steam explosion, alkaline and acidic pretreatments. Carbohydrate recoveries and enzymatic digestibility results showed that alkali and steam explosion pretreatments were effective for the biomass assayed. Due to a significant improvement (60%) of the glucose released by combining hemicellulases and cellulases only after the NaOH pretreatment, the most favorable process settled comprised an alkali-based pretreatment followed by a pre-saccharification and simultaneous saccharification and fermentation (PSSF). The produced ethanol reached 4.8% (w/w) as a result of an 80% conversion of the glucose from the pretreated biomass. Finally, an ethanol concentration of 3.2% (w/w) was obtained by means of a steam explosion followed by PSSF, representing a suitable start point to further develop a low environmental impact alternative for ethanol production. PMID- 29627652 TI - An integrated membrane bioreactor system with iron-dosing and side-stream co fermentation for enhanced nutrient removal and recovery: System performance and microbial community analysis. AB - An integrated membrane bioreactor (MBR) system was developed for enhanced nutrient (N and P) removal and effective P recovery in wastewater treatment. The system consisted of an iron-dosing MBR and side-stream fermentation for P removal and recovery and side-stream denitrification for N removal. Around 98.1% of the total phosphorus (TP) in wastewater was removed by ferric iron-induced precipitation and membrane filtration in the aerobic MBR, and nearly 53.4% of the TP could be recovered via anaerobic fermentation from the MBR sludge. In addition, the fermenter that allowed acidogenic co-fermentation with food waste provided sufficient soluble organics for biological denitrification, and an overall 91.8% total N removal was achieved through the side-stream denitrification. High-throughput sequencing was applied to analyse the microbial communities in the integrated system, and important functional bacteria were identified for nitrification, denitrification, acidogenic fermentation and dissimilatory iron reduction through the different components of the system. PMID- 29627653 TI - The mechanism of enhanced wastewater nitrogen removal by photo-sequencing batch reactors based on comprehensive analysis of system dynamics within a cycle. AB - To understand the mechanism of enhanced nitrogen removal by photo-sequencing batch reactors (photo-SBRs), which incorporated microalgal photosynthetic oxygenation into the aerobic phases of a conventional cycle, this study performed comprehensive analysis of one-cycle dynamics. Under a low aeration intensity (about 0.02 vvm), a photo-SBR, illuminated with light at 92.27 MU.mol.m-2.s-1, could remove 99.45% COD, 99.93% NH4+-N, 90.39% TN, and 95.17% TP, while the control SBR could only remove 98.36% COD, 83.51% NH4+-N, 78.96% TN, and 97.75% TP, for a synthetic domestic sewage. The specific oxygen production rate (SOPR) of microalgae in the photo-SBR could reach 6.63 fmol O2.cell-1.h-1. One-cycle dynamics shows that the enhanced nitrogen removal by photo-SBRs is related to photosynthetic oxygenation, resulting in strengthened nitrification, instead of direct nutrient uptake by microalgae. A too high light or aeration intensity could deteriorate anoxic conditions and thus adversely affect the removal of TN and TP in photo-SBRs. PMID- 29627654 TI - Synthesis, biological evaluation and molecular docking studies of aminochalcone derivatives as potential anticancer agents by targeting tubulin colchicine binding site. AB - A series of aminochalcone derivatives have been synthesized, characterized by HRMS, 1H NMR and 13C NMR and evaluated for their antiproliferative activity against HepG2 and HCT116 human cancer cell lines. The most of new synthesized compounds displayed moderate to potent antiproliferative activity against test cancer cell lines. Among the derivatives, compound 4 displayed potent inhibitory activity with IC50 values ranged from 0.018 to 5.33 MUM against all tested cancer cell lines including drug resistant HCT-8/T. Furthermore, this compound showed low cytotoxicity on normal human cell lines (LO2). The in vitro tubulin polymerization assay showed that compound 4 inhibited tubulin assembly in a concentration-dependent manner with IC50 value of 7.1 MUM, when compared to standard colchicine (IC50 = 9.0 MUM). Further biological evaluations revealed that compound 4 was able to arrest the cell cycle in G2/M phase. Molecular docking study demonstrated the interaction of compound 4 at the colchicine binding site of tubulin. All the results indicated that compound 4 is a promising inhibitor of tubulin polymerization for the treatment of cancer. PMID- 29627655 TI - New advances in synthesis and clinical aspects of pyrazolo[3,4-d]pyrimidine scaffolds. AB - Pyrazolo[3,4-d]pyrimidine ring system constitute an important class of heterocyclic compounds which can serve as a promising scaffold exhibiting many pharmacological activities. This ring system received much attention as it is a purine isostere by replacing imidazole ring in purine with pyrazole moiety in pyrazolo[3,4-d]pyrimidine. Here we concentrate on new advances in the synthesis of this important ring and other clinical aspects in an attempt to sheld the light to assist in discovery of new pyrazolo[3,4-d]pyrimidine derivatives. PMID- 29627656 TI - Design, synthesis and evaluation of some pyrazolo[3,4-d]pyrimidines as anti inflammatory agents. AB - New pyrazolo[3,4-d]pyrimidines substituted with various functionalities or attached to a substituted pyrazole ring through different linkages were synthesized. The synthesized compounds were evaluated for their anti-inflammatory activity using in vitro COX-1/COX-2 inhibition assay and in vivo formalin induced paw edema and cotton pellet-induced granuloma assays. Results revealed that compounds 17b and 18 possessed COX-1/COX-2 selectivity indices higher than diclofenac sodium and celecoxib. However, compounds 16a,b exhibited selectivity indices higher than diclofenac sodium and nearly equivalent to celecoxib, whereas, 9b displayed selectivity index comparable to diclofenac sodium. In vivo anti-inflammatory data showed that compounds 9b, 16a, 18 displayed anti inflammatory activity higher than both references in the formalin induced paw edema model. On the other hand, the pyrazolyl derivatives 9b, 16b and 17b displayed anti-inflammatory activity about 2-2.5-fold that of diclofenac sodium and nearly 8-10.5-fold that of celecoxib in the cotton pellet-induced granuloma assay. The ulcerogenic effect of the active compounds was also investigated and results revealed that compounds 16a, 17a,b and 18 showed good gastrointestinal safety profile. Based on this, compounds 16a and 18 were considered as safe and effective leads in managing acute inflammation, while, 17b was prominent in controlling chronic inflammation. PMID- 29627657 TI - Design, synthesis and in vitro evaluation of beta-glucuronidase-sensitive prodrug of 5-aminolevulinic acid for photodiagnosis of breast cancer cells. AB - Treatment of cancer cells by clinically approved hexyl ester of 5-aminolevulinic acid (ALA-Hex) induces accumulation of fluorescent porphyrins in tumors. This allows fluorescence photodiagnosis (PD) of bladder cancer by blue light illumination. However, PD of other cancers is hampered by acute toxicity of the compound limiting its use to local applications. We have designed and synthesized a new prodrug of ALA-Hex that tackles the stability-activity paradox of amino modified 5-ALA prodrugs. The glucuronide prodrug Glu-ALA-Hex demonstrates excellent stability under physiological conditions and activation in the presence of the target enzyme. beta-glucuronidase-triggered release of 5-ALA is programmed to yield fluorescence in tumor environment with elevated beta-glucuronidase activity, a characteristic of many solid tumors. Glu-ALA-Hex produces similar levels of fluorescence as ALA-Hex in breast cancer MCF7 cells in vitro but with much lower non-specific cell toxicity. PMID- 29627658 TI - Routine chest X-ray is unnecessary after ultrasound-guided central venous line placement in the operating room. AB - BACKGROUND: Central venous catheters (CVC) can be useful for perioperative monitoring and insertion has low complication rates. However, routine post insertion chest X-rays have become standard of care and contribute to health care costs with limited impact on patient management. METHODS: 200 patient charts who underwent pancreaticoduodenectomy with central line placement and early line removal were reviewed for clinical complications related to central line placement as well as radiographic evidence of malpositioning. A cost analysis was performed to estimate savings if CXR had not been performed across routine surgical procedures requiring central access. RESULTS: In 200 central line placements for Whipple procedures, 198 lines were placed in the right internal jugular and 2 were placed in the subclavian. No cases of pneumothorax or hemothorax were identified and 30 (15.3%) of CVCs were improperly positioned. Only 1 (0.5%) of these was deemed clinically significant and repositioned after the CXR was performed. CONCLUSION: Routine CXR consumes valuable time and resources (?$155,000 annually) and rarely affects management. Selection should be guided by clinical factors. PMID- 29627659 TI - Management of Amanita phalloides poisoning: A literature review and update. AB - Amanita phalloides poisoning with a high mortality is a serious health problem in the world. The typical clinical manifestations are usually characterized by the absence of any symptoms followed by severe gastrointestinal disorders and acute liver failure. Inhibition of RNA polymeraseII (RNAP II) activity, apoptosis, and oxidative stress are considered as the major mechanism of amatoxins intoxication. The current treatment measures mainly include prevention of amatoxins absorption, elimination of absorbed amatoxins, potential antidotes therapy, and liver transplantation. Nevertheless, there are no widely accepted treatment criteria for Amanita phalloides poisoning. This paper will focus on the treatment measures based on the previous studies and provide the currently available information for clinicians. PMID- 29627660 TI - Variation in mortality rates after admission to long-term acute care hospitals for ventilator weaning. AB - PURPOSE: We sought to examine variation in long-term acute care hospital (LTACH) quality based on 90-day in-hospital mortality for patients admitted for weaning from mechanical ventilation. METHODS: We developed an administrative risk adjustment model using data from Medicare claims. We validated the administrative model against a clinical model using data from LTACHs participating in a 2002 to 2003 clinical registry. We then used our validated administrative model to assess national variation in 90-day in-hospital mortality rates in LTACHs from 2013. RESULTS: The administrative risk-adjustment model was derived using data from 9447 patients admitted to 221 LTACHs in 2003. The model had good discrimination (C statistic=0.72) and calibration. Compared to a clinically derived model using data from 1163 patients admitted to 14 LTACHs, the administrative model generated similar performance estimates. National variation in risk-adjusted mortality was assessed using data from 20,453 patients admitted to 380 LTACHs in 2013. LTACH specific risk-adjusted mortality rates varied from 8.4% to 48.1% (median: 24.2%, interquartile range: 19.7%-30.7%). CONCLUSIONS: LTACHs vary widely in mortality rates, underscoring the need to better understand the sources of this variation and improve the quality of care for patients requiring long-term ventilator weaning. PMID- 29627661 TI - Effect of temperature on chlorine dioxide inactivation of Escherichia coli O157:H7, Salmonella typhimurium, and Listeria monocytogenes on spinach, tomatoes, stainless steel, and glass surfaces. AB - The objective of this study was to evaluate how treatment temperature influences the solubility of ClO2 gas and the antimicrobial effect of ClO2 gas against Escherichia coli O157:H7, Salmonella Typhimurium, and Listeria monocytogenes on produce and food contact surfaces. Produce and food contact surfaces inoculated with a combined culture cocktail of three strains each of the three foodborne pathogens were processed in a treatment chamber with 20 ppmv ClO2 gas at 15 or 25 degrees C under the same conditions of absolute humidity (11.2-12.3 g/m3) for up to 30 min. As treatment time increased, ClO2 gas treatment at 15 degrees C caused significantly more (p < 0.05) inactivation of the three pathogens than treatment at 25 degrees C. ClO2 gas treatment at 25 degrees C for 30 min resulted in 1.15 to 1.54, 1.53 to 1.88, and 1.00 to 1.78 log reductions of the three pathogens on spinach leaves, tomatoes, and stainless steel No.4, respectively. ClO2 gas treatment at 15 degrees C for 30 min caused 2.53 to 2.88, 2.82 to 3.23, and 2.37 to 3.03 log reductions of the three pathogens on spinach leaves, tomatoes, and stainless steel No.4, respectively. Treatment with ClO2 gas at 25 degrees C for 20 min resulted in 1.88 to 2.31 log reductions of the three pathogens on glass while >5.91 to 6.82 log reductions of these pathogens occurred after 20 min when treated at 15 degrees C. Residual ClO2 levels after gas treatment at 15 degrees C were significantly (p < 0.05) higher than those at 25 degrees C. The results of this study can help the food processing industry establish optimum ClO2 gas treatment conditions for maximizing the antimicrobial efficacy of ClO2 gas. PMID- 29627662 TI - Follow-up of fetuses with congenital diaphragmatic hernia: The quantitative lung index. AB - OBJECTIVE: To assess the longitudinal behavior of Quantitative Lung Index (QLI) for the follow-up of fetuses with congenital diaphragmatic hernia. STUDY DESIGN: Retrospective study of fetuses with isolated left congenital diaphragmatic hernia. The fetuses were assessed by ultrasound at different gestational ages and QLI was retrospectively calculated by means of previous lung-to-head ratio measurements. We used a random effects model (mixed model with repeated measurements) to compare the performance of the QLI in operated and non-operated fetuses throughout pregnancy. RESULTS: Fifty-eight cases of isolated left diaphragmatic hernia with complete follow-up were assessed in Hospital Universitari Vall d'Hebron in Barcelona (2003-2015). Thirty-eight of them were managed expectantly (non-TO) and the other 20 underwent tracheal occlusion (TO). All fetuses undergoing tracheal occlusion had lung-to-head ratio (LHR) <1, observed-to-expected LHR (o/eLHR) <=45%, QLI <0.6 and liver up inside the thorax. The survival rate was 87% for the non-TO group and 60% for the TO group (p = 0.02). The QLI remained constant throughout pregnancy in both groups. The QLI in the TO group had lower values than the non-TO group (p < 0.03). CONCLUSION: The quantitative lung index was constant during pregnancy. This index was lower in fetuses undergoing tracheal occlusion but no significant changes were seen in its performance during pregnancy. PMID- 29627663 TI - A cluster phase analysis for collective behavior in team sports. AB - Collective behavior can be defined as the ability of humans to coordinate with others through a complex environment. Sports offer exquisite examples of this dynamic interplay, requiring decision making and other perceptual-cognitive skills to adjust individual decisions to the team self-organization and vice versa. Considering players of a team as periodic phase oscillators, synchrony analyses can be used to model the coordination of a team. Nonetheless, a main limitation of current models is that collective behavior is context independent. In other words, players on a team can be highly synchronized without this corresponding to a meaningful coordination dynamics relevant to the context of the game. Considering these issues, the aim of this study was to develop a method of analysis sensitive to the context for evidence-based measures of collective behavior. PMID- 29627665 TI - Viability and membrane lipid composition under a 57mT static magnetic field in Salmonella Hadar. AB - The aim of this work is to demonstrate the effects of a static magnetic field (SMF) with an induction 12 equal to 57mT on the viability and membrane lipid composition of Salmonella Hadar. Results showed an increase in the viability of exposed bacteria compared to controls after 9h of exposure. Analysis with gas chromatography of total lipids (TLs) and different fractions of phospholipids: phosphatidylglycerols (PGs), phosphatidylethanolamines (PEs), and cardiolipins (CLs), separated by thin layer chromatography revealed changes in fatty acid levels during exposure. For TLs, the unsaturated fatty acids/saturated fatty acids ratio (UFAs/SFAs) had significantly increased after 9 h of exposure. The variation of this ratio seems to be essentially due to the increase of the proportion of unsaturated fatty acids with 18 carbons, in particular C18:1. The analyses of fatty acid composition carried out on the scale of each fraction of phospholipids showed that CLs contributed significantly to the increase of the proportion of the unsaturated fatty acids between 6 and 9h of exposure thanks to their unsaturated chains with 18 carbons (especially C18:2). CLs appear to be the main phospholipid involved in the adaptation of S. Hadar membranes to the SMF. PMID- 29627664 TI - The second phase of bipolar, nanosecond-range electric pulses determines the electroporation efficiency. AB - Bipolar cancellation refers to a phenomenon when applying a second electric pulse reduces ("cancels") cell membrane damage by a preceding electric pulse of the opposite polarity. Bipolar cancellation is a reason why bipolar nanosecond electric pulses (nsEP) cause weaker electroporation than just a single unipolar phase of the same pulse. This study was undertaken to explore the dependence of bipolar cancellation on nsEP parameters, with emphasis on the amplitude ratio of two opposite polarity phases of a bipolar pulse. Individual cells (CHO, U937, or adult mouse ventricular cardiomyocytes (VCM)) were exposed to either uni- or bipolar trapezoidal nsEP, or to nanosecond electric field oscillations (NEFO). The membrane injury was evaluated by time-lapse confocal imaging of the uptake of propidium (Pr) or YO-PRO-1 (YP) dyes and by phosphatidylserine (PS) externalization. Within studied limits, bipolar cancellation showed little or no dependence on the electric field intensity, pulse repetition rate, chosen endpoint, or cell type. However, cancellation could increase for larger pulse numbers and/or for longer pulses. The sole most critical parameter which determines bipolar cancellation was the phase ratio: maximum cancellation was observed with the 2nd phase of about 50% of the first one, whereas a larger 2nd phase could add a damaging effect of its own. "Swapping" the two phases, i.e., delivering the smaller phase before the larger one, reduced or eliminated cancellation. These findings are discussed in the context of hypothetical mechanisms of bipolar cancellation and electroporation by nsEP. PMID- 29627666 TI - An impedimetric biosensor for DNA damage detection and study of the protective effect of deferoxamine against DNA damage. AB - The detection and inhibition of DNA damage are of great importance in the prevention and treatment of diseases. Developing a simple and sensitive tool for this purpose would be a chance to monitor the DNA damage and could be helpful in introducing some drugs which can prevent this phenomenon. Here, we report a novel and sensitive electrochemical biosensor based on DNA/Au nanoparticles (AuNPs) modified screen printed gold electrode (DNA/AuNPs/SPGE) to investigate the DNA damage process and also to study the protective behavior of deferoxamine (DFO). The proposed biosensor was fabricated by electrodeposition of AuNPs onto SPGE, followed by chemical immobilisation of thiol-terminated DNA. Cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS) and scanning electron microscopy (SEM) have been used to characterise this biosensor. Hydroxyl radical (OH), which is generated during the Fenton reaction, is responsible for the induced damage to DNA. EIS technique was applied to monitor the DNA damage, and the increase in charge transfer resistance (Rct) following the DNA damage, was considered as an indicator. Furthermore, the ability of the electrochemical screening system was proved by the investigation of the antioxidant effect of DFO in prohibiting the DNA damage. PMID- 29627667 TI - Electrochemical study of acetaminophen oxidation by gold nanoparticles supported on a leaf-like zeolitic imidazolate framework. AB - Decoration of leaf-like zeolitic imidazolate framework (ZIF-L) with Au nanoparticles (NPs) by a simple self-assembly method was described in this work. The materials were characterized by Fourier transform infrared spectroscopy, energy-dispersive X-ray spectra, N2 adsorption, and thermogravimetric analysis. Acetaminophen (AP) is most commonly referred to as an over-the-counter antipyretic and analgesic, which is a key factor in relieving fever and pain. It is particular significant to take efforts and conduct research for the development of reliable methods to detect the AP. An electrochemical sensor for AP was constructed based on the Au/ZIF-L, which exhibited excellent electrocatalytic activity for the oxidation of AP with the catalytic rate constant (kcat) of 4.27 * 104 M-1 s-1 and diffusion coefficient (D) of of 8.31 * 10-5 cm2 s-1. Importantly, Au/ZIF-L was developed as an effective sensing platform for the detection of AP, which showed high analytical performance, such as a linear range of 3.50 MUM-0.056 mM with sensitivity of 37.28 MUA mM-1, a linear range of 0.056-0.56 mM with sensitivity of 25.10 MUA mM-1, and a low limit of detection of 1.02 MUM. The successfully fabricated Au/ZIF-L device can be used to accurately measure the amount of AP in pharmaceutical samples. Results implied the potential application of functionalized MOF composite materials in the field of electrocatalysis, making it particularly suitable for electroanalytical chemistry. PMID- 29627668 TI - Ag-Ag3VO4/AgIO3 composites with enhanced visible-light-driven catalytic activity. AB - Ag-Ag3VO4/AgIO3 composites composed of Ag-Ag3VO4 particles (major component) and AgIO3 nanosheets (minor component) were obtained via photoreduction of Ag3VO4/AgIO3 composites prepared by sequential precipitation. The optimal Ag Ag3VO4/AgIO3 catalysts (in particular, the one with an AgIO3/Ag3VO4 mass ratio of 6.4%) were found to be more active than AgIO3, Ag3VO4, and Ag-Ag3VO4 in the photocatalytic degradation of rhodamine B (RhB), methylene blue (MB), methyl orange (MO), and tetracycline hydrochloride (TC) under visible-light irradiation. Ag-Ag3VO4/AgIO3 can be reused in cycling experiments. Photogenerated holes (h+) and superoxide radical anions (O2-) were demonstrated by radical-capture experiments as the main active species in the photocatalytic degradation of RhB. The more efficient separation and transfer of photogenerated electron-hole pairs are responsible for the enhanced activity of Ag-Ag3VO4/AgIO3. A possible photocatalytic mechanism is proposed. PMID- 29627669 TI - Enhanced catalytic activity of the nanostructured Co-W-B film catalysts for hydrogen evolution from the hydrolysis of ammonia borane. AB - In this work, nanostructured Co-W-B films are successfully synthesized on the foam sponge by electroless plating method and employed as the catalysts with enhanced catalytic activity towards hydrogen evolution from the hydrolysis of ammonia borane (NH3BH3, AB) at room temperature. The particle size of the as prepared Co-W-B film catalysts is varied by adjusting the depositional pH value to identify the most suitable particle size for hydrogen evolution of AB hydrolysis. The Co-W-B film catalyst with the particle size of about 67.3 nm shows the highest catalytic activity and can reach a hydrogen generation rate of 3327.7 mL min-1 gcat-1 at 298 K. The activation energy of the hydrolysis reaction of AB is determined to be 32.2 kJ mol-1. Remarkably, the as-obtained Co-W-B film is also a reusable catalyst preserving 78.4% of their initial catalytic activity even after 5 cycles in hydrolysis of AB at room temperature. Thus, the enhanced catalytic activity illustrates that the Co-W-B film is a promising catalyst for AB hydrolytic dehydrogenation in fuel cells and the related fields. PMID- 29627670 TI - Characteristics of binary WO3@CuO and ternary WO3@PDA@CuO based on impressive sensing acetone odor. AB - A series of biomimetic electronic nose nanomaterials of WO3, WO3@PDA, WO3@PDA@CuO, WO3@CuO and CuO were prepared by a facile method and their microstructures, surface chemical composition and sensing ability for acetone odor were investigated systematically by a variety of technologies. The WO3@PDA@CuO and WO3@CuO particles are in nano-sized shape, about 20 nm. The sensing ability to different concentrations acetone odor (50, 100 and 200 ppm) is addressed. The effect of different sensitivity definitions (Rg/Ra or |Ra - Rg|/Ra * 100%) on the comparison of experiment results is discussed. The WO3@CuO sensing material shows the best sensing performance of all the sensors, being independent of concentration or sensitivity definitions. These results provide novel insights into the design and preparation of composite electronic nose sensing nanomaterials. PMID- 29627671 TI - One-pot synthesis of ceria and cerium phosphate (CeO2-CePO4) nanorod composites for selective catalytic reduction of NO with NH3: Active sites and reaction mechanism. AB - In this work, novel (CeO2)x-(CePO4)1-x (defined as CexP1-x) nanorod composites were prepared by a simple co-precipitation method, and the influence of CeO2 on the catalytic performance of CePO4 for selective catalytic reduction of NO by NH3 (NH3-SCR of NO) was investigated. The catalytic performance evaluation revealed that the CexP1-x catalysts, especially Ce0.2P0.8 exhibited a much better catalytic activity and H2O + SO2 resistance than CePO4. Structure characterizations via high-resolution transmission electron microscope (HRTEM) and Brunauer-Emmett-Teller (BET) revealed that the introduction of CeO2 had a little effect on the shape of CePO4 nanorods and it could promote the formation of new mesoporous then significantly enhance the surface area of catalyst. The analysis results of active sites suggested that phosphorus was the main adsorption site for NH3 and the redox sites were controlled by CeO2 on CexP1-x catalysts. Finally, reaction process study demonstrated that the NH3-SCR over CexP1-x was processed via Langmuir-Hinshelwood (L-H) mechanism. Combining the results of active sites and reaction mechanism analysis, it was drawn that the superior low temperature activity of CexP1-x could be attributed to its excellent redox properties, which promoted the oxidation of NO then facilitated the process of NH3-SCR via "fast SCR". PMID- 29627672 TI - Cd resistant characterization of mutant strain irradiated by carbon-ion beam. AB - Heavy metal pollution is harmful to the environment and to human health. Resistant strains can grow in adverse conditions and store heavy metals to reduce their damage. The Cd2+ resistant mutant strain C2, which was irradiated by the 12C6+ beams, can grow in Cd medium ranging from 20 to 100 mg L-1 when compared with the original strain. Attempting to discern the cause of the resistance, the phenotype and antioxidant defense system were analyzed. SEM images showed that when exposed to Cd2+, gaps on the cell surface were filled with a complex granular compound. FT-IR demonstrated that the alcoholic hydroxyl group, amino, and amide groups combined with ions. Moreover, responses of antioxidant defense system were different in the Cd2+ groups. The expression of SOD peaked at 24 h in high concentrations of Cd2+; the content of GSH increased gradually and was significantly affected by cultivation time. The MDA and CAT had the strongest response to 20 mg L-1 Cd2+, and the related metabolic pathway of CAT might play a key role in the resistance to high concentrations of Cd2+. The result indicated that the applicability of C2 could provide potential biotechnology for treatment of wastewaters and soils with Cd pollutions. PMID- 29627673 TI - Efficient extraction of uranium from aqueous solution using an amino functionalized magnetic titanate nanotubes. AB - In this paper, titanate nanotubes/cobalt ferrite/tetraethylenepentamine (TNTs/CoFe2O4/TEPA) adsorbents were prepared for the adsorption of uranium (VI) from the solution. Its morphology was observed by transmission electron microscopy (TEM) and exhibited the uniform well tubular structure. TNTs/CoFe2O4/TEPA composites were easily separated from solution by an external magnetic field. The removal of uranium (VI) from aqueous solution (ppm level) and simulated seawater (ppb level) were investigated by the TNTs/CoFe2O4/TEPA composites. Batch adsorption experiments were conducted to determine the effect of varying pH, contact time, and reaction temperature. The best fit for uranium (VI) adsorption was obtained with the Langmuir model, and the highest adsorption of TNTs/CoFe2O4/TEPA composites reached 509.89 mg-U/g-adsorbent at pH 6. From an investigation of the adsorption by XRD, FTIR and XPS, it is suggested that the surface complexation and cation exchange were the main adsorption mechanism. In addition, TNTs/CoFe2O4/TEPA composites maintained good adsorption properties after five sorption-desorption cycles. Therefore, we conclude that the adsorbents are promising materials for the removal of uranium (VI) from aqueous solutions. PMID- 29627674 TI - Is it good to be too light? Birth weight thresholds in hospital reimbursement systems. AB - Birth weight manipulation has been documented in per-case hospital reimbursement systems, in which hospitals receive more money for otherwise equal newborns with birth weight just below compared to just above specific birth weight thresholds. As hospitals receive more money for cases with weight below the thresholds, having a (reported) weight below a threshold could benefit the newborn. Also, these reimbursement thresholds overlap with diagnostic thresholds that have been shown to affect the quantity and quality of care that newborns receive. Based on the universe of hospital births in Germany from the years 2005-2011, we investigate whether weight below reimbursement relevant thresholds triggers different quantity and quality of care. We find that this is not the case, suggesting that hospitals' financial incentives with respect to birth weight do not directly impact the care that newborns receive. PMID- 29627675 TI - The effect of workforce assignment on performance: Evidence from home health care. AB - Effective workforce assignment has the potential for improving performance. Using novel home health data combining provider work logs, personnel data, and detailed patient records, we estimate the effect of provider handoffs-a marker of care discontinuity-on hospital readmissions, an important performance measure for healthcare systems. We use workflow interruption caused by attrition and providers' work inactivity as an instrument for nurse handoffs. We find handoffs to substantially increase hospital readmissions. Our estimates imply that a single handoff increases the likelihood of 30-day hospital readmission by 16 percent and one in four hospitalizations during home health care would be avoided if handoffs were eliminated. Moreover, handoffs are more detrimental for high severity patients and expedite hospital readmission. The frequency and sequencing of handoffs also affect the likelihood of rehospitalization. PMID- 29627676 TI - Perceived attachment security to parents and peer victimization: Does adolescent's aggressive behaviour make a difference? AB - Peer victimization is one of the most prominent problems during adolescence. Research has distinguished aggressive and non-aggressive victims; however, there are still significant drawbacks in understanding the social and family functioning of these different groups of victimized adolescents. This study aimed to compare social behavior and perceived attachment security to parents of Portuguese adolescents, classified as aggressive victims, non-aggressive victims and non-victims. The sample consisted of 222 adolescents (115 boys, 107 girls) who completed the Kerns Security Scale and the Extended Class Play, to assess perceived attachment security and social behavior, respectively. Controlling for age and sex, aggressive victims and non-aggressive victims differed in anxious withdrawal but shared a similar profile in peer exclusion and prosocial behavior. Only aggressive victims reported lower attachment security to mother and father when compared to non-victims. These findings underline that victimized adolescents constitute a heterogeneous group in terms of their social and family functioning. PMID- 29627677 TI - Preparation of high bioactivity multilayered bone-marrow mesenchymal stem cell sheets for myocardial infarction using a 3D-dynamic system. AB - : Cell sheet techniques offer a promising future for myocardial infarction (MI) therapy; however, insufficient nutrition supply remains the major limitation in maintaining stem cell bioactivity in vitro. In order to enhance cell sheet mechanical strength and bioactivity, a decellularized porcine pericardium (DPP) scaffold was prepared by the phospholipase A2 method, and aspartic acid was used as a spacer arm to improve the vascular endothelial growth factor crosslink efficiency on the DPP scaffold. Based on this scaffold, multilayered bone marrow mesenchymal stem cell sheets were rapidly constructed, using RAD16-I peptide hydrogel as a temporary 3D scaffold, and cell sheets were cultured in either the 3D-dynamic system (DCcs) or the traditional static condition (SCcs). The multilayered structure, stem cell bioactivity, and ultrastructure of DCcs and SCcs were assessed. The DCcs exhibited lower apoptosis, lower differentiation, and an improved paracrine effect after a 48 h culture in vitro compared to the SCcs. Four groups were set to evaluate the cell sheet effect in rat MI model: sham group, MI control group, DCcs group, and SCcs group. The DCcs group improved cardiac function and decreased the infarcted area compared to the MI control group, while no significant improvements were observed in the SCcs group. Improved cell survival, angiogenesis, and Sca-1+ cell and c-kit+ cell amounts were observed in the DCcs group. In conclusion, the DCcs maintained higher stem cell bioactivity by using the 3D-dynamic system to provide sufficient nutrition, and transplanting DCcs significantly improved the cardiac function and angiogenesis. STATEMENT OF SIGNIFICANCE: This study provides an efficient method to prepare vascular endothelial growth factor covalent decellularized pericardium scaffold with aspartic acid, and a multilayered bone marrow mesenchymal stem cell (BMSC) sheet is constructed on it using a 3D-dynamic system. The dynamic nutrition supply showed a significant benefit on BMSC bioactivity in vitro, including decreasing cell apoptosis, reducing stem cell differentiation, and improving growth factor secretion. These favorable bioactivity improved BMSC survival, angiogenesis, and cardiac function of the infarcted myocardium. The study highlights the importance of dynamic nutrition supply on maintaining stem cell bioactivity within cell sheet, and it stresses the necessity and significance of setting a standard for assessing cell sheet products before transplantation in the future application. PMID- 29627678 TI - Multiscale analysis of bamboo deformation mechanisms following NaOH treatment using X-ray and correlative microscopy. AB - : For hundreds of years, bamboo has been employed for a variety of applications ranging from load-bearing structures to textiles. Thanks to its hierarchical structure that is functionally graded and naturally optimised, bamboo displays a variation in properties across its stem that ensures exceptional flexural performance. Often, alkaline solutions are employed for the treatment of bamboo in order to alter its natural elastic behaviour and make it suitable for particular applications. In this work we study the effect of NaOH solutions of five different concentrations (up to 25%) on the elastic properties of bamboo. By exploiting the capabilities of modern experimental techniques such as in situ synchrotron X-ray scattering and Digital Image Correlation, we present detailed analysis of the deformation mechanisms taking place in the main constituents of bamboo, i.e. fibres and matrix (Parenchyma). The principal achievement of this study is the elucidation of the deformation mechanisms at the fibre scale, where the relative sliding of fibrils plays a crucial role in the property modification of the whole bamboo stem. Furthermore, we shed light on the parenchyma toughness variation as a consequence of alkali treatments. STATEMENT OF SIGNIFICANCE: Alkaline solutions are often employed for the treatment of bamboo in order to alter its natural elastic behaviour. In this work we study the effect of alkaline solutions on the elastic properties of bamboo. Using state of the art experimental techniques allowed shedding light on the deformation mechanisms occurring in the bamboo main constituents, i.e. fibres and matrix (parenchyma cells). Enhancement of fibre stiffness was experienced when up to 20% NaOH solution was employed, while for higher concentration a decay was observed. This effect was imputed to the modification of adhesion between fibrils induced by disruption of ligand elements (e.g. lignin). Modification of the matrix toughness was also experienced, that indicated an improved resistance to cracking when the concentration of NaOH is 25%, while reduction of toughness was revealed for lower concentrations. PMID- 29627679 TI - Bone tissue engineering strategy based on the synergistic effects of silicon and strontium ions. AB - : Multipotent human bone marrow mesenchymal stem cells (hBMSCs) are commonly used as seed cells in bone tissue engineering, but their clinical application is limited due to two challenges. One is the expansion of hBMSCs without loss of the stemness, and the other is the stimulation of osteogenic differentiation of hBMSCs when combined with biomaterials. In this study we demonstrated an approach by firstly elucidating the functional effects and optimal concentrations of Si and Sr ions on the proliferation and osteogenic differentiation of hBMSCs, and then designing bioactive bioceramic/alginate hydrogels which could release Si and Sr bioactive ions in the same optimal concentrations range for activation of the cells in vivo. The results showed that Si and Sr ions could synergistically stimulate cell proliferation without losing the stemness. Furthermore, at higher concentrations, Si and Sr ions stimulated osteogenic differentiation instead of enhancing proliferation. The designed bioactive hydrogels revealed activity to stimulate not only the osteogenic differentiation of encapsulated hBMSCs, but also the blood vessel formation in vivo. These results suggested that the design of biomaterials based on the biological function of different material elements was an effective approach for bone tissue engineering applications. STATEMENT OF SIGNIFICANCE: The clinical application of multipotent human bone marrow mesenchymal stem cells (hBMSCs) in bone tissue engineering is limited due to two challenges. One is the expansion of cells without loss of the stemness, and the other is the stimulation of osteogenic differentiation of hBMSCs within the biomaterial scaffolds. Herein, we demonstrated an approach by firstly elucidating the functional effects and optimal concentrations of Si and Sr ions on the proliferation without losing stemness and osteogenic differentiation of hBMSCs, and then designing a bioactive bioceramic/alginate hydrogel which could release Si and Sr ions for in vivo activation of cells. The bioactive hydrogels revealed activity to stimulate not only osteogenic differentiation of encapsulated hBMSCs, but also the blood vessel formation in vivo. Our work provided an effective approach to design effective biomaterials for tissue engineering. PMID- 29627680 TI - Carbamazepine-loaded solid lipid nanoparticles and nanostructured lipid carriers: Physicochemical characterization and in vitro/in vivo evaluation. AB - Solid lipid nanoparticles (SLN) and nanostructured lipid carriers (NLC) represent promising alternatives for drug delivery to the central nervous system. In the present work, four different nanoformulations of the antiepileptic drug Carbamazepine (CBZ) were designed and prepared by the homogenization/ultrasonication method, with encapsulation efficiencies ranging from 82.8 to 93.8%. The formulations remained stable at 4 degrees C for at least 3 months. Physicochemical and microscopic characterization were performed by photon correlation spectroscopy (PCS), transmission electron microscopy (TEM), atomic force microscopy (AFM); thermal properties by differential scanning calorimetry (DSC), thermogravimetry (TGA) and X-ray diffraction analysis (XRD). The results indicated the presence of spherical shape nanoparticles with a mean particle diameter around 160 nm in a narrow size distribution; the entrapped CBZ displayed an amorphous state. The in vitro release profile of CBZ fitted into a Baker-Lonsdale model for spherical matrices and almost the 100% of the encapsulated drug was released in a controlled manner during the first 24 h. The apparent permeability of CBZ-loaded nanoparticles through a cell monolayer model was similar to that of the free drug. In vivo experiments in a mice model of seizure suggested protection by CBZ-NLC against seizures for at least 2 h after intraperitoneal administration. The developed CBZ-loaded lipid nanocarriers displayed optimal characteristics of size, shape and drug release and possibly represent a promising tool to improve the treatment of refractory epilepsy linked to efflux transporters upregulation. PMID- 29627681 TI - Role of self-emulsifying drug delivery systems in optimizing the oral delivery of hydrophilic macromolecules and reducing interindividual variability. AB - Self-emulsifying drug delivery systems (SEDDS) have been widely employed to improve the oral bioavailability of poorly soluble drugs. In the past few years, SEDDS were extensively investigated to overcome various barriers encountered in the oral delivery of hydrophilic macromolecules (e.g., protein/peptide therapeutics and plasmid DNA (pDNA)), as well as in lowering the effect of food on drugs' bioavailability. However, the main mechanism(s) by which SEDDS could achieve such promising effects remains not fully understood. This review summarizes the recent progress in the use of SEDDS for protecting protein therapeutics and/or pDNA against enzymatic degradation and increasing the oral bioavailability of various drug substances regardless of the dietary condition. Understanding the underlying mechanism(s) of such promising applications will aid in the future development of rationally designed SEDDS. Entrapment of hydrophilic macromolecules in the oil phase of the formed emulsion is critical for protection of the loaded cargoes against enzymatic degradation and the enhancement of oral bioavailability. On the other hand, drug administration as a preconcentrated solution in the SEDDS preconcentrate allows the process of drug absorption to occur independently of the dietary condition, and thus reducing interindividual variability that results from concomitant food intake. PMID- 29627682 TI - Electrically polarized PLLA nanofibers as neural tissue engineering scaffolds with improved neuritogenesis. AB - Tissue engineering is evolving towards the production of smart platforms exhibiting stimulatory cues to guide tissue regeneration. This work explores the benefits of electrical polarization to produce more efficient neural tissue engineering platforms. Poly (l-lactic) acid (PLLA)-based scaffolds were prepared as solvent cast films and electrospun aligned nanofibers, and electrically polarized by an in-lab built corona poling device. The characterization of the platforms by thermally stimulated depolarization currents reveals a polarization of 60 * 10-10C cm-2 that is stable on poled electrospun nanofibers for up to 6 months. Further in vitro studies using neuroblastoma cells reveals that platforms' polarization potentiates Retinoic Acid-induced neuronal differentiation. Additionally, in differentiating embryonic cortical neurons, poled aligned nanofibers further increased neurite outgrowth by 30% (+70 MUm) over non-poled aligned nanofibers, and by 50% (+100 MUm) over control conditions. Therefore, the synergy of topographical cues and electrical polarization of poled aligned nanofibers places them as promising biocompatible and bioactive platforms for neural tissue regeneration. Given their long lasting induced polarization, these PLLA poled nanofibrous scaffolds can be envisaged as therapeutic devices of long shelf life for neural repair applications. PMID- 29627683 TI - Blunted vocal affect and expression is not associated with schizophrenia: A computerized acoustic analysis of speech under ambiguous conditions. AB - INTRODUCTION: Patients with schizophrenia are consistently rated by clinicians as having high levels of blunted vocal affect and alogia. However, objective technologies have often failed to substantiate these abnormalities. It could be the case that negative symptoms are context-dependent. OBJECTIVES: The present study examined speech elicited under conditions demonstrated to exacerbate thought disorder. METHODS: The Rorschach Test was administered to 36 outpatients with schizophrenia and 25 nonpatient controls. Replies to separate "perceptual" and "memory" phases were analyzed using validated acoustic analytic methods. RESULTS: Compared to nonpatient controls, schizophrenia patients did not display abnormal speech expression on objective measure of blunted vocal affect or alogia. Moreover, clinical ratings of negative symptoms were not significantly correlated with objective measures. CONCLUSIONS: These findings suggest that in patients with schizophrenia, vocal affect/alogia is generally unremarkable under ambiguous conditions. Clarifying the nature of blunted vocal affect and alogia, and how objective measures correspond to what clinicians attend to when making clinical ratings are important directions for future research. PMID- 29627684 TI - Incorporating temperature effects in California's on-road emission gridding process for air quality model inputs. AB - On-road mobile sources play a significant role in air quality modeling and these models require gridded, hourly emission inputs. Due to its geographical and meteorological diversity and stringent air quality regulations, California state always poses big challenge for air quality modelers and policy makers. At the same time, the impact of ambient temperature on vehicle emissions has been well researched in the past few decades and it is vital to prepare a reliable on-road gridded emission inventory for air quality modeling. This technical paper introduces a gridding method that takes temperature impacts into account, calculates emissions from grid-level to county, and attempts to quantify the likely effects of such a bottom-up, temperature sensitive approach on a gridded on-road emission inventory. To provide confidence in the proposed SMOKE-EMFAC method, a detailed analysis was carried out to compare the results with the default EMFAC output, and the results were within +/-1%. Applying detailed grid level temperatures, we also found that criteria pollutant distributions are sensitive to them, and they are in accordance with previous US-EPA study. The proposed method could be very useful while testing different complex emission regulations and policies due to its inherent flexibility. PMID- 29627685 TI - Structural equation modeling of PAHs in ambient air, dust fall, soil, and cabbage in vegetable bases of Northern China. AB - A series of field samples including ambient air (gaseous and particulate phases), dust fall, surface soil, rhizosphere soil and cabbage tissues (leaf, root and core), were collected in vegetable bases near a large coking manufacturer in Shanxi Province, Northern China, during a harvest season. A factor analysis was employed to apportion the emission sources of polycyclic aromatic hydrocarbons (PAHs), and the statistical results indicated coal combustion was the dominant emission source that accounted for different environmental media and cabbage tissues, while road traffic, biomass burning and the coking industry contributed to a lesser extent. A structural equation model was first developed to quantitatively explore the transport pathways of PAHs from surrounding media to cabbage tissues. The modeling results showed that PAHs in ambient air were positively associated with those in dust fall, and a close relationship was also true for PAHs in dust fall and in surface soil due to air-soil exchange process. Furthermore, PAHs in surface soil were correlated with those in rhizosphere soil and in the cabbage leaf with the path coefficients of 0.83 and 0.39, respectively. PAHs in the cabbage leaf may dominantly contribute to the accumulation of PAHs in the edible part of cabbages. PMID- 29627686 TI - SiSSR: Simultaneous subdivision surface registration for the quantification of cardiac function from computed tomography in canines. AB - Recent improvements in cardiac computed tomography (CCT) allow for whole-heart functional studies to be acquired at low radiation dose (<2mSv) and high-temporal resolution (<100ms) in a single heart beat. Although the extraction of regional functional information from these images is of great clinical interest, there is a paucity of research into the quantification of regional function from CCT, contrasting with the large body of work in echocardiography and cardiac MR. Here we present the Simultaneous Subdivision Surface Registration (SiSSR) method: a fast, semi-automated image analysis pipeline for quantifying regional function from contrast-enhanced CCT. For each of thirteen adult male canines, we construct an anatomical reference mesh representing the left ventricular (LV) endocardium, obviating the need for a template mesh to be manually sculpted and initialized. We treat this generated mesh as a Loop subdivision surface, and adapt a technique previously described in the context of 3-D echocardiography to register these surfaces to the endocardium efficiently across all cardiac frames simultaneously. Although previous work performs the registration at a single resolution, we observe that subdivision surfaces naturally suggest a multiresolution approach, leading to faster convergence and avoiding local minima. We additionally make two notable changes to the cost function of the optimization, explicitly encouraging plausible biological motion and high mesh quality. Finally, we calculate an accepted functional metric for CCT from the registered surfaces, and compare our results to an alternate state-of-the-art CCT method. PMID- 29627687 TI - Joint solution for PET image segmentation, denoising, and partial volume correction. AB - Segmentation, denoising, and partial volume correction (PVC) are three major processes in the quantification of uptake regions in post-reconstruction PET images. These problems are conventionally addressed by independent steps. In this study, we hypothesize that these three processes are dependent; therefore, jointly solving them can provide optimal support for quantification of the PET images. To achieve this, we utilize interactions among these processes when designing solutions for each challenge. We also demonstrate that segmentation can help in denoising and PVC by locally constraining the smoothness and correction criteria. For denoising, we adapt generalized Anscombe transformation to Gaussianize the multiplicative noise followed by a new adaptive smoothing algorithm called regional mean denoising. For PVC, we propose a volume consistency-based iterative voxel-based correction algorithm in which denoised and delineated PET images guide the correction process during each iteration precisely. For PET image segmentation, we use affinity propagation (AP)-based iterative clustering method that helps the integration of PVC and denoising algorithms into the delineation process. Qualitative and quantitative results, obtained from phantoms, clinical, and pre-clinical data, show that the proposed framework provides an improved and joint solution for segmentation, denoising, and partial volume correction. PMID- 29627688 TI - Chemosensitizing effects of metformin on cisplatin- and paclitaxel-resistant ovarian cancer cell lines. AB - BACKGROUND: Epithelial ovarian cancer (EOC) remains the most lethal gynecologic malignancy. Primary cytoreductive surgery with adjuvant taxane-platinum chemotherapy is the standard treatment to fight ovarian cancer, however, their side effects are severe, and chemoresistance emerges at high rates. Therefore, EOC clinic urges for novel treatment strategies to reverse chemoresistance and to improve the survival rates. Metformin has been shown to act in synergy with certain anti-cancer agents, overcoming chemoresistance in various types of tumors. This paper aims to investigate the use of metformin as a new treatment option for cisplatin- and paclitaxel-resistant ovarian cancer. METHODS: The effects of metformin alone or in combination with conventional drugs on resistant EOC cell lines were investigated using the MTT assay for cell proliferation; Flow Cytometry analysis for cell cycle and the mRNA expression was analyzed using the real-time PCR technique. RESULTS: We found that metformin exhibited antiproliferative effects in paclitaxel-resistant A2780-PR, and in cisplatin resistant ACRP cell lines. The combined therapy containing conventional drugs and metformin improved the effect of the treatment in cell proliferation rate, especially in the resistant cells. We found that metformin, in clinical relevant doses, could significantly reduce the mRNA expression of inflammatory cytokines and NF-kappaB signaling pathway. CONCLUSIONS: Taken together, our observations suggest that metformin inhibits the inflammatory pathway induced by paclitaxel and cisplatin treatment. Furthermore, metformin in combination with paclitaxel or cisplatin improved the sensitivity in drug-resistant ovarian cancer cells. Therefore, metformin may be beneficial treatment strategy, particularly in patients with tumors refractory to platinum and taxanes. PMID- 29627689 TI - Slower nicotine metabolism among postmenopausal Polish smokers. AB - BACKGROUND: A non-invasive phenotypic indicator of the rate of nicotine metabolism is nicotine metabolite ratio (NMR) defined as a ratio of two major metabolites of nicotine - trans-3'-hydroxycotinine/cotinine. The rate of nicotine metabolism has important clinical implications for the likelihood of successful quitting with nicotine replacement therapy (NRT). We conducted a study to measure NMR among Polish smokers. METHODS: In a cross-sectional study of 180 daily cigarette smokers (42% men; average age 34.6+/-13.0), we collected spot urine samples and measured trans-3'-hydroxycotinine (3-HC) and cotinine levels with LC MS/MS method. We calculated NMR (molar ratio) and analyzed variations in NMR among groups of smokers. RESULTS: In the whole study group, an average NMR was 4.8 (IQR 3.4-7.3). The group of women below 51 years had significantly greater NMR compared to the rest of the population (6.4; IQR 4.1-8.8 vs. 4.3; IQR 2.8 6.4). No differences were found among group ages of male smokers. CONCLUSIONS: This is a first study to describe variations in nicotine metabolism among Polish smokers. Our findings indicate that young women metabolize nicotine faster than the rest of population. This finding is consistent with the known effects of estrogen to induce CYP2A6 activity. Young women may require higher doses of NRT or non-nicotine medications for most effective smoking cessation treatment. PMID- 29627690 TI - Kaempferol modulates Angiopoietin-like protein 2 expression to lessen the mastitis in mice. AB - BACKGROUND: Mastitis is inflammation of a breast (or udder). Angiopoietin-like protein 2 (ANGPTL2) has been found as a key inflammatory mediator in mastitis. Purpose of this research was to investigate the mechanisms about repressing effect of kaempferol on mastitis. METHODS: Forty mice were randomly divided into 4 groups (n=10): C57BL/6J control mice, untreated murine mastitis, 10mg/kg kaempferol treated murine mastitis (ip), and 30mg/kg kaempferol treated murine mastitis (ip). Primary cultured mouse mammary epithelial cells (MMEC) were indiscriminately divided into seven groups including control group, 10mmol/L vehicle of kaempferol group, 10MUmol/L kaempferol treated group, 20MUg/mL LPS treated group, 1MUmol/L kaempferol plus LPS treated group, 3MUmol/L kaempferol plus LPS treated group, and 10MUmol/L kaempferol plus LPS treated group. RESULTS: In murine mastitis, kaempferol (10 or 30mg/kg) treatment prevented mastitis development, decreased myeloperoxidase (MPO) production, interleukin (IL)-6 level, tumour necrosis factor-alpha (TNF-alpha) concentration, and ANGPTL2 expression. In MMEC, kaempferol (1, 3 or 10MUM) reduced MPO production, TNF-alpha concentration, IL-6 level, and ANGPTL2 expression. CONCLUSIONS: The results in present study show that kaempferol modulates the expression of ANGPTL2 to lessen the mastitis in mice. PMID- 29627691 TI - Selective cytotoxic and genotoxic activities of 5-(2-bromo-5-methoxybenzylidene) thiazolidine-2,4-dione against NCI-H292 human lung carcinoma cells. AB - BACKGROUND: Thiazolidine-2,4-dione ring system is used as a pharmacophore to build various heterocyclic compounds aimed to interact with biological targets. In the present study, benzylidene-2,4-thiazolidinedione derivatives (compounds 2 5) were synthesized and screened against cancer cell lines and the genotoxicity and cytotoxicity of the most active compound (5) was investigated on normal and lung cancer cell line. METHODS: For in vitro cytotoxic screening, the MTT assay was used for HL60 and K562 (leukemia), MCF-7 (breast adenocarcinoma), HT29 (colon adenocarcinoma), HEp-2 (cervix carcinoma) and NCI-H292 (lung carcinoma) tumor cell lines and Alamar-blue assay was used for non-tumor cells (PBMC, human peripheral blood mononuclear cells) were used. Cell morphology was visualized after Giemsa-May-Grunwald staining. DNA content, phosphatidylserine externalization and mitochondrial depolarization were measured by flow cytometry. Genotoxicity was assessed by Comet assay. RESULTS: 5-(2-Bromo-5 methoxybenzylidene)-thiazolidine-2,4-dione (5) presented the most potent cytotoxicity, especially against NCI-H292 lung cancer cell line, with IC50 value of 1.26MUg/mL after 72h incubation. None of the compounds were cytotoxic to PBMC. After 48h incubation, externalization of phosphatidylserine, mitochondrial depolarization, internucleosomal DNA fragmentation and morphological alterations consistent with apoptosis were observed in NCI-H292 cells treated with compound (5). In addition, compound (5) also induced genotoxicity in NCI-H292 cells (2.8 fold increase in damage index compared to the negative control), but not in PBMC. CONCLUSION: Compound 5 presented selective cytotoxic and genotoxic activity against pulmonary carcinoma (NCI-H292 cells). PMID- 29627692 TI - Hemin blunts the depressant effect of chronic nicotine on reflex tachycardia via activation of central NOS/PI3K pathway in female rats. AB - BACKGROUND: Chronic nicotine administration impairs reflex chronotropic responses that follow arterial baroreceptor unloading in female rats with repleted, but not depleted (ovariectomized, OVX), estrogen (E2). This study investigated whether products of nitric oxide synthase (NOS) and/or heme oxygenase (HO) and related soluble guanylate cyclase (sGC)/phosphatidylinositol 3-kinase (PI3K)/mitogen activated protein kinases (MAPKs) signaling mediate the E2-sensitive depressant effect of nicotine on reflex tachycardia. METHODS: Baroreflex curves relating reflex tachycardic responses to falls in blood pressure (BP) generated by sodium nitroprusside (SNP) were established in conscious female rats and slopes of the curves were taken as measures of baroreflex sensitivity (BRS). RESULTS: Nicotine (2 mg/kg/day ip, 14 days) reduced BRS in OVX rats treated with E2 but not vehicle. Baroreceptor dysfunction in nicotine-treated OVXE2 rats was abolished after iv treatment with hemin (HO inducer) but not l-arginine (NOS substrate) denoting the importance of reduced availability of carbon monoxide, but not NO, in the nicotine effect. The favorable BRS effect of hemin was abolished after intracisternal (ic) administration of L-NAME (NOS inhibitor) or wortmannin (PI3 K inhibitor). Central circuits of MAPKs do not seem to contribute to the baroreflex facilitatory effect of hemin because the latter was preserved after central inhibition of MAPKERK (PD98059), MAPKp38 (SB203580) or MAPKJNK (SP600125). Likewise, sGC inhibition (ODQ) or E2 receptor blockade (ICI182780) failed to alter the hemin effect. CONCLUSION: The activation of central NOS/PI3K signaling following HO upregulation improves the E2-dependent depressant effect of nicotine on reflex tachycardia. PMID- 29627693 TI - In-silico evidences for binding of Glucokinase activators to EGFR C797S to overcome EGFR resistance obstacle with mutant-selective allosteric inhibition. AB - The tyrosine kinase inhibitors (TKI) against epidermal growth factor receptor (EGFR) are generally utilized as a part of patients with non-small cell lung carcinoma (NSCLC). However, EGFR T790M mutation results in resistance to most clinically available EGFR TKIs. Third-generation EGFR TKIs against the T790M mutation has been in active clinical development to triumph the resistance problem; they covalently bind with conserved Cys797 inside the EGFR active site, offering both potency and kinase-selectivity. Third generation drugs target C797, which makes the C797S resistance mutation more subtle. EGFR C797S mutation was accounted to be a main mechanism of resistance to the third-generation inhibitors. The C797S mutation gives off an impression of being an ideal target for conquering the acquired resistance to the third generation inhibitors. We have performed structure based-virtual screening strategies for binding of glucokinase activator to EGFR C797S, which can overcome EGFR resistance impediment with mutant-selective allosteric inhibition towards all kinds of mutant EGFR (T790M, L858R, TMLR) and WT EGFR. The final filter of Lipinski's Rule of Five, Jargan's Rule of Three and in silico ADME predictions gave 23 hits, which conform to Lipinski's rule and Jorgensen's rule and all their pharmacokinetic parameters are inside the appropriate range characterized for human use, in this manner demonstrating their potential as a drug-like molecule. PMID- 29627694 TI - Computational elucidation of phylogenetic, structural and functional characteristics of Pseudomonas Lipases. AB - Lipase (triacylglycerol acylhydrolase, EC 3.1.1.3) catalyzes tri-, di-, and monoacyl glycerol of fat into glycerol and fatty acids. It has important roles in the digestion of lipids in living organisms and industrially as laundry detergents along with proteases. The microbial lipases are more stable, active and economically feasible compared to plant and animal sources. Hence, much attention was given to the maximum production of the enzyme from the microbial sources. The phylogenetic analysis revealed that the amino acid sequence of lipase protein and their corresponding cDNA of Pseudomonas aeruginosa clustered with Pseudomonas stutzeri among different species of Pseudomonas, while P. aeruginosa PA1 clustered with P. aeruginosa SJTD-1 among different strains of P. aeruginosa. The lipase of P. aeruginosa PA1 was a monomeric, acidic and thermostable protein having a molecular weight ranging in between 32.72 to 34.89 kDa. The protein was abundant with random coils and alpha helices in its secondary structure. The tertiary model showed 96.310 score as an overall quality factor. Hence, this in silico study gives some useful information about the lipase protein without performing crystal structure assessment by X-ray Crystallography or NMR study in wet lab experiments which could be helpful for isolation and characterization of the enzyme in vitro. PMID- 29627696 TI - Effects of the -141C insertion/deletion polymorphism in the dopamine D2 receptor gene on the dopamine system in the striatum in patients with schizophrenia. AB - The relationships between -141C insertion/deletion (Ins/Del) polymorphisms in the dopamine D2 receptor gene and the two dopamine system integrators, i.e., dopamine and cAMP-regulated phosphoprotein of molecular weight 32 kDa (DARPP-32) and calcineurin (CaN), are still unclear. In this study, we assessed the effect of this polymorphism on DARPP-32 and CaN protein expression in the postmortem striatum of patients with schizophrenia and control individuals. The expression levels of truncated DARPP and CaN were lower in Del allele carriers. These findings provide important insights into the mechanism by which this genotype could result in a poor response to antipsychotic drugs. PMID- 29627695 TI - Mindfulness-based resilience training to reduce health risk, stress reactivity, and aggression among law enforcement officers: A feasibility and preliminary efficacy trial. AB - The primary objective of this study was to assess feasibility and gather preliminary outcome data on Mindfulness-Based Resilience Training (MBRT) for law enforcement officers. Participants (n = 61) were randomized to either an 8-week MBRT course or a no intervention control group. Self-report and physiological data were collected at baseline, post-training, and three months following intervention completion. Attendance, adherence, post-training participant feedback, and interventionist fidelity to protocol all demonstrated feasibility of MBRT for law enforcement officers. Compared to no intervention controls, MBRT participants experienced greater reductions in salivary cortisol, self-reported aggression, organizational stress, burnout, sleep disturbance, and reported increases in psychological flexibility and non-reactivity at post-training; however, group differences were not maintained at three-month follow-up. This initial randomized trial suggests MBRT is a feasible intervention. Outcome data suggest MBRT targets key physiological, psychological, and health risk factors in law enforcement officers, consistent with the potential to improve officer health and public safety. However, follow-up training or "booster" sessions may be needed to maintain training gains. A fully powered longitudinal randomized trial is warranted. PMID- 29627697 TI - Are the components of social reciprocity transdiagnostic across pediatric neurodevelopmental disorders? Evidence for common and disorder-specific social impairments. AB - Deficits in social communication are a core feature of autism spectrum disorder (ASD), yet significant social problems have been observed in youth with many neurodevelopmental disorders. In this preliminary investigation, we aimed to explore whether domains of social reciprocity (i.e., social communication, social cognition, social awareness, social motivation, and restricted and repetitive behaviors) represent transdiagnostic traits. These domains were compared across youth ages 7-17 with obsessive-compulsive disorder (OCD; N = 32), tic disorders (TD; N = 20), severe mood dysregulation (N = 33) and autism spectrum disorder (N = 35). While the ASD group was rated by parents as exhibiting the greatest social reciprocity deficits across domains, a high proportion of youth with severe mood dysregulation also exhibited pronounced deficits in social communication, cognition, and awareness. The ASD and severe mood dysregulation groups demonstrated comparable scores on the social awareness domain. In contrast, social motivation and restricted and repetitive behaviors did not appear to be transdiagnostic domains in severe mood dysregulation, OCD, or TD groups. The present work provides preliminary support that social awareness, and to a lesser extent social communication and cognition, may represent features of social reciprocity that are transdiagnostic across ASD and severe mood dysregulation. PMID- 29627698 TI - Differentiating positive schizotypy and mania risk scales and their associations with spontaneous eye blink rate. AB - Positive schizotypy and mania risk scales are strongly correlated, and both are linked to alterations in striatal dopamine. Previous research has not examined whether these risk scales form distinct factors or whether they are differentially related to other measures of psychopathology risk or striatal dopamine. In the current study (N = 596), undergraduate students completed both positive schizotypy and mania risk scales as well as scales assessing related psychopathology (i.e., negative and disorganized schizotypy; self-reported manic like episodes). Additionally, we measured spontaneous eye blink rate, which has been consistently associated with striatal dopamine levels. Positive schizotypy and mania risk factors were strongly correlated (factor correlation = 0.73). However, a two-factor model with positive schizotypy and mania risk as separate factors fit significantly better than a one-factor risk model. After removing shared variance, only positive schizotypy was positively associated with both negative and disorganized schizotypy, and only mania risk was related to self reported manic-like episodes. Furthermore, positive schizotypy was associated with decreased spontaneous eye blink rate, and mania risk was associated with increased spontaneous eye blink rate. Overall, these results suggest that positive schizotypy and mania risk can be distinguished as separate factors and that they might be differentially associated with striatal dopamine measures. PMID- 29627699 TI - The relationship between emotion regulation strategies, personality traits and skin picking behaviours in a non-clinical sample of Polish adults. AB - Although skin-picking is a relatively common behaviour, data concerning factors which underlie skin-picking severity and functional impairment caused by picking are still limited. In the present study we examined whether some emotion regulation strategies (cognitive reappraisal and expressive suppression) and personality features influence skin-picking in a university sample; the moderating role of personality traits in the relationship between emotion regulation strategies and skin-picking was also considered. A total sample of 252 adults (mean age 24.03; SD = 5.66) completed the Skin-Picking Scale-Revised, Temperament and Character Inventory and Emotion Regulation Questionnaire. The linear regression analyses indicated that the use of cognitive reappraisal as emotion regulation strategy decrease skin-picking severity. Reduced novelty seeking and reduced self-directedness were identified as significant predictors of skin-picking severity, whereas decreased self-directedness and elevated cooperativeness predicted functional impairment caused by skin-picking. Further moderation analysis revealed that cognitive reappraisal decreases skin-picking severity only among individuals with low and moderate novelty seeking, however, not among those with high novelty seeking. These results indicate that emotion regulation strategies and specific personality traits are important factors associated with skin-picking behaviours in a university sample. Further research is needed to establish the link between emotion regulation strategies and personality traits in clinical sample. PMID- 29627700 TI - PTSD's factor structure and measurement invariance across subgroups with differing count of trauma types. AB - To investigate the effect of the count of traumatizing event (TE) types on post trauma mental health, several studies have compared posttraumatic stress disorder (PTSD) severity between individuals experiencing one versus multiple TE types. However, the validity of these studies depends on the establishment of measurement invariance of the construct(s) of interest. The current study examined the stability of the most optimal PTSD Model symptom cluster constructs (assessed by the PTSD Checklist for DSM-5 [PCL-5]) across subgroups experiencing one versus multiple TE types. The sample included university students (n = 556) endorsing at least one TE (Stressful Life Events Screening Questionnaire). Using data from the entire sample, results suggest that the PCL-5-assessed Hybrid Model provided a significantly better fit compared to other models. Results also indicated invariance of factor loadings (metric), and intercepts (scalar) for the PCL-5-assessed Hybrid Model factors across subgroups endorsing one (n = 191) versus multiple TE types (n = 365). Our findings thus support the stability, applicability, and meaningful comparison of the PCL-assessed Hybrid Model factor structure (including subscale severity scores) across subgroups experiencing one versus multiple TE types. PMID- 29627701 TI - Comparing predictors of employment in Individual Placement and Support: A longitudinal analysis. AB - Individual Placement and Support (IPS) is an evidence-based model of supported employment for people with serious mental illness. We assessed the effects and relative contributions of predictors of employment among IPS recipients using measures of baseline client characteristics, local economic context, and IPS fidelity. A recent work history, less time on the Social Security rolls, greater cognitive functioning, and a lower local unemployment rate were associated with greater probability of employment. The ability of the model to discriminate between outcomes was limited, and substantial improvements in our understanding of IPS employment outcomes will require the study of novel client, environmental, and IPS implementation factors. PMID- 29627702 TI - Psychosocial impairment in DSM-5 intermittent explosive disorder. AB - The purpose of this study was to document the functional severity of DSM-5 IED in a clinical research sample. IED and control groups were compared on psychosocial functioning, life satisfaction, and on a variety of cognitive and behavioral issues. IED study participants reported significantly worse psychosocial function, quality of life, and higher job dysfunction than both psychiatric and healthy control study participants. The presence of DSM-5 IED is associated with significant psychosocial and functional impairment. Early intervention may aid in minimizing the consequences of impulsive aggressive behavior, and improving psychosocial functioning and quality of life. PMID- 29627703 TI - Suicide literacy predicts the provision of more appropriate support to people experiencing psychological distress. AB - Mental health literacy has been hailed as a public health priority to reduce stigma and increase help seeking. We examined the effect of suicide literacy on the type of help provided to those experiencing suicidal ideation. A community sample of 363 Australians were randomly assigned to read one of three messages from a member of their social network (the target). The target reported symptoms consistent with either (1) subclinical distress, (2) clinical depression, or (3) suicidal ideation. Participants were most likely to recommend social support and least likely to recommend professional help. Suicide literacy interacted with the target's presentation, such that participants with higher suicide literacy who considered a suicidal target were less likely to recommend self-help or no action, and more likely to recommend professional help. Suicide literacy was also associated with lower suicide stigma, and unexpectedly, this indirectly predicted more reluctance to recommend professional help. Overall, results indicated that the relationship between mental health literacy, stigma, and provision of help is not straightforward. While suicide literacy was associated with greater sensitivity to a person's risk of suicide, it also predicted fewer recommendations for professional help overall, partly due to the stigma associated with seeking professional help. PMID- 29627704 TI - Bipolar disorder and obsessive compulsive disorder: The comorbidity does not further impair the neurocognitive profile. AB - BACKGROUND: The comorbidity of bipolar disorder (BD) and obsessive-compulsive disorder (OCD) has been widely described. Several studies have investigated the cognitive profiles of BD and OCD patients, but studies that compare BD, BD-OCD, and OCD patients in neuropsychological domains do not exist. The purpose of this study was to compare set-shifting, decision making, and central coherence among BD, BD-OCD, and OCD patients. METHODS: A battery of neuropsychological tests was administered to 68 patients (22 BD, 26 BD-OCD, 20 OCD). The Young Mania Rating Scale and Hamilton Depression Rating Scale were used to evaluate manic and depressive symptoms, and OCD severity was assessed with the Yale Brown Obsessive Compulsive Scale. RESULTS: No significant differences emerged in decision-making and cognitive flexibility, whereas BD patients had lower scores in the Accuracy Index on Rey-Osterrieth Complex Figure Test and poor response speed on Hayling Sentence Completion Test Part A than OCD patients. LIMITATIONS: The small sample size with different BD patients, the cross-sectional design, and the study clinical nature. CONCLUSIONS: The most striking result is that, contrary to our hypothesis, comorbidity does not further impair the neurocognitive profile. The clinical relevance of our work could be a shift from the current cognitive rehabilitation model focusing on individualized pathways towards a new overlapping model for all three patient groups. This could make the cognitive rehabilitation faster and less costly. Notwithstanding, these disorders do not only need cognitive training but also various psycho-educative approaches and treatment according to their different clinical profile. PMID- 29627705 TI - 3D Imaging Detection of HER2 Based in the Use of Novel Affibody-Quantum Dots Probes and Ratiometric Analysis. AB - Patients with breast cancer (BC) overexpressing HER2 (HER2+) are selected for Trastuzumab treatment, which blocks HER2 and improves cancer prognosis. However, HER2+ diagnosis, by the gold standard, immunohistochemistry, could lead to errors, associated to: a) variability in sample manipulation (thin 2D sections), b) use of subjective algorithms, and c) heterogeneity of HER2 expression within the tissue. Therefore, we explored HER2 3D detection by multiplexed imaging of Affibody-Quantum Dots conjugates (Aff-QD), ratiometric analysis (RMAFI) and thresholding, using BC multicellular tumor spheroids (BC-MTS) (~120 MUm of diameter) as 3D model of BC. HER2+, HER2- and hybrid HER2+/- BC-MTS (mimicking heterogeneous tissue) were incubated simultaneously with two Aff-QD probes (anti HER2 and negative control (NC), respectively, (1:1)). Confocal XY sections were recorded along the Z distance, and processed by automatized RMAFI (anti-HER2 Aff QD/ NC). Quantifying the NC fluorescence allowed to predict the fraction of non specific accumulation of the anti-HER2 probe within the thick sample, and resolve the specific HER2 level. HER2 was detected up to 30MUm within intact BC-MTS, however, permeabilization improved detection up to 70MUm. Specific HER2 signal was objectively quantified, and HER2 3D-density of 9.2, 48.3 and 30.8% were obtained in HER2-, HER2+ and hybrid HER2+/- permeabilized BC-MTS, respectively. Therefore, by combining the multiplexing capacity of Aff-QD probes and RMAFI, we overcame the challenge of non-specific probe accumulation in 3D samples with minimal processing, yielding a fast, specific spatial HER2 detection and objective quantification. PMID- 29627706 TI - Dendritic Cell-Based Immunotherapy for Solid Tumors. AB - As a treatment for solid tumors, dendritic cell (DC)-based immunotherapy has not been as effective as expected. Here, we review the reasons underlying the limitations of DC-based immunotherapy for solid tumors and ask what can be done to improve immune cell-based cancer therapies. Several reports show that, rather than a lack of immune induction, the limited efficacy of DC-based immunotherapy in cases of renal cell carcinoma (RCC) likely results from inhibition of immune responses by tumor-secreted TGF-beta and an increase in the number of regulatory T (Treg) cells in and around the solid tumor. Indeed, unlike DC therapy for solid tumors, cytotoxic T lymphocyte (CTL) responses induced by DC therapy inhibit tumor recurrence after surgery; CTL responses also limit tumor metastasis induced by additional tumor-challenge in RCC tumor-bearing mice. Here, we discuss the mechanisms underlying the poor efficacy of DC-based therapy for solid tumors and stress the need for new and improved DC immunotherapies and/or combination therapies with killer cells to treat resistant solid tumors. PMID- 29627707 TI - Sediment diffusion method improves wastewater nitrogen removal in the receiving lake sediments. AB - Sediment microbes have a great potential to transform reactive N to harmless N2, thus decreasing wastewater nitrogen load into aquatic ecosystems. Here, we examined if spatial allocation of the wastewater discharge by a specially constructed sediment diffuser pipe system enhanced the microbial nitrate reduction processes. Full-scale experiments were set on two Finnish lake sites, Keuruu and Petajavesi, and effects on the nitrate removal processes were studied using the stable isotope pairing technique. All nitrate reduction rates followed nitrate concentrations, being highest at the wastewater-influenced sampling points. Complete denitrification with N2 as an end-product was the main nitrate reduction process, indicating that the high nitrate and organic matter concentrations of wastewater did not promote nitrous oxide (N2O) production (truncated denitrification) or ammonification (dissimilatory nitrate reduction to ammonium; DNRA). Using 3D simulation, we demonstrated that the sediment diffusion method enhanced the contact time and amount of wastewater near the sediment surface especially in spring and in autumn, altering organic matter concentration and oxygen levels, and increasing the denitrification capacity of the sediment. We estimated that natural denitrification potentially removed 3-10% of discharged wastewater nitrate in the 33 ha study area of Keuruu, and the sediment diffusion method increased this areal denitrification capacity on average 45%. Overall, our results indicate that sediment diffusion method can supplement wastewater treatment plant (WWTP) nitrate removal without enhancing alternative harmful processes. PMID- 29627708 TI - Hydroxyl radical dominated degradation of aquatic sulfamethoxazole by Fe0/bisulfite/O2: Kinetics, mechanisms, and pathways. AB - In this study, batch experiments were carried out to investigate the key factors on sulfamethoxazole (SMX) removal kinetics in a new AOPs based on the combination of zero valent iron (Fe0) and bisulfite (S(IV)). With the increase of Fe0 from 0.25 mM to 5 mM, the removal rate of SMX was linearly increased in the Fe0/S(IV)/O2 system by accelerating the activation of S(IV) and Fe0 corrosion to accelerate. In the first 10 min of reaction, the increasing concentration of S(IV) inhibited SMX removal after since the high S(IV) concentration quenched reactive oxidative species (ROS). Then SMX removal rate was accelerated with the increase of S(IV) concentration after S(IV) were consumed up. The optimal ratio of S(IV) concentrations to Fe0 concentration for SMX removal in the Fe0/S(IV)/O2 system was 1:1. With SMX concentrations increasing from 1 to 50 MUM, SMX removal rate was inhibited for the limitation of ROS yields. Although the presence of SO4 and OH was confirmed by electron paramagnetic resonance (EPR) spectrum, OH was identified as the dominant ROS in the Fe0/S(IV)/O2 system by chemical quenching experiments. Besides, strong inhibitive effects of 1,10-phenanthroline on SMX degradation kinetics by Fe0/S(IV)/O2 proved that the generation of ROS was rely on the release of Fe(II) and Fe(III). The generation of SO4- was ascribed to the activation of S(IV) by Fe(II)/Fe(III) recycling and the activation of HSO5- by Fe(II). And OH was simultaneously transformed from SO4- and generated by Fe0/O2. Density functional theory (DFT) calculation was conducted to reveal special reactive sites on SMX for radicals attacking and predicted intermediates. Finally, four possible SMX degradation pathways were accordingly proposed in the Fe0/S(IV)/O2 system based on experimental methods and DFT calculation. PMID- 29627709 TI - Rare emergence of drug resistance in HIV-1 treatment-naive patients receiving elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide for 144 weeks. AB - BACKGROUND: The single tablet regimen (STR) composed of elvitegravir (E), cobicistat (C), emtricitabine (F), and tenofovir alafenamide (TAF) (E/C/F/TAF) was compared to the STR composed of E, C, F, and tenofovir disoproxil fumarate (TDF) (E/C/F/TDF) in 2 phase 3 studies in 1733 HIV-1 infected treatment-naive adults. Superior efficacy of E/C/F/TAF compared to E/C/F/TDF was demonstrated at Week 144 with 84% treatment success compared to 80%, respectively, along with significantly better outcomes of bone and renal safety. OBJECTIVES: Analyze the emergence of HIV-1 resistance in treatment-naive adults receiving E/C/F/TAF for 144 weeks. STUDY DESIGN: We conducted an integrated resistance analysis of the 2 Phase 3 studies, comprising pretreatment HIV-1 sequencing for all participants (N = 1733) and post-baseline HIV-1 resistance analysis for participants with virologic failure (HIV-1 RNA >=400 copies/mL). RESULTS: Primary resistance associated mutations (RAMs) were observed pre-treatment in 7.4% (NRTI-RAMs), 18.1% (NNRTI-RAMs), and 3.3% (PI-RAMs) of enrolled subjects. Baseline HIV-1 subtype or pre-existing RAMs did not affect E/C/F/TAF treatment response at week 144. Virologic failure resistance analyses were conducted for 28/866 (3.2%) and 30/867 (3.5%) patients in the E/C/F/TAF and E/C/F/TDF arms, respectively. Over the 3-year study, the rate of resistance emergence remained low at 1.4% in each group (12/866 in E/C/F/TAF; 12/867 in E/C/F/TDF). Resistant virus emerged in 24 patients who developed resistance to antiretrovirals in the regimens (E/C/F/TAF: M184V/I [1.3%], INSTI-RAMs [0.9%], K65R/N [0.2%]; E/C/F/TDF: M184V/I [1.0%], INSTI-RAMs [0.9%], K65R/N [0.5%]). CONCLUSIONS: Resistance emergence was rare (1.4%) with similar patterns of emergent mutations in both groups. M184V/I was the most prevalent RAM (1.2% overall). PMID- 29627710 TI - Crash sequence based risk matrix for motorcycle crashes. AB - Considerable research has been conducted related to motorcycle and other powered two-wheeler (PTW) crashes; however, it always has been controversial among practitioners concerning with types of crashes should be first targeted and how to prioritize resources for the implementation of mitigating actions. Therefore, there is a need to identify types of motorcycle crashes that constitute the greatest safety risk to riders - most frequent and most severe crashes. This pilot study seeks exhibit the efficacy of a new approach for prioritizing PTW crash causation sequences as they relate to injury severity to better inform the application of mitigating countermeasures. To accomplish this, the present study constructed a crash sequence-based risk matrix to identify most frequent and most severe motorcycle crashes in an attempt to better connect causes and countermeasures of PTW crashes. Although the frequency of each crash sequence can be computed from crash data, a crash severity model is needed to compare the levels of crash severity among different crash sequences, while controlling for other factors that also have effects on crash severity such drivers' age, use of helmet, etc. The construction of risk matrix based on crash sequences involve two tasks: formulation of crash sequence and the estimation of a mixed-effects (ME) model to adjust the levels of severities for each crash sequence to account for other crash contributing factors that would have an effect on the maximum level of crash severity in a crash. Three data elements from the National Automotive Sampling System - General Estimating System (NASS-GES) data were utilized to form a crash sequence: critical event, crash types, and sequence of events. A mixed effects model was constructed to model the severity levels for each crash sequence while accounting for the effects of those crash contributing factors on crash severity. A total of 8039 crashes involving 8208 motorcycles occurred during 2011 and 2013 were included in this study, weighted to represent 338,655 motorcyclists involved in traffic crashes in three years (2011-2013)(NHTSA, 2013). The top five most frequent and severe types of crash sequences were identified, accounting for 23 percent of all the motorcycle crashes included in the study, and they are (1) run-off-road crashes on the right, and hitting roadside objects, (2) cross-median crashes, and rollover, (3) left-turn oncoming crashes, and head-on, (4) crossing over (passing through) or turning into opposite direction at intersections, and (5) side-impacted. In addition to crash sequences, several other factors were also identified to have effects on crash severity: use of helmet, presence of horizontal curves, alcohol consumption, road surface condition, roadway functional class, and nighttime condition. PMID- 29627711 TI - Simple DNA extraction of urine samples: Effects of storage temperature and storage time. AB - Urine samples are commonly analysed in cases with suspected illicit drug consumption. In events of alleged sample mishandling, urine sample source identification may be necessary. A simple DNA extraction procedure suitable for STR typing of urine samples was established on the Promega Maxwell(r) 16 paramagnetic silica bead platform. A small sample volume of 1.7mL was used. Samples were stored at room temperature, 4 degrees C and -20 degrees C for 100days to investigate the influence of storage temperature and time on extracted DNA quantity and success rate of STR typing. Samples stored at room temperature exhibited a faster decline in DNA yield with time and lower typing success rates as compared to those at 4 degrees C and -20 degrees C. This trend can likely be attributed to DNA degradation. In conclusion, this study presents a quick and effective DNA extraction protocol from a small urine volume stored for up to 100days at 4 degrees C and -20 degrees C. PMID- 29627712 TI - Accurate identification of opioid overdose deaths using coronial data. AB - INTRODUCTION: Defining drug-related mortality is complex as these deaths can include a wide range of diseases and circumstances. This paper outlines a method to identify deaths that are directly due to fatal opioid toxicity (i.e. overdose), utilising coronial data. MATERIALS AND METHODS: The National Coronial Information System (NCIS), an online coronial database containing information on all deaths that are reported to a coroner in Australia, is used to develop methods to more accurately identify opioid overdose deaths. The NCIS contains demographic information, Medical Cause of Death, and associated documentation on toxicology, clinical and police investigations. RESULTS: Identifying overdose deaths using the coroner determined Medical Cause of Death provided greater capture, and specificity, of opioid overdose deaths. Distinguishing morphine from heroin-related deaths presented challenges, requiring analysis of clinical and investigative information in addition to toxicology results. One-quarter of the deaths attributed to morphine were recorded to heroin as a result of further investigation. There was also some underestimation of codeine-related deaths. Access to clinical and investigative information also yields important information in relation to comorbid conditions among these decedents, such as history of chronic pain, substance use issues and mental health problems. CONCLUSIONS: Reliance on toxicology results alone leads to an underestimate of heroin-related deaths. Differentiating between heroin and pharmaceutical opioid (e.g. morphine) overdose deaths has important public health and policy implications, particularly in relation to prescribing practices and development of a strategic response. Understanding comorbidities among these decedents is also important in efforts to reduce preventable causes of death such as opioid overdose. PMID- 29627714 TI - Circulating endocannabinoids and affect regulation in human subjects. AB - The endocannabinoid (EC) system influences a wide variety of neurobiological processes including affect and emotionality as well as other neuropsychiatric functions. In this study we examined the relationship of circulating endocannabinoids [anandamide (AEA) and 2-arachidonoylglycerol (2-AG)] with affect and emotionality in 175 individuals with (n = 115) and without (n = 60) mood, anxiety, and/or personality disorders. Circulating AEA levels displayed a modest, though statistically significant, inverse relationship with a composite measure of affect regulation (beta = - 0.264, p = 0.009), due to its relationship with affect intensity (beta = - 0.225, p = 0.021) across all study participants. Neither AEA nor 2-AG level differed as a function of any syndromal/personality disorder and neither correlated significantly with state depression or state anxiety scores. These data suggest that circulating levels endocannabinoids may play a role in emotionality across individuals regardless of defined psychiatric disorder. PMID- 29627713 TI - Chronic stress, hair cortisol and depression: A prospective and longitudinal study of medical internship. AB - BACKGROUND: Stress plays a causal role in depression onset, perhaps via alteration of hypothalamic-pituitary-adrenal (HPA) axis functioning. HPA axis hyperactivity has been reported in depression, though inconsistently, and the nature of this relationship remains unclear, partly because cortisol measurement over time has been challenging. Development of hair cortisol assessment, a method that captures cortisol over prolonged periods of time, creates new possibilities. In this study, hair cortisol was incorporated into a prospective and longitudinal study of medical internship, stress and symptoms of depression. This provided a rare opportunity to 1) prospectively assess hair cortisol responses to stress, and 2) examine whether stress-induced changes in hair cortisol predict depressive symptom development. METHODS: Hair cortisol, depressive symptoms, and stress relevant variables (work hours, sleep, perceived stress, mastery/control) were assessed in interns (n = 74; age 25-33) before and repeatedly throughout medical internship. RESULTS: Hair cortisol sharply increased with stressor onset, decreased as internship continued, and rose again at year's end. Depressive symptoms rose significantly during internship, but were not predicted by cortisol levels. Hair cortisol also did not correlate with increased stressor demands (work hours, sleep) or stress perceptions (perceived stress, mastery/control); but these variables did predict depressive symptoms. DISCUSSION: Hair cortisol and depressive responses increased with stress, but they were decoupled, following distinct trajectories that likely reflected different aspects of stress reactivity. While depressive symptoms correlated with stressor demands and stress perceptions, the longitudinal pattern of hair cortisol suggested that it responded to contextual features related to anticipation, novelty/familiarity, and social evaluative threat. PMID- 29627715 TI - Prevalence and duration of reasons for enteral nutrition feeding interruption in a tertiary intensive care unit. AB - OBJECTIVES: Intensive care unit (ICU) enteral nutrition (EN) can involve frequent feeding interruption (FI). The prevalence, causes, and duration of such interruption were investigated. METHODS: Reasons for EN FI identified from extensive literature review were prospectively collected in adult mechanically ventilated critically ill patients. Results were reported by descriptive statistics. Baseline and nutritional characteristics between patients who died and those alive at day 60 were compared. RESULTS: A total of 148 patients receiving >=1 day of EN for the full 12-day observational period were included in the analysis. About 332 episodes of EN FI were recorded and contributed to 12.8% (4190 hours) of the total 1367 evaluable nutrition days. For each patient, FI occurred for a median of 3 days and the total duration of FI for the entire ICU stay was 24.5 hours. Median energy and protein deficits per patient due to FI for the entire ICU stay were -1780.23 kcal and -100.58 g, respectively. Duration of FI, days with FI, and the amount of energy and protein deficits due to FI were not different between patients who had died and those who were still alive at day 60 (all P > 0.05). About 72% of the total duration of EN FI was due to procedural related and potentially avoidable causes (primarily human factors), while only about 20% was due to feeding intolerances. CONCLUSIONS: EN FI occurred primarily due to human factors, which may be minimized by adherence to an evidence-based feeding protocol as determined by a nutrition support team. PMID- 29627716 TI - Preserved somatosensory discrimination predicts consciousness recovery in unresponsive wakefulness syndrome. AB - OBJECTIVE: To assess somatosensory discrimination and command following using a vibrotactile P300-based Brain-Computer Interface (BCI) in Unresponsive Wakefulness Syndrome (UWS), and investigate the predictive role of this cognitive process on the clinical outcomes. METHODS: Thirteen UWS patients and six healthy controls each participated in two experimental runs in which they were instructed to count vibrotactile stimuli delivered to the left or right wrist. A BCI determined each subject's task performance based on EEG measures. All of the patients were followed up six months after the BCI assessment, and correlations analysis between accuracy rates and clinical outcome were investigated. RESULTS: Four UWS patients demonstrated clear EEG-based indices of task following in one or both paradigms, which did not correlate with clinical factors. The efficacy of somatosensory discrimination strongly correlated (VT2: R = 0.89, p = 0.0000002, VT3: R = 0.81, p = 0.002) with the clinical outcome at 6-months. The BCI system also yielded the expected results with healthy controls. CONCLUSIONS: Neurophysiological correlates of somatosensory discrimination can be detected in clinically unresponsive patients and are associated with recovery of behavioural responsiveness at six months. SIGNIFICANCE: Quantitative measurements of somatosensory discrimination may increase the diagnostic accuracy of persons with DOCs and provide useful prognostic information. PMID- 29627717 TI - Transnasal sphenopalatine nerve block for patients with headaches. PMID- 29627718 TI - Cognitive flexibility and memory in pigeons, human children, and adults. AB - This work examines cognitive flexibility using a comparative approach. Pigeons (Experiment 1), human children (Experiment 2a), and human adults (Experiment 2b) performed a task that required changing responses to the same stimuli twice across the experiment. The results indicate that all three groups demonstrated robust memory for learned information. In addition, pigeons showed comparable and substantial perseveration following both response shifts. In contrast, both children and adults exhibited some perseveration following a first response shift, while exhibiting no cost following the second response shift. These findings are discussed in relation to memory-based theories of cognitive flexibility, according to which perseveration occurs as a result of competition between long-term and working memory, revealing important differences in memory and cognitive flexibility between species. PMID- 29627719 TI - Interference of DOACs in different DRVVT assays for diagnosis of lupus anticoagulants. AB - OBJECTIVE: Determination of lupus anticoagulants (LA) is an important, but still challenging test in the diagnosis of antiphospholipid syndrome (APS). This is especially the case in patients using one of the direct oral anticoagulants (DOACs). The aim of our study was to examine the influence of these drugs on DRVVT assays from two companies (in each case: screening test, confirming test and calculated ratio) and on aPTT and lupus-sensitive aPTT. METHODS: We used plasma samples from healthy volunteers spiked with the DOACs dabigatran, rivaroxaban and apixaban (0, 10, 30, 50, 100 ng/mL) for testing. Furthermore, samples from patients receiving a DOAC were investigated. The plasma concentrations of the DOACs were determined using ultra-performance liquid chromatography/electrospray ionization-tandem mass spectrometry (UPLC-MS/MS). RESULTS: Depending on type and concentration, all the DOACs resulted in pathological values in the DRVVT screening assays. In samples spiked with apixaban, no influence on the DRVVT normalized ratio of the two assays was observed, but 7 to 15% of samples from patients receiving apixaban displayed pathological values. In contrast, up to 71% of dabigatran-spiked samples showed normalized ratio values above the cut-off, whereas there was no influence in the patients' samples. In both spiked and patient samples containing rivaroxaban, the DRVVT assays were influenced. CONCLUSION: LA diagnostics should, under DOAC therapy, be limited to situations in which time-critical evaluation is warranted. It is crucial to take into account the finding that even samples containing DOAC concentrations below the limit of detection of the drugs may lead to false positive DRVVT measurements. PMID- 29627720 TI - Phenomenology of obsessive compulsive disorder in Bangladesh: A cross-sectional observation. PMID- 29627721 TI - Community-based comprehensive intervention for people with schizophrenia in Guangzhou, China: Effects on clinical symptoms, social functioning, internalized stigma and discrimination. AB - Comprehensive interventions including components of stigma and discrimination reduction in schizophrenia in low- and middle-income countries (LMICs) are lacking. We developed a community-based comprehensive intervention to evaluate its effects on clinical symptoms, social functioning, internalized stigma and discrimination among patients with schizophrenia. A randomized controlled trial including an intervention group (n = 169) and a control group (n = 158) was performed. The intervention group received comprehensive intervention (strategies against stigma and discrimination, psycho-education, social skills training and cognitive behavioral therapy) and the control group received face to face interview. Both lasted for nine months. Participants were measured at baseline, 6 months and 9 months using the Internalized Stigma of Mental Illness scale (ISMI), Discrimination and Stigma Scale (DISC-12), Global Assessment of Functioning (GAF), Schizophrenia Quality of Life Scale (SQLS), Self-Esteem Scale (SES), Brief Psychiatric Rating Scale (BPRS) and PANSS negative scale (PANSS-N). Insight and medication compliance were evaluated by senior psychiatrists. Data were analyzed by descriptive statistics, t-test, chi-square test or Fisher's exact test. Linear Mixed Models were used to show intervention effectiveness on scales. General Linear Mixed Models with multinomial logistic link function were used to assess the effectiveness on medication compliance and insight. We found a significant reduction on anticipated discrimination, BPRS and PANSS-N total scores, and an elevation on overcoming stigma and GAF in the intervention group after 9 months. These suggested the intervention may be effective in reducing anticipated discrimination, increasing skills overcoming stigma as well as improving clinical symptoms and social functioning in Chinese patients with schizophrenia. PMID- 29627722 TI - Economic Costs of Chikungunya Virus in Colombia. AB - OBJECTIVE: The aim of the present study was to estimate the economic impact of chikungunya virus (CHIKV) infection in Colombia from a societal perspective. METHODS: We conducted a retrospective, bottom-up cost-of-illness study in clinically confirmed cases during the first chikungunya (CHIK) outbreak in Colombia in 2014. Direct and indirect costs were estimated per patient. Economic costs were calculated by the addition of direct costs (direct medical costs and out-of-pocket heath expenditures) and indirect cost as a result of loss of productivity. RESULTS: A total of 126 patients (67 children and 59 adults) with CHIK were included. The median of the direct medical cost in children was US$257.9 (interquartile range [IQR] 121.7-563.8), and US$66.6 (IQR 26.5-317.3) for adults. The productivity loss median expenditures reached US$81.3 (IQR 72.2 203.2) per adult patient. The median economic cost in adults as a result of CHIK was US$152.9 (IQR 101.0-539.6), of which 53.2% was a result of indirect costs. Out-of-pocket expenditures comprised 3.3% of all economic costs. CONCLUSIONS: Our study can help health decision makers to properly assess the burden of disease caused by CHIK in Colombia, an endemic tropical country. We recommend to strength the health information systems and to continue investing in public health measures to prevent CHIK. PMID- 29627723 TI - Design, synthesis and biological evaluation of novel trimethylangelicin analogues targeting nuclear factor kB (NF-kB). AB - A series of trimethylangelicin (TMA) derivatives were designed and synthesized to overcome the unwanted effects of TMA, promising agent for treatment of inflammation-related diseases and other pathologies, such as cystic fibrosis. The new generation TMA analogues bore hindered substituents at the 4 position in order to minimize or avoid the photoreactions with DNA. Among them, the 4 isopropyl-6-ethyl derivative 23 exhibited TMA-like inhibitory activity on NF kappaB/DNA interactions but it proved unable to photoreact with pyrimidine bases of DNA, nor to induce any other DNA damage. The isopropyl analogue 23 was proven to lack mutagenicity when assayed through Ames test and exhibited no anti proliferative activity on cystic fibrosis IB3-1 cells, displaying at the same time inhibition of the TNF-alpha induced release of the NF-kappaB regulated PDGF B chain, IL-10, IL-15, IL-17 and IFN-gamma. Therefore compound 23 deserves further assay to determine its anti-inflammatory properties, since it lacks photoreaction properties and mutagenicity-related side effects. PMID- 29627724 TI - A tumor-targeted Ganetespib-zinc phthalocyanine conjugate for synergistic chemo photodynamic therapy. AB - Therapeutic effects of photodynamic therapy (PDT) are limited by the selectivity of photosensitizer (PS). Herein, a novel tumor-targeted drug-PS conjugate (Gan ZnPc) which integrated with zinc phthalocyanine (ZnPc) and Ganetespib has been developed. ZnPc is a promising PS with remarkable photosensitization ability. Ganetespib is a heat shock protein 90 (Hsp90) inhibitor with preferential tumor selectivity and conjugated to ZnPc as a tumor-targeted ligand. The multifunctional small molecule conjugate, Gan-ZnPc, could be bound to extracellular Hsp90 and then selectively internalized into the tumor cells, followed by the generation of abundant intracellular reactive oxygen species (ROS) upon irradiation. Besides, Gan-ZnPc can arrest cell proliferation and induce apoptosis by the inhibition of Hsp90. Herein, with combination of the inhibition of Hsp90 and the generation of cytotoxic ROS, Gan-ZnPc implements tumor selectivity, concentrated PDT and chemotherapy in a synergistic manner, which results in highly effective anti-tumor activity in vitro and in vivo. PMID- 29627726 TI - Generation of WAe001-A-15, a human embryonic stem cell line with miR-122 doxycycline-inducible expression. AB - MiR-122 is the most abundant miRNA in the human liver accounting for 52% of the entire hepatic miRNome. Previous studies have demonstrated that miR-122 is a valuable therapeutic target for liver diseases, including viral hepatitis, fibrosis, steatosis, and hepatocarcinoma. Here, we constructed a miR-122 doxycycline-inducible expression human embryonic stem cell line WAe001-A-15 using the piggyBac transposon system. The cell line retained its pluripotency, in vitro differentiation potential, normal morphology, and karyotype. PMID- 29627725 TI - Proteolysis Targeting Chimeras (PROTACs) of Anaplastic Lymphoma Kinase (ALK). AB - Anaplastic lymphoma kinase (ALK) activation has been associated with many types of human cancer. Significant efforts have been devoted to the development of ALK inhibitors to antagonize the kinase activity of ALK. Four ALK inhibitors have been approved by the FDA to date for treating patients with ALK-positive non small cell lung cancers (NSCLC). However, drug resistance has been observed in the majority of patients treated with these inhibitors. New therapeutic strategies (e.g., compounds with novel mechanisms of action) are needed to overcome the drug resistance issue. The emerging PROTAC (Proteolysis Targeting Chimera) technology has been successfully applied to selective degradation of multiple protein targets, but not ALK. Since ALK protein levels are not important for viability in mammals, ALK PROTACs could lead to novel therapeutics with minimal toxicity. Here we report the design, synthesis and biological evaluation of novel PROTACs (degraders) of ALK. MS4077 (5) and MS4078 (6) potently decreased cellular levels of oncogenic active ALK fusion proteins in a concentration- and time-dependent manner in SU-DHL-1 lymphoma and NCI-H2228 lung cancer cells. The ALK protein degradation induced by compounds 5 and 6 was cereblon and proteasome dependent. In addition, compounds 5 and 6 potently inhibited proliferation of SU DHL-1 cells. Furthermore, compound 6 displayed good plasma exposure in a mouse pharmacokinetic study, thus is suitable for in vivo efficacy studies. We also developed MS4748 (7) and MS4740 (8), very close analogs of 5 and 6 respectively, which are incapable to degrade the ALK fusion proteins, as negative controls. Compounds 5-8 are valuable chemical tools for investigating effects of ALK pharmacological degradation. Our study paved the way for developing the next generation of ALK PROTACs. PMID- 29627727 TI - Quantification of the total amount of black cohosh cycloartanoids by integration of one specific 1H NMR signal. AB - Quantitative analysis is an important field in the quality control of medicinal plants, aiming to determine the amount of pharmacologically active constituents in complex matrices. Often biological effects of herbal drugs are not restricted to single compounds, but are rather caused by a number of often biogenetically related plant metabolites. Depending on the complexity of the analyzed plant extract, conflicts between accuracy, such as total content assays using photometric or colorimetric methods, and comprehensiveness, e.g. quantification of one or a few lead compounds can occur. In this study, we present a qHNMR approach determining the total amount of cycloartanoids in black cohosh (Actaea racemosa) rhizomes. Perdeuterated methanol containing 1,2,4,5-tetrachloro-3 nitrobenzene as an internal standard was used for extraction. Amounts of cycloartanoids were then measured by integrating 1H NMR signals of all cycloartenoids' H-19 exo protons. Due to their unusually low chemical shifts, these signals are well separated from all remaining signals in crude extracts. Thus, accurate (recovery rates of 99.5-102.5%) and precise (relative standard deviations below 2.5%) quantification of cycloartanoids was accomplished. To the best of our knowledge, this is the first example of a quantification of the total amount of a pharmacologically relevant compound class by integration of one 1H NMR signal characteristic for all members of this particular compound class. Additionally, we propose a new term and unit for the evaluation of medicinal plants and herbal medicinal products: the "specific partial amount of substance" of pharmacologically active constituents, indicated in mmol/g. PMID- 29627728 TI - Implementation of a generic liquid chromatographic method development workflow: Application to the analysis of phytocannabinoids and Cannabis sativa extracts. AB - A generic liquid chromatographic method development workflow was developed and successfully applied to the analysis of phytocannabinoids and Cannabis sativa extracts. Our method development procedure consists in four steps: At the end, this method development workflow was performed in less than 4 days and minimizes the costs of the method development in liquid chromatography. PMID- 29627729 TI - Biomedical analysis of formalin-fixed, paraffin-embedded tissue samples: The Holy Grail for molecular diagnostics. AB - More than a century ago in 1893, a revolutionary idea about fixing biological tissue specimens was introduced by Ferdinand Blum, a German physician. Since then, a plethora of fixation methods have been investigated and used. Formalin fixation with paraffin embedment became the most widely used types of fixation and preservation method, due to its proper architectural conservation of tissue structures and cellular shape. The huge collection of formalin-fixed, paraffin embedded (FFPE) sample archives worldwide holds a large amount of unearthed information about diseases that could be the Holy Grail in contemporary biomarker research utilizing analytical omics based molecular diagnostics. The aim of this review is to critically evaluate the omics options for FFPE tissue sample analysis in the molecular diagnostics field. PMID- 29627730 TI - Determination of cobalt species in nutritional supplements using ICP-OES after microwave-assisted extraction and solid-phase extraction. AB - Cobalt content (as vitamin B12 and inorganic cobalt) in two nutritional supplements, namely Spirulina platensis and Saccharomyces cerevisiae known as a "superfood", has been determined using inductively coupled plasma optical emission spectrometry (ICP-OES). Several sample pre-treatment protocols have been applied and compared. Microwave-assisted acid digestion efficiently decomposed all cobalt-containing compounds, thus allowed obtaining total cobalt content in supplements examined. Vitamin B12 was extracted from the samples with acetate buffer and potassium cyanide solution exposed to mild microwave radiation for 30 min, and cyanocobalamin was separated from the extract by on-column solid phase extraction using C-18 modified silica bed. About 100% of cobalt species was extracted using the triple microwave-assisted extraction procedure. Total cobalt content was 20-fold greater in Spirulina tablets than the declared cobalamin content (as Co). The ICP-OES method precision was about 3% and detection limit was 1.9 and 2.7 ng Co mL-1 for inorganic cobalt or cyanocobalamin, respectively. PMID- 29627731 TI - Triple-helix molecular switch-based aptasensors and DNA sensors. AB - Utilization of traditional analytical techniques is limited because they are generally time-consuming and require high consumption of reagents, complicated sample preparation and expensive equipment. Therefore, it is of great interest to achieve sensitive, rapid and simple detection methods. It is believed that nucleic acids assays, especially aptamers, are very important in modern life sciences for target detection and biological analysis. Aptamers and DNA-based sensors have been widely used for the design of various sensors owing to their unique features. In recent years, triple-helix molecular switch (THMS)-based aptasensors and DNA sensors have been broadly utilized for the detection and analysis of different targets. The THMS relies on the formation of DNA triplex via Watson-Crick and Hoogsteen base pairings under optimal conditions. This review focuses on recent progresses in the development and applications of electrochemical, colorimetric, fluorescence and SERS aptasensors and DNA sensors, which are based on THMS. Also, the advantages and drawbacks of these methods are discussed. PMID- 29627732 TI - Responses of grapevine rootstocks to drought through altered root system architecture and root transcriptomic regulations. AB - Roots are the major interface between the plant and various stress factors in the soil environment. Alteration of root system architecture (RSA) (root length, spread, number and length of lateral roots) in response to environmental changes is known to be an important strategy for plant adaptation and productivity. In light of ongoing climate changes and global warming predictions, the breeding of drought-tolerant grapevine cultivars is becoming a crucial factor for developing a sustainable viticulture. Root-trait modeling of grapevine rootstock for drought stress scenarios, together with high-throughput phenotyping and genotyping techniques, may provide a valuable background for breeding studies in viticulture. Here, tree grafted grapevine rootstocks (110R, 5BB and 41B) having differential RSA regulations and drought tolerance were investigated to define their drought dependent root characteristics. Root area, root length, ramification and number of root tips reduced less in 110R grafted grapevines compared to 5BB and 41B grafted ones during drought treatment. Root relative water content as well as total carbohydrate and nitrogen content were found to be much higher in the roots of 110R than it was in the roots of other rootstocks under drought. Microarray-based root transcriptome profiling was also conducted on the roots of these rootstocks to identify their gene regulation network behind drought-dependent RSA alterations. Transcriptome analysis revealed totally 2795, 1196 and 1612 differentially expressed transcripts at the severe drought for the roots of 110R, 5BB and 41B, respectively. According to this transcriptomic data, effective root elongation and enlargement performance of 110R were suggested to depend on three transcriptomic regulations. First one is the drought-dependent induction in sugar and protein transporters genes (SWEET and NRT1/PTR) in the roots of 110R to facilitate carbohydrate and nitrogen accumulation. In the roots of the same rootstock, expression increase in osmolyte producer genes revealed another transcriptomic regulation enabling effective root osmotic adjustment under drought stress. The third mechanism was linked to root suberization with upregulation of transcripts functional in wax producing enzymes (Caffeic acid 3-O methyltransferase, Eceriferum3, 3-ketoacyl-CoAsynthase). These three transcriptomic regulations were suggested to provide essential energy and water preservation to the roots of 110R for its effective RSA regulation under drought. This phenotypic and genotypic knowledge could be used to develop root-dependent drought tolerant grapevines in breeding programs and could facilitate elucidation of genetic regulations behind RSA alteration in other plants. PMID- 29627733 TI - Improving tissue expansion protocols through computational modeling. AB - Tissue expansion is a common technique in reconstructive surgery used to grow skin in vivo for correction of large defects. Despite its popularity, there is a lack of quantitative understanding of how stretch leads to growth of new skin. This has resulted in several arbitrary expansion protocols that rely on the surgeon's personal training and experience rather than on accurate predictive models. For example, choosing between slow or rapid expansion, or small or large inflation volumes remains controversial. Here we explore four tissue expansion protocols by systematically varying the inflation volume and the protocol duration in a porcine model. The quantitative analysis combines three-dimensional photography, isogeometric kinematics, and finite growth theory. Strikingly, all four protocols generate similar peak stretches, but different growth patterns: Smaller filling volumes of 30 ml per inflation did not result in notable expander induced growth neither for the short nor for the long protocol; larger filling volumes of 60 ml per inflation trigger skin adaptation, with larger expander induced growth in regions of larger stretch, and more expander-induced growth for the 14-day compared to the 10-day expansion protocol. Our results suggest that expander-induced growth is not triggered by the local stretch alone. While stretch is clearly a driver for growth, the local stretch at a given point is not enough to predict the expander-induced growth at that location. From a clinical perspective, our study suggests that longer expansion protocols are needed to ensure sufficient growth of sizable skin patches. PMID- 29627734 TI - Ex vivo fracture resistance of teeth restored with glass and fiber reinforced composite resin. AB - OBJECTIVES: This study aims to compare the ex vivo fracture resistance of root canal treated (RCT) teeth restored with four different types of fibers under composite resin. SUBJECTS AND METHODS: One hundred and forty extracted mandibular first molar teeth were assigned to seven groups (n = 20/group). Group 1 was the control group. In groups 2-7, endodontic access and standard Mesio-occluso-distal (MOD) cavities were prepared. Following RCT, group 2 was left unrestored. In group 3, flowable composite resin (FCR) was used to line the cavities and restored with composite resin. In groups 4,5,6 and 7, Ribbond, Everstick, Dentapreg and Bioctris fibers were inserted in flowable resin and restored respectively. RESULTS: All the groups restored with fiber reinforced composite displayed higher fracture resistance than the group restored with only composite resin (p < 0.001). In addition, Groups restored with Everstick and Bioctris (Groups 5 and 7) showed higher fracture resistance when compared to Ribbond and Dentapreg (Groups 4 and 6). CONCLUSION: E glass fibers demonstrated highest fracture resistance and hence can be preferred over other fiber types to reinforce RCT teeth with weakened crown structures. PMID- 29627735 TI - Effect of multiscale structural parameters on the mechanical properties of rice stems. AB - The objective of this study was to investigate the relation between the structural parameters and the mechanical properties of rice stem at different scales. Tensile modulus and bending properties of different kinds of rice stems were measured through tensile and three-point bending tests. The morphology and microstructures of rice stems at different scales are detected by the scanning electron microscope (SEM), transmission electron microscope (TEM) and X-ray diffraction (XRD). It is found that the microfibril angle (MFA) and the volume fraction of the supporting materials dominate the tensile modulus of rice stem. Whereas, the bending properties of rice stem are more sensitive to the structural parameters of the matrix materials. Moreover, compared to the number or volume fraction of small/large vascular bundle, the volume fraction of the mechanical tissue layer in skin exerts a greater influence on the tensile modulus of the rice stem. PMID- 29627736 TI - Regression models to predict the behavior of the coefficient of friction of AISI 316L on UHMWPE under ISO 14243-3 conditions. AB - Friction is the natural response of all tribosystems. In a total knee replacement (TKR) prosthetic device, its measurement is hindered by the complex geometry of its integrating parts and that of the testing simulation rig operating under the ISO 14243-3:2014 standard. To develop prediction models of the coefficient of friction (COF) between AISI 316L steel and ultra-high molecular weight polyethylene (UHMWPE) lubricated with fetal bovine serum dilutions, the arthrokinematics and loading conditions prescribed by the ISO 142433: 2014 standard were translated to a simpler geometrical setup, via Hertz contact theory. Tribological testing proceeded by loading a stainless steel AISI 316L ball against the surface of a UHMWPE disk, with the test fluid at 37 degrees C. The method has been applied to study the behavior of the COF during a whole walking cycle. On the other hand, the role of protein aggregation phenomena as a lubrication mechanism has been extensively studied in hip joint replacements but little explored for the operating conditions of a TKR. Lubricant testing fluids were prepared with fetal bovine serum (FBS) dilutions having protein mass concentrations of 5, 10, 20 and 36 g/L. The results were contrasted against deionized, sterilized water. The results indicate that even at protein concentration as low as 5 g/L, protein aggregation phenomena play an important role in the lubrication of the metal-on-polymer tribopair. The regression models of the COF developed herein are available for numerical simulations of the tribological behavior of the aforementioned tribosystem. In this case, surface stress rather than film thickness should be considered. PMID- 29627737 TI - In-vitro biocompatibility, bioactivity, and mechanical strength of PMMA-PCL polymer containing fluorapatite and graphene oxide bone cements. AB - In this study, a bone cement consisting of poly methyl methacrylate (PMMA)-poly caprolactone (PCL)-fluorapatite (FA)-graphene oxide (GO) was synthesized as bone filler for application in orthopedic surgeries. The FA and GO particulates were homogenously distributed in the PMMA-PCL polymer matrix and no defects and agglomeration were found in the PMMA-PCL/FA/GO bone cement. The in-vitro bioactivity result exhibited that addition of FA and GO to the polymer cement (PMMA-PCL) improved the apatite formation ability on the surface of polymer. The results also showed that addition of FA to the polymer bone cement escalated the compressive strength and elastic modulus while reducing elongation to 8 +/- 2%. However, after addition of GO into the PMMA-PCL/FA bone cement, both compressive strength and elongation considerably increased to 101 +/- 5 MPa and 35 +/- 6%, respectively. Furthermore, tensile tests exhibited that inclusion of GO was favorable in improving the tensile modulus, UTS and elongation of the PMMA-PCL/FA bone cement. The cytotoxicity test pointed out that MG63 osteoblast cells viability increased to 279 +/- 15% after addition of FA and GO to the PMMA-PCL polymer bone cement. The DAPI (4',6-diamidino-2-phenylindole) staining demonstrated better spreading and attachment of MG63 cells on PMMA-PCL/FA/GO surface compared to the PMMA-PCL bone cements. These results confirm the suitable mechanical properties and favorable bioactivity along with high cells viability of PMMA-PCL/FA/GO bone cement, indicating its potentials for orthopedic applications. PMID- 29627738 TI - Polymerization shrinkage stress of resin-based dental materials: A systematic review and meta-analyses of composition strategies. AB - PURPOSE: A systematic review was conducted to determine whether there were composition strategies available to reduce and control polymerization shrinkage stress development in resin-based restorative dental materials. DATA SOURCES: This report was reported in accordance with the PRISMA Statement. Two reviewers performed a literature search up to December 2016, without restriction of the year of publication, in seven databases: PubMed, Web of Science, Scopus, SciELO, LILACS, IBECS, and BBO. STUDY SELECTION: Only laboratory studies that evaluated polymerization shrinkage stress by direct testing were included. Pilot studies, reviews and in vitro studies that evaluated polymerization shrinkage stress by indirect methods (e.g., microleakage or cuspal deflection measurements), finite elemental analysis, or theoretical and mathematical models were excluded. Of the 6113 eligible articles, 62 studies were included in the qualitative analysis, and the meta-analysis was performed with 58 studies. The composition strategy was subdivided according to the modified part of the material: filler phase, coupling agent, or resin matrix. A global comparison was performed with random-effects models (alpha = 0.05). The only subgroup that did not show a statistical difference between the alternative strategy and the control was 'the use of alternative photo-initiators' (p = 0.29). CONCLUSION: Modification of the resin matrix made the largest contribution to minimizing stress development. The technology used for decreasing stress in the formulation of low-shrinkage and bulk-fill materials was shown to be a promising application for reducing and controlling stress development. PMID- 29627739 TI - Viscoelastic characterization of woven Dacron for aortic grafts by using direction-dependent quasi-linear viscoelasticity. AB - In case of direction-dependent viscoelasticity, a simplified formulation of the three-dimensional quasi-linear viscoelasticity has been obtained manipulating the original Fung equation. The experimental characterization of the static hyperelastic behaviour, the relaxation, the dynamic modulus and the loss factor of woven Dacron from a commercial aortic prosthesis has been performed. An 11% difference of the reduced relaxation (after infinite time) between axial and circumferential directions has been observed for the woven Dacron. A very large increase in stiffness is obtained in case of harmonic loading with respect to the static loading. These findings are particularly relevant for dynamic modelling of currently used aortic grafts. PMID- 29627740 TI - Fatigability and functional performance among older adults with low-normal ankle brachial index: Cross-sectional findings from the Baltimore Longitudinal Study of Aging. AB - BACKGROUND AND AIMS: Peripheral artery disease (PAD) is associated with poor mobility and fatigue, but the relationship between preclinical ankle-brachial index (ABI) and early markers of fatigue and functional decline has not been defined. METHODS: 570 adults, 50 and older, from the Baltimore Longitudinal Study of Aging (N = 570), with normal values of ABI (1-1.39), were classified into ABI tertiles. Perceived fatigability was assessed after a 5-min, treadmill walk (1.5 mph) using the Borg rating of perceived exertion (RPE, range 6-20). Functional evaluation included the Health, Aging and Body Composition Physical Performance Battery (HABC PPB), time to complete a 400-m corridor walk (LDCW), and VO2 peak (ml/kg/min). High RPE and poor walking endurance (PWE) were defined as RPE>=10 and taking >5 min for the LDCW, respectively. Differences between tertiles in fatigability and functional measures were tested adjusting for demographics, behavioral characteristics, self-reported fatigue, and medical history. RESULTS: Mean LDCW time and RPE were greater for participants in the lowest tertile compared to those in the highest; mean VO2 peak and HABC PPB scores were lower, suggesting hierarchical associations between fatigability, functional performance, and ABI (p < 0.05 for all). Odds of PWE were greater for those in the lowest ABI tertile compared to the highest; odds of reporting high RPE were greater for those in the middle tertile. CONCLUSIONS: Lower ABI is associated with poorer physical function and increased fatigability, suggesting that early changes in ABI may infer greater risk of functional decline, even among those who may not progress to PAD. PMID- 29627741 TI - Effects of renal sympathetic denervation on myocardial structure, function and perfusion: A serial CMR study. AB - BACKGROUND AND AIMS: Echocardiographic studies have shown improvements in cardiac indices associated with renal sympathetic denervation (RDN), however, the benefits on myocardial perfusion have never been assessed. This trial was designed to study the effects of RDN on myocardial perfusion using cardiac magnetic resonance (CMR) imaging. METHODS: A total of 14 patients with resistant hypertension were recruited for RDN and myocardial perfusion, alongside other CMR indices, was assessed at baseline and at 6 months. RESULTS: RDN showed significant reduction of mean office blood pressures from 181/100 +/- 19/16 mmHg to 147/85 +/- 19/17 mmHg, 6 months after the procedure (p < 0.0001). This was combined with significant improvement in regional aortic distensibility (p < 0.02) and associated with trends of improved myocardial perfusion reserve index (baseline = 2.2 +/- 1; 6 months = 2.9 +/- 1 units) (p = 0.08). Left ventricular end systolic volume index decreased from baseline to 6 months post procedure, 27 +/- 13 ml/m2vs. 22 +/- 10 ml/m2 (p = 0.03), but there was no significant change in left ventricular end diastolic volume index (p = 0.09). There was significant improvement in mean left ventricular ejection fraction from 68 +/- 10% to 72 + 9%, 6 months post procedure (p = 0.04). T1 mapping failed to detect fibrosis in these patients at baseline and therefore no change was noted, however, extracellular volume percent improved from 46 +/- 4% at baseline to 41 +/- 8% at 6 months (p = 0.002). CONCLUSIONS: This study demonstrates that renal sympathetic denervation increased myocardial perfusion by 32% as assessed by CMR, and, this was associated with improvements in cardiac volumes and function. Larger well controlled and randomized studies are required to assess the clinical significance of these findings. PMID- 29627742 TI - Successful management of recurrent iliofemoral venous in-stent stenosis (ISR) with a drug coated balloon (DCB). PMID- 29627743 TI - The value of shear wave elastography in diffuse thyroid disease. AB - PURPOSE: The aim of this study is to discuss the value of ultrasound-based shear waveTM elastography (SWE) in diffuse thyroid disease (DTD). METHOD: Thyroid stiffness in 154 patients with DTD and 30 normal subjects was measured by SWE. The serum indicators of all subjects were detected. RESULTS: The area under the receiver operating characteristic (AUROC) curve for DTD by SWE was 0.852. The AUROCs of SWE for differentiating chronic autoimmune thyroiditis (CAT) from Graves' disease (GD) and subacute thyroiditis (SAT) were 0.549 and 0.989, respectively. The AUROCs for distinguishing GD from SAT by SWE and the fT3/fT4 ratio were 0.975 and 0.713, respectively. CONCLUSION: SWE aids in the diagnosis of DTD, and SWE is superior to the fT3/fT4 ratio for distinguishing GD from SAT. However, SWE was unsuitable for differentiating CAT from GD. PMID- 29627745 TI - Sorting cells alters their redox state and cellular metabolome. AB - A growing appreciation of the metabolic artifacts of cell culture has generated heightened enthusiasm for performing metabolomics on populations of cells purified from tissues and biofluids. Fluorescence activated cell sorting, or FACS, is a widely used experimental approach to purify specific cell types from complex heterogeneous samples. Here we show that FACS introduces oxidative stress and alters the metabolic state of cells. Compared to unsorted controls, astrocytes subjected to FACS prior to metabolomic analysis showed altered ratios of GSSG to GSH, NADPH to NADP+, and NAD+ to NADH. Additionally, a 50% increase in reactive oxygen species was observed in astrocytes subjected to FACS relative to unsorted controls. At a more comprehensive scale, nearly half of the metabolomic features that we profiled by liquid chromatography/mass spectrometry were changed by at least 1.5-fold in intensity due to cell sorting. Some specific metabolites identified to have significantly altered levels as a result of cell sorting included glycogen, nucleosides, amino acids, central carbon metabolites, and acylcarnitines. Although the addition of fetal bovine serum to the cell-sorting buffer decreased oxidative stress and attenuated changes in metabolite concentrations, fetal bovine serum did not preserve the metabolic state of the cells during FACS. We conclude that, irrespective of buffer components and data normalization strategies we examined, metabolomic results from sorted cells do not accurately reflect physiological conditions prior to sorting. PMID- 29627746 TI - Heatwave and elderly mortality: An evaluation of death burden and health costs considering short-term mortality displacement. AB - BACKGROUND: A heatwave can be a devastating natural disaster to human health, and elderly people are particularly vulnerable. With the continuing rise in earth's surface temperature alongside the world's aging population, research on the mortality burden of heatwave for the older population remains relatively sparse. The potential magnitude of benefits of averting such deaths may be considerable. OBJECTIVES: This paper examined the short-term mortality displacement (or "harvesting") of heatwave, characterized the heatwave-mortality relationship, and estimated death burden and health costs attributable to heatwave among the elderly in Australia. METHODS: We collected daily data on the temperature and deaths of people aged >=75 years in the five largest cities of Australia (Sydney, Melbourne, Brisbane, Perth and Adelaide), totaling 368,767 deaths in different periods between 1988 and 2011. A total of 15-tiered heatwave definitions, based on intensity (95th to 99th percentiles of temperature distribution) and duration (two or more consecutive days), were used to quantify heatwave effects, using time-series regression and random-effects meta-analysis. We calculated attributable deaths for each city and by different types of heatwave. Potential economic benefits in monetary terms were also estimated, considering that heat related deaths are avoidable. RESULTS: Among the Australian elderly population, we found significant associations between heatwave and deaths, with raised mortality immediately in the first few days followed by lower-than-expected mortality. In general, heatwave was associated with an average death increase of 28% (95% confidence interval: 15% to 42%), and greater increases were mostly observed for more intense heatwaves across multiple megacities. During the study period, there were dozens to hundreds of deaths attributable to heatwave for each city, equating to an economic loss of several million Australian dollars every year. Although the estimated attributable deaths varied by heatwave intensity and duration, the pattern was not consistent across cities. CONCLUSIONS: Heatwave caused harvesting effects on mortality in the elderly population of Australia, and contributed to a substantial amount of death burden and indirect financial costs. To lessen the health impacts of heatwave in the affected regions, effective heatwave early warning systems and interventions targeted at the elderly population could be beneficial, both now and in the future. PMID- 29627744 TI - A robust and versatile mass spectrometry platform for comprehensive assessment of the thiol redox metabolome. AB - Several diseases are associated with perturbations in redox signaling and aberrant hydrogen sulfide metabolism, and numerous analytical methods exist for the measurement of the sulfur-containing species affected. However, uncertainty remains about their concentrations and speciation in cells/biofluids, perhaps in part due to differences in sample processing and detection principles. Using ultrahigh-performance liquid chromatography in combination with electrospray ionization tandem mass spectrometry we here outline a specific and sensitive platform for the simultaneous measurement of 12 analytes, including total and free thiols, their disulfides and sulfide in complex biological matrices such as blood, saliva and urine. Total assay run time is < 10 min, enabling high throughput analysis. Enhanced sensitivity and avoidance of artifactual thiol oxidation is achieved by taking advantage of the rapid reaction of sulfhydryl groups with N-ethylmaleimide. We optimized the analytical procedure for detection and separation conditions, linearity and precision including three stable isotope labelled standards. Its versatility for future more comprehensive coverage of the thiol redox metabolome was demonstrated by implementing additional analytes such as methanethiol, N-acetylcysteine, and coenzyme A. Apparent plasma sulfide concentrations were found to vary substantially with sample pretreatment and nature of the alkylating agent. In addition to protein binding in the form of mixed disulfides (S-thiolation) a significant fraction of aminothiols and sulfide appears to be also non-covalently associated with proteins. Methodological accuracy was tested by comparing the plasma redox status of 10 healthy human volunteers to a well-established protocol optimized for reduced/oxidized glutathione. In a proof-of-principle study a deeper analysis of the thiol redox metabolome including free reduced/oxidized as well as bound thiols and sulfide was performed. Additional determination of acid-labile sulfide/thiols was demonstrated in human blood cells, urine and saliva. Using this simplified mass spectrometry-based workflow the thiol redox metabolome can be determined in samples from clinical and translational studies, providing a novel prognostic/diagnostic platform for patient stratification, drug monitoring, and identification of new therapeutic approaches in redox diseases. PMID- 29627747 TI - Intratumoral administration of carboplatin bearing poly (epsilon-caprolactone) nanoparticles amalgamated with in situ gel tendered augmented drug delivery, cytotoxicity, and apoptosis in melanoma tumor. AB - BACKGROUND AND OBJECTIVE: In a phase II clinical trial, carboplatin (CBDCA) displayed the response rate of 19% equivalent to dacarbazine in the treatment of malignant melanoma. However, besides desirable therapeutic profile, intravenous (i.v) administration of CBDCA delivers a subtherapeutic concentration at the target site. This entails administration of CBDCA through an alternate route by using nanovectors to achieve therapeutic efficacy in the treatment of melanoma. METHODS AND RESULTS: Carboplatin loaded poly(epsilon-caprolactone) nanoparticles (CBDCA-PCL-NPs) were formulated and amalgamated with chitosan-beta glycerophosphate gel (CBDCA-PCL-NPs-Gel) for intratumoral (i.t) administration. The mean particle size and zeta-potential of CBDCA-PCL-NPs were determined to be 54.5 +/- 6.3-nm and -8.1 +/- 0.9-mV, in addition to spherical shape of the nanoformulation. FT-IR spectroscopy denied any issue of chemical incompatibility between drug and polymer. XRD pattern indicated the amorphous lattice of CBDCA PCL-NPs. The drug loading capacity of CBDCA-PCL-NPs-Gel was estimated to be 152 mg/1 ml. CBDCA-PCL-NPs-Gel demonstrated prolonged drug release up to 48 h. Furthermore, CBDCA-PCL-NPs-Gel displayed the IC50 of 80.3-MUM significantly (P < 0.05) lower than 162.8-MUM of CBDCA-PCL-NPs and 248.5-MUM of CBDCA solution in B16F1, melanoma cancer cells. CBDCA-PCL-NPs-Gel verified 80.2% of apoptosis significantly (P < 0.01) higher than 57.6% of CBDCA-PCL-NPs and 43.4% of CBDCA solution. Continuation to this, CBDCA-PCL-NPs-Gel significantly (P < 0.01) suppressed the tumor volume to 95.5 +/- 8.4-mm3 as compared to 178.9 +/- 10.2-mm3 of CBDCA solution injected i.t. and 210.6 +/- 17.1-mm3 displayed by CBDCA solution injected i.v. vis-a-vis 815.4 +/- 17.1-mm3 tumor volume of B16F1 tumor bearing C57BL6J mice. CONCLUSION: The promising preclinical results of CBDCA-PCL NPs-Gel warrant further investigations under a set of stringent parameters for the treatment of melanoma. PMID- 29627748 TI - The social integration of healthcare agency workers in long-term care facilities: A cross-sectional study. AB - BACKGROUND: Patient care quality is a key concern for long-term care facilities and is directly related to effective collaboration between healthcare professionals. The use of agency staff in long-term care facilities creates important challenges in terms of coordination and communication within work units. OBJECTIVES: The purpose of this study is to assess the mediating effect of common in-group identity in the relationship between permanent employees' perceptions regarding the use of agency workers -namely distributive justice, perceptions of threat, perceived similarities with agency workers, and leader inclusiveness toward agency staff- and the permanent employees' adoption of collaborative behaviours. DESIGN: Cross-sectional study. SETTINGS: Three long term care facilities. PARTICIPANTS: 290 regular healthcare employees (nurses and care attendants). METHODS: Data were obtained through questionnaires filled out by employees. Hypotheses were tested using structural equation analyses. RESULTS: The results showed the indirect effects of perceived distributive justice, perceived similarity and leader inclusiveness toward agency workers on permanent employees' cooperation behaviours through common group identification. Perceptions of threat were not related to common group identification or collaborative behaviours. The results also showed that common in-group identification is related to cooperation behaviours only for employees without previous experience as agency workers. CONCLUSIONS: This study suggests that permanent healthcare employees who feel they are fairly compensated relative to agency workers, who consider these workers as similar to them, and who believe their supervisor appreciates agency workers' contributions tend to develop a common in-group identity, which fosters collaborative behaviours. Managers of long-term care facilities who wish to foster collaboration among their blended workforce should thus create an environment conducive of a more inclusive identity, particularly if their employees have no previous experience as agency workers. PMID- 29627749 TI - Nurses' responses to interruptions during medication tasks: A time and motion study. AB - BACKGROUND: The majority of interruption research has focused on the undesirable effects of interruptions, especially related to errors during medication tasks. However, there may be times when interruptions result in positive effects by providing new information to a situation or preventing an error. The study of nurses' responses to interruptions is limited. Since interruptions cannot (and possibly should not) be avoided, a reasonable method for handling interruptions might be to learn how best to prepare for and manage interruption-prone situations. OBJECTIVES: The purpose of this study was to examine nurses' responses to interruptions and explore contextual factors that influence interruption management during medication tasks. This is a secondary analysis of an original study aimed at describing interruptions and nurses' responses to interruptions during routine nursing work on medical-surgical units. DESIGN AND SETTING: This descriptive study was conducted in 5 medical and/or surgical units at 2 acute care facilities in the southern United States, during weekday shifts. PARTICIPANTS: Twenty registered nurses participated in the study. METHODS: The researcher observed nurse participants for at least 4.5 h during routine nursing work. Observation data were collected using time and motion software. Questionnaires were used to collect organizational, unit, and nurse level data. Interruptions during medication tasks were isolated and described as a secondary analysis. RESULTS: Approximately 39% of medication tasks were interrupted. Following an interruption, nurses were more likely to suspend the medication task to attend to the interruption task (51.1%) or multitask (40.3%) than delay responding to the interruption until the medication task was complete (12.6%). Several characteristics of the interruption task, including task type, source, method, and communication intent were associated with nurses' responses at the level of statistical significance. CONCLUSIONS: The findings of this study reveal that nurses are interrupted frequently during medication tasks. The range of nurses' responses to interruptions was surprising in relation to the frequency with which nurses accepted the interruption task and the infrequency of delay responses. Additional study of nurses' responses to interruptions during medication tasks and the effect of different responses on patient safety outcomes is indicated. PMID- 29627750 TI - Effect of interactive cognitive motor training on gait and balance among older adults: A randomized controlled trial. AB - BACKGROUND: Aging is a normal degenerative process that results in a decline in the gait and balance performance of older adults. Interactive cognitive motor training is an intervention that integrates cognitive and motor tasks to promote individuals' physical and cognitive fall risk factors. However, the additive effects of the interactive cognitive motor training on objective quantitative data and comprehensive descriptions of gait and balance warrants further investigation. OBJECTIVES: To investigate the effect of interactive cognitive motor training on older adults' gait and balance from immediate to long-term time points. DESIGN: A double-blind randomized control trial. SETTINGS: Four senior service centers and community service centers in Taiwan. PARTICIPANTS: 62 older adults who met the inclusion criteria. METHODS: The study participants were older adults without cognitive impairment, and they were randomly allocated to the experimental group or active control group. In both groups, older adults participated in three sessions of 30-min training per week for a total of 8 weeks, with the total number of training sessions being 24. The primary outcome was gait performance, which was measured using objective and subjective indicators. iWALK was used as an objective indicator to measure pace and dynamic stability; the Functional Gait Assessment was employed as a subjective indicator. The secondary outcome was balance performance, which was measured using iSWAY. A generalized estimating equation was used to identify whether the results of the two groups differ after receiving different intervention measures; the results were obtained from immediate to long-term posttests. RESULTS: Stride length in the pace category of the experimental group improved significantly in immediate posttest (p = 0.01), 3-month follow-up (p = 0.01), and 6-month follow-up (p = 0.04). The range of motion of the leg exhibited significant improvement in immediate posttest (p = 0.04) and 3-month follow-up (p = 0.04). The Functional Gait Assessment result indicated that statistically significant improvement was observed in immediate posttest (p = 0.02) and 12-month follow-up (p = 0.01). The results of balance performance showed that the experimental group attained statistically significant improvement in centroid frequency in the immediate posttest (p = 0.02). CONCLUSIONS: The research results validated that the 24 sessions of the interactive cognitive motor training intervention significantly improved gait and balance performance. Future studies should extend the sample to communities to promote the gait and balance performance of community-dwelling older adults without cognitive impairment and reduce their risk of falling and developing gait-related diseases. PMID- 29627751 TI - Ozone risk assessment is affected by nutrient availability: Evidence from a simulation experiment under free air controlled exposure (FACE). AB - Assessing ozone (O3) risk to vegetation is crucial for informing policy making. Soil nitrogen (N) and phosphorus (P) availability could change stomatal conductance which is the main driver of O3 uptake into a leaf. In addition, the availability of N and P could influence photosynthesis and growth. We thus postulated that the sensitivity of plants to O3 may be changed by the levels of N and P in the soil. In this study, a sensitive poplar clone (Oxford) was subject to two N levels (N0, 0 kg N ha-1; N80, 80 kg N ha-1), three P levels (P0, 0 kg P ha-1; P40, 40 kg P ha-1; P80, 80 kg P ha-1) and three levels of O3 exposure (ambient concentration, AA; 1.5 * AA; 2.0 * AA) for a whole growing season in an O3 free air controlled exposure (FACE) facility. Flux-based (POD0 to 6) and exposure-based (W126 and AOT40) dose-response relationships were fitted and critical levels (CLs) were estimated for a 5% decrease of total annual biomass. It was found that N and P availability modified the dose-response relationships of biomass responses to O3. Overall, the N supply decreased the O3 CLs i.e. increased the sensitivity of poplar to O3. Phosphorus alleviated the O3-caused biomass loss and increased the CL. However, such mitigation effects of P were found only in low N and not in high N conditions. In each nutritional treatment, similar performance was found between flux-based and exposure-based indices. However, the flux-based approach was superior, as compared to exposure indices, to explain the biomass reduction when all nutritional treatments were pooled together. The best O3 metric for risk assessments was POD4, with 4.6 mmol m-2 POD4 as a suitable CL for Oxford poplars grown under various soil N and P conditions. PMID- 29627752 TI - Halogenated flame retardants (HFRs) and water-soluble ions (WSIs) in fine particulate matter (PM2.5) in three regions of South China. AB - Halogenated flame retardants (HFRs) and water-soluble ions (WSIs) were investigated in fine particulate matter (PM2.5) collected from an urban site, a rural e-waste recycling (e-waste) site, and a background site in South China. Generally, the WSI concentrations were highest at the e-waste site and comparable at the other sites and secondary species (SO42-, NH4+, and NO3-) were dominant components at the three sites. The compositions and seasonal variations of WSIs at the e-waste site were distinct from those in the urban and background areas suggesting significant influence of e-waste recycling on PM2.5 components. Polybrominated diphenyl ethers (PBDEs) dominated the HFRs in PM2.5 from the e waste site, and their concentrations (median = 883 pg/m3) were significantly higher than those at the urban (375 pg/m3) and background site (52.4 pg/m3). However, novel decabromodiphenyl ethane (DBDPE) was the primary HFRs in the urban air, with noticeably elevated concentrations (median = 356 pg/m3) compared to those in the other two areas (medians = 62.3 and 5.09 pg/m3). The composition profiles of HFRs in the background air followed those in the e-waste areas, with substantial contributions of legacy chemicals. This was explained by the prevailing NE wind, which favored atmospheric transport of HFRs from the e-waste recycling area to the background area. Correlation analysis showed that most HFRs in the urban air are associated with Cl-, implying an industrial emission sources. In the e-waste area, HFRs are associated with organic and elemental carbons (OC and EC) and K+, confirming a common source of e-waste recycling. Significant correlations between HFRs and EC and Cl- in the background air suggest that their occurrence in this region was attributed to both the e-waste and urban areas. PMID- 29627753 TI - Cr(VI)-induced methylation and down-regulation of DNA repair genes and its association with markers of genetic damage in workers and 16HBE cells. AB - To examine the mechanism of hexavalent chromium [Cr(VI)]-induced carcinogenesis, a cross-sectional study in workers with or without exposure to Cr(VI) as well as in vitro administration of Cr(VI) in 16HBE cells was conducted. We explored the associations between Cr(VI) exposure, methylation modification of DNA repair genes and their expression levels, and genetic damage. Results showed that hypermethylation of CpG sites were observed in both occupationally exposed workers and 16HBE cells administrated Cr(VI). DNA damage markers including 8 hydroxydeoxyguanosine (8-OHdG) and micronucleus frequency in Cr(VI)-exposed workers were significantly higher than the control group. Among workers, blood Cr concentration was positively correlaed with the methylation level of CpG sites in DNA repair genes including CpG6,7, CpG8, CpG9,10,11 of MGMT, CpG11 of HOGG1; CpG15,16,17, CpG19 of RAD51, and genetic damage markers including 8-OHdG and micronucleus frequency. Significant negative association between methylation levels of CpG sites in DNA repair genes and corresponding mRNA was also observed in 16HBE cells. This indicated that Cr(VI) exposure can down-regulate DNA repair gene expression by hypermethylation, which leads to enhanced genetic damage. The methylation level of these CpG sites of DNA repair genes can be potential epigenetic markers for Cr(VI)-induced DNA damage. PMID- 29627754 TI - Long-term dim light during nighttime changes activity patterns and space use in experimental small mammal populations. AB - Artificial light at night (ALAN) is spreading worldwide and thereby is increasingly interfering with natural dark-light cycles. Meanwhile, effects of very low intensities of light pollution on animals have rarely been investigated. We explored the effects of low intensity ALAN over seven months in eight experimental bank vole (Myodes glareolus) populations in large grassland enclosures over winter and early breeding season, using LED garden lamps. Initial populations consisted of eight individuals (32 animals per hectare) in enclosures with or without ALAN. We found that bank voles under ALAN experienced changes in daily activity patterns and space use behavior, measured by automated radiotelemetry. There were no differences in survival and body mass, measured with live trapping, and none in levels of fecal glucocorticoid metabolites. Voles in the ALAN treatment showed higher activity at night during half moon, and had larger day ranges during new moon. Thus, even low levels of light pollution as experienced in remote areas or by sky glow can lead to changes in animal behavior and could have consequences for species interactions. PMID- 29627755 TI - Associations of hemoglobin biomarker levels of acrylamide and all-cause and cardiovascular disease mortality among U.S. adults: National Health and Nutrition Examination Survey 2003-2006. AB - BACKGROUND: The potential hazards of acrylamide (AA) have been proposed due to its lifelong exposure. However, the association between AA exposure and mortality remains unclear. OBJECTIVES: We evaluated the prospective association of AA hemoglobin adducts (HbAA and HbGA) with all-cause and cardiovascular disease (CVD) mortality in U.S. population from National Health and Nutrition Examination Survey (NHANES) 2003-2006. METHODS: We followed 5504 participants who were >=25 years of age for an average of 6.7 years at the baseline examination with annual linkage to the NHANES statistics database. Using AA hemoglobin biomarkers [HbAA, HbGA, sum of HbAA and HbGA (HbAA + HbGA), and ratio of HbGA to HbAA (HbGA/HbAA)], we determined mortality from all-causes and CVD through Cox proportional hazard regression analysis with multivariable adjustments both in non-smoker group and smoker group. In addition, subgroup analyses and sensitivity analyses were further conducted. RESULTS: After adjusting for sociodemographic, life behavioral and cardiovascular risk factors in non-smoker group, HbAA was positively associated with all-cause mortality (p for trend = 0.0197) and non-CVD mortality (p for trend = 0.0124). HbGA and HbGA/HbAA were inversely associated with all cause mortality (p for trend = 0.0117 and 0.0098, respectively) and CVD mortality (p for trend=0.0009 and 0.0036, respectively). The multivariable adjusted hazard ratios (HRs) [95% confidence intervals (CIs)] of the upper three quartiles were 0.472 (95% CI: 0.283-0.786), 0.517 (95% CI: 0.299-0.894) and 0.470 (95% CI: 0.288 0.766) between HbGA/HbAA and all-cause mortality comparing with the lowest quartile, respectively. No significant associations were found between HbAA + HbGA and mortality in non-smoker group, and between all AA hemoglobin biomarkers and mortality in smoker group. CONCLUSIONS: Hemoglobin biomarker levels of AA were strongly associated with mortality in general U.S. non-smoker adults. These findings proposed a continuous public health concern in relation to environmental and dietary exposure to AA. PMID- 29627756 TI - Role of extracellular polymeric substances in the acute inhibition of activated sludge by polystyrene nanoparticles. AB - Microplastics and nanoplastics in aquatic systems have become a global concern because of their persistence and adverse consequences to ecosystems and potentially human health. Though wastewater treatment plants (WWTPs) are considered a potential source of microplastics in the environment, the role of extracellular polymeric substances (EPS) of activated sludge on the fate of nanoplastics is not clear. In this study, the role of EPS in the influence of polystyrene nanoparticles (PS-NPs) on the endogenous respiration of activated sludge was investigated for the first time. The results showed that the acute inhibition of activated sludge by PS-NPs was enhanced with increasing PS-NPs concentration. X-ray photoelectron spectroscopy (XPS) results indicate that the functional groups involved in the interactions between PS-NPs and EPS were carbonyl and amide groups and the side chains of lipids or amino acids. Furthermore, the Fourier transform infrared (FTIR) spectroscopy results show that the protein secondary structures in EPS were changed by PS-NPs and lead to the bioflocculation of activated sludge, which provides a better understanding on the fate of nanoplastics in WWTPs. PMID- 29627757 TI - How do we facilitate international clinical placements for nursing students: A cross-sectional exploration of the structure, aims and objectives of placements. AB - BACKGROUND: International clinical placements provide undergraduate students with a unique and complex clinical learning environment, to explore cultural awareness, experience different health care settings and achieve clinical competencies. Higher education institutions need to consider how to structure these placements to ensure appropriate and achievable aims and learning outcomes. OBJECTIVES: In this study we described the structure, aims and learning outcomes associated with international clinical placement opportunities currently undertaken by Australian undergraduate nursing students in the Asia region. PARTICIPANTS: Forty eight percent (n = 18) of the institutions invited responded. Eight institutions met the inclusion criteria, one of which offered three placements in the region, resulting in 10 international placements for which data were provided. METHODS: An online survey tool was used to collect data during August and September 2015 on international clinical placements conducted by the participating universities. Descriptive data on type and numbers of placements is presented, along with results from the content analysis conducted to explore data from open ended questions on learning aims and outcomes. RESULTS: One hundred students undertook 10 International Clinical Placements offered in the Asian region by eight universities. Variations across placements were found in the length of placement, the number of students participating, facilitator to student ratios and assessment techniques used. Five categories related to the aims of the programs were identified: 'becoming culturally aware through immersion', 'working with the community to promote health', 'understanding the role of nursing within the health care setting', 'translating theory into professional clinical practice', and 'developing relationships in international learning environments'. Four categories related to learning outcomes were identified: 'understanding healthcare and determinants of health', 'managing challenges', 'understanding the role of culture within healthcare' and 'demonstrating professional knowledge, skills and behaviour'. CONCLUSIONS: International clinical placements in the Asia region appear to vary greatly from one education institution to the next with no clear consensus from either this study's findings or the literature on which structure, support and assessments lead to greater student learning. PMID- 29627758 TI - Teaching to transgress: Education as the practice of freedom. A relevant application to contemporary issues. PMID- 29627759 TI - Maternal exposure to particulate matter alters early post-natal lung function and immune cell development. AB - BACKGROUND: In utero exposure to particulate matter (PM) from a range of sources is associated with adverse post-natal health; however, the effect of maternal exposure to community-sampled PM on early post-natal lung and immune development is poorly understood. OBJECTIVES: Using a mouse model, we aimed to determine whether in utero exposure to PM alters early post-natal lung function and immune cell populations. We used PM collected from ceiling voids in suburban houses as a proxy for community PM exposure. METHODS: Pregnant C57BL/6 mice were intranasally exposed to ceiling derived PM, or saline alone, at gestational day (E) 13.5, 15.5, and 17.5. When mice were two weeks old, we assessed lung function by the forced oscillation technique, and enumerated T and B cell populations in the spleen and thymus by flow cytometry. RESULTS: Maternal exposure to PM impaired somatic growth of male offspring resulting in reduced lung volume and deficits in lung function. There was no effect on thymic T cell populations in dams and their male offspring but PM decreased the CD4 +CD25 + T cell population in the female offspring. In contrast, maternal exposure to PM increased splenic CD3 +CD4 + and CD3 +CD8 + T cells in dams, and there was some evidence to suggest inhibition of splenic T cell maturation in male but not female offspring. CONCLUSIONS: Our findings suggested that maternal exposure to ceiling void PM has the capacity to impair early somatic growth and alter early life immune development in a sex specific manner. PMID- 29627760 TI - Effects of exposure estimation errors on estimated exposure-response relations for PM2.5. AB - Associations between fine particulate matter (PM2.5) exposure concentrations and a wide variety of undesirable outcomes, from autism and auto theft to elderly mortality, suicide, and violent crime, have been widely reported. Influential articles have argued that reducing National Ambient Air Quality Standards for PM2.5 is desirable to reduce these outcomes. Yet, other studies have found that reducing black smoke and other particulate matter by as much as 70% and dozens of micrograms per cubic meter has not detectably affected all-cause mortality rates even after decades, despite strong, statistically significant positive exposure concentration-response (C-R) associations between them. This paper examines whether this disconnect between association and causation might be explained in part by ignored estimation errors in estimated exposure concentrations. We use EPA air quality monitor data from the Los Angeles area of California to examine the shapes of estimated C-R functions for PM2.5 when the true C-R functions are assumed to be step functions with well-defined response thresholds. The estimated C-R functions mistakenly show risk as smoothly increasing with concentrations even well below the response thresholds, thus incorrectly predicting substantial risk reductions from reductions in concentrations that do not affect health risks. We conclude that ignored estimation errors obscure the shapes of true C-R functions, including possible thresholds, possibly leading to unrealistic predictions of the changes in risk caused by changing exposures. Instead of estimating improvements in public health per unit reduction (e.g., per 10 ug/m3 decrease) in average PM2.5 concentrations, it may be essential to consider how interventions change the distributions of exposure concentrations. PMID- 29627761 TI - Following the patient's orders? Recommending vs. offering choice in neurology outpatient consultations. AB - The UK's Royal College of Surgeons (2016) has argued that health professionals must replace a 'paternalistic' approach to consent with 'informed choice'. We engage with these guidelines through analysis of neurology consultations in two UK-based neuroscience centres, where informed choice has been advocated for over a decade. Based on 223 recorded consultations and related questionnaire data (collected in 2012), we used conversation analysis (CA) to identify two practices for offering choice: patient view elicitors (PVEs) and option-lists. This paper reports further, mixed-methods analyses, combining CA with statistical techniques to compare the 'choice' practices with recommendations. Recommendations were overwhelmingly more common. There was little evidence that patient demographics determined whether choice was offered. Instead, decisional practices were associated with a range of clinical considerations. There was also evidence that individual neurologists tended to have a 'style', making it partly a matter of chance which decisional practice(s) patients encountered. This variability matters for the perception of choice: neurologists and patients were more likely to agree a choice had been offered if a PVE or option-list was used. It also matters for the outcome of the decision-making process: while recommendations nearly always ended in agreement to undertake the proffered course of action, option-lists and PVEs did so only about two-thirds of the time. While the direction of causality is unknown, this may indicate that patients are better enabled to refuse things they don't want when neurologists avoid recommending. We argue that our findings imply that neurologists tend to view choice as risky - in that the patient might make the 'wrong' choice - but that the inter-individual variation indicates that greater use of the more participatory practices is possible. PMID- 29627762 TI - A hybrid approach to increase the informedness of CE-based data using locus specific thresholding and machine learning. AB - The interpretation of genetic profiles require a robust and reliable method to discriminate true allelic information from noise, regardless of the instrumentation or methods used. Traditionally, static peak detection thresholds (analytical thresholds) have been applied to capillary electrophoresis generated data to distinguish the true allelic peaks from noise. While the rigid nature of these thresholds attempts to conservatively account for baseline variability across instrument runs, samples, capillaries, dye-channels, injection times, and voltage, its static nature is unable to adapt, leading to a loss of allelic information that exists below the threshold. The method described herein is able to account for this variability by collectively minimizing the incorrect detection of non-allelic artifacts (false positives) and the threshold-induced dropout of true allelic information (false negatives). This is accomplished by using a dynamic locus and sample specific analytical threshold and a machine learning-derived probabilistic artifact detection model. The system produced an allele detection accuracy of 97.2%, an 11.4% increase from the lowest static threshold (50 RFU), with a low incidence of incorrectly identified artifacts (0.79%). This adaptive method outperformed static thresholds in the retention of allelic information content at minimal cost. PMID- 29627763 TI - "Lipid raft aging" in the human frontal cortex during nonpathological aging: gender influences and potential implications in Alzheimer's disease. AB - Lipid rafts are highly dynamic membrane domains featured by distinctive biochemical composition and physicochemical properties compared with the surrounding plasma membrane. These microstructures are associated not only with cellular signaling and communication in normal nerve cells but also with pathological processing of amyloid precursor protein in Alzheimer's disease. Using lipid rafts isolated from human frontal cortex in nondemented subjects aging 24 to 85 years, we demonstrate here that lipid structure of lipid rafts undergo significant alterations of specific lipid classes and phospholipid-bound fatty acids as brain cortex correlating with aging. Main changes affect levels of plasmalogens, polyunsaturated fatty acids (especially docosahexaenoic acid and arachidonic acid), total polar lipids (mainly phosphatidylinositol, sphingomyelin, sulfatides, and cerebrosides), and total neutral lipids (particularly cholesterol and sterol esters). Besides, relevant relationships between main fatty acids and/or lipid classes were altered in an age-related manner. This "lipid raft aging" exhibits clear gender differences and appear to be more pronounced in women than in men, especially in older (postmenopausal) women. The outcomes led us to conclude that human cortical lipid rafts are modified by aging in a gender-dependent fashion. Given the central role of bilayer lipid matrix in lipid rafts functionality and neuronal signaling, we hypothesize that these findings might underlie the higher prevalence of cognitive decline evolving toward Alzheimer's disease in postmenopausal women. PMID- 29627765 TI - Scoliosis in association with the 22q11.2 deletion syndrome: an observational study. AB - OBJECTIVE: The 22q11.2 deletion syndrome (22q11.2DS) is the most common microdeletion syndrome in humans. It is characterised by wide phenotypic variability, including congenital heart disease (CHD), immunodeficiency and scoliosis. However, little is known regarding the prevalence and characteristics of scoliosis in patients with 22q11.2DS. The objective of this study is to assess the prevalence of scoliosis, its characteristics and the association with CHD in patients with 22q11.2DS. DESIGN: This prevalence study is based on physical examination and questionnaires of the world's largest 22q11.2DS longitudinal collected database (n=1393, Children's Hospital of Philadelphia) and was augmented with the scoliosis prevalence based on radiography in a smaller cohort (cross-sectional, University Medical Center Utrecht). PATIENTS: Patients with a laboratory-confirmed 22q11.2 deletion who visited the specialised outpatient clinics were considered for inclusion. MAIN OUTCOME MEASURES: (1) The prevalence of scoliosis, (2) its association with CHD, and (3) the similarity between 22q11.2DS curve patterns and adolescent idiopathic scoliosis (AIS) curve patterns. RESULTS: Within the Philadelphia cohort, the prevalence of scoliosis in patients older than 16 years (n=317) was 48% (n=152). A similar prevalence (49%) was shown for the younger Utrecht cohort (n=97). The occurrence of scoliosis was not associated with the presence of CHD. Sixty-three per cent of patients with scoliosis had a scoliotic curve pattern that resembled AIS. CONCLUSIONS: Clinicians should be aware that scoliosis is highly prevalent (48%-49%) in association with 22q11.2DS, irrespective of other clinical features (eg, the presence of CHD). Furthermore, 22q11.2DS may provide insights into the causes of AIS. PMID- 29627764 TI - Dynamic role of the transmembrane glycoprotein CD36 (SR-B2) in cellular fatty acid uptake and utilization. AB - The widely expressed transmembrane glycoprotein, cluster of differentiation 36 (CD36), a scavenger receptor class B protein (SR-B2), serves many functions in lipid metabolism and signaling. Here, we review CD36's role in facilitating cellular long-chain fatty acid uptake across the plasma membrane, particularly in heart and skeletal muscles. CD36 acts in concert with other membrane proteins, such as peripheral plasma membrane fatty acid-binding protein, and is an intracellular docking site for cytoplasmic fatty acid-binding protein. The cellular fatty-acid uptake rate is governed primarily by the presence of CD36 at the cell surface, which is regulated by the subcellular vesicular recycling of CD36 from endosomes to the plasma membrane. CD36 has been implicated in dysregulated fatty acid and lipid metabolism in pathophysiological conditions, particularly in high-fat diet-induced insulin resistance and diabetic cardiomyopathy. Current research is exploring signaling pathways and vesicular trafficking routes involving CD36 to identify metabolic targets to manipulate the cellular utilization of fatty acids. Because of its rate-controlling function in the use of fatty acids in the heart and muscle, CD36 would be a preferable target to protect myocytes against lipotoxicity. Despite a poor understanding of its mechanism of action, CD36 has emerged as a pivotal membrane protein involved in whole-body lipid homeostasis. PMID- 29627766 TI - We have to talk about health-related quality of life. PMID- 29627767 TI - Attended and Unattended Automated Office Blood Pressure Measurements Have Better Agreement With Ambulatory Monitoring Than Conventional Office Readings. AB - BACKGROUND: Automated office blood pressure (AOBP) measurement is superior to conventional office blood pressure (OBP) because it eliminates the "white coat effect" and shows a strong association with ambulatory blood pressure. METHODS AND RESULTS: We conducted a cross-sectional study in 146 participants with office hypertension, and we compared AOBP readings, taken with or without the presence of study personnel, before and after the conventional office readings to determine whether their variation in blood pressure showed a difference in blood pressure values. We also compared AOBP measurements with daytime ambulatory blood pressure monitoring and conventional office readings. The mean age of the studied population was 56+/-12 years, and 53.4% of participants were male. Bland-Altman analysis revealed a bias (ie, mean of the differences) of 0.6+/-6 mm Hg systolic for attended AOBP compared with unattended and 1.4+/-6 and 0.1+/-6 mm Hg bias for attended compared with unattended systolic AOBP when measurements were performed before and after conventional readings, respectively. A small bias was observed when unattended and attended systolic AOBP measurements were compared with daytime ambulatory blood pressure monitoring (1.3+/-13 and 0.6+/-13 mm Hg, respectively). Biases were higher for conventional OBP readings compared with unattended AOBP (-5.6+/-15 mm Hg for unattended AOBP and oscillometric OBP measured by a physician, -6.8+/-14 mm Hg for unattended AOBP and oscillometric OBP measured by a nurse, and -2.1+/-12 mm Hg for unattended AOBP and auscultatory OBP measured by a second physician). CONCLUSIONS: Our findings showed that independent of the presence or absence of medical staff, AOBP readings revealed similar values that were closer to daytime ambulatory blood pressure monitoring than conventional office readings, further supporting the use of AOBP in the clinical setting. PMID- 29627768 TI - Mitochondrial Ca2+ Influx Contributes to Arrhythmic Risk in Nonischemic Cardiomyopathy. AB - BACKGROUND: Heart failure (HF) is associated with increased arrhythmia risk and triggered activity. Abnormal Ca2+ handling is thought to underlie triggered activity, and mitochondria participate in Ca2+ homeostasis. METHODS AND RESULTS: A model of nonischemic HF was induced in C57BL/6 mice by hypertension. Computer simulations were performed using a mouse ventricular myocyte model of HF. Isoproterenol-induced premature ventricular contractions and ventricular fibrillation were more prevalent in nonischemic HF mice than sham controls. Isolated myopathic myocytes showed decreased cytoplasmic Ca2+ transients, increased mitochondrial Ca2+ transients, and increased action potential duration at 90% repolarization. The alteration of action potential duration at 90% repolarization was consistent with in vivo corrected QT prolongation and could be explained by augmented L-type Ca2+ currents, increased Na+-Ca2+ exchange currents, and decreased total K+ currents. Of myopathic ventricular myocytes, 66% showed early afterdepolarizations (EADs) compared with 17% of sham myocytes (P<0.05). Intracellular application of 1 MUmol/L Ru360, a mitochondrial Ca2+ uniporter-specific antagonist, could reduce mitochondrial Ca2+ transients, decrease action potential duration at 90% repolarization, and ameliorate EADs. Furthermore, genetic knockdown of mitochondrial Ca2+ uniporters inhibited mitochondrial Ca2+ uptake, reduced Na+-Ca2+ exchange currents, decreased action potential duration at 90% repolarization, suppressed EADs, and reduced ventricular fibrillation in nonischemic HF mice. Computer simulations showed that EADs promoted by HF remodeling could be abolished by blocking either the mitochondrial Ca2+ uniporter or the L-type Ca2+ current, consistent with the experimental observations. CONCLUSIONS: Mitochondrial Ca2+ handling plays an important role in EADs seen with nonischemic cardiomyopathy and may represent a therapeutic target to reduce arrhythmic risk in this condition. PMID- 29627769 TI - Development and validation of an admission prediction tool for emergency departments in the Netherlands. AB - OBJECTIVE: Early prediction of admission has the potential to reduce length of stay in the ED. The aim of this study is to create a computerised tool to predict admission probability. METHODS: The prediction rule was derived from data on all patients who visited the ED of the Rijnstate Hospital over two random weeks. Performing a multivariate logistic regression analysis factors associated with hospitalisation were explored. Using these data, a model was developed to predict admission probability. Prospective validation was performed at Rijnstate Hospital and in two regional hospitals with different baseline admission rates. The model was converted into a computerised tool that reported the admission probability for any patient at the time of triage. RESULTS: Data from 1261 visits were included in the derivation of the rule. Four contributing factors for admission that could be determined at triage were identified: age, triage category, arrival mode and main symptom. Prospective validation showed that this model reliably predicts hospital admission in two community hospitals (area under the curve (AUC) 0.87, 95% CI 0.85 to 0.89) and in an academic hospital (AUC 0.76, 95% CI 0.72 to 0.80). In the community hospitals, using a cut-off of 80% for admission probability resulted in the highest number of true positives (actual admissions) with the greatest specificity (positive predictive value (PPV): 89.6, 95% CI 84.5 to 93.6; negative predictive value (NPV): 70.3, 95% CI 67.6 to 72.9). For the academic hospital, with a higher admission rate, a 90% probability was a better cut-off (PPV: 83.0, 95% CI 73.8 to 90.0; NPV: 59.3, 95% CI 54.2 to 64.2). CONCLUSION: Admission probability for ED patients can be calculated using a prediction tool. Further research must show whether using this tool can improve patient flow in the ED. PMID- 29627770 TI - Essential medicines for emergency care in Africa. AB - OBJECTIVES: Essential medicines lists (EMLs) are efficient means to ensure access to safe and effective medications. The WHO has led this initiative, generating a biannual EML since 1977. Nearly all countries have implemented national EMLs based on the WHO EML. Although EMLs have given careful consideration to many public health priorities, they have yet to comprehensively address the importance of medicines for treating acute illness and injury. METHODS: We undertook a multistep consensus process to establish an EML for emergency care in Africa. After a review of existing literature and international EMLs, we generated a candidate list for emergency care. This list was reviewed by expert clinicians who ranked the medicines for overall inclusion and strength of recommendation. These medications and recommendations were then evaluated by an expert group. Medications that reached consensus in both the online survey and expert review were included in a draft emergency care EML, which underwent a final inperson consensus process. RESULTS: The final emergency care EML included 213 medicines, 25 of which are not in the 2017 WHO EML, but were deemed essential for clinical practice by regional emergency providers. The final EML has associated recommendations of desirable or essential and is subdivided by facility level. Thirty-nine medicines were recommended for basic facilities, an additional 96 for intermediate facilities (eg, district hospitals) and an additional 78 for advanced facilities (eg, tertiary centres). CONCLUSION: The 25 novel medications not currently on the WHO EML should be considered by planners when making rational formularies for developing emergency care systems. It is our hope that these resource-stratified lists will allow for easier implementation and will be a useful tool for practical expansion of emergency care delivery in Africa. PMID- 29627771 TI - Collateral status as the fifth dimension: warping the time clock for endovascular treatment in acute ischaemic stroke. PMID- 29627772 TI - Altered cerebral blood flow in the anterior cingulate cortex is associated with neuropathic pain. AB - OBJECTIVE: To assess the cerebral blood flow (CBF) in patients with diabetic neuropathic pain, and its changes after duloxetine therapy. METHODS: Using iodine 123-N-isopropyl-p-iodoamphetamine single-photon emission computed tomography (IMP SPECT), we performed a cross-sectional study of 44 patients with diabetes, and compared CBF in those with (n = 24) and without neuropathic pain (n = 20). In patients with neuropathic pain, we also longitudinally assessed changes in CBF 3 months after treatment with duloxetine. RESULTS: IMP-SPECT with voxel-based analyses showed a significant increase in cerebral blood flow in the right anterior cingulate cortex and a decrease in the left ventral striatum in patients with neuropathic pain, compared with those without pain. After duloxetine treatment, volume of interest analyses revealed a decrease in cerebral blood flow in the anterior cingulate cortex in patients with significant pain relief but not in non-responders. Furthermore, voxel-based whole brain correlation analyses demonstrated that greater baseline CBF in the anterior cingulate cortex was associated with better pain relief on the numerical rating scale. CONCLUSIONS: Our results suggest that the development of neuropathic pain is associated with increased activity in the anterior cingulate cortex, and greater baseline activation of this region may predict treatment responsiveness to pharmacological intervention. TRIAL REGISTRATION NUMBER: UMIN000017130;Results. PMID- 29627773 TI - Clinical outcome of Guillain-Barre syndrome after prolonged mechanical ventilation. AB - BACKGROUND: Patients with Guillain-Barre syndrome (GBS) may suffer from respiratory failure for months or longer. The aim of this study was to determine the frequency, clinical course and outcome of patients with GBS requiring prolonged mechanical ventilation (MV). METHODS: Prospectively collected data from 526 patients with GBS participating in previous trials were analysed to determine the frequency and duration of prolonged MV (longer than 2 months). In addition, a cross-sectional study was conducted in patients with GBS requiring MV to determine the clinical course and long-term outcome with the ability to walk unaided as primary endpoint. RESULTS: In the cohort study, 145 of 526 patients with GBS (28%) required MV, including 33 (6%) patients with prolonged MV. Patients requiring prolonged MV had a lower Medical Research Council sum score and more frequent bulbar involvement and inexcitable nerves compared with shorter ventilated patients. At 6 months, 18% of patients with prolonged MV were able to walk unaided compared with 76% of patients requiring shorter MV (P<0.001). In the cross-sectional study, 63 patients requiring MV were included with a median follow-up of 11 years (range 2-44 years). Twenty-six (41%) of these patients needed prolonged MV (median 93 days, range 62-261). Fifteen (58%) of these patients were able to walk unaided at maximum follow-up and eight (31%) reached this endpoint more than 1 year after diagnosis. CONCLUSIONS: Prolonged ventilation in GBS is associated with poor prognosis, yet patients requiring prolonged ventilation may show slow but persistent recovery for years and even reach the ability to walk and live independently. PMID- 29627774 TI - Acute lower limb ischaemia secondary to intestinal occlusion. AB - In general, acute lower limb ischaemia is caused by embolic, thrombotic or traumatic phenomena. Here, we describe the case of a 67-year-old woman in an emergency room setting who was initially assessed for paralysis and numbness of her lower left limb. On physical examination, the abdomen was distended and non compressible. An abdominal AngioScan showed complete occlusion of the left iliac artery by extrinsic compression of the dilated small intestine. After a review of the literature, no case was found describing a lower limb ischaemia by extrinsic vascular compression secondary to a compartment syndrome caused by small bowel obstruction. The treatment of this case required surgical decompression of the abdomen which led to an instantaneous reperfusion of the left leg. Unfortunately, the patient deceased a few hours after the surgery due to haemodynamic deterioration. PMID- 29627775 TI - Acute mucocutaneous methotrexate toxicity with marked tissue eosinophilia. AB - Methotrexate toxicity in mucocutaneous areas is usually not associated with tissue eosinophilia. We describe a case of acute methotrexate-induced mucocutaneous erosions with interface dermatitis and eosinophils. A 76-year-old African-American woman with a history of bullous pemphigoid on methotrexate therapy presented with lower extremity cellulitis, developing oral and cutaneous erosions during hospitalization after daily dosage of methotrexate. Shallow circular cutaneous erosions were found on chest, abdomen and limbs. Laboratory results showed pancytopaenia and elevated liver function tests. Skin biopsy revealed irregular acanthotic epidermis with interface dermatitis, individual dyskeratotic cells and superficial perivascular lymphocytic infiltrate with numerous eosinophils. Methotrexate was stopped and leucovorin was administered, leading to improvement. The histopathological changes in acute mucocutaneous toxicity range from pauci-inflammatory erosions with dyskeratotic keratinocytes to interface dermatitis and infrequently seen eosinophils. This case exemplifies that interface dermatitis with a marked eosinophilic infiltrate can be found in the setting of acute mucocutaneous methotrexate toxicity. PMID- 29627776 TI - Atypical mycobacteriosis in a poorly compliant patient. PMID- 29627777 TI - Good clinical history scores over extensive workup in unmasking a case of galactorrhoea. AB - The clinical presentation of a young woman with galactorrhoea is described in detail including the history and clinical examination findings. While the patient and her family members feared a serious medical condition which had so far been an obscurity despite a number of investigations, we tried to diagnose the patient starting from the basics, which after a proper history revealed a levosulpiride induced galactorrhoea. This again lays emphasis on the old adage in medical field that 'a proper history and examination are the key to diagnosis'. There are few reports pertaining to levosulpiride-induced galactorrhoea making it a rare side effect of this drug. We further try to discuss the different causes of galactorrhoea in a young non-pregnant woman which can be encountered in clinical practice. PMID- 29627778 TI - Bilateral pneumothorax, surgical emphysema and pneumomediastinum in a young male patient following MDMA intake. AB - MDMA (3,4-methylenedioxymethamphetamine) or 'Ecstasy' is an illicit drug frequently used by young people at parties and 'raves'. It is readily available in spite of the fact that it is illegal.1 It is perceived by a lot of young people as being 'harmless', but there have been a few high-profile deaths associated with its use.2 Known side effects of MDMA include hyperthermia, rhabdomyolysis, coagulopathy and cardiac arrhythmias.3 Rarer side effects include surgical emphysema and pneumomediastinum, which have been better described with cocaine abuse.4-6 We present a case of bilateral pneumothorax, surgical emphysema and pneumomediastinum in a young man after taking ecstasy. PMID- 29627779 TI - Low-dose warfarin maternal anticoagulation and fetal warfarin syndrome. AB - Fetuses exposed to warfarin during pregnancy are at an increased risk of developing an embryopathy known as fetal warfarin syndrome or warfarin embryopathy. The most consistent anomalies are nasal hypoplasia and stippling of vertebrae or bony epiphyses. Management of pregnant patients on anticoagulation is challenging. Current guidelines suggest the use of warfarin if the therapeutic dose is <=5 mg/day. We report the case of a newborn with signs of warfarin embryopathy born from a mother anticoagulated with warfarin due to mechanical mitral and aortic heart valves. Warfarin was required at the dose of 5 mg/day and was withheld without medical advice between weeks 8 and 10 with no other anticoagulation. The newborn presented with skeletal abnormalities and a ventricular septal defect that have not required specific treatment during the first year of life. Low-dose warfarin is associated with a lower risk of warfarin related fetopathy but the risk of embryopathy seems unchanged. PMID- 29627780 TI - Double venous compression due to duplicated inferior vena cava-induced right common iliac vein thrombosis. AB - Venous compression syndromes are caused by extrinsic venous compression of anatomical structures, such as the adjacent arteries and bones. Chronic venous compression and pulsative vibratory arterial pressure accelerate the development of deep vein thrombosis. Herein, we report the first case of double venous compressions due to a duplicated inferior vena cava-induced right-sided common iliac vein thrombosis. The thrombus was induced by left-sided inferior vena cava entrapment and right-sided common iliac vein compression, resembling nutcracker syndrome and May-Thurner syndrome, respectively. Bypass flow of the right inferior vena cava rendered the right lower extremity asymptomatic. Once daily anticoagulation edoxaban was effective. Congenital venous anomalies and bypass formations should be considered when a common iliac vein thrombus without symptoms in the lower extremities is observed, and a lifelong periodical follow up is mandatory, even after remission. PMID- 29627781 TI - Novel MRI of mediastinal masses: internal differentiation of a thymoma and lymphoma with T1 and T2 mapping. AB - Routine imaging for mediastinal malignancies includes chest X-ray, CT or MRI. T1 and T2 mapping are novel MRI techniques which may have a role in expanding the assessment of internal tumour characteristics. This case report details two middle-aged women who had similar clinical presentations of mediastinal masses of comparable size and appearance when assessed with routine imaging. T1 and T2 maps were acquired on MRI to investigate whether these tumours could be further differentiated prior to surgery. T1 and T2 mapping supported suspicion for which tumour components were solid and cystic, as subsequently confirmed histologically. Furthermore, comparison between the two tumours showed native T1 values differed within the solid components by 37%, correlating to differences in proteinaceous material within the tumour types. This radiological-pathological correlation provides evidence that T1 and T2 mapping has clinical utility in the assessment and differentiation of mediastinal masses. PMID- 29627782 TI - Pemphigoid gestationis successfully treated with intravenous immunoglobulin. AB - Pemphigoid gestationis (PG), also known as herpes gestationis, is a rare autoimmune blistering disease specific to pregnancy, which usually presents in the second or third trimesters and, in 15%-25% of cases, during the immediate postpartum period.1Although the ethiopathogeny of PG is not fully clarified, most patients develop antibodies against a 180 kDa transmembrane hemidesmosomal protein (BP180; BPAG2; collagen XVII).2 PG has a strong association with human leucocyte antigens DR3 and DR4.3We report a case of a 29-year-old female patient with PG successfully treated with intravenous immunoglobulin. PMID- 29627783 TI - Anti-N-methyl-D-aspartate receptor encephalitis relapse in the brainstem. PMID- 29627784 TI - Combined healthy lifestyle behaviours and incident disability in an elderly population: the Ohsaki Cohort 2006 Study. AB - BACKGROUND: The joint impact of healthy lifestyle behaviours (HLBs) on incident disability among elderly populations is still uncertain. This cohort study was conducted to estimate the population-attributable fraction (PAF) of combined HLBs for disability reduction in elderly Japanese. METHODS: We analysed 10-year follow up data for 9910 community-dwelling elderly people (>=65 years) in a prospective cohort study. Information on lifestyle behaviours and food consumption was collected via a questionnaire in 2006. The exposure variable was defined as a healthy lifestyle index (HLI), which represented the summed number of HLBs ('never or former smoker', 'time spent walking >=0.5 hour/day' and 'vegetable and fruit consumption volume >=median'). Data on incident disability were retrieved from the public Long term Care Insurance database. HRs and 95% CIs were estimated by Cox proportional regression and the PAFs and their 95% CIs were estimated with the multivariate-adjusted model. RESULTS: The 10-year incidence of disability was 35.7%. An inverse dose-response relationship was observed (HR (95% CI): 0.85(0.81 to 0.90) for each one-point increase of the HLI score, p-trend <0.001). Based on multivariate-adjustment, adherence to each one additional HLB gives PAF of 10.5%(95% CI 9.0% to 12.0%) for disability reduction. The PAF would have been 25.9%(14.2% to 36.0%) if all subjects had adhered to all three HLBs. CONCLUSION: Combined HLBs may have a substantial impact on reducing the risk of incident disability among elderly people. Even having one more healthy lifestyle habit may bring considerable benefit. PMID- 29627785 TI - Expanded access: growing importance to public health. PMID- 29627786 TI - Neuro Elutax SV drug-eluting balloon versus Wingspan stent system in symptomatic intracranial high-grade stenosis: a single-center experience. AB - BACKGROUND: Intracranial atherosclerotic disease is a well-known cause of ischemic stroke. Following the SAMMPRIS trial, medical treatment is favored over stenting. Drug-eluting balloons (DEB) are widely used in coronary angioplasty, showing better results than bare-surface balloons. There is little evidence of DEB employment in intracranial stenosis, especially of paclitaxel-eluted balloons (pDEB). The Neuro Elutax SV (Aachen Resonance) is the first CE certificated pDEB for intracranial use. OBJECTIVE: To compare pDEB Neuro Elutax SV (ElutaxDEB) with the Wingspan/Gateway stent system (WingspanStent). MATERIALS AND METHODS: A single-center, open-label, retrospective cohort study of 19 patients with symptomatic atherosclerotic intracranial high-grade stenosis treated with either ElutaxDEB or WingspanStent from a tertiary stroke center in Switzerland. RESULTS: Eight patients (42%) received ElutaxDEB. Median clinical follow-up was 10 months for the WingspanStent and 9.5 months for ElutaxDEB (P=0.36). No differences were found in the clinical baseline characteristics, with a median stenosis grade of 80% for the WingspanStent and 81% for the ElutaxDEB (P=0.87). The compound endpoint 'ischemic re-event and/or restenosis' was significantly lower for ElutaxDEB (13% vs 64%; P=0.03, OR 0.08 (95% CI 0.007 to 0.93; P=0.043) than for the WingspanStent. CONCLUSIONS: The ElutaxDEB may be a promising alternative treatment for patients with symptomatic high-grade intracranial stenosis showing a significantly lower rate of ischemic re-events or restenosis in comparison with the WingspanStent-treated patients with a similar safety profile. Further studies will be needed to definitively elucidate the role of pDEB in the management of symptomatic intracranial high-grade stenosis. PMID- 29627787 TI - Tyrosine kinase inhibitor induced rapidly progressive vasculopathy after intracranial stent placement. AB - Tyrosine kinase inhibitor (TKI) therapy for chronic myeloid leukemia (CML) has been associated with progressive peripheral arterial disease and, more recently, rare cases of intracranial vascular stenosis have been reported. We report the fourth case of TKI treatment associated intracranial vasculopathy and rapid progression of intracranial vascular stenosis following intracranial stent placement. This was a 49-year-old woman who developed right-sided weakness, paresthesias, numbness, and speech difficulties 7 years following TKI treatment for CML. Cerebral catheter angiography demonstrated 90% stenosis of the left supraclinoid internal carotid artery, for which the patient underwent intracranial stent placement with no residual stenosis and improved distal blood flow. Approximately 1 month following the procedure, the patient returned with similar symptoms. Catheter angiography demonstrated 70% and 50% stenosis just distal and proximal to the stent construct, respectively. Rapid disease progression and non-atherosclerotic vasculopathy may argue against endovascular therapy. PMID- 29627788 TI - Treatment of hemorrhagic head and neck lesions by direct puncture and n-BCA embolization. AB - Life-threatening bleeding in the head and neck region requires urgent management. These hemorrhagic lesions, for example, a ruptured pseudoaneurysm, are often treated by transarterial embolization (TAE), but prior intervention or surgery, inflammation, anatomic variants, and vessel tortuosity may render an endovascular approach challenging, time-consuming, and sometimes impossible. We report two cases of severe head and neck hemorrhages successfully embolized with n-butyl cyanoacrylate via direct puncture, and propose this approach as a fast, safe, and effective alternative to TAE. PMID- 29627789 TI - Late recanalization of basilar artery occlusion in a previously healthy 17-month old child. AB - Endovascular treatment of acute ischemic stroke in children is increasingly being reported, although the time window for intervention is unclear. We describe a previously healthy 17-month-old child who presented with vertebral artery thrombosis and cerebellar stroke requiring posterior fossa decompression. She later progressed to basilar artery thrombosis treated with mechanical thrombectomy 50 hours after clinical decline. At 3 month follow-up, the patient had a modified Rankin Scale score of 0. PMID- 29627790 TI - Embolization of a cavernous carotid fistula through the vein of Labbe: a new alternative transvenous access route. AB - Endovascular treatment of carotid cavernous fistulas (CCFs) via a transvenous approach is standard, but in rare cases this approach is challenging due to absence or thrombosis of the commonly used venous routes. A 61-year-old woman presented with a symptomatic CCF with all but one of the venous access routes to the CCF thrombosed, leaving an engorged superficial middle cerebral vein (SMCV) as the only venous outflow from the cavernous sinus. Access to the CCF was made possible after careful navigation of the sigmoid sinus, the vein of Labbe and the SMCV, bypassing the need for surgical access to the SMCV or for a direct transorbital puncture. The CCF was completely occluded by coiling and Onyx embolization. The patient made an uneventful recovery, with resolution of her symptoms. To the best of our knowledge, this access route has not been previously reported in the treatment of CCFs. PMID- 29627791 TI - Endovascular recanalisation with drug coated balloon for chronic symptomatic middle cerebral artery total occlusion. AB - The optimal treatment for patients with chronic symptomatic middle cerebral artery (MCA) total occlusion is not well established. In addition to medical therapy, vessel recanalisation with stenting has shown much promise, especially for patients with recurrent ischemic symptoms. Nevertheless, the incidence of symptomatic in-stent restenosis (ISR) is high, and is associated with an unfavorable prognosis. Drug coated balloons (DCBs) have been proven to be effective in treating and preventing ISR. However, the feasibility of DCBs for de novo intracranial atherothrombotic stenosis has not been previously described, especially for total occlusion lesions. Here we reported a patient with chronic left MCA total occlusion successfully treated with DCBs, with a good outcome at the 1 year follow-up. More studies are warranted to further compare the efficacy of DCBs and stentings for intracranial revascularisation. PMID- 29627792 TI - Thrombectomy for late occlusion of high flow extracranial-intracranial saphenous vein bypass graft after 27 years of patency. AB - High flow extracranial-intracranial (EC-IC) bypass with a saphenous vein graft (SVG) has been used for more than 40 years in patients with giant aneurysms of the posterior circulation refractory to medical management, and has demonstrated high long term patency rates. We report the case of a patient treated with external carotid artery (ECA)-posterior cerebral artery SVG bypass in 1989 who presented 27 years later with paresthesias and confusion, and was found to have partial occlusion of her SVG bypass graft and a basilar occlusion. She was treated with mechanical thrombectomy of the basilar occlusion via the partially thrombosed graft, the first report of such a procedure through a high flow posterior circulation EC-IC SVG, resulting in improvement of the patient's neurologic examination. At 27 years, this is the longest reported delay in thrombosis of a high flow SVG bypass graft, highlighting the long term patency of these grafts and the feasibility of thrombectomy through occluded bypass grafts. PMID- 29627793 TI - Lifting the veil on stroke outcomes: revisiting stroke centers' transparency through public reporting of metrics. AB - Public reporting of healthcare metrics provides transparency that allows patients and emergency medical providers to make informed decisions about where patients should receive care. Most previous reports about public reporting of health metrics have demonstrated significant improvements in outcome metrics after implementation. However, no mechanism exists, voluntary or otherwise, for the public reporting of outcomes of stroke care. We review the components of public reporting of health outcomes data and its limited history in stroke outcomes. We summarize the literature on public reporting in cardiovascular interventions, particularly percutaneous coronary interventions, as a close corollary to mechanical neurothrombectomy. The benefits, limitations, and controversies associated with reporting of cardiovascular outcomes are reviewed with a focus on the development of risk-avoidant behaviors. This article serves as a primer for discussion of the potential benefits, limitations, and unintended consequences of public reporting of stroke data. PMID- 29627795 TI - Delayed extrusion of embolic coils into the airway after embolization of an external carotid artery pseudoaneurysm. AB - Carotid blowout syndrome (CBS) is a known devastating complication of head and neck surgery. The risk of developing CBS increases in the setting of radiation therapy, wound breakdown, or tumor recurrence. Traditionally, the treatment of choice for CBS is surgical ligation of the bleeding artery; however, recently, endovascular occlusion has become a more common option. If a pseudoaneurysm is present, treatment consists of trapping with endovascular coils or occlusion with a liquid embolic agent. Delayed migration of embolization coils into the airway causing acute respiratory distress is a rare occurrence. This report presents a case of a 57-year-old woman who presented to her otolaryngologist after experiencing an episode of acute respiratory distress which resolved when she expectorated embolization coil material from her tracheostomy tube. Three months prior to the episode she underwent coil embolization of an external carotid artery pseudoaneurysm for life-threatening hemorrhage. PMID- 29627794 TI - Association of follow-up infarct volume with functional outcome in acute ischemic stroke: a pooled analysis of seven randomized trials. AB - BACKGROUND: Follow-up infarct volume (FIV) has been recommended as an early indicator of treatment efficacy in patients with acute ischemic stroke. Questions remain about the optimal imaging approach for FIV measurement. OBJECTIVE: To examine the association of FIV with 90-day modified Rankin Scale (mRS) score and investigate its dependency on acquisition time and modality. METHODS: Data of seven trials were pooled. FIV was assessed on follow-up (12 hours to 2 weeks) CT or MRI. Infarct location was defined as laterality and involvement of the Alberta Stroke Program Early CT Score regions. Relative quality and strength of multivariable regression models of the association between FIV and functional outcome were assessed. Dependency of imaging modality and acquisition time (<=48 hours vs >48 hours) was evaluated. RESULTS: Of 1665 included patients, 83% were imaged with CT. Median FIV was 41 mL (IQR 14-120). A large FIV was associated with worse functional outcome (OR=0.88(95% CI 0.87 to 0.89) per 10 mL) in adjusted analysis. A model including FIV, location, and hemorrhage type best predicted mRS score. FIV of >=133 mL was highly specific for unfavorable outcome. FIV was equally strongly associated with mRS score for assessment on CT and MRI, even though large differences in volume were present (48 mL (IQR 15-131) vs 22 mL (IQR 8-71), respectively). Associations of both early and late FIV assessments with outcome were similar in strength (rho=0.60(95% CI 0.56 to 0.64) and rho=0.55(95% CI 0.50 to 0.60), respectively). CONCLUSIONS: In patients with an acute ischemic stroke due to a proximal intracranial occlusion of the anterior circulation, FIV is a strong independent predictor of functional outcome and can be assessed before 48 hours, oneither CT or MRI. PMID- 29627796 TI - Ruptured aneurysm of the artery of Adamkiewicz: is conservative management the standard of treatment in the current era? AB - Spinal aneurysms are rare lesions, and their natural history is not well known. In particular, aneurysms arising from the artery of Adamkiewicz (AA) are an extremely rare phenomenon, and given the lack of solid evidence its management remains unclear. We present the case of a 54-year-old woman with spinal subarachnoid hemorrhage. A spinal angiogram demonstrated a fusiform aneurysm arising from the AA. Based on the location, the absence of evident collateral circulation to the anterior spinal artery, and the available literature supporting spontaneous thrombosis, we opted for conservative management. Fifteen days after the diagnosis, a spinal angiogram demonstrated complete occlusion of the aneurysm with no visualization of the AA. At 10-month follow-up, the patient was able to walk without assistance. Management should be done on a case-by-case basis with the goal of preserving spinal cord perfusion. Similar to previous articles, our report reinforces conservative management as a valid strategy. PMID- 29627797 TI - Taking the pressure off the spring: the case of rebounding smoking rates when antitobacco campaigns ceased. AB - OBJECTIVE: Smoking rates have been compared with a spring, requiring continuous downward pressure against protobacco forces, rather than a screw, which once driven down stays down. Quality antitobacco mass media campaigns put downward pressure on smoking rates. The suspension of a major Australian state campaign provided a natural experiment to assess effects on smoking. Furthermore, we document the positive influence of robust monitoring and mature advocacy on the political decision to reinstate funding. We also document the misuse by industry of South Australian smoking data from the period between Australia's implementation and subsequent evaluation of plain packaging. METHODS: A time series analysis was used to examine monthly smoking prevalence trends at each of four intervention points: (A) commencement of high-intensity mass media campaign (August 2010); (B) introduction of plain packaging (December 2012), (C) defunding of campaign (July 2013); and (D) reinstatement of moderate-intensity campaign (July 2014). FINDINGS: The suspension of the antitobacco campaign was disruptive to achieving smoking prevalence targets. There was an absence of a downward monthly smoking prevalence trajectory during the non-campaign period. Moreover, there was a significant decline in smoking prevalence during the period of high intensity advertising, which continued after the introduction of plain packaging laws, and at the recommencement of campaign activity. CONCLUSIONS: While the observed declines in smoking prevalence are likely due to a combination of interventions and cannot be attributed exclusively to antitobacco advertising, the results reinforce the political decision to reinstate the campaign and demonstrate the need for maintained investment to keep downward pressure on smoking rates. PMID- 29627800 TI - Cystic fibrosis pathogens survive for extended periods within cough-generated droplet nuclei. AB - The airborne route is a potential pathway in the person-to-person transmission of bacterial strains among cystic fibrosis (CF) populations. In this cross-sectional study, we investigate the physical properties and survival of common non Pseudomonas aeruginosa CF pathogens generated during coughing. We conclude that Gram-negative bacteria and Staphylococcus aureus are aerosolised during coughing, can travel up to 4 m and remain viable within droplet nuclei for up to 45 min. These results suggest that airborne person-to-person transmission is plausible for the CF pathogens we measured. PMID- 29627798 TI - Health Status Variation Across Practices in Outpatients With Heart Failure: Insights From the CHAMP-HF (Change the Management of Patients With Heart Failure) Registry. AB - BACKGROUND: Although a key treatment goal for patients with heart failure with reduced ejection fraction is to optimize their health status (their symptoms, function, and quality of life), the variability across outpatient practices in achieving this goal is unknown. METHODS AND RESULTS: In the CHAMP-HF (Change the Management of Patients With Heart Failure) registry, associations between baseline practice characteristics and Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary (OS) and Symptom Frequency (SF) scores were assessed in 3494 patients across 140 US practices using hierarchical regression after accounting for 23 patient and 11 treatment characteristics. We then calculated an adjusted median odds ratio to quantify the average difference in likelihood that a patient would have excellent (KCCQ-OS, >=75) health status or minimal (monthly or fewer) symptoms (KCCQ-SF, >=75) when treated at one practice versus another, at random. The mean (+/-SD) KCCQ-OS and KCCQ-SF were 64.2+/-24 and 68.9+/-25.6, with 40% (n=1380) and 50% (n=1760) having KCCQ scores >=75, respectively. The adjusted median odds ratio across practices, for KCCQ-OS >=75, was 1.70 (95% confidence interval, 1.54-1.99; P<0.001) indicating a median 70% higher odds of a patient having good-to-excellent health status when treated at one random practice versus another. In regard to KCCQ-SF, the adjusted median odds ratio for KCCQ-SF >=75 was 1.54 (95% confidence interval, 1.41-1.76; P=0.001). CONCLUSIONS: In a large, contemporary registry of outpatients with chronic heart failure with reduced ejection fraction, we observed significant practice-level variability in patients' health status. Quantifying patients' health status as a measure of quality should be explored as a foundation for improving care. CLINICAL TRIAL REGISTRATION: URL: https://www.centerwatch.com. Unique identifier: TX144901. PMID- 29627801 TI - The sense of smell in primary ciliary dyskinesia. PMID- 29627799 TI - Errors and discrepancies in the administration of intravenous infusions: a mixed methods multihospital observational study. AB - INTRODUCTION: Intravenous medication administration has traditionally been regarded as error prone, with high potential for harm. A recent US multisite study revealed few potentially harmful errors despite a high overall error rate. However, there is limited evidence about infusion practices in England and how they relate to prevalence and types of error. OBJECTIVES: To determine the prevalence, types and severity of errors and discrepancies in infusion administration in English hospitals, and to explore sources of variation, including the contribution of smart pumps. METHODS: We conducted an observational point prevalence study of intravenous infusions in 16 National Health Service hospital trusts. Observers compared each infusion against the medication order and local policy. Deviations were classified as errors or discrepancies based on their potential for patient harm. Contextual issues and reasons for deviations were explored qualitatively during observer debriefs. RESULTS: Data were collected from 1326 patients and 2008 infusions. Errors were observed in 231 infusions (11.5%, 95% CI 10.2% to 13.0%). Discrepancies were observed in 1065 infusions (53.0%, 95% CI 50.8% to 55.2%). Twenty-three errors (1.1% of all infusions) were considered potentially harmful; none were judged likely to prolong hospital stay or result in long-term harm. Types and prevalence of errors and discrepancies varied widely among trusts, as did local policies. Deviations from medication orders and local policies were sometimes made for efficiency or patient need. Smart pumps, as currently implemented, had little effect, with similar error rates observed in infusions delivered with and without a smart pump (10.3% vs 10.8%, p=0.8). CONCLUSION: Errors and discrepancies are relatively common in everyday infusion administrations but most have low potential for patient harm. Better understanding of performance variability to strategically manage risk may be a more helpful tactic than striving to eliminate all deviations. PMID- 29627803 TI - Danish Centre for Strategic Research in Type 2 Diabetes (DD2) project cohort of newly diagnosed patients with type 2 diabetes: a cohort profile. AB - PURPOSE: The aim of this article is to provide a detailed description of the ongoing nationwide Danish Centre for Strategic Research in Type 2 Diabetes (DD2) project cohort and biobank. The DD2 cohort continuously enrols newly diagnosed patients with type 2 diabetes (T2D) throughout Denmark. The overall goal of the DD2 project is to establish a large and data-rich T2D cohort that can serve as a platform for exhaustive T2D research including (1) improved genotypic and phenotypic characterisation of T2D, (2) intervention studies of more individualised T2D treatment, (3) pharmacoepidemiological studies and (4) long term follow-up studies on predictors of T2D complications and prognosis. PARTICIPANTS: Between 2010 and 2016, 7011 individuals with T2D have been enrolled and assessed at baseline. Information collected include interview data (eg, body weight at age 20 years, physical activity and alcohol consumption), clinical examination data (eg, hip-waist ratio and resting heart rate) and biological samples (whole blood, DNA, plasma and urine) stored at -80 degrees C and currently analysed for a range of biomarkers and genotypes. FINDINGS TO DATE: Registry linkage has provided extensive supplemental continuous data on glycosylated haemoglobin A, lipids, albuminuria, blood pressure, smoking habits, body mass index, primary care contacts, hospital diagnoses and procedures, medication use, cancer and mortality. Cross-sectional associations between biomarkers, family history, anthropometric and lifestyle measures and presence of complications at baseline have been reported. FUTURE PLANS: During 2016, a detailed follow-up questionnaire has been answered by 85% of initial participants, providing follow-up information on baseline variables and on presence of diabetic neuropathy. The DD2 cohort has now been followed for a total of 18 862 person-years, and nested intervention trials and follow-up studies are ongoing. In the future, the cohort will serve as a strong national and international resource for recruiting patients to nested case studies, clinical trials, postmarketing surveillance, large-scale genome studies and follow-up studies of T2D complications. PMID- 29627804 TI - Should total calcium be adjusted for albumin? A retrospective observational study of laboratory data from central Norway. AB - OBJECTIVES: Albumin-adjusted total calcium is often used as a surrogate marker for free calcium to evaluate hypocalcaemia or hypercalcaemia. Many adjustment formulas based on simple linear regression models have been published, and continue to be used in spite of questionable diagnostic accuracy. In the hope of finding a more pure albumin effect on total calcium, we used multiple linear regression models to adjust for other relevant variables. The regression coefficients of albumin were used to construct local adjustment formulas, and we tested whether the diagnostic accuracy was improved compared with previously published formulas and unadjusted calcium. DESIGN: A retrospective hospital laboratory data study. DATA SOURCES: The local hospital laboratory data system. SETTING: Norway, 2006-2015. PARTICIPANTS: 6549 patients above 2 years of age, where free calcium standardised at pH 7.40, total calcium, creatinine, albumin and phosphate had been analysed in a single blood draw, including hospitalised patients and patients from outpatient clinics and general practice. MAIN OUTCOME MEASURES: Diagnostic accuracy by Harrell's c and receiver operating characteristic curve analysis, using free calcium standardised at pH 7.40 as a gold standard, in subgroups with estimated glomerular filtration rate (eGFR) >=60 or <60 mL/min/1.73 m2. RESULTS: In the subgroup with eGFR <60 mL/min/1.73 m2, the Harrell's c of unadjusted total calcium (0.801) was significantly larger than those of the local formulas (0.790, p=0.002) and the best formula taken from literature (0.791, p=0.004). In the subgroup with eGFR >=60 mL/min/1.73 m2, no significant differences were found between these three formulas. CONCLUSIONS: Our study shows that the diagnostic accuracy of unadjusted total calcium is superior to several commonly used adjustment formulas, and we suggest that the use of such formulas should be abandoned in clinical practice. If the clinician does not trust total calcium to reflect the calcium status of the patient, free calcium should be measured. PMID- 29627802 TI - Cost-effectiveness of insulin pumps compared with multiple daily injections both provided with structured education for adults with type 1 diabetes: a health economic analysis of the Relative Effectiveness of Pumps over Structured Education (REPOSE) randomised controlled trial. AB - OBJECTIVES: To assess the long-term cost-effectiveness of insulin pumps and Dose Adjustment for Normal Eating (pumps+DAFNE) compared with multiple daily insulin injections and DAFNE (MDI+DAFNE) for adults with type 1 diabetes mellitus (T1DM) in the UK. METHODS: We undertook a cost-utility analysis using the Sheffield Type 1 Diabetes Policy Model and data from the Relative Effectiveness of Pumps over Structured Education (REPOSE) trial to estimate the lifetime incidence of diabetic complications, intervention-based resource use and associated effects on costs and quality-adjusted life years (QALYs). All economic analyses took a National Health Service and personal social services perspective and discounted costs and QALYs at 3.5% per annum. A probabilistic sensitivity analysis was performed on the base case. Further uncertainties in the cost of pumps and the evidence used to inform the model were explored using scenario analyses. SETTING: Eight diabetes centres in England and Scotland. PARTICIPANTS: Adults with T1DM who were eligible to receive a structured education course and did not have a strong clinical indication or a preference for a pump. INTERVENTION: Pumps+DAFNE. COMPARATOR: MDI+DAFNE. MAIN OUTCOME MEASURES: Incremental costs, incremental QALYs gained and incremental cost-effectiveness ratios (ICERs). RESULTS: Compared with MDI+DAFNE, pumps+DAFNE was associated with an incremental discounted lifetime cost of +L18 853 (95% CI L6175 to L31 645) and a gain in discounted lifetime QALYs of +0.13 (95% CI -0.70 to +0.96). The base case mean ICER was L142 195 per QALY gained. The probability of pump+DAFNE being cost-effective using a cost-effectiveness threshold of L20 000 per QALY gained was 14.0%. All scenario and subgroup analyses examined indicated that the ICER was unlikely to fall below L30 000 per QALY gained. CONCLUSIONS: Our analysis of the REPOSE data suggests that routine use of pumps in adults without an immediate clinical need for a pump, as identified by National Institute for Health and Care Excellence, would not be cost-effective. TRIAL REGISTRATION NUMBER: ISRCTN61215213. PMID- 29627805 TI - Social relationships and GP use of middle-aged and older adults in Europe: a moderator analysis. AB - OBJECTIVES: This paper investigates (1) how social relationships (SRs) relate to the frequency of general practitioner (GP) visits among middle-aged and older adults in Europe, (2) if SRs moderate the association between self-rated health and GP visits, and (3) how the associations vary regarding employment status. METHODS: Data stem from the Survey of Health, Ageing and Retirement in Europe project (wave 4, 56 989 respondents, 50 years or older). GP use was assessed by frequency of contacts with GPs in the last 12 months. Predictors were self-rated health and structural (Social Integration Index (SII), social contact frequency) and functional (emotional closeness) aspects of SR. Regressions were used to measure the associations between GP use and those predictors. Sociodemographic and socioeconomic factors were used as covariates. Additional models were computed with interactions. RESULTS: Analyses did not reveal significant associations of functional and structural aspects of SR with frequency of GP visits (SII: incidence rate ratio (IRR)=0.99, 95% CI 0.97 to 1.01, social contact frequency: IRR=1.04, 95% CI 1.00 to 1.07, emotional closeness: IRR=1.02, 95% CI 1.00 to 1.04). Moderator analyses showed that 'high social contact frequency people' with better health had more statistically significant GP visits than 'low social contact frequency people' with better health. Furthermore, people with poor health and an emotionally close network showed a significantly higher number of GP visits compared with people with same health, but less close networks. Three-way interaction analyses indicated employment status specific behavioural patterns with regard to SR and GP use, but coefficients were mostly not significant. All in all, the not employed groups showed a higher number of GP visits. CONCLUSIONS: Different indicators of SR showed statistically insignificantly associations with GP visits. Consequently, the relevance of SR may be rated rather low in quantitative terms for investigating GP use behaviour of middle-aged and older adults in Europe. Nevertheless, investigating the two way and three-way interactions indicated potential inequalities in GP use due to different characteristics of SR accounting for health and employment status. PMID- 29627806 TI - Long-term benzodiazepine use in patients taking antidepressants in a public health setting in Brazil: a cross-sectional study. AB - OBJECTIVE: The aims of the study were to investigate the prevalence of long-term use of benzodiazepines in patients taking antidepressants and to identify the risk factors associated with the prolonged use of benzodiazepines. DESIGN: Cross sectional study. SETTING: Public health system in Brazil. PARTICIPANTS: Outpatients using antidepressants from January 2008 to December 2009 were included. The data were obtained from pharmacy databases and medical records. All individuals in the database were included in the study and were classified into two categories: (1) patients who had not used benzodiazepines combined with antidepressants or had combined the use of antidepressants with benzodiazepines for a short period (up to 4 weeks), and (2) those who used antidepressants plus benzodiazepines for a longer period (more than 4 weeks). MAIN OUTCOME MEASURE: The outcome measure is prolonged use of benzodiazepines (more than 4 weeks). We conducted a multivariate analysis to identify the factors associated with prolonged use of benzodiazepines. RESULTS: Forty per cent of the 870 patients evaluated had prolonged use of benzodiazepines (more than 4 weeks). The risk factors associated with prolonged use were age above 35 years (prevalence ratio (PR): 2.18, 95% CI 1.55 to 3.06, P<0.001), female sex (PR: 1.47, 95% CI 1.07 to 2.02, P=0.019), diagnosis at least 3 years prior (PR: 2.1, 95% CI 1.6 to 2.8, P<0.001), use of selective serotonin reuptake inhibitor antidepressants (PR: 1.7, 95% CI 1.3 to 2.2, P<0.001) and having a prescription from a psychiatrist (PR: 6.5, 95% CI 3.2 to 13.2, P<0.001). CONCLUSIONS: Prolonged use of benzodiazepines occurs more frequently in women, adults diagnosed several years earlier, users of selective serotonin reuptake inhibitor antidepressants and those who received a prescription from a psychiatrist. Education of clinicians, especially with regard to these populations, may decrease the overuse and misuse of benzodiazepines. PMID- 29627807 TI - Risk of perinatal mortality in the first year of midwifery practice in New Zealand: analysis of a retrospective national cohort. AB - OBJECTIVES: To determine whether there was an increased risk of perinatal mortality among mothers booked for care with community lead maternity carer (LMC) midwives in their first compared with later years of practice. DESIGN: Retrospective cohort study using linked national maternity, mortality and workforce data; adjusted analysis using logistic regression. SETTING: New Zealand. PARTICIPANTS: Women under community LMC midwifery care birthing 2008 2014. MAIN OUTCOME MEASURES: Perinatal mortality (stillbirths and neonatal deaths of babies born from 20 weeks' gestation to the 27th day of postnatal life), excluding terminations and deaths associated with congenital abnormalities. RESULTS: There were 2045 deaths among 344 910 births booked with midwives.First year of practice midwives cared for women with higher risk of perinatal mortality, including Maori, Pacific, Indian, <20-year-old mothers, nullipara, smokers, women living in socioeconomic deprivation and with high body mass index, than midwives beyond first year of practice.There was a significant reduction in unadjusted odds of perinatal mortality among women under the care of midwives beyond the first year compared with those within the first year (OR 0.79, 95% CI 0.67 to 0.93) but no significant reduction in risk remained after adjusting for known risk factors, (OR 0.89, 95% CI 0.74 to 1.07).There was a significant increase in the adjusted odds of perinatal mortality among midwives booking a caseload of 15 or fewer mothers per year (1.34, 1.01 to 1.78) and 16 to 30 (1.25, 1.04 to 1.50) compared with midwives booking 51 to 80. CONCLUSIONS: Findings suggest that the first year of midwifery practice is not associated with an increased risk of perinatal mortality but there is evidence that early career midwives are caring for higher-risk women. These findings suggest inequity of access for higher-risk women to experienced midwives and highlight an opportunity to improve support for vulnerable women and new midwives. PMID- 29627808 TI - Descriptive epidemiology of changes in weight and weight-related behaviours of Australian children aged 5 years: two population-based cross-sectional studies in 2010 and 2015. AB - OBJECTIVE: Over the past 10-15 years there has been substantial investment in New South Wales (NSW), Australia, to reduce child obesity through interventions in children aged 0-5 years. We report changes in weight and weight-related behaviours of 5-year-old children. DESIGN: Cross-sectional surveys conducted in 2010 and 2015. SETTING: NSW schools (2010 n=44; 2015 n=41) PARTICIPANTS: Australian children in kindergarten (2010 n=1141 and 2015 n=1150). OUTCOME MEASURES: Change in anthropometry and indicators of diet, screen time, school travel and awareness of health recommendations. Additionally, we examined 2015 differences in weight-related behaviours by sociodemographic characteristics. RESULTS: Prevalence of overweight/obesity was 2.1% lower (adjusted OR (AOR) 0.83, 95% CI 0.67 to 1.04) and abdominal obesity 1.7% higher (AOR 1.35, 95% CI 0.93 to 1.98) in 2015 than 2010. Significant improvements in multiple weight-related behaviours were observed among children in the highest tertile of junk food consumption (AOR 0.63, 95% CI 0.50 to 0.80), rewarded for good behaviour with sweets (AOR 0.59, 95% CI 0.47 to 0.74) and had a TV in their bedroom (AOR 0.65, 95% CI 0.43 to 0.96). In 2015, children from low socioeconomic neighbourhoods and non-English-speaking backgrounds were generally less likely to engage in healthy weight-related behaviours than children from high socioeconomic status neighbourhoods and from English-speaking backgrounds. Children in these demographic groups were less likely to eat breakfast daily, have high junk food intake and eat fast food regularly. Children from rural areas tended to have healthier weight-related behaviours than children from urban areas. CONCLUSIONS: There were significant positive changes in 5-year-old children's weight-related behaviours but children from low socioeconomic neighbourhoods and from non English-speaking backgrounds were more likely to engage in unhealthy weight related behaviours than children from high socioeconomic neighbourhoods and English-speaking backgrounds. The findings indicate that there is a need to enhance population-level efforts and ensure community programmes are targeted and tailored to meet different subpopulation needs. PMID- 29627809 TI - Antithrombotic therapy in patients receiving saphenous vein coronary artery bypass grafts: a protocol for a systematic review and network meta-analysis. AB - INTRODUCTION: The current evidence for the prevention of saphenous vein graft failure (SVGF) after coronary artery bypass graft (CABG) surgery consists of direct head-to-head comparison of treatments (including placebo) in randomised controlled trials (RCTs) and observational studies. However, summarising the evidence using traditional pairwise meta-analyses does not allow the inclusion of data from treatments that have not been compared head to head. Exclusion of such comparisons could impact the precision of pooled estimates in a meta-analysis. Hence, to address the challenge of whether aspirin alone or in addition to another antithrombotic agent is a more effective regimen to improve SVG patency, a network meta-analysis (NMA) is necessary. The objectives of this study are to synthesise the available evidence on antithrombotic agents (or their combination) and estimate the treatment effects among direct and indirect treatment comparisons on SVGF and major adverse cardiovascular events, and to generate a treatment ranking according to their efficacy and safety outcomes. METHODS: We will perform a systematic review of RCTs evaluating antithrombotic agents in patients undergoing CABG. A comprehensive English literature search will be conducted using electronic databases and grey literature resources to identify published and unpublished articles. Two individuals will independently and in duplicate screen potential studies, assess the eligibility of potential studies and extract data. Risk of bias and quality of evidence will also be evaluated independently and in duplicate. We will investigate the data to ensure its suitability for NMA, including adequacy of the outcome data and transitivity of treatment effects. We plan to estimate the pooled direct, indirect and the mixed effects for all antithrombotic agents using a NMA. ETHICS AND DISSEMINATION: Due to the nature of the study, there are no ethical concerns nor informed consent required. We anticipate that this NMA will be the first to simultaneously assess the relative effects of multiple antithrombotic agents in patients undergoing CABG. The results of this NMA will inform clinicians, patients and guideline developers the best available evidence on comparative effects benefits of antithrombotic agents after CABG while considering the side effect profile to support future clinical decision-making. We will disseminate the results of our systematic review and NMA through a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42017065678. PMID- 29627810 TI - Cause-specific sickness absence trends by occupational class and industrial sector in the context of recent labour market changes: a Finnish panel data study. AB - OBJECTIVES: We aimed to provide previously unestablished information on population-based differences in cause-specific sickness absence trends between occupational classes and further between four large industrial sectors within the different occupational classes while controlling for other socioeconomic factors and employment patterns. We focused on the period 2005-2013, during which the labour market underwent large economic and structural changes in many countries. DESIGN: Register-based panel data study. SETTING: Large representative datasets on Finnish wage earners aged 25-59 years. OUTCOME MEASURE: Annual risk of sickness absence (>10 working days) based on repeated logistic regression. RESULTS: Between 2005 and 2013, the proportion of employees with sickness absence decreased. Occupational class differences in sickness absence trends varied by disease group. Overall, the decrease in absences was smallest among lower non manual employees. Sickness absence levels were highest in the health and social work sector and in the manufacturing sector within the non-manual and manual classes, respectively. Absences due to musculoskeletal diseases decreased temporarily during the peak of the economic recession in 2009, particularly in the manufacturing sector within the manual class. The decrease in absences due to musculoskeletal diseases was smallest in the trade sector within the lower occupational classes. Overall, education, income and employment patterns partly explained the differences in the absence levels, but not in the trends. CONCLUSIONS: We found a complex interplay between the associations of occupational class and industrial sector with sickness absence trends. During the economic recession, absences due to musculoskeletal diseases decreased temporarily in a segment of wage earners who were known to have been hit hard by the recession. However, the trend differences were not explained by the measured structural changes in the characteristics of the study population. Both occupational class and industrial sector should be taken into account when tackling problems of work disability. PMID- 29627811 TI - Global epidemiology and patterns of cerebral venous thrombosis: a systematic review and meta-analysis protocol. AB - INTRODUCTION: Venous thrombosis can affect all veins in the body including cerebral veins, where it causes cerebral venous thrombosis (CVT). CVT is an aetiology of stroke, particularly in children and young adults. Its clinical features vary widely according to the occluded vessel. Data concerning the epidemiology of CVT are scant. This protocol for a systematic review and meta analysis aims to critically synthesise data concerning prevalence, incidence, risk factors, anatomical patterns, diagnostic and therapeutic delays, and mortality rate of CVT in the global population. METHODS AND ANALYSIS: MEDLINE, EMBASE and ISI Web of Science databases will be searched for relevant abstracts of studies published between 1 January 1990 and 31 October 2017, without language restriction. After the screening of abstracts, study selection, data extraction and assessment of risk of bias, we will assess studies individually for heterogeneity. Random effects meta-analysis will then be used to pool studies judged to be clinically homogenous. Funnel plot analysis and Egger's test will be used to detect publication bias. Results will be presented according to economic level of the various countries (high-income vs low/middle-income countries). ETHICS AND DISSEMINATION: Since the current study will be based on published data, ethical approval is not required. This review is expected to provide relevant data to help in evaluating the global burden of CVT. The final report of this study will be published in a peer-reviewed journal. PROSPERO REGISTRATION NUMBER: CRD42017074266. PMID- 29627812 TI - Role of maternal characteristics and epidural analgesia on caesarean section rate in groups 1 and 3 according to Robson's classification: a cohort study in an Italian university hospital setting. AB - OBJECTIVE: To investigate the role of maternal characteristics and epidural analgesia (EA) on caesarean section (CS) rates in selected groups by using the Robson 10-Group Classification System (RTGCS). DESIGN: Cohort study. SETTING: Department of Obstetrics and Gynaecology, Fondazione Policlinico Universitario 'A. Gemelli', Rome, Italy. PATIENTS: A total of 12 098 deliveries in periods I (1998-1999) and II (2010-2011). MAIN OUTCOME MEASURES: CS rates in groups 1 and 3 of RTGCS. RESULTS: In group 1, 1144 (20%) patients were assigned to period I and 1302 (20.4%) to period II, while in group 3, 1587 (27.8%) were assigned to period I and 1502 (23.5%) to period II. CS rates were 16.4% and 23.1% in group 1 and 12.7% and 10.9% in group 3 in periods I and II, respectively. In group 1, significant and independent contributions to CS rate were provided by maternal age (p=0.018; OR 0.95 (95% CI 0.85 to 0.97)), body mass index (BMI) (p=0.022; OR 0.89 (95% CI 0.85 to 0.91)) and EA administration (p=0.037; OR 0.59 (95% CI 0.43 to 0.77)). In group 3, maternal age (p<0.001; OR 0.93 (95% CI 0.89 to 0.96)) and BMI (p=0.023; OR 0.98 (95% CI 0.96 to 0.99)) were found to be significantly associated with CS. CONCLUSIONS: RTGCS is an effective tool for analysing changes in obstetric care, allowing for the recognition of maternal age, BMI and EA administration in the strategic planning for mitigation of CS rates in selected groups. PMID- 29627813 TI - Pathways of association between maternal haemoglobin and stillbirth: path analysis of maternity data from two hospitals in England. AB - OBJECTIVE: To investigate the mechanisms that link maternal haemoglobin concentration with stillbirth. DESIGN: A retrospective cohort analysis using anonymised maternity data from two hospitals in England. SETTING: The Royal Wolverhampton NHS Trust and Guy's and St Thomas' NHS Foundation Trust. STUDY POPULATION: 12 636 women with singleton pregnancies >=24 weeks of gestation giving birth in the two hospitals during 2013-2015. METHOD: A conceptual framework of hypothesised pathways through birth weight-for-gestational age and maternal infection including potential confounders and other risk factors was developed and examined using path-analysis. Path-analysis was performed by fitting a set of regression equations using weighted least squares adjusted for mean and variance. Goodness-of-fit indices were estimated. MAIN OUTCOME MEASURES: Coefficient of association (beta) for relationship between each parameter, and direct, indirect and total effects via the postulated pathways. RESULTS: The path model showed a significant adjusted indirect negative effect of maternal haemoglobin on stillbirth mediated via birth weight-for-gestational age (standardised estimate (SE)=-0.01; 95% CI=-0.01 to -0.001; P=0.028). The effect through maternal infection was not significant at P<0.05 (SE=0.001; 95% CI=-0.004 to 0.01; P=0.610). There was a residual direct negative effect of maternal haemoglobin on stillbirth (SE=-0.12; 95% CI -0.23 to -0.02; P=0.020) after accounting for the two pathways. Total indirect SE=-0.004; 95% CI -0.01 to 0.003; P=0.267; total direct and indirect SE=-0.13; 95% CI -0.23 to -0.02; P=0.016. The goodness-of-fit indices showed a good fit between the model and the data. CONCLUSION: While some of the influence on risk of stillbirth acts through low birth weight-for-gestational age, the majority does not. Several new mechanisms have been suggested for how haemoglobin may be exerting its influence on the risk of stillbirth possibly involving genetic, epigenetic and/or alternative obstetric and nutritional pathologies, but much more research is needed. PMID- 29627814 TI - A systematic review of interventions by healthcare professionals to improve management of non-communicable diseases and communicable diseases requiring long term care in adults who are homeless. AB - OBJECTIVE: Identify, describe and appraise trials of interventions delivered by healthcare professionals to manage non-communicable diseases (NCDs) and communicable diseases that require long-term care or treatment (LT-CDs), excluding mental health and substance use disorders, in homeless adults. DESIGN: Systematic review of randomised controlled trials (RCTs), non-RCTs and controlled before-after studies. Interventions characterised using Effective Practice and Organisation of Care (EPOC) taxonomy. Quality assessed using EPOC risk of bias criteria. DATA SOURCES: Database searches (MEDLINE, Embase, PsycINFO, Scopus, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Applied Social Sciences Index and Abstracts (ASSIA) and Cochrane Central Register of Controlled Trials), hand searching reference lists, citation searches, grey literature and contact with study authors. SETTING: Community. PARTICIPANTS: Adults (>=18 years) fulfilling European Typology of Homelessness criteria. INTERVENTION: Delivered by healthcare professionals managing NCD and LT-CDs. OUTCOMES: Primary outcome: unscheduled healthcare utilisation. SECONDARY OUTCOMES: mortality, biological markers of disease control, adherence to treatment, engagement in care, patient satisfaction, knowledge, self-efficacy, quality of life and cost-effectiveness. RESULTS: 11 studies were included (8 RCTs, 2 quasi-experimental and 1 feasibility) involving 9-520 participants (67%-94% male, median age 37-49 years). Ten from USA and one from UK. Studies included various NCDs (n=3); or focused on latent tuberculosis (n=4); HIV (n=2); hepatitis C (n=1) or type 2 diabetes (n=1). All interventions were complex with multiple components. Four described theories underpinning intervention. Three assessed unscheduled healthcare utilisation: none showed consistent reduction in hospitalisation or emergency department attendance. Six assessed adherence to specific treatments, of which four showed improved adherence to latent tuberculosis therapy. Three concerned education case management, all of which improved disease-specific knowledge. No improvements in biological markers of disease (two studies) and none assessed mortality. CONCLUSIONS: Evidence for management of NCD and LT-CDs in homeless adults is sparse. Educational case-management interventions may improve knowledge and medication adherence. Large trials of theory-based interventions are needed, assessing healthcare utilisation and outcomes as well as assessment of biological outcomes and cost-effectiveness. PMID- 29627815 TI - Protocol for a mixed methods study of hospital readmissions: sensemaking in Veterans Health Administration healthcare system in the USA. AB - INTRODUCTION: Effective delivery of healthcare in complex systems requires managing interdependencies between professions and organisational units. Reducing 30-day hospital readmissions may be one of the most complex tasks that a healthcare system can undertake. We propose that these less than optimal outcomes are related to difficulties managing the complex interdependencies among organisational units and to a lack of effective sensemaking among individuals and organisational units regarding how best to coordinate patient needs. METHODS AND ANALYSIS: This is a mixed method, multistepped study. We will conduct in-depth qualitative organisational case studies in 10 Veterans Health Administration facilities (6 with improving and 4 with worsening readmission rates), focusing on relationships, sensemaking and improvisation around care transition processes intended to reduce early readmissions. Data will be gathered through multiple methods (eg, chart reviews, surveys, interviews, observations) and analysed using analytic memos, qualitative coding and statistical analyses. We will construct an agent-based model based on those results to explore the influence of sensemaking and specific care transition processes on early readmissions. ETHICS AND DISSEMINATION: Ethical approval has been obtained through the Institutional Review Board of the University of Texas Health Science Center at San Antonio (approval number: 14-258 hour). We will disseminate our findings in manuscripts in peer-reviewed journals, professional conferences and through short reports back to participating entities and stakeholders. PMID- 29627816 TI - Effects of dietary antioxidant vitamins on lung functions according to gender and smoking status in Korea: a population-based cross-sectional study. AB - OBJECTIVE: Cigarette smoke-induced oxidative stress plays an important role in the pathogenesis of chronic obstructive pulmonary disease (COPD). Dietary antioxidants are thought to prevent smoke-induced oxidative damage. The aim of this study was to investigate associations between lung function and the consumption of antioxidant vitamins in Korean adults. METHODS: In total, 21 148 participants from the Korean National Health and Nutrition Examination Survey (2007-2014) were divided into four groups based on smoking history and gender. Multivariate regression models were used to evaluate associations between lung function and intake of dietary antioxidants. RESULTS: Subjects in the highest intake quintile (Q5) of vitamin A, carotene and vitamin C intake had mean forced expiratory volume in 1 s (FEV1) measurements that were 30 mL, 32 mL and 36 mL higher than those of individuals in the lowest intake quintile (Q1), respectively (p for trend; p=0.008, p=0.010 and p<0.001, respectively). The risks of COPD for male smokers in Q1 increased 7.60-fold (95% CI 5.92 to 9.76), 7.16-fold (95% CI 5.58 to 9.19) and 7.79-fold (95% CI 6.12 to 9.92), for vitamin A, carotene and vitamin C, respectively, compared with those of female non-smokers in Q5. Among patients with COPD, men who smoked >20 pack-years had mean FEV1 measurements that were 192 mL, 149 mL and 177 mL higher than those of patients in Q1 (p for trend; p=0.018, p=0.024 and p=0.043, for vitamin A, carotene and vitamin C, respectively). CONCLUSIONS: These findings indicate that the influence of antioxidant vitamins on lung function depends on gender and smoking status in the Korean COPD population. PMID- 29627817 TI - Quantitative fibronectin to help decision-making in women with symptoms of preterm labour (QUIDS) part 1: Individual participant data meta-analysis and health economic analysis. AB - INTRODUCTION: The aim of the QUIDS study is to develop a decision support tool for the management of women with symptoms and signs of preterm labour, based on a validated prognostic model using quantitative fetal fibronectin (qfFN) concentration, in combination with clinical risk factors. METHODS AND ANALYSIS: The study will evaluate the Rapid fFN 10Q System (Hologic, Marlborough, Massachusetts) which quantifies fFN in a vaginal swab. In part 1 of the study, we will develop and internally validate a prognostic model using an individual participant data (IPD) meta-analysis of existing studies containing women with symptoms of preterm labour alongside fFN measurements and pregnancy outcome. An economic analysis will be undertaken to assess potential cost-effectiveness of the qfFN prognostic model. The primary endpoint will be the ability of the prognostic model to rule out spontaneous preterm birth within 7 days. Six eligible studies were identified by systematic review of the literature and five agreed to provide their IPD (n=5 studies, 1783 women and 139 events of preterm delivery within 7 days of testing). ETHICS AND DISSEMINATION: The study is funded by the National Institute of Healthcare Research Health Technology Assessment (HTA 14/32/01). It has been approved by the West of Scotland Research Ethics Committee (16/WS/0068). PROSPERO REGISTRATION NUMBER: CRD42015027590. VERSION: Protocol version 2, date 1 November 2016. PMID- 29627818 TI - Building motivation to participate in a quality improvement collaborative in NHS hospital trusts in Southeast England: a qualitative participatory evaluation. AB - OBJECTIVES: This study explores the barriers and facilitators that impact on the motivation of practitioners to participate in a quality improvement collaborative. DESIGN: A qualitative and formative evaluation using a participatory approach, the researcher-in-residence model which embraces the concept of 'coproducing' knowledge between researchers and practitioners using a range of research methods such as participant observation, interviews and documentary analysis. The design, creation and application of newly generated evidence are facilitated by the researcher through negotiation and compromise with team members. PARTICIPANTS: Senior and middle managers, doctors and nurses. SETTING: Two hospitals in Southeast England participating in a Patient Safety Improvement Collaborative and the facilitator (host) of the collaborative, based in Central London. RESULTS: The evaluation has revealed facilitators and barriers to motivation categorised under two main themes: (1) inherent motivation and (2) factors that influence motivation, interorganisational and intraorganisational features as well as external factors. Facilitators included collaborative 'champions,' individuals who drove the quality improvement agenda at a local level, raising awareness and inspiring colleagues. The collaborative itself acted as a facilitator, promoting shared learning as well as building motivation for participation. A key barrier was the lack of board engagement in the participating National Health Service organisations which may have affected motivation among front-line staff. CONCLUSIONS: Collaboratives maybe an important way of engaging practitioners in quality improvement initiatives. This study highlights that despite a challenging healthcare environment in the UK, there remains motivation among individuals to participate in quality improvement programmes as they recognise that improvement approaches may facilitate positive change in local clinical processes and systems. Collaboratives can harness this individual motivation to facilitate spread and adoption of improvement methodology and build engagement across their membership. PMID- 29627819 TI - Elements of integrated care approaches for older people: a review of reviews. AB - OBJECTIVE: The World Health Organization (WHO) recently proposed an Integrated Care for Older People approach to guide health systems and services in better supporting functional ability of older people. A knowledge gap remains in the key elements of integrated care approaches used in health and social care delivery systems for older populations. The objective of this review was to identify and describe the key elements of integrated care models for elderly people reported in the literature. DESIGN: Review of reviews using a systematic search method. METHODS: A systematic search was performed in MEDLINE and the Cochrane database in June 2017. Reviews of interventions aimed at care integration at the clinical (micro), organisational/service (meso) or health system (macro) levels for people aged >=60 years were included. Non-Cochrane reviews published before 2015 were excluded. Reviews were assessed for quality using the Assessment of Multiple Systematic Reviews (AMSTAR) 1 tool. RESULTS: Fifteen reviews (11 systematic reviews, of which six were Cochrane reviews) were included, representing 219 primary studies. Three reviews (20%) included only randomised controlled trials (RCT), while 10 reviews (65%) included both RCTs and non-RCTs. The region where the largest number of primary studies originated was North America (n=89, 47.6%), followed by Europe (n=60, 32.1%) and Oceania (n=31, 16.6%). Eleven (73%) reviews focused on clinical 'micro' and organisational 'meso' care integration strategies. The most commonly reported elements of integrated care models were multidisciplinary teams, comprehensive assessment and case management. Nurses, physiotherapists, general practitioners and social workers were the most commonly reported service providers. Methodological quality was variable (AMSTAR scores: 1 11). Seven (47%) reviews were scored as high quality (AMSTAR score >=8). CONCLUSION: Evidence of elements of integrated care for older people focuses particularly on micro clinical care integration processes, while there is a relative lack of information regarding the meso organisational and macro system level care integration strategies. PMID- 29627820 TI - Transdisciplinary research for impact: protocol for a realist evaluation of the relationship between transdisciplinary research collaboration and knowledge translation. AB - INTRODUCTION: Transdisciplinary teams are increasingly regarded as integral to conducting effective research. Similarly, knowledge translation is often seen as a solution to improving the relevance and benefits of health research. Yet, whether, how, for whom and under which circumstances transdisciplinary research influences knowledge translation is undertheorised, which limits its potential impact. The proposed research aims to identify the contexts and mechanisms by which transdisciplinary research contributes to developing shared understandings and behaviours of knowledge translation between team members. METHODS AND ANALYSIS: Using a longitudinal case-study design approach to realist evaluation, we outline a study protocol examining whether, how, if and for whom transdisciplinary collaboration can impact knowledge translation understandings and behaviours within a 5-year transdisciplinary Centre of Research Excellence. Data are being collected between February 2017 and December 2020 over four rounds of theory development, refinement and testing using interviews, observation, document review and visual elicitation as data sources. ETHICS AND DISSEMINATION: The Health Research Ethics Committee of the University of Adelaide approved this study. Findings will be communicated with team members at scheduled intervals throughout the study verbally and by means of creative reflective approaches (eg, arts elicitation, journalling). This research will be used to help support optimal team functioning by identifying strategies to support knowledge sharing and communication within and beyond the team to facilitate attainment of research objectives. Academic dissemination will occur through publication and presentations. PMID- 29627821 TI - Global Scientific Production on Illicit Drug Addiction: A Two-Decade Analysis. AB - AIMS: Addiction science has made great progress in the past decades. We conducted a scientometric study in order to quantify the number of publications and the growth rate globally, regionally, and at country levels. METHODS: In October 2015, we searched the Scopus database using the general keywords of addiction or drug-use disorders combined with specific terms regarding 4 groups of illicit drugs - cannabis, opioids, cocaine, and other stimulants or hallucinogens. All documents published during the 20-year period from 1995 to 2014 were included. RESULTS: A total of 95,398 documents were retrieved. The highest number of documents were on opioids, both globally (60.1%) and in each of 5 continents. However, studies on cannabis showed a higher growth rate in the last 5-year period of the study (2010-2014). The United States, the United Kingdom, Germany, Canada, Australia, France, Spain, Italy, China, and Japan - almost all studies were from high-income countries - occupied the top 10 positions and produced 81.4% of the global science on drug addiction. CONCLUSION: As there are important socio-cultural differences in the epidemiology and optimal clinical care of addictive disorders, it is suggested that low- and more affected middle-income countries increase their capacity to conduct research and disseminate the knowledge in this field. PMID- 29627822 TI - Gambogic Acid Efficiently Kills Stem-Like Colorectal Cancer Cells by Upregulating ZFP36 Expression. AB - BACKGROUND/AIMS: Gambogic acid (GA), the main active compound of Gamboge hanburyi, has been reported to be a potential novel antitumor drug. Whether GA inhibits putative cancer stem cells (CSCs), which are considered to be the major cause of cancer treatment failure, remains largely unknown. This study investigated whether GA inhibits the CSCs of colorectal cancer (CRC) and its possible mechanisms. METHODS: We performed CCK8 and tumor sphere formation assays, percentage analysis of both side population and CD133+CD44+ cells, and the detection of stem cells markers, in order to assess the role of GA in inhibiting the stem celllike features of CRC. An mRNA microarray was performed to identify the downstream gene affected by GA and rescue assays were performed to further clarify whether the downstream gene is involved in the GA induced decrease of the stem cell-like CRC population. CRC cells were engineered with a CSC detector vector encoding GFP and luciferase (Luc) under the control of the Nanog promoter, which were utilized to investigate the effect of GA on putative CSC in human tumor xenograft-bearing mice using in vivo bioluminescence imaging. RESULTS: Our results showed that GA significantly reduced tumor sphere formation and the percentages of side population and CD133+CD44+ cells, while also decreasing the expression of stemness and EMT-associated markers in CRC cells in vitro. GA killed stem-like CRC cells by upregulating the expression of ZFP36, which is dependent on the inactivation of the EGFR/ ERK signaling pathway. GFP+ cells harboring the PNanog-GFP-T2A-Luc transgene exhibited CSC characteristics. The in vivo results showed that GA significantly inhibited tumor growth in nude mice, accompanied by a remarkable reduction in the putative CSC number, based on whole-body bioluminescence imaging. CONCLUSION: These findings suggest that GA significantly inhibits putative CSCs of CRC both in vitro and in vivo by inhibiting the activation of the EGFR/ ERK/ZFP36 signaling pathway and may be an effective drug candidate for anticancer therapies. PMID- 29627823 TI - Alterations in Serum MicroRNA Profile During Hemodialysis - Potential Biological Implications. AB - BACKGROUND/AIMS: Hemodialysis implies significant alterations in the profile of serum components. microRNAs (miRNAs) are present in the human serum and are considered to target distant tissues where they can regulate gene expression, thus affecting homeostasis. Whether hemodialysis alters the profile of miRNAs in the serum is not known. METHODS: miRNA profiling in serum samples collected before and after hemodialysis was performed using miRNA qPCR arrays. The results were subsequently validated in an independent group of 10 hemodialyzed men. miRWalk database was used to identify mRNAs targeted by the miRNAs the levels of which changed after hemodialysis. The list of mRNAs was analyzed using the DAVID and PANTHER classification systems to identify pathways controlled by these miRNAs. RESULTS: miRNA profiling showed that the levels of the majority of circulating miRNAs were increased at least two-fold (115 out of 179 tested) while the levels of only five miRNAs were found at least two-fold lower after hemodialysis. Validation study confirmed the majority of the array results. Bioinformatics analysis of validated and significantly upregulated miRNAs revealed that gonadotropin-releasing hormone receptor, cell cycle and cell pluripotency-related pathways were targeted. CONCLUSION: Hemodialysis alters serum miRNA expression profile and this alteration may result in disruption of pathways contributing to subfertility and increased risk for cancer development being pathologies associated with hemodialysis. PMID- 29627824 TI - Protective Effect of Znt7 on High Glucose-Induced Epithelial-to-Mesenchymal Transition in Renal Tubular Epithelial Cells. AB - BACKGROUND/AIMS: Evidence from our and other groups has demonstrated that zinc transporter 7 in SLC30 family (ZnT7) inhibited epithelial-to-mesenchymal transition (EMT) and apoptosis in rat peritoneal mesothelial cells (RPMCs) under high glucose (HG) concentration. In the present study, we investigated the effect of ZnT7 on EMT of renal tubular epithelial cells (RTECs) in an in vitro model of diabetic nephropathy (DN). METHODS: A dual-fluorescent staining protocol was used for detection of ZnT7 in a normal rat kidney tubular epithelial cell line (NRK 52E cells). EMT was induced with HG (30 mM). NRK-52E cells were transfected with plasmids codifying for hZnT7-EGFP and interfering RNA for determination of the effect of ZnT7 over-expression and silencing, respectively. Expression of ZnT7, activation of the MAPK/ERK and TGF-beta/Smad pathways were analyzed with by means of Western blot. RESULTS: ZnT7 was localized in the perinuclear region and Golgi apparatus. In HG-induced EMT of NRK-52E cells, ZnT7 was up-regulated. Over expression of ZnT7 led to inhibition of HG-induced EMT, while knock-down of ZnT7 increased EMT. Furthermore, knock-down of ZnT7 and increased HG-induced EMT was accompanied by activation of the MAPK/ERK and TGF-beta/Smad pathways. CONCLUSION: The present study provides evidence that ZnT7 has a protective effect over EMT of RTECs in DN and suggests that the inhibition of HG-induced EMT may be achieved through the MAPK/ERK and TGF-beta/Smad pathways. Thereby, ZnT7 could be a potential target for translation medicine and prevention program in DN. PMID- 29627825 TI - Effect of CB1 Ligands on Neurogenic and Myogenic Contractile Responses in the Guinea-Pig Ileum. AB - This study aimed at investigating whether the synthetic cannabinoid receptor agonist (+)-WIN 55212-2 has neurogenic and myogenic relaxant effects on the longitudinal muscle-myenteric plexus (LMMP) strip of the guinea-pig ileum. (+) WIN 55212-2, 1-1,000 nmol/L, concentration-dependently inhibited both the electrical stimulation-induced cholinergic twitch responses as well as the myogenic smooth muscle contractions in the LMMP preparation. SR-141716A (rimonabant) 1-1,000 nmol/L, the cannabinoid CB1 receptor antagonist, being without effect on its own, antagonized the (+)-WIN 55212-2-induced effects. The allyl isothiocyanate (mustard oil, 100 umol/L) induced a relaxant effect in the guinea-pig ileum, which can be regarded as neurogenic and myogenic, was augmented by (+)-WIN 55212-2, and inhibited by SR-141716A. (+)-WIN 55212-2 only moderately modified the 60 mmol/L KCl-evoked contractions. These results provide functional evidence that the CB1 agonist (+)-WIN 55212-2-induced inhibitory effects in the guinea-pig ileum are exerted both at the neuronal as well as at the intestinal smooth muscle cell level. PMID- 29627826 TI - Meibomian Gland Dysfunction in Primary and Secondary Sjogren Syndrome. AB - PURPOSE: We hypothesized that women with primary (pSS) and secondary Sjogren syndrome (sSS; with systemic lupus erythematosus [SLE] or rheumatoid arthritis [RA]) have meibomian gland dysfunction (MGD). We sought to test our hypothesis. METHODS: Subjects with pSS, sSS + SLE, sSS + RA, and non-SS-related MGD were recruited from the Sjogren's Syndrome Foundation or outpatient clinics at Tufts University School of Dental Medicine or Brigham and Women's Hospital. The control population was recruited from the Greater Boston area. After providing written informed consent, the subjects underwent an eye examination and/or completed two questionnaires that assess symptoms of dry eye disease (DED). RESULTS: Our results demonstrate that pSS and sSS patients have MGD. These subjects had meibomian gland orifice metaplasia, an increased number of occluded meibomian gland orifices, and a reduced quality of meibomian gland secretions. Further, patients with pSS, sSS + SLE, sSS + RA, and MGD had significant alterations in their tear film, lid margin, cornea, and conjunctiva. Symptoms of DED were increased ~10-fold in all pSS, sSS, and MGD groups relative to controls. CONCLUSIONS: Our findings support our hypothesis and show that individuals with pSS, sSS + SLE, and sSS + RA have MGD. In addition, our study indicates that patients with pSS and sSS have both aqueous-deficient and evaporative DED. PMID- 29627828 TI - Two-Year Follow-Up Results of Transobturator Tape Procedure with and without Concomitant Vaginal Surgery. AB - OBJECTIVE: This study aims to evaluate the subjective and objective outcomes of the transobturator tape (TOT) procedure performed to treat stress urinary incontinence and to determine the efficacy and safety of the TOT procedure when used along with vaginal surgery. METHODS: This is a prospective review of 24 women who had the TOT procedure done only due to stress incontinence; 22 women who underwent concomitant TOT and pelvic floor repair; and 20 women who received concurrent TOT, transvaginal hysterectomy, and sacrospinous ligament fixation. RESULTS: When compared to the patients who had TOT with pelvic floor repair, the patients who underwent TOT with hysterectomy declared to have more dyspareunia (p = 0.008) and they were found to have significantly higher post-void residual volume (p = 0.014). When compared to the patients who had only TOT, the patients who underwent TOT with hysterectomy claimed to have more pelvic pain (p = 0.012) and significantly higher post-void residual volume (p = 0.020). CONCLUSION: The TOT procedure results in moderately high objective cure rates, and concurrent application of pelvic floor repair or transvaginal hysterectomy does not affect these rates. The relatively higher incidences for voiding problems and pelvic pain in women who underwent TOT, hysterectomy, and sacropinous fixation simultaneously suggest that the extent of surgery directly correlates with the severity of postoperative complications. PMID- 29627827 TI - Lgr5+CD44+EpCAM+ Strictly Defines Cancer Stem Cells in Human Colorectal Cancer. AB - BACKGROUND/AIMS: Although EpCAM+CD44+ cells exhibit more stem-like properties than did EpCAM-CD44- cells, the specificity of EpCAM combined with CD44 in defining CSCs needs further improvement. Lgr5 is used as a biomarker to isolate cancer stem cells (CSCs) in colorectal cancer. However, it remains unclear whether Lgr5, along with EpCAM and CD44, can further identify and define CSCs in colorectal cancer. METHODS: Lgr5+CD44+EpCAM+, Lgr5+CD44+EpCAM-, Lgr5+CD44-EpCAM+, Lgr5-CD44+EpCAM+, and Lgr5-CD44-EpCAM-cells were separately isolated using fluorescence-activated cell sorting (FACS). Colony formation, self-renewal, differentiation, and tumorigenic properties of these cells were investigated through in vitro experiments and in vivo tumor xenograft models. The expression of stemness genes and CSC- and epithelial-mesenchymal transition (EMT)-related genes, such as KLF4, Oct4, Sox2, Nanog, CD133, CD44, CD166, ALDH1, Lgr5, E cadherin, ZO-1, Vimentin, Snail, Slug, and Twist, was examined using real-time PCR. RESULTS: Lgr5-positive subpopulations exhibited higher capacities for colony formation, self-renewal, differentiation, and tumorigenicity as well as higher expression of stemness genes and mesenchymal genes and lower expression of epithelial genes than did Lgr5-negative subpopulations. CONCLUSION: Our data revealed that tumorigenic cells were highly restricted to Lgr5-positive subpopulations. Most importantly, Lgr5+CD44+EpCAM+ cells exhibited more pronounced CSC-like traits than did any other subpopulation, indicating that Lgr5 combined with CD44 and EpCAM can further improve the stem-like traits of CSCs in colorectal cancer. PMID- 29627829 TI - Effect of Lanthanum Carbonate on All-Cause Mortality in Patients Receiving Maintenance Hemodialysis: a Meta-Analysis of Randomized Controlled Trials. AB - BACKGROUND/AIMS: Hyperphosphatemia is common in patients on hemodialysis. The efficacy of lanthanum carbonate (LC) in the treatment of hyperphosphatemia in these patients remains controversial. The objective of this meta-analysis was to evaluate the effect of LC on all-cause mortality in patients on maintenance hemodialysis. METHODS: We electronically searched the PubMed, EMBASE, and Cochrane Library databases for all randomized controlled trials (RCTs) comparing LC with other phosphate binders used in adult hemodialysis patients, including calcium carbonate, calcium acetate, and sevelamer. RESULTS: Nine RCTs involving 2813 patients were suitable for inclusion. Our results showed that all-cause mortality was significantly lower in patients who received LC than in those who received standard therapy (odds ratio [OR]: 0.45, 95% confidence interval [CI]: 0.32-0.63, P<0.00001). Compared with the controls, patients who received LC had significantly lower serum calcium and higher serum intact parathyroid hormone levels. However, there was no significant difference between the groups in the cardiovascular event rate (OR: 0.58, 95% CI: 0.31-1.06, P=0.07) or in serum phosphorus levels. CONCLUSION: Compared with standard therapy, LC reduced all cause mortality in patients on hemodialysis but did not decrease the risk of cardiovascular events. The decrease in serum phosphorus level was similar between LC and the other phosphate binders, but the risk of hypercalcemia was lower in patients who received LC. PMID- 29627830 TI - Prediction of Biochemical Recurrence Following Radiotherapy among Patients with Persistent PSA after Radical Prostatectomy: A Single-Center Experience. AB - Radiotherapy (RT) is applied in prostate cancer patients with a biochemical recurrence (BcR) after radical prostatectomy (RP). However, for the patients with persistent PSA but not undergoing the process of BcR, it remains unknown whether the application of RT can exempt them from the upcoming BcR. In this study, we identified 104 patients treated with RP who had persistent PSA level >0.1 but <=0.2 ng/mL at 6-8 weeks after RP, of which 52 were treated with postoperative RT. Overall, 51 patients experienced BcR, among which 20 patients were treated with postoperative RT. The 5-year BCR-free survival rate of patients treated with or without postoperative RT was 96.2 and 50.0% respectively. Subgroup analysis showed that statistical differences in BcR-free survival were observed regarding to applying RT on patients with Gleason score <=7 (p = 0.0365), with pathological tumor stage T2 or T3 (p = 0.0210 and p = 0.0073, respectively), without or with lymph node invasion (p = 0.0118 and p = 0.0303, respectively), with positive surgical margins (p < 0.0001), and with Pre-RT PSA <=0.5 ng/mL (p < 0.0001). In multivariate analyses, PSA after surgery, Gleason score, pathological tumor stage, immediate androgen deprivation therapy after RP, and postoperative RT were significant predictors of BcR for patients with persistently elevated PSA (all p < 0.05). Finally, a coefficient-based nomogram was constructed with an excellent C-index for 5-year BCR prediction (0.76, 95% CI 0.73-0.79). These findings suggested that postoperative RT affords excellent control in BcR for patients with persistent PSA after surgery. PMID- 29627831 TI - Decreases of Life Expectancy Despite Decreases in Non-Communicable Disease Mortality: The Role of Substance Use and Socioeconomic Status. AB - With the epidemiological transition, causes of death shifted from communicable to non-communicable diseases (NCDs) and life expectancy increased, as these NCD deaths occurred later in life. However, in the United States, over the past years, life expectancy has been stagnating or decreasing despite decreasing NCD mortality rates. Analyses of the most important underlying causes of death with increasing premature mortality reveal that psychoactive substance use played a crucial role for these increases. Furthermore, it can be shown, that a high proportion of the increased premature mortality and decreased life expectancies happened in lower socio-economic strata. Substance use policies should thus focus on lowering the gap between substance-attributable mortality in higher versus lower socioeconomic strata. PMID- 29627832 TI - Somatically Acquired Isodicentric Y and Mosaic Loss of Chromosome Y in a Boy with Hypospadias. AB - Isodicentric Y chromosome [idic(Y)] represents a relatively common subtype of Y chromosomal rearrangements in the germline; however, limited evidence supports the postzygotic occurrence of idic(Y). Here, we report a boy with hypospadias and somatically acquired idic(Y). The 3.5-year-old boy has been identified in our previous study for patients with hypospadias. In the present study, cytogenetic analysis including FISH revealed a 45,X[5]/46,X,idic(Y)[7]/46,XY[8] karyotype. MLPA showed a mosaic deletion involving PPP1R12BP1 and RBMY2DP. The idic(Y) was likely to have been formed through aberrant recombination between P1 palindromes and subsequently underwent mosaic loss. The patient's phenotype was attributable to deletion of some Y chromosomal genes and/or mosaic loss of chromosome Y (mLOY). The results suggest that idic(Y) can originate in postzygotic cells via palindrome-mediated crossovers. Moreover, our data indicate that somatically acquired idic(Y) can trigger mLOY, which usually appears as an aging-related phenomenon in elderly men. PMID- 29627833 TI - Small Hyperintensities in the Area of the Perforating Arteries in Patients with Seizure. AB - BACKGROUND/AIM: We previously observed spotty hyperintense lesions in the region of the perforating arteries on peri-ictal diffusion-weighted imaging (DWI); however, no report has formally described these findings. The aim of this study was to investigate focal intensities on peri-ictal DWI, and to evaluate the clinical significance of these lesions. METHODS: We conducted a retrospective review of 677 consecutive patients with seizure who completed peri-ictal DWI within 24 h after seizure onset. Patients were grouped according to the presence or absence of diffusion hyperintense lesions (DHLs) in the region of the perforating arteries. We compared clinical and imaging characteristics between these 2 groups. RESULTS: Among 677 patients, 23 patients (3.4%) had DHLs. Analyses of apparent diffusion coefficient values and fluid attenuated inversion recovery images suggested that DHLs were acute or subacute ischemic lesions that had appeared prior to seizure onset. Patients with DHLs were more likely to be older in age, have atrial fibrillation, and coronary artery disease, and have more severe deep white matter hyperintensity or leukoaraiosis compared to patients without DHLs. CONCLUSION: DHLs detected on peri-ictal DWI may represent incidental acute cerebral microinfarcts in the aging brain, especially in patients with small vessel disease. PMID- 29627835 TI - Diagnosis of Hyperacute and Acute Ischaemic Stroke: The Potential Utility of Exosomal MicroRNA-21-5p and MicroRNA-30a-5p. AB - BACKGROUND: Early and accurate diagnosis of ischaemic stroke (IS) requires the use of an optimized biomarker. Exosomal microRNAs have the potential to serve as biomarkers owing to their stability and specificity. We investigated the expression levels of plasma-derived exosomal microRNA-21-5p and microRNA-30a-5p in the different phases of IS. METHODS: One hundred forty-three patients with IS and 24 non-stroke controls were enrolled. The patients were divided into the following 5 groups: 1 group for the hyperacute phase IS (HIS, within 6 h); two for the acute phase IS (AIS, including days 1-3 and days 4-7); one for the subacute phase IS (SIS, days 8-14); and one for the recovery phase IS (RIS, days >14). Plasma exosomes were isolated using a QIAGEN exoRNeasy kit and examined by transmission electron -microscopy, nanoparticle tracking, and flow cytometry. The expression levels of miRNA-21-5p and miRNA-30a-5p were detected by quantitative real-time polymerase chain reaction. RESULTS: The plasma exosomal miR-21-5p levels in SIS and RIS were significantly higher than that in controls (p < 0.05 and p < 0.01 respectively). The levels of miR-30a-5p in HIS were significantly higher (p < 0.05) and in AIS (days 1-3) were lower than that in controls (p < 0.05). In AIS (days 1-3), both miRNAs were decreased compared with the HIS group (p = 0.053 and 0.001, respectively). The area under the curve (AUC) of the miR-21 5p was 0.714 for SIS (95% CI 0.570-0.859, p = 0.007), 0.734 for RIS (95% CI 0.596 0.871, p = 0.003); the AUC of the miR-30a-5p was 0.826 for HIS (95% CI 0.665 0.988, p = 0.001), 0.438 for AIS (days 1-3; 95% CI 0.240-0.635, p = 0.516). CONCLUSIONS: The plasma-derived exosomal miR-21-5p and miRNA-30a-5p in combination are promising biomarkers for diagnosing IS and distinguishing among HIS, SIS, and RIS, especially miRNA-30a-5p for the diagnosis of the HIS phase. Our results provide a new reference for clinicians to apply in early-stage diagnosis and identifies the possible value of biomarkers for IS thrombolysis therapy. PMID- 29627834 TI - Effects of Long Non-Coding RNA LINC00963 on Renal Interstitial Fibrosis and Oxidative Stress of Rats with Chronic Renal Failure via the Foxo Signaling Pathway. AB - BACKGROUND/AIMS: Chronic renal failure (CRF) is usually associated with chronic diseases such as congestive heart failure and diabetes mellitus, the prevalence of which is increased with age. This study is designed to investigate the role of long intergenic non-coding RNA (lincRNA) LINC00963 in renal interstitial fibrosis (RIF) and oxidative stress (OS) of CRF via the forkhead box O (FoxO) signaling pathway. METHODS: Microarray data and annotated probe files related to CRF were downloaded by retrieving Gene Expression Omnibus (GEO) database to screen differentially expressed lncRNA. Multi Experiment Matrix (MEM) website and dual luciferase reporter gene assay were used to predict and verify the target gene of LINC00963, and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis to identify the major signaling pathways involved. A total of 60 Wistar male rats were randomly selected and divided into the sham (n = 10) and model (n = 50) groups. Five rats in the sham group and thirty rats in the model group were sub categorized into the control, blank, negative control (NC), LINC00963 vector, si LINC00963, si-FoxO3, and si-LINC00963 + si-FoxO3 groups (n = 5). Reverse transcription quantitative polymerase chain reaction (RT-qPCR) and western blot analysis were performed to evaluate the expressions of LINC00963, FoxO3a, TGF beta1, FN, GSH-PX, Bax, and Bcl-2. Measurement of changes in OS indexes including BUN, MDA, GSH-Px, SOD, and Na+-K+-ATP were conducted. Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of inflammatory factors including TNF-alpha, IL-6, ICAM-1 and FN. TUNEL staining was performed to evaluate cell apoptosis. RESULTS: LINC00963 was highly expressed in CRF rats and FoxO3 was predicted and then verified as a target gene of LINC00963. FoxO3 gene participated in the FOXO signaling pathway. Compared with the blank and NC groups, there were significantly decreased expressions of LINC00963, TGF-beta1, FN, and Bax in the si-LINC00963 group, while increased expressions of GSH-PX, FoxO3a, and Bcl-2. The vitality values of BUN and MDA in the si-LINC00963 group declined, while enzymatic activities of GSH-Px, SOD and Na+-K+-ATP elevated in comparison to the blank and NC groups. The levels of TNF-alpha, IL-6, ICAM-1 and FN, and cell apoptosis rate in the si-LINC00963 group decreased in comparison to the blank and NC groups. All the results in the si-LINC00963 group were opposite in the LINC00963 vector and si-FoxO3 groups. CONCLUSION: Taken together, we conclude that down-regulation of LINC00963 suppresses RIF and OS of CRF by activating the FoxO signaling pathway. PMID- 29627837 TI - Combination of Mean Platelet Volume/Platelet Count Ratio and the APACHE II Score Better Predicts the Short-Term Outcome in Patients with Acute Kidney Injury Receiving Continuous Renal Replacement Therapy. AB - BACKGROUND/AIMS: Both the Acute physiology and Chronic Health Evaluation (APACHE II) score and mean platelet volume/platelet count Ratio (MPR) can independently predict adverse outcomes in critically ill patients. This study was aimed to investigate whether the combination of them could have a better performance in predicting prognosis of patients with acute kidney injury (AKI) who received continuous renal replacement therapy (CRRT). METHODS: Two hundred twenty-three patients with AKI who underwent CRRT between January 2009 and December 2014 in a Chinese university hospital were enrolled. They were divided into survivals group and non-survivals group based on the situation at discharge. Receiver Operating Characteristic (ROC) curve was used for MPR and APACHE II score, and to determine the optimal cut-off value of MPR for in-hospital mortality. Factors associated with mortality were identified by univariate and multivariate logistic regression analysis. RESULTS: The mean age of the patients was 61.4 years, and the overall in-hospital mortality was 48.4%. Acute cardiorenal syndrome (ACRS) was the most common cause of AKI. The optimal cut-off value of MPR for mortality was 0.099 with an area under the ROC curve (AUC) of 0.636. The AUC increased to 0.851 with the addition of the APACHE II score. The mortality of patients with of MPR > 0.099 was 56.4%, which was significantly higher than that of the control group with of <= 0.099 (39.6%, P= 0.012). Logistic regression analysis showed that average number of organ failure (OR = 2.372), APACHE II score (OR = 1.187), age (OR = 1.028) and vasopressors administration (OR = 38.130) were significantly associated with poor prognosis. CONCLUSION: Severity of illness was significantly associated with prognosis of patients with AKI. The combination of MPR and APACHE II score may be helpful in predicting the short-term outcome of AKI. PMID- 29627838 TI - Assessment of Corneal Changes Associated with Topical Antiglaucoma Therapy Using in vivo Confocal Microscopy. AB - PURPOSE: Ocular surface disease (OSD) is highly prevalent in eyes treated with chronic, topical antiglaucoma (A/G) therapy. The purpose of this study was to utilize in vivo confocal microscopy (IVCM) to evaluate the corneal morphology, including characteristics of corneal epithelial cells, presence of epithelial dendritic cells (DCs), and characteristics of subbasal nerve plexus, of eyes under topical A/G therapy versus normal eyes. METHODS: Central corneal images were prospectively captured from 30 eyes of 16 patients under topical A/G therapy (>6 months) and 20 normal control eyes, using IVCM (HRT 3 RCM, Heidelberg, Germany). Demographic data were collected, as well as information on the types and duration of A/G therapy. In addition, OSD index (OSDI) score, tear film breakup time, Schirmer 1 test results, density of epithelial wing cells (WCs) and basal cells (BCs), subbasal nerve features (density, tortuosity, and reflectivity), and presence of DCs were all assessed and recorded by trained Doheny Image Reading Center graders. RESULTS: IVCM findings of 30 glaucomatous eyes and 20 normal control eyes were analyzed. The mean OSDI score was 8.72 in controls and 32.06 in patients under A/G therapy (p = 0.002). Nerve fiber density, nerve fiber reflectivity, and BC density were all decreased in the A/G group (1,789.07 +/- 785.70 MUm/frame, 2.79 +/- 0.83, 6,457.67 +/- 692.55 cells/mm2, respectively) as compared to controls (2,815.981 +/- 563.77 MUm/frame, 3.52 +/- 0.50, 7,854.13 +/- 1,073.69 cells/mm2, respectively) (p < 0.05), whereas the decrease in WC density was statistically nonsignificant (p = 0.5). Nerve tortuosity and DC density were both significantly greater in the A/G eyes (3.00 +/- 0.57, 71.24 +/- 61.74 cells/mm2, respectively) compared to controls (2.10 +/- 0.42, 34.08 +/- 11.70 cells/mm2, respectively) (p < 0.05). Tear film breakup time and Schirmer 1 test results were significantly lower in the A/G group as compared to controls (p < 0.001). CONCLUSIONS: Using IVCM, our study identified significant microstructural alterations in the corneas of eyes treated with topical A/G therapy. In addition, our study also revealed that glaucoma patients treated with topical A/G therapy report significantly higher OSDI scores compared to controls. Thus, IVCM may be a useful tool in providing structural parameters to correlate with the functional OSDI assessments in the evaluation of ocular surface toxicity associated with topical A/G therapy. PMID- 29627839 TI - Genotype-Phenotype Analysis in Pediatric Patients with Distal Renal Tubular Acidosis. AB - BACKGROUND/AIMS: Primary distal renal tubular acidosis (dRTA) in children is a rare genetic disorder, and three causative mutated genes have been identified: SLC4A1, ATP6V1B1, and ATP6V0A4. We analyzed the prevalence and phenotypic differences of genetic mutations in children with dRTA. METHODS: A total of 17 children with dRTA were enrolled in the study. All patients underwent genetic testing for all three candidate genes. RESULTS: Pathogenic mutations, including six novel mutations, were detected in 15 (88.2%) patients: dominant SLC4A1 mutations in ten (58.8%) patients, recessive ATP6V0A4 mutations in three (17.6%) patients, and recessive ATP6V1B1 mutations in two (11.8%) patients. Compared to other patients, patients with SLC4A1 mutations showed an older age of onset (3.7 +/- 2.6 years) and less severe metabolic acidosis at initial presentation. All patients developed nephrocalcinosis, and sensorineural hearing loss was observed in two patients with ATP6V1B1 mutations. Three (17.6%) patients had decreased renal function (chronic kidney disease stage 2), and five (29.4%) patients had persistent growth retardation at the last follow-up. Long-term prognosis showed no genotype-phenotype correlation. CONCLUSIONS: SLC4A1 is the most common defective gene in Korean children with dRTA. Patients with SLC4A1 mutations show later onset and milder disease severity. Long-term follow-up of hearing ability, renal function, and growth is necessary for patients with dRTA. PMID- 29627840 TI - Lung Dysfunction and Mortality in Patients with Chronic Kidney Disease. AB - BACKGROUND/AIMS: Lung dysfunction associates with increased mortality but the impact of chronic kidney disease (CKD) is less clear. We evaluated lung function and its association with mortality among individuals with normal to severely reduced glomerular filtration rate (GFR). METHODS: 404 individuals representing GFR category G1 (n=31; GFR >90 mL/min/1.73 m2), G2 (n=46), G3 (n=33), G4 (n=49) and G5 (n=245; GFR< 15 mL/min/1.73 m2) underwent spirometry yielding lung function indices forced vital capacity (FVC), forced expiratory volume in the first second (FEV1) and peak expiratory flow (PEF). Associations of lung function indices expressed as percentages of predicted values (%FEV1, %FVC and %PEF) with 5-year mortality were analyzed by competing-risk regression models. RESULTS: The prevalence of obstructive (6% in G1 and 11% in G5) and especially restrictive (9% in G1 to 36% in G5) lung dysfunction increased with declining GFR and with higher comorbidity burden. In patients (n=22) with protein-energy wasting, inflammation and cardiovascular disease, the prevalence of restrictive lung function was 64%. The highest tertiles of % FEV1 and %FVC associated with lower sub-hazard ratios (sHR) for all-cause mortality, 0.49 (95% CI, 0.27-0.88)) and 0.56 (95% CI, 0.32 0.98), and that of %FEV1 also with lower cardiovascular mortality risk (sHR 0.16; 95%CI 0.04-0.69) after adjusting for multiple confounders. Restrictive lung dysfunction (FEV1/FVC >= 0.70, and %FVC < 80) associated with increased mortality risk (sHR 1.80, 95%CI, 1.04-3.13) while the association with obstructive lung impairment was not statistically significant. CONCLUSION: Lung dysfunction and in particular restrictive lung dysfunction associates with degree of renal function impairment and presence of comorbidities, and is an independent predictor of increased mortality in CKD patients. PMID- 29627841 TI - Preeclampsia as a Form of Type 5 Cardiorenal Syndrome: An Underrecognized Entity in Women's Cardiovascular Health. AB - BACKGROUND: Preeclampsia is a multisystem vascular disorder of pregnancy that remains a leading cause of maternal and fetal morbidity and mortality. Preeclampsia remains an underrecognized risk factor for future cardiovascular and kidney disease in women and represents the confluence of preexisting vascular risk factors with superimposed endothelial injury from placental mediated anti angiogenic factors. SUMMARY: This review highlights the close relationship between preeclampsia and future cardiovascular and kidney disease. It describes the pathophysiology and current understanding of biomarkers that form the molecular signature for long-term endothelial dysfunction in preeclamptic women. Finally, it describes strategies for early identification and management of women with preeclampsia with elevated risk for cardiovascular and kidney disease. Key Messages: Future rigorous studies on cardiovascular risk modification in this phenotype of disease are essential to reduce the burden of cardiovascular and kidney disease, in women with preeclampsia. PMID- 29627842 TI - High Neutrophil-to-Lymphocyte Ratio is a Significant Predictor of Cardiovascular and All-Cause Mortality in Patients Undergoing Peritoneal Dialysis. AB - BACKGROUND/AIMS: Chronic inflammation is associated with increased risk of cardiovascular death in patients with end-stage renal disease (ESRD). Although elevated neutrophil-to-lymphocyte ratio (NLR), a novel inflammatory marker, has been shown to predict cardiovascular disease and all-cause mortality in the general population, limited evidence is available for its role in ESRD. METHODS: We enrolled 86 patients undergoing peritoneal dialysis (PD) for a 36-month follow up to investigate the association between the NLR and arterial stiffness markers, namely, carotid-femoral pulse wave velocity (cfPWV) and carotid augmentation index (AIx), and mortality in PD patients. The primary endpoints were cardiovascular mortality and all-cause mortality. Kaplan-Meier curves were used to show the cumulative incidence of cardiovascular mortality and all-cause mortality. RESULTS: High NLR was found to be a predictor of increased cfPWV (beta = 1.150; P < 0.001) and AIx (beta = 3.945; P < 0.001) in patients on PD. Patients with higher NLR had lower survival during follow-up. Kaplan-Meier curves showed that the cumulative incidences of both cardiovascular mortality and all-cause mortality were significantly higher in patients with NLR >= 4.5 (both P < 0.01). CONCLUSION: Our results suggest that high NLR is independently associated with arterial stiffness and predicts cardiovascular and all-cause mortality in PD patients. PMID- 29627843 TI - Spontaneous Ventriculostomy into the Subdural Space in a Neonate with Congenital Hydrocephalus. AB - We report a case of spontaneous temporary resolution of congenital hydrocephalus due to drainage into the subdural space, which is not a physiological space for cerebrospinal fluid (CSF). This is the first report of spontaneous drainage of CSF into the subdural space, and we term it "ventriculosubdurostomy." We highlight the fact that spontaneous resolution of hydrocephalus due to drainage into a nonphysiological CSF space is temporary. PMID- 29627844 TI - Alcohol Drinking Pattern Is Associated with Demographic Features of Primary Health Care Patients in Poland: A Cross-Sectional Study. AB - BACKGROUND The Optimizing Delivery of Health Care Interventions (ODHIN) project focused on the implementation of screening and brief intervention for hazardous and harmful alcohol consumption in primary health care. The aim of the present study was to investigate whether alcohol drinking pattern is associated with demographic features of primary health care patients in Poland and if it is possible to identify groups at highest risk for hazardous and harmful drinking. MATERIAL AND METHODS The study enrolled 8805 adult (mean age 54.98+/-16.94, M/F - 3581/5224) patients reporting to 30 general practitioners working in 10 primary health care units located in urban and partially rural areas in Poland. The shortened, 3-item version of the Alcohol Use Disorders Identification Test (AUDIT C) was the screening tool used. RESULTS Place of residence was significantly associated with higher odds of hazardous and harmful drinking diagnosis, referred to as AUDIT-C (+). Age and sex were significantly associated with AUDIT-C (+) and suspicion of alcohol dependence, referred to as AUDIT-C 38 scores. Logistic regression revealed that males had 5-fold higher odds for hazardous and harmful drinking diagnosis and almost 28-fold higher odds for suspected alcohol dependence compared to females. CONCLUSIONS Demographic features are associated with drinking pattern of primary health patients in Poland. Young males and those inhabiting rural areas are at highest risk of being hazardous or harmful drinkers and of being alcohol dependent. There is a growing need for development of national guidelines to address the prevention of alcohol-related health problems by general practitioners. PMID- 29627845 TI - Eicosapentaenoic Acid Improves Polycystic Ovary Syndrome in Rats via Sterol Regulatory Element-Binding Protein 1 (SREBP-1)/Toll-Like Receptor 4 (TLR4) Pathway. AB - BACKGROUND This study aimed to investigate the protective effect of eicosapentaenoic acid (EPA) on rats with polycystic ovary syndrome (PCOS). MATERIAL AND METHODS Rats with PCOS were intraperitoneally injected with different doses of EPA. Levels of follicle stimulating hormone (FSH), luteinizing hormone (LH), and testosterone (T) were measured using corresponding kits. HE staining was used to observe lesions in ovarian tissue. Levels of inflammatory factors in ovarian tissue of rats were detected by ELISA. RT-PCR was to detect the expression of SREBP1 mRNA and Western blot was used to detect the expression of SREBP1 and TLR4 protein. RESULTS The levels of LH and T were significantly higher and FDH was significantly lower in the Model group compared with the Control group. EPA treatment increased the number of follicular cell layers and promoted maturation of oocytes. Levels of IL-1beta, TNF-alpha, and IL-18 were significantly reduced after EPA treatment. Content of IL-10 was significantly increased after EPA treatment. Expression levels of SREBP1 and TLR4 were significantly deceased after EPA treatment. CONCLUSIONS EPA can improve PCOS through the SREBP1/TLR4 pathway. PMID- 29627846 TI - Upregulation of Ubiquitin Carboxyl-Terminal Hydrolase L1 (UCHL1) Mediates the Reversal Effect of Verapamil on Chemo-Resistance to Adriamycin of Hepatocellular Carcinoma. AB - BACKGROUND The aim of this study was to investigate the role of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) in the reversal effect of verapamil (VER) on chemo-resistance to Adriamycin (ADM) in treatment of hepatocellular carcinoma (HCC). MATERIAL AND METHODS HCC cell lines SMMC-7721 and BEL-7402 were used as model cell lines. High-throughput transcriptome sequencing based on Illumina technology was used to screen whether UCHL1 mediated the reversal effect of VER on chemo-resistance. Quantitative real-time PCR (qRT-PCR) was performed to determine the expression level of UCHL1 mRNA in HCC cells, and western blot analysis was performed to examine the protein expression of UCHL1 protein in HCC cells. Immunohistochemistry assay was performed to determine the protein expression of UCHL1 in tissue samples from patients presenting with either positive or negative responses to the reversal therapeutic regimen of VER. Moreover, cell models with UCHL1 knockdown and overexpression were established to examine the reversal effect of VER on chemo-resistance to ADM in HCC cells. Cell apoptosis was determined by flow cytometry following Annexin V-PI staining. RESULTS The expression levels of UCHL1 genes correlated with the level of apoptosis induced by ADM+VER. Overexpression of UCHL1 genes promoted apoptosis in cells treated with VER+ADM. UCHL1 knockdown using siRNA weakened the effect of ADM+VER, indicating that ADM+VER promotes HCC cell apoptosis and that UCHL1 genes participate in VER-mediated promotion in tumor cell apoptosis. CONCLUSIONS Upregulation of UCHL1 enhanced the reversal effect of VER on chemo-resistance to ADM and promoted cell apoptosis. The underlying mechanism of the function of UCHL1 and the signaling pathway involved in its effect are to be investigated in our future research. PMID- 29627847 TI - Pregnancy outcomes and superiorities of prophylactic cervical cerclage and therapeutic cervical cerclage in cervical insufficiency pregnant women. AB - PURPOSE: To compare the clinical effect of prophylactic cervical cerclage and therapeutic cervical cerclage on pregnancy outcome and operative factors in cervical insufficiency pregnant women. METHODS: A retrospective study was conducted between June 2014 and September 2016 in a maternity ward, which included women who have had a single pregnancy and have been carried out a McDonald cerclage. All maternal medical records were reviewed. The efficacy of cerclage for preventing late foetal loss was assessed using multivariable logistic regression analysis. RESULTS: The results showed that there were significant associations between cerclage operations and pregnancy outcomes in the duration of pregnancy prolongation in terms of live births, gestation age, live birth and cesarean section rate. In prophylactic cervical cerclage, compared with therapeutic cervical cerclage, cervical length before surgery was significantly longer (32.7 +/- 5.8 vs 19.9 +/- 7.3 mm, p < 0.0001). Mean operative duration and postoperative length of hospital stay in prophylactic cervical cerclage were shorter than those in therapeutic cervical cerclage (22.1 +/- 10.3 vs 28.9 +/- 13.0 min, p = 0.0241 and 5.6 +/- 1.8 vs 7.0 +/- 2.8 days, p = 0.0354), respectively. Compared with therapeutic cerclage, prophylactic cerclage had more advantages in gestational age at delivery (35.2 +/- 5.5 and 31.7 +/- 6.5 weeks, p = 0.0061), deliveries < 37 gestational weeks (40 vs 69.2%, p = 0.0159), live births (93.3 vs 69.2%, p = 0.0143) and the duration of pregnancy prolongation in terms of live births (19.5 +/- 5.0 vs 12.0 +/- 8.2 weeks, p = 0.0002). There was a higher cesarean section rate in prophylactic group than that in therapeutic group (50 vs 25.6%, p = 0.0383). The logistic analysis showed that the cervical length before surgery was the only independent prognostic factor [OR 2.860 (1.425, 5.742) p = 0.0031] for pregnancy outcome, and that is the cervical length before surgery affected late foetal loss. CONCLUSIONS: Our study suggests that, both prophylactic cervical cerclage and therapeutic cervical cerclage reduce the incidence of recurrent abortion or preterm birth and efficiently extend the length of the pregnancy with live births. The prophylactic cervical cerclage has more advantages in operative time, length of hospital stay after surgery, gestational age at delivery, live births and preterm birth. The length of the cervical before surgery is an independent risk factor for pregnancy outcomes when pregnant women appear in the cervical shortening is less than normal. Cervical cerclage is an effective surgical technique to prevent recurrent abortion or late foetal loss. PMID- 29627848 TI - Fixation augmentation using calcium-phosphate bone substitute improves outcomes of complex tibial plateau fractures. A matched, cohort study. AB - INTRODUCTION: Injectable cements have been developed to improve fixation's stability and thus obtain early return to adequate joint function. We aimed to compare post-operative radiographic and clinical outcomes of patients suffering from a complex tibial plateau fracture (TPF) fixed with calcium-phosphate bone substitutes (CPBS) augmentation to a matched group of patients with identical fracture pattern, treated with the same fixation's type, but augmented with bone grafting. METHODS: After local ethic committee approval, we retrospectively identified in a prospectively collected database, patients with complex comminuted metaphyseal and epiphysial bicondylar TPF (Schatzker type VI) admitted in our emergency department between January 2011 and December 2013. From those, 23 patients (14 males, 9 females) were treated with CPBS (Quickset-CP(r), Graftys, Aix-en-Provence, France) fixation augmentation. Patients' mean age were 44.4 years. We then created a control group using a 1:1 matching process on gender, age, fracture pattern, and method of fixation. Patients were evaluated prospectively at 3, 6, and then every six months using radiographic (AP/ML views) and clinical criteria (knee osteoarthritis outcomes score (KOOS) and EuroQOL-5D). RESULTS: Articular step-off and variation of articular step-off were significantly lower in the CPBS groups (mean step-off 1.4 +/- 1.9 (0.5-6.5 mm) and mean step-off Delta = 0.3 +/- 0.4 (0.5-2.2 mm)) than in the control group (mean step-off 3.6 +/- 2.1 (1-7.5 mm) and mean step-off Delta = 2.2 +/- 2 (0.5-7 mm) p < 0.01). At last follow-up, patients of the control group presented a higher rate of step-off > 2 mm and step-off Delta > 2 mm (respectively, 56 and 35%) than patients of the CPBS group (26 and 9%). Odd ratio of, respectively, 3.6 (95% CI (1.08-12.7) and p = 0.03) and 5.6 (95% CI (1.04-30.1) and p = 0.03).At mean follow-up of 29 months, KOOS pain subscore was significantly better in patients of the CPBS group (85.3 +/- 12.1) than in control patients (74.2 +/- 10.4 and p = 0.03). CONCLUSION: The present study demonstrates that calcium phosphate bone substitute used as synthesis augmentation improves mid-term radiological outcomes of patients suffering from complex tibial plateau fracture. Series reporting outcomes from a larger number of patients and longer follow-up must confirm clinical benefits and safety of this method. PMID- 29627849 TI - Patient-related outcomes after proximal tibial fractures. AB - PURPOSE: The purpose of the study was to assess patient-related outcomes at short term follow-up in patients with a proximal tibial fracture. METHODS: One hundred sixteen patients (119 fractures) treated at our institution during 2012 were retrospectively reviewed. Follow-up was 1.6 (SD +/- 0.4) years post-injury, including the short musculoskeletal function assessment and visual analog scale for pain and satisfaction. Fractures were classified by the Arbeitsgemeinschaft fur Osteosynthesefragen/Orthopaedic Trauma Association classification and divided in two groups: simple and complex. RESULTS: Patients with simple fractures reported lower short musculoskeletal function assessment indices and less pain on visual analog scale than those with complex fractures. No difference was found in short musculoskeletal function assessment between surgically and non-surgically treated patients. Non-surgically treated patients reported less pain and were more satisfied. The overall complication rate was 30 (25%) of 119 fractures, with surgical treatment carrying a 7.0 (95% CI: 1.5-34) odds ratio for local complications. CONCLUSIONS: This study provides information about realistic prognosis after proximal tibial fractures. The finding that surgically treated patients had similar outcomes to non-surgically treated ones may indicate that surgery improves the prognosis of complex fractures to a level comparable to the prognosis of less severe ones. However, the risk of complications after surgery should guide treatment when surgery is not clearly indicated. PMID- 29627850 TI - Clinical outcomes with the corticotomy-first technique associated with the Ilizarov method for the management of the septic long bones non-union. AB - PURPOSE: Corticotomy is an integral part of the Ilizarov method on management of infected nonunited fractures that are challenging orthopaedic surgeons. However, the presence of active draining sinuses may contaminate the operative field with the potential of developing corticotomy site infection. The authors present a surgical technique aiming at minimizing or avoiding the risk of surgical site infection (SSI) in the corticotomy zone. PATIENTS AND METHODS: A total of 144 cases of draining infected nonunions were treated by Ilizarov fixator using the corticotomy-first technique. The study included humeral (18 cases), femoral (52 cases), and tibial (74 cases) nonunions. The mean age was 44.48 years with 87 males and 57 females. The mean duration of nonunion was 28.69 months. After debridement, the combined shortening and nonunion gap averaged 5.98 (range 3-10) cm. Evaluation of bone and functional results was done according to Association for the Study and Application of the Method of Ilizarov (ASAMI) criteria. RESULTS: The follow-up period averaged 51.05 (range 36-72) months. None of the cases developed corticotomy site or distraction gap infection. Union was successfully achieved in 141 cases (97.92%). Nonunion persisted in three cases (2.08%) in the distal tibia. Infection was eventually controlled in 138 cases (95.83%). Bone grafting was not needed in any case. CONCLUSIONS: The Ilizarov fixator with the corticotomy-first technique was effective in the management of draining infected non-united fractures of long bones while avoiding the SSI in the corticotomy site in all cases. PMID- 29627851 TI - Metabolic engineering of Clostridium tyrobutyricum for enhanced butyric acid production with high butyrate/acetate ratio. AB - Butyric acid fermentation by Clostridium couples with the synthesis of acetic acid. But the presence of acetic acid reduces butyric acid yield and increases separation and purification costs of butyric acid. Hence, enhancing the butyrate/acetate ratio is important for economical butyric acid production. This study indicated that enhancing the acetyl-CoA to butyrate flux by overexpression of both the butyryl-CoA/acetate CoA transferase (cat1) and crotonase (crt) genes in C. tyrobutyricum could significantly reduce acetic acid concentration. Fed batch fermentation of ATCC 25755/cat1 + crt resulted in increased butyrate/acetate ratio of 15.76 g/g, which was 2.24-fold higher than that of the wild-type strain. Furthermore, in order to simultaneously increase the butyrate/acetate ratio, butyric acid concentration and productivity, the recombinant strain ATCC 25755/ppcc (co-expression of 6-phosphofructokinase (pfkA) gene, pyruvate kinase (pykA) gene, cat1, and crt) was constructed. Consequently, ATCC 25755/ppcc produced more butyric acid (46.8 vs. 35.0 g/L) with a higher productivity (0.83 vs. 0.49 g/L.h) and butyrate/acetate ratio (13.22 vs. 7.22 g/g) as compared with the wild-type strain in batch fermentation using high glucose concentration (120 g/L). This study demonstrates that enhancing the acetyl-CoA to butyrate flux is an effective way to reduce acetic acid production and increase butyrate/acetate ratio. PMID- 29627852 TI - Bioproduction of 2-phenylethanol and 2-phenethyl acetate by Kluyveromyces marxianus through the solid-state fermentation of sugarcane bagasse. AB - 2-Phenylethanol (2-PE) and 2-phenethyl acetate (2-PEA) are important aroma compounds widely used in food and cosmetic industries due to their rose-like odor. Nowadays, due to the growing demand for natural products, the development of bioprocesses for obtaining value-added compounds has become of great significance. 2-PE and 2-PEA can be produced through the biotransformation of L phenylalanine using the generally recognized as safe strain Kluyveromyces marxianus. L-phenylalanine bioconversion systems have been typically focused on submerged fermentation processes (SmF), but there is no information about other alternative productive approaches. Here, the solid-state fermentation (SSF) of sugarcane bagasse supplemented with L-phenylalanine was investigated as a sustainable alternative for producing 2-PE and 2-PEA in a residue-based system using Kluyveromyces marxianus as inoculum. An initial screening of the operational variables indicated that air supply, temperature, and initial moisture content significantly affect the product yield. Besides, it was found that the feeding strategy also affects the production and the efficiency of the process. While a basic batch system produced 16 mgproducts per gram of residue (dry basis), by using split feeding strategies (fed-batch) of only sugarcane bagasse, a maximum of 18.4 mgProducts g-1residue were achieved. Increase in product yield was also accompanied by an increase in the consumption efficiency of nutrients and precursor. The suggested system results as effective as other more complex SmF systems to obtain 2-PE and 2-PEA, showing the feasibility of SSF as an alternative for producing these compounds through the valorization of an agro-industrial residue. PMID- 29627853 TI - Insect symbionts as valuable grist for the biotechnological mill: an alkaliphilic silkworm gut bacterium for efficient lactic acid production. AB - Insects constitute the most abundant and diverse animal class and act as hosts to an extraordinary variety of symbiotic microorganisms. These microbes living inside the insects play critical roles in host biology and are also valuable bioresources. Enterococcus mundtii EMB156, isolated from the larval gut (gut pH >10) of the model organism Bombyx mori (Lepidoptera: Bombycidae), efficiently produces lactic acid, an important metabolite for industrial production of bioplastic materials. E. mundtii EMB156 grows well under alkaline conditions and stably converts various carbon sources into lactic acid, offering advantages in downstream fermentative processes. High-yield lactic acid production can be achieved by the strain EMB156 from renewable biomass substrates under alkaline pretreatments. Single-molecule real-time (SMRT) sequencing technology revealed its 3.01 Mbp whole genome sequence. A total of 2956 protein-coding sequences, 65 tRNA genes, and 6 rRNA operons were predicted in the EMB156 chromosome. Remarkable genomic features responsible for lactic acid fermentation included key enzymes involved in the pentose phosphate (PP)/glycolytic pathway, and an alpha amylase and xylose isomerase were characterized in EMB156. This genomic information coincides with the phenotype of E. mundtii EMB156, reflecting its metabolic flexibility in efficient lactate fermentation, and established a foundation for future biotechnological application. Interestingly, enzyme activities of amylase were quite stable in high-pH broths, indicating a possible mechanism for strong EMB156 growth in an alkaline environment, thereby facilitating lactic acid production. Together, these findings implied that valuable lactic acid-producing bacteria can be discovered efficiently by screening under the extremely alkaline conditions, as exemplified by gut microbial symbionts of Lepidoptera insects. PMID- 29627854 TI - Modulating the sensing properties of Escherichia coli-based bioreporters for cadmium and mercury. AB - Despite the large number of bioreporters developed to date, the ability to detect heavy metal(loid)s with bioreporters has thus far been limited owing to the lack of appropriate genetic systems. We here present a novel approach to modulate the selectivity and sensitivity of microbial whole-cell bioreporters (WCBs) for sensing metal(loid)s via the znt-operon from Escherichia coli, which were applied to quantify the bioavailability of these contaminants in environmental samples. The WCB harboring the fusion gene zntAp::egfp was used as a microbial metal(loid) sensor, which was turned on by the interaction between ZntR and metal(loid) ions. This design makes it possible to modulate the selectivity and sensitivity to metal(loid)s simply by changing the metal-binding property of ZntR and by disrupting the metal efflux system of E. coli, respectively. In fact, the E. coli cell-based bioreporter harboring zntAp::egfp showed multi-target responses to Cd(II), Hg(II), and Zn(II). However, the WCBs showed responses toward only Cd(II) and Hg(II) when the amino acid sequence of the metal-binding loop of ZntR was changed to CNHEPGTVCPIC and CPGDDSADC, respectively. Moreover, the sensitivity toward both Cd(II) and Hg(II) was enhanced when copA, which is known to export copper and silver, was deleted. Thus, our findings provide a strong foundation for expanding the target of WCBs from the currently limited number of genetic systems available. PMID- 29627855 TI - Biotransformation using halotolerant yeast in seawater: a sustainable strategy to produce R-(-)-phenylacetylcarbinol. AB - Acyloin condensation between benzaldehyde and decarboxylated pyruvate results in the production of R-(-)-phenylacetylcarbinol, a chiral precursor of the drug ephedrine. Huge research efforts have been made to improve the conditions of this reaction and to avoid the generation of by-products. Recently, we reported the advantages of using whole cells of the yeast Debaryomyces etchellsii as biocatalysts for this purpose. In this work, a new strategy, which fulfills green chemistry principles, is proposed and is based on using seawater as a gentle solvent. We demonstrate that, under these conditions, several improvements can be made compared to employing freshwater: (1) the conversion of the starting material in (R)-PAC is higher and with a minimum production of by-products; (2) it is possible to increase at least twofold the benzaldehyde load in the reaction medium; (3) cells can maintain their activity after several recycling rounds, which makes (R)-PAC production an easy and economical process. PMID- 29627857 TI - Do already grasped objects activate motor affordances? AB - This study investigated whether in a stimulus-response compatibility (SRC) task affordance effects in response to picture of graspable objects emerge when these objects appear as already grasped. It also assessed whether the observed effects could be explained as due to spatial compatibility between the most salient part in the object/display and the hand of response rather than to action potentiation. To this aim, we conducted three behavioural experiments in which participants were required to discriminate the vertical orientation (upright vs. inverted) of an object presented in the centre of the screen, while ignoring the right-left orientation of its handle. The object could be presented alone, as already grasped, as partially masked (Experiment 1) or with a human hand close to its graspable side (Experiment 2). In addition, to assess the role of perceptual salience, the object could be presented with a human hand or a non-biological (a geometrical shape) distractor located opposite to the object's graspable side. Results showed faster responses when the object's handle was located on the same side of the responding hand with a larger effect when upright objects were shown as already grasped (Experiment 1) or when a hand was displayed close to its handle (Experiment 2), and a smaller reversed effect when the hand or the geometrical shape was located opposite to the handled side (Experiment 3). We interpreted these findings as indicating that handle orientation effects emerging in SRC tasks may result from the interplay between motor affordance and spatial compatibility mechanisms. PMID- 29627856 TI - Generation and characterization of a novel recombinant scFv antibody specific for Campylobacter jejuni. AB - Campylobacter jejuni is a leading cause of foodborne illness worldwide, mainly due to consumption and handling of contaminated raw chicken. Rapid detection methods for C. jejuni are vital for monitoring contamination levels in chicken products and reducing human Campylobacteriosis cases. The 'gold standard' culture based method of Campylobacter detection takes 3-5 days and is too slow to permit effective intervention. Immuno-based methods are faster, but usually necessitate use of animals or hybridoma technology to produce antibodies; making them difficult and expensive to produce. Here, we report the generation and characterization of recombinant single-chain variable fragment (scFv) antibodies specific for C. jejuni cells, and evaluation of one scFv antibody for an immunomagnetic separation-quantitative PCR (IMS-qPCR) method to rapidly, sensitively, and specifically detect low numbers of C. jejuni. An scFv antibody phage-display library was constructed using spleen mRNA derived from a rabbit immunized with gamma-irradiated C. jejuni cells. This library was screened by surface biopanning against C. jejuni whole cells. Enriched clones were analyzed by enzyme-linked immunosorbent assay (ELISA). Two scFv antibodies that strongly and specifically recognized C. jejuni cell were expressed in Escherichia coli. Western blot analysis showed that one antibody, scFv80, was expressed as a soluble protein and retained its specific and strong binding to C. jejuni cells. This recombinant monoclonal scFv antibody was purified and used to covalently coat paramagnetic beads to be used for IMS-qPCR. The IMS-qPCR method was able to specifically and sensitively detect C. jejuni in mixed cultures within 3 h. PMID- 29627858 TI - First detection of Echinococcus granulosus sensu stricto (G1) in dogs in central Sudan. AB - Eighty-four stray dogs shot as a part of a governmental rabies control program in two neighboring towns of central Sudan were examined for the presence of Echinococcus spp. and other intestinal helminths. Echinococcus worms were identified to species level by PCR and gene sequencing. For comparative reasons, rectal content of the necropsied dogs was examined for helminth eggs and subjected to copro-PCR for Echinococcus. At necropsy, 51.2% (43/84) of the dogs harbored Echinococcus canadensis (G6/7) worms with worm burdens ranging from 22,000 to 80,000. Dipylidiun caninum was found in 53.6% of the dogs. At coproscopy, taeniid eggs were found in 37 of the 43 dogs which were positive for Echinococcus at necropsy, but none in the 41 necropsy-negative dogs. In addition, 58% of the rectal samples contained eggs of Toxocara spp., 34.5% eggs of Trichuris spp. (34.5%), and 26% eggs of Ancylostoma caninum. Copro-PCR gave positive results for E. canadensis with 97.5% (39/40) of nonhibiting samples from the necropsy positive dogs; the one remaining dog tested positive for E. granulosus sensu stricto (G1), whose partial cox1 and nad1 sequences showed a 100% identity with various reference sequences of the G1 genotype. 100% of 38 non inhibited samples taken from the necropsy-negative dogs were also negative in copro-PCR. This is the first study which combines prevalence and genetic identification of Echinococcus spp. in dogs of Sudan. Together with a recent report from cattle, it confirms the autochthonous presence, at low level, of E. granulosus sensu stricto in Central Sudan. PMID- 29627859 TI - Magnetic resonance imaging assessment of the normal knee anterolateral ligament in children and adolescents. AB - OBJECTIVE: To characterize the anterolateral ligament (ALL) in normal knees of pediatric patients by magnetic resonance imaging (MRI) and to establish the age at which it is possible to visualize its presence and whether there are differences between male and female populations. MATERIALS AND METHODS: MRI scans of patients younger than 18 years were retrospectively evaluated. The exams were performed in 1.5-T scanners. The ALL was characterized dichotomously as visualized or not visualized based on the assessment criteria of this structure in adult patients. The characterization of the ALL was divided according to sex and age. RESULTS: A total of 363 knee MRI scans were evaluated, 200 from male and 163 from female patients. The ALL was more frequently visualized in coronal sequences. The mean ALL visualization in pediatric patients was 69.4% and was lower in younger patients and higher in patients close to 18 years. It was not possible to visualize the ALL in female patients younger than 7 years or in male patients younger than 6 years. In patients between 17 and 18 years of age, the ALL was visualized in 100% of cases in both sexes. CONCLUSIONS: Visualization of the ALL increased with age in both sexes. Only after age 13 in females and age 15 in males was visualization of the ALL close to 70%; thus, below these ages, we believe that the characterization of this structure with conventional protocols is still imprecise. PMID- 29627860 TI - Spectroscopic investigations of a semi-synthetic [FeFe] hydrogenase with propane di-selenol as bridging ligand in the binuclear subsite: comparison to the wild type and propane di-thiol variants. AB - [FeFe] Hydrogenases catalyze the reversible conversion of H2 into electrons and protons. Their catalytic site, the H-cluster, contains a generic [4Fe-4S]H cluster coupled to a [2Fe]H subsite [Fe2(ADT)(CO)3(CN)2]2-, ADT = u(SCH2)2NH. Heterologously expressed [FeFe] hydrogenases (apo-hydrogenase) lack the [2Fe]H unit, but this can be incorporated through artificial maturation with a synthetic precursor [Fe2(ADT)(CO)4(CN)2]2-. Maturation with a [2Fe] complex in which the essential ADT amine moiety has been replaced by CH2 (PDT = propane-dithiolate) results in a low activity enzyme with structural and spectroscopic properties similar to those of the native enzyme, but with simplified redox behavior. Here, we study the effect of sulfur-to-selenium (S-to-Se) substitution in the bridging PDT ligand incorporated in the [FeFe] hydrogenase HydA1 from Chlamydomonas reinhardtii using magnetic resonance (EPR, NMR), FTIR and spectroelectrochemistry. The resulting HydA1-PDSe enzyme shows the same redox behavior as the parent HydA1-PDT. In addition, a state is observed in which extraneous CO is bound to the open coordination site of the [2Fe]H unit. This state was previously observed only in the native enzyme HydA1-ADT and not in HydA1-PDT. The spectroscopic features and redox behavior of HydA1-PDSe, resulting from maturation with [Fe2(PDSe)(CO)4(CN)2]2-, are discussed in terms of spin and charge density shifts and provide interesting insight into the electronic structure of the H-cluster. We also studied the effect of S-to-Se substitution in the [4Fe-4S] subcluster. The reduced form of HydA1 containing only the [4Fe-4Se]H cluster shows a characteristic S = 7/2 spin state which converts back into the S = 1/2 spin state upon maturation with a [2Fe]-PDT/ADT complex. PMID- 29627861 TI - Patients' Experience of Living with Cancer-associated thrombosis in Spain (PELICANOS). AB - INTRODUCTION: The previously reported Patients' Experience of LIving with CANcer associated thrombosis (PELICAN) identified several areas of unmet clinical and support need for cancer patients diagnosed with venous thromboembolism (VTE) in the UK. It is not known whether such experiences are restricted to one particular country's healthcare system and culture. We therefore undertook an evaluation of patients' experience of cancer-associated thrombosis (CAT) within a Spanish setting. METHODS: Twenty consecutive Spanish patients with CAT were interviewed about their experiences of living with CAT as per the previous PELICAN study. Where possible, spouses were interviewed in conjunction. Semi-structured interviews were audio recorded, transcribed and translated into English. Transcripts were coded using Nvivo software and data were analysed using framework analysis. A pragmatic approach was undertaken to allow explication of the potential cultural and operational differences that were not apparent in the UK dataset. RESULTS: Several commonalities between the UK and Spanish patients were identified including the traumatic nature of the experience, the need for information and adaptive behaviors through ritualisation. Within the major themes lay new themes as follows. (1) The traumatic experience of CAT impacted on the family dynamic with respect to discussions within the family unit and support needs of individuals other than the patient. It also had a profound impact on the patient's concept of self with increased awareness of their mortality and seriousness of the cancer. (2) The need for information extended to the family as well as the patients. This was needed at the point of CAT diagnosis as well as an opportunity to later address unanswered questions. (3) Adaptive behaviors were common with similar ritualisations seen in the UK patients. CONCLUSION: The distress experienced by patients with CAT is not isolated to the UK alone but is similar in Spanish patients as well. The patient information provided regarding LMWH injections is important, but there is a need to for patients and their families to be given additional information about CAT itself and future prognosis. CAT also has a profound impact on the patient's family who has similar support needs. It appears that there are several commonalities between UK and Spanish patients, as well as specific local issues. This study justifies expansion of the sampling to other countries. PMID- 29627862 TI - A phase II study of HMB/Arg/Gln against oral mucositis induced by chemoradiotherapy for patients with head and neck cancer. AB - PURPOSE: This phase II trial assessed the clinical benefit of beta-hydroxy-beta methylbutyrate, arginine, and glutamine (HMB/Arg/Gln) for preventing chemoradiotherapy (CRT)-induced oral mucositis (OM) in patients with head and neck cancer (HNC). METHODS: Patients with HNC receiving definitive or postoperative cisplatin-based CRT were enrolled. HMB/Arg/Gln was administered orally or per percutaneous endoscopic gastrostomy from the first day of CRT up to its completion. All patients received opioid-based pain control and oral care programs that we previously reported. The primary endpoint was the incidence of grade >= 3 OM (functional/symptomatic) according to the Common Terminology Criteria of Adverse Events version 3.0. Quality of life (EORTC QLQ-C30/PROMS) at baseline and upon radiotherapy at a dosage of 50 Gy were assessed. RESULTS: Thirty-five patients with HNC were enrolled. Sixteen of them (45.7%) developed grade >= 3 OM (i.e., functional/symptomatic). The incidence of grade <= 1 OM (functional/symptomatic) was 51.5% at 2 weeks and 82.9% at 4 weeks after radiotherapy completion. Clinical examination revealed that 10 patients (28.6%) developed grade >= 3 OM. The incidence of grade <= 1 OM (clinical exam) was 80.0% at 2 weeks and 100% at 4 weeks after radiotherapy completion. Adverse events related to HMB/Arg/Gln were an increase in blood urea nitrogen and diarrhea, but were easily managed. CONCLUSIONS: The addition of HMB/Arg/Gln to opioid-based pain control and oral care programs was feasible but still insufficient at reducing the incidence of CRT-induced severe OM. However, the benefit of HMB/Arg/Gln should not be neglected given the findings of clinical examinations and the rapid recovery from severe OM. TRIAL REGISTRATION: UMIN000016453. PMID- 29627863 TI - The codesign of an interdisciplinary team-based intervention regarding initiating palliative care in pediatric oncology. AB - PURPOSE: Children with advanced cancer are often not referred to palliative or hospice care before they die or are only referred close to the child's death. The goals of the current project were to learn about pediatric oncology team members' perspectives on palliative care, to collaborate with team members to modify and tailor three separate interdisciplinary team-based interventions regarding initiating palliative care, and to assess the feasibility of this collaborative approach. METHODS: We used a modified version of experience-based codesign (EBCD) involving members of the pediatric palliative care team and three interdisciplinary pediatric oncology teams (Bone Marrow Transplant, Neuro Oncology, and Solid Tumor) to review and tailor materials for three team-based interventions. Eleven pediatric oncology team members participated in four codesign sessions to discuss their experiences with initiating palliative care and to review the proposed intervention including patient case studies, techniques for managing uncertainty and negative emotions, role ambiguity, system level barriers, and team communication and collaboration. RESULTS: The codesign process showed that the participants were strong supporters of palliative care, members of different teams had preferences for different materials that would be appropriate for their teams, and that while participants reported frustration with timing of palliative care, they had difficulty suggesting how to change current practices. CONCLUSIONS: The current project demonstrated the feasibility of collaborating with pediatric oncology clinicians to develop interventions about introducing palliative care. The procedures and results of this project will be posted online so that other institutions can use them as a model for developing similar interventions appropriate for their needs. PMID- 29627864 TI - Exercise intensity and its impact on relationships between salivary immunoglobulin A, saliva flow rate and plasma cortisol concentration. AB - INTRODUCTION: Salivary secretory immunoglobulin A (sIgA), saliva flow rate and plasma cortisol concentrations have been shown to be influenced by exercise, particularly the intensity exercise is performed at, and circadian variation. The autonomic nervous system partly regulates salivary secretion, but it is not yet known whether cortisol also explains some variation in salivary parameters. METHODS: Twelve moderately trained male individuals ([Formula: see text]peak legs: 46.2 +/- 6.8 mL.kg-1.min-1) performed three 45-min constant load exercise trials in the morning: arm cranking exercise at 60%[Formula: see text]peak arms; moderate cycling at 60%[Formula: see text]peak legs; and easy cycling at 60%[Formula: see text]peak arms. Timed saliva samples and blood samples for plasma cortisol concentration determination were obtained before, post, 2 h post, and 4 h post-exercise. Saliva was collected in an additional resting trial at the same time points. RESULTS: At each time point for each exercise trial, negative correlations between cortisol and saliva flow rate (explaining 25 +/- 17% of the variance, R2 = 0.002-0.46) and positive correlations between cortisol and sIgA concentration (explaining 8 +/- 8% of the variance R2 = 0.002-0.24) were found. Saliva flow rate increased over time, whereas sIgA concentration and cortisol decreased over time for all trials (P < 0.05), there was no effect of time for sIgA secretion rate (P = 0.16). CONCLUSION: These results show a relationship between cortisol and saliva flow rate, which directly impacts on the concentration of salivary analytes. This study further confirms circadian variations in salivary parameters which must be acknowledged when standardising salivary data collection. PMID- 29627865 TI - Advances in Treatment of Cardiac Amyloid. AB - Systemic amyloidosis represents a complex group of diseases with a common feature characterized by misfolded autologous proteins depositing into tissues or organs throughout the body. Light chain amyloidosis (AL) and transthyretin (TTR) amyloid are the two most prevalent forms of this disease that commonly results in cardiac amyloidosis. In both of these conditions, the myocardium is a frequent site of infiltration and end-organ involvement often with devastating consequences. With cardiac amyloidosis becoming an increasingly identified disease that has previously been under-recognized, the purpose of this comprehensive review is to focus on the diagnosis and treatment of these two types of cardiac amyloidosis including a contemporary update on currently available therapies being investigated in clinical trials. Subsequently, we will detail potential therapeutic efficacy and limitations of these regimens, and then complete the review by highlighting newer treatment modalities. A high-level overview of modern therapeutic approaches for AL amyloid includes targeted therapies directed at reducing the production of precursor proteins and inhibitors intended to limit the deposition of fibrils in tissues. In the case of TTR amyloid, current therapy is focused on stabilization of TTR proteins, suppression of protein formation, and blocking the deposition of amyloid fibrils in tissue. Novel therapies are focused on removing amyloid fibril deposition from affected tissues. In summary, cardiac amyloidosis is a progressively devastating disease requiring swift recognition and treatment now with groundbreaking therapies on the horizon. PMID- 29627867 TI - Effect of obesity on postoperative outcomes in patients with left ventricular assist device. PMID- 29627866 TI - Replication timing of large Sorex granarius (Soricidae, Eulipotyphla) telomeres. AB - Previously, we described the unique feature of telomeric regions in Iberian shrew Sorex granarius: its telomeres have two ranges of size, very small (3.8 kb of telomeric repeats on average) and very large discontinuous telomeres (213 kb) interrupted with 18S rDNA. In this study, we have demonstrated extraordinary replication pattern of S. granarius large telomeres that have not been shown before in other studied mammal. Using the ReD-FISH procedure, we observed prolonged, through S period, large telomere replication. Furthermore, revealed ReD-FISH asymmetric signals were probably caused by partial replication of telomeres within an hour of 5-bromodeoxyuridine treatment due to the large size and special organization. We also found that in contrast to the telomeric halo from primary fibroblasts of bovine, mink, and common shrew, telomere halo of S. granarius consists of multiple loops bundled together, some of which contain rDNA. Here, we suggested several replicons firing possibly stochastic in each large telomere. Finally, we performed the TIF assay to reveal DNA damage responses at the telomeres, and along with TIF in nuclei, we found large bodies of telomeric DNA and ?-H2AX in the cytoplasm and on the surface of fibroblasts. We discuss the possibility of additional origin activation together with recombination-dependent replication pathways, mainly homologous recombination including BIR for replication fork stagnation overcoming and further S. granarius large telomere replication. PMID- 29627868 TI - Nitrogen removal performance and microbial community of an enhanced multistage A/O biofilm reactor treating low-strength domestic wastewater. AB - The low-strength domestic wastewater (LSDW) treatment with low chemical oxygen demand (COD) has drawn extensive attention for the poor total nitrogen (TN) removal performance. In the present study, an enhanced multistage anoxic/oxic (A/O) biofilm reactor was designed to improve the TN removal performance of the LSDW treatment. Efficient nitrifying and denitrifying biofilm carriers were cultivated and then filled into the enhanced biofilm reactor as the sole microbial source. Step-feed strategy and internal recycle were adopted to optimize the substrate distribution and the organics utilization. Key operational parameters were optimized to obtain the best nitrogen and organics removal efficiencies. A hydraulic retention time of 8 h, an influent distribution ratio of 2:1 and an internal recycle ratio of 200% were tested as the optimum parameters. The ammonium, TN and COD removal efficiencies under the optimal operational parameters separately achieved 99.75 +/- 0.21, 59.51 +/- 1.95 and 85.06 +/- 0.79% with an organic loading rate at around 0.36 kg COD/m3 d. The high throughput sequencing technology confirmed that nitrifying and denitrifying biofilm could maintain functional bacteria in the system during long-period operation. Proteobacteria and Bacteroidetes were the dominant phyla in all the nitrifying and denitrifying biofilm samples. Nitrosomonadaceae_uncultured and Nitrospira sp. stably existed in nitrifying biofilm as the main nitrifiers, while several heterotrophic genera, such as Thauera sp. and Flavobacterium sp., acted as potential genera responsible for TN removal in denitrifying biofilm. These findings suggested that the enhanced biofilm reactor could be a promising route for the treatment of LSDW with a low COD level. PMID- 29627869 TI - Regulation of Extracellular Matrix Synthesis by Shell Extracts from the Marine Bivalve Pecten maximus in Human Articular Chondrocytes- Application for Cartilage Engineering. AB - The shells of the bivalve mollusks are organo-mineral structures predominantly composed of calcium carbonate, but also of a minor organic matrix, a mixture of proteins, glycoproteins, and polysaccharides. These proteins are involved in mineral deposition and, more generally, in the spatial organization of the shell crystallites in well-defined microstructures. In this work, we extracted different organic shell extracts (acid-soluble matrix, acid-insoluble matrix, water-soluble matrix, guanidine HCl/EDTA-extracted matrix, referred as ASM, AIM, WSM, and EDTAM, respectively) from the shell of the scallop Pecten maximus and studied their biological activities on human articular chondrocytes (HACs). We found that these extracts differentially modulate the biological activities of HACs, depending on the type of extraction and the concentration used. Furthermore, we showed that, unlike ASM and AIM, WSM promotes maintenance of the chondrocyte phenotype in monolayer culture. WSM increased the expression of chondrocyte-specific markers (aggrecan and type II collagen), without enhancing that of the main chondrocyte dedifferentiation marker (type I collagen). We also demonstrated that WSM could favor redifferentiation of chondrocyte in collagen sponge scaffold in hypoxia. Thus, this study suggests that the organic matrix of Pecten maximus, particularly WSM, may contain interesting molecules with chondrogenic effects. Our research emphasizes the potential use of WSM of Pecten maximus for cell therapy of cartilage. PMID- 29627870 TI - Arterial Thrombosis in Patients with Cancer. AB - PURPOSE OF REVIEW: Cancer is a common cause of morbidity and mortality in the USA. While the association between venous thrombosis and malignancy is well established, arterial thrombosis has more recently been recognized as a serious complication of cancer and certain chemotherapeutic agents. This review aims to summarize the most recent literature regarding the incidence and risk factors for cancer-related arterial thrombosis, understand the pathophysiologic mechanisms of thrombosis, and highlight the specific diagnostic and treatment considerations relevant to cancer patients. RECENT FINDINGS: Based on a recent study looking at the Surveillance, Epidemiology, and End Results (SEER) database, the incidence of arterial thromboembolic events (ATEs) in patients with cancer at 6 months is 4.7%; the presence of an ATE is predictive of worse outcomes. Certain drugs such as platinum-based agents, vascular endothelial growth factor inhibitors, tyrosine kinase inhibitors, and taxanes have been associated with high rates of ATEs. Increased platelet reactivity appears crucial to development of arterial thrombosis in cancer patients. Cancer patients have an increased risk of arterial thrombosis that is likely due to both a cancer-associated procoagulant state as well as the adverse effects of certain chemotherapeutic agents. Treatment of arterial thromboembolism in cancer patients typically requires a multidisciplinary approach in part due to high rates of thrombocytopenia and stent thrombosis in the setting of percutaneous interventions. More studies are needed to investigate optimal prophylaxis, surveillance strategies, and treatments of cancer-related arterial thromboembolic disease. PMID- 29627871 TI - Autonomic Regulation and Ventricular Arrhythmias. AB - Autonomic nervous system (ANS) has a crucial role of regulating cardiac function in the physiological state and contributes to the pathogenesis of arrhythmias in the diseased state. The cardiac neuraxis consists of multiple feedback loops consisting of efferent and afferent limbs, mediating neurotransmission to and from the heart. Efferent parasympathetic neurotransmission is mediated by the vagus nerve, while paravertebral sympathetic ganglia relay efferent sympathetic neurotransmission to the heart. The association between autonomic activity and ventricular arrhythmias (VAs) has been studied extensively in both experimental models and humans. Efferent parasympathetic activity is felt to be antiarrhythmic, while the activation of efferent sympathetic signals is proarrhythmic. The cardiac neuraxis undergoes remodeling and becomes dysfunctional in the setting of myocardial infarction (MI), chronic cardiomyopathy (CMY), and structural heat disease. Altered ANS function has been shown to initiate and/or maintain VAs via various mechanisms. Interventions targeting the ANS have been used clinically to treat VAs, particularly in patients with hereditary heart rhythm disorders and structurally abnormal hearts. Clinical applications of cardiac neuraxial modulation at the level of spinal cord, stellate ganglion, and peripheral sympathetic and vagus nerve are being developed. In this review, the anatomy of cardiac autonomic innervation, the association between autonomic activity and ventricular arrhythmogenesis, and clinical applications of neuraxial modulation in the treatment of VAs are discussed. PMID- 29627872 TI - Hospital clinical pharmacy services in Vietnam. AB - Background Clinical pharmacy is key to the quality use of medicines. While there are different approaches in different countries, international perspectives may inform health service development. The Vietnamese Ministry of Health introduced a legal regulation of clinical pharmacy services in December 2012. Objective To describe the services, and to explore reported barriers and facilitators in implementing clinical pharmacy activities in Vietnamese hospitals after the introduction of Vietnamese Ministry of Health legal regulation. Setting Thirty nine hospitals in Hanoi, Vietnam, including 22 provincial and 17 district hospitals. Method A mixed methods study was utilized. An online questionnaire was sent to the hospitals. In-depth interviews were conducted with pairs of nominated pharmacists at ten of these hospitals. The questionnaire focused on four areas: facilities, workforce, policies and clinical pharmacy activities. Main outcome measure Proportion of clinical pharmacy activities in hospitals. Themes in clinical pharmacy practice. Results 34/39 (87%) hospitals had established clinical pharmacy teams. Most activities were non-patient-specific (87%) while the preliminary patient-specific clinical pharmacy services were available in only 8/39 hospitals (21%). The most common non-patient-specific activities were providing medicines information (97%), reporting adverse drug reactions (97%), monitoring medication usage (97%). The patient specific activities varied widely between hospitals and were ad hoc. The main challenges reported were: lack of workforce and qualified clinical pharmacists. Conclusion While most hospitals had hospital-based pharmacy activities, the direct patient care was limited. Training, education and an expanded work forces are needed to improve clinical pharmacy services. PMID- 29627874 TI - Meningiomas: skull base versus non-skull base. AB - To identify differences between skull base meningiomas (SBM) and non-skull base meningiomas (NSBM). All adult patients (18.0-69.9 years) operated for intracranial meningiomas between 1990 and 2010 at our institution were investigated. Al-Mefty's definition was used to dichotomize tumors into SBM and NSBM. Overall, 1148 consecutive patients were identified. Median age at surgery was 54.2 years [18.1-69.9]. Median follow-up was 7.4 years [0.0-20.9]. There were 562 patients (49%) with SBM and 586 (51%) with NSBM. The two groups were similar with respect to patient age, follow-up time, and number of patients. Overall female-to-male ratio was 2.6:1, but 3.2:1 in SBM and 2.2:1 in NSBM (p < 0.005). With respect to presenting symptoms, SBMs had more often neurological deficits (risk ratio (RR) 1.4; p < 0.0001) and less often seizures (RR 0.4; p < 0.0001). Gross total resections were less frequent in SBM than NSBM (62 vs 84%) (RR 1.3; p < 0.0001). SBMs had a lower risk of WHO grades II and III histology (4.5 vs 9.5%) (RR 0.5; p < 0.001). Worsening of neurological function was more frequent in SBM (21 vs 121%) (RR 1.8; p < 0.001). Retreatment-free survival at 5, 10, and 15 years, respectively, was 80, 70, and 62% for SBM versus 90, 82, and 74% for NSBM (p < 0.0001). Overall survival at 5, 10, and 15 years, respectively, was 93, 85, and 78% for SBM and 96, 91, and 79% for NSBM (p = 0.14). Patients with SBMs had more new-onset neurological deficits and significantly shorter retreatment-free survivals, but this did not adversely affect the overall survival. PMID- 29627873 TI - Disease-Modifying Treatment in Progressive Multiple Sclerosis. AB - PURPOSE OF REVIEW: Multiple sclerosis (MS) is an immune-mediated disorder that affects the central nervous system (CNS), often first affecting people in early adulthood. Although most MS patients have a relapsing-remitting course (RRMS) at disease onset, a substantial proportion later develop chronic progression, termed secondary progressive MS (SPMS). Approximately 10% of MS patients experience chronic progression from disease onset, termed primary progressive multiple sclerosis (PPMS). Although several disease-modifying treatment (DMT) options exist for relapsing forms of this disease, DMT options are few for progressive MS (PPMS and SPMS). Herein, we strive to define progressive MS, review major clinical trials aimed at progressive MS, and delineate potential strategies in the management of progressive MS. RECENT FINDINGS: In 2017, the first DMT for PPMS, the B lymphocyte-depleting monoclonal antibody, ocrelizumab, came to market. Ocrelizumab reduced 12-week confirmed disability progression (CDP) by 24% versus placebo. Siponimod, a selective sphingosine-1-phosphate receptor modulator, reduced 3-month CDP by 21% versus placebo in SPMS. Ibudilast slowed brain atrophy in PPMS and SPMS patients in a multicenter phase 2b study. Smaller early phase studies of alpha-lipoic acid and simvastatin each found slowing of rate of whole brain atrophy in SPMS patients. Reasons now exist for optimism in the search for DMTs for progressive MS. It remains a challenge to identify outcome measures that accurately reflect the underlying pathology in progressive MS, which is less inflammatory and more degenerative than RRMS. PMID- 29627875 TI - Realizing Women Living with HIV's Reproductive Rights in the Era of ART: The Negative Impact of Non-consensual HIV Disclosure on Pregnancy Decisions Amongst Women Living with HIV in a Canadian Setting. AB - To better understand the structural drivers of women living with HIV's (WLWH's) reproductive rights and choices, this study examined the structural correlates, including non-consensual HIV disclosure, on WLWH's pregnancy decisions and describes access to preconception care. Analyses drew on data (2014-present) from SHAWNA, a longitudinal community-based cohort with WLWH across Metro-Vancouver, Canada. Multivariable logistic regression was used to model the effect of non consensual HIV disclosure on WLWH's pregnancy decisions. Of the 218 WLWH included in our analysis, 24.8% had ever felt discouraged from becoming pregnant and 11.5% reported accessing preconception counseling. In multivariable analyses, non consensual HIV disclosure was positively associated with feeling discouraged from wanting to become pregnant (AOR 3.76; 95% CI 1.82-7.80). Non-consensual HIV disclosure adversely affects WLWH's pregnancy decisions. Supporting the reproductive rights of WLWH will require further training among general practitioners on the reproductive health of WLWH and improved access to women centred, trauma-informed care, including non-judgmental preconception counseling. PMID- 29627877 TI - Fever, edema, and shortness of breath: the Scrhodinger's cat paradox displayed on pericardium. PMID- 29627876 TI - Naringin Attenuates Cerebral Ischemia-Reperfusion Injury Through Inhibiting Peroxynitrite-Mediated Mitophagy Activation. AB - Excessive autophagy/mitophagy plays important roles during cerebral ischemia reperfusion (I/R) injury. Peroxynitrite (ONOO-), a representative reactive nitrogen species, mediates excessive mitophagy activation and exacerbates cerebral I/R injury. In the present study, we tested the hypothesis that naringin, a natural antioxidant, could inhibit ONOO--mediated mitophagy activation and attenuate cerebral I/R injury. Firstly, we demonstrated that naringin possessed strong ONOO- scavenging capability and also inhibited the production of superoxide and nitric oxide in SH-SY5Y cells exposed to 10 h oxygen glucose-deprivation plus 14 h of reoxygenation or ONOO- donor 3 morpholinosydnonimine conditions. Naringin also inhibited the expression of NADPH oxidase subunits and iNOS in rat brains subjected to 2 h ischemia plus 22 h reperfusion. Next, we found that naringin was able to cross the blood-brain barrier, and naringin decreased neurological deficit score, reduced infarct size, and attenuated apoptotic cell death in the ischemia-reperfused rat brains. Furthermore, naringin reduced 3-nitrotyrosine formation, decreased the ratio of LC3-II to LC3-I in mitochondrial fraction, and inhibited the translocation of Parkin to the mitochondria. Taken together, naringin could be a potential therapeutic agent to prevent the brain from I/R injury via attenuating ONOO- mediated excessive mitophagy. PMID- 29627878 TI - Discovery of a small-molecule inhibitor of Dvl-CXXC5 interaction by computational approaches. AB - The Wnt/beta-catenin signaling pathway plays a significant role in the control of osteoblastogenesis and bone formation. CXXC finger protein 5 (CXXC5) has been recently identified as a negative feedback regulator of osteoblast differentiation through a specific interaction with Dishevelled (Dvl) protein. It was reported that targeting the Dvl-CXXC5 interaction could be a novel anabolic therapeutic target for osteoporosis. In this study, complex structure of Dvl PDZ domain and CXXC5 peptide was simulated with molecular dynamics (MD). Based on the structural analysis of binding modes of MD-simulated Dvl PDZ domain with CXXC5 peptide and crystal Dvl PDZ domain with synthetic peptide-ligands, we generated two different pharmacophore models and applied pharmacophore-based virtual screening to discover potent inhibitors of the Dvl-CXXC5 interaction for the anabolic therapy of osteoporosis. Analysis of 16 compounds selected by means of a virtual screening protocol yielded four compounds that effectively disrupted the Dvl-CXXC5 interaction in the fluorescence polarization assay. Potential compounds were validated by fluorescence spectroscopy and nuclear magnetic resonance. We successfully identified a highly potent inhibitor, BMD4722, which directly binds to the Dvl PDZ domain and disrupts the Dvl-CXXC5 interaction. Overall, CXXC5-Dvl PDZ domain complex based pharmacophore combined with various traditional and simple computational methods is a promising approach for the development of modulators targeting the Dvl-CXXC5 interaction, and the potent inhibitor BMD4722 could serve as a starting point to discover or design more potent and specific the Dvl-CXXC5 interaction disruptors. PMID- 29627879 TI - Significance of circulating Epstein-Barr virus DNA monitoring after remission in patients with extranodal natural killer T cell lymphoma. AB - Circulating Epstein-Barr virus (EBV)-DNA has been established as a useful parameter for diagnosis and predicting prognosis in patients with extranodal natural killer T cell lymphoma (ENKTL); however, the role of monitoring of circulating EBV-DNA after complete remission (CR) is not well established. From January 2008 to August 2016, 328 ENKTL patents were enrolled in 2 lymphoma cohorts. Of 171 patients achieved a CR, 81 had available monitoring data for circulating EBV-DNA with negative post-treatment EBV-DNA. Measurement of circulating EBV-DNA was performed from unfractionated whole blood and calculated according to WHO international standards. Median duration of follow-up was 40.4 months. In 31 of the 81 patients (38.8%), circulating EBV-DNA was detected at least once during follow-up, and 16 of these patients (51.6%) experienced relapse. In contrast, only 7 out of 50 (14.0%) patients with consistently undetectable circulating EBV-DNA experienced relapse (p < 0.001). In multivariate analysis, positive conversion of circulating EBV-DNA was the only independent prognostic factor for occurrence of relapse (HR = 6.552, p < 0.001), progression free survival (HR = 4.549, p = 0.01), and overall survival (HR = 8.726, p < 0.001). Patients with a higher level of circulating EBV-DNA than 3310 IU/mL (3.52 log10 IU/mL) showed a strong tendency to relapse (73.3 vs. 31.3%, p = 0.019). In conclusion, positive conversion of circulating EBV-DNA was a valuable indicator of relapse and inferior survival, especially if the level was higher than 3310 IU/mL in ENKTL patients had achieved CR. Close follow-up is necessary for patients developed detectable circulating EBV-DNA after remission. PMID- 29627880 TI - Isolated Richter's syndrome of the brain: diagnosis in the eye of the beholder. PMID- 29627881 TI - Public Stigma Across Addictive Behaviors: Casino Gambling, eSports Gambling, and Internet Gaming. AB - The negative psychological effects of public stigma on disordered gamblers have been well documented. Public stigma deters treatment-seeking and other help seeking behaviors, and negatively impacts individuals' view of themselves. Different types of disordered gambling activities may attract different degrees of stigma. One increasingly popular form of gambling involves placing bets on the outcomes of competitive video games, also called eSports gambling. This activity shares characteristics with Internet gaming and gambling. The purpose of this study was to compare the degree of public stigma held towards traditional casino gamblers, eSports gamblers, and Internet gamers, as compared to an individual experiencing comparable levels of impairment and distress due to a financial crisis. Using an experimental between-groups vignette study design, we found that all three types of behavioral addictions were more heavily stigmatized than the control condition. The three behavioral addictions were seen as being highly controllable, engendered a significant amount of anger and blame, and resulted in higher levels of desired social distance. Traditional casino gamblers were seen as significantly more dangerous to be around and created a higher level of desired social distance than the Internet gamer. Differences between the Internet gamer and eSports better were less pronounced. These findings underscore the importance of reducing public stigma for gambling and other behavioral addictions, and provide information that can be used when developing interventions to impact stigma. PMID- 29627882 TI - An animal model of faecal incontinence and sacral neuromodulation. AB - The pudendal nerves can be injured during traumatic vaginal childbirth and result in faecal incontinence. Some of these incontinent patients benefit from chronic sacral neuromodulation and the mechanism of action of this therapy has been a focus of many studies. In 2008, a rodent model of neuropathic faecal incontinence was introduced and subsequently validated through a series of investigations. This review summarizes the decade-long contribution of Professor Ronan O'Connell to the inception and application of this rodent model of faecal incontinence and sacral neuromodulation. PMID- 29627883 TI - Platelet transfusion increases risk for acute respiratory distress syndrome in non-massively transfused blunt trauma patients. AB - PURPOSE: While damage control resuscitation is known to confer a survival advantage in severely injured patients, high-ratio blood component therapy should be initiated only in carefully selected trauma patients, due to the morbidity associated with blood product use. With this project, we aim to identify the effect of platelet transfusion in non-massively transfused bluntly injured patients. METHODS: The Glue Grant database was retrospectively queried and severely injured blunt trauma patients who underwent non-massive transfusion were identified. Patients were divided into quartiles depending on platelet volume they were transfused in the first 48 h. Outcomes of interest included mortality; ventilator, Intensive Care Unit (ICU) and hospital length of stay (LOS); infectious and non-infectious complications. Multivariable regression models were fitted for these outcomes, controlling for age, pre-existing comorbidities, injury severity, acute physiologic derangement, neurologic injury burden, and other fluid and blood product resuscitation. RESULTS: There was no difference in mortality, LOS, or the incidence of multi-organ failure and infectious complications. However, patients receiving >= 250 mL of platelets were more likely to develop acute respiratory distress syndrome (ARDS) compared to those who received < 250 mL [odds ratio 1.91 (95% CI 1.10-3.33, p = 0.022)]. CONCLUSIONS: Pre-emptive platelet transfusion should be avoided in non-massively transfused blunt injury victims in the absence of true or functional thrombocytopenia, as it increases risk for ARDS with no survival benefit. PMID- 29627886 TI - Operation evaluation in-human of a novel remote-controlled vascular interventional robot. AB - Remote-controlled vascular interventional robots (RVIRs) are being developed to increase the accuracy of surgical operations and reduce the number of occupational risks sustained by intervening physicians, such as radiation exposure and chronic neck/back pain. However, complex control of the RVIRs improves the doctor's operation difficulty and reduces the operation efficiency. Furthermore, incomplete sterilization of the RVIRs will increase the risk of infection, or even cause medical accidents. In this study, we introduced a novel method that provides higher operation efficiency than a previous prototype and allows for complete robot sterilization. A prototype was fabricated and validated through laboratory setting experiments and an in-human experiment. The results illustrated that the proposed RVIR has better performance compared with the previous prototype, and preliminarily demonstrated that the proposed RVIR has good safety and reliability and can be used in clinical surgeries. PMID- 29627885 TI - Establishment of Aromatic Pairs at the Surface of Chondroitinase ABC I: the Effect on Activity and Stability. AB - Removal of chondroitin sulfate glycosaminoglycan (GAG) chains with chondroitinase ABC I (chABC I) in CNS injury models promotes both saxon regeneration and plasticity. It has been suggested that direct interaction between an aromatic pair appears to contribute about - 1.3 kcal/mol to the stability of a folded protein, so introducing an aromatic pair by point mutation might increase the enzyme activity and thermal stability as in the case of mesophilic xylanase, although using this approach destabilized T4 lysozyme. In this study, we used site-directed mutagenesis to investigate the effect of new aromatic pairs on activity and stability of chABC I. We replaced Ile295, Ser581, and Gly730 adjacent to pre-existing aromatic residues with Tyr to obtain new aromatic pairs, i.e., Tyr295/His372, Tyr576/Tyr581, and Tyr623/Tyr730. Results showed that Km values of S581Y and G730Y variants decreased relative to wild-type enzyme while their catalytic efficiency (kcat/Km) increased but I295Y variant was inactive. Also, long-term and thermal stability of the active mutants was decreased. Fluorescence and circular dichroism studies showed that these mutations resulted in a more flexible enzyme structures: a finding which was confirmed by thermal and limited proteolytic studies. In conclusion, the activity of chABC I can be improved by introducing appropriate aromatic pairs at the enzyme surface. This approach did not provide any promising results regarding the enzyme stability. PMID- 29627887 TI - Clinical application of multicolour scanning laser imaging in diabetic retinopathy. AB - To compare the visualization of the lesions of diabetic retinopathy (DR) using multicolour scanning laser imaging (MSLI) and conventional colour fundus photography (CFP). The paired images of diabetic patients who underwent same-day MSLI and CFP examinations were reviewed. Combined multicolour (MC) images were acquired simultaneously using three laser wavelengths: blue reflectance (BR, lambda = 488 nm), green reflectance (GR, lambda = 518 nm) and infrared reflectance (IR, lambda = 820 nm). The number of positive DR lesions was calculated using fundus fluorescein angiography as the reference standard. The visibility of the microaneurysms (Mas) was graded using a scale, and the number of Mas for each method was counted by two masked readers. Eighty eyes of 42 diabetic patients were included. The average grading score for Mas visualization was significantly higher with MC (1.50 +/- 0.71) and GR (1.55 +/- 0.69) than with CFP (0.95 +/- 0.81). The average number of Mas was also significantly higher with MC (11.41 +/- 14.02) and GR (11.93 +/- 13.43) than with CFP (6.43 +/- 9.39). The number of positive Mas, diabetic macular edema (DME) and epiretinal membranes (ERM) were significantly higher with MC than CFP (P < 0.05), while the numbers of cotton wool spots, haemorrhages, hard exudates, venous beading and abnormal new vessels were not significantly different (P > 0.05). Mas and ERM were most effectively detected on GR images, and an elevated greenish shift was clearly visualized in patients with DME on the MC images. MSLI can effectively visualize Mas and other pathological lesions of DR compared with CFP. MSLI with superior resolution may be a useful complement for DME and ERM detection. PMID- 29627884 TI - The Influence of Post-Exercise Cold-Water Immersion on Adaptive Responses to Exercise: A Review of the Literature. AB - Post-exercise cold-water immersion (CWI) is used extensively in exercise training as a means to minimise fatigue and expedite recovery between sessions. However, debate exists around its merit in long-term training regimens. While an improvement in recovery following a single session of exercise may improve subsequent training quality and stimulus, reports have emerged suggesting CWI may attenuate long-term adaptations to exercise training. Recent developments in the understanding of the molecular mechanisms governing the adaptive response to exercise in human skeletal muscle have provided potential mechanistic insight into the effects of CWI on training adaptations. Preliminary evidence suggests that CWI may blunt resistance signalling pathways following a single exercise session, as well as attenuate key long-term resistance training adaptations such as strength and muscle mass. Conversely, CWI may augment endurance signalling pathways and the expression of genes key to mitochondrial biogenesis following a single endurance exercise session, but have little to no effect on the content of proteins key to mitochondrial biogenesis following long-term endurance training. This review explores current evidence regarding the underlying molecular mechanisms by which CWI may alter cellular signalling and the long-term adaptive response to exercise in human skeletal muscle. PMID- 29627888 TI - The effect of high-intensity versus low-level laser therapy in the management of plantar fasciitis: a randomized clinical trial. AB - We aimed to compare the efficacy of low-level laser therapy (LLLT) and high intensity laser therapy (HILT) in the treatment of plantar fasciitis (PF). Seventy patients were randomized into either the LLLT (8 men, 27 women; mean age 48.65 +/- 10.81 years) or HILT (7 men, 28 women; mean age 48.73 +/- 11.41 years) groups. LLLT (904 nm) and HILT (1064 nm) were performed three times per week, over a period of 3 weeks. Each treatment combined with silicone insole and stretching exercises. Patients' pain and functional status were evaluated with Visual Analog Scale, Heel Tenderness Index, and Foot and Ankle Outcome Score before and after treatment. A chi-square test was performed to compare demographic and clinical characteristics. Within-group and between-group differences were also investigated. Paired samples t test was used to analyze the differences between baseline and after treatment values, while independent samples t test was used to compare the two groups. Both groups contained similar demographic characteristics including age, sex, and body mass index (all p > 0.05). Three and two patients in the HILT and LLLT group, respectively, were lost to follow-up. At the study onset, there were no statistically significant differences between the two groups in the Visual Analog Scale, Heel Tenderness Index, and Foot And Ankle Outcome Scores. Three weeks later, both groups showed significant improvement in all parameters (p < 0.05). The HILT group demonstrated better improvement in all parameters than the LLLT group. Although both treatments improved the pain levels, function, and quality of life in patients with PF, HILT had a more significant effect than LLLT. PMID- 29627889 TI - Nonenzymatic determination of glucose at near neutral pH values based on the use of nafion and platinum black coated microneedle electrode array. AB - The authors report on a microneedle-based amperometric nonenzymatic glucose sensor for painless and continuous monitoring of glucose. It consists of 3 * 5 sharp stainless steel microneedles micromachined from a stainless steel substrate. The microneedles are 600 and 100 MUm in height and width, respectively. Nafion and platinum black were sequentially coated onto the tip of gold-coated microneedles and used for nonenzymatic (direct) sensing of glucose. Attractive features of the modified microneedle electrode include (a) a low working potential (+0.12 V vs. Ag/AgCl), (b) a linear response in the physiologically relevant range (1-40 mM), (c) a sensitivity as high as 175 MUA mM 1 cm-2, (d) a 23 MUM detection limit, and (e) a response time of 2 s. The sensor also exhibits good reproducibility and stability. The sensor is selective for glucose even in the presence of 10-fold higher concentrations of ascorbic acid, lactic acid, dopamine, uric acid, and acetaminophen. Graphical abstract Schematic representation of the fabrication sequence for a nonenzymatic electrochemical glucose sensor using Nafion and platinum black coated microneedle electrode array. The sensor is based on measuring the faradaic current at +0.12 V vs. Ag/AgCl by the direct electrochemical oxidation of glucose to gluconic acid on the surface of a Pt black sensing layer. PMID- 29627890 TI - Acidovorax monticola sp. nov., isolated from soil. AB - A novel strain K-4-16T was isolated from forest soil of Namsan Mountain, Seoul, South Korea, and was taxonomically characterized by a polyphasic approach. Strain K-4-16T was observed to be a Gram-staining negative, grayish white-coloured, motile with peritrichous flagella, and rod shaped bacterium. It was able to grow at 15-45 degrees C, at pH 4.5-10.5, and at 0-4% (w/v) NaCl concentration. Based on the 16S rRNA gene sequence analysis, strain K-4-16T belongs to the genus Acidovorax and is closely related to Acidovorax anthurii CFBP 3232T (98.3% sequence identity), Acidovorax konjaci K2T (97.9% sequence identity), Acidovorax valerianellae CFBP 4730T (97.8% sequence identity), and Acidovorax caeni R-24608T (97.8% sequence identity). The only respiratory quinone was ubiquinone-8. The major polar lipids were phosphatidylethanolamine, phosphatidylglycerol, and diphosphatidylglycerol. The predominant fatty acids of strain K-4-16T were summed feature 3 (C16:1omega7c and/or C16:1omega6c), C16:0, and summed feature 8 (C18:1omega7c and/or C18:1omega6c). The genomic DNA G+C content of this novel strain was 64.7 mol%. The DNA-DNA relatedness between strain K-4-16T and its reference strains were below the threshold value of 70%. The morphological, physiological, chemotaxonomic, and phylogenetic analyses clearly distinguished this strain from its close phylogenetic neighbors. Thus, strain K-4-16T represents a novel species of the genus Acidovorax, for which the name Acidovorax monticola sp. nov. is proposed. The type strain is K-4-16T (= KEMB 9005-570T = KACC 19171T = NBRC 113141T). PMID- 29627892 TI - Assessment of the 1% of Patients with Consistent < 15% Reduction in Low-Density Lipoprotein Cholesterol: Pooled Analysis of 10 Phase 3 ODYSSEY Alirocumab Trials. AB - PURPOSE: Clinical trials of statins and other lipid-lowering therapies (LLTs) often report large inter-individual variations in their effects on low-density lipoprotein cholesterol (LDL-C). We evaluated apparent hyporesponsiveness to the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab (defined as < 15% LDL-C reduction from baseline at all timepoints) using data from 10 Phase 3 trials (3120 hypercholesterolemic patients). METHODS: This report assessed the LDL-C percent reduction from baseline at weeks 4-104 (depending on study), and alirocumab serum levels and antidrug antibodies, in patients with apparent hyporesponsiveness. RESULTS: Among the 3120 patients evaluated, 98.9% responded to alirocumab, and 33 (1.1%) had < 15% LDL C reduction at all measured timepoints. Pharmacokinetics data indicated that 13/33 apparent hyporesponders had not received alirocumab; no pharmacokinetics data were available for 14/33, and 6/33 had detectable alirocumab. For the six patients with confirmed alirocumab receipt, the degree of adherence to pre-study concurrent LLTs could not be determined after study start; one of these patients had persistent antidrug antibodies. CONCLUSIONS: Apparent hyporesponsiveness to alirocumab appeared to be due to lack of receipt of alirocumab determined by serum alirocumab levels, possible lack of adherence to concurrent LLTs, a theoretical and rare possibility of biological non-responsiveness due to persistent antidrug antibodies, or other causes, as yet unidentified. PMID- 29627891 TI - Anabolic agents: what is beyond osteoporosis? AB - Osteoporosis is a common skeletal disorder characterized by low bone mass, which leads to reduced bone strength and an increased risk of fractures. Anabolic agents have been shown to improve bone mass and decrease fracture risk in osteoporosis patients by directly stimulating osteoblasts to produce new bone. Currently, two anabolic agents are available in the USA: recombinantly produced teriparatide (TPTD), which is the fully active (1-34) amino active sequence of human parathyroid hormone (PTH), and abaloparatide (APTD), a synthetic analog of parathyroid hormone-related peptide (PTHrP). At present, both agents are approved only for treatment of patients with osteoporosis at high risk of fracture. Nonetheless, their anabolic properties have led to off-label application in additional settings which include spine fusion, osteonecrosis of the jaw, arthroplasty, and fracture healing. In this article, we summarize available scientific literature regarding the efficacy, effectiveness, and safety of TPTD in these off-label settings. PMID- 29627893 TI - Fabrication of an immunosensor for early and ultrasensitive determination of human tissue plasminogen activator (tPA) in myocardial infraction and breast cancer patients. AB - Sensitive detection of biomarkers will mean accurate and early diagnosis of diseases. A tissue plasminogen activator (tPA) has a crucial role in many cardiovascular diseases and it is related to many processes such as angiogenesis in cancer cells. Therefore, sensitive determination of tPA is important in diagnosis and clinical research. tPA monoclonal antibody was covalently attached onto single-wall carbon nanotubes (SWCNTs) using diimide-activated imidation coupling. Functionalized SWCNTs were immobilized onto a glassy carbon electrode and the modification process was investigated by sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE), SEM, cyclic voltammetry (CV), and electrochemical impedance spectroscopy (EIS). Cyclic voltammograms (CVs) in a scan rate of 100 mVs-1 was studied and comparisons were made between the modified glassy carbon electrodes (immobilized with antibodies) as a working electrode before and after the formation of tPA-antibody complex. Results of the SDS-PAGE demonstrated that the antibody was covalently and site directly attached to the SWCNTs. The fabricated biosensor provided a good linear response range from 0.1 to 1.0 ng mL-1 with a low detection limit of 0.026 ng mL-1. The immunosensor showed selectivity, reproducibility, good sensitivity, and acceptable stability. Satisfactory results were observed for early and sensitive determination of tPA in human serum samples. For the first time, such specific biosensor is currently being fabricated for tPA in our laboratories and successfully could determine tPA in myocardial infraction and breast cancer patients. Graphical abstract Fabricated biosensor for determination of tPA. PMID- 29627894 TI - Prevention of Keshan Disease by Selenium Supplementation: a Systematic Review and Meta-analysis. AB - Systematic review (SR) of high-quality studies provides superior evidence, but an SR has not been conducted to evaluate the association between Keshan disease (KD) and selenium deficiency because SR was not available when KD was highly prevalent in the 1950s to 1970s. The objective of this study was to update our understanding of the etiology of KD and provide evidence for policies and strategies in KD surveillance, prevention, and control. We identified related studies by searching the CNKI, Wanfang, CQVIP, SinoMed, CMCI, PubMed, Embase, and EBSCO databases from January 1935 to April 2017. Community trials that met the inclusion criteria were included. Risk ratios (RR) with corresponding 95% confidence intervals (CI) were pooled to compare incidences between the two groups. A total of 17 articles (including 41 studies) were included. In total, the studies included 1,983,238 subjects, 683,075 of which were in experimental groups and 1,300,163 of which were in control groups. The protection rates were over 80% in 35 studies, and the overall effect (risk ratio) was 0.14 [95% CI (0.12, 0.16), P < 0.05]. Potential publication bias was observed in the funnel plots, but the results of Egger's and Begg's tests showed that there was no evidence of publication bias. Giving selenium supplements to the residents of KD endemic areas significantly reduced the incidence of KD. Selenium deficiency is therefore a cause of KD by the criterion of causation in modern epidemiology. Selenium should be included in the KD surveillance program. The description of "unknown cause" in the definition of KD may be inappropriate. PMID- 29627895 TI - Toosendanin mediates cisplatin sensitization through targeting Annexin A4/ATP7A in non-small cell lung cancer cells. AB - Cisplatin (CDDP) is used in the treatment of non-small cell lung cancer (NSCLC), but due to the development of resistance, the benefit has been limited. Toosendanin (TSN) has shown therapeutic effects on NSCLC; however, the role of TSN on CDDP sensitization in NSCLC remains unknown. The antitumor effects of TSN and CDDP sensitization mediated by TSN were explored. TSN was added in various amounts to measure dose- and time-dependent cytotoxicity. Intracellular CDDP was detected by high-performance liquid chromatography. The protein levels of ATP7A, ATP7B, hCTR1, MRP-2, P-gp and Annexin A4 (Anxa4) were analyzed. The tests were conducted using normal NSCLC (A549 cell line) and CDDP-resistant cells (A549/DDP cell line). Anxa4 promotes CDDP resistance by regulating ATP7A, so Anxa4 was overexpressed and silenced and also transfected with pcMV6 or siRNA/ATP7A, respectively. Mechanistic investigations revealed that TSN decreased relative viability in NSCLC cells. Remarkably, TSN significantly enhanced CDDPsensitization in invalid doses. TSN downregulated Anxa4 expression, enhanced intracellular CDDP, and had no effect on MRP-2, P-gp, ATP7A, ATP7B or hCTR1. Subsequently, overexpression of Anxa4 led to a significant decrease in intracellular CDDP concentration. The adjustment of CDDP concentration regulated by TSN disappeared in Anxa4 or ATP7A-silenced cells. TSN also enhanced CDDP sensitization in single ATP7A-overexpressing cells, but had no effect on cells with simultaneous ATP7A overexpression and Anxa4 silencing. The present study suggests that TSN can mediate CDDP sensitization in NSCLC through downregulation of Anxa4. PMID- 29627897 TI - Drug-drug interaction of cefiderocol, a siderophore cephalosporin, via human drug transporters. AB - PURPOSE: Cefiderocol, a siderophore cephalosporin, will be used concomitantly with other medications for treatment of bacterial infections. In vitro studies demonstrated inhibition potential of cefiderocol on organic anion transporter (OAT) 1, OAT3, organic cation transporter (OCT) 1, OCT2, multidrug and toxin extrusion (MATE) 2-K, and organic anion transporting polypeptide (OATP) 1B3. The aim of this study was to assess in vivo drug-drug interaction (DDI) potential of cefiderocol using probe substrates for these transporters. METHODS: DDI potentials of cefiderocol as inhibitors were assessed in a clinical study consisting of 3 cohorts. Twelve or 13 healthy adult subjects per cohort orally received a single dose of furosemide 20 mg (for OAT1/3), metformin 1000 mg (for OCT1/2 and MATE2-K), or rosuvastatin 10 mg (for OATP1B3) with or without co administration with cefiderocol 2 g every 8 h with 3-h infusion (a total of 3, 6, and 9 doses of cefiderocol with furosemide, metformin, and rosuvastatin, respectively). DDI potentials were assessed based on the pharmacokinetics of the substrates. RESULTS: Ratios (90% confidence intervals) of maximum plasma concentration and area under the plasma concentration-time curve were 1.00 (0.71 1.42) and 0.92 (0.73-1.16) for furosemide, 1.09 (0.92-1.28) and 1.03 (0.93-1.15) for metformin, and 1.28 (1.12-1.46) and 1.21 (1.08-1.35) for rosuvastatin, respectively. Exposures to furosemide or metformin did not change when co administered with cefiderocol. Slight increase in rosuvastatin exposure was observed with co-administered with cefiderocol, which was not considered to be clinically significant. Each treatment was well tolerated. CONCLUSIONS: Cefiderocol has no clinically significant DDI potential via drug transporters. PMID- 29627896 TI - Clinical connection between rheumatoid arthritis and liver damage. AB - When liver damage is present in rheumatoid arthritis (RA) patients, it is sometimes difficult to determine whether it is a hepatic manifestation of RA, associated primary liver disease or hepatotoxic liver disease which developed during the treatment of RA. Liver damage during RA is most common in the form of asymptomatic abnormal liver tests. Occasionally, liver damage may progress to cirrhosis. Patients with RA are more susceptible to an associated autoimmune liver disease. Medications used in rheumatology are often hepatotoxic and it is difficult to differentiate between hepatic manifestations of the primary disease and potential hepatotoxicity of the administered medications. The significance of the paper is in the fact that it includes the most relevant and the latest information on this commonly present problem in clinical practice. The aim of the author is to provide comprehensive but at the same time concise data which will be useful to the doctors who come into contact with RA patients with symptomatic or asymptomatic liver disease. Timely diagnosis and treatment of liver disease in RA patients can significantly influence the course and outcome of rheumatoid arthritis. PMID- 29627898 TI - Cross-sectional networks of depressive symptoms before and after antidepressant medication treatment. AB - PURPOSE: Recent reviews have questioned the efficacy of selective serotonin reuptake inhibitors (SSRIs) above placebo response, and their working mechanisms remain unclear. New approaches to understanding the effects of SSRIs are necessary to enhance their efficacy. The aim of this study was to explore the possibilities of using cross-sectional network analysis to increase our understanding of symptom connectivity before and after SSRI treatment. METHODS: In two randomized controlled trials (total N = 178), we estimated Gaussian graphical models among 20 symptoms of the Beck Depression Inventory-II before and after 8 weeks of treatment with the SSRI paroxetine. Networks were compared on connectivity, community structure, predictability (proportion explained variance), and strength centrality (i.e., connectedness to other symptoms in the network). RESULTS: Symptom severity for all individual BDI-II symptoms significantly decreased over 8 weeks of SSRI treatment, whereas interconnectivity and predictability of the symptoms significantly increased. At baseline, three communities were detected; five communities were detected at week 8. CONCLUSIONS: Findings suggest the effects of SSRIs can be studied using the network approach. The increased connectivity, predictability, and communities at week 8 may be explained by the decrease in depressive symptoms rather than specific effects of SSRIs. Future studies with larger samples and placebo controls are needed to offer insight into the effects of SSRIs. TRIAL REGISTRATION: The trials described in this manuscript were funded by the NIMH. Pennsylvania/Vanderbilt study: 5 R10 MH55877 ( https://projectreporter.nih.gov/project_info_description.cfm?aid=6186633&icde=283 4168&ddparam=&ddvalue=&ddsub=&cr=1&csb=default&cs=ASC&MMOpt= ). Washington study: R01 MH55502 ( https://projectreporter.nih.gov/project_info_description.cfm?aid=2034618&icde=283 4217&ddparam=&ddvalue=&ddsub=&cr=5&csb=default&cs=ASC ). PMID- 29627900 TI - The effect of an interactive follow-up program on ostomy adjustment of inpatients after their discharge from surgical wards of the hospitals affiliated to Isfahan University of Medical Sciences. AB - PURPOSE: Ostomy patients suffer from many physical and mental problems, which can be solved to a large extent with the help of education and follow-up programs. These follow-ups can be done in person or on the telephone by the nurses, or even, by sending a text message that is an easier way for the patients to adapt to their condition. This study aimed to investigate the effect of an interactive follow-up program on the adjustment of ostomy inpatients after being discharged. METHODS: This study is a clinical trial, conducted on 64 ostomy patients who were discharged from the surgical wards of the hospital affiliated to Isfahan University of Medical Sciences. Subjects in the experimental group participated in a 6-week follow-up program via text message. The information about the patients were collected by Olbrisch Ostomy Adjustment Scale. RESULTS: The obtained results have suggested that 34.4% of the patients in the experimental group and 28.1% of the patients in the control group were female. Before the intervention, comparing the mean score of ostomy adjustment and its dimensions in the two groups showed no significant difference (P > 0.05). However, a significant difference was observed between the two groups immediately after the intervention (P < 0.05) and 1 month after the intervention, except for dimension of negative acceptance (P > 0.05). CONCLUSIONS: The findings of this study suggested that using SMS can be considered as a proper tool or method for following up the ostomy patients. PMID- 29627899 TI - Influence of visual-functional mismatch on coronary flow profiles after percutaneous coronary intervention: a propensity score-matched analysis. AB - The aims of this study are to clarify whether discrepancies between angiographic and fractional flow reserve (FFR) measurements (visual-functional mismatch) influence coronary flow profiles after percutaneous coronary intervention. While current guidelines FFR-guided revascularization, clinical practice most commonly relies on angiographic evaluation, which may under- or over-estimate the functional relevance of the lesion. Our retrospective analysis involved 274 vessels from 264 patients with stable angina pectoris who underwent FFR, index of microvascular resistance, and coronary flow reserve (CFR) measurements before and after PCI. Visual-functional concordance and discordance (reverse mismatch) were defined as angiographic stenosis > 50% with FFR <= 0.80 and angiographic stenosis <= 50% with FFR <= 0.80, respectively. Propensity score-matched cohort included 132 lesions (66 lesions: concordant findings, 66 lesions: reverse mismatch). The change in coronary flow profiles after PCI was assessed in terms of FFR, CFR, index of microvascular resistance (IMR), and mean transit time (Tmn). Compared with concordant territories, reverse mismatch territories were associated with lower pre-PCI IMR, higher pre-PCI CFR, greater minimum lumen diameter and smaller reference diameter (all comparisons, P < 0.05). After propensity score matching, the prevalence and extent of coronary flow improvement after PCI, evaluated by CFR and Tmn, were both remained significantly greater in concordant territories (all comparisons, P < 0.05). The prevalence and extent of coronary flow improvement after PCI assessed by the physiologic indices was significantly greater in visual-functional concordant lesions, suggesting that these coronary physiologic changes were associated with discrepancy between angiographic measurements. PMID- 29627901 TI - Microbiological quality of air in free-range and box-stall stable horse keeping systems. AB - The aim of this study was to assess the microbiological quality of air in three horse riding centers differing in the horse keeping systems. The air samples were collected in one facility with free-range horse keeping system and two with box stalls of different sizes. The samples were collected over a period of 3 years (2015-2017), four times per year (spring, summer, autumn, winter) to assess the effect of seasonal changes. The prevalence of aerobic mesophilic bacteria, mold fungi, actinomycetes, Staphylococcus spp., and Escherichia coli was determined by the air collision method on Petri dishes with appropriate microbiological media. At the same time, air temperature, relative humidity, and particulate matter concentration (PM10, PM2.5) were measured. It was found that the horse keeping system affects the occurrence of the examined airborne microorganisms. Over the 3 year period of study, higher temperature and humidity, as well as particulate matter concentration-which notoriously exceeded limit values-were observed in the facilities with the box-stall system. The air sampled from the largest horse riding center, with the largest number of horses and the box-stall system of horse keeping, was also characterized by the heaviest microbiological contamination. Among others, bacteria from the following genera: Staphylococcus spp., Streptococcus spp., Bacillus spp., and E. coli and fungi from the genera Aspergillus, Fusarium, Mucor, Rhizopus, Penicillium, Trichothecium, Cladosporium, and Alternaria were identified in the analyzed samples. PMID- 29627902 TI - Rosmarinic acid and siRNA combined therapy represses Hsp27 (HSPB1) expression and induces apoptosis in human glioma cells. AB - High expression of Hsp27 in glioma cells has been closely associated with tumor cell proliferation and apoptosis inhibition. The aim of the present study was to asses the effects of rosmarinic acid (RA) on Hsp27 expression and apoptosis in non-transfected and transfected human U-87 MG cells. The effect of rosmarinic acid was compared to quercetin, which is known to be a good Hsp27 inhibitor. In order to block the expression of Hsp27 gene (HSPB1), transfection with specific siRNAs was performed. Western blotting technique was used to assess the Hsp27 expression, and caspase-3 colorimetric activity assay was performed to determine apoptosis induction. According to the results, it was found that RA and quercetin effectively silenced Hsp27 and both agents induced apoptosis by activating the caspase-3 pathway. Eighty and 215 MUM RA decreased the level of Hsp27 by 28.8 and 46.7% and induced apoptosis by 30 and 54%, respectively. For the first time, we reported that rosmarinic acid has the ability to trigger caspase-3 induced apoptosis in human glioma cells. As a result of siRNA transfection, the Hsp27 gene was silenced by ~ 50% but did not cause a statistically significant change in caspase-3 activation. It was also observed that apoptosis was induced at a higher level as a result of Hsp27 siRNA and subsequent quercetin or RA treatment. siRNA transfection and 215 MUM RA treatment suppressed Hsp27 expression level by 90.5% and increased caspase-3 activity by 58%. Herein, we demonstrated that RA administered with siRNA seems to be a potent combination for glioblastoma therapy. PMID- 29627903 TI - Rapid molecular identification and differentiation of common Salmonella serovars isolated from poultry, domestic animals and foodstuff using multiplex PCR assay. AB - Salmonella is widely distributed throughout the world and can be found in poultry industry, animal breeding centers, food and feedstuffs of all geographical regions. This study was conducted to determine and identify Salmonella serovars isolated from poultry, calves and foodstuffs (poultry and animals products such as egg and meat). A total of one hundred isolates of Salmonella serovars including Salmonella Typhimurium, Salmonella Enteritidis, Salmonella Infantis, Salmonella Gallinarum and Salmonella Pullorum consecutively were subjected to the conventional culture, biochemical and serological assays. The utility of molecular multiplex PCR was investigated to identify and differentiate among five Salmonella serovars which were identified according to the presence of rfbJ, fljB, invA, and fliC genes in S. Typhimurium, sefA, invA and spv genes in Salmonella Enteritidis, fljB, fliC and invA genes in Salmonella Infantis, hut and slgC genes in both Salmonella Gallinarum and Salmonella Pullorum and speC gene specifically in Salmonella Gallinarum. Biochemical assays and serotyping are complicated to directly differentiate between Salmonella Gallinarum and Salmonella Pullorum because of their antigenic similarity. According to the results, Multiplex PCR can be considered as simple, rapid, accurate and useful test to identify and differentiate among Salmonella serovars. PMID- 29627904 TI - Site-specific derivatization of human interferon beta-1a at lysine residues using microbial transglutaminase. AB - Microbial transglutaminase (TGase) has been successfully used to produce site specific protein conjugates derivatized at the level of glutamine (Gln) or lysine (Lys) residues with diverse applications. Here, we study the drug human interferon beta-1a (IFN) as a substrate of TGase. The derivatization reaction was performed using carbobenzoxy-L-glutaminyl-glycine to modify Lys residues and dansylcadaverine for Gln residues. The 166 amino acids polypeptide chain of IFN beta-1a contains 11 Lys and 11 Gln residues potential sites of TGase derivatization. By means of mass spectrometry analyses, we demonstrate the highly selective derivatization of this protein by TGase at the level of Lys115 and as secondary site at the level of Lys33, while no reactive Gln residue was detected. Limited proteolysis experiments were performed on IFN to determine flexible regions of the protein under physiological conditions. Interestingly, primary and secondary sites of limited proteolysis and of TGase derivatization occur at the same regions of the polypeptide chain, indicating that the extraordinary selectivity of the TGase-mediated reaction is dictated by the conformational features of the protein substrate. We envisage that the TGase-mediated derivatization of IFN can be used to produce interesting derivatives of this important therapeutic protein. PMID- 29627905 TI - A cost-saving measure for ultrasound-guided musculoskeletal injections. PMID- 29627906 TI - Transformation of Adolescent Peer Relations in the Social Media Context: Part 2 Application to Peer Group Processes and Future Directions for Research. AB - As social media use becomes increasingly widespread among adolescents, research in this area has accumulated rapidly. Researchers have shown a growing interest in the impact of social media on adolescents' peer experiences, including the ways that the social media context shapes a variety of peer relations constructs. This paper represents Part 2 of a two-part theoretical review. In this review, we offer a new model for understanding the transformative role of social media in adolescents' peer experiences, with the goal of stimulating future empirical work that is grounded in theory. The transformation framework suggests that the features of the social media context transform adolescents' peer experiences by changing their frequency or immediacy, amplifying demands, altering their qualitative nature, and/or offering new opportunities for compensatory or novel behaviors. In the current paper, we consider the ways that social media may transform peer relations constructs that often occur at the group level. Our review focuses on three key constructs: peer victimization, peer status, and peer influence. We selectively review and highlight existing evidence for the transformation of these domains through social media. In addition, we discuss methodological considerations and key conceptual principles for future work. The current framework offers a new theoretical perspective through which peer relations researchers may consider adolescent social media use. PMID- 29627908 TI - Marine environmental risk assessment and acute water quality criterion for pentachlorophenol in coastal waters. AB - Pentachlorophenol (PCP) is a organochlorine biocide that, unlike most other organochlorines, is still in use as timber preservative. Its water solubility, high toxicity, bioaccumulation potential, and the concentrations reported in estuarine waters (up to 0.1 ug L-1) indicate it may pose a risk in coastal environments. Aquatic environrmental regulations are commonly based on standard freshwater organisms that may not represent the sensitivity of marine species. The present study consists of a water quality criteira reevalutation of PCP in coastal waters based on toxicity tests conducted recording sensitive endpoints of marine species representative of coastal ecosystems, following QA/QC standard procedures. The toxicity thresholds (EC10) found were 4.69 ug L-1 for Paracentrotus lividus sea-urchin embryos, 6.47 ug L-1 for Mytilus galloprovincialis mussel larvae, and 78.4 ug L-1 for Isochrysis galbana cells. Therefore, there is only one order of magnitude between the predicted no-effect concentration (PNEC) for early life stages of bivalves and echinoderms and the maximum concentrations actually recorded in coastal water, which yields a remarkable risk quotient for PCP in these highly productive marine habitats. In addition, we have reviewed the ecotoxicological data on PCP toxicity on marine species representative of the main systematic groups, from algae to chordates, and derived a probabilistic acute saltwater quality criterion of 2.66 ug L-1, intended to protect 95% of the marine species. Lack of adequate protection for marine ecosystems in some current PCP national guidelines has been identified. PMID- 29627907 TI - Transformation of Adolescent Peer Relations in the Social Media Context: Part 1-A Theoretical Framework and Application to Dyadic Peer Relationships. AB - Investigators have long recognized that adolescents' peer experiences provide a crucial context for the acquisition of developmental competencies, as well as potential risks for a range of adjustment difficulties. However, recent years have seen an exponential increase in adolescents' adoption of social media tools, fundamentally reshaping the landscape of adolescent peer interactions. Although research has begun to examine social media use among adolescents, researchers have lacked a unifying framework for understanding the impact of social media on adolescents' peer experiences. This paper represents Part 1 of a two-part theoretical review, in which we offer a transformation framework to integrate interdisciplinary social media scholarship and guide future work on social media use and peer relations from a theory-driven perspective. We draw on prior conceptualizations of social media as a distinct interpersonal context and apply this understanding to adolescents' peer experiences, outlining features of social media with particular relevance to adolescent peer relations. We argue that social media transforms adolescent peer relationships in five key ways: by changing the frequency or immediacy of experiences, amplifying experiences and demands, altering the qualitative nature of interactions, facilitating new opportunities for compensatory behaviors, and creating entirely novel behaviors. We offer an illustration of the transformation framework applied to adolescents' dyadic friendship processes (i.e., experiences typically occurring between two individuals), reviewing existing evidence and offering theoretical implications. Overall, the transformation framework represents a departure from the prevailing approaches of prior peer relations work and a new model for understanding peer relations in the social media context. PMID- 29627909 TI - Technological Advances in Stent Therapies: a Year in Review. AB - Stent technology has rapidly evolved since the first stainless steel bare metal stents with substantial developments in scaffolding, polymer, drug choice, drug delivery, and elution mechanisms. Most recently, there has been the evolution of bioabsorbable vascular scaffolds, potentially eliminating the need for long-term foreign object retention. These rapid developments have led to an ever-expanding selection of new stents, making the choice of which to use in which patient challenging. Operators must balance potential short- and long-term clinical ramifications, namely stent thrombosis, in-stent restenosis, target lesion revascularization, and target lesion failure. In this review, we hope to provide insight for interventional cardiologists on the details of stent technology and how this impacts outcomes, stent selection, and duration of dual-antiplatelet therapy duration post drug-eluting stent implantation. PMID- 29627910 TI - Correction to: Smoking Policy Change Within Permanent Supportive Housing. AB - The original version of this article unfortunately contains mistakes. 1. On page 315, in the last sentence under the "Tobacco Use" subheading, the percentage should read "59.3%" rather than "55.6%". 2. On page 315, in the last sentence under the "Secondhand Smoke Exposure" subheading, the percentage "28.2%" should read "28.6%". 3. The presentation of "Post-policy" and "Pre-policy" terms in the Figs. 1 and 3 were incorrect. It should be read as: Figure 1: Pre-policy (n = 27); Post-policy (n = 16). Figure 3: Pre-policy (n = 55); Post-policy (n = 42). The corrected Figs. 1 and 3 are given below. PMID- 29627911 TI - Pertussis and the Minnesota State Fair: Demonstrating a Novel Setting for Efficiently Conducting Seroepidemiologic Studies. AB - Seroepidemiologic studies, which measure serum antibody levels produced in response to infection and/or vaccination, can be valuable tools for gaining insight into population level dynamics of infectious diseases. However, because seroepidemiologic studies are expensive and logistically challenging, they are not routinely conducted for surveillance purposes. We have identified a novel venue, state fairgrounds, in which annual sera samples from a population may be rapidly collected with minimal recruitment expenses. We conducted a pilot pertussis seroepidemiologic study over the course of 3 days at the 2016 Minnesota State Fair to determine if this setting, which hosts nearly 2 million visitors over 12 days each year, is viable for facilitating larger seroepidemiologic studies. A total of 104 adults and children were enrolled to provide a finger stick blood sample for serologic testing and to take a written survey regarding recent cough illness and pertussis vaccination. The survey was used to distinguish between antibodies induced by vaccination and pertussis infection. Elevated antibodies suggestive of recent infection were found among two adults. The prevalence of undetectable antibodies, suggestive of susceptibility, was 72.3% (95% CI 59.6, 85.1%) among 7-17 year olds, 53.8% (95% CI 26.7, 80.9%) among 1-6 year olds, and 23.3% (95% CI 8.2, 38.5%) among adults. Our ability to rapidly enroll participants and collect satisfactory specimens suggests that seroepidemiologic studies with 1000-2000 participants could efficiently be completed over the 12-day course of the Minnesota State Fair. This setting raises the possibility of efficiently conducting annual population-based seroepidemiologic studies to supplement traditional public health surveillance in estimating disease prevalence, monitoring vaccine impact, and identifying at-risk groups. PMID- 29627912 TI - Violent Behaviors, Weapon Carrying, and Firearm Homicide Trends in African American Adolescents, 2001-2015. AB - African American youths have the highest risk for firearm and other weapon related homicides. This study utilized the national Youth Risk Behavior Surveys from 2001 to 2015 to assess trends in violence related behaviors and weapon carrying of African American adolescents. Our analyses found statistically significant reductions in physical fighting and weapon carrying among African American male adolescents from 2007 to 2015. Planning suicide increased in both male and female African American adolescents since 2007. In addition, the number of firearm homicides increased in African American males. African American females and males had groups of items highly predictive of weapon carrying behaviors: alcohol, tobacco, and other drug use and violent risk behaviors. Both female and male students who made mostly A's or B's in school were significantly less likely to carry weapons in and out of school. Our findings indicate that firearm homicides have increased in African American adolescents, but weapon carrying in school going adolescents has significantly declined. School engagement and satisfactory school performance seems to have a significant protective effect on firearm homicides and violent behavior risks in African American adolescents. PMID- 29627913 TI - Retrospective Cohort Comparison of Fall Height in Children in the Greater Los Angeles Area: Targeting Populations for Injury Prevention. AB - The purpose of this study was to determine whether falls from significant height occur more frequently in young children. We conducted a 10-year (2004-2014), comparative study using a retrospective cohort of 4713 children (< 18 years) from the Los Angeles county trauma database who were evaluated for a fall. Exposure was fall height, dichotomized into < 10 ft/low-risk fall and > 10 ft/high-risk fall. Primary outcome was age of fall. Secondary outcomes were disposition from emergency department, injuries, resource utilization, and mortality. Of all falls, 4481 (95%) were low-risk and 232 (5%) high-risk. High-risk falls were more frequent in children 1-3 years old (58 vs. 30%, p < 0.01), associated with higher frequency of intracranial hemorrhage (19 vs. 10%, p < 0.01), intubation (11 vs. 1%, p < 0.01), and neurosurgical procedure (2 vs. 0.8%, p = 0.04). There was no difference in mortality (0.86 vs. 0.13%, p = 0.06). In Los Angeles County, children 1-3 years old are most likely to suffer high-risk falls, which are associated with serious injury. Integration of fall prevention education into routine anticipatory guidance should be strongly considered for children 1-3 years old. PMID- 29627914 TI - The Influence of Feed-Supplementation with Probiotic Strain Lactobacillus reuteri CCM 8617 and Alginite on Intestinal Microenvironment of SPF Mice Infected with Salmonella Typhimurium CCM 7205. AB - Alginite is a non-ore raw material arising by fossilization of accumulated organic (algae) and inorganic material, particularly clay, carbonates, quartz, and amorphous modification of silicic acid in the aqueous environment. Humic acids as a component of organic portion of alginite are known for very good buffering ability which allows them to stabilise pH throughout the digestion system of animals, stimulate receptors of the immune system in intestinal villi against pathogenic bacteria, and support proliferation and activity of beneficial bacteria (lactobacilli, bifidobacteria, and similar). Our investigations focused on the influence of a probiotic strain in combination with alginite on intestinal microenvironment of SPF mice infected with Salmonella Typhimurium. The 66 female mice (BALB/c) used in our study were divided to four experimental groups, control NC1, control NC2 (alginite), IC (alginite + Salmonella Typhimurium CCM 7205NAL), LAB (Lact. reuteri CCM 8617 + alginite + Salm. Typhimurium CCM 7205NAL). The group supplemented with Lact.reuteri CCM 8617 and alginite showed significant reduction in growth of Salm. Typhimurium in mice faeces at 24 and 72 h (P < 0.001) post infection. The supplementation of additives affected positively also nitrogen, enzymatic, hepatic and energy metabolism of mice. The demonstrable positive influence of additives alleviated the negative impact of Salm. Typhimurium infection on the morphology investigated in the jejunum and ileum of LAB group of mice. The livers of mice treated with both alginite and Lact.reuteri CCM 8617 showed marked reduction of overall inflammation, hepatocyte necrosis and size of typhoid nodules. PMID- 29627915 TI - Approaches to Catheter Ablation of Nonparoxysmal Atrial Fibrillation. AB - PURPOSE OF REVIEW: We describe the technical aspects and outcomes of several different ablation strategies for nonparoxysmal (persistent and long-standing persistent) atrial fibrillation (AF) and discuss our ablation strategy for these patients. RECENT FINDINGS: Catheter ablation is an effective treatment strategy for patients with AF. Outcomes of ablation in patients with nonparoxysmal forms of AF tend to be worse than in patients with paroxysmal AF. Several recent studies have examined the long-term ablation success rates of different ablation approaches in patients with nonparoxysmal AF. While observational studies have suggested benefit of several different ablation strategies for persistent AF, large randomized controlled studies have shown similar success rates with pulmonary vein isolation (PVI) alone as compared versus PVI plus additional ablation. The optimal ablation strategy to achieve long-term freedom from recurrent arrhythmias in patients with nonparoxysmal AF remains controversial. Achieving durable PVI should be the cornerstone of AF ablation. Additional large scale randomized controlled studies are necessary to determine whether additional ablation might result in improved long-term ablation success rates in these patients. PMID- 29627917 TI - Autosomal short tandem repeat variations and population genetic data on 23 systems in seven major subpopulations from Lebanon. AB - Population allele frequency is an indicator of population genetic diversity and plays significant roles in DNA profiling interpretation in human identification, kinship, and forensic testing. The Lebanese population is a mosaic of 18 religious communities with high rates of consanguinity and endogamy. Allele frequencies for 23 STR loci were estimated and analyzed in the seven major Lebanese religious subcommunities (Muslims Shiaa, Sunni, and Druze, and Christians Orthodox, Maronite, and Catholics), to assess possible significant differences among their STR allele frequencies. PMID- 29627916 TI - Necrotizing fasciitis: case series and review of the literature on clinical and medico-legal diagnostic challenges. AB - Necrotizing fasciitis (NF) is a life-threatening infection of soft tissues spreading along the fasciae to the surrounding musculature, subcutaneous fat and overlying skin areas that can rapidly lead to septic shock and death. Due to the pandemic increase of medical malpractice lawsuits, above all in Western countries, the forensic pathologist is frequently asked to investigate post mortem cases of NF in order to determine the cause of death and to identify any related negligence and/or medical error. Herein, we review the medical literature dealing with cases of NF in a post-mortem setting, present a case series of seven NF fatalities and discuss the main ante-mortem and post-mortem diagnostic challenges of both clinical and forensic interests. In particular, we address the following issues: (1) origin of soft tissue infections, (2) micro-organisms involved, (3) time of progression of the infection to NF, (4) clinical and histological staging of NF and (5) pros and cons of clinical and laboratory scores, specific forensic issues related to the reconstruction of the ideal medical conduct and the evaluation of the causal value/link of any eventual medical error. PMID- 29627919 TI - Acquired Methemoglobinemia Associated with Topical Lidocaine Administration: A Case Report. AB - A 55-year-old male was admitted to the hospital with pneumonia. During an intubation procedure, the patient received an application of endobronchial lidocaine (4% gel). Within 2 h of intubation, the patient developed worsening hypoxia, and investigation of arterial blood gasses revealed a pH of 7.21, carbon dioxide partial pressure (PaCO2) of 3.3 kPa, oxygen partial pressure (PaO2) of 55.1 kPa, and measured oxygen saturation of 49%. Co-oximetry of this sample returned a methemoglobin level of 53%. Intravenous methylthioninium chloride (1% solution at 1 mg/kg) was delivered, and subsequent arterial blood gasses, at 30 min and 1 h post administration, showed methemoglobin levels of 12 and 9%, respectively, with return of oxygen saturation to > 90%. PMID- 29627918 TI - Protective Effect of Moderate Exogenous Electric Field Stimulation on Activating Netrin-1/DCC Expression Against Mechanical Stretch-Induced Injury in Spinal Cord Neurons. AB - Nerve cells detect and respond to electric field stimulation and extrinsic chemical guidance cues during development and regeneration; therefore, the development and optimization of an approach for functional neuronal regeneration are necessary for a nerve injury. In this study, we proposed using electric field stimulation to repair a nerve injury triggered by serious mechanical stretch loading. A device that provides continuous mechanical stretch and constant electric field stimulation was designed. Primary dissociated spinal cord neurons were stimulated by mechanical stretch (tensile strain 2.5-10%) at different times (1, 4, 8, and 12 h) to set up a moderate nerve injury model. Stimulated samples were evaluated with respect to cell viability, density, and axonal elongation by the MTT and immunofluorescence assays. The results indicated that mechanical stretch (S, 5% tensile strain, 4 h) caused moderate axonal injury, resulting in significant loss of cell viability and a decrease in cell density. However, injured spinal cord neurons became viable after electric field stimulation (E, 33 mA/m2, 4 h) in the fluorescein diacetate assay. In addition, neuronal viability, density, and elongation increased significantly after electric field stimulation compared with those of stretch-injured neurons. Moreover, electric field stimulation significantly activated the axonal guidance cues Netrin-1 and deleted in colorectal cancer (DCC) receptor expression compared with the stretch-injury group. These results indicate that electric stimulation activates synergistic guidance cues of expression to improve axonal growth relevant to nerve injuries. Our study provides new insight into neuronal regeneration. PMID- 29627920 TI - Advances in Pharmacotherapy of Late-Life Depression. AB - : This paper reviews recent research on late-life depression (LLD) pharmacotherapy, focusing on updated information for monotherapy and augmentation treatments. We then review new research on moderators of clinical response and how to use the information for improved efficacy. RECENT FINDINGS: A recent review shows that sertraline, paroxetine, and duloxetine were superior to placebo for the treatment of LLD. There is concern that paroxetine could have adverse outcomes in the geriatric population due to anticholinergic properties; however, studies show no increases in mortality, dementia risk, or cognitive measures. Among newer antidepressants, vortioxetine has demonstrated efficacy in LLD, quetiapine has demonstrated efficacy especially for patients with sleep disturbances, and aripiprazole augmentation for treatment resistance in LLD was found to be safe and effective. Researchers have also been identifying moderators of LLD that can guide treatment. Researchers are learning how to associate moderators, neuroanatomical models, and antidepressant response. SSRI/SNRIs remain first-line treatment for LLD. Aripiprazole is an effective and safe augmentation for treatment resistance. Studies are identifying actionable moderators that can increase treatment response. PMID- 29627921 TI - On the use of cholera toxin. PMID- 29627922 TI - Genetics of Iranian Alpha-Thalassemia Patients: A Comprehensive Original Study. AB - Alpha thalassemia is the most prevalent monogenic gene disorder in the world, especially in Mediterranean countries. In the current hematological phenotype of patients with different genotypes, the effects of missense mutations on the protein function and also stability were evaluated in a large cohort study. A total of 1,560 subjects were enrolled in the study and divided into two groups: 259 normal subjects; and 1301 alpha-thalassemia carriers. Genomic DNA was extracted and analyzed using ARMS PCR, Multiplex Gap, and direct sequencing. The effects of single nucleotide change on the protein function and stability were predicted by freely available databases of human polymorphisms. Sixty-three different genotypes were seen in the patients. The more prevalent was heterozygote form of -alpha3.7 (41.4%) followed by -alpha3.7 homozygote (11.6%) and -MED (3.8%). The significant differences were seen in mean hemoglobin level [F = 20.5, p < 0.001] between the Alpha-globin genotypes, when adjusted for gender. Moreover, 28 different mutations were found in our study. A significant relationship was seen between ethnicity and the alpha-globin mutation frequency chi2 (df;8) = 38.36, p < 0.0001). Different genotypes could display as different phenotypes. The mutation frequency distributions in our region are different from those of other parts of Iran. Significant differences are seen in the spectrum of mutation frequency among various ethnicities. Finally, some missense mutations might not have considerable effect on the proteins, and they could be neutral mutations. PMID- 29627923 TI - Religious Fundamentalism, Satisfaction with Life and Posttraumatic Stress Symptoms Intensity in a Polish Sample of People Living with HIV/AIDS. AB - We investigated the relationship between religious fundamentalism, satisfaction with life and the intensity of posttraumatic stress symptoms in people living with HIV/AIDS. The study was conducted on 283 adults, including 242 HIV-positive patients and 41 individuals with AIDS, aged from 20 to 74. Religious fundamentalism was positively correlated with age and posttraumatic stress symptoms intensity. Negative correlation between satisfaction with life and posttraumatic stress intensity was also found. Religious fundamentalism and satisfaction with life accounted for 34% of the variance in posttraumatic stress symptoms intensity. The level of patients' education mediated the relationship between religious fundamentalism and the posttraumatic stress symptoms intensity. PMID- 29627924 TI - Repetition Compulsion Revisited in Relational Family Therapy: The Discovery of Old in Order to Develop Something New. AB - Psychoanalysis has always been full of diversity and controversy, in the theoretical field and especially in the plasticity and variety of its modalities and approaches. Yet all these theories are based on the premise that individuals compulsively repeat their old psycho-organic content, both in their personal lives and in analysis; the premise of Relational Family Therapy is that old emotional, behavioral and bodily complications must first be repeated before being fully processed so that something new can be created. PMID- 29627925 TI - Spirituality in African-American Breast Cancer Patients: Implications for Clinical and Psychosocial Care. AB - Spirituality has been shown to be important to many individuals dealing with a cancer diagnosis. While African-American breast cancer survivors have been reported to have higher levels of spirituality compared to White women, little is known about how levels of spirituality may vary among African-American breast cancer survivors. The aims of this study were to examine factors associated with spirituality among African-American survivors and test whether spirituality levels were associated with women's attitudes about treatment or health care. The primary outcome, spirituality, was nine-item scale (Cronbach's alpha = .99). Participants completed standardized telephone interviews that captured sociocultural, healthcare process, and treatment attitudes. Medical records were abstracted post-adjuvant therapy for treatment and clinical information. In bivariate analysis, age was not correlated with spirituality (p = .40). Married/living as married women had higher levels of spirituality (m = 32.1) than single women (m = 30.1). Contextual factors that were associated with higher levels spirituality were: collectivism (r = .44; p < 0.0001, Afrocentric worldview (r = .185; p = .01), and self-efficacy scale (r = .17; p = .02). In multivariable analysis, sociodemographic factors were not significant. Collectivism remained a robust predictor (p < 0.0001). Attitudes about the efficacy of cancer treatment were not associated with spirituality. The high levels of spirituality in African-American survivors suggest consideration of integrating spiritual care within the delivery of cancer treatment. Future studies should consider how spirituality may contribute to positive coping and/or behaviors in African-American women with high levels of spirituality. PMID- 29627926 TI - The Burden of Adverse Drug Reactions Due to Artemisinin-Based Antimalarial Treatment in Selected Ugandan Health Facilities: An Active Follow-Up Study. AB - INTRODUCTION: Uganda has rapidly increased access to antimalarial medicines in an effort to address the huge malaria disease burden. Pharmacovigilance information is important to guide policy decisions. OBJECTIVES: The purpose of this study was to establish the burden of adverse drug reactions (ADRs) and associated risk factors for developing ADRs to artemisinin-based antimalarial treatment in Uganda. METHODS: An active follow-up study was conducted between April and July 2017 in a cohort of patients receiving treatment for uncomplicated malaria in the Iganga, Mayuge, and Kampala districts. RESULTS: A total of 782 patients with a median age of 22 years (58.6% females) were recruited into this study, with the majority recruited from public health facilities (97%). Diagnostic tests before treatment were performed for 76% of patients, and 97% of patients received artemether/lumefantrine. The prevalence of ADRs was 22.5% (176/782); however, the total number of ADRs was 245 since some patients reported more than one ADR. The most commonly reported reactions were general body weakness (24%), headache (13%), and dizziness (11%). Women were more likely to develop an ADR (adjusted odds ratio [aOR] 1.8, 95% confidence interval [CI] 1.1-2.9), urban dwellers were more likely to develop an ADR than rural residents (aOR 9.9, 95% CI 5.4-17.9), and patients with comorbidities were more likely to develop an ADR than those without (aOR 7.4, 95% CI 4.4-12.3). CONCLUSION: The burden of ADRs is high among women and in patients from urban settings and those with comorbidities. Such risk factors need to be considered in order to optimise therapy. Close monitoring of ADRs is key in implementation of the malaria treatment policy. PMID- 29627927 TI - The effects of Roundup on gametes and early development of common carp (Cyprinus carpio L). AB - To determine the effects of Roundup, a commercial formulation of glyphosate, gametes, and embryos of common carp (Cyprinus carpio L) was exposed to wide range of herbicide concentrations (0.0, 0.1, 0.5, 2.0, 5.0, 10.0, 20.0, and 50.0 mg/l). The obtained results showed different effects of Roundup on common carp gametes. Herbicide reduced swelling of eggs (but the effect was not concentration related), while sperm showed low sensitivity to Roundup (time of spermatozoa motility was reduced in a significant way only at 20 mg/l, and at remaining concentrations, only a slight tendency was observed). During the embryonic development, Roundup caused a decrease of common carp embryonic survival (and the effect was concentration-related); however, it had no effect on development rate. During the embryogenesis, three types of embryo body malformation were observed: yolk sac edema, spine curvature, and shortening of body, but their frequencies were not associated with the presence or concentration of herbicide. However, Roundup affected quality of newly hatched larvae of common carp by increasing their mortality. No effect of herbicide on percentage of deformed larvae was observed but larvae hatched in water with Roundup tended to show more complex anomalies compared to those from the control. Obtained data showed that even low concentrations of this herbicide in waters can significantly reduce egg swelling, survival of embryos, and quality of fish larvae. PMID- 29627928 TI - Toxic effects of coal fly ash on wheat seedlings. AB - We studied heavy metal (HM) stress on wheat seedlings (AK-58) with and without coal fly ash (CFA) exposure. Three CFA spray rates were used to simulate air quality of the second level. Results show airborne particulates can directly enter plant leaves, affecting the whole plant. HM deposition decreases seedling size and mass and reduces activities of the chlorophyll family, photosynthesis enzymes (RuBP and PEPC), and photosynthesis efficiency. In leaves, HM deposition increases with the CFA spray rate. In roots, however, CFA exposure seems to reduce HM deposition, compared with the control without CFA exposure. A possible reason is that HM deposition in leaves from airborne particulates hinders photosynthesis, weakens the whole physiology of the seedlings, and consequently reduces root absorption of HMs from soil. CFA leads to chloroplast expansion, layer-stack disorder of grana, plastoglobule increase, and even chlorophyll membrane damage. PMID- 29627929 TI - First cardiac manifestation of hypotonia-cystinuria syndrome. AB - Hypotonia-cystinuria syndrome is a very rare autosomal recessive contiguous gene deletion syndrome of PREPL and SLC3A1 at 2p21 with neuromuscular and neuroendocrinologic presentation. We report a two-year-six-month-old affected female infant and her five-month-old affected brother with a novel homozygous deletion in SLC3A1 and PREPL gene. Both of siblings had mild facial dysmorphism, hypotonia, feeding problems, failure to thrive, developmental delay. She also had dilated cardiomyopathy which differ from other reported patients. Therefore cardiomyopathy may also be considered one of the features of hypotonia-cystinuria syndrome. With this case report, we present cardiac manifestation of hypotonia cystinuria syndrome for the first time. Because of two siblings had hyperechogenic bowel in prenatal sonography, it might be a prenatal marker for HCS. PMID- 29627930 TI - Flexor digitorum longus tendon transfer to the navicular: tendon-to-tendon repair is stronger compared with interference screw fixation. AB - PURPOSE: To assess whether early rehabilitation could be safe after flexor digitorum longus (FDL) tendon transfer, the current biomechanical study aimed to measure tendon displacement under cyclic loading and load to failure, comparing a traditional tendon-to-tendon (TT) repair with interference screw fixation (ISF). METHODS: 24 fresh-frozen cadaveric below knee specimens underwent FDL tendon transfer. In 12 specimens a TT repair was performed via a navicular bone tunnel. In a further 12 specimens ISF was performed. Using a materials testing machine, the FDL tendon was cycled 1000 times to 150 N and tendon displacement at the insertion site measured. A final load to failure test was then performed. Statistical analysis was performed using two-way ANOVA and an independent t test, with a significance level of p < 0.05. RESULT: No significant difference in tendon displacement occurred after cyclic loading, with mean tendon displacements of 1.9 +/- 1.2 mm (mean +/- SD) in the TT group and 1.8 +/- 1.5 mm in the ISF group (n.s.). Two early failures occurred in the ISF group, none in the TT group. Mean load to failure was significantly greater following TT repair (459 +/- 96 N), compared with ISF (327 +/- 76 N), p = 0.002. CONCLUSION: Minimal tendon displacement of less than 2 mm occurred during cyclic testing in both groups. The two premature failures and significantly reduced load to failure observed in the ISF group, however, indicate that the traditional TT technique is more robust. Regarding clinical relevance, this study suggests that early active range of motion and protected weight bearing may be safe following FDL tendon transfer for stage 2 tibialis posterior tendon dysfunction. PMID- 29627931 TI - Athletes experience a high rate of return to sport following hip arthroscopy. AB - PURPOSE: The purpose of this systematic review was to evaluate the rate at which patients return to sport following arthroscopic hip surgery. METHODS: The databases MEDLINE, EMBASE, and PubMed were searched by two reviewers, and titles, abstracts, and full-text articles screened in duplicate. English language studies investigating hip arthroscopy with reported return to sport outcomes were included. A meta-analysis of proportions was used to combine the rate of return to sports using a random effects model. RESULTS: Overall, 38 studies with 1773 patients (72% male), with a mean age of 27.6 years (range 11-65) and mean follow up of 28.1 months (range 3-144) were included in this review. The pooled rate of return to sport was: 93% [95% confidence interval (CI) = 87-97%] at any level of participation; 82% (95% CI = 74-88%) at preoperative level of sporting activity; 89% (95% CI = 84-93%) for competitive athletes; 95% (95% CI = 89-98%) in pediatric patients; and 94% (95% CI 89.2-98.0%) in professional athletes. There was significant correlation between a shorter duration of preoperative symptoms and a higher rate of return to sports (Pearson correlation coefficient = - 0.711, p = 0.021). CONCLUSION: Hip arthroscopy yields a high rate of return to sport, in addition to marked improvement in pain and function in the majority of patients. The highest rates of return to sport were noted in pediatric patients, professional athletes, and those with a shorter duration of preoperative symptoms. This study provides clinicians with evidence-based data on athletes' abilities to return to sport after arthroscopic hip surgery and identifies sub populations with the highest rates of return to sport. LEVEL OF EVIDENCE: IV, systematic review of Level II-IV studies. PMID- 29627932 TI - Brief Report: Service Use and Associated Expenditures Among Adolescents with Autism Spectrum Disorder Transitioning to Adulthood. AB - This study compared Medicaid service utilization and expenditures among adolescents with autism spectrum disorder (ASD) to adolescents with intellectual disability (ID) as they aged into adulthood. Medicaid Analytic eXtract (MAX) data was used to identify a national cohort. Winsorization was utilized to control for expenditure outliers. A greater proportion of adolescents with ASD utilized most services. Decreases in the use of key services, including psychiatric outpatient services, were observed for both groups. Changes in medical services, such as increases in inpatient and long term care services, among the ASD cohort suggest medical needs of adolescents with ASD change as they age. Information remains lacking on changing ASD symptom presentation during the transition to adolescence. PMID- 29627933 TI - Care Wounds: Precarious Vulnerability and the Potential of Exposure. AB - What does it mean to offer care when the act of caring is wounding to its giver? For peer specialists-individuals with lived experience as patients in the psychiatric system-this question shapes how they use their own histories to provide support for individuals experiencing psychiatric crisis. Peer support is unique in the way it draws on empathetic resonance and depends on carefully deployed vulnerability; where one connects with others through the recognition of shared experience and mutual hurt. For peers, care works when this guidance, reassurance, and "being with"-all of which draw upon their own stories of traumatic history and variegated suffering-mitigate the present crisis being experienced by another. Drawing on twenty-eight months of fieldwork with a peer staffed crisis respite center in the eastern United States, I argue that the peer specialist becomes the embodiment of a novel intersection of intimacy and compensation; one that poses vulnerability not as a consequence, casualty, or risk factor in the commodification of care, but as its principle vector of resonance and the assumption on which it is based. For peers, care that works-in that it creates a mutual resonance for the recipient-becomes simultaneously care that wounds its giver. PMID- 29627934 TI - Inhibition of MicroRNA-23 Contributes to the Isoflurane-Mediated Cardioprotection Against Oxidative Stress. AB - Isoflurane is one of the most frequently used volatile anesthetics in clinical practice for inhalational anesthesia. It is widely studied that isoflurane mediates cardioprotection during multiple pathological processes. However, the precise mechanisms have not been fully elucidated. Neonatal cardiomyocytes were isolated and cultured, followed by treatments with isoflurane at 0, 50, 100 or 200 uM. Rat cardiomyoblast cell line, H9c2, was treated with H2O2. Expression of miR-23 was measured by qRT-PCR. The cell survival rate of H9c2 in response to H2O2 treatments was evaluated by MTT assay. The ROS and GSH/GSSG levels were measured using Superoxide Detection Kit and GSH/GSSG Ratio Detection Assay Kit. In this study, we report an isoflurane-miR-23-antioxidant axis in cardiomyocyte. We observed that miR-23 was suppressed by isoflurane treatments at 50, 100 or 200 uM. Moreover, cardiomyocyte with isoflurane exposure was insensitive to H2O2 treatment in vitro. Inhibition of miR-23 protected cardiomyocyte against oxidative stress induced by H2O2 treatments at 30, 60, 90 or 120 uM. In addition, overexpression of miR-23 induced ROS generation over twofolds and rendered cardiomyocyte sensitive to H2O2 treatments. We demonstrate that miR-23 inhibited intracellular GSH, an antioxidant against oxidative stress. Our results reveal that with isoflurane exposure, overexpression of miR-23 rendered cardiomyocyte sensitive to H2O2 treatments at 20, 30, 40, 50 uM. Pretreatments with GSH in miR 23 overexpressing cells rescued the cell death under oxidative stress. In summary, our results illustrate that the isoflurane-mediated protection of cardiomyocytes under oxidative stress is through inhibition of miR-23. This study provides an aspect for the miRNAs-modulated cardiomyocyte sensitivity to oxidative stress, contributing to the development of therapeutic agents. PMID- 29627935 TI - Noradrenaline transporter availability on [11C]MRB PET predicts weight loss success in highly obese adults. AB - PURPOSE: Although the mechanisms by which the central noradrenaline (NA) system influences appetite and controls energy balance are quite well understood, its relationship to changes in body weight remains largely unknown. The main goal of this study was to further clarify whether the brain NA system is a stable trait or whether it can be altered by dietary intervention. METHODS: We aimed to compare central NA transporter (NAT) availability in ten obese, otherwise healthy individuals with a body mass index (BMI) of 42.4 +/- 3.7 kg/m2 (age 34 +/- 9 years, four women) and ten matched non-obese, healthy controls (BMI 23.9 +/- 2.5 kg/m2, age 33 +/- 10 years, four women) who underwent PET with the NAT-selective radiotracer (S,S)-[11C]O-methylreboxetine (MRB) before and 6 months after dietary intervention. RESULTS: MRI-based individual volume-of-interest analyses revealed an increase in binding potential (BPND) in the insula and the hippocampus of obese individuals, which correlated well with changes in BMI (-3.3 +/- 5.3%; p = 0.03) following completion of the dietary intervention. Furthermore, voxel-wise regression analyses showed that lower BPND in these regions, but also in the midbrain and the prefrontal cortex, at baseline was associated with higher achieved weight loss (e.g., hippocampal area R2 = 0.80; p < 0.0001). No changes were observed in non-obese controls. CONCLUSION: These first longitudinal interventional data on NAT availability in highly obese individuals indicate that the central NA system is modifiable. Our findings suggest that NAT availability before intervention could help predict the amount and success of weight loss in obese individuals and help adjust treatment options individually by allowing prediction of the benefit of a dietary intervention. PMID- 29627936 TI - Invasive fungal infections associated with prior respiratory viral infections in immunocompromised hosts. AB - BACKGROUND: Increased risk of invasive pulmonary aspergillosis after influenza infection has been reported; however data are limited. PURPOSE: To describe Invasive fungal infections (IFI) associated with preceding respiratory viral infection at a large referral center. METHODS: We reviewed all IFI cases among patients with positive influenza and/or RSV nasopharyngeal/lower respiratory tract PCR from October 2015 to December 2016. Cases of pulmonary IFI were classified as possible, probable, and definite based on EORTC-MSG definitions. RESULTS: We identified 8 cases (4 influenza, 4 RSV); 3 with probable Aspergillosis, 1 possible Aspergillosis, 1 probable Histoplasmosis, 1 probable Mucormycosis, and 2 possible IFI (consistent clinical and imaging findings). Half of our patients were men with a mean age of 64 years (SD 8) and median Charlson Comorbidity Score of 3.5 (IQR 3-7). Most common risk factors were stem cell transplant (75%) and neutropenia (62.5%). Four patients were on antifungal prophylaxis at presentation. All patients received anti-viral therapy with oseltamivir/ribavirin and 50% received empiric antibiotics. Median duration from onset of viral infection to diagnosis of IFI was 8.5 days (IQR 2.5-14) and 75% were diagnosed during the same admission. All received antifungal therapy; 62.5% required ICU care, and 37.5% died during index hospitalization. CONCLUSIONS: Our study supports earlier observations describing IFI following respiratory viral infection in immunocompromised hosts. Secondary IFI occurred in 1.4% of our cohort and most occurred during the index admission. IFI following viral illness is associated with high mortality and early detection and therapy may improve outcomes. PMID- 29627937 TI - Poor prognosis in Epstein-Barr virus-negative gastric cancer with lymphoid stroma is associated with immune phenotype. AB - BACKGROUND: Gastric cancer with lymphoid stroma (GCLS) is pathologically characterized by poorly developed tubular structures with a prominent lymphocytic infiltration. Its clinical and prognostic features differ in patients positive and negative for Epstein-Barr virus (EBV) infection. This study analyzed the expression of programmed cell death-1 (PD-1), programmed cell death ligand-1 (PD L1), and the density of tumor-infiltrating lymphocytes (TILs) including CD3+ and CD8+ T cells, as well as their prognostic significance in patients with GCLS. METHODS: The study included 58 patients with GCLS (29 EBV+ and 29 EBV-) who underwent curative resection. Expression of CD3, CD8, PD-1, and PD-L1 in tumor cells and TILs was analyzed using a quantitative multispectral imaging system (OpalTM), with these results validated by immuno-histochemical assays for PD-L1 on whole slide sections. RESULTS: The proportion of tumors overexpressing PD-L1 (31.0 vs. 0%, P = 0.002), TIL density (4548 vs. 2631/mm2, P < 0.001), and intra tumoral CD8+ T-cell density (2650 vs. 1060/mm2, P < 0.001) were significantly higher in EBV+ than in EBV- GCLS. In addition, CD8+/CD3+ T-cell ratio was higher in EBV+ than in EBV- GCLS (55.3 vs. 35.8%, P < 0.001). Lower TIL density, defined as < 1350/mm2, was a significant negative factor of survival. CONCLUSIONS: Despite histopathological similarity, quantitative multispectral imaging revealed differences in the tumor immune micro-environment between EBV+ and EBV- GCLS, indicating that the underlying pathogenesis differs in these two disease entities. TIL density may be a prognostic marker in patients with GCLS. PMID- 29627939 TI - Correction to: Secondary antibody deficiency: a complication of anti-CD20 therapy for neuroinflammation. AB - In the original article, the co-author's family name has been published incorrectly. The correct family name should be Constantinescu. PMID- 29627938 TI - Longitudinal cognitive biomarkers predicting symptom onset in presymptomatic frontotemporal dementia. AB - INTRODUCTION: We performed 4-year follow-up neuropsychological assessment to investigate cognitive decline and the prognostic abilities from presymptomatic to symptomatic familial frontotemporal dementia (FTD). METHODS: Presymptomatic MAPT (n = 15) and GRN mutation carriers (n = 31), and healthy controls (n = 39) underwent neuropsychological assessment every 2 years. Eight mutation carriers (5 MAPT, 3 GRN) became symptomatic. We investigated cognitive decline with multilevel regression modeling; the prognostic performance was assessed with ROC analyses and stepwise logistic regression. RESULTS: MAPT converters declined on language, attention, executive function, social cognition, and memory, and GRN converters declined on attention and executive function (p < 0.05). Cognitive decline in ScreeLing phonology (p = 0.046) and letter fluency (p = 0.046) were predictive for conversion to non-fluent variant PPA, and decline on categorical fluency (p = 0.025) for an underlying MAPT mutation. DISCUSSION: Using longitudinal neuropsychological assessment, we detected a mutation-specific pattern of cognitive decline, potentially suggesting prognostic value of neuropsychological trajectories in conversion to symptomatic FTD. PMID- 29627941 TI - False-negative diagnostic imaging of Wallenberg's syndrome by diffuse-weighted imaging: a case report and literature review. AB - Here, we report a case of a 64-year-old female with acute-onset vertigo, nausea, and vomiting. In an emergency imaging examination, the results of computed tomography (CT) and diffusion weighted imaging (DWI) were negative. However, on 1 day post-hospital admission, a small acute infarct in the posterolateral aspect of the left medulla was detected by DWI. Extra attention should be payed to the false-negative imaging results to avoid diagnosis and treatment delay. PMID- 29627940 TI - Effects of motor rehabilitation on mobility and brain plasticity in multiple sclerosis: a structural and functional MRI study. AB - BACKGROUND: Rehabilitation seems to promote brain plasticity, but objective measures of efficacy are lacking and there is a limited understanding of the mechanisms underlying functional recovery. OBJECTIVE: To study functional and structural brain changes induced by gait rehabilitation. METHODS: We enrolled MS inpatients (EDSS 4.5-6.5) undergoing a 4-week neurorehabilitation. Several clinical measures were obtained, including: 2-min walk test (2MWT), dynamic gait index (DGI), Berg balance scale (BBS). Furthermore, motor-task functional MRI (fMRI) of plantar dorsiflexion, resting state fMRI, and regional diffusion tensor imaging (DTI) metrics were obtained. All the assessments were performed at baseline (T0), after the end of the rehabilitation period (T1) and 3 months later (T2). RESULTS: Twenty-nine patients were enrolled at T0, 26 at T1, and 16 completed all timepoints. At T1, there was a significant improvement of 2MWT, DGI, and BBS scores, along with a reduced extent of the widespread activation related to the motor task at the fMRI and an increased functional connectivity in the precentral and post-central gyrus, bilaterally. None of these changes were maintained at T2. CONCLUSIONS: Our findings show a short-term beneficial effect of motor rehabilitation on gait performances in MS, accompanied by brain functional reorganization in the sensory-motor network. PMID- 29627942 TI - Orthostatic hypotension acutely impairs executive functions in Parkinson's disease. AB - Orthostatic hypotension is a frequent non-motor symptom of Parkinson's disease, with negative prognostic role on cognitive functions. Here we measured the acute effects of orthostatic hypotension on executive functions in Parkinson's disease patients devoid of hypertension, carotid artery stenosis, and significant chronic cerebrovascular pathology. Measurements were carried out during regular visits in outpatient setting. Twenty-eight Parkinson's disease patients were recruited and studied along scheduled outpatient visits. They were divided into two groups (n = 14 each) based on the presence or lack of orthostatic hypotension. This was diagnosed according to international guidelines. All patients were submitted to the Stroop's test and to the phonological and semantic verbal fluency test after 10-min resting in supine position and immediately upon standing in upright position. Testing lasted less than 5 min in either position. In upright position, subjects with orthostatic hypotension displayed significantly worse performances at the Stroop's test word reading time (22.1 +/- 4.1 vs. 14.9 +/- 4.0 s), interference time (56.1 +/- 12.3 vs. 41.4 +/- 11.8 s), and number of errors at the interference section (5.8 +/- 3.2 vs. 1.3 +/- 2.1) as compared to those without orthostatic hypotension. These results demonstrate that worsening of attentive function upon standing can be measured in Parkinson's disease patients with orthostatic hypotension during routine outpatient visits. These findings suggest that clinically asymptomatic orthostatic hypotension in Parkinson's disease patients may acutely worsen neuropsychological performances with possible negative impact on daily functioning. PMID- 29627943 TI - Therapeutic potential of vitamin E and its derivatives in traumatic brain injury associated dementia. AB - Traumatic brain injury is one of the most common causes for intervention in neurosurgery. Apart from its acute consequence, it can represent a further burden on individuals as well as society by being associated with significant comorbidity-mainly early-onset dementia. Oxidative stress is one of the crucial mechanisms conferring the damage to nervous tissue, and it is believed it could be, to some extent, influenced by dietary composition, largely by antioxidants contained in the diet. Under stressful conditions, cell-derived reactive oxygen species in the brain can induce the formation of lipid peroxides and the shifting of redox homeostasis. This review discusses the potential of vitamin E as a potent antioxidant and its derived molecules, including vitamin E-based lazaroids, in traumatic brain injury, summarizing the current state of knowledge of its role in TBI-associated dementia. PMID- 29627945 TI - Chernobyl-related thyroid cancer. PMID- 29627944 TI - Complete Versus Culprit-Only Revascularization in STEMI: a Contemporary Review. AB - PURPOSE OF REVIEW: In ST-segment elevation myocardial infarction, urgent revascularization of the culprit coronary vessel and restoration of coronary flow is the goal of the initial management. However, obstructive non-culprit disease is frequently concomitantly found during initial angiography and portends a poor prognosis. Management of non-culprit lesions in ST-segment elevation myocardial infarction (STEMI) has been the subject of extensive debate. This review will examine the currently available evidence, with a specific focus on randomized clinical trials performed to date. RECENT FINDINGS: Although early observational data suggested better outcomes with culprit-only revascularization, more recent data from several randomized trials have suggested improved outcomes with complete multivessel revascularization, either during the index PCI procedure or as a staged procedure. Data from recent randomized controlled trials have suggested the superiority of complete or multivessel revascularization and have subsequently led to changes to the most recent iterations of STEMI guidelines. However, the optimal management and timing of revascularization of non-culprit lesions in STEMI remain controversial. PMID- 29627946 TI - Role of Routine Abdominal Ultrasound Before Bariatric Surgery: Review of 937 Patients. AB - INTRODUCTION: Routine use of preoperative abdominal ultrasound for patients undergoing bariatric surgery is controversial. Despite that some physicians routinely implement it, others consider it unnecessary and not cost effective because it does not have a clear clinical significance in the preparation of bariatric patients. AIM OF THE STUDY: To investigate whether routine abdominal ultrasound prior to bariatric surgery affects the surgical plan or not. PATIENTS AND METHODS: We reviewed medical records of patients with abdominal ultrasound before bariatric surgery in Rashid Hospital between June 2014 and December 2016. Patients were divided into four groups: group 0 included patients with normal abdominal ultrasound, group 1 included abnormalities that did not affect timing or type of procedure, group 2 included findings that did not affect surgical plan but needed postoperative follow-up, and group 3 included abnormalities that had a direct impact on the procedure. RESULTS: One thousand one hundred twenty files were reviewed. Results were missing in 183 files, thus excluded; remaining 937 files were included. Mean age of patients was 37 +/- 12 years, 589 (63%) were females and 348 (37%) were males. Mean BMI was 45.1 +/- 9.8 kg/m2. Ultrasound was normal in 354 (37.7%) of patients and abnormal in 583 (62.3%). CONCLUSION: Routine abdominal ultrasound does not seem to have an important part in preoperative preparation of patients before bariatric surgery. Further studies could be helpful in discussing this role and building up clear solid evidence and guidelines that could be approved by international bariatric associations regarding the indication of preoperative abdominal ultrasound before bariatric surgery. PMID- 29627947 TI - Incidence and Risk Factors for Mortality Following Bariatric Surgery: a Nationwide Registry Study. AB - BACKGROUND: Although bariatric surgery (BS) is considered safe, concern remains regarding severe post-operative adverse events and mortality. Using a national BS registry, the aim of this study was to assess the incidence, etiologies, and risk factors for mortality following BS. METHODS: Prospective data from the National Registry of Bariatric Surgery in Israel (NRBS) including age, gender, BMI, comorbidities, and surgical procedure information were collected for all patients who underwent BS in Israel between June 2013 and June 2016. The primary study outcome was the 3.5-year post-BS mortality rate, obtained by cross-referencing with the Israel population registry. RESULTS: Of the 28,755 patients analyzed (67.3% females, mean age 42.0 +/- 12.5 years, and preoperative BMI 42.14 +/- 5.21 kg/m2), 76% underwent sleeve gastrectomy (SG), 99.1% of the surgeries were performed laparoscopically, and 50.8% of the surgeries were performed in private medical centers. Overall, 95 deaths occurred during the study period (146.9/100,000 person years). The 30-day rate of post-operative mortality was 0.04% (n = 12). Male gender (HR = 1.94, 95%CI 1.16-3.25), age (HR = 1.06, 95%CI 1.04-1.09), BMI (HR = 1.08, 95%CI 1.05-1.11), and depression (HR = 2.38, 95%CI 1.25-4.52) were independently associated with an increased risk of all-cause 3.5 year mortality, while married status (HR = 0.43, 95%CI 0.26-0.71) was associated with a decreased risk. CONCLUSION: Mortality after BS is low. Nevertheless, a variety of risk factors including male gender, advanced age, unmarried status, higher BMI, and preoperative depressive disorder were associated with higher mortality rates. Special attention should be given to these "at-risk" BS patients. PMID- 29627949 TI - Gastrointestinal Stromal Tumor After Laparoscopic Sleeve Gastrectomy: Be Awake Before, During, and After a Bariatric Procedure. PMID- 29627948 TI - Efficacy of Utilizing Argon Plasma Coagulation for Weight Regain in Roux-en-Y Gastric Bypass Patients: a Multi-center Study. AB - BACKGROUND: Endoscopic approaches exist for targeting weight regain after Roux-en Y gastric bypass (RYGB), including endoscopic suturing, clipping, and sclerotherapy. Argon plasma coagulation (APC) is a noncontact electrocoagulation method, and when used in RYGB patients, it has shown reduction in the diameter of the gastrojejunal anastomosis. OBJECTIVES: To study the effectiveness of APC for weight regain in terms of weight loss for RYGB patients, from eight bariatric centers. METHODS: A retrospective chart review was performed for 558 patients at eight bariatric centers in the USA (1) and Brazil (7) who underwent APC procedure between 31st July 2009 and 29th March 2017. APC was performed on patients who regained weight after RYGB procedure. RESULTS: Upon exploratory analysis of the individual BMI data, the mean BMI decreased slightly during the first 24 months and increased slightly afterwards following the APC intervention. The mean weight was 94.5 +/- 18.6 kg and the mean BMI was 34.0 kg/m2 at APC. Where data were available, the mean of lowest weight was 67.0 +/- 23.0 kg and the mean of lowest BMI was 24.1 kg/m2 following gastric bypass. The mean weight loss was 6.5, 7.7, and 8.3 kg at 6, 12, and 24 months, respectively, and the changes in weight over time was statistically significant (p < 0.0001). Multi-level for change model showed the low body mass index (BMI) group (BMI < 30 kg/m2) to have greater TWL than the high BMI (BMI >= 30 kg/m2) group at 6, 12, and 24 months. In the low BMI group, the mean TWL was 4.7, 6.1, 6.9, and 2.4%, at 6, 12, and 24 months, respectively. In the high BMI group, the mean TWL was 7.5, 10.4, 13.4, and 3.7%, at 6, 12, 24, and 36 months, respectively. Of the 333 patients in four centers who provided complication information, complications after APC included stenosis (n = 9), GJ ulcer (n = 3), vomiting (n = 3), GJ leakage (n = 2), and melena (n = 1). CONCLUSION: APC can be useful in reducing the regained weight after RYGB, and patients showed 6-10% total weight loss at 12 months. Randomized trials would be needed to validate the findings. PMID- 29627950 TI - Molecular-based diagnosis of Clostridium difficile infection is associated with reduced mortality. AB - Polymerase chain reaction (PCR) for the diagnosis of Clostridium difficile infection (CDI) might result in overdiagnosis. The clinical outcomes of symptomatic CDI patients diagnosed by PCR remain uncertain. We aimed to determine whether patients whose diagnosis of CDI was based on PCR had different characteristics and clinical outcomes than those diagnosed by toxin immunoassay. Consecutive CDI patients, hospitalized at Rabin Medical Center, Beilinson Hospital, Petah Tikva, Israel, between January 2013 and January 2016, were identified retrospectively and included in the study. Diagnosis of CDI was based on PCR or diagnosis by immunoassay for C. difficile toxin. The main outcome was 30- and 90-day all-cause mortality. The PCR group included 165 patients and the immunoassay group included 157 patients. In comparison to the immunoassay group, patients in the PCR group were more likely to be younger, to be independent, to undergo previous abdominal surgery, and to use laxatives. The 30-day mortality rate in the PCR group was significantly lower than that in the immunoassay group, 29/165 (18%) vs 49/157 (31%), respectively; p = 0.028. On multivariate analysis, PCR diagnosis was associated with reduced mortality, OR 0.48 (95% CI 0.26-0.88). PCR-based diagnosis of CDI is associated with reduced all-cause mortality rates. Further studies are needed to determine the management of patients with discrepant immunoassay and PCR diagnosis of CDI. PMID- 29627951 TI - Risk factors for recurrent Clostridium difficile infection in a tertiary hospital in Israel. AB - To estimate the rate and identified risk factors for recurrent Clostridium difficile infection (rCDI) in Israel. We conducted a retro-prospective case control study of all adult (age >= 18 years) patients with an initial episode of CDI (iCDI) at Tel Aviv Sourasky Medical Center from January 1, 2012 to December 31, 2014. We collected demographic, clinical, and epidemiological information for patients who were classified as recurrent (cases) and non-recurrent (control) groups. In total, 648 patients with iCDI were identified in the study. During the 36-month study period, 82 (12.7%) patients had at least one rCDI identified. We identified several factors as independent variables significantly associated with recurrent CDI: functional disability, severity of the initial infection, continuous non-Clostridium difficile antibiotic treatment with third-generation cephalosporins or clindamycin, and iCDI treatment with metronidazole and vancomycin; however, neutropenia had high measure of effect as a predictor for rCDI (adjusted odds ratio, 7.9; 95% confidence interval, 1.27-49.58; p = 0.026). The identification of the main modifiable risk factors for recurrent CDI, continuous non-Clostridium difficile antibiotics after diagnosis of the initial infection, and antibiotic treatment with third-generation cephalosporins or clindamycin are critical in reducing the spread of recurrent infection with Clostridium difficile in hospital. PMID- 29627952 TI - Loss of histone H3K27me3 identifies a subset of meningiomas with increased risk of recurrence. AB - Epigenetic patterns on the level of DNA methylation have already been shown to separate clinically relevant subgroups of meningiomas. We here set out to identify potential prognostic implications of epigenetic modification on the level of histones with focus on H3K27 trimethylation (H3K27me3). H3K27me3 was assessed by immunohistochemistry on 232 meningiomas from 232 patients. In 194 cases, trimethylation was detected in tumor cells. In 25 cases, staining was limited to vessels while all tumor cells were negative. Finally, 13 cases yielded equivocal staining patterns. Reduced abundance of H3K27me3 in cases with staining limited to vessels was confirmed by mass spectrometry on a subset of cases. Lack of staining for H3K27me3 in all tumor cells was significantly associated with more rapid progression (p = 0.009). In line, H3K27me3-negative cases were associated with a DNA methylation pattern of the more aggressive types among the recently introduced DNA methylation groups. Also, NF2 and SUFU mutations were enriched among cases with complete lack of H3K27me3 staining in tumor cells (p < 0.0001 and p = 0.029, respectively). H3K27me3 staining pattern added significant prognostic insight into WHO grade II cases and in the compound subset of WHO grade I and II cases (p = 0.04 and p = 0.007, respectively). However, it did not further stratify within WHO grade III cases. Collectively, these data indicate that epigenetic modifications beyond DNA methylation are involved in the aggressiveness of meningioma. It also suggests that H3K27me3 immunohistochemistry might be a useful adjunct in meningioma diagnostics, particularly for cases with WHO grade II histology or at the borderline between WHO grade I and II. PMID- 29627953 TI - Correction to: Solidification of hydatid cyst fluid with an injectable chitosan/carboxymethylcellulose/beta-glycerophosphate hydrogel for effective control of spillage during aspiration of hydatid cysts. AB - The original version of this article unfortunately contained a mistake: the spelling of the Shadi Hassanajili's name was incorrect. The corrected name is given above. PMID- 29627954 TI - Hemodynamic comparison of different multisites and multipoint pacing strategies in cardiac resynchronization therapies. AB - PURPOSE: In order to increase the responder rate to CRT, stimulation of the left ventricular (LV) from multiple sites has been suggested as a promising alternative to standard biventricular pacing (BIV). The aim of the study was to compare, in a group of candidates for CRT, the effects of different pacing configurations-BIV, triple ventricular (TRIV) by means of two LV leads, multipoint (MPP), and multipoint plus a second LV lead (MPP + TRIV) pacing-on both hemodynamics and QRS duration. METHODS: Fifteen patients (13 male) with permanent AF (mean age 76 +/- 7 years; left ventricular ejection fraction 33 +/- 7%; 7 with ischemic cardiomyopathy; mean QRS duration 178 +/- 25 ms) were selected as candidates for CRT. Two LV leads were positioned in two different branches of the coronary sinus. Acute hemodynamic response was evaluated by means of a RADI pressure wire as the variation in LVdp/dtmax. RESULTS: Per patient, 2.7 +/- 0.7 veins and 5.2 +/- 1.9 pacing sites were evaluated. From baseline values of 998 +/- 186 mmHg/s, BIV, TRIV, MPP, and MPP-TRIV pacing increased LVdp/dtmax to 1200 +/- 281 mmHg/s, 1226 +/- 284 mmHg/s, 1274 +/- 303 mmHg, and 1289 +/- 298 mmHg, respectively (p < 0.001). Bonferroni post-hoc analysis showed significantly higher values during all pacing configurations in comparison with the baseline; moreover, higher values were recorded during MPP and MPP + TRIV than at the baseline or during BIV and also during MPP + TRIV than during TRIV. Mean QRS width decreased from 178 +/- 25 ms at the baseline to 171 +/- 21, 167 +/- 20, 168 +/- 20, and 164 +/- 15 ms, during BIV, TRIV, MPP, and MPP-TRIV, respectively (p < 0.001). CONCLUSIONS: In patients with AF, the acute response to CRT improves as the size of the early activated LV region increases. PMID- 29627955 TI - T wave positivity in lead aVR is associated with mortality in patients with cardiac resynchronization therapy. AB - PURPOSE: Positive T wave polarity in lead aVR (TPaVR) is associated with a poor prognostic indicator in patients with heart failure reduce ejection fraction (HFrEF). Our aim was to investigate the relationship between positive TPaVR and mortality in patients with cardiac resynchronization therapy defibrillator (CRT D). METHODS: We included retrospectively 224 HFrEF patients with CRT-D in sinus rhythm. Laboratory, electrocardiographic (ECG), and echocardiographic data were recorded. T wave polarity was measured in lead DI, DII, and aVR from surface ECG. RESULTS: The patients were divided as living and deceased. They followed for 2.5 +/- 0.9 years. Thirty-three patients (14.7%) died. Six patients (18.2%) were TPaVR positive before CRT-D and this number increased to 22 (66.6%) after CRT-D in the deceased group. Pulse (p = 0.049), hyperlipidemia (p = 0.022), and NT proBNP levels were higher in the deceased group (p = 0.001). TPaVR before CRT-D (p < 0.001) and TPaVR after CRT-D (p < 0.001) were significantly positive in the deceased group. Positive TPaVR after CRT-D was the only independent predictor for mortality in binominal logistic regression analysis (OR 1.211, 95% CI 1.105 1.328, p < 0.001). CONCLUSIONS: In CRT-D patients, a positive TPaVR in surface ECG may be a strong mortality indicator. PMID- 29627956 TI - Dynamics of habitat selection in birds: adaptive response to nest predation depends on multiple factors. AB - According to theory, habitat selection by organisms should reflect underlying habitat-specific fitness consequences and, in birds, reproductive success has a strong impact on population growth in many species. Understanding processes affecting habitat selection also is critically important for guiding conservation initiatives. Northern pintails (Anas acuta) are migratory, temperate-nesting birds that breed in greatest concentrations in the prairies of North America and their population remains below conservation goals. Habitat loss and changing land use practices may have decoupled formerly reliable fitness cues with respect to nest habitat choices. We used data from 62 waterfowl nesting study sites across prairie Canada (1997-2009) to examine nest survival, a primary fitness metric, at multiple scales, in combination with estimates of habitat selection (i.e., nests versus random points), to test for evidence of adaptive habitat choices. We used the same habitat covariates in both analyses. Pintail nest survival varied with nest initiation date, nest habitat, pintail breeding pair density, landscape composition and annual moisture. Selection of nesting habitat reflected patterns in nest survival in some cases, indicating adaptive selection, but strength of habitat selection varied seasonally and depended on population density and landscape composition. Adaptive selection was most evident late in the breeding season, at low breeding densities and in cropland-dominated landscapes. Strikingly, at high breeding density, habitat choice appears to become maladaptive relative to nest predation. At larger spatial scales, the relative availability of habitats with low versus high nest survival, and changing land use practices, may limit the reproductive potential of pintails. PMID- 29627957 TI - Compensatory mortality in a recovering top carnivore: wolves in Wisconsin, USA (1979-2013). AB - Populations of large terrestrial carnivores are in various stages of recovery worldwide and the question of whether there is compensation in mortality sources is relevant to conservation. Here, we show variation in Wisconsin wolf survival from 1979 to 2013 by jointly estimating the hazard of wolves' radio-telemetry ending (endpoint) and endpoint cause. In previous analyses, wolves lost to radio telemetry follow-up (collar loss) were censored from analysis, thereby assuming collar loss was unconfounded with mortality. Our approach allowed us to explicitly estimate hazard due to collar loss and did not require censoring these records from analysis. We found mean annual survival was 76% and mean annual causes of mortality were illegal killing (9.4%), natural and unknown causes (9.5%), and other human-caused mortality such as hunting, vehicle collisions and lethal control (5.1%). Illegal killing and natural mortality were highest during winter, causing wolf survival to decrease relative to summer. Mortality was highest during early recovery and lowest during a period of sustained population growth. Wolves again experienced higher risk of human-caused mortality relative to natural mortality as wolves expanded into areas with more human activity. We detected partial compensation in human- and natural-caused mortality since 2004 as the population saturated more available habitat. Prior to 2004, we detected additivity in mortality sources. Assessments of wolf survival and cause of mortality rates and the finding of partial compensation in mortality sources will inform wolf conservation and management efforts by identifying sources and sinks, finding areas of conservation need, and assessing management zone delineation. PMID- 29627958 TI - Better kitchens and toilets: both needed for better health. AB - Both poor water, sanitation, hygiene (WaSH) and household air pollution (HAP) adversely affect the health of millions of people each year around the globe and specifically in developing countries. The objective of current work is to highlight the importance of HAP in parallel to WaSH for decision making to achieve better health specially in developing countries. There are examples, where developing countries are strengthening efforts to tackle the issue of poor water and sanitation such as 'Clean India Mission' was recently launched by the Government of India. However, there is lack of actions to address the issue related to HAP-to extend the coverage of clean fuel, efficient stoves and ventilated kitchens to the deprived population under the 'Clean India Mission'. Most of the rural household and urban slums in developing countries have only a single room, where people cook and sleep. This leads them to exposure to toxic HAP, which can be minimized by developing country specific indoor air quality guidelines and action framework. Hence, there should be policies to provide them not only the subsidy for clean fuel but also to build properly ventilated kitchens along with the promotion of clean toilets and water supplies. There is a need to strengthen global efforts, to jointly address the challenges associated with the risks related to WaSH and HAP in order to efficiently reduce the global burden of disease. Further, this will also help to timely attain the sustainable development goals for better health and environment. PMID- 29627959 TI - Increased associated effects of topography and litter and soil nutrients on soil enzyme activities and microbial biomass along vegetation successions in karst ecosystem, southwestern China. AB - Studying the influence of topography and litter and soil nutrients on soil enzymes and microbial biomass is important to the understanding of soil nutrient transformation and cycling, but these relationships in heterogeneous soils of karst ecosystem remains poorly understood. We determined environment factors influencing the urease (URS) and alkaline phosphatase (ALP) activity and microbial biomass C and N (MBC and MBN) with advancing vegetation succession. The results showed that ALP increased but URS decreased with the advancing vegetation succession. The MBC and MBN were highest in shrubland, but both were lowest in grassland. The URS was positively correlated with the surface cover of rock outcrops (SRO) but negatively correlated with litter N, and soil available N and pH. Conversely, ALP was positively correlated with litter N, soil organic carbon (SOC), and soil available N and pH, but negatively correlated with soil total N. The MBC was positively related to litter quantities and SOC but negatively related to soil pH; the MBN was positively related to slope gradient (SLG), SOC, and soil total P and available P. Additionally, the trends of the index URS/MBN were grassland > secondary forest > shrubland > primary forest, but the index ALP/MBN increased with advancing vegetation succession. It indicated that soil microorganism mainly exudate extracellular URS and ALP to soils. We also found the interactions of topography (SLG and SRO), litter (nutrients and quantity), and soil (nutrients and pH) explained 42.00, 87.00, and 66.00% of the variations in URS, ALP, and microbial biomass, respectively. Path analysis showed that the topography had a directly positive effect on litter nutrients and quantities, but not on soil nutrients; the litter nutrients and quantities had direct positive effect on soil nutrients, which had direct effect on soil enzymes and microbial biomass; the relationships (R2) between the independent variable and enzymes activities and microbial biomass increased with advancing successions. Thus, it suggested that high SLG and SRO are good for collecting litters back to soils and then the topography, litter, and soil factors increased its controlling effect on soil enzymes activities and microbial biomass with advancing successions in karst ecosystem. PMID- 29627960 TI - Reduced bioavailability and plant uptake of polycyclic aromatic hydrocarbons from soil slurry amended with biochars pyrolyzed under various temperatures. AB - Biochar has high potential for organic pollutant immobilization due to its powerful sorption capacity. Nevertheless, potential risks may exist when biochar sorbed organic pollutants are bioavailable. A direct plant exposure assay in combination with an organic solvent extraction experiment was carried out in this study to investigate the bioavailability of polycyclic aromatic hydrocarbons (PAHs) with the application of pine needle biochars pyrolyzed under different temperatures (100, 300, 400, and 700 degrees C; referred as P100-P700 accordingly). Biochar reduced solvent extractability and plant uptake of PAHs including naphthalene (Naph), acenaphthene (Acen), phenanthrene (Phen), and pyrene (Pyr), especially for three- and four-ring PAHs (Phen and Pyr) with high temperature biochar. Plant uptake assay validates with organic solvent extraction for bioavailability assessment. Sorption of PAHs to biochars reduced plant uptake of PAHs in roots and shoots by lowering freely dissolved PAHs. Aging process reduced the bioavailability of PAHs that were bound to biochar. High pyrolysis temperature can be recommended for biochar preparation for purpose of effectively immobilizing PAHs, whereas application of moderate-temperature biochar for PAH immobilization should concern the potential risks of desorption and bioavailability of PAHs. PMID- 29627961 TI - Selection of tawny owl (Strix aluco) flight feather shaft for biomonitoring As, Cd and Pb pollution. AB - In this study, we determined the concentrations of As, Cd and Pb in the shaft of all primary flight feathers from ten tawny owl (Strix aluco) specimens, with the aim of selecting which shaft of the corresponding primary feather should be used in biomonitoring surveys to enable inter-individual comparisons of the levels of these metals. The birds had died between 2006 and 2013 and their bodies were stored in the various Wildlife Recovery Centres in Galicia (NW Spain). The analyses revealed a high degree of inter-shaft variability, mainly in the concentrations of As and Cd. However, it was possible to identify the most representative samples in each case: for As, the shaft of primary flight feather number 5 (S5) (which represented 11% of the total As excreted in all of the primary flight feathers); for Cd, the shaft of primary flight feather number 2 (S2) (11% of the total excreted); and for Pb, the shaft of primary flight feather number 8 (S8) (14% of the total excreted). However, the difficulties associated with the analytical determination of these pollutants in the shaft should be taken into account when this technique is applied in biomonitoring studies. PMID- 29627962 TI - Rates of exposure to environmental tobacco smoke from various indoor environments among US children and nonsmoker adolescents and adults. AB - Data from National Health and Nutrition Examination Survey for 2013-2014 were used to compute rates of exposure (ROE) to environmental tobacco smoke (ETS) from various indoor environments among US children and nonsmoking adolescents and adults. In a typical week in USA, 473,000 infants (ROE, 11%), 3.36 million children aged 1-5 years (ROE, 16.4%), and 4.59 million children aged 6-11 years (ROE, 18.6%) are exposed to ETS from indoor environments only. ROE among children was found to be highest by inhaling tobacco smoke inside home, riding in a car, and when visiting other people's homes. In a typical week, 4.1 million nonsmoking adolescents (ROE, 29.2%) were being exposed to ETS. For every one adolescent smoker, 2.4 nonsmoker adolescents were being subjected to ETS exposure. Both non Hispanic White (NHW) and non-Hispanic Black (NHB) nonsmoking adolescents had higher ROE (p < 0.01) than Hispanics (HISP) and non-Hispanic Asians (NHAS). Also, in a typical week, 16.8 million nonsmoking adults (ROE, 29.2%) were being exposed to ETS. For every adult smoker, 0.7 nonsmoker adult was subjected to ETS exposure. Both NHW and NHB nonsmoking adults had higher ROE (p < 0.01) than HISP and NHAS and males had higher ROE than females (p < 0.01). PMID- 29627963 TI - Effectiveness of an improved form of insecticide-based diatomaceous earth against four stored grain pests on different grain commodities. AB - The effectiveness of Grain-Guard, an improved form of diatomaceous earth (DE), with low risk to the environment, was evaluated against the storage pests Liposcelis paeta, Cryptolestes ferrugineus, Rhyzopertha dominica, and Tribolium castaneum on four grain commodities, wheat, rice, maize and sorghum. The overall mortality of stored grain pests increased with the rise of application rate and exposure intervals of diatomaceous earth and decreased over 120 days of post treatment period. Our results revealed that mortality of adults 14 days post disclosure was > 80% on wheat at the start of post-treatment than rice, maize, and sorghum, respectively. During the first 60 days of post-treatment, adult mortality increased, whereas later on, a steady decrease in adult mortality was observed. Considerable differences in dose rates were observed on mortality levels along with grain commodities. Following 14 days of exposure, all adults of four species were dead on wheat at 100 ppm and on rice at 150 ppm except maize and sorghum. The suppression of progeny was noticeably higher at the beginning of post-treatment duration while after 60-days of post-treatment, progeny numbers started to increase with the rise in post-treatment durations. This new improved DE formulation was found to be effective at dose rates that are extensively lower than required with previous DE formulations and will contribute to lower the risk of health and environment. PMID- 29627964 TI - Evaluating concurrent validity of criminal justice and clinical assessments among women on probation. AB - BACKGROUND: Women in the criminal justice (CJ) system experience complex and comorbid medical, psychiatric, and substance use disorders, which often contribute to CJ involvement. To identify intersections between CJ and health needs, we calculated Spearman r correlations between concurrent CJ and clinical assessments from women on probation in Connecticut who were enrolled in a clinical trial. We examined longitudinal trends in CJ risk scores over 9 years of observation (2005-2014), modeling time to probation recidivism with shared gamma frailty models and comparing contiguous time points by Wilcoxon matched-pairs signed rank tests. RESULTS: Women (N = 31) were predominantly white (67.7%) with at least some high school education (58.1%) and mostly unemployed (77.4%) and unstably housed (83.9%). Most met clinical criteria for severe substance use and/or psychiatric disorders. Concurrent measures of substance use, mental health, social support, partnerships, and risk by the Level of Service Inventory Revised (LSI-R) and clinical assessments were not significantly correlated. The LSI-R personal/emotional sub-score, however, positively correlated with the Addiction Severity Index psychiatric composite score (r = 0.40, 95% CI 0.03-0.68, p = 0.03). After adjusting for age, race and number of previous events, having some high school education versus none marginally decreased the hazard for probation recidivism and having > 5 inpatient psychiatric admissions versus none increased the hazard of probation recidivism 7-fold (HR 7.49, 95% CI 1.33-42.12, p = 0.022). Women with 0-1 recurrent probation terms (n = 16) had a significantly lower mean LSI-R score than those with 2-4 recurrent probation terms (35.9 [SD 6.4] versus 39.2 [SD 3.0], p = 0.019), but repeated LSI-R scores did not change over time, nor vary significantly beyond the group mean. CONCLUSIONS: In this small, quantitative study of women on probation, widely used CJ assessment tools poorly reflected women's comorbid medical, psychiatric, and substance use needs and varied minimally over time. Findings illustrate the limitations of contemporary CJ assessment tools for women with complex needs. The field requires more comprehensive assessments of women's social and health needs to develop individualized targeted case plans that simultaneously improve health and CJ outcomes. PMID- 29627966 TI - Spatiotemporal heterogeneity and patterning of developing renal blood vessels. AB - The kidney vasculature facilitates the excretion of wastes, the dissemination of hormones, and the regulation of blood chemistry. To carry out these diverse functions, the vasculature is regionalized within the kidney and along the nephron. However, when and how endothelial regionalization occurs remains unknown. Here, we examine the developing kidney vasculature to assess its 3 dimensional structure and transcriptional heterogeneity. First, we observe that endothelial cells (ECs) grow coordinately with the kidney bud as early as E10.5, and begin to show signs of specification by E13.5 when the first arteries can be identified. We then focus on how ECs pattern and remodel with respect to the developing nephron and collecting duct epithelia. ECs circumscribe nephron progenitor populations at the distal tips of the ureteric bud (UB) tree and form stereotyped cruciform structures around each tip. Beginning at the renal vesicle (RV) stage, ECs form a continuous plexus around developing nephrons. The endothelial plexus envelops and elaborates with the maturing nephron, becoming preferentially enriched along the early distal tubule. Lastly, we perform transcriptional and immunofluorescent screens to characterize spatiotemporal heterogeneity in the kidney vasculature and identify novel regionally enriched genes. A better understanding of development of the kidney vasculature will help instruct engineering of properly vascularized ex vivo kidneys and evaluate diseased kidneys. PMID- 29627965 TI - Association of T/A polymorphism in miR-1302 binding site in CGA gene with male infertility in Isfahan population. AB - Infertility occurs in 10-15% of couples worldwide and close to half of it is caused by male factors. One of the genes that can affect male infertility is CGA. Polymorphisms in CGA gene may affect gene expression, therefore affecting male infertility by disrupting the regulation of this gene. One of the polymorphisms is the substitution of T with A in the miR-1302 binding site in the 3' untranslated region of the CGA gene. In this study, we explored this polymorphism in Isfahan population. In this case-control study, by the use of Tetra primer ARMS-PCR technique, rs6631 has been investigated in 224 infertile men and 196 controls. Infertile men were recruited from Isfahan Fertility and Infertility Center. Analysis of genotype and allele frequencies indicated that the differences between case and control populations were significant for rs6631 because P = 0.00 which is above the threshold. We found a significant relationship between this polymorphism and male infertility. This study which performed for the first time in Iran suggests that polymorphism in CGA gene can affect male infertility. Also, this polymorphism has high heterozygosity, so it can be used for further studies in different populations. PMID- 29627967 TI - Supervised exercise therapy versus home-based exercise therapy versus walking advice for intermittent claudication. AB - BACKGROUND: Although supervised exercise therapy (SET) provides significant symptomatic benefit for patients with intermittent claudication (IC), it remains an underutilized tool. Widespread implementation of SET is restricted by lack of facilities and funding. Structured home-based exercise therapy (HBET) with an observation component (e.g., exercise logbooks, pedometers) and just walking advice (WA) are alternatives to SET. This is the second update of a review first published in 2006. OBJECTIVES: The primary objective was to provide an accurate overview of studies evaluating effects of SET programs, HBET programs, and WA on maximal treadmill walking distance or time (MWD/T) for patients with IC. Secondary objectives were to evaluate effects of SET, HBET, and WA on pain-free treadmill walking distance or time (PFWD/T), quality of life, and self-reported functional impairment. SEARCH METHODS: The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register (December 16, 2016) and the Cochrane Central Register of Controlled Trials (2016, Issue 11). We searched the reference lists of relevant studies identified through searches for other potential trials. We applied no restriction on language of publication. SELECTION CRITERIA: We included parallel-group randomized controlled trials comparing SET programs with HBET programs and WA in participants with IC. We excluded studies in which control groups did not receive exercise or walking advice (maintained normal physical activity). We also excluded studies comparing exercise with percutaneous transluminal angioplasty, bypass surgery, or drug therapy. DATA COLLECTION AND ANALYSIS: Three review authors (DH, HF, and LG) independently selected trials, extracted data, and assessed trials for risk of bias. Two other review authors (MvdH and JT) confirmed the suitability and methodological quality of trials. For all continuous outcomes, we extracted the number of participants, mean outcome, and standard deviation for each treatment group through the follow-up period, if available. We extracted Medical Outcomes Study Short Form 36 outcomes to assess quality of life, and Walking Impairment Questionnaire outcomes to assess self-reported functional impairment. As investigators used different scales to present results of walking distance and time, we standardized reported data to effect sizes to enable calculation of an overall standardized mean difference (SMD). We obtained summary estimates for all outcome measures using a random-effects model. We assessed the quality of evidence using the GRADE approach. MAIN RESULTS: For this update, we included seven additional studies, making a total of 21 included studies, which involved a total of 1400 participants: 635 received SET, 320 received HBET, and 445 received WA. In general, SET and HBET programs consisted of three exercise sessions per week. Follow-up ranged from six weeks to two years. Most trials used a treadmill walking test to investigate effects of exercise therapy on walking capacity. However, two trials assessed only quality of life, functional impairment, and/or walking behavior (i.e., daily steps measured by pedometer). The overall methodological quality of included trials was moderate to good. However, some trials were small with respect to numbers of participants, ranging from 20 to 304.SET groups showed clear improvement in MWD/T compared with HBET and WA groups, with overall SMDs at three months of 0.37 (95% confidence interval [CI] 0.12 to 0.62; P = 0.004; moderate-quality evidence) and 0.80 (95% CI 0.53 to 1.07; P < 0.00001; high-quality evidence), respectively. This translates to differences in increased MWD of approximately 120 and 210 meters in favor of SET groups. Data show improvements for up to six and 12 months, respectively. The HBET group did not show improvement in MWD/T compared with the WA group (SMD 0.30, 95% CI -0.45 to 1.05; P = 0.43; moderate-quality evidence).Compared with HBET, SET was more beneficial for PFWD/T but had no effect on quality of life parameters nor on self-reported functional impairment. Compared with WA, SET was more beneficial for PFWD/T and self-reported functional impairment, as well as for some quality of life parameters (e.g., physical functioning, pain, and physical component summary after 12 months), and HBET had no effect.Data show no obvious effects on mortality rates. Thirteen of the 1400 participants died, but no deaths were related to exercise therapy. Overall, adherence to SET was approximately 80%, which was similar to that reported with HBET. Only limited adherence data were available for WA groups. AUTHORS' CONCLUSIONS: Evidence of moderate and high quality shows that SET provides an important benefit for treadmill-measured walking distance (MWD and PFWD) compared with HBET and WA, respectively. Although its clinical relevance has not been definitively demonstrated, this benefit translates to increased MWD of 120 and 210 meters after three months in SET groups. These increased walking distances are likely to have a positive impact on the lives of patients with IC. Data provide no clear evidence of a difference between HBET and WA. Trials show no clear differences in quality of life parameters nor in self-reported functional impairment between SET and HBET. However, evidence is of low and very low quality, respectively. Investigators detected some improvements in quality of life favoring SET over WA, but analyses were limited by small numbers of studies and participants. Future studies should focus on disease-specific quality of life and other functional outcomes, such as walking behavior and physical activity, as well as on long-term follow-up. PMID- 29627968 TI - From One Set of Pipes to Another: Gastrointestinal Illness following Sanitary Sewer Overflows. PMID- 29627969 TI - Distribution and academic significance of learning approaches among pre-clinical medical students at Trinity School of Medicine, St Vincent and the Grenadines. AB - PURPOSE: Different students may adopt different learning approaches: namely, deep and surface. This study aimed to characterize the learning strategies of medical students at Trinity School of Medicine and to explore potential correlations between deep learning approach and the students' academic scores. METHODS: The study was a questionnaire-based, cross-sectional, observational study. A total of 169 medical students in the basic science years of training were included in the study after giving informed consent. The Biggs's Revised Two-Factor Study Process Questionnaire in paper form was distributed to subjects from January to November 2017. For statistical analyses, the Student t-test, 1-way analysis of variance followed by the post-hoc t-test, and the Pearson correlation test were used. The Cronbach alpha was used to test the internal consistency of the questionnaire. RESULTS: Of the 169 subjects, 132 (response rate, 78.1%) completely filled out the questionnaires. The Cronbach alpha value for the items on the questionnaire was 0.8. The score for the deep learning approach was 29.4+/- 4.6, whereas the score for the surface approach was 24.3+/- 4.2, which was a significant difference (P< 0.05). A positive correlation was found between the deep learning approach and students' academic performance (r= 0.197, P< 0.05, df= 130). CONCLUSION: Medical students in the basic science years at Trinity School of Medicine adopted the deep learning approach more than the surface approach. Likewise, students who were more inclined towards the deep learning approach scored significantly higher on academic tests. PMID- 29627970 TI - Merkel cell carcinoma in the community setting: a case report. AB - Merkel cell carcinoma (MCC) is a rare neuroendocrine tumor of the skin initially believed to arise from the Merkel cells. In the community setting a general radiation oncologist may only encounter this pathology in a handful of cases over the course of their career. Due to the low incidence of this malignancy, few prospective randomized controlled trials have ever been conducted and therefore guidelines are based on relatively lower levels of evidence upon which the clinical recommendations are made. We discuss the case of a female in her 90s presenting with a classic MCC primary lesion, as well as satellite lesions proximal to both the primary and the draining regional lymph nodes with no evidence of nodal involvement. Here we discuss the presentation, management, treatment planning, underlying pathology, results and sequelae of treatment. We also review new treatment modalities, and the most current staging systems and guidelines. PMID- 29627972 TI - Semivolatile Organic Compounds (SOCs) in Fine Particulate Matter (PM2.5) during Clear, Fog, and Haze Episodes in Winter in Beijing, China. AB - Few efforts have been made to elucidate the influence of weather conditions on the fate of semivolatile organic compounds (SOCs). Here, daily fine particulate matter (PM2.5) during clear, haze, and fog episodes collected in the winter in Beijing, China was analyzed for polycyclic aromatic hydrocarbons (PAHs), brominated flame retardants (BFRs), and organophosphate flame retardants (OPFRs). The total concentrations of PAHs, OPFRs, and BFRs had medians of 45.1 ng/m3 and 1347 and 46.7 pg/m3, respectively. The temporal pattern for PAH concentrations was largely dependent on coal combustion for residential heating. OPFR compositions that change during colder period were related to enhanced indoor emissions due to heating. The mean concentrations of SOCs during haze and fog days were 2-10 times higher than those during clear days. We found that BFRs with lower octanol and air partition coefficients tended to increase during haze and fog episodes, be removed from PM2.5 during clear episodes, or both. For PAHs and OPFRs, pollutants that are more recalcitrant to degradation were prone to accumulate during haze and fog days. The potential source contribution function (PSCF) model indicated that southern and eastern cities were major source regions of SOCs at this site. PMID- 29627971 TI - How to tackle congestion in acute heart failure. AB - Acute heart failure is a common complication of chronic heart failure and is associated with a high risk for subsequent mortality and morbidity. In 90% of case acute heart failure is the resultant of congestion, a manifestation of fluid build-up due to increased filling pressures. As residual congestion at discharge following an acute heart failure episodes is one of the strongest predictors of poor outcome, the goal of therapy should be to resolve congestion completely. Important to comprehend is that increased cardiovascular filling pressures are not solely the resultant of intravascular volume excess but can also be induced by a decreased venous capacitance. This review article focusses on the pathophysiology, diagnoses, and treatment of congestion in acute heart failure. A clear distinction is made between states of volume overload (intravascular volume excess) or volume redistribution (decreased venous capacitance) contributing to congestion in acute heart failure. PMID- 29627973 TI - alpha-Diazo Ketones in On-Surface Chemistry. AB - Polymerization of a biphenyl bis alpha-diazo ketone on Cu(111) and Au(111) surfaces to provide furandiyl bridged poly-para-phenylenes is reported. Polymerization on Cu(111) occurs via initial N2 fragmentation leading to Cu biscarbene complexes at room temperature as polymeric organometallic structure. At 135 degrees C, carbene coupling affords polymeric alpha,beta-unsaturated 1,4 diketones, while analogous alkene formation on the Au(111) surface occurs at room temperature. Further temperature increase leads to deoxygenative cyclization of the 1,4-diketone moieties to provide alternating furandiyl biphenyl copolymers on Cu(111) (165 degrees C) and Au(111) (240 degrees C) surfaces. This work shows a new approach to generate Cu-biscarbene intermediates on surfaces, opening the pathway for the controlled generation of biphenyl copolymers. PMID- 29627974 TI - High Throughput Preparation of UV-Protective Polymers from Essential Oil Extracts via the Biginelli Reaction. AB - A high throughput (HTP) system has been developed to exploit new functional polymers. We synthesized 25 monomers in a mini-HTP manner through the tricomponent Biginelli reaction with high yields. The starting materials were five aldehydes extracted from essential oils. The 25 corresponding polymers were conveniently prepared via mini-HTP radical polymerization initially realizing the benefit of HTP methods to quickly fabricate sample libraries. The distinct radical scavenging ability of these Biginelli polymers was evaluated through a HTP measurement to choose the three best radical scavengers. This confirms the superiority of the HTP strategy to rapidly collect and analyze data. The selected polymers have been upgraded and screened according to different requirements for biomaterials and offer water-soluble and biocompatible copolymers that effectively protect cells from the fatal UV damage. This research is a straightforward way to establish new libraries of monomers with abundant diversity. It offers polymers with interesting functionalities. This suggests that a broader study of multicomponent reactions and HTP methods might be useful in many interdisciplinary fields. To the best of our knowledge, this is the first report of a HTP study of the Biginelli reaction to develop a promising polymeric biomaterial, which might have important implications for the organic chemistry and polymer communities. PMID- 29627975 TI - Wear Resistance of Cu/Ag Multilayers: A Microscopic Study. AB - The microscopic wear behavior of copper-silver multilayer samples was studied by performing sliding wear tests using a tribo-indenter. Multilayers with an average composition of Cu90Ag10 and Ag layer thicknesses ranging from 2 to 20 nm were grown by magnetron sputtering. For reference, a homogeneous Cu90Ag10 solid solution film was similarly grown. The thin films were subjected to two dimensional wear tests by rastering a cono-spherical diamond indenter under loads of 100-400 MUN for 1-20 consecutive passes or cycles. The wear volumes were determined by atomic force microscopy. Characterization of the specimens employed nanoindentation, nanoscratch, and transmission electron microscopy (TEM). Wear rates were found to reach steady state after five cycles or less. The hardness values of the as-grown and worn samples both increased with decreasing thickness of the Cu and Ag layers, whereas the steady-state wear rates decreased. Notably, the wear resistance increased faster than the corresponding increase in indentation hardness, indicating a deviation from the Archard's law. An inverse relationship between the wear rate and hardness was, however, recovered when using scratch hardness, suggesting that scratch hardness is a better predictor of wear resistance. Characterization of subsurface wear microstructures by TEM revealed that forced chemical mixing and dissolution of layers occur to a depth of ~40 to 50 nm, stabilizing a chemically homogeneous solid solution below the wear surface. Comparative wear tests on thicker multilayers revealed that Cu/Ag interfaces reduced the wear rate significantly, thus helping to rationalize the high wear resistance of thin multilayers. PMID- 29627976 TI - Determination of Osmium Concentration and Isotope Composition at Ultra-low Level in Polar Ice and Snow. AB - Here we use two chemical separation procedures to determine exceptionally low Os concentrations (~10-15 g g-1) and Os isotopic composition in polar snow/ice. Approximately 50 g of meltwater is spiked with 190Os tracer solution and frozen at -20 degrees C in quartz-glass ampules. A mixture of H2O2 and HNO3 is then added, and the sample is heated to 300 degrees C at 100 bar. This allows tracer Os to be equilibrated with the sample as all Os species are oxidized to OsO4. The resulting OsO4 is separated using either distillation (Method-I) or solvent extraction (Method-II), purified, and measured using negative thermal ionization mass spectrometry (N-TIMS). A new technique is presented that minimizes Re and Os blanks of the Pt filaments used in N-TIMS. We analyze snow collected from Summit, Greenland during 2009, 2014, and 2017. We find that the average Os concentration of the snow is 0.459 +/- 0.018 (95% C.I.) fg g-1 corresponding to an Os flux of 0.0579 +/- 0.0023 (95% C.I.) fmol cm-2 yr-1. The average R(187Os/188Os) ratio of the Summit snow is 0.264 +/- 0.026 (95% C.I.). Assuming that the volcanic source is negligible, the average ratio indicates that about 0.0518 +/- 0.0040 (95% C.I.) fmol cm-2 yr-1 of Os is of cosmic derivation, corresponding to an accretion rate of extra-terrestrial Os to the Earth of 264 +/- 21 mol yr-1. PMID- 29627977 TI - Total Synthesis of (+/-)-Cephanolides B and C via a Palladium-Catalyzed Cascade Cyclization and Late-Stage sp3 C-H Bond Oxidation. AB - Herein, we report the first total syntheses of complex cephalotaxus diterpenoids cephanolide B and C from commercially available 5-bromo-2-methylanisole. Key to the success of this synthetic route is a palladium-catalyzed cascade cyclization reaction, which allowed us to efficiently forge the 6-5-6 cis-fused tricyclic ring systems found in the entire family of cephalotaxus diterpenoids. Additionally, site-selective late-stage sp3 C-H bond oxidation served as a key strategic element in the chemical synthesis of cephanolide C. PMID- 29627978 TI - Interactions of Fipronil within Fish and Insects: Experimental and Molecular Modeling Studies. AB - Fipronil is an efficient phenylpyrazole insecticide that acts on insect gamma aminobutyric acid (GABA) receptors (GABARs) and has low toxicity to mammals but high toxicity to nontarget organisms such as fish. To develop novel efficient low toxicity insecticides, it is necessary to determine the detailed toxic mechanism at the molecular target level. In this work, methods including affinity chromatography, fluorescent-labeled binding assays, and molecular modeling were integrated to explore the binding of fipronil to GABARs in fish ( Aristichthys nobilis) and insects ( Musca domestica). Affinity chromatography revealed that fipronil acts on two different subunits of GABARs in fish and M. domestica. Moreover, fluorescence assays revealed that fipronil exhibits similar affinity to the two GABARs. The Kd and Bmax of fipronil binding to the A. nobilis GABAR were 346 +/- 6 nmol/L and 40.6 +/- 3.5 pmol/mg of protein, respectively. And the Kd and Bmax of fipronil binding to the GABAR in M. domestica brain were 109 +/- 9 nM and 21.3 +/- 2.5 pmol/mg of protein, respectively. In addition, similar fipronil binding positions but different binding modes were observed in docking studies with Brachydanio rerio var. and M. domestica GABARs. These findings indicated similar interactions of fipronil with fish and insects, leading to high toxicity. The different binding features of fipronil between the two species might be helpful for the design and development of highly selective insecticides with low toxicity to fish. PMID- 29627979 TI - In Vitro and In Vivo Photothermal Cancer Therapeutic Effects of Gold Nanorods Modified with Mushroom beta-Glucan. AB - The photothermal cancer therapeutic effect of the AuNR-Glu nanohybrids produced by coating native gold nanorods (AuNRs) with a natural mushroom biopolymer from the Pleurotus tuber-regium sclerotia (Glu) were studied in the second near infrared window (NIR-II). The AuNR-Glu exhibited low cytotoxicity and high biocompatibility due to the surface modification of Glu when compared with the native AuNRs. AuNR-Glu nanohybrids had a high photothermal transduction efficiency (eta) of 43.12%, causing effective in vitro cell ablation in both HT 29 (94.2 +/- 0.8% cell death) and SW480 (94.8 +/- 1.1% cell death) colon cancer cells under 1064 nm NIR-II laser irradiation at 1.0 W/cm2. Intravenous injection of AuNR-Glu nanohybrids followed by irradiation from a NIR-II laser at a safe dose (1.0 W/cm2 for 5 min) in nude mice implanted with HT-29 tumors was effective in significantly reducing the tumor growth, with no obvious harmful side effects, as evidenced by histological analysis of major organs. The present results have shown that AuNRs modified by natural biopolymers from mushroom beta-glucans are novel nanomaterials with low cytotoxicity and effective photothermal anticancer agents with potential biomedical applications. PMID- 29627980 TI - Porous Nanogold/Polyurethane Scaffolds with Improved Antibiofilm, Mechanical, and Thermal Properties and with Reduced Effects on Cell Viability: A Suitable Material for Soft Tissue Applications. AB - The use of implants carries on a series of problems, among them infections, poor biocompatibility, high levels of cytotoxicity, and significant mechanical differences between implants and host organs that promote stress shielding effects. These problems indicate that the materials used to make implants must meet essential requirements and high standards for implantations to be successful. In this work, we present the synthesis, characterization and evaluation of the antibiofilm, mechanical, and thermal properties, and cytotoxic effect of a nanocomposite-based scaffold on polyurethane (PU) and gold nanoparticles (AuNPs) for soft tissue applications. The effect of the quantity of AuNPs on the antibacterial activity of nanocomposite scaffolds was evaluated against Staphylococcus epidermidis and Klebsiella spp., with a resulting 99.99% inhibition of both bacteria using a small quantity of nanoparticles. Cytotoxicity was evaluated with the T10 1/2 test against fibroblast cells. The results demonstrated that porous nanogold/PU scaffolds have no toxic effects on fibroblast cells to the 5 day exposition. With respect to mechanical properties, stress-strain curves showed that the compressive modulus and yield strength of PU scaffolds were significantly enhanced by AuNPs (by at least 10 times). This is due to changes in the arrangement of hard segments of PU, which increase the stiffness of the polymer. Thermogravimetric analysis showed that the degradation onset temperature rises with an increase in the quantity of AuNPs. These properties and characteristics demonstrate that porous nanogold/PU scaffolds are suitable material for use in soft tissue implants. PMID- 29627982 TI - Structure-Odor Correlations in Homologous Series of Mercapto Furans and Mercapto Thiophenes Synthesized by Changing the Structural Motifs of the Key Coffee Odorant Furan-2-ylmethanethiol. AB - Furan-2-ylmethanethiol (2-furfurylthiol; 2-FFT, 1) is long-known as a key odorant in roast and ground coffee and was also previously identified in a wide range of thermally treated foods such as meat, bread, and roasted sesame seeds. Its unique coffee-like odor quality elicited at very low concentrations, and the fact that only a very few compounds showing a similar structure have previously been described in foods make 1 a suitable candidate for structure-odor activity studies. To gain insight into the structural features needed to evoke a coffee like odor at low concentrations, 46 heterocyclic mercaptans and thio ethers were synthesized, 32 of them for the first time, and their odor qualities and odor thresholds were determined. A movement of the mercapto group to the 3-position kept the coffee-like aroma but led to an increase in odor threshold. A separation of the thiol group from the furan ring by an elongation of the carbon side chain caused a loss of the coffee-like odor and also led to an increase in odor thresholds, especially for omega-(furan-2-yl)alkane-1-thiols with six or seven carbon atoms in the side chain. A displacement of the furan ring by a thiophene ring had no significant influence on the odor properties of most of the compounds studied, but the newly synthesized longer-chain 1-(furan-2-yl)- and 1-(thiophene 2-yl)alkane-1-thiols elicited interesting passion fruit-like scents. In total, only 4 out of the 46 compounds also showed a coffee-like odor quality like 1, but none showed a lower odor threshold. Besides the odor attributes, also retention indices, mass spectra, and NMR data of the synthesized compounds were elaborated, which are helpful in possible future identification of these compounds in trace levels in foods or other materials. PMID- 29627981 TI - Discovery of a Novel Small-Molecule Modulator of C-X-C Chemokine Receptor Type 7 as a Treatment for Cardiac Fibrosis. AB - C-X-C chemokine receptor type 7 (CXCR7) is involved in cardiac and immune pathophysiology. We report the discovery of a novel 1,4-diazepine CXCR7 modulator, demonstrating for the first time the role of pharmacological CXCR7 intervention in cardiac repair. Structure-activity-relationship (SAR) studies demonstrated that a net reduction in lipophilicity (log D) and an incorporation of saturated ring systems yielded compounds with good CXCR7 potencies and improvements in oxidative metabolic stability in human-liver microsomes (HLM). Tethering an ethylene amide further improved the selectivity profile (e.g., for compound 18, CXCR7 Ki = 13 nM, adrenergic alpha 1a Kb > 10 000 nM, and adrenergic beta 2 Kb > 10 000 nM). The subcutaneous administration of 18 in mice led to a statistically significant increase in circulating concentrations of plasma stromal-cell-derived factor 1alpha (SDF-1alpha) of approximately 2-fold. Chronic dosing of compound 18 in a mouse model of isoproterenol-induced cardiac injury further resulted in a statistically significant reduction of cardiac fibrosis. PMID- 29627983 TI - Fish Oil Supplementation Alleviates the Altered Lipid Homeostasis in Blood, Liver, and Adipose Tissues in High-Fat Diet-Fed Rats. AB - This study investigated the effects of dietary supplementation of fish oil on the signals of lipid metabolism involved in hepatic cholesterol and triglyceride influx and excretion in high-fat diet (HFD)-fed rats. Fish oil (FO) repressed body (HFD, 533 +/- 18.2 g; HFD+FO, 488 +/- 28.0 g, p < 0.05) and liver weights (HFD, 5.7 +/- 0.6 g/100 g of body weight; HFD+FO, 4.8 +/- 0.4 g/100 g of body weight, p < 0.05) in HFD-fed rats. Fish oil could also improve HFD-induced imbalance of lipid metabolism in blood, liver, and adipose tissues including the significant decreases in plasma and liver total cholesterol (TC) (plasma-HFD, 113 +/- 33.6 mg/dL; HFD+FO, 50.0 +/- 5.95 mg/dL, p < 0.05; liver-HFD, 102 +/- 13.0 mg/g liver; [corrected] HFD+FO, 86.6 +/- 7.81 mg/g liver, [corrected] p < 0.05), blood, liver, and adipose triglyceride (TG) (blood-HFD, 52.5 +/- 20.4 mg/dL; HFD+FO, 29.8 +/- 4.30 mg/dL, p < 0.05; liver-HFD, 56.2 +/- 10.0 mg/g liver; [corrected] HFD+FO, 30.3 +/- 5.28 mg/g liver, [corrected] p < 0.05; adipose-HFD, 614 +/- 73.2 mg/g liver, [corrected] HFD+FO, 409 +/- 334 mg/g of adipose tissue, [corrected] p < 0.05), and low density (HFD, 79.8 +/- 40.9 mg/dL; HFD+FO, 16.6 +/ 5.47 mg/dL, p < 0.05) and very-low-density (HFD, 49.7 +/- 33.3 mg/dL; HFD+FO, 10.4 +/- 3.45 mg/dL, p < 0.05) lipoprotein and the significant increases in fecal TC (HFD, 12.2 +/- 0.67 mg/g feces; [corrected] HFD+FO, 16.3 +/- 2.04 mg/g feces, [corrected] < 0.05) and TG (HFD, 2.09 +/- 0.10 mg/g feces; [corrected] HFD+FO, 2.38 +/- 0.22 mg/g feces, [corrected] p < 0.05) and lipoprotein lipase activity of adipose tissues (HFD, 16.6 +/- 3.64 MUM p-nitrophenol; HFD+FO, 24.5 +/- 4.19 MUM p-nitrophenol, p < 0.05). Moreover, fish oil significantly activated the protein expressions of hepatic lipid metabolism regulators (AMPKalpha and PPARalpha) and significantly regulated the lipid-transport-related signaling molecules (ApoE, MTTP, ApoB, Angptl4, ApoCIII, ACOX1, and SREBPF1) in blood or liver of HFD-fed rats. These results suggest that fish oil supplementation improves HFD-induced imbalance of lipid homeostasis in blood, liver, and adipose tissues in rats. PMID- 29627984 TI - OH Radical as a Probe of the Spin Polarizability in 1- and 2-Naphthol. AB - The relative yields for addition of the OH radical at the various positions of 1- and 2-naphthol provide a measure of the spin polarizability in the naphthols. The observed yields show that addition occurs predominantly at the naphthol positions that are conjugated with the OH substituent. They also show that the electronic structures of the naphthols are significantly affected by a concerted interaction between the OH substituent and the unsubstituted ring and that this effect is somewhat greater when the OH substituent is adjacent to the naphthol bridge. The yields for addition at the different naphthol positions correlate with the local spin polarizabilities at reactive carbons in the naphthol. The spin polarizability may be a general property governing the reactivity of closed-shell molecules with radicals. PMID- 29627985 TI - Strategic Approaches to Overcome Resistance against Gram-Negative Pathogens Using beta-Lactamase Inhibitors and beta-Lactam Enhancers: Activity of Three Novel Diazabicyclooctanes WCK 5153, Zidebactam (WCK 5107), and WCK 4234. AB - Limited treatment options exist to combat infections caused by multidrug resistant (MDR) Gram-negative bacteria possessing broad-spectrum beta-lactamases. The design of novel beta-lactamase inhibitors is of paramount importance. Here, three novel diazabicyclooctanes (DBOs), WCK 5153, zidebactam (WCK 5107), and WCK 4234 (compounds 1-3, respectively), were synthesized and biochemically characterized against clinically important bacteria. Compound 3 inhibited class A, C, and D beta-lactamases with unprecedented k2/ K values against OXA carbapenemases. Compounds 1 and 2 acylated class A and C beta-lactamses rapidly but not the tested OXAs. Compounds 1-3 formed highly stable acyl-complexes as demonstrated by mass spectrometry. Crystallography revealed that 1-3 complexed with KPC-2 adopted a "chair conformation" with the sulfate occupying the carboxylate binding region. The cefepime-2 and meropenem-3 combinations were effective in murine peritonitis and neutropenic lung infection models caused by MDR Acinetobacter baumannii. Compounds 1-3 are novel beta-lactamase inhibitors that demonstate potent cross-class inhibition, and clinical studies targeting MDR infections are warranted. PMID- 29627986 TI - Bacterial Cellulose Relieves Diphenoxylate-Induced Constipation in Rats. AB - This study was to probe the effects of bacterial cellulose (BC) on diphenoxylate induced constipation in rats. Administration with BC at 500 mg/kg of body weight in diphenoxylate-induced constipation rats distinctly improved the carmine propulsion rate (83.5 +/- 5.2%), shortened the defecating time of the first red feces (249.0 +/- 23.3 min), and increased the weight of carmine red feces within 5 h (2.7 +/- 1.3 g). The levels of aquaporins (AQP-2, AQP-3, and AQP-4) and inhibitory neurotransmitters (nitric oxide, nitric oxide synthetase, vasoactive intestinal peptide, and arginine vasopressin) in the BC-treated groups reduced by 31.9-40.0% ( p < 0.01) and 21.1-67.7% ( p < 0.01) compared to those in the constipation group, respectively. However, the secretion of excitability neurotransmitters (substance P and motilin) in the BC-treated groups was increased by 20.0-39.9% ( p < 0.01). The activities of ATPases in the colon of constipation rats were significantly weakened by BC administration ( p < 0.01). Histological morphology of the colon showed that BC supplementation could effectively increase the length of villus cells and the thickness of colonic mucosa and muscle ( p < 0.01). Moreover, BC supplementation could protect colonic smooth muscle cells against apoptosis. All of the findings suggest that BC supplementation effectively relieves constipation in rats and BC would be used as a great promising dietary fiber for alleviating constipation. PMID- 29627987 TI - Controlling the Oligomerization State of Abeta-Derived Peptides with Light. AB - A key challenge in studying the biological and biophysical properties of amyloid forming peptides is that they assemble to form heterogeneous mixtures of soluble oligomers and insoluble fibrils. Photolabile protecting groups have emerged as tools to control the properties of biomolecules with light. Blocking intermolecular hydrogen bonds that stabilize amyloid oligomers provides a general strategy to control the biological and biophysical properties of amyloid-forming peptides. In this paper we describe the design, synthesis, and characterization of macrocyclic beta-hairpin peptides that are derived from amyloidogenic peptides and contain the N-2-nitrobenzyl photolabile protecting group. Each peptide contains two heptapeptide segments from Abeta16-36 or Abeta17-36 constrained into beta-hairpins. The N-2-nitrobenzyl group is appended to the amide backbone of Gly33 to disrupt the oligomerization of the peptides by disrupting intermolecular hydrogen bonds. X-ray crystallography reveals that N-2-nitrobenzyl groups can either block assembly into discrete oligomers or permit formation of trimers, hexamers, and dodecamers. Photolysis of the N-2-nitrobenzyl groups with long-wave UV light unmasks the amide backbone and alters the assembly and the biological properties of the macrocyclic beta-hairpin peptides. SDS-PAGE studies show that removing the N-2-nitrobenzyl groups alters the assembly of the peptides. MTT conversion and LDH release assays show that decaging the peptides induces cytotoxicity. Circular dichroism studies and dye leakage assays with liposomes reveal that decaging modulates interactions of the peptides with lipid bilayers. Collectively, these studies demonstrate that incorporating N-2-nitrobenzyl groups into macrocyclic beta-hairpin peptides provides a new strategy to probe the structures and the biological properties of amyloid oligomers. PMID- 29627988 TI - Matrix Isolation and Ab Initio Study on the CHF3...CO Complex. AB - Intermolecular complexes between CHF3 and CO have been studied by ab initio calculations and IR matrix isolation spectroscopy. The computations at the MP2 and CCSD(T) levels of theory indicated five minima on the potential energy surface (PES). The most energetically favorable structure is the C(CO)-H(CHF3) coordinated complex ( Cs symmetry) with the stabilization energy of 0.84 kcal/mol as computed at the CCSD(T) level (with ZPVE and BSSE corrections). This is the only structure experimentally found in argon and krypton matrixes, whereas the weaker non-hydrogen-bonded complexes predicted by theory were not detected. The vibrational spectrum of this complex is characterized by a red-shift of the CF3 asymmetric stretching, splitting of the C-H bending mode, and blue-shifts of the C-H and C-O stretching vibrations as compared to the monomer molecules. The observed complexation-induced shifts of CHF3 and CO fundamentals are in good agreement with the computational predictions. It was shown that both MP2 and CCSD(T) calculations generally provided a reasonable description of the vibrational properties for the weak intermolecular complexes of fluoroform. PMID- 29627989 TI - Viscosity Peak due to Shape Transition from Wormlike to Disklike Micelles: Effect of Dodecanoic Acid. AB - Here, we have investigated the synergistic growth of long wormlike micelles and their transformation into disklike micelles, which occurs in three-component solutions composed of sodium lauryl ether sulfate (SLES; anionic), cocamidopropyl betaine (CAPB; zwitterionic), and dodecanoic acid (HC12; nonionic). The solution rheology is characterized in terms of zero-shear viscosities and characteristic times for micellar breaking and reptation. Furthermore, the microstructure evolution, leading to the observed rheological behavior, is revealed by cryo transmission electron microscopy (TEM) micrographs. In all cases, the CAPB-to SLES ratio is fixed, whereas the fatty acid concentration is varied. At a certain HC12 concentration, the solution viscosity passes through a maximum. The cryo-TEM imaging indicates that wormlike micelles appear before the peak, grow further up to the peak, and finally transform into disklike aggregates (a very rare micellar structure) after the peak. The transformation of worms into disks leads to a drop in viscosity because the length-to-thickness aspect ratio of the disks is significantly lower than that of the worms. In this article, we elucidate the structure-rheology relations in micellar solutions that might be applied for the design of personal-care and household formulations. PMID- 29627990 TI - The daily digital practice as a form of self-care: Using photography for everyday well-being. AB - Interest in the connection between involvement in digital communities and well being has increased as these communities become more commonplace. Specific models of interaction that affect well-being have emerged; here, we examine one of those models, termed 'digital daily practice'. Digital daily practices involve a commitment to doing one thing - exercise, photography and writing - every day and sharing it online. Participants in these practices agree that they provide an unexpected benefit of improving well-being. This article makes an in-depth examination of one digital daily practice, photo-a-day, using a practice theory framework to understand the affordances it offers for well-being. We engage with the literature on well-being and self-care, critiquing its presentation of well being as an individual trait. We present data from an ethnographic study including interviews and observations to highlight how photo-a-day as a practice functions as self-care and how communities are formed around it. Photo-a-day is not a simple and uncomplicated practice; rather it is the complex affordances and variance within the practice that relate it to well-being. We conclude that this practice has multi-faceted benefits for improving well-being. PMID- 29627991 TI - Rural Incarcerated Women: HIV/HCV Knowledge and Correlates of Risky Behavior. AB - Rural incarcerated women have an increased risk of acquiring the human immunodeficiency virus (HIV) and the hepatitis C virus (HCV) due to prevalent engagement in drug use and sexual behaviors. Limited research has investigated HIV and HCV knowledge in this high-risk population. Furthermore, the interplay of sociodemographic factors (i.e., education, age, income, and sexual orientation) and risky behavior is understudied in this population. The present study evaluated a sample of adult, predominately White women from rural Kentucky ( n = 387) who were recruited from local jails. The sample had high HIV and HCV knowledge but also reported extensive risk behaviors including 44% engaging in sex work and 75.5% reporting a history of drug injection. The results of multiple regression analysis for risky sexual behavior indicated that sexual minority women and those with less HIV knowledge were more likely to engage in high-risk sexual behaviors. The regression model identifying the significant correlates of risky drug behavior indicated that HIV knowledge, age, and income were negative correlates and that sexual minority women were more likely to engage in high-risk drug use. When HCV knowledge was added to the regression models already including HIV knowledge, the interaction was significant for drug risk. Interventions for rural imprisoned women should consider the varied impact of sociodemographic background and prioritize HIV education to more effectively deter risky sexual and drug behaviors. PMID- 29627992 TI - Beneficial Effect of the SGLT2 Inhibitor Empagliflozin on Glucose Homeostasis and Cardiovascular Parameters in the Cohen Rosenthal Diabetic Hypertensive (CRDH) Rat. AB - The effectiveness of empagliflozin (EMPA), a sodium glucose cotransporter type 2 inhibitor, on the kidney, pancreas, and heart was investigated in the Cohen Rosenthal diabetic hypertensive rat model (CRDH rat). Six-week-old CRDH male rats were fed a sugar diet (SD) and treated with the compound EMPA (group Drug/SD) or respective comparator with vehicle (group Veh/SD). A control group was fed a regular diet without treatment (group Veh/P). Preventive treatment with EMPA was measured during 4 months of follow-up. The treatment effect was evaluated according to results observed after 4 months in group Drug/SD when compared to those in group Veh/SD. Significant effect resulted in the following parameters: enhancement of urinary glucose excretion in association with diuresis; amelioration of postprandial hyperglycemia and fasting blood glucose levels; and decrease in calculated Homeostatic Model Assessment of Insulin Resistance (HOMA IR) as well as lower systolic and diastolic blood pressures. At the end of treatment, EMPA preserved nephrin integrity in the kidney, reduced proteinuria, and prevented diabetes-induced damage to glomerular diaphragm structure. In the pancreas, EMPA demonstrated an impressive decrease in fatty infiltration and atrophy. Blood pressure was significantly reduced in the EMPA-treated group (15 +/- 5.1 mm Hg, P < .05) in contrast to the vehicle and control groups. Finally, compared to controls, EMPA significantly reduced left ventricle (LV) mass and LV systolic dilatation, according to 2-dimensional echocardiography. The importance of the study lies in demonstrating the efficacy of an antidiabetic drug with beneficial effects on blood pressure, weight, kidney, and pancreas and a positive effect on the heart. PMID- 29627993 TI - The Diagnostic Dilemma of Traumatic Lumbar Puncture: Current Standing of Cerebrospinal Fluid Leukocyte Corrections and Our Experience With Cerebrospinal Fluid Biomarkers. AB - OBJECTIVE: To assess the diagnostic efficiency of cerebrospinal fluid markers of procalcitonin, lactate, and cerebrospinal fluid/serum lactate ratio for detecting bacterial meningitis during traumatic lumbar puncture, and to compare these markers with routinely used uncorrected and corrected leukocyte measurements. METHODS: Infants aged <=90 days with traumatic lumbar puncture were prospectively studied. The diagnostic characteristics of cerebrospinal fluid assays of uncorrected and corrected leukocyte count, procalcitonin, lactate, and lactate ratio were described and compared. RESULTS: Considering the area under the curve (95% CI) analysis and standard cutoff values, the lactate-ratio (0.985 [0.964 0.989] at cutoff 1.2) had the best test indexes for identifying meningitis, followed by lactate (0.964 [0.945-0.984] at cutoff 2.2 mmol/L) and procalcitonin (0.939 [0.891-0.986] at cutoff 0.33 ng/mL) measurement, whereas the corrected total leukocyte count assay (0.906 [0.850-0.962] at cutoff 350 cells/mm3) had diagnostic properties moderately superior to uncorrected total leukocyte count measurement (0.870 [0.798-0.943] at cutoff 430 cells/mm3). CONCLUSION: Cerebrospinal fluid levels of procalcitonin, lactate, and lactate-ratio are reliable markers to diagnose bacterial meningitis in blood-contaminated cerebrospinal fluid. PMID- 29627994 TI - The prevalence, low-density lipoprotein cholesterol levels, and treatment of patients at very high risk of cardiovascular events in the United Kingdom: a cross-sectional study. AB - OBJECTIVE: To assess the prevalence of patients at very high risk of cardiovascular (CV) events in the United Kingdom (UK) and evaluate low-density lipoprotein cholesterol (LDL-C) values and treatment patterns in these patients. METHODS: This cross-sectional study used primary care data from UK electronic medical records in the Clinical Practice Research Datalink (CPRD) in 2013. Very high-risk patients were defined per European Society of Cardiology guidelines as those with hyperlipidemia (assessed by co-medication) and documented cardiovascular disease (CVD) or hyperlipidemia and type 2 diabetes (DM2) without CVD (DM2w/oCVD). All analyses were descriptive. RESULTS: Data from 4,940,226 patients were captured in the CPRD in 2013. Of these, 5% of patients had received >=2 lipid-modifying therapy prescriptions and were at very high risk of CVD (3% [n = 138,536] had documented CVD, 2% [n = 98,743] had DM2w/oCVD). In documented CVD patients, coronary artery disease (73%) was the most frequent type of event (25% had myocardial infarction [MI]), followed by cerebrovascular disease (18%), and peripheral arterial disease (9%); 21% had experienced multiple CV events, 25% had DM2, and 3% had MI within 1 year. In documented CVD and DM2w/oCVD patients, >95% received statin treatment; 24% received high-intensity statin, and 1.5% statin plus ezetimibe. Across both populations, 64-66% had LDL-C levels >=1.8 mmol/L, 27-28% >=2.5 mmol/L, 6-7% >=3.5 mmol/L, and 3% had levels >=4.0 mmol/L, respectively. CONCLUSION: A well-defined proportion of patients remain at very high-risk of CVD. Statin therapy needs optimization, but, for some patients with high LDL-C levels, multiple CV events, MI within 1 year, or CVD and DM2, additional more intensive therapy may be needed. PMID- 29627995 TI - Perceptions of fall circumstances, injuries and recovery techniques among power wheelchair users: a qualitative study. AB - OBJECTIVE: To understand the circumstances surrounding the worst fall experienced by power wheelchair users in the past year and to examine injuries sustained and recovery methods. DESIGN: A qualitative study using a semi-structured interview. SETTING: Community. PARTICIPANTS: A self-selected volunteer sample of 19 power wheelchair users who utilize their device for at least 75% of mobility. The most common disability represented was cerebral palsy ( n = 8). The mean (SD) age of participants was 41.9 (7.6) years, who lived with their disability for a mean (SD) of 20.5 (8.62) years and used their current device for a mean (SD) of 3.9 (1.9) years. INTERVENTION: None. MAIN OUTCOME MEASURES: A semi-structured interview examined the circumstances surrounding the worst fall experienced in the past year, injuries sustained and recovery techniques used. RESULTS: Upon examination of the circumstances of the worst fall, four main themes emerged: (1) action-related fall contributors, (2) location of falls, (3) fall attributions and (4) time of fall. Each fall described was found to involve multiple factors. As a result of the fall, participants also reported the occurrence of physical injuries and a fear of falling. Physical injuries ranged from skin abrasion and bruises to fractures and head injuries. Participants also reported that fear of falling diminished their desire to participation in activities they enjoyed doing. Finally, most participants reported the need for physical assistance to recover from a fall. CONCLUSION: Participant descriptions provide an in-depth description of the circumstances and aftermath of falls experienced by power wheelchair users. PMID- 29627996 TI - Discrepancies between subjective perception and waist-to-height ratio measurement of obesity, and their policy implications. AB - In social sciences, researchers rely on subjective perceptions of obesity measures to examine the determinants of obesity and the likely effects of obesity on health outcomes. However, subjective perception tends to produce estimation biases. In this study, we investigated the misreporting behavior of individuals regarding obesity using waist-to-height ratio as an objective measurement of obesity. Using the Korean National Health and Nutrition Examination Survey for 2008-2011, we showed that false-reporting behavior was significantly associated with socio-economic status. Furthermore, we presented that subjective perception of obesity yielded misleading estimates in both the determinants and the consequences of obesity. PMID- 29627998 TI - Physical examination of the hemodialysis arteriovenous fistula to detect early dysfunction. AB - The maintenance of vascular access patency for end-stage renal disease patients on hemodialysis is necessary for survival. Many nephrologists, nurse practitioners, and nurses have limited experience with the physical examination of the arteriovenous fistula. In this review, we define key terms used in the assessment of an arteriovenous fistula. We discuss the arteriovenous fistula physical exam, including details of inspection, palpation, and auscultation. Using these concepts, we review the abnormal findings that can assist practitioners in determining the location of a stenosis. We review the existing literature that validates physical exam findings with gold standard tests such as ultrasound and angiography. Finally, we review data supporting the value of training physicians and nurses in arteriovenous fistula physical examination. PMID- 29627999 TI - Moral competence among nurses in Malawi: A concept analysis approach. AB - BACKGROUND: Nurses are expected to provide comprehensive, holistic and ethically accepted care according to their code of ethics and practice. However, in Malawi, this is not always the case. This article analyses moral competence concept using the Walker and Avant's strategy of concept analysis. OBJECTIVE: The aim of this article is to analyse moral competence concept in relation to nursing practice and determine defining attributes, antecedents and consequences of moral competence in nursing practice. METHOD: Analysis of moral competence concept was done using Walker and Avant's strategy of concept analysis. RESULTS: Deductive analysis was used to find the defining attributes of moral competence, which were kindness, compassion, caring, critical thinking, ethical decision making ability, problem solving, responsibility, discipline, accountability, communication, solidarity, honesty, and respect for human values, dignity and rights. The identified antecedents were personal, cultural and religious values; nursing ethics training, environment and guidance. The consequences of moral competence are team work spirit, effective communication, improved performance and positive attitudes in providing nursing care. CONCLUSION: Moral competence can therefore be used as a tool to improve care in nursing practice to meet patients' problems and needs and consequently increase public's satisfaction in Malawi. PMID- 29628000 TI - Preprints: What Role Do These Have in Communicating Scientific Results? PMID- 29628001 TI - Transmission of vibration through glove materials: effects of contact force. AB - This study investigated effects of applied force on the apparent mass of the hand, the dynamic stiffness of glove materials and the transmission of vibration through gloves to the hand. For 10 subjects, 3 glove materials and 3 contact forces, apparent masses and glove transmissibilities were measured at the palm and at a finger at frequencies in the range 5-300 Hz. The dynamic stiffnesses of the materials were also measured. With increasing force, the dynamic stiffnesses of the materials increased, the apparent mass at the palm increased at frequencies greater than the resonance and the apparent mass at the finger increased at low frequencies. The effects of force on transmissibilities therefore differed between materials and depended on vibration frequency, but changes in apparent mass and dynamic stiffness had predictable effects on material transmissibility. Depending on the glove material, the transmission of vibration through a glove can be increased or decreased when increasing the applied force. Practitioner summary: Increasing the contact force (i.e. push force or grip force) can increase or decrease the transmission of vibration through a glove. The vibration transmissibilities of gloves should be assessed with a range of contact forces to understand their likely influence on the exposure of the hand and fingers to vibration. PMID- 29627997 TI - Sulfidic Anion Concentrations on Early Earth for Surficial Origins-of-Life Chemistry. AB - A key challenge in origin-of-life studies is understanding the environmental conditions on early Earth under which abiogenesis occurred. While some constraints do exist (e.g., zircon evidence for surface liquid water), relatively few constraints exist on the abundances of trace chemical species, which are relevant to assessing the plausibility and guiding the development of postulated prebiotic chemical pathways which depend on these species. In this work, we combine literature photochemistry models with simple equilibrium chemistry calculations to place constraints on the plausible range of concentrations of sulfidic anions (HS-, HSO3-, SO32-) available in surficial aquatic reservoirs on early Earth due to outgassing of SO2 and H2S and their dissolution into small shallow surface water reservoirs like lakes. We find that this mechanism could have supplied prebiotically relevant levels of SO2-derived anions, but not H2S derived anions. Radiative transfer modeling suggests UV light would have remained abundant on the planet surface for all but the largest volcanic explosions. We apply our results to the case study of the proposed prebiotic reaction network of Patel et al. ( 2015 ) and discuss the implications for improving its prebiotic plausibility. In general, epochs of moderately high volcanism could have been especially conducive to cyanosulfidic prebiotic chemistry. Our work can be similarly applied to assess and improve the prebiotic plausibility of other postulated surficial prebiotic chemistries that are sensitive to sulfidic anions, and our methods adapted to study other atmospherically derived trace species. PMID- 29628002 TI - Physical employment standard for Canadian wildland fire fighters; developing and validating the test protocol. AB - Developing the Canadian initial attack (IA) wildland fire fighter (WFF) physical employment standard (WFX-FIT) began in a previous investigation with a physical demands analysis in which hand and back carrying a 28.5 kg pump, back carrying a 25 kg hose pack and advancing charged hose were identified as the critical IA emergency tasks. In the present study, a circuit was created incorporating simulations of the critical tasks with faster completion times required for provinces with more arduous terrains. The oxygen cost (mean +/- SD VO2 mL?kg 1?min-1) of performing IA WFF tasks sequentially on the job was 37 +/- 6 compared to 37 +/- 4 when performing the WFX-FIT, indicating strong construct validity. Content validation ratings comparing the likeness of on-the-job tasks to simulated tasks in the WFX-FIT provided strong agreement. These validations confirm that the physical demands involved in performing the WFX-FIT are the same as IA wildland fire fighting. Practitioner Summary: This paper details the process used to develop and validate the physical employment standard for jurisdictional employment and national exchange of IA WFF. The range of cut scores reflects the differences in jurisdictional physical demands due to terrain difficulty, fire management policy on fire risk and forest value index. PMID- 29628003 TI - The Diversity Challenge for High and Low Authoritarians: Multilevel and Longitudinal Effects Through Intergroup Contact and Threat. AB - The current studies integrate different frameworks on the positive and negative consequences of ethnic diversity for intergroup relations. Using a nationally stratified sample of Dutch majority members ( N = 680) from 50 cities in the Netherlands, Study 1 demonstrated that objective diversity was indirectly related to prejudice and to generalized, ingroup, and outgroup trust, through more positive and more negative contact. These indirect effects tended to be stronger for high versus low authoritarians. Furthermore, perceived diversity was indirectly related to less trust and greater prejudice, via more negative contact and threat. Again, these associations were more pronounced among high authoritarians. Study 2, using a representative sample of German majority members ( N = 412) nested within 237 districts, replicated the cross-sectional results regarding objective diversity and prejudice. In addition, longitudinal analyses indicated that objective diversity predicted more positive and more negative contact 2 years later, though only among moderate and high authoritarians. PMID- 29628004 TI - The Signs and Significance of Personality Coherence in Personal Stories and Strivings. AB - The concept of personality coherence refers to the extent of psychological unity and wholeness embodied within each individual. In the present research, we examined the extent to which the narrative, functional, and organismic conceptualizations of personality coherence interrelate, as well as their associations with psychological abilities and personal adjustment. College students ( N = 391) narrated accounts of three personal memories; listed five personal strivings that they subsequently compared and evaluated; completed performance measures of their intelligence, wisdom, and creativity; and rated their hedonic and eudaimonic well-being. Individuals who coherently organized their autobiographical memories were protected against feeling pressured or compelled in their personal strivings and against being steered toward need detracting futures. Narrative indicators of coherence were otherwise independent of the functional and organismic indicators, although all indicators of personality coherence correlated with personal adjustment. Wisdom and creativity predicted narrative coherence, which partially mediated the associations they demonstrated with eudaimonic well-being. PMID- 29628005 TI - Narcissism and Self- Versus Recipient-Oriented Imagery in Charitable Giving. AB - Prior research documents extensively that high-narcissism individuals largely tend to be self-centered and often lack empathy. This research outlines the charitable appeal types that can activate empathic responses and other-centered behaviors from high-narcissism individuals. Across four studies, we show that donors who are higher in narcissism exhibit greater charitable intentions when appealed to via imagine-self charitable appeals (as opposed to imagine-recipient types of appeals). Imagine-self appeals enable high-narcissism donors to project themselves into the recipient's situation and, in doing so, elicit greater empathy and, consequently, greater charity. This effect dissipates when projecting oneself is very difficult or impossible-such as with animal recipients or the other gender suffering a gender-specific ailment. We also explicate the underlying process role of self-focused imagination and empathy in heightening charitable outcomes from high-narcissism individuals. PMID- 29628006 TI - Laboratory test investigations on soil water characteristic curve and air permeability of municipal solid waste. AB - The air permeability coefficient has a high correlation with the water content of municipal solid waste. In this study, continuous drying methodology using a tension meter was employed to construct the soil water characteristic curve of municipal solid waste (M-SWCC). The municipal solid waste air permeability test was conducted by a newly designed apparatus. The measured M-SWCC was well reproduced by the van Genuchten (V-G) model and was used to predict the parameters of typical points in M-SWCC, including saturated water content, field capacity, residual water content and water content at the inflection point. It was found that the M-SWCC was significantly influenced by void ratio. The final evaporation and test period of M-SWCC increase with the increase in void ratio of municipal solid waste. The evolution of air permeability coefficient with water content of municipal solid waste depicted three distinct characteristic stages. It was observed that the water contents that corresponded to the two cut-off points of the three stages were residual water content and water content at the inflection point, respectively. The air permeability coefficient of municipal solid waste decreased with the increase of the water content from zero to the residual water content. The air permeability coefficient was almost invariable when the water content increased from residual water content to the water content at the inflection point. When the water content of municipal solid waste exceeded the water content at the inflection point, the air permeability coefficient sharply decreased with the increase of water content. PMID- 29628007 TI - The New National Registry for Gastrointestinal Surgery in Norway: NoRGast. AB - BACKGROUND AND AIMS: There is an increasing demand for high-quality data for the outcome of health care. Diseases of the gastro-intestinal tract involve large patient groups often presenting with serious or life-threatening conditions. Complications may affect treatment outcomes and lead to increased mortality or reduced quality of life. A continuous, risk-adjusted monitoring of major complications is important to improve the quality of health care to patients undergoing gastrointestinal resections. We present the development of the Norwegian Registry for Gastrointestinal Surgery, a national registry for colorectal, upper gastrointestinal, and hepato-pancreato-biliary resections in Norway. MATERIALS AND METHODS: A narrative and qualitative presentation of the development and current state of the registry. RESULTS: We present the variables and the analysis tools and provide examples for the potential in quality improvement and research. Core characteristics include a strictly limited set of variables to reflect important risk factors, the procedure performed, and the clinical outcomes. CONCLUSION: A registry with the potential to present complete national cohort data is a powerful tool for quality improvement and research. PMID- 29628008 TI - Abdominal Drainage After Laparoscopic Appendectomy in Children: An Endless Controversy? AB - BACKGROUND: Routine prophylactic abdominal drains after laparoscopic appendectomy for perforated appendicitis in children are still controversial. Throughout the history of surgery, potential benefits of the abdominal drains have been described. However, in recent studies, no benefits were observed and serious complications have been reported. METHODS: From January 2000 to December 2013, all charts of the pediatric patients who underwent laparoscopic appendectomy in our tertiary center were revised. The data from 1736 appendectomies were analyzed. We only included those patients with perforated appendicitis treated with early appendectomy (n = 192). Prophylactic drains were established according to the surgeon's preference. The sample was divided into two groups, those with drain (n = 117) and those without drain (n = 75). Demographics, operative findings, and postoperative outcomes were analyzed in both groups. RESULTS: Of all patients, 121 were male and 71 were female with a mean age of 7.77 +/- 3.4 years. There were not statistically significant differences between the groups in gender (p = 0.82) and mean age (p = 0.31). There were no statistically significant differences between the two groups in the rate of intra-abdominal abscess, wound infection, and bowel obstruction. However, the drainage group has been statistically associated with an increased requirement of antibiotic and analgesic medication, fasting time, operative time, and length of hospital stay. CONCLUSION: The prophylactic use of abdominal drainage after laparoscopic appendectomy for perforated appendicitis in children does not prevent postoperative complications and may be associated with negative outcomes. Prospective randomized studies will be necessary to verify this question. PMID- 29628009 TI - Aprotinin Impacts 8-Isoprostane after Coronary Artery Bypass Grafting. AB - BACKGROUND AND AIMS:: The lungs participate in the modulation of the circulating inflammatory factors induced by coronary artery bypass grafting. We investigated whether aprotinin-which has been suggested to interact with inflammation influences lung passage of key inflammatory factors after coronary artery bypass grafting. MATERIAL AND METHODS:: A total of 40 patients undergoing coronary artery bypass grafting were randomized into four groups according to aprotinin dose: (1) high dose, (2) early low dose, (3) late low dose, and (4) without aprotinin. Pulmonary artery and radial artery blood samples were collected for the evaluation of calculated lung passage (pulmonary artery/radial artery) of the pro-inflammatory factors interleukin 6 and interleukin 8, 8-isoprostane, myeloperoxidase and the anti-inflammatory interleukin 10 immediately after induction of anesthesia (T1), 1 min after releasing aortic cross clamp (T2), 15 min after releasing aortic cross clamp (T3), 1 h after releasing aortic cross clamp (T4), and 20 h after releasing aortic cross clamp (T5). RESULTS:: Pulmonary artery/radial artery 8-isoprostane increased in patients with high aprotinin dose as compared with lower doses (1.1 range 0.97 vs 0.9 range 1.39, p = 0.001). The main effect comparing high aprotinin dose with lower doses was significant (F(1, 38) = 7.338, p = 0.01, partial eta squared = 0.16) further supporting difference in the effectiveness of high aprotinin dose for pulmonary artery/radial artery 8 isoprostane. CONCLUSION:: According to the pulmonary artery/radial artery equation, the impact of aprotinin on 8-isoprostane after coronary artery bypass grafting is dose dependent. Aprotinin may aid the lung passage of circulating factors toward a beneficial anti-inflammatory milieu. PMID- 29628010 TI - Initial Electromyography Fails to Predict Long-Term Outcome of Isolated Serratus Palsy. AB - BACKGROUND AND AIMS:: The course of isolated serratus palsy is difficult to predict, especially if, in initial electromyographic examination, long thoracic nerve function is totally absent. How initial electromyography correlates with long-term outcome of isolated serratus palsy is unknown. We evaluated initial electromyographic examinations of isolated serratus palsy patients and compared these to their long-term outcome. We hypothesized that long-term outcome after electromyographic examination-verified partial nerve injuries is better than that seen in cases of total nerve injuries. PATIENTS AND METHODS:: We retrospectively reviewed 90 patients with isolated serratus palsy and with initial electromyographic examination treated by brace or observation only, by determining pain, range of motion, and degree of scapular winging after a mean follow-up of 17.8 years. RESULTS:: Initial electromyographic examination showed total denervation in 21 cases (22%), partial severe denervation in 30 (33%), and partial moderate or slight denervation in 39 (44%). Recovery of serratus muscle function occurred in 17/21 cases (81%) of total denervation and in 47/69 cases (68%) of partial denervation, p = 0.247. Mean flexion in total denervation recovered to 152 degrees and in partial to 157 degrees , p = 0.301, and abduction to 173 degrees and 174 degrees , p = 0.970. In total denervation, 60% of patients were pain-free, in partial, 48%, p = 0.338. The duration of scapular winging among those 42 who subjectively recovered averaged 15.1 months, in 13 patients with total denervation 15.9 months, and in 29 patients with partial denervation 14.7 months (p = 0.599). CONCLUSION:: Initial electromyographic examination does not predict clinical outcomes: ROM, pain, scapular winging and strength, but partial denervation may negatively predict subjective outcome. PMID- 29628011 TI - Long-Term Survival and Quality of Life After Hypothermic Circulatory Arrest in Aortic Surgery. AB - BACKGROUND AND AIMS:: Hypothermic circulatory arrest carries a high risk of mortality and neurological complications. An important part of assessing surgical treatment is the evaluation of long-term survival and postoperative health related quality of life. MATERIAL AND METHODS:: In this prospective study, 30 patients undergoing hypothermic circulatory arrest during surgery of the thoracic aorta, and 31 comparison patients undergoing elective coronary artery surgery without hypothermic circulatory arrest were evaluated for long-term survival and health-related quality of life, using the RAND 36-Item Health Survey questionnaire. The results were compared to national age- and sex-matched reference populations of the chronically ill and healthy adults. RESULTS:: After 4.6-8.0 years, available study (88%) and comparison (59%) patients were interviewed. The life expectancy was similar with 4- and 8-year survival of 90%, and 87% for the study group, and 94%, and 94% for the comparison group, respectively (log rank test, p = 0.62). The RAND-36 scores for study and comparison groups were congruent in all dimensions, describing physical, mental, and social domains. The study patients' health-related quality of life results were similar to the national reference population with chronic illnesses. CONCLUSION:: After hypothermic circulatory arrest, patients undergoing surgery of the thoracic aorta achieve a similar long-term life expectancy and health-related quality of life as do patients undergoing coronary surgery without hypothermic circulatory arrest, and a health-related quality of life similar to the national reference population with chronic illnesses. These results justify operative treatment in this high-risk patient population. PMID- 29628012 TI - Blunt Pharyngoesophageal Injuries: Current Management Strategies. AB - BACKGROUND:: Blunt pharyngoesophageal injuries pose a management challenge to the trauma surgeon. The purpose of this study was to explore whether these injuries can be managed expectantly without neck exploration. METHODS:: The National Trauma Databank datasets 2007-2011 were reviewed for blunt trauma patients who sustained a pharyngeal injury, including an injury to the cervical esophagus. Patients who survived over 24 h and were not transferred from other institutions were divided into two groups based on whether a neck exploration was performed. Outcomes included mortality and hospital stay. RESULTS:: A total of 545 (0.02%) patients were identified. The median age was 18 years and 69% were male. Facial fractures were found in 16%, while 13% had an associated traumatic brain injury. Of the 284 patients who survived over 24 h and were not transferred from another institution, 65 (23%) underwent a neck exploration. The injury burden was significantly higher in this group as indicated by the higher median Injury Severity Score (17 vs 10, p < 0.01) and need for intensive care unit admission (75% vs 31%, p < 0.01). The overall mortality was 2%: 3.1% for neck explorations versus 1.6% for conservative management (adjusted p = 0.54). Neck exploration patients were more likely to remain longer in the hospital (median 13 vs 10 days, adjusted p = 0.03). CONCLUSION:: Pharyngoesophageal injuries are rare following blunt trauma. Only a quarter require a neck exploration and this decision appears to be dictated by the injury burden. Selective non-operative management based on clinical status seems to be feasible and is not associated with increased mortality. PMID- 29628013 TI - Type V Collagen is Persistently Altered After Inguinal Hernia Repair. AB - BACKGROUND AND AIMS: Hernia formation is associated with alterations of collagen metabolism. Collagen synthesis and degradation cause a systemic release of products, which are measurable in serum. Recently, we reported changes in type V and IV collagen metabolisms in patients with inguinal and incisional hernia. The aim of this study was to determine if the altered collagen metabolism was persistent after hernia repair. MATERIAL AND METHODS: Patients who had undergone repairs for inguinal hernia (n = 11) or for incisional hernia (n = 17) were included in this study. Patients who had undergone elective cholecystectomy served as controls (n = 10). Whole venous blood was collected 35-55 months after operation. Biomarkers for type V collagen synthesis (Pro-C5) and degradation (C5M) and those for type IV collagen synthesis (P4NP) and degradation (C4M2) were measured by a solid-phase competitive assay. RESULTS: The turnover of type V collagen (Pro-C5/C5M) was slightly higher postoperatively when compared to preoperatively in the inguinal hernia group (P = 0.034). In addition, the results revealed a postoperatively lower type V collagen turnover level in the inguinal hernia group compared to controls (P = 0.012). In the incisional hernia group, the type V collagen turnover was higher after hernia repair (P = 0.004) and the postoperative turnover level was not different from the control group (P = 0.973). CONCLUSION: Patients with an inguinal hernia demonstrated a systemic and persistent type V collagen turnover alteration. This imbalance of the collagen metabolism may be involved in the development of inguinal hernias. PMID- 29628014 TI - Invasive Candidiasis in Critically Ill Patients: A Prospective Cohort Study in Two Tertiary Care Centers. AB - BACKGROUND: Invasive candidiasis is not uncommon in critically ill patients but has variable epidemiology and outcomes between intensive care units (ICUs). This study evaluated the epidemiology, characteristics, management, and outcomes of patients with invasive candidiasis at 6 ICUs of 2 tertiary care centers. METHODS: This was a prospective observational study of all adults admitted to 6 ICUs in 2 different hospitals between August 2012 and May 2016 and diagnosed to have invasive candidiasis by 2 intensivists according to predefined criteria. The epidemiology of isolated Candida and the characteristics, management, and outcomes of affected patients were studied. Multivariable logistic regression analyses were performed to identify the predictors of non-albicans versus albicans infection and hospital mortality. RESULTS: Invasive candidiasis was diagnosed in 162 (age 58.4 +/- 18.9 years, 52.2% males, 82.1% medical admissions, and admission Acute Physiology and Chronic Health Evaluation II score 24.1 +/- 8.4) patients at a rate of 2.6 cases per 100 ICU admissions. On the diagnosis day, the Candida score was 2.4 +/- 0.9 in invasive candidiasis compared with 1.6 +/- 0.9 in Candida colonization ( P < .01). The most frequent species were albicans (38.3%), tropicalis (16.7%), glabrata (16%), and parapsilosis (13.6%). In patients with candidemia, antifungal therapy was started on average 1 hour before knowing the culture result (59.6% of therapy initiated after). Resistance to fluconazole, caspofungin, and amphotericin B occurred in 27.9%, 2.9%, and 3.1%, respectively. The hospital mortality was 58.6% with no difference between albicans and non-albicans infections (61.3% and 54.9%, respectively; P = .44). The independent predictors of mortality were renal replacement therapy after invasive candidiasis diagnosis (odds ratio: 5.42; 95% confidence interval: 2.16 13.56) and invasive candidiasis leading/contributing to ICU admission versus occurring during critical illness (odds ratio: 2.87; 95% confidence interval: 1.22-6.74). CONCLUSIONS: In critically ill patients with invasive candidiasis, non-albicans was responsible for most cases, and mortality was high (58.6%). Antifungal therapy was initiated after culture results in 60% suggesting low preclinical suspicion. STUDY REGISTRATION: NCT01490684; registered in ClinicalTrials.gov on February 11, 2012. PMID- 29628015 TI - Clinical Outcomes of Weight-Based Norepinephrine Dosing in Underweight and Morbidly Obese Patients: A Propensity-Matched Analysis. AB - BACKGROUND: Weight-based dosing strategy for norepinephrine in septic shock patients with extremes of body mass index has been lesser studied. METHODS: This historical study of adult septic shock patients was conducted from January 1, 2010, to December 31, 2015, at all intensive care units (ICUs) in Mayo Clinic, Rochester. Patients with documented body mass index were classified into underweight (body mass index <18.5 kg/m2), normal weight (18.5-24.9 kg/m2), and morbidly obese (>=40 kg/m2) patients. Patients with repeat ICU admissions, ICU stay <1 day, and body mass index 25 to 39.9 kg/m2 were excluded. The primary outcome was in-hospital mortality, and secondary outcomes included cumulative norepinephrine exposure acute kidney injury, cardiac arrhythmias, and 1-year mortality. Two-tailed P < .05 was considered statistically significant. RESULTS: From 2010 to 2015, 2016 patients met inclusion-145, 1406, and 466 patients, respectively, in underweight, normal weight, and morbidly obese cohorts. Underweight patients used the highest peak dose and absolute exposure was greatest for morbidly obese patients. In-hospital mortality decreased with increasing log10 body mass index: 41.4% (underweight), 28.4% (normal weight), and 24.7% (morbidly obese), respectively ( P < .001); however, this relationship was not noted at 1 year. Unadjusted log10 norepinephrine cumulative exposure (mg) was associated with higher in-hospital mortality, acute kidney injury, cardiac arrhythmias, and 1-year mortality. After adjustment for demographics, body mass index, comorbidity, and illness severity, log10 norepinephrine exposure was an independent predictor of in-hospital mortality (odds ratio 2.4 [95% confidence interval, 2.0-2.8]; P < .001) and 1-year mortality (odds ratio 1.7 [95% confidence interval, 1.5-2.0]; P < .001). In a propensity-matched analysis of 1140 patients, log10 norepinephrine was an independent predictor of in-hospital mortality (odds ratio 2.2 [95% confidence interval, 1.8-2.6]; P < .001). CONCLUSIONS: Morbidly obese patients had lower in-hospital mortality but had higher 1-year mortality compared to normal weight and underweight patients. Cumulative norepinephrine exposure was highest in morbidly obese patients. Total norepinephrine exposure was an independent mortality predictor in septic shock. PMID- 29628016 TI - General and disease-specific pain trajectories as predictors of social and political outcomes in arthritis and cancer. AB - BACKGROUND: While the heterogeniety of pain progression has been studied in chronic diseases, the extent to which patterns of pain progression among people in general as well as across different diseases affect social, civic and political engagement is unclear. We explore these issues for the first time. METHODS: Using data from the English Longitudinal Study of Ageing, latent class growth models were used to estimate trajectories of self-reported pain in the entire cohort, and within subsamples reporting diagnoses of arthritis and cancer. These were compared at baseline on physical health (e.g. body mass index, smoking) and over time on social, civic and political engagement. RESULTS: Very similar four-trajectory models fit the whole sample and arthritis subsamples, whereas a three-trajectory model fit the cancer subsample. All samples had a modal group experiencing minimal chronic pain and a group with high chronic pain that showed slight regression (more pronounced in cancer). Biometric indices were more predictive of the most painful trajectory in arthritis than cancer. In both samples the group experiencing the most pain at baseline reported impairments in social, civic and political engagement. CONCLUSIONS: The impact of pain differs between individuals and between diseases. Indicators of physical and psychological health differently predicted membership of the trajectories most affected by pain. These trajectories were associated with differences in engagement with social and civic life, which in turn were associated with poorer health and well-being. PMID- 29628017 TI - Snail-borne parasitic diseases: an update on global epidemiological distribution, transmission interruption and control methods. AB - BACKGROUND: Snail-borne parasitic diseases, such as angiostrongyliasis, clonorchiasis, fascioliasis, fasciolopsiasis, opisthorchiasis, paragonimiasis and schistosomiasis, pose risks to human health and cause major socioeconomic problems in many tropical and sub-tropical countries. In this review we summarize the core roles of snails in the life cycles of the parasites they host, their clinical manifestations and disease distributions, as well as snail control methods. MAIN BODY: Snails have four roles in the life cycles of the parasites they host: as an intermediate host infected by the first-stage larvae, as the only intermediate host infected by miracidia, as the first intermediate host that ingests the parasite eggs are ingested, and as the first intermediate host penetrated by miracidia with or without the second intermediate host being an aquatic animal. Snail-borne parasitic diseases target many organs, such as the lungs, liver, biliary tract, intestines, brain and kidneys, leading to overactive immune responses, cancers, organ failure, infertility and even death. Developing countries in Africa, Asia and Latin America have the highest incidences of these diseases, while some endemic parasites have developed into worldwide epidemics through the global spread of snails. Physical, chemical and biological methods have been introduced to control the host snail populations to prevent disease. CONCLUSIONS: In this review, we summarize the roles of snails in the life cycles of the parasites they host, the worldwide distribution of parasite-transmitting snails, the epidemiology and pathogenesis of snail-transmitted parasitic diseases, and the existing snail control measures, which will contribute to further understanding the snail-parasite relationship and new strategies for controlling snail-borne parasitic diseases. PMID- 29628020 TI - CASA in invertebrates. AB - Sperm movement has been described in several phyla of invertebrates. Yet, sperm motility has only been quantified using computer-aided sperm analysis (CASA-Mot) in externally fertilising species (broadcast spawners) of two phyla, molluscs and echinoderms. In the present study we quantified in detail the nature of the sperm tracks, percentage motility groupings and detailed kinematics of rapid-, medium- and slow-swimming spermatozoa in the oyster Crassostrea gigas and four species never previously studied by CASA-Mot, namely the molluscs Choromytilus meridionalis, Donax serra and Haliotis midae and the echinoderm Parechinus angulosus. A feature common to all these species are the helical tracks, the diameter of which seems to be species specific. Using CASA-Mot, the behaviour of spermatozoa was also studied over time and in the presence of egg water and Ca2+ modulators such as caffeine and procaine hydrochloride. For the first time, we show that hyperactivation can be induced in all species in the presence of egg water (sea water that was mixed with mature eggs and then centrifuged) and/or caffeine, and these hyperactivated sperm tracks were characterised using CASA Mot. We relate the different patterns of sperm motility and behaviour to reproductive strategies such as broadcast spawning and spermcasting, and briefly review studies using CASA-Mot on other invertebrates. PMID- 29628018 TI - Barriers and facilitators affecting the implementation of substance use screening in primary care clinics: a qualitative study of patients, providers, and staff. AB - BACKGROUND: Alcohol and drug use are leading causes of morbidity and mortality that frequently go unidentified in medical settings. As part of a multi-phase study to implement electronic health record-integrated substance use screening in primary care clinics, we interviewed key clinical stakeholders to identify current substance use screening practices, barriers to screening, and recommendations for its implementation. METHODS: Focus groups and individual interviews were conducted with 67 stakeholders, including patients, primary care providers (faculty and resident physicians), nurses, and medical assistants, in two urban academic health systems. Themes were identified using an inductive approach, revised through an iterative process, and mapped to the Knowledge to Action (KTA) framework, which guides the implementation of new clinical practices (Graham et al. in J Contin Educ Health Prof 26(1):13-24, 2006). RESULTS: Factors affecting implementation based on KTA elements were identified from participant narratives. Identifying the problem: Participants consistently agreed that having knowledge of a patient's substance use is important because of its impacts on health and medical care, that substance use is not properly identified in medical settings currently, and that universal screening is the best approach. Assessing barriers: Patients expressed concerns about consequences of disclosing substance use, confidentiality, and the individual's own reluctance to acknowledge a substance use problem. Barriers identified by providers included individual-level factors such as lack of clinical knowledge and training, as well as systems-level factors including time pressure, resources, lack of space, and difficulty accessing addiction treatment. Adapting to the local context: Most patients and providers stated that the primary care provider should play a key role in substance use screening and interventions. Opinions diverged regarding the optimal approach to delivering screening, although most preferred a patient self administered approach. Many providers reported that taking effective action once unhealthy substance use is identified is crucial. CONCLUSIONS: Participants expressed support for substance use screening as a valuable part of medical care, and identified individual-level as well as systems-level barriers to its implementation. These findings suggest that screening programs should clearly communicate the goals of screening to patients and proactively counteract stigma, address staff concerns regarding time and workflow, and provide education as well as treatment resources to primary care providers. PMID- 29628021 TI - Regulation by 3,5,3?-tri-iodothyronine and FSH of cytochrome P450 family 19 (CYP19) expression in mouse granulosa cells. AB - Cytochrome P450 family 19 (CYP19) plays an important role in follicular development, which is regulated by FSH. Although 3,5,3'-tri-iodothyronine (T3) combines with FSH to induce preantral follicle growth and granulosa cell development, the mechanism involved remains unclear. The aim of the present study was to determine the cellular and molecular mechanisms by which thyroid hormone (TH) and FSH regulate CYP19 expression and sterol biosynthesis during preantral follicle growth. Mice were injected subcutaneously (s.c.) with eCG (Equine chorionic gonadotropin). The results showed that eCG increased CYP19 expression in ovarian cells. CYP19 expression in granulosa cells was increased after FSH treatment, and this response was enhanced by T3. Knockdown of CYP19 significantly decreased granulosa cell viability and hormone-stimulated proliferation. In addition, CYP19 knockdown also blocked T3- and FSH-induced oestradiol (E2) synthesis in granulosa cells. Furthermore, activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway was required for T3 and FSH regulation of CYP19 expression. In conclusion, the results of the present study indicate that CYP19 is important for T3- and FSH-induced granulosa cell development in the early stages. CYP19 could be a downstream effector of the PI3K/Akt pathway in regulating TH and FSH during follicular development and sterol biosynthesis. The findings suggest that CYP19 is a novel mediator of T3- and FSH-induced follicular development. PMID- 29628019 TI - Impact of five annual rounds of mass drug administration with ivermectin on onchocerciasis in Sierra Leone. AB - BACKGROUND: Onchocerciasis is endemic in 12 of the 14 health districts of Sierra Leone. Good treatment coverage of community-directed treatment with ivermectin was achieved between 2005 and 2009 after the 11-year civil conflict. Sentinel site surveys were conducted in 2010 to evaluate the impact of five annual rounds of ivermectin distribution. METHODS: In total, 39 sentinel villages from hyper- and meso-endemic areas across the 12 endemic districts were surveyed using skin snips in 2010. Results were analyzed and compared with the baseline data from the same 39 villages. RESULTS: The average microfilaridermia (MF) prevalence across 39 sentinel villages was 53.10% at baseline. The MF prevalence was higher in older age groups, with the lowest in the age group of 1-9 years (11.00%) and the highest in the age group of 40-49 years (82.31%). Overall mean MF density among the positives was 28.87 microfilariae (mf)/snip, increasing with age with the lowest in the age group of 1-9 years and the highest in the age group of 40-49 years. Males had higher MF prevalence and density than females. In 2010 after five rounds of mass drug administration, the overall MF prevalence decreased by 60.26% from 53.10% to 21.10%; the overall mean MF density among the positives decreased by 71.29% from 28.87 mf/snip to 8.29 mf/snip; and the overall mean MF density among all persons examined decreased by 88.58% from 15.33 mf/snip to 1.75 mf/snip. Ten of 12 endemic districts had > 50% reduction in MF prevalence. Eleven of 12 districts had >=50% reduction in mean MF density among the positives. CONCLUSIONS: A significant reduction of onchocerciasis MF prevalence and mean density was recorded in all 12 districts of Sierra Leone after five annual MDAs with effective treatment coverage. The results suggested that the onchocerciasis elimination programme in Sierra Leone was on course to reach the objective of eliminating onchocerciasis in the country by the year 2025. Annual MDA with ivermectin should continue in all 12 districts and further evaluations are needed across the country to assist the NTDP with programme decision making. PMID- 29628022 TI - Vitamin E supplementation improves high-densitiy lipoprotein and endothelial functions in end-stage kidney disease patients undergoing hemodialysis?. AB - BACKGROUND AND AIMS: Patients with end-stage kidney disease (ESKD) undergoing hemodialysis (HD) have been shown to be at increased risk for cardiovascular disease (CVD). Decreased high-density lipoprotein cholesterol (HDL-C) and impaired cholesterol efflux capacity (CEC) have been reported in such patients, and effects of vitamin E supplementation on HDL functions are poorly understood. Therefore, the present study aimed to investigate effects of vitamin E supplementation on HDL and endothelial functions in ESKD patients undergoing HD. We also assessed the influence of diabetes and haptoglobin (Hp) phenotype on the effects of vitamin E. MATERIALS AND METHODS: Vitamin E (300 mg daily) was supplemented for 12 weeks, followed by a 10-week washout phase in 40 ESKD patients undergoing HD (20 diabetic and 20 nondiabetic patients). HDL functions, including CEC, antioxidant capacity, and anti-inflammatory activity, were investigated. In diabetic patients, endothelial function, as represented by flow mediated vasodilatation (FMD), was also assessed. The findings were compared according to diabetic condition or Hp phenotype. RESULTS: Vitamin E significantly increased CEC, whereas antioxidant capacity and anti-inflammatory activity remained unchanged. Further, the improvement in CEC was maintained after the 10 week washout phase. Endothelial function was significantly improved in diabetic patients. Subanalyses based on diabetes or Hp phenotype revealed that neither diabetes nor Hp phenotype influenced the effects of vitamin E. CONCLUSION: In ESKD patients undergoing hemodialysis, vitamin E supplementation significantly improved the HDL function of CEC and, in diabetic patients, endothelial function. These effects were independent of Hp phenotype.?. PMID- 29628023 TI - Effects of erythropoietin on the clinical outcomes of patients with acute ST segment elevation myocardial infarction after percutaneous coronary intervention: A meta-analysis?. AB - AIMS: To investigate the effects of erythropoietin (EPO) on the clinical outcomes of patients with acute ST segment elevation myocardial infarction (STEMI) after percutaneous coronary intervention (PCI). MATERIAL AND METHODS: We collected randomized controlled studies conducted before April 15, 2017, and performed a meta-analysis using RevMan5.3 software. RESULTS: Compared with the conventional revascularization group, mortality (RR = 0.79; 95% Cl, 0.42 - 1.50; p = 0.47), stroke events (RR = 2.63; 95% Cl, 0.70 - 9.85; p = 0.15), recurrent myocardial infarction (RR = 0.99; 95% Cl, 0.44 - 2.20; p = 0.98), and other clinical endpoints were not significantly different in the EPO group. However, subgroup analysis showed a marginally significant difference between the high-dose EPO group and the control group (MD = 1.29; 95% CI, 0.02 - 2.56; p = 0.05) in ejection fraction. CONCLUSION: The administration of EPO has no effects on the clinical outcomes of patients with acute STEMI after PCI, whilst a high dose of EPO may increase patients' ejection fraction.?. PMID- 29628024 TI - The association between CYP2C9/2C19 polymorphisms and phenytoin maintenance doses in Asian epileptic patients: A systematic review and meta-analysis?. AB - OBJECTIVE: Therapeutic response to phenytoin (PHT), a first-line antiepileptic drug (AED), is highly variable, in part likely due to genetic factors. Genetic polymorphisms in cytochrome P450 (CYP) 2C9 and CYP2C19 are expected to affect the metabolism of PHT and consequently affect its maintenance doses. We aimed to clarify the effects of genetic polymorphisms in both enzymes on daily PHT maintenance dosage in Asian epileptic patients by meta-analysis. MATERIALS AND METHODS: A systematic literature search was conducted in PubMed and EMBASE for relevant studies published prior to April 14, 2017. RevMan 5.2.3 software was used to analyze the relationship between CYP2C9/2C19 polymorphisms and PHT maintenance doses. RESULTS: A total of 6 studies with 993 patients fulfilling the inclusion criteria were included in our meta-analysis. The homozygous and heterozygous CYP2C19 mutation group (i.e., CYP2C19*2/*2, CYP2C19*3/*3, or CYP2C19*2/*3 group) required significant decrease of PHT maintenance dose. The starting maintenance dose suggested in this group is 4.38 mg/kg/day. Patients with heterozygous CYP2C9 or both heterozygous CYP2C9 and CYP2C19 showed a trend but not a statistically-significant decrease of PHT dose, but dosage adjustment was recommended. CONCLUSION: The meta-analysis indicates that CYP2C9 and CYP2C19 polymorphisms are associated with lower PHT maintenance dosage in Asian epileptic patients. Ethnic differences can influence PHT maintenance dose.?. PMID- 29628026 TI - [Consensus document. Mild cognitive impairment. Detection and management. A public health challenge]. PMID- 29628025 TI - Focal myositis with neurogenic atrophy: A case report. AB - Focal myositis is a very rare form of inflammatory myopathy, with unknown etiology. We describe a 44-year-old previously healthy man who noticed a painless swelling on his left forearm, following trauma over the left cubital fossa. The swelling grew progressively over 2 years. He had otherwise no weakness complaints. Physical and neurological examinations were otherwise normal. Creatine kinase and aldolase levels were increased (1,009 U/L and 11.9 U/L, respectively); autoimmunity panel was negative. MRI showed diffuse edema and gadolinium enhancement of muscles innervated by the median nerve. EMG revealed repetitive complex discharges and patterns of continuous muscular activity. The mass was biopsied disclosing findings consistent with focal myositis. Focal myositis with muscular atrophy is a rare situation; the inflammatory mechanism is yet to be defined, but it seems to be a situation with slow progression, with tendency to stabilization.?. PMID- 29628027 TI - [Screening methods for mild cognitive impairment in primary care]. AB - Diagnosis of mild cognitive impairment (MCI) is always clinical and screening methods only indicate that the patient has a higher risk of this condition. In MCI, there is a slight decline in some cognitive abilities that does not affect activities of daily living and therefore does not produce social or occupational disability. The definitive diagnosis of MCI requires a considerable time investment that is very rarely possible to provide in primary care (PC) consultations. Hence the need for PC physicians to employ rapid and simple screening methods (brief cognitive assessment -BCA-) that allow objective identification of patients likely to have MCI in a few minutes. This article reviews the BCA tools that can truly be applied in less than 10 minutes. The phototest is a brief screening tool that is easy to use and interpret by physicians and is well accepted by patients. Consequently, it is one of the most useful tests in PC for screening of both MCI and dementia. In addition to BCA, instrumental activities of daily living scales should also be applied to differentiate MCI from dementia. PMID- 29628028 TI - [Disorders associated with mild cognitive impairment. Risk factors and predictors]. AB - Traditionally, cognitive impairment has been associated not only with ageing itself but also with concomitant comorbidities that interact in the disease continuum from the prodromic phases. Notable among these are delirium, nutritional alterations, balance and gait, infections and even a progressive incidence of neoplasms. However, with regard to diagnosis and staging, clinicians should perhaps remain especially alert to the possibility of pharmacological iatrogeny, which is not limited to psychopharmacological treatment. Traditional risk factors for cognitive impairment and factors predictive of progression to dementia include hypertension, hyperglycaemia, hyperlipidaemia, smoking, alcohol, and metabolic syndrome. Emerging factors include atrial fibrillation, inflammation, hyperhomocysteinaemia, and heart failure. Paradoxically, prevention of risk factors such as hypotension, hypoglycaemia, bradycardia, low cardiac output and even malnutrition become more important at more advanced ages. Lastly, some cognitive variables such as memory, language and reading abilities, and some alterations in the affective sphere should also be assessed as predictive factors for mild cognitive impairment. PMID- 29628029 TI - [Mild behavioral impairment: a new concept for the prodromic phases of dementia]. AB - Neuropsychiatric symptoms (NPS) are frequent in dementia. These symptoms are also present in patients with mild cognitive impairment (MCI) and can even constitute the first manifestations of a neurodegenerative process, preceding the development of cognitive symptoms. The presence of NPS is associated with higher rates of conversion to dementia in healthy persons and patients with MCI. Recognizing the importance of NPS, the Alzheimer Association created a working group that has designed the ISTAART criteria for mild behavioral impairment (MBI), including the following areas of assessment: motivation, affect, impulse control, social appropriateness and thoughts/perception. The ISTAART criteria allow identification of NPS to prospectively assess the risk of a person developing dementia. The Mild Behavioral Impairment-Checklist (MBI-C) has subsequently been developed, which allows the MBI construct to be specifically assessed by quantifying the distinct symptoms, thus enhancing the clinical utility of this construct in clinical practice and research. PMID- 29628030 TI - [Cognitive impairment/dementia: assessment and follow-up. Functional aspects]. AB - The importance of functional status is increasingly being recognized in current clinical management. This is especially important in mild cognitive impairment (MCI), which is a priority due to its direct relationship with dementia and awareness that functional alterations are what separates MCI from dementia. Adequate assessment of MCI during the follow-up of this condition allows identification of its progress, whether towards normal cognitive function or detection and diagnosis of the incipient stages of dementia, thus providing the benefits of early diagnosis. This article describes assessment tools for this condition, beginning with performance tests as an objective measure of mobility, followed by measurement of activities of daily living (ADL): advanced, instrumental and basic, with emphasis on the Sydney Test of Activities of Daily Living in Memory Disorders (STAM) and Mongil's tests of activities of daily living. Patient follow-up is essential and should combine assessment of performance tests and ADL measurement. Emphasis is placed on functional status not only because of its association with MCI but also because it has become a therapeutic target and an outcomes indicator. PMID- 29628031 TI - [Definition and prevalence of mild cognitive impairment]. AB - Cognition is the ability that allows humans to carry out their lives without difficulty, resolving problems and situations, and to continue to learn and correctly process information from the environment for its subsequent retrieval and use. In persons with normal or physiological brain ageing, this ability is maintained throughout their lives. However, individuals with abnormal or pathological ageing could be affected by distinct degrees of impairment of higher brain functions. The term mild cognitive impairment (MCI) entered the lexicon in 1988 to describe a syndrome encompassing greater than expected cognitive impairment for the person's age and cultural environment. At that time, MCI was considered a degenerative process that preceded dementia. In the last 30 years, it has become clear that not all patients with MCI will progress to dementia. Therefore, the concept and definition of this syndrome have been constantly updated, and distinct subtypes of MCI have been established according to the affected cognitive domain. There is a need to define MCI more clearly and identify its subtypes in order to establish its impact on an ageing society, identify persons at risk of progressing to dementia, and implement early intervention strategies aimed at improving the mental health of the elderly population. PMID- 29628032 TI - [Clinical assessment and diagnostic tools]. AB - The presence of cognitive impairment generates important changes in both affected individuals and their families and the health staff who must provide adequate care. Early identification of this alteration allows appropriate diagnosis and treatment and psychosocial and educational support, as well as the possibility of establishing care, life and financial plans. The interest of the scientific community in age-related cognitive alterations is demonstrated by the abundance of criteria and classifications. Obviously, there is a need to unify these criteria and implement longitudinal studies in order to reach reliable conclusions. Clinical assessment of the distinct cognitive domains should include careful history-taking and the use of diagnostic neuropsychological batteries. First, the ideal screening test would be one that could be administered in a few minutes, with a cut-off point that would identify patients requiring further assessment for correct diagnosis. The use of dynamic biomarkers is based on the hypothesis that they have a specific time-dependent model. These biomarkers include, firstly, markers of amyloidosis and, secondly, markers of neurodegeneration. Cognitive frailty is an emerging term inspired by a potential parallel with physical frailty syndrome. A subgroup of patients with cognitive impairment show a reduced capacity for recovery and functional decline that interact with physical frailty. The evidence suggests that cognitive status represents an important dimension of frailty syndrome. PMID- 29628034 TI - [Non-pharmacological interventions]. AB - Non-pharmacological therapies are currently one of the cornerstones of the prevention of the possible causes of cognitive impairment. Among other topics, the present article discusses the importance of identifying and working with elements such as a person's life history, interests, values, beliefs, and personal tastes and preferences and of combining them with techniques with proven effectiveness. PMID- 29628033 TI - [Pharmacological therapeutic intervention in mild cognitive impairment]. AB - Mild cognitive impairment (MCI) is a syndrome encompassing affective and behavioural symptoms and various subtypes. MCI is a heterogeneous clinical entity with varied causes (degenerative, vascular, psychiatric, non-neurological disorders), and there is wide variation in symptoms and clinical course. There are multiple causes and consequently various treatments can be applied and should be combined with non-pharmacological measures. This article describes both preventive and therapeutic pharmacological interventions: control of vascular risk factors, avoidance of iatrogeny, use of nutraceuticals, CDP-choline, and Ginkgo biloba EGb 761(r), and improvement in sense organs. PMID- 29628035 TI - ? PMID- 29628036 TI - ? PMID- 29628037 TI - [The Community Pharmacy in the Early Detection of Mild Cognitive Impairment. Warning Signs]. AB - Cognitive dysfunction and dementia in the elderly population constitute a significant health problem due to their magnitude and seriousness. Patients with mild cognitive impairment (MCI) are at increased risk of developing some form of dementia, including Alzheimer disease. Epidemiological studies support the existence of preventable risks for cognitive impairment: vascular factors and lifestyle-related factors. The aim is to detect possible cases of cognitive impairment in people aged over 55 years in the community pharmacy area. Community pharmacists work in close contact with the population, especially chronic patients who periodically collect their medication in community pharmacies. Consequently, these health professionals can be trained to detect the most frequent warning signs and symptoms and to refer these individuals to the doctor for an early diagnosis of MCI. PMID- 29628038 TI - [Patterns of detection of mild cognitive impairment in nursing]. AB - Mild cognitive impairment (MCI) is characterized by an acquired cognitive loss that places individuals, mainly older adults, in an intermediate stage between normal cognitive functioning and dementia. This impairment has a high risk of progression to dementia and is suitable for screening, which allows more effective early intervention. Nursing professionals, especially community-based primary care nurses, play an important role in the detection and follow-up of MCI and in interventions for this condition. The first step should be to take a thorough history from both the patient and his or her carers, which should assess the changes occurring in the patient's daily, family and social life through functional patterns. In subsequent assessment of cognitive function, brief screening tests can be used such as the Mini Mental State Examination (MMSE) or other similar tests. Special attention should be paid to the presence of affective or depressive symptoms, sensory deficits, polypharmacy, decompensated cardiovascular risk factors, and rapid functional deterioration, given their particular influence on MCI. Finally, various nurse-led, non-pharmacological interventions that are effective in MCI can be recommended, based on cardiovascular risk factor control, physical exercise, and cognitive and psychosocial interventions. PMID- 29628039 TI - [Economic impact of cognitive impairment and dementia]. AB - Increased life expectancy has had a corresponding socioeconomic impact due to the ageing population and, among other issues, has increased the incidence of diseases related to cognitive impairment, such as dementia. These changes particularly affect the most developed countries. Any analysis of economic costs aiming to study patients with health problems related to cognitive impairment or dementia should consider the reality of the distinct phases of these disorders and should be conducted from the perspective of the payer, that is, the publicly funded healthcare system. Moreover, given the complexity and importance of cognitive impairment, there is a need to consider both direct healthcare costs, such as hospitalization measures, medication for the treatment of these diseases, specialist consultations, transport (eg, ambulances in severe cases), and direct non-healthcare costs (eg, professional care, nonprofessional care). In addition, indirect costs (related to productivity losses such as sick leave) must be considered for these diseases. Lastly, in 2014, the annual total mean cost (direct and indirect costs) in Spain for each patient with cognitive impairment, dementia and Alzheimer disease, was around ?30 000. A large part of this economic burden was due especially to indirect costs, which are usually a borne by affected individuals and their families. PMID- 29628040 TI - [Patterns of brain ageing]. AB - Neuroplasticity lends the brain a strong ability to adapt to changes in the environment that occur during ageing. Animal models have shown alterations in neurotransmission and imbalances in the expression of neural growth factor. Changes at the morphometric level are not constant. Volume loss is related to alterations in neuroplasticity and involvement of the cerebral neuropil. Although there are no conclusive data, physical exercise improves the molecular, biological, functional and behavioural-cognitive changes associated with brain ageing. The aged human brain has been described as showing weight and volume loss and increased ventricular size. However, neuroimaging shows significant variation and many healthy elderly individuals show no significant macroscopic changes. In most brain regions, the number of neurons remains stable throughout life. Neuroplasticity does not disappear with ageing, and changes in dendritic arborization and the density of spines and synapses are more closely related to brain activity than to age. At the molecular level, although the presence of altered Tau and beta-amyloid proteins is used as a biomarker of neurodegenerative disease, postmortem studies show that these abnormal proteins are common in the brains of elderly people without dementia. Finally, due to the relationship between neurodegenerative diseases and metabolic alterations, this article analyses the influence of insulin-like growth factor and ageing, both in animal models and in humans, and the possible neuroprotective effect of insulin. PMID- 29628041 TI - Mitochondrial Dysfunction: At the Core of Psychiatric Disorders? PMID- 29628042 TI - A Comprehensive Analysis of Nuclear-Encoded Mitochondrial Genes in Schizophrenia. AB - BACKGROUND: The genetic risk factors of schizophrenia (SCZ), a severe psychiatric disorder, are not yet fully understood. Multiple lines of evidence suggest that mitochondrial dysfunction may play a role in SCZ, but comprehensive association studies are lacking. We hypothesized that variants in nuclear-encoded mitochondrial genes influence susceptibility to SCZ. METHODS: We conducted gene based and gene-set analyses using summary association results from the Psychiatric Genomics Consortium Schizophrenia Phase 2 (PGC-SCZ2) genome-wide association study comprising 35,476 cases and 46,839 control subjects. We applied the MAGMA method to three sets of nuclear-encoded mitochondrial genes: oxidative phosphorylation genes, other nuclear-encoded mitochondrial genes, and genes involved in nucleus-mitochondria crosstalk. Furthermore, we conducted a replication study using the iPSYCH SCZ sample of 2290 cases and 21,621 control subjects. RESULTS: In the PGC-SCZ2 sample, 1186 mitochondrial genes were analyzed, among which 159 had p values < .05 and 19 remained significant after multiple testing correction. A meta-analysis of 818 genes combining the PGC-SCZ2 and iPSYCH samples resulted in 104 nominally significant and nine significant genes, suggesting a polygenic model for the nuclear-encoded mitochondrial genes. Gene-set analysis, however, did not show significant results. In an in silico protein-protein interaction network analysis, 14 mitochondrial genes interacted directly with 158 SCZ risk genes identified in PGC-SCZ2 (permutation p = .02), and aldosterone signaling in epithelial cells and mitochondrial dysfunction pathways appeared to be overrepresented in this network of mitochondrial and SCZ risk genes. CONCLUSIONS: This study provides evidence that specific aspects of mitochondrial function may play a role in SCZ, but we did not observe its broad involvement even using a large sample. PMID- 29628043 TI - So Happy Together: The Storied Marriage Between Mitochondria and the Mind. PMID- 29628044 TI - Editorial -TICPT 2017. PMID- 29628045 TI - Musings about the role dietary fats after 40 years of fatty acid research. AB - Since the 1950's nutrition recommendations have focussed on the replacement of saturated fats in the diet with polyunsaturated fats, a strategy that continues to this day. Despite supporting evidence from clinical trials for the advantages of Mediterranean diets, there has been less attention paid to the role of monounsaturated fats. It has been known for many years that diets high in linoleic acid (LA) compete for the incorporation of omega 3 fatty acids into tissues. What is also clear is that diets rich in LA are not free from concerns and the discovery of oxlams, oxygenated derivatives of LA, having potent inflammatory effects may help us question the dogma of LA rich diets. Given that dietary oleic acid a prime constituent of Mediterranean diets can be metabolised to Mead acid (ETrA) has in the past been a cause for concern, but new data showing the anti-inflammatory effects of ETrA suggest that there is a need for further research about the benefits of monounsaturated oils on human health. Finally, there is a need to re-examine how dietary fats are monitored in clinical studies. The current method of focussing on esterified fatty acids may be too insensitive to detect clinically important changes. PMID- 29628046 TI - Mechanisms underlying the effects of n-3 polyunsaturated fatty acids on fear memory processing and their hypothetical effects on fear of cancer recurrence in cancer survivors. AB - The relationship of n-3 polyunsaturated fatty acids (PUFAs) and gut microbiota with brain function has been extensively reported. Here, we review how n-3 polyunsaturated fatty acids affect fear memory processing. n-3 PUFAs may improve dysfunctional fear memory processing via immunomodulation/anti-inflammation, increased BDNF, upregulated adult neurogenesis, modulated signal transduction, and microbiota-gut-brain axis normalization. We emphasize how n-3 PUFAs affect this axis and also focus on the hypothetical effects of PUFAs in fear of cancer recurrence (FCR), the primary psychological unmet need of cancer survivors. Its pathophysiology may be similar to that of post-traumatic stress disorder (PTSD), which involves dysfunctional fear memory processing. Due to fewer adverse effects than psychotropic drugs, nutritional interventions involving n-3 PUFAs should be acceptable for physically vulnerable cancer survivors. We are currently studying the relationship of FCR with n-3 PUFAs and gut microbiota in cancer survivors to provide them with a nutritional intervention that protects against FCR. PMID- 29628047 TI - Increased expression of CysLT2 receptors in the lung of asthmatic mice and role in allergic responses. AB - Compared with CysLT1 receptors, the functional role of CysLT2 receptors in asthma has not been clarified. The purpose of this study was to determine 1) whether CysLT2 receptors are expressed in the lung of mice and if expression increases in asthmatic mice, and 2) whether CysLT2 receptors are involved in allergic leukocyte infiltration into the lung and in the development of airway remodeling in asthmatic mice. BALB/c mice were sensitized with ovalbumin (OVA) + Al(OH)3, and intratracheally challenged with OVA 4 times. Lung tissue was isolated before and after the 4th OVA challenge for detection of CysLT2 receptors by immunohistochemistry and flow cytometry. The effect of a CysLT2 receptor antagonist BayCysLT2RA on multiple antigen challenge-induced leukocyte infiltration into the lung and the development of airway remodeling was evaluated. Even in non-challenged mice, CysLT2 receptors were expressed in bronchial smooth muscle. After multiple challenges, expression was also observed in leukocytes infiltrating into alveolar spaces. CysLT2R+ leukocytes included alveolar macrophages, conventional dendritic cells, and eosinophils. BayCysLT2RA significantly inhibited multiple antigen challenge-induced increases in eosinophils and mononuclear cells in the lung. The development of airway remodeling was tended to be suppressed by CysLT2 receptor antagonist. In conclusion, CysLT2 receptors were constitutively expressed in the lung, and expression was strengthened in asthmatic mice. Activation of CysLT2 receptors was functionally involved in allergic leukocyte infiltration into the lung. The CysLT2 receptor can be a molecular target for the development of new pharmacotherapies for asthma. PMID- 29628048 TI - Comprehensive study of rodent olfactory tissue lipid composition. AB - The peripheral olfactory tissue (OT) plays a primordial role in the detection and transduction of olfactory information. Recent proteomic and transcriptomic studies have provided valuable insight into proteins and RNAs expressed in this tissue. Paradoxically, there is little information regarding the lipid composition of mammalian OT. To delve further into this issue, using a set of complementary state-of-the-art techniques, we carried out a comprehensive analysis of OT lipid composition in rats and mice fed with standard diets. The results showed that phospholipids are largely predominant, the major classes being phosphatidylcholine and phosphatidylethanolamine. Two types of plasmalogens, plasmenyl-choline and plasmenyl-ethanolamine, as well as gangliosides were also detected. With the exception of sphingomyelin, substantial levels of n-3 polyunsaturated fatty acids, mainly docosahexaenoic acid (22:6n-3; DHA), were found in the different phospholipid classes. These findings demonstrate that the rodent OT shares several features in common with other neural tissues, such as the brain and retina. PMID- 29628049 TI - Identification of novel CYP4F2 genetic variants exhibiting decreased catalytic activity in the conversion of arachidonic acid to 20-hydroxyeicosatetraenoic acid (20-HETE). AB - CYP4F2 is an enzyme involved in the formation of 20-hydroxyeicosatetraenoic acid (20-HETE) from arachidonic acid and metabolizes vitamin K into an inactive form. Our objectives were to identify new CYP4F2 genetic variants and to characterize the functional consequences of the conversion of arachidonic acid into 20-HETE. We used direct DNA sequencing to identify a total of 20 single-nucleotide polymorphisms (SNPs) including four coding variants, A27V, R47C, P85A, and V433M, in 50 randomly selected subjects. Of these, A27V and P85A were new. Recombinant variant proteins were prepared using an Escherichia coli expression system, purified, and quantified via CO-difference spectral analysis. The conversion of arachidonic acid to 20-HETE by the coding variants was compared to that of the wild-type protein. Wild-type CYP4F2 exhibited the highest intrinsic clearance, followed by P85A, A27V, V433M, and R47C (40-65% of the wild-type value). The locations of the mutated residues in the three-dimensional protein structure were predicted by structural modeling, and the possible effects on 20-HETE synthesis discussed. In summary, we describe the allele frequency, haplotype distribution, and linkage disequilibrium of CYP4F2 and functionally analyze the CYP4F2 coding variants. Our findings suggest that individuals having the low-activity alleles of CYP4F2 may inefficiently convert arachidonic acid into 20-HETE. This may aid in our understanding of 20-HETE-related blood pressure problems and cardiovascular diseases when genotype-phenotype association studies are performed in the future. PMID- 29628050 TI - Abuse and Violence. PMID- 29628051 TI - Retrospective Chart Review of Skin-to-Skin Contact in the Operating Room and Administration of Analgesic and Anxiolytic Medication to Women After Cesarean Birth. AB - Transporting a newborn out of the operating room after cesarean birth can contribute to maternal awareness of discomfort, anxiety, and the need for administration of analgesics and anxiolytics for relief. This retrospective study analyzed the association between skin-to-skin contact in the operating room and administration of analgesics and anxiolytics to women in the operating and recovery rooms after cesarean birth. Our results indicated a trend toward decreased medication administration for women who experienced skin-to-skin contact and add to evidence supporting the incorporation of skin-to-skin contact in the operating room as the standard of care for cesarean birth. This practice has the potential to enhance the birth experience, promote breastfeeding, and provide greater safety with less exposure to opioids and benzodiazepines for women and their newborns. PMID- 29628052 TI - Promoting Best Practice for Perinatal Care of Deaf Women. AB - To evaluate perinatal nursing care for Deaf women, we conducted a pilot, descriptive study exploring women's prenatal, labor, and postpartum experiences. We used the Quality and Safety Education for Nurses (QSEN) framework to analyze women's responses and to explore implications for practice. Themes and women's stories are presented within the QSEN structure to promote informed and individualized perinatal nursing care for Deaf families. It is essential for nurses to stay abreast of resources and technological advances and to use culturally competent principles of communication. Nurses' knowledge of Deaf culture helps guide care, and their understanding of legal provisions and the Americans with Disabilities Act can lead to greater advocacy for Deaf women. Additional research is necessary to fill the current void in the literature about perinatal care for Deaf women. PMID- 29628053 TI - Community-Based Breastfeeding Support With the Tiger Babies Breastfeeding Support Tent. AB - The Tiger Babies Breastfeeding Support Tent was established by a baccalaureate nursing program in southeastern Alabama to increase community awareness of the importance of breastfeeding and to provide a clean, convenient, and private location for nursing mothers during community events. Local advertising was distributed before community events to promote awareness and support of the project. Survey results indicate that 80% of mothers who used the tent's services would recommend the tent to their friends and family members. PMID- 29628054 TI - Women's Self-Reported Factors That Influence Their Postpartum Exercise Levels. AB - The birth of a child is a life transition that can signal an opportunity to promote wellness and self-care. Nurses and other health care providers can encourage women to engage in exercise for physical and mental health and to enhance weight loss after birth. However, incorporating an exercise routine into life with an infant can be challenging. Sixty-two women provided feedback about their exercise patterns before and during pregnancy, and 18 of these women gave additional insight into barriers to and facilitators of exercise engagement after childbirth. Three broad categories were identified as influencing exercise patterns in the postpartum period: Time, Maternal Responsibilities, and Physical Status. Recommendations for increasing exercise include providing individualized activity suggestions, identifying exercise groups specific to postpartum women, and connecting exercise with social support for better adherence. PMID- 29628055 TI - Nursing Care of Women Veterans of the Iraq and Afghanistan Wars. AB - The Iraq and Afghanistan wars are unlike earlier wars, and the women veterans who have served in them are unlike veterans of earlier wars. Now these veterans are presenting with distinctive general, genitourinary, reproductive, and behavioral health issues. When seeking health care after deployment, they may be accessing multiple health care providers across numerous sites, including the Veterans Health Administration and civilian facilities. Enhanced levels of understanding, respect, and concern for the many combat-related health challenges experienced by these veterans will help civilian nurses and other clinicians provide optimum care. Provision of health care to women veterans should be multidisciplinary and effectively coordinated among various health care providers and facilities to ensure that their post-deployment health and wellness needs are met. PMID- 29628056 TI - Understanding the Two-Dose HPV Vaccine Schedule. AB - Recent advances in human papillomavirus (HPV) science have led to updates to national HPV vaccine recommendations. This column takes a second look at two recent studies that provide evidence to support the current two-dose HPV vaccination schedule for youth ages 9 to 14 years. This short review will help nurses and other clinicians understand the health and economic benefits of the current dosing recommendation. Nurses are leaders in national vaccination efforts; therefore, it is vital that they remain up to date on the latest evidence that supports vaccination practice as well as health counseling and HPV vaccine recommendations. PMID- 29628057 TI - Highlights From the U.S. Selected Practice Recommendations for Contraceptive Use. AB - The U.S. Centers for Disease Control and Prevention recently updated the U.S. Selected Practice Recommendations for Contraceptive Use to foster a reduction in unplanned pregnancy rates and to provide clinicians an evidence-based guide for contraception management. Nurses play an important role in helping women and families with reproductive life planning. By bridging knowledge gaps and removing access barriers with regard to contraception, nurses can contribute to reducing rates of unintended pregnancy. Nurses and other clinicians are encouraged to use the U.S. Selected Practice Recommendations for Contraceptive Use when counseling women about safe and effective contraception management. PMID- 29628058 TI - Nursing Care of Incarcerated Women During Pregnancy and the Postpartum Period. PMID- 29628059 TI - Use of Nitrous Oxide in Maternity Care: AWHONN Practice Brief Number 6. PMID- 29628060 TI - Embracing the Opportunity in Whitewater. PMID- 29628061 TI - Testing Causal Relationships Between Emotion Processing Circuitry and Behavior Using Noninvasive Brain Stimulation. PMID- 29628062 TI - Identifying Prefrontal Networks for Disease Vulnerability Versus Acute Illness in Major Depression. PMID- 29628064 TI - Long-Term Effects of Cognitive Behavioral Therapy on Planning and Prefrontal Cortex Function in Pediatric Obsessive-Compulsive Disorder. AB - BACKGROUND: Previous studies showed changes after cognitive behavioral therapy (CBT) in prefrontal cortex function and cognitive performance in pediatric obsessive-compulsive disorder (OCD). It remains unknown whether these changes are short lasting or persistent during a period of brain maturation. Here, we investigated the long-term effects of CBT on planning performance and brain function in pediatric OCD using a longitudinal design. METHODS: Fifteen pediatric OCD patients and 16 matched healthy control subjects ranging from the ages of 8 to 18 years performed the Tower of London planning task during functional magnetic resonance imaging at three time points: before treatment, after 16 sessions of CBT, and after 2 years of naturalistic follow-up. RESULTS: Group * time interaction analyses showed differential changes from baseline to long-term follow-up in planning performance and brain activity between patients and control subjects. At baseline, patients were slower but as accurate on the planning task and recruited the left inferior frontal gyrus, middle frontal gyrus, and anterior insula more often than control subjects did. These differences were no longer present after CBT and after 2 years of follow-up. CONCLUSIONS: Pediatric OCD patients, compared with healthy control subjects, showed longer reaction times and additional recruitment of frontal brain regions during planning. These differences tended to normalize after CBT, and the process continued during 2 years of follow-up. This longitudinal study shows long-lasting changes in cognitive performance and prefrontal cortex function after CBT and suggests that planning dysfunction in pediatric OCD is a state rather than a trait characteristic of the disorder. PMID- 29628063 TI - Cognitive Behavioral Therapy Is Associated With Enhanced Cognitive Control Network Activity in Major Depression and Posttraumatic Stress Disorder. AB - BACKGROUND: Both major depressive disorder (MDD) and posttraumatic stress disorder (PTSD) are characterized by depressive symptoms, abnormalities in brain regions important for cognitive control, and response to cognitive behavioral therapy (CBT). However, whether a common neural mechanism underlies CBT response across diagnoses is unknown. METHODS: Brain activity during a cognitive control task was measured using functional magnetic resonance imaging in 104 participants: 28 patients with MDD, 53 patients with PTSD, and 23 healthy control subjects; depression and anxiety symptoms were determined on the same day. A patient subset (n = 31) entered manualized CBT and, along with controls (n = 19), was rescanned at 12 weeks. Linear mixed effects models assessed the relationship between depression and anxiety symptoms and brain activity before and after CBT. RESULTS: At baseline, activation of the left dorsolateral prefrontal cortex was negatively correlated with Montgomery-Asberg Depression Rating Scale scores across all participants; this brain-symptom association did not differ between MDD and PTSD. Following CBT treatment of patients, regions within the cognitive control network, including ventrolateral prefrontal cortex and dorsolateral prefrontal cortex, showed a significant increase in activity. CONCLUSIONS: Our results suggest that dimensional abnormalities in the activation of cognitive control regions were associated primarily with symptoms of depression (with or without controlling for anxious arousal). Furthermore, following treatment with CBT, activation of cognitive control regions was similarly increased in both MDD and PTSD. These results accord with the Research Domain Criteria conceptualization of mental disorders and implicate improved cognitive control activation as a transdiagnostic mechanism for CBT treatment outcome. PMID- 29628065 TI - Modulating Emotion Perception: Opposing Effects of Inhibitory and Excitatory Prefrontal Cortex Stimulation. AB - BACKGROUND: Excitatory repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (dlPFC) is approved by the U.S. Food and Drug Administration for the treatment of adult patients with treatment-resistant major depressive disorder (MDD). This stimulation is supposed to restore excitability of prefrontal cortex regions that exhibit diminished regulation of emotion generative systems in MDD. Based on the valence lateralization hypothesis, inhibitory rTMS of the right dlPFC has also been applied in MDD. This approach has proved to be effective, although meta-analyses of emotional perception and affective regulation in healthy control subjects and patients with depression do not support functional asymmetries within dlPFC regions. METHODS: To shed more light on this discrepancy, the effects of excitatory and inhibitory rTMS of the right dlPFC on visual emotional perception were compared in two groups of 41 healthy participants overall. Before and after rTMS stimulation, participants viewed fearful and neutral faces while whole-head magnetoencephalography was recorded and supplemented by behavioral tests. RESULTS: Visual sensory processing of fearful facial expressions, relative to neutral facial expressions, was reduced after excitatory stimulation and was increased after inhibitory stimulation within right occipital and right temporal regions. Correspondingly, after excitatory rTMS compared with inhibitory rTMS, participants displayed relatively reduced reaction times in an emotion discrimination task and showed reduced emotional arousal. CONCLUSIONS: These results support the hypothesis that excitatory rTMS compared with inhibitory rTMS of the right dlPFC strengthens top down control of aversive stimuli in healthy control subjects, which should encourage more research on mechanisms of excitatory/inhibitory dlPFC-rTMS protocols in general and on neuromodulatory treatment of MDD. PMID- 29628066 TI - Abnormal Functional Connectivity of Frontopolar Subregions in Treatment Nonresponsive Major Depressive Disorder. AB - BACKGROUND: Approximately 30% of patients with major depressive disorder develop treatment-nonresponsive depression (TNRD); novel interventions targeting the substrates of this illness population are desperately needed. Convergent evidence from lesion, stimulation, connectivity, and functional neuroimaging studies implicates the frontopolar cortex (FPC) as a particularly important region in TNRD pathophysiology; regions functionally connected to the FPC, once identified, could present favorable targets for novel brain stimulation treatments. METHODS: We recently published a parcellation of the FPC based on diffusion tensor imaging data, identifying distinct medial and lateral subregions. Here, we applied this parcellation to resting-state functional magnetic resonance imaging scans obtained in 56 patients with TNRD and 56 matched healthy control subjects. RESULTS: In patients, the medial FPC showed reduced connectivity to the anterior midcingulate cortex and insula. The left lateral FPC showed reduced connectivity to the right lateral orbitofrontal cortex and increased connectivity to the fusiform gyri. In addition, TNRD symptom severity correlated significantly with connectivity of the left lateral FPC subregion to a medial orbitofrontal cortex region of the classical reward network. CONCLUSIONS: Taken together, these findings suggest that changes in FPC subregion connectivity may underlie several dimensions of TNRD pathology, including changes in reward/positive valence, nonreward/negative valence, and cognitive control domains. Nodes of functional networks showing abnormal connectivity to the FPC could be useful in generating novel candidates for therapeutic brain stimulation in TNRD. PMID- 29628068 TI - Negative Autobiographical Memory in Depression Reflects Elevated Amygdala Hippocampal Reactivity and Hippocampally Associated Emotion Regulation. AB - BACKGROUND: Dysregulated autobiographical recall is observed in major depressive disorder (MDD). However, it is unknown whether people with MDD show abnormalities in memory-, emotion-, and control-related brain systems during reactivity to and regulation of negative autobiographical memories. METHODS: We used functional magnetic resonance imaging to identify neural mechanisms underlying MDD-related emotional responses to negative autobiographical memories and the ability to downregulate these responses using a cognitive regulatory strategy known as reappraisal. We compared currently depressed, medication-free patients with MDD (n = 29) with control participants with no history of depression (n = 23). RESULTS: Relative to healthy control participants, medication-free MDD patients reported greater negative emotion during recall but relatively intact downregulation success. They also showed elevated amygdala activity and greater amygdala-hippocampal connectivity. This connectivity mediated the effect of MDD on negative emotional experience. When reappraising memories (vs. recalling from an immersed perspective), the MDD and control groups showed comparable recruitment of the prefrontal, parietal, and temporal cortices, and comparable downregulation of the amygdala and anterior hippocampus. However, MDD patients showed greater downregulation of the posterior hippocampus, and the extent of this downregulation predicted successful reduction of negative affect in MDD patients only. CONCLUSIONS: These data suggest amygdala-hippocampal connectivity and posterior hippocampal downregulation as brain mechanisms related to elevated emotional reactivity and atypical emotion regulation in MDD. PMID- 29628067 TI - Orbital and Medial Prefrontal Cortex Functional Connectivity of Major Depression Vulnerability and Disease. AB - BACKGROUND: Pathophysiology models of major depression (MD) center on the dysfunction of various cortical areas within the orbital and medial prefrontal cortex. While independent structural and functional abnormalities in these areas are consistent findings in MD, the complex interactions among them and the rest of the cortex remain largely unexplored. METHODS: We used resting-state functional magnetic resonance imaging connectivity to systematically map alterations in the communication between orbital and medial prefrontal cortex fields and the rest of the brain in MD. Functional connectivity (FC) maps from participants with current MD (n = 35), unaffected first-degree relatives (n = 36), and healthy control subjects (n = 38) were subjected to conjunction analyses to distinguish FC markers of MD vulnerability and FC markers of MD disease. RESULTS: FC abnormalities in MD vulnerability were found for dorsal medial wall regions and the anterior insula and concerned altered communication of these areas with the inferior parietal cortex and dorsal posterior cingulate, occipital areas and the brainstem. FC aberrations in current MD included the anterior insula, rostral and dorsal anterior cingulate cortex, and lateral orbitofrontal areas and concerned altered communication with the dorsal striatum, the cerebellum, the precuneus, the anterior prefrontal cortex, somatomotor cortex, dorsolateral prefrontal cortex, and visual areas in the occipital and inferior temporal lobes. CONCLUSIONS: Functionally delineated parcellation maps can be used to identify putative connectivity markers in extended cortical regions such as the orbital and medial prefrontal cortex. The anterior insula and the rostral anterior cingulate cortex play a central role in the pathophysiology of MD, being consistently implicated both in the MD vulnerability and MD disease states. PMID- 29628070 TI - Interactions Between Oxytocin Receptor Gene Methylation and Callous-Unemotional Traits Impact Socioaffective Brain Systems in Conduct-Disordered Offenders. AB - BACKGROUND: The developmental trajectory of psychopathy seemingly begins early in life and includes the presence of callous-unemotional (CU) traits (e.g., perturbed socioaffective reactivity and empathy, callousness) in youths with conduct disorder (CD). Whereas oxytocin receptor gene methylation (OXTRMeth) and its downstream neuromodulatory effects are deemed relevant to CU traits, nothing is known of how OXTRMeth interacts with CU traits to impact socioaffective brain systems in youngsters with CD. METHODS: Hence, we uniquely probed OXTRMeth * CU trait interactions on corticolimbic activity and amygdala subregional connections during recognition and resonance of distressing socioaffective stimuli (angry and fearful faces), in juvenile offenders with CD (n = 39) versus matched healthy control youths (n = 27). RESULTS: Relative to healthy control youths, elevated OXTRMeth and CU levels in youths with CD essentially interacted to predict frontoparietal hyperactivity and amygdalo-frontoparietal disconnection during task performance. Specifically, increasing OXTRMeth and CU levels in youths with CD interactively predicted midcingulate hyperactivity during both emotion conditions, with insular, temporoparietal, and precuneal hyperactivity additionally emerging during emotion recognition. Interactions between high OXTRMeth and CU levels in youths with CD additionally predicted centromedial amygdala decoupling from ventromedial/orbitofrontal regions during emotion recognition, along with basolateral amygdala decoupling from precuneal and temporoparietal cortices during emotion resonance. CONCLUSIONS: These results uniquely suggest that interactions between OXTRMeth and CU traits in youths with CD may affect brain systems critical to decoding and integrating socioaffective information. Developmental models of CU traits and psychopathy could thus possibly advance by further examining OXTR epigenetic effects, which may hold promise for indicated prevention and personalized treatment by targeting oxytocinergic function. PMID- 29628071 TI - Fatigue Is Associated With Altered Monitoring and Preparation of Physical Effort in Patients With Chronic Fatigue Syndrome. AB - BACKGROUND: Chronic fatigue syndrome (CFS) is characterized by disabling fatigue, which is suggested to be maintained by dysfunctional beliefs. Fatigue and its maintenance are recently conceptualized as arising from abnormally precise expectations about bodily inputs and from beliefs of diminished control over bodily states, respectively. This study used functional neuroimaging to identify the neural correlates of fatigue and its maintenance by beliefs during a physical effort task. METHODS: We isolated behavioral adjustments and cerebral activity during feedback processing and motor preparation, in the context of a task in which patients with CFS (n = 85) and healthy control subjects (n = 29) produced 30%, 50%, and 70% of their right-hand maximal voluntary contraction, and received directional feedback on performance (e.g., too little force). RESULTS: Patients with CSF showed an effort-dependent behavioral bias toward less effort investment in response to directional feedback for the highest effort level as compared with healthy control subjects. This bias was associated with reduced feedback-related activity in the dorsolateral prefrontal cortex. These effects were proportional to state-related fatigue and prior beliefs about CFS patients' ability to perform the task. Patients with CFS also showed higher activity in the supplementary motor area, proportional to their state-related fatigue, and reduced connectivity between the supplementary motor area and sensorimotor cortex during motor preparation as compared with control subjects. CONCLUSIONS: These findings link fatigue symptoms to alterations in behavioral choices on effort investment, prefrontal functioning, and supplementary motor area connectivity, with the dorsolateral prefrontal cortex being associated with prior beliefs about physical abilities. PMID- 29628072 TI - Corrigendum: A revealed preference approach to valuing non-market recreational fishing losses from the Deepwater Horizon spill (J. Environ. Manag. 145, 2014, 199-209). PMID- 29628069 TI - Experiences of Discrimination Are Associated With Greater Resting Amygdala Activity and Functional Connectivity. AB - BACKGROUND: Social discrimination, a type of psychological stressor, is associated with poorer physical and mental health outcomes, yet we have little understanding of how discrimination affects neural functions in marginalized populations. By contrast, the effects of psychological stress on neural functions are well documented, with evidence of significant effects on the amygdala-a neural region that is central to psychosocial functions. Accordingly, we conducted an examination of the relation between self-reported discrimination exposure and amygdala activity in a diverse sample of adults. METHODS: Seventy four adults (43% women; 72% African American; 23% Hispanic; 32% homosexual/bisexual) completed self-report ratings of discrimination exposure. Spontaneous amygdala activity and functional connectivity were assessed during resting-state functional magnetic resonance imaging. RESULTS: Greater discrimination exposure was associated with higher levels of spontaneous amygdala activity. Increases in discrimination were also associated with stronger functional connectivity between the amygdala and several neural regions (e.g., anterior insula, putamen, caudate, anterior cingulate, medial frontal gyrus), with the most robust effects observed in the thalamus. These effects were independent of several demographic (e.g., race, ethnicity, sex) and psychological (e.g., current stress, depression, anxiety) factors. CONCLUSIONS: Collectively, our findings provide the first evidence that social discrimination is independently associated with elevations in intrinsic amygdala activity and functional connectivity, thus revealing clear parallels between the neural substrates of discrimination and psychological stressors of other origins. Such results should spur future investigations of amygdala-based networks as potential etiological factors linking discrimination exposure to adverse physical and mental health outcomes. PMID- 29628073 TI - Wheezing in infants: A pandemic condition that need to be treated with patience. PMID- 29628075 TI - The production of formaldehyde and hydroxyacetone in methacrolein photooxidation: New insights into mechanism and effects of water vapor. AB - Methacrolein (MACR) is an abundant multifunctional carbonyl compound with high reactivity in the atmosphere. In this study, we investigated the hydroxyl radical initiated oxidation of MACR at various NO/MACR ratios (0 to 4.04) and relative humidities (<3% to 80%) using a flow tube. Meanwhile, a box model based on the Master Chemical Mechanism was performed to test our current understanding of the mechanism. In contrast to the reasonable predictions for hydroxyacetone production, the modeled yields of formaldehyde (HCHO) were twice higher than the experimental results. The discrepancy was ascribed to the existence of unconsidered non-HCHO forming channels in the chemistry of CH3C(CH2)OO, which account for approx. 50%. In addition, the production of hydroxyacetone and HCHO were affected by water vapor as well as the initial NO/MACR ratio. The yields of HCHO were higher under humid conditions than that under dry condition. The yields of hydroxyacetone were higher under humid conditions at low-NOx level, while lower at high-NOx level. The reasonable explanation for the lower hydroxyacetone yield under humid conditions at high-NOx level is that water vapor promotes the production of methacrolein nitrate in the reaction of HOCH2C(CH3)(OO)CHO with NO due to the peroxy radical-water complex formation, which was evidenced by calculational results. And the minimum equilibrium constant of this water complex formation was estimated to be 1.89*10-18cm3/molecule. These results provide new insights into the MACR oxidation mechanism and the effects of water vapor. PMID- 29628076 TI - An ex vivo assay for screening glucocorticoid signaling disruption based on glucocorticoid-response gene transcription in Xenopus tails. AB - There is a pressing need for developing in vivo or ex vivo assays to screen the glucocorticoid (GC) signaling disruption of chemicals. Thus, we aimed to establish an ex vivo assay for screening GC signaling disruption based on the GC response gene transcription in Xenopus laevis tails cultured ex vivo. Firstly, we investigated effects of corticosterone (CORT, a main GC in frogs) on GC-response gene expression, and determined the six genes as molecular endpoints for assaying the GC signaling disruption. CORT in the range of 1.56-400nmol/L was found to up regulate transcription of the six GC-response genes, exhibiting comparable or higher sensitivity than previously reported assays. To validate this ex vivo assay, then, we examined effects of dexamethasone (a known GC signaling agonist) on GC-response gene expression. Dexamethasone displayed an agonistic action in a concentration-dependent manner, further demonstrating the efficiency of the established assay. Finally, we applied the ex vivo assay to evaluate the GC signaling disruption of bisphenol A (BPA). In accordance with previous reports, we found a concentration-dependent agonistic activity of BPA, showing that the established assay is effective for detecting the GC signaling disrupting activity of environmental chemicals. Correspondingly, the GC signaling agonistic actions of CORT and BPA in ex vivo tails accorded with the observations in vivo, indicating that the ex vivo assay is able to detect the actions of chemicals in vivo. Overall, we established an ex vivo assay that can effectively screen GC signaling disruption of environmental chemicals. PMID- 29628077 TI - Characteristics of microbial community involved in early biofilms formation under the influence of wastewater treatment plant effluent. AB - Effluents from wastewater treatment plants (WWTPs) containing microorganisms and residual nutrients can influence the biofilm formation. Although the process and mechanism of bacterial biofilm formation have been well characterized, little is known about the characteristics and interaction of bacteria, archaea and eukaryotes in the early colonization, especially under the influence of WWTP effluent. The aim of this study was to characterize the important bacterial, archaeal and eukaryotic species in the early stage of biofilm formation downstream of the WWTP outlet. Water and biofilm samples were collected 24 and 48hr after the deposition of bio-cords in the stream. Illumina Miseq sequencing of the 16S and 18S rDNA showed that, among the three domains, the bacterial biofilm community had the largest alpha and beta diversity. The early bacterial colonizers appeared to be "biofilm-specific", with only a few dominant operational taxonomic units (OTUs) shared between the biofilm and the ambient water environment. Alpha-proteobacteria and Ciliophora tended to dominate the bacterial and eukaryotic communities, respectively, of the early biofilm already at 24hr, whereas archaea played only a minor role during the early stage of colonization. The network analysis showed that the three domains of microbial community connected highly during the early colonization and it might be a characteristic of the microbial communities in the biofilm formation process where co-occurrence relationships could drive coexistence and diversity maintenance within the microbial communities. PMID- 29628078 TI - Spatial-temporal characteristics of haze and vertical distribution of aerosols over the Yangtze River Delta of China. AB - Variation of haze events occurred in the Yangtze River Delta (YRD) of China, the characteristics of meteorological elements and the vertical distribution of aerosols during haze episodes were analyzed by utilizing data of ground observation, radiosonde and CALIPSO. The results illustrate that the frequency of haze events between 1981 and 2010 peaked in winter but bottomed out in summer and decreased from north to south in the YRD region, reaching at the lowest point in "low frequency center" - Shanghai. When haze happened, the most seriously affected area was 2-4km above the ground and the concentrated range of total backscattering coefficient (TBC) that decreased with altitude was 0.8*10-3-2.5*10 3km-1.sr-1. Particulate depolarization ratio (PDR) was less than 40% in a large part and 93% aerosols over the YRD area were regular particles, while the irregular ones concentrated on 2km above the surface and the irregularity rose up but the diversity diminished when altitude increased. Color ratio (CR) was lower than 1.2 mostly at all altitudes and distributed asymmetrically above the ground. Nearly 80% aerosols under 10km were fine particles (CR<1.0) and 22.54% coarse particles (CR>1.0) clustered at 2-4km. Large particles (CR>1.2) aggregated in lower troposphere massively yet relatively smaller ones gathered in middle and upper troposphere. In the YRD region, aerosols with more powerful capabilities were wider and less regular than the ones of Northwestern China. PMID- 29628079 TI - Allium cepa root tip assay in assessment of toxicity of magnesium oxide nanoparticles and microparticles. AB - Allium cepa bioassay had been used from decades for the assessment of toxicants and their harmful effects on environment as well as human health. Magnesium oxide (MgO) particles are being utilized in different fields. However, reports on the adverse effects of MgO nanoparticles on the environment and mankind are scarce. Hence, the toxicity of MgO particles is of concern because of their increased utilization. In the current study, A. cepa was used as an indicator to assess the toxicological efficiency of MgO nano- and microparticles (NPs and MPs) at a range of exposure concentrations (12.5, 25, 50, and 100MUg/mL). The toxicity was evaluated by using various bioassays on A. cepa root tip cells such as comet assay, oxidative stress and their uptake/internalization profile. Results indicated a dose dependent increase in chromosomal aberrations and decrease in mitotic index (MI) when compared to control cells and the effect was more significant for NPs than MPs (at p<0.05). Comet analysis revealed that the Deoxyribonucleic acid (DNA) damage in terms of percent tail DNA ranged from 6.8 30.1 over 12.5-100MUg/mL concentrations of MgO NPs and was found to be significant at the exposed concentrations. A significant increase in generation of hydrogen peroxide and superoxide radicals was observed in accordance with the lipid peroxidation profile in both MgO NPs and MPs treated plants when compared with control. In conclusion, this investigation revealed that MgO NPs exposure exhibited greater toxicity on A. cepa than MPs. PMID- 29628080 TI - Genotoxicity of gold nanoparticles functionalized with indolicidin towards Saccharomyces cerevisiae. AB - The toxic effects of gold nanoparticles surface-functionalized with the antimicrobial peptide indolicidin (AuNPs-indolicidin) towards the yeast Saccharomyces cerevisiae, one of the major eukaryotic model organisms, have been evaluated. Growth and survival, genotoxicity, as measured by comet assay, and expression of the YCA1, an apoptosis indicating gene, following 72hr exposure of yeast to AuNPs-indolicidin, and to AuNPs and indolicidin alone have been examined. The gold nanoparticles exerted toxicity with DNA damage, accompanied by reactive oxygen species production (ROS), but they do not inhibit yeast growth and viability. Genotoxicity was less pronounced for surface-functionalized nanoparticles, showing that S. cerevisiae is quite resistant to the complex AuNPs indolicidin. A progressive reduction of the genotoxic effect was observed along 72hr exposure, presumably due to the activation of DNA repair mechanisms. These findings suggest the occurrence of a physiological protective response of S. cerevisiae towards nanoparticles, thereby providing useful information to the assessment of the environmental impact of metal nanoparticles. PMID- 29628081 TI - Biogeochemical cycling of metals impacting by microbial mobilization and immobilization. AB - Microbial mobilization and immobilization processes can affect the bioavailability and mobility of metals thereby influencing their toxicity and can therefore be utilized to treat solid and liquid wastes contaminated by metals. However, the microbial mobilization and immobilization of metals depends on the microbial metabolism, the environment conditions. In this review, mobilization and immobilization of metals are discussed with regard to the presence and function of involved microorganisms and in relation to applications such as bioleaching. Furthermore, the biosorption process is evaluated as a possible approach for microbial immobilization of metal on the basis of four mechanisms: (1) physical adsorption, (2) ion exchange, (3) complexation, and (4) microprecipitation. In addition, sulfide precipitation by sulfate reducing bacteria was included as an example of an application of microbial immobilization. Based on the evaluation and recommendations in this paper, bioremediation strategies for metals can be improved thus increasing the opportunity for field applications. PMID- 29628082 TI - Epithelial-mesenchymal transition effect of fine particulate matter from the Yangtze River Delta region in China on human bronchial epithelial cells. AB - Epidemiological studies have demonstrated that fine particulate matter (PM2.5) exposure causes airway inflammation, which may lead to lung cancer. The activation of epithelial-mesenchymal transition (EMT) is assumed to be a crucial step in lung tumor metastasis and development. We assessed the EMT effect of low concentrations (0, 0.1, 1.0, and 5.0MUg/mL) of PM2.5 organic extract on a human bronchial epithelial cell line (BEAS-2B). PM2.5 samples were collected from three cities (Shanghai, Ningbo, and Nanjing) in the Yangtze River Delta (YRD) region in autumn 2014. BEAS-2B cells were exposed to the PM2.5 extract to assess cell viability, invasion ability as well as the relative mRNA and protein expressions of EMT markers. Our findings revealed that BEAS-2B cells changed from the epithelial to mesenchymal phenotype after exposure. In all groups, PM2.5 exposure dose-dependently decreased the expression of E-cadherin and increased the expression of Vimentin. The key transcription factors, including ZEB1 and Slug, were significantly up-regulated upon exposure. These results indicated that the PM2.5 organic extract induced different degrees of EMT progression in BEAS-2B cells. The cell invasion ability increased in a concentration-dependent manner after 48hr of treatment with the extract. This study offers a novel insight into the effects of PM2.5 on EMT and the potential health risks associated with PM2.5 in the YRD region. PMID- 29628083 TI - Treatment of coking wastewater by a novel electric assisted micro-electrolysis filter. AB - A newly designed electric assisted micro-electrolysis filter (E-ME) was developed to investigate its degradation efficiency for coking wastewater and correlated characteristics. The performance of the E-ME system was compared with separate electrolysis (SE) and micro-electrolysis (ME) systems. The results showed a prominent synergistic effect on COD removal in E-ME systems. Gas chromatography/mass spectrometry (GC-MS) analysis confirmed that the applied electric field enhanced the degradation of phenolic compounds. Meanwhile, more biodegradable oxygen-bearing compounds were detected. SEM images of granular activated carbon (GAC) showed that inactivation and blocking were inhibited during the E-ME process. The effects of applied voltage and initial pH in E-ME systems were also studied. The best voltage value was 1V, but synergistic effects existed even with lower applied voltage. E-ME systems exhibited some pH buffering capacity and attained the best efficiency in neutral media, which means that there is no need to adjust pH prior to or during the treatment process. Therefore, E-ME systems were confirmed as a promising technology for treatment of coking wastewater and other refractory wastewater. PMID- 29628084 TI - Comparative study of carbonic anhydrase activity in waters among different geological eco-environments of Yangtze River basin and its ecological significance. AB - This study provides the presence of carbonic anhydrase (CA) activity in waters of the Yangtze River basin, China, as well as the correlation of CA activity with HCO3- concentration and CO2 sink flux. Different degrees of CA activity could be detected in almost all of the water samples from different geological eco environments in all four seasons. The CA activity of water samples from karst areas was significantly higher than from non-karst areas (PP3- concentration (r=0.672, P2 sink flux (r=0.602, P=0.076) in karst areas. This suggests that CA in waters might have a promoting effect on carbon sinks for atmospheric CO2 in karst river basins. In conditions of similar geological type, higher CA activity was generally detected in water samples taken from areas that exhibited better eco-environments, implying that the CA activity index of waters could be used as an indicator for monitoring ecological environments and protection of river basins. These findings suggest that the role of CA in waters in the karst carbon sink potential of river basins is worthy of further in-depth studies. PMID- 29628085 TI - The effects of autophagy on vascular endothelial cells induced by airborne PM2.5. AB - The purpose of this study was to examine the direct toxicity of PM2.5 collected from Beijing on human umbilical vein endothelial cells (HUVEC). A Cell Counting Kit 8 (CCK8) assay demonstrated that PM2.5 exposure decreased the proliferation of HUVECs in a dose-dependent manner. We also found that PM2.5 exposure induced autophagy in HUVECs, as evidenced by: (1) an increased number of double-membrane vesicles; (2) enhanced conversion and punctuation of the microtubule-associated protein light chain 3 (LC3); and (3) decreased levels of the selective autophagy substrate p62 in a time-dependent manner. Furthermore, promoting autophagy in PM2.5-exposed HUVECs with rapamycin increased the cell survival rate, whereas inhibiting autophagy via 3-methyladenine significantly decreased cell survival. These results demonstrate that PM2.5 exposure can induce cytotoxicity and autophagy in HUVECs and that autophagy play a protective role against PM2.5 induced cytotoxicity. The findings of the present study imply a direct toxic effect of PM2.5 on HUVECs and provide novel insight into the mechanism of cardiovascular diseases caused by PM2.5 exposure. PMID- 29628086 TI - Chemical characteristics and source apportionment of PM2.5 between heavily polluted days and other days in Zhengzhou, China. AB - PM2.5 samples were collected in Zhengzhou during 3years of observation, and chemical characteristics and source contribution were analyzed. Approximately 96% of the daily PM2.5 concentrations and annual average values exceeded the Chinese National Ambient Air Quality Daily and Annual Standards, indicating serious PM2.5 pollution. The average concentration of water-soluble inorganic ions was 2.4 times higher in heavily polluted days (daily PM2.5 concentrations>250MUg/m3 and visibility <3km) than that in other days, with sulfate, nitrate, and ammonium as major ions. According to the ratio of NO3-/SO42-, stationary sources are still the dominant source of PM2.5 and vehicle emission could not be ignored. The ratio of secondary organic carbon to organic carbon indicated that photochemical reactivity in heavily polluted days was more intense than in other days. Crustal elements were the most abundant elements, accounting for more than 60% of 23 elements. Chemical Mass Balance results indicated that the contributions of major sources (i.e., nitrate, sulfate, biomass, carbon and refractory material, coal combustion, soil dust, vehicle, and industry) of PM2.5 were 13%, 16%, 12%, 2%, 14%, 8%, 7%, and 8% in heavily polluted days and 20%, 18%, 9%, 2%, 27%, 14%, 15%, and 9% in other days, respectively. Extensive combustion activities were the main sources of polycyclic aromatic hydrocarbons during the episode (Jan 1-9, 2015) and the total benzo[a]pyrene equivalency concentrations in heavily polluted days present significant health threat. Because of the effect of regional transport, the pollution level of PM2.5 in the study area was aggravated. PMID- 29628087 TI - Effect of Trichoderma viride biofertilizer on ammonia volatilization from an alkaline soil in Northern China. AB - Ammonia (NH3) volatilization is one of the primary pathways of nitrogen (N) loss from soils after chemical fertilizer is applied, especially from the alkaline soils in Northern China, which results in lower efficiency for chemical fertilizers. Therefore, we conducted an incubation experiment using an alkaline soil from Tianjin (pH8.37-8.43) to evaluate the suppression effect of Trichoderma viride (T. viride) biofertilizer on NH3 volatilization, and compared the differences in microbial community structure among all samples. The results showed that viable T. viride biofertilizer (T) decreased NH3 volatilization by 42.21% compared with conventional fertilizer ((CK), urea), while nonviable T. viride biofertilizer (TS) decreased NH3 volatilization by 32.42%. NH3 volatilization was significantly higher in CK and sweet potato starch wastewater (SPSW) treatments during the peak period. T. viride biofertilizer also improved the transfer of ammonium from soil to sweet sorghum. Plant dry weights increased 91.23% and 61.08% for T and TS, respectively, compared to CK. Moreover, T. viride biofertilizer enhanced nitrification by increasing the abundance of ammonium oxidizing archaea (AOA) and ammonium-oxidizing bacteria (AOB). The results of high-throughput sequencing indicated that the microbial community structure and composition were significantly changed by the application of T. viride biofertilizer. This study demonstrated the immense potential of T. viride biofertilizer in reducing NH3 volatilization from alkaline soil and simultaneously improving the utilization of fertilizer N by sweet sorghum. PMID- 29628088 TI - Managed grassland alters soil N dynamics and N2O emissions in temperate steppe. AB - Reclamation of degraded grasslands as managed grasslands has been increasingly accelerated in recent years in China. Land use change affects soil nitrogen (N) dynamics and nitrous oxide (N2O) emissions. However, it remains unclear how large scale grassland reclamation will impact the grassland ecosystem as a whole. Here, we investigated the effects of the conversion from native to managed grasslands on soil N dynamics and N2O emissions by field experiments in Hulunber in northern China. Soil (0-10cm), nitrate (NO3-), ammonium (NH4+), and microbial N were measured in plots in a temperate steppe (Leymus chinensis grassland) and two managed grasslands (Medicago sativa and Bromus inermis grasslands) in 2011 and 2012. The results showed conversion of L. chinensis grassland to M. sativa or B. inermis grasslands decreased concentrations of NO3--N, but did not change NH4+-N. Soil microbial N was slightly decreased by the conversion of L. chinensis grassland to M. sativa, but increased by the conversion to B. inermis. The conversion of L. chinensis grassland to M. sativa (i.e., a legume grass) increased N2O emissions by 26.2%, while the conversion to the B. inermis (i.e., a non-legume grass) reduced N2O emissions by 33.1%. The conversion from native to managed grasslands caused large created variations in soil NO3--N and NH4+-N concentrations. Net N mineralization rates did not change significantly in growing season or vegetation type, but to net nitrification rate. These results provide evidence on how reclamation may impact the grassland ecosystem in terms of N dynamics and N2O emissions. PMID- 29628089 TI - Effect of TiO2 nanoparticle aggregation on marine microalgae Isochrysis galbana. AB - TiO2 nanoparticles (NPs) could adversely impact aquatic ecosystems. However, the aggregation of these NPs could attenuate this effect. In this work, the biological effects of TiO2 NPs on a marine microalgae Isochrysis galbana were investigated. The aggregation kinetics of TiO2 NPs under different conditions was also investigated to determine and understand these effects. Results showed that, though TiO2 NPs had no obvious impact on the size and reproducibility of algal cells under testing conditions, they caused a negative effect on algal chlorophyll, which led to a reduction in photosynthesis. Furthermore, fast aggregation of TiO2 NPs occurred under all conditions, especially at the pH close to the pHzpc. Increasing ionic strength and NP concentration also enhanced the aggregation rate. The aggregation and the following sedimentation of TiO2 NPs reduced their adverse effects on I. galbana. PMID- 29628090 TI - Effect of air-exposed biocathode on the performance of a Thauera-dominated membraneless single-chamber microbial fuel cell (SCMFC). AB - To investigate the effect of air-exposed biocathode (AEB) on the performance of single-chamber microbial fuel cell (SCMFC), wastewater quality, bioelectrochemical characteristics and the electrode biofilms were researched. It was demonstrated that exposing the biocathode to air was beneficial to nitrogen removal and current generation. In Test 1 of 95% AEB, removal rates of ammonia, total nitrogen (TN) and chemical oxygen demand (COD) reached 99.34%+/-0.11%, 99.34%+/-0.10% and 90.79%+/-0.12%, respectively. The nitrogen removal loading rates were 36.38gN/m3/day. Meanwhile, current density and power density obtained at 0.7A/m3 and 104mW/m3 respectively. Further experiments on open-circuit (Test 2) and carbon source (Test 3) indicated that this high performance could be attributed to simultaneous biological nitrification/denitrification and aerobic denitrification, as well as bioelectrochemical denitrification. Results of community analysis demonstrated that both microbial community structures on the surface of the cathode and in the liquid of the chamber were different. The percentage of Thauera, identified as denitrifying bacteria, maintained at a high level of over 50% in water, but decreased gradually in the AEB. Moreover, the genus Nitrosomonas, Alishewanella, Arcobacter and Rheinheimera were significantly enriched in the AEB, which might contribute to both enhancement of nitrogen removal and electricity generation. PMID- 29628091 TI - Critical review of EPS production, synthesis and composition for sludge flocculation. AB - Extracellular polymeric substances (EPS) produced by microorganisms represent biological macromolecules with unfathomable potentials and they are required to be explored further for their potential application as a bioflocculant in various wastewater sludge treatment. Although several studies already exist on biosynthetic pathways of different classical biopolymers like alginate and xanthan, no dedicated studies are available for EPS in sludge. This review highlights the EPS composition, functionality, and biodegradability for its potential use as a carbon source for production of other metabolites. Furthermore, the effect of various extraction methods (physical and chemical) on compositional, structural, physical and functional properties of microbial EPS has been addressed. The vital knowledge of the effect of extraction method on various important attributes of EPS can help to choose the suitable extraction method depending upon the intended use of EPS. The possible use of different molecular biological techniques for enhanced production of desired EPS was summarized. PMID- 29628092 TI - Identification of a marine woloszynskioid dinoflagellate Biecheleriopsis adriatica and germination of its cysts from southern Chinese coasts. AB - A strain of small-sized dinoflagellates, isolated from the culture of sediment incubation collected from the coastal areas in southern China, has been identified under microscopical observation and rDNA sequence. Surface sediments from two sea areas in the southern Chinese coastal waters were incubated for 20 and 40days, and germinated vegetative cells were observed. The cells were identified as species in the Suessiaceae based on the morphological characteristics, ultrastructural features of the cell, as well as its swimming behavior. The studied strain clusters into a well-supported clade together with six sequences of Biecheleriopsis adriatica in the phylogenetic tree based on the large subunit (LSU) rDNA sequence. Therefore, the strain has been identified as B. adriatica based on morphological observation and phylogenetic analysis. B. adriatica was the dominant dinoflagellate species in the germinated phytoplankton community from both sea areas, which contributed 50%-83% to the total germinated dinoflagellates averagely. However, B. adriatica has not been reported in previous phytoplankton surveys, and was probably ignored or misidentified due to its small size and thin wall. The frequent and abundant occurrence of B. adriatica in the germinated phytoplankton community of many sea areas of the southern Chinese coastal waters suggests its wide and abundant distribution in these sea areas. PMID- 29628093 TI - Anaerobic treatment of source-separated domestic bio-wastes with an improved upflow solid reactor at a short HRT. AB - Anaerobic treatment is the core technology for resource and energy recovery from source-separated domestic bio-wastes. The higher efficiency of an improved upflow solid reactor (IUSR) designed in this study was demonstrated in the treatment of concentrated black water and kitchen waste. The highest methane production of 48L/person/day was achieved at the hydraulic retention time (HRT) of 7days, while the other measures of performance at the HRT of 8.3days were better than at the HRT of 7 or 10days, achieving a methane production of 43L/person/day, removal of total chemical oxygen demand (TCOD) of 89%, removal of soluble chemical oxygen demand (SCOD) of 92%, and conversion of chemical oxygen demand (COD) to methane of 71%. It is not recommended to decrease HRT lower than 7days due to the instability of the initial period. The concentrations of volatile fatty acids (VFAs) in the IUSR were less than 10mg/L, indicating that the anaerobic process was stable. Sludge bed development showed that sludge bed with high microbial activity was formed in the bottom and that the precipitation zone of effluents formed should preferably occupy 30% of the height of the IUSR. The effluents of the IUSR could be used for irrigation in agriculture in combination with a settling tank accompanied by disinfection to remove solids and pathogens. PMID- 29628094 TI - Low-temperature conversion of ammonia to nitrogen in water with ozone over composite metal oxide catalyst. AB - As one of the most important water pollutants, ammonia nitrogen emissions have increased year by year, which has attracted people's attention. Catalytic ozonation technology, which involves production of .OH radical with strong oxidation ability, is widely used in the treatment of organic-containing wastewater. In this work, MgO-Co3O4 composite metal oxide catalysts prepared with different fabrication conditions have been systematically evaluated and compared in the catalytic ozonation of ammonia (50mg/L) in water. In terms of high catalytic activity in ammonia decomposition and high selectivity for gaseous nitrogen, the catalyst with MgO-Co3O4 molar ratio 8:2, calcined at 500 degrees C for 3hr, was the best one among the catalysts we tested, with an ammonia nitrogen removal rate of 85.2% and gaseous nitrogen selectivity of 44.8%. In addition, the reaction mechanism of ozonation oxidative decomposition of ammonia nitrogen in water with the metal oxide catalysts was discussed. Moreover, the effect of coexisting anions on the degradation of ammonia was studied, finding that SO42- and HCO3- could inhibit the catalytic activity while CO32- and Br- could promote it. The presence of coexisting cations had very little effect on the catalytic ozonation of ammonia nitrogen. After five successive reuses, the catalyst remained stable in the catalytic ozonation of ammonia. PMID- 29628095 TI - A bibliometric review of nitrogen research in eutrophic lakes and reservoirs. AB - The global application of nitrogen is far greater than phosphorus, and it is widely involved in the eutrophication of lakes and reservoirs. We used a bibliometric method to quantitatively and qualitatively evaluate nitrogen research in eutrophic lakes and reservoirs to reveal research developments, current research hotspots, and emerging trends in this area. A total of 2695 articles in the past 25years from the online database of the Scientific Citation Index Expended (SCI-Expanded) were analyzed. Articles in this area increased exponentially from 1991 to 2015. Although the USA was the most productive country over the past 25years, China achieved the top position in terms of yearly publications after 2010. The most active keywords related to nitrogen in the past 25years included phosphorus, nutrients, sediment, chlorophyll-a, carbon, phytoplankton, cyanobacteria, water quality, modeling, and stable isotopes, based on analysis within 5-year intervals from 1991 to 2015 as well as the entire past 25years. In addition, researchers have drawn increasing attention to denitrification, climate change, and internal loading. Future trends in this area should focus on: (1) nutrient amounts, ratios, and major nitrogen sources leading to eutrophication; (2) nitrogen transformation and the bioavailability of different nitrogen forms; (3) nitrogen budget, mass balance model, control, and management; (4) ecosystem responses to nitrogen enrichment and reduction, as well as the relationships between these responses; and (5) interactions between nitrogen and other stressors (e.g., light intensity, carbon, phosphorus, toxic contaminants, climate change, and hydrological variations) in terms of eutrophication. PMID- 29628096 TI - Electronic-property dependent interactions between tetracycline and graphene nanomaterials in aqueous solution. AB - Understanding the interactions between graphene nanomaterials (GNMs) and antibiotics in aqueous solution is critical to both the engineering applications of GNMs and the assessment of their potential impact on the fate and transport of antibiotics in the aquatic environment. In this study, adsorption of one common antibiotic, tetracycline, by graphene oxide (GO) and reduced graphene oxide (RGO) was examined with multi-walled carbon nanotubes (MWCNTs) and graphite as comparison. The results showed that the tetracycline adsorption capacity by the four selected carbonaceous materials on the unit mass basis followed an order of GO>RGO>MWCNTs>graphite. Upon normalization by surface area, graphite, RGO and MWCNTs had almost the same high tetracycline adsorption affinity while GO exhibited the lowest. We proposed pi-electron-property dependent interaction mechanisms to explain the observed different adsorption behaviors. Density functional theory (DFT) calculations suggested that the oxygen-containing functional groups on GO surface reduced its pi-electron-donating ability, and thus decreased the pi-based interactions between tetracycline and GO surface. Comparison of adsorption efficiency at different pH indicated that electrostatic interaction also played an important role in tetracycline-GO interactions. Site energy analysis confirmed a highly heterogeneous distribution of the binding sites and strong tetracycline binding affinity of GO surface. PMID- 29628097 TI - Sustainable green technology on wastewater treatment: The evaluation of enhanced single chambered up-flow membrane-less microbial fuel cell. AB - This study demonstrated the potential of single chamber up-flow membrane-less microbial fuel cell (UFML-MFC) in wastewater treatment and power generation. The purpose of this study was to evaluate and enhance the performance under different operational conditions which affect the chemical oxygen demand (COD) reduction and power generation, including the increase of KCl concentration (MFC1) and COD concentration (MFC2). The results showed that the increase of KCl concentration is an important factor in up-flow membrane-less MFC to enhance the ease of electron transfer from anode to cathode. The increase of COD concentration in MFC2 could led to the drop of voltage output due to the prompt of biofilm growth in MFC2 cathode which could increase the internal resistance. It also showed that the COD concentration is a vital issue in up-flow membrane-less MFC. Despite the COD reduction was up to 96%, the power output remained constrained. PMID- 29628098 TI - Preparation and properties of chitosan-metal complex: Some factors influencing the adsorption capacity for dyes in aqueous solution. AB - Chitosan-metal complexes have been widely studied in wastewater treatment, but there are still various factors in complex preparation which are collectively responsible for improving the adsorption capacity need to be further studied. Thus, this study investigates the factors affecting the adsorption ability of chitosan-metal complex adsorbents, including various kinds of metal centers, different metal salts and crosslinking degree. The results show that the chitosan Fe(III) complex prepared by sulfate salts exhibited the best adsorption efficiency (100%) for various dyes in very short time duration (10min), and its maximum adsorption capacity achieved 349.22mg/g. The anion of the metal salt which was used in preparation played an important role to enhance the adsorption ability of chitosan-metal complex. SO42- ions not only had the effect of crosslinking through electrostatic interaction with amine group of chitosan polymer, but also could facilitate the chelation of metal ions with chitosan polymer during the synthesis process. Additionally, the pH sensitivity and the sensitivity of ionic environment for chitosan-metal complex were analyzed. We hope that these factors affecting the adsorption of the chitosan-metal complex can help not only in optimizing its use but also in designing new chitosan-metal based complexes. PMID- 29628099 TI - Protecting the photosynthetic performance of snap bean under free air ozone exposure. AB - Tropospheric ozone (O3) is a major air pollutant and causes serious injury to vegetation. To protect sensitive plants from O3 damage, several agrochemicals have been assessed, including cytokinin (e.g., kinetin, KIN) and ethylenediurea (EDU) with cytokinin-like activity. In higher plant, leaves are primarily injured by O3 and protective agrochemicals are often applied by leaf spraying. To our knowledge, the mitigating abilities of EDU and KIN have not been compared directly in a realistic setup. In the present research, impacts of elevated O3 (2* ambient O3, 24hr per day, for 8days) on an O3 sensitive line (S156) of snap bean (Phaseolus vulgaris), which is often used for biomonitoring O3 pollution, were studied in a free air controlled exposure system. The day before starting the O3 exposure, plants were sprayed with a solution of EDU (300ppm), KIN (1mmol/L) or distilled water, to compare their protective abilities. The results demonstrated that 2* ambient O3 inhibited net photosynthetic rate and stomatal conductance, increased the minimal fluorescence yield of the dark-adapted state, decreased the maximal quantum yield of PSII photochemistry, and led to visible injury. KIN and EDU alleviated the reduction of the photosynthetic performance, and visible injury under O3 fumigation. The plants sprayed with EDU showed greater ability to mitigate the O3 damage than those sprayed with KIN. Chlorophyll fluorescence imaging may have detected more precisely the differences in O3 response across the leaf than the conventional fluorometer. PMID- 29628100 TI - Competitive effects of humic acid and wastewater on adsorption of Methylene Blue dye by activated carbon and non-imprinted polymers. AB - Natural organic matter (NOM), present in natural waters and wastewater, decreases adsorption of micropollutants, increasing treatment costs. This research investigated mechanisms of competition for non-imprinted polymers (NIPs) and activated carbon with humic acid and wastewater. Three different types of activated carbons (Norit PAC 200, Darco KB-M, and Darco S-51) were used for comparison with the NIP. The lower surface area and micropore to mesopore ratio of the NIP led to decreased adsorption capacity in comparison to the activated carbons. In addition, experiments were conducted for single-solute adsorption of Methylene Blue (MB) dye, simultaneous adsorption with humic acid and wastewater, and pre-loading with humic acid and wastewater followed by adsorption of MB dye using NIP and Norit PAC 200. Both the NIP and PAC 200 showed significant decreases of 27% for NIP (p=0.087) and 29% for PAC 200 (p=0.096) during simultaneous exposure to humic acid and MB dye. There was no corresponding decrease for NIP or PAC 200 pre-loaded with humic acid and then exposed to MB. In fact, for PAC 200, the adsorption capacity of the activated carbon increased when it was pre-loaded with humic acid by 39% (p=0.0005). For wastewater, the NIP showed no significant increase or decrease in adsorption capacity during either simultaneous exposure or pre-loading. The adsorption capacity of PAC 200 increased by 40% (p=0.001) for simultaneous exposure to wastewater and MB. Pre loading with wastewater had no effect on MB adsorption by PAC 200. PMID- 29628101 TI - Theoretical study on the formation mechanism of polychlorinated dibenzothiophenes/thianthrenes from 2-chlorothiophenol molecules. AB - Homogeneous formation of polychlorinated dibenzothiophenes/thianthrenes (PCDT/TAs), sulfurated compounds analogous to polychlorinated dibenzo-p dioxin/dibenzofurans (PCDD/Fs), has been well-documented to occur via radical radical coupling reactions from chlorinated thiophenol precursors. However, the current understanding of the formation mechanism of PCDT/TAs is exclusively limited to the inherent point of view that chlorothiophenoxy radicals act as the only required intermediates for PCDT/TAs. This study investigates reaction pathways for the formation of PCDT/TAs involving two new types of radical species, i.e., substituted phenyl radicals and substituted thiophenoxyl diradicals. Taking 2-chlorothiophenol (2-CTP) as a model compound for chlorothiophenols, we found that apart from the mostly discussed chlorothiophenoxy radicals, substituted phenyl radicals and substituted thiophenoxyl diradicals could also be readily formed via the reaction of 2-CTP with H radicals. Furthermore, direct self- and cross-coupling of these radicals can result in the formation of PCDT/TAs, including 1-monochlorothianthrene (1 MCTA), 1,6-dichlorothianthrene (1,6-DCTA), 4,6-dichlorodibenzothiophene (4,6 DCDT) and 1,6-dichlorodibenzothiophene (1,6-DCDT). The pathways proposed in this work are proven to be both thermodynamically and kinetically favorable. Particularly, comparisons were made between the formation mechanisms of sulfurated and oxygenated dioxin systems from an energetic point view, showing that replacing oxygen with sulfur atoms greatly reduces the activation barriers of the rate-controlling steps involved in the PCDT/TA formation processes compared with those involved for PCDD/Fs. The calculated results in this work may improve our understanding of the formation mechanism of PCDT/TAs from chlorothiophenol precursors and should be informative to environmental scientists. PMID- 29628102 TI - Mesoporous WO3-graphene photocatalyst for photocatalytic degradation of Methylene Blue dye under visible light illumination. AB - Advanced oxidation technologies are a friendly environmental approach for the remediation of industrial wastewaters. Here, one pot synthesis of mesoporous WO3 and WO3-graphene oxide (GO) nanocomposites has been performed through the sol-gel method. Then, platinum (Pt) nanoparticles were deposited onto the WO3 and WO3-GO nanocomposite through photochemical reduction to produce mesoporous Pt/WO3 and Pt/WO3-GO nanocomposites. X-ray diffraction (XRD) findings exhibit a formation of monoclinic and triclinic WO3 phases. Transmission Electron Microscope (TEM) images of Pt/WO3-GO nanocomposites exhibited that WO3 nanoparticles are obviously agglomerated and the particle sizes of Pt and WO3 are ~10nm and 20-50nm, respectively. The mesoporous Pt/WO3 and Pt/WO3-GO nanocomposites were assessed for photocatalytic degradation of Methylene Blue (MB) as a probe molecule under visible light illumination. The findings showed that mesoporous Pt/WO3, WO3-GO and Pt/WO3-GO nanocomposites exhibited much higher photocatalytic efficiencies than the pure WO3. The photodegradation rates by mesoporous Pt/WO3-GO nanocomposites are 3, 2 and 1.15 times greater than those by mesoporous WO3, WO3 GO, and Pt/WO3, respectively. The key factors of the enhanced photocatalytic performance of Pt/WO3-GO nanocomposites could be explained by the highly freedom electron transfer through the synergetic effect between WO3 and GO sheets, in addition to the Pt nanoparticles that act as active sites for O2 reduction, which suppresses the electron hole pair recombination in the Pt/WO3-GO nanocomposites. PMID- 29628103 TI - Rates and processes affecting As speciation and mobility in lake sediments during aging. AB - Sediments from an arsenic (As) contaminated groundwater vent site were used to investigate As(III) binding, transformation and redistribution in native and iron oxide amended lake sediments using aging spiked batch reactions and a sequential extraction procedure that maintains As(V) and As(III) speciation. In the native sediments, fractionation analysis revealed that 10% of the spiked As(III) remained intact after a 32-day aging experiment and was predominantly adsorbed to the strongly sorbed (NH4H2PO4 extractable) and amorphous Fe oxide bound (H3PO4 extractable) fractions. Kinetic modelling of the experimental results allowed identifying the dominant reaction path for depletion of dissolved As(III) to As(III) absorbed on to the solid phase, followed by oxidation in the solid phase. Arsenite was initially adsorbed primarily to the easily exchangeable fraction ((NH4)2SO4 extractable), then rapidly transformed into As(V) and redistributed to the strongly sorbed and amorphous Fe oxide bound fractions. Oxidation of As(III) in recalcitrant fractions was less efficient. The iron oxide amendments illustrated the controls that iron oxides can have on As(III) binding and transformation rates. In goethite amended samples As(III) oxidation was faster and primarily occurred in the strongly sorbed and amorphous Fe oxide bound fractions. In these samples, 19.3MUg Mn was redistributed (compared to the native sediment) from the easily exchangeable and crystalline Fe oxide bound fractions to the strongly sorbed and amorphous Fe oxide bound fractions, indicating that goethite may act as a catalyst for Mn(II) oxidation, thereby producing sorbed Mn(III/IV), which then appears to be involved in rapidly oxidizing As(III). PMID- 29628104 TI - Potential of secondary aerosol formation from Chinese gasoline engine exhaust. AB - Light-duty gasoline vehicles have drawn public attention in China due to their significant primary emissions of particulate matter and volatile organic compounds (VOCs). However, little information on secondary aerosol formation from exhaust for Chinese vehicles and fuel conditions is available. In this study, chamber experiments were conducted to quantify the potential of secondary aerosol formation from the exhaust of a port fuel injection gasoline engine. The engine and fuel used are common in the Chinese market, and the fuel satisfies the China V gasoline fuel standard. Substantial secondary aerosol formation was observed during a 4-5hr simulation, which was estimated to represent more than 10days of equivalent atmospheric photo-oxidation in Beijing. As a consequence, the extreme case secondary organic aerosol (SOA) production was 426+/-85mg/kg-fuel, with high levels of precursors and OH exposure. The low hygroscopicity of the aerosols formed inside the chamber suggests that SOA was the dominant chemical composition. Fourteen percent of SOA measured in the chamber experiments could be explained through the oxidation of speciated single-ring aromatics. Unspeciated precursors, such as intermediate-volatility organic compounds and semi-volatile organic compounds, might be significant for SOA formation from gasoline VOCs. We concluded that reductions of emissions of aerosol precursor gases from vehicles are essential to mediate pollution in China. PMID- 29628105 TI - Nb2O5 nanowires in-situ grown on carbon fiber: A high-efficiency material for the photocatalytic reduction of Cr(VI). AB - Niobium oxide nanowire-deposited carbon fiber (CF) samples were prepared using a hydrothermal method with amorphous Nb2O5.nH2O as precursor. The physical properties of the samples were characterized by means of numerous techniques, including X-ray diffraction (XRD), energy-dispersive spectroscopy (EDS), scanning electron microscopy (SEM), transmission electron microscopy (TEM), selected-area electron diffraction (SAED), UV-visible spectroscopy (UV-vis), N2 adsorption desorption, Fourier transform infrared spectroscopy (FT-IR), and X-ray photoelectron spectroscopy. The efficiency for the removal of Cr(VI) was determined. Parameters such as pH value and initial Cr(VI) concentration could influence the Cr(VI) removal efficiency or adsorption capacity of the Nb2O5/carbon fiber sample obtained after hydrothermal treatment at 160 degrees C for 14hr. The maximal Cr(VI) adsorption capacity of the Nb2O5 nanowire/CF sample was 115mg/g. This Nb2O5/CF sample also showed excellent photocatalytic activity and stability for the reduction of Cr(VI) under UV-light irradiation: the Cr(VI) removal efficiency reached 99.9% after UV-light irradiation for 1hr and there was no significant decrease in photocatalytic performance after the use of the sample for 10 repeated cycles. Such excellent Cr(VI) adsorption capacity and photocatalytic performance was related to its high surface area, abundant surface hydroxyl groups, and good UV-light absorption ability. PMID- 29628106 TI - Single and multiple stressor effect of road deicers and Cu on Atlantic salmon (Salmo salar) alevins from hatching till swim-up. AB - Road salts are frequently used for deicing of roads in the Nordic countries. During snow-melt, the road run-off containing high concentrations of road salt and various metals such as Cu remobilized from sand, silt and dust may negatively influence organisms in downstream receiving water bodies. The present work focuses on the impact of road salt (NaCl) and Cu, separately and in mixtures on Atlantic salmon alevins from hatching till swim-up. The results showed that high road salt concentrations could induce a series of negative effects in alevins such as reduced growth, deformities, delayed swim-up and mortality. For alevins exposed to all tested road salt concentrations (100-1000mg/L), mortality was significantly higher compared to control. In exposure to Cu solutions (5 20MUgCu/L), no effects on growth, morphology, swim-up or mortality of alevins compared to control were observed. In mixture solutions (road salt and Cu), ultrafiltration of the exposure water demonstrated that only 20%-40% of Cu was present as positively charged low molecular mass (LMM) Cu species assumed to be bioavailable. When exposed to road salt and Cu mixtures, negative effects in alevins such as reduced growth, deformities, delayed swim-up and mortality were observed. The overall results indicated that the road salt application could seriously affect sensitive life stages of Atlantic salmon, and application of road salt should be avoided during the late winter-early spring period. PMID- 29628107 TI - Arsenate biotransformation by Microcystis aeruginosa under different nitrogen and phosphorus levels. AB - The arsenate (As(V)) biotransformation by Microcystis aeruginosa in a medium with different concentrations of nitrogen (N) and phosphorus (P) has been studied under laboratory conditions. When 15MUg/L As(V) was added, N and P in the medium showed effective regulation on arsenic (As) metabolism in M. aeruginosa, resulting in significant differences in the algal growth among different N and P treatments. Under 0.2mg/L P treatment, increases in N concentration (4-20mg/L) significantly stimulated the cell growth and therefore indirectly enhanced the production of dimethylarsinic acid (DMA), the main As metabolite, accounting for 71%-79% of the total As in the medium. Meanwhile, 10-20mg/L N treatments accelerated the ability of As metabolization by M. aeruginosa, leading to higher contents of DMA per cell. However, As(V) uptake by M. aeruginosa was significantly impeded by 0.5-1.0mg/L P treatment, resulting in smaller rates of As transformation in M. aeruginosa as well as lower contents of As metabolites in the medium. Our data demonstrated that As(V) transformation by M. aeruginosa was significantly accelerated by increasing N levels, while it was inhibited by increasing P levels. Overall, both P and N play key roles in As(V) biotransformation processes. PMID- 29628108 TI - Comparative toxicity of silver nanoparticles and silver ions to Escherichia coli. AB - : With the increase in silver (Ag)-based products in our lives, it is essential to test the potential toxicity of silver nanoparticles (AgNPs) and silver ions (Ag ions) on living organisms under various conditions. Here, we investigated the toxicity of AgNPs with Ag ions to Escherichia coli K-12 strain under various conditions. We observed that both AgNPs and Ag ions display antibacterial activities, and that Ag ions had higher toxicity to E. coli K-12 strain than AgNPs under the same concentrations. To understand the toxicity of AgNPs at a cellular level, reactive oxygen species (ROS) enzymes were detected for use as antioxidant enzymatic biomarkers. We have also studied the toxicity of AgNPs and Ag ions under various coexistence conditions including: fixed total concentration, with a varied the ratio of AgNPs to Ag ions; fixed the AgNPs concentration and then increased the Ag ions concentration; fixed Ag ions concentration and then increasing the AgNPs concentration. Exposure to AgNPs and Ag ions clearly had synergistic toxicity; however, decreased toxicity (for a fixed AgNPs concentration of 5mg/L, after increasing the Ag ions concentration) to E. coli K-12 strain. AgNPs and Ag ions in the presence of L-cysteine accelerated the bacterial cell growth rate, thereby reducing the bioavailability of Ag ions released from AgNPs under the single and coexistence conditions. Further works are needed to consider this potential for AgNPs and Ag ions toxicity across a range of environmental conditions. ENVIRONMENTAL SIGNIFICANCE STATEMENT: As silver nanoparticles (AgNPs)-based products are being broadly used in commercial industries, an ecotoxicological understanding of the AgNPs being released into the environment should be further considered. Here, we investigate the comparative toxicity of AgNPs and silver ions (Ag ions) to Escherichia coli K 12 strain, a representative ecotoxicological bioreporter. This study showed that toxicities of AgNPs and Ag ions to E. coli K-12 strain display different relationships when existing individually or when coexisting, and in the presence of L-cysteine materials. These findings suggest that the toxicology research of nanomaterials should consider conditions when NPs coexist with and without their bioavailable ions. PMID- 29628110 TI - Photocatalytic properties of P25-doped TiO2 composite film synthesized via sol gel method on cement substrate. AB - TiO2 films have received increasing attention for the removal of organic pollutants via photocatalysis. To develop a simple and effective method for improving the photodegradation efficiency of pollutants in surface water, we herein examined the preparation of a P25-TiO2 composite film on a cement substrate via a sol-gel method. In this case, Rhodamine B (RhB) was employed as the target organic pollutant. The self-generated TiO2 film and the P25-TiO2 composite film were characterized by X-ray diffraction (XRD), N2 adsorption/desorption measurements, scanning electron microscopy (SEM), transmission electron microscopy (TEM), and diffuse reflectance spectroscopy (DRS). The photodegradation efficiencies of the two films were studied by RhB removal in water under UV (ultraviolet) irradiation. Over 4day exposure, the P25 TiO2 composite film exhibited higher photocatalytic performance than the self generated TiO2 film. The photodegradation rate indicated that the efficiency of the P25-TiO2 composite film was enhanced by the addition of the rutile phase Degussa P25 powder. As such, cooperation between the anatase TiO2 and rutile P25 nanoparticles was beneficial for separation of the photo-induced electrons and holes. In addition, the influence of P25 doping on the P25-TiO2 composite films was evaluated. We found that up to a certain saturation point, increased doping enhanced the photodegradation ability of the composite film. Thus, we herein demonstrated that the doping of P25 powders is a simple but effective strategy to prepare a P25-TiO2 composite film on a cement substrate, and the resulting film exhibits excellent removal efficiency in the degradation of organic pollutants. PMID- 29628109 TI - Analysis of the influencing factors of PAEs volatilization from typical plastic products. AB - The primary emphasis of this research was to investigate the foundations of phthalate (PAEs) pollutant source researches and then firstly confirmed the concept of the coefficient of volatile strength, namely phthalate total content in per unit mass and unit surface area of pollutant sources. Through surveying and evaluating the coefficient of volatile strength of PAEs from typical plastic products, this research carried out reasonable classification of PAEs pollutant sources into three categories and then investigated the relationship amongst the coefficient of volatile strength as well as other environmental factors and the concentration level of total PAEs in indoor air measured in environment chambers. Research obtained phthalate concentration results under different temperature, humidity, the coefficient of volatile strength and the closed time through the chamber experiment. In addition, this study further explored the correlation and ratio of influencing factors that affect the concentration level of total PAEs in environment chambers, including environmental factors, the coefficient of volatile strengths of PAEs and contents of total PAEs in plastic products. The research created an improved database system of phthalate the coefficient of volatile strengths of each type of plastic goods, and tentatively revealed that the volatile patterns of PAEs from different typical plastic goods, finally confirmed that the coefficient of volatile strengths of PAEs is a major factor that affects the indoor air total PAEs concentration, which laid a solid foundation for further establishing the volatile equation of PAEs from plastic products. PMID- 29628111 TI - Photocatalytic degradation of aqueous Methyl Orange using nitrogen-doped TiO2 photocatalyst prepared by novel method of ultraviolet-assisted thermal synthesis. AB - A nitrogen-doped titanium dioxide composite photocatalyst (N-TiO2) with heterojunction structures is synthesized by three different approaches: a novel UV-assisted thermal synthesis, annealing, and microwave technique. Photocatalytic activities of synthesized photocatalysts are evaluated by the degradation of Methyl Orange under ultraviolet light types A (UV-A), B (UV-B), and C (UV-C), visible light, and direct sunlight irradiation. Results show that by using N-TiO2 photocatalyst prepared by the UV-assisted thermal synthesis and annealing, the degradation increases by 16.5% and 20.4%, respectively, compared to that by bare TiO2. The best results are obtained at a nitrogen to TiO2 mass ratio of 0.15 (N:TiO2). The enhancement of the photocatalytic activity observed in the visible range is mainly attributed to the increasing separation rate of photogenerated charge carriers. The novel UV-assisted thermal synthesis has produced encouraging results as a preparation method for the nitrogen-doped TiO2 photocatalyst; thus, further studies are recommended for process optimization, immobilization, and scale-up to evaluate its applicability in wastewater treatment. PMID- 29628112 TI - Production of ammonia from plasma-catalytic decomposition of urea: Effects of carrier gas composition. AB - Effects of carrier gas composition (N2/air) on NH3 production, energy efficiency regarding NH3 production and byproducts formation from plasma-catalytic decomposition of urea were systematically investigated using an Al2O3-packed dielectric barrier discharge (DBD) reactor at room temperature. Results show that the presence of O2 in the carrier gas accelerates the conversion of urea but leads to less generation of NH3. The final yield of NH3 in the gas phase decreased from 70.5%, 78.7%, 66.6% and 67.2% to 54.1%, 51.7%, 49.6% and 53.4% for applied voltages of 17, 19, 21 and 23kV, respectively when air was used as the carrier gas instead of N2. From the viewpoint of energy savings, however, air carrier gas is better than N2 due to reduced energy consumption and increased energy efficiency for decomposition of a fixed amount of urea. Carrier gas composition has little influence on the major decomposition pathways of urea under the synergetic effects of plasma and Al2O3 catalyst to give NH3 and CO2 as the main products. Compared to a small amount of N2O formed with N2 as the carrier gas, however, more byproducts including N2O and NO2 in the gas phase and NH4NO3 in solid deposits were produced with air as the carrier gas, probably due to the unproductive consumption of NH3, the possible intermediate HNCO and even urea by the abundant active oxygen species and nitrogen oxides generated in air DBD plasma. PMID- 29628113 TI - [Seasonal flu vaccination for older people: Evaluation of the adjuvanted vaccine. Positioning report]. AB - Flu is a major public health problem, particularly for older people, and creates an important clinical and economic burden. A high mortality rate was reported in Spain during the period 2015 to 2016; 3,101 serious cases were hospitalised with a confirmed diagnosis of flu, of which 11% died (352 cases). Furthermore, financial and health costs are greatly increased by the complications of flu; people aged over 65 years represent approximately 64% of the total costs. Seasonal flu vaccination is the fundamental strategy, as demonstrated by cost benefit and cost-effectiveness studies. A priority objective is to improve the vaccine's immune response and the search for and inclusion of adjuvants and immunostimulants in vaccines is a major line of research. This positioning report evaluates vaccination for older people and the importance of the adjuvanted vaccine in the elderly in strengthening immunogenicity, by means of a critical review of the literature based on the best evidence available on its immunogenicity and effectiveness, and an economic assessment. PMID- 29628114 TI - Measurement and Associations of the Optic Nerve Subarachnoid Space in Normal Tension Glaucoma and Primary Open-Angle Glaucoma. PMID- 29628115 TI - Retrospective analysis of factors associated with the success of stepwise excavation procedure in deep carious lesions. AB - BACKGROUND: Recent scientific evidence regarding the stepwise excavation procedure (SWP) has not addressed the consideration of patient factors when selecting SWP as treatment for deep carious lesions (DCLs). This study assessed patient factors predicting a successful SWP defined as a tooth restored with SWP and did not result in root canal treatment or a dental extraction. METHODS: SWPs completed in 626 patients without symptomatic irreversible pulpitis at the University of Iowa College of Dentistry from January 2004 through December 2012 were evaluated. Patient demographic and tooth-specific characteristics were assessed in their relationship with the main outcome. RESULTS: SWPs had a 75% success rate when evaluated within 36 months of the initial treatment. Findings showed that patients who had successful SWP treatment of DCLs were somewhat younger than patients whose SWP treatment was not successful (mean age, 37.4 years and 40.5 years, respectively; odds ratio, 0.981; 95% confidence interval, 0.967 to 0.994; P = .0058). Patients who returned to their second appointment within 5 to 9 months were more likely to have a successful SWP treatment than those returning sooner than 5 months (odds ratio, 0.338; 95% confidence interval, 0.210 to 0.545; p < .0001). CONCLUSION: Treatment of deep carious lesions with SWP is effective for pulp preservation and patient age may influence the outcome. PRACTICAL IMPLICATIONS: Although a somewhat younger mean patient age was associated with successful treatment of DCLs, SWP can be successful regardless of patient age and clinicians should consider SWP in treating DCLs. PMID- 29628116 TI - Mechanisms of pattern formation from dried sessile drops. AB - The formation of patterns after the evaporation of colloidal droplets deposited on a solid surface is an everyday natural phenomenon. During the past two decades, this topic has gained broader audience due to its numerous applications in biomedicine, nanotechnology, printing, coating, etc. This paper presents a detailed review of the experimental studies related to the formation of various deposition patterns from dried droplets of complex fluids (i.e., nanofluids, polymers). First, this review presents the fundamentals of sessile droplet evaporation including evaporation modes and internal flow fields. Then, the most observed dried patterns are presented and the mechanisms behind them are discussed. The review ends with the categorisation and exhaustive investigation of a wide range of factors affecting pattern formation. PMID- 29628117 TI - Re: Radiology-led lung escalation pathway: a streamlined innovative service expediting the diagnosis of lung cancer. PMID- 29628118 TI - Pliocene bats (Chiroptera) from Kanapoi, Turkana Basin, Kenya. AB - Fossil bats from the Pliocene of Africa are extremely rare, especially in East Africa where meager records have been reported only from two localities in the Omo River Basin Shungura Formation and from a scattering of localities in the Afar Depression, both in Ethiopia. Here we report on a diverse assemblage of bats from Kanapoi in the Turkana Basin that date to approximately 4.19 million years ago. The Kanapoi bat community consists of four different species of fruit bats including a new genus and two new species as well as five species of echolocating bats, the most common of which are two new species of the molossid genus Mops. Additionally, among the echolocating bats, a new species of the emballonurid Saccolaimus is documented at Kanapoi along with an additional Saccolaimus species and a potentially new species of the nycterid Nycteris. Compared to other East African Pliocene bat assemblages, the Kanapoi bat community is unique in preserving molossids and curiously lacks any evidence of cave dwelling bats like rhinolophids or hipposiderids, which are both common at other East African sites. The bats making up the Kanapoi community all typically roost in trees, with some preferring deeper forests and larger trees (molossids), while the others (pteropodids, nycterids and emballonurids) roost in trees near open areas. Living fruit bats that are related to Kanapoi species typically forage for fruits along the margins of forests and in open savannah. The echolocating forms from Kanapoi consist of groups that aerially hawk for insects in open areas between patches of forest and along water courses. The habitats preferred by living relatives of the Kanapoi bats are in agreement with those constructed for Kanapoi based on other lines of evidence. PMID- 29628119 TI - Viral induced overproduction of epithelial TSLP: Role in exacerbations of asthma and COPD? PMID- 29628120 TI - Immunomorphometric variations of sustentacular cells of the male viscacha adrenal medulla during the annual reproductive cycle. Effects of androgens and melatonin. AB - The adrenal medulla is crucial for the survival of species facing significant environmental changes. The parenchyma is composed mainly of chromaffin cells, ganglion cells and sustentacular cells (SC). The male viscacha exhibits seasonal variations of gonadal activity and other metabolic functions. The aim of this work was to investigate the influence of the reproductive conditions on the morphology of SC of this rodent. In addition, the effects of testosterone and melatonin on these cells were studied. Immunoexpression of S100 protein, GFAP and vimentin were analyzed. Furthermore, the distribution of adrenergic and noradrenergic chromaffin cells subpopulations was studied for the first time in this species. SC present long cytoplasmic processes in contact with chromaffin cells, probably generating an intraglandular communication network. Significant differences (p < 0.05) in the %IA (percentage of immunopositive area) for the S100 protein were observed according to winter (4.21 +/- 0.34) and summer (3.51 +/- 0.15) values. In castrated animals, the %IA (6.05 +/- 0.35) was significantly higher in relation to intact animals (3.95 +/- 0.40). In melatonin-treated animals the %IA (3.62 +/- 0.23) was significantly higher compared to control animals (2.65 +/- 0.26). GFAP immunoexpression was negative and no noradrenergic chromaffin cells were detected suggesting an adrenergic phenotype predominance. Vimentin was observed in SC, endothelial cells and connective tissue. Results indicate that SC exhibit variations along the annual reproductive cycle, along with castration and the melatonin administration. Our results suggest that in this rodent SC are not only support elements, but also participate in the modulation of the activity of the adrenal medulla; probably through paracrine effects. PMID- 29628121 TI - [Sexual and reproductive health in Roma women: the family planning programme of Poligono Sur in Seville (Spain)]. AB - OBJECTIVE: To describe the challenges, resources and strategies of the staff of the family planning programme of the Poligono Sur Healthcare Centre in Seville (Spain) in their care of Roma women. METHOD: This is a descriptive study in which in-depth interviews and discussion groups were held with all programme professionals, including a documentary review of the programme. The information was analyzed based on the Roma Health Integration Policy Index, a tool that evaluates the entitlement, accessibility, sensitivity and capacity for change of health programmes for the Roma population. RESULTS: The professionals encountered multiple challenges to implement the family planning programme with Roma women due to the characteristics of the users and the low sensitivity of the programme towards them. The absence of specific actions for Roma women within the family planning programme, agreed to by the healthcare district, obliges professionals to develop adaptations and strategies to ensure quality sexual and reproductive health services for their users. CONCLUSIONS: It is necessary to adapt sexual and reproductive health programmes targeted at Roma women by (a) detecting, evaluating, systematizing and disseminating good practices, (b) developing actions that address the multiple vulnerabilities of Roma women, (c) acknowledging professionals who advocate for the health of these women within their organizations, and (d) promoting reproductive justice as the goal of these programmes. PMID- 29628122 TI - [Inclusion of affective-sexual orientation and gender identities as social determinants of health]. PMID- 29628123 TI - MiR-1260b promotes the migration and invasion in non-small cell lung cancer via targeting PTPRK. AB - OBJECTIVE: Non-small cell lung cancer (NSCLC) accounts for 80-85% of lung cancer cases which cause most of cancer-related deaths globally. As our previous study discovered miR-1260b can be regarded as a specific signature for metastasis in NSCLC patients. However, the molecular mechanisms of miR-1260b underlying NSCLC progression and metastasis remain dismal. METHODS: The expression of miR-1260b in NSCLC tissues and cell lines were examined by real-time PCR, the effects of miR 1260b on cell migration, invasion and proliferation were evaluated in vitro. Furthermore, luciferase reporter assay was performed to identify the targets of miR-1260b, and the association between miR-1260b and its target gene was determined by real-time PCR and western blot assay. RESULTS: The results showed that miR-1260b was significantly upregulated in NSCLC cell lines. The inhibition of miR-1260b expression decreased the migratory and invasive rates in A549 cells while miR-1260b overexpression had the opposite effect. Furthermore, PTPRK was identified as a direct target of miR-1260b, and PTPRK expression was inversely correlated with miR-1260b in NSCLC cell lines and clinical tissues. CONCLUSIONS: These results suggested that miR-1260b may play an important role in NSCLC metastasis progression and could serve as a putative target for diagnosis and treatment of NSCLC. PMID- 29628125 TI - Modulation of the Innate Immune System: A Future Approach to the Treatment of Neurological Disease. PMID- 29628124 TI - Intraductal carcinoma of the prostate: What we know and what we do not know. AB - Intraductal carcinoma of the prostate (IDC-P) is a malignant, clonal proliferation of cells growing within the basement membrane-bound structures of the prostate. IDC-P is usually associated with unfavorable clinicopathologic parameters such as large tumor volume, high-grade Gleason score, extra prostatic extension and seminal vesicle invasion. Majority of laboratory and patient data suggest that IDC-P represents intraductal spread of invasive carcinoma, rather than a precursor lesion. Additionally, relationship of IDC-P and adjacent invasive carcinoma has been investigated in a series of molecular studies. The differential diagnosis of IDC-P from other lesions is critical for patient management. In this article, we summarize current literatures regarding what we know about IDC-P, including its pathological morphology, incidence, differential diagnosis, molecular features and clinical significance. In addition, we propose several issues that we currently do not know about IDC-P. Further research is needed to better understand the biological nature of IDC-P. PMID- 29628127 TI - Usefulness of Epicardial Area in the Short Axis to Identify Elevated Left Ventricular Mass in Men. AB - Left ventricular (LV) hypertrophy is strongly associated with increased cardiovascular morbidity and mortality. The 2-dimensional LV mass algorithms suffer from measurement variability that can lead to misclassification of patients with LV hypertrophy as normal, or vice versa. Among the 4 echocardiographic measurements required by the 2-dimensional LV mass algorithms, epicardial and endocardial area have the lowest interobserver variation and could be used to corroborate LV mass calculations. We sought cut-off values that are able to discriminate between elevated and normal LV mass based on endocardial or epicardial area alone. Using data from 664 men enrolled in the Mind Your Heart Study, we calculated the correlation of LV mass index with epicardial area and endocardial area. We then used receiver operator characteristic curves to identify epicardial and endocardial area cut-points that could discriminate subjects with normal LV mass and LV hypertrophy. LV mass index was more strongly correlated with epicardial area compared with endocardial area, r = 0.70 versus r = 0.27, respectively. Epicardial area had a significantly higher area under the receiver operator characteristic curve (p <0.001) compared with endocardial area, 0.90 (95% confidence interval 0.86 to 0.93) versus 0.63 (95% confidence interval 0.57 to 0.71). An epicardial area cut-point of >=38.0 cm2 corresponded to a sensitivity of 95.0% and specificity of 54.4% for detecting LV hypertrophy. In conclusion, epicardial area showed promise as a method of rapid screening for LV hypertrophy and could be used to validate formal LV mass calculations. PMID- 29628128 TI - Impact of Baseline Thrombocytopenia on Bleeding and Mortality After Percutaneous Coronary Intervention. AB - It is still controversial whether baseline thrombocytopenia is independently associated with adverse events after percutaneous coronary intervention. We evaluated the influence of baseline thrombocytopenia against ischemic, bleeding and mortality among the 19,353 patients whose baseline platelet counts were available in the pooled database from the 3 studies in Japan. Baseline thrombocytopenia was classified as follows: mild, >=100 and <150 * 109/L; moderate, >=50 and <100 * 109/L; and severe, <50 * 109/L. Primary ischemic outcome measure was defined as composite of myocardial infarction and ischemic stroke, and primary bleeding outcome measure was defined by the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded arteries trial as moderate or severe bleeding. There were 2,590 patients (13.4%) with baseline thrombocytopenia comprising 292 patients (1.5%) with moderate/severe (moderate: 277 and severe: 15) thrombocytopenia and 2,298 patients (11.9%) with mild thrombocytopenia, whereas 16,763 patients (86.6%) had no thrombocytopenia. During 3-year follow-up, the adjusted risks of moderate/severe and mild thrombocytopenia relative to none were neutral for primary ischemic outcome (hazard ratio [HR] 1.07 [95% confidence interval [CI] 0.72 to 1.60], p = 0.74, and HR 0.93 [0.79 to 1.09], p = 0.37, respectively) but were significantly higher for primary bleeding outcome (HR 2.35 [1.80 to 3.08], p <0.001, and HR 1.20 [1.03 to 1.40], p = 0.02), and for mortality (HR 2.34 [1.87 to 2.93], p <0.001, and HR 1.26 [1.11 to 1.43], p <0.001). In conclusion, patients with baseline thrombocytopenia, even a mild one, had a higher risk of bleeding events and all-cause death, but not for ischemic events after percutaneous coronary intervention. PMID- 29628129 TI - Comparison of the Association Between High-Sensitivity Troponin I and Adverse Cardiovascular Outcomes in Patients With Versus Without Chronic Kidney Disease. AB - It is unknown whether the association of high-sensitivity troponin I (hs-TnI) with adverse cardiovascular outcomes varies by the presence of chronic kidney disease (CKD). We examined the association of hs-TnI with adverse cardiovascular outcomes in those with and without CKD in 4,107 (mean age, 64 years; 63% men; 20% black) patients from the Emory Cardiovascular Biobank who underwent coronary angiography. CKD (n = 1,073) was defined as estimated glomerular filtration rate <60 ml/min/1.73 m2 or urine albumin/creatinine ratio >30 mg/g at baseline. Cox regression was used to compute hazard ratios (HR) for the association between hs TnI levels (per doubling of hs-TnI: log2[hs-TnI] + 1) and death, cardiovascular death, and major adverse cardiac events (MACE), separately. Hs-TnI was a stronger predictor of death (CKD: HR 1.23, 95% confidence interval [CI] 1.15 to 1.31; no CKD: HR 1.11, 95% CI 1.05 to 1.17, p-interaction = 0.023), cardiovascular death (CKD: HR 1.24, 95% CI 1.14 to 1.34; no CKD: HR 1.15, 95% CI 1.07 to 1.22, p interaction = 0.12), and MACE (CKD: HR 1.18, 95% CI 1.11 to 1.25; no CKD: HR 1.11, 95% CI 1.06 to 1.16, p-interaction = 0.095) in CKD compared with non-CKD. The association between hs-TnI and death in patients with CKD was stronger for patients without obstructive coronary artery disease (no obstructive coronary artery disease: HR 1.60, 95% CI 1.27 to 2.01; obstructive coronary artery disease: HR 1.19, 95% CI 1.11 to 1.27, p-interaction = 0.041). In conclusion, hs TnI is a stronger predictor of adverse cardiovascular events in patients who have CKD than those without, even in the absence of obstructive coronary artery disease. Hs-TnI may identify CKD patients who are high risk for adverse cardiovascular outcomes in whom aggressive risk factor modification strategies are warranted. PMID- 29628130 TI - Strain imaging of the lateral collateral ligament using high frequency and conventional ultrasound imaging: An ex-vivo comparison. AB - Recent first attempts of in situ ultrasound strain imaging in collateral ligaments encountered a number of challenges and illustrated a clear need for additional studies and more thorough validation of the available strain imaging methods. Therefore, in this study we experimentally validated ultrasound strain measurements of ex vivo human lateral collateral ligaments in an axial loading condition. Moreover, the use of high frequency ultrasound (>20 MHz) for strain measurement was explored and its performance compared to conventional ultrasound. The ligaments were stretched up to 5% strain and ultrasound measurements were compared to surface strain measurements from optical digital image correlation (DIC) techniques. The results show good correlations between ultrasound based and DIC based strain measures with R2 values of 0.71 and 0.93 for high frequency and conventional ultrasound, subsequently. The performance of conventional ultrasound was significantly higher compared to high frequency ultrasound strain imaging, as the high frequency based method seemed more prone to errors. This study demonstrates that ultrasound strain imaging is feasible in ex vivo lateral collateral ligaments, which are relatively small structures. Additional studies should be designed for a more informed assessment of optimal in vivo strain measurements in collateral knee ligaments. PMID- 29628131 TI - Order error in the calculation of continuous relative phase. AB - The aims of this study were to demonstrate "order error" in the calculation of continuous relative phase (CRP) and to suggest two alternative methods-(i) constructing phase-plane portraits by plotting position over velocity; and (ii), the Hilbert transform-to rectify it. Order error is the change of CRP order between two degrees of freedom (e.g., body segments) when using the conventional method of constructing phase-plane portraits (i.e., velocity over position). Both sinusoidal and non-sinusoidal simulated signals as well as signals from human movement kinematics were used to investigate order error and the performance of the two alternative methods. Both methods have been shown to lead to correct results for simulated sinusoidal and non-sinusoidal signals. For human movement data, however, the Hilbert transform is superior for calculating CRP. PMID- 29628133 TI - Radiostereometric analysis using clinical radiographic views: Development of a universal calibration object. AB - Radiostereometric analysis (RSA) is a highly accurate technique used to provide three-dimensional (3D) measurements of orthopaedic implant migration for clinical research applications, yet its implementation in routine clinical examinations has been limited. Previous studies have introduced a modified RSA procedure that separates the calibration examinations from the patient examinations, allowing routine clinical radiographs to be analyzed using RSA. However, in order to calibrate the wide range of clinical views, a new calibration object is required. In this study, a universal, isotropic calibration object was designed to calibrate any pair of radiographic views used in the clinic for RSA. A numerical simulation technique was used to design the calibration object, followed by a phantom validation test of a prototype to verify the performance of the novel object, and to compare the measurement reliability to the conventional calibration cage. The 3D bias for the modified calibration method using the new calibration object was 0.032 +/- 0.006 mm, the 3D repeatability standard deviation was 0.015 mm, and the 3D repeatability limit was 0.042 mm. Although statistical differences were present between the universal calibration object and the conventional cage, the differences were considered to be not clinically meaningful. The 3D bias and repeatability values obtained using the universal calibration object were well under the threshold acceptable for RSA, therefore it was successfully validated. The universal calibration object will help further the adoption of RSA into a more routine practice, providing the opportunity to generate quantitative databases on joint replacement performance. PMID- 29628132 TI - Biomechanics of osteochondral impact with cushioning and graft Insertion: Cartilage damage is correlated with delivered energy. AB - Articular cartilage is susceptible to impact injury. Impact may occur during events ranging from trauma to surgical insertion of an OsteoChondral Graft (OCG) into an OsteoChondral Recipient site (OCR). To evaluate energy density as a mediator of cartilage damage, a specialized drop tower apparatus was used to impact adult bovine samples while measuring contact force, cartilage surface displacement, and OCG advancement. When a single impact was applied to an isolated (non-inserted) OCG, force and surface displacement each rose monotonically and then declined. In each of five sequential impacts of increasing magnitude, applied to insert an OCG into an OCR, force rose rapidly to an initial peak, with minimal OCG advancement, and then to a second prolonged peak, with distinctive oscillations. Energy delivered to cartilage was confirmed to be higher with larger drop height and mass, and found to be lower with an interposed cushion or OCG insertion into an OCR. For both single and multiple impacts, the total energy density delivered to the articular cartilage correlated to damage, quantified as total crack length. The corresponding fracture toughness of the articular cartilage was 12.0 mJ/mm2. Thus, the biomechanics of OCG insertion exhibits distinctive features compared to OCG impact without insertion, with energy delivery to the articular cartilage being a factor highly correlated with damage. PMID- 29628134 TI - Sleep disturbance and symptom burden in sarcoidosis. AB - INTRODUCTION: Sarcoidosis is a systemic inflammatory disease associated with myriad symptoms, including fatigue. It can affect physiological processes like sleep, leading to poor sleep quality and excessive daytime sleepiness. We hypothesized that sarcoidosis patients would report more severe sleep disturbance than healthy controls and that relationships would be found with sleep disturbance and the severity of other symptoms. METHODS: We enrolled 84 sarcoidosis patients and 30 healthy controls and recorded demographic and clinical characteristics. Self-report measures were used to assess sleep disturbance, psychosocial symptoms, and quality of life at enrollment and longitudinally. Relationships between different self-report outcomes were analyzed using correlation statistics. RESULTS: Using the General Sleep Disturbance Scale, 54% of sarcoidosis patients reported frequent and occasional sleep disturbance compared to only 17% of healthy controls (p < 0.0001). This significant increase in sleep disturbance found in sarcoidosis patients strongly correlated with multiple psychosocial symptoms, including fatigue, depression, and cognitive dysfunction, and negatively impacted quality of life (p < 0.01). Traditional measures of sarcoidosis disease severity or activity were not associated with sleep disturbance. Sleep disturbance scores remained stable at follow-up (mean time between first and last administration of questionnaire was 17.3 months) in 56 of the sarcoidosis patients. CONCLUSIONS: Sarcoidosis patients experienced significant sleep disturbance that correlated with higher levels of fatigue, depression, and cognitive dysfunction, and poorer quality of life. These associations were present regardless of disease severity or activity and result in decrements in quality of life and mental health. PMID- 29628135 TI - Lung transplantation for scleroderma lung disease: An international, multicenter, observational cohort study. AB - BACKGROUND: Due to its multisystemic nature, scleroderma is considered a relative contraindication to lung transplantation at many centers. However, recent studies suggest similar post-transplant outcomes in patients with scleroderma compared to those with other causes of interstitial lung disease (ILD). Furthermore, it remains unknown whether scleroderma-associated pulmonary arterial hypertension (PAH) influences post-transplant outcomes. Our objective in this study was to assess the indications, survival, and prognostic factors of lung or heart-lung transplantation for scleroderma lung disease. METHODS: We retrospectively reviewed the data of 90 patients with scleroderma who underwent lung or heart lung transplantation between 1993 and 2016 at 14 European centers. International criteria were used to diagnose scleroderma. Pulmonary hypertension (PH) was diagnosed during right heart catheterization based on international guidelines. RESULTS: Survival rates after 1, 3, and 5 years were 81%, 68%, and 61%, respectively. By univariate analysis, borderline-significant associations with poorer survival were found for female gender (hazard ratio 2.11; 95% confidence interval [CI] 0.99 to 4.50; p = 0.05) and PAH as the reason for transplantation (hazard ratio 1.90; 95% CI 0.96 to 3.92; p = 0.06). When both these factors were present in combination, the risk of death was 3-fold that in males without PAH. The clinical and histologic presentation resembled veno-occlusive disease in 75% of patients with PAH. CONCLUSIONS: Post-transplant survival rates and freedom from chronic lung allograft dysfunction in patients with scleroderma were similar to those in patients with other reasons for lung transplantation. Female sex and PAH in combination was associated with lower survival. PMID- 29628136 TI - Balancing decisions in mechanical circulatory support: It's all in the timing. PMID- 29628137 TI - Department of Error. PMID- 29628138 TI - Department of Error. PMID- 29628139 TI - Drug repurposing in kidney disease. AB - Drug repurposing, is the re-tasking of known medications for new clinical indications. Advantages, compared to de novo drug development, include reduced cost and time to market plus the added benefit of a known pharmacokinetic and safety profiles. Suitable drug candidates are identified through serendipitous observations, data mining, or increased understanding of disease mechanisms. This review highlights drugs suited for repurposing in kidney disease. The main cause of mortality in patients with chronic kidney disease is cardiovascular disease. Hence, we have included CV endpoints for the drugs. This review begins with candidates in acute kidney injury: vasodilators levosimendan and vitamin D, followed by candidates in CKD, with particular focus on diabetic kidney disease, autosomal dominant polycystic kidney disease, and focal segmental glomerulosclerosis. Examples include glucose-lowering drugs (sodium glucose co transporter 2 inhibitors, glucagon-like peptide 1 agonists, and metformin), which have mechanistic potential for cardiac and/or renal protection beyond glucose lowering, with broader applicability to the nondiabetic population; xanthine oxidase inhibitors (allopurinol, febuxostat), selective endothelin receptor A antagonist (atrasentan), Janus kinase inhibitor (baricitinib), selective costimulation modulator (abatacept), pentoxyfylline, and the DNA demethylating agent/vasodilator (hydralazine). PMID- 29628140 TI - Disease-Causing Mutations in the G Protein Galphas Subvert the Roles of GDP and GTP. AB - The single most frequent cancer-causing mutation across all heterotrimeric G proteins is R201C in Galphas. The current model explaining the gain-of-function activity of the R201 mutations is through the loss of GTPase activity and resulting inability to switch off to the GDP state. Here, we find that the R201C mutation can bypass the need for GTP binding by directly activating GDP-bound Galphas through stabilization of an intramolecular hydrogen bond network. Having found that a gain-of-function mutation can convert GDP into an activator, we postulated that a reciprocal mutation might disrupt the normal role of GTP. Indeed, we found R228C, a loss-of-function mutation in Galphas that causes pseudohypoparathyroidism type 1a (PHP-Ia), compromised the adenylyl cyclase activating activity of Galphas bound to a non-hydrolyzable GTP analog. These findings show that disease-causing mutations in Galphas can subvert the canonical roles of GDP and GTP, providing new insights into the regulation mechanism of G proteins. PMID- 29628141 TI - Pseudouridylation of tRNA-Derived Fragments Steers Translational Control in Stem Cells. AB - Pseudouridylation (Psi) is the most abundant and widespread type of RNA epigenetic modification in living organisms; however, the biological role of Psi remains poorly understood. Here, we show that a Psi-driven posttranscriptional program steers translation control to impact stem cell commitment during early embryogenesis. Mechanistically, the Psi "writer" PUS7 modifies and activates a novel network of tRNA-derived small fragments (tRFs) targeting the translation initiation complex. PUS7 inactivation in embryonic stem cells impairs tRF mediated translation regulation, leading to increased protein biosynthesis and defective germ layer specification. Remarkably, dysregulation of this posttranscriptional regulatory circuitry impairs hematopoietic stem cell commitment and is common to aggressive subtypes of human myelodysplastic syndromes. Our findings unveil a critical function of Psi in directing translation control in stem cells with important implications for development and disease. PMID- 29628142 TI - A Kinesin-14 Motor Activates Neocentromeres to Promote Meiotic Drive in Maize. AB - Maize abnormal chromosome 10 (Ab10) encodes a classic example of true meiotic drive that converts heterochromatic regions called knobs into motile neocentromeres that are preferentially transmitted to egg cells. Here, we identify a cluster of eight genes on Ab10, called the Kinesin driver (Kindr) complex, that are required for both neocentromere motility and preferential transmission. Two meiotic drive mutants that lack neocentromere activity proved to be kindr epimutants with increased DNA methylation across the entire gene cluster. RNAi of Kindr induced a third epimutant and corresponding loss of meiotic drive. Kinesin gliding assays and immunolocalization revealed that KINDR is a functional minus-end-directed kinesin that localizes specifically to knobs containing 180 bp repeats. Sequence comparisons suggest that Kindr diverged from a Kinesin-14A ancestor ~12 mya and has driven the accumulation of > 500 Mb of knob repeats and affected the segregation of thousands of genes linked to knobs on all 10 chromosomes. PMID- 29628144 TI - Fatigue and acute coronary syndrome: a systematic review of contributing factors. AB - Fatigue is a symptom of ACS, but it remains unclear who is at risk and what factors contribute to fatigue. The purpose of the systematic review was to identify factors that influence fatigue in patients with ACS. The review was guided by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Literature published from 1981 to 2017 was reviewed, and of 983 articles screened, 36 met inclusion criteria. Variables contributing to fatigue fell into 3 categories: demographic characteristics, clinical characteristics, and other factors. More fatigue was found in women than men, and significant differences in fatigue were identified by race. Additionally, sleep deprivation, depression, and anxiety were associated with higher levels of fatigue. The findings highlight the importance of demographic, clinical, and other factors' impact on fatigue in ACS patients. Fatigue is an important symptom in ACS and healthcare providers must recognize how patient variables affect symptom expression. PMID- 29628145 TI - Percutaneous biventricular Impella support in therapy-refractory cardiogenic shock. AB - INTRODUCTION: Percutaneous mechanical circulatory support systems have increasingly been adopted as a bail out strategy in patients with cardiogenic shock. Since studies showed mostly mixed results, however, the use of support systems remains a case by case decision. CASE: Here, we report on a case of therapy-refractory cardiogenic shock due to acute myocardial infarction treated with percutaneous right and left ventricular assist devices (Impella RP and CP). CONCLUSION: Due to myocardial stunning, even patients with fulminant cardiogenic shock have the potential for full recovery. In the present case, we demonstrate the feasibility of biventricular Impella support in therapy-refractory cardiogenic shock facilitating bridge to recovery. PMID- 29628143 TI - Stress Granule Assembly Disrupts Nucleocytoplasmic Transport. AB - Defects in nucleocytoplasmic transport have been identified as a key pathogenic event in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) mediated by a GGGGCC hexanucleotide repeat expansion in C9ORF72, the most common genetic cause of ALS/FTD. Furthermore, nucleocytoplasmic transport disruption has also been implicated in other neurodegenerative diseases with protein aggregation, suggesting a shared mechanism by which protein stress disrupts nucleocytoplasmic transport. Here, we show that cellular stress disrupts nucleocytoplasmic transport by localizing critical nucleocytoplasmic transport factors into stress granules, RNA/protein complexes that play a crucial role in ALS pathogenesis. Importantly, inhibiting stress granule assembly, such as by knocking down Ataxin-2, suppresses nucleocytoplasmic transport defects as well as neurodegeneration in C9ORF72-mediated ALS/FTD. Our findings identify a link between stress granule assembly and nucleocytoplasmic transport, two fundamental cellular processes implicated in the pathogenesis of C9ORF72-mediated ALS/FTD and other neurodegenerative diseases. PMID- 29628146 TI - Finding your voice. PMID- 29628149 TI - Distribution of rotavirus genotypes associated with acute diarrhoea in Zimbabwean children less than five years old before and after rotavirus vaccine introduction. AB - BACKGROUND: Sentinel surveillance for diarrhoea is important to monitor changes in rotavirus epidemiological trends and circulating genotypes among children under 5 years before and after vaccine introduction. The Zimbabwe Ministry of Health and Child Care introduced rotavirus vaccine in national immunization program in May 2014. METHODS: Active hospital-based surveillance for diarrhoea was conducted at 3 sentinel sites from 2008 to 2016. Children aged less than 5 years, who presented with acute gastroenteritis as a primary illness and who were admitted to a hospital ward or treated at the emergency unit, were enrolled and had a stool specimen collected and tested for rotavirus by enzyme immunoassay (EIA). Genotyping of positive stools was performed using reverse-transcription polymerase chain reaction and genotyping assays. Pre-vaccine introduction, 10% of all positive stool specimens were genotyped and all adequate positive stools were genotyped post-vaccine introduction. RESULTS: During the pre-vaccine period, a total of 6491 acute gastroenteritis stools were collected, of which 3016 (46%) tested positive for rotavirus and 312 (10%) of the rotavirus positive stools were genotyped. During the post-vaccine period, a total of 3750 acute gastroenteritis stools were collected, of which 937 (25%) tested positive for rotavirus and 784 (84%) were genotyped. During the pre-vaccine introduction the most frequent genotype was G9P[8] (21%) followed by G2P[4] (12%), G1P[8] (6%), G2P[6] (5%), G12P[6] (4%), G9P[6] (3%) and G8P[4] (3%). G1P[8] (30%) was most dominant two years after vaccine introduction followed by G9P[6] (20%), G2P[4] (15%), G9P[8] (11%) and G1P[6] (4%). CONCLUSION: The decline in positivity rate is an indication of early vaccine impact. Diversity of circulating strains underscores the importance of continued monitoring and strain surveillance after vaccine introduction. PMID- 29628150 TI - Evaluation of adenovirus 19a as a novel vector for mucosal vaccination against influenza A viruses. AB - Since preexisting immunity and enhanced infection rates in a clinical trial of an HIV vaccine have raised some concerns on adenovirus (Ad) serotype 5-based vaccines, we evaluated the subgroup D adenovirus serotype Ad19a for its suitability as novel viral vector vaccine against mucosal infections. In BALB/c mice, we compared the immunogenicity and efficacy of E1/E3-deleted Ad19a vectors encoding the influenza A virus (IAV)-derived antigens hemagglutinin (HA) and nucleoprotein (NP) to the most commonly used Ad5 vectors. The adenoviral vectors were applied intranasally and induced detectable antigen-specific T cell responses in the lung and in the spleen as well as robust antibody responses. A prior DNA immunization significantly improved the immunogenicity of both vectors and resulted in full protection against a lethal infection with a heterologous H3N2 virus. Nevertheless, the Ad5-based vectors were slightly superior in reducing viral replication in the lung which corresponded to higher NP-specific T cell responses measured in the lungs. PMID- 29628151 TI - Safety of a two-dose investigational hepatitis B vaccine, HBsAg-1018, using a toll-like receptor 9 agonist adjuvant in adults. AB - BACKGROUND: Hepatitis B virus infection remains an important global public health problem. Approved alum-adjuvanted vaccines are well tolerated but require three doses and have reduced immunogenicity in adults. A two-dose vaccine containing hepatitis B surface antigen combined with a novel, Toll-like receptor 9 agonist adjuvant (HBsAg-1018 [HEPLISAV-B(r)]) has demonstrated significantly higher seroprotection rates than a three dose vaccine. METHODS: A post hoc analysis compared the safety of HBsAg-1018 with HBsAg-Eng (Engerix-B(r)), in three randomized, observer-blinded, active-controlled, multi-center phase 3 trials in adults. HBsAg-1018 was administered intramuscularly at weeks 0 and 4 and placebo at week 24 and HBsAg-Eng at weeks 0, 4, and 24. RESULTS: Post-injection reactions, adverse events, medically attended adverse events, and new-onset immune-mediated adverse events were balanced between vaccine groups. Anti-nuclear antibodies, anti-double stranded DNA antibodies, anti-neutrophil cytoplasmic antibodies, and antiphospholipid antibodies were balanced between groups. A transient increase in anti-beta2 glycoprotein 1 IgM was observed in the HBsAg 1018 group but was not associated with a thrombotic event. Serious adverse events and deaths were generally balanced between groups. CONCLUSION: HBsAg-1018 had a similar safety profile to HBsAg-Eng. With improved immunogenicity and fewer doses over a shorter time, HBsAg-1018 has the potential to provide improved seroprotection and a significant public health benefit to adults 18 years of age or older. PMID- 29628152 TI - Hepatitis A in the EU/EEA: The case for scaling up prevention. PMID- 29628153 TI - Letter to the editor: In reply to Sansone et al. PMID- 29628154 TI - [Severity of disease scoring systems and mortality after non-cardiac surgery]. AB - BACKGROUND: Mortality after surgery is frequent and severity of disease scoring systems are used for prediction. Our aim was to evaluate predictors for mortality after non-cardiac surgery. METHODS: Adult patients admitted at our surgical intensive care unit between January 2006 and July 2013 was included. Univariate analysis was carried using Mann-Whitney, Chi-square or Fisher's exact test. Logistic regression was performed to assess independent factors with calculation of odds ratio and 95% confidence interval (95% CI). RESULTS: 4398 patients were included. Mortality was 1.4% in surgical intensive care unit and 7.4% during hospital stay. Independent predictors of mortality in surgical intensive care unit were APACHE II (OR=1.24); emergent surgery (OR=4.10), serum sodium (OR=1.06) and FiO2 at admission (OR=14.31). Serum bicarbonate at admission (OR=0.89) was considered a protective factor. Independent predictors of hospital mortality were age (OR=1.02), APACHE II (OR=1.09), emergency surgery (OR=1.82), high-risk surgery (OR=1.61), FiO2 at admission (OR=1.02), postoperative acute renal failure (OR=1.96), heart rate (OR=1.01) and serum sodium (OR=1.04). Dying patients had higher scores in severity of disease scoring systems and longer surgical intensive care unit stay. CONCLUSION: Some factors influenced both surgical intensive care unit and hospital mortality. PMID- 29628155 TI - [Vocal cord paralysis after endotracheal intubation: an uncommon complication of general anesthesia]. AB - BACKGROUND: General anesthesia is a safe, frequent procedure in clinical practice. Although it is very unusual in procedures not related to head and or neck surgery, vocal cord paralysis is a serious and important complication. Incidence has been associated with patient age and comorbidities, as well as the position of the endotracheal tube and cuff. It can become a dangerous scenario because it predisposes aspiration. OBJECTIVES: To present a case and analyze the risk factors associated with increased risk of vocal cord paralysis described in the literature. CASE REPORT: 53 year-old diabetic man, who developed hoarseness in the postoperative period after receiving general anesthesia for an elective abdominal laparoscopic surgery. Otolaryngological evaluation showed left vocal cord paralysis. CONCLUSIONS: Vocal cord paralysis can be a serious complication of general anesthesia because of important voice dysfunction and risk of aspiration. The management is not yet fully established, so prevention and early diagnosis is essential. PMID- 29628157 TI - The transition away from coal is inevitable. PMID- 29628156 TI - Optimization of memory use of fragment extension-based protein-ligand docking with an original fast minimum cost flow algorithm. AB - The need to accelerate large-scale protein-ligand docking in virtual screening against a huge compound database led researchers to propose a strategy that entails memorizing the evaluation result of the partial structure of a compound and reusing it to evaluate other compounds. However, the previous method required frequent disk accesses, resulting in insufficient acceleration. Thus, more efficient memory usage can be expected to lead to further acceleration, and optimal memory usage could be achieved by solving the minimum cost flow problem. In this research, we propose a fast algorithm for the minimum cost flow problem utilizing the characteristics of the graph generated for this problem as constraints. The proposed algorithm, which optimized memory usage, was approximately seven times faster compared to existing minimum cost flow algorithms. PMID- 29628158 TI - Acquiring an operative sustainability expertise for health professionals. PMID- 29628159 TI - Threats to human health by great ocean garbage patches. PMID- 29628160 TI - Exiting the Paris climate accord: Trump administration misses the rising tide. PMID- 29628161 TI - Planetary health research in 2018: a call for abstracts. PMID- 29628162 TI - Antimicrobial use and resistance in animals and human beings. PMID- 29628163 TI - Protecting children's lungs by providing clean air during pregnancy? PMID- 29628164 TI - Air pollution: a largely neglected risk factor for osteoporosis. PMID- 29628165 TI - The urban built environment and temperature-related mortality risk in a warming climate. PMID- 29628166 TI - Displacement and mental health after natural disasters. PMID- 29628167 TI - Clinicopathological features of squamous cell carcinoma of the oral cavity and oropharynx in young patients. AB - Our aim was to examine the clinicopathological features of squamous cell carcinoma (SCC) of the oral cavity and oropharynx in a group of young patients who were dignosed during a 15-year period (2000-2014). Patients' clinical details, risk factors, and survival were obtained from medical records. Formalin fixed, paraffin-embedded, tissue was tested for high-risk human papillomavirus (HPV). The results were compared with those of a matching group of older patients. We identified 91 patients who were younger than 45 years old, and the 50 youngest patients were studied in detail. The male:female ratio was 2:1, with more tumours located in the oral cavity than in the oropharynx (35 compared with 15). HPV-related SCC was restricted to the oropharynx. When matched for site, stage and HPV status, five-year overall survival was similar in young and matched older patients (log-rank test, p=0.515). Our findings suggest that young patients with oral SCC have a disease profile similar to that of older patients with the condition. It is plausible that prognostic information generally available for oral cancers is applicable to young patients with the disease. PMID- 29628168 TI - Effect of a domiciliary facial cooling system on generic quality of life after removal of mandibular third molars. AB - To evaluate quality of life (QoL) and patients' perceptions of a domiciliary facial cooling system (Hilotherm(r), Hilotherapy UK Ltd, Coventry, UK), we asked 30 patients to complete a paper-based EQ-5D-3L QoL questionnaire (EuroQol Group 1990, Rotterdam, The Netherlands) each day for seven days after the removal of mandibular third molars. They were returned by 14 of the 20 patients who had not used the system and by all 10 who had. Patients aged between 18 and 25 who had their teeth removed in outpatients (in accordance with National Institute for Health and Care Excellence guidelines) under general anaesthesia (American Association of Anesthesiologists (ASA) class I or II) and did not smoke, were included. They were all treated by the same surgeon in the day surgery unit of a district general hospital. Patients found the system helpful and easy to use. They had no complications, their QoL was significantly improved (p<0.001), and the time taken to return to normal activities was reduced. The Hilotherm(r) domiciliary facial cooling system is safe and helps in the management of postoperative pain and swelling. Our findings confirm recently published meta analyses that show the effectiveness of hilotherapy after facial surgery. PMID- 29628169 TI - Impact of a structured oculoplastic surgery rotation on specialist training in oral and maxillofacial surgery. PMID- 29628170 TI - Preoperative assessment of the risk of postoperative death in patients with oral squamous cell carcinoma: a consideration beyond age, sex, and stage of cancer. AB - Despite improvements in the management of patients in critical care, about 3% patients who have an operation with curative intent for oral squamous cell carcinoma (SCC) do not survive their stay in hospital. Our aim was to assess the risk factors for postoperative death that were independent of the stage of the cancer, or the age and sex of the patients. We screened 4760 consecutive inpatients at a maxillofacial tertiary care centre from 2011 to 2016, and 34 of them had died within the first three months after operation. We matched them with a further 34 patients with the same TNM stage, age, and sex. General personal and clinical data and preoperative laboratory values were screened, and we applied a Charlson Comorbidity Score (for anaesthetic risk) for each group. Patients' mean (SD) age was 66 (12) years old. There was no significant difference in sex (p=1), age (p=0.718), or TNM classification. Those who died after operation had significantly more renal (p=0.027) and gastrointestinal (p=0.006) diseases, but cardiac diseases (p=0.468) and diabetes mellitus (p=1) were not significant risk factors in themselves. Patients who died postoperatively had significantly worse risk scores (p=0.001) overall. The most common causes of death were septic shock (n=10) and acute cardiac (n=9) or respiratory failure (n=7). Our findings suggested that general diseases were not intrinsically a contraindication for operation with curative intent. The Charlson Comorbidity Score helped to detect potentially fatal courses and could be useful in the preoperative assessment of patients whose general health is not good. PMID- 29628171 TI - "Run-through" training at specialist training year 1 and uncoupled core surgical training for oral and maxillofacial surgery in the United Kingdom: a snapshot survey. AB - Training in oral and maxillofacial surgery (OMFS) in the UK has undergone considerable changes during the last 10years, and "core" surgical training has replaced "basic" surgical training. In 2014 a pilot "run-through" training programme from specialist training year one (ST1)-ST7 was introduced to facilitate early entry into the speciality. Run-through training guarantees that a trainee, after a single competitive selection process and satisfactory progress, will be given training that covers the entire curriculum of the speciality, whereas uncoupled training requires a second stage of competitive recruitment after the first one (for OMFS only) or two years of "core" training to progress to higher specialty training. The first two years of run-through training (ST1-ST2) are the same as for core surgical training. Dual-qualified maxillofacial aspirants and those in their second degree course are curious to know whether they should go for the uncoupled core surgical training or the run through programme in OMFS. The General Medical Council (GMC) has now agreed that run-through training can be rolled out nationally in OMFS. To assess the two pathways we used an online questionnaire to gain feedback about the experience from all OMFS ST3 and run-through trainees (ST3/ST4) in 2016-2017. We identified and contacted 21 trainees, and 17 responded, including seven run-through trainees. Eleven, including five of the run-through trainees, recommended the run through training programme in OMFS. Six of the seven run-through trainees had studied dentistry first. The overall mean quality of training was rated as 5.5 on a scale 0-10 by the 17 respondents. This survey gives valuable feedback from the current higher surgical trainees in OMFS, which will be useful to the GMC, Health Education England, OMFS Specialist Advisory Committee, and those seeking to enter higher surgical training in OMFS. PMID- 29628173 TI - [The plague: An overview and hot topics]. AB - Plague is a bacterial zoonosis caused by Yersinia pestis, usually found in fleas and small rodents that constitute the reservoir of the disease. It is transmitted to humans by flea bite, contact with rodents or inhalation of infected droplets. There are three clinical forms: bubonic plague, pulmonary plague and septicemic plague. The usual presentation is a flu-like syndrome possibly accompanied by an inflammatory lymphadenopathy which appears after 1 to 7days of incubation. Bubonic plague has a case fatality rate of about 50% while other forms of plague are almost always fatal without treatment. Diagnosis can be confirmed by usual bacteriological techniques (Gram examination, culture) but also by serological examination, use of rapid diagnostic tests or PCR. Although aminoglycosides are traditionally regarded as the most effective treatment, fluoroquinolones or cyclins are currently recommended in France. Plague is one of the re-emerging diseases according to the WHO and Madagascar suffered in 2017 the most important plague epidemic of the 21st century with more than 2000 cases and 200 deaths. Peru and the Democratic Republic of Congo are also considered endemic areas. Public health measures and a relentless fight against poverty are the cornerstone of the control of the disease. Vaccine improvement in endemic areas may also play an important role. PMID- 29628172 TI - [Impact of an evaluation of the professional practices on the relevance of proton pump inhibitors prescriptions pertinence at the hospital]. AB - INTRODUCTION: Proton pump inhibitors (PPI) are widely prescribed for unrecognized indications, at high a dose and for a long duration, in spite of side effects and numerous drug interactions. In 2009, the HAS (French Health Authority) published recommendations of good prescription but the latter are poorly respected. In this context of over prescription and additional cost for the society, we performed a professional practice evaluation of on the model of the Deming wheel. The objective of this work was to optimize the relevance of the prescriptions of the IPP in two services of internal medicine and geriatrics through an evaluation of the professional practices. All PPI prescriptions introduced in outpatient visits or during hospitalization were analyzed. PATIENTS AND METHODS: Data collection was prospective, over two periods of 2 months and included 163 (first phase), then 139 patients (second phase). An assessment grid of PPI prescriptions was completed by physicians regarding the active substance, the dose, the duration and the indication of the prescription. The relevance of the prescription corresponded to PPI with a conformed indication and duration and to the prescriptions no recommended stopped. Following the first period of data collection, information was given to medical students and physicians on the relevance of their prescriptions with regard to the current recommendations and informative flyers were offered with the aim of improving the practices before the second period of evaluation (second phase). RESULTS: During the first phase, only 25% of the pre-hospital prescriptions and 33% of the hospital prescriptions respected the HAS recommendations. The main indication of the PPI was the prevention of peptic ulcers in a context of associated drug estimated at risk. An improvement of the global relevance of prescription was observed after awareness of the physicians: 26% relevance during the first phase and 60% in the second one (P<0.012). During the second phase, the part of PPI prescriptions introduced at hospital decreased from 33 to 17% and the discontinuation of the not corresponding prescriptions increased from 6 to 33%, with an additional information given to the general practitioner (P<0.001). However, during the second phase, 33% of the prescriptions introduced in hospitalization were always not corresponding and 61% of the not corresponding prescriptions begun in outpatient visits were always pursued on discharge, probably due to the lack of sufficient information to stop the prescription. CONCLUSION: Our study underlines the frequent disrespect of the indications in the prescription of PPI. Interestingly, a professional practices evaluation improved the relevance of the prescriptions with a more frequent withdrawal of the not corresponding exposure and a decrease in global not corresponding prescriptions. Our study suggests that it is crucial to regularly inform physicians on the good prescription of PPI. Patient information focused on the indications and the limited duration of PPI prescription, potentially severe side effects of chronic exposure and on the risk of drug interactions also remains necessary in order to facilitate the stop of the exposure and restrict self-medication. PMID- 29628174 TI - Early identification of anti-NMDA receptor encephalitis presenting cerebral lesions in unconventional locations on magnetic resonance imaging. AB - To facilitate the diagnosis of anti-NMDAR encephalitis presenting with brain lesions in unconventional locations (BLUL) on MRI, we retrospectively analyzed forty-five Chinese patients. Eighteen (40.0%) of their MRI initially exhibited one or more BLUL. These locations predominantly included cerebral gray matter (cortex, basal ganglia and thalamus), as well as white matter and brainstem. Due to these BLUL, thirteen (72.2%) patients were originally misdiagnosed with other diseases and developed poor clinical and imaging outcomes. Therefore, anti-NMDAR encephalitis has unpredictable MRI findings that easily obscure its diagnosis and cause serious sequelae. Anti-NMDAR antibody tests are highly recommended in patients with BLUL. PMID- 29628175 TI - Syndemics: A theory in search of data or data in search of a theory? AB - The concept of a syndemic was proposed more than two decades ago to explain how large-scale social forces might give rise to co-occurring epidemics that synergistically interact to undermine health in vulnerable populations. This conceptual instrument has the potential to help policymakers and program implementers in their endeavors to improve population health. Accordingly, it has become an increasingly popular heuristic for advocacy, most notably in the field of HIV treatment and prevention. However, most empirical studies purporting to validate the theory of syndemics actually do no such thing. Tomori et al. (2018) provide a novel case study from India illustrating how the dominant empirical approach fails to promote deeper understanding about how hazardous alcohol use, illicit drug use, depression, childhood sexual abuse, and intimate partner violence interact to worsen HIV risk among men who have sex with men. In this commentary, I relate the theory of syndemics to other established social science and public health theories of disease distribution, identify possible sources of conceptual and empirical confusion, and provide concrete suggestions for how to validate the theory using a mixed-methods approach. The hope is that more evidence can be mobilized -- whether informed by the theory of syndemics or not - to improve health and psychosocial wellbeing among vulnerable populations worldwide. PMID- 29628176 TI - Interpreting carbapenem susceptibility testing results for Pseudomonas aeruginosa. AB - OBJECTIVES: Carbapenems are among the most powerful antipseudomonal agents. Limited data is available on drug susceptibility testing by routine methods (disc diffusion and Etest) for meropenem and doripenem. We aimed to compare the in vitro activity of imipenem, meropenem, and doripenem against Pseudomonas aeruginosa. METHODS: A total of 311 P. aeruginosa strains isolated from respiratory specimens in 170 patients who developed ventilator-associated pneumonia in two intensive care units were collected over a period of 31 months. The susceptibility of these isolates to imipenem, meropenem, and doripenem were determined by Etest and disc diffusion method. RESULTS: Considering either all isolates or only the first isolates recovered per patient (311 and 170 respectively), the susceptibility rate for doripenem was higher than that for meropenem and imipenem. When MICs determined by Etest were converted into interpretative categories (S, I, R) using French (CA-SFM) guidelines, a poor correlation was observed for meropenem and doripenem. The percentages of correlation with the disc diffusion method were 90.6% and 89.7% for imipenem, 80.5% and 82.6% for meropenem, and 80.5% and 73.3% for doripenem, for the first isolates and all isolates, respectively. The rate of minor errors was as high as 17.7% and 16.1% for meropenem and 17.7% and 25.7% for doripenem for the first isolates and all isolates, respectively. CONCLUSION: The accuracy of disc diffusion using CA-SFM guidelines appears unsatisfactory for all three carbapenems justifying guideline update for P. aeruginosa and carbapenems. PMID- 29628177 TI - Cerebrospinal fluid monocytes in bacterial meningitis, viral meningitis, and neuroborreliosis. AB - OBJECTIVE: Cerebrospinal fluid (CSF) leukocytes analysis is commonly used to diagnose meningitis and to differentiate bacterial from viral meningitis. Interpreting CSF monocytes can be difficult for physicians, especially in France where lymphocytes and monocytes results are sometimes pooled. PATIENTS AND METHODS: We assessed SF monocytes in patients presenting with microbiologically confirmed meningitis (CSF leukocyte count>10/mm3 for adults or >30/mm3 for children<2 months), i.e. bacterial meningitis (BM), viral meningitis (VM), and neuroborreliosis (NB). RESULTS: Two-hundred patients (82 BM, 86 VM, and 32 NB) were included. The proportions of monocytes were higher in VM (median 8%; range 0 57%) than in BM (median 5%; range 0-60%, P=0.03) or NB (median 5%; range 0-53%, P=0.46), with a high value overlap between conditions. CONCLUSION: CSF monocytes should not be used to discriminate BM from VM and NB because of value overlaps. PMID- 29628178 TI - A new approach for the design of fractional delay by an FIR filter. AB - Fractional delay filters modeling non-integer delays are digital filters which ideally have flat group delays. In this letter, a new, simple, accurate and efficient FIR filter design to implement the digital ideal fractional delay is presented. The design technique is based on the MacLaurin series expansion formula which is applied to a given function to obtain a closed form FIR digital filter approximation of the digital ideal fractional delay operator z-alpha. The obtained FIR filter approximation formula of the digital ideal fractional delay operator z-alpha is similar to the well known Grunwald-Letnikov FIR digital filter approximation formula of the ideal analog fractional differentiator salpha. Some examples have been presented to illustrate the performance and the effectiveness of this new design method. Some comparisons results show that the proposed design yields better performances than the existing designs in the literature. PMID- 29628179 TI - Modeling and real time simulation of an HVDC inverter feeding a weak AC system based on commutation failure study. AB - This paper presents modeling and study of 12-pulse HVDC (High Voltage Direct Current) based on real time simulation where the HVDC inverter is connected to a weak AC system. In goal to study the dynamic performance of the HVDC link, two serious kind of disturbance are applied at HVDC converters where the first one is the single phase to ground AC fault and the second one is the DC link to ground fault. The study is based on two different mode of analysis, which the first is to test the performance of the DC control and the second is focalized to study the effect of the protection function on the system behavior. This real time simulation considers the strength of the AC system to witch is connected and his relativity with the capacity of the DC link. The results obtained are validated by means of RT-lab platform using digital Real time simulator Hypersim (OP-5600), the results carried out show the effect of the DC control and the influence of the protection function to reduce the probability of commutation failures and also for helping inverter to take out from commutation failure even while the DC control fails to eliminate them. PMID- 29628180 TI - Chaos synchronization of uncertain chaotic systems using composite nonlinear feedback based integral sliding mode control. AB - This paper proposes a combination of composite nonlinear feedback and integral sliding mode techniques for fast and accurate chaos synchronization of uncertain chaotic systems with Lipschitz nonlinear functions, time-varying delays and disturbances. The composite nonlinear feedback method allows accurate following of the master chaotic system and the integral sliding mode control provides invariance property which rejects the perturbations and preserves the stability of the closed-loop system. Based on the Lyapunov- Krasovskii stability theory and linear matrix inequalities, a novel sufficient condition is offered for the chaos synchronization of uncertain chaotic systems. This method not only guarantees the robustness against perturbations and time-delays, but also eliminates reaching phase and avoids chattering problem. Simulation results demonstrate that the suggested procedure leads to a great control performance. PMID- 29628181 TI - Acquired uterine arteriovenous malformation in caesarean scar after a previous ectopic pregnancy: A case report. PMID- 29628182 TI - [Group intervention from a sensorimotor approach to reduce the intensity of chronic pain]. AB - OBJECTIVE: To assess the effectiveness, on people with chronic pain, of an intervention (Time In) designed to reduce pain and to improve psychological symptoms. DESIGN: A randomized clinical trial with a control group, taking three measurements over three months. SETTING: Granada, Spain. PARTICIPANTS: A sample of 40 women aged 18 or older with a history (over 6 months) of chronic pain. The recruitment was in the Fibromyalgia Association of Granada, Spain (AGRAFIM). INTERVENTIONS: Time In is a sensorimotor intervention that combines biomechanical physiotherapeutic procedures and psychological strategies. A weekly session of 3h was planned and the total of the program was developed during five weeks. MAIN MEASUREMENTS: Independent variables: sociodemographic information, clinical history and Time In intervention. Dependent variables: Brief Pain Inventory (BPI S), Short-Form Health Survey (SF-12), Symptom Check List-90-R (SCL-90-R) and Clinical Outcome in Routine Evaluation (CORE-OM). RESULTS: Significant differences were observed between control group and intervention group of most of the scales used in postintervention and follow up measurements. Thus, significantly lower mean scores were obtained in intensity, interference and areas of pain, quality of life, psychological symptoms and behavioural change. Similar results were observed on d Cohen scores. They were 'very important' on intensity of pain (d=-1.01, d=-0.97) and interference of pain (d=-0.85, d=-0.74), with an improvement percentage from 21% to 30%. CONCLUSIONS: Time In intervention reduces pain and improves psychological symptoms in patients with fibromyalgia; this results in a better quality of life. PMID- 29628183 TI - The first French case of MATR3-related distal myopathy: Clinical, radiological and histopathological characterization. PMID- 29628184 TI - The Two-Bag Method for Treatment of Diabetic Ketoacidosis in Adults. AB - BACKGROUND: The "two-bag method" of management of diabetic ketoacidosis (DKA) allows for titration of dextrose delivery by adjusting the infusions of two i.v. fluid bags of varying dextrose concentrations while keeping fluid, electrolyte, and insulin infusion rates constant. OBJECTIVE: We aimed to evaluate the feasibility and potential benefits of this strategy in adult emergency department (ED) patients with DKA. METHODS: This is a before-and-after comparison of a protocol using the two-bag method operationalized in our adult ED in 2015. A retrospective electronic medical record search identified adult ED patients presenting with DKA from January 1, 2013 to June 30, 2016. Clinical and laboratory data, timing of medical therapies, and safety outcomes were collected and analyzed. RESULTS: Sixty-eight patients managed with the two-bag method (2B) and 107 patients managed with the one-bag method (1B) were identified. The 2B and 1B groups were similar in demographics and baseline metabolic derangements, though significantly more patients in the 2B group received care in a hybrid ED and intensive care unit setting (94.1% vs. 51.4%; p < 0.01). 2B patients experienced a shorter interval to first serum bicarbonate >= 18 mEq/L (13.4 vs. 20.0 h; p < 0.05), shorter duration of insulin infusion (14.1 vs. 21.8 h; p < 0.05), and fewer fluid bags were charged to the patient (5.2 vs. 29.7; p < 0.01). Frequency of any measured hypoglycemia or hypokalemia trended in favor of the 2B group (2.9% vs. 10.3%; p = 0.07; 16.2% vs. 27.1%; p = 0.09; respectively), though did not reach significance. CONCLUSIONS: The 2B method appears feasible for management of adult ED patients with DKA, and use was associated with earlier correction of acidosis, earlier discontinuation of insulin infusion, and fewer i.v. fluid bags charged than traditional 1B methods, while no safety concerns were observed. PMID- 29628185 TI - Revisiting colorectal cancer animal model - An improved metastatic model for distal rectosigmoid colon carcinoma. AB - Colorectal cancer (CRC) is the second most frequent and fatal cancer in Western countries. Understanding its biology with different incidence along the colon and rectum, genetic profile and how these factors contribute to local/distant progression, has been hampered by the lack of a suitable CRC model. We report a reproducible model, using human CRC cell lines (CL) (WiDr, LS1034, C2BBe1) injected (1 * 107 cells/animal) in RNU rats (n = 55) which underwent cecostomy and descending colostomy with mucosal-cutaneous fistula of the sigmoid colon. CL were characterized by immunohistochemistry: CK20, CDX2, P53, vimentin, Ki67, CD44, CD133, E-cadherin, beta-catenin and CEA; cancer stem cells-immune system interaction was studied and tumor progression was assessed with nuclear medicine imaging (99mTc-MIBI). Animals developed locally invasive tumors and with WiDr neural invasion was registered. Cancer stem cells were detected in WiDr (CD44 positive). All the cell lines stimulated the immune system, being WiDr the most aggressive. Imaging studies demonstrated tumor uptake. With this CRC model we can study the microenvironment role and tumor-stroma interactions. All CL developed primary disease, but only the WiDR established neural invasion which may represent a metastatic pathway. This model can help unveiling the underlying metastatic mechanisms, and ultimately test better therapeutic approaches for CRC. PMID- 29628187 TI - Reciprocal Circuits Linking the Prefrontal Cortex with Dorsal and Ventral Thalamic Nuclei. AB - Reciprocal interactions between the prefrontal cortex (PFC) and thalamus play a critical role in cognition, but the underlying circuits remain poorly understood. Here we use optogenetics to dissect the specificity and dynamics of cortico thalamo-cortical networks in the mouse brain. We find that cortico-thalamic (CT) neurons in prelimbic PFC project to both mediodorsal (MD) and ventromedial (VM) thalamus, where layer 5 and 6 inputs activate thalamo-cortical (TC) neurons with distinct temporal profiles. We show that TC neurons in MD and VM in turn make distinct connections in PFC, with MD preferentially and strongly activating layer 2/3 cortico-cortical (CC) neurons. Finally, we assess local connections from superficial CC to deep CT neurons, which link thalamo-cortical and cortico thalamic networks within the PFC. Together our findings indicate that PFC strongly drives neurons in the thalamus, whereas MD and VM indirectly influence reciprocally connected neurons in the PFC, providing a mechanistic understanding of these circuits. PMID- 29628186 TI - Amygdala Functional and Structural Connectivity Predicts Individual Risk Tolerance. AB - Risk tolerance, the degree to which an individual is willing to tolerate risk in order to achieve a greater expected return, influences a variety of financial choices and health behaviors. Here we identify intrinsic neural markers for risk tolerance in a large (n = 108) multimodal imaging dataset of healthy young adults, which includes anatomical and resting-state functional MRI and diffusion tensor imaging. Using a data-driven approach, we found that higher risk tolerance was most strongly associated with greater global functional connectivity (node strength) of and greater gray matter volume in bilateral amygdala. Further, risk tolerance was positively associated with functional connectivity between amygdala and medial prefrontal cortex and negatively associated with structural connectivity between these regions. These findings show how the intrinsic functional and structural architecture of the amygdala, and amygdala-medial prefrontal pathways, which have previously been implicated in anxiety, are linked to individual differences in risk tolerance during economic decision making. PMID- 29628188 TI - Dynamic ErbB4 Activity in Hippocampal-Prefrontal Synchrony and Top-Down Attention in Rodents. AB - Top-down attention is crucial for meaningful behaviors and impaired in various mental disorders. However, its underpinning regulatory mechanisms are poorly understood. We demonstrate that the hippocampal-prefrontal synchrony associates with levels of top-down attention. Both attention and synchrony are reduced in mutant mice of ErbB4, a receptor of neuregulin-1. We used chemical genetic and optogenetic approaches to inactivate ErbB4 kinase and ErbB4+ interneurons, respectively, both of which reduce gamma-aminobutyric acid (GABA) activity. Such inhibitions in the hippocampus impair both hippocampal-prefrontal synchrony and top-down attention, whereas those in the prefrontal cortex alter attention, but not synchrony. These observations identify a role of ErbB4-dependent GABA activity in the hippocampus in synchronizing the hippocampal-prefrontal pathway and demonstrate that acute, dynamic ErbB4 signaling is required to command top down attention. Because both neuregulin-1 and ErbB4 are susceptibility genes of schizophrenia and major depression, our study contributes to a better understanding of these disorders. VIDEO ABSTRACT. PMID- 29628189 TI - Development of a congenital cardiovascular computed tomography imaging registry: Rationale and implementation. AB - BACKGROUND: The cumulative exposure and risk of anesthesia, vascular access, contrast agents and radiation is emerging as a significant lifelong burden in patients with congenital heart disease (CHD). Latest generation computerized tomographic (CT) scanners are increasingly used for high resolution cardiovascular imaging and have both hardware and post processing radiation dose reduction strategies that can be implemented. Currently, these dose reduction strategies are not uniformly applied and there is a large variability in radiation dose used for the performance of CT in CHD. METHODS: We propose the development and implementation of a prospective, multi-center and multi-specialty consortium to measure the variability of use, risk and image quality of CT scans in patients of all ages with CHD. The primary goals of this collaboration are 1) define variability of use, diagnostic quality, and risk of cardiac CT 2) establish best practice guidelines designed to optimize diagnostic image quality with appropriate use of radiation and anesthesia exposure 3) provide institution specific feedback compared with the group norm across participating centers 4) improve the level of evidence for the use of CT in CHD through the collection of prospective and multi-institutional data. CONCLUSIONS: Prospective multi institutional data is needed to inform risk estimates of CT in CHD using current generation scanners and aggressive dose optimization techniques. This registry will provide a platform for future collaboration establishing a multi-modality risk assessment tool specific to patients with CHD. PMID- 29628191 TI - Approaching Fatigue and Error in Emergency Medicine: Narrowing the Gap Between Work as Imagined and Work as Really Done. PMID- 29628190 TI - Prognostic Utility of Initial Lactate in Patients With Acute Drug Overdose: A Validation Cohort. AB - STUDY OBJECTIVE: Previous studies have suggested that the initial emergency department (ED) lactate concentration may be an important prognostic indicator for inhospital mortality from acute drug poisoning. We conduct this cohort study to formally validate the prognostic utility of the initial lactate concentration in a larger, distinct patient population with acute drug overdose. METHODS: This observational, prospective, cohort study was conducted during 5 years at 2 urban teaching hospitals. Consecutive adult ED patients with acute drug overdose had serum lactate levels tested as part of clinical care. The primary outcome was inpatient fatality. Receiver operating characteristics were plotted to determine optimal cut points, test characteristics, area under the curve, odds ratios, and 95% confidence intervals (CIs). RESULTS: Of 3,739 patients screened, 1,406 were analyzed (56% women; mean age 43.1 years) and 24 died (1.7%). The difference in mean initial lactate concentration was 5.9 mmol/L (95% CI 3.4 to 8.1 mmol/L) higher in patients who died compared with survivors. The area under the curve for prediction of fatality was 0.85 (95% CI 0.73 to 0.95). The optimal lactate cut point for fatality was greater than or equal to 5.0 (odds ratio 34.2; 95% CI 13.7 to 84.2; 94.7% specificity). Drug classes for which lactate had the highest utility were salicylates, sympathomimetics, acetaminophen, and opioids (all area under the curve >=0.97); lowest utility was for diuretics and angiotensin converting enzyme inhibitors. CONCLUSION: Initial lactate concentration is a useful biomarker for early clinical decisionmaking in ED patients with acute drug overdose. Studies of lactate-tailored management for these patient populations are warranted. PMID- 29628192 TI - Synchronous glioblastoma multiforme and chondrosarcoma: A case report and review of the literature. AB - This case report describes the rare occurrence of two individually uncommon tumours found in synchronous manner in an otherwise healthy patient with no history of malignancy. We believe this to be the first reported case of synchronous glioblastoma and chondrosarcoma. While primary rib lesions metastasising to brain are rarely reported and primary brain lesions metastasising to rib are even rarer still, there were no previous reports in the literature of synchronous brain and rib dual primary pathology that we could identify. Unrelated dual pathology, while rare, must be considered amongst the list of differential diagnoses in patients who present with multiple lesions, and highlights the importance of separate histological confirmation prior to integrated management. PMID- 29628193 TI - Metabolism, Metabolomics, and Inflammation in Posttraumatic Stress Disorder. AB - Posttraumatic stress disorder (PTSD) is defined by classic psychological manifestations, although among the characteristics are significantly increased rates of serious somatic comorbidities, such as cardiovascular disease, immune dysfunction, and metabolic syndrome. In this review, we assess the evidence for disturbances that may contribute to somatic pathology in inflammation, metabolic syndrome, and circulating metabolites (implicating mitochondrial dysfunction) in individuals with PTSD and in animal models simulating features of PTSD. The clinical and preclinical data highlight probable interrelated features of PTSD pathophysiology, including a proinflammatory milieu, metabolomic changes (implicating mitochondrial and other processes), and metabolic dysregulation. These data suggest that PTSD may be a systemic illness, or that it at least has systemic manifestations, and the behavioral manifestations are those most easily discerned. Whether somatic pathology precedes the development of PTSD (and thus may be a risk factor) or follows the development of PTSD (as a result of either shared pathophysiologies or lifestyle adaptations), comorbid PTSD and somatic illness is a potent combination placing affected individuals at increased physical as well as mental health risk. We conclude with directions for future research and novel treatment approaches based on these abnormalities. PMID- 29628195 TI - Sixth cranial nerve palsy in an immunocompetent adult patient with varicella. PMID- 29628194 TI - Metabotropic Glutamate Receptor 5 as a Target for the Treatment of Depression and Smoking: Robust Preclinical Data but Inconclusive Clinical Efficacy. AB - The ability of novel pharmacological compounds to improve outcomes in preclinical models is often not translated into clinical efficacy. Psychiatric disorders do not have biological boundaries, and identifying mechanisms to improve the translational bottleneck between preclinical and clinical research domains is an important and challenging task. Glutamate transmission is disrupted in several neuropsychiatric disorders. Metabotropic glutamate (mGlu) receptors represent a diverse class of receptors that contribute to excitatory neurotransmission. Given the wide, yet region-specific manner of expression, developing pharmacological compounds to modulate mGlu receptor activity provides an opportunity to subtly and selectively modulate excitatory neurotransmission. This review focuses on the potential involvement of mGlu5 receptor disruption in major depressive disorder and substance and/or alcohol use disorders. We provide an overview of the justification of targeting mGlu5 receptors in the treatment of these disorders, summarize the preclinical evidence for negatively modulating mGlu5 receptors as a therapeutic target for major depressive disorders and nicotine dependence, and highlight the outcomes of recent clinical trials. While the evidence of mGlu5 receptor negative allosteric modulation has been promising in preclinical investigations, these beneficial effects have not translated into clinical efficacy. In this review, we identify key challenges that may contribute to poor clinical translation and provide suggested approaches moving forward to potentially improve the translation from preclinical to clinical domains. Such approaches may increase the success of clinical trials and may reduce the translational bottleneck that exists in drug discovery for psychiatric disorders. PMID- 29628196 TI - Effectiveness of Novel Adjuncts in Pain Management Following Total Knee Arthroplasty: A Randomized Clinical Trial. AB - BACKGROUND: Total knee arthroplasty (TKA) can be associated with significant pain which can negatively impact outcomes. Multiple strategies have been employed to reduce pain. The aim of this study is to compare the effectiveness of 3 different pain management modalities after TKA that included (1) our standardized knee injection cocktail and oral acetaminophen, (2) liposomal bupivacaine periarticular injection and oral acetaminophen, and (3) our standardized knee injection cocktail and intravenous (IV) acetaminophen. METHODS: A prospective randomized clinical trial was conducted with 3 perioperative pain management regimes: oral acetaminophen and our standardized knee injection cocktail (standard group), oral acetaminophen and liposomal bupivacaine periarticular injection (LB group), and IV acetaminophen and our standardized knee injection cocktail (IVA group). Primary outcome measures included visual analog scale, total morphine equivalents, and the opioid-related symptoms distress scale at 24 and 48 hours postoperatively. RESULTS: There were no significant differences on visual analog scale/opioid-related symptoms distress scale scores 24 hours after surgery. The LB group required significantly more narcotics (total morphine equivalents) than the standard (P = .025) and IVA groups (P = .032). No significant differences were observed on any of the outcomes measured at 48 hours after surgery. CONCLUSION: Our data suggest that there is no added benefit in the routine use of IV acetaminophen or liposomal bupivacaine after TKA. PMID- 29628197 TI - Bundled Payments for Care Improvement in the Private Sector: A Win for Everyone. AB - BACKGROUND: To help slow the rising costs associated with total joint arthroplasty (TJA), the Centers for Medicare and Medicaid Services introduced the Bundled Payments for Care Improvement (BPCI) initiative. The purpose of this study is to report our 1-year experience with BPCI in our 2 arthroplasty surgeon private practice. METHODS: In this series, a historical baseline group is compared with our first year under BPCI. We reviewed the cohorts with respect to hospital length of stay (LOS), readmission rates, discharge disposition, postacute care LOS, and overall savings on a per episode basis. RESULTS: The baseline group included 582 episodes from July 2009 to June 2012. The BPCI study group included 332 episodes from July 2015 to September 2016. We witnessed a substantial learning curve over the course of our involvement in the initiative. The total reduction in cost per episode for TJA was 20.0% (P = .10). Hospital LOS decreased from 4.9 to 3.5 days (P = .02). All-cause 90-day readmission rates decreased from 14.5% to 8.2% (P = .0078). Overall, discharges to home increased from 11.6% to 49.8% (P = .005). CONCLUSION: Our small, private, 2 arthroplasty surgeon orthopedic practice has shown improvement in postoperative management for TJA patients in 1 year under the BPCI initiative, with increased discharges to home, decreased skilled nursing admissions, days in skilled nursing, and overall readmissions. Because BPCI includes fracture care arthroplasty, the model could be made more equitable if these patients were reimbursed a rate commensurate with their increased costs and risks. PMID- 29628199 TI - Genome editing using CRISPR/Cas9-targeted mutagenesis: An opportunity for yield improvements of crop plants grown under environmental stresses. AB - Developing more crops able to sustainably produce high yields when grown under biotic/abiotic stresses is an important goal, if crop production and food security are to be guaranteed in the face of ever-increasing human population and unpredictable global climatic conditions. However, conventional crop improvement, through random mutagenesis or genetic recombination, is time-consuming and cannot keep pace with increasing food demands. Targeted genome editing (GE) technologies, especially clustered regularly interspaced short palindromic repeats (CRISPR)/(CRISPR)-associated protein 9 (Cas9), have great potential to aid in the breeding of crops that are able to produce high yields under conditions of biotic/abiotic stress. This is due to their high efficiency, accuracy and low risk of off-target effects, compared with conventional random mutagenesis methods. The use of CRISPR/Cas9 system has grown very rapidly in recent years with numerous examples of targeted mutagenesis in crop plants, including gene knockouts, modifications, and the activation and repression of target genes. The potential of the GE approach for crop improvement has been clearly demonstrated. However, the regulation and social acceptance of GE crops still remain a challenge. In this review, we evaluate the recent applications of the CRISPR/Cas9-mediated GE, as a means to produce crop plants with greater resilience to the stressors they encounter when grown under increasing stressful environmental conditions. PMID- 29628200 TI - Public Policy and Health Informatics. AB - OBJECTIVES: To provide an overview of the history of electronic health policy and identify significant laws that influence health informatics. DATA SOURCES: US Department of Health and Human Services. CONCLUSION: The development of health information technology has influenced the process for delivering health care. Public policy and regulations are an important part of health informatics and establish the structure of electronic health systems. Regulatory bodies of the government initiate policies to ease the execution of electronic health record implementation. These same bureaucratic entities regulate the system to protect the rights of the patients and providers. IMPLICATIONS FOR NURSING PRACTICE: Nurses should have an overall understanding of the system behind health informatics and be able to advocate for change. Nurses can utilize this information to optimize the use of health informatics and campaign for safe, effective, and efficient health information technology. PMID- 29628201 TI - Re: Influence on neonatal outcomes of rocuronium for rapid sequence induction of general anaesthesia for caesarean section. PMID- 29628198 TI - Slow-Wave Activity Enhancement to Improve Cognition. AB - Slow-wave activity (SWA), and its coupling with other sleep features, reorganizes cortical circuitry, supporting cognition. This raises the question: can cognition be improved through SWA enhancement? SWA enhancement techniques range from behavioral interventions (such as exercise), which have high feasibility but low specificity, to laboratory-based techniques (such as transcranial stimulation), which have high specificity but are less feasible for widespread use. In this review we describe the pathways through which SWA is enhanced. Pathways encompass enhanced neural activity, increased energy metabolism, and endocrine signaling during wakefulness; also direct enhancement during sleep. We evaluate the robustness and practicality of SWA-enhancement techniques, discuss approaches for determining a causal role of SWA on cognition, and present questions to clarify the mechanisms of SWA-dependent cognitive improvements. PMID- 29628202 TI - Health status of Afro-Asian refugees in an Italian urban area: a cross-sectional monocentric study. AB - OBJECTIVES: The recent sociopolitical events in the Mediterranean and Middle Eastern areas have significantly impacted international migration flows. As disease prevalence and type are different among western and Afro-Asian countries, physicians dealing with refugees should be aware of their specific health needs. We aimed at evaluating the health status and disease history of refugees at their arrival in the urban area of L'Aquila (Italy). STUDY DESIGN: This is a monocentric cross-sectional study. METHODS: Refugees hosted at the local reception center in L'Aquila (Italy) between July 2014 and December 2014 were cross-sectionally evaluated for anamnestic, clinical, and laboratory features. A subset of randomly selected participants underwent further assessments (screening for tuberculosis, hepatitis B/C, human immunodeficiency virus, syphilis; ambulatory blood pressure measurement [ABPM]) to better define their health status. RESULTS: Ninety-three adult male refugees (27.34 +/- 7.41 years) from Africa (76%) and Asia (24%) were enrolled. Overall, the most prevalent diseases according to the International Statistical Classification of Diseases and Related Health Problems 10th revision affected the digestive tract (15.6%) and musculoskeletal apparatus (14.4%). The analysis by continent of origin did not show significant differences in the distribution of diseases, although a trend toward some differences was observed. African refugees had a significantly greater prevalence of viral hepatitis (hepatitis B virus, P = 0.004; hepatitis C virus, P = 0.007) compared with Asians. Hypertension, as detected by ABPM, was uncommon. No written vaccination history was available. CONCLUSIONS: Health issues of our sample of Afro-Asian refugees span both non-communicable and communicable diseases, requiring attention for the safety of the individual and the community. National health systems should provide adequate information and shared guidelines for health professionals regarding identification and management of refugees' health needs. PMID- 29628203 TI - A comparative analysis of psychological trauma experienced by children and young adults in two scenarios: evacuation after a natural disaster vs forced migration to escape armed conflict. AB - OBJECTIVES: Little is known about the psychological trauma experienced by children and young adults (CYAs) following displacement after natural disasters vs migration from conflict zones. In both instances, the decision to leave is usually cast by the family, and the life of CYAs is suddenly disrupted by external circumstances. STUDY DESIGN: An anonymous survey. METHODS: The same survey instrument, provided by the National Child Traumatic Stress Network (NCTSN), was used to survey self-reported health needs among CYAs during the aftermath of Hurricane Katrina (Health Survey for Children and Adolescents After Katrina) in October 2005-February 2006 and again during the peak of refugee arrivals in Berlin between October 2015 and March 2016. A weighted index to measure cumulative exposure to traumatic stresses during migration was developed along with an unweighted psychological impact score based on the 22-item NCTS psychological impact questionnaire. Spearman's correlation coefficient (rho) was used to assess the correlation between age and the two psychological impact indices. The two-tailed t-test was used to investigate differences in trauma experienced and psychological impact by gender. Logistic regression was used to investigate differences in types of traumatic stress experienced and psychological impact among CYAs displaced because of Hurricane Katrina and those seeking asylum in Berlin. RESULTS: The Katrina cohort included a total of 1133 CYAs, the Berlin cohort, a total of 405 CYAs. The median age in the Katrina cohort was 6.73 years (standard deviation [SD] 5.67, range 0-24; 50.13% males) compared with 17.64 years (SD, range 0-24; 83% males) in the Berlin cohort. Comparative analyses were adjusted to age and gender and revealed significant differences between the two cohorts, both with regards to the amount of trauma experienced and the psychological impact. A statistically significant and moderate positive correlation was observed between trauma experienced and psychological impact of migration in the refugee population (rho = 0.4955, P < 0.001); the correlation was less pronounced but still significant in the Katrina cohort (rho = 0.0942, P = 0.0015). Free-text responses revealed that in addition to common concerns about health, housing and safety, refugees were also pre occupied with language acquisition and the adaptation to a new culture. CONCLUSIONS: The observed differences in the experience and the consequences of trauma in displaced CYAs warrant additional investigation. It was replicated that human-made disaster seems to show more traumatising potential than natural disaster. Stakeholders need to be aware of the potential medium and long-term consequences of migration/evacuation and allocate resources accordingly. PMID- 29628204 TI - [Evaluation of an automatic delineation system for organs at risk and target lymph nodes volumes for patients treated for breast cancer]. AB - PURPOSE: Intensity-modulated radiotherapy needs the strict delineation of target volumes as well as organs at risk and the time used for this procedure is long. The purpose of this study was to evaluate the Workflow Box system (Mirada Medical, UK) for automatic delineation and segmentation for everyday use of organs at risk and lymph nodes delineation in patients treated for early stage breast cancer. MATERIAL AND METHODS: Twenty patients' CT scans in treatment position for their breast cancer radiotherapy were delineated in respect of the ESTRO delineation guidelines to begin the creation of automatic delineation atlas. Then 30 other CT scans were delineated this time by the automatic delineation system and by the radiation oncologist (reference delineation plan). The precision of the delineation was evaluated using the overlap volume index and evaluation of standard deviation (SD). RESULTS: The study of organs at risk has shown that the mean overlap volumes were between 0.49 (SD=0.21) and 0.97 (ET=0.03). Five organs at risk out of nine had overlap volumes at least 0.8. The mean overlap volume for all organs at risk was 0.77 (SD=0.17). The system was less performing for the lymph nodes with a mean overlap volume of 0.43 (SD=0.1) and ranging between 0.23 (SD=0.13) and 0.52 (SD=0.1). The use of this system reduced the delineation time by 40% per patient. CONCLUSIONS: For patients with breast cancer, the system for automatic delineation and segmentation Workflow Box (Mirada Medical, UK) permitted to safely shorten the time for delineation with acceptable organs at risk delineation. Improvement of lymph node volumes is needed. A new evaluation will be realized after using the system in routine practice. PMID- 29628205 TI - Dose constraints for moderate hypofractionated radiotherapy for prostate cancer: The French genito-urinary group (GETUG) recommendations. AB - Considering recent phase III trials results, moderate hypofractionated radiotherapy can be considered as a standard treatment for low and intermediate risk prostate cancer management. This assessment call for a framework allowing homogeneous and reproducible practices in the different centers using this radiotherapy schedule. The French Genito-Urinary Group (GETUG) provides here recommendations for daily practice of moderate hypofractionated radiotherapy for prostate cancer, with indications, dose, fractionation, pre-treatment planning, volume of interest delineation (target volume and organs at risk) and margins, dose constraints and radiotherapy techniques. PMID- 29628207 TI - Inguinal hernia in preterms in neonatal intensive care units: Optimal timing of herniorrhaphy and necessity of contralateral exploration in unilateral presentation. AB - BACKGROUND: We sought to determine the optimal timing of IH repair in preterms and the need for routine contralateral exploration. METHODS: Medical records of 3690 pediatric patients who underwent unilateral IH repair between January 1998 and December 2009 were reviewed. We assessed medical record review and telephone interviews. In total, 1990 patients were enrolled in the study. Early, early delayed, and late repair were defined as herniorrhaphy performed within 7 days of diagnosis, later than 7 days of diagnosis, and after discharge from the NICU, respectively. RESULTS: Of 1990 patients, 90 preterms and 1900 full-terms were included. Among these, 7, 11 and 72 preterm patients received early, early delayed and late IH repairs, respectively. Preoperative incarceration and postoperative complication rates were not different, but the recurrence rate was higher in the early repair group. Two group analysis of early and early-delayed vs. late repairs indicated similar results. The rates of synchronous and metachronous bilateral IH (SBIH, MBIH) were observed to be higher and the diagnostic interval of MBIH was shorter in preterms than in full-terms (35.6% vs. 15.9%, P < 0.001; 12.2% vs. 6.3%, P < 0.001; 5.2 vs. 41.8 months, P = 0.003). CONCLUSION: Our results indicate that IH repair is safe to perform in preterm babies in the NICU at a delayed or late stage since the preoperative incarceration and recurrence rates were not different. Contralateral exploration could be considered in preterms because the rates of SBIH and MBIH were significantly higher and the MBIH diagnosis interval was shorter than in full terms. LEVEL OF EVIDENCE: III, treatment study. PMID- 29628206 TI - Odorant receptor might be related to sperm DNA integrity in Apis cerana cerana. AB - Olfactory receptors (ORs) are important for insects to recognize and discriminate odorants in the environment and are mainly expressed in olfactory and gustatory organs. Little is known about the potential OR functions in non-olfactory tissues. In the present study, we evaluated the possibility of odorant receptors AcerOr1 and AcerOr2 (AcerOr2 is orthologous to the co-receptor) mediating sperm DNA integrity, and the relationship between sperm DNA integrity and semen parameters in Apis cerana cerana. Based on previous findings in mammals, we speculated that the Ca2+/calmodulin (CaM)/CaM-dependent protein kinase II (CaMKII) signaling pathway might be involved in the regulation of sperm motility in A. cerana cerana. The results showed that both AcerOr1 and AcerOr2 are expressed in the sperms and testis, that components associated with the putative Ca2+/CaM/CaMKII signaling pathway are present in A. cerana cerana sperms, and that at least CaM and CaMKII are localized in the sperms and testis. The AcerOr2 agonist VUAA1 significantly improved sperm motility parameters and apoptosis of sperm cells effect DNA integrity, whereas the CaM inhibitor W7 decreased sperm motility parameters and apoptosis of sperm cells, which affects DNA integrity. We also found a positive correlation between sperm DNA integrity and semen quality. These results indirectly as well as directly suggest that OR-mediated sperm responses and the Ca2+/CaM/CaMKII signaling pathway might affect semen quality and might be useful in regulating insect reproduction in future. PMID- 29628208 TI - Complex gastroschisis: Clinical spectrum and neonatal outcomes at a referral center. AB - AIM OF THE STUDY: To evaluate the outcomes of neonates with complex gastroschisis (GC), and correlate outcomes with each type of complication. METHODS: Retrospective review of patients with complex GC owing to prenatal and/or postnatal abdominal complications; 2008-2016. Primary outcomes: time to discontinue parenteral nutrition (off-PN), length of stay (LOS) and neonatal survival. MAIN RESULTS: We treated 58 patients with complex gastroschisis owing to abdominal complications, which were: intestinal necrosis at birth (n=9), intestinal atresia (n=16), medical necrotizing enterocolitis (NEC) (n=15), surgical NEC (n=1), in utero volvulus (n=1), vanishing gastroschisis (n=2), severe intestinal dysmotility (n=1), delayed abdominal closure (n=3), abdominal compartment syndrome (n=2) and hiatal hernia/severe gastroesophageal reflux disease (GERD; n=11). The off-PN time and LOS of the whole group were 92 (35-255) and 119 (42-282) days, significantly longer than those of a demographically equivalent contemporaneous series of 125 patients with uncomplicated gastroschisis (off-PN 32 [12-105] days [p<0.001]; LOS 41 [18-150] days [p<0.001]). Patients with intestinal necrosis at birth or with intestinal atresia had the longest off-PN and LOS times (133 [38-255] / 157 [43-282] and 114 [36 222] / 143 [42-262] days, respectively), followed by patients with complications of the abdominal wall closure (n=5) (69 [43-93] / 89 [58-110] days), patients with hiatal hernias/severe GERD who required fundoplication (63 [35-84] / 89 [57 123] days) and patients who developed medical NEC (67 [35-103] / 76 [50-113] days). Short-bowel syndrome/PN-dependence occurred in 6/58 (10%) patients (2 vanishing gastroschisis, 1 in utero volvulus, 2 intestinal atresias and 1 bowel necrosis at birth). There were no neonatal mortalities. CONCLUSION: Gastroschisis can be complicated by a wide variety of prenatal and postnatal events. The most severe outcomes occur in patients with bowel necrosis at birth, intestinal atresias, or vanishing gastroschisis. Complications, however, did not affect neonatal survival in our experience. LEVEL OF EVIDENCE: III. PMID- 29628209 TI - Outcomes in patients with short bowel syndrome after autologous intestinal reconstruction: Does etiology matter? AB - BACKGROUND: Short bowel syndrome (SBS) is the most common cause of intestinal failure in children. Many factors have been investigated in an attempt to define which parameters influence most survival and ability to wean off parenteral nutrition (PN). The aim of this study was to investigate if aetiology of SBS affects the outcomes in paediatric patients treated with autologous gastrointestinal reconstructive surgery. METHODS: All children with SBS who underwent autologous gastrointestinal reconstructive surgery between 2002 and 2012 were retrospectively reviewed and outcome measures were recorded. RESULTS: Forty-three patients were divided into 4 groups according to aetiology (gastroschisis, volvulus, necrotizing enterocolitis (NEC), intestinal atresia). No significant differences were found among groups regarding survival and median age at surgery. The volvulus group had a lower pre-operative bowel length in comparison with gastroschisis and intestinal atresia and the lowest percentage of patients off PN (30%). Gastroschisis had the lowest rate of preserved ileocaecal valve (10%), while intestinal atresia had the highest (66%). For children who weaned off PN, intestinal atresia had also the longest time to achieve enteral autonomy (14.5months), while NEC had the shortest (3.5months), followed by gastroschisis (8.5months). None of the patients needed transplant. CONCLUSIONS: In our experience it does not appear that diagnosis is significantly related to outcome and this is consistent with the conclusions of other reviews. However, it should be noted that in our series patients with volvulus had the worse outcome in terms of weaning off PN when compared with intestinal atresia. TYPE OF STUDY: Retrospective Study. LEVEL OF EVIDENCE: II. PMID- 29628210 TI - Formation of Chromatin Subcompartments by Phase Separation. AB - Chromatin is partitioned on multiple length scales into subcompartments that differ from each other with respect to their molecular composition and biological function. It is a key question how these compartments can form even though diffusion constantly mixes the nuclear interior and rapidly balances concentration gradients of soluble nuclear components. Different biophysical concepts are currently used to explain the formation of "chromatin bodies" in a self-organizing manner and without consuming energy. They rationalize how soluble protein factors that are dissolved in the liquid nuclear phase, the nucleoplasm, bind and organize transcriptionally active or silenced chromatin domains. In addition to cooperative binding of proteins to a preformed chromatin structure, two different mechanisms for the formation of phase-separated chromatin subcompartments have been proposed. One is based on bridging proteins that cross link polymer segments with particular properties. Bridging can induce a collapse of the nucleosome chain and associated factors into an ordered globular phase. The other mechanism is based on multivalent interactions among soluble molecules that bind to chromatin. These interactions can induce liquid-liquid phase separation, which drives the assembly of liquid-like nuclear bodies around the respective binding sites on chromatin. Both phase separation mechanisms can explain that chromatin bodies are dynamic spherical structures, which can coalesce and are in constant and rapid exchange with the surrounding nucleoplasm. However, they make distinct predictions about how the size, density, and stability of chromatin bodies depends on the concentration and interaction behavior of the molecules involved. Here, we compare the different biophysical mechanisms for the assembly of chromatin bodies and discuss experimental strategies to distinguish them from each other. Furthermore, we outline the implications for the establishment and memory of functional chromatin state patterns. PMID- 29628212 TI - Chromatin Higher-Order Folding: A Perspective with Linker DNA Angles. AB - The mechanism by which the "beads-on-a-string" nucleosome chain folds into various higher-order chromatin structures in eukaryotic cell nuclei is still poorly understood. The various models depicting higher-order chromatin as regular helical fibers and the very opposite "polymer melt" theory imply that interactions between nucleosome "beads" make the main contribution to the chromatin compaction. Other models in which the geometry of linker DNA "strings" entering and exiting the nucleosome define the three-dimensional structure predict that small changes in the linker DNA configuration may strongly affect nucleosome chain folding and chromatin higher-order structure. Among those studies, the cross-disciplinary approach pioneered by Jorg Langowski that combines computational modeling with biophysical and biochemical experiments was most instrumental for understanding chromatin higher-order structure in vitro. Strikingly, many recent studies, including genome-wide nucleosome interaction mapping and chromatin imaging, show an excellent agreement with the results of three-dimensional computational modeling based on the primary role of linker DNA geometry in chromatin compaction. This perspective relates nucleosome array models with experimental studies of nucleosome array folding in vitro and in situ. I argue that linker DNA configuration plays a key role in determining nucleosome chain flexibility, topology, and propensity for self-association, thus providing new implications for regulation of chromatin accessibility to DNA binding factors and RNA transcription machinery as well as long-range communications between distant genomic sites. PMID- 29628213 TI - [Progressive elevation of CA 19-9 tumour marker in a nonagenarian with advanced idiopathic pulmonary fibrosis]. PMID- 29628211 TI - Major Determinants of Nucleosome Positioning. AB - The compact structure of the nucleosome limits DNA accessibility and inhibits the binding of most sequence-specific proteins. Nucleosomes are not randomly located on the DNA but positioned with respect to the DNA sequence, suggesting models in which critical binding sites are either exposed in the linker, resulting in activation, or buried inside a nucleosome, resulting in repression. The mechanisms determining nucleosome positioning are therefore of paramount importance for understanding gene regulation and other events that occur in chromatin, such as transcription, replication, and repair. Here, we review our current understanding of the major determinants of nucleosome positioning: DNA sequence, nonhistone DNA-binding proteins, chromatin-remodeling enzymes, and transcription. We outline the major challenges for the future: elucidating the precise mechanisms of chromatin opening and promoter activation, identifying the complexes that occupy promoters, and understanding the multiscale problem of chromatin fiber organization. PMID- 29628214 TI - [Neuroleptic malignant syndrome after withdrawal of levopoda]. PMID- 29628215 TI - [What is geriatrics for you?] PMID- 29628216 TI - [Doege-Potter syndrome: Presentation of a case]. PMID- 29628217 TI - Development and characterization of a point-of care rate-based transcutaneous respiratory status monitor. AB - Blood gas measurements provide vital clinical information in critical care. The current "gold standard" for blood gas measurements involves obtaining blood samples, which can be painful and can lead to bleeding, thrombus formation, or infection. Mass transfer equilibrium-based transcutaneous blood gas monitors have been used since the 1970s, but they require heating the skin to >=42 degrees C to speed up the transcutaneous gas diffusion. Thus, these devices have a potential risk for skin burns. Here we report a new generation of noninvasive device for respiratory status assessment. Instead of waiting for mass transfer equilibrium, the blood gas levels are monitored by measuring the transcutaneous diffusion rate, which is proportional to blood gas concentration. The startup time of this device is almost independent of skin temperature, so the measurement can be made at any body temperature. The test results show that this device can track the blood gas levels quickly even at normal body temperature. PMID- 29628218 TI - Effects of Sex Hormones and Age on Brain Volume in Post-Menopausal Women. AB - BACKGROUND: Investigation of the effect of sex hormones on the brain volume in women provides a unique opportunity to examine menopause-related morphometric alterations. AIM: To evaluate brain morphological alterations in post-menopausal women using voxel-based morphometry and its correlations with sex hormone levels. METHODS: 20 Pre-menopausal women and 20 post-menopausal women underwent structural MRI. OUTCOMES: T1-weighted magnetic resonance data were acquired and serum sex hormones including total estrogen, estriol, estradiol (E2), follicle stimulating hormone, free testosterone, SHBG, and luteinizing hormone were measured. RESULTS: Post-menopausal women showed decreased gray matter (GM) in the supplementary motor area (SMA), inferior frontal gyrus, olfactory cortex, and superior temporal gyrus as contrasted with pre-menopausal women using analysis of covariance (P < .05). The GM volume (GMV) values of the SMA, inferior frontal gyrus, and superior temporal gyrus were positively correlated with the levels of E2 in the pre-menopausal and post-menopausal women, in which the volume of the SMA was negatively correlated with the duration of time after menopause in post menopausal women. CLINICAL TRANSLATION: This finding is potentially applicable to assess the brain dysfunction with morphological changes in post-menopausal women. CONCLUSIONS: Our study is the first to evaluate a direct relationship between the level of E2 and GMV change. We directly compared pre-menopausal and menopausal women un-matched in age. This study highlights the menopause-related morphological alterations in post-menopausal women, suggesting that the reduced GMV were closely associated with the symptoms of menopause caused by the decreased levels of E2. Kim G-W, Park K, Jeong G-W. Effects of Sex Hormones and Age on Brain Volume in Post-Menopausal Women. J Sex Med 2018;15:662-670. PMID- 29628219 TI - Psychiatrists' and dentists' knowledge and attitudes regarding adverse drug reactions of psychotropic drugs. AB - Psychotropic drugs may induce impairments in the mouth, jaw and face area. Currently, appropriate pharmacoepidemiologic data are missing. Therefore, a questionnaire-based telephone survey of two non-representative samples of psychiatrists and dentists was conducted. Most of the psychiatrists (79.7%) and dentists (76.5%) indicated that psychotropic drugs may induce dental adverse drug reactions (ADR); in both samples there was an approximately equally sized, relevant proportion of participants who did not believe in the risk of dental ADR of psychotropic drugs (psychiatrists 20.3%; dentists 23.5%). About one third of the participants of both samples (psychiatrists 34.9%; dentists 35.9%) felt that dental ADRs of psychotropic drugs are a serious health problem. The majority of both groups (psychiatrists 97.8%; dentists 97.0%) had never reported a dental ADR. Most psychiatrists and dentists appeared to be aware of the risk of dental ADRs by psychotropic drugs. A relevant proportion of participants of both groups considered psychotropic drugs to be irrelevant regarding dental ADRs; therefore, there may be information needs in both groups. The willingness to report dental ADRs of psychotropic drugs was low in both groups; the evaluation of the actual relevance of this drug-related risk is impeded by the absence of reports of suspected ADRs. PMID- 29628220 TI - A Qualitative Exploration Into the Parent-Child Feeding Relationship: How Parents of Preschoolers Divide the Responsibilities of Feeding With Their Children. AB - OBJECTIVE: To explore the extent to which parents divide responsibilities of feeding (what, when, where, how much, and whether) with their children and the factors that influence parents' approach to feeding. DESIGN: Individual interviews. PARTICIPANTS: Parents (n = 40) of preschoolers. PHENOMENON OF INTEREST: Division of feeding responsibilities; motivation for feeding approach; challenges to feeding. ANALYSIS: Audio-recorded interviews were transcribed verbatim and coded using deductive and inductive content analysis. RESULTS: Parent's approaches to feeding varied widely. A few parents followed the Division of Responsibility approach closely. Instead, many parents gave their child more than the recommended amount of influence over what foods were served and offered children less than the recommended amount of autonomy over the whether and how much of eating. Meals and snacks were approached differently; parents exhibited less control over the timing of snacks as well as the types and amounts of foods eaten during snacks, compared with the control exhibited during meals. CONCLUSIONS AND IMPLICATIONS: These data support future research to understand the impact of this framework on child health outcomes when it is adhered to on all eating occasions, including snacks. Collaboration by researchers and clinicians to explore alternative frameworks that encourage parents to provide the structure and autonomy support may enhance positive outcomes in children. PMID- 29628221 TI - Validation of quantitative measurements and semi-quantitative estimates of emerging perfluoroethercarboxylic acids (PFECAs) and hexfluoroprolyene oxide acids (HFPOAs). AB - Legacy perfluorinated compounds exhibit significant environmental persistence and bioaccumulation potential, which has spawned an ongoing effort to introduce replacement compounds with reduced toxicological risk profiles. Many of these emerging chemical species lack validated quantitative methods, and, frequently, appropriate analytical standards for accurate monitoring and identification. To fill this knowledge gap, a general method for the quantitative determination of perfluoroether carboxylic acids (PFECAs) by LC-MS/MS was single-lab validated on spike-recovery samples in surface, drinking, and wastewater for a variety of perfluorinated ether standards. Relative error measurements for spike-recovery samples in each matrix ranged from 0.36% to 25.9%, with an average error of 10% overall. Coefficient of variation (CV) for each compound ranged from 10 to 28% with an average of 17%. The quantitative methodology was applied during repeated weekly monitoring of the Cape Fear River during remediation of PFECA hexafluoropropyloxide dimer-acid (HFPO-DA), known by the brand name "GenX." Semi quantitative concentration estimates for emerging PFECA compounds lacking analytical standards was also carried out using surrogate calibration curves and mass labeled HFPO-DA as an internal standard. Estimates of the emerging compounds were possible using matched standards, but application of the estimation methodology to compounds with known concentration revealed that such estimates may possess up to an order of magnitude, or more, in uncertainty due to the difficulty of matching with an appropriate standard. Nevertheless, the estimation biases are primarily systematic (extraction efficiency and instrument response) rather than stochastic, enabling the collection of time-course data; both HFPO-DA and the emerging compounds were reduced in surface water and drinking water concentration of several orders of magnitude after removal of the source waste stream. PMID- 29628222 TI - Time to discharge following diagnostic coronary procedures via transradial artery approach: A comparison of Terumo band and StatSeal hemostasis. AB - BACKGROUND: The transradial artery (TRA) approach for cardiac catheterization is associated with fewer complications, earlier mobilization and a shorter stay at the hospital. The objective of this study was to determine whether hemostasis with a combination of a compression band (Terumo TR bandTM) and a hemostatic patch (StatSealTM) decreases the time to discharge from the hospital compared to the Terumo (TR) band alone in patients undergoing diagnostic coronary catheterizations through a TRA approach. METHODS: We retrospectively looked at 445 patients who underwent diagnostic coronary angiography through the TRA approach at the Jack and Jane Hamilton Heart and Vascular Hospital, Dallas, Texas between July 2016 and June 2017. The difference in the time to discharge between the two groups was assessed by a Wilcoxon Rank-sum test. RESULTS: The combination of a TR band and a StatSeal hemostatic patch was used in 70.3% (313) of the patients. Comparison of the two groups demonstrated a statistically significant reduction in time from the end of the procedure to discharge (p < 0.001), with no significant alteration in safety among those with a combination of TR band and a StatSeal hemostatic patch. CONCLUSION: With increasing frequency of TRA procedures in the United States, we demonstrate one effective method to significantly reduce the time to radial hemostasis and reduce the time to patient discharge from the hospital. PMID- 29628223 TI - The distal left radial artery access for coronary angiography and intervention: A new era. AB - BACKGROUND: Patients' intra and post procedural comfort, quick recovery, as well as procedure success, are key elements for choosing the right arterial access site. Radial artery access has been of increasing interest since it was first described. Advanced treatments of coronary lesions, from primary percutaneous interventions during ST elevation myocardial infarction cases to chronic total occlusion cases, have been increasingly done through the radial access. Distal left trans radial artery (dlTRA) is a new technique first described by Kiemineij. We report the first documented US experience of the left distal radial artery access for coronary angiography and interventions. METHODS: dlTRA was attempted on 22 consecutive patients, consented for a cardiac catheterization. 7 patients underwent percutaneous coronary intervention. The left hand is prepped in the usual fashion, exposing the anatomical snuff box. Under ultrasound guidance, the artery is punctured and the sheath is inserted carefully. The cardiac catheterization is completed using standard diagnostic and guiding catheters, that are typically chosen for femoral artery access. Hemostasis was achieved with a radial band. Patients had the ability to use the right hand as well as bend their left wrist post procedure. RESULTS: dlTRA was successful in all 22 patients. 7 patients underwent PCI through this approach. Two patients required a multivessel complex PCI with multiple stents and additional equipment. There were no conversions to the right radial or femoral approach. All patients had excellent hemostasis with a radial band, with no complications. Pre discharge radial pulses were intact in the wrist as well as in the anatomical snuff box. CONCLUSION: Distal left trans radial access is feasible and safe in patients that are carefully selected and are deemed good candidates. There is a learning curve for developing such program, as is the case with conventional radial access. PMID- 29628224 TI - High-Dynamic-Range Ultrasound: Application for Imaging Tendon Pathology. AB - Raw ultrasound (US) signal has a very high dynamic range (HDR) and, as such, is compressed in B-mode US using a logarithmic function to fit within the dynamic range of digital displays. However, in some cases, hyper-echogenic tissue can be overexposed at high gain levels with the loss of hypo-echogenic detail at low gain levels. This can cause the loss of anatomic detail and tissue texture and frequent and inconvenient gain adjustments, potentially affecting the diagnosis. To mitigate these drawbacks, we employed tone mapping operators (TMOs) in HDR photography to create HDR US. We compared HDR US produced from three different popular TMOs (Reinhard, Drago and Durand) against conventional US using a simulated US phantom and in vivo images of patellar tendon pathologies. Based on visual inspection and assessments of structural fidelity, image entropy and contrast-to-noise ratio metrics, Reinhard and Drago TMOs substantially improved image detail and texture. PMID- 29628225 TI - Synthesis, characterization, and antifungal evaluation of diethoxyphosphoryl polyaminoethyl chitosan derivatives. AB - Botrytis cinerea, Phytophthora capsici Leonian, and Fusarium solani are important plant pathogenic fungi which can cause great crop losses worldwide, but their control methods are limited. It is necessary to develop efficient and green fungicides from abundant marine resources. Chitosan is a non-toxic, biodegradable, biocompatible marine polysaccharide which has prospective applications in agriculture. In this paper, to increase the antifungal activity of chitosan for application, novel water-soluble functional chitosan derivatives were synthesized by grafting polyaminoethyl and diethoxyphosphoryl groups in accordance with a strategy of improving protonation potential. The derivatives were characterized by FTIR, NMR, XRD, SEM, Gaussian 09 and elemental analysis. The antifungal activities against the three fungi and the cytotoxicity were estimated in vitro. The results showed that the derivatives had better antifungal activities and water solubility than chitosan, and had good biocompatibility. They confirmed that these chitosan derivatives can be developed as antifungal agents for plant protection purposes. PMID- 29628226 TI - Chitosan composites with Ag nanoparticles formed in carbonic acid solutions. AB - Chitosan-based hydrogels with stabilized Ag nanoparticles were synthesized in the aqueous solutions of carbonic acid, i.e. water saturated with CO2 under pressure in hundreds of bars. Such a medium is biocompatible and self-neutralizing at decompression. The influence of various parameters, such as chitosan molecular weight, molar ratio of chitosan to silver, additional stabilization of gels by genipin as a cross-linking agent, on the structure of the chitosan/Ag composites was investigated using transmission electron microscopy, scanning electron microscopy, X-ray diffraction analysis, rheology measurements. The distributions of chitosan-stabilized Ag nanoparticles in a chitosan matrix turned out to be uniform, their average size was in the range of 2-5 nm. The higher degree of Ag nanoparticles reduction could be achieved using self-eliminating gaseous hydrogen as an additional reducing agent being admixed to CO2. This was consistently confirmed by different research methods (TEM, XRDA, UV-vis spectroscopy). PMID- 29628227 TI - Structural characterization and anticancer activity of extracellular polysaccharides from ascidian symbiotic bacterium Bacillus thuringiensis. AB - In the present study, extracellular polysaccharides (EPS) producing bacterium Bacillus thuringiensis RSK CAS4 was isolated from ascidian Didemnum granulatum and its production was optimized by response surface methodology. Fructose and galactose were found as the major monosaccharides in the EPS from the strain RSK CAS4. Functional groups and structural characteristics of the EPS were characterized with FT-IR and 1HNMR. The purified EPS showed potent antioxidant properties in investigation against DPPH, hydroxyl, superoxide free radicals. In vitro anticancer activity of purified EPS was evaluated on HEp-2 cells, A549 and Vero cell lines. Growth of cancer cells was inhibited by the EPS in a dose dependent manner and maximum anticancer activity was found to be 76% against liver cancer at 1000 MUg/ml. The antioxidant and anticancer potentials of theEPS from marine bacterium Bacillusthuringiensis RSK CAS4 suggests it as a potential natural source and its scopeas an alternative to synthetics for pharmaceutical application. PMID- 29628228 TI - A wheat straw cellulose-based hydrogel for Cu (II) removal and preparation copper nanocomposite for reductive degradation of chloramphenicol. AB - A hydrogel (wheat straw cellulose-g-poly (acrylic acid)/poly (vinyl alcohol) (WSC g-PAA/PVA)) was prepared and applied firstly as adsorbent for Cu(II) ions recovery and secondly as a template for in situ preparation of Cu nanoparticles. The adsorption performance of the hydrogel towards Cu(II) ions removal was investigated, indicating the adsorption capacity was 142.7 mg/g. The copper nanoparticles embodied in hydrogel were analyzed and confirmed by SEM with EDS, TEM, XRD and AFM. The reductive degradation of chloramphenicol (CAP) by WSC-g PAA/PVA-Cu nanocomposite as catalyst with NaBH4 was optimized through response surface methodology. The effect of three variables (temperature, the amount of nanocomposite, the amount of NaBH4) was investigated using the Box-Behnken design. The optimization conditions of three factors were obtained as 0.03 g WSC g-PAA/PVA-Cu with 0.03 g NaBH4 at 20 degrees C and the obtained reduction rate of CAP was 90.59%. Activation energy was 21.41 kJ mol-1 for the reduction reaction. PMID- 29628229 TI - Insights into gelation kinetics and gel front migration in cation-induced polysaccharide hydrogels by viscoelastic and turbidity measurements: Effect of the nature of divalent cations. AB - Polysaccharide-based hydrogels were prepared by the diffusion of various divalent cations (X2+) into the polygalacturonate (polyGal) solution through a dialysis membrane. The diffusion of various divalent cations (Mg2+, Ca2+, Zn2+ and Ba2+) was investigated. The polyGal gel growth was studied as a function of the initial cation concentration by both viscoelastic and turbidity measurements. We have demonstrated for the first time that the determination of the spatiotemporal variation of turbidity during the gelation process allowed to study the gel front migration. For Ca-polyGal, Zn-polyGal and Ba-polyGal, the gel front migration was characterized by the presence of a peak at the sol/gel interface. This peak was not observed in the case of Mg-polyGal where the gel was not formed. The apparent diffusion coefficient of the gel front (Dapp) which was calculated from the evolution of this peak increased when the initial cation concentration was increased. Moreover, we have suggested a gelation mechanism based on the presence of a threshold molar ratio R* (=[X2+]/[Galacturonic unit]) in which some point like crosslinks are precursors of the formation of dimers and multimers inducing the contraction of the gel and thus the formation of the gel front. PMID- 29628230 TI - Chitosan stabilized nasal emulsion delivery system for effective humoral and cellular response against recombinant tetravalent dengue antigen. AB - Nasal vaccine delivery systems are emerging alternatives to the conventional sub unit vaccine delivery systems owing to their ability to stimulate potent antigen specific humoral and cellular immune responses. Additional virtue of nasal delivery is its close proximity of immune cells to external epithelial layer which is the route of entry to pathogens. Toxicity of emulsion based vaccine delivery systems may be attributed to the presence of high quantities of surfactants used for stabilizing the emulsions. A safer approach would be to reduce physiologically unwanted surfactant burden in the emulsion to the bare limit to necessity. Oleic acid was used as oil phase due to its ability to enhance penetration of system in nasal mucosa. This emulsion was designed with the purpose that it activates the innate (TLR 4) and adaptive immune systems apart from performing its antigen delivery function. Proving the hypothesis, emulsion when immunized along with recombinant tetravalent dengue antigen has elicited a profound antigen specific humoral and cellular response. Antigen cross presenting and sustained release of antigen by emulsion is the key factor in shaping this immune response. Moreover, the dose sparing effect of emulsion has also been proven which has a crucial role in modern day vaccine delivery. This significant humoral and cellular response elicited proves the suitability of this emulsion system for enhancing the protective effect of vaccines against various intracellular pathogens. PMID- 29628231 TI - Spin-coating: A new approach for improving dispersion of cellulose nanocrystals and mechanical properties of poly (lactic acid) composites. AB - This study systematically evaluated the influence of masterbatch preparation techniques, solvent casting and spin-coating methods, on composite properties. Composites were manufactured by combining CNCs masterbatches and PLA resin using twin screw extruder followed by injection molding. Different microscopy techniques were used to investigate the dispersion of CNCs in masterbatches and composites. Thermal, thermomechanical, and mechanical properties of composites were evaluated. Scanning electron microscopy (SEM) images showed superior dispersion of CNCs in spin-coated masterbatches compared to solvent cast masterbatches. At lower CNCs concentrations, both SEM and optical microscope images confirmed more uniform CNCs dispersion in spin-coated composites than solvent cast samples. Degree of crystallinity of PLA exhibited a major enhancement by 147% and 380% in solvent cast and spin-coated composites, respectively. Spin-coated composites with lower CNCs concentration exhibited a noticeable improvement in mechanical properties. However, lower thermal characteristics in spin-coated composites were observed, which could be attributed to the residual solvents in masterbatches. PMID- 29628232 TI - Base-free preparation of low molecular weight chitin from crab shell. AB - Low molecular weight (LMW) chitin exhibits antimicrobial activity, and its preparation generally employs high molecular weight chitin as raw material. Here we use raw crab shell as material to isolate LMW-chitin. The raw crab shell was treated with hydrochloric acid under different conditions, and the demineralization and deproteinization of acid to the raw and demineralized crab shell were examined. Under conditions of 3-5 wt% acid, 110 degrees C, and 180 600 min, the obtained LMW-chitin owns 92% purity and 53-80 kDa molecular weight. The method provides feasible one-step base-free strategy to directly obtain LMW chitin from raw crab shell, and could be potentially extended to other chitin sources. PMID- 29628233 TI - Fluorescence probe based carboxymethyl cellulose/Tb(III) nanocomposites for detection of Mn2+ with simpleness, rapidness and high sensitivity. AB - A novel, rapid, high selective and sensitive probe, carboxymethyl cellulose (CMC)/Tb(III) with green fluorescence, for detecting Mn2+ in aqueous solution during pH = 4-10 was proposed in this work. The probe's synthesis had benefits of mild reaction condition, organic solvent-free and facile operation. A linear relationship between the fluorescence intensity of CMC/Tb(III) probe at 544 nm with 0.046 MUM detection limitation and the concentration of Mn2+ in the range of 0.1-100 MUM was obtained. The probe was also used to detected Mn2+ in tap water and the recoveries were between 97.10% and 101.61%, and the relative standard deviations (RSD, n = 5) of all samples were less than 2.04%. The results by UV absorption spectrum and fluorescence quenching suggested that there might be a dynamic quenching occurred to the fluorescence of CMC/Tb(III) probe when Mn2+ was involved. PMID- 29628234 TI - Dextran derivatives application as flocculants. AB - A large variety of hydrophilic and amphiphilic polyelectrolytes based on dextran have been previously tested as coagulating and flocculating agents in model wastewater treatment and the results are presented in this review article. The dextran derivatives are either cationic, bearing (i) pendent quaternary ammonium groups, N-alkyl-N,N-dimethyl-N-(2-hydroxypropyl)ammonium chloride and (ii)1-(2 hydroxypropyl)-3-methyl imidazolium chloride, randomly distributed along the polymer backbone or anionic, (i) dextran monobasic phosphate with HP(O)(OH) groups and (ii) dextran derivatives with carboxylic groups namely, dextran-g poly(acrylamide-co-sodium acrylates). This paper will give an overview of the main results obtained in the separation of suspensions and emulsions containing either inorganic (clay, titanium dioxide, zirconium silicate (kreutzonit), zinc oxide and ferric oxide (hematite)) or organic (pesticides: Fastac 10EC, Decis, Dithane M45) contaminants. The investigations considered the influence of some polyelectrolyte characteristics (the charge density, the length of the alkyl substituent, the molecular mass), polyelectrolyte dose and initial concentration, as well as the properties of the model suspensions/emulsions (contaminants concentration, dispersion medium composition and pH) on the separation process. Turbidity/absorbance, zeta potential and particle dimensions measurements allowed to determine the polycation dose where the maximum separation efficiency was obtained, the flocculation mechanism and the floc size and distribution for each peculiar system. PMID- 29628235 TI - The synthesis of a new unsaturated derivative of chondroitin sulfate with increased antioxidant properties. AB - Chondroitin sulfate (CS) was regio-specifically modified to an unsaturated derivative (DeltaCS) with a double bond in positions 4 and 5 of N-acetyl-d galactosamine. The structure of DeltaCS was elucidated in detail by two dimensional nuclear magnetic resonance, ultraviolet spectroscopy and mass spectrometry. The introduction of a nucleophilic CC double bond into a polymer backbone had no influence on biocompatibility of CS, which was demonstrated by MTT live-dead assay and enzymatic degradation in vitro. On the other hand the chemical modification significantly enhanced the reactivity of DeltaCS towards numerous oxidizing agents, which might be promising for a variety of biomedical and cosmetic applications. PMID- 29628236 TI - Fabrication and evaluation of nanocellulose sponge for oil/water separation. AB - Nanocellulose sponge was fabricated by a facile method: freeze-drying of nanocellulose aqueous suspension to sponge state, following by hydrophobic treatment with stearoyl chloride at 50 degrees C for 1 h. The obtained nanocellulose sponge showed superhydrophobicity (160 degrees of water contact angle) and superoleophilicity with high protection from water but selective absorption of oil. Its absorption capacities for various kinds of oil and non polar liquids were 25-55 times higher than its dry weight and exhibited excellent selectivity for absorbing of oil which spilled on the surface of water or underwater with high separation efficiency. This superhydrophobic nanocellulose sponge can be easily recovered by simple squeezing and reused at least 10 cycles with remained high separation efficiency. It is expected that such a biodegradable nanocellulose sponge can be applied to solve the oil spill accident and treat the oily wastewater from households and industries. PMID- 29628237 TI - In situ observation of gelation of methylcellulose aqueous solution with viscosity measuring instrument in the diamond anvil cell. AB - Gelation of methylcellulose aqueous solution was investigated by a high-pressure viscosity measurement device which consisted of diamond anvil cell, microscope and CCD. And the temperature and pressure dependence of the viscosity of methylcellulose aqueous solution was measured utilizing a rolling-ball technique. The results showed that sol-gel thermal transition of methylcellulose solution occurred at the temperature of 53 degrees C under atmospheric pressure. Upon compression, it was indicated that the viscosity showed a dramatic change in the vicinity of the pressure of 500 MPa. Parabolic phase diagram of methylcellulose aqueous solution was constructed, and it showed that the melting point was an increasing function of pressure at the first stage and an decreasing function of pressure at the final stage. The mechanism of sol-gel transformation of methylcellulose aqueous solutions was also discussed, it might be assumed that both hydrogen and hydrophobic bonds were involved with the gel formation in the case of methylcellulose aqueous solution. PMID- 29628238 TI - Effects of konjac glucomannan on the structure, properties, and drug release characteristics of agarose hydrogels. AB - Pure agarose (AG) hydrogels have strong rigidity and brittleness, which greatly limit their applications. Therefore, in this study, konjac glucomannan (KGM) was used to improve the properties of AG hydrogels. The effect of KGM on the structure and properties of AG hydrogels was investigated by rotational rheometry, Fourier Transform Infrared Spectroscopy, X-ray Diffraction, and Scanning Electron Microscopy. The results showed that the flexibility of the composite hydrogels increases with KGM concentration, which may be attributed to a synergistic interaction between KGM and AG resulting in a compact network structure. In vitro drug release behavior of composite hydrogels was investigated under different environments using model drug ciprofloxacin. The results showed that the encapsulation, drug loading efficiencies, and sustained release capacity of AG hydrogels were enhanced by the incorporation of KGM. These results suggested that KGM has the potential to enhance the properties and drug release characteristics of AG hydrogels. PMID- 29628239 TI - Development of plasticized edible films from Opuntia ficus-indica mucilage: A comparative study of various polyol plasticizers. AB - Mucilage polysaccharide was extracted from Opuntia ficus-indica cladodes (Cactaceae) and its composition was determined by sugar analysis using HPLC-RID and its structural features were elucidated by FTIR and 1H and 13C NMR. Films from the extracted mucilage were loaded at 40% (w/w) with glycerol, sorbitol, PEG 200 or PEG 400. The physical, thermal, mechanical and barrier properties of the obtained films were investigated. The highest water vapor barrier properties of plasticized mucilage films were obtained with sorbitol reaching water vapor permeability (WVP) values up to 3 times lower than the other films. The tensile strength (TS) values of films plasticized with PEG 200 and sorbitol were about 2 times higher than those of glycerol-plasticized films. The significant effect of polyol type plasticizers on the different properties of mucilage edible films was related to their structural features that promote different interactions with mucilage polysaccharides as demonstrated by FTIR and thermal properties. PMID- 29628240 TI - Birch wood pre-hydrolysis vs pulp post-hydrolysis for the production of xylan based compounds and cellulose for viscose application. AB - Hydrothermal treatments of birch wood and kraft pulp were compared for their ability to extract the xylan and produce viscose-grade pulp. Water post hydrolysis of kraft pulp produced a high-purity cellulosic pulp with lower viscosity but higher cellulose yield than traditional pre-hydrolysis kraft pulping of wood. Post-hydrolysis of pulp also increased the crystallite dimensions and degree of crystallinity in cellulose, and promoted a higher extent of fibril aggregation. The lower specific surface area in post-hydrolyzed pulps, derived from their larger fibril aggregates, decreased the accessibility of OH groups. However, this lower accessibility did not seem to decrease the pulp reactivity to derivatizing chemicals. In the aqueous side-stream, the xylose yield was similar in both pre- and post-hydrolysates, although conducting post hydrolysis of pulp in a flow-through system enabled the recovery of high purity and molar mass (~10 kDa) xylan for high-value applications. PMID- 29628241 TI - Selective synthesis of curdlan omega-carboxyamides by Staudinger ylide nucleophilic ring-opening. AB - Chemoselective modification of polysaccharides is a significant challenge, and regioselective modification is even more difficult, due to the low and similar reactivity of the various polysaccharide hydroxyl groups. Bromination of glycans that possess free 6-OH groups is exceptional in that regard, giving regiospecific, high-yield access to 6-bromo-6-deoxyglycans. Herein we report a simple and efficient pathway for synthesizing 6-omega-carboxyalkanamido-6-deoxy containing polysaccharide derivatives in a sequence starting from 6-bromo-6 deoxycurdlan, via azide displacement, then conversion of the azide to the iminophosphorane ylide by triphenylphosphine (Ph3P). We take advantage of the nucleophilicity of the iminophosphorane nitrogen by subsequent regioselective ring-opening reactions of cyclic anhydrides. These reactions of the useful polysaccharide curdlan were essentially completely regio- and chemo-selective, proceeding under mild conditions in the presence of ester groups, yet preserving those groups. These interesting polysaccharide-based materials have pendant carboxyls attached through a hydrocarbon tether and hydrolytically stable amide linkage; as such they are promising for diverse application areas, including aqueous dispersions for coatings, adhesives, and other consumer products, and for amorphous solid dispersions in oral drug delivery. PMID- 29628242 TI - Biofunctionalization of beta-cyclodextrin nanosponges using cholesterol. AB - Cyclodextrins nanosponges (CD-NSPs) are highly microporous crosslinked polymers with potential applications in the delivery of small and macro-molecular therapeutic agents. Despite the potent host-guest inclusion property, their inherent lack of cellular binding ability has limited applications in drug delivery. Herein, we functionalized the surface of beta-cyclodextrin nanosponge (beta-CD-NSP) with cholesterol, which is endogenous physiological molecules, widely distributed in all cells, and responsible for cell interactions and protein binding. The surface grafting of synthesized beta-CD-NSP was confirmed with spectroscopic, microscopic, thermogravimetric, and chromatographic techniques. Moreover, beta-CD-NSP was found to be safe in cytotoxicity assay. Doxorubicin (Dox) was selected as a model drug for drug adsorption study of cholesterol hydrogen succinate (CHS) grafted beta-CD-NSP. The cellular uptake of NSP was found to be enhanced after CHS modification confirmed by confocal laser scanning microscopy (CLSM). Thus, proposed CHS modified beta-CD-NSP system could be used as a site-specific drug delivery carrier. PMID- 29628243 TI - Structural characterization and antitumor activity of a polysaccharide from ramulus mori. AB - This study investigated the chemical characterization and antitumor effects of a polysaccharide from ramulus mori. A water-soluble polysaccharide, RMP1 with the estimated molecular weight of 137 kDa, was isolated and purified from ramulus mori through gel permeation chromatography. RMP1 is mainly composed of arabinose, xylose, glucose, galactose and rhamnose in a ratio of 0.56:0.37:0.17:1.00:0.08. Methylation and NMR analysis revealed that RMP1 had a backbone composed of 1,6 beta-d-Galp, 1,3,6-beta-d-Galp and 1,3-beta-d-Galp residues, two main branches of 1,2-alpha-l-Araf, 1,3,6-beta-d-Galp and 1,4-beta-d-Xylp; it also had alpha-l-Araf and beta-d-Glcp as terminals. In the MTT assay, RMP1 showed significant anticancer effects against the SGC-7901 and HeLa cells. In addition, no cytotoxicity was observed on the HEK-293 and RAW 264.7 cells. Flow cytometry showed that RMP1 exerted a stimulatory effect on the SGC-7901 cells apoptosis and induced the cell cycle arrest at the S phases. These findings suggest that RMP1 may serve as a potential novel antitumor agent. PMID- 29628244 TI - Development of electrosprayed mucoadhesive chitosan microparticles. AB - The efficacy of chitosan (CS) to be used as drug delivery carrier has previously been reported. However, limited work has been pursued to produce stable and mucoadhesive CS electrosprayed particles for oral drug delivery, which is the aim of this study. Various CS types with different molecular weight (MW), degree of deacetylation (DD), and degree of polymerization (DP) were assessed. In addition, the effect of the solvent composition was also investigated. Results showed that stable CS electrosprayed particles can be produced by dissolving 3% w/v of low MW CS in mixtures of aqueous acetic acid and ethanol (50/50% v/v). The stable CS particles displayed diameters of approximately 1 MUm as determined by dynamic light scattering. The zeta potential of these particles was found to be approximately 40 mV confirming the mucoadhesion properties of these CS electrosprayed particles and its potential to be used as drug delivery carrier. PMID- 29628245 TI - Chitosan nanoparticle antigen uptake in epithelial monolayers can predict mucosal but not systemic in vivo immune response by oral delivery. AB - This study compared in vitro and in vivo antigen delivery effects of ultrapure chitosan (CS) chloride. CS nanoparticles were formulated to incorporate ovalbumin (OVA) as a model antigen and characterised for size, charge, OVA complexation and release. The effect of CS:OVA nanoparticles on cell viability, epithelial tight junctions and transepithelial permeation of OVA was tested on Caco-2 monolayer in vitro intestinal model. The system's ability to elicit immune responses was subsequently tested in vivo. The work confirmed that CS complexes with OVA into nano-size entities. Nanocomplexes displayed favourable delivery properties, namely OVA release and no notable cytotoxicity. CS:OVA markedly enhanced antigen delivery across Caco-2 monolayers. However, the system did not elicit notable in vivo immune responses (some mucosal response was apparent) following oral delivery. The study highlights that a clear effect on antigen permeability across epithelial monolayers in vitro may predict the in vivo mucosal but not systemic immune response following oral delivery. PMID- 29628246 TI - Preparation of elastic diglycolamic-acid modified chitosan sponges and their application to recycling of rare-earth from waste phosphor powder. AB - Inspired by the phenomenon of sponges soaking up water, a novel syringe-like adsorption device used diglycolamic-acid modified chitosan sponges (CSs-DGAA) as adsorbents is reported for recycling of rare-earth elements (REEs) by Squeezing & Soaking (S&S) operation. Integrating the elasticity of sponges and selective extraction ability of diglycolamic acid groups, the new device can efficiently recycle REEs from aqueous solutions. This device only needs 10 min to achieve adsorption equilibrium; squeezing the water from the sponges achieves solid liquid separation. This syringe-like adsorption method not only solves the pollution problem caused by the organic solvents used during liquidliquid extractions, but also improves the time needed to achieve adsorption equilibrium and uses significantly less energy than energy intensive solid-phase extractions of solid-liquid separations. Moreover, the environment-friendly adsorbents effectively recycle yttrium and europium from waste phosphor powders. These experimental results demonstrated that the S&S method based on polymeric sponges has potential application in hydrometallurgy and environmental remediation. PMID- 29628247 TI - New cellulose crystallinity estimation method that differentiates between organized and crystalline phases. AB - A new method is proposed for estimation of cellulose crystallinity (CrI) based on 93 cm-1 Raman band in spectra of cellulose I materials. In this method (93 Raman), CrI was determined based on regression that was developed using the ratios of peak-heights of the 93 and 1096 cm-1 Raman bands (I93/I1096). For calibration purposes, a set of eight samples, all derived from cotton microcrystalline cellulose Whatman CC31 were selected. When the peak intensity ratios (I93/I1096) were plotted against the calculated CrIs of the calibration set samples, the plot showed an excellent linear correlation (R2 = 0.9888). The 93-Raman method was used to estimate crystallinities of a number of cellulose materials including poplar wood samples that were hydrothermally treated at various temperatures. The wood 93-Raman CrI data showed that the method is able to differentiate between organized and crystalline phases of cellulose, a capability lacking in many other CrI estimation methods. PMID- 29628248 TI - Synthesis and evaluation of functional alginate hydrogels based on click chemistry for drug delivery applications. AB - Environment-sensitive alginate-based hydrogels for drug delivery applications are receiving increasing attention. However, most work in this field involves traditional cross-linking strategies which led to hydrogels with poor long-term stability. Herein, a series of chemically cross-linked alginate hydrogels was synthesized via click chemistry using Diels-Alder reaction by reacting furan modified alginate and bifunctional cross-linkers. Alginate was successfully functionalized with furfurylamine. Then, 3D architectures were synthesized with water-soluble bismaleimides. Different substitution degrees were achieved in order to study the effect of alginate modification and the cross-linking extent over the behaviour of the hydrogels. The ensuing hydrogels were analysed in terms of microstructure, swelling, structure modification and rheological behaviour. The materials response to external stimuli such as pH was also investigated, revealing a pulsatile behaviour in a large pH range (1-13) and a clear pH dependent swelling. Finally, vanillin release studies were conducted to demonstrate the potential of these biobased materials for drug delivery applications. PMID- 29628249 TI - Dextran hydrogels incorporated with bioactive glass-ceramic: Nanocomposite scaffolds for bone tissue engineering. AB - A series of nanocomposite scaffolds comprised of dextran (Dex) and sol-gel derived bioactive glass ceramic nanoparticles (nBGC: 0-16 (wt%)) were fabricated as bioactive scaffolds for bone tissue engineering. Scanning electron microscopy showed Dex/nBGC scaffolds were consisting of a porous 3D microstructure with an average pore size of 240 MUm. Energy-dispersive x-ray spectroscopy illustrated nBGC nanoparticles were homogenously distributed within the Dex matrix at low nBGC content (2 wt%), while agglomeration was observed at higher nBGC contents. It was found that the osmotic pressure and nBGC agglomeration at higher nBGC contents leads to increased water uptake, then reduction of the compressive modulus. Bioactivity of Dex/nBGC scaffolds was validated through apatite formation after submersion in the simulated body fluid. Dex/nBGC composite scaffolds were found to show improved human osteoblasts (HOBs) proliferation and alkaline phosphatase (ALP) activity with increasing nBGC content up to 16 (wt%) over two weeks. Owing to favorable physicochemical and bioactivity properties, the Dex/nBGC composite hydrogels can be offered as promising bioactive scaffolds for bone tissue engineering applications. PMID- 29628250 TI - Semi-IPN superabsorbent nanocomposite based on sodium alginate and montmorillonite: Reaction parameters and swelling characteristics. AB - Semi-interpenetrating polymer network (semi-IPN) superabsorbent nanocomposite based on montmorillonite (MMT) and sodium alginate (NaAlg)-g-poly(acrylic acid(AA))/polyvinylpyrrolidone (PVP) was synthesized. Chemical structure and surface morphology of the hydrogels were characterized by FTIR, XRD, thermogravimetric analysis (TGA), SEM, and TEM techniques. FTIR results revealed that graft polymerization, PVP interpenetration through hydrogel network, and nanocomposite formation have occurred. The coarse surface of the hydrogels was changed into interlinked porous structures in the presence of MMT. The effect of polymerization variables on water absorbency of the hydrogels was assessed and optimized. Semi-IPN superabsorbent nanocomposite presented higher equilibrium swelling capacity (618.92 g/g) compared with neat hydrogel (521.17 g/g). Swelling behavior of the hydrogels strongly depended on pH values of the solution as well as the type and concentration of saline solution. Semi-IPN superabsorbent nanocomposite possessed good reswelling capability, making it as an efficient water reservoir to supply required water to plants in agricultural applications. PMID- 29628251 TI - Assessing the potential of quartz crystal microbalance to estimate water vapor transfer in micrometric size cellulose particles. AB - This study aims at assessing the use of a quartz crystal microbalance (QCM) coupled with an adsorption system to measure water vapor transfer properties in micrometric size cellulose particles. This apparatus allows measuring successfully water vapor sorption kinetics at successive relative humidity (RH) steps on a dispersion of individual micrometric size cellulose particles (1 MUg) with a total acquisition duration of the order of one hour. Apparent diffusivity and water uptake at equilibrium were estimated at each step of RH by considering two different particle geometries in mass transfer modeling, i.e. sphere or finite cylinder, based on the results obtained from image analysis. Water vapor diffusivity values varied from 2.4 * 10-14 m2 s-1 to 4.2 * 10-12 m2 s-1 over the tested RH range (0-80%) whatever the model used. A finite cylinder or spherical geometry could be used equally for diffusivity identification for a particle size aspect ratio lower than 2. PMID- 29628252 TI - Processing and antibacterial properties of chitosan-coated alginate fibers. AB - The preparation of chitosan-coated alginate fibers by a wet spin process is presented and the characterization of the antibacterial activities of these fibers is discussed. Preformed calcium alginate fibers were passed in chitosan acetate solutions. The coagulation method of the coating consisted in the immersion of fibers in a bath of calcium dihydroxide solution (0.1 M). The antibacterial evaluation was achieved by a CFU (Colony-Forming Units) counting method after 6 h of incubation at 37 degrees C. The incorporation of chitosan on calcium alginate fibers brings antibacterial activities against Staphylococcus epidermidis, Escherichia coli and various Staphylococcus aureus strains namely MSSA (Methicillin Sensitive Staphylococcus aureus), CA-MRSA (Community Associated Methicillin Resistant Staphylococcus aureus) and HA-MRSA (Healthcare Associated Methicillin Resistant Staphylococcus aureus) which make these chitosan-coated fibers potential candidates for wound dressing materials. Developing a wound dressing with the haemostatic and healing properties of alginate combined with antibacterial properties of chitosan is envisioned for fighting against the infections and more particularly nosocomial diseases. PMID- 29628253 TI - Interactions between fava bean protein and dextrans produced by Leuconostoc pseudomesenteroides DSM 20193 and Weissella cibaria Sj 1b. AB - The aim of this study was to study the interactions between dextran and fava bean protein. Two dextrans produced by Leuconostoc pseudomesenteroides DSM 20193 and Weissella cibaria Sj 1b were purified and mixed with fava bean protein isolate (FPI) in water or in different buffers. The two isolated dextrans presented a typical dextran structure, mainly alpha-(1 -> 6) linkages (above 95%) and few alpha-(1 -> 3) branches, but they differed in molar mass and conformation. Dry heating incubation of FPI and dextran mixture facilitated the conjugation of dextran to FPI through the Maillard reaction. Both mixed and conjugated systems were further heat-treated, and different influences of the formed covalent bonds on rheological properties were observed. The W. cibaria Sj 1b dextran had a much higher gel-strengthening ability than the Ln. pseudomesenteroides DSM 20193 dextran. The intermolecular FPI-dextran interactions played an important role in stabilizing the mixed systems at different pH. PMID- 29628254 TI - Chitin nanocrystal enhanced wet adhesion performance of mussel-inspired citrate based soft-tissue adhesive. AB - Chitin nanocrystal (ChiNC) with its good biodegradability and biocompatibility as well as rod-like structure characteristic has become one of excellent nanofillers to enhance mechanical properties and bioactivity of biomedical polymers. For further extending its application fields, here, we dispersed ChiNC into a recently synthesized citrate-based tissue adhesive (POEC-d) and explored its effects on the adhesion and cytocompatibility of the adhesive. POEC-d, a mussel inspired wet adhesive, was prepared by a one-pot melt polycondensation of 1, 8 octanediol, poly(ethylene oxide) (PEO), citric acid (CA) and dopamine (DA). The good water-solubility of POEC-d allowed facilely blending ChiNC and POEC-d to ultimately acquire POEC-d/ChiNC nanocomposite adhesives. The results showed the ChiNCs were finely dispersed in the POEC-d matrix and endowed the adhesive with extra crosslinks to enhance the bulk cohesion property. Synchronously, the lap shear adhesion strengths measured by bonding wet porcine skins considerably improved with increasing the ChiNC content. In addition, the POEC-d/ChiNC nanocomposite adhesives exhibited lower swelling ratio as compared to the POEC-d adhesive as well as good cytocompatibility, revealing their superior applicability in soft-tissue adhesion. PMID- 29628255 TI - Molecular dynamics simulations of theoretical cellulose nanotube models. AB - Nanotubes are remarkable nanoscale architectures for a wide range of potential applications. In the present paper, we report a molecular dynamics (MD) study of the theoretical cellulose nanotube (CelNT) models to evaluate their dynamic behavior in solution (either chloroform or benzene). Based on the one-quarter chain staggering relationship, we constructed six CelNT models by combining the two chain polarities (parallel (P) and antiparallel (AP)) and three symmetry operations (helical right (HR), helical left (HL), and rotation (R)) to generate a circular arrangement of molecular chains. Among the four models that retained the tubular form (P-HR, P-HL, P-R, and AP-R), the P-R and AP-R models have the lowest steric energies in benzene and chloroform, respectively. The structural features of the CelNT models were characterized in terms of the hydroxymethyl group conformation and intermolecular hydrogen bonds. Solvent structuring more clearly occurred with benzene than chloroform, suggesting that the CelNT models may disperse in benzene. PMID- 29628256 TI - Chitosan/pvp-based mucoadhesive membranes as a promising delivery system of betamethasone-17-valerate for aphthous stomatitis. AB - Mucoadhesive membranes were proposed in this study as drug delivery system for betamethasone-17-valerate (BMV) in the treatment of recurrent aphthous stomatitis (RAS). The membranes were obtained by using the polymers chitosan (CHI) in both presence and absence of polyvinilpyrrolidone (PVP), following the solvent evaporation method. The presence of PVP in the membranes causes significant modifications in its thermal properties. Changes in the thermal events at 114 and 193 degrees C (related to BMV melting point), and losses in mass (39.38 and 30.68% for CH:PVP and CH:PVP-B, respectively), suggests the incorporation of BMV in these membranes. However, the morphological aspects of the membranes do not change after adding PVP and BMV. PVP causes changes in swelling ratios (>80%) of the membranes, and it is suggested that the reorganization of the polymer mesh was highlighted by the chemical interactions between the polymers leading to different percentages of BMV released ~40% and ~80% from CH-B and CH:PVP-B. BMV release profile follows Korsmeyer and Peppas model (n > 0.89) which suggests that the diffusion of the drug in the swollen matrix is driven by polymer relaxation. In addition, the membranes containing PVP (higher swelling ability) present high rates of tensile strength, and therefore, higher mucoadhesion. Moreover, given the results presented, the developed mucoadhesive membranes are a promising system to deliver BMV for the treatment of RAS. PMID- 29628257 TI - Atomic force microscopy of adsorbed proteoglycan mimetic nanoparticles: Toward new glycocalyx-mimetic model surfaces. AB - Blood vessels present a dense, non-uniform, polysaccharide-rich layer, called the endothelial glycocalyx. The polysaccharides in the glycocalyx include polyanionic glycosaminoglycans (GAGs). This polysaccharide-rich surface has excellent and unique blood compatibility. We report new methods for preparing and characterizing dense GAG surfaces that can serve as models of the vascular endothelial glycocalyx. The GAG-rich surfaces are prepared by adsorbing heparin or chondroitin sulfate-containing polyelectrolyte complex nanoparticles (PCNs) to chitosan-hyaluronan polyelectrolyte multilayers (PEMs). The surfaces are characterized by PeakForce tapping atomic force microscopy, both in air and in aqueous pH 7.4 buffer, and by PeakForce quantitative nanomechanics (PF-QNM) mode with high spatial resolution. These new surfaces provide access to heparin-rich or chondroitin sulfate-rich coatings that mimic both composition and nanoscale structural features of the vascular endothelial glycocalyx. PMID- 29628258 TI - Enzymatic extraction of pectin from artichoke (Cynara scolymus L.) by-products using Celluclast(r)1.5L. AB - The aim of this study was to optimise pectin extraction from artichoke by products with Celluclast(r)1.5L using an experimental design analysed by response surface methodology (RSM). The variables optimised were artichoke by-product powder concentration (2-7%, X1), enzyme dose (2.2-13.3 U g-1, X2) and extraction time (6-24 h, X3). The variables studied were galacturonic acid (GalA) (R2 93.9) and pectic neutral sugars (R2 92.8) content and pectin yield (R2 88.6). In the optimum extraction conditions (X1 = 6.5%; X2 = 10.1 U g-1; X3 = 27.2 h), pectin yield was 176 mgg-1 dry matter (DM). Considering 27.2 h of treatment as the +alpha value given by the design, the extraction time was increased up to 48 h obtaining a yield of 221 mg g-1 DM. The enzymatic method optimised allows obtaining artichoke pectin with good yield, high GalA (720 mg g-1 DM) and arabinose (127.6mgg-1 DM) contents and degree of methylation of 19.5%. PMID- 29628259 TI - Fucogalactan from the giant mushroom Macrocybe titans inhibits melanoma cells migration. AB - An aqueous extract containing polysaccharides was obtained from the giant mushroom Macrocybe titans, and it was purified by amylase treatment, freeze thawing process and dialysis. The purified fraction (ESP) was analyzed by HPSEC and GC-MS which showed a homogenous polysaccharide with Mw 14.2 * 103 g/mol composed by galactose and fucose. NMR and methylation analysis of ESP confirmed the presence of a fucogalactan with a (1 -> 6)-linked alpha-d-Galp main chain partially substituted at O-2 by non reducing end units of alpha-l-Fucp residues in the side chain. Its biological activity was evaluated against murine melanoma cells B16-F10. The fucogalactan did not alter the viability, proliferative capacity and morphology of cells. However, this polysaccharide was able to reduce the cell migration in vitro at 40% (100 MUg/mL) and 33% (250 MUg/mL). The results obtained showed that Macrocybe titans fucogalactan is a promising agent capable of altering melanoma cell migration without decrease the cell viability. PMID- 29628260 TI - Injectable self-crosslinking HA-SH/Col I blend hydrogels for in vitro construction of engineered cartilage. AB - The injectable self-crosslinking blend hydrogel by combination of collagen I and thiolated hyaluronic acid could alleviate collagen I contraction in vitro and overcome weak cell adhesive sites of hyaluronic acid. Five groups of injectable hydrogels with different ratios were prepared to investigate their gelation time, injection force, mechanical properties, swelling capacity and disintegration performance. These results indicated that Col7HA-SH3 hydrogel achieved the optimal controlled and injectable effect, the gelation time was just ten seconds with injection force at 3.5 N, and the storage modulus of hydrogel could reach 11 kPa with frequency at 10 Hz. Furthermore, the phenotype maintaining, biocompatibility and chondrocytes proliferation were administrated by CLSM, SEM, histological staining, immuohistochemical staining, MTT test and glycoaminoglycans quantification. Similarly, the Col7HA-SH3 blend hydrogel encapsulated chondrocytes presented most excellent proliferation potential, phenotype maintaining, biocompatibility and convenient operational characteristics. These findings might approach the underlying clinical application of blend hydrogel in cartilage repair. PMID- 29628261 TI - Activity diversity structure-activity relationship of polysaccharides from lotus root varieties. AB - The in vitro activities of 39 polysaccharides from different parts of 13 lotus root varieties were evaluated and introduced into multiple linear regression analysis to explore the structure-activity relationships using their chromatographic fingerprint features as independent variables. Their 2,2-diphenyl 1-picrylhydrazyl/hydroxyl radical scavenging abilities, ferric reducing antioxidant powers and growth-inhibitory effects against HepG2 and SGC7901 cancer cells were all diverse, with the variable-coefficients ranging from 24.49% to 87.76%, while their macrophage immunostimulatory activities evaluated by nitric oxide production and tumor necrosis factor-alpha secretion showed relatively low variations. Lotus root polysaccharides (LRPs) from the peels and nodes possessed stronger activities than those from the fleshes. Their fingerprint-activity relationship models indicated that monosaccharide composition was closely related to the activities, but not molecular weight. LRPs have health-improving potentials, and their activities can be partly predicted by the quantitative fingerprint-activity relationship model. PMID- 29628262 TI - Chitosan oligosaccharides improve the disturbance in glucose metabolism and reverse the dysbiosis of gut microbiota in diabetic mice. AB - The aim of this study is to investigate the effect of chitosan oligosaccharides (COS) on type 2 diabetes mellitus. Wild type C57BL/6J mice or diabetic db/db mice were treated with vehicle or COS for three months. COS treatment significantly decreased the blood glucose (P < 0.01) and reversed the insulin resistance (P < 0.05) in db/db mice, which was accompanied by suppressing the inflammation mediators (P < 0.05), down-regulating the lipogenesis (P < 0.01) and inhibiting the adipocyte differentiation (P < 0.05) in white adipose tissue. Additionally, COS treatment inhibited the reduction of occludin (P < 0.01) and relieved the gut dysbiosis in diabetic mice by promoting Akkermansia (P < 0.01) and suppressing Helicobacter (P < 0.05). Spearman's correlation analysis indicates that the COS modulated bacteria are positively correlated with inflammation, hyperglycemia and dyslipidemia. The functional profiling based on the microbiota composition implicated that COS treatment may regulate the metabolic pathways of gut microbiota. In summary, COS treatment remarkably improved the glucose metabolism and reshaped the unbalanced gut microbiota of diabetic mice. Our study provided the evidence for application of COS to the treatment of diabetes mellitus. PMID- 29628263 TI - Structure characterization and antitumor activity of the extracellular polysaccharide from the marine fungus Hansfordia sinuosae. AB - A neutral water soluble polysaccharide (HPA) was isolated from the marine fungus Hansfordia sinuosae. Monosaccharide composition analysis indicated that HPA was mainly composed of mannose with minor amounts of galactose and glucose. The molecular weight of HPA was approximately 22.5 kDa as analyzed by HPGPC. Structure analysis of HPA with methylation and 1D, 2D NMR indicated that HPA was composed of [alpha-d-Manp(1->], [->2)-alpha-d-Manp(1->], [->3)-alpha-d-Manp(1->] and [->2,6)-alpha-d-Manp(1->] with [alpha-d-Manp(1->] linked to C-6 position of [ >2,6)-alpha-d-Manp(1->]. The antitumor effect of HPA was evaluated in vitro. HPA showed remarkable inhibitory effect on human cervical carcinoma HeLa cells and human breast carcinoma MCF-7 cells. When cells were incubated with HPA at 400 MUg/mL for 48 h, the inhibition rate on HeLa and MCF-7 cells was 79.5% and 73.8%, respectively. Furthermore, for HeLa cells, HPA could increase intracellular ROS levels, induce cells apoptosis, decrease mitochondrial membrane potential, and elevate the expression of caspase-3. The results suggested that HPA could be explored as a potential antitumor agent. PMID- 29628264 TI - Enzymatic hydrolysis of biomimetic bacterial cellulose-hemicellulose composites. AB - The production of biofuels and other chemicals from lignocellulosic biomass is limited by the inefficiency of enzymatic hydrolysis. Here a biomimetic composite material consisting of bacterial cellulose and wood-based hemicelluloses was used to study the effects of hemicelluloses on the enzymatic hydrolysis with a commercial cellulase mixture. Bacterial cellulose synthesized in the presence of hemicelluloses, especially xylan, was found to be more susceptible to enzymatic hydrolysis than hemicellulose-free bacterial cellulose. The reason for the easier hydrolysis could be related to the nanoscale structure of the substrate, particularly the packing of cellulose microfibrils into ribbons or bundles. In addition, small-angle X-ray scattering was used to show that the average nanoscale morphology of bacterial cellulose remained unchanged during the enzymatic hydrolysis. The reported easier enzymatic hydrolysis of bacterial cellulose produced in the presence of wood-based xylan offers new insights to overcome biomass recalcitrance through genetic engineering. PMID- 29628265 TI - Dysfunction of antigen processing and presentation by dendritic cells in cancer. AB - The ability to mount an effective anti-tumor immune response requires coordinate control of CD4 T cell and CD8 T cell function by antigen presenting cells (APCs). Unfortunately, tumors create an immunosuppressive microenvironment that helps protect tumor cells from immune recognition. In many cases this defect can be traced back to a failure of APCs (most importantly dendritic cells (DCs)) to recognize, process, and present tumor antigens to T cells. In this review, we will summarize work addressing the role of different DC subsets in anti-tumor immunity and the various mechanisms used by tumor cells to suppress the ability of APCs to stimulate potent anti-tumor T cell responses. PMID- 29628267 TI - Active site pocket of Streptomycesd-stereospecific amidohydrolase has functional roles in aminolysis activity. AB - d-Stereospecific amidohydrolase from Streptomyces sp. 82F2 (DAH) recognizes d amino acyl ester derivatives as substrates and catalyzes hydrolysis and aminolysis to yield d-amino acids and d-amino acyl peptides or amide derivatives, respectively. Crystallographic analysis has revealed that DAH possesses a large cavity with a small pocket at the bottom. Because the pocket is close to the catalytic center and is thought to interact with substrates, we examined the function of the eight residues that form the pocket in terms of substrate recognition and aminolysis via mutational analysis. Formation of the acyl-enzyme intermediate and catalysis of aminolysis by DAH were changed by substitutions of selected residues with Ala. In particular, I338A DAH exhibited a significant increase in the condensation product of Ac-d-Phe methyl ester and 1,8 diaminooctane (Ac-d-Phe-1,8-diaminooctane) compared with the wild-type DAH. A similar effect was observed by the mutation of Ile338 to Gly and Ser. The pocket shapes and local flexibility of the mutants I338G, I338A, and I338S are thought to resemble each other. Thus, changes in the shape and local flexibility of the pocket of DAH by mutation presumably alter substrate recognition for aminolysis. PMID- 29628266 TI - The Missing Response to Selection in the Wild. AB - Although there are many examples of contemporary directional selection, evidence for responses to selection that match predictions are often missing in quantitative genetic studies of wild populations. This is despite the presence of genetic variation and selection pressures - theoretical prerequisites for the response to selection. This conundrum can be explained by statistical issues with accurate parameter estimation, and by biological mechanisms that interfere with the response to selection. These biological mechanisms can accelerate or constrain this response. These mechanisms are generally studied independently but might act simultaneously. We therefore integrated these mechanisms to explore their potential combined effect. This has implications for explaining the apparent evolutionary stasis of wild populations and the conservation of wildlife. PMID- 29628268 TI - Comprehensive analysis of triacylglycerol lipases in the oleaginous diatom Fistulifera solaris JPCC DA0580 with transcriptomics under lipid degradation. AB - Microalgal biofuels are desirable alternatives for traditional liquid fuels, but further improvements of productivity are necessary for microalgal biofuels to be economically feasible. As strategies for improving lipid productivity, repression of lipid degradation has a great potential because the lipid accumulation level is determined by a balance between lipid synthesis and degradation. However, studies of lipid degradation and its primary functioning enzyme triacylglycerol (TAG) lipases in microalgae are currently limited. In this study, we report the comprehensive analysis of TAG lipases in the oleaginous diatom Fistulifera solaris JPCC DA0580. First, we confirmed that TAGs in the lipid accumulation organelles, oil bodies, were degraded when the cells were transferred from the nutrient depleted conditions to nutrient replete condition. Further analysis revealed that, after eicosapentaenoic acid (C20:5n-3)-containing TAGs are were degraded, its molecular skeletons were likely to be recycled to produce glycolipids and phospholipids for chloroplast regeneration and cell growth, respectively. Next, we searched putative TAG lipase genes from the draft genome sequence of F. solaris, and discovered 42 candidates based on the amino acid sequence homology analysis. Subsequent transcriptome analysis revealed that 16 of the 42 lipase genes were up-regulated during lipid degradation. Among the up regulated lipases, a number of enzymes were predicted to localize in endoplasmic reticulum which is closely associated to the lipid accumulation organelles, oil bodies. Our study provided new insights of lipid degradation in oleaginous microalgae, and putative TAG lipases which could be candidates for metabolic engineering in future study to improve microalgal lipid productivity. PMID- 29628269 TI - Cerebellar abnormalities in first-episode, drug-naive schizophrenia at rest. AB - The cerebellum plays a crucial role in higher cortical functions through a cerebellar-cerebral circuit. However, the specific mechanisms through which the cerebellum contributes to the neurobiology of schizophrenia remain unclear. Forty nine first-episode, drug-naive patients with schizophrenia and 50 healthy controls underwent structural and resting-state functional magnetic resonance imaging (rs-fMRI). The MRI data were analyzed using voxel-based morphometry, amplitude of low-frequency fluctuations (ALFF), cerebellum homogeneity (CH), and seed-based functional connectivity (FC). Patients with schizophrenia did not have anatomical and CH alterations in the cerebellum compared with healthy controls. However, they exhibited decreased ALFF in the right Crus I and abnormal cerebellar FC with brain regions within the dorsal attention network, default mode network, and ventral attention network. The findings indicate that cerebellar abnormalities in first-episode schizophrenia are mainly in the cerebellar-cerebral connectivities, which may contribute to the neurobiology of schizophrenia. PMID- 29628271 TI - Functional network abnormalities consistent with behavioral profile in Autism Spectrum Disorder. AB - Autism spectrum disorder (ASD) is a neurodevelopmental disorder in which the severity of symptoms varies over subjects. The iCAPs model (innovation-driven co activation patterns) is a recently developed spatio-temporal model to describe fMRI data. In this study, the iCAPs model was employed to find functional imaging biomarkers for ASD in resting-state fMRI data. MRI data from 125 ASD patients and 243 healthy controls was selected from the online ABIDE data repository. Following standard fMRI preprocessing steps, the iCAP patterns were fitted to the data to obtain network time series. Furthermore, specific combinations of iCAPs were mapped to behavioral domain time series. To quantify to which extent the time series contribute to the fMRI dynamics, their (temporal) standard deviation was calculated and compared between patients and controls. Abnormalities were found in networks involving subcortical and limbic areas and default mode network regions. When mapping the network dynamics to behavioral domain time series, abnormalities were found in emotional and visual behavioral subdomains, and within the ASD spectrum were more pronounced in subjects with autism compared to Asperger's syndrome. Also a trend towards impairment in networks facilitating social cognition was found. The functional imaging abnormalities are consistent with the behavioral impairments typical for ASD. PMID- 29628272 TI - Altered grey matter volume and cortical thickness in patients with schizo obsessive comorbidity. AB - Recent findings suggest that schizo-obsessive comorbidity (SOC) may be a unique diagnostic entity. We examined grey matter (GM) volume and cortical thickness in 22 patients with SOC, and compared them with 21 schizophrenia (SCZ) patients, 22 obsessive-compulsive disorder (OCD) patients and 22 healthy controls (HCs). We found that patients with SOC exhibited reduced GM volume in the left thalamus, the left inferior semi-lunar lobule of the cerebellum, the bilateral medial orbitofrontal cortex (medial oFC), the medial superior frontal gyrus (medial sFG), the rectus gyrus and the anterior cingulate cortex (aCC) compared with HCs. Patients with SOC also exhibited reduced cortical thickness in the right superior temporal gyrus (sTG), the right angular gyrus, the right supplementary motor area (SMA), the right middle cingulate cortex (mCC) and the right middle occipital gyrus (mOG) compared with HCs. Together with the differences in GM volume and cortical thickness between patients with SOC and patients with only SCZ or only OCD, these findings highlight the GM changes specific to patients with SOC. PMID- 29628270 TI - Associations between adolescent cannabis use and brain structure in psychosis. AB - Associations between cannabis use and psychotic disorders suggest that cannabis may be a contributory risk factor in the neurobiology of psychosis. In this study, we examined brain structure characteristics, total and regional gray matter density (GMD), using Voxel Based Morphometry, in psychotic individuals, stratified by history of cannabis use (total n = 109). We also contrasted GMD estimates in individual diagnostic groups (schizophrenia/bipolar I disorder) with and without history of adolescent cannabis use (ACU). Individuals with psychosis as a whole, both with and without history of ACU, had lower total and regional GMD, compared to healthy controls. ACU was associated with attenuated GMD reductions, compared to non-users, especially in the schizophrenia cases, who showed robust GMD reductions in fronto-temporal and parietal cortex, as well as subcortical regions. Notably, total and regional GMD estimates in individuals with psychosis and ACU were not different from controls with no ACU. These data indicate that the history of ACU in psychotic individuals is associated with attenuated GMD abnormalities. Future investigations targeting potential unique etiological and risk factors associated with psychosis in individuals with ACU may help in understanding of the neurobiology of psychotic disorders and novel treatment options for these individuals. PMID- 29628273 TI - SPN at Work for You! PMID- 29628275 TI - Peripheral Serotonin Synthesis as a New Drug Target. AB - The first step in serotonin (5-HT) biosynthesis is catalyzed by tryptophan hydroxylase (TPH). There are two independent sources of the monoamine that have distinct functions: first, the TPH1-expressing enterochromaffin cells (ECs) of the gut; second, TPH2-expressing serotonergic neurons. TPH1-deficient mice revealed that peripheral 5-HT plays important roles in platelet function and in inflammatory and fibrotic diseases of gut, pancreas, lung, and liver. Therefore, TPH inhibitors were developed which cannot pass the blood-brain barrier to specifically block peripheral 5-HT synthesis. They showed therapeutic efficacy in several rodent disease models, and telotristat ethyl is the first TPH inhibitor to be approved for the treatment of carcinoid syndrome. We review this development and discuss further therapeutic options for these compounds. PMID- 29628276 TI - LDL particle size and composition and incident cardiovascular disease in a South European population: The Hortega-Liposcale Follow-up Study. AB - BACKGROUND: The association of low-density lipoprotein (LDL) particle composition with cardiovascular risk has not been explored before. The aim was to evaluate the relationship between baseline LDL particle size and composition (proportions of large, medium and small LDL particles over their sum expressed as small-LDL %, medium-LDL % and large-LDL %) and incident cardiovascular disease in a population based study. METHODS: Direct measurement of LDL particles was performed using a two-dimensional NMR-technique (Liposcale(r)). LDL cholesterol was assessed using both standard photometrical methods and the Liposcale(r) technique in a representative sample of 1162 adult men and women from Spain. RESULTS: The geometric mean of total LDL particle concentration in the study sample was 827.2 mg/dL (95% CI 814.7, 839.8). During a mean follow-up of 12.4 +/- 3.3 years, a total of 159 events occurred. Medium LDL particles were positively associated with all cardiovascular disease, coronary heart disease (CHD) and stroke after adjustment for traditional risk factors and treatment. Regarding LDL particle composition, the multivariable adjusted hazard ratios for CHD for a 5% increase in medium and small LDL % by a corresponding decrease of large LDL % were 1.93 (1.55, 2.39) and 1.41 (1.14, 1.74), respectively. CONCLUSIONS: Medium LDL particles were associated with incident cardiovascular disease. LDL particles showed the strongest association with cardiovascular events when the particle composition, rather than the total concentration, was investigated. A change in baseline composition of LDL particles from large to medium and small LDL particles was associated with an increased cardiovascular risk, especially for CHD. PMID- 29628274 TI - Macrophage-Targeted Therapeutics for Metabolic Disease. AB - Macrophages are cells of the innate immune system that are resident in all tissues, including metabolic organs such as the liver and adipose tissue (AT). Because of their phenotypic flexibility, they play beneficial roles in tissue homeostasis, but they also contribute to the progression of metabolic disease. Thus, they are ideal therapeutic targets for diseases such as insulin resistance (IR), nonalcoholic fatty liver disease (NAFLD), and atherosclerosis. Recently, discoveries in the area of drug delivery have facilitated phenotype-specific targeting of macrophages. In this review we discuss advances in potential therapeutics for metabolic diseases via macrophage-specific delivery. We highlight micro- and nanoparticles, liposomes, and oligopeptide complexes, and how they can be used to alter macrophage phenotype for a more metabolically favorable tissue environment. PMID- 29628277 TI - Effect of beta-adrenergic blockade on weight changes in patients with chronic heart failure. AB - BACKGROUND: Weight loss is common in patients with chronic heart failure (CHF) and is associated with adverse outcome. Activation of the sympathetic nervous system has been implicated in weight loss, wasting and cachexia. However, the effect of sympathetic antagonism on weight change in patients with CHF is not well defined. METHODS: We evaluated changes in body weight, the incidence of cachexia (weight loss >6%) and significant weight gain (>5%) in unselected patients with CHF due to left ventricular systolic dysfunction (LVSD) (LV ejection fraction (LVEF) <40%) and studied the effect of beta-blockade on weight change. RESULTS: Of the 1480 patients enrolled (median NTproBNP:1651 ng/L, median LVEF:31%), 86% received beta-blocker, 11% never had beta-blocker and 3% discontinued beta-blocker between baseline and 1 year. Patients who did not have or tolerate beta-blocker were more likely to develop cachexia (23% vs 10%, p < 0.001) and less likely to have significant weight gain (22% vs 24%, p < 0.001) than patient who had beta-blocker. During a median follow up of 1876 days (IQR: 993-3052 days), 894 (60%) patients died. Higher body mass index (BMI) at baseline, weight gain and beta-blocker therapy were associated with better outcome. Patients who had all 3 features: beta-blocker therapy, baseline BMI >= 25 and significant weight gain had the best outcome (22% mortality at 5 years). CONCLUSION: Patients with CHF due to LVSD who receive beta-blocker were less likely to develop cachexia and more likely to have significant weight gain and better outcome compared to patients who did not receive or tolerate beta-blocker. PMID- 29628278 TI - Left atrial dilatation: A target organ damage in young to middle-age hypertensive patients. The Campania Salute Network. AB - BACKGROUND: Left atrial (LA) volume is a predictor of outcome in hypertension. It is unclear whether or not this effect depends on coexisting target organ damage (TOD). PURPOSE: To investigate whether LA volume predicts outcome independently of TOD [left ventricular (LV) hypertrophy (LVH) and/or carotid plaque] in a registry of hypertensive treated patients. METHODS: From the Campania Salute Network registry, we selected 5844 young adult hypertensive patients <65 years old (mean age 50 +/- 9 years, 41% women, 8% diabetic) without prevalent CV or valvular heart disease more than mild, with normal LV ejection fraction, stage III or less CKD and available follow-up. LA volume was estimated from LA diameter applying a validated nonlinear equation, and indexed to body height in meters to the second power (eLAVI). Composite fatal and non-fatal stroke, myocardial infarction, sudden cardiac death, heart failure, TIA, myocardial revascularization, de novo angina, carotid stenting or atrial fibrillation (AF) were adjudicated as incident CV events. RESULTS: 565 (10%) patients exhibited dilated initial eLAVI. During a median follow-up of 49 months, 233 patients developed CV events. Multivariable Cox regression analysis, demonstrated that dilated eLAVI increased risk of incident composite CV events (HR 1.90, 95%CI 1.26 2.88, p = 0.002), independently of significant effect of older age, male sex, presence LVH and carotid plaque. Conclusions In middle aged, treated hypertensive patients, dilated eLAVI is associated with adverse CV risk profile and is a predictor of CV events independently of other markers of TOD. LA dilatation should be considered as a TOD. PMID- 29628279 TI - Reply to: "Inhibitory effects of colchicine on inflammasomes". PMID- 29628280 TI - EASL Clinical Practice Guidelines: Management of alcohol-related liver disease. PMID- 29628281 TI - EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. PMID- 29628282 TI - Pharmacist-nurse collaborations in medication adherence-enhancing interventions: A review. AB - OBJECTIVES: Healthcare providers play an important role in addressing medication adherence. Pharmacists and nurses are qualified in this field even though they have different expertise. They both claim their role at the patient's side in collaboration with physicians. To avoid care duplication, such interprofessional collaborations must be carefully defined. The objectives of our review were to: 1) identify medication adherence-enhancing interventions involving pharmacists and nurses; 2) describe their respective roles. METHODS: Literature searches were conducted in PubMed/Medline, Embase, Cochrane Library. Screening criteria were: medication adherence-enhancing interventions, at least a pharmacist and nurse collaborating with/without other healthcare professionals, role description, outpatient settings, at least one oral treatment, adult patients. RESULTS: After screening, 21 references fulfilled the inclusion criteria. Pharmacists and nurses were both in a strategic position to identify eligible patients for adherence interventions, to assess and promote adherence. Pharmacists specifically ensured treatment efficacy, security and access, they provided information on the medication and related lifestyle advice. Nurses clinically co-managed patients with physicians; they also provided patients with information on their disease. CONCLUSIONS: Pharmacist-nurse medication adherence-enhancing interventions are rare and often in a nascent phase. PRACTICE IMPLICATIONS: The results of our review should help in designing new pharmacist-nurse medication adherence enhancing interventions. PMID- 29628283 TI - Weathering the storm; a review of pre-pregnancy stress and risk of spontaneous abortion. AB - The Weathering Effect is a theory that links stress exposure, over the life course, with racial disparities in reproductive outcomes, through the effects of social adversity on a woman's body. The concept of maternal "weathering" captures cumulative somatic and psychological adversities that can exacerbate the effects of aging. Much of the evidence for weathering comes from observational studies linking self-report measures with reproductive outcomes. The purpose of this review is to explore biological mechanisms that underlie these observations. We focus on spontaneous abortion because this event is understudied despite evidence of racial disparities in this outcome. Spontaneous abortion is the most common pregnancy failure, and it happens early in pregnancy. Early pregnancy is a time most susceptible to the harmful effects of immune dysregulation that may, in part, result from adversities experienced before pregnancy begins. In exploring these mechanisms, we draw on well-defined signaling processes observed in the stressor-depression relationship. Pro-inflammatory dysregulation, for example, has particular relevance to immunological control occurring early in pregnancy. Early pregnancy immunologic changes affect the trajectories of pregnancy via control of trophoblastic invasion. Within the first few weeks of pregnancy, uterine derived cytokines operate within cytokine networks and play a critical role in this invasion. Programming for pro-inflammatory dysregulation can occur before conception. This dysregulation, brought into early pregnancy, has implications for viability and success of the index pregnancy. These patterns suggest early pregnancy health is susceptible to stress processing pathways that influence this immunologic control in the first six to eight weeks of pregnancy. In this review, we discuss the known mediating role of immune factors in the stressor-depression relationship. We also discuss how adversity experienced before the index pregnancy, or "pre-pregnancy" may influence these pathways, and subsequently influence early pregnancy health. There is a need to understand adversity, experienced before pregnancy, and mechanisms driving the effects of these experiences on pregnancy outcomes. This approach is a useful entry point for understanding racial inequities in pregnancy health through an understanding of differences in exposures to adversity. We hypothesize that spontaneous abortion involves cyclical changes within a woman's reproductive tract in response to stressors that are established well before a woman enters into pregnancy. Furthermore, we propose mechanisms that potentially drive weathering processes relevant to reproductive disparities. We also examine what is known about pre-pregnancy stress exposures associated with race, inequity, and adversity, and their potential impact on neuroendocrine and immune changes affecting early pregnancy risk. PMID- 29628284 TI - Severe esophagitis due to pinaverium bromide. PMID- 29628285 TI - Using electronic health record data for environmental and place based population health research: a systematic review. AB - PURPOSE: We conducted a systematic review of literature published on January 2000 May 2017 that spatially linked electronic health record (EHR) data with environmental information for population health research. METHODS: We abstracted information on the environmental and health outcome variables and the methods and data sources used. RESULTS: The automated search yielded 669 articles; 128 articles are included in the full review. The number of articles increased by publication year; the majority (80%) were from the United States, and the mean sample size was approximately 160,000. Most articles used cross-sectional (44%) or longitudinal (40%) designs. Common outcomes were health care utilization (32%), cardiometabolic conditions/obesity (23%), and asthma/respiratory conditions (10%). Common environmental variables were sociodemographic measures (42%), proximity to medical facilities (15%), and built environment and land use (13%). The most common spatial identifiers were administrative units (59%), such as census tracts. Residential addresses were also commonly used to assign point locations, or to calculate distances or buffer areas. CONCLUSIONS: Future research should include more detailed descriptions of methods used to geocode addresses, focus on a broader array of health outcomes, and describe linkage methods. Studies should also explore using longitudinal residential address histories to evaluate associations between time-varying environmental variables and health outcomes. PMID- 29628286 TI - School scoliosis screening by Moire topography - Overview for 33 years in Miyazaki Japan. AB - BACKGROUND: Since 1981, we have performed school scoliosis screening (SSS) using Moire topography in Miyazaki, Japan and attained a certain result in detecting scoliosis. However, this screening system was discontinued due to cessation of repair and production of Moire topographic equipment. The purpose of this study was to make clear both the results and the problems of SSS by Moire topography on the basis of our past 33 years' experiences. METHODS: The subjects were 689,293 students (5th grade boys in 200,329, 5th grade girls in 191,919, 8th grade boys in 151,351, and 8th grade girls in 145,694) who were screened by Moire topography between 1981 and 2013. The number of students received SSS, the positive rate of Moire topography, the discovery rate of scoliosis greater than 20 degrees , the reference rate to the second screening, and the positive predictive value of Moire topography to detect scoliosis greater than 20 degrees were investigated. RESULTS: The number of students received SSS achieved a peak in 1992. The positive rate of Moire topography and the discovery rate of scoliosis were highest in 8th grade girls. The reference rates to the second screening were 49.8% in 5th grade students and 41.4% in 8th grade students. The positive predictive values were 2.1% in 5th grade students and 7.6% in 8th grade students. CONCLUSION: SSS by Moire topography seemed to be effective in detecting scoliosis although both the positive predictive value and the reference rate to the second screening were low. PMID- 29628287 TI - Questions and Answers on Diagnosis and Management of Patients with Peripheral Arterial Diseases: A Companion Document of the 2017 ESC Guidelines for the Diagnosis and Treatment of Peripheral Arterial Diseases, in collaboration with the European Society for Vascular Surgery (ESVS). PMID- 29628288 TI - Assessment of EVAR Competence: Validity of a Novel Rating Scale (EVARATE) in a Simulated Setting. AB - OBJECTIVES: The aims of this study were to investigate the validity evidence for a novel procedure specific assessment tool of competence in endovascular aortic repair (EVAR) and to establish a pass/fail level for the assessment. METHODS: Computed tomography angiography data of a 55 mm in diameter infrarenal aortic aneurysm was implemented into an endovascular simulator. Twenty-three physicians with varying EVAR experiences were video-recorded when performing a standard EVAR procedure on the simulator. Two experienced EVAR operators assessed the participants using the novel rating scale, "EndoVascular Aortic Repair Assessment of Technical Expertise" (EVARATE). Validity was studied according to the framework endorsed by the American Educational Research Association. RESULTS: The EVARATE scale had a high internal consistency (Cronbach's alpha = .90). The inter rater reliability was acceptable (Intraclass Correlation Coefficient = .68, p = .005). Specific EVAR experience correlated significantly with the EVARATE score (Spearman's rho = .62, p = .002), but general endovascular experience did not. Consequence analysis showed that the EVARATE assessment could distinguish novices from intermediates (p < .01) and from experts (p < .001). A pass/fail score was determined using the contrasting groups' method. CONCLUSION: This paper presents the initial validity evidence for a novel procedure specific assessment tool, EVARATE, for operator competence in endovascular aortic repair investigated in a simulated setting. The assessment tool can be used to provide structured formative feedback to trainees. PMID- 29628289 TI - Novel class 1 integron (In1390) harboring blaGES-5 in a Morganella morganii strain recovered from a remote community. AB - Antimicrobial resistance in Morganella morganii has been mainly acquired via plasmids and class 1 integrons. We hereby report acquisition of blaGES-5 by a M. morganii isolated in a remote community from the Amazon region. Genomic analysis revealed that blaGES-5 was harbored by a novel class 1 integron designated as In1390. PMID- 29628291 TI - Citri Reticulatae Pericarpium (Chenpi): Botany, ethnopharmacology, phytochemistry, and pharmacology of a frequently used traditional Chinese medicine. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Citri Reticulatae Pericarpium (Rutaceae, CRP), commonly called as Chenpi () in Chinese, is most frequently used as a qi regulating drug in thousands of Chinese medicine prescriptions. CRP is found mainly in major citrus-producing areas such as the Guangdong, Guangxi, Sichuan, Fujian, and Zhejiang Provinces of China. Since thousands of years in China, CRP has been used widely in clinical practice to treat nausea, vomiting, indigestion, anepithymia, diarrhea, cough, expectoration, and so on. Currently, CRP is listed in the Pharmacopoeia of the People's Republic of China. The present paper reviews the botany, ethnopharmacology, phytochemistry, pharmacology, quality control, and toxicology of CRP. MATERIALS AND METHODS: Information on CRP was gathered from various sources including the books on traditional Chinese herbal medicine; scientific databases including Elsevier, PubMed, and ScienceDirect; Baidu Scholar; CNKI; and others and from different professional websites. RESULTS: Approximately 140 chemical compounds have been isolated and identified from CRP. Among them, volatile oils and flavonoids are generally considered as the main bioactive and characteristic ingredients. CRP possesses wide pharmacological effects such as having a beneficial effect on the cardiovascular, digestive, and respiratory systems, antitumor, antioxidant, and anti-inflammatory properties; and a protective effect on the liver and nerve. Moreover, hesperidin is chosen as an indicator in the quantitative determination of CRP, and the quantity of aflatoxin in CRP must not exceed the standard limit mentioned in the pharmacopoeia. CONCLUSIONS: In brief, CRP has a warming nature, and hence, it can be used in harmony with a lot of medicines. CRP not only exhibits its effects individually but also aids other medicines exhibit a better effect. CRP can be consumed with tea, food, alcohol, and medicine. Irrespective of the form it is being consumed, CRP not only shows a synergistic effect but also has strengths on its own. Modern pharmacological studies have demonstrated that CRP has marked bioactivities, especially on the diseases of the digestive and respiratory systems. The bioactivities of CRP are useful for its clinical application and provide prospects for the development of drugs as well as food and health products for people. Although CRP is a commonly used drug in the traditional Chinese herbal prescription, there is an urgent need for further research on its synergistic effect with other herbs based on the compatibility theory of TCM, which would further increase our understanding on the compatibility theory of TCM. PMID- 29628293 TI - Social media and outbreaks of emerging infectious diseases: A systematic review of literature. AB - BACKGROUND: The public often turn to social media for information during emerging infectious diseases (EIDs) outbreaks. This study identified the major approaches and assessed the rigors in published research articles on EIDs and social media. METHODS: We searched 5 databases for published journal articles on EIDs and social media. We then evaluated these articles in terms of EIDs studied, social media examined, theoretical frameworks, methodologic approaches, and research findings. RESULTS: Thirty articles were included in the analysis (published between January 1, 2010, and March 1, 2016). EIDs that received most scholarly attention were H1N1 (or swine flu, n = 15), Ebola virus (n = 10), and H7N9 (or avian flu/bird flu, n = 2). Twitter was the most often studied social media (n = 17), followed by YouTube (n = 6), Facebook (n = 6), and blogs (n = 6). Three major approaches in this area of inquiry are identified: (1) assessment of the public's interest in and responses to EIDs, (2) examination of organizations' use of social media in communicating EIDs, and (3) evaluation of the accuracy of EID related medical information on social media. CONCLUSIONS: Although academic studies of EID communication on social media are on the rise, they still suffer from a lack of theorization and a need for more methodologic rigor. PMID- 29628292 TI - Functional-guided radiotherapy using knowledge-based planning. AB - BACKGROUND AND PURPOSE: There are two significant challenges when implementing functional-guided radiotherapy using 4DCT-ventilation imaging: (1) lack of knowledge of realistic patient specific dosimetric goals for functional lung and (2) ensuring consistent plan quality across multiple planners. Knowledge-based planning (KBP) is positioned to address both concerns. MATERIAL AND METHODS: A KBP model was created from 30 previously planned functional-guided lung patients. Standard organs at risk (OAR) in lung radiotherapy and a ventilation contour delineating areas of high ventilation were included. Model validation compared dose-metrics to standard OARs and functional dose-metrics from 20 independent cases that were planned with and without KBP. RESULTS: A significant improvement was observed for KBP optimized plans in V20Gy and mean dose to functional lung (p = 0.005 and 0.001, respectively), V20Gy and mean dose to total lung minus GTV (p = 0.002 and 0.01, respectively), and mean doses to esophagus (p = 0.005). CONCLUSION: The current work developed a KBP model for functional-guided radiotherapy. Modest, but statistically significant, improvements were observed in functional lung and total lung doses. PMID- 29628294 TI - The Inpatient Assessment and Management of Motor Functional Neurological Disorders: An Interdisciplinary Perspective. AB - BACKGROUND: Motor functional neurologic disorders (FND)-previously termed "hysteria" and later "conversion disorder"-are exceedingly common and frequently encountered in the acute hospital setting. Despite their high prevalence, patients with motor FND can be challenging to diagnose accurately and manage effectively. To date, there is limited guidance on the inpatient approach to the neuropsychiatric evaluation of patients with functional (psychogenic) neurologic symptoms. OBJECTIVE: The authors outline an inpatient multidisciplinary approach, involving neurology, psychiatry, and physical therapy, for the assessment and acute inpatient management of motor FND. METHODS: A vignette of a patient with motor FND is presented followed by a discussion of general assessment principles. Thereafter, a detailed description of the neurologic and psychiatric assessments is outlined. Delivery of a "rule-in" diagnosis is emphasized and specific guidance for what can be accomplished postdiagnosis in the hospital is suggested. DISCUSSION: We encourage an interdisciplinary approach beginning at the early stages of the diagnostic assessment once an individual is suspected of having motor FND. CONCLUSIONS: Practical suggestions for the inpatient assessment of motor FND are presented. It is also important to individualize the diagnostic assessment. Future research should be conducted to test best practices for motor FND management in the acute inpatient hospital setting. PMID- 29628295 TI - Right Temporoparietal Junction Transcranial Magnetic Stimulation in the Treatment of Psychogenic Nonepileptic Seizures: A Case Series. PMID- 29628296 TI - Reduction of Muscle Contractions during Irreversible Electroporation Therapy Using High-Frequency Bursts of Alternating Polarity Pulses: A Laboratory Investigation in an Ex Vivo Swine Model. AB - PURPOSE: To compare the intensity of muscle contractions in irreversible electroporation (IRE) treatments when traditional IRE and high-frequency IRE (H FIRE) waveforms are used in combination with a single applicator and distal grounding pad (A+GP) configuration. MATERIALS AND METHODS: An ex vivo in situ porcine model was used to compare muscle contractions induced by traditional monopolar IRE waveforms vs high-frequency bipolar IRE waveforms. Pulses with voltages between 200 and 5,000 V were investigated, and muscle contractions were recorded by using accelerometers placed on or near the applicators. RESULTS: H FIRE waveforms reduced the intensity of muscle contractions in comparison with traditional monopolar IRE pulses. A high-energy burst of 2-MUs alternating polarity pulses energized for 200 MUs at 4,500 V produced less intense muscle contractions than traditional IRE pulses, which were 25-100 MUs in duration at 3,000 V. CONCLUSIONS: H-FIRE appears to be an effective technique to mitigate the muscle contractions associated with traditional IRE pulses. This may enable the use of voltages greater than 3,000 V necessary for the creation of large ablations in vivo. PMID- 29628297 TI - Evaluation of a CT-Guided Robotic System for Precise Percutaneous Needle Insertion. AB - PURPOSE: To assess overall targeting accuracy for CT-guided needle insertion using prototype robotic system for common target sites. MATERIALS AND METHODS: Using CT guidance, metallic (2 * 1 mm) targets were embedded in retroperitoneum (n = 8), kidneys (n = 8), and liver (n = 14) of 8 Yorkshire pigs (55-65 kg). Bronchial bifurcations were targeted in the lung (n = 13). CT datasets were obtained for planning and controlled needle placement of commercially available 17- to 19-gauge needles (length 15-20 cm) using a small, patient-mounted, CT guided robotic system with 5 degrees of motion. Mean distance to target was 92.9 mm +/- 19.7 (range, 64-146 mm). Planning included selection of target, skin entry point, and 4.6 +/- 1.3 predetermined checkpoints (range, 2-9) where additional CT imaging was performed to permit stepwise correction of needle trajectory path as needed. Scanning and needle advancement were coordinated with breath motion using respiratory gating. Accuracy was assessed as distance from needle tip to predefined target. RESULTS: Of 45 needle insertions performed, 2 were unsuccessful owing to technical issues. Accuracy of targeting was 1.2-1.4 mm +/- 0.6 for kidney, retroperitoneum, and lung (P = .51), with 2.9 mm +/- 1.9 accuracy for liver (P = .0003). This was achieved in 39 cases (91%) using a single insertion. Intraprocedural target movement was detected (3.5 mm +/- 2.1 in retroperitoneum and 6.4 mm +/- 3.9 in liver); the system compensated for 52.9% +/ 30.3 of this movement. One pneumothorax was the only complication (8%). CONCLUSIONS: Accurate needle insertion (< 3 mm error) can be achieved in common target sites when using a CT-guided robotic system. Stepwise checks with corrective angulation can potentially overcome issues of target movement during a procedure from organ deformity and other causes. PMID- 29628298 TI - Thermal Ablation of T1c Renal Cell Carcinoma: A Comparative Assessment of Technical Performance, Procedural Outcome, and Safety of Microwave Ablation, Radiofrequency Ablation, and Cryoablation. AB - PURPOSE: To evaluate perioperative outcomes of thermal ablation with microwave (MW), radiofrequency (RF), and cryoablation for stage T1c renal cell carcinoma (RCC). MATERIALS AND METHODS: A retrospective analysis of 384 patients (mean age, 71 y; range, 22-88 y) was performed between October 2006 and October 2016. Mean radius, exophytic/endophytic, nearness to collecting system or sinus, anterior/posterior, and location relative to polar lines; preoperative aspects and dimensions used for anatomic classification; and centrality index scores were 6.3, 7.9, and 2.7, respectively. Assessment of pre- and postablation serum blood urea nitrogen, creatinine, and estimated glomerular filtration rate was performed to assess functional outcomes. Linear regression analyses were performed to compare sedation medication dosages among the three treatment cohorts. Univariable and multivariable logistic regression analyses were performed to compare rates of residual disease and complications among treatment modalities. RESULTS: A total of 437 clinical stage T1N0M0 biopsy-proven RCCs measuring 1.2 6.9 cm were treated with computed tomography (CT)-guided MW ablation (n = 44; 10%), RF ablation (n = 347; 79%), or cryoablation (n = 46; 11%). There were no significant differences in patient demographic or tumor characteristics among cohorts. Complication rates and immediate renal function changes were similar among the three ablation modalities (P = .46 and P = .08, respectively). MW ablation was associated with significantly decreased ablation time (P < .05), procedural time (P < .05), and dosage of sedative medication (P < .05) compared with RF ablation and cryoablation. CONCLUSIONS: CT-guided percutaneous MW ablation is comparable to RF ablation or cryoablation for the treatment of stage T1N0M0 RCC with regard to treatment response and is associated with shorter treatment times and less sedation than RF ablation or cryoablation. In addition, the safety profile of CT-guided MW ablation is noninferior to those of RF ablation or cryoablation. PMID- 29628299 TI - Effectiveness and Safety of Sclerotherapy for Treatment of Low-Flow Vascular Malformations of the Oropharyngeal Region. AB - PURPOSE: To evaluate the efficacy and safety of sclerotherapy with sodium tetradecyl sulfate (STS) and bleomycin for treatment of venous malformations (VMs) of the oropharyngeal region. MATERIALS AND METHODS: A retrospective study of 33 patients with 46 VMs of the buccal and pharyngolaryngeal cavity associated with impairment of eating, respiration, or elocution was performed. Individual lesions were divided based on their anterior or posterior location, using the base of the tongue as an anatomic landmark. Lesion size was estimated with the use of orthogonal measurements on magnetic resonance or ultrasound images before and after treatment to assess radiologic response. Sclerotherapy sessions were performed under ultrasound, fluoroscopic, and, if needed, endoscopic guidance. Clinical response was assessed with the use of the Manchester Orofacial Pain Disability Scale. Methods for airway management were also compiled. RESULTS: Following sclerotherapy, average VM diameter was reduced by 31.4% (P < .0001) on a per-patient basis and by 30.8% (P < .0001) on a per-lesion basis. The Manchester score improved by an average of 37.0% (P = .013). Four patients reported a worsening of symptoms, and 11 patients experienced symptomatic recurrence. Complications include pneumonia (5 patients) and urgent placement of a post-procedure tracheostomy (4 patients). Patients with posterior malformations experienced more complications (emergency tracheostomies in 4 and pneumonias in 4). CONCLUSIONS: Sclerotherapy using STS is an efficient treatment for venous malformations of the buccal and pharyngolaryngeal cavity but can lead to significant complication for posterior lesions. Careful assessment of the airway is needed before treatment, and prophylactic tracheotomy should be considered in patients with posterior lesions. PMID- 29628300 TI - Long-Term Outcomes of Selective Renal Artery Embolization for Renal Arteriovenous Fistulae with Dilated Venous Sac. AB - PURPOSE: To retrospectively evaluate the role of selective renal artery embolization for renal arteriovenous fistulae (AVFs) with dilated venous sac. MATERIALS AND METHODS: Between 2002 and 2015, 14 patients (7 men and 7 women; mean age, 60 years) with a single renal AVF with dilated venous sac underwent selective renal artery embolization. Three patients presented with gross hematuria, 4 presented with occult blood in urine, and 1 presented with chronic heart failure. Five patients had a history of renal biopsy or partial nephrectomy. Embolic agents used included pushable fibered coils, detachable microcoils, hydrogel coils, N-butyl 2-cyanoactylate, and/or absolute ethanol. Technical success was defined as complete angiographic occlusion of the renal AVF without visualization of the venous sac. Clinical success was defined as the disappearance of the AVF on ultrasound and contrast-enhanced computed tomography, without any symptoms. RESULTS: Fifteen sessions of selective renal artery embolization were performed. Technical success was achieved in 13 sessions (86.7%). Clinical success was achieved in 13 patients (92.9%) after a mean follow up of 48 months (range, 6-155 months). Two major complications occurred-renal vein thrombosis (n = 1) and renovascular hypertension (n = 1)-and were successfully managed with warfarin and an angiotensin-II receptor blocker, respectively. The former patient required re-embolization because of recanalization. No significant changes were observed in the mean serum creatinine level (.86 mg/dL vs .85 mg/dL; P = .67) and the mean estimated glomerular filtration rate (66.0 mL/min/1.73m2 vs 67.4 mL/min/1.73m2; P = .4) after 6 months. CONCLUSIONS: Selective renal artery embolization is a safe and effective treatment for renal AVFs with dilated venous sac. PMID- 29628301 TI - Functional outcomes assessment following free muscle transfer for dynamic reconstruction of facial paralysis: A literature review. AB - Facial reanimation provides patients affected by chronic facial paralysis a chance to regain basic human functions such as emotional expression, verbal communication, and oral competence for eating and swallowing, but there is still no consensus as to the best way to measure surgical outcomes. We performed a literature review to investigate the different functional outcomes that surgeons use to evaluate facial function after reanimation surgery, focusing on outcomes other than facial expressions such as speech, oral competence, and patient quality of life/satisfaction. A total of 37 articles were reviewed, with the majority reporting outcomes through subjective facial expression ratings and only 15 dealing with other functional outcomes. In particular, outcomes related to oral competence and speech were reported inconsistently. Facial reanimation patients would benefit from a unified movement to create and validate through consensus, an outcomes reporting system incorporating not only facial expression, but also oral competence, speech, and patient-reported quality of life, to enable global patient assessment. PMID- 29628302 TI - Separation patterns of orbital wall and risk of optic canal injury in Le Fort 3 osteotomy. AB - PURPOSE: The authors hypothesized that the risks of optic canal injury in down fracturing after Le Fort 3 osteotomy vary depending on the separation patterns of the orbital walls. This study verifies this hypothesis using biomechanical simulation. METHODS: Ten finite-element skull models were produced using computer tomography data from ten persons. These models were modified to simulate Le Fort 3 osteotomy models by removing junctions between the neurocranium and facial cranium. The separation of the orbital wall was performed in four differing ways. In Type 1, all walls were completely separated. In Type 2, only the lateral wall was separated. In Type 3, the inferior wall was left unseparated. In Type 4, the lateral wall was left unseparated. Biomechanical simulation of down-fracturing was performed on the resulting 40 models. By observing irregular fractures occurring inside the orbit, the rate of optic canal involvement was evaluated for each of the four orbital-wall separation patterns. RESULTS: The rates of optic canal involvement were: Type 1 (0/10), Type 2 (0/10), Type 3 (0/10), and Type 4 (4/10). CONCLUSION: When the lateral wall is incompletely separated in Le Fort 3 osteotomy, irregular fracture can develop inside the orbit and involve the optic canal during the down-fracturing process. Hence, the lateral orbital wall should be completely separated to avoid potential blindness due to optic canal injury. PMID- 29628303 TI - Overexpression of TFEB Drives a Pleiotropic Neurotrophic Effect and Prevents Parkinson's Disease-Related Neurodegeneration. AB - The possible implication of transcription factor EB (TFEB) as a therapeutic target in Parkinson's disease has gained momentum since it was discovered that TFEB controls lysosomal biogenesis and autophagy and that its activation might counteract lysosomal impairment and protein aggregation. However, the majority of putative direct targets of TFEB described to date is linked to a range of biological processes that are not related to the lysosomal-autophagic system. Here, we assessed the effect of overexpressing TFEB with an adeno-associated viral vector in mouse substantia nigra dopaminergic neurons. We demonstrate that TFEB overexpression drives a previously unknown bona fide neurotrophic effect, giving rise to cell growth, higher tyrosine hydroxylase levels, and increased dopamine release in the striatum. TFEB overexpression induces the activation of the mitogen-activated protein kinase 1/3 (MAPK1/3) and AKT pro-survival pathways, phosphorylation of mTORC1 effectors 4E-binding protein 1 (4E-BP1) and S6 kinase B1 (S6K1), and increased protein synthesis. We show that TFEB overexpression prevents dopaminergic cell loss and counteracts atrophy and the associated protein synthesis decline in the MPTP mouse model of Parkinson's disease. Our results suggest that increasing TFEB activity might prevent neuronal death and restore neuronal function in Parkinson's disease and other neurodegenerative diseases through different mechanisms. PMID- 29628304 TI - Targeting Amyloid-beta Precursor Protein, APP, Splicing with Antisense Oligonucleotides Reduces Toxic Amyloid-beta Production. AB - Alterations in amyloid beta precursor protein (APP) have been implicated in cognitive decline in Alzheimer's disease (AD), which is accelerated in Down syndrome/Trisomy 21 (DS/TS21), likely due to the extra copy of the APP gene, located on chromosome 21. Proteolytic cleavage of APP generates amyloid-beta (Abeta) peptide, the primary component of senile plaques associated with AD. Reducing Abeta production is predicted to lower plaque burden and mitigate AD symptoms. Here, we designed a splice-switching antisense oligonucleotide (SSO) that causes skipping of the APP exon that encodes proteolytic cleavage sites required for Abeta peptide production. The SSO induced exon skipping in Down syndrome cell lines, resulting in a reduction of Abeta. Treatment of mice with the SSO resulted in widespread distribution in the brain accompanied by APP exon skipping and a reduction of Abeta. Overall, we show that an alternatively spliced isoform of APP encodes a cleavage-incompetent protein that does not produce Abeta peptide and that promoting the production of this isoform with an SSO can reduce Abeta in vivo. These findings demonstrate the utility of using SSOs to induce a spliced isoform of APP to reduce Abeta as a potential approach for treating AD. PMID- 29628306 TI - Tumor-Resident Dendritic Cells and Macrophages Modulate the Accumulation of TCR Engineered T Cells in Melanoma. AB - Ongoing clinical trials explore T cell receptor (TCR) gene therapy as a treatment option for cancer, but responses in solid tumors are hampered by the immunosuppressive microenvironment. The production of TCR gene-engineered T cells requires full T cell activation in vitro, and it is currently unknown whether in vivo interactions with conventional dendritic cells (cDCs) regulate the accumulation and function of engineered T cells in tumors. Using the B16 melanoma model and the inducible depletion of CD11c+ cells in CD11c.diphtheria toxin receptor (DTR) mice, we analyzed the interaction between tumor-resident cDCs and engineered T cells expressing the melanoma-specific TRP-2 TCR. We found that depletion of CD11c+ cells triggered the recruitment of cross-presenting cDC1 into the tumor and enhanced the accumulation of TCR-engineered T cells. We show that the recruited tumor cDCs present melanoma tumor antigen, leading to enhanced activation of TCR-engineered T cells. In addition, detailed analysis of the tumor myeloid compartment revealed that the depletion of a population of DT-sensitive macrophages can contribute to the accumulation of tumor-infiltrating T cells. Together, these data suggest that the relative frequency of tumor-resident cDCs and macrophages may impact the therapeutic efficacy of TCR gene therapy in solid tumors. PMID- 29628305 TI - miR-223-3p Inhibits Human Osteosarcoma Metastasis and Progression by Directly Targeting CDH6. AB - Cadherin-6 (CDH6) is aberrantly expressed in cancer and closely associated with tumor progression. However, the functions of CDH6 in human osteosarcoma and the molecular mechanisms underlying CDH6 in osteosarcoma oncogenesis remain poorly understood. In this work, we assessed the role of CDH6 in human osteosarcoma and identified that the expression of CDH6 was closely related with the overall survival and poor prognosis of osteosarcoma patients. MicroRNAs (miRNAs) have been implicated as important epigenetic regulators during the progression of osteosarcoma. Using dual-luciferase reporter assays, we showed that miR-223-3p suppresses CDH6 expression by directly binding to the 3' UTR of CDH6. miR-223-3p overexpression significantly inhibited cell invasion, migration, growth, and proliferation by suppressing the CDH6 expression in vivo and in vitro. Besides, CDH6 overexpression in the miR-223-3p-transfected osteosarcoma cells effectively rescued the inhibition of cell invasion, migration, growth, and proliferation mediated by miR-223-3p. Additionally, Kaplan-Meier analysis suggests that the expression of miR-223-3p predicts favorable clinical outcomes for osteosarcoma patients. Moreover, the expression of miR-223-3p was downregulated in osteosarcoma patients and was negatively associated with the expression of CDH6. Collectively, these data highlight that miR-223-3p/CDH6 axis is an important novel pleiotropic regulator and could early predict the metastatic potential in human osteosarcoma treatments. PMID- 29628307 TI - A Stress Response that Monitors and Regulates mRNA Structure Is Central to Cold Shock Adaptation. AB - Temperature influences the structural and functional properties of cellular components, necessitating stress responses to restore homeostasis following temperature shift. Whereas the circuitry controlling the heat shock response is well understood, that controlling the E. coli cold shock adaptation program is not. We found that during the growth arrest phase (acclimation) that follows shift to low temperature, protein synthesis increases, and open reading frame (ORF)-wide mRNA secondary structure decreases. To identify the regulatory system controlling this process, we screened for players required for increased translation. We identified a two-member mRNA surveillance system that enables recovery of translation during acclimation: RNase R assures appropriate mRNA degradation and the Csps dynamically adjust mRNA secondary structure to globally modulate protein expression level. An autoregulatory switch in which Csps tune their own expression to cellular demand enables dynamic control of global translation. The universality of Csps in bacteria suggests broad utilization of this control mechanism. PMID- 29628308 TI - Cracking the DNA Code for V(D)J Recombination. AB - To initiate V(D)J recombination for generating the adaptive immune response of vertebrates, RAG1/2 recombinase cleaves DNA at a pair of recombination signal sequences, the 12- and 23-RSS. We have determined crystal and cryo-EM structures of RAG1/2 with DNA in the pre-reaction and hairpin-forming complexes up to 2.75 A resolution. Both protein and DNA exhibit structural plasticity and undergo dramatic conformational changes. Coding-flank DNAs extensively rotate, shift, and deform for nicking and hairpin formation. Two intertwined RAG1 subunits crisscross four times between the asymmetric pair of severely bent 12/23-RSS DNAs. Location-sensitive bending of 60 degrees and 150 degrees in 12- and 23 RSS spacers, respectively, must occur for RAG1/2 to capture the nonamers and pair the heptamers for symmetric double-strand breakage. DNA pairing is thus sequence context dependent and structure specific, which partly explains the "beyond 12/23" restriction. Finally, catalysis in crystallo reveals the process of DNA hairpin formation and its stabilization by interleaved base stacking. PMID- 29628309 TI - JMJD6 Licenses ERalpha-Dependent Enhancer and Coding Gene Activation by Modulating the Recruitment of the CARM1/MED12 Co-activator Complex. AB - Whereas the actions of enhancers in gene transcriptional regulation are well established, roles of JmjC-domain-containing proteins in mediating enhancer activation remain poorly understood. Here, we report that recruitment of the JmjC domain-containing protein 6 (JMJD6) to estrogen receptor alpha (ERalpha)-bound active enhancers is required for RNA polymerase II recruitment and enhancer RNA production on enhancers, resulting in transcriptional pause release of cognate estrogen target genes. JMJD6 is found to interact with MED12 in the mediator complex to regulate its recruitment. Unexpectedly, JMJD6 is necessary for MED12 to interact with CARM1, which methylates MED12 at multiple arginine sites and regulates its chromatin binding. Consistent with its role in transcriptional activation, JMJD6 is required for estrogen/ERalpha-induced breast cancer cell growth and tumorigenesis. Our data have uncovered a critical regulator of estrogen/ERalpha-induced enhancer coding gene activation and breast cancer cell potency, providing a potential therapeutic target of ER-positive breast cancers. PMID- 29628310 TI - Gcn4 Binding in Coding Regions Can Activate Internal and Canonical 5' Promoters in Yeast. AB - Gcn4 is a yeast transcriptional activator induced by amino acid starvation. ChIP seq analysis revealed 546 genomic sites occupied by Gcn4 in starved cells, representing ~30% of Gcn4-binding motifs. Surprisingly, only ~40% of the bound sites are in promoters, of which only ~60% activate transcription, indicating extensive negative control over Gcn4 function. Most of the remaining ~300 Gcn4 bound sites are within coding sequences (CDSs), with ~75 representing the only bound sites near Gcn4-induced genes. Many such unconventional sites map between divergent antisense and sub-genic sense transcripts induced within CDSs adjacent to induced TBP peaks, consistent with Gcn4 activation of cryptic bidirectional internal promoters. Mutational analysis confirms that Gcn4 sites within CDSs can activate sub-genic and full-length transcripts from the same or adjacent genes, showing that functional Gcn4 binding is not confined to promoters. Our results show that internal promoters can be regulated by an activator that functions at conventional 5'-positioned promoters. PMID- 29628290 TI - The Immune Landscape of Cancer. AB - We performed an extensive immunogenomic analysis of more than 10,000 tumors comprising 33 diverse cancer types by utilizing data compiled by TCGA. Across cancer types, we identified six immune subtypes-wound healing, IFN-gamma dominant, inflammatory, lymphocyte depleted, immunologically quiet, and TGF-beta dominant-characterized by differences in macrophage or lymphocyte signatures, Th1:Th2 cell ratio, extent of intratumoral heterogeneity, aneuploidy, extent of neoantigen load, overall cell proliferation, expression of immunomodulatory genes, and prognosis. Specific driver mutations correlated with lower (CTNNB1, NRAS, or IDH1) or higher (BRAF, TP53, or CASP8) leukocyte levels across all cancers. Multiple control modalities of the intracellular and extracellular networks (transcription, microRNAs, copy number, and epigenetic processes) were involved in tumor-immune cell interactions, both across and within immune subtypes. Our immunogenomics pipeline to characterize these heterogeneous tumors and the resulting data are intended to serve as a resource for future targeted studies to further advance the field. PMID- 29628311 TI - A Family of Vertebrate-Specific Polycombs Encoded by the LCOR/LCORL Genes Balance PRC2 Subtype Activities. AB - The polycomb repressive complex 2 (PRC2) consists of core subunits SUZ12, EED, RBBP4/7, and EZH1/2 and is responsible for mono-, di-, and tri-methylation of lysine 27 on histone H3. Whereas two distinct forms exist, PRC2.1 (containing one polycomb-like protein) and PRC2.2 (containing AEBP2 and JARID2), little is known about their differential functions. Here, we report the discovery of a family of vertebrate-specific PRC2.1 proteins, "PRC2 associated LCOR isoform 1" (PALI1) and PALI2, encoded by the LCOR and LCORL gene loci, respectively. PALI1 promotes PRC2 methyltransferase activity in vitro and in vivo and is essential for mouse development. Pali1 and Aebp2 define mutually exclusive, antagonistic PRC2 subtypes that exhibit divergent H3K27-tri-methylation activities. The balance of these PRC2.1/PRC2.2 activities is required for the appropriate regulation of polycomb target genes during differentiation. PALI1/2 potentially link polycombs with transcriptional co-repressors in the regulation of cellular identity during development and in cancer. PMID- 29628312 TI - ALT-803, an IL-15 superagonist, in combination with nivolumab in patients with metastatic non-small cell lung cancer: a non-randomised, open-label, phase 1b trial. AB - BACKGROUND: Immunotherapy with PD-1 or PD-L1 blockade fails to induce a response in about 80% of patients with unselected non-small cell lung cancer (NSCLC), and many of those who do initially respond then develop resistance to treatment. Agonists that target the shared interleukin-2 (IL-2) and IL-15Rbetagamma pathway have induced complete and durable responses in some cancers, but no studies have been done to assess the safety or efficacy of these agonists in combination with anti-PD-1 immunotherapy. We aimed to define the safety, tolerability, and activity of this drug combination in patients with NSCLC. METHODS: In this non randomised, open-label, phase 1b trial, we enrolled patients (aged >=18 years) with previously treated histologically or cytologically confirmed stage IIIB or IV NSCLC from three academic hospitals in the USA. Key eligibility criteria included measurable disease, eligibility to receive anti-PD-1 immunotherapy, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received the anti-PD-1 monoclonal antibody nivolumab intravenously at 3 mg/kg (then 240 mg when US Food and Drug Administration [FDA]-approved dosing changed) every 14 days (either as new treatment or continued treatment at the time of disease progression) and the IL-15 superagonist ALT-803 subcutaneously once per week on weeks 1-5 of four 6-week cycles for 6 months. ALT-803 was administered at one of four escalating dose concentrations: 6, 10, 15, or 20 MUg/kg. The primary endpoint was to define safety and tolerability and to establish a recommended phase 2 dose of ALT-803 in combination with nivolumab. Analyses were per-protocol and included any patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT02523469; phase 2 enrolment of patients is ongoing. FINDINGS: Between Jan 18, 2016, and June 28, 2017, 23 patients were enrolled and 21 were treated at four dose levels of ALT 803 in combination with nivolumab. Two patients did not receive treatment because of the development of inter-current illness during enrolment, one patient due to leucopenia and one patient due to pulmonary dysfunction. No dose-limiting toxicities were recorded and the maximum tolerated dose was not reached. The most common adverse events were injection-site reactions (in 19 [90%] of 21 patients) and flu-like symptoms (15 [71%]). The most common grade 3 adverse events, occurring in two patients each, were lymphocytopenia and fatigue. A grade 3 myocardial infarction occurred in one patient. No grade 4 or 5 adverse events were recorded. The recommended phase 2 dose of ALT-803 is 20 MUg/kg given once per week subcutaneously in combination with 240 mg intravenous nivolumab every 2 weeks. INTERPRETATION: ALT-803 in combination with nivolumab can be safely administered in an outpatient setting. The promising clinical activity observed with the addition of ALT-803 to the regimen of patients with PD-1 monoclonal antibody relapsed and refractory disease shows evidence of anti-tumour activity for a new class of agents in NSCLC. FUNDING: Altor BioScience (a NantWorks company), National Institutes of Health, and Medical University of South Carolina Hollings Cancer Center. PMID- 29628313 TI - Combining top-ranked immunotherapeutics in lung cancer. PMID- 29628314 TI - Special Issue on Current Trends in Biotechnology for Waste Conversion (ETBWC 2017). PMID- 29628315 TI - A bigger suture diameter for anterior cruciate ligament all-inside graft link preparation leads to better graft stability: An anatomical specimen study. AB - BACKGROUND: In anterior cruciate ligament reconstruction, different suture types are used for graft link preparation. Thus the aim of this study was to determine whether differences in the diameter of the suture used influence biomechanical stability of the prepared graft. We hypothesized that the use of a greater suture diameter leads to a higher load to failure rate in tested graft links. METHODS: In an anatomic specimen study, ligament preparation was enrolled in 15 cadaveric knees. The material used was the semitendinosus/gracilis tendon, which was fresh frozen (-80 degrees ) after harvesting for four weeks. The grafts were then defrosted, randomized into two groups and prepared with the same technique: 12 with a suture; FiberWire No. 2 and 12 with a FiberWire No. 0. RESULTS: Overall, the group using FiberWire No. 2 presented with a mean load to failure rate of 730.67N, mean overall final elongation of the graft was 5.98mm. In the FiberWire No. 0 group mean load to failure was with a mean overall elongation of the graft of 6.96mm. Significant differences (P=0.006) between the two groups with regard to the load to failure rate were found, with FiberWire No. 2 withstanding forces better. There was no difference in elongation of the grafts or mode to failure between the two groups. CONCLUSIONS: Graft preparation with a bigger suture type is recommended to gain better load to failure rates, also in smaller-diameter grafts. Regarding the elongation rate, different suture types did not influence the outcome. LEVEL OF EVIDENCE: Anatomical specimen study, Level III. PMID- 29628316 TI - Improved surgical outcomes following radical cystectomy at high-volume centers influence overall survival. AB - OBJECTIVES: Positive surgical margins (PSM) and lymph node yield (LNY) following radical cystectomy (RC) for urothelial carcinoma of the bladder affect survival. Variations in PSM or LNY at different care facilities are poorly described. We evaluated the relationship between hospital surgical volume and academic hospital status with these surgical outcomes and overall survival (OS). METHODS AND MATERIALS: Patients with nonmetastatic urothelial carcinoma of the bladder who underwent RC were identified from the National Cancer Database (2004-2013). Treatment centers were categorized as academic (ACC) and community cancer centers (CCC). Logistic regression was used to identify factors associated with PSM status and LNY, and a multivariate Cox proportional hazards model was used to determine factors associated with OS. RESULTS: In our cohort, 39,274 patients underwent RC. A lower proportion of PSMs (10% vs.12%; P<0.001) and higher median LNY (14 vs. 8, P<0.001) was observed at ACCs compared to CCCs. On logistic regression, there were lower odds of PSM (OR = 0.89, 95% CI: 0.81-0.97) and higher odds of LNY >= 10 nodes (OR = 1.84, 95% CI: 1.74-1.96) among patients at ACCs compared to CCCs. Cox proportional hazards analysis demonstrated benefit to OS at high-volume centers (HR = 0.91, 95% CI: 0.87-0.95) but not based on ACC designation. The OS advantage at high-volume centers is attenuated (HR = 0.95, 95% CI: 0.91-0.99) by PSM status and LNY. CONCLUSIONS: ACCs demonstrate improved surgical outcomes following RC, and a survival advantage attributable to high surgical volume is identified. Centralization of care may lead to improved outcomes in this lethal malignancy. PMID- 29628317 TI - Circulating syndecan-1 is associated with chemotherapy-resistance in castration resistant prostate cancer. AB - OBJECTIVES: Docetaxel chemotherapy is a standard treatment for castration resistant prostate cancer (CRPC). Rapidly expanding treatment options for CRPC provide reasonable alternatives for those who are resistant to docetaxel. Therefore, prediction of docetaxel resistance has become of great clinical importance. Syndecan-1 (SDC1) has been currently shown to be involved in chemotherapy resistance in various malignancies including prostate cancer. The predicting value of serum SDC1 level has not been evaluated yet. PATIENTS AND METHODS: We assessed the baseline levels of SDC1 in serum samples of 75 patients with CRPC who received docetaxel therapy until the appearance of therapy resistance. In one patient who was treated with three treatment series, we assessed also 6 additional serum samples collected during a 1-year treatment period. Serum SDC1 levels were correlated with clinical outcomes as well as with serum levels of MMP7. RESULTS: Pretreatment SDC1 serum levels were not associated with patients' age, the presence of bone or visceral metastases. In univariable analyses, patients' performance status, the presence of bone or visceral metastases, high pretreatment prostate specific antigen and SDC1 levels were significantly associated with cancer-specific survival. In multivariable analysis patients' performance status (P = 0.005), presence of bone or visceral metastases (P = 0.013) and high SDC1 level (P = 0.045) remained independent predictors of patients' survival. In the patient with available follow-up samples serum SDC1 level increased from 50 to 300ng/ml at radiographic progression. Serum concentrations of SDC1 were correlated with those of MMP7 (r = 0.420, P = 0.006). CONCLUSIONS: Our present results together with currently published data suggest a role for SDC1 shedding in chemotherapy resistance. Determination of serum SDC1 may contribute to the prediction of docetaxel resistance and therefore may help to facilitate clinical decision-making regarding the type and timing of therapy for patients with CRPC. PMID- 29628319 TI - Facial nerve palsy and laryngospasm as a complication of local anaesthesia during adenotonsillectomy. AB - Tonsil surgeries are the most frequently performed surgical procedures in ENT departments. We would like to present the case of a 5-year-old patient who suffered from unilateral peripheral facial nerve palsy and laryngeal spasm following adenotonsillectomy. Paresis was observed immediately after the transfer of the patient to the postoperative room. The activity of facial muscles was restored within 2 hours from the beginning of the surgery. We assume that this was the direct effect of an anaesthetic on the extracranial processes of the facial nerve. PMID- 29628318 TI - Sociodemographic disparities in chemotherapy treatment and impact on survival among patients with metastatic bladder cancer. AB - OBJECTIVE: To evaluate how socioeconomic status and other demographic factors are associated with the receipt of chemotherapy and subsequent survival in patients diagnosed with metastatic bladder cancer. METHODS: Using data from the California Cancer Registry, we identified 3,667 patients diagnosed with metastatic urothelial carcinoma of the urinary bladder between 1988 and 2014. The characteristics of patients who did and did not receive chemotherapy as part of the first course of treatment were compared using chi-square tests. Logistic regression was used to identify predictors of chemotherapy treatment. Fine and Gray competing-risks regression and Cox proportional hazards regression were used to estimate bladder cancer-specific and all-cause mortality, respectively. RESULTS: Less than half (46.3%) of patients received chemotherapy. Patients from the lowest socioeconomic quintile were half as likely to have chemotherapy as those from highest quintile (odds ratio = 0.5, 95% CI: 0.4, 0.7). Unmarried patients were significantly less likely to receive treatment (odds ratio = 0.6, 95% CI: 0.5, 0.7). Not receiving chemotherapy was associated with greater mortality from bladder cancer (subdistribution hazard ratio = 1.4, 95% CI: 1.3, 1.5) and from all causes (hazard ratio = 2.0, 95% CI: 1.8, 2.1). CONCLUSIONS: We found clear disparities in chemotherapy treatment and survival with respect to socioeconomic and marital status. Future studies should explore the possible reasons why patients with low socioeconomic status and who are unmarried are less likely to have chemotherapy. PMID- 29628320 TI - Tumor Microenvironment Properties are Associated With Low CD68-positive Cell Infiltration and Favorable Disease-free Survival in EGFR-mutant Lung Adenocarcinoma. AB - BACKGROUND: The benefits of immune checkpoint inhibitors for first-line treatment in patients with lung adenocarcinoma harboring EGFR mutations are unclear. The effects of ICIs depend on the tumor microenvironment (TME). Differences in TME properties between mutant and wild-type EGFR have not been fully characterized. PATIENTS AND METHODS: We collected 105 surgically resected (50 EGFR mutated and 55 EGFR wild-type), treatment-naive lung adenocarcinoma tissues with clinical data to investigate the landscape and compartmentalization of tumor-infiltrating immune cells with respect to EGFR status by immunohistochemistry. The normalized FPKM values of data for 531 patients were obtained from The Cancer Genome Atlas (TCGA) Data Portal (https://portal.gdc.cancer.gov/). RESULTS: CD68-positive cells within the tumor niche exhibited more intensive infiltration in wild-type EGFR than in mutations, and was related to lymph node invasion. In the RNA-Seq analysis, MMP9 and VEGFA showed higher levels in wild-type EGFR than in mutant cases. The EGFR mutation independently predicted a favorable disease-free survival. CONCLUSION: The CD68-positive cells play a crucial role in discriminating the TME between different EGFR statuses. PMID- 29628322 TI - Vitamin D Status and Depressive Symptoms in Older Adults: A Role for Physical Functioning? AB - OBJECTIVES: Depressive symptoms and low vitamin D status are common in older persons and may be associated, but findings are inconsistent. This study investigated whether 25-hydroxyvitamin D (25(OH)D) concentrations are associated with depressive symptoms in older adults, both cross-sectionally and longitudinally. We also examined whether physical functioning could explain this relationship, to gain a better understanding of the underlying mechanisms. METHODS: Data from two independent prospective cohorts of the Longitudinal Aging Study Amsterdam were used: an older cohort (>=65 years, n = 1282, assessed from 1995-2002) and a younger-old cohort (55-65 years, n = 737, assessed from 2002 2009). MEASUREMENTS: Depressive symptoms were measured at baseline and after 3 and 6 years with the Center of Epidemiological Studies Depression Scale. Cross sectional and longitudinal linear regression techniques were used to examine the relationship between 25(OH)D and depressive symptoms. The mediating role of physical functioning was examined in the longitudinal models. RESULTS: Cross sectionally, associations were not significant after adjustment for confounders. Longitudinally, women in the older cohort with baseline 25(OH)D concentrations up to 75 nmol/L experienced 175 to 24% more depressive symptoms in the following 6 years, compared with women with 25(OH)D concentrations >75 nmol/L. Reduced physical performance partially mediated this relationship. In men and in the younger-old cohort, no significant associations were observed. CONCLUSIONS: Older women showed an inverse relationship between 25(OH)D and depressive symptoms over time, which may partially be explained by declining physical functioning. Replication of these findings by future studies is needed. PMID- 29628323 TI - Synthesis and radiofluorination of novel fluoren-9-one based derivatives for the imaging of alpha7 nicotinic acetylcholine receptor with PET. AB - By structure-activity relationship studies on the tilorone scaffold, the 'one armed' substituted dibenzothiophenes and the fluoren-9-ones were identified as the most potential alpha7 nAChR ligands. While the suitability of dibenzothiophene derivatives as PET tracers is recognized, the potential of fluoren-9-ones is insufficiently investigated. We herein report on a series of fluoren-9-one based derivatives targeting alpha7 nAChR with compounds 8a and 8c possessing the highest affinity and selectivity. Accordingly, with [18F]8a and [18F]8c we designed and initially evaluated the first fluoren-9-one derived alpha7 nAChR selective PET ligands. A future application of these radioligands is facilitated by the herein presented successful implementation of fully automated radiosynthesis. PMID- 29628321 TI - Association of Hippocampal Substructure Resting-State Functional Connectivity with Memory Performance in Older Adults. AB - OBJECTIVES: Hippocampal hyperactivation marks preclinical dementia pathophysiology, potentially due to differences in the connectivity of specific medial temporal lobe structures. Our aims were to characterize the resting-state functional connectivity of medial temporal lobe sub-structures in older adults, and evaluate whether specific substructural (rather than global) functional connectivity relates to memory function. METHODS: In 15 adults (mean age: 69 years), we evaluated the resting state functional connectivity of medial temporal lobe substructures: dentate/Cornu Ammonis (CA) 4, CA1, CA2/3, subiculum, the molecular layer, entorhinal cortex, and parahippocampus. We used 7-Tesla susceptibility weighted imaging and magnetization-prepared rapid gradient echo sequences to segment substructures of the hippocampus, which were used as structural seeds for examining functional connectivity in a resting BOLD sequence. We then assessed correlations between functional connectivity with memory performance (short and long delay free recall on the California Verbal Learning Test [CVLT]). RESULTS: All the seed regions had significant connectivity within the temporal lobe (including the fusiform, temporal, and lingual gyri). The left CA1 was the only seed with significant functional connectivity to the amygdala. The left entorhinal cortex was the only seed to have significant functional connectivity with frontal cortex (anterior cingulate and superior frontal gyrus). Only higher left dentate-left lingual connectivity was associated with poorer CVLT performance (Spearman r = -0.81, p = 0.0003, Benjamini-Hochberg false discovery rate: 0.01) after multiple comparison correction. CONCLUSIONS: Rather than global hyper-connectivity of the medial temporal lobe, left dentate lingual connectivity may provide a specific assay of medial temporal lobe hyper connectivity relevant to memory in aging. PMID- 29628324 TI - Synthesis and preliminary biological evaluation of a novel P2X7R radioligand [18F]IUR-1601. AB - The reference standard IUR-1601 ((S)-N-(2-chloro-3-(trifluoromethyl)benzyl)-1-(2 fluoroethyl)-5-oxopyrrolidine-2-carboxamide) was synthesized from tert-butyl (S) 5-oxopyrrolidine-2-carboxylate, fluoroethylbromide, and 2-chloro-3 (trifluoromethyl)benzylamine with overall chemical yield 12% in three steps. The target tracer [18F]IUR-1601 ((S)-N-(2-chloro-3-(trifluoromethyl)benzyl)-1-(2 [18F]fluoroethyl)-5-oxopyrrolidine-2-carboxamide) was synthesized from desmethyl GSK1482160 with 2-[18F]fluoroethyl tosylate, prepared from 1,2-ethylene glycol bis-tosylate and K[18F]F/Kryptofix2.2.2, in two steps and isolated by HPLC combined with SPE in 1-3% decay corrected radiochemical yield. The radiochemical purity was >99%, and the molar activity at end of bombardment (EOB) was 74-370 GBq/MUmol. The potency of IUR-1601 in comparison with GSK1482160 was determined by a radioligand competitive binding assay using [11C]GSK1482160, and the binding affinity Ki values for IUR-1601 and GSK1482160 are 4.31 and 5.14 nM, respectively. PMID- 29628325 TI - Novel thioureido-benzenesulfonamide derivatives with enaminone linker as potent anticancer, radiosensitizers and VEGFR2 inhibitors. AB - In this study, novel series of thioureido-benzenesulfonamide derivatives bearing an enaminone linker either meta or para oriented and having terminal linear or substituted aromatic or heteroaromatic ring system 5-16a,b were designed and synthesized based on the general pharmacophoric features of type II VEGFR2 inhibitors. Evaluation of the synthesized compounds against HEPG2 hepatocellular carcinoma cells in vitro identified compounds 5b, 6b and 10-13b as most active anticancer agents with IC50 equal to 0.12, 0.29, 0.58, 0.44, 0.42 and 0.66 uM, respectively. These compounds were evaluated for their ability to in vitro inhibit VEGFR2 kinase enzyme. The results demonstrated highly potent dose-related VEGFR2 inhibition with IC50 values in nanomolar range (33, 57, 210, 37, 37 and 220 nM, respectively). The radiosensitizing ability of the most promising compounds was studied which showed an increase in the cell killing effect of radiation after combination with the synthesized compounds which revealed lowered IC50 by nearly 50%. Molecular docking for the most potent compounds was performed to predict their possible binding mode within VEGFR2 active site and they showed binding affinity in a similar way to sorafenib. PMID- 29628326 TI - Identification of a novel selective small-molecule inhibitor of protein arginine methyltransferase 5 (PRMT5) by virtual screening, resynthesis and biological evaluations. AB - As one of the most promising anticancer target in protein arginine methyltransferase (PRMT) family, PRMT5 has been drawing more and more attentions, and many efforts have been devoted to develop its inhibitors. In this study, three PRMT5 inhibitors (9, 16, and 23) with novel scaffolds were identified by performing pharmacophore- and docking-based virtual screening combined with in vitro radiometric-based scintillation proximity assay (SPA). Substructure search based on the scaffold of the most active 9 afforded 26 additional analogues, and SPA results indicated that two analogues (9-1 and 9-2) showed increased PRMT5 inhibitory activity compared with the parental compound. Resynthesis of 9, 9-1, and 9-2 confirmed their PRMT5 enzymatic inhibition activity. In addition, compound 9-1 displayed selectivity against PRMT5 over other key homological members (PRMT1 and CARM1 (PRMT4)). While the structure-activity relationship (SAR) of this series of compounds was discussed to provide clues for further structure optimization, the probable binding modes of active compounds were also probed by molecular docking and molecular dynamics simulations. Finally, the antiproliferative effect of 9-1 on MV4-11 leukemia cell line was confirmed and its impact on regulating the target gene of PRMT5 was also validated. The hit compounds identified in this work have provided more novel scaffolds for future hit-to-lead optimization of small-molecule PRMT5 inhibitors. PMID- 29628327 TI - Reversible, orally available ADP receptor (P2Y12) antagonists Part I: Hit to lead process. AB - A hit to lead process to identify reversible, orally available ADP receptor (P2Y12) antagonists lead compounds is described. High throughput screening afforded 1. Optimization of 1, using parallel synthesis methods, a methyl scan to identify promising regions for optimization, and exploratory SAR on these regions, provided 22 and 23. Compound 23 is an orally available, competitive reversible antagonist (KB = 94 nM for inhibition of ADP-induced platelet aggregation). It exhibits high metabolic stability in human, rat and dog liver microsomes and is orally absorbed. Although plasma level after oral dosing of 22 and 23 to rats is low, reasonable levels were achieved to merit extensive lead optimization of this structural class. PMID- 29628328 TI - 5'-Hydroxy-5'-homoaristeromycin: Synthesis and antiviral properties. AB - Synthetically combining the C-4' side-chain structural features of the antiviral candidates 5'-methylaristeromycin and 5'-homoaristeromycin into a diastereomeric pair of C-4' side-chain dihydroxylated aristeromycins (6 and 7) is reported. Broad antiviral analyses of the both targets found promising effects towards HBV (6, 6.7 MUM and 7, 7.74 MUM) and HCMV (only 7, 0.72 MUM). No other activity was found. Neither of the diastereomers was cytotoxic in the assays performed. PMID- 29628329 TI - Structure-guided evolution of a 2-phenyl-4-carboxyquinoline chemotype into PPARalpha selective agonists: New leads for oculovascular conditions. AB - Small molecule agonism of PPARalpha represents a promising new avenue for the development of non-invasive treatments for oculovascular diseases like diabetic retinopathy and age-related macular degeneration. Herein we report initial structure-activity relationships for the newly identified quinoline-based PPARalpha agonist, Y-0452. Preliminary computational studies led to the hypothesis that carboxylic acid transposition and deconstruction of the Y-0452 quinoline system would enhance ligand-protein interactions and better complement the nature of the binding pocket. A focused subset of analogs was designed, synthesized, and assessed for PPARalpha agonism. Two key observations arose from this work 1) contrary to other PPARalpha agonists, incorporation of the fibrate "head-group" decreases PPARalpha selectivity and instead provides pan-PPAR agonists and 2) computational models reveal a relatively unexploited amphiphilic pocket in PPARalpha that provides new opportunities for the development of novel agonists. As an example, compound 10 exhibits more potent PPARalpha agonism (EC50 = ~6 uM) than Y-0452 (EC50 = ~50 uM) and manifests >20-fold selectivity for PPARalpha over the PPARgamma and PPARdelta isoforms. More detailed biochemical analysis of 10 confirms typical downstream responses of PPARalpha agonism including PPARalpha upregulation, induction of target genes, and inhibition of cell migration. PMID- 29628330 TI - Preliminary evidence from a Line-Bisection Task for visuospatial neglect in Parkinson's disease. PMID- 29628331 TI - Prediction of Endometriosis Fertility Index in patients with endometriosis associated infertility after laparoscopic treatment. AB - The effect of endometriosis on fecundity is unclear. Although surgery plays a vital role in the treatment of related infertility, pregnancy outcomes after laparoscopy are poorly correlated with the currently used staging system. To address this, the Endometriosis Fertility Index (EFI) was developed. This retrospective study was designed to assess the predictive value of the EFI for patients with endometriosis-associated infertility. A total of 1325 patients with endometriosis-associated infertility were eligible for inclusion, 1097 of whom were successfully interviewed and 228 lost to follow-up (17.21%). Cumulative pregnancy incidence (CPI) according to EFI scores were calculated by life table and by Kaplan-Meier survival curve analyses. The log-rank test was used to evaluate difference between the EFI groups. Receiver operating characteristic curves were plotted to obtain the optimal cut-off point for pregnancy prediction. A total of 505 (46.03%) patients conceived naturally. The difference in CPI among EFI scores 10, 7-9, 4-6, and 2-3 was statistically significant (P < 0.001) and increased with increasing EFI score. The optimal cut-off point was 7.5: sensitivity (68.51%); specificity (52.20%). This retrospective study indicates the value of the EFI score for predicting spontaneous pregnancy in women treated by laparoscopy for endometriosis-associated infertility. PMID- 29628332 TI - Patients' lived experience of intensive care when being on mechanical ventilation during the weaning process: A hermeneutic phenomenological study. AB - BACKGROUND: The medical and nursing care of the patient on mechanical ventilation has developed and proceeds in terms of ventilator functions, sedation strategies and patient participation. New data are needed to explore the weaning process from the patients' perspective. Therefore, the aim of this study was to explore the meaning of being a patient on mechanical ventilation during the weaning process in the intensive care unit. METHODS: This study used van Manen's hermeneutic phenomenological approach. Interviews were conducted, including twenty former intensive care patients from three different hospitals in Sweden. FINDINGS: Five themes emerged including thirteen related themes; Maintaining human dignity, Accepting the situation, Enduring the difficulties, Inadequate interaction and A sense of unreality. The experiences differed from each other and varied over time, and the same patient expressed both pleasant and unpleasant experiences. Weaning was not a separate experience but intertwined with that of being on mechanical ventilation in the intensive care unit. CONCLUSIONS: The patient's experiences differ and vary over time, with the same patient expressing various experiences. The favourable experiences were more clearly described, compared to previous research, this might depend on factors related to communication, participation and proximity to healthcare professionals and next of-kin. PMID- 29628333 TI - Multidisciplinary Difficult Airway Course: An Essential Educational Component of a Hospital-Wide Difficult Airway Response Program. AB - OBJECTIVE: A hospital-wide difficult airway response team was developed in 2008 at The Johns Hopkins Hospital with three central pillars: operations, safety monitoring, and education. The objective of this study was to assess the outcomes of the educational pillar of the difficult airway response team program, known as the multidisciplinary difficult airway course (MDAC). DESIGN: The comprehensive, full-day MDAC involves trainees and staff from all provider groups who participate in airway management. The MDAC occurs within the Johns Hopkins Medicine Simulation Center approximately four times per year and uses a combination of didactic lectures, hands-on sessions, and high-fidelity simulation training. Participation in MDAC is the main intervention being investigated in this study. Data were collected prospectively using course evaluation survey with quantitative and qualitative components, and prepost course knowledge assessment multiple choice questions (MCQ). Outcomes include course evaluation scores and themes derived from qualitative assessments, and prepost course knowledge assessment MCQ scores. SETTING: Tertiary care academic hospital center PARTICIPANTS: Students, residents, fellows, and practicing physicians from the departments of Surgery, Otolaryngology Head and Neck Surgery, Anesthesiology/Critical Care Medicine, and Emergency Medicine; advanced practice providers (nurse practitioners and physician assistants), nurse anesthetists, nurses, and respiratory therapists. RESULTS: Totally, 23 MDACs have been conducted, including 499 participants. Course evaluations were uniformly positive with mean score of 86.9 of 95 points. Qualitative responses suggest major value from high-fidelity simulation, the hands-on skill stations, and teamwork practice. MCQ scores demonstrated significant improvement: median (interquartile range) pre: 69% (60%-81%) vs post: 81% (72%-89%), p < 0.001. CONCLUSIONS: Implementation of a MDAC successfully disseminated principles and protocols to all airway providers. Demonstrable improvement in prepost course knowledge assessment and overwhelmingly positive course evaluations (quantitative and qualitative) suggest a critical and ongoing role for the MDAC course. PMID- 29628335 TI - Dental and skeletal changes associated with long-term oral appliance use for obstructive sleep apnea: A systematic review and meta-analysis. AB - An oral appliance (OA) is an effective treatment option for patients with obstructive sleep apnea (OSA), but dental and skeletal changes have been detected by many studies after long-term OA use. Better understanding of the long-term side effects may decrease discontinuation of OA use and assist clinicians to make informed decisions. Accordingly, a systematic review and meta-analysis were performed to evaluate the dental and skeletal changes associated with OAs designed to advance the mandible. The quality of the studies was determined by using the risk of bias assessment tool for non-randomized studies (RoBANS), and 12 studies were included in the meta-analysis. OA use was associated with a significant decrease of overjet (OJ) and overbite (OB), and it was suggested that both parameters decreased along with the duration of treatment. Meta-analysis also demonstrated a significant increase of L1-MP. However, there were no significant changes of skeletal modifications or mandibular rotation. Changes of incisor inclination were suggested to make a contribution to reduction of OJ and OB. In conclusion, long-term OA use was associated with dental changes. The results of this study provide information for clinicians about the long-term effects of OAs. PMID- 29628334 TI - Consolidative mechanisms of emotional processing in REM sleep and PTSD. AB - Research suggests sleep plays a role in the consolidation of recently acquired memories for long-term storage. rapid eye movement (REM) sleep has been shown to play a complex role in emotional-memory processing, and may be involved in subsequent waking-day emotional reactivity and amygdala responsivity. Interaction of the hippocampus and basolateral amygdala with the medial-prefrontal cortex is associated with sleep-dependent learning and emotional memory processing. REM is also implicated in post-traumatic stress disorder (PTSD), which is characterized by sleep disturbance, heightened reactivity to fearful stimuli, and nightmares. Many suffers of PTSD also exhibit dampened medial-prefrontal cortex activity. However, the effects of PTSD-related brain changes on REM-dependent consolidation or the notion of 'over-consolidation' (strengthening of memory traces to such a degree that they become resistant to extinction) have been minimally explored. Here, we posit that (in addition to sleep architecture changes) the memory functions of REM must also be altered in PTSD. We propose a model of REM dependent consolidation of learned fear in PTSD and examine how PTSD-related brain changes might interact with fear learning. We argue that reduced efficacy of inhibitory medial-prefrontal pathways may lead to maladaptive processing of traumatic memories in the early stages of consolidation after trauma. PMID- 29628336 TI - Efficacy and Safety of Xiaoyao Formula as an Adjuvant Treatment for Post-Stroke Depression: A Meta-Analysis. AB - OBJECTIVE: To systematically evaluate the efficacy and safety of Xiaoyao formula (XYF) as an adjuvant treatment of post-stroke depression (PSD) by conducting a meta-analysis. METHODS: Pubmed, Embase, Cochrane Library, CNKI, VIP, and Wanfang databases were searched up to May 2016. Randomized controlled trials investigating XYF plus antidepressants versus antidepressants alone for patients with PSD were considered. RESULTS: A total of 607 PSD patients were identified from 7 trials. Adjuvant treatment with XYF had additional benefits in terms of improved total response rates (risk ratio [RR] 1.21; 95% confidence interval [CI]: 1.12-1.30), reduced Hamilton's depressive scale (weighted mean difference [WMD] -5.21; 95% CI: -7.48 to -2.95), and decreased Scandinavian Stroke Scale (WMD -6.35; 95% CI: -8.27 to -4.43). No serious adverse events were observed in any of the included trials. CONCLUSIONS: Adjuvant treatment with XYF appears to have additional benefits in the treatment of PSD, without increasing serious adverse events. PMID- 29628337 TI - Long-term outcomes of endoscopic papillary balloon dilation for removal of bile duct stones in Billroth II gastrectomy patients. AB - BACKGROUND: Endoscopic papillary balloon dilation (EPBD) for common bile duct (CBD) stones removal in Billroth II gastrectomy patients is feasible. However, the long-term outcomes of this technique are not clear. The aim of this study was to evaluate the procedural and long-term outcomes of EPBD for removal of CBD stones in Billroth II gastrectomy patients. METHODS: The records of patients with previous Billroth II gastrectomy referred for CBD stones removal with endoscopic retrograde cholangiopancreatography (ERCP) between July 1, 2008 and September 1, 2016 were retrospectively reviewed. The main outcomes of stone clearance, ERCP related adverse events, and stone recurrence were analyzed. RESULTS: A total of 83 patients with previous Billroth II gastrectomy underwent ERCP in our center were reviewed. Forty-nine consecutive patients with previous Billroth II gastrectomy referred to EPBD for removal of CBD stones underwent 59 ERCP procedures were enrolled in the end. The overall successful CBD stones clearance was achieved in 42 patients (85.7%). ERCP-related adverse events was in 3 ERCP procedures (5.1%). Severe complications, including perforation and bleeding, were not observed. Six of 49 patients (12.2%) had stone recurrence after a median period of 22.5 months (range 6-71 months) from the end of stone removal treatment. Female [odds ratio (OR) = 11.352; 95% confidence interval (95% CI): 1.040-123.912; P = 0.046] and previous mechanical lithotripsy (OR = 13.423; 95% CI: 1.070-168.434; P = 0.044) were significantly associated with stone recurrence. CONCLUSIONS: At long-term follow-up, EPBD for removal of CBD stones appeared to be safe and effective in Billroth II gastrectomy patients. Female and previous mechanical lithotripsy may be risk factors for stone recurrence. PMID- 29628338 TI - Stroke in Human Immunodeficiency Virus-infected Individuals in Sub-Saharan Africa (SSA): A Systematic Review. AB - BACKGROUND: Human immunodeficiency virus (HIV) infection is associated with worse outcomes after stroke, but this association is less well-described in sub-Saharan Africa (SSA). We reviewed literature on stroke among people living with HIV (PLWH) in SSA. METHODS: We systematically reviewed published literature for original clinical stroke studies conducted in SSA that included PLWH. We included studies that reported data on presenting characteristics, risk factors, and/or outcomes after stroke. RESULTS: Seventeen studies (N = 478) met inclusion criteria. At the time of stroke presentation, PLWH had a median age ranging from 32 to 43 years. Subjects had low CD4 counts (median CD4, 108-225 cells/ul), and most were antiretroviral therapy-naive. Fever, seizures, and concurrent opportunistic infections were common at presentation. Ischemic stroke accounted for up to 96% of strokes, which were mostly located in the anterior circulation territory. In studies comparing PLWH with HIV-uninfected individuals, PLWH had more frequent coagulopathy, greater stroke severity, (72% versus 36% National Institutes of Health Stroke Scale >13, P = .02), longer hospital length of stay (30.5 versus <10 days), and a higher 30-day mortality rate (23% versus 10.5%, P = .007). CONCLUSION: Stroke in PLWH in SSA occurs at a young age, in those with advanced disease, and is associated with worse outcomes than in HIV-uninfected comparators. Stroke in young individuals in the region should prompt HIV testing, and ongoing efforts to promote early antiretroviral therapy initiation might also help decrease stroke incidence, morbidity, and mortality in the region. PMID- 29628339 TI - Ischemic Stroke Secondary to Paradoxical Embolism Through a Pulmonary Arteriovenous Malformation: Case Report and Review of the Literature. AB - Paradoxical embolism due to isolated pulmonary arteriovenous malformation (AVM) is an uncommon cause of ischemic stroke, with the majority occurring in patients who have not yet been diagnosed with their malformation. We report a 32-year-old man who presented with an abrupt onset of right facial weakness and expressive aphasia. Brain magnetic resonance imaging revealed an acute infarct in the left middle cerebral artery territory and chronic infarcts in the bilateral cerebellar hemispheres. A cardioembolic mechanism was initially considered in the setting of perimyocarditis diagnosed a few months earlier. Transthoracic and transesophageal echocardiograms revealed high volume right to left shunting, but no septal defects. A pulmonary AVM was confirmed with computed tomography angiography and fistualization was successfully treated with embolization. This report highlights a case of undiagnosed pulmonary AVM leading to recurrent paradoxical emboli to the brain. We review the epidemiology, pathophysiology, and management of pulmonary AVMs in relation to stroke risk. PMID- 29628340 TI - Breast Cancer and Ovulation Induction Treatments. AB - BACKGROUND: This study was performed to determine whether the use of ovulation induction drugs in treatment of infertility have a significant effect on the risk of breast cancer. PATIENTS AND METHODS: This case control study (928 cases, 928 controls), was performed in the gynecology and oncology clinics of Shahid Beheshti University of Medical Sciences between 2011 and 2013. Data were collected via in-person interviews using a questionnaire, which included demographic and gynecologic information. Statistical analysis was performed using SPSS statistics software version 20 (IBM Corp). RESULTS: The use of ovulation induction drugs was not significantly associated with an increased risk of breast cancer (odds ratio [OR], 1.13; 95% confidence interval [CI], 0.7-1.855) among women with infertility (OR, 1.28; 95% CI, 0.8-1.95). CONCLUSION: We observed no statistically significant relationship between infertility and ovulation induction drugs with the risk of breast cancer, except for significant increases in the risk of breast cancer among patients who had used fertility drugs for >6 months. PMID- 29628343 TI - Wrap it up! Should we take it? PMID- 29628344 TI - Ambulating femoral venoarterial extracorporeal membrane oxygenation bridge to heart-lung transplant. PMID- 29628342 TI - MEG3 Activated by Vitamin D Inhibits Colorectal Cancer Cells Proliferation and Migration via Regulating Clusterin. AB - The long non-coding RNA maternally expressed gene 3 (MEG3) is frequently dysregulated in human cancers; however, its roles in colorectal cancer (CRC) development are largely unknown. Here, we reported that MEG3 was down-regulated in CRC tissues and CRC patients with lower MEG3 showed poorer overall survival and disease-free survival than those with higher MEG3 level. MEG3 over-expression represses CRC cells proliferation and migration in vivo and in vitro, while MEG3 knockdown leads to the enhanced proliferation and metastasis of CRC cells. In CRC cells, MEG3 over-expression is related to decreased Clusterin mRNA and the corresponding protein levels, and it also directly binds to Clusterin protein through its 732-1174 region. In further, Clusterin over-expression rescues the compromised abilities of proliferation and metastasis induced by MEG3 over expression, suggesting that MEG3 inhibits the CRC progression through regulating the Clusterin activities. Additionally, we found that 1alpha,25-(OH)2D and vitamin D receptor (VDR) stimulate MEG3 expression in CRC cells through directly binding to its promoter. These results suggested that MEG3 functions as a tumor suppressor in CRC via regulating the Clusterin activities and may underlie the anticancer activities of vitamin D on CRC cells. The VDR/MEG3/Clusterin signaling pathway may serve as potential therapeutic targets and prognosis biomarkers for CRC patients in future. PMID- 29628345 TI - Aortic to right ventricular shunt for pulmonary atresia with intact ventricular septum and bilateral coronary ostial atresia. PMID- 29628346 TI - Concomitant surgical closure of left atrial appendage: A systematic review and meta-analysis. AB - OBJECTIVES: Although percutaneous closure of the left atrial appendage is supported as a potential alternative to lifelong anticoagulation in patients with atrial fibrillation, comprehensive evidence on surgical left atrial appendage closure in heart surgery is limited. METHODS: We conducted a meta-analysis of studies comparing patients who underwent open cardiac surgery with or without left atrial appendage closure. A literature search was performed on PubMed, Embase, and Cochrane Trials databases. Outcomes of interest were 30-day/in hospital mortality and cerebrovascular accident. I2 statistics were used to evaluate heterogeneity, and publication bias was evaluated by Begg's and Egger's tests. RESULTS: We reviewed 1284 articles and selected for main analysis 7 articles including 3897 patients (1963 in the left atrial appendage closure group and 1934 in the non-left atrial appendage closure group). Among the 7 studies, 3 were randomized-controlled studies, 3 were propensity-matched studies, and 1 was a case-matching study. At 30-day/in-hospital follow-up, left atrial appendage closure was significantly associated with decreased risk of mortality and cerebrovascular accident (odds ratio, 0.384, 95% confidence interval, 0.233-0.631 for mortality, and odds ratio, 0.622, 95% confidence interval, 0.388-0.998 for cerebrovascular accident). Stratified analysis demonstrated that this association was more prominent in preoperative atrial fibrillation strata. CONCLUSIONS: Concomitant surgical left atrial appendage closure should be considered at the time of open cardiac surgery, particularly among those in atrial fibrillation preoperatively. The benefit of left atrial appendage closure for patients not in atrial fibrillation and for those undergoing nonvalvular surgery is still unclear. Further prospective investigations are indicated. PMID- 29628341 TI - The Human Cytomegalovirus Strain DB Activates Oncogenic Pathways in Mammary Epithelial Cells. AB - BACKGROUND: Human cytomegalovirus (HCMV) establishes a persistent life-long infection and increasing evidence indicates HCMV infection can modulate signaling pathways associated with oncogenesis. Breast milk is an important route of HCMV transmission in humans and we hypothesized that mammary epithelial cells could be one of the main cellular targets of HCMV infection. METHODS: The infectivity of primary human mammary epithelial cells (HMECs) was assessed following infection with the HCMV-DB strain, a clinical isolate with a marked macrophage-tropism. The impact of HCMV-DB infection on expression of p53 and retinoblastoma proteins, telomerase activity and oncogenic pathways (c-Myc, Akt, Ras, STAT3) was studied. Finally the transformation of HCMV-DB infected HMECs was evaluated using soft agar assay. CTH cells (CMV Transformed HMECs) were detected in prolonged cultures of infected HMECs. Tumor formation was observed in NOD/SCID Gamma (NSG) mice injected with CTH cells. Detection of long non coding RNA4.9 (lncRNA4.9) gene was assessed in CTH cells, tumors isolated from xenografted NSG mice and biopsies of patients with breast cancer using qualitative and quantitative PCR. RESULTS: We found that HCMV, especially a clinical strain named HCMV-DB, infects HMECs in vitro. The clinical strain HCMV-DB replicates productively in HMECs as evidenced by detection of early and late viral transcripts and proteins. Following infection of HMECs with HCMV-DB, we observed the inactivation of retinoblastoma and p53 proteins, the activation of telomerase activity, the activation of the proto-oncogenes c-Myc and Ras, the activation of Akt and STAT3, and the upregulation of cyclin D1 and Ki67 antigen. Colony formation was observed in soft agar seeded with HCMV-DB-infected HMECs. Prolonged culture of infected HMECs resulted in the development of clusters of spheroid cells that we called CTH cells (CMV Transformed HMECs). CTH cells when injected in NOD/SCID Gamma (NSG) mice resulted in the development of tumors. We detected in CTH cells the presence of a HCMV signature corresponding to a sequence of the long noncoding RNA4.9 (lncRNA4.9) gene. We also found the presence of the HCMV lncRNA4.9 sequence in tumors isolated from xenografted NSG mice injected with CTH cells and in biopsies of patients with breast cancer using qualitative and quantitative PCR. CONCLUSIONS: Our data indicate that key molecular pathways involved in oncogenesis are activated in HCMV-DB-infected HMECs that ultimately results in the transformation of HMECs in vitro with the appearance of CMV-transformed HMECs (CTH cells) in culture. CTH cells display a HCMV signature corresponding to a lncRNA4.9 genomic sequence and give rise to fast growing triple-negative tumors in NSG mice. A similar lncRNA4.9 genomic sequence was detected in tumor biopsies of patients with breast cancer. PMID- 29628347 TI - Impact of selective digestive decontamination without systemic antibiotics in a major heart surgery intensive care unit. AB - PURPOSE: The incidence density of ventilator-associated pneumonia (VAP) is higher in patients undergoing major heart surgery than in other populations, despite the introduction of bundles of preventive measures, because many risk factors are not amenable to intervention. Selective digestive decontamination (SDD) has been shown to be efficacious for decreasing the frequency of VAP, although it has not been incorporated into the routine of most intensive care units. The objective of our study was to evaluate the efficacy of SDD without parenteral antibiotics for preventing VAP in a major heart surgery intensive care unit. METHODS: We compared the incidence of VAP before the introduction of SDD (17 months) and during the 17 months after the introduction of SDD and examined its ecologic influence. RESULTS: The rates of VAP in the overall population before and during the intervention were 16.26/1000 days and 6.80 episodes/1000 days of mechanical ventilation, respectively (P = .01). The rates of VAP in the 173 patients remaining under mechanical ventilation > 48 hours after surgery were, respectively, 25.85/1000 days of mechanical ventilation versus 12.06 episodes/1000 days of mechanical ventilation (P = .04). We found a significant reduction in the number of patients with multidrug-resistant microorganisms (P = .01) in the second period of the study. CONCLUSIONS: Our study shows that SDD without parenteral antibiotics can reduce the incidence of VAP in high-risk patients after major heart surgery, with no significant ecologic influence. PMID- 29628348 TI - Transcatheter aortic valve replacement for isolated aortic regurgitation is coming! PMID- 29628349 TI - Thoracic outlet syndrome for thoracic surgeons. PMID- 29628350 TI - Inspiratory muscle training for reducing postoperative pulmonary complications: A simple method that we hope is effective. PMID- 29628351 TI - Rationale and evidence for the development of a durable device-based cardiac neuromodulation therapy for hypertension. AB - We assessed the feasibility of achieving acute, sustained blood pressure reductions through the use of cardiac pacing algorithms delivered via standard dual-chamber pacing based on introducing short atrio-ventricular (AV) delays (SAVD). Eighteen hypertensive subjects (57.3 +/- 9.8 years old; 10 male and 8 female) with average initial systolic and diastolic blood pressures of 151.2 +/- 17.6/92.2 +/- 12.7 mmHg already scheduled to undergo an invasive electrophysiology procedure were included in this study. Pacing sequences were applied for ~1-minute intervals with AV delays of 80, 40, 20 and 2 ms, while making high fidelity blood pressure measurements. Average reductions of 19.6 +/- 7.7 mmHg in systolic pressure and 4.3 +/- 3.8 mmHg in diastolic pressure (P < .001 each) were demonstrated with 2 ms AV delay pacing. Initial SBP reductions were followed by rebound effects which diminished the SBP reducing effects of SAVD pacing, likely due to baroceptor activation causing increased peripheral resistance. This effect was eliminated by intermittent introduction of longer AV delay pacing which modulated the baroreflexes. These findings provide the rationale and evidence underlying recent data showing significant and long-term blood pressure reductions in response to this cardiac neuromodulation therapy in hypertensive patients despite medical therapy. PMID- 29628353 TI - James Ironside: modest manner, mighty impact. PMID- 29628352 TI - [Identification of yeasts from commercial attieke in Abidjan (Cote d'Ivoire): Preliminary study]. AB - OBJECTIVE: This study aims to identify yeasts from commercial attieke. PATIENTS AND METHODS: This descriptive cross-sectional survey involving 103 samples of attieke sold on the market from August to September 2017. It was conducted from the mycology laboratory of the Institut Pasteur of Cote d'Ivoire. The samples were seeded on YGC medium. The colonies of positive culture were counted and seeded again on chromogen medium. Identification of yeasts species was carried out by MALDI-TOF mass spectrometry (Vitek MS bioMerieux). RESULTS: As a whole, 63 samples were contaminated with fungi i.e. an overall prevalence of 61.1 %. Fifty nine of yeasts were identified i.e. 57.2 %. Candida rugosa was most frequently isolated (62.7 %), followed by Ccandida albicans (8.5 %), Candida krusei (8.5 %) et Candida tropicalis (8.5 %). Geotrichum candidum represented 6.8 % isolated yeasts. The yeast average load is 10,124*102 CFU/g with high contamination of commercial attieke in the commune of Abobo. CONCLUSION: The contamination of attieke by yeasts is a reality. C. rugosa was most frequently isolated. It would be necessary to investigate the food chain to determine the source of contamination. PMID- 29628354 TI - Ingrid Scheffer: improving patient outcomes in epilepsy. PMID- 29628355 TI - Cross-cultural adaptation and validation of a European Portuguese version of the 8-item Morisky medication adherence scale. AB - INTRODUCTION AND OBJECTIVE: The 8-Item Morisky Medication Adherence Scale (MMAS 8) is one of the most widely used instruments to assess medication adherence, but a validated European Portuguese version of MMAS-8 does not exist. Our aim was to develop and validate a European Portuguese version of the MMAS-8. METHODS: A process of translation and back-translation of the original MMAS-8 was performed. The questionnaire was administered in nine community pharmacies and one public hospital between March 2014 and September 2015. Adult patients taking at least one antihypertensive drug were invited to participate. A confirmatory factor analysis was performed and internal consistency, convergent validity and concurrent validity were examined. RESULTS: A total of 472 patients were enrolled in the study. The mean MMAS-8 score obtained was 6.74+/-1.39. One hundred and thirty-two patients were classified as low adherers (28%), 181 (38.3%) as medium adherers and 159 (33.7%) as high adherers. For the factorial structure of the Portuguese version of the MMAS-8, the fit indices of the final model (chi-square [18] 48.465, p<0.001) are suggestive of very good fit, with comparative fit index 0.95, root mean square error of approximation 0.06 (90% confidence interval 0.04 0.08), and standardized root mean square residual 0.04, confirming that the construct tested was unidimensional. The Cronbach's alpha for all items was 0.60, and the translated version presents convergent validity and concurrent validity. CONCLUSION: A European Portuguese version of the MMAS-8 was created that maintained a similar structure to the original MMAS-8 and good psychometric properties. PMID- 29628356 TI - Pyrocarbon implants for the hand and wrist. AB - Thanks to its remarkable mechanical properties and excellent biocompatibility, pyrocarbon is an ideal material for articular use. Various pyrocarbon implants for the hand and wrist have been developed over the past 25 years, with about 15 currently available for hemi-, total and interposition arthroplasty. This article describes the production methods and mechanical properties of pyrocarbon. The author summarizes the various implants available for each type of joint, their reported results in the literature, as well as his team's experience. PMID- 29628357 TI - Frailty and the gut. AB - Frailty, which is a syndrome that encompasses losses in physical, psychological and social domains, is responsible for enhanced vulnerability to endogenous and/or exogenous stressors. Frailty is a public health problem for an ageing society; however, it is poorly understood and often under-recognised in clinical settings. In particular, the impact of frailty on either intestinal functions, i.e. immune response, permeability, and absorption, or gut microbiota composition is as yet mostly unexplored. A better comprehension of the intestinal dysfunction occurring in the elderly would help in clarifying the mechanisms predisposing frail patients to a higher risk of infectious or inflammatory events. Moreover, recent evidence suggests that senescence-induced perturbations of the gut-brain axis are involved in the neuroinflammation process, thus raising the hypothesis that preserving gut permeability and preventing frailty-related changes in the microbiota composition might reduce the susceptibility to develop neurodegenerative disorders. In this review, we highlight the current insights concerning the relationship between frailty, intestinal functions, microbiota, and gut-brain axis. PMID- 29628358 TI - Direct-acting antivirals response in an acute nosocomial genotype 1b HCV outbreak. PMID- 29628360 TI - Mechanistic DNA damage simulations in Geant4-DNA part 1: A parameter study in a simplified geometry. AB - Mechanistic modelling of DNA damage in Monte Carlo simulations is highly sensitive to the parameters that define DNA damage. In this work, we use a simple testing geometry to investigate how different choices of physics models and damage model parameters can change the estimation of DNA damage in a mechanistic DNA damage simulation built in Geant4-DNA. The choice of physics model can lead to variations by up to a factor of two in the yield of physically induced strand breaks, and the parameters that determine scavenging, and physical and chemical single strand break induction can have even larger consequences. Using low energy electrons as primary particles, a variety of parameters are tested in this geometry in order to arrive at a parameter set consistent with past simulation studies. We find that the modelling of scavenging can play an important role in determining results, and speculate that high-scavenging regimes, where only chemical radicals within 1 nm of DNA are simulated, could provide a good means of testing mechanistic DNA simulations. PMID- 29628359 TI - Gene expression-phenotype associations in adults with eosinophilic esophagitis. AB - BACKGROUND: Gene expression patterns have not been extensively examined in the context of clinical features of eosinophilic esophagitis (EoE). AIMS: To assess whether gene expression is associated with clinically defined phenotypes in adults with EoE. METHODS: This was an analysis of prospectively collected esophageal biopsies in newly diagnosed EoE patients. We determined differential gene expression with a 94 gene panel in relation to clinical features and phenotypes. These included: endoscopic findings of esophageal rings, stricture, narrowing, linear furrows, exudates, edema, and dilation; an allergic phenotype; an inflammatory phenotype, and a fibrostenotic phenotype. RESULTS: In 89 EoE cases analyzed, patients with exudates on endoscopy had multiple differences in gene expression compared to patients without exudates, though patients with exudates also had higher eosinophil counts (172 vs 106eos/hpf; p=.01). Genes associated with esophageal narrowing included CCL26 (q-value=0.028), ALOX15 (q=0.011), GRK5 (q=0.029), CPA3 (q=0.012), and TRIM2 (q=0.0027). TRIM2 was also associated with the fibrostenotic phenotype (q=0.0051). No genes were associated with the inflammatory or atopic phenotypes, or with dilation. CONCLUSIONS: Multiple genes are associated with exudates, possibly related to higher eosinophil counts. However, a number of genes, including those related to both inflammation and remodelling, are associated with esophageal narrowing. In particular, TRIM2 is associated with clinical fibrotic phenotypes. PMID- 29628361 TI - Relationship between habitual physical activity, motor capacity, and capability in children with cerebral palsy aged 4-5 years across all functional abilities. AB - BACKGROUND: Children with cerebral palsy (CP) have lower habitual physical activity (HPA) than their typically developing peers. There are limited studies of HPA in young children with CP under the age of 5 years. OBJECTIVE: To investigate the relationships between HPA, sedentary time, motor capacity and capability in children with CP aged 4-5 years. METHODS: Sixty-seven participants were classified using Gross Motor Function Classification System (GMFCS), assessed for motor capacity using Gross Motor Function Measure (GMFM) and wore accelerometers for three days to measure HPA and sedentary time. Motor capability was assessed using parent-reported Pediatric Evaluation of Disability Inventory (PEDI) functional skills of mobility domain. Mixed-effects regression models were used for analyses. RESULTS: GMFM was positively associated with HPA (mean difference (MD) = 19.6 counts/min; 95%CI = 16.6 to 22.7, p < 0.001) and negatively associated with sedentary time (MD = -0.6%; 95%CI = -0.7 to -0.5, p < 0.001). The PEDI was also positively associated with HPA (MD = 16.0 counts/min; 95%CI = 13.1 to 18.8, p < 0.001) and negatively associated with sedentary time (MD = -0.5%; 95%CI = -0.6 to -0.4, p < 0.001). After stratification for ambulatory status, GMFM and PEDI were associated with HPA and sedentary time in ambulant participants but not in non-ambulant participants. CONCLUSIONS: Gross motor capacity and motor capability are related to HPA and sedentary time in ambulant children with CP aged 4-5 years. PMID- 29628362 TI - Investigation on the low-temperature pyrolysis of automotive shredder residue (ASR) for energy recovery and metal recycling. AB - The automotive shredder residue (ASR) or shredder light fraction (SLF) is the remaining fraction from the metal recovery of end-of-life vehicles (ELVs). While processes for metal recovery from ELVs are well developed, the similar process for ASR remains a challenge. In this work, low-temperature pyrolysis of the ASR fraction was investigated under the assumption that a low temperature and inert environment would enhance the metal recovery, i.e. the metals would not be further oxidised from their original state and the organic material could be separated from the metals in the form of volatiles and char. Pyrolysis experiments were performed in a tube reactor operating at 300, 400 and 500 degrees C. The gas and oil obtained by pyrolysis were analysed by micro-GC (micro Gas Chromatography) and GC/MS (Gas Chromatography/Mass Spectrometry), respectively. It was found that the gas produced contained a high amount of CO2, limiting the energy recovery from this fraction. The oil consisted of a high concentration of phenolic and aromatic compounds. The solid residue was crushed and fractionated into different particle sizes for further characterization. The pyrolysis temperature of 300 degrees C was found to be insufficient for metal liberation, while the char was easier to crush at tested temperature of 400 and 500 degrees C. The intermediate temperature of 400 degrees C is then suggested for the process to keep the energy consumption low. PMID- 29628363 TI - Mind and spirit: hypnagogia and religious experience. PMID- 29628364 TI - Antidepressants might work for people with major depression: where do we go from here? PMID- 29628365 TI - Building capacity for global mental health research: challenges to balancing clinical and research training. PMID- 29628366 TI - [Uterus transplant or gestational surrogacy: Is there a possible choice?] PMID- 29628367 TI - Butterfly cartilage tympanoplasty outcomes: A single-institution experience and literature review. AB - PURPOSE: In 1998, Dr. Eavey described the trans-canal inlay butterfly cartilage tympanoplasty technique, also known as cartilage button tympanoplasty. Many retrospective studies have since demonstrated its efficacy and decreased operative time when compared to underlay and overlay tympanoplasty techniques. The butterfly cartilage tympanoplasty approach uses only a cartilage graft to repair tympanic membrane perforations. The aim of this study was to review the literature for studies that examined butterfly cartilage tympanoplasty success rates and outcomes and compare them to outcomes from our cohort. MATERIALS AND METHODS: Butterfly cartilage tympanoplasties were performed in 23 pediatric patients and 7 adult patients. We evaluated the tympanic membrane perforation closure rate and hearing results measured by closure of the air-bone gap. RESULTS: The reviewed studies evaluating butterfly cartilage tympanoplasties demonstrated perforation closure rates between 71%-100%. The hearing outcomes in the reviewed literature varied, although the majority reported improved hearing. In our cohort, 21 of the 32 repaired tympanic membrane perforations demonstrated complete perforation closure. The mean follow-up length was 13.4 months. The mean air-bone gap decreased from 13.4 dB to 6.9 dB. CONCLUSIONS: The butterfly cartilage/cartilage button technique is effective in closing tympanic membrane perforations and decreasing the air-bone gap in both adults and children. PMID- 29628368 TI - Sebelipase alfa improves atherogenic biomarkers in adults and children with lysosomal acid lipase deficiency. AB - BACKGROUND: Measures of atherogenic cholesterol, with and without concomitant use of lipid-lowering medications (LLMs), are reported with up to 52 weeks of sebelipase alfa treatment in children and adults with lysosomal acid lipase deficiency (LAL-D) participating in the phase 3 Acid Lipase Replacement Investigating Safety and Efficacy study (NCT01757184). OBJECTIVE: To examine the effects of sebelipase alfa on levels of atherogenic biomarkers in the Acid Lipase Replacement Investigating Safety and Efficacy study. METHODS: Data were prospectively collected for LDL particle (LDL-P) number, LDL-C, HDL-C, apolipoprotein B (apoB), apolipoprotein A1 (apoA1), and LDL-P size. Differences at week 20 between the sebelipase alfa and placebo groups were assessed for the overall LAL-D cohort and for patients receiving and not receiving LLMs. Changes from baseline after up to 52 weeks of treatment were also calculated for the overall cohort and separately for patients receiving and not receiving LLMs. RESULTS: Baseline values for LDL-C, LDL-P number, and apoB were elevated while HDL-C and apoA1 were low. Treatment with sebelipase alfa for 20 weeks significantly improved atherogenic measures compared with placebo irrespective of LLM usage. The reduction in LDL-C with sebelipase alfa was associated with a reduction in the LDL-P number. Treatment for up to 52 weeks was associated with sustained improvements of LDL-P, LDL-C, HDL-C, apoB, and apoA1, regardless of LLM use. CONCLUSION: Patients with LAL-D have high atherogenic risk. It is essential to address the underlying LAL deficiency to restore cholesterol homeostasis in LAL-D patients, as treatment with sebelipase alfa improves atherogenic measures regardless of LLM use and for a sustained period. Sebelipase alfa appears to reduce LDL-C by decreasing the LDL-P number, suggesting improvement in cardiovascular disease risk in LAL-D patients. PMID- 29628369 TI - RNA Sequencing of Stentor Cell Fragments Reveals Transcriptional Changes during Cellular Regeneration. AB - While ciliates of the genus Stentor are known for their ability to regenerate when their cells are damaged or even fragmented, the physical and molecular mechanisms underlying this process are poorly understood. To identify genes involved in the regenerative capability of Stentor cells, RNA sequencing of individual Stentor polymorphus cell fragments was performed. After splitting a cell over the anterior-posterior axis, the posterior fragment has to regenerate the oral apparatus, while the anterior part needs to regenerate the hold fast. Altogether, differential expression analysis of both posterior and anterior S. polymorphus cell fragments for four different post-split time points revealed over 10,000 upregulated genes throughout the regeneration process. Among these, genes involved in cell signaling, microtubule-based movement, and cell cycle regulation seemed to be particularly important during cellular regeneration. We identified roughly nine times as many upregulated genes in regenerating S. polymorphus posterior fragments as compared to anterior fragments, indicating that regeneration of the anterior oral apparatus is a complex process that involves many genes. Our analyses identified several expanded groups of genes, such as dual-specific tyrosine-(Y)-phosphorylation-regulated kinases and MORN domain-containing proteins that seemingly act as key regulators of cellular regeneration. In agreement with earlier morphological and cell biological studies [1, 2], our differential expression analyses indicate that cellular regeneration and vegetative division share many similarities. PMID- 29628370 TI - The ER Contact Proteins VAPA/B Interact with Multiple Autophagy Proteins to Modulate Autophagosome Biogenesis. AB - The endoplasmic reticulum (ER) is the site of biogenesis of the isolation membrane (IM, autophagosome precursor) and forms extensive contacts with IMs during their expansion into double-membrane autophagosomes. Little is known about the molecular mechanism underlying the formation and/or maintenance of the ER/IM contact. The integral ER proteins VAPA and VAPB (VAPs) participate in establishing ER contacts with multiple membranes by interacting with different tethers. Here, we demonstrate that VAPs also modulate ER/IM contact formation. Depletion of VAPs impairs progression of IMs into autophagosomes. Upon autophagy induction, VAPs are recruited to autophagosome formation sites on the ER, a process mediated by their interactions with FIP200 and PI(3)P. VAPs directly interact with FIP200 and ULK1 through their conserved FFAT motifs and stabilize the ULK1/FIP200 complex at the autophagosome formation sites on the ER. The formation of ULK1 puncta is significantly reduced by VAPA/B depletion. VAPs also interact with WIPI2 and enhance the formation of the WIPI2/FIP200 ER/IM tethering complex. Depletion of VMP1, which increases the ER/IM contact, greatly elevates the interaction of VAPs with these autophagy proteins. The VAPB P56S mutation, which is associated with amyotrophic lateral sclerosis, reduces the ULK1/FIP200 interaction and impairs autophagy at an early step, similar to the effect seen in VAPA/B-depleted cells. Our study reveals that VAPs directly interact with multiple ATG proteins, thereby contributing to ER/IM contact formation for autophagosome biogenesis. PMID- 29628372 TI - Knowledgeable Lemurs Become More Central in Social Networks. AB - Strong relationships exist between social connections and information transmission [1-9], where individuals' network position plays a key role in whether or not they acquire novel information [2, 3, 5, 6]. The relationships between social connections and information acquisition may be bidirectional if learning novel information, in addition to being influenced by it, influences network position. Individuals who acquire information quickly and use it frequently may receive more affiliative behaviors [10, 11] and may thus have a central network position. However, the potential influence of learning on network centrality has not been theoretically or empirically addressed. To bridge this epistemic gap, we investigated whether ring-tailed lemurs' (Lemur catta) centrality in affiliation networks changed after they learned how to solve a novel foraging task. Lemurs who had frequently initiated interactions and approached conspecifics before the learning experiment were more likely to observe and learn the task solution. Comparing social networks before and after the learning experiment revealed that the frequently observed lemurs received more affiliative behaviors than they did before-they became more central after the experiment. This change persisted even after the task was removed and was not caused by the observed lemurs initiating more affiliative behaviors. Consequently, quantifying received and initiated interactions separately provides unique insights into the relationships between learning and centrality. While the factors that influence network position are not fully understood, our results suggest that individual differences in learning and becoming successful can play a major role in social centrality, especially when learning from others is advantageous. PMID- 29628371 TI - Direct Control of SPEECHLESS by PIF4 in the High-Temperature Response of Stomatal Development. AB - Environmental factors shape the phenotypes of multicellular organisms. The production of stomata-the epidermal pores required for gas exchange in plants-is highly plastic and provides a powerful platform to address environmental influence on cell differentiation [1-3]. Rising temperatures are already impacting plant growth, a trend expected to worsen in the near future [4]. High temperature inhibits stomatal production, but the underlying mechanism is not known [5]. Here, we show that elevated temperature suppresses the expression of SPEECHLESS (SPCH), the basic-helix-loop-helix (bHLH) transcription factor that serves as the master regulator of stomatal lineage initiation [6, 7]. Our genetic and expression analyses indicate that the suppression of SPCH and stomatal production is mediated by the bHLH transcription factor PHYTOCHROME-INTERACTING FACTOR 4 (PIF4), a core component of high-temperature signaling [8]. Importantly, we demonstrate that, upon exposure to high temperature, PIF4 accumulates in the stomatal precursors and binds to the promoter of SPCH. In addition, we find SPCH feeds back negatively to the PIF4 gene. We propose a model where warm-temperature activated PIF4 binds and represses SPCH expression to restrict stomatal production at elevated temperatures. Our work identifies a molecular link connecting high-temperature signaling and stomatal development and reveals a direct mechanism by which production of a specific cell lineage can be controlled by a broadly expressed environmental signaling factor. PMID- 29628373 TI - Hippocampal Neural Circuits Respond to Optogenetic Pacing of Theta Frequencies by Generating Accelerated Oscillation Frequencies. AB - Biological oscillations can be controlled by a small population of rhythmic pacemaker cells, or in the brain, they also can emerge from complex cellular and circuit-level interactions. Whether and how these mechanisms are combined to give rise to oscillatory patterns that govern cognitive function are not well understood. For example, the activity of hippocampal networks is temporally coordinated by a 7- to 9-Hz local field potential (LFP) theta rhythm, yet many individual cells decouple from the LFP frequency to oscillate at frequencies ~1 Hz higher. To better understand the network interactions that produce these complex oscillatory patterns, we asked whether the relative frequency difference between LFP and individual cells is retained when the LFP frequency is perturbed experimentally. We found that rhythmic optogenetic stimulation of medial septal GABAergic neurons controlled the hippocampal LFP frequency outside of the endogenous theta range, even during behavioral states when endogenous mechanisms would otherwise have generated 7- to 9-Hz theta oscillations. While the LFP frequency matched the optogenetically induced stimulation frequency, the oscillation frequency of individual hippocampal cells remained broadly distributed, and in a subset of cells including interneurons, it was accelerated beyond the new base LFP frequency. The inputs from septal GABAergic neurons to the hippocampus, therefore, do not appear to directly control the cellular oscillation frequency but rather engage cellular and circuit mechanisms that accelerate the rhythmicity of individual cells. Thus, theta oscillations are an example of cortical oscillations that combine inputs from a subcortical pacemaker with local computations to generate complex oscillatory patterns that support cognitive functions. PMID- 29628375 TI - Childhood origins of COPD. PMID- 29628374 TI - Myelination of Neuronal Cell Bodies when Myelin Supply Exceeds Axonal Demand. AB - The correct targeting of myelin is essential for nervous system formation and function. Oligodendrocytes in the CNS myelinate some axons, but not others, and do not myelinate structures including cell bodies and dendrites [1]. Recent studies indicate that extrinsic signals, such as neuronal activity [2, 3] and cell adhesion molecules [4], can bias myelination toward some axons and away from cell bodies and dendrites, indicating that, in vivo, neuronal and axonal cues regulate myelin targeting. In vitro, however, oligodendrocytes have an intrinsic propensity to myelinate [5-7] and can promiscuously wrap inert synthetic structures resembling neuronal processes [8, 9] or cell bodies [4]. A current therapeutic goal for the treatment of demyelinating diseases is to greatly promote oligodendrogenesis [10-13]; thus, it is important to test how accurately extrinsic signals regulate the oligodendrocyte's intrinsic program of myelination in vivo. Here, we test the hypothesis that neurons regulate myelination with sufficient stringency to always ensure correct targeting. Surprisingly, however, we find that myelin targeting in vivo is not very stringent and that mistargeting occurs readily when oligodendrocyte and myelin supply exceed axonal demand. We find that myelin is mistargeted to neuronal cell bodies in zebrafish mutants with fewer axons and independently in drug-treated zebrafish with increased oligodendrogenesis. Additionally, by increasing myelin production of oligodendrocytes in zebrafish and mice, we find that excess myelin is also inappropriately targeted to cell bodies. Our results suggest that balancing oligodendrocyte-intrinsic programs of myelin supply with axonal demand is essential for correct myelin targeting in vivo and highlight potential liabilities of strongly promoting oligodendrogenesis. PMID- 29628376 TI - Childhood predictors of lung function trajectories and future COPD risk: a prospective cohort study from the first to the sixth decade of life. AB - BACKGROUND: Lifetime lung function is related to quality of life and longevity. Over the lifespan, individuals follow different lung function trajectories. Identification of these trajectories, their determinants, and outcomes is important, but no study has done this beyond the fourth decade. METHODS: We used six waves of the Tasmanian Longitudinal Health Study (TAHS) to model lung function trajectories measured at 7, 13, 18, 45, 50, and 53 years. We analysed pre-bronchodilator FEV1 z-scores at the six timepoints using group-based trajectory modelling to identify distinct subgroups of individuals whose measurements followed a similar pattern over time. We related the trajectories identified to childhood factors and risk of chronic obstructive pulmonary disease (COPD) using logistic regression, and estimated population-attributable fractions of COPD. FINDINGS: Of the 8583 participants in the original cohort, 2438 had at least two waves of lung function data at age 7 years and 53 years and comprised the study population. We identified six trajectories: early below average, accelerated decline (97 [4%] participants); persistently low (136 [6%] participants); early low, accelerated growth, normal decline (196 [8%] participants); persistently high (293 [12%] participants); below average (772 [32%] participants); and average (944 [39%] participants). The three trajectories early below average, accelerated decline; persistently low; and below average had increased risk of COPD at age 53 years compared with the average group (early below average, accelerated decline: odds ratio 35.0, 95% CI 19.5-64.0; persistently low: 9.5, 4.5-20.6; and below average: 3.7, 1.9-6.9). Early-life predictors of the three trajectories included childhood asthma, bronchitis, pneumonia, allergic rhinitis, eczema, parental asthma, and maternal smoking. Personal smoking and active adult asthma increased the impact of maternal smoking and childhood asthma, respectively, on the early below average, accelerated decline trajectory. INTERPRETATION: We identified six potential FEV1 trajectories, two of which were novel. Three trajectories contributed 75% of COPD burden and were associated with modifiable early-life exposures whose impact was aggravated by adult factors. We postulate that reducing maternal smoking, encouraging immunisation, and avoiding personal smoking, especially in those with smoking parents or low childhood lung function, might minimise COPD risk. Clinicians and patients with asthma should be made aware of the potential long term implications of non-optimal asthma control for lung function trajectory throughout life, and the role and benefit of optimal asthma control on improving lung function should be investigated in future intervention trials. FUNDING: National Health and Medical Research Council of Australia; European Union's Horizon 2020; The University of Melbourne; Clifford Craig Medical Research Trust of Tasmania; The Victorian, Queensland & Tasmanian Asthma Foundations; The Royal Hobart Hospital; Helen MacPherson Smith Trust; and GlaxoSmithKline. PMID- 29628377 TI - Lung function trajectories from pre-school age to adulthood and their associations with early life factors: a retrospective analysis of three population-based birth cohort studies. AB - BACKGROUND: Maximal lung function in early adulthood is an important determinant of mortality and COPD. We investigated whether distinct trajectories of lung function are present during childhood and whether these extend to adulthood and infancy. METHODS: To ascertain trajectories of FEV1, we studied two population based birth cohorts (MAAS and ALSPAC) with repeat spirometry from childhood into early adulthood (1046 participants from 5-16 years and 1390 participants from 8 24 years). We used a third cohort (PIAF) with repeat lung function measures in infancy (V'maxFRC) and childhood (FEV1; 196 participants from 1 month to 18 years of age) to investigate whether these childhood trajectories extend from early life. We identified trajectories using latent profile modelling. We created an allele score to investigate genetic associations of trajectories, and constructed a multivariable model to identify their early-life predictors. FINDINGS: We identified four childhood FEV1 trajectories: persistently high, normal, below average, and persistently low. The persistently low trajectory (129 [5%] of 2436 participants) was associated with persistent wheezing and asthma throughout follow-up. In genetic analysis, compared with the normal trajectory, the pooled relative risk ratio per allele was 0.96 (95% CI 0.92-1.01; p=0.13) for persistently high, 1.01 (0.99-1.02; p=0.49) for below average, and 1.05 (0.98 1.13; p=0.13) for persistently low. Most children in the low V'maxFRC trajectory in infancy did not progress to the low FEV1 trajectory in childhood. Early-life factors associated with the persistently low trajectory included recurrent wheeze with severe wheezing exacerbations, early allergic sensitisation, and tobacco smoke exposure. INTERPRETATION: Reduction of childhood smoke exposure and minimisation of the risk of early-life sensitisation and wheezing exacerbations might reduce the risk of diminished lung function in early adulthood. FUNDING: None. PMID- 29628378 TI - Pegvaliase for the treatment of phenylketonuria: A pivotal, double-blind randomized discontinuation Phase 3 clinical trial. AB - INTRODUCTION: Pegvaliase is a recombinant Anabaena variabilis phenylalanine ammonia lyase (PAL) enzyme under investigation for treatment of adult phenylketonuria (PKU). This manuscript describes results of a randomized discontinuation trial (RDT) designed to evaluate the effects of pegvaliase treatment on blood phenylalanine (Phe) and neuropsychiatric outcomes in adults with PKU. METHODS: PRISM-2 is a 4-part, Phase 3 study that enrolled adults with PKU receiving pegvaliase treatment (initiated in a prior Phase 2 or Phase 3 study). The RDT, Part 2 of PRISM-2, was an 8-week trial that evaluated change in blood Phe concentrations, neuropsychiatric and neurocognitive measures, and safety outcomes in PRISM-2 participants who had achieved at least a 20% blood Phe reduction from pre-treatment baseline with pegvaliase treatment. Participants were randomized 2:1 to either continue pegvaliase (20 mg/day or 40 mg/day) or switch to matching placebo. RESULTS: The pooled pegvaliase group enrolled 66 participants and each placebo group enrolled 14 participants. The primary endpoint of change in blood Phe concentration from RDT entry to RDT Week 8 was met with clinically meaningful and statistically significant differences between the pegvaliase and placebo groups. Mean (SD) blood Phe at the beginning of the RDT when all participants were receiving pegvaliase was 563.9 MUM (504.6) in the group assigned to the 20 mg/day placebo group (n = 14), 508.2 MUM (363.7) in those assigned to the 40 mg/day placebo group (n = 14), and 503.9 MUM (520.3) in those assigned to continue pegvaliase treatment (n = 58). At Week 8 of the RDT, the least squares mean change (95% confidence interval) in blood Phe was 949.8 MUM (760.4 to 1139.1) for the 20 mg/day placebo group and 664.8 MUM (465.5 to 864.1) for the 40 mg/day placebo group in comparison to 26.5 MUM (-68.3 to 121.3) for the pooled (20 mg/day and 40 mg/day) pegvaliase group (P < 0.0001 for pooled pegvaliase group vs each placebo group). Adverse events (AEs) were usually lower in the pooled placebo group when compared to the pooled pegvaliase group. The most common AEs for the pooled pegvaliase and pooled placebo groups were arthralgia (13.6% and 10.3%, respectively), headache (12.1% and 24.1%), anxiety (10.6% and 6.9%), fatigue (10.6% and 10.3%), and upper respiratory tract infection (1.5% and 17.2%). CONCLUSION: Mean blood Phe reduction was sustained in the pegvaliase group, while placebo groups had mean blood Phe concentration increase toward pre-treatment baseline levels. Results from this study confirmed the efficacy of pegvaliase in maintaining reduced blood Phe concentrations with a manageable safety profile for most participants. PMID- 29628379 TI - Quadriceps Tendon Autograft for Primary Anterior Cruciate Ligament Reconstruction: A Systematic Review of Comparative Studies With Minimum 2-Year Follow-Up. AB - PURPOSE: To systematically review the literature in an effort to compare outcomes of patients undergoing primary anterior cruciate ligament reconstruction (ACLR) with a quadriceps tendon (QT) autograft versus a bone-patellar tendon-bone (BPTB) or hamstring tendon (HT) autograft. METHODS: A systematic review was performed by searching PubMed, the Cochrane Library, and Embase to locate studies (Level of Evidence I-III) comparing the clinical outcomes of the QT autograft versus the BPTB or HT autograft in patients undergoing primary ACLR. Patients were evaluated based on graft failure rate, examination of knee laxity, and patient-reported outcome scores. RESULTS: Eight studies (1 Level II, 7 Level III) were identified that met inclusion criteria, including a total of 368 patients undergoing primary ACLR with a QT autograft, 225 with a BPTB autograft, and 150 with an HT autograft. The average follow-up duration for all patients was 2.9 years. Overall, 2.8% of patients (17/603) experienced graft failure. Within the studies that compared the QT versus BPTB autograft, no study found a significant difference in graft failure rate between groups, and the odds ratio for graft failure between QT and BPTB was found to be 1.58 (95% confidence interval: 0.49 5.07; P = .44). Within the studies that compared graft failure rate between the QT and HT autograft, none found significant differences between groups, although a meta-analysis was not performed because of a low number of trials. Two studies found significantly greater postoperative knee laxity in HT patients compared with QT patients (P < .05), although there were no significant differences found in laxity measurements between QT and BPTB patients. CONCLUSIONS: Patients undergoing primary ACLR with either a QT, BPTB, or HT autograft can all be expected to experience improvement in clinical outcomes. QT patients experienced less knee laxity postoperatively compared with HT patients, although no significant differences were found in graft failure rate between groups. LEVEL OF EVIDENCE: Level III, systematic review of Level II and III studies. PMID- 29628380 TI - Quadriceps Tendon Autograft in Anterior Cruciate Ligament Reconstruction: A Systematic Review. AB - PURPOSE: To systematically review the current evidence to ascertain whether quadriceps tendon autograft (QT) is a viable option in anterior cruciate ligament reconstruction. METHODS: A literature review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Cohort studies comparing QT with bone-patellar tendon-bone autograft (BPTB) or hamstring tendon autograft (HT) were included. Clinical outcomes were compared, with all statistical analyses performed using IBM SPSS Statistics for Windows, version 22.0, with P < .05 being considered statistically significant. RESULTS: We identified 15 clinical trials with 1,910 patients. In all included studies, QT resulted in lower rates of anterior knee pain than BPTB. There was no difference in the rate of graft rupture between QT and BPTB or HT in any of the studies reporting this. One study found that QT resulted in greater knee stability than BPTB, and another study found increased stability compared with HT. One study found that QT resulted in improved functional outcomes compared with BPTB, and another found improved outcomes compared with HT, but one study found worse outcomes compared with BPTB. CONCLUSIONS: Current literature suggests QT is a viable option in anterior cruciate ligament reconstruction, with published literature showing comparable knee stability, functional outcomes, donor-site morbidity, and rerupture rates compared with BPTB and HT. LEVEL OF EVIDENCE: Level III, systematic review of Level I, II, and III studies. PMID- 29628381 TI - Biological Treatment for Osteoarthritis of the Knee: Moving from Bench to Bedside Current Practical Concepts. AB - Biological-based therapies for cartilage pathology have gained considerable recognition in the last few decades due to their potential benefits including their minimal invasiveness, capacity for unprecedented healing, and potential for rapid recovery. Consequently, these therapies are likely to have the most noteworthy impact on patients with degenerative joint changes who want to remain active. Currently, the most researched treatments include platelet-rich plasma (PRP), bone marrow aspirate concentrate (BMAC), and cell-based therapies. Although further basic science research and well-designed randomized clinical trials are needed to elucidate the long-term role of these therapies in the treatment of osteoarthritis, there is compelling evidence for their use for certain indications. This article aims to review the existing literature for biological-based treatment options for osteoarthritis, critically assessing the current evidence-based recommendations and identify potential avenues for development. PMID- 29628382 TI - Financial Strain, Quit Attempts, and Smoking Abstinence Among U.S. Adult Smokers. AB - INTRODUCTION: Cigarette smoking is substantially more prevalent and rates of smoking cessation are lower in low-SES adults. Financial strain may be one explanation for this. This study assessed the association between financial strain, quit attempts, and successful smoking cessation among adult smokers in the U.S. METHODS: Longitudinal data on adult current smokers (aged >=18 years) from Waves 1 and 2 of the nationally representative Population Assessment of Tobacco and Health Study (2013-2015) were analyzed in 2017. Negative binomial regression and logistic regression models assessed the association between financial strain and (1) quit attempts and (2) cigarette abstinence, adjusting for important confounders. RESULTS: Smokers with financial strain made more quit attempts than smokers without financial strain (adjusted incidence-rate ratio=1.34, 95% CI=1.07, 1.68), but financial strain was not associated with smoking abstinence at follow-up (AOR=0.86, 95% CI=0.70, 1.05). Low income was associated with less smoking abstinence at follow-up (AOR=0.66, 95% CI=0.50, 0.87, for <100% federal poverty level; AOR=0.64, 95% CI=0.48, 0.85, for 100%-199% of federal poverty level). Smokers with baseline financial strain who quit at follow-up had lower odds of financial strain at follow-up (AOR=0.57, 95% CI=0.36, 0.89). CONCLUSIONS: Financially strained smokers made slightly more quit attempts than non-strained smokers but were no more likely to successfully quit. Low income (less than 200% of the federal poverty level) smokers were less likely to quit than higher-income smokers, suggesting that financial strain alone may not explain the low quit rates in this population. Further efforts are needed to increase the success of quit attempts in low-income and financially strained smokers. PMID- 29628383 TI - Interferon-free treatment choice according to baseline RASs leads to high SVR rates in HCV genotype 1 infected patients. AB - AIM: Different combinations of direct antiviral agents (DAA) lead to high SVR rates in HCV genotype 1 infected patients. However, presence of baseline resistance-associated substitutions (RASs) represents a major risk factor for treatment failure. It is unknown whether choice of treatment based on RASs has the potential to decrease virologic failure rates. METHODS: Population-based sequencing of NS3 and NS5A genes was performed in HCV genotype 1 infected patients at a German university hospital. Treatment was individually selected based on resistance analyses. RESULTS: In total, 319 patients (50% treatment experienced and 30% with cirrhosis) were included. With the treatment choice based on the baseline NS3 and NS5A resistance profile SVR rates between 96 and 100% were observed in all subgroups, including treatment-experienced patients with cirrhosis and HCV genotype 1a infected cirrhotic patients. CONCLUSIONS: The choice of treatment based on the RASs status at baseline may be beneficial for optimizing treatment efficacy in patients with HCV genotype 1 infection and risk factors for treatment failure. PMID- 29628384 TI - Comprehensive analysis of prognostic factors in hospitalized patients with pneumonia occurring outside hospital: Serum albumin is not less important than pneumonia severity assessment scale. AB - PURPOSE: This study aimed to elucidate factors related to 30-day mortality of pneumonia occurring outside hospital by comprehensively analyzing data considered relevant to prognosis. METHODS: Data considered relevant to prognosis were retrospectively examined from clinical charts and chest X-ray images of all patients with pneumonia occurring outside hospital admitted to our hospital from 2010 to 2016. The primary outcome was 30-day mortality. RESULTS: Data were collected from 534 patients (317 community-acquired pneumonia and 217 nursing- and healthcare associated pneumonia patients; 338 men (63.3%); mean age, 76.2 years-old). Eighty-three patients (9.9%) died from pneumonia within 30 days from the date of admission. The numbers of patients with pneumonia severity index (PSI) classes of I/II/III/IV/V and age, dehydration, respiratory failure, orientation disturbance, pressure (A-DROP) scores of 0/1/2/3/4/5 were 29/66/127/229/83, and 71/107/187/132/30/7, respectively. Mean (standard deviation) body mass index (BMI), serum albumin, blood procalcitonin, white blood cell and C-reactive protein were 20.00 (4.12) kg/m2, 3.16 (0.60) g/dL, 3.69 (13.15) ng/mL, 11559.4 (5656.9)/mm3, and 10.92 (8.75) mg/dL, respectively. Chest X-ray images from 152 patients exhibited a pneumonia shadow over a quarter of total lung field. Logistic regression analysis revealed that PSI class or A-DROP score, BMI, serum albumin, and extent of pneumonia shadow were related to 30-day mortality. Receiver operating characteristics curve analysis revealed that serum albumin was superior to PSI class or A-DROP score for predicting 30-day mortality. CONCLUSION: Serum albumin is not less important than PSI class or A DROP score for predicting 30-day mortality in hospitalized patients with pneumonia occurring outside hospital. PMID- 29628385 TI - Change in genotype of methicillin-resistant Staphylococcus aureus (MRSA) affects the antibiogram of hospital-acquired MRSA. AB - Recently, the dissemination of community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) into hospitals has frequently been reported worldwide. Hospital-acquired MRSA (HA-MRSA) strains exhibit high-level resistance to multiple antimicrobial agents, whereas CA-MRSA strains are usually susceptible to non-beta-lactams. Thus, it is predicted that the antibiogram of the HA-MRSA population would change along with the change in genotype of MRSA. Here, we investigated the changes in the MRSA population along with the MRSA antibiogram in a hospital between 2010 and 2016. Staphylococcal cassette chromosome (SCC) mec typing showed that the predominant HA-MRSA strains in the hospital dramatically changed from SCCmec type II, which is the major type of HA-MRSA, to SCCmec type IV, which is the major type of CA-MRSA. Multilocus sequence typing revealed that the predominant SCCmec type IV strain was a clonal complex (CC) 8 clone, which is mainly found among CA-MRSA. Furthermore, the CC1-SCCmec type IV (CC1-IV) clone significantly increased. Both the CC8-IV and CC1-IV clones exhibited high antimicrobial susceptibility. The antibiogram change of the HA-MRSA population was consistent with the antimicrobial susceptibilities and increased prevalence of the CC8-IV and CC1-IV clones. Our data reveal that the change in the genotypes of MRSA strains could impact the antibiogram of HA-MRSA population. PMID- 29628386 TI - Caffeic acid, a coffee-related organic acid, inhibits infection by severe fever with thrombocytopenia syndrome virus in vitro. AB - Severe fever with thrombocytopenia syndrome (SFTS) virus (SFTSV) causes tick borne hemorrhagic fever in East Asia. The disease is characterized by high morbidity and mortality. Here, we evaluated the effects of caffeic acid (CA), a coffee-related organic acid with antiviral effects, against SFTSV infection. CA dose-dependently inhibited SFTSV infection in permissive human hepatoma Huh7.5.1 8 cells when SFTSV was added into the culture medium with CA. However, quinic acid (QA), another coffee-related organic acid, did not inhibit SFTSV infection. The 50% inhibitory concentration (IC50) of CA against SFTSV was 0.048 mM, whereas its 50% cytotoxic concentration was 7.6 mM. The selectivity index (SI) was 158. Pre-incubation of SFTSV with CA for 4 h resulted in a greater inhibition of SFTSV infection (IC50 = 0.019 mM; SI = 400). The pre-incubation substantially decreased viral attachment to the cells. CA treatment of the SFTSV-infected cells also inhibited the infection, albeit less effectively. CA activity after cell infection with SFTSV was more pronounced at a low multiplicity of infection (MOI) of 0.01 per cell (IC50 = 0.18 mM) than at a high MOI of 1 per cell (IC50 > 1 mM). Thus, CA inhibited virus spread by acting directly on the virus rather than on the infected cells. In conclusion, CA acted on SFTSV and inhibited viral infection and spread, mainly by inhibiting the binding of SFTSV to the cells. We therefore demonstrated CA to be a potential anti-SFTSV drug for preventing and treating SFTS. PMID- 29628388 TI - An outbreak of fluoroquinolone-resistant Pseudomonas aeruginosa ST357 harboring the exoU gene. AB - Antimicrobial-resistant isolates of Pseudomonas aeruginosa collected from 2005 to 2014 in a university hospital in Kyoto, Japan, were retrospectively analyzed by multilocus sequence typing (MLST), exoenzyme genotype determination, integron characterization, and clinical associations. During the study, 1573 P. aeruginosa isolates were detected, and 41 of these were resistant to more than two classes of antimicrobial agents. Twenty-five (61.0%) isolates were collected from urine. All isolates were resistant to ciprofloxacin, 8 (19.5%) isolates showed resistance to imipenem/cilastatin, and 8 (19.5%) isolates showed resistance to meropenem. None of the isolates fulfilled the clinical criteria for multidrug resistant P. aeruginosa. All isolates were negative in the metallo-beta lactamase test. Thirty-six (87.8%) isolates were of the exoS-exoU+ genotype and 5 (12.2%) isolates were of the exoS+exoU- genotype. Among 36 exoS-exoU+ isolates, 33 (80.5%) were ST357, and 3 (7.3%) were ST235. Five isolates of exoS+exoU- were ST186, ST244, ST314, ST508, and ST512. Thirty-three isolates were positive for class 1 integrons and four different class 1 integrons were detected: aminoglycoside (2') adenyltransferase and chloramphenicol transporter (AadB+CmlA6), OXA-4 beta-lactamase and aminoglycoside 3'-adenyltransferase (OXA4+AadA2), AadB alone, and aminoglycoside acetyltransferase alone (AacA31). Among the 41 patients from which the isolates originated, the most common underlying disease was cancer in 16 patients (39%), and 9 patients (22.0%) died during the hospitalization period. There was no statistical correlation between MLST, exoenzyme genotype, and patient mortality. The results indicated outbreaks of fluoroquinolone-resistant P. aeruginosa in immunocompromised patients mainly due to the propagation of potentially virulent ST357 isolates possessing the exoU+ genotype. PMID- 29628390 TI - Editorial. PMID- 29628389 TI - Effects of buprenorphine, butorphanol or tramadol premedication on anaesthetic induction with alfaxalone in common marmosets (Callithrix jacchus). AB - OBJECTIVE: To investigate the clinical and physiological effects of intravenous (IV) alfaxalone alone or in combination with buprenorphine, butorphanol or tramadol premedication in marmosets. STUDY DESIGN: Prospective, randomized, blinded, crossover design. ANIMALS: Nine healthy marmosets (391 +/- 48 g, 3.7 +/- 2.2 years old). METHODS: Meloxicam 0.20 mg kg-1 subcutaneously, atropine 0.05 mg kg-1 intramuscularly (IM) and either buprenorphine 20 MUg kg-1 IM (BUP-A), butorphanol 0.2 mg kg-1 IM (BUT-A), tramadol 1.5 mg kg-1 IM (TRA-A) or no additional drug (control) were administered to all marmosets as premedication. After 1 hour, anaesthesia was induced with 16 mg kg-1 alfaxalone IV. All animals received all protocols. The order of protocol allocation was randomized with a minimum 28 day wash-out period. During anaesthesia, respiratory and pulse rates, rectal temperature, haemoglobin oxygen saturation, arterial blood pressure, palpebral and pedal withdrawal reflexes and degree of muscle relaxation were assessed and recorded every 5 minutes. Quality of induction and recovery were assessed. Duration of induction, immobilization and recovery were recorded. Blood samples were analysed for aspartate aminotransferase, creatine kinase and lactate dehydrogenase concentrations. The protocols were compared using paired t tests, Wilcoxon's signed-rank test with Bonferroni's corrections and linear mixed effect models where appropriate. RESULTS: Out of nine animals, apnoea was noted in eight animals administered protocol BUP-A and two animals administered protocol BUT-A. With TRA-A and control protocols, apnoea was not observed. No other significant differences in any of the parameters were found; however, low arterial blood pressures and hypoxia occurred in TRA-A. CONCLUSIONS AND CLINICAL RELEVANCE: Our study employing different premedications suggests that the previously published dose of 16 mg kg-1 alfaxalone is too high when used with premedication because we found a high incidence of complications including apnoea (BUP-A), hypotension and hypoxaemia (TRA-A). Appropriate monitoring and countermeasures are recommended. PMID- 29628391 TI - Moderate hypoxia but not warming conditions at larval stage induces adverse carry over effects on hypoxia tolerance of European sea bass (Dicentrarchus labrax) juveniles. AB - Environmental conditions, to which organisms are exposed during all their life, may cause possible adaptive responses with consequences in their subsequent life history trajectory. The objective of this study was to investigate whether ecologically relevant combinations of hypoxia (40% and 100% air saturation) and temperature (15 degrees and 20 degrees C), occurring during the larval period of European sea bass larvae (Dicentrarchus labrax), could have long-lasting impacts on the physiology of resulting juveniles. Hypoxic challenge tests were performed over one year to give an integrative evaluation of physiological performance. We revealed that juvenile performance was negatively impacted by hypoxia but not by the thermal conditions experienced at larval stage. This impact was related to the prevalence of opercular abnormalities. The present study indicates that exposure to a moderate hypoxia event during larval stage may have adverse carry-over effects, which could compromise fitness and population recruitment success. PMID- 29628392 TI - Radiocesium in seawater, sediments, and marine megabenthic species in coastal waters off Fukushima in 2012-2016, after the 2011 nuclear disaster. AB - In bottom-sediment samples collected in 2012 from a coastal strip (~30 km * 120 km) off the Fukushima Daiichi Nuclear Power Plant (FDNPP), radiocesium activity concentrations were generally higher south of the FDNPP, with high activity concentration patches in the north. In periodic surveys conducted at nearshore sites during 2012-2016, no clear temporal trends were observed in radiocesium activity concentrations in seawater or bottom sediment, and activity concentrations were higher in fish than in invertebrates. During 2012-2014, radiocesium activity concentrations tended to decrease in fish, but during 2012 2013 in the south, some increases were observed. Radiocesium activity concentrations were significantly higher in some fish (e.g., Okamejei kenojei) directly offshore and south of the FDNPP than in the north. Activity concentrations in fish stomach contents were significantly correlated with those in muscle tissue, suggesting that the consumption of contaminated prey contributed greatly to radiocesium contamination in demersal fish. PMID- 29628393 TI - In Vivo Genetic Manipulation of Spermatogonial Stem Cells and Their Microenvironment by Adeno-Associated Viruses. AB - Adeno-associated virus (AAV) penetrates the blood-brain barrier, but it is unknown whether AAV penetrates other tight junctions. Genetic manipulation of testis has been hampered by the basement membrane of seminiferous tubules and the blood-testis barrier (BTB), which forms between Sertoli cells and divides the tubules into basal and adluminal compartments. Here, we demonstrate in vivo genetic manipulation of spermatogonial stem cells (SSCs) and their microenvironment via AAV1/9. AAV1/9 microinjected into the seminiferous tubules penetrated both the basement membrane and BTB, thereby transducing not only Sertoli cells and SSCs but also peritubular cells and Leydig cells. Moreover, when congenitally infertile KitlSl/KitlSl-d mouse testes with defective Sertoli cells received Kitl-expressing AAVs, spermatogenesis regenerated and offspring were produced. None of the offspring contained the AAV genome. Thus, AAV1/9 allows efficient germline and niche manipulation by penetrating the BTB and basement membrane, providing a promising strategy for the development of gene therapies for reproductive defects. PMID- 29628394 TI - Interleukin-6 Regulates Adult Neural Stem Cell Numbers during Normal and Abnormal Post-natal Development. AB - Circulating systemic factors can regulate adult neural stem cell (NSC) biology, but the identity of these circulating cues is still being defined. Here, we have focused on the cytokine interleukin-6 (IL-6), since increased circulating levels of IL-6 are associated with neural pathologies such as autism and bipolar disorder. We show that IL-6 promotes proliferation of post-natal murine forebrain NSCs and that, when the IL-6 receptor is inducibly knocked out in post-natal or adult neural precursors, this causes a long-term decrease in forebrain NSCs. Moreover, a transient circulating surge of IL-6 in perinatal or adult mice causes an acute increase in neural precursor proliferation followed by long-term depletion of adult NSC pools. Thus, IL-6 signaling is both necessary and sufficient for adult NSC self-renewal, and acute perturbations in circulating IL 6, as observed in many pathological situations, have long-lasting effects on the size of adult NSC pools. PMID- 29628396 TI - Influence of clinical features on cognition in bipolar disorder: Comment on the meta-analysis published by Bora (2018). PMID- 29628395 TI - hPSC-Derived Striatal Cells Generated Using a Scalable 3D Hydrogel Promote Recovery in a Huntington Disease Mouse Model. AB - Huntington disease (HD) is an inherited, progressive neurological disorder characterized by degenerating striatal medium spiny neurons (MSNs). One promising approach for treating HD is cell replacement therapy, where lost cells are replaced by MSN progenitors derived from human pluripotent stem cells (hPSCs). While there has been remarkable progress in generating hPSC-derived MSNs, current production methods rely on two-dimensional culture systems that can include poorly defined components, limit scalability, and yield differing preclinical results. To facilitate clinical translation, here, we generated striatal progenitors from hPSCs within a fully defined and scalable PNIPAAm-PEG three dimensional (3D) hydrogel. Transplantation of 3D-derived striatal progenitors into a transgenic mouse model of HD slowed disease progression, improved motor coordination, and increased survival. In addition, the transplanted cells developed an MSN-like phenotype and formed synaptic connections with host cells. Our results illustrate the potential of scalable 3D biomaterials for generating striatal progenitors for HD cell therapy. PMID- 29628398 TI - Defining clinically relevant measures of iron overload around haemopoietic stem cell transplantation. PMID- 29628397 TI - Enhanced labile plasma iron and outcome in acute myeloid leukaemia and myelodysplastic syndrome after allogeneic haemopoietic cell transplantation (ALLIVE): a prospective, multicentre, observational trial. AB - BACKGROUND: The effect of systemic iron overload on outcomes after allogeneic haemopoietic cell transplantation (HCT) has been a matter of substantial debate. We aimed to investigate the predictive value of both stored (MRI-derived liver iron content) and biologically active iron (enhanced labile plasma iron; eLPI) on post-transplantation outcomes in patients with acute myeloid leukaemia or myelodysplastic syndrome undergoing allogenic HCT. METHODS: The prospective, multicentre, observational, ALLogeneic Iron inVEstigators (ALLIVE) trial recruited patients at five centres in Germany. We enrolled patients with acute myeloid leukaemia or myelodysplastic syndrome undergoing allogeneic HCT. Patients underwent cytotoxic conditioning for a median of 6 days (IQR 6-7) before undergoing allogeneic HCT and were followed up for up to 1 year (+/-3 months) post-transplantation. eLPI was measured in serum samples with the FeROS eLPI kit (Aferrix, Tel-Aviv, Israel) and values greater than 0.4 MUmol/L were considered to represent raised eLPI. Liver iron content was measured by MRI. The primary endpoints were the quantitative delineation of eLPI dynamics during allogeneic HCT and the correlation coefficient between liver iron content before HCT and dynamic eLPI (eLPIdyn; maximum eLPI minus baseline eLPI). All patients with available data were included in all analyses. This is the final analysis of this completed trial, which is registered with ClinicalTrials.gov, number NCT01746147. FINDINGS: Between Dec 13, 2012, and Dec 23, 2014, 112 patients underwent allogeneic HCT. Liver iron content before allogeneic HCT was not significantly correlated with eLPIdyn (rho=0.116, p=0.22). Serum eLPI concentrations rapidly increased during conditioning, and most (79 [73%] of 108) patients had raised eLPI by the day of transplantation. Patients with a pretransplant liver iron content greater than or equal to 125 MUmol/g had an increased incidence of non relapse mortality (20%, 95% CI 14-26) compared with those with lower concentrations (7%, 2-12; p=0.039) at day 100. Patients who had raised eLPI at baseline also had a significantly increased incidence of non-relapse mortality at day 100 (33%, 15-52) compared with those who had normal eLPI at baseline (7%, 2 13; p=0.00034). INTERPRETATION: eLPI is a possible biological mediator of iron related toxicity. Peritransplantation eLPI-scavenging strategies could be explored in prospective interventional clinical trials for patients with systemic iron overload. FUNDING: The Technical University of Dresden and Novartis. PMID- 29628399 TI - LKB1: Controlling Quiescence and Genomic Integrity at Home. AB - The pleiotropic liver kinase B1 (LKB1) controls metabolism, cell polarity, and proliferation in an apparently cell- and context-specific manner. A recent study in Cell Reports has demonstrated that LKB1 is essential to maintain the characteristic quiescence of the liver and to secure genomic integrity during liver regeneration independently of AMPK. PMID- 29628400 TI - [Prevalence and prognostic value of non-thyroidal illness syndrome among critically ill children]. AB - INTRODUCTION: Alterations in thyroid hormones during critical illness, known as non-thyroidal illness syndrome (NTIS), were suggested to have a prognostic value. However, pediatric data is limited. The aim of this study was to assess prevalence and prognostic value of NTIS among critically ill children. MATERIALS AND METHODS: A prospective observational study conducted on 70 critically ill children admitted into pediatric intensive care unit (PICU). Free triiodothyronine (FT3), free thyroxine (FT4), and thyroid stimulating hormone (TSH) were measured within 24hours of PICU admission. Primary outcome was 30-day mortality. RESULTS: NTIS occurred in 62.9% of patients but it took several forms. The most common pattern was low FT3 with normal FT4 and TSH (25.7% of patients). Combined decrease in FT3, FT4, and TSH levels occurred in 7.1% of patients. An unusual finding of elevated TSH was noted in three patients, which might be related to disease severity. Low FT4 was significantly more prevalent among non survivors compared with survivors (50% versus 19.2%, P=.028). NTIS independently predicted mortality (OR=3.91; 95% CI=1.006-15.19; P=.0491). Concomitant decrease in FT3, FT4, and TSH was the best independent predictor of mortality (OR=16.9; 95% CI=1.40-203.04; P=.026). TSH was negatively correlated with length of PICU stay (rs=-0.35, P=.011). FT3 level was significantly lower among patients who received dopamine infusion compared with those who did not receive it (2.1+/-0.66 versus 2.76+/-0.91pg/mL, P=.011). CONCLUSION: NTIS is common among critically ill children and appears to be associated with mortality and illness severity. PMID- 29628387 TI - Gentamicin may have no effect on mortality of staphylococcal prosthetic valve endocarditis. AB - PURPOSE: To analyze the influence of adding gentamicin to a regimen consisting of beta-lactam or vancomycin plus rifampicin on survival in patients suffering from Staphylococcal prosthetic valve endocarditis (SPVE). METHODS: From January 2008 to September 2016, 334 patients with definite SPVE were attended in the participating hospitals. Ninety-four patients (28.1%) received treatment based on beta-lactam or vancomycin plus rifampicin and were included in the study. Variables were analyzed which related to patient survival during admission, including having received treatment with gentamicin. RESULTS: Seventy-seven (81.9%) were treated with cloxacillin (or vancomycin) plus rifampicin plus gentamicin, and 17 patients (18.1%) received the same regimen without gentamicin. The causative microorganism was Staphylococcus aureus in 40 cases (42.6%) and coagulase-negative staphylococci in 54 cases (57.4%). Overall, 40 patients (42.6%) died during hospital admission, 33 patients (42.9%) in the group receiving gentamicin and 7 patients in the group that did not (41.2%, P = 0.899). Worsening renal function was observed in 42 patients (54.5%) who received gentamicin and in 9 patients (52.9%) who did not (p = 0.904). Heart failure as a complication of endocarditis (OR: 4.58; CI 95%: 1.84-11.42) and not performing surgery when indicated (OR: 2.68; CI 95%: 1.03-6.94) increased mortality. Gentamicin administration remained unrelated to mortality (OR: 1.001; CI 95%: 0.29-3.38) in the multivariable analysis. CONCLUSIONS: The addition of gentamicin to a regimen containing vancomycin or cloxacillin plus rifampicin in SPVE was not associated to better outcome. PMID- 29628401 TI - [Generalised keratinocytic epidermal nevi]. PMID- 29628402 TI - Diagnostic Yield of Semi-rigid Thoracoscopy in the Molecular Characterization of Pulmonary Malignant Pleural Effusions. PMID- 29628404 TI - When the Reading Room Meets the Team Room: Resident Perspectives From Radiology and Internal Medicine on the Effect of Personal Communication After Implementing a Resident-Led Radiology Rounds. AB - OBJECTIVE: Current radiology and internal medicine (IM) residents have trained to varying degrees depending on program in the post picture archiving and communication systems implementation era and thus have largely missed out on the benefits of in-person, 2-way communication between radiologists and consulting clinicians. The purpose of this study is to broadly explore resident perspectives from these groups on the desire for personal contact between radiologists and referring physicians and the effect of improved contact on clinical practice. MATERIALS AND METHODS: A radiology rounds was implemented in which radiology residents travel to the IM teaching service teams to discuss their inpatients and review ordered imaging biweekly. Surveys were given to both cohorts following 9 months of implementation. RESULTS: A total of 23/49 diagnostic radiology (DR) and 72/197 IM residents responded. In all, 83% of DR and 96% of IM residents desired more personal contact between radiologists and clinicians. Of all, 92% of DR residents agree that contact with referring clinicians changes their approach to a study, 96% of IM residents agree that personal contact with a radiologist has changed patient management in a way that they otherwise would not have done having simply read a report, 85% of DR residents report that more clinician contact will improve resource use, and 96% report that it will improve care quality. Furthermore, 99% of IM residents report that increased access to a radiologist would make selecting the most appropriate imaging study easier in various clinical scenarios. A majority of IM residents prefer radiology reports that provide specific next-step recommendations and that include arrows/key-image series. CONCLUSION: We conclude that the newest generation of physicians is already attuned to the value of a radiologist who plays an active, in-person role in the clinical decision-making process. PMID- 29628403 TI - Spanish validation of the Negative Symptom Assessment-16 (NSA-16) in patients with schizophrenia. AB - INTRODUCTION: Negative symptoms are prevalent in schizophrenia and associated with a poorer outcome. Validated newer psychometric instruments could contribute to better assessment and improved treatment of negative symptoms. The Negative Symptom Assessment-16 (NSA-16) has been shown to have strong psychometric properties, but there is a need for validation in non-English languages. This study aimed to examine the psychometric properties of a Spanish version of the NSA-16 (Sp-NSA-16). MATERIAL AND METHOD: Observational, cross-sectional validation study in a sample of 123 outpatients with schizophrenia. ASSESSMENTS: NSA-16, PANSS, HDRS, CGI-SCH and PSP. RESULTS: The results indicate appropriate psychometric properties, high internal consistency (Cronbach's alpha=0.86), convergent validity (PANSS negative scale, PANSS Marder Negative Factor and CGI negative symptoms r values between 0.81 and 0.94) and divergent validity (PANSS positive scale and the HDRS r values between 0.10 and 0.34). In addition, the NSA 16 also exhibited discriminant validity (ROC curve=0.97, 95% CI=0.94 to 1.00; 94.3% sensitivity and 83.3% specificity). CONCLUSIONS: The Sp-NSA-16 is reliable and valid for measuring negative symptoms in patients with schizophrenia. This provides Spanish clinicians with a new tool for clinical practice and research. However, it is necessary to provide further information about its inter-rater reliability. PMID- 29628405 TI - Resting metabolic rate and weight loss after bariatric surgery. AB - BACKGROUND: There is an increased interest in understanding how variation in body composition (BC) and energy expenditure is related to successful weight loss after surgery. It has been suggested that low resting metabolic rate (RMR) could be associated with poor weight loss. OBJECTIVES: To determine the relation among changes in BC, RMR, and weight loss after bariatric surgery. SETTING: University tertiary care hospital, Brazil. METHODS: A cohort of 45 patients submitted to bariatric surgery was prospectively studied. BC was evaluated by bioelectrical impedance analysis and RMR by indirect calorimetry before and 6 months after surgery. The RMR value was adjusted per kilogram of weight (RMR/kg). The patients were divided in 4 groups, based on patterns of change in the RMR/kg after surgery. The RMR/kg could decrease (group 1), remain stable (group 2), have a small increase (group 3), or have a major increase (group 4). RESULTS: A significant relation between fat-free mass and RMR for both pre- (P<.01) and postoperative periods (P<.01) was observed. Excess weight loss had a significantly correlation only with post-RMR/kg (P<.01). The pattern of change in RMR/kg was strongly correlated with weight loss, considering an excess weight loss>50% a successful weight loss: No patients achieved success in group 1; 61% of patients did in group 2; 80% di in group 3; and all patients in group 4 had successful weight loss. CONCLUSIONS: We demonstrate a clearly correlation between the postoperative RMR and weight loss. The increase in RMR/kg after surgery is a major factor related to a satisfactory excess weight loss after surgery. PMID- 29628406 TI - Eccentric training combined to neuromuscular electrical stimulation is not superior to eccentric training alone for quadriceps strengthening in healthy subjects: a randomized controlled trial. AB - BACKGROUND: Both eccentric training and neuromuscular electrical stimulation (NMES) are used for quadriceps strengthening. However, the effects of these interventions combined are unclear. OBJECTIVES: To compare the effects of eccentric training combined to NMES and eccentric training alone on structure, strength, and functional performance of knee extensor muscles of healthy subjects. METHODS: This is a three-arm, single-blinded, randomized controlled trial. Forty-three volunteers (18-35 years) completed the full study schedule: control group (n=15); eccentric training group (ECC; n=15); and eccentric training combined to NMES group (ECC+NMES; n=13). Eccentric training program was performed twice a week for 6 weeks. A biphasic pulsed current (400MUs; 80Hz; maximal tolerated intensity) was applied simultaneously to voluntary exercise for ECC+NMES group. Muscle structure (ultrasonography of vastus lateralis - VL, and rectus femoris - RF), strength (isokinetic dynamometry) and functional capacity (single hop test) were assessed before and after the training program by blinded researchers to groups allocation. RESULTS: Control group had no changes throughout the study in any outcome. Eccentric training (with or without NMES) did not affect concentric peak torque, hop test, and VL pennation angle (effect sizes>0.2). ECC and ECC+NMES programs generated significant adaptations (small to moderate effect sizes) on isometric (8-11%) and eccentric (13%) peak torques, VL muscle thickness (5%), VL fascicle length (5-8%), RF muscle thickness (8-9%), RF pennation angle (-2%), and RF fascicle length (12%). CONCLUSION: NMES combined to eccentric training did not influence consistently the type or magnitude of adaptations provoked by knee extensor eccentric training alone in healthy subjects. PMID- 29628408 TI - Not all screens should be used in common living spaces. PMID- 29628407 TI - Posterior circumflex humeral artery pathology and digital ischemia in elite volleyball: Symptoms, risk factors & suggestions for clinical management. AB - OBJECTIVES: To assess the association between posterior circumflex humeral artery (PCHA) pathology (PCHAP), symptoms and associated risk factors, in elite volleyball players, and to suggest profiles for clinical management and monitoring. DESIGN: Cross-sectional study. METHODS: A questionnaire assessed symptoms of digital ischemia (DI) in the dominant hand and risk factors among 278 elite indoor and beach volleyball players of whom 6.1% (17/278) was diagnosed with PCHAP using ultrasound. Odds Ratios (OR) including 95% confidence intervals (95%CI) were calculated using binary logistic regression. RESULTS: All 278 players completed the questionnaire. Three participants with PCHAP were symptomatic (18%). Ninety-three of 96 symptomatic participants had no PCHAP (OR=0.39; 95% CI 0.13-1.13). Total years playing volleyball (OR 1.14; 95% CI 1.03 1.25) and age (OR 1.17; 95% CI 1.00-1.29) were dose-response related risk factors: a volleyball career of >=17 years and age of >=27 years were associated with a 9-fold and 14-fold increased risk of PCHAP, respectively. CONCLUSIONS: The volleyball career duration and age are dose-response related risk factors for PCHAP among elite indoor and beach volleyball players. DI symptoms are prevalent in a minority of athletes with PCHAP (3/17; 18%). To enable worldwide standardized care for these athletes at risk, four profiles for clinical management and monitoring have been suggested based on questionnaire and ultrasound outcomes. PMID- 29628409 TI - Prospective follow-up of a cohort of preterm infants<33 WG receiving ketamine for tracheal intubation in the delivery room: Neurological outcome at 1 and 2 years. AB - OBJECTIVE: Although ketamine analgesia is effective in reducing pain and facilitating the tracheal intubation of newborns in the delivery room, no data on the neurological effects of this treatment are available. This study compared the neurodevelopmental outcomes at 2 years of age in a cohort of preterm newborns having received ketamine prior to tracheal intubation at birth (the ketamine group) and in a control group. METHODS: We included newborns delivered at less than 33 weeks gestational age (WGA) having undergone tracheal intubation at birth. The Ages and Stages Questionnaire (ASQ) was completed at 1 and 2 years of age. The development quotient (DQ) was calculated from the revised Brunet-Lezine score assessed at a corrected age of 2 years. RESULTS: There were no statistically significant differences between the ketamine group (n=54 at 1 year and n=51 at 2 years) and the control group (n=16 at 1 and 2 years) in terms of the mean+/-standard deviation DQ at the age of 2 (98+/-12 vs. 103+/-9, respectively; P=0.17) and the ASQ score at the age of 2 (221+/-44 vs. 230+/-39, respectively; P=0.55). DISCUSSION: This prospective cohort of 51 preterm newborns having received ketamine at birth did not reveal any differences in terms of neurological development at the age of 2 (relative to a control group and the literature data). These preliminary results must be confirmed in a randomized trial with longer follow-up. PMID- 29628411 TI - Impact of Esophageal Atresia on the Success of Fundoplication for Gastroesophageal Reflux. AB - OBJECTIVES: Fundoplication is commonly performed in patients with a history of esophageal atresia (EA), however, the success of this surgery is reduced, as reflected by an increased rate of redo fundoplication. We aimed to determine whether EA impacts the prevalence of fundoplication, its timing, and performance of a redo operation. STUDY DESIGN: A single-center, retrospective review of all patients undergoing fundoplication over a 20-year period (1994-2013) was performed. Redo fundoplication was used as a surrogate for surgical failure. RESULTS: A total of 767 patients (patients with EA 85, those who did not have EA 682) underwent fundoplication during the study period. Median age (months) at primary fundoplication was lower in patients with EA (7.2 vs those who did not have EA 23.3; P < .001). Redo fundoplication rates between groups were not significantly different (EA 11/85 vs 53/682; P = .14). Median time (months) between primary and redo fundoplication was greater in patients with EA (36.2 vs 11.7; P = .03). CONCLUSIONS: Contrary to popular belief, the incidence of redo fundoplication was not significantly increased in patients with a history of EA. However, patients with EA underwent fundoplication at younger ages, which may be related to early life-threatening events in these patients. These results inform perioperative counseling, and highlight the importance of sustained surgical follow-up in patients with EA. PMID- 29628410 TI - Impact of Psychosocial Risk on Outcomes among Families Seeking Treatment for Obesity. AB - OBJECTIVES: To test the hypothesis that children with elevated psychosocial risk would have increased attrition and worse weight outcomes in weight management treatment. STUDY DESIGN: This was a prospective cohort study of 100 new patients, aged 4-12 years, in a weight management clinic. Parents completed the Psychosocial Assessment Tool. Logistic regression analyses were conducted to calculate the odds of attrition from the clinic and a nonmeaningful change in body mass index (BMI) z-score (ie, <0.1 unit decrease in BMI z-score) over a 6 month period based on psychosocial risk category, adjusting for child demographics and baseline weight category. RESULTS: The majority of patients were male (59%), black (36%) or white (43%), and had severe obesity (55%), and 59% of families were categorized as having moderate or high psychosocial risk. Over the 6-month period, 53% of families were lost to follow-up, and 67% did not have a clinically meaningful decrease in BMI z-score. Compared with children of families with low psychosocial risk, children of families with moderate or high psychosocial risk were 3.1 times (95% CI, 1.3-7.2 times) more likely to be lost to follow-up and 2.9 times (95% CI, 1.1-7.9 times) more likely to have a non clinically meaningful change in BMI z-score. CONCLUSIONS: Children presenting with increased psychosocial risk have higher attrition and poorer weight outcomes, supporting the need for psychosocial screening as a standard component of pediatric weight management treatment. PMID- 29628412 TI - The Left Ventricle in Congenital Diaphragmatic Hernia: Implications for the Management of Pulmonary Hypertension. PMID- 29628413 TI - Acrodermatitis-Like Rash in Kawasaki Disease. PMID- 29628414 TI - Catheter-Related Venous Thrombosis in Hospitalized Pediatric Patients with Inflammatory Bowel Disease: Incidence, Characteristics, and Role of Anticoagulant Thromboprophylaxis with Enoxaparin. AB - OBJECTIVE: To describe the incidence and characteristics of central venous catheter (CVC)-related thrombosis in hospitalized pediatric patients with active inflammatory bowel disease (IBD) and report the potential usefulness of anticoagulant thromboprophylaxis (AT). STUDY DESIGN: We conducted a retrospective study of patients who were admitted to our children's hospital in the last 2 years with active IBD and required a CVC and identified all patients with an objectively confirmed symptomatic CVC-related thrombosis. To assess the usefulness of a recently implemented institutional AT protocol, we compared the frequency of CVC-related thrombosis, nadir hemoglobin, and red blood cell transfusion requirements in patients who received AT with those who did not during the study period. RESULTS: A total of 40 patients with IBD who required 47 consecutive hospitalizations were included. AT was administered during 24 of 47 hospitalizations (51%). Patients who received AT were similar to those who did not receive AT with regard to demographics, IBD phenotypes, extent of colonic involvement, and thrombotic risk factors. CVC-related thrombosis occurred in 5 of 23 hospitalizations (22%) in which AT was withheld compared with 0 of 24 hospitalizations (0%) in which patients received AT (P = .02). The red blood cell transfusion requirements and nadir hemoglobin were not significantly different between the 2 groups. CONCLUSIONS: We observed a high incidence of CVC-related thrombosis in hospitalized children with IBD. Administration of AT in our population was associated with significant reduction in CVC-related thrombosis without evidence of increased bleeding. PMID- 29628415 TI - Review: Management of patients with kidney allograft failure. AB - Late allograft loss in kidney transplant recipients remains a common problem and is associated with high mortality and morbidity. The management of patients with a failed kidney allograft includes a few major dilemmas: when to start dialysis, what is the optimal management regarding immunosuppression, and should an allograft nephrectomy be performed. In suitable candidates for a repeated transplantation there are additional matters to take in consideration. In this review we will discuss these dilemmas by providing an overview of current evidence and gaps in our knowledge. As many of these issues are incompletely resolved, we conclude that more studies are needed to improve the management of patients with a failed kidney allograft. PMID- 29628416 TI - Can we incorporate geriatric assessment in the management of acute lymphoblastic leukemia in older adults? AB - Acute lymphoblastic leukemia (ALL) is an uncommon disease. Approximately 14% of new ALL cases occur in adults aged 60 and over, and the three-year overall survival in this population is poor at 12.8%. Older adults with ALL are heterogeneous in terms of their underlying health status, which can make treatment selection challenging given the disease rarity and limited inclusion of older patients in clinical trials. A comprehensive geriatric assessment (CGA) is a compilation of tools to assess multiple domains such as physical function and cognition, and may assist in guiding treatment selection and supportive care interventions. However, studies on the use of CGA are limited in older adults with ALL. In this review, we discuss the utility of CGA in patients with various hematologic malignancies. Using two patient cases of ALL, we also describe how CGA may be use to guide treatment and supportive care interventions. PMID- 29628417 TI - Alaska Mountain Wilderness Ski Classic: Alterations in Caloric Expenditure and Body Composition. AB - INTRODUCTION: The Alaska Mountain Wilderness Ski Classic is a self-supported ultramarathon cross-country skiing event that traverses one of the mountain ranges of Alaska each winter. Unique aspects of this event challenge athletes with a significant amount of physical and mental stress while in the chronically cold conditions of the Arctic. Assessment of energy requirements or body composition has never been performed during this event. The objective of the study was to evaluate the influence of the 2016 Alaska Mountain Wilderness Ski Classic on caloric expenditure and body composition. METHODS: Caloric expenditure was estimated using GT3x+ Actigraph accelerometers and ActiLife software. Lean tissue mass, total fat mass, visceral fat mass, and bone mineral density were measured using a General Electric iDXA before and after the event. Data are presented as mean+/-SD. Differences were analyzed using paired t tests with significance at P<0.05. RESULTS: Fifteen participants (age=32.7+/-6.6 years, body mass index=23.7+/-2.3 kg.m2) completed the study, 8 males and 7 females. Caloric expenditure was 6238+/-1390 kcal.day-1, and 37,163+/-8425 kcal for the entire event. Fat mass was reduced from pre-event (?1.3+/-0.7 kg, P=0.00003). There was an increase in lean tissue mass (?1.7+/-1.3 kg, P=0.0003) and relative skeletal muscle index (?0.2+/-0.2 kg.m2, P=0.001). There was no change in bone mineral density (?0+/-0 g.cm3, P=0.4). CONCLUSIONS: Despite the metabolic demands, fat mass was reduced and lean tissue mass was preserved. Future studies of this event should be directed toward assessment of the nutritional provisions utilized and the mechanisms responsible for the preservation of lean tissue mass. PMID- 29628418 TI - Immune Evasion in Tumor's Own Sweet Way. AB - Accumulating data suggest an important role of tumor metabolism during cancer development, metastasis, and therapeutic resistance. In Cell Metabolism, Cascone et al. (2018) show that increased tumor glycolysis suppresses anti-tumor immunity by impairing T cell killing and trafficking to the tumor microenvironment. PMID- 29628420 TI - ? PMID- 29628421 TI - A new methodology for automatic detection of reference points in 3D cephalometry: A pilot study. AB - OBJECTIVE: The aim of this study was to develop a new method for an automatic detection of reference points in 3D cephalometry to overcome the limits of 2D cephalometric analyses. MATERIALS AND METHODS: A specific application was designed using the C++ language for automatic and manual identification of 21 (reference) points on the craniofacial structures. Our algorithm is based on the implementation of an anatomical and geometrical network adapted to the craniofacial structure. This network was constructed based on the anatomical knowledge of the 3D cephalometric (reference) points. RESULTS: The proposed algorithm was tested on five CBCT images. The proposed approach for the automatic 3D cephalometric identification was able to detect 21 points with a mean error of 2.32mm. DISCUSSION: In this pilot study, we propose an automated methodology for the identification of the 3D cephalometric (reference) points. A larger sample will be implemented in the future to assess the method validity and reliability. PMID- 29628419 TI - Increased Tumor Glycolysis Characterizes Immune Resistance to Adoptive T Cell Therapy. AB - Adoptive T cell therapy (ACT) produces durable responses in some cancer patients; however, most tumors are refractory to ACT and the molecular mechanisms underlying resistance are unclear. Using two independent approaches, we identified tumor glycolysis as a pathway associated with immune resistance in melanoma. Glycolysis-related genes were upregulated in melanoma and lung cancer patient samples poorly infiltrated by T cells. Overexpression of glycolysis related molecules impaired T cell killing of tumor cells, whereas inhibition of glycolysis enhanced T cell-mediated antitumor immunity in vitro and in vivo. Moreover, glycolysis-related gene expression was higher in melanoma tissues from ACT-refractory patients, and tumor cells derived from these patients exhibited higher glycolytic activity. We identified reduced levels of IRF1 and CXCL10 immunostimulatory molecules in highly glycolytic melanoma cells. Our findings demonstrate that tumor glycolysis is associated with the efficacy of ACT and identify the glycolysis pathway as a candidate target for combinatorial therapeutic intervention. PMID- 29628422 TI - ? PMID- 29628423 TI - Micrographic study and torsional strength of grade 23 titanium mini-implants recycled for orthodontic purposes. AB - INTRODUCTION: The aim of this study was to identify the fracture resistance of grade 23 Titanium mini-implants recycled for orthodontic purposes and having stayed in the mouth during different periods of time. MATERIALS AND METHODS: A total of 52 hybrid-designed titanium mini-implants, threaded length L=8mm, self drilling and self-taping were used in 32 patients presenting orthodontic anomalies which required the use of mini-implants. Two types of tests were performed: polarizing optical imagery to assess the surface characteristics of the mini-implants (polarizing optical microscopy) and (mechanical) torsional strength tests, more quantitative, in order to establish the breaking point of the mini-implants during their re-use. RESULTS: For the mini-implants which had been in the mouth for a short period of time, (immediate removal or after two months of use), it must be noted that their surface characteristics revealed no defect at micron scale, the drilling head did not show any alteration, with a breaking point record of about 53Newton/cm2 (N/cm2). In contrast, the mini implants, which had stayed in the mouth for 12 and 14 months, showed surface alterations especially at the "screw-gingiva" interface and the rupture stress ranges from 42 to 39N/cm2, respectively. DISCUSSION: Our results show that the resistance to fracture of the re-used mini-implants is inversely proportional to the duration of stay in the mouth. PMID- 29628424 TI - Association between sella turcica bridging and palatal canine impaction: Evaluation using lateral cephalograms and CBCT. AB - INTRODUCTION: The purpose of this study was to find a correlation between sella turcica bridging and the presence of a palatal impacted canine, using lateral cephalograms and CBCT. MATERIAL AND METHOD: We selected the lateral cephalograms and CBCTs of 60 patients meeting specific criteria. The radiographs were analysed to study the relationship between sella turca bridging and several factors. The presence or absence of a partial or total bridging was deducted by measuring the dimensions of the sella turcica and by using an accurate scoring system. RESULTS AND CONCLUSION: Our study did not show any statistically significant association between sella turcica bridging as diagnosed on the lateral cephalogram and the CBCT images and the following factors: age, gender, facial type, skeletal class and the presence of an impacted canine. We found a significant difference for the classification of the sella turcica between these two radiographic methods. PMID- 29628425 TI - Corticotomy-assisted orthodontic camouflage in a class III adult patient with a severe transverse discrepancy. AB - A 25-year-old man presented with a maxillary transverse discrepancy, posterior cross bite, anterior open bite, molar and canine class III. Treatment included a corticotomy in the upper lateral and posterior teeth, a palatal expansor and a sectional archwire to assist the expansion. The following treatment phase included bonding with Incognito System lingual appliance, interproximal reduction to solve the crowding and bite blocks to control the verticality. Two months after the bonding intermaxillary class III elastics were used to solve the sagittal discrepancy and eight months after the bonding vertical elastics were used in order to solve the anterior open bite until the end of the treatment. A Boston splint was applied for the upper arch, an essix splint was applied for the lower arch. The patient compliance was an essential aspect in the success of the orthodontic treatment. PMID- 29628426 TI - ? PMID- 29628427 TI - External apical root resorption diagnosis by using FII human dentine fraction and salivary IGg. AB - BACKGROUND: External apical root resorption as a consequence of orthodontic treatment is an inflammatory pathological process that results in permanent loss of tooth structure from the root apex. OBJECTIVES: This study aimed to investigate the diagnostic potential of human dentine fractions and salivary IgG in external apical root resorption. PATIENTS AND METHODS: Saliva samples were collected from 10 patients before (T0) and after 3 (T3), 6 (T6) and 12 (T12) months of orthodontic treatment. The total dentinal extract, obtained from human third molars, was fractioned by gel filtration chromatography in three fractions denominated FI, FII and FIII. The root resorption analysis of the upper central incisors was performed by digital image subtraction method. Reactivity of salivary IgG to antigenic fractions of dentine was determined by enzyme-linked immunosorbent assay (Elisa). RESULTS: Regardless of treatment, FI dentin fraction with high MM (<300kDa) was the one that presented highest reactivity with salivary IgG. However, it was found higher salivary IgG reactivity for FII (69 to 45 kilodalton [kDa]) as compared to FIII (<45kDa) at (T6) and (T12), (P<0.05), the same periods in that the root resorptions were detected. CONCLUSION: Our results suggest that FII human dentine fraction and salivary IgG have potential to be used in diagnosis and monitoring of external apical root resorption. The development of a practical and accessible biochemical test using saliva and FII dentine fraction may help in the prevention of severe root resorption. PMID- 29628428 TI - ? PMID- 29628429 TI - ? PMID- 29628430 TI - ? PMID- 29628431 TI - Relationships between the obstructive character of the tonsils and the type of ventilation and lip posture. AB - INTRODUCTION: The role of obstructive tonsils in ventilatory disorders and abnormal lip posture is widely discussed in the literature but remains controversial. The data reported on the probable relationship between obstructive tonsils and an existing breathing disorder or lip incompetence were subjective. The purpose of this study was to evaluate the relationship between the obstructive character of the tonsils and the type of ventilation and lip posture. MATERIALS AND METHODS: This is a cross-sectional study performed in children aged from 6 to 12 years old. The subjects were divided into two groups (A and B) according to the obstructive or non-obstructive character of the palatal tonsils. Type of ventilation and lip posture at rest were recorded for each child. The collected data were analysed using the SPSS 20.0 software (for Windows). A Student's t-test and a Chi2 test were respectively used to compare quantitative and qualitative variables according to the obstructive character of the tonsils for each group. The level of significance is fixed at P=0.05. RESULTS: The subjects in group B with obstructive palatal tonsils were significantly more likely to oral breathing and lip incompetence than the subjects with non obstructive tonsils (group A). CONCLUSION: The clinical examination of children with ventilatory and postural disorders with lip incompetence must be directed towards the search for associated obstructive palatal tonsils in order to plan an early etiological treatment. This would allow to avoid subsequent problems in the dentofacial structures. PMID- 29628433 TI - Sensory Prediction Errors Are Less Modulated by Global Context in Autism Spectrum Disorder. AB - BACKGROUND: Recent predictive coding accounts of autism spectrum disorder (ASD) suggest that a key deficit in ASD concerns the inflexibility in modulating local prediction errors as a function of global top-down expectations. As a direct test of this central hypothesis, we used electroencephalography to investigate whether local prediction error processing was less modulated by global context (i.e., global stimulus frequency) in ASD. METHODS: A group of 18 adults with ASD was compared with a group of 24 typically developed adults on a well-validated hierarchical auditory oddball task in which participants listened to short sequences of either five identical sounds (local standard) or four identical sounds and a fifth deviant sound (local deviant). The latter condition is known to generate the mismatch negativity (MMN) component, believed to reflect early sensory prediction error processing. Crucially, previous studies have shown that in blocks with a higher frequency of local deviant sequences, top-down expectations seem to attenuate the MMN. We predicted that this modulation by global context would be less pronounced in the ASD group. RESULTS: Both groups showed an MMN that was modulated by global context. However, this effect was smaller in the ASD group as compared with the typically developed group. In contrast, the P3b, as an electroencephalographic marker of conscious expectation processes, did not differ across groups. CONCLUSIONS: Our results demonstrate that people with ASD are less flexible in modulating their local predictions (reflected in MMN), thereby confirming the central hypothesis of contemporary predictive coding accounts of ASD. PMID- 29628432 TI - Cognitive and psychological issues in postural tachycardia syndrome. AB - Postural tachycardia syndrome (POTS) is one of the most common forms of chronic orthostatic intolerance. In addition to orthostatic symptoms, many POTS patients report incapacitating cognitive dysfunction or "brain fog" even while lying down or seated. Consistent with these subjective reports, there is accruing objective evidence of specific cognitive difficulties in POTS, with studies showing mild to moderate cognitive impairment using standardized neuropsychological assessment batteries. The precise profile of cognitive dysfunction in POTS patients has been shown to vary among these studies potentially due to the neuropsychological tests used, postural position, comorbidities and length of illness, inclusion of adolescent versus adult patients, and sites of recruitment. The extent of the impact that this cognitive challenge has in patients justifies ongoing investigation and research into lifestyle and pharmacological treatments. Psychologically, patients face challenges congruent with many chronic illnesses, perhaps especially early in adjusting to the condition. POTS patients often exhibit mild to moderate depression symptoms as well as symptoms of anxiety disorders. Since even low levels of anxiety can exacerbate symptoms, and a high number of patients experience sub-clinical low mood and sleep disturbances, there is a likely role for psychotherapy in helping control adjustment-related issues, and possibly aberrant physiology, in POTS. PMID- 29628434 TI - Cellular Cyborgs: On the Precipice of a Drug Delivery Revolution. AB - Cell-based drug delivery systems offer the prospect of biocompatibility, large loading capacity, long in vivo lifespan, and active targeting of diseased sites. However, these opportunities are offset by an array of challenges, including safeguarding the integrity of the drug cargo and the cellular host, as well as ensuring that drug release occurs at the appropriate time and place. Emerging strategies that address these, and related, issues, are described herein. PMID- 29628437 TI - Chronic respiratory failure in patients with chronic obstructive pulmonary disease under home noninvasive ventilation: Real-life study. AB - BACKGROUND: Home noninvasive ventilation (NIV) has been increasingly used in stable chronic obstructive pulmonary disease (COPD) with chronic hypercapnic respiratory failure (CHRF). However its effectiveness remains debatable. AIM: To describe a follow-up of COPD patients under home NIV. METHODS: Retrospective descriptive study based on a prospective 3-year database that included COPD patients under home NIV between August 2011 and July 2014. RESULTS: Within the 334 patients initially screened, 109 (32.6%) had COPD with a mean+/-SD post bronchodilator FEV1 of 38.6+/-14.9% predicted; age of 65.6+/-9.6 years. The mean+/-SD duration of ventilation was 63.4+/-51.1 months. Heterogeneous comorbidities that can contribute to CHRF were not excluded: obstructive sleep apnea and obesity were the most prevalent. Sixty-two (56.9%) patients started NIV during admission with acute respiratory failure. During follow-up there was a significant increase in mean inspiratory positive airway pressure (IPAP) and respiratory rate (19.5+/-4.4 vs. 23.6+/-5.3cmH2O and 10.7+/-5.2 vs. 15.2+/-1.4 breaths/min, respectively, p<0.0001), with a significant improvement in hypercapnia (PaCO2: 52.9+/-7.7 vs. 49.5+/-7.5mmHg, p<0.0001), with 93.3% of patients compliant to NIV. Admissions and days spent in hospital for respiratory illness significantly decreased after institution of NIV (respectively, 1.2+/-1.1 vs. 0.7+/-1.8 and 15.0+/-16.8 vs. 8.8+/-19.4, p<0.001). At final evaluation, patients with severe hypercapnia (n=47; PaCO2 >=50mmHg) performing NIV at higher pressures (n=30; IPAP >=25cmH2O) were more compliant (10.1+/-3.3 vs. 6.1+/ 3.6h/day). Three-year mortality was 24.8% (27 of 109 patients). CONCLUSIONS: This is a real-life retrospective study in COPD patients with CHRF which results suggest benefit from home NIV. For most, NIV was effective and tolerable even at high pressures. PMID- 29628435 TI - Dependence on the Pyrimidine Biosynthetic Enzyme DHODH Is a Synthetic Lethal Vulnerability in Mutant KRAS-Driven Cancers. AB - Activating KRAS mutations are major oncogenic drivers in multiple tumor types. Synthetic lethal screens have previously been used to identify targets critical for the survival of KRAS mutant cells, but their application to drug discovery has proven challenging, possibly due in part to a failure of monolayer cultures to model tumor biology. Here, we report the results of a high-throughput synthetic lethal screen for small molecules that selectively inhibit the growth of KRAS mutant cell lines in soft agar. Chemoproteomic profiling identifies the target of the most KRAS-selective chemical series as dihydroorotate dehydrogenase (DHODH). DHODH inhibition is shown to perturb multiple metabolic pathways. In vivo preclinical studies demonstrate strong antitumor activity upon DHODH inhibition in a pancreatic tumor xenograft model. PMID- 29628436 TI - The Rheumatoid Arthritis-Associated Citrullinome. AB - Increased protein citrullination is linked to various diseases including rheumatoid arthritis (RA), lupus, and cancer. Citrullinated autoantigens, a hallmark of RA, are recognized by anti-citrullinated protein antibodies (ACPAs) which are used to diagnose RA. ACPA-recognizing citrullinated enolase, vimentin, keratin, and filaggrin are also pathogenic. Here, we used a chemoproteomic approach to define the RA-associated citrullinome. The identified proteins include numerous serine protease inhibitors (Serpins), proteases and metabolic enzymes. We demonstrate that citrullination of antiplasmin, antithrombin, t-PAI, and C1 inhibitor (P1-Arg-containing Serpins) abolishes their ability to inhibit their cognate proteases. Citrullination of nicotinamide N-methyl transferase (NNMT) also abolished its methyltransferase activity. Overall, these data advance our understanding of the roles of citrullination in RA and suggest that extracellular protein arginine deiminase (PAD) activity can modulate protease activity with consequent effects on Serpin-regulated pathways. Moreover, our data suggest that inhibition of extracellular PAD activity will be therapeutically relevant. PMID- 29628439 TI - Pleural lavage cytology after lung resection in patients with non-small cell lung cancer and the feasibility of 20 mL saline solution. AB - BACKGROUND: There are two issues to be discussed in pleural lavage cytology (PLC) for resected non-small cell lung cancer (NSCLC) whether it should be performed before (pre-PLC) or after (post-PLC) the lung resection and the dose of saline varies widely among the institutions. METHODS: We retrospectively reviewed the clinical records of 466 consecutive patients who underwent a curative resection for NSCLC and received both a pre- and post- PLC using 20 mL of saline from January 2001 to December 2011. RESULTS: There were 24/28 of positive pre- and post-PLC and 442/438 negative pre- and post-PLCs, respectively. Patients with a positive pre- or post-PLCs had significantly worse 5-year survival rates than those with negative results (pre-PLC positive/negative; 32.6%/69.9%, p = 0.001, post-PLC positive/negative; 21.4%/71.1%, p < 0.001, respectively). The post-PLC (p = 0.01) was an independent prognostic factor for the overall survival by a multivariate analysis, whereas the pre-PLC was not (p = 0.79). CONCLUSIONS: The post-PLC was a more significant prognostic factor than the pre-PLC. Further, 20 mL of saline seemed feasible because of the consistent results compared to the past reports using a greater dose of saline for regarding the positive rates of the PLC and its prognostic significance. PMID- 29628440 TI - Evaluation of versatility of use of island first dorsal metacarpal artery flap in reconstruction of dorsal hand defects. AB - BACKGROUND: Posttraumatic dorsal hand defects with exposed tendons and/or bones represent a challenge to reconstructive surgeons. Many options are suggested ranging from local, regional, distant up to free flaps. First dorsal metacarpal artery island flap was commonly prescribed for reconstructing the thumb or first web space defects. METHODS: During a 30 month's period, 23 patients, 15 males aged between 17 and 48 years and 8 females aged between 18 and 36 years presented by posttraumatic dorsal hand defects. Of them 18 had both exposed tendons and bones while 5 had exposed tendons only. The defects dimensions ranged between 3 * 4 cm and 4.5 * 6 cm. All defects were reconstructed by using a single stage first dorsal metacarpal artery island flaps. RESULTS: All flaps survived completely without complication during the mean follow up period of 2 years. All patients were very satisfied both functionally and aesthetically by the procedure. CONCLUSION: Island first dorsal metacarpal artery flap is a good option for reconstructing mild to moderate dorsal hand defects with acceptable functional and cosmetic results. PMID- 29628438 TI - An aggressive early gastric cancer: Kodama's PenA type. AB - BACKGROUND: To investigate the role of Kodama PenA subtype in influencing survival in patients with early gastric cancer (EGC). METHODS: All patients surgically treated for EGC at 7 Italian centers (Forli, Varese, Siena, Verona, Milan, Rome and Perugia) belonging to the Italian Research Group for Gastric Cancer (GIRCG) from January 1982 and December 2009 were included. RESULTS: PenA patients were 230 (21.5%) while other types were 839 (78.5%). Nodal metastases were more common in PenA (30.7%) than non-PenA (10.4%) EGCs. Among preoperative variables, only age (OR 1.02; 95% CI 1.00-1.03, p = 0.009) and macrotype III (OR 1.95; 95% CI 1.39-2.75, p = 0.0001) were significantly associated with Pen A type. Survival analysis performed on N0 patients demonstrated that only size >2 cm (HR 1.85; 95% CI 1.12-3.05, p = 0.017) and age (HR 1.06; 95% CI 1.03-1.08, p < 0.0001) were independent poor prognostic factor. Among N+ patients age (HR 1.04; 95% CI 1.00-1.07, p = 0.048), number of positive lymph nodes (HR 1.13; 95% CI 1.05-1.20, p = 0.0002) and PenA (HR 4.23; 95% CI 1.70-10.55, p = 0.002) were significantly correlated with poor prognosis at multivariate analysis. CONCLUSIONS: Kodama PenA subtype was the most powerful independent prognostic factor in patients with nodal metastases. Its status should always be investigated in EGCs patients. PMID- 29628442 TI - Obstructive sleep apnea and effects of continuous positive airway pressure on triglyceride-rich lipoprotein metabolism. AB - This study aimed to explore lipoprotein metabolism in obstructive sleep apnea (OSA) and the effects of continuous positive airway pressure (CPAP). We studied 15 men with severe OSA [apnea-hypopnea index (AHI) >=30 events/hour] and 12 age-, BMI-, and waist circumference-matched volunteers without OSA (AHI <5 events/hour). Carotid intima-media thickness (CIMT) was determined by a blind examiner. After 12 h fasting, a triglyceride-rich chylomicron-like emulsion, labeled with [14C]cholesteryl oleate and [3H]triolein, was injected intravenously followed by blood sample collection at preestablished times. Fractional clearance rate (FCR) of the radiolabeled lipids was estimated by compartmental analysis of radioisotope decay curves. Compared with controls, patients with OSA showed a significant delay in both cholesteryl ester FCR (0.0126 +/- 0.0187 vs. 0.0015 +/- 0.0025 min-1; P = 0.0313) and triglycerides FCR (0.0334 +/- 0.0390 vs. 0.0051 +/- 0.0074 min-1; P = 0.0001). CIMT was higher in the OSA group: 620 +/- 17 vs. 725 +/- 29 um; P = 0.004. Cholesteryl ester FCRs were inversely related to total sleep time <90% (r = -0.463; P = 0.029) and CIMT (r = -0.601; P = 0.022). The triglyceride FCR was inversely correlated with AHI (r = -0.537; P = 0.04). In a subgroup of patients treated with CPAP for 3 months (n = 7), triglyceride FCR increased 5-fold (P = 0.025), but the cholesteryl ester FCR was unchanged. In conclusion, severe OSA decreased lipolysis of triglyceride-rich lipoproteins and delayed removal of remnants. CPAP treatment may be effective to restore the lipolysis rates. PMID- 29628441 TI - The Original Social Network: White Matter and Social Cognition. AB - Social neuroscience has traditionally focused on the functionality of gray matter regions, ignoring the critical role played by axonal fiber pathways in supporting complex social processes. In this paper, we argue that research on white matter is essential for understanding a range of topics in social neuroscience, such as face processing, theory of mind, empathy, and imitation, as well as clinical disorders defined by aberrant social behavior, such as prosopagnosia, autism, and schizophrenia. We provide practical advice on how best to carry out these studies, which ultimately will substantially deepen our understanding of the neurobiological basis of social behavior. PMID- 29628443 TI - Structural analyses of Arabidopsis thaliana legumain gamma reveal differential recognition and processing of proteolysis and ligation substrates. AB - Legumain is a dual-function protease-peptide ligase whose activities are of great interest to researchers studying plant physiology and to biotechnological applications. However, the molecular mechanisms determining the specificities for proteolysis and ligation are unclear because structural information on the substrate recognition by a fully activated plant legumain is unavailable. Here, we present the X-ray structure of Arabidopsis thaliana legumain isoform gamma (AtLEGgamma) in complex with the covalent peptidic Ac-YVAD chloromethyl ketone (CMK) inhibitor targeting the catalytic cysteine. Mapping of the specificity pockets preceding the substrate-cleavage site explained the known substrate preference. The comparison of inhibited and free AtLEGgamma structures disclosed a substrate-induced disorder-order transition with synergistic rearrangements in the substrate-recognition sites. Docking and in vitro studies with an AtLEGgamma ligase substrate, sunflower trypsin inhibitor (SFTI), revealed a canonical, protease substrate-like binding to the active site-binding pockets preceding and following the cleavage site. We found the interaction of the second residue after the scissile bond, P2'-S2', to be critical for deciding on proteolysis versus cyclization. cis-trans-Isomerization of the cyclic peptide product triggered its release from the AtLEGgamma active site and prevented inadvertent cleavage. The presented integrative mechanisms of proteolysis and ligation (transpeptidation) explain the interdependence of legumain and its preferred substrates and provide a rational framework for engineering optimized proteases, ligases, and substrates. PMID- 29628444 TI - PH domain leucine-rich repeat protein phosphatase 2 (PHLPP2) regulates G-protein coupled receptor kinase 5 (GRK5)-induced cardiac hypertrophy in vitro. AB - PH domain leucine-rich repeat protein phosphatase (PHLPP) is a serine/threonine phosphatase that has been shown to regulate cell growth and survival through dephosphorylation of several members of the AGC family of kinases. G-protein coupled receptor kinase 5 (GRK5) is an AGC kinase that regulates phenylephrine (PE)-induced cardiac hypertrophy through its noncanonical function of directly targeting proteins to the nucleus to regulate transcription. Here we investigated the possibility that the PHLPP2 isoform can regulate GRK5-induced cardiomyocyte hypertrophy in neonatal rat ventricular myocytes (NRVMs). We show that removal of PHLPP2 by siRNA induces hypertrophic growth of NRVMs as measured by cell size changes at baseline, potentiated PE-induced cell size changes, and re-expression of fetal genes atrial natriuretic factor and brain natriuretic peptide. Endogenous GRK5 and PHLPP2 were found to interact in NRVMs, and PE-induced nuclear accumulation of GRK5 was enhanced upon down-regulation of PHLPP2. Conversely, overexpression of PHLPP2 blocked PE-induced hypertrophic growth, re expression of fetal genes, and nuclear accumulation of GRK5, which depended on its phosphatase activity. Finally, using siRNA against GRK5, we found that GRK5 was necessary for the hypertrophic response induced by PHLPP2 knockdown. Our findings demonstrate for the first time a novel regulation of GRK5 by the phosphatase PHLPP2, which modulates hypertrophic growth. Understanding the signaling pathways affected by PHLPP2 has potential for new therapeutic targets in the treatment of cardiac hypertrophy and failure. PMID- 29628445 TI - The telomerase inhibitor AZT enhances differentiation and prevents overgrowth of human pluripotent stem cell-derived neural progenitors. AB - Human pluripotent stem cell (hPSC)-based cell-replacement therapy has emerged as a promising approach for addressing numerous neurological diseases. However, hPSC transplantation has the potential to cause human cell overgrowth and cancer, which represents a major obstacle to implementing hPSC-based therapies. Inhibition of the overgrowth of transplanted cells could help reduce the risk for hPSC transplantation-induced tumorigenesis. In this study, we report that the telomerase inhibitor azidothymidine (3'-azido-3'-deoxythymidine; AZT) enhances the differentiation of cortical neurons and significantly suppresses the proliferation of hPSC-derived cortical progenitors. Using human embryonic stem cells and induced pluripotent stem cells in culture, we found that AZT effectively reduces the number of dividing progenitors without inducing cell death. Furthermore, AZT promoted differentiation of cortical progenitors and maturation of cortical neurons. Of note, AZT-pretreated, hPSC-derived neural progenitors exhibited decreased proliferation and increased differentiation into cortical neurons when transplanted into the mouse brain. In summary, our findings indicate that AZT prevents the overgrowth of hPSC-derived neural precursors and enhances the differentiation of cortical neurons in both cell cultures and hPSC transplanted mouse brain. We propose that our work could inform clinical applications of hPSC-based cell therapy. PMID- 29628448 TI - Editorial Note. PMID- 29628449 TI - Ethical Guidelines for Genetic Research on Alcohol Addiction and Its Applications. AB - Research on the genomic correlates to addiction raises ethical issues in a number of different domains. In this paper, we evaluate the status of genetic research on alcohol dependence as background to addressing the ethical issues raised in conducting research on addiction and the application of that research to the formulation of public policies. We conclude that genetic testing is not yet ready for use in the prediction of alcohol dependence liability. Pharmacogenetic testing for responses to treatments may have more clinical utility, although additional research is required to demonstrate utility and cost-effectiveness. Genetic research on addiction raises potential risks for participants that must be clearly communicated to participants, including limitations on the ability of researchers to protect their privacy. Responsible communication of research findings is essential to prevent common misunderstandings about the role of genetics in addiction liability, to prevent its premature or inappropriate use, and to reduce discrimination and stigmatization experienced by addicted individuals. More research is needed to determine the impact of genetic explanations on addicted individuals, treatment-seeking behavior, and on public attitudes towards addicted persons. Importantly, genetic research on addiction must not be at the expense of investments in social, behavioral, and psychological research on addiction. PMID- 29628446 TI - Assessment of LVEF using a new 16-segment wall motion score in echocardiography. AB - BACKGROUND: Simpson biplane method and 3D by transthoracic echocardiography (TTE), radionuclide angiography (RNA) and cardiac magnetic resonance imaging (CMR) are the most accepted techniques for left ventricular ejection fraction (LVEF) assessment. Wall motion score index (WMSI) by TTE is an accepted complement. However, the conversion from WMSI to LVEF is obtained through a regression equation, which may limit its use. In this retrospective study, we aimed to validate a new method to derive LVEF from the wall motion score in 95 patients. METHODS: The new score consisted of attributing a segmental EF to each LV segment based on the wall motion score and averaging all 16 segmental EF into a global LVEF. This segmental EF score was calculated on TTE in 95 patients, and RNA was used as the reference LVEF method. LVEF using the new segmental EF 15-40 65 score on TTE was compared to the reference methods using linear regression and Bland-Altman analyses. RESULTS: The median LVEF was 45% (interquartile range 32 53%; range from 15 to 65%). Our new segmental EF 15-40-65 score derived on TTE correlated strongly with RNA-LVEF (r = 0.97). Overall, the new score resulted in good agreement of LVEF compared to RNA (mean bias 0.61%). The standard deviations (s.d.s) of the distributions of inter-method difference for the comparison of the new score with RNA were 6.2%, indicating good precision. CONCLUSION: LVEF assessment using segmental EF derived from the wall motion score applied to each of the 16 LV segments has excellent correlation and agreement with a reference method. PMID- 29628450 TI - Support for Voluntary Euthanasia with No Logical Slippery Slope to Non-Voluntary Euthanasia. AB - This paper demonstrates that acceptance of voluntary euthanasia does not generate commitment to either non-voluntary euthanasia or euthanasia on request. This is accomplished through analysis of John Keown's and David Jones's slippery slope arguments, and rejection of their view that voluntary euthanasia requires physicians to judge patients as better off dead. Instead, voluntary euthanasia merely requires physicians to judge patients as within boundaries of appropriate deference. This paper develops two ways of understanding and defending voluntary euthanasia on this model, one focused on the independent value of patients' autonomy and the other on the evidence of well-being provided by patients' requests. Both avoid the purported slippery slopes and both are independently supported by an analogy to uncontroversial elements of medical practice. Moreover, the proposed analyses of voluntary euthanasia suggest parameters for the design of euthanasia legislation, both supporting and challenging elements of existing laws in Oregon and the Netherlands. PMID- 29628451 TI - Assessing Rehabilitation Eligibility of Older Patients: An Ethical Analysis of the Impact of Bias. AB - Hospitalized older patients are more vulnerable to physical or cognitive functional decline. Inpatient rehabilitation programs improve significantly their functional status and may prevent their admission to nursing homes. While inpatient rehabilitation institutions have established admission criteria that can be seen as objective, the risk of bias remains and raises the question of equitable access for more vulnerable populations such as older patients. This paper reviews some established eligibility criteria for inpatient rehabilitation by examining a framework used in Montreal, Quebec, Canada for assessing rehabilitation eligibility and by applying this framework to a case study. It also highlights the unique ethical challenges presented by the assessment of older patients. We conclude that in order to appropriately protect the vulnerable population of older patients in the context of priority setting and allocation of scarce resources, there is a need to establish more specific criteria that can better guide the assessment of this particular population. PMID- 29628452 TI - An Ethical Analysis of the SUPPORT Trial: Addressing Challenges Posed by a Pragmatic Comparative Effectiveness Randomized Controlled Trial. AB - The SUPPORT trial highlights ethical challenges raised by comparative effectiveness randomized controlled trials (ceRCTs) involving one or more usual care interventions. Debate about the SUPPORT trial has focused on whether study interventions posed "reasonably foreseeable risks" to enrolled infants and, thereby, reflects a preoccupation with U.S. regulations. As ceRCTs are conducted globally, our analysis of the SUPPORT trial is grounded in internationally accepted ethical principles. We argue that the central ethical issue raised by the SUPPORT trial is the following: should the SUPPORT trial interventions be conceptualized as practice, or research? The answer to this question has important implications for "downstream" ethical requirements-including whether the usual care interventions in ceRCTs require research ethics committee review, undergo harm-benefit analysis, and are included in informed consent documents-and it is antecedent to the development of ethical guidance for ceRCTs. PMID- 29628453 TI - Multiple acquired portosystemic shunts secondary to primary hypoplasia of the portal vein in a cat. AB - A 6-year 5-month-old spayed female Scottish Fold cat presented with a one-month history of gait abnormalities, increased salivation, and decreased activity. A blood test showed hyperammonemia and increased serum bile acids. Imaging tests revealed multiple shunt vessels indicating acquired portosystemic shunt. Histopathologic analysis of liver biopsy showed features consistent with liver hypoperfusion, such as a barely recognizable portal vein, increased numbers of small arterioles, and diffuse vacuolar degeneration of hepatocytes. These findings supported the diagnosis of primary hypoplasia of the portal vein/microvascular dysplasia, (PHPV/MVD). To our knowledge, this is the first case of feline PHPV/MVD that developed multiple acquired portosystemic shunts and presented with hepatic encephalopathy. PMID- 29628455 TI - Vascular Network Inside the Heart - Collateral Flow on Color Doppler Echo in a Child With Anomalous Left Coronary Artery From the Pulmonary Artery (ALCAPA). PMID- 29628454 TI - Mass-size distribution and concentration of metals from personal exposure to arc welding fume in pipeline construction: a case report. AB - We investigate exposure to welding fume metals in pipeline construction, which are responsible for severe respiratory problems. We analyzed air samples obtained using size-fractioning cascade impactors that were attached to the welders performing shielded metal and gas tungsten arc welding outdoors. Iron, aluminum, zinc, chromium, manganese, copper, nickel, and lead concentrations in the water soluble (WS) and water-insoluble (WI) portions were determined separately, using inductively coupled plasma mass spectrometry. The mass-size distribution of welding fume matches a log-normal distribution with two modes. The metal concentrations in the welding fume were ranked as follows: Fe>Al>Zn>Cr>Mn>Ni>Cu>Pb. In the WS portion, the capacities of metals dissolving in water are correlated with the metal species but particle sizes. Particularly, Zn, Mn, and Pb exhibit relatively higher capacities than Cu, Cr, Al, Fe, and Ni. Exposure of the gas-exchange region of the lungs to WS metals were in the range of 4.9% to 34.6% of the corresponding metals in air by considering the particle size selection in lungs, metal composition by particle size, and the capacities of each metal dissolving in water. PMID- 29628456 TI - Rapid-Growing Right Atrial Myxoma 7 Months After Catheter Ablation Under Anticoagulation Therapy - Serial Echocardiography and Computed Tomography. PMID- 29628457 TI - Hypocarnitinemia Observed in an Infant Treated with Short-Term Administration of Antibiotic Containing Pivalic Acid. AB - Carnitine is a water-soluble amino acid derivative required for beta-oxidation of long-chain fatty acids. In carnitine cycle abnormalities and low carnitine states, fatty acid beta-oxidation is inhibited during fasting, resulting in hypoglycemia. Pivalic acid is a substance used in prodrugs to increase absorption of parent drugs, and antibiotics containing pivalic acid are frequently used as wide spectrum antibiotics for pediatric patients in Japan. Pivalic acid released after absorption is conjugated with free carnitine to form pivaloylcarnitine, which is then excreted in urine. As a consequence, long-term administration of pivalic acid containing antibiotics has been associated with depletion of free carnitine, inhibition of energy production and subsequent hypoglycemia. Here we report a case of a 23-month-old boy treated with an antibiotic containing pivalic acid for 3 days for upper respiratory tract infection. Laboratory data at referral indicated hypoglycemia, decreased free carnitine and elevated five carbon acylcarnitine. Isomer separation confirmed the major component of increased five-carbon acylcarnitine to be pivaloylcarnitine, thereby excluding the possibility of a genetic metabolic disorder detected with similar acylcarnitine profile. The level of carnitine was normal when the antibiotic was not administered. Our case shows that the use of antibiotics containing pivalic acid in young children requires consideration of hypocarnitinemia, even with short-term administration. PMID- 29628458 TI - Low-Density Lipoprotein Cholesterol Goal Attainment Rates by Initial Statin Monotherapy Among Patients With Dyslipidemia and High Cardiovascular Risk in Japan - A Retrospective Database Analysis. AB - BACKGROUND: To understand the recent management status in Japan, we determined the low-density lipoprotein cholesterol (LDL-C) goal attainment (GA) rate of patients initiating statin monotherapy for dyslipidemia.Methods and Results:Dyslipidemic patients undergoing either primary prevention with high cardiovascular risk or secondary prevention (defined by 2012 Japan Atherosclerosis Society Guidelines) were retrospectively analyzed from a hospital based claims database. In both groups, the LDL-C levels and GA rates of patients treated with intensive or standard statin monotherapy for >=4 weeks (January 2012 August 2016) were evaluated. Among 1,501,013 dyslipidemic patients, 11,695 and 9,642 were included in the primary and secondary prevention groups, respectively. A total of 94% of patients underwent statin monotherapy as the initial lipid lowering therapy, of which most (>=80%) took intensive statins. The proportions of patients in the primary prevention group who achieved an LDL-C goal <120 mg/dL by intensive and standard statins were 81.1% and 61.2%, respectively, and the proportions of those who achieved a goal <100 mg/dL in the secondary prevention group were 73.3% and 48.1%, respectively. The GA rates were similar regardless of disease complications. CONCLUSIONS: Most patients (>70%) in both groups achieved LDL-C management goals using intensive statin monotherapy. Further treatment approaches are required for high-risk patients not achieving LDL-C goals by initial statin monotherapy. Continuous efforts are crucial for adherence and persistence of lipid-lowering therapies. PMID- 29628459 TI - Nutritional Status and Energy Intake as Predictors of Functional Status After Cardiac Rehabilitation in Elderly Inpatients With Heart Failure - A Retrospective Cohort Study. AB - BACKGROUND: Whether the short-term effect of cardiac rehabilitation (CR) in elderly patients with heart failure (HF) is influenced by nutritional status is uncertain, so the present study investigated the effect of nutritional status on functional recovery after CR in elderly HF inpatients.Methods and Results:We enrolled 145 patients admitted for treatment of HF who were aged >=65 years and had a low functional status defined as a Barthel index (BI) score <=85 points at the commencement of CR. Nutritional status was assessed by the Mini Nutritional Assessment Short Form (MNA-SF) and total energy intake per day. The primary endpoint was functional status determined by the BI score at discharge. The median CR period was 20 days (interquartile range: 14-34 days), and 87 patients (60%) were functionally dependent (BI score <=85) at discharge. Multivariate logistic regression analysis showed that MNA-SF score (odds ratio [OR]: 0.76, P=0.02) and total energy intake at the commencement of CR (OR: 0.91, P=0.02) were independent predictors of functional dependence after CR. MNA-SF score <=7 and total energy intake <=24.5 kcal/kg/day predicted functional dependence at discharge with moderate sensitivity and specificity. CONCLUSIONS: MNA-SF score and total energy intake at the commencement of CR are novel predictors of the extent of functional recovery of elderly HF inpatients after in-hospital CR. PMID- 29628461 TI - [Molecular mechanism for ET-1-induced insulin resistance in skeletal muscle cells]. AB - Insulin resistance is a condition where the sensitivity to insulin of the tissues expressing insulin receptor (InsR) is decreased due to a functional disturbance of InsR-mediated intracellular signaling. Insulin promotes the entry of glucose into the tissues and skeletal muscle is the most important tissue responsible for the insulin's action of decreasing blood glucose levels. Endothelin-1 (ET-1), a potent vasoconstrictor and pro-inflammatory peptide, induces insulin resistance through a direct action on skeletal muscle. However, the signaling pathways of ET 1-induced insulin resistance in skeletal muscle remain unclear. Here we show molecular mechanism underlying the inhibitory effect of ET-1 on insulin stimulated Akt phosphorylation and glucose uptake in myotubes of rat L6 skeletal muscle cell line. mRNA expression levels of differentiation marker genes, MyoD and myogenin, were increased during L6 myoblasts differentiation into myotubes. Some of myotubes possessed the ability to spontaneously contract. In myotubes, insulin promoted Akt phosphorylation at Thr308 and Ser473, and [3H]-labelled 2 deoxy-D-glucose ([3H]2-DG) uptake. The insulin-facilitated Akt phosphorylation and [3H]2-DG uptake were inhibited by ET-1. The inhibitory effect of ET-1 was counteracted by blockade of ET type A receptor (ETAR), inhibition of Gq/11 protein, and siRNA knockdown of G protein-coupled receptor kinase 2 (GRK2). The exogenously overexpressed GRK2 directly bound to endogenous Akt and their association was facilitated by ET-1. In summary, activation of ETAR with ET-1 inhibits insulin-induced Akt phosphorylation and [3H]2-DG uptake in a Gq/11 protein- and GRK2-dependent manner in skeletal muscle. These findings indicate that ETAR and GRK2 are potential targets for insulin resistance. PMID- 29628460 TI - Effect of QRS Morphology and Duration on Clinical Outcomes After Cardiac Resynchronization Therapy - Analysis of Japanese Multicenter Registry. AB - BACKGROUND: QRS duration (QRSd) and morphology are established response predictors of cardiac resynchronization therapy (CRT). However, evidence in Japanese populations is lacking.Methods and Results:We retrospectively analyzed the Japanese multicenter CRT database. We divided patients according to their intrinsic QRSd and morphology, and assessed echocardiographic responses and clinical outcomes. The primary endpoint was a composite of all-cause death or hospitalization because of heart failure. A total of 510 patients were enrolled: 200 (39%) had left bundle branch block (LBBB) and QRSd >=150 ms; 80 (16%) had LBBB (QRSd: 120-149 ms); 61 (12%) had non-LBBB (NLBBB) (QRSd: >=150 ms); 54 (11%) had NLBBB (QRSd: 120-149 ms); 115 (23%), narrow (<120 ms). The proportion of echocardiographic responders was higher in LBBB (QRSd >=150 ms) [74% vs. 51% vs. 38% vs. 52% vs. 50%, LBBB (QRSd >=150 ms) vs. LBBB (QRSd 120-149 ms) vs. NLBBB (QRSd >=150 ms) vs. NLBBB (QRSd 120-149 ms) vs. narrow, respectively, P<0.001]. During follow-up (3.2+/-1.5 years), the incidence of the primary endpoint was lowest in the LBBB group (QRSd >=150) (28.6% vs. 42.3% vs. 45.9% vs. 55.6% vs. 55.3%, respectively, P<0.001). This difference was still significant after adjusting for other baseline characteristics. CONCLUSIONS: In this Japanese patient population, LBBB intrinsic QRS morphology and prolonged QRSd (>=150 ms) exhibited the best response to CRT. PMID- 29628462 TI - [Long-term dietary nitrite and nitrate deficiency causes metabolic syndrome, endothelial dysfunction, and cardiovascular death in mice]. AB - Nitric oxide (NO) is synthesized not only from L-arginine by NO synthases (NOSs), but also from its inert metabolites, nitrite and nitrate. Green leafy vegetables are abundant in nitrate, however whether or not a deficiency in dietary nitrite/nitrate spontaneously causes disease remains to be clarified. In this study, we tested our hypothesis that long-term dietary nitrite/nitrate deficiency induces metabolic syndrome (MetS) in mice. To this end, we prepared a low nitrite/nitrate diet (LND) consisting of an amino acid-based low nitrite/nitrate chow in which the contents of L-arginine, fat, carbohydrates, protein, and energy were identical with a regular chow, and potable ultrapure water. Nitrite and nitrate were undetectable in both the chow and the water. Intriguingly, in comparison with a regular diet, 3 months of the LND significantly elicited visceral adiposity, dyslipidaemia, and glucose intolerance; 18 months of the LND significantly provoked increased body weight, hypertension, insulin resistance, and impaired endothelium-dependent relaxations to acetylcholine; and 22 months of the LND significantly led to death due to cardiovascular disease, including acute myocardial infarction. These abnormalities were reversed by simultaneous treatment with sodium nitrate, and were significantly associated with endothelial NOS down-regulation, adiponectin insufficiency, and gut microbiota dysbiosis. These results provide the first evidence that long-term dietary nitrite/nitrate deficiency gives rise to MetS, endothelial dysfunction, and cardiovascular death in mice, indicating a novel pathogenetic role of the exogenous NO production system in MetS and its vascular complications. PMID- 29628463 TI - [Vascular smooth muscle cell response to cyclic mechanical stretch and aortic dissection]. AB - Acute aortic dissection is the most common life-threatening vascular disease, with sudden onset of severe pain and a high fatality rate. The pulsatile nature of blood flow exposes vascular smooth muscle cells (VSMCs) in the vessel wall to cyclic mechanical stretch (CMS), which evokes VSMC death, phenotypic switching, and migration, leading to aortic dissection. We have revealed that CMS of rat aortic smooth muscle cells (RASMCs) caused JNK- and p38-dependent cell death and that a calcium channel blocker, azelnidipine and an angiotensin II receptor antagonist, olmesartan decreased the phosphorylation of JNK and p38 and, subsequently, decreased cell death by CMS. JNK and p38 inhibitors also inhibited CMS-induced cell death. In addition, we showed that the expression of Cxcl1 and Cx3cl1 chemokines was induced by CMS in a JNK-dependent manner. Expression of Cxcl1 was also induced in VSMCs by hypertension produced by abdominal aortic constriction in mouse. In addition, antagonists against the receptors for CXCL1 and CX3CL1 increased cell death, indicating that CXCL1 and CX3CL1 protect RASMCs from CMS-induced cell death. We also revealed that STAT1 is activated in RASMCs subjected to CMS. Taken together, these results indicate that CMS of VSMCs induces inflammation-related gene expression, including that of CXCL1 and CX3CL1, and activates JNK and p38 MAP kinases, which may play important roles in the stress response against CMS caused by acute rise in blood pressure. PMID- 29628464 TI - [Development of the next generation humanized mouse for drug discovery]. AB - A humanized mouse, which is efficiently engrafted human cells and tissues, is an important tool to mimic human physiology for biomedical researches. Since 2000s, severe combined immunodeficient mouse strains such as NOG, BRG, and NSG mice have been generated. They are great recipients to create humanized mouse models compared to previous other immunodeficient strains due to their multiple dysfunctions of innate and acquired immunity. Especially, the transfer of human hematopoietic stem cells into these immunodeficient mice has been enabled to reconstitute human immune systems, because the mice show high engraftment level of human leukocyte in peripheral blood (~50%), spleen and bone marrow (60~90%) and generate well-differentiated multilineage human immune cells including lymphoid and myeloid lineage cells. Using these mice, several human disease models such as cancer, allergy, graft-versus-host disease (GVHD), and etc. have been established to understand the pathogenic mechanisms of the diseases and to evaluate the efficacy and safety of novel drugs. In this review, I provide an overview of recent advances in the humanized mouse technology, including generation of novel platforms of genetically modified NOG (next generation NOG) mice and some applications of them to create human disease models for drug discovery in preclinical researches. PMID- 29628465 TI - [Pharmacological characteristics and clinical study results of the oral proteasome inhibitor ixazomib (NINLARO(r) capsules; 2.3 mg, 3 mg, and 4 mg)]. AB - Ixazomib (Ninlaro(r) capsule) is an oral small molecule 20S proteasome inhibitor created by Millennium Pharmaceuticals, Inc (Takeda Oncology Company). Ubiquitin proteasome system is a major regulatory system for maintaining protein homeostasis, and an important mechanism for degrading proteins, such as those involved in proliferation regulation, cell cycle regulation and apoptosis, in cells. Ixazomib selectively and reversibly binds to the beta5 subunit of the 20S proteasome, inhibits its chymotrypsin-like activity, and thereby accumulates ubiquitinated proteins. It induces ER stress and apoptosis of myeloma cells. The phase 3, randomized, double-blind, multicenter global study (TOURMALINE-MM1) in patients with relapsed and/or refractory multiple myeloma, who have received 1 to 3 prior lines of therapy, showed that addition of ixazomib to lenalidomide dexamethasone (ixazomib-Rd) demonstrated significant improvement in progression free survival (hazard ratio = 0.742, P = 0.012) versus placebo-Rd (20.6 vs. 14.7 months in the median) (data cut-off as of October 30, 2014). Ixazomib has been approved by the United States Food and Drug Administration in November 2015, and the European Medicines Agency in November 2016 for the treatment of multiple myeloma (MM) patients who have received at least one prior therapy. In Japan, ixazomib was approved for the treatment of relapsed and/or refractory MM in March, 2017. It is expected to demonstrate that the oral proteasome inhibitor ixazomib is an effective and convenient treatment option in clinical practice. PMID- 29628466 TI - Increase Carotid Flow by Double Sheath Connection Technique to Reduce Cerebral Ischemia for Transcatheter Aortic Valve Implantation through Transcarotid Approach. AB - PURPOSE: Transcarotid transcatheter aortic valve implantation (TAVI) is one alternative approach if unfavorable femoral access. However, this approach may cause cerebral vascular accidents (CVAs) by temporarily occluding common carotid artery (CCA). The purpose of this study is to develop a new method reducing cerebral ischemia during transcarotid TAVI. METHODS: We inserted an 8- and 18-Fr. sheath in CCA with tip toward brain and aortic arch, respectively, and connected their side arms to create a bypass flow. Medtronic CoreValve was then delivered and deployed in position after pre-TAVI balloon dilatation. RESULTS: Three patients received this implantation. There were no CVAs or transient ischemic attacks (TIAs) after the procedure and all patients had been followed up uneventfully for 1 year. CONCLUSION: Our technique is feasible and potentially reduces stroke in transcarotid TAVI. PMID- 29628467 TI - Targeted therapy according to next generation sequencing-based panel sequencing. AB - Targeted therapy against actionable gene mutations shows a significantly higher response rate as well as longer survival compared to conventional chemotherapy, and has become a standard therapy for many cancers. Recent progress in next generation sequencing (NGS) has enabled to identify huge number of genetic aberrations. Based on sequencing results, patients recommend to undergo targeted therapy or immunotherapy. In cases where there are no available approved drugs for the genetic mutations detected in the patients, it is recommended to be facilitate the registration for the clinical trials. For that purpose, a NGS based sequencing panel that can simultaneously target multiple genes in a single investigation has been used in daily clinical practice. To date, various types of sequencing panels have been developed to investigate genetic aberrations with tumor somatic genome variants (gain-of-function or loss-of-function mutations, high-level copy number alterations, and gene fusions) through comprehensive bioinformatics. Because sequencing panels are efficient and cost-effective, they are quickly being adopted outside the lab, in hospitals and clinics, in order to identify personal targeted therapy for individual cancer patients. PMID- 29628468 TI - Induction of anti-PF4/heparin antibodies after arthroplasty for rheumatic diseases. AB - Heparin-induced thrombocytopenia (HIT) is an immune complication of heparin therapy caused by antibodies to complexes of platelet factor 4 (PF4) and heparin. These pathogenic antibodies against PF4/heparin bind and activate cellular FcgammaRIIa on platelets to induce a hypercoagulable state culminating in thrombosis. Recent studies indicate several conditions, including joint surgery, induce spontaneous HIT, which can occur without exposure to heparin. To determine the real-world evidences concerning the incidences of venous thromboembolism (VTE) after total joint arthroplasty for rheumatic disease, we conducted a multicenter cohort study (J-PSVT) designed to document the VTE and seroconversion rates of anti-PF4/heparin antibody in 34 Japanese National hospital organization (NHO) hospitals. J-PSVT indicated that prophylaxis with fondaparinux, not enoxaparin, reduces the risk of deep vein thrombosis in patients undergoing arthroplasty. Multivariate analysis revealed that dynamic mechanical thromboprophylaxis (intermittent plantar device) was an independent risk factor for seroconversion of anti-PF4/heparin antibodies, which was also confirmed by propensity-score matching. Seroconversion rates of anti-PF4/heparin antibodies were significantly reduced in rheumatoid arthritis (RA) patients compared with osteoarthritis (OA) patients, which may link with the findings that IgG fractions isolated from RA patients not OA patients contained PF4. Our study indicated that a unique profile of anti-PF4/heparin antibodies is induced by arthroplasty for rheumatic diseases. PMID- 29628469 TI - Calcified Nodules Projecting into the Popliteal Artery Successfully Treated Through the Use of Myocardial Biopsy Forceps. AB - A 69-year-old man on maintenance dialysis underwent endovascular therapy for a refractory wound due to critical limb ischemia in the popliteal and below-knee arteries. Because of bulky calcified nodules projecting into the popliteal artery, conventional balloon angioplasty alone did not seem to provide a sufficient lumen area, and we ablated the calcified nodules by using myocardial biopsy forceps for lesion preparation. Under roadmap guidance, we repeated ablation 39 times to carefully tear off the bulky calcified nodules, and subsequently performed balloon angioplasty in the popliteal artery. Neither flow limiting dissection nor perforation occurred, and a sufficient lumen area was obtained. After treatment of the popliteal artery, conventional endovascular therapy was performed in the below-knee arteries. One month later, the wound was fully epithelialized. We report a case of critical limb ischemia with calcified nodules projecting into the popliteal artery, in which the use of myocardial biopsy forceps led to good results. PMID- 29628470 TI - A Rare Case of Rush Progression of Purulent Pericarditis by Escherichia coli in a Patient with Malignant Lymphoma. AB - Purulent pericarditis is a rare disease in the antibiotic era. The common pathogens of purulent pericarditis are gram-positive species such as Staphylococcus aureus. Streptococcus pneumoniae, Salmonella, Haemophilus, fungal pathogens/tuberculosis can also result in purulent pericarditis. We report an old male case of purulent pericarditis by Escherichia coli. He came to our hospital suffering from leg edema for 3 months. Echocardiography revealed the large amount of pericardial effusion, and he was admitted to test the cause of pericardial effusion without high fever, tachycardia, and shock vital signs. On the third day, he suddenly presented vital shock. We performed emergency cardiopulmonary resuscitation and pericardiocentesis. Appearance of pericardial effusion was hemorrhagic and purulent. The gram stain revealed remarkable E. coli invasion to pericardial space. Antibiotic therapy was immediately started; however, he died on sixth day with septic shock. The cytological examination of pericardial effusion suggested the invasion of malignant lymphoma to pericardium. This case showed subacute or chronic process of pericarditis without severe clinical and laboratory sings before admission. Nevertheless, bacterial purulent pericarditis usually shows acute clinical manifestation; the first process of this case was very silent. Immunosuppression of malignant lymphoma might make E. coli translocation from gastrointestinal tract to pericardial space, and bacterial pericarditis was progressed to purulent pericarditis. In the latter process, this case showed unexpected rush progression to death by sepsis from purulent pericarditis. Immediate pericardiocentesis should be performed for a prompt diagnosis of purulent pericarditis, and it might have improved the outcome of this case. PMID- 29628471 TI - A Case of a Cardiac Resynchronization Therapy-Defibrillator Exhibiting a Lower and Alternately Variable Basic Rate. AB - A cardiac resynchronization therapy defibrillator (CRT-D) (Medtronic Inc. Protecta XT) was implanted in a 67-year-old man who had cardiac sarcoidosis with extremely low cardiac function. He had ventricular tachycardia which was controlled by catheter ablation, medication and pacing. The programmed mode was DDI, lower rate was 90 beats/minute, paced AV delay was 150 ms, and the noncompetitive atrial pacing (NCAP) function was programmed as 300 ms.After his admission for pneumonia and heart failure, we changed his DDI mode to a DDD mode because he had atrial tachycardia, which led to inadequate bi-ventricular pacing. After a while, there were cycle lengths which were longer than his device setting and alternately varied. We were able to avoid this phenomenon with AV delay of 120 ms and NCAP of 200 ms.NCAP is an algorithm which creates a gap above a certain period after the detection of an atrial signal during the postventricular atrial refractory period of the pacemaker. This is to prevent atrial tachycardia and repetitive non-reentrant ventriculoatrial (VA) synchrony in the presence of retrograde VA conduction. But in this case, NCAP algorithm induced much lower rate than the programmed basic lower rate. This situation produced some arrhythmias and exacerbated symptoms of heart failure. This had to be paid attention to, especially when the device was programmed at high basic heart rate. PMID- 29628472 TI - HCN4-Overexpressing Mouse Embryonic Stem Cell-Derived Cardiomyocytes Generate a New Rapid Rhythm in Rats with Bradycardia. AB - A biological pacemaker is expected to solve the persisting problems of an artificial cardiac pacemaker including short battery life, lead breaks, infection, and electromagnetic interference. We previously reported HCN4 overexpression enhances pacemaking ability of mouse embryonic stem cell-derived cardiomyocytes (mESC-CMs) in vitro. However, the effect of these cells on bradycardia in vivo has remained unclear. Therefore, we transplanted HCN4 overexpressing mESC-CMs into bradycardia model animals and investigated whether they could function as a biological pacemaker. The rabbit Hcn4 gene was transfected into mouse embryonic stem cells and induced HCN4-overexpressing mESC CMs. Non-cardiomyocytes were removed under serum/glucose-free and lactate supplemented conditions. Cardiac balls containing 5 * 103 mESC-CMs were made by using the hanging drop method. One hundred cardiac balls were injected into the left ventricular free wall of complete atrioventricular block (CAVB) model rats. Heart beats were evaluated using an implantable telemetry system 7 to 30 days after cell transplantation. The result showed that ectopic ventricular beats that were faster than the intrinsic escape rhythm were often observed in CAVB model rats transplanted with HCN4-overexpressing mESC-CMs. On the other hand, the rats transplanted with non-overexpressing mESC-CMs showed sporadic single premature ventricular contraction but not sustained ectopic ventricular rhythms. These results indicated that HCN4-overexpressing mESC-CMs produce rapid ectopic ventricular rhythms as a biological pacemaker. PMID- 29628474 TI - Preoperative Simulation Using CT Virtual Endoscopy for Minimally Invasive Surgery of Hypertrophic Obstructive Cardiomyopathy. AB - Transaortic septal myectomy is a procedure that involves a learning curve for surgeons because the bulging interventricular septum usually interferes with the visualization of the deep parts of the left ventricular chamber. In this case report, we demonstrate computed tomography virtual endoscopy for preoperative simulation, which enabled us to clearly image the relationship among the bulging septum, the expected myectomy area, and the structures deep in the left ventricle, such as the papillary muscle and abnormal muscular bundles, which are hidden by the hypertrophic septum, thus preventing visualization. This approach could make minimally invasive transaortic septal myectomy safe and easy. PMID- 29628473 TI - Acute Inferior Wall ST Segment Elevation Myocardial Infarction Caused Atrial Lead Dysfunction Reversed by Primary Percutaneous Coronary Intervention. AB - The mechanism of atrial lead dysfunction varies in patients receiving pacemaker implantation and this needs to be investigated, especially when the causes are reversible. We report and discuss a 76-year-old female who had atrial lead dysfunction caused by acute myocardial infarction and who was recovered after primary percutaneous coronary intervention. The sequential electrocardiographic changes were demonstrated and the possible mechanisms were discussed. PMID- 29628475 TI - Prognostic Improvement of Acute Necrotizing Eosinophilic Myocarditis (ANEM) Through a Rapid Pathological Diagnosis and Appropriate Therapy. AB - We present the case of a patient with acute necrotizing eosinophilic myocarditis (ANEM) who rapidly recovered after receiving high-dose corticosteroid therapy. A previously healthy 29-year-old woman presented to our hospital with abdominal pain, nausea, and fever that had lasted for two days. Her clinical condition progressively declined and she ultimately presented with cardiogenic shock due to fulminant heart failure and atrioventricular dissociation due to sinus bradycardia, which required inotropic and ventilatory support. Endomyocardial biopsy results were consistent with ANEM. High-dose corticosteroids were promptly initiated, and her cardiac function rapidly improved, with almost complete cardiac recovery one week later. She survived with completely normalized left ventricular systolic and diastolic function after high-dose corticosteroid therapy. The prompt and definite pathological diagnosis based on endomyocardial biopsy in the acute phase might have been instrumental in improving the outcome. PMID- 29628477 TI - Rapid Desensitization to Overcome Contrast Allergy Prior to Urgent Coronary Angiography. AB - Allergic reactions to contrast media are a frequently reported complication of coronary angiography. The majority of patients experience mild, self-limited episodes, but in rare cases patients may experience severe, persistent symptoms. A strategy of premedication with corticosteroids and anti-histamines and an optimal selection of contrast agent is almost always successful in averting contrast reactions, yet a select few patients will continue to have breakthrough events. This is a case of recurrent, severe allergy to contrast media despite standard precautions complicating the treatment of non-ST elevation myocardial infarction (NSTEMI). Our patient was successfully managed with a strategy of rapid desensitization to iodinated contrast media achieved by administering progressively incremental doses of the media. PMID- 29628476 TI - A Novel Truncating LMNA Mutation in Patients with Cardiac Conduction Disorders and Dilated Cardiomyopathy. AB - The cardiac phenotype of laminopathies is characterized by cardiac conduction disorders (CCDs) and dilated cardiomyopathy (DCM). Although laminopathies have been considered monogenic, they exhibit a remarkable degree of clinical variability. This case series aimed to detect the causal mutation and to investigate the causes of clinical variability in a Japanese family with inherited CCD and DCM.Of the five family members investigated, four had either CCD/DCM or CCD alone, while one subject had no cardiovascular disease and acted as a normal control. We performed targeted resequencing of 174 inherited cardiovascular disease-associated genes in this family and pathological mutations were confirmed using Sanger sequencing. The degree of clinical severity and variability were also evaluated using long-term medical records. We discovered a novel heterozygous truncating lamin A/C (LMNA) mutation (c.774delG) in all four subjects with CCD. Because this mutation was predicted to cause a frameshift mutation and premature termination (p.Gln258HisfsTer222) in LMNA, we believe that this LMNA mutation was the causal mutation in this family with CCD and laminopathies. In addition, gender-specific intra-familiar clinical variability was observed in this Japanese family where affected males exhibited an earlier onset of CCD and more severe DCM compared to affected females. Using targeted resequencing, we discovered a novel truncating LMNA mutation associated with CCD and DCM in this family characterized by gender differences in clinical severity in LMNA carriers. Our results suggest that in patients with laminopathy, clinical severity may be the result of multiple factors. PMID- 29628478 TI - Arrhythmogenic Right Ventricular Cardiomyopathy with Multiple Thrombi and Ventricular Tachycardia of Atypical Left Branch Bundle Block Morphology. AB - A 61-year-old male patient was admitted to our hospital with recurrent palpitations and syncope. Electrocardiography, echocardiography, and contrast enhanced computed tomography were performed. The patient was diagnosed with arrhythmogenic right ventricular cardiomyopathy (ARVC) complicated by multiple thrombi, and ventricular tachycardia (VT) without typical left bundle branch block (LBBB) morphology. This case suggests that VT is not always the sole contributor to syncope and death in patients with ARVC, and pulmonary embolism should be considered. Furthermore, VT with typical LBBB morphology is not an absolute necessity as a major criterion for the diagnosis of ARVC when the right heart is extremely enlarged. PMID- 29628479 TI - The effect of rfaD and rfaF of Haemophilus parasuis on lipooligosaccharide induced inflammation by NF-kappaB/MAPKs signaling in porcine alveolar macrophages. AB - In Haemophilus parasuis, the rfa cluster has been identified as a virulence associated factor that is involved in lipooligosaccharide (LOS) biosynthesis. In this study, we assessed the roles of rfaD and rfaF genes in H. parasuis SC096 on LOS-induced pro-inflammatory factors and the related signaling pathways in porcine alveolar macrophages (PAMs) by real-time PCR and western blotting. The results showed that the LOSs of both rfaD and rfaF mutants (DeltarfaD-LOS and DeltarfaF-LOS) significantly decreased the mRNA expression of pro-inflammatory factors (IL-1alpha, IL-1beta, IL-6, IL-8 and TNF-alpha) in PAMs compared with H. parasuis SC096 LOS (WT-LOS). Furthermore, in DeltarfaD-LOS- and DeltarfaF-LOS treated cells, IkappaBalpha degradation was significantly inhibited and levels of phospho-p65 and phospho-p38 were significantly reduced in PAMs. These findings suggested that the rfaD and rfaF genes mediated LOS induction of pro-inflammatory cytokines in PAMs by regulating the NF-kappaB and MAPKs signaling pathways during H. parasuis infection. PMID- 29628480 TI - Immune complex glomerulonephritis of suspected iatrogenic origin in five Japanese Black calves. AB - Five Japanese Black embryo transfer calves from a single embryo flush, 30 to 45 days-old, including 4 live animals for clinical examination and 1 dead for necropsy, were presented with a history of decreased milk intake and hypoproteinemia. Consistent clinicopathological abnormalities in the 4 calves presented for clinical evaluation included hyperkalemia, hyperphosphatemia, hypoproteinemia, hypoalbuminemia, hyperbilirubinemia, increased creatine phosphokinase activity, and proteinuria. Four calves ultimately were necropsied and all had histologic evidence of immune complex glomerulonephritis. Glomerulonephritis in these calves was hypothesized to have resulted from the interaction of passively acquired antibodies at birth and active immunization at 7 and 28 days of age with a Salmonella Typhimurium core antigen vaccine. PMID- 29628481 TI - The Association Between Metabolically Healthy Obesity and the Risk of Proteinuria: The Kansai Healthcare Study. AB - BACKGROUND: Metabolically healthy obesity seems to be a unique phenotype for the risk of cardiometabolic diseases. However, it is not known whether this phenotype is associated with the risk of proteinuria. METHODS: Study subjects were 9,185 non-diabetic Japanese male workers aged 40-55 years who had no proteinuria, an estimated glomerular filtration rate >=60 mL/min/1.73 m2, no history of cancer, and no use of antihypertensive or lipid-lowering medications at baseline. Obesity was defined as body mass index >=25.0 kg/m2. Metabolic health was defined as the presence of no Adult Treatment Panel III components of the metabolic syndrome criteria, excluding waist circumference, and metabolic unhealth was defined as the presence of one or more metabolic syndrome components, excluding waist circumference. "Consecutive proteinuria" was considered positive if proteinuria was detected twice consecutively as 1+ or higher on urine dipstick at annual examinations to exclude chance proteinuria as much as possible. RESULTS: During the 81,660 person-years follow-up period, we confirmed 390 cases of consecutive proteinuria. Compared with metabolically healthy non-obesity, metabolically healthy obesity was not associated with the risk of consecutive proteinuria (multiple-adjusted hazard ratio [HR] 0.86; 95% confidence interval [CI], 0.37 1.99), but metabolically unhealthy non-obesity with >=2 metabolic syndrome components (HR 1.77; 95% CI, 1.30-2.42), metabolically unhealthy obesity with one component (HR 1.71; 95% CI, 1.12-2.61), and metabolically unhealthy obesity with >=2 metabolic syndrome components (HR 2.77; 95% CI, 2.01-3.82) were associated with an increased risk of consecutive proteinuria. CONCLUSIONS: Metabolically healthy obesity did not increase the risk of consecutive proteinuria in Japanese middle-aged men. PMID- 29628482 TI - Relationship between Long Interspersed Nuclear Element-1 DNA Methylation in Leukocytes and Dyslipidemia in the Japanese General Population. AB - AIM: Aberrant global DNA methylation is involved in the development of several diseases, including cardiovascular disease (CVD). We investigated whether the methylation of long interspersed nuclear element-1 (LINE-1) in leukocytes is associated with dyslipidemia, a major risk factor for CVD, in the Japanese general population. METHODS: We conducted a cross-sectional study consisting of 420 Japanese subjects (187 men and 233 women) without a clinical history of cancer, stroke, or ischemic heart disease. LINE-1 DNA methylation levels in leukocytes were measured using a pyrosequencing method. RESULTS: Significantly higher odds ratios (ORs) for hypermethylation were observed in the high LDL cholesterol and high LDL/HDL ratio groups than the corresponding normal group (high LDLC group: OR, 1.88; 95% confidence interval [CI], 1.20-2.96, high LDL/HDL ratio group: OR, 1.90; 95% CI, 1.20-3.01). Subjects with 2 or more lipid abnormalities had significantly higher ORs for hypermethylation than those with no lipid abnormality (OR, 2.31; 95% CI, 1.11-4.82). CONCLUSION: LINE-1 DNA hypermethylation in leukocytes was associated with CVD risk profiles: high LDLC, high LDL/HDL ratio, and the degree of abnormal lipid metabolism. PMID- 29628483 TI - Efficacy and Safety of Pemafibrate Versus Fenofibrate in Patients with High Triglyceride and Low HDL Cholesterol Levels: A Multicenter, Placebo-Controlled, Double-Blind, Randomized Trial. AB - AIM: To verify the superiority of pemafibrate over placebo and the non inferiority of pemafibrate to the maximum dose of fenofibrate for determining the percent change in fasting serum triglyceride (TG) levels and to investigate safety by assessing the incidence of adverse events (AEs) and adverse drug reactions (ADRs). METHODS: This phase III, placebo/active drug-controlled, randomized, double-blind, parallel group comparison study enrolled patients with high TG and low high-density lipoprotein cholesterol levels. Patients were randomly assigned to receive placebo; pemafibrate 0.1 mg/day, 0.2 mg/day, or 0.4 mg/day; or fenofibrate 100 mg/day or 200 mg/day for 12 weeks. RESULTS: Among 526 randomized patients, 489 completed the study, with drop-out rates of 0%, 6.7%, 5.5%, 5.9%, 8.2%, and 10.7% in the placebo; pemafibrate 0.1 mg/day, 0.2 mg/day, and 0.4 mg/day; and fenofibrate 100 mg/day and 200 mg/day groups. The study showed the non-inferiority of pemafibrate 0.4 mg/day and 0.2 mg/day to fenofibrate 200 mg/day as well the non-inferiority and superiority of all pemafibrate doses to fenofibrate 100 mg/day for reducing TG levels. No dose dependent increase in the incidence of AEs or ADRs was observed among the pemafibrate dose groups. The incidence of AEs and ADRs for all pemafibrate doses was similar to that for placebo and fenofibrate 100 mg/day and significantly lower than that for fenofibrate 200 mg/day (P<0.05). CONCLUSIONS: The favorable safety profile of pemafibrate, with fewer adverse effects on kidney/liver-related laboratory tests and fewer AEs/ADRs, including those leading to treatment discontinuation, over fenofibrate 200 mg/day may justify the use of this novel and potent treatment option for reducing TG levels in a broader range of patients. PMID- 29628484 TI - Isolation of High Carotenoid-producing Aurantiochytrium sp. Mutants and Improvement of Astaxanthin Productivity Using Metabolic Information. AB - The marine eukaryotic microheterotroph thraustochytrid genus Aurantiochytrium is a known producer of polyunsaturated fatty acids, carotenoids, and squalene. We previously constructed a lipid fermentation system for Aurantiochytrium sp. strains using underutilized biomass, such as canned syrup and brown macroalgae. To improve the productivity, in this study, Aurantiochytrium sp. RH-7A and RH-7A 7 that produced high levels of carotenoids, such as astaxanthin and canthaxanthin, were isolated through chemical mutagenesis. Moreover, metabolomic analysis of the strain RH-7A revealed that oxidative stress impacts carotenoid accumulation. Accordingly, the addition of ferrous ion (Fe2+), as an oxidative stress compound, to the culture medium significantly enhanced the production of astaxanthin by the mutants. These approaches improved the productivity of astaxanthin up to 9.5 mg/L/day at the flask scale using not only glucose but also fructose which is the main carbon source in fermentation systems with syrup and brown algae as the raw materials. PMID- 29628485 TI - Fatty Acid Profile, Phenolics and Flavonoids Contents in Olea europaea L. Callus Culture cv. cornicabra. AB - Olive trees are one of the most important oil crops in the world due to the sensorial and nutritional characteristics of olive oil, such as lipid composition and antioxidant content, and the medicinal properties of its leaves. In this paper, callus formation was induced using nodal segments of olive tree (Olea europaea cv. cornicabra) as explants. Fatty acid profile, total phenolic compounds and total flavonoid compounds were determined in callus culture after 15 weeks and compared with leaf and nodal segments tissues. There was no statistical difference in phenolic compounds among leaf, nodal segments and callus culture, whereas flavonoid compounds were higher in leaf. Fatty acid profile was similar in leaf, nodal segments and callus culture and was constituted by hexadecanoic acid, octadecanoic acid, cis-9-octadecenoic acid, cis 9,12-octadecadienoic acid, cis-9,12,15-octadecatrienoic acid. Hexadecanoic acid was the main fatty acid in callus, leaf and nodal segments with 35.0, 39.0 and 40.0% (w/w), of the lipid composition, respectively. With this paper, it is being reported for the first time the capacity of callus culture to accumulate fatty acids. Our results could serve to continue studying the production of fatty acids in callus cultivation as a biotechnological tool to improve different olive cultivars. PMID- 29628486 TI - The Effect of Microwave Roasting Over the Thermooxidative Degradation of Perah Seed Oil During Heating. AB - The impact of microwave roasting on the thermooxidative degradation of perah seed oil (PSO) was evaluated during heating at a frying temperature (170 degrees C). The roasting resulted significantly lower increment of the values of oxidative indices such as free acidity, peroxide value, p-anisidine, total oxidation (TOTOX), specific extinctions and thiobarbituric acid in oils during heating. The colour L* (lightness) value dropped gradually as the heating time increased up to 12 h, whereas a*(redness) and b* (yellowness) tended to increase. The viscosity and total polar compound in roasted PSO was lower as compared to that in unroasted one at each heating times. The tocol retention was also high in roasted samples throughout the heating period. The relative contents of polyunsaturated fatty acids (PUFAs) were decreased to 94.42% and saturated fatty acids (SFAs) were increased to 110.20% in unroasted sample, after 12 h of heating. On the other hand, in 3 min roasted samples, the relative contents of PUFAs were decreased to 98.08% and of SFAs were increased to 103.41% after 12 h of heating. Outcome from analyses showed that microwave roasting reduced the oxidative deteriorations of PSO during heating. PMID- 29628487 TI - Boosting Effect of Amphiphilic Random Copolymers for Bicontinuous Phases. AB - Amphiphilic random copolymers, poly(oxyethylene)/poly(oxypropylene) butyl ethers (C4EmPn), have been used as raw materials for cosmetics. This paper reports on the influence of amphiphilic random copolymers on mixtures of n-decane, water, and a nonionic surfactant, hexa(oxyethylene) dodecyl ether (C12E6). Bicontinuous phases are formed from decane/water/C12E6 mixtures at high C12E6 weight fractions (> 70 wt%). Adding C4EmPn to decane/water/C12E6 mixtures brings about the formation of bicontinuous phases and a decrease in the amount of the surfactant required for their formation, indicating efficiency boosting. The bicontinuous phase formation region in the phase diagram of the decane/water/C12E6+C4E5P5 system is largest at a specific C4E5P5 weight fraction in the C12E6/C4E5P5 mixture. When a hydrophobic polymer, in which the poly(ethylene oxide) group in C4EmPn is absent, is added to decane/water/C12E6 mixtures, no efficiency boosting is observed. These results suggest that the adjustment of the hydrophilicity hydrophobicity balance of C12E6/C4EmPn mixture causes the efficiency boosting. PMID- 29628488 TI - Carbonation of Epoxidized Methyl Soyates in Tetrabutylammonium Bromide-Based Deep Eutectic Solvents. AB - Carbonated methyl soyates have been successfully prepared by cycloaddition of carbon dioxide (CO2) to epoxidized methyl soyates in tetrabutylammonium bromide (TBAB)-based deep eutectic solvents (DES). Experimental parameters, i.e., reaction temperature, reaction time, CO2 pressure and TBAB concentration were evaluated. The different reaction conditions have a significant influence on the yields of carbonated methyl soyates. The use of TBAB-based DES (tetrabutylammonium bromide/triethylene glycol) significantly shortened the reaction time of the cycloaddition of CO2 to epoxidized methyl soyates. FT-IR and NMR analysis indicated that 95% of the yield of the five-membered cyclic carbonated methyl soyates were obtained at 120 degrees C with 1.0 MPa pressure of CO2. PMID- 29628489 TI - Production of Biodiesel from Candlenut Oil Using a Two-step Co-solvent Method and Evaluation of Its Gaseous Emissions. AB - Candlenut oil (CNO) is a potentially new feedstock for biodiesel (BDF) production. In this paper, a two-step co-solvent method for BDF production from CNO was examined. Firstly, esterification of free fatty acids (FFAs) (7 wt%) present in CNO was carried out using a co-solvent of acetonitrile (30 wt%) and H2SO4 as a catalyst. The content of FFAs was reduced to 0.8 wt% in 1 h at 65 degrees C. Subsequent transesterification of the crude oil produced was carried out using a co-solvent of acetone (20 wt%) and 1 wt% potassium hydroxide (KOH). Ester content of 99.3% was obtained at 40 degrees C in 45 min. The water content in BDF was 0.023% upon purification using vacuum distillation at 5 kPa. The components of CNO BDF were characterized using a Fourier-transform infrared spectrometry and gas chromatography-flame ionization detector. The physicochemical properties of BDF satisfied the ASTM D6751-02 standard. The gaseous exhaust emissions from the diesel engine upon combustion of the BDF blends (B0-B100) with petrodiesel were examined. The emissions of carbon monoxide and hydrocarbons were clearly lower, but that of nitrogen oxides was higher in comparison to those from petro-diesel. PMID- 29628490 TI - Facile and Low-cost Synthesis of Mesoporous Ti-Mo Bi-metal Oxide Catalysts for Biodiesel Production from Esterification of Free Fatty Acids in Jatropha curcas Crude Oil. AB - Mesoporous Ti-Mo bi-metal oxides with various titanium-molybdenum ratios were successfully fabricated via a facile approach by using stearic acid as a low-cost template agent. thermal gravity (TG) /differential scanning calorimetry (DSC) analysis, X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, nitrogen adsorption-desorption isotherm, NH3 temperature-programmed desorption (NH3-TPD), scanning electron microscopy (SEM) and transmission electron microscopy (TEM) measurements indicated these materials possessing mesoporous structure, sufficient pore size and high acid intensity. The catalytic performance of prepared catalysts was evaluated by esterification of free fatty acids in Jatropha curcas crude oil (JCCO) with methanol. The effects of various parameters on FFA conversion were investigated. The esterification conversion of 87.8% was achieved under the condition of 180 degrees C, 2 h, methanol to JCCO molar ratio of 20:1 and 3.0 wt.% catalyst (relative to the weight of JCCO). The mesoporous catalysts were found to exhibit high activities toward the simultaneous esterification and transesterification of JCCO. Furthermore, the catalyst could be recovered with a good reusability. PMID- 29628491 TI - Effect of Freeze-Thaw Treatment on the Precipitation of Octyl beta-D-Galactoside Hemihydrate Crystal from the Aqueous Solution. AB - Cryogenic treatment, like the freeze-thaw process, has been reported to be effective in modifying the physicochemical properties of polymeric hydrogels. However, not much attention has been paid to this process in terms of the precipitation of surfactant-water systems. In this study, two effective cryogenic methodologies were successfully reported to alter the physicochemical properties of a precipitate of an octyl beta-D-galactoside (Oct-Gal)-water system. First, hyperrapid cooling (i.e., cooling at 30 degrees C/min) was found to be an effective type of cryogenic treatment: the phase transition temperature (TK) and enthalpy at the phase transition (?HK) between the crystal-dispersed phase and the sol (micelle) phase significantly decreased. In addition, cryogenic treatment in the presence of electrolytes, such as NaCl, NaBr, and CsCl, was effective even in the absence of the hyperrapid cooling condition. The hyperrapid cooling or the addition of certain electrolytes was considered to prevent the precipitation of the Oct-Gal hemihydrate crystals prior to the complete freezing of ice and the electrolyte/ice eutectic. Hence, the size of the aggregated crystals prepared by the above-mentioned effective cryogenic treatments seemed to be decreased compared with that of the normal precipitated crystals, thereby changing TK and ?HK. Thus, two basic methodologies for the modification of the physicochemical properties of the crystal-dispersed phase of surfactant-water systems are discussed. PMID- 29628492 TI - A 43 MHz Low-Field Benchtop 1H Nuclear Magnetic Resonance Method to Discriminate Perilla Oil Authenticity. AB - The aim of this study was to discriminate the authenticity of perilla oils distributed in Korea using their 1H nuclear magnetic resonance (NMR) spectra acquired by a 43 MHz low-field benchtop NMR spectrometer. Significant differences existed in the integration values of all 6 peaks found in the spectrum between authentic and adulterated perilla oil samples. The integration values of 4 peaks that signify the methylene protons present in all fatty acids (FA) and allylic or olefinic protons present in all unsaturated FA were the best variables for establishing perilla oil authenticity. The procedure for applying the range of variables found in authentic perilla oil samples correctly discriminated between the samples of perilla oils with soybean oils added at concentrations of >= 6 vol%. The results demonstrated that this NMR procedure is a possible cost effective alternative to the high-field 1H NMR method for discriminating the authenticity of perilla oils. PMID- 29628493 TI - Effect of a High-sucrose Diet on Abdominal Aortic Aneurysm Development in a Hypoperfusion-induced Animal Model. AB - Abdominal aortic aneurysm (AAA) is a vascular disease that results in rupture of the abdominal aorta. The risk factors for the development of AAA include smoking, male sex, hypertension, and age. AAA has a high mortality rate, but therapy for AAA is restricted to surgery in cases of large aneurysms. Clarifying the effect of dietary food on the development of AAA would be helpful for patients with AAAs. However, the relationship between dietary habits and the development of AAA is largely unknown. In our previous study, we demonstrated that adipocytes in vascular wall can induce the rupture of AAA. Therefore, we focused on the diet induced abnormal triglyceride metabolism, which has the potential to drive AAA development. In this study, we have evaluated the effects of a high-sucrose diet on the development of AAA in a vascular hypoperfusion-induced animal model. A high sucrose diet induced high serum TG level and fatty liver. However, the AAA rupture risk and the AAA diameter were not significantly different between the control and high-sucrose groups. The intergroup differences in the elastin degradation score and collagen-positive area were insignificant. Moreover, matrix metalloproteinases, macrophages, and monocyte chemoattractant protein-1-positive areas did not differ significantly between groups. These results suggest that a high-sucrose diet does not affect the appearance of vascular adipocyte and AAA development under the vascular hypoperfusion condition. PMID- 29628494 TI - ISO standards on physical environments for worker performance and productivity. PMID- 29628495 TI - Pancreaticoduodenectomy with Preservation of Collateral Circulation or Revascularization for Biliary Pancreatic Cancer with Celiac Axis Occlusion: A Report of 2 Cases. AB - BACKGROUND In cases of celiac axis occlusion requiring pancreaticoduodenectomy for malignancy, both oncologic curability and control of hepatic arterial flow must be considered, but the operative strategy is undeveloped. CASE REPORT Case 1: A 74-year-old man was diagnosed with hilar cholangiocarcinoma with celiac axis stenosis. The collateral from the superior mesenteric artery ran through the pancreas head but no invasion was observed in preoperative imaging. Hepatopancreatoduodenectomy with preservation of a collateral was performed. Case 2: A 69-year-old woman was diagnosed with pancreas head cancer with celiac axis occlusion. The collateral from the superior mesenteric artery ran through pancreas head and tumor invasion was observed. Pancreaticoduodenectomy with bypass revascularization using a vein graft was performed. Both operations were performed safely oncologically under preoperative planning that was based on computed tomographic angiography. The operative procedure was ultimately determined by evaluation of perioperative blood flow under Doppler ultrasonography after clamping the gastroduodenal artery. CONCLUSIONS Preoperative simulations of arterial revascularization and perioperative evaluation of blood flow are necessary for the success of this procedure. PMID- 29628497 TI - Activated pancreatic stellate cells inhibit NK cell function in the human pancreatic cancer microenvironment. PMID- 29628496 TI - Ezrin/NF-kappaB Pathway Regulates EGF-induced Epithelial-Mesenchymal Transition (EMT), Metastasis, and Progression of Osteosarcoma. AB - BACKGROUND Epithelial-mesenchymal transition (EMT) is responsible for metastasis of cancers, and NF-kappaB can promote tumor progression. Ezrin is an important molecule participating in EMT. However, whether Ezrin mediates NF-kappaB in EGF induced osteosarcoma is unknown. MATERIAL AND METHODS Ezrin phosphorylation, NF kappaB activation, and EGF-induced EMT were studied in MG63 and U20S cells with NF-kappaB inhibition, silencing, or over-expressing Ezrin. Cell morphology, proliferation, migration, and motility were analyzed. An osteosarcoma model was established in mice by injecting MG63 and U20S and reducing Ezrin. RESULTS With EGF induction in vitro, Ezrin Tyr353 and Thr567 were phosphorylated, and EMT, proliferation, migration, and motility of osteosarcoma cells were promoted. Silencing Ezrin suppressed and over-expressing Ezrin promoted the nuclear translocation of p65 and phosphorylated IkappaBalpha (p-IkappaBalpha) in EGF induced osteosarcoma cells. NF-kappaB inhibitor blocked EGF-induced EMT in both cell types, as well as reserving cell morphology and suppressing proliferation, migration, and motility. In vivo, reducing Ezrin significantly suppressed metastasis of osteosarcoma xenografts, increased liver and lung weights, and activated NF-kappaB, which were both induced by EGF. CONCLUSIONS Ezrin/NF-kappaB regulated EGF-induced EMT, as well as progression and metastasis of osteosarcoma in vivo and in vitro. Ezrin/NF-kappaB may be a new therapeutic target to prevent osteosarcoma from deterioration. PMID- 29628498 TI - Tumor-infiltrating B cells: their role and application in anti-tumor immunity in lung cancer. AB - Evidence indicates that lung cancer development is a complex process that involves interactions between tumor cells, stromal fibroblasts, and immune cells. Tumor-infiltrating immune cells play a significant role in the promotion or inhibition of tumor growth. As an integral component of the tumor microenvironment, tumor-infiltrating B lymphocytes (TIBs) exist in all stages of cancer and play important roles in shaping tumor development. Here, we review recent clinical and preclinical studies that outline the role of TIBs in lung cancer development, assess their prognostic significance, and explore the potential benefit of B cell-based immunotherapy for lung cancer treatment. PMID- 29628499 TI - Special Issue on Synapse Assembly, Neural Circuit Development, and Brain Disorders. PMID- 29628500 TI - nArgBP2-SAPAP-SHANK, the core postsynaptic triad associated with psychiatric disorders. AB - Despite the complex genetic architecture, a broad spectrum of psychiatric disorders can still be caused by mutation(s) in the same gene. These disorders are interrelated with overlapping causative mechanisms including variations in the interaction among the risk-associated proteins that may give rise to the specific spectrum of each disorder. Additionally, multiple lines of evidence implicate an imbalance between excitatory and inhibitory neuronal activity (E/I imbalance) as the shared key etiology. Thus, understanding the molecular mechanisms underlying E/I imbalance provides essential insight into the etiology of these disorders. One important class of candidate risk genes is the postsynaptic scaffolding proteins, such as nArgBP2, SAPAP, and SHANK that regulate the actin cytoskeleton in dendritic spines of excitatory synapses. This review will cover and discuss recent studies that examined how these proteins, especially nArgBP2, are associated with psychiatric disorders. Next, we propose a possibility that variations in the interaction among these proteins in a specific brain region might contribute to the onset of diverse phenotypes of psychiatric disorders. PMID- 29628502 TI - Circular RNA F-circEA produced from EML4-ALK fusion gene as a novel liquid biopsy biomarker for non-small cell lung cancer. PMID- 29628501 TI - Excitatory and inhibitory synaptic dysfunction in mania: an emerging hypothesis from animal model studies. AB - Bipolar disorder (BD) is a common psychiatric disorder characterized by recurrent mood swings between depression and mania, and is associated with high treatment costs. The existence of manic episodes is the defining feature of BD, during which period, patients experience extreme elevation in activity, energy, and mood, with changes in sleep patterns that together severely impair their ability to function in daily life. Despite some limitations in recapitulating the complex features of human disease, several rodent models of mania have been generated and characterized, which have provided important insights toward understanding its underlying pathogenic mechanisms. Among the mechanisms, neuronal excitatory and inhibitory (E/I) synaptic dysfunction in some brain regions, including the frontal cortex, hippocampus, and striatum, is an emerging hypothesis explaining mania. In this review, we highlight recent studies of rodent manic models having impairments in the E/I synaptic development and function. We also summarize the molecular and functional changes of E/I synapses by some mood stabilizers that may contribute to the therapeutic efficacy of drugs. Furthermore, we discuss potential future directions in the study of this emerging hypothesis to better connect the outcomes of basic research to the treatment of patients with this devastating mental illness. PMID- 29628503 TI - Leucine-rich repeat-containing synaptic adhesion molecules as organizers of synaptic specificity and diversity. AB - The brain harbors billions of neurons that form distinct neural circuits with exquisite specificity. Specific patterns of connectivity between distinct neuronal cell types permit the transfer and computation of information. The molecular correlates that give rise to synaptic specificity are incompletely understood. Recent studies indicate that cell-surface molecules are important determinants of cell type identity and suggest that these are essential players in the specification of synaptic connectivity. Leucine-rich repeat (LRR) containing adhesion molecules in particular have emerged as key organizers of excitatory and inhibitory synapses. Here, we discuss emerging evidence that LRR proteins regulate the assembly of specific connectivity patterns across neural circuits, and contribute to the diverse structural and functional properties of synapses, two key features that are critical for the proper formation and function of neural circuits. PMID- 29628504 TI - Synapse development organized by neuronal activity-regulated immediate-early genes. AB - Classical studies have shown that neuronal immediate-early genes (IEGs) play important roles in synaptic processes critical for key brain functions. IEGs are transiently activated and rapidly upregulated in discrete neurons in response to a wide variety of cellular stimuli, and they are uniquely involved in various aspects of synapse development. In this review, we summarize recent studies of a subset of neuronal IEGs in regulating synapse formation, transmission, and plasticity. We also discuss how the dysregulation of neuronal IEGs is associated with the onset of various brain disorders and pinpoint key outstanding questions that should be addressed in this field. PMID- 29628505 TI - Synaptic and circuit development of the primary sensory cortex. AB - Animals, including humans, optimize their primary sensory cortex through the use of input signals, which allow them to adapt to the external environment and survive. The time window at the beginning of life in which external input signals are connected sensitively and strongly to neural circuit optimization is called the critical period. The critical period has attracted the attention of many neuroscientists due to the rapid activity-/experience-dependent circuit development that occurs, which is clearly differentiated from other developmental time periods and brain areas. This process involves various types of GABAergic inhibitory neurons, the extracellular matrix, neuromodulators, transcription factors, and neurodevelopmental factors. In this review, I discuss recent progress regarding the biological nature of the critical period that contribute to a better understanding of brain development. PMID- 29628507 TI - DeltaNp73 enhances HIF-1alpha protein stability through repression of the ECV complex. AB - Cellular responses to low oxygen conditions are mainly regulated by the Hypoxia inducible factors (HIFs). Induction of HIF-1alpha in tumor cells activates the angiogenic switch and allows for metabolic adaptations. HIF-1alpha protein levels are tightly regulated through ubiquitin-mediated proteosomal degradation; however, high levels of HIF-1alpha is a common feature in many solid tumors and is thought to enhance cancer cell proliferation, migration, and survival. Here, we report that the oncogenic p73 isoform, ?Np73, increases HIF-1alpha protein stability. We found that ?Np73 represses expression of genes encoding subunits of the ECV complex, in particular Elongin C, Elongin B, Cullin 2, and Rbx1. The ECV complex is an E3 ligase complex responsible for polyubiquitinating HIF-1alpha. Loss of ?Np73 increases ubiquitination of HIF-1alpha, leading to its degradation via the proteosomal pathway, and subsequent decrease of HIF-1alpha target genes. Taken together, our data demonstrates that high levels of ?Np73 stabilize HIF 1alpha protein, allowing for it to accumulate and further potentiating its transcriptional activity and supporting tumor progression. PMID- 29628506 TI - Zinc finger protein 746 promotes colorectal cancer progression via c-Myc stability mediated by glycogen synthase kinase 3beta and F-box and WD repeat domain-containing 7. AB - To elucidate the underlying oncogenic mechanism of zinc finger protein 746 (ZNF746), current study was conducted in colorectal cancers (CRCs). Herein, ZNF746 was overexpressed in HCT116, SW620, and SW480 cells, which was supported by CRC tissue microarray and TCGA analysis. Also, DNA microarray revealed the differentially expressed gene profile particularly related to cell cycle genes and c-Myc in ZNF746 depleted HCT116 cells. Furthermore, ZNF746 enhanced the stability of c-Myc via their direct binding through nuclear colocalization by immunoprecipitation and immunofluorescence, while ZNF746 and c-Myc exist mainly in nucleoplasm. Conversely, ZNF746 depletion attenuated phosphorylation of c-Myc (S62) and glycogen synthase kinase 3beta (GSK3beta) (S9) and also activated p-c Myc (T58), which was reversed by GSK3 inhibitors such as SB-216763 and Enza. Also, c-Myc degradation by ZNF746 depletion was blocked by knockdown of F-box/WD repeat-containing protein 7 (FBW7) ubiquitin ligase or proteosomal inhibitor MG132. Additionally, the growth of ZNF746 depleted HCT116 cancer cells was retarded with decreased expression of ZNF746 and c-Myc. Overall, these findings suggest that ZNF746 promotes CRC progression via c-Myc stability mediated by GSK3 and FBW7. PMID- 29628508 TI - A pilot study of ultra-deep targeted sequencing of plasma DNA identifies driver mutations in hepatocellular carcinoma. AB - Cellular components of solid tumors including DNA are released into the bloodstream, but data on circulating-free DNA (cfDNA) in hepatocellular carcinoma (HCC) are still scarce. This study aimed at analyzing mutations in cfDNA and their correlation with tissue mutations in patients with HCC. We included 8 HCC patients treated with surgical resection for whom we collected paired tissue and plasma/serum samples. We analyzed 45 specimens, including multiregional tumor tissue sampling (n = 24), peripheral blood mononuclear cells (PMBC, n = 8), plasma (n = 8) and serum (n = 5). Ultra-deep sequencing (5500* coverage) of all exons was performed in a targeted panel of 58 genes, including frequent HCC driver genes and druggable mutations. Mutations detected in plasma included known HCC oncogenes and tumor suppressors (e.g., TERT promoter, TP53, and NTRK3) as well as a candidate druggable mutation (JAK1). This approach increased the detection rates previously reported for mutations in plasma of HCC patients. A thorough characterization of cis mutations found in plasma confirmed their tumoral origin, which provides definitive evidence of the release of HCC-derived DNA fragments into the bloodstream. This study demonstrates that ultra-deep sequencing of cfDNA is feasible and can confidently detect somatic mutations found in tissue; these data reinforce the role of plasma DNA as a promising minimally invasive tool to interrogate HCC genetics. PMID- 29628510 TI - Adaptive and maladaptive perfectionism, and professional burnout among medical laboratory scientists. AB - BACKGROUND: The goal of this paper is to verify the correlations between adaptive and maladaptive perfectionism and the selected demographic and job characteristics vs. professional burnout among medical laboratory scientists in Poland. MATERIAL AND METHODS: The study group consisted of 166 laboratory scientists. The Polish Adaptive and Maladaptive Perfectionism Questionnaire (Szczucka) was used for testing perfectionism. The Oldenburg Burnout Inventory was used for examining burnout syndrome. RESULTS: Adaptive perfectionism was positively and maladaptive perfectionism was negatively correlated with both aspects of professional burnout: the disengagement from work and exhaustion. What is more, maladaptive perfectionism was correlated negatively with age and work experience. People in relationships have a higher level of disengagement and a higher level of exhaustion than single ones. The results of hierarchical regression analyses have revealed, after having controlled selected demographic and job factors, that a significant predictor of disengagement is the high level of adaptive perfectionism and low level of maladaptive perfectionism. In addition, a significant predictor of high level of exhaustion is the low level of maladaptive perfectionism. CONCLUSIONS: Professional burnout among medical laboratory scientists is of a specific nature. The "healthier" perfectionism they reveal, the higher level of burnout they present. In this profession, lower risk of burnout is represented by those who are characterized by the lack of confidence in the quality of their actions and a negative reaction to their own imperfections associated with imposed social obligation to be perfect. The individuals pursuing their internal high standards experience burnout faster. Med Pr 2018;69(3):253-260. PMID- 29628511 TI - Dolutegravir Neuropsychiatric Adverse Events: Specific Drug Effect or Class Effect. AB - Integrase strand transfer inhibitors (INSTIs) are a newer class of antiretroviral treatment for HIV-infected patient. INSTIs currently available for use are raltegravir, elvitegravir, dolutegravir (DTG), and bictegravir. Clinical studies using INSTIs have demonstrated an 80-90% efficiency in treating HIV-positive antiretroviral therapy - naive patients. They are recommended by internatioal guidelines as the preferred agents for the first-line regimen. INSTIs have also been demonstrated as safe and tolerable. In clinical trials, the rate of adverse events (AEs) such as neuropsychiatric AEs (NPSAEs) leading to discontinuation is very low. However, recent published cohort studies show growing concerns on DTG induced NPSAEs. In this paper, we will review available evidence about DTG - NPSAEs and analyze whether the backbone (abacavir or tenofovir) matters as well as discussing the possible mechanism behind this toxicity. PMID- 29628512 TI - Hot News: Sexually Transmitted Infections on the Rise in PrEP Users. AB - Pre-exposure prophylaxis (PrEP) with oral Truvada (tenofovir plus emtricitabine) is effective at preventing HIV infection in high-risk homosexual men. In the United States, PrEP was approved in 2012 and is reimbursed by Medicaid and the majority of private insurers. The situation is diverse and not uniform in the European Union, being PrEP more widely used in France than in the rest of countries. Concerns have been raised that PrEP use may be accompanied by the phenomena of risk compensation or behavioral disinhibition, whereby PrEP users' perception of decreased risk of HIV acquisition may lead them to engage in overall riskier sexual practices and increase their chances of acquiring sexually transmitted infections (STIs) (Blumenthal, et al. Virtual Mentor. 2014;16:909 15). Modifiable factors that may influence the acquisition of STI include condom use, number of partners, partner characteristics, and healthcare-seeking behaviors. In addition, MSM may alter HIV risk mitigation practices while on PrEP by decreasing seroadaptive practices such as serosorting that is seeking a partner of similar perceived serostatus (Khosopour, et al. AIDS Behav. 2017;21:2935-44). High rates of STI have been reported among PrEP users, as well as high rates of condomless sex, and increasing rates of STI over time (Liu, et al. JAMA Intern Med. 2016;176:75-84; Kojima, et al. AIDS, 2016;30:2251-2). In a new study conducted in Montreal, Canada, increases in the rates of STI in PrEP users were demonstrated measuring incidence rates of STI before and following the initiation of PrEP in the same cohort. The authors measured the incidence of gonorrhea, chlamydia, and/or syphilis in 109 HIV-seronegative homosexual men 12 months before and 12 months after beginning Truvada for HIV prevention (Nguyen, et al. AIDS. 2018;32:523-30). New episodes of gonorrhea, chlamydia, and/or syphilis rose in the cohort after providing Truvada, as shown in Figure 1. Moreover, the incidence of three or more STI increased from 3.7 to 9.2 cases per 100 personyears in this cohort. The Canadian study highlighted that the rate of STI with PrEP was also higher than in a group of 86 homosexual men that had undergone PEP in Montreal during 2010-2015. Other findings of the study we the high rate of STI with anorectal location, symptomless STI (e.g., chlamydia) and the frequency of sex partners contacted by internet. The increased rates of STI in PrEP users suggest a need to reinforce counseling and STI diagnosis and treatment efforts. Although PrEP may provide a public health benefit beyond the immediate prevention of HIV infection as result of bringing into care high-risk homosexual men who might not otherwise be seeking care for STI, doctors in charge must take this opportunity for informing adequately on STI and the risks inherent to multiple and occasional sexual contacts. PMID- 29628509 TI - Inhibition in the amygdala anxiety circuitry. AB - Inhibitory neurotransmission plays a key role in anxiety disorders, as evidenced by the anxiolytic effect of the benzodiazepine class of gamma-aminobutyric acid (GABA) receptor agonists and the recent discovery of anxiety-associated variants in the molecular components of inhibitory synapses. Accordingly, substantial interest has focused on understanding how inhibitory neurons and synapses contribute to the circuitry underlying adaptive and pathological anxiety behaviors. A key element of the anxiety circuitry is the amygdala, which integrates information from cortical and thalamic sensory inputs to generate fear and anxiety-related behavioral outputs. Information processing within the amygdala is heavily dependent on inhibitory control, although the specific mechanisms by which amygdala GABAergic neurons and synapses regulate anxiety related behaviors are only beginning to be uncovered. Here, we summarize the current state of knowledge and highlight open questions regarding the role of inhibition in the amygdala anxiety circuitry. We discuss the inhibitory neuron subtypes that contribute to the processing of anxiety information in the basolateral and central amygdala, as well as the molecular determinants, such as GABA receptors and synapse organizer proteins, that shape inhibitory synaptic transmission within the anxiety circuitry. Finally, we conclude with an overview of current and future approaches for converting this knowledge into successful treatment strategies for anxiety disorders. PMID- 29628513 TI - Hot News: Impact of Low-level Viremia on Treatment Outcomes During ART - Is it Time to Revise the Definition of Virological Failure? AB - The level of HIV-RNA in plasma (HIV viral load) is the main marker used to monitor the virological response to antiretroviral therapy (ART) in HIV-infected patients. The threshold used to define virological suppression has historically been dictated by the limits of detection of the commercial assays used to quantify the plasma viral load. Thus, as more sensitive assays have proliferated and become more widely available, the definition has shifted from < 400 cop/mL with the first generation assays, to < 50 cop/mL, to < 20 cop/mL currently. Thanks to the high efficacy of the new treatment combinations, most HIV treatment guidelines have since 2008 established that the goal of ART is to maintain virological suppression below < 50 cop/mL. However, some guidelines have continued to set the definition of virological failure as a confirmed plasma viral load > 200 cop/mL, or even > 1000 cop/mL according to the WHO guidelines for low-income and middle-income countries. Several studies have evaluated the impact of low-level viremia as intermittent episodes (blips) or persistent detectable low-level viremia (50-1000 cop/mL) on treatment outcomes during ART. Some of these studies have suggested a potential role for low-level viremia as a predictor of virological failure, although up to now the data have been insufficient and controversial to guide clinical management. Hermans et al. have recently published the results of a large (n = 70.930 HIV-infected patients) multicenter study (57 clinical sites in South Africa) with a median follow-up for more than 2 years, to evaluate the incidence and impact of low-level viremia (defined as HIV-RNA viral load of 51-999 cop/mL) and its association with virological failure (Hermans et al., Lancet Infect Dis 2018;18:188-97). This large cohort study concludes that overall, patients with low-level viremia are predisposed to subsequent virological failure. The risk of virological failure was 5 times higher for patients with low-level viremia ranging 400-999 cop/mL, and 2 times higher for those with viremia ranging 51-199 cop/mL, compared with patients maintaining viral load suppression (< 50 cop/mL). Interestingly, the risk of virological failure was significantly increased even after a single measurement of low-range low-level viremia ranging 51-199 cop/mL. Selection bias is a potential limitation of this study, mainly due to the inherent heterogeneity in the clinical management and treatment strategies among the 57 participating clinics. Despite this, the large sample size has allowed for performing a very detailed statistical analysis demonstrating the robustness of their conclusions. The results of this large-scale study strongly suggest that low-level viremia should be considered as a warning signal for subsequent virological failure. Given these findings, therefore, the relevance of lowlevel viremia in the treatment outcomes for HIV-infected patients on ART should be recognized and considered in clinical decision-making. Furthermore, current WHO guidelines for low-income and middleincome countries should be revised and updated. Although substantial differences exist in the clinical management and treatment options between HIV-infected patients in high-income countries compared with low-income and middle-income countries, the results of this study call for the revision of the current definition of virological failure as a confirmed viral load of > 200 cop/mL established for most current HIV treatment guidelines. The implementation of new recommendations for the management of low-level viremia may have a huge impact in controlling the HIV epidemic. In the current era of increased efforts toward ending the HIV epidemic, all strategies are needed to help in finally achieving this much-needed objective. PMID- 29628514 TI - State of the Art in HIV Drug Resistance: Surveillance and Regional Gaps. AB - This article is the second of a two-part review aiming to identify gaps in the knowledge and management of human immunodeficiency virus type 1 drug resistance (HIVDR) from global and regional perspectives. Here, we examine the policy and programmatic gaps in HIVDR surveillance, the affected populations and settings, and implications for clinical practice. The expert authorship of this review convened to identify gaps in HIVDR surveillance, with a particular focus on specific regional variations within and between Europe and Asia, to highlight directions for research and implementation. Further, evidence was gathered from a review of published studies, guidelines, and current practices. This review found that despite recent progress in the development, harmonization, and implementation of guidelines on HIVDR reporting and surveillance, programmatic, and policy gaps reflect the regional variability in HIV epidemics, clinical practice, and resources. The need for representative surveillance was identified as a key gap that has the potential to inform management policies. Monitoring must keep up with the evolution of transmission routes to adapt appropriately, and this will be further impacted by migration from areas with increasing levels of resistance. Analysis of the latest clinical data, regional practice, policy, and guidelines has identified a number of gaps in HIVDR population monitoring and surveillance. More efforts are needed to align surveillance platforms with harm reduction and patient education, particularly in vulnerable subgroups. Addressing these gaps will facilitate research into and progress in the management of HIV across a wide range of health-care settings. PMID- 29628515 TI - State of the Art in HIV Drug Resistance: Science and Technology Knowledge Gap. AB - Resistance to antiretroviral therapy (ART) threatens the efficacy of human immunodeficiency virus type 1 (HIV-1) treatment. We present a review of knowledge gaps in the science and technologies of acquired HIV-1 drug resistance (HIVDR) in an effort to facilitate research, scientific exchange, and progress in clinical management. The expert authorship of this review convened to identify data gaps that exist in the field of HIVDR and discuss their clinical implications. A subsequent literature review of trials and current practices was carried out to provide supporting evidence. Several gaps were identified across HIVDR science and technology. A summary of the major gaps is presented, with an expert discussion of their implications within the context of the wider field. Crucial to optimizing the use of ART will be improved understanding of protease inhibitors and, in particular, integrase strand transfer inhibitors (INSTI) in the context of HIVDR. Limited experience with INSTI represents an important knowledge gap in HIV resistance science. Utilizing such knowledge in a clinical setting relies on accurate testing and analysis of resistance-associated mutations. As next-generation sequencing becomes more widely available, a gap in the interpretation of data is the lack of a defined, clinically relevant threshold of minority variants. Further research will provide evidence on where such thresholds lie and how they can be most effectively applied. Expert discussion identified a series of gaps in our knowledge of HIVDR. Addressing prefsuch gaps through further research and characterization will facilitate the optimal use of ART therapies and technologies. PMID- 29628516 TI - Environmental Stigma: Resident Responses to Living in a Contaminated Area. AB - This article examined the extent to which residents living in the Midland-Saginaw Bay City area in Eastern Michigan felt stigmatized due to industrial contamination. Seventy in-depth interviews were conducted with local residents, focusing on the extent to which they experienced three aspects of stigma affective, cognitive, and behavioral. Results indicated that although some participants were not concerned with living in a contaminated community, local residents largely perceived dioxin as a risk to individual health and the local environment. Concern, shock, and irritation were typical affective responses at the time participants learned of the contamination. Several participants indicated a feeling of embarrassment and fear of being rejected by others because of the stigma associated with industrial contamination. Instead of actively seeking information about dioxin contamination and remediation, participants often relied on information provided to them by government officials. Behaviorally, participants avoided eating locally caught fish and prepared fish more carefully in order to avoid exposure to contaminants. As a whole, this study provided insight to understand affective, cognitive, and behavioral responses to environmental stigma. PMID- 29628517 TI - Do we hear what birds hear in birdsong? AB - Peter Marler's fascination with richness of birdsong included the notion that birds attended to some acoustic features of birdsong, likely in the time domain, which were inaccessible to human listeners. While a considerable amount is known about hearing and vocal communication in birds, how exactly birds perceive their auditory world still remains somewhat of a mystery. For sure, field and laboratory studies suggest that birds hear the spectral, gross temporal features (i.e. envelope) and perhaps syntax of birdsong much like we do. However, there is also ample anecdotal evidence that birds are consistently more sensitive than humans to at least some aspects of their song. Here we review several psychophysical studies supporting Marler's intuitions that birds have both an exquisite sensitivity to temporal fine structure and may be able to focus their auditory attention on critical acoustic details of their vocalizations. Zebra finches, Taeniopygia guttata, particularly, seem to be extremely sensitive to temporal fine structure in both synthetic stimuli and natural vocalizations. This finding, together with recent research highlighting the complexity of zebra finch vocalizations across contexts, raises interesting questions about what information zebra finches may be communicating in temporal fine structure. Together these findings show there is an acoustic richness in bird vocalizations that is available to birds but likely out of reach for human listeners. Depending on the universality of these findings, it raises questions about how we approach the study of birdsong and whether potentially significant information is routinely being encoded in the temporal fine structure of avian vocal signals. PMID- 29628518 TI - The Abundance of SiC2 in Carbon Star Envelopes: Evidence that SiC2 is a gas-phase precursor of SiC dust. AB - Context: Silicon carbide dust is ubiquitous in circumstellar envelopes around C rich AGB stars. However, the main gas-phase precursors leading to the formation of SiC dust have not yet been identified. The most obvious candidates among the molecules containing an Si-C bond detected in C-rich AGB stars are SiC2, SiC, and Si2C. To date, the ring molecule SiC2 has been observed in a handful of evolved stars, while SiC and Si2C have only been detected in the C-star envelope IRC +10216. Aims: We aim to study how widespread and abundant SiC2, SiC, and Si2C are in envelopes around C-rich AGB stars and whether or not these species play an active role as gas-phase precursors of silicon carbide dust in the ejecta of carbon stars. Methods: We carried out sensitive observations with the IRAM 30m telescope of a sample of 25 C-rich AGB stars to search for emission lines of SiC2, SiC, and Si2C in the lambda 2 mm band. We performed non-LTE excitation and radiative transfer calculations based on the LVG method to model the observed lines of SiC2 and to derive SiC2 fractional abundances in the observed envelopes. Results: We detect SiC2 in most of the sources, SiC in about half of them, and do not detect Si2C in any source, at the exception of IRC +10216. Most of these detections are reported for the first time in this work. We find a positive correlation between the SiC and SiC2 line emission, which suggests that both species are chemically linked, the SiC radical probably being the photodissociation product of SiC2 in the external layer of the envelope. We find a clear trend in which the denser the envelope, the less abundant SiC2 is. The observed trend is interpreted as an evidence of efficient incorporation of SiC2 onto dust grains, a process which is favored at high densities owing to the higher rate at which collisions between particles take place. Conclusions: The observed behavior of a decline in the SiC2 abundance with increasing density strongly suggests that SiC2 is an important gas-phase precursor of SiC dust in envelopes around carbon stars. PMID- 29628519 TI - STRUCTURE IN THE 3D GALAXY DISTRIBUTION: III. FOURIER TRANSFORMING THE UNIVERSE: PHASE AND POWER SPECTRA. AB - We demonstrate the effectiveness of a relatively straightforward analysis of the complex 3D Fourier transform of galaxy coordinates derived from redshift surveys. Numerical demonstrations of this approach are carried out on a volume-limited sample of the Sloan Digital Sky Survey redshift survey. The direct unbinned transform yields a complex 3D data cube quite similar to that from the Fast Fourier Transform (FFT) of finely binned galaxy positions. In both cases deconvolution of the sampling window function yields estimates of the true transform. Simple power spectrum estimates from these transforms are roughly consistent with those using more elaborate methods. The complex Fourier transform characterizes spatial distributional properties beyond the power spectrum in a manner different from (and we argue is more easily interpreted than) the conventional multi-point hierarchy. We identify some threads of modern large scale inference methodology that will presumably yield detections in new wider and deeper surveys. PMID- 29628520 TI - SUN-TO-EARTH MHD SIMULATION OF THE 14 JULY 2000 "BASTILLE DAY" ERUPTION. AB - Solar eruptions are the main driver of space-weather disturbances at the Earth. Extreme events are of particular interest, not only because of the scientific challenges they pose, but also because of their possible societal consequences. Here we present a magnetohydrodynamic (MHD) simulation of the 14 July 2000 "Bastille Day" eruption, which produced a very strong geomagnetic storm. After constructing a "thermodynamic" MHD model of the corona and solar wind, we insert a magnetically stable flux rope along the polarity inversion line of the eruption's source region and initiate the eruption by boundary flows. More than 1033 ergs of magnetic energy are released in the eruption within a few minutes, driving a flare, an EUV wave, and a coronal mass ejection (CME) that travels in the outer corona at ~1500 km s-1, close to the observed speed. We then propagate the CME to Earth, using a heliospheric MHD code. Our simulation thus provides the opportunity to test how well in situ observations of extreme events are matched if the eruption is initiated from a stable magnetic-equilibrium state. We find that the flux-rope center is very similar in character to the observed magnetic cloud, but arrives ~8.5 hours later and ~15 degrees too far to the North, with field strengths that are too weak by a factor of ~1.6. The front of the flux rope is highly distorted, exhibiting localized magnetic-field concentrations as it passes 1 AU. We discuss these properties with regard to the development of space weather predictions based on MHD simulations of solar eruptions. PMID- 29628521 TI - Distribution, habitat affinities and phenology of the Micrargus herbigradus species group (Araneae: Linyphiidae) in Poland. AB - We review the known information on the distribution and habitat affinities of the Micrargus herbigradus-species group in Poland. The analysis is based on a thorough literature survey, our own materials, and verification of some older collections. We give new diagnostic drawings and review the characters that are useful in identification of species within the group. Three species are present in Poland: M. herbigradus (Blackwall, 1854), M. apertus (O.-P. Cambridge, 1870) and M. georgescuae Millidge, 1976. The latter is recorded for the first time in the country, and we add numerous new localities for the two former species. Micrargus herbigradus is common and widespread in Poland, living in various habitats, with only a slight preference to forests. In contrast, M. apertus is widely distributed but rarely found, while its affinity to forests is the highest within the group. The records of this species are most numerous in lowland forests (up to c. 300 m a.s.l), but it can also be found at higher altitudes. M. georgescuae is found only in montane habitats, both in the Sudetes and the Carpathian Mountains, from above 650 m a.s.l. The adults of all three species occur the whole year round, but seem to be most abundant in May and June. PMID- 29628522 TI - Impact of windstorm on a community of centipedes (Chilopoda) in a beech forest in Western Poland. AB - The study was carried out in the years 2016-2017, five years after a windstorm which destroyed 1/3 of the protected beech forest area in the west of Poland. The community of centipedes in the area affected by the windstorm was depleted in terms of the species richness, diversity, and population density. The dominance structures were shortened and the species composition was rebuilt. The areas that proved to be the richest in terms of species richness and diversity among the sites affected by the windstorm were the one where windfallen trees were left and the other where beech trees had been planted by humans. In total, the quantitative and qualitative samples collected four times throughout a year featured 608 specimens from 11 species of two centipede orders - Lithobiomorpha and Geophilomorpha. Lithobius curtipes and L. forficatus were found in all of the investigated areas. L. pelidnus and L. piceus were captured at control sites exclusively. Only one species -L. erythrocephalus was found solely at the damaged site. The most numerous and most frequently found species in the community were L. curtipes, L. mutabilis, and Strigamia acuminata respectively. Although windstorms are natural phenomena their consequences may lead to significant changes in the community of the investigated soil animals. The importance of coarse woody debris, significantly contributing to the improvement and maintenance of species richness and diversity of Chilopoda, has once again been confirmed. PMID- 29628523 TI - Impact of environmental diversity of hunting complexes in the Lublin region on ontogenetic quality indicators in roe deer (Capreolus capreolus). AB - Populations of game are not confined to single ecosystems but function within higher-order units, e.g. ecological landscape. The basis for the establishment of the hunting complexes was the assumption that the existing game hunting grounds, i.e. the basic units implementing game management, are too small and do not cover the natural areas inhabited by game populations. Roe deer are flexible species and easily adapt to various site conditions, so they inhabit many different habitats, from large forest complexes, through small in-field tree stands and shrubs, to treeless grounds and field monocultures. The aim of the study was to determine a possible impact of environmental conditions prevailing in the hunting complexes of the Regional Directorate of State Forests (RDLP in Lublin) on the ontogenetic quality of roe deer. The study was conducted on 518 European roe deer (Capreolus capreolus) aged from 4 to 7 years (379 bucks and 139 does) harvested within hunting seasons 2010/2011-2013/2014. The results have shown that animals originating from areas with greater forest cover and denser stands are characterised by lower values of the mean ontogenetic quality parameters (carcase weight, kidney fat index, chest girth, weight of antlers) in comparison with animals from typical agricultural areas with fragmented forest complexes. These results indicate that, even in the case of such a eurytopic species as the roe deer, the ontogenetic quality differs between individual hunting complexes. The study has proved that strategies for hunting management of the roe deer should take into account the impact of the landscape structure, which provides a rationale behind creation of hunting complexes. PMID- 29628524 TI - Numerical study of gravity effects on phase separation in a swirl chamber. AB - The effects of gravity on a phase separator are studied numerically using an Eulerian/Lagrangian two-phase flow approach. The separator utilizes high intensity swirl to separate bubbles from the liquid. The two-phase flow enters tangentially a cylindrical swirl chamber and rotate around the cylinder axis. On earth, as the bubbles are captured by the vortex formed inside the swirl chamber due to the centripetal force, they also experience the buoyancy force due to gravity. In a reduced or zero gravity environment buoyancy is reduced or inexistent and capture of the bubbles by the vortex is modified. The present numerical simulations enable study of the relative importance of the acceleration of gravity on the bubble capture by the swirl flow in the separator. In absence of gravity, the bubbles get stratified depending on their sizes, with the larger bubbles entering the core region earlier than the smaller ones. However, in presence of gravity, stratification is more complex as the two acceleration fields - due to gravity and to rotation - compete or combine during the bubble capture. PMID- 29628525 TI - Understanding overpressure in the FAA aerosol can test by C3H2F3Br (2-BTP). AB - Thermodynamic equilibrium calculations, as well as perfectly-stirred reactor (PSR) simulations with detailed reaction kinetics, are performed for a potential halon replacement, C3H2F3Br (2-BTP, C3H2F3Br, 2-Bromo-3,3,3-trifluoropropene), to understand the reasons for the unexpected enhanced combustion rather than suppression in a mandated FAA test. The high pressure rise with added agent is shown to depend on the amount of agent, and is well-predicted by an equilibrium model corresponding to stoichiometric reaction of fuel, oxygen, and agent. A kinetic model for the reaction of C3H2F3Br in hydrocarbon-air flames has been applied to understand differences in the chemical suppression behavior of C3H2F3Br vs. CF3Br in the FAA test. Stirred-reactor simulations predict that in the conditions of the FAA test, the inhibition effectiveness of C3H2F3Br at high agent loadings is relatively insensitive to the overall stoichiometry (for fuel lean conditions), and the marginal inhibitory effect of the agent is greatly reduced, so that the mixture remains flammable over a wide range of conditions. Most important, the flammability of the agent-air mixtures themselves (when compressively preheated), can support low-strain flames which are much more difficult to extinguish than the easy-to extinguish, high-strain primary fireball from the impulsively released fuel mixture. Hence, the exothermic reaction of halogenated hydrocarbons in air should be considered in other situations with strong ignition sources and low strain flows, especially at preheated conditions. PMID- 29628526 TI - The impact of future forest dynamics on climate: interactive effects of changing vegetation and disturbance regimes. AB - Currently, the temperate forest biome cools the earth's climate and dampens anthropogenic climate change. However, climate change will substantially alter forest dynamics in the future, affecting the climate regulation function of forests. Increasing natural disturbances can reduce carbon uptake and evaporative cooling, but at the same time increase the albedo of a landscape. Simultaneous changes in vegetation composition can mitigate disturbance impacts, but also influence climate regulation directly (e.g., via albedo changes). As a result of a number of interactive drivers (changes in climate, vegetation, and disturbance) and their simultaneous effects on climate-relevant processes (carbon exchange, albedo, latent heat flux) the future climate regulation function of forests remains highly uncertain. Here we address these complex interactions to assess the effect of future forest dynamics on the climate system. Our specific objectives were (1) to investigate the long-term interactions between changing vegetation composition and disturbance regimes under climate change, (2) to quantify the response of climate regulation to changes in forest dynamics, and (3) to identify the main drivers of the future influence of forests on the climate system. We investigated these issues using the individual-based forest landscape and disturbance model (iLand). Simulations were run over 200 yr for Kalkalpen National Park (Austria), assuming different future climate projections, and incorporating dynamically responding wind and bark beetle disturbances. To consistently assess the net effect on climate the simulated responses of carbon exchange, albedo, and latent heat flux were expressed as contributions to radiative forcing. We found that climate change increased disturbances (+27.7% over 200 yr) and specifically bark beetle activity during the 21st century. However, negative feedbacks from a simultaneously changing tree species composition (+28.0% broadleaved species) decreased disturbance activity in the long run (-10.1%), mainly by reducing the host trees available for bark beetles. Climate change and the resulting future forest dynamics significantly reduced the climate regulation function of the landscape, increasing radiative forcing by up to +10.2% on average over 200 yr. Overall, radiative forcing was most strongly driven by carbon exchange. We conclude that future changes in forest dynamics can cause amplifying climate feedbacks from temperate forest ecosystems. PMID- 29628527 TI - High Abundances of Presolar Grains and 15N-rich Organic Matter in CO3.0 Chondrite Dominion Range 08006. AB - NanoSIMS C-, N-, and O-isotopic mapping of matrix in CO3.0 chondrite Dominion Range (DOM) 08006 revealed it to have in its matrix the highest abundance of presolar O-rich grains (257 +76/-96 ppm, 2sigma) of any meteorite. It also has a matrix abundance of presolar SiC of 35 (+25/-17, 2sigma) ppm, similar to that seen across primitive chondrite classes. This provides additional support to bulk isotopic and petrologic evidence that DOM 08006 is the most primitive known CO meteorite. Transmission electron microscopy of five presolar silicate grains revealed one to have a composite mineralogy similar to larger amoeboid olivine aggregates and consistent with equilibrium condensation, two non-stoichiometric amorphous grains and two olivine grains, though one is identified as such solely based on its composition. We also found insoluble organic matter (IOM) to be present primarily as sub-micron inclusions with ranges of C- and N-isotopic anomalies similar to those seen in primitive CR chondrites and interplanetary dust particles. In contrast to other primitive extraterrestrial materials, H isotopic imaging showed normal and homogeneous D/H. Most likely, DOM 08006 and other CO chondrites accreted a similar complement of primitive and isotopically anomalous organic matter to that found in other chondrite classes and IDPs, but the very limited amount of thermal metamorphism experienced by DOM 08006 has caused loss of D-rich organic moieties, while not substantially affecting either the molecular carriers of C and N anomalies or most inorganic phases in the meteorite. One C-rich grain that was highly depleted in 13C and 15N was identified; we propose it originated in the Sun's parental molecular cloud. PMID- 29628528 TI - Using Smart City Technology to Make Healthcare Smarter. AB - Smart cities use information and communication technologies (ICT) to scale services include utilities and transportation to a growing population. In this article we discuss how smart city ICT can also improve healthcare effectiveness and lower healthcare cost for smart city residents. We survey current literature and introduce original research to offer an overview of how smart city infrastructure supports strategic healthcare using both mobile and ambient sensors combined with machine learning. Finally, we consider challenges that will be faced as healthcare providers make use of these opportunities. PMID- 29628529 TI - SSC-EKE: Semi-Supervised Classification with Extensive Knowledge Exploitation. AB - We introduce a new, semi-supervised classification method that extensively exploits knowledge. The method has three steps. First, the manifold regularization mechanism, adapted from the Laplacian support vector machine (LapSVM), is adopted to mine the manifold structure embedded in all training data, especially in numerous label-unknown data. Meanwhile, by converting the labels into pairwise constraints, the pairwise constraint regularization formula (PCRF) is designed to compensate for the few but valuable labelled data. Second, by further combining the PCRF with the manifold regularization, the precise manifold and pairwise constraint jointly regularized formula (MPCJRF) is achieved. Third, by incorporating the MPCJRF into the framework of the conventional SVM, our approach, referred to as semi-supervised classification with extensive knowledge exploitation (SSC-EKE), is developed. The significance of our research is fourfold: 1) The MPCJRF is an underlying adjustment, with respect to the pairwise constraints, to the graph Laplacian enlisted for approximating the potential data manifold. This type of adjustment plays the correction role, as an unbiased estimation of the data manifold is difficult to obtain, whereas the pairwise constraints, converted from the given labels, have an overall high confidence level. 2) By transforming the values of the two terms in the MPCJRF such that they have the same range, with a trade-off factor varying within the invariant interval [0, 1), the appropriate impact of the pairwise constraints to the graph Laplacian can be self-adaptively determined. 3) The implication regarding extensive knowledge exploitation is embodied in SSC-EKE. That is, the labelled examples are used not only to control the empirical risk but also to constitute the MPCJRF. Moreover, all data, both labelled and unlabelled, are recruited for the model smoothness and manifold regularization. 4) The complete framework of SSC-EKE organically incorporates multiple theories, such as joint manifold and pairwise constraint-based regularization, smoothness in the reproducing kernel Hilbert space, empirical risk minimization, and spectral methods, which facilitates the preferable classification accuracy as well as the generalizability of SSC-EKE. PMID- 29628531 TI - Assimilation for skin SST in the NASA GEOS atmospheric data assimilation system. AB - The present article describes the sea surface temperature (SST) developments implemented in the Goddard Earth Observing System, Version 5 (GEOS-5) Atmospheric Data Assimilation System (ADAS). These are enhancements that contribute to the development of an atmosphere-ocean coupled data assimilation system using GEOS. In the current quasi-operational GEOS-ADAS, the SST is a boundary condition prescribed based on the OSTIA product, therefore SST and skin SST (Ts) are identical. This work modifies the GEOS-ADAS Ts by modeling and assimilating near sea surface sensitive satellite infrared (IR) observations. The atmosphere-ocean interface layer of the GEOS atmospheric general circulation model (AGCM) is updated to include near surface diurnal warming and cool-skin effects. The GEOS analysis system is also updated to directly assimilate SST-relevant Advanced Very High Resolution Radiometer (AVHRR) radiance observations. Data assimilation experiments designed to evaluate the Ts modification in GEOS-ADAS show improvements in the assimilation of radiance observations that extends beyond the thermal IR bands of AVHRR. In particular, many channels of hyperspectral sensors, such as those of the Atmospheric Infrared Sounder (AIRS), and Infrared Atmospheric Sounding Interferometer (IASI) are also better assimilated. We also obtained improved fit to withheld, in-situ buoy measurement of near-surface SST. Evaluation of forecast skill scores show marginal to neutral benefit from the modified Ts. PMID- 29628530 TI - Jamming transitions in cancer. AB - The traditional picture of tissues, where they are treated as liquids defined by properties such as surface tension or viscosity has been redefined during the last few decades by the more fundamental question: under which conditions do tissues display liquid-like or solid-like behaviour? As a result, basic concepts arising from the treatment of tissues as solid matter, such as cellular jamming and glassy tissues, have shifted into the current focus of biophysical research. Here, we review recent works examining the phase states of tissue with an emphasis on jamming transitions in cancer. When metastasis occurs, cells gain the ability to leave the primary tumour and infiltrate other parts of the body. Recent studies have shown that a linkage between an unjamming transition and tumour progression indeed exists, which could be of importance when designing surgery and treatment approaches for cancer patients. PMID- 29628532 TI - Social Network Implications of Normative School Transitions in Non-Urban School Districts. AB - This article expands research on normative school transitions (NSTs) from elementary to middle school or middle to high school by examining the extent to which they disrupt structures of friendship networks. Social network analysis is used to quantify aspects of connectedness likely relevant to student experiences of social support. Data were drawn from 25 communities followed from sixth to ninth grades. Variability in timing of NSTs permitted multi-level longitudinal models to disentangle developmental effects from transition effects. Results indicated that friendship networks were most interconnected in smaller schools and among older students. Beyond these effects, transitions from a single feeder school to a single higher level school were not associated with changes in friendship patterns. Transitions from multiple feeder schools to a single higher level school were associated with diminished friendship stability, more loosely connected friendship networks, increased social distance between students, and friendship segregation between students who formerly attended different schools. PMID- 29628533 TI - Alone on the Inside: The Impact of Social Isolation and Helping Others on AOD Use and Criminal Activity. AB - Because addiction is a socially isolating disease, social support for recovery is an important element of treatment planning. This study examines the relationship between social isolation, giving and receiving social support in Alcoholics Anonymous during treatment, and post-treatment outcomes among juvenile offenders court-referred to addiction treatment. Adolescents (N = 195) aged 14 to 18 years were prospectively assessed at treatment admission, treatment discharge, 6 months, and 12 months after treatment discharge. The influence of social isolation variables on relapse and severe criminal activity in the 12-months post treatment was examined using negative binomial logistic regressions and event history methods. Juveniles entering treatment with social estrangement were significantly more likely to relapse, be incarcerated, and commit a violent crime in the 12-months post-treatment. Giving help to others in Alcoholics Anonymous during treatment significantly reduced the risk of relapse, incarceration, and violent crime in the 12-months post-treatment whereas receiving help did not. PMID- 29628534 TI - LOWER EXTREMITY MUSCLE FATIGUE INFLUENCES NONLINEAR VARIABILITY IN TRUNK ACCELERATIONS. AB - Lower extremity fatigue has been associated with decline in postural stability, alteration of normal walking patterns and increased fall risk. Effects of lower extremity fatigue on amount of movement variability as assessed by linear variability such as standard deviation and root mean square is well known but there is lack of information about how fatigue influences nonlinear temporal structure of variability in healthy human gait. In this study ten subjects (5 males and 5 females) were asked to perform treadmill walking for three minutes with an Inertial Measurement Unit (IMU) sensor affixed at their trunk level, thereafter the participants conducted squatting exercises and fatigue was induced as per standard fatigue protocol. The participants were asked to walk again on treadmill at their preferred walking speed for three minutes. The signals derived from the inertial sensor were used to compute stride interval time series (SIT) and signal magnitude difference (SMD) time series signals. These SIT and SMD signals were analyzed for non-linear variability such as complexity (approximate entropy and multiscale entropy) and Detrended Fluctuation Analysis (DFA). It was found that that there was significantly higher complexity in SMD signals due to fatigue inducement (p=0.04). Similarly, it was also found that fatigue significantly decreased fractal properties of SMD signals (p=0.013). In conclusion, lower extremity localized muscle fatigue influences magnitude of kinematic variability and induced anti-persistence in the trunk kinematics. In future, more work is needed to understand how kinematic variability in angular velocities due to fatigue may affect fall risk in healthy adults. PMID- 29628536 TI - Count highly-cited papers instead of papers with h citations: use normalized citation counts and compare "like with like"! AB - Teixeira da Silva and Dobranszki (Scientometrics. 10.1007/s11192-018-2680-3, 2018) describe practical problems in using the h-index for the purpose of research evaluation. For example, they discuss the h-index differences among the bibliometric databases. In this Letter to the Editor, we argue for abstaining from using the h-index. One can use normalized indicators instead. PMID- 29628535 TI - TOWARD AN OBJECTIVE METHOD TO CLASSIFY TREMOR DOMINANT AND POSTURAL INSTABILITY AND GAIT DIFFICULTY SUBTYPES OF PARKINSON'S DISEASE: A PILOT STUDY. AB - Discriminating the two subtypes of tremor dominant (TD) and postural instability/gait difficulty (PIGD) in Parkinson's disease (PD) at early stage is highly valuable and crucial for progression treatment of disease for caregivers. However, there is no objective method or a subtype-specific biomarker yet available for identifying these two subtypes. A computational approach in frequency domain could be a good candidate to introduce biomarker since PD tremor had frequency range of 3-7 Hz. By using frequency component of the whole body Center Of Pressure (COP) signal, we propose a ratio between high and low frequency range. To evaluate this ratio, COP data of ten PD patients were utilized. The results suggest that identifying PD subtypes is attainable by using the frequency information of COP signals. PMID- 29628537 TI - Reflections around 'the cautionary use' of the h-index: response to Teixeira da Silva and Dobranszki. AB - In a recent Letter to the Editor Teixeira da Silva and Dobranszki (2018) present a discussion of the issues regarding the h-index as an indicator for the evaluation of individual scholars, particularly in the current landscape of the proliferation of online sources that provide individual level bibliometric indicators. From our point of view, the issues surrounding the h-index go far beyond the problems mentioned by TSD. In this letter we provide some overview of this, mostly by expanding TSD's original argument and discussing more conceptual and global issues related to the indicator, particularly in the outlook of a strong proliferation of online sources providing individual researcher indicators. Our discussion focuses on the h-index and the profusion of sources providing it, but we emphasize that many of our points are of a more general nature, and would be equally relevant for other indicators that reach the same level of popularity as the h-index. PMID- 29628538 TI - Evaluating models for polycaprolactone crystallization via simultaneous rheology and Raman spectroscopy. AB - The crystallization of a polymer melt is characterized by dramatic structural and mechanical changes that significantly impact the processing conditions used to generate industrially-relevant products. Relationships between crystallinity and rheology are necessary to simulate and monitor the effect of processing conditions on the properties of the final product. However, separate measurements of crystallinity and rheology are difficult to correlate due to differences in sample history, geometry, and temperature. Recently, we have developed a rheo Raman microscope for simultaneous rheology, Raman spectroscopy, and polarized reflection-mode optical measurements of soft materials, which allows for quantitative crystallinity measurements through features in the Raman spectrum. In this work, we apply this technique to monitor the isothermal crystallization of polycaprolactone to probe the relationship between structure, crystallinity, and rheology. Both crystallinity and the shear modulus vary over comparable timescales, but the birefringence increases much earlier in the crystallization process. We directly plot rheological parameters as a function of crystallinity to probe a range of suspension-based and empirical models relating the complex modulus to crystallinity, and we find that the previously developed models cannot describe the crystallinity-modulus relationship over the crystallization process. By developing a suspension-based model we can fit the complex modulus over the crystallization range. The crystallization process is characterized by a critical percolation fraction and a single scaling exponent. PMID- 29628539 TI - Variable Selection in Kernel Regression Using Measurement Error Selection Likelihoods. AB - This paper develops a nonparametric shrinkage and selection estimator via the measurement error selection likelihood approach recently proposed by Stefanski, Wu, and White. The Measurement Error Kernel Regression Operator (MEKRO) has the same form as the Nadaraya-Watson kernel estimator, but optimizes a measurement error model selection likelihood to estimate the kernel bandwidths. Much like LASSO or COSSO solution paths, MEKRO results in solution paths depending on a tuning parameter that controls shrinkage and selection via a bound on the harmonic mean of the pseudo-measurement error standard deviations. We use small sample-corrected AIC to select the tuning parameter. Large-sample properties of MEKRO are studied and small-sample properties are explored via Monte Carlo experiments and applications to data. PMID- 29628540 TI - Classifying heatwaves: Developing health-based models to predict high-mortality versus moderate United States heatwaves. AB - Heatwaves are divided between moderate, more common heatwaves and rare "high mortality" heatwaves that have extremely large health effects per day, which we define as heatwaves with a 20% or higher increase in mortality risk. Better projections of the expected frequency of and exposure to these separate types of heatwaves could help communities optimize heat mitigation and response plans and gauge the potential benefits of limiting climate change. Whether a heatwave is high-mortality or moderate could depend on multiple heatwave characteristics, including intensity, length, and timing. We created heatwave classification models using a heatwave training dataset created using recent (1987-2005) health and weather data from 82 large US urban communities. We built twenty potential classification models and used Monte Carlo cross-validations to evaluate these models. We ultimately identified several models that can adequately classify high mortality heatwaves. These models can be used to project future trends in high mortality heatwaves under different scenarios of a changing future (e.g., climate change, population change). Further, these models are novel in the way they allow exploration of different scenarios of adaptation to heat, as they include, as predictive variables, heatwave characteristics that are measured relative to a community's temperature distribution, allowing different adaptation scenarios to be explored by selecting alternative community temperature distributions. The three selected models have been placed on GitHub for use by other researchers, and we use them in a companion paper to project trends in high-mortality heatwaves under different climate, population, and adaptation scenarios. PMID- 29628541 TI - Projected trends in high-mortality heatwaves under different scenarios of climate, population, and adaptation in 82 US communities. AB - Some rare heatwaves have extreme daily mortality impacts; moderate heatwaves have lower daily impacts but occur much more frequently at present and so account for large aggregated impacts. We applied health-based models to project trends in high-mortality heatwaves, including proportion of all heatwaves expected to be high-mortality, using the definition that a high-mortality heatwave increases mortality risk by >=20 %. We projected these trends in 82 US communities in 2061 2080 under two scenarios of climate change (RCP4.5, RCP8.5), two scenarios of population change (SSP3, SSP5), and three scenarios of community adaptation to heat (none, lagged, on-pace) for large- and medium-ensemble versions of the National Center for Atmospheric Research's Community Earth System Model. More high-mortality heatwaves were expected compared to present under all scenarios except on-pace adaptation, and population exposure was expected to increase under all scenarios. At least seven more high-mortality heatwaves were expected in a twenty-year period in the 82 study communities under RCP8.5 than RCP4.5 when assuming no adaptation. However, high-mortality heatwaves were expected to remain <1 % of all heatwaves and heatwave exposure under all scenarios. Projections were most strongly influenced by the adaptation scenario- going from a scenario of on pace to lagged adaptation or from lagged to no adaptation more than doubled the projected number of and exposure to high-mortality heatwaves. Based on our results, fewer high-mortality heatwaves are expected when following RCP4.5 versus RCP8.5 and under higher levels of adaptation, but high-mortality heatwaves are expected to remain a very small proportion of total heatwave exposure. PMID- 29628543 TI - ELECTROMAGNETICALLY INDUCED DISTORTION OF A FIBRIN MATRIX WITH EMBEDDED MICROPARTICLES. AB - Blood clots occur in the human body when they are required to prevent bleeding. In pathological states such as diabetes and sickle cell disease, blood clots can also form undesirably due to hypercoagulable plasma conditions. With the continued effort in developing fibrin therapies for potential life-saving solutions, more mechanical modeling is needed to understand the properties of fibrin structures with inclusions. In this study, a fibrin matrix embedded with magnetic micro particles (MMPs) was subjected to a magnetic field to determine the magnitude of the required force to create plastic deformation within the fibrin clot. Using finite element (FE) analysis, we estimated the magnetic force from an electromagnet at a sample space located approximately 3 cm away from the coil center. This electromagnetic force coupled with gravity was applied on a fibrin mechanical system with MMPs to calculate the stresses and displacements. Using appropriate coil parameters, it was determined that application of a magnetic field of 730 A/m on the fibrin surface was necessary to achieve an electromagnetic force of 36 nN (to engender plastic deformation). PMID- 29628542 TI - Examination of the heterogeneity in PTSD and impulsivity facets: A latent profile analysis. AB - The experience of traumatizing events and resulting posttraumatic stress disorder (PTSD) symptomology relates to a range of impulsive behaviors. While both PTSD and impulsivity are heterogeneous and multidimensional constructs, no research has used person-centered approaches to examine subgroups of individuals based on these response endorsements. Hence, our study examined PTSD-impulsivity typologies and their construct validity in two samples: university students (n = 412) and community participants recruited through Amazon's MTurk (n = 346). Measures included the Stressful Life Events Screening Questionnaire (PTEs), PTSD Checklist for DSM-5 (PTSD severity), UPPS Impulsive Behavior Scale (negative urgency, lack of premeditation, lack of perseverance, sensation seeking). Dimensions of Anger Reaction Scale (anger), and the Patient Health Questionnaire 9 (depression). For both samples, results of latent profile analyses indicated a best-fitting 3-class solution: High, Moderate, and Low PTSD-Negative Urgency. Negative urgency was the most distinguishing impulsivity facet. Anger and depression severity significantly predicted membership in the more severe symptomatology classes. Thus, individuals can be meaningfully categorized into three subgroups based on PTSD and impulsivity item endorsements. We provide some preliminary evidence for a negative urgency subtype of PTSD characterized by greater depression and anger regulation difficulties; and underscore addressing emotional regulation skills for these subgroup members. PMID- 29628545 TI - The Role of Nonpharmacological Methods in Attenuation of Pain Due to Peripheral Venous Cannulation: A Randomized Controlled Study. AB - Background: Establishing an intravenous access is indispensable for safe administration of anesthesia. Most of the times, it is executed without any analgesia although the pain associated with this procedure is quite agonizing to the patients. Aims: This study aims to evaluate the role of 3 different nonpharmacological measures such as Valsalva maneuver, flash of light, and distraction method in attenuation of pain during venous cannulation. Design: A clinical randomized controlled study. Materials and Methods: Two hundred patients of either sex, aged between 18 and 65 years, posted for elective surgery were enrolled in this study. Patients were randomly allocated into four groups, Group C-control, Group V (valsalva) - blew into sphygmomanometer raising the mercury column up to 30 mm of Hg, Group D (distraction) - pressed a rubber ball and Group L (light) - photographed with a flash of light before venous cannulation. During the process of cannulation, patients were observed and questioned, and pain was graded using a 4- point scale. After the cannulation, pain during the procedure was also assessed using visual analog scale (VAS) score. Data analysis was done using SPSS statistical package version 17. Results: A significant reduction in the incidence of pain was noted in distraction group 36% as compared to 44% in Group L, 46% in Group V, and 100% in the control group. The severity of pain as assessed by 4-point score was significantly lowest in Group D (0.26 +/- 0.53) as compared to other three groups (Group V and L = 0.54 +/- 0.16, Group C = 1.64 +/- 0.6, P < 0.001). Mean VAS score was significantly low in Group D (0.6 +/- 1.11) and Group L (0.54 +/- 1.06) as compared to Group V (1.26 +/- 1.76) and Group C (5.0 +/- 1.21, P < 0.001). Conclusion: We conclude that distraction can be considered as a diligent, reasonable, and simple method to attenuate procedural pain during peripheral venous cannulation. PMID- 29628544 TI - Anesthetic Considerations for Carotid Endarterectomy: A Postgraduate Educational Review. AB - Carotid endarterectomy (CEA) has shown a significant benefit in preventing ipsilateral stroke when it is compared to conservative management. Surgical morbidity and mortality must be kept to a minimum to achieve this benefit. Neurological status of the CEA patients can be monitored easily during regional anesthesia depending on the awake testing (neurocognitive assessment) method of the CEA patients. In addition, specific parameters can help us to monitor and to predict the neurological status of the CEA patients during the procedures such as regional cerebral oxygen saturation (rSO2) and middle cerebral artery velocity (MCAv) changes. We conducted a computerized literature search involving humans, published in English until December 2017, and indexed through Medical Databases; MEDLINE/PubMed, EMBASE, and Web of Science. We reviewed articles performed for prospective and other types of studies related to CEA procedures and techniques which can predict patient's status during the procedure. Searching relevant articles and discussing the results to allow meaningful rate comparison, and to conclude a result view which benefits the CEA patients and the medical staff during the CEA procedures. In total, studies observed cerebral rSO2 and MCAv have significant value during CEA procedures. Patients with neurological symptoms during the procedures showed changes of cerebral rSO2 and MCAv more than the patients without neurological symptoms. Mentioned parameters (cerebral rSO2 and MCAv) showed significant increasing right after the procedure. Mostly, CEA surgeries under local anesthesia were observed, for monitoring patients' consciousness status and comparing it to patients who undergo general anesthesia, to view the reliability of these techniques during CEA procedures, and to predict and avoid intraoperative neurological symptoms. PMID- 29628546 TI - Hemodynamic Responses and Safety of Sedation Following Premedication with Dexmedetomidine and Fentanyl during Fiberoptic-assisted Intubation in Patients with Predicted Difficult Airway. AB - Background: Awake fiberoptic intubation (AFOI) is the gold standard for the management of predicted difficult airway, and inappropriate sedation is a major cause leading to its failure. Aims: The primary objective was to compare the heart rate (HR) changes that accompany AFOI following sedation with dexmedetomidine and fentanyl. Secondary objectives included comparison of changes in blood pressure, patient comfort, ease of intubation, and degree of sedation. Settings and Designs: This prospective double-blinded randomized study was conducted in a tertiary care institution. Subjects and Methods: Forty patients with anticipated difficult airway requiring AFOI were included in the study. Group A received dexmedetomidine 1 MUg/kg whereas Group B received fentanyl 2 MUg/kg. After topical anesthesia of the airway, AFOI was performed. Statistical Analysis Used: Fisher's exact test, independent two-sample t-test, and Mann Whitney U-test were used as applicable. Results: The hemodynamic parameters were comparable in both the groups except at 1 min postintubation when fentanyl group had significantly higher HR. There were lower alertness and muscle tone scores in dexmedetomidine group. Total comfort score was significantly higher in fentanyl group. Though more patients in dexmedetomidine group showed that no reaction to intubation and more patients in fentanyl had slight grimacing, the difference was insignificant. The ease of intubation was similar in both the groups. Conclusion: Though dexmedetomidine1 MUg/kg and fentanyl 2 MUg/kg premedication results in comparable hemodynamics and ease of intubation, in view of enhanced patient comfort, dexmedetomidine premedication is advantageous in patients with anticipated difficult airway undergoing AFOI. PMID- 29628547 TI - Ultrasound-guided Combined Fascial Plane Blocks as an Intervention for Pain Management after Laparoscopic Cholecystectomy: A Randomized Control Study. AB - Background: Pain associated with laparoscopic cholecystectomy is most severe during the first 24 h and the port sites are the most painful. Recent multimodal approaches target incisional pain instead of visceral pain which has led to the emergence of abdominal fascial plane blocks. This study embraces a novel combination of two independently effective fascial plane blocks, namely rectus sheath block and subcostal transversus abdominis plane (TAP) block to alleviate postoperative pain. Study Objective: The aim is to evaluate the effectiveness of the combination of rectus sheath block and subcostal TAP block, to compare its efficacy with that of subcostal TAP block alone and with conventional port site infiltration (PSI) in alleviating postoperative pain in patients undergoing laparoscopic cholecystectomy. Methodology: This prospective, randomized control, pilot study included 61 patients scheduled for elective laparoscopic cholecystectomy and distributed among three groups, namely Group 1: Combined subcostal TAP block with rectus sheath block (n = 20); Group 2: Oblique subcostal TAP block alone (n = 21); and Group 3: PSI group as an active control (n = 20). Results: Combined group had significantly lower pain scores, higher satisfaction scores, and reduced rescue analgesia both in early and late postoperative periods than the conventional PSI group. Conclusion: Ultrasound-guided combined fascial plane blocks is a novel intervention in pain management of patients undergoing laparoscopic cholecystectomy and should become the standard of care. PMID- 29628548 TI - Simple Predictor of Minute Ventilation: Holliday-Segar Revisited. AB - Background: Minute ventilation (MV) and calorific requirement (CR) are both functions of metabolic demand. The Holliday-Segar formula is a weight-based tool for predicting CR. This study was performed to derive an equation, based on the Holliday-Segar formula, for calculating resting MV from body-weight (BW), which is applicable for all age groups. Methods: MV for BW (obtained from Radford normogram) was plotted against CR for BW (as per Holliday-Segar formula), for BWs ranging from neonates to adults. From the scatter plot thus obtained, best-fit line, with the origin as intercept, was drawn. Linear regression analysis was used to obtain R2 coefficient and P value. Results: The plot of MV against CR yields a straight line passing through the origin with a slope = 46.87. R2 value is 0.98886, P < 0.001. Conclusion: MV can be easily and reliably estimated for all age groups from the equation: MV (mL/min) = 47 * CR (kcal/h). PMID- 29628549 TI - Comparison of Efficacy of Epidural Ropivacaine versus Bupivacaine for Postoperative Pain Relief in Total Knee Replacement Surgeries. AB - Background: Epidural analgesia has become the standard of care for knee replacement surgeries worldwide. Bupivacaine has been used successfully for many years. Epidural ropivacaine is now being used increasingly and seems to have benefits other than just pain relief, in terms of a better safety profile. Aim: To compare the efficacy of bupivacaine 0.125% (Group B) versus two concentrations of ropivacaine 0.1% (Group R1) and 0.2% (Group R2), in terms of pain scores, requirement of rescue analgesia, related adverse effects, and duration of postoperative (PO) hospital stay. Materials and Methods: A retrospective study was conducted from the acute pain service data of patients who underwent joint replacement surgeries in one or both limbs, over a span of 6 months. Patients were allocated to and analyzed under one of the three groups based on the drug concentration used postoperatively by epidural infusion. Data retrieved were demographic data, daily average visual analog scale (VAS) pain scores, rescue analgesia given, adverse effects, and PO hospital stay days for all three groups. Results: Demographic data were comparable between the three groups. Daily average VAS pain scores on days 1 and 2 were significantly higher in Group R1. Groups B and R2 were comparable. There was significantly more requirement of rescue analgesia in Group R1 on day 1. Day 2 showed no significant difference in rescue analgesic requirement in all three groups. Days of PO hospital stay were significantly higher in Group R1. Adverse effects such as hypotension and delayed motor block were higher in Group B. Conclusion: Ropivacaine 0.2% and bupivacaine 0.125% were equally efficacious in terms of VAS pain scores, rescue analgesic requirement, and duration of PO hospital stay, but ropivacaine had a better safety profile in terms of less hypotension and lesser motor block. PMID- 29628550 TI - Effect of Pregabalin Premedication on Emergence Agitation in Children after Sevoflurane Anesthesia: A Randomized Controlled Study. AB - Background: Emergence agitation (EA) is common in pediatrics after sevoflurane anesthesia. Aims: We intended to study the effect of preoperative pregabalin on EA in pediatrics after sevoflurane anesthesia. Settings and Design: This study design was a prospective randomized controlled double-blinded study. Patients and Methods: Sixty children with American Society of Anesthesiologists physical status Classes I-II, aged 4-10 years, prepared for adenotonsillectomy under sevoflurane anesthesia were randomized to two equal groups (control Group C and pregabalin Group P). Children received either placebo syrup (Group C) or pregabalin syrup 1.5 mg/kg (Group P) 1/2 h preoperatively. We recorded postoperative EA scale (EAS) (10, 20, and 30 min postoperatively), time to open the eye, time to extubate, postanesthesia care unit (PACU) duration of stay, number of paracetamol doses (15 mg/kg) given (to control postoperative pain), and complications as vomiting and dizziness on discharge. Statistical Analysis Used: Independent sample t-test and Chi-square test were used as appropriate. Results: Pregabalin Group P showed less EAS, less analgesic (paracetamol) requirement, and less vomiting with insignificant effects on time to open the eye or extubation and PACU duration of stay compared to control group. Conclusion: Preoperative pregabalin decreased postoperative EAS, analgesic (paracetamol) requirement, and vomiting in pediatrics after adenotonsillectomy using sevoflurane anesthesia without affecting time to open the eye or extubation and PACU duration of stay. PMID- 29628551 TI - Perianal Block: Is It as Good as Spinal Anesthesia for Closed Hemorrhoidectomies? AB - Background and Aims: This study compared if perianal block using ropivacaine and dexmedetomidine was as good as spinal anesthesia (SA) using bupivacaine (heavy) for closed hemorrhoidectomies. Methods: A prospective randomized study was conducted in sixty patients who underwent closed hemorrhoidectomy. Thirty patients of Group A received SA. Thirty patients in Group B received local perianal block. Patients were evaluated for onset of the block, total pain-free period, and time to ambulation. Patient satisfaction in terms of pain during injection and satisfaction with the anesthesia technique was assessed after 2 week telephonically. Data were statistically analyzed using unpaired t-test for the continuous variables and Fischer's exact test for categorical variables. Results: Onset of anesthesia was significantly earlier in Group B, mean (standard deviation [SD]) value being 3.17 (1.28) min as compared to Group A, 6.24 (4.28) min (P = 0.0004). Total pain-free period (mean [SD]) in minute was longer in Group B, 287 (120) min as compared to Group A, 128 (38) min. Time to ambulation was significantly earlier in Group B, 22.83 (29.32) min as compared to Group A 302 (92.41) min. Pain during injection between the two groups was comparable. However, more patients in Group B (60%) were satisfied with the anesthesia technique as compared to Group A (27.5%). Conclusion: Perianal block for hemorrhoidectomy with ropivacaine 0.2% using dexmedetomidine as an adjuvant is an effective and reliable technique which is as effective as SA. It provides prolonged postoperative analgesia and early ambulation. PMID- 29628552 TI - Ultrasonographic Optic Nerve Sheath Diameter as a Surrogate Measure of Raised Intracranial Pressure in Severe Pregnancy-induced Hypertension Patients. AB - Context: It is a well-known fact that severe pregnancy-induced hypertension (PIH) can be disastrous at times as it can cause a lot of complications to both pregnant women and her baby. Hence, it is always desirable to know the extent of severity by a real-time and easily accessible modality like ultrasound. Aims: The aim of the study was to evaluate the incidence of raised intracranial pressure (ICP) in severe preeclampsia and eclampsia patients using ocular ultrasonography with optic nerve sheath diameter (ONSD) measurement. Settings and Design: This study design was a prospective and clinically controlled blinded observational study. Materials and Methods: After taking necessary permissions from the Institution Ethical Committee, 75 patients were enrolled for the study. However, finally, 25 patients in severe preeclampsia and 24 in eclampsia group were compared with 25 normal term antenatal women. Demographic profiles, hemodynamic parameters, laboratory markers for severity of PIH, and ultrasonographic OSND were measured. Statistical Analysis Used: They were statistically analyzed and compared using one-way ANOVA and Tukey's test. Value of P < 0.05 was considered statistically significant. Results: All the three groups were comparable in terms of age, body weight, gestation age, gestity, and the number of primigravida in each group. There was a significant difference (P < 0.05) in mean levels of hepatic aminotransferase levels and platelet counts between groups. Aspartate transaminase and alanine transaminase levels were much higher in Group II and III as compared to Group I, while platelet levels were lower in study groups indicating increase in severity of PIH. There was also a significant difference for systolic blood pressure and diastolic blood pressure (P < 0.001) as both were significantly higher in study groups. Among severe PIH groups (Group II and III), the difference was comparable. Conclusions: OSND is a surrogate marker for raised ICP in severe PIH patients. It is a rapid, bedside, noninvasive, and readily accessible tool and could be a part of a holistic approach for managing such patients. PMID- 29628553 TI - A Comparative Study of Botulinum Toxin: A with Triamcinolone Compared to Triamcinolone alone in the treatment of Osteoarthritis of Knee. AB - Introduction: This study compares the efficacy in terms of pain relief and complications of intra-articular Botulinum toxin-A (BoNT-A) with intra-articular Triamcinolone versus Triamcinolone alone in the treatment of osteoarthritic knee pain of severe grade. If effective, BoNT-A may help in reducing the long term adverse effects due to prolonged analgesic consumption and reduce/delay requirement of knee replacement surgeries. Materials and Methods: In this prospective study, 30 patients of either sex, aged between 40 to 60 years with physical status ASA classes I or II suffering from knee joint osteoarthritis with knee pain and functional impairment were divided into 2 groups: The OA patients which received Botulinum toxin-A with Triamcinolone (Group A) & OA patients which received only Triamcinolone (Group B). Only patients with advanced OA of the knee; radiographically verified with a Joint space <2 mm were included. The efficacy of pain relief in the 2 groups were compared using Visual analog score (VAS) and Oxford knee Score and followed upto 6 months. Results and Conclusions: On comparing the VAS Score during the follow up period, there was a significant difference between groups A and B upto 3 months. During post treatment follow up, there was significant difference in pain relief as measured by the Oxford Knee score from 4 weeks to 6 months, where Group A patients fared much better in terms of pain relief than group B with a highly significant value of P =<0.001 during the time period of 6 weeks to 6 months. The study shows that the use intra articular Botulinum toxin-A with steroid is far superior to intra-articular steroid alone in terms of pain relief as well as functional outcome. PMID- 29628554 TI - Comparison of Ultrasound with Peripheral Nerve Stimulator-guided Technique for Supraclavicular Block in Upper Limb Surgeries: A Randomized Controlled Trial. AB - Background: The supraclavicular approach is considered to be the easiest and most effective approach to block the brachial plexus for upper limb surgeries. The classical approach using the anatomical landmark technique was associated with higher failure rates and complications. Ultrasonography (USG) guidance and peripheral nerve stimulator (PNS) have improved the success rates and safety margin. Aims: The aim of the present study is to compare USG with PNS in supraclavicular brachial plexus block for upper limb surgeries with respect to the onset of motor and sensory blockade, total duration of blockade, procedure time, and complications. Settings and Design: Prospective, randomized controlled study. Subject and Methods: Sixty patients aged above 18 years scheduled for elective upper limb surgery were randomly allocated into two groups. Group A patients received supraclavicular brachial plexus block under ultrasound guidance and in Group B patients, PNS was used. In both groups, local anesthetic mixture consisting of 15 ml of 0.5% bupivacaine and 10 ml of 2% lignocaine with 1:200,000 adrenaline were used. Statistical Analysis: Independent t-test used to compare mean between groups; Chi-square test for categorical variables. Results: The procedure time was shorter with USG (11.57 +/- 2.75 min) compared to PNS (21.73 +/- 4.84). The onset time of sensory block (12.83 +/- 3.64 min vs. 16 +/- 3.57 min) and onset of motor block (23 +/- 4.27 min vs. 27 +/- 3.85 min) were significantly shorter in Group A compared to Group B (P < 0.05). The duration of sensory block was significantly prolonged in Group A (8.00 +/- 0.891 h) compared to Group B (7.25 +/- 1.418 h). None of the patients in either groups developed any complications. Conclusion: The ultrasound-guided supraclavicular brachial plexus block can be done quicker, with a faster onset of sensory and motor block compared to nerve stimulator technique. PMID- 29628555 TI - The Role of Bolus Injection of Saline with Arm Elevation on Rocuronium onset Time: A Randomized Control Study. AB - Background: The onset time of neuromuscular blockade is a crucial time associated with the risk of hypoxia and pulmonary aspiration. Various strategies have been undertaken to shorten this onset time. Therefore, we investigated the effects of bolus of 20 ml saline followed by limb elevation after administration of rocuronium in a dose of 0.6 mg/kg to study the onset time. Methodology: Thirty patients were randomly allocated to the bolus saline group or control group. General anesthesia was induced and maintained with fentanyl and propofol. Rocuronium 0.6 mg/kg intravenous (IV) was administered followed by 20 ml saline bolus and limb elevation in the study group compared to administration of 0.6 mg/kg in a running drip only in the control. Onset of neuromuscular block was assessed by acceleromyography at the adductor pollicis muscle with train-of-four stimulation. Results: The lag time was shorter in bolus group (34 s median) than in control group (45 s median), P < 0.017. The onset time was shorter in bolus group (55 s median) than in control group (110 s median), P < 0.001. The T1 recovery to 25% was longer in bolus group (42 min median) than in control group (39 min median) which was statistically not significant. Conclusion: Rocuronium 0.6 mg/kg IV followed by bolus 20 ml saline and concomitant limb elevation resulted in shorter lag time, faster onset of neuromuscular blockade, good intubating conditions without prolonging clinical duration of action when compared to the control. PMID- 29628556 TI - Comparison of Three Different Concentrations of Levobupivacaine for Epidural Labor Analgesia: Clinical Effect and Pharmacokinetic Profile. AB - Background: The aim is to compare the clinical effect of three different concentrations of levobupivacaine (0.25%, 0.125%, and 0.0625%) on the sensory and motor block characteristics and mode of delivery during epidural labor analgesia. We also studied the pharmacokinetic profile of the three concentrations during labor. Materials and Methods: Sixty pregnant females undergoing normal vaginal delivery under epidural analgesia were divided into three groups according to the concentration of levobupivacaine used. All parturients received an epidural bolus dose of 15 ml of the desired concentration followed by a continuous infusion of the same concentration at 10 mL/h, each combined with fentanyl 2 MUg/mL. Sensory block was assessed by the visual analog score (VAS), whereas motor block was evaluated by the Bromage score. Assessments were performed every 5 min in the first 20 min after initiation of epidural analgesia and then at 30 min interval. The incidence of instrumental delivery and cesarean section was also recorded. The total plasma concentrations of levobupivacaine were determined before the start of epidural analgesia, 5 and 10 min after starting the infusion, at infusion stop time, and 3-8 h after infusion termination. Results: The VAS was significantly lower with levobupivacaine concentrations of 0.25% and 0.125% than 0.0625%. Motor block in the form of Bromage score 1 was observed in 39% of parturients receiving levobupivacaine 0.25% of which 43% were converted to cesarean delivery. No motor block was observed with the other two concentrations. Levobupivacaine peak plasma concentrations increased with increasing the concentration of the local anesthetic. There was no difference in other pharmacokinetic parameters between the three groups. Conclusion: levobupivacaine concentration of 0.125% is superior to other concentrations for epidural labor analgesia as it provides adequate analgesia without motor affection which reflects in a lower incidence of instrumental delivery or cesarean section. PMID- 29628557 TI - Intraocular Pressure Changes during Laparoscopic Surgery in Trendelenburg Position in Patients Anesthetized with Propofol-based Total Intravenous Anesthesia Compared to Sevoflurane Anesthesia: A Comparative Study. AB - Background: Intraocular pressure (IOP) is increased during laparoscopic surgery with Trendelenburg position and may contribute to deleterious effects on optic nerve in susceptible patients. Aims: The primary objective of this study is to compare the effects of propofol-based total intravenous anesthesia (TIVA) with those of sevoflurane anesthesia on IOP in patients undergoing lower abdominal laparoscopic surgery in Trendelenburg position. Secondary objectives are to compare hemodynamic changes, mean arterial pressure (MAP), end-tidal CO2, and peak inspiratory pressure changes. Materials and Methods: Sixty patients with physical status American Society of Anesthesiologists classes I and II were randomly allocated in two groups: Group A (propofol) and Group B (sevoflurane). IOP along with other parameters was measured at seven points including baseline (T0), 5 min after induction (T1), 5 min after CO2 pneumoperitoneum in supine position (T2), 30 min after CO2 pneumoperitoneum with Trendelenburg position (T3), 5 min after returning to supine position (T4), 5 min after CO2 desufflation (T5), and 5 min after extubation (T6). Results: The change in IOP was different between the two groups. Maximum rise in IOP was seen at T3, and mean +/- standard deviation IOP was 15.5 +/- 0.9 mmHg and 19.8 +/- 1.2 mmHg in Group A and Group B, respectively (P < 0.01). In Group A (propofol), IOP remained almost equal to the baseline value at T3 and the IOP difference was 0.3 +/- 0.9 mmHg less than baseline (statistically insignificant, P > 0.05), while in Group B (sevoflurane), IOP increased significantly at T3 and the difference was 4.0 +/- 1.2 mmHg (P < 0.001). The IOP was significantly greater (P < 0.01) from T2 to T6 in sevoflurane group than propofol group. Conclusion: Propofol-based TIVA is more effective than inhalational anesthesia with sevoflurane in attenuating the increase in IOP during laparoscopic surgery requiring CO2 pneumoperitoneum with Trendelenburg position. PMID- 29628558 TI - Comparison of Inhalational Vital Capacity Induction with Sevoflurane to Intravenous Induction with Propofol for Insertion of Laryngeal Mask Airway in Adults: A Randomized Study. AB - Background: Since the development of laryngeal mask airway (LMA) by Dr. Brain, it is extensively used for airway management; satisfactory insertion of LMA requires administration of an induction agent and suppression of airway reflexes. Among intravenous agents, propofol has been the drug of choice in view of better safety profile, relaxation and depression of upper airway reflexes. Sevoflurane on the other hand, with pleasant odor, nonirritating to the airways and with bronchodilator property are best among the volatile induction agents. While it is true both propofol and sevoflurane have their merits, still both have certain limitations. We aimed to compare the quality and ease of LMA insertion, hemodynamic changes, and complications with inhalation of 8% sevoflurane vital capacity breath and propofol. Materials and Methods: A prospective randomized study of 100 American Society of Anaesthesiologists' Class I and II patients was conducted equal distribution among two groups with 50 each undergoing gynecological procedures under general anesthesia. Group P received injection propofol and Group S received sevoflurane. At the end point of induction, the LMA insertion was attempted. Scoring systems were used to grade the conditions for insertion of the LMA. Induction characteristics, hemodynamic changes, and complications were assessed. Results: Sevoflurane took a longer time for induction and jaw relaxation than propofol. There was no statistically significant difference between the two groups, with respect to LMA insertion time, and conditions. Apnea time was more in propofol group. Fall in heart rate and mean blood pressure was more in propofol. Conclusion: Propofol is associated with faster induction while sevoflurane is associated with good hemodynamic stability. PMID- 29628560 TI - Effect of Esmolol and Diltiazem Infusions on Hemodynamic Response to Pneumoperitoneum on Laparoscopic Simple Nephrectomy: A Randomized Controlled Trial. AB - Background: Several studies have been conducted in search of appropriate drugs to attenuate hemodynamic responses in laparoscopic cholecystectomy, but till date, no such study has been conducted on patients undergoing laparoscopic nephrectomy. Aim: The study was designed to assess the effect of esmolol and diltiazem infusions on hemodynamic changes during routine laparoscopic transperitoneal simple nephrectomy. Settings and Design: A prospective double-blinded randomized control trial. Subjects and Methods: A total of 120 nonhypertensive patients of the American Society of Anesthesiologists physical Status I and II aged 20-60 years about to undergo laparoscopic nephrectomy were enrolled for the study after obtaining Institute Ethical committee approval. The patients were randomly allocated to one of the three groups. Group I (control group) received 10 ml normal saline intravenously (i.v.) before induction of anesthesia, followed by continuous infusion 10-20 ml/h. Group II (esmolol group) received i.v. esmolol 1 mg/kg diluted in 10 ml similarly, followed by continuous infusion of 10-20 ml/h (5-10 MUg/kg/min). Group III (diltiazem group) received i.v. diltiazem 0.2 mg/kg diluted in 10 ml before induction of anesthesia, followed by continuous infusion at 10-20 ml/h (0.08-1.25) MUg/kg/min. After completion of surgery, all the infusions were stopped. Data recording were done for changes in hemodynamics throughout the surgery. Statistical Analysis: was done using Chi-square test for categorical data and one-way ANOVA for continuous data. Tukey ("honestly significant difference") post hoc test was applied for intra- and inter-group comparison in cases where ANOVA was significant. P < 0.05 is considered statistically significant. Results: All hemodynamic data: Heart rate (HR), systolic, diastolic, and mean arterial pressure were observed to be significantly higher (P < 0.001) from baseline in control group at the time of creation of pneumoperitoneum, till 20 min thereafter. The values were comparable to baseline in both esmolol and diltiazem group. On intergroup comparison, the patients in esmolol group had significantly lower HR and blood pressures than in diltiazem group at the creation of pneumoperitoneum and at extubation (P < 0.05). Mean dose of esmolol and diltiazem used were 7.25 +/- 1.33 MUg/kg/min and 1.14 +/- 0.77 MUg/kg/min, respectively. Conclusion: Both esmolol and diltiazem infusion provide stable intraoperative hemodynamics and protection against stress response triggered by pneumoperitoneum in patients undergoing laparoscopic transperitoneal nephrectomy. PMID- 29628559 TI - Comparison of Postoperative Analgesic Efficacy of Wound Site Infiltration and Ultrasound-guided Transversus Abdominis Plane Block with 0.5% Ropivacaine in Lower Abdominal Surgeries under Spinal Anesthesia. AB - Context: Optimization and providing excellent quality of postoperative analgesia after total abdominal hysterectomy is a determinant factor of better clinical outcome, increases patient satisfaction, and allows early mobilization of the patient. Aims: The aim of this study is to compare the postoperative analgesic efficacy of wound site infiltration (WSI) and ultrasound-guided transversus abdominis plane block (TAPB) with 0.5% ropivacaine in lower abdominal surgeries under spinal anesthesia. Settings and Design: This was a randomized controlled study. Subjects and Methods: One hundred and ten patients undergoing lower abdominal surgeries were randomly allocated to two groups (WSI and TAP) of 55 patients in each. At the end of the surgical procedure, 2.5 mg/kg of the drug ropivacaine 0.5% was administered by an anesthesiologist through either of the routes of study. Visual analog score (VAS) assessment was done at every 30 min, for 11/2 h, every 2 for 24 h postoperatively. Injection diclofenac sodium 75 mg intramuscularly was given whenever VAS was >3 as rescue analgesic. Statistical Analysis Used: Epi Info 7.0 version software for Windows was used. All analyses were performed using Kolmogorov-Smirnov test. Mann-Whitney test was applied to detect the difference between the two groups. P < 0.05 was considered statistically significant. Results: Postoperative VAS scores in Group TAP were significantly reduced at 30 min, 1st h, 1 h 30 min, 2, 4, 6, 8, 10, 12, 18, and 24 h (P < 0.001). The total doses of rescue analgesics administered were also low in the Group TAP (1.41 +/- 0.538) with P < 0.0001 in comparison to Group WSI (2.24 +/- 0.637) with P < 0.001. Conclusions: The quality of analgesia along with lesser rescue analgesic requirement and their side effects makes the TAPB, a good and safer option for lower abdominal gynecological surgeries. Both WSI and USG TAPB are effective in providing postoperative analgesia as a part of multimodal analgesia in lower abdominal surgeries. However, in our study the quality of analgesia along with lesser rescue analgesic requirement and their side effects makes the TAPB, a good and safer option for lower abdominal gynecological surgeries. PMID- 29628561 TI - Norepinephrine versus Ephedrine to Maintain Arterial Blood Pressure during Spinal Anesthesia for Cesarean Delivery: A Prospective Double-blinded Trial. AB - Background: Ephedrine was conventionally regarded as the first-choice drug to maintain maternal blood pressure during spinal anesthesia for cesarean delivery, due to its stimulant activity on alpha- and beta-adrenergic receptors. Norepinephrine is a weak beta-adrenergic and potent alpha-adrenergic receptor agonist. Therefore, it may be suitable for maintaining blood pressure with less chronotropic effects compared to ephedrine. Patients and Methods: One hundred and forty healthy patients having cesarean delivery under spinal anesthesia were randomized to Group N (n = 61) who received a prophylactic bolus of norepinephrine 5 MUg intravenous (i.v.) at the time of intrathecal block or Group E (n = 61) who received a prophylactic bolus of i.v. ephedrine 10 mg. Rescue i.v. bolus interventions of norepinephrine 5 MUg or ephedrine 10 mg were given as required to maintain systolic blood pressure. Maternal and fetal hemodynamic variables, Apgar score, and number of boluses of vasopressors used were recorded. Results: The numbers of maternal hypotension and hypertension episodes and the frequency of bradycardia and tachycardia were significantly lower in Group N compared with Group E (P = 0.02, 0.003, 0.0002, and 0.008, respectively). The number of boluses of vasopressors used was also lower in Group N (P = 0.005). Uterine artery pulsatility index was lower in Group N compared to Group E (P = 0.01) when measured 5 min after spinal anesthesia. Moreover, it was higher at 5 min in Group E when compared with the baseline readings in the same group (P = 0.001). Conclusions: Norepinephrine is a suitable and potent drug to counterbalance the hemodynamic effects of spinal anesthesia during cesarean delivery. PMID- 29628563 TI - Postoperative Analgesia with Epidural Dexmedetomidine Compared with Clonidine following Total Abdominal Hysterectomies: A Prospective Double-blind Randomized Trial. AB - Background and Aims: Anesthesia for total abdominal hysterectomies is not only concerned with relieving pain during intraoperative period but also during the postoperative period. We compared clonidine and dexmedetomidine as an adjuvant to levobupivacaine for epidural analgesia with respect to onset and duration of sensory block, duration of analgesia, and adverse effects. Materials and Methods: A total of 80 individuals between the age of 45 and 65 years of American Society of Anesthesiologists (ASA) physical status Classes I and II who underwent total abdominal hysterectomies were randomly allocated into two groups, comprising 40 patients in each group. Group LC received 10 ml of 0.125% levobupivacaine and 2 MUg/kg of clonidine while Group LD received 10 ml of 0.125% levobupivacaine and 1 MUg/kg of dexmedetomidine through the epidural catheter. Onset of analgesia, time of peak effect, duration of analgesia, cardiorespiratory parameters, side effects, and need of rescue intravenous (IV) analgesics were observed. The data analysis was carried out with Z-test and Chi-square test. Results: The demographic profile and ASA physical classes were comparable between the groups. Group LD had early onset, early peak effect, prolonged duration, and stable cardiorespiratory parameters when compared with Group LC. Less number of patients (42.5%) in Group LD required IV rescue analgesics when compared to Group LC (70%) and was statistically significant. The side effects' profile was also comparable. Conclusion: Dexmedetomidine is a better neuraxial adjuvant compared with clonidine for providing early onset and prolonged postoperative analgesia and stable cardiorespiratory parameters. PMID- 29628562 TI - Comparative Study between Propofol and Dexmedetomidine for Conscious Sedation in Patients Undergoing Outpatient Colonoscopy. AB - Introduction: Colonoscopy is a mildly painful procedure requiring conscious sedation. Though propofol is a widely used anesthetic agent in day-care procedures due to its rapid onset and quick recovery has a drawback of requiring resuscitation maneuvers more often than the conventional methods. Dexmedetomidine, a newly introduced, highly selective alpha2-adrenergic receptor agonist possessing hypnotic, sedative, anxiolytic, sympatholytic, and analgesic properties with impressive safety margin, needs to be explored for use in conscious sedation for colonoscopy procedure among South Indian population. Materials and Methods: A prospective randomized comparative study was conducted on patients aged between 25 and 60 years with the American Society of Anesthesiologist physical status classes I and II posted for colonoscopy under monitored anesthesia care. Study group was randomly divided into two groups and administered propofol and dexmedetomidine. The primary outcome variable was assessments of sedation scores between the two groups. Secondary outcome variables were pain score assessments, hemodynamic comparisons, and adverse events among the two groups. Appropriate statistical tests were applied to compare the findings. Results: After comparisons between the two groups, we found that patients on dexmedetomidine had similar sedation score as that of patients on propofol. However, there was a significantly higher incidence of systemic hypotension. Requirement of rescue analgesia and adverse events and other hemodynamic fluctuation were similar in both the groups. Conclusion: We conclude that dexmedetomidine has similar efficacy as propofol for conscious sedation required during colonoscopy. Occurrence of systolic hypotension was, however, significantly more among the group receiving dexmedetomidine. PMID- 29628564 TI - Comparison of Magnesium Sulfate and Dexmedetomidine as an Adjuvant to 0.5% Ropivacaine in Infraclavicular Brachial Plexus Block. AB - Background: Magnesium sulfate and dexmedetomidine were used as adjuvants to local anesthesia to improve the quality of regional anesthesia. Aims: The aim of this study is to evaluate and compare the effects of magnesium sulfate and dexmedetomidine when added to ropivacaine on the quality of infraclavicular brachial plexus block (BPB). Settings and Design: This was a prospective randomized double-blinded controlled study. Patients and Methods: A total of 105 adult patients undergoing surgery in hands, wrist, and forearm using infraclavicular BPB were randomly assigned into three groups. Ultrasound-guided infraclavicular BPB was performed using 35 ml ropivacaine 0.5% diluted with 4 ml normal saline 0.9%. Magnesium sulfate 150 mg and dexmedetomidine 100 MUg were added in the magnesium sulfate group and dexmedetomidine group, respectively. Duration of analgesia, onset times and durations of sensory block (SB) and motor block (MB), patient's satisfaction, and complications were recorded. Statistical Analysis: Statistical software SPSS 16 was used for statistical analysis. Results: Dexmedetomidine and magnesium sulfate provided longer duration of analgesia and lesser consumption of postoperative rescue analgesia than the control group (P = 0. 000); dexmedetomidine provided the longest duration of analgesia versus control and magnesium sulfate groups (P = 0.000). Dexmedetomidine provided the quickest onset times and the longest durations of both SB and MB than control and magnesium sulfate groups (P = 0.000). Dexmedetomidine group had higher incidences of bradycardia and hypotension. Conclusions: Magnesium sulfate or dexmedetomidine is a useful adjuvant to ropivacaine for infraclavicular BPB in lengthening the duration of analgesia. Dexmedetomidine provided quicker onset and longer duration of both SB and MB and longer duration of analgesia with lesser consumption of postoperative rescue analgesia; however, it showed a higher incidence of intraoperative hypotension and bradycardia than magnesium sulfate. PMID- 29628565 TI - Postoperative Cognitive Dysfunction in Indian Patients Undergoing Total Knee Replacement Under Spinal Anesthesia. AB - Introduction: Total knee replacement is a common surgical procedure in the elderly. The number of surgeries has increased owing to the increasing life expectancy of the population and better functional outcomes postsurgery. Postoperative cognitive dysfunction (POCD) is an identified entity postsurgery in elderly but most of the studies have been on patients undergoing cardiac and other nonorthopaedic surgeries. The studies have shown variable incidence due to selection bias. We studied the incidence and probable predictive factors of POCD in elderly Indian population undergoing total knee replacement under spinal anesthesia. Materials and Methods: We designed a prospective, observational study at a single center including patients above 60 years of age undergoing total knee replacement under spinal anesthesia. Preoperative mini-mental scale examination, electrolytes, urea and creatinine levels were recorded. Postoperatively, mini mental scale evaluation (MMSE) was done 2 days postsurgery, at 3 months, 6 months, and 1 year follow-up. Laboratory values postoperatively were recorded. Results: The average preoperative MMSE was 27 and declined to 25.4 on second postoperative day the value increased to 25.9, 26.6, and 27 at 3 months, 6 months, and 1-year follow-up, respectively. Sixty-three out of 600 patients developed POCD at second postoperative day. Forty-three patients showed recovery in subsequent visits and 20 patients had persistent dysfunction at the end of 1 year. Electrolyte imbalance, oxygen saturation, and age over 80 years were factors that showed statistically significant difference in multiple comparison analysis. Conclusion: In our study, we have found POCD to be a definitive entity which can cause short- and long-term cognitive defect in elderly Indian population undergoing total knee replacement and electrolyte imbalance, age, and oxygen saturation were the significant factors in the patients who developed POCD. PMID- 29628566 TI - Comparison of the Laryngeal Mask Airways: Laryngeal Mask Airway-classic and Laryngeal Mask Airway-proseal in Children. AB - Introduction: In the past 25 years with the development of various supraglottic airway devices, the armamentarium for airway management has increased. In our study, the laryngeal mask airway (LMA)-ProSeal is compared with the LMA-Classic with respect to as follows: (a) Ease of insertion and number of insertion attempts, (b) Device positional stability and possible oropharyngeal leak, (c) Airway trauma, and (d) Hemodynamic changes; in children aged 3-15 years undergoing elective surgery under general anesthesia, hypothesizing that these would be different. Materials and Methods: Sixty consecutive American Society of Anesthesiologists Physical Status Classes I and II children aged 3-15 years and weighing 5-45 kg undergoing elective surgery in the supine position were randomized for airway management with the LMA-Classic or LMA-ProSeal. Results: Size of the LMA used in both LMA-Classic and LMA-ProSeal was 1.5, 2, and 2.5 and was statistically nonsignificant. There was no difference between LMA-Classic and LMA-ProSeal with regard to ease of insertion, number of attempts for insertion, device positional stability, airway trauma and hemodynamic changes. Conclusions: The complications of usage of the LMA are minimal and similar in both the devices. The LMA-ProSeal has advantages over LMA-classic such as the placement of gastric tube, adequate ventilation, and oxygenation without any gastric distension. PMID- 29628567 TI - Comparison of Upper Lip Bite Test and Ratio of Height to Thyromental Distance with Other Airway Assessment Tests for Predicting Difficult Endotracheal Intubation. AB - Background and Aims: Unanticipated difficult intubation or the failed intubation in operating room and in emergency department is an imperative source of anesthesia-related patient's mortality. The aim of this study is to compare the predictive value of upper lip bite test (ULBT) and ratio of height to thyromental distance (RHTMD) with other commonly used preoperative airway assessment tests for predicting difficult intubation in Indian population. Materials and Methods: In this prospective, single-blinded observational study, 260 adult patients of either sex, belonging to American Society of Anesthesiologists physical Status I and II undergoing elective surgical procedure under general anesthesia were included in the study. ULBT, RHTMD, inter-incisor gap, modified Mallampati grade, horizontal length of the mandible, head and neck movements, sternomental distance, and TMD were assessed preoperatively and correlated with Cormack and Lehane's grading during laryngoscopy under anesthesia. Statistical analysis was done by Chi-square and Fisher's exact test. Results: ULBT and RHTMD had highest sensitivity (66.7% and 63.3%), specificity (99.1% and 89.6%), positive predictive value (90.9% and 44.2%), and negative predictive value (96.9% and 95.0%), respectively, when compared to other parameters in predicting difficult airway. Conclusion: ULBT and RHTMD may be used as a simple bedside airway assessment tools for prediction of difficult intubation. PMID- 29628568 TI - Comparison of Prophylactic Intravenous Magnesium Sulfate with Tramadol for Postspinal Shivering in Elective Cesarean Section: A Placebo Controlled Randomized Double-blind Pilot Study. AB - Background and Aims: Cesarean sections are performed mostly under spinal anesthesia. Shivering is one of the distressing complications. The aim of the study was to compare the efficacy of intravenous (i.v) magnesium sulfate and tramadol with placebo (normal saline) on postspinal shivering in elective cesarean section when used as prophylaxis. Methods: One hundred and thirty-five pregnant women between 18 and 35 years age, belonging to the American Society of Anesthesiologists' physical Status II, undergoing elective cesarean section under spinal anesthesia were enrolled into the study. Patients belonging to Group C (control group, n = 45) received isotonic saline 100 mL i.v, Group T (tramadol group, n = 45) received tramadol 0.5 mg/kg in 100 mL isotonic saline i.v, whereas those in Group M (magnesium sulfate group, n = 45) received magnesium sulfate 30 mg/kg in 100 mL isotonic saline i.v after administering spinal anesthesia. Incidence and grades of shivering were noted. Data were analyzed using one-way ANOVA test and Chi-square test. Results: The incidence of shivering in Group C, Group T, and Group M were 67.5%, 43.9%, and 39%, respectively. The incidence of shivering in Group M and Group T was significantly low when compared to Group C (P = 0.008; P = 0.026), whereas there was no statistically significant difference between Groups T and M (P = 0.654). Conclusion: Magnesium sulfate and tramadol significantly reduce the incidence of shivering compared to placebo when used as prophylaxis in pregnant women undergoing cesarean section under spinal anesthesia. Magnesium sulfate reduces the severity of the shivering. PMID- 29628569 TI - Supraclavicular Brachial Plexus Block: Comparison of Varying Doses of Nalbuphine Combined with Levobupivacaine: A Prospective, Double-blind, Randomized Trial. AB - Background and Aims: The ideal dose of nalbuphine for brachial plexus block (BPB) is a matter of debate. This study was carried out to evaluate 5 mg or 10 mg of nalbuphine added to 0.375% levobupivacaine, with regard to the duration of analgesia. Our study also sought to assess the onset and duration of sensorimotor blockade, hemodynamic effects, sedation, and adverse effects. Materials and Methods: One hundred adult patients undergoing upper-limb surgeries under supraclavicular BPB were randomly allocated into two groups. Group LN5 received 29 ml of 0.375% levobupivacaine plus 5 mg of nalbuphine diluted in 1 ml of normal saline. Group LN10 received 29 ml of 0.375% levobupivacaine plus 10 mg of nalbuphine diluted in 1 ml of normal saline. Onset and duration of sensorimotor blockade, hemodynamic variables, duration of analgesia, and adverse effects were recorded. The data were analyzed with Students t-test and Chi-square test. Results: Onset of sensory block and motor block was 10.57 +/- 3.5 and 17.16 +/- 1.3 min, respectively, in Group LN5, while it was 8.64 +/- 1.7 and 14.3 +/- 1.2 min, respectively, in Group LN10. The duration of analgesia was significantly prolonged in Group LN10 compared to Group LN5 (833.55 +/- 141.6 vs. 698.44 +/- 138.6 min; P = 0.001). Postoperative visual analog scale value at 24 h was significantly lower in Group LN10 (P < 0.05). Conclusion: A higher dose of nalbuphine in BPB hastens the onset, and prolongs the duration of sensorimotor blockade and analgesia, without any significant side effects. PMID- 29628570 TI - Effect of C-MAC Video Laryngoscope-aided intubations Using D-Blade on Incidence and Severity of Postoperative Sore Throat. AB - Background: Video laryngoscope-aided intubations require less force to align oral, pharyngeal, and laryngeal planes to visualize the glottis opening during intubation. Aim: The primary objective of the study was to assess the incidence and severity of postoperative sore throat (POST) in patients who were intubated with C-MAC video laryngoscope using D-blade versus traditional Macintosh laryngoscope. Settings and Design: This prospective, randomized, open label study was conducted in a tertiary care institution. Subjects and Methods: A total of 130 patients undergoing short elective laparoscopic surgeries lasting <2 h were recruited. All patients received general anesthesia as per a standardized protocol. Laryngoscopy was performed using traditional Macintosh laryngoscope in Group M and with Storz(r) C-MAC video laryngoscope using D-Blade in Group V. The endotracheal tube cuff pressure was maintained at 20-22 cm of H2O intraoperatively. Statistical Analysis Used: Pearson's Chi-square test, Fisher's exact test, and Independent sample t-test were used in this study. Results: As compared to Group M, number of patients who had POST, hoarseness of voice, and cough was significantly low in Group V at 2, 6, 12, and 24 h. Severity, as well as the incidence of all these symptoms, showed a downward trend in both groups with time. Significantly more number of patients in Group M required rescue therapy for POST (44.6% as compared to 7.7%, P < 0.001). Conclusion: C-MAC video laryngoscope-aided intubations using D-blade significantly reduced the incidence and severity of POST, hoarseness of voice, and cough following orotracheal intubation as compared to use of traditional Macintosh laryngoscope. PMID- 29628571 TI - Epidural Volume Extension with Saline in Combined Spinal-Epidural Anesthesia for Hip Surgeries Using Low Dose of Intrathecal Hyperbaric Bupivacaine. AB - Background and Aims: The aim of the study was to evaluate the effectiveness of epidural volume extension (EVE) technique in terms of sensory and motor block characteristics along with hemodynamic parameters as a part of combined spinal epidural anesthesia (CSEA). Materials and Methods: A total of 60 patients undergoing hip surgeries were assigned to one of the two groups containing 30 patients each. Group I (the CSE-EVE group) patients were anesthetized using CSE with EVE and Group II (the CSE group) patients were anesthetized using CSE without EVE, using the same technique and low dose of intrathecal hyperbaric bupivacaine. Sensory block characteristics were recorded using pinprick method, whereas motor blockade was assessed by modified Bromage scale. Results: There was a statistically significant difference between the two groups regarding the level of maximum sensory block (P < 0.001), as Group I showed sensory block level extending to up to T4, whereas in Group II, it was limited to below T6. Time required for maximum sensory blockade was faster in Group I, ranging from 7 to 12 min (mean +/- standard deviation [SD]: 9.83 +/- 1.72), whereas in Group II, it ranged from 9 to 15 min (mean +/- SD: 12.33 +/- 1.83; P < 0.001). Two-segment regression was faster in Group II, ranging from 50 to 70 min (mean +/- SD: 60.0 +/- 6.30), whereas in Group I, it ranged from 80 to 105 min (mean +/- SD: 89.67 +/- 8.19; P < 0.001). The time required to reach the maximum motor block was faster in Group I, ranging from 2 to 4 min (mean +/- SD: 2.67 +/- 0.84), whereas in Group II, the time ranged from 2 to 6 min (mean +/- SD: 3.50 +/- 1.31; P < 0.001). Conclusion: CSEA with EVE is associated with early onset of sensory and motor blockade, high level of sensory block, and longer time of two-segment regression while maintaining hemodynamic stability due to decreased dose of intrathecal local anesthetic. PMID- 29628572 TI - Impact of Targeted Preoperative Optimization on Clinical Outcome in Emergency Abdominal Surgeries: A Prospective Randomized Trial. AB - Background: Perforation peritonitis continues to be one of the most common surgical emergencies that need a surgical intervention most of the times. Anesthesiologists are invariably involved in managing such cases efficiently in perioperative period. Aims: The assessment and evaluation of Acute Physiology and Chronic Health Evaluation II (APACHE II) score at presentation and 24 h after goal-directed optimization, administration of empirical broad-spectrum antibiotics, and definitive source control postoperatively. Outcome assessment in terms of duration of hospital stay and mortality in with or without optimization was also measured. Settings/Design: It is a prospective, randomized, double-blind controlled study in hospital setting. Materials and Methods: One hundred and one patients aged >=18 years, of the American Society of Anesthesiologists physical Status I and II (E) with clinical diagnosis of perforation peritonitis posted for surgery were enrolled. Enrolled patients were randomly divided into two groups. Group A is optimized by goal-directed optimization protocol in the preoperative holding room by anesthesiology residents whereas in Group S, managed by surgery residents in the surgical wards without any fixed algorithm. The assessment of APACHE II score was done as a first step on admission and 24 h postoperatively. Duration of hospital stay and mortality in both the groups were also measured and compared. Statistical Analysis: Categorical data are presented as frequency counts (percent) and compared using the Chi-square or Fisher's exact test. The statistical significance for categorical variables was determined by Chi-square analysis. For continuous variables, a two-sample t-test was applied. Results: The mean APACHE II score on admission in case and control groups was comparable. Significant lowering of serial scores in case group was observed as compared to control group (P = 0.02). There was a significant lowering of mean duration of hospital stay seen in case group (9.8 +/- 1.7 days) as compared to control group (P = 0.007). Furthermore, a significant decline in death rate was noted in case group as compared to control group (P = 0.03). Conclusion: Goal-directed optimized patients with perforation peritonitis were discharged early as compared to control group with significantly lesser mortality as compared with randomly optimized patients in the perioperative period. PMID- 29628573 TI - Does Restrictive Fluid Strategy during Robotic Pelvic Surgeries Obtund Intraoperative Rise in Intraocular Pressure? AB - Background: Robotic pelvic surgeries require steep Trendelenburg position which may result in rise in intraocular pressure (IOP). Aim: The aim of this study was to compare the changes that occur in IOP during robotic pelvic surgeries in steep Trendelenburg position with a restrictive intravenous fluid administration. Settings and Design: This prospective observational study was conducted in a tertiary care institution. Subjects and Methods: Twenty consenting patients scheduled for pelvic robotic gynecological surgeries were enrolled. All patients received general anesthesia following a standardized protocol. IOP was measured before induction of anesthesia, immediately after induction and intubation, at the end of surgery immediately after making the patient supine and immediately after extubation. Ringer's lactate was administered intravenously at a rate of 4 mL/kg/h targeting a mean arterial pressure of >65 mmHg and urine output of >0.5 mL/kg/h. Statistical Analysis Used: Paired t-test was used in this study. Results: There was a fall in IOP soon after induction from baseline which was not significant. Immediately, following intubation, there was a significant rise in IOP. At the end of surgery, though IOP remained high, it was not statistically significant. However, following extubation, IOP rose further and the difference from the baseline became statistically significant. Although there was a moderate increase in peak airway pressure and highest EtCO2 levels during Trendelenburg from baseline values, the differences were statistically insignificant. Conclusion: During robotic pelvic surgeries, adopting a restrictive intravenous fluid strategy with the maintenance of normal end-tidal carbon dioxide levels could abate effects of steep Trendelenburg position on IOP. PMID- 29628574 TI - Effects of Intravenous and Inhaled Nebulized Lignocaine on the Hemodynamic Response of Endotracheal Intubation Patients: A Randomized Clinical Trial. AB - Background: Endotracheal intubation is one of the most common measures in the Intensive Care Unit (ICU) which plays an important role in airway management of the critically ill patients. Aims: The study aimed to evaluate the effects of lignocaine spray on hemodynamic response of endotracheal intubation patients. Settings and Design: This study is a randomized clinical trial on a study population comprising patients admitted to the ICU. Subjects and Methods: The patients were divided into three groups using a permuted block randomization. In Group 1, inhaled nebulized lignocaine 4% (75.0 mg/kg) was sprayed around the patients' epiglottis and larynx. In Group 2, intravenous (IV) lignocaine 2% (75.0/mg/kg) was injected. No lignocaine was prescribed for or administered to the control group. One and four minutes after intubation, the patients' hemodynamic and vital signs were measured. Statistical Analysis Used: Data analysis was run using Stata 13 software through repeated measure ANOVA tests. Results: Although the mean arterial blood pressure (MAP) of Group 1 (inhaled nebulized lignocaine) was smaller than that of Group 2 (IV lignocaine), there was no significant difference between the two groups. Both groups' MAPs were significantly different from that of the control group. As for the average number of pulses, a significant difference was observed between the inhaled and IV lignocaine groups; hence, the average number of pulses in Group 1 (inhalation) was lower than that of Group 2 (IV injection). Conclusion: As blood pressure is considered to be normal under 140/90 and may not entail any hemodynamic complications, it can be concluded that inhaled nebulized lignocaine can control the hemodynamic changes of intubation more effectively than IV lignocaine. PMID- 29628575 TI - Hemodynamic, Airway Pressure, and Capnometric Changes and Perioperative Outcome in Pediatric Laparoscopic Inguinal Herniorrhaphy: A Comparison with Open Inguinal Herniorrhaphy. AB - Background: Laparoscopic procedures which are now established in pediatric population as well exposes the child to supplemental cardiorespiratory changes due to increase in intraabdominal pressure (IAP) and hypercarbia. Aims: This study aims to analyze the effects of pneumoperitoneum and postural modifications on cardiorespiratory system (primary outcome) during pediatric laparoscopic herniorrhaphy (LH) and its comparison with open herniorrhaphy (OH) and assessment of overall perioperative outcome (secondary outcome). Settings and Design: A prospective, observational study conducted in a tertiary care hospital. Materials and Methods: Fifty children undergoing either LH (n = 25) or OH (n = 25) were included in the study. Anesthetic procedure was standardized. Parameters monitored were heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressures (MAP), electrocardiogram lead-II, end tidal CO2 (ETCO2), airway pressures PPeak, PPlateau, PMean, pulse oximetry, IAP, minute ventilation/respiratory rate alterations. Statistical Analysis Used: Student's t-test and Chi-square test were applied to compare different variables between the two groups. Intragroup analysis was done using the analysis of variance test. Results: The HR was comparable in both groups. The rise in SBP, DBP, and MAP was 9% (102.88 +/- 6.91-121.32 +/- 6.63), 19% (60.88 +/- 4.94-77.00 +/- 9.75), and 14.8% (73.92 +/- 4.65-90.40 +/- 8.42), respectively, in group LH. The rise in peak, plateau, and mean airway pressures was 19.4% (14.20 +/- 2.00 18.00 +/- 2.54), 20.1% (13.32 +/- 1.89-16.89 +/- 2.60), and 16.1% (6.20 +/- 1.00 7.47 +/- 0.96), respectively, in group LH. ETCO2 showed a maximum rise of 19.4% (34.52 +/- 3.61-41.21 +/- 3.99) in group LH. In laparoscopic group, recurrence was seen in 3 patients. Conclusions: We found significant hemodynamic, airway pressure, and capnometric changes during pediatric LH with comparable perioperative outcome among the two groups. PMID- 29628576 TI - Comparison of Intranasal Dexmedetomidine Compared to Midazolam as a Premedication in Pediatrics with Congenital Heart Disease Undergoing Cardiac Catheterization. AB - Background: The intranasal route is a reliable way to administer preanesthetics and sedatives to children. The aim of this study was to compare the anxiolytic and sedative effect of intranasal dexmedetomidine and midazolam as a premedication in pediatrics with simple congenital heart disease undergoing cardiac catheterization. Patients and Methods: Sixty children 3-6 years old of either sex with simple congenital heart disease undergoing cardiac catheterization were randomly allocated into two groups: Dexmedetomidine group who received intranasal dexmedetomidine (0.1 MUg/kg) and midazolam group who received intranasal midazolam (0.2 mg/kg) 30 min before induction. Heart rate, mean arterial blood pressure, and oxygen saturation were monitored up to 30 min after drug administration. The sedation score, anxiety score, and child-parent separation score were recorded until the child taken to the operating room. The postoperative agitation score was also observed. Results and Conclusion: The premedication of children with intranasal dexmedetomidine attained satisfactory and significant sedation and lower anxiety level with better parental separation than those who received intranasal midazolam. PMID- 29628577 TI - Comparison of Dexamethasone and Buprenorphine as Adjuvant in Ultrasound-guided Brachial Plexus Blocks: A Randomized Controlled Trial. AB - Introduction: Effective postoperative analgesia is imperative for orthopedic surgeries to enhance recovery and facilitate early ambulation. Various additives have been used as adjuvants with local anesthetics in peripheral nerve blocks to provide postoperative analgesia. The aim of this study is to compare the duration of postoperative analgesia with buprenorphine and dexamethasone when administered as an adjuvant during ultrasound-guided brachial plexus blocks. Methodology: Sixty adult patients undergoing various upper arm surgeries were recruited for the study after acquiring ethics committee clearance. They were randomized into two groups of thirty; Group B was given ultrasound-guided supraclavicular block with 10 ml 2% lignocaine with adrenaline and 15 ml 0.5% bupivacaine and 4 mg dexamethasone as adjuvant. Group B was given the same amount of local anesthetics with 0.3 mg buprenorphine as the adjuvant. The duration of postoperative analgesia and incidence of adverse events if any were noted. Results: Both groups were comparable in demographics, time for onset of sensory, and motor block. The duration of postoperative analgesia was 17.4 +/- 3.4 h in the buprenorphine group and 18 +/- 3.49 h in the dexamethasone group. None of the patients had significant adverse effects. A single dose of buprenorphine and dexamethasone administered perineurally can provide significant postoperative analgesia for upper limb surgeries. PMID- 29628578 TI - Attenuation of Hemodynamic Response to Tracheal Extubation: A Comparative Study between Esmolol and Labetalol. AB - Background and Aims: Cardiovascular stress response to extubation can result in elevated heart rate (HR) and mean arterial blood pressures which can be detrimental in high-risk patients. Settings and Design: The objective of this study is to compare the esmolol and labetalol efficacy in attenuating hemodynamic response to tracheal extubation. Materials and Methods: Sixty patients scheduled for elective surgical procedures were selected randomly and divided into two groups of thirty each. Group I - esmolol 1.5 mg/kg and Group II - labetalol 0.25 mg/kg were administered 2 min before extubation after following a standard perioperative anesthetic management. Hemodynamic parameters recorded include HR, systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP) at baseline, reversal, study drug, 1 min after study drug, extubation, and at 1, 2, 3, 4, 5, and 15 min postextubation. Statistical Analysis: Student's t-test and analysis of variance have been used to find the significance of study parameters between groups of patients. P <0.05 was considered statistically significant. Results: Both esmolol and labetalol obtunded extubation response throughout the extubation and postextubation period. At extubation and immediately postextubation at 1st and 2nd min, there was statistical significance (P < 0.05) in SBP, DBP, and MAP which showed esmolol was better than labetalol. Whereas labetalol was more efficient in controlling HR at 5th and 15th min postextubation having statistical significance. Conclusions: Both esmolol and labetalol attenuated hemodynamic response. Esmolol was more efficient than labetalol at extubation and immediately postextubation. If patient has tachycardia at extubation, labetalol is preferred. If patient has raised blood pressure, then esmolol is a good option in blunting the response. PMID- 29628579 TI - Incidence of Postspinal Headache and Low Backache Following the Median and Paramedian Approaches in Spinal Anesthesia. AB - Background and Aims: Postspinal headache and low backache are common complaints following spinal anesthesia which regresses spontaneously but sometimes becomes very troublesome for the patient as well as for the anesthesiologists. The aim of this study was to evaluate the incidence of postspinal headache and low backache after spinal anesthesia in lower abdominal surgery. Materials and Methods: One hundred patients of 18-60 years of age group with patients physical status the American Society of Anesthesiologists Class I or II after due consent divided into equal numbers of two groups: median (M) approach and paramedian (P) approach scheduled for lower abdominal surgery. Group M (50 patients) received spinal by median approach while in Group P (50 patients) received spinal by paramedian approach. The incidence of postspinal headache and low backache was observed in each group. All the patients were observed up to 7 days postoperatively. Data collected was analyzed statistically by SPSS (IBM SPSS Statistics for Windows, Version 22.0. Armonk, NY: IBM Corp) and Chi-square test, and P < 0.05 considered as statistically significant. Results: Postspinal headache was observed to be 4% in paramedian approach and 20% in median approach group. Backache incidence recorded in both the groups was 2% and 10%, respectively. P value calculated statistically was < 0.05 and hence statistically significant in paramedian approach in respect of incidence of both postspinal headache and backache. Conclusion: Incidence of postspinal headache and low backache is less in paramedian approach than in median approach. PMID- 29628580 TI - Comparison of Intravenous Bolus and Infusion of Dexmedetomidine on Characteristics of Subarachnoid Block. AB - Aims: Dexmedetomidine is very dynamic drug, used for analgesia, sedation, blunting the laryngoscopic responses and as adjuvants in regional anesthesia. Studies have shown that intravenous (iv) dexmedetomidine given during spinal anesthesia increases the quality of subarachnoid block (SAB). In this study, we compare the two iv regimen of dexmedetomidine on analgesic effect of spinal anesthesia. One is bolus dose of dexmedetomidine and other is infusion during the surgery, both given after induction of spinal anesthesia. Subjects and Methods: Sixty American Society of Anesthesiologists I and II patients scheduled to undergo surgeries under SAB were randomly allocated into two groups namely B and I. After SAB with 3.0 ml of bupivacaine 0.5% heavy, Group B received 0.5 MUg/kg of dexmedetomidine bolus over 15 min, Group I received 0.5 MUg/kg/h of dexmedetomidine infusion until the end of surgery. Statistical Analysis Used: All parametric data were statistically analyzed using Student's t-test and nonparametric data analyzed using Chi-square test and Fischer exact test as appropriate. P < 0.05 was considered as statistically significant. Statistical analysis was performed using the SPSS. Results: Time to reach desired level T10 was quick in Group B compared to Group I. Regression of sensory and motor was prolonged in Group I compared to Group B. Total duration of analgesia was significantly prolonged in Group I 230.39 +/- 16.20 compared to Group B 196.01 +/ 14.32 and the difference is statistically significant (P = 0.0001). Both groups had Ramsay sedation score of 3 which lasted for 45 min in Group B while it was maintained in Group I. Side effects profile of both groups was comparable with few incidence of bradycardia and hypotension in both groups requiring treatment. Conclusions: We conclude that the continuous infusion of dexmedetomidine after SAB results in prolonged analgesia than just a bolus dose. Therefore, we suggest use of the maintenance dose of iv dexmedetomidine after SAB for prolonging the duration and achieving adequate sedation. PMID- 29628581 TI - Ease of Intubation with C-MAC Videolaryngoscope: Use of 60 degrees Angled Styletted Endotracheal Tube versus Intubation over Bougie. AB - Background: Although videolaryngoscopes improve glottic visualization, their actual usefulness in intubation is not yet established. Aims: The primary objective was to compare the ease of oral intubation with the use of 60 degrees angled styletted endotracheal tube versus that performed over bougie inserted under videolaryngoscopic guidance. The secondary objectives were assessment of incidence of airway loss, hemodynamic changes, and time and number of attempts at intubation. Settings and Design: This prospective randomized study was conducted in a tertiary care institution. Patients and Methods: Seventy surgical patients requiring oral intubation were randomly allotted to Group S or Group B. Laryngoscopy was performed with Storz(r) C-MAC videolaryngoscope using D-Blade. In Group S, patients were intubated with a 60 degrees angled stylletted endotracheal tube. In Group B, a bougie was introduced into the trachea and endotracheal tube was railroaded over the bougie. Statistical Analysis Used: Chi square test and independent sample t-test were used as applicable. Results: The ease of intubation was significantly more in patients of Group S as compared to Group B (88.6% vs. 25.7%, respectively, P < 0.001) with significantly shorter intubation time (16.97 +/- 7.91 vs. 77.43 +/- 35.55 s, respectively, P < 0.001). The requirement of more than one attempt at intubation was significantly higher in Group B [57.1% vs. 5.7% P < 0.001, respectively]. Group B showed a significantly high mean arterial pressure at 1 and 3 min following intubation with no significant change in heart rate. Conclusion: Use of 60 degrees angled styletted endotracheal tube resulted in easier and faster intubation as compared to intubation over a bougie when used with C-MAC videolaryngoscope. PMID- 29628582 TI - Predictors and Outcomes of Postoperative Pulmonary Complications following Abdominal Surgery in a South Indian Population. AB - Background: Postoperative pulmonary complications (PPC) following abdominal surgery are associated with increased morbidity and poorer outcomes. We prospectively examined risk factors associated with the development of PPC in patients undergoing abdominal surgery. Aims: The primary outcome was to determine the association of predefined risk factors in the prediction of PPC after abdominal surgery. Secondary outcomes were evaluation of outcomes of PPC. Setting and Design: This was a prospective study conducted in the gastrosurgical and urological units of a tertiary care referral hospital in patients undergoing abdominal surgery over a period of 6 months (November 2015-April 2016). Materials and Methods: Relevant preoperative and intraoperative variables were recorded by the anesthesiologist in a pro forma provided. Postoperatively, data from the Intensive Care Unit (ICU) were collected from data sheets. PPC were defined according to preset criteria and outcomes of the patients including ICU stay, hospital stay, and mortality were noted. Statistical Analysis: Chi-square test was used to find the association of risk factors of PPC. Mann-Whitney test was used for continuous variables and McNemar's test for postoperative respiratory variables. A final regression analysis was performed with factors with significant association (P < 0.1). Results: One hundred and fifty patients were included, and 24 patients (16%) developed PPC as defined by our criteria. Emergency surgery (44.4% of PPC) and cardiac comorbidity (23.9% of PPC) were significant associations for pulmonary complications. The length of ICU and hospital stay (LOICU, LOHS) and mortality were higher in the group with pulmonary complications (P < 0.001). Conclusions: Emergent surgery and cardiac comorbidities were independent predictors for the development of PPC. PPC are associated with increased LOHS, LOICU stay, and mortality. PMID- 29628583 TI - Pressure-controlled Volume Guaranteed Mode Improves Respiratory Dynamics during Laparoscopic Cholecystectomy: A Comparison with Conventional Modes. AB - Background: Pneumoperitoneum and altered positioning 1in laparoscopic cholecystectomy predispose to alterations in cardiorespiratory physiology. We compared the effects of volume controlled, pressure controlled, and the newly introduced pressure controlled-volume guaranteed ventilation (PCV-VG) modes of ventilation on respiratory mechanics and oxygenation during laparoscopic cholecystectomy. Materials and Methods: Seventy-five physical status American Society of Anesthesiologists Classes I and II patients with normal lungs undergoing laparoscopic cholecystectomy were randomly allocated to receive volume controlled ventilation (VCV), pressure-controlled ventilation (PCV), or PCV-VG modes of ventilation during general anesthesia. In all modes of ventilation, the tidal volume was set at 8 mL/kg, and respiratory rate was set at 12 breaths/min with inspired oxygen of 0.4. After pneumoperitoneum, respiratory rate was adjusted to maintain an end-tidal carbon dioxide between 32 and 37 mm Hg. The peak airway pressures, compliance, the mean airway pressures, oxygen saturation, end tidal carbon dioxide and hemodynamics were recorded at the time of intubation (T1), 15 min after pneumoperitoneum (T2) and after desufflation (T3) and were compared. Arterial oxygen tension, arterial carbon dioxide tension at T2 and T3 were compared. Results: PCV-VG and PCV mode resulted in lower peak airway pressures than VCV (23.04 +/- 3.43, 24.52 +/- 2.79, and 27.24 +/- 2.37 cm of water, respectively, P = 0.001). Compliance was better preserved in the pressure mediated modes than VCV (fall from baseline was 42%, 29%, and 30% in VCV, PCV, and PCV-VG). The arterial to end-tidal carbon dioxide gradient was lower in PCV VG and PCV compared to VCV. No difference in oxygenation and hemodynamics were observed. Conclusion: PCV and PCV-VG modes are superior to VCV mode in providing adequate oxygenation at lower peak inspiratory pressures. PMID- 29628584 TI - Evaluation of the Hemodynamic Response of Intravenous Clonidine versus Ropivacaine Scalp Block to Insertion of Scalp Pins in Neurosurgical Patients. AB - Background: The application of the skull-pin head-holder, used to stabilize the head during neurosurgical procedures, produces an intense nociceptive stimulus and results in abrupt increases in blood pressure and cerebral blood flow under general anesthesia. Different anesthetic and pharmacologic techniques, including local anesthetics, narcotics, antihypertensives, and deepening of anesthesia with inhalation anesthetics, have been used to blunt this deleterious effect with variable success. Aim: To compare the analgesic and hemodynamic effects of ropivacaine scalp block, and intravenous (IV) clonidine in attenuating the hemodynamic response to the scalp pin insertion in neurosurgical patients. Settings and Design: A comparative two group's clinical study of 64 patients undergoing elective craniotomy in Department of Anaesthesiology, Bangalore Medical College and Research Institute. Methodology: Sixty-four patients were allocated into any one of two groups of 32 patients each, by means of computer generated randomization: (1) Group S: Patients receiving scalp block with injected ropivacaine 0.25% 30 ml. (2) Group C: Patients receiving 2 MUg/kg IV clonidine. Statistical Methods: Descriptive and inferential statistical analysis has been carried out in the present study. Results on continuous measurements are presented on mean +/- standard deviation (minimum-maximum) and results on categorical measurements are presented in number (%). Significance is assessed at 5% level of significance. Results: Increase in heart rate and blood pressure during pin insertion was attenuated by clonidine hydrochloride (P < 0.001). The number of patients who required more fentanyl and propofol to stabilize the hypertensive response were more in control group than clonidine group. Conclusion: IV clonidine maximally attenuated the hemodynamic response to application of head pins in a dose of 2 MUg/kg compared to ropivacaine scalp block, thus maintaining intracranial pressure for neurosurgical anesthesia. PMID- 29628585 TI - Comparative Study of Efficacy of Preoperative Nalbuphine Hydrochloride and Pentazocine Lactate on Hemodynamic Response to Tracheal Intubation and Postoperative Analgesia. AB - Background: For General anaesthesia perioperative administration of opioids are choice of drugs to attenuate intubation response and to provide good intraoperative and postoperative analgesia. Mixed agonist-antagonist opioids produces powerful analgesia without undesirable side effects. Aim: Aim of present study to compare efficacy of Nalbuphine and Pentazocine on hemodynamic response to tracheal intubation and postoperative analgesia. Settings: Present study carried out in operation theater. Design: This is prospective randomized double blind controlled trial. Material and Methods: Patients of ASA physical status I and II, age 20-60 years undergoing abdominal surgical procedure of 1-2 hour duration were randomly divided into two groups of 30 patients each (Group N) receiving nalbuphine 0.3 mg.kg-1 and (Group P) receiving pentazocine 0.6 mg.kg-1 intravenously before induction. Baseline vital parameters were noted and then noted till 15 minutes after intubation to see hemodynamic response. Time of rescue analgesia required was noted postoperatively. Stastical Analysis: Chi square test, paired and unpaired t-test were used for statistical analysis. Results: There is rise in heart rate, blood pressure after intubation in both groups but rise was more with Pentazocine as compared to Nalbuphine (P < 0.05). Postoperatively within 30 minutes 60% of patient from Pentazocine group require rescue analgesia compare to only 16.60% of patient of Nalbuphine group (P = 0.05) which is highly significant. Conclusion: Nalbuphine is potent mixed opioid analgesic which can be used for attenuation of pressor response of tracheal intubation and for perioperative analgesia with minimal side effects. PMID- 29628586 TI - Postoperative Cardiac Surgery Outcomes in a Statin-Native Population. AB - Background: Statin utilization had been associated with improved survival after cardiac surgery. We aim to study whether perioperative treatment with statin could be associated with increased postoperative complications. Design: This was a retrospective, descriptive, single-center study. Settings: We analyzed morbidity after cardiac surgery as well as the outcome related to statin therapy in a tertiary cardiac center. Patients: A total of 202 consecutive patients were enrolled over 1 year after cardiac surgery. Intervention: Patients were divided into two groups; Group I - statin users and Group II - nonusers. Measurements: Measurements were baseline and follow-up laboratory markers for muscular injury including cardiac muscle and hepatic injuries and renal injuries. Results: The incidence of rhabdomyolysis and elevation of liver enzymes did not differ between both groups. Postoperative atrial fibrillation was significantly lower in the statin group (P = 0.02). In addition, peak cardiac troponin and creatine kinase MB did not differ significantly in the statin group. Statin-treated group had significant lower length of mechanical ventilation, and length of stay in the Intensive Care Unit and hospital (P = 0.036, 0.04, and 0.027, respectively). Conclusions: Therapy with statin before cardiac surgeries was not associated with high incidence of adverse events. PMID- 29628587 TI - Effects of Preoxygenation with Tidal Volume Breathing Followed by Apneic Oxygenation with and without Continuous Positive Airway Pressure on Duration of Safe Apnea Time and Arterial Blood Gases. AB - Background: Application of continuous positive airway pressure (CPAP) helps to recruit collapsed areas of the lung, which improves the oxygen reserve. Aim of the Study: To compare the time to desaturate to 90% during apnea following preoxygenation and apneic ventilation with tidal volume breathing for 3 min with and without the application of CPAP. Settings and Design: This prospective randomized study was conducted in a tertiary care institution. Subjects and Methods: Twenty adult surgical patients were allocated into two groups. Group C patients were preoxygenated with 100% oxygen with CPAP of 20 cm H2O for 3 min. Group P patients were preoxygenated for 3 min without CPAP. In Group C, apneic oxygenation was initiated following induction and neuromuscular blockade with CPAP of 20 cm H2O. In Group P, no CPAP was applied. The study was terminated when the patient desaturated to 90%. Statistical Analysis Used: Chi-square test and Mann-Whitney test. Results: Group C had a significantly longer apnea time as compared to Group P (816.00 +/- 30.98 vs. 348.00 +/- 122.64 s). Three patients in Group P desaturated to <90% by 3 min and the remaining soon after 6 min. No patient in Group C desaturated till 12 min of apnea. PaO2 was significantly higher in Group C at 3 and 6 min of apnea. At 3 and 6 min, Group P had significantly lower saturation as compared to Group C. Conclusion: Preoxygenation with CPAP significantly delayed desaturation during apnea with significantly higher arterial partial pressure of oxygen as compared to preoxygenation without CPAP. PMID- 29628588 TI - Effect of Dexamethasone on Characteristics of Supraclavicular Nerve Block with Bupivacaine and Ropivacaine: A Prospective, Double-blind, Randomized Control Trial. AB - Background: Dexamethasone as an adjuvant to bupivacaine and ropivacaine for supraclavicular brachial plexus (SCBP) block prolongs motor and sensory blockade. However, comparison of effect of dexamethasone (8 mg) when added to these two local anesthetics has not been well studied. This study was conducted to compare analgesic efficacy of dexamethasone as adjuvant to bupivacaine and ropivacaine in SCBP block. Subjects and Methods: Nerve stimulator-guided SCBP block was given to 120 patients, randomly assigned to one of four groups: (n = 30 in each group) Group B, BD, R, and RD received 30 ml (0.5%) bupivacaine + 2 ml saline, 30 ml (0.5%) bupivacaine + dexamethasone 8 mg, 30 ml (0.5%) ropivacaine + 2 ml saline, and 30 ml (0.5%) ropivacaine + dexamethasone 8 mg, respectively. Time for request of the first rescue analgesic, 24-h analgesic consumption, and different block characteristics were assessed. Student's t-test, Chi-square test, ANOVA were used for statistical analysis. Results: Dexamethasone significantly prolonged time for request of the first rescue analgesic of both ropivacaine (1211.83 +/- 32.86 vs. 283.17 +/- 7.71 min){ p R, RD < 0.001} and bupivacaine (1205.17 +/- 34.32 vs. 364.67 +/- 16.50 min) {p B, BD < 0.001}. 24-h requirement for rescue analgesics was more in Groups B and R when compared to Groups BD and RD. The increase in duration of analgesia was more when Groups R and RD (928.66 min) were compared than Groups B and BD (840.5 min). Similar results were seen with onset times and duration of sensory and motor block. Conclusion: The addition of dexamethasone to bupivacaine and ropivacaine in SCBP block prolonged time for first rescue analgesia and reduced the requirement of rescue analgesics with faster onset and prolonged duration of sensory and motor block, with the effect being stronger with ropivacaine. PMID- 29628589 TI - Clonidine as an Adjuvant to Caudal Epidural Ropivacaine for Lumbosacral Spine Surgeries. AB - Background: Caudal epidural analgesia is a proven technique for providing analgesia for spinal surgeries. Prolonged pain relief with no motor blockade is desired for early mobilization. Objective: The objective of this study is to compare the effect of adding 1 MUg/kg of clonidine to injection ropivacaine 0.2% with respect to duration of analgesia, hemodynamic effects, and associated side effects. Methodology: In this prospective double-blind study, a total of 60 patients undergoing lumbosacral spine surgery were randomized to receive 25 cc caudal epidural injection of either injection ropivacaine 0.2% (Group R, n = 30) or a mixture of injection ropivacaine 0.2% and injection clonidine 1 MUg/kg (Group RD, n = 30) under general anesthesia after the patient was positioned prone for surgery. Visual analog scale (VAS) scores, heart rate, blood pressures, and time to rescue analgesia and sedation score were recorded at regular intervals for the first 24 h. Results: Mean VAS scores were significantly lower in the RC Group for up to 12 h following the caudal block. The time to first rescue analgesic was prolonged in the RC group compared to the R Group, and it was statistically significant. No clinically significant hemodynamic changes were noted in either of the groups. No other side effects were seen in both the groups. Conclusion: These results suggest that injection clonidine is an effective additive to injection ropivacaine for caudal epidural analgesia in lumbosacral spine surgeries. PMID- 29628590 TI - Comparison of Arterial Oxygenation and Acid-Base Balance with the use of Transnasal Humidified Rapid-insufflation Ventilatory Exchange versus Tidal Volume Breathing with Continuous Positive Airway Pressure for Preoxygenation and Apneic Ventilation. AB - Background: Preoxygenation and apneic ventilation prolong apnea time without desaturation. Aims: The primary objective of this study is to compare arterial oxygenation during the periods of apnea following preoxygenation and apneic ventilation with tidal volume breathing for 3 min with continuous positive airway pressure (CPAP) versus with transnasal humidified rapid-insufflation ventilatory exchange (THRIVE). Settings and Designs: This prospective randomized study was conducted in 20 adult patients at a tertiary care institution. Subjects and Methods: Group C patients (n = 10) were preoxygenated with 100% oxygen using a face mask at a rate of 6 L/min for 3 min with CPAP of 15 cm of H2O. In Group H, oxygen was administered using THRIVE at 30 L/min for 3 min. Apneic ventilation was given in Group C with 10 L/min oxygen with CPAP of 15 cm H2O and in Group H with THRIVE at 60 L/min. The endpoint was desaturation to 90% or maximum duration of 12 min. Statistical Analysis Used: Chi-square test and Mann-Whitney test. Results: Both groups tolerated apnea for 12 min without desaturation. PaO2 in Group C was significantly higher than Group H from 3 min of apnea to 12 min. The PaCO2 was significantly lower in Group C from 6 min. The pH was comparable in both groups except at 12 min with Group H having significantly lower pH. Conclusion: Tidal volume breathing with CPAP resulted in significantly higher arterial oxygen levels than THRIVE, though both modalities were equally effective in prolonging apnea time without desaturation up to 12 min. Group C showed an added advantage of lower PaCO2 with less acidemia. PMID- 29628591 TI - Comparison of Levobupivacaine and Levobupivacaine with Dexmedetomidine in Infraumbilical Surgeries Under Spinal Anesthesia. AB - Introduction: Spinal anesthesia is a widely used technique providing faster onset with effective and uniformly distributed sensory and motor block. Due to decreased cardiovascular and central nervous system toxicity, levobupivacaine is a good alternative for spinal anesthesia. Dexmedetomidine when used intrathecally is associated with prolonged motor and sensory block, hemodynamic stability, and less requirement of rescue analgesia in 24 h. Materials and Methods: A prospective, randomized study was carried out which included 60 adult patients between the age group of 20 and 65 years of physical status American Society of Anesthesiologists Classes I and II who underwent infraumbilical surgeries. Group L patients received 3 ml (15 mg) of 0.5% isobaric levobupivacaine + 0.3 ml normal saline while Group LD patients received 3 ml (15 mg) of 0.5% isobaric levobupivacaine + 0.3 ml (3 MUg) dexmedetomidine. The two groups were compared with respect to the onset and duration of sensory and motor block and hemodynamic stability. Results: The mean duration of sensory block in Group L was 199.50 +/- 7.96 min while in Group LD was 340.20 +/- 11.78 min. All the differences were statistically highly significant between the two groups (P < 0.001). Mean duration of motor block in Group L and LD was 150.83 +/- 9.17 min and 190.20 +/- 9.61 min, respectively. Both the differences were highly significant (P < 0.001). Conclusion: It is concluded that Group LD has early-onset and prolonged duration of sensory and motor block and longer duration of postoperative analgesia than Group L. PMID- 29628593 TI - Comparison of Esmolol and Dexmedetomidine for Suppression of Hemodynamic Response to Laryngoscopy and Endotracheal Intubation in Adult Patients Undergoing Elective General Surgery: A Prospective, Randomized Controlled Double-blinded Study. AB - Context: Laryngoscopy and endotracheal intubation lead to strong sympathetic response which may precipitate arrhythmias, myocardial ischemia and cerebrovascular accidents in patients with preexisting cardiovascular disease. Aims: This study was aimed to compare the effect of dexmedetomidine and esmolol on hemodynamic response to laryngoscopy and endotracheal intubation in patients undergoing elective surgery under general anesthesia. Settings and Design: This was a prospective, randomized controlled double-blinded study. Materials and Methods: A total of ninety patients were selected and randomized into three groups of thirty patients each: Group C received infusion of 20 mL 0.9% normal saline (NS) over 10 min, Group D received infusion of dexmedetomidine 1 MUg/kg diluted in 20 mL NS over 10 min, and Group E received infusion of esmolol 1.5 mg/kg diluted in 20 mL NS over 10 min. Three minutes after the completion of infusion, patients were induced with general anesthesia. Baseline parameters such as heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial blood pressure (MAP), and rate pressure product (RPP) were recorded before administration of study drugs and at 1, 3, 5, 7, and 10 min after intubation. Statistical Analysis Used: One-way ANOVA was used for comparison among the groups and unpaired t-test was used for comparison within the groups along with Tukey's test for post test analysis. Results: Mean HR, SBP, DBP, MAP, and RPP values remained significantly lower in Group D than that of Group C and Group E at all time intervals up to 10 min after intubation. Conclusions: Both dexmedetomidine and esmolol suppressed the hemodynamic response to intubation when compared to control group, but dexmedetomidine is more effective than esmolol in maintaining hemodynamic stability following laryngoscopy and intubation. PMID- 29628592 TI - Magnesium Sulfate as a Preemptive Adjuvant to Levobupivacaine for Postoperative Analgesia in Lower Abdominal and Pelvic Surgeries under Epidural Anesthesia(Randomized Controlled Trial). AB - Background: Magnesium (Mg) has been evaluated as an adjuvant to local anesthetics for prolongation of postoperative epidural and intrathecal analgesia but not with epidural levobupivacaine in lower abdominal surgeries. Aim of the Study: The aim of the study was to evaluate the preemptive analgesic effect of Mg added to epidural levobupivacaine anesthesia in infraumbilical abdominal surgeries. Settings and Design: This study design was a prospective randomized controlled trial. Patients and Methods: Two groups, each with fifty patients undergoing lower abdominal and pelvic surgeries with epidural anesthesia. Group M received 15 ml of a mixture of 14 ml levobupivacaine 0.5%, 0.5 ml magnesium sulfate 10% (50 mg), and 0.5 ml 0.9 NaCl at induction. Group L received 15 ml of 14 ml levobupivacaine 0.5% and 1 ml 0.9 NaCl at induction. Then, continuous infusion was used as 5 ml/h of the specific mixture of each group till the end of the surgery. Statistical Analysis: Chi-square test, unpaired t-test or Mann-Whitney, and Wilcoxon sign rank test were used. Results: No statistically significant difference between the two groups regarding intraoperative hemodynamics (P > 0.05). Sensory and motor block onset was significantly shorter in Group M (14.5 [+/-1.51] and 12.42 [+/-1.69]) compared to Group L (19.86 [+/-1.39] and 19.34 [+/ 1.62]) (P = 0.001). Group M showed lower visual analog scale (VAS) pain score compared to Group L from the 2nd to the 5th h postoperatively. Time for first analgesic dose was longer in Group M (294.98 [+/-21.67]) compared to Group L (153.96 [+/-10.04]) (P = 0.001). Conclusions: Preoperative and intraoperative epidural Mg infusion with levobupivacaine resulted in prolonged postoperative analgesia and lower VAS. PMID- 29628594 TI - An Unusual Case of a Parturient with Uncorrected Pentalogy of Fallot Presenting for Elective Cesarean Section Delivery of Twins. AB - We present a 31-year-old primigravida with uncorrected pentalogy of Fallot, pregnant with monochorionic-diamniotic twins, undergoing elective lower segment cesarean section at 36 weeks gestation. Preoperative workup included a transthoracic echocardiogram which revealed a large ventricular septal defect of 1.8 cm with bidirectional shunting, a moderate size atrial septal defect of 1.8 cm with predominant left-to-right shunting, an overriding aorta, moderate right ventricular hypertrophy, and severe pulmonary valve stenosis. Notably, the patient was acyanotic with normal effort tolerance. Preoperative preparation involved the input of cardiologists and obstetric and cardiothoracic anesthetists. Issues such as the use of extracorporeal membrane oxygenation and cardiopulmonary support in the event of cardiac failure were discussed. Autotransfusion postdelivery was also addressed, and plans made for therapeutic venesection should need to arise. Intraoperatively, the planned anesthetic technique was slow and titrated combined spinal-epidural. However, a general anesthetic technique with rapid sequence induction was used in view of extreme patient anxiety. Intravenous induction was performed with ketamine and etomidate, followed by paralysis with succinylcholine. Anesthesia was maintained with desflurane on a mixture of air and oxygen. Phenylephrine infusion was titrated according to the patient's blood pressure and systemic vascular resistance. The uterotonic of choice was duratocin given as a slow bolus, followed by a 4-h infusion of oxytocin. The patient was put in a head-up position to prevent venous air embolism and to decrease autotransfusion to central circulation. Postoperatively, she was extubated and sent to the Intensive Care Unit for continuous monitoring with FloTrac(r). PMID- 29628595 TI - Anesthesia in a Child with Newly Diagnosed Hypertrophic Cardiomyopathy for Placement of Implantable Cardioverter Defibrillator. AB - Hypertrophic cardiomyopathy (HCM) is a genetic myocardial disease usually characterized by asymmetric ventricular septal hypertrophy. HCM is an important cause of sudden cardiac death in adolescents and young adults. We are presenting a case report, ten years boy came in emergency with sudden loss of consciousness (witness cardiac arrest). Child was revived after cardiopulmonary resuscitation and send to coronary care unit. Echocardiography findings were suggestive of HCM. There was history of sudden death of her mother and maternal uncle. After stabilization ICD was implanted under total intravenous anesthesia. Post procedure his hospital stay was uneventful. PMID- 29628596 TI - Subarachnoid Block a Safe Choice for Cesarean Section in Neurofibromatosis Patient with Severe Kyphoscoliosis. AB - Neurofibromatosis type 1 (NF1) is an autosomal-dominant neuroectodermal hereditary disorder, in which spinal skeletal deformities are one of the manifestations. Pectus carinatum, temporomandibular joint dysfunction, and kyphoscoliosis can be seen with this genetic disorder which can lead to cardiorespiratory system problems and can cause difficulty in airway management. We present the anesthetic management of a NF1 patient with a sharp thoracolumbar dystrophic kyphoscoliosis who have been posted for emergency cesarean section as a result of fetal distress. The operation was successfully performed with subarachnoid block. This case highlights the anesthetic challenges and the significance of early planning anesthetic technique. PMID- 29628597 TI - Anesthetic Management in Pediatric Patient for Percutaneous Endoscopic Gastrostomy with Mitochondrial Myopathy: Leigh Syndrome. AB - Leigh syndrome (LS) is a rare disease mainly affecting the central nervous system due to the abnormalities of mitochondrial energy generation and seen in early childhood with progressive loss of movement, mental abilities, seizures, nystagmus, ophthalmoparesis, optic atrophy, ataxia, dystonia, or respiratory failure. Anesthesia and surgery exacerbate the risks of aspiration, wheezing, and breathing difficulties. Tracheal irritability can be stimulated with the efforts of intubation. We report the anesthetic management of a rare case of an 11-year old boy with a severe form of LS for percutaneous endoscopic gastrostomy insertion. The patient was closely monitored during the procedure and the postoperative period. Carefully chosen anesthetic agents, good pain control, and close monitoring are essential. PMID- 29628598 TI - Transient Receptor Potential Channels as Blood Biomarkers for Pain Characteristics in Patients with Chronic Pain. AB - Transient receptor potential (TRP) channels play key roles for the transition from acute to chronic postoperative pain after surgery. To evaluate TRP channels in the peripheral blood cells as blood biomarkers for chronic pain, we collected blood samples for genome-wide assays of the mRNA expression and assessed pain intensity and the number of pain symptoms in 13 patients with chronic pain. There was a significant association between increases in the number of pain symptoms and increases in the TRP vanilloid 1 (TRPV1) expression. Decreases in the TRP ankyrin 1 (TRPA1) expression, however, tended to increase the number of pain symptoms. There was likely an inverse relationship for TRPV1 and TRPA1 expressions with regard to the number of pain symptoms in chronic pain patients. PMID- 29628599 TI - Temporomandibular Joint Ankylosis: "A Pediatric Difficult Airway Management". AB - Intubating a pediatric patient with temporomandibular joint ankylosis is a daunting task, and it becomes more challenging with limited mouth opening. Fiberoptic nasotracheal intubation technique is considered a gold standard. We describe an improvised technique of securing airway in the absence of appropriate sized fiberoptic scope. The endotracheal tube inserted in the left nostril for maintaining depth of anesthesia was advanced under vision by the fiberoptic scope inserted into the right nostril, and with external laryngeal manipulation, the airway was secured with no complications. PMID- 29628600 TI - Cardiopulmonary Arrest and Pneumoencephaly Developing after Epidural Oxygen-ozone Mixture Therapy. AB - Pain treatment can comprise a combination of pharmacological, interventional, surgical, physical, psycological methods. Interventional procedures, particularly minimally invasive percutaneous therapies, have been widely used in recent years. Corticosteroid, hyperbaric saline or oxygen-ozone therapy is a safe procedure for patients in whom pain cannot be relieved by epidural adhesiolysis or other treatments. Complication related to oxygen-ozone therapy have been reported rarely in lumbar sciatalgia. Herein, we present a patient who developed cardiopulmonary arrest and pneumoencephaly as a rare but life-threatening complication of oxygen-ozone therapy, for epidural lysis, applied to the epidural space due to low back pain. PMID- 29628601 TI - I-gelTM May be the Device of Choice for Controlled Ventilation in Patients with Hemophilia Undergoing Abdominal Laparoscopic Surgery. AB - Haemophilia is an inherited bleeding disorder with variable deficiency of Factor VIII in the plasma and is characterised by bleeding into joints, muscles and tissues either spontaneously or in response to trivial trauma. Perioperative care requires multidisciplinary involvement. Perioperative management involves the risk of excessive bleeding from surgical site as well as spontaneous bleeding into the brain in response to surgical stress in patients with previous history of intracerebral haemorrhage. Airway management of such patients during anaesthetic intervention is a challenge and entails the risk of life threatening haemorrhage into the airway. The I gel Supraglottic airway device may be best suited for the purpose considering its soft elastomeric non-inflatable cuff, ease of insertion, availability of gastric suction port and minimal leak fraction on controlled ventilation. The I Gel may be solution to avoiding airway instrumentation in patients with bleeding disorders. It may be an alternative to endotracheal intubation in patients with Haemophilia undergoing surgery. PMID- 29628603 TI - Zero Oxygen Saturation in Pulse Oximeter: Need for Clinical Correlation. PMID- 29628602 TI - Anosmia after Caudal Epidural Steroid Injection. AB - There are no reports for anosmia after caudal epidural steroid injections (CESIs). General anesthesia is among the reasons, but the reports up to date are extremely limited. There are no identifiable factors contributing to anosmia after epidural injection, so it is worth discussing. We present the case of a 50 year-old woman with no previous history of any sensory deficits. She experienced anosmia after CESI that had been performed due to her chronic low back pain and lasted for 4 months. Clinical and imaging studies did not reveal any pathology. After 4 months, the olfactory dysfunction demonstrated a significant improvement. Disorders of the olfactory system are unknown after regional anesthesia. The onset of the dysfunction in correlation with the imaging findings may indicate that anesthetics can affect the olfactory dysfunction. Further studies are needed. PMID- 29628604 TI - The Relationship Between Baseline Volume in Temporal Areas and Post-Treatment Naming Accuracy in Primary Progressive Aphasia. AB - Background: Structural imaging has not been used previously to predict the effect of treatment in primary progressive aphasia (PPA). Aims: This study examined relationships between baseline brain volume and the effects of phonological and orthographic treatments for anomia in PPA. It was predicted that lower baseline volume would be associated with lower post-treatment naming accuracy for treated items and smaller generalization effects. Methods & Procedures: Twenty-one individuals with PPA participated. The treatment stimuli consisted of nouns that were consistently named correctly at baseline (Prophylaxis items) and/or nouns that were consistently named incorrectly at baseline (Remediation items). All 21 participants had Prophylaxis items, while 10 participants had Remediation items. Naming accuracy for untrained and trained items (Exemplar set 1) was measured. In addition, stimulus generalization was examined by having participants name an alternative exemplar of each untrained and trained item (Exemplar set 2). Correlational analyses focused on the relationships between naming accuracy and volume of regions previously identified as having a role in naming and semantic processing. Outcomes & Results: Unexpectedly, there were no significant correlations between baseline volume and post-treatment accuracy for treated items. However, baseline volume within the left temporal pole was positively correlated with post-treatment accuracy for Untrained Exemplar set 2 Prophylaxis items, while baseline volume in the left inferior temporal gyrus was positively correlated with post-treatment accuracy for Untrained Exemplar set 1 Remediation items. Conclusions: These findings suggest that lower volume in the left temporal pole is associated with decline for Untrained items, while lower volume in the left inferior temporal gyrus is associated with a lack of improvement for Untrained items. Possible explanations for the different patterns observed across Exemplar sets are discussed. PMID- 29628605 TI - Getting What You Expect: Negative Social Expectations in Early Adolescence Predict Hostile Romantic Partnerships and Friendships Into Adulthood. AB - Adolescents' negative expectations of their peers were examined as predictors of their future selection of hostile partners, in a community sample of 184 adolescents followed from ages 13 to 24. Utilizing observational data, close friend- and self-reports, adolescents with more negative expectations at age 13 were found to be more likely to form relationships with observably hostile romantic partners and friends with hostile attitudes by age 18 even after accounting for baseline levels of friend hostile attitudes at age 13 and adolescents' own hostile behavior and attitudes. Furthermore, the presence of friends with hostile attitudes at age 18 in turn predicted higher levels of adult friend hostile attitudes at age 24. Results suggest the presence of a considerable degree of continuity from negative expectations to hostile partnerships from adolescence well into adulthood. PMID- 29628606 TI - Variation in age composition among colony sizes in Cliff Swallows. AB - Variation in group size is characteristic of most social species. The extent to which individuals sort among group sizes based on age may yield insight into why groups vary in size and the age-specific costs and benefits of different social environments. We investigated the age composition of Cliff Swallow (Petrochelidon pyrrhonota) colonies of different sizes over 18 years at a long-term study site in western Nebraska, USA. Using years elapsed since banding as a relative measure of age for over 194,000 birds, we found that the proportion of age-class-1 swallows (birds banded as nestlings or juveniles or adults in the year of banding) of both sexes increased in larger colonies and at colony sites becoming active later in the summer. Age composition was unrelated to how often a particular colony site was used. The effect of colony size most likely reflected the fact that older birds return to the same colony site in successive years even when the colony size there decreases, and that yearlings and immigrants benefit more from larger colonies than do older, more experienced individuals. The date effect probably resulted in part from later spring arrival by younger and/or immigrant swallows. At fumigated sites where ectoparasitic swallow bugs (Oeciacus vicarius) had been removed, age composition did not vary with either colony size or colony initiation date. The patterns reported here appear to be driven partially by the presence of ectoparasites and suggest that the hematophagous bugs influence variation in Cliff Swallow group composition. Our results are consistent with the hypothesis that variation in colony size reflects, in part, age-based sorting of individuals among groups. PMID- 29628607 TI - A Study of R2 Measure under the Accelerated Failure Time Models. AB - For right-censored data the accelerated failure time (AFT) model is an alternative to the commonly used proportional hazards regression model. It is a linear model for the (log-transformed) outcome of interest, and is particularly useful for censored outcomes that are not time-to-event, such as laboratory measurements. We provide a general and easily computable definition of the R2 measure of explained variation under the AFT model for right-censored data. We study its behavior under different censoring scenarios and under different error distributions; in particular, we also study its robustness when the parametric error distribution is misspecified. Based on Monte Carlo investigation results, we recommend the log-normal distribution as a robust error distribution to be used in practice for the parametric AFT model when the R2 measure is of interest. We apply our methodology to an alcohol consumption during pregnancy data set from Ukraine. PMID- 29628608 TI - Confidence, in Relation to the Practice of Interventional Radiology. PMID- 29628609 TI - Management of Chronic Deep Vein Thrombosis in Women. AB - Chronic deep vein thrombosis (DVT) affects hundreds of thousands of women in the United States. Chronic DVT can lead to pain, edema, venous ulcers, and varicosities. While there are limited data regarding the management of chronic DVT, several interventional radiology groups aggressively treat chronic DVT to aid patient symptom resolution. Recanalization of occluded veins and venous stenting re-establishes deep vein flow and decreases venous hypertension. PMID- 29628610 TI - Gender Differences in Peripheral Vascular Disease. AB - In the past 20 years, peripheral artery disease (PAD) has been increasingly recognized as a significant cause of morbidity and mortality in the United States. PAD has traditionally been identified as a male-dominant disease; however, recent population trends and studies in PAD suggest that women are affected at least as often as men. Women comprise a larger population of the elderly than men, as well as an increasing proportion of patients with PAD. Much of the existing research on PAD has focused on whole populations, and gender specific data on PAD is sparse. This review focuses on gender-specific differences in presentation, management, and outcomes of PAD intervention that are important considerations for the interventional radiologist. PMID- 29628611 TI - Updates on MR-Guided Focused Ultrasound for Symptomatic Uterine Fibroids. AB - Magnetic-resonance-guided focused ultrasound (MRgFUS), also called high-intensity focused ultrasound (HIFU) is an effective, noninvasive uterine-preserving treatment for symptomatic uterine fibroids. As the use of this therapeutic modality is not yet widespread, it may remain unfamiliar to many interventional radiologists. The purpose of this review is to discuss MRgFUS, including technology, patient selection, technique, outcomes, complications, and recent data on fertility and comparative effectiveness. PMID- 29628612 TI - Contraceptive Implant Migration and Removal by Interventional Radiology. AB - As the reversible contraceptive arm implants grow more popular, there is an increasing need to recognize the complications resulting from implant migration and removal. This review summarizes the findings of imaging and removal methods. When an implant is lost, the axillary region should be investigated first. If the implant still cannot be found, visualization though different methods have been employed for non-radiopaque implants. Real-time fluoroscopic-guided localization and removal can be accomplished for radiopaque Nexplanon. Once the implant has been located, standard removal method and other modified techniques can be used to safely remove the implant depending on the implant's location. PMID- 29628613 TI - Locoregional Therapies for the Treatment of Hepatic Metastases from Breast and Gynecologic Cancers. AB - Breast cancer is the most common women's malignancy in the United States and is the second leading cause of cancer death. More than half of patients with breast cancer will develop hepatic metastases; this portends a poorer prognosis. In the appropriately selected patient, there does appear to be a role for curative (surgery, ablation) or palliative (intra-arterial treatments) locoregional therapy. Gynecologic malignancies are less common and metastases to the liver are most often seen in the setting of disseminated disease. The role of locoregional therapies in these patients is not well reported. The purpose of this article is to review the outcomes data of locoregional therapies in the treatment of hepatic metastases from breast and gynecologic malignancies. PMID- 29628614 TI - Pelvic Congestion Syndrome: Systematic Review of Treatment Success. AB - Pelvic venous insufficiency is now a well-characterized etiology of pelvic congestion syndrome (PCS). The prevalence of CPP is 15% in females aged 18 to 50 years in the United States and up to 43.4% worldwide. In addition to individual physical, emotional, and quality-of-life implications of CPP, there are profound healthcare and socioeconomic expenses with estimated annual direct and indirect costs in the United States in excess of 39 billion dollars. PCS consists of clinical symptoms with concomitant anatomic and physiologic abnormalities originating in venous insufficiency. The etiology of PCS is diverse involving both mechanical and hormonal factors contributing to venous dilatation (>5 mm) and insufficiency. Factors affecting the diagnosis of PCS include variance of causes and clinical presentations of pelvic pain and relatively low sensitivity of noninvasive diagnostic imaging and laparoscopy to identify insufficiency compared with catheter venogram. A systematic review of the literature evaluating patient outcomes following percutaneous treatment of PCS is presented. PMID- 29628615 TI - Pelvic Artery Embolization for Treatment of Postpartum Hemorrhage. AB - Postpartum hemorrhage (PPH) is the leading cause of maternal perinatal morbidity and mortality worldwide. Defined as greater than 500 mL blood loss after vaginal delivery, and greater than 1,000 mL blood loss after cesarean delivery, PPH has many causes, including uterine atony, lower genital tract lacerations, coagulopathy, and placental anomalies. Correction of coagulopathy and identification of the cause of bleeding are mainstays of treatment. Medical therapies such as uterotonics, balloon tamponade, pelvic artery embolization, and uterine-sparing surgical options are available. Hysterectomy is performed when conservative therapies fail. Pelvic artery embolization is safe and effective, and is the first-line therapy for medically refractory PPH. A thorough knowledge of pelvic arterial anatomy is critical. Recognition of variant anatomy can prevent therapeutic failure. Pelvic embolization is minimally invasive, has a low complication rate, spares the uterus, and preserves fertility. PMID- 29628617 TI - Varicose Veins and Lower Extremity Venous Insufficiency. AB - Lower extremity venous insufficiency and varicose veins are common conditions, affecting up to 25% of women. Herein, we review the pathophysiology of lower extremity venous insufficiency and varicose veins, the epidemiology of varicose veins, clinical diagnosis, and ultrasonographic diagnosis. We also discuss treatment rationale, algorithms, and techniques, with a focus on endovenous great saphenous vein ablation. PMID- 29628616 TI - Updates on Uterine Artery Embolization. AB - Uterine fibroids (leiomyomas) are the most common benign neoplasm of the female pelvis and have a lifetime prevalence exceeding 80% among African American women and approaching 70% among Caucasian women. Approximately 50% of women with fibroids experience symptoms which may include menorrhagia that may result in anemia, bulk symptoms with bladder and bowel dysfunction and abdominal protrusion, dysmenorrhea, and infertility. Hysterectomy remains the most common treatment option for fibroids and concerns have been raised about the overuse of this procedure. Uterine artery embolization (UAE) is now a well-established uterine preserving and minimally invasive therapy for symptomatic fibroids. Since its introduction, strong evidence for safety and efficacy of UAE has been generated with low rates of complications. This review will discuss UAE for the management of symptomatic uterine fibroids with special focus on emerging technical approaches and novel periprocedural patient care. PMID- 29628619 TI - Intra- and Extrahepatic Collaterals: Pitfalls and Pathways for Locoregional Therapy. PMID- 29628618 TI - Female Pelvic Vascular Malformations. AB - Vascular malformations are classified primarily according to their flow characteristics, slow flow (lymphatic and venous) or fast flow (arteriovenous). They can occur anywhere in the body but have a unique presentation when affecting the female pelvis. With a detailed clinical history and the proper imaging studies, the correct diagnosis can be made and the best treatment can be initiated. Lymphatic and venous malformations are often treated with sclerotherapy while arteriovenous malformations usually require embolization. At times, surgical intervention of vascular malformations or medical management of lymphatic malformations has been implemented in a multidisciplinary approach to patient care. This review presents an overview of vascular malformations of the female pelvis, their clinical course, diagnostic studies, and treatment options. PMID- 29628620 TI - Automatic Analysis of Pronunciations for Children with Speech Sound Disorders. AB - Computer-Assisted Pronunciation Training (CAPT) systems aim to help a child learn the correct pronunciations of words. However, while there are many online commercial CAPT apps, there is no consensus among Speech Language Therapists (SLPs) or non-professionals about which CAPT systems, if any, work well. The prevailing assumption is that practicing with such programs is less reliable and thus does not provide the feedback necessary to allow children to improve their performance. The most common method for assessing pronunciation performance is the Goodness of Pronunciation (GOP) technique. Our paper proposes two new GOP techniques. We have found that pronunciation models that use explicit knowledge about error pronunciation patterns can lead to more accurate classification whether a phoneme was correctly pronounced or not. We evaluate the proposed pronunciation assessment methods against a baseline state of the art GOP approach, and show that the proposed techniques lead to classification performance that is more similar to that of a human expert. PMID- 29628621 TI - Behavioral Plasticity in Probing by Diaphorina citri (Hemiptera, Liviidae): Ingestion from Phloem Versus Xylem is Influenced by Leaf Age and Surface. AB - Diaphorina citri is a major pest of citrus because it transmits Candidatus Liberibacter asiaticus, a phloem-limited bacterium that putatively causes Huanglongbing (HLB). The disease moves slowly through a tree, and the vector facilitates further within-tree movement via transmission of the pathogen. However, this only happens when D. citri stylets contact the phloem, to inoculate bacteria during phloem salivation and acquire bacteria during phloem sap ingestion. Behavioral changes in D. citri associated with different plant parts would affect how long it takes to reach phloem and how long the psyllids stays in phloem to ingest, thereby influencing the risk of disease spread. D. citri feeding was recorded on the abaxial and adaxial surfaces of mature and immature citrus leaves. Adults in the field can be found on these surfaces at all times of year. On abaxial surface of immature leaves, phloem salivation would occur after 11 h on average, but rarely as soon as 0.56 h. The corresponding values on mature leaves were 16 and 2.7. In general, psyllids spent more time ingesting phloem sap on immature leaves than on mature leaves. Psyllids on abaxial surfaces spent more time ingesting from phloem, though the strength of this effect was less than for immature versus mature leaves. In contrast, xylem ingestion increased on mature leaves compared with young. The biological differences that could produce this outcome are discussed. The results discussed herein are of relevance to further studies on the efficacy of an insecticide to act quickly enough to prevent pathogen transmission. PMID- 29628622 TI - Aversive Learning in the Praying Mantis (Tenodera aridifolia), a Sit and Wait Predator. AB - Animals learn to associate sensory cues with the palatability of food in order to avoid bitterness in food (a common sign of toxicity). Associations are important for active foraging predators to avoid unpalatable prey and to invest energy in searching for palatable prey only. However, it has been suggested that sit-and wait predators might rely on the opportunity that palatable prey approach them by chance: the most efficient strategy could be to catch every available prey and then decide whether to ingest them or not. In the present study, we investigated avoidance learning in a sit-and-wait predator, the praying mantis (Tenodera aridifolia). To examine the effects of conspicuousness and novelty of prey on avoidance learning, we used three different prey species: mealworms (novel prey), honeybees (novel prey with conspicuous signals) and crickets (familiar prey). We sequentially presented the prey species in pairs and made one of them artificially bitter. In the absence of bitterness, the mantises consumed bees and crickets more frequently than mealworms. When the prey were made bitter, the mantises still continued to attack bitter crickets as expected. However, they reduced their attacks on bitter mealworms more than on bitter bees. This contrasts with the fact that conspicuous signals (e.g. coloration in bees) facilitate avoidance learning in active foraging predators. Surprisingly, we found that the bitter bees were totally rejected after an attack whereas bitter mealworms were partially eaten (~35%). Our results highlight the fact that the mantises might maintain a selection pressure on bees, and perhaps on aposematic species in general. PMID- 29628623 TI - Magnetic-field-induced dielectric behaviors and magneto-electrical coupling of multiferroic compounds containing cobalt ferrite/barium calcium titanate composite fibers. AB - Multiferroics have broad application prospects in various fields such as multi layer ceramic capacitors and multifunctional devices owing to their high dielectric constants and coupled magnetic and ferroelectric properties at room temperature. In this study, cobalt ferrite (CFO)/barium calcium titanate (BCT) composite fibers are prepared from BCT and CFO sols by an electrospinning method, and are then oriented by magnetic fields and sintered at high temperatures. The effects of magnetic fields and CFO contents on the nanostructures and magnetoelectric properties of the composites are investigated. Strong coupling between magnetic and ferroelectric properties occurs in CFO/BCT composites with magnetic orientation. More interestingly, the dielectric constants of CFO/BCT composites with magnetic orientation are found to be enhanced (by ~1.5-3.5 times) as compared with those of BCT and CFO/BCT without magnetic orientation. The boost of dielectric constants of magnetic-field orientated CFO/BCT is attributed to the magneto-electrical coupling between CFO and BCT, where the polar domains of BCT are pinned by the orientated CFO. Therefore, this work not only provides a novel and effective approach in enhancing the dielectric constants of ceramic ferroelectrics, which is of tremendous value for industrial applications, but also elucidates the interaction mechanisms between ferromagnetic phase and ferroelectric phase in multiferroic compounds. PMID- 29628624 TI - Fast 2D/3D object representation with growing neural gas. AB - This work presents the design of a real-time system to model visual objects with the use of self-organising networks. The architecture of the system addresses multiple computer vision tasks such as image segmentation, optimal parameter estimation and object representation. We first develop a framework for building non-rigid shapes using the growth mechanism of the self-organising maps, and then we define an optimal number of nodes without overfitting or underfitting the network based on the knowledge obtained from information-theoretic considerations. We present experimental results for hands and faces, and we quantitatively evaluate the matching capabilities of the proposed method with the topographic product. The proposed method is easily extensible to 3D objects, as it offers similar features for efficient mesh reconstruction. PMID- 29628625 TI - "Everybody Likes a Drink. Nobody Likes a Drunk". Alcohol, Health Education and the Public in 1970s Britain. AB - This article examines the development of alcohol health education in Britain during the 1970s, using this as a way to explore the nature of public health and the place of the public within it. Focusing on a set of local health education campaigns, an expert committee report on alcohol prevention and a public consultation exercise on alcohol, the article highlights the presence of three different 'publics'. Health education campaigns tended to focus on the individual drinker, but the drinking habits of the whole population were also of concern. So too were the rights and responsibilities of citizen-consumers. These three publics - drinkers, the population and citizen-consumers - were often in conflict with one another, and though it was drinkers that became the object of alcohol policy, the needs of the population, and of citizen-consumers, could not be ignored. PMID- 29628626 TI - Gene-environment correlations in the cross-generational transmission of parenting: Grandparenting moderates the effect of child 5-HTTLPR genotype on mothers' parenting. AB - Evidence suggests that parenting is associated cross-generationally and that children's genes may elicit specific parenting styles (evocative gene-environment correlation). This study examined whether the effect of children's genotype, specifically 5-HTTLPR, on mothers' parenting behaviors was moderated by her own parenting experiences from her mother. Two independent samples of three-year-olds (N = 476 and 405) were genotyped for the serotonin transporter gene, and observational measures of parenting were collected. Mothers completed measures of the parenting they received as children. The child having a short allele on 5 HTTLPR was associated with more maternal hostility (sample 1 and 2) and with less maternal support (sample 1), but only if the mother reported lower quality grandmothers' parenting (abuse and indifference in Sample 1 and lower levels of grandmother care in Sample 2). Results support the possibility of a moderated evocative gene-environment correlation. PMID- 29628627 TI - Monte Carlo Investigation of Photon Beam Characteristics and its Variation with Incident Electron Beam Parameters for Indigenous Medical Linear Accelerator. AB - Purpose: A Monte Carlo model of a 6 MV medical linear accelerator (linac) unit built indigenously was developed using the BEAMnrc user code of the EGSnrc code system. The model was benchmarked against the measurements. Monte Carlo simulations were carried out for different incident electron beam parameters in the study. Materials and Methods: Simulation of indigenously developed linac unit has been carried out using the Monte Carlo based BEAMnrc user-code of the EGSnrc code system. Using the model, percentage depth dose (PDD), and lateral dose profiles were studied using the DOSXYZnrc user code. To identify appropriate electron parameters, three different distributions of electron beam intensity were investigated. For each case, the kinetic energy of the incident electron was varied from 6 to 6.5 MeV (0.1 MeV increment). The calculated dose data were compared against the measurements using the PTW, Germany make RFA dosimetric system (water tank MP3-M and 0.125 cm3 ion chamber). Results: The best fit of incident electron beam parameter was found for the combination of beam energy of 6.2 MeV and circular Gaussian distributed source in X and Y with FWHM of 1.0 mm. PDD and beam profiles (along both X and Y directions) were calculated for the field sizes from 5 cm * 5 cm to 25 cm * 25 cm. The dose difference between the calculated and measured PDD and profile values were under 1%, except for the penumbra region where the maximum deviation was found to be around 2%. Conclusions: A Monte Carlo model of indigenous linac (6 MV) has been developed and benchmarked against the measured data. PMID- 29628628 TI - A Treatment Planning Method for Better Management of Radiation-Induced Oral Mucositis in Locally Advanced Head and Neck Cancer. AB - Purpose/Aim: To describe a two-phase intensity-modulated radiation therapy (IMRT) treatment planning approach, that is, promising for reduction of oral mucositis risk in locally advanced head-and-neck cancer. Materials and Methods: Ten locally advanced head-and-neck cancer patients who underwent RT were retrospectively collected. Conventional IMRT and volumetric-modulated arc therapy (VMAT) plans were generated for these patients following clinical protocol. Following the first phase of generating conventional IMRT plans, our approach utilized data from Monte Carlo-based kernel superposition dose calculations corresponding to beam apertures (generated from the conventional IMRT plans) and used an exact mathematical programming-based optimization approach applying linear programming (LP) to dose optimization in the second phase. Results: Compared with conventional IMRT and VMAT treatment plans, our novel method achieved better preservation of oral cavity (16%-29% lower mean dose, P < 0.01), parotid glands (6%-17% lower mean dose, P < 0.04), and spinal cord (3-11 Gy lower maximum dose, P < 0.03) and lower doses to nonorgan-at-risk/nontarget normal tissues, with the same or better target coverage. Conclusions: Our LP-based method can be practically implemented in routine clinical use with a goal of limiting radiation induced oral mucositis for head-and-neck cancer patients. PMID- 29628629 TI - Comparison of Volumetric Modulated Arc Therapy and Intensity Modulated Radiation Therapy for Whole Brain Hippocampal Sparing Treatment Plans Based on Radiobiological Modeling. AB - Introduction: In this article, we report the results of our investigation on comparison of radiobiological aspects of treatment plans with linear accelerator based intensity-modulated radiation therapy and volumetric-modulated arc therapy for patients having hippocampal avoidance whole-brain radiation therapy. Materials and Methods: In this retrospective study using the dose-volume histogram, we calculated and compared biophysical indices of equivalent uniform dose, tumor control probability, and normal tissue complication probability (NTCP) for 15 whole-brain radiotherapy patients. Results and Discussions: Dose response models for tumors and critical structures were separated into two groups: mechanistic and empirical. Mechanistic models formulate mathematically with describable relationships while empirical models fit data through empirical observations to appropriately determine parameters giving results agreeable to those given by mechanistic models. Conclusions: Techniques applied in this manuscript could be applied to any other organs or types of cancer to evaluate treatment plans based on radiobiological modeling. PMID- 29628630 TI - Interfraction Variations in Organ Filling and Their Impact on Dosimetry in CT Image Based HDR Intracavitary Brachytherapy. AB - Aim: Since anatomical and geometric variations occur with every fraction, planning, and dose optimization is necessary for every fraction of high-dose rate intracavitary brachytherapy of carcinoma cervix. In this study, we have tried to quantify the differences in doses to organs at risk (OAR) for each fraction of brachytherapy. Methods and Materials: One hundred and seventy computed tomography datasets of cervical cancer patients receiving intracavitary brachytherapy at our institution between January and April 2015 were analyzed. The volumes of the high risk clinical target volume and OAR contoured were recorded for every insertion. Dose-volume histograms were generated and D90 and D100CTV and D0.1, D1, and D2cc were recorded for bladder, rectum, and sigmoid for each insertion. Results: Sixty one percent had a decrease in bladder volume in the second fraction, 35% had an increase in bladder volume and 4% had no change in bladder volume. There was a strong positive correlation between increase in volume and dose (D2cc), which was statistically significant, rs = 0.441, P = 0.013. Nearly 49.4% of patients had an increase in rectal volume during the second fraction. 45.9% had decrease in rectal volume during the second fraction. There was a positive correlation between the increase in volume and dose (D2cc), which was statistically significant, rs = 0.393, P = 0.010. About 63.5% of the patients had a decrease in sigmoid volume during the second fraction, whereas 30.6% had an increase in volume and 5.9% had no change in volume. Conclusion: First, this study emphasizes the importance of imaging and planning for every fraction of brachytherapy to quantify the exact doses to the target and OAR s. Second, it is important to follow a uniform bladder protocol for every fraction, and adequate bowel preparation is needed for every fraction to minimize the interfraction variations. Finally, it also opens the realm of an adaptive planning strategy in cervical cancers which are known for rapid tumor regression during radiotherapy. PMID- 29628631 TI - Dosimetric and Radiobiological Evaluation of Patient Setup Accuracy in Head-and neck Radiotherapy Using Daily Computed Tomography-on-rails-based Corrections. AB - Introduction: This study evaluates treatment plans aiming at determining the expected impact of daily patient setup corrections on the delivered dose distribution and plan parameters in head-and-neck radiotherapy. Materials and Methods: In this study, 10 head-and-neck cancer patients are evaluated. For the evaluation of daily changes of the patient internal anatomy, image-guided radiation therapy based on computed tomography (CT)-on-rails was used. The daily acquired CT-on-rails images were deformedly registered to the CT scan that was used during treatment planning. Two approaches were used during data analysis ("cascade" and "one-to-all"). The dosimetric and radiobiological differences of the dose distributions with and without patient setup correction were calculated. The evaluation is performed using dose-volume histograms; the biologically effective uniform dose () and the complication-free tumor control probability (P+) were also calculated. The dose-response curves of each target and organ at risk (OAR), as well as the corresponding P+ curves, were calculated. Results: The average difference for the "one-to-all" case is 0.6 +/- 1.8 Gy and for the "cascade" case is 0.5 +/- 1.8 Gy. The value of P+ was lowest for the cascade case (in 80% of the patients). Discussion: Overall, the lowest PI is observed in the one-to-all cases. Dosimetrically, CT-on-rails data are not worse or better than the planned data. Conclusions: The differences between the evaluated "one-to-all" and "cascade" dose distributions were small. Although the differences of those doses against the "planned" dose distributions were small for the majority of the patients, they were large for given patients at risk and OAR. PMID- 29628632 TI - Expression of Bax and Bcl2 Genes in Peripheral Blood Lymphocytes of Patients with Differentiated Thyroid Cancer. AB - Context: Thyroid cancer is the most common endocrine malignancy worldwide. Iodine 131 is used in the treatment of thyroid cancer with dosage of 100 mCi. In the medical applications of ionizing radiation besides the advantages such as diagnosis and treatment of diseases, the risks arising from exposure should be considered as well. Aims: The present study aimed to evaluate the changes in expression levels of apoptotic Bax and Bcl-2 and the ratio of Bax/Bcl-2, in the peripheral blood lymphocytes (PBLs) of patients with differentiated thyroid cancer (DTC). Settings and Design: This study was conducted on fifty thyroid cancer patients who had undergone surgery and were under treatment with 100 and 150 mCi doses. Subjects and Methods: Blood samples were taken from the patients, one before iodine treatment and another 48 h after therapy. Bax and Bcl-2 gene expression levels were measured by using real-time reverse transcriptase polymerase chain reaction. Statistical Analysis Used: The data were analyzed using one-way analysis of variance followed by samples t-test and independent samples t-test. Results: Significant changes were observed in the percentage of apoptotic cells, in groups, after radioiodine therapy compared with before treatment. The ratio of Bax/Bcl-2 in both groups showed a significant increase (P < 0.001). The relative expression level of Bax gene showed a significant increase in comparison with the control group. Conclusions: Iodine therapy reduced expression of Bcl-2 and a significant expression of Bax and finally increased the ratio of Bax/Bcl-2. Iodine therapy led to apoptosis in the PBLs of patients with DTC. Therefore, it can be suggested that this method can be useful for monitoring and detecting destructive effects of ionizing radiation in nuclear medicine patients. PMID- 29628633 TI - Dosimetric Comparison of Treatment Plans Using Physical Wedge and Enhanced Dynamic Wedge for the Planning of Breast Radiotherapy. AB - The aim of this study is to compare the physical wedge (PW) with enhanced dynamic wedge (EDW) to determine the difference in the dose distribution affecting the treated breast and the contralateral breast, lungs, heart, esophagus, spine, and surrounding skin in the radiotherapy of breast cancer. Computed tomography (CT) data sets of 30 breast cancer patients were selected from the database for the study. The treatment plans which were executed with PW were re-planned with EDW without changing the beam parameters. Keeping the wedge angles same, the analytic anisotropic algorithm (AAA) with heterogeneity correction was used for dose calculation in all plans. The prescription was 50 Gy in 25 fractions. The dose- volume histogram (DVH) of the planning target volume (PTV) and critical structures of both PW and EDW plans were analyzed. The analysis showed that the maximum dose within the target volume is higher in EDW plan compared to PW plan. However the PTV conformity index (CI) remained the same in both plans. For all the critical structures, the EDW technique offered less dose compared to PW technique. The effect of volume of the contralateral breast on the dose to contralateral breast and the effect of volume of PTV breast for patients with carcinoma left breast on the dose to heart were studied and analyzed for the two wedges. No correlation between volumes and dose parameters was found for the two techniques. The number of monitor units to deliver a particular dose with EDW field is less than that of PW field due to change in wedge factor. As EDW produces less scattered dose to structures outside the treatment field, the risk of a second malignancy can be reduced with this technique. PMID- 29628634 TI - Dosimetric Effect of Jaw Tracking in Volumetric-Modulated Arc Therapy. AB - The aim of this study was to investigate the potential of jaw tracking with the volumetric-modulated arc therapy (VMAT) to reduce the normal tissue dose. Plans of nasopharynx, lung, and prostate cancers (10 plans for each) were used to perform VMAT with and without jaw tracking. The dose reduction was evaluated in terms of organ doses and integral doses. Organ-dose reduction with jaw tracking was statistically significant in the volume receiving a dose of 5 Gy (V5) of bladder, rectum, and lung, the volume receiving a dose of 10 Gy (V10) of bladder, rectum, and lung, and the mean dose of lung (P < 0.05). Integral-dose reduction with jaw tracking was statistically significant in almost all the treatment plans (P < 0.05). For organ-dose reduction, jaw tracking in VMAT plan was effective in reducing V5 and V10. For integral-dose reduction, jaw tracking in VMAT plan is an efficient method for decreasing V5. PMID- 29628635 TI - Brachytherapy Localization Radiographs with Conventional Diagnostic X-Ray Machine. AB - With conventional diagnostic X-ray machines with over couch X-ray tubes, it is not possible to obtain anteroposterior (AP) and lateral (Lat) radiographs without changing the posture of the patients. In an old 300 mA X-ray machine with a fluoroscopy screen (12.4 kg) (1995 model), by substituting the screen with suitable counterweight and making provision to take the hoist pillar up to the edge of the wall, we could get isocentric setup for a hospital stretcher kept near the chest stand. This setup provided acceptable AP-Lat radiographs for brachytherapy localization using "Perspex jig" (Nucletron, Netherlands) and field check radiographs in head and neck, esophagus patients for treatment planning. PMID- 29628636 TI - Bismuth-Silicon and Bismuth-Polyurethane Composite Shields for Breast Protection in Chest Computed Tomography Examinations. AB - The article aims at constructing protective composite shields for breasts in chest computed tomography and investigating the effects of applying these new bismuth composites on dose and image quality. Polyurethane and silicon with 5% of bismuth were fabricated as a protective shield. At first, their efficiency in attenuating the X-ray beam was investigated by calculating the total attenuation coefficients at diagnostic energy range. Then, a physical chest phantom was scanned without and with these shields at tube voltage of 120 kVp, and image parameters together with dose values were studied. The results showed that these two shields have great effects on attenuating the X-ray beam, especially for lower energies (<40 kV), and in average, the attenuation coefficients of bismuth polyurethane composite are higher in this energy range. The maximum relative differences between the average Hounsfield units (HUs) and noises of images without and with shield for both composites in 13 regions of interest were 4.5% and 15.7%, respectively. Moreover, primary investigation confirmed the ability of both shields (especially polyurethane-bismuth composite) in dose reduction. Comparing these two composites regarding the amount of dose reduction, the changes in HU and noise, and attenuation coefficients in diagnostic energy range, it seems that polyurethane composite is more useful for dose reduction, especially for higher tube voltages. PMID- 29628638 TI - Greetings from the editorial committee. PMID- 29628639 TI - Clinical performance of direct versus indirect composite restorations in posterior teeth: A systematic review. AB - Background: Composite resin, serves as esthetic alternative to amalgam and cast restorations. Posterior teeth can be restored using direct or indirect composite restorations. The selection between direct and indirect technique is a clinically challenging decision-making process. Most important influencing factor is the amount of remaining tooth substance. Aim: The aim of this systematic review was to compare the clinical performance of direct versus indirect composite restorations in posterior teeth. Materials and Methods: The databases searched included PubMed CENTRAL (until July 2015), Medline, and Cochrane Database of Systematic Reviews. The bibliographies of clinical studies and reviews identified in the electronic search were analyzed to identify studies which were published outside the electronically searched journals. The primary outcome measure was evaluation of the survival of direct and indirect composite restorations in posterior teeth. Results: This review included thirteen studies in which clinical performance of various types of direct and indirect composite restorations in posterior teeth were compared. Out of the thirteen studies which were included seven studies had a high risk of bias and five studies had a moderate risk of bias. One study having a low risk of bias, concluded that there was no significant difference between direct and indirect technique. However, the available evidence revealed inconclusive results. Conclusion: Further research should focus on randomized controlled trials with long term follow-up to give concrete evidence on the clinical performce of direct and indirect composite restorations. PMID- 29628640 TI - Biocompatibility and sealing ability of mineral trioxide aggregate and biodentine as root-end filling material: A systematic review. AB - Introduction: This systematic review intended to compare the biocompatibility and sealing ability of mineral trioxide aggregate (MTA) and biodentine as root-end filling material. Materials and Methods: A computerized literature search was performed on March 1, 2016, in MEDLINE, PubMed, and COCHRANE LIBRARY for data published from January 2011 to March 2016. Quality assessment of the selected studies was performed according to the PRISMA guidelines, 2009. Results: A total of 12 in vitro studies were included in this review. Of these, four studies compared the biocompatibility and eight compared the sealing ability. With regard to biocompatibility, two articles showed biodentine to be better and two showed comparable results, while in the case of sealing ability, one article showed MTA to be better, six articles showed biodentine to be better, and the rest one article showed the comparable result. Conclusion: It may be concluded that good sealing ability of biodentine along with its favorable biological properties show that materials can be used competently in clinical practice as a retrograde filling material. However, long-term assessment in clinical situations is necessary for further inferences. PMID- 29628641 TI - Effect of surface protection on the permeability of eroded dentin. AB - Context: Eroded dentin might present the opening of dentinal tubules, increasing permeability, and consequently dentinal hypersensitivity. Aims: This study evaluated the permeability of dentin surfaces exposed to different levels of erosion and methods of surface protection. Materials and Methods: Dentine samples (3 mm * 3 mm * 1 mm) were prepared from bovine incisors (n = 90) and divided into three groups according to the method of controlling erosive challenge: Negative control, topical fluoride application, and glass ionomer sealant. Subsequently, they were randomly divided into three subgroups according to the exposure of simulated gastric acid solution (Demineralization - DES) (5% HCl, pH = 2.2), and remineralization (RE); negative control, 9 and 18 cycles DES-RE. The dentin permeability was measured by assessing the hydraulic conductance (MUl/min.cmH2O.cm2). Statistical analysis was performed by two-way ANOVA and Tukey's test. Results and Conclusions: Greater permeability was observed after 18 erosive cycles, followed by exposure to 9 cycles and negative control (P < 0.0001). The application of glass ionomer sealant resulted in a major reduction of the hydraulic conductivity, regardless of the erosive challenge. Control groups and topical fluoride application showed similar results. In conclusion, the severity of erosive challenge contributed to the increase of dentin permeability. Besides, the glass ionomer sealant was the only protection agent that promoted significant effects in dentin permeability. PMID- 29628642 TI - Cytotoxicity of gypsum-based biomaterial for direct pulp capping using stem cells from human exfoliated deciduous teeth. AB - Aim: The aim of this study was to evaluate the cytotoxicity effects of experimental gypsum-based biomaterial prepared with various concentrations of chitosan (Gyp-CHT). Materials and Methods: The study was performed using cell viability assay for mitochondrial dehydrogenase activity in stem cells from human exfoliated deciduous teeth (SHED), after 1, 2, and 3 days of exposure to the biomaterial extracts of varying concentrations. Differences in mean cell viability values were assessed by one-way analysis of variance, followed by Dunnett T3 post hoc test for multiple comparisons (P < 0.05). Results: The cell viability to Gyp-CHT in low extract concentrations was statistically similar to that of the control and different from that of high extract concentrations. Gyp 5% CHT showed the highest percentage of cell viability with 110.92%, 108.56%, and 109.11%. The cell viability showed a tendency toward increment with low extract concentration and no constant effect of CHT on cell viability toward higher or lower. Conclusions: Gyp-CHT biomaterial has no cytotoxic effects on the cultured SHED. PMID- 29628643 TI - Protocols for sodium ascorbate application on intracoronary dentin bleached with high-concentrated agent. AB - Purpose: Composite resin restorations are normally replaced after the internal bleaching of endodontically treated-teeth because the bleaching agent does not alter the color of the restorative material. This study evaluated the effect of 10% sodium ascorbate (SA) applied at different protocols on bleached dentin. Materials and Methods: One-hundred slabs of intracoronary bovine dentin were divided into 5 groups: 2 controls-GI without bleaching (positive), GII bleached with 35% hydrogen peroxide (HP) (negative); and 3 experimentals - GIII. 35% HP + SA at protocol 1 (dripping, washing and drying the solution), GIV. 35% HP + SA at protocol 2 (dripping and aspirating the solution) and GV. 35% HP + SA at protocol 3 (dripping, rubbing and aspirating the solution). Sixty fragments were restored and subjected to shear bond strength test (n = 12). Forty fragments (n = 8) were prepared for chemical analysis (energy dispersive X-ray spectrometry) and surface morphology (scanning electron microscopy). Data were analyzed by ANOVA and Tukey test (P < 0.05). Results: GI (3.169 +/- 1.510a) had the highest means values, similar to GIV (2.752 +/- 0.961a) and GV (2.981 +/- 1.185a) (P < 0.05). Inferior values were obtained in GII (1.472 +/- 0.342b) and GIII (2.037 +/- 0.742ab) had intermediate values (P > 0.05). Oxygen concentration was reduced in groups treated with SA, and the surface exhibited residual granules of the solution. Conclusion: The 10% SA solution reestablishes the bond strength of restorative material to bleached dentin, especially if active protocols of application and aspiration were used. PMID- 29628644 TI - Cone-beam computed tomography evaluation of curved root canals prepared using reciprocal rotary files and rotational rotary files. AB - Aim: The aim of this study is to compare curved root canal preparation between reciprocal rotary files and rotational rotary files in extracted teeth using cone beam computed tomography (CBCT). The independent variable was the file type (reciprocal vs. rotary), and the primary outcome variable was the centering ratio of distance change after canal preparation. Secondary outcomes were canal transportation in extension and direction and the preparation time. Materials and Methods: Forty mesial root canals from extracted permanent molars with curvatures ranging between 25 degrees and 45 degrees were randomly divided into 4 groups. Canals were prepared with two types of reciprocal rotary files (WaveOne and Reciproc) and two types of rotational rotary files (ProTaper and Mtwo), ten canals in each group. The root canals were scanned before and after preparation using CBCT. Group differences in outcome variables were tested using ANOVA and 5% type I error probability. Results: At the middle third of canals, reciprocal rotary files yielded the least amount of deviation from the center in inner-outer furcal direction (P < 0.001). Transportation was shown from the original canal shape in all directions in four groups. The reciprocal rotary files took the least amount of preparation time as well (P < 0.001). Conclusions: Reciprocal files result in less transportation and working time than the rotational files. PMID- 29628645 TI - An ex vivo evaluation of effect of dentin pretreatment with various agents for varying time intervals on the shear bond strength of resin. AB - Background: This article highlights the contribution of collagen structure/stability to the bond strength. We hypothesize that induction of cross linking in dentin collagen fibrils improves dentin collagen stability and thus bond strength with composite also improves. Aims: The aim of the study was to evaluate the effect of collagen cross-linking agents on the shear bond strength of composite resins. Subjects and Methods: One hundred human permanent teeth were randomly divided into three groups: Group I (n = 20) - no dentin pretreatment done, Group II - dentin pretreatment with 10% sodium ascorbate for 5 min (IIa) and 10 min (IIb), and Group III - dentin pretreatment with 6.5% proanthocyanidin (PA) for 5 min (IIIa) and 10 min (IIIb). A composite resin was bonded on prepared surfaces and cured. Thermocycling was done, and shear bond strength of the prepared samples was tested using a universal testing machine. Results: Values of Group I (control) were lowest whereas that of Group II (sodium ascorbate) were highest. The following order of shear bond strength was observed: IIb > IIa > IIIb ~ IIIa > I. Results for sodium ascorbate were found to be time dependent, whereas for PA, differences were nonsignificant. Conclusions: Treatment of dentinal surfaces with collagen cross-linking agent increases the shear bond strengths. PMID- 29628646 TI - Antibacterial activity of dental restorative material: An in vitro study. AB - Aim: The study evaluated the antibacterial effects of dental restorations such as nano-hybrid composite (Empress), a glass ionomer cement (GIC Gold label Type 9) and silver amalgam against Streptococcus mutans. Materials and Methods: A modified bacterial suspension within the material assay was used to study the antibacterial effects. A volume of 20 MUl of bacterial suspensions were placed in a narrow conical cavity within the materials. They were incubated for 0, 3, 6, 12, 24, and 48 h at 37 degrees C. After the incubation period, the number of viable cells in the suspension was evaluated. In liquid culture assay, growth inhibition was measured at A600 nm up to 6 h in bacterial suspensions treated with the eluates of the restorative materials. Statistical Analysis: Kruskal Wallis test and Mann-Whitney's test were performed to determine the significant differences between the control and restorative materials for given incubation periods at 5% level of significance (P < 0.05). Results and Conclusion: After 6 h of incubation, all restorative materials showed an inhibitory effect when compared to the controls. Silver amalgam showed the highest inhibition, followed by GIC Type 9 and composite. Silver amalgam showed marked inhibition after 2 h in comparison to the other material groups. These techniques employed to study the antibacterial effects showed that the silver amalgam had the pronounced inhibitory effect followed by GIC and composite. Further research on these aspects is necessary to determine whether the material can prevent secondary caries formation. PMID- 29628650 TI - Cone-beam computed tomographic evaluation of remaining dentin thickness in bifurcated roots of maxillary first premolars after rotary instrumentation and post space preparation: An in vitro study. AB - Background: Intraradicular procedures remove radicular dentin and jeopardizing longevity of a tooth. Traditional in vitro methods used to determine the remaining dentin thickness (RDT) have limitations. Aim: The aim is to evaluate, using cone-beam computed tomography (CBCT), RDT following rotary instrumentation and post space preparation in buccal and palatal roots of maxillary first premolars. Materials and Methods: Twenty-three maxillary first premolars with two roots were selected. CBCT images were taken preoperatively, after instrumentation and Parapost 3 and 4 preparation (CBCT 1, 2, 3, and 4). RDT was measured 5 mm above apex, 1 mm below furcation, and 1 mm above furcation (Levels 1, 2, and 3). Data were analyzed using ANOVA and post hoc Tukey's test (P = 0.05). Results: Rotary instrumentation and post space preparation reduced RDT in all walls of buccal and palatal roots. Post space preparation with Parapost 3 and 4 reduced RDT in the palatal wall of buccal root to <1 mm and Parapost 4 reduced all walls to 1 mm of dentin. Conclusion: Post space preparation in maxillary first premolars should be performed cautiously. It is safer to place a post in the palatal root of this tooth and limit preparation to Parapost 3. PMID- 29628649 TI - Radiographic and micro-computed tomography classification of root canal morphology and dentin thickness of mandibular incisors. AB - Context: Root canal anatomy is evaluated using different methodologies. Aims: The aim of this study is to evaluate and classify root canal morphology and dentin thicknesses (DT), comparing radiographic and micro-computed tomography (CT) analysis. Materials and Methods: Canal diameter and DT of mandibular incisors (n = 520) were evaluated using digital radiographs in buccolingual (BL) and mesiodistal (MD) directions. The diameter ratio (DR) BL/MD was classified: flattened (FL, DR >4); oval (OV, 2<= DR >=4); rounded (RN, 1.1< DR >2); round (RO, 0.9<= DR >=1.1); and with BL flatness (BL, DR <0.9). OV (n = 110) were subjected to micro-CT. DT and DR were evaluated at 3, 6, and 9 mm. ANOVA, Tukey, and paired Wilcoxon tests (P < 0.05) were used. Results: Radiographic classification was 23.3% FL, 41.3% OV, 27.3% RN, 4.5% RO, and 3.6% BL. DT was similar. Radiographic DT at 3 and 9 mm was greater than micro-CT (P < 0.05) and was similar at 6 mm (P > 0.05). DR differed between the analyses. Oval canals were predominant at all levels radiographically and at 9 and 6 mm in micro-CT analysis, with greater variation at 3 mm. Conclusion: Oval root canals are predominant in mandibular incisors at 9 mm. Radiographic DT is larger than observed in micro-CT at 3 and 9 mm, and the classification differed in each root level. The classification at 9 mm is indicated. PMID- 29628648 TI - Resistance to fracture of teeth instrumented using novel EndoStar E5 rotary versus ProTaper NEXT and WaveOne file systems. AB - Aim: The current study compared the fracture resistance of samples instrumented by two rotary files and a reciprocating file, obturated with gutta-percha and AH Plus. Materials and Methods: A total of 60 freshly extracted mandibular premolar teeth with single roots and single canals were acquired and decoronated at or below the cementoenamel junction. The samples were randomly divided into four groups (n = 15). Group 1 control (noninstrumented/obturated), and for Groups 2-4 root canal instrumentation was done by EndoStar E5 (EE5), ProTaper NEXT (PTN), and WaveOne, respectively. Following instrumentation, the samples were obturated using gutta-percha cones and AH Plus sealer using lateral compaction. A week later, vertical load was applied to the specimen's canal in each group until fracture. The loads required for fracture were recorded and statistically analyzed. Results: The mean loads required to fracture (Newton; N) for the four groups were; 388.54 (+/-29.93), 310.35 (+/-26.05), 328.40 (+/-20.67), and 278.54 (+/-34.16). The loads exhibited highly significant difference (P < 0.0001; analysis variance). The following Tukey's post hoc test confirmed, both samples in Groups 2 and 3 required similar loads for fracture (P > 0.05) and significantly higher than Group 4 (P < 0.01). Conclusion: The samples instrumented by EE5 and PTN exhibit similar fracture resistance. PMID- 29628647 TI - Evaluation of degree of conversion and the effect of thermal aging on the color stability of resin cements and flowable composite. AB - Purpose: The aim of this in vitro study was to evaluate the color stability and degree of conversion (DC) of dual-cure and light-cure cements and flowable composites after thermal aging. Materials and Methods: A total of 50 human incisors were prepared and divided into six groups (n = 10). Veneers were fabricated using IPS Empress Direct composite resin were bonded with three types of luting agents: Light-cured, conventional dual, and flowable composite according to the manufacturer's instructions. The groups were as follows: Filtek Z350XT Flow/Single Bond 2, RelyX ARC/Single Bond 2, RelyX Veneer/Single Bond 2, Tetric N-Flow/Tetric N-Bond, and Variolink II/Tetric N-Bond. Commission Internationale de l'Eclairage L*, a* and b* color coordinates were measured 24 h after cementation procedure with a color spectrophotometer and reevaluated after 10,000 thermal cycles. To evaluate the DC 50 specimens (n = 10) of each resin material were obtained and Fourier transform infrared spectroscopy was used to evaluate the absorption spectra. Statistical analysis was performed with one-way ANOVA and Tukey's test (alpha = 0.05). Results: No statistically significant differences in DeltaE* occurred after aging. The greatest change in lightness occurred in the Variolink II resin cement. Changes in red-green hue were very small for the same cement and largest in the Tetric N-Flow flowable resin composite, while the greatest change in blue-yellow hue was a yellowing of the RelyX ARC luting cement. RelyX ARC exhibited the highest DC, and there were no statistically significant differences in DC among the other cements. Conclusions: Resin-based luting agent might affect the final of ceramic veneer restorations. The thermal aging affected the final color of the evaluated materials, and these were regarded as clinically unacceptable (DeltaE >3.3). PMID- 29628651 TI - A comparative evaluation of effect of modern-curing lights and curing modes on conventional and novel-resin monomers. AB - Aim: The aim of this study is to compare and to evaluate effect of curing light and curing modes on the nanohybrid composite resins with conventional Bis-GMA and novel tricyclodecane (TCD) monomers. Methodology: Two nanohybrid composites, IPS empress direct and charisma diamond were used in this study. Light-emitting diode (LED)-curing unit and quartz-tungsten-halogen (QTH)-curing unit which were operated into two different modes: continuous and soft start. Based on the composite resin, curing lights, and mode of curing used, the samples were divided into 8 groups. After polymerization, the samples were stored for 48 h in complete darkness at 37 degrees C and 100% humidity. The Vickers hardness (VK) of the surface was determined with Vickers indenter by the application of 200 g for 15 s. Three VK readings were recorded for each sample surface both on top and bottom surfaces. For all the specimens, the three hardness values for each surface were averaged and reported as a single value. The mean VK and hardness ratio were calculated. The depth of cure was assessed based on the hardness ratio. Results: Comparison of mean hardness values and hardness ratios was done using ANOVA with post hoc Tukey's test. Conclusion: Both QTH- and LED-curing units had shown the adequate depth of cure. Soft-start-curing mode in both QTH- and LED-curing lights had effectively increased microhardness than the continuous mode of curing. TCD monomer had shown higher hardness values compared with conventional Bis-GMA containing resin. PMID- 29628652 TI - Development of a dual-cure mineral trioxide aggregate-based cement: Biological, physical, and mechanical properties. AB - Purpose: The purpose of this study is to compare the physical, mechanical, and biocompatibility properties of a new dual-cure white mineral trioxide aggregate (D-W-MTA) and a commercial W-MTA. Materials and Methods: Diametral tensile strength (DTS), water sorption (WSp), and water solubility (WSl) tests were performed. Cytotoxicity was observed in primary culture of human pulp fibroblasts (HPFs) and mouse 3T3/NIH fibroblast lineage. Specimens of both materials were embedded in 1 mL of Dulbecco's modified essential medium for 24 h. Cells were incubated for 24 h with the eluates. Cytotoxicity was evaluated by the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and genotoxicity by micronucleus (MN) formation. Data were analyzed by ANOVA and Kruskal-Wallis tests considering P < 0.05. Results: D-MTA and W-MTA not showed cytotoxic effect on the two cell lines. However, D-MTA stimulated HPF growth. The MN count was similar to that of the control group for D-MTA and W-MTA. D-MTA presented lower DTS and WSl. Nevertheless, WSp was similar in the two groups. Conclusion: The results suggest that D-MTA is a promising material for pulp capping. Thus, in vivo tests should be performed to evaluate the performance of this material. PMID- 29628653 TI - Comparison of anti-bacterial efficiency of ibuprofen, diclofenac, and calcium hydroxide against Enterococcus faecalis in an endodontic model: An in vitro study. AB - Context: One of the important goals of root canal therapy is disinfection aided by irrigation and intracanal medicaments. Commonly used nonsteroidal anti inflammatory agents have shown anti-bacterial activity, thus, when used as intracanal medicaments, nonantibiotic agents have the potential to provide anti inflammatory, local analgesic, and anti-bacterial activity. Aim: The aim of this study is to evaluate and compare the anti-bacterial efficiency of anti inflammatory nonantibiotics ibuprofen and diclofenac, and routinely used intracanal dressing calcium hydroxide (Ca[OH]2), against Enterococcus faecalis, in an endodontic model. Materials and Methods: A total of 76 single-rooted mandibular premolar teeth were decoronated and instrumented up to F4-ProTaper rotary. Apical foramen was sealed with composite resin, and all external surfaces made impermeable with nail varnish, except for coronal access. Roots were autoclaved (121 degrees C for 20 min), placed in Eppendorf tubes, and contaminated with E. faecalis for 14 days. Colony-forming unit (CFU) counts were taken before (CFU-1), and after intracanal medication (CFU-2) by paper point sampling. Test medicaments (Group-1: ibuprofen, Group-2: diclofenac, Group-3: Ca[OH]2) were mixed with distilled water (1:1 w/v), placed into root canals, temporarily sealed, and incubated (37 degrees C; 7 days). Group-4 received no medicament (control). Kruskal-Wallis ANOVA was used to compare the four groups and Mann-Whitney U-test for pair-wise comparisons. Results: Within the limitations of the study, anti-inflammatory nonantibiotics (ibuprofen; diclofenac) were shown to have anti-bacterial effect against E. faecalis. Conclusion: Since nonsteroidal anti-inflammatory drugs (NSAIDs) have an anti bacterial effect, it is possible to replace Ca(OH)2 with NSAIDs, or even combine them to form a cocktail of local disinfectants to optimize canal disinfection. PMID- 29628654 TI - Scanning electron microscopic evaluation of marginal adaptation of AH-plus, GuttaFlow, and RealSeal at apical one-third of root canals - Part I: Dentin sealer interface. AB - Background: Complete seal at dentin-sealer-core interface of the root canal is required to maintain long-term periapical health. Aim: The aim of this in vitro scanning electron microscopic (SEM) study was to determine which of the commonly used root canal sealer among AH-Plus, GuttaFlow, and RealSeal provides a superior marginal adaptation with the dentin in the apical third region of root canals. Materials and Methods: Selected 30 human freshly extracted maxillary central incisors were biomechanically prepared, then divided equally into three groups and obturated with AH-Plus, GuttaFlow, and RealSeal using single-cone obturation technique. After sectioning longitudinally, apical third of the roots was observed under SEM; dentin-sealer-core interface was focused. Marginal adaptation and interfacial gaps at dentin-sealer interface of all the samples were evaluated and analyzed statistically in this part of the article. Statistical Analysis Used: Analysis of variance and post hoc Tukey's test. Results: GuttaFlow exhibited least average marginal gap of 2.38 +/- 1.43 MUm, followed by AH-Plus (4.11 +/- 2.85 MUm) and RealSeal (4.65 +/- 3.91 MUm) with no significant difference (P > 0.05) among the groups. Conclusions: As the dentin-sealer interfacial gap is seen to be minimum in GuttaFlow, it is better adapted to dentin in the apical third of root canals compared to AH-Plus and RealSeal. PMID- 29628655 TI - Scanning electron microscopic evaluation of marginal adaptation of AH-Plus, GuttaFlow, and RealSeal at apical one-third of root canals - Part II: Core-sealer interface. AB - Background: Not only the gaps at dentin-sealer interface but also at core-sealer interface may jeopardize the outcome of root canal treatment. Aim: The aim of this in vitro scanning electron microscopic (SEM) study was to determine which root canal sealer among AH-Plus, GuttaFlow, and RealSeal provides a superior marginal adaptation with the core obturating material in the apical third region of root canals. Materials and Methods: Selected 30 human freshly extracted maxillary central incisors were biomechanically prepared, then divided equally into three groups and obturated with AH-Plus, GuttaFlow, and RealSeal using single cone obturation technique. After sectioning longitudinally, apical third of the roots were observed under SEM dentin-sealer-core interface was focused. Marginal adaptation and interfacial gaps at core-sealer interface of all the samples were evaluated and analyzed statistically in this part of the article. Statistical Analysis Used: Analysis of variance and post hoc Tukey's test. Results: Mean average gap was significantly higher (P < 0.05) for AH-Plus (15.65 +/- 10.48 MUm), when compared to GuttaFlow (3.51 +/- 1.81 MUm) and RealSeal (6.01 +/- 2.51 MUm). Between RealSeal and GuttaFlow, the latter showed least marginal gap; however, this difference was not statistically significant (P > 0.05). Conclusions: GuttaFlow is better adapted in the apical third of root canals among 3 sealers. PMID- 29628656 TI - Comparative evaluation of the effect of 10% sodium ascorbate, 10% hesperidin, 1% riboflavin 5 phosphate, collagen cross-linkers, on the pushout bond strength of fiber postluted to radicular dentin: In vitro study. AB - Aims: The aim of the study was to evaluate the effect of 10% sodium ascorbate (SA),10% hesperidin, 1% riboflavin 5-phosphate, collagen cross-linkers, on the pushout bond strength of the fiber resin postluted to the radicular dentin. Materials and Methods: Twenty-eight, single-rooted extracted human teeth were collected. The cleaning shaping and obturation was done followed postspace preparation which was etched with 37% phosphoric acid for 15 s and then rinsed with normal saline. The specimens were divided into four groups and postspaces were irrigated, respectively with. (i) Group 1: Normal saline for 4 min, (ii) Group 2: 10% SA for 4 min, (iii) Group 3: 10% hesperidin for 4 min, and (iv) Group 4: 1% riboflavin 5 phosphate (RFV) for 4 min. The pushout bond strength of fiber postluted to root dentin, of all the above groups, was compared. Posts were luted using Rely X Arc luting cement. Each root was horizontally sectioned to obtain 2 mm thick, 28 dentinal disks, per group. The pushout bond strength test was carried out using Universal Testing Machine. The scores were statistically analyzed using Student's Unpaired "t" and ANOVA test. Results: Comparison of different collagen crosslinker showed that the highest pushout bond strength value was recorded with 10% hesperidin, followed by 1% RFV and 10% SA. Conclusion: All collagen cross-linkers so used, increased the bond strength. The highest push-out bond strength was achieved with 10% hesperidin. PMID- 29628657 TI - Effect of different antioxidants on reversing compromised resin bond strength after enamel bleaching: An in vitro study. AB - Objective: The effect of 10% sodium ascorbate, 10% alpha-tocopherol, 10% grape seed extract, and 10% guava seed extract solutions on the shear bond strength (SBS) of composite resin to bleached enamel was evaluated. Materials and Methods: Labial enamel surfaces of 72 extracted maxillary central incisors were bleached using 37.5% hydrogen peroxide. Sixty-four specimens were divided into four experimental groups (Group I-IV) comprising 16 specimens each and remaining eight specimens were placed in Group V. Groups I-IV were further divided into 2 subgroups: A (10 min) and B (120 min) comprising 8 specimens each. Eight unbleached specimens served as control (Group VI). Immediately following bleaching, Groups IA-IVA and IB-IVB specimens were treated with respective antioxidants for 10 min and 120 min. All specimens were then bonded with composite resin. Specimens were stored in distilled water for 24 h. SBS testing was done. Data were tabulated and subjected to statistical analysis using ANOVA and Tukey's honest significant difference test. Results: Group VI (unbleached) showed the highest SBS followed by Group IV (10% guava seed extract). Conclusion: Use of antioxidants effectively reversed the compromised bond strength of bleached enamel. About 10% guava seed extract application after bleaching showed best bond strength. PMID- 29628658 TI - Internal tunneling resorption associated with invasive cervical resorption. AB - Treating pathological defects that are caused by resorption in teeth can be challenging. The task is complicated further if the resorption extends beyond the restrains of the root. The aim of this report is to describe a case of extensive internal tunneling resorption (ITR) associated with invasive cervical resorption (ICR) in a maxillary right lateral incisor and its nonsurgical treatment. A 22 year-old male was referred to the department of endodontics with a chief complaint of discolored maxillary right lateral incisor or tooth 12 and a history of trauma. An extensive ITR associated with ICR accompanied by apical periodontitis was detected on a preoperative radiograph which was confirmed on a cone-beam computed tomography (CBCT) scan in a maxillary lateral incisor. After chemomechanical debridement and withdrawal of a separated file in the canal, calcium hydroxide was placed as an intracanal medicament for 2 weeks. Biodentine (BD) was used to obturate the defect as well as entire root canal system and to restore ICR. On a 5-year follow-up, the tooth was functional, and periapical healing was evident. Based on results of this case, successful repair of ITR associated with ICR with BD may lead to resolution of apical periodontitis. Trauma to teeth may lead to resorption which may be internal, external, and or a combination of both which may be asymptomatic in some patients. Preoperative assessment using CBCT imaging achieves visualization of location and extents of resorptive defects. Bioactive materials like BD may lead to favorable results in treating such extensive defects. PMID- 29628659 TI - Dens invaginatus with necrotic pulp in a right maxillary lateral incisor with preserved vitality. AB - Dens invaginatus (DI) is a dental malformation occurring in several morphologic types. Consequently, treatment of teeth affected by DI can get complicated because of the complex root canal anatomy. The aim is to describe how to manage a rare report of a DI with necrotic pulp held within the vital pulp of a maxillary lateral incisor. Oral fistula was found on the buccal mucosa of the apex of the vital maxillary lateral incisor with a DI having necrotic pulp. Endodontic treatment of the maxillary lateral incisor and of the tract canal of DI was realized. Clinical disappearance of oral sinus tract was observed after 10 days. On the contrary, the disappearance of radiolucent area occurred after 6 months. A proper and prompt diagnosis is necessary to carry out effective prevention protocols or prevent consequences generating nonrecoverable endo-perio diseases. PMID- 29628660 TI - Whats New in Emergencies, Trauma and Shock? Computed Tomography Profile and its Utilization in Traumatic Brain Injury. PMID- 29628661 TI - Early Predictive Factors of Hypofibrinogenemia in Acute Trauma Patients. PMID- 29628662 TI - Prehospital Ultrasound in Trauma: A Review of Current and Potential Future Clinical Applications. AB - Ultrasound (US) is an essential tool for evaluating trauma patients in the hospital setting. Many previous in-hospital studies have been extrapolated to out of hospital setting to improve diagnostic accuracy in prehospital and austere environments. This review article presents the role of prehospital US in blunt and penetrating trauma management with emphasis on its current clinical applications, challenges, and future implications of such use. PMID- 29628663 TI - Distribution of Laboratory Parameters in Trauma Population. AB - Background: Biochemical laboratory investigations help plan optimum management and communication in short- as well as long-term outcome to trauma victims. Objective: To assess the status of real-time values of biochemical laboratory investigations of different trauma patients and their association with overall mortality. Materials and Methods: Data based on prospective, observational registry of "Towards Improved Trauma Care Outcomes" (TITCO) from four Indian city hospitals. Hemoglobin, hematocrit, random blood sugar, blood urea nitrogen (BUN), and serum creatinine of patients on admission were recorded. Logistic regression was applied with all biochemical investigation as independent variable and overall mortality as dependent variable. Results: Among 17047 trauma patients, 3456 with available laboratory result details were considered for this study. Overall mortality was 20% (range 14%-21%). For the higher laboratory results, value mortality was 21%-70%, with highest death (70%) for higher hemoglobin patients, followed by hematocrit (44%) and then creatinine (43%). Odds of high hemoglobin compared to normal were 15.20; odds of higher and lower of normal creatinine were 3.80 and 1.65 and for BUN were 2.17 and 1.92, respectively. Gender-wise significant difference was in overall female mortality (29%)% compared males (18%). Similar differences were replicated with results of each laboratory tests. Conclusion: The study ascertained the composite additional explanatory values of laboratory parameters in predicting outcome among injured patients in our population from Indian settings. PMID- 29628664 TI - 7.5% NaCl Resuscitation Leads to Abnormal Clot Fibrinolysis after Severe Hemorrhagic Shock and its Correction with 7.5% NaCl Adenosine, Lidocaine, and Mg2. AB - Background: Hyperfibrinolysis is a common complication of hemorrhagic shock. Our aim was to examine the effect of small-volume 7.5% NaCl adenosine, lidocaine, and Mg2+ (ALM) on fibrinolysis in the rat model of hemorrhagic shock. Methods: Rats were anesthetized and randomly assigned to one of four groups: (1) baseline, (2) shock, (3) 7.5% NaCl controls, and (4) 7.5% NaCl ALM. Animals were bled for 20 min (42% blood loss) and left in shock for 60 min before resuscitation with 0.3 ml intravenous bolus 7.5% NaCl +/- ALM. Rats were sacrificed at 5, 10, 15, 30, and 60 min for rotation thromboelastometry and 15 and 60 min for ELISA analyses. Results: After hemorrhagic shock, 7.5% NaCl failed to resuscitate and exacerbated coagulopathy and fibrinolysis. At 15 and 60 min, the activation as extrinsically activated test using tissue factor (EXTEM) with aprotinin to inhibit fibrinolysis (APTEM) test showed little or no correction of fibrinolysis, indicating a plasmin independent fibrinolysis. Clots also had ~ 60% lower fibrinogen (fibrin-based EXTEM activated test with platelet inhibitor cytochalasin D A10) and 36%-50% reduced fibrinogen-to-platelet ratio (11%-14% vs. 22% baseline). In contrast, 7.5% NaCl ALM resuscitated mean arterial pressure and attenuated hyperfibrinolysis and coagulopathy by 15 min. Correction was associated with lower plasma tissue factor, higher plasminogen activator inhibitor-1, and lower D dimers (5% of controls at 60 min). Platelet selectin fell to undetectable levels in ALM animals, which may imply improved endothelial and platelet function during resuscitation. Conclusions: Small-volume 7.5% NaCl resuscitation exacerbated coagulopathy and fibrinolysis that was not corrected by APTEM test. Fibrinolysis appears to be associated with altered fibrin structure during early clot formation and elongation. In contrast, 7.5% NaCl ALM rapidly corrected both coagulopathy and hyperfibrinolysis. PMID- 29628665 TI - Computed Tomography Profile and its Utilization in Head Injury Patients in Emergency Department: A Prospective Observational Study. AB - Context: Based on Glasgow Coma Scale (GCS), head injury can be classified as minor (GCS 13-15), moderate (GCS 9-12), and severe (GCS 3-8). There is a lot of controversy in the use of computed tomography (CT) in head injury patients. Aims: This study was intended to estimate the rate of CT positivity in head injury patients and to define the criteria for doing CT in head injury patients. Settings and Design: This was a prospective observational study in the emergency department (ED) over a 12-month period. Subjects and. Methods: Study involved all head injury patients attending ED. Risk factors studied were a loss of consciousness (LOC), vomiting, seizures, ear bleed, nosebleed, external injuries, and alcohol intoxication. Statistical Analysis Used: Comparison of CT positivity with the patient's demographics and clinical characteristics was carried out using Chi-square. Results: A total of 1782 patients were included in this study. Overall CT positivity was 50.9%. In minor head injury (MHI), CT positivity rate was 38%. The study showed significant association of CT positivity with five variables: LOC >5 min, vomiting, seizures, ear bleed, and nosebleed. Conclusions: From the study, we recommend following: CT is indicated in all patients with moderate and severe head injury (GCS <=12). Low threshold for taking CT is advisable in elderly and alcohol-intoxicated patients. In MHI, CT is indicated if any one of the following risk factors are present: LOC >5 min, history of vomiting, history of seizures, history of ear bleed, and history of nosebleed. PMID- 29628666 TI - Cardiopulmonary Resuscitation: Unusual Techniques for Unusual Situations. AB - Background: The cardiopulmonary resuscitation (CPR) in prone position has been dealt with in 2010 American Heart Association (AHA) guidelines but have not been reviewed in 2015 guidelines. The guidelines for patients presenting with cardiac arrest under general anesthesia in lateral decubitus position and regarding resuscitation in confined spaces like airplanes are also not available in AHA guidelines. This article is an attempt to highlight the techniques adopted for resuscitation in these unusual situations. Aims: This study aims to find out the methodology and efficacy in nonconventional CPR approaches such as CPR in prone, CPR in lateral position, and CPR in confined spaces. Methods: We conducted a literature search using MeSH search strings such as CPR + Prone position, CPR + lateral Position, and CPR + confined spaces. Results: No randomized controlled trials are available. The literature search gives a handful of case reports, some simulation- and manikin-based studies but none can qualify for class I evidence. The successful outcome of CPR performed in prone position has shown compressions delivered on the thoracic spine with the same rate and force as they were delivered during supine position. A hard surface is required under the patient to provide uniform force and sternal counter pressure. Two rescuer technique for providing successful chest compression in lateral position has been documented in the few case reports published. Over the head CPR and straddle (STR), CPR has been utilized for CPR in confined spaces. Ventilation in operating rooms was taken care by an advanced airway in situ. Conclusion: A large number of studies of high quality are required to be conducted to determine the efficacy of CPR in such positions. PMID- 29628667 TI - Early Predictive Factors of Hypofibrinogenemia in Acute Trauma Patients. AB - Background: Uncontrolled hemorrhage still remains a major cause of trauma associated mortality. The events resulting in acute traumatic coagulopathy, particularly hypofibrinogenemia, make control of bleeding difficult. It is essential to timely predict, diagnose, and manage trauma-induced coagulopathy. Aims: The aim of this study is to determine clinical and easily available laboratory variables that are predictive of hypofibrinogenemia in acute trauma patients. Settings and Design: This 2-year retrospective work examined the data of major trauma patients that were referred to Shahid Rajaee Hospital's emergency room in hemorrhagic shock condition. Materials and Methods: Fibrinogen level was assessed for these patients on their arrival at our facility. Along with clinical and routine paraclinical variables, we evaluated the predictive value of these variables for a fibrinogen level below 100 mg/ml. Results: A total of 855 cases were included (females: 16.4%; and males: 83.6%) in the study. The mean +/- SD age was 36 +/- 17.9 years, and the mean +/- SD injury severity score was 12.2 +/- 9. Motor vehicle accident was the most common cause of injury. Three factors, including arterial pH (cut off point = 7.34; area under the curve [AUC]: 0.59), base excess (cutoff point = -4.3; AUC: 0.60), and patients' gender had a significant association with the fibrinogen level under 100 mg/ml. When three factors of pH, BE, and patients' gender are being assessed simultaneously, the AUC became 0.62 (the predictive ability improved). Conclusions: Variables, including arterial pH, BE level, and patients' gender have predictive value for fibrinogen transfusion in trauma. PMID- 29628668 TI - Evaluation of Change in Knowledge and Attitude of Emergency Medicine Residents after Introduction of a Rotation in Emergency Medical Services and Disaster Medicine. AB - Background: Saudi Board of Emergency Medicine (SBEM) graduates are involved in a 1-month rotation in emergency medical services (EMSs) and disaster medicine. The purpose of this study was to evaluate change in knowledge and attitude of EM residents after the introduction of the EMS and disaster medicine rotation. Materials and Methods: The study included 32 3rd-year SBEM residents. A pretest/posttest design and a five-point Likert scale were used. The data included a response to a questionnaire developed by EMS and disaster experts. The questionnaire was distributed on the 1st day of the rotation and 45 days after. Satisfaction questionnaires were distributed after the rotation. The data were analyzed using SPSS 20. Results: Twenty-five residents responded to the satisfaction survey (75%). The overall satisfaction with the course modules was high; the course content showed the highest level of satisfaction (96%), and the lowest satisfaction was for the air ambulance ride outs (56%). The results of the pre-/post-test questionnaire showed an increase of 18.5% in the residents mean score (P < 0.001). In the open-ended section, the residents requested that the schedule is distributed before the course start date, to have more field and hands-on experience, and to present actual disaster incidents as discussion cases. The residents were impressed with the organization and diversity of the lectures, and to a lesser extent for the ambulance ride outs and the mass casualty incident drill l. Seventy-one percent indicated that they would recommend this course to other residents. Conclusion/Recommendation: This study showed that a structured course in EMS and disaster medicine had improved knowledge and had an overall high level of satisfaction among the residents of the SBEM. Although overall satisfaction and improvement in knowledge were significant, there are many areas in need of better organization. PMID- 29628669 TI - Variation in the Practice of Central Venous Catheter and Chest Tube Insertions among Surgery Residents. AB - Objectives: Central venous catheter (CVC) and chest tube (CT) insertions are common bedside procedures frequently performed by surgery residents. Despite published guidelines, variability in the practice exists. We sought to characterize the surgery residents' practice patterns surrounding these two bedside procedures. Materials and Methods: Over the last 11/2 months of the academic year in 2012 and 2013, surgery residents across the US were surveyed online. Participants reported levels of agreement for 15 questions in a 5-point Likert scale format. Results: A total of 219 residents completed the survey. Majority of residents agreed that they received appropriate education and training. Over half of the respondents reported that they did not have attending staff physician's supervision during the procedures. Junior residents felt less confident in performing CVC or CT insertions. Those younger than 29 years old and of female sex were also less confident in performing CT insertion. Although almost all residents reported using maximal sterile barrier precautions, 7% reported not securing their gowns and another 7% reported inadequate draping of patients. About 1/3 reported no hand cleansing before the procedures. Those from community programs compared to university programs less frequently used antibiotics. Sixty-five percent of residents reported routine use of ultrasound for CVC insertion. Conclusion: Surgery residents do not strictly adhere to the guidelines for CVC and CT insertions, and there is substantial variation in the practice of the procedures, which may contribute to complications associated with these procedures. This survey opens new areas for in-service education, feedback, and practices for these procedures to reduce the risk of complications, especially the infectious one. PMID- 29628670 TI - Bilateral Hip Dislocation: An Indicator for Emergent Full-Body Computed Tomography Scan in Polytraumatized Patients? A Case Report and Review of the Literature. AB - We present a rare case of traumatic bilateral asymmetric hip dislocation with pelvic fractures and a traumatic diaphragmatic hernia. A 53-year-old machinist was transferred to our emergency department with the suspicion of a bilateral hip dislocation after he was trapped between an elevator and the roof. Immediate closed reduction of the hips was not performed because of the expected risk of increasing hemodynamic instability with muscular relaxation. An emergent full body computed tomography (CT) scan was made to assess injuries with need for further operative treatment. Thus, closed reduction of both hips was finally performed in the OR directly before the laparotomy for the diaphragmatic repair and the osteosynthesis of the anterior pelvic ring. A 12-month follow-up showed good general health condition with asymptomatic situation of the hip joints and the abdomen. The diagnostic work-up of patients with severe trauma is still debated, a randomized controlled trial showed no reduction of the in-hospital mortality with immediate full-body CT scan compared to a conventional radiological work-up. Traumatic hip dislocations (THDs) are always due to high energy trauma and additional injuries are frequent. To attempt a closed reduction of THD, under general anesthesia can be life-threatening with unrecognized associated injuries. Therefore, THD can serve as selection criteria for immediate full-body CT scan to facilitate diagnosis and treatment of associated injuries sustained by the patient. PMID- 29628671 TI - Scrotal Reconstruction with Integra Following Necrotizing Fasciitis. AB - Scrotal loss from Fournier's gangrene can be a devastating injury with esthetic and functional consequences. Local reconstructive options can be limited by the presence of infection or the loss of neighboring tissue from debridement. IntegraTM bilayer matrix wound dressing is a well-established reconstructive modality, but only one report exists of its use in scrotal reconstruction and this was not in the setting of Fournier's gangrene. We report the successful use of Integra and a subsequent split-thickness skin graft for reconstruction of the anterior scrotum and coverage of the exposed testes in a 43-year-old man who developed Group A Streptococcus necrotizing fasciitis of his right lower extremity, groin, and scrotum requiring serial operative debridements. Stable testicular coverage was achieved with closely matched skin and minimal donor-site morbidity. Further study and a larger sample size will be necessary to better understand the advantages and disadvantages of scrotal reconstruction with Integra. PMID- 29628672 TI - Globe Luxation and Optic Nerve Avulsion by Dog Bite. PMID- 29628673 TI - The "Case-Based Learning Conference" Model at EMINDIA2017: A Novel Implementation of Problem-Based Educational Paradigm. AB - INDUSEM was established as an INDO-US Satellite Knowledge Network in 2005. It brought together the academic leaders and innovators from India and the US with the goal of creating collaborative synergies and creative solutions to advance the knowledge and science of emergency medicine (EM) in India. Since 2005, the leadership of INDUSEM devoted substantial resources, effort, and expertise to ensure that newly implemented clinical institutes and training programs have the necessary resources and logistical support to effectively advance EM and Traumatology Sciences in India. As a result, significant synergies and progress were achieved toward establishing EM training programs and building clinical infrastructure through education, grant funding, research, skills development, bidirectional collaborations, and sustained influence on public health policy development. As INDUSEM's mission matures, its efforts will increasingly focus on creating long-term sustainability across clinical, didactic, educational, outreach, health policy, and research domains. In this joint statement, the authors describe the evolution of INDUSEM's institution of INDO-US Summit into the World Academic Congress of EM , with the parallel inception of an India centric academic enterprise, EMINDIA. PMID- 29628674 TI - The Intensive Care Unit Perspective of Becoming a Level I Trauma Center: Challenges of Strategy, Leadership, and Operations Management. AB - The primary purpose of this narrative is to elucidate the numerous significant changes that occur at the intensive care unit (ICU) level as a medical center pursues becoming a Level I trauma center. Specifically, we will focus on the following important areas: (1) leadership and strategy issues behind the decision to move forward with becoming a trauma center; (2) preparation needed to take a highly functioning surgical ICU and align it for the inevitable changes that happen as trauma go-live occurs; (3) intensivist staffing changes; (4) roles for and training of advanced practice practitioners; (5) graduate medical education issues; (6) optimizing interactions with closely related services; (7) nursing, staffing, and training issues; (8) bed allocation issues; and (9) reconciling the advantages of a "unified adult critical care service" with the realities of the central relationship between trauma and surgical critical care. PMID- 29628675 TI - Challenges, controversies, and innovations in arthroplasty. PMID- 29628676 TI - Metal hypersensitivity in total hip and knee arthroplasty: Current concepts. AB - Metal hypersensitivity (MHS) is a rare complication of total joint arthroplasty that has been linked to prosthetic device failure when other potential causes have been ruled out. The purpose of this review was to conduct an analysis of existing literature in order to get a better understanding of the pathophysiology, presentation, diagnosis, and management of MHS. It has been described as a type IV hypersensitivity reaction to the metals comprising prosthetic implants, often nickel and cobalt-chromium. Patients suffering from this condition have reported periprosthetic joint pain and swelling as well as cutaneous, eczematous dermatitis. There is no standard for diagnosis MHS, but tests such as patch testing and lymphocyte transformation testing have demonstrated utility, among others. Treatment options that have demonstrated success include administration of steroids and revision surgery, in which the existing metal implant is replaced with one of less allergenic materials. Moreover, the definitive resolution of symptoms has most commonly required revision surgery with the use of different implants. However, more studies are needed in order to understand the complexity of this subject. PMID- 29628677 TI - New alternate bearing surfaces in total hip arthroplasty: A review of the current literature. AB - As indications for total hip arthroplasty (THA) have expanded, the incidence of THA has increased among younger patients, who live longer and tend to place more strain on implants via higher activity levels. This demographical shift accentuates the importance of advancing innovation to ensure implant longevity for younger and more active patients. Future innovation, as it pertains to THA components, is likely to focus on modifying implant designs and tribology in conjunction with identification and application of newer biomaterials. By reviewing the literature for development status of various materials and novel design advancements in THA component outside of the standard highly cross-linked polyethylene, this investigation provided an update on the current and future status of design initiatives as they pertain to THA. Though the highlighted alternative bearing surfaces have shown promising in vitro and limited, yet encouraging clinical data, they lack larger and longer-term clinical trial results. Further research and innovation is warranted to identify the optimal bearing surface to most effectively accommodate for the trend of younger and more active patients undergoing THA. Implant longevity is crucial if the clinical success of THA is to be maintained. PMID- 29628678 TI - Unicompartmental knee replacement - Current perspectives. AB - Unicompartmental knee replacement (UKR) is an effective treatment for end-stage, symptomatic unicompartmental osteoarthritis of the knee. However, certain aspects of the procedure are still debated. These areas of discussion include patient selection criteria, implant design and the discrepancy in survival rates between national registries and independent case series. These may contribute in limiting the more widespread acceptance of unicompartmental knee replacement. The aim of this paper is to review the up-to-date evidence on UKR and discuss the most relevant controversies regarding this procedure. PMID- 29628679 TI - Patellofemoral arthroplasty: Current concepts. AB - Isolated patellofemoral arthritis (IPA) is a debilitating condition characterised by a loss of articular cartilage on the patella facets, the trochlear groove or both. By definition, patients with IPA must have normal cartilage in the tibiofemoral compartments of their knee. It is therefore logical to pursue arthroplasty which corrects the abnormality while sparing healthy bone and preserving the knee's native kinematics, which is the premise underpinning patellofemoral arthroplasty (PFA). However, its use remains controversial, with many surgeons still favouring total knee replacement (TKR) in these patients. This paper provides a comprehensive review of PFA in the literature to date and concludes, in carefully selected patients, PFA is worthy of consideration as a functionally superior and economically beneficial joint-preserving procedure - delaying TKR until implant failure or tibiofemoral osteoarthritis progression. PMID- 29628680 TI - Rotating hinge prosthesis for complex revision total knee arthroplasty: A review of the literature. AB - Introduction: The rotating hinge prosthesis was originally used and designed as a primary total knee arthroplasty implant, but was hampered due to poor outcomes and catastrophic failures. Newer rotating hinge implants can be utilized in complex revision total knee arthroplasties when appropriately indicated, but their outcome data is very difficult to interpret due to the strict and varied indications for use and subsequently small number of procedures performed. The goal of this review is to evaluate the current evidence on large cohort, rotating hinge knee prostheses used in the revision setting, in order to provide a clearer understanding of the indications, outcomes and complications. Methods: The PubMed database was utilized to search the available literature regarding "hinged knee," or "rotating hinge" devices. Exclusion criteria included papers focusing on primary arthroplasty, revision for oncologic issues, one-stage revision for infection or studies with less than fifty cases. Results: Review of 115 abstracts after initial search, led to ten studies in the literature that met our inclusion and exclusion criteria. The data shows that rotating hinge knee implants have good survivorship ranging from 51% to 92.5% at 10 years post-operatively. Complication rates range from 9.2% to 63% with infection and aseptic loosening as the most common complications. Conclusion: Rotating hinge knee prostheses are most commonly indicated for infection, aseptic loosening, instability and bone loss in the literature. They have good outcome scores and survivorship, but continue to have high complication and revision rates. The implant is a good option when utilized appropriately for patients that are not candidates for less constrained devices. PMID- 29628681 TI - Fallacies of CT based component size prediction in total knee arthroplasty - Are patient specific instruments the answer? AB - Background: The purpose of the study was to assess the accuracy of tibial and femoral component size prediction using computerised tomography (CT) based patient specific instruments in total knee arthroplasty. Methods: Eighty-eight knees in 58 patients underwent total knee arthroplasty (TKA) using CT based patient specific instruments between March 2015 to April 2016. All patients were assessed for the pre operative femoral and tibial component sizes predicted by the CT-based pre-operative plan. These sizes were compared with the actually implanted sizes during surgery, and the results were assessed. The data were evaluated using Wilcoxon signed rank tests, and p value set at <0.05 for significance. Results: Approximately 72% predicted tibia sizes matched the final implanted sizes whereas 66% femoral implants matched their pre-operative predicted sizes. The difference in the tibial implant size was not statistically significant (p-value > 0.05). However, the difference in the femoral size was statistically significant (p-value 0.009). The downsizing of the tibial component was needed in 14.8% knees whereas upsizing was required in 13.6% of the knees. At the femoral side, 22.7% components required downsizing at the time of implantation as compared to 11.4% components wherein a bigger component was used. Conclusions: We conclude that size prediction using CT-based technology for patient specific instrumentation is not fool proof. The size prediction accuracy for femoral and tibial components at 66% and 72% are low and cannot be relied upon at present. The patient specific technology using CT scan based jigs holds promise for the future, needs refining and fine tuning. PMID- 29628682 TI - Perioperative pain management following total joint arthroplasty: A review and update to an institutional pain protocol. AB - As the rate of total joint arthroplasty increases with the aging population of the United States, new focus on decreasing opioid use through the development of multimodal pain regimens (MPRs) is becoming an important area of research. MPRs use different agents and modes of delivery in order to synergistically address pain at many levels of the pain pathway. MPRs include a combination of acetaminophen, non-steroidal anti-inflammatory drugs (NSAIDs), gabapentinoids, opioids (short- and long-acting), spinal/epidural analgesia, regional nerve blocks, and local anesthetics. This review summarizes the available literature on major components of MPRs shown to be effective in the total joint arthroplasty population. Finally, the authors' preferred method for pain control in the TJA population is reviewed. PMID- 29628683 TI - Short term outcomes of long duration versus short duration tourniquet in primary total knee arthroplasty: A randomized controlled trial. AB - Introduction: A tourniquet is used during the total knee replacement surgery to improve the visibility, to reduce the blood loss and for better cementation. Indirectly it decreases the duration of surgery and enhances the recovery of the patient. Their use however is controversial due to some side effects associated with the use of tourniquet. They may increase the risk of deep vein thrombosis and pulmonary embolism by causing venous stasis, endothelial damage and increased platelet adhesion secondary to distal limb ischemia. Material and Methods: We conducted a randomized controlled trial (RCT) to examine the benefits and risks associated with the use of long duration over short duration tourniquets during TKA. The study was a prospective randomised control trial with a total of 80 knees (40 knees in each group) included in the study. The knees selected for surgery were randomly allocated to one of the two groups: Group A - long duration tourniquet (LT-group) or Group B - short duration tourniquet (ST-group). Result: The average operating time in Group A (43.53+/-3.11 minutes) was statistically less significant than that of Group B (51.7+/-2.56 minutes). Intra-operative blood loss in Group B, was significantly more than that of Group A. Post operative blood loss in the drain was more in long duration tourniquet group. Total blood loss (intra-operative + post-operative) was more in short duration tourniquet group. Pain score (using VAS scale) was comparable in both the groups at the end of the second and sixth week. At sixth weeks there was no significant difference in the range of motion in both the groups. The KSS score was not significantly different in both the groups in post operative period at first, second, and six weeks. There were no events of thrombo-embolism and deep vein thrombosis in either groups. In 11 patients (27.5%) of long duration tourniquet group, swelling, and redness of knee was seen post operatively as compared to three patients (7.5%) of short duration tourniquet group. Conclusion: The use of a short duration tourniquet during TKA gives better symptomatic pain relief in the early postoperative period as compared to long duration use of tourniquet. However, this is associated with increased blood loss, more operating time and not having a clear operative field. We suggest that a rational thinking and reconsidering the practice of routine use of long duration tourniquet in each and every case of TKA is required. PMID- 29628684 TI - Thirty-day mortality following total knee arthroplasty over 7 years at a tertiary referral centre of orthopaedic excellence. AB - Total Knee Arthroplasty (TKA) is one of the most successful orthopaedic procedures. Around 100,000 TKAs are performed yearly in the United Kingdom. The aim of this study was to report the mortality rate within 30 days after a TKA in an Orthopaedic Centre of Excellence. We reviewed prospectively collected data of 7067 TKAs performed between April 2009-November 2016. All mortalities within 30 days of a TKA were recorded. Data such as age, sex, ASA, comorbidities and cause of death was recorded. There were 14 (0.198%) deaths within 30 days of TKA. There were eight male patients and six female patients who died. No statistical difference was demonstrated between gender. (p = 0.37). The mean age was 77.9 years (66-94 years). Means days to death from post-op were 9.6 days (2-30 days). One patient was ASA 1, six patients were ASA 2, six patients were ASA 3 and one patient did not have an ASA recorded. There was no statistical difference between the difference ASA groups. (p = 0.27). Cause of death documented was as follow: acute left ventricular failure-3; myocardial infarction-2; pneumonia-2; pulmonary oedema-1; gastrointestinal bleed-1 and multiorgan failure-1. Four patients did not have their cause of death recorded. The 30-day mortality rate after TKA in our institute is low and is comparable to other institutes. This emphasizes that primary TKA is a safe procedure. The predominant cause of perioperative mortality is cardiopulmonary disease. PMID- 29628685 TI - Total hip replacement in tuberculosis of hip: A systematic review. AB - Total hip replacement (THR) in patients with tuberculous arthritis of the hip is controversial. The timing of surgery, type of prosthesis, reactivation of the disease, high complication rates and the long-term survival of the reconstruction are the major conc erns. There is little information regarding this concern in the literature. We conducted a systematic review of published studies on Total Hip Replacement in patients with Tuberculosis of the hip. A search of Pubmed and Google Scholar database articles published between January 2000 and July 2017 was performed. Thirteen articles were identified, comprising 226 patients. The mean follow-up was 5.48 years. Antituberculosis treatment was given for atleast 2 weeks pre-operatively and continued post-operatively for between six and 18 months after THR. Three patients had reactivation of infection. At the final follow-up, the mean Harris hip score was 89.98. Total Hip Replacement in tuberculosis of hip is safe and efficient way to save the joint function. The most important factors to achieve success include the accurate diagnosis, efficient pre- and postoperative anti-tuberculosis therapy, thorough debridement, two stage procedure for patients with sinus(es). PMID- 29628686 TI - Treatment options for chronic pelvic discontinuity. AB - Chronic pelvic discontinuity is a distinct and unique challenge seen during revision total hip arthroplasty (THA) in which the superior ilium is separated from the inferior ischiopubic segment through the acetabulum, rendering the anterior and posterior columns discontinuous. The operative management of acetabular bone loss in revision THA is one of the most difficult challenges today. Common treatment options include cage reconstruction with bulk acetabular allograft, custom triflange acetabular component, a cup-cage construct, jumbo acetabular cup with porous metal augments, or acetabular distraction with a porous tantalum shell with or without modular porous augments. PMID- 29628687 TI - Megaprosthesis versus Allograft Prosthesis Composite for massive skeletal defects. AB - Massive skeletal defects are encountered in the setting of tumors necessitating excision, failed total hip arthroplasty with periprosthetic bone loss, periprosthetic fracture, complex trauma, multiple failed osteosynthesis and infection. Reconstruction of the segmental defects poses a tremendous challenge to the orthopaedic surgeons. The goal of osseous reconstruction of these defects is to restore the bone length and function. Currently the most commonly employed methods for reconstruction are either a megaprosthesis or an Allograft Prosthesis Composite (APC). Megaprosthesis, initially created for the treatment in neoplastic pathologies are being used for the non-neoplastic pathologies as well. The longevity of these implants is an issue as majority of the patients receiving them are the survivors of oncologic issue or elderly population, both in which the life expectancy is limited. However, the early complications like instability, infection, prosthetic breakage and fixation failure have been extensively reported in several literatures. Moreover, the megaprostheses are non biological options preventing secure fixation of the soft tissue around the implant. The Allograft Prosthesis Composites were introduced to overcome the complications of megaprosthesis. APC is made of a revision-type prosthesis cemented into the skeletal allograft to which the remaining soft tissue sleeve can be biologically fixed. APCs are preferred in young and low risk patients. Though the incidence of instability is relatively low with the composites as compared to the megaprosthesis, apart from infection, the newer complications pertaining to APCs are inevitable that includes non-union, allograft resorption, periprosthetic fracture and potential risk of disease transmission. The current review aims to give an overview on the treatment outcomes, complications and survival of both the megaprostheses and APCs at different anatomic sites in both the upper and lower limbs. PMID- 29628688 TI - Nerve injuries associated with total hip arthroplasty. AB - Nerve injury is a relatively rare, yet potentially devastating complication of total hip arthroplasty (THA). Incidence of this ranges from 0.6 to 3.7%, and is highest in patients with developmental hip dysplasia and previous hip surgery. Apart from patient and surgeon dissatisfaction, this complication can have medico legal consequences. Therefore, the purpose of this study was to review the risk factors, etiology, diagnostic options, management strategies, prognosis, and prevention measures of nerve injuries associated with THA. We specifically evaluated the: 1) sciatic nerve; 2) femoral nerve; 3) obturator nerve; 4) superior gluteal nerve; and 5) the lateral femoral cutaneous nerve. PMID- 29628689 TI - Going forward with reverse shoulder arthroplasty. AB - Rotator cuff is a vital structure of glenohumeral joint, the dysfunction of which leads to debilitating pain and restricted movement. Arthroplasty using unconstrained anatomical prosthesis for treating these conditions have not been successful in the past. Reverse Shoulder Arthroplasty (RSA) is a novel technique specifically designed to address end stage glenohumeral arthritis in rotator cuff deficient joint. Short and mid-term studies have demonstrated a significant improvement in pain and range of motion of the shoulder joint. However there is a very high complication rate in comparison to total and hemiarthroplasty of shoulder joint. Over the years, there has been a steady increase in RSAs performed, both in volume and the indications for its use. This article discusses the biomechanical aspects, indications and critically reviews the clinical outcome following Reverse Shoulder Arthroplasty. PMID- 29628690 TI - The top 10 arthroplasty articles published in last 10 years by Indian authors. AB - Joint replacement surgery is becoming increasingly popular globally and recently,in India. The phenomenon of medical tourism has also contributed to increasing number of arthroplasty surgeries being done every year in our country. The surgeons who work in this highly specialized field of orthopedic surgery, have been publishing their research work in reputed journals. In this paper, we have discussed the most cited Indian papers in the field of arthroplasty. It was observed that publications in high impact and reputed journals attract more citations and therefore it is recommended that the 'good' scientific research work should preferably be submitted to these journals to create greater impact and awareness about ones' research. PMID- 29628691 TI - Prospective study of immunomodulation in osteoarticular tuberculosis non responsive to anti tubercular therapy. AB - Background: Tuberculosis is one of the common disease of Indian subcontinent. India has the highest TB burden, accounting for one fifth of the global incidence. Previous studies have shown positive response of immunomodulation in patients of ostearticular tuberculosis We did this prospective study to assess the role of immunomodulation in the cases of osteoarticular tuberculosis who were not responding to anti tubercular therapy. Materials and method: This study was conducted in our institute. New patients presenting to OPD who were diagnosed with tuberculosis with no previous history of taking anti tubercular treatment were enrolled. Total of 109 patients were diagnosed clinicoradiologically. Four patients, where diagnosis was not confirmed, histopathological examination of tissue was done and the diagnosis was confirmed as tubercular in origin. Newly diagnosed patients were put on anti tubercular therapy(ATT) after documenting there blood parameters (complete hemogram,ESR, serum proteins, CD4 & CD8 counts). After 3 months patients were re-evaluated and favourably responding patients were labelled group A. Those who did not respond to therapy were put on immunomodulation along with continuation of ATT. These were designated as group B and blood parameters were compared with pre immunomodulation values. Results: Out of total 109 patients registered, 73 patients were enlisted in group A, while 30 patients were found to be non-responsive to ATT and were included in non responder group B (six lost to follow up). In group B the blood parameters after one month of completion of immunomodulation showed statistically significant increase in CD4 & CD8 counts (p = 0.04). Mean CD4 count increased from 488/mm3 to 747/mm3 while CD8 count showed increment from 494/mm3 to 617/mm3. Mean haemoglobin values increased along with decrease in ESR and total leucocyte count. In group A mean CD4 and CD8 counts increased with ATT though the results were not significant statistically. Conclusion: Treatment: of tuberculosis has been a great success after introduction of chemotherapy specifically targeting Mycobacterium tuberculosis. In this study relationship between the increase in the peripheral T-cell count and a favourable clinical outcome was further associated with concomitant increase in the haemoglobin level as well as by a decrease in the ESR, total leucocyte count. In our study immunomodulation has shown a good promise to be of adjunctive use in patients on ATT with non responsiveness. PMID- 29628692 TI - Invasive fungal infection in immunocompetent trauma patients - A case series. AB - Zygomycosis is the third leading cause of invasive fungal infection after candidiasis and aspergillosis. Although zygomycosis mostly affects immunocompromised individuals trauma may potentiate infection in immunocompetent individuals. The mortality rate of Zygomycosis is around 50% due to angioinvasion. Here we report a series of 5 cases of angio invasive fungal infection in immunocompetent individuals who sustained trauma in urban areas, out of which only one patient survived following high above knee amputation. PMID- 29628693 TI - Wide resection versus curettage in giant cell tumor with pathological fracture? A systematic review and meta-analysis. AB - Introduction: Currently there is no consensus if wide resection and curettage in giant cell tumor have effect on local recurrence rate in the presence of a pathological fracture. Material and method: We conducted a comprehensive review and meta-analysis of papers which reported outcomes in patients of giant cell tumor with and without a pathological fracture. The odds ratio (OR) of local recurrence between wide resection and curettage group in giant cell tumor with pathological fracture was calculated. Results: 05 eligible papers were selected for final analysis. This included patients, of whom (18.0%) had a pathological fracture. The pooled OR for local recurrence between patients of pathological fracture treated with wide resection and curettage was 0.298% (95% Confidence interval (CI) 0.0669-1.329, p = 0.97). Conclusion: Wide resection and curettage in patients of giant cell tumor with pathological fracture has difference in local recurrence rates. However the presence of a pathological fracture should no be only influential factor in the decision making to perform wide resection or curettage. A proper planning and judicious approach is required in giant cell tumor with pathological fracture for deciding the appropriate treatment method. PMID- 29628694 TI - Changes in frictional coefficient with increased tendon surface tear-An experimental animal model. AB - Aim: Surface tribological properties of a tendon in terms of coefficient of friction and lubrication mechanism are expected to change with the progression of surface tears which can affect the optimal function of the tendon. This study investigated whether coefficient of friction proportionally increases with the progression of a surface tear in a bovine tendon model. Methods: The study was performed using a pin-on-glass tribometer and bovine tendon samples (n = 16) divided into 4 groups. One group of tendons had no surface tears and thus served as a control, whilst the other 3 groups comprised tendons with increasing severity of artificially-induced surface tears. The coefficient of friction and the lubrication mechanism of the four groups of samples were investigated, calculated and compared. Results: Statistical analysis showed significant change in coefficient of friction between the control group and the group with minimal tear (p < 0.05) while no difference noted between the groups of moderate to severe tear suggesting that the coefficient of friction increases initially with appearance of surface tears, though further progression to a significant tear do not cause a further increase in the frictional coefficient. There was no change in the lubrication mechanism between the groups. Conclusion: This finding appears to contradict the speculation that the frictional coefficient continues to increase with an increase in surface tear severity. The finding has not been reported before and requires validation in future with testing in human tissue. PMID- 29628695 TI - Medical textiles in orthopedics: An overview. AB - The use of textile in the medical field is not new; this has given rise to a new branch known as medical textiles. These are being used to repair or replace various other musculoskeletal tissues. The most common uses of biomaterials are to create aseptic conditions for protection, general health care, and hygiene including bedding and clothing, surgical gowns, face masks, head and shoe covers, sterilization wraps, suture anchors, fiber cast and braces/orthotics. These are also used as materials for preparation of wipes, swabs, wound dressings, bandages, gauzes, plasters, pressure garments, orthopedic belts and for new applications, such as heart valves, vascular grafts, artificial veins, artificial ligaments, artificial joints, artificial skin, and artificial cartilage. The truth is that nowadays the use of biomedical textiles is more rampant than anyone realizes. Commonly used materials for preparation of biomedical textiles includes Cotton, Nylon, Silk, Ultra-high molecular weight polyethylene, Polyester, Polypropylene, Poly tetra-fluoro ethylene, Polyether ether ketone, and Polyether ketone. These are prepared from various monomers in varying proportions as per the requirement of the material to be used. Various methods are used in their preparation like Braiding, Knitting, and Weaving, which helps in the development of certain kinds of materials with different specificity and character. Other important measures in the preparation of the medical textile include Denier (the filament counts in multifilament fibers), Tenacity (the strength per denier) and Heat shrink (the amount of shrinkage at a particular time and temperature). PMID- 29628696 TI - Do local antibiotics reduce periprosthetic joint infections? A retrospective review of 744 cases. AB - Periprosthetic joint infections (PJI) are uncommon but not rare and have significant morbidity and financial implications. Local antibiotics have been used successfully in other areas of orthopedics to reduce postoperative infections, but this method has not been proven in total joint arthroplasty (TJA). Beginning January 1, 2014, our primary investigators began using surgical site lavage with providone-iodine solution and administering 2 g of vancomcyin powder in the surgical wound prior to capsule closure for all primary and revision total hip and knee arthroplasties. We performed a retrospective chart review of patients two years prior to this date and two years after to compare occurrence of PJI. The groups were broken down into patients who received local antibiotics versus those who did not. The groups were further broken down by type of surgery performed; primary or revision total hip or knee arthroplasty. Administration of local antibiotics was preventative for PJI only in the primary total knee arthroplasty group (aOR = 0.28, 0.09-0.89). Administration of local antibiotics trended towards a preventative effect for PJI in the other groups but was not statistically significant. Patients receiving local antibiotics had similar blood urea nitrogen and creatinine levels postoperatively compared to the no antibiotics group indicating minimal systemic effects of local vancomycin powder. While the use of local antibiotics may prevent PJI, more data is required especially in the revision arthroplasty groups. PMID- 29628697 TI - Seasonal variation in orthopedic trauma patients-An experience from central India. AB - Objectives: This study aims to determine the various epidemiological factors responsible for orthopedic trauma cases: how do weather patterns, month, season and public working schedule influence the daily frequency of orthopedic trauma. Material and methods: This was a descriptive study performed in the Department of Orthopedics at a tertiary care centre in central India Participants: 7980 trauma cases reported in our study period. Study variables: Demographic characteristics of the cases, time, day, the month of injury and type of trauma and cause of trauma. etc. Statistical analysis: Proportions. Results: In our study period from 2005 to 2016, there were total 7980 admissions, the annual incidence of trauma was 22.78%. RTA was the commonest cause of injury (46.85%). Most common age group affected was 11-40 year age group (64.06%), with the predominance of Male (67.40%) and rural population (72%). The commonest victims of trauma were labourer (37.66%). Maximum cases of trauma occurred during summer (58.9%). Fracture of upper extremity especially around Elbow was common which were 987 (26.41%) amongst which the fracture supracondylar humerus in pediatric age group was most common around 456. And in rainy season and winter season, there was the dominance of lower extremity fracture which was fracture around Ankle and Foot (i.e 557; 23.59%) and fracture of tibia bone (i.e 516; 27.4%) respectively. Conclusion: Orthopedic trauma at a tertiary health care trauma center do vary significantly with the weather and are highest in the Summer season. PMID- 29628698 TI - Drug resistant Skeletal Tuberculosis in a tertiary care centre in South India. AB - Back ground: Drug resistant tuberculosis is alarmingly on the rise especially in developing countries. Skeletal tuberculosis accounts up to 10% of all extra pulmonary tuberculosis. World Health Organisation (WHO) has not formulated guidelines for the management of Multi-drug resistant skeletal tuberculosis. Results: A retrospective analysis of patients treated for musculoskeletal tuberculosis was done, to study drug resistance patterns. The outcome was assessed both clinically and radiologically.898 patients were treated for skeletal tuberculosis during the period of 2006-2013 (96 months). 478 (53.2%) patients were treated for tubercular spondylitis and 420 (46.8%) for extra-spinal skeletal tuberculosis. Ninety two patients (10.2%) had documented resistance to the anti-tubercular drugs. There were 42 mono resistant tuberculosis cases (4.7%), 13 poly resistant cases (1.4%), 33 multi-drug resistant cases (MDR TB) (3.7%) and 4 (0.4%) extremely drug resistant tuberculosis cases (XDR). All the patients were treated medically as per drug susceptibility patterns and protocols. Surgery was performed when indicated in 59 (66%) cases. 85% completed their course of treatment and were successfully healed as per pre-set clinical, biochemical and radiological criteria. The remaining were lost to follow up. One patient died as a result of post op respiratory infection. Conclusions: The prevalence of Multi-drug resistant tuberculosis patients in our centre was 3.7% and that of Extremely drug resistant tuberculosis cases was 0.4%. A Multi disciplinary approach with drug susceptibility tests, sensitive drugs, and surgery if required is essential. Health education is essential to improve awareness among health care professionals about the danger of drug resistance in tuberculosis. PMID- 29628699 TI - Grouping of body areas affected in traffic accidents. A cohort study. AB - Background: Traffic accidents are considered a public health problem and, according to the World Health Organization, currently is the eighth cause of death in the world. Specifically, pedestrians, cyclists and motorcyclists contribute half of the fatalities. Adequate clinical management in accordance with aggregation patterns of the body areas involved, as well as the characteristics of the accident, will help to reduce mortality and disability in this population. Methods: Secondary data analysis of a cohort of patients involved in traffic accidents and admitted to the emergency room (ER) of a high complexity hospital in Medellin, Colombia. They were over 15 years of age, had two or more injuries in different areas of the body and had a hospital stay of more than 24 h after admission. A cluster analysis was performed, using Ward's method and the linfinity similarity measure, to obtain clusters of body areas most commonly affected depending on the type of vehicle and the type of victim. Results: Among 2445 patients with traffic accidents, 34% (n = 836) were admitted into the Intensive Care Unit (ICU) and the overall hospital mortality rate was 8% (n = 201). More than 50% of the patients were motorcycle riders but mortality was higher in pedestrian-car accidents (16%, n = 34). The clusters show efficient performance to separate the population depending on the severity of their injuries. Pedestrians had the highest mortality after having accidents with cars and they also had the highest number of body parts clustered, mainly on head and abdomen areas. Conclusions: Exploring the cluster patterns of injuries and body areas affected in traffic accidents allow to establish anatomical groups defined by the type of accident and the type of vehicle. This classification system will accelerate and prioritize ER-care for these population groups, helping to provide better health care services and to rationalize available resources. PMID- 29628700 TI - Is there a need of Vitamin D supplementation programme in India (VDSPI)? A letter to the Editor. PMID- 29628702 TI - Acute coagulofibrinolytic and inflammatory changes in response to intramedullary nailing and its impact on outcome. PMID- 29628701 TI - Management of growth arrest: Current practice and future directions. AB - Introduction: Premature growth arrest can pose a challenge to the orthopedic surgeon. Various options for treating physeal arrest exist. Methods: Systematic searches were conducted on PubMed/Medline, ScienceDirect, OVID, and Cochrane Library. Secondary searching was performed, where certain articles from reference lists of the selected studies were reviewed that were not found in the primary search. Results: This review article discusses the different methods of management for premature growth arrest. Conclusions: The use of mesenchymal stem cells provides a promising alternative treatment modality. PMID- 29628703 TI - 3D printing and its applications in Orthopedics. PMID- 29628704 TI - Awareness among Indian professional football players about injury prevention strategies: A national survey. AB - Objective: To determine the awareness and application of the injury prevention strategies by professional Indian football players through Standard Questionnaire Based Survey. Design: Descriptive Epidemiological Study. Setting: Professional football clubs in India. Participants: Among 150 professional footballers playing in India, 109 football players participated.. Procedure: The online questionnaire was made in the Google drive application. An online URL (www.tinyurl.com/futbolscptrc) was made in Google accounts by Google drive. 150 professional footballers playing in India were identified and invited to participate in this descriptive epidemiological online survey. All duly filled questionnaire responses were automatically reached in the Google drive inbox. Descriptive analysis was used for the data analysis. Results: Questionnaires were distributed to 150 professional players at nine Indian League clubs. 109 players responded, which represents a response rate of 73%. The player age and number of years as a professional footballers were 25 (4) years (range 18-38 years) and 6 (4) years (range 1-16 years) respectively. The players were from one Premier (9), two Division One (6 and 16), and two Division Two (9 and 15) teams. Conclusions: Most of the professional Indian football players are aware about the injury prevention strategies. However, the application of these strategies is consistently followed by Premier division players. PMID- 29628705 TI - Ultrasound guided versus landmark guided corticosteroid injection in patients with rotator cuff syndrome: Randomised controlled trial. AB - Objective: Impingement syndrome is the most common differential in a patient presenting to an orthopaedic OPD with shoulder pain. Impingement syndrome is often managed with subacromial corticosteroid injection, which can be instilled using either landmark guided (LMG) approach or with the assistance of ultrasound (US). This study was envisaged to enquire whether ultrasound assistance improves the accuracy, efficacy or safety profile of the injection. Methods: 60 patients of rotator cuff syndrome underwent diagnostic ultrasound. They were randomly assigned to receive subacromial injection of 2 ml (40 mg/ml) methylprenisolone and 2 ml of 1% lignocaine combination either by US assistance (n = 30) or using LMG assistance (n = 30). The patients were evaluated before injection and on follow up visits at day 5, week 3, week 6 and 3rd month by a single assessor. The assessor was blinded of the treatment group to which patient belonged. Clinical assessment included demographic and clinical data, accuracy of injection, VAS (0 100) for pain, Constant score with goniometer evaluation of range of motion, patient's self assessment proforma and post injection side effects if any. Results: Initial demographic, clinical and US findings in the groups exhibited no significant differences. The accuracy of US guided injections (100%) was more when compared from LMG injection (93.3%). Both VAS and Constant score showed significant improvement following steroid injection up to 3 months of follow up. However the differences in the two groups were not significant suggesting comparable efficacy of the two approaches. (Mean VAS score decrease: 27.23 for US and 25.16 for LMG, p < 0.05: Mean constant score change: 14.73 for US and 15.00 for LMG, p < 0.05). The safety profile in both groups was comparable. Conclusion: Although US guided injections have a higher accuracy of drug placement in the subacromial bursa, there is no difference in terms of clinical outcomes or safety profile of either of the method. Hence US guided injections seems to be unjustified, when compared to equally efficacious and cost effective LMG steroid injection. PMID- 29628706 TI - Does operative fixation of isolated fractures of ulna shaft results in different outcomes than non-operative management by long arm cast? AB - Objective: The optimal treatment for isolated fractures of ulnar shaft is debatable. The purpose of this study was to compare functional outcomes and radiological union in patients treated for isolated fractures of the ulnar shaft by open reduction and internal fixation and a long arm cast. Methods: This prospective study was conducted at level I trauma center from November 2014 to March 2016. 30 patients with isolated fractures of ulnar shaft were randomized to two groups to receive treatment by open reduction and internal fixation by plates and screws and a long arm cast. Outcome assessment was done by Disabilities of Arm Shoulder and Hand (DASH) score, range of motion at wrist and elbow, grip strength and radiological union. Quantitative variables were summarized Mean or Median. Normality was assessed using Kolmogorov-Smirnov test. Independent samples t-test and Mann-Whitney test were used for normally distributed variables and non normally distributed variables respectively. Categorical variables were summarized as proportions. Effect of the intervention for categorical variables was assessed using Chi-square test. Results: There was no difference between the groups for pain on Visual Analogue Scale (VAS), grip strength, DASH score, and union at the end of 12 months. There was no difference between the groups for range of motion at the elbow and wrist. 12 (85.7%) patients in the ORIF group and 15 (93.7%) in the cast group united at the end of 12 months. The mean time to union was 13 weeks in the ORIF group and 18 weeks in the cast group. Conclusion: Open reduction and internal fixation results in anatomical restoration of ulna, but this does not translates to better functional outcomes in short term (12 months). PMID- 29628707 TI - Predictive factors determining outcomes in pulseless limb in paediatric supracondylar fractures of humerus. AB - Introduction: Amongst all the complications associated with paediatric supracondylar humerus fractures, significant vascular injury is reported in only 1% cases, of which, less than 1% develop Volkmann's ischemic contracture. This study evaluates factors, like delay in presentation of the injury, limb perfusion and pulse, in determining functional outcome in a supracondylar humerus fractures with pulseless limb. Materials & methods: Twenty-one paediatric patients with a pulseless supracondylar humerus fracture presenting from 2012 to 2014 were included. The patients were divided into 3 groups with Group A (pulse returned post-reduction, n = 13), Group B (pink pulseless hand, n = 7) and Group C (white pulseless hand, n = 1). 11 patients in group A and 4 patients in Group B presented within 6 h. of injury while the remaining patients presented after 6 h. The primary outcome was vascular status as indicated by radial pulse and perfusion, and secondary outcomes included functional parameters assessed with Mayo Elbow Performance Score and Flynn criteria. Results: Mean peripheral SpO2 in Group A patients was higher than Group B and Group C had a non-recordable oxygen saturation. Mean capillary refill time was more in Group A than Group B whereas in Group C patient had blanching and no capillary refill was seen. Mean Mayo Elbow Performance Score of Group A patients was highest as compared to Group B and Group C. Patients presenting within 6 h. of injury had a higher mean Mayo Elbow Performance score as compared to the patients presenting after 6 h of injury. Functional outcome as measured by Flynn Criteria was excellent in 13 patients. 6 patients had a good, 2 had fair outcome. A moderate negative correlation (R = -0.5798) was seen between the time elapsed from the injury and the Mayo Elbow Performance score. Conclusion: Duration to presentation since injury, limb perfusion and presence of peripheral pulses seem to be important predictive factors determining the outcomes in pulseless supracondylar fracture humerus. PMID- 29628708 TI - Management of displaced midshaft clavicle fractures in adolescent patients using intramedullary flexible nails: A case series. AB - Introduction: Clavicle fractures are common injuries in adolescent patients. In this study we present our technique and results for treating non-comminuted displaced midshaft clavicle fractures using flexible intra medullary nails. Methods: A retrospective review of prospectively collected data using the electronic medical record was performed. Adolescent patients presenting to a level one pediatric trauma center with acute displaced non comminuted clavicular shaft fractures who were treated with intra medullary flexible nails were included in this study. Results: Seven adolescent patients with non-comminuted displaced mid shaft clavicle fractures were treated with flexible nails over a period of five and half years with an average follow up time of 10 months. The average age was 14.6 years (range 14-16), and a 2 mm nail was used in all cases. Closed reduction was obtained in five cases with only two cases needing open reduction to pass the nail. One patient had skin breakdown over the nail entry and had the nail removed in clinic two months after surgery, all other patients healed with no complication. Sports and full shoulder activity were allowed when radiographic healing was seen at an average 8 weeks. Implant removal was performed four of the seven patients. Conclusion: Flexible intramedullary nailing is an effective minimally invasive method for the treatment of displaced midshaft clavicle fractures in the adolescent population. The surgeon should be aware that a 2 mm nail is likely the optimal diameter, and the nail is difficult to pass beyond the lateral 2-3 cm of the distal segment due to canal narrowing, but passage further than this is not necessary to achieve stability and union. Following these pearls will allow the surgeon to successfully perform the procedure. PMID- 29628709 TI - An unexpected healing of an established non union of the radial neck through teriparatide: A case report and review of literature. PMID- 29628710 TI - Management of completely displaced extention type supracondylar fractures of humerus in children based on a new classification. AB - Background: Paediatric supracondylar fractures are the most common childhood fractures under 8 years of age. Displaced paediatric supracondylar fractures are mostly classified on the basis of fracture geometry and none of the classification systems takes the clinical condition of the limb into consideration. Objective: The purpose of this study was to evaluate the functional outcome of displaced extention type supracondylar fractures of humerus in children managed on the basis of our new classification. Material and methods: A total of 207 children with displaced extention type supracondylar fractures of humerus were classified as per our classification system into simple and complex types, They were managed and followed over a mean period of 24 weeks, and the results were recorded at the final follow-up. Results: We had 175 simple and 32 complex fractures. There was a significant difference in mean surgical time between simple (19.64 +/- 3.52 min) and complex fractures (43.41 +/- 27.07 min). Mean duration of hospital stay was significantly lower in simple fractures (1.02 +/- 0.31 days) as compared to complex fractures (2.62 +/- 1.84 days). Out of 175 patients in simple group 167 (95.4%) had excellent result,6 (3.4%) had good result 1 (0.6%) had fair result and 1 (0.6%) had poor result whereas out of 32 patients in complex group 10 (31.3%) had excellent result, 5 (15.6%) had good result, 11 (34.4%) had fair result and 6 (18.8) had poor result. Overall results were better in simple group as compared to complex group as per Flynn criteria. Conclusions: Management of patients with displaced supracondylar fractures of humerus using Barza classification in emergency room gives good result and gives an idea about management and prognosis. PMID- 29628711 TI - Does the surgery time affect the final outcome of type III supracondylar humeral fractures? AB - Introduction: Supracondylar humeral fractures are common in the pediatric population, with displaced fractures requiring operative intervention. The purpose of this study was to look at our practice and assess whether a difference in clinical outcomes and requirement for open reduction was observed if surgery was delayed. Methods: This was a retrospective medical record and plain radiograph review of patients admitted with type III Gartland supracondylar fractures between January 2014 and December 2015. The patients were seen for up to 12 months postoperatively, and clinical assessment was performed at this stage. Results: There were 116 supracondylar humeral fractures admitted between January 2014 and December 2015, 23 of which were Gartland type III. The mean age of the patients was 6 years, and the mean time from emergency department presentation to surgery was 14 h. Seven of the 23 patients required conversion to open reduction. There were no reported complications and all fractures demonstrated radiographic union. The length of time to surgery did not increase the number of cases requiring open reduction. The results demonstrated that there was no difference in clinical outcomes found between those that had closed manipulation or required conversion to open reduction, nor the time taken to surgery. Conclusion: This study suggest that patients who present with type III supracondylar humeral fractures and have no neurovascular deficit, a delay in pinning of 12 h or more may not result in a significant difference in the need for open reduction or clinical outcomes. Level of evidence: Level IV. PMID- 29628712 TI - Best care paradigm to optimize functionality after extra-articular distal humeral fractures in the young patient. AB - For younger patients with extra-articular distal humerus fractures closed management is plagued with high rates of malunion, suboptimal functional outcomes, extended immobilization with loss of early motion, a delay in return to work, and a general period of lost productivity. Surgical management offers an appealing alternative. Maintaining respect for the triceps musculature and minimizing iatrogenic injury to the radial nerve are primary concerns with operative treatment. Accordingly, use of a triceps-sparing approach and single column plating may be the optimal treatment paradigm in the young patient presenting with an extra-articular distal humerus fracture. PMID- 29628713 TI - Rotator cuff tears in the pediatric population: Comparing findings on arthroscopic evaluation to pre-operative magnetic resonance imaging. PMID- 29628714 TI - A case report on partial scapulectomy with glenoid preservation for Chondromyxoid fibroma of scapula. AB - Chondromyxoid fibroma is a benign bone tumour accounting for less than 1% of all primary bone tumours. It usually affects the metaphyseal region of long bones in the first or second decade of life. It rarely occurs in scapula. We present a case of 29 year old female with biopsy proven Chondromyxoid fibroma of left scapula. She underwent wide marginal excision by partial scapulectomy with preservation of glenoid. Post operatively she has stable shoulder joint with normal range of movement & no recurrence on regular follow up. PMID- 29628715 TI - Solitary osteochondroma of the capitate, in a child. AB - Osteochondromas, are the most common tumors of the long bones in children. Osteochondromas are extremely rare in the carpal bones. They are diagnosed in adult life, in almost all cases in the literature. We report a 7 year old boy, who presented with a hard mass on the dorsum of his hand, with decreased wrist movements. Radiological examination showed a calcified tumor of the second row of the carpal bones, with spherical shape and covered with cartilage. He was surgically treated with removal of a cartilaginous mass that was arising from the capitate. Pathology confirmed the diagnosis of an osteochondroma. PMID- 29628716 TI - Clinical outcomes of percutaneous vertebroplasty for selective single segment dorsolumbar vertebral compression fractures. AB - Overview of literature: Elderly patients sustaining a trivial fall may develop vertebral compression fractures if they are predisposed to any factor that leads to decreased bone mineral density. Such patients suffer with severe pain and disability during the early healing stages. Percutaneous Vertebroplasty is mainly done to provide immediate pain relief and also believed to offer stability to the compressed vertebra by preventing further collapse. Methods: Selected patients [n = 20; Age = 57.9 +/- 7.9 years] with osteoporotic vertebral compression fracture of a single dorsolumbar vertebra were treated with percutaneous vertebroplasty after 2-3 weeks of conservative trail. Their Pain score was noted using numeric rating scale (NRS) before and after the procedure. Functional outcomes were analysed using Roland Morris Disability Questionnaire (RMDQ) score. Results: NRS pain score before procedure was 8.3 +/- 0.6. RMDQ score before procedure was 21.6 +/- 0.5. Third post procedural day NRS pain score was 4.7 +/- 1.2 (p < 0.0001), denoting significant decrease in pain. Functional outcome analysis using RMDQ score showed an average of 87 +/- 6.1 percent improvement (p < 0.0001), by 6 weeks following procedure. Considering pre-injury status all patients were in their best possible functional state by 6 weeks. Conclusions: Percutaneous Vertebroplasty serves its purpose adequately and economically. Under controlled circumstances, it offers immediate pain relief and stability, leading to early recovery in selective patients. Yet, underlying poor bone mineral density status needs to be treated. Study design: Observational Case Series (Level 4). PMID- 29628717 TI - Oblique "Scotty dog" versus antero-posterior (AP) views in performing x-ray guided facet joint injections. AB - Background: Facet joint pain contributes significantly to lower back pain. Image intensifier x-ray guidance is used to locate the facet joints. This can either be in the oblique "Scotty dog" or antero-posterior views. The aim is to investigate whether improved visualisation of facet joints using the oblique method would increase the accuracy of the injection and hence lead to enhanced pain relief effect when compared to AP views in Lumbar facet joints. Methods: Single centre, single blinded. A total of 42 consecutive patients were recruited between December 2014 and March 2015 at Colchester General Hospital. Patients randomly allocated into facet joint injections using the oblique or AP projection. Pre operatively the patients were asked to rate their back pain using a numerical 11 point pain rating scale in the questionnaire. Post-operatively patients were seen at 6 weeks and once again were asked to fill out the afore mentioned questionnaire. The results were collated and statistical analysis performed using Microsoft Excel. Results: 29 patients returned their post-op questionnaire at approximately 6 weeks post-op. 12 patients had oblique view and 17 patients had AP view. There was a statistically significant difference in the pain scores comparing pre and post op scores for both the Oblique and AP groups. However, there was no significant difference when comparing the post-op pain scores or the absolute changes in pain scores between the two groups. Discussion: Spinal facet joint injections provide significant relief at the 6 week post-op follow up with no difference between the oblique and AP techniques. PMID- 29628718 TI - Preliminary results of lumbar disk herniation surgery by Endoscopic Destandau Method. AB - Background: The incidence of Disc herniation is about 2-3% of population. Each year 300,000 procedures performed in USA. The aim of this paper is to describe the utility of endoscopic procedure in treatment of lumbar disc herniation. Methods: We operated 359 patients from September 2013 to December 2016 for lumbar disk herniation by Endoscopic DESTANDAU method (EDM). The average length of surgery was 47 min. We operated 211 male and 148 female patients. In average, patients had pain for 4.3 months before surgery. Results: 310 patients became pain free in six weeks and 332 after 3 months. We had 7 recurrent herniation. Among these patients 4 have been operated for the second time with success. Three patients refused to be operated. And had infiltration. We had 1 deep infection and 3 cutaneous infections. We have 7 two SCF fluid leak. Among them 3 needed second operation. Conclusions: The patients are admitted the day of surgery and are discharged the day after surgery. EDM is a good alternative surgery for lumbar disk herniation in comparison with classical surgery. The duration of hospitalization is shorter and recovery is faster. PMID- 29628719 TI - Extramedullary haematopoiesis: An unusual etiology of backache. PMID- 29628720 TI - Dyslipidemia and Breast Cancer. PMID- 29628721 TI - A Cross-Sectional Study to Assess and Correlate Osteoporosis and Periodontitis among Postmenopausal Women: A Dual Energy X-Ray Absorptiometry Study. AB - Background: Periodontitis and osteoporosis are two diseases found worldwide and increase in intensity with increasing age of the patients. The severity of osteoporosis and periodontitis are found to be more in women during menopause. The aim of this study was to assess and correlate osteoporosis and periodontal disease among post-menopausal women. Materials and Methods: The study consisted of 94 postmenopausal women in the age range of 45-65 years. All the women underwent dual-energy X-ray absorptiometry (DXA) scan to measure bone mineral density (BMD) and were graded as normal, osteopenic, and osteoporotic based on the T score obtained. Data regarding patient's educational level, socioeconomic status (SES), and body mass index (BMI) was recorded. A detailed periodontal examination was carried out using clinical parameters such as oral hygiene index (OHI), plaque Index (PI), probing pocket depth , and clinical attachment loss to check the level of periodontitis. The level of osteoporosis was correlated with the level of periodontitis. Results: The DXA scan revealed that four women were normal, 44 were osteopenic and 46 were osteoporotic. There was no association found between BMD and OHI, PI, educational status, SES, and BMI. Slight periodontitis was observed in eight women, moderate periodontitis in 62, and severe periodontitis in 24 women. Result suggests that there was a statistical correlation between periodontitis and osteoporosis (P = 0.045). Conclusion: There is a definite correlation found between the severity of periodontitis and osteoporosis among postmenopausal women. A close cooperation between general practitioners and dentists in early diagnosis and treatment of both the diseases will reduce the risk and morbidity among postmenopausal women. PMID- 29628722 TI - Yoga as a Therapeutic Intervention in the Management of Dysfunctional Uterine Bleeding: A Controlled Pilot Study. AB - Background: Dysfunctional uterine bleeding (DUB) is one of the most common gynecological disorders encountered in women during the reproductive age. Yoga therapy has shown promising benefits in several gynecological disorders. Methods: Thirty women between the ages of 20 and 40 years with primary DUB were randomly assigned to a yoga (n = 15) and a waitlist control group (n = 15). Participants in the yoga group received a 3-month yoga module and were assessed for hemoglobin values, endometrial thickness (ET), pictorial blood loss assessment chart (PBAC), State-Trait Anxiety Inventory, perceived stress scale, and Pittsburgh Sleep Quality Index (PSQI) before and after a 3-month follow-up period. Results: At the end of 3 months of intervention, the yoga group, unlike the control group, reported a significant reduction in the anxiety scores (P < 0.05) and perceived stress (P < 0.05). The PSQI scores indicated a reduction in sleep disturbances (P < 0.001) and the need for sleep medications (P < 0.01) and higher global scores (P < 0.001). However, there were no changes in PBAC and ET in both the groups. Conclusion: The results indicate that yoga therapy positively impacts the outcome of DUB by reducing the perceived stress and state anxiety and improving the quality of sleep. This warrants larger clinical trials to validate the findings of this pilot study. PMID- 29628723 TI - Prevalence of Postmenopausal Symptoms, Its Effect on Quality of Life and Coping in Rural Couple. AB - Aim: Menopause is a physiological process, with potential to lead to various pathological/psychological complications, leading to change in quality of life (QOL). Although literature suggests the effect of menopause on various aspects of life, there is scarcity of studies from rural setup in this regard. Thus, it is essential to assess extent of menopause-related changes, its awareness, and coping mechanisms in rural couple. This study aimed to find the prevalence of postmenopausal symptoms, its severity, and effect on QOL of rural women and the couples' coping mechanisms. Materials and Methodology: A cross-sectional survey was conducted by approaching 250 families from two villages of Gujarat, India. Inclusion criteria were any woman having attained menopause naturally within last 10 years and having her husband available for data collection. Hundred such couples consenting for participation were included in the study. Data on demographic variables, menopause-specific QOL, personal health of women, and coping of the couple were collected. Results: The prevalence of menopausal symptoms was found to be 47%. Mean (standard deviation) age at menopause was 44.9 (4.9) years. The prevalence of at least one symptom related to vasomotor was 21.3%, physical 91.5%, psychosocial 44.7%, and sexual was 0%. "QOL and Bother" analysis revealed that all those with menopausal symptoms also had their QOL affected from mild-to-moderate extent. The husbands of women with menopausal symptoms were aware of their condition; however, neither of them exhibited use of the active coping mechanism. The avoidant emotional coping strategy appeared to be followed by most. Conclusion: Couples were found to be aware of menopause; however, the symptoms arising as consequence of it seem to be accepted as natural age-related changes. This could possibly account for not taking any active coping strategy despite reporting of mild-to-moderate botheration by women and awareness in both. Rigorous health education and awareness about menopausal changes might be beneficial. PMID- 29628724 TI - Magnitude and Correlates of Anemia in Elderly Women of a Resettlement Colony of Delhi. AB - Background: Anemia of any degree contributes significantly to morbidity and mortality and has a significant effect on the quality of life of elderly women. Despite its clinical importance, anemia in the elderly women is underrecognized. Objectives: The objective of this study was to assess the magnitude and correlates of anemia in elderly women of a resettlement colony of Delhi. Materials and Methods: A community-based, cross-sectional study for the duration of 1 year was conducted among 512 geriatric women (>=60 years). Demographic characteristics, dietary assessment, and behavioral risk factors were determined by interview, and the participants underwent physical examination followed by hemoglobin estimation by HemoCue. Anemia was defined using the WHO criteria of hemoglobin <12 g/dl. Chi-square test was employed to study the association between sociodemographic factors and anemia followed by multivariate regression analysis. Results: The prevalence of anemia was 79.9% according to the WHO criteria of hemoglobin <12 g/dl in females. Age, education, marital status, financial dependence, diagnosed chronic disease, diet, calorie intake, history of worm infestation, and body mass index (BMI) were significantly associated with anemia on univariate analysis. In multivariate analysis, age, marital status, financial dependence, diagnosed chronic disease, diet, calorie intake, and BMI were significant explanatory variables for anemia. Conclusion: Our study points out high prevalence of and some of the major factors associated with anemia in elderly women. The need of the hour is to include our elderly women under the gamut of National Anemia Prophylaxis Program. PMID- 29628725 TI - Robotic-assisted Sacrocolpopexy with versus without Concomitant Midurethral Sling: A 2-year Follow-up of Urinary Symptoms and Quality of Life. AB - Objective: The objective of this study was to assess long-term postoperative urinary incontinence (UI) symptoms and quality of life (QOL) in patients after robotic-assisted sacrocolpopexy (RASC) with or without concomitant midurethral sling (MUS). Materials and Methods: This is a cross-sectional survey of patients comparing long-term postoperative urinary symptoms and QOL measurements in women who underwent RASC with or without MUS. We included all patients from 2011 to 2014 who had RASC with or without MUS. All patients had preoperative urodynamic testing (UDS). Patients who demonstrated stress UI on UDS underwent MUS at the time of RASC. Urinary symptoms and QOL were assessed through the validated Urinary Distress Inventory-6 (UDI-6) and Incontinence Impact Questionnaire-7 (IIQ 7) patient questionnaires. Results: Sixty-eight patients met inclusion criteria, 46 patients completed follow-up questionnaires, and were included in the final analysis. Average length of time to follow-up from surgery was 24 months (range: 6-36 months). A statistically significant difference in UDI-6 scores between the two groups (RASC vs. RASC + MUS) was observed. Median (25th and 75th percentiles) scores for UDI-6 were 22.92 (8.33 and 32.29, respectively) for the RASC group and 4.17 (0 and 13.54, respectively) for the RASC + MUS group (P = 0.0017). Median scores for IIQ-7 were 0 (0 and 29.73 for the 25th and 75th percentiles, respectively) for the RASC group and 0 (0 and 0, respectively) for the RASC + MUS group (P = 0.1691). Conclusion: Patients who underwent RASC + MUS scored significantly lower on the UDI-6, indicating fewer urinary distress symptoms. Although not statistically significant, patients in the RASC + MUS group had lower IIQ-7 scores, indicating less negative impact on QOL, compared to the RASC only group. PMID- 29628726 TI - Abnormal Uterine Bleeding- evaluation by Endometrial Aspiration. AB - : Endometrial evaluation is generally indicated in cases presenting with abnormal uterine bleeding (AUB), especially in women more than 35 years of age. AUB encompasses a variety of presentation, for example, heavy menstrual bleeding, frequent bleeding, irregular vaginal bleeding, postcoital and postmenopausal bleeding to name a few. Many methods are used for the evaluation of such cases, with most common being sonography and endometrial biopsy with very few cases requiring more invasive approach like hysteroscopy. Endometrial aspiration is a simple and safe office procedure used for this purpose. Materials and Methods: We retrospectively analyzed cases of AUB where endometrial aspiration with Pipette (Medgyn) was done in outpatient department between January 2015 and April 2016. Case records (both paper and electronic) were used to retrieve data. Results: One hundred and fifteen cases were included in the study after applying inclusion and exclusion criteria. Most cases were between 46 and 50 years of age followed by 41 45 years. No cases were below 25 or more than 65 years of age. Heavy menstrual bleeding was the most common presentation of AUB. Adequate samples were obtained in 86% of cases while 13.9% of cases' sample was inadequate for opinion, many of which were later underwent hysteroscopy and/or dilatation and curettage (D and C) in operation theater; atrophic endometrium was the most common cause for inadequate sample. Uterine malignancy was diagnosed in three cases. Discussion: Endometrial aspiration has been compared with traditional D and C as well as postoperative histopathology in various studies with good results. Many such studies are done in India as well as in western countries confirming good correlation with histopathology and adequate tissue sample for the pathologist to give a confident diagnosis. No complication or side effect was noted with the use of this device. Conclusion: Endometrial aspiration is a simple, safe, and effective method to sample endometrium in cases of AUB avoiding risk of anesthesia and is less time-consuming. Many similar devices are also available in the market and need to be popularized in all parts of the country. PMID- 29628727 TI - Inositols in Midlife. AB - This review describes the mechanistic, animal, and clinical data related to the use of inositols in midlife. It covers studies related to the mechanism of action of myo-inositol and D-chiro-inositol and randomized controlled trials conducted in postmenopausal women with metabolic syndrome and supports these data with the results of in vitro and animal studies on inositol in nephropathy and other related conditions. Recent advances related to biochemistry, pharmaceutical science, and genetics are discussed. It concludes that inositols have a potential role to play in maintaining metabolic health in postmenopausal women. PMID- 29628728 TI - Breast Abscess Mimicking Breast Carcinoma in Male. AB - Male breast can show almost all pathological entities described in female breast. Inflammatory conditions of the breast in male are not common; however, occasionally, it can be encountered in the form of an abscess. Clinically, gynecomastia always presents as a symmetric unilateral or bilateral lump in the retroareolar region, and any irregular asymmetric lump raises a possibility of malignancy. Radiology should be used as a part of the triple assessment protocol for breast lump along with fine-needle aspiration cytology for definite diagnosis and proper management. PMID- 29628729 TI - Xanthogranulomatous Oophoritis Mimicking an Ovarian Neoplasm: A Rare Case Report. AB - Xanthogranulomatous inflammation of female genital tract is uncommon and is usually seen in endometrium. Only a few cases involving the ovary have been reported. Its clinical manifestations, imaging modalities, and gross features can mimic ovarian malignancy. Thus, a preoperative diagnosis of this entity is important to avoid radical surgical treatment. We report a case of xanthogranulomatous oophoritis in a 24 years female, which was clinically and radiologically misdiagnosed as ovarian neoplasm. The approach to such a case and the differential diagnosis has also been discussed. PMID- 29628730 TI - Squamous Cell Carcinoma Arising in Mature Teratoma of the Ovary Masquerading as Abdominal Tuberculosis. AB - Pure squamous cell carcinoma (SCC) of the ovary is rare. SCC can arise in a mature teratoma (MT), ovarian endometriosis or in a Brenner tumor. SCC is the most common malignant transformation arising in MT and comprises 80% of all cases. Such neoplastic transformations are extremely difficult either to predict or detect early. The mechanism of malignant transformation has not been completely understood. Due to the rarity and the aggressive course, diagnosis and treatment constitute a big challenge. We report a case of SCC arising in MT presenting with a huge abdominopelvic mass and abundant peritoneal collections clinically masquerading as abdominal tuberculosis. A review of literature with special emphasis on prognosis and treatment modalities is also presented. PMID- 29628731 TI - Myofibroblastoma of the Breast: A Rare Cause of Breast Lump in a Postmenopausal Woman. AB - A breast mass in a postmenopausal age woman is treated with a high index of clinical suspicion for malignancy. Myofibroblastoma (MFB) of the breast is a very rare benign stromal tumor, predominantly occurring in menopausal women and older men. Owing to its rarity, nonspecific radiology, cytomorphology, and many variants, it can be confused with other malignant and benign breast lesions and hence can be a source of diagnostic pitfall. We present a case of an MFB of the breast in a 55-year-old female, which was detected on a routine screening mammography. Fine-needle aspiration cytology was inconclusive. Final diagnosis was made by histopathology and immunohistochemistry examination. We report this case as the likelihood of encountering MFB has increased in recent years due to routine mammographic screening, and this lesion should be kept in the differential diagnosis of spindle-cell lesions of the breast. PMID- 29628732 TI - Retraction: Current Concepts in Voiding Dysfunction and Dysfunctional Voiding: A Review from a Urogynaecologist's Perspective. AB - [This retracts the article on p. 104 in vol. 5, PMID: 25316994.][This retracts the article on p. 437 in vol. 27.]. PMID- 29628733 TI - Setting up dental sedation services for special care and medically compromised patients. PMID- 29628734 TI - The implications and applications of nanotechnology in dentistry: A review. AB - The emerging science of nanotechnology, especially within the dental and medical fields, sparked a research interest in their potential applications and benefits in comparison to conventional materials used. Therefore, a better understanding of the science behind nanotechnology is essential to appreciate how these materials can be utilised in our daily practice. The present paper will help the reader understand nanoscience, and the benefits and limitations of nanotechnology by addressing its ethical, social, and health implications. Additionally, nano applications in dental diagnostics, dental prevention, and in dental materials will be addressed, with examples of commercially available products and evidence on their clinical performance. PMID- 29628735 TI - Chilean Dentistry students, levels of empathy and empathic erosion: Necessary evaluation before a planned intervention: Levels of empathy, evaluation and intervention. AB - Objectives: To estimate the general empathy levels and the potential for empathic growth in Dentistry students and demonstrate that the empathic erosion model is not med. Material and methods: Exploratory and cross-sectional study. Population: First- to fifth-year Dentistry students at Universidad San Sebastian, Santiago Campus (Chile). The total student population (N) was 800. The participants completed the Jefferson Scale of Empathy in its Spanish version for medical students, validated and adapted in Chile. A two-factor analysis of variance (model III) was applied to find differences in the means between academic years, between genders, and in the interaction between these two factors. The data were described using simple arithmetic graphs and then processed with SPSS 22.0. The total growth potential was estimated. Results: The Sample (n) consisted of 534 students (66.88% of the population studied, 2016). Differences were found between academic years and genders in general empathy and some of its components. Conclusion: The behavior of empathy levels is not in line with the concept of empathic erosion. This suggests that empathic erosion is a particular and not a general phenomenon. There exists a considerable growth potential for empathy and its components. PMID- 29628736 TI - Comparative evaluation of dimensional stability of impression materials from developing countries and developed countries after disinfection with different immersion disinfectant systems and ultraviolet chamber. AB - Objectives: It was to analyse and compare the effect of different disinfectant systems on the dimensional stability of commonly used irreversible hydrocolloid and addition silicone impression materials from developing countries as compared to materials from developed countries. Material and methods: Disinfectant systems used were glutaraldehyde, sodium hypochlorite and ultraviolet chamber. The stability after disinfection of commonly used alginate and addition silicone of native origin (Algin-Gum & Ad-Sil) was compared with similar impression materials from developed countries (Vignette and Aquasil) and results compared. A CAD/CAM manufactured stainless steel die simulating maxilla with four metal studs at canine and molar region was used. Impressions were made and disinfected after rinsing and drying and casts poured. The cross arch distance, interabutment distance and the occluso-gingival length of the studs was measured under traveling microscope and observations were recorded and compared. ANOVA test and Bonferroni test was applied. Results: An increase in the interabutment and cross arch distance and decrease in occluso-gingival height was seen in the casts obtained. Glutaraldehyde immersion showed variation in the interabutment and cross arch distance for all materials studied. Ultraviolet chamber and sodium hypochlorite produced best results. Dimensional stability of impression materials like Vignette, Algin-Gum & Aquasil was found to within clinically acceptable limits after disinfection while maximum deviation was seen with Algin-Gum. Conclusion: Evaluated materials can be safely disinfected with sodium hypochlorite and ultraviolet chamber. Addition silicone of native origin is at par with impression materials from developed countries but same cannot be said about alginate. PMID- 29628737 TI - In vitro study of white spot lesion: Maxilla and mandibular teeth. AB - Aim: The aim of the study was to evaluate the effect of resin infiltration on colour changes and surface roughness of artificial white spot lesions (WSLs) on maxillary and mandibular premolar. Materials and methods: Sixty (60) extracted sound Maxilla (Mx) and Mandibular (Mn) premolars were randomly divided into 2 groups (test and control). Artificial WSLs were produced on buccal surface of teeth and were immersed in artificial saliva for 8 weeks. Colour components (L*, a*, b*) and surface roughness (Sa*) were assessed on 40 teeth using colour difference meter RD-100 and Alicona(r) Infinite Focus profilometer respectively. The measurements were done at baseline (T1), directly after artificial WSLs (T2), after 24 hours immersed in saliva and application of resin (T3) and immersion in artificial saliva for 1 (T4), 2 (T5), 4 (T6), 6 (T7) and 8 (T8) weeks. SEM images analysis were carried out on 20 teeth in four time points. Results: The values of L* (lightness), b* (yellow/blue) and Sa* (surface roughness) are gradually reduced to the baseline value. Whereas, the value of a* gradually increased with distinct treatment time to achieve the baseline value. The higher value of L* and Sa*, the whiter the lesion suggesting higher degree of enamel demineralization and surface roughness. Lower L* values suggest a masking colour effect. Conclusion: The material produced favorable esthetics on colour and the surface roughness of teeth at distinct treatment times. It is recommended to be used to improve WSL post orthodontic treatment. PMID- 29628738 TI - Calcification of the stylohyoid complex in Libyans. AB - Objective: To investigate the prevalence and pattern of calcification of the stylohyoid complex in Libyan population. Material and methods: Archived digital panoramic radiographs of 3343 patients were collected; 181 images were excluded for underage or poor image quality. Thus, the images of 3162 patients (1081 men, 2081 women; women-to-men ratio, 2:1; age range, 16-68 years; mean age, 36.7 years) retrieved and assigned to one of four morphological patterns of the stylohyoid complex: regular, elongated, calcified, and undetected. Data were analyzed with the Chi2 test using SPSS (Chicago, IL, USA); P values lower than 0.05 were considered statistically significant. Results: Out of 3162 images studied, the styloid process was demonstrated to be regular in 1935 (61.2%), elongated in 541 (17.2%), calcified in 565 (17.8%), and undetected in 121 (3.8%). Symmetric patterns were demonstrated on 2580 (81.6%) images. An elongated stylohyoid complex was significantly more common in women than in men (P = .0404). Conclusion: The anatomical patterns of the stylohyoid complex in Libyans were highly variable. Dental clinicians should recognize the various morphological patterns of the stylohyoid complex on panoramic radiographs. Computed tomography studies are recommended for further morphometric analysis of the stylohyoid complex. PMID- 29628739 TI - Maxillary lateral incisor agenesis; a retrospective cross-sectional study. AB - Objective: This study aims to estimate the prevalence of congenitally missing lateral incisors in a sample of 2662 dental patients in Palestine. Methods: A total of 2662 digital panoramic radiographs were retrospectively examined for the presence of congenitally missing permanent lateral incisors. The radiographs were obtained from the archival records of patients attending a local dental center at the city of Nablus in Palestine. Results: The prevalence of missing lateral incisors among the examined population (n = 2662) was found to be 1.91%. Unilateral agenesis accounted for 66.6% of the total cases that showed at least one missing lateral incisor. Around 79% of the unilateral cases were on the left side while 21% were on the right side. Bilateral agenesis accounted for 33.3% of 34 cases that had at least one congenitally missing permanent maxillary lateral incisor. Conclusion: The prevalence of missing maxillary lateral incisors in this study population was 1.91%) which was within the range reported in different populations. PMID- 29628740 TI - Total and soluble fluoride concentration present in various commercial brands of children toothpastes available in Saudi Arabia - A pilot study. AB - Objective: The aim of this pilot study was to perform chemical analysis and investigate the total and soluble fluoride concentrations in various brands of children toothpastes. Materials and methods: Three samples of five different commercial brands of children toothpastes were collected and divided into five groups; group A - Biorepair Oral Care toothpaste containing no fluoride (control), group B - Signal Kids Strawberry toothpaste having 500 ppm fluoride, group C - Aquafresh Milk Teeth toothpaste having 500 ppm fluoride, group D - Aquafresh Little Teeth toothpaste having 500 ppm fluoride, and group E - Siwak F Junior having 400 ppm F. The total fluoride (TF) and total soluble fluoride (TSF) concentration of the toothpastes was determined using fluoride ion selective electrode. Data were analysed using Paired sample t-test. Results: The measured TF values were inconsistent with that of the declared concentrations by the manufacturers. Mean TF found in the toothpastes ranged between 2.37 and 515.74 ppm whereas, the mean TSF ranged between 2.00 and 503.4 ppm. For two groups, TF was more than the declared TF whereas for the other three groups, it was less than the declared concentration. All the differences between the declared and observed TF concentration were statistically significant (p < .05) except for one group. All the toothpastes demonstrated mean TSF slightly lower than their respective observed mean TF concentrations. Conclusion: The analysis of TF and TSF concentrations revealed variations from the labelled claims. Therefore, some of the toothpastes may have doubtful anti-caries effectiveness owing to deficiency of total and soluble fluoride. PMID- 29628741 TI - Caries risk profiles in orthodontic patients: A 4-year follow-up study using the Cariogram model in governmental vs. private clinics. AB - Objectives: To (1) analyze caries-related factors and (2) evaluate caries risk using the Cariogram model for governmental and private orthodontic patients at de bonding and 4 years after de-bonding. Materials and methods: Forty orthodontic patients with mean age of 26.4 years were recruited from a governmental (G) group (n = 20) and private (P) group (n = 20) and were examined at de-bonding (T1) and 4 years after de-bonding (T2). The examination included a questionnaire, plaque scoring, caries examination, bitewing radiographs, and assessment of salivary secretion rate, buffering capacity and cariogenic microorganisms. The data were entered into the Cariogram program to illustrate the caries risk profiles. Results: The chance to avoid new cavities was higher in P-group compared to G group at T1 (58% and 31%, respectively) (P < 0.01) and T2 (77% and 52%, respectively) (P < 0.001). Plaque index was significantly higher in G-group, and fluoride was used significantly more in P-group at T1 and T2 (P < 0.05). The chance to avoid new cavities was higher at T2 compared to T1 (64% and 44%, respectively) (P < 0.001). Saliva secretion rate and buffer capacity were significantly increased, and the plaque index was significantly decreased at T2 compared to T1 (P < 0.01). Conclusion: According to the Cariogram, orthodontic patients were less likely to avoid new cavities at de-bonding and 4 years after de-bonding in government clinics compared to private clinics, and the caries risk significantly decreased 4 years after orthodontic treatment for all patients, regardless of the location of treatment. PMID- 29628742 TI - Risk of violence-related injury from alcohol consumption and its burden to society in Latin America and the Caribbean. AB - Objectives: The risk for violence-related injury from drinking and attributable burden in the Latin American and Caribbean region was explored. Methods: A probability sample of 1024 emergency department patients reporting a violence related injury was analyzed from 11 countries, using case-crossover fractional polynomial analysis of the number of drinks consumed prior to the event. Results: A dose-response relationship was observed with a six-fold increase in risk (RR=5.6) for less than two drinks prior to injury. Risk was higher for females than males at 10 or more drinks, and higher for those aged 30 and older compared to those younger at all volume levels. Overall, 32.7% of the violence-related injuries were attributable to alcohol. Alcohol attributable fraction (AAF) was nearly three times larger for males (38%) than for females (12.3%). Conclusions: A dose-response relationship was found between the volume of alcohol consumed prior to the event and risk of violence-related injury. Risk was not uniform across gender or age. At higher volumes, females compared to males were at greater risk of injury but had a lower AAF due to their lower prevalence of drinking at higher levels. PMID- 29628743 TI - Global existence and blow-up results for p-Laplacian parabolic problems under nonlinear boundary conditions. AB - This paper is devoted to studying the global existence and blow-up results for the following p-Laplacian parabolic problems: [Formula: see text] Here [Formula: see text], the spatial region D in [Formula: see text] ([Formula: see text]) is bounded, and ?D is smooth. We set up conditions to ensure that the solution must be a global solution or blows up in some finite time. Moreover, we dedicate upper estimates of the global solution and the blow-up rate. An upper bound for the blow-up time is also specified. Our research relies mainly on constructing some auxiliary functions and using the parabolic maximum principles and the differential inequality technique. PMID- 29628744 TI - Anti-periodic oscillations of bidirectional associative memory (BAM) neural networks with leakage delays. AB - In this article, we discuss anti-periodic oscillations of BAM neural networks with leakage delays. A sufficient criterion guaranteeing the existence and exponential stability of the involved model is presented by utilizing mathematic analysis methods and Lyapunov ideas. The theoretical results of this article are novel and are a key supplement to some earlier studies. PMID- 29628745 TI - Remoteness and distance, distance (signless) Laplacian eigenvalues of a graph. AB - Let G be a connected graph of order n. The remoteness of G, denoted by rho, is the maximum average distance from a vertex to all other vertices. Let [Formula: see text], [Formula: see text] and [Formula: see text] be the distance, distance Laplacian and distance signless Laplacian eigenvalues of G, respectively. In this paper, we give lower bounds on [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text], [Formula: see text] and [Formula: see text] and the corresponding extremal graphs are also characterized. PMID- 29628746 TI - Ostrowski type inequalities involving conformable fractional integrals. AB - In the article, we establish several Ostrowski type inequalities involving the conformable fractional integrals. As applications, we find new inequalities for the arithmetic and generalized logarithmic means. PMID- 29628747 TI - On the convergence rates of kernel estimator and hazard estimator for widely dependent samples. AB - In this paper, we establish a Bernstein-type inequality for widely orthant dependent random variables, and obtain the rates of strong convergence for kernel estimators of density and hazard functions, under some suitable conditions. PMID- 29628748 TI - Two inequalities about the pedal triangle. AB - Two conjectures about the pedal triangle are proved. For the first conjecture, the product of the distances from an interior point to the vertices is mainly considered and a lower bound is obtained by the geometric method. To prove the other one, an analytic expression of the distance between the circumcenter and an interior point is achieved by the distance geometry method. A procedure to transform the geometric inequality to an algebraic one is presented. And then the proof is finished with the help of a Maple package, Bottema. The proof process could be applied to similar problems. PMID- 29628749 TI - Hardy-type inequalities in fractional h-discrete calculus. AB - The first power weighted version of Hardy's inequality can be rewritten as [Formula: see text] where the constant [Formula: see text] is sharp. This inequality holds in the reversed direction when [Formula: see text]. In this paper we prove and discuss some discrete analogues of Hardy-type inequalities in fractional h-discrete calculus. Moreover, we prove that the corresponding constants are sharp. PMID- 29628750 TI - Enzyme Deposition by Polydimethylsiloxane Stamping for Biosensor Fabrication. AB - High-performance biosensors were fabricated by efficiently transferring enzyme onto Pt electrode surfaces using a polydimethylsiloxane (PDMS) stamp. Polypyrrole and Nafion were coated first on the electrode surface to act as permselective films for exclusion of both anionic and cationic electrooxidizable interfering compounds. A chitosan film then was electrochemically deposited to serve as an adhesive layer for enzyme immobilization. Glucose oxidase (GOx) was selected as a model enzyme for construction of a glucose biosensor, and a mixture of GOx and bovine serum albumin was stamped onto the chitosan-coated surface and subsequently crosslinked using glutaraldehyde vapor. For the optimized fabrication process, the biosensor exhibited excellent performance characteristics including a linear range up to 2 mM with sensitivity of 29.4 +/- 1.3 MUA mM-1 cm-2 and detection limit of 4.3 +/- 1.7 MUM (S/N = 3) as well as a rapid response time of ~2 s. In comparison to those previously described, this glucose biosensor exhibits an excellent combination of high sensitivity, low detection limit, rapid response time, and good selectivity. Thus, these results support the use of PDMS stamping as an effective enzyme deposition method for electroenzymatic biosensor fabrication, which may prove especially useful for the deposition of enzyme at selected sites on microelectrode array microprobes of the kind used for neuroscience research in vivo. PMID- 29628751 TI - Construction and Test Results of Coils 2 and 3 of a 3-Nested-Coil 800-MHz REBCO Insert for the MIT 1.3-GHz LTS/HTS NMR Magnet. AB - We present construction and test results of Coils 2 and 3 of a 3-coil 800-MHz REBCO insert (H800) for the MIT 1.3 GHz LTS/HTS NMR magnet currently under construction. Each of three H800 coils (Coils 1-3) is a stack of no-insulation REBCO double pancakes (DPs). The innermost 8.67-T Coil 1 (26 DPs) was completed in 2016; the middle 5.64-T Coil 2 (32 DPs) has been wound, assembled, and tested; and for the outermost 4.44-T Coil 3, its 38 DPs have been wound and preliminary tests were performed to characterize each DP at 77 K. Included for Coil 2 are: 1) 77-K data of critical current, index, and turn-to-turn characteristic resistivity of each DP; 2) stacking order of the 32 DPs optimized to maximize the Coil 2 current margin and minimize its Joule dissipation in the pancake-to-pancake joints; 3) procedure to experimentally determine and apply a room-temperature preload to the DP stack; 4) 77-K and 4.2-K test results after each of 64 pancakes was over-banded with 75-MUm-thick stainless steel tape for a radial thickness of 5 mm. Presented for each DP in Coil 3 are 77-K dada of critical current, index, and turn-to-turn characteristic resistivity. PMID- 29628752 TI - From "What the Hell Is Going on?" to the "Mushy Middle Ground" to "Getting Used to a New Normal": Young People's Biographical Narratives Around Navigating Parental Dementia. AB - The number of young people who have a parent with dementia is rising as a result of improvements in diagnosis of young onset variants and demographic shifts. There has, however, been very little research focusing on this group. Accounts elicited as part of the Perceptions and Experiences of Young People With a Parent With Dementia described the period, usually some years, leading up to a diagnosis of a dementia and then the progress of the condition post diagnosis. These narratives were characterized by confusion, uncertainty, trauma, and distress as the young people struggled to make sense of the significant and often extreme, behavioral and attitudinal changes that were symptoms of the illness. This article describes and discusses how the young people experienced and navigated the temporal messiness and consequent biographical disruption arising from parental dementia. PMID- 29628754 TI - The Role of Anaerobic Digestion in Wastewater Management. PMID- 29628753 TI - Motorized Micro-Forceps with Active Motion Guidance based on Common-Path SSOCT for Epiretinal Membranectomy. AB - In this study, we built and tested a handheld motion-guided micro-forceps system using common-path swept source optical coherence tomography (CP-SSOCT) for highly accurate depth controlled epiretinal membranectomy. A touch sensor and two motors were used in the forceps design to minimize the inherent motion artifact while squeezing the tool handle to actuate the tool and grasp, and to independently control the depth of the tool-tip. A smart motion monitoring and a guiding algorithm were devised to provide precise and intuitive freehand control. We compared the involuntary tool-tip motion occurring while grasping with a standard manual micro-forceps and our touch sensor activated micro-forceps. The results showed that our touch-sensor-based and motor-actuated tool can significantly attenuate the motion artifact during grasping (119.81 MUm with our device versus 330.73 MUm with the standard micro-forceps). By activating the CP-SSOCT based depth locking feature, the erroneous tool-tip motion can be further reduced down to 5.11MUm. We evaluated the performance of our device in comparison to the standard instrument in terms of the elapsed time, the number of grasping attempts, and the maximum depth of damage created on the substrate surface while trying to pick up small pieces of fibers (O 125 MUm) from a soft polymer surface. The results indicate that all metrics were significantly improved when using our device; of note, the average elapsed time, the number of grasping attempts, and the maximum depth of damage were reduced by 25%, 31%, and 75%, respectively. PMID- 29628755 TI - High frequency ultrasound: a novel instrument to quantify granuloma burden in cutaneous sarcoidosis. AB - Background: As is the case for many skin diseases, cutaneous sarcoidosis does not currently have an objective measure of disease burden to establish disease severity and response to treatment. The disease has traditionally been assessed by visual skin changes, including induration and erythema; however, such assessments may fail to quantify the total skin granuloma burden, as the majority of the granulomatous inflammation may lie deep within the dermis and not be reliably detected by sight or palpation. Objectives: The purpose of this pilot study is to evaluate the feasibility of high frequency ultrasound as an objective measure of granuloma burden in cutaneous sarcoidosis and to compare high frequency ultrasound to a previously validated clinical instrument (CSAMI) and histopathology evaluation. Results: A strong correlation was observed between the mean brightness of high frequency ultrasound images and both the lesional CSAMI score (Spearman's rho: 0.9710, p = 0.0012) and percent of dermis with granulomas histopathology (Spearman's rho: 0.8407 p = 0.0361). Conclusions: These results confirm high frequency ultrasound is a valid, objective measure of granuloma burden in cutaneous sarcoidosis and represents a novel, non-invasive measure of disease severity that correlates to the previously validated CSAMI clinical severity score and histopathology evaluation. PMID- 29628756 TI - Combination of ranibizumab and indomethacin for neovascular age-related macular degeneration: randomized controlled trial. AB - Purpose: The aim of this study was to evaluate whether indomethacin eye drops and intravitreal ranibizumab (IVR) injections would provide additional benefit over ranibizumab alone in the treatment of choroidal neovascularization (CNV). Participants and methods: This was a randomized, prospective pilot study of eyes with new-onset CNV. Fifty-eight patients were randomized 1:1 into a ranibizumab monotherapy (RM) group and a ranibizumab plus indomethacin (RI) group. All patients received monthly 0.5 mg IVR injections for 3 months, followed by monthly injections administered as needed. RI group patients also self-administered one drop of 0.5% indomethacin three times a day for 12 months. All patients were followed up for 12 months. Results: At 12 months, both groups showed significant improvement in best-corrected visual acuity (BCVA) and central retinal thickness (CRT). The mean BCVA change from baseline to 12 months was -0.12+/-0.04 LogMAR and -0.20+/-0.04 LogMAR in the RM and RI groups, respectively, with the degree of change being significantly different between the two groups (P=0.04). At 12 months, the mean CRT in the RM group (316+/-41.2 um) was significantly higher than that in the RI group (287+/-31.5 um; P=0.004). The mean required number of IVR injections was 7.38+/-0.78 and 6.34+/-0.67 in the RM and RI groups, respectively (P<0.001). Conclusion: Compared to IVR monotherapy, combination therapy with indomethacin eye drops and IVR provides superior anatomical and visual outcomes in patients with naive CNV lesions. Moreover, topical indomethacin might reduce the frequency of IVR injections, which is very beneficial considering the chronic and expensive nature of IVR therapy. PMID- 29628757 TI - The effects of presenting oncologic information in terms of opposites in a medical context. AB - Background: An extensive body of literature has demonstrated that many patients who have been asked to participate in clinical trials do not fully understand the informed consent forms. A parallel independent study has demonstrated that opposites have a special status in human cognitive organization: they are common to all-natural languages and are intuitively and naturally understood and learnt. Purpose: The study investigates whether, and how, the use of opposites impacts on doctor-patient communication: does using the terms "small-large" to describe a nodule (ie, bipolar communication) rather than speaking in terms of centimeters (ie, unipolar communication) affect a patient's understanding of the situation? And is it better to speak of "common-rare" side effects (ie, bipolar communication) instead of the number of people who have suffered from particular side effects (ie, unipolar communication)? Methods: Two questionnaires were created and used, one presenting the information in terms of opposites (ie, bipolar communication) and another using unipolar communication. Results: The participants' perception of their situation (in terms of feeling healthy-ill, being at high-low risk, and their treatment requiring high-low commitment) varied in the two conditions. Moreover, self-reported levels of understanding and satisfaction with how the information was communicated were higher when opposites were used. Limitations: Since this is the first study that addresses the merits of using bipolar structures versus unipolar structures in doctor-patient communication, further work is needed to consolidate and expand on the results, involving not only simulated but also real diagnostic contexts. Conclusion: The encouraging results imply that further testing of the use of opposites in informed consent forms and in doctor-patient communication is strongly advisable. PMID- 29628758 TI - Effect of anterior crowding or spacing on oral health-related quality of life: a cross-sectional study. AB - Introduction: Oral health-related quality of life (OHRQoL) involves many aspects such as chewing ability, sleeping, social interactions, self-esteem, and satisfaction with life and oral health. The increasing research interest in OHRQoL began only after the shortcomings of previous approaches of treating symptoms only and neglecting the patient's self-perception were revealed. Patients and methods: The current study design is a cross-sectional study of patients who attended King Abdulaziz University Dental Hospital (Jeddah, Saudi Arabia) and King Saud University Dental Hospital (Riyadh, Saudi Arabia). After obtaining their verbal consent, young adult and adult patients (mean age 25.19+/ 7.29 years old) with anterior spacing or crowding were recruited to participate in the study. They filled the Arabic short version of the oral-health impact profile-14 questionnaire after a clinical evaluation of the severity of their spacing or crowding. Parameters of spacing/crowding severity assessment were as follows: <4, mild; 4-8, moderate; and >8, severe. Data were analyzed using the chi-square test in SPSS statistical package. The level of significance was set to <0.05. Results: The sample size of this study was 308 subjects. Findings indicated a statistically significant (p=0.001) association between anterior spacing malocclusion (ASM) with Q5 "self-consciousness", since 64.2% of patients with ASM reported being self-conscious. Results indicated a statistically significant association between educational level with anterior crowding malocclusion (ACM; p=0.02) and ASM (p=0.01) with Q3 "painful aching". Moreover, findings indicated a statistically significant association (p=0.04) between income and ACM with Q5 "self-consciousness". On the other hand, results showed no significant association between gender with either ACM or ASM. Conclusion: This study sheds light on how anterior malocclusion (crowding or spacing) impacts OHRQoL negatively, especially heightening self-consciousness about their appearance. These effects should be addressed by the orthodontist during the course of treatment. PMID- 29628759 TI - The development of AZD7624 for prevention of exacerbations in COPD: a randomized controlled trial. AB - Background: p38 mitogen-activated protein kinase (MAPK) plays a central role in the regulation and activation of pro-inflammatory mediators. COPD patients have increased levels of activated p38 MAPK, which correlate with increased lung function impairment, alveolar wall inflammation, and COPD exacerbations. Objectives: These studies aimed to assess the effect of p38 inhibition with AZD7624 in healthy volunteers and patients with COPD. The principal hypothesis was that decreasing lung inflammation via inhibition of p38alpha would reduce exacerbations and improve quality of life for COPD patients at high risk for acute exacerbations. Methods: The p38 isoform most relevant to lung inflammation was assessed using an in situ proximity ligation assay in severe COPD patients and donor controls. Volunteers aged 18-55 years were randomized into the lipopolysaccharide (LPS) challenge study, which investigated the effect of a single dose of AZD7624 vs placebo on inflammatory biomarkers. The Proof of Principle study randomized patients aged 40-85 years with a diagnosis of COPD for >1 year to AZD7624 or placebo to assess the effect of p38 inhibition in decreasing the rate of exacerbations. Results: The p38 isoform most relevant to lung inflammation was p38alpha, and AZD7624 specifically inhibited p38alpha and p38beta isoforms in human alveolar macrophages. Thirty volunteers were randomized in the LPS challenge study. AZD7624 reduced the increase from baseline in sputum neutrophils and TNF-alpha by 56.6% and 85.4%, respectively (p<0.001). In the 213 patients randomized into the Proof of Principle study, there was no statistically significant difference between AZD7624 and placebo when comparing the number of days to the first moderate or severe exacerbation or early dropout. Conclusion: Although p38alpha is upregulated in the lungs of COPD patients, AZD7624, an isoform-specific inhaled p38 MAPK inhibitor, failed to show any benefit in patients with COPD. PMID- 29628760 TI - Support needs of patients with COPD: a systematic literature search and narrative review. AB - Introduction: Understanding the breadth of patients' support needs is important for the delivery of person-centered care, particularly in progressive long-term conditions such as chronic obstructive pulmonary disease (COPD). Existing reviews identify important aspects of managing life with COPD with which patients may need support (support needs); however, none of these comprehensively outlines the full range of support needs that patients can experience. We therefore sought to systematically determine the full range of support needs for patients with COPD to inform development of an evidence-based tool to enable person-centered care. Methods: We conducted a systematic search and narrative review of the literature. Medline (Ovid), EMBASE, PsycINFO, Cochrane Library, and CINAHL were systematically searched for papers which included data addressing key aspects of support need, as identified by patients with COPD. Relevant data were extracted, and a narrative analysis was conducted. Results: Thirty-one papers were included in the review, and the following 13 domains (broad areas) of support need were identified: 1) understanding COPD, 2) managing symptoms and medication, 3) healthy lifestyle, 4) managing feelings and worries, 5) living positively with COPD, 6) thinking about the future, 7) anxiety and depression, 8) practical support, 9) finance work and housing, 10) families and close relationships, 11) social and recreational life, 12) independence, and 13) navigating services. These 13 domains of support need were mapped to three of the four overarching categories of need commonly used in relevant national strategy documents (ie, physical, psychological, and social); however, support needs related to the fourth category (spiritual) were notably absent. Conclusion: This review systematically identifies the comprehensive set of domains of support need for patients with COPD. The findings provide the evidence base for a tool to help patients identify and express their support needs, which underpins a proposed intervention to enable the delivery of person-centered care: the Support Needs Approach for Patients (SNAP). PMID- 29628762 TI - Erratum: Development of transmucosal patch loaded with anesthetic and analgesic for dental procedures and in vivo evaluation [Corrigendum]. AB - [This corrects the article on p. 2901 in vol. 11, PMID: 27382279.]. PMID- 29628761 TI - Respiratory parameters predict poor outcome in COPD patients, category GOLD 2017 B. AB - Background: Respiratory parameters are important predictors of prognosis in the COPD population. Global Initiative for Obstructive Lung Disease (GOLD) 2017 Update resulted in a vertical shift of patients across COPD categories, with category B being the most populous and clinically heterogeneous. The aim of our study was to investigate whether respiratory parameters might be associated with increased all-cause mortality within GOLD category B patients. Methods: The data were extracted from the Czech Multicentre Research Database, a prospective, noninterventional multicenter study of COPD patients. Kaplan-Meier survival analyses were performed at different levels of respiratory parameters (partial pressure of oxygen in arterial blood [PaO2], partial pressure of arterial carbon dioxide [PaCO2] and greatest decrease of basal peripheral capillary oxygen saturation during 6-minute walking test [6-MWT]). Univariate analyses using the Cox proportional hazard model and multivariate analyses were used to identify risk factors for mortality in hypoxemic and hypercapnic individuals with COPD. Results: All-cause mortality in the cohort at 3 years of prospective follow-up reached 18.4%. Chronic hypoxemia (PaO2 <7.3 kPa), hypercapnia (PaCO2 >7.0 kPa) and oxygen desaturation during the 6-MWT were predictors of long-term mortality in COPD patients with forced expiratory volume in 1 second <=60% for the overall cohort and for GOLD B category patients. Univariate analyses confirmed the association among decreased oxemia (<7.3 kPa), increased capnemia (>7.0 kPa), oxygen desaturation during 6-MWT and mortality in the studied groups of COPD subjects. Multivariate analysis identified PaO2 <7.3 kPa as a strong independent risk factor for mortality. Conclusion: Survival analyses showed significantly increased all-cause mortality in hypoxemic and hypercapnic GOLD B subjects. More important, PaO2 <7.3 kPa was the strongest risk factor, especially in category B patients. In contrast, the majority of the tested respiratory parameters did not show a difference in mortality in the GOLD category D cohort. PMID- 29628763 TI - Marked differences in core beliefs about self and others, between sociotropy and autonomy: personality vulnerabilities in the cognitive model of depression. AB - Objective: The cognitive model of depression posits two distinctive personality vulnerabilities termed sociotropy and autonomy, each of which is composed of a cluster of maladaptive self-schemas. It is postulated that negative core beliefs about self underlie maladaptive self-schemas as a whole, whereas those about others may be implicated in the autonomous self-schemas. Therefore, the present study examined the relations of sociotropy and autonomy with core beliefs about self and others. Methods: The sample of this study consisted of 321 healthy Japanese volunteers. Sociotropy and autonomy were evaluated by the corresponding subscales of the Sociotropy-Autonomy Scale. Core beliefs about self and others were assessed by the negative-self, positive-self, negative-other and positive other subscales of the Brief Core Schema Scales. Results: In the forced multiple regression analysis, sociotropy scores were correlated with negative-self scores (beta = 0.389, P < 0.001). Meanwhile, autonomy scores were correlated with positive-self scores (beta = 0.199, P < 0.01) and negative-other scores (beta = 0.191, P < 0.01). Conclusion: The present study suggests marked differences in core beliefs about self and others between sociotropy and autonomy, further contrasting the two personality vulnerabilities to depression. PMID- 29628764 TI - Phenotypic characterization of an older adult male with late-onset epilepsy and a novel mutation in ASXL3 shows overlap with the associated Bainbridge-Ropers syndrome. AB - The additional sex combs like 3 gene is considered to be causative for the rare Bainbridge-Ropers syndrome (BRPS), which is characterized by severe intellectual disability, neonatal hypotonia, nearly absent development of speech and language as well as several facial dysmorphisms. Apart from disruptive autistiform behaviors, sleep disturbances and epileptic phenomena may be present. Here, a 47 year-old severely intellectually disabled male is described in whom exome sequencing disclosed a novel heterozygous frameshift mutation in the ASXL3 gene leading to a premature stopcodon in the last part of the last exon. Mutations in this very end 3' of the gene have not been reported before in BRPS. The phenotypical presentation of the patient including partially therapy-resistant epilepsy starting in later adulthood shows overlap with BRPS, and it was therefore concluded that the phenotype is likely explained by the identified mutation in ASXL3. PMID- 29628765 TI - Low rate of human papillomavirus vaccination among schoolgirls in Lebanon: barriers to vaccination with a focus on mothers' knowledge about available vaccines. AB - Background: Human papillomavirus (HPV) infection is an established predisposing factor of cervical cancer. In this study, we assessed the awareness about genital warts, cervical cancer, and HPV vaccine among mothers having girls who are at the age of primary HPV vaccination attending a group of schools in Lebanon. We also assessed the rate of HPV vaccination among these girls and the barriers to vaccination in this community. Subjects and methods: This is a cross-sectional, school-based survey. A 23-item, self-administered, anonymous, pretested, structured questionnaire with closed-ended questions was used to obtain data. The questionnaire was sent to the mothers through their student girls, and they were asked to return it within a week. Data were analyzed using the Statistical Package for Social Sciences version 21.0. Bivariate analysis was performed using the chi-square test to compare categorical variables, whereas continuous variables were compared using the Student's t-test. Fisher's exact test was used when chi-square test could not be employed. Results: The response rate in our survey was 39.4%. Among the responders, the rate of awareness about HPV infection was 34%, where 72% of the mothers had heard about cervical cancer, and 34% knew that a vaccine is available to prevent cervical cancer. HPV vaccination uptake rate was 2.5%. This lack of vaccination was primarily attributed to the low rate of mothers' awareness about the vaccine (34%). Factors significantly affecting awareness about the vaccine were the mothers' marital age, nationality, level of education, employment, and family income. Barriers to HPV vaccination, other than awareness, were uncertainty about safety or efficacy of the vaccine, conservative ideas of mothers regarding their girls' future sexual life, and relatively high price of the vaccine. Conclusion: Vaccine uptake is low among eligible girls attending this group of schools. The barriers to vaccination are multiple; the most important one is the mothers' lack of knowledge about HPV, cervical cancer, and the modes of prevention. Awareness campaigns along with a multimodal strategy that targets the identified barriers would be recommended to achieve higher rates of HPV vaccination. PMID- 29628766 TI - MiR-152 functioning as a tumor suppressor that interacts with DNMT1 in nasopharyngeal carcinoma. AB - Background: In recent years, miR-152 has been dysregulated in a variety of tumors and used as a tumor suppressor. Nevertheless, its role in nasopharyngeal carcinoma (NPC) remains unidentified. Materials and methods: Real-time quantitative PCR (polymerase chain reaction) was performed to analyze the expression of miR-152 in NPC cell lines. MiR-152 expression profiles in NPC tissues were obtained from Gene Expression Omnibus (GEO GSE36682). The effect of miR-152 on the invasion and proliferation of NPC cells was determined through cell invasion, wound healing, and cell viability assays. Apoptosis was examined by flow cytometry, and Western blot was performed to measure expression of the target gene. Pyrosequencing was used to detect the methylation level of NPC cells. Results: In this study, miR-152 was downregulated in the NPC tissues and cell lines. When miR-152 was enhanced, the invasion and migration of NPC cells were inhibited. However, miR-152 had no effect on the proliferation of NPC cells. Luciferase reporter gene analysis was performed, and the results showed that DNMT1 (DNA (cytosine-5)-methyltransferase 1) is a direct target of miR-152 in NPC cells. DNMT1 downregulation and miR-152 overexpression both reversed the effects of miR-152 inhibition on the NPC cells. In addition, miR-152 expression increased as a result of the inhibition of the methylation level of miR-152 when DNMT1 expression was downregulated. Conclusion: The overexpression of miR-152 inhibited the migration and invasion of NPC cells by targeting DNMT1. Furthermore, DNMT1 regulated miR-152 expression through DNA methylation. Overall, the novel miR-152 DNMT1 regulatory circuit may provide better understanding of the pathogenesis of NPC and new epigenetic therapeutic target in NPC. PMID- 29628767 TI - Interaction between rpsL and gyrA mutations affects the fitness and dual resistance of Mycobacterium tuberculosis clinical isolates against streptomycin and fluoroquinolones. AB - Background: The interaction between different drug-resistant mutations is important to the development of drug resistance and its evolution. In this study, we aimed to reveal the potential relationships between mutations conferring resistance to two important antituberculosis drugs streptomycin (STR) and fluoroquinolones (FLQ). Materials and methods: We used an in vitro competitive fitness assay to reveal the interactions between different mutations of rpsL and gyrA in drug-resistant Mycobacterium smegmatis, followed by the analysis of the frequency of rpsL and gyrA mutation combinations in 213 STR-FLQ dual-resistant clinical Mycobacterium tuberculosis isolates from Sichuan region, which was also investigated by the whole genome data from 3,056 global clinical M. tuberculosis isolates. Results: The strains with K43R and K88R mutation in rpsL showed no difference in relative fitness compared with their susceptible ancestor, while K43N, K43M, K43T, and K88E exhibited a significantly lower relative fitness (P<0.05). For the FLQ-resistant mutants, all mutation types showed no difference in their relative fitness. Among STR-FLQ dual-resistant M. smegmatis strains, a lower fitness was detected in those with K43N/M/T and K88E instead of K43R and K88R mutations in rpsL. Among M. tuberculosis isolates harboring rpsL and gyrA dual mutations, the most two frequent combinatorial mutation types were K43R/D94G (n=37) and K43R/A90V (n=24), with the former being the most frequent one by both in vitro tests and clinical survey. Conclusion: Our results suggest that the interaction between rpsL and gyrA mutations affects the fitness cost in STR-FLQ dual-resistant M. smegmatis and also the predilection of mutation combinations in clinical M. tuberculosis isolates. PMID- 29628768 TI - Outcomes and predictors of treatment response with sofosbuvir plus daclatasvir with or without ribavirin in Egyptian patients with genotype 4 hepatitis C virus infection. AB - Background and aims: Treatment of hepatitis C virus (HCV) changed dramatically with the introduction of oral direct-acting antiviral drugs due to their high antiviral potency and safety profile. Sofosbuvir plus daclatasvir combination therapy was extensively investigated in HCV genotypes 1, 2, and 3, while published data regarding its real-life application in the treatment of genotype 4 is lacking. Therefore, we conducted this study to assess the outcomes and predictors of treatment response with sofosbuvir plus daclatasvir with or without ribavirin in Egyptian patients with genotype 4 hepatitis C virus infection. Patients and methods: This prospective study included 300 Egyptian patients with chronic genotype 4 HCV, treated with sofosbuvir plus daclatasvir with or without ribavirin for 12-24 weeks. Primary outcome was the number of patients who achieved sustained virologic response (SVR12), and secondary outcome was the occurrence of adverse events. Results: A total of 92.67% of all patients achieved SVR12. SVR12 rates of 96.55% and 84.54% were reported in non-cirrhotic and cirrhotic patients, respectively. SVR12 in treatment-naive and treatment experienced patients were 94.12% and 87.01%, respectively. A total of 19.7% of patients experienced mild adverse events. Older age, cirrhosis, and low platelet count were the predictors of treatment non-response. Conclusion: Based on this multi-center prospective study, sofosbuvir plus daclatasvir with or without ribavirin for 12-24 weeks appears to have favorable outcomes in the treatment of genotype 4 HCV-infected Egyptian patients. Older age, cirrhosis, especially Child Pugh class B, and low platelet count are independent risk factors of treatment non-response. PMID- 29628769 TI - Antifungal susceptibility testing of vulvovaginal Candida species among women attending antenatal clinic in tertiary care hospitals of Peshawar. AB - Background: Vulvovaginal candidiasis (VVC) is considered as a pervasive gynecological problem among women worldwide. Owing to this fact, in the current study, we aimed at assessing the prevalence rate of Candida spp. causing VVC in symptomatic pregnant women and their antifungal susceptibility pattern. Methods: This study was carried out in the tertiary care hospitals of Peshawar during the period of July 1, 2016 to December 31, 2016. The study group included 450 pregnant women in the age group of 17-44 years with symptoms of excessive vaginal discharge, pain and pruritis. In all, 108 pregnant women were culture positive for Candida. Antimicrobial susceptibility testing (AST) was conducted on specimens against various azoles and polyene F group of antifungals. Results: Out of 108 Candida spp. isolated from vaginal swabs, there were 45 (41.7%) Candida albicans, 18 (16.7%) Candida tropicalis, 18 (16.7%) Candida krusei, 16 (14.8%) Candida glabrata and 11 (10.2%) Candida dubliniensis. According to age distribution, 27 years was the mean age. Pregnancy trimester distribution among patients was as follows: 21 (19.4%) patients were in their first trimester, 65 (60.2%) patients were in their second trimester and 22 (20.4%) patients were in the third trimester. Susceptibility of fluconazole was determined as follows: 33.3% of the Candida isolates were sensitive, 4.6% were susceptible dose dependent (SDD) and 62% were resistant. Susceptibility of Candida spp. with respect to nystatin in patients with VVC was as follows: 25% were sensitive, 16.7% were SDD and 58.3% were resistant. Susceptibility of clotrimazole was analyzed, and it was sensitive in 21.3% of patients, SDD in 19.4% of patients and resistant in 59.3% of patients. Voriconazole susceptibility was recorded to be sensitive in 85.2% of patients, SDD in 4.6% of patients and resistant in 10.2% of patients suffering from VVC. Susceptibility results for itraconazole in patients with VVC were as follows: 42.6% of patients were sensitive, 16.7% of patients were SDD, and 40.7% of patients were resistant. Conclusion: In this study, frequency of VVC was noted to be high in the second trimester of pregnancy, with the highest frequency of C. albicans isolated, followed by C. tropicalis and C. krusei. Antifungal susceptibility testing revealed that fluconazole was exceedingly resistant against Candida species (62%), followed by clotrimazole (59.3%) and nystatin (58.3%). On the contrary, voriconazole had the highest antimicrobial activity against Candida species (85.2%). PMID- 29628770 TI - Validation of a risk prediction model for Barrett's esophagus in an Australian population. AB - Background: Esophageal adenocarcinoma is a disease that has a high mortality rate, the only known precursor being Barrett's esophagus (BE). While screening for BE is not cost-effective at the population level, targeted screening might be beneficial. We have developed a risk prediction model to identify people with BE, and here we present the external validation of this model. Materials and methods: A cohort study was undertaken to validate a risk prediction model for BE. Individuals with endoscopy and histopathology proven BE completed a questionnaire containing variables previously identified as risk factors for this condition. Their responses were combined with data from a population sample for analysis. Risk scores were derived for each participant. Overall performance of the risk prediction model in terms of calibration and discrimination was assessed. Results: Scores from 95 individuals with BE and 636 individuals from the general population were analyzed. The Brier score was 0.118, suggesting reasonable overall performance. The area under the receiver operating characteristic was 0.83 (95% CI 0.78-0.87). The Hosmer-Lemeshow statistic was p=0.14. Minimizing false positives and false negatives, the model achieved a sensitivity of 74% and a specificity of 73%. Conclusion: This study has validated a risk prediction model for BE that has a higher sensitivity than previous models. PMID- 29628771 TI - Activation of spinal dorsal horn P2Y13 receptors can promote the expression of IL 1beta and IL-6 in rats with diabetic neuropathic pain. AB - Objective: The dorsal horn P2Y13 receptor is involved in the development of pain behavior induced by peripheral nerve injury. It is unclear whether the expression of proinflammatory cytokines interleukin (IL)-1beta and IL-6 at the spinal dorsal horn are influenced after the activation of P2Y13 receptor in rats with diabetic neuropathic pain (DNP). Methods: A rat model of type 1 DNP was induced by intraperitoneal injection of streptozotocin (STZ). We examined the expression of P2Y13 receptor, Iba-1, IL-1beta, IL-6, JAK2, STAT3, pTyr1336, and pTyr1472 NR2B in rat spinal dorsal horn. Results: Compared with normal rats, STZ-diabetic rats displayed obvious mechanical allodynia and the increased expression of P2Y13 receptor, Iba-1, IL-1beta, and IL-6 in the dorsal spinal cord that was continued for 6 weeks in DNP rats. The data obtained indicated that, in DNP rats, administration of MRS2211 significantly attenuated mechanical allodynia. Compared with DNP rats, after MRS2211 treatment, expression of the P2Y13 receptor, Iba-1, IL-1beta, and IL-6 were reduced 4 weeks after the STZ injection. However, MRS2211 treatment did not attenuate the expression of the P2Y13 receptor, Iba-1, IL 1beta, and IL-6 at 6 weeks after the STZ injection. MRS2211 suppressed JAK2 and STAT3 expression in the early stage, but not in the later stage. Moreover, pTyr1336 NR2B was significantly decreased, whereas pTyr1472 NR2B was unaffected in the dorsal spinal cord of MRS2211-treated DNP rats. Conclusion: Intrathecal MRS2211 produces an anti-nociceptive effect in early-stage DNP. A possible mechanism involved in MRS2211-induced analgesia is that blocking the P2Y13 receptor downregulates levels of IL-1beta and IL-6, which subsequently inhibit the activation of the JAK2/STAT3 signaling pathway. Furthermore, blocking the activation of the P2Y13 receptor can decrease NR2B-containing NMDAR phosphorylation in dorsal spinal cord neurons, thereby attenuating central sensitization in STZ-induced DNP rats. PMID- 29628772 TI - Incidence and association factors for the development of chronic post hysterectomy pain at 4- and 6-month follow-up: a prospective cohort study. AB - Chronic pain has major adverse effects on health-related quality of life and contributes to significant socioeconomic burden. Hysterectomy is a very common gynecological surgery, resulting in chronic post-hysterectomy pain (CPHP), an important pain syndrome. We conducted a prospective cohort study in 216 Asian women who underwent abdominal or laparoscopic hysterectomy for benign conditions. Demographic, psychological, and perioperative data were recorded. Postoperative 4 and 6-month phone surveys were conducted to assess the presence of CPHP and functional impairment. The incidence rates of CPHP at 4 and 6 months were 32% (56/175) and 15.7% (25/159), respectively. Women with CPHP at 4 and 6 months had pain that interfered with their activities of daily living. Independent association factors for CPHP at 4 months were higher mechanical temporal summation score, higher intraoperative morphine consumption, higher pain score in the recovery room, higher pain score during coughing and itching at 24 hours postoperatively, and preoperative pain in the lower abdominal region. Independent association factors for CPHP at 6 months were preoperative pain during sexual intercourse, higher mechanical temporal summation score, and higher morphine consumption during postoperative 24 and 48 hours. In a majority of cases, CPHP resolved with time, but may have significant impact on activities of daily living. PMID- 29628773 TI - The mutation of hepatitis B virus and the prognosis of hepatocellular carcinoma after surgery: a pilot study. AB - Background: Although hepatitis B virus (HBV) is still one of the most common etiological factors for hepatocellular carcinoma (HCC), the association between the HBV mutations and the clinical characteristics and prognosis of HBV-related HCC patients (HBV-HCC) after surgical resection remains largely unknown. Materials and methods: A cohort of 131 consecutive patients who received hepatectomy for HBV-HCC were retrospectively enrolled. The HBV genotype and 14 genomic mutations, which have been reported to relate to HCC in liver samples, were sequenced. The associations between the genomic mutations and clinical characteristics and outcomes were analyzed. Results: Both A1762T/G1764A mutation and Pre S deletion related to worse overall survival (OS, p=0.040 and p<0.001, respectively) and disease-free survival (DFS, p=0.040 and p<0.001, respectively), G1899A mutation related to worse OS (p=0.030), A1762T/G1764A mutation correlated with tumor size (r=0.204, p=0.019), G1899A mutation correlated with vascular invasion (r=0.332, p<0.001), and Pre S deletion correlated with alpha-fetoprotein (AFP; r=0.254, p=0.003) positively. Multivariate analysis with Cox proportional hazards model revealed that both A1762T/G1764A mutation and Pre S deletion were independent prognostic factors for OS (hazard ratio [HR]=3.701, 95% CI=1.390 9.855, p=0.009, and HR=4.816, 95% CI=2.311-10.032, p<0.001, respectively) and DFS (HR=3.245, 95% CI=1.400-7.521, p=0.006, and HR=2.437, 95% CI=1.311-4.530, p<0.001, respectively), and patients with dual mutations were found to have the worst OS and DFS (p<0.001 and p<0.001, respectively). Patients with A1762T/G1764A mutation or Pre S deletion were more likely to have early recurrence (p=0.042 and p=0.019, respectively). Conclusion: HBV DNA genomic mutations in A1762T/G1764A and Pre S deletion were associated with worse prognoses and early recurrence for HBV-HCC patients after surgery. PMID- 29628775 TI - Prognostic significance of leukopenia during the induction phase in adult B cell acute lymphoblastic leukemia. AB - The association between chemotherapy-induced leukopenia and clinical outcome has been reported for several types of cancer. The objective of the current study was to evaluate the association of chemotherapy-induced leukopenia during the induction phase with the clinical outcome of adult B cell acute lymphoblastic leukemia (B-ALL). Fifty-one cases of B-ALL, age >=14 years, were reviewed. The variables under consideration included age, sex, the initial white blood cell (WBC) count (WBC-0), as well as the WBC counts on days 8 (WBC-8), 15 (WBC-15), and 22 (WBC-22) during induction therapy, early bone marrow responses on day 15 during induction therapy, immunophenotype, and cytogenetics. Univariate analysis revealed that WBC-15 >=0.40*109/L was significantly associated with inferior event-free survival (EFS) (hazard ratio [HR]=2.95, P=0.004) and overall survival (OS) (HR=2.92, P=0.015). On multivariate analysis, high WBC-15 (>=0.40*109/L) remained an independent prognostic factor for EFS (HR=3.29, P=0.014) and OS (HR=3.29, P=0.038). Our results suggested that WBC-15 may contribute to refinements in the current risk stratification algorithms for adult B-ALL. PMID- 29628774 TI - Management of relapsed/refractory marginal zone lymphoma: focus on ibrutinib. AB - Marginal zone lymphomas (MZLs) consist of a diverse family of malignancies, which are derived from B-cells. The disease subtypes are recognized extranodal, nodal, and splenic MZLs. The disease characteristics, clinical course, and treatment vary considerably based on the site of involvement. In 2017, the US Food and Drug Administration approved ibrutinib, a first in class Bruton's tyrosine kinase inhibitor that revolutionized the care of chronic lymphocytic leukemia patients; for, the treatment of relapsed/refractory MZL based on pivotal open-label Phase II trial demonstrated an overall response rate of 48%, with a complete response rate of 3%, median progression-free survival of 14.2 months, and median overall survival not yet reached at a median follow-up of 19.4 months. In this review, we aim to summarize the current conundrums in the management of MZL and the evolving role of ibrutinib in the treatment of MZL. PMID- 29628776 TI - The association between long-term conditions and uptake of population-based screening for colorectal cancer: results from two English cohort studies. AB - Introduction: Uptake of screening for colorectal cancer (CRC) can reduce mortality, and population-based screening is offered in England. To date, there is little evidence on the association between having a long-term condition (LTC) and CRC screening uptake. The objective of this study was to examine the association between having an LTC and uptake of CRC screening in England with the guaiac fecal occult blood test, with a particular focus on common mental disorders. Methods: The study was a preregistered secondary analysis of two cohorts: first, a linked data set between the regional Yorkshire Health Study (YHS) and the National Health Service National Bowel Cancer Screening Program (BCSP, years 2006-2014); second, the national English Longitudinal Study of Ageing (ELSA, years 2014-2015). Individuals eligible for BCSP screening who participated in either the YHS (7,142) or ELSA Wave 7 (4,099) were included. Study registration: ClinicalTrials.gov, number NCT02503969. Results: In both the cohorts, diabetes was associated with lower uptake (YHS odds ratio [OR] for non uptake 1.35, 95% CI 1.03-1.78; ELSA 1.33, 1.03-1.72) and osteoarthritis was associated with increased uptake (YHS 0.75, 0.57-0.99; ELSA 0.76, 0.62-0.93). After controlling for broader determinants of health, there was no evidence of significantly different uptake for individuals with common mental disorders. Conclusion: Two large independent cohorts provided evidence that uptake of CRC screening is lower among individuals with diabetes and higher among individuals with osteoarthritis. Further work should compare barriers and facilitators to screening among individuals with either of these conditions. This study also demonstrates the benefits of data linkage for improving clinical decision-making. PMID- 29628777 TI - A study on the efficacy and safety of combining dental surgery with tonsillectomy in pediatrics. AB - Purpose: Few data exist on combining pediatric surgical procedures under a single general anesthetic encounter (general anesthesia). We compared perioperative outcomes of combining dental surgical procedures with tonsillectomy during one anesthetic vs separate encounters. Methods: We classified elective tonsillectomy +/- adenoidectomy and restorative dentistry as combined (group C) or separate (group S). Outcomes included anesthesia time, recovery duration, the need for overnight hospital stay, and postoperative complications. Results: Patients aged 4+/-1 years underwent tonsillectomy and dental surgery in combination (n=7) or separately (n=27). No differences were noted in total anesthesia time (C: median: 150, interquartile range [IQR]: 99, 165 vs S: median: 109, IQR: 92, 132; 95% CI of difference in median: -58, +10 minutes; P=0.115) and total recovery time (C: median: 54, IQR: 40, 108 vs S: median: 72, IQR: 58, 109; 95% CI of difference in median: -16, +48 minutes; P=0.307). The need for overnight stay (C: 4 of 7, S: 20 of 27; P=0.394) did not differ between the groups. No postoperative complications were noted in either group. Conclusion: These preliminary data support the potential feasibility of combining dental procedures with tonsillectomy during a single anesthetic encounter. Such care may not only reduce costs but also limit parental work absences and increase convenience for patient families. When compared with procedures performed separately, combined procedures did not result in increased morbidity or significant changes in postoperative outcomes. PMID- 29628778 TI - Effect of different semimonolithic designs on fracture resistance and fracture mode of translucent and high-translucent zirconia crowns. AB - Purpose: The aim of this study was to describe different designs of semimonolithic crowns made of translucent and high-translucent zirconia materials and to evaluate the effect on fracture resistance and fracture mode. Methods: One hundred crowns with different designs were produced and divided into five groups (n=20): monolithic (M), partially veneered monolithic (semimonolithic) with 0.3 mm buccal veneer (SM0.3), semimonolithic with 0.5 mm buccal veneer (SM0.5), semimonolithic with 0.5 mm buccal veneer supported by wave design (SMW), and semimonolithic with 0.5 mm buccal veneer supported by occlusal cap design (SMC). Each group was divided into two subgroups (n=10) according to the materials used, translucent and high-translucent zirconia. All crowns underwent artificial aging before loading until fracture. Fracture mode analysis was performed. Fracture loads and fracture modes were analyzed using two-way ANOVA and Fisher's exact probability tests (P<=0.05). Results: SM0.3 design showed highest fracture loads with no significant difference compared to M and SMW designs (P>0.05). SM0.5 design showed lower fracture loads compared to SMW and SWC designs. Crowns made of translucent zirconia showed higher fracture loads compared to those made of high-translucent zirconia. M, SM0.3, and all but one of the SMC crowns showed complete fractures with significant differences in fracture mode compared to SMW and SM0.5 crowns with cohesive veneer fractures (P<=0.05). Conclusion: Translucent and high-translucent zirconia crowns might be used in combination with 0.3 mm microcoating porcelain layer with semimonolithic design to enhance the esthetic properties of restorations without significantly decreasing fracture resistance of the crowns. If 0.5 mm porcelain layer is needed for a semimonolithic crown, wave design or cap design might be used to increase fracture resistance. In both cases, fracture resistance gained is likely to be clinically sufficient as the registered fracture loads were high in relation to expected loads under clinical use. PMID- 29628780 TI - Emerging treatment options for BRAF-mutant colorectal cancer. AB - The personalization of cancer care is rooted in the premise that there are subsets of patients with tumors harboring clinically relevant targets for patient specific treatments. Colorectal cancer (CRC) is a disease that has historically been notable for its dearth of biomarkers that are predictive of response to targeted therapies. In recent years, BRAFV600E-mutated CRC has emerged as a distinct biologic entity, typically refractory to standard chemotherapy regimens approved for the treatment of metastatic CRC and associated with a dismal prognosis. Multiple clinical trials sought to replicate the successes of targeted therapies seen in BRAFV600E-mutated melanoma without success; metastatic BRAFV600E-mutated CRC is clearly a distinct biologic entity. We review a number of recent studies demonstrating the evidence of modest responses to combinations of BRAF, EGFR, and/or MEK inhibition in patients with metastatic BRAFV600E mutated CRC; however, despite advances, overall survival remains far inferior for these patients compared to their BRAF-wild-type counterparts. Development of combination therapies to impede signaling through the MAPK pathway through alternate targets remains an area of active investigation. Reflecting the rapid evolution of efforts for this small subset of CRC patients, the first-ever Phase III study is now underway evaluating the combination of BRAF, EGFR, and MEK inhibition. Immunotherapies are also an area of active research, particularly for the subset of patients with tumors that are also microsatellite instability (MSI) high. Here, we summarize the current landscape and emerging data on the molecular, clinical, and therapeutic aspects of BRAF-mutant CRC. PMID- 29628779 TI - Role and inhibition of GLI1 protein in cancer. AB - GLI1 is a transcriptional regulator involved in the development of different types of cancer. GLI1 transcriptional activity is regulated within the Hedgehog pathway (canonical activity), but can also be controlled independently (non canonical activity) in the context of other signaling pathways. Experimental evidences show GLI1 involvement in both small- and non-small-cell lung cancers. Direct inhibition of the protein, in combination with other chemotherapeutic agents, represents a promising strategy for the treatment of different malignancies. PMID- 29628782 TI - Evaluation of PM surface concentrations simulated by Version 1 of NASA's MERRA Aerosol Reanalysis over Europe. AB - This article evaluates the concentrations of particulate matter (PM) and some of its chemical speciation such as sulfate, organic carbon, black carbon and sea salt particles simulated at the surface by Version 1 of the Aerosol Reanalysis of NASA's Modern-Era Retrospective Analysis for Research and Application (MERRAero) over Europe. Measurement data from the European Monitoring and Evaluation Programme database were used. The concentrations of coarse PM (PM10), fine PM (PM2.5), sulfate and black carbon particles are overall well simulated, despite a slight and consistent overestimation of PM10 concentration, and a slight and consistent underestimation of PM2.5 and sulfate concentrations throughout most of the year. The concentration of organic carbon was largely underestimated, especially in winter, caused by two specific monitoring stations in Italy, resulting in an overall poor performance for this particular species. After removing these two stations from the sample, the evaluation of OC substantially improved but an underestimation in winter remained. Carbon emissions originating from anthropogenic sources, such as residential wood burning in winter, unresolved by MERRAero provide a plausible explanation for this discrepancy.. The evaluation of PM2.5, sulfate and organic carbon concentrations improved during the summer. The concentration of fine sea salt particles was consistently and largely overestimated, but contributes relatively little to total PM2.5 concentration. PMID- 29628783 TI - Physical model of protein cluster positioning in growing bacteria. AB - Chemotaxic receptors in bacteria form clusters at cell poles and also laterally, and this clustering plays an important role in signal transduction. These clusters were found to be periodically arranged on the surface of the bacterium Escherichia coli, independent of any known positioning mechanism. In this work we extend a model based on diffusion and aggregation to more realistic geometries and present a means based on "bursty" protein production to distinguish spontaneous positioning from an independently existing positioning mechanism. We also consider the case of isotropic cellular growth and characterize the degree of order arising spontaneously. Our model could also be relevant for other examples of periodically positioned protein clusters in bacteria. PMID- 29628784 TI - The Relationship Between Social Media Use and Sleep Quality among Undergraduate Students. AB - Insufficient sleep is a growing health problem among University students, especially for freshmen during their first quarter/semester of college. Little research has studied how social media technologies impact sleep quality among college students. This study aims to determine the relationship between social media use and sleep quality among freshman undergraduates during their first quarter in college. Specifically, we explored whether variations in Twitter use across the time of day and day of the week would be associated with self-reported sleep quality. We conducted a study of Freshman Twitter-using students (N = 197) over their first quarter of college, between October to December of 2015. We collected students' tweets, labeled the content of the tweets according to different emotional states, and gave theme weekly surveys on sleep quality. Tweeting more frequently on weekday late nights was associated with lower sleep quality (beta = -0.937, SE = 0.352); tweeting more frequently on weekday evenings was associated with better quality sleep (beta = 0.189, SE = 0.097). Tweets during the weekday that were labeled related to the emotion of fear were associated with lower sleep quality (beta = -0.302, SE = 0.131). Results suggest that social media use is associated with sleep quality among students. Results provide can be used to inform future interventions to improve sleep quality among college students. PMID- 29628785 TI - Development of a passive phase separator for space and earth applications. AB - The limited amount of liquids and gases that can be carried to space makes it imperative to recycle and reuse these fluids for extended human operations. During recycling processes gas and liquid phases are often intermixed. In the absence of gravity, separating gases from liquids is challenging due to the absence of buoyancy. This paper describes development of a passive phase separator that is capable of efficiently and reliably separating gas-liquid mixtures of both high and low void fractions in a wide range of flow rates that is applicable to for both space and earth applications. PMID- 29628786 TI - Personalized medicine in oncology. New perspectives in management of gliomas. AB - Studies on genetic and epigenetic mechanisms of carcinogenesis have led to the discovery of crucial genetic events for many of particular malignancies. This was followed by invention of new therapeutic approaches based on molecular mechanisms underlying cancer development and progression that bears the name of personalised medicine. In the case of gliomas, ascertainment of genetic/epigenetic markers was the basis for re-classification of tumours that until now depended on histopathological analysis. This article reviews recent advances in personalised medicine and the new World Health Organisation classification of gliomas. PMID- 29628787 TI - Molecular profiling of tumours for precision oncology - high hopes versus reality. AB - Treatment based on molecular profiling of tumor is advertised however there are very limited clinical data supporting this approach so far. Only one, relatively small, randomized clinical trial (SHIVA) have not met its primary endpoint - prolongation of PFS. Some other unpublished series were reported during ASCO 2017 and are discussed in this review. There are many issues to be resolved before the tumor profiling will enter the clinical practice with significant benefit for patients, eg. spatial and temporal heterogeneity of tumor cells in individual patient, wide access to targeted therapies, toxicity of combined targeted therapies. PMID- 29628788 TI - The role of hypoxia in shaping the recruitment of proangiogenic and immunosuppressive cells in the tumor microenvironment. AB - Hypoxia characterizes growing tumors and contributes significantly to their aggressiveness. Hypoxia-inducible factors (HIFs 1 and 2) are stabilized and act differentially as transcription factors on tumor growth and are responsible for important cancer hallmarks such as pathologic angiogenesis, cellular proliferation, apoptosis, differentiation and genetic instability as well as affecting tumor metabolism, tumor immune responses, invasion and metastasis. Taking into account the tumor tissue as a whole and considering the interplay of the various partners which react with hypoxia in the tumor site lead to reconsideration of the treatment strategies. Key limitations of treatment success result from the adaptation to the hypoxic milieu sustained by tumor anarchic angiogenesis. This raises immune tolerance by influencing the recruitment of immunosuppressive cells as bone marrow derived suppressor cells (MDSC) or by impairing the infiltration and killing of tumor cells by cytotoxic cells at the level of the endothelial cell wall of the hypoxic tumor vessels, as summarized in the schematic abstract. PMID- 29628791 TI - Gastric cancer increases transmigratory potential of peripheral blood monocytes by upregulation of beta1- and beta2-integrins. AB - Introduction: Immune responses within the tumor depend on the ability of leukocytes to migrate from peripheral circulation into the local microenvironment. This process is controlled by mechanisms that guide leukocytes to the side of inflammation, allowing them to cross vascular endothelial barrier. Monocytes/macrophages are the predominant population of leukocyte infiltrate of many tumors, including, gastric cancer. However, to date mechanisms that control monocyte trafficking to the side of tumor growth are not fully elucidated. Aim of the study: It this study we aimed to evaluate transmigratory potential of peripheral blood monocytes from gastric cancer patients. Material and methods: By using multicolor flow cytometry we assessed expression of beta1- and beta2 integrins on peripheral blood monocytes from gastric cancer patients. Results: We found increased frequencies of VLA-4 and VLA-6 expressing monocytes and increased expression of analyzed beta2-integrins in gastric cancer patients when compared to age matched controls. Conclusions: In summary, this study revealed that gastric cancer increases transmigratory potential of peripheral blood monocytes. PMID- 29628789 TI - Immune consequences of anti-angiogenic therapyin renal cell carcinoma. AB - Current therapies of renal cell carcinoma (RCC), a highly vascularised tumour, mostly rely on anti-angiogenic treatment options. These include tyrosine kinase inhibitors (TKIs) and anti-VEGF monoclonal antibodies. Although these strategies aim at restraining vascularisation to control tumour growth, the effects of such therapies are much wider, as affecting the vessel structure deeply modifies the microenvironment of the tumour mass. The aim of this review is to provide an overview of current knowledge on the global effects of anti-angiogenic treatment, mostly TKIs, on the shaping of the immune component of the RCC microenvironment. The data supporting the modification of immunity by anti-angiogenic therapies are collected to reveal the potential of angiogenesis modulation as a strategy for the adjuvant anti-cancer approach in immunotherapy. PMID- 29628790 TI - Heme oxygenase inhibition in cancers: possible tools and targets. AB - Heme oxygenase-1 (HO-1, encoded by HMOX1) through degradation of pro-oxidant heme into carbon monoxide (CO), ferrous ions (Fe2+) and biliverdin, exhibits cytoprotective, anti-apoptotic and anti-inflammatory properties. All of these potentially beneficial functions of HO-1 may play an important role in tumors' development and progression. Moreover, HO-1 is very often upregulated in tumors in comparison to healthy tissues, and its expression is further induced upon chemo-, radio- and photodynamic therapy, what results in decreased effectiveness of the treatment. Consequently, HO-1 can be proposed as a therapeutic target for anticancer treatment in many types of tumors. Nonetheless, possibilities of specific inhibition of HO-1 are strongly limited. Metalloporphyrins are widely used in in vitro studies, however, they are unselective and may exert serious side effects including an increase in HMOX1 mRNA level. On the other hand, detailed information about pharmacokinetics and biodistribution of imidazole dioxolane derivatives, other potential inhibitors, is lacking. The genetic inhibition of HO-1 by RNA interference (RNAi) or CRISPR/Cas9 approaches provides the possibility to specifically target HO-1; however, the potential therapeutic application of those methods are distant at best. In summary, HO-1 inhibition might be the valuable anticancer approach, however, the ideal strategy for HO-1 targeting requires further studies. PMID- 29628792 TI - The emerging role of plasma exosomes in diagnosis, prognosis and therapies of patients with cancer. AB - Exosomes, small (30-150nm) extracellular vesicles of endocytic origin, are present in all body fluids of cancer patients. Tumor-derived exosomes, TEX, emerge as potentially promising non-invasive biomarkers of tumor progression and of immune cell dysfunction in cancer. Exosomes isolated from plasma by size exclusion chromatography can be fractionated into TEX and non-TEX by immune capture on beads. Profiling of molecular and genetic contents of TEX shows that levels if immunosuppressive proteins, such as PD-L1, carried by TEX associate with disease progression. The data suggest that TEX have a to serve as tumor surrogates, while immune cell-derived exosomes might serve as biomarkers of immune dysfunction in cancer. PMID- 29628793 TI - Challenging tumour immunological techniques that help to track cancer stem cells in malignant melanomas and other solid tumours. AB - Aim of the study: The arsenal of questions and answers about the minor cancer initiating cancer stem cell (CSC) population put responsible for cancer invasiveness and metastases, has left with an unsolved puzzle. Specific aims of a complex project were partly focused on revealing new biomarkers of cancer. We designed and set up novel techniques to facilitate the detection of cancerous cells. Materials and methods: As a novel approach, we investigated B cells infiltrating breast carcinomas and melanomas (TIL-B) in terms of their tumour antigen binding potential. By developing the TIL-B phage display technology we provide here a new technology for the specific detection of highly tumour associated antigens. Single chain Fv (scFv) antibody fragment phage ELISA, immunofluorescence (IF) FACS analysis, chamber slide technique with IF confocal laser microscopy and immunohistochemistry (IHC) in paraffin-embedded tissue sections were set up and standardized. Results: We showed strong tumour associated disialylated glycosphingolipid expression levels on various cancer cells using scFv antibody fragments, generated previously by uniquely invasive breast carcinoma TIL-B phage display library technology. Conclusions: We report herein a novel strategy to obtain antibody fragments of human origin that recognise tumour-associated ganglioside antigens. Our investigations have the power to detect privileged molecules in cancer progression, invasiveness, and metastases. The technical achievements of this study are being harnessed for early diagnostics and effective cancer therapeutics. PMID- 29628794 TI - Surface markers of cancer stem-like cells of ovarian cancer and their clinical relevance. AB - Cancer stem-like cells (CSLCs) are defined as cancer cells with stem cell characteristics. Although CSLCs constitute no more than a few percent of the tumor mass, they play important roles in cancer chemo-resistance, metastasis and disease recurrence. Ovarian cancer (OC) is considered the most aggressive gynecological malignancy in which the role of CSLCs is of major significance, although it remains to be specified. The studies describing ovarian CSLC phenotype vary in the definition of the molecular pattern of expression of the main markers such as CD133, CD44, CD117, and CD24. Stem-like features of OC have been shown to correlate with the clinical course of the disease and permit diagnosis, prognosis and treatment outcome to be improved. Identification of CSLC markers could provide hallmarks which, related to the chemo-resistance of the disease, will facilitate treatment selection. This review describes recent advances in research on stem-like cell status in OC, mainly focusing on surface markers of CSLCs and their clinical relevance. PMID- 29628795 TI - The revival of CpG oligonucleotide-based cancer immunotherapies. AB - The promising results of clinical trials using immune checkpoint inhibitors revived interests in cancer immunotherapy. However, it also became apparent that efficacy of immune checkpoint blockade can benefit from combining it with immunostimulatory strategies. Here, we review prior and re-emerging approaches using Toll-like Receptor 9 (TLR9) agonists, CpG oligodeoxynucleotides (ODNs), focused on the generation of antitumor immune responses in cancer patients. While numerous early clinical trials using TLR9 ligands in monotherapies provided evidence of CpG ODNs tolerability and safety, they failed to demonstrate sufficient antitumor efficacy. Recent studies unraveled multiple levels of negative regulation of immunostimulatory TLR9 signaling in immune cells by the tumor microenvironment that can stifle immune activity in cancer patients. Therefore, CpG ODNs-based strategies can greatly benefit from combination with strategies targeting immune checkpoint regulation. The most recent clinical trials of CpG ODNs together with immune checkpoint inhibitors have a chance to generate novel, more effective and safer cancer immunotherapies. PMID- 29628796 TI - Immunotherapy of melanoma. AB - The immunotherapy is currently changing the landscape of oncology. Nowadays the standard of care in metastatic or unresectable melanoma patients include immunomodulating modalities such as anti-PD-1 drugs (nivolumab, pembrolizumab) and anti-CTLA-4 antibody ipilimumab. The improvements of progression free survival and overall survival connected with those treatments were unprecedented and have been confirmed in stage III trials. The efficacy of immunotherapy in metastatic setting can be further upgraded in some groups of patients by combining both types of antibodies. Latest clinical data suggest that treatment with immunotherapy can be also favorable for patients in adjuvant setting. Other treatment approaches based on immunological response (e.g. oncolytic viruses or adoptive cell therapy) have been proven useful in specific clinical situations. The future of melanoma treatment is still evolving, new molecular targets are being invented and hopefully current endeavors will led to further improvement of patients' survival. This review aims to summarize current state of immunotherapy in melanoma and identifying possible directions of development. PMID- 29628797 TI - BRAF and MEK inhibitors in the era of immunotherapy in melanoma patients. AB - The treatment landscape in advanced melanoma is changing dramatically with the approval of new drugs. Vemurafenib was the first approved targeted agent for the treatment of BRAF-mutant advanced melanoma. However, treatment with a BRAF inhibitor is linked with acquired resistance occurring in half of the patients after approximately six months. Combination of MEK and BRAF inhibitor therapy results in extension of the time to resistance, translating into longer overall survival of treated patients. Similar clinical benefits are observed with therapy using antibodies against immune-checkpoint inhibitors in the same patient population. Due to the fact that results of randomised studies comparing these two treatment strategies back to back have not been presented yet, the best first and second line treatment option in patients with BRAF-mutant melanoma is unknown. Currently, phase 3 studies are also evaluating the efficacy of targeted therapy combined with immunotherapy in patients with BRAF-mutant and BRAF wild type advanced melanoma. Identifying a biomarker for the selection of patients benefiting most from the treatment will be crucial for further survival improvement in patients with advanced melanoma. PMID- 29628798 TI - Versatile CAR T-cells for cancer immunotherapy. AB - Chimeric antigen receptor (CAR) T-cell therapy has been clinically proven to efficiently combat haematological malignancies. However, continuous efforts are required to increase the specificity of CAR T-cells against tumour versus normal tissues, and are essential to improve their antitumour activity in solid tumours. This review summarises the structure of major CAR designs, and strategies to overcome immunosuppressive tumour microenvironment, and reduce toxicities. Along with reviewing currently available techniques that allow the elimination of CAR T cells after they fulfil their desired functions, using suicide genes, drug elimination strategies are also introduced. A better understanding of the strengths and pitfalls of CAR T-cell therapy will provide fundamental knowledge for the improvement of engineered T-cell therapy in the near future. PMID- 29628799 TI - Clinical and immunological correlates of long term survival in glioblastoma. AB - Glioblastoma (GBM) is the most common and most aggressive type of primary brain tumour in adults. It represents 54% of all gliomas and 16% of all brain tumours (Ostrom et al. 2016). Despite surgery and treatment with radiotherapy plus an oral alkylating agent, temozolomide (TMZ), tumours invariably recur, and the patient survival is an average of ~14-16 months. In this review we summarise the current understanding of multiple factors that may affect survival of patients with GBMs. In particular, we discuss recent advancements in surgery and detection of genomic-based markers with prognostic values, such as IDH1/2 mutations, MGMT gene promoter methylation, and TERT gene promoter alterations. We address the issue of tumour heterogeneity and evolution that may result in different parts of the same tumour exhibiting different GBM subtypes and in subtype switching, which may restrict the usefulness of the expression-based classification as a prognostic marker before relapse. The determinants of long-term survival in patients with IDH1/2wt GBM, beyond MGMT promoter methylation, remain to be identified, and even the absence of both IDH1/2 mutations and MGMT promoter methylation does not preclude long-term survival. These findings suggest that host-derived factors, such as immune system responsiveness may contribute to long term survival in such patients. We report the results of high-throughput approaches, suggesting links between long-term survival and enhanced immune related gene expression. The further search for new gene candidates, promoter methylation status, and specific features of host immunity should provide prognostic biomarkers for the evaluation of survival of IDH1 wild-type/non-G-CIMP GBMs. PMID- 29628800 TI - Modelling understorey dynamics in temperate forests under global change Challenges and perspectives. AB - The understorey harbours a substantial part of vascular plant diversity in temperate forests and plays an important functional role, affecting ecosystem processes such as nutrient cycling and overstorey regeneration. Global change, however, is putting these understorey communities on trajectories of change, potentially altering and reducing their functioning in the future. Developing mitigation strategies to safeguard the diversity and functioning of temperate forests in the future is challenging and requires improved predictive capacity. Process-based models that predict understorey community composition over time, based on first principles of ecology, have the potential to guide mitigation endeavours but such approaches are rare. Here, we review fourteen understorey modelling approaches that have been proposed during the last three decades. We evaluate their inclusion of mechanisms that are required to predict the impact of global change on understorey communities. We conclude that none of the currently existing models fully accounts for all processes that we deem important based on empirical and experimental evidence. Based on this review, we contend new models are needed to project the complex impacts of global change on forest understoreys. Plant functional traits should be central to such future model developments, as they drive community assembly processes and provide valuable information on the functioning of the understorey. Given the important role of the overstorey, a coupling of understorey models to overstorey models will be essential to predict the impact of global change on understorey composition and structure, and how it will affect the functioning of temperate forests in the future. PMID- 29628801 TI - Mapping watershed integrity for the conterminous United States. AB - Watershed integrity is the capacity of a watershed to support and maintain the full range of ecological processes and functions essential to sustainability. Using information from EPA's StreamCat dataset, we calculated and mapped an Index of Watershed Integrity (IWI) for 2.6 million watersheds in the conterminous US with first-order approximations of relationships between stressors and six watershed functions: hydrologic regulation, regulation of water chemistry, sediment regulation, hydrologic connectivity, temperature regulation, and habitat provision. Results show high integrity in the western US, intermediate integrity in the southern and eastern US, and the lowest integrity in the temperate plains and lower Mississippi Valley. Correlation between the six functional components was high (r = 0.85-0.98). A related Index of Catchment Integrity (ICI) was developed using local drainages of individual stream segments (i.e., excluding upstream information). We evaluated the ability of the IWI and ICI to predict six continuous site-level indicators with regression analyses - three biological indicators and principal components derived from water quality, habitat, and combined water quality and habitat variables - using data from EPA's National Rivers and Streams Assessment. Relationships were highly significant, but the IWI only accounted for 1-12% of the variation in the four biological and habitat variables. The IWI accounted for over 25% of the variation in the water quality and combined principal components nationally, and 32-39% in the Northern and Southern Appalachians. We also used multinomial logistic regression to compare the IWI with the categorical forms of the three biological indicators. Results were consistent: we found positive associations but modest results. We compared how the IWI and ICI predicted the water quality PC relative to agricultural and urban land use. The IWI or ICI are the best predictors of the water quality PC for the CONUS and six of the nine ecoregions, but they only perform marginally better than agriculture in most instances. However, results suggest that agriculture would not be appropriate in all parts of the country, and the index is meant to be responsive to all stressors. The IWI in its present form (available through the StreamCat website; https://www.epa.gov/national-aquatic resource-surveys/streamcat) could be useful for management efforts at multiple scales, especially when combined with information on site condition. The IWI could be improved by incorporating empirical or literature-derived relationships between functional components and stressors. However, limitations concerning the absence of data for certain stressors should be considered. PMID- 29628802 TI - Relationship Between Radiographic Lumbosacral Spine Mensuration and Chronic Low Back Pain Intensity: A Cross-sectional Study. AB - Objective: The purpose of this study was to investigate correlative factors affecting chronic low back pain (CLBP), with special emphasis on the radiographic postural findings in the sagittal lumbosacral spine. Methods: A cross-sectional study alongside a randomized trial was conducted. Standing lateral lumbar spine radiographs from 352 patients with CLBP enrolled in a randomized trial were analyzed and radiographic mensuration of lumbar lordosis, lumbosacral disc angle, and sacral inclination performed. These angles were correlated with baseline variables, including CLBP intensity, age, and sex. Multiple polynomial regressions were performed in which CLBP intensity was regressed on linear and quadratic terms of lumbar lordosis to investigate the possibility of greater pain with hypo- and/or hyperlordosis. Results: There was no significant correlation of the angles with pain and age (r <= 0.09, P > .05). Weak but statistically significant correlation was identified between all 3 measurements and sex (r = 0.12 to 0.21, P < .05). Greater pain was not noted for hypo- and hyperlordosis; regression coefficients for the linear and quadratic effects were approximately 0 (P > .05). Conclusion: This study determined that there was no correlation between lumbar lordosis and pain levels for people with CLBP; thus, use of lumbar spine radiographic mensuration in the management of pain for people with CLBP is not recommended. PMID- 29628803 TI - Lower Body Strength-Training Versus Proprioceptive Exercises on Vertical Jump Capacity: A Feasibility Study. AB - Objective: The purpose of this study was to test the feasibility of completing a study comparing the impact of lower body strength training to proprioceptive exercises on vertical jump capacity. Methods: Thirty-nine college students (age 27.9 +/- 6.4 y, height 1.69 +/- 0.10 m, body mass 73.4 +/- 15.9 kg: mean +/- standard deviation) underwent baseline and post-testing of their vertical jump capacity using a Vertical Challenger and VICON motion analysis system. Participants were randomly assigned to 3 interventional groups between testing sessions: (1) lower body strength training, (2) lower body proprioceptive training, and (3) a no training control. Group 1 underwent supervised exercises 3 days a week at 2 sets of 12 repetitions of squats, seated knee extensions, standing knee flexions, and standing calf raises at approximately 25% of their body weight. Group 2 participants engaged in 4 supervised proprioceptive exercise stations 3 days a week involving BOSU ball stance, Rocker board, Bodyblade, and 1 legged stance exercises at 4 minutes per station. A between-within repeated measures analysis of variance using between-participants factor "group" and within-participants factor "time" (baseline and post-test) was used to analyze data. Results: Analysis of group * time indicated a small positive improvement in overall group performance for jump height at post-test, F(2,36) = 5.527, P = .008, r = 0.36. However, post hoc testing identified no statistically significant difference between groups for dependent variables. Conclusions: This study determined that it was feasible to complete a study to compare 2 groups, but more than 1 week would be required to observe differences between lower body weight training and lower body proprioceptive training on vertical jump. PMID- 29628804 TI - A Preliminary Study of Chiropractors' Beliefs About Biomedical and Biopsychosocial Pain: A Survey of University of Western States Alumni. AB - Objective: The purpose of this preliminary study was to investigate differences between doctors of chiropractic with respect to their preference for the biomedical or biopsychosocial attitude and belief models. Methods: Alumni of the University of Western States doctor of chiropractic program were asked to complete an online survey that included the Pain Attitudes and Beliefs Scale for Physiotherapists. This scale yields a biomedical score (10-60 scale) and a biopsychosocial score (9-54 scale). These scores are reported for 5 participant characteristics: sex, country of residence (USA vs other), chiropractic program completed (University of Western States vs other), decade of graduation, and years in practice. Secondarily, multiple linear regression was performed to evaluate the independent effects of participant characteristics on the 2 Pain Attitudes and Beliefs Scale for Physiotherapists scales. Results: Of 3877 surveys, 233 were included in the analysis (response rate = 4.7%-7.4%). The mean biomedical scale score was 33.9 (standard deviation = 6.5), and the mean biopsychosocial scale score was 32.4 (standard deviation = 4.1). There was little variation in scores across the 5 participant characteristics (P > .05). Cronbach's alpha for the biomedical scale reached an acceptable level of internal consistency (0.74). In contrast, Cronbach's alpha for the biopsychosocial scale was 0.40. Conclusion: This preliminary study found that in a sample of chiropractic program alumni of the University of Western States, there were no differences with respect to preference for the biomedical or biopsychosocial attitude and belief models. A better understanding requires a larger study comparing attitudes/beliefs with behavior in practice. PMID- 29628805 TI - Accuracy of Motion Palpation Flexion-Extension Test in Identifying the Seventh Cervical Spinal Process. AB - Objective: The aim of this study was to evaluate the accuracy of a motion palpation procedure, the flexion-extension test, in localizing the spinous process of the seventh cervical vertebra (C7). Methods: We analyzed 101 adult participants with metal markers that permitted the identification of the C7 spinous process. This analysis occurred during a flexion-extension test and was confirmed by radiography. Data sample characteristics were analyzed by descriptive statistics, and the relationship between independent variables (weight, height, sex, age, and body mass index [BMI]) and dependent variables (coincidence between the most prominent vertebra and the stationary vertebra, as determined by the flexion-extension test) was determined via logistic regression. Results: The sample population was 48.5% male with a mean age of 56.8 years (standard deviation, +/-14.9) and a mean BMI of 25.54 kg/m2 (standard deviation, +/-5.5). In 54.5% of cases, the C7 spinous process was correctly identified by the flexion-extension test. The agreement between the flexion-extension test and radiography in accuracy of localization of the C7 spinous process was significant (P = .021), as was the correct localization of C7 (P = .05). Conclusion: The localization of the C7 spinous process was more accurate in individuals with a BMI <25 kg/m2 and whose most prominent vertebra coincided with the stationary vertebra as determined by the flexion-extension test. PMID- 29628806 TI - Reliability of Infrared Thermography Images in the Analysis of the Plantar Surface Temperature in Diabetes Mellitus. AB - Objective: The purpose of this study was to evaluate the intraexaminer and interexaminer reliability of image assessment of infrared thermography of the plantar surface of people with diabetes mellitus. Methods: Fifty-one participants with diabetes were included. The interexaminer reliability (test) consisted of measuring the temperature of the plantar surface by 2 evaluators who separately performed the analysis of thermographic images. The intraexaminer reliability (retest) consisted of the revaluation of the images by a single evaluator 10 days after the first analysis. Results: The analysis of intrareliability and interreliability indicated excellent levels of correlation (intraclass correlation coefficient >0.75, 95% confidence interval >0.70) in the plantar surface points analyzed. Conclusion: Infrared thermography image evaluation identified intrareliability and interreliability for temperature analysis of the plantar surface of people with diabetes mellitus. However, further studies need to be conducted to assess validity and its application in health care. PMID- 29628807 TI - Sensitivity and Specificity of Modified Bragard Test in Patients With Lumbosacral Radiculopathy Using Electrodiagnosis as a Reference Standard. AB - Objective: The purpose of this study was to assess the diagnostic accuracy of a modified Bragard test compared with the straight leg raise (SLR) test in patients presenting with electrodiagnostic evidence of L5 and S1 nerve root compression. Methods: This was a cross-sectional study conducted on 506 consecutive patients with signs and symptoms consistent with lumbosacral radiculopathy confirmed by electrodiagnostic study. Patients were evaluated from September 2013 to September 2015 in the physical medicine and rehabilitation outpatient clinic of Shahid Faghihi Teaching Hospital, Shiraz, Iran. The SLR test was investigated concomitantly to determine the sensitivity and specificity. Results: Electrodiagnostic study findings indicated lumbosacral radiculopathy in 312 patients. Of these participants, 198 were positive on SLR testing, and of 114 SLR negative patients, 79 were positive on Modified Bragard testing. Sensitivity of the Modified Bragard test was 69.3%, and specificity was 67.42%. Positive and negative predictive values were 73.15% and 63.16%, respectively. Positive likelihood ratio was 2.13, and negative likelihood ratio was 0.46. Diagnostic odds ratio was 4.63. In patients with symptom duration of less than 3 weeks, SLR sensitivity and specificity decreased as the Modified Bragard test diagnostic accuracy increased. Conclusions: The Modified Bragard test is easy to perform and has an acceptable test performance, which can help to increase the discriminative power of clinical examination in patients with L5 or S1 nerve root compression who exhibit a negative SLR test result, especially in the acute phase of disease. PMID- 29628808 TI - Dietary Fiber Intake and Type 2 Diabetes Mellitus: An Umbrella Review of Meta analyses. AB - Objective: The purpose of this study was to review previously published meta analyses on the effectiveness of dietary fiber on type 2 diabetes. Methods: An umbrella review of all published meta-analyses was performed. A PubMed search from January 1, 1980, to April 30, 2017, was conducted using the following search strategy: (fiber OR glucan OR psyllium) AND (meta-analysis OR systematic review). Only English-language publications that provided quantitative statistical analysis on type 2 diabetes, fasting blood glucose concentrations, or glycosylated hemoglobin were retrieved. Results: Sixteen meta-analyses were retrieved for inclusion in this umbrella review. In the meta-analyses comparing highest versus lowest dietary fiber intake, there was a statistically significant reduction in the relative risk (RR) of type 2 diabetes (RR = 0.81-0.85), with the greatest benefit coming from cereal fibers (RR = 0.67-0.87). However, statistically significant heterogeneity was observed in all of these meta analyses. In the meta-analyses of supplementation studies using beta-glucan or psyllium fibers on type 2 diabetic participants, statistically significant reductions were identified in both fasting blood glucose concentrations and glycosylated hemoglobin percentages. Conclusion: This review suggests that those consuming the highest amounts of dietary fiber, especially cereal fiber, may benefit from a reduction in the incidence of developing type 2 diabetes. There also appears to be a small reduction in fasting blood glucose concentration, as well as a small reduction in glycosylated hemoglobin percentage for individuals with type 2 diabetes who add beta-glucan or psyllium to their daily dietary intake. PMID- 29628809 TI - Cytokine Involvement in Biological Inflammation Related to Degenerative Disorders of the Intervertebral Disk: A Narrative Review. AB - Objective: The purpose of this narrative literature review is to discuss the literature regarding the potential role that cytokines play in degenerative disk disease. Methods: The inclusion criteria were studies that used inflammatory mediators in advancing disk disease processes. Research studies were limited to the last 3 decades that had free full-text available online in English. Exclusion criteria were review articles and articles pertaining to temporomandibular joints and other joints of the body other than the intervertebral disk. The following databases were searched: PubMed, EBSCOhost, and Google Scholar through March 13, 2017. Results: A total of 82 studies were included in this review. The papers were reviewed for complex mechanisms behind the degenerative cascade, emphasizing the role of proinflammatory cytokines, which may be instrumental in processes of inflammation, neurologic pain, and disk degeneration. Interleukin-1beta and tumor necrosis factor alpha were among the more notable cytokines involved in this cascade. Because monocyte chemoattractant protein-1 stimulates and activates macrophages in the event of infiltration, additional proinflammatory cytokines are released to act on molecules to promote blood and nerve ingrowth, resulting in pain signaling and tissue degradation. Excessive inflammation and/or tissue damage initiates a pathologic imbalance between anabolic and catabolic processes. Conclusions: This literature review describes how inflammatory and biochemical changes may trigger disk degeneration. Proinflammatory cytokines stimulate microvascular blood and nerve ingrowth, resulting in pain signaling and tissue degradation. This may sensitize a person to chemical and/or mechanical stimuli, contributing to severe low back pain. PMID- 29628810 TI - Rehabilitation of Tibial Plateau Fracture Following Anterior Cruciate Ligament Reconstruction: A Case Report. AB - Objective: The purpose of this case report was to describe the management of a tibial plateau fracture in a patient who had undergone anterior cruciate ligament (ACL) reconstruction 3.5 years earlier. Clinical Features: A 36-year-old man presented with pain and edema following a fall from a height of approximately 2 m while skateboarding. The patient reported having undergone arthroscopic ACL reconstruction with allograft and bioabsorbable screws 3.5 years earlier. Computed tomography scan revealed a comminuted fracture extending through the graft tunnel, as well as evidence of tunnel widening and incomplete bone resorption and generation within the tibial tunnel. Intervention and Outcome: A trauma surgeon repaired the plateau fracture with internal fixation. The patient was non-weight bearing for 8 weeks while undergoing rehabilitation in a chiropractic clinic (spinal manipulation, physiotherapy, nutritional support) twice per week and returned to full activity within 3 months. Conclusions: The patient responded favorably to the treatment protocol, which included rehabilitation by a doctor of chiropractic and co-management with a trauma surgeon. PMID- 29628811 TI - Isolated Stieda Process Fracture of Talus: A Case Study. AB - Objective: The purpose of this case report is to describe a patient with a fracture of the Stieda process. Clinical Features: A 39-year-old woman presented with pain and swelling of her left ankle immediately following a boogie boarding accident a few days earlier. Her clinical presentation was similar to that of an ankle sprain. Intervention and Outcome: Radiographs were ordered, and a fracture of a normal variant, the Stieda process, was identified. Non-displacement of the fracture fragment was managed with conservative treatment consisting of a short leg cast for 6 weeks. The fracture healed without complications. Conclusion: The importance of early recognition of this fracture helped with proper management and a favorable outcome. PMID- 29628812 TI - Exercise Therapy for a Patient With Parkinson Disease and Back Pain: A Case Report. AB - Objective: The purpose of this report is to describe an exercise intervention for an elderly patient with Parkinson disease with a chief complaint of lower back pain. Clinical Features: The patient was an 85-year-old man who had been diagnosed with Parkinson disease and kyphosis. Back pain was preventing him from carrying out activities of daily living. He was referred for physical therapy for treatment to reduce lower back pain and increase function. An initial examination consisted of testing flexibility and range of motion and administering a pain severity scale and a Lower Extremity Functional Index (LEFI); the patient's initial LEFI score was 14/80. Intervention and Outcome: Clinical observation was made during each of the patient's physical therapy sessions. After 5 weeks, the patient's LEFI score improved to 30/80. The patient reported that he had no more reoccurring back pain, was able to move much easier, and was able walk more efficiently and with better posture. Conclusion: The patient in this case responded positively to a 5-week course of physical therapy that included exercise therapy. His back pain diminished and his function increased after the course of care. PMID- 29628813 TI - Metabolic profiling of isolated mitochondria and cytoplasm reveals compartment specific metabolic responses. AB - Introduction: Subcellular compartmentalization enables eukaryotic cells to carry out different reactions at the same time, resulting in different metabolite pools in the subcellular compartments. Thus, mutations affecting the mitochondrial energy metabolism could cause different metabolic alterations in mitochondria compared to the cytoplasm. Given that the metabolite pool in the cytosol is larger than that of other subcellular compartments, metabolic profiling of total cells could miss these compartment-specific metabolic alterations. Objectives: To reveal compartment-specific metabolic differences, mitochondria and the cytoplasmic fraction of baker's yeast Saccharomyces cerevisiae were isolated and subjected to metabolic profiling. Methods: Mitochondria were isolated through differential centrifugation and were analyzed together with the remaining cytoplasm by gas chromatography-mass spectrometry (GC-MS) based metabolic profiling. Results: Seventy-two metabolites were identified, of which eight were found exclusively in mitochondria and sixteen exclusively in the cytoplasm. Based on the metabolic signature of mitochondria and of the cytoplasm, mutants of the succinate dehydrogenase (respiratory chain complex II) and of the FOF1-ATP synthase (complex V) can be discriminated in both compartments by principal component analysis from wild-type and each other. These mitochondrial oxidative phosphorylation machinery mutants altered not only citric acid cycle related metabolites but also amino acids, fatty acids, purine and pyrimidine intermediates and others. Conclusion: By applying metabolomics to isolated mitochondria and the corresponding cytoplasm, compartment-specific metabolic signatures can be identified. This subcellular metabolomics analysis is a powerful tool to study the molecular mechanism of compartment-specific metabolic homeostasis in response to mutations affecting the mitochondrial metabolism. PMID- 29628815 TI - Evaluation of Pathogenic Variability Based on Leaf Blotch Disease Development Components of Bipolaris sorokiniana in Triticum aestivum and Agroclimatic Origin. AB - Leaf blotch of wheat caused by Bipolaris sorokiniana is a major constraint to wheat production, causing significant yield reduction resulting in severe economic impact. The present study characterizes to determine and compare pathogenic variability exist/not based on components of leaf blotch disease development and level of aggressiveness due to agroclimatic condition of B. sorokiniana in wheat. A total of 169 virulent isolates of B. sorokiniana isolated from spot blotch infected leaf from different wheat growing agroclimate of Bangladesh. Pathogenic variability was investigated on a susceptible wheat variety 'kanchan' now in Bangladesh. A clear evidence of positive relationship among the components was recorded. From hierarchical cluster analysis five groups were originating among the isolates. It resolved that a large amount of pathogenic diversity exists in Bipolaris sorokiniana. Variation in aggressiveness was found among the isolates from different wheat growing areas. Most virulent isolates BS 24 and BS 33 belonging to High Ganges River Flood Plain agro-climatic zones considered by rice-wheat cropping pattern, hot and humid weather, high land and low organic matter content in soil. Positive relationship was found between pathogenic variability and aggressiveness with agro-climatic condition. PMID- 29628814 TI - The Current Status and Future Outlook of Quantum Dot-Based Biosensors for Plant Virus Detection. AB - Enzyme-linked immunosorbent assay (ELISA) and polymerase chain reaction (PCR), widely used for the detection of plant viruses, are not easily performed, resulting in a demand for an innovative and more efficient diagnostic method. This paper summarizes the characteristics and research trends of biosensors focusing on the physicochemical properties of both interface elements and bioconjugates. In particular, the topological and photophysical properties of quantum dots (QDs) are discussed, along with QD-based biosensors and their practical applications. The QD-based Fluorescence Resonance Energy Transfer (FRET) genosensor, most widely used in the biomolecule detection fields, and QD based nanosensor for Rev-RRE interaction assay are presented as examples. In recent years, QD-based biosensors have emerged as a new class of sensor and are expected to open opportunities in plant virus detection, but as yet there have been very few practical applications (Table 3). In this article, the details of those cases and their significance for the future of plant virus detection will be discussed. PMID- 29628816 TI - Specific and Sensitive Primers Developed by Comparative Genomics to Detect Bacterial Pathogens in Grains. AB - Accurate and rapid detection of bacterial plant pathogen is the first step toward disease management and prevention of pathogen spread. Bacterial plant pathogens Clavibacter michiganensis subsp. nebraskensis (Cmn), Pantoea stewartii subsp. stewartii (Pss), and Rathayibacter tritici (Rt) cause Goss's bacterial wilt and blight of maize, Stewart's wilt of maize and spike blight of wheat and barley, respectively. The bacterial diseases are not globally distributed and not present in Korea. This study adopted comparative genomics approach and aimed to develop specific primer pairs to detect these three bacterial pathogens. Genome comparison among target pathogens and their closely related bacterial species generated 15-20 candidate primer pairs per bacterial pathogen. The primer pairs were assessed by a conventional PCR for specificity against 33 species of Clavibacter, Pantoea, Rathayibacter, Pectobacterium, Curtobacterium. The investigation for specificity and sensitivity of the primer pairs allowed final selection of one or two primer pairs per bacterial pathogens. In our assay condition, a detection limit of Pss and Cmn was 2 pg/MUl of genomic DNA per PCR reaction, while the detection limit for Rt primers was higher. The selected primers could also detect bacterial cells up to 8.8 * 103 cfu to 7.84 * 104 cfu per gram of grain seeds artificially infected with corresponding bacterial pathogens. The primer pairs and PCR assay developed in this study provide an accurate and rapid detection method for three bacterial pathogens of grains, which can be used to investigate bacteria contamination in grain seeds and to ultimately prevent pathogen dissemination over countries. PMID- 29628817 TI - Ultrastructures of Colletotrichum orbiculare in Cucumber Leaves Expressing Systemic Acquired Resistance Mediated by Chlorella fusca. AB - Chlorella, one single-cell green algae organism that lives autotrophically by photosynthesis, can directly suppress some plant diseases. The objective of this study was to determine whether pre-spraying with Chlorella fusca suspension could induce systemic acquired resistance (SAR) in cucumber plants against anthracnose caused by Colletotrichum orbiculare. In order to illustrate SAR induced by algae, infection structures in host cells were observed under a transmission electron microscope (TEM). Cytological changes as defense responses of host mesophyll cells such as accumulation of vesicles, formation of sheath around penetration hyphae, and thickness of cell wells adjoining with intracellular hyphae were demonstrated in cucumber leaves. Similar defense responses were also found in the plant pre-treated with DL-3-aminobutyric acid, another SAR priming agent. Images showed that defense response of host cells was scarcely observed in untreated leaf tissues. These cytological observations suggest that C. fusca could induce SAR against anthracnose in cucumber plants by activating defense responses of host cells. PMID- 29628818 TI - Efficacy of Newer Molecules, Bioagents and Botanicals against Maydis Leaf Blight and Banded Leaf and Sheath Blight of Maize. AB - Maize (Zea mays L.; 2N=20) is major staple food crop grown worldwide adapted to several biotic and abiotic stresses. Maydis leaf blight (MLB) and banded leaf and sheath blight (BLSB) are serious foliar fungal diseases may cause up to 40% and 100% grain yield loss, respectively. The present studies were undertaken to work out the efficacy of chemicals, botanicals and bioagents for the management of MLB and BLSB under field condition for two seasons Kharif 2014 and 2015. Five molecules (propiconazole 25 EC, hexaconazole 25 EC, carbendazim 50 WP, mancozeb 75 WP and carbedazim 12 WP + mancozeb 63 WP), two bioagents i.e. Trichoderma harzianum and T. viridae and three botanicals namely azadirachtin, sarpagandha and bel pathar were tested for their efficacy against MLB. Eight newer fungicides viz., difenconazole 250 SC, hexaconazole 5 EC, carbendazim 50WP, validamycin 3 L, tebuconazole 250 EC, trifloxystrobin 50 WG + tebuconazole 50 WG, azoxystrobin 250 EC and pencycuron 250 SC were evaluated against BLSB. Analysis revealed significant effects of propiconazole at 0.1%, carbendazim 12 WP + mancozeb 63 WP at 0.125% and sarpagandha leaves at 10% against MLB pathogen, whereas validamycin at 0.1% and trifloxystrobin 25 WG + tebuconazole 50 WG at 0.05% were found effective against BLSB. The slow rate of disease control virtually by the bioagents might have not shown instant effect on plant response to the yield enhancing components. The identified sources of management can be used further in strengthening the plant protection in maize against MLB and BLSB. PMID- 29628820 TI - Virulence Phenotyping and Molecular Characterization of a New Virulence Type of Pyrenophora tritici-repentis the Causal Agent of Tan Spot. AB - Pyrenophoratritici-repentis is the causal agent of tan spot. According to their ability to produce necrosis and/or chlorosis on a set of four differential bread wheats, the isolates of this fungus are currently grouped into eight races. When durum wheat genotypes were added to the differential set, a new virulence type was identified in Algeria. The isolates showing this virulence pattern are unable to attack bread wheat while they cause necrosis in durum genotypes. In this work, characterization of those isolates was based on pathological and molecular aspects. This included inoculation of bread and durum wheat, and virulence gene analysis using PCR and sequencing. The results showed that all isolates caused a resistance on all bread wheats of the differential set, while they produced necrosis in durum. ToxA and ToxB genes were amplified in all isolates, whereas toxb was absent. Sequence analysis for both genes showed no differences with those found in the two functional genes. The presence of two genes, ToxA and ToxB, despite the absence of symptoms usually caused by their products, suggests the existence of a new homologous for these two genes yet unknown. The presence of ToxA in the isolate unable to produce necrosis in Glenlea is reported for the first time. PMID- 29628819 TI - Exploring the Potentiality of Novel Rhizospheric Bacterial Strains against the Rice Blast Fungus Magnaporthe oryzae. AB - Rice blast caused by Magnaporthe oryzae is a major disease. In the present study, we aimed to identify and evaluate the novel bacterial isolates from rice rhizosphere for biocontrol of M. oryzae pathogen. Sixty bacterial strains from the rice plant's rhizosphere were tested for their biocontrol activity against M. oryzae under in vitro and in vivo. Among them, B. amyloliquefaciens had significant high activity against the pathogen. The least disease severity and highest germination were recorded in seeds treated with B. amyloliquefaciens UASBR9 (0.96 and 98.00%) compared to untreated control (3.43 and 95.00%, respectively) under in vivo condition. These isolates had high activity of enzymes in relation to growth promoting activity upon challenge inoculation of the pathogen. The potential strains were identified based on 16S rRNA gene sequencing and dominance of these particular genes were associated in Bacillus strains. These strains were also confirmed for the presence of antimicrobial peptide biosynthetic genes viz., srfAA (surfactin), fenD (fengycin), spaS (subtilin), and ituC (iturin) related to secondary metabolite production (e.g., AMPs). Overall, the results suggested that application of potential bacterial strains like B. amyloliquefaciens UASBR9 not only helps in control of the biological suppression of one of the most devastating rice pathogens, M. grisea but also increases plant growth along with a reduction in application of toxic chemical pesticides. PMID- 29628821 TI - Comparison of Microbial Community Structure in Kiwifruit Pollens. AB - Flowers of kiwifruit are morphologically hermaphroditic and survivable binucleate pollen is produced by the male flowers. In this study, we investigated microbial diversity in kiwifruit pollens by analyzing amplicon sequences of 16S rRNA. Four pollen samples were collected: 'NZ' was imported from New Zealand, 'CN' from China in year of 2014, respectively. 'KR13' and 'KR14' were collected in 2013' and 2014' in South Korea. Most of the identified bacterial phyla in the four different pollens were Proteobacteria, Actinobacteria and Firmicutes. However, the imported and the domestic pollen samples showed different aspects of microbial community structures. The domestic pollens had more diverse in diversity than the imported samples. Among top 20 OTUs, Pseudomonas spp. was the most dominant specie. Interestingly, a bacterial pathogen of kiwifruit canker, Pseudomonas syringae pv. actinidiae was detected in 'NZ' by the specific PCR. This study provides insights microbial distribution and community structure information in kiwifruit pollen. PMID- 29628823 TI - Ultrasound and central neuraxial blocks. PMID- 29628822 TI - Identification of Two Novel Amalgaviruses in the Common Eelgrass (Zostera marina) and in Silico Analysis of the Amalgavirus +1 Programmed Ribosomal Frameshifting Sites. AB - The genome sequences of two novel monopartite RNA viruses were identified in a common eelgrass (Zostera marina) transcriptome dataset. Sequence comparison and phylogenetic analyses revealed that these two novel viruses belong to the genus Amalgavirus in the family Amalgaviridae. They were named Zostera marina amalgavirus 1 (ZmAV1) and Zostera marina amalgavirus 2 (ZmAV2). Genomes of both ZmAV1 and ZmAV2 contain two overlapping open reading frames (ORFs). ORF1 encodes a putative replication factory matrix-like protein, while ORF2 encodes a RNA dependent RNA polymerase (RdRp) domain. The fusion protein (ORF1+2) of ORF1 and ORF2, which mediates RNA replication, was produced using the +1 programmed ribosomal frameshifting (PRF) mechanism. The +1 PRF motif sequence, UUU_CGN, which is highly conserved among known amalgaviruses, was also found in ZmAV1 and ZmAV2. Multiple sequence alignment of the ORF1+2 fusion proteins from 24 amalgaviruses revealed that +1 PRF occurred only at three different positions within the 13-amino acid-long segment, which was surrounded by highly conserved regions on both sides. This suggested that the +1 PRF may be constrained by the structure of fusion proteins. Genome sequences of ZmAV1 and ZmAV2, which are the first viruses to be identified in common eelgrass, will serve as useful resources for studying evolution and diversity of amalgaviruses. PMID- 29628824 TI - Assessment of medical practitioners' knowledge of fibromyalgia in Saudi Arabia. AB - Background: Fibromyalgia (FM), a relatively common disease, is difficult to diagnose owing to its subjective symptoms and poor knowledge among medical practitioners. The purpose of this study was to assess the knowledge regarding FM among medical practitioners in Saudi Arabia and the need for educational programs at the undergraduate level. Subjects and Methods: An online survey was administered to physicians, nurses, and technologist/technicians in different regions of the country. Responses were obtained from 104 medical practitioners. Knowledge regarding FM including clinical symptoms, diagnosis, and treatment was assessed. Results: Only 26% of the respondents reported that FM was part of their undergraduate curriculum, and only 8.7% attended educational programs about FM. (Approximately 50% of the medical practitioners either referred FM patients to unrelated specialty or did not know whom to refer these patients to). Only 33.7% of the respondents were familiar with the diagnostic criteria. Physiotherapy (69.4%) and pharmacological treatment (63.9%) were predominantly reported as the appropriate treatment. Conclusions: Knowledge regarding FM among medical practitioners in Saudi Arabia is poor. Further education at the undergraduate level is needed to improve knowledge and avoid delays in diagnosis and treatment. PMID- 29628825 TI - Preperitoneal postcesarean section bupivacaine analgesia: Comparison between dexamethasone and dexmedetomidine as adjuvants. AB - Background: The peritoneal wound is frequently neglected during laparotomy. The preperitoneal local anesthetics and many adjuvants were effective for postcesarean analgesia. Analgesia may involve somatic and autonomic components. The preperitoneal bupivacaine and the promising adjuvants dexamethasone or dexmedetomidine were compared in this study. Patients and Methods: Sixty patients subjected to a cesarean section (CS) under general anesthesia divided into two groups using a bolus of preperitoneal bupivacaine 0.7 mg/kg with either 1ug/kg dexmedetomidine (Group P) or 8 mg dexamethasone (Group D). The time to the first analgesic request was the primary outcome. Results: There was a significantly prolonged time to the first analgesic request in the Group P than the Group D and less required preperitoneal injections in the Group P, also pain assessed by Numerical Rating Scale (NRS) was lower in the Group P than the Group D after 6 h postoperatively up to 24 h. Conclusions: Dexmedetomidine provided better analgesia than dexamethasone as an adjuvant to preperitoneal bupivacaine post-CS. PMID- 29628826 TI - Dexmedetomidine vs morphine and midazolam in the prevention and treatment of delirium after adult cardiac surgery; a randomized, double-blinded clinical trial. AB - Background: The aim of this clinical study was to evaluate the efficacy of neurobehavioral, hemodynamics and sedative characteristics of dexmedetomidine compared with morphine and midazolam-based regimen after cardiac surgery at equivalent levels of sedation and analgesia in improving clinically relevant outcomes such as delirium. Methods: Sixty patients were randomly allocated into one of two equal groups: group A = 30 patients received dexmedetomidine infusion (0.4-0.7 MUg/kg/h) and Group B = 30 patients received morphine in a dose of 10-50 MUg/kg/h as an analgesic with midazolam in a dose of 0.05 mg/kg up to 0.2 mg/kg as a sedative repeated as needed. Titration of the study medication infusions was conducted to maintain light sedation (Richmond agitation-sedation scale) (-2 to +1). Primary outcome was the prevalence of delirium measured daily through confusion assessment method for intensive care. Results: Group A was associated with shorter length of mechanical ventilation, significant shorter duration of intensive care unit (ICU) stay (P = 0.038), and lower risk of delirium following cardiac surgery compared to Group B. Group A showed statistically significant decrease in heart rate values 4 h after ICU admission (P = 0.015) without significant bradycardia. Group A had lower fentanyl consumption following cardiac surgery compared to Group B. Conclusion: Dexmedetomidine significantly reduced the length of stay in ICU in adult cardiac surgery with no significant reduction in the incidence of postoperative delirium compared to morphine and midazolam. PMID- 29628827 TI - A prospective randomized study on the impact of low-dose dexamethasone on perioperative blood glucose concentrations in diabetics and nondiabetics. AB - Background: Dexamethasone is a potent corticosteroid when administered alone or in combination alone has proven efficacious in preventing nausea and vomiting (PONV) perioperatively. However, the administration of even a single dose has been associated with hyperglycemia. This is the first study that evaluates the effect of two low-doses of dexamethasone (4 and 8 mg) on blood glucose concentrations among diabetics and nondiabetics in patients who have received spinal anesthesia. Materials and Methods: After obtaining ethical clearance and patient consent, 180 American Society of Anesthesiologists 1-3 patients undergoing the elective infraumbilical surgeries under spinal anesthesia aged between 18 and 70 years were included in this study. Ninety diabetic patients were allotted to the diabetic group (DM), and ninety nondiabetic patients were allotted to the nondiabetic group (ND). Group DM was divided into three subgroups DM0, DM4, and DM8. Group ND was divided into three subgroups ND0, ND4, and ND8. The patients in groups DM0 and ND0 served as controls. The patients in groups DM4 and ND4 received 4 mg dexamethasone. The patients in groups DM8 and ND8 received 8 mg dexamethasone. The blood glucose concentrations were monitored at 0 (baseline), 1, 2, 3, 4, 5, 6, and 8 h after giving the drug. Results: The baseline blood glucose values were higher in diabetics compared to nondiabetics (128.57 +/- 22.26 vs 94.99 +/- 12.82 mg/dL). There was a statistically significant increase in blood glucose concentrations in both diabetics and nondiabetics who received dexamethasone. The rise of blood glucose from baseline was similar in both diabetics and nondiabetics. Conclusion: The maximum rise in blood glucose was in the range of 40-45 mg/dl in the patients who received dexamethasone. The clinician should use his clinical judgment before administering dexamethasone for PONV prophylaxis/treatment. PMID- 29628828 TI - Pain assessment in the critically ill mechanically ventilated adult patients: Comparison between skin conductance algesimeter index and physiologic indicators. AB - Background and Objectives: Critically ill patients are unable to communicate effectively, so it is difficult to assess their pain and analgesic requirement. Skin conductance algesimeter (SCA) index is a device that primarily measures changes in skin conductance real time to assess pain. Methods: We planned this quantitative prospective observational study to assess pain in the critically ill mechanically ventilated patients in comparison to physiologic indicators such as blood pressure and heart rate. A repeated measures design was chosen, and a sample size of 180 was taken from 60 patients with sepsis, acute exacerbations of chronic obstructive pulmonary disease, community-acquired pneumonia, and postsurgical patients in the Intensive Care Unit (ICU). The two painful procedures chosen were tracheal suction and patient positioning. The data were collected at rest, at tracheal suctioning, 20 min later at positioning of the patient, and final reading 20 min later. Three testing periods, each including 4 assessments for a total of 12 pain assessments with sixty patients, were completed during each patient's ICU course. A total of six assessments were done with the patient at rest and three each with pain stimulus of tracheal suctioning and patient positioning. Results: There was a significant increase in both hemodynamic variables during painful procedures except for the heart rate during positioning. The correlation between the SCA index and Ramsay scale was negative and significant. Conclusions: This instrument might prove useful to measure pain in uncommunicative critically ill patients and to evaluate the effectiveness of analgesic treatment and adapt it. PMID- 29628829 TI - Using dexamethasone as an adjuvant to levobupivacaine in epidural anesthesia to change the pain intensity and duration in painless labor. AB - Background and Objective: This is a randomized controlled trial aiming at comparing the effectiveness of levobupivacaine alone versus a levobupivacaine with dexamethasone in the epidural injection for painless labor. Patients and Methods: This is a comparative randomized controlled double-blinded clinical trial with 49 patients were included in this study, all of them were primigravidas and were during vaginal delivery with a cervical dilatation >=4 cm. Patients were included randomly in one of two groups either Group C (26 cases) with epidural levobupivacaine 0.125% in normal saline or Group D (23 cases) with epidural levobupivacaine 0.125% in normal saline combined with dexamethasone 8 mg. The duration of a second dose request, total dose given, neonatal outcome and adverse effects of epidural were recorded. Results: Group D showed a longer duration of analgesia than Group C (80.5 +/- 12.39 min in Group D vs. 61.75 +/- 10.74 min in Group C) with a P < 0.05 (0.001). Furthermore, the patients in Group D received smaller dose of levobupivacaine than those in Group C with a statistically significant difference (90.87 +/- 33.42 vs. 127.21 +/- 40.68 mg with P = 0.002). There were no statistical differences between the two groups regarding hemodynamics, pain score, neonatal outcome, and complications. Conclusion: Dexamethasone in epidural analgesia for painless labor has a prolonged duration of analgesia with no complications for both the mother and the infant. PMID- 29628830 TI - Medical students' attitude toward anesthesia as a future career. AB - Objectives: The purpose of this study is to understand the attitude of medical students at King Saud bin Abdulaziz University for Health Sciences (KSAU-HS) toward anesthesia as a specialty and to determine common factors influencing their career choice options. Study Design: This was a cross-sectional study. Methods: The study was conducted between March 25, and April 20, 2017, at KSAU HS. The survey was distributed among 5th and 6th years medical students. Data were collected through a validated hardcopy questionnaire of 16 multiple choice questions. The questionnaire included demographic characteristics, specialty preferences, what factors attract Saudi medical students to choose their preferred specialty and how they view the option of choosing anesthesiology as a career. Results: A total of 236 students completed the questionnaire. The majority of respondents were in their 5th year of medical school representing (62%). The distribution of medical field interest ranged from (38%) surgery to (1%) anesthesiology. approximately, (60%) thought that controllable lifestyle was an important factor to consider in choosing a residency program. Only (45%) of respondents thought that prestige of specialty is a major factor that would influence their choice for a specialty. Conclusion: Based on the outcome of the study, it is recommended that medical undergraduate students exposure to anesthesia specialty should be magnified. Greater efforts have to be made to increase the number of medical students preferring anesthesia through emphasizing on the positive aspects of the specialty. PMID- 29628831 TI - Knowledge and attitudes of nurses toward pain management. AB - Background: Pain control is a vitally important goal because untreated pain has detrimental impacts on the patients as hopelessness, impede their response to treatment, and negatively affect their quality of life. Limited knowledge and negative attitudes toward pain management were reported as one of the major obstacles to implement an effective pain management among nurses. The main purpose for this study was to explore Saudi nurses' knowledge and attitudes toward pain management. Methods: Cross-sectional survey was used. Three hundred knowledge and attitudes survey regarding pain were submitted to nurses who participated in this study. Data were analyzed with the Statistical Package for the Social Sciences software (SPSS; version 17). Results: Two hundred and forty seven questionnaires were returned response rate 82%. Half of the nurses reported no previous pain education in the last 5 years. The mean of the total correct answers was 18.5 standard deviation (SD 4.7) out of 40 (total score if all items answered correctly) with range of 3-37. A significant difference in the mean was observed in regard to gender (t = 2.55, P = 0.011) females had higher mean score (18.7, SD 5.4) than males (15.8, SD 4.4), but, no significant differences were identified for the exposure to previous pain education (P > 0.05). Conclusions: Saudi nurses showed a lower level of pain knowledge compared with nurses from other regional and worldwide nurses. It is recommended to considered pain management in continuous education and nursing undergraduate curricula. PMID- 29628832 TI - Efficacy and safety of pulsed radiofrequency and steroid injection for intercostobrachial neuralgia in postmastectomy pain syndrome - A clinical trial. AB - Background: Breast cancer is a common neoplastic tumor in women, and the postmastectomy pain syndrome has been reported frequently after surgical treatment. The injury of the intercostobrachial nerve is considered the major cause of this type of pain. Purpose: Evaluation of efficacy and safety of pulsed radiofrequency (PRF) and steroid injection on the 2nd and 3rd thoracic (T2 and T3) dorsal root ganglions (DRGs) for intercostobrachial neuralgia (ICBN) postmastectomy. Patients and Methods: This study was conducted on 100 patients with ICBN postmastectomy. The PRF waves were applied for 120 s twice on T2 and T3 DRGs then 1 ml of 4 mg dexamethasone and 1 ml of bupivacaine 0.25% were injected at each level then the technique was repeated three times 1 week apart for each patient. Results: After 6 months from the latest intervention, the mean of visual analog scale dropped from 7.48 to 4.7 (P = 0.005712) and the mean of the quality of life scale improved to 6.88 after being 4.66 (P < 0.00001) before the intervention and 64.68% of the patients decided that they would certainly repeat the procedure if they could go back in time and 66.64% would certainly recommend the same procedure to a family member. The analgesics consumption decreased mainly in the 1st month but increased again after 6 months (not significant). No serious complications were recorded. Conclusions: PRF and steroid injection on T2 and T3 DRGs assumed an effective and safe method for ICBN postmastectomy treatment. PMID- 29628833 TI - Efficacy and safety of dexmedetomidine infusion for patients undergoing awake craniotomy: An observational study. AB - Background: The goal of awake craniotomy is to maintain adequate sedation, analgesia, respiratory, and hemodynamic stability and also to provide a cooperative patient for neurologic testing. An observational study carried out to evaluate the efficacy of dexmedetomidine sedation for awake craniotomy. Materials and Methods: Adult patients with age >18 year who underwent awake craniotomy for intracranial tumor surgery were enrolled. Those who were uncooperative and had difficult airway were excluded from the study. In the operating room, the patients received a bolus dose of dexmedetomidine 1 MUg/kg followed by an infusion of 0.2-0.7 MUg/kg/h (bispectral index target 60-80). Once the patients were sedated, scalp block was given with bupivacaine 0.25%. The data on hemodynamics at various stages of the procedure, intraoperative complications, total amount of fentanyl used, intravenous fluids required, blood loss and transfusion, duration of surgery, Intensive Care Unit (ICU), and hospital stay were collected. The patients were assessed for Glasgow outcome scale (GOS) score and patient satisfaction score (PSS). Results: A total of 27 patients underwent awake craniotomy during a period of 2 years. Most common intraoperative complication was seizures; observed in five patients (18.5%). None of these patients experienced any episode of desaturation. Two patients had tight brain for which propofol boluses were administered. The average fentanyl consumption was 161.5 +/- 85.0 MUg. The duration of surgery, ICU, and hospital stays were 231.5 +/- 90.5 min, 14.5 +/- 3.5 h, and 4.7 +/- 1.5 days, respectively. The overall PSS was 8 and GOS was good in all the patients. Conclusion: The use of dexmedetomidine infusion with regional scalp block in patients undergoing awake craniotomy is safe and efficacious. The absence of major complications and higher PSS makes it close to an ideal agent for craniotomy in awake state. PMID- 29628834 TI - Comparison of analgesic efficacy and safety of continuous epidural infusion versus local infiltration and systemic opioids in video-assisted thoracoscopic surgery decortication in pediatric empyema patients. AB - Introduction: The stripping of the densely innervated and inflamed parietal pleura in empyema during video-assisted thoracoscopic surgery (VATS) decortication can lead to significant pain and major postoperative respiratory compromise. Hence, we compared the analgesic efficacy of continuous epidural infusion versus local infiltration and systemic opioids in children undergoing VATS decortications. Methodology: Following ethics approval and informed consent, forty patients from 1 to 12 years of age were randomized into two groups, Group E (epidural) and Group L (local infiltration) after induction of anesthesia. In Group E, a thoracic epidural catheter was inserted between T4 and T8. A bolus dose of 0.5 ml/kg of 0.25% injection bupivacaine was given epidurally before incision. Postoperatively, the patients received epidural infusion with bupivacaine and fentanyl up to 48 h using an elastomeric balloon pump. In Group L, patients received local infiltration of bupivacaine (2 mg/kg) and lignocaine (5 mg/kg) at the port sites before incision and at the end of surgery. They also received injection tramadol 1 mg/kg intravenously TDS with thrice daily postoperatively. The pain scores (Face, Legs, Activity, Cry, Consolability/ Wong Baker FACES scale) were assessed every 4 h on the 1st day and 6 h on the 2nd day. Injection diclofenac 1 mg/kg intravenous was used as a rescue analgesic for pain scores more than 4. Side effects such as nausea, vomiting, constipation, and motor blockade were noted. Quantitative and categorical data were assessed using t-test and Chi-square test, respectively. Results: The pain scores were lower in the epidural group than in the local infiltration group at 0, 4, and 20 h postoperatively (P = 0.001, 0.01, and 0.038, respectively). Seventeen out of nineteen patients required rescue analgesia in the local infiltration group in the postoperative period as compared to five patients in the epidural group with a P value of 0.000081. Conclusion: Epidural analgesia can be considered as an effective modality of reducing pain in patients undergoing VATS decortication for empyema in pediatric patients. PMID- 29628835 TI - Analysis of functioning and efficiency of a code blue system in a tertiary care hospital. AB - Background: "Code blue" (CB) is a popular hospital emergency code, which is used by hospitals to alert their emergency response team of any cardiorespiratory arrest. The factors affecting the outcomes of emergencies are related to both the patient and the nature of the event. The primary objective was to analyze the survival rate and factors associated with survival and also practical problems related to functioning of a CB system (CBS). Materials and Methods: After the approval of hospital ethics committee, an analysis and audit was conducted of all patients on whom a CB had been called in our tertiary care hospital over 24 months. Data collected were demographic data, diagnosis, time of cardiac arrest and activation of CBS, time taken by CBS to reach the patient, presenting rhythm on arrival of CB team, details of cardiopulmonary resuscitation (CPR) such as duration and drugs given, and finally, events and outcomes. Chi-square test and logistic regression analysis were used to analyze the data. Results: A total of 720 CB calls were initiated during the period. After excluding 24 patients, 694 calls were studied and analyzed. Six hundred and twenty were true calls and 74 were falls calls. Of the 620, 422 were cardiac arrests and 198 were medical emergencies. Overall survival was 26%. Survival in patients with cardiac arrests was 11.13%. Factors such as age, presenting rhythm, and duration of CPR were found to have a significant effect on survival. Problems encountered were personnel and equipment related. Conclusion: A CBS is effective in improving the resuscitation efforts and survival rates after inhospital cardiac arrests. Age, presenting rhythm at the time of arrest, and duration of CPR have significant effect on survival of the patient after a cardiac arrest. Technical and staff related problems need to be considered and improved upon. PMID- 29628836 TI - Morphine versus fentanyl patient-controlled analgesia for postoperative pain control in major hepatic resection surgeries including living liver donors: A retrospective study. AB - Background: Liver resection surgery results in significant postoperative pain. However, it is still not clear which opioids used by patient-controlled analgesia (PCA) provides the best pain control and results in the least side effect in a patient with impaired liver function. Our hypothesis was that fentanyl is a better choice than morphine as it is a potent analgesic that its elimination half life does not depend on the hepatic uptake and metabolism. The Study Purpose: Is to compare morphine and fentanyl PCA in liver resection patients as regards the degree of pain control, the consumption of opioids, and the side effects. Methods: A retrospective case-control study of hepatic resection patients who received postoperative morphine (Morph) or fentanyl (Fent) PCA. The study compared the pain scores, the morphine equivalent dose (MED), the number of demands requested as recorded by the PCA infusion pump, and the side effects every 12 h for 48 h. Results: This study yielded 40 patients; with the majority were living donor hepatic resection patients. There was no significant difference in the pain scores. However, the MED and the demands were significantly less in the Morph group. The P < 0.000, 0.0001, 0.0005, and 0.003, demands P < 0.002, 0.006, 0.014, and 0.013 at 12, 24, 48, and 36 h, respectively. The overall side effects were not different between the 2 groups at all time intervals measured; however, Morph patients were significantly more sedated in the first 12 h. There was one case of respiratory depression in the Morph group compared to two cases in the in the Fent group that needed treatment with naloxone. Conclusions: Although both groups had adequate pain control. The Morphine group reached faster pain control with less MED and PCA requests in liver resection patients, although it was more sedating in the first 12 h. However, fentanyl patients were less sedated; both drugs need close monitoring in the immediate postoperative period due to reported respiratory depressive effect and the need to use naloxone. The dosage of the PCA settings needs to be studied further to reach to the best dose with a reduced side effect. Further studies are recommended to reduce PCA dosages by introducing a multimodal approach of pain management relying on other methods with no additional sedative effects as regional anterior abdominal blocks. PMID- 29628837 TI - Factors affecting reintubations after cardiac and thoracic surgeries in cardiac intensive care unit of a tertiary care hospital. AB - Background: Reintubation and readmission after cardiothoracic surgeries are not uncommon, and its reasons are multifactorial. The study goal was to identify the factors that contribute reintubation after cardiac and thoracic surgery in tertiary care hospital and to compare the outcome with international benchmark. Methodology: A prospective, observational study was planned in Cardiac Intensive Care Unit (CICU). The study included all those patients who required readmission in CICU due to endotracheal intubation following cardiac and thoracic surgeries. The study was conducted from January to December 2016. The primary focus was to identify the reasons for reintubation within 72 h of extubation after CICU discharge and its association with outcome. Results: Out of 750 patients who shifted out from CICU following successful extubation, only 32 were readmitted and among them in 25 patients (3.33%) were reintubated and their reasons reintubation were noted. Patients underwent a coronary artery bypass grafting (CABG) with valve replacement had a higher incidence of reintubation 3/39 (7.69%) when compared with CABG 13/517 (2.51%) and 4/135 (2.96%) valve procedure alone. Single cause of endotracheal reintubation was observed in 7 patients (28%), in which 5 patients (20%) had respiratory and 2 patients had (8%) cardiac reason while 18 patients (72%) were observed with multisystem involvement, in which 7 patients (28%) had both respiratory and cardiovascular causes, and 2 (8%) had both respiratory and neurological causes. More than 70% cause of endotracheal reintubation was both respiratory and cardiovascular. The CICU stay after reintubations was 12.88 +/- 16.88 days and the hospital stay prolonged to 23.84 +/- 21.61 days. Conclusion: Reasons of reintubation were mainly respiratory and cardiac. The rate of reintubations is high when multisystem involvement is there. CICU, hospital stay, and mortality are increases after reintubation. PMID- 29628838 TI - Evaluation of transversus abdominis plane block for renal transplant recipients - A meta-analysis and trial sequential analysis of published studies. AB - Background: Patients undergoing renal transplant (RT) have altered drug/opioid pharmacokinetics. Transversus abdominis plane (TAP) block in renal transplant recipients has been recently evaluated for analgesic and opioid-sparing potential by many trials. Methodology: The studies comparing TAP-block to conventional analgesic regimens for RT were searched. Comparisons were made for total opioids consumed (as morphine-equivalents) during the first postoperative 24-h (primary objective), intraoperative, and immediate-postoperative period. Pain scores and postoperative nausea-vomiting (PONV) were also evaluated. Trial sequential analysis (TSA) was used to quantify the strength of analysis. Results: Ten-trials with 258 and 237 patients in control and TAP-block group, respectively, were included. TAP-block decreased the 24-h (reported in 9-trials) opioid consumption by 14.61 +/- 4.34 mg (reduction by 42.7%, random-effects, P < 0.001, I2 = 97.82%). Sample size of the present analysis (472) was well past the required "information-size" variable (396) as per the TSA for a power of 85%. Intraoperative opioid consumption also decreased by 2.06 +/- 0.63 mg (reduction of 27.8%) (random effects, P < 0.001, I2 = 98.84%). Pain scores with TAP-block were significantly lower in both early and delayed postoperative phase. Odds ratio for PONV without TAP block was 1.99 +/- 1.05 (Fixed-effects, P = 0.04, I2 = 0%). Publication bias was likely (Egger's test, X-intercept=7.89, P < 0.05). Conclusions: TAP-block significantly lowers the intraoperative and cumulative postoperative 24-h opioid consumption in RT recipients. Persistent and better pain control is achieved when TAP-Block is used. Benefits of TAP block extend beyond the analgesic actions alone as it also decreases the 24-h incidence of postoperative nausea vomiting as well. The technique of the block needs standardization for RT recipients. PMID- 29628839 TI - A prospective randomized controlled study to evaluate and compare GlideScope with Macintosh laryngoscope for ease of endotracheal intubation in adult patients undergoing elective surgery under general anesthesia. AB - Background: The aim of the study was to compare the ease the intubation using GlideScope video laryngoscope and Macintosh laryngoscope in adult patients undergoing elective surgery under general anesthesia. Materials and Methods: A total of 200 American Society of Anesthesiologists I-II patients of either sex, in the age group of 18-60 years were included in the study. Patients were randomly allocated to two groups. We assessed ease of intubation depending on time to tracheal intubation, number of attempts, glottic view (Cormack-Lehane grade [CL grade] and percentage of glottis opening [POGO]) and intubation difficulty score (IDS), hemodynamic variables and any intra- and post-operative adverse events. Results: The rate of successful endotracheal intubation (ETI) in both groups was 100% in the first attempt. The time required for successful ETI was 24.89 +/- 5.574 in Group G and 20.68 +/- 3.637 in Group M (P < 0.001) found to be statistically significant. There was significant improvement in glottic view with GlideScope (as assessed by POGO score 66.71 +/- 29.929 and 94.40 +/- 10.476 in group G and 75.85 +/- 26.969 and 74.20 +/- 29.514 Group M and CL grading [P < 0.001]). A comparison of mean IDS between two groups revealed intubation was easier with the use of GlideScope. The hemodynamic response to intubation was significantly lesser with the use of GlideScope when compared with Macintosh laryngoscope. The incidence of adverse events, though minor like superficial lip or tongue bleed, was similar in two groups. Conclusions: GlideScope offers superiority over Macintosh laryngoscope in terms of laryngeal views and the difficulty encountered at ETI in an unselected population. PMID- 29628840 TI - Lumbar epidural depth using transverse ultrasound scan and its correlation with loss of resistance technique: A prospective observational study in Indian population. AB - Background and Objectives: The objective of the present study was to evaluate the skin-epidural space distance as assessed by ultrasonography and conventional loss of resistance (LOR) technique and to find the correlation of epidural depth with body mass index (BMI). Methods: Ninety-eight patients of either sex, American Society of Anesthesiology I/II, BMI <30 kg/m2 requiring lumbar epidural for surgery were enrolled. The epidural space was assessed with a curvilinear ultrasound (US) probe, 2-5 MHz, in the transverse plane at L3-L4 intervertebral space. Thereafter, the epidural depth from skin was assessed with conventional LOR method while performing the epidural. The needle depth (ND) was measured using a sterile linear scale, and any change in the needle direction or intervertebral space was noted. Results: The patients were demographically similar. Depth of epidural space measured by US depth (UD) was 3.96 +/- 0.44 cm (range 3.18-5.44 cm) and by ND was 4.04 +/- 0.52 cm (range 2.7-5.7 cm). The Pearson's correlation coefficient (r) between UD and ND was 0.935 (95% confidence interval: 0.72-0.92, r2 = 0.874, P < 0.001), and Bland-Altman analysis revealed the 95% limits of agreement -0.494-0.652 cm. Conclusion: The present study demonstrates a good correlation between UD and ND and shows that the preprocedural US scan in transverse plane provides accurate needle entry site with a high success rate in single attempt for lumbar epidurals in patients with a BMI <30 kg/m2. PMID- 29628841 TI - Appearance of Population, Intervention, Comparison, and Outcome as research question in the title of articles of three different anesthesia journals: A pilot study. AB - Background: It is well known in the evidence-based medicine practice that framing the research question is the most important and crucial part of the research integrity. Population, Intervention, Comparison, and Outcome (PICO) is a specialized framework used by most researchers to formulate a research question and to facilitate literature review. The aim of this study is to investigate the representation of the PICO frame in the title of published articles in three different anesthesia journals. Methods: We performed this double-blind, pilot study on papers published in three anesthesia journals, including Anesthesia and Intensive care (a), Saudi Journal of Anaesthesia (b), and Anesthesia Analgesia (c) from January 2016 to September 2017. We randomly selected 30 randomized controlled trials from each journal to check for the PICO frame in the title of each article. We used Chi-square test to compare the met variables in the three journals with respect to PICO frame. Met variables are those who met the PICO frame and not met are not. We assumed a statistically significant difference when P was <0.05. Results: Ninety randomized controlled trials articles (n = 90) were included in this study (n = 30 each journal A, B, and C). Corresponding estimates of the percent of papers that failed (not met) to adopt PICO elements were as follow for journal A, B, and C, respectively: Population: 30%, 30%, and 20%; Intervention: 50%, 30%, and 26.7%; Comparison: 53.3%, 60%, and 53.3%; and Outcome: 30%, 6.7%, and 0.0% with significant differences between journals A and C (P < 0.05). Conclusion: Researches adopting PICO elements usually receive higher citation percentages. There is a need to further investigate the PICO framework in a larger study to determine whether it can be well represented in the titles of different research designs. That, in turn, will help the precision of searches performed on a PICO-formatted screen to receive relevant citations. PMID- 29628842 TI - Correlation of different parity and school education with acceptance of labor analgesia among antenatal women: A questionnaire-based study. AB - Background and Aim: Pain relief is nearly regarded as the right of patients in modern day health care. Women undergo excruciating pain during normal vaginal delivery (NVD). However, the acceptance of labor analgesia (LA) has remained very poor. The present study was aimed to assess the correlation of previous exposure to such pain (parity) and school education with LA acceptance. Methods: The present comparative study was conducted with a total 400 consented participants. A questionnaire was used to collect sociodemographic variables, acceptance/nonacceptance of LA, and the reasons for not opting for LA in upcoming delivery were noted. Participants were divided into primiparous, multiparous, and nulliparous (control). They were also grouped as per school education and compared taking illiterates as controls. Data are presented in absolute number. Fisher's exact test is used for comparison; P < 0.05 was considered statistically significant. Results: Seventy (17.5%) multiparous and 38% primiparous participants were compared with 44.5% nulliparous women. Only 2.75% participants were illiterate. 69.50% were rural inhabitant and 81.50% believed in Hinduism. 87.14% multiparous, 84.21% primiparous, and 88.76% nulliparous women declined LA (P > 0.05). The desire to experience NVD without LA as a reason for nonacceptance was significantly less among primiparous and multiparous as compared to nulliparous (P < 0.0001), but not among literate and illiterate participants (P > 0.295 in all). Conclusion: Previous labor pain significantly reduces the desire to experience NVD without LA, but still more than 80% parturients of any parity do not want LA due to one or more reasons. School education has no impact on LA acceptance. PMID- 29628843 TI - Point-of-care ultrasound in the airway assessment: A correlation of ultrasonography-guided parameters to the Cormack-Lehane Classification. AB - Background and Aim: The sonographic assessment of airway in the preoperative period has encouraging results in predicting difficult laryngoscopy. Materials and Methods: The prospective, observational study was conducted on 120 patients scheduled for elective surgery requiring general anesthesia and tracheal intubation. The depth of the pre-epiglottic space (Pre-E), the distance from the epiglottis to the midpoint of the distance between the vocal cords (E-VC) was measured sonographically. Similarly, hyomental distance ratio (HMDR) was sonographically measured with head in neutral and extended positions. The primary outcome was the efficacy of Pre E/E-VC, HMDR for predicting difficult laryngoscopy (Cormack-Lehane [CL] Grade 3, 4). The secondary outcome was to correlate these parameters to CL grading. Results: Difficult intubation was observed in 12.5% of patients. The mean +/- standard deviation (SD) of Pre E/E-VC ratio was 1.33+/-0.335, 1.62+/-0.264 and 1.87+/-.243, 2.22+/-.29 for CL Grade 1, 2, 3, and 4, respectively (P = 0.00). The mean +/- SD of HMDR was 1.11+/-.35, 1.12+/-.29, and 1.07+/-.39, 1.04 +/- 0.01 for CL Grade 1, 2, 3, and 4, respectively (P = 0.00). Pre E/E-VC ratio of more than 1.77 cm had 82% sensitivity, specificity 80%, whereas HMDR less than1.085 had sensitivity 75% and specificity 85.3%, in predicting difficult laryngoscopy (P = 0.00). Conclusion: The sonographic measurement of the Pre E/E-VC ratio is a better predictor of CL grading as compared to HMDR. The noninvasive prediction of CL grading can be precisely done by Pre-E/E-VC ratio (range: 0-1.425 corresponds to CL Grade 1; 1.425-1.77 ~ CL Grade 2; 1.77-1.865 ~ CL Grade 3, more than 1.865 corresponds to CL Grade 4). PMID- 29628844 TI - Dexmedetomidine in a surgically inserted catheter for transversus abdominis plane block in donor hepatectomy: A prospective randomized controlled study. AB - Background: Transversus abdominis plane (TAP) block is a promising technique for analgesia after abdominal surgery. This prospective, randomized controlled trial assessed the effect of adding dexmedetomidine to bupivacaine in TAP block for donor hepatectomy. We hypothesized that this would improve postoperative morphine consumption and reduce analgesia related complication and inflammation. Methods: A total of 50 donor hepatectomy were enrolled in this study. Patients divided into two equal groups according to drugs used for TAP block. Group (B) received 20 ml of bupivacaine hydrochloride 0.25%, Group (BD) received 20 ml of bupivacaine hydrochloride 0.25% and 0.3 MUg/kg dexmedetomidine, on both sides at the end of surgery and every 8 h for 48 h at right side only through inserted catheter. Primary outcome objective was morphine consumption at first 72 h. Secondary outcome objectives were morphine requirement, numbers of intake, time to first intake, pain score numerical analog scale (NAS), postoperative analgesia related complications, recovery of intestinal motility, and inflammatory markers. Results: Data were analyzed, rescue morphine analgesia was significantly lower in (BD) group compared with (B) groups as considering total morphine consumption (B 4 +/- 1.9, BD 1.5 +/- 0.5, P = 0.03), numbers of morphine intake (P = 0.04), morphine requirement (P = 0.03), and first time of analgesia intake (P = 0.04). NAS was significantly lower in group (BD) compared with group (B) group in the first 12 h (NAS 0 - P = 0.001, NAS 1 - P = 0.03). Adding dexmedetomidine improved gut motility, first oral intake without detectable anti-inflammatory effect. Conclusion: Adding dexmedetomidine to bupivacine in a surgically inserted catheter for TAP block in donor hepatectomy reduced morphine consumption without detectable anti-inflammatory effect. PMID- 29628845 TI - Patient satisfaction and experience with anesthesia: A multicenter survey in Saudi population. AB - Background and Objectives: Patients' satisfaction of anesthesia outcomes is a major part of the overall quality of health care. The aim of this study is to evaluate patient's satisfaction whether pre- or post-operative as well as overall impression using a multicenter prespecified survey tool. Methods: Three hundred and three patients who underwent surgery regardless the type of anesthesia were surveyed. The interview conducted face-to-face before surgery then within the first 24 h of surgery. We recorded all basic demographics of patients, the quality of postoperative symptoms control, and the impression about anesthesia team. Results: The overall satisfaction level was moderate (56.5%) with nearly half of the patients dissatisfied with their anesthetic care due to different reasons. Nausea and vomiting control was the most common postoperative reasons for dissatisfaction followed by pain control with 35.6% and 31.7%, respectively. Conclusion: Type of anesthesia, giving an informative visit to the patient, and the control of postoperative symptoms are the most important predictors of patients' satisfaction. PMID- 29628848 TI - Wilm's tumor with intracardiac extension causing dynamic tricuspid valve obstruction: An anesthetic challenge. AB - Wilms' tumor (WT) is the most common pediatric renal tumor that often spreads to inferior vena cava and sometimes up to right atrium (RA). We describe successful management of 3-year-old child diagnosed with WT having extension up to RA. He was operated under cardiopulmonary bypass and extubated on postoperative day 2 and discharged. Perioperative anesthesia concerns were shock from dynamic tricuspid valve obstruction, intraoperative massive blood loss, and a higher risk of pulmonary thromboembolism during tumor manipulation. PMID- 29628846 TI - Intraoperative fluid management: Past and future, where is the evidence? AB - Currently, there is no consensus about the optimum intraoperative fluid therapy strategy. There is growing body of evidence supports the beneficial effects of adopting "Goal-directed therapy" over either the "liberal" or "restrictive" fluid therapy strategies. In this narrative review, we have presented the evidence to support the optimum strategy for intraoperative therapy. In conclusion, whatever the intravenous fluid replacement strategy used, the anesthesiologist must be prepared to adjust the composition and rate of the fluids administered to provide sufficient intravascular fluid volume for adequate perfusion of vital organs without overwhelming the glycocalyx function with fluid overloads. PMID- 29628847 TI - Bedside ultrasound assessment of gastric content in children noncompliant with preoperative fasting guidelines: Is it time to include this in our practice? AB - Ultrasound assessment of gastric contents and volume is gaining popularity in adults and children. At present, a preoperative verbal check is used to determine the fasting status. Due to fear of delay or cancellation of surgery, parents may not disclose noncompliance with fasting guidelines. Pulmonary aspiration of gastric contents is a potential cause of morbidity and mortality. Ultrasound assessment of gastric contents is noninvasive and easy to learn. We present a series of three cases to demonstrate how the use of ultrasound to assess gastric contents in children can provide an objective means for decision-making and impact anesthetic management when preoperative fasting status is uncertain. PMID- 29628849 TI - Pectoralis blocks for insertion of an implantable cardioverter defibrillator in two patients with Duchenne muscular dystrophy. AB - Patients with Duchenne muscular dystrophy (DMD) often have systemic manifestations with comorbid involvement of the cardiac and respiratory systems that increase the risk of anesthetic and perioperative morbidity. These patients frequently develop progressive myocardial involvement with cardiomyopathy, depressed cardiac function, and arrhythmias. The latter may necessitate the placement of an automatic implantable cardioverter defibrillator (AICD) insertion. As a means of avoiding the need for general anesthesia and its inherent potential of morbidity, regional anesthesia may be used in specific cases. We present two cases of successful AICD insertion in patients with DMD using unilateral pectoralis and intercostal nerve blocks supplemented with intravenous sedation. Relevant anatomy for this regional anesthetic technique is reviewed and benefits of this anesthetic technique compared to general anesthesia are discussed. PMID- 29628850 TI - Development of postoperative central anticholinergic syndrome due to low-dose intravenous fentanyl. AB - A 37-year-old female patient, 57 kg and 160 cm, underwent laparoscopic appendectomy. In the recovery room, fentanyl 100 mcg was intravenously administered for pain control. Three minutes after the administration, the patient developed intense and uncontrolled myoclonus, lower limb rigidity, agitation, aphasia, and periocular and neck swelling. The myoclonus and rigidity were suspected to be due to the opioid administration, and thus, naloxone was administered, but the symptoms were not improved. The patient's symptoms continued until the patient received administration of physostigmine. The patient was discharged 3 days later, following resolution of the symptoms. We report a case of central anticholinergic syndrome that developed after general anesthesia owing to the interaction of opioid at an analgesic dose for postoperative pain control with another anesthetic. PMID- 29628851 TI - Renal oxalate stones in children with Zellweger spectrum disorders. AB - Peroxisomal biogenesis disorders due to PEX gene defects are classified into many subgroups, of which Zellweger spectrum disorders (ZSDs) represent the major subgroup. The ZSDs are clinical and biochemical disorders divided into three phenotypes: neonatal, adolescence, or adult. Clinical presentations vary with severity of the condition. Metabolic abnormalities occur due to functional peroxisomal defects that could be detected in blood and urine. No cure or definitive management exists to date; only supportive and palliative measures are applied to prevent worse sequelae. We experienced a case of oxalate renal stones in a patient with ZSD. This patient had hyperoxaluria and hyperglycolic aciduria with clinically associated clues that correlate with urinary oxalate load. Urinary oxalate and glycolate excretion were assessed. Radiological workup revealed renal involvement with urolithiasis and nephrocalcinosis. Urinalysis and ultrasonography for stones and hyperoxaluria should be used to screen patients with ZSD for early intervention to prevent renal damage. PMID- 29628852 TI - Anesthetic and psychiatric implications of accidental awareness under general anesthesia during electroconvulsive therapy. AB - Accidental awareness under general anesthesia (AAGA) is a well-known phenomenon. However, little literature exists in its relation to the psychiatric field, particularly within the electroconvulsive therapy (ECT) setting. This report explores the case of a 52-year-old woman that describes her own experience of AAGA during ECT. Relevant anesthetic details are also provided along with its possible implications in AAGA. The aim of this case report is to increase awareness among clinicians in regard to AAGA and its occurrence during ECT. PMID- 29628853 TI - Crohn's disease-associated silent aspiration in the outpatient setting: Anesthesiologists beware. AB - Every anesthesia provider fears aspiration of gastric contents during an anesthetic, and it may occur even in the absence of overt signs such as coughing or choking. Whether the aspiration is frank or silent, catastrophic and deleterious consequences may ensue. Therefore, familiarity with risk factors for silent aspiration is essential. Crohn's disease reportedly delays gastric emptying making these patients more susceptible to silent aspiration during surgery. Anesthesia providers must be cognizant of this risk and vigilant in the recognition to formulate a specific treatment plan preoperatively. We present a case of an ambulatory surgical patient with suspected silent aspiration undiagnosed by the anesthesia care team before induction of anesthesia. PMID- 29628854 TI - Magnesium interscalene nerve block for the management of painful shoulder disorders. AB - Shoulder pain is a common and distressing disorder. Systemic multimodal analgesia may be ineffective, but interscalene nerve block provides effective therapy. Magnesium may increase the efficacy and duration of systemic or regional analgesia. This case series examines the utility of magnesium interscalene nerve block for the management of painful shoulder disorders. Six elderly patients with shoulder pain and dysfunction received interscalene nerve block with injection of bupivacaine and magnesium. The patients subsequently reported significant improvement in sleep, shoulder pain, and physical function for 16 weeks. This report highlights that magnesium interscalene nerve block provides safe, effective, and prolonged shoulder analgesia. PMID- 29628855 TI - Editorial commentary on: Using dexamethasone as an adjuvant to levobupivacaine in epidural anesthesia to change the pain intensity and duration in painless labor. PMID- 29628856 TI - Subcutaneous emphysema after endotracheal intubation: A case report. PMID- 29628857 TI - Limited mouth opening: Retrograde intubation revisited. PMID- 29628858 TI - Evaluation of a new laryngoscope according to preparation time. PMID- 29628859 TI - Ultrasound as a guide to reposition a misdirected central venous catheter. PMID- 29628860 TI - Pneumomediastinum following iatrogenic pharyngeal perforation during tracheoesophageal fistula repair. PMID- 29628861 TI - Asymptomatic congenital subglottic stenosis in a neonate - infant feeding tube as a "Guardian angel!" PMID- 29628862 TI - Algorithms for successful repositioning of misplaced left-sided double-lumen tube inserted during lung/thoracic surgery. PMID- 29628863 TI - Point-of-care lung ultrasound can detect endobronchial intubation during laparoscopic cholecystectomy. PMID- 29628864 TI - Fixed cervical flexion deformity: Difficult airway. PMID- 29628865 TI - Intranasal lignocaine spray for sphenopalatine ganglion block for postdural puncture headache. PMID- 29628866 TI - New technology: Handheld ultrasound-assisted localization of epidural space. PMID- 29628867 TI - Noncardiac surgery in two severe aortic stenosis patients: General or epidural anesthesia? PMID- 29628868 TI - Point-of-care ultrasonography for detection of tracheal tube cuff rupture following nasal intubation? PMID- 29628869 TI - Palliative surgical gastrostomy under ultrasound-guided bilateral rectus sheath blocks in a head and neck cancer patient. PMID- 29628870 TI - Intubation over a bougie: Nasal is not novel. PMID- 29628871 TI - Saviour in a mess: Spinal needle (Gaurav Technique). PMID- 29628872 TI - Excitation of the Auditory System as a Result of Non-invasive Extra-Cochlear Stimulation in Normal Subjects and Tinnitus Patients. AB - One of possible approach that may suppress tinnitus is electrical stimulation of the ear. At first invasive techniques were used (promontory or round window stimulation), nowadays a non-invasive method, namely hydrotransmissive electric stimulation (ES) through external acoustic canal, has been developed. The aim of the study is to investigate the effect of applying ES with positive and negative current polarities on the ears of healthy subjects and on the tinnitus ears of patients with tinnitus. This comparison further clarifies the mechanisms of operation of non-invasive extra-cochlear ear ES. A second aim is to assess the effects of ES on tinnitus in tinnitus patients. The material was composed of two groups: tinnitus group-49 patients suffering from tinnitus, and healthy students group-34 healthy individuals. ES was performed with the use of a custom-made apparatus. The active, silver probe-was immersed inside saline filling external ear canal. The passive electrode was placed on the forehead. Positive and next negative DC stimulation was provided with the use following frequencies: 0.25, 1, 2, 3, 4, 5, 6, 7, 8 kHz. We checked for the presence of the auditory percept (AP) and, if AP was present, the minimum current amplitude necessary to produce AP was measured. In our research both positive and negative polarities were efficient to evoke AP in the participants. This effect, however, was more pronounced for positive polarity in no tinnitus and normal hearing individuals (healthy students group). In the tinnitus group, current intensity needed to evoke AP was higher than in the healthy students group. However, comparing normal hearing vs. hearing loss patients within the tinnitus group, we did not observe the relationship between hearing threshold and current intensity evoking AP. Afterwards, we analyzed the effect of multi-frequency ES on tinnitus. It appeared to be effective in 75% of tinnitus ears (with a high score of disappearance-22%). Our study proved that extracochlear ES with positive and negative current was efficient to stimulate the auditory system. Stimulating tinnitus ears with two polarities we obtained a higher ratio of improvement (75%) comparing to positive stimulations. PMID- 29628874 TI - SAHA (Vorinostat) Corrects Inhibitory Synaptic Deficits Caused by Missense Epilepsy Mutations to the GABAA Receptor gamma2 Subunit. AB - The GABAA receptor (GABAAR) alpha1 subunit A295D epilepsy mutation reduces the surface expression of alpha1A295Dbeta2gamma2 GABAARs via ER-associated protein degradation. Suberanilohydroxamic acid (SAHA, also known as Vorinostat) was recently shown to correct the misfolding of alpha1A295D subunits and thereby enhance the functional surface expression of alpha1A295Dbeta2gamma2 GABAARs. Here we investigated whether SAHA can also restore the surface expression of gamma2 GABAAR subunits that incorporate epilepsy mutations (N40S, R43Q, P44S, R138G) known to reduce surface expression via ER-associated protein degradation. As a control, we also investigated the gamma2 K289M epilepsy mutation that impairs gating without reducing surface expression. Effects of mutations were evaluated on inhibitory postsynaptic currents (IPSCs) mediated by the major synaptic alpha1beta2gamma2 GABAAR isoform. Recordings were performed in neuron-HEK293 cell artificial synapses to minimise contamination by GABAARs of undefined subunit composition. Transfection with alpha1beta2gamma2 N40S , alpha1beta2gamma2 R43Q , alpha1beta2gamma2 P44S and alpha1beta2gamma2 R138G subunits produced IPSCs with decay times slower than those of unmutated alpha1beta2gamma2 GABAARs due to the low expression of mutant gamma2 subunits and the correspondingly high expression of slow-decaying alpha1beta2 GABAARs. SAHA pre-treatment significantly accelerated the decay time constants of IPSCs consistent with the upregulation of mutant gamma2 subunit expression. This increase in surface expression was confirmed by immunohistochemistry. SAHA had no effect on either the IPSC kinetics or surface expression levels of alpha1beta2gamma2 K289M GABAARs, confirming its specificity for ER-retained mutant gamma2 subunits. We also found that alpha1beta2gamma2 K289M GABAARs and SAHA-treated alpha1beta2gamma2 R43Q , alpha1beta2gamma2 P44S and alpha1beta2gamma2 R138G GABAARs all mediated IPSCs that decayed at significantly faster rates than wild type receptors as temperature was increased from 22 to 40 degrees C. This may help explain why these mutations cause febrile seizures (FS). Given that SAHA is approved by therapeutic regulatory agencies for human use, we propose that it may be worth investigating as a treatment for epilepsies caused by the N40S, R43Q, P44S and R138G mutations. Although SAHA has already been proposed as a therapeutic for patients harbouring the alpha1A295D epilepsy mutation, the present study extends its potential utility to a new subunit and four new mutations. PMID- 29628873 TI - Combined rTMS/fMRI Studies: An Overlooked Resource in Animal Models. AB - Repetitive transcranial magnetic stimulation (rTMS) is a non-invasive neuromodulation technique, which has brain network-level effects in healthy individuals and is also used to treat many neurological and psychiatric conditions in which brain connectivity is believed to be abnormal. Despite the fact that rTMS is being used in a clinical setting and animal studies are increasingly identifying potential cellular and molecular mechanisms, little is known about how these mechanisms relate to clinical changes. This knowledge gap is amplified by non-overlapping approaches used in preclinical and clinical rTMS studies: preclinical studies are mostly invasive, using cellular and molecular approaches, while clinical studies are non-invasive, including functional magnetic resonance imaging (fMRI), TMS electroencephalography (EEG), positron emission tomography (PET), and behavioral measures. A non-invasive method is therefore needed in rodents to link our understanding of cellular and molecular changes to functional connectivity changes that are clinically relevant. fMRI is the technique of choice for examining both short and long term functional connectivity changes in large-scale networks and is becoming increasingly popular in animal research because of its high translatability, but, to date, there have been no reports of animal rTMS studies using this technique. This review summarizes the main studies combining different rTMS protocols with fMRI in humans, in both healthy and patient populations, providing a foundation for the design of equivalent studies in animals. We discuss the challenges of combining these two methods in animals and highlight considerations important for acquiring clinically-relevant information from combined rTMS/fMRI studies in animals. We believe that combining rTMS and fMRI in animal models will generate new knowledge in the following ways: functional connectivity changes can be explored in greater detail through complementary invasive procedures, clarifying mechanism and improving the therapeutic application of rTMS, as well as improving interpretation of fMRI data. And, in a more general context, a robust comparative approach will refine the use of animal models of specific neuropsychiatric conditions. PMID- 29628875 TI - Profiling of Long Non-coding RNAs and mRNAs by RNA-Sequencing in the Hippocampi of Adult Mice Following Propofol Sedation. AB - Propofol is a frequently used intravenous anesthetic agent. The impairment caused by propofol on the neural system, especially the hippocampus, has been widely reported. However, the molecular mechanism underlying the effects of propofol on learning and memory functions in the hippocampus is still unclear. In the present study we performed lncRNA and mRNA analysis in the hippocampi of adult mice, after propofol sedation, through RNA-Sequencing (RNA-Seq). A total of 146 differentially expressed lncRNAs and 1103 mRNAs were identified. Bioinformatics analysis, including gene ontology (GO) analysis, pathway analysis and network analysis, were done for the identified dysregulated genes. Pathway analysis indicated that the FoxO signaling pathway played an important role in the effects of propofol on the hippocampus. Finally, four lncRNAs and three proteins were selected from the FoxO-related network for further validation. The up-regulation of lncE230001N04Rik and the down-regulation of lncRP23-430H21.1 and lncB230206L02Rik showed the same fold change tendencies but changes in Gm26532 were not statistically significant in the RNA-Seq results, following propofol sedation. The FoxO pathway-related proteins, PI3K and AKT, are up-regulated in propofol-exposed group. FoxO3a is down-regulated at both mRNA and protein levels. Our study reveals that propofol sedation can influence the expression of lncRNAs and mRNAs in the hippocampus, and bioinformatics analysis have identified key biological processes and pathways associated with propofol sedation. Cumulatively, our results provide a framework for further study on the role of lncRNAs in propofol-induced or -related neurotoxicity, particularly with regards to hippocampus-related dysfunction. PMID- 29628876 TI - Korean Red Ginseng Pretreatment Protects Against Long-Term Sensorimotor Deficits After Ischemic Stroke Likely Through Nrf2. AB - Endogenous neuroprotective mechanisms by which the brain protects itself against noxious stimuli and recovers from ischemic damage are key targets of stroke research, ultimately facilitating functional recovery. Transcriptional factor Nrf2, enriched in astrocytes, is a master regulator of endogenous defense systems against oxidative stress and inflammation. Korean Red Ginseng (Ginseng), one most widely used herbal medicine, has exhibited promising potentials in neuroprotection. Our study aimed to determine whether the standardized Ginseng extract pretreatment could attenuate acute sensorimotor deficits and improve long term functional recovery after ischemic stroke though Nrf2 pathway and whether reactive astrogliosis is associated with such effect. Adult Nrf2-/- and matched wildtype control (WT) mice were pretreated with Ginseng orally for 7 days prior to permanent distal middle cerebral artery occlusion (pdMCAO). Using an optimized method that can accurately assess either severe or mild pdMCAO-induced sensorimotor deficits, neurobehavioral tests were performed over 28 days. The progression of lesion volume and the evolution of astrocytic and microglial activation were determined in the acute stage of ischemic stroke after pdMCAO (0 3 days). Nrf2-downstream target antioxidant genes expression levels was assessed by Western blot. We found that Ginseng pretreatment ameliorated acute sensorimotor deficits and promoted long-term functional recovery, prevented the acute enlargement of lesion volume (36.37 +/- 7.45% on day 3), attenuated reactive astroglial progression but not microglia activation, and enhanced the induction of Nrf2-downstream target proteins after ischemic insult in WT mice, an effect which was lost in Nrf2 knockouts. The spatiotemporal pattern of reactive astrogliosis evaluation correlated well with acute ischemic damage progression in an Nrf2-dependent fashion during the acute phase of ischemia. In contrast, Nrf2 deficiency mice exhibited exacerbated ischemic condition compared to WT controls. Together, Ginseng pretreatment protects against acute sensorimotor deficits and promotes its long-term recovery after pdMCAO, at least partly, through Nrf2 activation, highlighting the potential efficacy of oral consumption of Ginseng for stroke preventative intervention in patients who are at great risk of recurrent stroke or transient ischemic attack. The attenuated reactive astrogliosis contributes to the Nrf2 pathway related neuroprotection against acute ischemic outcome and substantially long-term sensorimotor deficits in the context of ischemic stroke under pdMCAO. PMID- 29628878 TI - Writing About Past Failures Attenuates Cortisol Responses and Sustained Attention Deficits Following Psychosocial Stress. AB - Acute stress can harm performance. Paradoxically, writing about stressful events such as past failures-has been shown to improve cognitive functioning and performance, especially in tasks that require sustained attention. Yet, there is little physiological evidence for whether writing about past failures or other negative events improves performance by reducing stress. In this experiment, we studied the effects of an acute psychosocial stressor, the Trier Social Stress Test, on attentional performance and salivary cortisol release in humans. Additionally, we investigated whether an expressive writing task could reduce the detrimental effects of stress, both on performance and physiological response. We found that when individuals were asked to write about a past failure before experiencing a stressor, they exhibited attenuated stress responses. Moreover, those who wrote about a past failure before being exposed to stress also exhibited better behavioral performance. Our results suggest that writing about a previous failure may allow an individual to experience a new stressor as less stressful, reducing its physiological and behavioral effects. PMID- 29628877 TI - Source Reconstruction of Brain Potentials Using Bayesian Model Averaging to Analyze Face Intra-Domain vs. Face-Occupation Cross-Domain Processing. AB - We investigated the neural correlates of the access to and retrieval of face structure information in contrast to those concerning the access to and retrieval of person-related verbal information, triggered by faces. We experimentally induced stimulus familiarity via a systematic learning procedure including faces with and without associated verbal information. Then, we recorded event-related potentials (ERPs) in both intra-domain (face-feature) and cross-domain (face occupation) matching tasks while N400-like responses were elicited by incorrect eyes-eyebrows completions and occupations, respectively. A novel Bayesian source reconstruction approach plus conjunction analysis of group effects revealed that in both cases the generated N170s were of similar amplitude but had different neural origin. Thus, whereas the N170 of faces was associated predominantly to right fusiform and occipital regions (the so-called "Fusiform Face Area", "FFA" and "Occipital Face Area", "OFA", respectively), the N170 of occupations was associated to a bilateral very posterior activity, suggestive of basic perceptual processes. Importantly, the right-sided perceptual P200 and the face-related N250 were evoked exclusively in the intra-domain task, with sources in OFA and extensively in the fusiform region, respectively. Regarding later latencies, the intra-domain N400 seemed to be generated in right posterior brain regions encompassing mainly OFA and, to some extent, the FFA, likely reflecting neural operations triggered by structural incongruities. In turn, the cross-domain N400 was related to more anterior left-sided fusiform and temporal inferior sources, paralleling those described previously for the classic verbal N400. These results support the existence of differentiated neural streams for face structure and person-related verbal processing triggered by faces, which can be activated differentially according to specific task demands. PMID- 29628881 TI - Posture-Motor and Posture-Ideomotor Dual-Tasking: A Putative Marker of Psychomotor Retardation and Depressive Rumination in Patients With Major Depressive Disorder. AB - Background: Recent studies have demonstrated that the assessment of postural performance may be a potentially reliable and objective marker of the psychomotor retardation (PMR) in the major depressive disorder (MDD). One of the important facets of MDD-related PMR is reflected in disrupted central mechanisms of psychomotor control, heavily influenced by compelling maladaptive depressive rumination. In view of this we designed a research paradigm that included sequential execution of simple single-posture task followed by more challenging divided attention posture tasks, involving concurring motor and ideomotor workloads. Another difficulty dimension assumed executing of all the tasks with eyes open (EO) (easy) and closed (EC) (difficult) conditions. We aimed at investigating the interplay between the severity of MDD, depressive rumination, and efficiency of postural performance. Methods: Compared with 24 age- and body mass index-matched healthy controls (HCs), 26 patients with MDD sequentially executed three experimental tasks: (1) single-posture task of maintaining a quiet stance (ST), (2) actual posture-motor dual task (AMT); and (3) mental/imaginary posture-motor dual task (MMT). All the tasks were performed in the EO and the EC conditions. The primary dependent variable was the amount of kinetic energy (E) expended for the center of pressure deviations (CoPDs), whereas the absolute divided attention cost index showed energy cost to the dual-tasking vs. the single-posture task according to the formula: DeltaE = (EDual-task - ESingle task). Results: The signs of PMR in the MDD group were objectively indexed by deficient posture control in the EC condition along with overall slowness of fine motor and ideomotor activity. Another important and probably more challenging feature of the findings was that the posture deficit manifested in the ST condition was substantially and significantly attenuated in the MMT and AMT performance dual-tasking activity. A multiple linear regression analysis evidenced further that the dual-tasking energy cost (i.e., DeltaE) significantly predicted clinical scores of severity of MDD and depressive rumination. Conclusion: The findings allow to suggest that execution of concurrent actual or imaginary fine motor task with closed visual input deallocates attentional resources from compelling maladaptive depressive rumination thereby attenuating severity of absolute dual-tasking energy costs for balance maintenance in patients with MDD. Significance: Quantitative assessment of PMR through measures of the postural performance in dual-tasking may be useful to capture the negative impact of past depressive episodes, optimize the personalized treatment selection, and improve the understanding of the pathophysiological mechanisms underlying MDD. PMID- 29628880 TI - Real-Time Prediction of Observed Action Requires Integrity of the Dorsal Premotor Cortex: Evidence From Repetitive Transcranial Magnetic Stimulation. AB - Studying brain mechanisms underlying the prediction of observed action, the dorsal premotor cortex (PMd) has been suggested a key area. The present study probed this notion using repetitive transcranial magnetic stimulation (rTMS) to test whether interference in this area would affect the accuracy in predicting the time course of object directed actions performed with the right hand. Young and healthy participants observed actions in short videos. These were briefly occluded from view for 600 ms and resumed immediately afterwards. The task was to continue the action mentally and to indicate after each occlusion, whether the action was resumed at the right moment (condition in-time) or shifted. In a first run, single-pulse transcranial magnetic stimulation (sTMS) was delivered over the left primary hand-area during occlusion. In the second run, rTMS over the left PMd was applied during occlusion in half of the participants [experimental group (EG)]. The control group (CG) received sham-rTMS over the same area. Under rTMS, the EG predicted less trials correctly than in the sTMS run. Sham-rTMS in the CG had no effects on prediction. The interference in PMd interacted with the type of manipulation applied to the action's time course occasionally during occlusion. The performance decrease of the EG was most pronounced in conditions in which the continuations after occlusions were too late in the action's course. The present results extend earlier findings suggesting that real-time action prediction requires the integrity of the PMd. Different functional roles of this area are discussed. Alternative interpretations consider either simulation of specific motor programming functions or the involvement of a feature-unspecific predictor. PMID- 29628879 TI - Dopamine, Effort-Based Choice, and Behavioral Economics: Basic and Translational Research. AB - Operant behavior is not only regulated by factors related to the quality or quantity of reinforcement, but also by the work requirements inherent in performing instrumental actions. Moreover, organisms often make effort-related decisions involving economic choices such as cost/benefit analyses. Effort-based decision making is studied using behavioral procedures that offer choices between high-effort options leading to relatively preferred reinforcers vs. low effort/low reward choices. Several neural systems, including the mesolimbic dopamine (DA) system and other brain circuits, are involved in regulating effort related aspects of motivation. Considerable evidence indicates that mesolimbic DA transmission exerts a bi-directional control over exertion of effort on instrumental behavior tasks. Interference with DA transmission produces a low effort bias in animals tested on effort-based choice tasks, while increasing DA transmission with drugs such as DA transport blockers tends to enhance selection of high-effort options. The results from these pharmacology studies are corroborated by the findings from recent articles using optogenetic, chemogenetic and physiological techniques. In addition to providing important information about the neural regulation of motivated behavior, effort-based choice tasks are useful for developing animal models of some of the motivational symptoms that are seen in people with various psychiatric and neurological disorders (e.g., depression, schizophrenia, Parkinson's disease). Studies of effort-based decision making may ultimately contribute to the development of novel drug treatments for motivational dysfunction. PMID- 29628882 TI - Parietotemporal Stimulation Affects Acquisition of Novel Grapheme-Phoneme Mappings in Adult Readers. AB - Neuroimaging work from developmental and reading intervention research has suggested a cause of reading failure may be lack of engagement of parietotemporal cortex during initial acquisition of grapheme-phoneme (letter-sound) mappings. Parietotemporal activation increases following grapheme-phoneme learning and successful reading intervention. Further, stimulation of parietotemporal cortex improves reading skill in lower ability adults. However, it is unclear whether these improvements following stimulation are due to enhanced grapheme-phoneme mapping abilities. To test this hypothesis, we used transcranial direct current stimulation (tDCS) to manipulate parietotemporal function in adult readers as they learned a novel artificial orthography with new grapheme-phoneme mappings. Participants received real or sham stimulation to the left inferior parietal lobe (L IPL) for 20 min before training. They received explicit training over the course of 3 days on 10 novel words each day. Learning of the artificial orthography was assessed at a pre-training baseline session, the end of each of the three training sessions, an immediate post-training session and a delayed post-training session about 4 weeks after training. Stimulation interacted with baseline reading skill to affect learning of trained words and transfer to untrained words. Lower skill readers showed better acquisition, whereas higher skill readers showed worse acquisition, when training was paired with real stimulation, as compared to readers who received sham stimulation. However, readers of all skill levels showed better maintenance of trained material following parietotemporal stimulation, indicating a differential effect of stimulation on initial learning and consolidation. Overall, these results indicate that parietotemporal stimulation can enhance learning of new grapheme phoneme relationships in readers with lower reading skill. Yet, while parietotemporal function is critical to new learning, its role in continued reading improvement likely changes as readers progress in skill. PMID- 29628883 TI - Achieving Accurate Automatic Sleep Staging on Manually Pre-processed EEG Data Through Synchronization Feature Extraction and Graph Metrics. AB - Sleep staging, the process of assigning labels to epochs of sleep, depending on the stage of sleep they belong, is an arduous, time consuming and error prone process as the initial recordings are quite often polluted by noise from different sources. To properly analyze such data and extract clinical knowledge, noise components must be removed or alleviated. In this paper a pre-processing and subsequent sleep staging pipeline for the sleep analysis of electroencephalographic signals is described. Two novel methods of functional connectivity estimation (Synchronization Likelihood/SL and Relative Wavelet Entropy/RWE) are comparatively investigated for automatic sleep staging through manually pre-processed electroencephalographic recordings. A multi-step process that renders signals suitable for further analysis is initially described. Then, two methods that rely on extracting synchronization features from electroencephalographic recordings to achieve computerized sleep staging are proposed, based on bivariate features which provide a functional overview of the brain network, contrary to most proposed methods that rely on extracting univariate time and frequency features. Annotation of sleep epochs is achieved through the presented feature extraction methods by training classifiers, which are in turn able to accurately classify new epochs. Analysis of data from sleep experiments on a randomized, controlled bed-rest study, which was organized by the European Space Agency and was conducted in the "ENVIHAB" facility of the Institute of Aerospace Medicine at the German Aerospace Center (DLR) in Cologne, Germany attains high accuracy rates, over 90% based on ground truth that resulted from manual sleep staging by two experienced sleep experts. Therefore, it can be concluded that the above feature extraction methods are suitable for semi automatic sleep staging. PMID- 29628884 TI - Subtle Distinctions: How Attentional Templates Influence EEG Parameters of Cognitive Control in a Spatial Cuing Paradigm. AB - Using event-related potentials (ERPs) of the electroencephalogram, we investigated how cognitive control is altered by the scope of an attentional template currently activated in visual working memory. Participants performed a spatial cuing task where an irrelevant color singleton cue was presented prior to a target array. Blockwise, the target was either a red circle or a gray square and had to be searched within homogenous (gray circles) or heterogeneous non targets (differently colored circles or various shapes). Thereby we aimed to trigger the adoption of different attentional templates: a broader singleton or a narrower, more specific feature template. ERP markers of attentional selection and inhibitory control showed that the amount of cognitive control was overall enhanced when participants searched on the basis of a feature-specific template: the analysis revealed reduced selection (N2pc, frontal P2) and pronounced inhibition (negative shift of frontal N2) of the irrelevant color cue when participants searched for a feature target. On behavioral level attentional capture was most pronounced in the color condition with no differentiation between the task-induced scopes of the attentional template. PMID- 29628885 TI - A Statistically Representative Atlas for Mapping Neuronal Circuits in the Drosophila Adult Brain. AB - Imaging the expression patterns of reporter constructs is a powerful tool to dissect the neuronal circuits of perception and behavior in the adult brain of Drosophila, one of the major models for studying brain functions. To date, several Drosophila brain templates and digital atlases have been built to automatically analyze and compare collections of expression pattern images. However, there has been no systematic comparison of performances between alternative atlasing strategies and registration algorithms. Here, we objectively evaluated the performance of different strategies for building adult Drosophila brain templates and atlases. In addition, we used state-of-the-art registration algorithms to generate a new group-wise inter-sex atlas. Our results highlight the benefit of statistical atlases over individual ones and show that the newly proposed inter-sex atlas outperformed existing solutions for automated registration and annotation of expression patterns. Over 3,000 images from the Janelia Farm FlyLight collection were registered using the proposed strategy. These registered expression patterns can be searched and compared with a new version of the BrainBaseWeb system and BrainGazer software. We illustrate the validity of our methodology and brain atlas with registration-based predictions of expression patterns in a subset of clock neurons. The described registration framework should benefit to brain studies in Drosophila and other insect species. PMID- 29628886 TI - U1 snRNP Alteration and Neuronal Cell Cycle Reentry in Alzheimer Disease. AB - The aberrancy of U1 small nuclear ribonucleoprotein (snRNP) complex and RNA splicing has been demonstrated in Alzheimer's disease (AD). Importantly, the U1 proteopathy is AD-specific, widespread and early-occurring, thus providing a very unique clue to the AD pathogenesis. The prominent feature of U1 histopathology is its nuclear depletion and redistribution in the neuronal cytoplasm. According to the preliminary data, the initial U1 cytoplasmic distribution pattern is similar to the subcellular translocation of the spliceosome in cells undergoing mitosis. This implies that the U1 mislocalization might reflect the neuronal cell cycle reentry (CCR) which has been extensively evidenced in AD brains. The CCR phenomenon explains the major molecular and cellular events in AD brains, such as Tau and amyloid precursor protein (APP) phosphorylation, and the possible neuronal death through mitotic catastrophe (MC). Furthermore, the CCR might be mechanistically linked to inflammation, a critical factor in the AD etiology according to the genetic evidence. Therefore, the discovery of U1 aberrancy might strengthen the involvement of CCR in the AD neuronal degeneration. PMID- 29628887 TI - Disease Specific Aspects of Malnutrition in Neurogeriatric Patients. AB - Malnutrition in elderly patients is a common condition. Nevertheless, there is evidence on specific risk factors and problems of malnutrition in geriatric patients with neurological diseases. In this review, we summarize recent knowledge on malnutrition in different neurological diseases with a focus on elderly patients. This overview also provides strategies for a more specific and profound assessment of neurogeriatric patients to improve identification and treatment of malnutrition. Early and consequent treatment of malnutrition can lead to a decreased progression of the neurological disease and to a better quality of life in geriatric patients. PMID- 29628888 TI - Licochalcone A Upregulates Nrf2 Antioxidant Pathway and Thereby Alleviates Acetaminophen-Induced Hepatotoxicity. AB - Acetaminophen (APAP) overdose-induced fatal hepatotoxicity is majorly characterized by overwhelmingly increased oxidative stress while enhanced nuclear factor-erythroid 2-related factor 2 (Nrf2) is involved in prevention of hepatotoxicity. Although Licochalcone A (Lico A) upregulates Nrf2 signaling pathway against oxidative stress-triggered cell injury, whether it could protect from APAP-induced hepatotoxicity by directly inducing Nrf2 activation is still poorly elucidated. This study aims to explore the protective effect of Lico A against APAP-induced hepatotoxicity and its underlying molecular mechanisms. Our findings indicated that Lico A effectively decreased tert-butyl hydroperoxide (t BHP)- and APAP-stimulated cell apoptosis, mitochondrial dysfunction and reactive oxygen species generation and increased various anti-oxidative enzymes expression, which is largely dependent on upregulating Nrf2 nuclear translocation, reducing the Keap1 protein expression, and strengthening the antioxidant response element promoter activity. Meanwhile, Lico A dramatically protected against APAP-induced acute liver failure by lessening the lethality; alleviating histopathological liver changes; decreasing the alanine transaminase and aspartate aminotransferase levels, malondialdehyde formation, myeloperoxidase level and superoxide dismutase depletion, and increasing the GSH-to-GSSG ratio. Furthermore, Lico A not only significantly modulated apoptosis-related protein by increasing Bcl-2 expression, and decreasing Bax and caspase-3 cleavage expression, but also efficiently alleviated mitochondrial dysfunction by reducing c-jun N-terminal kinase phosphorylation and translocation, inhibiting Bax mitochondrial translocation, apoptosis-inducing factor and cytochrome c release. However, Lico A-inhibited APAP-induced the lethality, histopathological changes, hepatic apoptosis, and mitochondrial dysfunction in WT mice were evidently abrogated in Nrf2-/- mice. These investigations firstly implicated that Lico A has protective potential against APAP-induced hepatotoxicity which may be strongly associated with the Nrf2-mediated defense mechanisms. PMID- 29628889 TI - Inhibitory Effect of Kurarinone on Growth of Human Non-small Cell Lung Cancer: An Experimental Study Both in Vitro and in Vivo Studies. AB - Kurarinone, a flavonoid isolated from Sophora flavescens Aiton, has been reported to have significant antitumor activity. However, the cytotoxic activity of kurarinone against non-small cell lung cancer (NSCLC) cells is still under explored. In our study, we have evaluated the inhibitory effects of kurarinone on the growth of NSCLC both in vivo and in vitro as well as the molecular mechanisms underlying kurarinone-induced A549 cell apoptosis. The results showed that kurarinone effectively inhibited the proliferation of A549 cells with little toxic effects on human bronchial epithelial cell line BEAS-2B. FASC examination and Hoechst 33258 staining assay showed that kurarinone dose-dependently provoked A549 cells apoptosis. Mechanistically, kurarinone significantly decreased the ratio of Bcl-2/Bax, thereby causing the activation of caspase 9 and caspase 3, and reduced the expression of Grp78, which led to relieve the inhibition of caspase-12 and caspase-7, as well as suppressing the activity of AKT. Meanwhile, modeling results from the Surflex-Dock program suggested that residue Ser473 of Akt is a potential binding site for kurarinone. In vivo, kurarinone inhibited the growth of A549 xenograft mouse models without apparent signs of toxicity. Our study indicated that kurarinone has the potential effects of anti-NSCLC, implemented through activating mitochondria apoptosis signaling pathway, as well as repressing the activity of endoplasmic reticulum pathway and AKT in A549 cells. PMID- 29628890 TI - Anti-gout Potential of Malaysian Medicinal Plants. AB - Gout is a type of arthritis that causes painful inflammation in one or more joints. In gout, elevation of uric acid in the blood triggers the formation of crystals, causing joint pain. Malaysia is a mega-biodiversity country that is rich in medicinal plants species. Therefore, its flora might offer promising therapies for gout. This article aims to systematically review the anti-gout potential of Malaysian medicinal plants. Articles on gout published from 2000 to 2017 were identified using PubMed, Scopus, ScienceDirect, and Google Scholar with the following keyword search terms: "gout," "medicinal plants," "Malaysia," "epidemiology," "in vitro," and "in vivo." In this study, 85 plants were identified as possessing anti-gout activity. These plants had higher percentages of xanthine oxidase inhibitory activity (>85%); specifically, the Momordica charantia, Chrysanthemum indicum, Cinnamomum cassia, Kaempferia galanga, Artemisia vulgaris, and Morinda elliptica had the highest values, due to their diverse natural bioactive compounds, which include flavonoids, phenolics, tannin, coumarins, luteolin, and apigenin. This review summarizes the anti-gout potential of Malaysian medicinal plants but the mechanisms, active compounds, pharmacokinetics, bioavailability, and safety of the plants still remain to be elucidated. PMID- 29628891 TI - Training Load, Immune Status, and Clinical Outcomes in Young Athletes: A Controlled, Prospective, Longitudinal Study. AB - Introduction: Beside positive effects on athlete's health, competitive sport can be linked with an increased risk of illness and injury. Because of high relative increases in training, additional physical and psychological strains, and an earlier specialization and professionalization, adolescent athletes needs an increased attention. Training can alter the immune system by inducing a temporary immunosuppression, finally developing infection symptoms. Previous studies identified Epstein Barr Virus (EBV) as potential indicator for the immune status. In addition to the identification of triggering risk factors for recurrent infections, the aim was to determine the interaction between training load, stress sense, immunological parameters, and clinical symptoms. Methods: A controlled, prospective, longitudinal study on young athletes (n = 274, mean age: 13.8 +/- 1.5 yrs) was conducted between 2010 and 2014. Also 285 controls (students, who did not perform competitive sports, mean age: 14.5 +/- 1.9 yrs) were recruited. Athletes were examined 3 times each year to determine the effects of stress factors (training load: training hours per week [Th/w]) on selected outcome parameters (clinical [susceptibility to infection, WURSS-21: 21-item Wisconsin Upper Respiratory Symptom Survey], immunological, psychological end points). As part of each visit, EBV serostatus and EBV-specific IgG tiers were studied longitudinally as potential immune markers. Results: Athletes (A) trained 14.9 +/- 5.6 h weekly. Controls (C) showed no lower stress levels compared to athletes (p = 0.387). Twelve percent of athletes reported recurrent infections (C: 8.5%, p = 0.153), the presence of an upper respiratory tract infection (URTI) was achieved in 30.7%. EBV seroprevalence of athletes was 60.3% (C: 56.6%, p = 0.339). Mean EBV-specific IgG titer of athletes was 166 +/- 115 U/ml (C: 137 +/- 112 U/ml, p = 0.030). With increasing Th/w, higher stress levels were observed (p < 0.001). Analyzes of WURSS-21 data revealed no relationship to training load (p = 0.323). Also, training load had no relation to EBV serostatus (p = 0.057) or the level of EBV-specific IgG titers (p = 0.364). Discussion: Young elite athletes showed no increased sense of stress, no higher prevalence of recurrent infections, and no different EBV-specific serological parameters compared to controls. Also, no direct relationship between training loads, clinical complaints, and EBV-specific immune responses was found. With increasing training loads athletes felt more stressed, but significant associations to EBV-specific serological parameters were absent. In summary, EBV serostatus and EBV-specific IgG titers do not allow risk stratification for impaired health. Further investigations are needed to identify additional risk factors and immune markers, with the aim to avoid inappropriate strains by early detection and following intervention. PMID- 29628892 TI - The Effect of Oxygen Enrichment on Cardiorespiratory and Neuropsychological Responses in Workers With Chronic Intermittent Exposure to High Altitude (ALMA, 5,050 m). AB - It is estimated that labor activity at high altitudes in Chile will increase from 60,000 to 120,000 workers by the year 2020. Oxygenation of spaces improves the quality of life for workers at high geographic altitudes (<5,000 m). The aim of this study was to determine the effect of a mobile oxygen module system on cardiorespiratory and neuropsychological performance in a population of workers from Atacama Large Millimeter/submillimeter Array (ALMA, 5,050 m) radiotelescope in the Chajnantor Valley, Chile. We evaluated pulse oximetry, systolic and diastolic arterial pressure (SAP/DAP), and performed neuropsychological tests (Mini-Mental State examination, Rey-Osterrieth Complex Figure test) at environmental oxygen conditions (5,050 m), and subsequently in a mobile oxygenation module that increases the fraction of oxygen in order to mimic the higher oxygen partial pressure of lower altitudes (2,900 m). The use of module oxygenation at an altitude of 5,050 m, simulating an altitude of 2,900 m, increased oxygen saturation from 84 +/- 0.8 to 91 +/- 0.8% (p < 0.00001), decreased heart rate from 90 +/- 8 to 77 +/- 12 bpm (p < 0.01) and DAP from 96 +/ 3 to 87 +/- 5 mmHg (p < 0.01). In addition, mental cognitive state of workers (Mini-Mental State Examination) shown an increased from 19 to 31 points (p < 0.02). Furthermore, the Rey-Osterrieth Complex Figure test (memory) shown a significant increase from 35 to 70 (p < 0.0001). The results demonstrate that the use of an oxygen module system at 5,050 m, simulating an altitude equivalent to 2,900 m, by increasing FiO2 at 28%, significantly improves cardiorespiratory response and enhances neuropsychological performance in workers exposed to an altitude of 5,050 m. PMID- 29628893 TI - Changes of Ammonia-Metabolizing Enzyme Activity and Gene Expression of Two Strains in Shrimp Litopenaeus vannamei Under Ammonia Stress. AB - Ammonia stress can inhibit the survival and growth, and even cause mortality of shrimp. In this study, ammonia-metabolizing enzyme activities and gene expression were compared between two strains of L. vannamei under different ammonia-N ([Formula: see text]) concentrations (3.4, 13.8, and 24.6 mg/L). The results showed that elevated ammonia concentrations mainly increased glutamine synthetase (GSase) activities while inhibiting transglutaminase (TGase) activities in the muscle of both strains. Thus, we concluded that L. vannamei could accelerate the synthesis of glutamine from glutamate and [Formula: see text] to alleviate ammonia stress. Compared with the muscle, the hepatopancreas plays a major role in ammonia stress and might be a target tissue to respond to the ammonia stress. Compared to the control group, the treatment of high ammonia concentrations reduced the hepatopancreas TGase (TG) gene expression and increased the gene expression rates of glutamate dehydrogenase-beta (GDH-beta) and GSase (GS) in both the muscle and the hepatopancreas of the two strains (p < 0.05). These genes (GDH-beta and GS) in strain B were not only expressed earlier but also at levels higher than the expression range of strain A. At the gene level, strain B showed a more rapid and positive response than strain A. These data might help reveal the physiological responses mechanisms of shrimp adapt to ammonia stress and speed up the selective breeding process in L. vannamei. PMID- 29628894 TI - Insulin Receptor Substrate 2 Controls Insulin-Mediated Vasoreactivity and Perivascular Adipose Tissue Function in Muscle. AB - Introduction: Insulin signaling in adipose tissue has been shown to regulate insulin's effects in muscle. In muscle, perivascular adipose tissue (PVAT) and vascular insulin signaling regulate muscle perfusion. Insulin receptor substrate (IRS) 2 has been shown to control adipose tissue function and glucose metabolism, and here we tested the hypothesis that IRS2 mediates insulin's actions on the vessel wall as well as the vasoactive properties of PVAT. Methods: We studied PVAT and muscle resistance arteries (RA) from littermate IRS2+/+ and IRS2-/- mice and vasoreactivity by pressure myography, vascular insulin signaling, adipokine expression, and release and PVAT morphology. As insulin induced constriction of IRS2+/+ RA in our mouse model, we also exposed RA's of C57/Bl6 mice to PVAT from IRS2+/+ and IRS2-/- littermates to evaluate vasodilator properties of PVAT. Results: IRS2-/- RA exhibited normal vasomotor function, yet a decreased maximal diameter compared to IRS2+/+ RA. IRS2+/+ vessels unexpectedly constricted endothelin-dependently in response to insulin, and this effect was absent in IRS2 /- RA due to reduced ERK1/2activation. For evaluation of PVAT function, we also used C57/Bl6 vessels with a neutral basal effect of insulin. In these experiments insulin (10.0 nM) increased diameter in the presence of IRS2+/+ PVAT (17 +/- 4.8, p = 0.014), yet induced a 10 +/- 7.6% decrease in diameter in the presence of IRS2-/- PVAT. Adipocytes in IRS2-/- PVAT (1314 +/- 161 MUm2) were larger (p = 0.0013) than of IRS2+/+ PVAT (915 +/- 63 MUm2). Adiponectin, IL-6, PAI-1 secretion were similar between IRS2+/+ and IRS2-/- PVAT, as were expression of pro-inflammatory genes (TNF-alpha, CCL2) and adipokines (adiponectin, leptin, endothelin-1). Insulin-induced AKT phosphorylation in RA was similar in the presence of IRS2-/- and IRS2+/+ PVAT. Conclusion: In muscle, IRS2 regulates both insulin's vasoconstrictor effects, mediating ERK1/2-ET-1 activation, and its vasodilator effects, by mediating the vasodilator effect of PVAT. The regulatory role of IRS2 in PVAT is independent from adiponectin secretion. PMID- 29628895 TI - RPE vs. Percentage 1RM Loading in Periodized Programs Matched for Sets and Repetitions. AB - Purpose: To investigate differences between rating of perceived exertion (RPE) and percentage one-repetition maximum (1RM) load assignment in resistance-trained males (19-35 years) performing protocols with matched sets and repetitions differentiated by load-assignment. Methods: Participants performed squats then bench press 3x/weeks in a daily undulating format over 8-weeks. Participants were counterbalanced by pre-test 1RM then assigned to percentage 1RM (1RMG, n = 11); load-assignment via percentage 1RMs, or RPE groups (RPEG, n = 10); participant selected loads to reach target RPE ranges. Ultrasonography determined pre and post-test pectoralis (PMT), and vastus lateralis muscle thickness at 50 (VLMT50) and 70% (VLMT70) femur-length. Results: Bench press (1RMG +9.64 +/- 5.36; RPEG + 10.70 +/- 3.30 kg), squat (1RMG + 13.91 +/- 5.89; RPEG + 17.05 +/- 5.44 kg) and their combined-total 1RMs (1RMG + 23.55 +/- 10.38; RPEG + 27.75 +/- 7.94 kg) increased (p < 0.05) in both groups as did PMT (1RMG + 1.59 +/- 1.33; RPEG +1.90 +/- 1.91 mm), VLMT50 (1RMG +2.13 +/- 1.95; RPEG + 1.85 +/- 1.97 mm) and VLMT70 (1RMG + 2.40 +/- 2.22; RPEG + 2.31 +/- 2.27 mm). Between-group differences were non-significant (p > 0.05). Magnitude-based inferences revealed 79, 57, and 72% chances of mean small effect size (ES) advantages for squat; ES 90% confidence limits (CL) = 0.50 +/- 0.63, bench press; ES 90% CL = 0.28 +/- 0.73, and combined total; ES 90% CL = 0.48 +/- 0.68 respectively, in RPEG. There were 4, 14, and 6% chances 1RMG had a strength advantage of the same magnitude, and 18, 29, and 22% chances, respectively of trivial differences between groups. Conclusions: Both loading-types are effective. However, RPE-based loading may provide a small 1RM strength advantage in a majority of individuals. PMID- 29628896 TI - Inflammatory and Metabolic Responses to Different Resistance Training on Chronic Obstructive Pulmonary Disease: A Randomized Control Trial. AB - : Background: Low-grade inflammation can be present in chronic obstructive pulmonary disease (COPD), which may affect the regulation of muscle protein and body metabolism. Regular exercise show improvement in muscle strength and dyspnea in patients with COPD, however, the response to training on inflammatory and metabolic disorders is unclear. In this study, we compared the effects of resistance training using weight machines and elastic resistance (bands and tubes) on the inflammatory and metabolic responses in patients with COPD. Methods: Patients with COPD were randomized into three groups: elastic band group (EBG), elastic tube group (ETG), and weight machines equipment group (MG). EBG and ETG were analyzed together [elastic group (EG)]. The participants were evaluated for pulmonary function (spirometry), peripheral muscle strength (digital dynamometry), IL-6, TNF-alpha, IL-10, IL-15 (Immunoassay), glucose, triacylglycerol, total cholesterol, HDL-c, and albumin levels (Enzymatic colorimetric). Blood samples were collected to assess the acute and chronic exercise responses after 12 weeks of training protocol. Results: The patient's mean age was 71.53 +/- 6.97 years old. FEV1 (percent predicted) was 50.69 +/- 16.67 and 45.40 +/- 15.15% for EG and MG, respectively (p = 0.28). All groups increased muscle strength (p < 0.05) with no differences between groups. The acute response to exercise after 12 weeks of training showed improvement of inflammation when compared to baseline. Regarding the chronic effects, it was observed a decrease of all cytokines, except IL-10 (p < 0.05). After 12 weeks of training, the analysis of the metabolic profile presented a reduction in glucose concentration (p < 0.01), with no differences between groups (p = 0.30) and a decrease in triacylglycerol for the EG (p > 0.01). Conclusions: Training with elastic resistances or conventional weight machines showed improvement of inflammation response after 12 weeks of training. Chronically, both training groups showed anti-inflammatory effects, with the EG showing a strong tendency to improve IL-10/TNF-alpha ratio and IL-10 levels. TRIAL REGISTRATION: RBR-6V9SJJ. PMID- 29628897 TI - Stanniocalcin 2 Regulates Non-capacitative Ca2+ Entry and Aggregation in Mouse Platelets. AB - Stanniocalcin 2 (STC2) is a fish protein that controls body Ca2+ and phosphate metabolism. STC2 has also been described in mammals, and as platelet function highly depends on both extracellular and intracellular Ca2+, we have explored its expression and function in these cells. STC2-/- mice exhibit shorter tail bleeding time than WT mice. Platelets from STC2-deficient mice showed enhanced aggregation, as well as enhanced Ca2+ mobilization in response to the physiological agonist thrombin (Thr) and the diacylglycerol analog, OAG, a selective activator of the non-capacitative Ca2+ entry channels. Interestingly, platelets from STC2-/- mice exhibit attenuated interaction between STIM1 and Orai1 in response to Thr, thus suggesting that STC2 is required for Thr-evoked STIM1-Orai1 interaction and the subsequent store-operated Ca2+ entry (SOCE). We have further assessed possible changes in the expression of the most relevant channels involved in non-capacitative Ca2+ entry in platelets. Then, protein expression of Orai3, TRPC3 and TRPC6 were evaluated by Western blotting, and the results revealed that while the expression of Orai3 was enhanced in the STC2 deficient mice, others like TRPC3 and TRPC6 remains almost unaltered. Summarizing, our results provide for the first time evidence for a role of STC2 in platelet physiology through the regulation of agonist-induced Ca2+ entry, which might be mediated by the regulation of Orai3 channel expression. PMID- 29628899 TI - Editorial: Advances in Mechanisms of Renal Fibrosis. PMID- 29628898 TI - Postactivation Potentiation of the Plantar Flexors Does Not Directly Translate to Jump Performance in Female Elite Young Soccer Players. AB - High-intensity muscle actions have the potential to temporarily improve muscle contractile properties (i.e., postactivation potentiation, PAP) thereby inducing acute performance enhancements. There is evidence that balance training can improve performance during strength exercises. Taking these findings together, the purpose of this study was to examine the acute effects of a combined balance and strength (B+S) exercise vs. a strength only (S) exercise on twitch contractile properties, maximum voluntary strength, and jump performance in young athletes. Female elite young soccer players (N = 12) aged 14-15 years conducted three experimental conditions in randomized order: S included 3 sets of 8-10 dynamic leg extensions at 80% of the 1-repetition maximum, B+S consisted of 3 sets of 40 s double-leg stances on a balance board prior to leg extensions (same as S), and a resting control period. Before and 7 min after exercise, participants were tested for their electrically-evoked isometric twitches (i.e., twitch peak torque, twitch rate of torque development) and maximal voluntary contraction (MVC) torque of the plantar flexor muscles. Additionally, countermovement (CMJ) and drop jump (DJ) performances (i.e., CMJ/DJ height, DJ ground contact time) were assessed. Significant effects of condition on twitch contractile properties (p < 0.05, d = 1.1) and jump performance outputs (p < 0.05, 1.1 <= d <= 1.2) were found. Post-hoc tests revealed that S compared to control produced larger PAP for twitch peak torques by trend (p = 0.07, d = 1.8, 33 vs. 21%) and significantly larger PAP for twitch rate of torque development (p < 0.05, d = 2.4, 55 vs. 43%). Following B+S compared to control, significant improvements in CMJ height (p < 0.01, d = 1.9, 3%) and DJ contact time were found (p < 0.01, d = 2.0, 10%). This study revealed protocol-specific acute performance improvements. While S resulted in significant increases in twitch contractile properties, B+S produced significant enhancements in jump performance. It is concluded that PAP effects in the plantar flexors may not directly translate to improved jump performance in female elite young soccer players. Therefore, the observed gains in jump performance following B+S are most likely related to neuromuscular changes (e.g., intramuscular coordination) rather than improved contractile properties. PMID- 29628900 TI - Perception of Lexical Neutral Tone Among Adults and Infants. AB - Neutral tone (T0) is a special tone form in Mandarin that contains tonal and stress information. Compared with canonical tones, T0 has a much shorter duration and reduced pitch contour. Its tonal contour is determined by the preceding canonical tone. However, not much is known about the perception of tonal and stress information in T0. In the current study, we investigate (1) whether T0 can be perceived as lexically unstressed by stress-language listeners; and (2) how Mandarin (tone language)- and Dutch (stress language)-learning infants perceive T0. Three experiments were conducted. In Experiment 1, Dutch adults identified T0 as unstressed when presented with disyllabic sequences ending in T0. In Experiment 2, we used the visual fixation paradigm to test 4- to 6-month-old and 10- to 12-month-old Dutch and Mandarin infants on pseudoword discrimination (/pan1san4/ [high-level + high-falling] and /pan1san0/ [high-level + mid falling]). T4 and T0 each exhibit a similar falling contour. The results show that (1) after being habituated to neutral tone sequences (/pan1san0/), Dutch infants discriminated the T1T0-T1T4 contrast; and (2) neither age groups of Mandarin infants discriminated the tone contrast. Assuming Mandarin infants' lack of discrimination might be due to the similar F0 contours, we tested Mandarin infants in Experiment 3 using a more salient contrast, /pan1san2/ (high-level + mid-rising) and /pan1san0/. While no overall discrimination was observed, those who were habituated to /pan1san0/ demonstrated discrimination. The continuous discrimination of Dutch infants suggests that they might process neutral canonical tone contrast as lexical stress rather than as tonal information. Overall, Mandarin infants' failure implies that the representation of T0 is not complete during their 1st year of life; the acquisition of tonal categories may therefore take longer than we expected. PMID- 29628901 TI - Defending Oneself From Tourists: The Counter-Environmental Bubble. AB - According to the Environmental Bubble Theory, tourists perform a series of strategies in order to remain anchored to their residential spots. The environmental bubble is constituted by a sort of social pellicule able to immunize tourists from the identity/cultural attacks which the visit to a foreign country implies. Such a pellicule is activated by the tourists themselves as they decide to travel in group or, for example, to eat only at the restaurants proposing their own national cuisine, and so on. Generally the potential cultural shock of residents is not taken into consideration in literature, even if it is plausibile to make the hypothesis of a counter-environmental bubble performed by the residents in order to defend their own culture and their identity from the attacks of mass tourism, especially for cities that live on tourism, as, for example, Florence or Siena do. Our study aims at testing the access to local tradition made available in promotional material. The hypothesis we propose is that there should exist a difference in promoting cultural heritage and intimate culture. The intimate culture refers to the living culture, the way of living, comprehending cuisine, education, religion, the way by which the role of females and males are performed, and so on. On the other hand, the cultural heritage, or historical culture, makes reference to a culture meant as belonging to the whole mankind, as it happens, for example, for archeological sites or museums. In more detail, we propose the hypothesis that the intimate culture is maintained unaccessible for tourists' gaze, or at least accessible only in the shape of a spectacularized event, the so called pseudo-event of Boorstin. Using the software NUD*IST we analyzed the promotional material of the city of Siena. Our results confirm Boorstin's theory about pseudo-events realized for tourists. The difference between cultural heritage and intimate culture promotion we have revealed shows an additional lecture of the Boorstinian framework, which makes an echo to the environmental bubble theory (Cohen, 1972), stressing the risk in terms of social and cultural identity tourism implies for both residents and tourists. PMID- 29628902 TI - The Positive Effect of Authoritarian Leadership on Employee Performance: The Moderating Role of Power Distance. AB - Based on goal setting theory, this study explores the positive effect and influencing process of authoritarian leadership on employee performance, as well as the moderating role of individual power distance in this process. Data from 211 supervisor-subordinate dyads in Chinese organizations indicates that authoritarian leadership is positively associated with employee performance, and learning goal orientation mediates this relationship. Furthermore, power distance moderates the effect of authoritarian leadership on learning goal orientation, such that the effect was stronger when individual power distance was higher. The indirect effect of authoritarian leadership on employee performance via learning goal orientation is also moderated by power distance. Theoretical and managerial implications and future directions are also discussed. PMID- 29628903 TI - Hypoxia Worsens Affective Responses and Feeling of Fatigue During Prolonged Bed Rest. AB - Previous research, although limited, suggests that both hypoxia and bed rest influence psychological responses by exaggerating negative psychological responses and attenuating positive emotions. The present study investigated the effect of a 21-day prolonged exposure to normobaric hypoxia and bed rest on affective responses and fatigue. Eleven healthy participants underwent three 21 day interventions using a cross-over design: (1) normobaric hypoxic ambulatory confinement (HAMB), (2) normobaric hypoxic bed rest (HBR) and (3) normoxic bed rest (NBR). Affective and fatigue responses were investigated using the Activation Deactivation Adjective Check List, and the Multidimensional Fatigue Inventory, which were completed before (Pre), during (Day 7, Day 14, and Day 21) and after (Post) the interventions. The most negative psychological profile appeared during the HBR intervention. Specifically, tiredness, tension, general and physical fatigue significantly increased on days 7, 14, and 21, as well as at Post. After the HBR intervention, general and physical fatigue remained higher compared to Pre values. Additionally, a deterioration of psychological responses was also noted following HAMB and NBR. In particular, both hypoxia and BR per se induced subjective fatigue and negative affective responses. BR seems to exert a moderate negative effect on the sensation of fatigue, whereas exercise attenuates the negative effects of hypoxia as noted during the HAMB condition. In conclusion, our data suggest that the addition of hypoxia to bed rest-induced inactivity significantly worsens affective responses and feeling of fatigue. PMID- 29628904 TI - Safety Priorities and Underestimations in Recreational Scuba Diving Operations: A European Study Supporting the Implementation of New Risk Management Programmes. AB - Introduction: Scuba diving is an important marine tourism sector, but requires proper safety standards to reduce the risks and increase accessibility to its market. To achieve safety goals, safety awareness and positive safety attitudes in recreational scuba diving operations are essential. However, there is no published research exclusively focusing on scuba divers' and dive centres' perceptions toward safety. This study assessed safety perceptions in recreational scuba diving operations, with the aim to inform and enhance safety and risk management programmes within the scuba diving tourism industry. Materials and Methods: Two structured questionnaire surveys were prepared by the organisation Divers Alert Network and administered online to scuba diving operators in Italy and scuba divers in Europe, using a mixture of convenience and snowball sampling. Questions in the survey included experience and safety offered at the dive centre; the buddy system; equipment and accessories for safe diving activities; safety issues in the certification of new scuba divers; incidents/accidents; and attitudes toward safety. Results: 91 scuba diving centres and 3,766 scuba divers participated in the study. Scuba divers gave importance to safety and the responsiveness of service providers, here represented by the dive centres. However, they underestimated the importance of a personal emergency action/assistance plan and, partly, of the buddy system alongside other safety procedures. Scuba divers agreed that some risks, such as those associated with running out of gas, deserve attention. Dive centres gave importance to aspects such as training and emergency action/assistance plans. However, they were limitedly involved in safety campaigning. Dive centres' perceptions of safety in part aligned with those of scuba divers, with some exceptions. Conclusion: Greater responsibility is required in raising awareness and educating scuba divers, through participation in prevention campaigns and training. The study supports the introduction of programmes aiming to create a culture of safety among dive centres and scuba divers. Two examples, which are described in this paper, include the Hazard Identification and Risk Assessment protocol for dive centres and scuba divers, and the Diving Safety Officer programme to create awareness, improve risk management, and mitigate health and safety risks. PMID- 29628905 TI - Polar Coordinate Analysis of Relationships With Teammates, Areas of the Pitch, and Dynamic Play in Soccer: A Study of Xabi Alonso. AB - Research in soccer has traditionally focused on very specific aspects of the game, such as technical and physiological aspects, and has largely ignored important issues such as tactical performance and the role of individual players within the team. The aim of this study was to study the different relationships that Xabi Alonso, one of the world's best midfielders, establishes with his teammates during offensive play, and to investigate his connections with the pitch in terms of where his direct interventions started and finished, his use of technical actions, his involvement in set plays and interceptions, and his relationship with shots at goal. To do this, we analyzed all the matches played by the winner of the 2012 UEFA European Championship: Spain. We employed an observational methodology design (Anguera, 1979) using a modified version of the ad hoc soccer observation instrument designed by Amatria et al. (2016). The resulting data were analyzed by polar coordinate analysis (Gorospe and Anguera, 2000), which is a powerful data reduction technique with high predictive power. The results showed significant associations (Z > 1.96; p < 0.05) between Alonso and players in different positions, a wide sphere of influence on the pitch, both for the start and end of interventions, and a strong link with game interruptions and interceptions and with the use of different technical actions. No significant associations were detected for type of shot. Studies on tactical performance that take account of the multiple factors involved in soccer will lead to better decision-making by coaches and facilitate analysis of a player's true performance. PMID- 29628906 TI - Positive and Negative Affect Schedule-Short Form: Factorial Invariance and Optimistic and Pessimistic Affective Profiles in Spanish Children. AB - The distinction in recent years between positive affect (PA) and negative affect (NA) is becoming increasingly important due to their relationship with depression and anxiety. This work is composed of two studies. The first study aimed to validate the brief version of the Positive and Negative Affect Schedule for Children-Short Form (PANAS-C-SF) in a Spanish child sample. The second study sought to check the existence of four affective profiles: self-fulfilling (high PA and low NA), low affective (low PA and NA), high affective (high PA and NA), and self-destructive (low PA and high NA) and to relate them to optimism and pessimism. Samples for both studies were composed of 647 and 1,296 Spanish students (between 8 and 11 years), respectively. Through various multigroup confirmatory factor analyses (MCA), the invariance of the PANAS-SF and the lack of significant gender differences in the latent means were verified. In addition, cluster analysis confirmed the existence of the appropriate profiles. In this case, the self-fulfilling profile correlated with high scores in optimism and low scores pessimism, whereas the self-destructive profile correlated in the opposite direction. These contributions represent an advance in the study of child affect. PMID- 29628907 TI - Diagnostic Criteria for Parkinson's Disease: From James Parkinson to the Concept of Prodromal Disease. AB - The diagnosis of Parkinson's disease (PD) is based on clinical features and differently to the common opinion that detecting this condition is easy, seminal clinicopathological studies have shown that up one-fourth of patients diagnosed as PD during life has an alternative diagnosis at postmortem. The misdiagnosis is even higher when only the initial diagnosis is considered, since the diagnostic accuracy improves by time, during follow-up visits. Given that the confirmation of the diagnosis of PD can be only obtained through neuropathology, to improve and facilitate the diagnostic-therapeutic workup in PD, a number of criteria and guidelines have been introduced in the last three decades. In the present paper, we will critically re-appraise the main diagnostic criteria proposed for PD, with particular attention to the recently published criteria by the International Parkinson and Movement Disorder Society (MDS) task force, underlying their novelty and focusing on the diagnostic issues still open. We also emphasize that the MDS-PD criteria encompass the two main previous sets of diagnostic criteria (United Kingdom PD Society Brain Bank and Gelb's criteria), introducing at the same time new aspects as the use of non-motor symptoms as additional diagnostic features, and the adoption of the concept of prodromal PD, crucial to enroll in clinical trials PD patients in the very early phase of the disease. To better understand the real diffusion of the new MDS-PD diagnostic criteria among neurologists, we have also collected selective opinions of sixteen movement disorder experts from various world regions on their practical approach for the clinical diagnosis of PD. Results from this brief survey showed that, although innovative and complete, the revised diagnostic criteria produced by MDS task force are still scarcely employed among clinicians. We believe that both national and international scientific societies should operate in the future for a broader diffusion of these criteria with specific initiatives, including dedicated events and teaching courses. PMID- 29628908 TI - Editorial: Zika Virus Research. PMID- 29628910 TI - The Sub-Regional Functional Organization of Neocortical Irritative Epileptic Networks in Pediatric Epilepsy. AB - Between seizures, irritative network generates frequent brief synchronous activity, which manifests on the EEG as interictal epileptiform discharges (IEDs). Recent insights into the mechanism of IEDs at the microscopic level have demonstrated a high variance in the recruitment of neuronal populations generating IEDs and a high variability in the trajectories through which IEDs propagate across the brain. These phenomena represent one of the major constraints for precise characterization of network organization and for the utilization of IEDs during presurgical evaluations. We have developed a new approach to dissect human neocortical irritative networks and quantify their properties. We have demonstrated that irritative network has modular nature and it is composed of multiple independent sub-regions, each with specific IED propagation trajectories and differing in the extent of IED activity generated. The global activity of the irritative network is determined by long-term and circadian fluctuations in sub-region spatiotemporal properties. Also, the most active sub-region co-localizes with the seizure onset zone in 12/14 cases. This study demonstrates that principles of recruitment variability and propagation are conserved at the macroscopic level and that they determine irritative network properties in humans. Functional stratification of the irritative network increases the diagnostic yield of intracranial investigations with the potential to improve the outcomes of surgical treatment of neocortical epilepsy. PMID- 29628909 TI - Interhemispheric Cortical Inhibition Is Reduced in Young Adults With Developmental Coordination Disorder. AB - Introduction: While the etiology of developmental coordination disorder (DCD) is yet to be established, brain-behavior modeling provides a cogent argument that neuropathology may subserve the motor difficulties typical of DCD. We argue that a number of the core behavioral features of the DCD profile (such as poor surround inhibition, compromised motor inhibition, and the presence of mirror movements) are consistent with difficulties regulating inhibition within the primary motor cortex (M1). This study aimed to be the first account of the integrity of cortical inhibition in motor cortices in DCD. Method: The sample consisted of eight adults with DCD aged (18-30 years) and 10 aged matched neurotypical controls. Participants received a common battery of single and paired-pulse transcranial magnetic stimulation from which a series of neurophysiological measures classically used to measure intra- [e.g., short interval cortical inhibition (SICI), long-interval cortical inhibition (LICI), and cortical silent period] and inter hemispheric [e.g., ipsilateral silent period (ISP)] cortical inhibition of the M1 at rest were recorded. Results: While no group differences were observed for any measure of intrahemispheric cortical inhibition, individuals with DCD demonstrated significantly reduced interhemispheric cortical inhibition relative to controls, shown by consistently lower ISPratios. Conclusion: Our findings are consistent with the view that regulation of cortical inhibition of M1 activity may be atypical in individuals with DCD, indicating differential GABAergic operation. This effect, however, appears to be select to cortical inhibition. Importantly, our data support the notion that reduced interhemispheric M1 cortical inhibition may at least partly explain commonly reported difficulties with bimanual motor control in DCD. The neurochemical implications and limitations of this evidence will be discussed. PMID- 29628911 TI - Estimation of Muscle Force Based on Neural Drive in a Hemispheric Stroke Survivor. AB - Robotic assistant-based therapy holds great promise to improve the functional recovery of stroke survivors. Numerous neural-machine interface techniques have been used to decode the intended movement to control robotic systems for rehabilitation therapies. In this case report, we tested the feasibility of estimating finger extensor muscle forces of a stroke survivor, based on the decoded descending neural drive through population motoneuron discharge timings. Motoneuron discharge events were obtained by decomposing high-density surface electromyogram (sEMG) signals of the finger extensor muscle. The neural drive was extracted from the normalized frequency of the composite discharge of the motoneuron pool. The neural-drive-based estimation was also compared with the classic myoelectric-based estimation. Our results showed that the neural-drive based approach can better predict the force output, quantified by lower estimation errors and higher correlations with the muscle force, compared with the myoelectric-based estimation. Our findings suggest that the neural-drive based approach can potentially be used as a more robust interface signal for robotic therapies during the stroke rehabilitation. PMID- 29628912 TI - Response: Commentary: Efficacy of Follicle-Stimulating Hormone (FSH) Alone, FSH + Luteinizing Hormone, Human Menopausal Gonadotropin or FSH + Human Chorionic Gonadotropin on Assisted Reproductive Technology Outcomes in the "Personalized" Medicine Era: A Meta-analysis. PMID- 29628913 TI - A Retrospective Review of Microbiological Methods Applied in Studies Following the Deepwater Horizon Oil Spill. AB - The Deepwater Horizon (DWH) oil spill in the Gulf of Mexico in 2010 resulted in serious damage to local marine and coastal environments. In addition to the physical removal and chemical dispersion of spilled oil, biodegradation by indigenous microorganisms was regarded as the most effective way for cleaning up residual oil. Different microbiological methods were applied to investigate the changes and responses of bacterial communities after the DWH oil spills. By summarizing and analyzing these microbiological methods, giving recommendations and proposing some methods that have not been used, this review aims to provide constructive guidelines for microbiological studies after environmental disasters, especially those involving organic pollutants. PMID- 29628914 TI - Non-Saccharomyces in Wine: Effect Upon Oenococcus oeni and Malolactic Fermentation. AB - This work is a short review of the interactions between oenological yeasts and lactic acid bacteria (LAB), especially Oenococcus oeni, the main species carrying out the malolactic fermentation (MLF). The emphasis has been placed on non Saccharomyces effects due to their recent increased interest in winemaking. Those interactions are variable, ranging from inhibitory, to neutral and stimulatory and are mediated by some known compounds, which will be discussed. One phenomena responsible of inhibitory interactions is the media exhaustion by yeasts, and particularly a decrease in L-malic acid by some non-Saccharomyces. Clearly ethanol is the main inhibitory compound of LAB produced by S. cerevisiae, but non Saccharomyces can be used to decrease it. Sulfur dioxide and medium chain fatty acids (MCFAs) produced by yeasts can exhibit inhibitory effect upon LAB or even result lethal. Interestingly mixed fermentations with non-Saccharomyces present less MCFA concentration. Among organic acids derived as result of yeast metabolism, succinic acid seems to be the most related with MLF inhibition. Several protein factors produced by S. cerevisiae inhibiting O. oeni have been described, but they have not been studied in non-Saccharomyces. According to the stimulatory effects, the use of non-Saccharomyces can increase the concentration of favorable mediators such as citric acid, pyruvic acid, or other compounds derived of yeast autolysis such as peptides, glucans, or mannoproteins. The emergence of non-Saccharomyces in winemaking present a new scenario in which MLF has to take place. For this reason, new tools and approaches should be explored to better understand this new winemaking context. PMID- 29628915 TI - Gas Plasma Pre-treatment Increases Antibiotic Sensitivity and Persister Eradication in Methicillin-Resistant Staphylococcus aureus. AB - Methicillin-resistant Staphylococcus aureus (MRSA) is a major cause of serious nosocomial infections, and recurrent MRSA infections primarily result from the survival of persister cells after antibiotic treatment. Gas plasma, a novel source of ROS (reactive oxygen species) and RNS (reactive nitrogen species) generation, not only inactivates pathogenic microbes but also restore the sensitivity of MRSA to antibiotics. This study further found that sublethal treatment of MRSA with both plasma and plasma-activated saline increased the antibiotic sensitivity and promoted the eradication of persister cells by tetracycline, gentamycin, clindamycin, chloramphenicol, ciprofloxacin, rifampicin, and vancomycin. The short-lived ROS and RNS generated by plasma played a primary role in the process and induced the increase of many species of ROS and RNS in MRSA cells. Thus, our data indicated that the plasma treatment could promote the effects of many different classes of antibiotics and act as an antibiotic sensitizer for the treatment of antibiotic-resistant bacteria involved in infectious diseases. PMID- 29628916 TI - Multidrug-Resistant CTX-M-(15, 9, 2)- and KPC-2-Producing Enterobacter hormaechei and Enterobacter asburiae Isolates Possessed a Set of Acquired Heavy Metal Tolerance Genes Including a Chromosomal sil Operon (for Acquired Silver Resistance). AB - Bacterial resistance to antibiotics is concern in healthcare-associated infections. On the other hand, bacterial tolerance to other antimicrobials, like heavy metals, has been neglected and underestimated in hospital pathogens. Silver has long been used as an antimicrobial agent and it seems to be an important indicator of heavy metal tolerance. To explore this perspective, we searched for the presence of acquired silver resistance genes (sil operon: silE, silS, silR, silC, silF, silB, silA, and silP) and acquired extended-spectrum cephalosporin and carbapenem resistance genes (blaCTX-M and blaKPC) in Enterobacter cloacae Complex (EcC) (n = 27) and Enterobacter aerogenes (n = 8) isolated from inpatients at a general hospital. Moreover, the genetic background of the silA (silver-efflux pump) and the presence of other acquired heavy metal tolerance genes, pcoD (copper-efflux pump), arsB (arsenite-efflux pump), terF (tellurite resistance protein), and merA (mercuric reductase) were also investigated. Outstandingly, 21/27 (78%) EcC isolates harbored silA gene located in the chromosome. Complete sil operon was found in 19/21 silA-positive EcC isolates. Interestingly, 8/20 (40%) E. hormaechei and 5/6 (83%) E. asburiae co-harbored silA/pcoD genes and blaCTX-M-(15,2,or9) and/or blaKPC-2 genes. Frequent occurrences of arsB, terF, and merA genes were detected, especially in silA/pcoD positive, multidrug-resistant (MDR) and/or CTX-M-producing isolates. Our study showed co-presence of antibiotic and heavy metal tolerance genes in MDR EcC isolates. In our viewpoint, there are few studies regarding to bacterial heavy metal tolerance and we call attention for more investigations and discussion about this issue in different hospital pathogens. PMID- 29628917 TI - Discovery of Distinctin-Like-Peptide-PH (DLP-PH) From the Skin Secretion of Phyllomedusa hypochondrialis, a Prototype of a Novel Family of Antimicrobial Peptide. AB - Amphibian skin secretions are an important treasure house of bioactive antimicrobial peptides (AMPs). Despite having been the focus of decades of research in this context, investigations of phyllomedusine frogs continue to identify new AMPs from their skin secretions. In this study, the prototype of a novel family of AMP distinctin-like-peptide-PH (DLP-PH) was identified from the skin secretion of the otherwise well-studied Tiger-Legged Tree Frog Phyllomedusa hypochondrialis through cloning of its precursor-encoding cDNA from a skin secretion-derived cDNA library by a 3'-rapid amplification of cDNA ends (RACE) strategy. Subsequently, the mature peptide was isolated and characterized using reverse-phase HPLC and MS/MS fragmentation sequencing. DLP-PH adopted an alpha helical conformation in membrane mimetic solution and demonstrated unique structural features with two distinct domains that differed markedly in their physiochemical properties. Chemically synthesized replicates of DLP-PH showed antimicrobial activity against planktonic bacterial and yeast cells, but more potent against Escherichia coli at 32 MUg/mL. However, DLP-PH showed much weaker inhibitory activity against the growth of sessile cells in biofilms. In addition, DLP-PH exhibited anti-proliferative activity against human cancer cell lines, H157, and PC3, but with no major toxicity against normal human cell, HMEC-1. These combined properties make DLP-PH deserving further study as an antimicrobial agent and further investigations of its structure-activity relationship could provide valuable new insights into drug lead candidates for antimicrobial and/or anti-cancer purposes. PMID- 29628918 TI - Identification and Characterization of Fluoroquinolone Non-susceptible Streptococcus pyogenes Clones Harboring Tetracycline and Macrolide Resistance in Shanghai, China. AB - Streptococcus pyogenes, also known as group A Streptococcus (GAS), is one of the top 10 infectious causes of death worldwide. Macrolide and tetracycline resistant GAS has emerged as a major health concern in China coinciding with an ongoing scarlet fever epidemic. Furthermore, increasing rates of fluoroquinolone (FQ) non susceptibility within GAS from geographical regions outside of China has also been reported. Fluoroquinolones are the third most commonly prescribed antibiotic in China and is an therapeutic alternative for multi-drug resistant GAS. The purpose of this study was to investigate the epidemiological and molecular features of GAS fluoroquinolone (FQ) non-susceptibility in Shanghai, China. GAS (n = 2,258) recovered between 2011 and 2016 from children and adults were tested for FQ-non-susceptibility. Efflux phenotype and mutations in parC, parE, gyrA, and gyrB were investigated and genetic relationships were determined by emm typing, pulsed-field gel electrophoresis and phylogenetic analysis. The frequency of GAS FQ-non-susceptibility was 1.3% (30/2,258), with the phenotype more prevalent in GAS isolated from adults (14.3%) than from children (1.2%). Eighty percent (24/30) of FQ-non-susceptible isolates were also resistant to both macrolides (ermB) and tetracycline (tetM) including the GAS sequence types emm12, emm6, emm11, and emm1. Genomic fingerprinting analysis of the 30 isolates revealed that non-susceptibility may arise in various genetic backgrounds even within a single emm type. No efflux phenotype was observed in FQ non-susceptible isolates, and molecular analysis of the quinolone resistance-determining regions (QRDRs) identified several sequence polymorphisms in ParC and ParE, and none in GyrA and GyrB. Expansion of this analysis to 152 publically available GAS whole genome sequences from Hong Kong predicted 7.9% (12/152) of Hong Kong isolates harbored a S79F ParC mutation, of which 66.7% (8/12) were macrolide and tetracycline resistant. Phylogenetic analysis of the parC QRDR sequences suggested the possibility that FQ resistance may be acquired through inter species lateral gene transfer. This study reports the emergence of macrolide, tetracycline, and fluoroquinolone multidrug-resistant clones across several GAS emm types including emm1 and emm12, warranting continual surveillance given the extensive use of fluoroquinolones in clinical use. PMID- 29628919 TI - Fungal Endophytes: Beyond Herbivore Management. AB - The incorporation of entomopathogenic fungi as biocontrol agents into Integrated Pest Management (IPM) programs without doubt, has been highly effective. The ability of these fungal pathogens such as Beauveria bassiana and Metarhizium anisopliae to exist as endophytes in plants and protect their colonized host plants against the primary herbivore pests has widely been reported. Aside this sole role of pest management that has been traditionally ascribed to fungal endophytes, recent findings provided evidence of other possible functions as plant yield promoter, soil nutrient distributor, abiotic stress and drought tolerance enhancer in plants. However, reports on these additional important effects of fungal endophytes on the colonized plants remain scanty. In this review, we discussed the various beneficial effects of endophytic fungi on the host plants and their primary herbivore pests; as well as some negative effects that are relatively unknown. We also highlighted the prospects of our findings in further increasing the acceptance of fungal endophytes as an integral part of pest management programs for optimized crop production. PMID- 29628920 TI - Co-expression of Nisin Z and Leucocin C as a Basis for Effective Protection Against Listeria monocytogenes in Pasteurized Milk. AB - Nisin, an important bacteriocin from Lactococcus lactis subsp., is primarily active against various Gram-positive bacteria. Leucocin C, produced by Leuconostoc carnosum 4010, is a class IIa bacteriocin used to inhibit the growth of Listeria monocytogenes. Because two bacteriocins have different modes of action, the combined use of them could be a potential strategy for effective inhibition of foodborne pathogens. In this study, L. lactis N8-r-lecCI (N8 harboring lecCI gene) coexpressing nisin-leucocin C was constructed based on the food-grade carrier L. lactis N8. Production of both bacteriocins was stably maintained. Antimicrobial measurements showed that the recombinant strain is effectively against Listeria monocytogenes and Staphylococcus aureus and moderately against Salmonella enterica serovar Enteritidis and Escherichia coli because of its stronger antibacterial activity than the parental strain, this result first demonstrated that the co-expression of nisin and leucocin C results in highly efficient antimicrobial activity. The checkerboard assay showed that the antibacterial activity of L. lactis N8-r-lecCI supernatant was enhanced in the presence of low concentration of EDTA. Analysis of the scanning electron microscope image showed the biggest cellular morphology change in L. monocytogenes treated with a mixture of EDTA and L. lactis N8-r-lecCI supernatant. The practical effect was verified in pasteurized milk through time kill assay. The L. lactis N8-r-lecCI strain expressing both nisin and leucocin C has a promising application prospect in pasteurized milk processing and preservation because of its strong antibacterial activity. PMID- 29628921 TI - Prevalence and Characterization of Multi-Drug-Resistant Gram-Negative Bacilli Isolated From Lebanese Poultry: A Nationwide Study. AB - Currently, antimicrobial resistance is one of the most prominent public health issues. In fact, there is increasing evidence that animals constitute a reservoir of antimicrobial resistance. In collaboration with the Lebanese Ministry of Agriculture, the aim of this study was to determine the prevalence of intestinal carriage of multi-drug-resistant Gram-negative Bacilli in poultry farms at the national level. Between August and December 2015, 981 fecal swabs were obtained from 49 poultry farms distributed across Lebanon. The swabs were subcultured on MacConkey agar supplemented with cefotaxime (2 MUg/ml). Isolated strains were identified using MALDI-TOF mass spectrometry. Multilocus sequence typing analysis was performed for Escherichia coli. Phenotypic detection of extended spectrum beta-lactamases (ESBL) and AmpC production was performed using double disk synergy and the ampC disk test, respectively. beta-lactamase encoding genes blaCTX-M, blaTEM, blaSHV, blaFOX, blaMOX, blaEBC, blaACC, blaDHA, and blaCMY using PCR amplification. Out of 981 fecal swabs obtained, 203 (20.6%) showed bacterial growth on the selective medium. Of the 235 strains isolated, 217 were identified as E. coli (92%), eight as Klebsiella pneumoniae (3%), three as Proteus mirabilis (1%) and three as Enterobacter cloacae (1%). MLST analysis of E. coli isolates showed the presence of ST156, ST5470, ST354, ST155, and ST3224. The phenotypic tests revealed that 43.5, 28.5, and 20.5% of the strains were ampC, ESBL, and ampC/ESBL producers, respectively. The putative TEM gene was detected in 83% of the isolates, SHV in 20%, CTX-M in 53% and CMY ampC beta lactamase gene in 65%. Our study showed that chicken farms in Lebanon are reservoirs of ESBL and AmpC producing Gram-negative bacilli. The level of antibiotic consumption in the Lebanese veterinary medicine should be evaluated. Future studies should focus on the risk factors associated with the acquisition of multi-drug-resistant organisms in farm animals in Lebanon. PMID- 29628922 TI - The Applied Development of a Tiered Multilocus Sequence Typing (MLST) Scheme for Dichelobacter nodosus. AB - Dichelobacter nodosus (D. nodosus) is the causative pathogen of ovine footrot, a disease that has a significant welfare and financial impact on the global sheep industry. Previous studies into the phylogenetics of D. nodosus have focused on Australia and Scandinavia, meaning the current diversity in the United Kingdom (U.K.) population and its relationship globally, is poorly understood. Numerous epidemiological methods are available for bacterial typing; however, few account for whole genome diversity or provide the opportunity for future application of new computational techniques. Multilocus sequence typing (MLST) measures nucleotide variations within several loci with slow accumulation of variation to enable the designation of allele numbers to determine a sequence type. The usage of whole genome sequence data enables the application of MLST, but also core and whole genome MLST for higher levels of strain discrimination with a negligible increase in experimental cost. An MLST database was developed alongside a seven loci scheme using publically available whole genome data from the sequence read archive. Sequence type designation and strain discrimination was compared to previously published data to ensure reproducibility. Multiple D. nodosus isolates from U.K. farms were directly compared to populations from other countries. The U.K. isolates define new clades within the global population of D. nodosus and predominantly consist of serogroups A, B and H, however serogroups C, D, E, and I were also found. The scheme is publically available at https://pubmlst.org/dnodosus/. PMID- 29628923 TI - Evaluation of Antigen-Conjugated Fluorescent Beads to Identify Antigen-Specific B Cells. AB - Selection of single antigen-specific B cells to identify their expressed antibodies is of considerable interest for evaluating human immune responses. Here, we present a method to identify single antibody-expressing cells using antigen-conjugated fluorescent beads. To establish this, we selected Folate Receptor alpha (FRalpha) as a model antigen and a mouse B cell line, expressing both the soluble and the membrane-bound forms of a human/mouse chimeric antibody (MOv18 IgG1) specific for FRalpha, as test antibody-expressing cells. Beads were conjugated to FRalpha using streptavidin/avidin-biotin bridges and used to select single cells expressing the membrane-bound form of anti-FRalpha. Bead-bound cells were single cell-sorted and processed for single cell RNA retrotranscription and PCR to isolate antibody heavy and light chain variable regions. Variable regions were then cloned and expressed as human IgG1/k antibodies. Like the original clone, engineered antibodies from single cells recognized native FRalpha. To evaluate whether antigen-coated beads could identify specific antibody-expressing cells in mixed immune cell populations, human peripheral blood mononuclear cells (PBMCs) were spiked with test antibody-expressing cells. Antigen-specific cells could comprise up to 75% of cells selected with antigen-conjugated beads when the frequency of the antigen-positive cells was 1:100 or higher. In PBMC pools, beads conjugated to recombinant antigens FRalpha and HER2 bound antigen-specific anti FRalpha MOv18 and anti-HER2 Trastuzumab antibody-expressing cells, respectively. From melanoma patient-derived B cells selected with melanoma cell line-derived protein-coated fluorescent beads, we generated a monoclonal antibody that recognized melanoma antigen-coated beads. This approach may be further developed to facilitate analysis of B cells and their antibody profiles at the single cell level and to help unravel humoral immune repertoires. PMID- 29628925 TI - Human Endothelial Cells Modulate CD4+ T Cell Populations and Enhance Regulatory T Cell Suppressive Capacity. AB - Endothelial cells (ECs) line the luminal surface of blood vessels and have an active role in the recruitment of leukocytes, including immune cell activation. Regulatory T cells (Tregs) are immune suppressor cells that maintain peripheral tolerance and must interact with the endothelium as they traffic into tissue. We hypothesized that human ECs could modulate Tregs and their suppressor function. Cocultures of CD4+ T cells with human umbilical vein ECs (HUVECs) or dermal microvascular ECs (HDMECs) were conducted and analyzed for activation and proliferation after 72 and 120 h using flow cytometry. In monocyte-depleted cultures, human ECs were found to support CD4+ T cell proliferation in the presence of external mitogens phytohemagglutinin or anti-CD3/28 antibodies (aCD3/28). Activation was shown by CD25 expression in these cells that also transiently expressed the Treg transcription factor FOXP3. HUVECs supported the specific concurrent proliferation of both effector T cells and Tregs when cocultured with aCD3/28. Purified Tregs were also functionally activated by prior coculture with EC to suppress effector T (Teff) cell proliferation. Both direct coculture and indirect coculture of EC and Treg showed activation of the Treg suppressive phenotype. However, whereas HUVEC showed enhancement of suppression by both mechanisms, HDMEC only supported Treg suppressive activity via the contact-independent mechanism. In the contact-independent cultures, the soluble mediators IL-6, GM-CSF, or G-CSF released from ECs following interferon-gamma activation were not responsible for the enhanced Treg suppressor function. Following direct coculture, Treg expression of inhibitory receptors PD-1 and OX40 was elevated while activated EC expressed the counter ligands programmed death ligand (PD-L)1 and PD-L2. Therefore, human ECs have a role in supporting T cell proliferation and increasing Treg suppressor function. This ability of EC to enhance Treg function could offer novel targets to boost Treg activity during inflammatory disorders. PMID- 29628924 TI - Defective Phagocytic Properties of HIV-Infected Macrophages: How Might They Be Implicated in the Development of Invasive Salmonella Typhimurium? AB - Human immunodeficiency virus type 1 (HIV-1) infects and kills T cells, profoundly damaging the host-specific immune response. The virus also integrates into memory T cells and long-lived macrophages, establishing chronic infections. HIV-1 infection impairs the functions of macrophages both in vivo and in vitro, which contributes to the development of opportunistic diseases. Non-typhoidal Salmonella enterica serovar Typhimurium has been identified as the most common cause of bacterial bloodstream infections in HIV-infected adults. In this review, we report how the functions of macrophages are impaired post HIV infection; introduce what makes invasive Salmonella Typhimurium specific for its pathogenesis; and finally, we discuss why these bacteria may be particularly adapted to the HIV-infected host. PMID- 29628927 TI - Evaluating Human Immune Responses for Vaccine Development in a Novel Human Spleen Cell-Engrafted NOD-SCID-IL2rgammaNull Mouse Model. AB - The lack of preclinical models able to faithfully predict the immune responses which are later obtained in the clinic is a major hurdle for vaccines development as it increases markedly the delays and the costs required to perform clinical studies. We developed and evaluated the relevance to human immune responses of a novel humanized mouse model, humanized-spleen cells-NOD-SCID-gamma null (Hu-SPL NSG), in which we grafted human spleen cells in immunodeficient NOD-SCID-IL 2rgammanull (NSG) mice. We selected the malaria vaccine candidate, Liver Stage Antigen 3-Full Length, because we had previously observed a major discrepancy between preclinical and clinical results, and compared its immunogenicity with that of a shorter form of the molecule, LSA3-729. NSG mice engrafted with human spleen lymphocytes were immunized with either LSA3-FL or LSA3-729, both adjuvanted with montanide ISA720. We found that the shorter LSA3-729 triggered the production of human antibodies and a T-helper-type 1 cellular immune response associated with protection whereas LSA3-FL did not. Results were consistent in five groups receiving lymphocytes from five distinct human donors. We identified antigenic regions in the full-length molecule, but not in the shorter version, which induced T-regulatory type of cellular responses. These regions had failed to be predicted by previous preclinical experiments in a wide range of animal models, including primates. Results were reproducible using spleen cells from all five human donors. The findings in the Hu-SPL-NSG model were similar to the results obtained using LSA3-FL in the clinic and hence could have been used to predict them. The model does not present graft versus host reaction, low survival of engrafted B lymphocytes and difficulty to raise primary immune responses, all limitations previously reported in humanized immune-compromised mice. Results also point to the shorter construct, LSA3-729 as a more efficient vaccine candidate. In summary, our findings indicate that the Hu-SPL-NSG model could be a relevant and cost-saving choice for early selection of vaccine candidates before clinical development, and deserves being further evaluated. PMID- 29628928 TI - Impaired CD27+IgD+ B Cells With Altered Gene Signature in Rheumatoid Arthritis. AB - Natural antibodies, particularly natural IgM, are proved to play indispensable roles in the immune defenses against common infections. More recently, the protective roles of these natural IgM were also recognized in autoimmune diseases. They are mainly produced by B-1 and innate-like B cells (ILBs). Human CD19+CD27+IgD+ B cells, also termed as un-switched memory B cells, were proposed to be a kind of ILBs. However, functional features and characteristics of these cells in rheumatoid arthritis (RA) remained poorly understood. In this study, we found that human CD27+IgD+ B cells could produce natural antibody-like IgM. Under RA circumstance, the frequencies of these cells were significantly decreased. Moreover, the IgM-producing capacities of these cells were also dampened. Interestingly, the BCR repertoire of these cells was altered in RA, demonstrating decreased diversity with preferential usage alteration from VH3-23D to VH1-8. Single cell sequencing further revealed the proinflammatory biased features of these cells in RA. These CD27+IgD+ B cells were negatively correlated with RA patient disease activities and clinical manifestations. After effective therapy with disease remission in RA, these cells could be recovered. Taken together, these results have revealed that CD27+IgD+ B cells were impaired in RA with dysfunctional features, which might contribute to the disease perpetuation. PMID- 29628926 TI - Novel Platforms for the Development of a Universal Influenza Vaccine. AB - Despite advancements in immunotherapeutic approaches, influenza continues to cause severe illness, particularly among immunocompromised individuals, young children, and elderly adults. Vaccination is the most effective way to reduce rates of morbidity and mortality caused by influenza viruses. Frequent genetic shift and drift among influenza-virus strains with the resultant disparity between circulating and vaccine virus strains limits the effectiveness of the available conventional influenza vaccines. One approach to overcome this limitation is to develop a universal influenza vaccine that could provide protection against all subtypes of influenza viruses. Moreover, the development of a novel or improved universal influenza vaccines may be greatly facilitated by new technologies including virus-like particles, T-cell-inducing peptides and recombinant proteins, synthetic viruses, broadly neutralizing antibodies, and nucleic acid-based vaccines. This review discusses recent scientific advances in the development of next-generation universal influenza vaccines. PMID- 29628929 TI - Multiplex PCR Targeted Amplicon Sequencing (MTA-Seq): Simple, Flexible, and Versatile SNP Genotyping by Highly Multiplexed PCR Amplicon Sequencing. AB - Next-generation sequencing (NGS) technologies have enabled genome re-sequencing for exploring genome-wide polymorphisms among individuals, as well as targeted re sequencing for the rapid and simultaneous detection of polymorphisms in genes associated with various biological functions. Therefore, a simple and robust method for targeted re-sequencing should facilitate genotyping in a wide range of biological fields. In this study, we developed a simple, custom, targeted re sequencing method, designated "multiplex PCR targeted amplicon sequencing (MTA seq)," and applied it to the genotyping of the model grass Brachypodium distachyon. To assess the practical usability of MTA-seq, we applied it to the genotyping of genome-wide single-nucleotide polymorphisms (SNPs) identified in natural accessions (Bd1-1, Bd3-1, Bd21-3, Bd30-1, Koz-1, Koz-3, and Koz-4) by comparing the re-sequencing data with that of reference accession Bd21. Examination of SNP-genotyping accuracy in 443 amplicons from eight parental accessions and an F1 progeny derived by crossing of Bd21 and Bd3-1 revealed that ~95% of the SNPs were correctly called. The assessment suggested that the method provided an efficient framework for accurate and robust SNP genotyping. The method described here enables easy design of custom target SNP-marker panels in various organisms, facilitating a wide range of high-throughput genetic applications, such as genetic mapping, population analysis, molecular breeding, and genomic diagnostics. PMID- 29628930 TI - Tolerance of Ruppia sinensis Seeds to Desiccation, Low Temperature, and High Salinity With Special Reference to Long-Term Seed Storage. AB - Seeds are important materials for the restoration of globally-threatened marine angiosperm (seagrass) populations. In this study, we investigated the differences between different Ruppia sinensis seed types and developed two feasible long-term R. sinensis seed storage methods. The ability of R. sinensis seeds to tolerate the short-term desiccation and extreme cold had been investigated. The tolerance of R. sinensis seeds to long-term exposure of high salinity, cold temperature, and desiccation had been considered as potential methods for long-term seed storage. Also, three morphological and nine physiological indices were measured and compared between two types of seeds: Shape L and Shape S. We found that: (1) wet storage at a salinity of 30-40 psu and 0 degrees C were the optimal long-term storage conditions, and the proportion of viable seeds reached over 90% after a storage period of 11 months since the seeds were collected from the reproductive shoots; (2) dry condition was not the optimal choice for long-term storage of R. sinensis seeds; however, storing seeds in a dry condition at 5 degrees C and 33 +/- 10% relative humidity for 9 months had a relatively high percentage (74.44 +/ 2.22%) of viable seeds, consequently desiccation exposure could also be an acceptable seed storage method; (3) R. sinensis seeds would lose vigor in the interaction of extreme cold (-27 degrees C) and desiccation; (4) there were significant differences in seed weight, seed curvature, and endocarp thickness between the two types of seeds. These findings provided fundamental physiological information for R. sinensis seeds and supported the long-term storage of its seeds. Our results may also serve as useful reference for seed storage of other threatened seagrass species and facilitate their ex situ conservation and habitat restoration. PMID- 29628931 TI - The Novel Secreted Meloidogyne incognita Effector MiISE6 Targets the Host Nucleus and Facilitates Parasitism in Arabidopsis. AB - Meloidogyne incognita is highly specialized parasite that interacts with host plants using a range of strategies. The effectors are synthesized in the esophageal glands and secreted into plant cells through a needle-like stylet during parasitism. In this study, based on RNA-seq and bioinformatics analysis, we predicted 110 putative Meloidogyne incognita effectors that contain nuclear localization signals (NLSs). Combining the Burkholderia glumae-pEDV based screening system with subcellular localization, from 20 randomly selected NLS effector candidates, we identified an effector MiISE6 that can effectively suppress B. glumae-induced cell death in Nicotiana benthamiana, targets to the nuclei of plant cells, and is highly expressed in early parasitic J2 stage. Sequence analysis showed that MiISE6 is a 157-amino acid peptide, with an OGFr_N domain and two NLS motifs. Hybridization in situ verified that MiISE6 is expressed in the subventral esophageal glands. Yeast invertase secretion assay validated the function of the signal peptide harbored in MiISE6. Transgenic Arabidopsis thaliana plants expressing MiISE6 become more susceptible to M. incognita. Inversely, the host-derived RNAi of MiISE6 of the nematode can decrease its parasitism on host. Based on transcriptome analysis of the MiISE6 transgenic Arabidopsis samples and the wild-type samples, we obtained 852 differentially expressed genes (DEGs). Integrating Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses, we found that expression of MiISE6 in Arabidopsis can suppress jasmonate signaling pathway. In addition, the expression of genes related to cell wall modification and the ubiquitination proteasome pathway also have detectable changes in the transgenic plants. Results from the present study suggest that MiISE6 is involved in interaction between nematode-plant, and plays an important role during the early stages of parasitism by interfering multiple signaling pathways of plant. Moreover, we found homologs of MiISE6 in other sedentary nematodes, Meloidogyne hapla and Globodera pallida. Our experimental results provide evidence to decipher the molecular mechanisms underlying the manipulation of host immune defense responses by plant parasitic nematodes, and transcriptome data also provide useful information for further study nematode-plant interactions. PMID- 29628933 TI - FANCM Limits Meiotic Crossovers in Brassica Crops. AB - Meiotic crossovers (COs) are essential for proper chromosome segregation and the reshuffling of alleles during meiosis. In WT plants, the number of COs is usually small, which limits the genetic variation that can be captured by plant breeding programs. Part of this limitation is imposed by proteins like FANCM, the inactivation of which results in a 3-fold increase in COs in Arabidopsis thaliana. Whether the same holds true in crops needed to be established. In this study, we identified EMS induced mutations in FANCM in two species of economic relevance within the genus Brassica. We showed that CO frequencies were increased in fancm mutants in both diploid and tetraploid Brassicas, Brassica rapa and Brassica napus respectively. In B. rapa, we observed a 3-fold increase in the number of COs, equal to the increase observed previously in Arabidopsis. In B. napus we observed a lesser but consistent increase (1.3-fold) in both euploid (AACC) and allohaploid (AC) plants. Complementation tests in A. thaliana suggest that the smaller increase in crossover frequency observed in B. napus reflects residual activity of the mutant C copy of FANCM. Altogether our results indicate that the anti-CO activity of FANCM is conserved across the Brassica, opening new avenues to make a wider range of genetic diversity accessible to crop improvement. PMID- 29628932 TI - Gene Duplication and Transference of Function in the paleoAP3 Lineage of Floral Organ Identity Genes. AB - The floral organ identity gene APETALA3 (AP3) is a MADS-box transcription factor involved in stamen and petal identity that belongs to the B-class of the ABC model of flower development. Thalictrum (Ranunculaceae), an emerging model in the non-core eudicots, has AP3 homologs derived from both ancient and recent gene duplications. Prior work has shown that petals have been lost repeatedly and independently in Ranunculaceae in correlation with the loss of a specific AP3 paralog, and Thalictrum represents one of these instances. The main goal of this study was to conduct a functional analysis of the three AP3 orthologs present in Thalictrum thalictroides, representing the paleoAP3 gene lineage, to determine the degree of redundancy versus divergence after gene duplication. Because Thalictrum lacks petals, and has lost the petal-specific AP3, we also asked whether heterotopic expression of the remaining AP3 genes contributes to the partial transference of petal function to the first whorl found in insect pollinated species. To address these questions, we undertook functional characterization by virus-induced gene silencing (VIGS), protein-protein interaction and binding site analyses. Our results illustrate partial redundancy among Thalictrum AP3s, with deep conservation of B-class function in stamen identity and a novel role in ectopic petaloidy of sepals. Certain aspects of petal function of the lost AP3 locus have apparently been transferred to the other paralogs. A novel result is that the protein products interact not only with each other, but also as homodimers. Evidence presented here also suggests that expression of the different ThtAP3 paralogs is tightly integrated, with an apparent disruption of B function homeostasis upon silencing of one of the paralogs that codes for a truncated protein. To explain this result, we propose two testable alternative scenarios: that the truncated protein is a dominant negative mutant or that there is a compensational response as part of a back-up circuit. The evidence for promiscuous protein-protein interactions via yeast two hybrid combined with the detection of AP3 specific binding motifs in all B-class gene promoters provide partial support for these hypotheses. PMID- 29628934 TI - Gene Expression Pattern and Protein Localization of Arabidopsis Phospholipase D Alpha 1 Revealed by Advanced Light-Sheet and Super-Resolution Microscopy. AB - Phospholipase D alpha 1 (PLDalpha1, At3g15730) and its product phosphatidic acid (PA) are involved in a variety of cellular and physiological processes, such as cytoskeletal remodeling, regulation of stomatal closure and opening, as well as biotic and abiotic stress signaling. Here we aimed to study developmental expression patterns and subcellular localization of PLDalpha1 in Arabidopsis using advanced microscopy methods such as light-sheet fluorescence microscopy (LSFM) and structured illumination microscopy (SIM). We complemented two knockout pldalpha1 mutants with a YFP-tagged PLDalpha1 expressed under the PLDalpha1 native promoter in order to study developmental expression pattern and subcellular localization of PLDalpha1 in Arabidopsis thaliana under natural conditions. Imaging of tissue-specific and developmentally-regulated localization of YFP-tagged PLDalpha1 by LSFM in roots of growing seedlings showed accumulation of PLDalpha1-YFP in the root cap and the rhizodermis. Expression of PLDalpha1-YFP in the rhizodermis was considerably higher in trichoblasts before and during root hair formation and growth. Thus, PLDalpha1-YFP accumulated in emerging root hairs and in the tips of growing root hairs. PLDalpha1-YFP showed cytoplasmic subcellular localization in root cap cells and in cells of the root transition zone. In aerial parts of plants PLDalpha1-YFP was also localized in the cytoplasm showing enhanced accumulation in the cortical cytoplasmic layer of epidermal non dividing cells of hypocotyls, leaves, and leaf petioles. However, in dividing cells of root apical meristem and leaf petiole epidermis PLDalpha1-YFP was enriched in mitotic spindles and phragmoplasts, as revealed by co-visualization with microtubules. Finally, super-resolution SIM imaging revealed association of PLDalpha1-YFP with both microtubules and clathrin-coated vesicles (CCVs) and pits (CCPs). In conclusion, this study shows the developmentally-controlled expression and subcellular localization of PLDalpha1 in dividing and non-dividing Arabidopsis cells. PMID- 29628936 TI - Clinical and Functional Characterization of a Missense ELF2 Variant in a CANVAS Family. AB - Cerebellar ataxia with neuropathy and bilateral vestibular areflexia syndrome (CANVAS) is a rare disorder with an unknown etiology. We present a British family with presumed autosomal dominant CANVAS with incomplete penetrance and variable expressivity. Exome sequencing identified a rare missense variant in the ELF2 gene at chr4:g.140058846 C > T, c.10G > A, p.A4T which segregated in all affected patients. By using transduced BE (2)-M17 cells, we found that the mutated ELF2 (mt-ELF2) gene increased ATXN2 and reduced ELOVL5 gene expression, the causal genes of type 2 and type 38 spinocerebellar ataxias. Both, western blot and confocal microscopy confirmed an increase of ataxin-2 in BE(2)-M17 cells transduced with lentivirus expressing mt-ELF2 (CEE-mt-ELF2), which was not observed in cells transduced with lentivirus expressing wt-ELF2 (CEE-wt-ELF2). Moreover, we observed a significant decrease in the number and size of lipid droplets in the CEE-mt-ELF2-transduced BE (2)-M17 cells, but not in the CEE-wt ELF2-transduced BE (2)-M17. Furthermore, changes in the expression of ELOVL5 could be related with the reduction of lipid droplets in BE (2)-M17 cells. This work supports that ELF2 gene regulates the expression of ATXN2 and ELOVL5 genes, and defines new molecular links in the pathophysiology of cerebellar ataxias. PMID- 29628935 TI - Neurodevelopmental Genetic Diseases Associated With Microdeletions and Microduplications of Chromosome 17p13.3. AB - Chromosome 17p13.3 is a region of genomic instability that is linked to different rare neurodevelopmental genetic diseases, depending on whether a deletion or duplication of the region has occurred. Chromosome microdeletions within 17p13.3 can result in either isolated lissencephaly sequence (ILS) or Miller-Dieker syndrome (MDS). Both conditions are associated with a smooth cerebral cortex, or lissencephaly, which leads to developmental delay, intellectual disability, and seizures. However, patients with MDS have larger deletions than patients with ILS, resulting in additional symptoms such as poor muscle tone, congenital anomalies, abnormal spasticity, and craniofacial dysmorphisms. In contrast to microdeletions in 17p13.3, recent studies have attracted considerable attention to a condition known as a 17p13.3 microduplication syndrome. Depending on the genes involved in their microduplication, patients with 17p13.3 microduplication syndrome may be categorized into either class I or class II. Individuals in class I have microduplications of the YWHAE gene encoding 14-3-3epsilon, as well as other genes in the region. However, the PAFAH1B1 gene encoding LIS1 is never duplicated in these patients. Class I microduplications generally result in learning disabilities, autism, and developmental delays, among other disorders. Individuals in class II always have microduplications of the PAFAH1B1 gene, which may include YWHAE and other genetic microduplications. Class II microduplications generally result in smaller body size, developmental delays, microcephaly, and other brain malformations. Here, we review the phenotypes associated with copy number variations (CNVs) of chromosome 17p13.3 and detail their developmental connection to particular microdeletions or microduplications. We also focus on existing single and double knockout mouse models that have been used to study human phenotypes, since the highly limited number of patients makes a study of these conditions difficult in humans. These models are also crucial for the study of brain development at a mechanistic level since this cannot be accomplished in humans. Finally, we emphasize the usefulness of the CRISPR/Cas9 system and next generation sequencing in the study of neurodevelopmental diseases. PMID- 29628938 TI - Spontaneous Resolution of Post-Traumatic Direct Carotid-Cavernous Fistula. AB - Post-traumatic carotid-cavernous fistulas are due to a tear in the wall of the cavernous carotid artery, leading to shunting of blood into the cavernous sinus. These are generally high-flow fistula and rarely resolve spontaneously. Most cases require endovascular embolization. We report a case of Barrow type A carotid-cavernous fistula which resolved spontaneously. PMID- 29628937 TI - A Meta-Analysis of Genome-Wide Association Studies of Growth Differentiation Factor-15 Concentration in Blood. AB - Blood levels of growth differentiation factor-15 (GDF-15), also known as macrophage inhibitory cytokine-1 (MIC-1), have been associated with various pathological processes and diseases, including cardiovascular disease and cancer. Prior studies suggest genetic factors play a role in regulating blood MIC-1/GDF 15 concentration. In the current study, we conducted the largest genome-wide association study (GWAS) to date using a sample of ~5,400 community-based Caucasian participants, to determine the genetic variants associated with MIC 1/GDF-15 blood concentration. Conditional and joint (COJO), gene-based association, and gene-set enrichment analyses were also carried out to identify novel loci, genes, and pathways. Consistent with prior results, a locus on chromosome 19, which includes nine single nucleotide polymorphisms (SNPs) (top SNP, rs888663, p = 1.690 * 10-35), was significantly associated with blood MIC 1/GDF-15 concentration, and explained 21.47% of its variance. COJO analysis showed evidence for two independent signals within this locus. Gene-based analysis confirmed the chromosome 19 locus association and in addition, a putative locus on chromosome 1. Gene-set enrichment analyses showed that the"COPI mediated anterograde transport" gene-set was associated with MIC-1/GDF15 blood concentration with marginal significance after FDR correction (p = 0.067). In conclusion, a locus on chromosome 19 was associated with MIC-1/GDF-15 blood concentration with genome-wide significance, with evidence for a new locus (chromosome 1). Future studies using independent cohorts are needed to confirm the observed associations especially for the chromosomes 1 locus, and to further investigate and identify the causal SNPs that contribute to MIC-1/GDF-15 levels. PMID- 29628939 TI - Permanent Deployment of the Solitaire FRTM Device in the Basilar Artery in an Acute Stroke Scenario. AB - Background: Scarce reports exist of permanent deployment of Solitaire FRTM devices for arterial steno-occlusive disease as it is primarily indicated for temporary deployment for thrombectomy in large-vessel, anterior-circulation ischemic strokes. Even more scarce are reports describing permanent deployment of the Solitaire device for posterior circulation strokes. Summary: We present 2 cases where the Solitaire device was electrolytically detached to re-establish flow in an occluded or stenotic basilar artery in acutely symptomatic patients. In both cases, a 4 * 15 mm Solitaire device was positioned across the stenotic or occluded portion of the basilar artery and electrolytically detached to maintain vessel patency. Both cases had good clinical outcomes with a National Institutes of Health Stroke Scale (NIHSS) score of 1 (from 24) on 90-day follow-up and an NIHSS score of 2 (from 7) on 30-day follow-up. Key Messages: Permanent deployment of the Solitaire device may potentially be a safe and effective means of maintaining vessel patency in an occluded or stenotic basilar artery. PMID- 29628940 TI - Moderate to Severe Anemia Is Associated with Poor Functional Outcome in Acute Stroke Patients Treated with Mechanical Thrombectomy. AB - Background: Anemia will negatively affect cerebral collaterals and penumbra. Eventually, it may cause worse clinical outcomes and even increase mortality rates in stroke patients. Anemia has recently been suggested to be an independent risk factor for ischemic stroke. Therefore, we aimed to investigate the effects of the presence of anemia on clinical outcomes in ischemic stroke patients undergoing mechanical thrombectomy. Methods: This was a retrospective study involving the prospectively and consecutively collected data of 90 adult patients between January 2015 and August 2016. Hemoglobin (Hb) cutoff levels were accepted as 12 g/dL for women and 13 g/dL for men. Patients having anemia were further divided into three subgroups as severe anemia (Hb <8 g/dL for both genders), moderate anemia (Hb <10 g/dL for both genders), and mild anemia (Hb <13 g/dL for men and Hb <12 g/dL for women). Results: Forty of the subjects (44.4%) had anemia. Moderate anemia was detected in 14 out of 90 patients (15.5%) and severe anemia was found in only four of them (4.4%). Poor functional outcome (mRS 3-6) was similar in both anemic and non-anemic patients (37.5% vs. 38%, respectively, p = 0.08), but poor functional outcome was found to be statistically significant with severe anemic group (Hb <8 mg/dL) (p = 0.003). In multiple logistic regression analysis, moderate and severe anemia has been found to increase the mortality (p = 0.032). Conclusions: Our study demonstrated a poor functional outcome only in moderate to severe anemic patients. Clinicians should keep in mind the negative effect of moderate to severe anemia in the clinical course of acute stroke patients treated with mechanical thrombectomy. PMID- 29628941 TI - Early Outcome after Intracranial Hemorrhage Related to Non-Vitamin K Oral Anticoagulants. AB - Background: Intracranial hemorrhage (ICH) is a serious, life-threatening, but fortunately rare complication of non-vitamin K oral anticoagulant (NOAC) therapy. There are limited data on NOAC-related ICH prognosis. Methods: All consecutive patients admitted to a single center due to acute NOAC-related ICH from September 2012 until the beginning of 2017 were included. Risk factors, type of NOAC, and location of ICH were evaluated. Risk for ischemic and bleeding events and clinical status upon admission and at discharge were evaluated using standard scales. Results: Thirty-four patients aged 77.8 +/- 8.3 years with NOAC-related ICH were included. The main predisposing risk factors were age and arterial hypertension. The median CHA2DS2-VASc score was 3.4 and the median HAS-BLED score was 1.8. Eighteen patients were treated with rivaroxaban, 11 with dabigatran, and 5 with apixaban. Ten patients (29%) had a favorable outcome with a modified Rankin Scale score <=2 and 13 patients (38%) died. The location of the ICH was mainly intraparenchymal and subdural. Conclusions: Our retrospective single center study shows that the mortality rate with NOAC-related ICH is <40%, which makes it comparable to that with vitamin K antagonist-related ICH. PMID- 29628943 TI - Provocative Testing Prior to Anterior Cerebral Artery Fusiform Aneurysm Embolization. AB - : We report 2 cases of parent artery occlusion (PAO) for anterior cerebral artery (ACA) fusiform aneurysm embolization after superselective provocative testing was performed to confirm distal territory viability. The first case involves a patient in the second decade of life who presented with subarachnoid hemorrhage and underwent PAO after a balloon test occlusion in the distal ACA revealed no neurophysiology changes. The second case involves another patient in the forth decade of life who presented with an enlarging pseudoaneurysm and underwent PAO after a sodium amobarbital infusion in the distal ACA revealed no clinical change. Both patients tolerated PAO without clinical compromise. PAO after provocative testing may be a safe and effective strategy in the management of fusiform aneurysm treatment. Key Messages: Provocative testing with superselective balloon test occlusion and sodium amobarbital infusion are both viable options for clinical and physiological interrogation of brain tissue prior to parent vessel occlusion. Neurophysiological monitoring may be a useful surrogate for clinical examination after provocative testing, particularly if patients were treated under general anesthesia. PMID- 29628942 TI - Clinical and Angiographic Outcomes with the Combined Local Aspiration and Retriever in the North American Solitaire Stent-Retriever Acute Stroke (NASA) Registry. AB - Background: Various techniques are used to enhance the results of mechanical thrombectomy with stent-retrievers, including proximal arrest with balloon guide catheter (BGC), conventional large bore proximal catheter (CGC), or in combination with local aspiration through a large-bore catheter positioned at the clot interface (Aspiration-Retriever Technique for Stroke [ARTS]). We evaluated the impact of ARTS in the North American Solitaire Acute Stroke (NASA) registry. Summary: Data on the use of the aspiration technique were available for 285 anterior circulation patients, of which 29 underwent ARTS technique, 131 CGC, and 125 BGC. Baseline demographics were comparable, except that ARTS patients are less likely to have hypertension or atrial fibrillation. The ARTS group had more ICA occlusions (41.4 vs. 22% in the BGC, p = 0.04 and 26% in CGC, p = 0.1) and less MCA/M1 occlusions (44.8 vs. 68% in BGC and 62% in CGC). Time from arterial puncture to reperfusion or end of procedure with ARTS was shorter than with CGC (54 vs. 91 min, p = 0.001) and was comparable to the BGC time (54 vs. 67, p = 0.11). Final degree of reperfusion was comparable among the groups (TICI [modified Thrombolysis in Cerebral Infarction] score 2b or higher was 72 vs. 70% for CGC vs. 78% for BGC). Procedural complications, mortality, and good clinical outcome at 90 days were similar between the groups. Key Messages: The ARTS mechanical thrombectomy in acute ischemic stroke patients appears to yield better results as compared to the use of CGCs with no significant difference when compared to BGC. This early ARTS technique NASA registry data are limited by the earlier generation distal large bore catheters and small sample size. Future studies should focus on the comparison of ARTS and BGC techniques. PMID- 29628944 TI - Is the Efficacy of Endovascular Treatment for Acute Ischemic Stroke Sex-Related. AB - Background: Several reports refer to differences in stroke between females and males, namely in incidence and clinical outcome, but also in response to treatments. Driven by a recent analysis of the MR CLEAN trial, which showed a higher benefit from acute stroke endovascular treatment (EVT) in males, we intended to determine if clinical outcomes after EVT differ between sexes, in a real-world setting. Methods: We analyzed 145 consecutive patients submitted to EVT for anterior circulation large-vessel occlusion, between January 2015 and September 2016, and compared the outcomes between sexes. Results: Our population was represented by 81 (55.9%) females, with similar baseline characteristics (pre stroke disability, baseline NIHSS, and ASPECTS), rate of previous intravenous thrombolysis, time from onset to recanalization, and rate of revascularization; with the exception that women were on average 4 years older and had more hypertension, and men in turn had more tandem occlusions and atherosclerotic etiology (all p < 0.05). Even after adjusting for these statistically significant variables and for intravenous thrombolysis (as some studies advocate a different response to this treatment between sexes), there were no differences in intracranial hemorrhage, functional independence (mRS <=2 in 60.9% males vs. 66.7% in females, p = 0.48; adjusted p = 0.36), or mortality at 3 months. Conclusion: In a real-world setting, we found no sex differences in clinical and safety outcomes after acute stroke EVT. Our results support the idea that women are equally likely to achieve good outcomes as men after acute stroke EVT. PMID- 29628945 TI - Balloon-Assisted Cannulation for Difficult Anterior Cerebral Artery Access. AB - The anterior communicating artery is a common location for intracranial aneurysms. Compared to surgical clipping, endovascular coiling has been shown to improve outcomes for patients with ruptured aneurysms and we have seen a paradigm shift favoring this technique for treating aneurysms. Access to the anterior cerebral artery can be challenging, especially in patients with tortuous anatomy or subarachnoid hemorrhage or in patients presenting with vasospasm. We present a technique for cannulating the anterior cerebral artery using a balloon inflated in the proximal middle cerebral artery as a rebound surface. PMID- 29628946 TI - A Prospective Multicenter Trial of the TransForm Occlusion Balloon Catheter: Trial Design and Results. AB - Background and Purpose: Adjunctive treatments like balloon-assisted coil embolization (BACE) and stent-assisted coil embolization play a major role in the treatment of wide-neck and large intracranial aneurysms. The TransFormTM Occlusion Balloon Catheter (TOBC) registry is intended to evaluate the safety, efficacy, and efficiency of BACE using the TOBC. Method and Study Design: The TOBC registry is a prospective multicenter registry trial. Seven sites in the USA and 1 site in Spain participated and enrolled 81 patients. Results: The performance and safety of the TOBC was evaluated based on scoring for different variables. Scores were measured using a semiquantitative rating scale (1 = excellent, 5 = poor). The mean scores for these variables were as follows: visibility under fluoroscopy, 1.8; ability to reach the intended site, 1.6; stability during first positioning, 1.5; stability during inflation, 1.6; stability during deflation, 1.6; ability to temporarily stop flow, 1.6; and ability to assist in coil embolization, 1.7. The mean inflation and deflation times were 4.9 and 5.6 s, respectively. Complete obliteration of the aneurysm (Raymond class I) was achieved in 69.4% of the BACE cases. Thrombus formation occurred in 4/81 (4.8%) of the cases. In all cases, the thrombus resolved with medications, no patient suffered an infarction, and an underlying hypercoagulable state from subarachnoid hemorrhage was considered a contributing factor. Vessel rupture occurred in 1/81 (1.2%) of the cases, but was unrelated to TOBC use. Conclusion: BACE using the TOBC is safe and effective. All variables assessed for performance showed good-to-excellent results. PMID- 29628947 TI - Recommendations for Endovascular Care of Stroke Patients. AB - The field of neurointerventional radiology (NIR) therapy, including acute ischemic stroke intervention, endovascular intracranial aneurysm management, and treatment of intra- and extracranial large-vessel disease, has evolved over the past 18 years. To support this specialized advanced care requires nursing standards of care for staff to provide direct patient care in NIR suites and intensive management of this high-risk patient population. The intent of this paper is to provide a complementary document for the Stroke Interventional Laboratory Consensus (SILC) statement that will specifically address the nursing standards of care for patients in an NIR suite. PMID- 29628948 TI - Clinical and Imaging Outcomes of Endovascular Therapy in Patients with Acute Large Vessel Occlusion Stroke and Mild Clinical Symptoms. AB - Background: The minimal stroke severity justifying endovascular intervention remains elusive. However, a significant proportion of patients presenting with large vessel occlusion stroke (LVOS) and mild symptoms go untreated and face poor outcomes. We aimed to evaluate the clinical outcomes of patients presenting with LVOS and low symptom scores (National Institutes of Health Stroke Scale [NIHSS] score <=8) undergoing endovascular therapy (ET). Methods: We performed a retrospective analysis of a prospectively collected ET database between September 2010 and March 2016. Endovascularly treated patients with LVOS and a baseline NIHSS score <=8 were included. Baseline patient characteristics, procedural details, and outcome parameters were collected. Efficacy outcomes were the rate of good outcome (90-day modified Rankin Scale score 0-2) and of successful reperfusion (modified Treatment in Cerebral Infarction [mTICI] score 2b-3). Safety was assessed by the rate of parenchymal hematoma (parenchymal hematoma type 1 [PH-1] and parenchymal hematoma type 2 [PH-2]) and 90-day mortality. Logistic regression was used to identify predictors of good clinical outcomes. Results: A total of 935 patients were considered; 72 patients with an NIHSS score <=8 were included. Median [IQR] age was 61.5 years [56.2-73.0]; 39 patients (54%) were men. Mean (SD) baseline NIHSS score, computed tomography perfusion core volume, and ASPECTS were 6.3 (1.5), 7.5 mL (16.1), and 8.5 (1.3), respectively. Twenty-eight patients (39%) received intravenous tissue plasminogen activator. Occlusions locations were as follows: 29 (40%) proximal MCA-M1, 20 (28%) MCA-M2, 6 (8%) ICA terminus, and 9 (13%) vertebrobasilar. Tandem occlusion was documented in 7 patients (10%). Sixty-seven patients (93%) achieved successful reperfusion (mTICI score 2b-3); 52 (72%) had good 90-day outcomes. Mean final infarct volume was 32.2 +/- 59.9 mL. Parenchymal hematoma occurred in 4 patients (6%). Ninety day mortality was 10% (n = 7). Logistic regression showed that only successful reperfusion (OR 27.7, 95% CI 1.1-655.5, p = 0.04) was an independent predictor of good outcomes. Conclusion: Our findings demonstrate that ET is safe and feasible for LVOS patients presenting with mild clinical syndromes. Future controlled studies are warranted. PMID- 29628949 TI - Safety of Diagnostic Cerebral and Spinal Digital Subtraction Angiography in a Developing Country: A Single-Center Experience. AB - Background: Digital subtraction angiography (DSA) remains the gold standard imaging modality for cerebrovascular disorders. In contrast to developed countries, the safety of the procedure is not extensively reported from the developing countries. Herein, we present a retrospective analysis of the basic technique, indications, and outcomes in 286 patients undergoing diagnostic cerebral and spinal angiography in a developing country, Pakistan. Methods: A retrospective review of patient demographics, procedural technique and complication rates of 286 consecutive patients undergoing the diagnostic cerebral/spinal angiography procedure at one institution from May 2013 to December 2015 was performed. Neurological, systemic, or local complications occurring within and after 24 h of the procedure were recorded. Results: Mean age reported for all patients was 49.7 years. Of all the 286 cases, 175 were male (61.2%) and the rest female (111, 38.8%). Cerebral DSA was performed in 279 cases (97.6%), with 7 cases of spinal DSA (2.4%). Subarachnoid hemorrhage was the most common indication for DSA accounting for 88 cases (30.8%), closely followed by stroke (26.6%) and arteriosclerotic vascular disease (23.1%). No intra- or post procedural neurological complications of any severity were seen in any of the 286 cases. One case of asymptomatic aortic dissection was reported (0.3%) in the entire cohort of patient population. Conclusion: Diagnostic cerebral/spinal digital subtraction angiography was found to be safe in Pakistan, with complication rates at par with and comparable to those reported in the developed world. PMID- 29628950 TI - Safety Assessment of Endovascular Treatment of Cerebral Aneurysms in Patients with Fibromuscular Dysplasia. AB - Background: The prevalence of cerebral aneurysms is increased in fibromuscular dysplasia (FMD). The presence of FMD may serve as discouragement to elective endovascular aneurysm treatment. Outcomes of endovascular intervention for aneurysms through vessels affected by FMD have not been reported. Methods: A prospectively maintained database of patients undergoing intracranial embolization was reviewed for patients with FMD who underwent endovascular aneurysm treatment. Results: A total of 1,025 patients were screened and 31 (3.0%) had cerebrovascular FMD. These patients underwent a total of 43 embolization procedures; 27 of these procedures were performed through an affected vessel. All but 1 patient were female and the average age was 62 years. "String-of-pearls"-type FMD was the most common subtype (90%). The internal carotid arteries were more commonly affected (65%) than the vertebral arteries (48%). All patients underwent treatment of cerebral aneurysms, most of which (87%) were incidentally discovered; 6 patients (19%) also had incidental vessel dissection. The average aneurysm size was 7.1 mm. The morphology was saccular in 93% of the cases, and 86% were in the anterior circulation. The most commonly performed treatment was flow diversion (67%), in the majority of cases by pipeline embolization. Other procedures performed were coiling (19%), stent coiling (12%), and intrasaccular flow disruption (2%). All but 1 procedure (98%) were successful. There were no major complications; 1 patient experienced a transient ischemic attack. Follow-up angiography was performed in 88% of the cases, without evidence for disease progression after treatment. The average time to last angiographic follow-up was 17 months (+/-13). Conclusions: Elective embolization of intracranial aneurysms can be performed safely through vessels affected by FMD. PMID- 29628952 TI - Approximation of state variables for discrete-time stochastic genetic regulatory networks with leakage, distributed, and probabilistic measurement delays: a robust stability problem. AB - This work predominantly labels the problem of approximation of state variables for discrete-time stochastic genetic regulatory networks with leakage, distributed, and probabilistic measurement delays. Here we design a linear estimator in such a way that the absorption of mRNA and protein can be approximated via known measurement outputs. By utilizing a Lyapunov-Krasovskii functional and some stochastic analysis execution, we obtain the stability formula of the estimation error systems in the structure of linear matrix inequalities under which the estimation error dynamics is robustly exponentially stable. Further, the obtained conditions (in the form of LMIs) can be effortlessly solved by some available software packages. Moreover, the specific expression of the desired estimator is also shown in the main section. Finally, two mathematical illustrative examples are accorded to show the advantage of the proposed conceptual results. PMID- 29628951 TI - Clinical and Radiographic Predictors of Intracerebral Hemorrhage Outcome. AB - Background: Intracerebral hemorrhage (ICH) represents 10-15% of all stroke cases in the US annually. Fewer than 40% of these patients ever reach long-term functional independence, and mortality rate is roughly 40% at 1 month. Due to the high morbidity and mortality rates after ICH, early detection of high-risk patients would be beneficial in directing the management course and goals of care. This review aims to discuss relevant clinical and radiographic characteristics that can serve as predictors of poor prognosis and examine their efficacy in predicting patient outcomes after ICH. Summary: A literature review was conducted on various clinical and radiographic factors. They were examined for their predictive value in relation to ICH outcome. Studies that focused on each of these factors were included, and their results analyzed for trends with regard to incidence, patient outcome, and mortality rate. Key Message: In this review, we examined clinical and radiographic characteristics that have been found to be significantly associated to a varying degree with poor outcome. Clinical and radiographic predictors of poor patient outcome are invaluable when it comes to identifying high-risk patients and triaging accordingly as well as guiding decision-making. PMID- 29628953 TI - Internet Usage among Pregnant Women for Seeking Health Information: A Review Article. AB - Background: In recent years, the Internet has become one of the most popular sources of health information for users, and pregnant women are no exception. This study aimed to investigate Internet usage among pregnant women for achieving health information on the finding of related studies. Materials and Methods: This review study was conducted by searching databases such as IranMedex, Magiran, Scientific Information Database, Irandoc, PubMed, Science Direct, Cochrane, Google Scholar, and Scopus in December 2016. Restrictions were placed on publication to within 16 years and language of publication was restricted to English and Persian. Keywords used in the search included information-seeking behavior, information-seeking, information needs, access to information, pregnancy, and pregnant women. Results: This search resulted in 106 related publications and among them sixteen articles met inclusion criteria. This review showed that the use of the Internet by pregnant women was driven by information needs, ease, and speed of access and finding people with the same situation. Fetal development, symptoms, and complications of pregnancy, prenatal tests and nutrition, activities during pregnancy, and stages of delivery were the most often mentioned topics of interest. The benefits of internet use include reduced anxiety, personal support, creating an emotional connection and an increased confidence. Conclusions: Health providers must have sufficient ability for interpreting the achieved information from the Internet and should allocate efficient amount of time for discussing information-seeking manners with pregnant women. Furthermore, they must try to respond to the doubts of pregnant women and provide valid and reliable online educational resources. PMID- 29628954 TI - The Effect of Acupressure at Spleen 6 Acupuncture Point on the Anxiety Level and Sedative and Analgesics Consumption of Women during Labor: A Randomized, Single blind Clinical Trial. AB - Background: Labor pain is the most severe pain women would experience, which could lead to loss of emotional control that plays a key role in creating a traumatic delivery experience and psychological disorders. The goal of this study was to evaluate the effect of acupressure on anxiety level and sedative and analgesics consumption in women during labor. Materials and Methods: This study was a randomized, single-blind clinical trial performed at Maryam Hospital in Tehran, Iran. One hundred and thirty-one pregnant women in Labor Ward were selected by convenience sampling. Subjects were randomly allocated to three groups, namely experimental group (pressure group), control group 1(touh group) and, control group 2 (routine care group). The study data were gathered using demographic information form, and assessed with Faces Anxiety Scale (FAS). For participants belonging to the experimental group, pressure was applied to the Spleen 6 acupoint for 30 min, and for those with only light touch was applied to the Spleen 6 acupoint for 30 min. The collected data were analyzed using Statistical Package for the Social Sciences 16 and descriptive statistics. Results: There was a significant difference between the three groups in terms of the mean of anxiety after 30 min of starting the intervention and 30 min after termination of the intervention; the anxiety of the experimental group was significantly decreased (p = 0.03). Sedative and analgesics consumption was significantly lower in the experimental group compared to the other groups (p = 0.006). Conclusions: This study showed that compression of the Spleen 6 acupoint was an effective complementary method to decrease maternal anxiety and analgesic consumption, especially pethidine. PMID- 29628955 TI - The Effects of Mental Health Training Program on Stress, Anxiety, and Depression during Pregnancy. AB - Background: The process of becoming a mother is considered as an enjoyable and evolutionary event of women's life. However, due to physical and mental changes, it can be associated with some degree of stress and anxiety that may lead to mental health problems. This study aimed to compare the effects of mental health training during pregnancy on stress, anxiety, and depression between two groups of couples and pregnant women. Materials and Methods: This randomized clinical trial was conducted on 120 pregnant women referring to health centers in Isfahan, Iran, from September to February 2016. The participants were randomly divided into three groups: couples (with the partner present), pregnant women (without the partner present), and control group (routine care). After completing the pretest, the intervention groups received four sessions of pregnancy mental health training. Data were collected using the Depression, Anxiety, and Stress Scales (DASS-42) and a demographic characteristics form. The collected data were analyzed using Statistical Package for the Social Sciences software. Results: Before the intervention, no statistical difference was observed among the three groups in the mean scores of stress, anxiety, and depression. The mean score of depression, anxiety, and stress decreased significantly in the intervention groups 2 weeks after the intervention respectively (F=5.84, p=0.004), (F=14.76, p < 0.001) and (F=11.98, p < 0.001). No significant difference was observed between the couples and pregnant women groups in terms of depression (p = 0.140). Conclusions: The results of this study showed that mental health training for pregnant women, especially with the presence of the partner, is a useful intervention in preventing stress, anxiety, and depression. PMID- 29628956 TI - Postgraduate Nursing Students' Expectations of their Supervisors in Iran: A Qualitative Study. AB - Background: Exploring the expectations of postgraduate nursing students from their supervisors is required in order to meet the expectations, raise the general students' satisfaction, and enhance the students' capabilities to the highest degree possible. The present study was conducted to explore the expectations of postgraduate nursing students from their supervisors. Materials and Methods: This qualitative study was done through semi-structured individual interviews with seven PhD students and 14 master's students in two focus groups from three universities in Tehran, Iran. The data were analyzed using the inductive approach and through conventional content analysis. Results: The analysis of the data led to the extraction of five categories (support for the students, good communication skills, professional competence, guiding the students, and professionalism) within 12 subcategories. Conclusions: The results revealed that postgraduate students expect their supervisors not only to guide and support them in education and research but also have good communication skills, be professional, and value professionalism. Therefore, supervisors should try to meet these expectations and offer practical strategies for better realization of their needs. PMID- 29628957 TI - Hardiness and Optimism in Women with Breast Cancer. AB - Background: Hardiness and optimism are two general health promoting factors, which enable the individuals to remain both psychologically and physically healthy despite encountering negative life events. But there is lack of knowledge about the current state of these constructs and their relationship in breast cancer patients in an Iranian context. Materials and Methods: This was a descriptive study which was completed in Sayyed-AL-Shohda Hospital affiliated to Isfahan University of Medical Sciences, Iran, in 2015. Two hundred and ten women with breast cancer were conveniently selected to complete the personal/demographic/illness questionnaire, Hardiness Scale, and Life Orientation Test. Data were analyzed by t-test, analysis of variance, and Pearson correlation with a significance level of p < 0.05. Results: The mean (SD) age and duration of illness were 46.73 (10.12) years and 29.48 (19.70) months, respectively. Most patients were married (86.23%), without university education (92.61%) and unemployed (85.69%). Most patients received chemotherapy as their main treatment (39.43%). Also, 61.42 and 58.10% of patients had high hardiness and optimism, respectively. There was a significant positive correlation between the score of hardiness and optimism (r = 0.22, p <= 0.01). Conclusions: The results showed that most of the breast cancer patients had moderate to high hardiness and optimism, so healthcare providers can use these personality properties in their care planning to improve coping strategies. Also, the findings of this study can assist healthcare team in order to pay more attention to coping strategies in cancer patients during their treatment and also considering the relationship of these issues in their evaluations. PMID- 29628958 TI - Neonatal Intensive Care Nursing Curriculum Challenges based on Context, Input, Process, and Product Evaluation Model: A Qualitative Study. AB - Background: Weakness of curriculum development in nursing education results in lack of professional skills in graduates. This study was done on master's students in nursing to evaluate challenges of neonatal intensive care nursing curriculum based on context, input, process, and product (CIPP) evaluation model. Materials and Methods: This study was conducted with qualitative approach, which was completed according to the CIPP evaluation model. The study was conducted from May 2014 to April 2015. The research community included neonatal intensive care nursing master's students, the graduates, faculty members, neonatologists, nurses working in neonatal intensive care unit (NICU), and mothers of infants who were hospitalized in such wards. Purposeful sampling was applied. Results: The data analysis showed that there were two main categories: "inappropriate infrastructure" and "unknown duties," which influenced the context formation of NICU master's curriculum. The input was formed by five categories, including "biomedical approach," "incomprehensive curriculum," "lack of professional NICU nursing mentors," "inappropriate admission process of NICU students," and "lack of NICU skill labs." Three categories were extracted in the process, including "more emphasize on theoretical education," "the overlap of credits with each other and the inconsistency among the mentors," and "ineffective assessment." Finally, five categories were extracted in the product, including "preferring routine work instead of professional job," "tendency to leave the job," "clinical incompetency of graduates," "the conflict between graduates and nursing staff expectations," and "dissatisfaction of graduates." Conclusions: Some changes are needed in NICU master's curriculum by considering the nursing experts' comments and evaluating the consequences of such program by them. PMID- 29628959 TI - A Survey of Nurses' Compliance with Hand Hygiene Guidelines in Caring for Patients with Cancer in a Selected Center of Isfahan, Iran, in 2016. AB - Background: Hand hygiene is one of the key ways of preventing healthcare associated infections (HCAI), especially in patients with cancer. The aim of this study was to determine nurses' compliance with hand hygiene guidelines in caring for patients with cancer in a selected center in Isfahan, Iran, in 2016. Materials and Methods: The present observational study was conducted on nurses in a cancer center in Isfahan in 2016. The participants were selected via convenience sampling method. Nurses serving at bedsides and willing to participate were entered into the study. Data were collected through the direct observation of nurses during delivering routine care, using the standard checklist for direct observation of the "five moments for hand hygiene" approach. Results: In the present study, 94 nurses were studied at 500 clinical moments. The overall hand hygiene compliance rate was 12.80%. The highest hand hygiene compliance rate was observed in the after body fluid exposure moment (72.70%). In addition, hand hygiene compliance rate in preprocedure indications (before patient contact and before aseptic procedure) and postprocedure indications (after patient contact, after body fluid exposure, and after patient surrounding contact) were 3.40 and 21%, respectively, which had a significant correlation (p = 0.001). Conclusions: The findings indicate that the hand hygiene compliance rate among nurses was low. Further research in this regard is recommended in order to find the causes of low compliance with hand hygiene and design interventions for improvement in hand hygiene compliance rate among nurses. PMID- 29628960 TI - Relationship of Social Cognitive Theory Concepts to Dietary Habits of Pregnant Women. AB - Background: Nutrition during pregnancy is undoubtedly one of the most important factors affecting maternal health. In this regard, considering the cognitive behavioral factors associated with feeding, behaviors will play an important role in the effectiveness of interventions. Therefore, this study aimed to investigate the correlation between food habits and structures of social cognitive theory in pregnant women. Materials and Methods: In this cross-sectional study, 192 pregnant women were randomly selected. Data were collected using a questionnaire based on the social cognitive theory structures and food habits questionnaire in the questioning manner and was also analyzed using Pearson correlation and multiple linear regression with the software Statistical Package for the Social Sciences, version 19. Results: There was a significant correlation between nutritional behavior with self-regulation (p = 0.001), self-efficacy (p = 0.001), outcome expectations (p = 0.001), social support (p = 0.002), and access (p = 0.001). A significant correlation was observed between lack of consumption of unnecessary and unhelpful food with self-regulation (p = 0.02). In the multivariable regression analysis, only self-regulation revealed significant and direct contribution in relation to nutritional behavior (p < 0.001). Conclusions: Results of this study showed that self-regulation is one of the important factors associated with feeding behavior in pregnant women so that it is suggested to be considered in nutritional interventions in order to improve nutritional behavior. PMID- 29628961 TI - Comparison of the Relationship between Women' Empowerment and Fertility between Single-child and Multi-child Families. AB - Background: The reduction in fertility and increase in the number of single-child families in Iran will result in an increased risk of population aging. One of the factors affecting fertility is women's empowerment. This study aimed to evaluate the relationship between women's empowerment and fertility in single-child and multi-child families. Materials and Methods: This case-control study was conducted among 350 women (120 who had only 1 child as case group and 230 who had 2 or more children as control group) of 15-49 years of age in Isfahan, Iran, in 2016. For data collection, a 2-part questionnaire was designed. Data were analyzed using independent t-test, Chi-square test, and logistic regression analysis. Results: The difference between average scores of women's empowerment in the case group 54.08 (9.88) and control group 51.47 (8.57) was significant (p = 0.002). Simple logistic regression analysis showed that under diploma education, compared to postgraduate education, (OR = 0.21, p = 0.001) and being a housewife, compared to being employed, (OR = 0.45, p = 0.004) decreased the odds of having only 1 child. Multiple logistic regression results showed that the relationship between women's empowerment and fertility was not significant (p = 0.265). Conclusions: Although women in single-child families were more empowered, this was not the main reason for their preference to have only 1 child. In fact, educated and employed women postpone marriage and childbearing and limit fertility to only 1 child despite their desire. PMID- 29628962 TI - Iranian Nursing Student-patient Health Communication in Medical Surgical Wards. AB - Background: Health communication (HC) is considered an important task of nurses to provide high quality and holistic care as well as to improve patient health. The nursing student-patient HC is an abstract concept and needs to be clarified. Therefore, this study was conducted to increase the knowledge about nursing students' HC with patients by considering various participants' viewpoints. Materials and Methods: In this conventional qualitative content analysis, 18 semi structured interviews were conducted with six nursing students, six nursing instructors, and six patients in educational hospitals affiliated to the University of Medical Sciences. Credibility, confirmability, dependability, and transferability were established to validate the trustworthiness of the data. The process of data collection and analysis lasted 9 months. Results: After data analysis, two categories were generated: (A) "junior nursing student-patient communication," with two subcategories of "performing social communication with patients" and "failure to build therapeutic relationships with patients," and (B) "senior nursing student-patient communication" with two subcategories of "establishing effective communication with patients" and "performing one-way communication with patients." Conclusions: More attention should be paid to improve HC through shifting towards student-centered approaches in nursing curriculum. Further, role model nurses and clinical educators should guide nursing students for institutionalizing HC in future nurses. PMID- 29628963 TI - The Effect of Acupressure on Physiological Parameters of Myocardial Infarction Patients: A Randomized Clinical Trial. AB - Background: Myocardial infarction is a major complication of coronary heart disease, and due to high mortality, is a part of important medical emergencies. Today, complementary and alternative medicine, as nonpharmacological and health promotion methods is considered. Therefore, this study was designed to evaluate the effectiveness of acupressure on physiological parameters of patients with myocardial infarction. Materials and Methods: This clinical trial was carried out among two groups and three stages in 2015. Study participants included 64 patients hospitalized in Iran, Isfahan Shahid Chamran hospital. Acupressure in five points and at any point for 2 minutes, twice per day for 3 days was done in the experimental group and as the same at a false point for the control group. Physiological parameters were recorded before, immediately, and 30 minutes after intervention. Data were analyzed using SPSS 20 and independent t-tests, Chi square, Mann-Whitney test, repeated-measurements analysis of variance. Results: Independent t-test immediately and 30 minutes after the intervention showed that mean systolic blood pressure and arterial oxygen saturation in the intervention group were significantly lower and higher than the control group, respectively; however, mean diastolic blood pressure and heart rate were not significantly different. However, 30 minutes after intervention, diastolic blood pressure and heart rate were significantly lower in the intervention group. Conclusions: Acupressure in five points of body had a positive effect on physiological parameters, and showed that after a short time of interventions these parameters lead to promotion over time. PMID- 29628964 TI - Exploring the Needs of Family Caregivers of Children with Attention Deficit Hyperactivity Disorder: A Qualitative Study. AB - Background: Attention deficit hyperactivity disorder (ADHD) is one of the most common chronic childhood disorders that lead to dysfunction and disability in childhood and subsequently be careful. This study aimed to understand the needs of the children's caregivers in Iran. Materials and Methods: This qualitative research was conducted in 2016. Using purposive sampling, 27 participants from 20 families of children with ADHD were interviewed. Unstructured interviews were conducted within 6 months in Isfahan. Data gathering continued until no new data were accessed. Data were analyzed using qualitative content analysis. Results: The results of this research are shown in three main categories: (1) The caregiver's need for having sufficient information about the disorder, its cause and treatments (pharmacological and nonpharmacological); (2) the need to have enough knowledge about communication problems while caring for a sick child; and (3) the need to improve the performance of care. They were classified under the relevant concept. Conclusions: Caregivers of children with ADHD have different needs and problems and assessing them would decrease the child's problems and consequently, the family's problems. It would also increase the sense of control and authority over the child's condition in the caregivers. Since this disorder is chronic and permanent, ignoring the needs of caregivers not only would cut the process of the child's treatment but would also intensify the family's and child's problems. So it is recommended to conduct further studies about each of the resulted concepts in this study and the obstacles for reaching them. PMID- 29628965 TI - Improving and Expanding the Quality of Emergency Obstetric and Newborn Care Services in Rural Areas of Cambodia. PMID- 29628966 TI - Comparison of postnatal catch-up growth according to definitions of small for gestational age infants. AB - Purpose: Small for gestational age (SGA) is confusingly defined as birth weight (BW) either below 3rd percentile or 10th percentile for infants. This study aimed to compare postnatal catch-up growth between SGA groups according to different definitions. Methods: Data of 129 infants born with BW below the 10th percentile and admitted to Korea University Anam Hospital and Ansan Hospital were retrospectively reviewed. Height and weight were measured at 6, 12, and 24 months. Results were compared between group A (BW: <3rd percentile) and group B (BW: 3rd-10th percentile). Results: Group A included 66 infants and group B included 63. At age 6 months (n=122), 62.9% of group A and 71.7% (P=0.303) of group B showed catch-up growth in weight. At 6 months (n=69), 55.9% of group A and 80.0% of group B (P<0.05) showed catch-up growth in height. At 12 months (n=106), 58.5% of group A, and 75.5% (P=0.062) of group B showed catch-up growth in weight. At 12 months (n=75), 52.8% of group A and 64.1% of group B (P=0.320) showed catch-up growth in height. Up to age 24 months, 66.7%/80.0% in group A and 63.6%/80.0% in group B showed catch-up growth in weight/height. Conclusion: Despite different definitions, there were no significant differences between the two SGA groups in postnatal catch-up growth up to age 24 months, except for height at 6 months. Compared to infants with appropriate catch-up growth, low gestational age and BW were risk factors for failed catch-up growth at 6 months. PMID- 29628967 TI - Augmentation of respiratory muscle activities in preterm infants with feeding desaturation. AB - Purpose: Frequent desaturation due to immature incoordination of suck-swallow breathing in preterm infants can influence multiple organs such as the heart, lungs, and brain, which can then affect growth and development. Most notably in preterm infants, feeding desaturation may even affect pulmonary function during gavage feeding. Because respiratory muscle activities may reflect the work required during respiration, we evaluated the differences in these activities between full-term and preterm infants with feeding desaturation, and investigated the correlations with clinical variables. Methods: Nineteen preterm infants with feeding desaturation (group 1) and 19 age-matched full-term infants (group 2) were evaluated. Oromotor function was evaluated using video recording. The root mean-squre (RMS) envelope of the electromyography signal was calculated to quantify the activities of muscles involved in respiration. The differences in RMS between both groups and the correlation with clinical variables including gestational age (GA), birth weight (BW), and Apgar scores (AS) at 1 and 5 minutes after birth were evaluated. Results: The RMS values of the diaphragm (RMS-D) and rectus abdominis (RMS-R) were significantly greater in group 1 compared to group 2, and the 1- and 5-min AS were significantly lower in group 1 compared to group 2. RMS-D and RMS-R were inversely correlated with GA, BW, 1- and 5-min AS in all infants. Conclusion: This study showed that respiratory muscle activities were augmented during feeding in preterm infants compared to full-term infants. Additionally, respiratory muscle activities were inversely correlated with all clinical variables. PMID- 29628969 TI - Association between vitamin D and urinary tract infection in children. AB - Purpose: The present study aimed to determine the relationship between serum 25 hydroxyvitamin D (25(OH)D) level and Urinary tract infections (UTIs) in children. Methods: In this case-control study, 70 children with UTI (case group) were compared with 70 healthy children (control group) in terms of serum 25(OH)D levels. The children were between 1 month and 12 years of age. Serum 25(OH)D levels were measured using enzyme-linked immunosorbent assay (ELISA). The results were analyzed and compared between both groups. Results: Among 70 children with UTI (case group), 5 children (7.2%) were male and 65 (92.8%) were female. Among the healthy children (control group), 9 (12.8%) and 61 children (87.2%) were male and female, respectively (P=0.39). The mean+/-standard deviation of age in the case and control groups were 53.2+/-35.6 and 36.1+/-60.2 months, respectively (P=0.24). The mean level of serum 25(OH)D in the case group was significantly higher than that of the control group (20.4+/-8.6 ng/mL vs. 16.9+/-7.4 ng/mL, P=0.01). Conclusion: This study showed that there was a relationship between serum 25(OH)D levels and UTI in children. It seems that 25(OH)D plays a role in the pathogenesis of UTI. PMID- 29628968 TI - Clinical manifestation of Campylobacter enteritis in children. AB - Purpose: Timely antibiotic therapy in selected cases of diarrhea associated with bacterial infections can reduce the duration and severity of illness and prevent complications. The availability of a predictive index before identification of causative bacteria would aid in the choice of a therapeutic agent. Methods: The study included patients admitted to the pediatrics unit at Konyang University Hospital for acute inflammatory diarrhea from August 1, 2015 to July 31, 2016 who underwent multiplex polymerase chain reaction testing. Of 248 patients, 83 had positive results. The clinical symptoms and blood test results were examined in 61 patients with Campylobacter spp. (25 patients), Salmonella spp. (18 patients), and Clostridium perfringens (18 patients) infections. The mean age of the 61 patients (male:femal=31:30) was 84.0+/-54.8 months, and the mean hospital stay was 4.6+/-1.7 days. Results: There were no statistical differences in sex, age, clinical symptoms, or signs. Patients with Campylobacter infection were significantly older (P=0.00). C-reactive protein (CRP) levels in patients with Campylobacter infection were higher than those in the other 2 groups, at 9.6+/ 6.1 mg/dL. The results of receiver-operating characteristic curve analysis showed that the cutoff age was >=103.5 months (sensitivity, 72%; specificity, 86%) and the CRP cutoff level was >=4.55 mg/dL (sensitivity, 80%; specificity, 69%). Conclusion: Age (>=103.5 months) and higher CRP level (>=4.55 mg/dL) were good predictors of Campylobacter enterocolitis. If neither criterion was met, Campylobacter enterocolitis was unlikely (negative predictive value 97.2%). When both criteria were met, Campylobacter enterocolitis was highly likely. PMID- 29628970 TI - Acute kidney injury in pediatric patients with rhabdomyolysis. AB - Purpose: This study aimed to evaluate the clinical findings in pediatric rhabdomyolysis and the predictive factors for acute kidney injury (AKI) in Korean children. Methods: Medical records of 39 Korean children, who were newly diagnosed with rhabdomyolysis from January 2008 to December 2015, were retrospectively analyzed. The diagnosis was made from the medical history, elevated serum creatinine kinase level >1,000 IU/L, and plasma myoglobin level >150 ng/mL. Patients with muscular dystrophy and myocardial infarction were excluded. Results: The median patient age at diagnosis was 14.0 years (range, 3 18 years), and the male to female ratio was 2.5. The most common presenting symptom was myalgia (n=25, 64.1%), and 14 patients (35.9%) had rhabdomyolysis induced AKI. Eighteen patients (46.2%) had underlying diseases, such as epilepsy and psychotic disorders. Ten of these patients showed rhabdomyolysis-induced AKI. The common causes of rhabdomyolysis were infection (n=12, 30.7%), exercise (n=9, 23.1%), and trauma (n=8, 20.5%). There was no difference in the distribution of etiology between AKI and non-AKI groups. Five patients in the AKI group showed complete recovery of renal function after stopping renal replacement therapy. The median length of hospitalization was 7.0 days, and no mortality was reported. Compared with the non-AKI group, the AKI group showed higher levels of peak creatinine kinase and myoglobin, without statistical significance. Conclusion: The clinical characteristics of pediatric rhabdomyolysis differ from those observed in adult patients. Children with underlying diseases are more vulnerable to rhabdomyolysis-induced AKI. AKI more likely develops in the presence of a high degree of albuminuria. PMID- 29628971 TI - Establishment of a chronic obstructive pulmonary disease mouse model based on the elapsed time after LPS intranasal instillation. AB - Chronic obstructive pulmonary disease (COPD) was the 3rd leading cause of death in 2012 worldwide. It is particularly severe in the elderly, who are at risk of death by coughing, mucous hypersecretion, and finally breathlessness. Recently, anti-COPD drug development has increased, and many animal screening systems have been studied. Tobacco smoke animal models are the best known animal screening system, but have several preparation requirements, such as a tobacco smoke generator and a separate facility to prevent smoke release. Accordingly, we evaluated the properties of a lipopolysaccharide (LPS) murine model for COPD screening and the effect of the time elapsed from 0 to 72 hr after LPS intranasal instillation on various biomarkers of COPD severity, such as WBC and neutrophils in bronchoalveolar fluid (BALF), IgE in serum, histopathology in the lung, and cytokines (IL-8, TNF-alpha, IFN-gamma, and TGF-beta) and chemokines (CCL-2, CXCL1, CXCL9, CXCL10, and CXCL11) in the respiratory system. Although from 48 hr after LPS treatment several factors which could be evaluated as biomarkers for COPD establishment such as WBC and neutrophil in BALF, IgE in serum, cytokines (IL-8, TNF-alpha, and IFN-gamma), and chemokines (CCL-2, CXCL1, CXCL9, CXCL10, and CXCL11) increased at 72 hr the increment of important factors for COPD establishment such as IgE, fibrosis in the lung, and cytokines (IL-8, TNF-alpha, and IFN-gamma) was more clear. Based on our results, we concluded that the optimal time after LPS intranasal instillation is 72 hr. PMID- 29628972 TI - Ensuring reproducibility and ethics in animal experiments reporting in Korea using the ARRIVE guideline. AB - The aim of this study is to evaluate the reporting quality of animal experiments in Korea using the Animals in Research: Reporting In Vivo Experiments (ARRIVE) guideline developed in 2010 to overcome the reproducibility problem and to encourage compliance with replacement, refinement and reduction of animals in research (3R's principle). We reviewed 50 papers published by a Korean research group from 2013 to 2016 and scored the conformity with the 20-items ARRIVE guideline. The median conformity score was 39.50%. For more precise evaluation, the 20 items were subdivided into 57 sub-items. Among the sub-items, status of experimental animals, housing and husbandry were described under the average level. Microenvironment sub-items, such as enrichment, bedding material, cage type, number of companions, scored under 10%. Although statistical methods used for the studies were given in most publications (84%), sample size calculation and statistical assumption were rarely described. Most publications mentioned the IACUC approval, but only 8% mentioned welfare-related assessments and interventions, and only 4% mentioned any implications of experimental methods or findings for 3R. We may recommend the revision of the present IACUC proposal to collect more detailed information and improving educational program for animal researchers according to the ARRIVE guideline. PMID- 29628973 TI - Higher incidence of sperm granuloma in the epididymis of C57BL/6N mice. AB - C57BL/6N mice are inbred strains widely used in biomedical research. Hence, a large amount of basic data has been accumulated. However, in the field of histopathology, spontaneous data for relatively younger mice that are used more frequently are not yet abundant, in contrast to data for older mice and their neoplastic lesions. To acquire the essential background data required by various research and toxicological assessments, 120 mice of the C57BL/6N strain (10 and 13 weeks of age) were collected from two institutions (From Korea and Japan) and subjected to histopathological analyses of the major organs (liver, spleen, kidney, thymus, heart, testis, epididymis). The results showed significantly higher incidence of sperm granulomas in the epididymides (10-56%) of these mice, compared with that in other strains or species of lab animals. Upon closer inspection, oligospermia/clear cell hyperplasia, cellular debris, and tubular vacuolation were also observed in the epididymides with sperm granulomas. Moreover, diseased organs were significantly heavier than healthy ones. Immunohistochemical staining showed a significant increase in the chromatic figures of cysteine-dependent aspartate-directed proteases-3 (caspase-3) and cleaved-poly(ADP-ribose) polymerase (c-PARP), and damages to the tubule due to spontaneous apoptosis, which may have led to the sperms leaking out of the tubule, causing the granuloma. To conclude, spontaneous sperm granuloma can occur in 10- and 13-week-old C57BL/6N mice and may thus affect the results of various studies using these mice. Therefore, sperm granuloma in epididymis needs to be carefully considered as an important factor when design the study using C57BL/6N. PMID- 29628974 TI - The effect of near-infrared fluorescence conjugation on the anti-cancer potential of cetuximab. AB - This study investigated the anti-cancer potential of a near-infrared fluorescence (NIRF) molecule conjugated with Cetuximab (Cetuximab-NIRF) in six-week-old female BALB/c athymic (nu+/nu+) nude mice. A431 cells were cultured and injected into the animals to induce solid tumors. Paclitaxel (30 mg/kg body weight (BW)), Cetuximab (1 mg/kg BW), and Cetuximab-NIRF (0.25, 0.5 and 1.0 mg/kg BW) were intraperitoneally injected twice a week into the A431 cell xenografts of the nude mice. Changes in BW, tumor volume and weight, fat and lean mass, and diameter of the peri-tumoral blood vessel were determined after two weeks. Tumor volumes and weights were significantly decreased in the Cetuximab-NIRF (1 mg/kg BW) group compared with the control group (P<0.001). Lean mass and total body water content were also conspicuously reduced in the Cetuximab-NIRF (1 mg/kg BW) group compared with the vehicle control group. Peri-tumoral blood vessel diameters were very thin in the Cetuximab-NIRF groups compared with those of the paclitaxel group. These results indicate that the conjugation of Cetuximab with NIRF does not affect the anti-cancer potential of Cetuximab and NIRF can be used for molecular imaging in cancer treatments. PMID- 29628975 TI - Protective effects of cultured and fermented ginseng extracts against scopolamine induced memory loss in a mouse model. AB - This study was performed to investigate the effect of a concentrate of fermented wild ginseng root culture (HLJG0701) on memory improvement in the scopolamine (SPL)-induced memory-deficient mouse model. Eight-week-old male ICR mice were used to evaluate the protective effect of HLJG0701 against the SPL-induced memory loss animal model. The Morris water maze test, which measures hippocampus dependent learning ability, and the Y-maze test, a short-term memory assessment test, were performed and related markers were analyzed. HLJG0701-treated groups displayed significantly reduced acetylcholinesterase activity and increased acetylcholine level compared with the SPL-administered group (SPL-G) (P<0.05). In the Y-maze test, the spontaneous alternation in al HLJG0711-treated groups was significantly increased compared with that in SPL-G (P<0.05). In the Morris water maze test, the escape latency and time spent in the target quadrant in all HLJG0701-treated groups were significantly decreased and increased, respectively, compared with those in SPL-G (P<0.05). In addition, the brain-derived neurotrophic factor level in groups treated with HLJG0701 300 and 600 mg/kg body weight was significantly increased compared with that in SPL-G (P<0.05). These results suggest that the HLJG0701 may protect against memory loss by inhibiting acetylcholinesterase activity and preventing acetylcholine deficiency. PMID- 29628976 TI - Anti-coccidial activity of the ethanol extract of Tribulus terrestris fruits on Eimeria tenella. AB - Anti-coccidial effects of the fruits of Tribulus terrestris (Tribuli fructus) ethanol extract (TTE) were studied with animal experiment following per oral administration with Eimeria (E.) tenella. This experiment was performed on the 3 day-old chicks (n=30). The animals were divided with 3 groups; TFE 15mg per animal+infected (n=10), TTE untreated+infected (n=10) and non-infected control (n=10). Animals were administrated with or without TTE during 1 week, and then inoculated with E. tenella. The anti-coccidial activity were evaluated with oocysts shedding numbers in stools, body weights changes and food intake changes. The TTE-inoclated animals revealed significantly decreased stool oocysts numbers (P<0.05) when compared to the TTE untreated animals. Also, TTE-treated animals showed more increased body weight gains (P<0.05) than the TTE untreated animals. These results demonstrate that TTE produce anticoccidial activities against E. tenella. TTE could be a promising treatment for the coccidiosis. PMID- 29628977 TI - Erratum: Blood flow-improving activity of methyl jasmonate-treated adventitious roots of mountain ginseng. AB - [This corrects the article on p. 105 in vol. 33, PMID: 28747975.]. PMID- 29628978 TI - Basic Findings Regarding Breast Cancer in Korea in 2015: Data from a Breast Cancer Registry. AB - The Korean Breast Cancer Society (KBCS) has established a nationwide breast cancer database using an online registration program in 1996. The present study aimed to analyze the basic findings and trends of breast cancer in Korea in 2015 using the data provided by the Korea Central Cancer Registry and the KBCS. In 2015, a total of 22,550 patients were newly diagnosed with breast cancer, of which 3,331 were carcinoma in situ cases and 19,219 were invasive cancer cases. The incidence rate of breast cancer in Korea has steadily increased since the nationwide database was established, and the crude rate and age-standardized rate including that of carcinoma in situ, were 88.1 and 66.0 cases per 100,000 women, respectively. In terms of age, the incidence of breast cancer was the highest in the 40-49-year-old age group (7,889 patients, 35.0%). With regard to surgical procedure, breast-conserving surgery was frequently performed (62.3%). However, the rate of mastectomy has been gradually increasing since 2012, that is, from 32.3% in 2014 to 36.1% in 2015. The rate of early breast cancer has continued to increase, and that of stages III and IV breast cancer was only 9.1% at the time of diagnosis. However, the 5-year survival rate of patients with carcinoma in situ from 2011 to 2015 was 92.3%, which was 14.4% higher than that from 1993 to 1995 (77.9%). Analysis of data from the nationwide registry of breast cancer will not only help to understand the characteristics of breast cancer in individuals in Korea, but will also significantly contribute to the treatment and research of breast cancer. Therefore, a high quality database for breast cancer in Korea must be established by further initiating registration project and establishing an objective legal basis. PMID- 29628979 TI - Isomangiferin, a Novel Potent Vascular Endothelial Growth Factor Receptor 2 Kinase Inhibitor, Suppresses Breast Cancer Growth, Metastasis and Angiogenesis. AB - Purpose: Vascular endothelial growth factor (VEGF) signal transduction mainly depends on its binding to VEGF receptor 2 (VEGFR-2). VEGF downstream signaling proteins mediate several of its effects in cancer progression, including those on tumor growth, metastasis, and blood vessel formation. The activation of VEGFR-2 signaling is a hallmark of and is considered a therapeutic target for breast cancer. Here, we report a study of the regulation of the VEGFR-2 signaling pathway by a small molecule, isomangiferin. Methods: A human breast cancer xenograft mouse model was used to investigate the efficacy of isomangiferin in vivo. The inhibitory effect of isomangiferin on breast cancer cells and the underlying mechanism were examined in vitro. Results: Isomangiferin suppressed tumor growth in xenografts. In vitro, isomangiferin treatment inhibited cancer cell proliferation, migration, invasion, and adhesion. The effect of isomangiferin on breast cancer growth was well coordinated with its suppression of angiogenesis. A rat aortic ring assay revealed that isomangiferin significantly inhibited blood vessel formation during VEGF-induced microvessel sprouting. Furthermore, isomangiferin treatment inhibited VEGF-induced proliferation of human umbilical vein endothelial cells and the formation of capillary-like structures. Mechanistically, isomangiferin induced caspase dependent apoptosis of breast cancer cells. Furthermore, VEGF-induced activation of the VEGFR-2 kinase pathway was down-regulated by isomangiferin. Conclusion: Our findings demonstrate that isomangiferin exerts anti-breast cancer effects via the functional inhibition of VEGFR-2. Pharmaceutically targeting VEGFR-2 by isomangiferin could be an effective therapeutic strategy for breast cancer. PMID- 29628980 TI - Berberine Suppresses Fibronectin Expression through Inhibition of c-Jun Phosphorylation in Breast Cancer Cells. AB - Purpose: The exact mechanism regulating fibronectin (FN) expression in breast cancer cells has not been fully elucidated. In this study, we investigated the pharmacological mechanism of berberine (BBR) with respect to FN expression in triple-negative breast cancer (TNBC) cells. Methods: The clinical significance of FN mRNA expression was analyzed using the Kaplan-Meier plotter database (http://kmplot.com/breast). FN mRNA and protein expression levels were analyzed by real-time polymerase chain reaction and western blotting, respectively. Results: Using publicly available clinical data, we observed that high FN expression was associated with poor prognosis in patients with breast cancer. FN mRNA and protein expression was increased in TNBC cells compared with non-TNBC cells. As expected, recombinant human FN significantly induced cell spreading and adhesion in MDA-MB231 TNBC cells. We also investigated the regulatory mechanism underlying FN expression. Basal levels of FN mRNA and protein expression were downregulated by a specific activator protein-1 (AP-1) inhibitor, SR11302. Interestingly, FN expression in TNBC cells was dose-dependently decreased by BBR treatment. The level of c-Jun phosphorylation was also decreased by BBR treatment. Conclusion: Our findings demonstrate that FN expression is regulated via an AP-1-dependent mechanism, and that BBR suppresses FN expression in TNBC cells through inhibition of AP-1 activity. PMID- 29628981 TI - Troglitazone Inhibits Matrix Metalloproteinase-9 Expression and Invasion of Breast Cancer Cell through a Peroxisome Proliferator-Activated Receptor gamma Dependent Mechanism. AB - Purpose: Peroxisome proliferator-activated receptor gamma (PPARgamma) is involved in the pathology of numerous diseases including atherosclerosis, diabetes, obesity, and cancer. Matrix metalloproteinases (MMPs) play a significant role in tissue remodeling related to various processes such as morphogenesis, angiogenesis, tissue repair, invasion, and metastasis. We investigated the effects of PPARgamma on MMP expression and invasion in breast cancer cells. Methods: MCF-7 cells were cultured and then cell viability was monitored in an MTT assay. Western blotting, gelatin zymography, real-time polymerase chain reaction, and luciferase assays were performed to investigate the effect of the synthetic PPARgamma ligand troglitazone on MMP expression. Transcription factor DNA binding was analyzed by electrophoretic mobility shift assay. A Matrigel invasion assay was used to assess the effects of troglitazone on MCF-7 cells. Results: Troglitazone did not affect MCF-7 cell viability. 12-O tetradecanoylphorbol-13-acetate (TPA) induced MMP-9 expression and invasion in MCF-7 cell. However, these effects were decreased by troglitazone. TPA increased nuclear factor kappaB and activator protein-1 DNA binding, while troglitazone inhibited these effects. The selective PPARgamma antagonist GW9662 reversed MMP-9 inhibition by troglitazone in TPA-treated MCF-7 cells. Conclusion: Troglitazone inhibited nuclear factor kappaB and activator protein-1-mediated MMP-9 expression and invasion of MCF-7 cells through a PPARgamma-dependent mechanism. PMID- 29628982 TI - Endocrine Treatment-Related Symptoms and Patient Outcomes in Breast Cancer: A Meta-Analysis. AB - Purpose: An association between endocrine treatment-related symptoms and breast cancer recurrence has been suggested previously; however, conflicting results have been reported. We performed a meta-analysis of published studies to clarify this relationship. Methods: We systematically searched PubMed, Embase, Scopus, and the Cochrane database for studies investigating the association between endocrine treatment-related symptoms and patient survival. Random-effects meta analysis was conducted with recurrence rate as the primary outcome. Results: Out of 7,713 retrieved articles, six studies were included. In patients who received endocrine treatment, the presence of any endocrine treatment-related symptom was found to be associated with a lower recurrence rate in comparison to an absence of any symptoms (hazard ratio [HR], 0.76; 95% confidence interval [CI], 0.66 0.87). This relationship persisted in patients presenting with only vasomotor or only musculoskeletal symptoms (HR, 0.74, 95% CI, 0.63-0.87; HR, 0.69, 95% CI, 0.55-0.86, respectively). At both time-points of symptom evaluation (3 months and 12 months), patients with endocrine treatment-related symptoms had a lower recurrence rate (HR, 0.74, 95% CI, 0.66-0.84; HR, 0.79, 95% CI, 0.69-0.90, respectively). This association was also significant in pooled studies including patients with and without baseline symptoms (HR, 0.73, 95% CI, 0.54-0.99; HR, 0.76, 95% CI, 0.69-0.85, respectively). Conclusion: Endocrine treatment-related symptoms are significantly predictive of lower recurrence rate in breast cancer patients, regardless of the type of symptoms, time-point of evaluation, or inclusion of baseline symptoms. These symptoms could be biomarkers for the prediction of long-term responses to endocrine treatment in patients with breast cancer. PMID- 29628983 TI - FcrR3A-158 Polymorphism and Stromal Tumor-Infiltrating Lymphocytes and Survival among Patients with Metastatic HER2-Positive Breast Cancer Receiving Trastuzumab Based Treatment. AB - Purpose: The prognosis of human epidermal growth factor receptor 2 (HER2) positive breast cancer has markedly improved since the introduction of trastuzumab. We aimed to evaluate the association between stromal tumor infiltrating lymphocyte (sTIL) or FcrR polymorphisms and survival among patients with metastatic HER2-positive breast cancer who were treated with trastuzumab. Methods: A total of 56 women with recurrent or metastatic HER2-positive breast cancer who received the trastuzumab-taxane combination as first-line treatment were included in this retrospective analysis. The single-step multiplex allele specific real-time polymerase chain reaction technique was employed for FcrR3A genotyping. sTILs were identified via immunohistochemical analysis of surgical (n=34, 60.7%) or biopsy specimens of metastatic lesions (n=22, 39.3%). Results: We classified patients based on the sTIL level (<=10% [n=44] or >10% [n=12]); high sTIL counts were more commonly observed in patients with hormone receptor negative tumors than in those with hormone receptor-positive tumors (34.8% vs. 12.1%, p=0.02). There was a significant association between high sTIL levels and longer progression-free survival in comparison to low sTIL levels (median, 28.4 months vs. 16.8 months; p=0.03). With regard to the FcrR3A-158 genotype, patients were classified into the Phenylalanine/Phenylalanine group (23 patients, 41.1%), Phenylalanine/Valine group (23 patients, 41,1%), or Valine/Valine group (10 patients, 17.9%); these classifications were not associated with clinical outcomes. Conclusion: High sTIL expression may be associated with better efficacy of trastuzumab-containing therapy in patients with metastatic HER2-positive breast cancer. However, this finding warrants further evaluation in the larger population. PMID- 29628984 TI - Clinicopathologic and Prognostic Significance of the Zinc Finger of the Cerebellum Family in Invasive Breast Cancer. AB - Purpose: Five members of the zinc finger of the cerebellum (ZIC) family-ZIC1, ZIC2, ZIC3, ZIC4, and ZIC5-have been shown to be involved in various carcinomas. Here, we aimed to explore the clinicopathologic and prognostic roles of ZIC family members in invasive breast cancer patients using immunohistochemical analysis, western blotting analysis, and real-time quantitative polymerase chain reaction (RT-qPCR). Methods: A total of 241 female invasive breast cancer patients who underwent radical mastectomy between 2009 and 2011 were enrolled. ZIC proteins in 241 pairs of breast tumors and corresponding normal tissues were investigated using immunohistochemistry and the clinicopathologic roles of proteins were analyzed using Pearson's chi-square test. Kaplan-Meier curves and Cox regression analysis were also used to analyze the prognostic value of the ZIC proteins. In addition, 12 pairs of fresh-frozen breast tumors and matched normal tissues were used in the western blotting analysis and RT-qPCR. Results: Only ZIC1 expression in normal tissues was obviously higher than that in tumors (p<0.001). On multivariate analysis, ZIC1 expression (in overall survival analysis: hazard ratio [HR], 0.405, 95% confidence interval [CI], 0.233-0.702, p=0.001; in disease-free survival analysis: HR, 0.395, 95% CI, 0.234-0.669, p=0.001) was identified as a prognostic indicator of invasive breast cancer. Conclusion: ZIC1, but not the other proteins, was obviously decreased in breast tumors and associated with clinicopathologic factors. Thus, ZIC1 might be a novel indicator to predict the overall and disease-free survival of invasive breast cancer patients. PMID- 29628985 TI - Clinical Characteristics and Prognosis Associated with Multiple Primary Cancers in Breast Cancer Patients. AB - Purpose: Breast cancer is one of the most common malignancies worldwide and the second most common cancer among Korean women. The prognosis of breast cancer is poor in patients with other primary cancers. However, there have been few clinical studies regarding this issue. Therefore, we analyzed the characteristics and prognosis of patients with breast cancer with multiple primary cancers (MPCs). Methods: Data from the Korean Breast Cancer Society Registry were analyzed. Data from enrolled patients who underwent surgery for breast cancer were analyzed for differences in prognosis dependent on the presence of MPCs, and which MPC characteristics affected their prognosis. Results: Among the 41,841 patients analyzed, 913 patients were found to have MPCs, accounting for 950 total MPCs. There was a significant difference in survival rates between the breast cancer only group and the MPC group. The 5-year survival rates were 93.6% and 86.7% and the 10-year survival rates were 87.5% and 70.4%, respectively. Among the 913 patients with MPCs, patients with two or more MPCs had significantly worse prognoses than patients with a single MPC. With respect to the time interval between breast cancer and MPC occurrence, patients with a 5-year or greater interval had significantly better prognoses than patients with less than 1 year between occurrences. Among MPCs, thyroid cancer was the most common primary cancer. However, this type was not related to the prognosis of breast cancer. Gynecologic cancer, colorectal cancer, upper gastrointestinal cancer, and lung cancer were related to breast cancer prognosis. Conclusion: MPCs were a poor prognostic factor for patients with breast cancer. Two or more MPCs and a shorter time interval between occurrences were worse prognostic factors. Although MPCs were a poor prognostic factor, thyroid cancer did not affect the prognosis of patients with breast cancer. PMID- 29628986 TI - Chronological Improvement in Survival of Patients with Breast Cancer: A Large Scale, Single-Center Study. AB - Purpose: This study aimed to chronologically evaluate survival of patients with breast cancer in Korea and investigate the observed changes during the last 20 years. We also sought to determine factors that may influence outcomes and changes in the duration of survival over time. Methods: We retrospectively analyzed a total of 10,988 patients with breast cancer who were treated at our institution between January 1993 and December 2008. We divided the study period into three periods (P1, 1993-1997; P2, 1998-2002; and P3, 2003-2008). We retrospectively reviewed the collected data from the Asan database, including age at diagnosis, clinical manifestations, pathology report, surgical methods, types of adjuvant treatment modalities, type of recurrence, and follow-up period. Results: At a median follow-up of 8.2 years, we observed that survival outcomes have improved recently. The 5-year breast cancer-specific survival (BCSS) rate also increased from 82.8% in P1 to 92.6% in P3 (p<0.001). The survival rate in patients with tumors at each stage increased in similar patterns in all patients, and, remarkably, there was a significant survival improvement in patients with stage III breast cancer (P1 vs. P3: 5-year BCSS, 57.4% vs. 80.0%, p<0.001). The time period was a significant prognostic factor in multivariate analysis (P1 vs. P2: hazard ratio [HR], 0.83, p=0.035; P1 vs. P3: HR, 0.75, p=0.015). Conclusion: The study results suggest an improvement in breast cancer survival in Korea, which is consistent with the development of treatments and early detection. PMID- 29628987 TI - Benign Intraductal Papilloma without Atypia on Core Needle Biopsy Has a Low Rate of Upgrading to Malignancy after Excision. AB - Purpose: The management of benign intraductal papilloma (IDP) without atypia diagnosed on core needle biopsy (CNB) remains controversial. This study was performed to evaluate the rate of upgrading to malignancy or high-risk lesions after excision and to identify factors associated with upgrading using a large series of benign IDP cases without atypia. Methods: We included patients who were diagnosed as having benign IDP without atypia on CNB and underwent surgical or vacuum-assisted excision between 2010 and 2015. We analyzed the clinical, radiologic, and histopathologic features of IDPs that were upgraded to malignancy or high-risk lesions after excision. Results: A total of 511 benign IDPs without atypia diagnosed via CNB were identified, of which 398 cases were treated with excision. After reviewing these cases, four cases of high-risk lesions in adjacent tissue on CNB, two cases which were revealed as papilloma with atypia, and nine cases of malignancy in the same breast were excluded. In the remaining 383 cases, the rate of upgrading to malignancy and high-risk lesions after excision was 0.8% and 4.4%, respectively. The presence of concurrent contralateral breast cancer, the presence of symptoms, and multifocality were factors significantly associated with upgrading to malignancy on subsequent excision. Surgical excision rather than vacuum-assisted excision was significantly associated with upgrading to high-risk lesions or malignancy. Conclusion: The rate of upgrading to malignancy for benign IDP without atypia was very low, suggesting that close clinical and radiologic observation may be sufficient for patients with benign IDP without atypia on CNB under proper settings. PMID- 29628988 TI - Identification of the Thioredoxin-Like 2 Autoantibody as a Specific Biomarker for Triple-Negative Breast Cancer. AB - Triple-negative breast cancer (TNBC) has a higher risk of death within 5 years of being diagnosed than the other forms of breast cancer. It is the second leading cause of death due to cancer among women. Currently, however, no diagnostic blood based biomarker exists to identify the early stages of TNBC. To address this point, we utilized a human protein microarray system to identify serum autoantibodies that showed different expression patterns between TNBC and normal serum samples, and identified five autoantibodies showing TNBC-specific expression. Among them, we selected the thioredoxin-like 2 (TXNL2) autoantibody and evaluated its diagnostic relevance by dot blot analysis with the recombinant TXNL2 protein. We demonstrated that the TXNL2 autoantibody showed 2- to 6-fold higher expression in TNBC samples than in normal samples suggesting that serum TXNL2 autoantibodies are potential biomarkers for TNBC. PMID- 29628989 TI - Breast Cancer Epidemiology of the Working-Age Female Population Reveals Significant Implications for the South Korean Economy. AB - In this study, we aimed to evaluate the economic loss due to the diagnosis of breast cancer within the female South Korean working-age population. A population based cost analysis was performed for cancer-related diagnoses between 1999 and 2014, using respective public government funded databases. Among the five most common cancers, breast cancer mortality was strongly associated with the growth in gross domestic product between 1999 and 2014 (R=0.98). In the female population, breast cancer represented the greatest productivity loss among all cancers, which was a consequence of the peak in the incidence of breast cancer during mid-working age in the working-age population, in addition to being the most common and fastest growing cancer among South Korean women. Our study shows that breast cancer not only represents a significant disease burden for individual patients, but also contributes a real, nonnegligible loss in productivity in the South Korean economy. PMID- 29628990 TI - Malignant Melanoma of the Nipple: A Case Report. AB - Malignant melanoma rarely originates from the female nipple. Tumors that develop on the skin of the breast are often subject to a delayed diagnosis. Cytologic examination provides excellent diagnostic capabilities and is a safe procedure with a lower risk of local implantation, compared to needle or incisional biopsy. We herein report a patient who underwent surgical resection of a primary malignant melanoma of the nipple. An elastic soft nodule was observed on the left nipple, and no abnormal lesions were identified in the breast. Eventually, a malignant melanoma was diagnosed from the clinical and cytological evaluation findings. This bulky tumor was classified as a stage IIIC nodular melanoma, with a thickness of 12 mm. The patient received adjuvant chemotherapy and exhibits no evidence of recurrence 7 years after surgery. PMID- 29628991 TI - Retraction note to: Lentivirus-Mediated Short-Hairpin RNA Targeting Protein Phosphatase 4 Regulatory Subunit 1 Inhibits Growth in Breast Cancer. AB - [This retracts the article on p. 218 in vol. 18, PMID: 26472971.]. PMID- 29628992 TI - Understanding where and why Senegalese adolescents and young adults access health information: A mixed methods study examining contextual and personal influences on health information seeking. AB - Background: Adolescent and young adult years are critical to the development of behaviors that influence health across the life course. To reveal which health communication channels should be used to effectively reach and influence younger populations in Senegal, we used a mixed methods approach to identify and interpret the multifaceted influences surrounding where and why this population accesses health information. Methods: We conducted 16 focus group discussions among adolescents and young adults in Senegal in September 2012. We then collected survey data from a larger, more diverse sample of Senegalese youth in October-November 2014. Results: Our results demonstrate that information sources vary by health topic, differential access, age, and other demographics. While there is a greater perception of credibility and usefulness in information received from health professionals, stigma remains a barrier for obtaining information about HIV/AIDS from health centers. Older youth are also less likely to seek health information from adults, which may be influenced by preferred use of information technologies, especially for information about taboo health topics. Conclusions: Our findings support multi-pronged, targeted approaches to health communication efforts. We recommend that doctors continue to provide actionable information about preventing or treating specific diseases, whereas teachers should educate youth about general health topics and health promotion behaviors. The results suggest that traditional mass media, such as radio and television, are the best communication channels for information about HIV and sexual/reproductive health, especially for older adolescents and young adults. PMID- 29628993 TI - Synthesis of Star Polymers using Organocatalyzed Atom Transfer Radical Polymerization Through a Core-first Approach. AB - Synthetic routes to higher ordered polymeric architectures are important tools for advanced materials design and realization. In this study, organocatalyzed atom transfer radical polymerization is employed for the synthesis of star polymers through a core-first approach using a visible-light absorbing photocatalyst, 3,7-di(4-biphenyl)-1-naphthalene-10-phenoxazine. Structurally similar multifunctional initiators possessing 2, 3, 4, 6, or 8 initiating sites were used in this study for the synthesis of linear telechelic polymers and star polymers typically possessing dispersities lower than 1.5 while achieving high initiator efficiencies. Furthermore, no evidence of undesirable star-star coupling reactions was observed, even at high monomer conversions and high degrees of polymerization. The utility of this system is further exemplified through the synthesis of well-defined diblock star polymers. PMID- 29628994 TI - Antiangiogenic and antiapoptotic effects of green-synthesized zinc oxide nanoparticles using Sargassum muticum algae extraction. AB - Background: Algae are one of the natural materials used to green synthesis of nanoparticles. This method leads to minimize the toxicity of the chemical materials used to nanoparticle synthesis. Methods: In this study, zinc oxide nanoparticles (ZnO NPs) synthesized by Sargassum muticum algae extraction used to evaluate its cytotoxicity and apoptotic properties on human liver cancer cell line (HepG2). Results: Trypan blue assay results demonstrate a concentration dependent decrease in cell viability and MTT assay shows increased growth inhibition in time and dose-dependent manner. In addition, CAM assay confirmed the ability of ZnO NPs to inhibit angiogenesis, but chick morphology (both the CR and weight) was not changed. Apoptotic tests (annexin V/PI and AO/PI) show that green-synthesized ZnO NPs induce apoptosis in all three time points (24, 48 and 72h). Conclusions: Our results confirm the beneficial cytotoxic effects of green synthesized ZnO NPs on Human liver cancer cell. This nanoparticle decreased angiogenesis and induces apoptosis, so we conclude that these nanoparticles can be used as a supplemental drug in cancer treatments. PMID- 29628995 TI - The shape of progress. PMID- 29628996 TI - Regulatory mechanisms of branching morphogenesis in mouse submandibular gland rudiments. AB - Branching morphogenesis is an important developmental process for many organs, including the salivary glands. Whereas epithelial-mesenchymal interactions, which are cell-to-cell communications, are known to drive branching morphogenesis, the molecular mechanisms responsible for those inductive interactions are still largely unknown. Cell growth factors and integrins are known to be regulators of branching morphogenesis of salivary glands. In addition, functional microRNAs (miRNAs) have recently been reported to be present in the developing submandibular gland. In this review, the authors describe the roles of various cell growth factors, integrins and miRNAs in branching morphogenesis of developmental mouse submandibular glands. PMID- 29628999 TI - A review on non-syndromic tooth agenesis associated with PAX9 mutations. AB - Tooth agenesis in the reduction of tooth number which includes hypodontia, oligodontia and anodontia is caused by disturbances and gene mutations that occur during odontogenesis. To date, several genetic mutations that unlock the causes of non-syndromic tooth agenesis are being discovered; these have been associated with certain illnesses because tooth development involves the interaction of several genes for tooth epithelium and mesenchyme odontogenesis. Mutation of candidate genes PAX9 and MSX1 have been identified as the main causes of hypodontia and oligodontia; meanwhile, AXIN2 mutation is associated with anodontia. Previous study using animal models reported that PAX9-deficient knockout mice exhibit missing molars due to an arrest of tooth development at the bud stage. PAX9 frameshift, missense and nonsense mutations are reported to be responsible; however, the most severe condition showed by the phenotype is caused by haploinsufficiency. This suggests that PAX9 is dosage-sensitive. Understanding the mechanism of genetic mutations will benefit clinicians and human geneticists in future alternative treatment investigations. PMID- 29628998 TI - Role of Streptococcus mutans surface proteins for biofilm formation. AB - Streptococcus mutans has been implicated as a primary causative agent of dental caries in humans. An important virulence property of the bacterium is its ability to form biofilm known as dental plaque on tooth surfaces. In addition, this organism also produces glucosyltransferases, multiple glucan-binding proteins, protein antigen c, and collagen-binding protein, surface proteins that coordinate to produce dental plaque, thus inducing dental caries. Bacteria utilize quorum sensing systems to modulate environmental stress responses. A major mechanism of response to signals is represented by the so called two-component signal transduction system, which enables bacteria to regulate their gene expression and coordinate activities in response to environmental stress. As for S. mutans, a signal peptide-mediated quorum-sensing system encoded by comCDE has been found to be a regulatory system that responds to cell density and certain environmental stresses by excreting a peptide signal molecule termed CSP (competence stimulating peptide). One of its principal virulence factors is production of bacteriocins (peptide antibiotics) referred to as mutacins. Two-component signal transduction systems are commonly utilized by bacteria to regulate bacteriocin gene expression and are also related to biofilm formation by S. mutans. PMID- 29628997 TI - Cancer metabolism: New insights into classic characteristics. AB - Initial studies of cancer metabolism in the early 1920s found that cancer cells were phenotypically characterized by aerobic glycolysis, in that these cells favor glucose uptake and lactate production, even in the presence of oxygen. This property, called the Warburg effect, is considered a hallmark of cancer. The mechanism by which these cells acquire aerobic glycolysis has been uncovered. Acidic extracellular fluid, secreted by cancer cells, induces a malignant phenotype, including invasion and metastasis. Cancer cells survival depends on a critical balance of redox status, which is regulated by amino acid metabolism. Glutamine is extremely important for oxidative phosphorylation and redox regulation. Cells highly dependent on glutamine and that cannot survive with glutamine are called glutamine-addicted cells. Metabolic reprogramming has been observed in cancer stem cells, which have the property of self-renewal and are resistant to chemotherapy and radiotherapy. These findings suggest that studies of cancer metabolism can reveal methods of preventing cancer recurrence and metastasis. PMID- 29629001 TI - Semiparametric Minimax Rates. AB - We consider the minimax rate of testing (or estimation) of non-linear functionals defined on semiparametric models. Existing methods appear not capable of determining a lower bound on the minimax rate of testing (or estimation) for certain functionals of interest. In particular, if the semiparametric model is indexed by several infinite-dimensional parameters. To cover these examples we extend the approach of [1], which is based on comparing a "true distribution" to a convex mixture of perturbed distributions to a comparison of two convex mixtures. The first mixture is obtained by perturbing a first parameter of the model, and the second by perturbing in addition a second parameter. We apply the new result to two examples of semiparametric functionals:the estimation of a mean response when response data are missing at random, and the estimation of an expected conditional covariance functional. PMID- 29629000 TI - Two novel mechanisms for maintenance of stemness in mesenchymal stem cells: SCRG1/BST1 axis and cell-cell adhesion through N-cadherin. AB - Mesenchymal stem cells (MSCs) retain the ability to self-renew and differentiate into mesenchymal cells. Therefore, human MSCs are suitable candidates for use in regenerative medicine and cell therapies. Upon activation by tissue damage, MSCs contribute to tissue repair through a multitude of processes such as self renewal, migration, and differentiation. However, loss of self-renewal and multi lineage differentiation potential occurs at a high rate during cell doubling. Effective MSC therapies require the establishment of new techniques that preserve MSC multipotency after lengthy cell expansions. Here, two novel mechanisms are described for maintenance of stemness in MSCs via scrapie responsive gene 1 (SCRG1)/bone marrow stromal cell antigen-1 (BST1) ligand-receptor combination and cell-cell adhesion through N-cadherin. These two mechanisms findings provide a valuable tool for regenerative medicine and cell therapeutic methods that require the ex vivo expansion of human MSCs while maintaining native stem cell potential. PMID- 29629002 TI - Evaluation of patients' satisfaction after laparoscopic surgery in a tertiary hospital in Cameroon (Africa). AB - Introduction: Access to laparoscopy is low in Cameroon where customers' satisfaction has not been reported so far. We assessed patients' satisfaction with the process of care during laparoscopic surgery in a new tertiary hospital. Methods: A questionnaire was addressed to consenting patients (guardians for patients under 18) with complete medical records who underwent laparoscopy at the Douala Gynaeco-Obstetric and Paediatric Hospital (Cameroon) from November 1, 2015 to July 31, 2016. The following modified Likert's scale was used to assess satisfaction: very weak: 0-2.5; weak 2.6-5; good: 5.1-7.5; very good: 7.6-10. Only descriptive statistics were used. Results: Response rate was 90% (45/50). Of the 45 respondents, 39 (86.7%) were female, 14(31.1%) were referred and 39 (86.7%) paid by direct cash deposit. Mean age was 36.8+/-11.9 years. Laparoscopies were carried out in emergency for 3 (6.7%) patients. Digestive abnormalities indicated 13 (28.9%) laparoscopies while gynaecologic diseases accounted for 32 (71.1%) cases. Perception of the overall care process was good with a mean satisfaction score of 6.8 +/- 1.4. Scores in categories were: 0% (Very weak); 13.3% (weak); 57.8% (good) and 28.9% (very good). Specifically mean satisfaction scores were: 7.8 +/- 1.0 with doctors' care; 7.1 +/- 1.3 with hospital administration; 7.0 +/- 1.2 with nursing and 4.7 +/- 1.4 with the costs. Main complaints were: long waiting time (73.3%), constraining geographical access (66.7%) and expensiveness (48.9%). Conclusion: Patients were globally satisfied with the process of care but financial and geographical barriers should be addressed. PMID- 29629003 TI - Endovascular treatment of acute aortic isthmian ruptures: case study. AB - Traumatic rupture of the aortic isthmus is a rare lesion occurring in patients subjected to violent deceleration. Because of the forces involved, it is frequently associated with concomitant life-threatening injuries. The endovascular intervention has been described to be a feasible and efficient technique which may be proposed as a therapeutic option for patients with multiple traumas instead of delayed classical surgical repair after stabilization. We report the case of an adult who has had an accident with a traumatic rupture of the aortic isthmus associated with other lesions, our patient received endovascular treatment. The aortic prosthesis was imported from France and the surgery was done 3 days after the patient's admission. This procedure was performed for the first time in Morocco in our hospital with a multidisciplinary team. The prosthesis was implemented successfully and the result was very satisfactory on the heart level. PMID- 29629004 TI - Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome associated with cefotaxime and clindamycin use in a 6 year-old boy: a case report. AB - Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is a rare and potentially life-threatening idiosyncratic drug reaction. It presents with extensive rash, fever, lymphadenopathy, hematologic abnormalities (eosinophilia and/or atypical lymphocytosis) and internal organ involvement. It has been described in association with more than 50 drugs. To the best of our knowledge neither cefotaxime nor clindamycin has been previously reported to induce DRESS syndrome in children. Clindamycin was reported only in adults as a cause of DRESS syndrome in the literature. In this report, we aimed to present a child with DRESS syndrome that developed after cefotaxime and clindamycin treatment. A 6 year-old boy was diagnosed with the left lower lobe pneumonia and pleural effusion. Parenteral cefotaxime and clindamycin were then started, after which the patient improved clinically and was discharged 7 days later with oral amoxicillin clavulanate treatment. After four days he was readmitted to the hospital with fever and cough. Chest X-ray revealed left lower lobe pneumonia and pleural effusion. We considered that the pneumonia was unresponsive to oral antibiotic treatment, and therefore parenteral cefotaxime and clindamycin were re administered. As a result, his clinical and radiological findings were improved within 10 days. On the 12th of day of hospitalization, the body temperature has risen to 39 degrees C, which we considered to be caused by antibiotics and stopped antibiotic treatment. At the same day he developed generalized maculopapular erythematous rash, which was considered an allergic reaction secondary to antibiotics. Despite the antihistaminic drug administration, the clinical status quickly deteriorated with generalized edema, lymphadenopathies and hepatosplenomegaly. Laboratory tests revealed a white blood cell count of 4300/MUl, a lymphocyte count of 1300/MUl, a hemoglobin level of 11.2 gr/dl, a platelet count of 120.000/MUl, an eosinophilia ratio of 10% on peripheral blood smear, a C-reactive protein level of 20 mg/dl, a procalcitonin level of 23.94 ng/ml and an erythrocyte sedimentation rate of 48 mm/h. Anti nuclear antibody, anti-double stranded DNA, the serologic tests for Epstein Bar virus, herpes simplex virus, parvovirus, mycoplasma, toxoplasmosis, rubella, cytomegalovirus were all found negative. Bone marrow aspiration was consistent with an autoimmune reaction. An echocardiographic examination was normal. Thoracic tomography revealed multiple enlarged axillary, supraclavicular and anterior mediastinal lymph nodes. As the patient met 8 out of 9 RegiSCAR criteria for the diagnosis of DRESS, we started pulse methyl prednisolone (30 mg/kg/day) for three days followed by 2 mg/kg/day. On the 2nd day fever resolved and cutaneous rash and edema improved. Ten days after developing eruptions the patient was discharged. To our knowledge, we report the first pediatric case of DRESS syndrome following treatment with cefotaxime and clindamycin. Pediatricians should be aware of this potential complication associated with these commonly prescribed antibiotics. PMID- 29629005 TI - [Fistulized renal hydatic cyst in a patient on chronic hemodialysis]. AB - Hydatidosis is a parasitic infection caused by the larval stage of Echinococcus granulosus. Renal hydatic cyst is unusual. It may fistulize into the urinary excretory system, requiring specific management. The aim of our study was to highlight the diagnostic and therapeutic specificity of this pathology in patients on chronic hemodialysis among whom diuresis is not always preserved, in order to focus attention on hydaturia and to give an indication to diagnosis. We report the case of a 47-year old patient with a 4-year history of hemodialysis due to glomerular nephropathy detected at the final stage. Moreover, the patient had a 6-month histoiry of impaired general condition associated with right lower back pain, without fever. Abdominal CT scan showed right kidney measuring 13.4cm, with important ureteropyelocaliceal dilation, pushing the renal parenchyma associated with renal pelvis measuring 4.3cm, without detectable lithiasic obstacle. However, it showed membranous cyst at the level of the lower right renal polar parenchyma, measuring approximately 76.5 x 54 mm, contacting the renal pelvis, also containing a few membranes. The patient underwent thorough interview revealing the presence of hydaturia in the few drops of residual diuresis. Given that the patient had end stage chronic renal failure and that he was under renal replacement therapy, therapeutic approach was based on total nephrectomy. PMID- 29629006 TI - [Gastric Abrikossoff tumor: about a new case]. AB - Granular cell tumors (GCT) are uncommon tumors. They mainly occur at the level of the skin and the subcutaneous tissues. Gastric tumor is rare. We here report a new case of gastric Abrikossoff tumor as well as a brief literature review. This study aims to examine the clinical, endoscopic and therapeutic features of this rare disease. PMID- 29629007 TI - Knowledge, perceptions and practice of cervical cancer prevention among female public secondary school teachers in Mushin local government area of Lagos State, Nigeria. AB - Introduction: Cervical cancer is the most common gynecological cancer and a leading cause of cancer death in women in Nigeria. This study was aimed to assess the knowledge, perception, and practice of cervical cancer prevention among female public secondary school teachers in Mushin, Lagos. Methods: This was a cross-sectional study carried out among female secondary school teachers in Mushin, Lagos. The participants were selected by a two-stage random sampling method and relevant data were collected with the use a self-administered questionnaire. Data entry and analysis were done using Epi-info version 7.2 statistical software and descriptive statistics were computed for all data. Results: The knowledge of cervical cancer and its prevention was 100.0% among the respondents. The most commonly known method of cervical cancer screening identified by the respondents was Papanicolaou smear (91.4%). More than half of the women (67.0%) have had at least one cervical cancer screening done previously. Only 2.2% of the respondents have had HPV vaccine given to their female teenage children in the past despite the acceptance rate for HPV vaccination being 76.2%. Conclusion: This study, unlike most previous studies in other regions of Nigeria and most part of sub-Saharan Africa, has demonstrated a relatively high level of awareness about cervical cancer, its cause, risk factors and prevention. However, conversely, the absence of a national health programme means that screening and vaccination centers are not available, accessible or affordable. PMID- 29629008 TI - Assessment of utilization of long acting reversible contraceptive and associated factors among women of reproductive age in Harar City, Ethiopia. AB - Introduction: World health organization report indicated that, in 2013 alone, over 289,000 maternal death that resulted from pregnancy and delivery related complication were reported worldwide indicating a decline of 45% from 1990. The sub-Saharan Africa region alone accounted for 62% of maternal death followed by southern Asian country (24%). Provision of family planning is one of the effective intervention that prevent unwanted and ill spaced pregnancy there by reducing maternal mortality and morbidity. Given that its effectiveness and, associated fewer visits to health facilities, LARC are very important in tackling maternal mortality and morbidity. However, little is known regarding its prevalence in eastern Ethiopia. Thus, this study aimed to assess utilization of long acting reversible contraceptives and associated factors among women of reproductive age groups. Methods: A facility based cross-sectional study conducted in Harar city among 402 study participants. The study participants selected by using systematic random sampling method. The quantitative data collected using structured interviewer administered questionnaires. All variables with p-value of <= 0.25 in bivariate logistic regression were taken into multivariable model. Variables having p value <= 0.05 in the multivariate analysis were taken as significant predictors. Crude and adjusted odds ratios with their 95% confidence intervals were calculated. Results: The study identified that the utilization of long acting reversible contraceptive among mother of reproductive age was 38%. Study participants whose occupation was daily laborer were less likely to utilize long acting reversible contraceptive compared to those whose occupation was house wife (adjusted OR = 0.3; 95% CI 0.01 to 0.8). Moreover, those mothers who were unable to read and write utilize long acting reversible contraceptive 5 times more likely compared to those who were above grade 12 (adjusted OR = 4.9; 95% CI 1.2 to 19.6). Conclusion: The prevalence of long acting reversible contraceptive was found to be low. Maternal education and occupation were factors found to have a significant association with utilization of long acting reversible contraceptive. Community and facility level awareness creation should be reinforced to improve utilization of long acting reversible contraceptives. PMID- 29629009 TI - Comparison of ease of induction of spinal anaesthesia in sitting with legs parallel on the table versus traditional sitting position. AB - Introduction: It is sometimes difficult for some patients to optimally flex their hips and knees making traditional position for induction of spinal anaesthesia difficult to achieve. The ease of induction of spinal anaesthesia was compared with patients in sitting position with legs remaining on the table (new sitting method) versus legs placed on the side stool (traditional sitting method). Methods: One hundred eligible elderly patients, aged between 65 and 80 years, scheduled for open prostactectomy, were prospectively randomized to 2 groups, LS and LT. Patients in (LS group) had their spinal anaesthesia induced in sitting position with their legs placed on the stool while patients in (LT group) had their spinal anaesthesia induced in sitting position with their legs remaning on the operating table. The primary endpoint was correct needle placement. Numbers of attempts, needle redirections and patients' comfort were determined to compare outcome in the two groups. Results: More patients in LS group (78%) than those in the LT group (64%) had successful placement of spinal needle at first attempt (P = 0.12, RR = 1.6, 95% CI = 0.863-3.102). Needle redirections were similar at first attempt (52% versus 40%; P = 0.22). The groups were equivalent with respect to 100% overall success rate (P = 1.000). It took longer time to induce spinal anaesthesia in patients in LS group (240 vs 125s, p < 0.001). Patients in LT were more comfotable. Conclusion: The 100% overall success rate was comparable. However, patients were generally more comfortable with their legs placed on the table. PMID- 29629010 TI - Evaluation of cholera surveillance system in Osu Klottey District, Accra, Ghana (2011-2013). AB - Introduction: Cholera is an acute illness characterized by profuse watery diarrhea. It is caused by vibrio cholera subgroup 01 and 0139. Rapid administration of fluid replacement therapy and supportive treatment can reduce mortality to around 1%. By the close of 2011, 10,628 cases and 100 deaths were reported in Ghana with a case fatality rate of 0.99. It is important to evaluate the cholera surveillance system in Ghana to determine if it is meeting its objective. Methods: The study was conducted in Osu Klottey district in the Accra Metropolitan area in January 2014. We assessed the operations (attributes and performance) of the surveillance system for cholera using CDC guidelines (2001). Surveillance data records at the district level from 2011-2013 were extracted and analyzed for frequency using Microsoft excel. Stakeholders and key informants were interviewed using structured questionnaire. Records were also reviewed at some health facilities and at district levels. Results: In 2011 and 2012, case fatality rates (1.3% and 0.65%) respectively. Males were mostly affected. The most affected age group was 20-29. In 2011, Predictive value positive was 69.2% and 50% in 2012.Cholera peaked in March 2011 and April 2012. The Government of Ghana funded the system. The system is sensitive, simple, stable, flexible, acceptable and representative. It was also useful and data quality was relatively good. Predictive Value Positive was also good. Conclusion: The surveillance system is achieving its set out objectives. The system is sensitive, simple, stable, flexible, and acceptable. Predictive value positive was good. PMID- 29629011 TI - [Evolution of the National Health Information System in the Democratic Republic of the Congo between 2009 and 2015]. AB - Introduction: Launched in 1987, the National Health Information System (NHIS) in the Democratic Republic of the Congo (DR Congo) was evaluated in 2009 and 2015 using the HMN (Health Metrics Network) assessment tool. This study aimed to estimate the progress made between these two evaluations. Methods: We performed an analysis of the secondary data from the evaluations of the NHIS, which was based on the comparison of the satisfaction level between the six components of this tool between 2009 and 2015, namely: resources, indicators, data sources, data management, information products, dissemination and use of data. Results: Between 2009 and 2015, respondents' satisfaction level changed as follow: resouces 49% vs 61%; indicators 73% vs 88%; data sources 52% vs 61%; data management 41% vs 45%; information products 74% vs 77%; dissemination and use of data 51% vs 51%. In general the average score increased from 59% to 64% with "satisfactory" mark. Conclusion: Our study shows that the NHIS in the DR Congo has not changed significantly between 2009 and 2015 and that it couldn't provide real-time reliable health information for decision-making and health program planning. PMID- 29629012 TI - Clinico-hysteroscopic analysis of severe intrauterine adhesions among Nigerian infertile women. AB - Introduction: Severe intrauterine adhesions are difficult to manage and are associated with poor reproductive outcomes following treatment. The objective was to study the clinical presentation and hysteroscopic findings of severe intrauterine adhesions seen at hysteroscopy in two fertility/gynaecological endoscopy units in Nigeria. Methods: A prospective study of 19 out of 76 women managed for intrauterine adhesions in our units. Data were analyzed with STATA software, version 12.0 SE (Stata Corporation, TX, USA). Results: Severe intrauterine adhesion accounted for 19 (25.0%) of 76 cases of intrauterine adhesions managed during the period. This constituted 11.9% of 160 infertile women who had diagnostic hysteroscopies in our units over the study period. The mean duration of symptom was 4.2 years +/-3.2. Amenorrhea in association with infertility (68.4%) was the main presenting complaint. Secondary dysmenorrhea and cyclical abdominal pain were found in 10.8% and 31.6% of the women respectively. The main aetiological events were complicated caesarean section (42.1%) and abdominal myomectomy (26.3%). The adhesions were mainly dense (52.6%) and multiple (94.7%) with complete involvement of the uterine cavity in all the cases. Obliterative lesions were seen in 63.2% of the women. Conclusion: The main clinical presentation of severe IUA was amenorrhea and infertility while the major risk factors were complicated caesarean section and myomectomy. The adhesions were mainly multiple, dense, obliterative and complete. PMID- 29629013 TI - Prevalence and risk factors for genital high-risk human papillomavirus infection among women attending the out-patient clinics of a university teaching hospital in Lagos, Nigeria. AB - Introduction: Cervical cancer is the second most common cancer among women in the developing countries and the seventh commonest cancer in the developed countries. Human papillomavirus (HPV) is now known to be the main factor in the aetiology of cervical cancer with over 99.7% of cases being associated with previous high risk HPV (hrHPV) infection. This study was aimed to determine the prevalence and risk factors for genital hrHPV infection among women attending the out-patient clinics of the Lagos University Teaching Hospital. Methods: This was a cross-sectional study involving a total of 200 women. Questionnaires were administered to collect data such as sociodemographic, reproductive and sexual histories. Endocervical swab samples were then taken from each participant. Samples were analyzed by polymerase chain reaction (PCR) using consensus primers targeted against the hrHPV viruses. Results: The prevalence of hrHPV in the study was 36.5%. The most predominant HPV subtypes were 31 (25.0%), 35 (8.0%) and 16 (3.5%) with the largest proportion (76.1%) of the tested samples being positive for only a single hrHPV subtype. The study showed statistically significant associations between early age at coitarche (P = 0.032) and increasing number of lifetime sexual partners (P = 0.001) with genital hrHPV infection. Conclusion: The prevalence of hrHPV was high in Lagos with the majority of test positive samples having only a single HPV genotype. We demonstrated early age of sexual debut and increasing number of lifetime sexual partners as the most important factors associated with genital hrHPV infection. PMID- 29629014 TI - [Clinical and radiological features of gestational trophoblastic tumors]. AB - Gestational trophoblastic disease incorporates a group of diseases which differ from each other by their regressive evolution, their evolution to metastasis and to recurrence. It is a severe disease that affects women of childbearing age. Gestational trophoblastic tumors (GTT) are the malignant forms of gestational trophoblastic diseases. They are always a result of pregnancy, more often molar pregnancy (hydatidiform mole). The most common type of gestational trophoblastic tumors (GTT) is the invasive mole because, in most cases, the diagnosis is made when cancer is still confined to the uterus. Choriocarcinoma is a more rare type of tumor, often developing distant metastases. When there is a progression to a trophoblastic tumor, the assessment of locoregional extension and distant metastases is essential to establish an appropriate treatment protocol. We here report three clinical cases of GTT by describing their clinical presentations and the use of imaging techniques in the diagnosis and management of these disorders. PMID- 29629015 TI - Intimate partner violence in pregnancy among antenatal attendees at health facilities in West Pokot county, Kenya. AB - Introduction: The objective of this study was to investigate factors contributing to intimate partner violence in pregnancy among antenatal attendees at the health facilities in West Pokot Sub-County. The study was done in West Pokot Sub-County. Methods: Using cross sectional study design, a total of 238 antenatal attendees were systematically sampled for the study. Four focused group discussions and 20 key informant interviews were conducted for qualitative data collection. Qualitative data was consolidated into various themes while bivariate and logistic regression analysis was done to determine factors associated with experience of IPV in the index of pregnancy with P <= 0.05 being considered significant. Results: The study found prevalence of overall, physical, psychological and sexual IPV in pregnancy to be 66.9%, 29.9%, 55.8% and 39.2% respectively. After adjusting for confounders, Overall IPV in pregnancy was significantly associated with Alcohol intake by partner (OR 2.116, 95% CI 1.950 2.260, P 0.000) and partner's level of education (OR 1.265, 95% CI 1.079-1.487, P 0.031), while psychological and sexual IPV was significantly associated with age of partner (OR 2.292, 95% CI 2.123-2.722, P 0.007) and age of pregnant women (OR 1.174, 95% CI 1.001-1.397 P 0.049) respectively. The care offered to antenatal attendees experiencing IPV was not in line with WHO guidelines and standard on handling gender based violence cases. Conclusion: The study finding indicates that IPV in pregnancy among antenatal attendees in West Pokot is very high. This unearths the gaps on gender based violence interventions in the maternal and child health programs. PMID- 29629016 TI - Rural-urban disparity in lung function parameters of Nigerian children: effects of socio-economic, nutritional and housing factors. AB - Introduction: The effect of socio-demographic and nutritional factors on lung functions of African children is poorly studied. This study set out to determine the effects of these factors on lung functions of Nigerian school children. Methods: Rural and urban secondary schools students in Ilesa, Nigeria were selected by multistage sampling. The socio-demographic, nutritional status as well as lung function parameters measured using incentive Spirometry (MIR Spirolab III srl, Italy) of the children were obtained and compared among the rural and urban children. Results: A total of 250 children (128 rural and 122 urban) aged 9 to 17 years participated in the study over a 12 month period. Mean (SD) age was 12.6 (1.9) years and Male: Female 1:1.1. The urban children were heavier, taller and have larger lung volumes than their age and sex matched rural counterpart. Stunted rural males [Mean (SD) FVC 1.8 (0.3) L vs. 2.2 (0.6) L t test = 2.360; p = 0.022], underweight females [Mean (SD) FVC 1.8 (0.4) L vs. 2.2 (0.6) L; t-test = 2.855; p = 0.006] and those exposed to unclean fuel [Mean (SD) FVC 2.1 (0.6) L vs. 2.4 (0.5) L; t-test = 2.079; p = 0.041] had significantly lower lung volumes compared to their counterparts without these conditions. Conclusion: Undernutrition, low socio-economic class and use of unclean fuels adversely affect the lung functions of Nigerian children. Improved standard of living, use of clean fuel and adequate nutrition may ensure better lung health among these children. PMID- 29629017 TI - Barriers to self-care in women of reproductive age with HIV/AIDS in Iran: a qualitative study. AB - Introduction: Although increasing attention is paid to HIV/AIDS, patients with HIV still experience several barriers to self-care. These barriers have been previously identified in small quantitative studies on women with HIV, but qualitative studies are required to clarify barriers to self-care. Methods: We conducted our study using the grounded theory methodological approach. A total of 28 women with HIV and their family members, were interviewed. The data were analyzed with the Corbin and Strauss method (1998). Results: The key barriers to self-care in women with HIV/AIDS included social stigma, addiction, psychological problems, medication side-effects and financial problems. Conclusion: Women with HIV/AIDS face several barriers to self-care. Therefore, when designing self-care models for these women, social and financial barriers should be identified. Mental health treatment should also be incorporated into such models and patients' access to health care services should be facilitated. PMID- 29629018 TI - The legislative and regulatory framework governing herbal medicine use and practice in Kenya: a review. AB - Complementary and alternative medicine is an integral component of primary healthcare in Kenya. This is because the infrastructural health setup in the country is inadequate in catering for all the medical needs of the population. This particularly holds true in the rural areas where many rural folk rely on products of herbal origin to offset their healthcare needs. More often than not these products are an elaborate cacophony of several different substances of biological origin and thus need personnel adept in their preparation. Sadly, due to loopholes in legislation and regulation, quacks have a field day in the practice. Moreover, the process of planting, harvesting, preparation and storage of herbs and related products dictates that a significant number of people will ultimately be involved in the whole process. This is likely to set the stage for manipulation and compromise of the safety, quality and efficacy of these products. This state of affairs appears unabated especially in the context of the current legal and regulatory framework governing herbal medicine use and practice in Kenya. Not only are these laws inadequate, they are shrouded in ambiguity, open to interpretation and the authorities mandated to implement them often end up performing duplicate roles. The aim of this review is to critique the legal and regulatory provisions governing herbal medicine use and practice in Kenya. In conclusion, laws and regulations meant to control herbal medicine use and practice in Kenya are wanting. Clear and definitive legislation on herbal medicine use and practice coupled with effective implementation by mandated institutions will go a long way in inspiring confidence to all stakeholders of herbal medicine. PMID- 29629019 TI - Basins of attraction in human balance. AB - Falls are a recognized risk factor for unintentional injuries among older adults, accounting for a large proportion of fractures, emergency department visits, and urgent hospitalizations. Human balance and gait research traditionally uses linear or qualitative tests to assess and describe human motion; however, human motion is neither a simple nor a linear process. The objective of this research is to identify and to learn more about what factors affect balance using nonlinear dynamical techniques, such as basin boundaries. Human balance data was collected using dual force plates for leans using only ankle movements as well as for unrestricted leans. Algorithms to describe the basin boundary were created and compared based on how well each method encloses the experimental data points as well as captures the differences between the two leaning conditions. PMID- 29629021 TI - Long Term Outcomes of Left Atrial Reservoir Function in Children with a History of Kawasaki Disease. AB - Background: Decreased left atrial (LA) reservoir function is reported to be associated with elevated left ventricular (LV) end diastolic pressure and LV diastolic dysfunction. Echocardiographic parameters that reflect LA reservoir function include LA total emptying fraction [(maximum LA volume - minimum LA volume) / maximum LA volume], peak LA longitudinal strain (PLALS) at systole, and LA stiffness index (E/E'/PLALS). We aimed to investigate the long-term outcomes of LV diastolic function in children with a history of Kawasaki disease (KD) (KDHx group) by assessing LA reservoir function. Methods: Retrospectively, echocardiograms performed at a mean follow-up period of 5 years after the acute phase of KD in 24 children in the KDHx group were compared to those from 20 normal control subjects. LA total emptying fraction, PLALS, LA stiffness index, LV peak longitudinal systolic strain (epsilon), and strain rate (SR) were evaluated with conventional echocardiographic parameters. Results: The mean age at long term follow-up echocardiography in children in the KDHx group was 6.8 years. Five children (20.8%) had coronary artery lesions (CALs) in the acute stage of KD. No children showed CALs at a mean follow-up period of 5 years after the acute phase of KD. There were no significant differences in the conventional echocardiographic parameters and in LA total emptying fraction, PLALS, LA stiffness index, LV peak longitudinal systolic epsilon, and SR, between the children in the KDHx and control group. Conclusion: LV diastolic function assessed by LA reservoir function parameters at long-term follow-up in children in the KDHx group appears to be favorable. PMID- 29629022 TI - Impact of a Geometric Correction for Proximal Flow Constraint on the Assessment of Mitral Regurgitation Severity Using the Proximal Flow Convergence Method. AB - Background: Overestimation of the severity of mitral regurgitation (MR) by the proximal isovelocity surface area (PISA) method has been reported. We sought to test whether angle correction (AC) of the constrained flow field is helpful to eliminate overestimation in patients with eccentric MR. Methods: In a total of 33 patients with MR due to prolapse or flail mitral valve, both echocardiography and cardiac magnetic resonance image (CMR) were performed to calculate regurgitant volume (RV). In addition to RV by conventional PISA (RVPISA), convergence angle (alpha) was measured from 2-dimensional Doppler color flow maps and RV was corrected by multiplying by alpha/180 (RVAC). RV measured by CMR (RVCMR) was used as a gold standard, which was calculated by the difference between total stroke volume measured by planimetry of the short axis slices and aortic stroke volume by phase-contrast image. Results: The correlation between RVCMR and RV by echocardiography was modest [RVCMR vs. RVPISA (r = 0.712, p < 0.001) and RVCMR vs. RVAC (r = 0.766, p < 0.001)]. However, RVPISA showed significant overestimation (RVPISA - RVCMR = 50.6 +/- 40.6 mL vs. RVAC - RVCMR = 7.7 +/- 23.4 mL, p < 0.001). The overall accuracy of RVPISA for diagnosis of severe MR, defined as RV >= 60 mL, was 57.6% (19/33), whereas it increased to 84.8% (28/33) by using RVAC (p = 0.028). Conclusion: Conventional PISA method tends to provide falsely large RV in patients with eccentric MR and a simple geometric AC of the proximal constraint flow largely eliminates overestimation. PMID- 29629023 TI - Recurrent Acute Myocardial Infarction Caused by Intra-cardiac Metastatic Undifferentiated Pleomorphic Sarcoma during Cancer Treatment. PMID- 29629024 TI - A Rare Case of Left Ventricular Noncompaction in LEOPARD Syndrome. PMID- 29629020 TI - Diagnosis, Treatment, and Prevention of Cardiovascular Toxicity Related to Anti Cancer Treatment in Clinical Practice: An Opinion Paper from the Working Group on Cardio-Oncology of the Korean Society of Echocardiography. AB - Cardiovascular (CV) toxicity associated with anti-cancer treatment is commonly encountered and raises critical problems that often result in serious morbidity or mortality. Most cardiac toxicities are related to the cumulative dose of chemotherapy; however, the type of chemotherapy, concomitant agents, and/or conventional CV risk factors have been frequently implicated in CV toxicity. Approximately half of the patients exhibiting CV toxicity receive an anthracycline-based regimen. Therefore, serologic biomarkers or cardiac imagings are important during anti-cancer treatment for early detection and the decision of appropriate management of cardiotoxicity. However, given the difficulty in determining a causal relationship, a multidisciplinary collaborative approach between cardiologists and oncologists is required. In this review, we summarize the CV toxicity and focus on the role of cardiac imaging in management strategies for cardiotoxicity associated with anti-cancer treatment. PMID- 29629025 TI - Protective effects of perilla oil and alpha linolenic acid on SH-SY5Y neuronal cell death induced by hydrogen peroxide. AB - BACKGROUND/OBJECTIVE: Oxidative stress plays a key role in neuronal cell damage, which is associated with neurodegenerative disease. The aim of present study was to investigate the neuroprotective effects of perilla oil (PO) and its active component, alpha-linolenic acid (ALA), against hydrogen peroxide (H2O2)-induced oxidative stress in SH-SY5Y neuronal cells. MATERIALS/METHODS: The SH-SY5Y human neuroblastoma cells exposed to 250 uM H2O2 for 24 h were treated with different concentrations of PO (25, 125, 250 and 500 ug/mL) and its major fatty acid, ALA (1, 2.5, 5 and 25 u/mL). We examined the effects of PO and ALA on H2O2-induced cell viability, lactate dehydrogenase (LDH) release, and nuclear condensation. Moreover, we determined whether PO and ALA regulated the apoptosis-related protein expressions, such as cleaved-poly ADP ribose polymerase (PARP), cleaved caspase-9 and -3, BCL-2 and BAX. RESULTS: Treatment of H2O2 resulted in decreased cell viability, increased LDH release, and increase in the nuclei condensation as indicated by Hoechst 33342 staining. However, PO and ALA treatment significantly attenuated the neuronal cell death, indicating that PO and ALA potently blocked the H2O2-induced neuronal apoptosis. Furthermore, cleaved-PARP, cleaved caspase-9 and -3 activations were significantly decreased in the presence of PO and ALA, and the H2O2-mediated up-regulated BAX/BCL-2 ratio was blocked after treatment with PO and ALA. CONCLUSIONS: PO and its main fatty acid, ALA, exerted the protective activity from neuronal oxidative stress induced by H2O2. They regulated apoptotic pathway in neuronal cell death by alleviation of BAX/BCL-2 ratio, and down-regulation of cleaved-PARP and cleaved caspase-9 and -3. Although further studies are required to verify the protective mechanisms of PO and ALA from neuronal damage, PO and ALA are the promising agent against oxidative stress induced apoptotic neuronal cell death. PMID- 29629026 TI - Effect of vitamin C on azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced colitis-associated early colon cancer in mice. AB - BACKGROUND/OBJECTIVES: The objective of this study was to investigate the effects of vitamin C on inflammation, tumor development, and dysbiosis of intestinal microbiota in an azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced inflammation-associated early colon cancer mouse model. MATERIALS/METHODS: Male BALB/c mice were injected intraperitoneally with AOM [10 mg/kg body weight (b.w)] and given two 7-d cycles of 2% DSS drinking water with a 14 d inter-cycle interval. Vitamin C (60 mg/kg b.w. and 120 mg/kg b.w.) was supplemented by gavage for 5 weeks starting 2 d after the AOM injection. RESULTS: The vitamin C treatment suppressed inflammatory morbidity, as reflected by disease activity index (DAI) in recovery phase and inhibited shortening of the colon, and reduced histological damage. In addition, vitamin C supplementation suppressed mRNA levels of pro-inflammatory mediators and cytokines, including cyclooxygenase-2, microsomal prostaglandin E synthase-2, tumor necrosis factor-alpha, Interleukin (IL)-1beta, and IL-6, and reduced expression of the proliferation marker, proliferating cell nuclear antigen, compared to observations of AOM/DSS animals. Although the microbial composition did not differ significantly between the groups, administration of vitamin C improved the level of inflammation-related Lactococcus and JQ084893 to control levels. CONCLUSION: Vitamin C treatment provided moderate suppression of inflammation, proliferation, and certain inflammation-related dysbiosis in a murine model of colitis associated-early colon cancer. These findings support that vitamin C supplementation can benefit colonic health. Long-term clinical studies with various doses of vitamin C are warranted. PMID- 29629027 TI - Ethanol extract of Allium fistulosum inhibits development of non-alcoholic fatty liver disease. AB - BACKGROUND/OBJECTIVES: Non-alcoholic fatty liver disease (NAFLD) is a leading cause of chronic liver disease and is closely associated with metabolic syndrome. In the present study, we observed the effect of ethanol extract of Allium fistulosum (EAF) on NAFLD and have suggested the possibility of using EAF as a natural product for application in the development of a treatment for NAFLD. MATERIALS/METHODS: The preventive effect on hepatic lipid accumulation was estimated by using an oleic acid (OA)-induced NAFLD model in vitro and a Western diet (high-fat high-sucrose; WD)-induced obese mouse model. Animals were divided into three groups (n = 7): normal diet group (ND), WD group, and WD plus 1% EAF group. RESULTS: EAF reduced OA-stimulated lipid accumulation in HepG2 cells in the absence of cellular cytotoxicity and significantly blocked transcriptional activation of sterol regulatory element-binding protein 1 and fatty acid synthase genes. Subsequently, we investigated these effects in vivo in mice fed either ND or WD in the presence or absence of EAF supplementation. In comparison to the ND controls, the WD-fed mice exhibited increases in body weight, liver weight, epididymal fat weight, and accumulation of fat in hepatocytes, and these effects were significantly attenuated by EAF supplementation. CONCLUSIONS: Allium fistulosum attenuates the development of NAFLD, and EAF elicits anti-lipogenic activity in liver. Therefore, EAF represents a promising candidate for use in the development of novel therapeutic drugs or drug combinations for the prevention and treatment of NAFLD. PMID- 29629028 TI - Effects of glutathione s-transferase (GST) M1 and T1 polymorphisms on antioxidant vitamins and oxidative stress-related parameters in Korean subclinical hypertensive subjects after kale juice (Brassica oleracea acephala) supplementation. AB - BACKGROUND/OBJECTIVES: Glutathione s-transferase (GST) is involved in the formation of a multigene family comprising phase II detoxification enzymes, involved in the detoxification of reactive oxygen species. This study evaluated whether daily supplementation with kale juice could modulate levels of plasma antioxidant vitamins and oxidative stress-related parameters. We further examined whether this modulation was affected by combined GSTM1 and T1 polymorphisms. SUBJECTS/METHODS: Totally, 84 subclinical hypertensive patients having systolic blood pressure (BP) over 130 mmHg or diastolic BP over 85 mmHg, received 300 mL of kale juice daily for 6 weeks. Blood samples were drawn before start of study and after completion of 6 weeks. RESULTS: After supplementation, we observed significant decrease in DNA damage and increase in erythrocyte catalase activity in all genotypes. Plasma level of vitamin C was significantly increased in the wild/null and double null genotypes. The plasma levels of beta-carotene, erythrocyte glutathione peroxidase activity, and nitric oxide were increased only in the wild/null genotype after kale juice supplementation. CONCLUSIONS: The effect of kale juice was significantly greater in the GSTM1 null genotype and wild/null genotype groups, suggesting possibility of personalized nutritional prescriptions based on personal genetics. PMID- 29629029 TI - Reactive oxygen species-dependent apoptosis induction by water extract of Citrus unshiu peel in MDA-MB-231 human breast carcinoma cells. AB - BACKGROUND/OBJECTIVES: Although several recent studies have reported the anti cancer effects of extracts or components of Citrus unshiu peel, which has been used for various purposes in traditional medicine, the molecular mechanisms for their effects remain unclear. In the present study, the anti-cancer activity of a water-soluble extract of C. unshiu peel (WECU) in MDA-MB-231 human breast carcinoma cells at the level of apoptosis induction was investigated. MATERIALS/METHODS: Cytotoxicity was evaluated using the MTT assay. Apoptosis was detected using DAPI staining and flow cytometry analyses. Mitochondrial membrane potential, reactive oxygen species (ROS) assay, caspase activity and Western blotting were used to confirm the basis of apoptosis. RESULTS: The results indicated that WECU-induced apoptosis was related to the activation of caspase-8, and -9, representative initiator caspases of extrinsic and intrinsic apoptosis pathways, respectively, and caspase-3 accompanied by proteolytic degradation of poly(ADP-ribose) polymerase and down-regulation of the inhibitors of apoptosis protein family members. WECU also increased the pro-apoptotic BAX to anti apoptotic BCL-2 ratio, loss of mitochondrial membrane potential and cytochrome c release from mitochondria to cytoplasm. Furthermore, WECU provoked the generation of ROS, but the reduction of cell viability and induction of apoptosis by WECU were prevented when ROS production was blocked by antioxidant N-acetyl cysteine. CONCLUSIONS: These results suggest that WECU suppressed proliferation of MDA-MB 231 cells by activating extrinsic and intrinsic apoptosis pathways in a ROS dependent manner. PMID- 29629030 TI - Household food insecurity, diet quality, and weight status among indigenous women (Mah Meri) in Peninsular Malaysia. AB - BACKGROUND/OBJECTIVES: This cross-sectional study assessed household food security status and determined its association with diet quality and weight status among indigenous women from the Mah Meri tribe in Peninsular Malaysia. SUBJECTS/METHODS: The Radimer/Cornell Hunger and Food Insecurity Instrument and the Malaysian Healthy Eating Index (HEI) were used to assess household food security status and diet quality, respectively. Information on socio-demographic characteristics and 24-hour dietary recall data were collected through face-to face interview, and anthropometric measurements including weight, height, and body mass index (BMI) were obtained from 222 women. RESULTS: Majority of households (82.9%) experienced different levels of food insecurity: 29.3% household food insecurity, 23.4% individual food insecurity, and 30.2% fell into the child hunger group. The food-secure group had significantly fewer children and smaller household sizes than the food-insecure groups (P < 0.05). The mean household income, income per capita, and food expenditure significantly decreased as food insecurity worsened (P < 0.001). The food-secure group had significantly higher Malaysian HEI scores for grains and cereals (P < 0.01), as well as for meat, poultry, and eggs (P < 0.001), than the food-insecure groups. The child hunger group had significantly higher fat (P < 0.05) and sodium (P < 0.001) scores than the food-secure and household food-insecure groups. Compared to the individual food-insecure and child-hunger groups, multivariate analysis of covariance showed that the food-secure group was significantly associated with a higher Malaysian HEI score while the household food-insecure group was significantly associated with a higher BMI after controlling for age (P < 0.025). CONCLUSIONS: The majority of indigenous households faced food insecurity. Food insecurity at the individual and child levels was associated with lower quality of diet, while food insecurity at the household level was associated with higher body weight. Therefore, a substantial effort by all stakeholders is warranted to improve food insecurity among poorer households. The results suggest a pressing need for nutritional interventions to improve dietary intake among low income households. PMID- 29629031 TI - Determining attitudinal and behavioral factors concerning milk and dairy intake and their association with calcium intake in college students. AB - BACKGROUND/OBJECTIVES: Average intake of calcium among college students is below the recommended intake, and knowledge surrounding the attitudinal and behavioral factors that influence milk and dairy intake, a primary food source of calcium, is limited. The purpose of this study was to evaluate college students' attitudes and behaviors concerning milk and dairy consumption and their association with calcium intake. SUBJECTS/METHODS: Participants were 1,730 undergraduate students who completed an online survey (SurveyMonkey) as part of baseline data collection for a social marketing dairy campaign. The online survey assessed attitudes and behaviors concerning milk and dairy intake, and calcium intake. Questions about milk- and dairy-related attitudes and behaviors were grouped into 14 factors using factor analysis. Predictors of calcium intake were then evaluated. RESULTS: Median calcium intake across all participants was 928.6 mg/day, with males consuming higher calcium intakes than females (P < 0.001). Adjusted for gender, calcium intakes were most strongly (and positively) correlated with associating milk with specific eating occasions and availability (i.e., storing calcium-rich foods in one's dorm or apartment) (both P < 0.001). Other correlates of calcium intake included: positive-viewing milk as healthy (P = 0.039), having family members who drink milk) (P = 0.039), and taking calcium supplements (P = 0.056); and negative-parent rules concerning milk (P = 0.031) and viewing milk in dining halls negatively (P = 0.05). CONCLUSIONS: Calcium intakes among college students enrolled in the current study was below the recommended dietary allowance of 1,000 mg/day, reinforcing the need for dietary interventions in this target population, especially females. Practitioners and researchers should consider the factors found here to impact calcium intake, particularly associating milk with specific eating occasions (e.g., milk with breakfast) and having calcium-rich foods available in the dorm room or apartment, as intervention strategies in future efforts aimed at promoting milk and dairy foods and beverages for improved calcium intake in college students. PMID- 29629032 TI - Comparison of body image perception, nutrition knowledge, dietary attitudes, and dietary habits between Korean and Mongolian college students. AB - BACKGROUND/OBJECTIVES: College students are in transition from adolescence to adulthood, and it has been reported that they show poor dietary habits. This study was conducted to compare body image perception, nutrition knowledge, dietary attitudes, dietary habits, and health-related lifestyles between Korean college students (KCS) and Mongolian college students (MCS). SUBJECTS/METHODS: Subjects were 314 KCS and 280 MCS. The data includes results of self-administered questionnaires; statistical analysis was performed using the SPSS 23.0 program. RESULTS: With regards to body image perception, KCS perceived themselves to be fatter on current body image than ideal body image compared to MCS; 64.0% of KCS and 34.6% of MCS desired to be thinner. Total score of nutrition knowledge in KCS (17.0) was significantly higher compared to MCS (8.4) (P < 0.001), but total score of dietary attitudes in KCS (27.0) was significantly lower compared to MCS (31.2) (P < 0.001). Nutrition knowledge had a significantly positive correlation with dietary attitudes in MCS (P < 0.01). Meal consumption among male and female subjects was 2 and 3 times, respectively, in order in KCS, and 3 and 2 times, respectively, in order in MCS (P < 0.001). Rate of skipping breakfast in both genders was significantly higher in KCS than in MCS (male: P < 0.05, female: P < 0.001). In health-related lifestyles, KCS had a significantly higher rate in frequency of alcohol drinking (P < 0.001), exercise (P < 0.01), and mobile phone usage (P < 0.001), compared to MCS. CONCLUSIONS: This study suggests that development of nutrition education program which is effective and proper is required to improve healthy dietary habits among college students of both countries. Essential contents should include acquirement of nutrition knowledge and a motivation for its application to actual life for KCS, and improvement of healthy dietary habits for MCS. PMID- 29629033 TI - Associations of serum levels of vitamins A, C, and E with the risk of cognitive impairment among elderly Koreans. AB - BACKGROUND/OBJECTIVES: Korea is quickly becoming an aged society. Dementia is also becoming a vital public health problem in Korea. Cognitive impairment as a pre-stage of dementia shares most risk factors for dementia. The aim of the present study was to determine associations of serum levels of vitamins A, C, and E with the risk of cognitive impairment among elderly Koreans. SUBJECTS/METHODS: In this cross-sectional study, a total of 230 participants aged 60-79 years from Yangpyeong cohort were included. Cognitive function was assessed by the Korean version of the Mini-Mental State Examination for Dementia Screening. The logistic multivariable regression model was applied to determine the effect of serum vitamins A, C, and E on the risk of cognitive impairment. RESULTS: There was no significant association between the risk of cognitive impairment and serum levels of vitamin A and vitamin C. There was a significant odd ratio when the second tertile group of beta-gamma tocopherol level was compared to the first tertile group [odds ratio (OR) = 0.37, 95% confidence interval (CI) = 0.14-0.98, P for trend = 0.051]. In subgroup analyses, there were significant negative associations between beta-gamma tocopherol level and the risk of cognitive impairment in men (OR = 0.17, 95% CI = 0.03-0.87, P for trend = 0.028), non drinkers or former drinkers (OR = 0.13, 95% CI = 0.02-0.66, P for trend = 0.025), and non-smokers or former smokers (OR = 0.27, 95% CI = 0.09-0.82, P for trend = 0.017). CONCLUSION: Serum beta-gamma tocopherol levels tended to be inversely associated with the risk of cognitive impairment. Further prospective large scaled studies are needed to examine this association. PMID- 29629034 TI - Relationship between heavy drinking, binge drinking, and metabolic syndrome in obese and non-obese Korean male adults. AB - BACKGROUND/OBJECTIVES: Obesity and alcohol drinking are associated with metabolic syndrome. However, few studies show the relationship between alcohol drinking and metabolic syndrome according to varying degrees of obesity. This study aimed to determine the association between alcohol drinking and metabolic syndrome in obese and non-obese Korean male adults. SUBJECTS/METHODS: This cross-sectional study included 5,867 males aged >= 20 years who were examined at the Soonchunhyang University health promotion center during June 2008-December 2010. The subjects were divided into non-obese (body mass index [BMI] < 25 kg/m2) and obese (BMI >= 25 kg/m2) groups and further divided according to weekly alcohol consumption into nondrinking (0 drinks/week), moderate drinking (<= 14 drinks/week), and heavy drinking (> 14 drinks/week) groups. The subjects were also categorized into binge drinking and non-binge drinking groups. To obtain odds ratios (ORs) for metabolic syndrome, binary logistic regression analysis was performed. RESULTS: The overall metabolic syndrome prevalence was 27.3% (12.8%, non-obese group; 50.4%, obese group). After adjusting for age, physical activity, and smoking, in the non-obese group, the OR for heavy drinking with binge drinking (reference: nondrinking) was 1.56 (95% confidence interval [CI] = 1.12 2.18), with a significant increase in metabolic syndrome prevalence. In the obese group, the OR for heavy drinking with binge drinking was 1.42 (95% CI = 1.07 1.88), showing a significant increase in metabolic syndrome prevalence (P < 0.05). CONCLUSIONS: In both non-obese and obese Korean males, heavy drinking with binge drinking was associated with increased risk of metabolic syndrome. Thus, both non-obese and obese males should restrict their alcohol intake and not indulge in binge drinking. PMID- 29629035 TI - Erratum: Instant noodle consumption is associated with cardiometabolic risk factors among college students in Seoul. AB - [This corrects the article on p. 232 in vol. 11, PMID: 28584580.]. PMID- 29629036 TI - Health Inequality in Health Checkups. PMID- 29629037 TI - Association of Time to First Morning Cigarette and Chronic Obstructive Pulmonary Disease Measured by Spirometry in Current Smokers. AB - Background: Time to first cigarette after waking is an indicator of nicotine dependence. We aimed to identify the association between time to first cigarette and spirometry-proven obstructive respiratory impairment, especially chronic obstructive pulmonary disease, in current smokers. Methods: We included 392 subjects who visited the comprehensive medical examination center of Hallym University Sacred Heart Hospital between July 2014 and September 2015. Subjects with lung disease or anemia were excluded. Obstructive pulmonary impairment was defined as <70% of the predicted value of forced expiratory volume in 1 second/forced vital capacity. Subjects were classified into the early (<=30 minutes) and late (>30 minutes) groups based on the time to first cigarette. Logistic regression and linear regression analyses were used for data analysis. Results: Ninety-eight subjects (25%) were classified into the early group. After adjusting for smoking behaviors (cigarettes per day and smoking duration), socioeconomic status (education and income), age, and physical activity, an early time to first cigarette was found to be associated with an increased risk of obstructive pulmonary impairment measured using spirometry (adjusted odds ratio, 2.84; 95% confidence interval, 1.22-6.61). Conclusion: Compared to current smokers with a late time to first cigarette, those with an early time to first cigarette had a higher risk of obstructive pulmonary impairment, especially chronic obstructive pulmonary disease. Classifying smoking-related behaviors, especially time to first cigarette, may help target clinical screening for chronic obstructive pulmonary disease. PMID- 29629039 TI - Relationships of Serum Iron Parameters and Hemoglobin with Forced Expiratory Volume in 1 Second in Patients with Chronic Obstructive Pulmonary Disease. AB - Background: Although chronic obstructive pulmonary disease is a known cause of secondary polycythemia with elevated erythropoietic demands in response to hypoxemia, anemia is relatively common in patients with chronic obstructive pulmonary disease and is related to increased mortality. However, little is currently known about the relationship between various iron parameters and disease severity in chronic obstructive pulmonary disease patients. Methods: Data from the fifth Korean National Health and Nutrition Examination Survey, a population-based epidemiologic survey conducted in 2010-2012, were used. A total of 1,129 patients with chronic obstructive pulmonary disease were examined to reveal the associations between the forced expiratory volume in 1 second (FEV1) and hemoglobin and iron parameters, including serum iron, ferritin, total iron binding capacity, and transferrin saturation, using Spearman correlations and multiple linear regression analyses. Results: The FEV1 was positively correlated with serum hemoglobin (gamma=0.37, P<0.001), iron (gamma=0.20, P<0.001), transferrin saturation (gamma=0.19, P<0.001), and ferritin (gamma=0.22, P<0.001), and negatively correlated with age (gamma=-0.40, P<0.001) and lower in female patients (gamma=-0.56, P<0.001) in the Spearman correlation. The FEV1 was independently associated with serum iron (beta=0.049, P=0.035) and transferrin saturation (beta=0.049, P=0.035) after adjusting for age, sex, and body mass index in the multiple linear regression analyses. Conclusion: The serum iron and transferrin saturation levels were independently associated with FEV1 as a marker of chronic obstructive pulmonary disease severity. PMID- 29629038 TI - The Association between Fat Mass, Lean Mass and Bone Mineral Density in Premenopausal Women in Korea: A Cross-Sectional Study. AB - Background: We investigated the association between body composition, especially truncal or non-truncal fat mass (FM), and bone mineral density (BMD) in premenopausal women in Korea. Methods: A cross-sectional study was performed using data from the Korea National Health and Nutrition Examination Survey IV and V (2008-2011). Total lean mass (LM), total FM (TFM), truncal FM, and non-truncal FM, and BMD of the total femur, femoral neck (FN), and lumbar spine were measured using dual-energy X-ray absorptiometry. The association between body composition and BMD was analyzed using multiple linear regression. The risk of low BMD according to quartiles of TFM, truncal FM, and non-truncal FM was calculated using logistic regression. Subgroup analysis according to body mass index was also performed. Results: In 4,343 premenopausal women, total LM was positively associated with BMD regardless of weight adjustment. TFM, truncal FM, and non truncal FM were inversely associated with BMD after adjusting for weight. Odds ratios (ORs) for low BMD and 95% confidence intervals (CIs) of the highest quartile of TFM, truncal FM, and non-truncal FM compared with the lowest quartile were calculated. The risk of low BMD of the FN was higher in the highest quartile of TFM (OR, 4.48; 95% CI, 1.11-18.01) and truncal FM (OR, 5.48; 95% CI, 1.75 17.20). Truncal FM and not-truncal FM had an inverse association with BMD in the non-obese and obese subgroups of women. Conclusion: Total LM has a protective effect on BMD and FM can have a detrimental effect on BMD besides its skeletal loading effect. PMID- 29629040 TI - The Association between Smoking Status and Influenza Vaccination Coverage Rate in Korean Adults: Analysis of the 2010-2012 Korea National Health and Nutrition Examination Survey. AB - Background: Globally, smoking is one of the biggest challenges in public health and is a known cause of several important diseases. Influenza is preventable via annual vaccination, which is the most effective and cost-beneficial method of prevention. However, subjects who smoke have some unhealthy behaviours such as alcohol, low physical activity, and low vaccination rate. In this study, we analyzed the relationship between smoking status and factors potentially related to the influenza vaccination coverage rate in the South Korean adult population. Methods: The study included 13,565 participants aged >19 years, from 2010 to 2012 from the Korea National Health and Nutrition Examination Survey data. Univariate analyses were conducted to examine the association between influenza coverage rate and related factors. Multivariate analysis was obtained after adjusting for variables that were statistically significant. Results: The overall vaccination rate was 27.3% (n=3,703). Older individuals (P<0.0001), women (P<0.0001), non smokers (P<0.0001), light alcohol drinkers (P<0.0001), the unemployed (P<0.0001), and subjects with diabetes mellitus (P<0.0001), hypercholesterolemia (P<0.0001), and metabolic syndrome (P<0.0001) had higher influenza vaccination coverage than the others. In multivariate analyses, current smokers and heavy smokers showed lower vaccination rates (odds ratio, 0.734; 95% confidence interval, 0.63-0.854). Conclusion: In the current study, smokers and individuals with inadequate health promoting behaviors had lower vaccination rates than the others did. PMID- 29629041 TI - Comparison of Patient-Physician Interaction Scores of Clinical Practice Examination between Checklists and Rating Scale. AB - Background: The clinical practice examination (CPX) was introduced in 2010, and the Seoul-Gyeonggi CPX Consortium developed the patient-physician interaction (PPI) assessment tool in 2004. Both institutions use rating scales on classified sections of PPI but differ in their scoring of key components. This study investigated the accuracy of standardized patient scores across rating scales by comparing checklist methods and verified the concurrent validity of two comparable PPI rating tools. Methods: An educational CPX module dyspepsia case was administered to 116 fourth-year medical students at Hanyang University College of Medicine. One experienced standardized patient rated exams using two different PPI scales. She scored checklists composed of 43 items related to the two original PPI scales through video clips of the same students. From these checklists, we calculated Pearson's correlation coefficient. Results: The correlations of total PPI score between the checklist and rating scale methods were 0.29 for the Korean Medical Licensing Examination (KMLE) tool and 0.30 for the consortium tool. The correlations between the KMLE and consortium tools were 0.74 for checklists and 0.83 for rating scales. In terms of section scores, the consortium tool showed only three significant correlations between the two methods out of seven sections and the KMLE tool showed only two statistically significant correlations out of five sections. Conclusion: The rating scale and checklist methods exhibited a weak relationship in the PPI assessment, but a high correlation between assessment tools using the same method. However, the current rating scale requires modification by reorganizing key scoring components through factor analysis. PMID- 29629042 TI - Depression, Anxiety, and Perceived Social Support among Adults with Beta Thalassemia Major: Cross-Sectional Study. AB - Background: Considering the high prevalence of depression and anxiety among thalassemia patients and the role of social support in preventing mental disorders, this study aimed to determine prevalence of depression, anxiety, and perceived social support (PSS) among adults with beta-thalassemia major. Methods: This cross-sectional study was performed with 389 adults with beta-thalassemia major. Data were collected via a questionnaire consisting of three parts: demographic and medical information, the Persian version of the hospital anxiety and depression scale, and the Persian version of the Multidimensional Scale of Perceived Social Support. Data were analyzed using IBM SPSS ver. 23.0 (IBM Corp., Armonk, NY, USA) through analytical statistics (independent-samples t-test, one way analysis of variance, Pearson correlation coefficient, and multilevel linear regression), and the results less than 0.05 were considered to be significant. Results: The mean scores of depression, anxiety, and PSS of patients were 7.42+/ 3.17, 7.47+/-4.35, and 41.8+/-8.64, respectively. Of 389 patients, 19.8% had depression and 23.7% had an anxiety disorder. Relationships of depression and anxiety with age, the level of education, job, and family income were statistically significant, as were those of PSS with age, thalassemia center, family income, job, and the level of education. PSS from family, friends, and significant others were the significant predictive factors of depression and anxiety among adult patients with beta-thalassemia major. Conclusion: Considering the PSS as a factor influencing the reduction in depression and anxiety in thalassemia patients, social support from the social networks (spouse, family members, friends, and healthcare workers) should be integrated with interventions that are designed to improve the mental and physical health of thalassemia patients. PMID- 29629043 TI - Lower Levels of Serum Adiponectin and the T Allele of rs1501299 of the ADIPOQ Gene Are Protective against Polycystic Ovarian Syndrome in Jordan. AB - Background: Polycystic ovary syndrome (PCOS) is a common reproductive disorder. Obesity, which is linked with lower adiponectin levels, increases a woman's risk of developing PCOS; however, the association between adiponectin and PCOS is controversial. Adiponectin levels could be affected by single nucleotide polymorphisms (SNPs) in the ADIPOQ gene. This study aimed to test the relationship between serum adiponectin and PCOS in Jordan and the association between the rs2241766, rs1501299, and rs266729 SNPs in the ADIPOQ gene and PCOS. Methods: One hundred and fifty-four women with PCOS and 149 age- and body mass index-matched normally menstruating controls were recruited. Serum adiponectin levels were measured using enzyme-linked immunosorbent assay. Genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism analysis. Results: Serum adiponectin levels were significantly lower (P=0.0064) in PCOS women and rs1501299 (+276 G/T) genotype distributions were significantly different (P=0.01) between them and normally menstruating women. Multivariate analysis revealed that adiponectin levels remained significantly lower in PCOS women (P=0.001; odds ratio [OR], 0.9; 95% confidence interval [CI], 0.84-0.96). The GT genotype of rs1501299 increased the risk of PCOS (P<0.001; OR, 5.46; 95% CI, 2.42-12.33) and increased the risk of PCOS by three-fold (P<0.001; OR, 3.00; 95% CI, 1.36-6.60) relative to the TT genotype. The GG genotype increased the risk of PCOS as well (P<0.001; OR, 3:00; 95% CI, 1.36-6.60). Conclusion: PCOS is associated with lower serum adiponectin levels independent of age and body mass index. The T allele of the rs1501299 (+276 G/T) SNP of the ADIPOQ gene protects against PCOS. PMID- 29629044 TI - The Association between Socioeconomic Status and Adherence to Health Check-up in Korean Adults, Based on the 2010-2012 Korean National Health and Nutrition Examination Survey. AB - Background: We investigated the association between socioeconomic status and adherence to health check-ups in a Korean population aged 40 years or older. Methods: This cross-sectional study included 12,311 participants who participated in the 2010-2012 Korean National Health and Nutrition Examination Survey. Self reported questionnaires were used to assess each participant's socioeconomic status (household income, occupation, and education) and adherence to health check-ups. Results: Men with a higher income (highest vs. lowest: odds ratio [OR], 1.799; 95% confidence interval [CI], 1.296-2.497) and men with a higher education level (>=12 vs. <6 years: OR, 1.488; 95% CI, 1.078-2.054) and office workers compared with manual workers (men: OR, 1.431; 95% CI, 1.077-1.902; women: OR, 1.783; 95% CI, 1.256-2.532) appeared to undergo more health check-ups. In particular, men and women with a higher income and education appeared more likely to undergo opportunistic health check-ups (men: highest vs. lowest income: OR, 2.380; 95% CI, 1.218-4.653; >=12 vs. <6 years education: OR, 2.121; 95% CI, 1.142 3.936; women: highest vs. lowest income: OR, 4.042; 95% CI, 2.239-7.297; >=12 vs. <6 years education: OR, 2.475; 95% CI, 1.283-4.775). Conclusion: A higher socioeconomic status was associated with a higher rate of participation in health check-ups. More efforts are needed to identify the factors associated with disparity in adherence to health check-ups. PMID- 29629045 TI - Iatrogenic Development of Cerebrospinal Fluid Leakage in Diagnosing Spontaneous Intracranial Hypotension. AB - A 34-year-old woman came to the emergency room complaining of a severe orthostatic headache. Results of a cerebrospinal fluid tap and brain computed tomography were normal. Based on her history and symptoms, she was found to have spontaneous intracranial hypotension. She was hospitalized and her symptoms improved with conservative treatment. On the next day, her headache suddenly worsened. Cisternography was performed to confirm the diagnosis and determine the spinal level of her cerebrospinal fluid leak. It revealed multiple cerebrospinal fluid leaks in the lumbar and upper thoracic regions. It was strongly believed that she had an iatrogenic cerebrospinal fluid leak in the lumbar region. An epidural blood patch was performed level by level on the lumbar and upper thoracic regions. Her symptoms resolved after the epidural blood patch and she was later discharged without any complications. In this case, an iatrogenic cerebrospinal fluid leak was caused by a dural puncture made while diagnosing spontaneous intracranial hypotension, which is always a risk and hampers the patient's progress. Therefore, in cases of spontaneous intracranial hypotension, an effort to minimize dural punctures is needed and a non-invasive test such as magnetic resonance imaging should be considered first. PMID- 29629046 TI - A Diabetic Elderly Man with Finger Ulcer. AB - Fixed cutaneous sporotrichosis is a differential diagnosis that can be considered in diabetic patients who present with a poorly healing ulcer. Although its prevalence is low, it can occur in patients with immunocompromised status. Here we report a case of a 70-year-old man with diabetes mellitus who presented with a 1-month history of an unhealed ulcer over the tip of his left middle finger. He experienced a cat bite over his left middle finger 1 month prior to the appearance of the lesion. A skin biopsy revealed the presence of Sporothrix schenckii. Oral itraconazole 200 mg twice daily was started empirically and the patient showed marked improvement in the skin lesion after 2 months of therapy. PMID- 29629047 TI - Adequacy of Protein Intake among Korean Elderly: An Analysis of the 2013-2014 Korea National Health and Nutrition Examination Survey Data. AB - Background: Protein intake in South Korea is generally considered to be adequate; however, there is concern that it may be inadequate among the elderly. This study evaluated the adequacy of protein intake, the source of protein, and the distribution of protein intake in daily meals in the Korean elderly population. Methods: Data were obtained from 1,484 men and 2,028 women aged 60 years or older who had participated in the nutrition survey of the 2013-2014 Korea National Health and Nutrition Examination Survey. One-day (24-hour) recall data were used to estimate the daily protein intake. Results: The mean protein intake was 65.3+/ 1.0 g/d (13.1%+/-0.1% of energy) and 49.7+/-0.7 g/d (12.6%+/-0.1% of energy) for men and women, respectively. The protein intake was less than the estimated average requirement in 30.8%+/-1.4% of men and 42.6%+/-1.3% of women, and 47.9%+/ 1.6% and 60.1%+/-1.4%, respectively, consumed less than the recommended daily allowance. The protein intake was relatively evenly distributed among meals; however, the absolute amount of protein consumption per meal was very low. Only one-third of the protein intake came from animal sources. Conclusion: The quantity and quality of protein intake were inadequate in the elderly Korean population. PMID- 29629048 TI - Prophylactic effect of riboflavin on pediatric migraine: a randomized, double blind, placebo-controlled trial. AB - Background and aim: Riboflavin may have an acceptable effect on migraine among children. This study was carried out to determine the prophylactic effect of riboflavin on migraine in children. Methods: This randomized clinical trial study was performed at Shahid Beheshti Hospital in Kashan, Iran from December 2012 to February 2015. Ninety children with migraine were allocated randomly into 3 groups (placebo, low-dose and high-dose riboflavin). The outcomes (frequency, intensity and duration of headaches) were measured at baseline and 12 weeks of medication in each group, and the decrease of them were compared. SPSS software version 16 was used for analysis of the data. Descriptive statistics, Chi-square, Fisher's exact and t-test were used for statistical analyses. Results: There was a significant decrease of migraine frequency (p=0.000) and mean duration (p=0.000) in the high-dose group compared with the placebo group. No significant reduction of frequency and mean duration of attacks were reported in the low-dose group compared to the placebo group (p=0.49 and p=0.69 respectively). There was no significant reduction of migraine intensity in the low-dose and high-dose groups compared to the placebo group (p=0.71 and p=0.74 respectively). Conclusion: High-dose riboflavin is a safe, well tolerated, cost-effective method of prophylaxis for children with migraine. Trial registration: The trial was registered at the Iranian Clinical Trial Registry with number IRCT2013020412361N1. Funding: The study was supported by the Deputy of Research, Kashan University of Medical Sciences (grant number 91073). PMID- 29629050 TI - Perceptions of teenage women about marriage in adolescence in an Iranian setting: A qualitative study. AB - Background and aim: Early marriage threatens the health and human rights of millions of girls all around the world. The aim of this study was to explore the perceptions of Iranian teenage women about marriage in adolescence. Methods: A qualitative study was conducted based on the conventional content analysis approach on 14 teenage married women (aged13-19 years) who attended all urban rural healthcare centers (4 centers) in Ardabil, Iran between May 2016 and Jan 2017. Data were collected through in-depth semi-structured interviews. Purposeful sampling was continued until data saturation. The data were analyzed using the Graneheim and Landman strategies. Results: The mean age at marriage was 13.2 (SD=1.25) years and the duration of marital life ranged from 45 days to 3 years. During the data analysis, three main categories were extracted that each of them consisted of three sub-categories. The main categories, included "a false sense of sexual development", "death of dreams", and "threatened independence". Conclusion: Results of this study revealed that teenage women could not comprehend opportunities in life. These findings could help health care providers and policy makers to provide teenage women with special care and better support to prevent negative consequences of early marriage. PMID- 29629049 TI - Risk factors associated with congenital hypothyroidism: a case-control study in southeast Iran. AB - Background and aim: Congenital hypothyroidism (CH) is known as one of the most common preventable cause of mental retardation. This study aimed to determine factors associated with CH in Iran. Methods: This case-control study was conducted on 160 children under one year old in Zahedan in southeast Iran in 2016. The neonates who were born from March 1, 2015 to March 19, 2016 and had undergone a screening program for CH were the study population. The neonates with serum TSH > 10mIu/L and T4 < 6.5 or TSH > 30 mIu/L were considered as a case group. Each case was individually matched for sex, age at birth and place of residence with three neonates with normal TSH and T4 titers as a control group. Data was gathered using a standard checklist and analyzed using SPSS 20 and statistical tests, such as Chi-square and Fisher's exact tests. Multivariable logistic regression analysis was also used to identify independent predictors of CH. Results: About 25 of the 40 patients with CH (62.5%) were male who, in the univariate analysis, the following explanatory factors had no significant association with CH: history of parental consanguinity, type of delivery, weight at birth, height at birth, age of mother, sampling time, nationality, and birth season (p>0.05). Although, multivariate analysis showed no significant association between the studied factors and risk of CH (p>0.05), the likelihood of CH was greater among neonates born to consanguineous parents (AOR: 1.78, 95% CI: 0.82-3.89), those who were born to lower height at birth (AOR: 1.82, 95% CI: 0.85-3.91), neonates born to mothers younger than 18 years (AOR: 2.43, 95% CI: 0.57-10.29) and those who were born in the summer (AOR: 1.76, 95% CI: 0.57-5.44). Conclusion: None of the studied factors were predictors for CH. Since consanguineous marriages are frequent in the province, and it may be a major contributory factor, future studies should be conducted on the genetic causes. PMID- 29629051 TI - The challenges of strategic purchasing of healthcare services in Iran Health Insurance Organization: a qualitative study. AB - Background: Strategic purchasing in healthcare services is a key component in improving health system performance, and it has been one of the most important issues in health system reform around the world, especially Europe in the last decade. Iran health system and insurance, although sometimes considered the issue of strategic purchasing goals, has not been made possible to achieve or even to implement, due to the associated problems. Objective: To determine the associated problems of strategic purchasing in the Iran Health Insurance Organization (IHIO). Methods: This study is a qualitative study, and framework analysis which was conducted in Iran in 2014-15. The participants in this study were 34 individuals from decision-makers and executives in the IHIO purchasing process, and university experts who have been chosen purposefully. This study conducted frame analysis, by using MAXQDA 10. Results: The findings included associated problems of IHIO strategic purchasing in 12 themes and 65 subthemes. The themes included: Laws and regulations for purchasing, Organization of purchasing, Qualified and authorized providers, Right type of services, Right type of contracts, Target groups for purchasing, Resources allocation, financing and pricing system, Purchasing as improving performance and quality, Purchasing as shaping the market and competition, Purchasing as health progress state of people and society, Guided purchasing and stewardship of government, Structure of decision-making process in the health and welfare ministries. Conclusion: The findings of this study showed associated problems in IHIO strategic purchasing. To achieve strategic purchasing goals in Iran, identification of all issues and factors of the total insurers and health system sets which affect strategic purchasing is essential. PMID- 29629052 TI - Cosmic rays as a novel hypothetic explanation for the ancient mentioned effects of sleeping under the night sky. AB - Traditional medicine scientists believed that sleeping under the stars and moonlight is not healthy because it brings about nose bleeds and respiratory problems. In Avicenna's view, the spirit and its tendency to the light are introduced as main etiology, which cannot explain star light as a proper etiology. In modern knowledge, it seems cosmic rays that reach our planet's atmosphere by electron cascade, play a key role. Internal organs' electrical charge distribution disturbance caused by these electrons can lead to irregular spasms in the muscular walls of arteries and other organs. These interactions may finally lead to circulation (epistaxis and hypertension) and respiratory (catarrh) problems. PMID- 29629053 TI - Effective factors on menstrual health among female students in Bam city: a qualitative study. AB - Background: Menarche is an independent puberty event in a girl's life, and is associated with physical growth, ability in marriage and fertility. Therefore, poor menstrual health can be a major determinant of morbidity, as well as physical, mental and social problems in this age group. Objective: The aim of this study was to explore the effective factors on menstrual health among female students in Bam city. Methods: The qualitative study was conducted using content analysis approach in 2017. The participants were 32 individuals consisting of 13 students, 10 mothers of the same students, 9 school associates and health educators of 5 secondary schools in Bam city, who were selected based on an objective-oriented approach. The sampling was done until data saturation. Data collection methods were semi-structured and in-depth interview. Data analysis was performed using the steps suggested by Graneheim and Landman. Results: There were two categories (easy interaction and inappropriate adaptation to changes in health behavior), 13 sub-categories and 52 initial codes. The positive factors included easy access to sanitary pads, appropriate school education, easy access to health and therapeutic services and school flexibility on menstrual issues, while the negative factors included inadequate facilities for sanitary pad disposal, lack of access to informed people about menstrual issues, insufficient attention to menstrual problems, feeling ashamed, the high cost of menstrual health, self-medication with traditional medicines, inadequate self-directed education, lack of awareness and trust in health center staff, and following family and teachers in menstrual problems. Conclusion: Overall, this study indicated that economic, social, cultural and educational factors affect menstrual health. Therefore, the identification of each of these factors helps planners to apply the most appropriate methods and strategies for menstrual health improvement. PMID- 29629054 TI - Health information technology in ambulatory care in a developing country. AB - Background: Physicians need to apply new technologies in ambulatory care. At present, with regard to the extended use of information technology in other departments in Iran it has yet to be considerably developed by physicians and clinical technicians in the health department. Objective: To determine the rate of use of health information technology in the clinics of specialist- and subspecialist physicians in Semnan city, Iran. Methods: This was a 2016 cross sectional study conducted in physicians' offices of Semnan city in Iran. All physicians' offices in Semnan (130) were studied in this research. A researcher made and Likert-type questionnaire was designed, and consisted of two sections: the first section included demographic items and the second section consisted of four subscales (telemedicine, patient's safety, electronic patient record, and electronic communications). In order to determine the validity, the primary questionnaire was reviewed by one medical informatics- and two health information management experts from Semnan University of Medical Sciences. Utilizing the experts' suggestions, the questionnaire was rewritten and became more focused. Then the questionnaire was piloted on forty participants, randomly selected from different physicians' offices. Participants in the pilot study were excluded from the study. Cronbach's alpha was used to calculate the reliability of the instruments. Finally, SPSS version 16 was used to conduct descriptive and inferential statistics. Results: The minimum mean related to the physicians' use of E-mail services for the purpose of communicating with the patients, the physicians' use of computer-aided diagnostics to diagnose the patients' illnesses, and the level of the physicians' access to the electronic medical record of patients in the other treatment centers were 2.01, 3.58, and 1.43 respectively. The maximum mean score was related to the physicians' use of social networks to communicate with other physicians (3.64). The study showed that the physicians used less computerized systems in their clinic for the purpose of managing their patients' safety and there was a significant difference between the mean of the scores (p<0.001). Conclusion: The results showed that the physicians used some aspects of health information technology for the reduction of medical risks and increase of the patient's safety, by collecting the medical data of patients and the rapid and apropos recovering of them for adaptation of clinical decisions. PMID- 29629055 TI - Accuracy of immunoblotting assay for detection of specific IgE compared with ImmunoCAP in allergic patients. AB - Background and aim: Standardized techniques help us to better diagnosis and follow up of allergic diseases. In this study, we determined the sensitivity, accuracy, and specificity of an Immunoblotting test compared to ImmunoCAP as the reference in vitro test for detection of specific IgE in allergic patients. Methods: In this cross-sectional study, specific IgE level was determined in patients with allergic symptoms who referred to the Immunology, Asthma and Allergy Research Institute, Tehran, Iran from 2010-2016, by two techniques. Eleven different allergens (six aeroallergens and five food allergens) were determined, and 303 specific IgE tests were performed for the patients by each method. The Immunoblotting test is a multiplex assay on a nitrocellulose membrane coated with 20 selected allergens. ImmunoCAP is considered as the reference method for determination of in vitro specific IgE. Its principle is an automated sandwich immunoassay, and allergens were bound to the solid phase, covalently. Finally, the fluorescence of elute was determined. Specific IgE more than 0.35 KU/L was considered as a positive test. Sensitivity, specificity, accuracy, kappa coefficient, positive and negative likelihood ratio (+/- LR), and correlation coefficient (calculated with Spearman test) between two tests were determined using statistical analysis (SPSS software, version 18). Results: One hundred and thirty five patients entered this study. The median age of the patients was 3.75 years with the males constituting 54.8% of the population. The most common cheif complaints were respiratory (51.6%), skin (41.8%) and gastrointestinal (27.9%) symptoms, respectively. The sensitivity, specificity, accuracy, +LR and -LR were 83%, 97%, 92%, 27.66 and 0.17, respectively. The kappa coefficient of the immunoblotting test was 0.81 compared to the reference technique. The correlation coefficient for positive tests between the two methods was 0.71 (p<0.001). Conclusion: Regarding the presence of 20 allergens in a RIDA allergy panel and according to our findings, this immunoblotting test with high sensitivity could be used as a fast and cost-efficient screening test. However, ImmunoCAP is recommended when the accurate level of specific IgE is required. ImmunoCAP findings are particularly helpful for immunotherapy and the elimination diet. PMID- 29629056 TI - Prediction of internet addiction based on information literacy among students of Iran University of Medical Sciences. AB - Background: A considerable group of internet users consists of university users; however, despite internet benefits and capabilities, internet overuse is a threat to societies especially to young people and students. Objective: The objective of this study was to determine the predictive role of information literacy in internet addiction among students of Iran University of Medical Sciences during 2016. Methods: This analytical cross-sectional study was conducted in Iran University of Medical Sciences in 2016. Using stratified random sampling method, 365 students from different disciplines were selected. Measuring tools included the Information Literacy Questionnaire, the Yang Online Drug Addiction Scale and the General Health Questionnaire. The collected data were analyzed by Pearson product-moment correlation, independent samples t-test and multiple linear regression using SPSS version 22. Results: According to this study, 31.2% of students had internet addiction (29.9% were mildly addicted and 1.3% had severe addiction). There was a significant and inverse relationship between higher information literacy and internet addiction (R= -0.45) and (p<0.001). The predictor variable "Information literacy" explained 20% of the variation in the outcome variable "Internet addiction". Conclusion: Students play a substantial role in promoting the cultural and scientific level of knowledge in society; the higher their information literacy, the lower the level of Internet addiction, and consequently the general health of society will improve. It seems that wise planning by authorities of Iran's universities to prevent internet addiction and to increase information literacy among students is needed. PMID- 29629057 TI - Etiology of gastrointestinal bleeding in children referred to pediatric wards of Mashhad hospitals, Iran. AB - Background: Gastrointestinal (GI) bleeding, which has several clinical manifestation and origins, is known as one of the most life-threatening events in children. Several etiologies have been suggested for GI bleeding. Objective: To determine the most important causes of GI bleeding in children referred to Ghaem Hospital and Dr. Sheikh Hospital, Mashhad, Iran. Methods: In this cross-sectional study, after obtaining written informed consent of their parents, 113 patients aging from newborn infants to 18-year-old children with GI bleeding admitted to Ghaem Hospital and Dr. Sheikh hospital were enrolled in this study from June 2012 to June 2014. After performing routine diagnostic and therapeutic procedures, a checklist containing all necessary information including demographic data, clinical history of patients, endoscopy and pathology findings, clinical and preclinical information were collected. The data were then analyzed using Statistical Package for the Social Sciences (SPSS) version 16. Results: Of a total 113 study children, 61 (54%) were male and 52 (46%) were female. The results of this study showed that the most important causes of bleeding in upper GI among all admitted patients were prolapse gastropathy (18.6%), esophagitis (15.9%) and esophageal varices, gastritis, and coagulopathy (7.1% for each). The main causes of lower GI bleeding were polyp (32.5%), chronic nonspecific colitis (20.7%), and proctitis (18.2%). Conclusion: Findings of this study indicated that prolapse gastropathy and esophagitis are more prevalent causes of upper GI bleeding. Furthermore, esophageal varices were more common in children older than 13 years. Polyp, chronic nonspecific colitis and proctitis are the most prevalent causes of lower GI bleeding. PMID- 29629058 TI - Effect of propofol and isoflurane on gas exchange parameters following one-lung ventilation in thoracic surgery: a double-blinded randomized controlled clinical trial. AB - Background: The use of anesthetic drugs with minimal inhibitory effects on the hypoxic pulmonary vasoconstriction (HPV) could have a decisive role in preventing the hypoxemia during one-lung ventilation (OLV). Objective: The aim of this study was to compare the effects of propofol and isoflurane on the changes in gas exchange parameters following OLV in thoracic surgery. Methods: This double blinded randomized controlled clinical trial was conducted on patients who were candidates for elective right thoracotomy referred to the central operating room of Ghaem Hospital in Mashhad, Iran, during February 2016-2017. Patients with age range of 18 to 75 years, class I and II American Society of Anesthesiologists (ASA) and thoracotomy with OLV for pulmonary resection or cyst drainage were included. The patients were randomly allocated (1:1 ratio) into two groups of propofol (P, 50-100MUg/kg/min) and isoflurane (I, 1 minimum alveolar concentration (MAC) 1.1%). Partial pressure of carbon dioxide (PaCO2), partial pressure of oxygen (PaO2), end-tidal carbon dioxide (ETCO2) and arterial oxygen saturation (SPO2) were recorded before and 15 minutes after OLV and compared between the two groups. The comparison of the mean gas exchange parameters before and 15 minutes after OLV was performed using Mann-Whitney test in SPSS version 19 software. P<0.05 was considered statistically significant. Results: In this study, 122 patients with mean age of 59.4+/-14.1 years (two groups of 61) were studied. Both groups were matched for age or gender. The two groups had no significant difference in the gas exchange parameters before the OLV. Only PaCO2 (p=0.001) and ETCO2 (p=0.001) were significantly higher in the propofol group after 15 minutes OLV than in the isoflurane group. However, PaO2 (p=0.67), O2Sat (p=0.333) and PaCO2-ETCO2 gradient (p=0.809) showed no significant difference between the two groups at this minute. Conclusion: Based on the results of this study, the propofol or isoflurane selection seems to have no significant effect on the arterial oxygenation. On the other hand, isoflurane and propofol could be an appropriate anesthetic for thoracic surgery by normalizing the carbon dioxide gradient range during the OLV. Clinical Trial Registration: The study was also registered at the Iranian Registry of Clinical Trials (IRCT2015123013159N8). Funding: The study was financially supported by the Deputy of Research of Mashhad University of Medical Sciences (grant number: 940119). PMID- 29629059 TI - Effect of oral ginger on prevention of nausea and vomiting after laparoscopic cholecystectomy: a double-blind, randomized, placebo-controlled trial. AB - Background: Postoperative nausea and vomiting (PONV) are among the most frequent complications following laparoscopic cholecystectomy. Recently, some studies have shown ginger, as an herbal medicine, to be effective and safe in PONV prevention; however, there is no evidence of its efficacy in the Iranian population. Objective: The aim of this study was to determine the effect of oral ginger on PONV prevention after laparoscopic cholecystectomy. Methods: This double-blind, randomized, placebo-controlled clinical trial was performed on women who were undergoing laparoscopic cholecystectomy in Imam Raza Hospital, Mashhad, Iran between April and November, 2016. Patients were divided randomly into two groups of G) intervention group (n=75, received 2 capsules containing 250 mg ginger) and P) placebo group (n=75, received 2 placebo capsules) one hour before surgery. Nausea severity and vomiting frequency were evaluated at 2, 4, 6, and 12 hours after the operation. Data analysis was done by SPSS version 16.0 software with Chi-square test, Independent-sample-t-test, repeated measure ANOVA and Mann Whitney U test. Results: The two groups were homogenous in terms of age, gender and surgery duration. The severity of nausea was lower in the ginger group at the 2, 4, 6, and 12 hours after the operation; however, these differences were statically significant only at 2 (p=0.034) and 12 hours (p=0.043). Although the incidence of vomiting was higher in the placebo group in the 2nd and 12th hours after surgery, the number of vomiting episodes in 2, 4, 6 and 12 hours after surgery was statistically similar in the two groups (p>0.05). The nausea severity was significantly changed during 12 hours of study in both groups (p=0.001), however the nausea severity was always lower in the ginger group (p=0.078). Conclusion: This study demonstrated that 500mg oral ginger one hour before surgery in women who were undergoing laparoscopic cholecystectomy is effective in decreasing severity of PONV. Trial registration: The trial was registered at the Iranian Registry of Clinical Trials (http://www.irct.ir) with the Irct ID: IRCT2016122222218N2. Funding: The study was financially supported by Deputy of Research of Mashhad University of Medical Sciences. PMID- 29629060 TI - Reliability and validity assessment of gastrointestinal dystemperaments questionnaire: a novel scale in Persian traditional medicine. AB - Background: Development of a questionnaire based on the resources of Persian traditional medicine seems necessary. One of the problems faced by practitioners of traditional medicine is the different opinions regarding the diagnosis of general temperament or temperament of member. One of the reasons is the lack of validity tools, and it has led to difficulties in training the student of traditional medicine and the treatment of patients. The differences in the detection methods, have given rise to several treatment methods. Objective: The present study aimed to develop a questionnaire and standard software for diagnosis of gastrointestinal dystemperaments. Methods: The present research is a tool developing study which included 8 stages of developing the items, determining the statements based on items, assessing the face validity, assessing the content validity, assessing the reliability, rating the items, developing a software for calculation of the total score of the questionnaire named GDS v.1.1, and evaluating the concurrent validity using statistical tests including Cronbach's alpha coefficient, Cohen's kappa coefficient. Results: Based on the results, 112 notes including 62 symptoms were extracted from resources, and 58 items were obtained from in-person interview sessions with a panel of experts. A statement was selected for each item and, after merging a number of statements, a total of 49 statements were finally obtained. By calculating the score of statement impact and determining the content validity, respectively, 6 and 10 other items were removed from the list of statements. Standardized Cronbach's alpha for this questionnaire was obtained 0.795 and its concurrent validity was equal to 0.8. Conclusion: A quantitative tool was developed for diagnosis and examination of gastrointestinal dystemperaments. The developed questionnaire is adequately reliable and valid for this purpose. In addition, the software can be used for clinical diagnosis. PMID- 29629061 TI - Depression from the perspective of modern and Persian medicine. AB - Background: Depression is one of the five most-common diseases globally, and is expected to be the second leading cause of disability by 2020 and its economic and social burden is a major problem worldwide. Objective: The aim of this research was to elucidate the causes and symptoms of depression according to Persian Medicine (PM) and classic medicine. Methods: In this study, works that were investigated were the Canon of Medicine, Al-Hawi Fi Teb, Kamel Al-Sina'a, Zakhireh Kharazmshahi and Exir A'azam. Classic medicine sources investigated were Kaplan and Sadock's Synopsis of Psychiatry and related articles in the Web of Science, Medline, Scopus, SID and Magiran. Research was done from January through April 2017, using keywords. Results: To explain the biologic causes, various factors including humoral dystemperaments, cold and hot dystemperaments of chief organs especially heart and brain and some qualitative and quantitative changes in medical spirit should be considered. According to manuscripts some mental emotional events in life can cause these changes. They independently may cause depression. Semiologically some symptoms and signs happen consequently to in the above-mentioned causes which are in common with depression signs and symptoms including grief, crying, low libido, weight loss, appetite and sleep disorders, exhaustion, slow cognitive processing, indecisiveness and willingness to die. Conclusion: The major biological causes of depression is a group of dystemperamental syndromes (hot, cold, dry, and wet) on different bodily structures (humors, organs, and spirits). So preventive and therapeutic strategies for depression couldn't be the same for all patients and the treatment should be designed according to the exact diagnosis. PMID- 29629062 TI - Clinical outcomes of the simultaneous bilateral percutaneous nephrolithotomy (PCNL) in patients with kidney stones: A prospective cohort study. AB - Background: Urinary tract stones is one of the most frequent medical emergencies which leads to life-threatening complications, namely obstructive uropathy as well as renal failure in some situations. Previously, bilateral stones were treated with either open surgery or percutaneous nephrolithotomy (PCNL). However, these treatment options were associated with lengthy operation time, need for more anesthesia, further bleeding, and long hospitalization. Therefore, much effort has been made to treat both sides simultaneously. Objective: The aim of this study was an attempt to prospectively review cases undergoing simultaneous bilateral PCNL in terms of the therapy outcomes, complications, and consequences. Methods: In this prospective cohort study, 39 adult patients with bilateral renal stones were randomly recruited at Imam Reza hospital in Mashhad, Iran between January 2016 and January 2017. Adult patients with bilateral renal stones were included in this study. Exclusion criteria were as follows: Patients with severe heart or lung disease, patients with coagulation disorders, pregnant women, and cases with any contraindications for general anesthesia. After insertion of bilateral ureteral catheters, all patients underwent simultaneous bilateral PCNL in prone position. Transureteral lithotripsy was performed for patients with ureteral stones. The surgery was initially carried out on the symptomatic side and then iterated on the remaining kidney. Major complications including bleeding, fever, pain, urine leakage, and residual stones were recorded. SPSS software was used for data analysis. Data were expressed as percentage and mean +/- SD. P value less than 0.05 was considered significant. Results: A total of 39 patients (27 males with mean age of 37.6 years and 12 females with mean age of 45.7 years) were studied. As many as 15 (38%) patients received a unilateral nephrostomy. Three underwent totally tubeless surgery. Bleeding (41.0%) was the most common complication, followed by residual stones (20.5%) and fever (20.5%), urine leakage (15.3%), pain (12.8%), blood transfusion (2.5%) and colon perforation (2.5%). Conclusions: It was concluded that simultaneous bilateral PCNL was not associated with higher morbidity than the unilateral method. PMID- 29629063 TI - Major adverse cardiovascular event (MACE) after percutaneous coronary intervention in one-year follow-up study. AB - Background: Percutaneous coronary intervention (PCI) is the most common revascularization procedure, with over 1 million performed each year, worldwide. Over the past 20 years, the increasing experience of operators coupled with the advent of newer technologies, including coronary stents and a variety of adjuvant drug therapies, have permitted more successful procedures and decreased the morbidity associated with PCIs. Objective: To identify the incidence, predictors, and clinical implications of Major Adverse Cardiovascular Events (MACE) after PCIs. Methods: This descriptive cross-sectional study was done in Bandar Abbas in Iran in 2015. All patients which treated with PCI in Shahid Mohammadi Hospital during a one-year period were employed. A total of 192 patients were included. At one-year follow-up in this study, incidence and predictors of MACE were evaluated in a prospective study. The data were analyzed by SPSS 19.0 and descriptive tests included frequency and percentage and mean and standard deviation. Also, Chi square test was used for data analysis. A p value <0.05 was determined as significant. Result: Of the 192 patients, 126 (65.6%) were men and 66 patients were female. Stent had been implemented in 93.8% of patients. Sixty two percent of patients were treated with only one stent, two stents were deployed in 29.7% of patients and 3.6% of patients were treated with three or more stents. Of these patients, 46.9% were treated with Drug Eluted Stent (DES) and 40.1% were treated with Bare Metal Stent (BMS). Both types of stents were used in 8.3% of patients. Also, 4.7% of the patients were treated with balloon angioplasty (POBA). Angioplasty success rate was 95.3% and procedural success rate defined as achieving TIMI III flow with residual coronary stenosis under 30%. No in-hospital mortality or emergency CABG was reported. Re-admission in first year after PCI was required in 34 (17.7%) patients of which, 20 of them (10.4%) needed target vessel revascularization (TVR). Readmission was significantly higher (p=0.034) in the group with BMS compared to those who had DES. MI occurred in 8 patients. Conclusion: Our study showed the superiority of DES in comparison with BMS in decreasing readmission and less TVR, but no effect on long term mortality. We recommend more studies in this setting because patients in special groups may benefit more from DES or BMS. PMID- 29629064 TI - Plantago major in Traditional Persian Medicine and modern phytotherapy: a narrative review. AB - Plantago major has been used widely since ancient times, to manage a wide range of diseases including constipation, coughs and wounds. The aim of this study is to review the traditional application, botanical characterization, pharmacological activities, phytochemistry effects and toxicity of Plantago major. In this review study, medicinal properties of Plantago major are collected from credible pharmacopeias, textbooks of traditional Persian medicine (TPM) belonging to the 10-18th century AD, such as "The Canon of Medicine", "Makhzan-Al Advia" and so on. Moreover, electronic databases including Scopus, Medline and Web of science were explored for this purpose. Plantago major has been prescribed in various forms such as roasted seeds, decoction, syrup, liniment, gargle, rectal enema, vaginal suppository, eye and nasal drop for each illness by TPM scholars. Some of its traditional properties including wound healing, antipyretic, antitussive, anti-infective, anti-hemorrhagic, anti-inflammatory, diuretic, laxative, astringent and hemostatic have been confirmed in recent researches. Phytochemical investigations showed that Plantago major contains volatile compounds, triterpenoids, phenolic acids and flavonoids. Modern pharmacological studies have proven some of the traditional applications of Plantago major. Nevertheless, more investigations are required on this plant, because it has the potential to be used to produce various natural medications. PMID- 29629065 TI - Carotid arterial stent implantation follow-up and results in 50 patients: preliminary report. AB - Background: Carotid artery stenting (CAS) is considered as a safe and effective procedure for treatment of carotid artery stenosis. Evaluation of this procedure's complications is essential for proper clinical decision-making. Objective: This study aimed to evaluate the cardiovascular events after CAS among our patients in Isfahan, Iran. Methods: This case-series study was conducted on fifty patients from December 2013 to May 2016. These patients were referred to the cardiology centers of Isfahan, Iran by a neurologist, for stenting of extracranial carotid arteries. The second step was examining the patients by cardiac interventionist. Stenting was performed on symptomatic patients with carotid artery stenosis of more than 50 percent or asymptomatic patients with more than 70 percent carotid artery stenosis on Doppler ultrasonography. Neurologic evaluation was performed at baseline, during hospital stay, and follow up. Transient ischemic attack (TIA)/Stroke and Myocardial infarction (MI) questionnaires were filled out by a cardiologist over telephone interviews with the patients, for follow-up of one month, six months and at the end of study. Carotid Doppler ultrasonography was performed before and 6 months after stenting for evaluation of restenosis. Indeed, during the follow-up study, the major adverse cardiac events (MACE) were evaluated. All data were analyzed through SPSS v.17. Results: The mean age of patients was 70.73 (+/-14.01) years old (range: 48 89 years old). Composite endpoint of death, stroke, and MI was totally 8 percent. The rate of carotid arterial restenosis (Luminal arterial narrowing>50%) was 8%. Conclusions: Despite the fact that carotid stenting is new in our center, our results can be compared to other important studies. PMID- 29629066 TI - The challenges of clinical education in a baccalaureate surgical technology students in Iran: a qualitative study. AB - Background: Clinical education is an integral part of the surgical technology curriculum, in which students combine and integrate knowledge, skills, attitudes, values and philosophies of the profession. It is difficult to learn and adapt to different types of skills and roles in the operating room environment. Objective: This qualitative study examines the difference between the clinical education of Surgical Technology and other clinical settings, and the challenges faced by students in the field, within the course. Methods: This was a qualitative content analysis study conducted in 2016. The participants in this study were 16 baccalaureate surgical technology students of the University for Medical Sciences in Khorasan Razavi province. A semi-structured interview method was run to collect the required data. The sampling was initially purposive, then in the snowball method which continued until data saturation. All interviews were recorded, then transcribed, and analyzed using a continuous comparative method and conventional qualitative content analysis method. Results: From the deep and rich descriptions of the participants, three themes including "stressful environment", "controversy between anticipation of role and reality", and "humiliating experiences" as well as a general theme of "bitter education" were obtained. Conclusion: Students' orientation before attending the operating room, accompanying, supporting, and a full-time attendance of the specialist instructor, strengthening the prerequisite knowledge and skills for the students in this field, teaching ethics, and professional interactions, play an important role in the student's acceptance of the operating room, in the surgery team and the improvement of the quality of clinical education of these students. PMID- 29629067 TI - A prospective study of psychomotor performance of driving among two kinds of shift work in Iran. AB - Background and aim: Driving after a night shift imposes a risk on health care professionals and other road users. The aim of this study was to measure psychomotor performance of driving of night shift nurses compared to day-shift nurses. Methods: Forty-seven volunteer female nurses working at Sina hospital in Tehran, Iran, with a call in all departments of hospital, participated in this study (23 night shift and 24 day shift nurses) in 2016. The tests included RT for simple reaction time, ATAVT for perceptual speed, LVT for visual orientation and ZBA for time anticipation. Data collection tools were individual characteristics, 11-item circadian type inventory (CTI), Stanford sleepiness scale (SSS), and Swedish occupational fatigue inventory (SOFI-20) questionnaires. Psychomotor driving performance was assessed using validated computerized traffic psychological battery of Vienna Test System (VTS), before and after the shifts. Data analysis was performed using paired-samples t-test and Linear Regression. Results: The mean age of day and night-shift nurses were 31.4+/-5.6 and 28.7+/ 3.9 years respectively, no significant difference between two groups. Thirty percent of night shift and 16.7% of day shift nurses reported traffic accidents in the past year. The results revealed that, scores based on viewing times in visual orientation test (p=0.005), and median reaction time score in choice reaction time and reactive stress tolerance test (p=0.045), had a significant association with a 12-hour night shift with a 3-hour nap. Conclusions: Twelve hour night shift work impairs choice reaction time and visual orientation in nurses, even though they take a 3- hour nap during the shift. These skills are required for safe driving. PMID- 29629068 TI - MyD88 in antigen-presenting cells is not required for CD4+ T-cell responses during peptide nanofiber vaccination. AB - Self-assembled peptide nanofibers raise significant antibody and T cell responses without adjuvants, but the mechanism by which they achieve this has not been fully elucidated. Myeloid differentiation primary response gene 88 (MyD88) previously has been shown to be critical for the antibody response to antigens presented by peptide nanofibers. The present study sought to determine the cell subset in which MyD88 is essential for T cell responses. Mice deficient in MyD88 or CD11c+ cells had severely attenuated T cell responses. However, mice lacking MyD88 in only CD11c+ cells remained capable of internalizing, processing, and presenting nanofiber-derived epitopes to stimulate T cell responses. The necessity of inflammasome pathway was ruled out. Using adoptive transfer models where MyD88 was eliminated in CD4+ T cells or in the host, we observed that deficiency only in T cells or only in the host had no impact on the T cell response to nanofiber vaccines. Therefore, knocking out MyD88 in either antigen presenting cells (APCs) or CD4 T cells could not compromise the CD4 T cell responses, suggesting that self-assembled peptide nanofibers trigger redundant MyD88-dependent and MyD88-independent signaling pathways in APCs and T cells. Similar redundancy has been observed for other adjuvants, and this is discussed. PMID- 29629069 TI - Mechanochemistry of the mechanical bond. AB - Strong and stable under tension? In this review we present the recent efforts investigating the mechanochemical properties of interlocked structures by atomic force microscopy and polymer mechanochemistry. PMID- 29629070 TI - A lesson for site-selective C-H functionalization on 2-pyridones: radical, organometallic, directing group and steric controls. AB - A 2-pyridone ring is a frequently occurring subunit in natural products, biologically active compounds, and pharmaceutical targets. Thus, the selective synthesis of substituted 2-pyridone derivatives through decoration and/or formation of pyridone rings has been one of the important longstanding subjects in organic synthetic chemistry. This minireview focuses on recent advances in site-selective C-H functionalization on 2-pyridone. The reported procedures are categorized according to the site selectivity that is achieved, and the substrate scope, limitations, mechanism, and controlling factors are briefly summarized. PMID- 29629071 TI - Recent progress on exploring exceptionally high and anisotropic H+/OH- ion conduction in two-dimensional materials. AB - Ion conducting membranes/electrolytes have been employed extensively in some important industrial and biological systems, especially in fuel cells, water electrolyzers, gas separation, sensors and biological selective ion transport, acting as one of the core components and sometimes directly determining the device performance. However, the traditional polymeric proton exchange membranes (PEMs)/anion exchange membranes (AEMs) suffer from highly toxic preparation procedures, poor thermal and chemical stabilities, and unsatisfactory ion conductivities. This has triggered researchers worldwide to explore alternative inorganic building blocks with high ion conductivities and stabilities from the new materials library, hoping to solve the above long-lasting problems. The recent burgeoning research on two-dimensional (2D) materials has unveiled exceptionally high ionic conductivities, which raises the feasibility of fabricating high-performance nanosheet-based ion conductors/membranes. In this perspective, the recent advances in measuring and understanding the exceptionally high and anisotropic H+/OH- ion conductivities of representative 2D materials, e.g. graphene oxide (GO), vermiculite and layered double hydroxide (LDH) nanosheets, are reviewed. In particular, regarding the anisotropic ionic conduction in 2D nanosheets, possible design strategies and technological innovations for fabricating macroscopic nanosheet-based ionic conductors/membranes are proposed for maximizing the high in-plane conduction, which may serve to guide future development of high-performance industrial and biological systems relying on H+/OH- conducting membranes. PMID- 29629072 TI - Caged circular siRNAs for photomodulation of gene expression in cells and mice. AB - By means of RNA interference (RNAi), small interfering RNAs (siRNAs) play important roles in gene function study and drug development. Recently, photolabile siRNAs were developed to elucidate the process of gene silencing in terms of space, time and degree through chemical modification of siRNAs. We report herein a novel type of photolabile siRNA that was synthesized through cyclizing two ends of a single stranded RNA with a photocleavable linker. These circular siRNAs became more resistant to serum degradation. Using reporter assays of firefly/Renilla luciferase and GFP/RFP, the gene silencing activities of caged circular siRNAs for both genes were evaluated in HEK293 cells. The results indicated that the target genes were successfully photomodulated using these caged circular siRNAs that were formed by caged circular antisense guide RNAs and their linear complementary sense RNAs. Using the caged circular siRNA targeting GFP, we also successfully achieved photomodulation of GFP expression in mice. Upon further optimization, this new type of caged circular siRNA is expected to be a promising tool for studying gene therapy. PMID- 29629073 TI - Construction of an autonomously concatenated hybridization chain reaction for signal amplification and intracellular imaging. AB - Biomolecular self-assembly has spurred substantial research efforts for the development of low-cost point-of-care diagnostics. Herein, we introduce an isothermal enzyme-free concatenated hybridization chain reaction (C-HCR), in which the output of the upstream hybridization chain reaction (HCR-1) layer acts as an intermediate input to activate the downstream hybridization chain reaction (HCR-2) layer. The initiator motivates HCR-1 through the autonomous cross-opening of two functional DNA hairpins, yielding polymeric dsDNA nanowires composed of numerous tandem triggers T as output of the primary sensing event. The reconstituted amplicon T then initiates HCR-2 and transduces the analyte recognition into an amplified readout, originating from the synergistic effect between HCR-1 and HCR-2 layers. Native gel electrophoresis, atom force microscopy (AFM) and fluorescence spectra revealed that C-HCR mediated the formation of frond-like branched dsDNA nanowires and the generation of an amplified FRET signal. As a versatile and robust amplification strategy, the unpreceded C-HCR can discriminate DNA analyte from its mutants with high accuracy and specificity. By incorporating an auxiliary sensing module, the integrated C-HCR amplifier was further adapted for highly sensitive and selective detection of microRNA (miRNA), as a result of the hierarchical and sequential hybridization chain reactions, in human serum and even living cells through an easy-to-integrate "plug-and-play" procedure. In addition, the C-HCR amplifier was successfully implemented for intracellular miRNA imaging by acquiring an accurate and precise signal localization inside living cells, which was especially suitable for the ex situ and in situ amplified detection of trace amounts of analyte. The C-HCR amplification provides a comprehensive and smart toolbox for highly sensitive detection of various biomarkers and thus should hold great promise in clinical diagnosis and assessment. The infinite layer of multilayered C-HCR is anticipated to further strengthen the amplification capacity and reliability (anti-invasion performance) of intracellular imaging approach, which is of great significance for its bioanalytical applications. PMID- 29629074 TI - Bias-dependent local structure of water molecules at a metallic interface. AB - Understanding the local structure of water at the interfaces of metallic electrodes is a key issue in aqueous-based electrochemistry. Nevertheless a realistic simulation of such a setup is challenging, particularly when the electrodes are maintained at different potentials. To correctly compute the effect of an external bias potential applied to truly semi-infinite surfaces, we combine Density Functional Theory (DFT) and Non-Equilibrium Green's Function (NEGF) methods. This framework allows for the out-of-equilibrium calculation of forces and dynamics, and directly correlates to the chemical potential of the electrodes, which is introduced experimentally. In this work, we apply this methodology to study the electronic properties and atomic forces of a water molecule at the interface of a gold surface. We find that the water molecule tends to align its dipole moment with the electric field, and it is either repelled or attracted to the metal depending on the sign and magnitude of the applied bias, in an asymmetric fashion. PMID- 29629075 TI - A new generation of ferrociphenols leads to a great diversity of reactive metabolites, and exhibits remarkable antiproliferative properties. AB - Organometallic compounds bearing the redox motif [ferrocenyl-ene-phenol] have very promising antiproliferative properties which have been further improved by incorporating pertinent substituents able to engender new mechanisms. Here we show that novel ferrociphenols bearing a hydroxypropyl chain exhibit strong antiproliferative effects, in most cases much better than those of cisplatin, tamoxifen, or of previously described ferrociphenols devoid of this terminal OH. This is illustrated, in the case of one of these compounds, by its IC50 values of 110 nM for MDA-MB-231 triple negative breast cancer cells and of 300 nM for cisplatin-resistant A2780cisR human ovarian cancer cells, and by its GI50 values lower than 100 nM towards a series of melanoma and renal cancer cell lines of the NCI-60 panel. Interestingly, oxidative metabolism of these hydroxypropyl ferrociphenols yields two kinds of quinone methides (QMs) that readily react with various nucleophiles, such as glutathione, to give 1,6- and 1,8-adducts. Protonation of these quinone methides generates numerous reactive metabolites leading eventually to many rearrangement and cleavage products. This unprecedented and fully characterized metabolic profile involving a wide range of electrophilic metabolites that should react with cell macromolecules may be linked to the remarkable profile of antiproliferative activities of this new series. Indeed, the great diversity of unexpected reactive metabolites found upon oxidation will allow them to adapt to various situations present in the cancer cell. These data initiate a novel strategy for the rational design of anticancer molecules, thus opening the way to new organometallic potent anticancer drug candidates for the treatment of chemoresistant cancers. PMID- 29629076 TI - Forming next-generation antibody-nanoparticle conjugates through the oriented installation of non-engineered antibody fragments. AB - The successful development of targeted nanotherapeutics is contingent upon the conjugation of therapeutic nanoparticles to target-specific ligands, with particular emphasis being placed on antibody-based ligands. Thus, new methods that enable the covalent and precise installation of targeting antibodies to nanoparticle surfaces are greatly desired, especially those which do not rely on costly and time-consuming antibody engineering techniques. Herein we present a novel method for the highly controlled and oriented covalent conjugation of non engineered antibody F(ab) fragments to PLGA-PEG nanoparticles using disulfide selective pyridazinedione linkers and strain-promoted alkyne-azide click chemistry. Exemplification of this method with trastuzumab and cetuximab showed significant improvements in both conjugation efficiency and antigen binding capability, when compared to commonly employed strategies for antibody nanoparticle construction. This new approach paves the way for the development of antibody-targeted nanomedicines with improved paratope availability, reproducibility and uniformity to enhance both biological activity and ease of manufacture. PMID- 29629077 TI - Polarisation effects on the solvation properties of alcohols. AB - Alcohol solvents are significantly more polar than expected based on the measured H-bonding properties of monomeric alcohols in dilute solution. Self-association of alcohols leads to formation of cyclic aggregates and linear polymeric chains that have a different polarity from the alcohol monomer. Cyclic aggregates are less polar than the monomer, and the chain ends of linear polymers are more polar. The solvation properties of alcohols therefore depend on the interplay of these self-association equilibria and the equilibria involving interactions with solutes. Twenty-one different molecular recognition probes of varying polarity were used to probe the solvation properties of alkane-alcohol mixtures across a wide range of different solvent compositions. The results allow dissection of the complex equilibria present in these systems. Formation of a H-bond between two alcohol molecules leads to polarisation of the hydroxyl groups, resulting in an increase in binding affinity for subsequent interactions with the unbound donor and acceptor sites. The H-bond donor parameter (alpha) for these sites increases from 2.7 to 3.5, and the H-bond acceptor parameter (beta) increases from 5.3 to 6.9. Polarisation is a short range effect limited to the first H-bond in a chain, and formation of subsequent H-bonds in longer chains does not further increase the polarity of chain ends. H-bond donor sites involved in a H-bond are unavailable for further interactions, because the formation of a bifurcated three centre H-bond is three orders of magnitude less favourable than formation of a conventional two-centre H-bond. These findings are reproduced by quantum chemical calculations of the molecular electrostatic potential surfaces of alcohol aggregates. Thus, the overall solvation properties of alcohols depend on the speciation of different aggregates, the polarities of these species and the polarities of the solutes. At low alcohol concentrations, polar solutes are solvated by alcohol monomers, and at higher alcohol concentrations, solutes are solvated by the more polar chain ends of linear polymers. The less polar cyclic aggregates are less important for interactions with solutes. Similar behavior was found for ten different alcohol solvents. Tertiary alcohols are marginally less polar solvents than primary alcohols, due to steric interactions that destabilises the formation of polymeric aggregates leading to lower concentrations of polar chain ends. One alcohol with an electron-withdrawing substituent was studied, and this solvent showed slightly different behavior, because the H-bond donor and acceptor properties are different. PMID- 29629078 TI - Site-selective bromination of sp3 C-H bonds. AB - A method for converting sp3 C-H to C-Br bonds using an N-methyl sulfamate directing group is described. The reaction employs Rh2(oct)4 and a mixture of NaBr and NaOCl and is performed in aqueous solution open to air. For all sulfamates examined, oxidation occurs with high selectivity at the gamma-carbon, affording a uniquely predictable method for C-H bond halogenation. Results from a series of mechanistic experiments suggest that substrate oxidation likely proceeds by a radical chain process. Initial formation of an N-halogenated sulfamate followed by Rh-mediated homolysis generates an N-centered radical, which serves as the active oxidant. PMID- 29629079 TI - Enforcing Ising-like magnetic anisotropy via trigonal distortion in the design of a W(v)-Co(ii) cyanide single-chain magnet. AB - A new octacyanotungstate(v) based single chain magnet {[(Tpm)Co(DMF)W(CN)8]2[Co(DMF)4].2DMF} n (1, Tpm = 1,1,1-trispyrazoylmethane), with an effective barrier of 39.7(3) cm-1 is reported. The Ising-like magnetic anisotropy of the chain originates from the nearly parallel local orientations of the Co(ii) ions with the source of the uniaxial magnetic anisotropy being a trigonal distortion of the octahedral environment with the fac-tridentate capping Tpm ligand. PMID- 29629080 TI - Continuum tuning of nanoparticle interfacial properties by dynamic covalent exchange. AB - Surface chemical composition is fundamental to determining properties on the nanoscale, making precise control over surface chemistry critical to being able to optimise nanomaterials for virtually any application. Surface-engineering independent of the preparation of the underlying nanomaterial is particularly attractive for efficient, divergent synthetic strategies, and for the potential to create reactive, responsive and smart nanodevices. For monolayer-stabilised nanoparticles, established methods include ligand exchange to replace the ligand shell in its entirety, encapsulation with amphiphilic (macro)molecules, noncovalent interactions with surface-bound biomolecules, or a relatively limited number of covalent bond forming reactions. Yet, each of these approaches has considerable drawbacks. Here we show that dynamic covalent exchange at the periphery of the nanoparticle-stabilizing monolayer allows surface-bound ligand molecular structure to be substantially modified in mild and reversible processes that are independent of the nanoparticle-molecule interface. Simple stoichiometric variation allows the extent of exchange to be controlled, generating a range of kinetically stable mixed-monolayer compositions across an otherwise identical, self-consistent series of nanoparticles. This approach can be used to modulate nanoparticle properties that are defined by the monolayer composition. We demonstrate switching of nanoparticle solvent compatibility between widely differing solvents - spanning hexane to water - and the ability to tune solubility across the entire continuum between these extremes, all from a single nanoparticle starting point. We also demonstrate that fine control over mixed-monolayer composition influences the assembly of discrete, colloidally stable nanoparticle clusters. By carefully assessing monolayer composition in each state, using both in situ and ex situ methods, we are able to correlate the molecular-level details of the nanoparticle-bound monolayer with system-level properties and behaviour. These empirically determined relationships contribute fundamental insights on nanoscale structure-function relationships, which are currently beyond the capabilities of ab initio prediction. PMID- 29629081 TI - Reversible-deactivation anionic alternating ring-opening copolymerization of epoxides and cyclic anhydrides: access to orthogonally functionalizable multiblock aliphatic polyesters. AB - The alternating copolymerization of epoxides and cyclic anhydrides is an increasingly popular route to aliphatic polyesters that are of interest as biodegradable replacements for petroleum-based polymers and for use in the biomedical field. However, broad and bimodal molecular weight distributions in these polymerizations continues to be an issue, limiting synthesis of multiblock copolymers. By use of a bifunctional catalytic system, the reversible deactivation anionic alternating ring-opening copolymerization of epoxides and cyclic anhydrides gives unimodal polymers with D values generally less than 1.07. This allowed for the formation of well-defined triblock copolymers. Additionally, by incorporating both aldehyde and alkene functionalities into the polymer, orthogonal post-polymerization modification was achieved, giving access to well defined highly modifiable aliphatic polyesters. PMID- 29629083 TI - Impact electrochemistry reveals that graphene nanoplatelets catalyse the oxidation of dopamine via adsorption. AB - Graphene nanoplatelets are shown to electrocatalyse the oxidation of dopamine. Single entity measurements ('nano-impacts') coupled with microdisc voltammetry and UV-visible spectroscopy reveal that adsorption of dopamine and its oxidised product on the graphene nanoplatelets is the key factor causing the observed catalysis. Genetic implications are drawn both for the study of catalysts in general and for graphene nanoplatelets in particular. PMID- 29629082 TI - Metal-organic layers stabilize earth-abundant metal-terpyridine diradical complexes for catalytic C-H activation. AB - We report the synthesis of a terpyridine-based metal-organic layer (TPY-MOL) and its metalation with CoCl2 and FeBr2 to afford CoCl2.TPY-MOL and FeBr2.TPY-MOL, respectively. Upon activation with NaEt3BH, CoCl2.TPY-MOL catalyzed benzylic C-H borylation of methylarenes whereas FeBr2.TPY-MOL catalyzed intramolecular Csp3 -H amination of alkyl azides to afford pyrrolidines and piperidines. X-ray absorption near edge structure (XANES), extended X-ray absorption fine structure (EXAFS), X-ray photoelectron spectroscopy, UV-Vis-NIR spectroscopy, and electron paramagnetic spectroscopy (EPR) measurements as well as density functional theory (DFT) calculations identified M(THF)2.TPY-MOL (M = Co or Fe) as the active catalyst with a MII-(TPY)2- electronic structure featuring divalent metals and TPY diradical dianions. We believe that site isolation stabilizes novel MII (TPY)2- (M = Co or Fe) species in the MOLs to endow them with unique and enhanced catalytic activities for Csp3 -H borylation and intramolecular amination over their homogeneous counterparts. The MOL catalysts are also superior to their metal-organic framework analogs owing to the removal of diffusion barriers. Our work highlights the potential of MOLs as a novel 2D molecular material platform for designing single-site solid catalysts without diffusional constraints. PMID- 29629085 TI - Small molecular organic nanocrystals resemble carbon nanodots in terms of their properties. AB - The most commonly observed phenomena in carbon nanodots (CNDs) are the strong excitation wavelength dependent multicolor fluorescence emission and the particle size distribution between 3-5 nm observed using a transmission electron microscope (TEM). However, it is not evident yet whether the emission originates from the particles observed using a TEM. In this article, we show that hydrothermal treatment of citric acid produces methylenesuccinic acid, which gives rise to hydrogen-bonded nano-assemblies with CND-like properties. While single crystal X-ray crystallography confirms the structure of methylenesuccinic acid, fluorescence correlation spectroscopy (FCS) confirms the presence of a molecular fluorophore with an average hydrodynamic diameter of ~0.9 nm. This size is much smaller than the size of the particles observed using a TEM. We conclude that the particles observed using a TEM are the drying mediated nanocrystals of methylenesuccinic acid. PMID- 29629084 TI - Overcoming double-step CO2 adsorption and minimizing water co-adsorption in bulky diamine-appended variants of Mg2(dobpdc). AB - Alkyldiamine-functionalized variants of the metal-organic framework Mg2(dobpdc) (dobpdc4- = 4,4'-dioxidobiphenyl-3,3'-dicarboxylate) are promising for CO2 capture applications owing to their unique step-shaped CO2 adsorption profiles resulting from the cooperative formation of ammonium carbamate chains. Primary,secondary (1 degrees ,2 degrees ) alkylethylenediamine-appended variants are of particular interest because of their low CO2 step pressures (<=1 mbar at 40 degrees C), minimal adsorption/desorption hysteresis, and high thermal stability. Herein, we demonstrate that further increasing the size of the alkyl group on the secondary amine affords enhanced stability against diamine volatilization, but also leads to surprising two-step CO2 adsorption/desorption profiles. This two-step behavior likely results from steric interactions between ammonium carbamate chains induced by the asymmetrical hexagonal pores of Mg2(dobpdc) and leads to decreased CO2 working capacities and increased water co adsorption under humid conditions. To minimize these unfavorable steric interactions, we targeted diamine-appended variants of the isoreticularly expanded framework Mg2(dotpdc) (dotpdc4- = 4,4''-dioxido-[1,1':4',1''-terphenyl] 3,3''-dicarboxylate), reported here for the first time, and the previously reported isomeric framework Mg-IRMOF-74-II or Mg2(pc-dobpdc) (pc-dobpdc4- = 3,3' dioxidobiphenyl-4,4'-dicarboxylate, pc = para-carboxylate), which, in contrast to Mg2(dobpdc), possesses uniformally hexagonal pores. By minimizing the steric interactions between ammonium carbamate chains, these frameworks enable a single CO2 adsorption/desorption step in all cases, as well as decreased water co adsorption and increased stability to diamine loss. Functionalization of Mg2(pc dobpdc) with large diamines such as N-(n-heptyl)ethylenediamine results in optimal adsorption behavior, highlighting the advantage of tuning both the pore shape and the diamine size for the development of new adsorbents for carbon capture applications. PMID- 29629086 TI - Variations in the fuel structure control the rate of the back and forth motions of a chemically fuelled molecular switch. AB - This work deals with the use of 2-cyano-2-arylpropanoic acids as chemical fuels for an acid-base operated molecular switch that consists of a Sauvage-type catenand composed of two identical macrocycles incorporating a phenanthroline unit. When used as a base promoter of the decarboxylation of propanoic acid derivatives, the switch undergoes large amplitude motion from the neutral catenand to a protonated catenate and back again to the neutral state. The rate of back proton transfer, which determines the rate of the overall process, was markedly affected by para-substituents in the order Cl > H > CH3 > OCH3 (rho = +5.2). Thus, the time required to complete a full cycle was almost two days for the OCH3 derivative and dropped to a few minutes for the Cl derivative. These results show for the first time that the rate of operation of a molecular switch can be regulated by variations in the fuel structure. PMID- 29629087 TI - 3D chemical imaging of the brain using quantitative IR spectro-microscopy. AB - Three-dimensional (3D) histology is the next frontier for modern anatomo pathology. Characterizing abnormal parameters in a tissue is essential to understand the rationale of pathology development. However, there is no analytical technique, in vivo or histological, that is able to discover such abnormal features and provide a 3D distribution at microscopic resolution. Here, we introduce a unique high-throughput infrared (IR) microscopy method that combines automated image correction and subsequent spectral data analysis for 3D IR image reconstruction. We performed spectral analysis of a complete organ for a small animal model, a mouse brain with an implanted glioma tumor. The 3D-IR image is reconstructed from 370 consecutive tissue sections and corrected using the X ray tomogram of the organ for an accurate quantitative analysis of the chemical content. A 3D matrix of 89 * 106 IR spectra is generated, allowing us to separate the tumor mass from healthy brain tissues based on various anatomical, chemical, and metabolic parameters. We demonstrate that quantitative metabolic parameters can be extracted from the IR spectra for the characterization of the brain vs. tumor metabolism (assessing the Warburg effect in tumors). Our method can be further exploited by searching for the whole spectral profile, discriminating tumor vs. healthy tissue in a non-supervised manner, which we call 'spectromics'. PMID- 29629088 TI - Sublimable chloroquinolinate lanthanoid single-ion magnets deposited on ferromagnetic electrodes. AB - A new family of chloroquinolinate lanthanoid complexes of the formula A+[Ln(5,7Cl2q)4]-, with Ln = Y3+, Tb3+ and Dy3+ and A+ = Na+, NEt4+ and K0.5(NEt4)0.5+, is studied, both in bulk and as thin films. Several members of the family are found to present single-molecule magnetic behavior in bulk. Interestingly, the sodium salts can be sublimed under high vacuum conditions retaining their molecular structures and magnetic properties. These thermally stable compounds have been deposited on different substrates (Al2O3, Au and NiFe). The magnetic properties of these molecular films show the appearance of cusps in the zero-field cooled curves when they are deposited on permalloy (NiFe). This indicates a magnetic blocking caused by the interaction between the single-ion magnet and the ferromagnet. X-ray absorption spectroscopy confirms the formation of hybrid states at the molecule/metal interface. PMID- 29629089 TI - Brominated graphene as a versatile precursor for multifunctional grafting. AB - A non-destructive and versatile chemical reduction method was used to dissolve and subsequently brominate few-layer graphene sheets (FLGs); the direct covalent attachment of bromine to the graphene framework was demonstrated by X-ray photoelectron spectroscopy (XPS). The brominated few-layer graphenes (FLG-Br) provide a convenient, stable, liquid-phase precursor, suitable for the synthesis of a variety of directly functionalised graphenes. As an example, the FLG-Br species was used to initiate atom transfer radical polymerisation (ATRP), to obtain poly(methyl methacrylate) (PMMA)-grafted graphene (FLG-PMMA), which was six times more dispersible in acetone than controls. In addition, the FLG-Br is active for nucleophilic substitution reactions, as illustrated by the preparation of methoxypolyethylene glycol (mPEG)- and OH-substituted derivatives. The products were characterised by thermogravimetric analysis coupled with mass spectrometry (TGA-MS), XPS and Raman spectroscopy. Grafting ratios (GR) for these polymer-grafted materials varied between 6 and 25%; even at these GRs, all graphene derivatives showed increased solubility in organic solvents. PMID- 29629090 TI - Hydroxyl-triggered fluorescence for location of inorganic materials in polymer matrix composites. AB - There is a long-standing challenge to realize in situ visualization of incorporated inorganic materials in organic-inorganic composites in a post labeling manner, owing to the lack of specific fluorescent organic dye molecules for targeting inorganic materials. Herein, we observe that the specific covalent B-O binding between the hydroxyl groups of inorganic materials and commercially available aggregation-induced emission (AIE)-active boronic acid could lead to the formation of highly emissive solid-state fluorescent composite materials. The hydroxyl-triggered luminescent probe may serve as a practical method for in situ location of incorporated inorganic materials in polymer-matrix composites by simply dipping the composite film in boronic acid-modified AIE solution. This present work offers a non-invasive avenue to locate inorganic materials which possess hydroxyl-groups in polymer-matrix composites, thereby developing a convenient screening strategy for assessing the advanced properties of composites. This strategy can also be extended to the targeted tracing of other inorganic materials with inherent and functionalized carboxyl, amino, sulfhydryl and other groups via tuning the binding affinity between the inorganic materials and luminescent molecules. PMID- 29629091 TI - Unveiling hole trapping and surface dynamics of NiO nanoparticles. AB - The research effort in mesoporous p-type semiconductors is increasing due to their potential application in photoelectrochemical energy conversion devices. In this paper an electron-hole pair is created by band-gap excitation of NiO nanoparticles and the dynamics of the electron and the hole is followed until their recombination. By spectroscopic characterization it was found that surface Ni3+ states work as traps for both electrons and holes. The trapped electron was assigned to a Ni2+ state and the trapped hole to a "Ni4+" state positioned close to the valence band edge. The recombination kinetics of these traps was studied and related with the concept of hole relaxation suggested before. The time scale of the hole relaxation was found to be in the order of tens of ns. Finally the spectroscopic evidence of this relaxation is presented in a sensitized film. PMID- 29629092 TI - Direct monitoring of trace water in Li-ion batteries using operando fluorescence spectroscopy. AB - The direct monitoring of trace water in real time during electrochemical cycles is of vital importance because water impurities are one of the causes of reduced lifetimes and capacity fading in Li-ion batteries. However, the most common Karl Fischer titration lacks the ability to perform real-time monitoring of trace water while the battery is operating. Here, we demonstrate the use of nanosized coordination polymers as a sensing platform for the rapid and highly sensitive detection of water molecules, which gives a distinguishable turn-on fluorescence (FL) response toward water with a quantifiable detection range from 0 to 1.2% v/v, offering a novel opportunity to monitor trace water during electrochemical cycles. To demonstrate the practical value of our platform, we designed an in situ measurement system using nanosized coordination polymers as an electrolyte additive. Within the platform, the findings indicate that trace water is indeed generated during the first discharge process, in which the FL intensity shows a linear increase over time along with the gradual formation of water. We believe that this strategy provides new insights into the in situ monitoring of complex electrochemical processes, and it may help to pave the way for the development of new operando analytical techniques for lithium-ion batteries. PMID- 29629093 TI - Z-Selective iridium-catalyzed cross-coupling of allylic carbonates and alpha diazo esters. AB - A well-defined Ir-allyl complex catalyzes the Z-selective cross-coupling of allyl carbonates with alpha-aryl diazo esters. The process overrides the large thermodynamic preference for E-products typically observed in metal-mediated coupling reactions to enable the synthesis of Z,E-dieneoates in good yield with selectivities consistently approaching or greater than 90 : 10. This transformation represents the first productive merger of Ir-carbene and Ir-allyl species, which are commonly encountered intermediates in allylation and cyclopropanation/E-H insertion catalysis. Potentially reactive functional groups (aryl halides, ketones, nitriles, olefins, amines) are tolerated owing to the mildness of reaction conditions. Kinetic analysis of the reaction suggests oxidative addition of the allyl carbonate to an Ir-species is rate-determining. Mechanistic studies uncovered a pathway for catalyst activation mediated by NEt3. PMID- 29629094 TI - The Lewis superacid Al[N(C6F5)2]3 and its higher homolog Ga[N(C6F5)2]3 - structural features, theoretical investigation and reactions of a metal amide with higher fluoride ion affinity than SbF5. AB - Herein we present the synthesis of the two Lewis acids Al[N(C6F5)2]3 (ALTA) and Ga[N(C6F5)2]3 (GATA) via salt elimination reactions. The metal complexes were characterized by NMR-spectroscopic methods and X-ray diffraction analysis revealing the stabilization of the highly Lewis acidic metal centers by secondary metal-fluorine contacts. The Lewis acidic properties of Al[N(C6F5)2]3 and Ga[N(C6F5)2]3 are demonstrated by reactions with Lewis bases resulting in the formation of metallates accompanied by crucial structural changes. The two metallates [Cs(Tol)3]+[FAl(N(C6F5)2)3]- and [AsPh4]+[ClGa(N(C6F5)2)3]- contain interesting weakly coordinating anions. The reaction of Al[N(C6F5)2]3 with trityl fluoride yielded [CPh3]+[FAl(N(C6F5)2)3]- which could find application in the activation of metallocene polymerization catalysts. The qualitative Lewis acidity of Al[N(C6F5)2]3 and Ga[N(C6F5)2]3 was investigated by means of competition experiments for chloride ions in solution. DFT calculations yielded fluoride ion affinities in the gas phase (FIA) of 555 kJ mol-1 for Al[N(C6F5)2]3 and 472 kJ mol-1 for Ga[N(C6F5)2]3. Thus, Al[N(C6F5)2]3 can be considered a Lewis superacid with a fluoride affinity higher than SbF5 (493 kJ mol-1) whereas the FIA of the corresponding gallium complex is slightly below the threshold to Lewis superacidity. PMID- 29629095 TI - One-dimensional diamondoid polyaniline-like nanothreads from compressed crystal aniline. AB - Low-dimensional nanomaterials such as highly ordered polyaniline (PANI) have attracted considerable interest due to their expected extraordinary electronic and optoelectronic properties. In spite of several attempts, the attainment of atomically well-ordered PANI is a long-standing challenge. Pressure-induced polymerization of aromatic molecules in the crystal phase has been demonstrated as a practicable route for the synthesis of highly ordered polymers but this approach has never been tested to produce PANI. Here we show the synthesis of diamondoid polyaniline-like nanothreads at 33 GPa and 550 K by compressing aniline in crystal phase-II. Infrared spectroscopy, transmission electron microscopy, X-ray diffraction data, and DFT calculations support the formation of this totally new polyaniline-like nanothread. The NH2-enriched carbon nanothread combines the outstanding mechanical properties of carbon nanotubes with the versatility of NH2 groups decorating the exterior of the nanothreads representing potential active sites for doping and as linkers for molecules with biological interest and inorganic nanostructures. The synergy of all of these properties emphasizes the strong potential of this material to be applied in a broad range of areas, from chemistry to materials engineering. PMID- 29629096 TI - Ligand effect on the catalytic activity of porphyrin-protected gold clusters in the electrochemical hydrogen evolution reaction. AB - The "ligand effect" can be used as a novel strategy for enhancing the catalytic properties of metal clusters. Herein, we report the ligand effect of porphyrin derivatives on gold clusters (AuCs, size <2 nm) and gold nanoparticles (AuNPs, size >2 nm) in the electrochemical hydrogen evolution reaction (HER) at pH 6.7. The current density of porphyrin face-coordinated AuCs at -0.4 V vs. reversible hydrogen electrode (RHE) was 460% higher than that of phenylethanethiol-protected AuCs. X-ray photoemission spectroscopy indicated that the approach of porphyrin to the Au surface induced charge migration from the porphyrin to the Au core, leading to a shift in the 5d state of AuCs that resulted in enhanced HER activities. This ligand effect is pronounced in the cluster region due to the large surface-to-volume ratio. These results pave the way for enhancing catalytic activity of metal clusters using ligand design. PMID- 29629097 TI - Catalyst characterization in the presence of solvent: development of liquid phase structure-activity relationships. AB - Due to the low volatility and highly oxygenated nature of biomass derived feedstocks, biomass upgrade reactions are frequently conducted in the presence of solvent to improve substrate mass transfer to the catalyst surface. However, relevant catalyst characterization techniques are most often performed in vacuum or inert gas environments, where the effect of solvent on the catalytic sites is ignored. Comparatively, characterization techniques in the presence of solvent are relatively rare, which poses challenges in developing structure-activity relationships for liquid phase reactions. In this perspective, commonly utilized techniques for probing the solid-liquid interface are briefly covered, with a focus on the role of solvent on zeolite and solid acid catalysis. New applications of techniques are proposed, most notably with ATR-FTIR, in the context of extracting thermodynamic information for the further understanding of the role of solvent on broadly applicable catalyst properties, such as acidity, and to develop structure-activity relationships for solid catalysts in solvent. PMID- 29629098 TI - Challenges and opportunities for alkane functionalisation using molecular catalysts. AB - The conversion of vast low-value saturated hydrocarbons into valuable chemicals is of great interest. Thanks to the progression of organometallic and coordination chemistry, transition metal catalysed C sp3-H bond functionalisation has now become a powerful tool for alkane transformations. Specifically, methods for alkane functionalisation include radical initiated C-H functionalisation, carbene/nitrene insertion, and transition metal catalysed C-H bond activation. This perspective provides a systematic and concise overview of each protocol, highlighting the factors that govern regioselectivity in these reactions. The challenges of the existing catalytic tactics and future directions for catalyst development in this field will be presented. PMID- 29629099 TI - A label-free and enzyme-free platform with a visible output for constructing versatile logic gates using caged G-quadruplex as the signal transducer. AB - A complete set of binary basic logic gates (OR, AND, NOR, NAND, INHIBT, IMPLICATION, XOR and XNOR) is realized on a label-free and enzyme-free sensing platform using caged G-quadruplex as the signal transducer. In the presence of an appropriate input, the temporarily blocked G-rich sequence in the hairpin DNA is released through cleavage by the synergetically-stabilized Mg2+-dependent DNAzyme which can be made to function via the input-guided cooperative conjunction of the DNAzyme subunits. In the presence of hemin, the unblocked G-quadruplex DNAzyme catalyzes the oxidation of 3,3',5,5'-tetramethylbenzidine (TMB) by H2O2 to generate a colored readout signal which can be readily distinguished by the naked eye. This strategy is quite versatile and straightforward for logic operations. Two combinatorial gates (XOR + AND and XOR + NOR) are also successfully fabricated to demonstrate the modularity and scalability of the computing elements. The distinctive advantage of this logic system is that molecular events in aqueous solution could be translated into a color change which can be directly observed by the naked eye without resorting to any analytical instrumentation. Moreover, this work reveals a new route for the design of molecular logic gates that can be executed without any labeling and immobilization procedure or separation and washing step, which holds great promise for intelligent point-of care diagnostics and in-field applications. PMID- 29629100 TI - Understanding the origins of metal-organic framework/polymer compatibility. AB - The microscopic interfacial structures for a series of metal-organic framework/polymer composites consisting of the Zr-based UiO-66 coupled with different polymers are systematically explored by applying a computational methodology that integrates density functional theory calculations and force field-based molecular dynamics simulations. These predictions are correlated with experimental findings to unravel the structure-compatibility relationship of the MOF/polymer pairs. The relative contributions of the intermolecular MOF/polymer interactions and the flexibility/rigidity of the polymer with respect to the microscopic structure of the interface are rationalized, and their impact on the compatibility of the two components in the resulting composite is discussed. The most compatible pairs among those investigated involve more flexible polymers, i.e. polyvinylidene fluoride (PVDF) and polyethylene glycol (PEG). These polymers exhibit an enhanced contact surface, due to a better adaptation of their configuration to the MOF surface. In these cases, the irregularities at the MOF surface are filled by the polymer, and even some penetration of the terminal groups of the polymer into the pores of the MOF can be observed. As a result, the affinity between the MOF and the polymer is very high; however, the pores of the MOF may be sterically blocked due to the strong MOF/polymer interactions, as evidenced by UiO-66/PEG composites. In contrast, composites involving polymers that exhibit higher rigidity, such as the polymer of intrinsic microporosity-1 (PIM-1) or polystyrene (PS), present interfacial microvoids that contribute to a decrease in the contact surface between the two components, thus reducing the MOF/polymer affinity. PMID- 29629101 TI - Cooperative loading of multisite receptors with lanthanide containers: an approach for organized luminescent metallopolymers. AB - Metal-containing (bio)organic polymers are materials of continuously increasing importance for applications in energy storage and conversion, drug delivery, shape-memory items, supported catalysts, organic conductors and smart photonic devices. The embodiment of luminescent components provides a revolution in lighting and signaling with the ever-increasing development of polymeric light emitting devices. Despite the unique properties expected from the introduction of optically and magnetically active lanthanides into organic polymers, the deficient control of the metal loading currently limits their design to empirical and poorly reproducible materials. We show here that the synthetic efforts required for producing soluble multi-site host systems Lk are largely overcome by the virtue of reversible thermodynamics for mastering the metal loading with the help of only two parameters: (1) the affinity of the luminescent lanthanide container for a single binding site and (2) the cooperative effect which modulates the successive fixation of metallic units to adjacent sites. When unsymmetrical perfluorobenzene-trifluoroacetylacetonate co-ligands (pbta-) are selected for balancing the charge of the trivalent lanthanide cations, Ln3+, in six-coordinate [Ln(pbta)3] containers, the explored anti-cooperative complexation processes induce nearest-neighbor intermetallic interactions twice as large as thermal energy at room temperature (RT = 2.5 kJ mol-1). These values have no precedent when using standard symmetrical containers and they pave the way for programming metal alternation in luminescent lanthanidopolymers. PMID- 29629102 TI - Scalable thioarylation of unprotected peptides and biomolecules under Ni/photoredox catalysis. AB - Site-specific functionalization of unprotected native peptides and biomolecules remains a useful transformation in synthetic design and chemical biology, yet until recently, advancements in transition metal-catalyzed methods, which have prevailed in organic synthesis, have been relatively ineffective when applied to large and structurally complex biomolecules. Here, the mechanistically distinct, Ni/photoredox-catalyzed arylation of unprotected, native thiols (e.g., cysteine residues) is reported - a process initiated through a visible light-promoted, hydrogen atom transfer (HAT) event under ambient conditions. Sub-stoichiometric loadings of the dual-catalyst system (<=5 mol%) are employed, granting excellent site-specificity, broad substrate scope, and low chemical waste. Reaction scalability (from MUg to grams) has been achieved through modest reagent adjustments, and high throughput experimentation (HTE) demonstrates the ease of reaction setup, enabling prompt screening of aryl halide coupling partners and conditions. Scores of thiol substrates and aryl entities were examined and effectively conjugated, suggesting further diverse, practical applications. PMID- 29629103 TI - Expedient on-resin modification of a peptide C-terminus through a benzotriazole linker. AB - A convenient and efficient chemical toolbox was developed for the on-resin C terminal functionalization of various peptides. By transforming resin-bound 3,4 diaminobenzoic acid species with isoamyl nitrite, the resulting resin-bound benzotriazole entity can be efficiently displaced by nucleophiles during cleavage of the peptide-resin connection in a short reaction time. The resin cleavage step allowed for the use of various nucleophiles including water, EtOH, amines, thiol, and G5 poly(amidoamino) dendrimers with yields ranging from 66% to 82% within 5 h. This method was successfully applied to prepare the elastin sequence (VPGVG)4 through on-resin ligation in 77% yield in one day and a head-to-tail cyclic peptide, sunflower trypsin inhibitor-1, in 42% yield. PMID- 29629104 TI - Epimerization-free access to C-terminal cysteine peptide acids, carboxamides, secondary amides, and esters via complimentary strategies. AB - C-Terminal cysteine peptide acids are difficult to access without epimerization of the cysteine alpha-stereocenter. Diversification of the C-terminus after solid phase peptide synthesis poses an even greater challenge because of the proclivity of the cysteine alpha-stereocenter to undergo deprotonation upon activation of the C-terminal carboxylic acid. We present herein two general strategies to access C-terminal cysteine peptide derivatives without detectable epimerization, diketopiperazine formation, or piperidinylalanine side products. PMID- 29629105 TI - Water dispersible surface-functionalized platinum/carbon nanorattles for size selective catalysis. AB - Selective dealloying of metal nanoparticles results in rattle-type hollow carbon nanoshells enclosing platinum nanoparticles, which are able to perform size selective catalysis. Selective functionalization of the outer graphene-like carbon surface prevents agglomeration and leads to well dispersible nanocatalysts in aqueous solutions. The synthesis starts with the production of nanoparticles with a cobalt-platinum-alloy core surrounded by graphene-like carbon via reducing flame spray synthesis. After surface functionalization, simultaneous pore formation in the shell-wall and dissolution of the cobalt results in platinum encapsulated in hollow carbon nanospheres. Catalytic oxidation of differently sized sugars (glucose and maltoheptaose) reveales size-selective catalytic properties of these platinum nanorattles. PMID- 29629106 TI - Influences of the heme-lysine crosslink in cytochrome P460 over redox catalysis and nitric oxide sensitivity. AB - Ammonia (NH3)-oxidizing bacteria (AOB) derive total energy for life from the multi-electron oxidation of NH3 to nitrite (NO2-). One obligate intermediate of this metabolism is hydroxylamine (NH2OH), which can be oxidized to the potent greenhouse agent nitrous oxide (N2O) by the AOB enzyme cytochrome (cyt) P460. We have now spectroscopically characterized a 6-coordinate (6c) {FeNO}7 intermediate on the NH2OH oxidation pathway of cyt P460. This species has two fates: it can either be oxidized to the {FeNO}6 that then undergoes attack by NH2OH to ultimately generate N2O, or it can lose its axial His ligand, thus generating a stable, off-pathway 5-coordinate (5c) {FeNO}7 species. We show that the wild type (WT) cyt P460 exhibits a slow nitric oxide (NO)-independent conversion (kHis-off = 2.90 * 10-3 s-1), whereas a cross-link-deficient Lys70Tyr cyt P460 mutant protein underwent His dissociation via both a NO-independent (kHis-off = 3.8 * 10 4 s-1) and a NO-dependent pathway [kHis-off(NO) = 790 M-1 s-1]. Eyring analyses of the NO-independent pathways for these two proteins revealed a significantly larger (ca. 27 cal mol-1 K-1) activation entropy (DeltaS?) in the cross-link deficient mutant. Our results suggest that the Lys-heme cross-link confers rigidity to the positioning of the heme P460 cofactor to avoid the fast NO dependent His dissociation pathway and subsequent formation of the off-pathway 5c {FeNO}7 species. The relevance of these findings to NO signaling proteins such as heme-nitric oxide/oxygen binding (H-NOX) is also discussed. PMID- 29629107 TI - Palladium-catalyzed regiodivergent hydroaminocarbonylation of alkenes to primary amides with ammonium chloride. AB - Palladium-catalyzed hydroaminocarbonylation of alkenes for the synthesis of primary amides has long been an elusive aim. Here, we report an efficient catalytic system which enables inexpensive NH4Cl to be utilized as a practical alternative to gaseous ammonia for the palladium-catalyzed alkene hydroaminocarbonylation reaction. Through appropriate choice of the palladium precursors and ligands, either branched or linear primary amides can be obtained in good yields with good to excellent regioselectivities. Primary mechanistic studies were conducted and disclosed that electrophilic acylpalladium species were capable of capturing the NH2-moiety from ammonium salts to form amides in the presence of CO with NMP as a base. PMID- 29629108 TI - Photolabile coumarins with improved efficiency through azetidinyl substitution. AB - Azetidinyl substituents have been recently used to improve the fluorescence quantum yield of several classes of fluorophores. Herein, we demonstrate that other useful photochemical processes can be modulated using this strategy. In particular, we prepared and measured the quantum yield of photorelease of a series of 7-azetidinyl-4-methyl coumarin esters and compared it to their 7 diethylamino and julolidine-fused analogues. The efficiency of the photorelease reactions of the azetidinyl-substituted compounds was 2- to 5-fold higher than the corresponding diethylamino coumarins. We investigated the origin of this effect in model fluorophores and in the photoactivatable esters, and found that H bonding with the solvent seems to be the prominent deactivation channel inhibited upon substitution with an azetidinyl ring. We anticipate that this substitution strategy could be used to modulate other photochemical processes with applications in chemical biology, catalysis and materials science. PMID- 29629109 TI - Engineered Janus probes modulate nucleic acid amplification to expand the dynamic range for direct detection of viral genomes in one microliter crude serum samples. AB - The viral genome load in diverse clinical samples varies over several orders of magnitude (e.g. 1-104 copies per MUL), thus a dynamic range-extended and sensitive analysis method is highly desired. However, existing well-developed nucleic acid amplification systems always suffer from either a limited dynamic range or modest sensitivity for analysis of these samples. Herein, we propose a general engineered Janus probe to modulate the thermodynamics and kinetic properties of the amplification reaction. Through rational regulation, the Janus system improves the performance by both reducing the background and enhancing the signal, expanding the operative dynamic range by 2 orders of magnitude. This proposed approach achieves a detection limit for hepatitis B virus (HBV) DNA of down to 3 copies and can be successfully applied for direct quantification of the HBV genome in one microliter crude serum samples without any pretreatment. The results are consistent with clinical diagnosis and hold considerable potential to discriminate healthy volunteers and patients at different disease stages. Whereas, following the same operation, the representative well-developed system provided serious false-negative results using such trace amounts of samples from clinically confirmed positive patients. PMID- 29629110 TI - Synthesis of ultrathin platinum nanoplates for enhanced oxygen reduction activity. AB - Ultrathin Pt nanostructures exposing controlled crystal facets are highly desirable for their superior activity and cost-effectiveness in the electrocatalytic oxygen reduction reaction (ORR), and they are conventionally synthesized by epitaxial growth of Pt on a limited range of templates, such as Pd nanocrystals, resulting in a high cost and less structural diversity of the ultrathin Pt nanostructures. To solve this problem, we demonstrate that ultrathin Pt nanostructures can be synthesized by templating conveniently available Ag nanocrystals without involving galvanic replacement, which enables a much-reduced cost and controllable new morphologies, such as ultrathin Pt nanoplates that expose the {111} facets. The resulting ultrathin Pt nanoplates are ~1-2 nm in thickness, which show an ~22-fold increase in specific activity (5.3 mA cm-2), an ~9.5-fold increase in mass activity (1.62 A mg-1) and significantly enhanced catalytic stability in the ORR, compared with the commercial Pt/C catalyst. We believe this strategy opens a door to a highly extendable family of ultrathin noble metal nanostructures, thus promising excellent activity and stability in a broad range of catalytic applications. PMID- 29629111 TI - Tracking the picosecond deactivation dynamics of a photoexcited iron carbene complex by time-resolved X-ray scattering. AB - Recent years have seen the development of new iron-centered N-heterocyclic carbene (NHC) complexes for solar energy applications. Compared to typical ligand systems, the NHC ligands provide Fe complexes with longer-lived metal-to-ligand charge transfer (MLCT) states. This increased lifetime is ascribed to strong ligand field splitting provided by the NHC ligands that raises the energy levels of the metal centered (MC) states and therefore reduces the deactivation efficiency of MLCT states. Among currently known NHC systems, [Fe(btbip)2]2+ (btbip = 2,6-bis(3-tert-butyl-imidazol-1-ylidene)pyridine) is a unique complex as it exhibits a short-lived MC state with a lifetime on the scale of a few hundreds of picoseconds. Hence, this complex allows for a detailed investigation, using 100 ps X-ray pulses from a synchrotron, of strong ligand field effects on the intermediate MC state in an NHC complex. Here, we use time-resolved wide angle X ray scattering (TRWAXS) aided by density functional theory (DFT) to investigate the molecular structure, energetics and lifetime of the high-energy MC state in the Fe-NHC complex [Fe(btbip)2]2+ after excitation to the MLCT manifold. We identify it as a 260 ps metal-centered quintet (5MC) state, and we refine the molecular structure of the excited-state complex verifying the DFT results. Using information about the hydrodynamic state of the solvent, we also determine, for the first time, the energy of the 5MC state as 0.75 +/- 0.15 eV. Our results demonstrate that due to the increased ligand field strength caused by NHC ligands, upon transition from the ground state to the 5MC state, the metal to ligand bonds extend by unusually large values: by 0.29 A in the axial and 0.21 A in the equatorial direction. These results imply that the transition in the photochemical properties from typical Fe complexes to novel NHC compounds is manifested not only in the destabilization of the MC states, but also in structural distortion of these states. PMID- 29629112 TI - Beyond optical rotation: what's left is not always right in total synthesis. AB - This work describes the application of vibrational (VCD) and electronic (ECD) circular dichroism spectroscopy to solve the longstanding debate around the absolute configuration of (+)-frondosin B (1). The absolute configuration of (+) 1 could confidently be assigned as (R) using these spectroscopic techniques. The discrepancy in the optical rotation (OR) values obtained in previous studies can be attributed to an undetected minor impurity (ca. 7%) that arose unexpectedly in a key step late in the synthesis. Additionally, the conditions used in the final step of the previous reports for demethylation to form the natural product proceeded with significant loss of enantiopurity. The large OR measured for the impurity at its observed level, when compared to the small rotation for the less enantiopure natural product 1, led to a measured OR value for the synthetic material that had the opposite sign of the natural product. PMID- 29629113 TI - Strong polarization switching with low-energy loss in hydrogen-bonded organic antiferroelectrics. AB - The electric-field-induced phase transition from antipolar to polar structures is at the heart of antiferroelectricity. We demonstrate direct evidence of antiferroelectricity by applying a strong electric field to two antipolar crystals of squaric acid (SQA) and 5,5'-dimethyl-2,2'-bipyridinium chloranilate. The field-induced polarization of SQA is quite large and reasonably explained by the theoretically calculated polarization on the hydrogen-bonded sheet sublattice. The pseudo-tetragonal lattice of SQA permits unique switching topologies that produce two different ferroelectric phases of low and high polarizations. By tilting the applied field direction, the electrical switching mechanism can be attributed to a 90 degrees rotation of the sheet polarization. From the viewpoint of applications, the strong polarization, high switching field, and quite slim hysteresis observed in the polarization versus electric field curve for SQA are advantageous for excellent-efficiency energy storage devices. PMID- 29629114 TI - Origin of unusual spinel-to-layered phase transformation by crystal water. AB - It is well known that many layered transition metal oxides can transform into a spinel structure upon repeated battery cycling, but a phase transition in the opposite direction is rare. Recently, the transformation from spinel Mn3O4 to layered MnO2 was observed during the operation of a Mg battery in aqueous conditions, resulting in high performance Mg batteries. We hereby use ab initio calculations to unveil the mechanism by which crystal water plays a critical role in this unique transformation. Once inserted into the spinel form, a water molecule donates an electron, offering a key structural and thermodynamic driving force to initiate the transformation process. These crystal water molecules then get favorably clustered into a planar form in the layered structure and act as a stabilizing agent for birnessite. Kinetically, the inserted crystal water dramatically promotes the necessary rearrangement of Mn during the transition by lowering the activation barrier by >2 eV. The present structural, thermodynamic and kinetic understanding of the crystal water-driven phase transition provides novel insights to further the design of related low dimensional hydrated materials for multi-valent cathodes. PMID- 29629115 TI - H2O2-responsive and plaque-penetrating nanoplatform for mTOR gene silencing with robust anti-atherosclerosis efficacy. AB - The mammalian target of rapamycin (mTOR) that controls autophagy and lipid metabolism is pivotal for atherosclerosis initiation and progression. Although blocking the mTOR function with rapamycin and its analogs may stimulate autophagy and consequently attenuate lipid storage and atherosclerotic lesions, only limited success has been achieved in clinical applications due to the unsatisfactory efficacy and safety profiles. In this study, we engineered a cerium oxide nanowire (CeO2 NW)-based RNA interference (RNAi) oligonucleotide delivery nanoplatform for the effective silencing of mTOR and treatment of atherosclerosis. This nanoplatform is composed of the following three key components: (i) a stabilin-2-specific peptide ligand (S2P) to improve plaque targeting and penetration; (ii) polyethylene glycosylation (PEGylation) to extend in vivo circulation time; and (iii) a high aspect ratio CeO2 core to facilitate endosome escape and ensure "on-demand" release of the RNAi payloads through competitive coordination of cytosolic hydrogen peroxide (H2O2). Systemic administration of the nanoplatforms efficiently targeted stabilin-2-expressing plaque and suppressed mTOR expression, which significantly rescued the impaired autophagy and inhibited the atherosclerotic lesion progression in apolipoprotein E-deficient (ApoE-/-) mice fed with a high-fat diet. These results demonstrated that this H2O2-responsive and plaque-penetrating nanoplatform can be a potent and safe tool for gene therapy of atherosclerosis. PMID- 29629116 TI - One-step methodology for the direct covalent capture of GPCRs from complex matrices onto solid surfaces based on the bioorthogonal reaction between haloalkane dehalogenase and chloroalkanes. AB - Protein immobilization techniques play an important role in the development of assays for disease diagnosis and drug discovery. However, many of these approaches are not applicable to transmembrane proteins. G protein-coupled receptors (GPCRs) are the largest protein superfamily encoded by the human genome and are targeted by a quarter of all prescription drugs. GPCRs are highly dynamic and sensitive to changes in the ambient environment, and current immobilization methodologies are not suitable for GPCRs. We used haloalkane dehalogenase (Halo) as an immobilization tag fused to the beta2-adrenoceptor (beta2-AR), angiotensin II type 1 (AT1) and angiotensin II type 2 (AT2) receptors. The engineered Halo tag covalently binds to a specific substrate chloroalkane through Asp 106 in the catalytic pocket. The Halo-tagged GPCRs were expressed in Escherichia coli at a suitable yield. Accordingly, we loaded cell lysate containing Halo-tagged GPCRs onto a macroporous silica gel coated with chloroalkane. Morphological characterization indicated a homogeneous monolayer of immobilized Halo-tagged GPCRs on the silica gel surface. The immobilized receptors proved to be surrounded by specific bound phospholipids including PG C18:1/C18:1. We observed a radio-ligand binding ability and ligand-induced conformational changes in the immobilized GPCRs, suggesting the preservation of bioactivity. This method is a one-step approach for the specific immobilization of GPCRs from cell lysates and validates that immobilized receptors retain canonical ligand binding capacity. Our immobilization strategy circumvents labor-intensive purification procedures and minimizes loss of activity. The immobilized receptors can be applied to high throughput drug and interaction partner screening for GPCRs. PMID- 29629117 TI - Doping palladium with tellurium for the highly selective electrocatalytic reduction of aqueous CO2 to CO. AB - Designing highly selective and energy-efficient electrocatalysts to minimize the competitive hydrogen evolution reaction in the electrochemical reduction of aqueous CO2 remains a challenge. In this study, we report that doping Pd with a small amount of Te could selectively convert CO2 to CO with a low overpotential. The PdTe/few-layer graphene (FLG) catalyst with a Pd/Te molar ratio of 1 : 0.05 displayed a maximum CO faradaic efficiency of about 90% at -0.8 V (vs. a reversible hydrogen electrode, RHE), CO partial current density of 4.4 mA cm-2, and CO formation turnover frequency of 0.14 s-1 at -1.0 V (vs. a RHE), which were 3.7-, 4.3-, and 10-fold higher than those of a Pd/FLG catalyst, respectively. Density functional calculations showed that Te adatoms preferentially bind at the terrace sites of Pd, thereby suppressing undesired hydrogen evolution, whereas CO2 adsorption and activation occurred on the high index sites of Pd to produce CO. PMID- 29629118 TI - MoleculeNet: a benchmark for molecular machine learning. AB - Molecular machine learning has been maturing rapidly over the last few years. Improved methods and the presence of larger datasets have enabled machine learning algorithms to make increasingly accurate predictions about molecular properties. However, algorithmic progress has been limited due to the lack of a standard benchmark to compare the efficacy of proposed methods; most new algorithms are benchmarked on different datasets making it challenging to gauge the quality of proposed methods. This work introduces MoleculeNet, a large scale benchmark for molecular machine learning. MoleculeNet curates multiple public datasets, establishes metrics for evaluation, and offers high quality open-source implementations of multiple previously proposed molecular featurization and learning algorithms (released as part of the DeepChem open source library). MoleculeNet benchmarks demonstrate that learnable representations are powerful tools for molecular machine learning and broadly offer the best performance. However, this result comes with caveats. Learnable representations still struggle to deal with complex tasks under data scarcity and highly imbalanced classification. For quantum mechanical and biophysical datasets, the use of physics-aware featurizations can be more important than choice of particular learning algorithm. PMID- 29629120 TI - De novo design of constrained and sequence-independent peptide scaffolds with topologically-formidable disulfide connectivities. AB - Disulfide-rich peptides are interesting scaffolds for drug design and discovery. However, peptide scaffolds constrained by disulfide bonds, either naturally occurring or computationally designed, have been suffering from the elusive (oxidative) folding behavior complying with Anfinsen's dogma, which strongly restricts their applicability in bioactive peptide design and discovery; because when primary peptide sequences are extensively manipulated, their disulfide connectivities might become scrambled. Here we present the design of cysteine/penicillamine (C/Pen)-mixed peptide frameworks that are capable of folding into specific regioisomers without dependence on primary amino acid sequences. Even certain folds that are considered to be topologically formidable can be generated in high yields. Currently, almost all disulfide-rich peptide scaffolds are vitally correlated to primary amino acid sequences, but ours are exceptional. These scaffolds should be of particular interest for further designing constrained peptides with new structures and functions, and more importantly, the ultimately designed peptides would not suffer from general oxidative folding problems. PMID- 29629119 TI - Enantioselective synthesis of gem-diarylalkanes by transition metal-catalyzed asymmetric arylations (TMCAAr). AB - Chiral gem(1,1)-diaryl containing tertiary or quaternary stereogenic centers are present in many natural products and important pharmacophores. While numerous catalytic asymmetric methods enable access to 1,1-diaryl motifs, transition metal catalyzed asymmetric arylations (TMCAAr) are one of the most powerful methods to prepare enantiopure gem-diarylalkane compounds. The main methodology includes enantioselective 1,2- or 1,4-additions across C 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 O, C 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 N and C 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 C bonds by arylmetallic reagents; aryl cross-couplings of olefins, benzylic (pseudo)halides and aziridines; asymmetric aryl substitution reactions of allylic substrates; and isotopic benzylic C-H arylation. PMID- 29629121 TI - Guanine-oligothiophene conjugates: liquid-crystalline properties, photoconductivities and ion-responsive emission of their nanoscale assemblies. AB - We here report the supramolecular self-assembly of hydrogen-bonded motifs for the development of nanostructured materials that exhibit dynamic functions such as stimuli-responsive properties and molecular recognition behaviour. We have designed and synthesised new thermotropic bicontinuous and columnar liquid crystalline (LC) guanine-oligothiophene conjugates tethered with lipophilic chains, which exhibit ionic, electronic and photoluminescence properties. Their potassium salt complexes self-assemble into thermotropic columnar LC phases. Time of-flight photoconductivity measurements have revealed that the guanine oligothiophene conjugates in the LC states possess charge transport abilities with either electron or ambipolar mobility values of 10-4 to 10-3 cm2 V-1 s-1. Furthermore, we have found that the complexation of potassium ions with the guanine motif could lead not only to structural change and thermal stabilization of the LC phases but also to a photoluminescence colour change in the solid states. The strategy presented in this work could lead to the design of new functional LC materials that could potentially be applicable as sensors and electronic devices. PMID- 29629122 TI - Luminescent zero-dimensional organic metal halide hybrids with near-unity quantum efficiency. AB - Single crystalline zero-dimensional (0D) organic-inorganic hybrid materials with perfect host-guest structures have been developed as a new generation of highly efficient light emitters. Here we report a series of lead-free organic metal halide hybrids with a 0D structure, (C4N2H14X)4SnX6 (X = Br, I) and (C9NH20)2SbX5 (X = Cl), in which the individual metal halide octahedra (SnX64-) and quadrangular pyramids (SbX52-) are completely isolated from each other and surrounded by the organic ligands C4N2H14X+ and C9NH20+, respectively. The isolation of the photoactive metal halide species by the wide band gap organic ligands leads to no interaction or electronic band formation between the metal halide species, allowing the bulk materials to exhibit the intrinsic properties of the individual metal halide species. These 0D organic metal halide hybrids can also be considered as perfect host-guest systems, with the metal halide species periodically doped in the wide band gap matrix. Highly luminescent, strongly Stokes shifted broadband emissions with photoluminescence quantum efficiencies (PLQEs) of close to unity were realized, as a result of excited state structural reorganization of the individual metal halide species. Our discovery of highly luminescent single crystalline 0D organic-inorganic hybrid materials as perfect host-guest systems opens up a new paradigm in functional materials design. PMID- 29629123 TI - FAD roles in glucose catalytic oxidation studied by multiphase flow of extractive electrospray ionization (MF-EESI) mass spectrometry. AB - The role of the coenzyme flavin adenine dinucleotide (FAD) in the catalytic oxidation of glucose was elucidated by MS using a new extraction and ionization method. By a multiphase flow of liquid-gas, extractive electrospray ionization was achieved, and this technique (MF-EESI) decreased the salt-matrix interference effectively, avoided salt crystallizations at the capillary tip and increased ionization efficiency by a concentric-sprayed solvent. Notably, two intermediate complexes of FAD-glucose have been observed and differentiated for the first time using this MF-EESI technique. These intermediate complexes were demonstrated to be responsible for the hydride abstraction from glucose, as well as the cyclic coenzyme conversion of FAD during glucose oxidation. Online monitoring was also employed in MF-EESI, thereby providing a potential and informative tool to scrutinize enzymatic catalytic reactions. PMID- 29629124 TI - Nickel-catalyzed difunctionalization of allyl moieties using organoboronic acids and halides with divergent regioselectivities. AB - Efficient difunctionalization of alkenes allows the rapid construction of molecular complexity from simple building blocks in organic synthesis. We present herein a nickel-catalyzed dicarbofunctionalization of alkenes using readily available organoboronic acids and organic halides in a three-component fashion. In particular, an unprecedented regioselectivity of the 1,3 dicarbofunctionalization of N-allylpyrimidin-2-amine is achieved when aryl and methyl iodides are utilized. In contrast, the use of alkyl bromides with beta hydrogens results in 1,3-hydroarylation or oxidative 1,3-diarylation. Preliminary mechanistic studies suggest an isomerization involving nickel hydride in the 1,3 difunctionalization reactions. On the other hand, the use of alkenyl or alkynyl halides promotes alternative regioselectivities to deliver 1,2-alkenylcarbonation or intriguing 2,1-alkynylcarbonation products. Such 2,1-alkynylarylation is also applicable to N-allylbenzamide as a different class of substrates. Overall, this nickel-catalyzed process proves to be powerful in delivering versatile difunctionalized compounds using readily available reagents/catalysts and a simple procedure. PMID- 29629125 TI - Selective lithium ion recognition in self-assembled columnar liquid crystals based on a lithium receptor. AB - Lithium is recognized as being significantly important due to its various applications in different areas especially in energy technology. In the present study, self-assembled nanostructured liquid-crystalline (LC) materials, that selectively bind lithium cations, have been developed for the first time. Wedge shaped crown ether derivatives bearing dibenzo-14-crown-4 (DB14C4) or 12-crown-4 moieties are able to act as LC lithium-selective receptors. We have found that complexation of these receptors with lithium perchlorate induces liquid crystalline columnar phases, while sodium perchlorate is immiscible with both receptors. Remarkably, a receptor consisting of DB14C4 as an effective lithium selective ligand exhibits high selectivity for LiCl over NaCl, KCl, RbCl and CsCl. The lithium selectivity was demonstrated and investigated by 1H NMR, 1H COSY and FT-IR spectroscopic measurements. The preferred coordination number of four and the ideal cavity geometry of the DB14C4 moiety of the receptor are shown to be key factors for the high lithium selectivity. This new design of LC lithium selective receptors opens unexplored paths for the development of methods to fabricate nanostructured materials for efficient selective lithium recognition. PMID- 29629126 TI - Switching single chain magnet behavior via photoinduced bidirectional metal-to metal charge transfer. AB - The preparation of single-chain magnets (SCMs) with photo-switchable bistable states is essential for the development of high-density photo-recording devices. However, the reversible switching of the SCM behavior upon light irradiation is a formidable challenge. Here we report a well-isolated double zigzag chain {[Fe(bpy)(CN)4]2[Co(phpy)2]}.2H2O (bpy = 2,2'-bipyridine, phpy = 4 phenylpyridine), which exhibits reversible redox reactions with interconversion between FeIIILS(MU-CN)CoIIHS(MU-NC)FeIIILS (LS = low-spin, HS = high-spin) and FeIIILS(MU-CN)CoIIILS(MU-NC)FeIILS linkages under alternating irradiation with 808 and 532 nm lasers. The bidirectional photo-induced metal-to-metal charge transfer results in significant changes of anisotropy and intrachain magnetic interactions, reversibly switching the SCM behavior. The on-switching SCM behavior driven by light irradiation at 808 nm could be reversibly switched off by irradiation at 532 nm. The results provide an additional and independent way to control the bistable states of SCMs by switching in the 0 -> 1 -> 0 sequence, with potential applications in high density storage and molecular switches. PMID- 29629127 TI - A durable monolithic polymer foam for efficient solar steam generation. AB - Efficient and cost-effective solar steam generation requires self-floating evaporators which can convert light into heat, prevent unnecessary heat loss and greatly accelerate evaporation without solar concentrators. Currently, the most efficient evaporators (efficiency of ~80% under 1 sun) are invariably built from inorganic materials, which are difficult to mold into monolithic sheets. Here, we present a new polymer which can be easily solution processed into a self-floating monolithic foam. The single-component foam can be used as an evaporator with an efficiency at 1 sun comparable to that of the best graphene-based evaporators. Even at 0.5 sun, the efficiency can reach 80%. Moreover, the foam is mechanically strong, thermally stable to 300 degrees C and chemically resistant to organic solvents. PMID- 29629128 TI - Direct sulfonylation of anilines mediated by visible light. AB - Sulfones feature prominently in biologically active molecules and are key functional groups for organic synthesis. We report a mild, photoredox-catalyzed reaction for sulfonylation of aniline derivatives with sulfinate salts, and demonstrate the utility of the method by the late-stage functionalization of drugs. Key features of the method are the straightforward generation of sulfonyl radicals from bench-stable sulfinate salts and the use of simple aniline derivatives as convenient readily available coupling partners. PMID- 29629129 TI - Gold-catalyzed stereoselective dearomatization/metal-free aerobic oxidation: access to 3-substituted indolines/oxindoles. AB - An unprecedented dearomatization of indoles with diazoesters has been developed via cationic gold(i) catalysis. The functionalization selectively occurs at the C3-position to deliver methylene indole derivatives in good yields with excellent Z-selectivity, demonstrating unusual reactivity and selectivity compared with other noble metal catalysis. Importantly, simply followed by silica gel adsorption, an unprecedented metal-free aerobic oxidation occurs for indoles bearing N-electron donating substituents, providing a novel and efficient approach towards 3-substituted indolin-2-ones with a newly formed quaternary stereocenter in excellent stereoselectivity. Notably, these processes afford direct and selective access to a variety of valuable intermediates from abundant feedstock chemicals. PMID- 29629130 TI - Dual nickel and Lewis acid catalysis for cross-electrophile coupling: the allylation of aryl halides with allylic alcohols. AB - Controlling the selectivity in cross-electrophile coupling reactions is a significant challenge, particularly when one electrophile is much more reactive. We report a general and practical strategy to address this problem in the reaction between reactive and unreactive electrophiles by a combination of nickel and Lewis acid catalysis. This strategy is used for the coupling of aryl halides with allylic alcohols to form linear allylarenes selectively. The reaction tolerates a wide range of functional groups (e.g. silanes, boronates, anilines, esters, alcohols, and various heterocycles) and works with various allylic alcohols. Complementary to most current routes for the C3 allylation of an unprotected indole, this method provides access to C2 and C4-C7 allylated indoles. Preliminary mechanistic experiments reveal that the reaction might start with an aryl nickel intermediate, which then reacts with Lewis acid activated allylic alcohols in the presence of Mn. PMID- 29629131 TI - The price of flexibility - a case study on septanoses as pyranose mimetics. AB - Seven-membered ring mimetics of mannose were studied as ligands for the mannose specific bacterial lectin FimH, which plays an essential role in the first step of urinary tract infections (UTI). A competitive binding assay and isothermal titration calorimetry (ITC) experiments indicated an approximately ten-fold lower affinity for the seven-membered ring mannose mimetic 2-O-n-heptyl-1,6-anhydro-d glycero-d-galactitol (7) compared to n-heptyl alpha-d-mannopyranoside (2), resulting exclusively from a loss of conformational entropy. Investigations by solution NMR, X-ray crystallography, and molecular modeling revealed that 7 establishes a superimposable H-bond network compared to mannoside 2, but at the price of a high entropic penalty due to the loss of its pronounced conformational flexibility. These results underscore the importance of having access to the complete thermodynamic profile of a molecular interaction to "rescue" ligands from entropic penalties with an otherwise perfect fit to the protein binding site. PMID- 29629132 TI - Amide synthesis via nickel-catalysed reductive aminocarbonylation of aryl halides with nitroarenes. AB - Aminocarbonylation of aryl halides is one of the most useful methods in amide synthesis, but nitroarenes have not been used as a nitrogen source in this method even though they are more economical and accessible than anilines. Reported here is the development of nickel catalysis for the first three-component reactions of aryl halides, Co2(CO)8, and nitroarenes under reductive conditions to produce aryl amides. A wide range of (hetero)aryl iodides and bromides as well as nitro(hetero)arenes are suitable reaction partners, and high functional group compatibility has been achieved. The method might be used for the streamlined synthesis of aryl amides. PMID- 29629133 TI - Fast and accurate prediction of the regioselectivity of electrophilic aromatic substitution reactions. AB - While computational prediction of chemical reactivity is possible it usually requires expert knowledge and there are relatively few computational tools that can be used by a bench chemist to help guide synthesis. The RegioSQM method for predicting the regioselectivity of electrophilic aromatic substitution reactions of heteroaromatic systems is presented in this paper. RegioSQM protonates all aromatic C-H carbon atoms and identifies those with the lowest free energies in chloroform using the PM3 semiempirical method as the most nucleophilic center. These positions are found to correlate qualitatively with the regiochemical outcome in a retrospective analysis of 96% of more than 525 literature examples of electrophilic aromatic halogenation reactions. The method is automated and requires only a SMILES string of the molecule of interest, which can easily be generated using chemical drawing programs such as ChemDraw. The computational cost is 1-10 minutes per molecule depending on size, using relatively modest computational resources and the method is freely available via a web server at ; http://www.regiosqm.org. RegioSQM should therefore be of practical use in the planning of organic synthesis. PMID- 29629134 TI - A highly efficient double-hierarchical sulfur host for advanced lithium-sulfur batteries. AB - Li-S batteries have attracted enormous interest due to their potentially high energy density, non-toxicity and the low cost of sulfur. The main challenges of sulfur cathodes are the short cycling life and limited power density caused by the low conductivity of sulfur and dissolution of Li polysulfides. Here we design a new double-hierarchical sulfur host to address these problems. Hierarchical carbon spheres (HCSs), constructed from building blocks of hollow carbon nanobubbles for loading sulfur, are sealed within a thin, polar MoS2 coating composed of ultrathin nanosheets. Experimental and theoretical studies show a strong absorption of the MoS2 nanoshell to polysulfides, and the excellent stability of the MoS2 nanosheets after the adsorption of polysulfides. Moreover, MoS2 promotes the electrochemical redox kinetics in Li-S batteries. Benefiting from the unique hierarchical, hollow and compositional characteristics of the host, the S/MoS2@HCS composite electrode shows a high capacity of 1048 mA h g-1 at 0.2C, good rate capacity and long cycling life with a slow capacity decay of 0.06% per cycle. PMID- 29629135 TI - Cage-templated synthesis of highly stable palladium nanoparticles and their catalytic activities in Suzuki-Miyaura coupling. AB - We report the controlled synthesis of small palladium nanoparticles (PdNPs) with narrow particle size distribution (1.8 +/- 0.2 nm) using an organic molecular cage as a template. The well-defined cage structure and thioether anchoring groups inside the cavity are critical for the formation of narrowly distributed PdNPs, offering a confined organic molecular environment and guiding PdNP nucleation and growth. The resulting encapsulated PdNPs are resistant to agglomeration and stable in solution exposed to air at room temperature. When provided with a protective cage shell with minimum surface coverage, such PdNPs are capable of catalyzing organic reactions, showing high catalytic activity in Suzuki-Miyaura coupling reactions. PMID- 29629136 TI - Dynamics of recombination via conical intersection in a semiconductor nanocrystal. AB - Conical intersections are well known to introduce nonradiative decay pathways in molecules, but have only recently been implicated in nonradiative recombination processes in materials. Here we apply excited state ab initio molecular dynamics simulations based on a multireference description of the electronic structure to defective silicon nanocrystals up to 1.7 nm in diameter to search for accessible nonradiative recombination pathways. Dangling bond defects are found to induce conical intersections between the ground and first excited electronic states of five systems of various sizes. These defect-induced conical intersections are accessible at energies that are in the visible range (2.4-2.7 eV) and very weakly dependent on particle size. The dynamic simulations suggest that these intersections are accessed 40-60 fs after creation of a defect-localized excitation. This ultrafast recombination is attributed to the fact that Jahn Teller distortion on the first excited state drives the defect directly towards a conical intersection with the ground electronic state. PMID- 29629137 TI - Diastereodivergent asymmetric Michael-alkylation reactions using chiral N,N' dioxide/metal complexes. AB - A diastereodivergent asymmetric Michael-alkylation reaction between 3-chloro oxindoles and beta,gamma-unsaturated-alpha-ketoesters has been achieved using L RaPr2 /Sc(OTf)3 and L-PrPr2 /Mg(OTf)2 metal complexes as catalysts. Both rel (1R,2S,3R) and rel-(1S,2S,3R) chiral spiro cyclopropane oxindoles were constructed in good yields, diastereoselectivities and ee values. The diastereodivergent control may originate from different alkylation pathways after the Michael addition, with either intramolecular trapping of the aza-ortho xylylene intermediate or direct SN2 substitution. PMID- 29629138 TI - Conservation of direct dynamics in sterically hindered SN2/E2 reactions. AB - Nucleophilic substitution (SN2) and base-induced elimination (E2), two indispensable reactions in organic synthesis, are commonly assumed to proceed under stereospecific conditions. Understanding the way in which the reactants pre orient in these reactions, that is its stereodynamics, is essential in order to achieve a detailed atomistic picture and control over such processes. Using crossed beam velocity map imaging, we study the effect of steric hindrance in reactions of Cl- and CN- with increasingly methylated alkyl iodides by monitoring the product ion energy and scattering angle. For both attacking anions the rebound mechanism, indicative of a direct SN2 pathway, is found to contribute to the reaction at high relative collision energies despite being increasingly hindered. An additional forward scattering mechanism, ascribed to a direct E2 reaction, also contributes at these energies. Inspection of the product energy distributions confirms the direct and fast character of both mechanisms as opposed to an indirect reaction mechanism which leads to statistical energy redistribution in the reaction complex. This work demonstrates that nonstatistical dynamics and energetics govern SN2 and E2 pathways even in sterically hindered exchange reaction systems. PMID- 29629139 TI - Unravelling the enigma of ligninOX: can the oxidation of lignin be controlled? AB - As societal challenges go, the development of efficient biorefineries as a means of reducing our dependence on petroleum refineries is high on the list. One of the core strengths of the petroleum refinery is its ability to produce a huge range of different products using all of the components of the starting material. In contrast, the target of using all the biopolymers present in lignocellulosic biomass is far from realised. Even though our ability to use the carbohydrate based components has advanced, our plans for lignin lag behind (with the notable exception of vanillin production). One approach to lignin usage is its controlled depolymerisation. This study focuses on an increasingly popular approach to this challenge which involves highly selective lignin oxidation to give a material often referred to as ligninOX. But what do we mean by ligninOX? In this study we show that it is possible to form many different types of ligninOX depending on the oxidation conditions that are used. We show that variations in the levels of processing of the beta-O-4, the beta-beta and a third linkage occur. Through use of this information, we can form a well-defined ligninOX from six different hardwood lignins. This process is reproducible and can be carried out on a large scale. With a source of well-defined ligninOX in hand, we show that it can be converted to simple aromatic monomers and that any remaining ligninOX is sufficiently soluble for further processing to be carried out. PMID- 29629140 TI - Simultaneous sensitive detection of multiple DNA glycosylases from lung cancer cells at the single-molecule level. AB - DNA glycosylases are involved in the base excision repair pathway, and all mammals express multiple DNA glycosylases to maintain genome stability. However, the simultaneous detection of multiple DNA glycosylase still remains a great challenge. Here, we develop a single-molecule detection method for the simultaneous detection of human 8-oxoguanine DNA glycosylase 1 (hOGG1) and human alkyladenine DNA glycosylase (hAAG) on the basis of DNA glycosylase-mediated cleavage of molecular beacons. We designed a Cy3-labeled molecular beacon modified with 8-oxoguanine (8-oxoG) for a hOGG1 assay and a Cy5-labeled molecular beacon modified with deoxyinosine for a hAAG assay. hOGG1 may catalyze the removal of 8-oxoG from 8-oxoG/C base pairs to generate an apurinic/apyrimidinic (AP) site, and hAAG may catalyze the removal of deoxyinosine from deoxyinosine/T base pairs to generate an AP site. With the assistance of apurinic/apyrimidinic endonuclease (APE1), the cleavage of AP sites results in the cleavage of molecular beacons, with Cy3 indicating the presence of hOGG1 and Cy5 indicating the presence of hAAG. Both of the Cy3 and Cy5 signals can be simply quantified by total internal reflection fluorescence-based single-molecule detection. This method can simultaneously detect multiple DNA glycosylases with a detection limit of 2.23 * 10-6 U MUL-1 for hOGG1 and 8.69 * 10-7 U MUL-1 for hAAG without the involvement of any target amplification. Moreover, this method can be used for the screening of enzyme inhibitors and the simultaneous detection of hOGG1 and hAAG from lung cancer cells, having great potential for further application in early clinical diagnosis. PMID- 29629141 TI - Te-containing carbon dots for fluorescence imaging of superoxide anion in mice during acute strenuous exercise or emotional changes. AB - Acute strenuous exercise and emotional changes are closely related to important aspects of human health. The superoxide anion (O2-), as one of the primary reactive oxygen species (ROS), is intimately associated with major diseases. However, there is no relevant in vivo research for directly indicating the link between O2- level and acute physical exercise or emotional changes. Hence, we constructed three fluorescent probes for the detection of O2-, including a Te containing molecular probe and Se- and Te-containing CDs, and evaluated their properties such as selectivity, sensitivity, instantaneity and dynamic response to O2-. Through performance comparisons, we found that the Te-containing CDs exhibited reversibility, instantaneity and the highest sensitivity (LOD ~ 8.0 pM), under guarantees of specific recognition of O2-, which ensure they are suitable for tracing native level changes in O2- within living systems. The probe was applied for monitoring the levels of O2- in mice under the state of intense exercise, irritability and mild depression, which led to the levels of O2- significantly increasing compared to the normal condition. Furthermore, we used the Te-containing CDs for real-time and dynamic imaging of O2- fluxes in the brain of mild depression mice and witnessed a positive correlation between O2- levels and depression. This work provides a new strategy for studying the relationship between acute exercise or emotional changes and diseases at the level of ROS. PMID- 29629142 TI - A model for optical gain in colloidal nanoplatelets. AB - Cadmium chalcogenide nanoplatelets (NPLs) and their heterostructures have been reported to have low gain thresholds and large gain coefficients, showing great potential for lasing applications. However, the further improvement of the optical gain properties of NPLs is hindered by a lack of models that can account for their optical gain characteristics and predict their dependence on the properties (such as lateral size, concentration, and/or optical density). Herein, we report a systematic study of optical gain (OG) in 4-monolayer thick CdSe NPLs by both transient absorption spectroscopy study of colloidal solutions and amplified spontaneous emission (ASE) measurement of thin films. We showed that comparing samples with the same optical density at the excitation, the OG threshold is not dependent of the NPL lateral area, while the saturation gain amplitude is dependent on the NPL lateral area when comparing samples with the same optical density at the excitation wavelength. Both the OG and ASE thresholds increase with the optical density at the excitation wavelength for samples of the same NPL thickness and lateral area. We proposed an OG model for NPLs that can successfully account for the observed lateral area and optical density dependences. The model reveals that OG originates from stimulated emission from the bi-exciton states and the OG threshold is reached when the average number of excitons per NPL is about half the occupation of the band-edge exciton states. The model can also rationalize the much lower OG thresholds in the NPLs compared to QDs. This work provides a microscopic understanding of the dependence of the OG properties on the morphology of the colloidal nanocrystals and important guidance for the rational optimization of the lasing performance of NPLs and other 1- and 2-dimensional nanocrystals. PMID- 29629143 TI - Exciton coupling in diketopyrrolopyrrole-helicene derivatives leads to red and near-infrared circularly polarized luminescence. AB - Molecular and macromolecular chiral pi-conjugated diketopyrrolopyrrole (DPP) helicene derivatives were prepared and their chiroptical properties examined experimentally and theoretically. Exciton coupling leads to red and near-infrared circularly polarized absorption and luminescence arising from the achiral DPP units in the helical environment, highlighting an interesting synergy between the chiral helicene and the organic dye. PMID- 29629144 TI - Label-free Raman spectroscopy provides early determination and precise localization of breast cancer-colonized bone alterations. AB - Breast neoplasms frequently colonize bone and induce development of osteolytic bone lesions by disrupting the homeostasis of the bone microenvironment. This degenerative process can lead to bone pain and pathological bone fracture, a major cause of cancer morbidity and diminished quality of life, which is exacerbated by our limited ability to monitor early metastatic disease in bone and assess fracture risk. Spurred by its label-free, real-time nature and its exquisite molecular specificity, we employed spontaneous Raman spectroscopy to assess and quantify early metastasis driven biochemical alterations to bone composition. As early as two weeks after intracardiac inoculations of MDA-MB-435 breast cancer cells in NOD-SCID mice, Raman spectroscopic measurements in the femur and spine revealed consistent changes in carbonate substitution, overall mineralization as well as crystallinity increase in tumor-bearing bones when compared with their normal counterparts. Our observations reveal the possibility of early stage detection of biochemical changes in the tumor-bearing bones - significantly before morphological variations are captured through radiographic diagnosis. This study paves the way for a better molecular understanding of altered bone remodeling in such metastatic niches, and for further clinical studies with the goal of establishing a non-invasive tool for early metastasis detection and prediction of pathological fracture risk in breast cancer. PMID- 29629145 TI - Dual vicinal functionalisation of heterocycles via an interrupted Pummerer coupling/[3,3]-sigmatropic rearrangement cascade. AB - A dual vicinal functionalisation cascade involving the union of heterocycles and allyl sulfoxides is described. In particular, the approach provides efficient one step access to biologically relevant and synthetically important C3 thio, C2 carbo substituted indoles. The reaction operates under mild, metal free conditions and without directing groups, via an interrupted Pummerer coupling of activated allyl sulfoxides, generating allyl heteroaryl sulfonium salts that are predisposed to a charge accelerated [3,3]-sigmatropic rearrangement. PMID- 29629146 TI - Establishment of a universal and rational gene detection strategy through three way junction-based remote transduction. AB - The polymerase chain reaction and many isothermal amplifications are able to achieve super gene amplification. Unfortunately, most commonly-used transduction methods, such as dye staining and Taqman-like probing, still suffer from shortcomings including false signals or difficult probe design, or are incompatible with multi-analysis. Here a universal and rational gene detection strategy has been established by translating isothermal amplicons to enzyme-free strand displacement circuits via three-way junction-based remote transduction. An assistant transduction probe was imported to form a partial hybrid with the target single-stranded nucleic acid. After systematic optimization the hybrid could serve as an associative trigger to activate a downstream circuit detector via a strand displacement reaction across the three-way junction. By doing so, the detection selectivity can be double-guaranteed through both amplicon transducer recognition and the amplicon-circuit reaction. A well-optimized circuit can be immediately applied to a new target detection through simply displacing only 10-12 nt on only one component, according to the target. More importantly, this property for the first time enables multi-analysis and logic analysis in a single reaction, sharing a single fluorescence reporter. In an applicable model, trace amounts of Cronobacter and Enterobacteria genes have been clearly distinguished from samples with no bacteria or one bacterium, with ultra high sensitivity and selectivity. PMID- 29629147 TI - Target-activated streptavidin-biotin controlled binding probe. AB - Target-activated chemical probes are important tools in basic biological research and medical diagnosis for monitoring enzyme activities and reactive small molecules. Based on the fluorescence turn-on mechanism, they can be divided into two classes: dye-based fluorescent probes and caged-luciferin. In this paper, we introduce a new type of chemical probe in which the fluorescence turn-on is based on controlled streptavidin-biotin binding. Compared to conventional probes, the streptavidin-biotin controlled binding probe has several advantages, such as minimal background at its "OFF" state, multiple signal amplification steps, and unlimited selection of the optimal dyes for detection. To expand the scope, a new synthetic method was developed, through which a wider range of analyte recognition groups can be easily introduced to construct the binding probe. This probe design was successfully applied to image and study secreted peroxynitrite (ONOO-) at the cell surface of macrophages where information on ONOO- is difficult to obtain. As the signals are generated upon the binding of streptavidin to the biotin probe, this highly versatile design can not only be used in fluorescence detection but can also be applied in various other detection modes, such as electrochemical and enzyme-amplified luminescence detection. PMID- 29629148 TI - Surface-immobilized and self-shaped DNA hydrogels and their application in biosensing. AB - Hydrogels are of great interest in the field of biosensing for their good biocompatibility, plasticity, and capability of providing 3D scaffolds. Nevertheless, the application of hydrogels has not been linked with broad surface biosensing systems yet. To overcome the limitations, here for the first time, surface-immobilized pure DNA hydrogels were synthesized using a surficial primer induced strategy and adopted for biosensing applications. The DNA hydrogel 3D scaffold is successfully constructed on a transparent ITO electrode, which facilitates both colourimetric and electrochemical measurements. Results show that the hydrogel is able to wrap enzymes solidly and exhibits favourable stability under different conditions. Owing to the free diffusion of the micromolecular targets throughout the hydrogel, while isolating the enzymes from the macromolecular interferences outside the hydrogel, the direct colourimetric and electrochemical detection of hydrogen peroxide and bilirubin in serum is achieved. The detection limit of hydrogen peroxide in serum is 22 nM by colourimetric analysis and 13 nM by electrochemical measurement. The detection limit of bilirubin is 32 nM, a favourable limit that could be used in jaundice diagnosis. In addition, the enzyme@hydrogel can be easily regenerated and the catalytic activity is retained for a few cycles, thus allowing the recycling of the hydrogel-based biosensing system. The successful integration of DNA hydrogels with surface biosensing systems will greatly expand the applications of hydrogels for diagnostic and environmental monitoring purposes. PMID- 29629149 TI - Supramolecular assemblies of a nitrogen-embedded buckybowl dimer with C60. AB - A directly connected azabuckybowl dimer was synthesized via a palladium-catalysed C-H/C-Br coupling. The electron-donating nature of the pyrrolic nitrogen atoms of the azabuckybowl enabled a strong complexation with pristine C60. In the presence of two equivalents of C60, the azabuckybowl dimer formed crystals with a 1 : 2 stoichiometry. Conversely, in diluted solution, complexes with a 1 : 1 stoichiometry of the dimer and C60 were detected predominantly, and these precipitated upon increasing the concentration of C60. Scanning electron microscopy images of the precipitate showed fibre-like aggregates, indicating the formation of supramolecular assemblies with 1D chain structures. A variable temperature 1H NMR analysis revealed that the precipitate consists of the dimer and C60 in a 1 : 1 ratio. PMID- 29629150 TI - Quantum optical emulation of molecular vibronic spectroscopy using a trapped-ion device. AB - Molecules are one of the most demanding quantum systems to be simulated by quantum computers due to their complexity and the emergent role of quantum nature. The recent theoretical proposal of Huh et al. (Nature Photon., 9, 615 (2015)) showed that a multi-photon network with a Gaussian input state can simulate a molecular spectroscopic process. Here, we present the first quantum device that generates a molecular spectroscopic signal with the phonons in a trapped ion system, using SO2 as an example. In order to perform reliable Gaussian sampling, we develop the essential experimental technology with phonons, which includes the phase-coherent manipulation of displacement, squeezing, and rotation operations with multiple modes in a single realization. The required quantum optical operations are implemented through Raman laser beams. The molecular spectroscopic signal is reconstructed from the collective projection measurements for the two-phonon-mode. Our experimental demonstration will pave the way to large-scale molecular quantum simulations, which are classically intractable, but would be easily verifiable by real molecular spectroscopy. PMID- 29629151 TI - A three-in-one-bullet for oesophageal cancer: replication fork collapse, spindle attachment failure and enhanced radiosensitivity generated by a ruthenium(ii) metallo-intercalator. AB - Substitutionally inert ruthenium(ii) polypyridyl complexes have been developed as DNA intercalating agents yet cellular DNA damage responses to this binding modality are largely unexplored. Here, we show the nuclear-targeting complex [Ru(phen)2(tpphz)]2+ (phen = 1,10-phenanthroline, tpphz = tetrapyridophenazine) generates rapid and pronounced stalling of replication fork progression in p53 deficient human oesophageal cancer cells. In response, replication stress and double-strand break (DSB) DNA damage response (DDR) pathways are activated and cell proliferation is inhibited by growth arrest. Moreover, mitotic progression is compromised by [Ru(phen)2(tpphz)]2+, where the generation of metaphase chromosome spindle attachment failure results in spindle assembly checkpoint (SAC) activation. This dual mechanism of action results in preferential growth inhibition of rapidly-proliferating oesophageal cancer cells with elevated mitotic indices. In addition to these single-agent effects, [Ru(phen)2(tpphz)]2+ functions as a radiosensitizer with efficiency comparable to cisplatin, which occurs through a synergistic enhancement of DNA damage. These results establish that DNA replication is the target for [Ru(phen)2(tpphz)]2+ and provide the first experimental evidence that ruthenium-based intercalation targets multiple genome integrity pathways in cancer cells, thereby achieving enhanced selectivity compared to existing DNA-damaging agents such as cisplatin. PMID- 29629152 TI - Cost-effective 17O enrichment and NMR spectroscopy of mixed-metal terephthalate metal-organic frameworks. AB - 17O solid-state NMR spectroscopy is employed to investigate the cation disorder in metal-organic frameworks containing two different types of metal cations. Although NMR offers exquisite sensitivity to the local, atomic-scale structure, making it an ideal tool for the characterisation of disordered materials, the low natural abundance of 17O (0.037%) necessitates expensive isotopic enrichment to acquire spectra on a reasonable timescale. Using dry gel conversion and a novel steaming method we show that cost-effective and atom-efficient enrichment of MOFs is possible, and that high-resolution 17O NMR spectra are sensitive both to the structural forms of the MOF and the presence of guest molecules. For mixed-metal forms of MIL-53, NMR can also provide information on the final composition of the materials (notably different to that of the initial starting material) and the preference for cation clustering/ordering within the MOFs. For Al, Ga MIL-53, the distribution of cations results in a mixed-pore form upon exposure to water, unlike the different structures seen for the corresponding end members. This work shows that as good levels of enrichment can be achieved at reasonable cost, 17O NMR spectroscopy should be an invaluable tool for the study of these important functional materials. PMID- 29629153 TI - Excited state electron and energy relays in supramolecular dinuclear complexes revealed by ultrafast optical and X-ray transient absorption spectroscopy. AB - The kinetics of photoinduced electron and energy transfer in a family of tetrapyridophenazine-bridged heteroleptic homo- and heterodinuclear copper(i) bis(phenanthroline)/ruthenium(ii) polypyridyl complexes were studied using ultrafast optical and multi-edge X-ray transient absorption spectroscopies. This work combines the synthesis of heterodinuclear Cu(i)-Ru(ii) analogs of the homodinuclear Cu(i)-Cu(i) targets with spectroscopic analysis and electronic structure calculations to first disentangle the dynamics at individual metal sites by taking advantage of the element and site specificity of X-ray absorption and theoretical methods. The excited state dynamical models developed for the heterodinuclear complexes are then applied to model the more challenging homodinuclear complexes. These results suggest that both intermetallic charge and energy transfer can be observed in an asymmetric dinuclear copper complex in which the ground state redox potentials of the copper sites are offset by only 310 meV. We also demonstrate the ability of several of these complexes to effectively and unidirectionally shuttle energy between different metal centers, a property that could be of great use in the design of broadly absorbing and multifunctional multimetallic photocatalysts. This work provides an important step toward developing both a fundamental conceptual picture and a practical experimental handle with which synthetic chemists, spectroscopists, and theoreticians may collaborate to engineer cheap and efficient photocatalytic materials capable of performing coulombically demanding chemical transformations. PMID- 29629154 TI - Models for aerobic carbon monoxide dehydrogenase: synthesis, characterization and reactivity of paramagnetic MoVO(MU-S)CuI complexes. AB - Reaction of [CoCp2][TpiPrMoOS(OAr)] [Cp = eta5-cyclopentadienyl; TpiPr = hydrotris(3-isopropylpyrazol-1-yl)borate; OAr = phenolate or derivative thereof] with [Cu(NCMe)(Me3tcn)]BF4 (Me3tcn = 1,4,7-trimethyl-1,4,7-triazacyclononane) in MeCN at -30 degrees C results in the formation of red-brown/black, paramagnetic, MU-sulfido-Mo(v)/Cu(i) complexes, TpiPrMoO(OAr)(MU-S)Cu(Me3tcn). The complexes possess the MoO(MU-S)Cu core found in aerobic carbon monoxide dehydrogenases (CODHs) and exhibit X-band EPR spectra closely related to those of semi-reduced CODH, with giso ~ 1.937, hyperfine coupling to 95,97Mo (aiso = 39-42 * 10-4 cm-1) and strong superhyperfine coupling to 63,65Cu (aiso = 34-63 * 10-4 cm-1). Anisotropic spectra exhibit monoclinic symmetry with g1 ~ 1.996, g2 ~ 1.944 and g3 ~ 1.882, and nearly isotropic ACu values (75-90 * 10-4 cm-1). The X-ray structures of four derivatives (Ar = Ph, C6H4t Bu-2, C6H4sBu-2, C6H4Ph-4) are reported and discussed along with that of the Ar = C6H3t Bu2-3,5 derivative (communicated in C. Gourlay, D. J. Nielsen, J. M. White, S. Z. Knottenbelt, M. L. Kirk and C. G. Young, J. Am. Chem. Soc., 2006, 128, 2164). The complexes exhibit distorted octahedral oxo-Mo(v) and distorted tetrahedral Cu(i) centres bridged by a single bent MU-sulfido ligand, with Mo-S and Cu-S distances and Mo-S-Cu angles in the ranges 2.262-2.300 A, 2.111-2.134 A and 115.87-134.27 degrees , respectively. The 2 t-butyl derivative adopts a unique phenolate conformation with O 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 Mo-O-Calpha and O 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 1111111111111111111111111111111111 1111111111111111111111111111111111 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 0000000000000000000000000000000000 Mo-S-Cu torsion angles of 92.7 and 21.1 degrees , respectively, very different from those of the other structurally characterized derivatives (31-47 and 33-45 degrees , respectively) and exhibits a relatively short Mo...Cu distance [3.752(2) A vs. 3.806(7)-4.040(2) A]. As well, the aCu value of this complex (34.3 * 10-4 cm-1) is much lower than the values observed for other members of the series (55-63 * 10-4 cm-1), supporting the hypothesis that the electronic structure of the MoO(MU S)Cu core unit and the degree of intermetallic communication are strongly dependent on the geometry of the MoO(OR)(MU-S)Cu unit. The complexes participate in an electrochemically reversible Mo(vi)/Mo(v) redox couple and react with cyanide undergoing decupration and desulfurization reactions of the type observed for CODH. PMID- 29629155 TI - Molecular cage-bridged plasmonic structures with well-defined nanogaps as well as the capability of reversible and selective guest trapping. AB - Creating well-defined plasmonic hotspots with enormous field enhancements as well as the capability of selectively trapping targeted molecules into hotspots is of critical importance and a prerequisite for numerous plasmon-assisted applications, but it represents a great challenge. In this work, a robust molecular cage decorated with thioether moieties at the periphery was designed and synthesized. By using the synthesized cage as a linker, a series of molecular cage-bridged plasmonic structures with well-defined nanogaps (hotspots) were fabricated in an efficient and controllable fashion. It was found both experimentally and theoretically that the nanogaps of about 1.2 nm created by the molecular cage in the resultant plasmonic structures led to a strong plasmon coupling, thus inducing great field enhancement inside the nanogaps. More importantly, the embedded molecular cages endowed the formed hotspots with the capability of selectively trapping targeted molecules, offering huge opportunities for many emergent applications. As a demonstration, the hotspots constructed were used as a unique nanoreactor, and under mild conditions two types of plasmon-driven chemical transformation were successfully performed. All the results clearly indicate that the integration of the host-guest chemistry of the molecular cage with the plasmon-coupling effect of metal particles afforded a new class of plasmonic structures, showing great potential for facilitating a broad variety of plasmon-based applications. PMID- 29629156 TI - Peptide nucleic acid-templated selenocystine-selenoester ligation enables rapid miRNA detection. AB - The development of a rapid and chemoselective selenocystine-selenoester peptide ligation that operates at nanomolar reactant concentrations has been developed by utilising PNA templation. Kinetic analysis of the templated peptide ligation revealed that the selenocystine-selenoester reaction was 10 times faster than traditional native chemical ligation at cysteine and to our knowledge is the fastest templated ligation reaction reported to date. The efficiency and operational simplicity of this technology is highlighted through the formation of hairpin molecular architectures and in a novel paper-based lateral flow assay for the rapid and sequence specific detection of oligonucleotides, including miRNA in cell lysates. PMID- 29629157 TI - Ni-catalysed regioselective 1,2-diarylation of unactivated olefins by stabilizing Heck intermediates as pyridylsilyl-coordinated transient metallacycles. AB - We report a Ni-catalysed diarylation of unactivated olefins in dimethylpyridylvinylsilane by intercepting Heck C(sp3)-NiX intermediates, derived from aryl halides, with arylzinc reagents. This approach utilizes a modifiable pyridylsilyl moiety as a coordinating group that plays a dual role of intercepting oxidative addition species to promote Heck carbometallation, and stabilizing the Heck C(sp3)-NiX intermediates as transient metallacycles to suppress beta-hydride elimination, and facilitate transmetalation/reductive elimination. This method affords 1,2-diarylethylsilanes, which can be readily oxidized to 1,2-diarylethanols that occur as structural motifs in 3-aryl-3,4 dihydroisocoumarin and dihydrostilbenoid natural products. PMID- 29629158 TI - Deciphering the incognito role of water in a light driven proton coupled electron transfer process. AB - Light induced multisite electron proton transfer in two different phenol (simple and phenol carrying an intramolecularly hydrogen bonded base) pendants on acridinedione dye (ADD) and an NADH analogue was studied by following fluorescence quenching dynamics in an ultrafast timescale. In a simple phenol derivative (ADDOH), photo-excited acridinedione acquires an electron from phenol intramolecularly, coupled with the transfer of a proton to solvent water. But in a phenol carrying hydrogen bonded base (ADDDP), both electron and proton transfer occur completely intramolecularly. The sequence of this electron and proton transfer process was validated by discerning the pH dependency of the reaction kinetics. Since photo-excited ADDs are stronger oxidants, the sequential electron first proton transfer mechanism (ETPT) was observed in ADDOH and hence there is no change in the PCET reaction kinetics kETPT ~ 6.57 * 109 s-1 in the entire pH range (pH 2-12). But the phenol carrying hydrogen bonded base (ADDDP) unleashes concerted electron proton transfer where the PCET reaction rate decreases upon decreasing the pH below its pKa. Noticeably, the concerted EPT process in ADDDP mimics the donor side of photosystem II and it occurs by two distinct pathways: (i) through direct intramolecular hydrogen bonding between the phenol and amine, kDEPT ~ 12.5 * 1010 s-1 and (ii) through the bidirectional hydrogen bond extended by the water molecule trapped in between the proton donor and acceptor, which mediates the proton transfer and serves as a proton wire, kWMEPT ~ 2.85 * 1010 s 1. These results unravel the incognito role played by water in mediating the proton transfer process when the structural elements do not favor direct hydrogen bonding between the proton donor and acceptor in a concerted PCET reaction. PMID- 29629159 TI - Synthesis and electrokinetics of cationic spherical nanoparticles in salt-free non-polar media. AB - Cationic diblock copolymer nanoparticles have been prepared in n-dodecane via polymerization-induced self-assembly (PISA). A previously reported poly(stearyl methacrylate)-poly(benzyl methacrylate) (PSMA-PBzMA) PISA formulation (Chem. Sci. 2016, 7, 5078-5090) was modified by statistically copolymerizing an oil-soluble cationic methacrylic monomer, (2-(methacryloyloxy)ethyl)trimethylammonium tetrakis[3,5-bis(trifluoromethyl)phenyl]borate, with either SMA or BzMA, to produce either charged shell or charged core nanoparticles. The electrokinetics were studied as a function of many variables (function of volume function, particle size, solvent viscosity, and number of ions per chain). These data are consistent with electrophoresis controlled by counterion condensation, which is typically observed in salt-free media. However, there are several interesting and unexpected features of interest. In particular, charged shell nanoparticles have a lower electrophoretic mobility than the equivalent charged core nanoparticles, and the magnitude of the electrophoretic mobility increases as the fraction of cationic stabilizer chains in the shell layer is reduced. These results show that cationic PSMA-PBzMA spheres provide an interesting new example of electrophoretic nanoparticles in non-polar solvents. Moreover, they should provide an ideal model system to evaluate new electrokinetic theories. PMID- 29629160 TI - Organocatalytic nitrenoid transfer: metal-free selective intermolecular C(sp3)-H amination catalyzed by an iminium salt. AB - This report details the first organocatalytic method for nitrenoid transfer and its application to intermolecular, site-selective C(sp3)-H amination. The method utilizes a trifluoromethyl iminium salt as the catalyst, iminoiodinanes as the nitrogen source, and substrate as the limiting reagent. Activated, benzylic, and aliphatic substrates can all be selectively functionalized in yields up to 87%. A mechanistic proposal for the observed reactivity supported by experimental evidence invokes the intermediacy of a diaziridinium salt or related organic nitrenoid, species that have not been previously explored for the purpose of C-H amination. Finally, examples of late-stage functionalization of complex molecules highlight the selectivity and potential utility of this catalytic method in synthesis. PMID- 29629161 TI - Dye-sensitized electron transfer from TiO2 to oxidized triphenylamines that follows first-order kinetics. AB - Two sensitizers, [Ru(bpy)2(dcb)]2+ (RuC) and [Ru(bpy)2(dpb)]2+ (RuP), where bpy is 2,2'-bipyridine, dcb is 4,4'-dicarboxylic acid-2,2'-bipyridine and dpb is 4,4' diphosphonic acid-2,2'-bipyridine, were anchored to mesoporous TiO2 thin films and utilized to sensitize the reaction of TiO2 electrons with oxidized triphenylamines, TiO2(e-) + TPA+ -> TiO2 + TPA, to visible light in CH3CN electrolytes. A family of four symmetrically substituted triphenylamines (TPAs) with formal Eo(TPA+/0) reduction potentials that spanned a 0.5 eV range was investigated. Surprisingly, the reaction followed first-order kinetics for two TPAs that provided the largest thermodynamic driving force. Such first-order reactivity indicates a strong Coulombic interaction between TPA+ and TiO2 that enables the injected electron to tunnel back in one concerted step. The kinetics for the other TPA derivatives were non-exponential and were modelled with the Kohlrausch-William-Watts (KWW) function. A Perrin-like reaction sphere model is proposed to rationalize the kinetic data. The activation energies were the same for all of the TPAs, within experimental error. The average rate constants were found to increase with the thermodynamic driving force, consistent with electron transfer in the Marcus normal region. PMID- 29629162 TI - Enhancing the stability and porosity of penetrated metal-organic frameworks through the insertion of coordination sites. AB - Guided by the insertion of coordination sites within ligands, an interpenetrated metal-organic framework NKU-112 and a self-penetrated framework NKU-113 were obtained. The two MOFs have similar cage-based framework structures, while NKU 113 reveals enhanced porosity and stability compared with NKU-112, owing to the self-penetrated structure induced by the additional chelating bipyridine moiety in the ligand. To the best of our knowledge, this is the first study that attempts to shift the structure topology of a MOF from interpenetrated to self penetrated while achieving a delicate modulation of the location and distances within the penetrated structure by inserting new coordination sites. PMID- 29629163 TI - Cobalt-catalyzed regioselective stereoconvergent Markovnikov 1,2-hydrosilylation of conjugated dienes. AB - We report the first stereoconvergent Markovnikov 1,2-hydrosilylation of conjugated dienes using catalysts generated from bench-stable Co(acac)2 and phosphine ligands. A wide range of E/Z-dienes underwent this Markovnikov 1,2 hydrosilylation in a stereoconvergent manner, affording (E)-allylsilanes in high isolated yields with high stereoselectivities (E/Z = >99 : 1) and high regioselectivities (b/l up to > 99 : 1). Mechanistic studies revealed that this stereoconvergence stems from a sigma-pi-sigma isomerization of an allylcobalt species generated by the 1,4-hydrometalation of Z-dienes. In addition, a cobalt catalyst that can only catalyze the hydrosilylation of the E-isomer of an (E/Z) diene was identified, which allows the separation of the (Z)-isomer from an isomeric mixture of (E/Z)-dienes. Furthermore, asymmetric hydrosilylation of (E) 1-aryl-1,3-dienes was studied with Co(acac)2/(R)-difluorphos and good enantioselectivities (er up to 90 : 10) were obtained. PMID- 29629164 TI - Design of DNA nanostructure-based interfacial probes for the electrochemical detection of nucleic acids directly in whole blood. AB - Here we report a robust and sensitive DNA nanostructure-based electrochemical (E nanoDNA) sensor that utilizes tetrahedral DNA nanostructures (TDNs) as an interfacial probe to detect biomolecules in a single-step procedure. In this study, we have firstly demonstrated that the use of TDNs can significantly suppress electrochemical background signals compared to traditional linear DNA probes upon introduction of base mismatches in the edges of TDNs. After further optimization of the two functional strands in the TDNs, quantitative, one-step detection of DNA can be achieved in the picomolar range in less than 10 min, and directly in complex media. Moreover, the baseline drift of this biosensor can be greatly decreased even after several hours in flowing whole blood in vitro, which suggests that the sensor holds potential to be employed in live animals. Furthermore, through replacing functional strands with aptamers or other DNA elements, this E-nanoDNA sensor can be easily used to probe various analytes, broadening the application range of the proposed sensor. PMID- 29629165 TI - Rh(iii)-catalyzed regioselective intermolecular N-methylene Csp3-H bond carbenoid insertion. AB - A Rh(iii)-catalyzed regioselective intermolecular carbenoid insertion into the N methylene Csp3-H bond of acyclic aliphatic amides has been achieved, taking advantage of bidentate-chelation assistance. This methodology has been successfully applied to a broad range of linear and branched-chain N-alkylamides, thus providing a practical method for the assembly of diverse beta-amino esters. Mechanism studies and density functional theory (DFT) calculations revealed that a singlet Fischer type carbene insertion via an outer-sphere pathway was involved in this N-methylene Csp3-H bond carbenoid insertion. PMID- 29629166 TI - Are multiple oxygen species selective in ethylene epoxidation on silver? AB - The nature of the oxygen species active in ethylene epoxidation is a long standing question. While the structure of the oxygen species that participates in total oxidation (nucleophilic oxygen) is known the atomic structure of the selective species (electrophilic oxygen) is still debated. Here, we use both in situ and UHV X-ray Photoelectron Spectroscopy (XPS) to study the interaction of oxygen with a silver surface. We show experimental evidence that the unreconstructed adsorbed atomic oxygen (Oads) often argued to be active in epoxidation has a binding energy (BE) <= 528 eV, showing a core-level shift to lower BE with respect to the O-reconstructions, as previously predicted by DFT. Thus, contrary to the frequent assignment, adsorbed atomic oxygen cannot account for the electrophilic oxygen species with an O 1s BE of 530-531 eV, thought to be the active species in ethylene epoxidation. Moreover, we show that Oads is present at very low O-coverages during in situ XPS measurements and that it can be obtained at slightly higher coverages in UHV at low temperature. DFT calculations support that only low coverages of Oads are stable. The highly reactive species is titrated by background gases even at low temperature in UHV conditions. Our findings suggest that at least two different species could participate in the partial oxidation of ethylene on silver. PMID- 29629167 TI - Nitric oxide activatable photosensitizer accompanying extremely elevated two photon absorption for efficient fluorescence imaging and photodynamic therapy. AB - Elevated nitric oxide (NO) levels perform an important pathological role in various inflammatory diseases. Developing NO-activatable theranostic materials with a two-photon excitation (TPE) feature is highly promising for precision imaging and therapy, but constructing such materials is still a tremendous challenge. Here, we present the first example of a NO-activatable fluorescent photosensitizer (DBB-NO) accompanying extremely NO-elevated two-photon absorption (TPA) for efficient fluorescence imaging and photodynamic therapy (PDT). Upon responding to NO, DBB-NO shows not only a remarkably enhanced fluorescence quantum yield (PhiF, 0.17% vs. 9.3%) and singlet oxygen quantum yield (PhiDelta, 1.2% vs. 82%) but also an extremely elevated TPA cross-section (delta, 270 vs. 2800 GM). Simultaneous enhancement of PhiDelta, PhiF and delta allows unprecedented two-photon fluorescence brightness (delta * PhiF = 260.4 GM) and two-photon PDT (TP-PDT) efficiency (delta * PhiDelta = 2296 GM) which precedes the value for a commercial two-photon photosensitizer by two orders of magnitude. With these merits, the proof-of-concept applications of NO-activatable two-photon fluorescence imaging and TP-PDT in activated macrophages (in which NO is overproduced) were readily realized. This work may open up many opportunities for constructing two-photon theranostic materials with other pathological condition activatable features for precise theranostics. PMID- 29629168 TI - Hydrogen peroxide-triggered gene silencing in mammalian cells through boronated antisense oligonucleotides. AB - Hydrogen peroxide (H2O2) is a reactive oxygen species (ROS) involved in various diseases, including neurodegeneration, diabetes, and cancer. Here, we introduce a new approach to use H2O2 to modulate specific gene expression in mammalian cells. H2O2-responsive nucleoside analogues, in which the Watson-Crick faces of the nucleobases are caged by arylboronate moieties, were synthesized. One of these analogues, boronated thymidine (dTB ), was incorporated into oligodeoxynucleotides (ODNs) using an automated DNA synthesizer. The hybridization ability of this boronated ODN to complementary RNA was clearly switched in the off-to-on direction upon H2O2 addition. Furthermore, we demonstrated H2O2-triggered gene silencing in mammalian cells using antisense oligonucleotides (ASOs) modified with dTB . Our approach can be used for the regulation of any gene of interest by the sequence design of boronated ASOs and will contribute to the development of targeted disease therapeutics. PMID- 29629169 TI - Solar H2 generation in water with a CuCrO2 photocathode modified with an organic dye and molecular Ni catalyst. AB - Dye-sensitised photoelectrochemical (DSPEC) cells have emerged in recent years as a route to solar fuel production. However, fuel-forming photocathodes are presently limited by photo-corrodible narrow band gap semiconductors or the small range of available wide bandgap p-type semiconductors such as NiO that display low performance with dyes. Here, we introduce CuCrO2 as a suitable p-type semiconductor for visible light-driven H2 generation upon co-immobilisation of a phosphonated diketopyrrolopyrrole dye with a Ni-bis(diphosphine) catalyst. The hybrid CuCrO2 photocathode displays an early photocurrent onset potential of +0.75 V vs. RHE and delivers a photocurrent of 15 MUA cm-2 at 0.0 V vs. RHE in pH 3 aqueous electrolyte solution under UV-filtered simulated solar irradiation. Controlled potential photoelectrolysis at 0.0 V vs. RHE shows good stability and yields a Ni catalyst-based turnover number of 126 +/- 13 towards H2 after 2 h. This precious metal-free system outperforms an analogous NiO|dye/catalyst assembly and therefore highlights the benefits of using CuCrO2 as a novel material for DSPEC applications. PMID- 29629170 TI - Stereoselective construction of sterically hindered oxaspirocycles via chiral bidentate directing group-mediated C(sp3)-O bond formation. AB - The systematic investigation of chiral bidentate auxiliaries has resulted in the discovery of a chiral 2,2-dimethyl-1-(pyridin-2-yl)propan-1-amine-derived directing group that enables stereoselective palladium(ii)-catalyzed intramolecular C(sp3)-O bond formation. This new chiral directing group exhibited high reactivity in the activation of methylene C(sp3)-H bonds with excellent levels of stereoselectivity (a diastereomeric ratio of up to 39 : 1), which allowed the construction of a wide range of oxaspirocycles. Mechanistic investigations were also conducted to elucidate the reaction mechanism and understand the origin of the diastereoselectivity. DFT calculations suggest that only modest levels of diastereoselectivity are accomplished at the rate determining C-H metalation-deprotonation step and the d.r. is further enriched at the reductive elimination step. PMID- 29629171 TI - Catalytic asymmetric total syntheses of myrtucommuacetalone, myrtucommuacetalone B, and callistrilones A, C, D and E. AB - Herein, we describe a concise catalytic approach to the first asymmetric total syntheses of myrtucommuacetalone, myrtucommuacetalone B, and callistrilones A, C, D and E. The syntheses proceed in only 5-7 steps from the readily available compound 11, without the need for protecting groups. Key features of the syntheses include a unique organocatalytic asymmetric Friedel-Crafts-type Michael addition with high enantioselectivity and a broad substrate scope, a novel Michael-ketalization-annulation cascade reaction, and an oxidative [3 + 2] cycloaddition. Furthermore, the new compound 7 exhibited potent antibacterial activities against several multidrug-resistant strains (MRSA, VISA and VRE), and showed greater potency than vancomycin. PMID- 29623188 TI - New chimeric RNAs in acute myeloid leukemia. AB - Background: High-throughput next generation sequencing (NGS) technologies enable the detection of biomarkers used for tumor classification, disease monitoring and cancer therapy. Whole-transcriptome analysis using RNA-seq is important, not only as a means of understanding the mechanisms responsible for complex diseases but also to efficiently identify novel genes/exons, splice isoforms, RNA editing, allele-specific mutations, differential gene expression and fusion-transcripts or chimeric RNA (chRNA). Methods: We used Crac, a tool that uses genomic locations and local coverage to classify biological events and directly infer splice and chimeric junctions within a single read. Crac's algorithm extracts transcriptional chimeric events irrespective of annotation with a high sensitivity, and CracTools was used to aggregate, annotate and filter the chRNA reads. The selected chRNA candidates were validated by real time PCR and sequencing. In order to check the tumor specific expression of chRNA, we analyzed a publicly available dataset using a new tag search approach. Results: We present data related to acute myeloid leukemia (AML) RNA-seq analysis. We highlight novel biological cases of chRNA, in addition to previously well characterized leukemia chRNA. We have identified and validated 17 chRNAs among 3 AML patients: 10 from an AML patient with a translocation between chromosomes 15 and 17 (AML-t(15;17), 4 from patient with normal karyotype (AML-NK) 3 from a patient with chromosomal 16 inversion (AML-inv16). The new fusion transcripts can be classified into four groups according to the exon organization. Conclusions: All groups suggest complex but distinct synthesis mechanisms involving either collinear exons of different genes, non-collinear exons, or exons of different chromosomes. Finally, we check tumor-specific expression in a larger RNA-seq AML cohort and identify new AML biomarkers that could improve diagnosis and prognosis of AML. PMID- 29623189 TI - Mitochondrial dysfunction in an animal model of diabetic neuropathy is associated with a reduction of neurosteroid synthesis. AB - Background: Recent work in a model of diabetic neuropathy revealed that layer 2/3 cortical pyramidal neurones of the pain pathway exhibited reduced endogenous neurosteroid modulation of the GABA AR and exogenously applied neurosteroids had an exaggerated impact. It is postulated that this is related to reduced precursor synthesis, due to mitochondrial dysfunction in diabetic neuropathy. Benzodiazepines are also known to activate neurosteroidogenesis by binding to mitochondrial translocator protein (TSPO). This study explored the differential effect of diazepam on GABA AR modulation via neurosteroidogenesis in diabetic and wild type (WT) mice. Methods: Whole-cell patch-clamp technique was used on slices of neural tissue. Electrophysiological recordings were obtained from layer 2/3 cortical pyramidal neurons of the pain pathway from mice with type-II diabetic neuropathy ( ob/ob) and WT controls aged 60-80 days. Results: There was a key difference in the response of the WT and ob/ob cortical neurons to simultaneous incubation with diazepam and flumazenil. In contrast, diazepam and the 5a reductase inhibitor finasteride, individually or in combination, produced the same response in both strains. Conclusions: The exaggerated effect of diazepam on GABAergic inhibitory tone in the ob/ob, despite the presence of the GABA AR benzodiazepine antagonist flumazenil is likely observed due to physiological upregulation of key neurosteroidogenic enzymes in response to the reduced pregnenolone synthesis by the mitochondria. By increasing pregnenolone via TSPO activation, it is possible to promote enhanced neurosteroidogenesis and increase GABAergic inhibitory tone via an alternate route. In diabetic neuropathy, mitochondrial dysfunction may play an important role. Enhancing the GABAergic neurosteroid tone could be of potential therapeutic benefit. PMID- 29623190 TI - Maize Phyllosphere Microbial Community Niche Development Across Stages of Host Leaf Growth. AB - Background: The phyllosphere hosts a variety of microorganisms, including bacteria, which can play a positive role in the success of the host plant. Bacterial communities in the phylloplane are influenced by both biotic and abiotic factors, including host plant surface topography and chemistry, which change in concert with microbial communities as the plant leaves develop and age. Methods: We examined how the Zea mays L. leaf microbial community structure changed with plant age. Ribosomal spacer length and scanning electron microscopic imaging strategies were used to assess microbial community composition across maize plant ages, using a novel staggered experimental design. Results: Significant changes in community composition were observed for both molecular and imaging analyses, and the two analysis methods provided complementary information about bacterial community structure within each leaf developmental stage. Conclusions: Both taxonomic and cell-size trait patterns provided evidence for niche-based contributions to microbial community development on leaves. PMID- 29623190 TI - Maize Phyllosphere Microbial Community Niche Development Across Stages of Host Leaf Growth. AB - Background: The phyllosphere hosts a variety of microorganisms, including bacteria, which can play a positive role in the success of the host plant. Bacterial communities in the phylloplane are influenced by both biotic and abiotic factors, including host plant surface topography and chemistry, which change in concert with microbial communities as the plant leaves develop and age. Methods: We examined how the Zea mays L. leaf microbial community structure changed with plant age. Ribosomal spacer length and scanning electron microscopic imaging strategies were used to assess microbial community composition across maize plant ages, using a novel staggered experimental design. Results: Significant changes in community composition were observed for both molecular and imaging analyses, and the two analysis methods provided complementary information about bacterial community structure within each leaf developmental stage. Conclusions: Both taxonomic and cell-size trait patterns provided evidence for niche-based contributions to microbial community development on leaves. PMID- 29629176 TI - Practical Stability of Au25(SR)18-1/0/+1. AB - Superatom electron shell and/or geometric shell filling underlies the thermodynamic stability of coinage and alkali metal clusters in both theoretical and experimental results. Factors beyond simple shell filling contribute substantially to the lifetime of ligated clusters in solution. Such factors include the nature of the solvent, the atmosphere and the steric size of the ligand shell. Here we systematically lay out a 'practical' stability model for ligated metal clusters, which includes both shell-closing aspects and colloidal stability aspects. Cluster decomposition may follow either fusion or fission pathways. Solvent polarity can be determinative of the decomposition pathway. PMID- 29629177 TI - Risk factors for progression of and treatment options for NAFLD in children. PMID- 29629178 TI - Diabetes risk score in the United Arab Emirates: a screening tool for the early detection of type 2 diabetes mellitus. AB - Objective: The objective of this study was to develop a simple non-invasive risk score, specific to the United Arab Emirates (UAE) citizens, to identify individuals at increased risk of having undiagnosed type 2 diabetes mellitus. Research design and methods: A retrospective analysis of the UAE National Diabetes and Lifestyle data was conducted. The data included demographic and anthropometric measurements, and fasting blood glucose. Univariate analyses were used to identify the risk factors for diabetes. The risk score was developed for UAE citizens using a stepwise forward regression model. Results: A total of 872 UAE citizens were studied. The overall prevalence of diabetes in the UAE adult citizens in the Northern Emirates was 25.1%. The significant risk factors identified for diabetes were age (>=35 years), a family history of diabetes mellitus, hypertension, body mass index >=30.0 and waist-to-hip ratio >=0.90 for males and >=0.85 for females. The performance of the model was moderate in terms of sensitivity (75.4%, 95% CI 68.3 to 81.7) and specificity (70%, 95% CI 65.8 to 73.9). The area under the receiver-operator characteristic curve was 0.82 (95% CI 0.78 to 0.86). Conclusions: A simple, non-invasive risk score model was developed to help to identify those at high risk of having diabetes among UAE citizens. This score could contribute to the efficient and less expensive earlier detection of diabetes in this high-risk population. PMID- 29629180 TI - Exposure to physical and psychosocial stressors in relation to symptoms of common mental disorders among European professional football referees: a prospective cohort study. AB - Objectives: The study aim was to explore the association of physical and psychosocial stressors (severe injuries, surgeries, recent life events, social support) with one-season onset of symptoms of common mental disorders (CMDs) among European professional football referees. Methods: An observational prospective cohort study over a follow-up period of one season (2015-2016) was conducted among professional football referees from Belgium, Finland, France, Germany, Norway, Russia, Scotland and Sweden. Based on physical and psychosocial stressors as well as symptoms of CMD, an electronic questionnaire in English and French was set up and distributed by eight football federations involved. Results: The prevalence of symptoms of CMD ranged from 5.9% for distress to 19.2% for eating disorders. A higher number of severe injuries and a lower degree of satisfaction about social support were significantly related to the occurrence of symptoms of CMD with an OR of 2.63 and an OR of 1.10, respectively. Conclusion: A higher number of severe injuries and a lower degree on satisfaction about social support were found to be significantly associated with the onset of symptoms of CMD among European professional football referees. Referees suffering from severe injuries were nearly three times more likely to report symptoms of anxiety and depression. Referees who reported a low satisfaction of social support were significantly more likely to report symptoms of eating disorder. PMID- 29629179 TI - The relationship of gross upper and lower limb motor competence to measures of health and fitness in adolescents aged 13-14 years. AB - Introduction: Motor competence (MC) is an important factor in the development of health and fitness in adolescence. Aims: This cross-sectional study aims to explore the distribution of MC across school students aged 13-14 years old and the extent of the relationship of MC to measures of health and fitness across genders. Methods: A total of 718 participants were tested from three different schools in the UK, 311 girls and 407 boys (aged 13-14 years), pairwise deletion for correlation variables reduced this to 555 (245 girls, 310 boys). Assessments consisted of body mass index, aerobic capacity, anaerobic power, and upper limb and lower limb MC. The distribution of MC and the strength of the relationships between MC and health/fitness measures were explored. Results: Girls performed lower for MC and health/fitness measures compared with boys. Both measures of MC showed a normal distribution and a significant linear relationship of MC to all health and fitness measures for boys, girls and combined genders. A stronger relationship was reported for upper limb MC and aerobic capacity when compared with lower limb MC and aerobic capacity in boys (t=-2.21, degrees of freedom=307, P=0.03, 95% CI -0.253 to -0.011). Conclusion: Normally distributed measures of upper and lower limb MC are linearly related to health and fitness measures in adolescents in a UK sample. Trial registration number: NCT02517333. PMID- 29629181 TI - Comparison of baseline and postconcussion SCAT3 scores and symptoms in varsity athletes: an investigation into differences by sex and history of concussion. AB - Objective: To investigate the use of the Sport Concussion Assessment Tool 3 (SCAT3) as an assessment tool in the varsity population, as well as the effects of sex and concussion history on both baseline and postconcussion scores. Methods: A comparison between baseline and postconcussion SCAT3 scores of varsity level athletes was conducted through retrospective chart review. Differences in both baseline and postconcussion scores were further analysed by sex and history of concussion. Results: The only clinically significant change on the SCAT3 elicited by a concussion was that of self-reported symptoms. There were no clinically significant differences based on sex or history of concussion. Conclusion: The SCAT3 in its entirety may not be useful in this population. Additional research on sociocultural and sport aspects that may be affecting symptom reporting in this population is needed. PMID- 29629182 TI - Psychosocial stress factors, including the relationship with the coach, and their influence on acute and overuse injury risk in elite female football players. AB - Background: The relationship between specific types of stressors (eg, teammates, coach) and acute versus overuse injuries is not well understood. Objective: To examine the roles of different types of stressors as well as the effect of motivational climate on the occurrence of acute and overuse injuries. Methods: Players in the Norwegian elite female football league (n=193 players from 12 teams) participated in baseline screening tests prior to the 2009 competitive football season. As part of the screening, we included the Life Event Survey for Collegiate Athletes and the Perceived Motivational Climate in Sport Questionnaire (Norwegian short version). Acute and overuse time-loss injuries and exposure to training and matches were recorded prospectively in the football season using weekly text messaging. Data were analysed with Bayesian logistic regression analyses. Results: Using Bayesian logistic regression analyses, we showed that perceived negative life event stress from teammates was associated with an increased risk of acute injuries (OR=1.23, 95% credibility interval (1.01 to 1.48)). There was a credible positive association between perceived negative life event stress from the coach and the risk of overuse injuries (OR=1.21, 95% credibility interval (1.01 to 1.45)). Conclusions: Players who report teammates as a source of stress have a greater risk of sustaining an acute injury, while players reporting the coach as a source of stress are at greater risk of sustaining an overuse injury. Motivational climate did not relate to increased injury occurrence. PMID- 29629183 TI - Differences in the occurrence and characteristics of injuries between full-time and part-time dancers. AB - Background: Professional dancers are at significant risk of injury due to the physical demands of their career. Despite their high numbers, the experience of injury in freelance or part-time dancers is not well understood. Therefore, the aim of this study was to examine the occurrence and characteristics of injury in part-time compared with full-time Australian professional dancers. Methods: Data were collected using a cross-sectional survey distributed to employees of small and large dance companies and freelance dancers in Australia. Statistical comparisons between full-time and part-time dancer demographics, dance training, injury prevalence and characteristics were made using chi2, two-tailed Fisher's exact tests, independent t-tests and Mann-Whitney U tests. Results: A total of 89 full-time and 57 part-time dancers were included for analysis. A higher proportion of full-time dancers (79.8%) than part-time dancers (63.2%) experienced an injury that impacted on their ability to dance in the past 12 months (p=0.035). Injuries characteristics were similar between groups with fatigue being the most cited contributing factor. Part-time dancers took longer to seek treatment while a higher proportion of full-time dancers were unable to dance in any capacity following their injury. Conclusion: More full-time dancers sustained an injury in the past 12 months, and were unable to dance in any capacity following their injury. However injuries still commonly occurred in part time dancers without necessarily a large volume of dance activity. Part-time dancers often access general community clinicians for treatment, who may need additional education to practically advise on appropriate return to dance. PMID- 29629184 TI - How do orthopaedic surgeons and rehabilitation professionals interpret and assess 'toe touch' weight bearing and 'partial' weight bearing status in the rehabilitation setting? AB - Aim: To compare the interpretation of toe touch weight bearing (TTWB) and partial weight bearing (PWB) among orthopaedic surgeons, rehabilitation professionals and patients. Methodology: 78 consultant and middle-grade orthopaedic surgeons in the UK completed a questionnaire. 64 rehabilitation professionals (including physiotherapists) at Defence Medical Rehabilitation Centre Headley Court were also recruited. Both groups provided their interpretation of TTWB and PWB as a percentage of total body weight (%TBW). Each rehabilitation professional, then applied what they interpreted to be TTWB and PWB using a Lasar Posture weighing device. The predicted values were compared with the actual values demonstrated. Results: There was no significant difference between orthopaedic surgeons and rehabilitation professionals in their interpretation of TTWB and PWB, however there was a wide range of responses. There was a significant difference between the predicted %TBW and the actual values demonstrated by the 'educated patient' (mean difference 4.8 (TTWB) and 22.9 (PWB)). Conclusion: Healthcare professionals vary greatly in their interpretation of the terms TTWB and PWB. Therefore, for a consistency in rehabilitation delivery the terms should not be used in isolation without a further descriptor. Static measures of weight application are lower than people think they are applying. We encourage the use of loading practice with a scale to reassure and educate patients. PMID- 29629185 TI - Evaluation of spine MRIs in athletes participating in the Rio de Janeiro 2016 Summer Olympic Games. AB - Background/aim: In high-level Olympic athletes, many spinal pathologies arise from overuse, while others are the result of acute injury. Our aim is to analyse the epidemiology of spinal pathologies detected on MRI in athletes participating in the 2016 Rio de Janeiro Summer Olympics. Methods: In this retrospective study, all spine MRIs performed during the 2016 Rio Games were analysed. Descriptive data from the MRIs were tabulated and analysed for disc degeneration, spinal canal and/or neural foraminal narrowing, and acute/chronic fractures. Data were analysed by sport, continent of origin, age and sex. Results: Of 11 274 athletes participating in the Olympic games, 100 received spine MRI. Fifty-two of the 100 (52%) athletes who received cervical, thoracic and/or lumbar spine MRI showed moderate to severe spinal disease. The highest sport-specific incidence of moderate to severe spine disease was seen in aquatic diving athletes (67%, 3 per 100 divers). Weightlifting had the second highest sport-specific incidence of spine disease (67%, 1.5 per 100 weightlifters). Athletics used the most spine MRIs (31 of 107 MRIs, 29%). European athletes had more spine MRIs than all other continents combined (55 of 107 MRIs, 51%). Athletes over 30 years old had the highest rate of moderate to severe spine disease on MRI (24 of 37 athletes >30 years old, 65%). Conclusions: A high number of the world's premier athletes demonstrated moderate to severe spine disease on MRI during the 2016 Summer Olympics, including moderate/severe degenerative disc changes with varying degrees of disc bulges and herniations. PMID- 29629186 TI - Systematic review of acute physically active learning and classroom movement breaks on children's physical activity, cognition, academic performance and classroom behaviour: understanding critical design features. AB - Objective: To examine the impact of acute classroom movement break (CMB) and physically active learning (PAL) interventions on physical activity (PA), cognition, academic performance and classroom behaviour. Design: Systematic review. Data sources: PubMed, EBSCO, Academic Search Complete, Education Resources Information Center, PsycINFO, SPORTDiscus, SCOPUS and Web of Science. Eligibility criteria for selecting studies: Studies investigating school-based acute bouts of CMB or PAL on (PA), cognition, academic performance and classroom behaviour. The Downs and Black checklist assessed risk of bias. Results: Ten PAL and eight CMB studies were identified from 2929 potentially relevant articles. Risk of bias scores ranged from 33% to 64.3%. Variation in study designs drove specific, but differing, outcomes. Three studies assessed PA using objective measures. Interventions replaced sedentary time with either light PA or moderate to-vigorous PA dependent on design characteristics (mode, duration and intensity). Only one study factored individual PA outcomes into analyses. Classroom behaviour improved after longer moderate-to-vigorous (>10 min), or shorter more intense (5 min), CMB/PAL bouts (9 out of 11 interventions). There was no support for enhanced cognition or academic performance due to limited repeated studies. Conclusion: Low-to-medium quality designs predominate in investigations of the acute impacts of CMB and PAL on PA, cognition, academic performance and classroom behaviour. Variable quality in experimental designs, outcome measures and intervention characteristics impact outcomes making conclusions problematic. CMB and PAL increased PA and enhanced time on task. To improve confidence in study outcomes, future investigations should combine examples of good practice observed in current studies. PROSPERO registration number: CRD42017070981. PMID- 29629187 TI - Full-text publication of abstract-presented work in sport and exercise psychology. AB - Objectives: Meetings promote information sharing, but do not enable full dissemination of details. A systematic search was conducted for abstracts presented at the 2010 and 2011 Association of Applied Sport Psychology Annual Conferences to determine the full-text dissemination rate of work presented in abstract form and investigate factors influencing this rate. Methods: Systematic searches were sequentially conducted to determine whether the abstract-presented work had been published in full-text format in the 5 years following presentation. If a potential full-text publication was identified, information from the conference abstract (eg, results, number of participants in the sample(s), measurement tools used and so on) was compared with the full text to ensure the two entities represented the same body of work. Abstract factors of interest were assessed using logistic regression. Results: Ninety-four out of 423 presented abstracts (22.2%) were published in full text. Odds of full-text publication increased if the abstract was from an international institution, presented in certain conference sections or presented as a lecture. Conclusion: Those attending professional conferences should be cautious when translating data presented at conferences into their applied work because of the low rate of peer reviewed and full-text publication of the information. PMID- 29629188 TI - Lessons from a broad view of science: a response to Dr Robergs' article. AB - Dr Robergs suggested that the central governor model (CGM) is not a well-worded theory, as it deviated from the tenant of falsification criteria. According to his view of science, exercise researches with the intent to prove rather than disprove the theory contribute little to new knowledge and condemn the theory to the label of pseudoscience. However, exercise scientists should be aware of limitations of the falsification criteria. First, the number of potential falsifiers for a given hypothesis is always infinite so that there is no mean to ensure asymmetric comparison between theories. Thus, assuming a competition between CGM and dichotomised central versus peripheral fatigue theories, scientists guided by the falsification principle should know, a priori, all possible falsifiers between these two theories in order to choose the finest one, thereby leading to an oversimplification of the theories. Second, the failure to formulate refutable hypothesis may be a simple consequence of the lack of instruments to make crucial measurements. The use of refutation principles to test the CGM theory requires capable technology for online feedback and feedforward measures integrated in the central nervous system, in a real-time exercise. Consequently, falsification principle is currently impracticable to test CGM theory. The falsification principle must be applied with equilibrium, as we should do with positive induction process, otherwise Popperian philosophy will be incompatible with the actual practice in science. Rather than driving the scientific debate on a biased single view of science, researchers in the field of exercise sciences may benefit more from different views of science. PMID- 29629189 TI - Trust, fear, stigma and disruptions: community perceptions and experiences during periods of low but ongoing transmission of Ebola virus disease in Sierra Leone, 2015. AB - Social mobilisation and risk communication were essential to the 2014-2015 West African Ebola response. By March 2015, >8500 Ebola cases and 3370 Ebola deaths were confirmed in Sierra Leone. Response efforts were focused on 'getting to zero and staying at zero'. A critical component of this plan was to deepen and sustain community engagement. Several national quantitative studies conducted during this time revealed Ebola knowledge, personal prevention practices and traditional burial procedures improved as the outbreak waned, but healthcare system challenges were also noted. Few qualitative studies have examined these combined factors, along with survivor stigma during periods of ongoing transmission. To obtain an in-depth understanding of people's perceptions, attitudes and behaviours associated with Ebola transmission risks, 27 focus groups were conducted between April and May 2015 with adult Sierra Leonean community members on: trust in the healthcare system, interactions with Ebola survivors, impact of Ebola on lives and livelihood, and barriers and facilitators to ending the outbreak. Participants perceived that as healthcare practices and facilities improved, so did community trust. Resource management remained a noted concern. Perceptions of survivors ranged from sympathy and empathy to fear and stigmatisation. Barriers included persistent denial of ongoing Ebola transmission, secret burials and movement across porous borders. Facilitators included personal protective actions, consistent messaging and the inclusion of women and survivors in the response. Understanding community experiences during the devastating Ebola epidemic provides practical lessons for engaging similar communities in risk communication and social mobilisation during future outbreaks and public health emergencies. PMID- 29629192 TI - The ERAS project for VATS lobectomy-the Italian VATS Group. PMID- 29629191 TI - Chronic kidney disease care models in low- and middle-income countries: a systematic review. AB - Introduction: The number of persons with chronic kidney disease (CKD) living in low- and middle-income countries (LMIC) is increasing rapidly; yet systems built to care for them have received little attention. In order to inform the development of scalable CKD care models, we conducted a systematic review to characterise existing CKD care models in LMICs. Methods: We searched PubMed, Embase and WHO Global Health Library databases for published reports of CKD care models from LMICs between January 2000 and 31 October 2017. We used a combination of database-specific medical subject headings and keywords for care models, CKD and LMICs as defined by the World Bank. Results: Of 3367 retrieved articles, we reviewed the full text of 104 and identified 17 articles describing 16 programmes from 10 countries for inclusion. National efforts (n=4) focused on the prevention of end-stage renal disease through enhanced screening, public awareness campaigns and education for primary care providers. Of the 12 clinical care models, nine focused on persons with CKD and the remaining on persons at risk for CKD; a majority in the first category implemented a multidisciplinary clinic with allied health professionals or primary care providers (rather than nephrologists) in lead roles. Four clinical care models used a randomised control design allowing for assessment of programme effectiveness, but only one was assessed as having low risk for bias; all four showed significant attenuation of kidney function decline in the intervention arms. Conclusions: Overall, very few rigorous CKD care models have been reported from LMICs. While preliminary data indicate that national efforts or clinical CKD care models bolstering primary care are successful in slowing kidney function decline, limited data on regional causes of CKD to inform national campaigns, and on effectiveness and affordability of local programmes represent important challenges to scalability. PMID- 29629193 TI - Preface to enhanced recovery after surgery. PMID- 29629190 TI - Antibiotics and activity spaces: protocol of an exploratory study of behaviour, marginalisation and knowledge diffusion. AB - Background: Antimicrobial resistance (AMR) is a global health priority. Leading UK and global strategy papers to fight AMR recognise its social and behavioural dimensions, but current policy responses to improve the popular use of antimicrobials (eg, antibiotics) are limited to education and awareness-raising campaigns. In response to conceptual, methodological and empirical weaknesses of this approach, we study people's antibiotic-related health behaviour through three research questions.RQ1: What are the manifestations and determinants of problematic antibiotic use in patients' healthcare-seeking pathways?RQ2: Will people's exposure to antibiotic awareness activities entail changed behaviours that diffuse or dissipate within a network of competing healthcare practices?RQ3: Which proxy indicators facilitate the detection of problematic antibiotic behaviours across and within communities? Methods: We apply an interdisciplinary analytical framework that draws on the public health, medical anthropology, sociology and development economics literature. Our research involves social surveys of treatment-seeking behaviour among rural dwellers in northern Thailand (Chiang Rai) and southern Lao PDR (Salavan). We sample approximately 4800 adults to produce district-level representative and social network data. Additional 60 cognitive interviews facilitate survey instrument development and data interpretation. Our survey data analysis techniques include event sequence analysis (RQ1), multilevel regression (RQ1-3), social network analysis (RQ2) and latent class analysis (RQ3). Discussion: Social research in AMR is nascent, but our unprecedentedly detailed data on microlevel treatment-seeking behaviour can contribute an understanding of behaviour beyond awareness and free choice, highlighting, for example, decision-making constraints, problems of marginalisation and lacking access to healthcare and competing ideas about desirable behaviour. Trial registration number: NCT03241316; Pre-results. PMID- 29629194 TI - Enhanced recovery after surgery protocols in video-assisted thoracic surgery lobectomies: the best is yet still to come? PMID- 29629195 TI - Enhanced recovery pathways version 2.0 in thoracic surgery. PMID- 29629196 TI - A comprehensive protocol for physiokinesis therapy and enhanced recovery after surgery in patients undergoing video-assisted thoracoscopic surgery lobectomy. AB - Background: Video-assisted thoracoscopic surgery (VATS) lobectomy has recently been adopted as the gold standard surgical option for the treatment of early stage non-small cell lung cancer. Enhanced recovery after surgery (ERAS) is being progressively adopted in thoracic surgery to improve the postoperative outcomes. Even if the benefits of ERAS are universally accepted, to date a standardized and uniform approach has not been described in the medical literature. The Italian VATS group has recently proposed to include in the VATS lobectomy database a structured protocol for ERAS. Methods: The ERAS section of the Italian VATS group is proposing a comprehensive ERAS protocol within the VATS lobectomy database, allowing the prospective collection of a dedicated set of data. Separate sections of the protocol are dedicated to different topics of ERAS. This study is specifically dedicated to the section of physiokinesis therapy. The medical literature will be extensively reviewed and a physiotherapy (PT) protocol of ERAS will be presented and discussed. A seta of structured clinical pathways will also be suggested for adoption in the VATS Group database. Discussion: Pre- and post operative adoption of an ERAS protocol in patients undergoing VATS lobectomy may promote an improved post-operative course, a shorter hospital stay and an overall more comfortable patients' experience. The mainstays of a physiokinesis therapy ERAS protocol are patients' education, constant physical and respiratory therapy sessions, and adoption of adequate devices. Although many studies have investigated the usefulness of physical and respiratory physiokinesis therapy, a comprehensive ERAS protocol for VATS lobectomy patients has not yet been described. The proposed ERAS platform, adopted by the VATS Group database, will contribute to a prospective data collection and allow a scientific analysis of the results. PMID- 29629197 TI - Enhanced recovery after thoracic surgery: patient information and care-plans. AB - Many studies have confirmed that the implementation of enhanced recovery after surgery (ERAS) protocols has the advantages of reducing the potential complications after thoracic surgery and the length of hospital stay. The ERAS program involves a multidisciplinary team, aimed at integrating evidence-based knowledge into clinical practice in order to reduce the patient's stress response to the surgical procedure and improve the response to stress, guaranteeing a combination of better outcomes and cost savings. All this would not be possible without the improvement of minimally invasive surgical techniques, progression of anesthesia, pain control, and careful patient preparation. In this setting, a preoperative personal counselling may play a key role to reduce stress, fear or anxiety and improve the morbidity of patients, enabling them to achieve functional and psychological compensatory mechanisms more quickly. Preoperative patient counselling, performed using verbal, written or multimedia materials, is crucial in order to achieve the goal of the ERAS project: making the patient a potentially active participant and the main character of his recovery, able to positively impact himself throughout the surgical and healing process. This report is aimed at evaluating patient information and care-plans in thoracic surgery, reviewing the available evidence on ERAS pathways, and demonstrating our ideal program as discussed and shared among the Italian Thoracic Surgery Units accredited in the video-assisted thoracic surgery (VATS) group. PMID- 29629198 TI - Patient Health Engagement (PHE) model in enhanced recovery after surgery (ERAS): monitoring patients' engagement and psychological resilience in minimally invasive thoracic surgery. AB - In the last decade, the humanization of medicine has contributed to an important shift in medical paradigms (from a doctor-centered to a patient-centered approach to care). This paradigm shift promoted a greater acknowledgement of patient engagement as a crucial asset for healthcare due to its benefits on both clinical outcomes and healthcare sustainability. Particularly, patient engagement should be considered a vital parameter for the healthcare system as well as it is a marker of the patients' ability to be resilient to the illness experience and thus to be an effective manager of his/her own health after the diagnosis. For this reason, measuring and promoting patient engagement both in chronic and acute care is today a priority for healthcare systems all over the world. In this contribution, the authors propose the Patient Health Engagement (PHE) model and the PHE scale as scientific and reliable tools to orient clinical actions and organizational strategies based on the patient engagement score. Particularly, this work discusses the implication of the adoption of these scientific tools in the enhanced recovery after surgery (ERAS) experience and their potentialities for healthcare professionals working in thoracic surgery settings. PMID- 29629199 TI - Enhanced recovery pathways in thoracic surgery from Italian VATS group: nursing care program. AB - Enhanced recovery after surgery (ERAS) is an interprofessional program that can lead to hastened patient recovery and reduced time in hospital. Nursing staff play a key role in the implementation of enhanced recovery protocols. This issue focalizes the role of nurses in ERAS program for patients submitted to Thoracic Surgery, in particular for cases of major lung resection performed by a minimally invasive surgical approach (VATS, video assisted thoracic surgery). PMID- 29629200 TI - Enhanced recovery pathways in thoracic surgery from Italian VATS Group: preoperative optimisation. AB - Preoperative patient optimisation is a key point of enhanced recovery after thoracic surgery pathways. This could be particularly advantageous when considering video-assisted thoracic surgery (VATS) lobectomy, because reduced trauma related to minimally invasive techniques is one of the main factors favouring improved postoperative outcome. Main specific interventions for clinical optimisation before major lung resection include assessment and treatment of comorbidities, minimizing preoperative hospitalization, optimisation of pharmacological prophylaxis (antibiotic and thromboembolic) and minimizing preoperative fasting. Literature data and clinical evidences in this setting are reported and discussed. PMID- 29629201 TI - Anesthesia and fast-track in video-assisted thoracic surgery (VATS): from evidence to practice. AB - In thoracic surgery, the introduction of video-assisted thoracoscopic techniques has allowed the development of fast-track protocols, with shorter hospital lengths of stay and improved outcomes. The perioperative management needs to be optimized accordingly, with the goal of reducing postoperative complications and speeding recovery times. Premedication performed in the operative room should be wisely administered because often linked to late discharge from the post anesthesia care unit (PACU). Inhalatory anesthesia, when possible, should be preferred based on protective effects on postoperative lung inflammation. Deep neuromuscular blockade should be pursued and carefully monitored, and an appropriate reversal administered before extubation. Management of one-lung ventilation (OLV) needs to be optimized to prevent not only intraoperative hypoxemia but also postoperative acute lung injury (ALI): protective ventilation strategies are therefore to be implemented. Locoregional techniques should be favored over intravenous analgesia: the thoracic epidural, the paravertebral block (PVB), the intercostal nerve block (ICNB), and the serratus anterior plane block (SAPB) are thoroughly reviewed and the most common dosages are reported. Fluid therapy needs to be administered critically, to avoid both overload and cardiovascular compromisation. All these practices are analyzed singularly with the aid of the most recent evidences aimed at the best patient care. Finally, a few notes on some of the latest trends in research are presented, such as non intubated video-assisted thoracoscopic surgery (VATS) and intravenous lidocaine. PMID- 29629202 TI - Enhanced recovery pathways in thoracic surgery from Italian VATS Group: perioperative analgesia protocols. AB - Video-assisted thoracoscopic surgery (VATS) is a minimally invasive technique that allows a faster recovery after thoracic surgery. Although enhanced recovery after surgery (ERAS) principles seem reasonably applicable to thoracic surgery, there is little literature on the application of such a strategy in this context. In regard to pain management, ERAS pathways promote the adoption of a multimodal strategy, tailored to the patients. This approach is based on combining systemic and loco-regional analgesia to favour opioid-sparing strategies. Thoracic paravertebral block is considered the first-line loco-regional technique for VATS. Other techniques include intercostal nerve block and serratus anterior plane block. Nonsteroidal anti-inflammatory drugs and paracetamol are essential part of the multimodal treatment of pain. Also, adjuvant drugs can be useful as opioid-sparing agents. Nevertheless, the treatment of postoperative pain must take into account opioid agents too, if necessary. All above is useful for careful planning and execution of a multimodal analgesic treatment to enhance the recovery of patients. This article summarizes the most recent evidences from literature and authors' experiences on perioperative multimodal analgesia principles for implementing an ERAS program after VATS lobectomy. PMID- 29629203 TI - Enhanced recovery after surgery and video-assisted thoracic surgery lobectomy: the Italian VATS Group surgical protocol. AB - Enhanced recovery after surgery (ERAS(r)) is a strategy that seeks to reduce patients' perioperative stress response, thereby reducing potential complications, decreasing hospital length of stay and enabling patients to return more quickly to their baseline functional status. The concept was introduced in the late 1990s and was first adopted in patients undergoing open colorectal surgery. Since then, the concept of ERAS has been adopted by multiple surgical specialties. The diffusion of video-assisted thoracic surgery lobectomy (VATS-L) sets also the surgical treatment of lung cancer as a new area for ERAS development. In this paper, we present the Italian VATS Group (www.vatsgroup.org) surgical protocol as part of the ERAS clinical pathway belonging to the VATS-L national database. PMID- 29629204 TI - VATS Group ERAS Registry. AB - Enhanced recovery after surgery (ERAS) is a multimodal, polyhedral approach to surgical management for patients undergoing surgical therapy. Since ERAS is not a specific procedure, these protocols are not exclusively created for particular clinical settings but they are prone to be adapted to a large variety of healthcare programs after surgery. ERAS Society was the platform in which a new multidisciplinary methodology to promote a fast recovery, a considerable patient involvement and resource optimization has been developed. ERAS Society has also produced guidelines for different surgical specialties and has already generated some evidence regarding preoperative, intraoperative and postoperative practice. ERAS in Thoracic Surgery has had a slow-growing development but some hints suggest that introducing ERAS methodology in pulmonary resections for cancer could be feasible and effective with potential tangible benefits for patients, families, caregivers and welfare. There is no evidence yet concerning ERAS principles in Thoracic Surgery; for this reason, a new possibility for prospective data collection and analysis is created using the VATS Group Web Registry in which additional records, documents and facts have now the possibility to be registered and eventually explored to possibly adjust the ERAS protocols to major pulmonary resections. PMID- 29629205 TI - Enhanced recovery pathways in thoracic surgery: the Shanghai experience. AB - The attempts to implement the enhanced recovery (ER) program based on multiple specialties to minimize errors and complications in addition to speeding up the patient's treatment and recovery as much as possible. In China mainland, there is no unified hospital system and there are large differences between hospitals' results and protocols. The patient length of stay rate at the Shanghai Pulmonary Hospital (very high-volume referral hospital) is 7 days and may be considered a very good result compared to international rates. Perhaps thanks to these results may be due to our belief in the importance of minimally invasive approaches, and their positive effects on the patients and conduct as routinely as possible, in addition to starting to build our ER protocols. The patient should be involved in this program since his first visit to the clinic until the day he left the hospital after undergoing the operation. PMID- 29629206 TI - Enhanced recovery pathways in thoracic surgery: the Quebec experience. AB - Background: Canada has a universal public health system where all resources must be allocated to optimize cost-effectiveness. Rapid diagnostic assessment programs (DAPs) and enhanced recovery protocols (ERPs) may improve timeliness of care and postoperative outcomes and thus reduce costs. The use of DAPs and ERPs in lung cancer patients who undergo lobectomy via video-assisted thoracoscopic surgery (VATS) is still controversial. This study measured the time between preoperative workup and treatment with a DAP and evaluated the impact of an ERP postoperatively in patients with early-stage non-small cell lung cancer (NSCLC) who received a VATS lobectomy. Methods: We conducted a retrospective review of patients who underwent minimally invasive lobectomy for the primary treatment of lung cancer from January 2014 through May 2017 at our institution. Timelines of care were measured. Postoperatively, the duration of chest tube drainage, length of hospital stay, and incidence of complications were noted. Results: During the study period, 646 patients underwent VATS lobectomy for stage I or II NSCLC; of these, 384 (59%) were assessed within the DAP. Using the DAP, the median time between the patient's first clinic visit and referral to surgery was 30.0 days [interquartile range (IQR), 21.0-40.0 days), and the median time between surgical consult and treatment was 29.0 days (IQR, 15.0-47.5 days). With the ERP, the median duration of chest drainage was 3.0 days (IQR, 2.0-6.0 days), and median hospital stay was 4.0 days (IQR, 3.0-7.0 days). Conclusions: DAPs and ERPs have promising roles in thoracic surgical practice. A rapid DAP can expedite the care trajectory of patients with lung cancer and has allowed our institution to adhere to governmental standards for the management of lung cancer. ERPs are feasible to establish and can effectively improve clinical outcomes. PMID- 29629207 TI - A Comparison of Mangrove Canopy Height Using Multiple Independent Measurements from Land, Air, and Space. AB - Canopy height is one of the strongest predictors of biomass and carbon in forested ecosystems. Additionally, mangrove ecosystems represent one of the most concentrated carbon reservoirs that are rapidly degrading as a result of deforestation, development, and hydrologic manipulation. Therefore, the accuracy of Canopy Height Models (CHM) over mangrove forest can provide crucial information for monitoring and verification protocols. We compared four CHMs derived from independent remotely sensed imagery and identified potential errors and bias between measurement types. CHMs were derived from three spaceborne datasets; Very-High Resolution (VHR) stereophotogrammetry, TerraSAR-X add-on for Digital Elevation Measurement, and Shuttle Radar Topography Mission (TanDEM-X), and lidar data which was acquired from an airborne platform. Each dataset exhibited different error characteristics that were related to spatial resolution, sensitivities of the sensors, and reference frames. Canopies over 10 m were accurately predicted by all CHMs while the distributions of canopy height were best predicted by the VHR CHM. Depending on the guidelines and strategies needed for monitoring and verification activities, coarse resolution CHMs could be used to track canopy height at regional and global scales with finer resolution imagery used to validate and monitor critical areas undergoing rapid changes. PMID- 29629208 TI - A Highly Sensitive and Selective Colorimetric Hg2+ Ion Probe Using Gold Nanoparticles Functionalized with Polyethyleneimine. AB - A highly sensitive and selective colorimetric assay for the detection of Hg2+ ions was developed using gold nanoparticles (AuNPs) conjugated with polyethyleneimine (PEI). The Hg2+ ion coordinates with PEI, decreasing the interparticle distance and inducing aggregation. Time-of-flight secondary ion mass spectrometry showed that the Hg2+ ion was bound to the nitrogen atoms of the PEI in a bidentate manner (N-Hg2+-N), which resulted in a significant color change from light red to violet due to aggregation. Using this PEI-AuNP probe, determination of Hg2+ ion can be achieved by the naked eye and spectrophotometric methods. Pronounced color change of the PEI-AuNPs in the presence of Hg2+ was optimized at pH 7.0, 50 degrees C, and 300 mM.NaCl concentration. The absorption intensity ratio (A700/A514) was correlated with the Hg2+ concentration in the linear range of 0.003-5.0 MUM. The limits of detection were measured to be 1.72, 1.80, 2.00, and 1.95 nM for tap water, pond water, tuna fish, and bovine serum, respectively. Owing to its facile and sensitive nature, this assay method for Hg2+ ions can be applied to the analysis of water and biological samples. PMID- 29629209 TI - Rapid and Simultaneous Prediction of Eight Diesel Quality Parameters through ATR FTIR Analysis. AB - Quality assessment of diesel fuel is highly necessary for society, but the costs and time spent are very high while using standard methods. Therefore, this study aimed to develop an analytical method capable of simultaneously determining eight diesel quality parameters (density; flash point; total sulfur content; distillation temperatures at 10% (T10), 50% (T50), and 85% (T85) recovery; cetane index; and biodiesel content) through attenuated total reflection Fourier transform infrared (ATR-FTIR) spectroscopy and the multivariate regression method, partial least square (PLS). For this purpose, the quality parameters of 409 samples were determined using standard methods, and their spectra were acquired in ranges of 4000-650 cm-1. The use of the multivariate filters, generalized least squares weighting (GLSW) and orthogonal signal correction (OSC), was evaluated to improve the signal-to-noise ratio of the models. Likewise, four variable selection approaches were tested: manual exclusion, forward interval PLS (FiPLS), backward interval PLS (BiPLS), and genetic algorithm (GA). The multivariate filters and variables selection algorithms generated more fitted and accurate PLS models. According to the validation, the FTIR/PLS models presented accuracy comparable to the reference methods and, therefore, the proposed method can be applied in the diesel routine monitoring to significantly reduce costs and analysis time. PMID- 29629210 TI - Feasibility of Using an Electrolysis Cell for Quantification of the Electrolytic Products of Water from Gravimetric Measurement. AB - A gravimetric method for the quantitative assessment of the products of electrolysis of water is presented. In this approach, the electrolysis cell was directly powered by 9 V batteries. Prior to electrolysis, a known amount of potassium hydrogen phthalate (KHP) was added to the cathode compartment, and an excess amount of KHCO3 was added to the anode compartment electrolyte. During electrolysis, cathode and anode compartments produced OH-(aq) and H+(aq) ions, respectively. Electrolytically produced OH-(aq) neutralized the KHP, and the completion of this neutralization was detected by a visual indicator color change. Electrolytically produced H+(aq) reacted with HCO3-(aq) liberating CO2(g) from the anode compartment. Concurrent liberation of H2(g) and O2(g) at the cathode and anode, respectively, resulted in a decrease in the mass of the cell. Mass of the electrolysis cell was monitored. Liberation of CO2(g) resulted in a pronounced effect of a decrease in mass. Experimentally determined decrease in mass (53.7 g/Faraday) agreed with that predicted from Faraday's laws of electrolysis (53.0 g/Faraday). The efficacy of the cell was tested to quantify the acid content in household vinegar samples. Accurate results were obtained for vinegar analysis with a precision better than 5% in most cases. The cell offers the advantages of coulometric method and additionally simplifies the circuitry by eliminating the use of a constant current power source or a coulometer. PMID- 29629211 TI - Rapid Screening and Preparative Isolation of Antioxidants from Alpinia officinarum Hance Using HSCCC Coupled with DPPH-HPLC Assay and Evaluation of Their Antioxidant Activities. AB - An efficient method using high-speed counter-current chromatography (HSCCC) coupled with DPPH-HPLC assay has been developed for rapid screening and preparative isolation of antioxidants from ethyl acetate fraction of Alpinia officinarum Hance. Target-guided by DPPH-HPLC assay, two antioxidants, galangin and kaempferide, were targeted and further separated with purities of 99.3% and 98.5% by HSCCC using petroleum ether-ethyl acetate-methanol-water (0.8 : 1 : 1 : 0.8, v/v) as the solvent system. The antioxidant activities of galangin and kaempferide were further evaluated by measuring their inhibiting effects on superoxide anion radical, hydroxyl radical, and hydrogen peroxide in different luminol chemiluminescence (CL) systems. As a result, galangin and kaempferide both showed potent antioxidant activities. Results of the present study indicated that the combinative method by offline coupling DPPH-HPLC and HSCCC could be widely applied for rapid screening and isolation of antioxidants from complex TCM extract. PMID- 29629212 TI - A PCR Method That Can Be Further Developed into PCR-RFLP Assay for Eight Animal Species Identification. AB - There are many PCR-based methods for animal species identification; however, their detection numbers are limited or could not identify unknown species. We set out to solve this problem by developing a universal primer PCR assay for simultaneous identification of eight animal species, including goat, sheep, deer, buffalo, cattle, yak, pig, and camel. In this assay, the variable lengths of mitochondrial DNA were amplified using a pair of universal primers. PCR amplifications yielded 760 bp, 737 bp, 537 bp, 486 bp, 481 bp, 464 bp, 429 bp, and 359 bp length fragments for goat, sheep, deer, buffalo, cattle, yak, pig, and camel, respectively. This primer pair had no cross-reaction with other common domestic animals and fish. The limit of detection varied from 0.01 to 0.05 ng of genomic DNA for eight animal species in a 20 ul PCR mixture. Each PCR product could be further digested into fragments with variable sizes and qualitative analysis by SspI restriction enzyme. This developed PCR-RFLP assay was sufficient to distinguish all targeted species. Compared with the previous published related methods, this approach is simple, with high throughput, fast processing rates, and more cost-effective for routine identification of meat in foodstuffs. PMID- 29629213 TI - Different Spectrophotometric Methods for Simultaneous Determination of Trelagliptin and Its Acid Degradation Product. AB - New spectrophotometric and chemometric methods were carried out for the simultaneous assay of trelagliptin (TRG) and its acid degradation product (TAD) and applied successfully as a stability indicating assay to recently approved Zafatek(r) tablets. TAD was monitored using TLC to ensure complete degradation. Furthermore, HPLC was used to confirm dealing with one major acid degradation product. The proposed methods were developed by manipulating zero-order, first derivative, and ratio spectra of TRG and TAD using simultaneous equation, first derivative, and mean-centering methods, respectively. Using Spectra Manager II and Minitab v.14 software, the absorbance at 274 nm-260.4 nm, amplitudes at 260.4 nm-274.0 nm, and mean-centered values at 287.6 nm-257.2 nm were measured against methanol as a blank for TRG and TAD, respectively. Linearity and the other validation parameters were acceptable at concentration ranges of 5-50 MUg/mL and 2.5-25 MUg/mL for TRG and TAD, respectively. Using one-way analysis of variance (ANOVA), the optimized methods were compared and proved to be accurate for the simultaneous assay of TRG and TAD. PMID- 29629214 TI - Development and Validation of Gas Chromatography-Triple Quadrupole Mass Spectrometric Method for Quantitative Determination of Regulated Plasticizers in Medical Infusion Sets. AB - A method for the quantitative determination of dibutyl phthalate (DBP), benzyl butyl phthalate (BBP), bis(2-ethylhexyl) adipate (DEHA), bis(2-ethylhexyl) phthalate (DEHP), di-n-octyl phthalate (DNOP), dioctyl terephthalate (DOTP), diisononyl phthalate (DINP), and diisodecyl phthalate (DIDP) in medical infusion sets was developed and validated using gas chromatography coupled with triple quadrupole mass spectrometry (GC-MS/MS) in the multiple reaction monitoring (MRM) mode. Solvent extraction with polymer dissolution for sample preparation was employed prior to GC-MS/MS analysis. Average recoveries of the eight target analytes are typically in the range of 91.8-122% with the relative standard deviations of 1.8-17.8%. The limits of quantification (LOQs) of the analytical method were in the ranges of 54.1 to 76.3 ng/g. Analysis using GC-MS/MS provided reliable performance, as well as higher sensitivity and selectivity than GC-MS analysis, especially for the presence of minority plasticizers at different concentrations. PMID- 29629215 TI - Characterization of Urban Particulate Matter by Diffusive Gradients in Thin Film Technique. AB - A diffusive gradient in thin films (DGT) technique was employed in characterization of the particulate matter related to the urban area suffering from heavy traffic. Kinetics of mobilization metals fluxes from the metal contaminated particulate matter was investigated. To monitor responses of the particulate matter sample, DGT probes of various thickness of diffusion layer were deployed in aqueous model suspensions of the particulate matter for different time periods. Particulate matter samples and exposed DGT resin gels were decomposed in a mixture of nitric and hydrochloric acid in a microwave pressurized PTFE-lined system. Total content of some traffic-related elements (Cd, Co, Cu, Mo, Ni, Pb, Pd, Pt, Rh, Sb, and V) was determined by inductively coupled plasma mass spectrometry. DGT measurements revealed that two metals pools associated with particles could be recognized, which can be characterized as high soluble fraction and almost insoluble fraction. DGT-measured metal fluxes from the labile pool showed significant difference in mobilization and resupply fluxes of individual selected elements, which might reflect the origin of selected metals and their speciation in particulate matter. The DGT technique can be applied as a useful tool for characterization of metals mobilization from the particulate matter. PMID- 29629217 TI - Is Lymph Node Size a Reliable Factor for Estimating Lymph Node Metastasis in Early Gastric Cancer? AB - Purpose: Pre-operative lymph node (LN) size is a valuable parameter for determining treatment strategy for gastric cancer. However, a correlation between LN size and metastasis has not been established. Materials and Methods: Thirty six LN-positive (LNP) and matched 36 LN-negative (LNN) patients were included, and pathology slides of the LNs of these patients were reviewed. All the LNs were measured along the long-axis (LA) and short-axis (SA), manually. Results: Average retrieved LNs were 37.3+/-19.8 and 40.5+/-11.6 in the LNN and LNP groups, respectively. In total 2,800 LNs, including 136 metastatic LNs (MLNs) and 2,664 non-metastatic LNs (nMLNs), were evaluated. Mean length was significantly more in MLNs along both, the LA and SA (MLN_LA vs. nMLN_LA: 4.97+/-3.84 vs. 3.37+/-2.40 mm, MLN_SA vs. nMLN_SA: 3.86+/-3.19 vs. 2.43+/-1.59 mm; P<0.001). However, 92.6% (126/136) and 95.6% (130/136) of MLNs were <10 mm along the LA and SA, respectively. In addition, only 22.2% of the LNP group exhibited an MLN as the largest LN. Conclusions: Pre-operative multi-detector computed tomography has limited ability in estimating the presence of metastasis in LNs because most MLNs are less than 10 mm, and only a small proportion of the LNP group exhibits an MLN as the largest MLN. PMID- 29629216 TI - Novel Systemic Therapies for Advanced Gastric Cancer. AB - Gastric cancer (GC) is the second leading cause of cancer mortality and the fourth most commonly diagnosed malignant diseases. While continued efforts have been focused on GC treatment, the introduction of trastuzumab marked the beginning of a new era of target-specific treatments. Considering the diversity of mutations in GC, satisfactory results obtained from various target-specific therapies were expected, yet most of them were unsuccessful in controlled clinical trials. There are several possible reasons underlying the failures, including the absence of patient selection depending on validated predictive biomarkers, the inappropriate combination of drugs, and tumor heterogeneity. In contrast to targeted agents, immuno-oncologic agents are designed to regulate and boost immunity, are not target-specific, and may overcome tumor heterogeneity. With the successful establishment of predictive biomarkers, including Epstein Barr virus pattern, microsatellite instability status, and programmed death ligand 1 (PD-L1) expression, as well as ideal combination regimens, a new frontier in the immuno-oncology of GC treatment is on the horizon. Since the field of immuno-oncology has witnessed innovative, practice-changing successes in other cancer types, several trials on GC are ongoing. Among immuno-oncologic therapies, immune checkpoint inhibitors are the mainstay of clinical trials performed on GC. In this article, we review target-specific agents currently used in clinics or are undergoing clinical trials, and highlight the future clinical application of immuno-oncologic agents in inoperable GC. PMID- 29629218 TI - Safety of Laparoscopic Sentinel Basin Dissection in Patients with Gastric Cancer: an Analysis from the SENORITA Prospective Multicenter Quality Control Trial. AB - Purpose: We investigated complications after laparoscopic sentinel basin dissection (SBD) for patients with gastric cancer who were enrolled in a quality control study, prior to the phase III trial of sentinel lymph node navigation surgery (SNNS). Materials and Methods: We analyzed prospective data from a Korean multicenter prerequisite quality control trial of laparoscopic SBD for gastric cancer and assessed procedure-related and surgical complications. All complications were classified according to the Clavien-Dindo Classification (CDC) system and were compared with the results of the previously published SNNS trial. Results: Among the 108 eligible patients who were enrolled in the quality control trial, 8 (7.4%) experienced complications during the early postoperative period. One patient with gastric resection-related duodenal stump leakage recovered after percutaneous drainage (grade IIIa in CDC). The other postoperative complications were mild and patients recovered with supportive care. No complications were directly related to the laparoscopic SBD procedure or tracer usage, and there were no mortalities. The laparoscopic SBD complication rates and patterns that were observed in this study were comparable to those of a previously reported trial. Conclusions: The results of our prospective, multicenter quality control trial demonstrate that laparoscopic SBD is a safe procedure during SNNS for gastric cancer. PMID- 29629219 TI - Novel Endoscopic Stent for Anastomotic Leaks after Total Gastrectomy Using an Anchoring Thread and Fully Covering Thick Membrane: Prevention of Embedding and Migration. AB - Purpose: The endoscopic management of a fully covered self-expandable metal stent (SEMS) has been suggested for the primary treatment of patients with anastomotic leaks after total gastrectomy. Embedded stents due to tissue ingrowth and migration are the main obstacles in endoscopic stent management. Materials and Methods: The effectiveness and safety of endoscopic management were evaluated for anastomotic leaks when using a benign fully covered SEMS with an anchoring thread and thick silicone covering the membrane to prevent stent embedding and migration. We retrospectively reviewed the data of 14 consecutive patients with gastric cancer and anastomotic leaks after total gastrectomy treated from January 2009 to December 2016. Results: The technical success rate of endoscopic stent replacement was 100%, and the rate of complete leaks closure was 85.7% (n=12). The mean size of leaks was 13.1 mm (range, 3-30 mm). The time interval from operation to stent replacement was 10.7 days (range, 3-35 days) and the interval from stent replacement to extraction was 32.3 days (range, 18-49 days). The complication rate was 14.1%, and included a single jejunal ulcer and delayed stricture at the site of leakage. No embedded stent or migration occurred. Two patients died due to progression of pneumonia and septic shock 2 weeks after stent replacement. Conclusions: A benign fully covered SEMS with an anchoring thread and thick membrane is an effective and safe stent in patients with anastomotic leaks after total gastrectomy. The novelty of this stent is that it provides complete prevention of stent migration and embedding, compared with conventional fully covered SEMS. PMID- 29629220 TI - The Prognostic Significance of Compliance with Postoperative Adjuvant Chemotherapy in Patients with Stage III Gastric Cancer: an Observational Study. AB - Purpose: Postoperative adjuvant chemotherapy is usually prescribed to improve the survival of patients with advanced gastric cancer who undergo curative surgery. This study was designed to determine the impact that the degree of compliance with chemotherapy has on the prognosis of patients with gastric cancer. Materials and Methods: Among 252 patients with stage III gastric cancer who underwent curative surgery between July 2004 and December 2014, 85 patients were postoperatively treated with S-1, the oral fluoropyrimidine derivative, 23 received no chemotherapy, and 144 received other regimens. Overall survival was compared between the complete compliance group (who received 8 cycles of S-1 chemotherapy, n=44) and the incomplete compliance group (who received less than 8 cycles of S-1 chemotherapy, n=41). Factors that influenced patient compliance with chemotherapy were also analyzed. Results: The overall 5-year survival rate was significantly different between the complete chemotherapy and incomplete chemotherapy groups (80.0% vs. 42.7%, P<0.001). Based on univariate and multivariate survival analyses of patients who received S-1 chemotherapy, the independent prognostic factors were tumor, node, and metastasis (TNM) stage (IIIa vs. IIIb vs. IIIc) and compliance with chemotherapy. TNM stage and age are significant factors that influence compliance with chemotherapy. Conclusions: TNM stage and compliance with chemotherapy are independent prognostic factors in patients with stage III gastric cancer who received postoperative chemotherapy. TNM stage and age are significant factors that influence patient compliance with chemotherapy. PMID- 29629221 TI - Effect of Early Adjuvant Chemotherapy on Survival of Advanced Gastric Cancer Patients: a Propensity Score-matched Analysis. AB - Purpose: Generally, adjuvant chemotherapy (AC) should be initiated as soon as possible after surgery to eradicate microscopic cancer cells. In this study, we investigated the effect of early AC on the survival of stage II/III gastric cancer patients. Materials and Methods: Four hundred sixty patients who received AC (S-1 or XELOX) for pathologic stage II/III gastric cancer at Seoul National University Bundang Hospital between January 2008 and December 2014 were included. Patients were divided into 2 groups: early AC administration (within 4 weeks) and late AC administration (more than 4 weeks). Patients in the early AC group (n=174) were matched 1:1 with patients in the late AC group (n=174) by propensity scoring to adjust for clinical differences. Three-year relapse-free survival (RFS) was evaluated according to the timing of AC. Results: Three-year RFS was 98.1% in stage IIA (n=109), 85.0% in stage IIB (n=83), 87.4% in stage IIIA (n=96), 83.5% in stage IIIB (n=91), and 62.5% in stage IIIC (n=81). After propensity score matching, RFS was similar between early and late AC groups (hazard ratio [HR],1.04; 95% confidence interval [CI], 0.62-1.74; P=0.889). Pathologic stage and histological type were independent prognostic factors of RFS (HR, 2.05; 95% CI, 1.06-3.96; P=0.033 and HR, 2.61; 95% CI, 1.42-4.80; P=0.002, respectively). Conclusions: Early initiation of AC within 4 weeks does not affect survival rates in stage II/III gastric cancer. PMID- 29629222 TI - Survival Benefit of Perioperative Chemotherapy in Patients with Locally Advanced Gastric Cancer: a Propensity Score Matched Analysis. AB - Purpose: It has been reported that the survival of patients with locally advanced gastric cancer (LAGC) is better in East Asia countries than in developed western countries; however, the prognosis of LAGC remains poor. This study aimed to evaluate the effects of perioperative chemotherapy on the long-term survival of East Asia patients with LAGC. Materials and Methods: From October 2006 through August 2008, 43 patients with LAGC received perioperative S-1 combined with weekly docetaxel in a phase II study (neoadjuvant group). These patients were matched using propensity scores to patients who underwent surgery without neoadjuvant chemotherapy during the same period (surgery group). The surgical outcomes and long-term survivals were compared between the 2 groups. Results: After matching, 43 and 86 patients were included in the neoadjuvant and surgery groups, respectively, and there was no significant difference in their baseline characteristics. Although the operating time was longer in the neoadjuvant group, there was no significant difference in postoperative complications between the 2 groups. The neoadjuvant group had a significantly higher 5-year overall survival (OS) rate (73.3% vs. 51.1%, P=0.005) and a trend towards higher 5-year progression-free survival (PFS) (62.8% vs. 49.9%, P=0.145). In the multivariate analysis, perioperative chemotherapy was an independent factor for OS, with a hazard ratio of 0.4 (P=0.005) and a marginal effect on the PFS (P=0.054). Conclusions: Perioperative chemotherapy was associated with better long-term survival without increasing postoperative complications in the setting of D2 surgery for patients with LAGC, suggesting that perioperative chemotherapy can be a therapeutic option in East Asia countries. PMID- 29629223 TI - Early Detection is Important to Reduce the Economic Burden of Gastric Cancer. AB - Purpose: Early detection of gastric cancer is important to improve prognosis. Early detection enables local treatment, such as endoscopic submucosal dissection (ESD). Therefore, we investigated whether early detection of gastric cancer could reduce healthcare costs by comparison according to stage and treatment modalities. Materials and Methods: Medical care costs were investigated according to tumor stage and initial treatment modality in 1,188 patients newly diagnosed with gastric cancer at 7 medical institutions from December 2011 to June 2012. Total medical care costs during the first-year after diagnosis (total first-year costs) were examined, including the costs of initial treatment, post-initial treatment, and inpatient and outpatient visits. Results: Stage I (75.3%) was the most common cancer stage. ESD was the second most common treatment following surgery. Total first-year costs increased significantly from stages I to IV. The costs of initial treatment and post-initial treatment were lowest in patients with stage I cancer. Among patients with stage I cancer, total first-year costs were significantly lower when treated by ESD; in particular, initial ESD treatment costs were much lower than others. Conclusions: The cost of healthcare has increased significantly with increasing cancer stages. ESD can greatly reduce medical care costs of gastric cancer. Thus, early detection of gastric cancer is important to reduce healthcare costs. PMID- 29629224 TI - Successful Robotic Gastrectomy Does Not Require Extensive Laparoscopic Experience. AB - Purpose: We evaluated the learning curve and short-term surgical outcomes of robot-assisted distal gastrectomy (RADG) performed by a single surgeon experienced in open, but not laparoscopic, gastrectomy. We aimed to verify the feasibility of performing RADG without extensive laparoscopic experience. Materials and Methods: Between July 2012 and December 2016, 60 RADG procedures were performed by a single surgeon using the da Vinci(r) Surgical System (Intuitive Surgical). Patient characteristics, the length of the learning curve, surgical parameters, and short-term postoperative outcomes were analyzed and compared before and after the learning curve had been overcome. Results: The duration of surgery rapidly decreased from the first to the fourth case; after 25 procedures, the duration of surgery was stabilized, suggesting that the learning curve had been overcome. Cases were divided into 2 groups: 25 cases before the learning curve had been overcome (early cases) and 35 later cases. The mean duration of surgery was 420.8 minutes for the initial cases and 281.7 minutes for the later cases (P<0.001). The console time was significantly shorter during the later cases (168.6 minutes) than during the early cases (247.1 minutes) (P<0.001). Although the volume of blood loss during surgery declined over time, there was no significant difference between the early and later cases. No other postoperative outcomes differed between the 2 groups. Pathology reports revealed the presence of mucosal invasion in 58 patients and submucosal invasion in 2 patients. Conclusions: RADG can be performed safely with acceptable surgical outcomes by experts in open gastrectomy. PMID- 29629225 TI - IgG4-related Disease in the Stomach which Was Confused with Gastrointestinal Stromal Tumor (GIST): Two Case Reports and Review of the Literature. AB - Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated fibro inflammatory disorder characterized by specific pathological findings and elevated serum IgG4 level. IgG4-RD in the stomach is rare, and occasionally diagnosed as gastric subepithelial tumor (SET) by endoscopy or computed tomography scan. Two female patients in the age group of 40-50 years were diagnosed with 4 cm sized gastric SET. One underwent laparoscopic gastric wedge resection. Another one had a history of subtotal gastrectomy for early gastric cancer and idiopathic thrombocytopenic purpura with oral steroids administration. She underwent a completion total gastrectomy with splenectomy for the gastric SET and ITP. The pathology showed storiform fibrosis, and IgG4 was positive in immunohistochemistry (IHC) stain. IgG4-RD is known as a medical disease that could be treated with oral steroids. The difficulty in preoperative diagnosis of the disease occasionally causes unnecessary gastric resection. Thus, preoperative diagnostic methods for IgG4-RD such as deep biopsy with IHC stain or magnetic resonance imaging are needed. PMID- 29629226 TI - Endoscopy-assisted craniosynostosis surgery followed by helmet therapy. AB - Background: Surgical methods to treat craniosynostosis have evolved from a simple strip craniectomy to a diverse spectrum of partial or complete cranial vault remodeling with excellent results but often with high comorbidity. Therefore, minimal invasive craniosynostosis surgery has been explored in the last few decades. The main goal of minimal invasive craniosynostosis surgery is to reduce the morbidity and invasiveness of classical surgical procedures, with equal long term results, both functional as well as cosmetic. Methods: To reach these goals, we adopted endoscopy-assisted craniosynostosis surgery (EACS) supplemented with helmet molding therapy in 2005. Results: We present in detail our surgical technique used for scaphocephaly, trigonocephaly, plagiocephaly, complex multisutural, and syndromic cases of craniosynostosis. Conclusions: We conclude that EACS with helmet therapy is a safe and suitable treatment option for any type of craniosynostosis, if performed at an early age, preferably around 3 months of age. PMID- 29629227 TI - Obstructive hydrocephalus and facial nerve palsy secondary to vertebrobasilar dolichoectasia: Case Report. AB - Background: Symptomatic hydrocephalus due to vertebrobasilar dolichoectasia is a rare occurrence. Case Description: We report a patient who presented with acute confusion and vomiting. Neuroimaging revealed elongated and tortuous basilar artery indenting and elevating the floor of third ventricle causing obstructive hydrocephalus. Initially, the patient was treated with external ventricular drain and then with ventriculo-peritoneal shunt. Conclusion: We suggest prompt surgical intervention upon diagnosis as a first choice of treatment in order to avoid further complications. PMID- 29629228 TI - Cranial autologous bone flap resorption after a cranioplasty: A case report. AB - Background: Craniectomies and cranioplasty are common neurosurgical procedures performed after brain trauma, ischemia, tumor resection, or infection. Post cranioplasty autologous bone flap resorption may occur in patients after delayed cranial reconstruction. The occurrence is usually low when bone flaps are stored in subcutaneous abdominal tissue. We report a unique case of post-cranioplasty cranial bone flap. Case Description: We report a total autologous bone flap resorption in a 28-year-old man with a history of alcohol abuse. He was found unconscious in his bedroom with a head trauma of unknown mechanism. After an emergency room assessment, he was diagnosed with an acute subdural hematoma and underwent to emergency surgical drainage and a craniectomy. Three months later, a cranioplasty was performed and he exhibited exceptional outcomes. During a follow up assessment, 7 months post-cranioplasty, total bone flap resorption was observed on computerized tomography image. Conclusion: This case described an abnormal accelerated resorption of an autologous bone flap cranioplasty inserted after 3 months. Thus, to avoid bone flap resorption, an as early as possibly strategy may prevent this. Still, the exact mechanisms underlying bone resorption are poorly understood. PMID- 29629229 TI - Ambiguity in the Dural Tail Sign on MRI. AB - Background: Meningiomas give rise to the dural tail sign (DTS) on contrast enhanced magnetic resonance imaging (CEMRI). The presence of DTS does not always qualify for a meningioma, as it is seen in only 60-72% of cases. This sign has been described in various other lesions like lymphomas, metastasis, hemangiopericytomas, schwannomas and very rarely glioblastoma multiforme (GBM). The characteristics of dural-based GBMs are discussed here, as only eleven such cases are reported in the literature till date. Here we discuss the unique features of this rare presentation. Case Description: A 17-year-old male presented to the emergency department (ED) with, complaints of headache, recurrent vomiting, vision loss in right eye and altered sensorium. On examination patient was drowsy with right hemiparesis, secondary optic atrophy in the right eye and papilledema in the left eye. MRI brain showed, heterogeneous predominantly solid cystic lesion with central hypo-intense core suggestive of necrosis with heterogeneous enhancement and a positive DTS. Patient underwent emergency left parasagittal parieto-occipital craniotomy and gross total tumor excision including the involved dura and the falx. On opening the dura, tumor was surfacing, invading the superior sagittal sinus and the falx, greyish, soft to firm in consistency with central necrosis and highly vascular suggesting a high grade lesion. Postoperative computed tomography (CT) of the brain showed evidence of gross total tumor (GTR) excision. The postoperative course of the patient was uneventful. Histopathological analysis revealed GBM with PNET like components. The dura as well as the falx were involved by the tumor. Conclusion: GBMs can arise in typical locations along with DTS mimicking meningiomas. Excision of the involved dura and the falx becomes important in this scenario, so as to achieve GTR. Hence high index of suspicion preoperatively aided by Magnetic Resonance Imaging (MRS) can help distinguish GBMs from meningioma, thereby impacting upon the prognosis. PMID- 29629230 TI - Multinodular and vacuolating neuronal tumor: A case report and literature review. AB - Background: Multinodular and vacuolated neuronal tumor (MVNT) is a benign neuronal tumor that is newly recognized as architectural appearance that may be related to ganglion cell tumors in 2016 World Health Organization Classification of Tumors of the Central Nervous System. Herein, we report a case of MVNT in a 60 year-old man with a thorough literature review. Case Description: A 60-year-old male was pointed out the presence of intracerebral neoplasm located in left frontal lobe by a comprehensive medical examination. We suspected dysembryoplastic neuroepithelial tumors and proposed him to wait and see, but he wished to undergo surgery for diagnosis. We performed en bloc resection and pathological findings were consistent with MVNT. He was discharged on the 8th day after the operation without any complications. He remained stable without recurrence at the 16-month postoperative follow-up. Conclusions: Further studies may be helpful to fully understand the radiological and histological findings of MVNT development. As a result, we will be able to prevent the aggressive treatment if we established their major features. PMID- 29629231 TI - Internal auditory canal exostosis: A technical case report. AB - Background: Exostoses of the internal auditory canal is a rare finding that may present with disabling symptoms of dizziness, hearing loss, and vestibular dysfunction based on the extent of cranial nerve compression. The purpose of this case report is to discuss the presentation and outcomes in a patient who presented with this disorder. Case Description: A 19-year-old female presented to the neurotologist with left ear discomfort, pain with left lateral gaze, and dizziness. She underwent extensive evaluation including audiometric testing, videonystagmography, and neuroimaging, which confirmed left auditory and vestibular hypofunction and compression of the contents of the internal auditory canal from the exostosis. After extensive counseling, the patient elected to undergo a suboccipital craniectomy to remove the internal auditory canal exostosis. She experienced complete resolution of symptoms. Conclusions: Exostoses of the internal auditory canal, although rare, can present with severe symptoms of dizziness, hearing loss, and vestibular hypofunction based on the extent of cranial nerve compression. Imaging, particularly with thin-cut computed tomography, is invaluable in making the correct diagnosis. Severe cases can be treated successfully with surgery with minimal or no complications and excellent outcome. PMID- 29629232 TI - How to compare outcomes and complications in neurosurgery: We must make the mission possible! PMID- 29629233 TI - Large central lumbar disc herniation causing acute cauda equina syndrome with loss of evoked potentials during prone positioning for surgery. AB - Background: Few studies in the literature discuss operative positioning for lumbar surgery precipitating acute cauda equina syndromes (CES). Case Description: A 56-year-old male with a large L2-3-disc herniation was placed prone on a Jackson table. He immediately lost all motor and sensory evoked potentials. Signals returned to the baseline when surgery was aborted, and he was returned to the supine position. However, potentials were again lost when he was repositioned prone, following which the surgeons proceeded with surgical decompression with a good outcome. Conclusion: This case highlights the risk for patients with large acute lumbar disc herniation/stenosis and CES undergoing prone positioning for lumbar decompression. Here, despite the secondary loss of both sensory and motor evoked potentials, the patient successfully underwent lumbar decompressive surgery/discectomy performed on a Jackson table, resulting in full postoperative neurological recovery. PMID- 29629234 TI - A difficult-to-treat Acom aneurysm with the combined vascular anomaly of Acom fenestration and accessory anterior cerebral artery. AB - Background: Vascular anomaly and aneurysmal formation of an anterior communicating artery (Acom) complex has often been reported. Because of such a complicated relationship between the vascular structure and aneurysms, Acom aneurysm is one of the most difficult aneurysms to treat among other common anterior circulation aneurysms. We experienced an extremely rare and difficult-to treat case of ruptured Acom aneurysm with the combined vascular anomaly of the Acom fenestration and an accessory anterior cerebral artery (ACA). Case Description: A 29-year-old man underwent a clipping surgery for a ruptured Acom aneurysm with an Acom fenestration and an accessory ACA. By reasons of the complicated Acom structure and a posteriorly-projecting aneurysm, the patient was operated via an interhemispheric approach, which is generally reported to provide the best operative view for all types of Acom aneurysms. However, we could not help applying a clip in the narrow working space and the limited operative view, due to the poor mobilization of Acom complex and the interruption by an accessory ACA. Conclusion: The interhemispheric approach may exceptionally have a blind area behind the Acom complex in the case of Acom aneurysms with an accessory ACA. Additionally, the aneurysms arising from the Acom fenestration strongly require neurosurgeons to take a more accurate surgical approach to obtain a direct visualization for an aneurysmal neck. PMID- 29629235 TI - Variable Selection in Heterogeneous Datasets: A Truncated-rank Sparse Linear Mixed Model with Applications to Genome-wide Association Studies. AB - A fundamental and important challenge in modern datasets of ever increasing dimensionality is variable selection, which has taken on renewed interest recently due to the growth of biological and medical datasets with complex, non i.i.d. structures. Naively applying classical variable selection methods such as the Lasso to such datasets may lead to a large number of false discoveries. Motivated by genome-wide association studies in genetics, we study the problem of variable selection for datasets arising from multiple subpopulations, when this underlying population structure is unknown to the researcher. We propose a unified framework for sparse variable selection that adaptively corrects for population structure via a low-rank linear mixed model. Most importantly, the proposed method does not require prior knowledge of individual relationships in the data and adaptively selects a covariance structure of the correct complexity. Through extensive experiments, we illustrate the effectiveness of this framework over existing methods. Further, we test our method on three different genomic datasets from plants, mice, and humans, and discuss the knowledge we discover with our model. PMID- 29629236 TI - OC-2-KB: A software pipeline to build an evidence-based obesity and cancer knowledge base. AB - Obesity has been linked to several types of cancer. Access to adequate health information activates people's participation in managing their own health, which ultimately improves their health outcomes. Nevertheless, the existing online information about the relationship between obesity and cancer is heterogeneous and poorly organized. A formal knowledge representation can help better organize and deliver quality health information. Currently, there are several efforts in the biomedical domain to convert unstructured data to structured data and store them in Semantic Web knowledge bases (KB). In this demo paper, we present, OC-2 KB (Obesity and Cancer to Knowledge Base), a system that is tailored to guide the automatic KB construction for managing obesity and cancer knowledge from free text scientific literature (i.e., PubMed abstracts) in a systematic way. OC-2-KB has two important modules which perform the acquisition of entities and the extraction then classification of relationships among these entities. We tested the OC-2-KB system on a data set with 23 manually annotated obesity and cancer PubMed abstracts and created a preliminary KB with 765 triples. We conducted a preliminary evaluation on this sample of triples and reported our evaluation results. PMID- 29629237 TI - Effects of a Novel Mouthwash on Dental Remineralization. AB - Objective: The goal of this study was to evaluate the in vivo effects of a novel mouthwash on enamel remineralization. Materials and Methods: Ten healthy volunteers wore removable intra-oral appliances for three study arms with duration of 5 days each. In 1 study arm, subjects used Oral Essentials Sensitivity FormulaR mouthwash; in another arm they used SensodyneR mouthwash, and in the third arm they used no mouthwash at all. Sequence of mouthwash use was randomized, and study participants and researchers were blinded throughout the study. Subjects used Crest Total CareR toothpaste throughout the study. During a one week washout period before study begin and between each study arm, subjects also used Crest Total CareR toothpaste. A total of 300 enamel samples were included in this study, 150 served as baseline controls, and 150 as test samples subjected to demineralization prior to intra-oral wear. At the end of each study arm, enamel chips were removed from the appliance and underwent standard Microhardness (Knoop) measurements, as did the control samples. Enamel microhardness in the test vs the 2 control groups was compared using the Kruskal Wallis one-way analysis of variance with post-hoc Tukey's test to test for differences in remineralization between the 3 treatments. Results: Both mouthwashes demonstrated similar levels of recovery from demineralization as the "no mouthwash" arm of the study, with no significant differences for all groupings and comparisons (p>0.05). Conclusion: A novel mouthwash for sensitive teeth supports enamel recovery from demineralization. PMID- 29629238 TI - Validation of the UNC OCT Index for the Diagnosis of Early Glaucoma. AB - Purpose: To independently validate the performance of the University of North Carolina Optical Coherence Tomography (UNC OCT) Index in diagnosing and predicting early glaucoma. Methods: Data of 118 normal subjects (118 eyes) and 96 subjects (96 eyes) with early glaucoma defined as visual field mean deviation (MD) greater than -4 decibels (dB), aged 40 to 80 years, and who were enrolled in the Full-Threshold Testing Size III, V, VI comparison study were used in this study. CIRRUS OCT average and quadrants' retinal nerve fiber layer (RNFL); optic disc vertical cup-to-disc ratio (VCDR), cup-to-disc area ratio, and rim area; and average, minimum, and six sectoral ganglion cell-inner plexiform layer (GCIPL) measurements were run through the UNC OCT Index algorithm. Area under the receiver operating characteristic curve (AUC) and sensitivities at 95% and 99% specificity were calculated and compared between single parameters and the UNC OCT Index. Results: Mean age was 60.1 +/- 11.0 years for normal subjects and 66.5 +/- 8.1 years for glaucoma patients (P < 0.001). MD was 0.29 +/- 1.04 dB and 1.30 +/- 1.35 dB in normal and glaucomatous eyes (P < 0.001), respectively. The AUC of the UNC OCT Index was 0.96. The best single metrics when compared to the UNC OCT Index were VCDR (0.93, P = 0.054), average RNFL (0.92, P = 0.014), and minimum GCIPL (0.91, P = 0.009). The sensitivities at 95% and 99% specificity were 85.4% and 76.0% (UNC OCT Index), 71.9% and 62.5% (VCDR, all P < 0.001), 64.6% and 53.1% (average RNFL, all P < 0.001), and 66.7% and 58.3% (minimum GCIPL, all P < 0.001), respectively. Conclusions: The findings confirm that the UNC OCT Index may provide improved diagnostic perforce over that of single OCT parameters and may be a good tool for detection of early glaucoma. Translational Relevance: The UNC OCT Index algorithm may be incorporated easily into routine clinical practice and be useful for detecting early glaucoma. PMID- 29629239 TI - Sub-Airy Confocal Adaptive Optics Scanning Ophthalmoscopy. AB - Purpose: To demonstrate the viability of improving transverse image resolution in reflectance scanning adaptive optics ophthalmoscopy using sub-Airy disk confocal detection. Methods: The foveal cone mosaic was imaged in five human subjects free of known eye disease using two custom adaptive optics scanning light ophthalmoscopes (AOSLOs) in reflectance with 7.75 and 4.30 mm pupil diameters. Confocal pinholes of 0.5, 0.6, 0.8, and 1.0 Airy disk diameters (ADDs) were used in a retinal conjugate plane before the light detector. Average cone photoreceptor intensity profile width and power spectrum were calculated for the resulting images. Detected energy using a model eye was recorded for each pinhole size. Results: The cone photoreceptor mosaic is better resolved with decreasing confocal pinhole size, with the high spatial frequency content of the images enhanced in both the large- and small-pupil AOSLOs. The average cone intensity profile width was reduced by ~15% with the use of a 0.5 ADD pinhole when compared to a 1.0 ADD, with an accompanying reduction in signal greater than a factor of four. Conclusions: The use of sub-Airy disk confocal pinhole detection without increasing retinal light exposure results in a substantial improvement in image resolution at the cost of larger than predicted signal reduction. Translational Relevance: Improvement in transverse resolution using sub-Airy disk confocal detection is a practical and low-cost approach that is applicable to all point- and line-scanning ophthalmoscopes, including optical coherence tomographers. PMID- 29629240 TI - Factors Associated with Visceral Fat Loss in Response to a Multifaceted Weight Loss Intervention. AB - Background: Visceral adipose tissue is more metabolically active than other fat depots and is more closely associated with obesity-related diseases, such as cardiovascular disease and type 2 diabetes, than indicators of obesity, such as body mass index. Across various strategies to promote weight loss, including energy-reduced diet and exercise, variable effects on VAT compared to loss of total body fat have been reported. Methods: To examine the effect of a behavioral weight loss intervention using portion-controlled prepackaged entrees on VAT, we examined data and measurements from overweight/obese men and women (N=183) who were assigned to a weight loss intervention and prescribed a reduced-energy diet with either portion-controlled prepackaged entrees or self-selected meals in a randomized clinical trial. VAT was estimated with dual-energy X-ray absorptiometry at baseline and study end (12 weeks). Results: VAT loss was greater for the prepackaged entrees group (p=0.02), with an average loss of 29% compared to an average loss of 19% among participants consuming self-selected meals. VAT (mean [SEM]) was 1651 (71) g and 1546 (157) g at baseline and 1234 (59) g and 1278 (118) g at study end in the prepackaged entrees and self-selected meal groups, respectively. Greater VAT loss was associated with higher baseline weight and VAT, and greater weight loss, but not associated with age or physical activity. Conclusion: Prescribing portion-controlled prepackaged entrees in a behavioral weight loss intervention promotes a reduction in VAT, which should promote improved metabolic profile and reduced cardiovascular disease risk. PMID- 29629242 TI - Pumpkin powdery mildew disease severity influences the fungal diversity of the phyllosphere. AB - Phyllosphere microbiota play a crucial role in plant-environment interactions and their microbial community and function are influenced by biotic and abiotic factors. However, there is little research on how pathogens affect the microbial community of phyllosphere fungi. In this study, we collected 16 pumpkin (Cucurbita moschata) leaf samples which exhibited powdery mildew disease, with a severity ranging from L1 (least severe) to L4 (most severe). The fungal community structure and diversity was examined by Illumina MiSeq sequencing of the internal transcribed spacer (ITS) region of ribosomal RNA genes. The results showed that the fungal communities were dominated by members of the Basidiomycota and Ascomycota. The Podosphaera was the most dominant genus on these infected leaves, which was the key pathogen responsible for the pumpkin powdery mildew. The abundance of Ascomycota and Podosphaera increased as disease severity increased from L1 to L4, and was significantly higher at disease severity L4 (P < 0.05). The richness and diversity of the fungal community increased from L1 to L2, and then declined from L2 to L4, likely due to the biotic pressure (i.e., symbiotic and competitive stresses among microbial species) at disease severity L4. Our results could give new perspectives on the changes of the leaf microbiome at different pumpkin powdery mildew disease severity. PMID- 29629241 TI - State-of-the-Art Imaging in Human Chordoma of the Skull Base. AB - Purpose of Review: Chordoma are rare tumours of the axial skeleton which occur most often at the base of the skull and in the sacrum. Although chordoma are generally slow-growing lesions, the recurrence rate is high and the location makes it often difficult to treat. Both computed tomography (CT) and magnetic resonance imaging (MRI) are crucial in the initial diagnosis, treatment planning and post-treatment follow-up. Recent Findings: Basic MRI and CT characteristics of chordoma were described in the late 1980s and early 1990s. Since then, imaging techniques have evolved with increased resolution and new molecular imaging tools are rapidly evolving. New imaging tools have been developed not only to study anatomy, but also physiologic changes and characterization of tissue and assessment of tumour biology. Recent studies show the uptake of multiple PET tracers in chordoma, which may become an important aspect in the diagnosis, follow-up and personalized therapy. Summary: This review gives an overview of skull base chordoma histopathology, classic imaging characteristics, radiomics and state-of-the-art imaging techniques that are now emerging in diagnosis, treatment planning and disease monitoring of skull base chordoma. PMID- 29629243 TI - A walk in the maze: variation in Late Jurassic tridactyl dinosaur tracks from the Swiss Jura Mountains (NW Switzerland). AB - Background: Minute to medium-sized (footprint length (FL) less than 30 cm) tridactyl dinosaur tracks are the most abundant in the Late Jurassic tracksites of Highway A16 (Reuchenette Formation, Kimmeridgian) in the Jura Mountains (NW Switzerland). During excavations, two morphotypes, one gracile and one robust, were identified in the field. Furthermore, two large-sized theropod ichnospecies (Megalosauripus transjuranicus and Jurabrontes curtedulensis) and an ornithopod like morphotype (Morphotype II) have recently been described at these sites. Methods: The quality of morphological preservation (preservation grade), the depth of the footprint, the shape variation, and the footprint proportions (FL/footprint width (FW) ratio and mesaxony) along the trackways have been analyzed using 3D models and false-color depth maps in order to determine the exact number of small to medium-sized morphotypes present in the tracksites. Results: The study of footprints (n = 93) recovered during the excavations has made it possible to identify and characterize the two morphotypes distinguished in the field. The gracile morphotype is mainly characterized by a high FL/FW ratio, high mesaxony, low divarication angles and clear, sharp claw marks, and phalangeal pads (2-3-4). By contrast, the robust morphotype is characterized by a lower FL/FW ratio, weaker mesaxony, slightly higher divarication angles and clear, sharp claw marks (when preserved), whereas the phalangeal pads are not clearly preserved although they might be present. Discussion: The analysis does not allow the two morphotypes to be associated within the same morphological continuum. Thus, they cannot be extramorphological variations of similar tracks produced by a single trackmaker. Comparison of the two morphotypes with the larger morphotypes described in the formation (M. transjuranicus, J. curtedulensis, and Morphotype II) and the spatio-temporal relationships of the trackways suggest that the smaller morphotypes cannot reliably be considered as small individuals of any of the larger morphotypes. The morphometric data of some specimens of the robust morphotype (even lower values for the length/width ratio and mesaxony) suggest that more than one ichnotaxon might be represented within the robust morphotype. The features of the gracile morphotype (cf. Kalohipus isp.) are typical of "grallatorid" ichnotaxa with low mesaxony whereas those of the robust morphotype (cf. Therangospodus isp. and Therangospodus? isp.) are reminiscent of Therangospodus pandemicus. This work sheds new light on combining an analysis of variations in footprint morphology through 3D models and false color depth maps, with the study of possible ontogenetic variations and the identification of small-sized tridactyl ichnotaxa for the description of new dinosaur tracks. PMID- 29629244 TI - Uncertainty and sensitivity analysis of the basic reproduction number of diphtheria: a case study of a Rohingya refugee camp in Bangladesh, November December 2017. AB - Background: A Rohingya refugee camp in Cox's Bazar, Bangladesh experienced a large-scale diphtheria epidemic in 2017. The background information of previously immune fraction among refugees cannot be explicitly estimated, and thus we conducted an uncertainty analysis of the basic reproduction number, R0. Methods: A renewal process model was devised to estimate the R0 and ascertainment rate of cases, and loss of susceptible individuals was modeled as one minus the sum of initially immune fraction and the fraction naturally infected during the epidemic. To account for the uncertainty of initially immune fraction, we employed a Latin Hypercube sampling (LHS) method. Results: R0 ranged from 4.7 to 14.8 with the median estimate at 7.2. R0 was positively correlated with ascertainment rates. Sensitivity analysis indicated that R0 would become smaller with greater variance of the generation time. Discussion: Estimated R0 was broadly consistent with published estimate from endemic data, indicating that the vaccination coverage of 86% has to be satisfied to prevent the epidemic by means of mass vaccination. LHS was particularly useful in the setting of a refugee camp in which the background health status is poorly quantified. PMID- 29629245 TI - Selective attention on representations in working memory: cognitive and neural mechanisms. AB - Selective attention and working memory are inter-dependent core cognitive functions. It is critical to allocate attention on selected targets during the capacity-limited working memory processes to fulfill the goal-directed behavior. The trends of research on both topics are increasing exponentially in recent years, and it is considered that selective attention and working memory share similar underlying neural mechanisms. Different types of attention orientation in working memory are introduced by distinctive cues, and the means using retrospective cues are strengthened currently as it is manipulating the representation in memory, instead of the perceptual representation. The cognitive and neural mechanisms of the retro-cue effects are further reviewed, as well as the potential molecular mechanism. The frontal-parietal network that is involved in both attention and working memory is also the neural candidate for attention orientation during working memory. Neural oscillations in the gamma and alpha/beta oscillations may respectively be employed for the feedforward and feedback information transfer between the sensory cortices and the association cortices. Dopamine and serotonin systems might interact with each other subserving the communication between memory and attention. In conclusion, representations which attention shifts towards are strengthened, while representations which attention moves away from are degraded. Studies on attention orientation during working memory indicates the flexibility of the processes of working memory, and the beneficial way that overcome the limited capacity of working memory. PMID- 29629246 TI - PlasmidSeeker: identification of known plasmids from bacterial whole genome sequencing reads. AB - Background: Plasmids play an important role in the dissemination of antibiotic resistance, making their detection an important task. Using whole genome sequencing (WGS), it is possible to capture both bacterial and plasmid sequence data, but short read lengths make plasmid detection a complex problem. Results: We developed a tool named PlasmidSeeker that enables the detection of plasmids from bacterial WGS data without read assembly. The PlasmidSeeker algorithm is based on k-mers and uses k-mer abundance to distinguish between plasmid and bacterial sequences. We tested the performance of PlasmidSeeker on a set of simulated and real bacterial WGS samples, resulting in 100% sensitivity and 99.98% specificity. Conclusion: PlasmidSeeker enables quick detection of known plasmids and complements existing tools that assemble plasmids de novo. The PlasmidSeeker source code is stored on GitHub: https://github.com/bioinfo ut/PlasmidSeeker. PMID- 29629247 TI - Effects of mental health interventions for students in higher education are sustainable over time: a systematic review and meta-analysis of randomized controlled trials. AB - Background: Symptoms of depression, anxiety, and distress are more common in undergraduates compared to age-matched peers. Mental ill health among students is associated with impaired academic achievement, worse occupational preparedness, and lower future occupational performance. Research on mental health promoting and mental ill health preventing interventions has shown promising short-term effects, though the sustainability of intervention benefits deserve closer attention. We aimed to identify, appraise and summarize existing data from randomized control trials (RCTs) reporting on whether the effects of mental health promoting and mental ill health preventing interventions were sustained at least three months post-intervention, and to analyze how the effects vary for different outcomes in relation to follow-up length. Further, we aimed to assess whether the effect sustainability varied by intervention type, study-level determinants and of participant characteristics. Material and Methods: A systematic search in MEDLINE, PsycInfo, ERIC, and Scopus was performed for RCTs published in 1995-2015 reporting an assessment of mental ill health and positive mental health outcomes for, at least, three months of post-intervention follow up. Random-effect modeling was utilized for quantitative synthesis of the existing evidence with standardized mean difference (Hedges' g) used to estimate an aggregated effect size. Sustainability of the effects of interventions was analyzed separately for 3-6 months, 7-12 months, and 13-18 months of post intervention follow-up. Results: About 26 studies were eligible after reviewing 6,571 citations. The pooled effects were mainly small, but significant for several categories of outcomes. Thus, for the combined mental ill health outcomes, symptom-reduction sustained up to 7-12 months post-intervention (standardized mean difference (Hedges' g) effect size (ES) = -0.28 (95% CI [ 0.49, -0.08])). Further, sustainability of symptom-reductions were evident for depression with intervention effect lasting up to 13-18 months (ES = -0.30 (95% CI [-0.51, -0.08])), for anxiety up to 7-12 months (ES = -0.27 (95% CI [-0.54, 0.01])), and for stress up to 3-6 months (ES = -0.30 (95% CI [-0.58, -0.03])). The effects of interventions to enhance positive mental health were sustained up to 3-6 months for the combined positive mental health outcomes (ES = 0.32 (95% CI [0.05, 0.59])). For enhanced active coping, sustainability up to 3-6 months was observed with a medium and significant effect (ES = 0.75 (95% CI [0.19, 1.30])). Discussion: The evidence suggests long-term effect sustainability for mental ill health preventive interventions, especially for interventions to reduce the symptoms of depression and symptoms of anxiety. Interventions to promote positive mental health offer promising, but shorter-lasting effects. Future research should focus on mental health organizational interventions to examine their potential for students in tertiary education. PMID- 29629248 TI - GMPR: A robust normalization method for zero-inflated count data with application to microbiome sequencing data. AB - Normalization is the first critical step in microbiome sequencing data analysis used to account for variable library sizes. Current RNA-Seq based normalization methods that have been adapted for microbiome data fail to consider the unique characteristics of microbiome data, which contain a vast number of zeros due to the physical absence or under-sampling of the microbes. Normalization methods that specifically address the zero-inflation remain largely undeveloped. Here we propose geometric mean of pairwise ratios-a simple but effective normalization method-for zero-inflated sequencing data such as microbiome data. Simulation studies and real datasets analyses demonstrate that the proposed method is more robust than competing methods, leading to more powerful detection of differentially abundant taxa and higher reproducibility of the relative abundances of taxa. PMID- 29629250 TI - Factors Affecting the Geo-effectiveness of Shocks and Sheaths at 1 AU. AB - We identify all fast-mode forward shocks, whose sheath regions resulted in a moderate (56 cases) or intense (38 cases) geomagnetic storm during 18.5 years from January 1997 to June 2015. We study their main properties, interplanetary causes and geo-effects. We find that half (49/94) such shocks are associated with interacting coronal mass ejections (CMEs), as they are either shocks propagating into a preceding CME (35 cases) or a shock propagating into the sheath region of a preceding shock (14 cases). About half (22/45) of the shocks driven by isolated transients and which have geo-effective sheaths compress pre-existing southward Bz . Most of the remaining sheaths appear to have planar structures with southward magnetic fields, including some with planar structures consistent with field line draping ahead of the magnetic ejecta. A typical (median) geo-effective shock-sheath structure drives a geomagnetic storm with peak Dst of -88 nT, pushes the subsolar magnetopause location to 6.3 RE, i.e. below geosynchronous orbit and is associated with substorms with a peak AL-index of -1350 nT. There are some important differences between sheaths associated with CME-CME interaction (stronger storms) and those associated with isolated CMEs (stronger compression of the magnetosphere). We detail six case studies of different types of geo effective shock-sheaths, as well as two events for which there was no geomagnetic storm but other magnetospheric effects. Finally, we discuss our results in terms of space weather forecasting, and potential effects on Earth's radiation belts. PMID- 29629249 TI - Vortices in Saturn's Northern Hemisphere (2008-2015) Observed by Cassini ISS. AB - We use observations from the Imaging Science Subsystem on Cassini to create maps of Saturn's Northern Hemisphere (NH) from 2008 to 2015, a time period including a seasonal transition (i.e., Spring Equinox in 2009) and the 2010 giant storm. The processed maps are used to investigate vortices in the NH during the period of 2008-2015. All recorded vortices have diameters (east-west) smaller than 6000 km except for the largest vortex that developed from the 2010 giant storm. The largest vortex decreased its diameter from ~11000 km in 2011 to ~5000 km in 2015, and its average diameter is ~6500 km during the period of 2011-2015. The largest vortex lasts at least 4 years, which is much longer than the lifetimes of most vortices (less than 1 year). The largest vortex drifts to north, which can be explained by the beta drift effect. The number of vortices displays varying behaviors in the meridional direction, in which the 2010 giant storm significantly affects the generation and development of vortices in the middle latitudes (25-45 degrees N). In the higher latitudes (45-90 degrees N), the number of vortices also displays strong temporal variations. The solar flux and the internal heat do not directly contribute to the vortex activities, leaving the temporal variations of vortices in the higher latitudes (45-90 degrees N) unexplained. PMID- 29629251 TI - Abundance of adverse environmental conditions during critical stages of crop production in Northern Germany. AB - Background: Understanding the abundance of adverse environmental conditions e.g. frost, drought, and heat during critical crop growth stages, which are assumed to be altered by climate change, is crucial for an accurate risk assessment for cropping systems. While a lengthening of the vegetation period may be beneficial, higher frequencies of heat or frost events and drought spells are generally regarded as harmful. The objective of the present study was to quantify shifts in maize and wheat phenology and the occurrence of adverse environmental conditions during critical growth stages for four regions located in the North German Plain. First, a statistical analysis of phenological development was conducted based on recent data (1981-2010). Next, these data were used to calibrate the DSSAT-CERES wheat and maize models, which were then used to run three climate projections representing the maximum, intermediate and minimum courses of climate development within the RCP 8.5 continuum during the years 2021-2050. By means of model simulation runs and statistical analysis, the climate data were evaluated for the abundance of adverse environmental conditions during critical development stages, i.e. the stages of early crop development, anthesis, sowing and harvest. Results: Proxies for adverse environmental conditions included thresholds of low and high temperatures as well as soil moisture. The comparison of the baseline climate and future climate projections showed a significant increase in the abundance of adverse environmental conditions during critical growth stages in the future. The lengthening of the vegetation period in spring did not compensate for the increased abundance of high temperatures, e.g. during anthesis. Conclusions: The results of this study indicate the need to develop adaptation strategies, such as implementing changes in cropping calendars. An increase in frost risk during early development, however, reveals the limited feasibility of early sowing as a mitigation strategy. In addition, the abundance of low soil water contents that hamper important production processes such as sowing and harvest were found to increase locally. PMID- 29629252 TI - Prevention Efforts for Malaria. AB - Purpose of Review: Malaria remains a global burden contributing to morbidity and mortality especially in children under 5 years of age. Despite the progress achieved towards malaria burden reduction, achieving elimination in more countries remains a challenge. This article aims to review the prevention and control strategies for malaria, to assess their impact towards reducing the disease burden and to highlight the best practices observed. Recent Findings: Use of long-lasting insecticide-treated nets and indoor residual spraying has resulted a decline in the incidence and prevalence of malaria in Sub-Saharan Africa. Other strategies such as larval source management have been shown to reduce mosquito density but require further evaluation. New methods under development such as house improvement have demonstrated to minimize disease burden but require further evidence on efficacy. Development of the RTS,S/AS01 malaria vaccine that provides protection in under-five children has provided further progress in efforts of malaria control. Summary: There has been a tremendous reduction in malaria burden in the past decade; however, more work is required to fill the necessary gaps to eliminate malaria. PMID- 29629253 TI - Cardiovascular Multimodality Imaging: It is Time to Get on Board! A "Societa Italiana di Ecocardiografia e CardioVascular Imaging" Statement. PMID- 29629254 TI - Multimodality Imaging and Clinical Significance of Congenital Ventricular Outpouchings: Recesses, Diverticula, Aneurysms, Clefts, and Crypts. AB - The high spatial resolution of cardiac computed tomography (CT) and cardiac magnetic resonance (CMR) permit the diagnosis of congenital ventricular outpouchings (CVOs), including congenital ventricular diverticula (CVD), congenital ventricular aneurysms (CVA), clefts, and crypts. A unique classification has not been established, and these terms are used interchangeably with confounding terminology. Moreover, their significance is not univocal. A research was performed using PubMed on six subjects: (1) congenital left ventricular outpouchings; (2) congenital ventricular diverticulum; (3) congenital ventricular aneurysm; (4) ventricular clefts; (5) ventricular crypts; and (6) ventricular crevices. Usually, CVOs are small with a preserved contraction and in asymptomatic patients, the clinical relevance may be minimal, although electrocardiographic anomalies are often present. CVA and diverticula may carry an embolic risk and cases of arrhythmia and rupture are described. In the presence of clefts, or crypts a cardiomyopathy should be excluded. A simple classification can be proposed: CVD extend beyond the myocardial wall and fibrous type may be termed CVA, acquired forms should be kept distinct. Clefts, or crypts, are small recesses extending for more than 50% of the ventricular wall but not beyond its margin. The presence of fibrosis may be evaluated by CMR. A multicenter prospective registry would be helpful to investigate potential clinical implications and to exclude dubious forms of hypertrophic cardiomyopathy or ventricular noncompaction. In conclusion, CVOs have been described with different terminologies and classifications. Their significance needs to be interpreted in the clinical setting and with the help of a multimodality imaging, particularly of CMR. PMID- 29629255 TI - Obesity, Cardiac Remodeling, and Metabolic Profile: Validation of a New Simple Index beyond Body Mass Index. AB - Aim: The body mass index (BMI), the most used anthropometric index of obesity, has an important limitation, not taking into consideration the distribution of body fat. We developed a new simple index: the waist-corrected BMI (wBMI), calculated as waist circumference (WC) * BMI. The study aim was to assess the role of wBMI, compared to BMI, WC, and Waist-to-Height Ratio (WHtR) in predicting abnormal cardiac geometry, insulin resistance, increased arterial stiffness, and dyslipidemia. Methods: This was a cross-sectional study that included 805 patients referred to our Department of Preventive Cardiology for risk factors evaluation and treatment. Eleven echographic and laboratory parameters were determined, and receiver operating characteristic (ROC) curves were derived. Areas under ROC curves (AUC) were used to assess the accuracy of the four indexes to identify unfavorable characteristics. Results: There were 29% overweight, 59% obese, and 77% hypertensive patients. Of 11 echographic and laboratory parameters, wBMI, BMI, WHtR, and WC had the largest AUC for identifying 3, 1, 6, and 1 parameters, respectively, but with overlapping 95% confidence intervals. wBMI had the largest AUC for increased arterial stiffness and insulin resistance; also, it was superior to BMI for increased left atrial volume, relative wall thickness, and triglyceride level. Conclusions: In a large population with a high prevalence of obesity and hypertension, all four indexes were associated with unfavorable characteristics. wBMI has the theoretical advantage of taking into account simultaneously the global fat mass and distribution and might be useful for a better cardiovascular risk assessment. PMID- 29629256 TI - European Society of Cardiology-Proposed Diagnostic Echocardiographic Algorithm in Elective Patients with Clinical Suspicion of Infective Endocarditis: Diagnostic Yield and Prognostic Implications in Clinical Practice. AB - Background: Echocardiography plays a central role in diagnosing infective endocarditis (IE). Accordingly, the European Society of Cardiology (ESC) has proposed a diagnostic echocardiographic algorithm. However, new studies are still needed to evaluate the degree of implementation of these guidelines in clinical practice and their consequences on incidence and prognosis of IE. Aim: This study aims to investigate the diagnostic yield of the ESC proposed echocardiographic algorithm in patients with suspected IE. We also examined the association among IE diagnosis and clinical outcomes. Methods: Retrospective analysis of a series of patients undergoing the ESC algorithm for clinical suspicion of IE at our institution. Results: Between 2009 and 2013, 323 cases were managed by a multidisciplinary team for clinical suspicion of IE. Following ESC algorithm, 26 (8%) patients were diagnosed with IE and 297 (92%) had IE excluded. In 92% of patients with a good-quality negative transthoracic echocardiography (TTE) and low level of clinical suspicion, the first TTE was considered sufficient to rule out IE. During a mean follow-up of 2.3 +/- 1.4 years, patients who had a final diagnosis of IE showed similar mortality (P = 0.2) and rates of combined endpoint (all-cause death, stroke/transient ischemic attack, advanced atrioventricular block, and heart failure) compared to patients without echocardiographic diagnosis of IE (P = 0.5). Only 1% of the patients who had IE excluded experienced IE in the following 3 months, none of them in the subgroup of patients, in which a first negative TTE was considered sufficient to rule out IE. Conclusions: In spite of the current ESC recommendation TTE is used as part of a routine fever screen. Consequently, only a minority of patients had a final echocardiographic diagnosis of IE. Although in patients with low clinical suspicion a first negative TTE is sufficient to rule out IE, the incidence of clinical events is similar regardless the final diagnosis of IE. PMID- 29629257 TI - 12-year Temporal Trend in Referral Pattern and Test Results of Stress Echocardiography in a Tertiary Care Referral Center with Moderate Volume Activities and Cath-lab Facility. AB - Background: Data on stress echocardiography (SE) time-related changes in referral patterns and diagnostic yield for detection of inducible ischemia could enhance Echo Lab quality benchmarks and performance measures. Aim: This study aims to evaluate temporal trends in SE test results among ambulatory patients with suspected or known coronary artery disease (CAD) in a tertiary care referral center with moderate (>100/year) volume SE activities and Cath-Lab facility. Methods: From January 2004 to December 2015, 1954 patients (mean age 62 +/- 12 years, 42% women, 27% with known CAD) underwent SE (1673 exercise SE, 86%, 246 pharmacological SE, 12%, 35 pacing SE, 2%). Time was grouped into three 4 year periods, where clinical data and test results were evaluated. Results: Our series comprised low-to-intermediate pretest probability of CAD throughout the observation period (overall pretest probability of CAD 19% +/- 15%). A progressive decline over time in the rate of pharmacological SE instead of a dramatic increment of exercise SE (79%-96%, P < 0.0001) was noted. The use of beta-blockers increased (from 43% to 66%, P < 0.0001), while the use of nitrates decreased (from 11% to 4%, P < 0.0001) over time. We noted a very uncommon occurrence of abnormal test results with a further decrease in the last period (from 11% to 3%, P < 0.0001). Conclusions: We observed, over a 12-year period, a progressive decrease in the frequency of inducible myocardial ischemia among patients with known or suspected CADe referred to our Echo Lab for SE with Cath Lab facility, and this trend was parallel to changes in SE referral practice. These findings are particularly relevant if we consider the practical implications on diagnostic SE accuracy and risk assessment. PMID- 29629258 TI - Detection of Left Ventricular Remodeling in Acute ST Elevation Myocardial Infarction after Primary Percutaneous Coronary Intervention by Two Dimensional and Three Dimensional Echocardiography. AB - Background: Left ventricular remodeling (LVR) after ST-elevation myocardial infarction (STEMI) harbingers poor prognosis. Three-dimensional echocardiography (3DE) is more accurate than 2 D echo for the assessment of left ventricle (LV) shape. We assessed LV geometry with 3D ECHO 6 months after STEMI in patients who had primary angioplasty. Materials and Methods: In this prospective study, morphological and functional analysis of LV with 3D ECHO (volumes, LVEF, 3D sphericity index [SI]) was assessed up to 7 days and 6 months in 42 STEMI patients. The LVR was considered for increase >15% of the end diastolic volume of the LV (LVEDV) 6 months after the STEMI, compared to the LVEDV up to 7 days of it. Results: Sixteen (38%) patients had LVR. 3D Echocardiographic measurements up to 7 days after the acute myocardial infarction (AMI) 1-LVEDV in ventricular remodeling group was 99.8 +/- 19.1 ml and in no ventricular remodeling group was 87 +/- 18.2 mL (P = 0.037); 2-LVEF was 0.48 +/- 0.01 and 51 +/- 0.02 (P <.001); 3D-SI was 0.41 +/- 0.05 and 31 +/- 0.05 (P < 0.001) II-after 6 months: 1-LVEDV in remodeling group was 114.2 +/- 19.5 mL and no remodeling group was 94.2 +/- 18.6 (P = 0.002); 2-LVEF was 0.58 +/- 0.01 and 59 +/- .01 (P = 0.003); 3D-sphericity was 0.35 +/- 0.05 and 28 +/- .05 (P < 0.001). Conclusion: LVR was observed in 38% of the patients 6 months after AMI. The 3D SI has been associated with occurrence of LVR and can differentiate patients with and without subsequent development of LVR accurately and early on its basis. PMID- 29629259 TI - Hypoplasia or Absence of Posterior Leaflet: A Rare Congenital Anomaly of The Mitral Valve in Adulthood - Case Series. AB - We present a case series of two adult patients with almost complete absence of the posterior mitral valve leaflet and who are asymptomatic or mildly symptomatic, with two different degrees of mitral regurgitation. PMID- 29629260 TI - Acute Right Ventricular Failure Postintubation in a Mitral Stenosis Patient. AB - Mitral stenosis (MS) is prevalent in 0.02-0.2% of the population in developed countries. The pathophysiology of MS results in elevated left atrial pressures and over-time results in pulmonary hypertension (HTN) which ultimately affects the right ventricle. In addition, MS restricts the diastolic filling of the left ventricle. Therefore, during induction patients with MS are limited by their ability to increase cardiac output by increasing stroke volume. Anesthesia goals in severe MS are to avoid sudden changes in heart rate, as well as systemic and pulmonary artery pressures. We report a patient who sustained severe hypotension upon induction and intubation which was resistant to conventional medications. Intraoperative transesophageal echocardiography displayed unique right atrial and right ventricular dilatation. In addition, the leftward inter-ventricular, inter atrial septal shift and septal bounce were noted as the characteristic findings. Intravenous epinephrine bolus was administered to achieve normo-tension and normal chamber dimensions and interventricular septal position. PMID- 29629261 TI - An Unusual Left Atrial Mass in a Woman with Active Breast Cancer and Recent Cardiothoracic Surgery. AB - Atrial masses are rare and more often localized in the right atrium. They are usually detected incidentally, and the leading causes are tumors, thrombi, or infective vegetations. However, normal structures and artifacts ("pseudomasses") should also be considered in differential diagnosis, especially after cardiac and/or aortic surgery. We present a case of an unusual left atrial image observed on transthoracic echocardiography in an 83-year-old woman after an intervention of open-chest ascending aorta replacement and myocardial revascularization. PMID- 29629262 TI - Thrombolysis Followed by Apixaban for Massive Pulmonary Embolism and Free floating Thrombus in Right Ventricle in a Patient with Breast Cancer. AB - Free-floating thrombus in the right ventricle, associated with a massive acute pulmonary embolism (PE), is a rare phenomenon. PE is an important clinical entity with considerable mortality despite advances in diagnosis and treatment. The prognosis of PE depends on right ventricular dysfunction, myocardial injury markers, and early treatment. In this report, we present the case of a 71-year old woman with a history of breast cancer admitted to intensive care unit for PE complicated by syncope. Although our case may seem complex because it is not represented in the guidelines, the result was satisfactory and showed how treatment with new anticoagulants (in this case apixaban) after massive thrombolysis of PE could be considered and included in the new guidelines. PMID- 29629263 TI - A Biatrial Myxoma with Triple Ripples. AB - Cardiac myxoma is a benign tumor, but it is known for its space-occupying effect at the site of origin and frequent systemic embolization. This case report highlights a biatrial myxoma of interatrial septum who presented with significant tricuspid valve regurgitation, atrial fibrillation, and cardioembolic stroke of the left parietal lobe, i.e., a biatrial myxoma with triple ripples. PMID- 29629264 TI - Echocardiographic Assessment of Ventricular Septal Rupture and Left Ventricular Aneurysm after Inferior and Posterior Myocardial Infarction. AB - We present a case of posterior ventricular septal rupture associated to left ventricular aneurysm manged, during peri-operative period, by transthoracic and transesophageal echocardiography. Three-dimensional transesophageal echocardiography findings add adjunctive and more accurate information regarding morphological details of the ventricular septal rupture rather than two dimensional echocardiography, allowing, meanwhile, the detection of the outcome of the surgical repair. PMID- 29629265 TI - Ruptured Sinus of Valsalva: An Unusual Cause of Heart Failure. AB - A 35-year-old male patient presented with heart failure. On examination, there was a continuous murmur over the left sternum. Transthoracic echocardiography revealed a ruptured aneurysm arising from the noncoronary sinus of Valsalva and draining into the right atrium. PMID- 29629266 TI - Giant Left Ventricular Pseudoaneurysm as a Late Complication of Myocardial Infarction. AB - We present a case of a 63-year-old patient referred to a cardiology consultation due to progressive symptoms of heart failure. He had a history of an inferior ST elevation acute myocardial infarction 6 years ago. Echocardiogram revealed a giant left ventricular aneurysm/pseudoaneurysm involving the inferior and inferolateral left ventricular walls, with a massive mural thrombus. Additional characterization was done by cardiac magnetic resonance, essential in establishing the diagnosis of pseudoaneurysm and to guide subsequent management. In this case, we discuss the differential diagnosis between aneurysm and pseudoaneurysm and highlight the role of non-invasive multimodality imaging. PMID- 29629267 TI - Williams Syndrome and Right Ventricular Noncompaction: A Rare Association. AB - Ventricular noncompaction and Williams syndrome are genetic disorders with typical clinical and echocardiographic cardiovascular manifestations. Here, we describe a young patient with rare association of clinical phenotype suggestive of Williams syndrome and right ventricular noncompaction. PMID- 29629268 TI - Takotsubo Syndrome in Patient with Severe Mitral and Aortic Regurgitation. PMID- 29629269 TI - Right Ventricular Outflow Tract Systolic Excursion and Fractional Shortening for the Assessment of Right Ventricular Function. PMID- 29629270 TI - Left Atrial Function and Coronary Slow Flow: Is There Diastolic Dysfunction or Not? PMID- 29629271 TI - Infection control guidelines in hemodialysis facilities. PMID- 29629272 TI - Patient education for hyperphosphatemia management: Improving outcomes while decreasing costs? PMID- 29629273 TI - Korean clinical practice guidelines for preventing the transmission of infections in hemodialysis facilities. AB - Patients receiving hemodialysis are vulnerable to infectious diseases due to their impaired immunity and high risk of exposure to pathogens. To protect patients, staff, and visitors from potential infections, each hemodialysis unit should establish and follow standard infection control and prevention measures. Therefore, clinical practice guidelines were developed by a working group of nephrologists and infection control specialists to provide evidence-based guidance for dialysis physicians and nurses, with the aim of preventing infection transmission and controlling infection sources in hemodialysis facilities. The areas of infection control covered by these guidelines include standard precautions, isolation strategies, vascular access, water treatment, cleaning/disinfecting/sterilizing, and vaccination. This special report summarizes the key recommendations from the Korean clinical practice guidelines for preventing the transmission of infections in hemodialysis facilities. PMID- 29629274 TI - Current characteristics of dialysis therapy in Korea: 2016 registry data focusing on diabetic patients. AB - Diabetic nephropathy is the most frequent cause of end-stage renal disease worldwide. Dialysis patients with diabetes mellitus (DM) have more complications and shorter survival duration than non-DM dialysis patients, requiring more clinical attention and difficult management. The registry committee of the Korean Society of Nephrology has collected data about dialysis therapy in Korea through an on-line registry program and analyzed the characteristics of patients. A survey of dialysis patients in 2016 showed that 50.2% of new dialysis patients had DM nephropathy as the cause of end-stage renal disease. The proportion of patients receiving hemodialysis (HD) for more than 5 years was 38% in DM patients and 51% in non-DM patients. The mean pulse pressure in DM HD patients was 71.5 mmHg, compared with 62.6 mmHg in non-DM patients. The proportion of DM patients with native vessel arteriovenous fistula as vascular access for HD was lower than that of non-DM patients (73% vs. 78%). Mean serum creatinine of DM and non-DM dialysis patients was 8.4 mg/dL and 9.5 mg/dL respectively. As vascular access of the DM HD patients was poor, the dialysis adequacy of DM patients was slightly lower than that of non-DM patients. The 5-year survival rate for DM HD patients was 53.9%, which was much lower than that of chronic glomerulonephritis patients (78.2%). The proportion of patients with a full-time job was 17% for DM patients and 28% for non-DM patients. PMID- 29629275 TI - Human CD36 overexpression in renal tubules accelerates the progression of renal diseases in a mouse model of folic acid-induced acute kidney injury. AB - Background: Acute kidney injury (AKI) is a risk factor for progression to chronic kidney disease, with even subclinical AKI episodes progressing to chronic kidney disease. Several risk factors such as preexisting kidney disease, hyperglycemia, and hypertension may aggravate renal disease after AKI. However, mechanisms underlying the progression of AKI are still unclear. This study identified the effect of human cluster of differentiation 36 (CD36) overexpression on the progression of folic acid-induced AKI. Methods: Pax8-rtTA/tetracycline response element-human CD36 transgenic mice were used to elucidate the effect of human CD36 overexpression in the proximal tubules on folic acid-induced AKI. Results: Results of histological analysis showed severely dilated tubules with casts and albuminuria in folic acid-treated transgenic mice overexpressing human CD36 compared with folic acid-treated wild-type mice. In addition, analysis of mRNA expression showed a significant increase in the collagen 3a1 gene in folic acid treated transgenic mice overexpressing human CD 36 compared with folic acid treated wild type mice. Conclusion: Human CD36-overexpressing transgenic mice showed severe pathological changes and albuminuria compared with wild-type mice. Moreover, mRNA expression of the collagen 3a1 gene increased in folic acid treated transgenic mice. These results suggest that human CD36 overexpression is a risk factor of AKI and its progression to chronic kidney disease. PMID- 29629276 TI - Needle guides enhance tissue adequacy and safety of ultrasound-guided renal biopsies. AB - Background: Needle guides have recently come into use for ultrasound-guided percutaneous renal biopsies; however, it is not yet clear if the use of needle guides leads to decreased post-biopsy complication rates and improved tissue yields. Thus, we conducted a retrospective single center study comparing biopsy yield, adequacy, and rates of complications before and after utilization of a needle guide device. Methods: A retrospective analysis was performed on all native kidney biopsies performed before and after June 2015 corresponding to the start of needle guide use. All biopsies in the latter period of the study were performed by a single operator. We compared clinical characteristics, indications, type of investigation, tissue yield, adequacy of procedure, and rates of major and minor complications. Results: A total of 343 biopsies were analyzed, 140 in the pre-needle guide use period (Period I) and 203 in the needle guide use period (Period II). Biopsy yields were similar, irrespective of the use of needle guides. Tissue adequacy was better in Period II (93.7% vs. 84%, P < 0.001, with respect to pathologist-reported inconclusive biopsies. There were no differences in terms of major complications (1.7%) for the two periods; however, the rate of minor complications (8.4%) was significantly reduced in Period II (P = 0.006). According to multiple logistic regression analysis, not using a needle guide (odds ratio, 3.70; P < 0.001) along with low hemoglobin level, higher pre dialysis serum creatinine level, and high urinary red blood cell count were significant predictors of biopsy complications. Conclusion: Use of a needle guide improves biopsy adequacy and is associated with reduced rates of minor complications in native renal biopsies. Therefore, needle guides may be recommended in percutaneous renal biopsies, especially when transitioning to single-operator performed procedures. PMID- 29629277 TI - Weight loss has an additive effect on the proteinuria reduction of angiotensin II receptor blockers in hypertensive patients with chronic kidney disease. AB - Background: Weight reduction is a lifestyle intervention that has been introduced for prevention and management of chronic kidney disease (CKD). We investigate the additive anti-proteinuric effect of weight reduction on the usage of angiotensin II receptor blockers (ARBs) and its potential mechanisms in hypertensive CKD patients. Methods: This study is a subanalysis of data from an open-label, randomized, controlled clinical trial. Among the 235 participants, 227 were assigned to subgroups according to changes in body weight. Results: Fifty-eight participants (25.6%) were assigned to group 1 (>=1.5% decrease in body weight after 16 weeks), 32 participants (14.1%) were assigned to group 2 (1.5-0.1% decrease in body weight), and 136 participants (59.9%) were assigned to group 3 (>= 0.0% increase in body weight). Characteristics at enrollment were not different among the three groups, but mean differences in weight and percent changes in urinary sodium excretion over the period were statistically different (P < 0.001 and P = 0.017). Over the study period, unintentional weight loss independently increased the probability of reduced albuminuria (group 1, relative risk 6.234, 95% confidence interval 1.913-20.315, P = 0.002). Among urinary cytokines, only podocalyxin level decreased significantly in participants who lost weight (P = 0.013). Conclusion: We observed that weight loss had an additive effect on the anti-proteinuric effects of ARBs in nondiabetic hypertensive CKD patients, although it was minimal. An additive effect was shown in both obese and non-obese participants, and its possible mechanism is related to reduction of podocyte damage. PMID- 29629278 TI - Association of proton pump inhibitor use with renal outcomes in patients with coronary artery disease. AB - Background: Several studies have suggested that proton pump inhibitor (PPI) use is associated with adverse renal outcomes, but obvious evidence for this association is lacking. We investigated the association between PPI use and adverse renal outcomes in patients who had undergone percutaneous coronary intervention. Methods: Of the 1,284 patients hospitalized for percutaneous coronary intervention between January 2007 and May 2012, 934 patients with baseline estimated glomerular filtration rate greater than 60 mL/min/1.73 m2 were enrolled. Multivariable Cox models were used to examine whether PPI use was associated with acute and chronic adverse renal outcomes. Results: In adjusted time-dependent Cox models, PPI use was associated with acute kidney injury (hazard ratio [HR], 1.46; 95% confidence interval [95% CI], 1.05-2.02), especially in patients aged 65 years or younger (HR, 2.08; 95% CI, 1.09 3.96) or in patients with diabetes (HR, 2.00; 95% CI, 1.23-3.25). In multivariable Cox models, the association between duration of PPI use and chronic kidney disease development was not statistically significant (HR of heavy users, 1.50; 95% CI, 0.61-3.67), but a longer duration of PPI use was associated with mild renal progression in patients younger than 65 years (HR of heavy users, 2.24; 95% CI, 1.09-4.60). Conclusion: Our results suggest that PPI use increases the risk of AKI development, and that PPI use is more significantly associated with acute and chronic renal injuries in younger patients. PMID- 29629279 TI - Effects of education on low-phosphate diet and phosphate binder intake to control serum phosphate among maintenance hemodialysis patients: A randomized controlled trial. AB - Background: For phosphate control, patient education is essential due to the limited clearance of phosphate by dialysis. However, well-designed randomized controlled trials about dietary and phosphate binder education have been scarce. Methods: We enrolled maintenance hemodialysis patients and randomized them into an education group (n = 48) or a control group (n = 22). We assessed the patients' drug compliance and their knowledge about the phosphate binder using a questionnaire. Results: The primary goal was to increase the number of patients who reached a calcium-phosphorus product of lower than 55. In the education group, 36 (75.0%) patients achieved the primary goal, as compared with 16 (72.7%) in the control group (P = 0.430). The education increased the proportion of patients who properly took the phosphate binder (22.9% vs. 3.5%, P = 0.087), but not to statistical significance. Education did not affect the amount of dietary phosphate intake per body weight (education vs. control: -1.18 +/- 3.54 vs. -0.88 +/- 2.04 mg/kg, P = 0.851). However, the dietary phosphate-to-protein ratio tended to be lower in the education group (-0.64 +/- 2.04 vs. 0.65 +/- 3.55, P = 0.193). The education on phosphate restriction affected neither the Patient Generated Subjective Global Assessment score (0.17 +/- 4.58 vs. -0.86 +/- 3.86, P = 0.363) nor the level of dietary protein intake (-0.03 +/- 0.33 vs. -0.09 +/- 0.18, P = 0.569). Conclusion: Education did not affect the calcium-phosphate product. Education on the proper timing of phosphate binder intake and the dietary phosphate-to-protein ratio showed marginal efficacy. PMID- 29629281 TI - Use of fludrocortisone for intradialytic hypotension. AB - Intradialytic hypotension during dialysis adversely affects a patient's prognosis and increases mortality. We report a case in which intradialytic hypotension that persisted after the administration of midodrine was relieved after the use of fludrocortisone. Administration of 0.2 mg of fludrocortisone occurred 30 minutes before dialysis. We compared 45 sessions of dialysis without fludrocortisone administration and 45 sessions of dialysis with fludrocortisone administration in one patient. The number of times in which systolic blood pressure became lower than 80 mmHg and the number of early terminations of dialysis due to a decrease in systolic blood pressure were higher in the sessions without fludrocortisone administration than in the sessions with fludrocortisone administration (P < 0.05). Fludrocortisone may be helpful for the treatment of intradialytic hypotension that does not respond to midodrine administration. PMID- 29629280 TI - Effectiveness of group cognitive behavioral therapy with mindfulness in end-stage renal disease hemodialysis patients. AB - Background: Many patients with end-stage renal disease (ESRD) undergoing hemodialysis (HD) experience depression. Depression influences patient quality of life (QOL), dialysis compliance, and medical comorbidity. We developed and applied a group cognitive behavioral therapy (CBT) program including mindfulness meditation for ESRD patients undergoing HD, and measured changes in QOL, mood, anxiety, perceived stress, and biochemical markers. Methods: We conducted group CBT over a 12-week period with seven ESRD patients undergoing HD and suffering from depression. QOL, mood, anxiety, and perceived stress were measured at baseline and at weeks 8 and 12 using the World Health Organization Quality of Life scale, abbreviated version (WHOQOL-BREF), the Beck Depression Inventory II (BDI-II), the Hamilton Rating Scale for Depression (HAM-D), the Beck Anxiety Inventory (BAI), and the Perceived Stress Scale (PSS). Biochemical markers were measured at baseline and after 12 weeks. The Temperament and Character Inventory was performed to assess patient characteristics before starting group CBT. Results: The seven patients showed significant improvement in QOL, mood, anxiety, and perceived stress after 12 weeks of group CBT. WHOQOL-BREF and the self-rating scales, BDI-II and BAI, showed continuous improvement across the 12-week period. HAM-D scores showed significant improvement by week 8; PSS showed significant improvement after week 8. Serum creatinine levels also improved significantly following the 12 week period. Conclusion: In this pilot study, a CBT program which included mindfulness meditation enhanced overall mental health and biochemical marker levels in ESRD patients undergoing HD. PMID- 29629282 TI - Effects of 12 months of continuous positive airway pressure therapy on cognitive function, sleep, mood, and health-related quality of life in a peritoneal dialysis patient with obstructive sleep apnea. AB - This report describes the case of a hypertensive 51-year-old male with a 3-year history of peritoneal dialysis. We followed the patient through his diagnosis of severe obstructive sleep apnea (OSA) and treatment with continuous positive airway pressure (CPAP). Therapeutic use of CPAP led to the improvement of not only sleep-related problems, but also cognitive function and quality of life. To our knowledge, this is the first paper describing the benefits of long-term CPAP treatment in an OSA patient undergoing dialysis. This case report emphasizes the need for the proactive diagnosis and treatment of OSA in end-stage renal disease patients to improve patient-centered healthcare. PMID- 29629283 TI - Incidentally discovered renal arteriovenous malformation. PMID- 29629284 TI - Paroxysmal nocturnal hemoglobinuria: Kidney biopsy and magnetic resonance imaging. PMID- 29629285 TI - Erratum: Sustained uremic toxin control improves renal and cardiovascular outcomes in patients with advanced renal dysfunction: post-hoc analysis of the Kremezin Study against renal disease progression in Korea [Volume 36, Issue 1, March 2017, Pages 68-78]. AB - [This corrects the article on p. 68 in vol. 36, PMID: 28392999.]. PMID- 29629286 TI - The Kaleidoscope Model of Integrative Healthcare as a collaborative paradigm for cardiology and chiropractic: a call to action. AB - This review article proposes a model of integrative care for cardiovascular patients in institutional settings. We review relevant historic and contemporary examples of medical-chiropractic cooperation and a brief review of the literature illustrating the clinical benefits of chiropractic care for patients with cardiovascular disease. The groundwork proposes a distinct research and clinical practice model incorporating the doctor of chiropractic (D.C.) as a synergistic partner with the medical cardiologist coined the Kaleidoscope Model of Integrative Care (KM). While a traditional kaleidoscope does not alter the nature of light itself, the observer does see the 'raw data' of colors and shapes, wavelengths, etc. contained within the "potential" of the light itself; left unrecognized, even subtle re-orientations of the instrument changes the perspective. Similarly, the KM is intended as a conduit for slight reorientations to traditional medical-chiropractic-patient hierarchies, thus creating new treatment options and generating robust changes in inter-professional perception of the patient's condition(s) and treatment options. It is hoped that this model will not only serve future patients within hospitals, but that institutions will serve as incubators for better collaboration and research among the majority of free-standing medical and chiropractic practices ultimately benefitting the patient with cardiovascular disease. PMID- 29629287 TI - Infrequent use of medicinal plants from India in snakebite treatment. AB - Snakes have fascinated humankind for millennia. Snakebites are a serious medical, social, and economic problem that are experienced worldwide; however, they are most serious in tropical and subtropical countries. The reasons for this are 1) the presence of more species of the most dangerous snakes, 2) the inaccessibility of immediate medical treatment, and 3) poor health care. The goal of this study was to collect information concerning rare, less utilized, and less studied medicinal plants. More than 100 plants were found to have potential to be utilized as anti-snake venom across India. Data accumulated from a variety of literature sources revealed useful plant families, the parts of plants used, and how to utilize them. In India, there are over 520 plant species, belonging to approximately 122 families, which could be useful in the management of snakebites. This study was conducted to encourage researchers to create herbal antidotes, which will counteract snake venom. These may prove to be an inexpensive and easily assessable alternative, which would be of immense importance to society. Plants from families such as Acanthaceae, Arecaceae, Apocynaceae, Caesalpiniaceae, Asteraceae, Cucurbitaceae, Fabaceae, Euphorbiaceae, Lamiaceae, Rubiaceae, and Zingiberaceae are the most useful. In India, experts of folklore are using herbs either single or in combination with others. PMID- 29629288 TI - Natural therapeutic approach of Nigella sativa (Black seed) fixed oil in management of Sinusitis. AB - : Sinusitis is associated with inflammation and infections of air-filled cavities of sinuses. The aim of this study was to evaluate the potential efficacy of Nigella sativa seed fixed oil in management of sinusitis. The information was extracted from accessible international databases, traditional books, electronic resources, and unpublished data. Results: The results of investigations on N. sativa seed fixed oil showed its therapeutic potential in treatment of sinusitis by its anti-inflammatory, antioxidant, antihistaminic, immune-modulator, antimicrobial and analgesic effects. The use of N. sativa seed fixed oil can inhibit the inflammation of sinuses and respiratory airways, microbial infections and finally help the patients suffering from clinical symptoms of sinusitis such as coryza, nasal congestion, headache, neck pain, earache and toothache. Clinical studies are required to evaluate its efficacy in patients with sinusitis in future. PMID- 29629289 TI - Structural characteristics, bioavailability and cardioprotective potential of saponins. AB - Cardiovascular diseases are the leading cause of death, accounting about 31% deaths globally in 2012. The major risk factors causing cardiovascular diseases are coronary atherosclerosis, hyperlipidemia, myocardial infarction, and stroke. The dominating cause of cardiovascular diseases is accredited to our modern lifestyle and diet. Medicinal plants have been used for the prevention and treatment of cardiovascular diseases from centuries. The in built chirality and chemical space of natural products have been playing an important role in providing leads and templates for pharmacophore synthesis. This review highlights one of the important naturally occurring class saponins and their role in cardioprotection along with structural characteristics and pharmacological effects such as antioxidant, Ca2+ ion regulation, antiapoptotic, antiatherosclerosis, antihyperlipidemic, hypocholesterolemic, angiogenic, vasodilatory, and hypotensive. The characteristic cholesterol lowering, hemolytic, and anticoagulant properties of the saponins prompted us to select as one of the natural products class for cardioprotection. This review covers the most updated information on saponins related to their cardioprotective effects, mechanism of action, bioavailability, and structure activity relationship. PMID- 29629290 TI - The combination of exercise training and Zataria multiflora supplementation increase serum irisin levels in postmenopausal women. AB - Background: We examined the effect of antioxidant supplementation and exercise on irisin within postmenopausal women. Methods: Forty-eight participants (age: 55.7 +/- 4.9 years; weight: 68.0 +/- 6.3 kg; BMI 27.0 +/- 2.7; mean +/- SD) were randomized into four groups for the eight week intervention: control group (CG; n = 12), resistance training group (RTG; n = 12), supplementation with Zataria multiflora group (ZG; n = 12), or supplementation with Z. multiflora and resistance training group (ZRTG; n = 12). RTG and ZRTG performed circuit resistance training, and both ZG and ZRTG consumed 500 mg of Z. multiflora every day during the intervention. Blood samples were taken 48 hours before and after the intervention. Results: There was a significant difference in irisin at post training, with greater levels in ZRTG compared to CG. A significant increase was noted for irisin at post-training compared to pre-training for ZG, RTG, and ZRTG. Moreover, we identified a significant decrease in malondialdehyde in the RTG and ZRTG groups and increase in glutathione in the ZG, RTG, and ZRTG groups when compared to CG. Conclusion: These findings showed that exercise, Z. multiflora supplementation or their combination led to an increase in irisin. PMID- 29629291 TI - Zinc, copper, CD4 T-cell count and some hematological parameters of HIV-infected subjects in Southern Nigeria. AB - Background: Low concentration of trace elements has been associated with poor prognosis and mortality in HIV infection. Methods: A cross sectional study was conducted among 100 HIV-infected subjects (70 were on ART treatment, while 30 were ART naive). Fifty (50) apparently healthy controls were enrolled. Concentration of serum levels of zinc and copper was done using atomic absorption spectrometric method, while complete blood count was determined using automated blood analyzer. CD4+ T-cell count was done using cyflow cytometer. Aim and setting: The aim of this study was to investigate the level of some trace elements and some hematological parameters of HIV-seropositive subjects attending University of Calabar Teaching Hospital Clinic as well as prevalence of trace elements deficiency and anemic status and compare same with HIV-seronegative control. Results: Mean serum zinc, CD4+ T-cell count, Hb, PCV, RBC, MXD, were significantly (p < 0.05) reduced in the HIV-infected subjects, while copper/zinc ratio, MCV, MCH and platelet count were significantly (p < 0.05) raised in the HIV-infected subjects. The serum Cu level was comparable (p > 0.05) with the control. ART treatment had no effect on all the parameters assessed except CD4+ T cell count. Twenty five percent (25%), 3% and 56% of the HIV-infected subjects were zinc deficient, copper deficient and anemic, respectively. Gender was found as a predictor of zinc deficiency. Copper and zinc showed weak positive correlation with CD4+ T-cell count. Conclusion: ART treatment did not complement zinc status in HIV infection while improving CD4+ T-cell count, hence the need to consider supplementation. PMID- 29629292 TI - The definition and diagnosis of cold hypersensitivity in the hands and feet: Finding from the experts survey. AB - Background: Cold hypersensitivity in the hands and feet (CHHF) is a symptom patients usually feel cold in their hands and feet, but not dealt with a disease in western medicine. However, it is often appealed by patients at a clinic of Korean medicine (KM), considered to be a sort of key diagnostic indicator, and actively treated by physicians. Nevertheless, there is no standardized diagnostic definition for CHHF. Therefore, we surveyed KM experts' opinions to address the clinical definition, diagnostic criteria, and other relevant things on CHHF. Methods: We developed a survey to assess the definition, diagnosis, causes, and accompanying symptoms on CHHF. 31 experts who work at specialized university hospitals affiliated with KM hospitals consented to participation. Experts responded to survey questions by selecting multiple-choice answers or stating their opinions. Results: Vast majority of experts (83.8%) agreed with our definition on CHHF ("a feeling of cold as a symptom; that one's hands or feet become colder than those of average people in temperatures that are not normally perceived as cold"). 77.4% of experts considered subjective symptoms on CHHF were more important than medical instrument results. Constitution or genetic factors (87.1%) and stress (64.5%) were the most common causes reported for CHHF. Conclusions: This study offers an expert consensus regarding the themes, opinions, and experiences of practitioners with CHHF. Our results underscore the need for standardized definitions and diagnostic criteria for CHHF. PMID- 29629293 TI - Biopsychological and pathophysiological features of Cold-Heat subgroup of Sasang typology with Sasang Digestive Function Inventory, Sasang Personality Questionnaire and Body Mass Index. AB - Background: The Sasang typology is a traditional Korean personalized medicine and its Cold-Heat subgroup identification is essential for effective use of medical herbs and acupuncture. The purpose of this study was to discover differences between Cold-Heat subgroups with objective clinical measures and to examine its clinical usefulness. Methods: The pathophysiological symptoms of the digestive system, temperament and body shape of 241 patients were measured using the Sasang Digestive Function Inventory (SDFI), Sasang Personality Questionnaire (SPQ) and Body Mass Index (BMI). The differences between Cold and Heat subgroups of each Sasang types were tested by Analysis of Covariance considering age and sex, while the associations of SDFI, SPQ and BMI with Cold-Heat subgroup were examined by logistic regression analysis. Results: There were significant differences between Cold and Heat subgroups in SDFI, SPQ and BMI for the So-Yang, SDFI and BMI for the Tae-Eum type and SDFI-Digestion subscale for the So-Eum type. Moreover, the SDFI-Digestion was a substantial predictor for Cold-Heat subgroup identification in three Sasang types. The logistic regression model with SDFI, SPQ and BMI correctly predicted 81.9%, 77% and 75.5% of the Cold-Heat subgroups in So-Yang, Tae-Eum and So-Eum types, respectively. Conclusion: The results of the present study showed that the objective and validated clinical measures of SDFI, SPQ and BMI would be useful for differentiating Cold-Heat subgroups of Sasang typology. Further clinical studies on pathophysiological mechanisms in Cold-Heat subgroup are required to generalize these results. PMID- 29629294 TI - Validity of Yin-Yang temperament in Sasang Personality Questionnaire. AB - Background: The Yin-Yang is a pivotal concept of traditional East-Asian medicine, however the stability of Yin-Yang temperament in Sasang Personality Questionnaire (SPQ) over time has not been extensively studied. The purpose of this study was to examine the test-retest validity of SPQ with a large number of participants. Methods: SPQ test was conducted two times with three months interval in 247 Korean university students. The structural validity of first SPQ data was examined with Factor analysis and Cronbach's alpha, and the correlation between first and second measure of SPQ was attested with Pearson's correlation. Yang, Uncertain and Yin temperament groups were determined with SPQ total scores, and agreement of temperament group clustering between first and second measures were analyzed with Cohen's Kappa. Results: Three subscales of SPQ explained 55.25% of total variances, and internal consistency of SPQ total score was 0.772. The correlation coefficient between first and second measures of SPQ were 0.851 and 0.888 in male and female, respectively, and the agreement of first and second Yin Yang temperament group clustering as Cohen's Kappa was 0.536 for male and 0.637 for female. Conclusion: The repeatability of SPQ measuring Yin-Yang temperament at three months of interval was found to be satisfactory. The SPQ would be a reliable clinical measure for the biopsychological studies of traditional East Asian medicine. PMID- 29629295 TI - In vivo anti-arthritic and anti-nociceptive effects of ethanol extract of Moringa oleifera leaves on complete Freund's adjuvant (CFA)-induced arthritis in rats. AB - Background: The medicinal uses of plants are in many cases based exclusively on traditional knowledge without enough scientific evidences. Different parts of Moringa oleifera were traditionally used for the treatment of wide variety of ailments including arthritis and joints pain. The present study had been designed to evaluate the anti-arthritic and anti-nociceptive activities of ethanol extract of Moringa leaves, this being the most abundant plant part suitable for commercial mass production of botanical medicinal products. Methods: Complete Freund's adjuvant (CFA)-induced arthritis in rats was used as disease model. CFA induced inflammatory paw edema, body weight, arthritic index, X-ray radiography, hematological parameters, and walk track and locomotion analysis were all evaluated for the assessment of disease progression. In addition to that, anti nociceptive activity was examined at different dose levels in both normal and arthritic-induced rats using Eddy's hot plate and tail flick thermal analgesia. Results: The analysis of various arthritic assessment parameters used in this study revealed that Moringa extract has a considerable effect in preventing development or ameliorate arthritis disease severity. Moreover, the ethanol extract of Moringa leaves revealed significant anti-nociceptive activity at in both normal and CFA-induced arthritis rats in a dose-dependent manner. Conclusion: Ethanol extract of Moringa leaves appears to be a really promising as analgesic and arthritis medication, but a larger and more detailed preclinical and clinical studies especially in human is highly recommended. PMID- 29629296 TI - Effects of acupuncture in postmenopausal women with prehypertension or stage 1 hypertension: study protocol for a prospective, comparative, interventional cohort study. AB - Background: Hypertension is a major cause of cardiovascular disease and associated mortality, and postmenopausal women are at a high risk of hypertension. We aim to investigate the hypotensive effect and safety of acupuncture, focusing on postmenopausal women with prehypertension and stage 1 hypertension. In addition, we aim to investigate whether the effect of acupuncture treatment differed, depending on Sasang Constitution and cold-heat pattern. Methods: This study is designed as an intervention cohort study. Two hundred postmenopausal women aged <65 years with prehypertension or stage 1 hypertension living in Daejeon city in Korea will be recruited, and randomly assigned to either an acupuncture or no-treatment control group. The intervention will consist of four sessions; one session will include acupuncture performed 10 times for 4 weeks. There will be a 20-week observation period after each session, and the total study duration will be 96 weeks. Acupuncture will be applied at the bilateral Fengchi (GB20), Quchi (LI11), Zusanli (ST36), and Sameumgyo (SP6) acupoints. The effect of acupuncture will be evaluated by comparing the change in systolic and diastolic blood pressure between the acupuncture and control groups every 4 weeks until the end of the study. Discussion: To evaluate the success of blood pressure management, long-term observation is required, but no long-term studies have been conducted to evaluate the effect of acupuncture on blood pressure in postmenopausal women. To our knowledge, this study will be the first long-term study to investigate this issue for more than 6-8 weeks. PMID- 29629297 TI - Influences of Pinpoint Plantar Long-Wavelength Infrared Light Irradiation (Stress Free Therapy) on Chorioretinal Hemodynamics, Atherosclerosis Factors, and Vascular Endothelial Growth Factor. AB - Background: We previously reported that pinpoint plantar long-wavelength infrared light irradiation (stress-free therapy; SFT) is useful for alleviating insulin resistance and improving intracranial blood flow in patients with type 2 diabetes mellitus. This study was undertaken to evaluate the influences of SFT on chorioretinal hemodynamics (retinal artery and vein blood flows) as well as atherosclerosis-related factors (TG, LDL-C) and VEGF in patients with dyslipidemia. Methods: Four patients with dyslipidemia received 15-minute irradiation with a stress-free apparatus (far-infrared wavelength, 30 mW). Using laser speckle flowgraphy, associations of chorioretinal blood flow with peripheral atherosclerosis-inducing factors/VEGF levels before and after irradiation were analyzed. Results: Chorioretinal blood flow increased, while TG/LDL-C levels decreased, after irradiation. VEGF tended to rise in cases with pre-irradiation baseline levels at the lower limit but tended to decrease in cases in which baseline levels had exceeded the normal range. Conclusion: SFT was suggested to enhance chorioretinal circulation and to normalize VEGF, thereby possibly contributing to amelioration of atherosclerosis-inducing factors. Abnormalities in chorioretinal hemodynamics are known to be highly involved in the pathophysiology of diabetic retinopathy and age-related macular degeneration, and anti-VEGF antibody has been used for treating these conditions. The necessity of risk management, involving chorioretinal blood flow, has been pointed out when dealing with central retinal vein occlusion, diabetes mellitus, ischemic cerebral/cardiac disease, dementia and so on. SFT is therefore a potential complementary medical strategy which can be expected to contribute to normalization of chorioretinal blood flow and atherosclerosis-inducing factors/VEGF levels, and thereby to the prevention of lifestyle-related chronic diseases. PMID- 29629298 TI - Corrigendum to "Physiological indices for the categorization of Mibyeong severity" [Integr. Med. Res. 2017; 6: 88-92]. AB - [This corrects the article DOI: 10.1016/j.imr.2017.01.005.]. PMID- 29629299 TI - Ethnicity and nationality among Ethiopians in Canada's census data: a consideration of overlapping and divergent identities. AB - This article addresses the intersection of 'homeland' politics and diaspora identities by assessing whether geopolitical changes in Ethiopia affect ethno national identifications among Ethiopian-origin populations living abroad. Officials in Ethiopia's largest ethnically-defined states recently began working to improve diaspora-homeland relations, historically characterised by ethnically mobilized support for opposition and insurgency. The emergence of an 'Ethiopian Somali' identity indicated in recent research, previously regarded as a contradiction in terms, is the most striking of a series of realignments between ethnicity and nationality. Such realignments reflect new orientations towards the homeland that impact diaspora engagement in politics and development. While diaspora returnees constitute a visible presence in some formerly marginalized areas of Ethiopia-including the historically disputed Somali region-large-sample data on ethnicity and nationality from Canadian censuses suggest that diaspora outreach efforts to historically marginalized groups have not (yet) effected large-scale changes in ethno-national identity, and that ongoing tensions in Ethiopia's federal politics may have different impacts on the identities of different ethnic populations. PMID- 29629300 TI - Rare successful pregnancy in a patient with Swyer Syndrome. AB - Objective: To report a rare successful pregnancy after fertility treatment in a patient with Swyer syndrome. Design: Case report. Setting: Herts & Essex Fertility Centre, Cheshunt, UK. Patients: A 36-year-old patient with 46, XY gonadal dysgenesis. 31 year old husband with normal sperm analysis. Interventions: Chromosomal analysis, Saline infusion sonography, Pipelle endometrial scratch, ICSI using donor eggs, Embryo Transfer, and Caesarean delivery. Main Outcome Measures: Successful pregnancy and live birth. Results: Successful treatment with donor eggs, pregnancy, and delivery. Conclusions: A patient with 46, XY gonadal dysgenesis in a specially tailored fertility program, can maintain a normal pregnancy and delivery. PMID- 29629301 TI - Endometriosis inflammation mimicking pseudomyxoma peritonei: A case report. AB - *Endometriosis may mimic other pathologic processes*Fertility preservation can be considered in young women with atypical endometriosis*Referral to experienced surgeons for maligancy is warranted in atypical endometriosis. PMID- 29629302 TI - Coccidioidomycosis in pregnancy: Case report and literature review of associated placental lesions. AB - Background: Coccidioidomycosis is an endemic fungal infection found most commonly in the Southwestern United States, Northwestern Mexico, and parts of Central and South America. Although infection is relatively uncommon during pregnancy, it is imperative to have an index of suspicion in order to diagnose and begin timely treatment to prevent dissemination and dire consequences. Case report: A 33-year old Hispanic female was evaluated after she was involved in an automobile accident. Radiographic evaluation showed a 3.2 * 3.2 cm cavitary thick-walled lesion. A biopsy was negative for malignancy. Evaluation was positive for coccidioidomycosis by complement fixation reaction. Four months later, the patient presented 7 weeks into a pregnancy with massive hemoptysis. Bronchoscopy revealed bleeding from the right upper lobe and emergency embolization was performed. The patient had a spontaneous abortion 9 days after admission. The right upper and middle lobes of the lung were resected due to continuous bleeding. A subsequent pregnancy was un-eventful. Coccidioidomycosis titers remained negative throughout the second pregnancy. Discussion: This case demonstrates the potential for severe pulmonary coccidioidomycosis and vascular strain of pregnancy-associated vascular expansion in the first trimester of pregnancy and the possibility of a favorable pregnancy outcome in subsequent pregnancies after appropriate treatment. The route of feto-maternal transmission and placental lesions in coccidioidomycosis are discussed. PMID- 29629303 TI - Complete molar pregnancy with transformation to choriocarcinoma of the liver: A case report. AB - Objective: Highlight a complete molar pregnancy with possible complications and pertinent clinical information to aid doctors in recognizing the disease quickly to provide treatment to limit adverse outcomes. Context: Complete molar pregnancy is rare and compromises 1:500-1:2000 pregnancies [1-4]. As technology has improved, the presentation of complete molar pregnancy has changed [1,5-6]. Summary: A 19-year old African American female presented to the emergency room (ER) three times within 14 days for abdominal pain. A pregnancy test was positive and on the third visit quantitative beta-human chorionic gonadotropin (HCG) was elevated without signs of an intrauterine pregnancy (IUP). Dilation and curettage (D&C) was done with small perforation of the uterus. Pathology report indicated a complete molar pregnancy. The patient failed to follow-up and returned to ER 22 days later where an abdominal mass was found prompting surgery. Hematomas and abdominal adhesions were removed and again pathology showed a complete molar pregnancy. Follow-up HCG levels failed to decrease appropriately so the patient was referred to oncology where metastatic choriocarcinoma of the liver was diagnosed. Chemotherapy was initiated and HCG monitored. Patient was readmitted for infections and complications, but did eventually have her HCG return to zero. Data sources: Clinical Key, Purdue Library, and UpToDate were used to search for literature. Conclusion: Prompt recognition of a complete mole may lead to a less extensive disease process. Presentation has recently changed so it is important to know signs. Patient compliance likely results in fewer complications and costs. PMID- 29629304 TI - A case of bladder endometriosis that became symptomatic during the third trimester. AB - Background: The urinary tract endometriosis is observed in 1-2% of the patients and in 90% of these cases, there are endometriotic nodules in the bladder. With respect to knowledge, it is generally believed that pregnancy cures endometriosis. However in this case, symptoms developed during the third trimester of pregnancy. Case report: We report a case of 31 year old, 30 week pregnant woman with a vegetative mass with 33 * 33 * 21 mm dimensions and irregular borders on the posterior wall of the bladder. After the cesarean section, the vegetative and superiorly localized mass on the internal wall of the bladder was excised with partial bladder excision. The patient had no other apparent findings of pelvic endometriosis at operation but the pathology result indicated endometriosis. Conclusion: Although this case shows that endometriosis may become symptomatic during pregnancy, it has to be underlined that it cannot be discerned whether it is consequent to progress of the disease or to pregnancy mediated modifications of a pre-existing lesion. PMID- 29629305 TI - The role of fibrinogen in massive postpartum haemorrhage, a case report. AB - *A G2P1 with a complicated obstetric history of massive postpartum haemorrhage (7 L)*Monitoring of fibrinogen levels during pregnancy and labour*Fibrinogen suppletion resulted in only 2 L blood loss during the third stage of labour.*This case report and literature show that fibrinogen levels might play a role in massive postpartum hemorrhage. PMID- 29629306 TI - Chorioamnionitis due to Lactococcus lactis cremoris: A case report. AB - Lactococcus lactis cremoris is rarely involved in human pathology. A thirty two year old pregnant woman with premature rupture of membrane history presented with chorioamnionitis due to L. lactis cremoris. She underwent an emergency caesarian section and was treated with antibiotics including the association of amoxicillin and clavulanic acid. She was completely recovered. This is the first case to our knowledge of chorioamnionitis due to this organism. PMID- 29629307 TI - Finding a needle in a haystack: Ultrasound guided extraction of a sewing needle from the perineum. AB - *Self-insertion of foreign bodies for sexual gratification is on the rise.*The consequences of foreign bodies insertion can be life-threatening.*Insertion sites of foreign bodies can be difficult to visualize depending on location.*Difficult extractions can be performed in the operating room by a specialist.*Intra operative ultrasound can help in extracting foreign bodies. PMID- 29629308 TI - Discordance for Cri du Chat Syndrome in a dichorionic-diamniotic twin pregnancy. PMID- 29629310 TI - Wound haematoma: The first sign in a case of late postpartum HELLP syndrome. AB - HELLP syndrome, a severe manifestation of preeclampsia characterised by haemolysis, elevated liver enzymes, and thrombocytopaenia, occurs in 0.5-0.9% of pregnancies and is associated with significant maternal and fetal morbidity and mortality. We present the case of a 30 year old primigravida (RL) who developed a wound haematoma nearly 72 h after an emergency caesarean section for failure to progress, with no prior hypertension or proteinuria documented. Although RL remained completely asymptomatic, investigations for delayed bleeding revealed severe class I HELLP syndrome with a platelet count of < 50,000 MUL, significant haemolysis (haptoglobin < 0.06, LDH 1585), acute renal failure (eGFR 64, creatinine 103), fulminant hepatic failure (AST 2539, ALT 3200) and significant autoanticoagulation (INR 3.2, activated prothrombin time 46, fibrinogen 3.0). Paracetamol had been administered for post-operative analgesia and a paracetamol level was in the toxic level. Multidisciplinary input was sought from anaesthetics, intensive care, toxicology, general medicine, haematology and gastroenterology, with care subsequently coordinated in an intensive care unit. Blood pressure was strictly controlled with a sodium nitroprusside infusion. In addition to supportive care, vitamin K, a N-acetyl cysteine infusion, lactulose and mechanical thromboprophylaxis were administered. Eight weeks postpartum there were no residual biochemical abnormalities, the patient was well, and had a normal blood pressure. Our case reinforces the importance of a high level of clinical suspicion for the HELLP syndrome in women, irrespective of blood pressure in the first 48 h postpartum. PMID- 29629309 TI - Ectopic pregnancy after hysterectomy may not be so uncommon: A case report and review of the literature. AB - Background: Ectopic pregnancy after hysterectomy is a very uncommon event, but its frequency is increasing. Since first reported by Wendler in 1895, 71 cases of post-hysterectomy have been reported. Case: A woman, 2 years after an abdominal supracervical hysterectomy, presented with a ruptured fallopian tube ectopic pregnancy. Conclusion: Any woman, even after hysterectomy but with ovaries in situ, who presents with an acute abdomen or abdominal-pelvic pain should be screened for pregnancy. PMID- 29629311 TI - The path of least resistance: A case of cervical stenosis and uterocutaneous fistula. AB - Uterocutaneous fistula is exceedingly rare, and uniformly follows some type of operative procedure. In this case, a young woman underwent a cesarean delivery at an outlying clinic in rural Nigeria, following which she developed amenorrhea and cyclic pelvic pain. In attempts to resolve her condition, a second laparotomy was performed at the same medical center. She presented to us 2 weeks later, at which time an opening was present at the healing laparotomy scar, severe vaginal scarring and cervical stenosis were present, and marked hematometra was seen on ultrasound. Following a procedure to open her cervix, she began menstruating through a fistulous tract in her abdomen, which we subsequently excised and closed with no further problems for the patient. This case highlights the challenge in developing countries of surgical complications resulting from a lack of appropriately trained physicians in rural medical centers. We suggest that focus on excellent training of our young physicians and the creation of incentives to place and keep fully qualified physicians in such hospitals will improve this situation. PMID- 29629312 TI - Migration of a contraceptive subcutaneous device into the pulmonary artery. Report of a case. PMID- 29629313 TI - Successful management of the recurrent uterine rupture after the uterine septum resection. PMID- 29629314 TI - Surgical resection of pancreatic neuroendocrine neoplasm by minimally invasive surgery-the robotic approach? AB - Over the past decade, there has been increasing adoption of minimally invasive pancreatic surgery world-wide and this has naturally expanded to the management of pancreatic neuroendocrine neoplasms (PNENs). More recently, robotic pancreatic surgery (RPS) was introduced to overcome the limitations during laparoscopic pancreatic surgery (LPS). Due to the relative rarity of PNEN and the novelty of minimally invasive pancreatic surgery in particular RPS today, the evidence for robotic surgery in PNENs remains extremely limited. Presently, the available evidence is limited to a few low level retrospective case-control studies. These studies suggest that RPS may be associated with a higher splenic preservation rates and lower open conversion rates compared to conventional laparoscopic surgery. Ideally a prospective randomized trial should be performed but this would be extremely challenging due to the rarity of PNEN, making it almost impossible to conduct a sufficiently powered trial. PMID- 29629315 TI - Surgical resection of neuroendocrine tumors of the pancreas (pNETs) by minimally invasive surgery: the laparoscopic approach. AB - Neuroendocrine tumors of the pancreas (pNETs) are a rare group of neoplasms that originate from the endocrine portion of the pancreas. Tumors that either secrete or do not secrete compounds, resulting in symptoms, can be classified as functioning and non-functioning pNETs, respectively. The prevalence of such tumors has recently increased due to the use of more sensitive imaging techniques, such as multidetector computed tomography, magnetic resonance imaging and endoscopic ultrasound. The biological behavior of pNETs varies widely from indolent, well-differentiated tumors to those that are far more aggressive. The most effective and radical treatment for pNETs is surgical resection. Over the last decade, minimally invasive surgery has been increasingly used in pancreatectomy, with laparoscopic pancreatic surgery (LPS) emerging as an alternative to open pancreatic surgery (OPS) in patients with pNETs. Non comparative studies have shown that LPS is safe and effective. In well-selected groups of patients with pancreatic lesions, LPS was found to results in good perioperative outcomes, including reduced intraoperative blood loss, postoperative pain, time to recovery, and length of hospital stay. Despite the encouraging results of studies from highly specialized centers with extensive experience, no randomized trials to date have conclusively validated these findings. Indications for minimally invasive LPS for patients with pNETs remain unclear. This review presents the current state of LPS for pNETs. PMID- 29629316 TI - Management of functional neuroendocrine tumors of the pancreas. AB - Pancreatic neuroendocrine tumors (pNETs) constitute a heterogenous group of malignancies with varying clinical presentation, tumor biology and prognosis. The incidence of pNETs has steadily increased during the last decades with an estimated incidence 2012 of 4.8/100,000. Recent whole genome sequencing of pNETs has demonstrated mutations in the DNA repair genes MUTYH and point mutations and gene fusions in four main pathways from chromatin remodeling, DNA damage repair, activation of mechanistic target of rapamycin (mTOR) signaling and the telomere maintenance. This new information will be the foundation for new therapies in the near future for malignant pNETs. The functioning pNETs constitute about 30-40% of all pNETs displaying nine different clinical syndromes: insulinoma, Zollinger Ellison, Verner-Morrison, glucagonoma, somatostatinomas, ectopic adrenocorticotropic hormone (ACTH) and parathyroid hormone related peptide (PTH rP) syndromes. Single patients might also present carcinoid syndrome. The diagnostic work-up include histopathology with the new WHO 2017 Classification, biomarkers (CgA, NSE), radiology and molecular imaging including CT-scan, magnetic resonance imaging (MRI), ultrasound and PET-scan. A cornerstone in the treatment of pNETs is surgery which is rarely curative but can reduce the clinical symptoms by debulking which also include radiofrequency ablation, embolization of liver metastases. Medical treatment includes chemotherapy and the targeted agents such as everolimus, sunitinib and peptide receptor radiotherapy (PRRT). Somatostatin analogs has for the last decades been the main stay for management for clinical symptoms related to functioning pNETs and is often combined with new targeted agents as well as chemotherapy. Long-term management of functioning pNETs need a combination of different procedures, surgery, local ablation, targeted agents and somatostatin analogs. Future therapies might be based on the recent advances in molecular genetics and tumor biology. PMID- 29629317 TI - Surgical management of neuroendocrine tumor-associated liver metastases: a review. AB - Liver metastasis is common among patients who suffer from neuroendocrine tumors (NETs). Radical surgery is the standard treatment whenever possible but there is still controversies concerning the treatment strategies such as resection of the primary, role of debulking surgery, liver transplantation (LT) and neoadjuvant or adjuvant therapies. This article aims to review the current evidence available, together with some latest updates, focusing on the surgical management. PMID- 29629318 TI - Role of surgery in pancreatic neuroendocrine tumor. AB - Pancreatic neuroendocrine tumours (PNETs) are rare. They are generally accepted to be slow-growing and have an indolent course. These tumours can be non functioning or functioning, consisting of a biochemically heterogeneous group of tumours including insulinomas, gastrinomas, carcinoids and glucagonomas. Although surgery remains the mainstay of treatment, controversy still exists especially for non-functioning tumours <2 cm in size. Whether these should be resected or undergo intensive surveillance remains unclear. The surgical approach depends on local expertise. Many studies have shown comparable short-term surgical outcome with laparoscopic pancreatic resection compared to open techniques, however data on long-term oncological outcome are still lacking. On the other hand, liver metastasis occurs in as high as 80% of PNET patients. Five-year survival rate is only 30% if left untreated compared to 60-80% if complete resection is achieved. Current evidence supports liver resection with an aim for symptomatic control and to improve survival in those with respectable disease and no extra-hepatic metastasis. Palliative debunking can be considered in those with intractable symptoms. This article reviews the current evidence on pancreatic resection for PNETs, in particular the role of laparoscopic resection and the management of liver metastasis. PMID- 29629319 TI - Liver transplantation for unresectable pancreatic neuroendocrine tumors with liver metastases in an era of transplant oncology. AB - Patients with pancreatic neuroendocrine tumors (pNETs) very often present with a metastatic disease at the first diagnosis. Liver transplantation (LT) for unresectable pNET with liver metastases (pNETLM) has been described to prolong survival in highly selected patients, although outcomes were worse than those of patients who underwent LT for gastrointestinal NETLM (GI-NETLM). In this review, several proposed criteria are described with their rationale and controversies. Most of the data used to establish these criteria do not reflect the recent improvements of non-surgical treatments that has changed the landscape of treatment for pNETs, including the development of peptide receptor radionuclide therapy and molecular-targeted agents (sunitinib and everolimus). Properly designed studies are necessary to define the role of down-staging and bridging therapy prior to LT incorporating systemic chemotherapy using these molecular targeted agents. Also, given the indolent nature of low or intermediate grade pNETs, the best endpoint to compare the efficacy of each treatment option for patients with pNETLM has yet to be determined. Lastly, the definition of "unresectable" remains ambiguous. The indication of the conventional technique of two-staged liver resection with portal vein embolization or the new technique of associating liver partition and portal vein ligation for staged hepatectomy to expand the resectability of wide-spread metastatic liver tumors has been controversial. In an era of transplant oncology, LT should be the last resort for patients who are considered unresectable and otherwise untreatable after an exhaustive multidisciplinary team discussion by all experts in the field. In conclusion, although its long-term outcomes have been promising, the role of LT for unresectable pNETLM as a curative or palliative treatment remains unclear. A well-designed randomized control study is required to elucidate the clinical impact of LT for pNETLM. PMID- 29629321 TI - Laparoscopic distal pancreatectomy for neuroendocrine tumors of the pancreas. AB - The incidence of incidentally discovered nonfunctioning pancreatic neuroendocrine tumors (PNETs) is increasing because of the widespread use of radiologic imaging studies. Due to their mostly small size, PNETs in the body and tail of the pancreas are suited for laparoscopic surgery. This video described our technique of laparoscopic distal pancreatectomy with and without preservation of spleen and splenic vessels for PNET. The decision on preservation of spleen and splenic vessels was made according to the relative location of tumors to the splenic vessels. PMID- 29629320 TI - Combined associating liver partition and portal vein ligation for staged hepatectomy (ALPPS) followed by left trisectionectomy and Whipple operation for PNET. AB - Pancreatic neuroendocrine tumor (PNET) is slow-growing, and account only for 2% of all pancreatic primary tumors. Surgical resection is still the only curative treatment for PNET patients. Unfortunately, most of PNETs was found with unresectable multiple liver metastases and extrahepatic metastasis as their characteristics of non-functional and asymptomatic. With advances in liver surgery in these years, especially combined associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), provide a new curative surgical treatment for PNET with liver metastases patient. Here we report a PNET with multiple liver metastases case underwent ALPPS (followed by left trisectionectomy) and Whipple operation within one-stage. PMID- 29629322 TI - Oral Pathology in Forensic Investigation. AB - Forensic odontology is the subdiscipline of dentistry which analyses dental evidence in the interest of justice. Oral pathology is the subdiscipline of dentistry that deals with the pathology affecting the oral and maxillofacial regions. This subdiscipline is utilized for identification through oral and maxillofacial pathologies with associated syndromes, enamel rod patterns, sex determination using exfoliative cytology, identification from occlusal morphology of teeth, and deoxyribonucleic acid profiling from teeth. This subdiscipline is also utilized for age estimation studies which include Gustafson's method, incremental lines of Retzius, perikymata, natal line formation in teeth, neonatal line, racemization of collagen in dentin, cemental incremental lines, thickness of the cementum, and translucency of dentin. Even though the expertise of an oral pathologist is not taken in forensic investigations, this paper aims to discuss the role of oral pathology in forensic investigation. PMID- 29629323 TI - Anchorage in Orthodontics: Three-dimensional Scanner Input. AB - Aims and Objectives: The aim of this article is to re-evaluate anchorage coefficient values in orthodontics and their influence in the treatment decision through the usage of three-dimensional (3D) scanner. Materials and Methods: A sample of 80 patients was analyzed with the 3D scanner using the C2000 and Cepha 3DT softwares (CIRAD Montpellier, France). Tooth anatomy parameters (linear measurements, root, and crown volumes) were then calculated to determine new anchorage coefficients based on root volume. Data were collected and statistically evaluated with the StatView software (version 5.0). Results: The anchorage coefficient values found in this study are compared to those established in previous studies. These new values affect and modify our approach in orthodontic treatment from the standpoint of anchorage. Conclusion: The use of new anchorage coefficient values has significant clinical implications in conventional and in microimplants-assisted orthodontic mechanics through the selection and delivery of the optimal force system (magnitude and moment) for an adequate biological response. PMID- 29629324 TI - Immunohistochemical Analysis of the Role Connective Tissue Growth Factor in Drug induced Gingival Overgrowth in Response to Phenytoin, Cyclosporine, and Nifedipine. AB - Objective: To evaluate for the presence of connective tissue growth factor (CTGF) in drug (phenytoin, cyclosporine, and nifedipine)-induced gingival overgrowth (DIGO) and to compare it with healthy controls in the absence of overgrowth. Materials and Methods: Thirty-five patients were chosen for the study and segregated into study (25) and control groups (10). The study group consisted of phenytoin-induced (10), cyclosporine-induced (10), and nifedipine-induced (5) gingival overgrowth. After completing necessary medical evaluations, biopsy was done. The tissue samples were fixed in 10% formalin and then immunohistochemically evaluated for the presence of CTGF. The statistical analysis of the values was done using statistical package SPSS PC+ (Statistical Package for the Social Sciences, version 4.01). Results: The outcome of immunohistochemistry shows that DIGO samples express more CTGF than control group and phenytoin expresses more CTGF followed by nifedipine and cyclosporine. Conclusion: The study shows that there is an increase in the levels of CTGF in patients with DIGO in comparison to the control group without any gingival overgrowth. In the study, we compared the levels of CTGF in DIGO induced by three most commonly used drugs phenytoin, cyclosporine, and nifedipine. By comparing the levels of CTGF, we find that cyclosporine induces the production of least amount of CTGF. Therefore, it might be a more viable drug choice with reduced side effects. PMID- 29629325 TI - The Antiplaque Efficacy of Two Herbal-Based Toothpastes: A Clinical Intervention. AB - Aims: This study is the first of its kind in the United Arab Emirates, where these herbal plant extracts are commonly incorporated into toothpaste. The present study compares two herbal toothpastes (Meswak extract and tea tree oil [TTO]) and analyses their efficiency in reducing plaque accumulation. Materials and Methods: A total of 25 patients were examined for plaque and assigned a plaque score. They were then randomly assigned to use either Meswak-based toothpaste or TTO-based toothpaste. After 24 h, a new plaque score was recorded, and the patients used their regular brand for 2 weeks. The patients were then instructed to use the second of the two study toothpastes for 24 h, and a third set of plaque scores was obtained. Statistical data were analyzed using the SPSS software with a significance of P < 0.05 and Kruskal-Wallis test. Results: Analysis of plaque scores showed a reduction in plaque index after using either of the two herbal-based toothpastes; however, when compared with TTO, Meswak based toothpaste resulted in significantly less plaque. Conclusions: Brushing with Meswak-based toothpaste gave a significant drop in plaque score when compared with TTO-based paste. PMID- 29629326 TI - Association of Anxiety with Pain Perception following Periodontal Flap Surgery. AB - Aims and Objectives: Dental pain and anxiety are important factors that prevent patients from seeking dental care. The aim of this study was to assess the relationship between trait anxiety and state anxiety and also to determine the effects of age and sex on pain perception after periodontal flap surgery. Materials and Methods: In this descriptive-analytical study, 50 patients who need periodontal flap surgery were assessed in a private periodontal specialty clinic in Babol city. The amount of anxiety was measured by the Spielberger State-Trait Anxiety Inventory test, and visual analog scale scores were used for postsurgical pain perceptions in 7 times (immediately after surgery and days 1-6 after surgery). Data were analyzed and evaluated by SPSS V22.0 software (IBM, United States). Results: In the trait anxiety study, there was a significant difference in pain perception between different anxiety classes at times immediately after surgery, 1st day, and 2nd day after surgery (P < 0.05), and in the state anxiety study, there was a significant difference in pain perception between different anxiety classes at times immediately after surgery until the 5th day after surgery (P < 0.05). Furthermore, the results indicate that the pain perception in female was significantly higher than male, at times immediately after surgery, 3rd day, and 5th day after surgery (P < 0.05). However, there was no association between age and pain perception in different times (P > 0.05). Conclusions: Anxiety is associated with pain perception following periodontal flap surgery, and female experience more pain after surgery, whereas the amount of pain perception is not related to age. PMID- 29629328 TI - Knowledge, Attitudes, and Practices among Health-Care Providers Regarding Zika Virus Infection. AB - Aims and Objectives: Zika virus (ZIKV) is a mosquito-borne flavivirus that was first identified in Uganda in 1947 in monkeys. The study was designed to assess the knowledge, attitude, and practices regarding ZIKV infection among rural health-care providers in Aligarh district, Uttar Pradesh, India. Materials and Methods: A total of 600 health-care providers were selected through stratified random sampling in an interventional survey. A self-structured, closed-ended questionnaire was administered to each participant in two phases to record their demographic, professional characteristics, knowledge, attitude, and practices regarding ZIKV. Results: Out of 600 health-care workers contacted, 585 (97.5%) agreed to participate in the survey. Multivariable linear regression analysis was carried out to assess the association of participant's professional characteristics with their knowledge, attitude, and practices. Conclusion: It showed that there was a wide gap between the level of awareness, knowledge, and practice among the different categories of health-care providers about the ZIKV. This study revealed that there was a very high probability of the risk of transmission of ZIKAV through health-care settings and hence health-care personnel must strictly adhere to Universal Precautions to prevent it. PMID- 29629327 TI - Fracture Resistance of Ceramic Crowns Supported with Indirect Chair-side Composite Cores. AB - Aims and Objectives: To evaluate the influence of indirect chair-side polymerization of resin composite cores on the fracture resistance of overlaying IPS e.max Press crowns. Materials and Methods: Root canals of 60 extracted premolars were prepared to receive #2 fiber posts after the crowns were sectioned 2 mm above the cervical line. In Groups 1-3 (n = 10 each), posts were luted to the prepared dowel spaces using self-adhesive resin cement. Resin composite cores were then bonded and incrementally built-up using Filtek Z250 XT, Filtek P60, and Filtek P90 resin composites. In Groups 4-6 (n = 10 each), the fabricated post core systems were subjected to post-curing heat and pressure treatment before cementation to their respective teeth using self-adhesive resin cement. Another 10 sound premolars served as control. All teeth in the test and control groups were then subjected to standardized preparation to receive IPS e.max Press crowns before testing their fracture resistance and the mode of restorations' failure. The collected results were statistically analyzed using ANOVA, Kruskal-Wallis, and Tukey's tests on the past software used at alpha = 0.05 to stand on the significance of the detected differences. Results: Significant differences were detected between the fracture resistance of teeth in different groups (ANOVA, P = 2.857E-35). Crowns in Groups 4-6 provided higher fracture resistance than those in Groups 1-3 (Tukey's test, P < 0.05). Crowns in Groups 4 and 6 provided higher fracture resistance than the control, while those in Groups 2 and 3 provided lower fracture resistance than the control (Tukey's test, P < 0.05). Conclusion: Indirect composite cores improved the fracture resistance of IPS e.max Press crowns when compared to directly fabricated post and cores. The directly and indirectly polymerized nanohybrid, methacrylate-based composite (Filtek Z250 XT) cores yielded the highest fracture resistance for the utilized all-ceramic crowns. PMID- 29629329 TI - Relationship between Physicochemical Properties of Saliva and Dental Caries and Periodontal Status among Female Teachers Living in Central Iran. AB - Objectives: There are inconsistent data about the association between saliva properties, dental caries, and periodontal status. In this study, we tried to examine the association between dental caries and periodontal status with salivary viscosity, flow rate, pH, and buffering capacity in adults. Methods: In the present cross-sectional study, 450 female teachers were randomly selected from schools located in Yazd, Iran. Oral examinations were conducted, and unstimulated saliva samples were collected. Salivary viscosity, flow rate, pH, and buffering capacity were assessed. The salivary physicochemical properties were compared among teachers with different types of oral health. Analyses were done using the Statistical Package for the Social Sciences version 16. Results: In total, 431 female teachers aged 40.45 +/- 8.18 years were included in the study. Salivary flow rate, buffering capacity, pH, and viscosity, community periodontal index status were not significantly different in participants with and without tooth caries. There was a reverse linear association between salivary pH and flow rate with the decayed, missed, and filled teeth index (P < 0.05). The saliva buffering capacity was not significantly related to dental properties. Those with bleeding on probing had lower salivary pH, and buffering capacity compared to those with healthy gum. However, the salivary resting flow rate was not different in participants with bleeding on probing and healthy participants. Conclusion: Based on our results, saliva properties might be important predictors in oral health status. This means that any change in saliva combination might affect periodontal and dental diseases. Future prospective studies are recommended to confirm these results. PMID- 29629330 TI - An Evaluation of Shear Bond Strength of Admira (Ormocer) as an Alternative Material for Bonding Orthodontic Brackets: An In vitro Study. AB - Objective: To evaluate shear bond strength (SBS) of Ormocer-bonded orthodontic brackets with self-etching primer (SEP) and conventional adhesive system and also to assess the amount of adhesive remaining on the tooth surface after debonding using adhesive remnant index (ARI). Materials and Methods: The study was done on 90 extracted human upper first permanent maxillary premolars. The study sample was categorized into three groups of 30 each to assess the SBS using three adhesives, Ormocer, SEP, and conventional adhesive system. Following debonding, the surfaces of teeth were examined for residual adhesive remaining by means of the optical stereomicroscope at *50 magnification. ARI (Artun and Bergland) was used to classify the amount of residual adhesive. Obtained data were expressed as mean +/- standard deviation, and obtained data was expressed as mean +/- standard deviation (SD) and statistical analysis was done using one way ANOVA and Mann Whitney U-test [SPSS version 17 statistical package (SPSS Inc., Chicago, IL)]. Results: The mean SBS was maximum in Group I followed by Group II and Group III. The difference in the mean SBS among Group I (8.67 +/- 1.84 Mpa), Group II (7.72 +/- 1.82 MPa) and Group III (6.42 +/- 1.55 MPa) was statistically significant. ARI was maximum in Group I followed by Group II and minimum Group III. Conclusion: Ormocer may be utilized as a substitute to generally used bisphenol A glycidyl methacrylate-based adhesives; however, its effectiveness should be determined clinically by in vivo studies. PMID- 29629331 TI - A Scanning Electron Microscope Evaluation of Smear Layer Removal and Antimicrobial Action of Mixture of Tetracycline, Acid and Detergent, Sodium Hypochlorite, Ethylenediaminetetraacetic Acid, and Chlorhexidine Gluconate: An In vitro Study. AB - Objectives: The main objective is to evaluate the efficiency in removal of smear layer of mixture of tetracycline, acid and detergent (MTAD), sodium hypochlorite (NaOCl), ethylenediaminetetraacetic acid (EDTA) and chlorhexidine gluconate by scanning electron microscope (SEM) evaluation and also to evaluate the antimicrobial action of the same irrigants against standard culture strains of Enterococcus faecalis. Materials and Methods: This study included 60 extracted permanent teeth with single root canal. The sample was categorized into five groups with 12 teeth in each group. Root canals were enlarged till size 40 with K files. One group was kept as control and irrigated only with saline. Other four groups used 5% NaOCl as irrigant during instrumentation and MTAD, 5% NaOCl, 17% EDTA, and 2% chlorhexidine gluconate as final rinse. Teeth were split and examined under SEM. To test the antibacterial action, the zone of inhibition method using agar plates was used. Obtained data were statistically analyzed by SPSS version 17 (SPSS Inc., Chicago, IL, USA). Results: MTAD and 17% EDTA removed smear layer from all regions of the root canals. About 5% NaOCl and 2% chlorhexidine gluconate were ineffective in removing the smear layer. The mean zone of inhibition formed by the irrigants was in the following order; MTAD (40.5 mm), 2% chlorhexidine gluconate (29.375 mm), 17% EDTA (24.125 mm), 5% NaOCl (22.125 mm), and saline (zero). Conclusion: MTAD showed high smear layer removal efficacy, but no significant difference was found to that of 17% EDTA. As the dimensions of the zones of inhibition showed, MTAD has got highest antibacterial action against E. faecalis, followed by 2% chlorhexidine gluconate, 17% EDTA, and 5% NaOCl. However, the exact correlation of in vitro study results to clinical conditions is impossible due to the variables involved. PMID- 29629332 TI - Extent of Awareness Regarding Oral Health and Dental Treatment Needs among Individuals with Hearing and Speech Impairments in Saudi Arabia. AB - Objective: This study aims to evaluate the awareness level of the individuals with hearing and speech impairments (deaf and dumb individuals), in relation to their oral health and dental treatment needs. Materials and Methods: The approach of stratified randomization method of sampling was used for the selection of participants. About 240 people with hearing and speech impairments (deaf and dumb) were selected from four cities of Saudi Arabia, which includes AlKharj, Riyadh, Dammam and Abha. A questionnaire of two sections was distributed among the participants for collecting data. A simple descriptive analysis was done, and the data were expressed in terms of frequencies and percentages. Microsoft Excel has been used for compilation of data and execution of graphs. Moreover, the questionnaire data were subject to SPSS data analysis (IBM SPSS Statistics for Windows, Version 22.0, Armonk, IBM Corp. NY). Results: Most of the participants were not aware of the importance of oral health. Majority of the participants described that they did not visit qualified dentists in the past and many of them did not know the right way of doing tooth brushing. Hence, deaf and dumb individuals lack basic knowledge about oral health and dental treatment needs. Conclusion: The study concluded that the awareness level of oral health and dental treatment needs is low among individuals with hearing and speech impairments (deaf and dumb) in Saudi Arabia. PMID- 29629333 TI - Evaluation of the Knowledge and Attitudes of Dental Students toward Occupational Blood Exposure Accidents at the End of the Dental Training Program. AB - Aims and Objectives: This study was conducted to assess knowledge, attitudes, and behavior regarding occupational blood exposure accidents (OBEA) among dental students at the end of the whole dental education program. Materials and Methods: The survey was performed using a student self-administered questionnaire during July 2015 in the dental teaching hospital in Rabat. It was conducted on 117 dental students registered in the 5th year. The results were analyzed by SPSS Software, Version 13.0. Univariate analysis was performed by descriptive statistics, and bivariate analysis was used to identify correlations between different variables. Results: Eighty-three students answered the questionnaire (participation rate: 70%). Most participants had incomplete knowledge about the management and the risks of OBEA. Thirty-five participants (42%) experienced at least one occupational exposure to patients' blood. Needle recapping has been the main cause of such injuries (41%). Most accidents occurred, respectively, in the oral surgery (51%) and the restorative dentistry (17%) departments. According to many participants, they had received insufficient education concerning this topic. Conclusions: More effective education on prevention and management of OBEA is highly recommended to reduce the prevalence of such injuries. Dental schools should set up a local management unit for following and supporting the exposed students. PMID- 29629334 TI - Surgical Management of Double/Triple Mandibular Fractures Involving the Condylar Segment: Our Perspective. AB - A series of surgical cases operated in our unit are considered to analyze and evaluate the different techniques and sequencing employed in the surgical management of double/triple mandibular fractures involving a condylar fracture. Deviating from the normal sequence of reducing and fixing the dentate segment first, we addressed the condylar segment first. A combination of different approaches for different cases such as a periangular with a vestibular, a preauricular and a retromandibular with a vestibular were used according to the type of fractures. The accessibility to one difficult case with a medially displaced condyle was facilitated by using Hegar's uterine dilators. In all cases, good anatomical reduction was achieved with stable occlusion and without any signs of facial nerve impairment. The 'Condyle first' approach in the surgical management of double/triple mandibular fractures, is a reliable and efficient technique. PMID- 29629335 TI - Intraoperative Radiation "Boost" to the Surgical Resection Bed following Pancreaticoduodenectomy for a Borderline Resectable Pancreatic Carcinoma: A Case Report. AB - Neoadjuvant therapy including chemotherapy alone or concurrent chemotherapy with external bream radiation is a standard treatment strategy for borderline resectable pancreatic adenocarcinoma and is also used routinely for primary operable cancers at some institutions (1). The use of intraoperative radiation therapy (IORT) has been limited largely because of the logistical issues in delivery of radiation during surgery (2). This is the first reported case of a borderline resectable pancreas cancer patient who underwent neoadjuvant chemo radiation therapy followed by resection with the use of IORT using the mobile IntraBeam device to boost the resection bed and improve local control by dose escalation. PMID- 29629336 TI - Deciphering the Dichotomous Effects of PGC-1alpha on Tumorigenesis and Metastasis. AB - Metabolic reprogramming confers cancer cells the ability to grow and survive under nutrient-depleted or stressful microenvironments. The amplification of oncogenes, the loss of tumor suppressors, as well as context- and lineage specific determinants can converge and profoundly affect the metabolic status of cancer cells. Cumulating evidences suggest that highly glycolytic cells under the influence of oncogenes such as BRAF, or evolving in hypoxic microenvironments, will promote metastasis through modulation of multiple steps of tumorigenesis such as the epithelial-to-mesenchymal transition (EMT). On the contrary, increased reliance on mitochondrial respiration is associated with hyperplasic rather than metastatic disease. The PGC-1alpha transcriptional coactivator, a master regulator of mitochondrial biogenesis, has recently been shown to exert antimetastatic effects in cancer, notably through inhibition of EMT. Besides, PGC 1alpha has the opposite role in specific cancer subtypes, in which it appears to provide growth advantages. Thus, the regulation and role of PGC-1alpha in cancer is not univocal, and its use as a prognostic marker appears limited given its highly dynamic nature and its multifaceted regulation by transcriptional and posttranslational mechanisms. Herein, we expose key oncogenic and lineage specific modules that finely regulate PGC-1alpha to promote or dampen the metastatic process. We propose a unifying model based on the systematic analysis of its controversial implication in cancer from cell proliferation to EMT and metastasis. This short review will provide a good understanding of current challenges associated with the study of PGC-1alpha. PMID- 29629337 TI - Novel Therapeutic Targets in Cutaneous Squamous Cell Carcinoma. AB - Cutaneous squamous cell carcinoma (SCC) is one of the common cancers in Caucasians, accounting for 20-30% of cutaneous malignancies. The risk of metastasis is low in most patients; however, aggressive SCC is associated with very high mortality and morbidity. Although cutaneous SCC can be treated with surgical removal, radiation and chemotherapy singly or in combination, the prognosis of patients with metastatic SCC is poor. Recently, the usage of immune checkpoint blockades has come under consideration. To develop effective therapies that are less toxic than existing ones, it is crucial to achieve a detailed characterization of the molecular mechanisms that are involved in cutaneous SCC pathogenesis and to identify new drug targets. Recent studies have identified novel molecules that are associated with SCC carcinogenesis and progression. This review focuses on recent advances in molecular studies involving SCC tumor development, as well as in new therapeutics that have become available to clinicians. PMID- 29629338 TI - Metabolic Symbiosis and Immunomodulation: How Tumor Cell-Derived Lactate May Disturb Innate and Adaptive Immune Responses. AB - The tumor microenvironment (TME) is composed by cellular and non-cellular components. Examples include the following: (i) bone marrow-derived inflammatory cells, (ii) fibroblasts, (iii) blood vessels, (iv) immune cells, and (v) extracellular matrix components. In most cases, this combination of components may result in an inhospitable environment, in which a significant retrenchment in nutrients and oxygen considerably disturbs cell metabolism. Cancer cells are characterized by an enhanced uptake and utilization of glucose, a phenomenon described by Otto Warburg over 90 years ago. One of the main products of this reprogrammed cell metabolism is lactate. "Lactagenic" or lactate-producing cancer cells are characterized by their immunomodulatory properties, since lactate, the end product of the aerobic glycolysis, besides acting as an inducer of cellular signaling phenomena to influence cellular fate, might also play a role as an immunosuppressive metabolite. Over the last 10 years, it has been well accepted that in the TME, the lactate secreted by transformed cells is able to compromise the function and/or assembly of an effective immune response against tumors. Herein, we will discuss recent advances regarding the deleterious effect of high concentrations of lactate on the tumor-infiltrating immune cells, which might characterize an innovative way of understanding the tumor-immune privilege. PMID- 29629340 TI - Enterokinase Enhances Influenza A Virus Infection by Activating Trypsinogen in Human Cell Lines. AB - Cleavage and activation of hemagglutinin (HA) by trypsin-like proteases in influenza A virus (IAV) are essential prerequisites for its successful infection and spread. In host cells, some transmembrane serine proteases such as TMPRSS2, TMPRSS4 and HAT, along with plasmin in the bloodstream, have been reported to cleave the HA precursor (HA0) molecule into its active forms, HA1 and HA2. Some trypsinogens can also enhance IAV proliferation in some cell types (e.g., rat cardiomyoblasts). However, the precise activation mechanism for this process is unclear, because the expression level of the physiological activator of the trypsinogens, the TMPRSS15 enterokinase, is expected to be very low in such cells, with the exception of duodenal cells. Here, we show that at least two variant enterokinases are expressed in various human cell lines, including A549 lung-derived cells. The exogenous expression of these enterokinases was able to enhance the proliferation of IAV in 293T human kidney cells, but the proliferation was reduced by knocking down the endogenous enterokinase in A549 cells. The enterokinase was able to enhance HA processing in the cells, which activated trypsinogen in vitro and in the IAV-infected cells also. Therefore, we conclude that enterokinase plays a role in IAV infection and proliferation by activating trypsinogen to process viral HA in human cell lines. PMID- 29629339 TI - Metabolic Reprogramming in Thyroid Carcinoma. AB - Among all the adaptations of cancer cells, their ability to change metabolism from the oxidative to the glycolytic phenotype is a hallmark called the Warburg effect. Studies on tumor metabolism show that improved glycolysis and glutaminolysis are necessary to maintain rapid cell proliferation, tumor progression, and resistance to cell death. Thyroid neoplasms are common endocrine tumors that are more prevalent in women and elderly individuals. The incidence of thyroid cancer has increased in the Past decades, and recent findings describing the metabolic profiles of thyroid tumors have emerged. Currently, several drugs are in development or clinical trials that target the altered metabolic pathways of tumors are undergoing. We present a review of the metabolic reprogramming in cancerous thyroid tissues with a focus on the factors that promote enhanced glycolysis and the possible identification of promising metabolic targets in thyroid cancer. PMID- 29629341 TI - Role of Curcumin in Disease Prevention and Treatment. AB - Treatment based on traditional medicine is very popular in developing world due to inexpensive properties. Nowadays, several types of preparations based on medicinal plants at different dose have been extensively recognized in the diseases prevention and treatment. In this vista, latest findings support the effect of Curcuma longa and its chief constituents curcumin in a broad range of diseases cure via modulation of physiological and biochemical process. In addition, various studies based on animal mode and clinical trials showed that curcumin does not cause any adverse complications on liver and kidney function and it is safe at high dose. This review article aims at gathering information predominantly on pharmacological activities such as anti-diabetic, anti microbial, hepato-protective activity, anti-inflammatory, and neurodegenerative diseases. PMID- 29629342 TI - Comparison of Preoperative Infusion of Magnesium Sulfate and Mannitol on Intraocular Pressure Changes in Patients Undergoing Phacoemulsification Surgery. AB - Background: The present study has been designed to compare the effect of magnesium sulfate with mannitol on reducing intraocular pressure (IOP). Materials and Methods: During the phacoemulsification surgery, 105 patients randomly divided into three groups receiving 20% mannitol at a dose of 0.3 g/kg, 50% magnesium sulfate at a dose of 20 mg/kg, and placebo (normal saline), with the same volume (100 ml) and infusion time (10 min), were used for the first, second, and third groups, respectively. The IOP was measured before and immediately after the injection and 5 min after the end of the surgery and compared between the groups. Results: The mean IOP immediately after the injection had a significant difference in three groups (mannitol: 15.2 +/- 2.5, magnesium sulfate: 14.7 +/- 1.9, and normal saline: 13.8 +/- 2.8; P = 0.044), and the IOP had a significant difference between normal saline and mannitol groups (0.027) while there was no significant difference between mannitol and magnesium sulfate groups (P = 0.34) and also between magnesium sulfate and normal saline groups (P = 0.2). Conclusion: Using magnesium sulfate had no effect on changes in the IOP and hemodynamic of patients during the surgery. Using mannitol may be effective in reducing IOP while no effect of magnesium sulfate on IOP was found. PMID- 29629343 TI - Identification of Epithelial-Mesenchymal Transition-related Target Genes Induced by the Mutation of Smad3 Linker Phosphorylation. AB - Background: Smad3 linker phosphorylation plays essential roles in tumor progression and metastasis. We have previously reported that the mutation of Smad3 linker phosphorylation sites (Smad3-Erk/Pro-directed kinase site mutant constructs [EPSM]) markedly reduced the tumor progression while increasing the lung metastasis in breast cancer. Methods: We performed high-throughput RNA Sequencing of the human prostate cancer cell lines infected with adenoviral Smad3 EPSM to identify the genes regulated by Smad3-EPSM. Results: In this study, we identified genes which are differentially regulated in the presence of Smad3 EPSM. We first confirmed that Smad3-EPSM strongly enhanced a capability of cell motility and invasiveness as well as the expression of epithelial-mesenchymal transition marker genes, CDH2, SNAI1, and ZEB1 in response to TGF-beta1 in human pancreatic and prostate cancer cell lines. We identified GADD45B, CTGF, and JUNB genes in the expression profiles associated with cell motility and invasiveness induced by the Smad3-EPSM. Conclusions: These results suggested that inhibition of Smad3 linker phosphorylation may enhance cell motility and invasiveness by inducing expression of GADD45B, CTGF, and JUNB genes in various cancers. PMID- 29629344 TI - Esculetin Inhibits the Survival of Human Prostate Cancer Cells by Inducing Apoptosis and Arresting the Cell Cycle. AB - Background: Prostate cancer (PCa) is one of the most important causes of death in men and thus new therapeutic approaches are needed. In this study, antiproliferative and anti-migration properties of a coumarin derivative esculetin were evaluated. Methods: Human PCa cell lines PC3, DU145, and LNCaP were treated with various concentrations of esculetin for 24 to 72 hours, and cell viability was determined by the MTT test. Cell cycle and apoptosis were analyzed by using cell-based cytometer. Gene expression levels were assessed by reverse transcription and quantitative real-time PCR, cell migration was determined by the wound healing assay. The protein expression was measured by Western blotting. Results: Esculetin inhibited cell proliferation in a dose- and time-dependent manner. Cell migration was inhibited by esculetin treatment. Administration of esculetin significantly reduced the cells survival, induced apoptosis and caused the G1 phase cell cycle arrest shown by image-based cytometer. The induced expression of cytochrome c, p53, p21 and p27, and down regulated CDK2 and CDK4 may be the underlying molecular mechanisms of esculetin effect. Esculetin suppressed phosphorylation of Akt and enhanced protein expression of tumor-suppressor phosphatase and tensin homologue. Conclusions: Our findings showed that the coumarin derivative esculetin could be used in the management of PCa. However, further in vivo research is needed. PMID- 29629345 TI - Comparative Effects of Curcumin and Tetrahydrocurcumin on Dextran Sulfate Sodium induced Colitis and Inflammatory Signaling in Mice. AB - Background: Curcumin, a yellow ingredient of turmeric (Curcuma longa Linn, Zingiberaceae), has long been used in traditional folk medicine in the management of inflammatory disorders. Although curcumin has been reported to inhibit experimentally-induced colitis and carcinogenesis, the underlying molecular mechanisms remain largely unresolved. Methods: Murine colitis was induced by dextran sulfate sodium (DSS) which mimics inflammatory bowel disease. Curcumin or tetrahydrocurcumin was given orally (0.1 or 0.25 mmol/kg body weight daily) for 7 days before and together with DSS administration (3% in tap water). Collected colon tissue was used for histologic and biochemical analyses. Results: Administration of curcumin significantly attenuated the severity of DSS-induced colitis and the activation of NF-kappaB and STAT3 as well as expression of COX-2 and inducible nitric oxide synthase. In contrast to curcumin, its non electrophilic analogue, tetrahydrocurcumin has much weaker inhibitory effects. Conclusions: Intragastric administration of curcumin inhibited the experimentally induced murine colitis, which was associated with inhibition of pro-inflammatory signaling mediated by NF-kappaB and STAT3. PMID- 29629347 TI - beta-Carotene Inhibits Activation of NF-kappaB, Activator Protein-1, and STAT3 and Regulates Abnormal Expression of Some Adipokines in 3T3-L1 Adipocytes. AB - Background: Oxidative stress occurs in white adipose tissue and dysregulates the expression of adipokines secreted from adipocytes. Since adipokines influence inflammation, supplementation with antioxidants might be beneficial for preventing oxidative stress-mediated inflammation in adipocytes and inflammation associated complications. beta-Carotene is the most prominent antioxidant carotenoid and scavenges reactive oxygen species in various tissues. The purpose of this study was to determine whether beta-carotene regulates the expression of adipokines, such as adiponectin, monocyte chemoattractant protein-1 (MCP-1), and regulated on activation, normal T cell expressed and secreted (RANTES) in 3T3-L1 adipocytes treated with glucose/glucose oxidase (G/GO). Methods: 3T3-L1 adipocytes were cultured with or without beta-carotene and treated with G/GO, which produces H2O2. mRNA and protein levels in the medium were determined by a real-time PCR and an ELISA. DNA binding activities of transcription factors were assessed using an electrophoretic mobility shift assay. Results: G/GO treatment increased DNA binding affinities of redox-sensitive transcription factors, such as NF-kappaB, activator protein-1 (AP-1), and STAT3. G/GO treatment reduced the expression of adiponectin and increased the expression of MCP-1 and RANTES. G/GO induced activations of NF-kappaB, AP-1, and STAT3 were inhibited by beta carotene. G/GO-induced dysregulation of adiponectin, MCP-1, and RANTES were significantly recovered by treatment with beta-carotene. Conclusions: beta Carotene inhibits oxidative stress-induced inflammation by suppressing pro inflammatory adipokines MCP-1 and RANTES, and by enhancing adiponectin in adipocytes. beta-Carotene may be beneficial for preventing oxidative stress mediated inflammation, which is related to adipokine dysfunction. PMID- 29629346 TI - Lycopene Protects Against Spontaneous Ovarian Cancer Formation in Laying Hens. AB - Background: Dietary intake of lycopene has been associated with a reduced risk of ovarian cancer, suggesting its chemopreventive potential against ovarian carcinogenesis. Lycopene's molecular mechanisms of action in ovarian cancer have not been fully understood. Therefore, in the present study, we investigated the effects of lycopene on the ovarian cancer formation using the laying hen model, a biologically relevant animal model of spontaneous ovarian carcinogenesis due to high incidence rates similar to humans. Methods: In this study, a total of 150 laying hens at age of 102 weeks were randomized into groups of 50: a control group (0 mg of lycopene per kg of diet) and two treatment groups (200 mg or 400 mg of lycopene per kg of diet, or ~26 and 52 mg/d/hen, respectively). At the end of 12 months, blood, ovarian tissues and tumors were collected. Results: We observed that lycopene supplementation significantly reduced the overall ovarian tumor incidence (P < 0.01) as well as the number and the size of the tumors (P < 0.004 and P < 0.005, respectively). Lycopene also significantly decreased the rate of adenocarcinoma, including serous and mucinous subtypes (P < 0.006). Moreover, we also found that the serum level of oxidative stress marker malondialdehyde was significantly lower in lycopene-fed hens compared to control birds (P < 0.001). Molecular analysis of the ovarian tumors revealed that lycopene reduced the expression of NF-kappaB while increasing the expression of nuclear factor erythroid 2 and its major target protein, heme oxygenase 1. In addition, lycopene supplementation decreased the expression of STAT3 by inducing the protein inhibitor of activated STAT3 expression in the ovarian tissues. Conclusions: Taken together, our findings strongly support the potential of lycopene in the chemoprevention of ovarian cancer through antioxidant and anti inflammatory mechanisms. PMID- 29629348 TI - Why Don't Cancer Survivors Quit Smoking? An Evaluation of Readiness for Smoking Cessation in Cancer Survivors. AB - Background: Cancer survivors have a high rate of participation in cigarette smoking cessation programs but their smoking-abstinence rates remain low. In the current study, we evaluated the readiness to quit smoking in a cancer-survivor population. Methods: Cross-sectional data survey conducted among 112 adult cancer survivors who smoked cigarettes in Tennessee. Analyses were conducted using a two sample t-test, chi2 test, Fishers Exact test, and multivariable logistic regression with smoker's readiness to quit as the dependent variable. We operationally defined a smoker not ready to quit as anyone interested in quitting smoking beyond the next 6 months or longer (or not at all), as compared to those that are ready to quit within the next 6 months. Results: Thirty-three percent of participants displayed a readiness to quit smoking in the next 30 days. Smokers ready to quit were more likely to display high confidence in their ability to quit (OR = 4.6; 95% CI, 2.1-9.7; P < 0.0001) than those not ready to quit. Those ready to quit were nearly five times more likely to believe smoking contributed to their cancer diagnosis (OR = 4.9; 95% CI, 1.1-22.6; P = 0.0432). Those ready to quit were also much more likely to attempt smoking cessation when diagnosed with cancer (OR = 8.9; 95% CI, 1.8-44.3; P = 0.0076) than smokers not ready to quit. Finally, those ready to quit were more likely to endorse smoking more in the morning than other times of the day, compared to those not ready to quit (OR = 7.9; 95% CI, 1.5-42,3; P = 0.0148), which increased odds of readiness to quit within the next 6 months. Conclusions: Despite high participation in smoking cessation programs for cancer survivors, only one-third of participants were ready to quit. Future research is needed to develop programs targeting effective strategies promoting smoking cessation among cancer survivors who are both ready and not ready to quit smoking. PMID- 29629349 TI - Knowledge and Source of Information About Early Detection Techniques of Breast Cancer Among Women in Iran: A Systematic Review. AB - Background: An increase of access to knowledge about early detection techniques of breast cancer can reduce this mortality rate. This study aimed to determine the knowledge and source of information about early detection techniques of breast cancer among Iranian women. Methods: Both International (PubMed, Web of Science, and Google Scholar) and national (scientific information database [SID] and Magiran) databases were reviewed launching to September, 2017 to obtain related articles. Steps involving the screening, analysis of quality of the studies and extraction of papers were performed by two researchers. Results: Of the 749 studies searched initially, 25 studies performed on 11,756 people were selected for the final stage. General knowledge for breast cancer screening among women ranged from 4.5% to 45%. The number of people with sufficient knowledge about breast self-examination in various studies was between 5% and 79.8%. The most important source of information was the Healthcare team. Conclusions: Considering the poor knowledge and different source of information, it is suggested that educational programs be conducted around the country especially in at-risk populations. PMID- 29629350 TI - Is the "ghost surgery" the subject of legal punishment in Korea? AB - Purpose: Recently a controversy has arisen about so-called "ghost surgery" practices, and people have voiced their opinions for legal sanction against such practices, which clearly undermine the foundation of medical ethics. However, there has been a lack of legal basis for punishing those actions. The present study aims to examine which pre-existing legal provisions could be applied to regulate ghost surgery. Methods: The Korean Medical Service Act has a provision relating to informed consent to inhibit ghost surgery but does not include penalty provisions prohibiting ghost surgery itself. Also, the Korean Supreme Court precedents on this issue have not been settled as of yet. Therefore, this study referred to U.S precedents, law books, and related papers. Results: With respect to ghost surgery, we expect the charges of bodily harm, assault and battery, and fraud could be applied under Korean law, in addition to charges regarding the violation of medical law, such as the omission of entries or false entries in medical records. A patient provides consent to bodily harm prior to surgery, and only the person who is entrusted with such permission can become the operating surgeon in the operating room. Conclusion: In other words, even if other medical professionals are present in the operating room, the operating surgeon who received consent must take overall responsibility for the whole process of the surgery. A surgeon should bear in mind that a violation of such duty can constitute a criminal offense. PMID- 29629351 TI - Evaluation of prophylactic and therapeutic effects of ruscogenin on acute radiation proctitis: an experimental rat model. AB - Purpose: Radiation proctitis (RP) is inflammation and damage to the rectum, manifested secondary to ionizing radiation utilized for treatment. In this study, we evaluated the anti-inflammatory therapeutical and protective effects of ruscogenin in a model of acute RP. Methods: Thirty-two Sprague-Dawley rats were divided into 4 groups (n = 8) as sham, control, treatment, and prophylaxis groups. Prophylaxis group and treatment group were dosed ruscogenin by oral gavage for 14 days pre- and postradiation. At the end of the 28th day, all subjects were sacrificed. Results: Histopathological analysis showed a significant increase in cryptitis abscess, cryptitis and reactive atypia, and depth of lymphocytic infiltration of the control group, compared to the other groups (P < 0.05), while treatment and prophylaxis groups showed significant decreases (P < 0.05). Immunohistochemical analysis indicated that immunoreactivity were significantly higher in control group (P < 0.05, P < 0.001, and P < 0.01, respectively), but vice versa for treatment and prophylaxis groups. There was not any significant difference for fibroblast growth factor 2 immunoreactivity. The epithelium of control rectums indicated an increase in TNF alpha immunoreactivity while other groups had significant decrease (P < 0.01). Electron microscopical findings were parallel to light microscopy. Conclusion: In this study, ruscogenin was observed to be effective on prophylaxis or treatment of acute RP. Although there are various reports on the treatment of the rectum damaged by acute RP in the literature, this could be the first study since there is no research indicating the ultrastructural effect of ruscogenin. PMID- 29629352 TI - Prognosis of preoperative positron emission tomography uptake in hepatectomy patients. AB - Purpose: Preoperative F-18-fluoro-2-deoxy-glucose positron emission tomography (18F-FDG PET) imaging results appear to predict tumor recurrence and patient survival. The present study compared outcomes between PET-positive and PET negative groups with HBV-related hepatocellular carcinoma (HCC) who underwent curative hepatectomy and assessed the prognostic value of positive PET-CT for HCC recurrence and death. Methods: This study included patients who underwent liver resection of solitary HCC between 2007 and 2014 based on preoperative radiological images. There were 133 patients in the PET-positive group and 93 in the PET-negative group. Results: There were no statistically significant differences in baseline, perioperative, or pathologic characteristics between the 2 groups except HBsAg titer, tumor size, and presence of bile duct tumor thrombi. Multivariate analysis showed that tumor size >3.5 cm and HBsAg titer >1,000 cutoff index were predisposing factors of positive PET-CT. Disease-free survival and overall survival rate at 1, 3, and 5 years were 76.3%, 64.4%, 60.3% and 96.8%, 91.1%, 85.1% in the PET-negative group, respectively, compared with 70.7%, 62.2%, 58.9% and 98.5%, 97.0%, 97.0% in the PET-positive group (P = 0.547 and P = 0.046). Multivariate analysis showed that positive PET-CT was closely associated with increased patient survival, but was not related to HCC recurrence. Conclusion: These results suggest that positive PET findings are not a predisposing factor for recurrence of HBV-related HCC patients, but appear to be associated with improved patient survival. Further prospective studies are needed to confirm the prognostic value of 18F-FDG PET in these patients. PMID- 29629353 TI - Comparison of surgical outcomes of intracorporeal hepaticojejunostomy in the excision of choledochal cysts using laparoscopic versus robot techniques. AB - Purpose: Increasing surgical expertise in minimally invasive surgery has allowed laparoscopic surgery to be performed in many abdominal surgeries. Laparoscopic choledochal cyst excision and Roux-en-Y hepaticojejunostomy are challenging and sophisticated surgeries because of the difficult anastomosis. Recent advances in robotic surgery have enabled more delicate and precise movements, and Endowrist instruments allow for securing sutures during anastomosis. This study aimed to compare surgical outcomes of laparoscopic and robotic hepaticojejunostomy in choledochal cyst excision. Methods: Sixty-seven patients who underwent laparoscopic or robotic-hybrid choledochal cyst excision from 2004 to 2016 were retrospectively analyzed and compared. In robotic surgery, dissection was performed laparoscopically, and hepaticojejunostomy was performed using a robotic platform. Results: The mean operative time was significantly longer in robotic surgery than in laparoscopic surgery (247.94 +/- 54.14 minutes vs. 181.31 +/- 43.06 minutes, P < 0.05). The mean estimated blood loss (108.71 +/- 15.53 mL vs. 172.78 +/- 117.46 mL, respectively, P = 0.097) and postoperative hospital stay (7.33 +/- 2.96 days vs. 6.22 +/- 1.06 days, P = 0.128) were comparable between procedures. Compared to the laparoscopic approaches, robotic surgery had significantly less short-term complications (22.4% vs. 0%, P = 0.029). There were more biliary leakage (n = 7, 14.3%) observed during the first 30 days after surgery in laparoscopy while none were observed in the robotic method. Conclusion: Robotic surgery allow for more precise and secure sutures during anastomosis thereby reducing biliary complications. With expanding knowledge and expertise, robotic surgery may offer more advantages over laparoscopy in the era of minimally invasive surgery. PMID- 29629354 TI - Analysis of reduced-dose administration of oxaliplatin as adjuvant FOLFOX chemotherapy for colorectal cancer. AB - Purpose: An oxaliplatin-based regimen is the most common adjuvant chemotherapy for patients with stage II/III colorectal cancer, but many patients experience dose reduction or early termination of chemotherapy due to side effects. We conducted this study to verify the range of reduction with oncologic safety. Methods: Patients with stage II/III colorectal cancer who received adjuvant FOLFOX chemotherapy were enrolled in this study. The total amount of oxaliplatin administered per patient was calculated as a percentile based on 12 cycles of full-dose FOLFOX as a standard dose. The cutoff values showing significant differences in survival were calculated, and the clinicopathologic outcomes of patient groups classified by the value were compared. Results: Among a total of 611 patients, there were 107 stage II patients, and 504 stage III patients. At 60% of the standard dose of oxaliplatin, the patients in the dose reduction group were older (62 years vs. 58 years, P = 0.003), had lower body mass index (BMI) (23.1 kg/m2vs. 24.0 kg/m2, P = 0.005), and were more exposed to neoadjuvant treatment (18.0% vs. 9.1%, P = 0.003) in comparison to the standard group. At 60% of the standard dose, there were no significant differences in 5-year disease free survival (DFS) and overall survival (OS) between the 2 groups (5-year DFS: 73.5% vs. 74.2%, P = 0.519; 5-year OS: 71.9% vs. 81.5%, P = 0.256, respectively). Conclusion: Patients with old age, low BMI, and more frequent exposure to neoadjuvant treatment tended to show lower compliance with chemotherapy. More than 60% dose should be administered to patients with stage II/III colorectal cancer as adjuvant chemotherapy to achieve acceptable oncologic outcomes. PMID- 29629355 TI - Risk factors of stoma re-creation after closure of diverting ileostomy in patients with rectal cancer who underwent low anterior resection or intersphincteric resection with loop ileostomy. AB - Purpose: The aim of this study was to identify the risk factors of stoma re creation after closure of diverting ileostomy in patients with rectal cancer who underwent low anterior resection (LAR) or intersphincteric resection (ISR) with loop ileostomy. Methods: We retrospectively reviewed 520 consecutive patients with rectal cancer who underwent LAR or ISR with loop ileostomy from January 2005 to December 2014 at Chonnam National University Hwasun Hospital. Risk factors for stoma re-creation after ileostomy closure were evaluated. Results: Among 520 patients with rectal cancer who underwent LAR or ISR with loop ileostomy, 458 patients underwent stoma closure. Among these patients, 45 (9.8%) underwent stoma re-creation. The median period between primary surgery and stoma closure was 5.5 months (range, 0.5-78.3 months), and the median period between closure and re creation was 6.8 months (range, 0-71.5 months). Stoma re-creation was performed because of anastomosis-related complications (26, 57.8%), local recurrence (15, 33.3%), and anal sphincter dysfunction (3, 6.7%). Multivariate analysis showed that independent risk factors for stoma re-creation were anastomotic leakage (odds ratio [OR], 4.258; 95% confidence interval [CI], 1.814-9.993), postoperative radiotherapy (OR, 3.947; 95% CI, 1.624-9.594), and ISR (OR, 3.293; 95% CI, 1.462-7.417). Conclusion: Anastomotic leakage, postoperative radiotherapy, and ISR were independent risk factors for stoma re-creation after closure of ileostomy in patients with rectal cancer. PMID- 29629356 TI - Feasibility and oncologic safety of low ligation of inferior mesenteric artery with D3 dissection in cT3N0M0 sigmoid colon cancer. AB - Purpose: There is no standard consensus for the ligation level of the inferior mesenteric artery during radical resection of sigmoid colon cancer. Especially, there is little research about low ligation combined with D3 dissection. The study was performed to compare feasibility and oncologic safety between low ligation with D3 dissection to high ligation in intermediately advanced sigmoid colon cancer. Methods: From January 2008 to December 2013, 134 patients who underwent radical surgery for cT3N0M0 sigmoid colon cancer were evaluated retrospectively. Clinicopathologic factors and oncologic outcomes of high ligation (HL, n = 51) and low ligation (LL, n = 83) groups were compared. Results: The mean operative time was significantly shorter in LL, and there was no difference in complications, distal margin or number of retrieved lymph node. The tumor size was significantly larger in HL, but there was no difference in number of metastatic lymph node, pT or pN stage. There was no difference in overall survival, disease-free survival, or local and systemic recurrence. Conclusion: In cT3N0M0 sigmoid colon cancers, we suggest that low ligation with D3 dissection can be performed with feasibility and oncological safety. PMID- 29629357 TI - Living donor liver transplantation prior to multiple myeloma treatment in a patient with hepatitis B-associated hepatocellular carcinoma and liver cirrhosis: a case report. AB - Clinical outcomes of living donor liver transplantation (LDLT) for hepatocellular carcinoma (HCC) in patients with multiple myeloma (MM) have not been established in terms of HCC recurrence and MM deterioration after LDLT. A 51-year-old man with chronic hepatitis B was diagnosed with HCC and MM. Since the patient also had decompensated liver cirrhosis (LC), he underwent LDLT prior to autologous peripheral blood stem cell transplantation (PBSCT) to prevent fulminant hepatitis due to HBV reactivation. The patient received Epstein-Barr virus prophylaxis and a triple immunosuppressive regimen of tacrolimus, everolimus, and steroid after LDLT. Autologous PBSCT was performed 7 months after LDLT. He showed a complete response to treatment of MM without post-LT complications or HCC recurrence. In conclusion, LDLT could be adapted for treatment of MM patients with combined HCC and decompensated LC because it is an effective strategy of preventing HBV reactivation and HCC recurrence after induction therapy of MM. PMID- 29629358 TI - Successful use of VenaSeal system for the treatment of large great saphenous vein of 2.84-cm diameter. AB - Cyanoacrylate closure, VenaSeal system, for the treatment of incompetent saphenous vein is a new technique. We report a successful case with a large great saphenous vein of 2.84 cm in diameter. PMID- 29629359 TI - Extended-Duration Treatment of Superficial Vein Thrombosis of the Lower Limbs with Tinzaparin. AB - Purpose: To identify risk factors for recurrent thromboembolic events (RTEs) and define the optimum duration of treatment with tinzaparin in patients with superficial vein thrombosis (SVT) of the lower limbs. Materials and Methods: A total of 147 consecutive patients with significant SVT were treated with subcutaneously administered tinzaparin. The composite primary endpoint of the study was RTE, deep-vein thrombosis (DVT) and/or pulmonary embolism (PE) at 120 days. Patients were stratified into group A, where patients received a variable dose of tinzaparin for up to 60 days (n=98), and a subsequent group B-ext, where patients received a standardized intermediate dose of tinzaparin (n=49) for 90 days. Results: RTEs occurred in 15/147 patients (10.2%), including recurrent SVT (n=10), DVT (n=4) and fatal PE (n=1). RTEs were less frequent in group B-ext (0% vs. 15.3% for group A, P=0.004), a difference that remained significant at the one-year follow-up. Clinically extensive SVT was an independent predictor for RTEs (hazard ratio, 5.94; 95% confidence interval, 2.05-17.23; P=0.001, Cox regression). Predictors or DVT or PE in group A included clinically extensive SVT (P=0.004), absence of local pain (P=0.023) and the ultrasound findings of superficial axial vein thrombosis (any, P=0.006 or isolated, P=0.036) and multiple thrombosed superficial venous sites (P<0.001). Conclusion: An extended three-month regimen of tinzaparin in patients with SVT of the lower limbs is more effective than a shorter course and may be desirable in patients with risk factors. PMID- 29629360 TI - Adventitial Cystic Disease of the Iliac Artery with a Connection to the Hip Joint. AB - More than 700 adventitial cystic diseases (ACDs) have been reported in the literature, with most cases affecting the popliteal artery in young men. Here, we describe our treatment and etiologic consideration of a patient who presented with an ACD of the external iliac artery, known to be an extremely rare location. On preoperative imaging, the ACD had a connection to the nearby hip joint and was treated with resection of the affected segment, including ligation of the joint connection and interposition with a prosthetic graft. The pathogenesis of ACDs is not fully understood; however, we believe that joint connections are important in their development and treatment. PMID- 29629361 TI - Complications of Port-A-Caths in Children with Hematologic/Oncologic Diseases. PMID- 29629362 TI - Chronic Cerebro-Spinal Venous Insufficiency in Multiple Sclerosis: Is It the End? PMID- 29629363 TI - Pediatric Vital Sign Distribution Derived From a Multi-Centered Emergency Department Database. AB - Background: We hypothesized that current vital sign thresholds used in pediatric emergency department (ED) screening tools do not reflect observed vital signs in this population. We analyzed a large multi-centered database to develop heart rate (HR) and respiratory rate centile rankings and z-scores that could be incorporated into electronic health record ED screening tools and we compared our derived centiles to previously published centiles and Pediatric Advanced Life Support (PALS) vital sign thresholds. Methods: Initial HR and respiratory rate data entered into the CernerTM electronic health record at 169 participating hospitals' ED over 5 years (2009 through 2013) as part of routine care were analyzed. Analysis was restricted to non-admitted children (0 to <18 years). Centile curves and z-scores were developed using generalized additive models for location, scale, and shape. A split-sample validation using two-thirds of the sample was compared with the remaining one-third. Centile values were compared with results from previous studies and guidelines. Results: HR and RR centiles and z-scores were determined from ~1.2 million records. Empirical 95th centiles for HR and respiratory rate were higher than previously published results and both deviated from PALS guideline recommendations. Conclusion: Heart and respiratory rate centiles derived from a large real-world non-hospitalized ED pediatric population can inform the modification of electronic and paper-based screening tools to stratify children by the degree of deviation from normal for age rather than dichotomizing children into groups having "normal" versus "abnormal" vital signs. Furthermore, these centiles also may be useful in paper based screening tools and bedside alarm limits for children in areas other than the ED and may establish improved alarm limits for bedside monitors. PMID- 29629364 TI - Assessment of Sensory Processing and Executive Functions in Childhood: Development, Reliability, and Validity of the EPYFEI. AB - The aim of this study was to determine the psychometric properties of the "Assessment of Sensory Processing and Executive Functions in Childhood" (EPYFEI), a questionnaire designed to assess the sensory processing and executive functions of children aged between 3 and 11 years. The EPYFEI was completed by a sample of 1,732 parents of children aged between 3 and 11 years who lived in Spain. An exploratory factor analysis was conducted and showed five main factors: (1) executive attention, working memory, and initiation of actions; (2) general sensory processing; (3) emotional and behavioral self-regulation; (4) supervision, correction of actions, and problem solving; and (5) inhibitory. The reliability of the analysis was high both for the whole questionnaire and for the factors it is composed of. Results provide evidence of the potential usefulness of the EPYFEI in clinical contexts for the early detection of neurodevelopmental disorders, in which there may be a deficit of executive functions and sensory processing. PMID- 29629365 TI - Physiotherapy in Bangladesh: Inequality Begets Inequality. AB - Background: The demand for health services in developing countries often outweighs provision. This article describes the present condition of physiotherapy in Bangladesh. Physiotherapy is not recognized as a profession by the government. There is no single registration and regulation body. The health related and economic benefits of physiotherapy are not felt by the majority of Bangladeshi citizens. Areas covered: The burden of disease is changing, and Bangladesh needs a profession that specializes in physical rehabilitation to face these challenges. This article outlines the benefits to patients and the wider economy from a broad physiotherapy regime for all Bangladeshi citizens. It describes the many barriers the profession faces. Conclusion: Physiotherapy is efficacious in many post-trauma situations and long-term conditions. Economic evidence supports the provision physiotherapy as a cost-effective treatment which should be considered as part of the provision of a universal health-care service. Official recognition of the protected "physiotherapist" title and a single registration and regulation agency are recommended. PMID- 29629366 TI - Comparing the Cost-Effectiveness of Campaigns Delivered via Various Combinations of Television and Online Media. AB - Background: Reflecting the increasing prevalence of online media, many mass media health campaigns are now delivered using both television (TV) and online media formats. The aim of this study was to evaluate a smoking cessation mass media campaign according to the cost-effectiveness of the various combinations of TV and online media formats to inform future media buying decisions. Methods: A quasi-experimental interrupted time series approach was employed. The campaign was delivered in seven 1-week bursts using TV, online video (OV), or online display (OD) (e.g., banner ads) formats in isolation and in various combinations over a 13-week period. Campaign bursts were separated by "off-weeks" in which no campaign materials were delivered. Assessed outcomes were the number of campaign response "events" recorded (campaign web page views, calls to a smoking cessation telephone service, and registrations for smoking cessation services). The cost effectiveness of each individual and combined media format condition in terms of these outcome variables was calculated using attributed production and broadcasting costs. Results: Overall, OD alone was found to be the most cost effective means of achieving the nominated campaign outcomes, followed by a combination of OV and OD and a combination of TV and OV. The use of TV in isolation was the least cost-effective. Conclusion: The results of this evaluation indicate that online media constitute a promising means of enhancing the cost-effectiveness of smoking cessation campaigns. Future research assessing a broader range of outcomes, especially smoking cessation, is needed to provide a more comprehensive account of the cost-effectiveness of various campaign media. PMID- 29629367 TI - Perspectives from the Third International Summit on Medical Nutrition Education and Research. AB - Nutrition is an important component of public health and health care, including in education and research, and in the areas of policy and practice. This statement was the overarching message during the third annual International Summit on Medical Nutrition Education and Research, held at Wolfson College, University of Cambridge, United Kingdom, in August 2017. This summit encouraged attendees to think more broadly about the impact of nutrition policy on health and communities, including the need to visualize the complete food system from "pre-farm to post-fork." Evidence of health issues related to food and nutrition were presented, including the need for translation of knowledge into policy and practice. Methods for this translation included the use of implementation and behavior change techniques, recognizing the needs of health-care professionals, policy makers, and the public. In all areas of nutrition and health, clear and effective messages, supported by open data, information, and actionable knowledge, are also needed along with strong measures of impact centered on an ultimate goal: to improve nutritional health and wellbeing for patients and the public. PMID- 29629368 TI - Tracking of Short Distance Transport Pathways in Biological Tissues by Ultra Small Nanoparticles. AB - In this work, ultra-small europium-doped HfO2 nanoparticles were infiltrated into native wood and used as trackers for studying penetrability and diffusion pathways in the hierarchical wood structure. The high electron density, laser induced luminescence, and crystallinity of these particles allowed for a complementary detection of the particles in the cellular tissue. Confocal Raman microscopy and high-resolution synchrotron scanning wide-angle X-ray scattering (WAXS) measurements were used to detect the infiltrated particles in the native wood cell walls. This approach allows for simultaneously obtaining chemical information of the probed biological tissue and the spatial distribution of the integrated particles. The in-depth information about particle distribution in the complex wood structure can be used for revealing transport pathways in plant tissues, but also for gaining better understanding of modification treatments of plant scaffolds aiming at novel functionalized materials. PMID- 29629369 TI - Discovery of C-3 Tethered 2-oxo-benzo[1,4]oxazines as Potent Antioxidants: Bio Inspired Based Design, Synthesis, Biological Evaluation, Cytotoxic, and in Silico Molecular Docking Studies. AB - The discovery of C-3 tethered 2-oxo-benzo[1,4]oxazines as potent antioxidants is disclosed. All the analogs 20a-20ab have been synthesized via "on water" ultrasound-assisted irradiation conditions in excellent yields (upto 98%). All the compounds have been evaluated for their in vitro antioxidant activities using DPPH free radical scavenging assay as well as FRAP assay. The result showed promising antioxidant activities having IC50 values in the range of 4.74 +/- 0.08 to 92.20 +/- 1.54 MUg/mL taking ascorbic acid (IC50 = 4.57 MUg/mL) as standard reference. In this study, compounds 20b and 20t, the most active compound of the series, showed IC50 values of 6.89 +/- 0.07 MUg/mL and 4.74 +/- 0.08 MUg/mL, respectively in comparison with ascorbic acid. In addition, the detailed SAR study shows that electron-withdrawing group increases antioxidant activity and vice versa. Furthermore, in the FRAP assay, eight compounds (20c, 20j, 20m, 20n, 20r, 20u, 20z, and 20aa) were found more potent than standard reference BHT (C0.5FRAP = 546.0 +/- 13.6 MUM). The preliminary cytotoxic study reveals the non toxic nature of active compounds 20b and 20t in non-cancerous 3T3 fibroblast cell lines in MTT assay up to 250 MUg/mL concentration. The results were validated via carrying out in silico molecular docking studies of promising compounds 20a, 20b, and 20t in comparison with standard reference. To the best of our knowledge, this is the first detailed study of C-3 tethered 2-oxo-benzo[1,4]oxazines as potential antioxidant agents. PMID- 29629370 TI - Effect of Co-presentation of Adhesive Ligands and Short Hyaluronan on Lymphendothelial Cells. AB - Controlled activation of lymphangiogenesis through functional biomaterials represents a promising approach to support wound healing after surgical procedures, yet remains a challenge. In a synthetic biological approach, we therefore set out to mimic the basal microenvironment of human primary dermal lymphatic endothelial cells (LECs) during lymphangiogenesis. As the extracellular matrix component hyaluronan (HA) regulates lymphangiogenesis, we designed a bifunctional surface in which adhesive peptide ligands and short HA oligosaccharides (sHA) tethered to nanoparticles are copresented to the basal side of LECs in a controlled, concentration-dependent manner. Exposure of LECs to sHA in solution to mimic luminal stimulation of the cells did not result in modified metabolic activity. However, LECs grown on the bifunctional adhesive surfaces showed a biphasic change in metabolic activity, with increased metabolic activity being observed in response to increasing nanoparticle densities up to a maximum of 540 particles/MUm2. Thus, interfaces that concomitantly present adhesive ligands and sHA can stimulate LEC metabolism and might be able to trigger lymphangiogenesis. PMID- 29629371 TI - Effective potential for magnetic resonance measurements of restricted diffusion. AB - The signature of diffusive motion on the NMR signal has been exploited to characterize the mesoscopic structure of specimens in numerous applications. For compartmentalized specimens comprising isolated subdomains, a representation of individual pores is necessary for describing restricted diffusion within them. When gradient waveforms with long pulse durations are employed, a quadratic potential profile is identified as an effective energy landscape for restricted diffusion. The dependence of the stochastic effective force on the center-of-mass position is indeed found to be approximately linear (Hookean) for restricted diffusion even when the walls are sticky. We outline the theoretical basis and practical advantages of our picture involving effective potentials. PMID- 29629372 TI - Glomerular Endothelial Cells Stress and Cross-Talk With Podocytes in the Development of Diabetic Kidney Disease. AB - Diabetic kidney disease (DKD) is one of the major causes of morbidity and mortality in diabetic patients and also the leading single cause of end-stage renal disease in the United States. A large proportion of diabetic patients develop DKD and others don't, even with comparable blood glucose levels, indicating a significant genetic component of disease susceptibility. The glomerulus is the primary site of diabetic injury in the kidney, glomerular hypertrophy and podocyte depletion are glomerular hallmarks of progressive DKD, and the degree of podocyte loss correlates with severity of the disease. We know that chronic hyperglycemia contributes to both microvascular and macrovascular complications, as well as podocyte injury. We are beginning to understand the role of glomerular endothelial injury, as well as the involvement of reactive oxygen species and mitochondrial stress, which play a direct role in DKD and in other diabetic complications. There is, however, a gap in our knowledge that links genetic susceptibility to early molecular mechanisms and proteinuria in DKD. Emerging research that explores glomerular cell's specific responses to diabetes and cell cross-talk will provide mechanistic clues that underlie DKD and provide novel avenues for therapeutic intervention. PMID- 29629373 TI - Assessment of a Nutritional Rehabilitation Model in Two Modern Broilers and Their Jungle Fowl Ancestor: A Model for Better Understanding Childhood Undernutrition. AB - This article is the first in a series of manuscripts to evaluate nutritional rehabilitation in chickens as a model to study interventions in children malnutrition (Part 1: Performance, Bone Mineralization, and Intestinal Morphometric Analysis). Inclusion of rye in poultry diets induces a nutritional deficit that leads to increased bacterial translocation, intestinal viscosity, and decreased bone mineralization. However, it is unclear the effect of diet on developmental stage or genetic strain. Therefore, the objective was to determine the effects of a rye diet during either the early or late phase of development on performance, bone mineralization, and intestinal morphology across three diverse genetic backgrounds. Modern 2015 (Cobb 500) broiler chicken, 1995 Cobb broiler chicken, and the Giant Jungle Fowl were randomly allocated into four different dietary treatments. Dietary treatments were (1) a control corn-based diet throughout the trial (corn-corn); (2) an early phase malnutrition diet where chicks received a rye-based diet for 10 days, and then switched to the control diet (rye-corn); (3) a malnutrition rye-diet that was fed throughout the trial (rye-rye); and (4) a late phase malnutrition diet where chicks received the control diet for 10 days, and then switched to the rye diet for the last phase (corn-rye). At 10 days of age, chicks were weighed and diets were switched in groups 2 and 4. At day 20 of age, all chickens were weighed and euthanized to collect bone and intestinal samples. Body weight, weight gain, and bone mineralization were different across diet, genetic line, age and all two- and three-way interactions (P < 0.05). Overall, Jungle Fowl were the most tolerant to a rye-based diet, and both the modern and 1995 broilers were significantly affected by the high rye-based diet. However, the 1995 broilers consuming the rye based diet appeared to experience more permanent effects when compared with the modern broiler. The results of this study suggest that chickens have a great potential as a nutritional rehabilitation model in human trials. The 1995 broilers line was an intermediate genetic line between the fast growing modern line and the non-selected Jungle Fowl line, suggesting that it would be the most appropriate model to study for future studies. PMID- 29629375 TI - Arterial Stiffness Is Associated with Peripheral Sensory Neuropathy in Diabetes Patients in Ghana. AB - Objective: Peripheral sensory neuropathy (PSN) is among microvascular complications of diabetes that make patients prone to ulceration and amputation. Arterial stiffness is a predictor of cardiovascular diseases and microvascular complications associated with diabetes. We investigated the association between PSN and arterial stiffness, measured as aortic pulse wave velocity (PWVao) and cardio-ankle vascular index (CAVI). Method: In a case-control design, arterial stiffness was measured in 240 diabetes patients and 110 nondiabetic control. Large-fibre nerve function was assessed by vibration perception threshold (VPT) using a neurothesiometer. PSN was defined as the VPT > 97.5th percentile from age and gender-adjusted models in nondiabetic controls. Results: The overall prevalence of PSN was 16.6% in the entire study participants. Compared to non-PSN participants, PSN patients had higher levels of PWVao (9.5 +/- 1.7 versus 8.7 +/- 1.2 m/s, p = 0.016) and CAVI (8.4 +/- 1.3 versus 7.6 +/- 1.1, p = 0.001). In multiple regression models, VPT was associated with PWVao (beta = 0.14, p = 0.025) and CAVI (beta = 0.12, p = 0.04). PSN patients had increased odds of CAVI (OR = 1.51 (1.02-2.4), p = 0.043), but not PWVao (OR = 1.25 (0.91-1.71), p = 0.173). Conclusion: PWVao and CAVI were associated with VPT and PSN in diabetes patients in Ghana. Patients having PSN have increased odds of CAVI, independent of other conventional risk factors. PMID- 29629376 TI - Association of EPHX2 R287Q Polymorphism with Diabetic Nephropathy in Chinese Type 2 Diabetic Patients. AB - The aim of this study was to investigate the relationship between EPHX2 rs751141 (R287Q polymorphism) and diabetic nephropathy (DN) in Chinese type 2 diabetes (T2D). This case-control study explored the association between EPHX2 rs751141 and DN in a total of 870 Chinese T2D patients (406 T2D patients with DN and 464 T2D patients without DN). DNA was extracted from peripheral leukocytes of the patients and rs751141 was genotyped. The A allele frequency of rs751141 was significantly lower in DN patients (20.94%) compared with non-DN controls (27.8%) (P = 0.001), and the A allele of rs751141 was associated with a significantly lower risk of DN after adjustment for multiple covariates in the additive genetic model (OR = 0.68, 95% CI = 0.52-0.88, P = 0.004). Significant association between rs751141 and homocysteine (Hcy) level on the risk of DN was observed, indicating that in patients with the highest Hcy levels, the A allele showed marked association with lower risk of DN in all three genetic models. In conclusion, the A allele of exonic polymorphism in EPHX2 rs751141 is negatively associated with the incidence of DN in the Chinese T2D population, which could be modulated by Hcy level status. PMID- 29629377 TI - Four Plasma Glucose and Insulin Responses to a 75 g OGTT in Healthy Young Japanese Women. AB - The incidence of diabetes has been gradually increasing, not only in middle-aged individuals but also in young individuals. However, insulin and glucose patterns have not been investigated in apparently healthy young individuals, as they are typically grouped as controls. In this study, we investigated and classified glucose and insulin patterns in healthy young women. Sixty-two nonobese women without metabolic disease were recruited. The subjects underwent a 75 g oral glucose tolerance test (OGTT), physical measurements, and a biochemical examination. Two subjects displayed impaired glucose tolerance. The 62 subjects were categorized into four patterns by plasma glucose and insulin peak time during OGTT: normal type (n = 39), insulin-late type (n = 11), insulin- and glucose-late type (n = 7), and insulin-very late type (n = 5). OGTT glucose and insulin levels at all time points, insulinogenic index, HOMA-IR, and glucose area under the curve (AUC) significantly differed among the four groups. However, insulin AUC did not significantly differ. We did not detect significant differences in body condition or biochemical measurements. Our study demonstrated that some healthy young individuals might have delayed insulin secretion by OGTT. Early detection of altered glucose metabolism might be helpful to improve lifestyle choices and prevent progression to diabetes. PMID- 29629374 TI - RNA surveillance by the nuclear RNA exosome: mechanisms and significance. AB - The nuclear RNA exosome is an essential and versatile machinery that regulates maturation and degradation of a huge plethora of RNA species. The past two decades have witnessed remarkable progress in understanding the whole picture of its RNA substrates and the structural basis of its functions. In addition to the exosome itself, recent studies focusing on associated co-factors have been elucidating how the exosome is directed towards specific substrates. Moreover, it has been gradually realized that loss-of-function of exosome subunits affect multiple biological processes such as the DNA damage response, R-loop resolution, maintenance of genome integrity, RNA export, translation and cell differentiation. In this review, we summarize the current knowledge of the mechanisms of nuclear exosome-mediated RNA metabolism and discuss their physiological significance. PMID- 29629378 TI - The potential contributions of geographic information science to the study of social determinants of health in Iran. AB - Recent interest in the social determinants of health (SDOH) and the effects of neighborhood contexts on individual health and well-being has grown exponentially. In this brief communication, we describe recent developments in both analytical perspectives and methods that have opened up new opportunities for researchers interested in exploring neighborhoods and health research within a SDOH framework. We focus specifically on recent advances in geographic information science, statistical methods, and spatial analytical tools. We close with a discussion of how these recent developments have the potential to enhance SDOH research in Iran. PMID- 29629379 TI - Do highly cited clinicians get more citations when being present at social networking sites? AB - BACKGROUND AND AIMS: The advent of social networking sites has facilitated the dissemination of scientific research. This article aims to investigate the presence of Iranian highly cited clinicians in social networking sites. MATERIALS AND METHODS: This is a scientometrics study. Essential Science Indicator (ESI) was searched for Iranian highly cited papers in clinical medicine during November December 2015. Then, the authors of the papers were checked and a list of authors was obtained. In the second phase, the authors' names were searched in the selected social networking sites (ResearchGate [RG], Academia, Mendeley, LinkedIn). The total citations and h-index in Scopus were also gathered. RESULTS: Fifty-five highly cited papers were retrieved. A total of 107 authors participated in writing these papers. RG was the most popular (64.5%) and LinkedIn and Academia were in 2nd and 3rd places. None of the authors of highly cited papers were subscribed to Mendeley. A positive direct relationship was observed between visibility at social networking sites with citation and h-index rate. A significant relationship was observed between the RG score, citations, reads indicators in RG, and citation numbers and there was a significant relationship between the number of document indicator in Academia and the citation numbers. CONCLUSION: It seems putting the papers in social networking sites can influence the citation rate. We recommend all scientists to be present at social networking sites to have better chance of visibility and also citation. PMID- 29629380 TI - Association of sugary foods and drinks consumption with behavioral risk and oral health status of 12- and 15-year-old Indian school children. AB - AIM: This study aims to assess the association of sugary foods and drinks consumption with behavioral risk and oral health status of 12- and 15-year-old government school children in Udaipur. MATERIALS AND METHODS: A descriptive cross sectional study was conducted among of 12- and 15-year-old government schoolchildren of Udaipur. A survey pro forma designed based on HBSC (Health behaviour in School-aged Children) study protocol and WHO Oral Health Assessment Form for Children (2013) was used. Chi-Square test, Independent Sample t-test, and Multinomial Logistic Regression analysis were used with 95% confidence interval and 5% significance level. RESULTS: Out of 710 participants, 455 (64.1%) were males and 255 females (35.9%). Majority of 15 years age (57.3%) consumed more soft drinks than 12-year-old. Males showed a comparatively greater tendency to have sugar sweetened products than females. The decayed, missing, and filled teeth (dmft) and DMFT scores were relatively higher for subjects who consumed sugary substances more than once/day than who had less than once/day. Gingivitis was associated with high sugar diet. CONCLUSION: Sugary foods and drinks consumption is significantly associated with behavioral habits of children and is a clear behavioral risk for oral health. PMID- 29629381 TI - What are the predictor variables of social well-being among the medical science students? AB - CONTEXT: Individuals with social well-being can cope more successfully with major problems of social roles. Due to the social nature of human life, it cannot be ignored to pay attention the social aspect of health. AIMS: The purpose of this study was to identify variables that predict the social well-being of medical students. SETTINGS AND DESIGN: A descriptive-analytical study was conducted on 489 medical science students of Gilan Province, the North of Iran, during May to September 2016. SUBJECTS AND METHODS: The samples were selected using quota sampling method. Research instrument was a questionnaire consisting of two parts: demographic section and Keyes social well-being questionnaire. STATISTICAL ANALYSIS USED: Data analysis was done using SPSS software version 19 and with descriptive and inferential statistics (t-test, ANOVA, and linear regression). RESULTS: The results showed that majority of the students had average social well being. Furthermore, a significant relationship between the academic degree (P = 0.009), major (P = 0.0001), the interest and field's satisfaction (P = 0.0001), and social well-being was seen. The results of linear regression model showed that four variables (academic degree, major, group membership, and the interest and field's satisfaction) were significantly associated with the social well being (P < 0.05). CONCLUSIONS: The findings demonstrate that the different effects of the demographic factors on social well-being and the need for further consideration of these factors are obvious. Thus, health and education authorities are advised to pay attention students' academic degree, major, group membership, and the interest and field's satisfaction to upgrade and maintain the level of their social well-being. PMID- 29629382 TI - Get aware of hand hygiene: Implement it in your attitude. AB - BACKGROUND: Although there is advancement in the health-care system, the rates of hospital-acquired infections (HAIs) are still high. Poor hand hygiene (HH) among healthcare workers (HCWs) is identified as one of the major causes of HAIs. AIMS: The aim and objective of this study is to assess the awareness and attitude regarding hand hygiene (HH) among HCWs in a superspecialty hospital in Ghaziabad, Uttar Pradesh, India. SETTINGS AND DESIGN: A cross-sectional, semi-structured, questionnaire-based study was carried out in a superspecialty hospital, Uttar Pradesh, India. Questionnaires were distributed on the training session of HH organized in the eve of World HH Day on May 5th, 2016. SUBJECTS AND METHODS: A total 104 questionnaires were distributed among various HCWs. Each questionnaire was composed of 14 questions to test the awareness and attitude regarding HH. Awareness regarding HH among HCWs was graded as excellent (>80% correct response), satisfactory (80%-50%), and unsatisfactory (<50%). Attitude was graded on the basis of their response: excellent (strongly agree), satisfactory (agree), and unsatisfactory (other response). RESULTS: Awareness was found to be unsatisfactory regarding the most frequent source of germs in hospital setting (39.42%) and effective time of proper hand rub (42.30%). Lack of awareness regarding adequate time of hand wash among doctors (85.71%) was an important issue. PMID- 29629383 TI - Barriers to participation in medical research from the perspective of researchers. AB - BACKGROUND: The first step toward organizing research activities is to obtain a correct perception of available capabilities. This study was conducted to investigate the researchers' views about barriers affecting research activities. METHODS: This descriptive, cross-sectional study was conducted using the census method. The population consisted of the faculty members of Birjand University of Medical Sciences in 2014. The research tool was a questionnaire in six areas of financial, facility, professional, scientific, personal, and organizational- managerial barriers. The results were analyzed using descriptive statistics and Friedman test. RESULTS: Faculty members confirmed that although all barriers affected research activities, organizational-managerial barriers (3.73 +/- 0.63) had the greatest and scientific barriers (3.15 +/- 0.93) had the lowest effect, respectively. The results of Friedman test showed that there is a significant difference between the mean values of factors related to various barriers affecting research activities from the viewpoint of the participants' answers. CONCLUSIONS: Research activities are affected by numerous barriers. Strategies, such as empowering researchers, employing new technologies in the creation of research teams, and benefiting from research experts in various stages of research, may have a positive effect on the removal of the barriers. PMID- 29629384 TI - Knowledge, attitudes, and barriers toward research: The perspectives of undergraduate medical and dental students. AB - CONTEXT: Scientific research not only promotes health and combats diseases of an individual, but also it can strengthen the effectiveness of health systems. Hence, understanding of scientific methods becomes a crucial component in the medical profession. AIMS: This study was conducted to assess the knowledge, attitudes, and barriers toward research among undergraduate medical and dental students. SETTINGS AND DESIGN: This cross-sectional study was conducted among 295 undergraduate Bachelor of Medicine and Bachelor of Surgery (MBBS) and Bachelor of Dental Surgery (BDS) students from a private medical college in Malaysia. MATERIALS AND METHODS: We purposively selected 360 students attending the 3rd, 4th, and 5th year in MBBS course and BDS course in September 2015. A total of 295 students who were willing to provide written informed consent were included in this study. We collected data using a validated, self-administered, structured questionnaire which included 20 questions about knowledge toward scientific research, 21 attitude items in regard to scientific research, a list of 10 barriers toward conducting medical research, and 5 questions of confidence to conduct the medical research. STATISTICAL ANALYSIS USED: Data were analyzed using descriptive statistics, independent t-test, ANOVA, and multiple linear regression. RESULTS: Among the students, 56.9% had moderate knowledge while the majority (83.3%) had moderate attitude toward scientific research. The majorly cited barriers were the lack of time (79.9%), lack of knowledge and skills (72.1%), lack of funding (72.0%) and facilities (63.6%), and lack of rewards (55.8%). There was a significant association between age, academic year, and knowledge of research as the older age group, and 4th- and 5th-year students had higher knowledge score. The students of higher attitude score had better perceived barriers score toward research with regression coefficient 0.095 (95% confidence interval 0.032-0.159). CONCLUSIONS: Even though the students had the positive attitudes toward scientific research, a supportive and positive environment is needed to improve skills and knowledge of research and to overcome the barriers toward the conduct of scientific research. PMID- 29629385 TI - Barriers to medication adherence in patients with hypertension: A qualitative study. AB - INTRODUCTION: Barriers to medication adherence in patients with hypertension can have significant differences that made researchers confute to conclude that medication adherence is required to be more explored, and then, beneficial interventions develop to decrease these barriers. Thus, the current study was aimed to identify barriers to adherence in Iranian society. MATERIALS AND METHODS: A qualitative content analysis was carried out. Participants were as follow: Patients with hypertension who had clinic records in the health centers of Isfahan University of Medical Science. Purposive sampling method was conducted and continued until data saturation, as well. Semi-structured interview was selected as the best-qualified technique to select data. Data were analyzed using qualitative content, constant comparative analysis, and MAXQDA (Ver 10) software. RESULTS: After study and separation of basic concepts, 1620 basic codes were extracted from interviews. Classes were made based on codes and after multiple reviews, summarizing as well as similarity. Primary themes were identified using more explorations and comparison of classes. Based on the nature, the conceptual themes were named. These themes include (1) environmental challenges of life, (2) incompatibility of patients; (3) forget to take medicine, and (4) inefficient recommendations of family. CONCLUSION: Findings revealed that barriers to patient adherence to the treatment had four dimensions that may be likely useful for managers and planners in the health field to plan and intervene regarding medication adherence as the most critical preventing factor for patients with hypertension. PMID- 29629386 TI - Fish consumption based on transtheoretical model among housewives. AB - BACKGROUND: Consuming fish plays a key role in human health and prevention of diseases. The aim of this study was using transtheoretical model to analyze the trend of fish consumption among women. MATERIALS AND METHODS: In this descriptive analytic research, 383 housewives who referred to health centers in Bandar Abbas were selected through a stratified sampling method. Data were collected by a questionnaire to determine fish consumption based on transtheoretical model and analyzed by using SPSS software version 19.0. with the significance level of P < 0.05. RESULTS: Nearly 11.7% of the patients were found to be at the precontemplation stage; 3.9% were at the contemplation stage; 13.6% were at the preparation stage; 7.3% showed to be at the action stage, and 63.4% were at the maintenance stage. The results showed a significant relation of the constructs of the model with the stages of change of consuming one or two meals of fish a week. Moving through the stages of change from the precontemplation stage to maintenance stage was accompanied by an increase in decisional balance, self efficacy, and processes of change (P < 0.05). CONCLUSION: It is suggested that in designing educational interventions in the light of this model, more emphasis is placed on perceived benefits and self-efficacy. The processes of change are advised to be used more often, and perceived barriers to fish consumption need to be reduced as far as possible. PMID- 29629388 TI - A survey on scientific authenticity of health information in Iranian popular magazines: A case study. AB - BACKGROUND: The content of the mass media is a suitable tool for making changes to the society. One of the most read news in the mass media is nutritional information. The goal of this study is to assess the scientific authenticity of such information published in Iranian popular magazines. MATERIALS AND METHODS: This study is a qualitative study (content analysis) and uses bibliographic approach. A researcher-designed checklist is used as data gathering tool, and the statistical population included the messages obtained from the printed material in 173 volumes of 8 Iranian popular magazines. 10 most frequent messages were identified, and their scientific authenticity was investigated using Pubmed and IranMedex databases. The SPSS Software version 24 (IBM Corporation, Armonk, New York, USA) was applied in the analysis of this work. RESULTS: The findings indicated that preventive trends had the highest (86.8%) and the treatments had the lowest (4.2%) frequency. Concerning the type of cancer, more than half (51.2%) of the conclusions were about cancer. Regarding authorship, 68% of articles were author signed, but the profession of 66.4% of the authors was not clear. Regarding references, only 25.4% of the articles had validated references. CONCLUSION: It is revealed that 70% of the "nutrition information" related to cancer which was published in the popular magazines during 2012, considered to be acceptable according to scientific medical information sources. Although in some cases, the amount of evidence is not sufficient. Finally, it could be deduced that the nutrition information published in the Iranian popular magazines are still credible. PMID- 29629387 TI - Effect of dental erosion on oral health among employees of battery-manufacturing units in Baddi, Himachal Pradesh, India. AB - OBJECTIVE: The objective of the study was to obtain data on prevalence and severity of dental erosion among acid industry workers in Baddi (Himachal Pradesh). MATERIALS AND METHODS: A cross-sectional study was conducted among 800 battery industry workers. The demographic details were recorded on a prestructured pro forma. Type III examination was done. Dental erosion was recorded based on the index given by Bardsley (simplified scoring criteria for tooth wear index). Appropriate statistical tests were used to interpret the data. RESULTS: The prevalence of dental erosion was found to be 48.6%. Prevalence increased with the duration of employment. Dental erosion was most commonly found in the labial surfaces of maxillary anterior teeth. CONCLUSION: Erosion is a condition which is multifactorial and becomes more aggravating in the presence of acidic environment. Therefore, the workers working in such conditions should be more careful, and mandatory policies should also be followed by such industries to maintain the overall health of the workers. PMID- 29629389 TI - Promoting evidence-informed policymaking through capacity enhancement in implementation research for health researchers and policymakers in Nigeria: A cross-sectional study. AB - BACKGROUND: Capacity constraints on implementation research among policymakers and researchers are a major challenge to the evidence to policy link. This study was designed to bring together senior policymakers and researchers in Nigeria to consider issues around research-to-policy interface and enhance their capacity on implementation research. METHODS: The design was a cross-sectional study. A 3-day joint implementation research workshop was held for policymakers and researchers using World Health Organization/TDR Implementation Research Toolkit. Assessment of participants' capacity for evidence-informed policymaking and knowledge on implementation research was done using a 5-point Likert scale questionnaire. A postworkshop key informant interview was also conducted. RESULTS: A total of 20 researchers and 15 policymakers participated in the study. The interaction/partnership between policymakers and researchers was generally rare in terms of priority-setting process, involvement as coinvestigators, and executing strategies to support policymakers' use of research findings. The mean ratings (MNRs) recorded mostly ranged from 1.80 to 1.89 on the 5-point scale. Researchers were rarely involved in the generation of policy-relevant research that satisfies policymakers' needs with MNR very low at 1.74. The MNRs for capacity to acquire, assess, and adapt research were generally considerably higher among researchers (3.16-3.82) than policymakers (2.27-3.20). There was a general consensus that the training tremendously improved participants' understanding and use of implementation research. CONCLUSION: Policymakers and researchers are increasingly recognizing their need to work with each other in the interest of the health systems. There is a need to create more capacity enhancement platforms that will facilitate the interface between them. PMID- 29629390 TI - The effect of distance learning via SMS on academic achievement and satisfaction of medical students. AB - INTRODUCTION: Recently, medical education has made significant progress, and medical teachers are trying to find methods that have most impressive effects on learning. One of the useful learning methods is student active participation. One of the helpful teaching aids in this method is mobile technology. The present study aimed to determine the effect of sending educational questions through short message service (SMS) on academic achievement and satisfaction of medical students and compare that with lecture teaching. SUBJECTS AND METHODS: In an semi experimental, two chapters of urology reference book, Smiths General Urology 17th edition, were taught to 47 medical students of Isfahan University of Medical Sciences in urology course in 2013 academic year. Kidney tumors chapter was educated by sending questions through SMS, and bladder tumors part was taught in a lecture session. For each method, pretest and posttest were held, each consisting of thirty multiple choice questions. To examine the knowledge retention, a test session was held on the same terms for each chapter, 1 month later. At the end, survey forms were distributed to assess student's satisfaction with SMS learning method. Data were analyzed through using SPSS 20. RESULTS: The findings demonstrated a statistically significant difference between the two learning methods in the medication test scores. Evaluation of the satisfaction showed 78.72% of participants were not satisfied. CONCLUSIONS: The results of the study showed that distance learning through SMS in medical students could lead to increase knowledge, however, it was not effective on their satisfaction. PMID- 29629391 TI - Medical students' perceptions of small group teaching effectiveness in hybrid curriculum. AB - OBJECTIVES: The objective of this study was designed to investigate medical students' perceptions of small group teaching effectiveness in a hybrid curriculum. MATERIALS AND METHODS: A cross-sectional, descriptive survey was conducted at the School of Medicine, The University of the West Indies, St. Augustine where we collected the data from 195 undergraduate students. A self administered questionnaire consisting of 25 items was used to measure students' perception on the effectiveness of problem-based learning (PBL) with regard to learning experience, teamwork, confidence, communication skills, and role of the tutor. Statistical analyses included mean and standard deviation for the description of each item; t-test to compare the mean scores for gender and class year, and one-way analysis of variance between groups for age group comparisons. RESULTS: The students overall perceptions of small group teaching effectiveness showed that the PBL sessions were beneficial to their learning process (mean: 3.63 +/- 0.46). Students have positive perceptions toward small group effectiveness, particularly in learning experience (mean: 3.98 +/- 0.63) and teamwork (mean: 3.67 +/- 0.58). The mean scores, measuring teamwork, for 2nd year students was significantly higher than that for 1st year students (3.76 +/- 0.55 and 3.55 +/- 0.60 respectively, P = 013). A similar significant trend was observed between 2nd year and 1st year students on communication skills (3.48 +/- 0.67 and 3.29 +/- 0.55, respectively, P = 0.046). CONCLUSIONS: PBL is an effective small group teaching method for medical students. Faculty development and students' training programs are required before implementing PBL. PMID- 29629392 TI - Empowerment of women and mental health improvement with a Preventive approach. AB - AIM AND BACKGROUND: Mental health and empowerment are two of the women's essential needs. These two related concepts play an important role in women's lives. Therefore, this study aimed to investigate empowerment of women and its relation with mental health problem prevention during difficult situations. METHODS: This qualitative study was conducted through semi-structured interviews with 33 experts in the fields of psychology, social sciences, women studies, medicine and crisis management specialists using snowball sampling in cities of Tehran, Isfahan, Tabriz, and Mashhad during the year 1395 (March 2016-March 2017). Samples were selected heterogeneously. The interview transcripts and codes were presented to the participants, and structural analysis was used for data evaluation. RESULTS: The factors related to empowerment of women with consideration to their mental health were determined based on Longew theory and interviews and include: welfare (primary needs (biological and security) and developmental needs (social needs and dignity), access (facilities and values), knowledge (about inequalities and rights), participation (in politics, decision making and society), and control (implementation and institutionalization of the above-mentioned needs). CONCLUSIONS: The indicators determined in this study show that empowerment has an important role in determining women's real position in society. Since women make up half of the population and affect society as a whole, the advantages of empowerment of women will be felt in the entire society. PMID- 29629394 TI - Organotypic Explants of the Embryonic Rodent Hippocampus: An Accessible System for Transgenesis. AB - This protocol describes the technique of ex-vivo electroporation to target embryonic hippocampal progenitors in an organotypic slice preparation. This technique allows gene perturbation for examining developmental processes in the embryonic hippocampus while retaining the environment and connectivity of the cells. Gene perturbation can include Cre-mediated recombination, RNAi-mediated knockdown, gene overexpression, or a combination of any of these. Ex-vivo electroporation can be performed at a wide range of embryonic stages, giving temporal control to the experimenter. Spatial control can be achieved more easily by preparing the brain in a Petri dish to target particular regions of the hippocampus. The electroporated explant cultures provide a highly tractable system for the study of developmental processes that include progenitor proliferation, migration and cell fate acquisition. PMID- 29629393 TI - Heading for new shores! Overcoming pitfalls in BCI design. AB - Research in brain-computer interfaces has achieved impressive progress towards implementing assistive technologies for restoration or substitution of lost motor capabilities, as well as supporting technologies for able-bodied subjects. Notwithstanding this progress, effective translation of these interfaces from proof-of concept prototypes into reliable applications remains elusive. As a matter of fact, most of the current BCI systems cannot be used independently for long periods of time by their intended end-users. Multiple factors that impair achieving this goal have already been identified. However, it is not clear how do they affect the overall BCI performance or how they should be tackled. This is worsened by the publication bias where only positive results are disseminated, preventing the research community from learning from its errors. This paper is the result of a workshop held at the 6th International BCI meeting in Asilomar. We summarize here the discussion on concrete research avenues and guidelines that may help overcoming common pitfalls and make BCIs become a useful alternative communication device. PMID- 29629395 TI - Nanocomposite Carriers for Transarterial Chemoembolization of Liver Cancer. AB - The efficacy of conventional transarterial chemoembolization (TACE) approaches in liver cancer treatment is limited by the lack of effective drug carriers and/or the inability to monitor drug delivery to the targeted tumor tissues. Recent years have seen rapid advances in drug carriers for TACE. Bioabsorbable and MRI- or CT-visible microspheres that are trackable in vivo have been developed as a form of nanocomposite. Herein, we review notable progress in nanocomposite microspheres drug carriers available for TACE. PMID- 29629396 TI - Anti-NMDA receptor encephalitis and nonencephalitic HSV-1 infection. AB - Objective: To determine whether there is an association between nonencephalitic herpes simplex virus 1 (HSV-1) infection and anti-NMDA receptor encephalitis (anti-NMDARE). Methods: Antibody testing was performed using samples from 2 cohorts in a case-control observational study. The cohort "Philadelphia" included 16 serum samples of pediatric anti-NMDARE cases and 42 age-matched controls with other neuroinflammatory disorders studied at the Children's Hospital of Philadelphia and University of Pennsylvania. The cohort "Barcelona" contained 23 anti-NMDARE patient samples and 26 age-matched participants with other neuroinflammatory disorders studied at IDIBAPS-Hospital Clinic, University of Barcelona. The presence of HSV-1 IgG antibodies was examined by ELISA. As an additional control, IgG antibodies to cytomegalovirus (CMV) and Epstein-Barr virus viral capsid antigen (EBV-VCA) were determined. Results: In each cohort, more participants with anti-NMDARE than controls had anti-HSV-1 IgG antibodies. In the Philadelphia cohort (58 participants), 44% of anti-NMDARE cases had antibodies to HSV-1 compared with 14% controls (OR 4.67, 95% CI 1.3-17.3, p = 0.031). In the Barcelona cohort (49 participants), 52% of participants with anti NMDARE had antibodies to HSV-1 compared with 31% of controls (OR 2.45, 95% CI 0.7 7.9, p = 0.155). Overall, 49% of anti-NMDARE cases have antibodies to HSV-1 in these 2 combined cohorts compared with 21% of controls (Mantel-Haenszel OR 3.21, 95% CI 1.3-7.7, p = 0.007). Conclusion: Past HSV-1 infection was found in significantly more anti-NMDARE cases than controls. This suggests a meaningful association between nonencephalitic HSV-1 infection and development of anti NMDARE. PMID- 29629397 TI - Obinutuzumab, a potent anti-B-cell agent, for rituximab-unresponsive IgM anti-MAG neuropathy. PMID- 29629398 TI - Simulation of Spiral Waves and Point Sources in Atrial Fibrillation with Application to Rotor Localization. AB - Cardiac simulations play an important role in studies involving understanding and investigating the mechanisms of cardiac arrhythmias. Today, studies of arrhythmogenesis and maintenance are largely being performed by creating simulations of a particular arrhythmia with high accuracy comparable to the results of clinical experiments. Atrial fibrillation (AF), the most common arrhythmia in the United States and many other parts of the world, is one of the major field where simulation and modeling is largely used. AF simulations not only assist in understanding its mechanisms but also help to develop, evaluate and improve the computer algorithms used in electrophysiology (EP) systems for ablation therapies. In this paper, we begin with a brief overeview of some common techniques used in simulations to simulate two major AF mechanisms - spiral waves (or rotors) and point (or focal) sources. We particularly focus on 2D simulations using Nygren et al.'s mathematical model of human atrial cell. Then, we elucidate an application of the developed AF simulation to an algorithm designed for localizing AF rotors for improving current AF ablation therapies. Our simulation methods and results, along with the other discussions presented in this paper is aimed to provide engineers and professionals with a working-knowledge of application-specific simulations of spirals and foci. PMID- 29629399 TI - Pneumonia Complicating COPD: Are Corticosteroids a Help or a Hindrance? PMID- 29629400 TI - Long-Term Evaluation of the Effects of Aclidinium Bromide on Major Adverse Cardiovascular Events and COPD Exacerbations in Patients with Moderate to Very Severe COPD: Rationale and Design of the ASCENT COPD Study. AB - Introduction: Chronic obstructive pulmonary disease (COPD) is a heterogeneous illness characterized by persistent airflow obstruction and exacerbations. Patients typically experience a decline in lung function, increasingly impaired health-related quality of life, and high mortality. Poor lung function and exacerbations are associated with an increased risk of cardiovascular (CV) and cerebrovascular events, and approximately 30% of patients with COPD die from CV related disease. Treatment with inhaled long-acting bronchodilators, such as long acting muscarinic antagonists (LAMAs), is recommended; however, some studies have suggested that LAMAs may increase the risk of CV events. As patients with CV and cerebrovascular conditions are often excluded from clinical trials, an evaluation of the safety of COPD treatments in an at-risk population is vital. Aclidinium bromide is a LAMA approved for the long-term maintenance treatment of COPD. Methods and Objectives: The Phase 4, multicenter, double-blind, randomized, placebo-controlled, parallel-group Aclidinium Bromide on Long-Term Cardiovascular Safety and COPD Exacerbations in PatieNTs with Moderate to Very Severe COPD (ASCENT COPD) study (NCT01966107) is being conducted at 500 sites in the United States and Canada. The primary objectives are to evaluate the long-term effects of twice-daily aclidinium bromide 400 ug on CV safety and exacerbations in patients with moderate to very severe COPD with a history of cerebrovascular, coronary, or peripheral artery disease, or the presence of >=2 atherothrombotic risk factors. The primary safety and efficacy variables are time to first major adverse CV event (MACE) (on-study analysis) and rate of moderate to severe COPD exacerbations during the first year of treatment (on-treatment analysis), respectively. The study will be terminated after approximately 122 MACE have occurred. PMID- 29629401 TI - Pattern and Adherence to Maintenance Medication Use in Medicare Beneficiaries with Chronic Obstructive Pulmonary Disease: 2008-2013. AB - Background: Maintenance medications provide symptomatic relief, improve lung function and reduce the risk of exacerbations in patients with chronic obstructive pulmonary disease (COPD). Despite their proven benefits, limited information exists on maintenance medication use and adherence among users. Objective: We examined the patterns and factors associated with the receipt of and adherence to maintenance medication in individuals with COPD. Methods: A retrospective cross-sectional study of 5% of Medicare beneficiaries enrolled in Parts A, B and D with COPD who received maintenance medication from 2008 to 2013 was conducted. Maintenance medication includes: inhaled corticosteroids (ICSs), long-acting beta2- agonists (LABAs) and long-acting muscarinic antagonists (LAMAs) alone or in combination. We examined the proportion of beneficiaries with COPD who had at least one prescription filled for maintenance medication. Among users of maintenance medications, we also examined adherence, defined as proportion of days covered (PDC) >=80% over the year from the first maintenance medication prescription fill date. Results: Overall, maintenance medication (LAMAs, LABAs, ICSs and/or LABA/ICS) use increased from 67.8% in 2008 to 72.1% in 2013. The increase is related to increases in use of LABA/ICS, which rose from 41.1% in 2008 to 49.6% in 2013. Factors associated with receipt of maintenance medication include female gender, recent COPD hospitalization (odds ratio [OR] 1.63; 95% confidence interval [CI] 1.54-1.73), oxygen therapy (OR 1.74 95% CI, 1.68-1.81), dual eligibility status (OR 1.45; 95% CI 1.39-1.51), higher education level and evaluation by a pulmonary provider (OR 1.88; 95% CI 1.81-1.96). The overall adherence among maintenance medication users remained flat. The most important factor associated with adherence was dual eligibility status (OR, 1.67; 95% CI: 1.59-1.75). Conclusions: Receipt of maintenance medications increased during the study period and was higher in those with dual eligibility. Overall, adherence to maintenance medications was suboptimal and remained unchanged. PMID- 29629402 TI - The Short-term Impact of Symptom-defined COPD Exacerbation Recovery on Health Status and Lung Function. AB - Background: This study examined the short-term effects of symptom-defined exacerbation recovery on health status and pulmonary function in moderate to severe chronic obstructive pulmonary disease (COPD) patients. Methods: Secondary analyses of pooled data from two 12-week Phase II international, randomized controlled trials using the EXAcerbations of Chronic Pulmonary Disease Tool (EXACT) to identify symptom-defined exacerbations were conducted. Recovery was categorized as recovered, unrecovered (persistent worsening), or censored. Multiple regression analyses were used to test the effect of recovery status on change in the St George's Respiratory Questionnaire (SGRQ) and forced expiratory volume in 1 second (FEV1) from baseline to Week 12. Evaluating Respiratory Symptom scale (E-RS) scores were used to evaluate change in stable-state respiratory symptoms from baseline to Week 12. Results: Of 1346 eligible patients, 414 (31%) experienced >=1 symptom-defined exacerbation; 260 patients recovered from their events, 80 experienced an unrecovered event (persistent worsening), 74 patients had only censored events (excluded). Groups were similar at baseline, with the recovered group reporting significantly worse symptoms (p<0.01). Recovery group and baseline SGRQ were significant predictors of change in health status over 12 weeks (p=0.04; p<0.01); no effects were observed for lung function. Significant between-group differences in change in respiratory symptom severity from baseline to Week 12 were observed (p<0.01), with the persistent worsening group experiencing clinically meaningful deterioration in breathlessness and chest symptoms. Conclusions: Results suggest some patients have difficulty recovering from symptom-defined exacerbations, leading to a deterioration in health status, dyspnea, and chest symptoms without short-term effects on lung function. Further study of symptom-defined exacerbation recovery and health outcomes is warranted. PMID- 29629403 TI - Effectiveness of Umeclidinium-Vilanterol for Protocolized Management of Chronic Obstructive Pulmonary Disease Exacerbation in Hospitalized Patients: A Sequential Period Analysis. AB - Background: Bronchodilator therapy is a foundation of chronic obstructive pulmonary disease (COPD) exacerbation treatment. Although international guidelines recommend short-acting formulations given multiple times per day, long acting formulations have not been adequately evaluated. The objective of our study was to determine the effectiveness of umeclidinium-vilanterol (UME/VIL), long-acting beta2-agonist/long-acting muscarinic antagonist (LABA/LAMA) as a once daily alternative for treating COPD exacerbations in hospitalized patients. Methods: In this retrospective sequential period analysis, we reviewed electronic medical records of patients hospitalized for COPD exacerbations before (September 1, 2015 to February 29, 2016) and after (April 1, 2016 to September 30, 2016) incorporation of UME/VIL into our standard COPD protocol. Before implementation, patients received a daily anticholinergic plus twice-daily long-acting beta2 agonist therapy (tiotropium plus formoterol, n=65). After implementation, UME/VIL replaced the previous regimen (n=58). No other changes were made to the COPD protocol. The primary outcome was 30-day hospital readmission rate. Hospital length of stay, 30-day mortality, and cost of care were analyzed as secondary outcomes. Results: A trend toward increased 30-day readmission rates in the post intervention group (24.1% versus 10.8%, p=0.049) was no longer statistically significant after adjustment for severity of illness (based on case-mix index) and complications or comorbidities based on diagnosis-related group codes (adjusted odds ratio: 2.499; 95% confidence interval: 0.916-7.380; p=0.074). Conclusion: After adjustment for potential confounders,the implementation of a LABA/LAMA combination product was not statistically associated with an increased 30-day readmission rate but was associated with lower cost of care. PMID- 29629404 TI - Marijuana Use Associations with Pulmonary Symptoms and Function in Tobacco Smokers Enrolled in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS). AB - Background: Marijuana is often smoked via a filterless cigarette and contains similar chemical makeup as smoked tobacco. There are few publications describing usage patterns and respiratory risks in older adults or in those with chronic obstructive pulmonary disease (COPD). Methods: A cross-sectional analysis of current and former tobacco smokers from the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) study assessed associations between marijuana use and pulmonary outcomes. Marijuana use was defined as never, former (use over 30 days ago), or current (use within 30 days). Respiratory health was assessed using quantitative high-resolution computed tomography (HRCT) scans, pulmonary function tests and questionnaire responses about respiratory symptoms. Results: Of the total 2304 participants, 1130 (49%) never, 982 (43%) former, and 192 (8%) current marijuana users were included. Neither current nor former marijuana use was associated with increased odds of wheeze (odds ratio [OR] 0.87, OR 0.97), cough (OR 1.22; OR 0.93) or chronic bronchitis (OR 0.87; OR 1.00) when compared to never users. Current and former marijuana users had lower quantitative emphysema (P=0.004, P=0.03), higher percent predicted forced expiratory volume in 1 second (FEV1%) (P<0.001, P<0.001), and percent predicted forced vital capacity (FVC%) (p<0.001, P<0.001). Current marijuana users exhibited higher total tissue volume (P=0.003) while former users had higher air trapping (P<0.001) when compared to never marijuana users. Conclusions: Marijuana use was found to have little to no association with poor pulmonary health in older current and former tobacco smokers after adjusting for covariates. Higher forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) was observed among current marijuana users. However, higher joint years was associated with more chronic bronchitis symptoms (e.g., wheeze), and this study cannot determine if long-term heavy marijuana smoking in the absence of tobacco smoking is associated with lung symptoms, airflow obstruction, or emphysema, particularly in those who have never smoked tobacco cigarettes. PMID- 29629405 TI - Evaluation of Systemic Corticosteroids in Patients With an Acute Exacerbation of COPD and a Diagnosis of Pneumonia. AB - Background: Chronic obstructive pulmonary disease (COPD) and pneumonia are leading causes of morbidity and mortality and are frequently comorbid. Studies of systemic corticosteroids in pneumonia have shown conflicting outcomes, whereas studies in acute exacerbations of COPD (AECOPD) have shown significant benefits. No studies have evaluated systemic corticosteroids in patients with both an AECOPD and pneumonia. Purpose: To evaluate the use of systemic corticosteroids in patients with both an AECOPD and pneumonia. Patients and Methods: Patients with a diagnosis of both COPD or obstructive chronic bronchitis with exacerbation and pneumonia admitted to the University of Colorado Hospital between July 1, 2012 and May 20, 2016 were retrospectively evaluated. Patients who received systemic corticosteroids were compared to those that did not. The primary outcome was length of hospital stay (LOHS). Secondary outcomes were in-hospital treatment failure, a composite of intensive care unit (ICU) admission, ventilation, and escalation of steroid therapy, 30-day AECOPD or pneumonia readmission, and 30-day mortality. Results: A total of 138 patients were included-- 89 in the steroid group and 49 in the non-steroid group. No significant differences in baseline characteristic were noted. No difference was seen in mean LOHS (4.7+/-3.2 versus 4.2+/-2.1 days, p=0.27), in-hospital treatment failure (7% versus 4%, p=0.72), 30 day readmission or 30-day mortality between the steroid and non-steroid groups, respectively. There was a difference in mean LOHS for patients with severe pneumonia between the steroid and non-steroid groups (6.0+/-4.0 versus 4.3+/-1.8; p=0.03). Conclusions: This study suggests that systemic corticosteroids may not provide a clinical benefit to patients with an AECOPD and pneumonia. PMID- 29629406 TI - The COPD Pipeline XXXVII. PMID- 29629407 TI - New Treatment Options for COPD: How Do We Decide Phenotypes, Endotypes or Treatable Traits? PMID- 29629408 TI - Marijuana Lung. PMID- 29629409 TI - Genital herpes stigma: Toward the Measurement and Validation of a highly prevalent yet hidden public health problem. AB - Despite its highly prevalent and stigmatizing nature, genital herpes has received little attention from stigma researchers relative to other sexually transmitted infections. This limitation is of great relevance to researchers and practitioners in both clinical and healthcare settings, given that stigma can cause psychological distress and hinder disclosure to sexual partners, hence contributing to the spread of genital herpes. The present research developed and examined the psychometric properties of a quantitative measure of genital herpes stigma. Two hundred individuals diagnosed with genital herpes recruited through online genital herpes support groups completed a survey containing 37 items adapted from the HIV Stigma Scale, questions about demographic and herpes-related characteristics, and measures of relevant psychosocial variables. A confirmatory factor analysis yielded an 18-item scale with four factors: personalized stigma, disclosure concerns, negative self-image, and concern with public attitudes. All subscales demonstrated good internal consistency, with Cronbach alphas ranging from 0.74 to 0.87. Construct validity was supported by correlations with relevant psychosocial variables, including negative affect, rumination, and perceived social support. As a psychometrically sound assessment tool, the Genital Herpes Stigma Scale can be used in both clinical and research settings to facilitate future efforts to alleviate the negative psychological consequences of this incurable viral infection. PMID- 29629410 TI - Expanding the global prevalence of spinocerebellar ataxia type 42. PMID- 29629411 TI - Understanding Microbiome Stability in a Changing World. AB - Microbiomes underpin biogeochemical processes, sustain the bases of food webs, and recycle carbon and nutrients. Thus, microbes are frontline players in determining ecosystem responses to environmental change. My research team and I investigate the causes and consequences of microbiome stability. Our primary objective is to understand the responses of complex microbiomes to stressors associated with environmental change. This work is important because Earth is changing rapidly and drastically, and these changes are expected to have serious consequences for ecosystems, their inhabiting organisms, and their microbiomes. Therefore, we aim to understand the repercussions of alterations to microbiome structure and functions and to use this information to predict the responses of microbiomes to stressors. This research is critical to prepare for, respond to, and potentially moderate environmental change. We anticipate that the results of our research will contribute toward these goals and will broadly inform management or manipulation of microbiomes toward desired functions. PMID- 29629412 TI - The Life Aquatic at the Microscale. AB - There are more than one million microbial cells in every drop of seawater, and their collective metabolisms not only recycle nutrients that can then be used by larger organisms but also catalyze key chemical transformations that maintain Earth's habitability. Understanding how these microbes interact with each other and with multicellular hosts is critical to reliably quantify any functional aspect of their metabolisms and to predict their outcomes on larger scales. Following a large body of literature pioneered by Farooq Azam and colleagues more than 30 years ago, I emphasize the importance of studying microbial interactions at the appropriate scale if we want to fully decipher the roles that they play in oceanic ecosystems. PMID- 29629413 TI - Role of the Gut Microbiome in Vertebrate Evolution. AB - Darwin referred to life as a struggle. Organisms compete for limited resources in nature, and their traits influence the outcome. Victory carries great weight as winners survive, reproduce, and progenate subsequent generations. Consequently, organismal traits that influence fitness drive adaptation and their discovery clarifies evolution. Recent research implicates the vertebrate gut microbiome as an agent of fitness, selection, and evolution. Going forward, we must define the functional effects of the gut microbiome to determine how it impacts evolution. Specifically, we must quantify how gut microbiome function diversifies in concert with vertebrate radiation and resolve specific functions that influence natural selection. In so doing, we can discover and potentially capitalize upon the mechanisms by which our gut microbiomes impact our physiology and fitness. Ultimately, we may come to find that while life involves struggle, it also depends upon cooperation. PMID- 29629414 TI - Using Cultivated Microbial Communities To Dissect Microbiome Assembly: Challenges, Limitations, and the Path Ahead. AB - As troves of microbiome sequencing data provide improved resolution of patterns of microbial diversity, new approaches are needed to understand what controls these patterns. Many microbial ecologists are using cultivated model microbial communities to address this challenge. These systems provide opportunities to identify drivers of microbiome assembly, but key challenges and limitations need to be carefully considered in their development, implementation, and interpretation. How well do model microbial communities mimic in vitro communities in terms of taxonomic diversity, trophic levels, intraspecific diversity, and the abiotic environment? What are the best ways to manipulate and measure inputs and outputs in model community experiments? In this perspective, I briefly address some of these challenges on the basis of our experience developing fermented food model communities. Future work integrating genetic and molecular approaches with cultivated model microbial communities will allow microbial ecology to develop a more mechanistic understanding of microbiome diversity. PMID- 29629415 TI - Toward Personalized Control of Human Gut Bacterial Communities. AB - A key challenge in microbiology will be developing tools for manipulating human gut bacterial communities. Our ability to predict and control the dynamics of these communities is now in its infancy. To manage human gut microbiota, I am developing methods in three research domains. First, I am refining in vitro tools to experimentally study gut microbes at high throughput and in controlled settings. Second, I am adapting "big data" techniques to overcome statistical challenges confronting microbiota modeling. Third, I am testing study designs that can streamline human testing of microbiota manipulations. Assembling these methods creates new challenges, including training scientists who can work across disciplines such as engineering, ecology, and medicine. Nevertheless, I envision that overcoming these obstacles will enable my group to construct platforms that can personalize microbiota treatments, particularly ones based on diet. More broadly, I anticipate that such platforms will have applications across fields such as agriculture, biotechnology, and environmental management. PMID- 29629416 TI - Seven Billion Microcosms: Evolution within Human Microbiomes. AB - Rational microbiome-based therapies may one day treat a wide range of diseases and promote wellness. Yet, we are still limited in our abilities to employ such therapies and to predict which bacterial strains have the potential to stably colonize a person. The Lieberman laboratory is working to close this knowledge gap and to develop an understanding of how individual species and strains behave in the human microbiome, including with regard to their niche ranges, survival strategies, and the degree to which they adapt to individual people. We employ system-level approaches, with a particular emphasis on using de novo mutations and evolutionary inference to reconstruct the history of bacterial lineages within individuals. PMID- 29629417 TI - Insect Transmission of Plant Pathogens: a Systems Biology Perspective. AB - Insect-vectored pathogens pose one of the greatest threats to plant and animal, including human, health on a global scale. Few effective control strategies have been developed to thwart the transmission of any insect-transmitted pathogen. Most have negative impacts on the environment and human health and are unsustainable. Plant pathogen transmission by insect vectors involves a combination of coevolving biological players: plant hosts, insect vectors, plant pathogens, and bacterial endosymbionts harbored by the insect. Our ability to help growers to control vector-borne disease depends on our ability to generate pathogen- and/or disease-resistant crops by traditional or synthetic approaches and to block pathogen transmission by the insect vector. Systems biology studies have led to the reexamination of existing paradigms on how pathogens interact with insect vectors, including the bacterial symbionts, and have identified vector-pathogen interactions at the molecular and cellular levels for the development of novel transmission interdiction strategies. PMID- 29629418 TI - The Tripod for Bacterial Natural Product Discovery: Genome Mining, Silent Pathway Induction, and Mass Spectrometry-Based Molecular Networking. AB - Natural products are the richest source of chemical compounds for drug discovery. Particularly, bacterial secondary metabolites are in the spotlight due to advances in genome sequencing and mining, as well as for the potential of biosynthetic pathway manipulation to awake silent (cryptic) gene clusters under laboratory cultivation. Further progress in compound detection, such as the development of the tandem mass spectrometry (MS/MS) molecular networking approach, has contributed to the discovery of novel bacterial natural products. The latter can be applied directly to bacterial crude extracts for identifying and dereplicating known compounds, therefore assisting the prioritization of extracts containing novel natural products, for example. In our opinion, these three approaches-genome mining, silent pathway induction, and MS-based molecular networking-compose the tripod for modern bacterial natural product discovery and will be discussed in this perspective. PMID- 29629419 TI - Revival of Archaeal Methane Microbiology. AB - The methane concentration in the Earth's atmosphere is rising, and, as methane is a potent greenhouse gas, it contributes considerably to climate change. It is produced by methanogenic archaea that thrive in anoxic habitats and can be oxidized by methane-oxidizing bacteria or archaea. In this Perspective, recent innovations and discoveries in archaeal methane microbiology are discussed and a future outlook on how novel methane-metabolizing archaea might be cultivated is provided. PMID- 29629420 TI - Exploring Linkages between Taxonomic and Functional Profiles of the Human Microbiome. AB - Microbiome studies typically focus on characterizing the taxonomic and functional profiles of the microbes within a community. Functional profiling is generally thought to be superior to taxonomic profiling for investigating human-microbe interactions, but there are several limitations and challenges to existing approaches. This Perspective discusses the current sequencing and bioinformatic methods for producing taxonomic and functional profiles, recent studies utilizing and comparing these technologies, and the existing challenges and limitations of these data. In addition, functional versus taxonomic conservation across the population is questioned, while future research that focuses on investigating the taxonomic diversity of microbial functions is proposed. PMID- 29629421 TI - In Search of Model Ecological Systems for Understanding Specialized Metabolism. AB - Microbes occupy diverse habitats, forming interconnected, dynamic communities. Elucidating the principles of microbial community function is a grand challenge for microbiology, and it will entail experiments that engage microbiomes across multiple levels of complexity. For example, community-level hypotheses often require testing at the mechanistic and/or genetic levels, while mechanistic relationships require community-level evaluation to understand their importance in context. In this Perspective, we articulate the need for model microbiome systems that enable experimentation in both community and reductionist frameworks, with an emphasis on understanding the role of specialized metabolites in microbial communities. We consider essential criteria for developing such model microbiome systems and discuss potential future models that address the ecology of specialized metabolism. PMID- 29629422 TI - Can Diet Influence Our Health by Altering Intestinal Microbiota-Derived Fecal Metabolites? AB - The human gastrointestinal tract harbors a diverse, highly mutualistic microbial flora which could produce a myriad of specialized metabolites. These specialized metabolites are the chemical cellphones that gut microflora use to communicate with their human host and could potentially be used to cure diseases. Chemical compounds in diet also shape the gut flora. In order to understand which and how the gut microbe-derived specialized metabolites affect human health, the "gut microbiome-metabolomic-human health axis" is thus proposed. In our laboratory, a strategy combining genomic, chemical, phenotypical analyses has been implemented to mine the treasures of bioactive molecules found in our gut and stool. We believe that the cutting edge metabolomics will bridge microbiology and human health. PMID- 29629423 TI - Taxon Disappearance from Microbiome Analysis Reinforces the Value of Mock Communities as a Standard in Every Sequencing Run. AB - Mock communities have been used in microbiome method development to help estimate biases introduced in PCR amplification and sequencing and to optimize pipeline outputs. Nevertheless, the strong value of routine mock community analysis beyond initial method development is rarely, if ever, considered. Here we report that our routine use of mock communities as internal standards allowed us to discover highly aberrant and strong biases in the relative proportions of multiple taxa in a single Illumina HiSeqPE250 run. In this run, an important archaeal taxon virtually disappeared from all samples, and other mock community taxa showed >2 fold high or low abundance, whereas a rerun of those identical amplicons (from the same reaction tubes) on a different date yielded "normal" results. Although obvious from the strange mock community results, we could have easily missed the problem had we not used the mock communities because of natural variation of microbiomes at our site. The "normal" results were validated over four MiSeqPE300 runs and three HiSeqPE250 runs, and run-to-run variation was usually low. While validating these "normal" results, we also discovered that some mock microbial taxa had relatively modest, but consistent, differences between sequencing platforms. We strongly advise the use of mock communities in every sequencing run to distinguish potentially serious aberrations from natural variations. The mock communities should have more than just a few members and ideally at least partly represent the samples being analyzed to detect problems that show up only in some taxa and also to help validate clustering. IMPORTANCE Despite the routine use of standards and blanks in virtually all chemical or physical assays and most biological studies (a kind of "control"), microbiome analysis has traditionally lacked such standards. Here we show that unexpected problems of unknown origin can occur in such sequencing runs and yield completely incorrect results that would not necessarily be detected without the use of standards. Assuming that the microbiome sequencing analysis works properly every time risks serious errors that can be detected by the use of mock communities. PMID- 29629425 TI - Plasma DNA-based molecular diagnosis, prognostication, and monitoring of patients with EWSR1 fusion-positive sarcomas. AB - Purpose: Ewing Sarcoma (ES) and Desmoplastic Small Round Cell Tumors (DSRCT) are aggressive sarcomas molecularly characterized by EWSR1 gene fusions. As pathognomonic genomic events in these respective tumor types, EWSR1 fusions represent robust potential biomarkers for disease monitoring. Patients and Methods: To investigate the feasibility of identifying EWSR1 fusions in plasma derived cell-free DNA (cfDNA) from ES and DSRCT patients, we evaluated two complementary approaches in samples from 17 patients with radiographic evidence of disease. The first approach involved identification of patient-specific genomic EWSR1 fusion breakpoints in formalin-fixed, paraffin-embedded tumor DNA using a broad, hybridization capture-based next generation sequencing (NGS) panel, followed by design of patient-specific droplet digital PCR (ddPCR) assays for plasma cfDNA interrogation . The second approach employed a disease-tailored targeted hybridization capture-based NGS panel applied directly to cfDNA which included EWSR1 as well as several other genes with potential prognostic utility. Results: EWSR1 fusions were identified in 11/11 (100%) ES and 5/6 (83%) DSRCT samples by ddPCR, while 10/11 (91%) and 4/6 (67%) were identified by NGS. The ddPCR approach had higher sensitivity, ranging between 0.009-0.018% sensitivity. However, the hybrid capture-based NGS assay identified the precise fusion breakpoints in the majority of cfDNA samples, as well as mutations in TP53 and STAG2, two other recurrent, clinically significant alterations in ES, all without prior knowledge of the tumor sequencing results. Conclusion: These results provide a compelling rationale for an integrated approach utilizing both NGS and ddPCR for plasma cfDNA-based biomarker evaluations in prospective cooperative group studies. PMID- 29629424 TI - Supramolecular Chemistry of Anionic Dimers, Trimers, Tetramers and Clusters. AB - Two or more anions constrained in close proximity within a single pocket are found in a number of natural systems but a less common motif in artificial systems. This review summarizes work on anion receptors capable of stabilizing anionic dimers, trimers, tetramers and clusters in a well-defined fashion. These systems may provide insights into the fundamental chemistry of anion-anion interactions and provide a guide for understanding in greater detail a number of biological and environmental processes, as well as key tenants of relevance to supramolecular chemistry, extraction, transport, crystal engineering, and the like. The primary goal of this review is to provide a general introduction into multi-anion recognition chemistry for the benefit of supramolecular and non supramolecular chemists alike. PMID- 29629426 TI - TMPRSS2-ERG fusions unexpectedly identified in men initially diagnosed with nonprostatic malignancies. AB - Background: TMPRSS2-ERG gene fusions are frequently found in prostate cancer and are pathognomomic for prostatic origin. In a series of cancer cases assayed with comprehensive genomic profiling (CGP) in the course of clinical care, we reviewed the frequency of TMPRSS2-ERG fusions in patient tumors of various histologic subtypes. Methods: Frequency of TMPRSS2-ERG fusions was determined in comprehensive genomic profiles from 64,263 cancer cases submitted to Foundation Medicine to assess genomic alterations suggesting benefit from targeted therapy. Genomic results from an index case of prostate cancer that underwent evolution from adenocarcinoma to pure squamous cell carcinoma are presented. Results: TMPRSS2-ERG fusions were identified for 0.86% (250/29030) of male patients and not found for female patients (0/35233). TMPRSS2-ERG fusions were detected in six tumors that were classified as squamous carcinoma, five of which were of unknown primary site. The index case is a patient with a large left retrovesical mass diagnosed as squamous carcinoma by morphologic examination and a history of Gleason 9 prostate cancer with prior prostatectomy and salvage radiation therapy. TMPRSS2-ERG was detected by genomic profiling in the squamous cell tumor, the primary adenocarcinoma of the prostate, and in a metachronous prostatic adenocarcinoma metastasis. Based on these results, the patient received androgen deprivation therapy. A phylogenetic tree demonstrating clonal and histopathologic evolution of prostate cancer in the index patient was constructed. Conclusions: In this large CGP dataset, TMPRSS2-ERG fusion was seen in ~30% of prostate cancers regardless of histologic type; the fusion was on occasion detected in advanced cancers not initially carrying a diagnosis of prostate carcinoma. CGP of advanced cancers in men may reveal prostatic origin by detection of the pathognomomic TMPRSS2-ERG fusion gene. PMID- 29629427 TI - Reference Values for Shear Wave Elastography of Neck and Shoulder Muscles in Healthy Individuals. AB - Purpose: to establish reference values for ultrasound shear-wave elastography for pericranial muscles in healthy individuals (m. trapezius, m. splenius capitis, m. semispinalis capitis, m. sternocleidomastoideus and m. masseter). Also to evaluate day-to-day variations in the shear-wave speeds and evaluate the effect of the pennation of the muscle fibers, ie scanning parallel or perpendicularly to the fibers. Materials and Methods: 10 healthy individuals (5 males and 5 females) had their pericranial muscles examined with shear-wave elastography in two orthogonal planes on two different days for their dominant and non-dominant side. Mean shear wave speeds from 5 ROI's in each muscle, for each scan plane for the dominant and non-dominant side for the two days were calculated. The effect of the different parameters - muscle pennation, gender, dominant vs non-dominant side and day was evaluated. Results: The effect of scan plane in relation to muscle pennation was statistically significant (p<0.0001). The mean shear-wave speed when scanning parallel to the muscle fibers was significantly higher than the mean shear-wave speed when scanning perpendicularly to the fibers. The day-to day variation was statistically significant (p=0.0258), but not clinically relevant. Shear-wave speeds differed significantly between muscles. Mean shear wave speeds (m/s) for the muscles in the parallel plane were: for masseter 2.45 (SD:+/-0.25), semispinal 3.36 (SD:+/-0.75), splenius 3.04 (SD:+/-0.65), sternocleidomastoid 2.75 (SD:+/-0.23), trapezius 3.20 (SD:+/-0.27) and trapezius lateral 3.87 (SD:+/-3.87). Conclusion: The shear wave speed variation depended on the direction of scanning. Shear wave elastography may be a method to evaluate muscle stiffness in patients suffering from chronic neck pain. PMID- 29629428 TI - Spontaneous and Traumatic Splenic Rupture: Retrospective Clinical, B-Mode and CEUS Analysis in 62 Patients. AB - Introduction: Both B-mode ultrasound and contrast-enhanced ultrasound (CEUS) are well established procedures when diagnosing traumatic splenic ruptures (TSR). To date, there are no data about CEUS patterns in spontaneous splenic ruptures (SSR). It remains unknown whether TSR and SSR differ with respect to clinical characteristics, B-mode and CEUS characteristics. Patients and Methods: Between 12/2003 and 2/2010, n=33 SSRs and n=29 TSRs were diagnosed in a tertiary referral center. All patients were examined with B-mode and CEUS, and clinical data and the outcome were retrospectively analyzed. Results: Patients with SSR were significantly older than patients with TSR (62 years vs. 44 years; p=0.01). The 4 week mortality was significantly higher in SSR than in TSR (36% vs. 0%; p=0.001). No differences between the grading of TSR and SSR could be shown in B-mode or in CEUS. Notably, CEUS was significantly superior to B-mode with respect to the grading of splenic ruptures (p=0.01). Therefore, therapeutic management was influenced by CEUS. Conclusion: There are differences between SSR and TSR, especially concerning clinical data (age, course of disease and mortality). Regarding the sonographic pattern, SSR and TSR show identical grading. When splenic rupture is suspected, CEUS should always be performed to identify patients at risk who require interventional procedures. PMID- 29629430 TI - A Cognitive Task Analysis for an Emergency Management Serious Game. AB - The Bethesda Hospitals' Emergency Preparedness Partnership identified a need to design training systems for hospital emergency management scenarios that included incident command situations. As part of this partnership, the National Library of Medicine (NLM) was challenged to develop an engaging, learner-centered simulation to specifically address hospital procedures for highly infectious diseases (HIDs) for multiple hospital roles. A serious game approach was selected for the simulation because collaborative (multiplayer) immersive, game-based simulations have been proven to generate realistic and engaging learning experiences and, when properly designed, can enhance training while minimizing cost compared to full-scale disaster exercises (Spain et al., 2013). Although substantial research effort has been put into design and evaluation of serious games, less time has been spent on developing sound instructional design methodologies to support serious game development. So how does one collect the appropriate, relevant, contextualized content and then align with serious game design elements? This paper describes how a cognitive task approach supported by a live demonstration with a think-aloud protocol was used to collect the rich psychomotor, procedural, and cognitive data necessary for the design of a serious game for handling HIDs. Furthermore, the paper presents a process to translate the collected data into meaningful content to support rapid prototyping. Recommendations for data collection and translation for a serious game close the paper. PMID- 29629429 TI - IL-33 Drives Monocyte Recruitment to Lung Interstitium through Chemokine Upregulation. AB - Tissue infiltration by circulating monocytes is a critical step in the initiation and augmentation of type 2 inflammatory responses in the lungs. Our studies demonstrate that IL-33-/- mice have a defect in monocyte extravasation from the vasculature to the lung interstitium during induction of type 2 inflammatory responses. This result suggests that monocyte migration to the lungs is IL-33 dependent, and we found that administration of exogenous recombinant IL-33 is sufficient to restore monocyte localization to the lung interstitium. Further investigation of the effect of early administration of recombinant IL-33 on the lungs identified upregulation of multiple chemokines including the monocyte chemoattractants CCL2, CCL7, and CCL22. Importantly, blockade of G-protein coupled receptor-dependent signaling, and thereby chemokine receptor activity, inhibited IL-33-driven monocyte recruitment. CCR2 deficiency prevented recruitment of monocytes to the lung extravascular space during allergic sensitization, and resulted in reduced eosinophilia after allergen challenge. Thus, IL-33 plays a critical role in the initiation of type 2 inflammatory responses by inducing upregulation of chemokines that promote monocyte recruitment to the lung interstitium. PMID- 29629431 TI - RSTensorFlow: GPU Enabled TensorFlow for Deep Learning on Commodity Android Devices. AB - Mobile devices have become an essential part of our daily lives. By virtue of both their increasing computing power and the recent progress made in AI, mobile devices evolved to act as intelligent assistants in many tasks rather than a mere way of making phone calls. However, popular and commonly used tools and frameworks for machine intelligence are still lacking the ability to make proper use of the available heterogeneous computing resources on mobile devices. In this paper, we study the benefits of utilizing the heterogeneous (CPU and GPU) computing resources available on commodity android devices while running deep learning models. We leveraged the heterogeneous computing framework RenderScript to accelerate the execution of deep learning models on commodity Android devices. Our system is implemented as an extension to the popular open-source framework TensorFlow. By integrating our acceleration framework tightly into TensorFlow, machine learning engineers can now easily make benefit of the heterogeneous computing resources on mobile devices without the need of any extra tools. We evaluate our system on different android phones models to study the trade-offs of running different neural network operations on the GPU. We also compare the performance of running different models architectures such as convolutional and recurrent neural networks on CPU only vs using heterogeneous computing resources. Our result shows that although GPUs on the phones are capable of offering substantial performance gain in matrix multiplication on mobile devices. Therefore, models that involve multiplication of large matrices can run much faster (approx. 3 times faster in our experiments) due to GPU support. PMID- 29629432 TI - Emu: Engagement Modeling for User Studies. AB - Mobile technologies that drive just-in-time ecological momentary assessments and interventions provide an unprecedented view into user behaviors and opportunities to manage chronic conditions. The success of these methods rely on engaging the user at the appropriate moment, so as to maximize questionnaire and task completion rates. However, mobile operating systems provide little support to precisely specify the contextual conditions in which to notify and engage the user, and study designers often lack the expertise to build context-aware software themselves. To address this problem, we have developed Emu, a framework that eases the development of context-aware study applications by providing a concise and powerful interface for specifying temporal- and contextual constraints for task notifications. In this paper we present the design of the Emu API and demonstrate its use in capturing a range of scenarios common to smartphone-based study applications. PMID- 29629433 TI - CIDER: Enhancing the Performance of Computational Eyeglasses. AB - The human eye offers a fascinating window into an individual's health, cognitive attention, and decision making, but we lack the ability to continually measure these parameters in the natural environment. We demonstrate CIDER, a system that operates in a highly optimized low-power mode under indoor settings by using a fast Search-Refine controller to track the eye, but detects when the environment switches to more challenging outdoor sunlight and switches models to operate robustly under this condition. Our design is holistic and tackles a) power consumption in digitizing pixels, estimating pupillary parameters, and illuminating the eye via near-infrared and b) error in estimating pupil center and pupil dilation. We demonstrate that CIDER can estimate pupil center with error less than two pixels (0.6 degrees ), and pupil diameter with error of one pixel (0.22mm). Our end-to-end results show that we can operate at power levels of roughly 7mW at a 4Hz eye tracking rate, or roughly 32mW at rates upwards of 250Hz. PMID- 29629434 TI - CONTEXTUALIZING NATURALISTIC DRIVING DATA IN A RURAL STATE AMONG DRIVERS WITH AND WITHOUT OBSTRUCTIVE SLEEP APNEA. AB - In naturalistic studies, Global Positioning System (GPS) data and date/time stamps can link driver exposure to specific environments (e.g., road types, speed limits, night driving, etc.), providing valuable context for analyzing critical events, such as crashes, near crashes, and breaches of accelerometer limits. In previous work, we showed how to automate this contextualization, using GPS data obtained at 1 Hz and merging this with Geographic Information Systems (GIS) databases maintained by the Iowa Department of Transportation (DOT). Here we further demonstrate our methods by analyzing data from 80 drivers with obstructive sleep apnea (OSA) and 48 controls, and comparing the two groups with respect to several factors of interest. The majority of comparisons found no difference between groups, suggesting similar patterns of exposures to driving environments in OSA and control drivers. However, OSA drivers appeared to spend slightly more time on roads with annual traffic counts of 500-10,000 and less time driving on wider highways, during twilight, and on roads with 10,000-25,000 annual traffic counts. PMID- 29629435 TI - Understanding Barriers and Facilitators to Breast and Cervical Cancer Screening among Muslim Women in New York City: Perspectives from Key Informants. AB - Background: Muslims are one of the fastest growing religious groups in the US. However, little is known about their health disparities, and how their unique cultural, religious, and social beliefs and practices affect health behaviors and outcomes. Studies demonstrate Muslim women may have lower rates of breast and cervical cancer screening compared to the overall population. Methods: The purpose of this study was to: 1) conduct key-informant interviews with Muslim community leaders in New York City (NYC), to understand contextual factors that impact Muslim women's beliefs and practices regarding breast and cervical cancer screening; and 2) inform the development and implementation of a research study on breast and cervical cancer screening among Muslims. Twelve key-informant interviews were conducted. The sample included imams, female religious leaders, physicians, community-based organization leaders, and social service representatives. The interview guide assessed: 1) unique healthcare barriers faced by Muslim women; 2) cultural and social considerations in conducting research; 3) potential strategies for increasing screening in this population; and 4) content and venues for culturally tailored programming and messaging. Results: Key informants noted structure and culture as barriers and religion as a facilitator to breast and cervical cancer screening. Themes regarding the development of targeted health campaigns to increase screening included the importance of educational and in-language materials and messaging, and engaging mosques and religious leaders for dissemination. Conclusion: Although Muslim women face a number of barriers to screening, religious beliefs and support structures can be leveraged to facilitate screening and enhance the dissemination and promotion of screening. PMID- 29629436 TI - A T cell equation as a conceptual model of T cell responses for maximizing the efficacy of cancer immunotherapy. AB - Following antigen stimulation, the net outcomes of a T cell response are shaped by integrated signals from both positive co-stimulatory and negative regulatory molecules. Recently, the blockade of negative regulatory molecules (i.e. immune checkpoint signals) demonstrates promising therapeutic effects in treatment of human cancers, but only in a fraction of cancer patients. Since this therapy is aimed to enhance T cell responses to cancers, here we devised a conceptual model by integrating both positive and negative signals in addition to antigen stimulation that can evaluate strategies to enhance T cell responses. A digital range of adjustment of each signal is formulated in our model for prediction of a final T cell response. Our model provides a rational combination strategy for maximizing the therapeutic effects of cancer immunotherapy. PMID- 29629437 TI - Guest Editorial: Inter- and multidisciplinary oral health clinics can better serve patients with special needs and complex diseases. PMID- 29629438 TI - Influence of leukocyte- and platelet-rich fibrin (L-PRF) on the outcomes of impacted mandibular third molar removal surgery: A split-mouth randomized clinical trial. AB - OBJECTIVES: The purpose of this study was to evaluate the influence of leukocyte- and platelet-rich fibrin (L-PRF) on impacted mandibular third molar (IMTM) extraction wound healing, patient postoperative discomfort, and incidence of alveolar osteitis. METHOD AND MATERIALS: Thirty-four patients (20 female, 14 male) who met the inclusion criteria for this split-mouth randomized clinical trial were enrolled and 30 patients completed the study. Patients were randomized and underwent bilateral IMTM surgical extractions. Following extraction, one socket randomly received L-PRF, and the other socket served as a regular blood clot control. Postoperatively, the soft tissue healing index (HI), pain according to visual analog scale (VAS), facial swelling using a horizontal and vertical guide, and incidence of alveolar osteitis were evaluated 1, 3, 7, and 14 days after surgery. RESULTS: Sites treated with L-PRF resulted in improved HI (P = .001) and lower pain VAS scores (P = .001) in the first postoperative week. Significant reduction of facial swelling was recorded on first (P = .035) and third (P = .023) postoperative days in L-PRF sites versus controls, ceasing to nonsignificant difference at day 7 (P = .224). None of the L-PRF sites and four control sites were affected by alveolar osteitis (P = .001). CONCLUSION: Within the limitations of this split-mouth study, L-PRF improved soft tissue healing and reduced postoperative pain, swelling, and incidence of alveolar osteitis after IMTM surgical extractions. PMID- 29629439 TI - The dentist's role in the prevention and management of necrotizing stomatitis in the immunosuppressed. AB - Advances in transplant medicine and availability of effective immunosuppressive regimens have dramatically improved survival for patients afflicted with end stage organ failure. However, chronic immunosuppression predisposes transplant patients to infection caused by a wide spectrum of endogenous or exogenous pathogens as well as necrotizing periodontal conditions. This article reviews clinical features, diagnosis, and management of necrotizing stomatitis in the context of therapeutic immunosuppression and discusses the integral function of dentists in eliminating oral foci of infection in preparation for transplantation as well as life-long maintenance of oral health post-transplant. We also present a renal transplant patient who developed massive soft and hard tissue necrosis in the anterior mandible. Disproportionate periodontal destruction in relation to local factors raised suspicion of iatrogenic overimmunosuppression, and he was hospitalized for management of profound neutropenia. PMID- 29629440 TI - Incidental findings based on anatomical location and clinical significance in CBCT scans of dental implant patients. AB - OBJECTIVE: Several incidental findings with varying degrees of clinical significance are often found on cone beam computed tomography (CBCT) scans of the maxillofacial skeleton acquired for dental procedures. The present study analyzed CBCT scans of dental implant therapy patients to identify incidental findings and assign those findings an appropriate clinical significance. METHOD AND MATERIALS: A total of 500 CBCT scans of patients were evaluated for this study. The incidental findings recorded in different anatomical regions were assigned a clinical significance score of mild, moderate, or severe. These findings were further segregated based on age and sex to evaluate specific trends for prevalence of incidental findings and their clinical significance. RESULTS: Out of the 298 intracranial findings, four were categorized as moderate. Out of 407 sinonasal findings, 19 were categorized as severe. Most (43%) of the airway findings were classified as mild. Among the cervical vertebrae findings the severe category included degenerative changes and vertebral-body fusion along with other degenerative changes. Most (259 [51.8%]) of the vascular findings were categorized as severe. CONCLUSION: Patients referred for dental implant treatment present with a myriad of incidental radiographic findings in the head and neck region. It is important that care providers recognize and understand these findings so appropriate care and timely intervention may be initiated. PMID- 29629442 TI - Assessment of endocrine disruption potential of essential oils of culinary herbs and spices involving glucocorticoid, androgen and vitamin D receptors. AB - Essential oils (EOs) of culinary herbs and spices are consumed on a daily basis. They are multicomponent mixtures of compounds with already demonstrated biological activities. Taking into account regular dietary intake and the chemical composition of EOs, they may be considered as candidates for endocrine disrupting entities. Therefore, we examined the effects of 31 EOs of culinary herbs and spices on transcriptional activities of glucocorticoid receptor (GR), androgen receptor (AR) and vitamin D receptor (VDR). Using reporter gene assays in stably transfected cell lines, weak anti-androgen and anti-glucocorticoid activity was observed for EO of vanilla and nutmeg, respectively. Moderate augmentation of calcitriol-dependent VDR activity was caused by EOs of ginger, thyme, coriander and lemongrass. Mixed anti-glucocorticoid and VDR-stimulatory activities were displayed by EOs of turmeric, oregano, dill, caraway, verveine and spearmint. The remaining 19 EOs were inactive against all receptors under investigation. Analyses of GR, AR and VDR target genes by means of RT-PCR confirmed the VDR-stimulatory effects, but could not confirm the anti glucocorticoid and anti-androgen effects of EOs. In conclusion, although we observed minor effects of several EOs on transcriptional activities of GR, AR and VDR, the toxicological significance of these effects is very low. Hence, 31 EOs of culinary herbs and spices may be considered safe, in terms of endocrine disruption involving receptors GR, AR and VDR. PMID- 29629441 TI - Oxidation-induced generation of a mild electrophile for proximity-enhanced protein-protein crosslinking. AB - We report a strategy to introduce a reactive electrophile into proteins through the conversion of a chemically inert group into a bioreactive group in response to an inducer molecule. This strategy was demonstrated by oxidation-induced and proximity-enhanced protein-protein crosslinking in the presence of a large excess of free nucleophile. PMID- 29629443 TI - Rechargeable aluminum batteries utilizing a chloroaluminate inorganic ionic liquid electrolyte. AB - Rechargeable aluminum batteries composed of an aluminum anode, an expanded graphite cathode, and an inorganic chloroaluminate ionic liquid electrolyte show remarkably improved capacity, reversibility, and rate capability at 393 K compared to cells based on a common organic salt based ionic liquid, AlCl3-1 ethyl-3-methylimidazolium chloride. PMID- 29629444 TI - Tetrahydro-3H-pyrazolo[4,3-a]phenanthridine-based CDK inhibitor. AB - Cyclin-dependent kinases have emerged as important targets for cancer therapy. HSD992, containing a novel scaffold based on the tetrahydro-3H-pyrazolo[4,3 a]phenanthridine core, inhibits CDK2/3 but not other CDKs and also potently inhibits several cancer cell lines. PMID- 29629445 TI - Three-dimensional direct visualization of silica dispersion in polymer-based composites. AB - The uniform dispersion of silica fillers or other neutral fillers in the polymer matrix is significant for fabricating high-performance polymer-based composites. However, there is a long-standing challenge to provide a comprehensive, wide-area and real 3D distribution map to achieve direct visualization for the dispersion state of neutral silica. Herein, we propose a novel strategy for modifying silica fillers with commercial fluorophores to form fluorescent fillers in a standard manner. Through fluorescence imaging technology, we successfully observed the 2D planar and 3D-spatial dispersion states of silica fillers in the polymer matrix. This success not only provides a visualized evaluation method for the spatial dispersion of an oxide filler, but also offers great potential in the further establishment of industrialized standards for the polymer-based composite industry. PMID- 29629446 TI - Rectangle and [2]catenane from cluster modular construction. AB - Reaction of [Et4N][Tp*WS3] (1) with [Cu(MeCN)4]PF6, CsCl, isonicotinic acid and CuCN, and treatment of [Et4N][Tp*WS3(CuCl)3] (2)/[Et4N][{Tp*WS3Cu3Cl}2(MU Cl)2(MU4-Cl)] (3) with AgOTf and bpp (Tp* = hydridotris(3,5-dimethylpyrazol-1 yl)borate; bpp = 1,3-di(4-pyridyl)propane) give rise to [Et4N]2[{Tp*WS3Cu3(CN)0.5}2(MU-Cl)2(MU4-Cl)]2(PF6)2 (4) and [(Tp*WS3Cu3)2(MU3 Cl)2(bpp)3]2(OTf)4 (5), respectively. Compounds 4 and 5 feature cluster-based rectangle and [2]catenane architecture, and both exhibit enhanced third-order nonlinear optical responses relative to those of 1. PMID- 29629447 TI - Electrochemical signal-amplified detection of 5-methylcytosine and 5 hydroxymethylcytosine in DNA using glucose modification coupled with restriction endonucleases. AB - The levels of 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) in DNA (5-mC-DNA and 5-hmC-DNA) are strongly correlated with cancer occurrence and development. The ability to distinguish and quantitatively detect them is important for cancer research. We have developed a hybridization chain reaction (HCR)-based electrochemical assay for the signal-amplified detection of the relative contents of 5-mC-DNA and 5-hmC-DNA. The DNA duplexes (containing 5-mC DNA and 5-hmC-DNA with different percentages) were modified on a gold electrode. Electroactive [Ru(NH3)6]3+ (RuHex) was used as the signal reporter, because it binds to DNA double strands. The duplexes can be cleaved by MspJI endonuclease without HCR, and result in a small peak current. However, the cleavage can be blocked after the 5-hmC-DNA duplex is converted to beta-glucosyl-5 hydroxymethylcytosine (beta-glu-5-hmC) by T4 beta-glucosyltransferase (T4 beta GT), and with the addition of helper DNA, a long double-helix DNA was formed through HCR. A significantly amplified peak current can be achieved due to the adsorption of numerous RuHex. The electrochemical signal of RuHex is correlated to the content of 5-hmC-DNA. Upon fixing the total quantity of 5-mC-DNA and 5-hmC DNA on the electrode, the signals increase with the increase in the percentage of 5-hmC-DNA for the HCR. With this assay, a detection limit of 0.05% for 5-hmC-DNA was achieved. PMID- 29629448 TI - Bright violet-to-aqua-emitting cadmium-free Ag-doped Zn-Ga-S quantum dots with high stability. AB - Herein, we report a new series of ultra-stable Cd-free Ag:Zn-Ga-S/ZnS quantum dots (QDs) with an overall short emission wavelength tunable from 370 to 540 nm via a facile one-pot non-injection method. The highest PL quantum yield of the resultant core/shell QDs could be up to 85%, and the exceptional luminescence could be maintained not only at 300 degrees C but also after phase transfer. PMID- 29629449 TI - Post hoc support vector machine learning for impedimetric biosensors based on weak protein-ligand interactions. AB - Impedimetric biosensors for measuring small molecules based on weak/transient interactions between bioreceptors and target analytes are a challenge for detection electronics, particularly in field studies or in the analysis of complex matrices. Protein-ligand binding sensors have enormous potential for biosensing, but achieving accuracy in complex solutions is a major challenge. There is a need for simple post hoc analytical tools that are not computationally expensive, yet provide near real time feedback on data derived from impedance spectra. Here, we show the use of a simple, open source support vector machine learning algorithm for analyzing impedimetric data in lieu of using equivalent circuit analysis. We demonstrate two different protein-based biosensors to show that the tool can be used for various applications. We conclude with a mobile phone-based demonstration focused on the measurement of acetone, an important biomarker related to the onset of diabetic ketoacidosis. In all conditions tested, the open source classifier was capable of performing as well as, or better, than the equivalent circuit analysis for characterizing weak/transient interactions between a model ligand (acetone) and a small chemosensory protein derived from the tsetse fly. In addition, the tool has a low computational requirement, facilitating use for mobile acquisition systems such as mobile phones. The protocol is deployed through Jupyter notebook (an open source computing environment available for mobile phone, tablet or computer use) and the code was written in Python. For each of the applications, we provide step-by-step instructions in English, Spanish, Mandarin and Portuguese to facilitate widespread use. All codes were based on scikit-learn, an open source software machine learning library in the Python language, and were processed in Jupyter notebook, an open-source web application for Python. The tool can easily be integrated with the mobile biosensor equipment for rapid detection, facilitating use by a broad range of impedimetric biosensor users. This post hoc analysis tool can serve as a launchpad for the convergence of nanobiosensors in planetary health monitoring applications based on mobile phone hardware. PMID- 29629450 TI - First-principles investigation of the Lewis acid-base adduct formation at the methylammonium lead iodide surface. AB - We have here performed a campaign of ab initio calculations focusing on the anchoring mechanism and adduct formation of some Lewis bases, both aliphatic and aromatic, on a PbI2-rich flat (001) methylammonium lead iodide (MAPI) surface. Our goal is to provide theoretical support to the recently reported experimental techniques of MAPI surface passivation via Lewis acid-base neutralization and similarly of MAI.PbI2.(Lewis base) adduct formation. We tested several X-donor bases (X = :N, :O, :S), paying attention to the thermodynamic stability of the final MAPI.base adducts and to their electronic properties. Factors that impact on the passivation mechanism are the directionality of the Lewis base lone pair and its enhanced/reduced overlap with MAPI Pb p orbitals, the dipole moment of the base and, similarly, the electronegativity of the X donor atom. Also non covalent interactions, both at the surface side (intra, MAPI) and at the very interface (inter, MAPI.Lewis base), seem to contribute to the stability of the final adducts. Here we show that the thermodynamic stability does not necessarily correspond to the most effective base -> acid dative bond formation. Starting from a low coverage (12.5% of the undercoordinated Pb atoms available at the surface are passivated) this paper paves the way towards the study of cooperative and steric effects among Lewis bases at higher coverages representing, to the best of our knowledge, one of the very first studies focusing on the molecular anchoring on the surfaces of this very important class of materials. PMID- 29629451 TI - Flexible and rigid dicarboxylic acids enable the assembly of achiral and chiral 3D Co(ii) metal-organic frameworks. AB - Two novel 3D Co(ii) metal-organic frameworks induced by flexible and rigid dicarboxylic acids [Co3(MU3-OH)(1,4-ttb)3(sa)].3H2O (1) and Co2(MU3-OH)(1,4 ttb)(4,4'-bpdc) (2) (1,4-ttb = 1-(tetrazo-5-yl)-4-(triazo-1-yl)benzene, sa = succinic acid and 4,4'-bpdc = biphenyl-4,4'-dicarboxylic acid) have been successfully synthesized and characterized via X-ray single-crystal diffraction, powder X-ray diffraction (PXRD), FT-IR spectroscopy and TG analyses. In the structures of the compounds 1 and 2, the main ligand 1,4-ttb coordinates with Co(ii) ions to form 3D host frameworks with different cavities, and the auxiliary ligands sa and 4,4'-bpdc fill the 3D cavities. More strikingly, compound 2 is a chiral 3D metal-organic framework, in which 4,4'-bpdc acts as a rigid achiral ligand. Additionally, the electrochemical properties and magnetic properties of compounds 1 and 2 have been investigated. PMID- 29629453 TI - A novel route with a Cu(ii)-MOF-derived structure to synthesize Cu/Cu2O NPs@graphene: the electron transfer leads to the synergistic effect of the Cu(0) Cu(i) phase for an effective catalysis of the Sonogashira cross-coupling reactions. AB - A uniformly dispersed two-phase Cu/Cu2O NPs@graphene was obtained via an innovative "take" and "off" synthesis strategy with a Cu-MOF-derived jacket structure. The electron transfer between the Cu phase and Cu2O phase leads to the synergistic effect of the Cu(0)-Cu(i) phase for an efficient catalysis of the Sonogashira cross-coupling reactions. PMID- 29629452 TI - Bronsted base-catalyzed annulation of allyl ketones and alkynyl 1,2-diketones. AB - The discovery of new reaction modes mediated by easily available substrates is an important research topic in organic synthesis. Allyl ketones and related compounds have been demonstrated to undergo gamma- or alpha-selective additions to different electrophiles. We disclose here the Bronsted base-catalyzed reaction of allyl ketones and alkynyl 1,2-diketones, which undergo a unique alpha selective addition/intramolecular aldol-type annulation/C-C bond cleavage process, and a series of 2-acyloxycyclopent-3-enones can be obtained under very mild conditions. PMID- 29629454 TI - The photothermal effect in MOFs: covalent post-synthetic modification of MOFs mediated by UV-Vis light under solvent-free conditions. AB - Here, we report the covalent post-synthetic modification (CPSM) of MOFs using the photothermal effect. Specifically, we subjected mixtures of a photothermally active MOF and another reagent to irradiation with a UV-Vis lamp. This caused the MOF to heat up, which in turn caused the other reagent to melt and subsequently react with the functional groups on the walls of the MOF pores. We have exploited this dual function of MOFs as both heater and host for CPSMs to achieve rapid formation of amides from the reaction of representative MOFs (UiO-66-NH2 or MIL 101-NH2-(Al)) with anhydrides under solvent-free conditions. In addition, this approach enables more complex CPSMs in MOFs such as the formation of amides in UiO-66-NH2 by using an aldehyde through a cascade reaction. PMID- 29629455 TI - Lanthanide atom substitutionally doped blue phosphorene: electronic and magnetic behaviors. AB - The structure, energy, electronic and magnetic properties of lanthanide (La, Ce, Pr, Nd, Pm, Eu and Gd) doped blue phosphorene are systematically investigated by using the GGA+U method. The calculated results show that the semi-metallic or dilute magnetic semiconductor characteristics can be achieved by substitutional doping of lanthanide atoms in blue phosphorene. From La- to Gd-doped blue phosphorene, the calculated spin magnetic moments are respectively 0.0, 1.0, 2.0, 3.0, 4.0, 8.0 and 7.0 MUB, which are generally proportional to the number of the spin-parallel 4f electrons in dopants. The spin charge density and Bader charge analysis indicate that the magnetic moments of the lanthanide atom doped systems mainly originate from the lanthanide atoms. Specifically, the Pr-doped system has a magnetocrystalline anisotropy energy (MAE) of up to 66.68 meV with the easy axis parallel to the blue phosphorene plane, and the MAE could be enhanced to 103.51 meV by applying an electric field. The Pr-, Nd-, Pm- and Gd-doped blue phosphorenes have dilute magnetic semiconductor properties, while Ce- and Eu doped blue phosphorenes exhibit half-metallic behavior. Interestingly, the La, Pr and Nd atom doping can all lead to an indirect-to-direct band gap transition. This study indicates that lanthanide-doped blue phosphorene could be a novel dilute magnetic semiconductor material applied in spintronics and magnetic storage devices. PMID- 29629456 TI - Tunable CsPbBr3/Cs4PbBr6 phase transformation and their optical spectroscopic properties. AB - As a novel type of promising materials, metal halide perovskites are a rising star in the field of optoelectronics. On this basis, a new frontier of zero dimensional perovskite-related Cs4PbBr6 with bright green emission and high stability has attracted an enormous amount of attention, even though its photoluminescence still requires to clarification. Herein, the controllable phase transformation between three-dimensional CsPbBr3 and zero-dimensional Cs4PbBr6 is easily achieved in a facile ligand-assisted supersaturated recrystallization synthesis procedure via tuning the amount of surfactants, and their unique optical properties are investigated and compared in detail. Both Cs4PbBr6 and CsPbBr3 produce remarkably intense green luminescence with quantum yields up to 45% and 80%, respectively; however, significantly different emitting behaviors are observed. The fluorescence lifetime of Cs4PbBr6 is much longer than that of CsPbBr3, and photo-blinking is easily detected in the Cs4PbBr6 product, proving that the zero-dimensional Cs4PbBr6 is indeed a highly luminescent perovskite related material. Additionally, for the first time, tunable emissions over the visible-light spectral region are demonstrated to be achievable via halogen composition modulations in the Cs4PbX6 (X = Cl, Br, I) samples. Our study brings a simple method for the phase control of CsPbBr3/Cs4PbBr6 and demonstrates the intrinsic luminescence nature of the zero-dimensional perovskite-related Cs4PbX6 products. PMID- 29629457 TI - ESR evidence of the dynamic crossover in the supercooled liquid states of a series of solid n-alkanes. AB - A study of the rotation dynamics of the spin probe TEMPO by electron spin resonance (ESR) spectroscopy in a series of six short- and medium-sized n-alkanes is presented. In addition to the usual crossover effects connected with solid liquid phase transitions at temperature Tm and the solid-solid transition at Tss, we find a strong correlation between the change in reorientation at the characteristic ESR temperature TfastX1 < Tss and/or Tm with the ratio TfastX1/Tm = 0.76 +/- 0.03 and the characteristic dynamic temperature, TX, obtained from the viscosity data. This indicates the presence of local disordered regions in the crystalline structure which is indeed sensitive to dynamic change at the crossover temperature TX ? TfastX1. PMID- 29629458 TI - Chiral polymorphism in the self-assemblies of achiral molecules induced by multiple hydrogen bonds. AB - Owing to a wide range of applications within the areas such as chiral sensors, enantiomeric resolution, and asymmetric catalysis, understanding chiral adsorption phenomena at the interface is thereby of great importance. In particular, the role of multiple hydrogen bonds in inducing chiral diversiform morphologies has never been systematically investigated. Herein, by delicate control of the volume ratio of 1-octanoic acid and 1-octanol as the mixed solvent, a series of self-assembled nanostructures of 2-hydroxyl-7-pentadecyloxy fluorenone (HPF) were sequentially fabricated, including the achiral densely packed pattern, the chiral "6-2" pattern, the chiral alternate pattern, and the chiral double-rosette pattern. Eventually, those patterns would evolve into an achiral and thermodynamically favored zigzag pattern. Based on DFT calculations, we demonstrate that the stabilities of diversiform morphologies originate from different hydrogen bonding and molecular packing densities. In addition, quantum theory of atoms in molecule (QTAIM) analysis is further applied to interpret the nature of these hydrogen bonds. PMID- 29629459 TI - Effect of osmolytes on the thermal stability of proteins: replica exchange simulations of Trp-cage in urea and betaine solutions. AB - Although osmolytes are known to modulate the folding equilibrium, the molecular mechanism of their effect on thermal denaturation of proteins is still poorly understood. Here, we simulated the thermal denaturation of a small model protein (Trp-cage) in the presence of denaturing (urea) and stabilizing (betaine) osmolytes, using the all-atom replica exchange molecular dynamics simulations. We found that urea destabilizes Trp-cage by enthalpically-driven association with the protein, acting synergistically with temperature to induce unfolding. In contrast, betaine is sterically excluded from the protein surface thereby exerting entropic depletion forces that contribute to the stabilization of the native state. In fact, we find that while at low temperatures betaine slightly increases the folding free energy of Trp-cage by promoting another near-native conformation, it protects the protein against temperature-induced denaturation. This, in turn, can be attributed to enhanced exclusion of betaine at higher temperatures that arises from less attractive interactions with the protein surface. PMID- 29629460 TI - A zwitterionic aluminabenzene-alkylzirconium complex having half-zirconocene structure: synthesis and application for additive-free ethylene polymerization. AB - An aluminabenzene-alkylzirconium complex having a half-zirconocene structure was synthesized. X-ray crystallographic analysis of this complex revealed a zwitterionic structure consisting of cationic alkylzirconium chloride and four coordinated aluminate. In the presence of a catalytic amount of this complex, ethylene polymerization could proceed without any additives to form ultra-high molecular weight polyethylene. PMID- 29629461 TI - What dictates which ion, I- or Br-, mediates the growth of cubic Pd nanocrystals? AB - Cubic Pd nanocrystals (CPNCs) as one of typical nanostructures are generally fabricated using I- or Br- as capping ions. However, which ion, I- or Br-, exclusively mediates the growth of CPNCs in a given reaction system is not well understood. Herein, regardless of I- or Br- as the capping ion, we successfully achieved CPNCs in the same reaction system simply by adjusting the pH. Based on the Finke-Watzky kinetic model, an increase in pH accelerates the overall reduction rate of Pd2+, and the formation of CPNCs only occurs over the range of specific solution reduction rate constants (k1). This kinetically illuminates that the reduction rate of Pd2+ is the physicochemical parameter that determines which ion, I- or Br-, dictates the growth of CPNCs. Also, density functional theory (DFT) calculations further elucidate the dependence of the reduction rate of Pd2+ on pH and the configuration of the activated Pd2+ complex. PMID- 29629462 TI - Atomic-level design of CoOH+-hydroxyapatite@C catalysts for superfast degradation of organics via peroxymonosulfate activation. AB - We report a strategy for simultaneous cobalt removal and organic waste decomposition by using mesoporous hydroxyapatite nanoparticles wrapped in uniform carbon layers (HA@C). The in situ formation of CoOH+-HA@C due to ion exchange greatly improved the degradation efficiency by at least one order of magnitude compared to free Co2+. PMID- 29629463 TI - Exploring the alternatives of biological nitrogen fixation. AB - Most biological nitrogen fixation (BNF) results from the activity of the molybdenum nitrogenase (Mo-nitrogenase, Nif), an oxygen-sensitive metalloenzyme complex found in all known diazotrophs. Two alternative forms of nitrogenase, the vanadium nitrogenase (V-nitrogenase, Vnf) and the iron-only nitrogenase (Fe-only nitrogenase, Anf) have also been identified in the genome of some organisms that encode for Nif. It has been suggested that alternative nitrogenases were responsible for N2-fixation on early Earth because oceans were depleted of bioavailable Mo. Results of recent phylogenetic- and structure-based studies suggest, however, that such an evolutionary path is unlikely, and favor a new model for a stepwise evolution of nitrogenase where the V-nitrogenase and the Fe only nitrogenase are not the ancestor of the Mo-nitrogenase. Rather, Mo nitrogenase emerged within the methanogenic archaea and then gave rise to the alternative forms suggesting they arose later in response to the availability of fixed N2 and local environmental factors that influenced metal availability. This review summarizes the current state of knowledge on (1) the biochemistry of these complex systems highlighting the common and specific structural features and catalytic activities of the enzymes, (2) the recent progress in defining the discrete set of genes associated to N2-fixation and the regulatory features that coordinate the differential expression of genes in response to metal availability, and (3) the diverse taxonomic and phylogenic distribution of nitrogenase enzymes and the evolutionary history of BNF from the perspective of metal content and metal availability. PMID- 29629464 TI - Fundamental limitation of electrocatalytic methane conversion to methanol. AB - The electrochemical oxidation of methane to methanol at remote oil fields where methane is flared is the ultimate solution to harness this valuable energy resource. In this study we identify a fundamental surface catalytic limitation of this process in terms of a compromise between selectivity and activity, as oxygen evolution is a competing reaction. By investigating two classes of materials, rutile oxides and two-dimensional transition metal nitrides and carbides (MXenes), we find a linear relationship between the energy needed to activate methane, i.e. to break the first C-H bond, and oxygen binding energies on the surface. Based on a simple kinetic model we can conclude that in order to obtain sufficient activity oxygen has to bind weakly to the surface but there is an upper limit to retain selectivity. Few potentially interesting candidates are found but this relatively simple description enables future large scale screening studies for more optimal candidates. PMID- 29629465 TI - A thermoelectric copper-iodide composite from the pyrolysis of a well-defined coordination polymer. AB - Coordination polymer 1 was prepared from CuI and a flexible [SNS] ligand L in acetonitrile. The thermal decomposition of 1 yielded a CuI-rich thermoelectric carbon composite 2, which is relatively light, thermally stable and robust. Composite 2 possesses high Seebeck coefficients (700-950 MUV K-1) from rt to 204 degrees C after an optimization cycle. PMID- 29629466 TI - A high-valent di-MU-oxo dimanganese complex covalently anchored in a metal organic framework as a highly efficient and recoverable water oxidation catalyst. AB - A biomimetic di-MU-oxo dimanganese complex bearing two triazole-binding tridentate ligands is successfully anchored inside a metal-organic framework (MOF) through a covalent-functionalization-assisted coordination strategy, exhibiting high activity and reliable durability in the chemical water oxidation reaction. PMID- 29629467 TI - Currently used organophosphate flame retardants determined in the settled dust of masjids and hotels of Saudi Arabia, a new insight into human health implications of dust exposure. AB - Indoor settled dust particles are considered as an important source of human exposure to chemicals such as organophosphate flame retardants (PFRs). In recent decades the Kingdom of Saudi Arabia (KSA) has experienced tremendous growth in population, as a result the number of masjids has also increased significantly to provide sufficient space for the public to offer prayers. The hospitality industry in KSA is also expanding to cater for the ever-increasing number of pilgrims visiting the two holy cities of the kingdom. However, limited data are available on the indoor pollution of masjids and hotels. In this study, PFRs were analyzed in the settled dust collected from various hotels and masjids of Jeddah, KSA. Tris(1,3-dichloro-2-propyl) phosphate (TDCPP) and tris(1-chloro-2-propyl) phosphate (TCPP) were the major PFRs in masjid (median = 2490 and 2055 ngg-1) and hotel (median = 2360 and 3315 ngg-1) dust, respectively. A public health risk assessment was carried out by determining the incremental lifetime cancer risk (ILCR), and daily exposure via dust ingestion, inhalation, and dermal contact of PFRs. The calculated daily exposure via dust ingestion was well below the reference dose (RfD) values, and also the calculated hazardous quotient (HQ) and carcinogenic risk were well below the risk mark. However, the ILCR for PFRs was below the reference values of USEPA, which suggested that long-term exposure to these chemicals has a limited cause for concern. The study showed that the general public is exposed to PFRs in the studied microenvironments and the major exposure routes are dermal contact and ingestion. PMID- 29629468 TI - Co3O4 nanowire@NiO nanosheet arrays for high performance asymmetric supercapacitors. AB - Herein, we report a simple and facile sequential hydrothermal process for the synthesis of Co3O4 nanowire@NiO nanosheet arrays (CNAs). The as-synthesized CNAs were characterized in detail using various analytical techniques, which confirmed the high crystallinity, purity, and high-density growth of these nanomaterials. From an application point of view, the as-synthesized CNAs were directly used as supercapacitor electrodes, revealing a specific capacitance of up to 2018 mF cm-2 at a current density of 2 mA cm-2. Furthermore, a flexible asymmetric supercapacitor was fabricated using the as-synthesized CNAs as the anode and activated carbon as the cathode, which revealed a specific capacitance of 134.6 mF cm-2 at a current density of 2 mA cm-2. In addition, the supercapacitor showed excellent capacity retention of 73.5% after 10 000 cycles at a current density of 10 mA cm-2. PMID- 29629469 TI - Towards optimised drug delivery: structure and composition of testosterone enanthate in sodium dodecyl sulfate monolayers. AB - Surface tension and specular neutron reflectivity measurements have been used, for the first time to systematically study both the interfacial structure and composition of monolayers of the soluble surfactant, sodium dodecyl sulfate containing a low-dose, poorly water soluble drug, testosterone enanthate. Modelling of the specular neutron reflectivity data suggests that the hydrophobic testosterone enanthate was adsorbed in the C12 hydrophobic tail region of the surfactant monolayer, regardless of the concentration of surfactant at the interface and whether or not additional drug was added to the interface. The location of the hydrophobic drug in the tail region of the surfactant monolayer is supported by the results of classical, large-scale molecular dynamics simulations. The thickness of the surfactant monolayer obtained, in the presence and absence of drug, using molecular dynamics simulations was in good agreement with the corresponding values obtained from the specular neutron reflectivity measurements. The stoichiometry of surfactant:drug at the air-water interface at sodium dodecyl sulfate concentrations above the critical micelle concentration was determined from specular neutron reflectivity measurements to be approximately 3 : 1, and remained constant after the spreading of further testosterone enanthate at the interface. Significantly, this stoichiometry was the same as that obtained in the micelles from bulk solubilisation studies. Important insights into the preferred location of drug in surfactant monolayers at the air-water interface as well as its effect on the structure of the monolayer have been obtained from our combined use of experimental and simulation techniques. PMID- 29629470 TI - Biotinylated single-chain variable fragment-based enzyme-linked immunosorbent assay for glycocholic acid. AB - Glycocholic acid (GCA) has been identified as a novel selective and sensitive biomarker for hepatocellular carcinoma (HCC). In this work, a recombinant antibody, scFv-G11, which was shown previously to have selective reactivity for GCA, was labeled with biotin using a chemical and an enzymatic method, respectively. The enzymatic method proved superior giving sensitive scFv-biotin preparations. Based on biotinylated scFv against GCA and a biotin-streptavidin system for signal amplification, an indirect competitive biotin-streptavidin amplified enzyme-linked immunosorbent assay (BA-ELISA) has been established for the sensitive and rapid detection of GCA. Several physiochemical factors that influenced assay performance, such as organic cosolvent, ionic strength, and pH, were studied. Under the optimized conditions, the indirect competitive BA-ELISA based on the obtained biotinylated scFv antibodies indicated that the average concentration required for 50% inhibition of binding (IC50) and the limit of detection (LOD) for GCA were 0.42 MUg mL-1 and 0.07 MUg mL-1, respectively, and the linear response range extended from 0.14 to 1.24 MUg mL-1. Cross-reactivity of biotinylated scFv antibodies with various bile acid analogues was below 1.89%, except for taurocholic acid. The recoveries of GCA from urine samples via this indirect competitive BA-ELISA ranged from 108.3% to 131.5%, and correlated well with liquid chromatography-electrospray tandem mass spectrometry (LC-MS/MS), which indicated the accuracy and reliability of biotinylated scFv-based ELISA in the detection of GCA in urine samples. This study also demonstrates the broad utility of scFv for the development of highly sensitive immunoassays. PMID- 29629471 TI - Energy transfer and photoluminescence properties of lanthanide-containing polyoxotitanate cages coordinated by salicylate ligands. AB - Polyoxotitanate (POT) cages have attracted considerable attention recently; much of this from the fact that they can be considered to be structural models for the technologically important semiconductor TiO2. Among the reported POT cages, lanthanide-containing (Ln-POT) cages are of particular interest owing to the fascinating luminescence properties of Ln3+ ions and the versatile coordination environments that they can adopt. In the present study, we report the energy transfer mechanism and photoluminescence properties of a series of isostructural Ln-POT cages coordinated by salicylate ligands, of general formula [LnTi6O3(OiPr)9(salicylate)6] (Ln-1, Ln = La to Er excluding Pm). Both visible (for Pr-1, Sm-1, Eu-1, Ho-1 and Er-1) and near-infrared (for Nd-1 and Er-1) Ln3+ centred photoluminescence can be sensitised in solution, and most importantly, their excitation bands all extend well into the visible region up to 475 nm. With the assistance of steady-state and time-resolved photoluminescence spectroscopy, an energy-transfer mechanism involving the salicylate-to-Ti4+ charge-transfer state is proposed to account for the largely red-shifted excitation wavelengths of these Ln-1 cages. The photoluminescence quantum yield of Nd-1 upon excitation via the charge-transfer state reaches 0.30 +/- 0.01% in solution, making it among the highest reported values for Nd3+-complexes in the literature. PMID- 29629472 TI - Up-conversion monodispersed spheres of NaYF4:Yb3+/Er3+: green and red emission tailoring mediated by heating temperature, and greatly enhanced luminescence by Mn2+ doping. AB - Submicron sized, monodispersed spheres of Mn2+, Yb3+/Er3+ and Mn2+/Yb3+/Er3+ doped alpha-NaYF4 were easily autoclaved from mixed solutions of the component nitrates and ammonium fluoride (NH4F), in the presence of EDTA-2Na. Detailed characterizations of the resultant phosphors were obtained using XRD, Raman spectroscopy, FE-SEM, HR-TEM, STEM, PLE/PL spectroscopy, and fluorescence decay analysis. Finer structure and better crystal perfection was observed at a higher calcination temperature, and the spherical shape and excellent dispersion of the original particles was retained at temperatures up to 600 degrees C. Under the 980 nm infrared excitation, the Yb3+/Er3+-doped sample (calcined at 400 degrees C) exhibits a stronger green emission centered at ~524 nm (2H11/2 -> 4I15/2 transition of Er3+) and a weaker red emission centered at ~657 nm (4F9/2 -> 4I15/2 transition of Er3+). A 200 degrees C increase in the temperature from 400 degrees C to 600 degrees C resulted in the dominant red emission originating from the 4F9/2 -> 4I15/2 transition of Er3+, instead of the previously dominant green one. Mn2+ doping induced a remarkable more enhanced intensity at ~657 nm and ~667 nm (red emission area) than that at ~524 nm and ~546 nm (green emission area), because of the non-radiative energy transfer between Mn2+ and Er3+. However, a poor thermal stability was induced by Mn2+ doping. The observed upconversion luminescence of the samples calcined at 400 degrees C and 600 degrees C followed the two photon process and the four photon process, respectively. PMID- 29629473 TI - Structure elucidation and quantification of the reduction products of anticancer Pt(iv) prodrugs by electrochemistry/mass spectrometry (EC-MS). AB - Pt(iv) prodrugs are a class of promising anticancer agents, which are activated by reduction to the active Pt(ii) species. Consequently, the reduction process is a crucial parameter. Herein, a new approach using electrochemistry (EC) coupled to liquid chromatography (LC) and electrospray ionization-mass spectrometry (ESI MS) or inductively coupled plasma (ICP)-MS was applied. This enabled getting insights into the differences in the reduction and ligand release of platinum(iv) complexes with varying equatorial core structures. PMID- 29629474 TI - Helical carbon tubes derived from epitaxial Cu-MOF coating on textile for enhanced supercapacitor performance. AB - The design and development of the supercapacitors containing metal oxides and carbon materials is very important for energy-storage devices in laboratory and industry. In this study, we report a helical carbon tube material derived from epitaxial Cu-MOF coating on textile by calcination treatment. The electrochemical performance obtained from the cyclic voltammetry (CV), galvanostatic charge/discharge (GCD) and cyclic stability measurements indicates that such a hybrid carbon material with a unique structure has a very high areal capacitance of 1812 mF cm-2 at a current density of 1 mA cm-2, and the material also has a good recyclability of 90% after 2000 cycles. This study combines the advantages of MOF- and cotton textile-derived carbon materials, and this study can serve as a guidance to improve the capacitance performance of supercapacitors. PMID- 29629475 TI - Special Issue: Iconic Rice Varieties. PMID- 29629476 TI - Health and health care access for Syrian refugees living in Istanbul. AB - OBJECTIVES: The study was conducted to assess the health needs of urban refugees living in Istanbul. METHODS: A mixed methods approach was adopted to interview Syrian women from households, doctors, decision makers and NGO representatives. The data were collected between June and October 2015. RESULTS: The main challenges were the cost of living in Istanbul, increased rent and language barrier. Almost half (49.6%) of the interviewed women did not know about free health care rights for Syrians. In the last 30 days preceding the interview, 58.6% of the participants sought health care primarily through state hospitals, primary health care centres and pharmacies. The participants had difficulty in accessing health care due to the language barrier and a lack of knowledge of the Turkish health care system. Waiting time at hospitals and negative attitudes of health care staff reduced satisfaction in these services. CONCLUSIONS: In relation to life in Turkey, the main issues for Syrian refugees were not directly related to health. They have been given the right to access health care, although had many difficulties in understanding and accessing services in a crowded city. PMID- 29629477 TI - A method to accurately estimate the catheter length needed for a tunneled central catheter placement. AB - A typical method of placing a tunneled central catheter utilizes C-arm fluoroscopy for insertion and estimation of the length of the catheter needed. We describe a new technique to estimate the length more accurately using a C-arm fluoroscope. PMID- 29629478 TI - Shanyou 63: an elite mega rice hybrid in China. AB - Hybrid rice has been successfully used for commercial rice production for 40 years in China. Shanyou 63, a mega rice hybrid, derived from the parents Zhenshan 97A and Minghui 63, was a milestone for China's hybrid rice development and production because of its high yield and wide adaptability. It was planted in 16 provinces of the country on 17% of the national hybrid rice area annually during the 29 years from 1984 to 2012. The hybrid and its parents have also been widely used for basic and agronomic studies related to rice heterosis, stress tolerance, molecular markers and genomics. We review the development of the hybrid and its parents and their major characteristics for the purpose of learning from the history and guiding future hybrid rice development. The history and development experience show that a successful hybrid rice variety should have multiple traits, including high yield, wide adaptability, resistances to major diseases, and high rice quality that meets the demands of consumers. From the breeding aspect, hybrid rice provides the advantage of combining elite traits or genes from different types of parents, such as those from subspecies of indica and japonica, into a single variety. Farmers prefer not only a variety with high yield potential, but also stable yields and local adaptability. PMID- 29629479 TI - IR64: a high-quality and high-yielding mega variety. AB - High-yielding varieties developed in the 1960s and 1970s at the International Rice Research Institute (IRRI) and elsewhere benefited farmers and the public, ultimately increasing yields and reducing the cost of rice to consumers. Most of these varieties, however, did not have the optimum cooking quality that was possessed by many of the traditional varieties they replaced. In 1985, the IRRI developed indica variety IR64 was released in the Philippines. In addition to its high yield, early maturity and disease resistance, it had excellent cooking quality, matching that of the best varieties available. These merits resulted in its rapid spread and cultivation on over 10 million ha in the two decades after it was released. It has intermediate amylose content and gelatinization temperature, and good taste. It is resistant to blast and bacterial blight diseases, and to brown planthopper. Because of its success as a variety, it has been used extensively in scientific studies and has been well-characterized genetically. Many valuable genes have been introduced into IR64 through backcross breeding and it has been used in thousands of crosses. Its area of cultivation has declined in the past 10 years, but it has been replaced by a new generation of high-quality varieties that are mostly its progeny or relatives. Continued basic studies on IR64 and related varieties should help in unraveling the complex genetic control of yield and other desirable traits that are prized by rice farmers and consumers. PMID- 29629480 TI - Open-access programs for injury categorization using ICD-9 or ICD-10. AB - BACKGROUND: The article introduces Programs for Injury Categorization, using the International Classification of Diseases (ICD) and R statistical software (ICDPIC R). Starting with ICD-8, methods have been described to map injury diagnosis codes to severity scores, especially the Abbreviated Injury Scale (AIS) and Injury Severity Score (ISS). ICDPIC was originally developed for this purpose using Stata, and ICDPIC-R is an open-access update that accepts both ICD-9 and ICD-10 codes. METHODS: Data were obtained from the National Trauma Data Bank (NTDB), Admission Year 2015. ICDPIC-R derives CDC injury mechanism categories and an approximate ISS ("RISS") from either ICD-9 or ICD-10 codes. For ICD-9-coded cases, RISS is derived similar to the Stata package (with some improvements reflecting user feedback). For ICD-10-coded cases, RISS may be calculated in several ways: The "GEM" methods convert ICD-10 to ICD-9 (using General Equivalence Mapping tables from CMS) and then calculate ISS with options similar to the Stata package; a "ROCmax" method calculates RISS directly from ICD-10 codes, based on diagnosis-specific mortality in the NTDB, maximizing the C statistic for predicting NTDB mortality while attempting to minimize the difference between RISS and ISS submitted by NTDB registrars (ISSAIS). Findings were validated using data from the National Inpatient Survey (NIS, 2015). RESULTS: NTDB contained 917,865 cases, of which 86,878 had valid ICD-10 injury codes. For a random 100,000 ICD-9-coded cases in NTDB, RISS using the GEM methods was nearly identical to ISS calculated by the Stata version, which has been previously validated. For ICD-10-coded cases in NTDB, categorized ISS using any version of RISS was similar to ISSAIS; for both NTDB and NIS cases, increasing ISS was associated with increasing mortality. Prediction of NTDB mortality was associated with C-statistics of 0.81 for ISSAIS, 0.75 for RISS using the GEM methods, and 0.85 for RISS using the ROCmax method; prediction of NIS mortality was associated with C-statistics of 0.75-0.76 for RISS using the GEM methods, and 0.78 for RISS using the ROCmax method. Instructions are provided for accessing ICDPIC-R at no cost. CONCLUSIONS: The ideal methods of injury categorization and injury severity scoring involve trained personnel with access to injured persons or their medical records. ICDPIC-R may be a useful substitute when this ideal cannot be obtained. PMID- 29629481 TI - Trace Elements in Saliva as Markers of Type 2 Diabetes Mellitus. AB - To analyze Mg, Ca, and Zn levels in saliva, comparing patients with type 2 diabetes mellitus and a control group of healthy subjects. This transversal, observational, clinical study included a total sample of 147 patients, 74 with type 2 diabetes mellitus and a control group of 73 healthy subjects. Socio demographic, anthropometric, diabetological, and metabolic variables were registered. Trace elements in non-stimulated basal saliva were measured using inductively coupled plasma mass spectrometry (ICP-MS): Mg, Ca, and Zn. Concentrations of zinc, calcium, and magnesium were significantly higher in the diabetic group than the control group (p < 0.001). A relation was observed between waist circumference and high cardiovascular risk in men (based on two categories: waist circumference < 102 cm; waist circumference >= 102 cm), and magnesium levels in saliva (p = 0.003). Magnesium, zinc, and calcium levels in saliva could be useful markers for differentiating patients with type 2 diabetes mellitus from non-diabetics. The salivary magnesium could be used as a marker of high cardiovascular risk when associated with abdominal obesity represented by a waist circumference >= 102 cm in men. The present results do suggest that salivary zinc levels could act as a good marker of type 2 diabetes mellitus, in light of zinc's well-known role as a co-marker of insulin and its relationship to carbohydrate metabolism. PMID- 29629482 TI - Immunologist's Perspectives on Assessment and Management of Lung Disease in CVID: a Survey of the Membership of the Clinical Immunology Society and the European Society for Immunodeficiencies. PMID- 29629483 TI - Mott cell interstitial nephritis revealing Waldenstrom macroglobulinaemia. PMID- 29629484 TI - Light chain monoclonal gammopathy of undetermined significance is characterized by a high disappearance rate and low risk of progression on longitudinal analysis. AB - We determined the 10-year progression rate of light chain monoclonal gammopathy of undetermined significance (LCMGUS) and investigated potential associations with cancer utilizing the German population-based Heinz Nixdorf Recall Study. The Heinz Nixdorf Recall Study comprises 4814 men and women aged 45-75 years. Serum samples from baseline (2000-2003) and five-year (2006-2008) and 10-year (2011 2015) follow-up examinations were screened for monoclonal free light chains (FLC). LCMGUS was defined as abnormal FLC ratio, increase of involved FLC with complete loss of immunoglobulin heavy chain, and absence of a history of lymphoproliferative disease (LPD). Seventy-five individuals with LCMGUS were identified across all three evaluation time points (median age 64 years; 43 (57%) male; FLCR > 1.65 65 (87%); FLCR <= 0.65 10 (13%)). After a median observation time of 11.5 years, none of the LCMGUS cases had progressed to overt LPD; in particular, we did not observe incident light chain multiple myeloma. On serial analysis 17/31 (55%), LCMGUS could not be confirmed and disappearance of the monoclonal protein was associated with low concentrations of the involved FLC. Individuals with LCMGUS had a 1.5-fold increased risk of cancer but did not show differences in overall survival or renal function as compared to individuals with normal FLC. In conclusion, LCMGUS represents a relatively benign condition with a high disappearance rate of the monoclonal protein on longitudinal analysis and normal overall survival at least in the population-based setting. PMID- 29629485 TI - Has the Time Come to Be More Aggressive With Bariatric Surgery in Obese Patients With Chronic Systolic Heart Failure? AB - PURPOSE OF REVIEW: Obesity is a strong risk factor for the development of heart failure (HF). Diet, exercise, and weight-loss pharmacotherapies have limited potential to achieve significant and sustainable weight loss, especially in patients with symptomatic systolic HF. This review seeks to determine the role of bariatric surgery for patients with systolic HF and obesity. RECENT FINDINGS: Bariatric surgeries such as the laparoscopic sleeve gastrectomy (LSG) and Roux-en Y gastric bypass (RYGB) represent the most successful long-term strategy for achieving weight loss and diabetes and hypertension remission in the general obese population. These benefits translate to reductions in cardiovascular events and mortality, as well as improvements in myocardial structure and function. There is also now data supporting the safety of LSG or RYGB in patients with systolic dysfunction and a reduction in HF admissions post-operatively. Current literature and clinical experience suggest that the most appropriate bariatric surgery candidates with HF are patients aged < 50-60 years, with severely depressed systolic function and NYHA II-III symptoms, who have failed non surgical strategies and have a high likelihood of future cardiac transplantation candidacy after weight loss. This review seeks to determine the role of bariatric surgery for patients with systolic HF and obesity. PMID- 29629486 TI - Koshihikari: a premium short-grain rice cultivar - its expansion and breeding in Japan. AB - Koshihikari, a Japanese short-grain rice cultivar, was developed in 1956, more than 60 years ago. Despite its age, it has been the most widely grown cultivar in Japan for more than 35 years, making it the most important rice for the Japanese people. In its early days, there was no reason to predict that Koshihikari would become so widely disseminated. However, since the end of the post-World War II food shortage in the 1960s, Japanese preferences changed from high productivity to good eating quality. This triggered wide expansion of Koshihikari cultivation due to the cultivar's excellent taste and texture. With increasing cultivation of Koshihikari in Japan, several good agronomic characteristics beyond its high eating quality became apparent, such as its good adaptation to different environments, tolerance to pre-harvest sprouting, and cold tolerance during the booting stage. These characteristics outweigh drawbacks such as its low blast resistance and low lodging resistance. The popularity of Koshihikari influenced subsequent rice breeding trends at regional agricultural experimental stations, and the characteristics of newly developed rice cultivars in Japan are usually rated relative to Koshihikari, which is used as the benchmark. Koshihikari was the first japonica rice cultivar whose whole genome has been sequenced by means of next-generation sequencing. Furthermore, comparison of the genomes of Koshihikari and Nipponbare has provided detailed insights into the genetic diversity of Japanese rice cultivars relative to that in rice populations elsewhere in the world. Further progress in rice genomics is gradually unlocking the mechanisms that underlie the agronomic characteristics of Koshihikari. To support both research and the development of novel rice cultivars, a series of isogenic and near-isogenic lines in the Koshihikari genetic background have been continuously developed. These new findings and materials will facilitate genomics assisted rice breeding, eventually leading to superior cultivars. PMID- 29629487 TI - Quasispecies characters of hepatitis B virus in immunoprophylaxis failure infants. AB - Hepatitis B vaccination prevents 80-95% of transmission and reduces the incidence of HBV in children. The variations in the a determinant of HBV surface antigen (HBsAg) have been reported to be the most prevalent cause for vaccine or antibody escape. There is a conflicting evidence on as to whether escape mutants arise de novo in infected infants or whether the mutants, that have preexisted maternally, subsequently undergo selective replication in the infant under immune pressure. Here, we report that nearly 65% (55 of 85) vaccination failure in child patients has no amino acid substitution in a determinant as seen by Sanger sequencing. We further employed an Illumina sequencing platform-based method to detect HBV quasispecies in four immunoprophylaxis failure infants and their mothers. In our data, the substitution rate of amino acid located at a determinant is relatively low (< 10%), I/T126A, C124S, F134Y, K141Q, Q129H, D144A, G145V, and N146K, which showed no statistical difference to their mothers, proving that these vaccine escape mutants preexist maternally as minor variants. Besides that, bioinformatical analysis showed that the binding affinity of high variation epitopes (amino acid divergence in mother and their infants > 20%) to related HLA molecules was generally decreased, these traces of immune escape suggesting that immune pressure was present and was effective in all samples. PMID- 29629488 TI - Pusa Basmati 1121 - a rice variety with exceptional kernel elongation and volume expansion after cooking. AB - Pusa Basmati 1121 (PB 1121) is a landmark Basmati rice variety having Basmati quality traits introgressed from traditional Basmati varieties such as Basmati 370 and Type 3. It was released for commercial cultivation in 2003. It possesses extra-long slender milled grains (9.00 mm), pleasant aroma, and an exceptionally high cooked kernel elongation ratio of 2.5 with a cooked kernel length of up to 22 mm, volume expansion more than four times, appealing taste, good mouth feel and easy digestibility. Owing to its exceptional quality characteristics, it has set new standards in the Basmati rice market. The cumulative foreign exchange earnings through export of PB 1121 since 2008 have been US$ 20.8 billion, which has brought prosperity to millions of Basmati farmers. During 2017, the farmers cultivating PB 1121 earned on an average US$ 1400/ha as against US$ 650/ha cultivating traditional Basmati, making it a highly profitable enterprise. Currently, PB 1121 is grown in ~ 70% of the total area under Basmati rice cultivation in India. It is the most common Basmati rice variety in rice grain quality research for developing mapping populations, genetic analyses and molecular mapping of Basmati quality traits. Additionally, it has been widely used in the Basmati rice breeding program across India, because of its superior quality attributes. This article presents an account of development of PB 1121, its major characteristic features and its flagship role in heralding a Basmati rice revolution. The prospective role of PB 1121 in Basmati rice improvement and future Basmati rice research as a whole is also presented. PMID- 29629489 TI - Inhibitory properties of some heavy metals on carbonic anhydrase I and II isozymes activities purified from Van Lake fish (Chalcalburnus Tarichi) gill. AB - In this study, CA I and II isoenzymes were purified from Van Lake fish gills by using Sepharose-4B-L-tyrosine-sulfanilamide affinity chromatography and to determine the effects of some metals on the enzyme activities. For purified CA I isoenzyme, yield, specific activity, and purification fold were obtained as 42.07%, 4948.12 EU/mg protein, and 116.61 and for CA II isoenzyme, 7%, 1798.56 EU/mg protein, and 42.38 respectively. Activity of CA was determined by measuring "CO2-hydratase activity". Purity control was checked by SDS-PAGE. In vitro inhibitory effect of Cu2+, Ag+, Cd2+, Ni2+ metal ions, and arsenic (V) oxide were also examined for both isozymes activities. Whereas Cu2+, Ag+, Cd2+, and Ni2+ ions showed inhibitory effects on both isozymes, arsenic (V) oxide showed activation effect. IC50 values were calculated by drawing activity %-[I] graphs for metal ions exhibiting inhibitory effects. IC50 values were determined as 3.39, 6.38, 13.52, and 206 MUM for CA I isozyme and 6.16, 20.29, 46, and 223 MUM for CA II isozyme respectively. PMID- 29629490 TI - Long-Term Follow-Up Study of Liver-Related Outcome After Bilio-Pancreatic Diversion in Patients with Initial, Significant Liver Damage. AB - BACKGROUND: Obesity is associated with NAFLD, and bariatric surgery has significant impact on this liver disease, with reported improvement in hepatic fibrosis. AIMS: To investigate the effects of bariatric surgery on long-term liver disease-related outcome in obese patients with nonalcoholic fatty liver disease (NAFLD) and significant liver damage. METHODS: This study included 56 NAFLD patients who underwent bilio-pancreatic diversion for morbid obesity and who had significant fibrosis at intraoperative liver biopsy. Data were analyzed at 1, 3, and 5 years of follow-up, and at the latest available visit in patients who had longer follow-up. We assessed the incidence of clinically relevant liver events (ascites, hepatic encephalopathy, portal hypertension-related bleeding, and jaundice) as well as modifications of a validated biochemical index such as the NAFLD score. RESULTS: During a median follow-up of 78 months, median weight decreased from 119 to 78 kg (P < 0.0001), and median body mass index decreased from 45.2 to 29.0 kg/m2 (P < 0.0001). None of the patients developed clinical complications of liver disease, and none died due to liver-related causes. Median NAFLD score significantly decreased (P = 0.0005) during follow-up from - 0.929 (- 1.543 to - 0.561) to - 1.609 (- 2.056 to - 1.102). The NAFLD score category was unchanged in 32 patients (57%), improved in 18 (32%), and worsened in 6 (11%). CONCLUSIONS: Patients with NAFLD and proven histological liver damage at surgery do not develop complications of liver disease in long term after bilio-pancreatic diversion. Moreover, noninvasive parameters of liver damage improve. Thus, preexisting liver damage does not seem to be a contraindication to bilio pancreatic diversion. PMID- 29629492 TI - The influence of implant-abutment connection on the screw loosening and microleakage. AB - BACKGROUND: There are some spaces between abutment and implant body which can be a reservoir of toxic substance, and they can penetrate into subgingival space from microgap at the implant-abutment interface. This penetration may cause periimplantitis which is known to be one of the most important factors associated with late failure. In the present study, three kinds of abutment connection system, external parallel connection (EP), internal parallel connection (IP), and internal conical connection (CC), were studied from the viewpoint of microleakage from the gap between the implant and the abutment and in connection with the loosening of abutment screw. METHODS: We observed dye leakage from abutment screw hole to outside through microgap under the excessive compressive and tensile load and evaluated the anti-leakage characteristics of these connection systems. RESULTS: During the experiment, one abutment screw for EP and two screws for IP, out of seven samples in each group, were fractured. After the 2000 cycles of compressive tensile loadings, removal torque value (RTV) of abutment screw represented no statistical differences among three groups. Standard deviation was largest in the RTV of EP and smallest in that of CC. The results of microleakage of toluidine blue from implant-abutment connection indicated that microleakage generally increased as loading procedure progressed. The amount of microleakage was almost plateau at 2000 cycles in CC, but still increasing in other two groups. The value of microleakage greatly scattered in EP, but the deviation of that in CC is significantly smaller. At 500 cycles of loading, there were no significant differences in the amount of microleakage among the groups, but at 1000, 1500, and 2000 cycles of loading, the amount of microleakage in CC was significantly smaller than that in IP. Throughout the experiment, the amount of microleakage in EP was largest, but no statistical difference was indicated due to the high standard deviation. CONCLUSIONS: Within the limitation of the present study, CC was stable even after the loading in the RTV of abutment screw and it prevented microleakage from the microgap between the implant body and the abutment, among the three tested connections. PMID- 29629491 TI - Regulation of Autophagy Affects the Prognosis of Mice with Severe Acute Pancreatitis. AB - BACKGROUND: Acute pancreatitis (AP) is a common inflammatory disease that may develop to severe AP (SAP), resulting in life-threatening complications. Impaired autophagic flux is a characteristic of early AP, and its accumulation could activate oxidative stress and nuclear factor kappaB (NF-kappaB) pathways, which aggravate the disease process. AIM: To explore the therapeutic effects of regulating autophagy after the onset of AP. METHODS: In this study, intraperitoneal injections of 3-methyladenine (3-MA) and rapamycin (RAPA) in the L-arginine or cerulein plus lipopolysaccharide (LPS) Balb/C mouse model. At 24 h after the last injection, pulmonary, intestinal, renal and pancreatic tissues were analyzed. RESULTS: We found that 3-MA ameliorated systemic organ injury in two SAP models. 3-MA treatment impaired autophagic flux and alleviated inflammatory activation by modulating the NF-kappaB signaling pathway and the caspase-1-IL-1beta pathway, thus decreasing the injuries to the organs and the levels of inflammatory cytokines. CONCLUSION: Our study found that the regulation of autophagy could alter the progression of AP induced by L-arginine or cerulein plus LPS in mice. PMID- 29629493 TI - Double-Sided Personality: Effects of Arsenic Trioxide on Inflammation. AB - In 1992, arsenic trioxide (As2O3, ATO) was demonstrated to be an effective therapeutic agent against acute promyelocytic leukemia (APL), rekindling attention to ATO applications in U.S. Food and Drug Administration clinical trials for the treatment of cancers, such as leukemia, lymphomas, and solid tumors. ATO is a potent chemotherapeutic drug that can also be used to treat other diseases, such as autoimmune diseases, because it affects multiple pathways including apoptosis induction, differentiation stimulation, and proliferation inhibition. As inflammation is a critical component of disease progression, ATO is a feasible treatment option based on its ability to protect against inflammation. However, ATO is also a well-known carcinogen because of its pro inflammatory effect. This review will focus on the double-sided effects of ATO on inflammation as well as the relevant mechanisms underlying these effects, aiming to provide a rational understanding of how ATO effects the immune system. We especially aim to provide a comprehensive overview of our current knowledge of how ATO influences inflammation. PMID- 29629494 TI - Cold Stimuli Facilitate Inflammatory Responses Through Transient Receptor Potential Melastatin 8 (TRPM8) in Primary Airway Epithelial Cells of Asthmatic Mice. AB - Bronchial asthma is a chronic inflammatory airway disease that can be aggravated by cold air. However, its mechanism remains largely unknown. As a thermo-sensing cation channel, transient receptor potential melastatin 8 (TRPM8) can be activated by cold stimuli (8-22 degrees C) and cooling agents. Whereas TRPM8 activation leads to enhanced expression of inflammatory cytokines and mucus hypersecretion in human bronchial epithelial cell lines, no previous study has examined its role in regulating the cold-induced inflammatory responses and its mechanism in asthmatic airway epithelium. Airway epithelial cells were isolated from asthma model mice and exposed to low temperature (18 degrees C). The TRPM8 overexpression plasmid and siRNA lentivirus were transfected to up- or downregulate the TRPM8 level. The expression of mRNAs of inflammatory cytokines was tested using real-time reverse transcription-polymerase chain reaction (RT PCR). The activities of phosphorylated protein kinase C (PKC) and phosphorylated inhibitor of nuclear factor kappa B (IkappaB) were measured using the immunofluorescence assay. The expression of mRNAs of inflammatory cytokines [interleukin (IL)-1beta, IL-4, IL-6, IL-8, IL-10, IL-13, granulocyte macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor (TNF)-alpha] increased significantly under cold conditions, which was boosted after TRPM8 overexpression and augmented further in the presence of PKC inhibitor, calphostin C. However, the downregulation of TRPM8 and nuclear factor kappa B (NF-kappaB) impaired the transcription of these cytokine genes. In addition, the phosphorylated PKC and phosphorylated IkappaB were activated by cold stimuli. Moreover, the expression of phosphorylated IkappaB protein improved in the presence of TRPM8, while disruption with the TRPM8 gene or TRPM8 antagonist prohibited the activation of IkappaB. Cold air could induce inflammatory responses through the TRPM8-mediated PKC/NF-kappaB signal pathway in primary airway epithelial cells of asthmatic mice. PMID- 29629496 TI - Commentary on "Commercial Genetic Testing and the Future of the Genetic Counseling Profession". PMID- 29629495 TI - Lewy Body Disease: Clinical and Pathological "Overlap Syndrome" Between Synucleinopathies (Parkinson Disease) and Tauopathies (Alzheimer Disease). AB - Lewy body disease (LBD) is a neurodegenerative disease resulting in dementia. It shares clinical and pathological features with Parkinson disease (PD), the most frequent synucleinopathy, Parkinson disease dementia (PDD), and Alzheimer disease (AD), a tauopathy. Even though the diagnostic criteria for these neurodegenerative diseases are clearly established, and recently revised for LBD, their precise clinical diagnosis is often difficult because LBD, PD, PDD, and AD share epidemiological, clinical, and pathological characteristics. This manuscript discusses current understanding of overlapping symptoms and the particular features of LBD, PD, and AD. It also describes features that could facilitate the diagnosis of each of these diseases. We concluded that the concept of neurodegenerative "overlap" syndrome, which includes the accepted diagnosis of LBD, may be taken in account and should contribute to clarifying LBD and definitions of close differential diagnoses. This should allow clinicians to suspect LBD at an earlier stage and provide better patient care. PMID- 29629498 TI - Multifocal alterations of white matter accompany the transition from normal cognition to dementia in Parkinson's disease patients. AB - The purpose of the present study was to investigate the pattern of white matter (WM) changes associated with Parkinson's disease (PD)-related cognitive impairment by using fractional anisotropy (FA), mean diffusivity (MD), axial diffusivity (AD) and radial diffusivity (RD) measures. Diffusion Tensor Imaging (DTI) was performed in 21 PD-patients with dementia (PDD) and in an age-matched control group including 40 PD-patients without dementia (PD-CTRL). The Parkinson's disease-Cognitive Rating Scale (PD-CRS) was used for patients' neuropsychological assessment. Local microstructural WM differences associated with the presence of cognitive impairment were tested using tract-based spatial statistics analysis. Multiple regression models investigated the association of DTI indices with total PD-CRS score, PD-CRS raw items and other clinical measures across the whole study sample. Significant FA decreases were found in PDD compared to PD-CTRL patients mainly in the body of corpus callosum, corona radiata and cingulum. Lower PD-CRS score was significantly associated with decreased FA, MD and AD values in multiple WM tracts primarily located in prefrontal and limbic areas as well as across the corpus callosum. Lower performance in specific PD-CRS raw items was also associated with FA decreases in major WM tracts. The results suggest that multifocal microstructural changes of WM accompany the transition from normal to demented cognitive state in PD patients. The corpus callosum, the corona radiata and the cingulum are among the regions mostly affected during this course. A progressive axonal degeneration is proposed as a key underlying mechanism. PMID- 29629497 TI - Advanced maternal age during pregnancy and the risk for malignant morbidity in the childhood. AB - : In the past several decades, rates of delayed childbearing have increased, and as a result, maternal age has advanced. Our objective was to evaluate whether advanced maternal age is independently associated with an increased risk of childhood cancers in the offspring. A retrospective cohort study of women who delivered between the years 1991 and 2014 was conducted. Elderly parturients (>= 35 years) were divided into two sub-categories: 35-39 and 40-50 years. The comparison group consisted of parturients aged 20-34 years. All hospitalizations of offspring up to the age of 18 years involving malignant morbidity were compared between the groups. A Kaplan-Meier survival curve was used to compare cumulative malignant morbidity incidence of the offspring. A Weibull regression model was used to control for confounders. During the study period, 201,738 deliveries met the inclusion criteria. Of them, 16.3% (n = 32,804) occurred in mothers aged 35 years or more (35-39 years old n = 26,145, 79.7%; 40-50 years old n = 6659, 20.3%). In the Weibull regression model, advanced maternal age exhibited no association with general malignant morbidity in the offspring up to 18 years of age (mothers aged 35-39: adjusted HR 1.06, 95% CI 0.76-1.48, p = 0.727; mothers aged 40-50: adjusted HR 0.73, 95% CI 0.36-1.46, p = 0.373). For leukemia, the regression model exhibited an independent association in maternal ages of 35-39 (adjusted HR 2.23, 95% CI 1.34-3.69, p = 0.002). CONCLUSION: Advanced maternal age does not appear to raise the risk for future malignancy in the offspring up to the age 18 years. The specific nature of the association between maternal age and leukemia of the offspring necessitates further investigation. What is Known: * Advanced maternal age is associated with a marked elevation in the risk of different pregnancy complications and adverse pregnancy outcomes. What is New: * Advanced maternal age does not appear to raise the risk for future malignancy in the offspring up to the age 18 years. * Leukemia of the offspring may be associated with advanced maternal age although the specific nature of the association necessitates further investigation. PMID- 29629499 TI - Reduced brain entropy by repetitive transcranial magnetic stimulation on the left dorsolateral prefrontal cortex in healthy young adults. AB - Entropy indicates system irregularity and the capacity for information processing. Recent research has identified interesting voxel-wise entropy distribution patterns in normal brain and its changes due to aging and brain disorders. A question of great scientific and clinical importance is whether brain entropy (BEN) can be modulated using non-invasive neuromodulations. The purpose of this study was to address this open question using high-frequency repetitive transcranial magnetic stimulation (rTMS). BEN was calculated from resting state fMRI at each voxel acquired before and after applying 20 Hz rTMS or SHAM (control) stimulation. As compared to SHAM, 20 Hz rTMS reduced BEN in medial orbito-frontal cortex and subgenial anterior cingulate cortex (MOFC/sgACC), suggesting a reduced information processing therein, probably as a result of the enhanced top-down regulation by the left DLPFC rTMS. No significant changes were observed to the functional connectivity (FC) between the left DLPFC (the target site) to the rest of the brain, suggesting that rTMS may not affect FC though it might use FC to transfer its effects or the ad hoc information. Our data proved that rTMS can modulate BEN and BEN can be used to monitor rTMS effects. PMID- 29629500 TI - Altered structural brain connectivity involving the dorsal and ventral language pathways in 16p11.2 deletion syndrome. AB - Copy number variants at the chromosomal locus 16p11.2 contribute to neurodevelopmental disorders such as autism spectrum disorders, epilepsy, schizophrenia, and language and articulation disorders. Here, we provide detailed findings on the disrupted structural brain connectivity in 16p11.2 deletion syndrome (patients: N = 21, age range: 8-16 years; typically developing (TD) controls: 18, 9-16 years) using structural and diffusion MRI. We performed global short-, middle-, long-range, and interhemispheric connectivity analysis in the whole brain using gyral topology-based cortical parcellation. Using region of interest analysis, we studied bilateral dorsal (3 segments of arcuate fasciculus (AF)) and ventral (inferior fronto-occipital fasciculus (IFOF), inferior longitudinal fasciculus (ILF), uncinate fasciculus (UF)) language pathways. Our results showed significantly increased axial (AD) and radial (RD) diffusivities in bilateral anterior AF, decreased volume for left long AF, increased mean diffusivity (MD) and RD for right long AF, and increased AD for bilateral UF in the 16p11.2 deletion group in the absence of significant abnormalities in the whole-brain gyral and interhemispheric connectivity. The selective involvement of the language networks may aid in understanding effects of altered white matter connectivity on neurodevelopmental outcomes in 16p11.2 deletion. PMID- 29629502 TI - Correction to: Percutaneous Creation of a Central Iliac Arteriovenous Anastomosis for the Treatment of Arterial Hypertension. AB - In the March 2018 issue of Current Hypertension Reports, the second author's name Nathan A. Sobotka was inadvertently left out of the byline. Also, the author names were changed from initials to spelled out. The corrected author list is given above. The original article has been corrected. PMID- 29629501 TI - Gray matter volume covariance patterns associated with gait speed in older adults: a multi-cohort MRI study. AB - Accelerated gait decline in aging is associated with many adverse outcomes, including an increased risk for falls, cognitive decline, and dementia. Yet, the brain structures associated with gait speed, and how they relate to specific cognitive domains, are not well-understood. We examined structural brain correlates of gait speed, and how they relate to processing speed, executive function, and episodic memory in three non-demented and community-dwelling older adult cohorts (Overall N = 352), using voxel-based morphometry and multivariate covariance-based statistics. In all three cohorts, we identified gray matter volume covariance patterns associated with gait speed that included brain stem, precuneus, fusiform, motor, supplementary motor, and prefrontal (particularly ventrolateral prefrontal) cortex regions. Greater expression of these gray matter volume covariance patterns linked to gait speed were associated with better processing speed in all three cohorts, and with better executive function in one cohort. These gray matter covariance patterns linked to gait speed were not associated with episodic memory in any of the cohorts. These findings suggest that gait speed, processing speed (and to some extent executive functions) rely on shared neural systems that are subject to age-related and dementia-related change. The implications of these findings are discussed within the context of the development of interventions to compensate for age-related gait and cognitive decline. PMID- 29629503 TI - Characterization of bioactive compounds of Annona cherimola L. leaves using a combined approach based on HPLC-ESI-TOF-MS and NMR. AB - Annona cherimola Mill. (cherimoya) has widely been used as food crop. The leaves of this tree possess several health benefits, which are, in general, attributed mainly to its bioactive composition. However, literature concerning a comprehensive characterization based on a combined approach, which consists of nuclear magnetic resonance (NMR) and high-performance liquid chromatography coupled with time-of-flight mass spectrometry (HPLC-TOF-MS), from these leaves is scarce. Thus, the aim of this work was to study the polar profile of full extracts of cherimoya leaves by using these tools. Thus, a total of 77 compounds have been characterized, 12 of which were identified by both techniques. Briefly, 23 compounds were classified as amino acids, organic acids, carbohydrates, cholines, phenolic acid derivatives, and flavonoids by NMR, while 66 metabolites were divided into sugars, amino acids, phenolic acids and derivatives, flavonoids, phenylpropanoids, and other polar compounds by HPLC-TOF-MS. It is worth mentioning that different solvent mixtures were tested and the total phenolic content in the extracts quantified (TPC via HPLC-TOF-MS). The tendency observed was EtOH/water 80/20 (v/v) (17.0 +/- 0.2 mg TPC/g leaf dry weight (d.w.)) >= acetone/water 70/30 (v/v) (16.1 +/- 0.7 mg TPC/g leaf d.w.) > EtOH/water 70/30 (v/v) (14.0 +/- 0.3 mg TPC/g leaf d.w.) > acetone/water 80/20 (v/v) (13.5 +/- 0.4 mg TPC/g leaf d.w.). Importantly, flavonoids derivatives were between 63 and 76% of the TPC in those extracts. Major compounds were sucrose, glucose (alpha and beta), and proline, and chlorogenic acid and rutin for NMR and HPLC-TOF-MS, respectively. Graphical abstract The combined use of LC-HRMS and NMR is a potential synergic combination for a comprehensive metabolite composition of cherimoya leaves. PMID- 29629504 TI - Searching for Better Asthma Control? PMID- 29629505 TI - Marijuana Promotion Online: an Investigation of Dispensary Practices. AB - Marijuana product advertising will become more common, as the use of medical and/or recreational marijuana becomes increasingly legal in the USA. In this study, we investigate the marketing tactics being used on marijuana dispensary websites in the USA that could influence substance use behaviors. One hundred dispensary websites were randomly selected from 10 states that allowed the legal use of medical or recreational marijuana and had at least 10 operational dispensaries. Three dispensaries were excluded due to non-functioning websites, leaving a sample of 97 dispensaries. Content analysis was conducted on these dispensaries' websites, with the primary areas of focus including website age verification, marijuana effects, warnings, and promotional tactics. Among the 97 dispensaries, 75% did not include age verification. Roughly 30% offered online ordering and 21% offered delivery services. Sixty-seven percent made health claims pertaining to medical conditions that could be treated by their marijuana products, with moderate or conclusive evidence to support their claims. Less than half of the dispensaries (45%) advised consumers of possible side effects, and only 18% included warnings about contraindications. Nearly half (44%) offered reduced prices or coupons, 19% offered "buy one get one free" offers, and 16% provided giveaways or free samples. Our findings indicate that marijuana dispensary websites are easily accessible to youth. In addition, only a small amount of the websites advised consumers about possible side effects or contraindications. This study suggests the need for surveillance of marijuana commercialization and online advertising especially in the context of state policy reforms. PMID- 29629506 TI - What Influences Parental Engagement in Early Intervention? Parent, Program and Community Predictors of Enrolment, Retention and Involvement. AB - Poor participant engagement undermines individual and public health benefits of early intervention programs. This study assessed the extent to which three types of engagement (participant enrolment, retention and involvement) were influenced by individual, program and contextual factors. Data were from a cluster randomised controlled trial (N = 1447) of a community-based parenting program, delivered at two levels of intensity (group sessions with and without individualised home coaching) conducted in Victoria, Australia. Individual (parent and family) factors and program factors were assessed by parent report and administrative records, and contextual factors by area-level population statistics. Data were analysed using multilevel logistic or linear regression models. Individual and contextual factors predicted enrolment, while family and program factors were more influential on program retention and parents' active involvement. Provision of individualised support was important to all forms of engagement, particularly for families experiencing the greatest barriers to participation. These findings indicate that different strategies are required to effectively support families in the processes of enrolling, continuing to attend and actively participating in early intervention programs. PMID- 29629507 TI - The Protecting Strong African American Families Program: a Randomized Controlled Trial with Rural African American Couples. AB - This study presents results from a randomized controlled trial of the Protecting Strong African American Families (ProSAAF) program, a family-centered intervention designed to promote strong couple, coparenting, and parent-child relationships in two-parent African American families. A total of 346 African American couples with an early adolescent child participated; all families lived in rural, low-income communities in the southern USA. Intent-to-treat growth curve analyses involving three waves and spanning 17 months indicated that ProSAAF participants, compared with control participants, reported greater improvements in relationship communication, confidence, satisfaction, partner support, coparenting, and parenting. More than 80% of the couples attended all six of the in-home, facilitator-led sessions; costs to implement the program averaged $1739 per family. The findings inform the ongoing debate surrounding prevention programs for low-income and ethnic minority couples. PMID- 29629508 TI - Contextual Risk Profiles and Trajectories of Adolescent Dating Violence Perpetration. AB - Social ecological and developmental system perspectives suggest that interactions among factors within and across multiple contexts (e.g., neighborhood, peer, family) must be considered in explaining dating violence perpetration. Yet, to date, most extant research on dating violence has focused on individual, rather than contextual predictors, and used variable-centered approaches that fail to capture the configurations of factors that may jointly explain involvement in dating violence. The current study used a person-centered approach, latent profile analysis, to identify key configurations (or profiles) of contextual risk and protective factors for dating violence perpetration across the neighborhood, school, friend and family contexts. We then examine the longitudinal associations between these contextual risk profiles, assessed during middle school, and trajectories of psychological and physical dating violence perpetration across grades 8 through 12. Five contextual risk profiles were identified: school, neighborhood, and family risk; school and family risk; school and friend risk; school and neighborhood risk; and low risk. The highest levels of psychological and physical perpetration across grades 8 through 12 were among adolescents in the profile characterized by high levels of school, neighborhood, and family risk. Results suggest that early interventions to reduce violence exposure and increase social regulation across multiple social contexts may be effective in reducing dating violence perpetration across adolescence. PMID- 29629509 TI - Awareness of HPV and Cervical Cancer Prevention Among University Health Sciences Students in Cyprus. AB - Cervical cancer is preventable; however, despite the existence of primary and secondary means of prevention, its incidence is still higher in certain socioeconomic groups and countries, suggesting gaps in cervical cancer prevention. The objective of this study was to evaluate the knowledge and awareness of health sciences university students in Cyprus regarding HPV and cervical cancer in order to better guide the future development of educational programs to improve cervical cancer prevention. This was a cross-sectional study of 178 university health sciences students in Cyprus using a validated questionnaire on HPV and cervical cancer prevention. Analysis of the completed questionnaires revealed moderate levels of knowledge and awareness with an overall mean score of 23.32 out of 33 on HPV and 8.12 out of 13 on cervical cancer, a score of 9.25 out of 14 on HPV vaccines, and a score of 5.93 out of 9 on cervical cancer screening. Older students achieved higher scores compared to younger students (mean score of 6.76 for 18-22 years old, 9.44 for 23-28 years old, and 10.25 for 29-38 years old; p < 0.001). The study found several gaps in the students' knowledge and awareness on cervical cancer prevention. We suggest the design of education programs targeting this population possibly by incorporation of cervical cancer prevention education within students' curriculum to increase knowledge such that the spread of the virus is minimized and these health sciences students are prepared to educate their communities as part of their future practice in health professions. PMID- 29629510 TI - Endoscopic ultrasound-guided coil or glue injection in post-cyanoacrylate gastric variceal re-bleed. AB - BACKGROUND AND AIMS: N-butyl-cyanoacrylate injection is recommended in bleeding/recently bled gastric varices. However, cyanoacrylate injection is associated with re-bleed in 25% to 50% of patients. Endoscopic ultrasound (EUS) guided coil application is an emerging treatment modality for bleeding gastric varices. The aim of this study was to compare EUS-guided coil application combined with or without cyanoacrylate glue injection to injection alone in post glue gastric variceal re-bleed. METHODS: A retrospective analysis of a prospectively maintained database was performed. Thirty patients who re-bled after cyanoacrylate injection and who had EUS-guided coil application to gastric varices were included. The comparison was done with data of 51 patients who had only repeat cyanoacrylate injection. Both groups had a follow up for 12 months. EUS-guided coil application was done under endosonographic guidance. A single coil was placed in 7, two coils in each of 13 patients, three in 5, four in 3, five in one, and 6 coils in one patient. In addition, cyanoacrylate glue injection was given in 15 patients. Eight patients had repeat EUS-guided coil application 1 month later. Re-bleed and mortality were assessed. RESULTS: Coilng: Six out of 30 (20%) patients re-bled during follow up of 9 to 365 days. Three out of 30 (10%) died. One patient died 9 days after the procedure due to acute respiratory distress syndrome, one died 4 months after the procedure due to a re bleed and one 5 months after the procedure due to spontaneous bacterial peritonitis. Glue only: 26/51 (51%) re-bled during follow up of 45 to 365 days. EUS-guided coil application resulted in significantly less re-bleed than glue only (Kaplan-Meir survival analysis with log-rank test, z = 5.4, p < 0.001). Two out of 51 (4%) died 59 and 186 days after the procedure. CONCLUSION: EUS-guided coil application with/without cyanoacrylate injection for the obliteration of gastric varices is effective for post-cyanoacrylate gastric variceal re-bleed. PMID- 29629511 TI - Repeated Administration of 3,4-Methylenedioxymethamphetamine (MDMA) Elevates the Levels of Neuronal Nitric Oxide Synthase in the Nigrostriatal System: Possible Relevance to Neurotoxicity. AB - Previous studies have consistently demonstrated that the amphetamine-related drug 3,4-methylenedioxymethamphetamine (MDMA) induces dopaminergic damage in the mouse brain, and that this effect is most marked in the nigrostriatal system. Moreover, it has been suggested that the overproduction of nitric oxide (NO) may participate in the dopaminergic damage induced by MDMA. To further elucidate this issue, we evaluated the levels of the enzyme nitric oxide synthase (nNOS), which catalyzes the production of NO, in mice treated with regimens of MDMA that induce progressive and persistent neurotoxicity in the dopaminergic nigrostriatal system. Mice received 14, 28, or 36 administrations of MDMA (10 mg/kg i.p.), twice a day/twice a week, and were sacrificed at different time-points after treatment discontinuation. Thereafter, the number of nNOS-positive neurons was quantified by immunohistochemistry in the caudate-putamen (CPu) and substantia nigra pars compacta (SNc). MDMA elevated the numbers of nNOS-positive neurons in the CPu of mice that received 28 or 36 drug administrations. This effect was still detectable at 3 months after treatment discontinuation. Moreover, MDMA elevated the numbers of nNOS-positive neurons in the SNc. However, this effect occurred only in mice that received 28 drug administrations and were sacrificed 3 days after treatment discontinuation. These results are in line with the hypothesis that activation of the NO cascade participates in the toxic effects induced by MDMA in the dopaminergic nigrostriatal system. Moreover, they suggest that activation of the NO cascade induces toxic effects that are more marked in striatal terminals, compared with nigral neurons. PMID- 29629512 TI - L-Theanine Decreases Orofacial Dyskinesia Induced by Reserpine in Rats. AB - Reserpine (RES)-induced orofacial dyskinesia (OD) has been used as an animal model for human tardive dyskinesia (TD) for decades, due to its strong pathophysiological association with striatal oxidative stress and neural cytoarchitecture alteration. L-Theanine (LT), one of the major amino acid components in green tea, has potent antioxidative, anti-inflammatory, and neuroprotective effects. In this study, we examined the potential protective effects of LT on RES-induced behavioral and neurochemical dysfunction in rats. RES treatment (1 mg/kg s.c., 3 injections 1 day apart) induced significant increases (p < 0.001) in the frequency of vacuous chewing movements (VCM), tongue protrusion (TP), as well as the duration of facial twitching (FT). LT treatment (100, 300 mg/kg orally for 14 days, starting 10 days before RES injection) was able to prevent most of the RES-induced OD. Moreover, LT treatment reduced the RES-induced lipid peroxidation (LPO) production, increased the antioxidation power and catecholamines in the striatum, and significantly reduced the levels of neuroinflammatory and apoptotic markers. Our results indicated that LT was able to counteract the increased oxidative damage, neurotransmitter deficiency, neuroinflammation, and apoptosis induced by RES, and these results have demonstrated the possible neuroprotective effects of LT against RES-induced OD, including antioxidation, neurochemical deficiency prevention, antineuroinflammation, and antiapoptosis. These findings, therefore, suggest a potential role for LT to have a clinically relevant therapeutic effect in delaying or treating human TD. PMID- 29629513 TI - Postoperative radiotherapy is dispensable for OSCC patients with micrometastases in lymph nodes. AB - Lymph node metastasis is a decisive factor for performing postoperative radiotherapy for oral squamous cell carcinoma (OSCC). However, whether OSCC patients with only micrometastasis need postoperative radiotherapy is unclear. In this study, OSCC patients (n = 311) with negative (n = 247), only micrometastasis (n = 44) and macrometastasis (n = 20) were detected and selected by HE staining. Micrometastasis was re-assessed using immunohistochemical staining of cytokeratin (CK) in HE-negative patients to find out the false negative cases. The results indicated that, among the negative lymph node cases (n = 247), the positive rate of CK was 4.94% (n = 12). Besides, the clinical features of the primary tumor in relation to the only micrometastatic status and the value of the postoperative radiotherapy on the only micrometastasis patients were evaluated. Patients with only micrometastasis had higher T stage and inferior worst pattern of invasion (WPOI) than patients without micrometastasis, but they had longer overall survival (OS), metastasis-free survival (MFS), and disease-free survival (DFS) than macrometastasis patients. However, the survival time of only micrometastasis patients with or without postoperative radiotherapy was comparable, even in patients with inferior WPOI. Radiotherapy, however, may only benefit patients with IV/V levels of micrometastasis. These data indicated that postoperative radiotherapy is dispensable for only micrometastasis OSCC patients. PMID- 29629514 TI - Neonatal intrapericardial teratoma. PMID- 29629515 TI - Cavernous hemangioma of the interatrial septum. PMID- 29629516 TI - Safety and Efficacy of Tolvaptan in Korean Patients with Hyponatremia Caused by the Syndrome of Inappropriate Antidiuretic Hormone. AB - BACKGROUND: The aim of this multicenter study was to evaluate the safety and efficacy of tolvaptan (TLV) in Korean patients with the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). METHODS: Of 51 enrolled patients with SIADH, 39 patients (16 female patients, aged 70.8 +/- 11.3 years) were included in an intention to treat analysis. All patients received 15 mg/day as the initial dose, and the dose was then increased up to 60 mg/day (as needed) until day 4. RESULTS: Serum sodium increased significantly from baseline during the first 24 hours (126.8 +/- 4.3 vs. 133.7 +/- 3.8 mmol/L, P < 0.001), rose gradually between days 1 and 4 (133.7 +/- 3.8 vs. 135.6 +/- 3.6 mmol/L, P < 0.05), and then plateaued until day 11 (136.7 +/- 4.5 mmol/L). The correlation between the change in serum sodium for the first 24 hours and initial serum sodium concentration was significant (r = -0.602, P < 0.001). In severe hyponatremia (< 125 mmol/L), the change was significantly higher (11.1 +/- 4.8 mmol/L) than in moderate (6.4 +/- 2.5 mmol/L, P < 0.05) or mild hyponatremia (4.3 +/- 3.3 mmol/L, P < 0.01). In addition, logistic regression analysis showed that body weight (odds ratio [OR], 0.858; 95% confidence interval [CI], 0.775-0.976; P = 0.020) and body mass index (BMI) (OR, 0.692; 95% CI, 0.500-0.956; P = 0.026) were associated with rapid correction. No serious adverse events were reported, but in 13% of patients hyponatremia was overcorrected. CONCLUSION: TLV is effective in correcting hyponatremia and well-tolerated in Korean patients with SIADH. However, those with low body weight, low BMI or severe hyponatremia, could be vulnerable to overcorrection with the initial dose of 15 mg TLV. PMID- 29629517 TI - Trial Comparing a Combined Regimen of Amikacin and Ciprofloxacin to Ciprofloxacin Alone as Transrectal Prostate Biopsy Prophylaxis in the Era of High Fluoroquinolone-Resistant Rectal Flora. AB - BACKGROUND: To investigate whether addition of amikacin to fluoroquinolone (FQ) antimicrobial prophylaxis reduces infections after transrectal ultrasound-guided prostate biopsy (TRUSPB). METHODS: A total of 503 patients undergoing rectal swab were divided into three groups. Patients with FQ-sensitive rectal flora (group 1, n = 248) were administered ciprofloxacin before TRUSPB, and patients with FQ resistant rectal flora were either administered ciprofloxacin (group 2, n = 97) or amikacin and ciprofloxacin (group 3, n = 158) before TRUSPB. RESULTS: Based on the rectal swab, FQ resistance was 54.9%, and extended-spectrum beta-lactamase (ESBL) positivity was 17.2%. The incidence of infectious complication in group 1 was 1.6%. Groups 2 and 3, with FQ-resistant rectal flora, tended to have increased infectious complications (5.2% and 4.4%, respectively) but the difference between those results is not statistically significant. The most common pathogens of infectious complications in patients with FQ-resistant rectal flora were FQ-resistant and ESBL-producing Escherichia coli. E. coli pathogens isolated in Group 3 were amikacin-susceptible species. The operation history and ESBL positivity of rectal flora increased the incidence of infectious complications (odds ratio [OR] = 3.68; P = 0.035 and OR = 4.02; P = 0.008, respectively). DM and antibiotics exposure were risk factors for FQ resistance (OR = 2.19; P = 0.002) and ESBL positivity of rectal flora (OR = 2.96; P = 0.005), respectively. CONCLUSION: Addition of amikacin to ciprofloxacin prophylaxis could not reduce infectious complications in patients with FQ resistant rectal flora. Despite the amikacin sensitivity of infectious complications, single-dose amikacin addition to ciprofloxacin prophylaxis has limitations. PMID- 29629518 TI - Atypical Presentation of Pneumocystis jirovecii Infection in HIV Infected Patients: Three Different Manifestations. AB - Advances in the treatment and prevention of Pneumocystis jirovecii infection (PJI) in human immunodeficiency virus (HIV) patients decreased incidence and mortality dramatically, however, it may be associated with an increased frequency of unusual manifestation such as cystic formation, pneumothorax, focal infiltration, nodular formation, or extrapulmonary lesions. We report three cases of PJI with atypical manifestations. Each case demonstrates different clinical features: multiple nodular pulmonary lesion (32-year-old man with abnormal chest X-ray finding), subpleural mass-like lesion (43-year-old man with left visual loss and right pleuritic chest pain), and extrapulmonary mass-like lesions in the liver, lymph nodes, and small bowel (39-year-old man with cough, sputum, and dyspnea). P. jirovecii was confirmed in all 3 cases and they were treated well. It is necessary to understand that PJI shows variable clinical features. PMID- 29629519 TI - Association between Parents' Country of Birth and Adolescent Depressive Symptoms: the Early Stages of Multicultural Society. AB - BACKGROUND: This study aims to determine whether significant associations exist between the parents' country of birth and adolescent depressive symptoms in the early stages of a multicultural society. METHODS: We used data from the 2012-2016 Korea Youth Risk Behavior Web-based Survey, which included responses from 327,357 individuals. Participants were classified into groups according to their parent's country of birth. Logistic regression analysis was used to examine the significance of the associations. RESULTS: Adolescents whose parents were born abroad are more likely to have depressive symptoms (odds ratio [OR] = 1.68; 95% confidence interval [CI], 1.33-2.12) than adolescents whose parents were native Koreans. Respondents whose father was born in North Korea or Japan or Taiwan show greater odds of depressive symptoms than respondents whose parents were native Korean. CONCLUSION: Adolescents whose parents were born abroad are more likely to have depressive symptoms. Multicultural family support policies should be implemented in consideration of the characteristics of the parents' country of birth. PMID- 29629520 TI - Training Effect on the Inter-observer Agreement in Endoscopic Diagnosis and Grading of Atrophic Gastritis according to Level of Endoscopic Experience. AB - BACKGROUND: Endoscopic diagnosis of atrophic gastritis can contribute to risk stratification and thereby tailored screening for gastric cancer. We aimed to evaluate the effect of training on inter-observer agreement in diagnosis and grading of endoscopic atrophic gastritis (EAG) according to the level of endoscopists' experience. METHODS: Twelve endoscopists (six less-experienced and six experienced) participated in this prospective study. The training session consisted of 1) four interventions with two-week intervals, and 2) a follow-up period (two follow-up assessments without feedback). EAG was categorized as C1 to O3 according to the Kimura-Takemoto classification. Kappa statistics were used to calculate inter-observer agreement. RESULTS: At baseline, kappa indexes were 0.18 in the less-experienced group and 0.32 in the experienced group, respectively. After four interventions with feedback, the kappa index improved in both groups and was sustained during the follow-up period. Overall diagnostic yields of EAG were 43.1% +/- 10.7% in pre-intervention and 46.8% +/- 5.9% in post-intervention. Variability in the rate of diagnosis of EAG significantly decreased in the less experienced group (r = 0.04, P = 0.003). CONCLUSION: Irrespective of experience level, inter-observer agreement for diagnosis and grading of EAG improved after training and remained stable after intervention. PMID- 29629521 TI - Anaplastic lymphoma kinase (ALK)-expressing Lung Adenocarcinoma with Combined Neuroendocrine Component or Neuroendocrine Transformation: Implications for Neuroendocrine Transformation and Response to ALK-tyrosine Kinase Inhibitors. AB - BACKGROUND: Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) are usually effective in lung adenocarcinoma patients with anaplastic lymphoma kinase (ALK) rearrangement. However, even after a good response to ALK-TKI therapy, most patients acquire resistance to these agents. Histological transformation is one of several suggested mechanisms of acquired resistance to ALK-TKIs. The clinicopathologic features of four patients with ALK-expressing adenocarcinoma and neuroendocrine features were analyzed. METHODS: We selected combined neuroendocrine differentiation in pulmonary adenocarcinoma cases with positive ALK immunostaining. Neuroendocrine differentiation was confirmed by CD56 immunohistochemical stain. Additional ALK fluorescence in situ hybridization (FISH) study and epidermal growth factor receptor (EGFR) mutation tests were also performed. RESULTS: All four cases were positive for ALK immunohistochemistry and no EGFR mutations were detected. Interestingly, the results of ALK FISH assays showed rearrangement in only two cases. Three cases showed combined adenocarcinoma and neuroendocrine component without history of ALK-TKI administration; one of them was treated with crizotinib and experienced partial tumor regression. The remaining case had an adenocarcinoma at initial biopsy and she showed a partial response to crizotinib, and neuroendocrine changes were visible on second biopsy. Then she was treated with ceritinib and achieved a partial response. CONCLUSION: We suggest that ALK-rearranged adenocarcinoma with combined neuroendocrine component is responsive to ALK-TKIs. Moreover, even after neuroendocrine transformation as a result of resistance to ALK-TKIs, the tumor may have partial response to second generation ALK-TKIs. PMID- 29629522 TI - The Influence of Sex in Stroke Thrombolysis: A Systematic Review and Meta Analysis. AB - BACKGROUND AND PURPOSE: There is increasing recognition of the importance of stroke in females to both clinical and public health. The natural course of stroke is worse in females than in males, but the evidence regarding sex disparities in the responses to thrombolysis in stroke patents is still controversial. We compared outcomes after thrombolysis treatment between females and males. METHODS: Clinical trials reported in the Embase, PubMed, and Cochrane Library electronic databases up to March 13, 2017 were included in this analysis. Two reviewers independently extracted the data and conducted quality assessments. Statistical tests were performed to check for heterogeneity and publication bias. Sensitivity analysis was also performed to evaluate the stability of the conclusions. RESULTS: Sixteen reports involving 60,159 patients were available for analysis. The female patients were a 0.89-fold [95% confidence interval (CI)=0.87-0.90, p<0.001], 0.89-fold (95% CI=0.87-0.91, p<0.001), and 1.24-fold (95% CI=1.11-1.36, p<0.001) more likely to obtain good, excellent, and poor functional outcomes, respectively, with no significant difference in the complications of symptomatic intracranial hemorrhage among the sexes [risk ratios (RR)=0.99, 95% CI=0.92-1.07, p=0.81] after thrombolysis treatment. In addition, the prevalence of a good functional outcome did not differ significantly between females and males in the intra-arterial thrombolysis (IAT) group (RR=1.05, 95% CI=0.85-1.29, p=0.67) in a subgroup analysis. CONCLUSIONS: This study has demonstrated that females often exhibit a worse outcome than males after intravenous thrombolysis (IVT), whereas no relevant sex differences were found in outcome or recanalization after IAT, with safety regarding hemorrhage complications from thrombolysis being the same for the sexes. However, IVT should not be withheld from female stroke patients solely based on their sex before the findings are confirmed in further large-scale research. PMID- 29629523 TI - Attention Deficit Hyperactivity Disorder in Neurofibromatosis Type 1: Evaluation with a Continuous Performance Test. AB - BACKGROUND AND PURPOSE: The objective of this study was to determine if the MOXO visual- and vocal-distractors-based continuous performance test distinguishes patients with attention deficit hyperactivity disorder (ADHD) and neurofibromatosis type 1 (NF1) from those without NF1. METHODS: Thirty-five patients (16 males; mean age 9.91 years) attending a multidisciplinary NF1 clinic completed the MOXO test. The findings were compared to 532 healthy age-matched standardized control subjects (285 males) without ADHD. RESULTS: The overall performance in the MOXO text was significantly worse in the NF1 group than in controls (p<0.01), but no group-specific pattern was identified. Impulsivity and hyperactivity were significantly more prominent in males than females (p<0.01). Compared to controls, the NF1 group exhibited significantly more failures to respond to target stimuli in the presence of visual distractors. CONCLUSIONS: MOXO scores are abnormal in patients with NF1, but the test cannot differentiate between NF1 with ADHD characteristics and ADHD. The test highlights sex differences in ADHD characteristics in NF1. Overreactivity to visual distractors may form part of the attention deficit in NF1. PMID- 29629524 TI - Glucose Hypometabolism in Hippocampal Subdivisions in Alzheimer's Disease: A Pilot Study Using High-Resolution 18F-FDG PET and 7.0-T MRI. AB - BACKGROUND AND PURPOSE: Atrophy of the hippocampus is an important clinical diagnostic marker of Alzheimer's disease (AD), and so assessments of hippocampal activity and its subdivisions might provide invaluable information. This study compared the glucose metabolism of hippocampal subdivisions in mild-AD patients and healthy controls. METHODS: High-resolution T2*-weighted gradient-echo magnetic resonance imaging (MRI) images and 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) images were acquired using 7.0-T MRI and high resolution research tomograph FDG-PET, respectively, in 9 early-stage AD patients and 10 healthy subjects. The hippocampal body was divided into three equal parts (anterior, middle, and posterior), and in each part a region of interest (ROI) was drawn over the cornus ammonis (CA)1, CA2/3, CA4/dentate gyrus (DG), and subiculum. The standardized uptake values of the hippocampal subdivisions were calculated for each ROI as ratios relative to the pons standardized uptake value. Statistical analysis was conducted using the Mann-Whitney U test. RESULTS: Patients with early-stage AD patients showed significantly less metabolic activity than healthy controls focally in the middle (p=0.050) and posterior (p=0.034) CA2/3 regions of the right hippocampus, and significantly less activity throughout the left hippocampal body in the anterior CA2/3 (p=0.027) and CA4/DG (p=0.027) regions, the middle CA1 region (p=0.011), and the posterior CA1 (p=0.034), CA2/3 (p=0.007), and CA4/DG (p=0.014) regions. CONCLUSIONS: It was possible to use high-resolution PET-MRI fusion images to identify hippocampus subdivisions and assess glucose metabolism in the subfields. Reductions in metabolic activity were found to vary along the hippocampal axis in early-stage AD patients. PMID- 29629525 TI - High Dietary Glycemic Load is Associated with Poor Functional Outcome in Patients with Acute Cerebral Infarction. AB - BACKGROUND AND PURPOSE: Elevated postprandial blood glucose is a critical risk factor for stroke. The dietary glycemic load (GL) and glycemic index (GI) are frequently used as markers of the postprandial blood glucose response to estimate the overall glycemic effect of diets. We hypothesized that high dietary GL, GI, or total carbohydrate intake is associated with a poor functional outcome in patients with acute ischemic stroke. METHODS: We prospectively included 263 first ever ischemic stroke patients who completed a semiquantitative food-frequency questionnaire. The dietary GL, GI, and total carbohydrate intake were investigated by examining the average frequency of intake during the previous year based on reference amounts for various food items. Poor functional outcome was defined as a score on the modified Rankin Scale (mRS) of >=3 at 3 months after stroke. RESULTS: The patients were aged 65.4+/-11.7 years (mean+/-standard deviation), and 58.2% of them were male. A multivariate analysis adjusted for age, sex, marital status, prestroke mRS score, diabetes mellitus, hyperlipidemia, body mass index, triglycerides, low-density lipoprotein, hemoglobin A1c, stroke classification, and National Institutes of Health Stroke Scale score, early neurological deterioration, and high-grade white-matter hyperintensities revealed that the dietary GL and total carbohydrate intake were associated with a poor functional outcome, with odds ratios for the top quartile relative to the bottom quartile of 28.93 (95% confidence interval=2.82-296.04) and 36.84 (95% confidence interval=2.99-453.42), respectively (p for trend=0.002 and 0.002, respectively). In contrast, high dietary GI was not associated with a poor functional outcome (p for trend=0.481). CONCLUSIONS: Increased dietary GL and carbohydrate intake were associated with a poor short-term functional outcome after an acute ischemic stroke. PMID- 29629526 TI - Underregistration and Underreporting of Stem Cell Clinical Trials in Neurological Disorders. AB - BACKGROUND AND PURPOSE: Research on stem cells (SC) is growing rapidly in neurology, but clinical applications of SC for neurological disorders remain to be proven effective and safe. Human clinical trials need to be registered in registries in order to reduce publication bias and selective reporting. METHODS: We searched three databases-clinicaltrials.gov, the Clinical Research Information System (CRIS), and PubMed-for neurologically relevant SC-based human trials and articles in Korea. The registration of trials, posting and publication of results, and registration of published SC articles were examined. RESULTS: There were 17 completed trials registered at clinicaltrials.gov and the CRIS website, with results articles having been published for 5 of them. Our study found 16 publications, of which 1 was a review article, 1 was a protocol article, and 8 contained registered trial information. CONCLUSIONS: Many registered SC trials related to neurological disorders are not reported, while many SC-related publications are not registered in a public registry. These results support the presence of biased reporting and publication bias in SC trials related to neurological disorders in Korea. PMID- 29629527 TI - An 8-Week Low-Intensity Progressive Cycling Training Improves Motor Functions in Patients with Early-Stage Parkinson's Disease. AB - BACKGROUND AND PURPOSE: The effects of high-intensity cycling as an adjuvant therapy for early-stage Parkinson's disease (PD) were highlighted recently. However, patients experience difficulties in maintaining these cycling training programs. The present study investigated the efficacy of cycling at a mild-to moderate intensity in early-stage PD. METHODS: Thirteen PD patients were enrolled for 16 serial cycling sessions over a 2-month period. Motor function was assessed using the Unified Parkinson's Disease Rating Scale part III (UPDRS III) and Timed Up and Go (TUG) test as primary outcomes. The Montreal Cognitive Assessment (MoCA), modified Hoehn and Yahr Stage (mHYS), total UPDRS, Falls Efficacy Scale, New Freezing of Gait Questionnaire, Schwab and England Activities of Daily Living, 39-item Parkinson's Disease Questionnaire, Patient Global Impression of Change, and gait performance were assessed as secondary outcomes. RESULTS: The age and the age at onset were 59.67+/-7.24 and 53.23+/-10.26 years (mean+/-SD), respectively. The cycling cadence was 53.27+/-8.92 revolutions per minute. The UPDRS III score improved significantly after 8 training sessions (p=0.011) and 16 training sessions (T2) (p=0.001) in the off-state, and at T2 (p=0.004) in the on state compared to pretraining (T0). The TUG duration was significantly shorter at T2 than at T0 (p<0.05). The findings of MoCA, total UPDRS, double limb support time, and mHYS (in both the off- and on-states) also improved significantly at T2. CONCLUSIONS: Our pioneer study has demonstrated that a low-intensity progressive cycling exercise can improve motor function in PD, especially akinesia. The beneficial effects were similar to those of high-intensity rehabilitation programs. PMID- 29629529 TI - Questioning the Diagnosis of Recurrent Optic Neuritis Associated with Neuro Behcet's Disease. PMID- 29629528 TI - Prevalence of Multiple Sclerosis in a Turkish City Bordering an Iron and Steel Factory. AB - BACKGROUND AND PURPOSE: Multiple sclerosis (MS) is an autoimmune disease characterized by inflammatory demyelination. Recent studies have shown that long term exposure to air pollutants (including PM10 particulates) is potentially an environmental risk factor for MS. We aimed to determine the prevalence rates of MS in two cities with different levels of air pollution. METHODS: This door-to door population-based study was conducted between April 2014 and June 2015. Two cities were screened for the prevalence rates of MS: 1) Karabuk, which borders an iron-and-steel factory, and 2) Akcakoca, which is a coastal city located in the same region. A validated survey form was used for screening MS. The 2010 McDonald Criteria were used for diagnosing MS. The patients were examined twice, first by a neurology assistant in the field and then by a senior neurologist in public health centers in the cities. RESULTS: The prevalence of MS was 95.9/100,000 in Karabuk and 46.1/100,000 in Akcakoca. In total, 33 patients were diagnosed with clinically definite MS. The female/male ratio was 1.5, and 21 patients were diagnosed with relapsing-remitting MS, 9 with secondary progressive MS, and 3 with primary progressive MS. CONCLUSIONS: We found that the prevalence of MS was more than two fold higher in Karabuk than in Akcakoca, which supports a link between air pollution and the pathogenesis of MS. However, larger etiological and epidemiological studies are needed to confirm this hypothesis. PMID- 29629530 TI - Paraneoplastic Neuromyelitis Optica Associated with Lung Adenocarcinoma in a Young Woman. PMID- 29629531 TI - Pathogenic Variant of REEP1 in a Korean Family with Autosomal-Dominant Hereditary Spastic Paraplegia. PMID- 29629532 TI - Self-Injurious Behavior Revealing Advanced Primary Progressive Multiple Sclerosis with a Massive Right Temporal Lesion. PMID- 29629533 TI - Central Trochlear Palsy as an Isolated Finding with Metastatic Tumor. PMID- 29629534 TI - Multiple Cranial-Nerve Palsies: An Unusual Culprit. PMID- 29629535 TI - Is Corticospinal Tract Degeneration Caused by Sjogren Syndrome? PMID- 29629536 TI - Coexistence of Amyotrophic Lateral Sclerosis in the Proband of an X-Linked Charcot-Marie-Tooth Disease Type 1 Pedigree in China. PMID- 29629537 TI - Different Associations of Plasma Biomarkers in Alzheimer's Disease, Mild Cognitive Impairment, Vascular Dementia, and Ischemic Stroke. AB - BACKGROUND AND PURPOSE: Cognitive and cerebrovascular diseases are common in the elderly, but differences in the plasma levels and associations of plasma biomarkers in these diseases remain elusive. METHODS: The present study investigated differences in plasma fatty acids [eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)], adiponectin, reptin, plasma markers of inflammation [high-sensitivity C-reactive protein (hsCRP) and serum amyloid A (serum AA)], and plasma lipids [high-density lipoprotein and low-density lipoprotein (LDL)] in patients with Alzheimer's disease (AD) (n=266), mild cognitive impairment (MCI) (n=44), vascular dementia (VaD) (n=33), and ischemic stroke (IS) (n=200) in comparison to normal controls (n=130). RESULTS: The serological data showed that lower EPA and DHA levels and higher reptin and LDL levels were associated with AD and IS, the reptin/adiponectin ratio was strongly associated with IS, the hsCRP level was more strongly associated with VaD and IS, and the serum AA level was associated with all three cognitive diseases and IS. CONCLUSIONS: This is the first report of differences in the expression levels of plasma biomarkers and peripheral arterial tonometry among AD, MCI, VaD, and IS patients and normal controls. These different associations indicate that diverse pathological mechanisms underlie these diseases. PMID- 29629538 TI - Changes in the Common Carotid Artery after Radiotherapy: Wall Thickness, Calcification, and Atherosclerosis. AB - BACKGROUND AND PURPOSE: Since the long-term survival rate has improved in laryngeal cancer patients who receive radiotherapy, concerns about postradiation complications (including carotid atherosclerosis) have increased. We followed changes in the common carotid artery (CCA) after radiotherapy and identified the underlying risk factors. METHODS: Consecutive patients with laryngeal cancer who underwent radiotherapy between January 1999 and December 2009 and who had received computed tomography (CT) both pre- and postradiotherapy were enrolled. Changes in the wall thickness and in the vessel and lumen areas as well as the presence of calcification or atherosclerosis were investigated. Demographics and risk factors were compared between patients with and without atherosclerosis at follow-up CT. RESULTS: In total, 125 patients were enrolled. The wall thickness had increased and the lumen area had decreased several months after radiotherapy. These changes were not associated with vascular risk factors and were not progressive. Calcification and atherosclerosis were observed in 37 (29.6%) and 71 (56.8%) patients, respectively. Diabetes was associated with calcification (p=0.02). The prevalence of hyperlipidemia was higher in patients with atherosclerosis (28.2% vs. 11.1%, p=0.02) and for a longer period postradiation [62.7+/-32.1 vs. 40.0+/-24.2 months (mean+/-SD), p<0.001]. Atherosclerosis occurred mostly in the middle portion of the CCA (n=31, 24.6%), followed by the proximal CCA at the intrathoracic level (n=26, 20.6%) and the distal CCA (n=6, 4.8%). Positive remodeling was also observed, but this was less common in patients with calcification (p=0.02). CONCLUSIONS: Various types of postradiation changes occur in the CCA and can be easily observed in postradiation CT. The prevalence and burden of postradiation atherosclerosis increased in a close relationship with baseline cholesterol levels and the time after radiotherapy. Postradiation atherosclerosis was observed at unusual sites of the CCA. PMID- 29629539 TI - Prevalence, Incidence, and Recurrence of Febrile Seizures in Korean Children Based on National Registry Data. AB - BACKGROUND AND PURPOSE: Febrile seizures (FS) are the most common type of seizure during childhood, reportedly occurring in 2-5% of children aged 6 months to 5 years. However, there are no national data on the prevalence of FS in Korea. This study determined the prevalence, incidence, and recurrence rates of FS in Korean children using national registry data. METHODS: The data were collected from the Korea National Health Insurance Review and Assessment Service for 2009-2013. Patients with febrile convulsion as their main diagnosis were enrolled. The overall prevalence of FS in more than 2 million children younger than 5 years was estimated, and the incidence and recurrence rates of FS were determined for children born in 2009. RESULTS: The average prevalence of FS in children younger than 5 years based on hospital visit rates in Korea was 6.92% (7.67% for boys and 6.12% for girls). The prevalence peaked in the second to third years of life, at 27.51%. The incidence of FS in children younger than 5 years (mean 4.5 years) was 5.49% (5.89% for boys and 5.06% for girls). The risk of first FS was highest in the second year of life. The overall recurrence rate was 13.04% (13.81% for boys and 12.09% for girls), and a third episode of FS occurred in 3.35%. CONCLUSIONS: Our study determined the overall prevalence of FS using data for the total population in Korea. The prevalence was comparable to that reported for other countries. Patients with three episodes of FS need to be monitored carefully. PMID- 29629540 TI - Role of Language-Related Functional Connectivity in Patients with Benign Childhood Epilepsy with Centrotemporal Spikes. AB - BACKGROUND AND PURPOSE: Benign childhood epilepsy with centrotemporal spikes (BECTS) does not always have a benign cognitive outcome. We investigated the relationship between cognitive performance and altered functional connectivity (FC) in the resting-state brain networks of BECTS patients. METHODS: We studied 42 subjects, comprising 19 BECTS patients and 23 healthy controls. Cognitive performance was assessed using the Korean version of the Wechsler Intelligence Scale for Children-III, in addition to verbal and visuospatial memory tests and executive function tests. Resting-state functional magnetic resonance imaging was acquired in addition to high-resolution structural data. We selected Rolandic and language-related areas as regions of interest (ROIs) and analyzed the seed-based FC to voxels throughout the brain. We evaluated the correlations between the neuropsychological test scores and seed-based FC values using the same ROIs. RESULTS: The verbal intelligence quotient (VIQ) and full-scale intelligence quotient (FSIQ) were lower in BECTS patients than in healthy controls (p<0.001). The prevalence of subjects with a higher performance IQ than VIQ was significantly higher in BECTS patients than in healthy controls (73.7% vs. 26.1%, respectively; p=0.002). Both the Rolandic and language-related ROIs exhibited more enhanced FC to voxels in the left inferior temporal gyrus in BECTS patients than in healthy controls. A particularly interestingly finding was that the enhanced FC was correlated with lower cognitive performance as measured by the VIQ and the FSIQ in both patients and control subjects. CONCLUSIONS: Our findings suggest that the FC alterations in resting-state brain networks related to the seizure onset zone and language processing areas could be related to adaptive plasticity for coping with cognitive dysfunction. PMID- 29629541 TI - Clinical and Pathologic Findings of Korean Patients with RYR1-Related Congenital Myopathy. AB - BACKGROUND AND PURPOSE: This study was designed to investigate clinical and pathologic characteristics of five Korean patients with RYR1-related congenital myopathy (CM). METHODS: Five patients from unrelated families were diagnosed with RYR1-related CM via direct or targeted sequencing of RYR1. Their clinical, mutational, and pathologic findings were then analyzed. RESULTS: Seven different mutations were identified, including two novel mutations: c.5915A>T and c.12250C>T. All of the patients presented at infancy with proximal dominant weakness and delayed motor milestones. Other clinical findings were scoliosis in three patients, winged scapula in two, hip dislocation in one, and pectus excavatum in one. Ophthalmoplegia was observed in one patient with a novel recessive mutation. Two of three muscle specimens revealed a myopathic pattern with core. CONCLUSIONS: We have identified a novel compound heterozygous RYR1 mutation and demonstrated clinical and pathologic findings in five Korean patients with RYR1-related CM. PMID- 29629542 TI - Diagnostic Utility of the Three-Step Test According to the Presence of the Trochlear Nerve in Superior Oblique Palsy. AB - BACKGROUND AND PURPOSE: To determine the diagnostic utility of the three-step test in unilateral superior oblique palsy (SOP) according to the presence of the trochlear nerve using high-resolution thin-section magnetic resonance imaging. METHODS: In total, 166 patients with congenital and acquired unilateral SOP were included, comprising 87 with a normal trochlear nerve (present group) and 79 without a trochlear nerve (absent group). The sensitivity of each component of the three-step test was evaluated as well as factors related to the sensitivity. RESULTS: All three steps were positive in 78% of those in the present group and 72% of those in the absent group, demonstrating no intergroup difference (p=0.471). Superior rectus muscle (SR) contracture was more frequent in patients who exhibited at least one negative step (incomplete group) (p=0.014). The incomplete group was significantly related to larger hypertropia in ipsilateral gaze (p<0.001), smaller hypertropia in contralateral gaze (p<0.001), and smaller differences in hypertropia between ipsilateral head tilt and the primary position (p=0.012). CONCLUSIONS: The diagnostic utility of the three-step test in unilateral SOP did not differ according to the presence of the trochlear nerve. SR contracture was the main cause of exceptions of the three-step test in unilateral SOP. PMID- 29629543 TI - Partial Conduction Block as an Early Nerve Conduction Finding in Neurolymphomatosis. AB - BACKGROUND AND PURPOSE: Neurolymphomatosis is a rare manifestation of hematological malignancy and is characterized by direct infiltration of the peripheral nervous system. The objective of this study was to identify the clinical and electrophysiological features of neurolymphomatosis. METHODS: We retrospectively analyzed the medical records of 13 patients with neurolymphomatosis. Seven (54%) of the patients were men, and the median age at symptom onset was 60.0 years. RESULTS: The most common type of underlying malignancy was diffuse large B-cell lymphoma (69%). Twelve patients had painful asymmetric neuropathies. The median survival time after diagnosis was 7 months, and 12 patients died during the study period. Thirty-eight motor nerve conduction studies (NCSs) were performed in the affected nerves. Ten and 28 motor nerves were classified into the conduction-block and simple-axon-degeneration groups, respectively. The median time interval between symptom onset and the NCS was significantly shorter in the conduction-block group than in the simple-axon degeneration group (p=0.032). However, no significant differences in the motor nerve conduction velocities, terminal latencies, and distal compound muscle action potential amplitudes were identified between the conduction-block and simple-axon-degeneration groups. The conduction-block group showed excessive temporal dispersion in only five of the ten NCSs (50%). Follow-up NCSs revealed that partial conduction blocks had changed into axonal degeneration patterns. CONCLUSIONS: This is the first study to analyze the electrophysiological features of patients with neurolymphomatosis. Our findings showed that a partial conduction block is not rare and is an early nerve conduction abnormality in neurolymphomatosis. PMID- 29629544 TI - A Prospective Study of Chronic Oxaliplatin-Induced Neuropathy in Patients with Colon Cancer: Long-Term Outcomes and Predictors of Severe Oxaliplatin-Induced Neuropathy. AB - BACKGROUND AND PURPOSE: The objective of this study was to determine the incidence and long-term outcomes of oxaliplatin-induced peripheral neuropathy (OIPN), as well as predictors of its severe form. METHODS: Sixty-nine patients who were taking oxaliplatin for colon cancer were prospectively followed prior to starting chemotherapy and after 4, 8, and 12 cycles of chemotherapy. Thirty-six patients completed the follow-up at 1 year after the end of chemotherapy. The patients were assessed using clinical assessment scales and nerve conduction studies (NCS) at each follow-up visit. RESULTS: By applying the National Cancer Institute Common Toxicity criteria, OIPN was classified as grade 1 in 30 (44%) patients, grade 2 in 25 (36%), and grade 3 in 10 (14%) at the completion of therapy. At 1 year after the treatment, OIPN of grades 1, 2, and 3 was found in 50, 3, and 11% of the patients, respectively. Multivariate analysis showed that reductions of the amplitude of the sensory action potential of >11.5% in the median nerve between baseline and four cycles of chemotherapy (odds ratio=5.603, p=0.031) and of >22.5% in the sural nerve between four and eight cycles of chemotherapy (odds ratio=5.603, p=0.031) were independently associated with the risk of developing grade-3 OIPN. CONCLUSIONS: While the severity of OIPN can improve after oxaliplatin discontinuation, more than half of the patients in this study still had OIPN at 1 year after discontinuation. Early changes in the NCS results for sensory nerves can predict the development of severe OIPN during treatment. PMID- 29629545 TI - Diagnosis of Early-Stage Idiopathic Parkinson's Disease Using High-Resolution Quantitative Susceptibility Mapping Combined with Histogram Analysis in the Substantia Nigra at 3 T. AB - BACKGROUND AND PURPOSE: To test whether nigrosome-1 imaging using high-resolution quantitative susceptibility mapping (QSM) combined with histogram analysis can improve the diagnostic accuracy in early-stage idiopathic Parkinson's disease (IPD) patients. METHODS: Three-dimensional multiecho gradient-recalled echo images (0.5*0.5*1.0 mm3) were obtained at 3 T for QSM in 38 patients with IPD and 25 healthy subjects. To segment the substantia nigra (SN), regions of interest (ROIs) were semiautomatically drawn at the location below the red nucleus, and the normal-appearing nigrosome-1 was determined by manual correction. QSM histograms were obtained within the ROI. The segmented SN regions on the right and left that had higher mean susceptibility values and fewer voxels with susceptibility values lower than 60, 65, 70, 75, and 80 ppb were chosen for comparisons between the IPD patients and healthy subjects. These results were compared with those of the visual assessments of nigrosome-1 in susceptibility map-weighted imaging (SMWI) by analyzing receiver operating characteristics curves. RESULTS: The proportion of voxels with susceptibility values lower than 70 ppb showed the best diagnostic performance, with its value differing significantly between the IPD patients (median=0, interquartile range=0-0.23) and healthy subjects (median=10.67, interquartile range=5.98-21.57) (p<0.0001). The number of voxels with susceptibility values lower than 60, 65, 70, 75, and 80 ppb showed worse diagnostic performances but were still significantly better than that of the mean susceptibility value (p=0.0249, 0.0192, 0.0183, 0.0191, and 0.0186, respectively), which also differed significantly between the two groups: 125.81+/-16.27 ppb (mean+/-standard deviation) in IPD versus 98.41+/-11.70 ppb in healthy subjects (p<0.0001). Additionally, using the proportion of voxels with susceptibility values lower than 70 ppb provided significantly better diagnostic performance than did visual assessments of SMWI (p=0.0143). CONCLUSIONS: High spatial-resolution QSM combined with histogram analysis at 3 T can improve the diagnostic accuracy of early-stage IPD. PMID- 29629546 TI - Emergence of Myasthenia Gravis with Myositis in a Patient Treated with Pembrolizumab for Thymic Cancer. PMID- 29629547 TI - Wolff-Parkinson-White Syndrome in a Patient with Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like Episodes Syndrome Mimicking Juvenile Myoclonic Epilepsy. PMID- 29629548 TI - Ictal Epileptic Headache in an Elderly Patient with a Hippocampal Tumor. PMID- 29629549 TI - Neuromyelitis Optica Spectrum Disorder Presenting with Pseudoathetosis. PMID- 29629550 TI - Successful Treatment of Tolosa-Hunt Syndrome after a Single Infusion of Infliximab. PMID- 29629551 TI - Totally thoracoscopic left atrial occlusion concomitant to endoscopic atraumatic coronary artery bypass grafting (EACAB). AB - Atrial fibrillation, as the most prevalent arrhythmia, has more impact on morbidity and mortality than any other rhythm disorder. It is often concomitant with structural heart diseases like coronary artery disease. The worst complication of atrial fibrillation is stroke, but the double or triple antithrombotic therapy especially in fragile and elderly patients is associated with significant risk of bleeding. The left atrial appendage occlusion may reduse both the risk of stroke and drug intake. Here we present, to our knowledge, the first description of a simultaneous totally thoracoscopic 3D augmented coronary artery bypass grafting and left atrial appendage occlusion. PMID- 29629552 TI - Combined cryo-maze procedure and mitral valve repair through a ministernotomy. AB - Atrial fibrillation is associated with increased morbidity and mortality in patients undergoing mitral valve surgery. There is a growing consensus that patients with preexisting atrial fibrillation should undergo surgical ablation at the time of mitral valve surgery. Novel surgical ablation techniques, including cryoablation, have been developed to facilitate concurrent minimally invasive procedures. This video tutorial describes a combined cryo-maze procedure and mitral valve repair through an upper ministernotomy in a patient with long standing persistent atrial fibrillation and severe mitral regurgitation. PMID- 29629553 TI - Open radial artery harvesting. AB - The radial artery is a versatile bypass conduit that is being used with increasing frequency for an arterial coronary bypass strategy due to its excellent long-term patency and survival benefits. Open radial artery harvesting allows for careful dissection of the radial artery with minimal risk for endothelial damage, which helps to prevent vasospasm. Our technique for open radial artery harvesting and preparation is presented here. PMID- 29629554 TI - Single stage thoracic aortic replacement and aortic valve replacement via clamshell thoracotomy. AB - Aortic surgery is sometimes complicated by aortic arch anomalies. This tutorial illustrates the technique of single-stage thoracic aorta replacement and aortic valve replacement via a clamshell thoracotomy in acute aortic arch dissection with proximal aneurysms of the left subclavian artery and an aberrant right subclavian artery. The advantage of this technique is that only brief partial hypothermic circulatory arrest is required and the procedure can be performed with one quadrifurcated tube graft. PMID- 29629555 TI - Transcatheter valve with a hollow balloon for aortic valve insufficiency. AB - During the past decade transcatheter aortic valve implantation (TAVI) has revolutionized our approach to heart valve disease. Although largely applied to patients with calcific aortic valve stenosis, there is an unmet clinical need to also treat patients with aortic valve insufficiency in patients with non-calcific aortic valve disorders. The following Techno-College tutorial demonstrates our pre-clinical experience with a novel non-occlusive, self-homing TAVI system, developed with Strait Access Technologies, that we hope will improve outcomes for treatment of non-calcific aortic valve insufficiency. PMID- 29629556 TI - Aortic re-implantation in a case of anomalous origin of the left coronary artery from the right pulmonary artery in a toddler. AB - This tutorial demonstrates correction of the rarest congenital coronary anomaly, anomalous origin of the left coronary artery from the right pulmonary artery (ALCAPA RPA). We present the features of surgical repair in the case of a toddler patient with an associated atrial septal defect. PMID- 29629557 TI - Structural Basis for Recognition of L-lysine, L-ornithine, and L-2,4-diamino Butyric Acid by Lysine Cyclodeaminase. AB - L-pipecolic acid is a non-protein amino acid commonly found in plants, animals, and microorganisms. It is a well-known precursor to numerous microbial secondary metabolites and pharmaceuticals, including anticancer agents, immunosuppressants, and several antibiotics. Lysine cyclodeaminase (LCD) catalyzes beta-deamination of L-lysine into L-pipecolic acid using beta-nicotinamide adenine dinucleotide as a cofactor. Expression of a human homolog of LCD, MU-crystallin, is elevated in prostate cancer patients. To understand the structural features and catalytic mechanisms of LCD, we determined the crystal structures of Streptomyces pristinaespiralis LCD (SpLCD) in (i) a binary complex with NAD+, (ii) a ternary complex with NAD+ and L-pipecolic acid, (iii) a ternary complex with NAD+ and L proline, and (iv) a ternary complex with NAD+ and L-2,4-diamino butyric acid. The overall structure of SpLCD was similar to that of ornithine cyclodeaminase from Pseudomonas putida. In addition, SpLCD recognized L-lysine, L-ornithine, and L 2,4-diamino butyric acid despite differences in the active site, including differences in hydrogen bonding by Asp236, which corresponds with Asp228 from Pseudomonas putida ornithine cyclodeaminase. The substrate binding pocket of SpLCD allowed substrates smaller than lysine to bind, thus enabling binding to ornithine and L-2,4-diamino butyric acid. Our structural and biochemical data facilitate a detailed understanding of substrate and product recognition, thus providing evidence for a reaction mechanism for SpLCD. The proposed mechanism is unusual in that NAD+ is initially converted into NADH and then reverted back into NAD+ at a late stage of the reaction. PMID- 29629558 TI - delta-Catenin Increases the Stability of EGFR by Decreasing c-Cbl Interaction and Enhances EGFR/Erk1/2 Signaling in Prostate Cancer. AB - delta-Catenin, a member of the p120-catenin subfamily of armadillo proteins, reportedly increases during the late stage of prostate cancer. Our previous study demonstrates that delta-catenin increases the stability of EGFR in prostate cancer cell lines. However, the molecular mechanism behind delta-catenin-mediated enhanced stability of EGFR was not explored. In this study, we hypothesized that delta-catenin enhances the protein stability of EGFR by inhibiting its lysosomal degradation that is mediated by c-casitas b-lineage lymphoma (c-Cbl), a RING domain E3 ligase. c-Cbl monoubiquitinates EGFR and thus facilitates its internalization, followed by lysosomal degradation. We observed that delta catenin plays a key role in EGFR stability and downstream signaling. delta Catenin competes with c-Cbl for EGFR binding, which results in a reduction of binding between c-Cbl and EGFR and thus decreases the ubiquitination of EGFR. This in turn increases the expression of membrane bound EGFR and enhances EGFR/Erk1/2 signaling. Our findings add a new perspective on the role of delta catenin in enhancing EGFR/Erk1/2 signaling-mediated prostate cancer. PMID- 29629559 TI - IFIT1 Expression Patterns Induced by H9N2 Virus and Inactivated Viral Particle in Human Umbilical Vein Endothelial Cells and Bronchus Epithelial Cells. AB - IFIT1 (also known as ISG56) is a member of the interferon-inducible protein with tetratricopeptide repeats (IFITs) family. IFITs are strongly induced by type I interferon (IFN), double-stranded RNA and virus infection. Here, we investigated IFIT1 expression in human umbilical vein endothelial cells (HUVECs) and in human bronchus epithelial cells (BEAS-2Bs) induced by the H9N2 virus and inactivated viral particle at different time points. We also investigated the effect of H9N2 virus and viral particle infection on IFN-alpha/beta production, and assessed whether hemagglutinin or neuraminidase protein induced IFIT1 expression. Results showed that both H9N2 virus infection and viral particle inoculation induced the expression of IFIT1 at mRNA and protein levels in the two cell lines. Hemagglutinin or neuraminidase protein binding alone is not sufficient to induce IFIT1 expression. Surprisingly, the expression patterns of IFIT1 in response to H9N2 virus and viral particles in the two cell lines were opposite, and production kinetics of IFN-alpha/beta also differed. An additional finding was that induction of IFIT1 in response to H9N2 virus infection or viral particle inoculation was more sensitive in HUVECs than in BEAS-2Bs. Our data offers new insight into the innate immune response of endothelial cells to H9N2 virus infection. PMID- 29629560 TI - Impact of Phospholipids and Tocopherols on the Oxidative Stability of Soybean Oil in-Water Emulsions. AB - Phospholipids have been shown to act synergistically with tocopherols and delay lipid oxidation in bulk oil. The synergistic activity between phospholipids and tocopherols is due to the ability of amino-group-containing phospholipids (e.g., phosphatidylethanolamine (PE) and phosphatidylserine (PS)) to convert oxidized tocopherol back into tocopherols. This study shows the effect of PE and PS on the antioxidant activity of different tocopherol homologues in oil-in-water emulsions. Effect of emulsifier type on the interaction between tocopherols and phospholipids was also studied. delta-Tocopherol and PE exhibited greater antioxidant activity as compared to alpha-tocopherol and PE. PS displayed 1.5-3 times greater synergism than PE with Tween 20 as emulsifier whereas both PE and PS had a similar antioxidant activity in the presence of alpha-tocopherol when bovine serum albumin was used as the emulsifier. This study is the first to show that PE and PS can act synergistically with tocopherols to inhibit lipid oxidation in oil-in-water emulsions and can present a new clean label antioxidant strategy for food emulsions. PMID- 29629561 TI - The Fate of Major Royal Jelly Proteins during Proteolytic Digestion in the Human Gastrointestinal Tract. AB - Royal jelly (RJ) is a beehive product with a complex composition, major royal jelly proteins (MRJPs) being the most abundant proteins. Cell culture and animal studies suggest various biological activities for the full-length/native MRJPs. In the field of apitherapy, it is assumed that MRJPs can positively affect human health. However, whenever RJ is administered orally, the availability for assimilation in the gastrointestinal tract is a prerequisite for MRJPs to have any effect on humans. We here show that MRJPs vary in resistance to pepsin digestion with MRJP2 being most stable and still present as full-length protein after 24 h of digestion. In the intestinal phase, using trypsin and chymotrypsin, MRJPs are rapidly digested with MRJP2 again showing longest stability (40 min), suggesting that MRJPs can reach the small intestine as full-length proteins but then have to be resorbed quickly if full-length proteins are to fulfill any biological activity. PMID- 29629562 TI - A Polyaromatic Nano-nest for Hosting Fullerenes C60 and C70. AB - A "Janus" type of hexa- cata-hexabenzocoronene with three triptyceno subunits fused symmetrically on the periphery of coronene has been synthesized using a covalent self-assembly strategy. The triptyceno subunits form a nanosized nest on one side of the aromatic plane with space-matching fullerenes such as C60 and C70 to afford shape-complementary supramolecular complexes. The formation of the complexes in solution was confirmed by 1H NMR and fluorescence titration. Four complexes with C60 or C70 were obtained and studied by single-crystal X-ray diffraction analysis. In the crystal structure, the host shows a proper tunability to adjust its conformation in accordance with the shape of the guest. The different stoichiometric ratios and various stacking patterns of the complexes suggest the diversity of this nonplanar polyaromatic host in complexation with fullerenes. PMID- 29629563 TI - Changes in collegiate ice hockey player anthropometrics and aerobic fitness over 3 decades. AB - Over the past several decades, an increased emphasis on fitness training has emerged among collegiate ice hockey teams, with the objective of improving on-ice performance. However, it is unknown if this increase in training has translated over time into changes in the anthropometric and fitness profiles of collegiate ice hockey players. The purposes of this study were to describe anthropometric (height, weight, body mass index (BMI), percent body fat (%fat)) and aerobic fitness (peak oxygen consumption) characteristics of collegiate ice hockey players over a period of 36 years and to evaluate whether these characteristics differ among player positions. Anthropometric and physiologic data were obtained through preseason fitness testing of players (N = 279) from a National Collegiate Athletic Association Division I men's ice hockey team from the years 1980 through 2015. Changes over time in the anthropometric and physiologic variables were evaluated via regression analysis using linear and polynomial models, and differences among player positions were compared via ANOVA (p < 0.05). Regression analysis revealed that a cubic model best predicted changes in mean height (R2 = 0.65), weight (R2 = 0.77), and BMI (R2 = 0.57), whereas a quadratic model best fit change in %fat by year (R2 = 0.30). Little change was observed over time in the anthropometric characteristics. Defensemen were significantly taller than forwards (184.7 +/- 12.1 vs. 181.3 +/- 5.9 cm) (p = 0.007), and forwards had a higher relative peak oxygen consumption compared with defensemen (58.7 +/- 4.7 vs. 57.2 +/- 4.4 mL.kg-1.min-1) (p = 0.032). No significant differences were observed in %fat or weight by position. Although average player heights and weights fluctuated over time, increased emphasis on fitness training did not affect the athletes' relative aerobic fitness. Differences in height and aerobic fitness levels were observed among player positions. PMID- 29629564 TI - Thrombin-Activatable Fibrinolysis Inhibitor Polymorphisms and Cerebral Venous Thrombosis in Mexican Mestizo Patients. AB - Thrombin-activatable fibrinolysis inhibitor (TAFI) gene polymorphisms have been proposed as a predisposing factor for cerebral venous thrombosis (CVT). We analyzed the association between CVT and TAFI single-nucleotide polymorphisms (rs3742264, rs2146881, and rs1926447) compared to healthy controls. Mexico Mestizo confirmed cases with CVT and age- and sex-matched controls with no history of venous thrombotic events were recruited from July 2006 to July 2015. Demographic, clinical, and imaging information was included in the analysis. Genotyping single-nucleotide polymorphisms were performed by allele-specific polymerase chain reaction. Allelic univariate analysis, haplotype association, and Hardy-Weinberg equilibrium were assessed. A total of 113 CVT cases (94 females [83.2%]; median age 35 years [interquartile range 27-43 years]) and 134 age- and sex-matched controls were included. The main risk factors for CVT were pregnancy/puerperium (30.9%), oral contraceptive use (19.5%), and hereditary thrombophilia (7.1%). We found no significant association for heterozygous and homozygous models for rs3742264 ( P = .30 and P = .69, respectively), rs2146881 ( P = .90 and P = .17, respectively), or rs1926447 ( P = .40 and P = .52, respectively) compared to controls; these findings were consistent in subgroup and haplotype analyses. In conclusion, TAFI rs3742264, rs2146881, and rs1926447 polymorphisms do not increase the risk of CVT in comparison to healthy controls. PMID- 29629565 TI - A reliable and stable method for the determination of foretinib in human plasma by LC-MS/MS: Application to metabolic stability investigation and excretion rate. AB - Foretinib (GSK1363089) is a multiple receptor tyrosine kinases inhibitor. In this study, a reliable, fast liquid chromatography-tandem mass spectrometric method was described for assaying foretinib in plasma, urine, and rat liver microsome samples. Simple extraction procedure by protein preciptation with acetonitrile was implemented for foretinib and brigatinib (internal standard) analysis. Chromatographic resolution of analytes was achieved on C18 column with the help of isocratic mobile phase. The binary mobile phase consisted of 60% ammonium formate (10 mM, pH 4.2) and 40% acetonitrile at a flow rate of 0.25 mL/min. Run time was 3 min, and both foretinib and brigatinib were eluted within 0.74 and 1.95 min; they were detected in positive ion mode utilizing multiple reactions monitoring mode. Linearity of the proposed method ranged from 5 to 500 ng/mL (r2 >= 0.9993) in the human plasma. Lower limit of quantification and detection were 6.0 and 1.8 ng/mL, respectively. Intraday and interday precision and accuracy were 0.16 to 1.67 % and -2.39 to -0.52 %. In vitro half-life and intrinsic clearance were 24.93 min and 6.56 mL/min/kg, respectively. Literature review showed that no previous studies have been proposed for the analytical quantification of foretinib in human plasma or its metabolic stability. The established method was also applied to estimate the rate of foretinib excretion in rat urine. The developed method can be used for foretinib pharmacokinetic applications. PMID- 29629566 TI - Why does chemotherapy stop affecting the cells of ovarian and breast tumors? PMID- 29629567 TI - Influence of foliar spray of ethephon and water stress on the essential oil composition and impact on the cytotoxic activity of Thymus vulgaris aerial parts. AB - Thymus vulgaris, (Lamiaceae), essential oils composition and yield, were found to be greatly influenced by water stress and growth enhancers. Therefore, three controlled cultivation conditions were applied to achieve the highest essential oil productivity of T. vulgaris. The essential oils obtained by hydro distillation of the aerial parts were analyzed using (GC-MS). The tested plant subjected to drought showed a 66% increase in the essential oil yield, while those subjected to drought stress and foliar spray showed 57.1% increase and the regularly irrigated group with foliar spraying showed 23.8% increase relative to the control group. The cytotoxic activity of T. vulgaris essential oils was evaluated against lung (A-549), colon (HCT-116), intestinal (CACO2) and breast (MCF-7) carcinoma using the cell viability assay. The lowest IC50 values 0.44 and 0.33 MUg/mL were seen against (HCT-116) and (CACO2) cells respectively. These IC50 values were lower than that of doxorubicin used as reference drug. PMID- 29629568 TI - RNA-Seq analysis and comparison of the enzymes involved in ionone synthesis of three cultivars of Osmanthus. AB - To comprehend the molecular mechanisms that control the differences in the composition of Osmanthus essential oils, the RNA-seq data and differentially expressed genes in different cultivar Osmanthus were studied. cDNA libraries of "jinqiugui," "baijie," and "rixianggui" were sequenced using Illumina HiSeq TM 2000. All of the enzymes involved in ionone synthesis were verified. DEGs were revealed and their enriched pathways were analyzed. A total of 20 DEGsencoding four enzymes that were potential candidates involved in ionone biosynthesis, as well as ispH, GPPS, ZDS, and CCD. It provided a way for Osmanthus oil monomer material to be synthesized in vitro. PMID- 29629569 TI - Reversible versus irreversible inhibition modes of ERK2: a comparative analysis for ERK2 protein kinase in cancer therapy. AB - AIM: Irreversible covalent drug inhibition is an emerging paradigm; however, critical gaps in unraveling the efficacy of molecular determinants still persist. METHODOLOGY: We compare two ERK2 inhibitors with different binding modes. A 5-7 Oxozeaenol is selective inhibitor which irreversibly binds ERK2 by the formation of covalent bond with Cys166 while 5-iodotubercidin binds noncovalently. Result & discussion: Covalent inhibition showed greater protein stability, favorable binding energetics (irreversible inhibition binding free energy [DeltaGbind] = 40.4354 kcal/mol and reversible inhibition DeltaGbind = -26.2515 kcal/mol); higher correlation in residual movement and multiple van der Waals interactions as evident from residue interaction analysis. CONCLUSION: This investigation of the different inhibition modes of ERK2 would assist toward the design of more potent and highly site-specific covalent inhibitors in cancer therapy. PMID- 29629570 TI - Modulatory Effects of Rosemary Leaves Aqueous Extraction against oxidative stress and related damages in experimental model of CCl4-induced cardiac toxicity in mice. PMID- 29629571 TI - Learning from nature: the role of albumin in drug delivery. AB - Graphical Abstract [Formula: see text]. PMID- 29629572 TI - Anti-cancer effect of toosendanin and its underlying mechanisms. AB - Toosendanin (TSN) is a triterpenoid purified from the medicinal herb Melia toosendan Sieb. et Zucc and has been used as an insecticide for decades. Recent studies have attracted increasing interest of TSN due to its novel anti-cancer effect in diverse cancer models. The broad spectrum anti-cancer activity suggests that TSN inhibits multiple pathways/targets that are critical for cancer cell survival and proliferation. Our recent study indicated that TSN has anti-cancer effect in glioblastoma through induction of estrogen receptor beta (ERbeta) and p53. This review highlights the anti-cancer efficacy of TSN and provides proof-of principle insight into the underlying mechanisms. PMID- 29629573 TI - A Membranome-Centered Approach Defines Novel Biomarkers for Cellular Subtypes in the Intervertebral Disc. AB - Objective Lack of specific marker-sets prohibits definition and functional distinction of cellular subtypes in the intervertebral disc (IVD), such as those from the annulus fibrosus (AF) and the nucleus pulposus (NP). Design We recently generated immortalized cell lines from human NP and AF tissues; these comprise a set of functionally distinct clonal subtypes. Whole transcriptome analyses were performed of 12 phenotypically distinct clonal cell lines (4* NP-Responder, 4* NP nonResponder, 2* AF-Sheet forming, and 2* AF-nonSheet forming). Data sets were filtered for membrane-associated marker genes and compared to literature. Results Comparison of our immortal cell lines to published primary NP, AF, and articular chondrocytes (AC) transcriptome datasets revealed preservation of AF and NP phenotypes. NP-specific membrane-associated genes were defined by comparison to AF cells in both the primary dataset (46 genes) and immortal cell-lines (161 genes). Definition of AF-specific membrane-associated genes yielded 125 primary AF cell and 92 immortal cell-line markers. Overlap between primary and immortal NP cells yielded high-confidence NP-specific marker genes for NP-R ( CLDN11, TMEFF2, CA12, ANXA2, CD44) and NP-nR (EFNA1, NETO2, SLC2A1). Overlap between AF and immortal AF subtypes yielded specific markers for AF-S ( COLEC12, LPAR1) and AF-nS ( CHIC1). Conclusions The current study provides a reference platform for preclinical evaluation of novel membrane-associated cell type-specific markers in the IVD. Future research will focus on their biological relevance for IVD function in development, homeostasis, and degenerate conditions. PMID- 29629574 TI - Acetabular Delamination: Epidemiology, Histological Features, and Treatment. AB - Objective The International Cartilage Repair Society classification is the one mainly used to define chondral defects. However, this classification does not include delamination. The objective of the study is to describe the characteristics of this lesion to better explain its classification in the context of chondral lesions of the hip. Design We performed a retrospective analysis of 613 patients who underwent hip arthroscopy. In this group, the incidence, localization, histological characteristics, and association to femoroacetabular impingement as well as to other intraarticular lesions of acetabular delamination (AD) were analyzed. Preoperative magnetic resonance imaging accuracy and the different treatment options were also evaluated. Results In our series, the incidence of the AD was 37% (226 patients over 613). The average age of this group was significantly lower (39.3 years) than the entire group of patients. Isolated cam ( P < 0.01) and pincer morphologies ( P < 0.05) had a significant statistical association with the AD. This lesion was primarily localized at the acetabular chondrolabral junction, mainly on the anterosuperior quadrant. The intraarticular lesions more frequently associated to AD were labral lesions (94.25%, P < 0.01), ligamentum teres lesions (28.32%, P < 0.05), and femoral head chondral lesions (19.9%, P < 0.01). The histological examination of the AD was characterized by hypocellularity and structural disorder of the matrix, with fissures. Treatment remains controversial. Conclusion AD represents an intermediate stage in chondral damage and can be classified as a "2a" grade lesion. Histological examination confirms the intermediate and progressive character of this injury. PMID- 29629575 TI - Adult hospital admissions associated with multiple sclerosis in Finland in 2004 2014. AB - INTRODUCTION: Treatment of multiple sclerosis (MS) has developed significantly and several new immunotherapeutic drugs have become available in Finland since 2004. We studied whether this is associated with changes in hospital admission frequencies and healthcare costs and whether admission rates due to infection have increased. METHODS: The national Care Register for Health Care was searched for all discharges from neurological, medical, surgical, neurosurgical and intensive care units with MS as a primary diagnosis or an auxiliary diagnosis for primary infection diagnosis in 2004-2014. Only patients >=16 years of age were included. RESULTS: We identified 12,276 hospital admissions for 4296 individuals. The number of admissions declined by 4.6% annually (p = .0024) in both genders. Proportion of admissions with an infection as the primary diagnosis increased but no change in their frequency was found. They were longer than admissions with MS as the primary diagnosis and were associated with increased in-hospital mortality. The annual aggregate cost of hospital admissions declined by 51% during the study period. CONCLUSIONS: This study shows that hospital admission rates and costs related to MS hospital admissions have markedly declined from 2004 to 2014 in Finland, which coincides with an increase in the use of disease modifying therapies. Key message Hospital admission rates and costs related to MS hospital admissions have markedly declined from 2004 to 2014 in Finland. Proportion of admission related to infection has increased and they are associated with longer hospitalizations and increased in-hospital mortality pointing out the importance of infection prevention. PMID- 29629576 TI - Spinal infections in children. AB - Aims: This multicentre, retrospective study aimed to improve our knowledge of primary pyogenic spinal infections in children by analyzing a large consecutive case series. Patients and Methods: The medical records of children with such an infection, treated at four tertiary institutions between 2004 and 2014, were analyzed retrospectively. Epidemiological, clinical, paraclinical, radiological, and microbiological data were evaluated. There were 103 children, of whom 79 (76.7%) were aged between six months and four years. Results: We confirmed a significant male predominance in the incidence of primary pyogenic spinal infections in children (65%). The lumbar spine was the most commonly affected region, and 27 infections (26.2%) occurred at L4/5. The white blood cell count was normal in 61 children (59%), and the CRP level was normal in 43 (42%). Blood cultures were performed in 95 children, and were positive in eight (8%). A total of 20 children underwent culture of biopsy or aspiration material, which was positive in eight (40%). Methicillin-sensitive Staphylococcus aureus (MSSA) and Kingella ( K.) kingae were the most frequently isolated pathogens. Conclusion: MSSA remains the most frequently isolated pathogen in children with primary pyogenic infection of the spine, but K. kingae should be considered as an important pathogen in children aged between six months and four years. Therefore, an empirical protocol for antibiotic treatment should be used, with consideration being made for the triphasic age distribution and specific bacteriological aetiology. In the near future, the results of polymerase chain reaction assay on throat swabs may allow the indirect identification of K. kingae spondylodiscitis in young children and thus aid early treatment. However, these preliminary results require validation by other prospective multicentre studies. Cite this article: Bone Joint J 2018;100-B:542-8. PMID- 29629577 TI - Usage of unicompartmental knee arthroplasty. AB - Unicompartmental knee arthroplasty (UKA) has numerous advantages over total knee arthroplasty (TKA) and one disadvantage, the higher revision rate. The best way to minimize the revision rate is for surgeons to use UKA for at least 20% of their knee arthroplasties. To achieve this, they need to learn and apply the appropriate indications and techniques. This would decrease the revision rate and increase the number of UKAs which were implanted, which would save money and patients would benefit from improved outcomes over their lifetime. Cite this article: Bone Joint J 2018;100-B:432-5. PMID- 29629578 TI - Dorsal bridge plating or transarticular screws for Lisfranc fracture dislocations. AB - Aims: The aim of this retrospective study was to compare the functional and radiological outcomes of bridge plating, screw fixation, and a combination of both methods for the treatment of Lisfranc fracture dislocations. Patients and Methods: A total of 108 patients were treated for a Lisfranc fracture dislocation over a period of nine years. Of these, 38 underwent transarticular screw fixation, 45 dorsal bridge plating, and 25 a combination technique. Injuries were assessed preoperatively according to the Myerson classification system. The outcome measures included the American Orthopaedic Foot and Ankle Society (AOFAS) score, the validated Manchester Oxford Foot Questionnaire (MOXFQ) functional tool, and the radiological Wilppula classification of anatomical reduction. Results: Significantly better functional outcomes were seen in the bridge plate group. These patients had a mean AOFAS score of 82.5 points, compared with 71.0 for the screw group and 63.3 for the combination group (p < 0.001). Similarly, the mean Manchester Oxford Foot Questionnaire score was 25.6 points in the bridge plate group, 38.1 in the screw group, and 45.5 in the combination group (p < 0.001). Functional outcome was dependent on the quality of reduction (p < 0.001). A trend was noted which indicated that plate fixation is associated with a better anatomical reduction (p = 0.06). Myerson types A and C2 significantly predicted a poorer functional outcome, suggesting that total incongruity in either a homolateral or divergent pattern leads to worse outcomes. The greater the number of columns fixed the worse the outcome (p < 0.001). Conclusion: Patients treated with dorsal bridge plating have better functional and radiological outcomes than those treated with transarticular screws or a combination technique. Cite this article: Bone Joint J 2018;100-B:468-74. PMID- 29629579 TI - Anatomical total shoulder arthroplasty in young patients with osteoarthritis. AB - Aims: Controversy about the use of an anatomical total shoulder arthroplasty (aTSA) in young arthritic patients relates to which is the ideal form of fixation for the glenoid component: cemented or cementless. This study aimed to evaluate implant survival of aTSA when used in patients aged < 60 years with primary glenohumeral osteoarthritis (OA), and to compare the survival of cemented all polyethylene and cementless metal-backed glenoid components. Materials and Methods: A total of 69 consecutive aTSAs were performed in 67 patients aged < 60 years with primary glenohumeral OA. Their mean age at the time of surgery was 54 years (35 to 60). Of these aTSAs, 46 were undertaken using a cemented polyethylene component and 23 were undertaken using a cementless metal-backed component. The age, gender, preoperative function, mobility, premorbid glenoid erosion, and length of follow-up were comparable in the two groups. The patients were reviewed clinically and radiographically at a mean of 10.3 years (5 to 12, sd 26) postoperatively. Kaplan-Meier survivorship analysis was performed with revision as the endpoint. Results: A total of 26 shoulders (38%) underwent revision surgery: ten (22%) in the polyethylene group and 16 (70%) in the metal backed group (p < 0.0001). At 12 years' follow-up, the rate of implant survival was 74% (sd 0.09) for polyethylene components and 24% (sd 0.10) for metal-backed components (p < 0.0002). Glenoid loosening or failure was the indication for revision in the polyethylene group, whereas polyethylene wear with metal-on-metal contact, instability, and insufficiency of the rotator cuff were the indications for revision in the metal-backed group. Preoperative posterior subluxation of the humeral head with a biconcave/retroverted glenoid (Walch B2) had an adverse effect on the survival of a metal-backed component. Conclusion: The survival of a cemented polyethylene glenoid component is three times higher than that of a cementless metal-backed glenoid component ten years after aTSA in patients aged < 60 years with primary glenohumeral OA. Patients with a biconcave (B2) glenoid have the highest risk of failure. Cite this article: Bone Joint J 2018;100-B:485 92. PMID- 29629580 TI - Current concepts in the surgical management of adolescent idiopathic scoliosis. AB - Adolescent idiopathic scoliosis (AIS) is a complex 3D deformity of the spine. Its prevalence is between 2% and 3% in the general population, with almost 10% of patients requiring some form of treatment and up to 0.1% undergoing surgery. The cosmetic aspect of the deformity is the biggest concern to the patient and is often accompanied by psychosocial distress. In addition, severe curves can cause cardiopulmonary distress. With proven benefits from surgery, the aims of treatment are to improve the cosmetic and functional outcomes. Obtaining correction in the coronal plane is not the only important endpoint anymore. With better understanding of spinal biomechanics and the long-term effects of multiplanar imbalance, we now know that sagittal balance is equally, if not more, important. Better correction of deformities has also been facilitated by an improvement in the design of implants and a better understanding of metallurgy. Understanding the unique character of each deformity is important. In addition, using the most appropriate implant and applying all the principles of correction in a bespoke manner is important to achieve optimum correction. In this article, we review the current concepts in AIS surgery. Cite this article: Bone Joint J 2018;100-B:415-24. PMID- 29629581 TI - Vascularized fibular epiphyseal transfer for proximal humeral reconstruction in children with a primary sarcoma of bone. AB - Aims: Preserving growth following limb-salvage surgery of the upper limb in children remains a challenge. Vascularized autografts may provide rapid biological incorporation with the potential for growth and longevity. In this study, we aimed to describe the outcomes following proximal humeral reconstruction with a vascularized fibular epiphyseal transfer in children with a primary sarcoma of bone. We also aimed to quantify the hypertrophy of the graft and the annual growth, and to determine the functional outcomes of the neoglenofibular joint. Patients and Methods: We retrospectively analyzed 11 patients who underwent this procedure for a primary bone tumour of the proximal humerus between 2004 and 2015. Six had Ewing's sarcoma and five had osteosarcoma. Their mean age at the time of surgery was five years (two to eight). The mean follow-up was 5.2 years (1 to 12.2). Results: The overall survival at five and ten years was 91% (confidence interval (CI) 95% 75% to 100%). At the time of the final review, ten patients were alive. One with local recurrence and metastasis died one-year post-operatively. Complications included seven fractures, four transient nerve palsies, and two patients developed avascular necrosis of the graft. All the fractures presented within the first postoperative year and united with conservative management. One patient had two further operations for a slipped fibular epiphysis of the autograft, and a hemi-epiphysiodesis for lateral tibial physeal arrest. Hypertrophy and axial growth were evident in nine patients who did not have avascular necrosis of the graft. The mean hypertrophy index was 65% (55% to 82%), and the mean growth was 4.6 mm per annum (2.4 to 7.6) in these nine grafts. At final follow-up, the mean modified functional Musculoskeletal Tumour Society score was 77% (63% to 83%) and the mean Toronto Extremity Salvage Score (TESS) was 84% (65% to 94%). Conclusion: Vascularized fibular epiphyseal transfer preserves function and growth in young children following excision of the proximal humerus for a malignant bone tumour. Function compares favourably to other limb-salvage procedures in children. Longer term analysis is required to determine if this technique proves to be durable into adulthood. Cite this article: Bone Joint J 2018;100-B:535-41. PMID- 29629582 TI - Arthroscopically assisted fixation of Hawkins type II talar neck fractures. AB - Aims: Arthroscopically controlled fracture reduction in combination with percutaneous screw fixation may be an alternative approach to open surgery to treat talar neck fractures. The purpose of this study was thus to present preliminary results on arthroscopically reduced talar neck fractures. Patients and Methods: A total of seven consecutive patients (four women and three men, mean age 39 years (19 to 61)) underwent attempted surgical treatment of a closed Hawkins type II talar neck fracture using arthroscopically assisted reduction and percutaneous screw fixation. Functional and radiological outcome were assessed using plain radiographs, as well as weight-bearing and non-weight-bearing CT scans as tolerated. Patient satisfaction and pain sensation were also recorded. Results: Primary reduction was obtained arthroscopically in all but one patient, for whom an interposed fracture fragment had to be removed through a small arthrotomy to permit anatomical reduction. The quality of arthroscopic reduction and restoration of the talar geometry was excellent in the remaining six patients. There were no signs of talar avascular necrosis or subtalar degeneration in any of the patients. In the whole series, the functional outcome was excellent in five patients but restricted ankle movement was observed in two patients. All patients had a reduction in subtalar movement. At final follow-up, all patients were satisfied and all but one patient were pain free. Conclusion: Arthroscopically assisted reduction and fixation of talar neck fractures was found to be a feasible treatment option and allowed early functional rehabilitation. Cite this article: Bone Joint J 2018;100-B:461-7. PMID- 29629583 TI - Additive manufacturing. AB - Increasing innovation in rapid prototyping (RP) and additive manufacturing (AM), also known as 3D printing, is bringing about major changes in translational surgical research. This review describes the current position in the use of additive manufacturing in orthopaedic surgery. Cite this article: Bone Joint J 2018;100-B:455-60. PMID- 29629585 TI - Mortality and cause of death postoperatively in patients with a hip fracture. AB - Aims: The aim of this study was to compare the rate of mortality and causes of death in Korean patients who undergo surgery for a fracture of the hip, up to 11 years after the injury, with a control group from the general population. Materials and Methods: National cohort data from Korean Health Insurance Review and Assessment Service - National Sample Cohort were used. A ratio of 1:4 matched patients with a fracture who underwent surgery (3383, fracture group) between 2003 and 2012, and controls (13 532) were included. The matches were processed for age, gender, income, and region of residence. We also undertook analyses of subgroups according to age and gender. The mean follow-up was 4.45 years (1 to 11). Results: The prevalence of hypertension, diabetes, and stroke was significantly higher in the fracture group and dyslipidemia in the controls. Both crude and adjusted hazard ratios (HR) for the rate of mortality in the fracture group were > 2 (crude HR 2.03, 95% confidence interval (CI) 1.91 to 2.17, p < 0.001; adjusted HR 2.07, 95% CI 1.94 to 2.21, p < 0.001). The HRs were also > 2 for both men and women, and for both those aged >= 50 years and < 50 years. However, for those aged < 50 years, they were insignificant. The rates of mortality due to all 11 major causes of death classified following Korean standard classification of diseases were significantly higher in the fracture group compared with the control group, except those in the mental and behavioral disorders category. Conclusion: The rate of mortality in the fracture group was significantly higher than in the control group up to 11 years after the surgery. The rate of death due to almost every major cause was significantly higher in the fracture group compared with the control group. Cite this article: Bone Joint J 2018;100-B:436-42. PMID- 29629584 TI - Improving quality and safety in paediatric spinal surgery. AB - Aims: The aim of this study was to evaluate improvements in the quality and safety of paediatric spinal surgery following the implementation of a specialist Paediatric Spinal Surgical Team (PSST) in the operating theatre. Patients and Methods: A retrospective consecutive case study of paediatric spinal operations before (between January 2008 and December 2009), and after (between January 2012 and December 2013) the implementation of PSST, was performed. A comparative analysis of outcome variables including surgical site infection (SSI), operating time (ORT), blood loss (BL), length of stay (LOS), unplanned staged procedures (USP) and transfusion rates (allogenic and cell-saver) was performed between the two groups. The rate of complications during the first two postoperative years was also compared between the groups. Results: There were 130 patients in the pre PSST group and 277 in the post-PSST group. The age, gender, body mass index (BMI), preoperative Cobb angle of the major curve and the number of levels involved were similar between the groups. There were statistically significant differences in SSI, ORT, LOS, allogenic blood transfusion volume (ABTV), and USPs between the groups. There was a 94% decrease in the rate of SSI's in the post PSST group. Patients in the post-PSST group had a mean reduction in ORT of 53 minutes (sd 7.7) (p = 0.013), LOS by 5.4 days (sd 1.8) (p = 0.019), and ABTV by 226.3 ml (sd 28.4) (p < 0.001). There were significantly more USPs in the pre PSST group (6.2%) compared with the post-PSST group (2.9%) (p = 0.001). Multivariate regression showed that the effect of PSST remained significant for ORT, LOS, BL, ABVT and cell-saver amount transfused (p = 0.0001). The odds of having a SSI were tenfold higher and the odds of receiving a blood transfusion were 2.4 times higher, respectively, in the pre-PSST group (p = 0.004 and p = 0.011). The rate of complications within the first two postoperative years was significantly higher in the pre-PSST group (13.1%) compared with the post-PSST group (4.3%) (p < 0.001). Conclusion: The implementation of a PSST in the operating theatre significantly improves the outcomes in paediatric spinal surgery. Cite this article: Bone Joint J 2018;100-B:493-8. PMID- 29629586 TI - Patients with unilateral transfemoral amputation treated with a percutaneous osseointegrated prosthesis. AB - Aims: The aim of this study was to compare the cost-effectiveness of treatment with an osseointegrated percutaneous (OI-) prosthesis and a socket-suspended (S-) prosthesis for patients with a transfemoral amputation. Patients and Methods: A Markov model was developed to estimate the medical costs and changes in quality adjusted life-years (QALYs) attributable to treatment of unilateral transfemoral amputation over a projected period of 20 years from a healthcare perspective. Data were collected alongside a prospective clinical study of 51 patients followed for two years. Results: OI-prostheses had an incremental cost per QALY gained of ?83 374 compared with S-prostheses. The clinical improvement seen with OI-prostheses was reflected in QALYs gained. Results were most sensitive to the utility value for both treatment arms. The impact of an annual decline in utility values of 1%, 2%, and 3%, for patients with S-prostheses resulted in a cost per QALY gained of ?37 020, ?24 662, and ?18 952, respectively, over 20 years. Conclusion: From a healthcare perspective, treatment with an OI-prosthesis results in improved quality of life at a relatively high cost compared with that for S-prosthesis. When patients treated with S-prostheses had a decline in quality of life over time, the cost per QALY gained by OI-prosthesis treatment was considerably reduced. Cite this article: Bone Joint J 2018;100-B:527-34. PMID- 29629587 TI - An NIHR-approved two-year observational study on magnetically controlled growth rods in the treatment of early onset scoliosis. AB - Aims: The primary aim of this study was to evaluate the performance and safety of magnetically controlled growth rods in the treatment of early onset scoliosis. Secondary aims were to evaluate the clinical outcome, the rate of further surgery, the rate of complications, and the durability of correction. Patients and Methods: We undertook an observational prospective cohort study of children with early onset scoliosis, who were recruited over a one-year period and followed up for a minimum of two years. Magnetically controlled rods were introduced in a standardized manner with distractions performed three-monthly thereafter. Adverse events which were both related and unrelated to the device were recorded. Ten children, for whom relevant key data points (such as demographic information, growth parameters, Cobb angles, and functional outcomes) were available, were recruited and followed up over the period of the study. There were five boys and five girls. Their mean age was 6.2 years (2.5 to 10). Results: The mean coronal Cobb angle improved from 57.6 degrees (40 degrees to 81 degrees ) preoperatively, 32.8 degrees (28 degrees to 46 degrees ) postoperatively, and 41 degrees (19 degrees to 57 degrees ) at two years. Five children had an adverse event, with four requiring return to theatre, but none were related to the device. There were no neurological complications or infections. No devices failed. One child developed a proximal junctional kyphosis. The mean gain in spinal column height from T1 to S1 was 45.4 mm (24 to 81) over the period of the study. Conclusion: Magnetically controlled growth rods provide an alternative solution to traditional growing rods in the surgical management of children with early onset scoliosis, supporting growth of the spine while controlling curve progression. Their use has clear psychosocial and economic benefits, with the reduction of the need for repeat surgery as required with traditional growing rods. Cite this article: Bone Joint J 2018;100-B:507-15. PMID- 29629589 TI - Flexed-knee gait in children with cerebral palsy. AB - Aims: The purpose of this study was to evaluate the long-term outcome of adolescents with cerebral palsy who have undergone single-event multilevel surgery for a flexed-knee gait, followed into young adulthood using 3D motion analysis. Patients and Methods: A total of 59 young adults with spastic cerebral palsy, with a mean age of 26 years (sd 3), were enrolled into the study in which their gait was compared with an evaluation that had taken place a mean of 12 years (sd 2) previously. At their visits during adolescence, the children walked with excessive flexion of the knee at initial contact and surgical or therapeutic interventions were not controlled between visits. Results: Based on the change in flexed-knee gait over approximately ten years, improvements were seen in increased Gait Deviation Index (p < 0.001) and decreased flexion of the knee at initial contact (p < 0.001). Greater popliteal angle (p < 0.001), reduced Gross Motor Function Measure section D (p = 0.006), and reduced speed of gait (p = 0.007) suggested a mild decline in function. Quality-of-life measures showed that these patients fell within normal limits compared with typical young adults in areas other than physical function. Conclusion: While some small significant changes were noted, little clinically significant change was seen in function and gait, with gross motor function maintained between adolescence and young adulthood. Cite this article: Bone Joint J 2018;100-B:549-56. PMID- 29629588 TI - Reliable outcomes and survivorship of unicompartmental knee arthroplasty for isolated compartment osteonecrosis. AB - Aims: Primary (or spontaneous) and secondary osteonecrosis of the knee can lead to severe joint degeneration, for which either total or unicompartmental arthroplasty may be considered. However, there are limited studies analyzing outcomes of unicompartmental knee arthroplasties (UKAs) for osteonecrosis involving an isolated compartment of the knee. The aims of this study were to analyze outcomes of UKAs for osteonecrosis with specific focus on 1) survivorship free of any revision or reoperation, 2) risk factors for failure, 3) clinical outcomes, and 4) complications. Patients and Methods: A total of 45 patients underwent 46 UKAs for knee osteonecrosis between 2002 and 2014 at our institution (The Mayo Clinic, Rochester, Minnesota). Twenty patients (44%) were female; the mean age of the patients was 66 years, and mean body mass index (BMI) was 31 kg/m2. Of the 46 UKAs, 44 (96%) were medial UKAs, and 35 (76%) were fixed-bearing design. Mean mechanical axis postoperatively was 1.5 degrees varus (0 degrees to 5 degrees varus); 41 UKAs (89%) were performed for primary osteonecrosis. Mean follow-up was five years (2 to 12). Results: Survivorship free of any revision in the cohort was 89% (95% CI 77 to 99) and 76% (95% CI 53 to 99) at five and ten years, respectively. In patients undergoing UKA for primary osteonecrosis survivorship free of any revision was 93% (95% CI 83 to 100)at both five and ten years. Secondary osteonecrosis was a significant risk factor for poorer survivorship free of any revision or reoperation (hazard ratio 7.7, p = 0.03). Three medial UKAs (6.5%) were converted to total knee arthroplasties (TKAs): two for lateral compartment degeneration and one for development of lateral osteonecrosis. No implants were revised for loosening, fracture, or wear. Knee Society scores improved from a mean of 60 (44 to 72) preoperatively to a mean of 94 postoperatively (82 to 100) (p < 0.001). There were no surgical complications. Conclusion: When done for primary osteonecrosis of the knee, UKA resulted in reliable clinical improvement, minimal complications, and durable estimated implant survivorship free of revision at ten years. UKA done for secondary osteonecrosis was substantially less durable at mid-term follow-up. Progression of knee degeneration, rather than implant failure or loosening, was most common indication for conversion to TKA. Cite this article: Bone Joint J 2018;100-B:450-4. PMID- 29629590 TI - Higher preoperative sensitivity to pain and pain at rest are associated with worse functional outcome after stemless total shoulder arthroplasty. AB - Aims: The aims of this study were to investigate any possible relationship between a preoperative sensitivity to pain and the degree of pain at rest and on exertion with postoperative function in patients who underwent stemless total shoulder arthroplasty (TSA). Patients and Methods: In this prospective study, we included 63 patients who underwent stemless TSA and were available for evaluation one year postoperatively. There were 31 women and 32 men; their mean age was 71 years (53 to 89). The pain threshold, which was measured using a Pain Matcher (PM) unit, the degree of pain (visual analogue scale at rest and on exertion, and function using the short version of the Disabilities of the Arm, Shoulder and Hand questionnaire (QuickDASH), were recorded preoperatively, as well as three and 12 months postoperatively. Results: We found an inverse relationship between both the preoperative PM threshold and pain (VAS) at rest and the 12-month postoperative QuickDASH score (Pearson correlation coefficient (r) >= 0.4, p < 0.05). A linear regression analysis showed that the preoperative PM threshold on the affected side and preoperative pain (VAS) at rest were the only factors associated with the QuickDASH score at 12 months. Conclusion: These findings indicate the importance of central sensitization in the restoration of function after TSA. Further studies are required to investigate whether extra analgesia and rehabilitation could influence the outcome in at risk patients. Cite this article: Bone Joint J 2018;100-B:480-4. PMID- 29629591 TI - Displaced femoral neck fractures in patients 60 years of age or younger: results of internal fixation with the dynamic locking blade plate. AB - Aims: The objective of this study was to investigate bone healing after internal fixation of displaced femoral neck fractures (FNFs) with the Dynamic Locking Blade Plate (DLBP) in a young patient population treated by various orthopaedic (trauma) surgeons. Patients and Methods: We present a multicentre prospective case series with a follow-up of one year. All patients aged <= 60 years with a displaced FNF treated with the DLBP between 1st August 2010 and December 2014 were included. Patients with pathological fractures, concomitant fractures of the lower limb, symptomatic arthritis, local infection or inflammation, inadequate local tissue coverage, or any mental or neuromuscular disorder were excluded. Primary outcome measure was failure in fracture healing due to nonunion, avascular necrosis, or implant failure requiring revision surgery. Results: In total, 106 consecutive patients (mean age 52 years, range 23 to 60; 46% (49/106) female) were included. The failure rate was 14 of 106 patients (13.2%, 95% confidence interval (CI) 7.1 to 19.9). Avascular necrosis occurred in 11 patients (10.4%), nonunion in six (5.6%), and loss of fixation in two (1.9%). Conclusion: The rate of fracture healing after DLBP fixation of displaced femoral neck fracture in young patients is promising and warrants further investigation by a randomized trial to compare the performance against other contemporary methods of fixation. Cite this article: Bone Joint J 2018;100-B:443-9. PMID- 29629592 TI - Revision of failed total ankle arthroplasty to a hindfoot fusion. AB - Aims: The aim of this study was to present a series of patients with aseptic failure of a total ankle arthroplasty (TAA) who were treated with fusion of the hindfoot using a nail. Patients and Methods: A total of 23 TAAs, in 22 patients, were revised for aseptic loosening and balloon osteolysis to a hindfoot fusion by a single surgeon (NH) between January 2012 and August 2014. The procedure was carried out without bone graft using the Phoenix, Biomet Hindfoot Arthrodesis Nail. Preoperative investigations included full blood count, CRP and ESR, and radiological investigations including plain radiographs and CT scans. Postoperative plain radiographs were assessed for fusion. When there was any doubt, CT scans were performed. Results: The mean follow-up was 13.9 months (4.3 to 37.2). Union occurred at the tibiotalar joint in 22 ankles (95.6%) with one partial union. Union occurred at the subtalar joint in 20 ankles (87%) of cases with two nonunions. The nail broke in one patient with a subtalar nonunion and revision was undertaken. The only other noted complication was one patient who suffered a stress fracture at the proximal aspect of the nail, which was satisfactorily treated conservatively. Conclusion: This study represents the largest group of patients reported to have undergone revision TAA to fusion of the hindfoot with good results Cite this article: Bone Joint J 2018;100-B:475-9. PMID- 29629593 TI - Enhanced care pathways have multiple benefits. PMID- 29629594 TI - A qualitative study of patient experience of an open fracture of the lower limb during acute care. AB - Aims: The aim of this study was to explore the patients' experience of recovery from open fracture of the lower limb in acute care. Patients and Methods: A purposeful sample of 20 participants with a mean age of 40 years (20 to 82) (16 males, four females) were interviewed a mean of 12 days (five to 35) after their first surgical intervention took place between July 2012 and July 2013 in two National Health Service (NHS) trusts in England, United Kingdom. The qualitative interviews drew on phenomenology and analysis identified codes, which were drawn together into categories and themes. Results: The findings identify the vulnerability of the patients expressed through three themes; being emotionally fragile, being injured and living with injury. The participants felt a closeness to death and continued uncertainty regarding loss of their limb. They experienced strong emotions while also trying to contain their emotions for the benefit of others. Their sense of self changed as they became a person with visible wounds, needed intimate help, and endured pain. When ready, they imagined what it would be like to live with injury. Conclusion: Recovery activities require an increased focus on emotional wellbeing. Surgeons are aware of the need for clinical expertise and for adequate pain relief but may not be as aware that their patients require support regarding their body image and help to imagine their future life. Cite this article: Bone Joint J 2018;100-B:522-6. PMID- 29629595 TI - A comparison of the biomechanical stability of pedicle-lengthening screws and traditional pedicle screwsan in vitro instant and fatigue-resistant pull-out test. AB - Aims: The aim of this study was to compare the peak pull-out force (PPF) of pedicle-lengthening screws (PLS) and traditional pedicle screws (TPS) using instant and cyclic fatigue testing. Materials and Methods: A total of 60 lumbar vertebrae were divided into six groups: PLS submitted to instant pull-out and fatigue-resistance testing (groups A1 and A2, respectively), TPS submitted to instant pull-out and fatigue-resistance testing (groups B1 and B2, respectively) and PLS augmented with 2 ml polymethylmethacrylate, submitted to instant pull-out and fatigue-resistance testing (groups C1 and C2, respectively). The PPF and normalized PPF (PPFn) for bone mineral density (BMD) were compared within and between all groups. Results: In all groups, BMD was significantly correlated with PPF (r = 0.83, p < 0.001). The PPFn in A1 was significantly less than in B1 (p = 0.006) and C1 (p = 0.002). The PPFn of A2 was significantly less than in B2 (p < 0.001) and C2 (p < 0.001). The PPFn in A1, B1, and C1 was significantly greater than in A2 (p = 0.002), B2 (p = 0.027), and C2 (p = 0.003). There were no significant differences in PPFn between B1 and C1, or between B2 and C2. Conclusion: Pedicle lengthening screws with cement augmentation can provide the same fixation stability as traditional pedicle screws and may be a viable clinical option. Cite this article: Bone Joint J 2018;100-B:516-21. PMID- 29629596 TI - Spinal tuberculosis. AB - Tuberculosis (TB) remains endemic in many parts of the developing world and is increasingly seen in the developed world due to migration. A total of 1.3 million people die annually from the disease. Spinal TB is the most common musculoskeletal manifestation, affecting about 1 to 2% of all cases of TB. The coexistence of HIV, which is endemic in some regions, adds to the burden and the complexity of management. This review discusses the epidemiology, clinical presentation, diagnosis, impact of HIV and both the medical and surgical options in the management of spinal TB. Cite this article: Bone Joint J 2018;100-B:425 31. PMID- 29629597 TI - Minimally invasive spinal decompression for degenerative lumbar spondylolisthesis and stenosis maintains stability and may avoid the need for fusion. AB - Aims: The aim of this study was to investigate the clinical and radiographic outcomes of microendoscopic laminotomy in patients with lumbar stenosis and concurrent degenerative spondylolisthesis (DS), and to determine the effect of this procedure on spinal stability. Patients and Methods: A total of 304 consecutive patients with single-level lumbar DS with concomitant stenosis underwent microendoscopic laminotomy without fusion between January 2004 and December 2010. Patients were divided into two groups, those with and without advanced DS based on the degree of spondylolisthesis and dynamic instability. A total of 242 patients met the inclusion criteria. There were 101 men and 141 women. Their mean age was 68.1 years (46 to 85). Outcome was assessed using the Japanese Orthopaedic Association and Roland Morris Disability Questionnaire scores, a visual analogue score for pain and the Short Form Health-36 score. The radiographic outcome was assessed by measuring the slip and the disc height. The clinical and radiographic parameters were evaluated at a mean follow-up of 4.6 years (3 to 7.5). Results: There were no significant differences in the preoperative measurements between the group and no significant differences between the clinical parameters at the final follow-up. The mean percentage slip was 17.1% preoperatively and 17.7% at the final follow-up (p = 0.35). Progressive instability was noted in 13 patients (8.2%) with DS and 6 patients (7.0%) with advanced DS, respectively (p = 0.81). There was radiological evidence of restabilization of the spine in 30 patients (35%) with preoperative instability. The success rate of microendoscopic laminotomy was good/excellent in 166 (69%), fair in 49 (20%) and poor in 27 patients (11%) in both groups. Conclusion: Microendoscopic laminotomy is an effective form of surgical treatment for patients with DS and stenosis. Preservation of the stabilizing structures using this technique prevents postoperative instability. Cite this article: Bone Joint J 2018;100-B:499-506. PMID- 29629598 TI - Which echocardiographic parameters improve the risk prediction for peri-operative outcomes in patients undergoing coronary bypass surgery: a prospective study. AB - OBJECTIVE: To assess the performance of transthoracic echocardiographic parameters to predict operative mortality and morbidity in patients undergoing coronary artery bypass grafting, and to assess its incremental prognostic value as compared to the Society of Thoracic Surgeons (STS) score. MATERIALS AND METHODS: We prospectively collected the clinical and biological data required to calculate the STS score in patients hospitalised for coronary artery bypass grafting. Preoperative transthoracic echocardiography was performed for each patient. The primary endpoint was 30-day mortality or major morbidity (i.e. stroke, renal failure, prolonged ventilation, deep sternal wound infection, reoperation) as defined by the STS. The secondary endpoint was prolonged hospitalisation for over 14 days. RESULTS: A total of 172 patients was included (mean age 66.1+/-10.2 years, 12.2% were women). The primary endpoint occurred in 33 patients (19.2%), and 28 patients (16.3%) had a prolonged hospital stay. Independent predictive factors for the primary endpoint were an increased left atrial volume (>31 mL/m2; odds ratio (OR) 3.55, 95% confidence interval (CI) 1.38 9.12; P=0.004) and a decreased tricuspid annular plane systolic excursion (<20 mm; OR 3.45, 95% CI 1.47-8.21; P=0.008). The predictive value of the multivariate model increased when the two echocardiographic parameters were added to the STS score (area under the curve 0.598 vs. 0.695, P=0.001; integrated discrimination improvement 7.44%). CONCLUSION: In patients undergoing coronary artery bypass grafting, preoperative assessment of left atrial size and tricuspid annular plane systolic excursion should be performed systematically, as it provides additional prognostic information to the STS score. PMID- 29629599 TI - Remission of chronic headache: An 11-year follow-up study. Data from the Nord Trondelag Health Surveys 1995-1997 and 2006-2008. AB - OBJECTIVES: To estimate remission rates of chronic headache and predictors of remission. METHODS: In this longitudinal population-based cohort study, we used validated headache questionnaire data from the second (1995-1997, baseline; n = 51,856 aged >= 20 years, response rate: 55%) and third wave (2006-2008, follow up, response rate: 42%) of the Nord-Trondelag Health Study. Chronic headache was defined as >=15 headache days/month during the last year. Chronic headache remission was defined as headache less than 15 days/month at follow-up. Potential predictors of remission were evaluated using logistic regression. RESULTS: At baseline, 1266 (2.4%) participants reported chronic headache. Of these, 605 (48%) answered headache questions at follow-up. Remission was observed in 452 (74.7%), the proportion being almost identical in men and women (74.4% vs. 74.9, p = 0.92). In analyses adjusting for age, gender and education level, remission at follow-up was more than two times more likely among individuals without medication overuse headache (OR = 2.4, 95% CI 1.7-3.6) and without chronic musculoskeletal complaints (OR = 2.9, 95% CI 1.5-5.0) at baseline. CONCLUSIONS: In this longitudinal population-based cohort study, three-quarters of chronic headache participants remitted from chronic headache. Remission was associated with no medication overuse headache and no chronic musculoskeletal complaints at baseline. PMID- 29629600 TI - Visual symptoms and childhood migraine: Qualitative analysis of duration, location, spread, mobility, colour and pattern. AB - AIM: To examine the characteristics of visual symptoms during attacks of migraine in children and adolescents. METHOD: A qualitative analysis of prospectively collected data over 5 years, on characteristics of visual symptoms during migraine attacks. Diagnosis of migraine and aura was based on the International Classification of Headache Disorders 3rd edition beta version. We also provided the opportunity for patients to illustrate their visual aura symptoms to aid in diagnosis. RESULTS: Visual symptoms were reported by 387/1079 (36%) of migraineurs. Of these, 172 (16%) patients fulfilled the International Classification of Headache Disorders Criteria A, B, C iv and D, but missed one (n = 75; 43.5%) or two (n = 97; 56.5%) of the remaining items of criteria C as the visual symptoms were of non-gradual spread (n = 35; 20%), appeared in both visual fields (n = 99; 58%), or lasted less than 5 minutes or more than 60 minutes (n = 129; 75%). CONCLUSION: The International Classification of Headache Disorders 3rd edition beta version criteria are useful in diagnosis of migraine with visual aura in children and adolescents, but visual symptoms varied considerably in duration, pattern, mobility, location, mode of onset and colours. Providing opportunity for patients to illustrate their symptoms can provide additional diagnostic information. The pathophysiology and the clinical concept of typical MVA is still to an extent an assumption and needs further evaluation. APPROVAL: The study was approved by the Health Research Authority - London and the local Research and Innovation Department at Barking Havering and Redbridge National Health Service Trust. Formal parental consent was not considered essential for this type of study. PMID- 29629601 TI - Occipital neuralgia associates with high cervical spinal cord lesions in idiopathic inflammatory demyelinating disease. AB - Background The association of trigeminal neuralgia with pontine lesions has been well documented in multiple sclerosis, and we tested the hypothesis that occipital neuralgia in multiple sclerosis is associated with high cervical spinal cord lesions. Methods We retrospectively reviewed the records of 29 patients diagnosed with both occipital neuralgia and demyelinating disease by a neurologist from January 2001 to December 2014. We collected data on demographics, clinical findings, presence of C2-3 demyelinating lesions, and treatment responses. Results The patients with both occipital neuralgia and multiple sclerosis were typically female (76%) and had a later onset (age > 40) of occipital neuralgia (72%). Eighteen patients (64%) had the presence of C2-3 lesions and the majority had unilateral symptoms (83%) or episodic pain (78%). All patients with documented sensory loss (3/3) had C2-3 lesions. Most patients with progressive multiple sclerosis (6/8) had C2-3 lesions. Of the eight patients with C2-3 lesions and imaging at onset of occipital neuralgia, five (62.5%) had evidence of active demyelination. None of the patients with progressive multiple sclerosis (3/3) responded to occipital nerve blocks or high dose intravenous steroids, whereas all of the other phenotypes with long term follow-up (eight patients) had good responses. Conclusions A cervical spine MRI should be considered in all patients presenting with occipital neuralgia. In patients with multiple sclerosis, clinical features in occipital neuralgia that were predictive of the presence of a C2-3 lesion were unilateral episodic symptoms, sensory loss, later onset of occipital neuralgia, and progressive multiple sclerosis phenotype. Clinical phenotype predicted response to treatment. PMID- 29629602 TI - Deactivation of mitochondrial complex I after hypoxia-ischemia in the immature brain. AB - Mortality from perinatal hypoxic-ischemic (HI) brain injury reached 1.15 million worldwide in 2010 and is also a major factor for neurological disability in infants. HI directly influences the oxidative phosphorylation enzyme complexes in mitochondria, but the exact mechanism of HI-reoxygenation response in brain remains largely unresolved. After induction of HI-reoxygenation in postnatal day 10 rats, activities of mitochondrial respiratory chain enzymes were analysed and complexome profiling was performed. The effect of conformational state (active/deactive (A/D) transition) of mitochondrial complex I on H2O2 release was measured simultaneously with mitochondrial oxygen consumption. In contrast to cytochrome c oxidase and succinate dehydrogenase, HI-reoxygenation resulted in inhibition of mitochondrial complex I at 4 h after reoxygenation. Immediately after HI, we observed a robust increase in the content of deactive (D) form of complex I. The D-form is less active in reactive oxygen species (ROS) production via reversed electron transfer, indicating the key role of the deactivation of complex I in ischemia/reoxygenation. We describe a novel mechanism of mitochondrial response to ischemia in the immature brain. HI induced a deactivation of complex I in order to reduce ROS production following reoxygenation. Delayed activation of complex I represents a novel mitochondrial target for pathological-activated therapy. PMID- 29629603 TI - Evaluation of EMLA cream for relieving pain during needle insertion on totally implantable venous access device. AB - PURPOSE:: Needle insertion is a routine procedure performed on cancer patients with totally implantable venous access device. Although this procedure is painful for most of the patients, it is regularly performed without topical application of local anesthetics. In our study, we assess the degree of pain associated with different duration times of EMLA cream. METHODS:: A total of 361 cancer patients with totally implantable venous access devices were randomly divided into three groups: group 1-placebo, group 2-30 min after application of EMLA, and group 3-60 min after application of EMLA. In this double-blinded prospective study, the efficacy of EMLA cream was compared with a placebo cream by comparing the degree of pain experienced by the patient who was evaluated during and after needle insertion on a numeric rating scale. RESULTS:: The mean +/- standard deviation of pain experienced by the patients was significantly (p < 0.05) lower in group C (0.69 +/- 0.98) than groups B (1.11 +/- 1.14) and A (1.91 +/- 1.40). No significant (p > 0.05) difference was found in mean scores from inexperienced and experienced procedures of needle insertions among three groups. Comparing male patients, the female patients in group 1 and group 2 had lower numeric rating scale (1.59 +/- 0.94, 1.39 +/- 1.35; p < 0.01). CONCLUSION:: The present results review that the application of EMLA cream for 30 min is suitable, acceptable, and convenient in cancer patients with totally implantable venous access device undergoing needle insertion. PMID- 29629604 TI - The Assessment of HER2 Gene Status by Fluorescence In Situ Hybridization in Invasive Breast Carcinomas With Equivocal HER2 Immunostaining: Experience From a Single Institution. AB - BACKGROUND: A subset of breast carcinomas harbors overexpression of the human epidermal growth factor receptor 2 (HER2). Fluorescence in situ hybridization (FISH) should be performed in breast carcinomas with equivocal HER2 immunostaining (immunohistochemistry [IHC] HER2 2+). The aim of our study is to investigate clinicopathologic factors associated with HER2 status in breast invasive carcinomas with IHC HER2 2+ through FISH analysis. METHODS: This is a retrospective study including the FISH analysis of 111 patients with invasive breast carcinomas with equivocal HER2 immunostaining. RESULTS: The mean age was 49.51 +/- 10.48 years, and invasive breast carcinoma of no special type was the most histological type in our study (96.4%). Most patients had tumors positive for hormones receptors (88.2% positive for estrogen receptor and 81.4% for progesterone receptor). On FISH, the HER2 amplification rate was 22.5%. There was no significant association of HER2 status with any clinicopathologic factors ( P > .05). CONCLUSIONS: Our study shows that there are no reliable clinicopathologic factors to predict the HER2 status in breast tumors with equivocal HER2 immunostaining, supporting the necessary usage of FISH in such circumstances. PMID- 29629605 TI - ECTRIMS/ACTRIMS 2017: Closing in on neurorepair in progressive multiple sclerosis. AB - BACKGROUND: While there is now a multitude of potent medications for relapsing remitting multiple sclerosis (RRMS), effective therapies targeting neurodegeneration in progressive multiple sclerosis types are still lacking. Stimulation of neurorepair in this disease remains a pathogenetically defined treatment goal. However, therapeutic progress is slowed by the still inadequate tool set to capture "regeneration/repair" in MS and to define appropriate outcomes in clinical trials. OBJECTIVES: In this review, we discuss studies investigating promising regenerative agents for progressive MS which were recently presented during the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS)/Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) 2017 meeting in Paris. PMID- 29629607 TI - Predictors of fracture risk in patients with systemic lupus erythematosus. AB - Objectives Bone loss in systemic lupus erythematosus is multifactorial. Recent studies demonstrate corticosteroids, previous fractures and increasing age decrease bone mineral density. The effect of body mass index and fat mass are less well characterized. We sought to determine fracture risk factors in patients undergoing dual-energy X-ray absorptiometry scanning at a district hospital in 2004-2015. Methods Standard dual-energy X-ray absorptiometry parameters were recorded, plus rheumatoid arthritis diagnosis, smoking status, alcohol consumption, family history of fractures, history of secondary operation and corticosteroid use. Data were analyzed using Fisher's exact test for categorical data and logistic regression for continuous data. Results One hundred and fifty patients (141 women, nine men) with SLE were included; 52 (34.6%) had sustained at least one fracture. Fracture risk increased with increased age, body mass index, fat mass and average tissue thickness, and decreased lean mass (adjusted for steroid use), as well as with smoking and rheumatoid arthritis. Increased femoral and vertebral bone mineral density conversely decreased fracture risk. Conclusion Our study suggests increased age, body mass index, fat mass, smoking and/or rheumatoid arthritis increase fracture risk in SLE patients. To our knowledge, this is the first demonstration of a correlation between increased fat mass, adjusted for steroid use and fracture risk, in adults, potentially indicating a differential effect of fat on bone metabolism and lessening of lean body mass. PMID- 29629608 TI - Intravenous pulses of methylprednisolone to treat flares of immune-mediated diseases: how much, how long? AB - Introduction Glucocorticoids are widely used in the treatment of immune-mediated diseases. Despite their widespread use, details on dosing, effectiveness and adverse effects are yet to be determined. Objective To know the current use of methylprednisolone (MTP) in the management of immune-mediated conditions, evaluating the relationship among doses, therapeutic response and adverse effects. Methodology A multicenter retrospective cohort study was designed, including patients who received intravenous pulses of MTP between 1 January 2013 and 12 December 2015 in three different hospitals in Uruguay. The patients included received MTP to treat systemic autoimmune diseases (SADs), hematological, nephrological and neurologic diseases and others. The following variables were analyzed: age, gender, MTP cumulative dose, duration of treatment, clinical response (complete, partial and no response) and adverse effects. Results In total, 164 cases were identified, of which 118 (72%) were female. The median age was 48.4 (SD: 18) years. The indications for MTP included: neuroimmune mediated 92 (56.1%), SADs 29 (17.5%), hematological 15 (9.1%), nephrological 12 (7.3%) and others 16 (9.9%). The median dose to achieve complete response was 3.2 g (SD: 1.5); the median dose to accomplish a partial response was 3.5 g (SD: 1.25); the median dose for non-responders was 3.3 g (SD 1.2) ( p > 0.05). The median dose in those patients with adverse effects was 3.4 g (SD 1.5) and the median dose for those who did not experience adverse effects was 3.3 g (SD: 1.3) ( p > 0.05). The most frequent adverse effects were infectious (22/164, 13.4%). Diabetics were found to have the highest incidence of adverse effects (13/16, 81%) in comparison to non-diabetics, p < 0.05. Discussion Our study suggests a wide range of doses and duration of treatments with MTP. No major associations were found between clinical response and the use of high MTP doses, but the latter was associated with a large proportion of severe infections. No severe infections were identified with MTP doses lower than 1.5 g. The diabetic population is known to be at risk of experiencing varied adverse effects to MTP. These observations reinforce the need for protocolized use of MTP in order to achieve a better relationship among doses, effectiveness and safety profile. PMID- 29629606 TI - Cancer and Complementary Therapies: Current Trends in Survivors' Interest and Use. AB - BACKGROUND: Cancer survivors use complementary therapies (CTs) for a variety of reasons; however, with interest and use reportedly on the rise and a widening range of products and practices available, there is a need to establish trends in and drivers of interest. We aimed to determine (1) frequencies of use, level of interest, and barriers for 30 specific CTs and (2) whether physical symptoms, perceived stress (PS), or spiritual well-being were related to interest levels. METHOD: A total of 212 cancer outpatients were surveyed at the Tom Baker Cancer Centre in Calgary, Canada. RESULTS: Overall, up to 75% of survivors already used some form of CTs since their diagnosis. The most highly used were the following: vitamins B12 and D, multivitamins, calcium, and breathing and relaxation exercises. Those who had not used CTs indicated highest interest in massage, vitamin B12, breathing and relaxation, mindfulness-based stress reduction, and antioxidants. The most frequently reported barriers for all CTs were not knowing enough about what a therapy was and not having enough evidence on whether it worked. High PS predicted higher interest for all CTs, but spirituality was not significantly related to any. Physical symptoms, anxiety, and depression were significant predictors of interest for some CTs. CONCLUSION: These findings provide a blueprint for future clinical efficacy trials and highlight the need for clinical practice guidelines. PMID- 29629610 TI - Erratum. PMID- 29629609 TI - Long-term behaviors of phosphate-based rapid repairing material for concrete shafts in coal mines. AB - INTRODUCTION: Concrete structures in shaft linings are apt to deteriorate prematurely and therefore prompt restoration is required. In considering this, desulphurization fly ash and machine-made tuff sand are employed to fabricate a phosphate-based rapid repairing material. METHODS: The long-term efficiency of the material is evaluated based on combined factors, so drying shrinkage, interfacial bonding strength, corrosion resistance, and combustibility of the specimens are tested and researched in this paper. RESULTS: Experimental results showed that, under a dry circumstance, the material goes through a minor expansion at an early stage. It goes into a stage of rapid contraction after one day and a stable contraction after seven days. After 28 days, the total deformation is 67 micro-strains. On the other hand, the fabricated material manifests an excellent mechanical property. The one hour bending strength and compressive strength were 9.2 MPa and 32.6 MPa, respectively. A long-term mine water flushing simulation demonstrates that only 10% bending strength is lost and the corrosion resistance coefficient stays above 0.8, so a very good corrosion resistance is thus achieved. CONCLUSIONS: What is more, this repairing material retains its stability even at a high temperature of 1000 degrees C, revealing its good thermo-stability. All these prominent properties make it a good prospective material for real restoration applications. PMID- 29629611 TI - A safe speed guidance model for highways. AB - This paper presents a fuzzy logic model to support decisions for the suggested speed limit for sections of highways as they become affected by adverse road conditions, environmental factors and differing traffic levels. The definition of the main factors, and their weight, that reduce safety on highways was conducted by the Delphi method, consulting traffic engineering experts. The survey served as a basis for structuring indicators and indexes in a soft decision tree, structured by a fuzzy logic system. The system can be used to support the decisions of those that manage the roads, indicating to drivers' speeds, by visual, audible or combined systems. PMID- 29629612 TI - The 9p21 locus as a potential therapeutic target and prognostic marker in colorectal cancer. AB - Colorectal cancer (CRC) is a major cause of cancer-related-death worldwide. Despite extensive efforts to identify valid biomarkers for the risk stratification of CRC patients, there are few of proven clinical utility. It is recognized that genetic factors play a major role in determining susceptibility to CRC. Recent genome-wide association studies have demonstrated common genetic variants in a region on chromosome 9p21 associated with an increased risk of CRC. Several genetic polymorphisms have been identified in this region that are associated with CRC. Three genes are located at this locus; CDKN2B(encoding p15ink4b), CDKN2A (encoding-p16ink4a/p14ARF) and 3' end of CDKN2BAS (termed antisense-noncoding-RNA in the INK4-locus [ANRIL]). ANRIL has a post transcriptional modulatory activity, which has been shown to perturb the expression of nearby genes. It also plays an important role in coordinating tissue remodeling through regulation of cell proliferation, apoptosis, aging, extra-cellular matrix remodeling and inflammatory response. However, the role of ANRIL is not well understood in CRC. Hypermethylation of the p14ARF and p16INK4a genes is often found in some tumors, including CRC. However, further studies are necessary to explore the clinical utility of these putative markers in risk stratification, and in the assessment of prognosis. In this review, we have summarized the prognostic and therapeutic potential of the p14ARF and p16INK4a genes in patients with colorectal cancer. PMID- 29629614 TI - Physical Impairments in Adults With Ankle Osteoarthritis: A Systematic Review and Meta-analysis. AB - Study Design Systematic review with meta-analysis. Background Lower-limb osteoarthritis (OA) is associated with pain and reduced function. Most research focuses on hip and knee OA- related impairments; consequently, impairments that characterize ankle OA are not well understood. Objective To systematically review available evidence of physical impairments in individuals with ankle OA. Methods A comprehensive search of electronic databases was conducted from their inception to July 2017. Studies were screened using predefined inclusion/exclusion criteria. Studies that compared physical measures (excluding gait) between individuals with ankle OA and healthy controls or the unaffected ankle were included. Two reviewers rated studies for quality. Meta-analyses with random effects were conducted when appropriate. Results Of 4565 identified studies (563 participants), 8 satisfied the inclusion criteria and 3 studies were included in meta-analyses. All studies evaluated a range of impairments at end-stage OA, and exhibited poor reporting of missing data, assessor blinding, and measurement validity. Meta-analyses revealed large impairments of ankle sagittal plane motion and strength. Evidence from single studies indicated large deficits of ankle frontal plane motion and strength, talar translation and rotation on arthrometry, balance, and electromyography of ankle joint muscles. There were also abnormal bony alignments and greater fatty infiltrate in all calf muscle compartments. Conclusion The results of this literature review suggest significant ankle motion, strength, and functional impairments in individuals with ankle OA. The strength of the conclusions is limited, due to the small number and methodological limitations of published studies. Level of Evidence Symptom prevalence, level 1a. J Orthop Sports Phys Ther 2018;48(6):449-459. Epub 7 Apr 2018. doi:10.2519/jospt.2018.7569. PMID- 29629613 TI - The search for drug-targetable diagnostic, prognostic and predictive biomarkers in chronic graft-versus-host disease. AB - INTRODUCTION: Chronic graft-versus-host disease (cGVHD) continues to be the leading cause of late morbidity and mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT), which is an increasingly applied curative method for both benign and malignant hematologic disorders. Biomarker identification is crucial for the development of noninvasive and cost-effective cGVHD diagnostic, prognostic, and predictive test for use in clinic. Furthermore, biomarkers may help to gain a better insight on ongoing pathophysiological processes. The recent widespread application of omics technologies including genomics, transcriptomics, proteomics and cytomics provided opportunities to discover novel biomarkers. Areas covered: This review focuses on biomarkers identified through omics that play a critical role in target identification for drug development, and that were verified in at least two independent cohorts. It also summarizes the current status on omics tools used to identify these useful cGVHD targets. We briefly list the biomarkers identified and verified so far. We further address challenges associated to their exploitation and application in the management of cGVHD patients. Finally, insights on biomarkers that are drug targetable and represent potential therapeutic targets are discussed. Expert commentary: We focus on biomarkers that play an essential role in target identification. PMID- 29629616 TI - Four simple ways to increase power without increasing the sample size. AB - Underpowered experiments have three problems: true effects are harder to detect, the true effects that are detected tend to have inflated effect sizes and as power decreases so does the probability that a statistically significant result represents a true effect. Many biology experiments are underpowered and recent calls to change the traditional 0.05 significance threshold to a more stringent value of 0.005 will further reduce the power of the average experiment. Increasing power by increasing the sample size is often the only option considered, but more samples increases costs, makes the experiment harder to conduct and is contrary to the 3Rs principles for animal research. We show how the design of an experiment and some analytical decisions can have a surprisingly large effect on power. PMID- 29629615 TI - Optimal Screening for Prediction of Referral and Outcome (OSPRO) for Musculoskeletal Pain Conditions: Results From the Validation Cohort. AB - Study Design Observational, prospective cohort. Background Musculoskeletal pain is a common reason to seek health care, and earlier nonpharmacological treatment and enhancement of personalized care options are 2 high-priority areas. Validating concise assessment tools is an important step toward establishing better care pathways. Objectives To determine the predictive validity of Optimal Screening for Prediction of Referral and Outcome (OSPRO) tools for individuals with neck, low back, shoulder, or knee pain. Methods A convenience sample (n = 440) was gathered by Orthopaedic Physical Therapy-Investigator Network clinics (n = 9). Participants completed demographic, clinical, and comorbidity questionnaires and the OSPRO tools, and were followed for 12-month outcomes in pain intensity, region-specific disability, quality of life, and comorbidity change. Analyses predicted these 12-month outcomes with models that included the OSPRO review-of-systems (OSPRO-ROS) and yellow flag (OSPRO-YF) tools and planned covariates (accounting for comorbidities and established demographic and clinical factors). Results The 10-item OSPRO-YF tool (baseline and 4-week change score) consistently added to predictive models for 12-month pain intensity, region specific disability, and quality of life. The 10-item OSPRO-ROS tool added to a predictive model for quality of life (mental summary score), and 13 additional items of the OSPRO-ROS+ tool added to prediction of 12-month comorbidity change. Other consistent predictors included age, race, income, previous episode of pain in same region, comorbidity number, and baseline measure for the outcome of interest. Conclusion The OSPRO-ROS and OSPRO-YF tools statistically improved prediction of multiple 12-month outcomes. The additional variance explained was small, and future research is necessary to determine whether these tools can be used as measurement adjuncts to improve management of musculoskeletal pain. J Orthop Sports Phys Ther 2018;48(6):460-475. Epub 7 Apr 2018. doi:10.2519/jospt.2018.7811. PMID- 29629617 TI - Color matters: They would choose if they could (see)! AB - Concerning standardization of laboratory animal husbandry, only exiguous changes of habitat can potentially influence animal physiology or results of behavioral tests. Routinely, mice chow is dyed when different types of diets are dispensed. Given the fact that the dye itself has no effects on food odor or flavor, we wanted to test the hypothesis that the color of chow has an impact on food uptake in mice. Twelve-week-old male mice of different strains (C57BL/6J, DBA/2J, C3H/HeJ, BALB/cJ; n = 12/strain) were single-housed in PhenoMaster(r) cages. After acclimatization standard mice chow in different colors was administered. Food intake was monitored as a two-alternative choice test of different color combinations. All animals had an average food intake of 3 g/d and no preferences were observed when a combination of identically colored food was offered. Preference tests yielded significant aversion to blue food and significant attraction to yellow and green food in C57BL/6 and DBA/2J mice. In C3H/HeJ and BALB/cJ mice no color-related pattern occurred. Selected mice strains have known differences concerning functionality of their visual sense. C57BL/6 and DBA/2 mice are considered to be normal sighted at testing age, BALB/c is representative for albino strains and C3H mice carry mutations resulting in retinal alterations. Results suggesting that normal-sighted mice would be selective concerning food color when given the choice. Nevertheless, this does not influence overall quantity of food intake when animals were provided solely with food colored with a single dye. Moreover, visually impaired mice showed no color-related food preferences. PMID- 29629618 TI - Text-document clustering-based cause and effect analysis methodology for steel plant incident data. AB - The purpose of this study is to develop a text clustering-based cause and effect analysis methodology for incident data to unfold the root causes behind the incidents. A cause-effect diagram is usually prepared by using experts' knowledge which may fail to capture all the causes present at a workplace. On the other hand, the description of incidents provided by the workers in the form of incident reports is typically a rich data source and can be utilized to explore the causes and sub-causes of incidents. In this study, data were collected from an integrated steel plant. The text data were analysed using singular value decomposition (SVD) and expectation-maximization (EM) algorithm. Results suggest that text-document clustering can be used as a feasible method for exploring the hidden factors and trends from the description of incidents occurred at workplaces. The study also helped in finding out the anomaly in incident reporting. PMID- 29629619 TI - On the population pharmacokinetics and the enterohepatic recirculation of total ezetimibe. AB - Ezetimibe is a potent cholesterol absorption inhibitor, with an erratic pharmacokinetic (PK) profile, attributed to an extensive enterohepatic recirculation (EHC). The aim of this study was to develop a population PK model able to adequately characterize the complex distribution processes of total ezetimibe. The analysis was performed on the individual concentration-time data obtained from 28 healthy subjects who participated in a bioequivalence study comparing two oral ezetimibe formulations. The population PK analysis was performed using nonlinear mixed effect modeling, where different EHC models were developed and evaluated for their performance. Total ezetimibe pharmacokinetics was best described by a four-compartment model featuring EHC through the inclusion of an additional gallbladder compartment, which was assumed to release drug at specific time-intervals consistent with food intake. The final PK model was able to adequately estimate the population pharmacokinetic parameters and to allow for a formal characterization of the pharmacokinetic profile and the secondary peaks due to enterohepatic recirculation. PMID- 29629620 TI - Differential training loads and individual fitness responses to pre-season in professional rugby union players. AB - We aimed to compare differentiated training loads (TL) between fitness responders and non-responders to an eight-week pre-season training period in a squad of thirty-five professional rugby union players. Differential TL were calculated by multiplying player's perceptions of breathlessness (sRPE-B) and leg muscle exertion (sRPE-L) with training duration for each completed session. Performance based fitness measures included the Yo-Yo Intermittent Recovery Test Level 1 (YYIRTL1), 10-, 20-, and 30-m linear sprint times, countermovement jump height (CMJ) and predicted one-repetition maximum back squat (P1RM Squat). The proportion of responders (>= 75% chance that the observed change in fitness was > typical error and smallest worthwhile change) were 37%, 50%, 52%, 82% and 70% for YYIRTL1, 20/30-m, 10-m, CMJ and P1RM Squat, respectively. Weekly sRPE-B-TL was very likely higher in YYIRTL1 responders (mean difference = 18%; +/-90% confidence limits 11%), likely lower in 20/30-m (19%; +/-20%) and 10-m (18%; +/ 17%) responders, and likely higher in CMJ responders (15%; +/-16%). All other comparisons were unclear. Weekly sRPE-B discriminate between rugby union players who respond to pre-season training when compared with players who do not. Our findings support the collection of differential ratings of perceived exertion and the use of individual response analysis in team-sport athletes. PMID- 29629621 TI - PDGFR-beta restores blood-brain barrier functions in a mouse model of focal cerebral ischemia. AB - Although platelet-derived growth factor receptor beta (PDGFR-beta) mediates the recruitment of vascular pericytes into ischemic lesion to restore the blood-brain barrier (BBB) dysfunction, its mechanisms still remain elusive . Compared with control PDGFR-betafloxed/floxed mice (Floxed), postnatally induced systemic PDGFR beta knockout mice (Esr-KO) not only showed severe brain edema, neurologic functional deficits, decreased expression of tight junction (TJ) proteins, abundant endothelial transcytosis, and deformed TJs in the BBB, but also showed reduced expression of transforming growth factor-beta (TGF-beta) protein after photothrombotic middle cerebral artery occlusion (MCAO). In endothelial-pericyte co-culture, an in vitro model of BBB, the increment in the barrier function of endothelial monolayer induced by pericyte co-culture was completely cancelled by silencing PDGFR-beta gene expression in pericytes, and was additively improved by PDGFR-beta and TGF-beta receptor signals under hypoxia condition. Exogenous PDGF BB increased the expression of p-Smad2/3, while anti-TGF-beta1 antibody at least partially inhibited the phosphorylation of Smad2/3 after PDGF-BB treatment in vitro. Furthermore, pre-administration of TGF-beta1 partially alleviated edema formation, neurologic dysfunction, and TJs reduction in Esr-KO mice after MCAO. Accordingly, PDGFR-beta signalling, via TGF-beta signalling, may be crucial for restoration of BBB integrity after cerebral ischemia and therefore represents a novel potential therapeutic target. PMID- 29629622 TI - Tolerance of Sulfolobus SMV1 virus to the immunity of I-A and III-B CRISPR-Cas systems in Sulfolobus islandicus. AB - Sulfolobus islandicus Rey15A encodes one Type I-A and two Type III-B systems, all of which are active in mediating nucleic acids interference. However, the effectiveness of each CRISPR system against virus infection was not tested in this archaeon. Here we constructed S. islandicus strains that constitutively express the antiviral immunity from either I-A, or III-B, or I-A plus III-B systems against SMV1 and tested the response of each host to SMV1 infection. We found that, although both CRISPR immunities showed a strong inhibition to viral DNA replication at an early stage of incubation, the host I-A CRISPR immunity gradually lost the control on virus proliferation, allowing accumulation of cellular viral DNA and release of a large number of viral particles. In contrast, the III-B CRISPR immunity showed a tight control on both viral DNA replication and virus particle formation. Furthermore, the SMV1 tolerance to the I-A CRISPR immunity did not result from the occurrence of escape mutations, suggesting the virus probably encodes an anti-CRISPR protein (Acr) to compromise the host I-A CRISPR immunity. Together, this suggests that the interplay between viral Acrs and CRISPR-Cas systems in thermophilic archaea could have shaped the stable virus host relationship that is observed for many archaeal viruses. PMID- 29629623 TI - Meeting Abstracts - AMCP Managed Care & Specialty Pharmacy Annual Meeting 2018. AB - The AMCP Managed Care & Specialty Pharmacy Annual Meeting 2018 in Boston, Massachusetts, is expected to attract more than 3,800 managed care pharmacists and other health care professionals who manage and evaluate drug therapies, develop and manage networks, and work with medical managers and information specialists to improve the care of all individuals enrolled in managed care programs. The AMCP Abstracts program provides a forum through which authors can share their insights and outcomes of advanced managed care practice. Abstracts are presented as posters on Wednesday, April 25, from 12:30 pm to 2:30 pm. Posters will also be displayed on Tuesday, April 24, from 5:45 pm to 7:30 pm, and on Thursday, April 26, from 9:30 am to 11:00 am. Podium presentations for the Platinum award-winning abstracts are Thursday, April 26, from 8:00 am to 9:15 am. Professional abstracts that have been reviewed are published in the Journal of Managed Care & Specialty Pharmacy's Meeting Abstracts supplement. PMID- 29629625 TI - The perils of public transport: Insanity in practice. PMID- 29629624 TI - Identification of the 7S and 11S globulins as percutaneously sensitizing soybean allergens as demonstrated through epidermal application of crude soybean extract. AB - Cutaneous exposure to food allergens can predispose individuals to food allergies. Soybean, a major allergenic food, is an ingredient in various cosmetic products. However, the types of soybean proteins that are percutaneously sensitizing in humans or animal models remain unknown. In this study, BALB/c mice were dorsally shaved and epicutaneously exposed to a crude soybean extract including sodium dodecyl sulfate or distilled water alone. Specific IgEs secreted in response to 7S globulin (Gly m 5), 11S globulin (Gly m 6), Gly m 3, and Gly m 4 were measured using enzyme-linked immunosorbent assays or immunoblots. Exposure to soybean extract elicited the secretion of soybean-specific IgEs. Of the soybean proteins, 7S and 11S globulins acted as percutaneous sensitizers in 6/9 mice (67%). Additionally, IgE bound specifically and preferentially to the 7S globulin beta subunit. In conclusion, this is the first report to identify percutaneously sensitizing soybean allergens in a mouse model. PMID- 29629627 TI - Robert Hare's Theory of Galvanism: A Study of Heat and Electricity in Early Nineteenth-Century American Chemistry. AB - As a professor of chemistry at the University of Pennsylvania, Robert Hare actively shaped early American science. He participated in a large network of scholars, including Joseph Henry, Francois Arago, and Jacob Berzelius, and experimented with and wrote extensively about electricity and its associated chemical and thermal phenomena. In the early nineteenth century, prominent chemists such as Berzelius and Humphry Davy proclaimed that a revolution had occurred in chemistry through electrical research. Examining Robert Hare's contributions to this discourse, this paper analyzes how Hare's study of electricity and the caloric theory of heat led him to propose a new theory of galvanism. It also examines the reception of Hare's work in America and Great Britain, highlighting the contributions of early American chemists to the development of electrochemistry. PMID- 29629626 TI - The role of neutrophil to lymphocyte ratio for the assessment of liver fibrosis and cirrhosis: a systematic review. AB - INTRODUCTION: Neutrophil to lymphocyte ratio (NLR) is widely used to assess inflammatory diseases. We performed a systematic review to explore the prognostic role of NLR for the assessment of liver fibrosis and cirrhosis. Areas covered: We searched the PubMed and EMBASE databases for the eligible papers which explored the association between NLR and liver fibrosis/cirrhosis or investigated the prognostic value of NLR in cirrhotic patients. Expert commentary: In accordance with assessment of liver fibrosis stage, we classified papers into four subgroups by etiology. For the patients with nonalcoholic fatty liver disease (NAFLD) there was a significant association between NLR and fibrosis stage and nonalcoholic fatty liver disease activity score (NAS), while NLR had a negative correlation with fibrosis stage for the patients with chronic hepatitis B (CHB). As for the patients with and chronic hepatitis C (CHC), NLR might not be significantly associated with fibrosis stage. Moreover, NLR seemed to be significantly useful for predicting outcomes in cirrhotic patients. Hence, NLR might be associated with liver fibrosis stage, especially in patients with NAFLD. Furthermore, NLR might be a useful biomarker for evaluating the prognosis in cirrhotic patients. PMID- 29629629 TI - Spatial extreme learning machines: An application on prediction of disease counts. AB - Extreme learning machines have gained a lot of attention by the machine learning community because of its interesting properties and computational advantages. With the increase in collection of information nowadays, many sources of data have missing information making statistical analysis harder or unfeasible. In this paper, we present a new model, coined spatial extreme learning machine, that combine spatial modeling with extreme learning machines keeping the nice properties of both methodologies and making it very flexible and robust. As explained throughout the text, the spatial extreme learning machines have many advantages in comparison with the traditional extreme learning machines. By a simulation study and a real data analysis we present how the spatial extreme learning machine can be used to improve imputation of missing data and uncertainty prediction estimation. PMID- 29629628 TI - Neuroprotective effect of polysaccharide separated from Perilla frutescens Britton var. acuta Kudo against H2O2-induced oxidative stress in HT22 hippocampus cells. AB - This study was carried out to evaluate the neuroprotective activity of polysaccharide extracts isolated from Perilla frutescens (PEPF) in H2O2-treated HT22 hippocampus cells. The PEPF treatment was found to increase the anti-oxidant activities of HT22 hippocampus cells. PEPF treatment resulted in a significant protection of HT22 hippocampus cells against H2O2-induced neurotoxicity, this protection ultimately occurred through an inhibition of ROS-mediated intracellular Ca2+ levels leading to MAPKs and NF-kappaB, as well as the accumulation of PI3K/AKT and Nrf2-mediated HO-1/NQO1 pathways. Furthermore, PEPF not only decreased the expression of Bax, cytochrome c, and cleaved caspases-3, 8, and -9, but also increased the expression of PARP and Bcl-2 in the H2O2 treated HT22 hippocampus cells, which overall contributed to the neuroprotective action. PEPF retains its mitochondrial membrane potential and reduces the elevated levels of sub-G1 phase and apoptotic morphological features induced by H2O2. It also reduces the malondialdehyde levels and enhances the intracellular SOD activity. PMID- 29629630 TI - Survival strategy of the salt-tolerant lactic acid bacterium, Tetragenococcus halophilus, to counteract koji mold, Aspergillus oryzae, in soy sauce brewing. AB - In soy sauce brewing, the results of the fermentation of lactic acid greatly affect the quality of soy sauce. The soy sauce moromi produced with Aspergillus oryzae RIB40 allows the growth of Tetragenococcus halophilus NBRC 12172 but not T. halophilus D10. We isolated and identified heptelidic acid (HA), an inhibitor of glyceraldehyde-3-phosphate dehydrogenase (GAPDH), produced by A. oryzae RIB40 as the growth inhibitor of the salt-tolerant lactic acid bacteria. The growth inhibition of T. halophilus D10 by HA was suggested to be associated with the direct inhibition of GAPDH activity under high salt environment. The difference in the susceptibility to HA among various strains of T. halophilus was caused by the mutations in the gene encoding GAPDH. PMID- 29629631 TI - The epidemiology of teaching and training practices in North-East England. AB - INTRODUCTION: Teaching and training practices in England serve less ethnically diverse and urban environments than non-teaching practices. However, it is not known if these trends are consistent across the country. METHODS: We linked data on teaching and training status for all North-East England practices to practice characteristics, locality and patient variables, calculated the association with each variable and compared to the national figures. RESULTS: Teaching and training practices in North-East England are larger than non-teaching and non training practices (mean list size (SD) 9109 (4080) vs. 5547 (5325), p < 0.001), have fewer patients per GP (1649 (404) vs. 2302 (1245), p < 0.001), higher patient satisfaction (43.45 (1.61) vs. 42.77 (2.14), p < 0.005) and quality and outcomes framework scores (98.3% (2.2%) vs. 95.5% (6.9%), p < 0.001), and are less likely to be in deprived areas (OR = 0.63; 95% CI 0.42-1.44). However, rurality, ethnic diversity, and patients' health status were not significantly associated with teaching and training status. CONCLUSIONS: In North-East England, general practices' teaching and training status is not associated with serving an urban or more ethnically diverse locality, in contrast with the national picture. The national profile may mask significant regional variations. PMID- 29629632 TI - Improving the specific antitumor efficacy of ONC by fusion with N-terminal domain of transferrin. AB - Onconase (ONC) as a novel anti-tumor drug has a significant killing effect on a variety of tumor cells. Drug delivery system mediated by transferrin (TF) and TF receptor (TfR), which can significantly increase the amount of drug uptake in the tumor cells, enhance the initiative target efficiency of drugs and reduce its toxic side effects. It has been widely used in drug delivery and clinical trials. In this study, the rONC-TFn was expressed in Escherichia coli by linking ONC with the N-terminal domain of TF (TFn). ELISA and competitive binding analysis demonstrated that rONC-TFn can bind to TfR. The rONC-TFn protein showed much higher cytotoxicity to the cultured HepG2 and Hela cells than rONC. These results suggested that the N-terminal domain protein of TF promoted the tumor targeting of ONC, and thus the rONC-TFn fusion protein may be further developed as a potential targeted anti-tumor drug. PMID- 29629634 TI - "Why Should I, the One Who Was Raped, Be Forced to Take Training in What Sexual Assault Is?" Sexual Assault Survivors' and Those Who Know Survivors' Responses to a Campus Sexual Assault Education Program. AB - This study critically examines sexual assault survivors' (people with histories of sexual assault) and those who know survivors' (those who know and/or who are close to people with histories of sexual assault) responses to a mandatory online campus sexual assault education program using both quantitative survey data ( N = 1,899) and qualitative narratives ( n = 41) from a sample of students at a large southern university with special attention to gender, sexual identity, race, ethnicity, college group affiliations (student athletics, fraternities/sororities, LGBTQ [lesbian, gay, bisexual, and transgender, queer] ally programs), and the intersections between these identities and affiliations. The quantitative findings show that knowing/being a woman survivor is positively related to supportive attitudes toward the sexual assault education program and inversely, knowing/being a man survivor is negatively related to support of the program. In addition, being a woman, being gay/lesbian, being Black/African American, Asian/Pacific Islander, Native American/Alaskan Native, or another race, and being a sorority member are all significantly related to supportive attitudes toward the sexual assault education program. Furthermore, qualitative analyses revealed that the majority of personal survivors' narratives indicated traumatic/triggering responses whereas most of those who provided narratives about knowing survivors(s) indicated praiseworthy reactions. Overall, the current study offers empirically driven sexual assault education program implications that acknowledge survivors' and those who know survivors' experiences with the ultimate goal of determining how to best meet students' needs. PMID- 29629633 TI - Autoregressive and Cross-Lagged Associations Between Psychological Intimate Partner Aggression and Psychopathology in Newlyweds. AB - Most research to date relies on cross-sectional data to identify associations between psychopathology (i.e., internalizing and externalizing disorders) and intimate partner aggression (IPA). Studies that utilize longitudinal data tend to survey only one member of a dyad, examine only perpetration or victimization, and/or use statistical methods that converge within- and between-person effects. The current study examines the associations between psychopathology, psychological IPA perpetration, and psychological IPA victimization at three time points over the course of 1 year in a sample of newlyweds. An autoregressive latent trajectory model with structured residuals (ALT-SR) tested the hypotheses that within-person internalizing and externalizing psychopathology would predict IPA perpetration and victimization at each subsequent time point, and IPA victimization would predict subsequent internalizing and externalizing symptoms. Results of the ALT-SR model did not support hypotheses. Rather, results suggest internalizing symptoms were negatively associated with externalizing symptoms at subsequent time points, and vice versa. IPA perpetration was positively associated with IPA victimization at the following time points. These results elucidate the interplay between psychopathology and IPA, suggesting that although these constructs show bivariate relationships with one another, psychopathology is not a significant within-person predictor of subsequent psychological IPA. PMID- 29629635 TI - Juror Decision Making in Acquaintance and Marital Rape: The Influence of Clothing, Alcohol, and Preexisting Stereotypical Attitudes. AB - Stereotypical biases about women's roles in intimate relationships including their marital status and lifestyle choices such as clothing and alcohol use influence juror attributions of rape case defendant guilt, potentially reducing access to justice for victims. Across two mock-juror decision-making experiments, participants read identical fictitious sexual assault vignettes varying in intoxicated defendant-complainant relationship (married vs. acquaintance), accompanied by photographs of complainant clothing at the crime (body revealing vs. plain) and in court (smart vs. casual). Experiment 2 additionally described the defendant's alcohol consumption as either under or over the drink drive limit. Most participants delivered guilty verdicts (Experiment 1: 86.7%; Experiment 2: 75.5%), recommending mean prison sentences of 5.04 years in Experiment 1 ( n = 218 students) and 4.33 years in Experiment 2 ( n = 1,086 members of public). In Experiment 1, guilty verdict rates and sentences were significantly higher when the married-but not the acquaintance-complainant dressed smartly rather than casually in court. In Experiment 2, significantly more guilty verdicts were delivered by females (80.3%) than males (66.9%), while sentence lengths were longer in acquaintance ( M = 4.52 years) than married conditions ( M = 4.10). Significant interactions between defendant alcohol use and clothing choice of the married-but not the acquaintance complainant-at the crime also influenced sentencing decisions. Higher scores on additionally administered scales measuring rape myth acceptance and sexist attitudes, but not alcohol expectancies, predicted lenient sentencing decisions in both experiments. These findings highlight how "rape myths" concerning marriages drive juror decisions. Prosecuting lawyers should use these results to better challenge these attitudes in court. Internationally, rape is often unreported to the police, and married victims may be more willing to come forward if they believe unbiased access to justice is likely. PMID- 29629636 TI - Men Selling Sex to Men in Sweden: Balancing Safety and Risk. AB - The purpose of this study is to examine how men who sell sex to men perceive the risks in this activity and what experiences they have of actual denigration, threats, and violence in their relations with customers. We also discuss the self defense strategies they have used to protect themselves. The study is based on an Internet survey on Swedish websites. Statistical analyses have been carried out, and in interpreting the results, Finkelhor and Asdigian's revised routine activities theory has been used. The results show that the vulnerability of sellers of sex is greatest during the time when the sexual act is being performed, and that this is primarily linked to the customer's antagonism and seeking gratification by overstepping agreed boundaries, particularly with regard to sexual services including BDSM. Their vulnerability was also connected to the seller's diminished capacity for self-protection due to personal and external pressures. A smaller proportion of the men described risk prevention activities. These involved refusing a customer after an initial contact, protecting themselves from infection, being on their guard during the whole process, selecting the place, and deciding not to carry out certain sexual acts. An important implication concerns the occupational health and safety that men who sell sex to men can develop for themselves, while remaining within the law. International studies have demonstrated that selling sex in collective, indoor forms provides the greatest security. For decades, Swedish prostitution policy has had the ambition of reducing prostitution through targeting those who purchase sex, and those who promote prostitution in criminal legislation. This effectively prevents more systematic and collective attempts to create safer conditions for selling sex. In conclusion, it can be stated that while it is legal to sell sex in Sweden, this is done at the seller's own risk. PMID- 29629637 TI - Childhood Sexual Violence in Indonesia: A Systematic Review. AB - There has been relatively little research into the prevalence of childhood sexual violence (CSV) as well as the risk and protective factors for CSV in low- and middle-income countries including Indonesia. Systematic searches conducted in English and Bahasa Indonesia in this review identified 594 records published between 2006 and 2016 in peer-reviewed journals and other literature including 299 Indonesian records. Fifteen studies, including nine prevalence studies, met the quality appraisal criteria developed for this review. The review found that CSV research is scarce: Only one study included nationally representative prevalence estimates. Varying definitions for CSV, survey methods, and sample characteristics limited the generalizability of the data. The available evidence points to significant risk of sexual violence affecting both girls and boys across many geographical and institutional settings. Married adolescent girls are vulnerable to sexual violence by partners in their homes. Children in schools are vulnerable to CSV by peers and adults. Victims seldom disclose incidents and rarely seek support. In addition, early childhood experiences of trauma were strongly associated with later perpetration of sexual violence and revictimization. Limited information is available about protective factors. This review synthesizes evidence about what is currently known about CSV in Indonesia and identifies the strengths and weaknesses of the existing research. A more robust evidence base regarding CSV is required to better inform policy and justify investment into prevention programs. PMID- 29629638 TI - Fluctuations in clinical symptoms with changes in serum 25(OH) vitamin D levels in autistic children: Three cases report. AB - Autism spectrum disorder (ASD) is a common neurodevelopmental disorder caused by complicated interactions between genetic and environmental factors. Clinical trials, including case reports, case-control studies, and a double-blinded randomized clinical study, have suggested that high-dose vitamin D3 regimens may ameliorate the core symptoms of ASD. Vitamin D3 supplementation was effective in about three-quarters of children with ASD. To further investigate the relationship between vitamin D and ASD symptoms in vitamin D-responsive autistic children, changes in symptoms were assessed in three children with ASD who were given vitamin D3 supplementation followed by a long interruption. The core symptoms of ASD were remarkably improved during the vitamin D3 supplementation period when serum 25-hydroxyvitamin D [25(OH)]D levels reached over 40.0 ng/mL. However, symptoms reappeared after the supplementation was stopped, when serum 25(OH)D levels fell below 30.0 ng/mL but were again improved with re administration of vitamin D3 after the interruption, when serum 25(OH)D levels exceeded 40.0 ng/mL. Overall, these results showed that the core symptoms of ASD fluctuated in severity with changes in serum 25(OH)D levels in children, indicating that maintaining a responsive 25(OH)D level is important for treating ASD. Maintaining a serum 25(OH)D level between 40.0 and 100.0 ng/ml may be optimal for producing therapeutic effects in vitamin D-responsive individuals with ASD. PMID- 29629639 TI - Do Advances in Science Benefit Chronic Wound Healing? PMID- 29629640 TI - Full thickness macular hole without necrosis in a case of viral retinitis. PMID- 29629641 TI - Chemical Industry, the Environment, and Russian Provincial Society: The Case of the Kokshan Chemical Works (1850-1925). AB - This article explores interactions between the chemical industry, the environment, and Russian provincial society in the late nineteenth and early twentieth centuries, using the example of the Kokshan chemical works, in the Elabuga District, Viatka Province, Russian Empire (today Mendeleevsk District, Republic of Tatarstan, Russian Federation). The plant's location facilitated its rapid development due to a number of factors, including a cheap labour force, the availability of raw materials, and the absence of local competition. However, the factory's development came in conjunction with the deterioration of the environment and subsequent health problems for employees and the surrounding population. Conflicts connected with the Kokshan works illustrate differences between this case and similar examples in Russia and Europe. In Viatka Province, the local community remained mostly silent regarding these issues, and made no demands for improving sanitary control and working conditions or reducing pollution; rather, it was distant activists who personally suffered no harm who intervened in the interest of social justice. The history of the company reflects the contrast between the transfer of European technological innovations to Russia and laborious efforts to increase national wealth on the one hand, and the exploitation of the environment and endangerment of workers' health on the other. PMID- 29629642 TI - Reliability of kinesiography vs magnetic resonance in internal derangement of TMJ diagnosis: A systematic review of the literature. AB - OBJECTIVE: The aim of this systematic review was to evaluate the accuracy and the diagnostic reliability of kinesiography and magnetic resonance imaging (MRI) in diagnosis of patients presenting temporomandibular disorders. METHODS: A literature survey carried out through PubMed, SCOPUS, LILIACS, and the Cochrane Library from the inceptions to the last access on August 18 2016 was performed to locate randomized clinical trials, controlled trials, prospective cohort studies, or retrospective studies (with or without a control group), that examined the diagnostic reliability of recording devices of mandibular movements in comparison to MRI. RESULTS: From the results, it was found that a significant correlation between these electronic devices and MR images could not be detected in case of disc displacement. DISCUSSION: The scientific evidence does not support the usefulness in clinical practice of the jaw-tracking devices to diagnose temporomandibular disorders because their diagnostic reliability is poor. PMID- 29629644 TI - Development and validation of direct PCR and quantitative PCR assays for the rapid, sensitive, and economical detection of porcine circovirus 3. AB - Since the identification of species Porcine circovirus 2, the relevance of genus Circovirus has increased given its impact on the swine industry. A new species ( Porcine circovirus 3, PCV-3) has been detected in association with various clinical conditions. Consequently, there is an urgent need for reliable and widely accessible tests for both routine diagnostic and research purposes. We developed a direct PCR (requiring no DNA extraction) and a quantitative (q)PCR targeting the conserved rep gene to detect the PCV-3 genome. Test performance was assessed by testing 120 field samples within different matrices. Both methods were sensitive (detection of 10 viral genome/uL), specific, and repeatable. The substantially perfect agreement between the 2 assays strongly supports their high sensitivity and specificity. The low cost and short processing time of the direct PCR protocol, together with the reliable quantitative results provided by qPCR, support the establishment of common testing guidelines. PMID- 29629645 TI - Development and application of two multiplex real-time PCR assays for detection and speciation of bacterial pathogens in the koala. AB - Infectious diseases have contributed to the decline in the health of koala ( Phascolarctos cinereus) populations in the wild in some regions of Australia. Herein we report the development and validation of 2 multiplex real-time PCR (rtPCR) panels for the simultaneous detection of Mycoplasma spp., Ureaplasma spp., Bordetella bronchiseptica, and Chlamydia, including speciation and quantification of Chlamydia, in ocular, reproductive, and nasal swab samples in addition to semen and male urogenital and reproductive tissues, from koalas. Each rtPCR panel was developed for use as a single-tube reaction using pathogen specific primers and fluorescently labeled probe sets. DNA extracted from reference strains and isolates was used for validation of sequence gene targets for the multiplex rtPCR panels. Each panel was shown to be sensitive and specific in detecting and differentiating the bacterial pathogens. The multiplex rtPCR panels were used to screen clinical samples from free-ranging and hospitalized koalas for multiple pathogens simultaneously. The multiplex rtPCR will improve turnaround time compared to individual-pathogen rtPCR methods used, to date, for confirmation of diagnosis and will provide the wildlife clinician with the ability to make treatment decisions more rapidly. PMID- 29629646 TI - Fibroblastic osteosarcoma with epithelioid and squamous differentiation in a dog. AB - A fibroblastic osteosarcoma with epithelioid and squamous differentiation in the distal femur of a 9-y-old spayed female Greyhound dog is described. Grossly, the tumor consisted of a pale-white, firm-to-hard mass that replaced the medullary and cortical areas of the distal end of the right femur. Histologically, the mass was composed predominantly of spindle cells admixed with areas of mineralized and non-mineralized osteoid matrix that were surrounded by stellate osteoblasts and scattered multinucleate giant cells, consistent with the diagnosis of a fibroblastic osteosarcoma. In addition, well-demarcated clusters of neoplastic epithelioid cells and foci of squamous differentiation with keratin pearls were present throughout the neoplasm. The spindle cells, epithelioid cells, and areas of squamous differentiation expressed cytoplasmic immunostaining for osteocalcin and osteonectin. The spindle cells and epithelioid cells were also immunopositive for vimentin. Epithelioid cells also expressed occasional cytoplasmic immunostaining for pancytokeratin (PCK) Lu-5, and areas of squamous differentiation were immunoreactive for PCK Lu-5 and high molecular weight CK; these areas were inconsistently immunoreactive for CK 5-6 and immunonegative for low molecular weight CK. Foci of squamous differentiation were not located within blood or lymphatic vessels, given that no immunoreactivity for factor VIII related antigen was observed around these areas. A thorough autopsy and an evaluation of the medical history excluded a primary carcinoma or other neoplasm elsewhere in the dog. The findings were consistent with a diagnosis of fibroblastic osteosarcoma with epithelioid and squamous differentiation. PMID- 29629647 TI - Immunohistochemical detection of p53, PTEN, Rb, and p16 in canine osteosarcoma using tissue microarray. AB - Although inactivating mutations of tumor suppressor genes are well described in cell lines of canine osteosarcoma (OS), expression of tumor suppressor proteins in spontaneous disease is poorly characterized. We determined the immunohistochemical expression of p53, PTEN, Rb, and p16 in a large cohort of dogs with OS. Formalin-fixed, paraffin-embedded samples of canine OS were analyzed retrospectively. Primary tumor samples from 145 dogs, collected between 2003 and 2008, were evaluated by tissue microarray. Streptavidin-biotin complex immunohistochemistry was performed using monoclonal antibodies for Rb and PTEN and polyclonal antibodies for p16 and p53. The average age of dogs was 7.6 y, and 118 of 145 (81%) were purebred. Most commonly represented purebreds were Greyhound (23%), Rottweiler (11%), and Labrador Retriever (10%). Immunohistochemical detection of p53, PTEN, Rb, and p16 was 81%, 61%, 66%, and 66%, respectively. The staining pattern for p16 was primarily cytoplasmic; the predominant pattern for PTEN, Rb, and p53 was cytoplasmic and nuclear. Exclusively cytoplasmic staining was noted in 19% of samples positive for p53 and 8% of samples positive for Rb. Kaplan-Meier curves showed that protein expression was not associated with significant differences in overall survival ( p > 0.191). We documented heterogeneity in both immunostaining and subcellular localization of tumor suppressor proteins, providing further characterization of canine OS. PMID- 29629648 TI - Cutaneous squamous cell carcinoma associated with Zalophus californianus papillomavirus 1 in a California sea lion. AB - Papillomaviruses (PVs) are found in many species and infect epithelial cells at both mucosal and cutaneous sites. PVs are generally species-specific and cause benign epithelial proliferations, often forming papillomas or plaques. Rarely, these infections can persist, allowing progression to in situ and invasive cancers. We describe herein a case of multiple cutaneous pigmented plaques from a California sea lion ( Zalophus californianus) that progressed to in situ and invasive squamous cell carcinoma (SCC). The lesions were characterized by epithelial hyperplasia, hyperkeratosis, and hypergranulosis that bordered more dysplastic areas, and, at one site, bordered an invasive SCC. Immunohistochemistry for papillomavirus antigen revealed strong nuclear immunoreactivity within keratinocytes in the hyperplastic epidermis. PCR was performed using degenerate and specific primers to detect papillomavirus DNA. Specific primers were used to amplify Zalophus californianus papillomavirus 1 (ZcPV-1), the only sea lion papillomavirus known to date. We detected ZcPV-1 DNA within the pigmented plaque, and in both in situ and invasive SCC samples. PMID- 29629649 TI - Two diseases, same person: moving toward a combined HIV and tuberculosis continuum of care. AB - The human immunodeficiency virus (HIV) and Mycobacterium tuberculosis syndemic remains a global public health threat. Separate HIV and tuberculosis (TB) global targets have been set; however, success will depend on achieving combined disease control objectives and care continua. The objective of this study was to review available policy, budgets, and data to reconceptualize TB and HIV disease control objectives by combining HIV and TB care continua. For 22 World Health Organization (WHO) TB and TB/HIV priority countries, we used 2015 data from the HIV90-90-90watch website, UNAIDS AIDSinfo, and WHO 2016 and 2017 Global TB Reports. Global resources available in TB and HIV/TB activities for 2003-2017 were collected from publicly available sources. In 22 high-burden countries, people living with HIV on antiretroviral therapy ranged from 9 to 70%; viral suppression was 38-63%. TB treatment success ranged from 71 to 94% with 14 (81% HIV/TB burden) countries above 80% TB treatment success. From 2003 to 2017, reported global international and domestic resources for HIV-associated TB and TB averaged $2.85 billion per year; the total for 2003-2017 was 43 billion dollars. Reviewing combined HIV and TB targets demonstrate disease control progress and challenges. Using an integrated HIV and TB continuum supports HIV and TB disease control efforts focused on improving both individual and public health. PMID- 29629650 TI - Fusarium keratoplasticum infection in an HIV-infected patient. AB - Fusarium infections are very rare in HIV-infected patients, even in patients in advanced stages of immunosuppression. All the reported cases in the literature are of disseminated infection, and with poor outcomes despite prompt and appropriate treatment. To the best of our knowledge, this is the first report of a localized infection with Fusarium keratoplasticum in an HIV-positive patient, successfully treated with a combination of antifungal therapy and surgical removal of the focus. PMID- 29629651 TI - Designing a brief behaviour change intervention to reduce sexually transmitted infections: a discrete choice experiment. AB - To understand whether people attending sexual health (SH) clinics are willing to participate in a brief behavioural change intervention (BBCI) to reduce the likelihood of future sexually transmitted infections (STIs) and to understand their preferences for different service designs, we conducted a discrete choice experiment (DCE) with young heterosexual adults (aged 16-25 years), and men who have sex with men (MSM) aged 16 or above, attending SH clinics in England. Data from 368 participants showed that people particularly valued BBCIs that involved talking (OR 1.45; 95%CI 1.35, 1.57 compared with an 'email or text'-based BBCIs), preferably with a health care professional rather than a peer. Findings also showed that 26% of respondents preferred 'email/texts' to all other options; the remaining 14% preferred not to participate in any of the offered BBCIs. These results suggest that most people attending SH clinics in England are likely to participate in a BBCI if offered, but the type/format of the BBCI is likely to be the single important determinant of uptake rather than characteristics such as the length and the number of sessions. Moreover, participants generally favoured 'talking'-based options rather than digital alternatives, which are likely to require the most resources to implement. PMID- 29629652 TI - Utility of antitreponemal IgM testing in the diagnosis of early and repeat syphilis among HIV-infected and non-infected patients. AB - Until now only non-treponemal tests (e.g. rapid plasma reagin [RPR]) have been used to monitor syphilis activity (e.g. distinguishing between treated, untreated and repeat disease) and efficacy of treatment. However, they usually require manual operation and are less specific than treponemal tests. The aim of the current study was to evaluate the use of the antitreponemal IgM testing in the diagnosis of early and repeat syphilis in HIV-infected and non-infected patients. One hundred and seventeen patients with early syphilis were included in this prospective study. RPR and anti- Treponema pallidum-IgM (TP-IgM) tests were conducted at onset and at three-month intervals during 24-month follow-up after initial treatment. In 31 of 117 syphilitic patients the co-occurrence of HIV infection was diagnosed. A positive TP-IgM test was present in 78.6% of patients with newly-diagnosed primary syphilis, 95.8% with secondary and 57.9% with early latent syphilis, but only in 38.5% patients with syphilis reinfection. There was a significant correlation between primary and secondary syphilis, higher baseline RPR titre and the pre-treatment IgM test reactivity. Regardless of the syphilis stage, HIV-seropositive individuals were more frequently positive for TP-IgM, both during the first onset of the disease (90.3%), and reinfection (71.4%), as compared to the HIV-seronegative group (71.4% and 0%, respectively, P < 0.03). TP IgM seroreversion was observed in 115 out of 117 patients studied (98.3%) during follow-up (mean time to seroreversion 6.9 months). The time to TP-IgM seroreversion after treatment was significantly shorter in patients with early symptomatic syphilis (mean 4.9 months) when compared to early latent syphilis (7.7 months, P < 0.05). A negative TP-IgM test was found in approximately 20% and 40% of individuals with primary and early latent syphilis, respectively. The value of IgM testing in the diagnosis of syphilis reinfection is doubtful. PMID- 29629653 TI - Defining and surveying key populations at risk of HIV infection: Towards a unified approach to eligibility criteria for respondent-driven sampling HIV biobehavioral surveys. AB - Substantial resources are invested in human immunodeficiency virus biobehavioral surveys using respondent-driven sampling for measuring progress towards the UNAIDS 90-90-90 goals and to obtain other essential data on key populations. Survey data are used to meet country needs as well those of development partners, whose data needs may sometimes diverge. Surveys using differing eligibility criteria impede comparisons across surveys. With scant literature and guidelines on how to approach eligibility criteria, diverse criteria are used within and across countries. We conducted a review of peer-reviewed human immunodeficiency virus respondent-driven sampling biobehavioral survey literature published through December 2013. We describe eligibility criteria of 137 articles representing 214 surveys. Reporting on age, risk behavior, and reference period of risk behavior was nearly universal; however, reporting on gender, geography, and language was less common. Multiple definitions were used for each criterion, making comparisons challenging. We provide a framework for how to approach defining eligibility to improve consistency and comparability across surveys. PMID- 29629654 TI - Reproductive decision-making among postpartum HIV-infected women in rural South Africa. AB - Despite pregnancy spacing recommendations to optimize health outcomes among mothers and neonates, unplanned pregnancy in sub-Saharan Africa is common among women living with human immunodeficiency virus (HIV) (WLHIV). This study examined factors associated with reproductive decision-making among WLHIV to inform pregnancy-planning interventions. WLHIV in rural South Africa (n = 165) were assessed at 12 months postpartum. The relative importance of factors associated with reproductive decision-making was estimated. Women were a mean of 28 years old (SD = 5.71). Risk of mother-to-child transmission (MTCT) of HIV (Mean = 0.43; SD = 0.33) had the greatest impact on decision-making, followed by partners' desires (M = 0.22; SD = 0.18), family preferences (M = 0.18; SD = 0.13), and community opinion (M = 0.17; SD = 0.13). MTCT was most important to women with greater HIV knowledge. However, WLHIV who had been diagnosed with HIV for a longer time placed more emphasis on partner preference and community opinion, and less importance on MTCT risk. Prevention of mother-to-child transmission (PMTCT) was less important to women experiencing intimate partner violence and those with depression. Findings highlight the need for tailored, focused interventions to support the unique circumstances of WLHIV and support the inclusion of families and/or partners in the counseling process. Results underscore the need for perinatal preconception counseling for women during routine HIV care. PMID- 29629655 TI - Impact and barriers of an HIV rapid test program implementation at an oncological referral center in Mexico. AB - The aim of this study was to evaluate the implementation of human immunodeficiency virus (HIV) screening with rapid tests in an oncologic center in Mexico City, report the HIV prevalence, and describe contacts screening and linkage to HIV care while identifying barriers to the performance of the program. In 2014, an HIV rapid test program was implemented in four departments of the hospital "Instituto Nacional de Cancerologia". From 2014 to 2016, 3032 HIV rapid tests were performed in the hospital. The overall HIV prevalence was 0.8%, with the highest prevalence in the Hematology Department (2.4%). In the Gynecology Department, prevalence was 0.05%. Only 25 and 22 tests were performed in the lung cancer and germ cell tumor clinic, respectively, with one positive test. The health staff not offering the test was the main limitation to the full implementation of the program in those departments. The contacts screening led to three positive cases. The acceptance of the test was 99%. Patients who tested positive were seen by an infectious diseases physician on the same day the test was performed. Rapid HIV tests are a useful tool to expand HIV diagnosis in patients with cancer and to establish a rapid linkage to HIV care. Staff education needs to be improved to raise awareness of the health staff for a successful scale up of the program. PMID- 29629656 TI - A novel carbohydrate-binding surface layer protein from the hyperthermophilic archaeon Pyrococcus horikoshii. AB - In Archaea and Bacteria, surface layer (S-layer) proteins form the cell envelope and are involved in cell protection. In the present study, a putative S-layer protein was purified from the crude extract of Pyrococcus horikoshii using affinity chromatography. The S-layer gene was cloned and expressed in Escherichia coli. Isothermal titration calorimetry analyses showed that the S-layer protein bound N-acetylglucosamine and induced agglutination of the gram-positive bacterium Micrococcus lysodeikticus. The protein comprised a 21-mer structure, with a molecular mass of 1,340 kDa, as determined using small-angle X-ray scattering. This protein showed high thermal stability, with a midpoint of thermal denaturation of 79 degrees C in dynamic light scattering experiments. This is the first description of the carbohydrate-binding archaeal S-layer protein and its characteristics. PMID- 29629657 TI - Advances in the Use of Anti-inflammatory Agents to Manage Chemotherapy-induced Oral and Gastrointestinal Mucositis. AB - Mucositis is a side effect associated with the use of chemotherapy, and has a significant impact on the quality of life. Mucositis, by definition, refers to the inflammation of the mucosa and occurs throughout the alimentary tract from the mouth to anus. Nuclear Factor kappa B (NFkappaB) encompasses a family of transcription factors, which upregulate pro-inflammatory cytokines. These are recognized as key targets in developing therapeutic interventions for chemotherapy-induced mucositis, and cyclooxygenase (COX)-2 inhibition may also be beneficial in reducing the severity and duration. This review focuses on the pathobiology of chemotherapy-induced oral and gastrointestinal mucositis and recent research examining the role of agents with anti-inflammatory activity in treatment and prevention of the condition. We consider agents in clinical use as well as some others under current investigation including plant-derived and other natural medicines. PMID- 29629658 TI - Comparative Study of the Effects Exerted by N-Valproyl-L-Phenylalanine and N valproyl-L-tryptophan on CA1 Hippocampal Epileptiform Activity in Rat. AB - BACKGROUND: The research on the improvement of epilepsy therapy is constantly growing. Valproyl-LPhenylalanine (VPA-Phen) and N-valproyl-L-tryptophan (VPA Tryp) were synthesized to increase the antiepileptic efficacy of valproic acid. METHODS: VPA-Phen and VPA-Tryp were comparatively tested on CA1 hippocampal epileptiform bursting activity obtained by increasing potassium and lowering calcium and magnesium concentrations in the fluid perfusing rat brain slices. Each slice was treated with a single concentration (0.2, 0.5, 1 mM) of VPA-Phen or VPA-Tryp. Both burst duration and interburst frequency, during and after treatment, were off-line compared with baseline values. For both parameters, either the latency or the duration of drug-induced statistically significant responses was calculated, as well as the response magnitude. RESULTS: VPA-Phen significantly reduced both burst frequency and duration. Comparative analyses show that VPA-Phen and VPA-Tryp exert almost equivalent actions on both latency and magnitude of the observed inhibitory effects. The main observed difference between the two tested molecules concerned the duration of inhibitory effects, since VPA-Phen-dependent actions on both burst rate and duration were significantly shorter than the VPA-Tryp-induced ones. In addition, in some slices the above reported inhibitory responses were preceded by a "paradoxical" transient increase, more present at lower drug concentrations. CONCLUSIONS: Both VPA-Phen and VPA-Tryp exert significant inhibitory effects on hippocampal burst activity parameters. Although of comparable magnitude, VPA-Phen-dependent effects have a shorter duration than VPATryp- induced ones. Nevertheless, the present results confirm that the conjugation between VPA and aminoacids represents a valid tool to improve the efficacy of antiepileptic drugs and, as well as for VPA Tryp, propose VPAPhen as a novel VPA derivative with enhanced pharmacological features. PMID- 29629659 TI - Porphyrin-containing Gadolinium Complex as a Tumor-targeting Magnetic Resonance Imaging (MRI) Contrast Agent. AB - OBJECTIVE: Gadolinium diethylenetriaminepentaacetic di[5-(4'-amidophenyl) 10,15,20- tris(4'-sulfonatophenyl) porphyrin trisodium salt] (Gd-DTPA-2APTSPP) was synthesized by the reaction of diethylenetriaminepentaacetic dianhydride with 5-(4'-aminophenyl)-10,15,20-tris(4'-sulfonatophenyl) porphyrin and subsequently chelation with gadolium chloride. METHODS: This gadolinium complex was characterized and its properties in vitro and in vivo were also evaluated. Compared with Gd-DTPA, Gd-DTPA-2APTSPP possessed high relaxivity r1, low cytotoxicity to HeLa cells and high enhanced signal intensities of the VX2 carcinoma in rabbits for a prolonged time. CONCLUSION: Moreover, Gd-DTPA-2APTSPP can distinguish the VX2 carcinoma from the reactive hyperplasia incited by inflammation and normal tissues in rabbits. Therefore, Gd-DTPA-2APTSPP can be taken up selectively by tumors and show the potential as a tumor-targeting MRI contrast agent. PMID- 29629660 TI - In vitro Evaluation of Genipin-crosslinked Na-alginate/Chitosan Hydrogel Films for Delivery of Metformin: Effect of Chitosan Molecular Weight. AB - OBJECTIVES: In this study, central composite factorial design was used for the preparation and optimization of chitosan/Na-alginate hydrogel films containing metformin via solvent evaporation technique. METHODS: Low and high molecular weight (MW) chitosan was used as a polymer in different concentrations while genipin was used as a crosslinking agent. Drug release studies were performed in simulated gastric and intestinal fluids at pH 1.2 and 7.4 of formulated hydrogels. RESULTS: For low MW chitosan hydrogel, the highest drug release at pH 1.2 was observed i.e., 9.82% for 2 hrs while at pH 7.4, 95.52% drug release was observed after 12 hrs. In case of high MW chitosan hydrogel 9.67% drug release at ph1.2 for 2 hrs and 90.63% drug release at pH 7.4 after 12 hrs was observed. The highest T50% of low MW and high MW chitosan hydrogel was observed as 22.72 and 33.34 hrs, respectively, while the highest dynamic swelling was observed as 8.21 and 7.9, respectively. CONCLUSION: It was found that by changing the ratios of polymers as well as crosslinking agent, the release rate of metformin can be modified. Low MW chitosan hydrogel showed an increased release rate than high MW chitosan hydrogel and by increasing the concentration of crosslinking agent, the release rate was found to be decreased and vice versa. PMID- 29629661 TI - Preparation and In vitro Evaluation of Efficacy and Toxicity of Polysorbate 80 coated Bovine Serum Albumin Nanoparticles containing Amphotericin B. AB - OBJECTIVE: In this study, bovine serum albumin (BSA) nanoparticles coated with polysorbate- 80 (PS-80) and containing amphotericin B (AmB) were developed using a coacervation method. METHODS: The nanoparticles were spherical, had a uniform size distribution (polydispersity < 0.25), a small mean size (185 +/- 5 nm), a high zeta potential (-38.0 +/- 0.7 mV), and a high AmB encapsulation efficiency (93 +/- 1%). The AmB release profile was prolonged and diffusion-controlled, resulting in a low degree of AmB aggregation in solution. The physicochemical characteristics of these AmB containing nanoparticles were evaluated by X-ray diffraction, Fourier transform infrared spectroscopy, differential scanning calorimetry, and derivative thermogravimetry and showed that the nanoencapsulation process lead to AmB amorphization while maintaining its chemical integrity. RESULTS: In a hemolysis assay, AmB-loaded PS-80-coated BSA nanoparticles demonstrated an absence of cytotoxicity toward erythrocytes, whereas pure and commercial AmB were highly hemolytic. CONCLUSION: In an assay to assess antifungal activity against Cryptococcus neoformans, AmB-charged PS-80 coated BSA nanoparticles were effective, however, due to the prolonged AmB release from the nanoparticles, the MIC was higher than for pure or commercial AmB. PS-80-coated BSA nanoparticles are potential carriers for the delivery of AmB for the treatment of Cryptococcus sp infections. PMID- 29629662 TI - Vitamin E TPGS Emulsified Vinorelbine Bitartrate Loaded Solid Lipid Nanoparticles (SLN): Formulation Development, Optimization and In vitro Characterization. AB - BACKGROUND: Vinorelbine bitartrate (VRL), a semi synthetic vinca alkaloid approved for breast cancer, has been proven to be beneficial as first line and subsequent therapies. However, its hydrophilic and thermo labile nature provides hindrance to oral clinical translation. OBJECTIVES: The current work focused on the application of DOE a modern statistical optimization tool for the development and optimization of a solid lipid nanoparticle (SLN) formulation that can encapsulate hydrophilic and thermolabile Vinorelbine bitartrate (VRL) to a maximum extent without compromising integrity and anticancer activity of the drug. METHODS: SLNs were prepared by solvent diffusion technique employing Taguchi orthogonal array design with optimized formulation and process variables. The emulsifying nature and low melting point of glyceryl mono-oleate (GMO) were exploited to enhance entrapment and minimizing temperature associated degradation, respectively. Moreover, two types of surfactants, Vitamin E TPGS (TPGS) and Poloxamer-188 were utilized to obtain TPGS-VRL-SLNs and PL-VRL-SLNs, respectively. The SLNs were characterized for various physicochemical properties, in-vitro drug release kinetics and anticancer activity by MTT assay on MCF-7 cancer cell lines. RESULTS: The SLNs were found to be spherical in shape with entrapment efficiency (EE) up to 58 %. Invitro release studies showed biphasic release pattern following Korsemeyer peppas model with fickian release kinetics. Results of MTT assay revealed that TPGS-VRL-SLNs and PL-VRL-SLNs were 39.5 and 18.5 fold more effective, respectively, compared to the pristine VRL. CONCLUSION: DOE approach was successfully applied for the development of VRL-SLNs. Enhanced entrapment and anticancer efficacy of TPGS-VRL-SLN can be attributed to emulsifying nature of GMO and inherent cytotoxic nature of TPGS, respectively, which synergizes with VRL. Therefore, TPGS associated SLNs may be potential carrier in cancer chemotherapeutics. PMID- 29629663 TI - The Effect of Combination Antiretroviral Therapy Use Among HIV Positive Children on the Hazard of AIDS Using Calendar Year as an Instrumental Variable. AB - BACKGROUND: Instrumental variable (IV) analyses are a common causal inference technique used in the absence of randomized data. Combination Antiretroviral Therapy (cART) was first introduced in 1996 and calendar periods have been used as a proxy for cART use. However, cART use misclassification can bias IV analyses. OBJECTIVE: We aim to highlight the differences in the effects of antiretroviral therapy on clinical outcomes between the applications of traditional and adapted IV analysis techniques. METHODS: This study includes children with perinatal human immunodeficiency virus (HIV-1) infection followed from 1988 to 2009. We describe an application of traditional and adapted IV analysis techniques. Noncompliance adjustments were applied to correct the misclassification of cART-use. Weighting the inverse probability of calendar era, the selected covariates were performed to control for variables that may be related to both the IV and outcome. RESULTS: During 48,380 person-days, 78 HIV positive children progressed to an initial stage-3- defining diagnosis or death. The Intention to Treat (ITT) rate ratio (RR) of stage-3-defining diagnosis or death comparing the pre-cART and cART eras was estimated at 2.67 (95% confidence interval (CI): 1..47, 4.84). The IV estimator was used to adjust for cART use misclassification, yielding an IV RR of 5.42 (95% CI: 2.99, 9.83). Weighting analyses did not markedly alter the results. CONCLUSION: cART use decreased progression to stage-3-defining diagnosis or death. The use of noncompliance adjustments for cART misclassification in IV analyses may provide more robust evidence of cART's effectiveness than traditional ITT analysis. PMID- 29629664 TI - Impact of a Psycho-Educational Team in early Breast Cancer Patients' Coping Strategies: The Venere Project. AB - AIMS AND BACKGROUND: The main purpose of our psycho-educational groups was to help women with breast cancer, learn how to cope with the physical, emotional, and lifestyle changes associated with cancer as well as with medical treatments that can be painful and traumatic. With this study, we wanted to detect the effects that group action had on the women who participated in it. METHODS: We studied a total of 97 patients who participated in 13 psycho-education groups. The whole sample was female patients who had breast cancer with no recurrence or metastases. RESULTS: All patients were evaluated with the Hospital Anxiety and Depression Scale (HADS) and the Body Image Scale (BIS). We found no significant effect on anxiety and body image for the brief psycho- educational group for women with breast cancer in this study. It is possible to highlight a statistical difference and hence an improvement between the results of the HADS depression test at T0 (first evaluation at the first meeting) and T1 (retest in the final meeting). CONCLUSION: The tests did not show a significant effect on anxiety and body image perception, but the patients reported that the psycho-educational group was an important intervention for their life. Outcome measurement is more complex in psychosocial research because many variables come into play and each phase of treatment is characterized by different types of problems for the patient: physical, relational and psychological aspects are involved. PMID- 29629665 TI - Overall and Multiphasic Findings of the Prostate, Lung, Colorectal and Ovarian (PLCO) Randomized Cancer Screening Trial. AB - BACKGROUND: Screening tests are typically evaluated for a single disease, but multiple tests for multiple diseases are performed in practice. The Prostate, Lung, Colorectal and Ovarian (PLCO) cancer screening trial assessed testing for four cancers simultaneously and can be viewed as a multiphasic cancer intervention. This paper presents overall and multiphasic findings of this trial. METHODS: The PLCO trial was a randomized multi-center trial conducted at ten screening centers in the US. Participants were 76,682 men and 78,215 women ages 55 - 74 and free of the target cancers at trial entry. Screening tests were PSA and digital rectal examination for prostate cancer, chest x-ray for lung cancer, flexible sigmoidoscopy for colorectal cancer, CA125 and transvaginal ultrasound for ovarian cancer. Outcomes and harms of screening were assessed including compliance, test results, incidence, mortality, false positives and overdiagnosis. RESULTS: Screening compliance was 82%, 72,820 (8%) of 906,064 exams were positive, the overall PPV was 4.2% and the cancer detection rate was 3.38/1000. A mortality reduction was observed only for colorectal cancer (RR 0.72, 95% CI 0.61 - 0.85) with no effect on all-cause mortality. Ninety-six percent of positive exams were falsely positive and there was a suggestion of overdiagnosis of prostate and possibly ovarian cancers. Multiphasic testing resulted in 7374 men and 2748 women experiencing multiple false positive results from multiple types of tests. CONCLUSION: Multiphasic cancer screening led to reduced mortality for one target cancer and imposed a burden on the health care system that included substantial false positives and likely overdiagnosis. PMID- 29629666 TI - Clinical Significance of Anti-Ribosomal P Protein Antibodies in Patients with Lupus Nephritis. AB - BACKGROUND: Systemic Lupus Erythematosus (SLE) is a chronic inflammatory disorder affecting multiple systems of the body. Clinical features show wide variations in patients with the different ethnic background. Renal involvement is a predictor of poor prognosis. Immunological workup is an integral part of SLE diagnostic criteria. Anti-ribosomal P Protein (anti-P) antibodies are highly specific for SLE. They may be present in Antinuclear Antibodies (ANA) negative SLE patients. Their role in Lupus Nephritis (LN) is under debate, some researchers found them associated with poor prognosis whereas others found favorable effect of these antibodies on renal disease. OBJECTIVE: In this study, we investigated frequency of anti-P antibodies and the effect of these antibodies on renal functions in the LN patients. METHODS: A total of 133 SLE patients were enrolled in this study. All patients had ANA in their sera. Anti-P antibodies along with other autoantibodies against extractable nuclear antigens (anti-Sm, anti- SS-A, anti-SS B, anti-histones and anti-RNP) were detected by Immunoblot assay. Anti-dsDNA antibodies were detected by indirect Immunofluorescence Assay (IFA). RESULTS: We found anti-P antibodies in 10.5% LN patients. Interestingly their presence in association with anti-dsDNA was associated with improved renal functions in comparison to those who had antidsDNA antibodies in isolation (serum creatinine: 1.3 +/- 0.8 mg/dl vs. 3.0 +/- 3.0; P= 0.091). CONCLUSION: Anti-dsDNA antibodies are directly involved in renal pathology in SLE patients. As these antibodies are nephrotoxic, concomitant occurrence of anti-P antibodies seems to offer a shielding effect on renal functions, which was evident by normal serum creatinine levels. Therefore, anti-P antibodies may be considered as a good prognostic marker in these patients. PMID- 29629667 TI - Anticancer Pyrrolizines: Design, Synthesis, Caspase-3 activation and Micronucleus (MN) Induction. AB - For further exploration of the promising pyrrolizine scaffold and in continuation of our previous work, that proved the potential anticancer activity of the hit compound I, a new series of pyrrolizines 2-5 and 7-9 were designed and synthesized. Structures of the new compounds were confirmed by IR, 1H-NMR, 13C NMR and elemental analysis. Antitumor activity for the prepared compounds against human breast adenocarcinoma (MCF-7), liver (HEPG2) and colon (HCT116) cancer cell lines was evaluated using SRB assay method. Compounds 2, 3 and 5 were the most potent on colon cancer cells, their IC50 values were less than 5 uM. Compounds 2, 3 and 8 were the most potent on liver cancer cells, their IC50 values were less than 10 uM. As for MCF7, compounds 2, 7, 8 and 9 were the most active with IC50 values less than 10 uM. We can conclude that combining pyrrolizine scaffold with urea gave abroad spectrum anticancer agent 2 against the three tested cell lines. Micronucleus assays showed that compounds 2, 3, 8 are mutagenic and can induce apoptosis. In addition, caspase-3 activation was evaluated and compound 2 showed increase in the level of caspase-3 (9 folds) followed by 3 (8.28 folds) then 8 (7.89 folds). The obtained results encourage considering these three compounds as novel anticancer prototypes. PMID- 29629668 TI - Using DNA Barcoding to Detect Adulteration in Different Herbal Plant- Based Products in the United Arab Emirates: Proof of Concept and Validation. AB - BACKGROUND: Commercially available herbal and medicinal plants-based products are susceptible to substitution or contamination with other unlabeled or undesired materials. This will reduce the quality of the product, and may lead to intoxication and allergy. METHODS: DNA barcoding is a molecular technology that allows the identification of plant materials at the species level, by sequencing short stretches of standardized gene sequences from nuclear or organelle genome in an easy, rapid, accurate and cost-effective manner. The aim of this research is to apply DNA barcoding to investigate the authenticity of commercially available herbal and medicinal plant-based products within the UAE markets. A total of 30 samples were analyzed, covering six different herbal products (thyme, cardamom, anise, basil, turmeric, and ginger), obtained in fresh and dried forms. DNA was extracted and three barcode loci including (rbcL), (matK) and (ITS) were amplified, sequenced and analyzed by BLAST. RESULTS: In terms of amplification efficiency, the results suggest that rbcL is the most suitable marker for species identification giving 75% of successful amplification, followed by ITS with 66.67%, whereas matK had the lowest with 18.52%. Adulteration was detected in two samples, ginger powder and dry thyme leave samples. The adulterants were from Triticum and Oryza genera. CONCLUSION: Clearly, the results from this report provide evidence that DNA barcoding technique is efficient in the recognition of commercial plant products. Thus, it can be considered as a fast, effective, and reliable method to detect adulteration in plant-based products in the UAE market. PMID- 29629670 TI - Tuberculin conversion and tuberculosis disease in infants and young children from the Drakenstein Child Health Study: A call to action. AB - Although tuberculosis (TB) is widely acknowledged as a major driver of global morbidity and mortality in adults, the disease's impact on children has been underappreciated. Global estimates of mortality among children aged <5 years, derived largely from vital registration and verbal autopsy records, have excluded paediatric TB as a contributing cause. PMID- 29629669 TI - A connectomic approach to the lateral geniculate nucleus. AB - Although the core functions and structure of the lateral geniculate nucleus (LGN) are well understood, this core is surrounded by questions about the integration of feedforward and feedback connections, interactions between different channels of information, and how activity dependent development restructures synaptic networks. Our understanding of the organization of the mouse LGN is particularly limited given how important it has become as a model system. Advances in circuit scale electron microscopy (cellular connectomics) have made it possible to reconstruct the synaptic connectivity of hundreds of neurons within in a circuit the size of the mouse LGN. These circuit reconstructions can reveal cell type-to cell type canonical wiring diagrams as well as the higher order wiring motifs that are only visible in reconstructions of intact networks. Connectomic analysis of the LGN therefore not only can answer longstanding questions about the organization of the visual thalamus but also presents unique opportunities for investigating fundamental properties of mammalian circuit formation. PMID- 29629671 TI - Celebrating 50 years of heart transplant surgery: A missed opportunity to honour Hamilton Naki. AB - Reply to Mankahla N, Dlamini S, Taunyane IC, Maqungo S, Cairncross L, Chiliza B. Celebrating 50 years of heart transplant surgery: A missed opportunity to honour Hamilton Naki. S Afr Med J 2018;108(3):151. https://doi.org/10.7196/SAMJ.2018.v108i3.13114. PMID- 29629672 TI - Considerations regarding point-of-care testing. PMID- 29629673 TI - Pan drug-resistant Serratia marcescens: An emerging threat. PMID- 29629674 TI - Life-threatening hereditary angio-oedema: Challenges of care in South Africa. AB - The report and description by Coovadia et al.[1] in this issue of SAMJ of a large cohort of patients in the Western Cape Province of South Africa (SA) suffering from type 1 hereditary angio-oedema (HAE) not only documents for the first time a significant presence of this life-threatening condition on the African continent but highlights the challenges of diagnosis and management in the SA socioeconomic and healthcare context. PMID- 29629675 TI - The current aetiology of malignant pleural effusion in the Western Cape Province, South Africa. AB - BACKGROUND: Malignant pleural effusion (MPE) represents a very common cause of pleural exudates, and is one of the most challenging pleural disorders to manage. This could be attributed to the paucity of high-quality experimental evidence, and inconsistent practice worldwide. South Africa (SA) currently has no data regarding the aetiology of MPE. OBJECTIVES: To identify the most common malignancies causing MPE in a population served by a large tertiary hospital in SA, and specifically the relative contribution of mesothelioma. A secondary objective was to evaluate the efficacy of chemical pleurodesis in a subset of patients. METHODS: We retrospectively included all known cases of MPE evaluated at our institution over a 3-year period with a tissue diagnosis of MPE. RESULTS: The most common causes of MPE in a total of 274 patients were lung cancer (n=174, 63.5%), breast cancer (n=32, 11.7%), unknown primary (n=22, 11.7%) and mesothelioma (n=27, 9.9%). Talc pleurodesis was performed in 81 of 194 patients (41.8%) referred to our division, and was radiologically successful in 22 of 25 (88.0%) followed up to 3 months. CONCLUSIONS: The main cause of MPE in our setting was lung cancer, followed by breast cancer, unknown primary and mesothelioma. Chemical pleurodesis was a viable palliative measure for MPE in this population. PMID- 29629676 TI - A proposed management algorithm for late-onset efavirenz neurotoxicity. AB - A high proportion of HIV-positive patients in South Africa receive concomitant efavirenz (EFV) and isoniazid (INH) therapy. EFV is metabolised in the liver via CYP2B6, and genetic polymorphism of CYP2B6 is known to result in slowed metabolism of the drug. INH is also metabolised in the liver, causing inhibition of a pathway that plays an important role in slow EFV metabolisers. Concomitant INH use therefore affects plasma levels of EFV. EFV is well known to cause neuropsychiatric side-effects on initiation, and a recent adult case series described late-onset neurotoxicity in the form of subacute ataxia and encephalopathy in patients treated with EFV for a median of 2 years, in association with toxic plasma levels of the drug. We have seen an increase in cases of EFV toxicity presenting to our neurology referral unit. All cases have been in the context of recent initiation of concomitant INH. We therefore conducted a retrospective case record audit to describe these seven cases with the additional advantage of tertiary-level assessment. We outline the clinical features and investigation results, as well as outcomes after EFV was stopped. Our main objectives are to highlight the probable role of concomitant INH use in the development of this syndrome, and to suggest that only limited work-up may be warranted in suspected cases. PMID- 29629677 TI - Blood and virus detection on barber clippers. AB - BACKGROUND: Bleeding from the popular clean-shave 'chiskop' haircut was recently reported as prevalent in South Africa (SA), a country with 6.9 million HIV infected people. OBJECTIVES: To investigate the prevalence of barber hair clipper contamination with blood and HIV and hepatitis B viruses. METHODS: Fifty barbers from three townships in Cape Town, SA, were invited to participate. One clipper from each barber was collected immediately after it had been used for a clean shave haircut. Each clipper was rinsed with phosphate-buffered saline and then submerged in viral medium. The polymerase chain reaction (PCR) was used to identify the blood-specific RNA marker haemoglobin beta (HBB), hepatitis B virus (HBV) and HIV. RESULTS: The clean-shave haircut was the most common haircut requested by clients (78%). Of the clippers collected, 42% were positive for HBB, confirming detection of blood, none were positive for HIV, and 4 (8%) were positive for HBV. Two clippers (clippers 16 and 20) were positive on qualitative HBV PCR. HBV DNA from clipper 16 clustered with genotype A sequences from SA, India, Brazil and Martinique, while clipper 20 clustered with SA genotype D sequences. The clipper 20 sequence was identical to a subtype D sequence (GenBank accession AY233291) from Gauteng, SA. CONCLUSIONS: This study confirms that there is significant contamination of barber hair clippers with blood and blood-borne viruses. Hepatitis B was detected with enough DNA copies to pose a risk of transmitting infection. Although HIV was not detected in this small study, the risk of transmission should be quantified. Further studies to investigate barber clipper sterilisation practices and whether the clean-shave hairstyle is an independent risk factor for HIV, HBV and hepatitis C virus infections are warranted. Public education on individual clipper ownership (as is the case with a toothbrush) should be advocated for clean-shave and blade-fade haircuts. PMID- 29629678 TI - Hereditary angio-oedema in the Western Cape Province, South Africa. AB - BACKGROUND: Hereditary angio-oedema (HAE) is an autosomal dominant condition caused by a deficiency in the C1-esterase inhibitor protein, resulting in increased bradykinin release. It presents clinically with recurrent attacks of angio-oedema, commonly affecting the limbs, face, upper airway and gastrointestinal tract. Little is known about this condition in sub-Saharan Africa. OBJECTIVES: To analyse and report on the clinical presentation and treatment of patients with HAE in the Western Cape Province, South Africa. METHODS: A retrospective analysis was conducted on a series of 60 cases of HAE seen between 2010 and 2015 at the Allergy Diagnostic and Clinical Research Unit, University of Cape Town Lung Institute, and the Allergy Clinic at Groote Schuur Hospital, Cape Town. The findings in 43 cases of type 1 HAE are described. Parameters assessed included age, gender, age of diagnosis, duration of illness, family history, identifiable triggers, average duration of attack, number of attacks per year and type of attack. RESULTS: A total of 43 patients were included in this study. Of these, 65.1% (28/43) were female. The median age at diagnosis was 20 years (interquartile range (IQR) 10 - 27) and the median duration of illness 10.5 years (IQR 6 - 22). Of the patients, 62.8% (27/43), 32.6% (14/43) and 4.7% (2/43) were of mixed ancestry, white and black African, respectively; 51.2% (22/43) were index cases, with the remaining 48.8% (21/43) diagnoses via family member screening, 12 families making up the majority of the cohort. The mean (standard deviation) duration of an acute attack was 49 (25.8) hours, and 64.3% (27/42), 71.4% (30/42), 14.3% (6/42) and 88.1% (37/42) of patients experienced facial or upper airway, abdominal, external genitalia and limb attacks, respectively. Danazol for long-term prophylaxis was used in 21 patients, while C1-inhibitor concentrate (Berinert) was accessed for short-term prophylaxis in only four patients. Acute life-threating attacks were treated with fresh frozen plasma in 11 patients, and only four accessed icatibant. The mortality rate for the period 2010 - 2015 was 4.5% (2/43). The prevalence of HAE in the Western Cape was estimated to be 1:140 000. CONCLUSIONS: HAE occurs in South Africans of all ethnicities, and life-threatening attacks occur in almost two-thirds of patients. Despite limited therapeutic options and very limited access to gold-standard therapies available in the developed world, our mortality rate is very low, with both the deaths related to inability to access emergency treatment rapidly. PMID- 29629679 TI - Feasibility and acceptability of conducting HIV vaccine trials in adolescents in South Africa: Going beyond willingness to participate towards implementation. AB - BACKGROUND: HIV/AIDS remains a leading cause of death in adolescents (aged 15 - 25 years), and in sub-Saharan Africa HIV-related deaths continue to rise in this age group despite a decline in both adult and paediatric populations. This is attributable in part to high adolescent infection rates and supports the urgent need for more efficacious prevention strategies. In particular, an even partially effective HIV vaccine, given prior to sexual debut, is predicted to significantly curb adolescent infection rates. While adolescents have indicated willingness to participate in HIV vaccine trials, there are concerns around safety, uptake, adherence, and ethical and logistic issues. OBJECTIVES: To initiate a national, multisite project with the aim of identifying obstacles to conducting adolescent HIV vaccine trials in South Africa (SA). METHOD: A simulated HIV vaccine trial was conducted in adolescents aged 12 - 17 years across five SA research sites, using the already licensed Merck human papillomavirus vaccine Gardasil as a proxy for an HIV vaccine. Adolescents were recruited at community venues and, following a vaccine discussion group, invited to participate in the trial. Consent for trial enrolment was obtained from a parent or legal guardian, and participants aged 16 - 17 years were eligible only if sexually active. Typical vaccine trial procedures were applied during the five study visits, including the administration of vaccination injections at study visits 2, 3 and 4. RESULTS: The median age of participants was 14 years (interquartile range 13 - 15), with 81% between the ages of 12 and 15 years at enrolment. Overall, 98% of screened participants opted to receive the vaccine, 588 participants enrolled, and 524 (89%) attended the final visit. CONCLUSIONS: This trial showed that adolescents can be recruited, enrolled and retained in clinical prevention trials with parental support. While promising, these results were tempered by the coupling of sexual-risk eligibility criteria and the requirement for parental/guardian consent, which was probably a barrier to the enrolment of high-risk older adolescents. Further debate around appropriate consent approaches for such adolescents in HIV prevention studies is required. PMID- 29629680 TI - Understanding the types of fraud in claims to South African medical schemes. AB - BACKGROUND: Medical schemes play a significant role in funding private healthcare in South Africa (SA). However, the sector is negatively affected by the high rate of fraudulent claims. OBJECTIVES: To identify the types of fraudulent activities committed in SA medical scheme claims. METHODS: A cross-sectional qualitative study was conducted, adopting a case study strategy. A sample of 15 employees was purposively selected from a single medical scheme administration company in SA. Semi-structured interviews were conducted to collect data from study participants. A thematic analysis of the data was done using ATLAS.ti software (ATLAS.ti Scientific Software Development, Germany). RESULTS: The study population comprised the 17 companies that administer medical schemes in SA. Data were collected from 15 study participants, who were selected from the medical scheme administrator chosen as a case study. The study found that medical schemes were defrauded in numerous ways. The perpetrators of this type of fraud include healthcare service providers, medical scheme members, employees, brokers and syndicates. Medical schemes are mostly defrauded by the submission of false claims by service providers and syndicates. Fraud committed by medical scheme members encompasses the sharing of medical scheme benefits with non-members (card farming) and non-disclosure of pre-existing conditions at the application stage. CONCLUSIONS: The study concluded that perpetrators of fraud have found several ways of defrauding SA medical schemes regarding claims. Understanding and identifying the types of fraud events facing medical schemes is the initial step towards establishing methods to mitigate this risk. Future studies should examine strategies to manage fraudulent medical scheme claims. PMID- 29629681 TI - Antibiotic prescribing practice and adherence to guidelines in primary care in the Cape Town Metro District, South Africa. AB - BACKGROUND: Knowledge of antibiotic prescribing practice in primary care in South Africa is limited. As 80% of human antibiotic use is in primary care, this knowledge is important in view of the global problem of antibiotic resistance. OBJECTIVES: To assess antibiotic prescribing in primary care facilities in the Cape Town Metro District and compare it with current national guidelines, and to assess the reasons why prescriptions were not adherent to guidelines. METHODS: A retrospective medical record review was performed in April/May 2016. Records of all patients seen over 2 days in each of eight representative primary care facilities in the Cape Town Metro District were reviewed. The treatment of any patient who raised a new complaint on either of those days was recorded. Prophylactic antibiotic courses, tuberculosis treatment and patients with a non infection diagnosis were excluded. Treatment was compared with the Standard Treatment Guidelines and Essential Medicines List for South Africa, Primary Healthcare Level, 2014 edition. RESULTS: Of 654 records included, 68.7% indicated that an antibiotic had been prescribed. Overall guideline adherence was 45.1%. Adherence differed significantly between facilities and according to the physiological system being treated, whether the prescription was for an adult or paediatric patient, and the antibiotic prescribed. Healthcare professional type and patient gender had no significant effect on adherence. The main reasons for non-adherence were an undocumented diagnosis (30.5%), antibiotic not required (21.6%), incorrect dose (12.9%), incorrect drug (11.5%), and incorrect duration of therapy (9.5%). CONCLUSIONS: This study demonstrates poor adherence to guidelines. Irrational use of antibiotics is associated with increased antibiotic resistance. There is an urgent need to improve antibiotic prescribing practice in primary care in the Cape Town Metro District. PMID- 29629682 TI - Impact of 'Ideal Clinic' implementation on patient waiting time in primary healthcare clinics in KwaZulu-Natal Province, South Africa: A before-and-after evaluation. AB - BACKGROUND: Long waiting times are a major source of dissatisfaction for patients attending public healthcare facilities in South Africa (SA). The National Department of Health has identified this as one of six priority areas for improvement. Health system-strengthening (HSS) interventions to improve patient waiting time are being implemented in public health facilities across SA as part of the 'Ideal Clinic' model. The effect of these interventions on patient waiting time needs to be assessed and evidence generated for system improvement. OBJECTIVES: To determine the effect of Ideal Clinic HSS intervention on patient waiting time in public health facilities in Amajuba District, KwaZulu-Natal Province, SA. METHODS: We implemented 12 months of HSS activity, including facility reorganisation and patient appointment scheduling. The major outcome of interest was the total time spent by patients in a facility during a visit. This was calculated as the median time spent, obtained through a 'before-and-after' intervention survey. Univariate and multivariate factors associated with waiting time were determined. RESULTS: A total of 1 763 patients from nine clinics were surveyed before and after the intervention (n=860 at baseline and n=903 at follow up). The median overall waiting time after the intervention was 122 minutes (interquartile range (IQR) 81 - 204), compared with 116 minutes (IQR 66 - 168) before (p<0.05). Individual facility results after the intervention were mixed. Two facilities recorded statistically significant reductions in patient waiting time, while three recorded significant increases (p<0.05). Patient load per nurse, type of service received and time of arrival in facilities were all independently associated with waiting time. Patients' arrival patterns, which were determined by appointment scheduling, played a significant role in the results obtained. CONCLUSIONS: Implementation of the Ideal Clinic model in the selected facilities led to changes in patient waiting time. Observed changes were positive when a clinic appointment system was successfully implemented and negative when this was unsuccessful. We recommend strengthening of the appointment system component of the Ideal Clinic model to improve patient waiting time. Assessing facility waiting time performance in terms of average time spent by patients during a clinic visit was shown to be inadequate, and we suggest the inclusion of 'proportion of clients who spent above the national waiting time threshold during their visit' as a sensitive measure of performance. PMID- 29629683 TI - Near-real-time tracking of gaps in prevention of mother-to-child transmission of HIV in three districts of KwaZulu-Natal Province, South Africa. AB - BACKGROUND: Identifying and addressing gaps in the prevention of mother-to-child transmission of HIV (PMTCT) is required if South Africa (SA) is to achieve targets for eliminating MTCT (eMTCT). Potential PMTCT gaps that increase MTCT risk include late maternal HIV diagnosis, lack of or delayed antiretroviral therapy (ART) during pregnancy and breastfeeding, and lack of effective prophylaxis for HIV-exposed infants. OBJECTIVES: To investigate, in near real time, PMTCT gaps among HIV-infected infants in three districts of KwaZulu-Natal Province, SA. METHODS: Between May and September 2016, PMTCT co-ordinators from eThekwini, uMgungundlovu and uMkhanyakude districts received daily email notification of all HIV polymerase chain reaction (PCR)-positive results. Co ordinators reviewed facility records for each infant to identify gaps in PMTCT care, including maternal age, timing of maternal HIV diagnosis, maternal treatment history and maternal viral load (VL) monitoring. Data were submitted via the mobile phone SMS (text message) service using Rapid Pro technology and analysed in Stata 14. RESULTS: Data on PMTCT gaps were received for 367 (91.8%) of 400 infants with HIV PCR-positive results, within a median time of 12.5 days (interquartile range (IQR) 6 - 23). The median maternal age was 25 years (IQR 22 30), with 48 teenage mothers (15 - 19 years). The sample size was too small to determine whether there were significant differences in PMTCT gaps between the 48 teenage mothers and 293 older (20 - 34 years) mothers. Of the mothers, 220 (60.0%) were first diagnosed prior to conception or at their first antenatal care (ANC) visit, and 127 (34.6%) at or after delivery; 137 (37.3%) transmitted HIV to their infants despite receiving >12 weeks of ART. VL results were unavailable for 70.0% of women. Only 41 (17.5%) of women known to be HIV-positive during ANC had confirmed virological suppression. No statistically significant differences in PMTCT gaps were observed between districts, owing to small sample sizes in uMgungundlovu and uMkhanyakude. CONCLUSIONS: The findings highlight the need to improve services during ANC, in particular prioritising maternal VL monitoring. We intend to use improved technology to streamline data collection and reporting towards eMTCT. PMID- 29629684 TI - Hypertension as the trigger for posterior reversible encephalopathy syndrome in paediatric renal patients: An important diagnosis that should not be missed. AB - BACKGROUND: Posterior reversible encephalopathy syndrome (PRES) is a reversible neurological condition presenting with seizures and visual disturbances and diagnosed on magnetic resonance imaging (MRI). Little is understood about its pathogenesis, particularly in children, but it is thought to be related to hypertension. OBJECTIVES: To review the presentation, diagnosis and outcome of PRES in paediatric renal patients at Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa, between 1 January 2000 and 31 January 2017 and compare these with published case reports to date. METHODS: This was a retrospective analysis of five new cases and a review of the existing literature. RESULTS: The five reported patients were all hypertensive at the time of diagnosis and presented with seizures. Most (91%) of the 64 reviewed patients were also hypertensive at initial presentation. All five of the reported and 91% of the reviewed patients presented with seizures. The most common pattern of change on MRI occurred in the parietal and occipital regions. Complete neurological recovery occurred in four of the five reported and 87.5% of the reviewed patients. CONCLUSION: All patients presented clinically with hypertensive crises and radiological evidence of PRES. Seizures were the most common presenting symptom. The prognosis for paediatric patients with PRES is favourable, so it is important to confirm the diagnosis in low-resource settings where intensive care is limited. PMID- 29629685 TI - Evaluating the effect of ward-based outreach teams on primary healthcare performance in North West Province, South Africa: A plausibility design using routine data. AB - BACKGROUND: North West Province (NWP), South Africa, was an early adopter of the primary healthcare (PHC) ward-based outreach team (WBOT) strategy and has made considerable progress in implementing it. Given the interest in and expectations of greater investment in WBOTs, assessing their impact on and contribution to PHC outputs and health outcomes is becoming increasingly important. OBJECTIVES: To describe the application of a plausibility evaluation design for assessing the contribution of WBOTs to PHC performance in NWP, comparing changes in coverage, utilisation and outcome indicators in facilities with and without WBOTs. METHODS: Routine data from the District Health Information System on both WBOTs and PHC facilities for the period 2011/12 (prior to implementation) to 2014/15 (3 years after implementation began) were extracted. Analysis involved the following three steps: (i) selection of indicators sensitive to community-based action; (ii) data cleaning; and (iii) comparison of the degree of change in median indicator values between 2011/12 and 2014/15 in facilities with and without WBOTs (a difference-in differences analysis). RESULTS: Changes in indicator values in facilities were grouped into four categories: (i) indicators where there was greater (statistically significant) improvement in facilities with WBOTs (couple year protection rate, measles immunisation coverage in children aged <1 year, incidence of children aged <5 years with severe diarrhoea with dehydration); (ii) indicators that declined or worsened, but less so in facilities with WBOTs at statistically significant levels (antenatal first visits as a percentage of children born in that year, PHC utilisation rate of children aged <5 years); (iii) indicators that improved in all facilities with no significant difference between facilities with and without WBOTs (antenatal attendance before 20 weeks, prophylactic vitamin A coverage to children aged 12 - 59 months); and (iv) indicators that remained unchanged in all facilities (immunisation coverage in children aged <1 year, postnatal mother visits at 6 days, cervical cancer screening coverage in women aged >=30 years, PHC utilisation rate of children aged >=5 years). CONCLUSION: Notwithstanding the limitations of routine data and the need to approach the findings with caution, this analysis suggests that WBOTs plausibly had some positive effects on the overall performance of the PHC system. We propose a methodology to monitor the performance of WBOTs using routine PHC indicators that programme managers could apply elsewhere. PMID- 29629686 TI - An investigation of barriers to the use of the World Health Organization Surgical Safety Checklist in theatres. AB - BACKGROUND: The World Health Organization (WHO) has implemented the Surgical Safety Checklist (SSCL) as part of the Safe Surgery Saves Lives campaign. This is aimed at improving surgical safety worldwide. Despite many perceived benefits of the SSCL, compliance and acceptance in many areas remain poor. OBJECTIVES: To investigate perceptions of theatre staff regarding the checklist and to identify reasons and barriers for poor compliance and implementation. METHODS: Questionnaires were handed out to theatre teams across all surgical disciplines at two large hospitals in Durban, South Africa, over a 2-week period. Data collected included role in theatre, intention of the SSCL, training received, as well as questions regarding previously identified barriers and staff perceptions. RESULTS: Questionnaires were distributed to 225 practitioners, with a response rate of 81.7% from 51 nurses, 54 anaesthetists and 79 surgeons. Rank of medical staff included 52 seniors (consultants) and 81 juniors (registrars and medical officers). The majority (95%) of respondents perceived the SSCL as intended to improve safety, prevent errors or reduce morbidity and mortality. A total of 146 respondents (79.3%) received no SSCL training. No new barriers were identified, but previously identified barriers were confirmed. Our key factors were time related issues and lack of buy-in from team members. Surgeons were perceived as being supportive by 45.1% of respondents, in contrast to nurses (62.5%), anaesthetists (70.1%) and management (68.5%). When compared with junior staff, senior staff were 5-fold more likely to feel that staff did not need to be trained and 8-fold more likely to indicate that the checklist did not improve patient safety. CONCLUSIONS: The WHO SSCL is an important tool in the operating room environment. The barriers in our setting are similar to those identified in other settings. There needs to be widespread training in the use of the SSCL, including adaptation of the checklist to make it fit for purpose in our setting. Improving use of the checklist will allow theatre staff to work together towards ensuring a safer theatre environment for both patients and staff. PMID- 29629687 TI - The usefulness of routine histological examination of appendicectomy specimens in a South African tertiary centre. AB - BACKGROUND: It is accepted surgical practice to send all appendicectomy specimens for histological examination, but the usefulness and cost associated with this practice have not been established in our setting, a tertiary hospital in KwaZulu Natal Province, South Africa (SA). OBJECTIVES: To determine the histological diagnoses of appendicectomy specimens in our centre, and the cost of identifying an alternative histological diagnosis requiring further treatment. METHODS: Clinical data on patients undergoing appendicectomy for suspected acute appendicitis during the study period December 2012 - August 2015 were retrospectively retrieved from the hybrid electronic medical registry. Histological data were then extracted from the National Health Laboratory Service database. The cost of an appendicitis histology report was sourced from a private laboratory service. RESULTS: A total of 290 patients were identified during the study period. Males had a significantly higher risk (p<0.0001) than females of histologically confirmed appendicitis (odds ratio 3.2, 95% confidence interval 1.7 - 5.8). The negative appendicectomy rate was 22.4% (65/290). In 5.9% of specimens (17/290) an alternative diagnosis was made on histological examination, which influenced the management plan. These were parasitic co-infections in 13 cases (4.5%), premalignant conditions in 2 and tuberculosis in 2. The average cost of processing each appendicectomy specimen was ZAR871. The cost of identifying each patient with an alternative diagnosis that required treatment was ZAR14 858 ([290 * ZAR871]/17). CONCLUSIONS: This audit correlates with other SA studies showing that the aetiological differential for appendicitis is broad. Histological examination therefore remains critical in the management of patients with suspected acute appendicitis in our clinical setting. PMID- 29629688 TI - Potential latitudinal variation in orodigestive tract cancers in Africa. AB - BACKGROUND: Previous studies have alluded to a causal relationship between pathological entities and geographical variations, but there is a paucity of studies from Africa discussing the effect of latitudinal variation on orodigestive cancers in this region. It seems plausible that the burden of orodigestive cancer would differ as a result of variations in diet, cultural habits, climate and environmental conditions down the length of Africa. OBJECTIVES: To analyse regional variations in prevalence, incidence and mortality data in the global cancer statistics database (GLOBOCAN 2012) curated by the World Health Organization and the International Agency for Research on Cancer. Basic descriptive statistical tools were used to depict regional variations in cancer morbidity and mortality. METHODS: Data on 13 African countries between longitude 200 and 300 east and latitude 350 north and 350 south were examined for variation in age-standardised orodigestive cancer prevalence, incidence and mortality. Possible regional causes for orodigestive tract cancer development were investigated. Data on lip and oral cavity, oesophageal, gastric, colorectal, liver, gallbladder and pancreatic cancers in the 13 countries were compared. RESULTS: Our empirical findings from this preliminary study support the notion that the incidence and prevalence of orodigestive cancers vary within Africa. This effect may be due to environmental, economic, political and possibly genetic factors. CONCLUSIONS: Considering the heterogeneity of the above factors across Africa, disbursement of funding for cancer research and therapy in Africa should be focused in terms of regional variations to make best use of the fiscal allocation by African governments, non-governmental organisations and international agencies. PMID- 29629689 TI - Seasonal variations in Schistosoma haematobium egg excretion in school-age girls in rural KwaZulu-Natal Province, South Africa. AB - BACKGROUND: A predominant feature of Schistosoma haematobium infection is urinary egg excretion, and microscopic egg detection remains the accepted standard field diagnostic tool. Praziquantel is the drug of choice for schistosomiasis, and the World Health Organization recommends that it should be administered to all children >4 years of age living in schistosomiasis-endemic areas. The frequency of mass drug administration depends on the prevalence rate in the community. Urinary schistosome egg output has a day-to-day and hour-to-hour intrasubject variation. Therefore, it is important to assess possible seasonal variations in egg excretion to improve the planning of drug treatment. OBJECTIVES: To assess the influence of seasonality on urinary schistosome egg excretion in South Africa (SA). METHODS: We performed a prospective cohort study, exploring seasonal variations of S. haematobium egg excretion in 184 girls aged 10 - 12 years from randomly selected schools in a rural area of KwaZulu-Natal Province, SA. The area has a subtropical climate characterised by a cool dry season and a hot humid season. For children, water contact is higher in the latter season. At baseline, 108 girls were examined in the hot season, and 76 in the cold season. In the next year's cold season the untreated patients were re-investigated before treatment. RESULTS: There was a decrease in infection in the group initially tested in the hot season compared with the group tested in the cold season at both time points when adjusted for age and water contact (adjusted odds ratio 3.61 (95% confidence interval 1.14 - 11.44); p=0.03). CONCLUSIONS: This unique study shows that schistosomiasis prevalence determined by microscopy exhibits seasonal variation, with a higher prevalence in the hot rainy season. Precise community prevalence estimations are key in decisions to treat communities. There was significantly lower egg output in the cold season, and sampling in that season may therefore underestimate the prevalence of urinary schistosomiasis. The study indicates that sampling in SA should be done in the hot season. PMID- 29629691 TI - Beneath the White Coat. PMID- 29629690 TI - Osteosarcoma: a comprehensive review. AB - Osteosarcoma (OS) is a relatively rare tumor of bone with a worldwide incidence of 3.4 cases per million people per year. For most of the twentieth century, five year survival rates for classic OS were very low. In the 1970s, the introduction of adjuvant chemotherapy in the treatment of OS increased survival rates dramatically. The current article reviews the various types of OS and analyzes the clinical and histological features. We also examine historical and current literature to present a succinct review of methods for diagnosis and staging, as well as treatment, and we also discuss some of the future directions of treatment. PMID- 29629692 TI - Cooling Therapy for Neonatal Encephalopathy in Low- and Middle-income Countries. PMID- 29629693 TI - Therapeutic Hypothermia in Neonates: Is Phase Changing Material the Game Changer? PMID- 29629694 TI - Effect of Gastric Lavage on Meconium Aspiration Syndrome and Feed Intolerance in Vigorous Infants Born with Meconium Stained Amniotic Fluid - A Randomized Control Trial. AB - OBJECTIVE: To compare the incidence of meconium aspiration syndrome and feed intolerance in infants born through meconium stained amniotic fluid with or without gastric lavage performed at birth. SETTING: Neonatal unit of a teaching hospital in New Delhi, India. DESIGN: Parallel group unmasked randomized controlled trial. PARTICIPANTS: 700 vigorous infants of gestational age >=34 weeks from through meconium stained amniotic fluid. INTERVENTION: Gastric lavage in the labor room with normal saline at 10 mL per kg body weight (n=350) or no gastric lavage (n=350). Meconiumcrit was measured and expressed as <=30% and >30%. OUTCOME MEASURES: Meconium aspiration syndrome, feed intolerance and procedure-related complications during 72 h of observation. RESULTS: 5 (1.4%) infants in lavage group and 8 (2.2%) in no lavage group developed meconium aspiration syndrome (RR 0.63, 95% CI 0.21, 1.89). Feed intolerance was observed in 37 (10.5%) and 53 infants (15.1%) in lavage and no lavage groups, respectively (RR 0.70, 95% CI 0.47, 1.03). None of the infants in either group developed apnea, bradycardia or cyanosis during the procedure. CONCLUSIONS: Gastric lavage performed in the labor room does not seem to reduce either meconium aspiration syndrome or feed intolerance in vigorous infants born through meconium stained amniotic fluid. PMID- 29629695 TI - Carnitine Deficiency in Chinese Children with Epilepsy on Valproate Monotherapy. AB - OBJECTIVE: To explore the incidence and independent risk-factors of secondary carnitine deficiency in Chinese children with epilepsy on valproate monotherapy. METHODS: The free carnitine and acylcarnitines levels in 299 children with epilepsy on valproate monotherapy between June 2014 and September 2015 were compared with age- and sex-matched 299 healthy controls. RESULTS: Children with valproate monotherapy had lower free carnitine levels [23.86 (10.60) umol/L] than the controls [36.37 (9.37) umol/L] (P<0.01). Most acylcarnitines were significantly lower in children with valproate monotherapy than controls. 63 children (21.1%) with epilepsy had carnitine deficiency; 54 were asymptomatic. Female gender (OR 2.1), high alanine aminotransferase levels (OR 1.0) and long duration of VPA treatment (1-12 mo) (OR 1.9) were independent risk factors for secondary carnitine deficiency induced by VPA. CONCLUSION: Carnitine deficiency with valproate is more likely in females, those with transaminitis, and those receiving the drug for 1-12 months. PMID- 29629696 TI - Non-pharmacological Interventions for Pediatric Cancer Patients: A Comparative Review and Emerging Needs in India. AB - CONTEXT: Evidence-based research on psycho-oncology in last three decades lays emphasis upon the critical role of psychological services for better illness adjustment, improved quality of life, reduced distress and cognitive problems among the rapidly increasing pediatric cancer population. JUSTIFICATION: This review aims to summarize the evidence-based psychological interventions in childhood cancer over the two decades and addresses the wide gap that existed between intervention studies worldwide and India, thus highlighting the need for research and appropriate services. EVIDENCE ACQUISITION: We searched electronic databases such as MedLine, PubMed, PsycINFO, and Google Scholar. Key search terms were pediatric cancer, psycho-oncology, children with cancer + psychological intervention, or multimodal treatment, psychotherapy, cognitive training, behavioral, social skills+ feasibility study, pilot, randomized controlled trial, case study, systematic reviews. RESULTS: 28 full papers published between 1996 to 2016, including survivors and under-treatment children below 18 years, were reviewed. Various types of key interventions were psychosocial, physical, cognitive behavioral, cognitive, music art therapy and play therapy. Generally, intervention settings were either hospital or home, and were designed to promote psychological well-being. Psychological interventions were more in customised formats in these studies. A generic intervention module was not available for replication. CONCLUSION: Development of culture-specific generic intervention module and using the same in randomized control studies with larger effect size are needed in India for larger coverage of patients. PMID- 29629697 TI - Rapid Diagnostic Tests in Childhood Infections. AB - Presumptive treatment of infections often results in irrational antimicrobial use resulting in detrimental spread of drug resistance and untoward side effects. A rapid diagnostic test (RDT) is a test that delivers a result earlier than conventional testing methods employed in the past to identify the offending microorganism. RDTs help in early definitive therapy, reduction in hospital stay and cost, and in degree of morbidity and mortality associated with the infection. To select a proper RDT, one should consider how specific and sensitive the test is. Most RDTs gives a qualitative result not quantitative; hence disease severity, monitoring of the disease, prognostication and therapeutic efficacy cannot be assessed. A RDT should be easy to perform, should not require sophisticated machines, and kits should be stable in extremes of temperature. RDTs may be of immense help in remote places where conventional diagnostic facilities are unavailable or lack quality. RDTs hold promise of reasonable diagnostic accuracy if done in a optimal clinical background. They should never be ordered as a shotgun approach to exclude all possible infections but should be used judiciously with appropriate interpretation. PMID- 29629698 TI - Extra Hepatic Portal Vein Obstruction - Unobstructed. PMID- 29629699 TI - Interprofessional Education: An Approach to Improve Healthcare Outcomes. AB - Interprofessional education (IPE) approach allows learners from different health professions viz. - medical, dental, nursing, physiotherapy, psychotherapy, psychology etc., learn from, learn with, and learn about, each other. The scope of learning depends upon the requirements and curriculum. Interprofessional education can help in creating a workforce that learns to perform collaborative practice thereby ensuring better health-care outcomes. Medical educators' and practitioners' understanding about teaching, learning, and assessment of IPE is rudimentary. Strategies to incorporate IPE in regular curricula need to be debated and barriers associated with its implementation require to be identified. This review highlights the teaching-learning and assessment tools for IPE and discusses potential challenges in its implementation. PMID- 29629700 TI - Isolated Mediastinal Pseudocyst of the Pancreas. AB - BACKGROUND: Mediastinal pancreatic pseudocyst is a rare complication of pancreatitis. CASE CHARACTERISTICS: An 8-year-old boy with chest pain and shortness of breath. Computed tomography of chest showed a cystic mass in the mediastinum. The cyst aspirate revealed high amylase and lipase levels, suggestive of pancreatic pseudocyst. OUTCOME: The patient gradually recovered after Roux-en-Y cystojejunostomy. MESSAGE: Cysto-jejunostomy is a viable treatment option for mediastinal pancreatic pseudocyst, especially with failure of medical therapy. PMID- 29629701 TI - Peripheral Precocious Puberty Caused by Human Chorionic Gonadotropin Producing Pineal Gland Tumor. AB - BACKGROUND: Pineal gland lesions usually present with central precocious puberty. CASE CHARACTERISTICS: A 31/2-yr-old boy presented with precocious puberty. Clinically and biochemically, it was gonadotropin releasing hormone (GnRH) independent. Serum and CSF beta-hCG levels were increased. Thin section magnetic resonance imaging of brain revealed a pineal gland tumor. OUTCOME: He received chemotherapy followed by radiotherapy and responded well. MESSAGE: CSF beta-hCG should be measured in all cases of peripheral precocity, and if CSF beta-hCG is elevated, thin section magnetic resonance imaging of brain should be considered. PMID- 29629702 TI - Galactomannan Antigen Test for Early Diagnosis of Invasive Aspergillus Infection in Pediatric Febrile Neutropenia. AB - Invasive aspergillosis is a major concern in neutropenic patients. We studied the utility of Galactomannan antigen detection test in serum using ELISA technique for early detection of invasive aspergillosis. Diagnostic accuracy of Galactomannan index (GMI) test was maximum at a cut-off of > 1.5 with a negative predictive value of more than 95%. PMID- 29629703 TI - Pediatric Trauma - An Emerging Epidemic. AB - We enrolled 911 children aged <12 years presenting to the trauma center of a tertiary-care hospital (over a period of 18 months) with history of injuries. Majority (582; 63.9%) of children had sustained injuries at home; 56 (6.1%) had severe injuries based on Pediatric Trauma Score. Of road traffic accidents victims (n=232), majority (40.5%) were two-wheeler pillion riders or pedestrians (31.9%). More Indian data are required and efforts are needed to prioritize injury prevention efforts in children. PMID- 29629704 TI - Autoimmune Encephalitis Following Herpes Simplex Virus Encephalitis in an Infant. PMID- 29629705 TI - Evaluation of Asthma Control in Children Using Questionnaires. PMID- 29629706 TI - Evaluation of Asthma Control in Children Using Questionnaires: Author's Reply. PMID- 29629707 TI - Two Novel Missense Mutations in Very Long Chain Acyl-CoA Dehydrogenase Deficiency. PMID- 29629708 TI - Dipyridamole-loaded biodegradable PLA nanoplatforms as coatings for cardiovascular stents. AB - Cardiovascular stents are commonly used for the treatment of cardiovascular diseases that in developed societies are the most frequent causes of mortality and morbidity. In recent years, thorough research and development of drug-eluting stents has been done, with emphasis on coronary stenting to avoid the most common complication, in-stent thrombosis. Dipyridamole (DPM) is a medication that inhibits blood clot formation. Drug delivery nanoplatforms consisting of biodegradable polymers can be fabricated via electrospinning deposition, known for its cost-effective and versatile advantages, that produces fibrous scaffolds that are able to sustain and control drug release. A novel drug delivery nanosystem of polylactic acid fibrous scaffold loaded with the anti-platelet drug DPM was fabricated by electrospinning as coating for cardiovascular stents. The surface morphology and topography that were evaluated via atomic force microscopy, scanning electron microscopy and optical microscopy, were found to be good and suitable for tissue engineering. Contact angle measurements established the hydrophobic behavior of these fibrous nanoplatforms. Drug-release kinetics and degradation studies were conducted and revealed a sustained and controllable release of DPM, through this fibrous matrix over time. Finally, cytotoxicity studies took place to evaluate the cytocompatibility of the scaffold that confirmed its compatible behavior. The successful performance of this nanoplatform can lead to it being a valuable tool for atherosclerosis treatment. PMID- 29629709 TI - Modeling cell-substrate de-adhesion dynamics under fluid shear. AB - Changes in cell-substrate adhesion are believed to signal the onset of cancer metastasis, but such changes must be quantified against background levels of intrinsic heterogeneity between cells. Variations in cell-substrate adhesion strengths can be probed through biophysical measurements of cell detachment from substrates upon the application of an external force. Here, we investigate, theoretically and experimentally, the detachment of cells adhered to substrates when these cells are subjected to fluid shear. We present a theoretical framework within which we calculate the fraction of detached cells as a function of shear stress for fast ramps as well as the decay in this fraction at fixed shear stress as a function of time. Using HEK and 3T3 fibroblast cells as experimental model systems, we extract characteristic force scales for cell adhesion as well as characteristic detachment times. We estimate force-scales of ~500 pN associated to a single focal contact, and characteristic time-scales of [Formula: see text] s representing cell-spread-area dependent mean first passage times to the detached state at intermediate values of the shear stress. Variations in adhesion across cell types are especially prominent when cell detachment is probed by applying a time-varying shear stress. These methods can be applied to characterizing changes in cell adhesion in a variety of contexts, including metastasis. PMID- 29629710 TI - Enhancement of resistive switching properties in Al2O3 bilayer-based atomic switches: multilevel resistive switching. AB - Atomic switches are considered to be building blocks for future non-volatile data storage and internet of things. However, obtaining device structures capable of ultrahigh density data storage, high endurance, and long data retention, and more importantly, understanding the switching mechanisms are still a challenge for atomic switches. Here, we achieved improved resistive switching performance in a bilayer structure containing aluminum oxide, with an oxygen-deficient oxide as the top switching layer and stoichiometric oxide as the bottom switching layer, using atomic layer deposition. This bilayer device showed a high on/off ratio (105) with better endurance (~2000 cycles) and longer data retention (104 s) than single-oxide layers. In addition, depending on the compliance current, the bilayer device could be operated in four different resistance states. Furthermore, the depth profiles of the hourglass-shaped conductive filament of the bilayer device was observed by conductive atomic force microscopy. PMID- 29629711 TI - Man-made flows from a fish's perspective: autonomous classification of turbulent fishway flows with field data collected using an artificial lateral line. AB - The lateral line system provides fish with advanced mechanoreception over a wide range of flow conditions. Inspired by the abilities of their biological counterparts, artificial lateral lines have been developed and tested exclusively under laboratory settings. Motivated by the lack of flow measurements taken in the field which consider fluid-body interactions, we built a fish-shaped lateral line probe. The device is outfitted with 11 high-speed (2.5 kHz) time synchronized pressure transducers, and designed to capture and classify flows in fish passage structures. A total of 252 field measurements, each with a sample size of 132 000 discrete sensor readings were recorded in the slots and across the pools of vertical slot fishways. These data were used to estimate the time averaged flow velocity (R2 = 0.952), which represents the most common metric to assess fishway flows. The significant contribution of this work is the creation and application of hydrodynamic signatures generated by the spatial distribution of pressure fluctuations on the fish-shaped body. The signatures are based on the collection of the pressure fluctuations' probability distributions, and it is shown that they can be used to automatically classify distinct flow regions within the pools of three different vertical slot fishways. For the first time, field data from operational fishway measurements are sampled and classified using an artificial lateral line, providing a completely new source of bioinspired flow information. PMID- 29629713 TI - Immunometabolism: Itaconate helps KEAP1's cool. PMID- 29629712 TI - L-Theanine Protects H9C2 Cells from Hydrogen Peroxide-Induced Apoptosis by Enhancing Antioxidant Capability. AB - BACKGROUND L-theanine is a non-protein amino acid in green tea, and its hepatoprotection and neuroprotection have been verified. However, whether L theanine can prevent cardiomyocytes from apoptosis is unclear yet. This study evaluated the protective effects of L-theanine on H2O2-induced heart injury in vitro. MATERIAL AND METHODS The certified H9C2 cells were pretreated with L theanine (0 mM, 4 mM, 8 mM, and 16 mM) for 24 h, followed by 160 uM H2O2 solution for 4 h. The cell viability and antioxidant indices were assayed. Quantitative evaluation of apoptosis was performed by flow cytometric analysis. Nuclear morphology of the cells was monitored by 4',6-diamidino-2-phenylindole staining. Expression of Caspase-3, poly ADP-ribose polymerase (PARP), c-Jun N-terminal kinase (JNK), and mitogen-activated protein kinase p38 was assayed by Western blot. RESULTS Compared to the H2O2 treatment, all doses of L-theanine treatments increased the cell viability, glutathione level, and the activities of glutathione peroxidase and superoxide dismutase (P<0.001). The contents of reactive oxygen species, nitric oxide, and oxidized glutathione were decreased by L-theanine treatments (P<0.001). Meanwhile, L-theanine treatments decreased the apoptosis ratio of H2O2-induced H9C2 cells (P<0.001). Pro-Caspase-3 expression was upregulated and cleavaged-PARP expression was inhibited by L-theanine (P<0.001). However, the phosphorylation of JNK and p38 was not affected by L theanine treatments (P>0.05). CONCLUSIONS These data indicate that L-theanine pretreatment prevents H2O2-induced apoptosis in H9C2 cells, probably via antioxidant capacity improvement. Therefore, it might be a promising potential drug candidate for prophylaxis of ischemia/reperfusion-induced heart diseases. PMID- 29629714 TI - Discovering transcriptional signatures of disease for diagnosis versus mechanism. PMID- 29629715 TI - Genetics: An integrated genetic analysis of disease. PMID- 29629716 TI - Radiosynthesis of the anticancer nucleoside analogue Trifluridine using an automated 18F-trifluoromethylation procedure. AB - Trifluoromethyl groups are widespread in medicinal chemistry, yet there are limited 18F-radiochemistry techniques available for the production of the complementary PET agents. Herein, we report the first radiosynthesis of the anticancer nucleoside analogue trifluridine, using a fully automated, clinically applicable 18F-trifluoromethylation procedure. [18F]Trifluridine was obtained after two synthetic steps in <2 hours. The isolated radiochemical yield was 3% +/ 0.44 (n = 5), with a radiochemical purity >99%, and a molar activity of 0.4 GBq MUmol-1 +/- 0.05. Biodistribution and PET-imaging data using HCT116 tumour bearing mice showed a 2.5 %ID g-1 tumour uptake of [18F]trifluridine at 60 minutes post-injection, with bone uptake becoming a prominent feature thereafter. In vivo metabolite analysis of selected tissues revealed the presence of the original radiolabelled nucleoside analogue, together with deglycosylated and phosphorylated [18F]trifluridine as the main metabolites. Our findings suggest a potential role for [18F]trifluridine as a PET radiotracer for elucidation of drug mechanism of action. PMID- 29629717 TI - Helical nanoparticle-induced enantiospecific adsorption of N3 dyes. AB - It is of fundamental demand for heterogeneous asymmetric catalysis on generating intrinsically chiral metal catalysts without modification of chiral ligands on which molecular substrates can be enantiospecifically adsorbed, which is lack of investigation. Herein, we demonstrate that the anchoring of N3 dyes on plasmonic helical nanoparticles (PhNPs) made of silver through the formation of NCS-Ag contacts leads to enantiospecific adsorption of N3 dyes. The enantiospecific configuration of the immobilized N3 dyes is primarily determined by the helical handedness, and the maximization of the adsorption enantiospecificity occurs at a nominal helical pitch of ~15 nm, probably ascribed to the formation of supramolecular chiral complexes and/or the helical handedness-induced break of mirror symmetry of adsorption configuration. This study may pave the way for developing of PhNPs to function as intrinsically chiral catalysts and devising an alternative method to operate heterogeneous asymmetric catalysis with high enantioselectivity, which is practically desired for the manufacture of prominent single-enantiomer chemicals. PMID- 29629718 TI - Nitroxide-nitroxide and nitroxide-metal distance measurements in transition metal complexes with two or three paramagnetic centres give access to thermodynamic and kinetic stabilities. AB - Fundamentally, the stability of coordination complexes and of templated (bio)macromolecular assemblies depends on the thermodynamic and kinetic properties of the intermediates and final complexes formed. Here, we used pulse EPR (electron paramagnetic resonance) spectroscopy to determine the stabilities of nanoscopic assemblies formed between one or two nitroxide spin-labelled tridentate 2,2':6',2''-terpyridine (tpy) ligands and divalent metal ions (FeII, ZnII, CoII and CuII). In three distinct approaches we exploited (a) the modulation depth of pulsed electron-electron double resonance (PELDOR) experiments in samples with increasing metal-to-ligand ratios, (b) the frequencies of PELDOR under broadband excitation using shaped pulses and (c) the distances recovered from well-resolved PELDOR data in fully deuterated solvents measured at 34 GHz. The results demonstrate that PELDOR is highly sensitive to resolving the stability of templated dimers and allows to readily distinguish anti-cooperative binding (for CuII ions) from cooperative binding (for CoII or FeII ions). In the case of paramagnetic ions (CoII and CuII) the use of broadband PELDOR allowed to identify the cooperativity of binding from the time domain and distance data. By using a second labelled tpy ligand and by mixing two homoleptic complexes of the same metal centre we could probe the kinetic stability on a timescale of tens of seconds. Here, tpy complexes of CuII and ZnII were found to be substitutionally labile, CoII showed very slow exchange and FeII was inert under our conditions. Not only do our chemical models allow studying metal-ligand interactions via PELDOR spectroscopy, the design of our study is directly transferable to (bio)macromolecular systems for determining the kinetic and thermodynamic stabilities underpinning (templated) multimerisation. Considering the limited methods available to obtain direct information on the composition and stability of complex assemblies we believe our approach to be a valuable addition to the armoury of methods currently used to study these systems. PMID- 29629719 TI - A rapid and concise setup for the fast screening of FRET pairs using bioorthogonalized fluorescent dyes. AB - One of the most popular means to follow interactions between bio(macro)molecules is Forster resonance energy transfer (FRET). There is large interest in widening the selection of fluorescent FRET pairs especially in the region of the red/far red range, where minimal autofluorescence is encountered. A set of bioorthogonally applicable fluorescent dyes, synthesized recently in our lab, were paired (Cy3T/Cy5T; Cy1A/Cy3T and Cy1A/CBRD1A) based on their spectral characteristics in order to test their potential in FRET applications. For fast elaboration of the selected pairs we have created a bioorthogonalized platform based on complementary 17-mer DNA oligomers. The cyclooctynylated strands were modified nearly quantitatively with the fluorophores via bioorthogonal chemistry steps, using azide- (Cy1; CBRD1) or tetrazine-modified (Cy3; Cy5) dyes. Reactions were followed by capillary electrophoresis using a method specifically developed for this project. FRET efficiencies of the fluorescent dye pairs were compared both in close proximity (5' and 3' matched) and at larger distance (5' and 5' matched). The specificity of FRET signals was further elaborated by denaturation and competition studies. Cy1A/Cy3T and Cy1A/CBRD1A introduced here as novel FRET pairs are highly recommended for FRET applications based on the significant changes in fluorescence intensities of the donor and acceptor peaks. Application of one of the FRET pairs was demonstrated in live cells, transfected with labeled oligos. Furthermore, the concise installation of the dyes allows for efficient fluorescence modification of any selected DNA strands as was demonstrated in the construction of Cy3T labeled oligomers, which were used in the FISH-based detection of Helicobacter pylori. PMID- 29629720 TI - Structural transformation of h-BN overlayers on Pt(111) in oxidative atmospheres. AB - Interaction of hexagonal boron nitride (h-BN) with gases is of great importance for its properties and applications. In the present work, the structural changes of h-BN overlayers on Pt(111) in oxidative atmospheres including O2 and NO2 have been investigated by using low energy electron microscopy, Auger electron spectroscopy, X-ray photoelectron spectroscopy (XPS), and near ambient pressure XPS. We find that h-BN islands can be intercalated by oxygen in 10-6 Torr O2 at 200 degrees C, while oxygen intercalation of full layer h-BN around 200 degrees C requires near ambient pressure O2 (0.1 Torr) or such a strong oxidant as NO2 (10-6 Torr). h-BN overlayers can be etched away in the gases at much high temperatures, e.g. 800 degrees C. Upon mild oxidation in O2 or NO2 at temperatures of 400-450 degrees C, h-BN is transformed to boron oxide (BOx) overlayers, which can be converted back to h-BN by heating in NH3 at 800 degrees C. PMID- 29629721 TI - Crystallization characteristic and scaling behavior of germanium antimony thin films for phase change memory. AB - Amorphous Ge8Sb92 thin films with various thicknesses were deposited by magnetron sputtering. The crystallization kinetics and optical properties of the Ge8Sb92 thin films and related scaling effects were investigated by an in situ thermally induced method and an optical technique. With a decrease in film thickness, the crystallization temperature, crystallization activation energy and data retention ability increased significantly. The changed crystallization behavior may be ascribed to the smaller grain size and larger surface-to-volume ratio as the film thickness decreased. Regardless of whether the state was amorphous or crystalline, the film resistance increased remarkably as the film thickness decreased to 3 nm. The optical band gap calculated from the reflection spectra increases distinctly with a reduction in film thickness. X-ray diffraction patterns confirm that the scaling of the Ge8Sb92 thin film can inhibit the crystallization process and reduce the grain size. The values of exponent indices that were obtained indicate that the crystallization mechanism experiences a series of changes with scaling of the film thickness. The crystallization time was estimated to determine the scaling effect on the phase change speed. The scaling effect on the electrical switching performance of a phase change memory cell was also determined. The current-voltage and resistance-voltage characteristics indicate that phase change memory cells based on a thinner Ge8Sb92 film will exhibit a higher threshold voltage, lower RESET operational voltage and greater pulse width, which implies higher thermal stability, lower power consumption and relatively lower switching velocity. PMID- 29629722 TI - The effect of Lactobacillus acidophilus and Lactobacillus casei on the in vitro bioaccessibility of flaxseed lignans (Linum usitatissimum L.). AB - Secoisolariciresinol (SECO) is present in flaxseeds as a glucoside, secoisolariciresinol diglucoside (SDG), which can be metabolized to enterodiol (ED) and enterolactone (EL) by the human intestinal microbiota. The aim of this study was to evaluate the effect of Lactobacillus casei and Lactobacillus acidophilus on the bioaccessibility of flaxseed lignans from a complete in vitro digestion of whole flaxseeds (WFs) and flaxseed flour (FF). Lignans are only detected in the large intestine. The bioaccessibility of SDG for FF digestion can be ordered as follows: control (without probiotics) > L. casei > L. acidophilus; and for WF digestion, only in the presence of L. casei SDG was detected. For SECO and EL, the presence of both probiotics had no effect on FF and WF digestion. However, in the digestion of WF both L. casei and L. acidophilus increased ED bioaccessibility in the first 12 h; but both probiotics had no significant effect on FF digestion. PMID- 29629723 TI - Comparison Between the Pouch-Perineum Distance in Neonates With a Low-Type Anorectal Malformation With and Without an Opened Fistula: Pitfall of Measuring the Pouch-Perineum Distance on Sonography. AB - OBJECTIVE: An anorectal malformation (ARM) in neonates requires urgent surgery, with the type of surgery being dependent on the type of malformation (low, intermediate, or high). Distal rectal pouch and perineum (pouch-perineum) distance is reported to be useful for differentiating the type of ARM; however, the impact of an opened fistula on pouch-perineum distance is not well known. The purpose of this study was to evaluate the difference in pouch-perineum distance between neonates with a low-type ARM with and without an opened fistula. METHODS: We included 24 neonates with low-type ARM who underwent sonography before surgery. Eight neonates already had an opened fistula before sonography, and 16 did not. The pouch-perineum distance was measured using the perineal approach. Mann-Whitney U and Spearman's correlation coefficient tests were used for statistical analysis. RESULTS: The mean pouch-perineum distance in all neonates with a low-type ARM was 8.3 +/- 2.9 mm. The pouch-perineum distance was substantially longer for an ARM with than without an opened fistula (10.6 +/- 3.4 mm vs. 7.1 +/- 1.7 mm; P = .02). No appreciable correlation was identified between the pouch-perineum distance and the postnatal day of examination (rho = .23, P = .26) or birth weight (rho = .15, P = .47). CONCLUSION: The pouch perineum distance is substantially longer in neonates with an ARM with an opened fistula than in those without an opened fistula. Caution should be exercised by the sonographic examiner in evaluating pouch-perineum distance in neonates with an opened fistula to prevent an incorrect surgical procedure based on misdiagnosis of the type of ARM. PMID- 29629724 TI - Born in Auschwitz and Survived: A Triumph Over Murderers. AB - BACKGROUND: The discovery of Jewish babies who were born in Nazi concentration camps and survived seems miraculous, but this phenomenon did occur toward the end of World War II. The lives of a small group of mothers and surviving children are of both historical and medical interests. Their survival shows additional support for the hypothesis that maternal nutrition can induce metabolic syndrome and bone demineralization in their offspring. Information obtained through direct contact with some of the surviving children is the basis for this article. PMID- 29629725 TI - Aging of Holocaust Survivors: Discrepancies Between Subjective and General Health in the greater Tel Aviv Area. AB - BACKGROUND: Aging has been associated with perceived lowering of health, especially in post-traumatic individuals. The effects may be more complex or even different for Holocaust survivors as they age due to their inherited resilience and life perspective. A cross-sectional study was conducted of Holocaust survivors and a matched comparison group recruited from the general Israeli population. All participants underwent a personal interview and completed the Cumulative Illness Rating Scale and a survey of subjective Likert-scale questions about perceived health. The study comprised 214 older adults: 107 Holocaust survivors and 107 comparison participants; 101 women and 113 men. The mean age for the participants was 80.7 +/- 4.7 years (range 68-93). Holocaust survivors did not differ from comparison subjects in general health measures (mean 51.50 +/ 3.06 vs. 52.27 +/- 3.24, respectively). However, the Holocaust survivors' subjective health was significantly lower, F (2,211) = 4.18, P < 0.05, and associated with decreased quality of life. The present study demonstrates the complex interplay between general and subjective health and suggests that future interventions need to focus on improving the psychological and social well-being of Holocaust survivors to achieve successful aging. PMID- 29629726 TI - The Significance of Routine Computer Tomography in Evaluation of Asymptomatic Postoperative War Trauma Patients Transferred from Syria for Further Treatment. PMID- 29629727 TI - The Association of an Elevated Thrombocyte Count with Clinicopathological Prognostic Factors and Survival in Patients with Uterine Carcinosarcoma. AB - BACKGROUND: Uterine carcinosarcoma (UCS) is a rare tumor with a poor prognosis. An elevated thrombocyte count and thrombocytosis were found to be associated with poor prognosis in several gynecological tumors. Data regarding an elevated thrombocyte count and thrombocytosis, particularly in UCS, are scarce. OBJECTIVES: To assess the frequency of a preoperative elevated thrombocyte count and of thrombocytosis in UCS patients and their association with clinicopathological prognostic factors and survival. METHODS: The preoperative thrombocyte count of 29 consecutive verified USC patients diagnosed in our medical center from January 2000 to July 2015 was recorded, and clinicopathological data of these patients were abstracted from hospital files. RESULTS: Thrombocytosis was found in two patients (6.8 %) and both died of the disease. An elevated thrombocyte count was found in nine patients (31.0%). The percentage of patients with the poor prognostic factors who had a preoperative elevated thrombocyte count was not statistically different from those without these risk factors. The cumulative survival of patients with an elevated count was 22.1 months and that of those without an elevated count was 31.1 months. This difference was statistically not significant (P = 0.85). There was also no difference between the groups regarding the progression free survival. CONCLUSIONS: No association between an elevated thrombocyte count and prognosis was found. Larger studies are needed to clarify this issue. PMID- 29629728 TI - The Impact of Drug Metabolism Gene Polymorphisms on Therapeutic Response and Survival in Diffuse Large B-Cell Lymphoma Patients. AB - BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) accounts for 30% of all non Hodgkin lymphomas (NHL) and 80% of agressive lymphomas. Besides the traditional International Prognostic Index (IPI), some other factors may also influence the prognosis of DLBCL patients. OBJECTIVES: To study how the genetic polymorphisms in the metabolic pathway influence the event-free and overall survivals and therapeutic responses in DLBCL. METHODS: The study was comprised of 51 patients (32 men, 19 women). The average age was 53.1 years. DLBCL was diagnosed between 2011 and 2016 and the average follow-up time was 3.78 years. These patients received 1-8 cycles (an average of 6.2 cycles) of rituximab, cyclophosphamide, doxorubicin, vincristin, prednisolon (R-CHOP) immunochemotherapy. Real-time polymerase chain reaction was used to determine the genetic polymorphisms of CYP2E1, GSTP1, NAT1, and NAT2 genes. RESULTS: Our results showed that the polymorphisms of CYP2E1, GSTP1, and NAT1 genes did not influence the prognosis of DLBCL patients significantly. In terms of the NAT2 gene, GG homozygous patients showed slightly better therapeutic response and survival results compared to those bearing an A allele; however, the differences were not statistically significant. CONCLUSIONS: Our results could not confirm that genetic polymorphism in metabolic pathways has any predictive role in DLBCL. PMID- 29629729 TI - Depression Among Older Adults with Diabetes in Israel: Pattern of Symptoms and Risk Factors. PMID- 29629730 TI - Icatibant Outcome Survey in Patients with Hereditary Angioedema: Experience in Israel Compared with Other Countries. AB - BACKGROUND: Management of patients with hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) is evolving worldwide. Evaluating the Israeli experience may provide valuable insights. OBJECTIVES: To compare demographics and icatibant treatment patterns and outcomes in patients with C1-INH-HAE enrolled in the Icatibant Outcome Survey (IOS) in Israel with those in other countries. METHODS: The IOS is an ongoing observational study that prospectively monitors real-world icatibant safety/tolerability and treatment outcomes. RESULTS: By July 2016, 58 patients from Israel and 594 patients from other countries were enrolled. Median age at diagnosis (16.7 vs. 21.3 years, P = 0.036) and median delay between symptom onset and diagnosis (0.8 vs. 6.6 years, P = 0.025) were lower in Israel compared with other countries, respectively. Differences in attack severity were not significant (P = 0.156); however, during follow-up, Israeli patients were less likely to miss > 7 days of work/school due to C1-INH-HAE-related complications (P = 0.007). A trend was also shown in Israel for earlier time to treatment (median 0.5 vs. 1.3 hours, P = 0.076), attack duration was shorter (median 5.0 vs. 9.0 hours, P = 0.026), and patients more often self-administered icatibant (97.2% vs. 87.5%, P = 0.003), respectively. However, Israeli patients were less likely to treat attacks (P = 0.036). Whereas patients in Israel reported exclusive use of danazol for long-term prophylaxis, those in other countries used various agents, including C1-INH. CONCLUSIONS: Recognition of C1 INH-HAE and timeliness of icatibant treatment appear more favorable, and attack duration shorter, in Israel compared with other countries. PMID- 29629731 TI - The Effect of Mineralocorticoid Receptor Antagonists on Recruitment and Function of Endothelial Progenitor Cells in Patients with Congestive Heart Failure. AB - BACKGROUND: Circulating endothelial progenitor cells have an important role in the process of vascular repair. Impaired recruitment and function of endothelial progenitor cells is related to the pathophysiology of congestive heart failure. Endothelial progenitor cells have been shown to express the mineralocorticoid receptor. OBJECTIVES: To investigate the effect of mineralocorticoid receptor antagonists on endothelial progenitor cells in patients with heart failure. METHODS: Twenty-four patients with compensated heart failure, who were not under mineralocorticoid receptor antagonist therapy, were recruited. Either eplerenone (n=8) or spironolactone (n=16) therapy was initiated. Circulating endothelial progenitor cell level, identified as the proportion of mononuclear cells expressing vascular endothelial growth factor receptor 2 (VEGFR-2), CD133, and CD34, was evaluated by flow cytometry at baseline and after 8 weeks. Following 7 days of culture, colonies were counted by microscopy and MTT assay was performed on randomly selected patients (n=12) to estimate viability. RESULTS: Both median CD34+/VEGFR2+ and median CD133+/VEGFR2+ increased significantly (P = 0.04 and 0.02, respectively). However, the number of colonies and viability of the cells after therapy (as assessed by the MTT assay) was not significantly different compared with the baseline. CONCLUSIONS: These preliminary results suggest that mineralocorticoid receptor blockade may enhance endothelial progenitor cells recruitment in patients with compensated heart failure. PMID- 29629732 TI - Effect of Tocilizumab on Fatigue and Bone Mineral Density in Patients with Rheumatoid Arthritis. AB - BACKGROUND: Chronic fatigue is common among patients with rheumatoid arthritis (RA), affecting quality of life. Osteoporosis is a prevalent co-morbidity in RA patients. OBJECTIVES: To assess the effect of long-term treatment with tocilizumab on fatigue and bone mineral density (BMD) in RA patients with inadequate response to synthetic or biologic disease-modifying anti-rheumatic drugs. METHODS: In this multicenter, open-label, non-controlled, single-arm study, patients >= 18 years of age received intravenous tocilizumab 8 mg/kg every 4 weeks for 96 weeks. The primary outcome was the change in Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue score from baseline to weeks 24, 48, 72, and 96. BMD was assessed before and 96 weeks after treatment. RESULTS: The study comprised 145 patients (mean age 53.4 +/- 13.4 years, 83.4% women). Of these, 88 (60.7%) completed the 2 year treatment period. The mean FACIT-Fatigue score improved consistently starting from week 4 and showed a statistically significant increase of 5.0 +/- 9.7, 6.8 +/- 10.5, 7.3 +/- 10.9, and 7.3 +/- 10.4 from baseline to weeks 24, 48, 72, and 96, respectively (P < 0.0001). Mean BMD of femoral neck and total spine remained stable. Disease activity, acute phase reactants, and composite efficacy measures decreased during the study, while hemoglobin levels increased. Adverse events and serious adverse events were as expected for the known and previously described data. CONCLUSIONS: Tocilizumab therapy for 2 years significantly and clinically decreased fatigue. BMD remained stable and no new safety issue was reported. PMID- 29629733 TI - Exercise Hemodynamics for the Diagnosis of Diastolic Dysfunction in Dyspneic Patients with Systemic Sclerosis. AB - OBJECTIVES: To assess the added diagnostic value of using exercise hemodynamics during RHC in assessment of patients with symptomatic SSc. METHODS: We performed 22 RHCs in 17 SSc patients with dyspnea and/or pulmonary arterial hypertension (PAH). Exercise was performed in 15 RHCs using isotonic arm exercises while holding a 1 kg weight in each hand. Measurements of pulmonary arterial pressure (PAP), pulmonary arterial wedge pressure (PAWP), and cardiac output (CO) were taken at rest and during peak exercise. RESULTS: Normal resting RHC (PAP 22 ? 3 mmHg, PAWP 11 ? 3 mmHg) was found in seven cases. Of these, exercise induced elevation in PAP was found in three (38 ? 7 mmHg), and exercise induced elevation in PAWP was found in four (24 ? 6 mmHg). Elevated resting PAP was found in 15 (41 ? 11 mmHg) with minor changes in exercise. Of the 22 RHCs, elevation of the PAWP was found in 11 (50%), half of which were in response to exercise. CONCLUSIONS: In symptomatic SSc patients, exercise hemodynamics provides important information on diastolic dysfunction that is not available with non-invasive testing. Findings on exercise RHC can explain patient symptoms in up to 50% of cases. Earlier and more accurate diagnosis of patient symptoms can aid in tailoring the correct therapy for each. PMID- 29629734 TI - Changes of Sperm Parameters Along Time Among Groups of Different Qualities. AB - BACKGROUND: Male infertility is solely responsible for approximately 20% of all infertility in couples. Various factors have been proposed as having a negative effect on sperm quality; however, the reasons for the global decline in sperm parameters during the last few decades are still controversial. OBJECTIVES: To investigate the fluctuations of semen parameters (sperm concentration, motility, and morphology) in three sperm quality groups and to examine the trends of those parameters in the same men over time. RESULTS: Our data showed deterioration in all semen parameters assessed in the group of men originally considered as having normal semen values according to the 2010 criteria of the World Health Organization. In contrast, we found significant improvement over time in all semen parameters in the group of men with severe oligo-terato-asthenozoospermia. CONCLUSIONS: Our results suggest that, although there were changes in sperm quality over time in the groups assessed, the clinical significance is negligible and does not necessarily justify a change in the therapeutic approach to infertility or sperm cryopreservation. PMID- 29629735 TI - The Task Force for the Promotion of the Status of Women in Medicine in Israel. AB - BACKGROUND: In this article, we offer a brief summary of the report from the Task Force for the Promotion of the Status of Women in Medicine in Israel. The task force, formed by the Israel Medical Association in 2013, published a comprehensive report in May 2015 dedicated to the promotion of equal opportunities for female doctors in the Israeli healthcare system and in the academic world. The aim of this paper is to present the work of the task force and to highlight its main principles and recommendations against the backdrop of the gender revolution in the Israeli healthcare system and worldwide. PMID- 29629736 TI - Degenerative Osteoarthritis with Multiple Joint Arthroplasties Due to Alkaptonuria, a Rare Inborn Error of Tyrosine Metabolism. PMID- 29629737 TI - Self-limited Rheumatoid Meningitis as a Presenting Symptom of Rheumatoid Arthritis. PMID- 29629738 TI - Impact of body weight on clinical symptoms and endoscopic changes in patients with gastroesophageal reflux disease. AB - Introduction: Gastroesophagealreflux disease (GERD) is connectedwith body mass index (BMI) accordingto some recent studies. However, thelink between overweight and severityof GERD symptoms is still unclear. Objectives: The aim of our studyis to assess the influence of BMI onclinical presentation and occurrenceof inflammatory changes in the esophagusin patients with GERD. Material and Methods: 121 clinicallydiagnosed GERD patients: 66 males(54.5%) and 55 females (45.5%), aged19 - 89 years were involved in thestudy. After the detailed anamnesisBMI was counted and gastroscopywas performed. All individuals whoagreed for upper endoscopy weredivided into three groups. 42 patients(34.7%) were classified as Non-ErosiveReflux Disease (NERD), 53 patients(43.8%) were diagnosed with ErosiveEsophagitis (EE), 11 patients (9.1%)with Barrett's esophagus (BE). AmongEE group 34 patients were diagnosedwith grade A of esophagitis accordingto Los Angeles scale, 17 with grade B,2 with grade C and none with grade D.The differences between groups wereassessed using statistical analysis. Results: The mean age of patientswas 50.2+/-12.9 years and the meanBMI was 25.5+/-4.2 kg/m2. Patients withBE were older (61.2+/-12.0 years) thanNERD (48.5+/-13.6 years); (p=0.028) andEE (50.4+/-11.4 years); (p=0.008). BE hadhigher BMI (27.0+/-4.4 kg/m2) as comparedto NERD (24.0+/-3.3 kg/m2); (p=0.022)and EE (24.4+/-3.1 kg/m2); (p=0.048). Hiatalhernia was more frequent in EE andBE (79.2% and 90.9%, respectively) ascompared to NERD (45.2%); (p<0.001).Patients EE and BE more frequentlycomplained to heartburn (84.9% and72.7%, respectively) than patients withno mucosal injury (42.9%); (p<0.001).Sleeping problems were encounteredby patients with higher levels of BMI. Conclusion: This study demonstratesthat overweight predispose toesophageal inflammation and increasethe frequency of heartburn and sleepproblems in GERD patients. PMID- 29629739 TI - The quality of life with regard to the sexual sphere and acceptance of the disease in young adults suffering from multiple sclerosis. AB - Introduction: Multiple sclerosisas a disease of various dynamic andunpredictable consequences at differentperiods of the disease can lead toquality of life reduction. Oneof the guarantors for maintaininga good quality of life is accepting thedisease.The aim of the study was to evaluatethe quality of life, taking into accountthe sexual sphere and acceptanceof the disease among young adultswith multiple sclerosis. Material and methods: The studyincluded 120 people of both sexes,aged from 18 to 35 years of age sufferingfrom multiple sclerosis duringremission, independent in everydayactivities or requiring a minimum ofhelp. The study used a questionnaireMSQOL-54 instrument and the AISscale. The statistical analysis usedthe following: Kruskal-Wallis test,Mann-Whitney test, Chi2, Spearmancoefficient. Program Statistica 7.1 wasalso used. The level of significancewas p <0.05. Results: The overall quality of lifeincreases with the acceptance of thedisease (Spearmanr-0.364; p=0.000). It has been demonstratedthe existence of significantstatistical positive correlation betweensatisfaction with the sexual sphere andacceptance of the disease (Spearman'sr 0.271; p=0.005) and satisfaction withthe sexual sphere and quality of life(Spearman's r 0.467; p=0.000). Conclusion: The factor determiningthe quality of life of patients withMS is the acceptance of the disease.Satisfaction with sexual life is a significantfactor in assessing the qualityof life by patients and the acceptanceof their illness. PMID- 29629740 TI - Vascular effects of simvastatin are similar to hormone replacement therapy in postmenopausal women. AB - Aim of the study: To compareeffect of six month transdermal 17beta-estradiol supplementation with oralmedroxyprogresterone acetate to oralsimvastatin treatment on nitric oxide(NO), endothelin-1, beta-thromboglobulin,vascular endothelial growth factor(VEGF) and von Willebrand factor(vWF) levels during standard exercisetest in post menopausal women. Patients and Methods: 32 womenwere included to the study. Group 1treated with 17beta-estradiol combinedwith medroxyprogesterone. Group 2treated with simvastatin, group 3 wasthe controls. VEGF plasma levels aswell as basal and standard exercisetest induced levels of vWF, NO, endothelin-1, beta-thromboglobulin were measuredat the beginning of the study, at3rd and 6th month of the study. Duringstandard exercise test these parameterswere measured three times: at thebeginning, at peak exercise and at the15th minute of recovery. Results: 17beta-estradiol supplementationand simvastatin treatmentreduced basal and exercise testinduced endothelin-1 plasma level.17beta-estradiol supplementation graduallyincreased NO release, whereassimvastatin initially reduced andfinally increased nitric oxide release.NO/ET-1 ratio was increased at peakexercise and recovery time in group1 whereas only at peak exercise ingroup 2. Basal VEGF plasma level andbeta thromboglobulin level at recoverytime were reduced after 6 month ofsimvastatin therapy. Conclusion: Six months long oralsimvastatin exerted beneficial influenceon endothelial function equalto that of continuous transdermal17beta estradiol supplementation combinedwith medroxyprogesteroneacetate. Simvastatin only exerted beneficaleffect on platelet function. Theprotective effect of both therapies wasmore pronounced during exercise andrecovery time. PMID- 29629741 TI - [Office and 24-hour ambulatory blood pressure measurements in hypertension assessment in children with chronic kidney disease]. AB - Introduction: Hypertension (HT) isone of the major risk factors of chronickidney disease (CKD) progression andcardiovascular complications.The aim of the study was to analyzeblood pressure (BP) values and assessthe usefulness of clinical measurementsin BP monitoring in childrenwith chronic kidney disease. Material and methods: The studywas conducted in 62 children (40boys and 22 girls) aged 4,2 18,6 years(median age 12.4 (9.1; 16.0) with CKDstages 1 + 2 (n = 9), 3 (n = 17), 4 (n = 15)and 5. Creatinine concentration wasmeasured and glomerular filtration ratewas calculated using the Schwartz formula.Each of the patients underwentclinical BP measurements and 24-hourambulatory blood pressure monitoring(ABPM). Results: Based on clinical meaurementselevated BP values were foundin 25 patients (40.3%): in stages 1 + 2in 33.3%, in stage 3 in 41.2%, in stage4 in 46.6% and in stage 5 in 38.1% patients.Hypertension was diagnosedwith ABPM in 30 patients (48.4% of thestudied population): in stages 1 + 2 - 3patients (33.3%), in stage 3 - 8 patients(47, 1%), in stage 4 - 7 patients (46.7%)and stage 5 - 12 patients (57.1%). Only12 patients (19.4%) had hypertensiondiagnosed in both clinical and ABPMmeasurements. White coat effectwas found in 13 children (21.0%) andmasked HT in 18 children (29.0%). In24-hour BP monitoring the highestvalues of systolic, diastolic and meanBP values were found in children withmasked HT. In children with maskedHT higher values of 24-hour systolic(120 vs. 105.5 mmHg, p<0.001) anddiastolic (75 vs. 65 mmHg, p<0.001)BP compared with clinical values weredetected. Children with masked HT hadsignificantly higher nighttime diastolicBP compared with children with HT(1.43 vs. 0.74 z-score, p<0.001). Conclusions: The large percentageof children with masked hypertensionis an indication for frequent ABPMmeasurements in children with chronickidney diseses. Office measurements are not sufficient todetect HT in children with CKD. The best diagnostic methodto confirm and monitor hypertension in patients with CKDis 24-hour ambulatory blood pressure monitoring. PMID- 29629742 TI - Morphology and Optical Properties of RF Sputtering Deposited Indium Nitride Layers Under Different N2/Ar Ratio. AB - InN thin films were prepared using reactive radio frequency sputtering on (111) Si substrates under different N2/Ar ratio. The surface morphology and optical properties of InN thin films were characterized by X-ray diffraction, atomic force microscopy, scanning electron microscope, energy dispersive spectrometer, and UV-visible-NIR spectrophotometer at room temperature. It was found that the growth rate and surface RMS roughness of InN layers all significantly decreased with the increasing of N2 content in the sputtering gas. All the InN films were wurtzite structure with the proportion of N2 increasing from 40% to 100% in the mixture gas. The highly c-axis orientation InN films could only be obtained in the composition ratios of N2 higher than 90%. The atomic percentage of N is much higher than that of In at high N2 content films, which mainly due to the chemical reaction on the surface of Si substrate. The apparent optical band gap energy is estimated at 1.83 eV. However, the InN absorption band tail is strongly influenced by the sputtering due to a change in the species of the plasma. PMID- 29629743 TI - [Effect of free fatty acids on CYP19A1 (aromatase) gene expression in human adipose tissue stromal vascular fraction cells]. AB - : Aromatase plays an important rolein the estrogen biosynthesis. Its gen(CYP19A1) is expressed in preadipocytes(stromal vascular fraction, SVF)of adipose tissue. Estrogens are foundto be protective for metabolism homeostasis,and cardiovascular system.Disturbed dietary and endogenousfatty acids (FAs) turnover is responsiblefor development of metabolicsyndrome and it complications.Aim of the work was to investigatethe effect of physiological concentrationsof acids: arachidonic (AA), oleic(OA), palmitynoic (PA) and eikozapentaenoic(EPA) on CYP19A1 expressionin differentiating human SVF, able toform adipocytes as well as endothelialcells. Material and Methods: Human (n=38 healthy woman) SVF cells wereisolated from subcutaneous adiposetissue harvested intrasurgery. SVFcells were incubated in proadipogenicor angiogenic media to obtainadipocytes (Adipo SVF) or endothelial(Angio-SVF) cells (confirmed bymicroarray). Changes in the CYP19A1expression induced by 24hs incubationin the presence of FAs (10 - 30MUM )were monitored by the Real timePCR (qRT -PCR). Results: The aromatase gene expressioncorrelated positively withBMI of patients, but only in groupof obese or overweight women. Thenegative correlation was found inthe group of young, slim women. Thehighest expression of aromatase wasfound in the fresh, not differentiatedSVF. In differentiating to endothelialcells (Angio - SVF) OA inhibited(p=0.008), when n-3 polyunsaturatedAA activated (p=0.003) the CYP19A1gene expression. In differentiating topreadipocytes (Adipo-SVF) AA significantly(p=0.031) inhibited CYP19A1expression. Conclusion: The changes in thearomatase gene expression in differentiatingSVF has been confirmed. Thedifferent effect of the dietary FA (OA vs.AA) on the aromatase gene expression argue for the roleof the locally formed proangiogenic estrogens. PMID- 29629744 TI - Diketopyrrolopyrrole-Based Metallated Polymer for Bulk-Heterojunction Solar Cells and Organic Field-Effect Transistors. AB - We report the synthesis and optoelectronic properties of novel platinum-based polymers (p-Pt-DPP) incorporating 3,6-di-2-thienyl-2,5-dihydro-2,5 diethylhexylpyrrolo[3,4-c]pyrrole-1,4-dione. The synthesized amorphous metallated polymer exhibited long wavelength absorption in the range of 500-684 nm and a band-gap as low as 1.75 eV. Organic field-effect transistors (OFETs) fabricated from p-Pt-DPP showed hole mobility of 1.6 * 10-3 cm2 . V-1s-1 and an on/off ratio of 5 * 104. In addition, polymer solar cells (PSCs) based on p-Pt-DPP and PC71BM exhibited a photovoltaic efficiency of 1.22% under AM 1.5 G conditions with an illumination of 100 mW.cm-2 without any annealing process. PMID- 29629745 TI - [Could the cytokines concentration be a marker of IBD activity and be useful in evaluation of IBD differentiation?] AB - Background: In inflammatory boweldisease (IBD) the imbalance betweencytokines pro and antinflammatory isobserved.The aim of this study was the assessmentof interleukin-10 (IL-10),interleukin-6 (IL-6) and tumor necrosisfactor-alpha (TNF alpha) concentration usefulnessin the evaluation of the activityof ulcerative colitis (UC) and Cohn'sdisease (CD). Methods: 35 patients diagnosedwith UC and 39 with CD were examined.The control group (CG) consistedof 35 healthy volunteers. Diagnosis ofthe disease was confirmed by videocolonoscopyand histopathologicalevaluation of intestinal biopsies.Disease activity of UC was assessedaccording to the Mayo Scoring Systemand by the Crohn Disease Activiti Index(CDAI) in CD patients. Among patientswith UC 18 (51%) had severe, 14 (40%)moderate and 3 (9%) mild disease.Among patients with CD 7 (18%) wasdiagnosed with high, 27 (69%) moderate,and 5 (13%) with low activity ofthe disease. WBC, PLT, serum concentrationof TNF-alpha, IL-6 i IL-10 weredetermined. Results: The average concentrationof TNF-alpha in UC patients was: 14.3(IQR=12.6), in CD: 12.6 (IQR=11.9), inthe CG: 3.1 (IQR=1.7). The averageconcentration of IL-6 in UC was: 19.6(IQR=21), in CD: 10.8 (IQR=7.6), in CG: 3.2 (IQR=1.6). The average concentrationof IL-10 in UC was: 14.4 (IQR=5.9),in CD: 10.4 (IQR=9.3), in the CG: 3.3(IQR=2.5). In the IBD TNF-alpha, IL-6 andIL-10 concentration was significantlyhigher than in CG. However, IL-10 wassignificantly higher in UC than CD. Inpatients with UC statistically significantpositive correlation between theconcentration of TNF-alpha, IL-6 and IL-10and disease activity was noticed. Therewere no correlation between TNF-alpha,IL-6 and IL-10 concentration and CDactivity. Conclusion: Determination ofTNF-alpha, IL-6 and IL-10 serum concentrationcan be used for noninvasiveevaluation of inflammation activity inpatients with IBD. IL-10 concentrationmay be helpful in differentiation of UC and CD. PMID- 29629746 TI - [Psychological health's predictors of patients after bone marrow transplantation (BMT) 40 years of psychological researches of patients with blood cancers]. AB - A study on the psychologicalhealth's predictors of patents afterBMT is presented. The theoreticalbase of researches is Helena Wrona-Polanska's Functional Model of Health(FMH Wrona-Polanska 2003), in whichhealth is a function of creative copingwith stress. 110 patients after BMT - 64males and 46 females - at the HematologyClinic of Jagiellonian Universityof Collegium Medicum, were studiedclinically. Examined methods were thequestionnaires: Spielberger's STAI,Endler's, Parker's CISS and CHIP,Antonovsky's SOC-29, Rosenberg'sself-esteem scale, 10-point ratingscales: of sense of health, sense ofcalm and sense of anxiety. Objectivehealth was examined by physicianon the 10-point rating scale. Clusteranalysis to show psychologicalhealth's predictors of patients afterBMT: level of stress, styles and effectivecoping strategies with stress,personal resources, temporal factorsince transplantation and gender. Thepsychological predictors of healthare the base of health promotion ofpatients after BMT. PMID- 29629747 TI - Electrochemical Deposition of CuSCN Nanorod Arrays by Using EDTA as Chelating Agent. AB - In this study we report on the electrodeposition of copper thiocynate (CuSCN) nanorod arrays on ITO substrate from an EDTA-chelated aqueous solution. Effects of molecule ratio of EDTA/Cu2+ and deposition time on the properties of CuSCN layers were studied. Results showed that films deposited from an electrolyte with low EDTA amounts were consisted of densely packed nano-crystals, while films deposited with high molecule ratios of EDTA/Cu2+ (>0.5) were composed of homogeneous nanorods with their (001) plane perpendicular to the substrate. Further time-dependent study showed that the formation of CuSCN nanorods was initiated at the very beginning of potential application and no intermediate or transitional products were detected during the electrochemical process. Optical analysis showed that films of CuSCN nanorods with a thickness of 100-400 nm had good optical quality, and exhibited the fundamental absorption edge at 320 nm. PMID- 29629748 TI - [The prevalence of chronic kidney disease among patients of the Emergency Department of the Regional Hospital in Kielce]. AB - The prevalence of chronic kidneydisease (CKD) in the world is constantlyincreasing. This is related tothe eldering of the societies, growingnumbers of patients with diabetes,hypertension, atherosclerosis andobesity. The progress of the diseaseincreases the risk of complications andmortality, especially from cardiovascularcauses and leads to end-stage renaldisease requiring renal replacementtherapy. The analysis involving 1452patients (762 women and 690 menaged 57.4 years +/- 19.8 years) fromthe Emergency Department in Kielcerevealed reduced eGFR below 60 ml/min/1,73 m2 in 474 (32.6%) of participantsand mean values of eGFR was68.6 +/- 22.3 ml/min/1.73 m2. Such highpercentage of patients fulfilling criteriaof CKD may be due to the fact that tothe Emergency Department comingpatients with high comorbidity andwith increased risk of kidney disease. PMID- 29629749 TI - Crystal Structure, Magnetic and Optical Properties of Mn-Doped BiFeO3 by Hydrothermal Synthesis. AB - In this paper, Mn doped BiFeO3 were firstly synthesized by hydrothermal process. The influence of Mn doping on structural, optical and magnetic properties of BiFeO3 was studied. The different amounts of Mn doping in BiFeO3 were characterized by X-ray diffraction, Scanning Electron Microscope, Energy Dispersive X-ray Spectroscope, UV-Vis diffuse reflectance spectroscopy and magnetic measurements. The X-ray diffraction (XRD) patterns confirmed the formation of pure phase rhombohedral structure in BiFe(1-x) Mn (x) O3 (x = 0.01, 0.03, 0.05, 0.07) samples. The morphologies and chemical compositions of as prepared samples could be observed by Scanning Electron Microscope (SEM) and Energy Dispersive X-ray Spectroscope (EDS). A relative large saturated magnetization (Ms) of 0.53 emu/g for x = 0.07 sample was obtained at room temperature, which is considered to be Mn ions doping. UV-Vis diffuse reflectance spectroscopy showed strong absorption of light in the range of 200-1000 nm, indicating the optical band gap in the visible region for these samples. This implied that BiFe(1-x) Mn(x)O3 may be a potential photocatalyst for utilizing solar energy. PMID- 29629751 TI - Incorporation of Silicon-Oxygen Tetrahedron into Novel High-Nuclearity Nanosized 3d-4f Heterometallic Clusters. AB - By the anionic template strategy, we have, for the first time, succeeded in introducing SiO44- into 3d-4f huge clusters, obtaining two novel nanosized clusters with interesting nanosized cores of [Ln78Ni64(62)Si6] (1, Ln = Gd; 2, Ln = Eu). To the best of our knowledge, they are the largest heterometallic clusters incorporated with Si-O tetrahedra. In addition, compound 1 shows a maximum magnetic entropy (-Delta Sm) of 40.63 J kg-1 K-1 at 3.0 K at 7 T. PMID- 29629750 TI - [Analysis of lifestyle and risk factors of atherosclerosis in students of selected universities in Krakow]. AB - Introduction: Reduction of riskfactors of atherosclerosis, lifestylemodification significantly cause the reductionin the incidence, morbidity andmortality of cardiovascular diseases(CVDs). Objective: To evaluate cardiovascularrisk factors and analyze thelifestyle of students finishing the firstyear of studies at selected universitiesin Krakow. Material and Methods: The studywas performed in 2015roku. 566 studentsfinishing the first year of study,including 319 (56.4%) men and 247(43.6%) women were examined. Thestudents were in age from 18 to 27years, an average of 20.11+/- 1.15 years.They represented 6 different universitiesin Cracow. In order to assesseating habits, lifestyle and analysis ofrisk factors of cardiovascular diseasewas used method of diagnostic surveyusing the survey technique. BMIwas calculated from anthropometricmeasurements. The program Statistica12.0 were used in statistical analysis. Results: The analysis showed thatmost fruits and vegetables consumeUR students and AWF, least of AGH.Only 34.8% of students regularly consumefish of the sea, there were nosignificant differences between universities.Sports frequently cultivate thestudents of AWF (93% of the studentsof this university). Academy of FineArts students drink the most coffee.Students of AGH frequently consumealcohol. 60% of all students nevertried drugs, but only 25.7% of studentof Fine Arts never tried drugs. Overweightoccurs in 12.6% of students,and obesity in 1.1%. Conclusions: The most risk factors of atherosclerosisoccur in students of AGH and ASP.The results of the study clearly indicateon the necessity of implementation ofprevention and improvement of healthbehaviors in students of AGH and ASPuniversities. PMID- 29629753 TI - Analytical Pipeline for Discovery and Verification of Glycoproteins from Plasma Derived Extracellular Vesicles as Breast Cancer Biomarkers. AB - Glycoproteins comprise more than half of current FDA-approved protein cancer markers, but the development of new glycoproteins as disease biomarkers has been stagnant. Here we present a pipeline to develop glycoproteins from extracellular vesicles (EVs) through integrating quantitative glycoproteomics with a novel reverse phase glycoprotein array and then apply it to identify novel biomarkers for breast cancer. EV glycoproteomics show promise in circumventing the problems plaguing current serum/plasma glycoproteomics and allowed us to identify hundreds of glycoproteins that have not been identified in blood. We identified 1,453 unique glycopeptides representing 556 glycoproteins in EVs, among which 20 were verified significantly higher in individual breast cancer patients. We further applied a novel glyco-specific reverse phase protein array to quantify a subset of the candidates. Together, this study demonstrates the great potential of this integrated pipeline for biomarker discovery. PMID- 29629752 TI - Alkali Cation Effects on Redox-Active Formazanate Ligands in Iron Chemistry. AB - Noncovalent interactions of organic moieties with Lewis acidic alkali cations can greatly affect structure and reactivity. Herein, we describe the effects of interactions with alkali-metal cations within a series of reduced iron complexes bearing a redox-active formazanate ligand, in terms of structures, magnetism, spectroscopy, and reaction rates. In the absence of a crown ether to sequester the alkali cation, dimeric complexes are isolated wherein the formazanate has rearranged to form a five-membered metallacycle. The dissociation of these dimers is dependent on the binding mode and size of the alkali cation. In the dimers, the formazanate ligands are radical dianions, as shown by X-ray absorption spectroscopy, Mossbauer spectroscopy, and analysis of metrical parameters. These experimental measures are complemented by density functional theory calculations that show the spin density on the bridging ligands. PMID- 29629754 TI - Preparation of Boron Nitride Nanoparticles with Oxygen Doping and a Study of Their Room-Temperature Ferromagnetism. AB - In this work, oxygen-doped boron nitride nanoparticles with room-temperature ferromagnetism have been synthesized by a new, facile, and efficient method. There are no metal magnetic impurities in the nanoparticles analyzed by X-ray photoelectron spectroscopy. The boron nitride nanoparticles exhibit a parabolic shape with increase in the reaction time. The saturation magnetization value reaches a maximum of 0.2975 emu g-1 at 300 K when the reaction time is 12 h, indicating that the Curie temperature ( TC) is higher than 300 K. Combined with first-principles calculation, the coupling between B 2p orbital, N 2p orbital, and O 2p orbital in the conduction bands is the main origin of room-temperature ferromagnetism and also proves that the magnetic moment changes according the oxygen-doping content change. Compared with other room temperature ferromagnetic semiconductors, boron nitride nanoparticles have widely potential applications in spintronic devices because of high temperature oxidation resistance and excellent chemical stability. PMID- 29629755 TI - Interligand Charge-Transfer Interactions in Electroactive Coordination Frameworks Based on N, N'-Dicyanoquinonediimine (DCNQI). AB - Coordination frameworks containing DCNQI2- (DCNQI = N, N'-dicyanoquinonediimine ligand) are produced by deprotonation of DCNQIH2 in the presence of a metal center and a co-ligand. This approach has yielded two-dimensional (2D) sheet compounds [Cd(DCNQI)(L)2] (where L = pyridine (py) or isoquinoline (isoquin)) that can be partially oxidized via solid-state electrochemical and in situ spectroelectrochemical methods to materials that contain DCNQI as its radical monoanion. The new frameworks display charge-transfer bands that are indicative of interligand charge-transfer interactions as supported by TD-DFT computational calculations. The redox-state dependent spectral properties of the frameworks have been probed using a newly developed solid-state spectroelectrochemical cell. Coupled with computational calculations, the experimental data provide an understanding of the fundamental charge-transfer processes that may underpin long range functional properties such as conductivity in framework materials. PMID- 29629757 TI - Nanoplasmonically Engineered Interfaces on Amorphous TiO2 for Highly Efficient Photocatalysis in Hydrogen Evolution. AB - The nanoplasmonic metal-driven photocatalytic activity depends heavily on the spacing between metal nanoparticles (NPs) and semiconductors, and this work shows that ethylene glycol (EG) is an ideal candidate for interface spacer. Controlling the synthetic systems at pH 3, the composite of Ag NPs with EG-stabilized amorphous TiO2 (Ag/TiO2-3) was synthesized by the facile light-induced reduction. It is verified that EG spacers can set up suitable geometric arrangement in the composite: the twin hydroxyls act as stabilizers to bind Ag NPs and TiO2 together and the nonconductive alkyl chains consisting only of two CH2 are able to separate the two building blocks completely and also provide the shortest channels for an efficient transfer of radiation energies to reach TiO2. Employed as photocatalysts in hydrogen evolution under visible light, amorphous TiO2 hardly exhibits the catalytic activity due to high defect density, whereas Ag/TiO2-3 represents a remarkably high catalytic efficiency. The enhancement mechanism of the reaction rate is proposed by the analysis of the compositional, structural, and optical properties from a series of Ag/TiO2 composites. PMID- 29629756 TI - An Emerging Pathway of Doxorubicin Cardiotoxicity Mediated through CYP2J2. PMID- 29629758 TI - Synthesis and Crystal Structure of the Acentric Indium Borate InB6O9(OH)3. AB - The new acentric indium borate InB6O9(OH)3 was synthesized in a Walker-type multianvil apparatus at extreme pressure and temperature conditions of 12.3 GPa and 1500 degrees C. Single-crystal X-ray diffraction provided the data for the crystal structure solution and refinement. InB6O9(OH)3 crystallizes in the orthorhombic space group Fdd2 ( Z = 8) with the lattice parameters a = 39.011(8), b = 4.4820(9), c = 7.740(2) A, and V = 1353.3(5) A3. The structure of InB6O9(OH)3 is basically built of corner-sharing BO4 tetrahedra and isolated InO6 octahedra. The presence of hydroxyl groups was confirmed with vibrational spectroscopic methods (IR and Raman). Furthermore, the second harmonic signal of an InB6O9(OH)3 powder sample yielded more than twice the intensity of quartz. PMID- 29629759 TI - Evolution of a Thermophilic Strand-Displacing Polymerase Using High-Temperature Isothermal Compartmentalized Self-Replication. AB - Strand-displacing polymerases are a crucial component of isothermal amplification (IA) reactions, where the lack of thermal cycling reduces equipment needs and improves the time to answer, especially for point-of-care applications. In order to improve the function of strand-displacing polymerases, we have developed an emulsion-based directed evolution scheme, high-temperature isothermal compartmentalized self-replication (HTI-CSR) that does not rely on thermal cycling. Starting from an algorithm-optimized shuffled library of exonuclease deficient Family A polymerases from Geobacillus stearothermophilus (Bst LF) and Thermus aquaticus (Klentaq), we have applied HTI-CSR to generate a more thermostable strand-displacing polymerase variant that performs well in loop mediated isothermal amplification and rolling circle amplification, even after thermal challenges of up to 95 degrees C that lead to better primer annealing. The new enzyme (v5.9) is also capable of a variety of new reactions, including isothermal hyperbranched rolling circle amplification. The HTI-CSR method should now prove useful for evolving additional beneficial phenotypes in strand displacing polymerases. PMID- 29629760 TI - Use of Rapid Reduced Electric Field Switching to Enhance Compound Specificity for Proton Transfer Reaction-Mass Spectrometry. AB - The high sensitivity of proton transfer reaction-mass spectrometry (PTR-MS) makes it a suitable analytical tool for detecting trace compounds. Its specificity is primarily determined by the accuracy of identifying the m/ z of the product ions specific to a particular compound. However, specificity can be enhanced by changing the product ions (concentrations and types) through modifying the reduced electric field. For current PTR-MS systems, this is not possible for trace compounds that would only be present in the reaction chamber of a PTR-MS for a short time (seconds). For such circumstances, it is necessary to change the reduce electric field swiftly if specificity enhancements are to be achieved. In this paper we demonstrate such a novel approach, which permits any compound that may only be present in the drift tube for seconds to be thoroughly investigated. Specifically, we have developed hardware and software which permits the reaction region's voltages to be rapidly switched at a frequency of 0.1-5 Hz. We show how this technique can be used to provide a higher confidence in the identification of compounds than is possible by keeping to one reduced electric field value through illustrating the detection of explosives. Although demonstrated for homeland security applications, this new technique has applications in other analytical areas and disciplines where rapid changes in a compound's concentration can occur, for example, in the Earth's atmosphere, plant emissions and in breath. Importantly, this adaptation provides a method for improved selectivity without expensive instrumental changes or the need for high mass resolution instruments. PMID- 29629762 TI - Initial Conformation of Adsorbed Proteins at an Air-Water Interface. AB - We present the results of time-resolved X-ray reflectivity measurements carried out to investigate the early stage of protein adsorption and deformation at an air-water interface. Three globular proteins [lysozyme, myoglobin, and bovine serum albumin (BSA)] were studied, and we observed that the proteins adsorbed at the air-water interface initially possessed a thinner conformation than their native structures. The degree of deformation increased in the order myoglobin < lysozyme < BSA, which was inconsistent with the order of molecular flexibility. The initial rate of protein adsorption increased in the order lysozyme < BSA < myoglobin as determined by the dynamic surface tension. More flexible proteins generally adsorb at the interface more rapidly; however, proteins with hydrophobic patches on the protein surface, such as myoglobin, adsorb at the interface with little deformation. These results provide evidence that protein unfolding during adsorption only takes place if the kinetics of adsorption are similar to or slower than the kinetics of unfolding. PMID- 29629761 TI - Small Gd(III) Tags for Gd(III)-Gd(III) Distance Measurements in Proteins by EPR Spectroscopy. AB - The C7-Gd and C8-Gd tags are compact hydrophilic cyclen-based lanthanide tags for conjugation to cysteine residues in proteins. The tags are enantiomers, which differ in the configuration of the 2-hydroxylpropyl pendant arms coordinating the lanthanide ion. Here, we report the electron paramagnetic resonance (EPR) performance of the C7-Gd ( S configuration) and C8-Gd ( R configuration) tags loaded with Gd(III) on two mutants of the homodimeric ERp29 protein. The W-band EPR spectra were found to differ between the tags in the free state and after conjugation to the protein. In addition, the spectra were sensitive to the labeling position, which may originate from an environment-dependent charge density on the Gd(III)-coordinating oxygens. This is in agreement with previous NMR experiments with different lanthanide ions, which suggested sensitivity to H bonding. W-band 1H-ENDOR (electron-electron double resonance) experiments detected effects from orientation selection in the central transition, due to a relatively narrow distribution in the ZFS parameters as indicated by simulations. In contrast, the distance distributions derived from DEER (double electron electron resonance) measurements were insensitive to the R or S configuration of the tags and did not exhibit any orientation selection effects. The DEER measurements faithfully reflected the different widths of the distance distributions at the different protein sites in agreement with previous DEER measurements using other Gd(III) tags. Due to their small size, short tether to the protein, and a broad central EPR transition, the C7-Gd and C8-Gd tags are attractive Gd(III) tags for measurements of relatively short (<4 nm) distances by EPR spectroscopy. PMID- 29629763 TI - Synthesis, Structure, and Properties of the Layered Oxyselenide Ba2CuO2Cu2Se2. AB - A new layered oxyselenide, Ba2CuO2Cu2Se2, was synthesized under high-pressure and high-temperature conditions and was characterized via structural, magnetic, and transport measurements. It crystallizes into space group I4/ mmm and consists of a square lattice of [CuO2] planes and antifluorite-type [Cu2Se2] layers, which are alternately stacked along the c axis. The lattice parameters are obtained as a = b = 4.0885 A and c = 19.6887 A. The Cu-O bond length is given by half of the lattice constant a, i.e., 2.0443 A. Ba2CuO2Cu2Se2 is a semiconductor with a resistivity of ~18 mOmega.cm at room temperature. No magnetic transition was found in the measured temperature range, and the Curie-Weiss temperature was obtained as -0.2 K, suggesting a very weak exchange interaction. The DFT+ Ueff calculation demonstrates that the band gap is about 0.2 eV for the supposed antiferromagnetic order, and the density of state near the top of the valence band is mainly contributed from the Se 4p electrons. PMID- 29629764 TI - pH and Salt Response of Mixed Brushes Made of Oppositely Charged Polyelectrolytes Studied by in Situ AFM Force Measurements and Imaging. AB - The response of mixed brushes made of poly(acrylic acid) and poly(2-vinyl pyridine) with a mixing ratio of about 60:40 was studied using atomic force microscopy (AFM) force measurements with colloidal probes and AFM imaging with a sharp tip in the pH range between 2.5 and 8 and at varying KCl concentrations up to 1 M. It was found that under all conditions a dense polyelectrolyte complex layer coexists with excess polyelectrolyte chains in varying swelling states depending on pH and salt concentration. The mixed brush thus combines typical features of polyelectrolyte brushes and complexes. So, the increase of the salt concentration not only led to a transition from osmotic to salted brush regime but also to salt-induced softening or partial decomposition of the complex layer. Attractive forces at high salt concentrations indicated the presence of P2VP chains in the swollen layer even at high pH values. PMID- 29629765 TI - Spontaneous Spreading of a Droplet: The Role of Solid Continuity and Advancing Contact Angle. AB - Spontaneous spreading of a droplet on a solid surface is poorly understood from a macroscopic level down to a molecular level. Here, we investigate the effect of surface topography and wettability on spontaneous spreading of a water droplet. Spreading force is measured for a suspended droplet that minimizes interference of kinetic energy in the spontaneous spreading during its contact with solid surfaces of discontinuous (pillar) and continuous (pore) patterns with various shapes and dimensions. Results show that a droplet cannot spread spontaneously on pillared surfaces regardless of their shapes or dimensions because of the solid discontinuity. On the contrary, a droplet on pored surfaces can undergo spontaneous spreading whose force increases with a decrease in the advancing contact angle. Theoretical models based on both the system free energy and capillary force along the contact line validate the direct and universal dependency of the spontaneous spreading force on the advancing contact angle. PMID- 29629767 TI - Correction to "Enantioselective Synthesis of beta-Allenoates via Phosphine Catalyszed and ZnI2-Promoted Preparation of Oxazolidines and Propargylamines Using Chiral Amines, 1-Alkynes, and Propiolates". PMID- 29629768 TI - Mechanistic Study on Cu(II)-Catalyzed Oxidative Cross-Coupling Reaction between Arenes and Boronic Acids under Aerobic Conditions. AB - Substantial attention has been given to modern organocopper chemistry in recent years since copper salts are naturally abundant, cheap, and less toxic in comparison to precious metals. Copper salts also exhibit versatility in catalyzing and mediating carbon-carbon and carbon-heteroatom bond forming reactions. Despite the wide applications of copper salts in catalysis, reaction mechanisms have remained elusive. Using azacalix[1]arene[3]pyridine, an arene embedded macrocycle, and its isolated and structurally well-defined ArCu(II) and ArCu(III) compounds as molecular tools, we now report an in-depth experimental and computational study on the mechanism of a Cu(II)-catalyzed oxidative cross coupling reaction between arenes and boronic acids with air as the oxidant. Stoichiometric reaction of organocopper compounds with p-tolylboronic acid validated arylcopper(II) rather than arylcopper(III) as a reactive organometallic intermediate. XPS, EPR, 1H NMR, HRMS, and UV-vis spectroscopic evidence along with the isolation and quantification of all products and copper speciation, combined with computational analysis of the electronic structure and energetics of the transient intermediates, suggested a reaction sequence involving electrophilic metalation of arene by Cu(II), transmetalation of arylboronate to ArCu(II), the redox reaction between the resulting ArCu(II)Ar' and ArCu(II) to form respectively ArCu(III)Ar' and ArCu(I), and finally reductive elimination of ArCu(III)Ar'. Under aerobic catalytic conditions, all Cu(I) ions released from reductive elimination of ArCu(III)Ar' and from protolysis of ArCu(I) were oxidized by oxygen to regenerate Cu(II) species that enters into the next catalytic cycle. The unraveled reactivity of arylcopper(II) compounds and the catalytic cycle would enrich our knowledge of modern organocopper chemistry and provide useful information in the design of copper-catalyzed reactions. PMID- 29629766 TI - Enantioselective gamma-C(sp3)-H Activation of Alkyl Amines via Pd(II)/Pd(0) Catalysis. AB - Pd(II)-catalyzed enantioselective gamma-C(sp3)-H cross-coupling of alkyl amines via desymmetrization and kinetic resolution has been realized for the first time using chiral acetyl-protected aminomethyl oxazoline ligands (APAO). A diverse range of aryl- and vinyl-boron reagents can be used as coupling partners. The chiral gamma-arylated alkylamine products are further transformed into chiral 2 substituted 1,2,3,4-tetra-hydroquinolines and spiro-pyrrolidines as important structural motifs in natural products and biologically active molecules. PMID- 29629769 TI - Developing Equipotent Teixobactin Analogues against Drug-Resistant Bacteria and Discovering a Hydrophobic Interaction between Lipid II and Teixobactin. AB - Teixobactin, targeting lipid II, represents a new class of antibiotics with novel structures and has excellent activity against Gram-positive pathogens. We developed a new convergent method to synthesize a series of teixobactin analogues and explored structure-activity relationships. We obtained equipotent and simplified teixobactin analogues, replacing the l- allo-enduracididine with lysine, substituting oxygen to nitrogen on threonine, and adding a phenyl group on the d-phenylalanine. On the basis of the antibacterial activities that resulted from corresponding modifications of the d-phenylalanine, we propose a hydrophobic interaction between lipid II and the N-terminal of teixobactin analogues, which we map out with our analogue 35. Finally, a representative analogue from our series showed high efficiency in a mouse model of Streptococcus pneumoniae septicemia. PMID- 29629770 TI - Adsorption of Denaturated Lysozyme at the Air-Water Interface: Structure and Morphology. AB - The application of protein deuteration and high flux neutron reflectometry has allowed a comparison of the adsorption properties of lysozyme at the air-water interface from dilute solutions in the absence and presence of high concentrations of two strong denaturants: urea and guanidine hydrochloride (GuHCl). The surface excess and adsorption layer thickness were resolved and complemented by images of the mesoscopic lateral morphology from Brewster angle microscopy. It was revealed that the thickness of the adsorption layer in the absence of added denaturants is less than the short axial length of the lysozyme molecule, which indicates deformation of the globules at the interface. Two dimensional elongated aggregates in the surface layer merge over time to form an extensive network at the approach to steady state. Addition of denaturants in the bulk results in an acceleration of adsorption and an increase of the adsorption layer thickness. These results are attributed to incomplete collapse of the globules in the bulk from the effects of the denaturants as a result of interactions between remote amino acid residues. Both effects may be connected to an increase of the effective total volume of macromolecules due to the changes of their tertiary structure, that is, the formation of molten globules under the influence of urea and the partial unfolding of globules under the influence of GuHCl. In the former case, the increase of globule hydrophobicity leads to cooperative aggregation in the surface layer during adsorption. Unlike in the case of solutions without denaturants, the surface aggregates are short and wormlike, their size does not change with time, and they do not merge to form an extensive network at the approach to steady state. To the best of our knowledge, these are the first observations of cooperative aggregation in lysozyme adsorption layers. PMID- 29629771 TI - Evidence for Redox Mechanisms in Organometallic Chemisorption and Reactivity on Sulfated Metal Oxides. AB - The chemical and electronic interactions of organometallic species with metal oxide support materials are of fundamental importance for the development of new classes of catalytic materials. Chemisorption of Cp*(PMe3)IrMe2 on sulfated alumina (SA) and sulfated zirconia (SZ) led to an unexpected redox mechanism for deuteration of the ancillary Cp* ligand. Evidence for this oxidative mechanism was provided by studying the analogous homogeneous reactivity of the organometallic precursors toward trityl cation ([Ph3C]+), a Lewis acid known to effect formal hydride abstraction by one-electron oxidation followed by hydrogen abstraction. Organometallic deuterium incorporation was found to be correlated with surface sulfate concentration as well as the extent of dehydration under thermal activation conditions of SA and SZ supports. Surface sulfate concentration dependence, in conjunction with a computational study of surface electron affinity, indicates an electron-deficient pyrosulfate species as the redox-active moiety. These results provide further evidence for the ability of sulfated metal oxides to participate in redox chemistry not only toward organometallic complexes but also in the larger context of their application as catalysts for the transformation of light alkanes. PMID- 29629772 TI - Pd-Induced Double C-H Bond Activation in Annulative Syntheses of Bipyrrole Boomerangs: Mechanistic Insights from NMR Spectroscopy and Computation. AB - 1, n-Dipyrrolylalkanes can be efficiently converted into extensively pi conjugated bipyrroles by PdII-mediated annulative double C-H activation, and this approach might be further developed into tandem processes involving further cyclization of substituents or oxygenation of pyrrolic alpha-positions. Herein, the mechanism of these transformations is explored using NMR spectroscopy and DFT calculations. The kinetics of the annulation are found to depend on the conjugation extent and donor-acceptor character of the pyrroles, as well as on substitution and the linker length. Combined experimental and theoretical evidence indicates that a change of the rate-determining step occurs for the most electron-deficient substrates. The unprecedented double alpha-oxygenation of bipyrroles is found to be a stepwise process, involving alpha-acetoxylated intermediates. PMID- 29629773 TI - Conformational Plasticity in Tyrosine Kinase Inhibitor-Kinase Interactions Revealed with Fluorescence Spectroscopy and Theoretical Calculations. AB - To understand drug-protein dynamics, it is necessary to account for drug molecular flexibility and binding site plasticity. Herein, we exploit fluorescence from a tyrosine kinase inhibitor, AG1478, as a reporter of its conformation and binding site environment when complexed with its cognate kinase. Water-soluble kinases, aminoglycoside phosphotransferase APH(3')-Ia and mitogen activated protein kinase 14 (MAPK14), were chosen for this study. On the basis of our prior work, the AG1478 conformation (planar or twisted) was inferred from the fluorescence excitation spectrum and the polarity of the AG1478-binding site was deduced from the fluorescence emission spectrum, while red-edge excitation shift (REES) probed the heterogeneity of the binding site (protein conformation and hydration) distributions in the protein conformational ensemble. In the AG1478 APH(3')-Ia complex, both twisted (or partially twisted) and planar AG1478 conformations were evidenced from emission wavelength-dependent excitation spectra. The binding site environment provided by APH(3')-Ia was moderately polar (lambdamax = 480 nm) with evidence for considerable heterogeneity (REES = 34 nm). In contrast, in the AG1478-MAPK14 complex, AG1478 was in a predominantly planar conformation with a lower degree of conformational heterogeneity. The binding site environment provided by the MAPK14 protein was of relatively low polarity (lambdamax = 430 nm) with a smaller degree of heterogeneity (REES = 11 nm). The results are compared with the available X-ray data and discussed in the context of our current understanding of tyrosine kinase inhibitor conformation and protein conformational ensembles. PMID- 29629774 TI - Polymer Valence Isomerism: Poly(Dewar- o-xylylene)s. AB - Poly( o-xylylene) (POX) has long been a challenging synthetic target despite its simple structure and potentially useful physical properties. In this report, we demonstrate a valence isomer strategy that leads to the formation of high molecular weight POX via an intermediate polymer of a unique structure, namely poly(Dewar- o-xylylene) (PDOX). We show that the free radical polymerization of highly strained Dewar- o-xylylene (DOX) monomer afforded PDOX, a material with a high density of Dewar benzene units in the backbone through ring-retaining propagation. The thermal- and photoinduced isomerizations of PDOX to produce POX were investigated. This chemistry yields POXs that are difficult to obtain using traditional methods. Moreover, it also provides a potential entry into new reconfigurable materials featuring highly efficient postpolymerization main chain structural transformations. PMID- 29629775 TI - Resin-Bound Crypto-Thioester for Native Chemical Ligation. AB - The resin-bound N-sulfanylethylanilide (SEAlide) peptide was found to function as a crypto-thioester peptide. Exposure of the peptide resin to an aqueous solution under neutral conditions in the presence of thiols affords thioesters without accompanying racemization of C-terminal amino acids. Furthermore, the resin-bound SEAlide peptides react with N-terminal cysteinyl peptides in the absence of phosphate salts to afford ligated products, whereas soluble SEAlide peptides do not. This unexpected difference in reactivity of the SEAlide peptides allows for a one-pot/three-fragment ligation using resin-bound and unbound peptides. PMID- 29629776 TI - Pd-Catalyzed Direct C-H Alkenylation and Allylation of Azine N-Oxides. AB - A Pd-catalyzed direct C2-alkenylation of azine N-oxides with allyl acetate is disclosed. The products are formed through an allylation/isomerization cascade process. The use of a tri- tert-butylphosphonium salt as the ligand precursor and KF is mandatory for optimal yields. When cinnamyl acetate is used, the same catalytic system promotes C2-cinnamylation of the azine N-oxide without subsequent isomerization. A mechanism is proposed on the basis of experimental studies and DFT calculations. PMID- 29629777 TI - Using a Novel Supramolecular Gel Cryopreservation System in Microchannel to Minimize the Cell Injury. AB - The storage of living cells is the major challenge for cell research and cell treatment. Here, we introduced a novel supramolecular gel cryopreservation system which was prepared in the microchannel, and the supramolecular gel (BDTC) was self-assembled by gelator Boc- O-dodecyl-l-tyrosine (BDT). This cryopreservation system could obviously minimize the cell injury because the BDTC supramolecular gel had a more compact three-dimensional network structure when the BDT gelator self-assembled in the confined space of microchannel. This compact structure could confine the growth of the ice crystal, reduce the change rate of cell volumes and osmotic shock, decrease the freezing point of the cryopreservation system, and possess better protection capability. Furthermore, the results of functionality assessments showed that the thawed cells could grow and proliferate well and remain the same growth trend of the fresh cells after the RSC96 cells flowed out from the microchannel. This novel method has potential to be used for the cryopreservation of cells, cell therapy, and tissue engineering. PMID- 29629778 TI - Teacher coaching supported by formative assessment for improving classroom practices. AB - The present study is a wait-list controlled, randomized study investigating a teacher coaching approach that emphasizes formative assessment and visual performance feedback to enhance elementary school teachers' classroom practices. The coaching model targeted instructional and behavioral management practices as measured by the Classroom Strategies Assessment System (CSAS) Observer and Teacher Forms. The sample included 89 general education teachers, stratified by grade level, and randomly assigned to 1 of 2 conditions: (a) immediate coaching, or (b) waitlist control. Results indicated that, relative to the waitlist control, teachers in immediate coaching demonstrated significantly greater improvements in observations of behavior management strategy use but not for observations of instructional strategy use. Observer- and teacher-completed ratings of behavioral management strategy use at postassessment were significantly improved by both raters; ratings of instructional strategy use were significantly improved for teacher but not observer ratings. A brief coaching intervention improved teachers' use of observed behavior management strategies and self-reported use of behavior management and instructional strategies. (PsycINFO Database Record PMID- 29629779 TI - Muslim Americans' safety and well-being in the wake of Trump: A public health and social justice crisis. AB - This study examined the perceived impact of religious discrimination and Islamophobia on Muslim Americans' well-being during the 2016 United States presidential election campaign. Data were collected from a national sample of 1,130 Muslim Americans. Perceived religious discrimination (PRD) was measured using the Perceived Religious Discrimination Scale. Results of canonical correlation analysis showed that perceived Islamophobia was associated with safety (beta = .45, p < .001), level of stress (beta = -.25, p < .001), level of religiosity (beta = -.11, p < .05), and employment (beta = .11, p < .05). PRD was associated with preexposure to religious-based discrimination; beta = -.12, p < .05), safety (.47, p < .001), level of stress (beta = -.33, p < .001), religiosity (beta = -.15, p < .010), and years in the United States (beta = .16, p < .010). Results also suggest that some Muslim subgroups, such as women and older people, may face "double jeopardy" based on multiple stigmatized identities. When addressing mental health concerns in marginalized groups, it is necessary to link health with social justice and examine how social injustices may affect people's well-being. (PsycINFO Database Record PMID- 29629780 TI - Emotional prosody of task-irrelevant speech interferes with the retention of serial order. AB - Task-irrelevant speech and other temporally changing sounds are known to interfere with the short-term memorization of ordered verbal materials, as compared to silence or stationary sounds. It has been argued that this disruption of short-term memory (STM) may be due to (a) interference of automatically encoded acoustical fluctuations with the process of serial rehearsal or (b) attentional capture by salient task-irrelevant information. To disentangle the contributions of these 2 processes, the authors investigated whether the disruption of serial recall is due to the semantic or acoustical properties of task-irrelevant speech (Experiment 1). They found that performance was affected by the prosody (emotional intonation), but not by the semantics (word meaning), of irrelevant speech, suggesting that the disruption of serial recall is due to interference of precategorically encoded changing-state sound (with higher fluctuation strength of emotionally intonated speech). The authors further demonstrated a functional distinction between this form of distraction and attentional capture by contrasting the effect of (a) speech prosody and (b) sudden prosody deviations on both serial and nonserial STM tasks (Experiment 2). Although serial recall was again sensitive to the emotional prosody of irrelevant speech, performance on a nonserial missing-item task was unaffected by the presence of neutral or emotionally intonated speech sounds. In contrast, sudden prosody changes tended to impair performance on both tasks, suggesting an independent effect of attentional capture. (PsycINFO Database Record PMID- 29629781 TI - The architecture of interaction between visual working memory and visual attention. AB - In five experiments, we examined whether a task-irrelevant item in visual working memory (VWM) interacts with perceptual selection when VWM must also be used to maintain a template representation of a search target. This question is critical to distinguishing between competing theories specifying the architecture of interaction between VWM and attention. The single-item template hypothesis (SIT) posits that only a single item in VWM can be maintained in a state that interacts with attention. Thus, the secondary item should be inert with respect to attentional guidance. The multiple-item template hypothesis (MIT) posits that multiple items can be maintained in a state that interacts with attention; thus, both the target representation and the secondary item should be capable of guiding selection. This question has been addressed previously in attention capture studies, but the results have been ambiguous. Here, we modified these earlier paradigms to optimize sensitivity to capture. Capture by a distractor matching the secondary item in VWM was observed consistently across multiple types of search task (abstract arrays and natural scenes), multiple dependent measures (search reaction time (RT) and oculomotor capture), multiple memory dimensions (color and shape), and multiple search stimulus dimensions (color, shape, common objects), providing strong support for the MIT. (PsycINFO Database Record PMID- 29629783 TI - Abstract shape representation in human visual perception. AB - The ability to form shape representations from visual input is crucial to perception, thought, and action. Perceived shape is abstract, as evidenced when we can see a contour specified only by discrete dots, when a cloud appears to resemble a fish, or when we match shapes across transformations of scale and orientation. Surprisingly little is known about the formation of abstract shape representations in biological vision. We report experiments that demonstrate the existence of abstract shape representations in visual perception and identify the time course of their formation. In Experiment 1, we varied stimulus exposure time in a task that required abstract shape and found that it emerges about 100 ms after stimulus onset. The results also showed that abstract shape representations are invariant across certain transformations and that they can be recovered from spatially separated dots. Experiment 2 found that encoding of basic visual features, such as dot locations, occurs during the first 30 ms after stimulus onset, indicating that shape representations require processing time beyond that needed to extract spatial features. Experiment 3 used a convergent method to confirm the timing and importance of abstract shape representations. Given sufficient time, shape representations form automatically and obligatorily, affecting performance even in a task in which neither instructions nor accurate responding involved shape. These results provide evidence for the existence, emergence, and functional importance of abstract shape representations in visual perception. We contrast these results with "deep learning" systems and with proposals that deny the importance of abstract representations in human perception and cognition. (PsycINFO Database Record PMID- 29629782 TI - A longitudinal event-level investigation of alcohol intoxication, alcohol-related blackouts, childhood sexual abuse, and sexual victimization among college students. AB - Sexual assault is a troubling epidemic that plagues college campuses across the United States, and is often proceeded by drinking by the perpetrator and/or victim. The goal of this study was to examine the effect of level of intoxication, history of alcohol-related blackouts, and childhood sexual abuse (CSA) on the likelihood of being a victim or perpetrator of coercive sexual activities. Participants (N = 2,244) were part of a 6-year longitudinal study which explored alcohol use and associated behavioral risks during college. A subsample (N = 1,423) completed 30 days of daily diary surveys across four years of college. Participants provided daily reports of their alcohol consumption, sexual coercion perpetration, and sexual coercion victimization. Using hierarchical linear models, results indicated that increases in daily estimated blood alcohol concentration (eBAC) were associated with a greater likelihood of being a victim and a perpetrator of sexual coercion. In addition, main effects of CSA and history of blackouts predicted a greater likelihood of being coerced into sexual activity, but blackouts were not associated with being a perpetrator. A significant interaction between blackouts and event-level eBAC indicated that individuals with a history of blackouts had a greater likelihood of sexual coercion victimization relative to those without prior blackouts. Finally, having a history of blackouts and CSA was predictive of a lower likelihood of being a perpetrator of sexual coercion at higher eBACs relative to those without a history of blackouts. Thus, prevention efforts should integrate the impact of blackouts and CSA on sexual coercion victimization and perpetration. (PsycINFO Database Record PMID- 29629784 TI - Implementing the Bounce Back trauma intervention in urban elementary schools: A real-world replication trial. AB - The current study provides the first replication trial of Bounce Back, a school based intervention for elementary students exposed to trauma, in a different school district and geographical area. Participants in this study were 52 1st through 4th graders (Mage = 7.76 years; 65% male) who were predominately Latino (82%). Schools were randomly assigned to immediate treatment or waitlist control. Differential treatment effects (Time * Group Interaction) were found for child reported posttraumatic stress disorder (PTSD) and parent-reported child coping, indicating that the immediate treatment group showed greater reductions in PTSD and improvements in coping compared with the delayed group. Differential treatment effects were not significant for depression or anxiety. Significant maintenance effects were found for both child-reported PTSD and depression as well as parent-reported PTSD and coping for the immediate treatment group at follow-up. Significant treatment effects were also found in the delayed treatment group, showing reductions in child-reported PTSD, depression, and anxiety as well as parent-reported depression and coping upon receiving treatment. In conclusion, the current study suggests that Bounce Back is an effective intervention for reducing PTSD symptoms and improving coping skills, even among a sample experiencing high levels of trauma and other ongoing stressors. (PsycINFO Database Record PMID- 29629785 TI - Evaluating referral, screening, and assessment procedures for middle school trauma/grief-focused treatment groups. AB - There is a need to delineate best practices for referring, assessing, and retaining students suspected of posttraumatic stress (PTS) and maladaptive grief (MG) in school-based treatment. Evidence-based risk-screening procedures should accurately include students who are appropriate for group treatment and exclude students who do not require treatment or who are better served by other forms of intervention and support. We described and evaluated the sequence of steps used to screen 7th- and 8th-grade students (N = 89) referred by school staff as candidates for an open trial of group-based Trauma and Grief Component Therapy for Adolescents (TGCTA; Saltzman et al., in press). We used t tests to compare included versus excluded students on PTS symptom and MG reaction scores (University of California at Los Angeles Posttraumatic Stress Disorder Reaction Index; Grief Screening Scale) during the group screen, individual interview, and treatment-implementation phases. Logistic regressions tested the incremental utility of including measures of both trauma exposure and related emotional and conduct problems (Strengths and Difficulties Questionnaire) in the screening battery. Results suggest that the group screen helped to detect mental health needs and that the individual interview further identified students with PTS and emotional problems. Conduct problems and trauma exposure predicted attrition among students who qualified for treatment. MG incrementally predicted students who advanced from the group screening to the individual interview, and trauma exposure incrementally predicted attrition from treatment. Findings yield implications for improving research and practice, including procedures for enhancing school-based referral, screening, assessment, and selection procedures. (PsycINFO Database Record PMID- 29629786 TI - A comparative analysis of family adaptability and cohesion ratings among traumatized urban youth. AB - OBJECTIVE: Given the need to identify psychological risk factors among traumatized youth, this study examined the family functioning of traumatized youth with or without PTSD and a nonclinical sample. METHOD: The Family Adaptability and Cohesion Evaluation Scales, second edition (FACES II; Olson, Portner, & Bell, 1982), scores of youth with posttraumatic stress disorder (PTSD; n = 29) were compared with the scores of trauma-exposed youth without PTSD (n = 48) and a nontraumatized comparison group (n = 44). Child diagnostic interviews determined that all participants were free of major comorbid disorders. RESULTS: The FACES II scores of the participants with PTSD were not significantly different from the scores of trauma-exposed youth without PTSD and the nontraumatized comparison group. FACES II scores were also not significantly different between the trauma-exposed youth without PTSD and the nontraumatized comparison group. CONCLUSIONS: PTSD and trauma-exposure without PTSD were not associated with variations in the perception of family functioning as measured by the FACES II. (PsycINFO Database Record PMID- 29629787 TI - A systematic review of trauma screening measures for children and adolescents. AB - Traumatized youth are at an increased risk of a host of negative academic and psychoeducational outcomes. Screening and identification of students who experience potentially traumatic events may help schools provide support to at risk students. In light of this, the current study examines the availability and use of trauma screening measures to detect early indicators of risk among youth in schools. A systematic review was conducted to identify measures available to screen children and youth for trauma exposure and/or symptoms, as well as the associated psychometric properties to support each instrument's applied use in schools. Eighteen measures met inclusion criteria, which consisted primarily of student self-report rating scales and clinical interviews. While many instruments measure the symptomology or exposure to trauma among children and youth, very little psychometric evidence was available to support the use of these measures in schools. Additional research is needed to endorse and expand the use of trauma screening measures in schools. (PsycINFO Database Record PMID- 29629788 TI - Statewide implementation of an evidence-based trauma intervention in schools. AB - The goal of the current article is to describe the implementation and outcomes of an innovative statewide dissemination approach of the evidence-based trauma intervention Cognitive Behavioral Intervention for Trauma in Schools (CBITS). In the context of a 2-year statewide learning collaborative effort, 73 CBITS groups led by 20 clinicians from 5 different school-based mental health provider organizations served a total of 350 racially and ethnically diverse (66.9% Hispanic, 26.2% Black/African American, 43.7% White, and 30.1% Other), majority female (61%) children, averaging 12.2 years (SD = 2.4, range 8-19). Of the 350 children who began CBITS, 316 (90.3%) successfully completed treatment. Children demonstrated significant reductions in child posttraumatic stress disorder (PTSD) symptoms (42% reduction, d = .879) and problem severity (25% reduction, d = .396), and increases in child functioning, t(287) = -3.75, p < .001 (5% increase, d = .223). Findings point to the need, feasibility, and positive impact of implementing and scaling up school-based interventions for students suffering from posttraumatic stress. (PsycINFO Database Record PMID- 29629789 TI - Bullying victimization and student engagement in elementary, middle, and high schools: Moderating role of school climate. AB - Bullying is the most common form of school violence and is associated with a range of negative outcomes, including traumatic responses. This study used hierarchical linear modeling to examine the multilevel moderating effects of school climate and school level (i.e., elementary, middle, and high schools) on the association between bullying victimization and student engagement. Participants included 25,896 students in 4th to 12th grades from 114 schools. Results indicated that, after controlling for student and school demographic factors, positive school climate was associated with higher behavioral/cognitive and emotional engagement of students across all grades. This highlights the critical and fundamental role of positive school climate in bullying prevention and intervention, among students across all grade levels, including those with frequent bullying victimization experience. Results also showed that negative associations between student-level bullying victimization and engagement were intensified in more positive school climates. This finding suggests that, in comparison with students in schools with less positive school climates, the engagement of bullying victims in schools with a more positive school climate might be more negatively influenced by their victimization experience. Additionally, the relation between student-level bullying victimization and emotional engagement was significantly different across middle and high schools. (PsycINFO Database Record PMID- 29629790 TI - The association between adverse childhood experience (ACE) and school success in elementary school children. AB - We explored the feasibility of using school personnel as reporters to examine the relationship between the level of adverse childhood experiences (ACEs) exposure in a nonclinical sample of public elementary schoolchildren and academic risk. We selected a random sample of 2,101 children from kindergarten through 6th grade classroom rosters at 10 elementary schools. Students were 50% male, 78% White, and 55% free and reduced meal program participants. School personnel reported their factual knowledge of 10 ACEs and academic risk in a database controlled by the schools. Data were de-identified prior to analysis. A high prevalence of ACEs exposure was reported (44%), with 13% of students experiencing 3 or more ACEs. Binary logistic regression analyses revealed a dose-response effect between the number of ACEs and risk of poor school attendance, behavioral issues, and failure to meet grade-level standards in mathematics, reading, or writing. Using elementary school personnel reports of child ACE exposure minimized family burden and potential intrusion while producing prevalence estimates consistent with those of caregiver report from the National Survey of Children's Health. Results suggest that understanding and responding to a child's ACE profile might be an important strategy for improving the academic trajectory of at-risk children. (PsycINFO Database Record PMID- 29629791 TI - At what cost? Examining the cost effectiveness of a universal social-emotional learning program. AB - Although implementation of universal social-emotional learning programs is becoming more common in schools, few studies have examined the cost-effectiveness of such programs. As such, the purpose of this article is two fold. First, we provide an overview of cost-effectiveness methods for school-based programs, and second, we share results of a cost-effectiveness analysis (CEA) of a universal social-emotional learning (SEL) program, the Social Skills Improvement System Classwide Intervention Program (SSIS-CIP; Elliott & Gresham, 2007). Specifically, we compared the cost-effectiveness of SSIS-CIP implementation across first- and second-grade classrooms, and results indicated that second grade is the more cost effective option for implementing the SSIS-CIP. Several considerations are discussed regarding cost-effectiveness analysis of universal SEL programs as well as the importance of using CEA results to inform programming decisions. (PsycINFO Database Record PMID- 29629792 TI - Screening for behavioral risk: Identification of high risk cut scores within the Social, Academic, and Emotional Behavior Risk Screener (SAEBRS). AB - The purpose of this study was to support the identification of Social, Academic, and Emotional Behavior Risk Screener (SAEBRS) cut scores that could be used to detect high-risk students. Teachers rated students across two time points (Time 1 n = 1,242 students; Time 2 n = 704) using the SAEBRS and the Behavioral and Emotional Screening System (BESS), the latter of which served as the criterion measure. Exploratory receiver operating characteristic (ROC) curve analyses of Time 1 data detected cut scores evidencing optimal levels of specificity and borderline-to-optimal levels of sensitivity. Cross-validation analyses of Time 2 data confirmed the performance of these cut scores, with all but one scale evidencing similar performance. Findings are considered particularly promising for the SAEBRS Total Behavior scale in detecting high-risk students. (PsycINFO Database Record PMID- 29629793 TI - 3D Ultrashort TE MRI for Evaluation of Cartilaginous Endplate of Cervical Disk In Vivo: Feasibility and Correlation With Disk Degeneration in T2-Weighted Spin-Echo Sequence. AB - OBJECTIVE: The purpose of this study was to evaluate the feasibility of 3D ultrashort TE (UTE) MRI in depicting the cartilaginous endplate (CEP) and its abnormalities and to investigate the association between CEP abnormalities and disk degeneration on T2-weighted spin-echo (SE) MR images in cervical disks in vivo. SUBJECTS AND METHODS: Eight healthy volunteers and 70 patients were examined using 3-T MRI with the 3D UTE cones trajectory technique (TR/TE, 16.1/0.032, 6.6). In the volunteer study, quantitative and qualitative assessments of CEP depiction were conducted for the 3D UTE and T2-weighted SE imaging. In the patient study, CEP abnormalities were analyzed. Intersequence agreement between the images obtained with the first-echo 3D UTE sequence and the images created by subtracting the second-echo from the first-echo 3D UTE sequence (subtracted 3D UTE) and the intraobserver and interobserver agreements for 3D UTE overall were also tested. The CEP abnormalities on the 3D UTE images correlated with the Miyazaki grading of the T2-weighted SE images. RESULTS: In the volunteer study, the CEP was well visualized on 3D UTE images but not on T2-weighted SE images (p < 0.001). In the patient study, for evaluation of CEP abnormalities, intersequence agreements were substantial to almost perfect, intraobserver agreements were substantial to almost perfect, and interobserver agreements were moderate to substantial (p < 0.001). All of the CEP abnormalities correlated with the Miyazaki grade with statistical significance (p < 0.001). CONCLUSION: Three dimensional UTE MRI feasibly depicts the CEP and CEP abnormalities, which may be associated with the severity of disk degeneration on T2-weighted SE MRI. PMID- 29629794 TI - Does the Addition of DWI to Fluid-Sensitive Conventional MRI of the Sacroiliac Joints Improve the Diagnosis of Sacroiliitis? AB - OBJECTIVE: The purpose of this study was to determine whether adding DWI to conventional MRI of the sacroiliac joints improves the diagnostic performance of MRI readers in the detection of sacroiliitis. MATERIALS AND METHODS: MR images of the sacroiliac joints of 63 patients with lower back pain obtained between January 2016 and December 2016 were analyzed retrospectively. Three readers reviewed the MRI studies for bone marrow edema lesions around the sacroiliac joints as a marker of active sacroiliitis and gave a diagnostic confidence score of 0-4 using MRI without DWI and MRI with DWI in separate sessions. The normalized apparent diffusion coefficient mean (nADCmean) was measured. Clinical and radiologic data using the Assessment of Spondyloarthritis International Society criteria were the reference for the diagnosis of sacroiliitis. Diagnostic performance, confidence scores, and interreader agreement for the MRI methods were compared. The nADCmean values of patients with and those without sacroiliitis were compared. RESULTS: The accuracy, sensitivity, and specificity of MRI without DWI were 68.3%, 69.0%, and 67.6% and for MRI with DWI were 74.6%, 69.0%, and 79.4% (accuracy and sensitivity, p > 0.100; specificity, p = 0.039). The mean confidence score for MRI without DWI was 3.60 and for MRI with DWI was 3.67 (p = 0.270). The kappa coefficient for MRI without DWI was 0.28 and for MRI with DWI was 0.46 (p = 0.041). The nADCmean in patients with sacroiliitis was 3.86 and in patients without sacroiliitis was 1.6 (p <= 0.001). The nADCmean AUC was 0.758 (95% CI, 0.67-0.83). CONCLUSION: The addition of DWI to conventional MRI does not significantly improve overall diagnostic performance in terms of accuracy, sensitivity, or confidence in the detection of inflammatory sacroiliitis, but it does have increased specificity and interobserver agreement. ADC threshold values can be used as predictors of sacroiliitis but give no added advantage over MRI with DWI. PMID- 29629795 TI - MRI Detection of Intratumoral Fat in Colorectal Liver Metastases After Preoperative Chemotherapy. AB - OBJECTIVE: The objective of this study was to investigate the incidence and clinical significance of intratumoral fat deposition in colorectal liver metastases (CLMs) after preoperative chemotherapy using dual-echo gradient recalled echo MRI. MATERIALS AND METHODS: Our institutional review board approved this retrospective radiographic study and waived the requirement for informed patient consent. Fifty-nine patients (33 men, 26 women; median age, 62 years old) who underwent preoperative MRI and curative hepatic resection for colorectal liver metastases after chemotherapy were selected. Twenty patients also underwent MRI before chemotherapy. On dual-echo gradient-recalled echo MR images, intratumoral fat deposition and fat signal fraction at the densest areas of fat deposition in colorectal liver metastases were evaluated. Predictors of overall survival and intratumoral fat deposition after chemotherapy were identified by multivariate analyses. RESULTS: Before and after chemotherapy, 0 (0%) and 32 (54%) of the patients exhibited intratumoral fat deposition, respectively. Independent predictors of poor overall survival were presence of five or more CLMs (p < 0.001), fat signal fraction of 12% or more (p = 0.01), age of 65 years or older (p = 0.02), and tumor response classified as progressive or stable disease by the Response Evaluation Criteria in Solid Tumors 1.1 (p = 0.049). Predictors of tumor fat signal fraction being 12% or greater after chemotherapy were largest tumor size of 5 cm or more (p = 0.005), tumor calcification (p = 0.008), and history of cetuximab or panitumumab administration (p = 0.04). CONCLUSION: CLMs after preoperative chemotherapy frequently exhibit intratumoral fat deposition. PMID- 29629796 TI - Advances in Pancreatic CT Imaging. AB - OBJECTIVE: The purpose of this article is to discuss the advances in CT acquisition and image postprocessing as they apply to imaging the pancreas and to conceptualize the role of radiogenomics and machine learning in pancreatic imaging. CONCLUSION: CT is the preferred imaging modality for assessment of pancreatic diseases. Recent advances in CT (dual-energy CT, CT perfusion, CT volumetry, and radiogenomics) and emerging computational algorithms (machine learning) have the potential to further increase the value of CT in pancreatic imaging. PMID- 29629797 TI - Comparison of Performance Characteristics of American College of Radiology TI RADS, Korean Society of Thyroid Radiology TIRADS, and American Thyroid Association Guidelines. AB - OBJECTIVE: The American College of Radiology (ACR) Thyroid Imaging Reporting and Data System (TI-RADS) provides guidelines to practitioners who interpret sonographic examinations of thyroid nodules. The purpose of this study is to compare the ACR TI-RADS system with two other well-established guidelines. MATERIALS AND METHODS: The ACR TI-RADS, the Korean Society of Thyroid Radiology (KSThR) Thyroid Imaging Reporting and Data System (TIRADS), and the American Thyroid Association guidelines were compared using 3422 thyroid nodules for which pathologic findings were available. The composition, echogenicity, margins, echogenic foci, and size of the nodules were assessed to determine whether a recommendation would be made for fine-needle aspiration or follow-up sonography when each system was used. The biopsy yield of malignant findings, the yield of follow-up, and the percentage of malignant and benign nodules that would be biopsied were determined for all nodules and for nodules 1 cm or larger. RESULTS: The percentage of nodules that could not be classified was 0%, 3.9%, and 13.9% for the ACR TI-RADS, KSThR TIRADS, and ATA guidelines, respectively. The biopsy yield of malignancy was 14.2%, 10.2%, and 10.0% for nodules assessed by the ACR TI-RADS, KSThR TIRADS, and ATA guidelines, respectively. The percentage of malignant nodules that were biopsied was 68.2%, 78.7%, and 75.9% for the ACR TI RADS, the KSThR TIRADS, and the ATA guidelines, respectively, whereas the percentage of malignant nodules that would be either biopsied or followed was 89.2% for the ACR TI-RADS. The percentage of benign nodules that would be biopsied was 47.1%, 79.7%, and 78.1% for the ACR TI-RADS, the KSThR TIRADS, and the ATA guidelines, respectively. The percentage of benign nodules that would be either biopsied or followed was 65.2% for the ACR TI-RADS. CONCLUSION: The ACR TI RADS performs well when compared with other well-established guidelines. PMID- 29629798 TI - Value of 18F-FDG PET/CT Combined With Tumor Markers in the Evaluation of Ascites. AB - OBJECTIVE: The purpose of this study is to investigate the value of 18F-FDG PET/CT combined with assessment of tumor markers in serum or ascites for the diagnosing and determining the prognosis of benign and malignant ascites. MATERIALS AND METHODS: Patients with ascites of unknown cause who underwent evaluation with FDG PET/CT were included in this retrospective study. The maximum standardized uptake value (SUVmax) and levels of the tumor markers carbohydrate antigen-125 (CA-125) and carcinoembryonic antigen (CEA) in serum and ascites were recorded. The diagnostic values of FDG PET/CT, CEA and CA-125 levels in serum or ascites, and the combination of imaging plus tumor marker assessment were evaluated. Factors that were predictive of survival were also analyzed. RESULTS: A total of 177 patients were included. Malignant ascites was eventually diagnosed in 104 patients, and benign ascites was diagnosed in the remaining 73 patients. With the use of FDG PET/CT, 44 patients (42.3%) were found to have primary tumors. The sensitivity, specificity, and accuracy of FDG PET/CT were 92.3%, 83.6%, and 88.7%, respectively. CA-125 levels in serum and ascites showed much better sensitivity than did CEA levels, but they showed significantly lower specificity. If the combination of tumor markers and FDG PET/CT was analyzed, the sensitivity, specificity, and accuracy of tumor markers in serum were 96.6%, 78.1%, and 88.7%, and those of tumor markers in ascites were 97.7%, 80.0%, and 90.4%, respectively. Sex may be an important factor affecting survival time (hazard ratio, 0.471; p = 0.004), but age, CEA level, and FDG PET/CT findings could not predict survival. CONCLUSION: FDG PET/CT combined with assessment of tumor markers, especially CEA, increased the efficacy of diagnosis of ascites of unknown causes. Male sex conferred a poorer prognosis, whereas age, CEA level, and FDG uptake had no predictive significance in patients with malignant ascites. PMID- 29629799 TI - Acute Jejunoileal Diverticulitis: Multicenter Descriptive Study of 33 Patients. AB - OBJECTIVE: Acute jejunoileal diverticulitis is a very rare and potentially serious disease affecting mostly elderly patients. The diagnosis is based on imaging but remains underrecognized. The purpose of this study is to describe the clinical and CT features and the outcomes of patients with acute jejunoileal diverticulitis. MATERIALS AND METHODS: Cases of acute jejunoileal diverticulitis managed at three French hospitals November 2005 through January 2015 were identified retrospectively. The final diagnosis relied either on a clinical and radiologic data review by a panel of experts or on surgical findings. Demographic, clinical, laboratory, and 18-month outcome data were collected. CT scans were reviewed by two radiologists who reached a consensus about the presence of an inflammatory diverticulum, evidence of complications, and presence of other bowel diverticula. RESULTS: We identified 33 cases of acute jejunoileal diverticulitis in 33 patients with a median age of 78 years, including 30 (91%) patients in whom an inflammatory diverticulum was identified at the jejunum (n = 26, 87%) or ileum (n = 4, 13%). Extraintestinal gas was seen in 10 (30%) patients and extraintestinal fluid in 11 (33%) patients. Other small-bowel diverticula were visible in all 33 patients. The diverticulitis was mild and resolved with nonoperative treatment in 22 (67%) patients and was severe in the remaining 11 (33%) patients, eight of whom required emergent surgery. CONCLUSION: Acute jejunoileal diverticulitis is a rare and usually nonserious condition that chiefly involves the jejunum. A detailed CT assessment may allow nonoperative treatment. PMID- 29629800 TI - Comparison of Visualization Rates of LI-RADS Version 2014 Major Features With IV Gadobenate Dimeglumine or Gadoxetate Disodium in Patients at Risk for Hepatocellular Carcinoma. AB - OBJECTIVE: The purpose of this study is to compare visualization rates of the major features covered by Liver Imaging Reporting and Data System (LI-RADS) version 2014 in patients at risk for hepatocellular carcinoma using either gadobenate dimeglumine or gadoxetate disodium IV contrast agent. MATERIALS AND METHODS: This retrospective study included liver MRI examinations performed with either gadobenate dimeglumine or gadoxetate disodium contrast enhancement. Using age, sex, underlying liver disease, and presence of cirrhosis, patients were placed into matched cohorts. All hepatic nodules 1 cm or larger (up to five per subject) were included, resulting in 63 subjects with 130 nodules (median nodule size, 1.9 cm) imaged with gadobenate and 64 subjects with 117 nodules (median nodule size, 2.0 cm) imaged with gadoxetate. Three radiologists reviewed the studies for LI-RADS major features independently. Bootstrap resampling with 10,000 repetitions was used to compare feature detection rates. RESULTS: Arterial phase hyperenhancement was seen in a similar number of nodules with gadobenate dimeglumine (mean, 91.5% [119/130]) and gadoxetate disodium (mean, 88.0% [103/117]) (p = 0.173). Dynamic phase washout was more commonly seen with gadobenate dimeglumine (mean, 60.2% [78.3/130]) than with gadoxetate disodium (mean, 45.3% [53/117]) (p = 0.006). The capsule feature was more often visualized with gadobenate dimeglumine (mean, 50.2% [65.3/130]) than with gadoxetate disodium (mean, 33.3% [39/117]) (p < 0.001). Interreader agreement for arterial phase enhancement and dynamic phase washout was almost perfect for both contrast agents (kappa > 0.83). Agreement for the capsule feature was moderate for gadobenate dimeglumine (kappa = 0.52) and substantial for gadoxetate disodium (kappa = 0.67). CONCLUSION: The rates of visualization of arterial phase hyperenhancement are similar in studies performed with gadobenate dimeglumine and gadoxetate disodium, but dynamic phase washout and capsule appearance are more commonly visualized with gadobenate dimeglumine. PMID- 29629801 TI - Modified National Comprehensive Cancer Network Criteria for Assessing Resectability of Pancreatic Ductal Adenocarcinoma. AB - OBJECTIVE: The objective of our study was to assess the preoperative resectability of pancreatic ductal adenocarcinoma (PDAC) using the National Comprehensive Cancer Network (NCCN) guideline, the general rules of the Japan Pancreas Society (JPS), and both of them combined. MATERIALS AND METHODS: Eighty six consecutive patients with PDAC (50 men and 36 women; mean age +/- SD, 70.8 +/ 9.0 years; age range, 49-86 years) underwent dynamic contrast-enhanced CT. Following the NCCN guideline, the degree of vascular invasion was evaluated to determine the NCCN score: 0 points for absence of vascular invasion, 1 point for tumor contact <= 180 degrees , and 2 points for tumor contact > 180 degrees . Direct invasion to adjacent structures was rated according to the general rules of JPS to determine the JPS score: 0 points for absence and 1 point for presence. The NCCN score, JPS score, and sum of the two scores, which we refer to as the "combined score," were compared with histopathologic or intraoperative findings as well as for the differentiation of R0 resection (negative resection margins) from R1 (microscopic tumor infiltration) and R2 (macroscopic residual tumor) using ROC curve analysis. RESULTS: The sensitivities, specificities, and areas under the ROC curves (AUCs) for the differentiation of R0 from R1 and R2 were 100.0%, 40.0%, and 0.725, respectively, with the NCCN score; 63.9%, 84.0%, and 0.824 with the JPS score; and 86.9%, 68.0%, and 0.874 with the combined score. The AUC of the combined score was significantly greater than that of the NCCN score (p = 0.0059). CONCLUSION: The assessment of resectability of PDAC based on the combined criteria of the NCCN guideline and general rules of JPS was superior to that based on either criterion alone. PMID- 29629802 TI - Anastomotic Leaks After Small- and Large-Bowel Surgery: Diagnostic Performance of CT and the Importance of Intraluminal Contrast Administration. AB - OBJECTIVE: The objective of our study was to evaluate the diagnostic performance of CT in the identification of anastomotic leaks. MATERIALS AND METHODS: This was a study of patients who underwent bowel surgery and a subsequent postoperative CT examination performed specifically for investigating for an anastomotic leak. The study group included patients with surgically confirmed anastomotic leaks (n = 59), and the control group included patients without anastomotic leaks (n = 48) confirmed by either repeat surgery or uneventful clinical follow-up for at least 6 months. Two radiologists and two radiology residents independently reviewed each CT examination for specific CT findings from a set of predetermined imaging predictors. The sensitivity and specificity for each imaging predictor were calculated for each reader, and the interobserver agreement was calculated using the Cohen kappa coefficient. Diagnostic performance was assessed using ROC curve analysis. RESULTS: The most sensitive imaging predictor was intraabdominal free fluid (95.3%). Leakage of intraluminal contrast agent was also a highly specific imaging predictor (96.6%). Substantial interobserver agreement was shown for intraabdominal free gas (kappa = 0.76) and leakage of intraluminal contrast agent (kappa = 0.76). Overall diagnostic performance in correctly identifying surgically confirmed leaks, as assessed by the area under the ROC curve, ranged from 0.76 to 0.86. Diagnostic performance was higher for all readers when intraluminal contrast agent was used and reached the anastomosis, with the exception of one reader, whose diagnostic performance remained unchanged. CONCLUSION: Diagnostic performance of CT was highest when an intraluminal contrast agent was used. Meticulous and careful use of an intraluminal contrast agent is therefore important in this patient population. PMID- 29629803 TI - Dynamic CT for Parathyroid Adenoma Detection: How Does Radiation Dose Compare With Nuclear Medicine? AB - OBJECTIVE: Dynamic CT is increasingly used for preoperative localization of parathyroid adenomas, but concerns remain about the radiation effective dose of CT compared with that of 99mTc-sestamibi scintigraphy. The purpose of this study was to compare the radiation dose delivered by three-phase dynamic CT with that delivered by 99mTc-sestamibi SPECT/CT performed in accordance with our current protocols and to assess the possible reduction in effective dose achieved by decreasing the scan length (i.e., z-axis) of two phases of the dynamic CT protocol. MATERIALS AND METHODS: The effective dose of a 99mTc-sestamibi nuclear medicine parathyroid study performed with and without coregistration CT was calculated and compared with the effective dose of our current three-phase dynamic CT protocol as well as a proposed protocol involving CT with reduced scan length. RESULTS: The median effective dose for a 99mTc-sestamibi nuclear medicine study was 5.6 mSv. This increased to 12.4 mSv with the addition of coregistration CT, which is higher than the median effective dose of 9.3 mSv associated with the dynamic CT protocol. Reducing the scan length of two phases in the dynamic CT protocol could reduce the median effective dose to 6.1 mSv, which would be similar to that of the dose from the 99mTc-sestamibi study alone. CONCLUSION: Dynamic CT used for the detection of parathyroid adenoma can deliver a lower radiation dose than 99mTc-sestamibi SPECT/CT. It may be possible to reduce the dose further by decreasing the scan length of two of the phases, although whether this has an impact on accuracy of the localization needs further investigation. PMID- 29629804 TI - Quantitative Assessment of Degenerative Cartilage and Subchondral Bony Lesions in a Preserved Cadaveric Knee: Propagation-Based Phase-Contrast CT Versus Conventional MRI and CT. AB - OBJECTIVE: The aim of this study was to quantitatively assess hyaline cartilage and subchondral bone conditions in a fully preserved cadaveric human knee joint using high-resolution x-ray propagation-based phase-contrast imaging (PBI) CT and to compare the performance of the new technique with conventional CT and MRI. MATERIALS AND METHODS: A cadaveric human knee was examined using an x-ray beam of 60 keV, a detector with a 90-mm2 FOV, and a pixel size of 46 * 46 MUm2. PBI CT images were reconstructed with both the filtered back projection algorithm and the equally sloped tomography method. Conventional 3-T MRI and CT were also performed. Measurements of cartilage thickness, cartilage lesions, International Cartilage Repair Society scoring, and detection of subchondral bone changes were evaluated. Visual inspection of the specimen akin to arthroscopy was conducted and served as a standard of reference for lesion detection. RESULTS: Loss of cartilage height was visible on PBI CT and MRI. Quantification of cartilage thickness showed a strong correlation between the two modalities. Cartilage lesions appeared darker than the adjacent cartilage on PBI CT. PBI CT showed similar agreement to MRI for depicting cartilage substance defects or lesions compared with the visual inspection. The assessment of subchondral bone cysts showed moderate to strong agreement between PBI CT and CT. CONCLUSION: In contrast to the standard clinical methods of MRI and CT, PBI CT is able to simultaneously depict cartilage and bony changes at high resolution. Though still an experimental technique, PBI CT is a promising high-resolution imaging method to evaluate comprehensive changes of osteoarthritic disease in a clinical setting. PMID- 29629805 TI - Comparison Between Image-Guided and Landmark-Based Glenohumeral Joint Injections for the Treatment of Adhesive Capsulitis: A Cost-Effectiveness Study. AB - OBJECTIVE: The purpose of this study was to determine the cost-effectiveness of landmark-based and image-guided intraarticular steroid injections for the initial treatment of a population with adhesive capsulitis. MATERIALS AND METHODS: A decision analytic model from the health care system perspective over a 6-month time frame for 50-year-old patients with clinical findings consistent with adhesive capsulitis was used to evaluate the incremental cost-effectiveness of three techniques for administering intraarticular steroid to the glenohumeral joint: landmark based (also called blind), ultrasound guided, and fluoroscopy guided. Input data on cost, probability, and utility estimates were obtained through a comprehensive literature search and from expert opinion. The primary effectiveness outcome was quality-adjusted life years (QALY). Costs were estimated in 2017 U.S. dollars. RESULTS: Ultrasound-guided injections were the dominant strategy for the base case, because it was the least expensive ($1280) and most effective (0.4096 QALY) strategy of the three options overall. The model was sensitive to the probabilities of getting the steroid into the joint by means of blind, ultrasound-guided, and fluoroscopy-guided techniques and to the costs of the ultrasound-guided and blind techniques. Two-way sensitivity analyses showed that ultrasound-guided injections were favored over blind and fluoroscopy guided injections over a range of reasonable probabilities and costs. Probabilistic sensitivity analysis showed that ultrasound-guided injections were cost-effective in 44% of simulations, compared with 34% for blind injections and 22% for fluoroscopy-guided injections and over a wide range of willingness-to-pay thresholds. CONCLUSION: Ultrasound-guided injections are the most cost-effective option for the initial steroid-based treatment of patients with adhesive capsulitis. Blind and fluoroscopy-guided injections can also be cost-effective when performed by a clinician likely to accurately administer the medication into the correct location. PMID- 29629807 TI - Clinical Feasibility of MR Elastography in Patients With Biliary Obstruction. AB - OBJECTIVE: The purpose of this study is to evaluate the clinical effect of liver stiffness measured using MR elastography (MRE) in patients with cholestasis due to biliary obstruction. MATERIALS AND METHODS: In this retrospective study, 69 consecutive patients with no history of diffuse liver disease who underwent pancreaticobiliary imaging with MRE were included. Quantitative MRI parameters (i.e., liver stiffness, apparent diffusion coefficient, R2*, and proton density fat fraction) and laboratory results (i.e., aspartate aminotransferase, alanine aminotransferase, and total bilirubin levels) were measured. Patients were classified as having either normal bilirubin (group A; n = 49) or hyperbilirubinemia (group B; n = 20). Continuous variables were compared using the independent t test or Mann-Whitney U test. Correlation between parameters was analyzed using the Pearson correlation coefficient. The ROC curve analysis was used to evaluate the diagnostic performance and clinical effect of MRE. RESULTS: Liver stiffness was significantly higher in group B (mean +/- SD, 3.8 +/- 0.7 kPa) than in group A (2.8 +/- 0.5 kPa) (p < 0.001); there were no differences in other MRI parameters. There were positive correlations between liver stiffness and total bilirubin (r = 0.609; p < 0.001), aspartate aminotransferase (r = 0.376; p = 0.001), and alanine aminotransferase (r = 0.285; p = 0.017) levels. There was a negative correlation between the degree of biliary decompression 1 week after bile drainage and liver stiffness (r = -0.71; p = 0.003). The sensitivity and specificity for predicting biliary decompression were 83.3% and 100%, respectively, at a liver stiffness cutoff of 4.0 kPa. CONCLUSION: Liver stiffness measured by MRE increases as cholestasis increases and can be a predictive factor for the sufficiency of biliary decompression after biliary drainage. PMID- 29629806 TI - Comparative Effectiveness of Transarterial Embolization and Sorafenib for Hepatocellular Carcinoma: A Population-Based Study. AB - OBJECTIVE: The purpose of this study was to compare the clinical effectiveness of embolization with that of sorafenib in the management of hepatocellular carcinoma as practiced in real-world settings. MATERIALS AND METHODS: This population-based observational study was conducted with the Surveillance, Epidemiology, and End Results-Medicare linked database. Patients 65 years old and older with a diagnosis of primary liver cancer between 2007 and 2011 who underwent embolization or sorafenib treatment were identified. Patients were excluded if they had insufficient claims records, a diagnosis of intrahepatic cholangiocarcinoma, or other primary cancer or had undergone liver transplant or combination therapy. The primary outcome of interest was overall survival. Inverse probability of treatment weighting models were used to control for selection bias. RESULTS: The inclusion and exclusion criteria were met by 1017 patients. Models showed good balance between treatment groups. Compared with those who underwent embolization, patients treated with sorafenib had significantly higher hazard of earlier death from time of treatment (hazard ratio, 1.87; 95% CI, 1.46-2.37; p < 0.0001) and from time of cancer diagnosis (hazard ratio, 1.87; 95% CI, 1.46-2.39; p < 0.0001). The survival advantage after embolization was seen in both intermediate- and advanced-stage disease. CONCLUSION: This comparative effectiveness study of Medicare patients with hepatocellular carcinoma showed significantly longer overall survival after treatment with embolization than with sorafenib. Because these findings conflict with expert opinion-based guidelines for treatment of advanced-stage disease, prospective randomized comparative trials in this subpopulation would be justified. PMID- 29629808 TI - Intraductal Papillary Neoplasm of the Bile Duct: Clinical, Imaging, and Pathologic Features. AB - OBJECTIVE: We outline the concept of intraductal papillary neoplasm of the bile duct (IPNB), discuss the morphologic features of IPNB and the differential diagnoses, and describe the radiologic approaches used in multidisciplinary management. CONCLUSION: The concept of IPNB has been evolving. Because the imaging features of IPNB can be variable, different mimickers according to IPNB subtype can be considered. A multimodality approach is essential to obtain an optimal diagnosis and establish treatment plans. PMID- 29629809 TI - Imaging and Management of Intrathoracic Renal Cell Carcinoma Metastases. AB - OBJECTIVE: Renal cell carcinoma (RCC) has a propensity to metastasize to the chest, with the lungs being the most common distant metastatic site. The histologic subtype of RCC has implications for prognosis. CONCLUSION: Significant advances have been made in the management of metastatic RCC, both in systemic and locoregional therapies. The aim of this article is to review appearances of intrathoracic metastases from RCC and to discuss treatment considerations. PMID- 29629810 TI - Tomosynthesis Impact on Breast Cancer Screening in Patients Younger Than 50 Years Old. AB - OBJECTIVE: The question of benefits versus harms of breast cancer screening for women younger than 50 years old has been the subject of debate. We investigate if the addition of tomosynthesis to mammography improves screening performance outcomes for women in this age group. MATERIALS AND METHODS: Screening performance for 59,921 patients (41,542 digital mammography and 18,379 tomosynthesis) younger than 50 years old was collected from a community-based screening network from January 1, 2015, to December 31, 2015. Patients were offered tomosynthesis if it was available. Parameters including recall, biopsy, and cancer detection rates were compared. Mixed effects regression analysis was used to estimate rates with screening modality, age, and density as fixed effects and screening site as a random effect. Rates for patients with dense breast tissue were also evaluated. RESULTS: Model adjusted rates per 1000 screenings with digital mammography were compared with digital mammography plus tomosynthesis, respectively: recall rate decreased from 117 to 108 (difference, 8.3; p = 0.003); biopsy rate increased from 13.5 to 16.6 (difference, 3.1; p = 0.003); and cancer detection rate increased from 1.9 to 2.6 (difference, 0.8; p = 0.060). Model adjusted rates for patients with dense breast tissue were: recall rate decreased from 135 to 132 (difference, -3.2; p = 0.44); biopsy rate increased from 16.0 to 20.5 (difference, 4.5; p = 0.004); and cancer detection rate increased from 2.1 to 3.5 (difference, 1.3; p = 0.03). CONCLUSION: Tomosynthesis in a community setting resulted in decreased recall rates for patients younger than 50 years old. For the subgroup of women with dense breast tissue, cancer detection rates also increased. PMID- 29629812 TI - Telehealth for Chronic Obstructive Pulmonary Disease: Promises, Populations, and Personalized Care. PMID- 29629811 TI - Transgender Patients: What Radiologists Need to Know. AB - OBJECTIVE: The purposes of this article are to examine a few of the barriers the transgender population faces in achieving equitable health care, to suggest ways radiologists and radiology staff can help to address these obstacles and provide high-quality care to transgender patients, and to discuss a number of evidence based guidelines regarding appropriate imaging and screening tests for the transgender population. CONCLUSION: Lesbian, gay, bisexual, and transgender individuals face numerous health care disparities, including stigmatization and discrimination in health care environments. Radiology personnel can help to remove such barriers by providing a welcoming clinical environment, practicing cultural humility, and staying up-to-date with rapidly changing recommendations related to transgender care. Continued research will help to provide even stronger evidence-based guidelines for transgender care. PMID- 29629813 TI - Summative Report on Time Out of Play for Major and Minor League Baseball: An Analysis of 49,955 Injuries From 2011 Through 2016. AB - BACKGROUND: Recent epidemiologic reports have demonstrated rising injury rates in Major League Baseball (MLB) and Minor League Baseball (MiLB). Although several studies have recently been published on specific injuries, the majority of injuries have not yet been formally studied. PURPOSE: The purpose of this study is to (1) generate a summative analysis of all injuries that occur in MLB and MiLB, (2) identify the 50 most common injuries, and (3) generate focused reports and fact sheets on the characteristics of each of those diagnoses. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: The MLB Health and Injury Tracking System was used to identify injuries occurring in MLB and MiLB players from 2011 to 2016. Injuries were defined as those that occurred during normal baseball activity and resulted in at least 1 day out of play. A multitude of player and injury characteristics were analyzed, and detailed reports of the 50 most commonly occurring injuries were generated. RESULTS: A total of 49,955 injuries occurred during the study period; 45,123 were non-season ending, and they resulted in 722,176 days out of play. The mean (median) days missed per injury was 16 (6) days. Overall, 39.1% of all injuries occurred in pitchers. The upper extremity was involved in 39% of injuries, while 35% occurred in the hip/groin/lower extremity. Surgery was required in 6.5% of cases, and 9.7% of injuries were season ending. Hamstring strains were the most common injury (n = 3337), followed by rotator cuff strain/tear (n = 1874), paralumbar muscle strain (n = 1313), biceps tendinitis (n = 1264), oblique strain (n = 1249), and elbow ulnar collateral ligament injury (n = 1191). The diagnoses that were most likely to end a player's season were elbow ulnar collateral ligament injury (60% season ending) and superior labrum anterior and posterior tear (50.9% season ending). CONCLUSION: Contrary to prior reports relying on disabled list data, the annual number of injuries in professional baseball remained steady from 2011 to 2016. Similar trends were noted for the annual number of days missed and mean days missed per injury. Although the mean days missed per injury was high (16), the median was much lower at 6 days. PMID- 29629814 TI - Association between HLA-B*15:02 and oxcarbazepine-induced cutaneous adverse reaction: a meta-analysis. AB - AIM: HLA-B*15:02 has been demonstrated as a key risk factor for carbamazepine induced severe cutaneous adverse reaction (sCAR), especially in Asian population. Oxcarbazepine (OXC) is a drug that has a similar structure of carbamazepine. However, the relationship between HLA-B*15:02 and induced cutaneous adverse reaction (cADR) remains unknown. This study aims to analyze this association in the published literature. METHOD: After filtering studies, eight studies were finally included for meta-analysis, including 32 sCAR cases, 112 mild cutaneous adverse reaction (mcADR) cases, 281 OXC tolerant control and 946 population control cases. RESULT: In the tolerant control group, an association was found between HLA-B*15:02 genotype and OXC-induced sCAR (odds ratio [OR]: 18.13; 95% CI: 6.77-48.56), but not in mcADR (OR: 1.43; 95% CI: 0.56-3.64). In population control group, an association was found between HLA-B*15:02 genotype and OXC induced sCAR, (OR: 8.22; 95% CI: 3.03-22.34), but not in mcADR (OR: 2.06; 95% CI: 0.91-4.67). DISCUSSION: Our study demonstrates that the genetic risk factor HLA B*15:02 may be a factor in OXC-induced sCAR. PMID- 29629815 TI - Data Monitoring Committees: Current issues. AB - Maintaining confidentiality of emerging data and ensuring the independence of Data Monitoring Committees are best practices of considerable importance to the ability of these committees to achieve their mission of safeguarding the interests of study participants and enhancing the integrity and credibility of clinical trials. Even with the wide recognition of these principles, there are circumstances where confidentiality issues remain challenging, controversial or inconsistently addressed. First, consider settings where a clinical trial's interim data could provide the evidence regulatory authorities require for decisions about marketing approval, yet where such a trial would be continued post-approval to provide more definitive evidence about principal safety and/or efficacy outcomes. In such settings, data informative about the longer term objectives of the trial should remain confidential until pre-specified criteria for trial completion have been met. Second, for those other than Data Monitoring Committee members, access to safety and efficacy outcomes during trial conduct, even when presented as data pooled across treatment arms, should be on a limited "need to know" basis relating to the ability to carry out ethical or scientific responsibilities in the conduct of the trial. Third, Data Monitoring Committee members should have access to unblinded efficacy and safety data throughout the trial to enable timely and informed judgments about risks and benefits. Fourth, it should be recognized that a mediator potentially could be useful in rare settings where the Data Monitoring Committee would have serious ethical or scientific concerns about the sponsor's dissemination or lack of dissemination of information. Data Monitoring Committee Contract Agreements, Indemnification Agreements and Charters should be developed in a manner to protect Data Monitoring Committee members and their independence, in order to enhance the Data Monitoring Committee's ability to effectively address their mission. PMID- 29629816 TI - Factor analysis and validation of a self-report measure of impaired fear inhibition. AB - Difficulties with inhibiting fear have been associated with the emergence of anxiety problems and poor response to cognitive-behavioural treatment. Fear inhibition problems measured using experimental paradigms involving aversive stimuli may be inappropriate for vulnerable samples and may not capture fear inhibition problems evident in everyday life. We present the Fear Inhibition Questionnaire (FIQ), a self-report measure of fear inhibition abilities. We assess the FIQ's factor structure across two cultures and how well it correlates with fear inhibition indices derived experimentally. Adolescent participants from Hong Kong and England completed the FIQ, with the English participants also completing a conditioning and extinction task to assess fear inhibition problems. Across both cultures, the FIQ showed a single factor structure and low FIQ scores, or worse fear inhibition problems, were associated with self-reports of heightened anxiety. Correlation of FIQ scores with experimental indices, whilst controlling for anxious symptoms, suggests that the FIQ represents a valid and unique measure of fear inhibition abilities. The FIQ might be used to assess more ecologically valid fear inhibition problems particularly amongst people who have or who are at risk of anxiety diagnoses. PMID- 29629817 TI - Trends in patented chromones for skin diseases. PMID- 29629818 TI - Prevalence of Exclusive Breastfeeding and Factors Associated With Exclusive Breastfeeding of Children in Trongsa District, Bhutan. AB - The World Health Organization estimated that about 800 000 infant deaths could be prevented annually by exclusively breastfeeding infants for the first 6 months of life. This study aimed to examine the prevalence of exclusive breastfeeding and its associated factors. A total of 192 mothers participated. The prevalence of exclusive breastfeeding practice in Trongsa district was 97% at 1 month, declining to 58% at 6 months. Mothers who returned to formal work were less likely to exclusively breastfeed than those who were farmers or housewives. The main reasons stated by the mothers for not exclusively breastfeeding were lack of the mother's self-confidence that the child is getting enough breastmilk and mothers having to return to work, 59% and 22%, respectively. The rate of exclusive breastfeeding in Trongsa district of Bhutan is high, and every effort should be made to maintain and improve this rate. PMID- 29629820 TI - Recent gene delivery patents for treatment of atherosclerosis. PMID- 29629821 TI - Traffic-associated air pollution as a risk factor for cancer in individuals with coronary artery disease. PMID- 29629822 TI - Opt-Out Parental Consent in Online Surveys: Ethical Considerations. AB - This article aims to foster discussion and debate around seeking parental consent from young people recruited online. The growth of social media, particularly for young people, has led to increased interest in young people's online activities as both a research topic and recruitment setting. In a health-related study, which sought to recruit young people aged 13 to 18 years old from YouTuber fan communities to an online survey, the question arose of how parental consent could be sought from young people below 16 when no link existed between researcher and parents/guardians. A practical strategy is proposed which combines novel communication methods for participant information, opt-out online consent and age verification to address this issue. Strengths and limitations of these approaches are discussed. PMID- 29629823 TI - Durable response to bevacizumab in adults with recurrent pilocytic astrocytoma. AB - BACKGROUND: Adult pilocytic astrocytomas are rare and highly vascular tumors. AIM: We hypothesized that they may be uniquely responsive to bevacizumab (BEV). PATIENTS: We present four adult patients with pathologically diagnosed WHO grade I pilocytic astrocytoma who had robust and durable responses to BEV at time of recurrence. Three patients developed radiographic changes on MRI, consistent with progressive disease based on response assessment in neuro-oncology criteria. Median time to recurrence was 8.5 months. METHODS: All patients were treated with six cycles of BEV for recurrence. RESULTS: At the end of treatment, all patients had achieved a clinical and radiographic response. Median follow-up time after BEV is 20.5 months. CONCLUSION: This suggests that BEV may have true antitumor activity in adult pilocytic astrocytomas and may be important for achieving durable disease control. PMID- 29629824 TI - Making Room for Second Language Phonotactics: Effects of L2 Learning and Environment on First Language Speech Perception. AB - Language-specific restrictions on sound sequences in words can lead to automatic perceptual repair of illicit sound sequences. As an example, no Spanish words begin with /s/-consonant sequences ([#sC]), and where necessary (e.g., foreign loanwords) [#sC] is repaired by inserting an initial [e], (e.g. foreign loanwords, cf., esnob, from English snob). As a result, Spanish speakers tend to perceive an illusory [e] before [#sC] sequences. Interestingly, this perceptual illusion is weaker in early Spanish-English bilinguals, whose other language, English, allows [#sC]. The present study explored whether this apparent influence of the English language on Spanish is restricted to early bilinguals, whose early language experience includes a mixture of both languages, or whether later learning of second language (L2) English can also induce a weakening of the first language (L1) perceptual illusion. Two groups of late Spanish-English bilinguals, immersed in Spanish or English, were tested on the same Spanish AX (same different) discrimination task used in a study by Carlson et al., (2016) and their results compared with the Spanish monolinguals from Carlson et al.'s study. Like early bilinguals, late bilinguals exhibited a reduced impact of perceptual prothesis on discrimination accuracy. Additionally, late bilinguals, particularly in English immersion, were slowest when responding against the Spanish perceptual illusion. Robust L1 perceptual illusions thus appear to be malleable in the face of later L2 learning. It is argued that these results are consonant with the need for late bilinguals to navigate alternative, conflicting representations of the same acoustic material, even in unilingual L1 speech perception tasks. PMID- 29629825 TI - CYP3A pharmacogenetic association with tacrolimus pharmacokinetics differs based on route of drug administration. AB - Tacrolimus is prescribed to the majority of transplant recipients to prevent graft rejection, and although patients are maintained on oral administration, nonoral routes of administration are frequently used in the initial post transplant period. CYP3A5 genotype is an established predictor of oral tacrolimus dose requirements, and clinical guideline recommendations exist for CYP3A5-guided dose selection. However, the association between CYP3A5 and nonoral tacrolimus administration is currently poorly understood, and differs from the oral tacrolimus relationship. In addition to CYP3A5, other pharmacogenes associated with CYP3A activity, including CYP3A4, CYP3A7 and POR have also been identified as predictors of tacrolimus exposure. This review will describe the current understanding of the relationship between these pharmacogenes and tacrolimus pharmacokinetics after oral and nonoral administration. PMID- 29629826 TI - Cure of human diabetic neuropathy by HPLC validated bark extract of Onosma echioides L. root. AB - HPLC validated hexane bark extract of Onosma echioides L. root (OE) was evaluated for cure of human diabetic neuropathy in human neuroblastoma cell line. HPLC analysis was performed. Human neuroblastoma cells were grouped into control, normal glucose, high glucose (HG) and HG plus different concentrations of OE extract (10, 25 and 50 MUg/mL). MTT, DCFH-DA staining and nuclear condensation assays were performed on neuroblastoma cells to evaluate antiproliferative activity, ROS activity level and apoptotic effect of OE. HPLC analysis revealed the existence of maximum yield of shikonin in n-hexane extract of OE. Exposure with different concentrations of OE effectively decreased ROS level and apoptosis of cells and as a result improved the viability of cells in a dose dependent manner in response to HG-induced oxidative stress. Thus, OE possesses the property to cure human diabetic neuropathy and further can be clinically tested for its use in diabetic neuropathy. PMID- 29629827 TI - Statin guidelines: Friend or foes? PMID- 29629828 TI - A Qualitative Evaluation of Telephone-Based Cognitive-Behavioral Therapy for Postpartum Mothers. AB - The purpose of this study was to explore postpartum women's perceptions of a telephone-based cognitive-behavioral therapy (T-CBT). Using an exploratory qualitative design, a purposeful sample of 39 first-time Chinese mothers who had participated in the T-CBT was interviewed at 6 weeks postpartum. Data were collected using semi-structured interviews and analyzed by content analysis. The findings revealed that Chinese women perceived T-CBT to be helpful in increasing their confidence in the maternal role, enhancing their emotional control, and increasing their sense of support. The effectiveness of T-CBT was enhanced by the delivery of the intervention by health care professional and the flexibility of intervention to provide individualized and timely information. The evidence suggests T-CBT is a feasible modality with the potential to support mothers in managing the demands of parental transition. T-CBT could be incorporated into perinatal services on an ongoing and regular basis, and therefore readily accessible to all postpartum women. PMID- 29629829 TI - Nanosized carriers based on amphiphilic poly-N-vinyl-2-pyrrolidone for intranuclear drug delivery. AB - AIM: Ability to deliver drugs into the cell nuclei can significantly increase the efficacy of cancer therapies, in particular in the case of multidrug-resistant cancer Results: Polymer nanocarriers based on amphiphilic thiooctadecyl terminated poly-N-vinyl-2-pyrrolidone were produced and loaded with a model hydrophobic drug, curcumin. Two commonly used loading approaches - emulsification and ultrasonic dispersion - were found to lead to two different size distributions with distinctively different biological effect. While nanocarriers produced via the emulsion method penetrated cells by dynamin-dependent endocytic mechanisms, sub-100 nm dispersion-produced nanocarriers were capable of crossing the membranes via biologically independent mechanisms. CONCLUSION: This finding opens an intriguing possibility of intranuclear delivery by merely tailoring the size of polymeric carriers, thus promising a new approach for cancer therapies. PMID- 29629830 TI - Molecular dynamics simulations showing 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) membrane mechanoporation damage under different strain paths. AB - Continuum finite element material models used for traumatic brain injury lack local injury parameters necessitating nanoscale mechanical injury mechanisms be incorporated. One such mechanism is membrane mechanoporation, which can occur during physical insults and can be devastating to cells, depending on the level of disruption. The current study investigates the strain state dependence of phospholipid bilayer mechanoporation and failure. Using molecular dynamics, a simplified membrane, consisting of 72 1-palmitoyl-2-oleoyl-phosphatidylcholine (POPC) phospholipids, was subjected to equibiaxial, 2:1 non-equibiaxial, 4:1 non equibiaxial, strip biaxial, and uniaxial tensile deformations at a von Mises strain rate of 5.45 * 108 s-1, resulting in velocities in the range of 1 to 4.6 m.s-1. A water bridge forming through both phospholipid bilayer leaflets was used to determine structural failure. The stress magnitude, failure strain, headgroup clustering, and damage responses were found to be strain state-dependent. The strain state order of detrimentality in descending order was equibiaxial, 2:1 non equibiaxial, 4:1 non-equibiaxial, strip biaxial, and uniaxial. The phospholipid bilayer failed at von Mises strains of .46, .47, .53, .77, and 1.67 during these respective strain path simulations. Additionally, a Membrane Failure Limit Diagram (MFLD) was created using the pore nucleation, growth, and failure strains to demonstrate safe and unsafe membrane deformation regions. This MFLD allowed representative equations to be derived to predict membrane failure from in-plane strains. These results provide the basis to implement a more accurate mechano physiological internal state variable continuum model that captures lower length scale damage and will aid in developing higher fidelity injury models. PMID- 29629831 TI - Why regular church-goers have lower cardiovascular disease risks. PMID- 29629832 TI - Allelopathic activity and chemical constituents of extracts from roots of Euphorbia heterophylla L. AB - Euphorbia heterophylla L. is regarded as a major weed worldwide. Its high aggressiveness in agricultural environment prompted us to investigate the allelopatic activity and chemical constitution of extracts from roots of this plant. Hexane extract showed low phytotoxic activity. Methanol extract at 2.0 mg mL-1 inhibited 100% of germination, root and shoot growth of the indicator plants Sorghum bicolor and Lactuca sativa. beta-sitosterol, stigmasterol, and esters of lupeol, germanicol, taraxasterol, pseudotaraxasterol, alpha-amyrin and beta amyrin were isolated from the hexane extract and their structures elucidated on the basis of MS and 1H, 13C and DEPT-135 NMR data. GC-MS analysis of the derivatized methanol extract allowed for identifying a series of allelopathic organic acids potentially involved in allelopathic interactions of E. heterophylla. This is the first study on the allelopathic activity of extracts and identification of metabolites from roots of E. heterophylla. PMID- 29629835 TI - Why ginseng has protective functions on the heart. PMID- 29629833 TI - Aerobic exercise training differentially affects ACE C- and N-domain activities in humans: Interactions with ACE I/D polymorphism and association with vascular reactivity. AB - INTRODUCTION: Previous studies have linked angiotensin-converting enzyme ( ACE) insertion (I)/deletion (D) polymorphism (II, ID and DD) to physical performance. Moreover, ACE has two catalytic domains: NH2 (N) and COOH (C) with distinct functions, and their activity has been found to be modulated by ACE polymorphism. The aim of the present study is to investigate the effects of the interaction between aerobic exercise training (AET) and ACE I/D polymorphism on ACE N- and C domain activities and vascular reactivity in humans. MATERIALS AND METHODS: A total of 315 pre-selected healthy males were genotyped for II, ID and DD genotypes. Fifty completed the full AET (II, n = 12; ID, n = 25; and DD, n = 13), performed in three 90-minute sessions weekly, in the four-month exercise protocol. Pre- and post-training resting heart rate (HR), peak O2 consumption (VO2 peak), mean blood pressure (MBP), forearm vascular conduction (FVC), total circulating ACE and C- and N-domain activities were assessed. One-way ANOVA and two -way repeated-measures ANOVA were used. RESULTS: In pre-training, all variables were similar among the three genotypes. In post-training, a similar increase in FVC (35%) was observed in the three genotypes. AET increased VO2 peak similarly in II, ID and DD (49+/-2 vs. 57+/-1; 48+/-1 vs. 56+/-3; and 48+/-5 vs. 58+/-2 ml/kg/min, respectively). Moreover, there were no changes in HR and MBP. The DD genotype was also associated with greater ACE and C-domain activities at pre- and post-training when compared to II. AET decreased similarly the total ACE and C-domain activities in all genotypes, while increasing the N-domain activity in the II and DD genotypes. However, interestingly, the measurements of N-domain activity after training indicate a greater activity than the other genotypes. These results suggest that the vasodilation in response to AET may be associated with the decrease in total ACE and C-domain activities, regardless of genotype, and that the increase in N-domain activity is dependent on the DD genotype. CONCLUSIONS: AET differentially affects the ACE C- and N-domain activities, and the N-domain activity is dependent on ACE polymorphism. PMID- 29629834 TI - Second-generation nitazoxanide derivatives: thiazolides are effective inhibitors of the influenza A virus. AB - AIM: The only small molecule drugs currently available for treatment of influenza A virus (IAV) are M2 ion channel blockers and sialidase inhibitors. The prototype thiazolide, nitazoxanide, has successfully completed Phase III clinical trials against acute uncomplicated influenza. RESULTS: We report the activity of seventeen thiazolide analogs against A/PuertoRico/8/1934(H1N1), a laboratory adapted strain of the H1N1 subtype of IAV, in a cell culture-based assay. A total of eight analogs showed IC50s in the range of 0.14-5.0 MUM. Additionally a quantitative structure-property relationship study showed high correlation between experimental and predicted activity based on a molecular descriptor set. CONCLUSION: A range of thiazolides show useful activity against an H1N1 strain of IAV. Further evaluation of these molecules as potential new small molecule therapies is justified. PMID- 29629836 TI - Use of a tracheal dilator for percutaneous insertion of 27F and 31F Avalon(c) dual-lumen cannulae for veno-venous extracorporeal membrane oxygenation in adults. AB - Veno-venous extracorporeal membrane oxygenation can be performed either by two cannulae or by a single dual-lumen cannula. The dual-lumen cannulation configuration offers multiple advantages: it avoids the femoral site which may be at greater risk of infection, it improves patient mobility, eases prone positioning and greatly reduces recirculation. The Avalon was the first commercially available dual-lumen cannula for adults. It has gained much popularity, but, for more than a year now, the adult vascular access kit with the 30Fr dilator has been discontinued in the United Kingdom. In this article, we share our experience with an alternative insertion method, using a percutaneous dilatational tracheostomy kit. This off-label use of the tracheostomy dilator appears to be safe. It may allow the continuing use of Avalon dual-lumen cannulae while waiting for a more permanent solution to be provided by the manufacturer. PMID- 29629837 TI - Impact of hypertension on early outcomes and long-term survival of patients undergoing aortic repair with Stanford A dissection. AB - INTRODUCTION: Stanford A acute aortic dissection (AAD) is a life-threatening emergency, typically occurring in hypertensive patients, requiring immediate surgical repair. The aim of this study was to evaluate early outcomes and long term survival of hypertensive patients in comparison to normotensive patients suffering from Stanford A AAD. METHODS: In our center, 240 patients with Stanford A AAD underwent aortic surgical repair from January 2006 to April 2015. After statistical and logistic regression analysis, Kaplan-Meier survival estimation was performed, with up to 9-year follow-up. RESULTS: The proportion of hypertensive patients suffering from Stanford A AAD was 75.4% (n=181). There were only few statistically significant differences in terms of basic demographics, comorbidities, preoperative baseline and clinical characteristics of hypertensive patients in comparison to normotensive patients. Hypertensive patients were significantly older (p=0.008), more frequently received hemi-arch repair (p=0.028) and selective brain perfusion (p=0.001). Our study showed similar statistical results in terms of 30-day mortality (p=0.196), long-term overall cumulative survival of patients (Log-Rank p=0.506) and survival of patients free from cerebrovascular events (Log-Rank p=0.186). Furthermore, subgroup analysis for long-term survival in terms of men (Log-Rank p=0.853), women (Log-Rank p=0.227), patients under and above 65 years of age (Log-Rank p=0.188 and Log-Rank p=0.602, respectively) and patients undergoing one of the three types of aortic repair surgery showed similar results for normotensive and hypertensive patient groups. Subgroup analysis for long-term survival of patients free from cerebrovascular events for women, patients under 65 years of age and patients undergoing aortic arch repair showed significant differences between the two groups in favor of hypertensive patients. CONCLUSIONS: Hypertensive patients suffering from Stanford A AAD were older, more frequently received hemi-arch replacement and were not associated with increased risk of 30-day mortality and poorer long-term survival compared to normotensive patients. PMID- 29629838 TI - A genetic polymorphism in the CYP1B1 gene in patients with squamous cell carcinoma of the esophagus: an Iranian Mashhad cohort study recruited over 10 years. AB - AIM: Esophageal cancer is the eighth most common cancer globally and the seventh most common cause of cancer-related deaths in men. Recent studies have shown that CYP450, family 1, subfamily B, polypeptide 1, which plays a role in the metabolism of xenobiotics, is associated with several cancers. Therefore, in the present study we investigated the association between a genetic variant, CYP1B1 rs1056836 gene, with the clinical characteristics of patients with squamous cell carcinoma of the esophagus (ESCC). METHOD: In this study, 117 patients with ESCC and 208 healthy controls were recruited. DNA was extracted and genotyped using real-time PCR-based TaqMan. Kaplan-Meier curves were utilized to assess overall and progression-free survival. To evaluate the relationship between clinicopathological data, genotypic frequencies, disease prognosis and survival, Pearson's chi2 and t-test were used. Logistic regression was utilized to assess the association between the risk of ESCC and genotypes. RESULTS: The genotypic frequency for GG, GC and CC were 58.6, 29.8 and 11.5%, respectively, in the healthy subjects and 51.8, 36.14 and 12% in the ESCC group. An association between the GG genotype and stage of ESCC was found. Also, statistically significant results were not found for this variation and risk of ESCC. CONCLUSION: Our findings suggest a relationship between the CYP1B1-rs1056836 genetic polymorphism and clinical features of ESCC, supporting further studies in larger populations in different ethnic groups, taking into account potentially important environmental factors such as diet. PMID- 29629839 TI - Advances in patented interpenetrating polymeric networks for biomedical applications. PMID- 29629840 TI - Proteomics detection of S100A6 in tumor tissue interstitial fluid and evaluation of its potential as a biomarker of cholangiocarcinoma. AB - Tumor interstitial fluid contains tumor-specific proteins that may be useful biomarkers for cancers. In this study, we identified proteins present in cholangiocarcinoma interstitial fluid. Proteins derived from three samples of tumor interstitial fluid and paired samples of adjacent normal interstitial fluid from cholangiocarcinoma patients were subjected to two-dimensional liquid chromatography with tandem mass spectrometry. Candidate proteins were selected based on a greater than twofold change in expression levels between tumor interstitial fluid and normal interstitial fluid. Upregulation of six proteins in tumor interstitial fluid, including S100 calcium binding protein A6 (S100A6), S100 calcium binding protein A9, aldo-keto reductase family 1 member C4, neuropilin-1, 14-3-3 zeta/delta, and triosephosphate isomerase was assessed by western blot and immunohistochemistry. Their potential as markers was evaluated in human cholangiocarcinoma tissue arrays, and in serum using enzyme-linked immunosorbent assay. Expression of S100A6 was higher in tumor interstitial fluid than in normal interstitial fluid and showed the highest positive rate (98.96%) in cholangiocarcinoma tissues. Serum levels of S100A6 did not differ between cholangitis and cholangiocarcinoma patients, but were significantly higher than in healthy individuals ( p < 0.0001). In cholangiocarcinoma cases, S100A6 level was associated with vascular invasion ( p = 0.007) and could distinguish cholangiocarcinoma patients from healthy individuals as effectively as the carbohydrate antigen 19-9. In addition, potential for drug treatment targeting S100A6 and other candidate proteins was also demonstrated using STITCH analysis. In conclusion, proteomics analysis of tumor interstitial fluid could be a new approach for biomarker discovery, and S100A6 is a potential risk marker for screening of cholangiocarcinoma. PMID- 29629841 TI - Self-efficacy and planning strategies can improve physical activity levels in women with a recent history of gestational diabetes mellitus. AB - INTRODUCTION: Regular physical activity can reduce the risk of developing diabetes in high risk populations including in women with gestational diabetes mellitus (GDM). This study applied the Health Action Process Approach (HAPA) to determine the motivational and volitional factors important in increasing physical activity among women with previous GDM. METHODS: Women with GDM receiving obstetric care at a teaching hospital in Sri Lanka were invited to participate in a survey 6-36 months post-delivery. At baseline and 8 weeks later, 152 women completed postal and telephone surveys that collected socio-cognitive and physical activity data. The study hypotheses were tested using structural equation modelling. RESULTS: The modified model fit the data well (CFI = .95, TLI = .94, RMSEA = .057) and explained 11% of the variance in behaviour. Action self efficacy was the only important predictor of intention to be physically active. Intention as well as maintenance self-efficacy predicted planning, which, in turn, predicted physical activity. Planning mediated the effect of intention and self-efficacy (maintenance and recovery) on physical activity. CONCLUSION: This study has identified predictors of physical activity among women with previous GDM that can inform intervention studies. Interventions targeting this population need to include planning strategies and enhance self-efficacy. PMID- 29629842 TI - The Prevalence of "Late-Onset" ADHD in a Clinically Referred Adult Sample. AB - OBJECTIVE: Three recent prospective longitudinal studies of population cohorts reported nontrivial rates of "adult-onset" ADHD. Given that this result is at odds with the neurodevelopmental conceptualization of ADHD, as well as with general clinical experience, we obtained report of onset of symptoms in a clinical sample of adults diagnosed with ADHD. METHOD: One hundred four adults diagnosed with ADHD completed retrospective ratings of DSM-IV/DSM-5 ADHD symptoms between the ages of 5 and 12 years. RESULTS: Fifty percent of the sample met full retrospective child diagnostic symptom criteria of six ADHD symptoms in either the inattentive or hyperactive-impulsive domains. Seventy-five percent met a less stringent criterion of four symptoms in either domain. DISCUSSION: These results are interpreted in light of a dimensional model of ADHD that posits emergence of ADHD symptoms and corresponding impairment as a function of increasing performance demands and/or decreasing environmental supports during the course of development. PMID- 29629843 TI - Folate biosynthesis pathway: mechanisms and insights into drug design for infectious diseases. AB - Folate pathway is a key target for the development of new drugs against infectious diseases since the discovery of sulfa drugs and trimethoprim. The knowledge about this pathway has increased in the last years and the catalytic mechanism and structures of all enzymes of the pathway are fairly understood. In addition, differences among enzymes from prokaryotes and eukaryotes could be used for the design of specific inhibitors. In this review, we show a panorama of progress that has been achieved within the folate pathway obtained in the last years. We explored the structure and mechanism of enzymes, several genetic features, strategies, and approaches used in the design of new inhibitors that have been used as targets in pathogen chemotherapy. PMID- 29629844 TI - Aspirin suppresses components of lymphangiogenesis and lymphatic vessel remodeling by inhibiting the NF-kappaB/VCAM-1 pathway in human lymphatic endothelial cells. AB - Lymphangiogenesis is the process of new vessel formation from pre-existing lymphatic vessels. The process mainly involves cell adhesion, migration, and tubule formation of lymphatic endothelial cells. Tumor-induced lymphangiogenesis is an important factor contributing to promotion of tumor growth and cancer metastasis via the lymphatic system. Finding the non-toxic agents that can prevent or inhibit lymphangiogenesis may lead to blocking of lymphatic metastasis. Recently, aspirin, a non-steroidal anti-inflammatory drug (NSAID), has been reported to inhibit in vivo lymphangiogenesis in tumor and incision wound models, but the mechanisms of actions of aspirin on anti-lymphangiogenesis have been less explored. In this study, we aim to explore the mechanism underlying the anti-lymphangiogenic effects of aspirin in primary human dermal lymphatic microvascular endothelial (HMVEC-dLy) cells in vitro. Pretreatment of aspirin at non-toxic dose 0.3 mM significantly suppressed in vitro cord formation, adhesion, and the migration abilities of the HMVEC-dLy cells. Western blotting analysis indicated that aspirin decreased expression of vascular cell adhesion molecule-1 (VCAM-1), at both protein and mRNA levels, and these correlated with the reduction of NF-kappaB p65 phosphorylation. By using NF kappaB inhibitor (BAY-11-7085) and VCAM-1 siRNA, we showed that VCAM-1 expression is downstream of NF-kappaB activation, and this NF-kappaB/VCAM-1 signaling pathway controls cord formation, adhesion, and the migration abilities of the HMVEC-dLy cells. In summary, we demonstrate the potential of aspirin as an anti lymphangiogenic agent, and elucidate its mechanism of action. PMID- 29629845 TI - Ticagrelor in Peripheral Artery Disease Endovascular Revascularization (TI-PAD): Challenges in clinical trial execution. AB - There is limited evidence to guide clinical decision-making for antiplatelet therapy in peripheral artery disease (PAD) in the setting of lower extremity endovascular treatment. The Ticagrelor in Peripheral Artery Disease Endovascular Revascularization Study (TI-PAD) evaluated the role of ticagrelor versus aspirin as monotherapy in the management of patients following lower extremity endovascular revascularization. The trial failed to recruit the targeted number of patients, likely due to aspects of the design including the lack of option for dual antiplatelet therapy, and inability to identify suitable patients at study sites. In response, the protocol underwent amendments, but these changes did not adequately stimulate recruitment, and thus TI-PAD was prematurely terminated. This article describes the rationale for TI-PAD and challenges in trial design, subject recruitment and trial operations to better inform the conduct of future trials in PAD revascularization. ClinicalTrials.gov Identifier: NCT02227368. PMID- 29629846 TI - Molecular profiling of pancreatic neuroendocrine tumors (pNETS) and the clinical potential. AB - INTRODUCTION: Pancreatic neuroendocrine tumors (pNETs) represent a small part of pancreatic neoplasms, and the knowledge about their indolent clinical course remains a subject of investigation. They occur sporadically or as part of familial cancer syndromes and are classified by WHO in 3 categories. There is ongoing research to understand their molecular profiling and leading mutations. Areas covered: The aim of this review is to clarify the overall aspects of tumorigenesis, to expose the latest developments in understanding the course of the disease and the possible therapeutic implications of these. The review also discusses functional and non-functional pNETs and associated inherited syndromes as well as pNET molecular profiling and its possible guidance in the use of targeted therapy. Expert commentary: In the next decade, a more extensive application of new technologies will help improve quality of life and survival, individualizing treatment protocols and identifying which therapeutic strategy is more suitable for each kind of NET. PMID- 29629847 TI - Understanding the Cognitive and Affective Mechanisms that Underlie Proxy Risk Perceptions among Caregivers of Asthmatic Children. AB - OBJECTIVE: Medical decisions made on behalf of another person-particularly those made by adult caregivers for their minor children-are often informed by the decision maker's beliefs about the treatment's risks and benefits. However, we know little about the cognitive and affective mechanisms influencing such "proxy" risk perceptions and about how proxy risk perceptions are related to prominent judgment phenomena. METHODS: Adult caregivers of minor children with asthma ( N = 132) completed an online, cross-sectional survey assessing 1) cognitions and affects that form the basis of the availability, representativeness, and affect heuristics; 2) endorsement of the absent-exempt and the better-than-average effect; and 3) proxy perceived risk and unrealistic comparative optimism of an asthma exacerbation. We used the Pediatric Asthma Control and Communication Instrument (PACCI) to assess asthma severity. RESULTS: Respondents with higher scores on availability, representativeness, and negative affect indicated higher proxy risk perceptions and (for representativeness only) lower unrealistic optimism, irrespective of asthma severity. Conversely, respondents who showed a stronger display of the better-than-average effect indicated lower proxy risk perceptions but did not differ in unrealistic optimism. The absent-exempt effect was unrelated to proxy risk perceptions and unrealistic optimism. CONCLUSION: Heuristic judgment processes appear to contribute to caregivers' proxy risk perceptions of their child's asthma exacerbation risk. Moreover, the display of other, possibly erroneous, judgment phenomena is associated with lower caregiver risk perceptions. Designing interventions that target these mechanisms may help caregivers work with their children to reduce exacerbation risk. PMID- 29629848 TI - Setting Dead at Zero: Applying Scale Properties to the QALY Model. AB - INTRODUCTION: Scaling severe states can be a difficult task. First, the method of measurement affects whether a health state is considered better or worse than dead. Second, in discrete choice experiments, different models to anchor health states on 0 (dead) and 1 (perfect health) produce varying amounts of health states worse than dead. RESEARCH QUESTION: Within the context of the quality adjusted life year (QALY) model, this article provides insight into the value assigned to dead and its consequences for decision making. Our research questions are 1) what are the arguments set forth to assign dead the number 0 on the health utility scale? And 2) what are the effects of the position of dead on the health utility scale on decision making? METHODS: A literature review was conducted to explore the arguments set forth to assign dead a value of 0 in the QALY model. In addition, scale properties and transformations were considered. RESULTS: The review uncovered several practical and theoretical considerations for setting dead at 0. In the QALY model, indifference between 2 health episodes is not preserved under changes of the origin of the duration scale. Ratio scale properties are needed for the duration scale to preserve indifferences. In combination with preferences and zero conditions for duration and health, it follows that dead should have a value of 0. CONCLUSIONS: The health-utility and duration scales have ratio scale properties, and dead should be assigned the number 0. Furthermore, the position of dead should be carefully established, because it determines how life-saving and life-improving values are weighed in cost-utility analysis. PMID- 29629850 TI - Debating the ethics of gene drives. PMID- 29629849 TI - Driving towards ecotechnologies. AB - The prospect of using genetic methods to target vector, parasite, and reservoir species offers tremendous potential benefits to public health, but the use of genome editing to alter the shared environment will require special attention to public perception and community governance in order to benefit the world. Public skepticism combined with the media scrutiny of gene drive systems could easily derail unpopular projects entirely, especially given the potential for trade barriers to be raised against countries that employ self-propagating gene drives. Hence, open and community-guided development of thoughtfully chosen applications is not only the most ethical approach, but also the most likely to overcome the economic, social, and diplomatic barriers. Here we review current and past attempts to alter ecosystems using biological methods, identify key determinants of social acceptance, and chart a stepwise path for developers towards safe and widely supported use. PMID- 29629851 TI - The effect of Glut1 and c-myc on prognosis in esophageal squamous cell carcinoma of Kazakh and Han patients. AB - AIM: Glucose transporter type 1 (Glut1) plays a crucial role in cancer-specific metabolism. We explored the expression of Glut1 and c-myc, the relationship between them and the effect of Glut1, c-myc on prognosis in esophageal squamous cell carcinoma. MATERIALS & METHODS: Immunohistochemistry was used to examine the expression of Glut1 and c-myc. chi2 test analyzes the relationship between c-myc, Glut1 and pathological parameters. Spearman correlation analyzes the relationship between c-myc and Glut1. Survival analysis was used to investigate the effect of Glut1 and c-myc on prognosis. RESULTS: Glut1 positivity was associated with tumor size (p < 0.01), depth of invasion (p = 0.021), Tumor, Node, Metastasis stage (IA+IB,II+IIB,IIIA+IIIB,IVA+IVB; p = 0.004), lymph node metastasis (p = 0.002) and nerve invasion (p = 0.050). C-myc positivity was associated with tumor location (p = 0.015), depth of invasion (p = 0.022) and lymph node metastasis (p = 0.035). There was a positive correlation between c-myc and Glut1 (r = 0.321). Patients with Glut1 c-myc co-expression had poorer prognosis. CONCLUSION: Inhibiting Glut1 c-myc co-expression may improve the prognosis of esophageal squamous cell carcinoma. PMID- 29629852 TI - Raltegravir versus lopinavir/ritonavir for treatment of HIV-infected late presenting pregnant women. AB - Background Late-presenting pregnant women pose a challenge in the prevention of HIV-1 mother-to-child-transmission. We compared the safety and efficacy of raltegravir and lopinavir/ritonavir for this population. Methods We did a single center, pilot, open-label, randomized trial in Brazil (N = 44). We randomly allocated late-presenting HIV-infected pregnant women (older than 18 years with a plasma HIV-1 RNA >1000 copies/mL) to receive raltegravir 400 mg twice a day or lopinavir/ritonavir 400/100 mg twice a day plus zidovudine and lamivudine (1:1). The primary endpoint was virological suppression at delivery (HIV-1 RNA <50 copies per mL), in all patients who received at least one dose of study drugs (modified intention-to-treat analysis). Missing information was treated as failure. We assessed safety in all patients. Results We enrolled and randomly assigned treatment to 33 patients (17 in raltegravir group) between June 2015 and June 2017. The study was interrupted by the IRB because a significant difference between arms was detected in an interim analysis. All patients completed follow up at delivery. At delivery, virological suppression was achieved by 13/17 (76.5%) of patients in raltegravir group, versus 4/16 (25.0%) in lopinavir/ritonavir group (RR 3.1, 95% CI: 1.3-7.4). Patients in raltegravir group had significantly higher proportion of virological suppression at 2, 4, and 6 weeks than lopinavir/ritonavir group. Adverse events were most of mild intensity, but patients in lopinavir/ritonavir group had significantly more gastrointestinal adverse events. There was neither discontinuation nor deaths in this trial. Conclusion Raltegravir might be a first-line option for treatment of HIV-infected late-presenting pregnant women. PMID- 29629853 TI - [Determining depth of burns using laser Doppler imaging]. AB - Early accurate assessment of burn depth is important to determine the optimal treatment of burns (conservative versus surgery). Laser Doppler imaging (LDI) is a technique that allows accurate measurement of burn depth by measuring dermal perfusion. Although it has been demonstrated that LDI led to faster decisions as to whether or not to operate, this has not lead to shorter wound healing time or cost savings in Dutch burn care. LDI is used in all Dutch burn centres. In case of doubt about the depth of a burn in primary or secondary care, referral to a burn centre is advisable. PMID- 29629855 TI - Salinirubellus salinus gen. nov., sp. nov., isolated from a marine solar saltern. AB - A halophilic archaeal strain, designated ZS-35-S2T, was isolated from Zhoushan marine solar saltern in Zhejiang Province, China. Cells were pleomorphic, Gram stain-negative and formed red-pigmented colonies on agar plates. The cells lysed in distilled water and the minimal NaCl concentration to prevent cell lysis was 8 % (w/v). Strain ZS-35-S2T was able to grow at 25-50 degrees C (optimum, 37 degrees C), with 1.4-4.8 M NaCl (optimum, 2.1 M), with 0-1.0 M MgCl2 (optimum, 0.1 M) and at pH 5.0-9.5 (optimum, pH 7.5). Phylogenetic tree reconstructions based on 16S rRNA genes and rpoB' genes revealed that strain ZS-35-S2T was distinct from the related genera Halomarina, Natronomonas, Halorientalis, Salinirubrum and Halobaculum of the order Halobacteriales. The major polar lipids of the strain were phosphatidylglycerol, phosphatidylglycerol phosphate methyl ester and three unidentified glycolipids. The two major glycolipids were chromatographically identical to S-DGD-1 and DGD-1, respectively. The DNA G+C content of strain ZS-35-S2T is 67.0 mol%. The phenotypic, chemotaxonomic and phylogenetic properties suggested that strain ZS-35-S2T (=CGMCC 1.12551T=JCM 30036T) represents a novel species of a new genus within the order Halobacteriales, for which the name Salinirubellus salinus gen. nov., sp. nov. is proposed. PMID- 29629854 TI - Flavobacterium aurantiibacter sp. nov., an orange-pigmented bacterium isolated from cyanobacterial aggregates in a eutrophic lake. AB - A bacterial strain, designated TH167T, was isolated from cyanobacterial aggregates in eutrophic Lake Taihu in China. Cells were observed to be slightly curved rod-shaped, motile by gliding, aerobic, Gram-stain-negative, proteorhodopsin-containing. Optimal growth was obtained at pH 7.0 (range: 6.0 9.0), 28 degrees C (range: 4-32 degrees C) and 0 % (w/v) NaCl (range: 0-2.0 %) in Reasoner's 2A broth. No growth was observed at 37 degrees C. The cells were found to be positive for catalase and oxidase activities. The major fatty acids (>10 %) were identified as iso-C15 : 0, iso-C15 : 1 G and anteiso-C15 : 0. The major polar lipids of the isolate comprised phosphatidylethanolamine, one unidentified phospholipid and two unidentified aminolipids. The major respiratory quinone was menaquinone-6. The genomic G+C content of strain TH167T was 40.4 mol% based on total genome calculations. Based on similarities of 16S rRNA gene sequences, strain TH167T was affiliated with the genus Flavobacterium, exhibiting the highest sequence similarities to Flavobacterium eburneum SA31T (94.16 %), Flavobacterium yanchengensehgT (94.09 %) and Flavobacterium lacus NP180T (93.95 %). The phenotypic, chemotaxonomic and phylogenetic properties, and genome analysis suggested that strain TH167T represented a novel species within the genus Flavobacterium, for which the name Flavobacterium aurantiibacter sp. nov. is proposed. The type strain is TH167T (=CGMCC 1.15805T=LMG 29719T). PMID- 29629857 TI - A simple mung bean infection model for studying the virulence of Pseudomonas aeruginosa. AB - Here we highlight the development of a simple and high-throughput mung bean model to study virulence in the opportunistic pathogen Pseudomonas aeruginosa. The model is easy to set up, and infection and virulence can be monitored for up to 10 days. In a first test of the model, we found that mung bean seedlings infected with PAO1 showed poor development of roots and high mortality rates compared to uninfected controls. We also found that a quorum-sensing (QS) mutant was significantly less virulent when compared with the PAO1 wild-type. Our work introduces a new tool for studying virulence in P. aeruginosa that will allow for high-throughput virulence studies of mutants and testing of the in vivo efficacy of new therapies at a time when new antimicrobial drugs are desperately needed. PMID- 29629856 TI - Use of genomics to design a diagnostic assay to discriminate between Streptococcus pneumoniae and Streptococcus pseudopneumoniae. AB - Distinuishing the species of mitis group streptococci is challenging due to ambiguous phenotypic characteristics and high degree of genetic similarity. This has been particularly true for resolving atypical Streptococcus pneumoniae and Streptococcus pseudopneumoniae. We used phylogenetic clustering to demonstrate specific and separate clades for both S. pneumoniae and S. pseudopneumoniae genomes. The genomes that clustered within these defined clades were used to extract species-specific genes from the pan-genome. The S. pneumoniae marker was detected in 8027 out of 8051 (>99.7 %) S. pneumoniae genomes. The S. pseudopneumoniae marker was specific for all genomes that clustered in the S. pseudopneumoniae clade, including unresolved species of the genus Streptococcus sequenced by the BC Centre for Disease Control Public Health Laboratory that previously could not be distinguished by other methods. Other than the presence of the S. pseudopneumoniae marker in six of 8051 (<0.08 %) S. pneumoniae genomes, both the S. pneumoniae and S. pseudopneumoniae markers showed little to no detectable cross-reactivity to the genomes of any other species of the genus Streptococcus or to a panel of over 46 000 genomes from viral, fungal, bacterial pathogens and microbiota commonly found in the respiratory tract. A real-time PCR assay was designed targeting these two markers. Genomics provides a useful technique for PCR assay design and development. PMID- 29629858 TI - Pseudomonas aeruginosa PumA acts on an endogenous phenazine to promote self resistance. AB - The activities of critical metabolic and regulatory proteins can be altered by exposure to natural or synthetic redox-cycling compounds. Many bacteria, therefore, possess mechanisms to transport or transform these small molecules. The opportunistic pathogen Pseudomonas aeruginosa PA14 synthesizes phenazines, redox-active antibiotics that are toxic to other organisms but have beneficial effects for their producer. Phenazines activate the redox-sensing transcription factor SoxR and thereby induce the transcription of a small regulon, including the operon mexGHI-opmD, which encodes an efflux pump that transports phenazines, and PA14_35160 (pumA), which encodes a putative monooxygenase. Here, we provide evidence that PumA contributes to phenazine resistance and normal biofilm development, particularly during exposure to or production of strongly oxidizing N-methylated phenazines. We show that phenazine resistance depends on the presence of residues that are conserved in the active sites of other putative and characterized monooxygenases found in the antibiotic producer Streptomyces coelicolor. We also show that during biofilm growth, PumA is required for the conversion of phenazine methosulfate to unique phenazine metabolites. Finally, we compare ?mexGHI-opmD and ?pumA strains in assays for colony biofilm morphogenesis and SoxR activation, and find that these deletions have opposing phenotypic effects. Our results suggest that, while MexGHI-OpmD-mediated efflux has the effect of making the cellular phenazine pool more reducing, PumA acts on cellular phenazines to make the pool more oxidizing. We present a model in which these two SoxR targets function simultaneously to control the biological activity of the P. aeruginosa phenazine pool. PMID- 29629859 TI - The ClpY-ClpQ protease regulates multicellular development in Bacillus subtilis. AB - ATP-dependent proteases play essential roles in both protein quality control and the regulation of protein activities in bacteria. ClpYQ (also known as HslVU) is one of several highly conserved ATP-dependent proteases in bacteria. The regulation and biological function of ClpYQ have been well studied in Gram negative bacteria, but are poorly understood in Gram-positive species. In this study, we showed that in the Gram-positive bacterium Bacillus subtilis, the DeltaclpYQ deletion mutant formed early and robust biofilms, while swarming motility was severely impaired. Colonies of the DeltaclpYQ mutant were also much less mucoid on agar plates, indicating the loss of the production of secreted gamma-poly-dl-glutamic acid (gamma-PGA). Global proteomic analysis using isobaric tags for relative and absolute quantification (iTRAQ) confirmed that a number of proteins involved in motility, chemotaxis and the production of gamma-PGA were less abundant in the DeltaclpYQ mutant. The results from both iTRAQ and Western immunoblotting showed that levels of the biofilm master repressor SinR were modestly reduced in the DeltaclpYQ mutant, but probably significantly enough to alter biofilm regulation due to the ultrasensitivity of the expression of biofilm genes to SinR protein levels. Western immunoblotting also showed that the abundance of CodY, whose gene is clustered with clpYQ in the same operon, was not impacted on by DeltaclpYQ. Lastly, our results suggested that, unlike in Escherichia coli, ClpYQ does not play an essential role in heat-shock response in both B. subtilis and Bacillus cereus. In conclusion, we propose that the ClpYQ protease is primarily involved in multicellular development in B. subtilis. PMID- 29629860 TI - Publish and/or perish: A urological perspective on predatory publications. AB - INTRODUCTION: It is an accepted axiom that academics must publish to be considered successful. Open-source journals are quickly gaining traction in the scientific community as an effective way to disseminate important research. The open-access movement includes many successful, well-respected operations, but has also spawned a plethora of journals, some predatory and others that appear to be amateurish academic traps. We provide a first look at open-source journals, both reputable and predatory, specifically pertaining to urology. METHODS: A review of the email inbox of a single academic urologist was examined for journal article solicitations over a four-month span. Journals were excluded if they did not pertain to urology. Journals were analyzed according to journal-centred metrics (H-index, number of documents published, total citations, and number of citations per document) over one publishing year (2015). RESULTS: A total of 32 journals contacting a single academic urologist were included in this review. The majority of journals originated from North America (84.3%) with a mean cost of $1567 CAD. Of the 32 journals, only seven were listed on reputable databases. Of these journals, analysis of journal-specific metrics showed, on average, a journal H index of 6.71, total documents published over one year of 66.14, and number of citations per document of 0.59. Some publications were found to make false claims of listing in vetted academic databases. CONCLUSIONS: Choices for open-source journal publication are rapidly increasing in the field of urology. They are not all created equal. Publication in many of these journals will increase the risk of seeing academic careers perish rather than flourish. PMID- 29629861 TI - Age-stratified perioperative mortality after urological surgeries. AB - INTRODUCTION: More elderly patients are presenting for surgical consultation. Understanding the risk of mortality by age group after urological surgery is important for patient selection and counselling. METHODS: A historical cohort study of The American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database from 2006-2015 was performed. Current procedural terminology (CPT) codes for similar surgical procedures were grouped for analyses. Urological procedures commonly performed in elderly patients were identified and stratified by patient age and surgical approach (open vs. laparoscopic/robotic). The primary outcome was the absolute risk of death by 30 days stratified by age for each surgical procedure. The secondary outcome was risk of death by surgical approach (open vs. laparoscopic/robotic). RESULTS: Twelve urological procedures were reviewed including 124 262 patients. A total of 1011 (0.8%) deaths occurred by 30 days after surgery. The procedure with the highest incidence of mortality by 30 days was open nephroureterectomy (2.9 %). In patients 80 years and over, the procedure with the highest incidence of death was open radical nephrectomy (5.32%). There was an increased risk of mortality with increasing age group for all procedures. Unadjusted risk of mortality was consistently higher in patients who receive open compared to laparoscopic surgery. CONCLUSIONS: There is an increasing risk of mortality with age and with open surgical approach in urology. Knowledge regarding the absolute risk of mortality in patients receiving common urological surgeries may improve patient selection and counselling. PMID- 29629862 TI - Identifying the use and barriers to the adoption of renal tumour biopsy in the management of small renal masses. AB - INTRODUCTION: Renal tumour biopsies (RTBs) can provide the histology of small renal masses (SRMs) prior to treatment decision-making. However, many urologists are reluctant to use RTB as a standard of care. This study characterizes the current use of RTB in the management of SRMs and identifies barriers to a more widespread adoption. METHODS: A web-based survey was sent to members of the Canadian and Quebec Urological Associations who had registered email address (n=767) in June 2016. The survey examined physicians' practice patterns, RTB use, and potential barriers to RTB. Chi-squared tests were used to assess for differences between respondents. RESULTS: The response rate was 29% (n=223), of which 188 respondents were eligible. A minority of respondents (12%) perform RTB in >75% of cases, while 53% never perform or perform RTB in <25% of cases. Respondents with urological oncology fellowship training were more likely to request a biopsy than their colleagues without such training. The most frequent management-related reason for not using routine RTB was a belief that biopsy won't alter management, while the most frequent pathology-related reason was the risk of obtaining a false-negative or a non-diagnostic biopsy. CONCLUSIONS: Adoption of RTBs remains low in Canada. Concerns about the accuracy of RTB and its ability to change clinical practice are the largest barriers to adoption. A knowledge translation strategy is needed to address these concerns. Future studies are also required in order to define where RTB is most valuable and how to best to implement it. PMID- 29629863 TI - Early experience with topical meloxicam and lidocaine combination for the treatment of vulvodynia. AB - INTRODUCTION: We report our early clinical observations on the use of topical meloxicam and lidocaine gel for patients with vulvodynia. METHODS: This is an early experience in participants with a history of vulvodynia evaluated and treated at the Queen's University Pelvic and Bladder Pain Clinic. Combination meloxicam 0.3% and lidocaine 5% were provided to the participants and they were instructed to apply 5 cc to the vulvar area twice daily. Standardized assessment was conducted for each participant before the start of the topical therapy and again at one week, and included Interstitial Cystitis Symptom Index (ICSI), Interstitial Cystitis Problem Index (ICPI), and pain scoring (Likert) for vulvar pain, in addition to a subjective global assessment after a week of treatment. RESULTS: Of the eight participants, six had a subjective improvement in their symptoms with the use of the combination gel. They reported between one- and four point reductions on the Likert pain scale and mild to moderate improvement of symptoms. Common side effects reported were burning and stinging. CONCLUSIONS: The results from this early experience are promising for a potentially effective topical treatment for vulvodynia. PMID- 29629864 TI - Natural history of prostatic lesions on serial multiparametric magnetic resonance imaging. AB - INTRODUCTION: The natural history of prostatic lesions identified on multiparametric magnetic resonance imaging (mpMRI) is largely unknown. We aimed to describe changes observed over time on serial MRI. METHODS: All patients with >=2 MRI studies between 2008 and 2015 at our institution were identified. MRI progression was defined as an increase in Prostate Imaging Reporting and Data System (PI-RADS; version 2) or size of existing lesions, or the appearance of a new lesion PIRADS >=4. Patients on active surveillance (AS) were analyzed for correlation of MRI progression to biopsy reclassification. RESULTS: A total of 83 patients (54 on AS and 29 for diagnostic purposes) underwent serial MRI, with a mean interval of 1.9 years between scans. At baseline, 115 lesions (66 index, 49 non-index) were identified. Index lesions were more likely than non-index lesions to increase in size >=2 mm (36.2 vs. 7.3 %; p=0.002). Overall progression was more likely to be seen among the index cohort (34.8 vs. 7.6%; p<0.001). New lesions with PIRADS >=4 were seen on second imaging in 13 (16.5%) men, and became the index lesion in 29 cases (34.9%). Eighteen men on AS showed evidence of MRI progression (five with new lesions, 13 with progression of a previous lesion). Biopsy reclassification was present in three men (16.7%) with and seven men without MRI progression (19.4%). CONCLUSIONS: Overall changes in size and PIRADS scores of index lesions on MRI were small. New lesions were common, but usually did not alter management. PMID- 29629865 TI - Clinicopathological significance of galectin-1 expression and percentage of galectin-1-expressing T cells in clear-cell renal cell carcinoma. AB - INTRODUCTION: This study investigates the clinical significance of galectin-1 expression in carcinoma tissues, plasma, and lymphocytes of patients with clear cell renal cell carcinoma (RCC). METHODS: Galectin-1 expression was investigated, using immunohistochemistry, in 91 clear-cell RCC tissue sections, five angioleiolipomas tissue sections, and three oncocytomas tissue sections. As controls, normal tissue sections adjacent to each tumour and six benign renal tumour sections were examined. Plasma galectin-1 levels as measured by ELISA were compared in 39 patients. Proportions of galectin-1 expressing CD4+ and galectin-1 expressing CD8+ T lymphocytes in peripheral blood of these patients were detected by flow cytometry. RESULTS: The positive expression rate of galetin-1 in 91 clear cell RCC tissues sections by immunohistochemistry was 87 (95.6%), with weak expression rate of 35.2 (32/91), moderate expression rate of 51.6% (47/91), and strong expression rate of 13.2% (12/91); whereas 25% (2/8) of renal benign tumour sections showed weak galectin-1 expression, 91.2% (83/91) of non-tumor tissues adjacent to carcinomas had negative expression of galectin-1, and another six (75%) renal benign tumour sections had negative galectin-1 expression. Plasma galectin-1 levels between patients with clear-cell RCC and with benign tumours were not significantly difference (p>0.05). In patients with clear-cell RCC, we found a significantly higher proportion of galectin-1-expressing CD4+ lymphocytes (p<0.05) and galectin-1-expressing CD8+ lymphocytes (p<0.05) than in patients with benign tumours. Moreover, the level of galectin-1 expression was positively associated with stage and Fuhrman grade of clear-cell RCC. CONCLUSIONS: Our results suggest that high level of galectin-1 expression in clear-cell RCC tissues may be a useful marker for clear-cell RCC. Our findings also reveal a new clinical significance of galectin-1 - that high proportions of galectin-1 expressing CD4+ and CD8+ lymphocytes were positively associated with poor clinicopathological features. PMID- 29629866 TI - Prognostic and predictive clinical factors in patients with metastatic castration resistant prostate cancer treated with cabazitaxel. AB - INTRODUCTION: Cabazitaxel is one of several treatment options available for patients with metastatic castration-resistant prostate cancer who have progressed on docetaxel. Little is known about clinical factors that influence prognosis or treatment response for patients receiving cabazitaxel. Identifying prognostic and predictive factors could contribute to the optimal selection of patients for treatment after docetaxel. METHODS: A retrospective review of patients enrolled on the cabazitaxel Canadian Early Access Program (C-EAP) was performed. Clinical factors were analyzed by univariable and multivariable Cox proportional hazards and logistic regression analysis to identify independent predictors of prognosis and response. RESULTS: Forty-five patients from five centres in Canada were included in this study. On multivariable analysis, lower hemoglobin was associated with shorter survival. No other factors were independently associated with survival, prostate-specific antigen (PSA) response, or primary PSA progression. CONCLUSIONS: Clinical factors predicting survival or treatment response were not identified for men with castration-resistant prostate cancer receiving cabazitaxel. Larger studies may be necessary to identify clinical factors and biomarkers that identify whether patients should or should not receive cabazitaxel. PMID- 29629867 TI - Recurrence and upstaging rates of T1 high-grade urothelial carcinoma of the bladder on repeat resection in a Canadian, resource-limited, healthcare system. AB - INTRODUCTION: Non-muscle-invasive bladder cancer is the most expensive malignancy to treat. Current Canadian guidelines recommend repeat transurethral resection of bladder tumour (TURBT) within six weeks after initial resection of T1 high-grade (T1HG) urothelial carcinoma, prior to initiation of intravesical bacillus Calmette-Guerin treatment. This is a burden on operating room usage and adds further cost and risk of complications. Internationally, major cancer centres report significant rates of recurrence and upstaging on repeat resection, however, minimal Canadian data is available. We aimed to determine the rate of recurrence and upstaging in a resource-limited, Canadian healthcare system. METHODS: A retrospective review of patients receiving TURBT between November 2009 and November 2014 was performed. Patients were included if they had all three of the following: a pathological diagnosis of T1HG, adequate muscularis propria present in the specimen, and a repeat resection. RESULTS: We reviewed 3166 patients who underwent TURBT and found 173 to meet our inclusion criteria. The overall recurrence and upstaging rates were 57.2% and 9.2%, respectively. Tumour recurrence and upstaging occurred more often in patients who had repeat resection after 12-24 weeks compared to those patients whose repeat resection occurred within 12 weeks. CONCLUSIONS: Although recurrence rates are similar, we have found upstaging rates to be three- to four-fold lower than those previously reported. Despite this, one in 10 patients will be upstaged, justifying use of this resource within our healthcare system. Finally, timely repeat resection, within 12 weeks appears to be associated with preventing disease progression. PMID- 29629868 TI - Computed tomography identified factors that preclude living kidney donation. AB - INTRODUCTION: The purpose of this study was to determine the variety and prevalence of renal and non-renal abnormalities detected on multidetector computed tomography (MDCT) that precluded patients from donating a kidney. METHODS: Institutional review board approval was obtained and the requirement for informed consent was waived. A retrospective, single-centre review of 701 patients (444 female, 257 male; age range 18-86 years; mean age 43.2+/-11.9 years) that underwent renal donor protocol MDCT was conducted. A systematic review of the CT report, records from multidisciplinary renal transplantation rounds, and electronic medical records was performed to determine which patients were approved or declined as live renal donors. If declined as a donor, CT identified reasons were categorized as abnormalities of renal vasculature, renal parenchyma, collecting system, or extra-renal. RESULTS: A total of 81 patients were excluded as renal donors on the basis of CT findings. Abnormalities of the collecting system accounted for the most frequent cause of exclusion (n=41), with asymptomatic renal calculi being detected in 39 patients. Complex vascular anatomy and vascular abnormalities resulted in the exclusion of 29 patients. Supernumerary arteries and early arterial branching resulted in the exclusion of 20 patients, while renal vein anomalies leading to exclusion were uncommon (n=2). Abnormalities of renal parenchyma resulted in the exclusion of nine patients. Three patients were diagnosed with autosomal dominant polycystic kidney disease, two patients had renal cell carcinoma, and two patients had areas of cortical scarring. A complex cystic lesion requiring surveillance imaging was encountered in one patient and a large area of renal infarction related to prior adrenalectomy was demonstrated in one patient. Extra-renal abnormalities leading to exclusion were limited to two patients with pulmonary nodules. CONCLUSIONS: MDCT plays a critical role in the preoperative assessment of potential renal donors by identifying contraindications to donor nephrectomy and providing accurate vascular mapping. This study is anticipated to be informative for those involved in the workup of potential living renal donors by quantifying the incidence and reasons for donor exclusion identified on CT. PMID- 29629869 TI - A population of adult satellite-like cells in Drosophila is maintained through a switch in RNA-isoforms. AB - Adult stem cells are important for tissue maintenance and repair. One key question is how such cells are specified and then protected from differentiation for a prolonged period. Investigating the maintenance of Drosophila muscle progenitors (MPs) we demonstrate that it involves a switch in zfh1/ZEB1 RNA isoforms. Differentiation into functional muscles is accompanied by expression of miR-8/miR-200, which targets the major zfh1-long RNA isoform and decreases Zfh1 protein. Through activity of the Notch pathway, a subset of MPs produce an alternate zfh1-short isoform, which lacks the miR-8 seed site. Zfh1 protein is thus maintained in these cells, enabling them to escape differentiation and persist as MPs in the adult. There, like mammalian satellite cells, they contribute to muscle homeostasis. Such preferential regulation of a specific RNA isoform, with differential sensitivity to miRs, is a powerful mechanism for maintaining a population of poised progenitors and may be of widespread significance. PMID- 29629871 TI - Communities creating change. AB - Women scientists across India are working together to build and advocate for family-friendly policies at their institutes. PMID- 29629870 TI - Multivalency of NDC80 in the outer kinetochore is essential to track shortening microtubules and generate forces. AB - Presence of multiple copies of the microtubule-binding NDC80 complex is an evolutionary conserved feature of kinetochores, points of attachment of chromosomes to spindle microtubules. This may enable multivalent attachments to microtubules, with implications that remain unexplored. Using recombinant human kinetochore components, we show that while single NDC80 complexes do not track depolymerizing microtubules, reconstituted particles containing the NDC80 receptor CENP-T bound to three or more NDC80 complexes do so effectively, as expected for a kinetochore force coupler. To study multivalency systematically, we engineered modules allowing incremental addition of NDC80 complexes. The modules' residence time on microtubules increased exponentially with the number of NDC80 complexes. Modules with two or more complexes tracked depolymerizing microtubules with increasing efficiencies, and stalled and rescued microtubule depolymerization in a force-dependent manner when conjugated to cargo. Our observations indicate that NDC80, rather than through biased diffusion, tracks depolymerizing microtubules by harnessing force generated during microtubule disassembly. PMID- 29629874 TI - Object discrimination using electrotactile feedback. AB - OBJECTIVE: A variety of bioengineering systems are being developed to restore tactile sensations in individuals who have lost somatosensory feedback because of spinal cord injury, stroke, or amputation. These systems typically detect tactile force with sensors placed on an insensate hand (or prosthetic hand in the case of amputees) and deliver touch information by electrically or mechanically stimulating sensate skin above the site of injury. Successful object manipulation, however, also requires proprioceptive feedback representing the configuration and movements of the hand and digits. APPROACH: Therefore, we developed a simple system that simultaneously provides information about tactile grip force and hand aperture using current amplitude-modulated electrotactile feedback. We evaluated the utility of this system by testing the ability of eight healthy human subjects to distinguish among 27 objects of varying sizes, weights, and compliances based entirely on electrotactile feedback. The feedback was modulated by grip-force and hand-aperture sensors placed on the hand of an experimenter (not visible to the subject) grasping and lifting the test objects. We were also interested to determine the degree to which subjects could learn to use such feedback when tested over five consecutive sessions. MAIN RESULTS: The average percentage correct identifications on day 1 (28.5% +/- 8.2% correct) was well above chance (3.7%) and increased significantly with training to 49.2% +/- 10.6% on day 5. Furthermore, this training transferred reasonably well to a set of novel objects. SIGNIFICANCE: These results suggest that simple, non invasive methods can provide useful multisensory feedback that might prove beneficial in improving the control over prosthetic limbs. PMID- 29629872 TI - Radical and lunatic fringes modulate notch ligands to support mammalian intestinal homeostasis. AB - Notch signalling maintains stem cell regeneration at the mouse intestinal crypt base and balances the absorptive and secretory lineages in the upper crypt and villus. Here we report the role of Fringe family of glycosyltransferases in modulating Notch activity in the two compartments. At the crypt base, RFNG is enriched in the Paneth cells and increases cell surface expression of DLL1 and DLL4. This promotes Notch activity in the neighbouring Lgr5+ stem cells assisting their self-renewal. Expressed by various secretory cells in the upper crypt and villus, LFNG promotes DLL surface expression and suppresses the secretory lineage . Hence, in the intestinal epithelium, Fringes are present in the ligand presenting 'sender' secretory cells and promote Notch activity in the neighbouring 'receiver' cells. Fringes thereby provide for targeted modulation of Notch activity and thus the cell fate in the stem cell zone, or the upper crypt and villus. PMID- 29629875 TI - Development of half metallicity within mixed magnetic phase of Cu1-x Co x MnSb alloy. AB - Cubic half-Heusler Cu1-x Co x MnSb ([Formula: see text]) compounds have been investigated both experimentally and theoretically for their magnetic, transport and electronic properties in search of possible half metallic antiferromagnetism. The systems (Cu,Co)MnSb are of particular interest as the end member alloys CuMnSb and CoMnSb are semi metallic (SM) antiferromagnetic (AFM) and half metallic (HM) ferromagnetic (FM), respectively. Clearly, Co-doping at the Cu-site of CuMnSb introduces changes in the carrier concentration at the Fermi level that may lead to half metallic ground state but there remains a persistent controversy whether the AFM to FM transition occurs simultaneously. Our experimental results reveal that the AFM to FM magnetic transition occurs through a percolation mechanism where Co-substitution gradually suppresses the AFM phase and forces FM polarization around every dopant cobalt. As a result a mixed magnetic phase is realized within this composition range while a nearly HM band structure is developed already at the 10% Co-doping. Absence of T 2 dependence in the resistivity variation at low T-region serves as an indirect proof of opening up an energy gap at the Fermi surface in one of the spin channels. This is further corroborated by the ab initio electronic structure calculations that suggests that a nearly ferromagnetic half-metallic ground state is stabilized by Sb-p holes produced upon Co doping. PMID- 29629873 TI - A Maternally Sequestered, Biopolymer-Stabilized Vascular Endothelial Growth Factor (VEGF) Chimera for Treatment of Preeclampsia. AB - BACKGROUND: Preeclampsia is a hypertensive syndrome that complicates 3% to 5% of pregnancies in the United States. Preeclampsia originates from an improperly vascularized and ischemic placenta that releases factors that drive systemic pathophysiology. One of these factors, soluble fms-like tyrosine kinase-1, is believed to sequester vascular endothelial growth factor (VEGF), leading to systemic endothelial dysfunction and hypertension. With the goal of targeting soluble fms-like tyrosine kinase-1 while simultaneously preventing fetal exposure to VEGF, we fused VEGF to elastin-like polypeptide, a biopolymer carrier that does not cross the placental barrier (ELP-VEGF). METHODS AND RESULTS: ELP-VEGF restored in vitro endothelial cell tube formation in the presence of plasma from placental ischemic rats. Long-term administered ELP-VEGF in pregnant rats accumulated in maternal kidneys, aorta, liver, and placenta, but the protein was undetectable in the pups when administered at therapeutic doses in dams. Long term administration of ELP-VEGF in a placental ischemia rat model achieved dose dependent attenuation of hypertension, with blood pressure equal to sham controls at a dose of 5 mg/kg per day. ELP-VEGF infusion increased total plasma soluble fms-like tyrosine kinase-1 levels but dramatically reduced free plasma soluble fms-like tyrosine kinase-1 and induced urinary excretion of nitrate/nitrite, indicating enhanced renal nitric oxide signaling. ELP-VEGF at up to 5 mg/kg per day had no deleterious effect on maternal or fetal body weight. However, dose dependent adverse events were observed, including ascites production and neovascular tissue encapsulation around the minipump. CONCLUSIONS: ELP-VEGF has the potential to treat the preeclampsia maternal syndrome, but careful dosing and optimization of the delivery route are necessary. PMID- 29629876 TI - Electrochemical energy storage performance of carbon nanofiber electrodes derived from 6FDA-durene. AB - Carbon nanofibers (CNFs) are promising electrode materials for electrochemical double layer capacitors due to their high porosity and electrical conductivity. CNFs were prepared by electrospinning and subsequent thermal treatment of a new precursor polymer, 6FDA-durene, without the addition of pore generating agents. The conversion of precursor nanofibers into CNFs was confirmed using Raman spectroscopy. CNFs were activated and annealed, and nitrogen adsorption/desorption measurements were conducted to determine surface area and porosity. These activated/annealed CNFs were used as binderless electrodes in coin cells with an ionic liquid electrolyte. The devices displayed a specific capacitance of 128 F g-1, an energy density of 63.4 Wh kg-1 (at 1 A g-1), and a power density of 11.0 KW kg-1 (at 7 A g-1). PMID- 29629877 TI - Ultrasensitive interdigitated capacitance immunosensor using gold nanoparticles. AB - Immunosensors based on interdigitated electrodes (IDEs), have recently demonstrated significant improvements in the sensitivity of capacitance detection. Herein, a novel type of highly sensitive, compact and portable immunosensor based on a gold interdigital capacitor has been designed and developed for the rapid detection of hepatitis B surface antigen (HBsAg). To improve the efficiency of antibody immobilization and time-saving, a self assembled monolayer (SAM) of 2-mercaptoethylamine film was coated on IDEs. Afterwards, carboxyl groups on primary antibodies were activated through 1-ethyl 3-(3-dimethylaminopropyl)carbodiimide and were immobilized on amino-terminated SAM for better control of the oriented immobilization of antibodies on gold IDEs. In addition, gold nanoparticles conjugated with a secondary antibody were used to enhance the sensitivity. Under optimal conditions, the immunosensor exhibited the sensitivity of 0.22 nF.pg ml-1, the linear range from 5 pg ml-1 to 1 ng ml-1 and the detection limit of 1.34 pg ml-1, at a signal-to-noise ratio of 3. PMID- 29629878 TI - Spin-glass polyamorphism induced by a magnetic field in LaMnO3 single crystal. AB - We present experimental evidence of field-driven transition in spin-glass state, similar to pressure-induced transition between amorphous phases in structural and metallic glasses, attributed to the polyamorphism phenomena. Cusp in temperature dependences of ac magnetic susceptibility of weakly disordered LaMnO3 single crystal is registered below the temperature of magnetic ordering. Frequency dependence of the cusp temperature proves its spin-glass origin. The transition induced by a magnetic field in spin-glass state, is manifested by peculiarity in dependence of cusp temperature on applied magnetic field. Field dependent maximum of heat capacity is observed in the same magnetic field and temperature range. PMID- 29629879 TI - A nanofabricated optoelectronic probe for manipulating and recording neural dynamics. AB - OBJECTIVE: The convergence of optogenetic and large-scale neural recording technologies opens enormous opportunities for studying brain function. However, compared to the widespread use of optogenetics or recordings as standalone methods, the joint use of these techniques in behaving animals is much less well developed. A simple but poorly scalable solution has been to implant conventional optical fibers together with extracellular microelectrodes. A more promising approach has been to combine microfabricated light emission sources with multielectrode arrays. However, a challenge remains in how to compactly and scalably integrate optical output and electronic readout structures on the same device. Here we took a step toward addressing this issue by using nanofabrication techniques to develop a novel implantable optoelectronic probe. APPROACH: This device contains multiple photonic grating couplers connected with waveguides for out-of-plane light emission, monolithically integrated with a microlectrode array on the same silicon substrate. To demonstrate the device's operation in vivo, we record cortical activity from awake head-restrained mice. MAIN RESULTS: We first characterize photo-stimulation effects on electrophysiological signals. We then assess the probe's ability to both optogenetically stimulate and electrically record neural firing. SIGNIFICANCE: This device relies on nanofabrication techniques to integrate optical stimulation and electrical readout functions on the same structure. Due to the device miniaturization capabilities inherent to nanofabrication, this optoelectronic probe technology can be further scaled to increase the throughput of manipulating and recording neural dynamics. PMID- 29629880 TI - Influence of nerve cuff channel count and implantation site on the separability of afferent ENG. AB - OBJECTIVE: Recording of neural signals from intact peripheral nerves in patients with spinal cord injury or stroke survivors offers the possibility for the development of closed-loop sensorimotor prostheses. Nerve cuffs have been found to provide stable recordings from peripheral nerves for prolonged periods of time. However, questions remain over the design and positioning of nerve cuffs such that the separability of neural data recorded from the peripheral nerves is improved. APPROACH: Afferent electroneurographic (ENG) signals were recorded with nerve cuffs placed on the sciatic nerve of rats in response to various mechanical stimuli to the hindpaw. The mean absolute value of the signal was extracted and input to a classifier. The performance of the classifier was evaluated under two conditions: (1) when information from either a 3- or 16-channel cuff was used; (2) when information was available from a cuff placed either distally or proximally along the nerve. MAIN RESULTS: We show that both 3- and 16-channel cuffs were able to separate afferent ENG signals with an accuracy greater than chance. The highest classification scores were achieved when the classifier was fed with information obtained from a 16-channel cuff placed distally. While the 16-channel cuff always outperformed the 3-channel cuff, the difference in performance was increased when the 16-channel cuff was placed distally rather than proximally on the nerve. SIGNIFICANCE: The results indicate that increasing the complexity of a nerve cuff may only be advantageous if the nerve cuff is to be implanted distally, where the nerve has begun to divide into individual fascicles. PMID- 29629881 TI - Propofol: a safe anaesthetic drug in experimental cardiac surgery in rabbits. AB - ACKGROUND: Experimental surgery needs a pharmacological approach that can interfere with cardiac function. CASE REPORT: In a animal model of regenerative medicine of myocardium we use an anaesthesiological protocol that included Propofol, a benzodiazepine (Midazolam) and an alpha-2 adrenergic agent. RESULTS: In a group of 15 rabbits undergoing cardiac surgery we reported 1 arrhythmic complication during stem cell injection. DISCUSSION: The functional cardio- respiratory depressor activity of Propofol was compensated by alpha-2 adrenergic drugs, avoiding serious complications. We hypothesize that the functional cardio respiratory depressor of different anaesthesiological drugs can be reversed by the contemporary administration of with adrenergic agents. KEY WORDS: Arrhythmias, Cardiac ischemia, Cardiovascular toxicity, Propofol. PMID- 29629882 TI - Rosuvastatin administered intraperitoneally reduces the formation of postoperative adhesions in rats. AB - OBJECTIVES: The purpose of the present experimental research was to assess the efficacy of intraperitoneal administration of rosuvastatin in preventing the formation of postoperative peritoneal adhesions. MATERIAL AND METHOD: Peritoneal adhesions were induced in 120 male rats of the Wistar-Bratislava breed, divided into 4 groups (n=30), using a parietal and visceral abrasion model. Group I was designated as the control group; in the case of group II, a saline solution was administered intraperitoneally, while in the case of groups III and IV, rosuvastatin solution with a concentration of 10 mg/kg and 5 mg/kg, respectively, was administered in a single dose, during laparotomy. All rats were sacrificed on the 14th postoperative day and the peritoneal adhesions were assessed macroscopically and microscopically. RESULTS: The formation of peritoneal adhesions (assessed macroscopically by appreciating their number, the area covered, and the degree of severity) was statistically significantly more reduced in the subjects that received rosuvastatin (groups III and IV) as compared to the control group (p<0.05). The degree of fibrosis assessed microscopically was also statistically significantly reduced in groups III and IV as compared to the control group (p<0.05). CONCLUSIONS: Rosuvastatin administered intraperitoneally correlates with a reduction of peritoneal adhesions in rats. KEY WORDS: Rosuvastatin, Peritoneal adhesions, Prevention. PMID- 29629883 TI - Factors affecting mortality in patients with splenic injuries. AB - : there are not a sufficient number investigating the factors in splenic injuries influencing mortality. In this study, we aimed to investigate the factors affecting mortality in splenic injuries. MATERIALS AND METHODS: All 237 patients with splenic injury between 2005 to 2014 were retrospectively analyzed. The patients were divided into two groups, survivors and non-survivors. Age, gender, mechanism of injury, grade of splenic injury, pulse, respiratory rate, systolic blood pressure, hemoglobin levels, number of transfusions, surgical procedure, ISS, RTS and hospitalization period were recorded. Univariate and multivariate analysis were used to compare survivors and non-survivors. RESULTS: The average age of the patients was 32 and most (82.7%) were male. Mortality was observed in 18 patients (7.6%). Mortality was found significantly lower in patients who had isolated splenic injury (p=0.048). In univariate analyses, decreased RTS (p<0.001), increased number of blood transfusion (p<0.001), decreased hemoglobin level (p=0, 025) and increased ISS (p<0.001) were found significant in non survivors. In multivariate analysis; number of transfusions, ISS and RTS were found as independent risk factors for mortality. CONCLUSIONS: We found high number of transfusions, high ISS and low RTS as independent risk factors for mortality in patients with splenic injury. KEY WORDS: Mortality, ISS, RTS, Splenic trauma. PMID- 29629884 TI - Aspetti deontologici e giuridici della Responsabilita professionale del chirurgo in Italia. Evoluzione storica a partire dal '900. AB - E pleonastico ricordare che ogni individuo raziocinante delle essere responsabile delle sue azioni: deve agire con la coscienza degli scopi che si propone evitando possibili conseguenze negative dei suoi atti. In ambito medico questo tipo di responsabilita e codificata con le norme della "deontologia". Per secoli l'arte terapeutica e stata praticata da individui dotati di una particolare vocazione ed una particolare cultura acquisita da Maestri dell'arte ancor prima che dalla propria esperienza, con nozioni di erboristeria e di elementari conoscenze anatomiche e di fisiologia, circondati da un'aura sacerdotale e da un rispetto derivante dal timore e dall'ammirazione per il coraggio e auspicabilmente dai successi, e facendo riferimento nell'occidente mediterraneo alle regole operative fissate nel Giuramento di Ippocrate, di significato tra il sacro ed il deontologico. Lo sviluppo delle tecniche anestesiologiche a partire dalla seconda meta dell'800 ha determinato l'ampliamento delle iniziative chirurgiche di tipo elettivo, a fianco con gli storici interventi in emergenza per la cura di lesioni traumatiche, ancor prima delle acquisizioni riguardanti le infezioni. Con l'espansione del campo di azione della chirurgia, le possibili complicanze ed i possibili insuccessi hanno fatto da contrappeso ai sentimenti di rispetto e di fiducia nei confronti dei chirurghi, giungendo a far assimilare in tali casi la loro opera quale causa all'origine di danni, provocati rientrando quindi nella categoria dei reati sottoposti alla Legge penale. Cosi, al termine deontologico di "responsabilita" valido per ogni iniziativa ed ogni professione, per i medici e venuto ad associarsi la qualifica di "professionale", con un significato di presunta colpevolezza. Da una parte le regole deontologiche si sono ampliate, ed hanno coinvolto direttamente il paziente nella fase decisionale delle terapie chirurgiche, formalizzate programmaticamente in moderni codici deontologici ed operativamente nel documento del "consenso informato". Per altro verso le leggi innovative del Codice Civile definito nel 1942, che al posto delle pene del codice penale introduceva il criterio della risarcibilita economica del danno in caso di riconosciuta "responsabilita professionale", ha determinato il coinvolgimento di altre figura professionali, e cioe di avvocati e di medici legali, oltre che delle organizzazioni assicurative, con detrimento alla serenita nell'espletamento delle professioni sanitarie e con l'insorgenza per reazione della cosidetta "medicina difensiva". La concretezza di queste problematiche hanno richiesto l'interessamento attivo della Giurisprudenza con una serie di sentenze, ed una formulazione di decreti e nuove leggi parlamentari, ancora in pieno assestamento nel corso del 2017, lasciano in qualche modo ancora irrisolti alcuni nodi. PMID- 29629885 TI - Jaw bones regeneration using mesenchymal stem cells. A single-center experience. AB - PURPOSE: Mesenchymal stem cells (MSC), which are multipotent stromal cells, are considered to be a promising resource in tissue engineering and tissue regeneration. MSCs have been used to generate new maxillary bone with clinically successful results. The aim of this study was to determine the role of MSC in bone regeneration procedures in patients with benign maxillary lesions. METHODS: A study was conducted on five patients treated for maxillary bone defects resulting from biopsy of benign lesions at the University Hospital of Magna Graecia, Catanzaro, Italy from January 2015 to October 2016. MSC from autologous bone marrow were used for bone regeneration. The bone mineral density was compared, using the Hounsfield scale, before and after treatment. Follow-up was monthly for six months, and the patients underwent a computed tomography scan of the maxilla at 6 months. RESULTS: Five patients, who underwent biopsy of osteolytic odontogenic benign tumors, were included in the study. There were no intraoperative or postoperative complications. The mean volume of the newly formed bone was 2.44cm3 (range 2,0-3,1) and the mean bone density was 1137 Hounsfield Units (range 898-1355). CONCLUSIONS: Bone regeneration with MSC from autologous bone marrow appears to be a valid treatment option for maxillary bone defects. KEY WORDS: Bone regeneration, Mesenchymal stem cells, BM-MSC, Upper jaw, Mandible. PMID- 29629886 TI - Postoperative nausea and vomiting (PONV) in outpatient repair of inguinal hernia. AB - PURPOSE: Nausea and vomiting are among the most frequent complications following anesthesia and surgery. Due to anesthesia seems to be primarily responsible for post operative nausea and vomiting (PONV) in Day Surgery facilities, the aim of the study is to evaluate how different methods of anesthesia could modify the onset of postoperative nausea and vomiting in a population of patients undergoing inguinal hernia repair. METHODS: Ninehundredten patients, aged between 18 and 87 years, underwent open inguinal hernia repair. The PONV risk has been assessed according to Apfel Score. Local anesthetic infiltration, performed by the surgeon in any cases, has been supported by and analgo-sedation with Remifentanil in 740 patients; Fentanyl was used in 96 cases and the last 74 underwent deep sedation with Propofol . RESULTS: Among the 910 patients who underwent inguinal hernia repair, PONV occurred in 68 patients (7.5%). Among patients presenting PONV, 29 received Remifentanil, whereas 39 received Fentanyl. In the group of patients receiving Propofol, no one presented PONV. This difference is statistically significant (p < .01). Moreover, only 50 patients of the total sample received antiemetic prophylaxis, and amongst these, PONV occurred in 3 subjects. CONCLUSIONS: Compared to Remifentanil, Fentanyl has a major influence in causing PONV. Nonetheless, an appropriate antiemetic prophylaxis can significantly reduce this undesirable complication. Key words: Day Surgery, Fentanyl, Inguinal, Hernia repair, Nausea, Vomiting. PMID- 29629887 TI - The correlation between laboratory markers and computed tomography severity index in acute appendicitis. AB - : A M: This study aimed to evaluate and to investigate the association of some laboratory markers with the stage of the acute appendicitis. MATER AL AND METHODS: The hematological parameters (white blood cell count, red cell distribution width, platellet distribution width, mean corpuscular volume, and mean platelet volume values) and tomography scans of 200 patients who admitted to the emergency department with abdominal pain were retrospectively reviewed. Computed tomography grading about the severity of the cases was carried out by two radiologists, as grade 0 for normal appendix to grade 3 for perforated appencities. The hematological results of the patients were recorded for each severity group and were compared to detect whether there was a change in the hematological parameters as the severity in CT increases. RESULTS: There was no difference in white blood cell count and red cell distribution width levels but mean platelet volume seemed to decrease as the tomography severity index increased. CONCLUS ONS: Our data suggests that the most reliable instrument to detect appendicitis in the emergency environment is the computed tomography. KEY WORDS: Acute appencitis, Computed tomography, RDW, PDW, MPV, MCV. PMID- 29629888 TI - Comparison of the ultrasound-guided tru-cut biopsy with postoperative histopathology results in patients with breast mass. AB - AIM: We aimed to compare the tru-cut biopsy and postoperative pathology results of breast lesions with suspicion of malignancy. Furthermore we aimed to determine the efficacy, specificity and sensitivity of the tru-cut biopsy. METHODOLOGY: 140 patients who were operated due to breast mass following tru-cut biopsy were retrospectively evaluated. Patients' demographic characteristics, imaging findings, biopsy and histopathology results were compared. RESULTS: The mean age of 140 patients was 51.3 (Ranged: 17-83 ages). Malignancy was statistically more common in patients older than 45 years old. According to tru-cut biopsy results 103 (73.5%) lesions were malign, 32 (23%) benign, and 5 (3,5%) suspicious. Histopathological evaluation established 113 (% 80.7) malign and 27 (19,3%) benign lesions. Tru-cut biopsy had a sensitivity, specifity, positive predictive value, negative predictive value and diagnostic accuracy of 93.5%, 95.4%, 99%, 75% and 80%, respectively in this study. CONCLUSIONS: Our findings have confirmed that tru-cut biopsy is an accurate, reliable and as effective as open surgery for breast cancer diagnosis. The higher success rates may achieve by accordance of triple assessment which includes clinical, radiological and pathological evaluation with tru-cut biopsy. KEY WORDS: Breast cancer, Core needle biopsy, Preoperative evaluation, Tru-cut biops. PMID- 29629889 TI - Necrotizing fasciitis. Possible profiles of professional liability with reference to two cases. AB - : Necrotizing fasciitis is one of the most dangerous complication of an abscess and it is still a disease with a high mortality. In this work, we decided to consider two cases: the first one concerns a male subject, aged 66, deceased because of a fatal necrotizing fasciitis associated to a cervical descending mediastinitis, which evolved from a primary peritonsillar abscess; the second is about a 50-year-old woman with a perineal abscess, then evolved into necrotizing fasciitis associated to a fatal septis shock. After a systematic consideration of necrotizing fasciitis as pathology and an analysis of the possible related risks to a diagnostic or therapeutic delay, we analyzed the particular history of both cases to underline the possible critical issues in professional behavior of the medical staff intervened. KEY WORDS: Abscess, Medical malpractice, Mortality, Necrotizing fasciitis, Professional liability. PMID- 29629890 TI - Infective complications after free flaps reconstruction in patients affected by head and neck cancer Our experience on 77 cases. AB - AIM: The success rates of free flaps in patients undergoing head and neck cancer (HNC) surgery are very high (95%- 97%) but the development of a surgical site infection (SSI) can put flap viability at risk. The aim of our study is to identify the risk factors for SSI in patients undergo free flaps reconstruction after head and neck cancer removal. MATERIAL OF STUDY: Seventyseven patients (44 male and 33 female) from April 2006 to April 2015 admitted at the Department of Maxillofacial Surgery of the University of Naples "Federico II" were included in this study. All the patients underwent free flap reconstruction for HNC. RESULTS: A microbiological analysis in 32 patients with signs of SSIs was performed, and 27 (35%) patients showed positive cul ture results, 5 patients were false positives. DISCUSSION: SSIs are one of the most common nosocomial infec tions that increase medical costs. HNC surgery frequently requires opening of the mouth floor, oropharynx, nasopharynx, or proximal esophagus, and these areas are likely to be contaminat ed by local microbiotics. Positive significant correlation between long operation timing and SSIs. CONCLUSION: Was observed the factors contributing to postoperative infections for patients affected by head and neck tumor. 35% of our study population devel oped an SSI (27/77). The most commonly discovered pathogen was MRSA (Methicillin-resistant Staphylococcus aureus). Were examinated sex, cardiovascular disease, blood loss more than 560 mL, and a long operation time >= 6 hours were significant risk factors for SSI. KEY WORDS: Free flaps, Head and neck cancer, Infective complications. PMID- 29629891 TI - Ureterocele fenestration with holmium laser in neonates. AB - AIM: To evaluate the effectiveness of holmium-laser fenestration of intravesical ureteroceles in neonatal period. MATERIAL AND METHOD: We retrospectively analyzed the results of the holmium-laser puncture in ten neonates with intravesical ureterocele, between September 2013 and September 2016. Laser probe was placed through the cystoscope to the lowest and medial portion of the ureterocele, near the bladder floor. Few punctures (4 to 8) were made, until ureterocele has been collapsed. RESULTS: Mean duration of general anesthesia was 16 minutes (range, 10 24) and duration of hospitalization was 1-3 days (mean, 1.3 days). There weren't complications regarding endoscopic treatment. There was the need for retreatment in one (10%) patient. Obstruction was found in one (10%) patient on ultrasound after one month. After three months there was no obstruction on ultrasound in any patient. In patients in whom VCUG was performed, vesicoureteral reflux was not found three months after the surgery. DISCUSSION: The relief of the obstruction, prevention of the vesicoureteral reflux and the urinary tract infection are the reasons for the immediate treatment in the neonatal period. In that way, the preservation of renal function is enabled. The reason for laser fenestration was better endoscopic control of the extensibility of the ablation. The moment of ureterocele collapsing can be visualized directly. CONCLUSIONS: Holmium-laser fenestration is a minimally invasive, highly effective and safe kind of treatment for ureterocele in neonatal period with minimal complication rate. Further clinical studies with a greater number of patients will offer more reliable information regarding this procedure. KEY WORDS: Fenestration, Holmium-laser, Neonates, Ureterocele. PMID- 29629892 TI - Does digestive symptoms require esophago gastroscopy prior to bariatric procedure? Assessment of 6 years' experience. AB - AIM: Performance of routine preoperative esophagogastroduodenal endoscopy (EGE) in patients undergoing bariatric surgery is still a controversial subject. The purpose of our study was to evaluate the benefits of performing preoperative EGE in a cohort of bariatric patients. MATERIAL AND METHODS: The present retrospective study was performed between March 2010 and June 2016. We divided the study participants into two groups: group A comprised subjects without disturbing upper digestive signs, while group B comprised patients with disturbing upper digestive signs. Logistic regression analysis was used to identify the predictors that might be associated with abnormal outcomes. RESULTS: Our study included 232 patients (who had undergone sleeve gastrectomy, gastric bypass, ileal interposition, or transit bipartition). The average age was 41.4 +/ 10.3 years, and the average body mass index (BMI) was 43.6 +/- 5.1 kg/m2. Of all the observed gastroscopic abnormalities, the prevalence for gastritis (17.3%), followed by esophagitis (10.2%), hiatus hernia (9.4%), and bulbitis (8.7%). In multivariate regression analysis, the Gastrointestinal Symptom Rating Scale (GSRS) score and upper gastric symptoms were found to be the only independent predictive markers (OR = 2.822, 95% CI: 1.674-3.456 and OR =2.735, 95% CI: 1.827 3.946, respectively). We identified a positive correlation between abnormal EGE findings and postoperative complications. CONCLUSION: Preoperative EGE had a high rate of detection for the possible abnormalities prior to bariatric surgery. Upper gastric symptoms are significant predictive factors of postoperative complications. Performing preoperative EGE for symptomatic patients could help reduce the morbidity and mortality rates in these patients. KEY WORDS: Bariatric surgery, Preoperative endoscopy, Upper digestive symptoms. PMID- 29629893 TI - Management of non-vascular complications following renal transplantation using percutaneous approach. AB - OBJECTIVE: Non-vascular complications following renal transplantation can cause graft failure. In this study, we present our two-year experience with percutaneous treatment for non-vascular complications following renal transplantation. PATIENTS AND METHODS: A total of 30 patients who underwent percutaneous radiological treatment between March 2014 and July 2016 were included in the study. RESULTS: Following renal transplantation, a total of 36 percutaneous radiological procedures which includes hydronephrosis secondary to ureteral stricture (n. 15), clinical symptom-producing lymphocele due to pressure (14) and creatinine elevated nondilated grafts (n. 7) after excluding other reasons of creatinine elevation, were performed. Six patients received percutaneous treatment for both ureteral stricture and lymphocele. The patients underwent balloon dilatation and double- J ureteral stent due to ureteral stricture. The mean pre- and post-procedural creatinine levels were 4.36 +/- 2.84mg/dL and 2.17 +/- 1.24 mg/dL respectively (p=0.004), indicating a significant difference. For lymphocele treatment, sclerosing agents were injected and lymphatic leakage areas were injected with percutaneous glue. The mean pre- and post-procedural creatinine values were 2.97 +/- 1.78 mg/dL and 1.75 +/- 1.18 respectively (p=0.002), indicating a significant difference. Nephrostomy catheters were placed for patients with elevated creatinine levels and non dilated collecting system. The mean pre- and post- nephrostomy creatinine levels were 3.55 +/- 2.36 mg/dL and 2.57 +/- 1.82 mg/dL respectively (p>0.05), indicating no statistically significant difference. CONCLUSION: The results of our study suggest that percutaneous treatment is an effective method for the treatment of non-vascular complications following renal transplantation, and, therefore, should be the first option for the preservation of graft functions. KEY WORDS: Percutaneous treatment, Renal transplantation. PMID- 29629894 TI - Pulmonary aspiration in adjustable gastric banding carriers undergoing a second surgical procedure. Considerations on personal experience and review of the literature. AB - BACKGROUND: The observation of a relatively high number of pulmonary aspirations (PA) among gastric band (GB) carriers undergoing a second surgery, prompted us to modify our strategy for GB patients candidate to further operation under general anesthesia. MATERIAL OF STUDY AND RESULTS: In January 2013, following the occurrence of PA at the induction of general anesthesia in 1 GB carrier undergoing a further operation, we reviewed our Data Base between January 2005 and 2013, to explore the rate of pulmonary aspiration in patients GB carriers undergoing a second surgery. Considering the rate (3/172 - 1.7%) too high in comparison with non-GB carriers, we decided to deflate the banding before any further surgery planned under general anesthesia. We then retrospectively reviewed the occurrence of PA after having changed the protocol. Since February 2013, through December 2016, 81 GB carriers underwent a second surgery and not a single episode of PA occurred (0/81). DISCUSSION: The occurrence of PA in patients with GB seems greater than in non-GB patients. Larger series should be examined to assess the incidence of PA among this specific population. Awareness of the increased risk is important to general anesthesiologists and surgeons, considering the increasing number of GB carriers who may be in need of surgery. Our result after adopting the deflation policy, even though not statistically significant, seems highly suggestive. CONCLUSION: We believe that, considering the potentially severe consequences of PA, the gastric band should be deflated before any planned procedure requiring general anesthesia. Further data are needed. KEY WORDS: Adjustable gastric banding, Aspiration Pneumonia, Bariatric surgery, Morbid obesity, Pulmonary Aspiration. PMID- 29629895 TI - Oxidative stress and DNA damage due to one-lung ventilation. AB - AIM: One-lung ventilation (OLV) is an anesthesia technique used to provide visualization in thoracoscopic lung surgeries and increase surgical site visibility during operation. In OLV, atelectasis occurs and blood from the lung participates in circulation without receiving oxygen. We designed a prospective study on patients we implemented surgery in order to research whether OLV leads to oxidative stress and DNA damage or not. METHODS: It was taken 5cc blood samples 4 times from these patients in the postoperative preparatory stage (T1), on the 60th minute after the start of OLV (T2), on the 60th minute after the termination of OLV (T3) and 24 hours after surgery (T4). Total antioxidant capacity (TAC), total oxidant status (TOS), oxidative stress index (OSI) values were examined with regards to DNA damages in the blood samples taken. RESULTS: DNA damage was statistically increased with OLV compared to baseline level (p<0.05) and statistically decreased in 24 hour (p<0.05). TAC level was statistically decreased with OLV compared to baseline level and statistically increased in 24 hour (p<0.05 ). TOS level was statistically increased with OLV compared to baseline level (p<0.05) and statistically decreased in 24 hour (p<0.05 ). OSI level was statistically increased with OLV compared to baseline level (p<0.05) and statistically decreased in 24 hour (p<0.05 ). CONCLUSION: To the best of our knowledge this is the first study showing DNA damage in thoracic surgery which was operated with OLV. This DNA damage found to be decreased in first postoperative day and might be related to changes in oxidative status of this patient group. KEY WORDS: Oxidative stress, lung ventilation, DNA damage. PMID- 29629896 TI - The V-Y flap technique in complicated and recurrent pilonidal sinus disease. AB - OBJECT VES: This study presents early and long term (5 years) outcome of 61 complicated pilonidal sinus disease cases undergoing V-Y advancement flap method together with the literature data. METHOD: Data of 336 patients undergoing surgery for pilonidal sinus disease between 2008 and 2012 were retrospectively analyzed. Patients with defect size >= 10 cm, and more than one subcutaneous sinus tunnels were assumed to have complicated pilonidal sinus disease. A total of 61 patients were included in the study. Age, gender, type of surgery, duration of hospitalization, time of drain removal, pre-operative complications, and relapse rates at post-operative 5th year were analyzed. RESULTS: Of the 66 patients, 51 underwent unilateral V-Y advancement and 10 patients had bilateral V Y plasty. Mean duration of operations was 66.87+/-18.37 minutes for total, 61.02+/-12.30 minutes for unilateral V-Y plasty, and 96.70+/-15.04 minutes for bilateral V-Y plasty. Hemovac drains were removed at 5.59+/-1.91 days averagely, 5.16+/-1.37 in unilateral group, and 7.80+/-2.74 in bilateral V-Y plasty group. Of the 4 patients who developed wound site infection, 2 had unilateral and 2 had bilateral V-Y flap advancement. Postoperative hematomas developed in 2 patients with unilateral flap and one patient with bilateral flapss. Seroma occurred in 2 patients with unilateral flap and one patient with bilateral flaps. Dehiscence developed two patients, one patient from each group. The mean duration of hosptalization was 5.98+/-2.21 days; 5.49+/-1.52 in unilateral group, and 8.50+/ 3.34 in bilateral group. Early or late relapse was not seen in any groups. CONCLUS ON: V-Y advancement flap technique can be applied as an efficient method in the treatment of complicated pilonidal sinus disease due to low relapse and complication rates. KEY WORDS: Advancement flap, Complicated pilonidal sinus, Pilonidal sinus, V-Y flap. PMID- 29629897 TI - Ectopic upregulation of membrane-bound IL6R drives vascular remodeling in pulmonary arterial hypertension. AB - Pulmonary arterial hypertension (PAH) is characterized by a progressive accumulation of pulmonary artery smooth muscle cells (PA-SMCs) in pulmonary arterioles leading to the narrowing of the lumen, right heart failure, and death. Although most studies have supported the notion of a role for IL-6/glycoprotein 130 (gp130) signaling in PAH, it remains unclear how this signaling pathway determines the progression of the disease. Here, we identify ectopic upregulation of membrane-bound IL-6 receptor (IL6R) on PA-SMCs in PAH patients and in rodent models of pulmonary hypertension (PH) and demonstrate its key role for PA-SMC accumulation in vitro and in vivo. Using Sm22a-Cre Il6rfl/fl, which lack Il6r in SM22A-expressing cells, we found that these animals are protected against chronic hypoxia-induced PH with reduced PA-SMC accumulation, revealing the potent pro survival potential of membrane-bound IL6R. Moreover, we determine that treatment with IL6R-specific antagonist reverses experimental PH in two rat models. This therapeutic strategy holds promise for future clinical studies in PAH. PMID- 29629898 TI - Classical IL-6 signaling: a promising therapeutic target for pulmonary arterial hypertension. AB - Current therapies for pulmonary arterial hypertension (PAH) provide symptomatic relief and improve prognosis but fall short of improving long-term survival. There is emerging evidence for a role of inflammatory mediators, primarily IL-6, in the pathogenesis of PAH. However, the mechanisms by which IL-6 potentially affects PAH are unknown. In this issue of the JCI, Tamura, Phan, and colleagues identified ectopic upregulation of the membrane-bound IL-6 receptor (IL6R), indicating classical IL-6 signaling in the smooth muscle layer of remodeled vessels in human and experimental PAH. They performed a series of in vitro and in vivo experiments that provide deeper insights into the mechanisms of classical IL 6 signaling and propose interventions directed against IL6R as a potential therapeutic strategy for PAH. PMID- 29629899 TI - ASK1/2 signaling promotes inflammation in a mouse model of neutrophilic dermatosis. AB - Mice homozygous for the Tyr208Asn amino acid substitution in the carboxy terminus of Src homology region 2 (SH2) domain-containing phosphatase 1 (SHP-1) (referred to as Ptpn6spin mice) spontaneously develop a severe inflammatory disease resembling neutrophilic dermatosis in humans. Disease in Ptpn6spin mice is characterized by persistent footpad swelling and suppurative inflammation. Recently, in addition to IL-1alpha and IL-1R signaling, we demonstrated a pivotal role for several kinases such as SYK, RIPK1, and TAK1 in promoting inflammatory disease in Ptpn6spin mice. In order to identify new kinases involved in SHP-1 mediated inflammation, we took a genetic approach and discovered apoptosis signal regulating kinases 1 and 2 (ASK1 and ASK2) as novel kinases regulating Ptpn6 mediated footpad inflammation. Double deletion of ASK1 and ASK2 abrogated cutaneous inflammatory disease in Ptpn6spin mice. This double deletion further rescued the splenomegaly and lymphomegaly caused by excessive neutrophil infiltration in Ptpn6spin mice. Mechanistically, ASK regulates Ptpn6spin-mediated disease by controlling proinflammatory signaling in the neutrophils. Collectively, the present study identifies SHP-1 and ASK signaling crosstalk as a critical regulator of IL-1alpha-driven inflammation and opens future avenues for finding novel drug targets to treat neutrophilic dermatosis in humans. PMID- 29629901 TI - Blocking immune intrusion into the brain suppresses epilepsy in Rasmussen's encephalitis model. AB - Rasmussen's encephalitis (RE) is a neuroinflammatory disease that typically affects only one hemisphere of the brain, resulting in severe seizures. Sixty years after the disease was first described, the preferred and best treatment option for RE is grotesque and involves removing a hemisphere of the brain (hemispherectomy); therefore, a better understanding of this seizure disorder may provide additional, less invasive therapeutic options. In this issue of the JCI, Carmant and colleagues have developed an animal model of this focal seizure disorder. The model provides experimental insights into the pathogenesis of RE and potential new treatments for this disease. PMID- 29629900 TI - Recipient mucosal-associated invariant T cells control GVHD within the colon. AB - Mucosal-associated invariant T (MAIT) cells are a unique innate-like T cell subset that responds to a wide array of bacteria and yeast through recognition of riboflavin metabolites presented by the MHC class I-like molecule MR1. Here, we demonstrate using MR1 tetramers that recipient MAIT cells are present in small but definable numbers in graft-versus-host disease (GVHD) target organs and protect from acute GVHD in the colon following bone marrow transplantation (BMT). Consistent with their preferential juxtaposition to microbial signals in the colon, recipient MAIT cells generate large amounts of IL-17A, promote gastrointestinal tract integrity, and limit the donor alloantigen presentation that in turn drives donor Th1 and Th17 expansion specifically in the colon after BMT. Allogeneic BMT recipients deficient in IL-17A also develop accelerated GVHD, suggesting MAIT cells likely regulate GVHD, at least in part, by the generation of this cytokine. Indeed, analysis of stool microbiota and colon tissue from IL 17A-/- and MR1-/- mice identified analogous shifts in microbiome operational taxonomic units (OTU) and mediators of barrier integrity that appear to represent pathways controlled by similar, IL-17A-dependent mechanisms. Thus, MAIT cells act to control barrier function to attenuate pathogenic T cell responses in the colon and, given their very high frequency in humans, likely represent an important population in clinical BMT. PMID- 29629902 TI - Humanized mouse model of Rasmussen's encephalitis supports the immune-mediated hypothesis. AB - Rasmussen's encephalitis (RE) is a chronic inflammatory brain disorder that causes frequent seizures and unilateral hemispheric atrophy with progressive neurological deficits. Hemispherectomy remains the only treatment that leads to seizure freedom for this refractory epileptic syndrome. The absence of an animal model of disease has been a major obstacle hampering the development of effective therapies. Here, we describe an experimental mouse model that shares several clinical and pathological features with the human disease. Immunodeficient mice injected with peripheral blood mononuclear cells from RE patients and monitored by video electroencephalography developed severe seizures of cortical origin and showed intense astrogliosis and accumulation of human IFN-gamma- and granzyme B expressing T lymphocytes in the brain compared with mice injected with immune cells from control subjects. We also provide evidence for the efficacy of alpha4 integrin blockade, an approved therapy for the treatment of multiple sclerosis and Crohn's disease, in reducing inflammatory markers associated with RE in the CNS. This model holds promise as a valuable tool for understanding the pathology of RE and for developing patient-tailored experimental therapeutics. PMID- 29629903 TI - ZMYND8 acetylation mediates HIF-dependent breast cancer progression and metastasis. AB - Altered epigenetic reprogramming contributes to breast cancer progression and metastasis. How the epigenetic reader mediates breast cancer progression remains poorly understood. Here, we showed that the epigenetic reader zinc finger MYND type containing 8 (ZMYND8) is induced by HIF-1 and HIF-2 in breast cancer cells and also upregulated in human breast tumors, and is correlated with poor survival of patients with breast cancer. Genetic deletion of ZMYND8 decreases breast cancer cell colony formation, migration, and invasion in vitro, and inhibits breast tumor growth and metastasis to the lungs in mice. The ZMYND8's oncogenic effect in breast cancer requires HIF-1 and HIF-2. We further showed that ZMYND8 interacts with HIF-1alpha and HIF-2alpha and enhances elongation of the global HIF-induced oncogenic genes by increasing recruitment of BRD4 and subsequent release of paused RNA polymerase II in breast cancer cells. ZMYND8 acetylation at lysines 1007 and 1034 by p300 is required for HIF activation and breast cancer progression and metastasis. These findings uncover a primary epigenetic mechanism of HIF activation and HIF-mediated breast cancer progression, and discover a possible molecular target for the diagnosis and treatment of breast cancer. PMID- 29629905 TI - Presurgical pazopanib for renal cell carcinoma with inferior vena caval thrombus: a single-institution study. AB - The aim of this study was to investigate the clinical benefit of presurgical therapy with pazopanib in renal cell carcinoma (RCC) patients with a tumor thrombus extending to a high level in the vena cava. A retrospective review was performed for seven consecutive patients with RCC and tumor thrombus involving the vena cava above the hepatic vein (level 3-4, Mayo Clinic classification) treated with pazopanib without initial cytoreductive nephrectomy at our institution. The effect of pazopanib was assessed in terms of the primary site response, thrombus diameter, and height (before and after treatment) on computed tomography or MRI. The tumor thrombus level before the induction of pazopanib was 3 in one patient and 4 in the remaining six patients. After pazopanib, shrinkage of the primary site and thrombus diameter and length were observed in all patients except one (with a rhabdoid tumor). The mean decreases of primary tumor diameter, tumor thrombus diameter, and length were 14, 9, and 31 mm, respectively. The tumor thrombus level decreased in three (43%) patients and remained stable in the remaining patient. Our findings suggest that presurgical treatment with pazopanib may shrink the tumor thrombus and decrease the surgical invasiveness in RCC patients with a high-level tumor thrombus. PMID- 29629906 TI - Low Rates of Retention Into Hepatocellular Carcinoma (HCC) Surveillance Program After Initial HCC Screening. AB - GOALS: To evaluate rates and predictors of retention into hepatocellular carcinoma (HCC) surveillance beyond initial screening among underserved cirrhosis patients. BACKGROUND: Although initial HCC screening among cirrhosis patients remains low, few studies have evaluated retention to HCC surveillance beyond initial screening. METHODS: We retrospectively evaluated all consecutive adults with cirrhosis from 2014 to 2017 at a single underserved safety net hospital system to determine rates of HCC surveillance at 6 months and at 1 year beyond initial screening. Rates of HCC surveillance was stratified by sex, race/ethnicity, and etiology of liver disease. Multivariate Cox proportional hazards models evaluated predictors of retention into HCC surveillance. RESULTS: Among 235 cirrhosis patients [hepatitis C virus: 35.7%, hepatitis B virus (HBV): 15.7%, alcoholic cirrhosis: 36.2%, nonalcoholic steatohepatitis (NASH): 8.1%], mean age of cirrhosis diagnosis was 54.2+/-8.9 years. Overall, 74.8% received initial screening within 1 year of cirrhosis diagnosis. Among those who completed initial screening, 47.6% [95% confidence interval (CI), 41.4-54.2) received second surveillance within 1 year. On multivariate analyses, patients with NASH and HBV were significantly more likely to receive second HCC surveillance compared with hepatitis C virus, HBV (hazard ratio, 2.32; 95% CI, 1.18-4.56; P=0.014) and NASH (hazard ratio, 2.49; 95% CI, 1.22-5.11; P=0.012). No sex or race-specific/ethnicity-specific differences in HCC surveillance retention were observed. CONCLUSIONS: Although overall rates of initial HCC screening among cirrhosis patients is nearly 75%, retention into continued HCC surveillance is poor, with less than half of patients undergoing subsequent HCC surveillance. Cirrhosis patients with HBV and NASH were more likely to be retained into HCC surveillance. PMID- 29629904 TI - Group B streptococcus exploits vaginal epithelial exfoliation for ascending infection. AB - Thirteen percent of pregnancies result in preterm birth or stillbirth, accounting for fifteen million preterm births and three and a half million deaths annually. A significant cause of these adverse pregnancy outcomes is in utero infection by vaginal microorganisms. To establish an in utero infection, vaginal microbes enter the uterus by ascending infection; however, the mechanisms by which this occurs are unknown. Using both in vitro and murine models of vaginal colonization and ascending infection, we demonstrate how a vaginal microbe, group B streptococcus (GBS), which is frequently associated with adverse pregnancy outcomes, uses vaginal exfoliation for ascending infection. GBS induces vaginal epithelial exfoliation by activation of integrin and beta-catenin signaling. However, exfoliation did not diminish GBS vaginal colonization as reported for other vaginal microbes. Rather, vaginal exfoliation increased bacterial dissemination and ascending GBS infection, and abrogation of exfoliation reduced ascending infection and improved pregnancy outcomes. Thus, for some vaginal bacteria, exfoliation promotes ascending infection rather than preventing colonization. Our study provides insight into mechanisms of ascending infection by vaginal microbes. PMID- 29629907 TI - Incidence, Admission Rates, and Predictors, and Economic Burden of Adult Emergency Visits for Acute Pancreatitis: Data From the National Emergency Department Sample, 2006 to 2012. AB - INTRODUCTION: Acute pancreatitis (AP) is the most common gastroenterology-related reason for hospital admission, and a major source of morbidity and mortality in the United States. This study examines the National Emergency Database Sample, a large national database, to analyze trends in emergency department (ED) utilization and costs, risk factors for hospital admission, and associated hospital costs and length of stay (LOS) in patients presenting with AP. METHODS: The National Emergency Database Sample (2006 to 2012) was evaluated for trends in ED visits, ED charges, hospitalization rates, hospital charges, and hospital LOS in patients with primary diagnosis of AP (further subcategorized by age and etiology). A survey logistic-regression model was used to determine factors predictive of hospitalization. RESULTS: A total of 2,193,830 ED visits were analyzed. There was a nonsignificant 5.5% (P=0.07) increase in incidence of ED visits for AP per 10,000 US adults from 2006 to 2012, largely driven by significant increases in ED visits for AP in the 18 to <45 age group (+9.2%; P=0.025), AP associated with alcohol (+15.9%; P=0.001), and AP associated with chronic pancreatitis (+59.5%; P=0.002). Visits for patients aged >=65 decreased over the time period. Rates of admission and LOS decreased during the time period, while ED and inpatient costs increased (62.1%; P<0.001 and 7.9%; P=0.0011, respectively). Multiple factors were associated with increased risk of hospital admission from the ED, with the strongest predictors being morbid alcohol use [odds ratio (OR), 4.53; P<0.0001], advanced age (age>84 OR, 3.52; P<0.0001), and smoking (OR, 1.75; P<0.0001). CONCLUSIONS: Despite a relative stabilization in the overall incidence of ED visits for AP, continued increases in ED visits and associated costs appear to be driven by younger patients with alcohol-associated and acute on chronic pancreatitis. While rates of hospitalization and LOS are decreasing, associated inflation-adjusted costs are rising. In addition, identified risk factors for hospitalization, such as obesity, alcohol use, and increased age, should be explored in further study for potential use in predictive models and clinical improvement projects. PMID- 29629908 TI - The Modern Surgeon Scientist. PMID- 29629909 TI - Exploring Nurse Manager Support of Evidence-Based Practice: Clinical Nurse Perceptions. AB - OBJECTIVE: The study identifies what constitutes nurse manager (NM) support and other resources that enable clinical nurses (CNs) to engage in evidence-based practice (EBP). BACKGROUND: Clinical nurses report that NM support enables them to use EBP but what constitutes NM support is still unclear. METHODS: Nurse managers, CNs, and EBP mentors received specialized education and use a team approach for EBP. Data were collected preintervention, mid-intervention, and postintervention from observations, interviews, journaling, and surveys. RESULTS: Results demonstrate how NMs can perform their role responsibilities and still engage CNs to develop a spirit of inquiry, seek answers to their clinical questions using EBP, and advance their clinical performance to improve patient outcomes. Four NM supportive behaviors emerged: cultivating a shared EBP vision, ensuring use of EBP, communicating the value of EBP, and providing resources for EBP. CONCLUSION: Through education and support, NMs describe supportive behaviors necessary for the successful conduction of EBP by CNs. PMID- 29629910 TI - Conceptualization and Operationalization of Certification in the US and Canadian Nursing Literature. AB - OBJECTIVE: To identify how certification is defined, conceptualized, and discussed in the nursing literature. BACKGROUND: Although it is hypothesized that credentialing is associated with better patient outcomes, the evidence is relatively limited. Some authors have suggested that the lack of consistency used to define certification in nursing literature may be one of the dominant obstacles in credentialing research. METHODS: This scoping review was guided by Arksey and O'Malley's framework, and quantitative and qualitative analyses were conducted. RESULTS: The final data set contained a total of 36 articles, of which 14 articles provided a referenced definition of certification. Thematic analysis of the definitions yielded 8 dominant themes. CONCLUSION: The lack of a common definition of certification in nursing must be addressed to advance research into the relationship between certification processes in nursing and healthcare outcomes. PMID- 29629911 TI - National Study of Nursing Research Characteristics at Magnet(r)-Designated Hospitals. AB - OBJECTIVE: To describe the research infrastructure, culture, and characteristics of building a nursing research program in Magnet(r)-designated hospitals. BACKGROUND: Magnet recognition requires hospitals to conduct research and implement evidence-based practice (EBP). Yet, the essential characteristics of productive nursing research programs are not well described. METHODS: We surveyed 181 nursing research leaders at Magnet-designated hospitals to assess the characteristics in their hospitals associated with research infrastructure, research culture, and building a nursing research program. RESULTS: Magnet hospitals provide most of the needed research infrastructure and have a culture that support nursing research. Higher scores for the 3 categories were found when hospitals had a nursing research director, a research department, and more than 10 nurse-led research studies in the past 5 years. CONCLUSIONS: While some respondents indicated their nurse executives and leaders support the enculturation of EBP and research, there continue to be barriers to full implementation of these characteristics in practice. PMID- 29629912 TI - Technical Pitfall in 68Ga-Prostate Specific Membrane Antigen Imaging: Altered Biodistribution Caused by Free 68Ga-Citrate Due to Radiolysis Showing Increased Vascular Activity. AB - As with any new molecular imaging modality, accurate characterization of abnormalities on Ga-PSMA PET/CT imaging can be accomplished only if one is aware of the normal distribution pattern, physiological variants, and potential sources of false imaging findings. Altered biodistribution can have a significant impact on scan interpretation. Presented here is a rare case in which radiopharmaceutical radiolysis occurred causing excessive free Ga-citrate showing as an increased vascular activity. As Ga-PSMA PET/CT imaging is a relatively new imaging technique, it is important to be aware of such a potential technical pitfall in clinical practice in order to prevent scan misinterpretation. PMID- 29629913 TI - Automated Reporting of DXA Studies Using a Custom-Built Computer Program. AB - Dual-energy x-ray absorptiometry (DXA) scans are a critical population health tool and relatively simple to interpret but can be time consuming to report, often requiring manual transfer of bone mineral density and associated statistics into commercially available dictation systems. We describe here a custom-built computer program for automated reporting of DXA scans using Pydicom, an open source package built in the Python computer language, and regular expressions to mine DICOM tags for patient information and bone mineral density statistics. This program, easy to emulate by any novice computer programmer, has doubled our efficiency at reporting DXA scans and has eliminated dictation errors. PMID- 29629914 TI - 123I-FP-CIT SPECT and MRI Findings in a Patient With Parkinsonism After Fenpyroximate Intoxication. AB - Fenpyroximate is a widely used acaricide. Its main action is to inhibit the mitochondrial respiratory chain. Chronic exposure to fenpyroximate is associated with dopaminergic cell loss and parkinsonism; however, to date, there has not been a reported case of parkinsonism as a result of acute fenpyroximate intoxication. Here, we report a 58-year-old man who developed parkinsonism after deliberate fenpyroximate intoxication, but with normal presynaptic I-Ioflupane SPECT image. PMID- 29629915 TI - Endothelial Dysfunction is Related to Glycemic Variability and Quality and Duration of Sleep in Adults With Type 1 Diabetes. AB - BACKGROUND: Elevated cardiovascular disease risk in people with type 1 diabetes (T1DM) is incompletely understood. Glycemic control, glycemic variability, and sleep quality and duration may relate to cardiovascular disease risk in this population via endothelial dysfunction. OBJECTIVE: The aim of this study was to examine relationships among glycemic control, glycemic variability, sleep quality and duration, and endothelial function in adults with T1DM. METHODS: Endothelial function was measured using flow-mediated dilation. Glycemic control and glycemic variability were measured using A1C and a continuous glucose monitor, respectively; sleep quality and duration were measured with the Pittsburgh Sleep Quality Index. RESULTS: Twenty subjects were recruited. Reduced flow-mediated dilation and higher glucose levels were associated with poorer sleep quality (r = -0.51, P = .01; r = 0.52, P = .03). Subjects with shorter sleep duration had greater glycemic variability. CONCLUSIONS: Endothelial dysfunction (a precursor to cardiovascular disease) relates to glycemic control, glycemic variability, and sleep quality in T1DM. PMID- 29629916 TI - Distal Femoral Varus Osteotomy for the Management of Valgus Deformity of the Knee. AB - Distal femoral varus osteotomy is a well-described treatment option for patients with valgus malalignment associated with a variety of underlying conditions. This procedure may be the definitive treatment option in active patients with isolated lateral compartment osteoarthritis or posttraumatic arthritis. It may be a useful concomitant procedure in young patients with lateral meniscus deficiency, focal chondral defects, chronic medial collateral ligament insufficiency, and/or patellofemoral instability. Distal femoral varus osteotomy can be performed with medial closing wedge or lateral opening wedge techniques. Variable outcomes and complication rates have been reported. A framework for the use of distal femoral varus osteotomy can aid the orthopaedic surgeon in the evaluation and treatment of patients with symptomatic valgus malalignment. PMID- 29629917 TI - Patient-reported Outcome Measurement for Patients With Total Knee Arthroplasty. PMID- 29629918 TI - Form Follows Function: Partnering for Success. PMID- 29629919 TI - Hibernoma Mimicking Atypical Lipomatous Tumor: 64 Cases of a Morphologically Distinct Subset. AB - Hibernoma is a benign adipocytic tumor with predilection for subcutaneous tissue of the thigh, upper trunk, and neck of middle-aged adults. 11q13 rearrangement resulting in MEN1/AIP codeletion is characteristic. Hibernomas are composed, in varying proportions, of brown fat cells, mature adipocytes, and microvacuolated lipoblast-like cells. Examples containing predominantly multivacuolated lipoblast like cells are uncommon and distinction from atypical lipomatous tumor (ALT) is important for clinical management. We herein present the clinicopathologic features of 64 hibernomas histologically mimicking ALT. MDM2 and CDK4 immunohistochemistry as well as MDM2 fluorescence in situ hybridization were performed in a subset of cases. Clinical and follow-up information were obtained from referring pathologists. Thirty-four patients were male and 30 female, with a median age of 43 years (range, 24 to 78 y). The tumors were well circumscribed and mostly deeply located (53/64 cases, 83%) with a median tumor size of 12.9 cm (range, 3.5 to 23 cm) and predilection for the thigh (42/64 cases, 66%). Histologically, large cells with prominent lipoblast-like cytoplasmic fatty vacuoles and small central nuclei were present to a prominent degree in all cases, along with mature univacuolated adipocytes and smaller numbers of large, finely vacuolated cells with eosinophilic granular cytoplasm. Nuclear atypia and mitoses were absent. None of the 39 cases tested showed CDK4 and MDM2 overexpression or MDM2 amplification. Follow-up, available for 16/64 cases (median, 47 mo; range, 1 to 165 mo), revealed no recurrences or metastases. Hibernoma mimicking ALT shows predilection for deep soft tissue, especially in the thigh. These tumors behave in a benign manner and MDM2/CDK4 negativity may be useful in excluding ALT. PMID- 29629921 TI - Assessment of cardiac thrombosis in patients with left ventricular assist device using multidetector cardiac computed tomography. PMID- 29629920 TI - Pleural effusions in hematologic malignancies and their management with indwelling pleural catheters. AB - PURPOSE OF REVIEW: Pleural effusions in patients with hematologic malignancy may represent malignant pleural effusion (MPE) or occur secondary to infection, treatment effects, and other common causes. The impact of MPE on prognosis in this cohort remains unclear. Indwelling pleural catheters (IPCs) are routinely placed for palliation of recurrent symptomatic MPEs, but perceived concerns over infection and bleeding may limit their use in patients with hematologic malignancies. However, recent evidence suggests IPCs are both well tolerated and effective in this cohort. In this review, the evaluation of pleural effusions in hematologic malignancies and their management with an IPC are outlined. RECENT FINDINGS: Two retrospective studies have been published regarding the use of IPCs in hematologic malignancies. Lymphomatous effusions are the most common cause of MPE in this cohort. The rates of complications and pleurodesis with IPC in hematologic malignancies are similar to those with solid organ tumors. SUMMARY: Pleural effusions in patients with hematologic malignancies may be managed safely with an IPC. Sterile technique, barrier protection, standardized algorithms for placement and removal, and quality assurance initiatives are crucial to centers that place IPCs for all patients. The safety of IPC in hematologic malignancies warrants a paradigm shift in the management of pleural disease for this cohort. PMID- 29629922 TI - Medicaid Managed Care in Florida and Racial and Ethnic Disparities in Preventable Emergency Department Visits. AB - BACKGROUND: In an effort to address health care spending growth, coordinate care, and improve access to primary care in the Medicaid program, Florida implemented the Statewide Mandatory Managed Care (SMMC) program in May of 2014. OBJECTIVES: The objective of this study is to investigate the impact of implementation of mandatory managed care in Medicaid on the preventable emergency department (ED) utilizations, with a focus on racial/ethnic minorities. RESEARCH DESIGN: The primary data source is the universe of Florida ED visit and inpatient discharge data from 2010 to 2015, maintained by the Florida Agency for Health Care Administration. We adopt the New York University Billing's ED Classification Algorithm to create measures for preventable ED visits. Using difference-in differences estimation, we examine preventable ED visits for Florida residents aged 18-64 with a primary payer of Medicaid (treatment group) and private health insurance (control group) pre-SMMC and post-SMMC reform. RESULTS: Our findings show that SMMC is statistically significantly associated with more reductions in preventable ED visits among non-Hispanic African American (incidence rate ratio=0.81; 95% confidence interval, 0.70-0.94) and Hispanic (incidence rate ratio=0.72; 95% CI, 0.60-0.87) Medicaid enrollees relative to their white counterparts. We also find significant reduction of racial/ethnic disparities only in counties with above median preimplementation Medicaid managed care penetration rate. CONCLUSIONS: Our findings suggest that implementation of Medicaid mandatory managed care in Florida is associated with reduced racial/ethnic disparities in preventable ED visits. PMID- 29629924 TI - Thrombosis in Obstetrics and Gynecology. PMID- 29629923 TI - Organizational Processes and Patient Experiences in the Patient-centered Medical Home. AB - BACKGROUND: There is increasing emphasis on the use of patient-reported experience data to assess practice performance, particularly in the setting of patient-centered medical homes. Yet we lack understanding of what organizational processes relate to patient experiences. OBJECTIVE: Examine associations between organizational processes practices adopt to become PCMH and patient experiences with care. RESEARCH DESIGN: We analyzed visit data from patients (n=8356) at adult primary care practices (n=22) in a large health system. We evaluated the associations between practice organizational processes and patient experience using generalized estimating equations (GEE) with an exchangeable correlation structure to account for patient clustering by practice in multivariate models, adjusting for several practice-level and patient-level characteristics. We evaluated if these associations varied by race/ethnicity, insurance type, and the degree of patient comorbidity MEASURES:: Predictors include overall PCMH adoption and adoption of six organizational processes: access and communications, patient tracking and registry, care management, test referral tracking, quality improvement and external coordination. Primary outcome was overall patient experience. RESULTS: In our full sample, overall PCMH adoption score was not significantly associated with patient experience outcomes. However, among subpopulations with higher comorbidities, the overall PCMH adoption score was positively associated with overall patient experience measures [0.2 (0.06, 0.4); P=0.006]. Differences by race/ethnicity and insurance type in associations between specific organizational processes and patient experience were noted. CONCLUSION: Although some organizational processes relate to patients' experiences with care irrespective of the background of the patient, further efforts are needed to align practice efforts with patient experience. PMID- 29629925 TI - Reducing Maternal Mortality and Severe Maternal Morbidity: The Role of Critical Care. AB - Throughout most of the 20th century, the risk of maternal mortality in high resource countries decreased dramatically; however, this trend recently has stalled in the United States and appears to have reversed. Equally alarming is that for every reported maternal death, there are numerous severe maternal morbidities or near misses. Shifting maternal demographics (eg, obesity, advanced maternal age, multifetal pregnancies), with attendant significant medical comorbidities (eg, hypertension, diabetes, cardiac disease) and the increase in cesarean deliveries significantly contribute to increased maternal morbidity and mortality. This chapter focuses on the role of critical care in reducing maternal mortality and morbidity. PMID- 29629926 TI - Neuroprognostication postcardiac arrest: translating probabilities to individuals. AB - PURPOSE OF REVIEW: Predicting neurological recovery in patients who are comatose after cardiac arrest is an important activity during postarrest care, and this prediction can affect survival. As no early test or clinical finding perfectly predicts potential for recovery, guidelines recommend using data from multiple examinations or tests to estimate patient prognosis. RECENT FINDINGS: Studies reported accuracy of initial clinical examination, progression of clinical examination, early (<24 h) brain imaging, electroencephalography (EEG), evoked potentials, later (>24 h) brain imaging, blood markers of brain injury, and cerebral oximetry for predicting good or poor outcome. In multiple cohorts, patients with status myoclonus with particular clinical or EEG features have potential for good outcome. When multiple tests were compared, each test provided independent information. SUMMARY: Absence of cortical functional recovery over time is detected using multiple testing modalities and remains strongly associated with poor outcome. Early recovery of cortical function increases the probability of good outcome. Concordant assessments from multiple tests increase confidence in prognostication. PMID- 29629927 TI - Physiology-directed cardiopulmonary resuscitation: advances in precision monitoring during cardiac arrest. AB - PURPOSE OF REVIEW: We review the recent advances in physiologic monitoring during cardiac arrest and offer an evidence-based framework for prioritizing physiologic targets during cardiopulmonary resuscitation (CPR). RECENT FINDINGS: Current CPR guidelines recommend a uniform approach for all patients in cardiac arrest, but newer data support a precision strategy that uses the individual patient's physiology to guide resuscitation. Coronary perfusion pressure and arterial DBP are associated with survival outcomes in recent animal and human studies. End tidal carbon dioxide is a reasonable noninvasive alternative, but may be inferior to invasive hemodynamic endpoints. Cerebral oximetry and cardiac ultrasound are emerging physiologic indicators of CPR effectiveness. SUMMARY: Physiologic monitoring can and should be used to deliver precision CPR whenever possible and may improve outcomes after cardiac arrest. PMID- 29629928 TI - Pancreatic Chymotrypsin Activity Rather Than Amylase Level Better Predicts Postoperative Pancreatic Fistula: Retraction. PMID- 29629930 TI - In the Next Issue. PMID- 29629929 TI - Safety of Overlapping Surgery at a High-volume Referral Center. PMID- 29629931 TI - Magnetic Resonance Imaging in Neurocritically Ill Patients: Who Fails and How? AB - OBJECTIVES: Performing magnetic resonance imaging (MRI) in neurocritically ill patients is challenging because it often requires sedation and withholding care in the neurological intensive care unit. This study investigated the incidence of and reasons for failed or complicated MRI (MRI-FC) in such patients. METHODS: A consecutive series of 218 neurocritically ill patients who underwent brain MRI were retrospectively evaluated. Failed or complicated MRI included failure to obtain all ordered sequences, unscheduled sedative administration, decrease in oxygen saturation to less than 90%, hypotension (>=40-mm Hg decrease and/or use of inotropic agents), and cardiac or respiratory arrest. RESULTS: Failed or complicated MRI occurred in 66 patients (30.3%) and included failure to obtain MRI sequences (n = 13), unscheduled use of sedatives (n = 62), oxygen desaturation (n = 9), and hypotension (n = 6). Cardiac or respiratory arrest did not occur. Use of sedative agents while in intensive care (P < 0.01), high Acute Physiology and Chronic Health Evaluation II score (P = 0.031), and low Glasgow Coma Scale score on admission (P = 0.047) were associated with MRI-FC. Scan times were longer (P = 0.004) and Glasgow Coma Scale (P < 0.001) and Richmond Agitation Sedation Scale (P = 0.003) scores were lower (P = 0.004) after imaging in patients with MRI-FC. Previous use of sedative agents was independently associated with MRI-FC (adjusted odds ratio = 3.57, 95% confidence interval = 1.78 to 7.24, P < 0.001). CONCLUSIONS: Failed or complicated MRI was common and was associated with the use of sedative agents, severity of illness, and lower level of consciousness. Studies to ensure effective and safe performance of MRI in neurocritically ill patients are needed. PMID- 29629932 TI - The Effect of Concept Maps on Undergraduate Nursing Students' Critical Thinking. AB - AIM: The aim of the study was to evaluate the effect of using concept maps as a teaching and learning strategy on students' critical thinking abilities and examine students' perceptions toward concept maps utilizing the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. BACKGROUND: Researchers have found that almost two thirds of nurse graduates do not have adequate critical thinking skills for a beginner nurse. Critical thinking skills are required for safe practice and mandated by accrediting organizations. Nursing educators should consider teaching and learning strategies that promote the development of critical thinking skills. METHOD: A literature review was conducted using "concept maps, nursing education, and critical thinking" as the combined search terms. Inclusion criteria were studies that measured the effects of concept mapping on critical thinking in nursing students. RESULTS: Seventeen articles were identified. CONCLUSION: Concept maps may be useful tools to promote critical thinking in nursing education and for applying theory to practice. PMID- 29629933 TI - Using Tabletop Exercises as an Innovative and Practical Teaching Strategy in Response to External Disaster Scenarios. AB - Transferring previous learning to novel and unfamiliar health care situations is a challenge that nurses face daily. As a nursing classroom experience, tabletop exercises provide nursing students with open-ended decision-making opportunities to manage realistic practice problems. This article describes an innovative tabletop exercise with a disaster healthcare context and patient scenarios that senior nursing students used to demonstrate foundational nursing education knowledge, skills, and abilities. Students demonstrated a transfer of knowledge from early medical-surgical coursework to a complex, novel situation using the nursing process and evidence-based clinical judgment. PMID- 29629935 TI - CORR Insights(r): What Markers Best Guide the Timing of Reimplantation in Two stage Exchange Arthroplasty for PJI? A Systematic Review and Meta-analysis. PMID- 29629934 TI - Faculty Mentorship: Making It Work Across the Career Continuum Through Development, Implementation, and Evaluation of a Formal Mentorship Program. AB - Mentoring is a way to foster personal and professional career development within professional disciplines such as nursing. The National League for Nursing has described the nurse faculty role as multidimensional and difficult to balance. A school of nursing implemented a faculty mentorship program focused on the school's core values: caring, professionalism, respect, integrity, diversity, and excellence (CPRIDE). This program combines traditional and nontraditional mentoring models to create an environment in which junior faculty form relationships with senior faculty who possess expertise in a particular field. PMID- 29629936 TI - Letter to the Editor: 2017 Chitranjan S. Ranawat Award: Does Computer Navigation in Knee Arthroplasty Improve Functional Outcomes in Young Patients? A Randomized Study. PMID- 29629937 TI - Reply to the Letter to the Editor: 2017 Chitranjan S. Ranawat Award: Does Computer Navigation in Knee Arthroplasty Improve Functional Outcomes in Young Patients? A Randomized Study. PMID- 29629938 TI - CORR Insights(r): Vitamin E Phosphate Coating Stimulates Bone Deposition in Implant-related Infections in a Rat Model. PMID- 29629940 TI - The Reduction of Measles Transmission During School Vacations. AB - BACKGROUND: Historically, measles incidence has shown clear seasonal patterns driven by the school calendar, but since the start of mass vaccination in developed countries there are only occasional outbreaks, which may have changed the effect of school vacations on transmission. In 2013-2014, a large measles epidemic took place in a low vaccination coverage area in The Netherlands, allowing us to quantify current-day measles transmission and the effect of school vacations. METHODS: We fitted a dynamic transmission model to notification and hospitalization time series data of the Dutch 2013-2014 measles epidemic. Our primary aim was to estimate the reduction in contact rate during school vacations and the number of cases averted due to the vacation. In addition, because the summer vacations were time-staggered in three regions, we could distinguish within-region from across-region effects of school vacations. RESULTS: We estimated a 53% (95% credible interval: 45%, 60%) reduction in contact rate during school vacations, resulting in 4900 (3400-7100) averted cases (estimated outbreak size: 16,600 [12,600-23,200]). There was a shift from mainly local transmission during school term to mainly cross-regional transmission during vacations. With seroprevalence data, we derived a current-day estimate of 15 to 27 for R0 (number of secondary cases per primary case in a susceptible population). CONCLUSIONS: School vacations are associated with greatly reduced overall measles transmission. However, transmission is not eliminated, and increased long-distance travel may even promote spread to other areas. Therefore, we estimate that school closure is unlikely to prevent measles epidemics unless there are still few cases and the community is well vaccinated. PMID- 29629939 TI - Depressive Symptoms, Antidepressant Use, and Hypertension in Young Adulthood. AB - BACKGROUND: Among adults, depressive symptoms are associated with higher rates of cardiovascular disease; however, the evidence is mixed regarding the association between depressive symptoms and hypertension, especially among young adults. The deleterious effects of some antidepressant medications on blood pressure may contribute to mixed findings. METHODS: Adolescents enrolled in Add Health (N = 11,183) (1994-2008) completed an abbreviated Center for Epidemiologic Studies Depression Scale at three waves (mean ages, 16, 22, and 29). Antidepressant use was measured at age 22 and at age 29. Hypertension at age 29 was defined as measured systolic blood pressure of 140 mm Hg or greater, diastolic blood pressure of 90 mm Hg or greater, or staff-inventoried anti-hypertensive medication use. RESULTS: The prevalence of hypertension at age 29 was 20%. High depressive symptoms in adolescence or young adulthood were not associated with hypertension in young adulthood. Antidepressant use at age 29 was associated with increased prevalence of hypertension (prevalence ratio [PR], 1.4; 95% CI, 1.2, 1.7) and an interaction with sex was observed (PRMen, 1.6; 95% CI, 1.2, 2.0; PRWomen, 1.2; 95% CI, 0.89, 1.6; pinteraction = 0.0227). Selective serotonin reuptake inhibitor and non-selective serotonin reuptake inhibitor antidepressant use were associated with hypertension (PRSSRI, 1.3; 95% CI, 1.0, 1.6; PRnon-SSRI, 1.6; 95% CI, 1.2, 2.1). CONCLUSIONS: In this sample, antidepressant use, but not depressive symptoms, was associated with hypertension in young adulthood. Further research is recommended to examine joint and independent relationships between depression and antidepressant use and hypertension among young adults. See video abstract at, http://links.lww.com/EDE/B355. PMID- 29629941 TI - B cells in multiple sclerosis. AB - PURPOSE OF REVIEW: Although it is becoming increasingly clear that B cells play important roles in multiple sclerosis (MS) pathogenesis, it is incompletely understood how they contribute. The purpose of this review is to provide an overview of the current knowledge about B cells in MS taking into account MS heterogeneity. RECENT FINDINGS: The efficacy of B cell-depleting therapies has provided strong evidence for the involvement of these cells in MS pathogenesis. Although pathogenic antibodies were found in some MS patients, the observation that plasma cells and antibodies remain largely unchanged after B-cell depletion suggests that B cells are involved in MS by other mechanisms than antibody production. SUMMARY: MS is an autoimmune disease, in which T and B cells play a crucial role. B cells can be involved in MS by different mechanisms such as presentation of antigens to T cells, transport of antigens from tissues to secondary lymphoid organs, secretion of pro-inflammatory or anti-inflammatory cytokines and in a subgroup of patients also production of pathogenic antibodies. As several B-cell/antibody-directed therapies are available, it is important to understand how these different functions of B cells and antibodies vary among patients in order to identify which could benefit best from the different therapies. PMID- 29629942 TI - Paediatric multiple sclerosis and other acute demyelinating diseases. AB - PURPOSE OF REVIEW: Neuroimmunological diseases encompass a wide spectrum of diseases in children. Apart from the discovery of autoantibodies affecting primarily grey matter structures and the improved clinical characterization of rare entities such as N-methyl D-aspartate receptor-R- encephalitis, important strides have also been made in autoimmune-mediated white matter diseases, including paediatric multiple sclerosis (pedMS) and other acute demyelinating syndromes (ADS) often associated with antibodies (abs) against myelin oligodendrocyte-glycoprotein (MOG). This review will cover findings of recent studies in pedMS, in the emerging field of non-MS acute demyelinating episodes associated with MOG abs and lastly from new imaging techniques such as diffusion tensor imaging (DTI) revealing new insights in the pathogenesis of ADS in children. RECENT FINDINGS: The first prospective randomized clinical pedMS trial assessing the clinical and radiological efficacy of fingolimod versus a standard disease-modifying agent has shown clear superiority of fingolimod. The clinical spectrum of MOG-associated diseases has been characterized in more detail revealing clinical subtypes distinct from pedMS. A recent large European study further showed that MOG-associated diseases do not respond to first-line disease modifying treatment (DMT) in MS but fare better with B-cell modulating therapies including regular intravenous immunoglobulin (IVIG). SUMMARY: Recent findings strongly indicate that in particular in highly active pedMS characterized by new relapses or accrual of new MRI lesions despite first-line DMT treatment should be escalated. Secondly, several studies have shown that MOG-spectrum diseases include children with monophasic and recurrent subtypes other than MS with different clinical, radiological characteristics and treatment challenges. PMID- 29629943 TI - Primary aldosteronism in the primary care setting. AB - PURPOSE OF REVIEW: The aim of the present manuscript is to provide an overview of the most updated studies on the prevalence of primary aldosteronism in primary care and to compare these figures with the actual rate of diagnosis in clinical practice and with the prevalence of primary aldosteronism in specific subgroup of patients. RECENT FINDINGS: Over the last 20 years the clinical spectrum of low renin hypertension and primary aldosteronism has changed dramatically. Once considered only in the presence of severe hypertension and hypokalemia, it is now well known that primary aldosteronism is not uncommon even in patients with mild forms of hypertension and/or normokalemia. Moreover, recent evidence points toward a large proportion of normotensive study participants as being affected by subclinical primary aldosteronism, which represents a strong risk factor for incident hypertension. Moreover, primary aldosteronism patients are exposed to an increased risk of cardio and cerebrovascular events and metabolic comorbidities compared with patients affected by essential hypertension. Disappointingly, primary aldosteronism remains a largely underdiagnosed and undertreated disorder. SUMMARY: These recent findings further highlight the importance of widening the spectrum of patients who should be screened for primary aldosteronism, to reduce the cardiovascular risk associated with this medical condition. PMID- 29629944 TI - Human Endometriosis Tissue Microarray Reveals Site-specific Expression of Estrogen Receptors, Progesterone Receptor, and Ki67. AB - Most available therapies for endometriosis are hormone-based and generally broadly used without taking into consideration the ovarian hormone receptor expression status. This contrasts strikingly with the standard of care for other hormone-based conditions such as breast cancer. We therefore aimed to characterize the expression of ovarian steroid hormone receptors for estrogen alpha (ESR1), estrogen beta (ESR2), and progesterone (PGR) in different types of endometriotic lesions and eutopic endometrium from women with endometriosis and controls using a tissue microarray (TMA). Nuclear expression levels of the receptors were analyzed by tissue (ie, ectopic vs. eutopic endometrium) and cell type (ie, glands vs. stroma). Ovarian lesions showed the lowest expression of ESR1 and PGR, and the highest expression of ESR2, whereas the fallopian tube lesions showed high expression of the 3 receptors. Differences among endometria included lower expression of ESR1 and higher expression of ESR2 in stroma of proliferative endometrium from patients versus patients, and a trend towards loss of PGR nuclear positivity in proliferative endometrium from patients. The largest ESR2:ESR1 ratios were observed in ovarian lesions and secretory endometrium. The highest proportion of samples with >10% Ki67 positive nuclei was in glands of fallopian tube (54%) and extrapelvic lesions (75%); 60% of glands of secretory endometrium from patients had >10% Ki67 positivity compared with only 15% in controls. Our results provide a better understanding of endometriosis heterogeneity by revealing lesion type-specific differences and case-by-case variability in the expression of ovarian hormone receptors. This knowledge could potentially predict individual responses to hormone therapies, and set the basis for the application of personalized medicine approaches for women with endometriosis. PMID- 29629945 TI - Clonal Evolution in Primary Diffuse Large B-Cell Lymphoma of the Central Nervous System. AB - Primary diffuse large B-cell lymphoma (DLBCL) of the central nervous system (CNS) is an aggressive subtype of DLBCL with characteristic clinicopathologic features. Relapse outside the CNS involving extranodal locations has been found in a fraction of cases (16%). Here we describe a case of DLBCL arising in the CNS that relapsed 18 months after the initial diagnosis in the testis and bilateral adrenal glands. Both tumors showed equivalent morphology, phenotype, cytogenetic features, and clonal relationship. Somatic mutation analysis by next generation sequencing demonstrated MYD88L265P mutation in both tumors and de novo CD79B Y196S mutation exclusive to the relapse. The pattern of mutations suggest that the 2 tumors might have evolved from a common progenitor clone with MYD88L265P being the founder mutation. A meta-analysis of the literature shows a significantly high frequency of concurrent MYD88L265P and CD79B ITAM mutations in primary CNS lymphoma and testicular DLBCL, underscoring the role of B cell receptor and nuclear factor kB activation by somatic mutations in these lymphomas that colonize immune-privileged sites. In summary, here we illustrate that targeted next generation sequencing for the detection of hot spot somatic mutations in relapsed DLBCL is useful to confirm ABC phenotype and discovers relevant information that might influence therapeutic decision. PMID- 29629946 TI - Efficacy of GATA3 Versus BRST2 for the Identification of Metastatic Breast Carcinoma in the Upper GI Tract: Which Performs Better? AB - Distinguishing primary diffuse-type gastric carcinoma (PDGC) versus gastric involvement by metastatic breast carcinoma (mBC), particularly the lobular subtype, is difficult on histology alone. Both can appear morphologically similar. GATA3, a novel transcription factor, is used in certain scenarios as an immunohistochemical marker of breast origin. Our objective was to investigate the efficacy of GATA3 in differentiating PDGC and mBC and how it compares to another breast marker, BRST2. We retrospectively stained 40 cases of PDGC and 10 control cases of mBC from upper gastrointestinal tract specimens for antibodies: GATA3, BRST2, CDX2, and estrogen receptor. Staining of tumor cells was semiquantified with a modified Allred score. GATA3 and BRST2 were positive in 17.5% and 12.5% of PDGC cases, respectively, and in 100% of mBC cases. Allred scores for GATA3 were significantly greater in mBC cases compared with PDGC (P=0.001). Allred scores were not significantly different for BRST2 due to low levels of staining in mBC cases. Although sensitivity and specificity were similar, differences in staining between PDGC and mBC were more decisive for GATA3 versus BRST2 and thus easier to interpret. In addition, 50% of PDGC cases were positive for CDX2 and none for estrogen receptor. Overall, our results show that GATA3 can reliably and correctly identify cases of mBC to the upper gastrointestinal tract. However, because a minority of PDGC were positive for GATA3, it should still be used within an antibody panel to resolve this diagnostic dilemma. PMID- 29629947 TI - Identification of "Double Hit" Lymphomas Using Updated WHO Criteria: Insights From Routine MYC Immunohistochemistry in 272 Consecutive Cases of Aggressive B Cell Lymphomas. AB - Aggressive lymphomas with MYC and BCL2 and/or BCL6 translocations ("double hit" lymphomas, DHL) represent a distinct diagnostic category in the updated World Health Organization (WHO) classification. The diagnostic yield of MYC immunohistochemistry (IHC) for the identification of DHL is currently uncertain. MYC IHC was performed in 272 consecutive cases of aggressive B-cell lymphoma, and results correlated with fluorescence in situ hybridization (FISH) for MYC translocations. Among 156 patients with IHC and FISH data, MYC IHC identified MYC translocations with 89% sensitivity, 38% specificity, 92% negative predictive value, and 29% positive predictive value. Three of 15 (20%) of DHL were MYC IHC negative. One case contained a MYC translocation detectable IGH/MYC fusion probes but not MYC break-apart probes. A subset of DHL lack MYC protein expression, and recognition of this subset of cases requires FISH testing. These results provide an appropriate diagnostic algorithm for implementation of 2016 WHO diagnostic criteria. PMID- 29629948 TI - PAX8 Expression Variability in Cerebellar Hemangioblastoma: Case Series and Review of the Literature. AB - Hemangioblastomas are benign tumors of undetermined origin, and account for up to 2.5% of all intracranial tumors. They may occur either sporadically or as a manifestation of von Hippel-Lindau (VHL) syndrome. Central nervous system (CNS) hemangioblastomas are pathologically diagnosed by gross and microscopic morphology, with further support of the diagnosis conferred by a characteristic immunohistochemistry profile including PAX8 negativity. Although renal hemangioblastomas have previously been reported to be PAX8 positive, CNS hemangioblastoma positive PAX8 expression has never been reported. We reviewed 11 cases of cerebellar hemangioblastoma from our institution over a 7-year period (2010 to 2017). Tissue was stained for PAX8 to determine immunohistochemical labeling. Of 11 reviewed cases of cerebellar hemangioblastoma, 7 exhibited PAX8 immunohistochemical expression. A review of the literature found no previously reported cases of positive PAX8 labeling in cerebellar hemangiomas. PAX8 negativity is not as specific for cerebellar hemangioblastoma as previously thought, and caution must be used when relying solely on a panel of PAX2, PAX8, and inhibin A for pathologic diagnosis. PMID- 29629949 TI - Cooperation of Indian Hedgehog and Vascular Endothelial Growth Factor in Tumor Angiogenesis and Growth in Human Hepatocellular Carcinomas, an Immunohistochemical Study. AB - The Hedgehog pathway was recently shown to be involved in vascular development and neovascularization in human embryogenesis and disease. However, the role of Hedgehog pathway in modulating tumor angiogenesis is still unexplored. In the current study, we investigated the expression of Indian Hedgehog (Ihh) and vascular endothelial cell growth factor (VEGF) in human hepatocellular carcinomas (HCCs) with immunohistochemical staining and compared the immunoreaction data with various clinicopathologic characteristics. Immunoreactivity of Ihh and VEGF proteins was observed in 61.5% (56/91) and 64.5% (59/91) cases of HCC tumor tissues, respectively, which was considerably higher than the adjacent nonmalignant tissues. Ihh protein was observed predominantly in the cytoplasm of the tumor cells with a staining pattern of which was sparse and dot-like, or circular around the cell membrane. VEGF protein was expressed heterogenously in the cytoplasm in tumor cells and was negative in peritumoral areas in all cases. CD34 showed diffuse staining in the tumor parenchyma in most HCC specimens. The association of expression of Ihh and VEGF with tumor size was statistically significant (P<0.05), but there was no significant association with other clinicopathologic parameters. Moreover, there was a significant association of the expressions of Ihh and VEGF proteins in HCC (r=0.6, P<0.0001), and of Ihh and CD34 staining (r=0.261, P=0.012). Our findings suggest that Ihh is involved in the development of HCC. These findings are also consistent with the concept that cooperation of Ihh and VEGF modulate HCC tumor angiogenesis and growth. PMID- 29629950 TI - A Survey of Somatic Mutations in 41 Genes in a Cohort of T-Cell Lymphomas Identifies Frequent Mutations in Genes Involved in Epigenetic Modification. AB - Here, we utilize a high throughput sequencing panel that covers several genes known to be recurrently mutated in certain T-cell lymphoma subtypes as well as genes frequently mutated in other hematolymphoid malignancies, including myeloid neoplasms. This panel was applied to formalin-fixed, paraffin-embedded tissue from 84 biopsies from 78 patients selected for this study. The biopsies included ones a with a diagnosis of T-cell lymphoma (n=79), including peripheral T-cell lymphoma not otherwise specified (PTCL-NOS; n=26) and angioimmunoblastic T-cell lymphoma (AITL; n=13), as well as 5 cases of atypical T-cell proliferations. KMT2C and KMT2D, which code for proteins involved in histone modifications, were the 2 most frequently mutated genes in our cohort and were altered across a range T-cell lymphomas. Mutations in TET2 and DNMT3A, which are involved in regulating DNA methylation, were also found in a variety of T-cell lymphoma categories. The RHOA G17V mutation that is frequently found in AITL was identified 5 of 13 (40%) cases of AITL and in 3 of 26 (12%) cases of PTCL-NOS, but not in biopsies involved by other T-cell proliferations. Our study adds to the already significant evidence from other investigators that, among T-cell lymphomas, the RHOA G17V variant is specific for AITL and PTCL-NOS. In contrast, variants in epigenetic modifier genes do not appear to be particularly specific for T-cell lymphoma subcategories evaluated in our study. PMID- 29629951 TI - Immunohistochemical Analysis of Endothelial Cells in Vascular Transformation of Lymph Node Sinuses: Vascular or Lymphatic Differentiation? AB - INTRODUCTION: Vascular transformation of sinuses (VTS) is an uncommon and benign lesion, defined by conversion of lymph node sinuses into complex, anatomizing and endothelial-lined channels. Despite the name of VTS, which implies a change in differentiation from lymphatic to vascular endothelium, very few studies have systematically examined VTS with modern immunohistochemical markers commonly used in clinical laboratories. It is unclear whether endothelial cells in VTS display pure vascular or lymphatic differentiation, or both. DESIGN: A total of 11 cases with a diagnosis of VTS (identified in the tissue archives of the Cleveland Clinic between 1992 and 2015) were reviewed and confirmed. Twenty cases of benign lymph nodes without specific diagnoses were used as control tissues. Immunohistochemical stains were performed on formalin-fixed, paraffin-embedded lymph node tissue using an automated immunohistochemistry platform with antibodies against CD31, CD34, D2-40, and ERG. Positivity in the VTS lesions was defined as distinct expression in the appropriate cell compartment in >=20% of cells. In control cases, staining was evaluated in both vascular and lymphatic channels-vascular structures were identified by presence of red cells or well formed vascular walls and lymphatics by anatomic location and absence of vascular features. RESULTS: In the VTS lesions, D2-40 expression was absent in the lesional endothelial cells of 5/11 (45%) cases. In the cases lacking D240 expression, uninvolved lymphatic endothelium maintained expression. CD34 expression was also seen in 6/11 (54%), CD31 was seen in 10/11 (90%), and ERG expression was seen in all cases. In all the control cases, D240 expression was exclusively seen in lymphatic endothelial cells and not seen in vascular endothelial cells (eg, vascular channels in the hilum). CD34 was weakly positive in the lymphatic endothelium of only 7/20 (35%) control cases, but expressed in 20/20 (100%) control cases in the vascular endothelium. 20/20 (100%) of control cases showed expression of CD31 and ERG in both vascular and lymphatic endothelium. CONCLUSION: VTS lesional endothelial cells demonstrate patterns of vascular markers that show mixed blood vascular and lymphatic features. There appears to be a degree of alignment toward endothelial differentiation with decreased expression of D2-40 in some cases. PMID- 29629952 TI - The Expression of TMEM74 in Liver Cancer and Lung Cancer Correlating With Survival Outcomes. AB - Transmembrane 74 (TMEM74), a transmembrane protein as an autophagy inducer, has been proven to promote tumor cell (including cervical cancer cell line HeLa and hepatic carcinoma cell line HepG2) proliferation by triggering autophagy. To further determine the role of TMEM74 in cancer, we performed immunohistochemical staining on tissue array, and the results showed that TMEM74 exhibited significantly higher expression in several tumor types, especially in hepatocellular carcinoma, lung adenocarcinoma, and squamous carcinoma. Furthermore, higher expression level of TMEM74 in HepG2, A549, and H1299 cell lines were also detected compared with the corresponding normal cell lines, as detected by western blot. Meanwhile, further analysis showed that the levels of TMEM74 expression were closely correlated to survival period of patients-the higher expression of TMEM74 was correlated with shorter survival period. Moreover, the in vitro experiments showed that overexpression of TMEM74 led to accelerated proliferation of A549 and H1299 cells, while knockdown of TMEM74 reversed the outcomes. In conclusion, the results suggested that TMEM74 acts as an oncogene and a potential diagnostic marker and a therapeutic target for liver cancer and lung cancer. PMID- 29629953 TI - Utility of Ber-EP4 and MOC-31 in Basaloid Skin Tumor Detection. AB - Ber-EP4 has been the traditional immunostain used for the detection of basaloid skin tumors. Recently, MOC-31 has shown be superior to Ber-EP4 in the detection of basosquamous basal cell carcinoma (BCC) and many centers are now using both Ber-EP4 and MOC-31 antibodies together to detect these lesions. The objective of this study was to compare the utility of using both Ber-EP4 and MOC-31 immunostains in the detection of basaloid skin tumors and to better characterize the previously unknown staining properties of MOC-31 in cutaneous lesions. To do this, 76 basaloid skin tumors stained with both Ber-EP4 and MOC-31 were obtained. Diagnoses included basosquamous BCC, Merkel cell carcinoma, adenoid cystic carcinoma, microcystic adnexal carcinoma, sebaceous carcinoma, trichoepithelioma, trichoblastoma, sebaceous adenoma, sebaceoma, and follicular induction overlying dermatofibroma. The distribution and intensity of Ber-EP4 and MOC-31 staining in these lesions was scored. These scores were analyzed using a truth table, chi test, and Pearson correlation tests. The overall mean and SD of the scores were also obtained. Overall, we found Ber-EP4 and MOC-31 to be statistically equivalent immunostains for the diagnosis of basaloid skin tumors. We recommend the use of only one of these antibodies and favor MOC-31 for the detection of basaloid skin tumors. We also describe MOC-31 staining properties in different cutaneous lesions. PMID- 29629954 TI - Ovarian Clear Cell Carcinoma: From Morphology to Molecular Biology. AB - Ovarian clear cell carcinoma (oCCC) is a distinctive subtype of ovarian carcinoma, with peculiar genetic and environmental risk factors, precursor lesions, molecular events during oncogenesis, patterns of spread, and response to treatment. Because of low response to chemotherapy and poor prognosis in advanced stages, there is growing interest in investigating the molecular pathways involved in oCCC development, in order to individualize novel/molecular targeted therapies. Until now, the main molecular genetic changes associated with oCCC remain to be identified, and, although several molecular changes have been reported in clear cell tumors, most studies have analyzed a limited number of cases; therefore, the true prevalence of those changes is not known. The present review will present the clinicopathologic features of oCCC, from morphology to molecular biology, discussing the diagnostic and treatment challenges of this intriguing ovarian carcinoma. PMID- 29629955 TI - How to manage food dependent exercise induced anaphylaxis (FDEIA). AB - PURPOSE OF REVIEW: In recent years, the number of reports on food-dependent exercise-induced anaphylaxis (FDEIA) has been increasing. This review aims to describe the standard management of FDEIA including provocation tests and identify the issues that remain unclear. RECENT FINDINGS: Provocation tests with aspirin for FDEIA enable us to confirm the definitive diagnosis and to make differential diagnosis. In some cases, FDEIA symptoms can be induced by aspirin and the causative food without exercise. Exercise may only be an augmenting factor of FDEIA, similar to aspirin or alcohol. SUMMARY: The mechanisms of FDEIA development remain unclear. It has been suggested that in FDEIA, exercise lowers the threshold of a food allergy. Further research is needed to elucidate the mechanism of FDEIA and to establish strategies for effective disease management. PMID- 29629956 TI - What you should not miss from the systematic reviews and meta-analyses on allergen-specific immunotherapy in 2017. AB - PURPOSE OF REVIEW: Allergen immunotherapy (AIT) is a well recognized and extensively studied therapeutic intervention for some allergic diseases. Every year new systematic reviews and meta-analysis provide the most powerful source of evidence to orient decision making on prevention or efficacy of AIT. We here discuss systematic reviews and meta-analyses on AIT (published January 2017 to February 2018). RECENT FINDINGS: We identified 4 systematic reviews and 10 meta analyses. Subcutaneous and sublingual AIT (SCIT/SLIT) significantly reduced the development of asthma in children-adolescents with moderate/severe allergic rhinitis, but evidence for a short-term, preventive effect for new allergic sensitizations was nonconclusive. SCIT/SLIT proved to significantly improve symptom and medication scores versus placebo or active comparators in respiratory allergy, with various effect sizes. Oral immunotherapy for IgE-mediated food allergy resulted in substantial benefit in desensitization rates. Data on venom AIT and latex AIT, although limited in quantity and quality, respectively, suggest a large and discrete beneficial effect. SUMMARY: Although current evidence extracted from meta-analyses and systematic reviews support AIT as an effective, relatively safe, and well tolerated alternative for some allergic diseases, heterogeneity and some methodological inconsistencies represent matters of concern as they may affect the validity and applicability of their results, especially in the context of individual, real-life settings. PMID- 29629957 TI - How to actively treat food allergy. AB - PURPOSE OF REVIEW: In the last years, food allergy treatment is moving away from food avoidance to interventional treatments. We review here the recent developments on immunotherapy with food allergens. RECENT FINDINGS: Oral immunotherapy remains the best studied form of food immunotherapy. In 2017, further evidence has been added to its efficacy. Its mechanisms of action are under scrutiny. To reduce its side effects, studies have been dedicated to the simultaneous use of biologics, in particular omalizumab. Among the other forms of food immunotherapy that are being developed, the epicutaneous application of food allergens is promising. SUMMARY: The immunologic trajectories of the development of food tolerance may be intercepted by different forms of food immunotherapy. Research efforts aim to make these therapies feasible at the clinical level. PMID- 29629958 TI - Guanylyl Cyclase A in Both Renal Proximal Tubular and Vascular Endothelial Cells Protects the Kidney against Acute Injury in Rodent Experimental Endotoxemia Models. AB - WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Natriuretic peptides are used, based on empirical observations, in intensive care units as antioliguric treatments. We hypothesized that natriuretic peptides prevent lipopolysaccharide-induced oliguria by activating guanylyl cyclase A, a receptor for natriuretic peptides, in proximal tubules and endothelial cells. METHODS: Normal Sprague-Dawley rats and mice lacking guanylyl cyclase A in either endothelial cells or proximal tubular cells were challenged with lipopolysaccharide and assessed for oliguria and intratubular flow rate by intravital imaging with multiphoton microscopy. RESULTS: Recombinant atrial natriuretic peptide efficiently improved urine volume without changing blood pressure after lipopolysaccharide challenge in rats (urine volume at 4 h, lipopolysaccharide: 0.6 +/- 0.3 ml . kg . h; lipopolysaccharide + fluid resuscitation: 4.6 +/- 2.0 ml . kg . h; lipopolysaccharide + fluid resuscitation + atrial natriuretic peptide: 9.0 +/- 4.8 ml . kg . h; mean +/- SD; n = 5 per group). Lipopolysaccharide decreased glomerular filtration rate and slowed intraproximal tubular flow rate, as measured by in vivo imaging. Fluid resuscitation restored glomerular filtration rate but not tubular flow rate. Adding atrial natriuretic peptide to fluid resuscitation improved both glomerular filtration rate and tubular flow rate. Mice lacking guanylyl cyclase A in either proximal tubules or endothelium demonstrated less improvement of tubular flow rate when treated with atrial natriuretic peptide, compared with control mice. Deletion of endothelial, but not proximal tubular, guanylyl cyclase A augmented the reduction of glomerular filtration rate by lipopolysaccharide. CONCLUSIONS: Both endogenous and exogenous natriuretic peptides prevent lipopolysaccharide induced oliguria by activating guanylyl cyclase A in proximal tubules and endothelial cells. PMID- 29629959 TI - Baseline Cerebral Metabolic Rate Is a Critical Determinant of the Cerebral Vasodilating Potency of Volatile Anesthetic Agents. AB - A Comparison of the Direct Cerebral Vasodilating Potencies of Halothane and Isoflurane in the New Zealand White Rabbit. By Drummond JC, Todd MM, Scheller MS, and Shapiro HM. ANESTHESIOLOGY 1986; 65:462-7. Reprinted with permission.Halothane is commonly viewed as a more potent cerebral vasodilator than isoflurane. It was speculated that the lesser vasodilation caused by isoflurane might be the result of the greater reduction in cerebral metabolic rate (CMR) that it causes, and that the relative vasodilating potencies of halothane and isoflurane would be similar if the two agents were administered in a situation that precluded volatile-agent-induced depression of CMR. To test this hypothesis, cerebral blood flow (CBF) and the cerebral metabolic rate for oxygen (CMRO2) were measured in two groups of rabbits before and after the administration of 0.75 MAC halothane or isoflurane. One group received a background anesthetic of morphine and N2O, which resulted in an initial CMRO2 of 3.21 +/- 0.17 (SEM) ml . 100 g . min; second group received a background anesthetic of high-dose pentobarbital, which resulted in an initial CMRO2 of 1.76 +/- 0.16 ml . 100 g . min. In rabbits receiving a background of morphine sulfate/N2O, halothane resulted in a significantly greater CBF (65 +/- 10 ml . 100 g . min) than did isoflurane (40 +/- 5 ml . 100 g . min). Both agents caused a reduction in CMRO2, but CMRO2 was significantly less during isoflurane administration. By contrast, with a background of pentobarbital anesthesia, CBF increased by significant and similar amounts with both halothane and isoflurane. With halothane, CBF increased from 22 +/- 2 ml . 100 g . min in the control stage to 39 +/- 3, and with isoflurane from 24 +/- to 38 +/- 2 ml . 100 g . min. CMRO2 was not depressed further by either halothane or isoflurane. These results suggest that the relative effects of halothane and isoflurane on CBF are dependent on the CMR present prior to their administration. When the preexistent CMR is not markedly depressed, isoflurane decreases CMR and causes less cerebral vasodilation than does halothane. When initial CMR is depressed, halothane and isoflurane have similar vasodilating potencies. PMID- 29629960 TI - Complete revascularization for everyone: anatomic, functional, or neither? It depends! PMID- 29629961 TI - Reduction of thrombus burden: a still unmet need in patients with ST-segment elevation myocardial infarction. PMID- 29629962 TI - Elevated serum uric acid: a marker and mediator of increased stress on myocardium. PMID- 29629963 TI - Health Care-Seeking Characteristics of Women With Pelvic Floor Disorders After Obstetric Anal Sphincter Injury. AB - OBJECTIVES: Obstetric anal sphincter injury (OASIS) is a potentially serious complication of vaginal delivery and can lead to both short-term and long-term sequelae. This study sought to identify health care seeking patterns of women who developed pelvic floor symptoms including pelvic pain after OASIS. It also identified demographic and clinical factors associated with seeking subspecialty care from a pelvic floor specialist and demographic and clinical factors associated with seeking care for pelvic pain after OASIS. METHODS: This study is a retrospective cohort study of 69 women who developed pelvic floor disorders after OASIS. RESULTS: For women diagnosed with a pelvic floor symptom, the mean time to follow-up was 2.4 years, the mean number of visits until diagnosis was 2.2 visits, and 2.9 visits were needed for treatment. The most common diagnoses were pelvic pain, lower urinary tract symptoms including incontinence, and defecatory dysfunction. Twenty-five percent of the cohort received treatment from a pelvic floor specialist. These women were more likely to be older and have urinary incontinence. Women with pain were more likely to be seen by a primary care provider and have longer time to diagnosis. CONCLUSIONS: The study showed that multiple visits were needed to both diagnose and treat pelvic floor disorders (PFD) after OASIS. Pelvic pain was the most common primary PFD after OASIS. There should be a high level of suspicion for pelvic floor disorders, especially pain disorders, in women who have sustained a third- or fourth-degree laceration. PMID- 29629964 TI - Efficacy and Safety of Second-Line 5-Day Dactinomycin in Case of Methotrexate Failure for Gestational Trophoblastic Neoplasia. AB - OBJECTIVE: The objective of this study was to evaluate the characteristics and outcomes of patients treated for gestational trophoblastic neoplasia (GTN) with second-line 5-day dactinomycin after failed first-line 8-day methotrexate. METHODS: From 1999 to 2017, patients with methotrexate resistant GTN treated with second line dactinomycin were identified at the French Trophoblastic Disease Reference Center. Using univariate and multivariate analysis, we identified significant predictive factors of second line dactinomycin failure. RESULTS: A total of 877 GTN patients were treated with first-line 8-day methotrexate, of which 103 required second-line 5-day dactinomycin for methotrexate failure. Complete response was observed in 78 patients (75.7% [95% confidence interval, 66.3-83.6]; P < 0.0001), whereas 25 needed third-line treatment, 13 for dactinomycin resistance and 12 for post-dactinomycin relapse. Overall survival of patients treated with dactinomycin was 100%. An interval of greater than or equal to 7 months between antecedent pregnancy termination and methotrexate initiation was a predictive factor significantly associated with second-line dactinomycin failure in multivariate analysis (exact odds ratio, 9.17 [95% confidence interval, 1.98-50.70]; P = 0.0029). No grades 4 and 5 adverse effects were experienced and the most common toxicity being grade 1 nausea (14.6%). CONCLUSION: Given a 75.7% complete response rate in methotrexate failed low-risk GTN patients treated with second-line dactinomycin and an overall survival rate of 100% after third-line treatment, the use of dactinomycin should be favored as second-line, regardless of human chorionic gonadotropin level at the time of dactinomycin initiation. However, an interval between the termination of the antecedent pregnancy and methotrexate initiation longer than 6 months should encourage considering alternative therapeutic strategies. PMID- 29629966 TI - Sleep and the Athlete. PMID- 29629967 TI - Abdominal Bracing for Minimizing Excessive Pelvic Motion During Running. PMID- 29629968 TI - Sports Drinks on the Edge of a New Era. PMID- 29629969 TI - Collegiate eSport: Where Do We Fit In? PMID- 29629970 TI - Blood Flow Restriction Training for Postoperative Lower-Extremity Weakness: A Report of Three Cases. PMID- 29629971 TI - Found in the Field - A Soldier With Heat Stroke, Exercise-Associated Hyponatremia, and Kidney Injury. PMID- 29629972 TI - U.S. Army Platoon Gets Struck by Lightning, A Case Series. PMID- 29629973 TI - The Application of Blood Flow Restriction: Lessons From the Laboratory. AB - Blood flow restriction by itself or in combination with exercise has been shown to produce beneficial adaptations to skeletal muscle. These adaptations have been observed across a range of populations, and this technique has become an attractive possibility for use in rehabilitation. Although there are concerns that applying blood flow restriction during exercise makes exercise inherently more dangerous, these concerns appear largely unfounded. Nevertheless, we have advocated that practitioners could minimize many of the risks associated with blood flow-restricted exercise by accounting for methodological factors, such as cuff width, cuff type, and the individual to which blood flow restriction is being applied. The purpose of this article is to provide an overview of these methodological factors and provide evidence-based recommendations for how to apply blood flow restriction. We also provide some discussion on how blood flow restriction may serve as an effective treatment in a clinical setting. PMID- 29629974 TI - Menthol Use for Performance in Hot Environments. AB - Menthol is a compound of plant origin and has recently been used to aid exercise performance in hot, humid environments. Menthol creates a sensation of coolness when applied to the skin or mucosal surfaces stimulating the cold receptors. In these environments, fatigue is known to be accelerated and feelings of being hot are one of the main contributors to the early onset of fatigue. However, current research indicates that nonthermal perceptual cooling interventions could alter behavior in the heat by reducing thermal perception. This would allow the athlete to feel cooler when exercising at the same work rate in the heat. Menthol has been investigated as an internal and external intervention. Greater benefits have currently been found for internal interventions than external methods. Future research should focus on the mechanisms, dosage, and timing of both internal and external interventions, and the role menthol could play within speed or strength. PMID- 29629975 TI - No more buts. PMID- 29629976 TI - Developing a staffing plan to meet inpatient unit needs. PMID- 29629977 TI - Clinicopathologic Features and Genetic Alterations of a Primary Osteosarcoma of the Uterine Corpus. AB - Primary osteosarcoma (OS) of the uterus is distinctly rare. We report a case of primary uterine OS with pulmonary metastasis in a 74-yr-old woman. Histopathologic features of the uterine tumor were in keeping with a pure chondroblastic OS composed of neoplastic cells with osteoblastic/chondroblastic differentiation and neoplastic bone formation. Despite treatment with Doxorubicin and Olaratumab and later with palliative radiation therapy, the patient died 7 mo after hysterectomy due to multiple distant metastases. A targeted next-generation sequencing assay based on a 637-gene panel was performed to analyze genetic alterations in this highly aggressive tumor, but no somatic mutations that are amenable to targeted therapy were detected. Rather, a 51-nucleotide deletion mutation including partial exon 2 of mediator complex subunit 12 (MED12), a gene commonly mutated in leiomyoma, breast fibroadenoma and phyllodes tumor, was identified. Given the MED12 mutation in this uterine OS, we propose possible mechanisms that account for the origin and development of this tumor. PMID- 29629978 TI - Wilms Tumor of the Uterus. AB - Wilms tumor (WT) is an uncommon malignant neoplasm that occurs predominantly in the kidney of pediatric patients; its extrarenal counterpart is exceedingly rare. We present the case of an adult female diagnosed with uterine WT. Following hysterectomy due to a uterine mass, histopathologic examination demonstrated a triphasic malignancy composed of epithelial, stromal, and blastemal elements. The characteristic morphologic features, which were supported by immunohistochemical analysis, were diagnostic of WT of the uterus. A summary of the main clinicopathologic parameters, along with a review of all previously reported cases, are described. PMID- 29629979 TI - Pulmonary aspiration only increases the risk of right-sided pneumonia in children: comparison of salivagrams and chest radiographs. AB - PURPOSE: A salivagram is often used to detect pulmonary aspiration, whereas chest radiography is often used to diagnose pneumonia. This study analysed the relationship between pulmonary aspiration and aspiration pneumonia in children, and the differences between lungs. PATIENTS AND METHODS: The salivagram and chest radiography results of 696 children (466 boys and 230 girls; aged 1-54 months; mean age, 4.7 months; median age, 3 months) diagnosed with respiratory tract infections between December 2013 and June 2017 were retrospectively analysed. Patients were classified as positive or negative on the basis of their salivagram results, and the radiography positivity rates were analysed. RESULTS: Among all paediatric patients, 197 were salivagram positive and 499 were salivagram negative. The positivity rate was 28.3% (197/696); the positivity rate of the right side was 98.0% (193/197). The radiography positivity rates of the right side in the positive group, negative group and the total sample were 84.3% (166/197), 69.5% (347/499) and 73.7% (513/696), respectively. The radiography positivity rates of the left side were 69.5% (137/197), 68.5% (342/499) and 68.8% (479/696), respectively. Inter-group comparisons of the radiography positivity rates of the right side showed significant differences between the positive group and the total sample, as well as between the positive and negative groups (P=0.001 and 0.000, respectively). There were no significant differences in the radiography positivity rates of the left side (P=0.846 and 0.796, respectively). The radiography positivity rate of the right side in the positive group was 14.8% higher than that in the negative group. CONCLUSION: Pulmonary aspiration tends to occur in the right side and only increases the risk of right-sided pneumonia. PMID- 29629980 TI - Development of an enhanced recovery protocol for children undergoing gastrointestinal surgery. AB - PURPOSE OF REVIEW: Enhanced recovery protocols (ERPs) have been adopted for a variety of adult surgical conditions and resulted in markedly improved outcomes, including decreased length of stays, complications, costs, and narcotic utilization. In this review, we describe the development and implementation of an ERP for children undergoing gastrointestinal surgery. RECENT FINDINGS: Existing ERP components from adult and pediatric surgical populations were reviewed and modified through an iterative process that included literature review, a national survey of practicing pediatric surgeons, and appropriateness assessment by a multidisciplinary expert panel. A single-center pilot implementing a gastrointestinal ERP demonstrated a steady increase in the number of ERP elements being employed over time with a simultaneous decrease in length of stays, decrease in median time to regular diet, decrease in median dose of intraoperative and postoperative narcotics, and decrease in median volume of intraoperative fluids. Balancing measures such as complication rates and 30-day readmission rates were stable or trended toward improved outcomes. SUMMARY: ERPs for children undergoing gastrointestinal surgery appear feasible, safe, and associated with improved outcomes. Further validation of these results and expansion to a wider breadth of children's surgical care will help to establish ERPs as a new standard of surgical care. PMID- 29629981 TI - Abnormal gray matter asymmetry in alcohol dependence. AB - Previous voxel-based morphometry studies have provided evidence that patients with alcohol dependence (AD) have widespread gray matter morphological abnormalities. However, brain structural asymmetry in AD has not been assessed to date. Here, we aimed to use a recently developed voxel-based morphometry-based approach to investigate global and regional gray matter asymmetry alterations in AD. A total of 39 male individuals, including 19 AD patients and 20 age-matched healthy controls, underwent high-resolution structural MRI. Global and voxel-wise gray matter asymmetries were measured separately by the Dice coefficient and the asymmetry index, which were compared between the two groups. We found no difference in the global gray matter asymmetry between AD patients and healthy controls. However, voxel-wise gray matter asymmetry analysis showed that AD patients and healthy controls had different distribution patterns of brain regions with a rightward asymmetry and a leftward asymmetry Furthermore, we observed an increased rightward asymmetry of gray matter in the hemispheric I-IV and V of the cerebellum and lingual gyrus in AD patients. These findings suggest that abnormal structural asymmetry in the cerebellum and the primary visual cortex may be the neural mechanisms contributing toward motor and visual impairments in AD. PMID- 29629982 TI - End-of-Life Care in ICUs in East Asia: A Comparison Among China, Korea, and Japan. AB - OBJECTIVES: To compare physicians' perceptions and practice of end-of-life care in the ICU in three East Asian countries cultures similarly rooted in Confucianism. DESIGN: A structured and scenario-based survey of physicians who managed ICU patients from May 2012 to December 2012. SETTING: ICUs in China, Korea, and Japan. SUBJECTS: Specialists who are either intensivists or nonintensivist primary attending physicians in charge of patients (195 in China, 186 in Korea, 224 in Japan). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Country was independently associated with differences in the practice of limiting multiple forms of life-sustaining treatments on multivariable generalized linear model analysis. Chinese respondents were least likely to apply do-not-resuscitate orders, even if they existed (p < 0.001). Japanese respondents were most likely to practice do not resuscitate for terminally ill patients during cardiac arrest, even when no such prior order existed (p < 0.001). Korean respondents' attitudes were in between those of Chinese and Japanese respondents as far as withdrawing total parenteral nutrition, antibiotics, dialysis, and suctioning was concerned. Chinese respondents were most uncomfortable discussing end-of-life care issues with patients, while Japanese respondents were least uncomfortable (p < 0.001). Chinese respondents were more likely to consider financial burden when deciding on limiting life-sustaining treatment (p < 0.001). Japanese respondents felt least exposed to personal legal risks when limiting life-sustaining treatment (p < 0.001), and the Korean respondents most wanted legislation to guide this issue (p < 0.001). The respondents' gender, religion, clinical experience, and primary specialty were also independently associated with the different perceptions of end-of-life care. CONCLUSIONS: Despite similarities in cultures and a common emphasis on the role of family, differences exist in physician perceptions and practices of end-of-life ICU care in China, Korea, and Japan. These findings may be due to differences in the degree of Westernization, national healthcare systems, economic status, and legal climate. PMID- 29629983 TI - Impact of ICU Structure and Processes of Care on Outcomes After Severe Traumatic Brain Injury: A Multicenter Cohort Study. AB - OBJECTIVES: It is uncertain whether dedicated neurocritical care units are associated with improved outcomes for critically ill neurologically injured patients in the era of collaborative protocol-driven care. We examined the association between dedicated neurocritical care units and mortality and the effects of standardized management protocols for severe traumatic brain injury. DESIGN: We surveyed trauma medical directors from centers participating in the American College of Surgeons Trauma Quality Improvement Program to obtain information about ICU structure and processes of care. Survey data were then linked to the Trauma Quality Improvement Program registry, and random-intercept hierarchical multivariable modeling was used to evaluate the association between dedicated neurocritical care units, the presence of standardized management protocols and mortality. SETTING: Trauma centers in North America participating in Trauma Quality Improvement Program. PATIENTS: Data were analyzed from 9,773 adult patients with isolated severe traumatic brain injury admitted to 134 Trauma Quality Improvement Program centers between 2011 and 2013. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Only 50 ICUs (37%) were dedicated neurocritical care units, whereas 84 (63%) were general ICUs. Rates of standardized management protocols were similar comparing dedicated neurocritical care units and general ICUs. Among severe TBI patients admitted to trauma centers enrolled in Trauma Quality Improvement Program, care in a dedicated neurocritical care unit did not improve risk-adjusted in-hospital survival (odds ratio, 0.97; 95% CI, 0.80-1.19; p = 0.79). However, the presence of a standardized management protocol for these patients was associated with lower risk-adjusted in-hospital mortality (odds ratio, 0.77; 95% CI, 0.63-0.93; p = 0.009). CONCLUSIONS: Compared with dedicated neurocritical care models, standardized management protocols for severe traumatic brain injured patients are process-targeted intervention strategies that may improve clinical outcomes. PMID- 29629984 TI - Early Enteral Nutrition Provided Within 24 Hours of ICU Admission: A Meta Analysis of Randomized Controlled Trials. AB - OBJECTIVES: To identify, appraise, and synthesize the most current evidence to determine whether early enteral nutrition alters patient outcomes from critical illness. DATA SOURCES: Medline and Embase were searched. The close out date was November 20, 2017. STUDY SELECTION: Early enteral nutrition was defined as a standard formula commenced within 24 hours of ICU admission. Comparators included any form of nutrition support "except" early enteral nutrition. Only randomized controlled trials conducted in adult patients requiring treatment in an ICU were eligible for inclusion. DATA EXTRACTION: The primary outcome was mortality. Secondary outcomes included pneumonia, duration of mechanical ventilation, and ICU and hospital stay. DATA SYNTHESIS: Six-hundred ninety-nine full-text articles were retrieved and screened. Sixteen randomized controlled trials enrolling 3,225 critically ill participants were included. Compared with all other types of nutrition support, commencing enteral nutrition within 24 hours of ICU admission did not result in a reduction in mortality (odds ratio, 1.01; 95% CI, 0.86-1.18; p = 0.91; I = 32%). However, there was a differential treatment effect between a priori identified subgroups (p = 0.032): early enteral nutrition reduced mortality compared with delayed enteral intake (odds ratio, 0.45; 95% CI, 0.21 0.95; p = 0.038; I = 0%), whereas a mortality difference was not detected between early enteral nutrition and parenteral nutrition (odds ratio, 1.04; 95% CI, 0.89 1.22; p = 0.58; I = 30%). Overall, patients who were randomized to receive early enteral nutrition were less likely to develop pneumonia (odds ratio, 0.75; 95% CI, 0.60-0.94; p = 0.012; I = 48%). CONCLUSIONS: Overall, there was no difference between early enteral nutrition and all other forms of nutrition support. A priori planned subgroup analysis revealed early enteral nutrition reduced mortality and pneumonia compared with delayed enteral intake; however, there were no clear clinical advantages of early enteral nutrition over parenteral nutrition. PMID- 29629985 TI - Ventilator Bundle and Its Effects on Mortality Among ICU Patients: A Meta Analysis. AB - OBJECTIVES: To assess the effectiveness of the ventilator bundle in the reduction of mortality in ICU patients. DATA SOURCES: PubMed, Scopus, Web of Science, Cochrane Library for studies published until June 2017. STUDY SELECTION: Included studies: randomized controlled trials or any kind of nonrandomized intervention studies, made reference to a ventilator bundle approach, assessed mortality in ICU-ventilated adult patients. DATA EXTRACTION: Items extracted: study characteristics, description of the bundle approach, number of patients in the comparison groups, hospital/ICU mortality, ventilator-associated pneumonia related mortality, assessment of compliance to ventilator bundle and its score. DATA SYNTHESIS: Thirteen articles were included. The implementation of a ventilator bundle significantly reduced mortality (odds ratio, 0.90; 95% CI, 0.84 0.97), with a stronger effect with a restriction to studies that reported mortality in ventilator-associated pneumonia patients (odds ratio, 0.71; 95% CI, 0.52-0.97), to studies that provided active educational activities was analyzed (odds ratio, 0.88; 95% CI, 0.78-0.99), and when the role of care procedures within the bundle (odds ratio, 0.87; 95% CI, 0.77-0.99). No survival benefit was associated with compliance to ventilator bundles. However, these results may have been confounded by the differential implementation of evidence-based procedures at baseline, which showed improved survival in the study subgroup that did not report implementation of these procedures at baseline (odds ratio, 0.82; 95% CI, 0.70-0.96). CONCLUSIONS: Simple interventions in common clinical practice applied in a coordinated way as a part of a bundle care are effective in reducing mortality in ventilated ICU patients. More prospective controlled studies are needed to define the effect of ventilator bundles on survival outcomes. PMID- 29629986 TI - Inclusion of Unstructured Clinical Text Improves Early Prediction of Death or Prolonged ICU Stay. AB - OBJECTIVES: Early prediction of undesired outcomes among newly hospitalized patients could improve patient triage and prompt conversations about patients' goals of care. We evaluated the performance of logistic regression, gradient boosting machine, random forest, and elastic net regression models, with and without unstructured clinical text data, to predict a binary composite outcome of in-hospital death or ICU length of stay greater than or equal to 7 days using data from the first 48 hours of hospitalization. DESIGN: Retrospective cohort study with split sampling for model training and testing. SETTING: A single urban academic hospital. PATIENTS: All hospitalized patients who required ICU care at the Beth Israel Deaconess Medical Center in Boston, MA, from 2001 to 2012. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Among eligible 25,947 hospital admissions, we observed 5,504 (21.2%) in which patients died or had ICU length of stay greater than or equal to 7 days. The gradient boosting machine model had the highest discrimination without (area under the receiver operating characteristic curve, 0.83; 95% CI, 0.81-0.84) and with (area under the receiver operating characteristic curve, 0.89; 95% CI, 0.88-0.90) text-derived variables. Both gradient boosting machines and random forests outperformed logistic regression without text data (p < 0.001), whereas all models outperformed logistic regression with text data (p < 0.02). The inclusion of text data increased the discrimination of all four model types (p < 0.001). Among those models using text data, the increasing presence of terms "intubated" and "poor prognosis" were positively associated with mortality and ICU length of stay, whereas the term "extubated" was inversely associated with them. CONCLUSIONS: Variables extracted from unstructured clinical text from the first 48 hours of hospital admission using natural language processing techniques significantly improved the abilities of logistic regression and other machine learning models to predict which patients died or had long ICU stays. Learning health systems may adapt such models using open-source approaches to capture local variation in care patterns. PMID- 29629987 TI - Markedly Deranged Injury Site Metabolism and Impaired Functional Recovery in Acute Spinal Cord Injury Patients With Fever. AB - OBJECTIVES: To characterize the effect of fever after acute, traumatic spinal cord injury on injury site metabolism and patient outcome. DESIGN: Longitudinal cohort study. In 44 patients (London cohort), we determined the effect of fever on intrathecal injury site metabolism by analyzing 1,767 hours of intraspinal pressure and 759 hours of microdialysis data. We also determined the effect of fever burden, computed for the first 2 weeks in hospital, on neurologic outcome. A distinct cohort of 33 patients (Berlin cohort) was used to independently validate the effect of fever burden on outcome. SETTING: ICUs in London and Berlin. PATIENTS: Seventy-seven patients with acute, traumatic spinal cord injuries. INTERVENTIONS: In the London patients, a pressure probe and a microdialysis catheter were placed intradurally on the surface of the injured cord for up to a week. MEASUREMENTS AND MAIN RESULTS: Fever (> 37.5 degrees C) occurs frequently (37% of the time) after spinal cord injury. High-grade fever (>= 38 degrees C) was associated with significantly more deranged metabolite levels than normothermia (36.5-37.5 degrees C), that is, lower tissue glucose (median 2.0 vs 3.3 mM), higher lactate (7.8 vs 5.4 mM), higher glutamate (7.8 vs 6.4 uM), and higher lactate-to-pyruvate ratio (38.9 vs 29.3). High-grade fever was particularly detrimental on injury site metabolism when the peripheral leukocyte count was high. In the London and Berlin cohorts, high fever burden correlated with less neurologic improvement. CONCLUSIONS: Early after spinal cord injury, fever is associated with more deranged injury site metabolism than normothermia and worse prognosis. PMID- 29629988 TI - Early Evidence of Sepsis-Associated Hyperperfusion-A Study of Cerebral Blood Flow Measured With MRI Arterial Spin Labeling in Critically Ill Septic Patients and Control Subjects. AB - OBJECTIVES: Mechanisms underlying sepsis-associated encephalopathy remain unclear, but reduced cerebral blood flow, alone or in conjunction with altered autoregulation, is reported as a potential contributor. We compared cerebral blood flow of control subjects and vasopressor-dependent septic patients. DESIGN: Randomized crossover study. SETTING: MRI with arterial spin labeling. PATIENTS: Ten sedated septic patients on mechanical ventilation (four with controlled chronic hypertension) and 12 control subjects (six with controlled chronic hypertension) were enrolled. Mean +/- SD ages were 61.4 +/- 10.2 and 44.2 +/- 12.8 years, respectively (p = 0.003). Mean Acute Physiology and Chronic Health Evaluation II score of septic patients at ICU admission was 27.7 +/- 6.6. INTERVENTIONS: To assess the potential confounding effects of sedation and mean arterial pressure, we measured cerebral blood flow with and without sedation with propofol in control subjects and at a target mean arterial pressure of 65 mm Hg and greater than or equal to 75 mm Hg in septic patients. The sequence of sedation versus no sedation and mean arterial pressure targets were randomized. MEASUREMENTS AND MAIN RESULTS: In septic patients, cerebral blood flow measured at a mean arterial pressure target of 65 mm Hg (40.4 +/- 10.9 mL/100 g/min) was not different from cerebral blood flow measured at a mean arterial pressure target of greater than or equal to 75 mm Hg (41.3 +/- 9.8 mL/100 g/min; p = 0.65). In control subjects, we observed no difference in cerebral blood flow measured without and with sedation (24.8 +/- 4.2 vs 24.9 +/- 5.9 mL/100 g/min; p = 0.93). We found no interaction between chronic hypertension and the effect of sedation or mean arterial pressure targets. Cerebral blood flow measured in sedated septic patients (mean arterial pressure target 65 mm Hg) was 62% higher than in sedated control subjects (p = 0.001). CONCLUSIONS: In septic patients, cerebral blood flow was higher than in sedated control subjects and did not vary with mean arterial pressure targets. Further research is required to understand the clinical significance of cerebral hyperperfusion in septic patients on vasopressors and to reassess the neurologic effects of current mean arterial pressure targets in sepsis. PMID- 29629989 TI - An Open-Loop, Physiologic Model-Based Decision Support System Can Provide Appropriate Ventilator Settings. AB - OBJECTIVES: To evaluate the physiologic effects of applying advice on mechanical ventilation by an open-loop, physiologic model-based clinical decision support system. DESIGN: Prospective, observational study. SETTING: University and Regional Hospitals' ICUs. PATIENTS: Varied adult ICU population. INTERVENTIONS: Advice were applied if accepted by physicians for a period of up to 4-8 hours. MEASUREMENTS AND MAIN RESULTS: Seventy-two patients were included for data analysis. Acceptance of advice was high with 95.7% of advice applied. In 41 patients in pressure support ventilation, following system advice led to significant decrease in PS, with PS reduced below 8 cm H2O in 15 patients (37%), a level not prohibiting extubation. Fraction of end-tidal CO2 values did not change, and increase in respiratory rate/VT was within clinical limits, indicating that in general, the system maintained appropriate patient breathing effort. In 31 patients in control mode ventilation, pressure control and tidal volume settings were decreased significantly, with tidal volume reduced below 8 mL/kg predicted body weight in nine patients (29%). Minute ventilation was maintained by a significant increase in respiratory rate. Significant reductions in FIO2 were seen on elevated baseline median values of 50% in both support and control mode-ventilated patients, causing clinically acceptable reductions in oxygen saturation. CONCLUSIONS: The results indicate that during a short period, the clinical decision support system provided appropriate suggestions of mechanical ventilation in a varied ICU population, significantly reducing ventilation to levels which might be considered safe and beneficial. PMID- 29629991 TI - Failed Vacuum and the Long-term Hematologic Morbidity of the Offspring. AB - OBJECTIVE: We aimed to investigate the effect of failed vacuum delivery leading to an emergency cesarean delivery on the long-term pediatric hematologic morbidity of the offspring. STUDY DESIGN: In this population-based cohort study, the risk of long-term hematologic morbidity (up to the age of 18 y) was evaluated in children born following successful vacuum vaginal delivery, as compared with that of children born following a failed procedure leading to an emergent cesarean delivery. Multiple pregnancies and fetuses with congenital malformations were excluded. A Kaplan-Meier survival curve was constructed to compare cumulative pediatric hematologic morbidity, and a Cox proportional hazards model was used to control for confounders. RESULTS: A total of 7978 neonates met the inclusion criteria. Vacuum delivery was successful in 7733 cases (96.9%), whereas it failed in 245 cases (3.1%). Total hematologic morbidity of the offspring up to 18 years of age was comparable between the groups (1.6% vs. 0.8%, P=0.8). The Kaplan-Meier survival curve showed no difference in the cumulative incidence of total hematologic morbidity (log rank, P=0.22). In the Cox regression model, failed vacuum delivery was not independently associated with long-term hematologic morbidity, as compared with a successful procedure, while adjusting for multiple confounders (adjusted hazards ratio [HR], 1.8; 95% confidence interval, 0.7-5.0; P=0.25). CONCLUSIONS: Failed vacuum delivery does not seem to be associated with an increased risk for pediatric hematologic morbidity of the offspring up to 18 years of age. PMID- 29629990 TI - Clinical Outcomes and Mortality Impact of Hyperbaric Oxygen Therapy in Patients With Carbon Monoxide Poisoning. AB - OBJECTIVES: Carbon monoxide poisoning affects 50,000 per year in the United States alone. Mortality is approximately 3%, and up to 40% of survivors suffer from permanent neurocognitive and affective deficits. Hyperbaric oxygen therapy has shown benefit on reducing the long-term neurologic sequelae of carbon monoxide poisoning but has not demonstrated improved survival. The objective of this study is to assess the efficacy of hyperbaric oxygen for acute and long-term mortality in carbon monoxide poisoning using a large clinical databank. DESIGN: Retrospective analysis. SETTING: University of Pittsburgh Medical Center healthcare system (Pittsburgh, PA). PATIENTS: One-thousand ninety-nine unique encounters of adult patients with carbon monoxide poisoning. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Baseline demographics, laboratory values, hospital charge transactions, discharge disposition, and clinical information from charting were obtained from the electronic medical record. In propensity-adjusted analysis, hyperbaric oxygen therapy was associated with a reduction in inpatient mortality (absolute risk reduction, 2.1% [3.7-0.9%]; p = 0.001) and a reduction in 1-year mortality (absolute risk reduction, 2.1% [3.8-0.4%]; p = 0.013). CONCLUSIONS: These data demonstrate that hyperbaric oxygen is associated with reduced acute and reduced 1-year mortality. Further studies are needed on the mortality effects of hyperbaric oxygen therapy in carbon monoxide poisoning. PMID- 29629992 TI - Management of Children With beta-Thalassemia Intermedia: Overview, Recent Advances, and Treatment Challenges. AB - Our knowledge of the various clinical morbidities that thalassemia intermedia (TI) patients endure has substantially increased over the past decade. It is mandatory to grasp a solid understanding of disease-specific complications in order to tailor management. The optimal course of management for TI patients has been hard to identify, and several controversies remain with regard to the best treatment plan. Although advances in TI are moving at a fast pace, many complications remain with no treatment guidelines. Studies that expand our understanding of the mechanisms and risk factors, as well as clinical trials evaluating the roles of available treatments, will help establish management guidelines that improve patient care. Novel therapeutic modalities are now emerging. This article focuses on the management of children with beta-TI. We present various clinical morbidities and their association with the underlying disease pathophysiology and risk factors. All therapeutic options, recent advances, and treatment challenges were reviewed. PMID- 29629993 TI - Secondary pulmonary arterial hypertension: to treat or not to treat? AB - PURPOSE OF REVIEW: The purpose of this review is to review recent literature related to mechanisms and treatment options for 'secondary' (i.e., WHO Groups 3 and 5) pulmonary arterial hypertension (PAH). RECENT FINDINGS: Published randomized controlled trials, in general, do not support the use of approved therapies for 'primary' (i.e., WHO Group 1) PAH patients in patients with Group 3 PAH because of the small numbers of patients and inconsistent benefit. Therefore, we currently recommend against the use of these medications for Group 3 PAH. Similarly, there is limited evidence supporting the use of Group 1 PAH medications in Group 5 patients. In most patients with Group 5 PAH, treatment should be directed to the underlying disease. SUMMARY: The utility of PAH specific therapy in WHO Group 3 PAH is unclear because of the small numbers of patients evaluated and inconsistent beneficial effects observed. There is limited evidence supporting the use of PAH medications in Group 5 patients, and they may be harmful in some cases. PMID- 29629994 TI - The Achilles' heel of left ventricular assist device therapy: right ventricle. AB - PURPOSE OF REVIEW: Many patients suffer from either persistent right ventricular failure (RVF) at the time of left ventricular assist device (LVAD) or have ongoing symptoms consistent with RVF during chronic mechanical circulatory support. The lack of long-term right ventricular assist devices (RVADs) has limited the impact that mechanical circulatory support can provide to patients with biventricular failure. We aim to review the entire spectrum of RVF in patients receiving LVADs and reflect on why this entity remains the Achilles' heel of LVAD therapy. RECENT FINDINGS: In the early postoperative period, LVAD implantation reduces right ventricle (RV) afterload, but RV dysfunction may be exacerbated secondary to increased venous return. With prolonged therapy, the decreased RV afterload leads to improved RV contractile function. Bayesian statistical models outperform previously published preoperative risk scores by considering inter-relationships and conditional probabilities amongst independent variables. Various echocardiographic parameters and the pulmonary artery pulsatility index have shown promise in predicting post-LVAD RVF. Recent publications have delineated the emergence of 'delayed' RVF. Several devices are currently being investigated for use as RVADs. SUMMARY: Post-LVAD RVF depends on the RV's ability to adapt to acute hemodynamic changes imposed by the LVAD. Management options are limited due to the lack of an easily implantable, chronic use RVAD. PMID- 29629995 TI - Single vs. bilateral lung transplantation: when and why. AB - PURPOSE OF REVIEW: Lung transplantation is a life-saving treatment for several end stage lung diseases. Over the last two decades, the number of lung transplantation performed worldwide has steadily increased but several thousand people still die every year waiting for lung transplantation. However, the optimal procedure for lung transplantation in non-septic lung conditions remains debatable. RECENT FINDINGS: In pulmonary fibrosis and COPD, many recent studies suggest superiority of bilateral lung transplantation over single lung transplantation when long-term survival is evaluated; consequently, bilateral lung transplantation has been favored by many lung transplantation centers. However, the quality of evidence to support the superiority of bilateral lung transplantation remains low in the absence of prospective studies, and other available studies do not show differences in outcomes between the two types of procedure. SUMMARY: In the absence of good high quality evidence, it is difficult to make strong general recommendations for the type of lung transplant, and the decision often has to be individualized. However, the number of recipients on the wait list continues to surpass the amount of available organs and due consideration needs to be given to single lung transplantation as an option whenever possible. PMID- 29629996 TI - Normothermic liver preservation, current status and future directions. AB - PURPOSE OF REVIEW: Normothermic machine perfusion (NMP) is an emerging technology for liver preservation. Early clinical results demonstrate beneficial effects in reconditioning high-risk grafts. This review discusses the role of normothermic perfusion as a tool to assess graft viability and as a platform for graft intervention and modification. RECENT FINDINGS: The potential benefits of NMP extend far beyond organ reconditioning. Recent pilot studies have identified clinically relevant viability criteria, which now require validation in large randomized control trials prior to implementation. Furthermore, preclinical studies demonstrate tremendous potential for NMP as a method to extend the preservation period, thus improving transplant logistics as well as serve as a platform for graft-targeted interventions to optimize the preservation period. SUMMARY: NMP is a multifunctional tool with potential to transform liver preservation and the field of transplantation. Large clinical trials are necessary to optimize perfusion protocols, clarify indications for NMP therapy and justify use as the standard preservation modality. PMID- 29629997 TI - Effects of hyperglycemia on fluorine-18-fluorodeoxyglucose biodistribution in a large oncology clinical practice. AB - AIM: Suggested cutoff points of blood glucose levels (BGL) before F-FDG PET/CT scanning vary between 120 and 200 mg/dl in current guidelines. This study's purpose was to compare the frequency of abnormal fluorine-18-fluorodeoxyglucose (F-FDG) biodistribution on PET/CT scans of patients with various ranges of abnormal BGL and to determine the effect of BGL greater than 200 mg/dl on F-FDG uptake in various organs. PATIENTS AND METHODS: F-FDG PET/CT scans were retrospectively reviewed for 325 patients with BGL greater than 120 mg/dl at the time of scan and 112 with BGL less than or equal to 120 mg/dl. F-FDG biodistribution was categorized as normal, mildly abnormal, or abnormal by visual analysis of brain, background soft tissue, and muscle. Mean standardized uptake values (SUVmean) in brain, liver, fat (flank), gluteal muscle, and blood pool (aorta) were recorded. F-FDG biodistribution frequencies were assessed using a nonparametric chi-test for trend. Normal organ SUVs were compared using Kruskal Wallis tests using the following BGL groupings: <=120, 121-150, 151-200, and >=201 mg/dl. RESULTS: Although higher BGL were significantly associated with an increased proportion of abnormal biodistribution (P<0.001), most patients with BGL less than or equal to 200 mg/dl had normal or mildly abnormal biodistribution. Average brain SUVmean significantly decreased with higher BGL groupings (P<0.001). Average aorta, gluteal muscle, and liver SUVmean did not significantly differ among groups with BGL greater than 120 mg/dl (P=0.66, 0.84, and 0.39, respectively), but were significantly lower in those with BGL less than or equal to 120 mg/dl (P<=0.001). Flank fat SUVmean was not significantly different among BGL groups (P=0.67). CONCLUSION: Abnormal F-FDG biodistribution is associated with higher BGL at the time of scan, but the effects are negligible or mild in most patients with BGL less than 200 mg/dl. Although mildly increased soft tissue uptake is seen with BGL greater than 120 mg/dl, decline in brain metabolic activity correlated the most with various BGL. PMID- 29629998 TI - Predictive and prognostic value of left ventricular mechanical dyssynchrony assessed by myocardial perfusion single photon emission computed tomography in asymptomatic patients under hemodialysis. AB - BACKGROUND: Patients under hemodialysis (HD) have an increased risk of major adverse cardiac events (MACEs). In these patients, myocardial perfusion scintigraphy (MPS) provides useful prognostic information. Left ventricular mechanical dyssynchrony (LVD) has been proven to predict all-cause death in patients under HD. It remains unclear, whether the same prognostic value pertains also to the prediction of MACEs. PATIENTS AND METHODS: Ninety patients under HD (duration range: 2-216 months) with neither history nor symptoms of coronary artery disease at the time of MPS were retrospectively evaluated. All underwent clinical evaluation and MPS with dipyridamole stress test. MPS was reprocessed to derive left ventricular ejection fraction (EF), perfusion scores [summed stress score (SSS) and summed difference score (SDS)] and LVD (phase histogram bandwidth and phase SD).ResultsMACEs were reported in 10 (11.1%) patients as assessed at more than 2 years of follow-up (median 29 months). At univariate analysis, a correlation was demonstrated between MACEs and LVD (P<0.001), BMI (P=0.04), ECG changes during stress (P=0.03), dyspnea (P=0.02), SSS (P=0.04) and SDS (P=0.02). At stepwise multivariate analysis, only LVD (P<0.001), SSS (P=0.01) and SDS (P=0.001) were independent predictors of MACEs. No thresholds of SSS or SDS showed predictive value (P=0.79 for SSS >=4, P=0.10 for SSS >8 and P=0.66 for SDS >=2). At survival analysis, patients with LVD had a significantly shorter MACE free survival (P<0.001). This predictive value held true even in patients with an unremarkable pattern of perfusion. CONCLUSION: In asymptomatic patients without known coronary artery disease under HD, LVD is highly predictive of the onset of MACEs at more than 2 years of follow-up and provides incremental value over perfusion scores alone. A phase analysis on gated MPS should be routinely performed in these patients to yield useful prognostic information. PMID- 29629999 TI - Cholesterol transfer at endosomal-organelle membrane contact sites. AB - PURPOSE OF REVIEW: Cholesterol is delivered to the limiting membrane of late endosomes by Niemann-Pick Type C1 and C2 proteins. This review summarizes recent evidence that cholesterol transfer from endosomes to the endoplasmic reticulum and other organelles is mediated by lipid-binding proteins that localize to membrane contact sites (MCS). RECENT FINDINGS: LDL-cholesterol in the late endosomal/lysosomes is exported to the plasma membrane, where most cholesterol resides, and the endoplasmic reticulum, which harbors the regulatory complexes and enzymes that control the synthesis and esterification of cholesterol. A major advance in dissecting these cholesterol transport pathways was identification of frequent and dynamic MCS between endosomes and the endoplasmic reticulum, peroxisomes and plasma membrane. Positioned at these MCS are members of the oxysterol-binding protein (OSBP) and steroidogenic acute regulatory protein related lipid-transfer family of lipid transfer proteins that bridge the opposing membranes and directly or indirectly mediate cholesterol transfer. OSBP-related protein 1L (ORP1L), ORP5 and ORP6 mediate cholesterol transfer to the endoplasmic reticulum that regulates cholesterol homeostasis. ORP1L and STARD3 also move cholesterol from the endoplasmic reticulum-to-late endosomal/lysosomes under low cholesterol conditions to facilitate intraluminal vesicle formation. Cholesterol transport also occurs at MCS with peroxisomes and possibly the plasma membrane. SUMMARY: Frequent contacts between organelles and the endo-lysosomal vesicles are sites for bidirectional transfer of cholesterol. PMID- 29630000 TI - What have we learnt from the clinical outcomes trials with the cetrapibs? AB - PURPOSE OF REVIEW: The current review considers what we have learnt from the clinical outcome trials with the cetrapibs; the inhibitors of cholesteryl ester transfer protein that increase HDL cholesterol levels; torcetrapib, dalcetrapib, evacetrapib and anacetrapib. RECENT FINDINGS: Although an off-target increase in blood pressure may have contributed to the failure of torcetrapib in Investigation of Lipid Level Management to Understand its Impact in Atherosclerotics Events, recent evidence shows that torcetrapib also increased atherogenic apoproteins, and this may have contributed to its failure. Evacetrapib and anacetrapib also increase atherogenic apoproteins. This may have contributed to lack of effect of evacetrapib in Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes. The success of anacetrapib in Randomized Evaluation of the Effects of Anacetrapib through Lipid Modification is more likely to have been due to lowering LDL cholesterol than to increasing HDL cholesterol. The lack of potency in increasing HDL cholesterol was initially considered as a reason for the failure of dalcetrapib in dal-OUTCOMES, but recent genomic studies suggest that dalcetrapib may be effective in subjects with a particular genotype, and this is being clinically tested. SUMMARY: Collectively, these clinical outcome trials do not support raising HDL cholesterol by inhibiting cholesteryl ester transfer protein, as a mechanism for improving cardiovascular outcomes, in the total population of subjects with coronary artery disease. PMID- 29630001 TI - Prevention, Diagnosis, and Treatment of Complications of the IPAA for Ulcerative Colitis. PMID- 29630002 TI - Modified Pfannenstiel Open Approach as an Alternative to Laparoscopic Total Proctocolectomy and IPAA: Comparison of Short- and Long-term Outcomes and Quality of Life. AB - BACKGROUND: A laparoscopic approach to total proctocolectomy with IPAA has been suggested to have better short-term outcomes and cosmesis, whereas open surgery by midline incision may result in shorter operative times. We hypothesized that a modified Pfannenstiel open approach would combine the advantages of both techniques. OBJECTIVE: The purpose of this study was to compare outcomes of open total proctocolectomy with IPAA using a modified Pfannenstiel incision versus those following the laparoscopic approach. DESIGN: This was a retrospective study comparing patients submitted to open IPAA using modified Pfannenstiel incision versus laparoscopy from 1998 to 2014. SETTINGS: The study was conducted at a high volume tertiary referral center. PATIENTS: Among 1275 patients, 119 patients underwent the laparoscopic approach and 33 underwent the modified Pfannenstiel approach. MAIN OUTCOME MEASURES: Short- and long-term outcomes were evaluated, and quality-of-life questionnaires were assessed. RESULTS: Patients who underwent the modified Pfannenstiel approach were younger, more often women, and had lower BMI and ASA classification compared with those who underwent laparoscopy. Surgical time was lower in Pfannenstiel, and no difference was observed in length of hospital stay. No difference was observed in postoperative complications, pouch failure rate, or quality of life. Patients were then matched 1:1 by diagnosis, sex, age (+/-5 y) and BMI (+/-5 kg/m). The Pfannenstiel approach still had a shorter surgical time. No difference was observed in the length of hospital stay, complications, pouch failure, or quality of life. In long-term follow-up, pouchitis symptoms occurred more frequently in Pfannenstiel (mean follow-up = 7.3 y), and seepage was more frequently observed in the laparoscopy group (mean follow-up = 4.2 y). These differences were not observed in matched patients. LIMITATIONS: The study was limited by its retrospective design and inherent selection bias. CONCLUSIONS: The modified Pfannenstiel approach provides equivalent short- and long-term outcomes and similar quality of life compared with laparoscopy but with a significantly shorter operative time. The modified Pfannenstiel approach to total proctocolectomy with IPAA may be the most efficient method in selected patients. See Video Abstract at http://links.lww.com/DCR/A562. PMID- 29630003 TI - Use of Primary Anastomosis With Diverting Ileostomy in Patients With Acute Diverticulitis Requiring Urgent Operative Intervention. AB - BACKGROUND: Previous studies suggest that urgent colectomy and primary anastomosis with diversion is safe for perforated diverticulitis. Current guidelines support this approach. OBJECTIVE: The purpose of this study was to describe the use of urgent or emergent primary anastomosis with diversion in diverticulitis before the 2014 American Society of Colon and Rectal Surgeons guidelines and compare national outcomes of primary anastomosis with diversion to the Hartmann procedure. DESIGN: This was a national retrospective cohort study. SETTINGS: The study was conducted with a national all-payer US sample from 1998 to 2011. PATIENTS: Patients included those admitted and treated with urgent or emergent colectomy for diverticulitis. Exclusion criteria were age <18 years, concurrent diagnosis of colorectal cancer or IBD, no fecal diversion performed, and operations >24 hours after admission. MAIN OUTCOME MEASURES: In-hospital mortality was measured. RESULTS: A total of 124,198 patients underwent emergent or urgent colectomy for acute diverticulitis; 67,721 underwent concurrent fecal diversion, including 65,084 (96.1%) who underwent end colostomy and 2637 (3.9%) who underwent anastomosis with ileostomy. The rate of primary anastomosis with diverting ileostomy increased from 30 to 60 diverting ileostomy cases per 1000 operative diverticulitis cases in 1998 versus 2011 (incidence rate ratio = 2.04 (95% CI, 1.70-2.50). However, overall use remained low, with >90% of patients undergoing end colostomy. Complication rates were higher (32.1% vs 23.3%; p < 0.001) and in-hospital mortality rates were higher (16.0% vs 6.4%; p < 0.001) for primary anastomosis with diversion patients compared with end colostomy. These findings were consistent on multivariable logistic regression. Other factors that contributed to in-hospital mortality included increasing age, increasing comorbid disease burden, and socioeconomic status. LIMITATIONS: Billing data can be inaccurate or biased because of nonmedically trained professional data entry. Selection bias could have affected the results of this retrospective study. CONCLUSIONS: The use of primary anastomosis with proximal diversion for urgent colectomy in diverticulitis increased over our study period; however, overall use remained low. Poor national outcomes after primary anastomosis with proximal diversion might affect compliance with new guidelines. See Video Abstract at http://links.lww.com/DCR/A600. PMID- 29630004 TI - Characteristics of Older Adults Who Are Unable to Perform a Floor Transfer: Considerations for Clinical Decision-Making. AB - BACKGROUND AND PURPOSE: The ability to get down and up from the floor or to perform a floor transfer (FT) is a vital and useful skill for older adults at risk of falling. Little is known about the health-related factors that separate older adults who can perform FT independently from those who cannot. Therefore, the specific aims of this cross-sectional study are to (1) describe and compare health-related factors among older adults who were independent, assisted, or dependent in FT performance; and (2) establish the parallel reliability between self-reported and actual performance of FT. METHODS: A total of 46 community dwelling adults ages 65 to 96 years were recruited using a stratified sampling technique based on self-reported levels of FT ability: independent (n = 15), assisted (n = 15), or dependent (n = 15). Participants were asked to perform the actual FT test and were categorized according to test result as independent (n = 18), assisted (n = 10), or dependent (n = 17). Sociodemographic and health related factors of participants were separated into 3 FT test outcome groups. The Kruskal-Wallis test was used to compare these factors across the 3 FT test outcome groups. The quadratic-weighted kappa coefficient was calculated to determine the agreement between self-reported FT ability and FT test performance. RESULTS: Significant differences were observed among the FT test outcome groups based on all sociodemographic and health-related factors (P < .05). Older adults who were dependent in FT were older and dependent in instrumental activities of daily living (IADL, 100%). Also, this group required some type of help during basic activities of daily living (ADL, 35.3%), which reflected a homebound status and the need for caregiver support, including the use of 2-handed assistive devices during ambulation. More than half the participants in this category had fallen at least once in the past 6 months. Conversely, older adults who were independent in FT were younger and living independently in the community (83.3%). The parallel reliability between the self-reported FT ability and actual FT test performance was 0.92 (95% confidence interval, 0.88-0.97). CONCLUSION: Sociodemographic and health-related factors were significantly different among older adults who demonstrated varying abilities on the FT test. This study has shown that the self-reported FT ability and actual FT test performance represented reliable alternative forms to assess the ability to transfer from a standing to a supine position on the floor and then back to an erect position. Evaluation of FT ability and/or performance is recommended as a standard component of geriatric functional assessment to make more informed clinical decision in providing effective physical therapy interventions. PMID- 29630005 TI - An Exploration of Equine-Assisted Therapy to Improve Balance, Functional Capacity, and Cognition in Older Adults With Alzheimer Disease. AB - BACKGROUND AND PURPOSE: Alzheimer disease (AD) is a chronic, progressive dementia syndrome that features cognitive and behavioral symptoms, as well as physical and functional limitations that develop over the course of the disease. As an activity that involves physical and cognitive aspects, equine-assisted therapy (EAT) could be a useful therapeutic approach in conditions that involve physical and cognitive decline. However, to date, there are no reports of the use of this therapy in participants with AD. Within this context, the objective of this case series was to describe the effects of EAT on balance, functional capacity, and cognition in older adults diagnosed with AD. METHODS: We enrolled 9 subjects, of both sexes, with a mean age of 79.7 (7.8) years and a diagnosis of AD. The study intervention comprised 20 sessions of EAT. We evaluated participants at baseline and at the end of the intervention. Outcome measures were balance (force plate), functional capacity (Timed Up and Go test and 30-second chair stand test), and cognition (verbal fluency and Mini-Mental State Examination). RESULTS: Comparison between the pre- and postintervention time points (Wilcoxon test) revealed significant improvements in balance (center of pressure in the anterior-posterior direction, P = .017) and functional capacity (Timed Up and Go test, P = .036, and 30-second chair stand test, P = .012). CONCLUSION: These findings provide evidence of an association between EAT and improved balance and functional capacity in older adults with AD, with no significant impact on cognitive performance. PMID- 29630006 TI - Reliability and Validity of the Patient-Specific Functional Scale in Community Dwelling Older Adults. AB - BACKGROUND AND PURPOSE: Clinical measurement of physical function that is both specific to the individual and generates comparable outcome data is a fundamental need in physical therapy examination. The Patient-Specific Functional Scale (PSFS) has been found to be a reliable and valid measure of physical function in patients with musculoskeletal disorders and may have applications for other patient populations. However, the reliability and the validity of the PSFS have not been evaluated in older adults. The purpose of this study was to investigate the reliability and the validity of the PSFS in community-dwelling older adults. METHODS: Thirty-one community-dwelling older adults (11 males, 20 females), mean age = 81.1 (8.3) years, were included. Participants completed the PSFS, Lower Extremity Functional Scale (LEFS), Activity-specific Balance Confidence Scale (ABC), Short Physical Performance Battery (SPPB), Berg Balance Scale, and the Timed Up and Go on 2 separate days, 48 hours apart. Assessment scores were compared between testing days and reliability was analyzed using the intraclass correlation coefficient (ICC) and minimal detectable change (MDC). Validity of the PSFS was assessed by comparing initial scores with the other measures using the Pearson correlation coefficient, scatter plots, and Bland-Altman plots. RESULTS: The ICC and the MDC for the PSFS were 0.82 (95% confidence interval = 0.67-0.91) and 2.8, respectively. Significant correlations (P < .05) were found when the PSFS was compared with the ABC (r = 0.68), LEFS (r = 0.81), and SPPB (r = 0.37). Bland-Altman plots and 95% limits of agreement (LOA) using z scores indicated considerable agreement between the PSFS versus the ABC (LOA =-1.6 to 1.6), LEFS (LOA =-1.2 to 1.2), and SPPB (LOA =-2.1 to 2.1). CONCLUSION: The PSFS is a reliable and valid measure of physical function in community-dwelling older adults. A change of 2.8 or greater on the PSFS suggests a true change in physical function in this population. PMID- 29630008 TI - Ovarian Cancer Prevention and Screening. AB - There has been much progress in ovarian cancer screening and prevention in recent years. Improved tools that combine genetic and epidemiologic factors to predict an individual's ovarian cancer risk are set to become available for tailoring preventive and screening approaches. The increasing evidence on tubal origins of a proportion of ovarian cancer has paved the way to use of opportunistic bilateral salpingectomy at tubal ligation and hysterectomy in the general population. Clinical trials are in progress to estimate the long-term effects on endocrine function. In women at high risk, risk reducing salpingo-oophorectomy remains the standard of care with the current focus on management of resulting noncancer outcomes, especially sexual dysfunction in younger women. This has led to evaluation of early bilateral salpingectomy and delayed oophorectomy in this population. Meanwhile, modeling suggests that BRCA mutation carriers should consider using the oral contraceptive pill for chemoprevention. In the general population, the largest ovarian cancer screening trial to date, the UK Collaborative Trial of Ovarian Cancer Screening reported a stage shift with annual multimodal screening using the longitudinal CA 125 Risk of Ovarian Cancer Algorithm but not with annual transvaginal ultrasound screening. There was no definitive mortality reduction with either screening strategy compared with no screening. Further follow-up until December 2018 in now underway. Stage shift and higher rates of optimal cytoreduction were also reported during 3- to 4-monthly multimodal screening in the United Kingdom and U.S. high-risk screening trials. Although all agree that there is not yet evidence to support general population screening, recommendations for high-risk screening vary between countries. A key finding from the screening trials has been the better performance of longitudinal algorithms compared with a single cutoff for CA 125. A major focus of ovarian cancer biomarker discovery work has been tumor DNA markers in both plasma and novel specimens such as cervical cytology samples. PMID- 29630007 TI - Optimizing Blood Transfusion Practices Through Bundled Intervention Implementation in Patients With Gynecologic Cancer Undergoing Laparotomy. AB - OBJECTIVE: To examine blood transfusion practices and develop a standardized bundle of interventions to address the high rate of perioperative red blood cell transfusion among patients with ovarian and endometrial cancer. METHODS: This was a retrospective cohort study. Our primary aim was to determine whether an implemented bundled intervention was associated with a reduction in perioperative red blood cell transfusions among cases of laparotomy for cancer. Secondary aims included comparing perioperative demographic, surgical, complication, and cost data. Interventions included blood transfusion practice standardization using American Society of Anesthesiologists guidelines, an intraoperative hemostasis checklist, standardized intraoperative fluid status communication, and evidence based use of tranexamic acid. Prospective data from women undergoing laparotomy for ovarian or endometrial cancer from September 28, 2015, to May 31, 2016, defined the study cohort and were compared with historical controls (September 1, 2014, to September 25, 2015). Outcomes were compared in the full unadjusted cohorts and in propensity-matched cohorts. RESULTS: In the intervention and historical cohorts, respectively, 89 and 184 women underwent laparotomy for ovarian cancer (n=74 and 152) or advanced endometrial cancer (n=15 and 32). Tranexamic acid was administered in 54 (60.7%) patients. The perioperative transfusion rate was lower for the intervention group compared with historical controls (18.0% [16/89] vs 41.3% [76/184], P<.001), a 56.4% reduction. This improvement in the intervention group remained significant after propensity matching (16.2% [13/80] vs 36.2% [29/80], P=.004). The hospital readmission rate was also lower for the intervention group compared with historical controls (1.1% [1/89] vs 12.5% [23/184], P=.002); however, this improvement did not attain statistical significance after propensity matching (1.2% [1/80] vs 7.5% [6/80], P=.12). Cost analysis demonstrated that this intervention was cost-neutral during index hospitalization plus 30-day follow-up. CONCLUSION: Application of a standardized bundle of evidence-based interventions was associated with reduced blood use in our gynecologic oncology practice. PMID- 29630009 TI - Pregnancy Exercise and Nutrition With Smartphone Application Support: A Randomized Controlled Trial. AB - OBJECTIVE: To evaluate the effect of a healthy lifestyle package (an antenatal behavior change intervention supported by smartphone application technology) on the incidence of gestational diabetes mellitus (GDM) in overweight and obese women. METHODS: Women with body mass indexes (BMIs) 25-39.9 were enrolled into this randomized controlled trial. The intervention consisted of specific dietary and exercise advice that addressed behavior change supported by a tailor-designed smartphone application. Women in the control group received usual care. The primary outcome was the incidence of GDM at 28-30 weeks of gestation. To reduce GDM from 15% to 7.2%, we estimated that 506 women would be required to have 80% power to detect this effect size at a significance of .05, that is, 253 in each group. RESULTS: Between March 2013 and February 2016, 565 women were recruited with a mean BMI of 29.3 and mean gestational age of 15.5 weeks. The incidence of GDM did not differ between the two groups, 37 of 241 (15.4%) in the intervention group compared with 36 of 257 (14.1%) in the control group (relative risk 1.1, 95% CI 0.71-1.66, P=.71). CONCLUSIONS: A mobile health-supported behavioral intervention did not decrease the incidence of GDM. CLINICAL TRIAL REGISTRATION: ISRCTN registry, https://www.isrctn.com/, ISRCTN29316280. PMID- 29630010 TI - Perinatal Outcomes in Women With a History of Chronic Hypertension but Normal Blood Pressures Before 20 Weeks of Gestation. AB - OBJECTIVE: To compare the perinatal outcomes of normotensive women with those of women with a history of chronic hypertension with normal blood pressures before 20 weeks of gestation, stratifying the latter by whether they were receiving antihypertensive medication. METHODS: We conducted a retrospective cohort study of all singletons with a history of chronic hypertension from 2000 to 2014. Exclusions were blood pressure greater than 140/90 mm Hg before 20 weeks of gestation, fetal anomalies, major medical problems other than hypertension, and diabetes. For the same time period, a randomly selected group without a diagnosis of chronic hypertension was chosen using the same exclusion criteria. Outcomes were compared among women without chronic hypertension, women with chronic hypertension on no antihypertensive medication but with blood pressures less than 140/90 mm Hg before 20 weeks of gestation, and women with chronic hypertension on antihypertensive medication with blood pressures less than 140/90 mm Hg before 20 weeks of gestation. The primary outcome was a perinatal composite of stillbirth, neonatal death, respiratory support at birth, arterial cord pH less than 7, 5 minute Apgar score 3 or less, and seizures. Secondary outcomes assessed were preterm birth before 37 and 34 weeks of gestation, small for gestational age, and preeclampsia. RESULTS: Of 830 women with chronic hypertension and blood pressures less than 140/90 mm Hg before 20 weeks of gestation, 212 (26%) were not taking antihypertensive medication and 618 (74%) were. These groups were compared with 476 women without chronic hypertension. Women with hypertension were more likely to be older and have baseline renal disease and diabetes compared with women in the no hypertension group. The perinatal composite was more common in both hypertensive groups: no antihypertensive medication (9.9%) and antihypertensive medication (14.6%) compared with women in the control group (2.9%) (adjusted odds ratio [OR] 2.9, 95% CI 1.21-6.85 no antihypertensive medications compared with no chronic hypertension; adjusted OR 5.0, 95% CI 2.38-10.54 antihypertensive medications vs no chronic hypertension). The risk of early preterm birth, small for gestational age, and preeclampsia was not significantly increased in women with chronic hypertension and no antihypertensive medications compared with women without chronic hypertension. CONCLUSION: Despite normal baseline blood pressures without medications before 20 weeks of gestation, women with chronic hypertension are at an increased risk of adverse perinatal outcomes compared with women without. PMID- 29630011 TI - A Comparison of Methods for the Diagnosis of Fetal Growth Restriction Between the Royal College of Obstetricians and Gynaecologists and the American College of Obstetricians and Gynecologists. AB - OBJECTIVE: The Royal College of Obstetricians and Gynaecologists (RCOG) defines fetal growth restriction as ultrasound-estimated fetal weight less than the 10th percentile or abdominal circumference less than the 10th percentile; the American College of Obstetricians and Gynecologists (ACOG) defines fetal growth restriction as estimated fetal weight less than the 10th percentile alone. We compared each method's ability to predict small for gestational age (SGA) at birth. METHODS: For this retrospective study of diagnostic accuracy, we reviewed deliveries at the University of New Mexico Hospital from January 1, 2013, to March 31, 2017. We included mothers with singleton, well-dated pregnancies and nonanomalous fetuses undergoing indicated fetal growth restriction surveillance with an ultrasound-estimated fetal weight within 30 days of delivery. Estimated fetal weights and percentiles were calculated using the Hadlock intrauterine growth curve. Small for gestational age was defined as birth weight less than the 10th percentile based on a recent, sex-specific curve. We calculated the area under the curve, sensitivity, specificity, and positive and negative likelihood ratios for various approaches using abdominal circumference and estimated fetal weight to diagnose fetal growth restriction, including the definitions endorsed by ACOG and RCOG. RESULTS: We included 1,704 pregnancies with a mean ultrasonography-to-delivery interval of 14.0 days (+/-8.6). There were 235 SGA neonates (13.8%). The rate of fetal growth restriction was 13.6% when using ACOG's criteria and 16.9% according to RCOG's criteria (P=.007). The area under the curve of RCOG's diagnostic approach was 0.78 (95% CI 0.76-0.80), which was higher than ACOG's (0.76, 95% CI 0.74-0.78, P=.01). Sensitivities and specificities of the various methods were similar. Adopting estimated fetal weight or abdominal circumference less than the 10th percentile instead of estimated fetal weight alone to predict SGA at birth would correctly identify one additional case of SGA for each 14 patients assessed. CONCLUSION: The diagnostic approach endorsed by RCOG is a marginally better predictor of SGA at birth compared with the method endorsed by ACOG. Future research should consider the potential benefits and harms of the different methods in different populations. PMID- 29630012 TI - Identifying Maternal Deaths in Texas Using an Enhanced Method, 2012. AB - OBJECTIVE: To more accurately estimate the 2012 maternal mortality ratio for Texas using an enhanced method for identifying maternal deaths. METHODS: This population-based descriptive study used both data matching and record review to verify pregnancy or delivery within 42 days for 147 deaths with obstetric cause of-death codes, and used data matching alone to identify additional maternal deaths within the same timeframe. Crude maternal mortality ratios were calculated for confirmed maternal deaths overall, by race and ethnicity, and by age. These maternal mortality ratios were compared with maternal mortality ratios computed using obstetric cause-of-death codes alone (standard method). RESULTS: Fifty-six maternal deaths were confirmed to have occurred during pregnancy or within 42 days postpartum. Using our enhanced method, the 2012 maternal mortality ratio for Texas was 14.6 maternal deaths per 100,000 live births, less than half that obtained using the standard method (n=147). Approximately half (50.3%) of obstetric-coded deaths showed no evidence of pregnancy within 42 days, and a large majority of these incorrectly indicated pregnancy at the time of death. Insufficient information was available to determine pregnancy for 15 obstetric coded deaths, which were excluded from the 2012 maternal mortality ratio estimate; however, had these deaths been included, the resulting maternal mortality ratio would still be significantly lower than that reported using the standard method. CONCLUSION: Relying solely on obstetric codes for identifying maternal deaths appears to be insufficient and can lead to inaccurate maternal mortality ratios. A method enhanced with data matching and record review yields more accurate ratios. Results likely have national implications, because miscoding of obstetric deaths with the standard method may affect the accuracy of other states' maternal mortality ratios. PMID- 29630013 TI - Intrauterine Device Insertion Before and After Mandated Health Care Coverage: The Importance of Baseline Costs. AB - OBJECTIVE: To evaluate changes in out-of-pocket cost for intrauterine device (IUD) placement before and after mandated coverage of contraceptive services and to examine how changes in out-of-pocket cost influence IUD insertion as a function of baseline cost. METHODS: We conducted a cross-sectional pre-post analysis at the plan level using a large deidentified medical claims database to analyze our primary outcome, new IUD insertions among women enrolled in employer sponsored health plans in 2009 and 2014, and our secondary outcome, out-of-pocket cost. Patient costs and utilization were aggregated by plan and year to conduct a plan-specific analysis. Plans were classified by mean out-of-pocket cost level: no out-of-pocket cost, low out-of-pocket cost (less than the 75th percentile), and high out-of-pocket cost (75th percentile or greater). A generalized estimating equation was used to evaluate average plan utilization of IUD services in 2009 and 2014 as a function of plan cost category and year. RESULTS: Overall, average plan utilization of IUD services demonstrated a significant increase between 2009 (12.5%, 95% CI 11.6-13.4%) and 2014 (13.8%, 95% CI 13.0-14.7%; P<.001). When plans were grouped by out-of-pocket cost level, significant differences in plan utilization over time were observed. Plans that went from high out-of-pocket cost in 2009 to no out-of-pocket cost in 2014 saw a higher average increase in the rate of plan IUD insertions over time (2.4%, 95% CI 0.04 4.5%) compared with plans with no out-of-pocket cost in both 2009 and 2014 ( 1.0%, 95% CI -3.3 to 1.4%, P=.02). Among all women in all plans, the 75th percentile of out-of-pocket cost in 2009 was $368; this number dropped to $0 in 2014. CONCLUSION: Women in plans with the greatest reduction in out-of-pocket cost after mandated coverage of contraception had the greatest gains in IUD insertion. This suggests that baseline cost should be considered in evaluations of this policy and others that eliminate patient out-of-pocket cost. PMID- 29630014 TI - Influenza Vaccination, Pregnancy Safety, and Risk of Early Pregnancy Loss. AB - Since 2004, the Centers for Disease Control and Prevention and the American College of Obstetricians and Gynecologists have recommended routine influenza vaccination for all pregnant women in any trimester. Maternal influenza vaccination has been shown to decrease the risk of influenza and its complications among pregnant women and their infants in the first 6 months of life. In a recent article published in Vaccine, Donahue and colleagues reported a possible association between influenza vaccination when given very early in the first trimester and spontaneous abortion. There are limited conclusions that should be drawn from this study given the case-control design as well as the small number of patients included in the subanalysis that is the basis for the report. A prior first-trimester safety study from this group, using a similar study design, had not observed any association with spontaneous abortion, and other reports of first-trimester vaccine safety have not observed an association. The lack of a biologically plausible mechanism for the suggested association between previous influenza vaccination and early pregnancy loss is of concern. The study's reported observation is not definitive and needs be replicated in appropriately designed studies before changing clinical practice. Pregnant women are at high risk for severe influenza-related complications, including death, and health care providers have an obligation to their patients to continue to recommend and provide influenza vaccinations. PMID- 29630015 TI - Maternal Pyrexia and Villitis of Unknown Etiology. AB - BACKGROUND: Villitis of unknown etiology is an inflammatory placental condition associated with adverse pregnancy outcomes, including fetal growth restriction and preterm birth. CASE: We describe maternal pyrexia with daily rigors in the third trimester of two consecutive pregnancies in the same woman. In her second pregnancy, we found no evidence of infection despite an extensive antenatal investigation (blood and urine cultures, serologies, chest X-ray, abdominal ultrasonogram, echocardiogram). The fetus was closely monitored for growth and well-being until spontaneous labor ensued at 36 weeks of gestation, followed by the birth of a vigorous female neonate who weighed 2.235 kg and was healthy. Placental pathology was consistent with villitis of unknown etiology and displayed more prominent abscess formation than is usually described. The patient's first pregnancy 4 years previously followed a similar but milder pattern, without preterm delivery but with similar placental pathology. CONCLUSION: Maternal pyrexia in both pregnancies was ultimately attributed to placental inflammation secondary to a maternal immunologic response to the fetal placental unit. A placental origin for maternal pyrexia should be considered in cases in which a maternal cause cannot be identified and the pregnancy managed in light of the possible association with adverse fetal outcomes. PMID- 29630017 TI - Research in Obstetric Fistula: Addressing Gaps and Unmet Needs. AB - Although obstetric fistula has likely plagued women since the beginning of time, very little research proportionally exists. This article summarizes the most substantial research on the topic and delineates research gaps and future needs. Existing research demonstrates that access to care is the underlying cause of obstetric fistula and that the first attempt at closure holds the highest chance at success, ranging between 84% and 94%. For simple cases, 10 days of a catheter is sufficient, although what constitutes as simple is unclear. Circumferential fistulas are at high risk for ongoing urethral continence. Psychosocial programs are helpful for all women, but those who are "dry" tend to reintegrate into society, whereas those still leaking need additional support. Prenatal care and scheduled cesarean delivery are recommended to avoid another fistula. Gaps in research include accurate prevalence and incidence, interventions to improve access to care, surgical technique, especially for complex cases, and ways to prevent ongoing incontinence, among many others. In all areas, more rigorous research is needed. PMID- 29630016 TI - Opioid Detoxification During Pregnancy: A Systematic Review. AB - OBJECTIVE: To systematically review maternal and neonatal outcomes associated with opioid detoxification during pregnancy. DATA SOURCES: PubMed, PsycINFO, EMBASE, Cochrane, and ClinicalTrials.gov databases were searched from January 1, 1966, to September 1, 2016. METHODS OF STUDY SELECTION: English-language studies that reported outcomes associated with opioid detoxification among pregnant women with opioid use disorder were included. Nonoriginal research articles (case reports, editorials, reviews) and studies that failed to report outcomes for detoxification participants were excluded. Bias was assessed using the Cochrane Collaboration's tool for assessing risk of bias and quality was assessed using the U.S. Preventive Service Task Force Quality of Evidence scale. TABULATION, INTEGRATION, AND RESULTS: Of 1,315 unique abstracts identified, 15 met criteria for inclusion and included 1,997 participants, of whom 1,126 underwent detoxification. Study quality ranged from fair to poor as a result of the lack of a randomized control or comparison arm and high risk of bias across all studies. Only nine studies had a comparison arm. Detoxification completion (9-100%) and illicit drug relapse (0-100%) rates varied widely across studies depending on whether data from participants who did not complete detoxification or who were lost to follow-up were included in analyses. The reported rate of fetal loss was similar among women who did (14 [1.2%]) and did not undergo detoxification (17 [2.0%]). CONCLUSIONS: Evidence does not support detoxification as a recommended treatment intervention as a result of low detoxification completion rates, high rates of relapse, and limited data regarding the effect of detoxification on maternal and neonatal outcomes beyond delivery. PMID- 29630019 TI - Transfer of Inhaled Cannabis Into Human Breast Milk. AB - OBJECTIVE: To evaluate the transfer of delta-9-tetrahydrocannabinol and its metabolites into human breast milk after maternal inhalation of 0.1 g cannabis containing 23.18% delta-9-tetrahydrocannabinol. METHODS: In this pilot pharmacokinetic study, breast milk samples were collected from mothers who regularly consumed cannabis, were 2-5 months postpartum, and exclusively breastfeeding their infants. Women were anonymously recruited for the study. After discontinuing cannabis for at least 24 hours, they were directed to obtain a baseline breast milk sample, then smoke a preweighed, analyzed, standardized strain of cannabis from one preselected dispensary, and collect breast milk samples at specific time points: 20 minutes and 1, 2, and 4 hours. Quantification of delta-9-tetrahydrocannabinol and its metabolites in these collected breast milk samples was performed by high-performance liquid chromatography tandem mass spectrometry. RESULTS: A total of eight women were enrolled. Most were occasional cannabis smokers and one a chronic user. Delta-9-tetrahydrocannabinol was detected at low concentrations at all the time points beyond time zero. No metabolites were detected at any time point. Delta-9-tetrahydrocannabinol was transferred into mother's milk such that exclusively breastfeeding infants ingested an estimated mean of 2.5% of the maternal dose (the calculated relative infant dose=2.5%, range 0.4-8.7%). The estimated daily infant dose was 8 micrograms per kilogram per day. CONCLUSION: This study documents inhaled delta-9 tetrahydrocannabinol transfer into the mother's breast milk. Low concentrations of delta-9-tetrahydrocannabinol were detected. The long-term neurobehavioral effect of exposure to delta-9-tetrahydrocannabinol on the developing brain is unclear. Mothers should be cautious using cannabis during pregnancy and breastfeeding. PMID- 29630018 TI - Prescription and Other Medication Use in Pregnancy. AB - OBJECTIVE: To characterize prescription and other medication use in a geographically and ethnically diverse cohort of women in their first pregnancy. METHODS: In a prospective, longitudinal cohort study of nulliparous women followed through pregnancy from the first trimester, medication use was chronicled longitudinally throughout pregnancy. Structured questions and aids were used to capture all medications taken as well as reasons they were taken. Total counts of all medications taken including number in each category and class were captured. Additionally, reasons the medications were taken were recorded. Trends in medications taken across pregnancy and in the first trimester were determined. RESULTS: Of the 9,546 study participants, 9,272 (97.1%) women took at least one medication during pregnancy with 9,139 (95.7%) taking a medication in the first trimester. Polypharmacy, defined as taking at least five medications, occurred in 2,915 (30.5%) women. Excluding vitamins, supplements, and vaccines, 73.4% of women took a medication during pregnancy with 55.1% taking one in the first trimester. The categories of drugs taken in pregnancy and in the first trimester include the following: gastrointestinal or antiemetic agents (34.3%, 19.5%), antibiotics (25.5%, 12.6%), and analgesics (23.7%, 15.6%, which includes 3.6%; 1.4% taking an opioid pain medication). CONCLUSION: In this geographically and ethnically diverse cohort of nulliparous pregnant women, medication use was nearly universal and polypharmacy was common. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT01322529. PMID- 29630020 TI - Disparities in Adherence to National Comprehensive Cancer Network Treatment Guidelines and Survival for Stage IB-IIA Cervical Cancer in California. AB - OBJECTIVE: To evaluate the association of sociodemographic and hospital characteristics with adherence to National Comprehensive Cancer Network treatment guidelines for stage IB-IIA cervical cancer and to analyze the relationship between adherent care and survival. METHODS: This is a retrospective population based cohort study of patients with stage IB-IIA invasive cervical cancer reported to the California Cancer Registry from January 1, 1995, through December 31, 2009. Adherence to National Comprehensive Cancer Network guideline care was defined by year- and stage-appropriate surgical procedures, radiation, and chemotherapy. Multivariate logistic regression, Kaplan-Meier estimate, and Cox proportional hazard models were used to examine associations between patient, tumor, and treatment characteristics and National Comprehensive Cancer Network guideline adherence and cervical cancer-specific 5-year survival. RESULTS: A total of 6,063 patients were identified. Forty-seven percent received National Comprehensive Cancer Network guideline-adherent care, and 18.8% were treated in high-volume centers (20 or more patients/year). On multivariate analysis, lowest socioeconomic status (adjusted odds ratio [OR] 0.69, 95% CI 0.57-0.84), low middle socioeconomic status (adjusted OR 0.76, 95% CI 0.64-0.92), and Charlson Deyo comorbidity score 1 or higher (adjusted OR 0.78, 95% CI 0.69-0.89) were patient characteristics associated with receipt of nonguideline care. Receiving adherent care was less common in low-volume centers (45.9%) than in high-volume centers (50.9%) (effect size 0.90, 95% CI 0.84-0.96). Death from cervical cancer was more common in the nonadherent group (13.3%) than in the adherent group (8.6%) (effect size 1.55, 95% CI 1.34-1.80). Black race (adjusted hazard ratio 1.56, 95% CI 1.08-2.27), Medicaid payer status (adjusted hazard ratio 1.47, 95% CI 1.15-1.87), and Charlson-Deyo comorbidity score 1 or higher (adjusted hazard ratio 2.07, 95% CI 1.68-2.56) were all associated with increased risk of dying from cervical cancer. CONCLUSION: Among patients with early-stage cervical cancer, National Comprehensive Cancer Network guideline-nonadherent care was independently associated with increased cervical cancer-specific mortality along with black race and Medicaid payer status. Nonadherence was more prevalent in patients with older age, lower socioeconomic status, and receipt of care in low volume centers. Attention should be paid to increase guideline adherence. PMID- 29630022 TI - Access to Fertility Treatment for Mixed-Status Couples With Human Immunodeficiency Virus. AB - In an effort to place the recent Centers for Disease Control and Prevention Morbidity and Mortality Weekly Report publications regarding conception options for mixed-status couples with human immunodeficiency virus (HIV) in perspective, we review the historical evolution of conception options for mixed-status couples with HIV with particular focus on the potential need for fertility treatment and the feasibility of accessing such treatment. PMID- 29630021 TI - Changing Patterns and Factors Associated With Mode of Delivery Among Pregnant Women With Human Immunodeficiency Virus Infection in the United States. AB - OBJECTIVE: To describe patterns and factors associated with mode of delivery among pregnant women with human immunodeficiency virus (HIV) infection in the United States in relation to evolving HIV-in-pregnancy guidelines. METHODS: We conducted an analysis of two observational studies, Pediatric AIDS Clinical Trials Group and International Maternal Pediatric Adolescent AIDS Clinical Trials Network Protocol P1025, which enrolled pregnant women with HIV infection from 1998 to 2013 at more than 60 U.S. acquired immunodeficiency syndrome clinical research sites. Multivariable analyses of factors associated with an HIV indicated cesarean delivery (ie, for prevention of mother-to-child transmission) compared with other indications were conducted and compared according to prespecified time periods of evolving HIV-in-pregnancy guidelines: 1998-1999, 2000-2008, and 2009-2013. RESULTS: Among 6,444 pregnant women with HIV infection, 21% delivered in 1998-1999, 58% in 2000-2008, and 21% in 2009-2013; 3,025 (47%) delivered by cesarean. Cesarean delivery increased from 30% in 1998 to 48% in 2013. Of all cesarean deliveries, repeat cesarean deliveries increased from 16% in 1998 to 42% in 2013; HIV-indicated cesarean deliveries peaked at 48% in 2004 and then dropped to 12% by 2013. In multivariable analyses, an HIV diagnosis during pregnancy, initiation of antiretroviral therapy in the third trimester, a plasma viral load 500 copies/mL or greater, and delivery between 37 and 40 weeks of gestation increased the likelihood of an HIV-indicated cesarean delivery. In analyses by time period, an HIV diagnosis during pregnancy, initiation of antiretroviral therapy in the third trimester, and a plasma viral load of 500 copies/mL or greater were progressively more likely to be associated with an HIV indicated cesarean delivery over time. CONCLUSION: Almost 50% of pregnant women with HIV infection underwent cesarean delivery. Over time, the rate of repeat cesarean deliveries increased, whereas the rate of HIV-indicated cesarean deliveries decreased; cesarean deliveries were more likely to be performed in women at high risk of mother-to-child transmission. These findings reinforce the need for both early diagnosis and treatment of HIV infection in pregnancy and the option of vaginal delivery after cesarean among pregnant women with HIV infection. PMID- 29630023 TI - Timing of Etonogestrel Implant Insertion After Dilation and Evacuation: A Randomized Controlled Trial. AB - OBJECTIVE: To compare the 6-month use rate of the etonogestrel implant placed immediately after dilation and evacuation (D&E) with placement 2-4 weeks postprocedure. METHODS: This is a randomized controlled trial of women seeking abortion between 14 0/7 and 23 5/7 weeks of gestation and desiring the etonogestrel contraceptive implant at an urban family planning clinic. Participants were randomized to device insertion immediately after the D&E compared with delayed insertion in 2-4 weeks. The primary outcome was implant use rate at 6 months after insertion and was determined by follow-up phone interviews. Secondary outcomes included repeat pregnancy rates and method satisfaction. The sample size of 120 participants was calculated based on a power of 0.80 to demonstrate a 20% difference in implant use rates between groups assuming 40% of women overall are not using the device 6 months after the procedure. RESULTS: Between November 2015 and October 2016, 148 participants were enrolled. Seventy-three participants (49.3%) were randomized to and underwent immediate implant insertion after D&E. The remaining 75 (50.6%) were randomized to delayed insertion. There were no significant differences in sociodemographic characteristics between the groups. Placement rate was 100% in the immediate group compared with 42.7% in the delayed group (P<.01). At 6 months, 40 of 43 (93%) women from the immediate group who completed follow-up continued use of the implant, whereas 19 of 30 (63.3%) women from the delayed group who completed follow-up were using the device (P=.002). Follow-up rates were low at 58.9% in the immediate group compared with 40.0% in the delayed group. CONCLUSION: Women were more likely to be using the etonogestrel implant at 6 months after D&E if they underwent immediate compared with delayed insertion. The very high loss to follow-up rate makes it difficult to draw conclusions about acceptability of the device and pregnancy rates. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, 02037919. PMID- 29630024 TI - An Evaluation of the Implementation of Pharmacist-Prescribed Hormonal Contraceptives in California. AB - OBJECTIVE: To evaluate the implementation of pharmacist-prescribed hormonal contraceptives in California after a recent expansion of pharmacists' scope of practice. METHODS: A probability sample of 480 licensed California retail pharmacies (stratified by nonrural or rural location and independent or chain status) was included in a cross-sectional "secret shopper" telephone survey assessing the availability of pharmacist-prescribed hormonal contraceptives and service details. Survey data were analyzed using weighted descriptive statistics, CIs, and Wald tests. RESULTS: Findings included data from 457 pharmacies (response rate 95.2%). Only 5.1% of pharmacies reported providing pharmacist prescribed hormonal contraceptives (95% CI 2.9-7.2%). This proportion did not differ significantly between rural and nonrural pharmacies (P=.83) nor between independent and chain pharmacies (P=.40). Five of the 22 pharmacies that were providing pharmacist-prescribed hormonal contraceptives informed secret shoppers that all allowed hormonal methods were available; most of these pharmacies (77.3%) did proactively describe that a health history was required before receiving medications. Only half of pharmacies providing pharmacist-prescribed hormonal contraceptives would do so for minors although this was allowed by law. CONCLUSION: In the first year after statewide protocol implementation, only a small proportion of retail pharmacies across California has begun offering hormonal contraception services. In the absence of additional supportive legislation regarding reimbursement for pharmacist services, increases in scope of practice regulations to build a larger network of contraceptive providers may not be effective in increasing access to birth control. PMID- 29630025 TI - Direct Percutaneous Endoscopic Jejunostomy for the Management of Gastroparesis in Pregnancy. AB - BACKGROUND: Providing meaningful nutrition in cases of refractory hyperemesis during pregnancy can be challenging; although intragastric enteral nutrition is the most common approach, it is contraindicated in certain cases and carries the risk of increased nausea and vomiting. CASE: A 36-year-old primigravid woman with a history of gastroparesis presented at 16 weeks of gestation with nausea and vomiting. With no improvement with conventional approaches and signs of malnutrition, a direct percutaneous endoscopic jejunostomy was placed. Her nutritional status improved, and the pregnancy ended in the delivery of a healthy neonate. CONCLUSION: Direct percutaneous endoscopic jejunostomy in pregnancy is an option in patients in whom intragastric feeding is contraindicated and may offer a more secure approach than percutaneous gastrojejunostomy. PMID- 29630026 TI - Making Vital Statistics Count: Preventing U.S. Maternal Deaths Requires Better Data. PMID- 29630027 TI - What Is New in Sexually Transmitted Infections?: Best Articles From the Past Year. AB - This month we focus on current research in sexually transmitted infections. Dr. Ros discusses four recent publications, which are concluded with a "bottom line" that is a take-home message. A complete reference for each can be found in on this page along with direct links to abstracts. PMID- 29630028 TI - Connect the Dots-May 2018. PMID- 29630029 TI - Female adolescents and sexual health: "I think I'm okay, but am I?" PMID- 29630030 TI - HIV Serostatus and Having Access to a Physician for Regular Hepatitis C Virus Care Among People Who Inject Drugs. AB - BACKGROUND: People who inject drugs (PWIDs) and who are living with HIV and hepatitis C virus (HCV) infection are vulnerable to a range of health-related harms, including liver cirrhosis, hepatocellular carcinoma, and death. There is limited evidence describing how HIV serostatus shapes access to a physician for regular HCV care among PWID. SETTING: Data were collected through the Vancouver Injection Drug Users Study (VIDUS), the AIDS Care Cohort to evaluate Exposure to Survival Services (ACCESS), and the At-Risk Youth Study (ARYS), 3 prospective cohorts involving people who use illicit drugs in Vancouver, Canada, between 2005 and 2015. METHODS: Using generalized estimating equations, we examined the relationship between HIV-seropositivity and having access to a physician for regular HCV care. We conducted a mediation analysis to examine whether this association was mediated by increased frequency of engagement in health care. RESULTS: In total, 1627 HCV-positive PWID were eligible for analysis; 582 (35.8%) were HIV-positive at baseline; and 31 (1.9%) became HIV-positive during follow up. In multivariable analyses, after adjusting for a range of confounders, HIV serostatus [adjusted odds ratio = 1.99; 95% confidence interval: 1.77 to 2.24] was significantly associated with having access to HCV care. Approximately 26% of the effect was due to mediation. CONCLUSION: Our results demonstrate a positive relationship between HIV-seropositivity and having access to a physician for regular HCV care, which is partially explained through increased frequency of engagement in health care. These findings highlight the need to address patterns of inequality in access to HCV care among PWID. PMID- 29630031 TI - Elevated Cell-Free Mitochondrial DNA in Filtered Plasma Is Associated With HIV Infection and Inflammation. AB - BACKGROUND: Increased cell-free DNA levels are associated with poor health outcomes, and cell-free mitochondrial DNA (cf-mtDNA) has proinflammatory properties. Given that HIV infection is associated with chronic inflammation, we investigated the relationship between cf-mtDNA and proinflammatory cytokine interleukin-6 (IL-6) in the context of HIV infection. We also optimized separation of cell-free plasma from blood. SETTING: In this retrospective cross sectional study, we collected blood, demographic information, and clinical data from 99 HIV-infected and 103 HIV-uninfected adults and children enrolled in the Children and Women: AntiRetrovirals and Markers of Aging pan-Canadian (CARMA) cohort. METHODS: Plasma was separated from blood by 14,000g centrifugation followed by 0.45-MUm filtration to remove cells and platelets. Cf-mtDNA and cell free nuclear DNA were quantified simultaneously via monochrome, multiplex, quantitative polymerase chain reaction. IL-6 was measured using enzyme-linked immunosorbent assay. RESULTS: Higher speed centrifugation and filtration was necessary to isolate truly cell-free plasma. Higher cf-mtDNA levels were univariately associated with HIV infection, elevated IL-6 levels, younger age, higher white blood cell count, and higher cell-free nuclear DNA levels but not blood mtDNA content or HIV viral load. In a multivariable model, HIV infection (P < 0.001), elevated IL-6 (P = 0.021), younger age (P < 0.001), and higher blood nDNA levels (P = 0.007) were independently associated with higher cf-mtDNA. CONCLUSIONS: People living with HIV have higher levels of circulating cf-mtDNA than their uninfected peers. Increased levels of inflammatory marker IL-6 are associated with elevated cf-mtDNA, independent of the effect of HIV infection. Higher cf-mtDNA levels and white blood cell count in younger people may reflect higher cell turnover in that population. PMID- 29630032 TI - Perineural Versus Systemic Dexamethasone in Front-Foot Surgery Under Ankle Block: A Randomized Double-Blind Study. AB - BACKGROUND AND OBJECTIVES: Among the different adjuvants, dexamethasone is one of the most accepted to prolong the effect of local anesthetics. This study aims to determine the superiority of perineural over systemic dexamethasone administration after a single-shot ankle block in metatarsal osteotomy. METHODS: We performed a prospective, double-blind, randomized study. A total of 100 patients presenting for metatarsal osteotomy with an ankle block were randomized into 2 groups: 30 mL ropivacaine 0.375% + perineural dexamethasone 4 mg (1 mL) + 2.5 mL of systemic saline solution (PNDex group, n = 50) and 30 mL ropivacaine 0.375% + 1 mL of perineural saline solution + intravenous dexamethasone 10 mg (2.5 mL) (IVDex group, n = 50). The primary end point was the duration of analgesia defined as the time between the performance of the ankle block and the first administration of rescue analgesia with tramadol. RESULTS: Time period to first rescue analgesia with tramadol was similar in the IVDex group and the PNDex group. Data are expressed as mean (SD) or median (range). Duration of analgesia was 23.2 (9.5) hours in the IVDex group and 19 (8.2) hours in the PNDex group (P = 0.4). Consumption of tramadol during the first 48 hours was 0 mg (0-150 mg) in the IVDex group versus 0 mg (0-250 mg) in the PNDex group (P = 0.59). Four (8%) and 12 (24%) patients reported nausea or vomiting in the IVDex group and the PNDex group, respectively (P = 0.03). CONCLUSIONS: In front-foot surgery, perineural and systemic administrations of dexamethasone are equivalent for postoperative pain relief when used as an adjuvant to ropivacaine ankle block. CLINICAL TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov, identifier NCT02904538. PMID- 29630033 TI - A Randomized Comparison Between Interscalene and Small-Volume Supraclavicular Blocks for Arthroscopic Shoulder Surgery. AB - BACKGROUND AND OBJECTIVES: This randomized trial compared ultrasound (US)-guided interscalene block (ISB) and small-volume supraclavicular block (SCB) for arthroscopic shoulder surgery. We hypothesized that SCB would provide equivalent analgesia to ISB 30 minutes after surgery without the risk of hemidiaphragmatic paralysis (HDP). METHODS: All patients received an US-guided intermediate cervical plexus block. In the ISB group, US-guided ISB was performed with 20 mL of levobupivacaine 0.5% and epinephrine 5 MUg/mL. In the SCB group, US-guided SCB was carried out using 20 mL of the same local anesthetic agent: 3 and 17 mL were deposited at the "corner pocket" (ie, intersection of the first rib and subclavian artery) and posterolateral to the brachial plexus, respectively. A blinded investigator assessed ISBs and SCBs every 5 minutes until 30 minutes using a composite scale that encompassed the sensory function of the supraclavicular nerves, the sensorimotor function of the axillary nerve, and the motor function of the suprascapular nerve. We considered the blocks complete if, at 30 minutes, a composite score equal or superior to 6 points (out of 8 points) was achieved. Thus, onset time was defined as the time required to reach a minimal composite score of 6 points. The blinded investigator also assessed the presence of HDP at 30 minutes with US. Subsequently, all patients underwent general anesthesia. Postoperatively, a blinded investigator recorded pain scores at rest at 0.5, 1, 2, 3, 6, 12, and 24 hours. Patient satisfaction at 24 hours, consumption of intraoperative and postoperative narcotics, and opioid-related adverse effects were also tabulated. RESULTS: Both groups displayed equivalent postoperative pain scores at 0.5, 1, 2, 3, 6, 12, and 24 hours. Interscalene blocks resulted in a higher incidence of HDP (95% vs 9%; P < 0.001), a shorter onset time, and a higher proportion of patients with minimal composite scores of 6 points at 30 minutes (100% vs 77%; P = 0.048). However, no intergroup differences were found in terms of performance time, procedural pain, number of needle passes, intraoperative/postoperative opioid consumption, adverse effects, and patient satisfaction at 24 hours. CONCLUSIONS: Compared with ISB, small volume SCB results in equivalent postoperative analgesia and a lower incidence of HDP. Because the latter cannot be completely avoided with small-volume SCB, further trials are required to investigate the optimal diaphragm-sparing nerve block for shoulder surgery. CLINICAL TRIAL REGISTRATION: This study was registered at ClinicalTrials.gov, identifier NCT03224884. PMID- 29630034 TI - Effective Dose of Intravenous Dexmedetomidine to Prolong the Analgesic Duration of Interscalene Brachial Plexus Block: A Single-Center, Prospective, Double Blind, Randomized Controlled Trial. AB - BACKGROUND AND OBJECTIVES: Intravenous (IV) dexmedetomidine (DEX) is reported to prolong the analgesic duration after single-shot interscalene brachial plexus block (ISBPB). However, the effective analgesic dose of IV DEX remains undetermined. Therefore, we aimed to elucidate the clinically relevant dose of IV DEX to prolong the analgesic duration of ISBPB. METHODS: Seventy-two patients scheduled for arthroscopic shoulder surgery received ISBPB with 15 mL of 0.5% ropivacaine with 1:200,000 epinephrine and were randomly assigned to 1 of 4 groups (n = 18, each): (1) IV normal saline (control), (2) IV DEX 0.5 MUg/kg (DEX 0.5), (3) IV DEX 1.0 MUg/kg (DEX 1.0), and (4) IV DEX 2.0 MUg/kg (DEX 2.0). The primary outcome was time to the first pain at surgical site. RESULTS: The median (interquartile range) duration of analgesia was significantly prolonged for the DEX 2.0 (874 minutes [727-1153 minutes]) compared with 656 minutes (590-751 minutes), 703 minutes (644-761 minutes), and 696 minutes (615-814 minutes) for the control, DEX 0.5 and DEX 1.0 groups, respectively (P = 0.001, P = 0.008, and P = 0.003, respectively). Postoperative cumulative IV morphine equivalent consumption at 24 hours was significantly lower in the DEX 2.0 compared with the control, DEX 0.5 and DEX 1.0 groups (P < 0.001, P < 0.001, and P = 0.007, respectively). There were no significant differences in the incidence of intraoperative hypotension and the number of patients who required ephedrine after the pairwise group analysis. Also, there were no significant differences on the durations of motor blockade and sedation and the incidence of bradycardia. CONCLUSIONS: Intravenous DEX at a dose of 2.0 MUg/kg significantly increased the duration of ISBPB analgesia without prolonging motor blockade and reduced the cumulative opioid consumption at the first 24 hours in patients undergoing arthroscopic shoulder surgery. CLINICAL TRIAL REGISTRATION: This study was registered at the Clinical Trial Registry of Korea, identifier KCT0002119. PMID- 29630035 TI - An Optogenetic Method to Control and Analyze Gene Expression Patterns in Cell-to cell Interactions. AB - Cells should respond properly to temporally changing environments, which are influenced by various factors from surrounding cells. The Notch signaling pathway is one of such essential molecular machinery for cell-to-cell communications, which plays key roles in normal development of embryos. This pathway involves a cell-to-cell transfer of oscillatory information with ultradian rhythms, but despite the progress in molecular biology techniques, it has been challenging to elucidate the impact of multicellular interactions on oscillatory gene dynamics. Here, we present a protocol that permits optogenetic control and live monitoring of gene expression patterns in a precise temporal manner. This method successfully revealed that intracellular and intercellular periodic inputs of Notch signaling entrain intrinsic oscillations by frequency tuning and phase shifting at the single-cell resolution. This approach is applicable to the analysis of the dynamic features of various signaling pathways, providing a unique platform to test a functional significance of dynamic gene expression programs in multicellular systems. PMID- 29630036 TI - Paraffin Embedding and Thin Sectioning of Microbial Colony Biofilms for Microscopic Analysis. AB - Sectioning via paraffin embedding is a broadly established technique in eukaryotic systems. Here we provide a method for the fixation, embedding, and sectioning of intact microbial colony biofilms using perfused paraffin wax. To adapt this method for use on colony biofilms, we developed techniques for maintaining each sample on its growth substrate and laminating it with an agar overlayer, and added lysine to the fixative solution. These optimizations improve sample retention and preservation of micromorphological features. Samples prepared in this manner are amenable to thin sectioning and imaging by light, fluorescence, and transmission electron microscopy. We have applied this technique to colony biofilms of Pseudomonas aeruginosa, Pseudomonas synxantha, Bacillus subtilis, and Vibrio cholerae. The high level of detail visible in samples generated by this method, combined with reporter strain engineering or the use of specific dyes, can provide exciting insights into the physiology and development of microbial communities. PMID- 29630037 TI - A Recovery Cardiopulmonary Bypass Model Without Transfusion or Inotropic Agents in Rats. AB - Cardiopulmonary bypass (CPB) is indispensable in cardiovascular surgery. Despite the dramatic refinement of CPB technique and devices, multi-organ complications related to prolonged CPB still compromise the outcome of cardiovascular surgeries, and may worsen postoperative morbidity and mortality. Animal models recapitulating the clinical usage of CPB enable the clarification of the pathophysiological processes that occur during CPB, and facilitate pre-clinical studies to develop strategies protecting against these complications. Rat CPB models are advantageous because of their greater cost-effectiveness, convenient experimental processes, abundant testing methods at the genetic or protein levels, and genetic consistency. They can be used for investigating the immune system activation and synthesis of proinflammatory cytokines, compliment activation, and production of oxygen free radicals. The rat models have been refined and have gradually taken the place of large-animal models. Here, we describe a simple CPB model without transfusion and/or inotropic agents in a rat. This recovery model allows the study of the long-term multiple organ sequelae of CPB. PMID- 29630038 TI - Atmospheric Pressure Fabrication of Large-Sized Single-Layer Rectangular SnSe Flakes. AB - Tin selenide (SnSe) belongs to the family of layered metal chalcogenide materials with a buckled structure like phosphorene, and has shown potential for applications in two-dimensional nanoelectronics devices. Although many methods to synthesize SnSe nanocrystals have been developed, a simple way to fabricate large sized single-layer SnSe flakes remains a great challenge. Herein, we show the experimental method to directly grow large-sized single-layer rectangular SnSe flakes on commonly used SiO2/Si insulating substrates using a straightforward two step fabrication method in an atmospheric pressure quartz tube furnace system. The single-layer rectangular SnSe flakes with an average thickness of ~6.8 A and lateral dimensions of about 30 um * 50 um were fabricated by a combination of vapor transport deposition technique and nitrogen etching route. We characterized the morphology, microstructure, and electrical properties of the rectangular SnSe flakes and obtained excellent crystallinity and good electronic properties. This article about the two-step fabrication method can help researchers grow other similar two-dimensional, large-sized, single-layer materials using an atmospheric pressure system. PMID- 29630039 TI - G2-seq: A High Throughput Sequencing-based Technique for Identifying Late Replicating Regions of the Genome. AB - Numerous techniques have been developed to follow the progress of DNA replication through the S phase of the cell cycle. Most of these techniques have been directed toward elucidation of the location and timing of initiation of genome duplication rather than its completion. However, it is critical that we understand regions of the genome that are last to complete replication, because these regions suffer elevated levels of chromosomal breakage and mutation, and they have been associated with both disease and aging. Here we describe how we have extended a technique that has been used to monitor replication initiation to instead identify those regions of the genome last to complete replication. This approach is based on a combination of flow cytometry and high throughput sequencing. Although this report focuses on the application of this technique to yeast, the approach can be used with any cells that can be sorted in a flow cytometer according to DNA content. PMID- 29630040 TI - Gel-seq: A Method for Simultaneous Sequencing Library Preparation of DNA and RNA Using Hydrogel Matrices. AB - The ability to amplify and sequence either DNA or RNA from small starting samples has only been achieved in the last five years. Unfortunately, the standard protocols for generating genomic or transcriptomic libraries are incompatible and researchers must choose whether to sequence DNA or RNA for a particular sample. Gel-seq solves this problem by enabling researchers to simultaneously prepare libraries for both DNA and RNA starting with 100 - 1000 cells using a simple hydrogel device. This paper presents a detailed approach for the fabrication of the device as well as the biological protocol to generate paired libraries. We designed Gel-seq so that it could be easily implemented by other researchers; many genetics labs already have the necessary equipment to reproduce the Gel-seq device fabrication. Our protocol employs commonly-used kits for both whole transcript amplification (WTA) and library preparation, which are also likely to be familiar to researchers already versed in generating genomic and transcriptomic libraries. Our approach allows researchers to bring to bear the power of both DNA and RNA sequencing on a single sample without splitting and with negligible added cost. PMID- 29630041 TI - Tracking Drosophila Larval Behavior in Response to Optogenetic Stimulation of Olfactory Neurons. AB - The ability of insects to navigate toward odor sources is based on the activities of their first-order olfactory receptor neurons (ORNs). While a considerable amount of information has been generated regarding ORN responses to odorants, the role of specific ORNs in driving behavioral responses remains poorly understood. Complications in behavior analyses arise due to different volatilities of odorants that activate individual ORNs, multiple ORNs activated by single odorants, and the difficulty in replicating naturally observed temporal variations in olfactory stimuli using conventional odor-delivery methods in the laboratory. Here, we describe a protocol that analyzes Drosophila larval behavior in response to simultaneous optogenetic stimulation of its ORNs. The optogenetic technology used here allows for specificity of ORN activation and precise control of temporal patterns of ORN activation. Corresponding larval movement is tracked, digitally recorded, and analyzed using custom written software. By replacing odor stimuli with light stimuli, this method allows for a more precise control of individual ORN activation in order to study its impact on larval behavior. Our method could be further extended to study the impact of second-order projection neurons (PNs) as well as local neurons (LNs) on larval behavior. This method will thus enable a comprehensive dissection of olfactory circuit function and complement studies on how olfactory neuron activities translate in to behavior responses. PMID- 29630042 TI - An Objective and Reproducible Test of Olfactory Learning and Discrimination in Mice. AB - Olfaction is the predominant sensory modality in mice and influences many important behaviors, including foraging, predator detection, mating, and parenting. Importantly, mice can be trained to associate novel odors with specific behavioral responses to provide insight into olfactory circuit function. This protocol details the procedure for training mice on a Go/No-Go operant learning task. In this approach, mice are trained on hundreds of automated trials daily for 2-4 weeks and can then be tested on novel Go/No-Go odor pairs to assess olfactory discrimination, or be used for studies on how odor learning alters the structure or function of the olfactory circuit. Additionally, the mouse olfactory bulb (OB) features ongoing integration of adult-born neurons. Interestingly, olfactory learning increases both the survival and synaptic connections of these adult-born neurons. Therefore, this protocol can be combined with other biochemical, electrophysiological, and imaging techniques to study learning and activity-dependent factors that mediate neuronal survival and plasticity. PMID- 29630043 TI - Characterization of Cell Membrane Extensions and Studying Their Roles in Cancer Cell Adhesion Dynamics. AB - The cell membrane's extension repertoire modulates various malignant behaviors of cancer cells, including their adhesive and migratory potentials. The ability to accurately classify and quantify cell extensions and measure the effect on a cell's adhesive capacity is critical to determining how cell-signaling events impact cancer cell behavior and aggressiveness. Here, we describe the in vitro design and use of a cell extension quantification method in conjunction with an adhesion capacity assay in an established in vitro model for adrenocortical carcinoma (ACC). Specifically, we test the effects of DKK3, a putative tumor suppressor and a pro-differentiation factor, on the membrane extension phenotype of the ACC cell line, SW-13. We propose these assays to provide relatively simple, reliable, and easily interpretable metrics to measures these characteristics under various experimental conditions. PMID- 29630044 TI - High-resolution Volume Imaging of Neurons by the Use of Fluorescence eXclusion Method and Dedicated Microfluidic Devices. AB - Volume is an important parameter regarding physiological and pathological characteristics of neurons at different time scales. Neurons are quite unique cells regarding their extended ramified morphologies and consequently raise several methodological challenges for volume measurement. In the particular case of in vitro neuronal growth, the chosen methodology should include sub micrometric axial resolution combined with full-field observation on time scales from minutes to hours or days. Unlike other methods like cell shape reconstruction using confocal imaging, electrically-based measurements or Atomic Force Microscopy, the recently developed Fluorescence eXclusion method (FXm) has the potential to fulfill these challenges. However, although being simple in its principle, implementation of a high-resolution FXm for neurons requires multiple adjustments and a dedicated methodology. We present here a method based on the combination of fluorescence exclusion, low-roughness multi-compartments microfluidic devices, and finally micropatterning to achieve in vitro measurements of local neuronal volume. The high resolution provided by the device allowed us to measure the local volume of neuronal processes (neurites) and the volume of some specific structures involved in neuronal growth, such as growth cones (GCs). PMID- 29630045 TI - Investigation of Protein Recruitment to DNA Lesions Using 405 Nm Laser Micro irradiation. AB - The DNA Damage Response (DDR) uses a plethora of proteins to detect, signal, and repair DNA lesions. Delineating this response is critical to understand genome maintenance mechanisms. Since recruitment and exchange of proteins at lesions are highly dynamic, their study requires the ability to generate DNA damage in a rapid and spatially-delimited manner. Here, we describe procedures to locally induce DNA damage in human cells using a commonly available laser-scanning confocal microscope equipped with a 405 nm laser line. Accumulation of genome maintenance factors at laser stripes can be assessed by immunofluorescence (IF) or in real-time using proteins tagged with fluorescent reporters. Using phosphorylated histone H2A.X (gamma-H2A.X) and Replication Protein A (RPA) as markers, the method provides sufficient resolution to discriminate locally recruited factors from those that spread on adjacent chromatin. We further provide ImageJ-based scripts to efficiently monitor the kinetics of protein relocalization at DNA damage sites. These refinements greatly simplify the study of the DDR dynamics. PMID- 29630046 TI - Multimodal Hierarchical Imaging of Serial Sections for Finding Specific Cellular Targets within Large Volumes. AB - Targeting specific cells at ultrastructural resolution within a mixed cell population or a tissue can be achieved by hierarchical imaging using a combination of light and electron microscopy. Samples embedded in resin are sectioned into arrays consisting of ribbons of hundreds of ultrathin sections and deposited on pieces of silicon wafer or conductively coated coverslips. Arrays are imaged at low resolution using a digital consumer like smartphone camera or light microscope (LM) for a rapid large area overview, or a wide field fluorescence microscope (fluorescence light microscopy (FLM)) after labeling with fluorophores. After post-staining with heavy metals, arrays are imaged in a scanning electron microscope (SEM). Selection of targets is possible from 3D reconstructions generated by FLM or from 3D reconstructions made from the SEM image stacks at intermediate resolution if no fluorescent markers are available. For ultrastructural analysis, selected targets are finally recorded in the SEM at high-resolution (a few nanometer image pixels). A ribbon-handling tool that can be retrofitted to any ultramicrotome is demonstrated. It helps with array production and substrate removal from the sectioning knife boat. A software platform that allows automated imaging of arrays in the SEM is discussed. Compared to other methods generating large volume EM data, such as serial block face SEM (SBF-SEM) or focused ion beam SEM (FIB-SEM), this approach has two major advantages: (1) The resin-embedded sample is conserved, albeit in a sliced-up version. It can be stained in different ways and imaged with different resolutions. (2) As the sections can be post-stained, it is not necessary to use samples strongly block-stained with heavy metals to introduce contrast for SEM imaging or render the tissue blocks conductive. This makes the method applicable to a wide variety of materials and biological questions. Particularly prefixed materials e.g., from biopsy banks and pathology labs, can directly be embedded and reconstructed in 3D. PMID- 29630047 TI - Simple and Rapid Method to Obtain High-quality Tumor DNA from Clinical pathological Specimens Using Touch Imprint Cytology. AB - It is critical to determine the mutational status in cancer before administration and treatment of specific molecular targeted drugs for cancer patients. In the clinical setting, formalin-fixed paraffin-embedded (FFPE) tissues are widely used for genetic testing. However, FFPE DNA is generally damaged and fragmented during the fixation process with formalin. Therefore, FFPE DNA is sometimes not adequate for genetic testing because of low quality and quantity of DNA. Here we present a method of touch imprint cytology (TIC) to obtain genomic DNA from cancer cells, which can be observed under a microscope. Cell morphology and cancer cell numbers can be evaluated using TIC specimens. Furthermore, the extraction of genomic DNA from TIC samples can be completed within two days. The total amount and quality of TIC DNA obtained using this method was higher than that of FFPE DNA. This rapid and simple method allows researchers to obtain high-quality DNA for genetic testing (e.g., next generation sequencing analysis, digital PCR, and quantitative real time PCR) and to shorten the turnaround time for reporting results. PMID- 29630048 TI - A Method for Targeted 16S Sequencing of Human Milk Samples. AB - Studies of microbial communities have become widespread with the development of relatively inexpensive, rapid, and high throughput sequencing. However, as with all these technologies, reproducible results depend on a laboratory workflow that incorporates appropriate precautions and controls. This is particularly important with low-biomass samples where contaminating bacterial DNA can generate misleading results. This article details a semi-automated workflow to identify microbes from human breast milk samples using targeted sequencing of the 16S ribosomal RNA (rRNA) V4 region on a low- to mid-throughput scale. The protocol describes sample preparation from whole milk including: sample lysis, nucleic acid extraction, amplification of the V4 region of the 16S rRNA gene, and library preparation with quality control measures. Importantly, the protocol and discussion consider issues that are salient to the preparation and analysis of low-biomass samples including appropriate positive and negative controls, PCR inhibitor removal, sample contamination by environmental, reagent, or experimental sources, and experimental best practices designed to ensure reproducibility. While the protocol as described is specific to human milk samples, it is adaptable to numerous low- and high-biomass sample types, including samples collected on swabs, frozen neat, or stabilized in a preservation buffer. PMID- 29630049 TI - Phthalic Acid Ester-Binding DNA Aptamer Selection, Characterization, and Application to an Electrochemical Aptasensor. AB - Phthalic acid esters (PAEs) areone of the major groups of persistent organic pollutants. The group-specific detection of PAEs is highly desired due to the rapid growing of congeners. DNA aptamers have been increasingly applied as recognition elements on biosensor platforms, but selecting aptamers toward highly hydrophobic small molecule targets, such as PAEs, is rarely reported. This work describes a bead-based method designed to select group-specific DNA aptamers to PAEs. The amino group functionalized dibutyl phthalate (DBP-NH2) as the anchor target was synthesized and immobilized on the epoxy-activated agarose beads, allowing the display of the phthalic ester group at the surface of the immobilization matrix, and therefore the selection of the group-specific binders. We determined the dissociation constants of the aptamer candidates by quantitative polymerization chain reaction coupled with magnetic separation. The relative affinities and selectivity of the aptamers to other PAEs were determined by the competitive assays, where the aptamer candidates were pre-bounded to the DBP-NH2 attached magnetic beads and released to the supernatant upon incubation with the tested PAEs or other potential interfering substances. The competitive assay was applied because it provided a facile affinity comparison among PAEs that had no functional groups for surface immobilization. Finally, we demonstrated the fabrication of an electrochemical aptasensor and used it for ultrasensitive and selective detection of bis(2-ethylhexyl) phthalate. This protocol provides insights for the aptamer discovery of other hydrophobic small molecules. PMID- 29630050 TI - A Minimally Invasive Model to Analyze Endochondral Fracture Healing in Mice Under Standardized Biomechanical Conditions. AB - Bone healing models are necessary to analyze the complex mechanisms of fracture healing to improve clinical fracture treatment. During the last decade, an increased use of mouse models in orthopedic research was noted, most probably because mouse models offer a large number of genetically-modified strains and special antibodies for the analysis of molecular mechanisms of fracture healing. To control the biomechanical conditions, well-characterized osteosynthesis techniques are mandatory, also in mice. Here, we report on the design and use of a closed bone healing model to stabilize femur fractures in mice. The intramedullary screw, made of medical-grade stainless steel, provides through fracture compression an axial and rotational stability compared to the mostly used simple intramedullary pins, which show a complete lack of axial and rotational stability. The stability achieved by the intramedullary screw allows the analysis of endochondral healing. A large amount of callus tissue, received after stabilization with the screw, offers ideal conditions to harvest tissue for biochemical and molecular analyses. A further advantage of the use of the screw is the fact that the screw can be inserted into the femur with a minimally invasive technique without inducing damage to the soft tissue. In conclusion, the screw is a unique implant that can ideally be used in closed fracture healing models offering standardized biomechanical conditions. PMID- 29630051 TI - Flow Cytometry to Estimate Leukemia Stem Cells in Primary Acute Myeloid Leukemia and in Patient-derived-xenografts, at Diagnosis and Follow Up. AB - Acute myeloid leukemia (AML) is a heterogeneous, and if not treated, fatal disease. It is the most common cause of leukemia-associated mortality in adults. Initially, AML is a disease of hematopoietic stem cells (HSC) characterized by arrest of differentiation, subsequent accumulation of leukemia blast cells, and reduced production of functional hematopoietic elements. Heterogeneity extends to the presence of leukemia stem cells (LSC), with this dynamic cell compartment evolving to overcome various selection pressures imposed upon during leukemia progression and treatment. To further define the LSC population, the addition of CD90 and CD45RA allows the discrimination of normal HSCs and multipotent progenitors within the CD34+CD38- cell compartment. Here, we outline a protocol to detect simultaneous expression of several putative LSC markers (CD34, CD38, CD45RA, CD90) on primary blast cells of human AML by multiparametric flow cytometry. Furthermore, we show how to quantify three progenitor populations and a putative LSC population with increasing degree of maturation. We confirmed the presence of these populations in corresponding patient-derived-xenografts. This method of detection and quantification of putative LSC may be used for clinical follow-up of chemotherapy response (i.e., minimal residual disease), as residual LSC may cause AML relapse. PMID- 29630052 TI - From Molecules to Materials: Engineering New Ionic Liquid Crystals Through Halogen Bonding. AB - Herein, we demonstrate that a bottom-up approach, based on halogen bonding (XB), can be successfully applied for the design of a new type of ionic liquid crystals (ILCs). Taking advantages of the high specificity of XB for haloperfluorocarbons and the ability of anions to act as XB-acceptors, we obtained supramolecular complexes based on 1-alkyl-3-methylimidazolium iodides and iodoperfluorocarbons, overcoming the well-known immiscibility between hydrocarbons (HCs) and perfluorocarbons (PFCs). The high directionality of the XB combined with the fluorophobic effect, allowed us to obtain enantiotropic liquid crystals where a rigid, non-aromatic, XB supramolecular anion acts as mesogenic core. X-ray structure analysis of the complex between 1-ethyl-3-methylimidazolium iodide and iodoperfluorooctane showed the presence of a layered structure, which is a manifestation of the well-known tendency to segregation of perfluoroalkyl chains. This is consistent with the observation of smectic mesophases. Moreover, all the reported complexes melt below 100 degrees C, and most are mesomorphic even at room temperature, despite that the starting materials were non-mesomorphic in nature. The supramolecular strategy reported here provides new design principles for mesogen design allowing a totally new class of functional materials. PMID- 29630053 TI - Formation of Covalent DNA Adducts by Enzymatically Activated Carcinogens and Drugs In Vitro and Their Determination by 32P-postlabeling. AB - Covalent DNA adducts formed by chemicals or drugs with carcinogenic potency are judged as one of the most important factors in the initiation phase of carcinogenic processes. This covalent binding, which is considered the cause of tumorigenesis, is now evaluated as a central dogma of chemical carcinogenesis. Here, methods are described employing the reactions catalyzed by cytochrome P450 and additional biotransformation enzymes to investigate the potency of chemicals or drugs for their activation to metabolites forming these DNA adducts. Procedures are presented describing the isolation of cellular fractions possessing biotransformation enzymes (microsomal and cytosolic samples with cytochromes P450 or other biotransformation enzymes, i.e., peroxidases, NADPH:cytochrome P450 oxidoreductase, NAD(P)H:quinone oxidoreductase, or xanthine oxidase). Furthermore, methods are described that can be used for the metabolic activation of analyzed chemicals by these enzymes as well as those for isolation of DNA. Further, the appropriate methods capable of detecting and quantifying chemical/drug-derived DNA adducts, i.e., different modifications of the 32P postlabeling technique and employment of radioactive-labeled analyzed chemicals, are shown in detail. PMID- 29630054 TI - Technique and Patient Selection Criteria of Right Anterior Mini-Thoracotomy for Minimal Access Aortic Valve Replacement. AB - Aortic valve stenosis has become the most prevalent valvular heart disease in developed countries, and is due to the aging of these populations. The incidence of the pathology increases with growing age after 65 years. Conventional surgical aortic valve replacement through median sternotomy has been the gold standard of patient care for symptomatic aortic valve stenosis. However, as the risk profile of patients worsens, other therapeutic strategies have been introduced in an attempt to maintain the excellent results obtained by the established surgical treatment. One of these approaches is represented by transcatheter aortic valve implantation. Although the outcomes of high-risk patients undergoing treatment for symptomatic aortic valve stenosis have improved with transcatheter aortic valve replacement, many patients with this condition remain candidates for surgical aortic valve replacement. In order to reduce the surgical trauma in patients who are candidates for surgical aortic valve replacement, minimally invasive approaches have garnered interest during the past decade. Since the introduction of right anterior thoracotomy for aortic valve replacement in 1993, right anterior mini-thoracotomy and upper hemi-sternotomy have become the predominant incisional approaches among cardiac surgeons performing minimal access aortic valve replacement. Beside the location of the incision, the arterial cannulation site represents the second major landmark of minimal access techniques for aortic valve replacement. The two most frequently used arterial cannulation sites include central aortic and peripheral femoral approaches. With the purpose of reducing surgical trauma in these patients, we have opted for a right anterior mini-thoracotomy approach with a central aortic cannulation site. This protocol describes in detail a technique for minimally invasive aortic valve replacement and provides recommendations for patient selection criteria, including cardiac computer tomography measurements. The indications and limitations of this technique, as well as its alternatives, are discussed. PMID- 29630055 TI - Use of Anti-phospho-girdin Antibodies to Visualize Intestinal Tuft Cells in Free Floating Mouse Jejunum Cryosections. AB - The actin binding protein girdin is a cytosolic protein that is required for actin remodeling to trigger cell migration in various tissues. Girdin is phosphorylated by both receptor and non-receptor tyrosine kinases at tyrosine 1798. Omori et al. developed site- and phosphorylation status-specific antibodies against human girdin at tyrosine-1798 (pY1798), which specifically bind to phosphorylated tyrosine-1798, but not to unphosphorylated tyrosine-1798. pY1798 antibodies have been used to specifically label tuft cells (TCs) that are present in mammalian gastrointestinal tissues, but the function of these cells is unclear. This protocol allows the robust visualization of TCs in the jejunum using pY1798 antibodies and immunofluorescence. To ensure successful and simple TC visualization, this protocol includes two histological techniques: production of free-floating cryosections from gelatin-filled jejunum tissue, and low temperature antigen retrieval at 50 degrees C for 3 h. Filling the jejunum with gelatin maintains the shape of free-floating sections throughout the staining procedure, whereas low-temperature antigen retrieval ensures robust signals from TCs. Successful use of this protocol results in pY1798 staining of TCs distributed from villus tip to crypt. Stained TCs have a spool-shaped soma and fluorescent signals condense at the lumenal tip, which corresponds to the protruding 'tuft.' Phalloidin staining colocalized with pY1798-positive TCs at the thickened brush border, and corresponds to a rootlet mass extending from the TC tuft. This protocol could be used to examine TCs in human biopsy samples collected with gastrointestinal endoscopes. Furthermore, TCs were recently reported to accumulate following parasite infection in mice, suggesting that this protocol could have applications for diagnosis of parasite infections in the human gut. PMID- 29630056 TI - Electrochemiluminescence Assays for Human Islet Autoantibodies. AB - Pinpointing islet autoantibodies associated with type 1 diabetes (T1D) leads the way to project and deter this disease in the general population. A novel ECL assay is a nonradioactive fluid phase assay for islet autoantibodies with higher sensitivity and specificity than the current 'gold' standard radio-binding assay (RBA). ECL assays can more precisely define the onset of presymptomatic T1D by distinguishing the high-risk, high-affinity autoantibodies from the low-risk, low affinity autoantibodies generated in RBAs, and conventional enzyme-linked immunosorbent assays (ELISA). The antigen protein used in this ECL assay is labeled with Sulfo-tag and Biotin, respectively. Each ECL autoantibody assay that uses a particular antigen protein needs an optimization step before it can be used for laboratory application. This step is especially vital in determining the requirements for serum acid treatments, concentrations, and ratios of the two different antigens labeled with Sulfo-tag and Biotin. To perform the assay, serum samples are mixed with Sulfo-tag-conjugated and biotinylated capture antigen protein in phosphate buffered solution (PBS), containing 5% Bovine Serum Albumin (BSA). Afterwards, the samples are incubated overnight at 4 degrees C. The same day, a streptavidin-coated plate is prepared with blocker buffer and incubated overnight at 4 degrees C. On the second day, wash the streptavidin plate and transfer the serum-antigen mixture onto the plate. Place the plate on the plate shaker, set it at low speed, and incubate at room temperature for 1 h. Subsequently, the plate is washed again, and reader buffer is added. The plate is then counted on the plate reader machine. The results are conveyed through an index, which is generated from internal standard positive and negative control serum samples. PMID- 29630057 TI - A Simple Method for High Throughput Chemical Screening in Caenorhabditis Elegans. AB - Caenorhabditis elegans is a useful organism for testing chemical effects on physiology. Whole organism small molecule screens offer significant advantages for identifying biologically active chemical structures that can modify complex phenotypes such as lifespan. Described here is a simple protocol for producing hundreds of 96-well culture plates with fairly consistent numbers of C. elegans in each well. Next, we specified how to use these cultures to screen thousands of chemicals for effects on the lifespan of the nematode C. elegans. This protocol makes use of temperature sensitive sterile strains, agar plate conditions, and simple animal handling to facilitate the rapid and high throughput production of synchronized animal cultures for screening. PMID- 29630058 TI - Chemical Amputation and Regeneration of the Pharynx in the Planarian Schmidtea mediterranea. AB - Planarians are flatworms that are extremely efficient at regeneration. They owe this ability to a large number of stem cells that can rapidly respond to any type of injury. Common injury models in these animals remove large amounts of tissue, which damages multiple organs. To overcome this broad tissue damage, we describe here a method to selectively remove a single organ, the pharynx, in the planarian Schmidtea mediterranea. We achieve this by soaking animals in a solution containing the cytochrome oxidase inhibitor sodium azide. Brief exposure to sodium azide causes extrusion of the pharynx from the animal, which we call "chemical amputation." Chemical amputation removes the entire pharynx, and generates a small wound where the pharynx attaches to the intestine. After extensive rinsing, all amputated animals regenerate a fully functional pharynx in approximately one week. Stem cells in the rest of the body drive regeneration of the new pharynx. Here, we provide a detailed protocol for chemical amputation, and describe both histological and behavioral methods to assess successful amputation and regeneration. PMID- 29630059 TI - Model Surgical Training: Skills Acquisition in Fetoscopic Laser Photocoagulation of Monochorionic Diamniotic Twin Placenta Using Realistic Simulators. AB - Fetoscopic laser coagulation of arterio-venous anastomoses (AVA) in a monochorionic placenta is the standard of care for twin-twin transfusion syndrome (TTTS), but is technically challenging and can lead to significant complications. Acquiring and maintaining the necessary surgical skills require consistent practice, a critical caseload, and time. Training on realistic surgical simulators can potentially shorten this steep learning curve and enables several proceduralists to acquire procedure-specific skills simultaneously. Here we describe realistic simulators designed to allow the user familiarity with the equipment and specific steps required in the surgical treatment of TTTS, including fetoscopic handling, approaches to anterior and posterior placenta, recognition of anastomoses, and efficient coagulation of vessels. We describe the skills that are especially important in conducting placental laser coagulation that the surgeon can practice on the model and apply in a clinical case. These models can be adapted easily depending on the availability of materials and require standard fetoscopy equipment. Such training systems are complementary to traditional surgical apprenticeships and can be useful aids for fetal medicine units that provide this clinical service. PMID- 29630061 TI - FateID infers cell fate bias in multipotent progenitors from single-cell RNA-seq data. AB - To understand stem cell differentiation along multiple lineages, it is necessary to resolve heterogeneous cellular states and the ancestral relationships between them. We developed a robotic miniaturized CEL-Seq2 implementation to carry out deep single-cell RNA-seq of ~2,000 mouse hematopoietic progenitors enriched for lymphoid lineages, and used an improved clustering algorithm, RaceID3, to identify cell types. To resolve subtle transcriptome differences indicative of lineage biases, we developed FateID, an iterative supervised learning algorithm for the probabilistic quantification of cell fate bias in progenitor populations. Here we used FateID to delineate domains of fate bias and enable the derivation of high-resolution differentiation trajectories, thereby revealing a common progenitor population of B cells and plasmacytoid dendritic cells, which we validated by in vitro differentiation assays. We expect that FateID will improve understanding of the process of cell fate choice in complex multi-lineage differentiation systems. PMID- 29630060 TI - Systematic Assessment of Well-Being in Mice for Procedures Using General Anesthesia. AB - In keeping with the 3R Principle (Replacement, Reduction, Refinement) developed by Russel and Burch, scientific research should use alternatives to animal experimentation whenever possible. When there is no alternative to animal experimentation, the total number of laboratory animals used should be the minimum needed to obtain valuable data. Moreover, appropriate refinement measures should be applied to minimize pain, suffering, and distress accompanying the experimental procedure. The categories used to classify the degree of pain, suffering, and distress are non-recovery, mild, moderate, or severe (EU Directive 2010/63). To determine which categories apply in individual cases, it is crucial to use scientifically sound tools. The well-being-assessment protocol presented here is designed for procedures during which general anesthesia is used. The protocol focuses on home cage activity, the Mouse Grimace Scale, and luxury behaviors such as burrowing and nest building behavior as indicators of well being. It also uses the free exploratory paradigm for trait anxiety-related behavior. Fecal corticosterone metabolites as indicators of acute stress are measured over the 24-h post-anesthetic period. The protocol provides scientifically solid information on the well-being of mice following general anesthesia. Due to its simplicity, the protocol can easily be adapted and integrated in a planned study. Although it does not provide a scale to classify distress in categories according to the EU Directive 2010/63, it can help researchers estimate the degree of severity of a procedure using scientifically sound data. It provides a way to improve the assessment of well-being in a scientific, animal-centered manner. PMID- 29630062 TI - Real-time 3D single-molecule localization using experimental point spread functions. AB - We present a real-time fitter for 3D single-molecule localization microscopy using experimental point spread functions (PSFs) that achieves minimal uncertainty in 3D on any microscope and is compatible with any PSF engineering approach. We used this method to image cellular structures and attained unprecedented image quality for astigmatic PSFs. The fitter compensates for most optical aberrations and makes accurate 3D super-resolution microscopy broadly accessible, even on standard microscopes without dedicated 3D optics. PMID- 29630063 TI - Correction: Evaluation of spine MRIs in athletes participating in the Rio de Janeiro 2016 Summer Olympic Games. AB - [This corrects the article DOI: 10.1136/bmjsem-2017-000335.][This corrects the article DOI: 10.1136/bmjsem-2017-000335.]. PMID- 29630064 TI - Erratum: Novel Genetic Associations Between Lung Cancer and Indoor Radon Exposure. AB - [This corrects the article on p. 234 in vol. 22, PMID: 29302581.]. PMID- 29630065 TI - Erratum: Economic burden of the management of metastatic castrate-resistant prostate cancer in Italy: a cost of illness study [Corrigendum]. AB - [This corrects the article on p. 789 in vol. 9, PMID: 29263702.]. PMID- 29630066 TI - The Microbe Directory: An annotated, searchable inventory of microbes' characteristics. AB - The Microbe Directory is a collective research effort to profile and annotate more than 7,500 unique microbial species from the MetaPhlAn2 database that includes bacteria, archaea, viruses, fungi, and protozoa. By collecting and summarizing data on various microbes' characteristics, the project comprises a database that can be used downstream of large-scale metagenomic taxonomic analyses, allowing one to interpret and explore their taxonomic classifications to have a deeper understanding of the microbial ecosystem they are studying. Such characteristics include, but are not limited to: optimal pH, optimal temperature, Gram stain, biofilm-formation, spore-formation, antimicrobial resistance, and COGEM class risk rating. The database has been manually curated by trained student-researchers from Weill Cornell Medicine and CUNY-Hunter College, and its analysis remains an ongoing effort with open-source capabilities so others can contribute. Available in SQL, JSON, and CSV (i.e. Excel) formats, the Microbe Directory can be queried for the aforementioned parameters by a microorganism's taxonomy. In addition to the raw database, The Microbe Directory has an online counterpart ( https://microbe.directory/) that provides a user-friendly interface for storage, retrieval, and analysis into which other microbial database projects could be incorporated. The Microbe Directory was primarily designed to serve as a resource for researchers conducting metagenomic analyses, but its online web interface should also prove useful to any individual who wishes to learn more about any particular microbe. PMID- 29630068 TI - Erratum: Knowledge, Attitude, and Awareness among Diabetic Patients in Davangere about the Association between Diabetes and Periodontal Disease. AB - [This corrects the article on p. 381 in vol. 7, PMID: 29387625.]. PMID- 29630067 TI - Respiratory Effects of Thoracic Load Carriage Exercise and Inspiratory Muscle Training as a Strategy to Optimize Respiratory Muscle Performance with Load Carriage. AB - Many occupational and recreational settings require the use of protective and/or load-bearing apparatuses worn over the thoracic cavity, known as thoracic load carriage (LC). Compared to normal, unloaded exercise, thoracic LC exercise places an additional demand on the respiratory and limb locomotor systems by altering ventilatory mechanics as well as circulatory responses to exercise, thus accelerating the development of fatigue in the diaphragm and accessory respiratory muscles compared to unloaded exercise. This may be a consequence of the unique demands of thoracic LC, which places an additional mass load on the thoracic cavity and can restrict chest wall expansion. Therefore it is important to find effective strategies to ameliorate the detrimental effects of thoracic LC. Inspiratory muscle training is an intervention that aims to increase the strength and endurance of the diaphragm and accessory inspiratory muscle and may therefore be a useful strategy to optimize performance with thoracic LC. PMID- 29630069 TI - SOCRAT Platform Design: A Web Architecture for Interactive Visual Analytics Applications. AB - The modern web is a successful platform for large scale interactive web applications, including visualizations. However, there are no established design principles for building complex visual analytics (VA) web applications that could efficiently integrate visualizations with data management, computational transformation, hypothesis testing, and knowledge discovery. This imposes a time consuming design and development process on many researchers and developers. To address these challenges, we consider the design requirements for the development of a module-based VA system architecture, adopting existing practices of large scale web application development. We present the preliminary design and implementation of an open-source platform for Statistics Online Computational Resource Analytical Toolbox (SOCRAT). This platform defines: (1) a specification for an architecture for building VA applications with multi-level modularity, and (2) methods for optimizing module interaction, re-usage, and extension. To demonstrate how this platform can be used to integrate a number of data management, interactive visualization, and analysis tools, we implement an example application for simple VA tasks including raw data input and representation, interactive visualization and analysis. PMID- 29630070 TI - Erratum: Intrathecal Hyperbaric Bupivacaine with Varying Doses of Buprenorphine for Postoperative Analgesia after Cesarean Section: A Comparative Study. AB - [This corrects the article on p. 952 in vol. 11, PMID: 29284855.]. PMID- 29630071 TI - Commentary: The neural basis of human female mate copying: An empathy-based social learning process. PMID- 29630072 TI - Erratum to pulmonary embolism concurrent with lung cancer and central emboli predict mortality in patients with lung cancer and pulmonary embolism. AB - [This corrects the article DOI: 10.21037/jtd.2017.12.32.]. PMID- 29630073 TI - The plumbing of land surface models: is poor performance a result of methodology or data quality? AB - The PALS Land sUrface Model Benchmarking Evaluation pRoject (PLUMBER) illustrated the value of prescribing a priori performance targets in model intercomparisons. It showed that the performance of turbulent energy flux predictions from different land surface models, at a broad range of flux tower sites using common evaluation metrics, was on average worse than relatively simple empirical models. For sensible heat fluxes, all land surface models were outperformed by a linear regression against downward shortwave radiation. For latent heat flux, all land surface models were outperformed by a regression against downward shortwave, surface air temperature and relative humidity. These results are explored here in greater detail and possible causes are investigated. We examine whether particular metrics or sites unduly influence the collated results, whether results change according to time-scale aggregation and whether a lack of energy conservation in flux tower data gives the empirical models an unfair advantage in the intercomparison. We demonstrate that energy conservation in the observational data is not responsible for these results. We also show that the partitioning between sensible and latent heat fluxes in LSMs, rather than the calculation of available energy, is the cause of the original findings. Finally, we present evidence suggesting that the nature of this partitioning problem is likely shared among all contributing LSMs. While we do not find a single candidate explanation for why land surface models perform poorly relative to empirical benchmarks in PLUMBER, we do exclude multiple possible explanations and provide guidance on where future research should focus. PMID- 29630074 TI - Oil on Paper: A Collaborative Conservation Challenge. AB - The application of oil-based leather dressing, while once considered a best practice in libraries, led to undesirable long-term consequences for bound materials. At the National Institutes of Health (NIH) in the National Library of Medicine (NLM), many leather-bound volumes had multiple applications of a mixture of neatsfoot oil and lanolin dressings liberally applied. The oils not only absorbed into the leather bindings but also migrated onto the pastedowns, end sheets, gutters, and text blocks. The oiling process at NLM was documented by call number, year(s), number of applications, and dressing formula. While investigating treatment options, the NLM senior conservator consulted a paintings and objects conservator for insight on viable options for the removal of oil from artifacts. An art-on-paper conservator joined the collaborative effort to develop a treatment protocol for NLM's oil saturated collections. Together, they investigated the issue and devised an effective method for removal of this oil from the NIH collection materials. The protocol involves washing with an alkaline solution followed by alternating applications of petroleum ether and acetone applied either over suction or by immersion. Oil components are solubilized by the alternating polarities of the solvents and then removed from the paper using suction or immersion. After the oil is removed, the paper is washed again with alkaline water to remove any remaining water soluble discoloration. This article will explore further details of the treatment protocol, its development and applications, and the benefits of cross-disciplinary collaboration. PMID- 29630075 TI - Correction: Cracking the code for maintaining quality training in Olympic distance triathlon: lessons learnt from a squad of elite Scandinavian athletes. AB - [This corrects the article DOI: 10.1136/bmjsem-2017-000274.][This corrects the article DOI: 10.1136/bmjsem-2017-000274.]. PMID- 29630076 TI - A demographic dividend of the FP2020 Initiative and the SDG reproductive health target: Case studies of India and Nigeria. AB - Background: The demographic dividend, defined as the economic growth potential resulting from favorable shifts in population age structure following rapid fertility decline, has been widely employed to advocate improving access to family planning. The current framework focuses on the long-term potential, while the short-term benefits may also help persuade policy makers to invest in family planning. Methods: We estimate the short- and medium-term economic benefits from two major family planning goals: the Family Planning 2020 (FP2020)'s goal of adding 120 million modern contraceptive users by 2020; Sustainable Development Goals (SDG) 3.7 of ensuring universal access to family planning by 2030. We apply the cohort component method to World Population Prospects and National Transfer Accounts data. India and Nigeria, respectively the most populous Asian and African country under the FP2020 initiative, are used as case studies. Results: Meeting the FP2020 target implies that on average, the number of children that need to be supported by every 100 working-age people would decrease by 8 persons in India and 11 persons in Nigeria in 2020; the associated reduction remains at 8 persons in India, but increases to 14 persons in Nigeria by 2030 under the SDG 3.7. In India meeting the FP2020 target would yield a saving of US$18.2 billion (PPP) in consumption expenditures for children and youth in the year 2020 alone, and that increased to US$89.7 billion by 2030. In Nigeria the consumption saved would be US$2.5 billion in 2020 and $12.9 billion by 2030. Conclusions: The tremendous economic benefits from meeting the FP2020 and SDG family planning targets demonstrate the cost-effectiveness of investment in promoting access to contraceptive methods. The gap already apparent between the observed and targeted trajectories indicates tremendous missing opportunities. Accelerated progress is needed to achieve the FP2020 and SDG goals and so reap the demographic dividend. PMID- 29630077 TI - Isolated Fe and Co dual active sites on nitrogen-doped carbon for a highly efficient oxygen reduction reaction. AB - We successfully prepared Fe and Co isolated single atoms on metal-organic framework derived nitrogen-doped carbon (FeCo-ISAs/CN) by an adsorption calcination strategy. The obtained FeCo-ISAs/CN exhibited top-level catalytic reactivity for the alkaline oxygen reduction reaction (ORR) with a half-wave potential of 0.920 V, which was 70 mV more positive than that of commercial Pt/C. Moreover, the catalyst was durable and showed negligible activity decay in the alkaline ORR during 5000 voltage cycles. PMID- 29630079 TI - Outstanding Reviewers for Organic & Biomolecular Chemistry in 2017. PMID- 29630078 TI - Applications of zeolites in biotechnology and medicine - a review. AB - Zeolites are microporous tectosilicates of natural or synthetic origin, which have been extensively used in various technological applications, e.g. as catalysts and as molecular sieves, for separating and sorting various molecules, for water and air purification, including removal of radioactive contaminants, for harvesting waste heat and solar heat energy, for adsorption refrigeration, as detergents, etc. These applications of zeolites were typically related with their porous character, their high adsorption capacity, and their ion exchange properties. This review is focused on potential or already practically implemented applications of zeolites in biotechnology and medicine. Zeolites are promising for environment protection, detoxication of animal and human organisms, improvement of the nutrition status and immunity of farm animals, separation of various biomolecules and cells, construction of biosensors and detection of biomarkers of various diseases, controlled drug and gene delivery, radical scavenging, and particularly tissue engineering and biomaterial coating. As components of scaffolds for bone tissue engineering, zeolites can deliver oxygen to cells, can stimulate osteogenic cell differentiation, and can inhibit bone resorption. Zeolites can also act as oxygen reservoirs, and can improve cell performance in vascular and skin tissue engineering and wound healing. When deposited on metallic materials for bone implantation, zeolite films showed anticorrosion effects, and improved the osseointegration of these implants. In our studies, silicalite-1 films deposited on silicon or stainless steel substrates improved the adhesion, growth, viability and osteogenic differentiation of human osteoblast-like Saos-2 cells. Zeolites have been clinically used as components of haemostatics, e.g. in the Advanced Clotting Sponge, as gastroprotective drugs, e.g. Absorbatox(r) 2.4D, or as antioxidative agents (Klinobind(r)). Some zeolites are highly cytotoxic and carcinogenic, e.g. erionite. However, in other zeolites, the antiproliferative and pro-apoptotic effects can be used for tumor therapy. PMID- 29630080 TI - The synthesis of mono-alkyl phosphates and their derivatives: an overview of their nature, preparation and use, including synthesis under plausible prebiotic conditions. AB - Nucleic acids, phospholipids and other organic phosphates play central roles in biological pathways. n-Alkyl phosphates and their derivatives have been recognized as amphiphilic molecules for nearly two centuries. In the last 50 years, n-alkyl phosphate derivatives such as di-alkyl phosphates, mono-alkyl phosphatidyl ethanol amines and mono-alkyl phosphocholines have become predominant compounds with applications in different areas, from food chemistry to life science. The aim of this review is to summarize the most relevant progress made in the field of the synthesis of these molecules and to provide a concise perspective on the use of these amphiphiles as possible prebiotic membrane constituents. The first part of the review is dedicated to the analysis of the most relevant syntheses carried out in recent years with respect to those reported from the second half of the nineteenth century. The second part is dedicated to a description of the latest reports on prebiotic synthesis of mono alkyl phosphates. In this part, the authors did not report the phosphorylation of other relevant biomolecules, such as nucleosides, which have been excellently reviewed elsewere. PMID- 29630081 TI - Cyrene as a bio-based solvent for HATU mediated amide coupling. AB - Amide bonds are one of the underpinning linkages in all living systems and are fundamental within drug discovery. Current methods towards their synthesis frequently rely on the use of dipolar aprotic solvents; however, due to increasingly stringent regulations and growing societal pressures, safe and more sustainable alternatives are highly sought after. Herein, we evaluate the application of the bio-based solvent CyreneTM in the HATU mediated synthesis of amides and peptides. We found that Cyrene functioned as a competent replacement for DMF in the synthesis of a series of lead-like compounds and dipeptides (25 examples, 63-100%). PMID- 29630082 TI - Pulmonary Hydatid Disease with Aspergillosis - An Unusual Association in an Immunocompetent Host. AB - Echinococcosis is a common cause of pulmonary cavities. Aspergillus fumigatus, a saprophytic fungus, can colonise pulmonary cavities caused by tuberculosis, sarcoidosis, echinococcosis, bronchiectasis and neoplasms. Infection by Aspergillus is often seen in immunosuppressed cases. However, co-infection of Aspergillus with pulmonary echinococcosis is unexpected and very unusual, especially in an immunocompetent patient. We present the case of a 45-year-old immunocompetent male who came with non-resolving pneumonia and fever for 8 months and dyspnoea since 15 days accompanied by recurrent episodes of hemoptysis since 5 days. Chest X Ray and Computed Tomography scan showed a cystic lesion in the middle lobe of the right lung. Middle lobectomy with video-assisted thoracoscopic surgery was performed and histopathology revealed ectocyst of Hydatid cyst which was also colonised by septate fungal hyphae exhibiting acute angled branching, morphologically consistent with Aspergillus. Gomori Methanamine Silver and Periodic Acid Schiff stains highlighted the hyphae of Aspergillus as well as the lamellated membranes of ectocyst and an occasional scolex of Echinococcus. Sections from surrounding lung parenchyma also showed these fungal hyphae within an occasional dilated bronchus. Thus a diagnosis of dual infection of Aspergillosis and Pulmonary Echinococcosis was established. The possibility of dual infection by a saprophytic fungus must be kept in mind while dealing with a case of a cavitary lesion in long-standing and non-resolving pneumonia, even in an immunocompetent patient. Establishing the correct diagnosis of Aspergillosis with Echinococcosis is essential for proper and complete management. PMID- 29630083 TI - Renal Microsporidiosis in Pediatric Bone Marrow Transplant Recipients: A Case Series. AB - Microsporidiosis is a rare, but emerging opportunistic infection in solid organ transplant and stem cell transplant recipients. Renal involvement in microsporidiosis is very rarely seen in these recipients. We describe two cases of pediatric renal microsporidiosis, diagnosed on renal biopsies, following bone marrow transplantation presenting as severe acute kidney injury. The first patient died, whereas the second survived due to early diagnosis based on high index of suspicion and prompt treatment with Albendazole. We believe these are the first such reported cases of renal microsporidiosis in pediatric bone marrow transplant recipients. PMID- 29630084 TI - Evaluation of p53 and Ki67 Expression Profiles in Basal Cell Carcinomas in a Usual and an Unusual Location. AB - OBJECTIVE: Owing to their importance in cell proliferation in cutaneous malignancies, we aimed to immunohistochemically compare the expression profiles of p53 and Ki67 in basal cell carcinoma (BCC) cases in both a usual and an unusual locations in this study. MATERIAL AND METHOD: In this study we included 12 in an unusual location of BCC cases and 21 BCC cases in a usual location. Immunohistochemical expression of p53 and Ki67 antibodies were studied in 33 paraffin-embedded tissue specimens of basal cell carcinoma. We compared the p53 and Ki67 staining scores with clinicopathologic features. RESULTS: The tumor size was found to be greater in BCC cases in an unusual location than those in a usual location. The relationship between age and tumor size was also evaluated in both groups and it was found that tumor size increased with age. A comparative study between the two groups showed no difference p53 and Ki67 expression percentages. There was a linear correlation between the Ki67 and p53 marker staining rates (rho=0.420; p=0.015). In the samples taken from cases in a usual region, there was a linear and moderate relationship between the markers (rho=0.513; p=0.017). Median tumor diameter results were similar to the marker staining score (p > 0.05). CONCLUSION: This is the first study comparing the expression profiles of p53 and Ki67 of BCC cases in an unusual and a usual location. No significant difference was found concerning Ki67 and p53 expression levels between the two groups. PMID- 29630085 TI - EZH2, Endothelin-1, and CD34 as Biomarkers of Aggressive Cervical Squamous Cell Carcinoma: An Immunohistochemical Study. AB - OBJECTIVE: Cervical cancer has an increasing incidence in developing countries with a predominance of squamous cell carcinoma. In this work, we aimed to analyze the role of EZH2, Endothelin-1, and CD34 as indicators of the aggressiveness in cervical squamous cell carcinoma. MATERIAL AND METHOD: Immunohistochemical expression of EZH2, Endothelin-1, and CD34 was studied in 54 paraffin-embedded tissue specimens of cervical squamous cell carcinoma. Their correlation to the clinicopathologic features and the potential angiogenic role were analyzed. RESULTS: High EZH2 expression was noted in 78% of cervical squamous cell carcinoma with a significant relation with tumor grade, FIGO stage and lymph node metastasis (p= < 0.001, p=0.007, p=0.03 respectively). Endothelin-1 overexpression was detected in 63% of the studied cases with a significant association with tumor size, FIGO stage and lymph node metastasis (p=0.009, p=0.002, p=0.02 respectively). High CD34 expression (MVD) was noted in 56% of the cases and associated with the tumor size, FIGO stage and lymph node metastasis (p < 0.001, p < 0.001, p=0.04 respectively). The three markers were significantly associated (p < 0.05). CONCLUSION: EZH2, ET-1, and CD34 may act as biomarkers of aggressive cervical squamous cell carcinoma. They may contribute to the signaling pathway of angiogenesis. Therefore, they could potentially be used in targeted therapy. PMID- 29630086 TI - Isolated Epitrochlear Filarial Lymphadenopathy: Cytomorphological Diagnosis of an Unusual Presentation. AB - Filariasis is a major public health problem in tropical countries like India. Despite the large number of people at risk, detection of eggs with or without larva (microfilaria) on fine-needle aspiration cytology is very unusual, especially in an uncommon site or incidentally detected in clinically unsuspected cases of filariasis with the absence of microfilariae in the peripheral blood. A 19-year-old male presented with swelling over medial aspect of left arm (just above the elbow), with no other specific signs and symptoms. Fine needle aspiration cytology revealed an adult gravid female filarial worm in a background of reactive lymphoid cells and lymphohistiocytic clusters. We report a case with elaborate fine needle aspiration cytology findings of filarial worm infestation with unusual presentation of isolated epitrochlear lymph node involvement in a clinically unsuspected case and recommend clinicians and pathologists to consider a high index of suspicion for such infections at uncommon sites especially in endemic territories, as early diagnosis and treatment prevent the more severe manifestations of disease. PMID- 29630087 TI - Evaluation of All Surgical Margins in Pancreatic Resection Specimens by Proper Grossing Techniques: Surgical Pathology Experience of 285 Cases. AB - OBJECTIVE: The aim of this study was to review our series of pancreatic resection specimen handling results and focus on the positivity of the tumor in various retroperitoneal surgical margins. MATERIAL AND METHOD: Our archival cases from 2008 to 2018 were retrospectively examined, especially for the surgical margins. The demographics, tumor locations, and the diagnoses were recorded. The state of all of the retropancreatic surgical margins (anterior, posterior, superior, inferior, superior mesenteric vein and artery) were recorded. RESULTS: There were 285 cases, of which 157 were male and 128 female. The mean and median ages were 63.3 and 64, respectively. Invasive ductal adenocarcinoma was the most common diagnosis [202 cases (70.8%)]. Positivity was observed in 90 (31.5%) margins. The majority was in the superior mesenteric vein margin [n:24 (8.4%)]. This was followed by the anterior, resection and SMA margins. CONCLUSION: Pancreatic resections should macroscopically be sampled by recommended methods in order to detect positivity in individual margins by proper grossing techniques. When this is applied, the superior mesenteric vein margin is the margin most prone to be positive for the tumor. PMID- 29630088 TI - Gastrointestinal Stromal Tumors: A Clinicopathological and Immunohistochemical Study of 65 Cases. AB - OBJECTIVE: The clinical behavior of gastrointestinal stromal tumors is divergent. The aim of the present study was to define the clinicopathological features that determine the patient's outcome. MATERIAL AND METHOD: Sixty-five gastrointestinal stromal tumors were reviewed with their histological, immunohistochemical and clinical features and compared with their clinical outcome statistically. RESULTS: Tumors were located in the stomach (n=39, 60%), small intestine (n=22, 33.8%) and large intestine (n=4, 6.2%). Immunohistochemically, CD 117 positivity was found in 90.8%, whereas CD34, Smooth muscle actin, Desmin and S100 positivity was found in 73.3%, 61.7%, 11.7% and 28.3% of tumors respectively. All six ''CD 117-negative'' cases expressed DOG-1. The mean Ki-67 proliferation index was 8.69%+/-12.76. Liver metastasis was detected in seven cases. A significant association was detected between decreased mean survival time and increased tumor size (p < 0.001), large bowel localization (p=0.047), mitosis (p < 0.001), the presence of necrosis (p=0.001), metastasis (p=0.033), Ki-67 proliferation index (p=0.002) and risk category (p < 0.001). CD 34 positivity was mostly seen in the stomach (p=0.001), and CD 34 positive tumors had longer overall survival (92.85.+/-5.77 months versus 67.21+/-13.68 months) (p=0.046). Higher Ki-67 proliferation index (>=6%) was also correlated with the presence of metastases (p=0.015). CONCLUSION: Our study indicates that in addition to well-known risk factors such as increased tumor size, high mitotic activity and metastasis; higher Ki-67 proliferation index, the presence of necrosis, and CD34 negativity also correlate with shorter survival time. PMID- 29630089 TI - LncRNA SNHG8 participates in the development of endometrial carcinoma through regulating c-MET expression by miR-152. AB - OBJECTIVE: To investigate the possible function and mechanism of lncRNA SNHG8 in the pathogenesis of endometrial carcinoma. PATIENTS AND METHODS: We utilized qRT PCR to detect the expression of SNHG8 in 60 cases of endometrial carcinoma and 25 cases of normal endometrium; after that, the endometrial carcinoma cell lines were screened. SNHG8 was transfected into endometrial carcinoma cells by Lipofectamine and the proliferative activity of cells was detected by cell counting kit-8 (CCK-8) assay. Bioinformatics methods were used to detect the target microRNA. miR-152 is predicted to bind to SNHG8 and target genes of c-MET. Luciferase reporter assay was performed to detect the relative luciferase activity between miR-152 and c-MET, SNHG8. The interactions between SNHG8, miR 152, and c-MET were further verified by transfection of miR-152 mimics, miR-152 mimics + OE-SNHG8, SNHG8 siRNA, and SNHG8 siRNA + miR-152 inhibitor. RESULTS: SNHG8 expression in endometrial carcinoma tissue was significantly higher than that in normal endometrium. After transfection with SNHG8 siRNA, the cell viability of AN3CA cells decreased, whereas the activity of Ishikawa was increased after transfection with SNHG8 overexpression plasmid. Bioinformatics predictions and dual luciferase reporter assay illustrated that SNHG8 was bound to miR-152 and miR-152 targeted on c-MET. In addition, miR-152 mimics inhibited the expression of c-MET, and the inhibitory effect was reversed after SNHG8 overexpression. Silencing SNHG8 reduced c-MET expression, and c-MET expression was reversed after addition of miR-152 inhibitor. CONCLUSIONS: SNHG8 is highly expressed in endometrial carcinoma, and SNHG8 targets c-MET through miR-152 to regulate the proliferation of endometrial cancer cells. PMID- 29630090 TI - MiRNA-155 and colorectal cancer, the role of real time PCR in laboratory diagnosis. PMID- 29630091 TI - LncRNA colon cancer-associated transcript 1 (CCAT1) in ovarian cancer. PMID- 29630092 TI - Comment on "The effect and mechanism of metallothionein MT1M on hepatocellular carcinoma cell". PMID- 29630093 TI - Comment about "The hyperthermic intraoperative intraperitoneal chemotherapy in the treatment of advanced abdominopelvic cancer. Personal experience on 103 procedures during a seventeen year period in a single Italian center". PMID- 29630094 TI - MiR-4421 regulates the progression of preeclampsia by regulating CYP11B2. AB - OBJECTIVE: Preeclampsia is a serious disease that affects maternal and fetal health in pregnancy. Mechanism of miRNA in preeclampsia has gradually been explored. This study mainly investigated the mechanism of miR-4421 in preeclampsia. PATIENTS AND METHODS: The expression of miR-4421 in 42 preeclampsia tissues and 42 normal pregnancy placentas tissues was detected by qRT-PCR. The relationship between the miR-4421 level and clinicopathological features of preeclampsia was analyzed. After miR-4421 was overexpressed, cell proliferation, cell cycle, and apoptosis were examined. The target gene CYP11B2 of miR-4421 was detected by luciferase reporter assay. The protein expressions were accessed by Western blot. RESULTS: miR-4421 was highly expressed in the placenta of preeclampsia. Clinical data analysis revealed higher systolic blood pressure, diastolic blood pressure, and urinary protein level in preeclampsia patients with high expression of miR-4421 compared with those in low expression group. Birth weight of fetuses was significantly lower than those born from normal pregnant women. After overexpression of miR-4421, trophoblast proliferation was significantly inhibited and cell cycle was significantly blocked. Luciferase reporter assay and Western blot showed that CYP11B2 can be served as a target gene of miR-4421. CONCLUSIONS: MiR-4421 was highly expressed in preeclampsia, which may promote the progression of preeclampsia by down-regulating the expression of CYP11B2. PMID- 29630095 TI - Pathogenicity of high risk HPV infection in pseudocondyloma of vulvae and its carcinogenicity in inducing cervical lesions. AB - OBJECTIVE: To identify high-risk human papillomavirus (HPV) infection in pseudocondyloma of vulvae (PV) and the causal relationship between high-risk HPV infection and cervical cancer. PATIENTS AND METHODS: The patients were divided into condyloma acuminatum group, PV groups and PV high-risk HPV infection group according to the clinical data and morphological features. Condyloma acuminatum group and PV group were two control groups. The exfoliated cells were detected and typed by human HPV nucleic acid typing kit. The gene fusion site of HPV and its potential gene integration mechanism were investigated using genome-wide sequencing and high-throughput virus integration screening techniques. The HPV integration frequencies of some key gene integration sites were calculated and some novel genes integration sites were identified. RESULTS: The samples from PV high-risk HPV infection group showed both the pathologic manifestations of PV and the koilocytes caused by the virus infection. Suspected HPV virus particles with a density different from chromatin were observed from the samples of PV high-risk HPV infection group under transmission electron microscopy (TEM). The intercellular desmosomes were regularly connected, and autophagosomes can also be observed in some cases. HPV genome was not detected in PV groups and PV high-risk HPV infection group due to the low copy number. HPV genome was only detected in condyloma acuminatum group. CONCLUSIONS: PV high-risk HPV infection showed both the symptoms of PV and HPV infection with suspected HPV virus particles in cells. PMID- 29630096 TI - Effects of testosterone on PPARgamma and P450arom expression in polycystic ovary syndrome patients and related mechanisms. AB - OBJECTIVE: Polycystic ovary syndrome (PCOS) causes ovulation disorder and infertility in female patients. This study recruited PCOS patients and adopted testosterone therapy to analyze its effect on expression of nuclear peroxisome proliferation activated receptor gamma (PPARgamma), and cytochrome P450 aromatase (P450arom) in ovary granular cells of patients. PATIENTS AND METHODS: PCOS and non-PCOS patients were treated with testosterone at 1.0 nmol/L, 10 nmol/L. qRT PCR was used to detect the expressions of PPARgamma and P450arom while Western blot was performed for the evaluation of protein expression. RESULTS: In the experimental group, the level of PPARgamma mRNA was significantly elevated whilst the expression of P450arom was statistically decreased (p < 0.05). The treatment of 10 nmol/l testosterone significantly elevated PPARgamma mRNA and protein expression, and decreased P450arom expression (p < 0.05). The level of PPARgamma was positively correlated with testosterone concentration, and was negatively correlated with P450arom expression (p < 0.05). CONCLUSIONS: Testosterone causes hyperandrogenism microenvironment of PCOS patients, with a correlated increase of PPARgamma and reduction of P450arom. PMID- 29630097 TI - Effect of FGF2 on the activity of SPRYs/DUSP6/ERK signaling pathway in endometrial glandular epithelial cells of endometriosis. AB - OBJECTIVE: We aimed at exploring the positive feedback loop in eutopic and ectopic endometrial glandular epithelial cells (EuECs and EECs) in endometriosis. MATERIALS AND METHODS: Normal epithelial cells (NECs), EuECs and EECs were treated with fibroblast growth factor (FGF)2, FGF2 neutralizing antibody, mitogen activated protein kinases (MAPKs) inhibitors U0126 and PD98059. FGF2 protein level was detected by enzyme-linked immunosorbent assay (ELISA). The expressions of FGF2, FGF receptor 1 (FGFR1), extracellular signal-regulated kinase (ERK)1/2/pERK1/2 and Sproutys (SPRYs) (Sprouty1, Sprouty2, Sprouty4) and dual specificity phosphatase 6 (DUSP6) were detected by Western blot. The mRNA levels of FGF2, FGFR1 (FGF receptor 1), SPRYs (Sprouty1, Sprouty2, Sprouty4) and DUSP6 mRNA were detected by RT-PCR. RESULTS: Among treatment groups, the content of FGF2 in EuECs and EECs was significantly higher than that in NECs (p < 0.05). The mRNA and protein levels of FGF2, FGFR1, SPRYs (Sprouty1, Sprouty2, Sprouty4) and DUSP6 in EuECs and EECs were increased after adding FGF2 (p < 0.05), but decreased after adding FGF2 neutralizing antibody, no significant change was found in NECs (p > 0.05). The inhibitory effect of PD9805 on NECs was not significantly different from that of U0126 (p > 0.05); however, the inhibitory effects of PD9805 on EuECs and EECs were significantly lower than those of U0126 (p< 0.05). CONCLUSIONS: The positive feedback loop existed in EuECs and EECs, but maybe not in NECs. The results may provide the guideline to treat endometriosis patients. PMID- 29630098 TI - LPS at low concentration promotes the fracture healing through regulating the autophagy of osteoblasts via NF-kappaB signal pathway. AB - OBJECTIVE: To investigate the effect of low-concentration lipopolysaccharide (LPS) on proliferation and apoptosis of osteoblasts and to discover the mechanism of low-concentration LPS in facilitating the proliferation of osteoblasts. MATERIALS AND METHODS: MC3T3-E1 osteoblasts were treated with LPS, 3 methyladenine (3-MA, autophagy inhibitor), and BAY11-7082 (inhibitor of nuclear factor-kappa b, NF-kappaB), respectively. The cell cycles were detected using a flow cytometer. Cell proliferation and activity of MC3T3-E1 osteoblasts were explored by cell counting kit-8. Western blotting and immunofluorescence assay were performed to detect the protein level. RNA expression was measured through polymerase chain reaction (PCR) and immunofluorescence assay. RESULTS: At the third day after cell culture, cell infusion reached 80%, and cells were taken as the subjects. At 6 h after treatment with low-concentration LPS, the proliferation and activity of cells were higher than those at 1 h and 12 h after treatment, and the apoptotic level was significantly lower than that in cells at 12 h after treatment. The proliferation and activity of cells in the low concentration LPS group were significantly higher than those in the control group, 3-MA group and BAY11-7082 group, and the apoptotic level was lower than those in these groups. Compared with those of cells in control group and BAY11 7082 group, the messenger RNA (mRNA) and protein expressions and nuclear transfer of cells in low-concentration LPS group were significantly elevated, but there were no statistically significant differences in comparisons with the 3-MA group. In the experiment of cell autophagy, the autophagic level in cells in low concentration LPS group was higher than those in the control group, 3-MA group and BAY11-7082 group. CONCLUSIONS: Through the NF-kappaB signaling pathway in osteoblasts, low-concentration LPS can activate the autophagy and promote cell proliferation, thereby inhibiting cell apoptosis and accelerating the fracture healing. PMID- 29630099 TI - Upregulation of miR-132 attenuates osteoblast differentiation of UC-MSCs. AB - OBJECTIVE: Wnt/beta-catenin signaling pathway plays a role in upregulating expression of osteoblast (OB) specific transcriptional factor Osterix and promoting OB differentiation. It was shown that the elevation of the miR-132 level was associated with sclerotizing inhibition. Bioinformatics analysis revealed the complementary binding site between miR-132 and 3'-UTR of beta catenin. This study investigated the influence of miR-214 in regulating beta catenin expression and differentiation of umbilical cord mesenchymal stem cells (UC-MSCs) into OB. MATERIALS AND METHODS: UC-MSCs were induced to differentiate to OB. The expressions of miR-132, beta-catenin, Osterix, and ALP, together with ALP activity were detected on day 0, 5, 10, and 15. The regulatory relationship between miR-132 and beta-catenin was confirmed by dual luciferase reporter gene assay. UC-MSCs were divided into five groups, including agomir-control, miR-132 agomir, pGPH1-NC, pGPH1-beta-catenin, and miR-132 agomir + pGPH1-beta-catenin groups. beta-catenin, Osterix, and ALP expressions, together with ALP activity were tested after induction for 15 days. RESULTS: MiR-132 was downregulated, while beta-catenin Osterix and ALP expressions, together with ALP activity were enhanced in the process of UC-MSCs differentiating into OBs. MiR-132 agomir and/or pGPH1-beta-catenin transfection significantly reduced beta-catenin expression, downregulated Wnt/beta-catenin signaling pathway activity, declined Osterix level, weakened ALP expression and activity, and attenuated OB differentiation of UC-MSCs. CONCLUSIONS: The level of beta-catenin was enhanced, while the miR-132 level was decreased in the process of UC-MSCs differentiating into OBs. Upregulation of miR-132 inhibited the differentiation of UC-MSCs through suppressing beta-catenin expression, attenuating Wnt/beta-catenin signaling pathway activity, and downregulating Osterix level. PMID- 29630100 TI - Effect of IFN-lambda2 on combined allergic rhinitis with nasal polyps. AB - OBJECTIVE: This study sought to investigate the expression of interferon-lambda2 (IFN-lambda2) in patients with combined allergic rhinitis and nasal polyps (AR+NP), analyze the correlation between IFN-lambda2 and tryptase, interleukin 10 (IL-10), and interleukin 12 (IL-12), and identify its peripheral blood cell origins. PATIENTS AND METHODS: ELISA kits were used to investigate plasma levels of IFN-lambda2, tryptase, IL-10, and IL-12 in AR+NP patients and healthy controls (HC). Flow cytometry analysis was carried out to detect IFN-lambda2 expression in peripheral blood leukocytes. Immunocytochemical staining was performed to detect nasal polyp IFN-lambda2 expression in AR+NP patients. RESULTS: Elevated plasma IFN-lambda2 levels and positive correlations between plasma IFN-lambda2 and tryptase levels in AR+NP patients indicated that IFN-lambda2 likely contributes to AR+NP pathogenesis. IFN-lambda2 expression was upregulated in cytotoxic T cells and eosinophils in AR+NP patients. Nasal polyp mast cells and macrophages in AR+NP patients expressed IFN-lambda2. CONCLUSIONS: The close correlation between IFN-lambda2 expression and AR+NP may provide experimental evidence for a possible effect of IFN-lambda2 against the allergic inflammatory reaction. Therefore, IFN-lambda2 actions may have a potential utility for the treatment and prevention of AR+AP. PMID- 29630101 TI - Efficacy of computed tomography-guided implantation of 125I seeds in the treatment of refractory malignant tumors accompanied with cancer pain and its influence on tumor markers in the serum. AB - OBJECTIVE: This study intended to explore the efficacy of computed tomography (CT)-guided implantation of iodine-125 (125I) seeds in the treatment of refractory malignant tumors with cancer pain and its influence on tumor markers in the serum. PATIENTS AND METHODS: 76 patients with refractory malignant tumors accompanied by cancer pain that received treatments in LongHua Hospital Shanghai University of Traditional Chinese Medicine from September 2013 to August 2014 were selected. They were divided into control group and observation group using a random number table (38 patients in each group). Patients in the control group received simple chemotherapy, while those in the observation group undergone CT guided implantation of 125I seeds in combination with chemotherapy. Recent efficacy and 1-3-year survival rate were compared between the two groups of patients. The degree of pain relief after treatment was also compared between the two groups of patients. Electrochemiluminescence method was used to detect the concentrations of carcinoembryonic antigen (CEA), sugar chain antigen 199 (CA 199), sugar chain antigen 125 (CA 125), neuron-specific enolase (NSE) and cytokeratin-19-fragment (CYFRA21-1) in the two groups of patients before treatment, and 3 days, 7 days and 30 days after treatment. RESULTS: Recent disease control rate of the patients in the observation group was higher than that of the patients in the control group (p<0.05). The 1-3-year survival rate after surgery in the observation group was significantly higher than that in the control group (p<0.05). The total efficiency of pain control in the observation group was significantly higher than that in the control group (p<0.05). The levels of tumor markers in the two groups of patients were significantly decreased after treatment, while the reduction in the observation group was more evident than that in the control group (p<0.05). CONCLUSIONS: Our results showed that CT-guided implantation of 125I seeds is effective for the treatment of patients with refractory malignant tumors accompanied by cancer pain. It can reduce the levels of tumor markers, improve the survival rate and prolong the survival time of the patients. PMID- 29630102 TI - MicroRNA-384 downregulates SETD8 expression to suppress cell growth and metastasis in osteosarcoma cells. AB - OBJECTIVE: MiR-384 was reported to be downregulated and functioned as a tumor suppressor in several cancers. However, the expression and function of miR-384 in osteosarcoma (OS) have not been investigated. In the present study, we aimed to analyze the effect and mechanism of miR-384 in the progression of OS. PATIENTS AND METHODS: Quantitative Real-time polymerase chain reaction (qRT-PCR) was used to determine the expression of miR-384 in OS tissues and cells. MTT assay, colony formation analysis, Transwell assays were performed to analyze the role of miR 384 in human OS cells. Western blotting was applied to analyze the expression of SETD8, and the luciferase reporter assay was used to assess the target gene of miR-384 in OS cells. RESULTS: We found that miR-384 was significantly lowly expressed in OS tissues and OS cell lines compared with the adjacent noncancerous tissues and normal bone cell lines, respectively. Further functional analysis indicated that up-regulation of miR-384 significantly inhibited OS cells proliferation, migration, and invasion, but down-regulation of miR-384 had the opposite effects on OS cells in vitro. Moreover, SETD8 was identified as the potential target of miR-384 using dual luciferase assay, qRT-PCR and Western blot. Finally, we observed that upregulation of SETD8 reversed the effects of overexpressing of miR-384 on the proliferation, migration, and invasion of OS. CONCLUSIONS: Our data provided the first evidence which supported the function of miR-384 as a tumor suppressor in OS by targeting SETD8. PMID- 29630103 TI - Effect of lncRNA LET on proliferation and invasion of osteosarcoma cells. AB - OBJECTIVE: To investigate the expression of long non-coding RNA (LncRNA) LET in osteosarcoma and its effect on the proliferation, apoptosis, migration and invasion of osteosarcoma cells. PATIENTS AND METHODS: The expression of lncRNA LET was detected in osteosarcoma tissues and cell lines (MG63 and hFOB1.19). MG63 cells stably overexpressing lncRNA LET were constructed by lentiviral. The effects of lncRNA LET overexpression on the proliferation, apoptosis, migration and invasion of osteosarcoma cells were detected by cell counting kit-8 (CCK-8), flow cytometry and transwell chamber assay. RESULTS: The expression of lncRNA LET in osteosarcoma tissues and MG63 cells was significantly down-regulated. Overexpression of lncRNA LET significantly inhibited the proliferation, migration, invasion, and induced apoptosis of MG63 cells. CONCLUSIONS: LncRNA LET was participated in the development of osteosarcoma, and may be used as a potential molecular target for the treatment of osteosarcoma. PMID- 29630104 TI - Early diagnostic role of PSA combined miR-155 detection in prostate cancer. AB - OBJECTIVE: As a kind of malignant tumor in the male genitourinary system, prostate cancer exhibits significantly increased occurrence. Prostate-specific antigen (PSA) expression can be seen in the prostate cancer, prostatitis, and other diseases, therefore, lack of diagnostic specificity. The miR-155 expression is abnormally increased in the tumors. Therefore, this study aims to explore the clinical significance of PSA combined miR-155 detection in the early diagnosis of prostate cancer. PATIENTS AND METHODS: A total of 86 patients diagnosed with prostate cancer were enrolled in this study. PSA and miR-155 gene expression in tumor tissue were detected by using Real-time PCR. The serum levels of PSA were measured by using enzyme-linked immunosorbent assay (ELISA). The correlation of PSA and miR-155 expression with age, body mass index (BMI), tumor volume, tumor node-metastasis (TNM) stage, lymph node metastasis (LNM), and other clinicopathological features were analyzed, respectively. RESULTS: Serum PSA expression and PSA gene in tumor tissue were significantly higher compared to that in adjacent tissues (p<0.05). PSA gene and protein increased significantly with the clinical stage of TNM and decreased following the increase of grade (p<0.05). The miR-155 level was significantly elevated in the tumor tissue compared with para-carcinoma tissue (p<0.05). PSA and miR-155 expressions were positively correlated with TNM stage, tumor volume, and LNM, and negatively correlated with grade (p<0.05). CONCLUSIONS: PSA and miR-155 were closely related to the clinicopathological features of prostate cancer. Combined detection is helpful for the early diagnosis of prostate cancer. PMID- 29630105 TI - MiR-1182 inhibited metastasis and proliferation of ovarian cancer by targeting hTERT. AB - OBJECTIVE: To investigate the potential effect of miR-1182 on the development of ovarian cancer and the relevant mechanism. PATIENTS AND METHODS: The expression levels of miR-1182 were detected in ovarian cancer tissues and cells (SKOV3) comparing with corresponding adjacent normal tissues and normal ovarian cell (IOSE80). Luciferase assay was performed to evaluate the interaction between miR 1182 and hTERT. The effects of the miR-1182/hTERT axis on SKOV3 cells were determined by subsequent experiments including cell proliferation, expression level of hTERT, the invasion and metastasis detection. RESULTS: miR-1182 was found repressed in ovarian cancer tissues and we got the same results at the cellular level. In order to research potential target of miR-1182, we checked it in three publicly available algorithms, TargetScan, miRDB and microRNA. We found that hTERT is a direct target of miR-1182, and luciferase assays confirmed our hypothesis. The subsequent experiments showed that decreased expression of hTERT resulting from the up-regulation of miR-1182 could decelerate cell proliferation, invasion, and metastasis in ovarian cancer cells. CONCLUSIONS: Our research discovers the suppressor function of miR-1182 in ovarian cancer by targeting hTERT, revealing that miR-1182/hTERT axis may be a potential therapeutic target for the treatment of ovarian cancer. PMID- 29630106 TI - To evaluate the correlation between the change of immune system function before and after the treatment of malignant obstructive type jaundice treated with biliary stent. AB - OBJECTIVE: To evaluate the correlation between the change of immune system function before and after the treatment of malignant obstructive type jaundice (MOJ) treated with a biliary stent. PATIENTS AND METHODS: 148 patients who were admitted to the Department of Digestive System for malignant obstructive jaundice were selected according to the standardized criterion. Amongst the total sample size, 78 were male patients and 70 were female patients, with an average age of (43.6 +/- 5.5) years. After admission, the patients completed the blood routine examination and received biliary stent treatment to relieve the sign and symptoms of jaundice. Follow-up observation included total white blood cells, CD4+T cell count, CD8+T cell count, the ratio of CD4+/CD8, neutrophil counts neutrophils percentage, total bilirubin, free bilirubin, alanine aminotransferase (ALT), and inflammatory factors. RESULTS: After three weeks of follow-up visit, CD4+T lymphocyte absolute value of patients markedly increased compared with that of pre-operation, and the difference had statistical significance (p < 0.05). The total bilirubin, free bilirubin, ALT, and inflammatory factors, such as hs-CRP, TNF-alpha in plasma of patients was significantly lower than that before the operation and the difference was statistically significant (p < 0.05). After six weeks of follow-up visit, the ratio of CD4+/CD8+ increased and the difference had statistical significance (p < 0.05) compared with that before biliary stent implantation. However, the white blood cell and neutrophil granulocyte did not improve significantly. It was found that CD4+/CD8+T lymphocyte had relation with the level of hs-CRP. CONCLUSIONS: The patients with the (MOJ) treated with implanted biliary stent revealed relive in the obstruction of the biliary tract, which will further significantly improve the cholestasis. The ratio of CD4+/CD8+T lymphocyte increased, which will improve the immune system function of the patients, decreases the possibility of infection, and improves the overall survival quality. PMID- 29630107 TI - LINC00963 promotes hepatocellular carcinoma progression by activating PI3K/AKT pathway. AB - OBJECTIVE: To explore the role of LINC00963 in the pathogenesis of hepatocellular carcinoma and its underlying mechanisms. PATIENTS AND METHODS: The expression level of LINC00963 in 48 cases of hepatocellular carcinoma (HCC) tissues and paracancerous tissues were detected by quantitative Real-time (qRT-PCR). Survival analysis was carried out based on the expression level of LINC00963. The association between the expression level of LINC00963 and clinical characteristics of these subjects was analyzed by x2-test. The proliferation and cell cycle of HCC cells after transfection of LINC00963 overexpression plasmids were evaluated by cell counting kit-8 (CCK-8) assay and flow cytometry, respectively. RESULTS: The expression level of LINC00963 in HCC tissues was remarkably higher than that in paracancerous tissues, indicating a potential diagnostic significance of LINC00963. The progression-free -with the tumor size and TNM stage, but not with age, gender, histological type and lymph node metastasis. Overexpression of LINC00963 significantly enhanced the proliferation ability of HepG2 and HCC cells and prolonged their G0/G1 phase. Furthermore, the PI3K/AKT expression was increased after overexpression of LINC00963, while AKT siRNA effectively reversed the prolonged G0/G1 phase caused by LINC00963 overexpression. CONCLUSIONS: Our data revealed that LINC00963 was upregulated in HCC, which significantly extended the G0/G1 phase of HCC cells by activating PI3K/AKT pathway and promoting the proliferative ability of HCC cells. LINC00963 may be involved in the HCC development. PMID- 29630108 TI - Expression of embryonic liver fodrin (ELF) and stem cell markers in CD13 liver cancer stem cells. AB - OBJECTIVE: Investigating the molecular signaling pathways using CD13 as a marker for Cancer Stem Cells (CSCs) in human liver cancer. PATIENTS AND METHODS: In the present study, liver carcinoma biopsies were obtained from the liver cancer patients, as well as healthy controls. Immunohistochemistry and Immunoblotting experiments were performed accordingly to conclude the data. RESULTS: Immunohistochemistry along with immunoblot data showed the expression of Oct-4, STAT3 and interestingly Embryonic Liver Fodrin (ELF) in the CD13 positive liver cancer stem cells. Though embryonic liver fodrin (ELF) is a pro-differentiation protein, it was expressed in the CD13 positive liver cancer stem cells along with stem cell markers such as Oct-4 and STAT3. CONCLUSIONS: Our finding concludes that an association of ELF expression was noted in liver cancer patients. Hence, ELF may have value as prognostic indicators and may facilitate the development of novel therapeutics for liver cancer. PMID- 29630109 TI - Effects of long non-coding RNA URHC on proliferation, apoptosis and invasion of colorectal cancer cells. AB - OBJECTIVE: To investigate the effect of long non-coding RNA URHC on the proliferation, apoptosis and invasion of colorectal cancer cells. PATIENTS AND METHODS: The expression of lncRNA-URHC in tissues and cells was tested by Real time quantitative PCR. The expression of lncRNA-URHC was down-regulated by RNA interference (siRNA). The Real-time quantitative polymerase chain reaction (PCR) method was used to detect the interference efficiency. Cell counting kit-8 (CCK 8), flow cytometry, and transwell were used to detect the effect of lncRNA-URHC on the proliferation, apoptosis and invasion of colorectal cancer cells. The effect of lncRNA-URHC on epithelial-mesenchymal transition (EMT)-related markers was detected by Western blot. RESULTS: LncRNA-URHC expression was significantly increased in colorectal cancer cells compared with normal cells, and the expression of lncRNA-URHC in colorectal cancer cells was higher than that in the normal cell. After down-regulated the expression of lncRNA-URHC, the proliferation and invasion of colorectal cancer cells were decreased, while cells apoptosis was promoted. Down-regulation of lncRNA-URHC could enhance the expression of E-cadherin and reduce the expression of N-cadherin, vimentin and snail. CONCLUSIONS: Down-regulation of lncRNA-URHC can inhibit the progression of colorectal cancer. PMID- 29630110 TI - Overexpression of UBE2C correlates with poor prognosis in gastric cancer patients. AB - OBJECTIVE: The ubiquitin-conjugating enzyme E2C (UBE2C) has been known as a crucial factor upregulated in various tumors. The functions of UBE2C is mainly involved in the pathway protein ubiquitination. This study investigates the expression of UBE2C in gastric cancers and its correlation with overall survival rate. MATERIALS AND METHODS: Real-time PCR (RT-PCR) and Western blotting were performed to determine the expression of UBE2C in gastric cancer samples and adjacent normal tissues. Immunohistochemical staining was used to assess the expression of UBE2C in 216 paraffin-embedded gastric cancer tissues. RESULTS: The mRNA and relevant protein levels of UBE2C in gastric cancer tissues are significantly greater than those in the adjacent normal tissues. Also, the expression of UBE2C is found to correlate with lymphatic metastasis, serosa invasion, TNM (Malignant Tumors) staging and Lauren's classification (p<0.05). The univariate analysis shows that the overexpression of UBE2C associates with poor prognosis (p=0.001). The multivariate analysis demonstrates that expression of UBE2C, lymphatic metastasis, and TNM staging are independent prognostic indicators. CONCLUSIONS: This study shows that overexpression of UBE2C contributes to the development of gastric cancer, and UBE2C has the potential to be exploited as a therapeutic target. PMID- 29630111 TI - MiR-1298 expression correlates with prognosis and inhibits cell proliferation and invasion of gastric cancer. AB - OBJECTIVE: To explore the association between miR-1298 expression and clinicopathological factors, prognosis of gastric cancer (GC) patients and biological functions underlying the GC progression. PATIENTS AND METHODS: Expression of miR-1298 was examined by qRT-PCR in GC tissues and cells, the adjacent normal tissues and normal gastric cell line GES-1 cells were used as controls. Association of disease-free survival (DFS) and overall survival (OS) time with miR-1298 expression was analyzed by Kaplan-Meier analysis and log-rank test. Univariate and multivariate analysis were also performed to analyze relative prognostic risk factors of GC patients. Cell proliferation and invasion assays were used to examine cell proliferation and invasion capacities in vitro. The relative protein expression was analyzed by Western blot analysis. RESULTS: MiR-1298 expression was lower in GC tissues and cells, compared to adjacent normal tissues and GES-1 cells, respectively. Lower miR-1298 expression levels were associated with lymph node metastasis and TNM stage. Kaplan-Meier analysis showed that lower miR-1298 expression predicted poor DFS and OS of GC patients. Furthermore, we demonstrated that lymph node metastasis, TNM stage, and lower miR 1298 expression were independent risk factors for DFS and OS in GC patients. In vitro, miR-1298 overexpression inhibited cell proliferation and invasion abilities. Additionally, our results revealed that miR-1298 overexpression suppressed PI3K/AKT signaling pathway in GC cells. CONCLUSIONS: Our evidence indicated that miR-1298 may provide a specifically promising target for therapy of GC patients. PMID- 29630112 TI - Interstitial brachytherapy of oral squamous cell carcinoma with ultrasound-guided iodine-125 radioactive seed implantation. AB - OBJECTIVE: In this study, we investigated the clinical effect of interstitial brachytherapy on oral squamous cell carcinoma (OSCC) with ultrasound or CT-guided 125I radioactive seed implantation. PATIENTS AND METHODS: 116 patients with advanced oral squamous cell carcinoma, who received initial treatment or retreatment, were enrolled. Therein, 35 patients in the control group were treated with external radiation, systemic chemotherapy or conservative treatment, 41 patients in the ultrasound group were treated with ultrasound-guided125I radioactive seed interstitial implantation brachytherapy, and 40 patients in the CT group were treated with CT-guided 125I radioactive seed interstitial implantation. The median follow-up time was 15.0 months. The clinical outcomes were compared. RESULTS: At the time of one month after treatment, the tumor diameters of the ultrasound group and the CT group were significantly decreased (p<0.05), which were less than the control group (p<0.05), and there was no difference in comparison between the ultrasound group and the CT group (p>0.05). At the time of one month after treatment, the effective rates were significantly higher in the ultrasound group and the CT group than the control group (p<0.001), and there was no difference in comparison between the ultrasound group and the CT group. And there was no difference in comparison of complication between these two groups (p>0.05). At the time of one month after treatment, the VAS scores of pain were significantly lower in the ultrasound group and the CT group than the control group (p<0.05). There were no differences in comparisons of T lymphocyte subset percentages before and after treatment (p>0.05), and T lymphocyte subset percentages in the control group were significantly decreased (p<0.05). The progression-free survivals, median survival times, and survival rates were significantly higher in the ultrasound group and the CT group than those in the control group (p<0.05), and there were no differences in comparisons between the ultrasound group and the CT group (p>0.05). CONCLUSIONS: Both ultrasound and CT guided iodine-125 radioactive seed interstitial implantation brachytherapy in the treatment of OSCC can achieve better short-term and long-term clinical effects. PMID- 29630113 TI - lncRNA CCHE1 increased proliferation, metastasis and invasion of non-small lung cancer cells and predicted poor survival in non-small lung cancer patients. AB - OBJECTIVE: Lung cancer is common cancer worldwide. Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancers. Thus, we studied whether long non coding RNAs influence malignancy in NSCLC to discover new therapeutic targets for increasing the survival rate of NSCLC patients. lncRNA has been proven to be important in different cancer progression. In this study, we mainly focused on the role of lncRNA CCHE1 (cervical carcinoma high expressed 1) expressed PCNA regulatory lncRNA in NSCLC cancer. PATIENTS AND METHODS: qRT-PCR was used to detect the expression of CCHE1 in 126 cases of NSCLC tissue and adjacent tissue, and the clinical significance was also analyzed. Cell Counting Kit-8 (CCK8) assay was used to detect the proliferation ability of NSCLC cancer cell lines, and Western-blot was used to measure the expression of the protein when the expression of CCHE1 was suppressed. RESULTS: We found that the CCHE1 was highly expressed in the NSCLC tissue, compared with the adjacent tissue. We also found that the expression of CCHE1 was closely related to the size and survival time of patients. Moreover, CCHE1 could promote the proliferation, metastasis, and invasion of NSCLC cell line via increasing the expression of ERK/MAPK signaling pathway. CONCLUSIONS: According to the results, we found that CCHE1 was closely related the progression of NSCLC, which could be a potential target for treating NSCLC. PMID- 29630114 TI - Targeting the HMGA2 oncogene by miR-498 inhibits non-small cell lung cancer biological behaviors. AB - OBJECTIVE: Previous study reported that miR-498 served as a tumor suppressor in non-small cell lung cancer (NSCLC), but the underlying mechanism remains largely unknown. The aim of this study is to investigate the role of miR-498 and its target gene HMGA2 in NSCLC progression. PATIENTS AND METHODS: The expression of miR-498 was assessed in clinical NSCLC specimens and cell lines using RT-PCR. Overexpression of miR-498 and transfection of pLenti-HMGA2 were performed in A549 cells. Cell proliferation, apoptosis, migration, and invasion were determined using cell counting kit-8 (CCK-8) assay, clone formation assay, flow cytometry, and transwell assay, respectively. Luciferase reporter assays were performed to analyze the regulation of putative target of miR-498. Western blot was used to detect the levels of HMGA2 in A549 cells. RESULTS: MiR-498 was found to be down regulated in NSCLC tissues and cell lines. After miR-498 mimics transfection, cell proliferation, migration, and invasion were significantly suppressed in the NSCLC cells. Mechanistically, bioinformatic analysis predicted that miR-498 may target the 3'-UTR of HMGA2 and suppressed its translation, and was further confirmed by luciferase assay. Furthermore, restoration of HMGA2 expression completely rescued the inhibitory effect of miR-498 in NSCLC cells. CONCLUSIONS: This paper revealed that miR-498 may serve as a tumor suppressor in NSCLC through targeting HMGA2, suggesting that miR-498 could represent a novel target for effective therapies. PMID- 29630115 TI - MicroRNA-520a-3p suppresses non-small-cell lung carcinoma by inhibition of High Mobility Group Box 1 (HMGB1). AB - OBJECTIVE: Currently, pathogenesis of non-small cell lung carcinoma (NSCLC) is still unknown and the treatment is far from ideal. Therefore, we investigated the effect of inhibiting microRNA-520a-3p in NSCLC cells. MATERIALS AND METHODS: NCI H157 cells were treated with microRNA-520a-3p analogs for 48 h, or microRNA-520a 3p analogs and its inhibitor, for a total of 48 h. Many tests were performed, including MTT, flow cytometry, wound healing assay and transwell assay. The tumor model was established, and HMGB1 mRNA was detected by RT-PCR. Protein levels of HMGB1, MMP-2, MMP-9, Bcl-2, Bax, and Caspase-3 were assessed by Western Blot. RESULTS: microRNA-520a-3p could significantly inhibit the proliferation, migration and invasion of NCI-H157 cells, inducing their apoptosis. microRNA-520a 3p inhibited tumor growth and decreased the mRNA and protein levels of HMGB1. Additionally, it decreased the Bcl-2/Bax ratio, MMP-2 and MMP-9 expression, and increased caspase-3 expression. CONCLUSIONS: microRNA-520a-3p exhibited an effective inhibition on NCI-H157 tumor growth likely by inhibiting HMGB1 expression. PMID- 29630116 TI - Effects of miR-143 overexpression on proliferation, apoptosis, EGFR and downstream signaling pathways in PC9/GR cell line. AB - OBJECTIVE: The functions of microRNAs in the regulation of apoptosis in non-small cell lung cancer (NSCLC) and the application in the therapeutical treatments were intensively studied. However, whether overexpression of miR-143 in lung cancer cells will affect the cell behaviors, such as proliferation or some underlying pathway, is largely unknown. This study aimed to examine the effect of miR-143 in PC9/GR cell line on the proliferation, apoptosis, EGFR and downstream signal pathways. MATERIALS AND METHODS: The non-small cell lung cancer (PC9/GR) cells were treated with concentration-increased gefitinib to acquire gefitinib resistance. Then, the acquired gefitinib-resistance cells were divided into 3 groups, blank control group (BC group), negative control group (NC group), and miR-143 transfected group (miR-143 group). miR-143 mRNA was detected by quantitative PCR. The proliferation was detected by CCK-8. The cell apoptosis was determined by flow cytometry. The expression of EGFR and downstream signal pathway factors of p-EGFR, AKT, p-AKT, ERK1/2 and p-ERK1/2 were detected by Western blot. RESULTS: The cell proliferation in miR-143 transfected group was significantly suppressed compared with BC and NC group, while the apoptosis was dramatically increased. The p-EGFR, p-AKT, p-ERK1/2 protein expression was significantly inhibited. CONCLUSIONS: These results demonstrated that overexpression of miR-143 downregulated cell proliferation, promoted the apoptosis, and suppressed the phosphorylation of EGFR, AKT and ERK1/2; thus, miR 143 may play a role in treatment of NSCLC to enhance therapeutic efficacy. PMID- 29630117 TI - URG4-silencing suppresses cell proliferation in nasopharyngeal carcinoma through induction of apoptosis. AB - OBJECTIVE: To investigate the expression and function of up-regulator of gene-4 (URG4) in nasopharyngeal carcinoma (NPC). PATIENTS AND METHODS: Fresh NPC tumor tissue samples with paired adjacent normal nasopharyngeal tissues samples of 9 NPC patients were collected from NPC curative resection surgery. NPC cell lines (CNE1, CNE2 and HONE1) were cultured. Lentivirus-mediated URG4-specific short hairpin RNA (shRNA) stable transfection was done. The effect of URG4 on CNE4 and HONE1 cells viability was determined via 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT). The plate-colony-formation assay was performed. Apoptosis analysis was done by flow cytometry. The expression levels of protein and RNA were detected by Western blotting and quantitative polymerase chain reaction (qPCR). RESULTS: We determined the expression of URG4/URGCP in NPC tissues and cell lines using qPCR analysis and found it was significantly upregulated in NPC. After that, stable URG4-silencing NPC cells were constructed by transfection with lentivirus-mediated shRNA. Functionally analyses indicated that knockdown of URG4 significantly impaired cell viability and colony formation ability, as confirmed by MTT and colony formation assays. Furthermore, URG4 silencing NPC cells showed more cells in the stage of early and late apoptosis compared with controls by flow cytometry assay. Western blot analysis further confirmed that knockdown of URG4 enhanced the expression of cleaved caspase-3, cleaved PARP and Bax, while decreased the expression of Bcl-2 and survivin. CONCLUSIONS: URG4/URGCP might play an essential role in NPC cell growth and proliferation and its silencing might be as a potential therapeutic target for NPC. PMID- 29630118 TI - Increased expression of miR-330-3p: a novel independent indicator of poor prognosis in human breast cancer. AB - OBJECTIVE: Previous study has reported that miR-330-3p was highly expressed in breast cancer (BC) patients. However, the effect of miR-330-3p in BC progression remains largely unclear. The purpose of this study was to investigate the clinical significance of miR-330-3p expression in BC. PATIENTS AND METHODS: The expression of miR-330-3p was detected by quantitative Real-time PCR in BC tissues and matched normal breast tissues. The association of miR-330-3p expression with clinicopathological factors of BC patients was also analyzed by x2-test. Prognosis value of patients with BC was assessed by Kaplan-Meier method and Cox proportional hazards model, respectively. RESULTS: Quantitative real-time PCR analysis showed that the expression level of miR-330-3p was significantly higher in BC specimens than that in corresponding noncancerous tissues (p < 0.01). The levels of miR-330-3p were positively correlated with the status of TNM stage (p = 0.011) and lymph node metastasis (p = 0.006). Kaplan-Meier analysis revealed that 5-year overall survival of BC patients with high miR-330-3p expression was shorter compared to those patients with low miR-330-3p expression (p < 0.0001). Moreover, univariate and multivariate regression analysis demonstrated that miR 330-3p was an independent prognostic factor in BC. CONCLUSIONS: Our data suggest that miR-330-3p upregulation maybe concurrently associated with prognosis in patients with BC, suggesting that miR-330-3p may be a potential prognostic biomarker and therapeutic target for patients with BC. PMID- 29630119 TI - Intramuscular islet allotransplantation in type 1 diabetes mellitus. AB - OBJECTIVE: Alternative sites to the liver for islet transplantation have been studied for a long time. Intramuscular islet transplantation appears to be an alternative site to the liver because of the ease of access. First islet autotransplantations were reported in patients after total pancreatectomies. The transplanted islets showed a proper revascularization and their function was observed for up to 2 years after the implant. However, only a few cases of autotransplantation and no allotransplantation have been performed. The aim of this study was to verify the feasibility of islet allotransplantation into muscles. PATIENTS AND METHODS: In four patients affected by type 1 diabetes mellitus in which liver islet allotransplantation was contraindicated, human islets were transplanted into patients' arm muscle with local anesthesia. RESULTS: The surgery was minimally invasive, without complications. In one patient a moderate local inflammatory reaction was observed at the site of the implant, which resolved spontaneously within 4 days. Islet graft function was observed after transplantation in all patients, but it progressively disappeared in 3 out 4 patients within a short time. CONCLUSIONS: In this first ever-reported intramuscular pancreatic islet allotransplantation, the procedure appears feasible but new strategies must be envisaged to significantly improve islet engraftment and the long-term graft function. PMID- 29630120 TI - The role of miR-146b-5p in TLR4 pathway of glomerular mesangial cells with lupus nephritis. AB - OBJECTIVE: MicroRNAs (miRNAs) are now recognized as important regulators of gene expression. The aim of the study was to investigate the role of miR-146b-5p in the TLR4 pathway and provide the basis for the treatment of lupus nephritis. MATERIALS AND METHODS: The glomerular mesangial cells were cultured in vitro and divided into 3 groups: control group, a group of miR-146b-5p mimic added, and a group of miR-146b-5p inhibitor added. The levels of IL-6 and IL-8 in the cell culture supernatant of the three groups were detected by ELISA. The cell proliferation was detected by MTT. The expressions of MiR-146b-5p and TLR4 pathway-associated factor TRAF6 were detected by RT- PCR. The expression of TRAF6 and IRAK1 protein was detected by Western blot. RESULTS: The overexpression of miR-146b-5p could reduce the level of IL6 and IL8 in cell culture and inhibit glomerular mesangial cell proliferation in some degree. Also, the overexpression of miR-146b-5p could inhibit the expressions of TLR4 pathway-associated factor TRAF6 and IRAK1mRNA, and the expressions of TRAF6 and IRAK1 protein. CONCLUSIONS: MiR-146b-5p attenuated the inflammatory response of glomerular mesangial cells by inhibiting the expressions levels of TRAF6 and IRAK1 in lupus nephritis. PMID- 29630121 TI - The additional role of 18F-FDG PET/CT in prosthetic valve endocarditis. AB - OBJECTIVE: The purpose of the present review is an update on the diagnosis of prosthetic valve endocarditis (PVE), evaluating the additional value of 18F fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) to the standard modified DUKE criteria on which for a long time is based the diagnostic strategy of the disease. MATERIALS AND METHODS: We did a comprehensive research on the studies reported in the literature and regarding the employment of 18F-FDG PET/CT in the early diagnosis of PVE in patients with suspected disease. Scientific databases have been examined such as Medline and PubMed, followed by a review of citations and reference lists. The research included the following terms: infective endocarditis, prosthetic heart valve and cardiac valve replacement infections, 18F-FDG PET/CT and endocarditis. RESULTS: The recent studies reported in the literature on the PVE diagnostic approaches showed elevated sensitivity and specificity values of 18F-FDG PET/CT ranging from 73 to 96.6% and from 80 to 94%, respectively, reducing the number of misdiagnosed patients. The usefulness of the radioisotopic procedure is even more important when the other diagnostic conventional diagnostic tools, such as echocardiography, are inconclusive or negative in patients in whom the diagnosis of PVE is definitively ascertained. However, false negative and positive results of 18F-FDG PET/CT were also ascertained in some studies interfering with image interpretation even if such limitation can be reduced with an adequate patient preparation, with a better knowledge of clinical course of the disease, of the treatment in progress and of the different technical aspects of the method. CONCLUSIONS: In different studies reported in the literature, 18F-FDG PET/CT proved to improve the diagnostic accuracy of the conventional modified DUKE criteria in patients with suspected IE, and in particular with PVE, giving the highest diagnostic performance and providing additional diagnostic benefits. Thus, the radioisotopic hybrid procedure should be included in the diagnostic protocol of PVE as complementary tool to modified DUKE criteria. Finally, the usefulness of 18F-FDG PET/CT in monitoring the response to antibiotic therapy, although the few data reported in the literature are encouraging, needs more numerous studies and with a major number of cases. PMID- 29630122 TI - Analysis of the correlation between the neutrophil-lymphocyte ratio in peripheral blood and perioperative myocardial damage in pediatric patients with frequent ventricular premature beat. AB - OBJECTIVE: The objective of the present study was to investigate the relationship between the neutrophil-lymphocyte ratio (NLR) in peripheral blood and myocardial damage in pediatric patients with frequent ventricular premature beat (FVPB), and provide a reference for myocardial preservation in these patients. PATIENTS AND METHODS: A total of 212 pediatric patients who were treated in the Department of Cardiology, Xuzhou Children's Hospital between December 2014 and March 2016 for FVPB, were selected. The results of routine blood exam, and levels of cardiac troponin I (cTnI) and creatine kinase-MB (CK-MB) in patients after the onset of FVPB were analyzed, and NLR was calculated. According to NLR levels, patients were divided into four groups using quartiles. RESULTS: With increases of NLR, the proportion of patients with a history of hypertension and ejection fraction < 50% increased gradually, and white blood cells (WBCs), the peaks of CK-MB and cTnI, and serum creatinine levels were significantly increased (p<0.05, p<0.01). There were no significant differences (p>0.05) in age, sex, body mass index, serum creatinine before treatment, fasting blood glucose, TG, TC, LDL-C, and HDL C among the four groups. Multiple stepwise regression analysis showed that for patients with FVPB, NLR in peripheral blood was positively correlated with the peak of cTnI (r=0.538, p<0.05). NLR was positively correlated with levels of WBCs (r=0.661, p<0.05) and there was no correlation between NLR and history of hypertension, ejection fraction, and the laboratory results of creatinine peak and CK-MB. The differences were not statistically significant (p>0.05). However, the peak of cTnI was positively correlated with the levels of WBCs (r=0.189, p=0.003). CONCLUSIONS: NLR and WBCs in patients with FVPB are positively related to the peak of cTnI. NLR may serve as an excellent marker that reflects myocardial damage in pediatric patients with FVPB. PMID- 29630123 TI - IL-33 induced inflammation exacerbated the development of chronic obstructive pulmonary disease through oxidative stress. AB - OBJECTIVE: We aimed at exploring the role of IL-33 in mouse chronic obstructive pulmonary disease and its potential molecular mechanism. MATERIALS AND METHODS: The chronic obstructive pulmonary disease (COPD) mice model was established by cigarette smoking (CS). COPD mice were randomly assigned into PBS group and IL-33 antibody group. The peripheral blood and lung tissues of mice from two groups were collected for the following experiments. Pathological changes of the lung tissues in both groups were analyzed by hematoxylin and eosin (HE) staining. IL 33 positive cells in lung tissues were detected by immunohistochemistry. Then, the mRNA and protein levels of IL-33, sST2, ERK and TNF-alpha in the mice peripheral blood of the two groups were accessed by Real-time polymerase chain reaction (RT-PCR) and Western blot. Finally, the indicators related to oxidative stress, including superoxide dismutase (SOD), malondialdehyde (MDA) and reactive oxygen species (ROS) in the mice serum of two groups were measured. RESULTS: After successful construction of COPD mouse model by CS, HE staining illustrated that the structure of airway wall of lung tissue in mice from PBS group was irregular. The ciliated columnar epithelium presented significant degeneration, necrosis and shedding. A large amount of inflammation cell infiltration was observed in vascular tissues. The alveolar epithelial structure was severely damaged and alveolar septum was narrowed and ruptured. Adjacent alveoli were found to be fused into larger cysts. The above pathological changes were relatively better in mice from IL-33 antibody group. Immunohistochemical results demonstrated that IL-33 was remarkably deposited in the lung tissue of PBS group. The mRNA and protein levels of IL-33, sST2, ERK and TNF-alpha in peripheral blood of PBS group were much higher than those of IL-33 antibody group. At the same time, SOD level in PBS group decreased, while MDA level and ROS production increased. CONCLUSIONS: IL-33 aggravates lung injury in COPD mice by increasing inflammation response and oxidative stress, which may serve as a target for predicting and treating COPD. PMID- 29630124 TI - Study of candidate gene cHRNA4 for familial epilepsy syndrome. AB - OBJECTIVE: To screen a three-generation familial partial epilepsy with variable foci (FPEVF) family with epilepsy to identify the cHRNA4 gene (a candidate gene). PATIENTS AND METHODS: A total of 18 members of the three-generation FPEVF family with partial epilepsy were selected, and 18 blood samples were collected for investigation. Among them, five members were affected by epilepsy, and another 13 members were not affected. A pedigree chart was mapped to comprehensively analyze the clinical characteristics of each member, including ictal semiology, electroencephalogram (EEG), past medical history, MRI features, neuropsychological MMSE (mini-mental state examination) scores, etc. PCR and Sanger sequencing method were used to screen the mutant gene cHRNA4. RESULTS: cHRNA4 genes of all affected members were positively mutated, and that of the unaffected members were negative. The positive mutation was base A instead of base G. CONCLUSIONS: cHRNA4 is the causative gene of FPEVF, and genes of the affected members are all heterozygotes mutations. PMID- 29630125 TI - Effects of sevoflurane post-conditioning in cerebral ischemia-reperfusion injury via TLR4/NF-kappaB pathway in rats. AB - OBJECTIVE: The aim of the study was to investigate the anti-inflammatory effect of sevoflurane post-conditioning on cerebral ischemia-reperfusion injury in rats. MATERIALS AND METHODS: Thirty Sprague Dawley (SD) rats were randomly divided into 3 groups: sham operation group (Sham), ischemia/reperfusion injury (I/R) group and sevoflurane post-conditioning group (Se). Hematoxylin-eosin (HE) staining was used to observe the inflammatory response in the brain tissue. The levels of TNF alpha, IL-1beta, IL-6 in serum were measured by ELISA. The mRNA and protein expression of TLR4 and NF-kappaB p65 were detected by RT-PCR and Western blot in the brain tissue. RESULTS: The post-conditioning of sevoflurane decreased the level of inflammatory reaction in ischemic-reperfusion rat cerebral infarction area and reduced the levels of pro-inflammatory cytokines such as TNF-alpha, IL 1beta, IL-6 in rats with ischemia-reperfusion injury. In addition, after treatment with sevoflurane, the mRNA and protein expression of TLR4 and NF kappaBp65 in TLR4/NF-kappaB pathway was inhibited. CONCLUSIONS: Sevoflurane post conditioning can decrease the inflammatory reaction in cerebral infarct area induced by cerebral ischemia-reperfusion injury in rats. The neuroprotective effect mechanism of sevoflurane may be related to TLR4/NF-kappaB signaling pathway. PMID- 29630126 TI - Clinical application of kelp micro gelation (KMG) in partial splenic embolization. AB - OBJECTIVE: We aimed to compare and analyze the long-term efficacy and safety between kelp micro gelation (KMG) and gelfoam particles in partial splenic embolization (PSE). PATIENTS AND METHODS: This study retrospectively included 65 liver cirrhosis patients with comorbidity of hypersplenism who were admitted in Nanfang Hospital from July 2008 to May 2012. Among the included patients, 33 patients were in KMG-PSE group, and 32 cases were included in Gelfoam-PSE group. According to the Child-Pugh criteria, all cases were divided into grade A, B, and C, respectively. All eligible subjects received CT or MR examination and laboratory examination. RESULTS: Our results showed that both KMG and gelfoam particles could substantially improve the short-term efficacy of thrombocytopenia leukopenia. However, the efficacy of KMG is superior to that of gelfoam. Due to the characteristic of KMG as a permanent agent, KMG may result in an obvious pain in the spleen after PSE, especially in patients with megalosplenia. KMG was more expensive than gelfoam particles. The complication rate in patents with great embolization was much higher than that with less embolization. CONCLUSIONS: The efficacy of KMG is superior to that of gelfoam in both short-term and long-term. To effectively control the occurrence of severe complication, the embolization should be controlled less than 70% regardless of the embolization agents. PMID- 29630127 TI - Research and analysis of 74 bloodstream infection cases of Acinetobacter baumannii and drug resistance. AB - OBJECTIVE: We aimed at investigating the clinical and bacteriological features and drug resistance of bloodstream infection of Acinetobacter baumannii, so as to provide new evidence for treatment of bloodstream infection of Acinetobacter baumannii. PATIENTS AND METHODS: Statistical analysis was carried out for the clinical and bacteriological features and drug sensitivity of 74 bloodstream infection cases of Acinetobacter baumannii who were admitted to this hospital between July 2016 and June 2017. RESULTS: Among 74 patients, about 72.0% of them were admitted to the ICU and Respiratory Department; the average age of these patients was 63 years old. Among 74 patients, 62 patients stayed in the hospital for over 2 weeks (83.8%), and 35 for over 1 month (47.3%); 72.0% of patients experienced intrusive operation, in which 28.0% of patients dead. The experiment of drug sensitivity showed that tigecycline had the highest sensitivity (100%), sequentially followed by amikacin (over 90.0%) and other anti-bacterial drugs (less than 40.0%). Pan-drug resistance was identified in 42 patients, accounting for 56.8%. Comparison between the pan-drug resistant and non-pan-drug resistant patients showed that in the first two weeks before the positive blood culture, there were statistically significant differences in administration of carbapenem antibiotics and intrusive operation (p<0.05). Among the patients, the lowest resistance to carbapenem antibiotics was 8.16%, while the rate of resistance to other 12 antibiotics was more than 40.00%. Multiple-resistant strain mainly originated from the ICU and the burn center. CONCLUSIONS: In patients with bloodstream infection of Acinetobacter baumannii, the pan-drug resistant strains account for a vast majority with a high mortality rate. Age, intrusive operation and length of stay in hospital longer than 2 weeks are the common susceptible factors, while the administration of carbapenem antibiotics and intrusive operations might be the high-risk factors leading to pan-drug resistant cases. PMID- 29630128 TI - Therapeutic dosage of ozone inhibits autophagy and apoptosis of nerve roots in a chemically induced radiculoneuritis rat model. AB - OBJECTIVE: Radiculoneuritis characterizes by the neurogenic pain along the back of patients. This study aims to investigate the therapeutic effects of ozone on radiculoneuritis and the associated mechanisms in rat models. MATERIALS AND METHODS: A chemical radiculoneuritis rat model was successfully established. The rats were divided into 3 groups, including radiculoneuritis Model rats group (Model group, n=18), Ozone therapy group (n=18), and Normal control group (n=18). Ozone was administered at a dosage of 1 mg/kg/day. The electron microscope was used to observe autophagosomes in the cytoplasm. Immunohistochemistry assay was performed to examine cleaved caspase 3 and double-labeled immunofluorescence assay was used to detect light chain 3B (LC3B) and neuronal nuclear antigen (NeuN) expression. Quantitative Real-time PCR (RT-PCR) and Western blot were employed to evaluate the expression of LC3B, Beclin 1, phosphodiesterase 2A (PDE2A), and nuclear factor-kB p65 (NF-kBp65). RESULTS: Ozone significantly decreased autophagosomes formation and inhibited autophagy of nerve root cells in radiculoneuritis rat model. Ozone significantly decreased levels of autophagosomes initiator, LC3B, compared to Model group (p<0.05). Ozone significantly decreased cleaved caspase 3 expressions and alleviated apoptosis of nerve root cells compared to that of Model group (p<0.05). According to RT-PCR and Western blot assay, ozone significantly suppressed LC3B and Beclin 1 expression compared to that of Model group (p<0.05). Ozone significantly decreased PDE2A and NF-kB p65 expression compared to that of the Model group (p<0.05). CONCLUSIONS: Therapeutic dosage of ozone inhibits autophagy by suppressing LC3B and Beclin 1 expression and reduces apoptosis by blocking NF-kB signaling pathway. PMID- 29630129 TI - A meta-analysis of pharmacological neuroprotection in noncardiac surgery: focus on statins, lidocaine, ketamine, and magnesium sulfate. AB - OBJECTIVE: Non-cardiac surgery is associated with perioperative cerebral complications (delirium, postoperative cognition dysfunction, stroke). While rare, these complications can lead to disabilities and deaths. Information is ambiguous as to whether pharmacological preoperative treatment exerts neuroprotection. We wished to systematically assess potential modulation by statins, lidocaine, ketamine or magnesium sulfate of the relative risk of cerebral complications in noncardiac surgery. Selection of these pharmacological agents was based on their known neuroprotective abilities. PATIENTS AND METHODS: By searching Medline, EMBASE and Cochrane databases, we identified 4 suitable publications that collectively enrolled 1358 patients (intent-to-treat population), of which 679 patients were treated preoperatively with statins (404 patients on atorvastatin and 275 on rosuvastatin) and 679 patients with preoperative placebo. The reported cerebral outcome was stroke, assessed either within 30 days (4 publications) or 6 months (2 publications) after surgery. RESULTS: Episodes of stroke within 30 days and 6 months postoperatively were observed in several publications, enabling aggregate analyses. No modulation by statins of the relative risk of stroke at 30 days was observed (risk ratio 1.59, 95% confidence interval 0.08-30.97; p = 0.76). At 6 months, statins showed an insignificant trend toward neuroprotection (risk ratio 0.33, 95% confidence interval 0.05-2.10; p = 0.24). CONCLUSIONS: The available clinical data are still scarce. Our analyses indicate no protective effects by statins against perioperative stroke but some favorable trends toward delayed stroke. Further randomized trials are needed to unequivocally assess the neuroprotective potential of current pharmacological agents in non-cardiac surgery. PMID- 29630130 TI - Inhibitive effects of microRNA-34a on protecting against ischemia-reperfusion injury of vital organs in hemorrhagic shock pregnant mice. AB - OBJECTIVE: Hemorrhagic shock is a common vital condition in obstetrics, and major treatment consists of bleeding control and liquid resuscitation. MicroRNA (miR) has been found to regulate multiple diseases. However, its expression profile in hemorrhagic shock or effects on the ischemia-reperfusion injury in pregnant mice has not been reported yet. PATIENTS AND METHODS: This study generated rat hemorrhagic shock pregnant model, on which real-time quantitative PCR was used to measure miR-34a expressions. MiR-34a inhibitor was applied to specifically suppress miR-34a expression. Serum malondialdehyde (MDA) and superoxide dismutase (SOD) levels were measured by using the commercial kit. Ischemia-reperfusion injury on rat kidney, lung, liver and intestine tissues was evaluated by using hematoxylin-eosin (HE) staining. RESULTS: In a hemorrhagic shock pregnant rat model, miR-34a expression level was significantly elevated compared to the Normal group (p < 0.05). Application of miR-34a inhibitor effectively suppressed the miR 34a expression in rat kidney, lung, liver and intestine tissues (p < 0.05 compared to normal group). Model rats also had significantly elevated serum MDA and significantly lower SOD levels compared to Normal group (p < 0.05). miR-34a inhibitor reversed this abnorma lity to certain extents (p < 0.05 compared to model group). HE results showed ischemia-reperfusion damage in rat kidney, lung, liver and intestine tissues. miR-34a inhibitor improved such injury. CONCLUSIONS: Suppression of miR-34a could alleviate multi-organ damage after re-perfusion of hemorrhagic shock pregnant rats, probably due to the suppression of oxidative stress. Suppression of miR-34a might work as the treatment target treating multi organ damage caused by hemorrhagic shock. PMID- 29630131 TI - Butorphanol attenuates myocardial ischemia reperfusion injury through inhibiting mitochondria-mediated apoptosis in mice. AB - OBJECTIVE: To investigate the role of the opioid receptors agonist butorphanol on mice myocardial ischemia reperfusion (I/R) injury. MATERIALS AND METHODS: The left anterior descending of coronary artery was ligatured for 30 min and then reperfusion for 6 h was performed to mimic the mouse myocardial I/R injury. All mice were randomly divided into three groups: sham group, I/R group and I/R + butorphanol group. Blood samples were collected for the measurement of cardiac troponin I (CTnI) and creatine kinase MB (CK-MB) levels. The infarct size was stained by triphenyltetrazolium chloride. The mitochondria morphology was observed by electron microscopy. The expressions of cleaved caspase-9 and -3, p38, ERK and JNK were detected by Western blot. RESULTS: The myocardial infarct size, serum CK-MB and CTn I levels, expression of cleaved caspase-9 and -3, phosphorylation of p38 and JNK were all increased in the I/R group compared with the sham group (all p < 0.01). Butorphanol reduced the myocardial infarct size, serum CTn I and CK-MB levels, expression of cleaved caspase-9 and -3, and phosphorylation levels of p38 and JNK (all p < 0.01). The number of mitochondria and the individual mitochondrial cross-sectional areas were decreased in the I/R mice compared with the sham-operated mice (all p < 0.01). Butorphanol reversed these changes in mitochondrial morphology (all p < 0.01). CONCLUSIONS: Butorphanol attenuates myocardial I/R injury through reducing cardiomyocyte apoptosis by inhibiting mitochondria-mediated apoptotic pathway, and blockage of p38 and JNK phosphorylation. PMID- 29630132 TI - Effects of sevoflurane or propofol combined with remifentanil anesthesia on clinical efficacy and stress response in pregnant women with pregnancy-induced hypertension. AB - OBJECTIVE: To compare the effects of sevoflurane or propofol combined with remifentanil anesthesia on the clinical efficacy and stress response of pregnancy induced hypertension (PIHS) in cesarean section. PATIENTS AND METHODS: 150 patients with PIHS and treated with cesarean section in our hospital from May 2015 to September 2016 were selected. All patients were randomly divided into sevoflurane-remifentanil group (n=75) and propofol-remifentanil (n=75). The elbow blood of patients in both groups were collected, the levels of Norepinephrine (NE) adrenaline (AD), cortisol and blood glucose in plasma were compared at before anesthesia induction (T0), operation 30 min (T1), end of operation (T2), 2 h after operation (T3), 24 h after operation (T4). The blood pressure control, muscle control, anesthesia onset time, maternal pain and complications were compared between the two groups. RESULTS: The patients in the sevoflurane group were superior to the propofol group (p<0.05) in terms of muscle control effect, anesthesia onset time and maternal pain. There was no significant difference between the two groups in terms of blood pressure control and anesthesia complications (p>0.05). There was no significant difference in plasma AD, NE, cortisol and blood glucose between the two groups before induction of anesthesia (p>0.05). However, the plasma markers of the two groups began to increase after anesthesia induction and reached peak at T2 or T3, returned back to preoperative level or higher than before surgery at T4. The levels of AD, NE, cortisol and blood glucose in plasma of sevoflurane group were significantly lower than those in propofol group at T1-T4 time point, the difference was statistically significant (p<0.05). CONCLUSIONS: The clinical efficacy of sevoflurane combined with remifentanil anesthesia is better than that of propofol combined with remifentanil, and it can effectively reduce the stress of pregnant women with pregnancy-induced hypertension treated with cesarean section. PMID- 29630133 TI - Ketamine alleviates LPS induced lung injury by inhibiting HMGB1-RAGE level. AB - OBJECTIVE: Inflammatory cytokines secretion is an important reason to promote lung tissue inflammation in acute lung injury (ALI). High mobility group box 1 (HMGB-1) and its receptor for advanced glycation end products (RAGEs) play a role in ALI. Ketamine can significantly alleviate ALI, whereas its specific mechanism has not been fully elucidated. MATERIALS AND METHODS: A total of 60 male Wistar rats were equally randomly divided into three groups, including ALI group which was established by 10 mg/kg LPS femoral vein injection, ketamine group which was constructed by 50 mg/kg ketamine femoral vein injection based on ALI model, and control group. Blood gas analysis was applied to detect arterial blood oxygen partial pressure (PaO2) and pH. Lung tissue wet/dry weight ratio (W/D), myeloperoxidase (MPO) and superoxide dismutase (SOD) activity were detected. Real time PCR and ELISA were used to test HMGB-1 expression in lung tissue and serum. RAGE and NF-kappaB changes were determined by Real-time PCR and Western blot. RESULTS: Compared with control, ALI group presented decreased PaO2 and PH, elevated W/D, enhanced MPO activity, declined SOD activity, upregulated HMGB-1 mRNA, increased HMGB-1 secretion, and increased RAGE and NF-kappaB mRNA and protein (p < 0.05). Ketamine treatment significantly elevated PaO2 and PH, reduced W/D, declined MPO activity, enhanced SOD activity, inhibited HMGB-1 mRNA and secretion, and downregulated RAGE and NF-kappaB mRNA and protein (p < 0.05). CONCLUSIONS: Ketamine can alleviate LPS induced lung injury through inhibiting HMGB1-RAGE level. It could be treated as a new choice for ALI treatment. PMID- 29630134 TI - Clinical efficacy of sequential therapy with voriconazole on COPD patients in acute phase with pulmonary aspergillosis and effects on cytokines and pulmonary functions. AB - OBJECTIVE: To explore the clinical efficacy of sequential therapy with voriconazole on chronic obstructive pulmonary disease (COPD) patients in acute phase with pulmonary aspergillosis and its effects on cytokines and pulmonary functions. PATIENTS AND METHODS: A total of 110 COPD patients in acute phase with pulmonary aspergillosis who were admitted to the hospital between February 2015 and November 2016 were enrolled. We divided them randomly into two groups, i.e., the control group (n = 55) and the treatment group (n = 55). Patients in the control group took itraconazole capsules orally (200 mg/time, twice per day for three days followed by once per day). Patients in treatment group underwent sequential treatment with voriconazole through intravenous infusion at a dose of 5 mg/kg/time twice a day for 3 days followed by a dose of 4 mg/kg/time, twice a day for 8 days. Then, patients took voriconazole orally at a dose of 150 mL/time, twice a day for 6 days. Patients in two groups received the treatment for a total of 14 days. After treatment, we evaluated the levels of tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), and IL-8. The total lung capacity (TLC), diffusing capacity of the lung for carbon monoxide (DLco), and arterial oxygen saturation (SaO2), were measured as well. RESULTS: The total effectiveness rates of the treatment group and the control group were 83.63% and 61.82%. The differences had statistical significance (p < 0.01). After treatment, the incidence of chest pain, cough, sputum-coughing, hemoptysis, cyanosis, and dyspnea in the treatment group was significantly fewer than that in the control group (p < 0.05). TCL, DLco, and SaO2 in the two groups were significantly ameliorated by treatment (p < 0.05). The amelioration in the treatment group was more prominent than that in the control group (p < 0.05). The levels of TNF alpha, IL-8, and IL-6 in the two groups were decreased dramatically by the treatments. The decrease in the treatment group was significantly lower than those in the control group (p < 0.05). Occurrence of adverse reactions in treatment group and control group were 8.33% and 6.25%, respectively; (p > 0.05). CONCLUSIONS: Sequential therapy with voriconazole exhibits promising clinical efficacy in COPD patients in acute phase with pulmonary aspergillosis. The treatment ameliorated the clinical symptoms and vital signs of patients significantly. It also improved the pulmonary functions and inhibited the inflammatory responses of patients with evident clinical efficacy. PMID- 29630135 TI - Magnesium bioavailability after administration of sucrosomial(r) magnesium: results of an ex-vivo study and a comparative, double-blinded, cross-over study in healthy subjects. AB - OBJECTIVE: We conducted an ex-vivo analysis and a study in healthy subjects to compare magnesium bioavailability after administration of Sucrosomial(r) magnesium or commercially available preparations of magnesium citrate, magnesium oxide and magnesium bisglycinate. MATERIALS AND METHODS: In the ex-vivo study we simulated magnesium intestinal absorption after digestion through sections of intestinal mucosa isolated from rats. We compared the absorption of magnesium oxide and Sucrosomial(r) magnesium at two different concentrations: 32.9 mg/ml and 329 mg/ml. The human study was a single day double-blinded repeated crossover study in healthy subjects. Each subject was administered 350 mg magnesium in different formulations (Sucrosomial(r) magnesium, magnesium citrate, magnesium oxide or magnesium bisglycinate) after 1 week of washout. We collected blood and urine samples to measure magnesium concentration in blood, urine and red blood cells. RESULTS: The ex-vivo evaluation showed that magnesium absorption after administration of Sucrosomial(r) magnesium was faster and with higher rates compared to a standard formulation of magnesium oxide. This finding was further confirmed by the results of the study in healthy subjects, that showed a more evident increase in magnesium concentration after administration of Sucrosomial(r) magnesium compared to the other formulations. In particular, the increase in magnesium concentration from baseline to 24 h was statistically higher in blood and in urine for Sucrosomial(r) magnesium compared to magnesium oxide, while in red blood cells Sucrosomial(r) magnesium had a statistically significant advantage compared to magnesium bisglycinate. CONCLUSIONS: Our findings suggest that Sucrosomial(r) magnesium leads to an increased bioavailability of magnesium compared to other formulations. Further studies are needed to investigate if this advantage turns into more evident clinical efficacy. PMID- 29630136 TI - Body fat changes in HIV patients on highly active antiretroviral therapy (HAART): a longitudinal DEXA study. AB - OBJECTIVE: We aimed to quantitatively evaluate body fat composition in a group of HIV patients treated with Highly Active Anti-retroviral Therapy (HAART) to ascertain both fat loss and fat distribution changes and to identify possible therapeutic and host related associated risk factors. PATIENTS AND METHODS: A total of 180 patients with available total body DEXA scan were assigned to a) Group 1, with clinically evident body fat changes, (BFC) and b) Group 2, without BFC. Clinical and immunovirologic data were collected. We used Student t-test and x2 or Fisher exact test to compare the characteristics of the two groups. Paired t-test was used to compare basal and follow-up data. The relationships between variables were evaluated by calculating Pearson's correlation coefficient and its significance. RESULTS: HAART duration was significantly (p<0.0001) higher for patients in Group 1 than in Group 2, as well as PI (p<0.02) and NRTI (p<0.002) therapy duration. Current CD4 count and CD4 rise from nadir resulted significantly higher in Group 1 than in Group 2 (p<0.02 and 0.006, respectively). Whole Body Fat (WBF), Peripheral Fat (PF) and Leg (L) fat negatively correlated with PI and NRTI therapy duration, while Trunk Fat (TF)/PF positively correlated with PI and NNRTI duration. No significant correlation was found, instead, with NNRTI therapy duration. At 5-year follow-up, we registered a further increase in TF, Arms (A) and L fat, especially in PI-treated patients. CONCLUSIONS: Body fat changes should always be considered when dealing with HIV-affected patients on HAART. The fat loss seemed to involve mainly peripheral regions, while fat accumulation tendency occurred in the trunk. PMID- 29630137 TI - The cardiovascular macrophage: a missing link between gut microbiota and cardiovascular diseases? AB - The prevalence of cardiovascular diseases is on the rise. Interventions that would aid prevention or treatment of these diseases are essential. The microbes residing in the gut, collectively called "gut microbiota", produce a plethora of compounds that enter the bloodstream and affect the cardiovascular system. Signals ascending from gut microbiome are believed to modulate differentiation and functional activity of macrophages residing in perivascular tissue, atherosclerotic plaques, and perivascular areas of the brain. Cardiovascular macrophages may be the key players that transform the signals ascending from gut microbiome into increased predisposition to cardiovascular diseases. The present review summarizes the knowledge to date on potential relationships between gut microbiota, cardiovascular macrophages, and cardiovascular diseases. PMID- 29630138 TI - Adhesives for fixed orthodontic brackets. AB - BACKGROUND: Bonding of orthodontic brackets to teeth is important to enable effective and efficient treatment with fixed appliances. The problem is bracket failure during treatment which increases operator chairside time and lengthens treatment time. A prolonged treatment is likely to increase the oral health risks of orthodontic treatment with fixed appliances one of which is irreversible enamel decalcification. This is an update of the Cochrane Review first published in 2003. A new full search was conducted on 26 September 2017 but no new studies were identified. We have only updated the search methods section in this new version. The conclusions of this Cochrane Review remain the same. OBJECTIVES: To evaluate the effects of different orthodontic adhesives for bonding. SEARCH METHODS: Cochrane Oral Health's Information Specialist searched the following databases: Cochrane Oral Health's Trials Register (to 26 September 2017), the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 8) in the Cochrane Library (searched 26 September 2017), MEDLINE Ovid (1946 to 26 September 2017), and Embase Ovid (1980 to 26 September 2017). The US National Institutes of Health Ongoing Trials Register (ClinicalTrials.gov) and the World Health Organization International Clinical Trials Registry Platform were searched for ongoing trials. No restrictions were placed on the language or date of publication when searching the electronic databases. SELECTION CRITERIA: Trials were selected if they met the following criteria: randomised controlled trials (RCTs) and controlled clinical trials (CCTs) comparing two different adhesive groups. Participants were patients with fixed orthodontic appliances. The interventions were adhesives that bonded stainless steel brackets to all teeth except the molars. The primary outcome was debond or bracket failure. DATA COLLECTION AND ANALYSIS: Data were recorded on decalcification as a secondary outcome, if present. Information regarding methods, participants, interventions, outcome measures and results were extracted in duplicate by pairs of review authors. Since the data were not presented in a form that was amenable to meta analysis, the results of the review are presented in narrative form only. MAIN RESULTS: Three trials satisfied the inclusion criteria. A chemical cured composite was compared with a light cured composite (one trial), a conventional glass ionomer cement (one trial) and a polyacid-modified resin composite (compomer) (one trial). The quality of the trial reports was generally poor. AUTHORS' CONCLUSIONS: There is no clear evidence on which to make a clinical decision of the type of orthodontic adhesive to use. PMID- 29630139 TI - [Preventive effects of curcumin and resveratrol in Alzheimer's disease]. AB - Demographic study of the lastyears clearly indicates the tendencyof population aging, particularly in Europe.It can lead to an increased risk ofdiseases typical for old-age, includingneurodegenerative diseases, amongothers Alzheimer's disease (AD).Thus, the prevention of these diseasespresents a major challenge for globalpublic health. The development of ADis mainly attributed to environmentalfactors, in particular: diet, smoking,cardiovascular diseases, type 2diabetes and serious cranio-cerebralinjuries. The dominant theory of theAD development is amyloid cascadehypothesis, but at the same time, importantin the etiology of this disease isthe overphosphorylation of tau protein.Despite many years of research, so far,there are no drugs that allow for effectivetherapy, hence the ongoing intensiveexploration of natural substancesthat can prevent the AD development.Bioactive components of plant originhave recently received considerableattention, because they are relativelysafe and cheap due to the wide availability,and quite promising in thisgroup are curcumin and resveratrol. PMID- 29630140 TI - [Endocrine abnormalities in liver diseases]. AB - The liver is an organ implicated ina wide range of functions includingprotein, lipid and carbohydrate metabolismas well as hormone modificationand degradation. Hence, liverdisorders, comprising inflammatoryprocesses and liver failure, may significantlyinfluence endocrine homeostasis.Liver dysfunction leads toimpaired protein synthesis, includinghormone production disorders. Furthermore,endocrine disorders may becausally connected not only with primaryliver disease, but they may alsodevelop secondary to liver diseasetherapy. On the other hand, endocrineglands influence cell metabolism anddistribution of body fat, and therefore,may contribute to development ofliver diseases, such as non alcoholicfatty liver disease (NAFLD) and nonalcoholicsteatohepatitis (NASH). Theincreased incidence of these diseasesis inseparably related to growing epidemicof obesity. The aim of this reviewis to discuss changes in endocrinehomeostasis in the presence of liverdysfunction. According to vast literatureregarding glucose homeostasisand adipokines in liver diseases, thisproblem will not be discussed in ourreview. PMID- 29630141 TI - Tapioca Cellulose Based Copper Nanoparticles for Chemoselective N-Alkylation. AB - Biomaterials as a support for catalysts are of prime importance. Tapioca root which is an abundant biopolymer source was used to synthesize cellulose supported bio-heterogeneous poly(hydroxamic acid) copper nanoparticles (CuN@PHA) and was characterized by Fourier transform infrared spectroscopy (FTIR), ultraviolet visible spectroscopy (UV-Vis), field emission scanning electron microscopy (FESEM), X-ray photoelectron spectroscopy (XPS), inductively coupled plasma atomic emission spectroscopy (ICP-AES), transmission electron microscopy (TEM) analyses. The tapioca cellulose supported CuN@PHA (50 mol ppm) effectively catalyzed N-alkylation reaction of aliphatic amines with alpha,beta-unsaturated compounds to give the corresponding alkylated products. High yields up to 95% were achieved for the converted products. The reusability of the cellulose supported nanoparticles was found to be excellent with no significant reduction of its catalytic activity over several cycles. The catalyst showed high catalytic activity having turnover number (TON) 18000 and turnover frequency (TOF) 2250 h 1. PMID- 29630142 TI - [Alternatives for antibiotics - antimicrobial peptides and phages]. AB - The constant increase in the numberof bacteria resistant to antibioticsposes a substantial problem forthe therapy of infectious diseasesof different etiologies. The growinginsensitivity of pathogens on the classicalmethods of treatment is associatedmainly with multiple mechanismsof resistance created by bacteria.Furthermore, no proper antibiotictreatment causes the appearance ofresistant strains even at the last linedrugs. Therefore, there are still beingsought alternatives in the treatmentof difficult to eradicate pathogens.The antimicrobial peptides includingcathelicidins, defensins, lysozyme,lactoferrin, histatins and bacteriocinsarouse huge interest as potential therapeutics.They exhibit a broad spectrumof activity against many Gram-positiveand Gram-negative bacteria, but alsoagainst fungi. Moreover, they are consideredmuch safer than antibiotics,due to the fact that they are present inall eukaryotic organisms, in which theyare an essential element of the immunesystem. In addition, phage therapy isalso strongly recommended as alternativeantibacterial approach. In thisreview we highlight the potential usesof antimicrobial peptides and bacteriophagesin the treatment of infectionsof various etiologies. PMID- 29630143 TI - [Metabolic acidosis in a patient with an orthotopic neobladder]. AB - We present a case of 62-year-oldpatient after cystectomy with intestinalneobladder due to bladder cancer,complicated by severe acid balancedisturbances. Due to poor clinical conditionand metabolic acidosis patienttemporarily required renal replacementtherapy. After obtaining thestabile clinical status the patient wasdischarged with the recommendationof chronic oral treatment with thealkalizing agents and regular bloodgas control. In the 6 month follow-upthere were neither symptoms of uremianor significant abnormalities in waterelectrolytebalance. PMID- 29630144 TI - The Influence of Chitosan Substrate and Its Nanometric Form Toward the Green Power Generation in Sediment Microbial Fuel Cell. AB - A simple, environmental friendly and biologically important sediment interfaced fuel cell was developed for the green energy generation. The soil sediment used for the study is enriched of rich anthropogenic free organic carbon, sufficient manganese and high level potassium contents as evidenced from the geochemical characterizations. The saccharides produced by the catalytic reaction of substrate chitosan were utilized for the growth of microorganisms and electron shuttling processes. Chitosan substrate influenced sediment microbial fuel cells exhibited the nearly two fold power increment over the substrate free fuel cells. The fuel cell efficiencies were further increased by bringing the substrate chitosan at nanometric level, which is nearly three and two fold higher than that of substrate free and chitosan influenced sediment microbial fuel cells, respectively, and the influential parameters involved in the power and longevity issues were addressed with different perspectives. PMID- 29630145 TI - [The history of discovery of the meaning of erythrocyte sedimentation rate (ESR) in the human pathology (in the 150th birth anniversary of the Polish phisician and scientist, Edmund Biernacki)]. PMID- 29630146 TI - Unipolar Nonvolatile Resistive Switching in Pt/MgO/Ta/Ru Structures Deposited by Magnetron Sputtering. AB - The recent realization of memristors, nanodevices exhibiting non-volatile resistive switching, has sparked tremendous interest for applications in fields such as nonvolatile memories. Here we report unipolar resistive switching in Pt/MgO/Ta/Ru structures, with an oxide barrier thickness of only 15 nm. No electroforming process was required to achieve resistive switching and an ohmic conduction mechanism is associated with the ON state. We observed an inverse dependence of the ON state resistance on the SET current compliance and average values of 1.61 V and 1.38 V for the SET and RESET voltages, respectively. We show the stability of the switching for over 40 cycles and a clear separation of the ON (101 Omega) and OFF (102 Omega) states during at least 104 s. PMID- 29630147 TI - [An influence of changes in the levels of leptin on the risk of preterm delivery in patients with excessive BMI]. AB - Introduction: In the literature arefound in only a few reports on the roleof leptin in the etiology of preterm birthin pregnant women with excessiveBMI. The aim of the study was to evaluatethe relationship between leptin levelsand the prevalence of symptoms ofpreterm labor as well as assessment ofchanges in leptin levels depending onthe BMI and the effect of leptin on thestate of postnatal neonatal determinedby Apgar scale. Material and method: Prospective analysis applied to thedata obtained from 80 patients hospitalizedin the Department of Obstetricsand Perinatology University Hospitalin Cracow. The study was prospectiveand cohort. The study includedpregnant single diagnosed with a BMIgreater than or equal to 25. Results: It had significantly higherlevels of leptin in the group of patientswith symptoms of pre-term labor andBMI>=25 compared to lower concentrationsof leptin from the group ofpatients with a BMI <25 (p = 0.01414).It has been found higher levels ofplasma leptin in patients with BMI>=25compared to patients with a BMI <25,in the groups of patients during thenascent (0.0492). Conclusions: Pregnant with symptomsof preterm labor and excessiveBMI had higher levels of leptin thanwomen giving birth on time with abnormal,excessive BMI. It was foundhigher levels of leptin in the group ofpatients with symptoms of pre-termlabor in comparison to the controlgroups, which may favor the severityof inflammation which is the causeof the symptoms of preterm labor.There was no correlation between thechanges in leptin levels during pregnancyand the state natal infants basedon the Apgar scale. PMID- 29630148 TI - Representation and treatment allocation of racial groups in dermatologic therapy trials: A 2-year review of the literature. AB - Although most investigators would agree that including minority races in clinical trials is important, recruitment and retention may differ among these populations. The objective of this review was to perform an audit of phase III dermatologic therapy trials to determine representation for minority groups and to explore the possibility of racial allocation bias. In this review of 11 dermatology or general medicine journals in 2015-16, we did not find evidence of systemic racial allocation bias. We did however note variation in the proportion of minority races included in studies; whereas some trials had high success in recruiting minorities, many did not. Furthermore, most studies did not provide information on individual racial groups and rather presented an 'other' category. This supports findings from previous reviews of dermatologic therapy trials that suggest that most participants are white, race data are not included for many studies, and there is underrepresentation of some racial groups. We conclude that although there is no evidence of racial allocation bias in the previous two years, there remains a need for standardization in the reporting of racial groups and for increased participant diversity in dermatologic therapy trials. PMID- 29630149 TI - An updated assessment of social media usage by dermatology journals and organizations. AB - Despite the increasing prevalence of social media usage, the activity of dermatology journals and professional and patient-centered organizations on top social media platforms has not been investigated since 2012. We investigated a total of 124 dermatology journals, 242 professional organizations, and 78 patient centered organizations to assess their presence and popularity on social media. Searches were conducted to identify journals and organizations on Facebook and Twitter. Similar searches were done for organizations on LinkedIn. The number of Facebook likes, Twitter followers, and LinkedIn followers of the dermatological entities were quantified. There were 22 (17.7%) dermatology journals active on Facebook and 21 (16.9%) on Twitter. Amongst the professional organizations, 114 (47.1%) were on Facebook, 69 (28.5%) on Twitter, and 50 (20.7%) on LinkedIn. In comparison, 68 (87.2%) patient-centered organizations were on Facebook, 56 (71.8%) on Twitter, and 56 (71.8%) on LinkedIn. Our results demonstrate that the popularity of dermatology journals and professional and patient-centered organizations on top social networking sites has grown markedly since 2012. Although the number of dermatology journals on social media has increased since 2012, their presence continues to trail behind professional and patient-centered dermatological organizations, suggesting underutilization of a valuable resource. PMID- 29630150 TI - A possible role for dupilumab (Dupixent) in the management of idiopathic chronic eczematous eruption of aging. AB - Aging individuals can develop generalized, exquisitely-pruritic, eczematous eruptions of uncertain etiology that can be therapeutically-refractory and life altering. Limited information exists in the literature to guide clinicians in the diagnosis and management of such patients. It is suggested that in approximately 40% of such patients a known cause for their chronic pruritic eruptions cannot be identified. In this report we will refer to this subgroup of patients as having idiopathic chronic eczematous eruption of aging (CEEA). Idiopathic CEEA must be distinguished from other established eczematous dermatoses. Idiopathic CEEA patients often require long-term systemic immunosuppressive drugs to make living bearable. Elder-onset atopic dermatitis is the most difficult of the known dermatoses to distinguish from idiopathic CEEA. Because of their clinical similarities we questioned whether dupilumab (Dupixent(r)), the first FDA approved biologic for atopic dermatitis, might be valuable in the management of idiopathic CEEA. We report the case of an elderly man with idiopathic CEEA of four-years' duration who had a complete clinical response to the initiation of treatment with dupilumab. This case is presented to stimulate more discussion and systematic study of a possible role for dupilumab in otherwise-refractory idiopathic CEEA patients. We also propose a set of diagnostic criteria for idiopathic CEEA. PMID- 29630151 TI - Paraneoplastic pemphigus without antibodies to desmoglein 1 and 3. AB - Paraneoplastic pemphigus is a severe autoimmune blistering disease presenting in the setting of underlying malignancy. Paraneoplastic pemphigus is associated with diffuse painful stomatitis throughout the oral cavity with extension to the lips. The cutaneous findings are varied and have been described as lichenoid, pemphigoid, and targetoid lesions. Herein, we report a patient with paraneoplastic pemphigus whose routine testing led to a diagnosis of pemphigus vulgaris. However, further testing was pursued revealing an antibody profile consistent with paraneoplastic pemphigus. Subsequent neoplastic workup revealed an intra-abdominal mass. Our case represents a subtle, non-classic presentation of paraneoplastic pemphigus and suggests the importance of a comprehensive investigative work-up in atypical cases of pemphigus. PMID- 29630152 TI - Lamellar ichthyosis in a female neonate without a collodion membrane. AB - The term, autosomal recessive congenital ichthyosis (ARCI), describes a group of rare genetic skin diseases of cornification involving hyperkeratotic scaling at birth. The defective skin barrier function may lead to dehydration, body temperature instability, and high susceptibility to infections. In most cases of ARCI, neonates are born with a collodion membrane covering the body, often presenting with ectropion and eclabium. We report a premature female neonate presenting with hyperkeratotic scaling at birth without a collodion membrane. She was managed with placement in a humidified isolette, prophylactic antibiotics, dilute bleach baths, petrolatum ointment, and artificial eye drops. By the fourth week of life, there was marked improvement in her skin with the large, brown, plate-like scales on the trunk and extremities becoming lighter in color and finer in appearance. The ichthyosis genetic panel showed mutations in the ABCA12 gene resulting in the lamellar ichthyosis phenotype of ARCI. Our literature review revealed at least 28 patients with ARCI who were not born as collodion babies. Although collodion babies are a hallmark of most ARCI cases, clinicians should be aware of neonates with ARCI born without a collodion membrane and expedite appropriate workup and treatment. PMID- 29630153 TI - Successful management of congenital/infantile fibrosarcoma presenting as large, non-healing buttock ulceration. AB - A two-year-old boy presented with a large, non-healing ulceration on his left buttock, which was originally noted as a brown patch present at birth. Punch skin biopsy was performed and histopathology revealed an atypical, pleomorphic, spindled proliferation in whorled fascicles replacing the dermis and trapping fat in the subcutis, consistent with a diagnosis of congenital/infantile fibrosarcoma. No evidence of metastatic spread was seen on imaging. The tumor was initially deemed unresectable owing to extent of local invasion. Neo-adjuvant chemotherapy caused significant tumor shrinkage and the patient underwent complete resection. PMID- 29630154 TI - Asymptomatic flesh-colored lobular nodule on the nose. AB - Chondroid syringoma is a rare benign tumor of the skin appendages. Chondroid syringoma is mostly manifested by a slow-growing, painless, well defined subcutaneous or intradermal nodule. A 43-year-old man presented to our clinic with the complaint of an asymptomatic nodule on the dorsum of the nose for 8 months. The lesion was totally excised. Histopathological examination was notable for epithelial islets embedded in the chondroid matrix in the dermis. The patient was diagnosed with chondroid syringoma in light of the clinical and histopathological findings. PMID- 29630155 TI - A mixed form of intravascular papillary endothelial hyperplasia in an uncommon location: case and literature review. AB - Intravascular papillary endothelial hyperplasia (IPEH) is an unusual benign, non neoplastic vascular lesion that usually occurs in skin, but is uncommon in the oral cavity. Herein, we review the pertinent literature of oraiiPEH and report a new mixed form. A 61-year- old man presented with an ulcerated nodule in the lingual portion of the gingiva related to the left mandibular canine. An excisional biopsy was performed presuming the clinical diagnosis of pyogenic granuloma. Histopathological analysis showed areas of granulation tissue consistent with pyogenic granuloma. But in addition, there were thin-wall dilated vessels with papillary projections of endothelial cells producing vascular channels, associated with an area of organizing thrombus. These microscopic findings led to the diagnosis of pyogenic granuloma associated with IPEH. The immunohistochemical reactions revealed a diffuse positivity of the vascular cells for CD-34 and smooth muscle actin antibodies.In addition,there was partial positivity for podoplanin and negativity for CD-1OS in the IPEH areas. No signs of recurrence were observed after 6 months of follow-up. The most prevalent site of IPEH in the oral region is the lower lip. IPEH is slightly more common in women and exhibits peaks of prevalence between the fourth and sixth decades of life. PMID- 29630156 TI - Ulcerative cellulitis of the arm: a case of primary cutaneous cryptococcosis. AB - Cutaneous cryptococcosis is usually secondary to the hematogenous dissemination of pulmonary or meningeal Cryptococcus neoformans. Primary cutaneous cryptococcosis (PCC) is a rare form of the infection, typically caused by direct inoculation from trauma to the skin [1]. Most cases of PCC present as a localized cellulitis, abscess, nodule, or ulceration. Herein, we present a case of a rapidly spreading cellulitis characterized by bullae and ulceration, caused by direct inoculation from a fall. PMID- 29630157 TI - An intensely pruritic pebbled presentation. AB - Lichen amyloidosis (LA) is a form of primary localized cutaneous amyloidosis (PLCA) characterized by bilateral intensely itchy domed scaly hyperkeratotic papules. Lichen amyloidosis is rare and affects men more than women. It is uncommonly seen in the western world but more prevalent in Asia. These papules most typically affect the shins and occasionally the arms and torso. Lichen amyloidosis has been reported in association with autoimmune disorders and after prolonged exfoliation and friction of affected skin. We present a 40-year-old woman with LA. In LA, the characteristic histological finding is apple-green birefringence of Congo red-stained preparations observed under polarized light. However, this is not always strongly positive, as in our patient. Other findings may include eosinophilia, periodic acid-Schiff positivity, staining with thioflavin T, and metachromasia after staining with crystal violet or methyl violet. Treatment of LA is difficult and complete clinical remission is seldom achieved. Recent trials revealed beneficial outcomes with topical calcipotriol, phototherapy, acitretin, cyclophosphamide, and laser treatments. A combination of acitretin, antihistamines, topical steroids, and hydrocolloid dressings have been beneficial in our patient with LA. PMID- 29630158 TI - A case illustrating successful eradication of recurrent, aggressive basal cell carcinoma located in a scar with vismodegib. AB - Vismodegib is a small molecule inhibitor of the Hedgehog signaling pathway that has shown efficacy in the control of locally advanced or metastatic basal cell carcinoma, although proof of its effectiveness in the elimination of aggressive tumors is lacking. We report a case and provide complete histological evidence of a 69-year-old gentleman who presented with a recurrent, infiltrative, and sclerosing (morpheiform) basal cell carcinoma on his left upper lip that was entirely eradicated with a three-month course of vismodegib 150 mg daily. Complete histologic clearance of a tumor in a recurrent, infiltrative, and sclerosing basal cell carcinoma with vismodegib is uncommon. PMID- 29630159 TI - Growth of mobile applications in dermatology - 2017 update. AB - BACKGROUND: More than 80% of households in the US have a smartphone. Growth of mobile applications (apps) has grown in parallel with access to smartphones. Mobile health apps are used in medical fields, including dermatology. These apps allow patients to access information regarding dermatology conditions as well as access physicians via teledermatology. PURPOSE: To analyze changes in number of dermatology mobile apps since 2014 and discuss benefits and drawbacks of mobile application growth to dermatology. METHODS: Apple, Android, and Windows were queried for dermatology-related apps. The apps were categorized by purpose and compared to previously published data to assess growth and change in dermatology apps. RESULTS: A total of 526 dermatology mobile apps were found corresponding to an 80.8% growth in dermatology apps since 2014. The market share of teledermatology increased from 11.0% in 2014 to 20.1% in 2017. CONCLUSIONS: Dermatology apps continue to grow at a comparable pace to general app growth. Teledermatology apps experienced significant growth from 2014 to 2017. This growth has allowed time-efficient and cost-effective access to dermatologists, especially in rural areas. The growth of dermatology apps targeting patients allows for patient autonomy but also can result in access to inaccurate information regarding dermatology conditions. PMID- 29630160 TI - Wardenburg syndrome type 2 in a woman with no genomic mutation commonly associated with the syndrome. AB - Waardenburg Syndrome (WS) is a condition characterized by pigmentary changes of the hair or skin, hearing loss, heterochromia iridis, and dystopia canthorum. There are four main types of WS, which can be commonly caused by mutations in the PAX3, MITF, EDNRB, EDN3, SNAI2, or SOX10 genes. Herein, we present a patient with Waardenburg Syndrome type 2 with no findings of mutations in the commonly associated genes. PMID- 29630161 TI - Bullous lichen sclerosus: isolated vulvar involvement. AB - We present a patient with the bullous form of lichen sclerosus of the vulva. She had no lesions in other cutaneous and mucosal areas. We used topical tacrolimus and topical clobetasol propionate. The patient was lesion free at the first-year follow-up. PMID- 29630162 TI - Fluctuating lesion of the scalp after a journey to the tropics: a case of furunculoid myiasis. AB - Fluctuating lesions or furuncles of the scalp occur frequently in dermatological practice. This clinical condition is often caused by gram positive bacteria (e.g. staphylococcal or streptococcal skin infection) or fungal infection (e.g. Kerion celsi). However, a rare diagnosis such as myiasis might be considered, especially if a journey to an endemic area is reported. Herein, we present a case of furunculoid myiasis of the scalp and review the pathogenesis and therapeutic options to treat this condition. PMID- 29630163 TI - A report and follow up of a patient with disseminated superficial actinic porokeratosis (DSAP) undergoing novel systemic treatment with palifermin (a keratinocyte growth factor) during chemotherapy. AB - Disseminated superficial actinic porokeratosis (DSAP) is an inherited dermatosis triggered by chronic ultraviolet light exposure. Cosmetic improvement has been noted with topical therapies or laser treatment. Lesions of DSAP are precancerous, having been reported to develop into squamous cell carcinomas (SCCs) or basal cell carcinomas (BCCs) occasionally. We describe a patient with longstanding DSAP who developed a primary CNS lymphoma. Palifermin (a keratinocyte growth factor analogue) was used as an adjuvant for his chemotherapy to minimize mucositis. Our patient noted marked clinical improvement of his DSAP following his chemotherapy for lymphoma. Follow-up has shown a sustained improvement of his DSAP with no development of any SCCs. Palifermin may be safe for use in individuals at high risk of developing SCCs and further research into keratinocyte growth factors and risk of development of SCC is warranted. Systemic chemotherapy appears to improve DSAP lesions. PMID- 29630164 TI - Comprehensive outreach, prevention education, and skin cancer screening for Utah ski resorts. AB - Outdoor recreation can lead to substantial sun exposure. Employees of outdoor recreation establishments with extended time outdoors have amplified cumulative exposure to ultraviolet (UV) radiation and an increased risk of skin cancer. The "Sun Safe on the Slopes" program was created by Huntsman Cancer Institute at the University of Utah and the Utah Cancer Action Network to address increased UV exposure and skin cancer risk with free skin cancer screenings, outreach, and prevention education to local ski resorts. Herein, we describe the processes and barriers to implementation of a ski resort skin screening and education program and our 5-year report of the experience and screening data. Nine free skin cancer screenings were held at Utah ski resorts between 2011 and 2016, resulting in the presumptive diagnosis of 38 skin cancers (9.6%) in 394 participants. Behavioral data collected from participants indicates suboptimal sun safety practices, including underuse of sunscreen and protective clothing. Ski resort employees who experience sun exposure during peak hours at high altitudes and UV reflection from the snow are at an increased risk of skin cancer. These data indicate a need for emphasis on sun safety education and screening and can serve as a model for future endeavors. PMID- 29630165 TI - Distance to pharmacy and risk of medication primary nonadherence. AB - Primary nonadherence, a form of prescription nonadherence, is defined as failure to fill and pick up a prescription medication. Little is known about the relationship between distance to pharmacy and primary nonadherence in dermatology. In this study, we investigated the association between primary nonadherence and distance between a patient's home and pharmacy. We focused on a low-income patient population within the dermatology clinic of a large, urban county hospital system in which patients were enrolled in a pharmacy benefit within a closed-system. Among 678 patients who were prescribed a total of 1156 prescription medications for dermatologic conditions, 11.7% did not pick up any of their prescriptions. After adjusting for patient demographics of race/ethnicity, sex, age, language, and relationship status, there was no association between primary nonadherence and distance traveled between a patient's home and pharmacy. Results of this study are consistent with other studies in non-dermatologic patients and suggtableest that distance from a pharmacy may not be strongly associated with primary nonadherence for dermatologic medications. PMID- 29630166 TI - Phytophotodermatitis induced by wild parsnip. AB - Phytophotodermatitis results when skin is exposed to ultraviolet light after previous contact with a phototoxic compound. Wild parsnip (Pastinia sativa), a member of the Umbelliferae family, is an invasive plant species introduced to North America as a root vegetable. Although cultivated less commonly today, the plant is increasingly found growing wild in prairies and roadsides. The stems and leaves contain furocoumarins, which upon activation by UV light interact with oxygen. Resultant reactive oxygen species induce tissue damage manifesting initially as blistering and later as hyperpigmentation. We report the case of a woman who developed phytophoto-dermatitis after encountering wild parsnip on a midwestern prairie. PMID- 29630167 TI - [The effects of security camera, past littering, environment, and signboards on littering prevention]. AB - Two experiments were conducted to assess litter control at a riverside location. Experiment 1 examined theeffects of a security camera (presence/absence), past littering (presence/absence), and environmental features(tussock/plain ground/flowerbed). Two scenes containing combinations of these factors were presented.Participants chose the scene in which they felt it was to easier to litter. Participants also reported their emotionalresponse to the presence/absence of a security camera and environmental features in scenes with litter. The resultsrevealed that the presence of a security camera, no past littering, flowerbeds, and plain ground inhibited littering.Littering in the presence of a security camera facilitated discomfort, anger, and shame, and littering in flowerbedscaused discomfort, anger, shame, and sadness. Using a similar method, Experiment 2 addressed the particulareffects of a security camera combined with other factors: past littering, environmental features, and signboards(no sign/sign with eyes/security camera images). The results demonstrated the effectiveness of a security camera,no past littering, flowerbeds, plain ground, signboards presenting eyes, and images from a security camera inpreventing littering. PMID- 29630168 TI - [Dual process in large number estimation under uncertainty]. AB - According to dual process theory, there are two systems in the mind: an intuitive and automatic System 1 anda logical and effortful System 2. While many previous studies about number estimation have focused on simpleheuristics and automatic processes, the deliberative System 2 process has not been sufficiently studied. This studyfocused on the System 2 process for large number estimation. First, we described an estimation process basedon participants' verbal reports. The task, corresponding to the problem-solving process, consisted of creatingsubgoals, retrieving values, and applying operations. Second, we investigated the influence of such deliberativeprocess by System 2 on intuitive estimation by System 1, using anchoring effects. The results of the experimentshowed that the System 2 process could mitigate anchoring effects. PMID- 29630169 TI - [The characteristics of altruistic behavior that can sustain generalized exchange in a society composed of two groups]. AB - Previous studies on generalized exchange have argued that group plays an important role in the emergenceof cooperative society. To examine to what extent the role of a group is important, we conducted computersimulations in which players decide whether to give resources to members of a society composed of two groups.We examined whether a society consisting of any of the possible conceivable strategies (65536 strategies total)could resist invasion by an unconditional defector (ALLD) and an unconditional cooperator (ALLC). Theresults showed that universalist strategies, which give resources to both in-group members and out-groupmembers equally, and in-group favoring strategies, which give resources to in-group members more than outgroupmembers, could resist invasion. Furthermore, we found that in-group favoring strategies could excludeALLC from the circle of resource flow more easily than universalist strategies. These results imply that it may benecessary to employ an in-group favoring strategy that utilizes the group membership information of other peoplein order to maintain generalized exchange in a society composed of two groups. PMID- 29630170 TI - [Effective encoding for the recognition of spatial configuration and color]. AB - Three experiments examined the types of encoding that were effective for the recognition of spatial and color information. In Experiments 1 and 2, four experimental groups (each asked to form a different type of mental image of stimuli) and one control group (not asked to form an image) were presented spatial configuration patterns with different numbers of black dots. In both experiments, for the group that formed motor images with actual movement, the average score was higher for stimuli with a larger number of dots than for stimuli with fewer dots. Two groups, which formed dynamic visual images and motor images with no actual movement, respectively, showed similar limited effects. In Experiment 3, the five groups were presented two types of chromatic stimuli (colored panels and colored dots). Static visual images were effective for encoding the colored panels; however, static visual images and motor images with actual movement were effective for encoding the colored dots. These results suggest that motor and dynamic encodings facilitate memory for objects where spatial configuration is important for identification, while static visual images of the whole picture facilitate memory for objects where multiple colors are significant. PMID- 29630171 TI - [Motivational influences of task difficulty information on task effort]. AB - Two studies were conducted to investigate the motivational influences of information about task difficulty on task effort. In both studies, an anagram task was used as the experimental task and task motivation was measured with rating scales. In experiment 1, 60 participants were presented anagrams labeled as "easy" or "difficult", both of which were actually impossible to solve. Results revealed that participants low in intrinsic motivation put in more effort on anagrams labeled "easy" than "difficult". In experiment 2, 60 participants were assigned to two groups (30 each) and task outcomes were manipulated (positive and negative). Results revealed that participants with positive outcomes could maintain task motivation and put in more effort on the challenging anagrams than those with negative outcomes. These results suggest that information about task difficulty can promote regulation of task effort and task motivation for sustained studying, especially for computer-based learning. PMID- 29630172 TI - [Social capital is associated with students' subjective well-being in 1st year university life]. AB - The purpose of this study was to examine how university social capital and subjective social capital could predict undergraduate students' subjective well being including depression, school satisfaction, and life satisfaction. In this cross-sectional study, we conducted multilevel structural equation modeling on the data of 2,021 students at 38 universities in Japan. At the university level, we found the associations between social capital (fellows) and depression, social capital (classmates) and life satisfaction, and social capital (faculty) and school satisfaction. At the student level, all subjective social capital (fellows, classmates, and faculty) were associated with all the factors of subjective well-being. These results suggest the influence of university social capital and that of subjective social capital are associated with students' subjective well-being. PMID- 29630173 TI - [Effects of parental parenting attitudes on adolescents' socialization via adolescents' perceived parenting]. AB - The domain-specific approach to socialization has classified socialization mechanisms into several domains, including the protection and control domains, and postulates that parent-child interactions that promote socialization in each domain are different. However, there are few empirical investigations of the domain-specific approach. This study examined whether parental parenting attitudes affected early adolescents' empathy, including empathic concern and perspective taking, and social cognitive biases, including cognitive distortion and general beliefs about aggression, through the mediation of adolescents' perceptions. Junior high school students and their parents (N = 448) completed a questionnaire. Results of structural equation modeling indicated (a) parental acceptance and control increased empathy via adolescents' perceived acceptance and control, (b) parental acceptance and control decreased social cognitive biases via adolescents' perceived acceptance and control, and (c) parental control directly increased empathy. In addition, multiple group analyses indicated the validity of gender- and age-invariant models. These findings suggest that parental parenting attitudes are essential for appropriate socialization during early adolescence. PMID- 29630174 TI - [A comparison of evaluation among different media stimulation of housing space]. AB - The purpose of this study is to show the differences in impression evaluation among different media stimuli for housing space. We conducted an impression evaluation experiment for a pamphlet, material samples, and real rooms for media stimulation using an SD method with 85 participants to extract similar and the dissimilar impression evaluations among the media stimuli. The results indicated that the evaluations for real rooms were more positive than those for a pamphlet or material samples as a whole; especially, for brightness and youthfulness among different forms of stimulation. The evaluation structure by factor analysis of a pamphlet and real rooms were almost same; however, those by material samples were different, suggesting that a pamphlet is useful to express a real room, but material samples assist in stimulation of the residential space. PMID- 29630175 TI - Full-Automated Thermal Cycler in Nucleic Acid Testing Workstation. AB - Integrated automation in laboratory has recruited many traditional standalone devices provided by various vendors, however, because of semi-automatization or lack of standard control interfaces, current available devices are difficult to be integrated into workstation. This paper reported a full-automated thermal cycler system (AutoTCS) equipped with a typical 96-well thermo-cycler module, and especially with a well-designed sliding hot lid for polymerase chain reaction (PCR), which makes it very suitable for using in an automatic nucleic acid testing (NAT) workstation. By a PC software or the touch screen on AutoTCS with user-friendly graphical user interface (GUI), the presented system can not only serve as a PCR module of a NAT workstation, but also can be treated as a single PCR system. Experiments have demonstrated that the AutoTCS achieved a temperature accuracy of +/-0.1 degrees C, a heating rate of approximately 2.5 degrees C/sec, and cooling rate of approximately 1.6 degrees C/sec. The AutoTCS was tested with PLCE1 gene and hepatitis B virus (HBV) DNA, and this had successfully achieved an excellent PCR performance. PMID- 29630176 TI - [Validation of a Japanese version of the Experience in Close Relationship- Relationship Structure]. AB - The purpose of this study was to translate the Experience of Close Relationship Relationship Structure (ECRRS) and evaluate its validity. In study 1 (N = 982), evidence based internal structure (factor structure, internal consistency, and correlation among sub-scales) and evidence based relations to other variables (depression, reassurance seeking and self-esteem) were confirmed. In study 2 (N = 563), evidence based on internal structure was reconfirmed, and evidence based relations to other variables (IWMS, RQ, and ECR-GO) were confirmed. In study 3 (N = 342), evidence based internal structure (test-retest reliability) was confirmed. Based on these results, we concluded that ECR-RS was valid for measuring adult attachment style. PMID- 29630177 TI - [Visual processing of names in mental rotation tasks]. AB - In this study, we examined the difference in the processing of one's own name and other people's names using a mental rotation task. In Experiment 1, the observer's own name and other common names were presented visually. In Experiment 2, the observer's name and the names of people who were familiar to the observer were presented. The observer saw the name and judged whether it was mirror reversed or not. The results show that reaction times and error rates were shorter, when the observer processed his/her own name compared to when processing others names. These findings might be due to peculiarities and familiarity of one's own name. PMID- 29630178 TI - [Communication with weak ties and its effect on career reflection]. AB - This study examined the hypothesis that communicating with the weak ties promotes professional self-efficacy and work engagement, which mediates reflection of one's past career. As a preliminary survey, semi-structured interviews were conducted with incumbent employees and analyzed regarding career reflection arising from communication with weak ties. As part of this survey, Japanese employees (n = 340) were asked to respond to questionnaires that measured communication between weak ties, career reflection, professional self-efficacy, and work engagement. Factor analysis of the scores for career reflection extracted four factors: re-evaluation of own work styles, rebuilding of non-work activities, improvement of work autonomy, and evocation of work crisis awareness. Covariance structure analysis indicated that communication about work-related contents and expectations of the future with weak ties promoted the re-evaluation of the employees' own work styles, which was shown to promote professional self efficacy and work engagement. These results support the original hypothesis and suggest that communicating with weak ties is an important resource for promoting positive change in employees' sense of work. PMID- 29630179 TI - [What factors of prosocial behavior evoke recipients' gratitude and indebtedness? An experimental examination]. AB - We examined two psychological processes of prosocial behavior: feeling gratitude and indebtedness. First, we asked if the value of the behavior for the receiver promotes gratitude; and second if the cost of the behavior for the giver promotes indebtedness. Gratitude and indebtedness were measured as behavioral indices of a quid pro quo (indirect reciprocity and direct reciprocity) to avoid social desirability effects in self-report measures. In Study 1, 119 undergraduates recalled a past experience in which they had been the recipients of prosocial behavior while emphasizing the value, cost, or situation (control) of the event. The level of gratitude was higher, and indirect reciprocity was observed more frequently, in the value condition than in the cost and control conditions. Indebtedness, however, did not differ across the conditions. In Study 2, 59 participants received a gift (the value and cost of which were manipulated) from an imaginary confederate. The value manipulation promoted indirect reciprocity, and both value and cost manipulations encouraged direct reciprocity. Implications for adaptive functions of gratitude in social selection processes are discussed. PMID- 29630180 TI - [Measuring end-of-life care efficacy and related factors in the staff members of elderly care facilities]. AB - Based on Bandura's social learning theory, this study conceptualized the end-of life care efficacy (EoLCE) of elderly care facility staff. In Analysis 1, an EoLCE scale was developed. Factor analysis identified two factors --instrumental care efficacy and emotional care efficacy- with psychometric adequacy. In Analysis 2, a path analysis was used to examine the relationships between EoLCE and the number of care experiences provided (Care Experiences) as well as the four theory-based sources of self-efficacy: the frequency of feeling a sense of achievement (Achievement), number of opportunities to observe role models, number of opportunities to receive linguistic persuasions (Linguistic Persuasions), and negative emotional responses to end-of-life care. After controlling for these sources, we found that Care Experiences negatively influenced emotional care efficacy. Achievement had the strongest significant relationship with EoLCE. The three other sources showed significant relationships with EoLCE, but there was no relationship between instrumental care efficacy and Linguistic Persuasions. To increase EoLCE, the subjective number of social learning experiences relevant to end-of-life care was important, rather than the number of care experiences provided. PMID- 29630181 TI - Metallic Nanostructures for Multispectral Filters. AB - A metal-dielectric-metal structure with cross-shaped-hole array in metal thin films is studied for plasmonic multispectral filters, which covers visible to near-infrared wavelengths. Surface plasmons are induced from incident wave by a periodic array of nanostructures, then the localized surface plasmon polaritons oscillate in the cavity, which is formed by the two layers of metals through near field excitation. The transmission spectrum of the metal-dielectric-metal structure with cross-shaped-hole array is investigated with the finite-difference time-domain method; our simulations show that the features of the hole, and the refractive index and the thickness of the dielectric layer all affect the optical spectral performance. This metal-dielectric-metal structure provides additional flexibility in tuning transmission spectrum due to its Fabry-Perot cavity property. Our study shows that it is possible to obtain desired multispectral filters by programming the refractive index and thickness of the dielectric layer, and these parameters of the metallic structures. PMID- 29630182 TI - [Keep changing to remain unchanged: A way to maintain a cultural custom in the face of environmental change]. AB - This is a micro-ethnographic study focusing on a traditional custom at Toshi Island in Japan. When first-born sons in the island graduate from junior high school, they form a small group of neya-ko (quasi-brothers) and sleep over at neya-oyas' (quasi-parents) house every night until they become 26 years old. They keep the quasi-family relationship alive and help each other all through life. We investigated the maintenance process of this cultural custom by participant observations and unstructured interviews. Because of the recent drastic environmental changes around the island, people face difficulties maintaining the custom. In spite of these circumstances, they have been able to maintain the custom not by challenging the environmental changes, but by constantly changing the custom itself to fit the environment. Their flexible decision making may derive from their ecological basis as fishermen. Based on the findings, we discuss the sustainability of cultural customs facing environmental changes. PMID- 29630183 TI - [Mind-wandering enhances creative problem solving]. AB - An "incubation period" refers to an individual's temporary shift away from an unsolved problem, which ultimately facilitates better problem solving. In this study, we experimentally examined whether creative problem solving was facilitated in accordance with the frequency of mind-wandering during an incubation period. Fifty-nine Japanese undergraduate participants (23 men and 36 women) were asked to complete the Unusual Uses Test (UUT) twice; the UUT is a traditional measurement of the various aspects of divergent thinking (including fluency, flexibility, and originality). They were also asked to rate the frequency in which they engaged in mind-wandering during the interval between UUTs, which was considered as the incubation period. The results indicated that participants who reported a higher frequency of mind-wandering during incubation exhibited more creative solutions on the UUT, especially in terms of flexibility and originality, than did those reporting a lower frequency of mind-wandering. PMID- 29630184 TI - Correlation Between Two-Dimensional Electron Gas Mobility and Crystal Quality in AlGaN/GaN High-Electron-Mobility Transistor Structure Grown on 4H-SiC. AB - We investigated the correlation between the crystal quality and two-dimensional electron gas (2DEG) mobility of an AlGaN/GaN high-electron-mobility transistor (HEMT) structure grown by metal-organic chemical vapor deposition. For the structure with an AlN nucleation layer grown at 1100 degrees C, the 2DEG mobility and sheet carrier density were 1627 cm2/V.s and 3.23 * 1013 cm-2, respectively, at room temperature. Further, it was confirmed that the edge dislocation density of the GaN buffer layer was related to the 2DEG mobility and sheet carrier density in the AlGaN/GaN HEMT. PMID- 29630185 TI - [Development of the Compassionate and Self-Image Goals Scale in Japanese]. AB - Three studies tested the reliability and validity of a Japanese version of the scale that measures compassionate goals to support others' well-being and self image goals to construct and defend a desired self-image. Consistent with Crocker and Canevello's (2008) original English scale, the Japanese scale had a correlated two-factor structure and showed high reliability. Study 1 found that when controlling for self-image goals, compassionate goals were associated with lower zero-sum thinking, lower validation-seeking, higher growth-seeking, and higher independent self-construal. Controlling for compassionate goals, self image goals were associated with higher validation-seeking and higher interdependent self-construal. In Studies 2 and 3, compassionate goals were associated with self-compassion and private self-consciousness to a greater extent than self-image goals, whereas self-image goals were associated with insecure attachment and with public self-consciousness to a greater extent than compassionate goals. A promotion focus and a prevention focus were moderately associated with both goals, suggesting that compassionate and self-image goals are different from these constructs. PMID- 29630186 TI - [Measuring sociosexuality: Japanese translation of the revised Sociosexual Orientation Inventory]. AB - The term sociosexuality is used to describe individual differences in people's willingness to engage in uncommitted sexual relationships. The authors developed the revised Sociosexual Orientation Inventory in Japanese (SOI-J) to assess sociosexuality. In addition, we examined the effect of sociosexuality on flirting behaviors. In study 1 and study 2, we translated the revised Sociosexual Orientation Inventory into Japanese and confirmed its reliability and validity. The results of study 3 showed that male sociosexuality had an effect on male and female flirting behaviors. On the other hand, the results showed that female sociosexuality had no effect on male and female flirting behaviors. These results suggest that relationship initiation is controlled by females. PMID- 29630187 TI - [Development of the Japanese Indecisiveness (Yujufudan) Scale]. AB - Previous research has explored whether the Japanese concept of Indecisiveness is different from western cultures. The aim of the study was to develop a questionnaire scale to measure the concept of Japanese Indecisiveness (Yujufudan). In the first study, a factor analysis was carried out using data from 255 college students. Four different factors, "reflection" "procrastination" "referring to others" and "anxiety" were obtained. In the second study, a decision-making task was administered to 55 college students. The scores obtained from the factor analysis in the first study predicted performance on the decision making task. These results demonstrated the validity and reliability for the Japanese Indecisiveness Scale to measure Japanese Indecisiveness (Yujufudan). PMID- 29630188 TI - [Development of the Life Skills Scale for Adolescents and Adults]. AB - The present study aims to develop and examine the reliability, internal validity, and criterion validity of the Life Skills Scale for Adolescents and Adults (LSSAA) that would enable measurement of the level of life skills in Japanese adolescents and adults. In study 1, 238 university students completed a 41-item questionnaire for the LSSAA based on a previous study (Kase et al., 2016). Exploratory factor analysis was divided into four sub-scales: decision-making (8 items), interpersonal relationships (5 items), effective communication (5 items), and coping with emotion (3 items). In study 2, the reliability, content validity, and criterion validity of the LSSAA were examined by administering the questionnaire to 500 Japanese adolescents and adults. Confirmatory factor analysis and correlation analysis showed that the LSSAA had high reliability and validity. Additionally, it was confirmed that the LSSAA was effective for measuring the life skills needed for a satisfactory social life for a wide range (based on sex and/or age) of Japanese adolescents and adults. PMID- 29630291 TI - Fabrication of Heterojunction Diode Based on n-ZnO Nanowires/p-Si Substrate: Temperature Dependent Transport Characteristics. AB - Herein, we report the growth and characterizations of well-crystalline n-ZnO nanowires assembled in micro flower-shaped morphologies. The nanowires are grown on p-Silicon substrate and characterized in terms of their structural, morphological and electrical properties. Temperature dependent transport characteristics of the fabricated n-ZnO/p-Si heterojunction diode were examined. The morphological studies revealed that the nanowires are grown in high-density and arrange in special micro flower shaped morphology. The structural characterizations confirmed that the nanowires are well-crystalline and possessing wurtzite hexagonal phase. The electrical properties were evaluated by examining the I-V characteristics of the fabricated n-ZnO/p-Si heterojunction diode. The I-V characteristics were studied at temperature <300 K and >=300 K in the forward and reverse bias conditions. The detailed temperature dependent electrical properties revealed that the fabricated heterojunction assembly shows a diode-like behavior with a turn-on voltage of 5 V at almost all temperatures and the delivered current changes between ~1 to ~5 MUA when temperature changes from 77 K to 425 K. The rectifying behavior of the fabricated heterojunction diode, at 5 V, was demonstrated by rectifying ratio of ~4 at 77 K which decreases to ~1.5 at 425 K. This analysis also showed that the mean potential barrier of the fabricated heterojunction (~1.2 eV) is larger than the energy difference (0.72 eV) of the work functions between Si and ZnO. PMID- 29630292 TI - [Risk factors for mental health problems and complicated grief in bereaved families of motor vehicle accident victims]. AB - This study examined the risk factors for mental health problems and complicated grief in bereaved families using a nationwide sample of 453 Japanese adults who had lost a family member to a motor vehicle accident within three years. The results indicate that 31.0% of participants had K6 scores > 13 and 61.0% had ICG (Inventory of Complicated Grief) scores > 26. A higher K6 score was associated with secondary victimization and support seeking, whereas a higher ICG score was associated with the death of a child. Dispute over the liability for the accident and the resulting anxiety, measured by the Japanese version of ECR (Experiences in Close Relationships), were common predictors of higher K6 and ICG scores. The results suggest that complicated grief is more dependent on the circumstances of the death, whereas mental health problems are more affected by a participant's coping after the death, implying that effective support and interventions are necessary for mental health problems and complicated grief after a violent death. PMID- 29630293 TI - [The promotion of social inclusion by adoption of the Private Finance Initiative on a correctional institution]. AB - This study focuses on two questionnaire surveys that were conducted about the adoption of the Private Finance Initiative (PFI prison) method in Japan as a new correctional system. For study 1, a Web questionnaire was administered to residents of within a 30 km zone of Tokyo as well as those in Yamaguchi Prefecture to determine familiarity and resistance to the PFI prison systems. For study 2, a questionnaire survey was administered to residents of a neighborhood near a PFI prison in Mine city. The results showed that the attitudes toward the PFI prison were more positive in this area. Furthermore, contact with the correctional systems promoted residents' acceptance of prisoners and former prisoners. Finally, we discuss social and institutional support and contact with social systems to promote social inclusion. PMID- 29630294 TI - [The influence of prosocial behaviors on evaluations of morality and warmth]. AB - This study examined the influence of prosocial behaviors on evaluations of morality and warmth. There were four patterns of interaction: positive reciprocity (with both cost and benefit), only-cost (with cost but without benefit), negative reciprocity (without either cost or benefit), and only-benefit (with benefit but without cost). Three-hundred-fourteen undergraduate students participated in this study. The participants read an example of interaction and evaluated the actors' morality and warmth. Results of one-way ANOVA showed that the ratings of morality and warmth differed significantly between the conditions. There was no significant difference of perceived morality between only-cost and positive reciprocity. In contrast, warmth was evaluated higher in only-cost than in positive reciprocity. This suggests that people evaluated morality and warmth differently depending on whether the prosocial behavior was obligatory or optional. PMID- 29630295 TI - [Selection of goal-directed information triggers removal of irrelevant information from working memory]. AB - This study investigated the triggers for removing irrelevant information from working memory. Based on the perspective that removal is a unique process of updating working memory (Ecker et al., 2010), we hypothesized that the removal process begins after selection of task-relevant information. To test this hypothesis, we employed a modified Sternberg task that reflects the time-course for the removal of information. In a standard procedure of this task, the removal process is thought to be completed in approximately 1,500 ms after directing relevant information. If selection induces removal, removal might not end within 1,500 ms when selection requires more time. To increase the time for selection, we created a circumstance with high interference. Experiment 1 showed that removal was incomplete within 2,000 ms after directing relevant information. Experiment 2 showed that removal could be completed given more time. These results support the hypothesis that the trigger for the removal process is the completion of selection. This is in consistent with recent frameworks concerning executive functions. PMID- 29630297 TI - Sponge-Like Li4Ti5O12 Constructed on Graphene for High Li Electroactivities. AB - A sponge-like Li(4)Ti(5)O(12)/graphene composite was prepared via sequential hydrothermal process and solid-state heat treatment process for the application to high-power lithium ion batteries. The as-prepared electrode showed outstanding Li electroactivities with a rapid and reversible Li insertion/ extraction of up to 10 C-rate (1.75 A/g). It delivered a discharge capacity of 174 mAh/g at 0.5 C, near the theoretical capacity of Li(4)Ti(5)O(12), with good rate capability and cyclic stability. First-principles calculations revealed the intimate interaction of the Li(4)Ti(5)O(12) and graphene, which implies that graphene functions as an 'electron tunnel.' Electrochemical impedance spectroscopy also proved that the graphene-hybridization and the unique structure of the Li(4)Ti(5)O(12) material significantly reduce the resistive behavior of electrodes. The 3D structured Li(4)Ti(5)O(12)/graphene hybrid reported herein could be a promising candidate for a safe, low-cost, high-power anode for lithium ion batteries, and our seeding growth-sintering method for decorating graphene with active material will offer an effective upgrade on highly insulating Li(4)Ti(5)O(12) materials. PMID- 29630298 TI - [Prisoners' reasons for confessions and interviewing styles]. AB - This study examined the relationships between the reasons for confessions and interviewing styles by administering a self-reported questionnaire to new male adult prison inmates across Japan. The three factors proposed by Gudjonsson and his colleagues (1991, 1992, 1994, 1999), namely, perception of proof, internal pressure, and external pressure, were investigated. When participants had decided to confess prior to interviews, they were more likely to confess due to perception of proof and internal pressure compared to their counterparts. Furthermore, participants who experienced a relationship-focused interviewing style, which stressed active listening and rapport-building while talking about the criminal incidents directly, were more likely to confess due to internal pressure and less likely to confess due to external pressure. PMID- 29630299 TI - [Development of the Interpersonal Sensitivity/Privileged Self Scale: The measurement of a psychological characteristic related to "Modern-type Depression"]. AB - We developed the Interpersonal Sensitivity/Privileged Self Scale (IPS) to measure personality traits related to "modern-type depression," and assessed its validity and reliability through three surveys completed by 804 undergraduates. Factors for validity were examined by confirmatory factor analysis. As predicted, the scale comprised two superordinate factors: interpersonal sensitivity (IS) and privileged self (PS). Criterion-related validity for the IPS scale was assessed by examining its relationship with depressive symptoms and typus melancholicus, and by comparing subscale scores regarding depression types (i.e., melancholic, atypical). All subscale scores were positively correlated with depressive symptoms. Correlations between typus melancholicus and subscales showed that the interpersonal sensitivity subscale was positively correlated with typus melancholicus, while the privileged self subscale was not correlated. An analysis of variance revealed that the "self-righteousness" score was significantly higher for the atypical depression group compared to the melancholic depression group. The test-retest correlation indicated good test-retest reliability for all subscales. Overall, the findings indicated that the IPS has high validity and reliability. PMID- 29630300 TI - Synthesis and Dielectric Properties of Nanocrystalline Strontium Bismuth Niobate. AB - Herein, we report the synthesis, characterization and dielectric properties of nanocrystalline ferroelectric ceramic of strontium bismuth niobate (SrBi2Nb2O9; SBN). The material was prepared by simple sol-gel combustion route using strontium nitrate, bismuth nitrate pentahydrate and niobium oxide in presence of sucrose. During synthesis, the sucrose played dual role, i.e., as the gelling agent and combustion fuel. The prepared material was characterized in detail using several techniques such as differential thermal analysis and thermogravimetric (DTA-TG), X-ray diffraction (XRD), Fourier transform infrared (FTIR) spectroscopy, transmission electron microscopy (TEM) and scanning electron microscope (SEM). These techniques were utilized to describe the thermal stability, crystal structure, crystallite size and morphologies of the prepared material. Further, the dielectric properties of the prepared SBN sample were investigated at various frequencies and temperatures. PMID- 29630301 TI - [Classification of serial homicide and comparison of serial homicide with single homicide in Japan]. AB - It is reported that there are no victim-offender relationships in serial homicides, so offender profiling is useful for resolution of serial homicide cases. The present study aimed to describe characteristics of serial homicide offenders as a part of offender profiling and compare characteristics of serial homicide with those of single homicide offenders. We found that serial homicide characteristics were divided into 3 types (Destruction, Mission, and Antisocial). On the other hand, single homicide characteristics were divided into 4 types, which included Domestic in addition to the 3 types mentioned above. Overall, serial homicide offenders try to avoid detection of their murders compared to single homicide offenders. However, there was not much difference between the patterns of serial homicides and those of single homicides. Therefore, we conclude that there are few qualitative differences between serial and single homicide offenders. PMID- 29630302 TI - [The stress symptoms and posttraumatic growth of dispatched firefighters following the Great East Japan Earthquake]. AB - This study investigated posttraumatic stress symptoms and posttraumatic growth among 534 fire fighters who were dispatched to the disaster area following the Great East Japan Earthquake. Specifically, we investigated the effect of acute stress symptoms and social support from peers and family on posttraumatic stress symptoms, depression, and posttraumatic growth one year after being dispatched. We found that dispatched fire fighters experienced posttraumatic growth as well as posttraumatic stress symptoms following disaster work. Moreover, social support from peers was positively associated with professional growth as a disaster worker, whereas social support from family positively associated with gratitude. These results imply that it is useful to take into consideration supporting the posttraumatic growth of fire fighters as an opportunity for professional growth with respect to stress management programs as well as relieving posttraumatic symptoms with early intervention. PMID- 29630303 TI - [A review of definitions and measurement scales for financial literacy]. AB - This paper examines the definitions and measurement scales for financial literacy presented in previous studies in order to develop a new financial literacy scale. The early definition of financial literacy basically meant "financial knowledge," but the latest definition has been extended to include or refer to consumers' financial behaviours, consumers' interactions with their social and economic environments, and the effect of cognitive biases on consumers' financial behaviours. On the other hand, conventional measurement scales for financial literacy are generally composed of declarative knowledge questions and numerical ability tests concerning personal finance. This paper addresses the fact that previous financial literacy scales have been based on the traditional concept of "Homo economicus". We suggest that it is necessary to develop a new financial literacy scale that is comprised of critical thinking disposition such as "awareness for logical thinking" or "evidence-based judgment." PMID- 29630304 TI - Graphene Based Biosensor Model for Escherichia Coli Bacteria Detection. AB - As a new nanomaterial, graphene demonstrates great potential as an electrode for biomedical applications in sensing molecules and cells. Thus, development of biosensors based on graphene is gaining much interest due to its exceptional properties such as, large surface-to-volume ratio, high conductivity and high flexibility. In this work a liquid gated graphene field effect transistor based biosensor model is analytically developed for electrical detection of Escherichia Coli O157:H7 bacteria. The effect of graphene functionalization on the graphene conductance in the presence of E. coli is investigated. E. coli absorption effects on the graphene surface in the form of conductance variation are considered. Therefore the graphene conductance as a function of E. coli concentration which controls the current-voltage characteristics of biosensors is presented. According to the simulated results, the proposed sensor model can be applied as a powerful tool to predict the biosensor performance. PMID- 29630305 TI - [The mutual interference of facial and vocal information in Chinese and Japanese people's perception of emotions]. AB - In this study, we investigated cultural differences in multisensory perception of emotion between Chinese and Japanese participants, focusing on mutual interference of visual and auditory emotional information. In this experiment, the face-voice pairs were consisted of congruent or incongruent emotions (e.g., a happy (an angry) face with a happy (an angry) voice in congruent pairs, and a happy (an angry) face with an angry (a happy) voice in incongruent pairs). Participants were asked to judge the emotion of targets focusing on either face or voice while ignoring the other modality's information. In the voice-focus condition, the effect of to-be-ignored facial information was smaller in Japanese than Chinese participants, only when the participant and the target belonged to the same cultures (in-group). This indicated that Japanese people were more likely to be based on the voice information in multisensory perception of emotion of in-group. Our study illuminated that although both Japanese and Chinese people belonged to the Eastern culture, there were cultural differences in perceiving emotion from visual and auditory cues. PMID- 29630306 TI - [The effects of question types for introduction on substantive information provided by Japanese children in interviews]. AB - The effects of two introductory styles on substantive information provided by Japanese children were investigated. Children aged 5-6 years (n = 42) and 7-8 years (n = 40) took a simulated physical examination. One week later, the participants were interviewed about the examination in a narrative introductory condition using open-ended questions, or a non-narrative introductory condition using directive and yes/no questions. Substantive information provided by the children in the two conditions was compared. Results indicated that in the narrative condition, the participants provided more accurate information about the examination in response to open-ended questions. Additionally, the 7-8 year old children in the narrative condition provided a wider range of critical information. These findings suggest that an open-ended introductory style is effective in eliciting more accurate information from children, including preschoolers, and more varied information from school-age children. PMID- 29630307 TI - [Independence of old and new item processing in recognition judgment]. AB - This study investigated the independence of old and new item processing in recognition judgment. Conventional recognition studies have focused on the "memory" aspects of recognition judgment, while new item processing has been treated as a "residual response" of old item processing. However, prior studies on confidence ratings and the brain research suggest the possibility that old and new items are independently processed. This study conducted recognition judgment tests with the number of learned items as independent variables, and response times for four answer categories (hit, miss, correct rejection, and false alarm) as dependent variables. Hit response times were consistently shorter than misses for all old items, while correct rejection (CR) and false alarm (FA) response times approached equivalence (CR = FA) for new items as the number of old (memorized) items increased. These results suggest that recognition judgment changes according to the number of old (memorized) items. We discuss the idea that new item and old item processing in recognition judgment occur independently. PMID- 29630308 TI - [Japanese response bias: Cross-level and cross-national comparisons on response styles]. AB - This study attempts to identify response styles of Japanese students by cross level and cross-national analyses. Tasaki and Ninomiya (2013) demonstrated the existence of an acquiescence response behavior of Japanese students based on the model by Billet and McClendon(2000), who measured latent response characteristics as "style factor." In this study, we used a different response style measurement model proposed by Weijters, Schillewaert, & Geuens (2008) positing that response styles are psychological constructs and observed response style variables are summary indicators derived from sets of various, but independent, test items. Results of cross-national analyses indicated that Japanese and Korean participants were more likely to choose a mid-point response (MRS) and less likely to choose an acquiescence response (ARS) than American counterparts, but no significant difference was observed for an extreme response (ERS) among participants from the three nations. Within the Japanese response style model, cross-level analyses showed that ARS scores were significantly higher than ERS scores, indicating that Japanese participants had an acquiescence response style, consistent with the findings from Tasaki & Ninomiya (2013). PMID- 29630309 TI - Designing Self-Standing Three Dimensional Composite SiCu Thin Films as Anodes for Lithium Ion Battery. AB - Three dimensional nanostructured silicon based electrodes are promising for high capacity anodes in lithium ion battery. Though the specific capacity of silicon is very high compared to the conventional graphite anode, its large volume changes in cycling results in poor cycle life, which eventually restricts Si use in commercial applications. This problem could be overcomed by producing selfstanding nanostructures that can provide facile relaxation to prevent electrode pulverization. Plus, nanostructured electrodes maintain effective electrical contacts in cycling and provide short Li diffusion distances improving their electrochemical performances. In this paper, by using electron beam evaporation glancing angle deposition method three dimensional Si based composite (10%at. Cu) self-standing nanostructures with different porosities are produced. After the morphological and structural characterizations, their potential uses as anodes in lithium ion batteries are evaluated by means of electrochemical tests. PMID- 29630310 TI - [Do the explanations regarding the safety of Fukushima-produced foods ease consumer's concerns about disease?] AB - Consumers have had concerns over the safety of Fukushima-produced foods since the Fukushima-Daiichi nuclear power plant accident. To dispel these concerns, the public administration has distributed the informational leaflets, which guarantee the safety of Fukushima-produced foods in the marketplace. We investigated the effectiveness of the leaflets. Previous research showed that the activation of behavioral immune system exacerbated prejudice toward out-group members. Therefore, we investigated whether reading the leaflets about the safety of foods would increase prejudice toward foreigners. Participants (N = 50) were asked to read a leaflet either relevant or irrelevant to the safety of Fukushima-produced foods and then complete a Japanese-Foreigners Implicit Association Test and Perceived Vulnerability to Disease Scale. As predicted, participants high in chronic germ aversion (GA) were more prejudiced against foreigners when reading the leaflet relevant to the safety of Fukushima-produced foods than when reading the leaflet irrelevant to the issue. No such effect was observed among participants low in GA. These results indicated the possibility that the current leaflet about the safety of Fukushima foods might backfire. PMID- 29630311 TI - [Effects of perceived benefits about when and how to use a learning strategy]. AB - Previous studies have shown a positive correlation between the use of a learning strategy and perceived benefits. However, the impact of perceived benefits as conditional knowledge in metacognitive knowledge has not been examined. The present study investigated the effect of perceived benefits about when (short and long) and how (persistent and suitable) to use learning strategies using two surveys. Each survey utilized a sample of undergraduate students from three different Japanese universities, and the Bayesian hierarchical modeling and within-person variance were used to verify the relationship between the use of a learning strategy and perceived benefits. The students completed questionnaires regarding cognitive (Survey 2a) and metacognitive (Survey 2b) strategies (Survey 1 included two strategies), and achievement goals (without Survey 1). Findings revealed the effects of long-term and short-term persistent perceived benefits on the use of a learning strategy in all the surveys. These results suggest that persistent benefits be emphasized in order to promote the use of learning strategies, and that the appropriate perceived benefits be emphasized in order to become an adaptive learner. PMID- 29630313 TI - [Effects of help-seeker's predictions about helper's emotions and costs of help seeking intentions]. AB - The present study examined effects of predictions made by a help-seeker about the emotions and costs of a helper on help-seeking behavior. We surveyed undergraduate and graduate students who completed a questionnaire and scenario task. The scenario presented that a person would face the trouble. The questionnaire presented a case where a person was troubled. Respondents were required to answer the following questions: (a) whether they would seek help; (b) whether the helper would respond to help-seeking; (c) the helper's costs; (d) the negative moods of the helper. Covariance structure analysis of 189 participant responses revealed that help-seeker predictions about the helper's emotions and costs were used to predict the intentions of the helper, which affected the intentions to seek help. We discuss these results with respect to interpersonal cognition in intimate relationships. PMID- 29630312 TI - [Development of a Japanese version of the Interpersonal Reactivity Index]. AB - Empathy is a multi-dimensional concept with emotional and cognitive components. The Interpersonal Reactivity Index (IRI) is a multi-dimensional scale of empathic traits. Although some researchers have attempted to translate the IRI into Japanese, these translated scales had limitations with content and construct validity, and measurement invariance. We therefore attempt to overcome these limitations by developing a new Japanese version of the IRI (IRI-J). We used three approaches to assess the validity and measurement invariance of the IRI-J. In Study 1, content validity was tested using back-translation, and construct validity was confirmed through a comprehensive investigation of a web-based survey using six other scales. Results indicate that the factor structure of the IRI-J was equivalent to that of the original version, and that the IRI-J had adequate reliability and construct validity. In Study 2, measurement invariance by gender was confirmed using data from four web-based surveys. These results suggest that the factor model of IRI-J for each gender is equivalent. The present study thus provides an improved measure of empathic traits for the Japanese population. PMID- 29630314 TI - [Information on student counseling center websites in Japan, the United States, the United Kingdom, and Taiwan]. AB - This study aimed to compare information provided on student counseling center websites of universities and colleges in Japan, the United States, the United Kingdom, and Taiwan. A survey was conducted on websites of 315 centers in Japan, 282 centers in the United States, 70 centers in the United Kingdom and 61 centers in Taiwan. Trends in the provision of information on websites in each country were analyzed and compared for the rate and quantity of information published. Results of multiple correspondence analyses indicated two basic dimensions of information that could effectively distinguish information provided in the four countries. These were provision of necessary information and provision of information for use of individual counseling or support of community. Finally, issues related to websites in student counseling centers of Japanese universities and colleges are discussed. PMID- 29630315 TI - [Relationships between motivational regulation strategies, motivational factors, and learning behaviors outside the classroom]. AB - This study examined the relationships among motivational regulation strategies, motivational factors, and learning behaviors outside the classroom. There are three subtypes of motivational regulation strategies: autonomous regulation strategies, cooperative strategies, and performance-focused strategies. Motivational factors included in the investigation were self-efficacy and task value, while behavioral and emotional engagement and study time were selected as learning behaviors outside the classroom. A self-report questionnaire was administered to 322 undergraduates from two universities. Multiple regression analysis revealed the use of autonomous regulation strategies, and that task value was positively correlated with engagement and study time. Moreover, self efficacy positively predicted study time. In contrast, the use of performance strategies negatively predicted engagement. The use of cooperative strategies did not predict learning behaviors. These results indicate that motivation, as well as the regulation of motivation, were important for learning outside the classroom. The effects of regulation of motivation and motivation on learning outside the classroom are discussed in light of the current findings. PMID- 29630316 TI - Fabrication and Process Optimization of Poly(2-hydroxyethyl methacrylate) Nanofibers by Response Surface Methodology. AB - In this study, Response Surface Methodology (RSM) was used to model and optimize the electrospinning parameters to obtain poly(2-hydroxylethyl methacrylate) (pHEMA) nanofibers which is challenging in terms of evaluating the optimum conditions in nanofiber production. A second order (quadratic model) polynomial function was used for correlation between electrospinning parameters (flow rate, applied voltage, polymer/ethanol concentration) and average fiber diameter. An electro-spinning set-up was used to fabricate nanofibers and scanning electron microscopy (SEM) was used to determine the morphology and the size of the nanofibers with diameter ranging from 211 nm to 1661 nm. Results concluded that the concentration of polymer solution played an important role in distribution of fiber diameter. Based on RSM, the optimum pHEMA fibers with 245+/-35 nm diameter were collected at 13 MUL/min flow rate, 12 kV applied voltage at an ethanol:pHEMA ratio of 1.76. PMID- 29630318 TI - Control of ZnO Nanorod Defects to Enhance Carrier Transportation in p-Cu2O/i-ZnO Nanorods/n-IGZO Heterojunction. AB - The p-Cu2O/i-ZnO nanorods/n-IGZO heterojunctions were fabricated by electrochemical and sputtering method. ZnO nanorods were grown on conductive indium gallium zinc oxide (IGZO) thin film and then p-Cu2O layer was deposited on ZnO nanorods to form the heterojunction. ZnO nanorods play an important role in carrier transport mechanisms and performance of the junction. The changing of defects in ZnO nanorods by annealing samples in air and vacuum have studied. The XRD, photoluminescence (PL) spectroscopy, and FTIR were used to study about structure, and defects in ZnO nanorods. The SEM, i-V characteristics methods were also used to define structure, electrical properties of the heterojunctions layers. The results show that the defects in ZnO nanorods affected remarkably on performance of heterojunctions of solar cells. PMID- 29630317 TI - Facile Synthesis of Monodisperse Nanostructured Silver Micro-Colloids via Controlled Agglomeration and Coalescence. AB - Silver nanostructures have expansive applications in catalysis, photonic and electronic devices. In this work, nanostructured silver micro-colloids (MCs) with uniform in size and shape (size distribution <5%) were synthesized via rapid reduction of silver nitrate by ascorbic acid with controlled agglomeration and coalescence. We further propose that the formation of silver MCs was controlled by the chemical reaction kinetics which is governed by the concentration of reduced silver, Ago formed in solution. Preliminary electrical measurements of the highly conductive silver MCs demonstrated their potential application as inks for printed electronics. PMID- 29630319 TI - Moving evidence into clinical practice: Implementing surgical safety checklists in the operating room. AB - Surgical safety checklists have been shown to improve teamwork and reduce the risk of wrong site surgery (WHO, 2008). PMID- 29630321 TI - Entropy, Electric Field and Heavily Doped Nanowires. AB - In this paper an attempt is made to study, the entropy in the presence of intense electric field in nanowires (NWs) of heavily doped (HD) III-V and optoelectronic materials on the basis of newly formulated electron dispersion relations within the frame work of k -> ? p -> formalism. It is found taking HD NWs of InSb, InAs, Hg(1- x) Cd (x)Te and In(1- x) Ga( x) As( y) P(1- y) lattice matched to InP as examples III-V, ternary and quaternary compounds that the entropy increases with increasing electron concentration per unit length and decreasing film thickness in different spiky manners, since the coincidence of Fermi energy with the sub-band energy leads to the step functional dependence of the density state function and this fact is being reflected in the quantized variations of the entropy with the said variables. The entropy increases with increasing electric field and decreasing alloy composition respectively. The numerical values of entropy with all the physical variables are totally band structure dependent for all the cases. The most striking features are that the presence of poles in the dispersion relation of the materials in the absence of band tails creates the complex energy spectra in the corresponding opto-electronic HD NWs and the effective electron mass exists within the band gap which is impossible without the concept of band tailing. The well-known classical result of entropy for non-degenerate bulk semiconductors having parabolic energy bands has been obtained as a special case of our generalized formulation and thus confirming the compatibility test. The content of this paper finds four important applications in the field of quantum effect devices of nanoscience and nanotechnology. PMID- 29630320 TI - Tying it all together - Ratios, the BPF and patient safety. PMID- 29630322 TI - Magnetic Properties of Pure and Doped Gallium Nitride Nanocrystals. AB - In the present paper, Ga(1- x) Co(x) N, Ga(1- x) Ni(x) N and Ga(1- x) Tb(x) N (0 <= x <= 0.1) nanocrystals have been synthesized by a facile solvothermal method. Crystallographic characterization of synthesized materials has been done using powder X-ray diffraction technique. Recorded diffraction patterns reveal the formation of wurtzite (hexagonal) structured GaN nanocrystals. Electron microscopic studies have been carried for the detailed topographical and morphological analyses of synthesized nanomaterials. Recorded electron micrographs indicate the formation of nearly mono-disperse nanoparticles, having average size ~4 nm. Magnetic measurements of doped nanocrystals revealed ferromagnetic behavior at room temperature however pure GaN is diamagnetic at room temperature. PMID- 29630323 TI - Communication is key in any relationship. AB - A good work environment for nurses and midwives requires an institutional culture that values and respects professional nursing and midwifery as a force for quality patient outcomes. PMID- 29630324 TI - Single nurse posts. AB - The murder of South Australian Remote Area Nurse Gayle Woodford shocked the Australian public, triggering a nation-wide campaign to abolish single nurse posts. PMID- 29630325 TI - Photoluminescence and Growth Mechanism of Oriented Hierarchical Fibrous-Like ZnO Nanowires. AB - Oriented hierarchical fibrous-like ZnO nanowires with the diameter of about 30-50 nm and the length of about 15-30 um were successfully synthesized on the seed coated Zn substrates by a simple two-step process. The morphology and structure of the obtained samples were characterized by X-ray diffraction (XRD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM). It is shown that fibrous-like ZnO nanowires with the aspect ratio of about 500~1000 present the dense reticular structure, which are grown on ZnO nanowire arrays. But beyond that, as-prepared samples are found to be good single crystalline with hexagonal wurtzite structure and preferential grow along the c-axis. A possible growth mechanism of oriented hierarchical fibrous-like ZnO nanowires is presented in detail, revealing that the synthesis of fibrous-like ZnO nanowires should be attributed to differences in the growth rate of the different crystallographic planes and the two growth ways. The photoluminescence (PL) spectra of oriented hierarchical fibrous-like ZnO nanowires grown at 240 min shows the 5 nm blue shift and enhanced intensity property in the UV emission. PMID- 29630326 TI - Protect our health care system. AB - When I first arrived in Australia from the United States in 1996, I couldn't get over how accessible health care was here. PMID- 29630328 TI - Landmark report examines indigenous health. PMID- 29630327 TI - Bringing safe midwifery care - and hope - to remote PNG. AB - In 2008 with our children now young adults, my husband Neil and I decided to take off without them. PMID- 29630329 TI - Tunable Synthesis, Characterization and Magnetic Properties of Core-Shell Cu@M (M = Co or Ni) Nanowires. AB - The ultralong Cu@M (M = Co or Ni) nanowires (NWs) with core-shell structure were fabricated by a simple method by using the prepared Cu NWs as template. The crystal phases of Cu@M (M = Co or Ni) NWs were confirmed by X-ray diffraction (XRD). The morphology and microstructure of NWs were characterized by scanning electro microscopy (SEM) and transmission electro microscopy (TEM). Different diameters of Cu@M (M = Co or Ni) NWs varying from 120 to 550 nm with length about 10 MUm were obtained via controlling the amounts of cobalt (nickel) nitrates in the reduction process. The magnetic properties of samples were measured using vibrating sample magnetometer (VSM). Results revealed that Cu NWs has a characteristic of paramagnetism after coating Co or Ni. The coercivity (H(c)) values of Cu@ Ni and Cu@Co NWs were 114.6 and 102.5 Oe, respectively. Possible formation mechanism for Cu@M (M = Co or Ni) NWs was preliminarily proposed. PMID- 29630330 TI - Single-Step Synthesis and Optical Properties of Bimetallic Fe-Ag Nanoparticles. AB - Bimetallic nanoparticles containing ferromagnetic iron (Fe) and plasmonic silver (Ag) are synthesized by one-step chemical reduction process. Structural and optical properties of nanoparticles are studied by transmission electron microscopy, X-ray diffraction technique, UV-Visible spectroscopy and photoluminescence measurement. Tunable optical properties with the variation of Ag percentage in the Fe-Ag nanoparticles are observed. Sharp absorption peak due to localized surface plasmon resonance (LSPR) is observed in the visible spectrum range for Fe-Ag nanoparticles which is absent in Fe nanoparticles. LSPR peak shows redshift due to variation in shape and size of the nanoparticles having higher Ag content. Enhanced photoluminescence in the bimetallic nanoparticles is attributed to the observed surface plasmon resonance. PMID- 29630331 TI - Hysteretic Characteristics of Pulsed Laser Deposited 0.5Ba(Zr0.2Ti0.8)O3 0.5(Ba0.7Ca0.3)TiO3/ZnO Bilayers. AB - In the present work, we study the hysteretic behavior in the electric-field dependent capacitance and the current characteristics of 0.5Ba(Zr0.2Ti0.8)O3 0.5(Ba0.7Ca0.3)TiO3 (BCZT)/ZnO bilayers deposited on 0.7 wt % Nb-doped (001) SrTiO3 (Nb:STO) substrates in a metal-ferroelectric-semiconductor (MFS) configuration. The X-ray diffraction measurements show that the BCZT and ZnO layers are highly oriented along the c-axis and have a single perovskite and wurtzite phases, respectively, whereas high-resolution transmission electron microscopy revealed very sharp Nb:STO/BCZT/ZnO interfaces. The capacitance electric field ( C- E) characteristics of the bilayers exhibit a memory window of 47 kV/cm and a capacitance decrease of 22%, at a negative bias. The later result is explained by the formation of a depletion region in the ZnO layer. Moreover, an unusual resistive switching (RS) behavior is observed in the BCZT films, where the RS ratio can be 500 times enhanced in the BCZT/ZnO bilayers. The RS enhancement can be understood by the barrier potential profile modulation at the depletion region, in the BCZT/ZnO junction, via ferroelectric polarization switching of the BCZT layer. This work builds a bridge between the hysteretic behavior observed either in the C- E and current-electric field characteristics on a MFS structure. PMID- 29630332 TI - Enhanced Corrosion Resistance of Superhydrophobic Layered Double Hydroxide Films with Long-Term Stability on Al Substrate. AB - A superhydrophobic ZnAl-layered double hydroxide (LDH)-La film was prepared by a hydrothermal method and further modification by laurate anions in this work. Comprehensive characterizations of this film were performed in terms of morphology, composition, structure, roughness, and wettability by scanning electronic microscopy, energy-dispersive X-ray spectroscopy, X-ray diffraction, three-dimensional laser scanning confocal microscopy. The long-term corrosion protection effect of this superhydrophobic film was investigated deeply by monitoring the changes of the electrochemical impedance spectra for a long time of up to a month in 3.5 wt % NaCl solution. In the meantime, the changes of the contact angle were also recorded with the evolution of the immersion time. The result indicated that the stable superhydrophobic ZnAl-LDH-La film was able to provide efficient protection for the underlying Al substrate for a long time. In addition, the capability of the superhydrophobic surface against harsh conditions, including chemical damages and physical damages, was emphatically investigated. It was found that the superhydrophobic surface was chemically stable toward acid (pH >= 3), alkali, and heating, and it also exhibited high ultraviolet (UV) radiation resistance. This superhydrophobic coating maintained superhydrophobicity for 7 days of radiation in an UV chamber equipped with a 40 W UV lamp (lambda = 254 nm), indicating superior ability of adapting to outdoor environment. This comprehensive investigation of the superhydrophobic ZnAl-LDH-La film is considerably helpful for researchers and engineers to get deep insight into its potential for practical applications in the field of corrosion and protection. PMID- 29630333 TI - Different Positron Emission Tomography Tau Tracers Bind to Multiple Binding Sites on the Tau Fibril: Insight from Computational Modeling. AB - Using the recently reported cryo-EM structure for the tau fibril [ Fitzpatrick et al. (2017) Nature 547, 185-190 ], which is a potential target concerning Alzheimer's disease, we present the first molecular modeling studies on its interaction with various positron emission tomography (PET) tracers. Experimentally, based on the binding assay studies, at least three different high affinity binding sites have been reported for tracers in the tau fibril. Herein, through integrated modeling using molecular docking, molecular dynamics, and binding free energy calculations, we provide insight into the binding patterns of various tracers to the tau fibril. We suggest that there are four different high affinity binding sites available for many of the studied tracers showing varying binding affinity to different binding sites. Thus, PBB3 binds most strongly to site 4, and interestingly, this site is not a preferable site for any other tracers. For THK5351, our data show that it strongly binds to sites 3 and 1, the former one being more preferable. We also find that MK6240 and T807 bind to site 1 specifically. The modeling data also give some insight into whether a tracer bound to a specific site can be replaced by others or not. For example, the displacement of T807 by PBB3 as reported experimentally can also be explained and attributed to the larger binding affinity of the latter compound in all binding sites. The binding free energy results explain very well the small binding affinity of THK523 compared to all the aryl quinoline moieties containing THK tracers. The ability of certain tau tracers, like FDDNP and THK523, to bind to amyloid fibrils has also been investigated. Furthermore, such off-target interaction of tau tracers with amyloid beta fibrils has been validated using a quantum mechanical fragmentation approach. PMID- 29630334 TI - Underwater Curvature-Driven Transport between Oil Droplets on Patterned Substrates. AB - Roughness contrast patterns were generated on copper surfaces by a simple one step site-selective oxidation process using a felt-tipped ink pen masking method. The patterned surface exhibited strong underwater oil wettability contrast which allows oil droplet confinement. Oil droplets placed on two patterned smooth dots (reservoirs) connected by a patterned smooth channel will spontaneously exchange liquid as a result of Laplace pressure differences until their shapes have reached equilibrium. In our experiments, residual solubility of the oil in water was overcome by using saturated oil-in-water solutions as the aqueous medium. In the saturated solution, the dependence of pattern geometry and oil viscosity on transported volume and the flow rate in the underwater oil transport process was investigated for dichloromethane and hexadecane. Experimental results were in good agreement with a simple model for Laplace pressure-driven flow. Depending on droplet curvatures, oil can be transported from large to small reservoirs or vice versa. The model predictions enable the design of reservoir and channel dimensions to control liquid transport in the water-solid surface-oil system. The patterning technique was extended to more complex patterns with multiple reservoirs for smart oil separation and mixing processes. The concepts demonstrated in this study can be employed to seed droplet arrays with specific initial drop volumes and achieve subsequent droplet mixing at controlled flow rates for potential lab-on-a-chip applications ranging from oil-droplet-based miniature reactors and sensors to high-throughput assays. PMID- 29630335 TI - Facile Synthesis of the O-Functionalized Ladder-Type Dipyran Building Block and Its Application in Polymer Solar Cells. AB - A new centrosymmetrical dipyran unit (DTDP) is successfully prepared by means of an efficient and universal way, and a series of PDTDP polymers have been prepared so as to assess their potential application in organic photovoltaic. The function of pyran moiety is not merely limited to tune the electron-donating roles and energy levels but it also contributes to solubility improvement. Interestingly, all pyran-based polymers displayed wide absorption ranging from 350 to 780 nm, but varied aggregation phenomena are observed. Furthermore, the quantum chemistry calculations for dimers, morphology study and grazing-incidence wide-angle X-ray scattering analysis for blend films have been utilized to understand the variations at photovoltaic performances. Finally, PDTDP-4 achieved the highest power conversion efficiency of 7.26% ( Voc = 0.72 V, FF = 0.66, and Jsc = 15.30 mA/cm2), demonstrating promising usage for high-efficiency polymer donors in polymer solar cells. In all, not only a promising dipyran building block is provided by this study, more dipyran derivatives and polymers could be prepared via this facile synthetic route. PMID- 29630336 TI - Unconventional Three-Armed Luminogens Exhibiting Both Aggregation-Induced Emission and Thermally Activated Delayed Fluorescence Resulting in High Performing Solution-Processed Organic Light-Emitting Diodes. AB - In this work, three-armed luminogens IAcTr-out and IAcTr-in were synthesized and used as emitters bearing triazine and indenoacridine moieties in thermally activated delayed fluorescence organic light-emitting diodes (OLEDs). These molecules could form a uniform thin film via the solution process and also allowed the subsequent deposition of an electron transporting layer either by vacuum deposition or by an all-solution coating method. Intriguingly, the new luminogens displayed aggregation-induced emission (AIE), which is a unique photophysical phenomenon. As a nondoped emitting layer (EML), IAcTr-in showed external quantum efficiencies (EQEs) of 11.8% for the hybrid-solution processed OLED and 10.9% for the all-solution processed OLED with a low efficiency roll off. This was evident by the higher photoluminescence quantum yield and higher rate constant of reverse intersystem crossing of IAcTr-in, as compared to IAcTr out. These AIE luminogens were used as dopants and mixed with the well-known host material 1,3-bis( N-carbazolyl)benzene (mCP) to produce a high-efficiency OLED with a two-component EML. The maximum EQE of 17.5% was obtained when using EML with IAcTr-out doping (25 wt %) into mCP, and the OLED with EML bearing IAcTr-in and mCP showed a higher maximum EQE of 18.4% as in the case of the nondoped EML based device. PMID- 29630338 TI - Low Temperature, Selective Atomic Layer Deposition of Nickel Metal Thin Films. AB - We report the growth of nickel metal films by atomic layer deposition (ALD) employing bis(1,4-di- tert-butyl-1,3-diazadienyl)nickel and tert-butylamine as the precursors. A range of metal and insulating substrates were explored. An initial deposition study was carried out on platinum substrates. Deposition temperatures ranged from 160 to 220 degrees C. Saturation plots demonstrated self-limited growth for both precursors, with a growth rate of 0.60 A/cycle. A plot of growth rate versus substrate temperature showed an ALD window from 180 to 195 degrees C. Crystalline nickel metal was observed by X-ray diffraction for a 60 nm thick film deposited at 180 degrees C. Films with thicknesses of 18 and 60 nm grown at 180 degrees C showed low root mean square roughnesses (<2.5% of thicknesses) by atomic force microscopy. X-ray photoelectron spectroscopies of 18 and 60 nm thick films deposited on platinum at 180 degrees C revealed ionizations consistent with nickel metal after sputtering with argon ions. The nickel content in the films was >97%, with low levels of carbon, nitrogen, and oxygen. Films deposited on ruthenium substrates displayed lower growth rates than those observed on platinum substrates. On copper substrates, discontinuous island growth was observed at <=1000 cycles. Film growth was not observed on insulating substrates under any conditions. The new nickel metal ALD procedure gives inherently selective deposition on ruthenium and platinum from 160 to 220 degrees C. PMID- 29630337 TI - DARK Classics in Chemical Neuroscience: Cocaine. AB - In this Review, we consider the story of cocaine from its humble origins in South America to its status as one of the most abused substances in 21st century society. The synthesis and biosynthesis of cocaine are discussed, as well as its pharmacokinetics, metabolism, pharmacology, and importance in modern neuroscience and molecular imaging. PMID- 29630340 TI - Self-Assembled Nanocrystals of Polycyclic Aromatic Hydrocarbons Show Photostable Single-Photon Emission. AB - Quantum technologies could largely benefit from the control of quantum emitters in sub-micrometric size crystals. These are naturally prone to integration in hybrid devices, including heterostructures and complex photonic devices. Currently available quantum emitters in nanocrystals suffer from spectral instability, preventing their use as single-photon sources for most quantum optics operations. In this work we report on the performances of single-photon emission from organic nanocrystals (average size of hundreds of nm), made of anthracene (Ac) and doped with dibenzoterrylene (DBT) molecules. The source has hours-long photostability with respect to frequency and intensity, both at room and at cryogenic temperature. When cooled to 3 K, the 00-zero phonon line shows linewidth values (50 MHz) close to the lifetime limit. Such optical properties in a nanocrystalline environment recommend the proposed organic nanocrystals as single-photon sources for integrated photonic quantum technologies. PMID- 29630339 TI - Pathway-Specific Alterations of Cortico-Amygdala Transmission in an Arthritis Pain Model. AB - Medial prefrontal cortex (mPFC) and amygdala are closely interconnected brain areas that play a key role in cognitive-affective aspects of pain through their reciprocal interactions. Clinical and preclinical evidence suggests that dysfunctions in the mPFC-amygdala circuitry underlie pain-related cognitive affective deficits. However, synaptic mechanisms of pain-related changes in these long-range pathways are largely unknown. Here we used optogenetics and brain slice physiology to analyze synaptic transmission in different types of amygdala neurons driven by inputs from infralimbic (IL) and prelimbic (PL) subdivisions of the mPFC. We found that IL inputs evoked stronger synaptic inhibition of neurons in the latero-capsular division of the central nucleus (CeLC) of the amygdala than PL inputs, and this inhibition was impaired in an arthritis pain model. Furthermore, inhibition-excitation ratio in basolateral amygdala neurons was increased in the pain model in the IL pathway but not in the PL pathway. These results suggest that IL rather than PL controls CeLC activity, and that changes in this acute pain model occur predominantly in the IL-amygdala pathway. PMID- 29630341 TI - High-Performance All 2D-Layered Tin Disulfide: Graphene Photodetecting Transistors with Thickness-Controlled Interface Dynamics. AB - Tin disulfide crystals with layered two-dimensional (2D) sheets are grown by chemical vapor deposition using a novel precursor approach and integrated into all 2D transistors with graphene (Gr) electrodes. The Gr:SnS2:Gr transistors exhibit excellent photodetector response with high detectivity and photoresponsivity. We show that the response of the all 2D photodetectors depends upon charge trapping at the interface and the Schottky barrier modulation. The thickness-dependent SnS2 measurements in devices reveal a transition from the interface-dominated response for thin crystals to bulklike response for the thicker SnS2 crystals, showing the sensitivity of devices fabricated using layered materials on the number of layers. These results show that SnS2 has photosensing performance when combined with Gr electrodes that is comparable to other 2D transition metal dichalcogenides of MoS2 and WS2. PMID- 29630342 TI - Ultrafine Pt Nanoparticles and Amorphous Nickel Supported on 3D Mesoporous Carbon Derived from Cu-Metal-Organic Framework for Efficient Methanol Oxidation and Nitrophenol Reduction. AB - The development of novel strategy to produce new porous carbon materials is extremely important because these materials have wide applications in energy storage/conversion, mixture separation, and catalysis. Herein, for the first time, a novel 3D carbon substrate with hierarchical pores derived from commercially available Cu-MOF (metal-organic framework) (HKUST-1) through carbonization and chemical etching has been employed as the catalysts' support. Highly dispersed Pt nanoparticles and amorphous nickel were evenly dispersed on the surface or embedded within carbon matrix. The corresponding optimal composite catalyst exhibits a high mass-specific peak current of 1195 mA mg-1 Pt and excellent poison resistance capacity ( IF/ IB = 1.58) for methanol oxidation compared to commercial Pt/C (20%). Moreover, both composite catalysts manifest outstanding properties in the reduction of nitrophenol and demonstrate diverse selectivities for 2/3/4-nitrophenol, which can be attributed to different integrated forms between active species and carbon matrix. This attractive route offers broad prospects for the usage of a large number of available MOFs in fabricating functional carbon materials as well as highly active carbon-based electrocatalysts and heterogeneous organic catalysts. PMID- 29630343 TI - Homogeneous Oxygenase Catalysis. AB - Oxygenases-catalyzed reductive activation of molecular oxygen and incorporation of O atoms into an organic molecule is undoubtedly one of the most attractive research areas. Typically, these oxygenation reactions proceed with high selectivity and reactivity, which is seldom found in its "biomimetic" chemocatalytic counterparts. Furthermore, enzymatic oxygenation can avoid undesired overoxidation, which is frequently observed in (industrial) chemical transformation. Therefore, it is not surprising that tremendous attention has been paid to enzymatic oxygenation. Their application in organic synthesis has been steadily growing over the years. The goal of the present Review is to provide a handy reference for chemists interested in using homogeneous oxygenase catalysis and those interested in discovering new types of biomimetic oxidations and oxygenations with dioxygen. In this Review, we will review the recent advances in in homogeneous oxygenase catalysis to reveal the great achievements and potentials in this field. PMID- 29630344 TI - Insights on Chemistry of Mercury Species in Clouds over Northern China: Complexation and Adsorption. AB - Cloud effects on heterogeneous reactions of atmospheric mercury (Hg) are poorly understood due to limited knowledge of cloudwater Hg chemistry. Here we quantified Hg species in cloudwater at the summit of Mt. Tai in northern China. Total mercury (THg) and methylmercury (MeHg) in cloudwater were on average 70.5 and 0.15 ng L-1, respectively, and particulate Hg (PHg) contributed two-thirds of THg. Chemical equilibrium modeling simulations suggested that Hg complexes by dissolved organic matter (DOM) dominated dissolved Hg (DHg) speciation, which was highly pH dependent. Hg concentrations and speciation were altered by cloud processing, during which significant positive correlations of PHg and MeHg with cloud droplet number concentration ( Nd) were observed. Unlike direct contribution to PHg from cloud scavenging of aerosol particles, abiotic DHg methylation was the most likely source of MeHg. Hg adsorption coefficients Kad (5.9-362.7 L g-1) exhibited an inverse-power relationship with cloud residues content. Morphology analyses indicated that compared to mineral particles, fly ash particles could enhance Hg adsorption due to more abundant carbon binding sites on the surface. Severe particulate air pollution in northern China may bring substantial Hg into cloud droplets and impact atmospheric Hg geochemical cycling by aerosol-cloud interactions. PMID- 29630345 TI - Quantum Interference, Graphs, Walks, and Polynomials. AB - In this paper, we explore quantum interference (QI) in molecular conductance from the point of view of graph theory and walks on lattices. By virtue of the Cayley Hamilton theorem for characteristic polynomials and the Coulson-Rushbrooke pairing theorem for alternant hydrocarbons, it is possible to derive a finite series expansion of the Green's function for electron transmission in terms of the odd powers of the vertex adjacency matrix or Huckel matrix. This means that only odd-length walks on a molecular graph contribute to the conductivity through a molecule. Thus, if there are only even-length walks between two atoms, quantum interference is expected to occur in the electron transport between them. However, even if there are only odd-length walks between two atoms, a situation may come about where the contributions to the QI of some odd-length walks are canceled by others, leading to another class of quantum interference. For nonalternant hydrocarbons, the finite Green's function expansion may include both even and odd powers. Nevertheless, QI can in some circumstances come about for nonalternants from cancellation of odd- and even-length walk terms. We report some progress, but not a complete resolution, of the problem of understanding the coefficients in the expansion of the Green's function in a power series of the adjacency matrix, these coefficients being behind the cancellations that we have mentioned. Furthermore, we introduce a perturbation theory for transmission as well as some potentially useful infinite power series expansions of the Green's function. PMID- 29630346 TI - Conducting Polymers in the Fields of Energy, Environmental Remediation, and Chemical-Chiral Sensors. AB - Conducting polymers (CPs), thanks to their unique properties, structures made on demand, new composite mixtures, and possibility of deposit on a surface by chemical, physical, or electrochemical methodologies, have shown in the last years a renaissance and have been widely used in important fields of chemistry and materials science. Due to the extent of the literature on CPs, this review, after a concise introduction about the interrelationship between electrochemistry and conducting polymers, is focused exclusively on the following applications: energy (energy storage devices and solar cells), use in environmental remediation (anion and cation trapping, electrocatalytic reduction/oxidation of pollutants on CP based electrodes, and adsorption of pollutants) and finally electroanalysis as chemical sensors in solution, gas phase, and chiral molecules. This review is expected to be comprehensive, authoritative, and useful to the chemical community interested in CPs and their applications. PMID- 29630347 TI - Evaluating Environmental Governance along Cross-Border Electricity Supply Chains with Policy-Informed Life Cycle Assessment: The California-Mexico Energy Exchange. AB - This paper presents a "policy-informed" life cycle assessment of a cross-border electricity supply chain that links the impact of each unit process to its governing policy framework. An assessment method is developed and applied to the California-Mexico energy exchange as a unique case study. CO2-equivalent emissions impacts, water withdrawals, and air quality impacts associated with California's imports of electricity from Mexican combined-cycle facilities fueled by natural gas from the U.S. Southwest are estimated, and U.S. and Mexican state and federal environmental regulations are examined to assess well-to-wire consistency of energy policies. Results indicate most of the water withdrawn per kWh exported to California occurs in Baja California, most of the air quality impacts accrue in the U.S. Southwest, and emissions of CO2-equivalents are more evenly divided between the two regions. California energy policy design addresses generation-phase CO2 emissions, but not upstream CO2-eq emissions of methane during the fuel cycle. Water and air quality impacts are not regulated consistently due to varying U.S. state policies and a lack of stringent federal regulation of unconventional gas development. Considering local impacts and the regulatory context where they occur provides essential qualitative information for functional-unit-based measures of life cycle impact and is necessary for a more complete environmental impact assessment. PMID- 29630348 TI - Municipal Wastewater as a Microbial Surveillance Platform for Enteric Diseases: A Case Study for Salmonella and Salmonellosis. AB - Municipal wastewater (MW) contains a conglomeration of human enteric microbiota from a community and, hence, represents a potential surveillance tool for gastrointestinal infectious disease burden at the community level. To evaluate this, the concentration of Salmonella in MW samples from Honolulu, Hawaii, was monitored over a 54-week period, which showed positive and significant linear and rank correlation with clinical salmonellosis case numbers over the same period. Salmonella isolates were obtained from the MW samples and then compared with clinical isolates obtained by the Hawaii Department of Health State Laboratories over the same period. The MW isolate collection contained 34 serotypes, and the clinical isolate collection contained 47 serotypes, 21 of which were shared between the two isolate collections, including nine of the 12 most commonly detected clinical serotypes. Most notably, nine Salmonella strains, including one outbreak-associated Paratyphi B strain and eight other clinically rare strains, were shared and concurrently detected between the MW and the clinical isolate collections, indicating the feasibility of using enteric pathogens in the MW as a timely indication of community enteric disease activity. PMID- 29630349 TI - Crystal Structures of Cystathionine beta-Synthase from Saccharomyces cerevisiae: One Enzymatic Step at a Time. AB - Cystathionine beta-synthase (CBS) is a key regulator of sulfur amino acid metabolism, taking homocysteine from the methionine cycle to the biosynthesis of cysteine via the trans-sulfuration pathway. CBS is also a predominant source of H2S biogenesis. Roles for CBS have been reported for neuronal death pursuant to cerebral ischemia, promoting ovarian tumor growth, and maintaining drug-resistant phenotype by controlling redox behavior and regulating mitochondrial bioenergetics. The trans-sulfuration pathway is well-conserved in eukaryotes, but the analogous enzymes have different enzymatic behavior in different organisms. CBSs from the higher organisms contain a heme in an N-terminal domain. Though the presence of the heme, whose functions in CBSs have yet to be elucidated, is biochemically interesting, it hampers UV-vis absorption spectroscopy investigations of pyridoxal 5'-phosphate (PLP) species. CBS from Saccharomyces cerevisiae (yCBS) naturally lacks the heme-containing N-terminal domain, which makes it an ideal model for spectroscopic studies of the enzymological reaction catalyzed and allows structural studies of the basic yCBS catalytic core (yCBS cc). Here we present the crystal structure of yCBS-cc, solved to 1.5 A. Crystal structures of yCBS-cc in complex with enzymatic reaction intermediates have been captured, providing a structural basis for residues involved in catalysis. Finally, the structure of the yCBS-cc cofactor complex generated by incubation with an inhibitor shows apparent off-pathway chemistry not normally seen with CBS. PMID- 29630350 TI - Highly Sensitive Hill-Type Small-Molecule pH Probe That Recognizes the Reversed pH Gradient of Cancer Cells. AB - A hallmark of cancer cells is a reversed transmembrane pH gradient, which could be exploited for robust and convenient intraoperative histopathological analysis. However, pathologically relevant pH changes are not significant enough for sensitive detection by conventional Henderson-Hasselbalch-type pH probes, exhibiting an acid-base transition width of 2 pH units. This challenge could potentially be addressed by a pH probe with a reduced acid-base transition width (i.e., Hill-type probe), appropriate p Ka, and membrane permeability. Yet, a guideline to allow rational design of such small-molecule Hill-type pH probes is still lacking. We have devised a novel molecular mechanism, enabled sequential protonation with high positive homotropic cooperativity, and synthesized small molecule pH probes (PHX1-3) with acid-base transition ranges of ca. 1 pH unit. Notably, PHX2 has a p Ka of 6.9, matching the extracellular pH of cancer cells. Also, PHX2 is readily permeable to cell membrane and allowed direct mapping of both intra- and extracellular pH, hence the transmembrane pH gradient. PHX2 was successfully used for rapid and high-contrast distinction of fresh unprocessed biopsies of cancer cells from normal cells and therefore has broad potentials for intraoperative analysis of cancer surgery. PMID- 29630351 TI - Doping Polymer Semiconductors by Organic Salts: Toward High-Performance Solution Processed Organic Field-Effect Transistors. AB - Solution-processed organic field-effect transistors (OFETs) were fabricated with the addition of an organic salt, trityl tetrakis(pentafluorophenyl)borate (TrTPFB), into thin films of donor-acceptor copolymer semiconductors. The performance of OFETs is significantly enhanced after the organic salt is incorporated. TrTPFB is confirmed to p-dope the organic semiconductors used in this study, and the doping efficiency as well as doping physics was investigated. In addition, systematic electrical and structural characterizations reveal how the doping enhances the performance of OFETs. Furthermore, it is shown that this organic salt doping method is feasible for both p- and n-doping by using different organic salts and, thus, can be utilized to achieve high-performance OFETs and organic complementary circuits. PMID- 29630352 TI - Toward Self-Control Systems for Neurogenic Underactive Bladder: A Triboelectric Nanogenerator Sensor Integrated with a Bistable Micro-Actuator. AB - Aging, neurologic diseases, and diabetes are a few risk factors that may lead to underactive bladder (UAB) syndrome. Despite all of the serious consequences of UAB, current solutions, the most common being ureteric catheterization, are all accompanied by serious shortcomings. The necessity of multiple catheterizations per day for a physically able patient not only reduces the quality of life with constant discomfort and pain but also can end up causing serious complications. Here, we present a bistable actuator to empty the bladder by incorporating shape memory alloy components integrated on flexible polyvinyl chloride sheets. The introduction of two compression and restoration phases for the actuator allows for repeated actuation for a more complete voiding of the bladder. The proposed actuator exhibits one of the highest reported voiding percentages of up to 78% of the bladder volume in an anesthetized rat after only 20 s of actuation. This amount of voiding is comparable to the common catheterization method, and its one time implantation onto the bladder rectifies the drawbacks of multiple catheterizations per day. Furthermore, the scaling of the device for animal models larger than rats can be easily achieved by adjusting the number of nitinol springs. For neurogenic UAB patients with degraded nerve function as well as degenerated detrusor muscle, we integrate a flexible triboelectric nanogenerator sensor with the actuator to detect the fullness of the bladder. The sensitivity of this sensor to the filling status of the bladder shows its capability for defining a self-control system in the future that would allow autonomous micturition. PMID- 29630353 TI - Paper-Based 3D Scaffold for Multiplexed Single Cell Secretomic Analysis. AB - Despite rapid progresses in single-cell analysis technologies, efforts to control the three-dimensional microenvironment for single cell measurements have been lacking. Here, we report a simple method to incorporate three-dimensional scaffolds, including polyvinylidene fluoride (PVDF) membranes and PVDF membrane replicated analog polydimethylsiloxane, into multiplexed single cell secretomic analysis platforms (including a microwell array and a single cell barcode microchip) to mimic the extracellular physical matrix and mechanical support for single cells. Applying this platform to brain tumor cell line U87 to investigate single cell protein secretion behavior on different substrates, we revealed that single cell protein secretions were regulated differently in three-dimensional (3D) microenvironments. This finding was further verified with intracellular cytokine staining, highlighting the significance of 3D single cell microenvironments. This new single cell biomimetic platform can be easily adaptable to other three-dimensional cell culture scaffolds or other single cell assays and may become a broadly applicable three-dimensional single cell analysis system to study the effect of microenvironment conditions on cellular functional heterogeneity in vitro. PMID- 29630354 TI - Structure Effects of 2D Materials on alpha-Nickel Hydroxide for Oxygen Evolution Reaction. AB - To engineer low-cost, high-efficiency, and stable oxygen evolution reaction (OER) catalysts, structure effects should be primarily understood. Focusing on this, we systematically investigated the relationship between structures of materials and their OER performances by taking four 2D alpha-Ni(OH)2 as model materials, including layer-stacked bud-like Ni(OH)2-NB, flower-like Ni(OH)2-NF, and petal like Ni(OH)2-NP as well as the ultralarge sheet-like Ni(OH)2-NS. For the first three (layer-stacking) catalysts, with the decrease of stacked layers, their accessible surface areas, abilities to adsorb OH-, diffusion properties, and the intrinsic activities of active sites increase, which accounts for their steadily enhanced activity. As expected, Ni(OH)2-NP shows the lowest overpotential (260 mV at 10 mA cm-2) and Tafel slope (78.6 mV dec-1) with a robust stability over 10 h among the samples, which also outperforms the benchmark IrO2 (360 mV and 115.8 mV dec-1) catalyst. Interestingly, Ni(OH)2-NS relative to Ni(OH)2-NP exhibits even faster substance diffusion due to the sheet-like structure, but shows inferior OER activity, which is mainly because the Ni(OH)2-NP with a smaller size possesses more active boundary sites (higher reactivity of active sites) than Ni(OH)2-NS, considering the adsorption properties and accessible surface areas of the two samples are quite similar. By comparing the different structures and their OER behaviors of four alpha-Ni(OH)2 samples, our work may shed some light on the structure effect of 2D materials and accelerate the development of efficient OER catalysts. PMID- 29630355 TI - U(VI) Reduction by Biogenic and Abiotic Hydroxycarbonate Green Rusts: Impacts on U(IV) Speciation and Stability Over Time. AB - Green rusts (GRs) are redox active FeII-FeIII minerals that form in the environment via various biotic and abiotic processes. Although both biogenic (BioGR) and abiotic (ChemGR) GRs have been shown to reduce UVI, the dynamics of the transformations and the speciation and stability of the resulting UIV phases are poorly understood. We used carbonate extraction and XAFS spectroscopy to investigate the products of UVI reduction by BioGR and ChemGR. The results show that both GRs can rapidly remove UVI from synthetic groundwater via reduction to UIV. The initial products in the ChemGR system are solids-associated UIV carbonate complexes that gradually transform to nanocrystalline uraninite over time, leading to a decrease in the proportion of carbonate-extractable U from ~95% to ~10%. In contrast, solid-phase UIV atoms in the BioGR system remain relatively extractable, nonuraninite UIV species over the same reaction period. The presence of calcium and carbonate in groundwater significantly increase the extractability of UIV in the BioGR system. These data provide new insights into the transformations of U under anoxic conditions in groundwater that contains calcium and carbonate, and have major implications for predicting uranium stability within redox dynamic environments and designing approaches for the remediation of uranium-contaminated groundwater. PMID- 29630356 TI - Trivalent Rare-Earth-Metal Bis(trimethylsilyl)amide Halide Complexes by Targeted Oxidations. AB - In contrast to previously applied salt metathesis protocols the targeted rare earth-metal compounds Ln[N(SiMe3)2]2(halogenido) were accessed by oxidation of Ln(II) silylamide precursors. Treatment of Sm[N(SiMe3)3]2(thf)2 with 0.5 equiv of C2Cl6 or 0.25 equiv of TeBr4 in thf and crystallization thereof gave [Sm{N(SiMe3)2}2(MU-X)(thf)]2 (X = Cl, Br). A similar reaction/crystallization procedure performed with 0.5 equiv of 1,2-diiodoethane gave monomeric Sm[N(SiMe3)2]2I(thf)2. Switching to Yb[N(SiMe3)2]2(thf)2, the aforementioned oxidants generated monomeric five-coordinate complexes Yb[N(SiMe3)2]2X(thf)2 (X = Cl, Br, I). The reaction of Eu[N(SiMe3)2]2(thf)2 with 0.5 equiv of C2Cl6 in thf yielded the separated ion pair [Eu{N(SiMe3)2}3Cl][(thf)5Eu(MU-Cl)2Eu(thf)5]. Performing the chlorination in n-hexane led to oxidation followed by rapid disproportionation into EuCl3(thf) x and Eu[N(SiMe3)2]3. The bromination reaction did not afford crystalline material, while the iodination gave crystals of divalent EuI2(thf)5. Use of trityl chloride (Ph3CCl) as the oxidant in thf accomplished the Eu(III) species [Eu{N(SiMe3)2}2(MU-Cl)(thf)]2. In situ oxidation of putative [Tm{N(SiMe3)2}2(thf) x] using 0.5 equiv of C2Cl6 in thf followed by crystallization from n-hexane led to the formation of a mixture of [Tm{N(SiMe3)2}2(MU-Cl)(thf)]2 and Tm[N(SiMe3)2]3. Switching the oxidant to 0.5 equiv of 1,2-diiodoethane and crystallizing from thf repeatedly afforded the bis halogenated complex Tm[N(SiMe3)2]I2(thf)3. PMID- 29630357 TI - High-Temperature-Phase Bi4RhI2: Electronic Localization by Structural Distortion. AB - The metal-rich compound Bi4RhI2 was discovered in a thorough investigation of the Bi-Rh-I phase system. The monoclinic crystal structure was solved via single crystal X-ray diffraction. It consists of infinite strands of face-sharing distorted square antiprisms infinity1[RhBi8/2]2+, which are separated by iodide ions. Bi4RhI2 is the high-temperature phase related to the weak three-dimensional topological insulator Bi14Rh3I9 (Bi4.67RhI3) and forms peritectically at 441 degrees C, where Bi14Rh3I9 decomposes. The structure of Bi4RhI2 is compared with Bi4RuI2 and Bi9Rh2I3, all three sharing a similar intermetallic strand-like structure, although their overall count of valence electrons differs. A chemical bonding analysis of Bi4RhI2 via the electron localizability indicator reveals a complex bonding pattern with covalent bonds between rhodium and bismuth, as well as between bismuth atoms and suggests a possible explanation for the formation of this structure type. Band structure calculations indicate a narrow band gap of 157 meV, which was verified by resistivity measurements on a pressed powder pellet and on single crystals. In a broader context, this strandlike structure type accounts for unusual physical phenomena, such as the transition into a charge-density-wave phase. PMID- 29630358 TI - Properties of Site-Specifically Incorporated 3-Aminotyrosine in Proteins To Study Redox-Active Tyrosines: Escherichia coli Ribonucleotide Reductase as a Paradigm. AB - 3-Aminotyrosine (NH2Y) has been a useful probe to study the role of redox active tyrosines in enzymes. This report describes properties of NH2Y of key importance for its application in mechanistic studies. By combining the tRNA/NH2Y-RS suppression technology with a model protein tailored for amino acid redox studies (alpha3X, X = NH2Y), the formal reduction potential of NH2Y32(O*/OH) ( E degrees ' = 395 +/- 7 mV at pH 7.08 +/- 0.05) could be determined using protein film voltammetry. We find that the Delta E degrees ' between NH2Y32(O*/OH) and Y32(O*/OH) when measured under reversible conditions is ~300-400 mV larger than earlier estimates based on irreversible voltammograms obtained on aqueous NH2Y and Y. We have also generated D6-NH2Y731-alpha2 of ribonucleotide reductase (RNR), which when incubated with beta2/CDP/ATP generates the D6-NH2Y731* alpha2/beta2 complex. By multifrequency electron paramagnetic resonance (35, 94, and 263 GHz) and 34 GHz 1H ENDOR spectroscopies, we determined the hyperfine coupling (hfc) constants of the amino protons that establish RNH2* planarity and thus minimal perturbation of the reduction potential by the protein environment. The amount of Y in the isolated NH2Y-RNR incorporated by infidelity of the tRNA/NH2Y-RS pair was determined by a generally useful LC-MS method. This information is essential to the utility of this NH2Y probe to study any protein of interest and is employed to address our previously reported activity associated with NH2Y-substituted RNRs. PMID- 29630359 TI - C(alkenyl)-H Activation via Six-Membered Palladacycles: Catalytic 1,3-Diene Synthesis. AB - A catalytic method to prepare highly substituted 1,3-dienes from two different alkenes is described using a directed, palladium(II)-mediated C(alkenyl)-H activation strategy. The transformation exhibits broad scope across three synthetically useful substrate classes masked with suitable bidentate auxiliaries (4-pentenoic acids, allylic alcohols, and bishomoallylic amines) and tolerates internal nonconjugated alkenes, which have traditionally been a challenging class of substrates in this type of chemistry. Catalytic turnover is enabled by either MnO2 as the stoichiometric oxidant or co-catalytic Co(OAc)2 and O2 (1 atm). Experimental and computational studies were performed to elucidate the preference for C(alkenyl)-H activation over other potential pathways. As part of this effort, a structurally unique alkenylpalladium(II) dimer was isolated and characterized. PMID- 29630360 TI - Methyl Jasmonate Increases Isoflavone Production in Soybean Cell Cultures by Activating Structural Genes Involved in Isoflavonoid Biosynthesis. AB - Isoflavonoids are a class of biologically active natural products that accumulate in soybean ( Glycine max L.) seeds during development, play vital roles in plant defense, and act as phytoestrogens with important human health benefits. Plant cell suspension cultures represent an excellent source of biologically important secondary metabolites. We found that methyl jasmonate (MJ) treatment increased isoflavone production in soybean suspension cell cultures. To investigate the underlying mechanism, we examined the expression of structural genes ( CHS6, CHS7, CHI1, IFS1, IFS2, IFMaT, and HID) in the isoflavonoid biosynthesis pathways in soybean suspension cells under various abiotic stress conditions. MJ treatment had the most significant effect on gene expression and increased the production of three glycosidic isoflavones (daidzin, malonyldaidzin, and malonylgenistin), with the maximum total isoflavone production (~10-fold increase) obtained on day 9 after MJ application. MJ treatment significantly increased total phenolic contents and upregulated isoflavonoid biosynthesis genes, shedding light on the underlying mechanism. PMID- 29630361 TI - Advances on Fungal Phytotoxins and Their Role in Grapevine Trunk Diseases. AB - Grapevines are produced worldwide with important impact on local economies. Several biotic stresses induce serious diseases of grapevine, which severely affect the quantity and quality of production. One of the most important problems of vineyards worldwide is the high incidence of grapevine trunk diseases (GTD) induced by fungi belonging to several genera. Environmentally friendly methods for GTD control are being studied. This perspective offers an advanced overview on the fungal phytotoxins involved in GTD and their eventual role in the development of disease symptoms. PMID- 29630362 TI - A Simple Additive Potential Model for Simulating Hydrogen Peroxide in Chemical and Biological Systems. AB - Hydrogen peroxide (H2O2) has numerous industrial, environmental, medical, cosmetic, and biological applications. Given its importance, we provide a simple model as an alternative to experiment for studying the properties of pure liquid H2O2 and its concentrated aqueous solutions, which are hazardous, and for understanding the biological roles of H2O2 at the molecular level. A four-site additive model is calibrated for H2O2 based on the ab initio and experimental properties of the gaseous monomer and the density and heat of vaporization of liquid H2O2 at 0 degrees C. Our model together with the TIP3P water model reproduce the ab initio binding energies of (H2O2) m, H2O2. nH2O, and nH2O2.H2O clusters ( m = 2, 3 and n = 1, 2) calculated at the MP2 level using the 6 311++G(d,p) or the 6-311++G(3df,3pd) basis set. It yields structure, the self diffusion coefficient, heat capacity, and densities at temperatures up to 200 degrees C of the pure liquid in good agreement with experiment. The model correctly predicts the hydration free energy of H2O2 and reproduces the experimental density of aqueous H2O2 solutions at 0-96 degrees C. Investigation of the solvation of H2O2 and H2O in aqueous H2O2 solutions reveals that, as in the gas phase, H2O2 is a better H-bond donor but poorer acceptor than H2O and the bonding stability follows the order Op-Hp...Ow > Ow-Hw...Ow >= Op-Hp...Op > Ow Hw...Op. Stronger H-bonding in H2O/H2O2 mixtures than in the pure liquids is consistent with exothermic heats of mixing and explains why the observed density and vapor pressure of the aqueous solutions are higher and lower, respectively, than expected from ideal mixing. Results also show that H2O2 adopts a skewed equilibrium geometry in gas and liquid phases but more polar cis and nonpolar trans conformations also are accessible and will stabilize H2O2 in environments of different polarity. In sum, our simple model presents a reliable tool for simulating H2O2 in chemistry and biology. PMID- 29630364 TI - Design of Aminopeptidase N Inhibitors as Anti-cancer Agents. AB - Aminopeptidase N (APN) is an important metalloenzyme. It regulates multivariate cellular functions by different mechanisms such as enzymatic cleavage of peptides. This may play a role in endocytosis and regulate signal transduction. APN, a member of the M1 zinc metallopeptidase family, plays crucial roles in a variety of functions such as migration and invasion, and angiogenesis and metastasis of tumor cells. Therefore, APN inhibitors may be useful for the treatment of cancer. In this Perspective, structure-activity relationships of APN inhibitors are discussed to get an idea of possible lead candidates. APN inhibitors should possess an aryl hydrophobic function along with a zinc binding group attached to the hydrophobic group(s) to achieve high potency. This and other design aspects of APN inhibitors are discussed in this Perspective. PMID- 29630363 TI - Molybdenum Sulfide Induce Growth Enhancement Effect of Rice ( Oryza sativa L.) through Regulating the Synthesis of Chlorophyll and the Expression of Aquaporin Gene. AB - Molybdenum sulfide (MoS2) has been applied widely in industrial and environmental application, leading to increasing release into environment. So far, no studies have been investigated with regard to the potential effect of MoS2 on plants. Herein, we studied the impact of MoS2 on the growth, chlorophyll content, lipid peroxidation, antioxidase system, and aquaporins of rice for the first time. Results showed that MoS2 did not significantly affect the germination of rice seeds, malonaldehyde (MDA) content, and the antioxidant enzyme activity. While the length and biomass of rice root and shoot, chlorophyll content index (CCI), and expression of aquaporin genes were significantly increased. Based on these results, we concluded that MoS2 promoted rice growth through (i) the promotion of nitrogen source assimilation, (ii) the enhancement of photosynthesis, enzymatic related biochemical reactions, and metabolic processes, subsequently, (iii) the acceleration of cell division and expansion, furthermore (iv) no abiotic stress and favorable condition of antioxidant enzyme system. These results provided an important insight into the further application of MoS2 on agriculture and environment. PMID- 29630365 TI - Steric Hindrance Underestimated: It is a Long, Long Way to Tri- tert-alkylamines. AB - Ten different processes (Methods A-J) were tested to prepare tertiary amines bearing bulky alkyl groups. In particular, SN1 alkylation of secondary amines with the help of 1-adamantyl triflate (Method D) and reaction of N chlorodialkylamines with organometallic reagents (Method H), but also attack of the latter reagents at iminium salts, which were generated in situ by N alkylation of imines (Method J), led to trialkylamines with unprecedented steric congestion. These products showed a restriction of the rotation about the C-N bond. Consequently, equilibration of rotamers was slow on the NMR time scale resulting in distinguishable sets of NMR data at room temperature. Furthermore, tertiary amines with bulky alkyl substituents underwent Hofmann-like elimination when heating in toluene to form an olefin and a secondary amine. Since the tendency to take part in this decay reaction correlated with the degree of steric hindrance around the nitrogen atom, Hofmann elimination at ambient temperature, which made the isolation of the tertiary amine difficult, was observed in special cases. PMID- 29630366 TI - Discovery of Inhibitor of Wnt Production 2 (IWP-2) and Related Compounds As Selective ATP-Competitive Inhibitors of Casein Kinase 1 (CK1) delta/epsilon. AB - Inhibitors of Wnt production (IWPs) are known antagonists of the Wnt pathway, targeting the membrane-bound O-acyltransferase porcupine (Porcn) and thus preventing a crucial Wnt ligand palmitoylation. Since IWPs show structural similarities to benzimidazole-based CK1 inhibitors, we hypothesized that IWPs could also inhibit CK1 isoforms. Molecular modeling revealed a plausible binding mode of IWP-2 in the ATP binding pocket of CK1delta which was confirmed by X-ray analysis. In vitro kinase assays demonstrated IWPs to be ATP-competitive inhibitors of wtCK1delta. IWPs also strongly inhibited the gatekeeper mutant M82FCK1delta. When profiled in a panel of 320 kinases, IWP-2 specifically inhibited CK1delta. IWP-2 and IWP-4 also inhibited the viability of various cancer cell lines. By a medicinal chemistry approach, we developed improved IWP derived CK1 inhibitors. Our results suggest that the effects of IWPs are not limited to Porcn, but also might influence CK1delta/epsilon-related pathways. PMID- 29630367 TI - Rapid Li Ion Dynamics in the Interfacial Regions of Nanocrystalline Solids. AB - Diffusive processes are ubiquitous in nature. In solid state physics, metallurgy and materials science the diffusivity of ions govern the functionality of many devices such as sensors or batteries. Motional processes on surfaces, across interfaces or through membranes can be quite different to that in the bulk. A direct, quantitative description of such local diffusion processes is, however, rare. Here, we took advantage of 7Li longitudinal nuclear magnetic relaxation to study, on the atomic length scale, the diffusive motion of lithium spins in the interfacial regions of nanocrystalline, orthorhombic LiBH4. Magnetization transients and free induction decays revealed a fast subset of Li ions having access to surface pathways that offer activation barriers (0.18 eV) much lower than those in the crystalline bulk regions (0.55 eV). These observations make orthorhombic borohydride a new nanostructured model system to study disorder induced enhancements in interfacial diffusion processes. PMID- 29630368 TI - Unusual Photooxidation of S-Bonded Mercaptopyridine in a Mixed Ligand Ruthenium(II) Complex with Terpyridine and Bipyridine Ligands. AB - An unusual photooxidation of a coordinated 4-mercaptopyridine ( SpyH) ligand in the [Ru(Hmctpy)(dmbpy)(kappa S-SpyH)]2+complex (Hmctpy = 4'-carboxy-2,2';6',2" terpyridine, dmbpy = 4,4'-dimethyl-2,2'-bipyridine) takes place under visible and UV irradiation, in aerated acetonitrile. The [Ru(mctpy)(dmbpy)(kappa S-SO2py)] sulfinato product has been characterized by a variety of methods, including X-ray diffraction which supports the presence of the Ru-kappa S-SpyH isomer in the starting complex. The photooxidation of the 4-mercaptopyridine ligand enhances the back-bonding interactions in the complex by means of the strongly acceptor 4 pyridinesulfinato-SO2py species, increasing the redox potential of the Ru(III)/Ru(II) couple significantly from 1.23 to 1.62 V. It also led to pronounced changes in the electronic and NMR spectra of the complexes, corroborated by DFT and ZINDO-S calculations. A possible mechanism based on referenced data of photooxidation has been proposed, which involves the formation of a reactive oxygen species and intermediate endoperoxide species, yielding a very stable Ru-sulfinato product. This novel species exhibits stronger luminescence (Phi f = 0.004) than the starting complex under UV excitation. PMID- 29630369 TI - Correction to "Oxygen-Vacancy-Mediated Exciton Dissociation in BiOBr for Boosting Charge-Carrier-Involved Molecular Oxygen Activation". PMID- 29630370 TI - Thermoelectric Properties of Variants of Cu4Mn2Te4 with Spinel-Related Structure. AB - Thermoelectric properties of Cu4Mn2Te4, which is antiferromagnetic with a Neel temperature TN = 50 K and crystallizes in a spinel-related structure, have been investigated comprehensively here. The phase transition occurring at temperatures 463 and 723 K is studied by high-temperature X-ray diffraction (XRD) and differential scanning calorimetry (DSC), and its effect on thermoelectric properties is examined. Hypothetically Cu4Mn2Te4 is semiconducting according to the formula (Cu+)4(Mn2+)2(Te2-)4, while experimentally it shows p-type metallic conduction behavior, exhibiting electrical conductivity sigma = 2500 Omega-1 cm-1 and Seebeck coefficient alpha = 20 MUV K-1 at 325 K. Herein, we show that the carrier concentration and thus the thermoelectric transport properties could be further optimized through adding electron donors such as excess Mn. Discussions are made on the physical parameters contributing to the low thermal conductivity, including Debye temperature, speed of sound, and the Gruneisen parameter. As a result of simultaneously boosted power factor and reduced thermal conductivity, a moderately high zT = 0.65 at 680 K is obtained in an excess Mn?In co-added sample, amounting to 5 times that of the pristine Cu4Mn2Te4. This value ( zT = 0.65) is the best result ever reported for spinel and spinel-related chalcogenides. PMID- 29630371 TI - Marine-Natural-Product Development: First Discovery of Nortopsentin Alkaloids as Novel Antiviral, Anti-phytopathogenic-Fungus, and Insecticidal Agents. AB - Nortopsentin alkaloids were found to have potent antiviral, anti-phytopathogenic fungus, and insecticidal activities for the first time. Antiviral-activity tests revealed that these compounds were very sensitive to substituents, so a series of nortopsentin derivatives were designed, synthesized, and systematically evaluated for their antiviral activities against TMV, their fungicidal activities, and their insecticidal activities on the basis of a structural-diversity-derivation strategy. Compounds 2e (in vivo inactivation-, curative-, and protective-activity inhibitory rates of 50, 59, and 56%, respectively, at 500 MUg/mL) and 2k (in vivo inactivation-, curative-, and protective-activity inhibitory rates of 60, 58, and 52%, respectively, at 500 MUg/mL), with excellent antiviral activities and good physicochemical properties, emerged as new lead compounds for novel-antiviral agent development. Further fungicidal-activity tests revealed that these alkaloids displayed broad-spectrum fungicidal activities. Compounds 2f, 2h, and 2j emerged as new lead compounds for antifungal-activity research. Additionally, all the compounds displayed good insecticidal activities against five kinds of insects, including Mythimna separate, Helicoverpa armigera, Ostrinia nubilalis, Plutella xylostella, and Culex pipiens pallens. PMID- 29630372 TI - Facile Multicomponent Polymerizations toward Unconventional Luminescent Polymers with Readily Openable Small Heterocycles. AB - Heterocyclic polymers have gained enormous attention for their unique functionalities and wide applications. In contrast with the well-studied polymer systems with five- or six-membered heterocycles, functional polymers with readily openable small-ring heterocycles have rarely been explored due to their large synthetic difficulty. Herein, a facile one-pot multicomponent polymerization to such polymers is developed. A series of functional polymers with multisubstituted and heteroatom-rich azetidine frameworks are efficiently generated at room temperature in high atom economy from handy monomers. The four-membered azetidine rings in the polymer skeletons can be easily transformed into amide and amidine moieties via a fast and efficient acid-mediated ring-opening reaction, producing brand-new polymeric materials with distinctive properties. All the as-prepared azetidine-containing polymers exhibit intrinsic visible luminescence in the solid state under long-wavelength UV irradiation even without conventionally conjugated structures. Such unconventional luminescence is attributed to the clusteroluminogens formed by through-space electronic interactions of heteroatoms and phenyl rings. All the obtained polymers show excellent optical transparency, high and tunable refractive indices, low optical dispersions and good photopatternability, which make them promising materials in various advanced electronic and optoelectronic devices. The ring-opened polymers can also function as a lysosome-specific fluorescent probe in biological imaging. PMID- 29630373 TI - Crystal Structure of Magnetoelectric Ba2MnGe2O7 at Room and Low Temperatures by Neutron Diffraction. AB - For a symmetry-consistent theoretical description of the ferroelectric phase of Ba2MnGe2O7 melilite compound, a precise knowledge of its crystal structure is a prerequisite. Here we report results of single-crystal neutron diffraction experiments on Ba2MnGe2O7 at room (300 K) and low (10 K) temperatures. The structural model based on the tetragonal space group P421 m describes the Ba2MnGe2O7 symmetry both at room and low temperatures. We found reflections forbidden in the typical P421 m melilite-type structure. A comparison of the experimental data collected by means of both thermal and cold neutrons with simulated multiple diffraction patterns allows us to unambiguously demonstrate that forbidden peaks originate from multiple diffraction (Renninger effect) rather than from real symmetry lowering. The precise structural parameters at 300 and 10 K are presented for the first time and compared with those of other magnetoelectric melilite-type germanates. PMID- 29630374 TI - Effect of Hydrogen-Bonding Interaction on the Arrangement and Dynamics of Water Confined in a Polyamide Membrane: A Molecular Dynamics Simulation. AB - An increasing demand for freshwater inspires further understanding of the mechanism of water diffusion in reverse-osmosis membranes for the development of high-performance membranes for desalination. Water diffusion has a close relationship with the structural and dynamical characteristics of hydrogen bonds, which is not well-understood for the confining environment inside the polyamide membrane at the molecular level. In this work, an atomistic model of a highly cross-linked polyamide membrane was built with an equilibrated mixture of m phenylenediamine and trimesoyl chloride monomers. The structure and dynamics of water in the regions from the bulk phase to the membrane interior were investigated by molecular dynamics simulations. Explicit hydrogen bond criteria were determined for hydrogen-bonding analysis. The local distribution and orientation of water reveal that the hydrogen-bonding affinity of the hydrophilic functional groups of polymers inhibits water diffusion inside the membrane. The affinity helps to produce percolated water channels across the membrane. The hydrogen-bonding structures of water in different regions indicate dehydration is required for the entry of water into the polyamide membrane, which dominates water flux across the membrane. This paper not only deepens the understanding of the structure and dynamics of water confined in the polyamide membrane but also stimulates the future work on high-performance reverse-osmosis membranes. PMID- 29630375 TI - Truncated Cross Effect Dynamic Nuclear Polarization: An Overhauser Effect Doppelganger. AB - The discovery of a truncated cross-effect (CE) in dynamic nuclear polarization (DNP) NMR that has the features of an Overhauser-effect DNP (OE-DNP) is reported here. The apparent OE-DNP, where minimal MUw power achieved optimum enhancement, was observed when doping Trityl-OX063 with a pyrroline nitroxide radical that possesses electron-withdrawing tetracarboxylate substituents (tetracarboxylate ester-pyrroline or TCP) in vitrified water/glycerol at 6.9 T and at 3.3 to 85 K, in apparent contradiction to expectations. While the observations are fully consistent with OE-DNP, we discover that a truncated cross-effect ( tCE) is the underlying mechanism, owing to TCP's shortened T1e. We take this observation as a guideline and demonstrate that a crossover from CE to tCE can be replicated by simulating the CE of a narrow-line (Trityl-OX063) and a broad-line (TCP) radical pair, with a significantly shortened T1e of the broad-line radical. PMID- 29630376 TI - Spacer Chains Prevent the Intramolecular Complexation in Miktoarm Star Polymers. AB - The influence of spacer chains on the intramolecular complexation in star-shaped heteroarm (miktoarm) polymers is investigated. To overcome the mutual attraction of different polymeric components present in a miktoarm star with different homopolymeric arms, spacer chains of different length are attached to the core of the star at three different positions. In most of the investigated cases, this leads to diblock copolymer arms within the miktoarm star. Hereby, the inner spacer separates the outer blocks from their attractively interacting homopolymeric arms. The effect on the intramolecular complexation and the structure of the star polymer is obtained by Monte Carlo simulations of a simple bead-spring model. Then, long spacers can completely prevent the complexation. Both, local shielding by the spacer chains and the increased distance between the complex-forming polymers due to the spacer chains inhibit the complex formation. For a range of spacer positions and lengths, an equilibrium between a system forming a complex and a complex free system is found. The spacer chains can be used as a tool to tune the intramolecular complexation. PMID- 29630377 TI - Mechanism of Inhibition of Beta Amyloid Toxicity by Supramolecular Tweezers. AB - The Abeta1-42 dimer is the smallest oligomer of the 42-residue Abeta peptide (Abeta1-42), which is involved in Alzheimer's disease. The molecular tweezer CLR01 is a synthetic molecule that selectively binds lysine and arginine residues to inhibit toxic aggregation of amyloidogenic peptides. Here, we performed replica exchange molecular dynamics simulations of Abeta1-42 in explicit water to study, at the molecular level, the effect of CLR01 binding to the lysine and arginine residues in the dimer. We found that CLR01 molecules encapsulate both lysine residues of each Abeta1-42 monomer while only establishing labile interactions with the arginine residues. This encapsulation leads to the noncovalent disruption of inter- and intramolecular interactions involving the monomers. Additionally, the total beta-sheet content in the Abeta1-42 dimer decreases because of this binding. With CLR03, a negative control molecule that shares the charged core of CLR01 but does not form inclusion complexes, Abeta1-42 dimer formation is observed, similar to the reference system without ligands. Our work allows establishing a molecular mechanism for the modulation of protein protein interactions in Abeta1-42 by CLR01. This mechanism is characterized by an aggregation pathway driven by the encapsulation of lysine residues as well as by the secondary interactions of tweezers with the peptide units and with other CLR01 molecules. PMID- 29630378 TI - Machine Learning of Biomolecular Reaction Coordinates. AB - We present a systematic approach to reduce the dimensionality of a complex molecular system. Starting with a data set of molecular coordinates (obtained from experiment or simulation) and an associated set of metastable conformational states (obtained from clustering the data), a supervised machine learning model is trained to assign unknown molecular structures to the set of metastable states. In this way, the model learns to determine the features of the molecular coordinates that are most important to discriminate the states. Using a new algorithm that exploits this feature importance via an iterative exclusion principle, we identify the essential internal coordinates (such as specific interatomic distances or dihedral angles) of the system, which are shown to represent versatile reaction coordinates that account for the dynamics of the slow degrees of freedom and explain the mechanism of the underlying processes. Moreover, these coordinates give rise to a free energy landscape that may reveal previously hidden intermediate states of the system. PMID- 29630379 TI - Probing the Binding Affinity by Jarzynski's Nonequilibrium Binding Free Energy and Rupture Time. AB - Binding affinity of a small ligand to a receptor is the important quantity in drug design, and it might be characterized by different quantities. The most popular one is the binding free energy, which can be estimated by several methods in conventional molecular dynamics simulation. So far in steered molecular dynamics (SMD), one can use either the rupture force or nonequilibrium pulling work as a measure for binding affinity. In this paper, we have shown that the nonequilibrium binding free energy Delta GneqJar, obtained by Jarzynski's equality at a finite pulling speed, has good correlation with experimental data on inhibition constants, implying that this quantity can be used as a good scoring function for binding affinity. A similar correlation has also been disclosed for binding and unbinding free energy barriers. Applying the SMD method to unbinding of 23 small compounds from the binding site of beta-lactamase protein, a bacteria-produced enzyme, we have demonstrated that the rupture or unbinding time strongly correlates with experimental data with correlation level R ~ 0.84. As follows from the Jarzynski's equality, the rupture time depends on the unbinding barrier exponentially. We show that Delta GneqJar, the rupture time, and binding and unbinding free energy barriers are good descriptors for binding affinity. Our observation may be useful for fast screening of potential leads as the SMD simulation is not time-consuming. On the basis of nonequilibrium simulation, we disclosed that, in agreement with the experiment, the binding time is much longer than the unbinding one. PMID- 29630380 TI - Iron(II) and Iron(III) Spin Crossover: Toward an Optimal Density Functional. AB - Spin crossover (SCO) plays a major role in biochemistry, catalysis, materials, and emerging technologies such as molecular electronics and sensors, and thus accurate prediction and design of SCO systems is of high priority. However, the main tool for this purpose, density functional theory (DFT), is very sensitive to applied methodology. The most abundant SCO systems are Fe(II) and Fe(III) systems. Even with average good agreement, a functional may be significantly more accurate for Fe(II) or Fe(III) systems, preventing balanced study of SCO candidates of both types. The present work investigates DFT's performance for well-known Fe(II) and Fe(III) SCO complexes, using various design types and customized versions of GGA, hybrid, meta-GGA, meta-hybrid, double-hybrid, and long-range-corrected hybrid functionals. We explore the limits of DFT performance and identify proficient Fe(II)-Fe(III)-balanced functionals. We identify and quantify remarkable differences in the DFT description of Fe(II) and Fe(III) systems. Most functionals become more accurate once Hartree-Fock exchange is adjusted to 10-17%, regardless of the type of functionals involved. However, this typically introduces a clear Fe(II)-Fe(III) bias. The most accurate functionals measured by mean absolute errors <10 kJ/mol are CAMB3LYP-17, B3LYP*, and B97-15 with 15-17% Hartree-Fock exchange, closely followed by CAMB3LYP and CAMB3LYP-15, OPBE, rPBE-10, and B3P86-15. While GGA functionals display a small Fe(II)-Fe(III) bias, they are generally inaccurate, except the O exchange functional. Hybrid functionals (including B2PLYP double hybrids and meta hybrids) tend to favor HS too much in Fe(II) vs Fe(III), which is important in many studies where the oxidation state of iron can vary, e.g. rational SCO design and studies of catalytic processes involving iron. The only functional with a combined bias <5 kJ/mol and a decent MAE (15 kJ/mol) is our customized PBE0-12 functional. Alternatively one has to sacrifice Fe(II)-Fe(III) balance to use the best functionals for each group separately. We also investigated the precision (measured as the standard deviation of errors) and show that the target accuracy for iron SCO is 10 kJ/mol for accuracy and 5 kJ/mol for precision, and DFT is probably not going to break this limit in the near future. Importantly, all four types of functional behavior (accurate/precise, accurate/imprecise, inaccurate/precise, inaccurate/imprecise) are observed. More generally, our work illustrates the importance not only of overall accuracy but also of balanced accuracy for systems likely to occur in context. PMID- 29630381 TI - Gas-Phase Ion Chemistry of Metalloporphyrin Anions with Molecular Oxygen: Probing the Influence of the Oxidation and Spin State of the Central Transition Metal by Experiment and Theory. AB - We performed a comprehensive gas-phase experimental and quantum-chemical study of the binding properties of molecular oxygen to iron and manganese porphyrin anions. Temperature-dependent ion-molecule reaction kinetics as probed in a Fourier-transform ion-cyclotron resonance mass spectrometer reveal that molecular oxygen is bound by, respectively, 40.8 +/- 1.4 and 67.4 +/- 2.2 kJ mol-1 to the FeII or MnII centers of isolated tetra(4-sulfonatophenyl)metalloporphyrin tetraanions. In contrast, FeIII and MnIII trianion homologues were found to be much less reactive-indicating an upper bound to their dioxygen binding energies of 34 kJ mol-1. We modeled the corresponding O2 adsorbates at the density functional theory and CASPT2 levels. These quantum-chemical calculations verified the stronger O2 binding on the FeII or MnII centers and suggested that O2 binds as a superoxide anion. PMID- 29630382 TI - Access to Densely Functionalized Chalcone Derivatives with a 2-Pyridone Subunit via Pd/Cu-Catalyzed Oxidative Furan-Yne Cyclization of N-(2-Furanylmethyl) Alkynamides under Air. AB - A protocol for synthesis of chalcone derivatives with a 2-pyridone subunit from N (2-furanylmethyl) alkynamides is reported. This synthesis involves Pd/Cu catalyzed oxidative furan-yne cyclization at room temperature in air and may proceed via nucleopalladation of the alkyne to form a vinylpalladium intermediate, with a furan ring acting as the nucleophile. PMID- 29630383 TI - Identification of an Actual Strain-Induced Effect on Fast Ion Conduction in a Thin-Film Electrolyte. AB - Strain-induced fast ion conduction has been a research area of interest for nanoscale energy conversion and storage systems. However, because of significant discrepancies in the interpretation of strain effects, there remains a lack of understanding of how fast ionic transport can be achieved by strain effects and how strain can be controlled in a nanoscale system. In this study, we investigated strain effects on the ionic conductivity of Gd0.2Ce0.8O1.9-delta (100) thin films under well controlled experimental conditions, in which errors due to the external environment could not intervene during the conductivity measurement. In order to avoid any interference from perpendicular-to-surface defects, such as grain boundaries, the ionic conductivity was measured in the out of-plane direction by electrochemical impedance spectroscopy analysis. With varying film thickness, we found that a thicker film has a lower activation energy of ionic conduction. In addition, careful strain analysis using both reciprocal space mapping and strain mapping in transmission electron microscopy shows that a thicker film has a higher tensile strain than a thinner film. Furthermore, the tensile strain of thicker film was mostly developed near a grain boundary, which indicates that intrinsic strain is dominant rather than epitaxial or thermal strain during thin-film deposition and growth via the Volmer-Weber (island) growth mode. PMID- 29630384 TI - A Parametric Rosetta Energy Function Analysis with LK Peptides on SAM Surfaces. AB - Although structures have been determined for many soluble proteins and an increasing number of membrane proteins, experimental structure determination methods are limited for complexes of proteins and solid surfaces. An economical alternative or complement to experimental structure determination is molecular simulation. Rosetta is one software suite that models protein-surface interactions, but Rosetta is normally benchmarked on soluble proteins. For surface interactions, the validity of the energy function is uncertain because it is a combination of independent parameters from energy functions developed separately for solution proteins and mineral surfaces. Here, we assess the performance of the RosettaSurface algorithm and test the accuracy of its energy function by modeling the adsorption of leucine/lysine (LK)-repeat peptides on methyl- and carboxy-terminated self-assembled monolayers (SAMs). We investigated how RosettaSurface predictions for this system compare with the experimental results, which showed that on both surfaces, LK-alpha peptides folded into helices and LK-beta peptides held extended structures. Utilizing this model system, we performed a parametric analysis of Rosetta's Talaris energy function and determined that adjusting solvation parameters offered improved predictive accuracy. Simultaneously increasing lysine carbon hydrophilicity and the hydrophobicity of the surface methyl head groups yielded computational predictions most closely matching the experimental results. De novo models still should be interpreted skeptically unless bolstered in an integrative approach with experimental data. PMID- 29630385 TI - Development of a Disease-Specific Ureteral Calculus Patient Reported Outcome Measurement Instrument. AB - INTRODUCTION: Patient reported outcome measures (PROMs) are powerful instruments to assess the impact of a disease on health from the patient's perspective. We describe the process of designing, testing, and validating the Cambridge Ureteral Stone PROM (CUSP). MATERIALS AND METHODS: Patients recently diagnosed with ureteral stones were approached for participation in focus groups, structured interviews, and test-retest validation studies. Statistical tests included Cronbach's alpha for internal consistency, Spearman's and Pearson's correlation coefficients for test-retest validity, permutation tests of equality of means and Spearman's correlation coefficients for discriminant validity. RESULTS: Forty three patients participated in the development of the CUSP. Twenty-two patients were involved in the focus groups and structured interviews and a further 21 participated in the prospective test-retest study. Expressed comments were grouped into seven broad health domains: pain, fatigue, sleep disturbance, work and daily activities, anxiety, gastrointestinal (GI) symptoms, and urinary symptoms. Items were selected from established PROM platforms to form the draft (dCUSP) instrument, which was then used for test-retest validation and item reduction. All domains scored highly for Cronbach's alpha (>0.8), with the exception of GI symptoms. Large Spearman's (>0.76) and Pearson's correlation estimates (>0.83) were obtained for test-retest validity, suggesting that answers were reliable through the time period tested. The estimates of the Spearman's correlation coefficient between each pair of domains ranged from 0.17 to 0.78 and the upper bounds of the corresponding 95% confidence intervals were all smaller than 0.95, suggesting that each domain measures something different. The tests of equality of the mean of scores of the control (n = 25) and patient groups were all significant, suggesting that CUSP successfully discriminated patients suffering from ureteral stones for every domain. CONCLUSION: CUSP is a patient derived ureteral stone PROM, which can be used to measure ureteral stone disease health outcomes from the patient's point of view. PMID- 29630387 TI - Examination of Hospital, Maternal, and Infant Characteristics Associated with Breastfeeding Initiation and Continuation Among Opioid-Exposed Mother-Infant Dyads. AB - OBJECTIVES: Among opioid-exposed newborns, breastfeeding is associated with less severe withdrawal signs, yet breastfeeding rates remain low. We determined the extent to which hospital, maternal, and infant characteristics are associated with breastfeeding initiation and continuation among opioid-exposed dyads. MATERIALS AND METHODS: We examined breastfeeding initiation and continuation until infants' discharge among opioid-exposed dyads from 2006 to 2016. Among dyads meeting hospital breastfeeding guidelines, we assessed hospital (changes in breastfeeding guidelines and improvement initiatives [using delivery year as a proxy]), maternal (demographics, comorbid conditions, methadone versus buprenorphine treatment, and delivery mode), and infant (gestational age and birth weight) characteristics. We used multivariable logistic regression to examine independent associations of characteristics with breastfeeding initiation and continuation. RESULTS: Among 924 opioid-exposed dyads, 61% (564) met breastfeeding criteria. Overall, 50% (283/564) of dyads initiated and 33% (187/564) continued breastfeeding until discharge. Breastfeeding initiation and continuation rates increased from 38% and 8% in 2006, to 56% and 34% in 2016, respectively. In adjusted models, infants born after reducing restrictions in hospital breastfeeding guidelines and prenatal breastfeeding education (adjusted odds ratio, aOR 2.6 [95% confidence interval, CI 1.5-4.5]) had increased odds of receiving any maternal breast milk versus infants born with earlier hospital policies. Cesarean versus vaginal delivery (aOR 0.3 [95% CI 0.2-0.6]) and length of infant hospitalization (aOR 0.94 [95% CI 0.92-0.97]) were negatively associated with breastfeeding continuation. CONCLUSIONS: Despite increasing breastfeeding rates among opioid-exposed dyads, rates remain suboptimal. Hospital level factors were the greatest predictor of breastfeeding initiation. The findings suggest that changes in hospital guidelines and initiatives can impact breastfeeding initiation among this vulnerable population. PMID- 29630388 TI - Risk Factors for Elbow and Shoulder Injuries in Adolescent Baseball Players: A Systematic Review. AB - BACKGROUND: The incidence of shoulder and elbow injuries among adolescent baseball players is on the rise. These injuries may lead to surgery or retirement at a young age. PURPOSE: To identify independent risk factors for elbow and shoulder injuries in adolescent baseball players. A secondary aim was to determine whether the literature supports the Major League Baseball and USA Baseball Pitch Smart guidelines. STUDY DESIGN: Systematic review. METHODS: A systematic review was performed in accordance with PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines utilizing MEDLINE, SPORTDiscus, and Web of Science. Because of study heterogeneity, a quantitative synthesis was not performed. A qualitative review was performed on 19 independent risk factors for elbow and shoulder injuries in adolescent baseball players. Level of evidence was assigned per the Oxford Centre for Evidence-Based Medicine Working Group, and risk of bias was graded per the Newcastle-Ottawa Scale. RESULTS: Twenty-two articles met criteria for inclusion. Of the 19 independent variables that were analyzed, age, height, playing for multiple teams, pitch velocity, and arm fatigue were found to be independent risk factors for throwing arm injuries. Pitches per game appears to be a risk factor for shoulder injuries. Seven independent variables (innings pitched per game, showcase participation, games per year, training days per week, pitch type, shoulder external rotation, and shoulder total range of motion) do not appear to be significant risk factors. The data were inconclusive for the remaining 6 variables (weight, months of pitching per year, innings or pitches per year, catching, shoulder horizontal adduction, and glenohumeral internal rotation deficit). CONCLUSION: The results from this study demonstrate that age, height, playing for multiple teams, pitch velocity, and arm fatigue are clear risk factors for throwing arm injuries in adolescent baseball players. Pitches per game appears to be a risk factor for shoulder injuries. Other variables are either inconclusive or do not appear to be specific risk factors for injuries. PMID- 29630389 TI - A Modified Application of Peritoneal Dialysis Catheter Implantation: A Revolution from the Laparoscope- to the Nephroscope-Assisted Surgery. AB - INTRODUCTION: A laparoscope provides many advantages when establishing abdominal access for peritoneal dialysis (PD), particularly with direct observation and correction of the catheter's position. However, laparoscopic placement requires specialized equipment and usually requires using more than one working port, which may increase the potential for complications, including dialysis leakage. We modified the surgical technique by using a nephroscope, rather than a laparoscope. This study aimed to illustrate this modified technique step by step and compare the postoperative outcomes. MATERIALS AND METHODS: This study was based on a retrospective chart review of 397 consecutive patients who underwent either laparoscope- or nephroscope-assisted PD catheter insertion between September 2005 and December 2016 in our institute, as performed by a single surgeon. Data were collected and analyzed to compare the characteristics of the patients, including age and gender, along with surgical outcomes and complications between the two groups. RESULTS: Two-hundred fourteen patients underwent laparoscopy implantation, whereas 183 patients received the nephroscope assisted method. More patients had previously undergone abdominal surgery in the nephroscopy group (29% vs 18.7%, p = 0.035) than those in the laparoscopy group. There was no significant difference in the 1-year catheter survival (82.5% vs 79.4%, p = 0.734) rate between the two groups. A total of five patients experienced dialysis leakage within the laparoscopy group, whereas none had dialysis leakage in the nephroscopy group. CONCLUSIONS: The surgical times were significantly shorter in the nephroscopy group. Although comparison of the complication rate between the two groups revealed no statistical significance, there were trends that showed there were less early surgical complications in the nephroscopy group. PMID- 29630386 TI - The importance of the vascular endothelial barrier in the immune-inflammatory response induced by radiotherapy. AB - Altered by ionising radiation, the vascular network is considered as a prime target to limit normal tissue damage and improve tumour control in radiotherapy (RT). Irradiation damages and/or activates endothelial cells, which then participate in the recruitment of circulating cells, especially by overexpressing cell adhesion molecules, but also by other as yet unknown mechanisms. Radiation induced lesions are associated with infiltration of immune-inflammatory cells from the blood and/or the lymph circulation. Damaged cells from the tissues and immune-inflammatory resident cells release factors that attract cells from the circulation, leading to the restoration of tissue balance by fighting against infection, elimination of damaged cells and healing of the injured area. In normal tissues that surround the tumours, the development of an immune inflammatory reaction in response to radiation-induced tissue injury can turn out to be chronic and deleterious for the organ concerned, potentially leading to fibrosis and/or necrosis of the irradiated area. Similarly, tumours can elicit an immune-inflammation reaction, which can be initialised and amplified by cancer therapy such as radiotherapy, although immune checkpoints often allow many cancers to be protected by inhibiting the T-cell signal. Herein, we have explored the involvement of vascular endothelium in the fate of healthy tissues and tumours undergoing radiotherapy. This review also covers current investigations that take advantage of the radiation-induced response of the vasculature to spare healthy tissue and/or target tumours better. PMID- 29630390 TI - The added value of tomosynthesis in endoscopic retrograde cholangiography with radiography for the detection of choledocholithiasis. AB - OBJECTIVE: The diagnostic performance of endoscopic retrograde cholangiography (ERC) with radiography is imperfect. We assessed the value of adding tomosynthesis to ERC with radiography for the detection of choledocholithiasis. METHODS: This study included 102 consecutive patients (choledocholithiasis/non choledocholithiasis, n = 57/45), who underwent both radiography and tomosynthesis for ERC in the same examination and were not diagnosed with malignancy. The reference standard for the existence of choledocholithiasis was confirmed by endoscopic stone extraction during ERC, intraoperative cholangiography, or follow up with magnetic resonance cholangiopancreatography (n = 78, 11, and 13, respectively). A gastroenterologist and a radiologist independently evaluated the radiographs and the combination of tomosynthesis and radiographic images in a blinded and randomised manner. Receiver operating characteristic analysis was used for statistical analysis. RESULTS: The areas under the receiver operating characteristic curve for combined tomosynthesis and radiography were significantly higher than those for radiography alone for both readers: Reader 1/Reader 2, 0.929/0.956 [95% confidence interval (CI), 0.861-0.965/0.890-0.983) vs 0.803/0.769 (95% confidence interval, 0.707-0.873/0.668-0.846), respectively (p = 0.0047/< 0.0001). CONCLUSION: Adding tomosynthesis to radiography improved the diagnostic performance of ERC for detection of choledocholithiasis. Advances in knowledge: Adding tomosynthesis to radiography improves detection of choledocholithiasis and tomosynthesis images can be obtained easily after radiographs and repeated immediately. PMID- 29630392 TI - Rapid Biophysical Analysis of Host Immune Cell Variations Associated with Sepsis. PMID- 29630391 TI - Reduced field-of-view diffusion-weighted MRI in patients with cervical cancer. AB - OBJECTIVE: Diffusion-weighted imaging (DWI) with reduced field-of-view (FOV) has been shown to provide high spatial resolution with reduced distorsion in the spinal cord, breast, pancreas, and prostate gland. Therefore, we performed this study to evaluate the qualitative image quality and quantitative ADC value of reduced FOV DWI in patients with cervical cancer in comparison with conventional DWI. METHODS: This study retrospectively included 22 patients (mean age, 53.9 years) with biopsy-proven cervical cancer who underwent pelvic MR imaging including conventional DWI and reduced FOV DWI before therapy. Two observers independently rated image quality for reduced FOV DWI and conventional DWI regarding anatomic detail, lesion conspicuity, presence of artifacts, and overall image quality using the following 4-point scale. Quantitative analysis was performed by measuring the ADC value of the tumor. The Wilcoxon signed-rank test was used to compare qualitative scores and mean ADC value between two DWI sequences. RESULTS: Reduced FOV DWI achieved significantly better anatomic detail, lesion conspicuity, presence of artifacts, and overall image quality compared to conventional DWI (p < 0.05). There was no significant difference in mean tumor ADC value between the two DWI sequences (0.990 * 10-3 mm2 s-1 +/- 0.364 at reduced FOV DWI vs 1.253 * 10-3 mm2 s-1 +/- 0.387 at conventional DWI) (p = 0.067). CONCLUSION: Reduced FOV DWI shows better image quality in terms of anatomic detail and lesion conspicuity with fewer artifacts compared to conventional DWI. Advance in knowledge: Reduced FOV DWI may enhance diagnostic performance for evaluation of cervical cancer. PMID- 29630393 TI - Everolimus-induced Chylous Effusion. PMID- 29630394 TI - Excessive Masturbation Successfully Treated with Fluoxetine in an Adolescent with Autism Spectrum Disorder and Coexisting Depression. PMID- 29630395 TI - Investigating factors influencing drivers' speed selection behavior under reduced visibility conditions. AB - OBJECTIVE: Driving speed is a major concern for driving safety under reduced visibility conditions. Many factors affect speed selection in low visibility, but few studies have been conducted examining drivers' characteristics, particularly in China. The present study aimed to investigate the correlation between drivers' demographic information, driving ability, and speed choice in low-visibility conditions using a sample of Chinese drivers. METHODS: A self-designed driving ability scale was used to assess driving ability in reduced visibility conditions. The reliability and validity of 306 gathered questionnaires were examined in this article, and a structural equation model (SEM) was built to explore the predictors of drivers' speed selection behavior under reduced visibility conditions and to measure the relationships between various factors. RESULTS: Age and driving experience have no direct relationship to speed selection behavior in reduced visibility, but the frequency of using expressways and annual mileage are significantly related to the speed on roads that have a speed restriction of 80 or 120 km/h. Under reduced visibility conditions, driving ability has a significant effect on speed selection behavior, and driving skill (DS) is the most influential on speed selection behavior on roads with a speed limit of 120 km/h; otherwise, the effect of risk perception (RP) does not differ by speed choice on 3 roads with different speed limits. Driving speed in good weather also has a positive influence on speed selection behavior in low visibility. CONCLUSION: Driving ability is directly associated with speed selection in reduced visibility conditions, and some demographic data indirectly influence speed selection. This study provides useful recommendations for drivers' training programs to reduce casualties from accidents in low-visibility conditions. PMID- 29630396 TI - Pathogenicity of a variant goose parvovirus, from short beak and dwarfism syndrome of Pekin ducks, in goose embryos and goslings. AB - The pathogenicity of a variant goose parvovirus (GPV), isolated from short beak and dwarfism syndrome of Pekin ducks (strain Cherry Valley), was investigated in embryonating goose eggs and goslings. The virus was easily grown in GPV antibody free goose embryos and caused high mortality and severe lesions of goose embryos, indicating that the variant GPV has good adaptation and high pathogenicity to embryonated goose eggs similar to the classical GPV. Like the third egg-passage virus (strain H) of a classical GPV, the third egg-passage virus (strain JS1) of the variant GPV caused Derzsy's disease in 2-day-old goslings with high mortality. The findings suggest that the variant GPV strain, which had specifically adapted to Pekin ducks, still retained high pathogenicity for its original host. The mortality (73.3-80%) caused by the first and third egg passages of the variant GPV was somewhat lower than that (93.3%) caused by the third passage virus of the classical GPV, reflecting the higher pathogenicity of the classical GPV for its original host. These findings are likely to reinforce the importance of surveillance for parvoviruses in different waterfowl species and stimulate further study to elucidate the impact of mutations in the GPV genome on its pathogenicity to goslings and ducks. PMID- 29630397 TI - Patterns in Outcomes Reporting of Operatively Managed Pediatric Patellofemoral Instability: A Systematic Review and Meta-analysis. AB - BACKGROUND: Traumatic patellofemoral dislocation is a common injury in pediatric patients, and surgical treatment is often recommended. Increasingly, it has been recognized that clinical studies need to report age-appropriate treatment outcomes. However, the variability and appropriateness of outcomes reporting in the youth patellar instability literature are unknown. PURPOSE: To analyze the patterns of outcomes reporting in studies published in high-impact orthopaedic journals after operative management of pediatric patellar instability. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: Six high-impact orthopaedic journals were searched using PubMed and EMBASE to identify studies reporting outcomes of operative management of pediatric patellar instability. Studies containing adults were excluded. Clinical and radiographic outcomes were recorded from included articles. Descriptive statistics were calculated for overall instability recurrence rates, return-to-activity rates, and changes in Kujala and Tegner scores. RESULTS: Of 545 identified articles, 8 studies met the inclusion criteria. These studies encompassed 213 patients and 230 knees (mean age, 13.2 years; range, 4.5-18.3 years). Seven of 8 studies reported patients' physeal status, but only 4 studies limited their outcomes reporting to patients with open physes. Two studies reported postoperative radiographic measures, and 5 studies reported preoperative radiographic findings. Six studies reported patient reported outcome measures (PROMs). Seven unique PROMs were reported. All but one study reported complication rates and types of complications. The mean postoperative change in Tegner scores was -0.07 (range, -0.6 to 1.0). Among studies examining medial patellofemoral ligament reconstruction with adequate data, the mean return-to-activity rate was 86% (range, 81%-92%), the instability recurrence rate was 3% +/- 20%, and the mean improvement in Kujala scores postoperatively was 22.1 (range, 19.9-26). CONCLUSION: There is a need for more pediatric-specific outcomes studies regarding operatively managed traumatic patellofemoral instability. Of the outcomes reported, both radiographic outcomes and PROMs should be standardized. Among radiographic outcomes, there is a need for more studies that report tibial tubercle-trochlear groove distances and use Caton-Deschamps and/or Blackburne-Peel indices to assess patellar height. Among PROMs, there is a need for studies that use PROMs validated in pediatric populations, such as the International Knee Documentation Committee Pediatric Form or the Hospital for Special Surgery Pediatric Functional Activity Brief Scale. PMID- 29630398 TI - 18F-NaF/223RaCl2 theranostics in metastatic prostate cancer: treatment response assessment and prediction of outcome. AB - Theranostics refers to companion agents with identical or similar structure targeted to a specific biological entity for imaging and treatment. Although the concept has a long history with radioiodine in thyroidology, but it has experienced remarkable recent renaissance in management of neuroendocrine tumors and prostate cancer. Bone scintigraphy based on osteoblastic reaction and targeted radionuclide therapy with the alpha-particle calcium-mimetic agent, 223RaCl2, also form a theranostic model for imaging and treatment of osseous metastatic disease. Since the regulatory approval of 223RaCl2 in 2013, there has been accumulating evidence on the potential use of 18F-NaF PET scintigraphy in the assessment of response and prediction of outcome in males with metastatic castrate-resistant prostate cancer who undergo 223RaCl2 therapy. We review the 18F-NaF/223RaCl2 as theranostic companion in the management of prostate cancer with emphasis on the utility of 18F-NaF and other relevant PET radiotracers in the therapy response and prognosis assessments. PMID- 29630399 TI - Quantitative Sensory Testing, Antihistamines, and Beta-Blockers for Management of Persistent Breast Pain: A Case Series. AB - BACKGROUND: It is not uncommon for mothers to have persistent pain with breastfeeding beyond the first few weeks after birth. Persistent pain can be multifactorial, with neuropathic pain maintained by central sensitization being one dimension. Our knowledge in delineating categories of persistent pain is simple and not very sophisticated. METHODS: We have developed and tested a Lactation Quantitative Sensory Test (L-QST) to quantify the neuropathic component of persistent breastfeeding pain. We present three case reports of neuropathic breastfeeding pain and treatment, and we discuss the potential role of histamine and catecholamines in persistent breastfeeding-associated pain. CONCLUSIONS: The L-QST can be a useful tool to quantify neuropathic pain. Further studies are needed to test inter-observer reliability and reproducibility of this tool. Antihistamines can be considered for treating persistent pain in breastfeeding women with a history of allergy or atopy, and beta-blockers may be helpful in women with multiple pain disorders. PMID- 29630400 TI - How Well Do Big Five Measures Capture HEXACO Scale Variance? AB - We examined the ability of several Big Five measures to account for variance in HEXACO Personality Inventory-Revised (HEXACO-PI-R) scales and vice versa. Some Big Five measures accounted for more variance in HEXACO Honesty-Humility than did others, but these differences were largely offset by opposing differences in accounting for variance in HEXACO Agreeableness and Emotionality. As a consequence, the various Big Five measures showed similarly large overall deficiencies in accounting for HEXACO scale variance, relative to variance accounted for in Big Five scales by HEXACO-PI-R scales. The results imply that the use of Big Five instead of HEXACO scales entails a large loss of information, about equal to the amount that would be lost by discarding one of the Big Five scales. PMID- 29630402 TI - Prostatic-Specific Antigen Levels in Men from Two Andean Cities of Peru. PMID- 29630403 TI - Crash safety concerns for out-of-position occupant postures: A look toward safety in highly automated vehicles. AB - OBJECTIVE: Highly automated vehicle occupants will all be passengers and may be free to ride while in postures for which existing occupant safety systems such as seat belts and airbags were not originally designed. These occupants could therefore face increased risk of injury when a crash occurs. Given that current vehicles are capable of supporting a variety of occupant postures outside of the normal design position, such as reclined or turned passengers, an evaluation of current field data was performed to better understand the risks of being out of position. METHODS: We investigated the frequency, demographics, and injury outcomes for out-of-position occupants using NASS-CDS. A matched analysis was performed to compare injury outcomes for out-of-position passengers with in position drivers involved in similar crashes. Finally, case studies for out-of position occupants were examined in the Crash Injury Research (CIREN) database. RESULTS: Only 0.5% of occupants in NASS-CDS with a coded posture were out of position at the time of crash. Of the out-of-position occupants, being turned or seated sideways was almost as likely as being reclined. Out-of-position occupants were younger and less likely to be belted than their in-position counterparts. Analysis of the injury data indicated a trend that being out of position was associated with an elevated risk for serious injury. However, the number of out of-position occupants was too small to provide a definitive or statistically significant conclusion on injury outcome. CONCLUSION: Though highly automated vehicles may eventually reduce the number of crashes and traffic fatalities in the future, there will be a transition period when these vehicles remain at risk from collisions with human-driven vehicles. These crashes could cause higher than anticipated rates of injury if occupants are less likely to be belted or tend to be in positions for which restraints are not optimized. This study highlights the need for future research on occupant response and countermeasure design for out of-position occupants. PMID- 29630405 TI - Erratum. PMID- 29630404 TI - PROGINS Polymorphism of the Progesterone Receptor Gene and the Susceptibility to Uterine Leiomyomas: A Systematic Review and Meta-Analysis. AB - AIMS: Steroid hormones play a central role in modulating the growth of uterine leiomyoma, and several studies have suggested that polymorphisms in genes encoding these hormones and their receptors may be risk factors for developing the disease. Progesterone is a potent antagonist of estrogen-induced proliferation in the endometrium, and the PROGINS polymorphisms have been associated with leiomyoma, but the results are inconsistent. In this study, we aimed to investigate the possible associations between the PROGINS polymorphisms and uterine leiomyoma. MATERIALS AND METHODS: MEDLINE using PubMed, Science Direct, and Google Scholar databases was searched using the terms "PROGINS," "progesterone receptor," "polymorphism," and "leiomyoma." We estimated risk with odds ratios [ORs] and 95% confidence intervals using standard genetic models (homozygous, recessive, dominant, and codominant). RESULTS: Six studies were included in this meta-analysis based on 837 cases and 1011 controls. Subjects in three studies were Asian (365 cases/391 controls), and five were non-Asian (472 cases/620 controls). Our findings showed no association between PROGINS and leiomyoma in the overall analysis (OR 0.91-1.07, p = 0.15-0.57) nor in either of the subgroups (Asian: OR 0.84-1.04, p = 0.68-0.98; or non-Asian: OR 0.77-1.34, p = 0.33-0.93), in all genetic models. CONCLUSION: The PROGINS polymorphisms cannot be considered a risk factor for developing uterine leiomyoma. PMID- 29630407 TI - The endogenous bioactive lipid prostaglandin D2-glycerol ester reduces murine colitis via DP1 and PPARgamma receptors. AB - Cyclooxygenase-2 (COX-2) has long been implicated in the pathogenesis of inflammatory bowel diseases (IBDs). COX-2 is mostly known for the production of prostaglandins (PGs) from arachidonic acid. However, it also metabolizes the endocannabinoids 2-arachidonoylglycerol (2-AG) and anandamide into the less well studied bioactive lipids PG-glycerol esters (PG-Gs) and PG-ethanolamides (PG-EAs or prostamides). We previously showed that PGD2-G, a product of 2-AG oxygenation by COX-2, has anti-inflammatory effects. Therefore, we used the dextran sulfate sodium (DSS)-induced model of colitis in mice to explore the role of PGD2-G in murine models of IBD. Colon inflammation was assessed using macroscopic and histologic scores, myeloperoxidase activity, and expression of inflammatory mediators by real-time quantitative PCR and ELISA. We also compared the effects of PGD2-G with those of PGD2 and PGD2-EA. Finally, we used receptor antagonists to gain mechanistic insight into the receptors responsible for the observed effects. PGD2-G reduced DSS-induced colitis, but PGD2 and PGD2-EA did not have the same effect. Furthermore, we showed that PGD2-G is an agonist of the PGD2 receptor 1 (DP1) and that some of the effects of PGD2-G were blocked by antagonism of peroxisome proliferator-activated receptor gamma and DP1. Therefore, PGD2-G could be one of the products from the COX-2/prostaglandin D synthase axis to exert beneficial effects in colitis.-Alhouayek, M., Buisseret, B., Paquot, A., Guillemot-Legris, O., Muccioli, G. G. The endogenous bioactive lipid prostaglandin D2-glycerol ester reduces murine colitis via DP1 and PPARgamma receptors. PMID- 29630406 TI - Genetic ablation of histone deacetylase 2 leads to lung cellular senescence and lymphoid follicle formation in COPD/emphysema. AB - Histone deacetylase 2 (HDAC2), a critical determinant of chromatin remodeling, is reduced as a consequence of oxidative stress-mediated DNA damage and impaired repair. Cigarette smoke (CS) exposure causes DNA damage and cellular senescence. However, no information is available on the role of HDAC2 in CS-induced DNA damage, stress-induced premature senescence (SIPS), and senescence-associated secretory phenotype (SASP) during the pathogenesis of chronic obstructive pulmonary disease (COPD)/emphysema. We hypothesized that CS causes persistent DNA damage and cellular senescence via HDAC2-dependent mechanisms. We used HDAC2 global knockout (KO) and HDAC2 lung epithelial cell-specific KO [Clara cell specific HDAC2 deletion (HDAC2 CreCC10)] mice to determine whether HDAC2 is a major player in CS-induced oxidative stress, SIPS, and SASP. HDAC2 KO mice exposed to CS show exaggerated DNA damage, inflammatory response, and decline in lung function leading to airspace enlargement. Chronic CS exposure augments lung senescence-associated beta-galactosidase activity in HDAC2 KO, but not in HDAC2 CreCC10 mice. HDAC2 lung epithelial cell-specific KO did not further augment CS induced inflammatory response and airspace enlargement but instead caused an increase in lymphoid aggregate formation. Our study reveals that HDAC2 is a key player regulating CS-induced DNA damage, inflammatory response, and cellular senescence leading to COPD/emphysema.-Sundar, I. K., Rashid, K., Gerloff, J., Rangel-Moreno, J., Li, D., Rahman, I. Genetic ablation of histone deacetylase 2 leads to lung cellular senescence and lymphoid follicle formation in COPD/emphysema. PMID- 29630408 TI - Concentration-dependent, dual roles of IL-10 in the osteogenesis of human BMSCs via P38/MAPK and NF-kappaB signaling pathways. AB - Microenvironmental conditions can influence the differentiation and functional roles of mesenchymal stem cells (MSCs). Recent studies have suggested that an inflammatory microenvironment can significantly affect the osteogenic differentiation of MSCs. Here, we show, for the first time, that IL-10 has concentration-dependent, dual roles in the osteogenesis of human bone marrow mesenchymal stem cells (hBMSCs). Low physiologic concentrations of IL-10 (0.01 1.0 ng/ml) activate the p38/MAPK signaling pathway to promote the osteogenesis of hBMSCs, but higher pathologic doses of IL-10 (10-100 ng/ml) inhibit p38/MAPK signaling by activating NF-kappaB, inhibiting osteogenesis. These results demonstrate that p38/MAPK and NF-kappaB signaling mediates the double-edged sword effect of IL-10 on hBMSCs. The osteogenic impairment was reversed at higher doses of IL-10 when cells were supplemented with the NF-kappaB inhibitor BAY11-7082. These data provide important insights into the regulatory effects of IL-10 on the biologic behavior of hBMSCs.-Chen, E., Liu, G., Zhou, X., Zhang, W., Wang, C., Hu, D., Xue, D., Pan, Z. Concentration-dependent, dual roles of IL-10 in the osteogenesis of human BMSCs via P38/MAPK and NF-kappaB signaling pathways. PMID- 29630409 TI - A new morphinandienone alkaloid from the stems of Fissistigma tungfangense. AB - A new morphinandienone alkaloid, fissistigmine A (1), together with three known alkaloids (2-4), were isolated and identified from the stems of Fissistigma tungfangense. Among them, fissistigmine A (1) represents the first example of a novel naturally occurring morphinandienone alkaloid with a unique cleavage of the C-9-N-17 bond. All isolated compounds were evaluated for their anti-rheumatoid arthritis activities via examining their anti-proliferative effects on synoviocytes in vitro. Compound 1 exhibited inhibitory effect on the proliferation of synoviocytes with an IC50 value of 114.6 +/- 2.2 MUM. PMID- 29630410 TI - Clinical News. PMID- 29630411 TI - Selecting the "Best" Factor Structure and Moving Measurement Validation Forward: An Illustration. AB - Despite the broad literature base on factor analysis best practices, research seeking to evaluate a measure's psychometric properties frequently fails to consider or follow these recommendations. This leads to incorrect factor structures, numerous and often overly complex competing factor models and, perhaps most harmful, biased model results. Our goal is to demonstrate a practical and actionable process for factor analysis through (a) an overview of six statistical and psychometric issues and approaches to be aware of, investigate, and report when engaging in factor structure validation, along with a flowchart for recommended procedures to understand latent factor structures; (b) demonstrating these issues to provide a summary of the updated Posttraumatic Stress Disorder Checklist (PCL-5) factor models and a rationale for validation; and (c) conducting a comprehensive statistical and psychometric validation of the PCL-5 factor structure to demonstrate all the issues we described earlier. Considering previous research, the PCL-5 was evaluated using a sample of 1,403 U.S. Air Force remotely piloted aircraft operators with high levels of battlefield exposure. Previously proposed PCL-5 factor structures were not supported by the data, but instead a bifactor model is arguably more statistically appropriate. PMID- 29630412 TI - Translation, Transcultural Adaptation, and Validation of the Empathy, Spirituality, and Wellness in Medicine Scale to the Brazilian Portuguese Language. AB - : Construct: The Empathy, Spirituality, and Wellness in Medicine Scale (ESWIM) is a 43-item multidimensional scale developed to investigate different dimensions of physicians and medical students. BACKGROUND: Medical education research requires the use of several different instruments with dozens of items that evaluate each construct separately, making their application slow and increasing the likelihood of students providing a large number of incomplete or missing responses. To provide an alternative measure, this study aims to translate, adapt, and validate the multidimensional ESWIM instrument for Brazilian medical students. This is a very promising instrument because it is multidimensional, relatively short, and cost free; it evaluates important constructs; and it has been explicitly designed for use in the medical context. APPROACH: The English-language instrument was translated and adapted into the Brazilian Portuguese language using standard procedures: translation, transcultural adaptation, and back-translation. ESWIM was administered to students in all years of the medical curriculum. A retest was given 45 days later to evaluate reliability. To assess validity, the questionnaire also included sociodemographic data, the Duke Religion Index, the Empathy Inventory, the brief version of the World Health Organization Quality of Life (WHOQOL-Bref), and the Oldenburg Burnout Inventory. RESULTS: A total of 776 medical students (M age = 22.34 years, SD = 3.11) were assessed. The Brazilian Portuguese version of ESWIM showed good internal consistency for the factor of Empathy (alpha = 0.79-0.81) and borderline internal consistency for the other factors: Openness to Spirituality (alpha = 0.61-0.66), Wellness (alpha = 0.57 0.68), and Tolerance (alpha = 0.56-0.65). The principal component analysis revealed a four-factor structure; however, the confirmatory factor analysis showed a better fit for a three-factor structure. We found a significant positive correlation between ESWIM empathy and empathy measured by the Empathy Inventory (r = .444, p < .01), as well as negative correlations between ESWIM empathy and burnout (r = -.145 to -.224, p < .01). ESWIM openness to spirituality was also significantly correlated with different subscales of religiosity (r = .301-.417, p < .01), and ESWIM wellness was significantly correlated with the WHOQOL-Bref factors (r = .390-.673, p < .01). The test-retest reliability (applied to 83 students) was high for all factors except Tolerance. CONCLUSION: This study provides supportive evidence regarding the reliability and validity of ESWIM empathy scores. The ESWIM scale opens a new field of research in relation to openness to spirituality by introducing a scale that measures this openness attitude. Despite borderline internal consistency, ESWIM wellness was strongly associated with quality of life and had good test-retest reliability. Thus, ESWIM appears to be a valid option for evaluating these constructs in medical students. PMID- 29630413 TI - Factors Associated with Early Referral to Palliative Care in Outpatients with Advanced Cancer. AB - BACKGROUND: Although timely palliative care is recommended for patients with advanced cancer, referrals to palliative care services are often late. OBJECTIVES: To identify factors associated with early referral to an oncology palliative care clinic and to describe symptom severity according to timing of referral. DESIGN: We conducted a retrospective review of 337 patients with advanced cancer referred to outpatient palliative care at a comprehensive cancer center. We gathered data related to patient demographics, diagnosis, and referral. Timing of referral was categorized as early (>12 months before death), intermediate (6-12 months before death), or late (<6 months before death). Ordinal logistic regression was used to determine factors related to referral timing, and the Kruskal-Wallis test to determine symptom severity in each referral timing category. RESULTS: Of the 337 patients, 232 (69%) referrals were late, 60 (18%) intermediate, and 45 (13%) early. On multivariable analysis, earlier referral was associated with earlier primary cancer diagnosis (p = 0.004), and referral for pain and symptom management (p = 0.001). Patients who were referred late had worse overall Edmonton Symptom Assessment System distress scores, as well as worse tiredness, nausea, drowsiness, appetite, and wellbeing (all p <= 0.001). Severity of pain, shortness of breath, anxiety, and depression did not differ based on time of referral. CONCLUSIONS: A longer disease course and referral for symptom management were associated with earlier referral, whereas overall symptom burden was higher for late referrals. Further research is required on combining symptom screening with timely referral to improve symptom management in advanced cancer. PMID- 29630414 TI - Effects of intracerebroventricularly injected glucagon-like peptide-2 on ethanol induced gastric mucosal damage in rats. AB - PURPOSE: The present study aims to investigate the effects of intracerebroventricularly (i.c.v.)-injected glucagon-like peptide-2 (GLP-2) on ethanol-induced gastric mucosal damage and to reveal the mechanisms involved in this effect. MATERIALS AND METHODS: Rats received absolute ethanol orally via an orogastric tube 30 minutes after GLP-2 (1-200 ng/10 ul; i.c.v.) or saline (10 ul) injections. They were decapitated 1 hour later, their stomachs were removed, and the gastric mucosal damage was scored. RESULTS: A total of 100 ng GLP-2 inhibited the gastric mucosal damage by 67%. This effect was abolished by the calcitonin gene-related peptide (CGRP) receptor antagonist CGRP-(8-37) (10 ug/kg; s.c.), but was not affected by either the nitric oxide (NO) synthase inhibitor L-NAME (30 mg/kg; s.c.) or the cyclooxygenase inhibitor indomethacin (5 mg/kg; i.p.). The most effective gastroprotective dose of GLP-2 (100 ng/10 ul; i.c.v.), but not the higher doses (150 or 200 ng/10 ul; i.c.v.) prevented the decrease in gastric mucosal blood flow caused by ethanol. In conclusion, i.c.v. GLP-2 protects against ethanol-induced gastric mucosal damage and this effect is mediated by CGRP receptor activation and gastric mucosal blood flow, but not by NO or prostaglandins. PMID- 29630415 TI - Tear Film Stability and Tear Break Up Time (TBUT) in Laboratory Rabbits-A Systematic Review. AB - Several older studies on rabbits indicated that the pre-corneal tear film was unusually stable and this perspective was revisited recently. However, the methods used for these studies were very different from those generally used in human studies. A literature search was undertaken for the time period of 1965 through 2017, mainly using PubMed, to identify studies where values for the tear break up time (TBUT) were reported for the eyes of nominally normal (healthy) laboratory rabbits regardless of breed or age and where the methods were more similar to those routinely used in human clinical studies. For 20 reports identified where sodium fluorescein was used, the average TBUT values in any particular study ranged from 1.9 to 51 s, with a group mean of 21.8 +/- 11.9 s (SD), with the inter-study variability in TBUT (as the coefficient of variation) being 19.4%. For four studies not using fluorescein, the mean break up time reported was 32.7 +/- 16.2 s, while a separate study (also not using fluorescein) reported an average break up time of 1788 s. Most reports of the pre-corneal tear film stability in laboratory rabbits, especially as reported over the last 10 years, indicate break up times of less than 60 s have been observed, although has been little consistency in the methods used. Overall, this outcome is not consistent with a perspective that the rabbit (as routinely used in experimental studies) has an extraordinarily stable tear film. PMID- 29630416 TI - Perceived Activities and Participation Outcomes of a Yoga Intervention for Individuals with Parkinson's Disease: A Mixed Methods Study. AB - Parkinson's disease (PD) often leads to poor balance, increased falls, and fear of falling, all of which can reduce participation in life activities. Yoga, which usually includes physical exercise, can improve functioning and life participation; however, limited research has been conducted on the effects of yoga on life participation of individuals with PD. This study had two purposes: (1) to identify and understand the perceived activities and participation outcomes associated a therapeutic yoga intervention for individuals with PD; and (2) to compare the perceived activities and participation outcomes with the outcomes measured in the clinical trial. A single-blind, randomized, waitlist controlled, phase II exploratory pilot study using an after-trial embedded mixed methods design (clinical trial Pro00041068) evaluated the effect of an 8-week Hatha Yoga intervention on individuals with PD. Directed content analysis was used to analyze focus group interviews with participants who completed the yoga intervention. Quantitative and qualitative data were merged and compared using a data comparison matrix. Qualitative analysis indicated many activities and participation outcomes. Comparison of qualitative and quantitative data indicated the yoga intervention led to improved balance, mobility, and functional gait, and fewer falls. These outcomes reached beyond the intervention and into participants' daily lives. Results support the use of Hatha Yoga as a community based rehabilitation intervention for individuals with PD. Yoga, as part of an interdisciplinary approach to treatment, can improve many types of activities and participation outcomes (e.g., mobility, social relationships, self-care, handling stress, recreation). PMID- 29630417 TI - The effect of early child care attendance on childhood asthma and wheezing: A meta-analysis. AB - OBJECTIVE: Research evidence offers mixed results regarding the relationship between early child care attendance and childhood asthma and wheezing. A meta analysis was conducted to synthesize the current research evidence of the association between early child care attendance and the risk of childhood asthma and wheezing. METHOD: Peer reviewed studies published from 1964-January 2017 were identified in MEDLINE, CINAL, and EMBASE using MeSH headings relevant to child care and asthma. Two investigators independently reviewed the selected articles from this search. All relevant articles that met our inclusion criteria were selected for further analysis. Data were extracted from studies that had sufficient data to analyze the odds of asthma or wheezing among children who attended child care. RESULTS: The meta-analysis of 32 studies found that (1) early child care attendance is protective against asthma in children 3-5 years of age but not for children with asthma 6 years of age or older. (2) Early child care attendance increases the risk of wheezing among children 2 years of age or younger, but not the risk of wheezing for children over 2 years of age. CONCLUSIONS: This meta-analysis shows that early child care attendance is not significantly associated with the risk of asthma or wheeze in children 6 years of age or older. PMID- 29630419 TI - Crab Shell Extract Improves Sperm Parameters and Antioxidant Status in Testes of Diabetic Rats. AB - Crab shell (CS), which contains antioxidant compounds, has been used as a promising nutritional and medical compound in traditional medicine. Oxidative stress plays a critical role in the development of diabetes. This study aims to investigate the effects of CS extract (CSE) on sperm parameters, antioxidant status, and histopathology changes of testes in diabetic rats. In this experimental study, 40 Wistar male rats were investigated in five groups (n = 8/group): diabetic rats treated with different CS concentrations (i.e., 100, 200, and 400 mg/kg), diabetic group, and nondiabetic control. To induce diabetes, a single dose (60 mg/kg) of streptozotocin (STZ) was injected intraperitoneally; three days later, treatment with CSE was begun and conducted for 14 days. The fasting blood glucose, testes weight, and viability, number, and motility of sperm were assessed. In addition, the levels of ferric reducing antioxidant power (FRAP) and nitric oxide (NO) were estimated in the testes. Testes were examined using histological analysis. The results of this study revealed that sperm number, motility, and serum testosterone levels of CSE-treated diabetic rats increased significantly (p = .000) compared with the untreated diabetic group in a dose-depended manner while the number of immotile sperm decreased significantly (p = .017). CS also reduced the testicular level of nitric oxide and fasting blood glucose; however, it led to significant growth in the FRAP levels of testes (p = .002). Our results suggest that CSE improves sperm parameters and protects the testicular tissue against the oxidative stress damage induced by diabetes. PMID- 29630418 TI - Comparison of Keratometry Obtained by a Swept Source OCT-Based Biometer with a Standard Optical Biometer and Scheimpflug Imaging. AB - PURPOSE: To assess agreement of a swept source-optical coherence tomography (SS OCT) based Biometer with a standard IOLMaster device and Scheimpflug Imaging (SI) to acquire keratometric measurements in cataract patients. METHODS: In this prospective comparative study, 101 eyes of 101 cataract surgery candidates, aged 24-81 years, were sequentially examined using three devices. Keratometry values at the flat (K1) and steep (K2) axis, mean corneal power (Km) and magnitude of corneal astigmatism as well as J0 and J45 vectoral components of astigmatism obtained with the SS-OCT based biometer (IOLMaster 700) were compared with those obtained with the IOLMaster 500 and SI. The agreement between measurements was evaluated by the Bland-Altman method, intraclass correlation coefficients (ICCs) and repeated-measures analysis of variance. RESULTS: Mean K1 values from the three devices were similar (p = 0.09). Mean K2 and Km values of IOLMaster 700 were higher than SI and lower than IOLMaster 500 (p = 0.04 for K2 and p = 0.02 for Km). There was a strong correlation between K1, K2, Km and magnitude of astigmatism obtained with all devices (r >= 0.80 and p < 0.01). The 95% limits of agreement (LoA) width for each keratometric value were highest for the comparison between IOLMaster 500 and SI and lowest for the comparison between IOLMaster 700 and 500. The mean differences (width of 95% LoA) for J0 and J45 vectoral components were 0.005 (2.19) and 0.12 (2.92) for the measurements obtained by IOLMaster 700 vs IOLMaster 500 and 0.06 (1.79) and 0.02 (1.58) for the measurements obtained by IOLMaster 700 vs SI, respectively. CONCLUSIONS: With ICCs close to 1, the agreement between all devices was excellent for keratometric measurements. Mean K2, Km and astigmatism measurements from IOLMaster 700 were lower than IOLMaster 500 and higher than SI. However, the differences were quite small and are not expected to affect the final IOL power. PMID- 29630420 TI - Evaluation of Optical Quality: Ocular Scattering and Aberrations in Eyes Implanted with Diffractive Multifocal or Monofocal Intraocular Lenses. AB - PURPOSE: To compare objective optical quality, ocular scattering and aberrations of eyes implanted with an aspheric monofocal intraocular lens (IOL) or an aspheric apodized diffractive multifocal IOL three months after surgery. METHODS: Prospective consecutive nonrandomized comparative cohort study. A total of 80 eyes from 57 cataract patients were bilaterally or unilaterally implanted with monofocal (AcrySof IQ SN60WF) or multifocal (AcrySof IQ ReSTOR SN6AD1) IOLs. Respectively, 40 eyes of 27 patients were implanted with monofocal IOLs, and 40 eyes of 30 patients were implanted with multifocal IOLs. Ocular high-order aberration (HOA) values were obtained using Hartmann-Shack aberrometer; objective scatter index (OSI), modulation transfer function (MTF) cutoff, Strehl ratio (SR), and contrast visual acuity OV at 100%, 20%, and 9% were measured using Objective Quality Analysis System II (OQAS II). RESULTS: Ocular aberrations performed similar in both groups (p > 0.05). However, significantly higher values of OSI and lower values of MTF cutoff, SR and OV were found in the SN6AD1 group (p < 0.05). CONCLUSIONS: Both ocular scattering and wave-front aberrations play essential role in retinal image quality, which may be overestimated when only aberrations were taken into account. Combining the effect of ocular scattering with HOA will result in a more accurate assessment of the visual and optical quality. PMID- 29630421 TI - Neuroimaging in amyotrophic lateral sclerosis: current and emerging uses. AB - INTRODUCTION: Several neuroimaging techniques have been used to define in vivo markers of pathological alterations underlying amyotrophic lateral sclerosis (ALS). Growing evidence supports the use of magnetic resonance imaging (MRI) and positron emission tomography (PET) for the non-invasive detection of central nervous system involvement in patients with ALS. Areas covered: A comprehensive overview of structural and functional neuroimaging applications in ALS is provided, focusing on motor and extra-motor involvement in the brain and the spinal cord. Implications for pathogenetic models, patient diagnosis, prognosis, monitoring, and the design of clinical trials are discussed. Expert commentary: State-of-the-art neuroimaging techniques provide fundamental instruments for the detection and quantification of upper motor neuron and extra-motor brain involvement in ALS, with relevance for both pathophysiologic investigation and clinical practice. Network-based analysis of structural and functional connectivity alterations and multimodal approaches combining several neuroimaging measures are promising tools for the development of novel diagnostic and prognostic markers to be used at the individual patient level. PMID- 29630422 TI - Investigation on the mechanical properties of polyurea (PU)/melamine formaldehyde (MF) microcapsules prepared with different chain extenders. AB - There is lack of understanding on controlling of mechanical properties of moisture-curing PU/MF microcapsules which limited its further application. PU/MF microcapsules containing a core of isophorone diisocyanate (IPDI) were prepared with different chain extenders, polyetheramine D400, H2O, triethylenetetramine and polyetheramine (PEA) D230 by following a two-step synthesis method in this study. Fourier transform infra-red (FTIR) spectroscopy, Malvern particle sizing, scanning electron microscopy (SEM), and transmission electron microscopy (TEM). And micromanipulation technique was used to identify chemical bonds in the shell, size distributions, structure, thickness, and mechanical properties of microcapsules. The results show that PU/MF microcapsules were successfully prepared. Tr increased from 46.4 +/- 13.9 N/m to 75.8 +/- 23.3 N/m when extender changed from D400 to D230. And the Tr increased from 51.3 +/- 14.1 to 94.8 +/- 17.5 N/m when the swelling time increased from 1 to 3h. Morphologies of the shell were utilised to understand the mechanism of reactions in forming the shell materials. PMID- 29630423 TI - An Amplifying Cascade of Contact Lens-Related End-of-Day Hyperaemia and Dryness Symptoms. AB - End-of-day (EOD) symptoms of dryness are too often the cause of poor soft contact lens (SCL) tolerance and abandonment of wear. This review examines an amplifying cascade model for these symptoms, which involve thin tear layers on contact lens (CL) front surfaces being susceptible to evaporation-related short tear breakup (TBU) times. Susceptibility to faster tear loss by evaporation may be exacerbated by other forms of tear instability, such as lipid and mucin deficiencies as well as lens surface soiling. Bulbar and palpebral conjunctival hyperaemia and associated faster evaporation of warmer pre-conjunctival tears could also contribute to evaporative dry eye EOD symptoms. In CL wearers, a cascade of increasing hyperaemia toward the end of day, associated increasing tear temperature and evaporative loss, shortened TBU times (TBUTs) and increased osmolarity, all elevate the risk of higher symptom levels according to progressive amplification of this cascade. Chronic wound healing responses to SCL wear, perhaps related to limbal conjunctival trauma, stem cell deficiency and persistent epitheliopathy, as well as one or more immune responses, may contribute directly or indirectly to inflammation and the amplifying evaporative dryness cascade. A diurnal cycle that culminates in EOD symptoms appears to involve a process of recovery from causal mechanisms after lens removal, which allows lenses to be worn comfortably, at least initially the next day. Possible recovery processes are discussed in this review as are procedures that may help de-amplify an inflammatory, evaporative dryness cascade and alleviate EOD symptoms. Evidence of an accrual of adverse responses over long periods of more or less successful lens wear indicate an incremental failure to recover from EOD hyperaemia. Such incremental failure could help explain how SCL wear too often needs to be abandoned after many years of comfortable wear. PMID- 29630424 TI - Looking beyond the checklist: An ethnography of interprofessional operating room safety cultures. AB - The Surgical Safety Checklist (SSC) has been adopted in operating rooms (OR) worldwide to reduce medical errors, increase patient safety and improve interprofessional communication. Despite often high compliance rates, recent studies suggested the SSC has not been associated with significant reductions in operative mortality or complications. This ethnographic study sought to understand this disconnection through approximately 50 hours of observation in the OR and 10 in-depth semi-structured interviews with surgeons, nurses, and anaesthesiologists in orthopaedic surgery. Inductive thematic analysis was used to analyse the data. By spending time in the OR and listening to the staff, this study was able to look beyond what "ought" to be happening in the OR and garner a deep understanding of the realities of OR work that acknowledges the complexities of surgical culture in which the SSC is being implemented. This study found SSC compliance was influenced by the perceived (un)importance of individual checklist items within the orthopaedic setting. Additionally, there remains a need to further explore patients' involvement in their operative experience. PMID- 29630425 TI - Suppressive effects of metformin on T-helper 1-related chemokines expression in the human monocytic leukemia cell line THP-1. AB - PURPOSE OF THE STUDY: Type 1 and type 2 diabetes mellitus (DM) are chronic T-cell mediated inflammatory diseases. Metformin is a widely used drug for type 2 DM that reduces the need for insulin in type 1 DM. However, whether metformin has an anti-inflammatory effect for treating DM is unknown. We investigated the anti inflammatory mechanism of metformin in the human monocytic leukemia cell line THP 1. MATERIALS AND METHODS: The human monocytic leukemia cell line THP-1 was pretreated with metformin and stimulated with lipopolysaccharide (LPS). The production of T-helper (Th)-1-related chemokines including interferon-gamma induced protein-10 (IP-10) and monocyte chemoattractant protein-1 (MCP-1), Th2 related chemokine macrophage-derived chemokine, and the proinflammatory chemokine tumor necrosis factor-alpha was measured using enzyme-linked immunosorbent assay. Intracellular signaling pathways were investigated using Western blot analysis and chromatin immunoprecipitation assay. RESULTS: Metformin suppressed LPS induced IP-10 and MCP-1 production as well as LPS-induced phosphorylation of c Jun N-terminal kinase (JNK), p38, extracellular signal-regulated kinase (ERK), and nuclear factor-kappa B (NF-kappaB). Moreover, metformin suppressed LPS induced acetylation of histones H3 and H4 at the IP-10 promoter. CONCLUSIONS: Metformin suppressed the production of Th1-related chemokines IP-10 and MCP-1 in THP-1 cells. Suppressive effects of metformin on IP-10 production might be attributed at least partially to the JNK, p38, ERK, and NF-kappaB pathways as well as to epigenetic regulation through the acetylation of histones H3 and H4. These results indicated the therapeutic anti-inflammatory potential of metformin. PMID- 29630426 TI - Preparation and anti-cancer evaluation of promiximab-MMAE, an anti-CD56 antibody drug conjugate, in small cell lung cancer cell line xenograft models. AB - Antibody-drug conjugates (ADCs) have been successfully applied clinically as target drugs for cancer. In this study, anti-neural cell adhesion molecule also called CD56 antibody-monomethyl auristatin E (MMAE) conjugate named Promiximab MMAE was prepared by conjugation of microtubule inhibitor MMAE with Promiximab. The average drug-to-antibody ratio (DAR) of Promiximab-MMAE was 3.13 as analysed by liquid chromatography-mass spectrometry/ mass spectrometry (LC-MS/MS). The targeting capacity and affinity kinetics of Promiximab-MMAE were similar to that of Promiximab after being conjugated with MMAE as tested by flow cytometry and biolayer interferometry analysis. Promiximab-MMAE showed effective anti proliferation on CD56-positive cell lines (NCI-H524, NCI-H526, and NCI-H69), with the half maximal inhibitory concentration (IC50) values of 19.24, 5.23, and 0.32 nmol/L in vitro, respectively. Promiximab-MMAE of 10 mg/kg every three days with a total of three times was administered in vivo. Results showed that the tumour regression was not recrudesced in NCI-H69 and NCI-H526 xenograft mice models till 52 and 56 days. Moreover, body weight and histopathology of the major organs (liver, spleen, heart, lung, and kidney) showed no significant changes after treatment with Promiximab-MMAE. In conclusion, Promiximab-MMAE is a potential candidate for the treatment of CD56 positive small cell lung cancer. PMID- 29630427 TI - Evidence on the use of progesterone in menopausal hormone therapy. AB - A need exists for a regulatory agency-approved hormone therapy (HT) with naturally occurring hormones combining progesterone (P4) and estradiol (E2), since no single product contains both endogenous hormones. Many women choose HT with P4 and millions of women around the world are using unapproved, poorly regulated compounded HT. The use of natural P4 in HT results, for the most part, in favorable outcomes without deleterious effects, as shown in clinical studies of postmenopausal women. Importantly, P4 used in HT prevents endometrial hyperplasia from estrogens while helping relieve vasomotor symptoms and improving quality-of-life measures. Additionally, risk of venous thromboembolism and breast cancer does not appear to increase with use of P4 plus estrogens as shown with synthetic progestins plus estrogens in large observations studies, and no detrimental effects of P4 in HT have been found on outcomes related to cardiovascular disease or cognition. A regulatory agency-approved HT with naturally occurring E2/P4 could be an option for the millions of women who desire a bioidentical product and/or are exposed to potential risks of inadequately studied and under-regulated compounded HT. PMID- 29630428 TI - Low dose-rate irradiation with [3H]-labelled valine to selectively target hypoxic cells in a human colorectal cancer xenograft model. AB - BACKGROUND: Earlier in vitro studies show that irradiation with an ultra-low dose rate of 15 mGy/h delivered with [3H]-valine leads to loss of clonogenicity in hypoxic T-47D cells. Here, the aim was to determine if [3H]-valine could be used to deliver low dose-rate irradiation in a colorectal cancer model. METHODS: Clonogenicity was measured in cultured cancer cell line HT29 irradiated with 15 mGy/h combined with intermittent hypoxia. Mice with HT29 xenografts were irradiated by repeated injections of [3H]-valine intravenously. The activity in the tumor tissue was measured by scintillation counting and tumor growth, hypoxic fraction and tritium distribution within tumors were assessed by pimonidazole staining and autoradiography. RESULTS: Ultra-low dose-rate irradiation decreased clonogenicity in hypoxic colorectal cancer cells. In vivo, the tumor growth, hypoxic fraction and weight of the mice were similar between the treated and untreated group. Autoradiography showed no [3H]-valine uptake in hypoxic tumor regions in contrast to aerobic tissue. CONCLUSION: Continuous low-dose-rate irradiation was well tolerated by aerobic tissue. This indicates a potential use of low dose-rate irradiation to target hypoxic tumor cells in combination with high dose-rate irradiation to eradicate the well oxygenated tumor regions. However, [3H]-valine is not the appropriate method to deliver ultra-low dose-rate irradiation in vivo. PMID- 29630429 TI - Early Help in Early Years: Developing a Universal Assessment Tool. AB - Effective assessment tools are an essential element of early identification of problems, enabling early intervention in the first two or so years of life. This article reports on the development and evaluation of a Universal Assessment Tool for Early Help in Early Years. The project aim was to develop, pilot and evaluate a new universal assessment tool named "My Family Profile" for use within Northamptonshire, United Kingdom, from pregnancy until a child reaches 2/2.5 years of age. A flowchart demonstrates the stages of the process including how each step contributed toward the tool and end report (Neill et al., 2015). The project used an intervention design enabling collaborative inter-agency working and ensured parents were engaged throughout the process. The methods used in developing the tool incorporated collaborative working, content analysis, format requirements, questioning styles and information sharing. The tool was evaluated using focus groups and individual interviews with parents, an online evaluation questionnaire and audit of completed assessment forms with practitioners. The resulting report (Neill et al., 2015) contained "My Family Profile" highlighted five key recommendations: (1) It is developed in a digital format with secure "cloud" storage, accessible from all IT platforms in use by child health/care professionals; (2) it is implemented with a comprehensive training program for professionals; (3) it is formally evaluated following implementation; (4) it is extended up to school entry and through school years; and (5) it is developed for use within other locations in the United Kingdom. PMID- 29630430 TI - Making the Case: The Importance of Using 10 Key Preconception Indicators in Understanding the Health of Women of Reproductive Age. AB - In 2006, the Preconception Care (PCC) Work Group and the Select Panel on PCC published 10 recommendations promoting preconception health (PCH) and healthcare for women of reproductive age. In the years following the recommendations, much research focused on specific PCH behaviors, clinical provision of care, and care financing, but no comprehensive, well-defined set of indicators was identified. In 2011, seven states developed a set of 45 PCH indicators; however, to date, no one publication has assessed the usefulness of all 45 indicators in addressing PCH. This report makes the case for reducing the original 45 indicators to a condensed set of 10 for national and state reporting by describing the use of the 45 indicators to date, describing development of evaluation criteria for narrowing the number of indicators, and identifying gaps in indicator development for provision of PCC. Using the condensed set, states can set priorities, revise and develop programs and policies, implement system changes, and better allocate resources to support interventions to improve the health of women of reproductive age during the preconception and interconception periods. PMID- 29630432 TI - Mediating Systems of Care: Emergency Calls to Long-Term Care Facilities at Life's End. AB - BACKGROUND: Nursing home (NH) residents account for over 2.2 million emergency department visits yearly; the majority are cared for and transported by prehospital providers (emergency medical technicians and paramedics). OBJECTIVE: The purpose of this study was to investigate prehospital providers' perceptions of emergency calls at life's end. This article focuses on perceptions of end-of life calls in long-term care (LTC). DESIGN: This pilot study employed a descriptive cross-sectional design. Concepts from the symbolic interaction theory guided the exploration of perceptions and interpretations of emergency calls in LTC facilities. SETTING/SUBJECTS: A purposeful sample of prehospital providers was developed from one agency in a small northeastern U.S. city. MEASUREMENTS: Semistructured interviews were conducted with 43 prehospital providers to explore their perceptions of factors that trigger emergency end-of-life calls in LTC facilities. Qualitative data analysis involved iterative coding in an inductive process that included open, systematic, focused, and axial coding. RESULTS: Interview themes illustrated the contributing factors as follows: care crises; dying-related turmoil; staffing ratios; and organizational protocols. Distress was crosscutting and present in all four themes. CONCLUSIONS: The findings illuminate how prehospital providers become mediators between NHs and emergency departments by managing tension, conflict, and challenges in patient care between these systems and suggest the importance of further exploration of interactions between LTC staff, prehospital providers, and emergency departments. Enhanced communication between LTC facilities and prehospital providers is important to address potentially inappropriate calls and transport requests and to identify means for collaboration in the care of sick frail residents. PMID- 29630431 TI - Gender-Based Violence, Physiological Stress, and Inflammation: A Cross-Sectional Study. AB - BACKGROUND: Female sex workers (FSWs) are at high risk for gender-based violence (GBV) and HIV infection. This study aimed to identify associations between GBV exposure in the past 12 months and biomarkers of physiologic stress and inflammation that may play a role in increased HIV risk among Kenyan FSWs. MATERIALS AND METHODS: Participating women responded to a detailed questionnaire on GBV and mental health. Plasma was collected for assessment of systemic C reactive protein (CRP) and interleukin-6 (IL-6) levels. Hair proximal to the scalp was collected to measure cortisol concentration. CRP and IL-6 were measured by enzyme-linked immunosorbent assay, and hair cortisol concentration was determined by enzyme immunoassay. Log-transformed biomarker values were compared across GBV exposure categories using Kruskal-Wallis or Wilcoxon rank sum tests. Multivariable linear regression was used to explore associations between recent GBV and hair cortisol concentration. RESULTS: Two hundred eighty-three women enrolled, of whom 112 (39.6%) reported physical, sexual, or emotional violence in the past 12 months, 134 (47.3%) reported more remote exposure, and 37 (13.1%) reported no exposure. CRP and IL-6 levels did not differ across groups (p = 0.57 and p = 0.62, respectively). Among 141 women who provided hair, cortisol concentrations were higher among recently exposed women compared to the other two groups combined (p = 0.02). In multivariable regression, recently exposed women had higher hair cortisol levels than remotely exposed or unexposed women (adjusted beta = 0.52, 95% confidence interval 0.02-1.02, p = 0.04). CONCLUSIONS: While CRP and IL-6 levels did not differ by GBV category, recent GBV was associated with increased hair cortisol concentration. GBV-related increases in cortisol could affect health outcomes and merit study in relation to HIV acquisition risk. PMID- 29630433 TI - Prospective evaluation of relationships between radiotherapy dose to masticatory apparatus and trismus. AB - AIMS: This feasibility study aimed to identify relationships between radiation doses to the masticatory apparatus as a combined block or as individual subunits with changes in trismus following radiotherapy. MATERIAL AND METHODS: Twenty patients from a single center were recruited prospectively as part of a randomized trial comparing proactive exercises in the management of trismus. Patients with stage III/IV oral cavity or oropharyngeal squamous cell cancers received intensity-modulated radiotherapy with concurrent systemic therapy. All patients had trismus prior to radiotherapy. Maximal inter-incisor distance (MID) was measured pre- and 6 months from the start of radiotherapy. Bilateral muscles of mastication: medial and lateral pterygoids (MP and LP), masseters (M), temporalis (T), temporomandibular joint (TMJ) were contoured on CT images. The block comprised all muscles excluding the TMJ below the orbital floor. Mean dose, equivalent uniform dose (EUD) and V35-V60 Gy were compared with change in MID. RESULTS: In six patients, the MID deteriorated at 6 months from the start of radiotherapy compared with 14 whose MID improved. No significant association was observed between age, gender, smoking, alcohol status, exercise compliance, cisplatin, tumor site, stage, V35-V60 Gy or EUD with change in MID. A clinical outlier was excluded. Without the outlier (n = 19), a significant association was seen between mean dose and change in MID at 6 months for the ipsilateral block (p = .01), LP (p = .04) and M (p < .01). All patients where trismus deteriorated at 6 months received mean doses >40 Gy to the block. CONCLUSION: Higher mean radiation doses to the ipsilateral block, LP and M were significantly associated with deterioration in trismus. Limiting dose to these structures to <=40 Gy for tumors not invading the masticatory muscles may improve treatment-related sequelae. The ipsilateral block, LP and M should be studied further as possible alternative avoidance structures in radiotherapy treatment planning. PMID- 29630434 TI - Nucleoside diphosphate kinase B promotes osteosarcoma proliferation through c Myc. AB - Osteosarcoma (OS) is one of the most common primary bone tumors and has a high disablity rate and case-fatality rate. The protracted stagnancy of the chemotherapy program and surgical technology for OS treatment prompted us to focus on the mechanisms of cancer carcinogenesis progression in OS. Nucleoside diphosphate kinase B (NME2) is a type of nucleoside diphosphate kinase that plays an important role in cellular processes. In this study, we report overexpression of NME2 in OS cell lines and correlate this overexpression with the clinicopathologic features of osteosarcoma. We used si-NME2 to downregulate expression of NME2 in OS cell lines. The results of the CCK8 and clone forming assays show that NME2 promotes OS cell line proliferation. Western blot assays show that deregulation of NME2 results in enhanced the expression of c-Myc, which promotes OS proliferation. PMID- 29630435 TI - Autosomal dominant retinitis pigmentosa with macular involvement associated with a disease haplotype that included a novel PRPH2 variant (p.Cys250Gly). AB - BACKGROUND: It is known that PRPH2 variants appear to be rare causes of retinitis pigmentosa (RP) in the Japanese population. The purpose of this study was to describe clinical and genetic features in autosomal dominant RP (adRP) patients with a novel disease-causing variant in the PRHP2 gene. MATERIALS AND METHODS: A total of 57 unrelated Japanese probands with adRP were investigated in this study. Comprehensive ophthalmic examinations include fundus photography, fundus autofluorescence imaging, spectral-domain optical coherence tomography, and electroretinography. Whole exome sequencing or Sanger sequencing for 25 targeted exons of multiple genes causing adRP was performed to identify disease-causing variants. Co-segregation and haplotype analyses were performed to determine a disease-causing gene variant and its haplotype. RESULTS: Genetic analysis identified a novel heterozygous PRPH2 variant (c.748T>G, p.Cys250Gly) as disease causing in four probands from four families. The variant co-segregated with the RP phenotype in the eight affected patients in all families. At least three of the four families shared the same haplotype for the variant allele. Clinically, seven of the eight affected patients exhibited typical RP presentation, as well as variable macular involvement including cystoid macular change, vitelliform like appearance, choroidal neovascularization, and macular atrophy. CONCLUSIONS: The same disease haplotype that included a novel PRPH2 variant (p.Cys250Gly) was identified in three of the four Japanese families with adRP, suggesting a founder effect. Our clinical findings indicate that adRP caused by the p.Cys250Gly variant may accompany macular involvement with high frequency. PMID- 29630436 TI - The Apnea-Hypopnea Index Underestimates Systemic Inflammation in Women with Sleep Disordered Breathing. AB - BACKGROUND: Evidence suggests that sleep-related respiratory and related metabolic compromise may vary between females and males with sleep-disordered breathing (SDB). Our purpose was to elucidate possible gender differences in sleep-associated respiratory and inflammatory parameters in patients with SDB. MATERIALS AND METHODS: A consecutive number of SDB patients (46 females and 167 males) who underwent polysomnography were retrospectively reviewed. Fibrinogen and C-reactive protein (CRP) concentration, apnea index (ApnI), hypopnea index (HypI), apnea-hypopnea index (AHI), average and minimal SpO2, duration of snoring, age, and body mass index (BMI) were compared between sexes. Spearman's rho correlation coefficients between parameters were also calculated. RESULTS: ApnI and AHI were significantly higher in males. Correlation analysis revealed striking gender differences: only in females, CRP concentration was highly correlated with snoring duration (r = 0.4393), BMI (r = 0.7147), minimal SpO2 (r = -0.4357), and average SpO2 (r = -0.4547); in females, HypI was more strongly correlated with AHI (r = 0.8778), average SpO2 (r = -0.5765), minimal SpO2 (r = 0.5817), and fibrinogen concentration (r = 0.4614) than in males (r = 0.4373; 0.3295; -0.2969; and 0.0887, respectively); in females, age had a much more pronounced effect on ApnI, HypI, AHI, average oxygen saturation (SaO2), minimal SaO2, snoring duration, and CRP and fibrinogen concentration. CONCLUSIONS: Respiratory compromise in females with SDB is more strongly associated with systemic inflammation than in males with SDB. Although females display a pathological AHI less frequently than males, they reach quite similar pathological SaO2, CRP, and fibrinogen values. Therefore, AHI may underestimate the pathophysiological systemic effects of SDB in females. PMID- 29630437 TI - Mechanical and Oral Antibiotic Bowel Preparation in the Era of Minimally Invasive Surgery and Enhanced Recovery. AB - INTRODUCTION: In the modern era of minimally invasive colorectal surgery and enhanced recovery pathways, the value of preoperative bowel preparation remains debated. In this review, we evaluate evidence regarding the use of mechanical bowel preparation (MBP) and oral antibiotic bowel preparation to make recommendations for their application in contemporary practice. METHODS: We searched the PubMed database through December 2017 for relevant randomized controlled trials, Cochrane Reviews, American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) database studies, and other reviews pertaining to MBP and oral antibiotic bowel preparation in elective colorectal surgery and conducted a narrative review. RESULTS: The combination of MBP and oral antibiotics reduces the incidence of surgical site infection, anastomotic leak, and postoperative sepsis. MBP improves laparoscopic surgical viewing and facilitates intraoperative manipulation of the bowel in minimally invasive surgery. CONCLUSION: Based on existing data, we recommend that preoperative care includes MBP and oral antibiotics in elective minimally invasive colorectal surgery. PMID- 29630438 TI - Immune response to the hepatitis B antigen in the RTS,S/AS01 malaria vaccine, and co-administration with pneumococcal conjugate and rotavirus vaccines in African children: A randomized controlled trial. AB - The RTS,S/AS01 malaria vaccine (Mosquirix) reduces the incidence of Plasmodium falciparum malaria and is intended for routine administration to infants in Sub Saharan Africa. We evaluated the immunogenicity and safety of 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV; Synflorix) and human rotavirus vaccine (HRV; Rotarix) when co administered with RTS,S/AS01 ( www.clinicaltrials.gov NCT01345240) in African infants. 705 healthy infants aged 8-12 weeks were randomized to receive three doses of either RTS,S/AS01 or licensed hepatitis B (HBV; Engerix B) vaccine (control) co-administered with diphtheria-tetanus-acellular pertussis-Haemophilus influenzae type-b-conjugate vaccine (DTaP/Hib) and trivalent oral poliovirus vaccine at 8-12-16 weeks of age, because DTaP/Hib was not indicated before 8 weeks of age. The vaccination schedule can still be considered broadly applicable because it was within the age range recommended for EPI vaccination. PHiD-CV or HRV were either administered together with the study vaccines, or after a 2-week interval. Booster doses of PHiD-CV and DTaP/Hib were administered at age 18 months. Non-inferiority of anti-HBV surface antigen antibody seroprotection rates following co-administration with RTS,S/AS01 was demonstrated compared to the control group (primary objective). Pre-specified non-inferiority criteria were reached for PHiD-CV (for 9/10 vaccine serotypes), HRV, and aP antigens co administered with RTS,S/AS01 as compared to HBV co-administration (secondary objectives). RTS,S/AS01 induced a response to circumsporozoite protein in all groups. Pain and low grade fever were reported more frequently in the PHiD-CV group co-administered with RTS,S/AS01 than PHiD-CV co-administered with HBV. No serious adverse events were considered to be vaccine-related. RTS,S/AS01 co administered with pediatric vaccines had an acceptable safety profile. Immune responses to RTS,S/AS01 and to co-administered PHiD-CV, pertussis antigens and HRV were satisfactory. PMID- 29630439 TI - Immunogenicity and safety of a second booster dose of an acellular pertussis vaccine combined with reduced antigen content diphtheria-tetanus toxoids 10 years after a first booster in adolescence: An open, phase III, non-randomized, multi center study. AB - Pertussis is a highly contagious disease, for which periodic peaks in incidence and an increasing number of outbreaks have been observed over the last decades. The reduced-antigen-content tetanus-diphtheria-acellular pertussis vaccine (Tdap) can be used to boost individuals aged >=10 years, vaccinated in infancy with a diphtheria-tetanus-acellular pertussis vaccine (DTaP), to reduce pertussis morbidity and maintain protection against diphtheria and tetanus throughout adolescence and adulthood. This phase III, open-label, non-randomized, multicenter follow-up study (NCT01738477) enrolled 19-30-year-old participants from the United States who had received booster vaccination 10 years earlier with either Tdap (Tdap group) or Td (Td group). In total, 128 (Tdap group) and 37 (Td group) participants received Tdap vaccination. After administration of Tdap, all participants were seroprotected (antibody concentrations >=0.1 international units [IU]/ml) against diphtheria and tetanus. Immune responses to a second Tdap dose in the Tdap group were shown to be non-inferior to responses elicited by a first Tdap dose in the Td group for diphtheria and tetanus and to a 3-dose DTaP vaccination during infancy for pertussis antigens (primary objectives). Post booster vaccination, all participants in both groups had antibody concentrations above assay cut-offs and antibody geometric mean concentrations increased by 3.8 15.5-fold compared to pre-booster levels for all antigens. The incidence of adverse events was similar in the Td (80.6%) and Tdap (85.6%) groups (no serious adverse events reported). A Tdap dose administered after previous Td or Tdap vaccination was shown to be immunogenic and well-tolerated in young adults, supporting repeated vaccination with Tdap at 10-year intervals. PMID- 29630440 TI - A Simulation Model to Support Laparoscopic Pyloromyotomy Teaching. AB - INTRODUCTION: A key concern regarding laparoscopic pyloromyotomy (LP) lies with the process of learning this skill. The learning processes for open pyloromyotomy and LP appear to be different, with an earlier increased risk of perforation or incomplete pyloromyotomy (IP) for LP. Our aim was to develop a simple simulation tool to reduce these specific complications. MATERIALS AND METHODS: A model of hypertrophic pyloric stenosis was created and inserted into a pediatric laparoscopic surgery simulator. A cohort of experts completed a six-item questionnaire, using a 4-point scale regarding the model's realistic nature and accuracy. Evaluation of the LP procedure was based on a dedicated Objective Structured Assessment of Technical Skills score. Surgical residents and students were enrolled for the final evaluation to assess the relative performance of trainees who had practiced with this model (Group 1) versus those who had observed its use (Group 2). RESULTS: Reproducibility of the model construction was considered to be satisfactory. The experts agreed that the model accurately simulated essential components of LP (mean 3.03 +/- 0.7). They scored significantly better than the residents (27.2 +/- 1.8 versus 22.8 +/- 2.9; P < .001), with a lower rate of complications. Group 1 (39 trainees) performed significantly better than Group 2 (26 trainees), with a significant decrease in the risk of an IP (P < .05). CONCLUSIONS: This model appears to be sufficiently accurate to teach LP. In light of this, it can be considered to be an efficient tool for LP simulation teaching in our fellows' educational program. PMID- 29630442 TI - High Thyroid Cancer Mortality Rate in Japan: A Result of Nonaggressive Treatment Strategy, or Just an Aging Population? PMID- 29630441 TI - Mind the Gap: What explains the education-related inequality in missed opportunities for vaccination in sub-Saharan Africa? Compositional and structural characteristics. AB - Missed opportunities for vaccination (MOV) is an important barrier hindering full immunisation coverage among eligible children. Though factors responsible for MOV are well documented in literature, little attention has been paid to the role of inequalities. The aim of this study is to examine the association between structural or compositional factors and education inequalities in MOV. Blinder Oaxaca decomposition technique was used to explain the factors contributing to the average gap in missed opportunities for vaccination between uneducated and educated mothers in sub-Saharan Africa using DHS survey data from 35 sub Saharan African countries collected between 2007 and 2016. The sample contained 69,657 children aged 12 to 23 months. We observed a wide variation and inter-country differences in the prevalence of missed opportunity for vaccination across populations and geographical locations. Our results show that the prevalence of MOV in Zimbabwe among uneducated and educated mothers was 9% and 21% respectively while in Gabon corresponding numbers were 85% and 89% respectively. In 15 countries, MOV was significantly prevalent among children born to uneducated mothers (pro-illiterate inequality) while in 5 countries MOV was significantly prevalent among educated mothers (pro-educated inequality). Our results suggest that education-related inequalities in missed opportunities for vaccination are explained by compositional and structural characteristics; and that neighbourhood socio-economic status was the most important contributor to education-related inequalities across countries followed by either the presence of under-five children, media access or household wealth index. The results showed that differential effects such as neighbourhood socio-economic status, presence of under-five children, media access and household wealth index, primarily explained education-related inequality in MOV. Interventions to reduce gaps in education related inequality in MOV should focus on social determinants of health. PMID- 29630443 TI - Safety Assessment for Thoracoscopic Day Case Surgery in Children with Congenital Pulmonary Malformation. AB - BACKGROUND: No data exist evaluating the utilization and safety of outpatient thoracoscopy in children. The aim of this study was to investigate the safety of outpatient thoracoscopy and to assess parental opinions on the advantages and disadvantages of a pediatric thoracoscopy outpatient setting. METHODS: A retrospective review of data from patients treated by thoracoscopy for congenital pulmonary malformation between 2013 and 2016 was performed. Study focused on patients who underwent outpatient thoracoscopy. All were placed in a flank position and underwent a three-port (5-mm optical trocar and two 5-mm trocars) thoracoscopy. Insufflation pressure required was 5 mmHg with bilateral lung ventilation. Pain control was provided with multimodal postoperative analgesia and the use of paravertebral block for regional analgesia. No drain was inserted. Outcomes of interest included 30-day overall morbidity, readmission, reoperation, and parental opinions through a phone call questionnaire. RESULTS: A total of 37 thoracoscopies were identified; 11 (30%) with a median age of 5.3 months (4.2 12.3) were performed as an outpatient procedure (10 sequestration, 1 bronchogenic cyst). Median operating time was 51 minutes (34-87). No conversion and no transfusion occurred. No complications occurred (no morbidity, no readmission, and no reoperation). According to parents' view the outpatient setting has no disadvantages. CONCLUSION: This first analysis of a small monocentric dataset demonstrates that pediatric patients can safely undergo thoracoscopy, an outpatient procedure, with a high rate of parental satisfaction. PMID- 29630444 TI - The case for ring vaccinations with special consideration of oral cholera vaccines. AB - Ring vaccinations create a zone of immune contacts around a case to prevent further disease transmission and have been successfully employed in the eradication of smallpox and the control of other infections. Millions of oral cholera vaccine (OCV) doses have been effectively deployed through mass vaccination campaigns. But there are situations when the OCV supply, resources, and time are limited and alternative strategies need to be considered. People living in close proximity of cholera cases often share risk factors such as contaminated water supply and poor sanitation. Targeting people within a given radius around a cholera case for intervention including vaccination, improved water supply and sanitation may be a practical and effective approach. A ring oral cholera vaccination strategy could be considered before, after or as an alternative to a mass vaccination approach. We review here the use of the ring vaccinations in general and specifically during cholera outbreaks. PMID- 29630445 TI - Removal of Nonylphenol by using Fe-doped NaBiO3 compound as an efficient visible light-heterogeneous Fenton-like catalyst. AB - Fe-doped NaBiO3 nanoscaled compounds were prepared by hydrothermal method and evaluated as a highly efficient photo-Fenton-like catalyst under visible light irradiation. The Fe-doped NaBiO3 compound had a specific surface area of 41.42 m2 g-1, which is considerably larger than that of NaBiO3 nanoparticles (28.81 m2 g 1). The compound exhibited an excellent visible light-Fenton-like catalysis activity, which is influenced by the iron content of the compound and the pH value of the solution. Under the optimal conditions, the Fe-doped NaBiO3 compound led to fast degradation of Nonylphenol with an apparent rate constant of 5.71 * 10-2 min-1, which was 8.23-fold of that achieved by using NaBiO3. The significantly enhanced visible light-Fenton-like catalytic property of the Fe doped NaBiO3 was attributed to the large surface area and the high adsorption capacity of the compound, and the Fenton catalytic ability of iron in the compound. PMID- 29630446 TI - 47-mG2a: A Mouse IgG2a-Type of PcMab-47 Useful for Detecting Podocalyxin in Esophageal Cancers by Immunohistochemistry. AB - Esophageal cancer is one of the highly malignant cancers. It comprises two of the most common histological tumor types: squamous cell carcinoma (SCC) and adenocarcinoma. SCC accounts for about 90% of esophageal cancers. Despite developments in treatment strategies, the prognosis and survival rate remain poor. Podocalyxin (PODXL) is a highly glycosylated type-I transmembrane protein. It is expressed in normal tissues such as kidney, heart, breast, and pancreas. Upregulation of PODXL correlates with tumor progression, invasion, and metastasis. Therefore, this glycoprotein could be a potential biomarker for predicting the prognosis of some cancers, for instance, brain, colorectal, oral, lung, bladder, prostate, and ovarian cancers. We previously developed a specific and sensitive anti-PODXL monoclonal antibody (mAb), PcMab-47 (mouse IgG1, kappa) and its mouse IgG2a-type (47-mG2a). We showed their utility in immunohistochemical analysis of oral cancers. Herein, we demonstrate that PcMab 47 and 47-mG2a can also be used to detect esophageal squamous cell carcinoma (ESCC) with this technique. These two antibodies, respectively, stained 123/130 (94.6%) and 127/130 (97.7%) ESCC cases, indicating that they can detect PODXL with high sensitivity in this carcinoma. Of more than 3+ cases, 47-mG2a was more effective than PcMab-47, respectively, staining 56/127 (44.1%) and 41/123 (33.3%). Therefore, 47-mG2a can be used for the detection of PODXL in ESCC using immunohistochemical analysis. PMID- 29630447 TI - Lower Senescence of Adipose-Derived Stem Cells than Donor-Matched Bone Marrow Stem Cells for Surgical Ventricular Restoration. AB - Surgical ventricular reconstruction (SVR) can restore cardiac function for left ventricular aneurysm to some extent. However, the patches used in this treatment have some limitations such as stiffness and calcification. Engineering heart tissues (EHTs) have emerged as a promising biomaterial to repair damaged heart. Nevertheless, selecting optimal candidate cells for EHTs has been controversial. Aging is a major consideration for seed cells derived from elderly patients. Hence, this study was aimed to assess the proliferation of, antiapoptosis potential of, and expression of senescence-associated factors (eg, SA-beta-Gal, cyclin-dependent kinase inhibitor 2A (P16), cyclin-dependent kinase inhibitor 1 (P21) in adipose-derived stem cells (ADSCs), and bone marrow stem cells (BMSCs) in vitro. In addition, cardiac function, cell survival, and angiogenesis of ADSCs and BMSCs after SVR were assessed in vivo. The in vitro results showed that old ADSCs (OAs) grew faster; expressed lower levels of SA-beta-Gal, P16, and P21; and possessed more pronounced antiapoptosis activity than old BMSCs (OBs). The in vivo results demonstrated that 28 days after patch implantation, animals that received OAs patches showed better restoration of cardiac function than animals that received OBs patches. Meanwhile, old ADSCs possessed more potential regarding cell survival and angiogenesis. These results suggest that ADSCs may be superior to BMSCs with regard to autologous cell transplantation in elderly patients. PMID- 29630448 TI - Sorafenib-loaded polymeric micelles as passive targeting therapeutic agents for hepatocellular carcinoma therapy. AB - AIM: The clinical application of sorafenib is limited because of its hydrophobicity, low bioavailability and unsatisfying treatment effect. Therefore, sorafenib-loaded PEG-poly (epsilon-caprolactone) micelles (SF micelles) were fabricated for sorafenib delivery. MATERIALS & METHODS: In vitro assays investigated the solubility, dispersity, stability, cytotoxicity and uptake capacity of SF micelles. In vivo biodistribution and therapeutic effects were studied using HepG2-Luc tumor-bearing mice. RESULTS: SF micelles had a regular spherical structure with good water solubility. In vivo imaging results showed PEG-poly (epsilon-caprolactone) micelles could elevate the sorafenib concentration in tumor tissues. Meanwhile, SF micelles exhibited higher tumor growth inhibition in vivo. CONCLUSION: SF micelles might be a potential drug delivery system, which could enhance the therapeutic effects of sorafenib. PMID- 29630449 TI - Nardostachys jatamansi DC Extract Alleviates Insulin Resistance and Regulates Glucose Metabolism in C57BL/KsJ-db/db Mice Through the AMP-Activated Protein Kinase Signaling Pathway. AB - This study investigated whether Nardostachys jatamansi DC extract (NJE) improved insulin sensitivity and suppressed hepatic glucose production in an animal model of type 2 diabetes. C57BL/KsJ-db/db mice were divided into three dietary groups: regular diet (control), NJE, and rosiglitazone. After 6 weeks of feeding, blood glucose, glycosylated hemoglobin, and plasma insulin levels were significantly lower in NJE than in diabetic control group mice. The oral glucose tolerance test also revealed a positive effect of NJE on increasing insulin sensitivity. The homeostatic index of insulin resistance was significantly lower in NJE than in diabetic control group mice. NJE markedly lowered the plasma lipid concentration compared to diabetic control group mice. In the skeletal muscle, the expression of phosphorylated AMP-activated protein kinase, pAkt substrate of 160 kDa, and plasma membrane glucose transporter type 4 increased more in NJE compared to diabetic control group mice. NJE also decreased the expression of glucose-6 phosphatase and phosphoenolpyruvate carboxykinase in the liver. These findings demonstrate that NJE alleviates hyperglycemia by improving insulin sensitivity and inhibiting gluconeogenesis in the liver. PMID- 29630450 TI - Comparison of the Effects of Nonfermented and Fermented Panax ginseng Root Against Hypertriglycemia in High-Fat Diet-Fed Mice. AB - Panax ginseng (P. ginseng C.A. Meyer, Araliaceae) is used as a therapeutic agent for various diseases. P. ginseng saponins, known as ginsenosides, are the main bioactive compounds responsible for its pharmacological activities. In this work, we have developed a new method of P. ginseng root processing termed solid-state fermentation and examined its effects compared with nonfermented P. ginseng. Mice were fed a high-fat diet (HFD) to induce hyperlipidemia and then received 100 mg.kg bw-1.day-1 of fermented or nonfermented P. ginseng orally for 3 weeks. We assessed the activities of lipogenic pathways and lipid levels in the liver and plasma. The administration of either nonfermented or fermented P. ginseng improved hepatic lipid transfer protein profiles. Nonfermented P. ginseng exhibited significant effects on the regulation of lipid synthesis and oxidation. However, apolipoprotein A4 (apoA4) expression was increased by the administration of fermented P. ginseng. When ginsenosides were analyzed by high-performance liquid chromatography (HPLC), the amounts of the ginsenosides, Rg2, Rc, Rh1(S), Rh1(R), and Rd, were increased by fermentation, with Rd becoming a major constituent of fermented P. ginseng. These findings imply that nonfermented P. ginseng improves hypertriglycemia in HFD-fed mice through regulation of the hepatic lipogenic pathway. In contrast, the effects of fermented P. ginseng were mediated through increased apoA4, leading to decreased triglycerides. The HPLC profiles of ginsenosides suggest that the compositional changes in P. ginseng caused by fermentation processing could be useful in the development of novel triglyceride-lowering therapies. PMID- 29630452 TI - Infections and Inflammation Occurring in the Subretinal Space. PMID- 29630451 TI - Surgical Site and Graft Infections in Endovascular and Open Abdominal Aortic Aneurysm Surgery. AB - BACKGROUND: Surgical site infections (SSIs) constitute one of many major complications after aortic aneurysm surgery and its details and outcome have not been evaluated extensively. This research evaluates the incidence and outcome of SSI and graft infection in open and endovascular abdominal aortic aneurysm surgery. PATIENTS AND METHODS: A retrospective study was performed, including all patients who underwent surgery for aortoiliac aneurysmatic disease between January 2000 and December 2016 in the Amphia Hospital, Breda, The Netherlands. Surgical site infections were defined in accordance with criteria of the U.S. Centers for Disease Control and Prevention (CDC). Aortic graft infection was diagnosed by a combination of computed tomography imaging and microbiologic results. RESULTS: Between January 2000 and December 2016, 845 patients (mean age, 72.80 +/- 7.15 y, 86.3% male) underwent abdominal aneurysm surgery (477 endovascular, 368 open). The total SSI rate was 3.1% (12 endovascular [2.5%], 14 open [3.8%], p = 0.318) with 0.8% deep SSI (26.9% of SSIs). No difference in SSIs was found between acute and elective surgery (2.9% vs. 3.1%, p = 1.000). Patients with SSI had a longer duration of stay (mean, 27.65 +/- 30.74 d vs. 9.79 +/- 12.50 d, p < 0.0001) but no difference in 30-day or 1-year mortality. Twenty-four graft infections occurred (4.3% of open vs. 1.7% of endovascular surgery, p = 0.023) of which 20 (83.3%) required surgery. Two-year mortality was higher when graft infections occurred (33.3% vs. 16.3%, p = 0.046). Surgical site infections (odds ratio [OR] 7.10, 95% [CI] 2.10-23.98) and mycotic aneurysms (OR 9.38, 95% CI 1.78-54.19) are independent determinants for graft infections. CONCLUSION: This study shows that SSIs after endovascular aortic surgery are as common as after open aortic surgery. Furthermore, this study supports the concept that aortic graft infection is highly associated with SSIs and mycotic aneurysms. Studies evaluating the prevention or early diagnosis of graft infection after SSIs through intensified imaging follow-up or even long-term antibiotic treatment should be considered. PMID- 29630454 TI - Human Vaccines & Immunotherapeutics: News. PMID- 29630455 TI - Letter from the Editor. PMID- 29630456 TI - Trends in age at first marriage in women and related factors: A population-based study in southwestern Iran. AB - Marriage and related processes seem to show individual tendencies but are in fact social phenomena. The aim of this study was to identify, among women, trends in age at first marriage and its related factors. In this cross-sectional study, the target population was women in households in Fars Province, Iran. To identify main effects of variables associated with age at marriage, multiple linear regression modeling was used without interactions. Women's age, women's and their husbands' occupations and educational levels, and place of residence were included in multiple linear regression modeling. A total of 3074 ever-married women were interviewed. A steep upward trend over time in age marriage was observed. The mean age at first marriage was 16.9 +/- 3.4 years in women who married during the period from 1954 to 1974, and 21.9 +/- 4.1 years among those who married during 2005-2014. Age at first marriage was significantly positively associated with women's and men's educational levels and with husband's employment status as laborers (p = 0.017) and negatively associated with husbands being employees (compared to being unemployed) (p < 0.001). Health providers should focus on increasing public awareness of factors associated with early and with delayed marriage. PMID- 29630458 TI - The Rosalie Wolf Memorial Lecture: Abuse-free Care in a World of Age-friendly Health Systems. PMID- 29630457 TI - How acceptable is paternalism? A survey-based study of clinician and nonclinician opinions on paternalistic decision making. AB - We conducted an empirical study to explore clinician and lay opinions on the acceptability of physician paternalism. Respondents read a vignette describing a patient with brain hemorrhage facing urgent surgery that would be lifesaving but would result in long-term severe disability. Cases were randomized to show either low or high surrogate distress and certain or uncertain prognosis, with respondents rating the acceptability of not offering brain surgery. Clinicians (N = 169) were more likely than nonclinicians (N = 649) to find the doctor withholding surgery acceptable (30.2% vs. 11.4%, p <= 0.001). Among clinicians, the doctor withholding surgery was more acceptable when prognosis was certain to be poor (odds ratio [OR] 2.04, 95% confidence interval [CI] 1.04, 4.01). There was no effect of surrogate distress on clinician ratings. Responses among lay public were more variable. Given the differences in attitudes across clinicians and lay public, there is an ongoing need to engage stakeholders in the process of end-of-life decision making. PMID- 29630459 TI - Attachment Style, Perceived Loneliness, and Psychological Well-Being in Smoking and Non-Smoking University Students. AB - The growing rate of smoking cigarettes among the youths necessitates examining its contributing factors. Accordingly, we aimed to compare smoking and nonsmoking university students in their attachment styles, perceived loneliness, and psychological well-being. To this end, we recruited 100 current smokers and 100 nonsmoking students by using a convenience sampling method from Shahid Beheshti University, Tehran, Iran. All participants completed the Adult Attachment Scale, Loneliness Scale, and General Health Questionnaire. Data analysis indicated that compared to nonsmokers, smokers had a more anxious attachment style and they felt lonelier. Moreover, current results showed that smokers suffered from higher rates of psychological problems than nonsmokers. These results suggest that smoking is influenced by a set of psychological factors and therefore, prevention and treatment programs targeting these factors may be effective in reducing the rate of smoking cigarettes among university students. PMID- 29630460 TI - Evaluating Diagnostic Accuracy of Noninvasive Tests in Assessment of Significant Liver Fibrosis in Chronic Hepatitis C Egyptian Patients. AB - Stage of liver fibrosis is critical for treatment decision and prediction of outcomes in chronic hepatitis C (CHC) patients. We evaluated the diagnostic accuracy of transient elastography (TE)-FibroScan and noninvasive serum markers tests in the assessment of liver fibrosis in CHC patients, in reference to liver biopsy. One-hundred treatment-naive CHC patients were subjected to liver biopsy, TE-FibroScan, and eight serum biomarkers tests; AST/ALT ratio (AAR), AST to platelet ratio index (APRI), age-platelet index (AP index), fibrosis quotient (FibroQ), fibrosis 4 index (FIB-4), cirrhosis discriminant score (CDS), King score, and Goteborg University Cirrhosis Index (GUCI). Receiver operating characteristic curves were constructed to compare the diagnostic accuracy of these noninvasive methods in predicting significant fibrosis in CHC patients. TE FibroScan predicted significant fibrosis at cutoff value 8.5 kPa with area under the receiver operating characteristic (AUROC) 0.90, sensitivity 83%, specificity 91.5%, positive predictive value (PPV) 91.2%, and negative predictive value (NPV) 84.4%. Serum biomarkers tests showed that AP index and FibroQ had the highest diagnostic accuracy in predicting significant liver fibrosis at cutoff 4.5 and 2.7, AUROC was 0.8 and 0.8 with sensitivity 73.6% and 73.6%, specificity 70.2% and 68.1%, PPV 71.1% and 69.8%, and NPV 72.9% and 72.3%, respectively. Combined AP index and FibroQ had AUROC 0.83 with sensitivity 73.6%, specificity 80.9%, PPV 79.6%, and NPV 75.7% for predicting significant liver fibrosis. APRI, FIB-4, CDS, King score, and GUCI had intermediate accuracy in predicting significant liver fibrosis with AUROC 0.68, 0.78, 0.74, 0.74, and 0.67, respectively, while AAR had low accuracy in predicting significant liver fibrosis. TE-FibroScan is the most accurate noninvasive alternative to liver biopsy. AP index and FibroQ, either as individual tests or combined, have good accuracy in predicting significant liver fibrosis, and are better combined for higher specificity. PMID- 29630461 TI - Impacts of feedlot floor condition, deposition frequency, and inhibitors on N2O and CH4 emissions from feedlot dung and urine patches. AB - : Patches of dung and urine are major contributors to the feedlot gas emissions. This study investigated the impacts of dung deposition frequency (partly reflecting animal stocking density of a feedlot), dairy feedlot floor conditions (old floor indicated with the presence of consolidated manure pad [CMP] vs. new floor with the absence of consolidated manure pad [CMPn]), and application of dicyandiamide (DCD) and hydroquinone (HQ) on nitrous oxide (N2O) and methane (CH4) emissions from patches in the laboratory, and the integrative impacts were expressed in terms of global warming potential (CO2-equivalent). Dung deposition frequency, feedlot floor condition, and application of inhibitors showed inverse impacts on N2O and CH4 emissions from patches. Greenhouse gas (GHG) emissions from the dung, urine, and dung+urine patches on the CMP feedlot surface were approximately 7.48, 87.35, and 7.10 times those on the CMPn feedlot surface (P < 0.05). Meanwhile, GHG emissions from CMP and CMPn feedlot surfaces under high deposition frequency condition were approximately 10 and 1.7 times those under low-frequency condition. Moreover, application of HQ slightly reduced the GHG emission from urine patches, by 14.9% (P > 0.05), while applying DCD or DCD+HQ significantly reduced the GHG, by 60.3% and 65.0%, respectively (P < 0.05). Overall, it is necessary to include feedlot management such as animal stocking density and feedlot floor condition to the process of determining emission factors for feedlots. In the future, field measurements to quantitatively evaluate the relative contribution of nitrification and denitrification to the N2O emissions of feedlot surfaces are highly required for effective N2O control. IMPLICATIONS: This study shows that feedlot CH4 and N2O emissions inversely respond to the dicyandiamide (DCD) application. Applying DCD significantly reduces GHG emissions of feedlot urine patches. Feedlot floor condition and stocking density strongly impact feedlot GHG emissions. Including feedlot floor condition and stocking density in the feedlot EF determining process is necessary. PMID- 29630462 TI - Weight Loss Associated With Consumption of Apples: A Review. AB - Apples are known as a major source of polyphenols, dietary fiber, carotenoids, and other nutrients. There are many documents and studies that show fruit polyphenols likely promote anti-obesity effects and exert their beneficial effects via scavenging free radicals, regulating gene expression, and altering signal transduction in target cells and tissues, especially fat tissues.The goal of this review is to presenti the major components of apple and the evidence that indicates its potential to diminution weight gain risk from in vitro, animal, and epidemiological and clinical studies. This review summarizes data about the apple and apple products that been have reported to reduce weight gain by various mechanisms, including antioxidant, antiproliferative, and cell signaling pathways. An extensive search was performed in PubMed, Science Direct, Scopus, and Google Scholar to identify human, animal, and cell culture studies on the association between weight loss and apple consumption, published from inception up to journey 15, 2017. The feeding of apples rats (7-10 mg/kg/d) in different forms in 8 experiments have shown that this caused weight loss during 3 to 28 weeks. In agreement with this, the obtained results from 5 experiments on humans have revealed that consumption of the whole apple or apple juice (240-720 mg/d) in 4-12 weeks by fat people can cause weight loss. Experiments on animals and humans have shown that the consumption of apples in different forms can cause weight loss in overweight ones. However, the main questions are which kind of apple, which part of it, how much, and how long overweight persons should consume them to reduce their body fat and body mass index (BMI). Then, it is necessary to do a meta-analysis to show how these factors affect the body fat percentage and whether this weight-lowering effect is statistically significant or not. PMID- 29630465 TI - The American Telemedicine Association ATA18 Conference Abstracts. PMID- 29630463 TI - Medicaid retrenchment politics: fragmented or unified? AB - Medicaid has grown substantially over time; indeed, more than half of all Americans have some connection to the program. Considering that Medicaid retrenchment is the centerpiece of recent proposals to repeal and replace the Patient Protection and Affordable Care Act, we ask: How will the American public react to massive reductions in Medicaid funding? Using a nationally representative survey, our study investigates whether adults with elderly parents who have used long-term care services and supports (LTSS), compared to other constituency groups, (1) perceive the Medicaid program as more important, (2) are more knowledgeable about program benefits, and (3) are more likely to oppose Medicaid funding cuts. Results show that people with any connection to the Medicaid program are more likely to view the program as important than those with no connection. However, when it comes to understanding specific Medicaid benefits and protecting Medicaid against retrenchment, adults with elderly parents who have used LTSS are significantly more knowledgeable and more likely to favor protection, compared both to other connected groups and the nonconnected. These findings suggest that Medicaid retrenchment politics could be characterized by fragmentation and infighting among constituency groups, unless significant mobilizing work is done to create a broad-based Medicaid coalition. PMID- 29630466 TI - Trends and Topics. PMID- 29630468 TI - Protective effect of Paeoniae radix alba root extract on immune alterations in mice with atopic dermatitis. AB - Atopic dermatitis is a progressive inflammatory disease characterized by type 2 helper T cell (TH2) reactivity. The aim of this study was to examine the therapeutic effects of Paeoniae radix alba root extract using a murine model of atopic dermatitis. Atopic dermatitis was induced in a murine model characterized by immune alterations skewed toward TH2 reactivity and pathophysiological dermal alterations which resemble human atopic dermatitis. The root extract at 1% or 6% was applied to the mouse dorsal skin for 3 weeks following induction of atopic dermatitis. Splenocytes were stimulated with immobilized anti-CD3 for 48 h to measure cytokine production. Levels of serum IgE, IgG1, and IgG2a were quantitated. Epidermal thickness and numbers of skin mast cells were determined. Mice in which atopic dermatitis was induced displayed increased numbers of skin mast cells, increased frequency of scratching, elevated serum IgE levels, increased ratios of IgG1 to IgG2a, and ratios of IL-4 to IFN-gamma. The frequency of scratching was significantly decreased following application of 1% or 6% extract for 1 week. The root extract also reversed TH2 skewing, as serum IgE levels, ratio of serum IgG1 to IgG2a, and ratio of IL-4 to IFN-gamma production by in vitro-stimulated splenocytes were all suppressed following application of 1% or 6% extract for 3 weeks. Taken together Paeoniae radix alba root extract is suggested to reverse the immunological alterations and skin manifestations symptoms found in atopic dermatitis. PMID- 29630469 TI - Open-path, closed-path, and reconstructed aerosol extinction at a rural site. AB - : The Handix Scientific open-path cavity ringdown spectrometer (OPCRDS) was deployed during summer 2016 in Great Smoky Mountains National Park (GRSM). Extinction coefficients from the relatively new OPCRDS and from a more well established extinction instrument agreed to within 7%. Aerosol hygroscopic growth (f(RH)) was calculated from the ratio of ambient extinction measured by the OPCRDS to dry extinction measured by a closed-path extinction monitor (Aerodyne's cavity-attenuated phase shift particulate matter extinction monitor [CAPS PMex]). Derived hygroscopicity (relative humidity [RH] < 95%) from this campaign agreed with data from 1995 at the same site and time of year, which is noteworthy given the decreasing trend for organics and sulfate in the eastern United States. However, maximum f(RH) values in 1995 were less than half as large as those recorded in 2016-possibly due to nephelometer truncation losses in 1995. Two hygroscopicity parameterizations were investigated using high-time-resolution OPCRDS+CAPS PMex data, and the kappaext model was more accurate than the gamma model. Data from the two ambient optical instruments, the OPCRDS and the open path nephelometer, generally agreed; however, significant discrepancies between ambient scattering and extinction were observed, apparently driven by a combination of hygroscopic growth effects, which tend to increase nephelometer truncation losses and decrease sensitivity to the wavelength difference between the two instruments as a function of particle size. There was not a statistically significant difference in the mean reconstructed extinction values obtained from the original and the revised IMPROVE (Interagency Monitoring of Protected Visual Environments) equations. On average, IMPROVE reconstructed extinction was ~25% lower than extinction measured by the OPCRDS, which suggests that the IMPROVE equations and 24-hr aerosol data are moderately successful in estimating current haze levels at GRSM. However, this conclusion is limited by the coarse temporal resolution and the low dynamic range of the IMPROVE reconstructed extinction. IMPLICATIONS: Although light extinction, which is directly related to visibility, is not directly measured in U.S. National Parks, existing IMPROVE protocols can be used to accurately infer visibility for average humidity conditions, but during the large fraction of the year when humidity is above or below average, accuracy is reduced substantially. Furthermore, nephelometers, which are used to assess the accuracy of IMPROVE visibility estimates, may themselves be biased low when humidity is very high. Despite reductions in organic and sulfate particles since the 1990s, hygroscopicity, particles' affinity for water, appears unchanged, although this conclusion is weakened by the previously mentioned nephelometer limitations. PMID- 29630470 TI - Interprofessional training: Geriatrics and palliative care principles for primary care teams in an ACO. AB - There is a well-described need to increase the competence of the primary care workforce in the principles of geriatrics and palliative care, and as value-based payment models proliferate, there is increased incentive for the acquisition of these skills. Through a Geriatric Workforce Enhancement Program grant, we developed an adaptable curriculum around commonly encountered topics in palliative care and geriatrics that can be delivered to multidisciplinary clinicians in primary care settings. All participants in this training were part of an Accountable Care Organization (ACO) and were motivated to improve to care for complex older adults. A needs assessment was performed on each practice or group of learners and the curriculum was adapted accordingly. With the use of patient education and screening tools with strong validity evidence, the participants were trained in the principals of geriatrics and palliative care with a focus on advance care planning and assessing for frailty and functional decline. Comparison of pre- and post-test scores demonstrated increased confidence and knowledge in goals of care and basic geriatric assessment. Participants described feeling more able to address needs, have conversations around goals of care, and more able to recognize patients who would benefit from collaboration with geriatrics and palliative care. PMID- 29630471 TI - Physician Communication to Enhance Patient Acupuncture Engagement in Family Medicine. AB - Integrating complementary therapies (acupuncture) into conventional medicine has garnered recent support. Given the health benefits, low cost, and minimal risks, the military has advocated for acupuncture and begun training family medicine physicians. Little is known about the role of physician communication in patients' acupuncture engagement (uptake and adherence) in conventional medicine settings. We interviewed physicians (N = 15) and patients (N = 17) to capture physician communication they perceived affected treatment engagement. Data for each group were thematically analyzed. Physicians and patients prioritized different communication approaches and associated strategies. Physicians identified four approaches that enhance treatment engagement: (1) using shared decision-making (e.g., treatment options); (2) not being pushy (e.g., in tone); (3) carefully choosing language (e.g., Eastern versus Western terms); and (4) explaining treatment outcomes (e.g., efficacy). Patients also prioritized explaining treatment outcomes but differently (e.g., timing clarity), with two additional approaches: (5) talking with the same physician (e.g., continuity) and (6) being responsive to patient (e.g., flexibility). Findings highlight how physicians and patients prioritize patient-centered communication differently and how it is embedded within a unique, complex therapy. Data showcase authentic narratives that could be translated into physician communication skills training to promote treatment engagement in integrative care. PMID- 29630472 TI - Proanthocyanidins: novel treatment for psoriasis that reduces oxidative stress and modulates Th17 and Treg cells. AB - Psoriasis is a common, chronic, inflammatory skin disease that affects 2%-4% of the global population. Recent studies have shown that increased oxidative stress (OS) and T-cell abnormalities are central to the pathogenesis of this disease. The resulting reactive oxygen species (ROS) induces proliferation and differentiation of Th17/Th1/Th22 cells and inhibits the anti-inflammatory activities of regulatory T lymphocytes (Treg). Subsequent secretions of inflammatory cytokines, such as interleukin (IL)-17, IL-22, tumor necrosis factor alpha (TNF-alpha), and interferon-gamma (IFN-gamma), and vascular endothelial growth factor (VEGF), stimulate keratinocyte proliferation and angiogenesis. Proanthocyanidins are a class of flavonoids from plants and fruits, and have various antioxidant, anti-inflammatory, and anti-angiogenic properties. Numerous reports have demonstrated therapeutic effects of proanthocyanidins for various diseases. Among clinical activities, proanthocyanidins suppress cell proliferation, prevent OS, and regulate Th17/Treg cells. Because the pathogenesis of psoriasis involves OS and T cells dysregulation, we reviewed the effects of proanthocyanidins on OS, Th17 and Treg cell activities, and keratinocyte proliferation and angiogenesis. Data from multiple previous studies warrant consideration of proanthocyanidins as a promising strategy for the treatment of psoriasis. PMID- 29630473 TI - Identifying the Social Demographic Correlates of Suicide Bereavement. AB - We investigated the demographic correlates associated with suicide bereavement among a representative sample of U.S. adults from the 2016 General Social Survey. A secondary aim of this study was to use this representative data platform to cross-check official data findings of U.S. completed suicides. Questions on suicide bereavement were administered to 1,432 GSS 2016 respondents and these were cross-tabulated with various demographic and social activity variables included in this omnibus survey to investigate whether suicide bereaved respondents shared any distinctive demographic characteristics. Findings showed that friends of the suicide deceased person outnumbered the deceased's first degree relatives by at least 2 to 1. We also observed older, White, Non-Hispanic, and native born women were over-represented among the suicide bereaved. The suicide bereaved were also less likely to live in the Pacific region, and to live in the nation's largest cities, and were more likely to come from homes where a gun was owned by someone in the household. More of the suicide bereaved reported themselves to be in poorer physical health and bereaved women were more likely to be Facebook subscribers. These findings are consistent with other data on U.S. suicide patterns and the greater likelihood of firearms being utilized in suicide deaths. These revealed demographic correlates of suicide offer valuable information to helping agencies seeking to reach potential clients among the suicide bereaved. PMID- 29630474 TI - Association of sociodemographic and reproductive variables with menopause specific quality of life using principal component analysis. AB - We aimed to determine whether sociodemographic and reproductive variables jointly or independently were associated with menopause-specific quality of life (MENQOL). A total of 250 Bengali-speaking Hindu women (peri- and postmenopausal) were recruited from West Bengal, India. Data on MENQOL (vasomotor, physical, psychosocial, sexual, and quality-of-life domains), sociodemographic, and reproductive variables were collected. Principal component (PC) analysis was used to identify PCs for sociodemographic and/or reproductive variables: PC1 (sociodemographic), PC2 (sociodemographic and reproductive), PC3, and PC4 (reproductive). PC scores were used in multiple regression analyses to determine associations with MENQOL. For perimenopausal women, PC1 and PC3 were inversely associated with the sexual domain; PC2 was positively associated with vasomotor, sexual domain, and quality of life; and PC3 was positively associated with the physical domain. For postmenopausal women, PC1 and PC3 were inversely associated with the sexual and psychosocial domains, respectively; PC2 was positively associated with the sexual domain and quality of life; and PC4 was positively associated with the psychosocial domain. The factors associated with MENQOL PCs were similar for perimenopausal and postmenopausal women. Health planners should consider early and midlife factors associated with MENQOL to improve women's midlife health. PMID- 29630475 TI - Serologic Study of Bartonella henselae in Patients with Acute Undifferentiated Febrile Illness in Korea. AB - BACKGROUND: Bartonella infection is an emerging cause of acute febrile illness; however, its significance has not been thoroughly investigated. We studied the antibody specific to Bartonella henselae in patients with various febrile diseases in Korea. MATERIALS AND METHODS: A total of 177 patients with acute febrile illness who were managed at the Inha University Hospital from February 2012 to January 2013 were evaluated with an in-house immunofluorescent antibody test to detect B. henselae immunoglobulin G (IgG) antibody. The clinical features of the patients included fever of undetermined origin (n = 88 patients), lymphadenopathy (n = 28), febrile rash (n = 17), respiratory infection (n = 12), aseptic meningitis (n = 7), intra-abdominal infection (n = 5), arthritis (n = 4), and other conditions (n = 16). We reviewed the medical records of these patients and collected demographic data, clinical features, and their histories of animal exposure. RESULTS: Among the 177 patients with acute febrile illness, 23.7% (42/177) had elevated levels of IgG antibodies to B. henselae (>=1:160). Of these seropositive patients, 32.4% (12/37) had contact with animals and had developed arthralgia (29.5%), headache (25%), or lymphadenopathy (15.9%). Seven (16.7%) of the 42 patients had higher IgG titers (>=1:640). Among them, four patients presented fourfold increase/decrease of IgG in convalescent serum. According to the clinical diagnosis, the antibody positivity rates were as follows: 24/88 with undifferentiated fever, 8/28 with lymphadenopathy, 4/17 with febrile rash, 2/12 with respiratory infection, 2/7 with aseptic meningitis, and 2/16 with other illnesses. CONCLUSIONS: There was high prevalence of B. henselae in patients with undifferentiated fever in Korea, for which further research is needed. PMID- 29630476 TI - The relationships of multiple factors to menopausal symptoms in different racial/ethnic groups of midlife women: The structural equation modeling. AB - The purpose of the present study was to examine the relationships of multiple factors to menopausal symptoms in different racial/ethnic groups of midlife women. This secondary analysis was conducted with the data from 980 midlife women that were collected from 2005 to 2013 using the Midlife Women's Symptom Index. Structural equation modeling was used to analyze the data. The model had the highest fit indices for non-Hispanic (NH) White midlife women, and prominent racial/ethnic differences were observed in the relationships of multiple factors to menopausal symptoms. In all racial/ethnic groups (except in Hispanic women), perceived health status was significantly positively associated with menopausal symptoms (beta = -0.149 for NH African-American; beta = -0.207 for NH Asians; beta = -0.162 for NH Whites). Body mass index was significantly positively associated with menopausal symptoms only in NH Asians (beta = 0.118) and Hispanics (beta = 0.210). The racial/ethnic differences in the relationships of multiple factors to menopausal symptoms could have resulted from the different cultural contexts in which women undergo during their menopausal transitions. Further cultural studies on the associations of racial/ethnic-specific factors with menopausal symptoms would help in understanding possible causes for racial/ethnic differences in the factors significantly associated with menopausal symptoms. PMID- 29630477 TI - Monoclonal Antibody Against HA Protein of the European Avian-Like H1N1 Swine Influenza Virus. AB - The purified whole-virus proteins derived from A/swine/Shanghai/1/2014 (H1N1) (SH1) were chosen to immunize BALB/c mice to prepare the monoclonal antibody (MAb) against hemagglutinin (HA) protein of an European avian-like (EA) H1N1 swine influenza virus (SIV). After cloning three times by limiting dilution, one strain of hybridoma cells named 3C7 secreting anti-HA protein MAb was obtained by hybridoma technique. The results of indirect immunofluorescence assay and western blot analyses showed that the MAb 3C7 specifically reacted with the HA protein of EA H1N1 SIV. This work indicated that the MAb 3C7 would be a valuable tool as a specific diagnostic reagent for SIV epidemiological surveys and identification of HA protein epitopes of the EA H1N1 SIVs in the future. PMID- 29630478 TI - Modulation of Differentiation Processes in Murine Embryonic Stem Cells Exposed to Parabolic Flight-Induced Acute Hypergravity and Microgravity. AB - Embryonic developmental studies under microgravity conditions in space are very limited. To study the effects of short-term altered gravity on embryonic development processes, we exposed mouse embryonic stem cells (mESCs) to phases of hypergravity and microgravity and studied the differentiation potential of the cells using wide-genome microarray analysis. During the 64th European Space Agency's parabolic flight campaign, mESCs were exposed to 31 parabolas. Each parabola comprised phases lasting 22 s of hypergravity, microgravity, and a repeat of hypergravity. On different parabolas, RNA was isolated for microarray analysis. After exposure to 31 parabolas, mESCs (P31 mESCs) were further differentiated under normal gravity (1 g) conditions for 12 days, producing P31 12-day embryoid bodies (EBs). After analysis of the microarrays, the differentially expressed genes were analyzed using different bioinformatic tools to identify developmental and nondevelopmental biological processes affected by conditions on the parabolic flight experiment. Our results demonstrated that several genes belonging to GOs associated with cell cycle and proliferation were downregulated in undifferentiated mESCs exposed to gravity changes. However, several genes belonging to developmental processes, such as vasculature development, kidney development, skin development, and to the TGF-beta signaling pathway, were upregulated. Interestingly, similar enriched and suppressed GOs were obtained in P31 12-day EBs compared with ground control 12-day EBs. Our results show that undifferentiated mESCs exposed to alternate hypergravity and microgravity phases expressed several genes associated with developmental/differentiation and cell cycle processes, suggesting a transition from the undifferentiated pluripotent to a more differentiated stage of mESCs. PMID- 29630479 TI - Associations of office workers' objectively assessed occupational sitting, standing and stepping time with musculoskeletal symptoms. AB - We examined the association of musculoskeletal symptoms (MSS) with workplace sitting, standing and stepping time, as well as sitting and standing time accumulation (i.e. usual bout duration of these activities), measured objectively with the activPAL3 monitor. Using baseline data from the Stand Up Victoria trial (216 office workers, 14 workplaces), cross-sectional associations of occupational activities with self-reported MSS (low-back, upper and lower extremity symptoms in the last three months) were examined using probit regression, correcting for clustering and adjusting for confounders. Sitting bout duration was significantly (p < 0.05) associated, non-linearly, with MSS, such that those in the middle tertile displayed the highest prevalence of upper extremity symptoms. Other associations were non-significant but sometimes involved large differences in symptom prevalence (e.g. 38%) by activity. Though causation is unclear, these non linear associations suggest that sitting and its alternatives (i.e. standing and stepping) interact with MSS and this should be considered when designing safe work systems. Practitioner summary: We studied associations of objectively assessed occupational activities with musculoskeletal symptoms in office workers. Workers who accumulated longer sitting bouts reported fewer upper extremity symptoms. Total activity duration was not significantly associated with musculoskeletal symptoms. We underline the importance of considering total volumes and patterns of activity time in musculoskeletal research. PMID- 29630480 TI - Effect of Surface Sealants and Polishing Time on Composite Surface Roughness and Microhardness. AB - The objective of this study was to evaluate the effect of surface sealants and polishing delay time on a nanohybrid resin composite roughness and microhardness. Eighty disc specimens were made with a nanohybrid resin (Esthet-X HD, Dentsply). The specimens were divided into two groups (n=40) according to polishing time: immediate, after 10 minutes; delayed, after 48 hours. Each group was subdivided into four groups (n=10), according to the surface treatment: CG, control-rubber points (Jiffy Polishers, Ultradent); PP, rubber points + surface sealant (PermaSeal, Ultradent); PF, rubber points + surface sealant (Fortify, Bisco); PB, rubber points + surface sealant (BisCover, Bisco). Surface roughness (Ra) and microhardness (50 g/15 seconds) were measured. Surface morphology was analyzed by scanning electron microscopy and atomic force microscopy. The data were analyzed statistically using one-way analysis of variance and the Games-Howell post hoc test (alpha=0.05). PermaSeal roughness (G2) in the delayed polishing group was significantly higher ( p=0.00) than that of the other groups. No difference was observed among the groups between immediate and delayed polishing ( p=1.00), except for PermaSeal ( p=0.00). Moreover, PermaSeal showed the lowest microhardness values ( p=0.00) for immediate polishing. Microhardness was higher at delayed polishing for all the surface treatments ( p=0.00) except Fortify ( p=0.73). Surface smoothness similar to polishing with rubber points was achieved when surface sealants were used, except for PermaSeal surface sealant, which resulted in a less smooth resin composite surface. However, surface sealant application did not significantly improve composite resin microhardness. PMID- 29630481 TI - Accuracy of Buccal Scan Procedures for the Registration of Habitual Intercuspation. AB - CLINICAL RELEVANCE:: Accurate reproduction of the jaw relationship is important in many fields of dentistry. Maximum intercuspation can be registered with digital buccal scan procedures implemented in the workflow of many intraoral scanning systems. OBJECTIVE:: The aim of this study was to investigate the accuracy of buccal scan procedures with intraoral scanning devices for the registration of habitual intercuspation in vivo. The hypothesis was that there is no statistically significant difference for buccal scan procedures compared to registration methods with poured model casts. METHODS AND MATERIALS:: Ten individuals (full dentition, no dental rehabilitations) were subjects for five different habitual intercuspation registration methods: (CI) poured model casts, manual hand registration, buccal scan with inEOS X5; (BC) intraoral scan, buccal scan with CEREC Bluecam; (OC4.2) intraoral scan, buccal scan with CEREC Omnicam software version 4.2; (OC4.5beta) intraoral scan, buccal scan with CEREC Omnicam version 4.5beta; and (TR) intraoral scan, buccal scan with Trios 3. Buccal scan was repeated three times. Analysis of rotation (Rot) and translation (Trans) parameters was performed with difference analysis software (OraCheck). Statistical analysis was performed with one-way analysis of variance and the post hoc Scheffe test ( p<0.05). RESULTS:: Statistical analysis showed no significant ( p>0.05) differences in terms of translation between groups CI_Trans (98.74+/ 112.01 MUm), BC_Trans (84.12+/-64.95 MUm), OC4.2_Trans (60.70+/-35.08 MUm), OC4.5beta_Trans (68.36+/-36.67 MUm), and TR_Trans (66.60+/-64.39 MUm). For rotation, there were no significant differences ( p>0.05) for groups CI_Rot (0.23+/-0.25 degrees ), BC_Rot (0.73+/-0.52 degrees ), OC4.2_Rot (0.45+/-0.31 degrees ), OC4.5beta_Rot (0.50+/-0.36 degrees ), and TR_Rot (0.47+/-0.65 degrees ). CONCLUSIONS:: Intraoral scanning devices allow the reproduction of the static relationship of the maxillary and mandibular teeth with the same accuracy as registration methods with poured model casts. PMID- 29630482 TI - Stability of the Light Output, Oral Cavity Tip Accessibility in Posterior Region and Emission Spectrum of Light-Curing Units. AB - OBJECTIVES: This study evaluated the light output from six light-emitting diode dental curing lights after 25 consecutive light exposures without recharging the battery, tip accessibility in the posterior region, and light beam spread from light-curing units. METHODS: Irradiance, spectral peak, and radiant exposure were measured with the battery fully charged (Bluephase Style, ESPE Cordless, Elipar S10, Demi Ultra, Valo Cordless, and Radii-Cal) and monitored for 25 light exposures (each lasting 10 seconds). The tip diameter was measured to identify the beam size and the ability of the six light-curing units to irradiate all areas of the lower second molar in the standard output setting. RESULTS: Four curing lights delivered a single peak wavelength from 454 to 462 nm, and two (Bluephase Style and Valo Cordless) delivered multiple emission peaks (at 410 and 458 nm and 400, 450, and 460 nm, respectively). The irradiance and radiant exposure always decreased after 25 exposures by 2% to 8%, depending on the light unit; however, only ESPE Cordless, Valo Cordless, and Radii-Cal presented a statistical difference between the first and the last exposure. The tip diameter ranged from 6.77 mm to 9.40 mm. The Radii-Cal delivered the lowest radiant exposure and irradiance. This light was also unable to access all the teeth with the tip parallel to the occlusal surface of the tooth. CONCLUSION: Not all of the blue-emitting lights deliver the same emission spectra, and some curing lights delivered a lower irradiance (as much as 8% lower) after the 25th exposure. PMID- 29630483 TI - Influence of Different CAM Strategies on the Fit of Partial Crown Restorations: A Digital Three-dimensional Evaluation. AB - OBJECTIVE: CAM fabrication is an important step within the CAD/CAM process. The internal fit of restorations is influenced by the accuracy of the subtractive CAM procedure. Little is known about how CAM strategies might influence the fit of CAD/CAM fabricated restorations. The aim of this study was to three-dimensionally evaluate the fit of CAD/CAM fabricated zirconia-reinforced lithium silicate ceramic partial crowns fabricated with three different CAM strategies. The null hypothesis was that different CAM strategies did not influence the fitting accuracy of CAD/CAM fabricated zirconia-reinforced lithium silicate ceramic partial crowns. METHODS AND MATERIALS: Preparation for a partial crown was performed on a maxillary right first molar on a typodont. A chairside CAD/CAM system with the intraoral scanning device CEREC Omnicam (Dentsply Sirona, York, PA, USA) and the 3+1 axis milling unit CEREC MCXL was used. There were three groups with different CAM strategies: step bur 12 (12), step bur 12S (12S), and two step-mode (12TWO). The zirconia-reinforced lithium silicate ceramic Celtra Duo (Dentsply Sirona) was used as the CAD/CAM material. A new 3D method for evaluating the fit was applied, consisting of the quadrant scan with the intraoral scanning device CEREC Omnicam. The scan of the PVS material adherent to the preparation and the preparation scan were matched, and the difference analysis was performed with special software OraCheck (Cyfex AG, Zurich, Switzerland). Three areas were selected for analysis: margin (MA), axial (AX), and occlusal (OC). Statistical analysis was performed using 80% percentile, one way ANOVA, and the post hoc Scheffe test with alpha=0.05. RESULTS: Statistically significant differences were found both within and between the test groups. The aspect axial fit results varied from 90.5 +/- 20.1 MUm for the two-step milling mode (12TWO_AX) to 122.8 +/- 12.2 MUm for the milling with step bur 12S (12S_AX). The worst result in all groups was found for the aspect occlusal fit with the highest value for group 12S of 222.8 +/- 35.6 MUm. Group two-step milling mode (12TWO) performed statistically significantly better from groups 12 and 12S for the occlusal fit ( p<0.05). Deviation patterns were visually analyzed with a color-coded scheme for each restoration. CONCLUSIONS: CAM strategy influenced the internal adaptation of zirconia-reinforced lithium silicate partial crowns fabricated with a chairside CAD/CAM system. Sensible selection of specific areas of internal adaptation and fit is an important factor for evaluating the CAM accuracy of CAD/CAM systems. PMID- 29630484 TI - Effect of Different Adhesive Systems Used for Immediate Dentin Sealing on Bond Strength of a Self-Adhesive Resin Cement to Dentin. AB - OBJECTIVE: The purpose of this study was to investigate the immediate and three month water storage behavior of adhesives when used for immediate dentin sealing (IDS). METHODS AND MATERIALS: Four adhesive systems were used to perform IDS: a one-step self-etch (Xeno V), a two-step self-etch (Clearfil SE Bond), a two-step etch-and-rinse (XP Bond), and a three-step etch-and-rinse (Optibond FL). For the control group, IDS was not performed. The self-adhesive resin cement RelyX Unicem was used for the luting procedures. After seven days of water storage, specimens (n=6) were sectioned into beams (n=5) with an approximately 1-mm2 cross-sectional area. Half of the specimens were tested in tension after seven days of water storage at 37 degrees C, while the other half was stored for three months prior to testing in tension using a universal testing machine (1 mm/min). The failure pattern was determined using a stereomicroscope and scanning electron microscopy. Microtensile bond strength (MUTBS) data were statistically analyzed by two-way analysis of variance and Tukey post hoc test (alpha=0.05). RESULTS: After seven days, the control group presented the lowest MUTBS but did not differ from XP Bond and Clearfil SE Bond. After three months, there was no MUTBS difference between the IDS groups and the control. CONCLUSIONS: After seven days of water storage, the groups with IDS presented higher MUTBS values than the control group, although XP Bond and Clearfil SE Bond did not present significant differences. However, after three months of storage in water, IDS groups did not differ significantly from control group, which did not receive IDS. PMID- 29630485 TI - Properties of a New Nanofiber Restorative Composite. AB - A new nanofiber-reinforced hybrid composite (NovaPro Fill, Nanova) was recently introduced with reportedly improved mechanical properties. The purpose of this study was to compare the properties (flexural strength/modulus, degree of conversion [DC], depth of cure, and polymerization shrinkage) of the nanofiber composite to those of traditional hybrid composites (Filtek Z250, 3M ESPE; Esthet X HD, Dentsply). To determine flexural strength and modulus, composite was placed in a rectangular mold, light-cured, stored for 24 hours, and then fractured in a universal testing machine. For degree of conversion, composite was placed in a cylindrical mold, light-cured, and stored for 24 hours. Measurements were made at the top and bottom surfaces using Fourier Transform Infrared Spectroscopy. To determine depth of cure, composite was placed in a cylindrical mold and light cured. Uncured composite was scraped until polymerized resin was reached. Remaining composite was measured and divided by two. Polymerization shrinkage was determined by placing the composite material on a pedestal in a video-imaging device while light-curing. Shrinkage was determined after 10 minutes. Data were analyzed with one-way analysis of variance and Tukey post hoc test per property (alpha=0.05). Compared to Filtek Z250, NovaPro Fill had significantly lower flexural strength and modulus, greater volumetric shrinkage, and similar depth of cure, but greater top and bottom DC. Compared to Esthet-X HD, NovaPro Fill had similar flexural strength, shrinkage, and top and bottom DC, but significantly greater depth of cure and flexural modulus. PMID- 29630486 TI - Incremental and Bulk-fill Techniques With Bulk-fill Resin Composite in Different Cavity Configurations. AB - PURPOSE:: To compare the microtensile bond strengths of incremental and bulk-fill techniques under different C-factor and compliance conditions. METHODS AND MATERIALS:: Extracted human third molars were divided into three experimental groups. For group I, Class I cavities were prepared. For group II, MOD cavities of the same size were prepared. For group III, the cavities were prepared the same way as group II only with high compliance cavity walls. The cavity wall compliance of the specimens was evaluated. Each of these groups was divided into four subgroups. The teeth were restored using two different materials: TB (Tetric N-Ceram Bulk Fill; Ivoclar Vivadent, Hanau, Germany) and VB (Venus Bulk Fill; Heraeus Kulzer, Armonk, NY, USA), and two methods, either an incremental or bulk fill technique. Then, the microtensile bond strengths (MU-TBSs) were measured and compared. The polymerization stresses of the composites were calculated using a custom-made device. The results were statistically analyzed using the Kruskal Wallis test and Weibull analysis. RESULTS:: In group I, the MU-TBS obtained using the incremental technique was significantly higher than that obtained by the bulk fill technique ( p<0.05). In contrast, no difference of the MU-TBS value was observed between the two techniques in groups II and III. The MU-TBS value of group I was significantly lower than those of groups II and III ( p<0.05). No statistical difference in the MU-TBS was observed when the cavities were filled with either TB or VB ( p>0.05). CONCLUSIONS:: The incremental technique showed higher bond strength than did the bulk-fill technique in high C-factor cavities. However, no difference was found between the two techniques in the low C-factor cavities. The bond strength in the high C-factor cavities was significantly lower than that of the low C-factor cavities. PMID- 29630487 TI - Color and Translucency of Resin-based Composites: Comparison of A-shade Specimens Within Various Product Lines. AB - OBJECTIVES:: The purpose of this study was to examine and compare the color and translucency of currently available resin-based composites (RBCs) with respect to the shade numbers within each product line. METHODS AND MATERIALS:: Four A-shades (A1, A2, A3, and A3.5) of nine RBC products (Beautifil II, Ceram-X One, Estelite Sigma Quick, Esthet-X HD, Filtek Z250, Filtek Z350 XT, Gradia Direct, Herculite Precis, and Tetric N-Ceram) were investigated. Ten disk-shaped specimens of two different thicknesses (1 and 2 mm) were prepared for each shade of the RBCs. The maximum blue light irradiance (Imax) through the specimen was recorded using a digital optometer. The color measurements were made according to the CIELAB color scale (quantifying L*, a*, and b*) using a colorimeter, and the translucency parameter (TP) was calculated. The L*, a*, b*, TP, and Imax values were compared among the different shades and thicknesses of each product using one-way analysis of variance followed by Tukey's post hoc test. RESULTS:: There were significant differences in the color and translucency among the shades and thicknesses within each product line ( p<0.001). The L*, Imax, and TP of the 1-mm specimens were higher than those of the 2-mm specimens. The specimens showed equal or lower L* and Imax for higher shade numbers. The a* values differed only slightly among the shades, whereas the b* values were distributed over a relatively wide range. The TP values were independent of the order of shade numbers. CONCLUSIONS:: Within the limitations of this study, the RBCs became darker and yellowish as the shade number increased. The blue light irradiance decreased in increasing order of the shade numbers. Changes in the translucency demonstrated different trends among the shades, depending on the product line. PMID- 29630488 TI - Does Shortened Application Time Affect Long-Term Bond Strength of Universal Adhesives to Dentin? AB - OBJECTIVE: This study evaluated the effect of shortened application time on long term bond strength with universal adhesives. METHODS AND MATERIALS: Three universal adhesives were used: Clearfil Universal Bond (CU, Kuraray Noritake Dental Inc, Tokyo, Japan), Scotchbond Universal Adhesive (SB, 3M ESPE, St Paul, MN, USA) or G-Premio Bond (GP, GC Corp, Tokyo, Japan). Sixty molars were cut to expose midcoronal dentin and prepared with a regular diamond bur. Each adhesive was applied either according to the manufacturer's instruction or with shortened time. Specimens were stored in distilled water at 37 degrees C for 24 hours and then cut into resin-dentin sticks. Microtensile bond strength (MUTBS) was tested after either 24 hours or 1 year of water storage. Data were analyzed by the three way ANOVA and Duncan tests ( alpha=0.05). Fracture modes were analyzed under a scanning electron microscope (SEM). One dentin stick per group was selected after fracture mode analysis and further observed using transmission electron microscopy (TEM). Six additional dentin discs were prepared and conditioned with each adhesive under the different application time to observe the adhesive-smear layer interaction by SEM. RESULTS: Shortened application time affected the MUTBS ( p<0.001) while storage time did not affect bond strength ( p=0.187). A significant effect of shortened application time on MUTBS was observed in the CU at 1 year and in the GP at both storage times. CONCLUSIONS: One-year storage time had no effect on the MUTBS of universal adhesives to bur-cut dentin. The performance of universal adhesives can be compromised when applied using a shortened application time. PMID- 29630489 TI - Clinical Follow-up of a Fissure Sealant Placed Using Different Adhesive Protocols: A 24-month Split-mouth Study. AB - The purpose of this study was to evaluate the retention rates of a fissure sealant placed using different adhesive protocols over 24 months. Twenty-four subjects with no restorations or caries received fissure sealants (Clinpro Sealant, 3M ESPE) placed using different adhesive protocols. A total of 292 sealants were placed as follows by two previously calibrated dentists using a table of random numbers (n=73): group I, acid-etch/without adhesive; group II, with a self-etch adhesive (Adper Easy Bond, 3M ESPE); group III, with an etch-and rinse adhesive (Adper Single Bond 2, 3M ESPE); group IV, with acid + self-etch adhesive (Adper Easy Bond). Two other calibrated examiners independently evaluated the sealants at baseline and at six-, 12-, 18-, and 24-month recalls. Each sealant was evaluated in terms of caries formation being present or absent and retention using the following criteria: 1 = total retention, 2 = partial loss, and 3 = total loss. Pearson's chi2 test was used to evaluate differences in retention rates among the sealants for each evaluation period. At the end of 24 months, total retention rates were 57.5%, 27.4%, 84.9%, and 76.7% in the acid etch, self-etch adhesive, etch-and-rinse adhesive, and acid + self-etch adhesive groups, respectively. Although there were no statistically significant differences between the retention rates among the adhesive protocols at 6 months ( p=0.684), significant differences were observed at the 12-, 18-, and 24-month evaluations. At 24 months, the lowest retention rates were observed in the self etch group ( p<0.05). No caries development was observed in any of the groups. The retention rate of sealants placed using self-etch adhesive was poor compared with the other groups. PMID- 29630490 TI - Gender-based tobacco policies in Bangladesh and India: A prerequisite to counter the smokeless tobacco epidemic. AB - This study examined gender differences in patterns of smokeless tobacco (SLT) use among various socioeconomic and demographic segments in Bangladesh and India, which are home to 80 percent of global SLT users and share similar sociocultural milieus. The objective was to provide evidence of whether gender-focused interventions and policies might be helpful for SLT cessation programs. Data from the Global Adult Tobacco Survey were used for the analysis. In Bangladesh, data were collected between July and August 2009, and 9,629 individuals were successfully interviewed. In India, data were collected from June 2009 to January 2010, and 69,296 individuals were interviewed. Tests of proportions revealed that the prevalence of SLT use was highest among women in Bangladesh (27.9 percent) and among men (32.9 percent) in India. Logistic regression models revealed that the odds of SLT use was lower among Bangladeshi females in the highest age category. However, in India, a similar observation was made only for females with rural residences. In addition, the odds of SLT use was less among those with a higher level of education and wealth, irrespective of the sex or country. The present findings suggest a need for gender-specific policies and interventions for SLT control. PMID- 29630491 TI - A longitudinal study assessing depression in hepatitis C: Does gender play a role in the new-onset depression during interferon-alpha treatment? AB - In this prospective study conducted from October 2013 to June 2015 in Brighton, England, we examined differences between men and women in new-onset major depressive disorder (MDD) during interferon-alpha-based (IFN-alpha) therapy for hepatitis C virus (HCV). We included 155 HCV-infected patients (47 women), eligible to receive HCV therapy, including direct-acting antivirals. The Semi Structured Clinical Interview was used to assess MDD. Severity of depressive symptoms was assessed using the Hamilton Depression Rating Scale. Patients were assessed at baseline, during treatment and 6 months after treatment completion. A significant increase in depressive symptoms was observed in the total sample from baseline to week 4, and a significant decrease was observed from end of treatment (week 24) to the sustained virological response (SVR) end point at 6 months posttreatment. Women were more likely to have a MDD at week 24. In both men and women, neurovegetative and mood-cognitive syndromes increased significantly at the early stage of treatment but remitted by the end of HCV therapy. Proportions with SVR were similar among females and males (91.5 percent vs. 87 percent). Under an inflammatory condition, boosted by interferon-based treatments, these results suggest that female gender is not associated with increased vulnerability for developing depression during IFN-alpha therapy. PMID- 29630492 TI - Informing the knowledge economy: Options for extending the reach of research. PMID- 29630494 TI - Plant Physiology Launches Associate Features Editors. PMID- 29630495 TI - New Faces behind the Scenes. PMID- 29630493 TI - Small molecule induced oligomerization, clustering and clathrin-independent endocytosis of the dopamine transporter. AB - Clathrin-independent endocytosis (CIE) mediates internalization of many transmembrane proteins but the mechanisms of cargo recruitment during CIE are poorly understood. We found that the cell-permeable furopyrimidine AIM-100 promotes dramatic oligomerization, clustering and CIE of human and mouse dopamine transporters (DAT), but not of their close homologues, norepinephrine and serotonin transporters. All effects of AIM-100 on DAT and the occupancy of substrate binding sites in the transporter were mutually exclusive, suggesting that AIM-100 may act by binding to DAT. Surprisingly, AIM-100-induced DAT endocytosis was independent of dynamin, cholesterol-rich microdomains and actin cytoskeleton, implying that a novel endocytic mechanism is involved. AIM-100 stimulated trafficking of internalized DAT was also unusual: DAT accumulated in early endosomes without significant recycling or degradation. We propose that AIM 100 augments DAT oligomerization through an allosteric mechanism associated with the DAT conformational state, and that oligomerization-triggered clustering leads to a coat-independent endocytosis and subsequent endosomal retention of DAT. PMID- 29630496 TI - Auxin and Vesicle Traffic. PMID- 29630497 TI - Vesicles Accumulating Auxin in Vitro Are Not "Presynaptic". PMID- 29630498 TI - Coordinating Cell Walls and Cell Growth: A Role for LRX Extensin Chimeras. PMID- 29630500 TI - CORRECTION: Vol. 176: 2231-2250, 2018. PMID- 29630499 TI - A Novel Role of Ring Chromosomes as Evolutionary Drivers of Herbicide Resistance. PMID- 29630501 TI - CORRECTION: Vol. 173: 2041-2059, 2017. PMID- 29630502 TI - Clinical performance of a new point-of-care cardiac troponin I test. AB - BACKGROUND: We evaluated the clinical performance of the Minicare cardiac troponin-I (cTnI), a new point-of-care (POC) cTnI test for the diagnosis of acute myocardial infarction (AMI) in a prospective, multicentre study (ISRCTN77371338). METHODS: Of 474 patients (>=18 years) admitted to an emergency department (ED) or chest pain unit (CPU) with symptoms suggestive of acute coronary syndrome (ACS; <=12 h from symptom onset), 465 were eligible. Minicare cTnI was tested immediately, 3 h and 6 h after presentation. AMI diagnoses were adjudicated independently based on current guidelines. RESULTS: The diagnostic performance of the Minicare cTnI test at 3 h was similar for whole blood and in plasma: sensitivity 0.92 vs. 0.90; specificity 0.91 vs. 0.90; positive predictive value (PPV) 0.68 vs. 0.66; negative predictive value (NPV) 0.98 vs. 0.98; positive likelihood ratio (LR+) 10.18 vs. 9.41; negative likelihood ratio (LR-) 0.09 vs. 0.11. The optimal diagnostic performance was obtained at 3 h using cut-offs cTnI >43 ng/L plus cTnI change from admission >=18.5 ng/L: sensitivity 0.90, specificity 0.96, PPV 0.81, NPV 0.98, and LR+ 21.54. The area under the receiver operating characteristics (ROC) curve for cTnI whole blood baseline value and absolute change after 3 h curve was 0.93. CONCLUSIONS: These data support the clinical usefulness of Minicare cTnI within a 0 h/3 h-blood sampling protocol supported by current guidelines for the evaluation of suspected ACS. PMID- 29630503 TI - Role of laboratory medicine in collaborative healthcare. AB - Healthcare delivery and responsibility is changing. Patient-centered care is gaining international acceptance with the patient taking greater responsibility for his/her health and sharing decision making for the diagnosis and management of illness. Laboratory medicine must embrace this change and work in a tripartite collaboration with patients and with the clinicians who use clinical laboratory services. Improved communication is the key to participation, including the provision of educational information and support. Knowledge management should be targeted to each stakeholder group. As part of collaborative healthcare clinical laboratory service provision needs to be more flexible and available, with implications for managers who oversee the structure and governance of the service. Increased use of managed point of care testing will be essential. The curriculum content of laboratory medicine training programs will require trainees to undertake practice-based learning that facilitates interaction with patients, clinicians and managers. Continuing professional development for specialists in laboratory medicine should also embrace new sources of information and opportunities for collaborative healthcare. PMID- 29630504 TI - Salivary biomarkers and cardiovascular disease: a systematic review. AB - BACKGROUND: The purpose of this systematic review is to summarize the literature examining associations between salivary biomarkers and cardiovascular disease (CVD) status. CONTENTS: An advanced search was conducted using MeSH terms related to salivary biomarkers and CVD, and entered into the PubMed, Web of Science, and Google Scholar search databases. Four hundred and thirty-three records were narrowed to 22 accepted articles. Included titles were assessed for quality using the Newcastle-Ottawa scale, and ranked into categories of low, moderate, or high. SUMMARY: A total of 40 salivary biomarkers were analyzed among accepted articles. The most studied markers were salivary creatine kinase isoform MB, C-reactive protein (CRP), matrix metalloproteinase-9, troponin I, myeloperoxidase, myoglobin, and brain natriuretic peptide. Salivary CRP provided the most consistent trends. Statistically significant increases of salivary CRP were present with CVD in every study that analyzed it. The remaining six markers demonstrated varying patterns. OUTLOOK: Existing studies provide insufficient data to draw definitive conclusions. Current research shows that there is an association between some salivary biomarkers and CVD, but the details of existing studies are conflicting. Despite inconclusive results, the diagnostic potential of saliva shows promise as a non-invasive means of cardiovascular risk assessment. PMID- 29630505 TI - Exploring the microbiota to better understand gastrointestinal cancers physiology. AB - Gastrointestinal cancers account for around 40% of cancer-related deaths worldwide, representing a global health burden. There is a growing body of evidence highlighting the link between microbiota and gastrointestinal tumorigenesis and/or resistance to therapy. In the present manuscript, we reviewed the published studies on the relationship between the microbiota and the different gastrointestinal tumors, namely, gastric, colorectal and esophageal, including also the cancer of accessory organs such as liver and pancreas. There is an emergent interest in the manipulation of gastrointestinal microflora in order to understand the gastrointestinal tumorigenesis' processes and the establishment of chemoresistance mechanisms. PMID- 29630506 TI - Immunoglobulin G (IgG) and IgG subclass reference intervals in children, using Optilite(r) reagents. AB - BACKGROUND: Immunoglobulin G (IgG) and IgG subclass assays are indicated in patients with suspected primary immunodeficiency (PID). Commercially available assays for IgG subclass determination are calibrated against various preparations, and so specific reference values are required for each of them. Using Optilite(r) reagents from The Binding Site Group Ltd., we sought to determine the pediatric IgG and IgG subclass reference intervals with respect to the ERM-DA470k certified reference material. METHODS: Levels of IgG and IgG subclasses were analyzed in serum samples collected from a large cohort of PID free children and adolescents. Reference intervals were calculated for previously published age groups (6-12 months, 12-18 months, 18 months-2 years, 2-3 years, 3 4 years, 4-6 years, 6-9 years, 9-12 years and 12-18 years), according to the Clinical and Laboratory Standards Institute's C28-A3c protocol. RESULTS: A total of 456 serum samples were analyzed. The correlation between the total IgG and the sum of the IgG subclasses was good (r2=0.96). No statistically significant gender specific differences were observed. Our results for the changes over time in IgG and IgG subclass levels are consistent with previous reports. The differences between our lower/upper reference limits and those in the literature are probably due to variations in calibration. CONCLUSIONS: Our present results provide a reliable basis for the diagnosis of PIDs in childhood and for the accreditation of laboratories using Optilite(r) immunoturbidimetric reagents for IgG subclass measurement. Laboratory scientists and clinicians should be aware of the need for manufacturer-specific IgG subclass reference intervals. PMID- 29630507 TI - Observational studies on macroprolactin in a routine clinical laboratory. AB - BACKGROUND: It is now recommended that all samples with raised prolactin should be examined for the presence of macroprolactin. We performed a retrospective review of our experience of macroprolactin to determine the incidence and the natural history of macroprolactin. METHODS: A retrospective study of macroprolactin was made in a large clinical laboratory. Macroprolactin was measured on those samples where it is requested and where the total prolactin is >1000 mIU/L. Prolactin was measured using the Siemens Centaur and macroprolactin was measured following polyethylene glycol (PEG)-precipitation. RESULTS: The incidence of macroprolactin in samples where the total prolactin was >1000 mIU/L was 36/670 (5.4%). During this period, 12,064 samples were received for prolactin analysis. Over the period since 2006, 22 subjects had a sample with an isolated macroprolactin measurement followed by another sample without macroprolactin after a median period of 0.46 years. Twenty-five subjects had multiple consecutive measurements of macroprolactin lasting a median period of 2.1 years. Fourteen subjects had more than six samples which had been subjected to PEG precipitation. In these subjects, the reproducibility of PEG precipitation over a median of 6 years was 1.1% CV (recovery 75% [26-110] (median [range])). CONCLUSIONS: The presence of macroprolactin can change over time and we cannot advise that once a test for macroprolactinemia has been performed that it is not necessary to repeat the investigation if a subsequent sample is hyperprolactinemic; nor can one assume that macroprolactin will not develop even if it has been excluded previously. PMID- 29630508 TI - Can calculated total nitrogen replace Kjeldahl total nitrogen measurements in 24 h urine samples? PMID- 29630509 TI - Harmonization of laboratory hematology: a long and winding journey. PMID- 29630510 TI - Finding best practice in internal quality control procedures using external quality assurance performance. PMID- 29630511 TI - Interference of glucose and total protein on Jaffe-based creatinine methods: mind the covolume. PMID- 29630512 TI - Hemolysis interference studies: freeze method should be used in the preparation of hemolyzed samples. PMID- 29630513 TI - Basic pituitary-ovarian hormones and ultrasound parameters of uterine appendages in full-term and preterm neonate girls. AB - Objective To determine the basic pituitary-ovarian hormones and ultrasound parameters of uterine appendages in full-term and preterm newborn girls. Materials and methods One hundred full-term and premature newborn girls (58 and 42, respectively) were studied with clinical, instrumental, laboratory (enzyme immunoassay) and statistical methods. Results Statistically significant differences in the pituitary-ovarian hormones and ultrasound parameters of uterine appendages in preterm neonate girls compared to full-term girls were defined. The pituitary hormone levels (follicle-stimulating and luteinizing hormone levels) were higher in preterm newborn girls [0.15 (0.06-0.53) and 0.06 (0.05-0.08) (p = 0.0001); 0.03 (0.00-0.23) and 0.00 (0.00-0.03), (p = 0.003)]; the ovarian hormone levels (estradiol, anti-Mullerian hormone and inhibin V levels) were lower [0.44 (0.25-0.85) and 1.55 (1.06-1.84) (p = 0.0001); 2.73 (2.12-3.65) and 3.66 (2.59-5.0), (p = 0.026), 60.81 (37.19-128.80) and 104.75 (54.35-159.18), (p = 0.019), respectively]. Ultrasound investigation showed that the ovarian reserve in preterm neonates was smaller compared to the full-term neonates [38.48 (22.01-56.49) and 102.47 (85.36-111.37), (p = 0.0001); 36.95 (25.21-70.59) and 108.05 (91.74-116.44), (p = 0.0001), respectively (p = 0.0001)]. The number of antral follicles in the slice was also statistically significantly smaller [2 - in the right ovary, 1 - in the left ovary, vs. 4 and 4, respectively (p = 0.0001)]. Conclusion Premature neonates have different pituitary-ovarian hormones and ovarian size compared to full-term babies. PMID- 29630514 TI - Determinants of HIV testing and receipt of test results among adolescent girls in Nigeria: the role of assets and decision-making. AB - Purpose Many adolescent girls in Nigeria do not test for HIV despite being at high risk. While the influence of psychosocial factors on HIV testing has been examined, there is less evidence regarding the impact of assets and control of assets on HIV testing. This study investigated the protective effects of specific adolescent girls' assets on decision-making regarding HIV testing. Methods Cross sectional data from the 2013 Nigeria Demographic and Health Survey was analyzed. The main outcome variables were self-reports of having been tested for HIV and knowledge of a place that offers HIV testing. Binary logistic regression was used with employment, education, wealth index, home ownership, land ownership and decision making as potential predictors. Demographic characteristics were controlled in the analysis. Results Age [odds ratio (OR = 1.49)], employment (OR = 3.38), education (OR = 3.16), wealth index (OR = 1.33) and decision making (OR = 3.16) were positively associated with HIV testing. Age (OR = 1.20), employment (OR = 1.33), education (OR = 1.38), wealth (OR = 1.64), land ownership (OR = 1.42), and decision making (OR = 1.26) were positively associated with knowledge of an HIV testing location. Conclusion Our findings suggest that assets play an important role with HIV testing decisions for adolescent girls. Further research to elucidate the specific asset-based needs of adolescent girls will be needed to enhance decisions surrounding uptake of HIV testing and receipt of test results in Nigeria. PMID- 29630515 TI - The relationship between spiritual intelligence and aggression in medical science students in the southeast of Iran. AB - Background Due to their presence in clinical educational settings when dealing with patients, medical science students are more affected by mental disorders than other students. Some experts believe that spiritual intelligence enhances people adaptability and compatibility and creates calm in humans, especially in stressful situations. Objective The objective of this study was to investigate the relationship between spiritual intelligence and aggression among students of medical sciences in the southeast of Iran. Methods This analytical-descriptive study was conducted among bachelor students of Medical Sciences in the Southeast of Iran and examples of the research were selected from the Schools of Nursing and Midwifery, Public Health, Paramedical and Management by a stratified random sampling method. To examine samples questionnaires were used which examined students' demographic information, and included King's 24-item Questionnaire of Spiritual Intelligence and the Buss-Perry Aggression Questionnaire (AQ). After completing the questionnaires, data were analyzed using statistical analysis software (SPSS version18) with a significance level (p < 0.05). Results The results showed that there is a significant negative correlation between spiritual intelligence and aggression of students (r = -0/19, p = 0/001). Results also showed that Students of Medical Sciences in the Southeast of Iran with a spiritual intelligence average score of 52.28 have an average spiritual intelligence and those with an aggression average score of 78.57 have higher aggression than average. Conclusion The results showed that with increasing spiritual intelligence, aggression decreases. The results can be used by policymakers and managers to take steps to reduce aggressive behaviors and mental disorders and for the promotion of spiritual intelligence of students of medical sciences. PMID- 29630516 TI - Effectiveness of basic body awareness therapy in adolescents with idiopathic scoliosis: A randomized controlled study1. AB - BACKGROUND: In scoliosis, curve progresses due to muscle imbalance and poor posture. Basic body awareness therapy (BBAT) aims to improve posture, coordination, and balance by increasing body awareness, which may help decrease deformities. OBJECTIVE: This study aimed to investigate effects of Basic body awareness therapy (BBAT) on curve magnitude, trunk asymmetry, cosmetic deformity, and quality of life in adolescent idiopathic scoliosis (AIS) patients. METHODS: Twenty female AIS patients were randomly assigned to BBAT and traditional exercises (TEs) groups. The BBAT group received BBAT and traditional exercises (TEs), while the TEs group received only TEs. The following assessments were included: Cobb angles using X-ray, angle of trunk rotation (ATR) using scoliometer, trunk asymmetry using the Posterior Trunk Symmetry Index (POTSI), cosmetic deformity using the Walter Reed Visual Assessment Scale (WRVAS), and quality of life using the SRS-22 test. Measurements were conducted at baseline examination and ten weeks later. Patients were instructed to wear their brace 23 h daily. Results were analyzed using the Wilcoxon rank-sum test to compare repeated measurements and Mann-Whitney U test to compare the groups. RESULTS: The BBAT group had greater improvement in the thoracic Cobb angle than the TEs group. Cosmetic deformity improved in both groups, whereas body asymmetry improved in only the BBAT group. SRS-22 scores were unchanged in both groups. CONCLUSIONS: BBAT as an additive to bracing and TEs improve curve magnitude, body symmetry and trunk deformity. PMID- 29630517 TI - LncRNA SNHG12 promotes the proliferation and metastasis of papillary thyroid carcinoma cells through regulating wnt/beta-catenin signaling pathway. AB - OBJECTIVE: To investigate the expression and role of long non-coding RNA (lncRNA) small nucleolar RNA host gene 12 (SNHG12) in papillary thyroid carcinoma (PTC). METHODS: The relative expression levels of lncRNA SNHG12 (hereinafter referred to as SNHG12) in 42 pairs of PTC tissues and para-carcinoma tissues were detected via quantitative reverse transcription polymerase chain reaction (qRT-PCR). SNHG12 specific interference sequences were designed and synthesized. The relative expression level and transfection efficiency of SNHG12 in PTC cells were detected via qRT-PCR. After the interference in SNHG12 expression, the change in cell proliferation capacity was detected via methyl thiazolyl tetrazolium (MTT) assay, the change in cell cycle distribution was detected via flow cytometry, the changes in cell migration and invasion capacities were detected via Transwell assay and wound healing assay, and the changes in expressions of molecular markers of Wnt/beta-catenin pathway were detected via Western blotting. The pulmonary metastasis model of nude mice was established, and the changes in migration and invasion capacities of tumor cells were studied via the in-vivo experiment after the interference in SNHG12 expression. RESULTS: The results of qRT-PCR showed that the SNHG12 expression was up-regulated in 30 pairs of PTC tissues and cells. The results of MTT assay showed that the cell proliferation capacity was inhibited after the interference in SNHG12. The results of flow cytometry showed that the cell cycle progression was blocked in G1-G0 phase after the knockdown of SNHG12 expression. The results of Transwell assay and Western blotting showed that the interference in SNHG12 could inhibit the invasion and metastasis capacities of tumor cells through influencing the Wnt/beta-catenin signaling pathway. Metastatic tumor model of nude mice showed that SNHG12 could affect the invasion and metastasis of tumor cells in vivo. CONCLUSION: The SNHG12 expression is relatively high in PTC tissues and cells. In-vivo/in-vitro experiments prove that SNHG12 can promote the proliferation and metastasis of PTC cells through influencing the Wnt/beta-catenin signaling pathway. PMID- 29630518 TI - Circulating HOTAIR expression predicts the clinical response to neoadjuvant chemotherapy in patients with breast cancer. AB - BACKGROUND: Long noncoding RNA HOTAIR has been detected in the serum of patients with various malignances and may be served as novel biomarker for diagnosis and prognosis prediction of breast cancer. However, the value of circulating HOTAIR to predict the response to neoadjuvant chemotherapy (NAC) remains unclear. OBJECTIVE: In the present study, we analyzed whether pretreatment circulating HOTAIR levels predict the response to NAC and investigated prognostic impact of circulating HOTAIR on disease-free survival (DFS) in breast cancer patients treated with NAC. METHODS: Circulating HOTAIR levels in the serum of 112 breast cancer patients before NAC were measured using quantitative real-time PCR. The correlation of circulating HOTAIR with the clinicopathologic status and the response to NAC were analyzed. Kaplan-Meier survival analysis and log-rank test were used to estimate the DFS. RESULTS: In 112 serum samples obtained before NAC, high circulating HOTAIR was associated with larger tumor size, more positive lymph nodes as well as more distant metastasis. However, there was no significant correlation between the circulating HOTAIR levels and age, Ki67 status or hormone receptor. Furthermore, patients with high circulating HOTAIR achieved less clinical response as well as pathologic complete response than those with low circulating HOTAIR (p< 0.05). The Kaplan-Meier survival curve with a median follow-up of 48 months demonstrated that patients with high circulating HOTAIR expression had a worse disease-free survival than those with low circulating HOTAIR (log-rank p= 0.012). CONCLUSIONS: High circulating HOTAIR level correlates with less response to neoadjuvant chemotherapy as well as a worse prognosis in breast cancer patients. Therefore, the present study provides a favorable basis to use circulating HOTAIR as a predictor of neoadjuvant chemotherapy response. PMID- 29630519 TI - Prognostic value of baseline carcinoembryonic antigen and cytokeratin 19 fragment levels in advanced non-small cell lung cancer. AB - BACKGROUND: Serum carcinoembryonic antigen (CEA) and cytokeratin 19 fragment (CYFRA 21-1) levels are prognostic predictors in non-small cell lung cancer (NSCLC). However, even in patients with the same stage of cancer, the serum levels of those markers often vary. OBJECTIVE: We investigated the association between the initial biomarker levels and prognosis. METHODS: We retrospectively reviewed 445 patients with advanced NSCLC and their baseline serum CEA and CYFRA 21-1 levels. Patients were divided into four groups according to the initial levels of those markers: the NN, HN, NH, and HH group. Kaplan-Meier survival analysis with Log-rank test and Cox proportional hazards regression analysis were performed. RESULTS: The 5-year overall survival (OS) rate in the HN group was the highest (32.2%). Multivariate analyses indicated that the HN group (HR 0.520, 95% CI 0.309-0.878, P= 0.014), female sex (HR 0.685, 95% CI 0.498-0.944, P= 0.021), serum CRP level (HR 1.057, 95% CI 1.034-1.080, P< 0.001), chemotherapy (HR 0.324, 95% CI 0.228-0.460, P< 0.001), and chemotherapy/radiotherapy (HR 0.266, 95% CI 0.171-0.414, P< 0.001) were independent prognostic factors for overall survival. CONCLUSIONS: In advanced NSCLC, patients with baseline high serum CEA but low CYFRA 21-1 level have a significant longer overall survival regardless of clinical stage. PMID- 29630520 TI - Phytochemical and anti-inflammatory activities of aqueous leaf extract of Indian borage (oregano) on rats induced with inflammation. AB - BACKGROUND: The Indian borage (Plectranthus amboinicus) also called Oregano contains many effective antioxidants, which includes caffeic acid, rosmarinic acid and flavonoids. It has been employed in traditional medicine for its several health benefits including the prevention and cure of many debilitating diseases. Anti-inflammatory properties of Plectranthus amboinicus grown within this environment have not been adequately explored. OBJECTIVE: The protective and therapeutic effects of Oregano against endotoxaemia and inflammation were evaluated using lipopolysaccharide (LPS)-induced rat models. MATERIALS AND METHODS: A total of 30 Wistar rats were randomly selected for this study and divided into six groups, with each group having 5 rats. Inflammation was induced on appropriate animal groups using LPS injection at a concentration of 4 mg/kg. Aqueous leaf extract of Indian borage was administered orally in four doses (100 mg/kg, 200 mg/kg, 400 mg/kg post-LPS exposure and 150 mg/kg pre-LPS exposure) to respective treatment rat groups. Haematological profile, toxicity profile of liver and kidney and levels of biomarkers of inflammation were assayed using standard methods. RESULTS: Rats injected with LPS showed severe anaemia and marked leucopoenia with significant decrease in monocytes compared to the control group (p< 0.05). There was increased expression of interleukin-8 (IL-8) and tumor necrosis factor-alpha (TNF-alpha) (p< 0.05) in the peripheral circulation of rats exposed to LPS. Treatment with Indian borage significantly (p< 0.05) reduced the toxic effects in the LPS-treated animals and attenuated the increase in the expression of circulating proinflammatory cytokines; tumor necrosis factor alpha (TN-Falpha) and interleukin-8 (IL-8) caused by LPS. Indian borage pretreatment also significantly (p< 0.05) counteracted the associated haematological dyscrasias caused by exposure to LPS. The extract elicited a significant protective effect on the kidney and liver as evidenced by the decreased renal markers and hepatic enzyme activities when compared with the control. The extract demonstrated protective and suppressive role against the overexpression of inflammatory mediators by ameliorating the induced inflammation and endotoxaemic conditions in the affected rat groups thereby validating its folkloric use. CONCLUSION: Our study thus reveals that the extract might be an active, natural and non-toxic drug lead against endotoxaemia-induced inflammation and toxicity. PMID- 29630521 TI - Prognostic and predictive value of long non-coding RNA GAS5 and mircoRNA-221 in colorectal cancer and their effects on colorectal cancer cell proliferation, migration and invasion. AB - BACKGROUND: LncRNA and microRNA play an important role in the development of human cancers; they can act as a tumor suppressor gene or an oncogene. LncRNA GAS5, originating from the separation from tumor suppressor gene cDNA subtractive library, is considered as an oncogene in several kinds of cancers. The expression of miR-221 affects tumorigenesis, invasion and metastasis in multiple types of human cancers. However, there's very little information on the role LncRNA GAS5 and miR-221 play in CRC. Therefore, we conducted this study in order to analyze the association of GAS5 and miR-221 with the prognosis of CRC and preliminary study was done on proliferation, metastasis and invasion of CRC cells. In the present study, we demonstrate the predictive value of long non-coding RNA GAS5 (lncRNA GAS5) and mircoRNA-221 (miR-221) in the prognosis of colorectal cancer (CRC) and their effects on CRC cell proliferation, migration and invasion. METHODS: One hundred and fifty-eight cases with CRC patients and 173 cases of healthy subjects that with no abnormalities, who've been diagnosed through colonoscopy between January 2012 and January 2014 were selected for the study. After the clinicopathological data of the subjects, tissue, plasma and exosomes were collected, lncRNA GAS5 and miR-221 expressions in tissues, plasma and exosomes were measured by reverse transcription quantitative polymerase chain reaction (RT-qPCR). The diagnostic values of lncRNA GAS5 and miR-221 expression in tissues, plasma and exosomes in patients with CRC were analyzed using receiver operating characteristic curve (ROC). Lentiviral vector was constructed for the overexpression of lncRNA GAS5, and SW480 cell line was used for the transfection of the experiment and assigned into an empty vector and GAS5 groups. The cell proliferation, migration and invasion were tested using a cell counting kit-8 assay and Transwell assay respectively. RESULTS: The results revealed that LncRNA GAS5 was upregulated while the miR-221 was downregulated in the tissues, plasma and exosomes of patients with CRC. The results of ROC showed that the expressions of both lncRNA GAS5 and miR-221 in the tissues, plasma and exosomes had diagnostic value in CRC. While the LncRNA GAS5 expression in tissues, plasma and exosomes were associated with the tumor node metastasis (TNM) stage, Dukes stage, lymph node metastasis (LNM), local recurrence rate and distant metastasis rate, the MiR-221 expression in tissues, plasma and exosomes were associated with tumor size, TNM stage, Dukes stage, LNM, local recurrence rate and distant metastasis rate. LncRNA GAS5 and miR-221 expression in tissues, plasma and exosomes were found to be independent prognostic factors for CRC. Following the overexpression of GAS5, the GAS5 expressions was up-regulated and miR-221 expression was down regulated; the rate of cell proliferation, migration and invasion were decreased. PMID- 29630522 TI - Elevated MACC1 expression predicts poor prognosis in small invasive lung adenocarcinoma. AB - BACKGROUND: Patients with small (? 2 cm) invasive lung adenocarcinoma are at high risk of poor prognosis and disease recurrence after complete surgical resection. Therefore, identification of high-risk individuals from these patients emerges as an urgent problem. Elevated MACC1 expression predicts a poor prognosis in multiple types of cancer that are independent of TNM staging. This study investigated the prognostic value of MACC1 expression in patients with small invasive lung adenocarcinoma. OBJECTIVE: The current study aimed to evaluate the relationship between MACC1 expression in patients' tumor tissue and prognosis in small invasive lung adenocarcinoma. METHODS: The records of 131 patients with small invasive lung adenocarcinoma who underwent complete surgical resection were reviewed. The MACC1 expression was detected by immunohistochemical staining in all specimens. Meanwhile, western blot and real-time quantitative PCR were used to examine the expression level of MACC1 in human lung adenocarcinoma cell lines. The effect of clinicopathological risk factors on patients' survival was analyzed using the Kaplan-Meier approach and multivariable Cox models. RESULTS: Elevated MACC1 expression was observed in 53 (40.5%) specimens, and in A549, H358, H460 and H322 lung adenocarcinoma cell lines. MACC1 overexpression was associated with differentiation (P= 0.005) and blood vessel invasion (P= 0.001). Compared with low MACC1 expression, elevated MACC1 expression was associated with significantly shorter overall survival (odds ratio = 6.515; 95% confidence interval: 1.382 30.721; P= 0.018) and disease-free survival (odds ratio = 3.270; 95% confidence interval: 1.117-9.569; P= 0.031). Multivariate analyses demonstrated high MACC1 expression is an independent risk factor of worse overall survival (odds ratio = 5.684; 95% confidence interval: 1.145-28.210; P= 0.034) and disease-free survival (odds ratio = 4.667; 95% confidence interval: 1.372-15.877; P= 0.014). CONCLUSION: MACC1 is an independent prognostic marker in patients with small invasive lung adenocarcinoma after complete surgical resection. Differential outcomes are associated with MACC1 expression level. PMID- 29630523 TI - MicroRNA profiles as predictive markers of response to azacitidine therapy in myelodysplastic syndromes and acute myeloid leukemia. AB - BACKGROUND: Azacitidine (AZA) is a nucleoside analog used for treatment of myelodysplasia and the prediction of AZA responsiveness is important for the therapy management. METHODS: Using microarrays and reverse-transcription quantitative-PCR, we analyzed microRNA (miRNA) expression in bone marrow CD34+ cells of 27 patients with higher-risk myelodysplastic syndromes or acute myeloid leukemia with myelodysplasia-related changes before and during AZA treatment. RESULTS: At baseline, we found that future overall response rate was significantly higher in patients with upregulated miR-17-3p and downregulated miR 100-5p and miR-133b. Importantly, the high level of miR-100-5p at baseline was associated with shorter overall survival (HR = 4.066, P= 0.008). After AZA treatment, we observed deregulation of 30 miRNAs in responders (including downregulation of miR-10b-5p, miR-15a-5p/b-5p, miR-24-3p, and miR-148b-3p), while their levels remained unchanged in non-responders. CONCLUSIONS: Our study demonstrates that responders and non-responders have distinct miRNA patterns and that the level of specific miRNAs before therapy may predict the efficacy of AZA treatment. PMID- 29630524 TI - Serum miR-658 induces metastasis of gastric cancer by activating PAX3-MET pathway: A population-based study. AB - BACKGROUND AND OBJECTIVE: MiR-658, paired box gene 3 (PAX3) and met proto oncogene (MET) are overexpressed in gastric cancer while PAX3 and MET can be regulated by miRNA. Serum miR-658 may be associated with metastasis of gastric cancer (MGC) by affecting PAX3-MET pathway. METHODS: Ninety-eight gastric carcinoma patients with distant MGC (DM group) and ninety-six gastric carcinoma patients with no MGC (NM group) were recruited. Serum miR-658 was validated between DM and NM groups by using quantitative reverse transcription PCR (qRT PCR). PAX3 and MET levels were measured by Western Blot. The molecular mechanism for the function of serum miR-658 was further validated in gastric cell lines. RESULTS: The results demonstrate that serum level of miR-658 is significantly lower in the NM group than in the DM group (P< 0.001). Meanwhile, the levels of PAX3 and MET are lower in the NM group than in the DM group too (P< 0.01). Both overexpression and silence of miR-658 significantly up-regulate or down-regulate the levels of PAX3 and MET in gastric cell lines (P< 0.05). CONCLUSIONS: The present findings demonstrate that elevated circulating miR-658 is associated with MGC by activating PAX3-MET pathway. PMID- 29630526 TI - Down-regulation of hsa_circ_0001649 in hepatocellular carcinoma predicts a poor prognosis. AB - BACKGROUND: Circular RNAs (circRNA)are involved in the progression of cancers, and previous study showed that hsa_circ_0001649 expression is down-regulated in hepatocellular carcinoma (HCC). OBJECTIVE: To explore whether hsa_circ_0001649 is a prognostic biomarker for HCC and to investigate the biological functions of hsa_circ_0001649 in HCC. METHODS: Hsa_circ_0001649 expression was measured in 77 pairs of HCC and adjacent no-tumor tissues by quantitative Real-Time polymerase chain reaction. Kaplan-Meier curve and Cox regression were used to analyze its prognostic significance for HCC patients. In addition, the hsa_circ_0001649 was over-expressed using a circRNA-forming plasmid in HCC cells, and the biological function of hsa_circ_0001649 was investigated in vitro. RESULTS: We verified that hsa_circ_0001649 was down-regulated in HCC tissues compared with adjacent non tumor tissues. In addition, low hsa_circ_0001649 expression was associated with the poor overall survival of HCC patients, and Cox multivariate analysis showed that hsa_circ_0001649 is a novel independent prognostic factor for HCC patients. Furthermore, the in vitro experiments demonstrated that over-expressed hsa_circ_0001649 inhibits the proliferation, migration, and invasion and promotes the apoptosis of HCC cells. CONCLUSIONS: Hsa_circ_0001649 could act as a novel prognostic biomarker for HCC patients. In addition, hsa_circ_ 0001649 might be a potential therapeutic target for HCC. PMID- 29630525 TI - Diagnostic and prognostic implications of serum miR-101 in osteosarcoma. AB - Blood-circulating microRNAs (miRNAs) have been reported to be used as potential biomarkers in various cancers. MiR-101 has been found to act as a tumor suppressor in many tumor types, but little is known for osteosarcoma. The purpose of this study was to investigate miR-101 expression in osteosarcoma patients and assess its correlation with clinical features and prognosis. Serum samples from 152 osteosarcoma patients and 70 healthy controls were detected using quantitative reverse-transcription polymerase chain reaction (qRT-PCR). The data showed that miR-101 expression levels were remarkably underexpressed in serum samples from osteosarcoma patients compared to controls, and the post-treatment serum miR-101 expression was significantly higher than that in the pre-treatment expression. Low serum miR-101 expression was positively associated with advanced clinical stage and distant metastasis. Receiver operating characteristic (ROC) curve analysis showed that serum miR-101 could serve as a useful marker for osteosarcoma diagnosis, with a high sensitivity and specificity. Moreover, patients with high miR-101 expression had longer overall survival and recurrence free survival than those with low miR-101 expression. In addition, both univariate and multivariate analyses showed that serum miR-101 downregulation was associated with shorter overall survival and recurrence free survival. Our present results implicated serum miR-101 might be a useful biomarker for the clinical diagnosis and prognosis of osteosarcoma. PMID- 29630527 TI - MiR-29a suppresses cell proliferation by targeting SIRT1 in hepatocellular carcinoma. AB - OBJECTIVES: MicroRNAs (miRNAs) were identified to be involved in various biological functions by regulating the degradation or suppressing the translation of their downstream target genes. Recent studies have identified miR-29a acts as tumor suppressor in hepatocellular carcinoma (HCC) progression. However, the underlying functions for miR-29a in HCC still to be investigated. METHODS: The expression of miR-29a expression in HCC tissues and corresponding adjacent normal tissues was detected using qRT-PCR analyses. Cell proliferation ability was assessed using CCK8 assay, cell colony forming and flow cytometry analysis. Bioinformatics, the dual luciferase reporter assay, qRT-PCR and western blot analysis were used to demonstrate that SIRT1 was a target of miR-29a. RESULTS: Here, we demonstrated that miR-29a was significantly downregulated in HCC tissues compared with corresponding adjacent normal tissues. Lower miR-29a expression associated with tumor size and vascular invasion of HCC. Furthermore, Lower miR 29a predicted a poor disease free survival (DFS) and overall survival (OS) time for HCC patients. Function assays showed that overexpression of miR-29a effectively suppressed cell proliferation, cell colony forming ability, and cell cycle progression. MiR-29a overexpression also inhibited the cell cycle related protein expression of CyclinD1 and CDK4, but increasing the P21 expression. Furthermore, Bioinformatics and the dual luciferase reporter assay analysis results demonstrated that miR-29a specifically targeted the 3'-UTR of SIRT1 mRNA and regulated its protein expression. Increased SIRT1 expression rescued the inhibited effects induced by miR-29a overexpression in HCC cells. CONCLUSIONS: Thus, these results indicated that miR-29a may serve as a potential target of HCC treatment. PMID- 29630528 TI - A two-stage multi-view learning framework based computer-aided diagnosis of liver tumors with contrast enhanced ultrasound images. AB - OBJECTIVE: With the fast development of artificial intelligence techniques, we proposed a novel two-stage multi-view learning framework for the contrast enhanced ultrasound (CEUS) based computer-aided diagnosis for liver tumors, which adopted only three typical CEUS images selected from the arterial phase, portal venous phase and late phase. MATERIALS AND METHODS: In the first stage, the deep canonical correlation analysis (DCCA) was performed on three image pairs between the arterial and portal venous phases, arterial and delayed phases, and portal venous and delayed phases respectively, which then generated total six-view features. While in the second stage, these multi-view features were then fed to a multiple kernel learning (MKL) based classifier to further promote the diagnosis result. Two MKL classification algorithms were evaluated in this MKL-based classification framework. We evaluated proposed DCCA-MKL framework on 93 lesions (47 malignant cancers vs. 46 benign tumors). RESULTS: The proposed DCCA-MKL framework achieved the mean classification accuracy, sensitivity, specificity, Youden index, false positive rate, and false negative rate of 90.41 +/- 5.80%, 93.56 +/- 5.90%, 86.89 +/- 9.38%, 79.44 +/- 11.83%, 13.11 +/- 9.38% and 6.44 +/- 5.90%, respectively, by soft margin MKL classifier. CONCLUSION: The experimental results indicate that the proposed DCCA-MKL framework achieves best performance for discriminating benign liver tumors from malignant liver cancers. Moreover, it is also proved that the three-phase CEUS image based CAD is feasible for liver tumors with the proposed DCCA-MKL framework. PMID- 29630529 TI - Contrast-enhanced ultrasonography in differential diagnosis of focal gallbladder adenomyomatosis and gallbladder cancer. AB - BACKGROUND: Focal gallbladder adenomyomatosis (ADM) is a common disease that mimics gallbladder cancer (GBC) on ultrasonography. OBJECTIVE: Here we aim to assess the value of contrast-enhanced ultrasound (CEUS) in differentiating ADM from GBC. METHODS: Forty-one histopathologically proven focal ADMs and 34 GBCs (<=T2 stage) were enrolled in the study. Lesion location, blood flow signals, contrast pattern and appearance on contrast-enhanced ultrasound (CEUS) were compared respectively. RESULTS: Lesions were detected in fundus, body, neck at the rates of 61.0% (25/41), 26.8% (11/41) and 12.2% (5/41), respectively, in ADM patients, in comparison to 29.4% (10/34), 32.4% (11/34) and 38.2% (13/34), respectively, in GBC patients (p = 0.009). Blood flow signals were detected in 19.5% (8/41) of cases in ADMs, compared to 58.8% (20/34) in GBCs (p = 0.001). On CEUS, iso-enhancement, hypo-enhancement, intramural anechoic space and intactness of GB wall were detected in 41.5% (17/41), 39.0% (16/41), 56.1% (23/41) and 80.5% (33/41) cases of ADMs, in contrast to 17.6% (6/34), 20.6% (7/34), 20.6% (7/34) and 17.6% (6/34) of GBCs (p = 0.001, p = 0.001, p = 0.002, p < 0.001, respectively). The prior Youden's index were 0.81 based on intactness of GB wall on CEUS. CONCLUSION: Combined with CEUS helps improve the differential diagnosis accuracy of focal gallbladder ADMs. PMID- 29630530 TI - Bioresorbable everolimus-eluting vascular scaffold for patients presenting with non STelevation-acute coronary syndrome: A three-years follow-up1. AB - AIM: To investigate three-year outcomes of patients presenting with nonSTelevation acute coronary syndrome (NSTE-ACS) treated with bioresorbable everolimus-eluting vascular scaffolds (BRS). METHODS AND RESULTS: The study included a total of 488 consecutive patients, enrolled between May 2012 and December 2013 (median age 65 [56-74], 392 men. 269 patients presented with either NSTEMI or unstable angina at the time of enrolling, 219 patients with stable or silent angina. The primary device-oriented endpoint (Target Lesion Failure, TLF) was defined as a combination of cardiovascular death, target vessel myocardial infarction or clinically driven target lesion revascularization.Among the cardiac risk factors, NSTE-ACS patients were more frequently smokers (P = 0.028), had less frequently dyslipidemia (P = 0.003) and a history of prior PCI (P < 0.01).The median follow-up was 1070[763-1197] days. The three-years incidence of TLF was slightly higher but did not differ significantly between groups (NSTE ACS: 16.3% vs. 15.9%, p = 0.163). Accordingly, there was no difference in any of the other endpoints. CONCLUSION: Treatment of NSTE-ACS with BRS appears to be safe and effective. In this group, risk factors for events during follow up did not differ as compared to the general population. PMID- 29630531 TI - Cutaneous microcirculation during operations with a cardiopulmonary bypass. AB - BACKGROUND: Cutaneous microcirculation (cMC) is influenced by many factors. In cardiac surgery, most operations are performed with a cardiopulmonary bypass (CPB) and cardiac arrest induced by cardioplegic solutions. OBJECTIVES: Aim of this study was to examine a correlation between cMC and hemodynamic parameters in patients undergoing heart surgery with two different cardioplegic solutions. METHODS: 20 patients were included and divided into Histidine-Tryptophane-alpha Ketoglutarate solution- (HTK, n = 10) and blood cardioplegia- (BCP, n = 10) groups. With initiation of CPB, cMC was continuously monitored with Laser-Doppler Perfusion (LDP) until termination of CPB. Additionally, we measured hemoglobin concentration (HbC) with a Blood-Parameter-Monitoring-System. RESULTS: LDP pulsation was almost equal before and after CPB and decreased during aortic cross clamping. The following factors influenced LDP: central venous pressure (CVP), mean arterial pressure (MAP), total peripheral resistance (TPR) and flow of the heart-lung machine. We measured relative LDP and HbC (RLDP; RHbC). Five and 25 min after administration of cardioplegia, RLDP (1.22+/-0.8; 1.17+/-0.94) and RHbC (0.92+/-0.06; 0.96+/-0.09) in the HTK-group were lower than in the BCP-group: RLDP (1.58+/-1.11; 1.58+/-2.2) and RHbC (1.00+/-0.05; 0.99+/-0.13). HTK-patients with a body surface area (BSA) <2 m2 showed a lower RLDP (0.75+/-0.50), than patients over 2 m2 (RLDP = 1.64+/-0.97). CONCLUSIONS: The cMC is influenced by CPB. Cutaneous LDP monitoring is a non-invasive method, for estimating hemodynamics intraoperatively. PMID- 29630532 TI - Lower limb ischemia and microrheological alterations in patients with diabetic retinopathy. AB - BACKGROUND: Diabetes mellitus is frequently associated with vascular pathologies and hemorheological disorders. METHODS: 105 patients with diabetic retinopathy (DRP) (mean age 64.64+/-9.01 years, 56 males, 49 females), 35 age-matched non diabetic (mean age 61.65+/-7.6 years, 14 males and 21 females) and 42 young healthy volunteers (mean age 25.52+/-3.32 years, 22 males, 20 females) were recruited. Lower extremity artery disease (LEAD) and microcirculatory alterations were screened by hand-held Doppler, transcutaneous partial tissue oxygen tension (tcpO2), tuning fork test, 6-minute walk test, erythrocyte aggregation and deformability. RESULTS: High prevalence of LEAD was detected in diabetic population: 55.3% fulfilled the criteria of LEAD based on ankle-brachial index; severely impaired tcpO2 was measured in 18.6%. The results of non-invasive measurements of the diabetic patients were significantly worse than those of the control groups (p < 0.05). Hemorheological disturbances could be characterized by the significantly higher erythrocyte aggregation (p < 0.05) and lower erythrocyte deformability (p < 0.05) in the diabetic population. CONCLUSION: Macro- and microcirculatory lower limb disorders could be revealed at high prevalence in diabetic patients with retinopathy. Measurement of tcpO2 and hemorheological variables could be useful to discover patients at higher risk for diabetic foot complications. PMID- 29630533 TI - Effects and influencing factors on hemorheological variables taken into consideration in surgical pathophysiology research. AB - In surgical pathophysiology ischemia-reperfusion, inflammatory processes, sepsis, vascular interventions, tissue trauma, shock, all mean conditions in which hemorheological parameters show alterations. Despite of numerous clinical and experimental studies, the in vivo hemorheology is not completely understood yet, and several fundamental questions still need to be answered. Investigating these issues, experimental surgical models are important, in point of view of the translational research as well. In this paper we aimed to make an attempt on summarizing the possible factors and conditions that might have an effect on hemorheological results in experimental surgical studies. Hemorheological parameters show alterations in surgical pathophysiological processes in a complex way. However, the changes are dominantly non-specific. Standardized experimental conditions, related to the experimental animal (species, animal welfare) anesthesia-medications, operation, sampling and, if applicable, conditions of the postoperative period, are inevitable for a safe assessment of valuable (hemorheological) results. Parallel investigations - such as microcirculatory monitoring, imaging techniques, other laboratory methods, histomorphology- have great importance, together with individual analysis of changes, for a better understanding of the changes and for comparability with clinical results. PMID- 29630534 TI - Albumin solder covalently bound to a polymer membrane: New approach to improve binding strength in laser tissue soldering in-vitro. AB - Laser tissue soldering (LTS) based on indocyanine green (ICG)-mediated heat denaturation of proteins might be a promising alternative technique for micro suturing, but up to now the problem of too weak shear strength of the solder welds in comparison to sutures is not solved. Earlier reports gave promising results showing that solder supported by carrier materials can enhance the cohesive strength of the liquid solder. In these studies, the solder was applied to the carriers by dip coating. Higher reliability of the connection between the solder and the carrier material is expected when the solder is bound covalently to the carrier material. In the present study a poly(ether imide) (PEI) membrane served as carrier material and ICG-supplemented albumin as solder substrate. The latter was covalently coupled to the carrier membrane under physiological conditions to prevent structural protein changes. As laser source a diode continuous-wave laser emitting at 808 nm with intensities between 250 mW and 1500 mW was utilized. The albumin functionalized carrier membrane was placed onto the tunica media of explanted pig thoracic aortae forming an overlapping area of approximately 0.5*0.5 cm2. All tests were performed in a dry state to prevent laser light absorption by water. Infrared spectroscopy, spectro-photometrical determination of the secondary and primary amine groups after acid orange II staining, contact angle measurements, and atomic force microscopy proved the successful functionalization of the PEI membrane with albumin. A laser power of 450 mW LTS could generate a membrane-blood vessel connection which was characterized by a shear strength of 0.08+/-0.002 MPa, corresponding to 15% of the tensile strength of the native blood vessel. Theoretically, an overlapping zone of 4.1 mm around the entire circumference of the blood vessel could have provided shear strength of the PEI membrane-blood vessel compound identical to the tensile strength of the native blood vessel. These in-vitro results confirmed the beneficial effects of solder reinforcement by carrier membranes, and suggest LTS with covalently bound solders on PEI substrates for further studies in animal models. PMID- 29630535 TI - DIBI, a polymeric hydroxypyridinone iron chelator, reduces ocular inflammation in local and systemic endotoxin-induced uveitis. AB - BACKGROUND/OBJECTIVE: Non-infectious uveitis is an inflammatory disease of the eye commonly treated by corticosteroids, though important side effects may result. A main mediator of inflammation are oxygen free radicals generated in iron-dependent pathways. As such, we investigated the efficacy of a novel iron chelator, DIBI, as an anti-inflammatory agent in local and systemic models of endotoxin induced uveitis (EIU). METHODS: Firstly, the effects of DIBI in systemic EIU in Lewis rats were established. 2 hours post intravenous LPS or LPS/DIBI injections, leukocyte activation and functional capillary density (FCD) were examined using intravital microscopy (IVM) of the iridial microcirculation. Secondly, the toxicity of DIBI was evaluated in BALB/C mice for both acute and chronic dosages through gross ocular examination, intraocular pressure measurements and hematoxylin-eosin staining of ocular tissue. Lastly, three groups of BALB/C mice, control, LPS or DIBI + LPS, were studied to evaluate the effectiveness of DIBI in treating local EIU. Five hours post-local intravitreal (i.v) injection, leukocyte activation and capillary density were examined via IVM. RESULTS: Treatment of systemic EIU with DIBI resulted in a reduction of leukocyte activation and FCD improvement within the iridial microcirculation. Toxicity studies suggested that acute and chronic DIBI administration had no adverse effects in the eye. In the local EIU model, DIBI was shown to reduce leukocyte activation and restored the FCD/DCD ratio, providing evidence for its anti-inflammatory properties. CONCLUSIONS: Our study has provided evidence that DIBI has anti-inflammatory effects in experimental uveitis. Additionally, no local ocular toxicity was observed. PMID- 29630536 TI - Timolol effects on erythrocyte deformability and nitric oxide metabolism. AB - Timolol maleate is a compound used in treatment for reducing increased intra ocular pressure by limiting aqueous humor production. Decreased erythrocyte deformability (ED), increased activity of erythrocyte acetylcholinesterase (AChE), increased values of nitrosoglutathione (GSNO) and nitic oxide (NO) and decreased plasma levels of NO metabolites, were described in primary open angle glaucoma patients. In healthy human red blood cells (RBCs), timolol is an inhibitor of AChE and induces NO efflux and GSNO efflux from that blood component in lower concentration than those obtained in presence of the natural AChE substrate, acetylcholine (ACh). The signal transduction pathway in RBCs described for NO in dependence of AChE-ACh active complex involves Gi protein, protein tyrosine kinase (PTK like Syk and p53/56Lyn), protein tyrosine phosphatase (PTP) and adenylyl cyclase (AC).The aim of this in vitro study was to verify the effect of timolol maleate in ED, NO efflux and NO derivatives molecules (NOx) like nitrite (NO2-), nitrate (NO3-, peroxynitrite (-ONOO) and GSNO under the presence of PTK, PTP, AC and guanylyl cyclase (GC) enzyme proteins inhibitors.Blood samples from healthy donors were each one divided and were performed aliquots in absence (control aliquots) and presence of timolol or timolol plus each inhibitor and Gi protein uncoupling. No significant differences in erythrocyte NO efflux, GSNO, peroxynitrite, nitrite and nitrate concentrations in response to timolol when compared with the untreated blood samples aliquots were obtained.It was observed an increase in erythrocyte deformability at high shear stresses induced by the simultaneous presence of timolol and band 3 protein dephosphorylation by PTK syk inhibitor. No significant differences where verified in peroxynitrite levels in the blood aliquots in presence of timolol plus each enzyme inhibitor and Gi protein uncoupling in relation to the control aliquots. No variation of GSNO concentration occurs under the presence of timolol and AMGT (PTK lyn inhibitor) besides the significant higher values observed with each one of the other inhibitors. Nitrate concentration increases significantly in all aliquots with timolol plus each one of the inhibitors. The same was observe with nitrite levels with exception of the aliquots with timolol plus AMGT or timolol plus Gi protein uncoupling showing no significant values in relation to the control aliquots.Besides the changes in NO derivative molecules and NO efflux from RBCs obtained in this study with blood samples of healthy donors under the effect of timolol plus each inhibitor of the proteins participants in NO signal transduction mechanism, further analogue studies must be promoted with blood samples of patients with glaucoma or any other inflammatory vascular disease. PMID- 29630537 TI - Effects of extracts prepared from modified porous poly(ether imide) microparticulate absorbers on cytotoxicity, macrophage differentiation and proinflammatory behavior of human monocytic (THP-1) cells. AB - Remaining uremic toxins in the blood of chronic renal failure patients represent one central challenge in hemodialysis therapies. Highly porous poly(ether imide) (PEI) microparticles have been recently introduced as candidate absorber materials, which show a high absorption capacity for uremic toxins and allow hydrophilic surface modification suitable for minimization of serum protein absorption. In this work, the effects of extracts prepared from PEI microparticles modified by nucleophilic reaction with low molecular weight polyethylene imine (Pei) or potassium hydroxide (KOH), on human monocytic (THP-1) cells are studied. The obtained results suggested that the extracts of Pei and KOH modified PEI absorbers have no negative effect on THP-1 cell viability and do not initiate the critical differentiation towards macrophages. The extracts did not enhance transcript or protein levels of investigated proinflammatory markers in THP-1 cells, namely, TNFMU, MCP1, IL6 and IL8. Based on these findings such modified PEI microparticles should be qualified for further pre-clinical evaluation i.e. in an in vivo animal experiment. PMID- 29630538 TI - Causative treatment of acid aspiration induced acute lung injury - Recent trends from animal experiments and critical perspective. AB - Aspiration of low-pH gastric fluid leads to an initial pneumonitis, which may become complicated by subsequent pneumonia or acute respiratory distress syndrome. Current treatment is at best supportive, but there is growing experimental evidence on the significant contribution of both neutrophils and platelets in the development of this inflammatory pulmonary reaction, a condition that can be attenuated by several medicinal products. This review aims to summarize novel findings in experimental models on pathomechanisms after an acid aspiration event. Given the clinical relevance, specific emphasis is put on deduced potential experimental therapeutic approaches, which make use of the characteristic alteration of microcirculation in the injured lung. PMID- 29630539 TI - Contrast-enhanced ultrasound (CEUS) as a new technique to characterize suspected renal transplant malignancies in renal transplant patients in comparison to standard imaging modalities. AB - BACKGROUND: Renal transplant patients have a higher risk for malignancies of the renal transplant. In most cases suspected renal malignancies will be detected during the regular ultrasound follow-up and will require cross-sectional imaging to rule out a malignant aetiology. But it is well known that contrast agents for computed tomography or magnetic resonance imaging are critical in patients with limited renal function. OBJECTIVE: This study aims to compare the sensitivity and specificity of contrast-enhanced ultrasound (CEUS) and gold standard imaging modalities in characterizing suspected renal transplant malignancies in renal transplant patients. METHODS: A total of 22 renal transplant patients who underwent one or more CEUS examinations and at least one standard imaging modality (CT or MRI) between 2005 and 2017 were included. Patient ages ranged from 28.2 years to 74.6 (mean age 55.7 years; SD+/-13.0 years). CEUS of 22 patients was correlated with a standard imaging modality, CT (15 out of 22) or MRI (7 out of 22), serving as gold standard. RESULTS: CEUS showed a sensitivity of 100%, a specificity of 94.4%, a positive predictive value (PPV) of 80%, and a negative predictive value (NPV) of 100%. CONCLUSIONS: CEUS is an eligible method to help characterizing suspected renal malignancies in renal transplant patients compared to the well-established imaging modalities CT and MRI. As an imaging modality with no nephrotoxic effects CEUS can be used repeatedly even in patients with limited renal function. PMID- 29630540 TI - Vascular rejection in renal transplant: Diagnostic value of contrast-enhanced ultrasound (CEUS) compared to biopsy. AB - BACKGROUND: Despite of the more potent immunosuppressive medication, vascular rejection is still a major issue after renal transplantation. Renal biopsy is the gold standard diagnostic to evaluate acute and chronic allograft rejection. As it is an invasive diagnostic there is the risk of complications like haematoma, arteriovenous fistulas, active bleeding or infection. Contrast-enhanced ultrasound is a non-invasive imaging modality that allows visualising renal transplant perfusion. OBJECTIVE: To analyse the sensitivity and specificity of contrast-enhanced ultrasound (CEUS) compared to biopsy as gold standard in diagnosing vascular rejection in renal transplant patients. METHODS: A total of 57 renal transplant recipients with poor renal allograft function with initial diagnostic imaging between 2006 and 2017 were included in the study. Clinical data and imaging studies were analysed retrospectively. The diagnostic accuracy of CEUS in diagnosing vascular rejection of the renal transplant was compared to renal biopsy as gold standard. Out of 57 patients 7 patients showed signs of vascular rejection in biopsy. In 6 out of these 7 patients CEUS described irregularities in renal perfusion suspicious of vascular rejection. RESULTS: CEUS showed a sensitivity of 85.7%, a specificity of 100%, a positive predictive value (PPV) of 100%, and a negative predictive value (NPV) of 98.0%. CONCLUSIONS: CEUS is a safe, non-nephrotoxic imaging modality for the initial imaging of renal transplant recipients with elevated kidney function parameters suspicious of vascular rejection. Compared to renal biopsy as gold standard CEUS shows a high specificity and PPV in detecting signs of vascular rejection. Since sub-types of vascular rejection with cellular and humoral components with greater risk for allograft loss have been described renal biopsy is inevitable in these cases. PMID- 29630541 TI - Diagnostic performance of contrast-enhanced ultrasound (CEUS) for the evaluation of gallbladder diseases1. AB - BACKGROUND: Contrast-enhanced ultrasound (CEUS) has been used as an additional imaging technique to conventional ultrasound in order to clarify gallbladder findings, CEUS is easy and fast to perform, overcomes the limitations of gray scale ultrasonography and is a safe tool. OBJECTIVE: The aim of this retrospective mono-center analysis study is to evaluate the diagnostic performance of CEUS in the assessment of gallbladder disease by comparing its results with additional CT findings. METHODS: A total of 24 patients between 2009 and 2017 with unclear gallbladder appearance were retrospectively analysed. The contrast agent administered was a second-generation blood pool agent (SonoVue(r), Bracco, Milan, Italy). Examinations were performed and interpreted by a single experienced radiologist with more than fifteen years' experience. RESULTS: 24 patients were successfully examined without any adverse reaction. CEUS presented a sensitivity of 75%, a specificity of 100.0%, a positive predictive value of 100.0% and a negative predictive value of 95%. CONCLUSIONS: In conclusion, the excellent results in this study acknowledged that CEUS is a feasible alternative tool to differentiate gallbladder pathologic alterations. PMID- 29630542 TI - In vitro hemocompatability evaluation of gold nanoparticles capped with Lactobacillus plantarum derived lipase1. AB - BACKGROUND: Gold nanoparticles (GNPs) are key diagnostic and therapeutic agents in biomedical sciences. Several studies have been carried out in different therapeutic areas such as in cancer treatment, antibacterial topical agents, imaging agents etc. There is a necessity to evaluate the gold nanoparticles cytotoxicity at all fronts. Since blood is the first point of contact in any therapy, it is required to have a thorough in vitro investigation of gold nanoparticles to avoid any adverse effects. OBJECTIVE: The objective of the current study is to evaluate the effect of gold nanoparticles capped with lipase on blood clotting factors, platelets, coagulation time and blood clotting strength. METHODS: Whole blood samples were drawn from healthy volunteers. Plasma and plasma with platelets were isolated from the blood and all the samples were treated with lipase capped gold nanoparticles, except control. Plasma fibrinogen formed in the blood coagulation process after contacting with nanoparticles was quantitatively evaluated. In addition, platelet aggregation, blood clotting kinetics, strength of the blood clot and time were evaluated post nanoparticle treatment. RESULTS: The work primarily explores the effect of GNPs on blood with changing concentrations of lipase capping. Plasma fibrinogen levels of plasma samples were found to be moderately elevated, however, there is no significant effect on blood clotting kinetics, strength, and platelet aggregation. Also, the study showed that lipase capped GNPs did not result in aggregation upon interaction with plasma components and remained stable for 1 hour after incubation. CONCLUSIONS: Our study revealed that lipase capped GNPs synthesized using NaBH4 approach were stable and hemocompatible. There is an increase in fibrinogen levels after the exposure to nanoparticles, an observation which is consistent with other studies. However, the functional consequences of such increase are unknown. The results of no significant platelet aggregation, change in blood clotting time, kinetics, and clot strength revealed the non-toxic effect of lipase capped GNPs towards blood components, which is essential for any in vivo applications. PMID- 29630543 TI - Evaluation of dynamic effects of therapy-induced changes in microcirculation after percutaneous treatment of vascular malformations using contrast-enhanced ultrasound (CEUS) and time intensity curve (TIC) analyses. AB - : The aim of this follow-up study was to demonstrate the effect of percutaneous interventional treatment on local microcirculation of peripheral vascular malformations using CEUS and TIC analysis. MATERIAL AND METHODS: Retrospective analysis of 197 patients (136 female; 61 male; 3-86 years) with 135 venous (VM), 39 arterio-venous (AVM), 8 lymphatic and 15 veno-lymphatic peripheral vascular malformations before and after the first percutaneous treatment.CEUS was performed after i.v. injection of 1-2.4 ml of sulfur hexafluoride microbubbles (SonoVue(r)) using a 6-9 MHz linear probe. Digitally stored cine loops (starting in the early arterial phase for 60 sec) were read by independent readers in consensus. Regions of interest (ROI) were defined in the center and at the margins of the malformation, as well as in the healthy surrounding tissue. TIC analyses with Time to Peak (TTP) and Area under the Curve (AUC) were calculated using integrated perfusion software. RESULTS: After the treatment there was a significant decrease for median AUC in VM in the center from 297.8 (14.5-2167.6) rU down to 243.3 (0.1-1678.8) rU (p = 0.043) and in the surrounding tissue down to 107.7 (20.2-660.2) rU (p = 0.018). For the other malformations AUC decreased in the center and the margins as well. TTP rose, however these changes did not reach the level of significance. CONCLUSION: Analyzing the capillary microcirculation TICs offer a possibility of monitoring therapy-induced capillary changes of vascular malformations. PMID- 29630544 TI - Blood rheology in children with the S/beta+-thalassemia syndrome. AB - The aim of the present study was to compare blood rheological parameters between children with homozygous sickle cell disease (SS), sickle cell SC disease or S/beta+-thalassemia syndrome, and healthy children (AA) and to test the associations between blood rheology and the clinical severity in S/beta+ thalassemia. Sixty-two SS, 14 SC, 11 S/beta+-thalassemia and 12 healthy children participated in this study. Blood viscosity was measured with a cone-plate viscometer at 225 s-1. Red blood cell (RBC) deformability was measured by ektacytometry and RBC aggregation, by syllectometry. Nitric oxide and nitrotyrosine levels were determined for each child. While most of the hematological parameters were not different between SC and S/beta+-thalassemia children, we demonstrated that SC patients had lower RBC deformability and aggregation than S/beta+ individuals. Nitrotyrosine level, which indicates peroxynitrite production, was similar and lower in both healthy and S/beta+ compared to SS children. However, S/beta+-thalassemia children who experienced vaso-occlusive crises (VOC) in the 2 previous years had lower NOx and higher nitrotyrosine levels than those who never had VOC within the same period. These findings suggest that vascular function could be impaired in the most severe S/beta+-thalassemia children compared to the less severe one. PMID- 29630545 TI - ATP-based cell viability assay is superior to trypan blue exclusion and XTT assay in measuring cytotoxicity of anticancer drugs Taxol and Imatinib, and proteasome inhibitor MG-132 on human hepatoma cell line HepG2. AB - BACKGROUND: Drug-induced liver injury (DILI) is the most common reason for withdrawal of anticancer drugs from the market. To prevent adverse side effects of drugs, it is important to investigate potential toxicity in vitro. However, outcome of cytotoxicity screenings can differ remarkably depending on the method used. OBJECTIVE: We aimed to compare XTT, ATP-based CellTiter-Glo(r)2.0 and trypan blue exclusion (TBE) assays regarding their sensitivity in detecting acute cytotoxicity on HepG2 cells after incubation with the classical anticancer drugs Taxol and Imatinib or with the proteasome inhibitor MG-132. METHODS: HepG2 cells were treated for 48 h and cell viability was analysed by XTT, CellTiter-Glo(r)2.0 or TBE assay. RESULTS: All tested compounds showed a reduction of viability of HepG2 cells. However, assay results differed significantly: Both ATP-based and TBE assay showed concentration-dependent cytotoxic effects, but outcomes were less pronounced with TBE. In contrast, the widely used XTT assay did not detect any acute cytotoxicity of Taxol and Imatinib. CONCLUSIONS: Acute cytotoxic effects of tested compounds could be revealed. However, results were significantly different from each other with ATP assay being the most sensitive one under the conditions tested. Thus, acute cytotoxicity can be dramatically underestimated if only standard XTT test is used. PMID- 29630546 TI - Red blood cell deformability in multiple myeloma1. AB - The aim of this study was the evaluation of the erythrocyte deformability in multiple myeloma (MM). We enrolled 29 MM patients and we evaluated, on fasting venous blood, the erythrocyte deformability, expressed as elongation index, and examined using the diffractometric method. By comparing normal controls and MM patients, a significant decrease in erythrocyte deformability, especially at low shear stresses, was found. In this research paper we evaluated all the hypothesis for a possible explanation of the behaviour of red blood cell deformability in MM, even considering how the alteration of erythrocyte deformability worsens the microcirculatory flow in these patients in association with the marked increase in plasma viscosity. PMID- 29630547 TI - Assessing Mild Cognitive Impairment Progression using a Spherical Brain Mapping of Magnetic Resonance Imaging. AB - BACKGROUND: The early diagnosis of Alzheimer's Disease (AD), particularly in its prodromal stage, mild cognitive impairment (MCI), still remains a challenge. Many computational tools have been developed to successfully explore and predict the disease progression. In this context, the Spherical Brain Mapping (SBM) proved its ability in detecting differences between AD and aged subjects without symptoms of dementia. Being a very visual tool, its application in predicting MCI conversion to AD could be of great help to understand neurodegeneration and the disease progression. OBJECTIVE: In this work, we aim at predicting the conversion of MCI affected subjects to AD more than 6 months in advance of their conversion session and understanding the progression of the disease by predicting neuropsychological test outcomes from MRI data. METHODS: In order to do so, SBM is applied to a series of MRI scans from the Alzheimer's Disease Neuroimaging Initiative (ADNI). The resulting spherical brain maps show statistical and morphological information of the brain in a bidimensional plane, performing at the same time a significant feature reduction that provides a feature vector used in classification analysis. RESULTS: The study achieves up to 92.3% accuracy in the AD versus normal controls (CTL) detection, and up to a 77.6% in detection a of MCI conversions when trained with AD and CTL subjects. The prediction of neuropsychological test outcomes achieved R2 rates up to more than 0.5. Significant regions according to t-test and correlation analysis match reported brain areas in the literature. CONCLUSION: The results prove that Spherical Brain Mapping offers good ability to predict conversion patterns and cognitive state, at the same time that provides an additional aid for visualizing a two dimensional abstraction map of the brain. PMID- 29630548 TI - White Matter Hyperintensities and Cognition in Mild Cognitive Impairment and Alzheimer's Disease: A Domain-Specific Meta-Analysis. AB - BACKGROUND: White matter hyperintensities (WMHs) are related to cognitive dysfunction in the general population. The clinical relevance of WMHs in patients with Alzheimer's disease (AD) and mild cognitive impairment (MCI) is, however, unclear. OBJECTIVE: This meta-analysis aimed to quantify the association of WMHs and specific cognitive domains in patients with MCI or AD. METHODS: PubMed (January 1990-January 2017) was searched for studies that used MRI to quantify WMHs, and measured cognitive functioning (>=1 predefined cognitive domain with >=1 test) in a well-defined population of persons diagnosed with MCI or AD. Fischer's Z was used as the common metric for effect size. Modifying effects of demographics, MMSE, and WMH location were examined. RESULTS: Twelve cross sectional studies on AD (total n = 1,370, median age 75 years) and 10 studies on MCI (9 cross-sectional, 1 longitudinal; total n = 2,286, median age 73 years) were included. The association between WMHs and overall cognition was significantly stronger for MCI (-0.25, -0.36 to -0.14) than for AD (-0.11, -0.14 to -0.08; QM = 10.7, p < 0.05). For both groups, largest effect sizes were found in attention and executive functions (-0.26, -0.36 to -0.15) and processing speed (-0.21, -0.35 to -0.12). No significant modifying effects of age and gender were found. CONCLUSION: WMHs have a medium-sized association with different cognitive functions in patients with MCI and a small, but statistically significant, association with cognition in AD. These result underscore the role of co occurring vascular brain damage in MCI and AD. PMID- 29630549 TI - Brazilian Green Propolis Prevents Cognitive Decline into Mild Cognitive Impairment in Elderly People Living at High Altitude. AB - BACKGROUND: Systemic inflammation is known as a risk factor of cognitive decline. OBJECTIVE: To investigate the effects of propolis on cognitive decline and systemic inflammation in elderly people living at high altitude. METHODS: Sixty participants (average 72.8 years) living at altitude (2,260 meters) were randomized to receive propolis (0.83 g, n = 30) or placebo (n = 30) for 24 months. Cognitive outcomes were assessed using MMSE and serum cytokine levels were measured for 24 months in a double-blind study. RESULTS: MMSE scores were 26.17 at baseline and 23.87 at 24 months in placebo group. Compared to placebo group, improvements of MMSE scores were significant in propolis-treated subjects (p = 0.007) with a response emerging over time (time points*group interaction, p = 0.016). In addition, the serum IL-1beta and IL-6 levels were significantly different across treatments (p < 0.0001) showing upward and downward trends in placebo- and propolis-treated subjects, respectively (p < 0.0001). Serum levels of TNF-alpha were not significantly different across treatment (p = 0.0528) but with a response emerging over time (time points*group interaction, p = 0.016). In contrast, serum levels of TGFbeta1 were significantly different across treatments (p < 0.0001) showing downward and upward trends in placebo- and propolis-treated subjects, respectively. Serum levels of IL-10 were significant for the effect of groups (p = 0.0411). Furthermore, MMSE scores correlated with the decrease in IL 1beta and the increase in TGFbeta1 in serum. CONCLUSION: Elderly people living at high altitude developed to MCI in 24 months with exacerbation of systemic inflammation. Ingestion of propolis (>12 months) protected against cognitive decline after systemic inflammation was reduced. PMID- 29630550 TI - Predicting Imminent Progression to Clinically Significant Memory Decline Using Volumetric MRI and FDG PET. AB - BACKGROUND: Brain imaging measurements can provide evidence of possible preclinical Alzheimer's disease (AD). Their ability to predict individual imminent clinical conversion remains unclear. OBJECTIVE: To investigate the ability of pre-specified volumetric magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography (FDG-PET) measurements to predict which cognitively unimpaired older participants would subsequently progress to amnestic mild cognitive impairment (aMCI) within 2 years. METHODS: From an apolipoprotein E4 (APOE4) enriched prospective cohort study, 18 participants subsequently progressed to the clinical diagnosis of aMCI or probable AD dementia within 1.8+/-0.8 years (progressors); 20 participants matched for sex, age, education, and APOE allele dose remained cognitively unimpaired for at least 4 years (nonprogressors). A complementary control group not matched for APOE allele dose included 35 nonprogressors. Groups were compared on baseline FDG-PET and MRI measures known to be preferentially affected in the preclinical and clinical stages of AD and by voxel-wise differences in regional gray matter volume and glucose metabolism. Receiver Operating Characteristic, binary logistic regression, and leave-one-out procedures were used to predict clinical outcome for the a priori measures. RESULTS: Compared to non-progressors and regardless of APOE-matching, progressors had significantly reduced baseline MRI and PET measurements in brain regions preferentially affected by AD and reduced hippocampal volume was the strongest predictor of an individual's imminent progression to clinically significant memory decline (79% sensitivity/78% specificity among APOE-matched cohorts). CONCLUSION: Regional MRI and FDG-PET measurements may be useful in predicting imminent progression to clinically significant memory decline. PMID- 29630552 TI - Decreased Event-Related Beta Synchronization During Memory Maintenance Marks Early Cognitive Decline in Mild Cognitive Impairment. AB - Mild cognitive impairment (MCI) refers to a measurable deficit in cognition in the absence of dementia or impairment in activities of daily living. Working memory impairment is among the earliest signs of MCI. Oscillatory analysis of working memory might be a potential tool for identifying patients at increased risk of developing dementia. Our study aimed to assess the temporospatial pattern of spectral differences during working memory maintenance between MCI patients and healthy controls and to compare the sources of oscillatory activity between the two groups. Event-related spectral perturbation of 17 MCI patients and 21 healthy control participants was studied with 128-channel EEG during the Sternberg working memory task. Source localization was performed by using the eLORETA software. Among the participants, 13 MCI and 15 control participants underwent a structural brain MRI examination. Event-related synchronization (ERS) in the alpha and beta frequency band was significantly lower in MCI patients compared to healthy control participants during retention. Both study groups showed significant memory load-related enhancement in both frequency band. In the MCI group, source localization revealed significantly attenuated beta oscillatory activity in the inferior and middle temporal gyrus, in the fusiform gyrus, and in the cuneus. Beta ERS correlated significantly with the size of the hippocampus, entorhinal cortex, and parahippocampal gyrus. During the retention period, MCI is characterized by decreased alpha and beta ERS compared to controls indicating early impairment in neural networks serving working memory maintenance. The assessment of electrophysiological changes in the beta frequency range may provide a useful diagnostic tool for the early detection of cognitive impairment. PMID- 29630553 TI - Heparin Modulates the Kinetics of Zinc-Induced Aggregation of Amyloid-beta Peptides. AB - Zinc-induced aggregation of amyloid-beta peptides (Abeta) is considered to contribute to the pathogenesis of Alzheimer's disease. While glycosaminoglycans (GAGs) that are commonly present in interneuronal space are known to enhance Abeta self-aggregation in vitro, the impact of GAGs on the formation of zinc induced amorphous Abeta aggregates has not yet been thoroughly studied. Here, employing dynamic light scattering, bis-ANS fluorimetry, and sedimentation assays, we demonstrate that heparin serving as a representative GAG modulates the kinetics of zinc-induced Abeta42 aggregation in vitro by slowing the rate of aggregate formation and aggregate size growth. By using synthetic Abeta16 peptides to model the Abeta metal-binding domain (MBD), heparin was found to effectively interact with MBDs in complex with zinc ions. We suggest that heparin adsorbs to the surface of growing zinc-induced Abeta42 aggregates via electrostatic interactions, thus creating a steric hindrance that inhibits further inclusion of monomeric and/or oligomeric zinc-Abeta42 complexes. Furthermore, the adsorbed heparin can interfere with the zinc-bridging mechanism of Abeta42 aggregation, requiring the formation of two zinc-mediated interaction interfaces in the MBD. As revealed by computer simulations of the zinc-Abeta16 homodimer complexed with a heparin chain, heparin can interact with the MBD via polar contacts with residues Arg-5 and Tyr-10, resulting in a conformational rearrangement that hampers the formation of the second zinc-mediated interaction in the MBD interface. The findings of this study suggest that GAGs, which are common in the in vivo macromolecular environment, may have a substantial impact on the time course of zinc-induced Abeta aggregation. PMID- 29630554 TI - Association of Plasma Neurofilament Light Chain with Neocortical Amyloid-beta Load and Cognitive Performance in Cognitively Normal Elderly Participants. AB - BACKGROUND: The disruption of neurofilament, an axonal cytoskeletal protein, in neurodegenerative conditions may result in neuronal damage and its release into the cerebrospinal fluid and blood. In Alzheimer's disease (AD), neurofilament light chain (NFL), a neurofilament subunit, is elevated in the cerebrospinal fluid and blood. OBJECTIVE: Investigate the association of plasma NFL with preclinical-AD features, such as high neocortical amyloid-beta load (NAL) and subjective memory complaints, and cognitive performance in cognitively normal older adults. METHODS: Plasma NFL concentrations were measured employing the single molecule array platform in participants from the Kerr Anglican Retirement Village Initiative in Ageing Health cohort, aged 65- 90 years. Participants underwent a battery of neuropsychological testing to evaluate cognitive performance and were categorized as low NAL (NAL-, n = 65) and high NAL (NAL+, n = 35) assessed via PET, and further stratified into subjective memory complainers (SMC; nNAL- = 51, nNAL+ = 25) and non-SMC (nNAL- = 14, nNAL+ = 10) based on the Memory Assessment Clinic- Questionnaire. RESULTS: Plasma NFL inversely correlated with cognitive performance. No significant difference in NFL was observed between NAL+ and NAL- participants; however, within APOEE4 non-carriers, higher NAL was observed in individuals with NFL concentrations within quartiles 3 and 4 (versus quartile 1). Additionally, within the NAL+ participants, SMC had a trend of higher NFL compared to non-SMC. CONCLUSION: Plasma NFL is inversely associated with cognitive performance in elderly individuals. While plasma NFL may not reflect NAL in individuals with normal global cognition, the current observations indicate that onset of axonal injury, reflected by increased plasma NFL, within the preclinical phase of AD may contribute to the pathogenesis of AD. PMID- 29630555 TI - Brain Metabolic, Structural, and Behavioral Pattern Learning for Early Predictive Diagnosis of Alzheimer's Disease. AB - Alzheimer's disease (AD) is a devastating neurodegenerative disorder affecting millions of people worldwide. Laboratory research and longitudinal clinical studies have helped to reveal various information about the disease but the exact causal process is not known yet. Patterns from alteration of neurochemicals (e.g., glutathione depletion, etc.), hippocampal atrophy, and brain effective connectivity loss as well as associated behavioral changes have generated important characteristic features. These imaging-based readouts and neuropsychological outcomes along with supervised clinical review are critical for developing a comprehensive artificial intelligence strategy for early predictive AD diagnosis and therapeutic development. PMID- 29630551 TI - Tau Proteolysis in the Pathogenesis of Tauopathies: Neurotoxic Fragments and Novel Biomarkers. AB - With predictions showing that 131.5 million people worldwide will be living with dementia by 2050, an understanding of the molecular mechanisms underpinning disease is crucial in the hunt for novel therapeutics and for biomarkers to detect disease early and/or monitor disease progression. The metabolism of the microtubule-associated protein tau is altered in different dementias, the so called tauopathies. Tau detaches from microtubules, aggregates into oligomers and neurofibrillary tangles, which can be secreted from neurons, and spreads through the brain during disease progression. Post-translational modifications exacerbate the production of both oligomeric and soluble forms of tau, with proteolysis by a range of different proteases being a crucial driver. However, the impact of tau proteolysis on disease progression has been overlooked until recently. Studies have highlighted that proteolytic fragments of tau can drive neurodegeneration in a fragment-dependent manner as a result of aggregation and/or transcellular propagation. Proteolytic fragments of tau have been found in the cerebrospinal fluid and plasma of patients with different tauopathies, providing an opportunity to develop these fragments as novel disease progression biomarkers. A range of therapeutic strategies have been proposed to halt the toxicity associated with proteolysis, including reducing protease expression and/or activity, selectively inhibiting protease-substrate interactions, and blocking the action of the resulting fragments. This review highlights the importance of tau proteolysis in the pathogenesis of tauopathies, identifies putative sites during tau fragment mediated neurodegeneration that could be targeted therapeutically, and discusses the potential use of proteolytic fragments of tau as biomarkers for different tauopathies. PMID- 29630556 TI - Ventral Tegmental Area in Prodromal Alzheimer's Disease: Bridging the Gap between Mice and Humans. AB - Alzheimer's disease (AD) is a progressive neurological disorder characterized by several cognitive and non-cognitive symptoms, with episodic memory being the earliest and most prominently impaired cognitive function. Dopaminergic signals are required for encoding hippocampal memory for new events and the ventral tegmental area (VTA), together with the locus coeruleus, are the primary sources of dopamine acting on dopaminergic receptors in the hippocampus. With this in mind, a recent study on a validated mouse model of AD highlighted on the hippocampal dysfunction and its correlation with an early degeneration of dopaminergic neurons in the VTA. In this issue, De Marco and Venneri test the hypothesis that the volume of the VTA nucleus in humans might be associated with cognitive features of AD. PMID- 29630557 TI - Newly discovered COLQ gene mutation and its clinical features in patients with acetyl cholinesterase deficiency. AB - To investigate the relationship between acetyl cholinesterase associated collagen gene (COLQ) mutation in patients with acetyl cholinesterase deficiency and its clinical characteristics. Serum and red blood cell acetyl cholinesterase from patients with acetyl cholinesterase deficiency (n=6) and normal controls (n=20) were measured by butyryl thiocholine substrate. COLQ gene variations were detected by sequencing. And the cholinesterase (ChE) genotypes were measured by dibucaine inhibition in vitro. The distributions of ChE surrounded the blood vessels and nerve fibers in lung or pancreas tissues were detected by immunohistochemical staining and indirect immunofluorescence. Serum lactic acid, ammonia and other clinical data were analyzed. Serum ChE in patients with acetyl cholinesterase deficiency were only 1/50 to 1/1000 fold of normal controls. Comparing to controls, dibucaine inhibition values of patients were significantly lower, while there were no differences in red blood cells acetyl cholinesterase. Serum lactic acid and ammonia in patients were significantly higher than controls. Inser 1281-1282 GC of COLQ gene was found in 2 patients, while IVS 6 + 21 T > A, IVS 6 + 30 G > T, IVS 6 + 34 T > C and IVS66 + 12 inser T mutations were found in the other 4 patients, respectively. In addition, the patients with COLQ gene mutation were resistant to regular doses of anesthetics. COLQ gene mutation may be an important reason for the lack of serum ChE in patients with acetyl cholinesterase deficiency. PMID- 29630558 TI - The impact of Snoezelen in pediatric complex continuing care: A pilot study. AB - PURPOSE: Snoezelen is an environment that provides sensory stimulation to individuals in health care and rehabilitative settings. With the presentation of various instruments and materials, individuals can encounter a range of sensory experiences including visual, tactile, and auditory with the purpose of inducing relaxation and restoration. Little is known about how children and adolescents experience this form of sensory stimulation, particularly those in complex continuing care who may have limited verbal and mobility capacity. METHODS: This pilot study examined autonomic physiological responses and observational data on five children and adolescents in complex continuing care within a large rehabilitation hospital. Responses to Snoezelen and watching television were compared against baseline data collected during pre-intervention phases. RESULTS: Using a single-subject design, this preliminary study found that individual participant responses varied considerably. Four of the five participants exhibited significant changes between sessions on one or two distinct physiological measures. The authors call on additional studies that apply unique and multiple methods capable of accessing the preferences of children and adolescent in rehabilitative care. CONCLUSIONS: As an outcome, contributions to evidence-based practice can be made while supporting children's participation rights in health care decision making. PMID- 29630559 TI - Caregiver-report of symptoms following traumatic brain injury in a small clinical sample of preschool-aged children. AB - PURPOSE: Preschool-aged children have a high rate of traumatic brain injuries (TBI). Anecdotally, caregivers of young children describe symptoms not typically associated with TBI. The objective of this study was to preliminarily describe symptoms reported following TBI in an outpatient sample of preschool-aged children. METHODS: Retrospective chart review was completed of the first specialty clinic visit by 28 children ages 3 through 5 years with TBI (32% mild, 50% moderate, 18% severe) to identify post-injury symptoms elicited by caregiver interview including querying of symptoms listed on the Acute Concussion Evaluation (ACE) plus an open-ended request to describe any other symptoms. RESULTS: Visits occurred on average 38 days post-injury. Caregivers endorsed typical post-concussive symptoms, with headache being most common. In addition, caregivers described other symptoms not captured by the ACE which were grouped into the following categories: Appetite Changes, Behavioral Dysregulation, Decreased Engagement, Disrupted Sleep, Enuresis, Increased Dependence, and Stomachaches. CONCLUSIONS: Caregivers of preschool-aged children with TBI endorse that young children experience many typical post-concussive symptoms but also a range of other symptoms which may not be typically associated with TBI. Additional work is needed to determine whether specialized evaluation tools and educational materials may be useful for this age group. PMID- 29630560 TI - Are clinic-based walking measures associated with community walking activity in children with cerebral palsy? AB - PURPOSE: To examine the relationship between clinic-based walking capacity measures and community-based walking activity in ambulatory children with cerebral palsy (CP). METHODS: A secondary analysis of a cross-sectional cohort was employed at tertiary care children's hospital; n= 128, ages 2-9 years, Gross Motor Function Classification System (GMFCS) I-III. Walking capacity was captured with 1- and 6-minute walk tests (1MWT, 6MWT), Gross Motor Function Measure walk/run/jump score (GMFM-E), and Activity Scale for Kids performance version (ASKp-30). Walking activity performance in the community was quantified by StepWatch (SW). RESULTS: Moderate correlations were documented for 6MWT to SW outputs of walking level, moderate high intensity, 60-minute peak and peak activity index (r= 0.55-0.58, p< 0.01). GMFM-E correlated with all SW outputs (r= 0.55-0.69, p< 0.01) except 1-minute peak walking rate. Per regression modeling, GMFM-E was associated with walking level and intensity (p< 0.02) and 6MWT related to high intensity walking (p< 0.4, R=2 0.28-0.48). CONCLUSION: 6MWT and GMFM-E have the strongest associations with level, amount and intensity of walking in daily life. Results suggest that the 6MWT and GMFM-E can be employed to estimate community walking activity in ambulatory children with CP. Future studies should focus on environmental and personal factors that influence community walking performance. PMID- 29630561 TI - Informing pediatric rehabilitation: Language-based neuropsychological profile following traumatic brain injury and stroke secondary to arteriovenous malformation. AB - PURPOSE: To describe language-based neuropsychological outcomes following brain injury in two pediatric populations commonly treated in rehabilitation settings, namely severe traumatic brain injury (sTBI) and stroke secondary to arteriovenous malformation (AVM). METHODS: Investigated were children between the ages of 6 and 16 who were admitted to a brain injury rehabilitation program in a pediatric rehabilitation hospital and who were diagnosed with a left-sided sTBI (n= 16; mean age = 13.2) or a left-hemispheric stroke secondary to AVM (n= 16, mean age = 10.7). Groups were compared on demographic information, as well as general cognitive and language-based neuropsychological measures, controlling for age. RESULTS: Children in the AVM group presented with greater deficits, at trend levels, relative to the sTBI group on measures of working memory, verbal fluency, and an aphasia screening tool. CONCLUSIONS: This study represents an initial step in understanding the language-based neuropsychological outcomes of children diagnosed with sTBI compared to those with stroke secondary to AVM, which will help inform the rehabilitation process. With this knowledge, clinicians, families, and educators will be better equipped to provide informed individual rehabilitation programs, recommendations, and education for children and adolescents with brain injuries. PMID- 29630563 TI - Fibrocartilaginous emboli in the pediatric population: The role of rehabilitation in facilitating functional recovery. AB - A 12 year-old female presented to the emergency department with a right hemiparesis, headache, and neck pain. Initial neural imaging studies were unremarkable. However, a repeat MRI of the cervical spine during her acute hospitalization showed an acute spinal infarct. Neurological workup was consistent with fibrocartilaginous embolism (FCE) as the etiology. After several weeks of intensive inpatient rehabilitation, the patient demonstrated remarkable functional progress. This case report reviews the comprehensive pediatric literature on FCE with focus on the mechanism of injury, role of imaging studies, treatment options and prognosis. Awareness of the typical clinical history, as well as the signs and symptoms characteristic of FCE will improve the identification of this rare cause of abrupt weakness and potentially facilitate functional recovery. PMID- 29630562 TI - Computer Assisted REhabilitation (CARE) Lab: A novel approach towards Pediatric Rehabilitation 2.0. AB - Pediatric Rehabilitation therapists have always worked using a variety of off-the shelf or custom-made objects and devices, more recently including computer based systems. These Information and Communication Technology (ICT) solutions vary widely in complexity, from easy-to-use interactive videogame consoles originally intended for entertainment purposes to sophisticated systems specifically developed for rehabilitation.This paper describes the principles underlying an innovative "Pediatric Rehabilitation 2.0" approach, based on the combination of suitable ICT solutions and traditional rehabilitation, which has been progressively refined while building up and using a computer-assisted rehabilitation laboratory. These principles are thus summarized in the acronym EPIQ, to account for the terms Ecological, Personalized, Interactive and Quantitative. The paper also presents the laboratory, which has been designed to meet the children's rehabilitation needs and to empower therapists in their work. The laboratory is equipped with commercial hardware and specially developed software called VITAMIN: a virtual reality platform for motor and cognitive rehabilitation. PMID- 29630564 TI - Interventions to improve sensory and motor outcomes for young children with central hypotonia: A systematic review. AB - OBJECTIVE: To evaluate evidence supporting physical and occupational therapy interventions used to improve sensory and motor outcomes for children 0-6 years with central hypotonia. METHODS: Four electronic databases were searched from 1996 to March 2017. Level of evidence and study conduct was evaluated using American Academy of Cerebral Palsy and Developmental Medicine criteria. Traffic lighting classification identified interventions that were green (proven effective), yellow (possibly effective) or red (proven ineffective or contraindicated). RESULTS: Thirty-seven articles were included. Nine studies measured orthotic interventions while four distinct studies published over nine articles measured treadmill interventions. Remaining studies measured impact of compression garments, massage, motor and sensori-motor interventions, positioning and mobility interventions. CONCLUSIONS: Green light evidence supports treadmill training (to promote ambulation and gait characteristics) and massage (to positively affect muscle tone, motor development and use of vision) for infants with Down syndrome. These interventions are considered Yellow (possibly effective) for other populations. Green light evidence supports impact of orthoses on foot alignment for ambulatory children with hypotonia, while impact on gait characteristics is Yellow light and motor development may be negatively impacted (Red light) in pre-ambulatory children. All other interventions rated Yellow (possibly effective) and therapists should monitor using sensitive outcome measures. PMID- 29630567 TI - Journal of Pediatric Rehabilitation Medicine announces new Editor-in-Chief. PMID- 29630568 TI - Erratum. PMID- 29630569 TI - Editorial. PMID- 29630570 TI - Randomized, prospective, monocentric study to compare the outcome of continuous passive motion and controlled active motion after total knee arthroplasty. AB - BACKGROUND: The number of patients requiring a total knee arthroplasty (TKA) is increasing and postoperative care is an important factor for the recovery of knee function. It is discussed controversially, if the benefits of controlled active motion (CAM) therapies are comparable to continuous passive motion (CPM) therapies. OBJECTIVE: Comparison of postoperative outcomes using a device in CAM and CPM settings, in addition to standard physiotherapeutical exercises immediately after TKA. METHODS: TKA patients were randomized to either CAM or CPM therapy performed with an identical device (ARTROMOT(r) ACTIVE-K, Ormed GmbH). All patients received an additional physiotherapeutic program. Pain, knee associated problems (KOOS), active range of motion (ROM), and adverse events were documented before surgery, during the stationary stay and after an outpatient period. RESULTS: We included 50 patients (70 +/- 8 years). During the postoperative period, KOOS scales improved significantly in both groups, but the CAM group showed a significantly better improvement of pain and quality of life scale. Furthermore, postoperative course of pain intensity and knee flexion was significantly better in the CAM group. CONCLUSIONS: CAM and CPM lead to significant improvements after TKA, but CAM shows better results in terms of flexion, pain and quality of life. PMID- 29630571 TI - Training set extension for SVM ensemble in P300-speller with familiar face paradigm. AB - BACKGROUND: P300-spellers are brain-computer interface (BCI)-based character input systems. Support vector machine (SVM) ensembles are trained with large scale training sets and used as classifiers in these systems. However, the required large-scale training data necessitate a prolonged collection time for each subject, which results in data collected toward the end of the period being contaminated by the subject's fatigue. OBJECTIVE: This study aimed to develop a method for acquiring more training data based on a collected small training set. METHODS: A new method was developed in which two corresponding training datasets in two sequences are superposed and averaged to extend the training set. The proposed method was tested offline on a P300-speller with the familiar face paradigm. RESULTS: The SVM ensemble with extended training set achieved 85% classification accuracy for the averaged results of four sequences, and 100% for 11 sequences in the P300-speller. In contrast, the conventional SVM ensemble with non-extended training set achieved only 65% accuracy for four sequences, and 92% for 11 sequences. CONCLUSION: The SVM ensemble with extended training set achieves higher classification accuracies than the conventional SVM ensemble, which verifies that the proposed method effectively improves the classification performance of BCI P300-spellers, thus enhancing their practicality. PMID- 29630572 TI - Design and development of a smart knee pain relief pad based on vibration and alternate heating and cooling treatments. AB - Knee pain is one of the main health issues faced by different people in different parts of the world. Over one fourth of the people above the age of fifty suffer from knee pain. Though there are several physiotherapy treatments for treating knee pain they are not self-applicable and those which are self-applicable by the patient are not highly efficient. This paper deals with an approach towards the use of combining two effective physiotherapy treatments which include vibrations at acupressure points on knee and alternate heating and cooling treatments. These treatments are controlled by a smart phone in which the user can choose their setting depending on intensity and places of pain. The knee pad controlled using the smart phone serves as a self-applicable and effective knee pain treatment especially for the elderly. Heating and cooling combination therapy will be a suitable alternative for treatment of musculoskeletal diseases, decreases muscle spasms, muscular pain/tension and also increases the speed of nerve conduction, thus improving range of motion. This methodology also helps to relieve the sinusitis pain, chronic low back pain and muscular sprain in athletes. PMID- 29630573 TI - An effective method for monitoring tissue temperature using low-field MRI system. AB - This technical note describes an effective method for monitoring temperature based on the minimum curvature surface fitting (MCSF) referenceless proton resonance frequency shift (PRFs) at 0.35 T. Experimental tests on phantom, ex vivo porcine livers and human brain were conducted. A comparison study between the proposed method and a fiber optic temperature probe was conducted for microwave (MW) ablation. Experimental results showed that temperature root mean square error (RMSE) calculated by MCSF model were lower than those computed by high-order polynomial fitting. For ablation experiments, the temperature errors between temperature probe and MCSF method were all less than 2?C. PMID- 29630574 TI - Awkward trunk postures and their relationship with low back pain in hospital nurses. AB - BACKGROUND: Low back pain (LBP) is the most common work-related musculoskeletal problem among healthcare workers including nurses. Awkward trunk postures have been recognized as one common problem in this groupOBJECTIVE:The aims of this study were to: a) continuously assess trunk postures for an entire shift work in various hospital wards, and b) examine the relationship between the duration of exposure to awkward trunk postures and the occurrence of low back pain (LBP) among nurses. METHODS: Eighty nurses from eight wards in a hospital participated in this cross-sectional study. The prevalence of LBP was determined using the revised Nordic Musculoskeletal Questionnaire. Full-shift work trunk posture exposure was measured using an inclinometer. RESULTS: The prevalence of LBP among hospital nurses was 72%. The highest percentage of time spent in awkward postures in the sagittal plane (trunk flexion >=45 degrees ) and in the frontal plane (lateral bend >=20 degrees ) was recorded in the general (65.6% +/- 12.2) and orthopedic (48.4% +/- 7.4) wards, respectively. Logistic regression analyses showed that the duration of exposure to awkward trunk postures had a significant relationship with LBP (P < 0.05). CONCLUSIONS: The results highlight the potential risks of nursing job in terms of frequent and extreme trunk awkward postures, which may lead to the development of LBP. The findings can help to develop guidelines regarding prioritizing ergonomic interventions to reduce the prevalence of LBP among hospital nurses. PMID- 29630575 TI - A comparison of manual anthropometric measurements with Kinect-based scanned measurements in terms of precision and reliability. AB - BACKGROUND: Collecting anthropometric data for real-life applications demands a high degree of precision and reliability. It is important to test new equipment that will be used for data collectionOBJECTIVE:Compare two anthropometric data gathering techniques - manual methods and a Kinect-based 3D body scanner - to understand which of them gives more precise and reliable results. METHODS: The data was collected using a measuring tape and a Kinect-based 3D body scanner. It was evaluated in terms of precision by considering the regular and relative Technical Error of Measurement and in terms of reliability by using the Intraclass Correlation Coefficient, Reliability Coefficient, Standard Error of Measurement and Coefficient of Variation. RESULTS: The results obtained showed that both methods presented better results for reliability than for precision. Both methods showed relatively good results for these two variables, however, manual methods had better results for some body measurements. CONCLUSION: Despite being considered sufficiently precise and reliable for certain applications (e.g. apparel industry), the 3D scanner tested showed, for almost every anthropometric measurement, a different result than the manual technique. Many companies design their products based on data obtained from 3D scanners, hence, understanding the precision and reliability of the equipment used is essential to obtain feasible results. PMID- 29630576 TI - Posture and discomfort assessment in computer users while using touch screen device as compared with mouse-keyboard and touch pad-keyboard. AB - BACKGROUND: Touch screen computers require significant arm and hand movements. This can result to body discomfort and biomechanical load in users. OBJECTIVES: This study was carried out to examine posture and users' discomfort while using touch screen device as compared with mouse-keyboard and touch pad-keyboard. METHODS: Twenty three (23) students participated in this experimental study. The subjects completed pre-defined tasks in three 15 min trials by means of touch screen, touch pad-keyboard and mouse-keyboard as input devices. Postural angles were measured by Qualisys motion capture system. Body discomfort was assessed by a 10-cm visual analog scale. Rating scale was employed to assess the perception of subjects on the posture of body parts while utilizing the three devices. RESULTS: There was no significant difference in head inclination when using the three types of devices. Nevertheless, the mean of neck (p = 0.005) and trunk (p < 0.0001) inclinations as well as arm angle (p < 0.0001) while using touch screen, differed significantly from the two other devices and were more deviated from neutral posture. The type of input device was found to have significant effect on the right shoulder (p = 0.017), right elbow (p = 0.031), right wrist/hand (p = 0.004) and whole body discomfort (p = 0.026). Touch screen caused more discomfort in the mentioned regions when compared to the other two devices. Friedman test showed that differences of mean ratings for perceived shoulder and elbow postures in the 3 trials were significant (p = 0.005 and p = 0.011, respectively). Touch screen was the most unfavorable input device based on the subjects' judgment. CONCLUSION: Touch screen caused more deviated postural angles, increased body discomfort and unfavorable postures. PMID- 29630578 TI - Are core self-evaluations a suitable moderator in stressor-detachment relationships? A study among managers' perceived job demands, detachment and strain reactions. AB - BACKGROUND: The relationships among job demands, personality factors, recovery and psychological health receive increasing attention but are not well understoodOBJECTIVE:Therefore, the present study tests moderating effects among a sample of managers as proposed by the stressor-detachment model. We aimed to determine whether core self-evaluations (CSE) had an influence on the correlations between detachment and strain reactions (depressive symptoms, irritation, exhaustion) and between job demands and detachment. Further, we tested whether detachment attenuates the positive relation between job demands and strain reactions. METHODS: A convenience sample of managers in three German settings (N = 282) participated in the cross-sectional study. RESULTS: Results based on hierarchical regression analysis showed that high CSE significantly weakened the negative relationship between detachment and depressive symptoms in this sample. However, CSE did not moderate the negative relationship between job demands and detachment. Moreover, results revealed that detachment moderated the positive relation between job demands and exhaustion. CONCLUSIONS: The authors tested whether CSE was able to moderate the relationship between job demands, psychological detachment and different stress reactions. Although we found a significant interaction effect, CSE may be too distal to moderate all respective associations. PMID- 29630579 TI - Forces involved when sliding a patient up in bed. AB - BACKGROUND: This study investigated the effects of 3 different types of slide sheets upon hand forces while sliding a patient up in bed. METHODS: The sheets used included the reusable Arjo Maxislide, the McAuley disposable sheet, and a standard cotton sheet. Hand forces were measured from 38 male and female participants as they slid a 'patient' up in bed. A repeated measures ANOVA with 5 levels to the repeated factor (number of sheets and sheet type) was used, along with post-hoc repeated measures contrasts to compare differences between each condition. RESULTS: A significant reduction in required force occurred when using the friction reducing sheets as compared to the cotton sheets when used according to manufacturer recommendations, as well as a reduction in one of the single friction reducing sheet categories compared to the cotton. However, it is important to note that there was still substantial force being placed on the participants. CONCLUSIONS: This study illustrates the importance of using friction reducing slide sheets while engaging in manual patient handling. Future research should investigate the forces involved with other friction reducing materials and methods as well as the possibility of combining said materials and methods. PMID- 29630580 TI - Hand luggage in the train toilet. AB - BACKGROUND: The train toilet can form a barrier for those wishing to travel by train as it is perceived as being dirty, and therefore its use as being unpleasant. In addition, Dutch train toilet users have the additional issue of storing their hand luggage in the toilet's confined spaceOBJECTIVE:In this article, we examine the issue of Dutch travelers with hand luggage in relation to their use of train toilets. We investigate the type of hand luggage train travelers have with them and lastly, we study what travelers do with their hand luggage when using the toilet. METHODS: As part of an overarching study, we asked two specific questions on what travelers do with their hand luggage in a train toilet environment, followed by 22 observations from observational research. RESULTS: In the questionnaire, train travelers reported that bringing hand luggage into the train toilet is a problem because of the lack of storage space, and their fear of losing their seat. From the observational research, we noted that the participants mainly held their hand luggage on their bodies, and to a lesser extent, they placed it on the floor of the train toilet itself. None of the 22 participants used the hook to hang up their bag and/ or their coat. CONCLUSIONS: Travelers need a facility in the train toilet to store their hand luggage. Women have a stronger need for this than men, as they almost always carry an item with them. In addition, they use the toilet in hovering position or seated, with their backs to the wall, so they have limited space to store hand luggage on their backs or shoulders as men do. Most participants kept their hand luggage at a distance from the bowl, and the majority kept it off the floor (14 of the 22) because they were aware of the hygiene. The positioning of the coat/luggage hook at 1840 mm above the floor was considered to be too high, out of people's comfort area. PMID- 29630581 TI - Managers' social support: Facilitators and hindrances for seeking support at work. AB - BACKGROUND: Previous research has shown that social support is important for health and performance at work, but there is a lack of research regarding managers' social support at work, and if it needs to be improvedOBJECTIVE:To investigate managers' perception of work-related social support, and facilitators and hindrances that influence their seeking of social support at work. METHODS: Semi-structured interviews with sixty-two managers in two Swedish organizations. RESULTS: Work-related support, which strengthened their managerial image of being competent, was sought from sources within the workplace. Sensitive and personal support, where there was a risk of jeopardizing their image of being competent, was sought from sources outside the workplace. Access to arenas for support (location of the workplace, meetings, and vocational courses) and the managerial role could facilitate their support-seeking, but could also act as hindrances. Because attending different arenas for support were demanding, they refrained from seeking support if the demands were perceived as too high. CONCLUSIONS: Different supportive sources are distinguished based on what supportive function they have and in which arenas they are found, in order to preserve the confidence of the closest organization and to maintain the image of being a competent and performing manager. PMID- 29630582 TI - A concept of psychological work capacity demands: First evaluation in rehabilitation patients with and without mental disorders. AB - BACKGROUND: Work capacity demands are a concept to describe which psychological capacities are required in a job. Assessing psychological work capacity demands is of specific importance when mental health problems at work endanger work ability. Exploring psychological work capacity demands is the basis for mental hazard analysis or rehabilitative action, e.g. in terms of work adjustmentOBJECTIVE:This is the first study investigating psychological work capacity demands in rehabilitation patients with and without mental disorders. METHODS: A structured interview on psychological work capacity demands (Mini-ICF Work; Muschalla, 2015; Linden et al., 2015) was done with 166 rehabilitation patients of working age. All interviews were done by a state-licensed socio medically trained psychotherapist. Inter-rater-reliability was assessed by determining agreement in independent co-rating in 65 interviews. For discriminant validity purposes, participants filled in the Short Questionnaire for Work Analysis (KFZA, Prumper et al., 1994). RESULTS: In different professional fields, different psychological work capacity demands were of importance. The Mini-ICF Work capacity dimensions reflect different aspects than the KFZA. Patients with mental disorders were longer on sick leave and had worse work ability prognosis than patients without mental disorders, although both groups reported similar work capacity demands. CONCLUSIONS: Psychological work demands - which are highly relevant for work ability prognosis and work adjustment processes - can be explored and differentiated in terms of psychological capacity demands. PMID- 29630583 TI - Stakeholders identify similar barriers but different strategies to facilitate return-to-work: A vignette of a worker with an upper extremity condition. AB - BACKGROUND: Stakeholders involved in the return-to-work (RTW) process have different roles and qualificationsOBJECTIVE:To explore the perspectives of Australian stakeholders of the RTW barriers and strategies for a worker with an upper extremity condition and a complex workers' compensation case. METHODS: Using a case vignette, stakeholders were asked to identify barriers and recommend strategies to facilitate RTW. Content analysis was performed on the open-ended responses. The responses were categorised into RTW barriers and strategies using the biopsychosocial model. Pearson's Chi Square and ANOVA were performed to establish group differences. RESULTS: 621 participants (488 healthcare providers (HCPs), 62 employers, 55 insurers and 16 lawyers) identified 36 barriers (31 modifiable): 4 demographic; 8 biological; 15 psychological and 9 social barriers. 484 participants reported 16 RTW strategies: 4 biological; 6 psychological and 6 social strategies. 'Work relationship stressors' (83.4%) and 'Personal relationship stressors' (64.7%) were the most frequently nominated barriers. HCPs most frequently nominated 'Pain management' (49.6%), while employers, insurers and lawyers nominated 'RTW planning/Suitable duties programs' (40.5%; 42.9%; 80%). CONCLUSIONS: Stakeholders perceived similar barriers for RTW but recommended different strategies. Stakeholders appeared to be more proficient in identifying barriers than recommending strategies. Future research should focus on tools to both identify RTW barriers and direct intervention. PMID- 29630584 TI - Nonfatal agricultural work-related injuries: A case study from Northeast India. AB - BACKGROUND: Occupational injuries are a major problem in agriculture worldwide. In the Northeast region of India, most of the farm operations are carried out manually with hand operated tools and equipment. These tools also cause some nonfatal accidents. In the absence of reliable data on accidents in this region, injury prevention policy cannot be madeOBJECTIVE:The aim of this study was to survey injury causing agricultural accidents occurring during 2010 to 2013 in Arunachal Pradesh of the northeast region to know their magnitude, causes and severity. PARTICIPANTS: In this study, four districts of Arunachal Pradesh namely Papum Pare, Lower Subansiri, West Siang and East Siang were chosen using purposive sampling. From each district, 15 villages were selected. In these villages, a total of 50614 agricultural workers participated and 174 and 48 injuries were found for male and female workers respectively. METHOD: A case control study was carried out in Arunachal Pradesh. The questionnaire-based approach was used for data collection. The questionnaire contains detailed information on the demographic and injury characteristics. The Demographic information included gender, age, educational background, etc. and injury characteristics included the nature of the injury, the body part injured, and type of tools and equipment that caused the injury. RESULTS: The results showed that farm tools and equipment-related accidents were maximum i.e. 144 (60%) caused due to dao followed by 19 from spade (8%), 18 from sickle (7%) and 8 from axe (3%). The foot and legs were the most frequently injured body parts. From this study, it was also revealed that male agricultural workers are more affected as compared to their female counterparts. CONCLUSIONS: Agricultural accident incident rate (AIR) was found to be 589 per 1,00,000 workers per year. The AIR for males is 462 per 100,000 workers per year which is 3.6 times higher than female workers. The root causes of accidents are the use of traditional tools and equipment in various agricultural activities. Therefore, any ergonomic interventions in designing tools and equipment will significantly improve the occupational health and safety of workers. PMID- 29630585 TI - More than a job: Career development of individuals with cystic fibrosis. AB - BACKGROUND: Cystic fibrosis and its employment corollaries have received little attention despite the fact that complications of CF represent numerous theorized barriers to optimal career outcomes. OBJECTIVES: The objective of the study was to conduct grounded theory research that results in an understanding of the employment experiences of people with CF and ultimately a substantive grounded theory of career development applicable to individuals with this disease. METHODS: This study utilized the grounded theory method of qualitative inquiry. A purposive sample of ten young adults with CF participated in in-depth semi structured qualitative interviews. Analysis of the interview transcripts followed the constant comparative approach to coding, which identified core themes and sub themes and culminated in a conceptual framework of variables influencing employment and career development. RESULTS: An ecologically-based grounded theory of career development was developed. Major themes that influenced employment and career development were illness appraisal, occupational compromise, persistence, and altruism. Two patterns of career development outcomes emerged - the uninterrupted and the interrupted. CONCLUSIONS: A complicated interaction of numerous ecological variables (individual characteristics, personal contextual factors, mediating factors, and the environment) collectively influenced career development. The presence of CF alone did not guarantee negative effects on career development. PMID- 29630586 TI - Healthcare providers' experience with the management of mental health conditions in the context of Workers' Compensation. AB - BACKGROUND: Little is known about how healthcare providers (HCPs) in Canada manage mental health claims and the return to work (RTW) of injured workersOBJECTIVE:To examine HCPs' experience and challenges on the treatment of mental health conditions (MHCs) in the context of Workers' Compensation (WC) processes and their involvement in RTW. METHODS: Ninety-seven interviews with HCPs (general practitioners, n = 59; allied HCPs, n = 19; specialists, n = 19) were conducted in British Columbia, Manitoba, Ontario and Newfoundland. A thematic content analysis was used to analyze interviews. RESULTS: HCPs reported that while RTW is extolled at virtually all costs by WC boards, they did not always see it as beneficial. Most HCPs were convinced that successful recovery and RTW depend on being aware of how mental and physical health is intertwined and treating both issues. Organizational barriers within WC processes and adversarial relationships between injured workers (IWs) and WC boards made it difficult for HCPs to adequately treat patients and facilitate RTW. Dealing with IWs' MHCs and their emotional distress due to 'going through WC systems' was challenging. CONCLUSIONS: WC boards must identify how policies can be modified to mitigate compensation processes and RTW for WC claimants with MHC. PMID- 29630587 TI - Occupational physical and emotional fitness. AB - Sports medicine is a wide field of knowledge with a focus on the physical and psychological aspects of individuals; unfortunately, it is not well-known among occupational therapy practitioners. If at all, it is focused on exercise therapy for physical injuries and pain. We agree there are many types of physical pain and injuries among workers in different occupations, but not all that pain is related to physical overuse. Recently, new recommendations were presented by the American College of Sports Medicine highlighting particularly the psychological aspects of occupational emotional fitness. However, there is very little research about the concurrent effects of cost-effective packages of therapy for occupational emotional and physical fitness. Accordingly, this commentary reviews the occupational physical and emotional fitness aspects of sports medicine. In addition, this work makes suggestions to examine packages and protocols of physical and emotional fitness, with therapeutic targets for occupational cultures in different societies for employees and employers. PMID- 29630588 TI - Trunk Muscle Endurance in Individuals With and Without a History of Anterior Cruciate Ligament Reconstruction. AB - Werner, DM and Barrios, JA. Trunk muscle endurance in individuals with and without a history of anterior cruciate ligament reconstruction. J Strength Cond Res XX(X): 000-000, 2017-Anterior cruciate ligament (ACL) rupture is one of the most common knee injuries and often leads to surgery. Second injury after an ACL reconstruction (ACLR) is a major risk after rehabilitation, and may be linked to persistent postoperative deficits in muscular strength and endurance. Trunk muscle endurance has not been well studied after ACLR. Therefore, the purpose of this study was to compare trunk endurance using the established McGill testing battery in 20 individuals who had previously undergone ACLR at least 1 year before with 20 controls matched for sex frequency, limb dominance, age, body mass index, and activity level. Four static positional holds to failure were performed in random order, with time in seconds recorded as the primary dependent variable. Mann-Whitney U tests using an alpha level of 0.05 were conducted comparing hold times for all positions between groups. Effect sizes were also calculated between groups. Deficits in trunk extension endurance were observed in the surgical group. The results of this study suggest that contemporary rehabilitation schemes after ACLR do not fully address trunk endurance deficits. Health care professionals delivering postoperative rehabilitation after ACLR may consider direct assessment of trunk endurance and targeted exercise training to address potential deficits. PMID- 29630589 TI - The Effect of Perioperative Cimetidine Administration on Time to Colorectal Cancer Recurrence. AB - BACKGROUND: Studies have reported that the perioperative use of cimetidine, a histamine type 2 receptor antagonist, in addition to chemotherapy in patients with lymph node-positive colorectal cancer (CRC) improves the survival. STUDY QUESTION: To determine if time to CRC recurrence could be prolonged with cimetidine. STUDY DESIGN: Cimetidine was prescribed to American Joint on Cancer Committee (AJCC) stage III CRC patients perioperatively. Tumor recurrence was defined as the time (in days) between tumor resection and CRC recurrence. Medical charts of patients diagnosed with CRC between 1996 and 2006 were reviewed. Inclusion criteria were patients with (a) AJCC stage III CRC, (b) who had undergone surgical resection of the tumor, and (c) who received chemotherapy (5 fluorouracil). MEASURES AND OUTCOMES: AJCC stage III CRC patients who did and did not receive cimetidine as part of the treatment regimen were compared with respect to their clinical outcomes using univariate analysis and Kaplan-Meier modeling. RESULTS: Between 1996 and 2006, 38 patients met our inclusion criteria. Twenty-six percent (10/38) received perioperative cimetidine (mean daily dose, 750 mg; mean duration, 369 days; mean total cumulative cimetidine dose, 274,070 mg/d) in addition to chemotherapy. Time to recurrence and cancer deaths were prolonged in the chemotherapy plus cimetidine group compared with the group that received chemotherapy alone (mean +/- SD: 1078 +/- 290 vs. 446 +/- 62; P = 0.03). In addition, we found a significant positive relationship between the duration of cimetidine therapy (days) and survival duration (correlation coefficient = 0.94, P = 0.02) and time until cancer recurrence (correlation coefficient = 0.99, P = 0.04). Moreover, there was a significant positive relationship between the total cumulative cimetidine dose and survival duration (correlation coefficient = 0.92, P = 0.03). CONCLUSIONS: Prolonged duration of cimetidine may be superior to shorter courses in prolonging recurrence of CRC and thus survival. PMID- 29630590 TI - Postoperative Adverse Cardiovascular Events Associated with Leptin and Adverse Age After Elective Major Non-Cardiac Surgery: An Asian Single-Center Study. AB - BACKGROUND The postoperative adverse cardiovascular events (PACE) after surgery can result in prolonged length of stay and poorer prognosis. The purpose of this Asian single-center study was to investigate the potential predicative role of leptin for PACE in elderly patients undergoing major non-cardiac surgery. MATERIAL AND METHODS The patients in the study were prospectively recruited from a series of elderly patients (>=60 years) undergoing elective major non-cardiac surgery (>=2 hours) in our hospital from June 2013 to June, 2016. The demographic and clinical data and the preoperative serum biomarkers of each participant were recorded in details. Suspected PACE were assessed by the same experienced expert based on clinical, blood, and other accessory tests. The univariate and multiple logistic regression analyses were plotted to evaluate the potential independent predictive factors for PACE. RESULTS A total of 270 elderly patients (145 males and 125 females), undergoing major elective non-cardiac surgery, were finally enrolled in this study. Older age, higher revised cardiac risk index score, higher levels of systolic blood pressure, B-type natriuretic peptide and leptin, the preoperative medication of beta blocker and lipid-lowering agents were positive predictors of PACE by univariate analyses (p<0.05). Our results indicated that preoperative leptin level (OR 1.84, 95% CI 1.08-3.42; p=0.015) and advanced age (OR 0.24, 95% CI 0.09-0.94; p=0.041) were significantly associated with the occurrence of PACE by multiple logistic regression analyses. CONCLUSIONS Preoperative serum leptin level and advanced age were two independent risk factors for PACE among elderly patients undergoing elective major non-cardiac surgery. PMID- 29630591 TI - Nitric oxide-mediated posttranslational modifications control neurotransmitter release by modulating complexin farnesylation and enhancing its clamping ability. AB - Nitric oxide (NO) regulates neuronal function and thus is critical for tuning neuronal communication. Mechanisms by which NO modulates protein function and interaction include posttranslational modifications (PTMs) such as S nitrosylation. Importantly, cross signaling between S-nitrosylation and prenylation can have major regulatory potential. However, the exact protein targets and resulting changes in function remain elusive. Here, we interrogated the role of NO-dependent PTMs and farnesylation in synaptic transmission. We found that NO compromises synaptic function at the Drosophila neuromuscular junction (NMJ) in a cGMP-independent manner. NO suppressed release and reduced the size of available vesicle pools, which was reversed by glutathione (GSH) and occluded by genetic up-regulation of GSH-generating and de-nitrosylating glutamate-cysteine-ligase and S-nitroso-glutathione reductase activities. Enhanced nitrergic activity led to S-nitrosylation of the fusion-clamp protein complexin (cpx) and altered its membrane association and interactions with active zone (AZ) and soluble N-ethyl-maleimide-sensitive fusion protein Attachment Protein Receptor (SNARE) proteins. Furthermore, genetic and pharmacological suppression of farnesylation and a nitrosylation mimetic mutant of cpx induced identical physiological and localization phenotypes as caused by NO. Together, our data provide evidence for a novel physiological nitrergic molecular switch involving S-nitrosylation, which reversibly suppresses farnesylation and thereby enhances the net-clamping function of cpx. These data illustrate a new mechanistic signaling pathway by which regulation of farnesylation can fine-tune synaptic release. PMID- 29630592 TI - Toward a theory of coactivation patterns in excitable neural networks. AB - The relationship between the structural connectivity (SC) and functional connectivity (FC) of neural systems is of central importance in brain network science. It is an open question, however, how the SC-FC relationship depends on specific topological features of brain networks or the models used for describing neural dynamics. Using a basic but general model of discrete excitable units that follow a susceptible-excited-refractory activity cycle (SER model), we here analyze how the network activity patterns underlying functional connectivity are shaped by the characteristic topological features of the network. We develop an analytical framework for describing the contribution of essential topological elements, such as common inputs and pacemakers, to the coactivation of nodes, and demonstrate the validity of the approach by comparison of the analytical predictions with numerical simulations of various exemplar networks. The present analytic framework may serve as an initial step for the mechanistic understanding of the contributions of brain network topology to brain dynamics. PMID- 29630593 TI - A multitask clustering approach for single-cell RNA-seq analysis in Recessive Dystrophic Epidermolysis Bullosa. AB - Single-cell RNA sequencing (scRNA-seq) has been widely applied to discover new cell types by detecting sub-populations in a heterogeneous group of cells. Since scRNA-seq experiments have lower read coverage/tag counts and introduce more technical biases compared to bulk RNA-seq experiments, the limited number of sampled cells combined with the experimental biases and other dataset specific variations presents a challenge to cross-dataset analysis and discovery of relevant biological variations across multiple cell populations. In this paper, we introduce a method of variance-driven multitask clustering of single-cell RNA seq data (scVDMC) that utilizes multiple single-cell populations from biological replicates or different samples. scVDMC clusters single cells in multiple scRNA seq experiments of similar cell types and markers but varying expression patterns such that the scRNA-seq data are better integrated than typical pooled analyses which only increase the sample size. By controlling the variance among the cell clusters within each dataset and across all the datasets, scVDMC detects cell sub populations in each individual experiment with shared cell-type markers but varying cluster centers among all the experiments. Applied to two real scRNA-seq datasets with several replicates and one large-scale droplet-based dataset on three patient samples, scVDMC more accurately detected cell populations and known cell markers than pooled clustering and other recently proposed scRNA-seq clustering methods. In the case study applied to in-house Recessive Dystrophic Epidermolysis Bullosa (RDEB) scRNA-seq data, scVDMC revealed several new cell types and unknown markers validated by flow cytometry. MATLAB/Octave code available at https://github.com/kuanglab/scVDMC. PMID- 29630594 TI - Community knowledge, attitudes and practices on Yellow fever in South Omo area, Southern Ethiopia. AB - BACKGROUND: Yellow fever (Yf) outbreak was recently reported in South Omo of Southern Ethiopia. This area was also highly affected by Yf outbreak in the 1960s. However, there is no reliable information on the level of community knowledge attitudes and practices about the disease in the area. The objective of the current study was to assess level of community knowledge, attitudes and practices about Yf. METHODS: Between March and May 2017, a community-based cross sectional survey was conducted in two districts of the South Omo area. During the survey, 612 randomly selected adults were interviewed about Yf using structured questionnaire. RESULTS: Out of the 612 study participants, 508 (83.0%) reported that they heard about Yf which is locally known as "a disease that causes vomiting blood". Most (90.4%) of the study participants also said that Yf is different from malaria. Two hundred thirteen (41.9%) participants said that Yf can be transmitted from a patient to another person, while only 80 (37.6%) mentioned that the disease is transmitted through mosquitoes bite. Out of 333 (65.7%) study participants who believed that Yf is a preventable disease, 280 (84.1%) mentioned vaccine as a preventive method. The majority believed that the disease is a killer (97.2%) and a newly emerging (69.4%). Among the total of 612 study participants, 221(36.1%) were considered as having a high level of overall knowledge of Yf. Having educational level above 7th grade (AOR = 3.25, 95% CI: 1.39, 7.57, p = 0.006) and being resident of Bena-Tsemay district (AOR = 1.77, 95% CI: 1.12, 2.78, P = 0.014) were significantly associated with having a high level of overall knowledge of Yf. Agro-pastoralism as an occupation compared to farming was associated with having a low level of overall knowledge of Yf (AOR = 0.51, 95% CI, 0.33, 0.79, P = 0.003). CONCLUSION: The findings indicate that most of the study community members had a low level of overall knowledge of Yf, especially about its cause, mode of transmission and preventive methods. Thus, there is a need to increase people's knowledge and practices regarding the cause, mode of transmission and preventive methods like avoiding mosquitoe breeding sites beside vaccination through various strategies like disseminating information through community health extension workers and community leaders in the study area. PMID- 29630595 TI - A comparative work on the magnetic field-dependent properties of plate-like and spherical iron particle-based magnetorheological grease. AB - In this study, a new magnetorheological (MR) grease was made featuring plate-like carbonyl iron (CI) particles, and its magnetic field-dependent rheological properties were experimentally characterized. The plate-like CI particles were prepared through high-energy ball milling of spherical CI particles. Then, three different ratios of the CI particles in the MR grease, varying from 30 to 70 wt% were mixed by dispersing the plate-like CI particles into the grease medium with a mechanical stirrer. The magnetic field-dependent rheological properties of the plate-like CI particle-based MR grease were then investigated using a rheometer by changing the magnetic field intensity from 0 to 0.7 T at room temperature. The measurement was undertaken at two different modes, namely, a continuous shear mode and oscillation mode. It was shown that both the apparent viscosity and storage modulus of the MR grease were heavily dependent on the magnetic field intensity as well as the CI particle fraction. In addition, the differences in the yield stress and the MR effect between the proposed MR grease featuring the plate-like CI particles and the existing MR grease with the spherical CI particles were investigated and discussed in detail. PMID- 29630597 TI - Spatial modeling of the membrane-cytosolic interface in protein kinase signal transduction. AB - The spatial architecture of signaling pathways and the interaction with cell size and morphology are complex, but little understood. With the advances of single cell imaging and single cell biology, it becomes crucial to understand intracellular processes in time and space. Activation of cell surface receptors often triggers a signaling cascade including the activation of membrane-attached and cytosolic signaling components, which eventually transmit the signal to the cell nucleus. Signaling proteins can form steep gradients in the cytosol, which cause strong cell size dependence. We show that the kinetics at the membrane cytosolic interface and the ratio of cell membrane area to the enclosed cytosolic volume change the behavior of signaling cascades significantly. We suggest an estimate of average concentration for arbitrary cell shapes depending on the cell volume and cell surface area. The normalized variance, known from image analysis, is suggested as an alternative measure to quantify the deviation from the average concentration. A mathematical analysis of signal transduction in time and space is presented, providing analytical solutions for different spatial arrangements of linear signaling cascades. Quantification of signaling time scales reveals that signal propagation is faster at the membrane than at the nucleus, while this time difference decreases with the number of signaling components in the cytosol. Our investigations are complemented by numerical simulations of non-linear cascades with feedback and asymmetric cell shapes. We conclude that intracellular signal propagation is highly dependent on cell geometry and, thereby, conveys information on cell size and shape to the nucleus. PMID- 29630596 TI - Massive lateral transfer of genes encoding plant cell wall-degrading enzymes to the mycoparasitic fungus Trichoderma from its plant-associated hosts. AB - Unlike most other fungi, molds of the genus Trichoderma (Hypocreales, Ascomycota) are aggressive parasites of other fungi and efficient decomposers of plant biomass. Although nutritional shifts are common among hypocrealean fungi, there are no examples of such broad substrate versatility as that observed in Trichoderma. A phylogenomic analysis of 23 hypocrealean fungi (including nine Trichoderma spp. and the related Escovopsis weberi) revealed that the genus Trichoderma has evolved from an ancestor with limited cellulolytic capability that fed on either fungi or arthropods. The evolutionary analysis of Trichoderma genes encoding plant cell wall-degrading carbohydrate-active enzymes and auxiliary proteins (pcwdCAZome, 122 gene families) based on a gene tree / species tree reconciliation demonstrated that the formation of the genus was accompanied by an unprecedented extent of lateral gene transfer (LGT). Nearly one-half of the genes in Trichoderma pcwdCAZome (41%) were obtained via LGT from plant-associated filamentous fungi belonging to different classes of Ascomycota, while no LGT was observed from other potential donors. In addition to the ability to feed on unrelated fungi (such as Basidiomycota), we also showed that Trichoderma is capable of endoparasitism on a broad range of Ascomycota, including extant LGT donors. This phenomenon was not observed in E. weberi and rarely in other mycoparasitic hypocrealean fungi. Thus, our study suggests that LGT is linked to the ability of Trichoderma to parasitize taxonomically related fungi (up to adelphoparasitism in strict sense). This may have allowed primarily mycotrophic Trichoderma fungi to evolve into decomposers of plant biomass. PMID- 29630598 TI - Odorant binding protein 69a connects social interaction to modulation of social responsiveness in Drosophila. AB - Living in a social environment requires the ability to respond to specific social stimuli and to incorporate information obtained from prior interactions into future ones. One of the mechanisms that facilitates social interaction is pheromone-based communication. In Drosophila melanogaster, the male-specific pheromone cis-vaccenyl acetate (cVA) elicits different responses in male and female flies, and functions to modulate behavior in a context and experience dependent manner. Although it is the most studied pheromone in flies, the mechanisms that determine the complexity of the response, its intensity and final output with respect to social context, sex and prior interaction, are still not well understood. Here we explored the functional link between social interaction and pheromone-based communication and discovered an odorant binding protein that links social interaction to sex specific changes in cVA related responses. Odorant binding protein 69a (Obp69a) is expressed in auxiliary cells and secreted into the olfactory sensilla. Its expression is inversely regulated in male and female flies by social interactions: cVA exposure reduces its levels in male flies and increases its levels in female flies. Increasing or decreasing Obp69a levels by genetic means establishes a functional link between Obp69a levels and the extent of male aggression and female receptivity. We show that activation of cVA-sensing neurons is sufficeint to regulate Obp69a levels in the absence of cVA, and requires active neurotransmission between the sensory neuron to the second order olfactory neuron. The cross-talk between sensory neurons and non neuronal auxiliary cells at the olfactory sensilla, represents an additional component in the machinery that promotes behavioral plasticity to the same sensory stimuli in male and female flies. PMID- 29630600 TI - Interactions of spatial strategies producing generalization gradient and blocking: A computational approach. AB - We present a computational model of spatial navigation comprising different learning mechanisms in mammals, i.e., associative, cognitive mapping and parallel systems. This model is able to reproduce a large number of experimental results in different variants of the Morris water maze task, including standard associative phenomena (spatial generalization gradient and blocking), as well as navigation based on cognitive mapping. Furthermore, we show that competitive and cooperative patterns between different navigation strategies in the model allow to explain previous apparently contradictory results supporting either associative or cognitive mechanisms for spatial learning. The key computational mechanism to reconcile experimental results showing different influences of distal and proximal cues on the behavior, different learning times, and different abilities of individuals to alternatively perform spatial and response strategies, relies in the dynamic coordination of navigation strategies, whose performance is evaluated online with a common currency through a modular approach. We provide a set of concrete experimental predictions to further test the computational model. Overall, this computational work sheds new light on inter-individual differences in navigation learning, and provides a formal and mechanistic approach to test various theories of spatial cognition in mammals. PMID- 29630599 TI - Functional diversification accompanies gene family expansion of MED2 homologs in Candida albicans. AB - Gene duplication facilitates functional diversification and provides greater phenotypic flexibility to an organism. Expanded gene families arise through repeated gene duplication but the extent of functional divergence that accompanies each paralogous gene is generally unexplored because of the difficulty in isolating the effects of single family members. The telomere associated (TLO) gene family is a remarkable example of gene family expansion, with 14 members in the more pathogenic Candida albicans relative to two TLO genes in the closely-related species C. dubliniensis. TLO genes encode interchangeable Med2 subunits of the major transcriptional regulatory complex Mediator. To identify biological functions associated with each C. albicans TLO, expression of individual family members was regulated using a Tet-ON system and the strains were assessed across a range of phenotypes involved in growth and virulence traits. All TLOs affected multiple phenotypes and a single phenotype was often affected by multiple TLOs, including simple phenotypes such as cell aggregation and complex phenotypes such as virulence in a Galleria mellonella model of infection. No phenotype was regulated by all TLOs, suggesting neofunctionalization or subfunctionalization of ancestral properties among different family members. Importantly, regulation of three phenotypes could be mapped to individual polymorphic sites among the TLO genes, including an indel correlated with two phenotypes, growth in sucrose and macrophage killing. Different selective pressures have operated on the TLO sequence, with the 5' conserved Med2 domain experiencing purifying selection and the gene/clade specific 3' end undergoing extensive positive selection that may contribute to the impact of individual TLOs on phenotypic variability. Therefore, expansion of the TLO gene family has conferred unique regulatory properties to each paralog such that it influences a range of phenotypes. We posit that the genetic diversity associated with this expansion contributed to C. albicans success as a commensal and opportunistic pathogen. PMID- 29630601 TI - Blade and bladelet production at Hohle Fels Cave, AH IV in the Swabian Jura and its importance for characterizing the technological variability of the Aurignacian in Central Europe. AB - Hohle Fels Cave in the Ach Valley of Southwestern Germany exhibits an Aurignacian sequence of 1 m thickness within geological horizons (GH) 6-8. The deposition of the layers took place during mild and cold phases between at least 42 ka (GI 10) and 36 ka calBP (GI 7). We present below a technological study of blade and bladelet production from AH IV (GH 7) at Hohle Fels. Our analyses show that blade manufacture is relatively constant, while bladelet production displays a high degree of variability in order to obtain different blanks. Knappers used a variety of burins as cores to produce fine bladelets. The results reveal a new variant of the Aurignacian in the Swabian Jura primarily characterized by the production of bladelets and microliths from burin-cores. The artefacts from the Swabian Aurignacian are technologically and functionally more diverse than earlier studies of the Geibetaenklosterle and Vogelherd sequences have suggested. The technological analyses presented here challenge the claim that the typo chronological system from Southwestern Europe can be applied to the Central European Aurignacian. Instead, we emphasize the impact of technological and functional variables within the Aurignacian of the Swabian Jura. PMID- 29630603 TI - Unintended consequences and the paradox of control: Management of emerging pathogens with age-specific virulence. AB - We project forward total Zika virus disease (ZVD) under varying hazards of infection and consider how the age distribution of disease burden varies between these scenarios. Pathogens with age structured disease outcomes, such as rubella and Zika virus, require that management decisions consider their impact not only on total disease incidence but also on distribution of disease burden within a population. Some situations exhibit a "paradox of control" in which reductions of overall transmission decrease the total incidence but increase the incidence of severe disease. This happens because of corresponding increases in the average age of infection. Beginning with the current population structure and demographic rates of Brazil, we project forward total ZVD burden as measured by cases occurring in pregnant women and document the scenarios under which a paradox of control for ZVD management emerges. We conclude that while a paradox of control can occur for ZVD, the higher total costs from increasing the average age of infection will only be realized after several decades and vanish under conservative discounting of future costs. This indicates that managers faced with an emerging pathogen are justified to prioritize current disease incidence over potential increases in severe disease outcomes in the endemic state. PMID- 29630602 TI - Comprehensive Geriatric Assessment and quality of life after localized prostate cancer radiotherapy in elderly patients. AB - INTRODUCTION: Radiotherapy can diminish quality of life (QoL) for prostate cancer patients. Our objective was to evaluate the effect of radiotherapy on QoL in men aged 75 years or older treated with radiotherapy for a localized prostate cancer, and to identify predictors of reduced QoL. PATIENTS AND METHODS: We prospectively administered a battery of geriatric (MNA, GDS, Get up and Go Test, CIRS-G, ADL, IADL, MMSE), toxicity (IPSS; IIEF 5), and QoL (QLQ C30) screening tests in 100 elderly patients before and two months after prostate cancer radiotherapy (NCT 02876237). Patients >= 75 years undergoing radiotherapy with a curative intent for localized prostate cancer with or without androgen deprivation therapy (ADL) were eligible for study inclusion. Correlations between patient-assessed QoL and tumor characteristics, radiotherapy treatment or CGA parameters were sought using the Fisher or the Mann and Whitney tests. Changes in QoL parameters over time were analyzed using the Wilcoxon signed-rank test. RESULTS: At study entry, scores for IADL impairments were present in 51%, reduced autonomy in activities of daily living in 16%, cognitive impairment found in 20%, depression-related symptoms in 31%, and 66% of patients had significant co-morbidities. Eight percent were judged to be at risk of fall and 2% were found to be undernourished. Severely impaired (IPSS >= 20) urinary function was observed in 11.2% and 13.5% of patients before and two months after completion of radiotherapy respectively. Significantly decreased QoL (> 20 points) at two months after treatment was found in 13% of patients and a moderate but clinically relevant reduction (10 to 20 points) in 17% of patients. No tumor characteristic, treatment, or oncogeriatric parameter was predictive of reduced QoL following prostate cancer radiotherapy. CONCLUSION: Despite sometimes markedly diminished oncogeriatric parameters, prostate cancer radiotherapy was generally well tolerated in these elderly patients. We found no predictive factor to determine which patients would experience impaired quality of life following radiotherapy. PMID- 29630604 TI - Readmission prediction via deep contextual embedding of clinical concepts. AB - OBJECTIVE: Hospital readmission costs a lot of money every year. Many hospital readmissions are avoidable, and excessive hospital readmissions could also be harmful to the patients. Accurate prediction of hospital readmission can effectively help reduce the readmission risk. However, the complex relationship between readmission and potential risk factors makes readmission prediction a difficult task. The main goal of this paper is to explore deep learning models to distill such complex relationships and make accurate predictions. MATERIALS AND METHODS: We propose CONTENT, a deep model that predicts hospital readmissions via learning interpretable patient representations by capturing both local and global contexts from patient Electronic Health Records (EHR) through a hybrid Topic Recurrent Neural Network (TopicRNN) model. The experiment was conducted using the EHR of a real world Congestive Heart Failure (CHF) cohort of 5,393 patients. RESULTS: The proposed model outperforms state-of-the-art methods in readmission prediction (e.g. 0.6103 +/- 0.0130 vs. second best 0.5998 +/- 0.0124 in terms of ROC-AUC). The derived patient representations were further utilized for patient phenotyping. The learned phenotypes provide more precise understanding of readmission risks. DISCUSSION: Embedding both local and global context in patient representation not only improves prediction performance, but also brings interpretable insights of understanding readmission risks for heterogeneous chronic clinical conditions. CONCLUSION: This is the first of its kind model that integrates the power of both conventional deep neural network and the probabilistic generative models for highly interpretable deep patient representation learning. Experimental results and case studies demonstrate the improved performance and interpretability of the model. PMID- 29630605 TI - Large and finite sample properties of a maximum-likelihood estimator for multiplicity of infection. AB - Reliable measures of transmission intensities can be incorporated into metrics for monitoring disease-control interventions. Genetic (molecular) measures like multiplicity of infection (MOI) have several advantages compared with traditional measures, e.g., R0. Here, we investigate the properties of a maximum-likelihood approach to estimate MOI and pathogen-lineage frequencies. By verifying regulatory conditions, we prove asymptotical unbiasedness, consistency and efficiency of the estimator. Finite sample properties concerning bias and variance are evaluated over a comprehensive parameter range by a systematic simulation study. Moreover, the estimator's sensitivity to model violations is studied. The estimator performs well for realistic sample sizes and parameter ranges. In particular, the lineage-frequency estimates are almost unbiased independently of sample size. The MOI estimate's bias vanishes with increasing sample size, but might be substantial if sample size is too small. The estimator's variance matrix agrees well with the Cramer-Rao lower bound, even for small sample size. The numerical and analytical results of this study can be used for study design. This is exemplified by a malaria data set from Venezuela. It is shown how the results can be used to determine the necessary sample size to achieve certain performance goals. An implementation of the likelihood method and a simulation algorithm for study design, implemented as an R script, is available as S1 File alongside a documentation (S2 File) and example data (S3 File). PMID- 29630606 TI - Livelihood opportunities amongst adults with and without disabilities in Cameroon and India: A case control study. AB - Proven links between disability and poverty suggest that development programmes and policies that are not disability-inclusive will leave persons with disabilities behind. Despite this, there is limited quantitative evidence on livelihood opportunities amongst adults with disabilities in Low and Middle Income Countries. This study adds to the limited evidence base, contributing data from one African and one Asian Setting. We undertook a population-based case control study of adults (18+) with and without disabilities in North-West Cameroon and in Telangana State, India. We found that adults with disabilities were five times less likely to be working compared to age-sex matched controls in both settings. Amongst adults with disabilities, current age, marital status and disability type were key predictors of working. Inclusive programmes are therefore needed to provide adequate opportunities to participate in livelihood prospects for adults with disabilities in Cameroon and India, on an equal basis as others. These findings are of crucial importance at this stage of the Sustainable Development Agenda, to ensure that the mandate of inclusive development is achieved. PMID- 29630607 TI - Leveraging long acting reversible contraceptives to achieve FP2020 commitments in sub-Saharan Africa: The potential of implants. AB - BACKGROUND: In developing regions, an estimated 214 million women have an unmet need for family planning. Reaching Family Planning 2020 (FP2020) commitments will require a shift in modern contraceptive promotion, including improved access to long-acting reversible contraceptives (LARCs). Until now, a lack of market data limited understanding of the potential of LARCs to increase contraceptive access and choice. METHODS: From 2015, the FPwatch Project conducted representative surveys in Ethiopia, Nigeria, and Democratic Republic of Congo (DRC) using a full census approach in selected administrative areas. In these areas, every public and private sector outlet with the potential to sell or distribute modern contraceptives was approached. In outlets with modern contraceptives, product audits and provider interviews assessed contraceptive market composition, market share, availability, price, and outlet readiness to perform services. RESULTS: Fifty-four percent of outlets in Ethiopia had LARC commodities or services available at the time of the survey, versus 7% and 8% of outlets in Nigeria and DRC, respectively. When present, LARCs were usually available with at least two other methods (99%, 39%, and 84% of public health facilities in Ethiopia, Nigeria and DRC, respectively). Many public facilities had both implants and IUDs in stock (76%, 47%, and 53%, respectively). Lack of readiness to provide LARCs was mostly due to a lack of equipment, private room, or the commodity itself. Market share for implants in the public sector was 60%, 53%, and 37% of Couple Years of Protection (CYP) in Ethiopia, Nigeria, and DRC. DISCUSSION: Limited availability of LARCs in Nigeria and DRC restricts contraceptive choice and makes it difficult for women to adopt and use modern contraception consistently. Brand-specific subsidies, task shifting, and promotion of methods that require less equipment and training are promising strategies for increasing uptake. Substantial government investment is required to improve availability and affordability. Investment in implants should be prioritized to make progress towards FP2020 commitments. PMID- 29630608 TI - Sensitivity to linguistic register in 20-month-olds: Understanding the register listener relationship and its abstract rules. AB - Linguistic register reflects changes in speech that depend on the situation, especially the status of listeners and listener-speaker relationships. Following the sociolinguistic rules of register is essential in establishing and maintaining social interactions. Recent research suggests that children over 3 years of age can understand appropriate register-listener relationships as well as the fact that people change register depending on their listeners. However, given previous findings that infants under 2 years of age have already formed both social and speech categories, it may be possible that even younger children can also understand appropriate register-listener relationships. The present study used Infant-Directed Speech (IDS) and formal Adult-Directed Speech (ADS) to examine whether 20-month-old toddlers can understand register-listener relationships. In Experiment 1, we used a violation-of-expectation method to examine whether 20-month-olds understand the individual associations between linguistic registers and listeners. Results showed that the toddlers looked significantly longer at a scene in which the adult was talked to in IDS than when the infant was talked to in IDS. In contrast, there was no difference when the adult and the infant were talked to in formal ADS. In Experiments 2 and 3, we used a habituation switch paradigm to examine whether 20-month-olds understand the abstract rule that a change of register depends on listeners rather than on speakers. Results showed that the toddlers looked significantly longer at the scene where the register rule was violated. The present findings provide new evidence that even 20-month-olds already understand that people change their way of speaking based on listeners, although their understanding of individual register-listener relationships is immature. PMID- 29630609 TI - Identification of ASB7 as ER stress responsive gene through a genome wide in silico screening for genes with ERSE. AB - The endoplasmic reticulum (ER) not only performs its basic function of regulating calcium homeostasis, lipid biosynthesis, folding, modifying and transporting proteins but also plays a decisive role in regulating multiple cellular processes ranging from cell growth and differentiation to apoptosis and autophagy. Disturbances in ER homeostasis initiate the unfolded protein response (UPR) implicated in the pathogenesis of many human diseases. Drugging the UPR components for therapeutic interventions has received considerable attention. The purpose of this study is to identify genes that are previously unsuspected to be regulated under ER stress. Because ER stress-inducible gene expression is majorly regulated under ERSE elements, we screened human genome by adopting an in silico approach using ERSE elements (I, II, III) as probes and identified 337 candidate genes. Having knowledge of the importance of E3 ubiquitin ligase in the ERAD machinery; we validated our preliminary search by focusing on one of the hits i.e. ASB7 gene that encodes E3 ubiquitin ligase. In HeLa cells, we found that pharmacological induction of ER stress led to an increase in the expression of ASB7 with simultaneous activation of UPR pathways. Although knockdown of ASB7 expression leads to significant reduction in GRP78 and CHOP mRNA levels, it did not protect cells from ER stress-induced cell death. Also, an up-regulation in the expression of pro-inflammatory genes like TNF-alpha and IL-1beta in ASB7 knockdown cells was observed under ER stress. Collectively, our findings suggest that ASB7 is regulated under ER stress and this study also identifies several other genes that could apparently be regulated under ER stress. PMID- 29630611 TI - XJB-5-131-mediated improvement in physiology and behaviour of the R6/2 mouse model of Huntington's disease is age- and sex- dependent. AB - We have reported that the radical scavenger XJB-5-131 attenuates or reverses progression of the disease phenotype in the HdhQ(150/150) mouse, a slow onset model of HD. Here, we tested whether XJB-5-131 has beneficial effects in R6/2 mice, a severe early onset model of HD. We found that XJB-5-131 has beneficial effects in R6/2 mice, by delaying features of the motor and histological phenotype. The impact was sex-dependent, with a stronger effect in male mice. XJB 5-131 treatment improved some locomotor deficits in female R6/2 mice, but the effects were, in general, greater in male mice. Chronic treatment of male R6/2 mice with XJB-5-1-131 reduced weight loss, and improved the motor and temperature regulation deficits, especially in male mice. Treatment with XJB-5-131 had no effect on the lifespan of R6/2 mice. Nevertheless, it significantly slowed somatic expansion at 90 days, and reduced the density of inclusions. Our data show that while treatment with XJB-5-131 had complex effects on the phenotype of R6/2 mice, it produced a number of significant improvements in this severe model of HD. PMID- 29630610 TI - The deferred embryo transfer strategy improves cumulative pregnancy rates in endometriosis-related infertility: A retrospective matched cohort study. AB - BACKGROUND: Controlled ovarian stimulation in assisted reproduction technology (ART) may alters endometrial receptivity by an advancement of endometrial development. Recently, technical improvements in vitrification make deferred frozen-thawed embryo transfer (Def-ET) a feasible alternative to fresh embryo transfer (ET). In endometriosis-related infertility the eutopic endometrium is abnormal and its functional alterations are seen as likely to alter the quality of endometrial receptivity. One question in the endometriosis ART-management is to know whether Def-ET could restore optimal receptivity in endometriosis affected women leading to increase in pregnancy rates. OBJECTIVE: To compare cumulative ART-outcomes between fresh versus Def-ET in endometriosis-infertile women. MATERIALS AND METHODS: This matched cohort study compared def-ET strategy to fresh ET strategy between 01/10/2012 and 31/12/2014. One hundred and thirty five endometriosis-affected women with a scheduled def-ET cycle and 424 endometriosis-affected women with a scheduled fresh ET cycle were eligible for matching. Matching criteria were: age, number of prior ART cycles, and endometriosis phenotype. Statistical analyses were conducted using univariable and multivariable logistic regression models. RESULTS: 135 in the fresh ET group and 135 in the def-ET group were included in the analysis. The cumulative clinical pregnancy rate was significantly increased in the def-ET group compared to the fresh ET group [58 (43%) vs. 40 (29.6%), p = 0.047]. The cumulative ongoing pregnancy rate was 34.8% (n = 47) and 17.8% (n = 24) respectively in the Def-ET and the fresh-ET groups (p = 0.005). After multivariable conditional logistic regression analysis, Def-ET was associated with a significant increase in the cumulative ongoing pregnancy rate as compared to fresh ET (OR = 1.76, CI95% 1.06-2.92, p = 0.028). CONCLUSION: Def-ET in endometriosis-affected women was associated with significantly higher cumulative ongoing pregnancy rates. Our preliminary results suggest that Def-ET for endometriosis-affected women is an attractive option that could increase their ART success rates. Future studies, with a randomized design, should be conducted to further confirm those results. PMID- 29630612 TI - First- and second-line bevacizumab in ovarian cancer: A Belgian cost-utility analysis. AB - BACKGROUND: Currently, in Belgium, bevacizumab is reimbursed for ovarian cancer patients, based on a contract between the Minister and the manufacturer including confidential agreements. This reimbursement will be re-evaluated in 2018. OBJECTIVE: To support the reimbursement reassessment by calculating the cost effectiveness of bevacizumab: (1) in addition to first-line chemotherapy; (2) in the treatment of recurrent ovarian cancer (platinum-sensitive or platinum resistant). METHODS: A health economic model has been developed for the Belgian situation according to the Belgian guidelines for economic evaluations. The lifetime Markov model was set up from the perspective of the health care payer (government and patient), including direct healthcare related costs. Results are expressed as the extra costs per quality-adjusted life year (QALY). Calculations were based on results of four international trials. Both probabilistic and one way sensitivity analyses were performed. RESULTS: Incremental cost-effectiveness ratios (ICERs) of first-line bevacizumab are on average 158 000/QALY (GOG-0218 trial) and 443 000/QALY (ICON7 trial). The most favourable scenario is based on the stage IV subgroup of the GOG-0218 trial (?52 000/QALY). Since subgroup findings are often exploratory and require confirmatory studies, results of the economic evaluation based on this subgroup analysis should be considered with caution. For second-line bevacizumab, ICERs are on average ?587 000/QALY (OCEANS trial) and ?172 000/QALY (AURELIA trial). Sensitivity analysis shows that results are most sensitive to the price of bevacizumab. CONCLUSION: From a health economic perspective, ICERs of bevacizumab are relatively high. The most favourable results are found for first-line treatment of stage IV ovarian cancer patients. Price reductions have a major impact on the estimated ICERs. It is recommended to take these findings into account when re-evaluating the reimbursement of bevacizumab in ovarian cancer. PMID- 29630613 TI - Immunoglobulin G subclass switching impacts sensitivity of an immunoassay targeting Francisella tularensis lipopolysaccharide. AB - The CDC Tier 1 select agent Francisella tularensis is a small, Gram-negative bacterium and the causative agent of tularemia, a potentially life-threatening infection endemic in the United States, Europe and Asia. Currently, there is no licensed vaccine or rapid point-of-care diagnostic test for tularemia. The purpose of this research was to develop monoclonal antibodies (mAbs) specific to the F. tularensis surface-expressed lipopolysaccharide (LPS) for a potential use in a rapid diagnostic test. Our initial antigen capture ELISA was developed using murine IgG3 mAb 1A4. Due to the low sensitivity of the initial assay, IgG subclass switching, which is known to have an effect on the functional affinity of a mAb, was exploited for the purpose of enhancing assay sensitivity. The ELISA developed using the IgG1 or IgG2b mAbs from the subclass-switch family of 1A4 IgG3 yielded improved assay sensitivity. However, surface plasmon resonance (SPR) demonstrated that the functional affinity was decreased as a result of subclass switching. Further investigation using direct ELISA revealed the potential self association of 1A4 IgG3, which could explain the higher functional affinity and higher assay background seen with this mAb. Additionally, the higher assay background was found to negatively affect assay sensitivity. Thus, enhancement of the assay sensitivity by subclass switching is likely due to the decrease in assay background, simply by avoiding the self-association of IgG3. PMID- 29630616 TI - Forecasting new product diffusion using both patent citation and web search traffic. AB - Accurate demand forecasting for new technology products is a key factor in the success of a business. We propose a way to forecasting a new product's diffusion through technology diffusion and interest diffusion. Technology diffusion and interest diffusion are measured by the volume of patent citations and web search traffic, respectively. We apply the proposed method to forecast the sales of hybrid cars and industrial robots in the US market. The results show that that technology diffusion, as represented by patent citations, can explain long-term sales for hybrid cars and industrial robots. On the other hand, interest diffusion, as represented by web search traffic, can help to improve the predictability of market sales of hybrid cars in the short-term. However, interest diffusion is difficult to explain the sales of industrial robots due to the different market characteristics. Finding indicates our proposed model can relatively well explain the diffusion of consumer goods. PMID- 29630618 TI - A giant Late Triassic ichthyosaur from the UK and a reinterpretation of the Aust Cliff 'dinosaurian' bones. AB - The largest reported ichthyosaurs lived during the Late Triassic (~235-200 million years ago), and isolated, fragmentary bones could be easily mistaken for those of dinosaurs because of their size. We report the discovery of an isolated bone from the lower jaw of a giant ichthyosaur from the latest Triassic of Lilstock, Somerset, UK. It documents that giant ichthyosaurs persisted well into the Rhaetian Stage, and close to the time of the Late Triassic extinction event. This specimen has prompted the reinterpretation of several large, roughly cylindrical bones from the latest Triassic (Rhaetian Stage) Westbury Mudstone Formation from Aust Cliff, Gloucestershire, UK. We argue here that the Aust bones, previously identified as those of dinosaurs or large terrestrial archosaurs, are jaw fragments from giant ichthyosaurs. The Lilstock and Aust specimens might represent the largest ichthyosaurs currently known. PMID- 29630619 TI - Comparing gender discrimination and inequality in indie and traditional publishing. AB - In traditional publishing, female authors' titles command nearly half (45%) the price of male authors' and are underrepresented in more prestigious genres, and books are published by publishing houses, which determined whose books get published, subject classification, and retail price. In the last decade, the growth of digital technologies and sales platforms have enabled unprecedented numbers of authors to bypass publishers to publish and sell books. The rise of indie publishing (aka self-publishing) reflects the growth of the "gig" economy, where the influence of firms has diminished and workers are exposed more directly to external markets. Encompassing the traditional and the gig economy, the book industry illuminates how the gig economy may disrupt, replicate, or transform the gender discrimination mechanisms and inequality found in the traditional economy. In a natural experiment spanning from 2002 to 2012 and including over two million book titles, we compare discrimination mechanisms and inequality in indie and traditional publishing. We find that indie publishing, though more egalitarian, largely replicates traditional publishing's gender discrimination patterns, showing an unequal distribution of male and female authors by genre (allocative discrimination), devaluation of genres written predominantly by female authors (valuative discrimination), and lower prices within genres for books by female authors (within-job discrimination). However, these discrimination mechanisms are associated with far less price inequality in indie, only 7%, in large part due to the smaller and lower range of prices in indie publishing compared to traditional publishing. We conclude that, with greater freedom, workers in the gig economy may be inclined to greater equality but will largely replicate existing labor market segmentation and the lower valuation of female-typical work and of female workers. Nonetheless, price setting for work may be more similar for workers in the gig economy due to market competition that will compress prices ranges. PMID- 29630617 TI - The prognosis significance and application value of peritoneal elastic lamina invasion in colon cancer. AB - OBJECTIVES: The aims of this study were to evaluate the associations between peritoneal elastic lamina invasion (ELI) and the clinicopathological prognostic factors of colon cancer, to evaluate the feasibility of ELI with use of an elastic stain to help diagnose serosal invasion of colon cancer in routine practice, so as to help us to provide a more accurate estimate for prognosis and stage of patients and a marker for postoperative treatment. METHODS: 254 cases with colon cancer were included in the study. According to the presence of elastic lamina (EL) and elastic lamina invasion (ELI), all cases were divided into four groups: pT3 EL negative (pT3 EL (-)), pT3 ELI positive (pT3 ELI (+)), pT3 ELI negative (pT3 ELI (-)) and pT4a. Statistical analysis was used to analyze the relationship between elastic lamina invasion and other established adverse histologic features. RESULTS: The EL and ELI positive rates were 81.5% and 42.1% respectively. There were significant differences in mph node metastasis, venous invasion and tumor buds between pT3 ELI (-) and pT3 ELI (+), pT3 ELI (-) and pT4a. There was no significant difference in same factors between pT3 ELI (+) and pT4a. In pT3 stage, there were significant differences in lymph node metastasis, perineural invasion and tumor buds between EL (-) and ELI (+). There were no significant differences in same factors between EL (-) and ELI (-). EL was detected less frequently in right-sided tumors compared with left-sided tumors. CONCLUSIONS: ELI might be the prognostic factors of colon cancer with II stage and might be the marker of postoperative adjuvant chemotherapy. Patients with pT3 ELI (+) might have similar prognosis to patients with pT4a. For patients with pT3 colon cancer, EL(-) might have similar prognosis as ELI (-) and might take the same therapy. In addition, the right half colon EL positive rate was lower than the left colon. Elastic staining might be a useful tool to help determine the invasive depth and stage of colon cancer. PMID- 29630615 TI - Impact of depression and recreational drug use on emergency department encounters and hospital admissions among people living with HIV in Ontario: A secondary analysis using the OHTN cohort study. AB - INTRODUCTION: Nearly half of HIV-positive patients experience mental health and substance use problems, but many do not receive adequate or ongoing mental health or addiction care. This lack of ongoing care can result in the use of costly acute care services. Prospective evaluations of the relationship between psychiatric and substance use disorders and acute care services use are lacking, and this information is needed to understand unmet needs and improve access to appropriate services. METHODS: We conducted a secondary data analysis from a multicenter, longitudinal, prospective cohort study (n = 3,482 adults) between October 1, 2007 and March 31, 2013. We used explanatory extended Cox proportional hazard regression models to examine the impact of current depression and recreational drug use on acute care services use, and to explore whether current depression and recreational drug use were associated with potentially avoidable acute care services use. RESULTS: Over our 5.5 year study period, HIV-positive participants with current depression-only (aHR [95% CI]:1.2[1.1-1.4]), recreational drug use-only (1.3[1.1-1.6]), or co-occurring depression and recreational drug use (1.4[1.2-1.7]) were associated with elevated hazard of emergency department (ED) encounters compared to participants without these conditions. Over half of ED encounters were potentially avoidable. Participants with current depression-only (1.3[1.1-1.5];1.3[1.03-1.6]), recreational drug use only (1.3[1.04-1.6];1.5[1.1-1.9]), or co-occurring depression and recreational drug use (1.3[1.04-1.7];1.4[1.06-1.9]) were associated with elevated hazard of low-acuity or repeated ED encounters respectively. CONCLUSIONS: We found a significant increase in ED services use and potentially avoidable ED encounters (including low-acuity or repeated ED encounters), particularly among those with either current depression or recreational drug use. These findings emphasize the challenges in managing HIV and mental health/addiction co-morbidities in the current HIV care model. Future research should evaluate integrated and collaborative care programs for improving the coordination of care and effectively treat mental health and addiction problems among HIV-positive patients in Ontario. PMID- 29630620 TI - A novel single nucleotide polymorphism in exon 3 of MYOC enhances the risk of glaucoma. AB - Genetic polymorphismsof MYOCalter the myocilin protein,which leads to disruption of thenormal regulation of intraocular pressure (IOP) that ultimately causes glaucoma.Theaim of the present study was to identify the polymorphism in exon 3 of the MYOC gene of theglaucoma patients in Lahore, Pakistan. We conducted a case control study with 100 patients and 100 controls subjects. We extracted DNA from blood samples,amplified the target DNA fragmentby PCR, and identifiedpolymorphisms through sequencing. We observed that the allelic and genotypic frequencies of rs74315341 and rs879255525 were associated with glaucoma in our patient population. The polymorphism atrs74315341 led to the substitutionof serine for arginine,whereas the polymorphism at rs879255525 led to the substitution ofasparagine for lysine. The haplotype TGAAGCCATTTC was associated with disease onset, whereas the haplotype GGAAGCCATTTC was protective against disease development. In conclusion, weidentified MYOC gene polymorphisms in susceptible regions that were associated withglaucoma onset among the Lahore patient population.This is the first report to identify a novel mutation in rs879255525 in exon 3 of the MYOC genethat is associated withglaucoma. PMID- 29630621 TI - In vitro aging behavior of dental composites considering the influence of filler content, storage media and incubation time. AB - OBJECTIVE: Over time dental composites age due to mechanical impacts such as chewing and chemical impacts such as saliva enzymes and food ingredients. For this research, the focus was placed on chemical degradation. The objective of this study was to simulate hydrolysis by using different food simulating liquids and to assess their impact on the mechanical parameter Vickers microhardness (MHV) and the physicochemical parameter contact angle (CA). METHODS: Specimen of three composites (d = 6 mm, h = 2 mm; n = 435) classified with respect to their filler content (wt%), namely low-filled, medium-filled and highly-filled, were stored for 0, 14, 30, 90 and 180 days in artificial saliva (pH 7), citric acid (pH 3; pH 5), lactic acid (pH 3; pH 5) and ethanol (40%vol; 60%vol) and assessed regarding to MHV and CA. Statistics: Kruskal-Wallis test, stepwise linear regression, bivariate Spearman Rank Correlation (p < 0.05). RESULTS: While stored in artificial saliva, acid and ethanol the CA decreased especially for the low- and medium-filled composites. It was shown that rising the filler content caused less surface changes in the CA. Storage in ethanol led to a significant decrease of MHV of all composites. Regression analysis showed that the effect of in vitro aging on MHV was mainly influenced by the composite material and therefore by filler content (R2 = 0.67; p < 0.05). In contrast, the CA is more influenced by incubation time and filler content (R2 = 0.2; p < 0.05) leading to a higher risk of plaque accumulation over time. Significance: In vitro aging showed significant changes on the mechanical and physicochemical properties of dental composites which may shorten their long-term functionality. In conclusion, it can be stated, that the type of composite material, especially rising filler content seems to improve the materials' resistance against the processes of chemical degradation. PMID- 29630623 TI - Effects of atmospheric pressure plasma jet operating with DBD on Lavatera thuringiaca L. seeds' germination. AB - The paper presents the results of an experiment on the effect of pre-sowing stimulation of seeds with atmospheric pressure plasma jet operating with dielectric barrier discharge (DBD plasma jet) on the process of germination of Thuringian Mallow (Lavatera thuringiaca L.). Five groups of seeds characterized by a different exposure times (1, 2, 5, 10 and 15 minutes) as well as untreated seeds-control were used. Pre-sowing plasma stimulation of seeds improved germination parameters such as: germination capacity and germination energy for all tested groups relative to control. The highest germination parameters were obtained for seeds stimulated with plasma for the exposure times of 2 and 5 min. The analysis of the contact surface angle indicated the decrease of its' mean values upon seed stimulation while no statistical effects were observed. Analysis of the SEM scans revealed the increase in seed pattern intensity which could be attributed to removing of the surface parts of cuticle possibly covered with wax upon short time-2 and 5 min plasma treatment. Such a phenomenon can act similarly to mechanical scarification of seeds. Longer exposure of seeds to plasma resulted in affecting the deeper zone of cuticle and damage or fracture of some parts of the cuticle. Lower germination parameters of seeds upon longer exposure times to plasma may indicate mechanical damage of the seeds. PMID- 29630624 TI - Correction: Methyl pyruvate protects a normal lung fibroblast cell line from irinotecan-induced cell death: Potential use as adjunctive to chemotherapy. AB - [This corrects the article DOI: 10.1371/journal.pone.0182789.]. PMID- 29630622 TI - High-threshold motor unit firing reflects force recovery following a bout of damaging eccentric exercise. AB - Exercise-induced muscle damage (EIMD) is associated with impaired muscle function and reduced neuromuscular recruitment. However, motor unit firing behaviour throughout the recovery period is unclear. EIMD impairment of maximal voluntary force (MVC) will, in part, be caused by reduced high-threshold motor unit firing, which will subsequently increase to recover MVC. Fourteen healthy active males completed a bout of eccentric exercise on the knee extensors, with measurements of MVC, rate of torque development and surface electromyography performed pre exercise and 2, 3, 7 and 14 days post-exercise, on both damaged and control limb. EIMD was associated with decreased MVC (235.2 +/- 49.3 Nm vs. 161.3 +/- 52.5 Nm; p <0.001) and rate of torque development (495.7 +/- 136.9 Nm.s-1 vs. 163.4 +/- 163.7 Nm.s-1; p <0.001) 48h post-exercise. Mean motor unit firing rate was reduced (16.4 +/- 2.2 Hz vs. 12.6 +/- 1.7 Hz; p <0.01) in high-threshold motor units only, 48h post-exercise, and common drive was elevated (0.36 +/- 0.027 vs. 0.56 +/- 0.032; p< 0.001) 48h post-exercise. The firing rate of high-threshold motor units was reduced in parallel with impaired muscle function, whilst early recruited motor units remained unaltered. Common drive of motor units increased in offset to the firing rate impairment. These alterations correlated with the recovery of force decrement, but not of pain elevation. This study provides fresh insight into the central mechanisms associated with EIMD recovery, relative to muscle function. These findings may in turn lead to development of novel management and preventative procedures. PMID- 29630625 TI - The relationship between functional status, physical fitness and cognitive performance in physically active older adults: A pilot study. AB - OBJECTIVE: Ageing is associated with a progressive decline in physical function and cognitive performance which could result in a shift from an independent to a more dependent lifestyle. The aim of this research study was to assess the fitness, functional performance and cognitive ability in independently living older South Africans and to determine which fitness parameters and functional performance tests best explain the variance in cognitive function. DESIGN: Descriptive observational study. PARTICIPANTS: Older adults with a mean age 71+/ 4.7 years (n = 70; 28 men and 42 women) were recruited. Sixty percent of the sample completed at least secondary schooling and more than two-thirds were taking medication for a chronic medical condition. MEASUREMENTS: Self-reported physical activity was assessed using the Yale Physical Activity Survey. Fitness tests included the 6-minute walk test and Bicep Curls. The functional performance tests were; Static and Dynamic balance, Timed Up and Go, Sit to Stand, Grip strength and Functional Reach. The Stroop Task and 6-Item cognitive impairment test were used to measure cognitive performance. Bivariate and multivariate analyses were conducted between performance on the novel cognitive Stroop Task and functional and cognitive tests. RESULTS: We found significant relationships between the number of correct responses on the Stroop Task and scores on the 6 Item Cognitive Impairment test (-0.520, p < 0.01) and grip strength (r = 0.42, p< 0.01). The number of incorrect responses was inversely associated with functional reach (r = -0.445, p< 0.01). The final regression model included: age, dynamic balance, right arm grip strength and the score on the 6-item cognitive impairment test, and explained 44% of the variance in performance of the Stroop Task. CONCLUSIONS: The results of this study showed that measures of physical function were associated with cognitive performance even in highly functioning older South African adults. Further research is needed to determine the extent to which exercise training can improve functional capacity and the effect on cognitive performance. PMID- 29630626 TI - Decreasing muscle performance associated with increasing disease activity in patients with rheumatoid arthritis. AB - OBJECTIVES: Increasing evidence suggests that inflammation has a detrimental effect on muscle strength. Our objective was to analyse the association between muscle performance and different disease activity levels in patients with rheumatoid arthritis (RA). METHOD: A total of 199 consecutive outpatients were subject to cross-sectional assessment. Measurements of grip strength, endurance of the upper and lower limbs and trunk strength were combined as a muscle performance composite score (MPCS), using a standardised method. The disease activity for 28 joints (DAS28), radiographs of small joints (Larsen score), rheumatoid factor, body mass index (BMI), comorbidities and anti-rheumatic drugs were verified. Patients' questionnaires included sociodemographic information, pain level, global disease activity, the Beck Depression Inventory, the mental and physical component scores of Short Form-36 and physical activity level. RESULTS: Of the 199 patients, 36%, 17% and 47% patients had remission, low/moderate and high DAS28, respectively. The patients in remission had significantly shorter disease duration, better parameters in terms of pain, physician's assessment, Larsen, Beck or physical component score of Short Form 36, and they were more physically active than other patients. After adjustments for age, sex, RA duration, radiographs and BMI, the decreasing MPCS associated linearly with the increasing DAS28 activity levels (linearity, P <0.001). CONCLUSION: Poorer MPCS is clearly associated with higher disease activity in patients with RA. Muscle performance is a modifiable risk factor. The findings suggest evaluating muscle performance in clinical practice as a part of patient care. PMID- 29630628 TI - Morphological and molecular analyses of Anodontinae species (Bivalvia, Unionidae) of Lake Baikal and Transbaikalia. AB - The diversity and taxonomy of anodontine species in Lake Baikal and Transbaikalia region has been contentious since it is based on a typological species concept, the so called "Comparatory Method". Using this method, six Comparatory anodontine species have been described for the study area as belonging to the genus Colletopterum. This genus was separated from Anodonta based on shell characteristics and further split into two subgenera, i.e. Colletopterum sensu stricto and Colletopterum (Piscinaliana). However, many authors do not recognize this separation maintaining all Colletopterum forms within Anodonta. The current study clarifies the taxonomy and systematics of Anodontinae in this region, using a combination of molecular, morphological and anatomical data. All previously recognized Comparatory forms are here recognized as a single species, i.e. Anodonta anatina. PMID- 29630627 TI - Health care providers' compliance with the notifiable diseases surveillance system in South Africa. AB - BACKGROUND: The optimal performance of a notifiable disease surveillance system (NDSS) is dependent on health care provider (HCP) compliance with communicable disease notification. HCP compliance ensures appropriate investigation and control measures by relevant health care authorities. This study examines the compliance of HCPs with the NDSS in South Africa and factors associated with their compliance. METHODS: A cross-sectional survey was carried out in three randomly selected provinces. We stratified by type of facility, and recruited clusters of HCPs on survey day to participate. All consenting HCPs in the randomly selected health care facilities on the day of the survey, completed a questionnaire that elicited information on socio-demographic characteristics and notification practices. The data were analysed using STATA(r) 14, using the identifiers for stratum and cluster as well as the calculated sampling weights. RESULTS: The study found that 58% of 919 HCPs diagnosed a notifiable disease in the year preceding the survey. The majority of these professionals (92%) indicated that they had reported the disease, but only 51% of those notified the disease/s correctly to the Department of Health. Paediatricians were less likely to notify correctly (OR 0.01, 95% CI 0.00-0.12, p = 0.001). The factors that influenced notification were HCPs perceptions of workload (OR 0.84, 95% CI 0.70 0.99, p = 0.043) and that notification data are not useful (OR 0.84, 95% CI 0.71 0.99, p = 0.040). The study found no association between correct notification and HCPs' willingness to notify, experience or training on the NDSS, understanding of the purpose of the NDSS, knowledge of what to notify, or perception of feedback given. CONCLUSIONS: The compliance of HCPs in South Africa with the NDSS is suboptimal. In light of the important role of HCPs in the effective functioning of the NDSS, information on NDSS usefulness and guidelines on correct notification procedures are needed to increase their compliance. PMID- 29630629 TI - Ocular residual and corneal astigmatism in a clinical population of high school students. AB - PURPOSE: Total refractive astigmatism is usually the first consideration that guides the selection of contact lens type (e.g., spherical or toric), while the ocular source of the astigmatism is a second, but more important consideration, for the final clinical decision. This study was conducted to provide detailed data on this topic by evaluating astigmatic components in Chinese adolescents. METHODS: Participants were recruited from healthy high school students undergoing an annual ocular examination at a local hospital. Total astigmatism (TA), corneal astigmatism (CA), and ocular residual astigmatism (ORA) were determined by a Hartmann-Shack wavefront analyzer system (KR-1W, Topcon) with the natural pupil. The axis relationship between CA and ORA was placed into three categories: on axis, defined as an axis with a difference of 0 +/- 10 degrees ; opposite-axis, a difference of 90 +/- 10 degrees ; and the rest defined as oblique-axis. RESULTS: The study consisted of 1,466 students (57.84% girls, age: 16.49 +/- 1.05 years). ORA was present in 83.97%, 66.64%, and 45.23% of participants, according to the various criteria for astigmatism (>= 0.50 D, >= 0.75 D, and >= 1.00 D, respectively). While with-the-rule was the most common axis orientation for both TA (76.28%) and CA (89.94%), against-the-rule predominated in ORA (93.82%; chi2 = 1688.544, p < 0.001). Opposite-axis was the major type of axis difference (90.96%) of clinical significance (i.e., >= 1.00 D) between CA and ORA, which also prevailed in all levels of TA (range: 56.25-82.26%). CONCLUSIONS: ORA is common in high school students and usually demonstrates a compensation relationship with CA, which should be taken into consideration when determining the design of contact lenses to correct refractive error. PMID- 29630614 TI - Information presentation through a head-worn display ("smart glasses") has a smaller influence on the temporal structure of gait variability during dual-task gait compared to handheld displays (paper-based system and smartphone). AB - The need to complete multiple tasks concurrently is a common occurrence both daily life and in occupational activities, which can often include simultaneous cognitive and physical demands. As one example, there is increasing availability of head-worn display technologies that can be employed when a user is mobile (e.g., while walking). This new method of information presentation may, however, introduce risks of adverse outcomes such as a decrement to gait performance. The goal of this study was thus to quantify the effects of a head-worn display (i.e., smart glasses) on motor variability during gait and to compare these effects with those of other common information displays (i.e., smartphone and paper-based system). Twenty participants completed four walking conditions, as a single task and in three dual-task conditions (three information displays). In the dual-task conditions, the information display was used to present several cognitive tasks. Three different measures were used to quantify variability in gait parameters for each walking condition (using the cycle-to-cycle standard deviation, sample entropy, and the "goal-equivalent manifold" approach). Our results indicated that participants used less adaptable gait strategies in dual-task walking using the paper-based system and smartphone conditions compared with single-task walking. Gait performance, however, was less affected during dual-task walking with the smart glasses. We conclude that the risk of an adverse gait event (e.g., a fall) in head-down walking conditions (i.e., the paper-based system and smartphone conditions) were higher than in single-task walking, and that head-worn displays might help reduce the risk of such events during dual-task gait conditions. PMID- 29630630 TI - Validation of automated lobe segmentation on paired inspiratory-expiratory chest CT in 8-14 year-old children with cystic fibrosis. AB - OBJECTIVES: Densitometry on paired inspiratory and expiratory multidetector computed tomography (MDCT) for the quantification of air trapping is an important approach to assess functional changes in airways diseases such as cystic fibrosis (CF). For a regional analysis of functional deficits, an accurate lobe segmentation algorithm applicable to inspiratory and expiratory scans is beneficial. MATERIALS AND METHODS: We developed a fully automated lobe segmentation algorithm, and subsequently validated automatically generated lobe masks (ALM) against manually corrected lobe masks (MLM). Paired inspiratory and expiratory CTs from 16 children with CF (mean age 11.1+/-2.4) acquired at 4 time points (baseline, 3mon, 12mon, 24mon) with 2 kernels (B30f, B60f) were segmented, resulting in 256 ALM. After manual correction spatial overlap (Dice index) and mean differences in lung volume and air trapping were calculated for ALM vs. MLM. RESULTS: The mean overlap calculated with Dice index between ALM and MLM was 0.98+/-0.02 on inspiratory, and 0.86+/-0.07 on expiratory CT. If 6 lobes were segmented (lingula treated as separate lobe), the mean overlap was 0.97+/-0.02 on inspiratory, and 0.83+/-0.08 on expiratory CT. The mean differences in lobar volumes calculated in accordance with the approach of Bland and Altman were generally low, ranging on inspiratory CT from 5.7+/-52.23cm3 for the right upper lobe to 17.41+/-14.92cm3 for the right lower lobe. Higher differences were noted on expiratory CT. The mean differences for air trapping were even lower, ranging from 0+/-0.01 for the right upper lobe to 0.03+/-0.03 for the left lower lobe. CONCLUSIONS: Automatic lobe segmentation delivers excellent results for inspiratory and good results for expiratory CT. It may become an important component for lobe-based quantification of functional deficits in cystic fibrosis lung disease, reducing necessity for user-interaction in CT post-processing. PMID- 29630631 TI - Dynamics and control of the ERK signaling pathway: Sensitivity, bistability, and oscillations. AB - Cell signaling is the process by which extracellular information is transmitted into the cell to perform useful biological functions. The ERK (extracellular signal-regulated kinase) signaling controls several cellular processes such as cell growth, proliferation, differentiation and apoptosis. The ERK signaling pathway considered in this work starts with an extracellular stimulus and ends with activated (double phosphorylated) ERK which gets translocated into the nucleus. We model and analyze this complex pathway by decomposing it into three functional subsystems. The first subsystem spans the initial part of the pathway from the extracellular growth factor to the formation of the SOS complex, ShC Grb2-SOS. The second subsystem includes the activation of Ras which is mediated by the SOS complex. This is followed by the MAPK subsystem (or the Raf-MEK-ERK pathway) which produces the double phosphorylated ERK upon being activated by Ras. Although separate models exist in the literature at the subsystems level, a comprehensive model for the complete system including the important regulatory feedback loops is missing. Our dynamic model combines the existing subsystem models and studies their steady-state and dynamic interactions under feedback. We establish conditions under which bistability and oscillations exist for this important pathway. In particular, we show how the negative and positive feedback loops affect the dynamic characteristics that determine the cellular outcome. PMID- 29630632 TI - Dynamics of cholera epidemics from Benin to Mauritania. AB - BACKGROUND: The countries of West Africa are largely portrayed as cholera endemic, although the dynamics of outbreaks in this region of Africa remain largely unclear. METHODOLOGY/PRINCIPAL FINDINGS: To understand the dynamics of cholera in a major portion of West Africa, we analyzed cholera epidemics from 2009 to 2015 from Benin to Mauritania. We conducted a series of field visits as well as multilocus variable tandem repeat analysis and whole-genome sequencing analysis of V. cholerae isolates throughout the study region. During this period, Ghana accounted for 52% of the reported cases in the entire study region (coastal countries from Benin to Mauritania). From 2009 to 2015, we found that one major wave of cholera outbreaks spread from Accra in 2011 northwestward to Sierra Leone and Guinea in 2012. Molecular epidemiology analysis confirmed that the 2011 Ghanaian isolates were related to those that seeded the 2012 epidemics in Guinea and Sierra Leone. Interestingly, we found that many countries deemed "cholera endemic" actually suffered very few outbreaks, with multi-year lulls. CONCLUSIONS/SIGNIFICANCE: This study provides the first cohesive vision of the dynamics of cholera epidemics in a major portion of West Africa. This epidemiological overview shows that from 2009 to 2015, at least 54% of reported cases concerned populations living in the three urban areas of Accra, Freetown, and Conakry. These findings may serve as a guide to better target cholera prevention and control efforts in the identified cholera hotspots in West Africa. PMID- 29630633 TI - Healthcare utilisation prior to the diagnosis of inflammatory bowel diseases and the influence of livestock exposure: A longitudinal case-control study. AB - An increased prevalence of the inflammatory bowel diseases, ulcerative colitis and Crohn's disease, was found amongst residents in a livestock dense area. We hypothesised that exposure to livestock farms might be a substantial environmental factor that contributes to the development of these diseases and that in the lead up to inflammatory bowel diseases potential risk factors can be identified. This study aimed to investigate the contribution of livestock exposure to the development of these diseases and the clinical events prior to the diagnosis. Electronic health records from 2006-2013 of general practices were used. The study population consisted of patients with a new diagnosis of inflammatory bowel diseases resident in areas with a high (n = 141) or lower (n = 109) livestock density. Patients with low back pain (n = 10,469) were used as controls. For those in a livestock dense area, distance to livestock farms was determined. Associations between morbidities and drug prescriptions in the reporting year and three years previous to the diagnosis, and the residential proximity to livestock exposure were investigated with multivariable logistic regression analyses. Acute and chronic morbidity of the gastrointestinal tract and associated drug prescriptions were predictive for the development of inflammatory bowel diseases. In addition, a positive association was found between infections and living within 500 meter of poultry farms and the development of inflammatory bowel diseases [OR: 3.3 (1.1-9.9)]. Nonetheless, overall livestock exposure contributed little to the development of these diseases. These results suggest that exposure to livestock farms on its own contributes minimal to the development of inflammatory bowel diseases. Nonetheless, having infections appeared to be a risk factor for neighbouring residents of poultry farms. More research is warranted to explain the increased prevalence of inflammatory bowel diseases amongst residents in areas with a high density of livestock. PMID- 29630635 TI - Approximating net interactions among rigid domains. AB - Many physical simulations aim at evaluating the net interaction between two rigid bodies, resulting from the cumulative effect of pairwise interactions between their constituents. This is manifested particularly in biomolecular applications such as hierarchical protein folding instances where the interaction between almost rigid domains directly influences the folding pathway, the interaction between macromolecules for drug design purposes, self-assembly of nanoparticles for drug design and drug delivery, and design of smart materials and bio-sensors. In general, the brute force approach requires quadratic (in terms of the number of particles) number of pairwise evaluation operations for any relative pose of the two bodies, unless simplifying assumptions lead to a collapse of the computational complexity. We propose to approximate the pairwise interaction function using a linear predictor function, in which the basis functions have separated forms, i.e. the variables that describe local geometries of the two rigid bodies and the ones that reflect the relative pose between them are split in each basis function. Doing so replaces the quadratic number of interaction evaluations for each relative pose with a one-time quadratic computation of a set of characteristic parameters at a preprocessing step, plus constant number of pose function evaluations at each pose, where this constant is determined by the required accuracy of approximation as well as the efficiency of the used approximation method. We will show that the standard deviation of the error for the net interaction is linearly (in terms of number of particles) proportional to the regression error, if the regression errors are from a normal distribution. Our results show that proper balance of the tradeoff between accuracy and speed up yields an approximation which is computationally superior to other existing methods while maintaining reasonable precision. PMID- 29630634 TI - Electrophysiological mechanisms of vandetanib-induced cardiotoxicity: Comparison of action potentials in rabbit Purkinje fibers and pluripotent stem cell-derived cardiomyocytes. AB - Vandetanib, a multi-kinase inhibitor used for the treatment of various cancers, has been reported to induce several adverse cardiac effects. However, the underlying mechanisms of vandetanib-induced cardiotoxicity are unclear. This study aimed to investigate the mechanism of vandetanib-induced cardiotoxicity using intracellular electrophysiological recordings on human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs), rabbit Purkinje fibers, and HEK293 cells transiently expressing human ether-a-go-go-related gene (hERG; the rapidly activating delayed rectifier K+ channel, IKr), KCNQ1/KCNE1 (the slowly activating delayed rectifier K+ current, IKs), KCNJ2 (the inwardly rectifying K+ current, IK1) or SCN5A (the inward Na+ current, INa). Purkinje fiber assays and ion channel studies showed that vandetanib at concentrations of 1 and 3 MUM inhibited the hERG currents and prolonged the action potential duration. Alanine scanning and in silico hERG docking studies demonstrated that Y652 and F656 in the hERG S6 domain play critical roles in vandetanib binding. In hiPSC-CMs, vandetanib markedly reduced the maximum rate of depolarization during the AP upstroke. Ion channel studies revealed that hiPSC-CMs were more sensitive to inhibition of the INa by vandetanib than in a heterogeneously expressed HEK293 cell model, consistent with the changes in the AP parameters of hiPSC-CMs. The subclasses of Class I antiarrhythmic drugs inhibited INa currents in a dose-dependent manner in hiPSC-CMs and SCN5A-encoded HEK293 cells. The inhibitory potency of vandetanib for INa was much higher in hiPSC-CMs (IC50: 2.72 MUM) than in HEK293 cells (IC50: 36.63 MUM). These data suggest that AP and INa assays using hiPSC-CMs are useful electrophysiological models for prediction of drug-induced cardiotoxicity. PMID- 29630636 TI - Adhesion performance of a universal adhesive in the root canal: Effect of etch and-rinse vs. self-etch mode. AB - PURPOSE: Universal adhesives are new systems that can be used in etch-and-rinse (ER) and self-etch (SE) modes. This in vitro study evaluated the bonding performance of a universal adhesive in ER mode and SE mode with two irrigants for luting fiber posts in the root canal. MATERIALS AND METHODS: After separation of the roots from the crowns of 56 maxillary central incisors and endodontic treatment, 10-mm post space was prepared. The roots were divided into seven groups according to irrigant/adhesive protocol used for cementation of posts: 1) sodium hypochlorite (NaOCl) irrigant + acid etching + One-Step Plus, 2) NaOCl + Clearfil SE Bond (CSE) and 3) EDTA + CSE as controls; 4) NaOCl + All-Bond Universal (AB) in ER mode, 5) NaOCl + AB in SE mode, 6) EDTA + AB in SE mode, 7) distilled water + AB in SE mode. Posts were luted using Duo-link. The bonded roots were sectioned into microslices. After push-out bond strength (PBS) testing, data in MPa were analyzed with two-way ANOVA and Tukey test (alpha = 0.05). RESULTS: PBS was significantly affected by irrigation/adhesive protocol and root region (P<0.05), with no significant interaction of these factors. PBS of ABU in ER mode with NaOCl and in SE mode with NaOCl or EDTA was comparable to that in the respective controls. The highest and lowest PBSs were recorded for ABU in the SE mode with EDTA (15.38 +/- 4) and NaOCl (10.17 +/- 3.5), respectively. PBS of AB in ER and SE modes was similar when distilled water was used in the SE mode. CONCLUSION: Adhesive performance of AB in the ER mode was comparable to or different from the SE mode, depending on the irrigant used to prepare post space in SE approach. AB could behave as a reliable bonding for post cementation. PMID- 29630637 TI - Parkinson's disease-related non-motor features as risk factors for post-operative delirium in spinal surgery. AB - BACKGROUND: The clinical features of postoperative delirium are similar to the core features of alpha synuclein-related cognitive disorders, such as Parkinson's disease dementia (PDD) or dementia with Lewy bodies (DLB). Therefore, we hypothesized that the non-motor symptoms (NMSs) in Parkinson's disease (PD), which precede the cardinal motor features of PD, are likely to be risk factors for developing postoperative delirium. We investigated the association between PD related NMSs and postoperative delirium in old people undergoing elective spinal surgery. METHODS: This study was a prospective study. Participants were aged 65 years and older and scheduled to undergo elective spinal surgery. During the enrollment period, 338 individuals were screened, 104 participants were included in the analysis. We assessed eight easily-assessed and representative PD-related NMSs 1 day before the scheduled surgery using tests or questionnaires for each symptom. The presence of delirium was determined by using the short version of the Confusion Assessment Method (CAM). RESULTS: Fifteen (14.4%) of the 104 participants (age, 71.7 +/- 4.7 years; men, 34.6%) met the CAM criteria for post operative delirium. Multivariate logistic analysis showed that decreased olfactory function (odds ratio [OR] 0.63, 95% CI 0.44-0.91) and exhibiting rapid eye movement sleep behavior disorder (RBD, OR 1.45, 95% CI 1.09-1.93) were significantly independent predictors of postoperative delirium. CONCLUSIONS: Our study shows that hyposmia and RBD are significantly independent risk factors for postoperative delirium in general elderly population. Considering that NMSs may represent burden of alpha synuclein deposit, we postulate that an underlying alpha synucleinopathy may correlates with postoperative delirium. SIGNIFICANCE: This study gives a novel insight for the risk factor of postoperative delirium. PMID- 29630638 TI - Quantitative validation of nicotine production in tea (Camellia sinensis L.). AB - Endogenous nicotine was confirmed to be present in tea plants (Camellia sinensis L.) by liquid chromatography-tandem mass spectrometry of tea samples from tea producing regions in six Asian countries. All samples contained nicotine (0.011 0.694 MUg g-1 dry weight). Nicotine contents remained constant during manufacturing of green, oolong and black teas, implying that nicotine is stable against heating, drying, enzymatic oxidation and mechanical damage during processing. Flower buds and seeds of cultivar Yabukita also contained nicotine (0.030-0.041 MUg g-1 dry weight). A comparison of two cultivars revealed that higher nicotine contents were found in the black tea cultivar Benifuki. All plant parts of hydroponic Yabukita contained nicotine (0.003-0.013 MUg g-1 dry weight). Tea cells cultured in B5 medium as well as roots and stems of tea seedlings contained nicotine levels similar to those of new leaves from field-grown plants. Although the levels of endogenous nicotine in tea plants are extremely low and sample contamination cannot be discounted, these levels exceed the maximum acceptable limit in Japan (0.01 MUg g-1 dry weight). PMID- 29630639 TI - Phenylephrine does not improve oxygenation during one-lung ventilation: A randomized, double-blind, cross-over study. AB - BACKGROUND: Phenylephrine is an alpha1 adrenergic receptor agonist that causes pulmonary vasoconstriction, and so may effectively enhance hypoxic pulmonary vasoconstriction (HPV). However, there is little evidence that phenylephrine augments HPV in clinical situations. This study aimed to evaluate the clinical effects of phenylephrine infusion on oxygenation during one-lung ventilation (OLV) in patients undergoing thoracic surgery. METHODS: This was a prospective, randomized, double-blind, cross-over study. Included patients were those undergoing elective thoracic surgery in the lateral decubitus position with OLV. Patients were randomly allocated to two groups. The N-P group initially had OLV with normal saline infusion for 30 minutes; after a 10 minute interval, OLV was then maintained with phenylephrine infusion for 30 minutes. The P-N group had the drug-infusion in the reverse order. The primary outcome was arterial partial pressure of oxygen. Secondary outcomes were mean arterial pressure, heart rate, pulse pressure variation, perfusion index, and difference between bladder and skin temperature. Statistical analysis was performed using the student t-test, Fisher's exact test, and ANOVA for Cross-over design. P < 0.05 was considered statistically significant. RESULTS: Twenty-nine patients were analyzed. Although phenylephrine infusion significantly increased mean arterial pressure (P < 0.001), arterial partial pressure of oxygen did not differ between the two timepoints (P = 0.19). There was no carryover effect in arterial partial pressure of oxygen (P = 0.14). Phenylephrine infusion significantly decreased heart rate (P = 0.02) and pulse pressure variation (P < 0.001). CONCLUSIONS: Phenylephrine infusion did not improve oxygenation during OLV. The present results indicate that phenylephrine does not have clinically meaningful effects on HPV. TRIAL REGISTRATION: University Hospital Medical Information Network 000024317. PMID- 29630641 TI - Effects of low temperature plasmas and plasma activated waters on Arabidopsis thaliana germination and growth. AB - Two plasma devices at atmospheric pressure (air dielectric barrier discharge and helium plasma jet) have been used to study the early germination of Arabidopsis thaliana seeds during the first days. Then, plasma activated waters are used during the later stage of plant development and growth until 42 days. The effects on both testa and endospserm ruptures during the germination stage are significant in the case of air plasma due to its higher energy and efficiency of producing reactive oxygen species than the case of helium plasma. The latter has shown distinct effects only for testa rupture. Analysis of germination stimulations are based on specific stainings for reactive oxygen species production, peroxidase activity and also membrane permeability tests. Furthermore, scanning electron microscopy (SEM) has shown a smoother seed surface for air plasma treated seeds that can explain the plasma induced-germination. During the growth stage, plants were watered using 4 kinds of water (tap and deionized waters activated or not by the low temperature plasma jet). With regards to other water kinds, the characterization of the tap water has shown a larger conductivity, acidity and concentration of reactive nitrogen and oxygen species. Only the tap water activated by the plasma jet has shown a significant effect on the plant growth. This effect could be correlated to reactive nitrogen species such as nitrite/nitrate species present in plasma activated tap water. PMID- 29630642 TI - Risk of new-onset diabetes among patients treated with statins according to hypertension and gender: Results from a nationwide health-screening cohort. AB - BACKGROUND: Statins have been known to increase the risk of incident type 2 diabetes mellitus (DM); however, other factors, especially hypertension, are also associated with DM development. OBJECTIVE: We investigated whether statin use increases the risk of DM and further analyzed whether the relation between statin use and incident DM differs according to the presence of hypertension and gender. METHODS: From a nationwide health-screening cohort, 40,164 participants with total cholesterol levels >=eve mg/dL and without pre-diagnosed DM, cardiovascular disease, or cancer, who underwent a series of regular health check-ups, were enrolled. Statin users were defined as participants who were prescribed statins more than twice during 6 months. RESULTS: There were 17,798 statin non-users and 22,366 statin users. During 7.66+/-3.21 years of follow-up, incident DM developed in 5.68% of statin non-users and 7.64% of statin users. Among the entire study population, statin use was associated with new-onset DM after adjusting for clinical risk factors. In sub-analysis according to hypertension, statin use significantly increased the risk of incident DM only in normotensive patients [hazard ratio (HR) 1.31, 95% confidence interval (CI) 1.09 to 1.58, p = 0.004], and not in hypertensive patients (p>0.05). Furthermore, continuous statin use was strongly associated with new-onset DM in women, regardless of hypertension presence (all p<0.05). However, in men, statin was associated with new-onset DM only in normotensive males (HR 1.61, 95% CI 1.35 to 1.92, p<0.001) and not in hypertensive males (p>0.05). CONCLUSIONS: Statin use increased the risk of new onset DM only in normotensive patients and hypertensive women, suggesting that these groups should be more carefully monitored for the development of DM during the course of follow-up. PMID- 29630640 TI - Oxygen microbubbles improve radiotherapy tumor control in a rat fibrosarcoma model - A preliminary study. AB - Cancer affects 39.6% of Americans at some point during their lifetime. Solid tumor microenvironments are characterized by a disorganized, leaky vasculature that promotes regions of low oxygenation (hypoxia). Tumor hypoxia is a key predictor of poor treatment outcome for all radiotherapy (RT), chemotherapy and surgery procedures, and is a hallmark of metastatic potential. In particular, the radiation therapy dose needed to achieve the same tumor control probability in hypoxic tissue as in normoxic tissue can be up to 3 times higher. Even very small tumors (<2-3 mm3) comprise 10-30% of hypoxic regions in the form of chronic and/or transient hypoxia fluctuating over the course of seconds to days. We investigate the potential of recently developed lipid-stabilized oxygen microbubbles (OMBs) to improve the therapeutic ratio of RT. OMBs, but not nitrogen microbubbles (NMBs), are shown to significantly increase dissolved oxygen content when added to water in vitro and increase tumor oxygen levels in vivo in a rat fibrosarcoma model. Tumor control is significantly improved with OMB but not NMB intra-tumoral injections immediately prior to RT treatment and effect size is shown to depend on initial tumor volume on RT treatment day, as expected. PMID- 29630643 TI - An antibody with Fab-constant domains exchanged for a pair of CH3 domains. AB - We have designed a complete antibody-like construct where the CH1 and Ckappa domains are exchanged for a pair of the CH3 domains and efficient pairing of the heavy and light variable domain is achieved using "Knobs-into-Holes" strategy. This construct, composed of only naturally occurring immunoglobulin sequences without artificial linkers, expressed at a high level in mammalian cells, however exhibited low solubility. Rational mutagenesis aimed at the amino acid residues located at the interface of the variable domains and the exchanged CH3 domains was applied to improve the biophysical properties of the molecule. The domain exchanged construct, including variable domains of the HER2/neu specific antibody trastuzumab, was able to bind to the surface of the strongly HER2/neu positive cell line SK-BR3 4-fold weaker than trastuzumab, but could nevertheless incite a more potent response in an antibody-dependent cell cytotoxicity (ADCC) reporter assay with FcgammaRIIIa-overexpressing T-cells. This could be explained with a stronger binding to the FcgammaRIIIa. Importantly, the novel construct could mediate a specific ADCC effect with natural killer cells similar to the parental antibody. PMID- 29630645 TI - Long-term exposure to ambient air pollutants and mental health status: A nationwide population-based cross-sectional study. AB - There is a suspected but unproven association between long-term exposure to ambient air pollution and mental health. The aim of this study is to investigate the association between long-term exposure to ambient air pollution and subjective stress, depressive disorders, health-related quality of life (QoL) and suicide. We selected 124,205 adults from the Korean Community Health Survey in 2013 who were at least 19 years old and who had lived in their current domiciles for > five years. Based on the computer-assisted personal interviews to measure subjective stress in daily life, EuroQoL-5 dimensions, depression diagnosis by a doctor, suicidal ideation, and suicidal attempts, we evaluated the risk of mental disorders using multiple logistic regression analysis according to the quartiles of air pollutants, such as particulate matter <10MUm (PM10), nitrogen dioxide (NO2), carbon monoxide (CO), and sulfur dioxide, using yearly average concentration between August 2012 and July 2013. The prevalence of high stress, poor QoL, depressiveness, diagnosis of depression, and suicide ideation was positively associated with high concentrations of PM10, NO2, and CO after adjusting for confounding factors. Men were at increased risk of stress, poor QoL, and depressiveness from air pollution exposure than were women. The risk of higher stress or poor QoL in subjects < age 65 increased with air pollution more than did that in subjects >= age 65. Long-term exposure to ambient air pollution may be an independent risk factor for mental health disorders ranging from subjective stress to suicide ideation. PMID- 29630644 TI - Selection for growth rate and body size have altered the expression profiles of somatotropic axis genes in chickens. AB - The growth hormone / insulin-like growth factor-1 (GH/IGF-1) pathway of the somatotropic axis is the major controller for growth rate and body size in vertebrates, but the effect of selection on the expression of GH/IGF-1 somatotropic axis genes and their association with body size and growth performance in farm animals is not fully understood. We analyzed a time series of expression profiles of GH/IGF-1 somatotropic axis genes in two chicken breeds, the Daweishan mini chickens and Wuding chickens, and the commercial Avian broilers hybrid exhibiting markedly different body sizes and growth rates. We found that growth rate and feed conversion efficiency in Daweishan mini chickens were significantly lower than those in Wuding chickens and Avian broilers. The Wuding and Daweishan mini chickens showed higher levels of plasma GH, pituitary GH mRNA but lower levels of hepatic growth hormone receptor (GHR) mRNA than in Avian broilers. Daweishan mini chickens showed significantly lower levels of plasma IGF-1, thigh muscle and hepatic IGF-1 mRNA than did Avian broilers and Wuding chickens. These results suggest that the GH part of the somatotropic axis is the main regulator of growth rate, while IGF-1 may regulate both growth rate and body weight. Selection for growth performance and body size have altered the expression profiles of somatotropic axis genes in a breed-, age-, and tissue specific manner, and manner, and alteration of regulatory mechanisms of these genes might play an important role in the developmental characteristics of chickens. PMID- 29630646 TI - Ultrasound-guided lumbar puncture with a needle-guidance system: A prospective and controlled study to evaluate the learnability and feasibility of a newly developed approach. AB - OBJECTIVE: To evaluate the learnability and feasibility of a new technique comprising a needle-guidance-system (NGS) for ultrasound-assisted lumbar puncture. METHOD: Using a randomized crossover study design, 24 medical students were asked to perform an ultrasound-assisted lumbar puncture on a gel phantom using two different techniques that each included a paramedian insertion site. Procedure 1 (P1) used a pre-procedural ultrasound scan to predetermine the ideal insertion point. Procedure 2 (P2) applied a new technique comprising an NGS for performing real-time ultrasound-guided lumbar puncture. Success rates and performance times for both procedures were compared. Participants were also asked to complete a post-study questionnaire, both to quantitatively assess the workload involved and state their personal preferences. RESULTS: In comparison to the pre-procedural scan (P1), the NGS (P2) was associated with a significant increase in the number of successful punctures per participant (5 (P2) [interquartile range: 3.3-5.0] vs. 3 (P1) [interquartile range: 1.3-4.0], p = 0.005), and led to a significant reduction in performance time (118 seconds vs. 80.6 seconds, p < 0.001). In terms of workload perception, NGS use was associated with significantly better performances and lower frustration levels, as rated by students in the post-study questionnaire. Finally, 23/24 participants stated their preference for P2. CONCLUSION: Our newly-developed technique for real-time ultrasound-guided lumbar puncture proved to be learnable and feasible for novices, and only required a small amount of training. The use of an NGS therefore has the potential to serve as a key feature of the ultrasound-assisted lumbar puncture. PMID- 29630647 TI - Does cyclic water stress damage wheat yield more than a single stress? AB - The occurrence of water stress during wheat growth is more frequent due to climate change. Three experiments (cyclic drought, cyclic waterlogging, and cyclic drought plus waterlogging) were conducted to investigate the effects of mild and severe cyclic/single water stress at elongation and heading stages on winter wheat (Triticum aestivum L.) yield. The effect of either mild drought at elongation or mild waterlogging at heading on wheat yield was not significant; however, significance did occur under other single water stresses. As the stress becomes more severe, the yield loss significantly increases. Extreme drought/waterlogging treatment at elongation caused a greater yield penalty than stress at heading stage. Except the combination of mild drought and mild waterlogging treatment, cyclic water stress significantly decreased wheat yields. The decrease in wheat yield under cyclic severe drought and waterlogging was significantly higher than any other treatment, with percentage decreases of 71.52 and 73.51%, respectively. In general, a yield reduction from mild cyclic water stress did not indicate more severe damage than single treatments; in contrast, grain yield suffered more when water stress occurred again after severe drought and waterlogging. Drought during elongation significantly decreased kernel number, whereas drought at heading/waterlogging during elongation and heading decreased the spike weight, which might be the main reason for the yield penalty. Furthermore, water stress caused variation in the decrease of total biomass and/or harvest index. The present study indicates comprehensive understanding of the types, degree, and stages of water stress are essential for assessing the impact of multiple water stresses on wheat yield. PMID- 29630648 TI - Thiopurine methyltransferase genotype and activity cannot predict outcomes of azathioprine maintenance therapy for antineutrophil cytoplasmic antibody associated vasculitis: A retrospective cohort study. AB - OBJECTIVE: Azathioprine is a widely used immunosuppressive drug. Genetic polymorphisms and activity of the enzyme thiopurine methyltransferase (TPMT) have been associated with azathioprine efficacy and toxicity in several populations. We investigated whether these associations also exist for ANCA associated vasculitis (AAV) patients, who receive azathioprine maintenance therapy after remission induction with cyclophosphamide. METHODS: 207 AAV patients treated with cyclophosphamide induction and azathioprine maintenance therapy were included and followed for 60 months. TPMT genotype and tertiles of TPMT activity were compared to relapse free survival and occurrence of adverse events, particularly leukopenia. Multivariable regression was performed to account for confounders. RESULTS: In univariable analysis, relapse free survival was not significantly associated with TPMT genotype (P = 0.41) or TPMT activity (P = 0.07), although it tended to be longer in lower tertiles of TPMT activity. There was no significant association of TPMT genotype and activity with occurrence of any adverse event. In multiple regression, leukocyte counts at the end of cyclophosphamide induction were related to risk of leukopenia during azathioprine therapy [P<0.001; OR 0.54 (95% CI 0.43-0.68)] and risk of relapse during follow-up [P = 0.001; HR 1.17 (95% CI 1.07-1.29)] irrespective of TMPT genotype or activity. CONCLUSION: TPMT genotype and activity were not independent predictors of relapse, and could not predict leukopenia or other adverse effects from azathioprine. Leukocyte counts after cyclophosphamide induction were related to both outcomes, implying a greater influence of cyclophosphamide response compared to azathioprine and TPMT in AAV patients. PMID- 29630649 TI - Colorectal cancer patients with different C-reactive protein levels and 5-year survival times can be differentiated with quantitative serum proteomics. AB - Over 1.4 million people are diagnosed with colorectal cancer (CRC) each year, making it the third most common cancer in the world. Increased screening and therapeutic modalities including improved combination treatments have reduced CRC mortality, although incidence and mortality rates are still increasing in some areas. Serum-based biomarkers are mainly used for follow-up of cancer, and are ideal due to the ease and minimally invasive nature of sample collection. Unfortunately, CEA and other serum markers have too low sensitivity for screening and preoperative diagnostic purposes. Increasing interest is focused on the possible use of biomarkers for predicting treatment response and prognosis in cancer. In this study, we have performed mass spectrometry analysis (UPLC-UDMSE) of serum samples from 19 CRC patients. Increased levels of C-reactive protein (CRP), which occur during local inflammation and the presence of a systemic inflammatory response, have been linked to poor prognosis in CRC patients. We chose to analyze samples according to CRP values by dividing them into the categories CRP <30 and >30, and, separately, according to short and long 5-year survival. The aim was to discover differentially expressed proteins associated with poor prognosis and shorter survival. We quantified 256 proteins and performed detailed statistical analyses and pathway analysis. We discovered multiple proteins that are up- or downregulated in patients with CRP >30 as compared to CRP <30 and in patients with short as compared to long 5-year survival. Pathways that were enriched include LXR/RXR activation, FXR/RXR activation, complement and coagulation cascades and acute phase signaling response, with some of the proteins we identified having roles in these pathways. In this study, we have identified multiple proteins, of which a few have been previously identified as potential biomarkers, and others that have been identified as potential biomarkers for CRC for the first time, to the best of our knowledge. While these proteins still need to be validated in larger patient series, this pilot study will pave the way for future studies aiming to provide better biomarkers for patients with CRC. PMID- 29630650 TI - Self-assembly and clustering of magnetic peapod-like rods with tunable directional interaction. AB - Based on extensive Langevin Dynamics simulations we investigate the structural properties of a two-dimensional ensemble of magnetic rods with a peapod-like morphology, i.e, rods consisting of aligned single dipolar beads. Self-assembled configurations are studied for different directions of the dipole with respect to the rod axis. We found that with increasing misalignment of the dipole from the rod axis, the smaller the packing fraction at which the percolation transition is found. For the same density, the system exhibits different aggregation states for different misalignment. We also study the stability of the percolated structures with respect to temperature, which is found to be affected by the microstructure of the assembly of rods. PMID- 29630651 TI - Backlash against gender stereotype-violating preschool children. AB - While there is substantial evidence that adults who violate gender stereotypes often face backlash (i.e. social and economic penalties), less is known about the nature of gender stereotypes for young children, and the penalties that children may face for violating them. We conducted three experiments, with over 2000 adults from the US, to better understand the content and consequences of adults' gender stereotypes for young children. In Experiment 1, we tested which characteristics adults (N = 635) believed to be descriptive (i.e. typical), prescriptive (i.e. required), and proscriptive (i.e. forbidden) for preschool aged boys and girls. Using the characteristics that were rated in Experiment 1, we then constructed vignettes that were either 'masculine' or 'feminine', and manipulated whether the vignettes were said to describe a boy or a girl. Experiment 2 (N = 697) revealed that adults rated stereotype-violating children as less likeable than their stereotype-conforming peers, and that this difference was more robust for boys than girls. Experiment 3 (N = 731) was a direct replication of Experiment 2, and revealed converging evidence of backlash against stereotype-violating children. In sum, our results suggest that even young children encounter backlash from adults for stereotype violations, and that these effects may be strongest for boys. PMID- 29630653 TI - Weak population structure and no genetic erosion in Pilosocereus aureispinus: A microendemic and threatened cactus species from eastern Brazil. AB - Succulent cacti (Cactaceae) are among the most threatened taxonomic groups assessed to date. Here we evaluated the genetic diversity and population structure of a narrow endemic columnar cactus Pilosocereus aureispinus. This species is only found in a small area of c. 300 km2 of rocky savanna from eastern Brazil and it is currently classified as vulnerable (VU) on the International Union for Conservation of Nature (IUCN) red list. Eight microsatellite loci were genotyped for 91 individuals from four localities of the known P. aureispinus range. In contrast with expectations for narrow endemic species, we found relatively high levels of genetic diversity (e.g., HE = 0.390 to 0.525; HO = 0.394 to 0.572) and very low population structure based on the variation of six loci. All the analyzed individuals were clustered in one unique genetic group in assignment tests. We also generated the sequences of two plastid markers (trnT trnL and psbD-trnT) and found no variation on a subsample of 39 individuals. We used Landsat 8 images and Normalized Difference Vegetation Index to estimate a potential extent of occurrence of c. 750 km2 for this species. Our results showed that P. aureispinus is not suffering from erosion of nuclear genetic variability due to its narrow distribution. However, we advocate that because of the extremely limited extent of occurrence, the ongoing anthropogenic disturbances in its habitat, and phylogenetic distinctiveness of P. aureispinus, this species should be classified as endangered (EN) on the IUCN Red List. PMID- 29630654 TI - "We did not know what was wrong"-Barriers along the care cascade among hospitalized adolescents with HIV in Gaborone, Botswana. AB - High mortality among adolescents with HIV reflects delays and failures in the care cascade. We sought to elucidate critical missed opportunities and barriers to care among adolescents hospitalized with HIV at Botswana's tertiary referral hospital. We enrolled all HIV-infected adolescents (aged 10-19 years) hospitalized with any diagnosis other than pregnancy from July 2015 to January 2016. Medical records were reviewed for clinical variables and past engagement in care. Semi-structured interviews of the adolescents (when feasible) and their caregivers explored delays and barriers to care. Twenty-one eligible adolescents were identified and 15 were enrolled. All but one were WHO Clinical Stage 3 or 4. Barriers to diagnosis included lack of awareness about perinatal HIV infection, illness or death of the mother, and fear of discrimination. Barriers to adherence to antiretroviral therapy included nondisclosure, isolation, and mental health concerns. The number of hospitalized HIV-infected adolescents was lower than expected. However, among those hospitalized, the lack of timely diagnosis and subsequent gaps in the care cascade elucidated opportunities to improve outcomes and quality of life for this vulnerable group. PMID- 29630655 TI - Genetic diversity of Spanish Prunus domestica L. germplasm reveals a complex genetic structure underlying. AB - European plum (Prunus domestica L.) is an ancient domesticated species cultivated in temperate areas worldwide whose genetic structure has been scarcely analyzed to date. In this study, a broad representation of Spanish European plum germplasm collected in Northeastern Spain and a representative set of reference cultivars were compared using nuclear and chloroplast markers. The number of alleles per locus detected with the SSR markers ranged from 8 to 39, with an average of 23.4 alleles, and 8 haplotypes were identified. Bayesian model-based clustering, minimum spanning networks, and the analysis of molecular variance showed the existence of a hierarchical structure. At the first level, two genetic groups were found, one containing 'Reine Claude' type reference cultivars altogether with ca. 25% of local genotypes, and a second one much more diverse. This latter group split in two groups, one containing most (ca. 70%) local genotypes and some old Spanish and French reference cultivars, whereas the other included 24 reference cultivars and only six local genotypes. A third partition level allowed a significant finer delineation into five groups. As a whole, the genetic structure of European plum from Northeastern Spain was shown to be complex and conditioned by a geographical proximity factor. This study not only contributes to genetic conservation and breeding for this species at the national level, but also supports the relevance of undertaking similar tasks of collection and characterization in other unexplored areas. Moreover, this kind of research could lead to future coordinated actions for the examination of the whole European plum diversity, to define conservation strategies, and could be used to better understand the genetic control of traits of horticultural interest through association mapping. PMID- 29630656 TI - Quality of pediatric anesthesia: A cross-sectional study of a university hospital in a low-income country. AB - OBJECTIVE: To evaluate the quality of pediatric anesthesia in a university hospital in Dar es Salaam, Tanzania. METHOD: A cross-sectional study conducted using a new tool that was developed from the literature and WHO recommendations including 28 parameters as standards for pediatric anesthesia. These 28 parameters consisted of 17 structure parameters of the equipment and medicines that should be present in theatre before any surgery starts, and 11 process parameters of actions taken by staff. Adverse events occurring during the anesthesia were recorded. RESULTS: 30 patients were included, aged between 1.5 months to 5 years with a mean of 2.4 years. 26 of the patients underwent elective surgery and 4 patients emergency surgery. Nine parameters were always present and one parameter (bag and mask) was not available for any of the patients. The structure index ranged from 71% to 94% with a mean of 84%. The process index had a mean score of 71% with a range from 50% to 90%: lower than the structure index (p<0.001). With the structure and process index combined the average score was 79% with a low of 67% and high of 89%. 70 adverse events were observed with a range from 0 to 7 adverse events per patient. The most common adverse event was hypoxia at extubation in 20 (69%) patients. Nine patients had an episode of severe hypoxia at extubation. CONCLUSION: Pediatric anesthesia in low resource settings suffers from deficiencies in the structures and processes of providing good quality care. Improvement efforts may be best focused on improving the consistency and quality of the process of care and a reduction in adverse events rather than the structures available. Use of the assessment tool developed for this research could be useful for systematic quality-improvement efforts and to assess the needs in different settings. PMID- 29630652 TI - Skeletal muscle loss is an independent negative prognostic factor in patients with advanced lower rectal cancer treated with neoadjuvant chemoradiotherapy. AB - BACKGROUND: The impact of body composition on the short- or long-term outcomes of patients with surgically treated advanced rectal cancer after neoadjuvant chemoradiotherapy remains unclear. This study examined the correlation between low skeletal muscle mass and morbidity and survival in patients with advanced lower rectal cancer. METHODS: We enrolled 144 clinical stage II/III patients with advanced lower rectal cancer who underwent neoadjuvant chemoradiotherapy followed by curative resection between 2004 and 2011. The cross-sectional skeletal muscle area at the third lumbar vertebra (L3) level was evaluated by computed tomography before chemoradiotherapy, and this was normalized by the square of the height to obtain the skeletal muscle index. Low skeletal muscle mass was defined as the sex specific lowest quartile of the L3 skeletal muscle index. The association between low skeletal muscle mass and morbidity, relapse-free survival, or overall survival was assessed. RESULTS: Low skeletal muscle mass was identified in 37 (25.7%) patients. Age and body mass index were associated with low skeletal muscle mass. By multivariate analysis, we found that low skeletal muscle mass was independently associated with poor overall survival (hazard ratio = 2.93; 95%CI: 1.11-7.71; p = 0.031) and relapse-free survival (hazard ratio = 2.15; 95%CI: 1.06 4.21; p = 0.035), but was not associated with the rate of postoperative complications. CONCLUSIONS: Low skeletal muscle mass is an independent negative prognostic factor for relapse-free and overall survival in patients with advanced lower rectal cancer treated with neoadjuvant chemoradiotherapy. PMID- 29630658 TI - Increasing prevalence, molecular characterization and antifungal drug susceptibility of serial Candida auris isolates in Kuwait. AB - Candida auris is an emerging yeast pathogen of global significance. Its multidrug resistant nature and inadequacies of conventional identification systems pose diagnostic and therapeutic challenges. This study investigated occurrence of C. auris in clinical specimens in Kuwait and its susceptibility to antifungal agents. Clinical yeast strains isolated during 3.5-year period and forming pink colored colonies on CHROMagar Candida were studied by wet mount examination for microscopic morphology and Vitek 2 yeast identification system. A simple species specific PCR assay was developed for molecular identification and results were confirmed by PCR-sequencing of rDNA. Antifungal susceptibility testing of one isolate from each patient was determined by Etest. The 280 isolates forming pink colored colonies on CHROMagar Candida, were identified by Vitek 2 as Candida haemulonii (n = 166), Candida utilis (n = 49), Candida kefyr (n = 45), Candida guilliermondii (n = 9), Candida famata (n = 6) and Candida conglobata (n = 5). Species-specific PCR and PCR-sequencing of rDNA identified 166 C. haemulonii isolates as C. auris (n = 158), C. haemulonii (n = 6) and Candida duobushaemulonii (n = 2). C. auris isolates originated from diverse clinical specimens from 56 patients. Of 56 C. auris isolates tested, all were resistant to fluconazole, 41/56 (73%) and 13/56 (23%) were additionally resistant to voriconazole and amphotericin B, respectively. Eleven (20%) isolates were resistant to fluconazole, voriconazole and amphotericin B. One isolate was resistant to caspofungin and micafungin. Increasing isolation of C. auris in recent years from diverse clinical specimens including bloodstream shows that C. auris is an emerging non-albicans Candida species in Kuwait causing a variety of infections. Inability of conventional identification methods to accurately identify this pathogen and multidrug-resistant nature of many strains calls for a greater understanding of its epidemiology, risk factors for acquiring C. auris infection and management strategies in high-risk patients. This is the first comprehensive study on the emergence of this multidrug-resistant yeast from Kuwait and the Middle East. PMID- 29630657 TI - Trends in alcohol use among young people according to the pattern of consumption on starting university: A 9-year follow-up study. AB - AIM: To identify differences in Risky Consumption (RC) and Binge drinking (BD) trends in students who already followed these patterns of alcohol consumption on starting university and those who did not, and also to try to understand what leads students to engage in these types of behaviour at university. MATERIAL AND METHODS: Cohort study among university students in Spain (n = 1382). BD and RC were measured with the Alcohol Use Disorders Identification Test at ages 18, 20, 22, 24 and 27 years. Multilevel logistic regression for repeated measures was used to calculate the adjusted Odds Ratios (ORs). RESULTS: The prevalence rates of RC and BD were lower throughout the study in students who did not follow these patterns of consumption at age 18. For RC and BD, the differences at age 27 years, expressed as percentage points (pp), were respectively 24 pp and 15 pp in women and 29 pp and 25 pp in men. Early age of onset of alcohol use increased the risk of engaging in RC and BD patterns at university, for men (OR = 2.91 & 2.80) and women (OR = 8.14 & 5.53). The same was observed in students living away from the parental home for BD (OR = 3.43 for men & 1.77 for women). Only women were influenced by having positive expectancies for engaging in RC (OR = 1.82) and BD (OR = 1.96). CONCLUSIONS: The prevalence rates of both RC and BD at age 27 years were much higher among university students who already followed these patterns of consumption at age 18 years, with the differences being proportionally higher among women. Focusing on the age of onset of alcohol consumption and hindering access to alcohol by minors should be priority objectives aimed at preventing students from engaging in these patterns of alcohol consumption at university. PMID- 29630660 TI - Suicide attempts in Spain according to prehospital healthcare emergency records. AB - OBJECTIVE: To analyze the number and characteristics of suicide attempts by reviewing records of the public emergency healthcare service information system. METHOD: A retrospective observational study was conducted of emergency telephone calls received between January 1 2007 and December 31 2013 throughout the Andalusia region (Southern Spain). Cases were selected based on phone operator or healthcare team labeling. Data were analyzed on the characteristics of the individuals, the timing and severity of attempts, their prioritization, and their outcome. RESULTS: Between January 1 2007 and December 31 2013, 20.942 calls related to suicide attempts were recorded, a rate of 34.7 attempts per 100,000 inhabitants. Most cases were classified by the public emergency healthcare service (Empresa Publica de Emergencias Sanitarias, EPES) as code X84 (The International Statistical Classification of Diseases, tenth revision, ICD-10) or 305(The International Statistical Classification of Diseases, ninth revision, ICD 9). Attempts were more frequent in the 35-49-year age group and there were similar proportions of males and females. The lowest number of calls for suicide attempts were in 2007 and the highest in 2013. Calls were more frequent during the summer months, at weekends, and between 16:00 and 23:00 h. The likelihood of evacuation to the hospital emergency department was almost two-fold lower in over 65-yr-olds than in younger individuals. Significant (p = 0.001) gender differences were found in call outcome and prioritization. The most influential factor for evacuation to a hospital emergency department was the code assigned by the attending healthcare team. CONCLUSIONS: Information obtained from extra hospital emergency services provides valuable data on the characteristics and timing of calls related to suicide attempts, complementing information from hospital emergency departments or population surveys. There is a need to standardize the definition and recording of a suicide attempt. PMID- 29630661 TI - Association between OH/ECW and echocardiographic parameters in CKD5 patients not undergoing dialysis. AB - BACKGROUND: Echocardiography is the most valuable tool for assessing cardiac abnormalities of chronic kidney disease (CKD) patients even though it has its limitations, including high equipment cost and the need for specialized personnel. Assessment of volume status is important not only for volume management, but also for prevention of cardiovascular disease of the CKD patients. Recently, bioimpedance is gaining acceptance as a way to quantitatively assess patient hydration status at bedside. METHODS: 127 patients who were admitted for planning their first dialysis treatment were enrolled. The echocardiography and bioimpedance spectroscopy (BIS) were performed. The association between echocardiographic data and clinical values such as NT-proBNP and OH/ECW was examined. RESULTS: OH/ECW, which indicates relative fluid overload, was positively associated with LA dimension (r = 0.25, P = 0.007), LAVI (r = 0.32, P < 0.001), and E/e' ratio (r = 0.38, P < 0.001). While OH/ECW was not significantly associated with echocardiographic values such as LVEDD, LVEDV, LVMI, and LVEF, NT-proBNP were significantly associated with all echocardiographic parameters. Multivariate logistic regression analysis showed E/e' ratio (odds ratio, 1.14 [95% confidence interval (CI), 1.01 to 1.29]; P = 0.031), NT-proBNP (odds ratio, 4.78 [95% CI, 1.51 to 15.11]; P = 0.008), and albumin (odds ratio, 0.22 [95% CI, 0.08 to 0.66]; P = 0.007) were significantly associated with OH/ECW. CONCLUSIONS: Since OH/ECW measured by BIS is associated with echocardiographic parameters related to diastolic dysfunction, preliminary screening through laboratory findings, including serum albumin in conjunction with OH/ECW and NT-proBNP, may find patient with risk of diastolic dysfunction. Our study suggests that a timely detection of fluid overload in patients with CKD as well as their proper treatment may help reduce diastolic dysfunction. Further research may be needed to validate the consistency of this association across other stages of CKD. PMID- 29630662 TI - Metabolism and prebiotics activity of anthocyanins from black rice (Oryza sativa L.) in vitro. AB - Anthocyanins are naturally active substances. In this study, anthocyanins from black rice were obtained by membrane filtration and column chromatography separation. Five anthocyanin monomers in black rice extract were identified by HPLC-MS/MS, and the major anthocyanin monomer (cyanidin-3-glucoside, C3G) was purified by preparative HPLC (Pre-HPLC). The proliferative effects of the anthocyanins on Bifidobacteria and Lactobacillus were investigated by determining the media pH, bacterial populations and metabolic products. After anaerobic incubation at 37 degrees C for 48 h, not only the pH of the media containing C3G was lower than that of the extract of black rice anthocyanin (BRAE), but the numbers of both Bifidobacteria and Lactobacillus were also significantly increased. Furthermore, hydroxyphenylpropionic, hydroxyphenylacetic, and hydroxybenzoic acids and other metabolites were detected by GC-MS in vitro. Our results revealed that the anthocyanins and anthocyanin monomers from black rice had prebiotic activity and they were metabolized into several small molecules by Bifidobacteria and Lactobacillus. PMID- 29630659 TI - STAT3 activation by E6 is essential for the differentiation-dependent HPV18 life cycle. AB - Human papillomaviruses (HPV) activate a number of host factors to control their differentiation-dependent life cycles. The transcription factor signal transducer and activator of transcription (STAT)-3 is important for cell cycle progression and cell survival in response to cytokines and growth factors. STAT3 requires phosphorylation on Ser727, in addition to phosphorylation on Tyr705 to be transcriptionally active. In this study, we show that STAT3 is essential for the HPV life cycle in undifferentiated and differentiated keratinocytes. Primary human keratinocytes containing high-risk HPV18 genomes display enhanced STAT3 phosphorylation compared to normal keratinocytes. Expression of the E6 oncoprotein is sufficient to induce the dual phosphorylation of STAT3 at Ser727 and Tyr705 by a mechanism requiring Janus kinases and members of the MAPK family. E6-mediated activation of STAT3 induces the transcription of STAT3 responsive genes including cyclin D1 and Bcl-xL. Silencing of STAT3 protein expression by siRNA or inhibition of STAT3 activation by small molecule inhibitors, or by expression of dominant negative STAT3 phosphorylation site mutants, results in blockade of cell cycle progression. Loss of active STAT3 impairs HPV gene expression and prevents episome maintenance in undifferentiated keratinocytes and upon differentiation, lack of active STAT3 abolishes virus genome amplification and late gene expression. Organotypic raft cultures of HPV18 containing keratinocytes expressing a phosphorylation site STAT3 mutant display a profound reduction in suprabasal hyperplasia, which correlates with a loss of cyclin B1 expression and increased differentiation. Finally, increased STAT3 expression and phosphorylation is observed in HPV positive cervical disease biopsies compared to control samples, highlighting a role for STAT3 activation in cervical carcinogenesis. In summary, our data provides evidence of a critical role for STAT3 in the HPV18 life cycle. PMID- 29630663 TI - Correction: A systematic review and meta-analysis of the protective effects of metformin in experimental myocardial infarction. AB - [This corrects the article DOI: 10.1371/journal.pone.0183664.]. PMID- 29630664 TI - Correction: Profiles of a broad spectrum of epigenetic DNA modifications in normal and malignant human cell lines: Proliferation rate is not the major factor responsible for the 5-hydroxymethyl-2'-deoxycytidine level in cultured cancerous cell lines. AB - [This corrects the article DOI: 10.1371/journal.pone.0188856.]. PMID- 29630666 TI - Viral chimeras decrypt the role of enterovirus capsid proteins in viral tropism, acid sensitivity and optimal growth temperature. AB - Despite their genetic similarities, enteric and respiratory enteroviruses (EVs) have highly heterogeneous biophysical properties and cause a vast diversity of human pathologies. In vitro differences include acid sensitivity, optimal growth temperature and tissue tropism, which reflect a preferential in vivo replication in the respiratory or gastrointestinal tract and are thus key determinants of EV virulence. To investigate the underlying cause of these differences, we generated chimeras at the capsid-level between EV-D68 (a respiratory EV) and EV-D94 (an enteric EV). Although some chimeras were nonfunctional, EV-D94 with both the capsid and 2A protease or the capsid only of EV-D68 were both viable. Using this latter construct, we performed several functional assays, which indicated that capsid proteins determine acid sensitivity and tropism in cell lines and in respiratory, intestinal and neural tissues. Additionally, capsid genes were shown to also participate in determining the optimal growth temperature, since EV-D94 temperature adaptation relied on single mutations in VP1, while constructs with EV-D68 capsid could not adapt to higher temperatures. Finally, we demonstrate that EV-D68 maintains residual binding-capacity after acid-treatment despite a loss of infectivity. In contrast, non-structural rather than capsid proteins modulate the innate immune response in tissues. These unique biophysical insights expose another layer in the phenotypic diversity of one of world's most prevalent pathogens and could aid target selection for vaccine or antiviral development. PMID- 29630665 TI - An ADAM-10 dependent EPCR shedding links meningococcal interaction with endothelial cells to purpura fulminans. AB - Purpura fulminans is a deadly complication of Neisseria meningitidis infections due to extensive thrombosis of microvessels. Although a Disseminated Intra vascular Coagulation syndrome (DIC) is frequently observed during Gram negative sepsis, it is rarely associated with extensive thrombosis like those observed during meningococcemia, suggesting that the meningococcus induces a specific dysregulation of coagulation. Another specific feature of N. meningitidis pathogenesis is its ability to colonize microvessels endothelial cells via type IV pili. Importantly, endothelial cells are key in controlling the coagulation cascade through the activation of the potent anticoagulant Protein C (PC) thanks to two endothelial cell receptors among which the Endothelial Protein C Receptor (EPCR). Considering that congenital or acquired deficiencies of PC are associated with purpura fulminans, we hypothesized that a defect in the activation of PC following meningococcal adhesion to microvessels is responsible for the thrombotic events observed during meningococcemia. Here we showed that the adhesion of N. meningitidis on endothelial cells results in a rapid and intense decrease of EPCR expression by inducing its cleavage in a process know as shedding. Using siRNA experiments and CRISPR/Cas9 genome edition we identified ADAM10 (A Disintegrin And Metalloproteinase-10) as the protease responsible for this shedding. Surprisingly, ADAM17, the only EPCR sheddase described so far, was not involved in this process. Finally, we showed that this ADAM10-mediated shedding of EPCR induced by the meningococcal interaction with endothelial cells was responsible for an impaired activation of Protein C. This work unveils for the first time a direct link between meningococcal adhesion to endothelial cells and a severe dysregulation of coagulation, and potentially identifies new therapeutic targets for meningococcal purpura fulminans. PMID- 29630669 TI - Vitamin D status and its relation to exercise performance and iron status in young ice hockey players. AB - OBJECTIVES: The aim was to examine the association between serum vitamin D concentration and isometric strength of various muscle groups, vertical jump performance, and repeated sprint ability in young ice hockey players. The secondary aim was to determine the association between vitamin D deficiency and indices of iron status. METHODS: Fifty male ice hockey players (17.2+/-0.9 years) participated in this cross-sectional study. Exercise performance was evaluated using isometric strength measures of upper and lower extremities, vertical jump performance and repeated sprint ability (RSA). Blood samples were collected for the determination of serum 25-hydroxyvitamin D (25(OH)D) and multiple indicies of iron status. RESULTS: The mean serum 25(OH)D concentration was 30.4 ng.ml-1 and ranged from 12.5 to 91.4 ng.ml-1. Eleven participants (22%) had vitamin D deficiency and 20 athletes (40%) had vitamin D insufficiency. Serum 25(OH)D concentration was not positively correlated with isometric muscle strength, vertical jump performance, or RSA after adjusting for age, training experience, fat mass, fat free mass and height. Serum 25(OH)D concentration was not associated with indices of iron status. CONCLUSION: Vitamin D insufficiency is highly prevalent in ice hockey players, but 25(OH)D concentration but it is not associated with exercise performance or indices of iron status. PMID- 29630670 TI - DNA barcoding reveals seasonal shifts in diet and consumption of deep-sea fishes in wedge-tailed shearwaters. AB - The foraging ecology of pelagic seabirds is difficult to characterize because of their large foraging areas. In the face of this difficulty, DNA metabarcoding may be a useful approach to analyze diet compositions and foraging behaviors. Using this approach, we investigated the diet composition and its seasonal variation of a common seabird species on the Ogasawara Islands, Japan: the wedge-tailed shearwater Ardenna pacifica. We collected fecal samples during the prebreeding (N = 73) and rearing (N = 96) periods. The diet composition of wedge-tailed shearwater was analyzed by Ion Torrent sequencing using two universal polymerase chain reaction primers for the 12S and 16S mitochondrial DNA regions that targeted vertebrates and mollusks, respectively. The results of a BLAST search of obtained sequences detected 31 and 1 vertebrate and mollusk taxa, respectively. The results of the diet composition analysis showed that wedge-tailed shearwaters frequently consumed deep-sea fishes throughout the sampling season, indicating the importance of these fishes as a stable food resource. However, there was a marked seasonal shift in diet, which may reflect seasonal changes in food resource availability and wedge-tailed shearwater foraging behavior. The collected data regarding the shearwater diet may be useful for in situ conservation efforts. Future research that combines DNA metabarcoding with other tools, such as data logging, may provide further insight into the foraging ecology of pelagic seabirds. PMID- 29630672 TI - Correction: Climate change versus deforestation: Implications for tree species distribution in the dry forests of southern Ecuador. AB - [This corrects the article DOI: 10.1371/journal.pone.0190092.]. PMID- 29630668 TI - HIV-specific Fc effector function early in infection predicts the development of broadly neutralizing antibodies. AB - While the induction of broadly neutralizing antibodies (bNAbs) is a major goal of HIV vaccination strategies, there is mounting evidence to suggest that antibodies with Fc effector function also contribute to protection against HIV infection. Here we investigated Fc effector functionality of HIV-specific IgG plasma antibodies over 3 years of infection in 23 individuals, 13 of whom developed bNAbs. Antibody-dependent cellular phagocytosis (ADCP), complement deposition (ADCD), cellular cytotoxicity (ADCC) and cellular trogocytosis (ADCT) were detected in almost all individuals with levels of activity increasing over time. At 6 months post-infection, individuals with bNAbs had significantly higher levels of ADCD and ADCT that correlated with antibody binding to C1q and FcgammaRIIa respectively. In addition, antibodies from individuals with bNAbs showed more IgG subclass diversity to multiple HIV antigens which also correlated with Fc polyfunctionality. Germinal center activity represented by CXCL13 levels and expression of activation-induced cytidine deaminase (AID) was found to be associated with neutralization breadth, Fc polyfunctionality and IgG subclass diversity. Overall, multivariate analysis by random forest classification was able to group bNAb individuals with 85% sensitivity and 80% specificity based on the properties of their antibody Fc early in HIV infection. Thus, the Fc effector function profile predicted the development of neutralization breadth in this cohort, suggesting that intrinsic immune factors within the germinal center provide a mechanistic link between the Fc and Fab of HIV-specific antibodies. PMID- 29630667 TI - Green tea extracts ameliorate high-fat diet-induced muscle atrophy in senescence accelerated mouse prone-8 mice. AB - Muscle atrophy (loss of skeletal muscle mass) causes progressive deterioration of skeletal function. Recently, excessive intake of fats was suggested to induce insulin resistance, followed by muscle atrophy. Green tea extracts (GTEs), which contain polyphenols such as epigallocatechin gallate, have beneficial effects on obesity, hyperglycemia, and insulin resistance, but their effects against muscle atrophy are still unclear. Here, we found that GTEs prevented high-fat (HF) diet induced muscle weight loss in senescence-accelerated mouse prone-8 (SAMP8), a murine model of senescence. SAMP8 mice were fed a control diet, an HF diet, or HF with 0.5% GTEs (HFGT) diet for 4 months. The HF diet induced muscle weight loss with aging (measured as quadriceps muscle weight), whereas GTEs prevented this loss. In HF diet-fed mice, blood glucose and plasma insulin concentrations increased in comparison with the control group, and these mice had insulin resistance as determined by homeostasis model assessment of insulin resistance (HOMA-IR). In these mice, serum concentrations of leukocyte cell-derived chemotaxin 2 (LECT2), which is known to induce insulin resistance in skeletal muscle, were elevated, and insulin signaling in muscle, as determined by the phosphorylation levels of Akt and p70 S6 kinases, tended to be decreased. In HFGT diet-fed mice, these signs of insulin resistance and elevation of serum LECT2 were not observed. Although our study did not directly show the effect of serum LECT2 on muscle weight, insulin resistance examined using HOMA-IR indicated an intervention effect of serum LECT2 on muscle weight, as revealed by partial correlation analysis. Accordingly, GTEs might have beneficial effects on age related and HF diet-induced muscle weight loss, which correlates with insulin resistance and is accompanied by a change in serum LECT2. PMID- 29630671 TI - Fecal parasite risk in the endangered proboscis monkey is higher in an anthropogenically managed forest environment compared to a riparian rain forest in Sabah, Borneo. AB - Understanding determinants shaping infection risk of endangered wildlife is a major topic in conservation medicine. The proboscis monkey, Nasalis larvatus, an endemic primate flagship species for conservation in Borneo, is endangered through habitat loss, but can still be found in riparian lowland and mangrove forests, and in some protected areas. To assess socioecological and anthropogenic influence on intestinal helminth infections in N. larvatus, 724 fecal samples of harem and bachelor groups, varying in size and the number of juveniles, were collected between June and October 2012 from two study sites in Malaysian Borneo: 634 samples were obtained from groups inhabiting the Lower Kinabatangan Wildlife Sanctuary (LKWS), 90 samples were collected from groups of the Labuk Bay Proboscis Monkey Sanctuary (LBPMS), where monkeys are fed on stationary feeding platforms. Parasite risk was quantified by intestinal helminth prevalence, host parasite species richness (PSR), and eggs per gram feces (epg). Generalized linear mixed effect models were applied to explore whether study site, group type, group size, the number of juveniles per group, and sampling month predict parasite risk. At the LBPMS, prevalence and epg of Trichuris spp., strongylids, and Strongyloides spp. but not Ascaris spp., as well as host PSR were significantly elevated. Only for Strongyloides spp., prevalence showed significant changes between months; at both sites, the beginning rainy season with increased precipitation was linked to higher prevalence, suggesting the external life cycle of Strongyloides spp. to benefit from humidity. Higher prevalence, epgs, and PSR within the LBPMS suggest that anthropogenic factors shape host infection risk more than socioecological factors, most likely via higher re-infection rates and chronic stress. Noninvasive measurement of fecal parasite stages is an important tool for assessing transmission dynamics and infection risks for endangered tropical wildlife. Findings will contribute to healthcare management in nature and in anthropogenically managed environments. PMID- 29630674 TI - Correction: Awareness and attitude of the public toward personalized medicine in Korea. AB - [This corrects the article DOI: 10.1371/journal.pone.0192856.]. PMID- 29630673 TI - Weather and risk of ST-elevation myocardial infarction revisited: Impact on young women. AB - BACKGROUND: During the last decade, the incidence and mortality rates of ST elevation myocardial infarction (STEMI) has been steadily increasing in young women but not in men. Environmental variables that contribute to cardiovascular events in women remain ill-defined. METHODS AND RESULTS: A total of 2199 consecutive patients presenting with acute ST-elevation myocardial infarction (STEMI, 25.8% women, mean age 62.6+/-12.4 years) were admitted at the Montreal Heart Institute between June 2010 and December 2014. Snow fall exceeding 2cm/day was identified as a positive predictor for STEMI admission rates in the overall population (RR 1.28, 95% CI 1.07-1.48, p = 0.005), with a significant effect being seen in men (RR 1.30, 95% CI 1.06-1.53, p = 0.01) but not in women (p = NS). An age-specific analysis revealed a significant increase in hospital admission rates for STEMI in younger women <=55 years, (n = 104) during days with higher outside temperature (p = 0.004 vs men <=55 years) and longer daylight hours (p = 0.0009 vs men <=55 years). Accordingly, summer season, increased outside temperature and sunshine hours were identified as strong positive predictors for STEMI occurrence in women <=55 years (RR 1.66, 95% CI 1.1-2.5, p = 0.012, RR 1.70, 95% CI 1.2-2.5, p = 0.007, and RR 1.67, 95% CI 1.2-2.5, p = 0.011, respectively), while an opposite trend was observed in men <=55 years (RR for outside temperature 0.8, 95% CI 0.73-0.95, p = 0.01). CONCLUSION: The impact of environmental variables on STEMI is age- and sex-dependent. Higher temperature may play an important role in triggering such acute events in young women. PMID- 29630676 TI - Psychosocial and demographic factors influencing pain scores of patients with knee osteoarthritis. AB - BACKGROUND: Pain levels in patients with osteoarthritis (OA) of the knee are commonly assessed by using a numeric scoring system, but results may be influenced by factors other than the patient's actual physical discomfort or disease severity, including psychosocial and demographic variables. We examined the possible relation between knee-pain scores and several psychosocial, sociodemographic, disease, and treatment variables in 355 patients with knee OA. METHODS: The pain-evaluation instrument was a 0- to 10-point rating scale. Data obtained retrospectively from the patients' medical records were demographic characteristics, body mass index (BMI), concomitant disorders, illicit and prescription drug use, alcohol use, smoking, knee OA treatment, and severity of knee OA indicated by Kellgren-Lawrence (KL) radiographic grade. Univariate and multivariate analyses were performed to determine whether these variables correlated with reported pain scores. RESULTS: On univariate analysis, higher pain scores were significantly associated with Native American or Hispanic ethnicity; a higher BMI; current prescription for an opioid, antidepressant, or gabapentinoid medication; depression; diabetes mellitus; fibromyalgia; illicit drug use; lack of health insurance; smoking; previous knee injection; and recommendation by the clinician that the patient undergo knee surgery. Neither the patient's sex nor the KL grade showed a correlation. On multivariate analysis, depression, current opioid prescription, and Native American or Hispanic ethnicity retained a significant association with higher pain scores. CONCLUSIONS AND IMPLICATIONS: Our results in a large, ethnically diverse group of patients with knee OA suggest that psychosocial and sociodemographic factors may be important determinants of pain levels reported by patients with knee OA. PMID- 29630675 TI - Effects of mechanical stretching on the morphology of extracellular polymers and the mRNA expression of collagens and small leucine-rich repeat proteoglycans in vaginal fibroblasts from women with pelvic organ prolapse. AB - To determine the effect of mechanical stretching load and the efficacy of postmenopausal estrogen therapy (ET) on pelvic organ prolapse (POP), vaginal fibroblasts isolated from postmenopausal women with or without POP were subjected to 0.1-Hz uniaxial cyclic mechanical stretching (CS) with 10% elongation and 10-8 M 17-beta-estradiol (E2) treatment. We investigated the morphological characteristics of extracellular polymers using scanning electron microscopy (SEM) and monitored the mRNA expression of type I collagen (COL I) and type III collagen (COL III) as well as the small leucine-rich proteoglycan (SLRP) family members decorin (DCN), biglycan (BGN), fibromodulin (FMO), and lumican (LUM), using real-time quantitative polymerase chain reaction (RT-PCR). Using SEM, certain viscoelastic polymers were found to be randomly distributed among fibroblasts, which for normal fibroblasts formed clusters of plum flower-like patterns under static-culture conditions and resembled stretched strips when stretched in culture, whereas polymers among POP fibroblasts resembled stretched strips under static-cultured conditions and presented broken networks when stretched in culture. RT-PCR revealed that COL I, DCN, BGN, FMO, and LUM mRNA expression was significantly higher in POP than in normal fibroblasts under static-culture condition. Following CS, COL I and BGN mRNA expression was significantly up-regulated in normal fibroblasts, and DCN and FMO mRNA expression was down-regulated in POP fibroblasts. Following concomitant CS and E2 treatment, significantly elevated COL I and DCN mRNA expression was observed in normal fibroblasts, and significantly elevated COL I and BGN mRNA expression was observed in POP fibroblasts. COL III mRNA expression was not significantly different between the POP and normal group, and CS did not significantly affect expression in either group, though COL III was down-regulated in normal fibroblasts concomitantly treated with E2 and CS. We conclude that the morphological distribution of extracellular polymers in POP fibroblasts exhibited higher sensitivity and lower tolerance to stretching loads than do normal fibroblasts. These mechanical properties were further reflected in the transcription of COL I. Defects in the compensatory function of BGN for DCN and LUM for FMO exist in POP fibroblasts, which further affect the structure and function of COL I in response to stretching load, ultimately resulting in abnormal reconstruction of pelvic supportive connective tissues and the occurrence of POP. ET can maintain stretching-induced elevations in COL I and DCN transcription in healthy women and improve stretching-induced COL I, DCN, BGN, and FMO transcriptional changes in POP women to prevent and improve POP. Only down-regulated COL III transcription was observed upon concomitant CS and E2 treatment in normal fibroblasts, which suggests that the tensile strength, not the elasticity, of the supportive connective tissues is damaged in POP and that the higher tensile strength induced by ET in healthy fibroblasts prevents POP. These findings confirm the role of higher sensitivity and lower tolerance to mechanical stretching in the pathogenesis of POP and further provide evidence supporting the use of ET to prevent and inhibit POP in postmenopausal women. PMID- 29630678 TI - ERASE-Seq: Leveraging replicate measurements to enhance ultralow frequency variant detection in NGS data. AB - The accurate detection of ultralow allele frequency variants in DNA samples is of interest in both research and medical settings, particularly in liquid biopsies where cancer mutational status is monitored from circulating DNA. Next-generation sequencing (NGS) technologies employing molecular barcoding have shown promise but significant sensitivity and specificity improvements are still needed to detect mutations in a majority of patients before the metastatic stage. To address this we present analytical validation data for ERASE-Seq (Elimination of Recurrent Artifacts and Stochastic Errors), a method for accurate and sensitive detection of ultralow frequency DNA variants in NGS data. ERASE-Seq differs from previous methods by creating a robust statistical framework to utilize technical replicates in conjunction with background error modeling, providing a 10 to 100 fold reduction in false positive rates compared to published molecular barcoding methods. ERASE-Seq was tested using spiked human DNA mixtures with clinically realistic DNA input quantities to detect SNVs and indels between 0.05% and 1% allele frequency, the range commonly found in liquid biopsy samples. Variants were detected with greater than 90% sensitivity and a false positive rate below 0.1 calls per 10,000 possible variants. The approach represents a significant performance improvement compared to molecular barcoding methods and does not require changing molecular reagents. PMID- 29630679 TI - Protection by and maintenance of CD4 effector memory and effector T cell subsets in persistent malaria infection. AB - Protection at the peak of Plasmodium chabaudi blood-stage malaria infection is provided by CD4 T cells. We have shown that an increase in Th1 cells also correlates with protection during the persistent phase of malaria; however, it is unclear how these T cells are maintained. Persistent malaria infection promotes protection and generates both effector T cells (Teff), and effector memory T cells (Tem). We have previously defined new CD4 Teff (IL-7Ralpha-) subsets from Early (TeffEarly, CD62LhiCD27+) to Late (TeffLate, CD62LloCD27-) activation states. Here, we tested these effector and memory T cell subsets for their ability to survive and protect in vivo. We found that both polyclonal and P. chabaudi Merozoite Surface Protein-1 (MSP-1)-specific B5 TCR transgenic Tem survive better than Teff. Surprisingly, as Tem are associated with antigen persistence, Tem survive well even after clearance of infection. As previously shown during T cell contraction, TeffEarly, which can generate Tem, also survive better than other Teff subsets in uninfected recipients. Two other Tem survival mechanisms identified here are that low-level chronic infection promotes Tem both by driving their proliferation, and by programming production of Tem from Tcm. Protective CD4 T cell phenotypes have not been precisely determined in malaria, or other persistent infections. Therefore, we tested purified memory (Tmem) and Teff subsets in protection from peak pathology and parasitemia in immunocompromised recipient mice. Strikingly, among Tmem (IL-7Ralphahi) subsets, only TemLate (CD62LloCD27-) reduced peak parasitemia (19%), though the dominant memory subset is TemEarly, which is not protective. In contrast, all Teff subsets reduced peak parasitemia by more than half, and mature Teff can generate Tem, though less. In summary, we have elucidated four mechanisms of Tem maintenance, and identified two long-lived T cell subsets (TemLate, TeffEarly) that may represent correlates of protection or a target for longer-lived vaccine-induced protection against malaria blood-stages. PMID- 29630680 TI - Mortality in long-distance running races in Sweden - 2007-2016. AB - BACKGROUND: During the last decade, an increasing popularity of marathons has been seen. Although running has been shown to have considerable positive health effects, the risk of sudden death, most often due to sudden cardiac arrests, is also a risk runners expose themselves to. Whilst there are some studies on the mortality amongst long-distance runners, much of the evidence is dated. Given the increased popularity in running during the 21st century as well as the improvements in medical care at marathons, more knowledge is required on the mortality risk. MATERIALS AND METHOD: Publicly available racing and news databases were used to identify the number of entrants and finishers in half to full marathons in Sweden between 2007 and 2016 and the number of deaths that occurred in conjunction with the races. RESULTS: A total of 1,156,271 runners entered a long distance (21-42km) running race in Sweden between 2007 and 2016, and 834,412 runners finished the races (72.2%). A large majority of the finishers (677,050 (81%)) competed in distances under a full marathon. Two deaths occurred during the time period, meaning that the death rate was 0.24 (95% confidence interval 0.04-0.79) per 100,000 finishers. CONCLUSIONS: This study can show that death rates in long distance running races between 2007 and 2016 in Sweden are very low, compared to previous studies. When added to the existing literature, the combined picture suggests a general downward trend in the risk of death during marathons since the 1980s. PMID- 29630677 TI - The crystal structure of XdpB, the bacterial old yellow enzyme, in an FMN-free form. AB - Old Yellow Enzymes (OYEs) are NAD(P)H dehydrogenases of not fully resolved physiological roles that are widespread among bacteria, plants, and fungi and have a great potential for biotechnological applications. We determined the apo form crystal structure of a member of the OYE class, glycerol trinitrate reductase XdpB, from Agrobacterium bohemicum R89-1 at 2.1 A resolution. In agreement with the structures of the related bacterial OYEs, the structure revealed the TIM barrel fold with an N-terminal beta-hairpin lid, but surprisingly, the structure did not contain its cofactor FMN. Its putative binding site was occupied by a pentapeptide TTSDN from the C-terminus of a symmetry related molecule. Biochemical experiments confirmed a specific concentration-dependent oligomerization and a low FMN content. The blocking of the FMN binding site can exist in vivo and regulates enzyme activity. Our bioinformatic analysis indicated that a similar self-inhibition could be expected in more OYEs which we designated as subgroup OYE C1. This subgroup is widespread among G-bacteria and can be recognized by the conserved sequence GxxDYP in proximity of the C termini. In proteobacteria, the C1 subgroup OYEs are typically coded in one operon with short-chain dehydrogenase. This operon is controlled by the tetR-like transcriptional regulator. OYEs coded in these operons are unlikely to be involved in the oxidative stress response as the other known members of the OYE family because no upregulation of XdpB was observed after exposing A. bohemicum R89-1 to oxidative stress. PMID- 29630681 TI - Can a single pulse transcranial magnetic stimulation targeted to the motor cortex interrupt pain processing? AB - The modulatory role of the primary motor cortex (M1), reflected by an inhibitory effect of M1-stimulation on clinical pain, motivated us to deepen our understanding of M1's role in pain modulation. We used Transcranial Magnetic Stimulation (TMS)-induced virtual lesion (VL) to interrupt with M1 activity during noxious heat pain. We hypothesized that TMS-VL will effect experimental pain ratings. Three VL protocols were applied consisting of single-pulse TMS to transiently interfere with right M1 activity: (1) VLM1- TMS applied to 11 subjects, 20 msec before the individual's first pain-related M1 peak activation, as determined by source analysis (sLORETA), (2) VL-50 (N = 16; TMS applied 50 ms prior to noxious stimulus onset), and (3) VL+150 (N = 16; TMS applied 150 ms after noxious stimulus onset). Each protocol included 3 conditions ('pain-alone', ' TMS-VL', and 'SHAM-VL'), each consisted of 30 noxious heat stimuli. Pain ratings were compared, in each protocol, for TMS-VL vs. SHAM-VL and vs. pain alone conditions. Repeated measures analysis of variance, corrected for multiple comparisons revealed no significant differences in the pain ratings between the different conditions within each protocol. Therefore, our results from this exploratory study suggest that a single pulse TMS-induced VL that is targeted to M1 failed to interrupt experimental pain processing in the specific three stimulation timing examined here. PMID- 29630686 TI - A Case of Preventable Vision Loss. PMID- 29630683 TI - The use of plant lectins to regulate H1N1 influenza A virus receptor binding activity. AB - We applied an in vitro selection approach using two different plant lectins that bind to alpha2,3- or alpha2,6-linked sialic acids to determine which genetic changes of the A/California/04/09 (H1N1) virus alter hemagglutinin (HA) receptor binding toward alpha2,3- or alpha2,6-linked glycans. Consecutive passages of the A/California/04/09 virus with or without lectins in human lung epithelial Calu-3 cells led to development of three HA1 amino acid substitutions, N129D, G155E, and S183P, and one mutation in the neuraminidase (NA), G201E. The S183P mutation significantly increased binding to several alpha2,6 SA-linked glycans, including YDS, 6'SL(N), and 6-Su-6'SLN, compared to the wild-type virus (?3.6-fold, P < 0.05). Two other HA1 mutations, N129D and G155E, were sufficient to significantly increase binding to alpha2,6-linked glycans, 6'SLN and 6-Su-6'SLN, compared to S183P (?4.1-fold, P < 0.05). These HA1 mutations also increased binding affinity for 3'SLN glycan compared to the wild-type virus as measured by Biacore surface plasmon resonance method. In addition, the HA1 N129D and HA1 G155E substitutions were identified as antigenic mutations. Furthermore, the G201E mutation in NA reduced the NA enzyme activity (?2.3-fold). These findings demonstrate that the A/California/04/09 (H1N1) virus can acquire enhanced receptor affinity for both alpha2,3- and alpha2,6-linked sialic receptors under lectin-induced selective pressure. Such changes in binding affinity are conferred by selection of beneficial HA1 mutations that affect receptor specificity, antigenicity, and/or functional compatibility with the NA protein. PMID- 29630682 TI - Identification of G-quadruplex forming sequences in three manatee papillomaviruses. AB - The Florida manatee (Trichechus manatus latirotris) is a threatened aquatic mammal in United States coastal waters. Over the past decade, the appearance of papillomavirus-induced lesions and viral papillomatosis in manatees has been a concern for those involved in the management and rehabilitation of this species. To date, three manatee papillomaviruses (TmPVs) have been identified in Florida manatees, one forming cutaneous lesions (TmPV1) and two forming genital lesions (TmPV3 and TmPV4). We identified DNA sequences with the potential to form G quadruplex structures (G4) across the three genomes. G4 were located on both DNA strands and across coding and non-coding regions on all TmPVs, offering multiple targets for viral control. Although G4 have been identified in several viral genomes, including human PVs, most research has focused on canonical structures comprised of three G-tetrads. In contrast, the vast majority of sequences we identified would allow the formation of non-canonical structures with only two G tetrads. Our biophysical analysis confirmed the formation of G4 with parallel topology in three such sequences from the E2 region. Two of the structures appear comprised of multiple stacked two G-tetrad structures, perhaps serving to increase structural stability. Computational analysis demonstrated enrichment of G4 sequences on all TmPVs on the reverse strand in the E2/E4 region and on both strands in the L2 region. Several G4 sequences occurred at similar regional locations on all PVs, most notably on the reverse strand in the E2 region. In other cases, G4 were identified at similar regional locations only on PVs forming genital lesions. On all TmPVs, G4 sequences were located in the non-coding region near putative E2 binding sites. Together, these findings suggest that G4 are possible regulatory elements in TmPVs. PMID- 29630685 TI - Association of Whole-Body Computed Tomography With Mortality Risk in Children With Blunt Trauma. AB - Importance: Although several studies have demonstrated an improvement in mortality for injured adults who receive whole-body computed tomography (WBCT), it is unclear whether children experience the same benefit. Objective: To determine whether emergent WBCT is associated with lower mortality among children with blunt trauma compared with a selective CT approach. Design, Setting, and Participants: A retrospective, multicenter cohort study was conducted from January 1, 2010, to December 31, 2014, using data from the National Trauma Data Bank on children aged 6 months to 14 years with blunt trauma who received an emergent CT scan in the first 2 hours after emergency department arrival. Data analysis was conducted from February 2 to December 29, 2017. Exposures: Patients were classified as having WBCT if they received CT head, CT chest, and CT abdomen/pelvis scans in the first 2 hours and as having a selective CT if they did not receive all 3 scans. Main Outcomes and Measures: The primary outcome was in-hospital mortality in the 7 days after ED arrival. To adjust for potential confounding, propensity score weighting was used. Subgroup analyses were performed for those with the highest mortality risk (ie, occupants and pedestrians involved in motor vehicle crashes, children with a Glasgow Coma Scale score lower than 9, children with hypotension, and those admitted to the intensive care unit). Results: Of the 42 912 children included in the study (median age [interquartile range], 9 [5-12] years; 27 861 [64.9%] boys), 8757 (20.4%) received a WBCT. Overall, 405 (0.9%) children died within 7 days. After adjusting for the propensity score, children who received WBCT had no significant difference in mortality compared with those who received selective CT (absolute risk difference, -0.2%; 95% CI, -0.6% to 0.1%). All subgroup analyses similarly showed no significant association between WBCT and mortality. Conclusions and Relevance: Among children with blunt trauma, WBCT, compared with a selective CT approach, was not associated with lower mortality. These findings do not support the routine use of WBCT for children with blunt trauma. PMID- 29630687 TI - Pharmaceutical Industry Payments and Oncologists' Selection of Targeted Cancer Therapies in Medicare Beneficiaries. PMID- 29630688 TI - Of Loss and Love-A Physician's Odyssey of Spousal Caretaking. PMID- 29630684 TI - Proceedings of the 2nd BEAT-PCD conference and 3rd PCD training school: part 1. AB - Primary ciliary dyskinesia (PCD) is a rare heterogenous condition that causes progressive suppurative lung disease, chronic rhinosinusitis, chronic otitis media, infertility and abnormal situs. 'Better Experimental Approaches to Treat Primary Ciliary Dyskinesia' (BEAT-PCD) is a network of scientists and clinicians coordinating research from basic science through to clinical care with the intention of developing treatments and diagnostics that lead to improved long term outcomes for patients. BEAT-PCD activities are supported by EU funded COST Action (BM1407). The second BEAT-PCD conference, and third PCD training school were held jointly in April 2017 in Valencia, Spain. Presentations and workshops focussed on advancing the knowledge and skills relating to PCD in: basic science, epidemiology, diagnostic testing, clinical management and clinical trials. The multidisciplinary conference provided an interactive platform for exchanging ideas through a program of lectures, poster presentations, breakout sessions and workshops. Three working groups met to plan consensus statements. Progress with BEAT-PCD projects was shared and new collaborations were fostered. In this report, we summarize the meeting, highlighting developments made during the meeting. PMID- 29630689 TI - Risk of Unnatural Mortality in People With Epilepsy. AB - Importance: People with epilepsy are at increased risk of mortality, but, to date, the cause-specific risks of all unnatural causes have not been reported. Objective: To estimate cause-specific unnatural mortality risks in people with epilepsy and to identify the medication types involved in poisoning deaths. Design, Setting, and Participants: This population-based cohort study used 2 electronic primary care data sets linked to hospitalization and mortality records, the Clinical Practice Research Datalink (CPRD) in England (from January 1, 1998, to March 31, 2014) and the Secure Anonymised Information Linkage (SAIL) Databank in Wales (from January 1, 2001, to December 31, 2014). Each person with epilepsy was matched on age (within 2 years), sex, and general practice with up to 20 individuals without epilepsy. Unnatural mortality was determined using International Statistical Classification of Diseases and Related Health Problems, Tenth Revision codes V01 through Y98 in the Office for National Statistics mortality records. Hazard ratios (HRs) were estimated in each data set using a stratified Cox proportional hazards model, and meta-analyses were conducted using DerSimonian and Laird random-effects models. The analysis was performed from January 5, 2016, to November 16, 2017. Exposures: People with epilepsy were identified using primary care epilepsy diagnoses and associated antiepileptic drug prescriptions. Main Outcomes and Measures: Hazard ratios (HRs) for unnatural mortality and the frequency of each involved medication type estimated as a percentage of all medication poisoning deaths. Results: In total, 44 678 individuals in the CPRD and 14 051 individuals in the SAIL Databank were identified in the prevalent epilepsy cohorts, and 891 429 (CPRD) and 279 365 (SAIL) individuals were identified in the comparison cohorts. In both data sets, 51% of the epilepsy and comparison cohorts were male, and the median age at entry was 40 years (interquartile range, 25-60 years) in the CPRD cohorts and 43 years (interquartile range, 24-64 years) in the SAIL cohorts. People with epilepsy were significantly more likely to die of any unnatural cause (HR, 2.77; 95% CI, 2.43 3.16), unintentional injury or poisoning (HR, 2.97; 95% CI, 2.54-3.48) or suicide (HR, 2.15; 95% CI, 1.51-3.07) than people in the comparison cohort. Particularly large risk increases were observed in the epilepsy cohorts for unintentional medication poisoning (HR, 4.99; 95% CI, 3.22-7.74) and intentional self-poisoning with medication (HR, 3.55; 95% CI, 1.01-12.53). Opioids (56.5% [95% CI, 43.3% 69.0%]) and psychotropic medication (32.3% [95% CI, 20.9%-45.3%)] were more commonly involved than antiepileptic drugs (9.7% [95% CI, 3.6%-19.9%]) in poisoning deaths in people with epilepsy. Conclusions and Relevance: Compared with people without epilepsy, people with epilepsy are at increased risk of unnatural death and thus should be adequately advised about unintentional injury prevention and monitored for suicidal ideation, thoughts, and behaviors. The suitability and toxicity of concomitant medication should be considered when prescribing for comorbid conditions. PMID- 29630691 TI - Correcting Errors That Modify Descriptive Statistics. PMID- 29630690 TI - Appropriate Time for Chronic Dialysis Initiation: A Cause for Humility. PMID- 29630693 TI - Presence and Profile of Innate Lymphoid Cells in Human Breast Milk. PMID- 29630694 TI - Patients' experience of IV insertion. PMID- 29630696 TI - Toenails as the "Hemoglobin A1c" of Functional Independence-Beyond the Polished Wingtips. PMID- 29630695 TI - Dialysis Initiation and Mortality Among Older Veterans With Kidney Failure Treated in Medicare vs the Department of Veterans Affairs. AB - Importance: The benefits of maintenance dialysis for older adults with end-stage renal disease (ESRD) are uncertain. Whether the setting of pre-ESRD nephrology care influences initiation of dialysis and mortality is not known. Objective: To compare initiation of dialysis and mortality among older veterans with incident kidney failure who received pre-ESRD nephrology care in fee-for-service Medicare vs the Department of Veterans Affairs (VA). Design, Setting, and Participants: Retrospective cohort study of patients from the US Medicare and VA health care systems evaluated 11 215 veterans aged 67 years or older with incident kidney failure between January 1, 2008, and December 31, 2011. Data analysis was performed March 15, 2016, through September 20, 2017. Exposures: Pre-ESRD nephrology care in Medicare vs VA health care systems. Main Outcome and Measures: Dialysis treatment and death within 2 years. Results: Of the 11 215 patients included in the study, 11 085 (98.8%) were men; mean (SD) age was 79.1 (6.9) years. Within 2 years of incident kidney failure, 7071 (63.0%) of the patients started dialysis and 5280 (47.1%) died. Patients who received pre-ESRD nephrology care in Medicare were more likely to undergo dialysis compared with patients who received pre-ESRD nephrology care in VA (82% vs 53%; adjusted risk difference, 28 percentage points; 95% CI, 26-30 percentage points). Differences in dialysis initiation between Medicare and VA were more pronounced among patients aged 80 years or older and patients with dementia or metastatic cancer, and less pronounced among patients with paralysis (P < .05 for interaction). Two-year mortality was higher for patients who received pre-ESRD care in Medicare compared with VA (53% vs 44%; adjusted risk difference, 5 percentage points; 95% CI, 3-7 percentage points). The findings were similar in a propensity-matched analysis. Conclusions and Relevance: Veterans who receive pre-ESRD nephrology care in Medicare receive dialysis more often yet are also more likely to die within 2 years compared with those in VA. The VA's integrated health care system and financing appear to favor lower-intensity treatment for kidney failure in older patients without a concomitant increase in mortality. PMID- 29630692 TI - Associations Between Brain Structure and Connectivity in Infants and Exposure to Selective Serotonin Reuptake Inhibitors During Pregnancy. AB - Importance: Selective serotonin reuptake inhibitor (SSRI) use among pregnant women is increasing, yet the association between prenatal SSRI exposure and fetal neurodevelopment is poorly understood. Animal studies show that perinatal SSRI exposure alters limbic circuitry and produces anxiety and depressive-like behaviors after adolescence, but literature on prenatal SSRI exposure in humans is limited and mixed. Objective: To examine associations between prenatal SSRI exposure and brain development using structural and diffusion magnetic resonance imaging (MRI). Design, Setting, and Participants: A cohort study conducted at Columbia University Medical Center and New York State Psychiatric Institute included 98 infants: 16 with in utero SSRI exposure, 21 with in utero untreated maternal depression exposure, and 61 healthy controls. Data were collected between January 6, 2011, and October 25, 2016. Exposures: Selective serotonin reuptake inhibitors and untreated maternal depression. Main Outcomes and Measures: Gray matter volume estimates using structural MRI with voxel-based morphometry and white matter structural connectivity (connectome) using diffusion MRI with probabilistic tractography. Results: The sample included 98 mother (31 [32%] white, 26 [27%] Hispanic/Latina, 26 [27%] black/African American, 15 [15%] other) and infant (46 [47%] boys, 52 [53%] girls) dyads. Mean (SD) age of the infants at the time of the scan was 3.43 (1.50) weeks. Voxel-based morphometry showed significant gray matter volume expansion in the right amygdala (Cohen d = 0.65; 95% CI, 0.06-1.23) and right insula (Cohen d = 0.86; 95% CI, 0.26-1.14) in SSRI-exposed infants compared with both healthy controls and infants exposed to untreated maternal depression (P < .05; whole-brain correction). In connectome level analysis of white matter structural connectivity, the SSRI group showed a significant increase in connectivity between the right amygdala and the right insula with a large effect size (Cohen d = 0.99; 95% CI, 0.40-1.57) compared with healthy controls and untreated depression (P < .05; whole connectome correction). Conclusions and Relevance: Our findings suggest that prenatal SSRI exposure has an association with fetal brain development, particularly in brain regions critical to emotional processing. The study highlights the need for further research on the potential long-term behavioral and psychological outcomes of these neurodevelopmental changes. PMID- 29630698 TI - Making the Case for Value-Based Payment Reform in Children's Health Care. PMID- 29630697 TI - Approach for Achieving Effective Care for High-Need Patients. PMID- 29630699 TI - Prevalence of Mathematical and Visuospatial Learning Disabilities in Patients With Posterior Cortical Atrophy. AB - Importance: Increased prevalence of language-based learning disabilities (LDs) has been previously reported in patients with primary progressive aphasia (PPA). This study hypothesized that patients with focal neurodegenerative syndromes outside the language network, such as posterior cortical atrophy (PCA), would have a higher rate of nonlanguage LDs, congruent with their mainly visuospatial presentation. Objective: To investigate the prevalence and type of LD (language and/or mathematical and visuospatial) in a large cohort of patients with PCA compared with patients with logopenic variant PPA (lvPPA) and amnestic Alzheimer disease (AD). Design, Setting, and Participants: This case-control study reviewed 279 medical records from a university-based clinic and research center for patients with neurodegenerative diseases for LD history, including patients with PCA (n = 95), patients with lvPPA (n = 84), and a matched cohort with amnestic AD (n = 100). No records were excluded. The study compared cognitive and neuroimaging features of patients with PCA with and without LDs. A review of the records of patients presenting from March 1, 1999, to August 31, 2014, revealed 95 PCA cases and 84 lvPPA cases. Then 100 patients with amnestic AD from this same period were chosen for comparison, matching against the groups for age, sex, and disease severity. Data analysis was performed from September 8, 2013, to November 6, 2017. Main Outcomes and Measures: Prevalence of total LD history and prevalence of language and mathematical or visuospatial LD history across all cohorts. Results: A total of 179 atypical AD cases (95 with PCA and 84 with lvPPA) and 100 disease control cases (amnestic AD) were included in the study. The groups were not statistically different for mean (SD) age at first visit (PCA, 61.9 [7.0] years; lvPPA, 65.1 [8.7] years; amnestic AD, 64.0 [12.6] years; P = .08), mean (SD) age at first symptom (PCA, 57.5 [7.0] years; lvPPA, 61.1 [9.0] years; amnestic AD, 59.6 [13.7] years; P = .06), or sex (PCA, 66.3% female; lvPPA, 56.0% female; amnestic AD, 57.0% female; P = .30) but differed on non right-hand preference (PCA, 18.3%; lvPPA, 20.2%; amnestic AD, 7.7%; P = .04), race/ethnicity (PCA, 88.3% white; lvPPA, 99.0% white; amnestic AD, 80.0% white; P < .001), and mean (SD) educational level (PCA, 15.7 [3.2] years; lvPPA, 16.2 [3.3] years; amnestic AD, 14.8 [3.5] years; P = .02). A total of 18 of the 95 patients with PCA (18.9%) reported a history of LD, which is greater than the 3 of 100 patients (3.0%) in the amnestic AD cohort (P < .001) and the 10.0% expected rate in the general population (P = .007). In the PCA cohort, 13 of 95 patients (13.7%) had a nonlanguage mathematical and/or visuospatial LD; this rate was greater than that in the amnestic AD (1 of 100 [1.0%]; P < .001) and lvPPA (2 of 84 [2.4%]; P = .006) cohorts and greater than the 6.0% expected general population rate of mathematical LD (P = .003). Compared with the patients with PCA without LDs, the group with LDs had greater preservation of global cognition and a more right-lateralized pattern of atrophy. Conclusions and Relevance: Nonlanguage mathematical and visuospatial LDs were associated with focal, visuospatial predominant neurodegenerative clinical syndromes. This finding supports the hypothesis that neurodevelopmental differences in specific brain networks are associated with phenotypic manifestation of later-life neurodegenerative disease. PMID- 29630700 TI - Defining Death-Making Sense of the Case of Jahi McMath. PMID- 29630701 TI - Molecular Epidemiology and the Transformation of HIV Prevention. PMID- 29630702 TI - Cardiovascular Safety of Varenicline, Bupropion, and Nicotine Patch in Smokers: A Randomized Clinical Trial. AB - Importance: Quitting smoking is enhanced by the use of pharmacotherapies, but concerns have been raised regarding the cardiovascular safety of such medications. Objective: To compare the relative cardiovascular safety risk of smoking cessation treatments. Design, Setting, and Participants: A double-blind, randomized, triple-dummy, placebo- and active-controlled trial (Evaluating Adverse Events in a Global Smoking Cessation Study [EAGLES]) and its nontreatment extension trial was conducted at 140 multinational centers. Smokers, with or without established psychiatric diagnoses, who received at least 1 dose of study medication (n = 8058), as well as a subset of those who completed 12 weeks of treatment plus 12 weeks of follow up and agreed to be followed up for an additional 28 weeks (n = 4595), were included. Interventions: Varenicline, 1 mg twice daily; bupropion hydrochloride, 150 mg twice daily; and nicotine replacement therapy, 21-mg/d patch with tapering. Main Outcomes and Measures: The primary end point was the time to development of a major adverse cardiovascular event (MACE: cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke) during treatment; secondary end points were the occurrence of MACE and other pertinent cardiovascular events (MACE+: MACE or new-onset or worsening peripheral vascular disease requiring intervention, coronary revascularization, or hospitalization for unstable angina). Results: Of the 8058 participants, 3553 (44.1%) were male (mean [SD] age, 46.5 [12.3] years). The incidence of cardiovascular events during treatment and follow-up was low (<0.5% for MACE; <0.8% for MACE+) and did not differ significantly by treatment. No significant treatment differences were observed in time to cardiovascular events, blood pressure, or heart rate. There was no significant difference in time to onset of MACE for either varenicline or bupropion treatment vs placebo (varenicline: hazard ratio, 0.29; 95% CI, 0.05-1.68 and bupropion: hazard ratio, 0.50; 95% CI, 0.10-2.50). Conclusions and Relevance: No evidence that the use of smoking cessation pharmacotherapies increased the risk of serious cardiovascular adverse events during or after treatment was observed. The findings of EAGLES and its extension trial provide further evidence that smoking cessation medications do not increase the risk of serious cardiovascular events in the general population of smokers. Trial Registration: clinicaltrials.gov Identifier: NCT01574703. PMID- 29630704 TI - Deaths in Epilepsy: What We Are Missing. PMID- 29630705 TI - Out of Sight, Out of Mind? Measuring the Relationship between Privatization and Medicaid Self-Reporting. AB - Privatization has grown exponentially, both in salience and in form, over the past several decades. This shifting of administrative authority away from the state can make it difficult for program recipients to link their use of a federal program back to government, a disconnect known as "submerging" the state. However, privatization is a process that occurs in degrees, and not all privatization initiatives look alike. This study leverages variation in the implementation of Medicaid managed care, which is the most widespread form of Medicaid privatization, to examine how privatization maps onto state submersion and affects state visibility. This analysis shows that, although Medicaid managed care enrollment, at large, does not relate to recipients' self-reported Medicaid enrollment, when privatized Medicaid plans introduce administrative designs that obscure the role of government, Medicaid self-reporting declines. These findings demonstrate that policy recipients are less able to recognize both the personal relevance of a specific public program and the public nature of this interaction when privatized programs utilize design features that attenuate signals of government involvement. In highlighting this disconnect, this article shows how privatization makes it more difficult for policy recipients to engage in the civic sphere as informed advocates for their self-interest. PMID- 29630703 TI - Sex Differences in Outcomes After STEMI: Effect Modification by Treatment Strategy and Age. AB - Importance: Previous works have shown that women hospitalized with ST-segment elevation myocardial infarction (STEMI) have higher short-term mortality rates than men. However, it is unclear if these differences persist among patients undergoing contemporary primary percutaneous coronary intervention (PCI). Objective: To investigate whether the risk of 30-day mortality after STEMI is higher in women than men and, if so, to assess the role of age, medications, and primary PCI in this excess of risk. Design, Setting, and Participants: From January 2010 to January 2016, a total of 8834 patients were hospitalized and received medical treatment for STEMI in 41 hospitals referring data to the International Survey of Acute Coronary Syndromes in Transitional Countries (ISACS TC) registry (NCT01218776). Exposures: Demographics, baseline characteristics, clinical profile, and pharmacological treatment within 24 hours and primary PCI. Main Outcomes and Measures: Adjusted 30-day mortality rates estimated using inverse probability of treatment weighted (IPTW) logistic regression models. Results: There were 2657 women with a mean (SD) age of 66.1 (11.6) years and 6177 men with a mean (SD) age of 59.9 (11.7) years included in the study. Thirty-day mortality was significantly higher for women than for men (11.6% vs 6.0%, P < .001). The gap in sex-specific mortality narrowed if restricting the analysis to men and women undergoing primary PCI (7.1% vs 3.3%, P < .001). After multivariable adjustment for comorbidities and treatment covariates, women under 60 had higher early mortality risk than men of the same age category (OR, 1.88; 95% CI, 1.04-3.26; P = .02). The risk in the subgroups aged 60 to 74 years and over 75 years was not significantly different between sexes (OR, 1.28; 95% CI, 0.88-1.88; P = .19 and OR, 1.17; 95% CI, 0.80-1.73; P = .40; respectively). After IPTW adjustment for baseline clinical covariates, the relationship among sex, age category, and 30-day mortality was similar (OR, 1.56 [95% CI, 1.05-2.3]; OR, 1.49 [95% CI, 1.15-1.92]; and OR, 1.21 [95% CI, 0.93-1.57]; respectively). Conclusions and Relevance: Younger age was associated with higher 30-day mortality rates in women with STEMI even after adjustment for medications, primary PCI, and other coexisting comorbidities. This difference declines after age 60 and is no longer observed in oldest women. PMID- 29630707 TI - State-Level Community Benefit Regulation and Nonprofit Hospitals' Provision of Community Benefits. AB - Do nonprofit hospitals provide enough community benefits to justify their tax exemptions? States have sought to enhance nonprofit hospitals' accountability and oversight through regulation, including requirements to report community benefits, conduct community health needs assessments, provide minimum levels of community benefits, and adhere to minimum income eligibility standards for charity care. However, little research has assessed these regulations' impact on community benefits. Using 2009-11 Internal Revenue Service data on community benefit spending for more than eighteen hundred hospitals and the Hilltop Institute's data on community benefit regulation, we investigated the relationship between these four types of regulation and the level and types of hospital-provided community benefits. Our multivariate regression analyses showed that only community health needs assessments were consistently associated with greater community benefit spending. The results for reporting and minimum spending requirements were mixed, while minimum income eligibility standards for charity care were unrelated to community benefit spending. State adoption of multiple types of regulation was consistently associated with higher levels of hospital-provided community benefits, possibly because regulatory intensity conveys a strong signal to the hospital community that more spending is expected. This study can inform efforts to design regulations that will encourage hospitals to provide community benefits consistent with policy makers' goals. PMID- 29630706 TI - Communicating about Mental Illness and Violence: Balancing Stigma and Increased Support for Services. AB - In the ongoing national policy debate about how to best address serious mental illness (SMI), a major controversy among mental health advocates is whether drawing public attention to an apparent link between SMI and violence, shown to elevate stigma, is the optimal strategy for increasing public support for investing in mental health services or whether nonstigmatizing messages can be equally effective. We conducted a randomized experiment to examine this question. Participants in a nationally representative online panel (N = 1,326) were randomized to a control arm or to read one of three brief narratives about SMI emphasizing violence, systemic barriers to treatment, or successful treatment and recovery. Narratives, or stories about individuals, are a common communication strategy used by policy makers, advocates, and the news media. Study results showed that narratives emphasizing violence or barriers to treatment were equally effective in increasing the public's willingness to pay additional taxes to improve the mental health system (55 percent and 52 percent, vs. 42 percent in the control arm). Only the narrative emphasizing the link between SMI and violence increased stigma. For mental health advocates dedicated to improving the public mental health system, these findings offer an alternative to stigmatizing messages linking mental illness and violence. PMID- 29630708 TI - How Intense Policy Demanders Shape Postreform Politics: Evidence from the Affordable Care Act. AB - The implementation of the Affordable Care Act (ACA) has been a politically volatile process. The ACA's institutional design and delayed feedback effects created a window of opportunity for its partisan opponents to launch challenges at both the federal and state level. Yet as recent research suggests, postreform politics depends on more than policy feedback alone; rather, it is shaped by the partisan and interest-group environment. We argue that "intense policy demanders" played an important role in defining the policy alternatives that comprised congressional Republicans' efforts to repeal and replace the ACA. To test this argument, we drew on an original data set of bill introductions in the House of Representatives between 2011 and 2016. Our analysis suggests that business contributions and political ideology affected the likelihood that House Republicans would introduce measures repealing significant portions of the ACA. A secondary analysis shows that intense policy demanders also shaped the vote on House Republicans' initial ACA replacement plan. These findings highlight the role intense policy demanders can play in shaping the postreform political agenda. PMID- 29630709 TI - Supporting Transformation through Delivery System Reform Incentive Payment Programs: Lessons from New York State. AB - The New York Delivery System Reform Incentive Payment (DSRIP) waiver was viewed as a prototype for Medicaid and safety net redesign waivers in the Affordable Care Act (ACA) era. After the insurance expansions of the ACA were implemented, it was apparent that accountability, value, and quality improvement would be priorities in future waivers in many states. Despite New York's distinct provider relationships, previous coverage expansions, and local and state politics, it is important to understand the key characteristics of the waiver so that other states can learn how to better incorporate value-based arrangements into future waivers or attempts to limit spending under proposed Medicaid per-capita caps or block grants. In this article, we examine the New York DSRIP waiver by drawing on its design, early experiences, and evolution to inform recommendations for the future renewal, implementation, and expansion of redesigned or transformational Medicaid waivers. PMID- 29630713 TI - Missing Funding Information. PMID- 29630714 TI - Errors in Abstract, Results Section, and Table 2. PMID- 29630712 TI - Selective Genetic Overlap Between Amyotrophic Lateral Sclerosis and Diseases of the Frontotemporal Dementia Spectrum. AB - Importance: Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by loss of upper and lower motor neurons. Although novel ALS genetic variants have been identified, the shared genetic risk between ALS and other neurodegenerative disorders remains poorly understood. Objectives: To examine whether there are common genetic variants that determine the risk for ALS and other neurodegenerative diseases and to identify their functional pathways. Design, Setting, and Participants: In this study conducted from December 1, 2016, to August 1, 2017, the genetic overlap between ALS, sporadic frontotemporal dementia (FTD), FTD with TDP-43 inclusions, Parkinson disease (PD), Alzheimer disease (AD), corticobasal degeneration (CBD), and progressive supranuclear palsy (PSP) were systematically investigated in 124 876 cases and controls. No participants were excluded from this study. Diagnoses were established using consensus criteria. Main Outcomes and Measures: The primary outcomes were a list of novel loci and their functional pathways in ALS, FTD, PSP, and ALS mouse models. Results: Among 124 876 cases and controls, genome wide conjunction analyses of ALS, FTD, PD, AD, CBD, and PSP revealed significant genetic overlap between ALS and FTD at known ALS loci: rs13302855 and rs3849942 (nearest gene, C9orf72; P = .03 for rs13302855 and P = .005 for rs3849942) and rs4239633 (nearest gene, UNC13A; P = .03). Significant genetic overlap was also found between ALS and PSP at rs7224296, which tags the MAPT H1 haplotype (nearest gene, NSF; P = .045). Shared risk genes were enriched for pathways involving neuronal function and development. At a conditional FDR P < .05, 22 novel ALS polymorphisms were found, including rs538622 (nearest gene, ERGIC1; P = .03 for ALS and FTD), which modifies BNIP1 expression in human brains (35 of 137 females; mean age, 59 years; P = .001). BNIP1 expression was significantly reduced in spinal cord motor neurons from patients with ALS (4 controls: mean age, 60.5 years, mean [SE] value, 3984 [760.8] arbitrary units [AU]; 7 patients with ALS: mean age, 56 years, mean [SE] value, 1999 [274.1] AU; P = .02), in an ALS mouse model (mean [SE] value, 13.75 [0.09] AU for 2 SOD1 WT mice and 11.45 [0.03] AU for 2 SOD1 G93A mice; P = .002) and in brains of patients with PSP (80 controls: 39 females; mean age, 82 years, mean [SE] value, 6.8 [0.2] AU; 84 patients with PSP: 33 females, mean age 74 years, mean [SE] value, 6.8 [0.1] AU; beta = -0.19; P = .009) or FTD (11 controls: 4 females; mean age, 67 years; mean [SE] value, 6.74 [0.05] AU; 17 patients with FTD: 10 females; mean age, 69 years; mean [SE] value, 6.53 [0.04] AU; P = .005). Conclusions and Relevance: This study found novel genetic overlap between ALS and diseases of the FTD spectrum, that the MAPT H1 haplotype confers risk for ALS, and identified the mitophagy-associated, proapoptotic protein BNIP1 as an ALS risk gene. Together, these findings suggest that sporadic ALS may represent a selectively pleiotropic, polygenic disorder. PMID- 29630715 TI - Homeopathic medicinal products for preventing and treating acute respiratory tract infections in children. AB - BACKGROUND: Acute respiratory tract infections (ARTIs) are common and may lead to complications. Most children experience between three and six ARTIs each year. Although these infections are self limiting, the symptoms can be distressing. Many treatments are used to control symptoms and shorten the duration of illness. They often have minimal benefit and may lead to adverse effects. Oral homeopathic medicinal products could play a role in the treatment of ARTIs for children if evidence for effectiveness is established. OBJECTIVES: To assess the effectiveness and safety of oral homeopathic medicinal products compared with placebo or conventional therapy to prevent and treat acute respiratory tract infections in children. SEARCH METHODS: We searched CENTRAL (2017, Issue 11), which contains the Cochrane Acute Respiratory Infections Specialised Register, MEDLINE (1946 to 27 November 2017), Embase (2010 to 27 November 2017), CINAHL (1981 to 27 November 2017), AMED (1985 to December 2014), CAMbase (searched 29 March 2018), British Homeopathic Library (searched 26 June 2013 - no longer operating). We also searched the WHO ICTRP and ClinicalTrials.gov trials registers (29 March 2018), checked references, and contacted study authors to identify additional studies. SELECTION CRITERIA: Double-blind, randomised controlled trials (RCTs) or double-blind cluster-RCTs comparing oral homeopathy medicinal products with identical placebo or self selected conventional treatments to prevent or treat ARTIs in children aged 0 to 16 years. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included eight RCTs of 1562 children receiving oral homeopathic medicinal products or a control treatment (placebo or conventional treatment) for upper respiratory tract infections (URTIs). Four treatment studies examined the effect on recovery from URTIs, and four studies investigated the effect on preventing URTIs after one to three months of treatment and followed up for the remainder of the year. Two treatment and two prevention studies involved homeopaths individualising treatment for children. The other studies used predetermined, non-individualised treatments. All studies involved highly diluted homeopathic medicinal products.We found several key limitations to the included studies, in particular methodological inconsistencies and high attrition rates, failure to conduct intention-to-treat analysis, selective reporting, and apparent protocol deviations. We assessed three studies as at high risk of bias in at least one domain, and many had additional domains with unclear risk of bias. Three studies received funding from homeopathy manufacturers; one reported support from a non-government organisation; two received government support; one was cosponsored by a university; and one did not report funding support.Methodological inconsistencies and significant clinical and statistical heterogeneity precluded robust quantitative meta-analysis. Only four outcomes were common to more than one study and could be combined for analysis. Odds ratios (OR) were generally small with wide confidence intervals (CI), and the contributing studies found conflicting effects, so there was little certainty that the efficacy of the intervention could be ascertained. All studies assessed as at low risk of bias showed no benefit from oral homeopathic medicinal products; trials at uncertain and high risk of bias reported beneficial effects.We found low-quality evidence that non-individualised homeopathic medicinal products confer little preventive effect on ARTIs (OR 1.14, 95% CI 0.83 to 1.57). We found low-quality evidence from two individualised prevention studies that homeopathy has little impact on the need for antibiotic usage (N = 369) (OR 0.79, 95% CI 0.35 to 1.76). We also assessed adverse events, hospitalisation rates and length of stay, days off school (or work for parents), and quality of life, but were not able to pool data from any of these secondary outcomes.There is insufficient evidence from two pooled individualised treatment studies (N = 155) to determine the effect of homeopathy on short-term cure (OR 1.31, 95% CI 0.09 to 19.54; very low-quality evidence) and long-term cure rates (OR 1.01, 95% CI 0.10 to 9.96; very low-quality evidence). Adverse events were reported inconsistently; however, serious events were not reported. One study found an increase in the occurrence of non-severe adverse events in the treatment group. AUTHORS' CONCLUSIONS: Pooling of two prevention and two treatment studies did not show any benefit of homeopathic medicinal products compared to placebo on recurrence of ARTI or cure rates in children. We found no evidence to support the efficacy of homeopathic medicinal products for ARTIs in children. Adverse events were poorly reported, so conclusions about safety could not be drawn. PMID- 29630716 TI - A review of bullous pemphigoid associated with PD-1 and PD-L1 inhibitors. AB - BACKGROUND: Dermatologic toxicity represents a substantial portion of all immune related adverse events (irAEs) associated with PD-1/PD-L1 inhibitors. Bullous pemphigoid (BP) is a rare cutaneous side effect of these medications, which can initially be clinically indistinguishable from other, low-grade cutaneous toxicity. OBJECTIVE: To better characterize the clinical features of BP associated with PD-1/PD-L1 inhibitors, evaluate the efficacy of various treatment regimens, determine the frequency of prodromal pruritus, and assess whether immunological diagnostic studies for BP are warranted in patients treated with checkpoint inhibitors who develop intractable pruritus. METHODS: A comprehensive review of the English-language medical literature was performed using key terms. Papers published on any date and from all origins were considered. Fourteen publications, containing 21 patient cases, were selected independently by two reviewers and deemed relevant to the present publication. RESULTS: Pruritus was a prominent feature of the majority (12/21) of cases and preceded or occurred concurrently with BP development. Bullae developed within 6-8 months of initiation of PD-1/PD-L1 inhibitors; however, a smaller subset of patients did not develop bullae for 1-1.5 years following initiation of therapy. Mean time to pruritus was similar for pembrolizumab and nivolumab at 19 and 21 weeks, respectively. Development of BP required discontinuation of immunotherapy in 76% (16/21) of cases. CONCLUSION: Prodromal or "non-bullous" variants of BP must be considered in patients treated with checkpoint inhibitors who develop protracted or worsening pruritus. Early diagnostic immunological evaluation of the skin may lead to improved patient outcomes by facilitating timely initiation of treatment and prevent disruptions in cancer therapy. PMID- 29630717 TI - Retreat to refugia: Severe habitat contraction projected for endemic alpine plants of the Olympic Peninsula. AB - PREMISE OF THE STUDY: The unique geography of the Olympic Peninsula in Washington State, USA has promoted a flora with exceptional endemism that may face high rates of extinction due to climate change. The Olympic Mountains provide an unparalleled opportunity to test predicted responses in topographically complex environments and inform conservation plans for threatened alpine taxa. METHODS: We estimated the potential impact of climate change for five endemic alpine plants of the Olympic Peninsula. We used Principal Components Analysis (PCA) to visualize changes in climate niche-space in the alpine zone and the exposure of the endemics to changing conditions. We then constructed climate and topographic based Species Distribution Models (SDMs) to estimate changes in the distribution of habitat for each taxon. KEY RESULTS: The Olympic alpine zone will experience novel environmental conditions in the future, with a pronounced decrease in winter snow and an increase in growing-season moisture stress. When topography was taken into account, the losses were more dramatic than the impact of climate alone. Indeed, 85-99% of the suitable habitat will be lost for each of the five focal taxa by 2080, with thermal refugia remaining only on the highest peaks of the eastern Olympics. CONCLUSIONS: The Olympic alpine endemics are stranded on ever-shrinking habitat islands. Within a few, isolated thermal refugia, the distribution of micro-topography may be a critical factor in determining long term survival. The Olympic Mountains and their alpine taxa are a model system for endemics worldwide, illustrating the biogeographic characteristics that underpin vulnerability to climate change. PMID- 29630718 TI - The best of both worlds? A review of delayed selfing in flowering plants. AB - PREMISE OF STUDY: In a seminal body of theory, Lloyd showed that the fitness consequences of selfing will depend on its timing in anthesis. Selfing that occurs after opportunities for outcrossing or pollen dispersal can provide reproductive assurance when pollinators are limited and is expected to incur little cost, even when inbreeding depression is high. As a result, delayed selfing is often interpreted as a "best-of-both-worlds" mating system that combines the advantages of selfing and outcrossing. METHODS: We surveyed 65 empirical studies of delayed selfing, recording floral mechanisms and examining information on inbreeding depression, autofertility, and other parameters to test the support for delayed selfing as a best-of-both-worlds strategy. KEY RESULTS: Phylogenetic distribution of the diverse floral mechanisms suggests that some basic floral structures may predispose plant taxa to evolve delayed selfing. Delayed selfing appears to serve as a best-of-both-worlds strategy in some but not all species. While the capacity for autonomous selfing is often high, it is lower, in some cases, than in related species with earlier modes of selfing. In other delayed-selfers, low inbreeding depression and reduced investment in corollas and pollen suggest limited benefits from outcrossing. CONCLUSIONS: Despite a growing literature on the subject, experimental evidence for delayed selfing is limited and major gaps in knowledge remain, particularly with respect to the stability of delayed selfing and the conditions that may favor transitions between delayed and earlier selfing. Finally, we suggest a potential role of delayed selfing in facilitating transitions from self-incompatibility to selfing. PMID- 29630719 TI - GABA: no longer the faithful neurotransmitter. PMID- 29630720 TI - The root coverage esthetic score: Intra-examiner reliability among dental students and dental faculty. AB - BACKGROUND: The root coverage esthetic score (RES) was published in 2009 as an esthetic scoring system to measure visible final outcomes of root coverage procedures performed on Miller I and II recession defects. The aim of this study was to evaluate the intra-examiner, intra-group, and inter-examiner reliability of the RES when used among periodontal faculty, post-graduate students in periodontology, and pre-doctoral DMD students when using the RES at Tufts University School of Dental Medicine (TUSDM). METHODS: Thirty-three participants (12 second-year DMD students, 11 periodontal residents, and 10 faculty members) were assembled to evaluate 25 baseline and 6-month post-treatment outcomes of mucogingival surgeries using the RES. Each projection was shown for 30 seconds during which the participants were asked to use the RES scoring system to evaluate the surgical outcomes. The results were then recorded on a standardized worksheet grid. To test intra-examiner reliability, seven of the 25 projections were shown twice. Intra-examiner reliability and inter-examiner reliability were assessed using intraclass correlation coefficient using a two-way mixed effect model, and stratified by education level. RESULTS: Post-graduate (PG) residents had the highest tendency to agree with each other with an interclass correlation (ICC) of 0.53 (95% confidence interval [CI] 0.36 to 0.74). DMD students had an ICC: 0.51 (95% CI: 0.33 to 0.75), and PG faculty members produced an ICC: 0.41 (95% CI: 0.24 to 0.64). There was no statistically significant difference in ICC among the three groups of participants (Kruskal-Wallis test, P = 0.2440). When the data for each RES element were then combined, the mean ICC for the total inter-rater agreement for RES was 0.48 (95% CI: 0.32 to 0.71). This corresponds to an overall moderate agreement among all participants using the RES to evaluate the 25 surgical outcomes. The intra-examiner reliability within each of the three groups was quite high. The highest mean ICC was produced by PG faculty (0.908). The mean ICCs for PG residents was 0.867, and the mean ICC for DMD students was 0.855. The Kruskal-Wallis test (P = 0.46) failed to find any statistical difference in intra-examiner reliability among the three groups of participants. CONCLUSIONS: The RES is a "moderately" reliable scoring system for mucogingival treatments in a dental school setting and can be used even by operators with different levels of periodontal experience. This scoring system can be repeated by the same examiner to obtain reliable results. PMID- 29630721 TI - Clinical evaluation of efficacy, tolerability and pharmacokinetics of yimitasvir phosphate in patients infected with hepatitis C virus. AB - OBJECTIVE: Yimitasvir phosphate, an inhibitor of nonstructural protein 5A (NS5A) replication complex of hepatitis C virus (HCV), was evaluated in a double-blind, placebo-controlled, parallel, multiple-dose study. METHODS: Twenty-four patients with chronic HCV genotype 1 infection were randomized to receive a 7-day course of yimitasvir phosphate at daily doses of 30, 100 or 200 mg or placebo. Antiviral efficacy, resistance profile, pharmacokinetics (PK), safety and tolerability were assessed. KEY FINDINGS: The maximal reduction in HCV RNA from baseline was 5.17 log10 IU/ml. However, most patients experienced viral rebound on or before day 3 after yimitasvir treatment was initiated. The PK profile revealed median peak plasma concentrations at 4-12 h postdose and a mean terminal half-life of 14.47 17.09 h, the basis for daily dosing. Steady drug state was achieved following 5 days of daily dosing. The accumulation rate was low (1.29-1.73). There were no significant alterations in vital signs and laboratory findings among all participants. CONCLUSIONS: This study shows that yimitasvir phosphate was well tolerated, and the PK profile supported daily dosing regimens. A 1-week (7-day) treatment course led to a quick and significant reduction in HCV RNA level in this cohort with HCV GT-1 infection. PMID- 29630722 TI - Too Much of a Good Thing: How Novelty Biases and Vocabulary Influence Known and Novel Referent Selection in 18-Month-Old Children and Associative Learning Models. AB - Identifying the referent of novel words is a complex process that young children do with relative ease. When given multiple objects along with a novel word, children select the most novel item, sometimes retaining the word-referent link. Prior work is inconsistent, however, on the role of object novelty. Two experiments examine 18-month-old children's performance on referent selection and retention with novel and known words. The results reveal a pervasive novelty bias on referent selection with both known and novel names and, across individual children, a negative correlation between attention to novelty and retention of new word-referent links. A computational model examines possible sources of the bias, suggesting novelty supports in-the-moment behavior but not retention. Together, results suggest that when lexical knowledge is weak, attention to novelty drives behavior, but alone does not sustain learning. Importantly, the results demonstrate that word learning may be driven, in part, by low-level perceptual processes. PMID- 29630723 TI - Linking puberty and error-monitoring: Relationships between self-reported pubertal stages, pubertal hormones, and the error-related negativity in a large sample of children and adolescents. AB - The error-related negativity (ERN) is a negative deflection in the event-related potential occurring when individuals make mistakes. The ERN has been proposed as a biomarker for anxiety and a substantial amount of research suggests the ERN increases across development. Further, the ERN may relate to individual differences and the development of cognitive control. Despite the large quantity of research on this topic, there have been no studies focusing on the relationship between pubertal hormones and the ERN. Previous work suggests developmental increases may begin sooner for girls than for boys, suggesting that puberty may impact the ERN. The current study examined the relationship between pubertal hormones and the ERN amplitude in a sample of 99 females between 8 and 14 years old. Each participant and the parent who accompanied them completed the Pubertal Developmental Scale (PDS) to assess the degree to which pubertal indicators are present. Participants also completed a Go/NoGo Task while EEG was recorded and participants provided saliva samples for hormone assays. Results indicated that ERN was significantly related to both the dehydroepiandrosterone (DHEA) hormone and PDS scores. A simultaneous multivariate regression suggested that DHEA levels significantly predict the ERN, even when controlling for age, behavioral variables, and PDS. These findings suggest that ERN amplitude is related to DHEA levels, further linking puberty to developmental increases in the ERN. Future research should examine this relationship in the context of developmental increases in anxiety symptoms. PMID- 29630725 TI - First person: William Kaelin Jr, MD: The scientist's discoveries have paved the way for improved treatments of kidney cancer and other diseases. PMID- 29630724 TI - Prospective cohort study comparing outcomes between vacuum extraction and second stage cesarean delivery at a Ugandan tertiary referral hospital. AB - OBJECTIVE: To compare maternal and perinatal outcomes between vacuum extraction and second-stage cesarean delivery (SSCD). METHODS: The present observational cohort study was conducted among women with term vertex singleton pregnancies who underwent vacuum extraction or SSCD at Mulago National Referral Hospital, Kampala, Uganda, between November 25, 2014, and July 8, 2015. Severe maternal outcomes (mortality, uterine rupture, hysterectomy, re-laparotomy) and perinatal outcomes (mortality, trauma, low Apgar score, convulsions) were compared between initial delivery mode. RESULTS: Among 13 152 deliveries, 358 women who underwent vacuum extraction and 425 women who underwent SSCD were enrolled in the study. No maternal deaths occurred after vacuum extraction versus five deaths from complications of SSCD. Vacuum extraction was associated with less severe maternal outcomes compared with SSCD (3 [0.8%] vs 18 [4.2%]; adjusted odds ratio [aOR] 0.24, 95% confidence interval [CI] 0.07-0.84). Fetal death during the decision-to delivery interval was also less common in the vacuum extraction group (3 [0.9%] vs 18 [4.4%]; aOR 0.24, 95% CI 0.07-0.84); however, the perinatal mortality rate did not differ between the vacuum extraction and SSCD groups (29 [8.4%] vs 45 [11.0%], respectively; aOR 0.83, 95% CI 0.49-1.41). One infant in each group exhibited neurodevelopmental anomalies at 6 months. CONCLUSION: Vacuum extraction had better maternal outcomes and equivalent perinatal outcomes compared with SSCD. These findings encourage re-introduction of vacuum extraction. PMID- 29630726 TI - Survivors of childhood cancer remain in jobs to keep health insurance. PMID- 29630728 TI - American Society of Clinical Oncology says 5% to 6% of new cancers and cancer deaths are attributable to alcohol consumption. PMID- 29630727 TI - Erratum. PMID- 29630729 TI - Rho-kinase inhibitor Y-27632 downregulates LPS-induced IL-6 and IL-8 production via blocking p38 MAPK and NF-kappaB pathways in human gingival fibroblasts. AB - BACKGROUND: Porphyromonas gingivalis lipopolysaccharide (LPS) plays a major role in the initiation and progression of chronic periodontitis. Human gingival fibroblasts (HGFs) interact with bacteria or bacterial products and trigger inflammatory signaling pathways that destroy periodontal tissues. RhoA regulates cytokine production in various cell types. This study investigated the role of Rho-kinase inhibitor Y-27632 in LPS-induced nuclear factor-kappa B (NF-kappaB) and p-38 mitogen-activated protein kinase (MAPK) activation, and inflammatory cytokine production in HGFs. METHODS: Effects of Y-27632, SB203580 (p38 MAPK inhibitor), and BAY11-7082 (NF-kappaB inhibitor) were assessed in lipopolysaccharide (LPS)-treated HGFs. Cytotoxicity assays were used to determine the effect of the drugs on HGF viability. Enzyme-linked immunosorbent assays and quantitative real-time polymerase chain reaction were applied to evaluate the levels of interleukin (IL)-6, IL-8, and Toll-like receptors (TLRs). NF-kappaB and p38 MAPK pathway activation was detected by western blot and immunocytochemistry. RESULTS: P. gingivalis LPS at 5 MUg/mL, 10 MUM Y-27632, 10 MUM SB203580, and 5 MUM BAY11-7082 exhibited no toxicity in HGFs. LPS activated NF-kappaB and p38 MAPK by increasing degradation of IkappaBalpha and phosphorylation of IkappaBalpha, p65, and p38, and facilitating p65 translocation from the cytoplasm to nuclei. The activation of NF-kappaB and p38 MAPK induced overproduction of IL 6 and IL-8 at both mRNA and protein levels. However, Y-27632 attenuated LPS induced NF-kappaB and p38 MAPK activation and inflammatory cytokine production. CONCLUSIONS: Rho-kinase inhibitor Y-27632 downregulates LPS-induced IL-6 and IL-8 production by blocking NF-kappaB and p38 MAPK activation in HGFs. PMID- 29630730 TI - Glucocorticosteroid-free versus glucocorticosteroid-containing immunosuppression for liver transplanted patients. AB - BACKGROUND: Liver transplantation is an established treatment option for end stage liver failure. Now that newer, more potent immunosuppressants have been developed, glucocorticosteroids may no longer be needed and their removal may prevent adverse effects. OBJECTIVES: To assess the benefits and harms of glucocorticosteroid avoidance (excluding intra-operative use or treatment of acute rejection) or withdrawal versus glucocorticosteroid-containing immunosuppression following liver transplantation. SEARCH METHODS: We searched the Cochrane Hepato-Biliary Group Controlled Trials Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, Science Citation Index Expanded and Conference Proceedings Citation Index - Science, Literatura Americano e do Caribe em Ciencias da Saude (LILACS), World Health Organization International Clinical Trials Registry Platform, ClinicalTrials.gov, and The Transplant Library until May 2017. SELECTION CRITERIA: Randomised clinical trials assessing glucocorticosteroid avoidance or withdrawal versus glucocorticosteroid containing immunosuppression for liver transplanted people. Our inclusion criteria stated that participants should have received the same co-interventions. We included trials that assessed complete glucocorticosteroid avoidance (excluding intra-operative use or treatment of acute rejection) versus short-term glucocorticosteroids, as well as trials that assessed short-term glucocorticosteroids versus long-term glucocorticosteroids. DATA COLLECTION AND ANALYSIS: We used RevMan to conduct meta-analyses, calculating risk ratio (RR) for dichotomous variables and mean difference (MD) for continuous variables, both with 95% confidence intervals (CIs). We used a random-effects model and a fixed effect model and reported both results where a discrepancy existed; otherwise we reported only the results from the fixed-effect model. We assessed the risk of systematic errors using 'Risk of bias' domains. We controlled for random errors by performing Trial Sequential Analysis. We presented our results in a 'Summary of findings' table. MAIN RESULTS: We included 17 completed randomised clinical trials, but only 16 studies with 1347 participants provided data for the meta analyses. Ten of the 16 trials assessed complete postoperative glucocorticosteroid avoidance (excluding intra-operative use or treatment of acute rejection) versus short-term glucocorticosteroids (782 participants) and six trials assessed short-term glucocorticosteroids versus long-term glucocorticosteroids (565 participants). One additional study assessed complete post-operative glucocorticosteroid avoidance but could only be incorporated into qualitative analysis of the results due to limited data published in an abstract. All trials were at high risk of bias. Only eight trials reported on the type of donor used. Overall, we found no statistically significant difference for mortality (RR 1.15, 95% CI 0.93 to 1.44; low-quality evidence), graft loss including death (RR 1.15, 95% CI 0.90 to 1.46; low-quality evidence), or infection (RR 0.88, 95% CI 0.73 to 1.05; very low-quality evidence) when glucocorticosteroid avoidance or withdrawal was compared with glucocorticosteroid containing immunosuppression. Acute rejection and glucocorticosteroid-resistant rejection were statistically significantly more frequent when glucocorticosteroid avoidance or withdrawal was compared with glucocorticosteroid-containing immunosuppression (RR 1.33, 95% CI 1.08 to 1.64; low-quality evidence; and RR 2.14, 95% CI 1.13 to 4.02; very low-quality evidence). Diabetes mellitus and hypertension were statistically significantly less frequent when glucocorticosteroid avoidance or withdrawal was compared with glucocorticosteroid containing immunosuppression (RR 0.81, 95% CI 0.66 to 0.99; low-quality evidence; and RR 0.76, 95% CI 0.65 to 0.90; low-quality evidence). We performed Trial Sequential Analysis for all outcomes. None of the outcomes crossed the monitoring boundaries or reached the required information size. Hence, we cannot exclude random errors from the results of the conventional meta-analyses. AUTHORS' CONCLUSIONS: Many of the benefits and harms of glucocorticosteroid avoidance or withdrawal remain uncertain because of the limited number of published randomised clinical trials, limited numbers of participants and outcomes, and high risk of bias in the trials. Glucocorticosteroid avoidance or withdrawal appears to reduce diabetes mellitus and hypertension whilst increasing acute rejection, glucocorticosteroid-resistant rejection, and renal impairment. We could identify no other benefits or harms of glucocorticosteroid avoidance or withdrawal. Glucocorticosteroid avoidance or withdrawal may be of benefit in selected patients, especially those at low risk of rejection and high risk of hypertension or diabetes mellitus. The optimal duration of glucocorticosteroid administration remains unclear. More randomised clinical trials assessing glucocorticosteroid avoidance or withdrawal are needed. These should be large, high-quality trials that minimise the risk of random and systematic error. PMID- 29630732 TI - Impact of cross-sex hormone therapy on bone mineral density and body composition in transwomen. AB - OBJECTIVE: Cross-sex hormone therapy (CSHT) has been associated with changes in bone and lean/fat mass. This study assessed bone mineral density (BMD), appendicular lean mass (ALM), and total fat mass in transwomen undergoing CSHT. PATIENTS AND DESIGN: We evaluated 142 transwomen (mean age: 33.7 +/- 10.3 years; BMI: 25.4 +/- 4.6; 86.6% with previous CSHT) during the first 3 months of regular oestrogen treatment (with or without anti-androgens). A reference group including 22 men and 17 cis women was also studied. MEASUREMENTS: Clinical and hormonal evaluation and dual-energy X-ray absorptiometry (DXA). RESULTS: Bone mineral density was similar in trans and reference women, and lower at all sites in transwomen vs men. Low bone mass for age was observed in 18% of transwomen at baseline vs none of the reference women or men. Appendicular lean mass and total fat mass were positively correlated with L1-L4 BMD, explaining 14.9% of the observed variation in lumbar spine BMD and 20.6% of the variation in total femur BMD. Appendicular lean mass was similar in trans and reference women, and lower in transwomen vs men. Total fat mass was lower in trans vs reference women. Densitometry was repeated after a mean of 31.3 +/- 6.5 months in 46 transwomen. There was a significant increase in total fat mass and a significant decrease in ALM. Bone mineral density remained stable over time. CONCLUSIONS: The fairly high prevalence of low bone mass in this sample of transwomen from southern Brazil seems to be related to lower ALM. Non-pharmacological lifestyle-related strategies for preventing bone loss could be beneficial for transgender women receiving long-term CSHT. PMID- 29630731 TI - Long non-coding RNA SNHG15 promotes CDK14 expression via miR-486 to accelerate non-small cell lung cancer cells progression and metastasis. AB - Long non-coding RNAs (lncRNAs) have been validated to play important role in multiple cancers, including non-small cell lung cancer (NSCLC). In present study, our team investigate the biologic role of SNHG15 in the NSCLC tumorigenesis. LncRNA SNHG15 was significantly upregulated in NSCLC tissue samples and cells, and its overexpression was associated with poor prognosis of NSCLC patients. In vitro, loss-of-functional cellular experiments showed that SNHG15 silencing significantly inhibited the proliferation, promoted the apoptosis, and induced the cycle arrest at G0//G1 phase. In vivo, xenograft assay showed that SNHG15 silencing suppressed tumor growth of NSCLC cells. Besides, SNHG15 silencing decreased CDK14 protein expression both in vivo and vitro. Bioinformatics tools and luciferase reporter assay confirmed that miR-486 both targeted the 3'-UTR of SNHG15 and CDK14 and was negatively correlated with their expression levels. In summary, our study conclude that the ectopic overexpression of SNHG15 contribute to the NSCLC tumorigenesis by regulating CDK14 protein via sponging miR-486, providing a novel insight for NSCLC pathogenesis and potential therapeutic strategy for NSCLC patients. PMID- 29630733 TI - People with multiple sclerosis report cognitive rehabilitation is effective in increasing strategy use and quality of life but they recommend more caregiver involvement and personal feedback to enhance outcomes. PMID- 29630734 TI - Reporting rigorous qualitative results: Moving beyond small sample sizes. PMID- 29630735 TI - Low-intensity, goal-directed occupational therapy and physiotherapy did not produce clinically meaningful differences in activities for people with mild to moderate Parkinson's Disease. PMID- 29630737 TI - Progressing knowledge translation in occupational therapy. PMID- 29630738 TI - The epilepsy phenotypic spectrum associated with a recurrent CUX2 variant. AB - OBJECTIVE: Cut homeodomain transcription factor CUX2 plays an important role in dendrite branching, spine development, and synapse formation in layer II to III neurons of the cerebral cortex. We identify a recurrent de novo CUX2 p.Glu590Lys as a novel genetic cause for developmental and epileptic encephalopathy (DEE). METHODS: The de novo p.Glu590Lys variant was identified by whole-exome sequencing (n = 5) or targeted gene panel (n = 4). We performed electroclinical and imaging phenotyping on all patients. RESULTS: The cohort comprised 7 males and 2 females. Mean age at study was 13 years (0.5-21.0). Median age at seizure onset was 6 months (2 months to 9 years). Seizure types at onset were myoclonic, atypical absence with myoclonic components, and focal seizures. Epileptiform activity on electroencephalogram was seen in 8 cases: generalized polyspike-wave (6) or multifocal discharges (2). Seizures were drug resistant in 7 or controlled with valproate (2). Six patients had a DEE: myoclonic DEE (3), Lennox-Gastaut syndrome (2), and West syndrome (1). Two had a static encephalopathy and genetic generalized epilepsy, including absence epilepsy in 1. One infant had multifocal epilepsy. Eight had severe cognitive impairment, with autistic features in 6. The p.Glu590Lys variant affects a highly conserved glutamine residue in the CUT domain predicted to interfere with CUX2 binding to DNA targets during neuronal development. INTERPRETATION: Patients with CUX2 p.Glu590Lys display a distinctive phenotypic spectrum, which is predominantly generalized epilepsy, with infantile onset myoclonic DEE at the severe end and generalized epilepsy with severe static developmental encephalopathy at the milder end of the spectrum. Ann Neurol 2018;83:926-934. PMID- 29630740 TI - The Bursts and Lulls of Multimodal Interaction: Temporal Distributions of Behavior Reveal Differences Between Verbal and Non-Verbal Communication. AB - Recent studies of naturalistic face-to-face communication have demonstrated coordination patterns such as the temporal matching of verbal and non-verbal behavior, which provides evidence for the proposal that verbal and non-verbal communicative control derives from one system. In this study, we argue that the observed relationship between verbal and non-verbal behaviors depends on the level of analysis. In a reanalysis of a corpus of naturalistic multimodal communication (Louwerse, Dale, Bard, & Jeuniaux, ), we focus on measuring the temporal patterns of specific communicative behaviors in terms of their burstiness. We examined burstiness estimates across different roles of the speaker and different communicative modalities. We observed more burstiness for verbal versus non-verbal channels, and for more versus less informative language subchannels. Using this new method for analyzing temporal patterns in communicative behaviors, we show that there is a complex relationship between verbal and non-verbal channels. We propose a "temporal heterogeneity" hypothesis to explain how the language system adapts to the demands of dialog. PMID- 29630741 TI - Comparison of hyperspectral classification methods for the analysis of cerium oxide nanoparticles in histological and aqueous samples. AB - Hyperspectral imaging (HSI) and classification are established methods that are being applied in new ways to the analysis of nanoscale materials in a variety of matrices. Typically, enhanced darkfield microscopy (EDFM)-based HSI data (also known as image datacubes) are collected in the wavelength range of 400-1000 nm for each pixel in a datacube. Utilising different spectral library (SL) creation methods, spectra from pixels in the datacube corresponding to known materials can be collected into reference spectral libraries (RSLs), which can be used to classify materials in datacubes of experimental samples using existing classification algorithms. In this study, EDFM-HSI was used to visualise and analyse industrial cerium oxide (CeO2 ; ceria) nanoparticles (NPs) in rat lung tissues and in aqueous suspension. Rats were exposed to ceria NPs via inhalation, mimicking potential real-world occupational exposures. The lung tissues were histologically prepared: some tissues were stained with hematoxylin and eosin (H&E) and some were left unstained. The goal of this study was to determine how HSI and classification results for ceria NPs were influenced by (1) the use of different RSL creation and classification methods and (2) the application of those methods to samples in different matrices (stained tissue, unstained tissue, or aqueous solution). Three different RSL creation methods - particle filtering (PF), manual selection, and spectral hourglass wizard (SHW) - were utilised to create the RSLs of known materials in unstained and stained tissue, and aqueous suspensions, which were then used to classify the NPs in the different matrices. Two classification algorithms - spectral angle mapper (SAM) and spectral feature fitting (SFF) - were utilised to determine the presence or absence of ceria NPs in each sample. The results from the classification algorithms were compared to determine how each influenced the classification results for samples in different matrices. The results showed that sample matrix and sample preparation significantly influenced the NP classification thresholds in the complex matrices. Moreover, considerable differences were observed in the classification results when utilising each RSL creation and classification method for each type of sample. Results from this study illustrate the importance of appropriately selecting HSI algorithms based on specific material and matrix characteristics in order to obtain optimal classification results. As HSI is increasingly utilised for NP characterisation for clinical, environmental and health and safety applications, this investigation is important for further refining HSI protocols while ensuring appropriate data collection and analysis. PMID- 29630743 TI - Will Open Access Close the Door on Traditional Journal Publishing? PMID- 29630742 TI - Stress-Generative Effects of Posttraumatic Stress Disorder: Transactional Associations Between Posttraumatic Stress Disorder and Stressful Life Events in a Longitudinal Sample. AB - Longitudinal studies have demonstrated transactional associations between psychopathology and stressful life events (SLEs), such that psychopathology predicts the occurrence of new SLEs, and SLEs in turn predict increasing symptom severity. The association between posttraumatic stress disorder (PTSD), specifically, and stress generation remains unclear. This study used temporally sequenced data from 116 veterans (87.9% male) to examine whether PTSD symptoms predicted new onset SLEs, and if these SLEs were associated with subsequent PTSD severity. The SLEs were objectively rated, using a clinician-administered interview and consensus-rating approach, to assess the severity, frequency, and personal dependence (i.e., if the event was due to factors that were independent of or dependent on the individual) of new-onset SLEs. A series of mediation models were tested, and results provided evidence for moderated mediation whereby baseline PTSD severity robustly predicted personally dependent SLEs, B = 0.03, p = .006, and dependent SLEs predicted increases in follow-up PTSD symptom severity, B = -0.04, p = .003, among participants with relatively lower baseline PTSD severity. After we controlled for baseline PTSD severity, personality traits marked by low constraint (i.e., high impulsivity) were also associated with an increased number of dependent SLEs. Our results provide evidence for a stress generative role of PTSD and highlight the importance of developing interventions aimed at reducing the occurrence of personally dependent stressors. PMID- 29630744 TI - MicroRNA-326 and microRNA-200c: Two novel biomarkers for diagnosis and prognosis of pediatric acute lymphoblastic leukemia. AB - Multidrug resistance (MDR) is considered as the major obstacle for treating pediatric acute lymphoblastic leukemia (ALL). MicroRNAs (miRNAs) are small non coding RNAs which may potentially regulate response to chemotherapy. In this study, total RNA was isolated from bone marrow samples of 46 children with de novo ALL and 16 controls. Quantitative reverse transcriptase polymerase chain reaction was used to investigate the expression profile of the predicted miRNAs; miR-326 and miR-200c, and their predicted targets ABCA2, and ABCA3 transporters. The presence of minimal residual disease was studied using PCR-SSCP (single strand conformation polymorphism) 1 year after treatment. The association between the miRNA expression and drug resistance was analyzed statistically. Results showed a significant down-regulation of both miR-326 and miR-200c expressions in ALL patients compared with non-cancer controls (P = 0.0002, AUC = 0.813 and P = 0.035, AUC = 0.79, respectively). A considerable negative association between miR 326 expression and MDR was identified which could raise the risk of chemoresistance by 4.8- fold. The expression profiles of miR-326 and ABCA2 transporter were inversely correlated. Data revealed, a novel diagnostic role for miR-326 and miR-200c as potential biomarkers of pediatric ALL. Down-regulation of miR-326 was introduced, for the first time, as a prognostic factor for drug resistance in childhood ALL. To the best of our knowledge, this is the first time that ABCA2 transporter is proposed as a target gene for miR-326, through which it can exert its impact on drug resistance. These data may provide novel approaches to new therapeutics and diagnostics. PMID- 29630745 TI - Toxicological and chemical studies of wastewater from hydraulic fracture and conventional shale gas wells. AB - New technology has enabled recovery of inaccessible natural gas shale deposits; however, the potential impacts to human health from the migration of brines into drinking water or surface spills are unknown. To provide information that can inform these potential impacts, chemical characterization and in vitro toxicologic testing were conducted using pre- and postinjection waters from conventional and unconventional oil and gas wells. Wastewater concentrations may be diluted or reduced by fate and transport processes when released into the environment by unknown amounts, and laboratory studies only imply potential effects. In acute cytotoxicity and wound healing assays, there was dose-dependent toxicity in human and rat cells with growth promotion at low concentrations. Lethality was measured in time studies up to 10 d postinjection. Produced water samples from both well types were equally toxic to human cells and were corrosive at high concentrations. Measurement of protein and gene expression identified metabolic pathways responding to both well types as NADPH quinone oxidoreductase oxidative stress-responsive enzyme and tight junction protein genes. A KCl sample of matched ionic strength showed a different toxicity profile from produced waters, indicating that salts alone were not the cause of toxicity. Organic chemicals and branched alkanes were present in hydraulic fracture wells, and mainly branched alkanes were present in conventional wells. One organic substance was still present after 240 d. The known properties of these chemicals include potential toxicity to multiple human organs, sensitization, irritation, developmental effects, and tumor promotion, depending on the concentrations and synergistic effects of chemicals during exposure. Environ Toxicol Chem 2018;37:2098-2111. (c) 2018 SETAC. PMID- 29630746 TI - Effects of Aging on the Human Brain: A Proton and Phosphorus MR Spectroscopy Study at 3T. AB - BACKGROUND AND PURPOSE: To investigate accumulative aging effects on neurometabolism in human brain and to collect a reference dataset. METHODS: Fifty four healthy volunteers aged evenly between 22 and 73 years were studied using whole-brain 1 H-MR spectroscopic imaging in combination with 31 P-MRS at 3T. Global metabolite concentrations of brain N-acetylaspartate (NAA), total choline (tCho), and total creatine (tCr), as well as phosphocreatine (PCr), adenosine-5' triphosphate (ATP), phosphomonoesters (PME), phosphodiesters (PDE), and inorganic phosphate (Pi) were determined. Fractional volumes of brain gray matter (FVGM), white matter (FVWM), and total tissue (FVTB, GM+WM) were also estimated. RESULTS: With age, NAA, ATP, and PME, as well as FVTB and FVGM decreased and tCho and FVWM increased linearly. Positive correlations were found between FVGM and global concentrations of NAA, ATP, PME, and Pi. CONCLUSION: Age-related accumulative metabolic changes in aging human brain correlated with reduced neuronal metabolic activity and density, reflected by decreased NAA, reduced mitochondrial activity by decreased ATP, and reduced membrane synthesis by decreased PME. These changes are associated with age-related decrease of neuronal volume. Global NAA and ATP might be used as surrogate biomarker for monitoring aging in human brain. PMID- 29630747 TI - Kinetic demands of sprinting shift across the acceleration phase: Novel analysis of entire force waveforms. AB - A novel approach of analyzing complete ground reaction force waveforms rather than discrete kinetic variables can provide new insight to sprint biomechanics. This study aimed to understand how these waveforms are associated with better performance across entire sprint accelerations. Twenty-eight male track and field athletes (100-m personal best times: 10.88 to 11.96 seconds) volunteered to participate. Ground reaction forces produced across 24 steps were captured during repeated (two to five) maximal-effort sprints utilizing a 54-force-plate system. Force data (antero-posterior, vertical, resultant, and ratio of forces) across each contact were registered to 100% of stance and averaged for each athlete. Statistical parametric mapping (linear regression) revealed specific phases of stance where force was associated with average horizontal external power produced during that contact. Initially, antero-posterior force production during mid-late propulsion (eg, 58%-92% of stance for the second ground contact) was positively associated with average horizontal external power. As athletes progressed through acceleration, this positive association with performance shifted toward the earlier phases of contact (eg, 55%-80% of stance for the eighth and 19%-64% for the 19th ground contact). Consequently, as athletes approached maximum velocity, better athletes were more capable of attenuating the braking forces, especially in the latter parts of the eccentric phase. These unique findings demonstrate a shift in the performance determinants of acceleration from higher concentric propulsion to lower eccentric braking forces as velocity increases. This highlights the broad kinetic requirements of sprinting and the conceivable need for athletes to target improvements in different phases separately with demand specific exercises. PMID- 29630748 TI - gamma-Herringbone Polymorph of 6,13-Bis(trimethylsilylethynyl)pentacene: A Potential Material for Enhanced Hole Mobility. AB - The introduction of the trialkylsilylethynyl group to the acene core is known to predominantly transform the herringbone structure of pentacene to a slip-stacked packing. However, herein, the occurrence of an unforeseen polymorph of 6,13 bis(trimethylsilylethynyl)pentacene (TMS-pentacene), with an atypical gamma herringbone packing arrangement, is reported. Intermolecular noncovalent interactions in the gamma-herringbone polymorph are determined from Hirshfeld surface and quantum theory of atoms-in-molecules (QTAIM) analyses. Furthermore, a comparative truncated symmetry-adapted perturbation theory (SAPT(0)) energy decomposition analysis discloses the role of exchange repulsions that govern molecular packing in the gamma-herringbone polymorph. Moreover, the computationally predicted electronic coupling and anisotropic mobility reveal the possibility of enhanced hole transport (MUh =3.7 cm2 V-1 s-1 ) in the gamma herringbone polymorph, in contrast to the reported polymorph with a hole mobility of MUh =0.1 cm2 V-1 s-1 . PMID- 29630749 TI - The association between immunoexpression levels of oxidant and antioxidant enzymes and lip squamous cell carcinoma. AB - The aim of this study was to investigate the associations among the immunoexpression levels of manganese superoxide dismutase (Mn-SOD), glutathione peroxidase (GPx), and myeloperoxidase (MPO) in lip squamous cell carcinoma (LSCC) tissues and the clinicopathological characteristics, and prognostic factors in patients with LSCC. The immunoexpression levels of Mn-SOD, GPx, and MPO were examined in 76 LSCC tissue samples using immunohistochemical staining on tissue microarray slides, and compared to those in normal lip mucosa adjacent to venous lakes (normal controls), normal tissue adjacent to corresponding tumors (NTACT), and recurrent tumors. Associations between immunoexpression levels and clinicopathological characteristics were analyzed using the Student's t-test. The prognostic factors were analyzed using Cox regression. The immunoexpression levels of Mn-SOD, GPx, and MPO were significantly different among the normal controls, NTACTs, tumors, and recurrent tumors (Mn-SOD: p = 0.001, GPx: p < 0.001, MPO: p < 0.001). Lower lip cancer was associated with higher Mn-SOD immunoexpression levels (p = 0.04) and probably indicated higher oxidative stress. Lymph node involvement with a lower immunoexpression level of MPO (p = 0.007) indicated compensatory mechanism to attenuate oxidative damage. A low Mn SOD immunoexpression level was borderline significantly associated with a worse prognosis for disease-specific survival, and it was probably related to a lower capacity for coping with oxidative stress. PMID- 29630750 TI - A qualitative exploration of the meaning of the term "survivor" to young women living with a history of breast cancer. AB - There has been a recent increase in research considering the perceptions of the term "cancer survivor" held by individuals who have or have had cancer. This article explores the meaning of the term to young women living with a history of breast cancer. Twenty women participated in semi-structured interviews about their experience of breast cancer. The methodology was informed by social constructionist grounded theory. Three of the women interviewed said they would use the term survivor to describe themselves, but most of the women felt it did not fit with their experiences. The accounts of those who accepted and rejected the survivor identity are explored, and subthemes in the latter are "survivor as somebody else" and "cancer's ongoing presence." This article calls into question the basing of intervention strategies on the notion of the "cancer survivor," and the assumption that younger women favour the survivor identity. Participants struggled with the demand to live up to the ideal of the survivor, which implied a high degree of agency where in reality, cancer was a disempowering experience. Being labelled a survivor obscured ongoing impacts of cancer on the young women's lives. PMID- 29630751 TI - Labor pain in women with and without severe fear of childbirth: A population based, longitudinal study. AB - BACKGROUND: This prospective study aims to investigate whether severe fear of childbirth increases pain perceptions during birth and whether co-occurring maternal health and birth factors as well as length and weight of the child explain the association. METHODS: The study sample comprised women with a vaginal delivery and was drawn from the Akershus Birth Cohort. Data from the hospital birth's record and questionnaires at weeks 17-19 and 32 of pregnancy and 8 weeks postpartum were used (n = 1649). Analysis of variance and analysis of covariance were conducted to examine whether ratings of labor pain differed significantly between women with and without severe fear of childbirth and which factors explained the difference. RESULTS: Women with severe fear of childbirth experienced significantly more labor pain than women without severe fear of childbirth (P < .01). However, when controlling for symptoms of maternal depression and anxiety, use of epidural/spinal anesthetic or nitrous oxide gas, and menstrual pain, this difference was no longer significant (P = .09). DISCUSSION: Although the results show that labor pain is related to multiple physiological and psychological factors in a complex manner, symptoms of maternal depression and anxiety seem to play a central role for the experience of labor pain, and should therefore be focused on by health practitioners. PMID- 29630752 TI - Interface pressure, perceptual, and mean arterial pressure responses to different blood flow restriction systems. AB - This study examined the cuff to limb interface pressure during blood flow restriction (BFR), and the perceptual and mean arterial pressure responses, in different BFR systems. Eighteen participants attended three experimental sessions in a randomised, crossover, counterbalanced design. Participants underwent inflations at 40% and 80% limb occlusive pressure (LOP) at rest and completed 4 sets of unilateral leg press exercise at 30% of one repetition maximum with BFR at 80% LOP. Different BFR systems were used each session: an automatic rapid inflation (RI), automatic personalized tourniquet (PT) and manual handheld pump and sphygmomanometer (HS) system. Interface pressure was measured using a universal interface device with pressure sensors. Perceived exertion and pain were measured after each set, mean arterial pressure (MAP) was measured pre-, 1 minute post- and 5-minutes post-exercise. Interface pressure was lower than the set pressure in all BFR systems at rest (P < .05). Interface pressure was, on average, 10 +/- 8 and 48 +/- 36 mm Hg higher than the set pressure in the RI and HS system (P < .01), with no differences observed in the PT system (P > .05), during exercise. Pain and exertion were greater in sets 3 and 4 in the RI and HS system compared to the PT system (P < .05). MAP was higher in the RI and HS system compared to the PT system at 1-minute and 5-minutes post-exercise (P < .05). BFR systems applying higher pressures amplify mean arterial pressure and perceptual responses. Automatic BFR systems appear to regulate pressure effectively within an acceptable range during BFR exercise. PMID- 29630753 TI - Almost five minutes of ventricular fibrillation and living to tell the tale (spontaneously resolved long-duration ventricular fibrillation). PMID- 29630754 TI - Association of the novel susceptible locus rs9266150 with clinical features of psoriasis vulgaris in the Chinese Han population. AB - Psoriasis is a chronic multifactorial disease and is considered to be strongly associated with the major histocompatibility complex (MHC) region. We have discovered an independent, novel and susceptible psoriasis risk HLA loci, rs9266150; P = 4.52 * 10-9 for the first time. In this study, we aimed to verify the relationship between the susceptible locus and the subphenotypes of psoriasis vulgaris (PV), including geographic location, gender, age of onset, family history and present skin lesion types (chronic plaque and guttate). To investigate the distribution and association of the rs9266150 gene with clinical phenotypes of PV in Chinese Han population, we conducted an analysis in case control and case-only subjects in the 9906 controls and 8744 cases by MHC targeted sequencing stratified analysis in this study. Significant associations were found with a northern geographic location in the case-only (P = 1.97 * 10-4 ) and the subphenotype-control analyses (P = 5.57 * 10-5 ), males in the case only (P = 4.77 * 10-3 ) and the subphenotype-control analyses (P = 7.31 * 10-4 ), and guttate psoriasis in the case-only (P = 4.08 * 10-3 ) and the subphenotype control analyses (P = 1.27 * 10-3 ). There were no significant differences observed between the age of onset (OR = 1.062, 95% CI: 0.9725-1.16, P = 1.8 * 10 1 ) and the family history of psoriasis (OR = 0.981, 95% CI: 0.9048-1.064, P = 6.43 * 10-1 ). The recessive model provided the best fit for rs9266150 (P = 4.38 * 10-7 ). Our results implied that rs9266150 might not only play an important role in the development of psoriasis, but also be positively associated with the geographic location, gender and present skin lesion in the Chinese population. PMID- 29630756 TI - Utility of volumetric contrast-enhanced and diffusion-weighted MRI in differentiating between common primary hypervascular liver tumors. AB - BACKGROUND: Differentiating between hepatocellular carcinoma (HCC), focal nodular hyperplasia (FNH), and hepatocellular adenoma (HCA) is usually achievable by MRI. However, in some cases with atypical imaging findings accurate diagnosis may be difficult. PURPOSE: To assess the diagnostic value of volumetric contrast enhanced (CE) and volumetric diffusion-weighted imaging (DWI) in differentiating between HCC, FNH, and HCA. STUDY TYPE: Retrospective. SUBJECTS: In all, 143 patients (206 lesions): 42 HCA (81 lesions), 51 FNH (65 lesions), and 50 HCC (60 lesions). FIELD STRENGTH/SEQUENCE: 1.5T MRI, T1 -T2 WI, DWI. ASSESSMENT: Patients underwent CE-MRI and DWI (b = 0, 750 mm2 /s). Volumetric assessment of lesions' contrast enhancement and apparent diffusion coefficient (ADC) was performed with semiautomatic software after 3D image registration and segmentation by an observer and compared between three lesion groups. The diagnosis of lesions was based on histopathology, typical MRI findings, and/or follow-up. STATISTICAL TESTS: Independent t-test was used to compare parameters between two groups, one way analysis of variance (ANOVA) between three groups, and receiver operator characteristic curve (ROC) analysis to define under-curve area and optimal cutoff. RESULTS: Mean values (+/-standard deviation) for HCC, FNH, and HCA, respectively, were: 1) arterial enhancement (%), 40.5 +/- 13.2, 88.6 +/- 32.6, 69.6 +/- 25.1; 2) venous enhancement (%) 72.4 +/- 22.1, 95.2 +/- 30.9, 80.7 +/- 30.6; and 3) ADC (10-6 mm2 /s) 1404.5 +/- 168.1, 1413.4 +/- 232.1, 1070.1 +/- 232.1. ADC was the best differentiator of HCA from FNH (at 1211 * 10-6 mm2 /s; sensitivity 80.4%, specificity 71.7%) and arterial enhancement was the best differentiator of HCC from both HCA (at 48%; sensitivity 80.0%, specificity 80.5%) and FNH (at 52%; sensitivity 85.7%, specificity 85.4%). A combination of arterial enhancement and ADC (at 50% and 1227 * 10-6 mm2 /s) differentiated three types of tumors with high specificity (87.9%). DATA CONCLUSION: Volumetric CE-MRI and volumetric DWI can help to differentiate between HCC, FNH, and HCA. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;48:1080 1090. PMID- 29630755 TI - Reproducible automated breast density measure with no ionizing radiation using fat-water decomposition MRI. AB - BACKGROUND: Increased breast density is a significant independent risk factor for breast cancer, and recent studies show that this risk is modifiable. Hence, breast density measures sensitive to small changes are desired. PURPOSE: Utilizing fat-water decomposition MRI, we propose an automated, reproducible breast density measurement, which is nonionizing and directly comparable to mammographic density (MD). STUDY TYPE: Retrospective study. POPULATION: The study included two sample sets of breast cancer patients enrolled in a clinical trial, for concordance analysis with MD (40 patients) and reproducibility analysis (10 patients). FIELD STRENGTH/SEQUENCE: The majority of MRI scans (59 scans) were performed with a 1.5T GE Signa scanner using radial IDEAL-GRASE sequence, while the remaining (seven scans) were performed with a 3T Siemens Skyra using 3D Cartesian 6-echo GRE sequence with a similar fat-water separation technique. ASSESSMENT: After automated breast segmentation, breast density was calculated using FraGW, a new measure developed to reliably reflect the amount of fibroglandular tissue and total water content in the entire breast. Based on its concordance with MD, FraGW was calibrated to MR-based breast density (MRD) to be comparable to MD. A previous breast density measurement, Fra80-the ratio of breast voxels with <80% fat fraction-was also calculated for comparison with FraGW. STATISTICAL TESTS: Pearson correlation was performed between MD (reference standard) and FraGW (and Fra80). Test-retest reproducibility of MRD was evaluated using the difference between test-retest measures (Delta1-2 ) and intraclass correlation coefficient (ICC). RESULTS: Both FraGW and Fra80 were strongly correlated with MD (Pearson rho: 0.96 vs. 0.90, both P < 0.0001). MRD converted from FraGW showed higher test-retest reproducibility (Delta1-2 variation: 1.1% +/ 1.2%; ICC: 0.99) compared to MD itself (literature intrareader ICC <=0.96) and Fra80. DATA CONCLUSION: The proposed MRD is directly comparable with MD and highly reproducible, which enables the early detection of small breast density changes and treatment response. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 1 J. Magn. Reson. Imaging 2018;48:971-981. PMID- 29630757 TI - 3D phase contrast MRI in models of human airways: Validation of computational fluid dynamics simulations of steady inspiratory flow. AB - BACKGROUND: Knowledge of airflow patterns in the large airways is of interest in obstructive airways disease and in the development of inhaled therapies. Computational fluid dynamics (CFD) simulations are used to study airflow in realistic airway models but usually need experimental validation. PURPOSE: To develop MRI-based methods to study airway flow in realistic 3D-printed models. STUDY TYPE: Case control. PHANTOM: Two 3D-printed lung models. FIELD STRENGTH/SEQUENCE: 1.5-3T, flow MRI. ASSESSMENT: Two human airway models, respectively including and excluding the oral cavity and upper airways derived from MR and CT imaging, were 3D-printed. 3D flow MRI was performed at different flow conditions corresponding to slow and steady airflow inhalation rates. Water was used as the working fluid to mimic airflow. Dynamic acquisition of 1D velocity profiles was also performed at different locations in the trachea to observe variability during nonsteady conditions. STATISTICAL TESTS: Linear regression analysis to compare both flow velocity fields and local flow rates from CFD simulations and experimental measurement with flow MRI. RESULTS: A good agreement was obtained between 3D velocity maps measured with flow MRI and predicted by CFD simulations, with linear regression R-squared values ranging from 0.39 to 0.94 when performing a pixel-by-pixel comparison of each velocity component. The flow distribution inside the lung models was also similar, with average slope and R-squared values of 0.96 and 0.99, respectively, when comparing local flow rates assessed at different branching locations. In the model including the upper airways, a turbulent laryngeal jet flow was observed with both methods and affected remarkably the velocity profiles in the trachea. DATA CONCLUSION: We propose flow MRI using water as a surrogate fluid to air, as a validation tool for CFD simulations of airflow in geometrically realistic models of the human airways. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2018;47:1400-1409. PMID- 29630758 TI - Structural insights into suppressor of cytokine signaling 1 protein- identification of new leads for type 2 diabetes mellitus. AB - The study considers the Suppressor of cytokine signaling 1 (SOCS1) protein as a novel Type 2 diabetes mellitus (T2DM) drug target. T2DM in human beings is also triggered by the over expression of SOCS proteins. The SOCS1 acts as a ubiquitin ligase (E3), degrades Insulin Receptor Substrate 1 and 2 (IRS1 and IRS2) proteins, and causes insulin resistance. Therefore, the structure of the SOCS1 protein was evaluated using homology-modeling and molecular dynamics methods and validated using standard computational protocols. The Protein-Protein docking study of SOCS1 with its natural substrates, IRS1 and IRS2, and subsequent solvent accessible surface area analysis gave insight into the binding region of the SOCS1 protein. The in silico active site prediction tools highlight the residues Val155 to Ile211 in SOCS1 being implicated in the ubiquitin mediated protein degradation of the proteins IRS1 and IRS2. Virtual screening in the active site region, using large structural databases, results in selective lead structures with 3-Pyridinol, Xanthine, and Alanine moieties as Pharmacophore. The virtual screening study shows that the residues Glu149, Gly187, Arg188, Leu191, and Ser205 of the SOCS1 are important for binding. The docking study with current anti-diabetic therapeutics shows that the drugs Glibenclamide and Glyclopyramide have a partial affinity towards SOCS1. The predicted ADMET and IC50 properties for the identified ligands are within the acceptable range with drug-like properties. The structural data of SOCS1, its active site, and the identified lead structures are expedient in the development of new T2DM therapeutics. PMID- 29630760 TI - Catheter ablation of atrial fibrillation in heart failure with reduced ejection fraction. AB - Atrial fibrillation and heart failure are increasing in prevalence, and frequently coexist. Despite the desire to restore sinus rhythm in heart failure patients, large studies comparing rate control to pharmacologic rhythm control have failed to show superiority of either approach. This may in part be due to the inefficacy and higher risk of adverse effects with antiarrhythmic drugs in HF patients. As such, catheter ablation for atrial fibrillation in patients with heart failure with reduced ejection fraction has been increasingly explored as a treatment modality. We review the contemporary evidence regarding patient selection, efficacy, safety, and impact of catheter ablation on outcomes in patients with atrial fibrillation and heart failure with reduced ejection fraction. PMID- 29630759 TI - Molecular interaction of some cardiovascular drugs with human serum albumin at physiological-like conditions: A new approach. AB - In the present study, the interaction of human serum albumin (HSA) with some cardiovascular drugs (CARs) under physiological conditions was investigated via the fluorescence spectroscopic and Fourier transform infrared spectroscopy. The CAR included Captopril, Timolol, Propranolol, Atenolol, and Amiodarone. Cardiovascular drugs can effectively quench the endogenous fluorescence of HSA by static quenching mechanism. The fluorescence quenching of HSA is mainly caused by complex formation of HSA with CAR. The binding reaction of CAR with HSA can be concluded that hydrophobic and electrostatic interactions are the main binding forces in the CAR-HSA system. The results showed that CAR strongly quenched the intrinsic fluorescence of HSA through a static quenching procedure, and nonradiation energy transfer happened within molecules. Fourier transform infrared spectroscopy absorption studies showed that the secondary structure was changed according to the interaction of HSA and CAR. The binding reaction of CAR with HSA can be concluded that hydrophobic and electrostatic interactions are the main binding forces in the CAR-HSA system. The results obtained herein will be of biological significance in pharmacology and clinical medicines. PMID- 29630761 TI - Epitope imprinting of iron binding protein of Neisseria meningitidis bacteria through multiple monomers imprinting approach. AB - Epitope imprinting is a promising technique for fabrication of novel diagnostic tools. In this study, an epitope imprinted methodology for recognition of target epitope sequence as well as targeted protein infused by bacterial infection in blood samples of patients suffering from brain fever is developed. Template sequence chosen is a ferric iron binding fbp A protein present in Neisseria meningitidis bacteria. To orient the imprinting template peptide sequence on gold surface of electrochemical quartz crystal microbalance (EQCM), thiol chemistry was utilized to form the self-assembled monolayer on EQCM electrode. Here, synergistic effects induced by various noncovalent interactions extended by multiple monomers (3-sulfopropyl methacrylate potassium-salt and benzyl methacrylate) were used in fabricating the imprinting polymeric matrix with additional firmness provided by N,N-methylene-bis-acrylamide as cross-linker and azo-isobutyronitrile as initiator. Extraction of template molecule was carried out with phosphate buffer solution. After extraction of epitope molecules from the polymeric film, epitope molecularly imprinted polymeric films were fabricated on EQCM electrode surface. Nonimprinted polymers were also synthesized in the similar manner without epitope molecule. Detection limit of epitope molecularly imprinted polymers and imprinting factor (epitope molecularly imprinted polymers/nonimprinted polymers) was calculated 1.39 ng mL-1 and 12.27 respectively showing high binding capacity and specific recognition behavior toward template molecule. Simplicity of present method would put forward a fast, facile, cost-effective diagnostic tool for mass health care. PMID- 29630762 TI - O2 -Mediated Oxidation of Aminoboranes through 1,2-N Migration. AB - In analogy to the classical reaction of C-B bonds with peroxides, the first oxidative functionalization of aminoboranes through a 1,2-N migration was realized. Readily available aliphatic nitro compounds are thereby transformed into N- and O-functionalized hydroxylamines in a single synthetic operation. Addition of hazardous peroxides is avoided. Instead, the insertion of O2 , as the terminal oxidant, into Zn-C bonds provides the necessary peroxides. The required zinc organyls, in turn, are formed through a boron-to-zinc exchange, from an organoboronic ester byproduct of the nitro-to-aminoborane transformation. PMID- 29630763 TI - Community-acquired Acute Kidney Injury Among Children Seen in the Pediatric Emergency Department. AB - OBJECTIVES: Acute kidney injury (AKI) is a significant risk factor for morbidity and mortality in children. Little is known about community-acquired AKI (CA-AKI) in the pediatric emergency department (PED). Early recognition of AKI allows for nephroprotective measures. The goal of this investigation was to determine the incidence of CA-AKI and the frequency of clinician identified CA-AKI to better inform future nephroprotective interventions. METHODS: This was a retrospective cross-sectional study in the PED of a children's hospital. Children 1 month to 18 years of age seen in the PED from January 1 to December 31, 2015, and in whom at least one creatinine level was obtained were included. Patients with chronic kidney disease or end-stage renal disease or who died in the PED were excluded. Patients had CA-AKI based on modified Kidney Disease-Improving Global Outcomes criteria using the creatinine obtained in the PED compared to age-specific norms. Patients were considered identified if the PED clinician diagnosed AKI. The primary outcome was the incidence of CA-AKI. Secondary outcomes included frequency of AKI identification, nephrotoxic medication use, hospital length of stay, renal replacement therapy, and death. Fisher exact test or Pearson's chi square test was used to calculate odds ratio (OR) with 95% confidence intervals (CIs); multivariable analyses were performed using logistic regression. RESULTS: In 2015 there were 119,151 PED visits; 15,486 met inclusion criteria. CA-AKI was present in 239 of 15,486 (1.5%) encounters. AKI was identified by PED clinicians in 46 of 239 (19%) of encounters and by the inpatient team in 123 of 199 (62%) of the encounters admitted. AKI was never recognized by a PED or inpatient clinician in 74 of 199 (37%) encounters. Encounters with AKI correctly diagnosed were older (13 years old vs. 10 years old, p = 0.0114), had more severe (stage 2 or 3) AKI (OR = 5.5, 95% CI = 2.6-11.8), and were more likely to be admitted (OR = 10.3, 95% CI = 1.38-77.4) than encounters with missed AKI. CONCLUSIONS: CA-AKI remains an underrecognized entity in the PED. Better tools for early recognition of AKI in the busy PED environment are needed. PMID- 29630764 TI - Histiocytic sarcoma in a child-successful management and long-term survival with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. AB - Histiocytic sarcoma is an extremely rare tumor in children. It may occur sporadically or in association with other hematological malignancies. It arises most commonly in the lymph nodes but may occur anywhere in the body and clinical presentation is usually with advanced disease. Following tissue diagnosis and staging, management is with chemotherapy though there are no standard regimes. Surgery has been used successfully for local control. This is the first description of the use of peritonectomy and hyperthermic intraperitoneal chemotherapy to treat histiocytic sarcoma. The 4-year-old patient has been disease free for 6 years. PMID- 29630765 TI - Contemporary management of adult-acquired buried penis. AB - OBJECTIVES: To describe our buried penis repair technique that includes penile release, tissue resection, wound closure, and penile reconstruction. PATIENTS AND METHODS: In all, 73 patients were treated from 2007 to 2017. Patients can be categorised into five stages: Stage I, involves only a phimotic band; Stage 2, required excision of diseased penile skin with split-thickness skin grafting (STSG); Stage 3, requires scrotal excision; Stage 4, requires escutcheonectomy; and Stage 5, requires panniculectomy. Successful treatment hinges on adequate excision of diseased skin and de-bulking followed by replacement of deficient skin with STSG. RESULTS: In all, 36 of 73 (49%) patients had Stage 1-3 disease, whilst 37 of 73 (51%) were Stage 4-5. There were complications within the first 30 days in 44 of 73 (60%) patients. In all, 62 of 73 (85%) patients either had no complications or Clavien-Dindo grade I-II complications and nine (12%) had complications beyond 30 days. Only five of 36 (14%) patients with Stage 1-3 disease had complications. One patient developed recurrent phimosis. CONCLUSION: The buried penis is a challenging surgical entity where conservative treatment will most likely lead to failure. Surgery is the only means for a lasting cure in these patients and should be used as a first-line treatment. One should expect complications postoperatively, especially within the first 30 days; however, these are mostly limited to Clavien-Dindo grade I-II complications. PMID- 29630766 TI - Autophagy during ageing - from Dr Jekyll to Mr Hyde. AB - Autophagy is a ubiquitous catabolic process, which causes cellular bulk degradation through vesicular engulfment of obsolete, damaged or harmful cytoplasmic components. While autophagy regulates cellular homeostasis during development and in youth, there is mounting evidence that autophagy becomes increasingly dysfunctional with age. Recent work in Caenorhabditis elegans even suggests that late-life dysfunctional autophagy exhibits detrimental effects that drive the ageing process. Other studies link elevated autophagy closely to increased health and longevity. This review aims to put these apparently opposing views into perspective and define our current understanding of the role of autophagy during ageing. PMID- 29630767 TI - Outcome of renal tumors registered in Japan Wilms Tumor Study-2 (JWiTS-2): A report from the Japan Children's Cancer Group (JCCG). AB - BACKGROUND: Japan Wilms Tumor Study-2 (JWiTS-2) mandated central pathology review for all case registrations. The study aimed to compare the outcomes of patients with unilateral Wilms tumor enrolled on the JWiTS-1 and JWiTS-2 trials. PROCEDURE: The JWiTS-2 trial (2006-2014), a prospective, single-arm study, required compulsory submission of histologic slides to central pathology, while in the JWiTS-1 trial, such submission was not compulsory. Relapse-free survival (RFS) and overall survival (OS) versus cases in the JWiTS-1 trial (1996-2005) were statistically evaluated. RESULTS: Of 277 enrolled patients with primary renal tumors diagnosed by the central pathology review system, 225 patients with unilateral renal tumors were followed up over 9 years. The RFS and OS of Wilms tumor (n = 178) were 90.4% (P = 0.0003) and 96.8% (P = 0.054), respectively, as compared to 74.9% and 89.4% in JWiTS-1. RFS rates of stages I-III Wilms tumor in JWiTS-2 were more than 90%, although the outcome of stage IV Wilms tumor was significantly poorer (RFS: 66.2%) (P = 0.0094). RFS and OS of clear cell sarcoma of the kidney (CCSK; n = 31) were 82.4% (P = 0.30) and 91.3% (P = 0.42), respectively, as compared to 68.8% and 81.3% in JWiTS-1, and those of rhabdoid tumor of the kidney (RTK; n = 16) were 18.8% (P = 0.88) and 25.0% (P = 0.80), respectively, as compared to 23.5% and 23.5% in JWiTS-1. CONCLUSIONS: RFS and OS for stages I-III Wilms tumor were improved in JWiTS-2 compared to JWiTS-1, whereas outcomes for stage IV Wilms tumor, CCSK, and RTK did not improve. PMID- 29630769 TI - Does N-terminal huntingtin function as a 'holdase' for inhibiting cellular protein aggregation? AB - Proteolytic cleavage of huntingtin gives rise to N-terminal fragments. While the role of truncated mutant huntingtin is described in Huntington's disease (HD) pathogenesis, the function of N-terminal wild-type protein is less studied. The yeast model of HD is generated by the presence of FLAG tag and absence of polyproline tract as flanking sequences of the elongated polyglutamine stretch. We show that the same sequence derived from wild-type huntingtin exon1 is able to inhibit the aggregation of proteins in vitro and in yeast cells. It is able to stabilize client proteins as varied as luciferase, alpha-synuclein, and p53 in a soluble but non-native state. This is somewhat similar to the 'holdase' function of small heat shock proteins and 'nonchaperone proteins' which are able to stabilize partially unfolded client proteins in a nonspecific manner, slowing down their aggregation. Mutagenesis studies show this property to be localized at the N17 domain preceding the polyglutamine tract. Distortion of this ordered segment, either by deletion of this segment or mutation of a single residue (L4A), leads to decreased stability and increased aggregation of client proteins. It is interesting to note that the helical conformation of the N17 domain is also essential for aggregation of the N-terminal mutant protein. Our results provide evidence for a novel function for the amphipathic helix derived from exon1 of wild-type huntingtin. PMID- 29630770 TI - Implicit Statistical Learning: A Tale of Two Literatures. AB - Implicit learning and statistical learning are two contemporary approaches to the long-standing question in psychology and cognitive science of how organisms pick up on patterned regularities in their environment. Although both approaches focus on the learner's ability to use distributional properties to discover patterns in the input, the relevant research has largely been published in separate literatures and with surprisingly little cross-pollination between them. This has resulted in apparently opposing perspectives on the computations involved in learning, pitting chunk-based learning against probabilistic learning. In this paper, I trace the nearly century-long historical pedigree of the two approaches to learning and argue for their integration under the heading of "implicit statistical learning." Building on basic insights from the memory literature, I sketch a framework for statistically based chunking that aims to provide a unified basis for understanding implicit statistical learning. PMID- 29630768 TI - Enhancer of zeste homolog 2 promotes cisplatin resistance by reducing cellular platinum accumulation. AB - Enhancer of zeste homolog 2 (EZH2), which is overexpressed in a wide range of tumors, contributes to ovarian cancer malignancy in several different ways. We aimed to illustrate the role of EZH2 in ovarian cancer cisplatin resistance and to identify possible underlying mechanisms of this role that may provide a rationale for targeting EZH2 in cancer treatment. Here, we present data indicating that EZH2 overexpression is associated with cisplatin resistance and intracellular platinum drug accumulation. Measurements of EZH2 in 84 ovarian cancer patients suggested that patients with high EZH2 levels tend to have poor responses to cisplatin. The EZH2 level progressively increased in cells receiving repeated cisplatin exposure. Downregulation of EZH2 not only sensitized cellular reactions to cisplatin and increased cellular platinum accumulation when cells were exposed to both cisplatin and BODIPY-Pt (a fluorescent cisplatin complex) but also protected copper transporter 1, a high-affinity copper transporter closely related to cisplatin resistance, from cisplatin-induced proteasomal degradation. Overall, these findings identify a new mechanism that expands the unrecognized role of EZH2 in ovarian cancer cisplatin resistance. PMID- 29630771 TI - Nonalcoholic fatty liver disease is an increasing indication for liver transplantation in the Nordic countries. AB - BACKGROUND & AIMS: Nonalcoholic fatty liver disease(NAFLD) is the second most common cause of liver transplantation in the US. Data on NAFLD as a liver transplantation indication from countries with lower prevalences of obesity are lacking. We studied the temporal trends of NAFLD as an indication for liver transplantation in the Nordic countries, and compared outcomes for patients with NAFLD to patients with other indications for liver transplantation. METHOD: Population-based cohort study using data from the Nordic Liver Transplant Registry on adults listed for liver transplantation between 1994 and 2015. NAFLD as the underlying indication for liver transplantation was defined as a listing diagnosis of NAFLD/nonalcoholic steatohepatitis, or cryptogenic cirrhosis with a body mass index >=25 kg/m2 and absence of other liver diseases. Waiting time for liver transplantation, mortality and withdrawal from the transplant waiting list were registered. Survival after liver transplantation was calculated using multivariable Cox regression, adjusted for age, sex, body mass index and model for end-stage liver disease. RESULTS: A total of 4609 patients listed for liver transplantation were included. NAFLD as the underlying indication for liver transplantation increased from 2.0% in 1994-1995 to 6.2% in 2011-2015 (P = .01) and was the second most rapidly increasing indication. NAFLD patients had higher age, model for end-stage liver disease and body mass index when listed for liver transplantation, but overall survival after liver transplantation was comparable to non--NAFLD patients (aHR 1.03, 95% CI 0.70-1.53 P = .87). CONCLUSION: NAFLD is an increasing indication for liver transplantation in the Nordic countries. Despite more advanced liver disease, NAFLD patients have a comparable survival to other patients listed for liver transplantation. PMID- 29630772 TI - Preventing neurodegeneration by adrenergic astroglial excitation. AB - Impairment of the main noradrenergic nucleus of the human brain, the locus coeruleus (LC), which has been discovered in 1784, represents one of defining factors of neurodegenerative diseases progression. Projections of LC neurons release noradrenaline/norepinephrine (NA), which stimulates astrocytes, homeostatic neuroglial cells enriched with adrenergic receptors. There is a direct correlation between the reduction in noradrenergic innervations and cognitive decline associated with ageing and neurodegenerative diseases. It is, therefore, hypothesized that the resilience of LC neurons to degeneration influences the neural reserve that in turn determines cognitive decline. Deficits in the noradrenergic innervation of the brain might be reversed or restrained by increasing the activity of existing LC neurons, transplanting noradrenergic neurons, and/or using drugs that mimic the activity of NA on astroglia. Here, these strategies are discussed with the aim to understand how astrocytes integrate neuronal network activity in the brain information processing in health and disease. PMID- 29630773 TI - Ruthenium Complexes for Catalytic Dehydrogenation of Hydrazine and Transfer Hydrogenation Reactions. AB - Catalytic dehydrogenation of hydrazine was achieved over iminopyridine ligated ruthenium-arene complexes, where the release of H2 gas, as confirmed by GC-TCD, from hydrazine depends on reaction temperature, base, and solvents. NMR and MS studies indicated an in situ generation of a hydrazine-coordinated ruthenium species, a key intermediate of hydrazine dehydrogenation, via a coordination assisted activation pathway. PMID- 29630774 TI - When Do Misunderstandings Matter? Evidence From Survey Interviews About Smoking. AB - This paper examines when conceptual misalignments in dialog lead to consequential miscommunication. Two studies explore misunderstanding in survey interviews of the sort conducted by governments and social scientists, where mismeasurement can have real social costs. In 131 interviews about tobacco use, misalignment between respondents' and researchers' conceptions of ordinary expressions like "smoking" and "every day" was quantified by probing respondents' interpretations of survey terms and re-administering the survey questionnaire with standard definitions after the interview. Respondents' interpretations were surprisingly variable, and in many cases they did not match the conceptions that researchers intended them to use. More often than one might expect, this conceptual variability was consequential, leading to answers (and, in principle, to estimates of the prevalence of smoking and related attributes in the population) that would have been different had conceptualizations been aligned; for example, fully 12% of respondents gave a different answer about having smoked 100 cigarettes in their entire life when later given a standard definition. In other cases misaligned interpretations did not lead to miscommunication, in that the differences would not have led to different survey responses. Although clarification of survey terms during the interview sometimes improved conceptual alignment, this was not guaranteed; in this corpus some needed attempts at clarification were never made, some attempts did not succeed, and some seemed to make understanding worse. The findings suggest that conceptual misalignments may be more frequent in ordinary conversation than interlocutors know, and that attempts to detect and clarify them may not always work. They also suggest that at least some unresolved misunderstandings do not matter in the sense that they do not change the outcome of the communication-in this case, the survey estimates. PMID- 29630775 TI - PR-10 proteins as potential mediators of melatonin-cytokinin cross-talk in plants: crystallographic studies of LlPR-10.2B isoform from yellow lupine. AB - : LlPR-10.2B, a Pathogenesis-related class 10 (PR-10) protein from yellow lupine (Lupinus luteus) was crystallized in complex with melatonin, an emerging important plant regulator and antioxidant. The structure reveals two molecules of melatonin bound in the internal cavity of the protein, plus a very well-defined electron density near the cavity entrance, corresponding to an unknown ligand molecule comprised of two flat rings, which is most likely a product of melatonin transformation. In a separate LlPR-10.2B co-crystallization experiment with an equimolar mixture of melatonin and trans-zeatin, which is a cytokinin phytohormone well recognized as a PR-10-binding partner, a quaternary 1 : 1 : 1 : 1 complex was formed, in which one of the melatonin-binding sites has been substituted with trans-zeatin, whereas the binding of melatonin at the second binding site and binding of the unknown ligand are undisturbed. This unusual complex, when compared with the previously described PR-10/trans-zeatin complexes and with the emerging structural information about melatonin binding by PR-10 proteins, provides intriguing insights into the role of PR-10 proteins in phytohormone regulation in plants, especially with the involvement of melatonin, and implicates the PR-10 proteins as low-affinity melatonin binders under the conditions of elevated melatonin concentration. DATABASES: Atomic coordinates and processed structure factors corresponding to the final models of the LlPR 10.2B/melatonin and LlPR-10.2B/melatonin + trans-zeatin complexes have been deposited with the Protein Data Bank (PDB) under the accession codes 5MXB and 5MXW. The corresponding raw X-ray diffraction images have been deposited in the RepOD Repository at the Interdisciplinary Centre for Mathematical and Computational Modelling (ICM) of the University of Warsaw, Poland, and are available for download with the following Digital Object Identifiers (DOI): https://doi.org/10.18150/repod.9923638 and https://doi.org/10.18150/repod.6621013. PMID- 29630777 TI - The Emotions of Abstract Words: A Distributional Semantic Analysis. AB - Recent psycholinguistic and neuroscientific research has emphasized the crucial role of emotions for abstract words, which would be grounded by affective experience, instead of a sensorimotor one. The hypothesis of affective embodiment has been proposed as an alternative to the idea that abstract words are linguistically coded and that linguistic processing plays a key role in their acquisition and processing. In this paper, we use distributional semantic models to explore the complex interplay between linguistic and affective information in the representation of abstract words. Distributional analyses on Italian norming data show that abstract words have more affective content and tend to co-occur with contexts with higher emotive values, according to affective statistical indices estimated in terms of distributional similarity with a restricted number of seed words strongly associated with a set of basic emotions. Therefore, the strong affective content of abstract words might just be an indirect byproduct of co-occurrence statistics. This is consistent with a version of representational pluralism in which concepts that are fully embodied either at the sensorimotor or at the affective level live side-by-side with concepts only indirectly embodied via their linguistic associations with other embodied words. PMID- 29630778 TI - Comment on: Comparison of hypersensitivity rates to intravenous and intramuscular PEG-asparaginase in children with acute lymphoblastic leukemia: A meta-analysis and systematic review. PMID- 29630776 TI - Causal Association of Overall Obesity and Abdominal Obesity with Type 2 Diabetes: A Mendelian Randomization Analysis. AB - OBJECTIVE: This study aimed to compare the causal effect of overall obesity and abdominal obesity on type 2 diabetes among Chinese Han individuals. METHODS: The causal relationship of BMI and waist-to-hip ratio (WHR) with the risk of glucose deterioration and glycemic traits was compared using two different genetic instruments based on 30 BMI loci and 6 WHR loci with Mendelian randomization (MR) in three prospective cohorts (n = 6,476). RESULTS: Each 1-SD genetically instrumented higher WHR was associated with a 65.7% higher risk of glucose deterioration (95% CI = 1.069-2.569, P = 0.024), whereas no significant association of BMI with glucose deterioration was observed. Furthermore, a causal relationship was found only between BMI and homeostatic model assessment beta cell function (HOMA-B) (beta = 0.143, P = 0.001), and there was a nominal association with Stumvoll second-phase insulin secretion traits (beta = 0.074, P = 0.022). The significance level did not persist in sensitivity analyses, except in the causal estimate of WHR on the Gutt index in MR-Egger (beta = -0.379, P = 0.022) and the causal estimate of BMI on homeostatic model assessment beta-cell function in weighted median MR (beta = 0.128, P = 0.017). CONCLUSIONS: The data from this study support the potential causal relationship between abdominal obesity and hyperglycemia, which may be driven by aggravated insulin resistance, in contrast with the potential causal relationship between overall obesity and insulin secretion. PMID- 29630779 TI - Scrambler therapy efficacy and safety for neuropathic pain correlated with chemotherapy-induced peripheral neuropathy in adolescents: A preliminary study. AB - PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a common side effect of chemotherapy, in need of effective treatment. Preliminary data support the efficacy of scrambler therapy (ST), a noninvasive cutaneous electrostimulation device, in adults with CIPN. We test the efficacy, safety, and durability of ST for neuropathic pain in adolescents with CIPN. PATIENTS AND METHODS: We studied nine pediatric patients with cancer and CIPN who received ST for pain control. Each patient received 45-min daily sessions for 10 consecutive days as a first step, but some of them required additional treatment. RESULTS: Pain significantly improved comparing Numeric Rate Scale after 10 days of ST (9.22 +/- 0.83 vs. 2.33 +/- 2.34; P < 0.001) and at the end of the optimized cycle (EOC) (9.22 +/- 0.83 vs. 0.11 +/- 0.33, P < 0.001). The improvement in quality of life was significantly reached on pain interference with general activity (8.67 +/- 1.66 vs. 3.33 +/- 2.12, P < 0.0001), mood (8.33 +/- 3.32 vs. 2.78 +/- 2.82, P < 0.0005), walking ability (10.00 vs. 2.78 +/- 1.22, P < 0.0001), sleep (7.56 +/- 2.24 vs. 2.67 +/- 1.41, P < 0.001), and relations with people (7.89 +/- 2.03 vs. 2.11 +/- 2.03, P < 0.0002; Lansky score 26.7 +/- 13.2 vs. 10 days of ST 57.8 +/- 13.9, P < 0.001; 26.7 +/- 13.2 vs. EOC 71.1 +/- 16.2, P < 0.001). CONCLUSION: Based on these preliminary data, ST could be a good choice for adolescents with CIPN for whom pain control is difficult. ST caused total relief or dramatic reduction in CIPN pain and an improvement in quality of life, durable in follow-up. It caused no detected side effects, and can be retrained successfully. Further larger studies should be performed to confirm our promising preliminary data in pediatric patients with cancer. PMID- 29630780 TI - 4-(4-Hydroxyphenyl)-2-butanol (rhododendrol)-induced melanocyte cytotoxicity is enhanced by UVB exposure through generation of oxidative stress. AB - 4-(4-Hydroxyphenyl)-2-butanol (rhododendrol, RD), a skin-whitening agent, was reported to cause skin depigmentation in some users, which is attributed to its cytotoxicity to melanocyte. It was reported that cytotoxicity to melanocyte is possibly mediated by oxidative stress in a tyrosinase activity-dependent manner. We examined the effect of UV radiation (UVR) on RD-induced melanocyte cytotoxicity as an additional aggravating factor. UVR enhanced RD-induced cytotoxicity in normal human epidermal melanocytes (NHEMs) via the induction of endoplasmic reticulum (ER) stress. Increased generation of intracellular reactive oxygen species (ROS) was detected. Pretreatment with N-acetyl cysteine (NAC), antioxidant and precursor of glutathione significantly attenuated ER stress induced cytotoxicity in NHEMs treated with RD and UVR. Increase in cysteinyl-RD catechol and RD-pheomelanin in NHEMs treated with RD and UVR suggested that, after UVR excitation, RD or RD metabolites are potent ROS-generating substances and that the tendency to produce RD-pheomelanin during melanogenesis amplifies ROS generation in melanocytes. Our results help to elucidate the development mechanisms of RD-induced leukoderma and provide information for innovation of safe skin-whitening compounds. PMID- 29630781 TI - In this Issue: Volume 109, Issue 4, April 2018. PMID- 29630782 TI - Acute toxicity of craniospinal irradiation with volumetric-modulated arc therapy in children with solid tumors. AB - BACKGROUND: Craniospinal irradiation (CSI) is an important part of curative radiation therapy (RT) for many types of pediatric brain or solid tumors. After conventional CSI, long term survivors may experience sequelae due to unintended dose to normal tissue. Volumetric modulated arc therapy (VMAT) CSI reduces off target doses at the cost of greater complexity and error risk, and we describe our initial experience in a group of pediatric patients with solid tumors presenting with disseminated or recurrent disease. PROCEDURE: Pediatric patients with brain tumors were identified at Children's Hospital Los Angeles from 2013 to 2015. Clinical characteristics, acute toxicity, and radiotherapy data were abstracted from their medical records. We identified 19 patients who received VMAT CSI. Quality assurance was performed with a cylindrical detector array and ion chamber measurements at the arc junctions. RESULTS: Patients had medulloblastoma or supratentorial primitive neuro-ectodermal tumor (n = 14, 11 high risk), germ cell tumors (two), relapsed neuroblastoma (two), and atypical teratoid/rhabdoid tumor (one). The most common acute toxicity was hematologic, including leukopenia (11% grade [Gr] 2, 26% Gr 3, and 63% Gr 4), anemia (89% Gr 2), and thrombocytopenia (16% Gr 1-2, 26% Gr 3, and 37% Gr 4). Despite leukopenia, we encountered only two Gr 3 infections (urinary tract and lung). The majority required blood products (89% red blood cells and 68% platelets). Weight loss was also common (47% Gr 1 and 26% Gr 2). CONCLUSIONS: VMAT CSI, along with chemotherapy and anesthesia, is feasible with supportive care. Daily image-guided RT improves accuracy and reduces the risk of spinal cord overdose without increasing treatment time. Further research is needed to determine whether reducing doses to organs, such as thyroid, heart, or hippocampus, offsets the risk of increased volume of low-dose irradiation. PMID- 29630783 TI - Malignant tumors misdiagnosed as benign vascular anomalies. AB - BACKGROUND: Malignant soft tissue tumors are rare and difficult to diagnose in children. These can initially be misdiagnosed as benign vascular anomalies. Management of these two conditions differs drastically and delay in diagnosis may impact overall survival. PURPOSE: To predict qualities that may increase the index of suspicion for malignancy in patients presenting with lesions initially considered vascular anomalies. METHODS: A retrospective review at a quaternary hemangioma and vascular malformation center of all patients who presented between 2008 and 2016 with an initial diagnosis of a benign vascular malformation, which on further work-up was noted to be a malignancy. Demographics, clinical presentation, and laboratory and radiologic studies were analyzed. RESULTS: Eleven patients were identified; the median age at presentation was 2 months (0 24years). Ten out of 11 lesions had rapid growth, which prompted biopsy. Pain was an inconsistent finding (36%). Tumor markers were positive in only one case. Median follow-up was 3 years (range 6 months to 8 years); seven patients have no evidence of disease, two patients are under treatment for progression or relapse of disease, and two patients have died. CONCLUSION: Although malignant vascular tumors are rare, a clear index of suspicion needs to be maintained particularly with rapid growth or increasing symptoms. Differentiation of malignant tumor from benign lesions relies on the comprehensive evaluation of clinical manifestations, evolution of the lesion, and abnormal clinical behavior, by an experienced multidisciplinary vascular malformation team. There should be a low threshold for biopsy of unclear vascular lesions. PMID- 29630785 TI - Erratum. PMID- 29630784 TI - Proton therapy for central nervous system tumors in children. AB - Proton therapy is a form of particle therapy with physical properties that provide a superior dose distribution compared to photons. The ability to spare healthy, developing tissues from low dose radiation with proton therapy is well known. The capability to decrease radiation exposure for children has been lauded as an important advance in pediatric cancer care, particularly for central nervous system (CNS) tumors. Favorable clinical outcomes have been reported and justify the increased cost and burden of this therapy. In this review, we summarize the current literature for proton therapy for pediatric CNS malignancies, with a focus on clinical outcomes to date. PMID- 29630786 TI - Exploring the use of economic evidence to inform investment in disease prevention - a qualitative study. AB - OBJECTIVE: In the context of growing financial pressures on health budgets, cost effective prevention strategies are needed to address the burden from non communicable disease in Australia. We explored how decision makers use economic evidence to inform such investment and how such evidence generated can more effectively meet the needs of end users. METHODS: Thematic analysis of in-depth interviews with 15 high level stakeholders (Treasury, state health departments and the insurance industry), supplemented by documentary analysis. RESULTS: Types of prevention approaches and economic evidence relevant to decision makers differed by organisational perspective. Capacity building in understanding economic evaluations and research evidence that addresses the differing criteria for investment used by different organisations is needed. The task of determining investment priorities in disease prevention comes with significant challenges including ideological barriers, delayed outcome measures, and implementation uncertainties. Conclusions and Implications for public health: Promoting the greater use of economic evidence in prevention requires more work on two fronts: tailoring the methods used by economists to better match the organisational imperatives of end users; and promoting greater consideration of broader societal and health sector perspectives among end users. This will require significant infrastructure development, monitoring and evaluation, stronger national leadership and a greater emphasis on evidence coproduction. PMID- 29630787 TI - Erosion protection efficacy of a 0.454% stannous fluoride dentifrice versus an arginine-containing dentifrice. AB - PURPOSE: To assess the anti-erosion effects of a 0.454% stannous fluoride dentifrice versus a marketed dentifrice in an in situ clinical study. METHODS: This was a double-blind, randomized and controlled, two-treatment, four-period crossover clinical study involving healthy adults. Each study period was 10 days. Subjects were randomized to one of two dentifrice products each period: an experimental 0.454% stannous fluoride dentifrice (1,100 ppm fluoride) or a marketed 1.5% arginine-containing dentifrice (Colgate Maximum Cavity Protection, 1,450 ppm fluoride). Subjects wore an intra-oral appliance fitted with two polished human enamel samples for 6 hours per day, swishing with the assigned dentifrice slurry twice a day in addition to sipping and swishing with 250 ml of orange juice for 10 minutes (in increments of 25 ml each minute) four times each day. Contact profilometry was used to measure surface loss of tooth enamel over the course of the study. Two measurements for each sample were taken at baseline and Day 10. RESULTS: 35 subjects were randomized to treatment and 31 completed the study (mean age = 40 years). At Day 10, enamel loss means were 0.128 um for the stannous fluoride dentifrice and 1.377 um for the arginine-containing dentifrice, respectively (P< 0.001). This represents 90.7% less enamel loss for the stannous fluoride dentifrice. Both products were well tolerated. CLINICAL SIGNIFICANCE: The 0.454% stannous fluoride dentifrice demonstrated significantly greater protection to human enamel against erosive acid challenges relative to the marketed 1.5% arginine-containing dentifrice in this in situ clinical study. PMID- 29630788 TI - Effect of pulsed ultrasound toothbrush on Streptococcus mutans biofilm removal. AB - PURPOSE: To evaluate the effect of pulsed ultrasound toothbrush on the removal of biofilm formed by Streptococcus mutans (S. mutans). METHODS: S. mutans biofilm grown on apatite pellet was destructed with four different sonic action toothbrushes: 1) pulsed ultrasound with sonic vibration (PUV); 2) continuous ultrasound with sonic vibration (CUV); 3) sonic vibration only (SV); and 4) no ultrasound nor sonic vibration (control). After 3 minutes of noncontact brushing, the amount of water-insoluble glucan was measured, and the residual biofilm was observed by scanning electron microscopy. RESULTS: PUV group revealed the smallest amount of the residual water-insoluble glucans (32 +/- 19%), followed by the CUV group (54 +/- 12%) and the SV group (64 +/- 13%). The PUV group showed a significantly lower amount of the residual water-insoluble glucan than the SV group, while no significant difference was found between SV and CUV. The bacterial adherence and aggregation notably decreased in the PUV group, compared to the remaining three groups. CLINICAL SIGNIFICANCE: The sonic vibration with pulsed ultrasound showed more reduction of the biofilm compared to the control and the sonic vibration with and without continuous ultrasound. Thus, pulsed ultrasound action may be beneficial for biofilm removal of interproximal regions. PMID- 29630789 TI - An exploratory study to investigate stain build-up with long term use of a stannous fluoride dentifrice. AB - PURPOSE: To monitor extrinsic stain formation over 24 weeks with twice-daily use of an anhydrous 0.454% SnF2 dentifrice containing 5% sodium tripolyphosphate (STP) ('Test'), compared to a standard fluoride dentifrice (0.76% fluoride as sodium monofluorophosphate [SMFP?) ('Comparator') following a professional prophylaxis. METHODS: Primary efficacy variables were between-treatment differences in extrinsic dental stain of anterior teeth after 4, 8, 12, and 24 weeks' use using mean area and intensity scores of the MacPherson modification of the Lobene stain index (MLSI), and to monitor oral tolerability. RESULTS: Overall, 214 subjects were randomized to treatment. The Test dentifrice group demonstrated statistically significantly less stain compared with the Comparator at each timepoint for all outcome variables (MLSI - Area * Intensity, Area only, and Intensity only) with the exception of MLSI (Area * Intensity) at Week 12. Products were generally well tolerated with 26 treatment-related adverse events (TRAEs) reported (10 with Test, 16 with Comparator). Five subjects withdrew from the 24-week study due to TRAEs, three in the Test group, two in the Comparator group. Statistically significantly less anterior tooth staining was observed with up to 24 weeks twice-daily brushing with a 0.454% SnF2/5% STP anhydrous dentifrice compared to a marketed fluoride dentifrice with 0.76% SMFP. CLINICAL SIGNIFICANCE: Long term use of a SnF2/STP dentifrice demonstrated minimal stain build-up after 24 weeks, twice-daily use; products were generally well-tolerated. PMID- 29630790 TI - Effect of ultrasonic, sonic and rotating-oscillating powered toothbrushing systems on surface roughness and wear of white spot lesions and sound enamel: An in vitro study. AB - PURPOSE: To evaluate the effect of ultrasonic, sonic and rotating-oscillating powered toothbrushing systems on surface roughness and wear of white spot lesions and sound enamel. METHODS: 40 tooth segments obtained from third molar crowns had the enamel surface divided into thirds, one of which was not subjected to toothbrushing. In the other two thirds, sound enamel and enamel with artificially induced white spot lesions were randomly assigned to four groups (n=10) : UT: ultrasonic toothbrush (Emmi-dental); ST1: sonic toothbrush (Colgate ProClinical Omron); ST2: sonic toothbrush (Sonicare Philips); and ROT: rotating-oscillating toothbrush (control) (Oral-B Professional Care Triumph 5000 with SmartGuide). The specimens were analyzed by confocal laser microscopy for surface roughness and wear. Data were analyzed statistically by paired t-tests, Kruskal-Wallis, two-way ANOVA and Tukey's post-test (alpha= 0.05). RESULTS: The different powered toothbrushing systems did not cause a significant increase in the surface roughness of sound enamel (P> 0.05). In the ROT group, the roughness of white spot lesion surface increased significantly after toothbrushing and differed from the UT group (P< 0.05). In the ROT group, brushing promoted a significantly greater wear of white spot lesion compared with sound enamel, and this group differed significantly from the ST1 group (P< 0.05). None of the powered toothbrushing systems (ultrasonic, sonic and rotating-oscillating) caused significant alterations on sound dental enamel. However, conventional rotating oscillating toothbrushing on enamel with white spot lesion increased surface roughness and wear. CLINICAL SIGNIFICANCE: None of the powered toothbrushing systems (ultrasonic, sonic and rotating-oscillating) tested caused significant alterations on sound dental enamel. However, conventional rotating-oscillating toothbrushing on enamel with white spot lesion increased surface roughness and wear. PMID- 29630791 TI - A 12-week randomized clinical study investigating the anti-gingivitis efficacy of a 0.454% w/w stannous fluoride dentifrice. AB - PURPOSE: To evaluate and compare gingival health, as measured by a bleeding index (BI), a modified gingival index (MGI), number of bleeding sites, and blood in expectorate following twice daily use of a non-aqueous 0.454% weight/weight (w/w) stannous fluoride dentifrice ('Test dentifrice') compared to a sodium monofluorophosphate (SMFP) dentifrice (' Negative Control') over 12 weeks, in subjects with moderate gingivitis and gingival bleeding following tooth brushing. METHODS: This was a single-center, examiner-blinded, randomized, stratified, two treatment arm, parallel group, 12-week clinical study in healthy adult volunteers with moderate gingivitis who demonstrated gingival bleeding following tooth brushing. Subjects were assessed at baseline for MGI, visible blood in dentifrice expectorate and BI. Following randomization, eligible subjects underwent a thorough dental prophylaxis and flossing. After 4 and 12 weeks of twice daily brushing with their allocated treatment, subjects returned to the site for MGI, visible blood in dentifrice expectorate, and BI assessments. RESULTS: Of 317 screened subjects, 253 were randomized, and 238 completed the study. Statistically significant differences between treatments were observed in favor of the Test dentifrice compared to the Negative Control dentifrice in terms of gingival bleeding (number of bleeding sites and bleeding index), and visual signs of gingival inflammation (MGI) (P< 0.0001 at Weeks 4 and 12 for all). The visual assessment of the level of blood in expectorate following brushing demonstrated large reductions from baseline, however no significant difference between treatments was observed. Treatments were generally well tolerated. CLINICAL SIGNIFICANCE: Use of a dentifrice containing 0.454% w/w stannous fluoride led to significantly greater control of gingivitis (gingival bleeding and visual signs of gingival inflammation) compared to a SMFP dentifrice over a 12-week period. This study was conducted in subjects with moderate gingivitis and in a population represented by individuals who experience gingival bleeding on brushing, and is therefore considered representative of individuals who may opt for treatment therapies in the form of a daily use toothpaste. PMID- 29630792 TI - Physical and biological properties of a newly developed calcium silicate-based self-adhesive cement. AB - PURPOSE: To evaluate the physical and biological properties of a novel calcium silicate-based self-adhesive resin cement (TheraCem) by comparison with a traditional self-adhesive resin cement (UniCem 2) and a resin-modified glass ionomer cement (FujiCEM 2). METHODS: pH of the cements was measured with moist pH strips. Antimicrobial activity was evaluated by a modified disk diffusion assay. Calcium release of TheraCem in water or lactic acid was measured with an ion selective pH meter for 56 days. Shear bond strength of the cements to zirconia after incubation in water or lactic acid for 7 days was assayed according to ISO 29022:2013, and the fractured surface of zirconia and cement were observed with a stereomicroscope and a scanning electron microscope, respectively. RESULTS: TheraCem started with an acidic pH value of 4.0 and stabilized at pH 9.0, whereas the other two cements remained acidic. TheraCem and FujiCEM 2 displayed antimicrobial activity, but not UniCem 2. Calcium release was observed from TheraCem, which was higher in lactic acid than in deionized water. TheraCem showed highest shear bond strength to zirconia among the three cements, which was not impaired by incubation in lactic acid. In contrast, bond strength of UniCem 2 and FujiCEM 2 decreased significantly under the acidic condition. Consistently, scanning electron micrographs demonstrated marginal degradation of UniCem 2 and FujiCEM 2, but not TheraCem, samples in the acid. The results suggest that TheraCem had features that would help reduce or prevent secondary caries. CLINICAL SIGNIFICANCE: The new calcium silicate-based self-adhesive resin cement, TheraCem, had an alkaline pH and could be desirable in clinical applications with advantages such as bond strength and stability, antimicrobial activity, as well as calcium release. PMID- 29630793 TI - Effects of various polishing techniques and thermal cycling on the surface roughness and color change of polymer-based CAD/CAM materials. AB - PURPOSE: To investigate and compare the effects of several polishing systems and thermal cycling on the surface roughness and color change of various polymer based CAD/CAM materials. METHODS: Bar-shaped specimens (GC CeraSmart, CS; Lava Ultimate, LU and Vita Enamic, VE) were prepared. All specimens were polished with SiC papers. The specimens in Group A served as control and no additional surface polishing was applied. Final polishing was performed using diamond polishing paste (Diapolisher Paste) in Group B. In Group C, aluminum oxide abrasive discs (Sof-Lex XT Pop on) were used. Group D was polished with diamond impregnated spiral polishing system (EVE Diacomp Plus Twist). In Group E, polishing was done with rubber-based silicon abrasives (Polydentia). Thereafter, the specimens were submitted to thermal cycling. The surface roughness and color measurements were performed. Kruskal-Wallis and the Mann-Whitney U tests were applied for the evaluation of DeltaE00 data. Ra data were evaluated using three-way ANOVA. Pearson's correlation between Ra and DeltaE00 was further investigated. RESULTS: Neither the CAD/CAM materials nor thermal cycling affected the Ra data (P> 0.05). In contrast, significant difference was found among the polishing methods (P< 0.001). On the other hand, VE showed the highest color change whereas LU showed the lowest (P< 0.05). Additionally, the specimens in Group D exhibited significantly higher color change than other tested groups (P< 0.05). A moderate positive correlation was seen between Ra and DeltaE00 data of LU (rho = 0.390, P= 0.01). CLINICAL SIGNIFICANCE: The diamond impregnated two-stage polishing procedure may not be an appropriate method for the tested CAD/CAM materials, as it resulted in the highest color change. On the other hand, all tested materials exhibited visually perceptible, but clinically acceptable color changes following the different polishing techniques. Additionally, diamond paste polishing could be a clinically acceptable procedure in terms of surface roughness. PMID- 29630795 TI - Fluoride activity of antibacterial ammonium hexafluorosilicate solution for the prevention of dentin caries. AB - PURPOSE: To evaluate the acid resistance of various antibacterial ammonium hexafluorosilicate (SiF) solutions. METHODS: Antibacterial SiF solutions were prepared with the addition of chlorhexidine (CHX), cetylpyridinium chloride (CPC), isopropyl methylphenol (IPMP), or epigallocatechin gallate (EGCG). Hydroxyapatite pellets were treated with SiF solution with or without antibacterial agents for 3 minutes. The demineralized depth of hydroxyapatite pellets after SiF treatment was measured using a surface roughness analyzer. RESULTS: SiF+CPC solution showed equivalent acid resistance to SiF and AgF treatment. In contrast, the original acid resistance activity of SiF solution was diminished by the addition of other antibacterial agents (CHX, IPMP and EGCG). SiF with the addition of CPC was the most effective for reducing the demineralized depth, showing the same levels as those of SiF and AgF. CLINICAL SIGNIFICANCE: The addition of CPC to the SiF solution did not reduce its fluoride activity, indicating that it may be useful for the prevention of dental caries. SiF with added antibacterial agents may have the potential to prevent dental caries. PMID- 29630794 TI - Retention of CAD/CAM resin composite crowns following different bonding protocols. AB - PURPOSE: To evaluate the effect of different surface treatments and primers with a CAD/CAM resin composite block on its crown retention. METHODS: 120 human molars were prepared with a 24 degrees total convergence angle, 1.5 mm height, and axial walls in dentin. Surface area was measured by digital microscopy. Crowns were machined from CAD/CAM resin composite blocks. Teeth were randomly allocated to 12 groups (n= 10) based on possible combinations of three surface treatments: [Control, Alumina air abrasion (50-um Al2O3 at 0.28 MPa) ]; 5% hydrofluoric acid etch (20-second scrub); silane application (with or without Kerr Silane primer); and adhesive application (with or without Optibond XTR Adhesive). Optibond XTR Adhesive was applied to the tooth preparations and crowns were bonded with MaxCem Elite cement. Crowns were fatigued for 100,000 cycles at 100 N in water and debonded in tension (1 mm/minute). Crown retention strength (maximum load/surface area) values were analyzed using a three-way ANOVA with Tukey's post-hoc tests (alpha= 0.05). RESULTS: Surface treatment, silane and adhesive applications independently affect retention force (P< 0.05). All interactions were not significant (P> 0.05). Alumina airborne abrasion surface treatment, silane and adhesive applications all improve retention strength. Therefore, CAD/CAM resin composite crowns can withstand debonding while undergoing mechanical fatigue. Although all forms of surface treatment and primer application improve bond strength, the highest mean retention strength values were recorded when the crowns were alumina particle abraded and coated with adhesive (with or without silane). CLINICAL SIGNIFICANCE: In order to improve the bonding of resin composite crowns, application of alumina airborne particle abrasion and a coat of adhesive (proceeded by an optional coat of silane) is recommended. If hydrofluoric acid is utilized, the crowns should be treated with a coat of silane followed by adhesive application. PMID- 29630796 TI - Sealing of restorations with marginal defects does not affect their longevity. AB - PURPOSE: To evaluate sealed amalgam and resin-based composite restorations after 12 years to determine whether sealing minor defects (micro-repairs) enhanced the longevity of restorations. METHODS: 34 subjects aged 18-80 were recruited. This sample group underwent 137 restorations, including 51 resin-based composite (RC) and 86 amalgam (AM) restorations. Existing restorations with localized, marginal defects were assigned to one of two groups: (a) the Sealing group (n=48, 27 AM; 21 RC) or (b) the Control group (n=89, 59 AM; 30 RC). The quality of each restoration was scored according to the modified USPHS criteria by two examiners at the beginning of the study and after 1-5, 10, and 12 years. Kaplan Meier survival curves were created and a Cox regression was applied to investigate survival variables. Mantel Cox, Wilcoxon, and Friedman tests were performed for comparisons within groups. RESULTS: After 12 years, no statistically significant differences were observed for the variables "restorative material" (P= 0.538) or "sealing yes/no" (P= 0.136) with respect to the longevity of the restorations. All groups behaved similarly with regard to marginal adaptation, secondary caries, and tooth sensitivity (P>= 0.05). Cumulatively, after a 12-year observation period, sealing minor restoration defects did not affect the longevity of the restorations. CLINICAL SIGNIFICANCE: Sealing minor marginal defects for resin composites or amalgam restorations did not affect their longevity. This intervention may be considered over-treatment for patients with low-to-medium risks for developing dental caries. PMID- 29630797 TI - Effects of cigarette smoke on color change of resin composites. AB - PURPOSE: To evaluate the color change caused by cigarette smoke in both microhybrid and nanohybrid resin composites of three different manufacturers (Z100, Z350, Charisma, and Opallis). METHODS: Samples of microhybrid (n= 40) and nanohybrid (n= 40) resin composites (A2) were prepared for each resin brand, totaling 240 samples. The samples were divided into subgroups: Control: control group without exposure; C5: five cigarettes, 25 minutes/ exposure; C10: 10 cigarettes, 50 minutes/ exposure; C20: 20 cigarettes, 100 minutes/ exposure. The samples were then photographed and color change was measured by a computerized image analysis. L*a*b* values were obtained and color change was calculated. The Kolmogorov-Smirnov test was used to examine data normality; color change associated with an individual brand and the number of smoked cigarettes was analyzed with differentiation across the groups by the Tukey test (P<= 0.05). The student t-test (P<= 0.05) was used for the differentiation of inorganic fillers. RESULTS: The color change was significant between five and 10 cigarettes (P= 0.01), between five and 20 cigarettes (P= 0.000), and not significant between 10 and 20 cigarettes (P= 0.585). Charisma showed a significant color change when compared to Opallis (P= 0.008) and Z100 and Z350 (P= 0.000). CLINICAL SIGNIFICANCE: Different brands, inorganic fillers, and number of smoked cigarettes are variables that influence color change of resin composites. Nanohybrid resins Z100, Z350, and Opallis exhibited less color variation when they were exposed to cigarette smoke. PMID- 29630798 TI - Improved marginal adaptation of composite restorations by using different placement and light polymerization techniques. AB - PURPOSE: To verify the influence of placement and polymerization technique on the gap width between dentin and composite restoration. METHODS: Standardized cylindrical cavities (3 mm in diameter, 2 mm deep) with all margins in dentin were prepared on buccal and oral surfaces of 30 extracted human third molars. With regard to the different resin composite filling techniques used, the samples were randomly divided into three groups (n=20): bulk; incremental; pin. Each group was further subdivided into subgroups based on different light polymerization techniques): continuous (40 seconds); discontinuous (2 seconds of activation, followed by 10 seconds of dark interval, then light polymerization continued for 38 seconds). After finishing procedures, impressions were made using polyvinylsiloxane, and epoxy resin replicas were obtained and prepared for scanning electron microscopy. The percentage of the marginal gaps in relation to the whole margin was recorded and statistically analyzed (P)<= 0.05). RESULTS: Marginal adaptation of composite restorations placed into the dentin cavities using pin and discontinuously light polymerized presented significantly better results than other two tested groups polymerized in the same manner. CLINICAL SIGNIFICANCE: The proposed modified incremental placement technique with a transparent glass pin reduces marginal leakage at the interface between composite restoration and dentin; leakage which can jeopardize the longevity of the restoration. PMID- 29630799 TI - In-office bleaching for the remineralization of enamel lesions filled with organic components of red wine. AB - PURPOSE: To investigate the effects of in-office bleaching on the remineralization of enamel lesions filled with organic components of red wine. METHODS: Enamel specimens were exposed to 0.1% NaF solution for 1 minute immersed in red wine for 5 days at 37 degrees C, and subjected to in-office bleaching followed by remineralization in 1.5 mM CaCl2, 0.9 mM KH2PO4, 130 mM KCl, 20 mM HEPES, pH 7.0, at 37 degrees C for 28 days. The presence of organic substances on the enamel surface was detected by Raman spectroscopy. The specimens were also subjected to transverse microradiography (TMR). RESULTS: Raman spectroscopy of baseline lesions showed characteristic peaks at 1,300-1,600 cm-1 which disappeared in bleached specimens. TMR showed that red wine formed subsurface lesions with surface content at approximately 22 mineral volume %. The integrated mineral loss (IML) was significantly lower in unbleached remineralized specimens than at baseline (P< 0.05). The IML of bleached remineralized specimens was lower than that of unbleached specimens, although not significantly (P> 0.05). Lesion depth was significantly lower in the bleached than in the unbleached group (P< 0.05). CLINICAL SIGNIFICANCE: In-office bleaching can enhance the remineralization of enamel lesions filled with organic components of red wine. PMID- 29630800 TI - A 24-week randomized clinical study investigating the anti-gingivitis efficacy of a 0.454% w%#47;w stannous fluoride dentifrice. AB - PURPOSE: To evaluate and compare gingival health, as measured by a bleeding index (BI), a modified gingival index (MGI), a dental plaque index (PI), and number of bleeding sites following twice daily use of an anhydrous 0.454% weight/weight (w/w) stannous fluoride dentifrice (Test Dentifrice) compared to a sodium monofluorophosphate (SMFP) dentifrice (Negative Control) over 24 weeks. METHODS: This was a single-center, examiner-blinded, randomized [by gender and baseline mean MGI score (Low <= 2.00/High > 2.00)], stratified, two-treatment arm, parallel group, 24-week clinical study in healthy adult volunteers with moderate gingivitis. At baseline, after abstaining from toothbrushing overnight, subjects underwent BI, MGI and PI assessments. Following randomization, eligible subjects underwent a thorough dental prophylaxis and flossing. After 12 and 24 weeks of twice daily brushing with their allocated treatment, subjects returned to the site with overnight plaque (having abstained from oral hygiene procedures for at least 8 hours) for BI, MGI and PI assessments. RESULTS: Of 109 screened subjects, 104 were randomized and 98 completed the study. Statistically significant differences between treatments were observed in favor of the Test Dentifrice compared to the Negative Control dentifrice for all outcome measures including not only BI, MGI and PI indices but also number of bleeding sites (P< 0.0001 at Week 12 and Week 24 for all). Data observation showed that the percentage of sites that decreased was more, and those that increased was less, with the Test Dentifrice than with the Negative Control dentifrice at both 12 and 24 weeks. Treatments were generally well tolerated. CLINICAL SIGNIFICANCE: Use of a dentifrice containing 0.454% w/w stannous fluoride led to significantly greater control of gingivitis (gingival bleeding and visual signs of gingival inflammation) and plaque compared to a SMFP dentifrice over a 24-week period. PMID- 29630801 TI - Influence of surface coating sealer on resin composite water absorption and discoloration: An in vitro study. AB - PURPOSE: To evaluate the in vitro efficacy of surface coating sealer (SCS) in reducing the amount of water absorption and stain formation in resin composites. METHODS: To evaluate the amount of water sorption, 40 stainless steel round molds (n=10 per composite) were filled with Filtek Supreme XTE; Venus Diamond; Clearfil Majesty ES-2; Gradia Direct Anterior. Groups were further divided into two subgroups (n=5) according to the presence/absence of SCS (Easy Glaze). Their masses were measured at baseline and reweighed at 1, 4, 12, and 20 weeks. For staining evaluation, 48 resin composite discs, 2 mm-thick, were obtained with the same composites and SCS was applied on a single surface of each sample. After baseline color assessment, samples were immersed in vials containing 5 mL of six different staining solutions. Color evaluation was performed again after 1, 4, 12, and 20 weeks. Three-way ANOVA was performed to evaluate differences in weight gain and color changes (P< 0.05). RESULTS: A significant protective action of SCS (P< 0.001), but not of the composites (P= 0.366) was found. Differences in weight and color change were not influenced by the resin composite, but only by the presence of the coating on the surface of the samples. SCS are well-established materials for polishing and protecting composite restorations from water sorption and color changes. Different staining solutions can still produce different effects on resin composite. CLINICAL SIGNIFICANCE: Surface coating sealers are able to reduce water uptake and discoloration from resin composites, thus leading to less degradation of composite restorations over time. PMID- 29630802 TI - Impact of dentifrice abrasivity and remineralization time on erosive tooth wear in vitro. AB - PURPOSE: To investigate the in vitro effects of simulated dentifrice slurry abrasivity (L-low, M-medium and H-high) and remineralization time (0, 30, 60 and 120 minutes) on erosive tooth wear. METHODS: Enamel and root dentin specimens were prepared from bovine incisors (n= 8) and submitted to a cycling protocol including erosion, remineralization at the test times, and brushing with each of the tested slurries, for 5 days. Dental surface loss (SL) was determined by optical profilometry. Data was analyzed using mixed-model ANOVA and Fisher's PLSD tests (alpha= 0.05). RESULTS: SL generally increased along with the increase in slurry abrasive level, with significance dependent upon the specific substrate and remineralization times. H showed the highest SL on both enamel and dentin; remineralization for 30 minutes reduced SL significantly (P< 0.05), but only for enamel. M showed intermediate SL values, with remineralization benefit clearly seen only after 120 minutes of remineralization (P< 0.05). L caused the least SL for both enamel and dentin, which was further reduced after remineralization for 120 and 30 minutes, respectively (both P< 0.05). Overall, root dentin had significantly higher SL than enamel. Less abrasive dentifrice slurries were able to reduce toothbrushing abrasion on both enamel and root dentin. This protection was enhanced by remineralization for all abrasive levels on enamel, but only for L on root dentin. CLINICAL SIGNIFICANCE: High-risk erosion patients should avoid highly abrasive toothpastes, as remineralization can only partially compensate for their deleterious effects on eroded dental surfaces. Lower abrasive toothpastes are recommended. PMID- 29630803 TI - Influence of dentin and enamel on the fracture resistance of restorations at several thicknesses. AB - PURPOSE: To investigate the effect of substrate and thickness on the fracture resistance of bonded dental restorative materials. METHODS: Cylindrical restorations (d = 4.0 mm) of resin composites Filtek Supreme XTE, Clearfil AP-X, Lava Ultimate and glass-ceramic IPS e.max CAD were fabricated at thicknesses of 0.5 mm, 1.0 mm and 2.0 mm respectively (n = 10 per group) and adhesively bonded to bovine enamel or dentin. The load to failure (LtF in N) of all specimens was determined in a universal testing machine and two one-way ANOVAs with a post hoc LSD tests and separate independent samples t-tests, performed at a significance level of 5%. RESULTS: At 0.5 and 1.0 mm, direct resin composites bonded to dentin showed a higher LtF than when bonded to enamel, while the indirect materials showed reversed results (P< 0.05). At 2.0 mm there was no difference except for LU. A direct relationship between LtF and increasing thicknesses on enamel was found, while on dentin the LtF of direct resin composite restorations was less dependent on the thickness. CLINICAL SIGNIFICANCE: For restorations up to 1 mm thickness, a substrate with a matching elastic modulus has a positive effect on the fracture resistance of glass-ceramics and resin composite restorations. When bonded to enamel, restoration thickness plays an important role in the fracture resistance. When bonded to dentin, thickness only affects the fracture resistance of indirect restoratives. PMID- 29630804 TI - Fracture resistance of three different all-ceramic crowns: In vitro study. AB - PURPOSE: To evaluate the fracture resistance and failure mode of three different all-ceramic crowns; CEREC Bloc, IPS e.Max Press and Cercon in a simulated clinical situation. METHODS: 30 extracted maxillary premolars were prepared and randomly assigned to three groups equally according to the type of crown used. The first was the CEREC group: monolithic feldspathic crowns (CEREC Blocs). The second was the E.Max group: monolithic lithium disilicate crowns (IPS e.Max Press). The third group was the Cercon group: bilayered partially stabilized zirconia crowns (Cercon). All crowns were cemented using dual-cured resin cement (ParaCore). The specimens were then subjected to thermocycling (5-55 degrees C/500 cycles) and loaded to failure at an angle of 45 degrees to the occlusal surface of the crown. Failure data was statistically analyzed using one-way ANOVA and Tukey's HSD post hoc test at alpha= 0.05. Fractographic analysis was performed to determine the fracture modes of the failed specimens. RESULTS: The mean fracture values for CEREC, E.Max and Cercon groups were 387+/- 60 N, 452 +/- 86 N, and 540 +/- 171 N, respectively. Significant differences were found between CEREC and Cercon groups (P< 0.05). Catastrophic fracture within the ceramic crown was the major failure mode of the CEREC group. For E.Max and Cercon groups, the major failure mode was exhibiting severe tooth fracture while the ceramic crown remained intact. CLINICAL SIGNIFICANCE: CEREC, IPS e.Max Press and Cercon crowns are clinically applicable as they exceeded the normal masticatory forces. However, the CEREC crown is preferred as it maintains the integrity of the natural abutment. PMID- 29630805 TI - Effect of surface characteristics of soft liners and tissue conditioners and saliva on the adhesion and biofilm formation. AB - PURPOSE: To investigate the influence of surface characteristics and saliva on the adhesion and biofilm formation of Candida glabrata and methicillin-resistant Staphylococcus aureus (MRSA) to soft liners and tissue conditioners. METHODS: For each material (Ufi Gel P - UG; Sofreliner S - SS; Trusoft - TR; Coe Comfort - CC; Softone - ST), specimens were prepared and roughness (Ra), hydrophobicity (water contact angles-WCA) and surface free energy (SFE) were measured. Surface morphology was also analyzed using scanning electron microscopy (SEM). Specimens were incubated in C. glabrata or MRSA suspensions for 90 minutes (adhesion) or 48 hours (biofilm). The absorbance (AB) was measured by XTT assay. Experiments were performed using specimens that were either uncoated or had been coated with saliva. Data were analyzed using one- or two-way ANOVAs, followed by Tukey's test (alpha= 0.05). RESULTS: TR exhibited the highest Ra and UG the lowest. SEM images also showed that UG and SS had smooth surfaces, while TR presented several irregularities and pores. In the absence of saliva, UG and SS presented higher WCA and lower SFE than the other materials. XTT results showed that, in the C. glabrata adhesion assay, the AB value was higher for TR followed by UG > CC> SS> ST. For the biofilm formation of C. glabrata, AB values were in the following order TR > CC = UG > ST = SS. In the adhesion assay, AB values obtained for MRSA were TR > UG = CC > ST > SS and for the biofilm formation were TR > ST > CC > UG > SS. Saliva decreased the WCA and increased the SFE for all materials. In general, the presence of saliva decreased the adhesion and biofilm formation of both microorganisms to the acrylic-based material (TR) and tissue conditioners (CC and ST), and increased for the silicone-based soft liners (UH and SS). Surface characteristics and the influence of saliva varied among materials. Roughness seemed to favor C. glabrata and MRSA adhesion and biofilm formation. CLINICAL SIGNIFICANCE: The presence of microorganisms on denture liners can irritate the oral tissues and contribute to systemic diseases. Colonization with more tolerant microorganisms such as C. glabrata and MRSA may expose patients to a greater risk of infection, mainly in immunocompromised hosts, such as aged individuals after treatment of oral cancer. For this, it is important to investigate the surface characteristics of soft liners and tissue conditioners, as well as saliva, and their influence on the adhesion and biofilm formation of C. glabrata and methicillin-resistant Staphylococcus aureus. PMID- 29630806 TI - Penetration and bactericidal efficacy of two oral care products in an oral biofilm model. AB - PURPOSE: To investigate the immediate penetration and bactericidal effect of two oral care products marketed in China on an intact natural plaque biofilm model at different time points. METHODS: Eight subjects (aged 20 to 30 years; Turesky Plaque Index Score 2 to 3) were enrolled in the study according to the inclusion criteria. Plaque accumulators were worn by the subjects for 6 and 48 hours for harvesting the dental biofilm. Then the biofilms from different groups were stained with the LIVE/DEAD BacLight fluorescence system to investigate the changes in thickness and fluorescence intensity of living bacteria in biofilm 5 and 15 minutes post-treatment with a mouthrinse containing 0.074% cetylpyridinium chloride (1-minute treatment) or a toothpaste supernatant containing 1.16% stannous chloride (2-minute treatment). In addition, a specific Sn2+ probe was utilized to evaluate the penetration of Sn2+ in the biofilm. Fluorescent images were collected using confocal laser scanning microscopy. Analysis of covariance was used for statistical analyses. All comparisons were two-sided using a 5% level of significance. RESULTS: The thickness of generated plaque biofilm increased gradually from 7.352+/-4.22 um at 6 hours to 16.73+/-7.38 um at 48 hours (P< 0.05), whereas the thickness and fluorescence intensity of living bacteria stayed unchanged over time. After the treatment of toothpaste supernatant, the ratios of living bacteria thickness and fluorescence intensity of 6- and 48-hour plaque biofilm were significantly decreased (P< 0.05). Treatment of mouthrinse reduced the ratio of living bacteria thickness, but showed no significant impact on overall fluorescence intensity of living bacteria. For 48-hour biofilm, toothpaste supernatant significantly reduced fluorescence intensity of living bacteria from outer layer through inner layer, whereas the mouthrinse showed bactericidal effect only in the outer layer and middle layer. A wide distribution of Sn2+ was shown in the biofilm with the treatment of the tested toothpaste. CLINICAL SIGNIFICANCE: This biofilm model proved to be useful and appropriate for pre-clinical testing of anti-plaque agents. A brief exposure of the biofilm to the tested toothpaste produced significant losses in bacteria viability across outer-middle-inner layers. The tested mouthrinse exerted its bactericidal effect mostly in outer and middle layers of biofilm. The penetration of Sn2+ in the biofilm performed an important function in the bactericidal effect of the toothpaste. PMID- 29630807 TI - Empowering midwives to address childbirth fear. AB - An innovative midwife-led counseling program for women with childbirth fear is being introduced at the Gold Coast University Hospital. PMID- 29630808 TI - Investing in a highly qualified workforce. PMID- 29630809 TI - The role of unions and why they matter. AB - Unions are even more important today than any other time in history, especially the Queensland Nurses' Union. PMID- 29630810 TI - Negative Differential Resistance Device from Organic/Inorganic Hybrid Nanostructures. AB - Negative differential resistance device (NDR) fabricated by spin coating of organic/inorganic hybrid nanostructures at room temperature, is reported in the present paper. The coated organic layer is MEH-PPV (poly-[2-methoxy-5-(2'-ethyl hexyloxy)-1,4-phenylenevinylene] and inorganic layer is ZnO nanoparticles. The device shows negative differential resistance at low voltage and I-V characteristics of the device show multiple peaks at low voltage values. A value of 13 and 4 for the peak- to-valley ratio of current are reported in bi-layer and single layer structures respectively. Depending on the observed NDR signature, operating mechanisms are explored based on carrier (resonant) tunneling process and donor like trap mechanisms. This results show that the MEH-PPV/ZnO thin films gives good performance and is relevant for applications in optoelectronic devices such as a negative differential resistance. PMID- 29630811 TI - NCREN - Summary of our experiences. PMID- 29630812 TI - An institutional commitment to quality care. AB - A good work environment has an institutional culture that values and respects professional nursing and midwifery as a force for quality patient outcomes. PMID- 29630813 TI - Synthesis and Characterization of Polyethylene/Starch Nanocomposites: A Spherical Starch-Supported Catalyst and In Situ Ethylene Polymerization. AB - In the present article, a novel spherical starch-supported vanadium (V)-based Ziegler-Natta catalyst was synthesized. The active centers of the obtained catalyst well dispersed in the starch through the SEM-EDX analysis. The effects of reaction conditions on ethylene polymerization were studied. The synthesized catalyst exhibited high activity toward ethylene polymerization in the presence of ethylaluminium sesquichloride (EASC) cocatalyst. Interestingly, the fiber shape PE was obtained directly during the polymerization process. PMID- 29630814 TI - The hidden time takers. PMID- 29630815 TI - Size-Tunable Low Molecular Weight Pectin-Based Electrospun Nanofibers Blended with Low Content of Poly(ethylene oxide). AB - Pectin, a natural plant polysaccharide, holds great potential for biomedicine. Developing low molecular weight (Mw) pectin-based nanofibers is desirable for biomedical applications in which fast degradation and elimination of polymer from the body are required. Here, we report the first work on fabricating low Mw pectin-based nanofibers through electrospinning, among which the content of carrier polymer, poly(ethylene oxide) (PEO), can be minimized to 10%. Surfactant (Triton X-100), high polymer concentration and cosolvent were essential to electrospin bead-free nanofibers at low PEO content. The size of pectin nanofibers was dependent on polymer concentration and cosolvent. The presence of cosolvent inhibited the crystallization of PEO, but enhanced the crystallization of pectin. Meanwhile, glycerol as cosolvent could lead to phase separation of polymers. This work provides a new prospective for the fabrication of low Mw pectin nanofibers suitable for in vivo applications with the demand of fast degradation. PMID- 29630816 TI - In Situ Generation of Plasmonic Nanoparticles for Manipulating Photon-Plasmon Coupling in Microtube Cavities. AB - In situ generation of silver nanoparticles for selective coupling between localized plasmonic resonances and whispering-gallery modes (WGMs) is investigated by spatially resolved laser dewetting on microtube cavities. The size and morphology of the silver nanoparticles are changed by adjusting the laser power and irradiation time, which in turn effectively tune the photon plasmon coupling strength. Depending on the relative position of the plasmonic nanoparticles spot and resonant field distribution of WGMs, selective coupling between the localized surface plasmon resonances (LSPRs) and WGMs is experimentally demonstrated. Moreover, by creating multiple plasmonic nanoparticle spots on the microtube cavity, the field distribution of optical axial modes is freely tuned due to multicoupling between LSPRs and WGMs. The multicoupling mechanism is theoretically investigated by a modified quasipotential model based on perturbation theory. This work provides an in situ fabrication of plasmonic nanoparticles on three-dimensional microtube cavities for manipulating photon-plasmon coupling which is of interest for optical tuning abilities and enhanced light-matter interactions. PMID- 29630817 TI - Single-Chain Nanoparticles as Catalytic Nanoreactors. AB - The need for efficient, tailor-made catalysts has inspired chemists to fuse the design principles of natural enzymes with synthetic macromolecular architectures. A highly interesting pathway mimics a metallo-enzyme's tertiary structure via the target placement of metal-ions in a tailor-made polymeric framework, resulting in catalytically active single-chain nanoparticles. Initial studies reveal unusual and promising effects, regarding both new catalyst characteristics and a high impact on product formation. These multifunctional nanoreactors, constructed from simple folded polymer chains, will lead to advanced bioinspired catalytic systems. As found in enzymes, their impact lies specifically within the defined construction of a polymeric pocket around the catalytic active cores for substrate recognition. PMID- 29630819 TI - AMOEBA Polarizable Force Field Parameters of the Heme Cofactor in Its Ferrous and Ferric Forms. AB - We report the first parameters of the heme redox cofactors for the polarizable AMOEBA force field in both the ferric and ferrous forms. We consider two types of complexes, one with two histidine side chains as axial ligands and one with a histidine and a methionine side chain as ligands. We have derived permanent multipoles from second-order Moller-Plesset perturbation theory (MP2). The sets of parameters have been validated in a first step by comparison of AMOEBA interaction energies of heme and a collection of biologically relevant molecules with MP2 and Density Functional Theory (DFT) calculations. In a second validation step, we consider interaction energies with large aggregates comprising around 80 H2O molecules. These calculations are repeated for 30 structures extracted from semiempirical PM7 DM simulations. Very encouraging agreement is found between DFT and the AMOEBA force field, which results from an accurate treatment of electrostatic interactions. We finally report long (10 ns) MD simulations of cytochromes in two redox states with AMOEBA testing both the 2003 and 2014 AMOEBA water models. These simulations have been carried out with the TINKER-HP (High Performance) program. In conclusion, owing to their ubiquity in biology, we think the present work opens a wide array of applications of the polarizable AMOEBA force field on hemeproteins. PMID- 29630818 TI - An 18F-Labeled Poly(ADP-ribose) Polymerase Positron Emission Tomography Imaging Agent. AB - Poly(ADP-ribose) polymerase (PARP) is involved in repair of DNA breaks and is over-expressed in a wide variety of tumors, making PARP an attractive biomarker for positron emission tomography (PET) and single photon emission computed tomography imaging. Consequently, over the past decade, there has been a drive to develop nuclear imaging agents targeting PARP. Here, we report the discovery of a PET tracer that is based on the potent PARP inhibitor olaparib (1). Our lead PET tracer candidate, [18F]20, was synthesized and evaluated as a potential PARP PET radiotracer in mice bearing subcutaneous glioblastoma xenografts using ex vivo biodistribution and PET-magnetic resonance imaging techniques. Results showed that [18F]20 could be produced in a good radioactivity yield and exhibited specific PARP binding allowing visualization of tumors over-expressing PARP. [18F]20 is therefore a potential candidate radiotracer for in vivo PARP PET imaging. PMID- 29630820 TI - Polarization Rotation in Ultrathin Ferroelectrics Tailored by Interfacial Oxygen Octahedral Coupling. AB - Multiple polar states and giant piezoelectric responses could be driven by polarization rotation in ferroelectric films, which have potential functionalities in modern material applications. Although theoretical calculations have predicted polarization rotation in pure PbTiO3 films without domain walls and strains, direct experiment has rarely confirmed such polar states under this condition. Here, we observed that interfacial oxygen octahedral coupling (OOC) can introduce an oxygen octahedral rotation, which induces polarization rotation in single domain PbTiO3 films with negligible strains. We have grown ultrathin PbTiO3 films (3.2 nm) on both SrTiO3 and Nb:SrTiO3 substrates and applied aberration-corrected scanning transmission electron microscopy (STEM) to study the interfacial OOC effect. Atomic mappings unit cell by unit cell demonstrate that polarization rotation occurs in PbTiO3 films on both substrates. The distortion of oxygen octahedra in PbTiO3 is proven by annular bright-field STEM. The critical thickness for this polarization rotation is about 4 nm (10 unit cells), above which polarization rotation disappears. First-principles calculations manifest that the interfacial OOC is responsible for the polarization rotation state. These results may shed light on further understanding the polarization behavior in ultrathin ferroelectrics and be helpful to develop relevant devices as polarization rotation is known to be closely related to superior electromechanical responses. PMID- 29630821 TI - Both Chemical and Non-Chemical Steps Limit the Catalytic Efficiency of Family 4 Glycoside Hydrolases. AB - The glycoside hydrolase family 4 (GH4) alpha-galactosidase from Citrobacter freundii (MelA) catalyzes the hydrolysis of fluoro-substituted phenyl alpha-d galactopyranosides by utilizing two cofactors, NAD+ and a metal cation, under reducing conditions. In order to refine the mechanistic understanding of this GH4 enzyme, leaving group effects were measured with various metal cations. The derived betalg value on V/ K for strontium activation is indistinguishable from zero (0.05 +/- 0.12). Deuterium kinetic isotope effects (KIEs) were measured for the activated substrates 2-fluorophenyl and 4-fluorophenyl alpha-d galactopyranosides in the presence of Sr2+, Y3+, and Mn2+, where the isotopic substitution was on the carbohydrate at C-2 and/or C-3. To determine the contributing factors to the virtual transition state (TS) on which the KIEs report, kinetic isotope effects on isotope effects were measured on these KIEs using doubly deuterated substrates. The measured D V/ K KIEs for MelA-catalyzed hydrolysis of 2-fluorophenyl alpha-d-galactopyranoside are closer to unity than the measured effects on 4-fluorophenyl alpha-d-galactopyranoside, irrespective of the site of isotopic substitution and of the metal cation activator. These observations are consistent with hydride transfer at C-3 to the on-board NAD+, deprotonation at C-2, and a non-chemical step contributing to the virtual TS for V/ K. PMID- 29630822 TI - Theoretical Investigations of the Role of Mutations in Dynamics of Kinesin Motor Proteins. AB - Motor proteins are active enzymatic molecules that are critically important for a variety of biological phenomena. It is known that some neurodegenerative diseases are caused by specific mutations in motor proteins that lead to their malfunctioning. Hereditary spastic paraplegia is one of such diseases, and it is associated with the mutations in the neuronal conventional kinesin gene, producing the decreased speed and processivity of this motor protein. Despite the importance of this problem, there is no clear understanding on the role of mutations in modifying dynamic properties of motor proteins. In this work, we investigate theoretically the molecular basis for negative effects of two specific mutations, N256S and R280S, on the dynamics of kinesin motor proteins. We hypothesize that these mutations might accelerate the adenosine triphosphate (ATP) release by increasing the probability of open conformations for the ATP binding pocket. Our approach is based on the use of coarse-grained structure based molecular dynamics simulations to analyze the conformational changes and chemical transitions in the kinesin molecule, which is also supplemented by investigation of a mesoscopic discrete-state stochastic model. Computer simulations suggest that mutations N256S and R280S can decrease the free energy difference between open and closed biochemical states, making the open conformation more stable and the ATP release faster, which is in agreement with our hypothesis. Furthermore, we show that in the case of N256S mutation, this effect is caused by disruption of interactions between alpha helix and switch I and loop L11 structural elements. Our computational results are qualitatively supported by the explicit analysis of the discrete-state stochastic model. PMID- 29630823 TI - Stabilized Cyclic Peptides as Scavengers of Autoantibodies: Neutralization of Anticitrullinated Protein/Peptide Antibodies in Rheumatoid Arthritis. AB - The occurrence of autoantibodies is a hallmark of rheumatoid arthritis, specifically those autoantibodies targeting proteins containing the arginine derived amino acid citrulline. There is strong evidence showing that the occurrence of anticitrullinated protein/peptide antibodies (ACPA) are involved in disease progression, and ACPA was recently shown to induce pain in animals. Here, we explore a novel concept useful for research, diagnostics, and possibly therapy of autoimmune diseases, namely, to directly target and neutralize autoantibodies using peptide binders. A high-affinity peptide-based scavenger of ACPA was developed by grafting a citrullinated epitope derived from human fibrinogen into a naturally occurring stable peptide scaffold. The best scavenger comprises the truncated epitope alpha-fibrinogen, [Cit573]fib(566-580), grafted into the scaffold sunflower trypsin inhibitor-1, SFTI-1. The final peptide demonstrates low nanomolar apparent affinity and superior stability. PMID- 29630824 TI - Differential Enzyme Flexibility Probed Using Solid-State Nanopores. AB - Enzymes and motor proteins are dynamic macromolecules that coexist in a number of conformations of similar energies. Protein function is usually accompanied by a change in structure and flexibility, often induced upon binding to ligands. However, while measuring protein flexibility changes between active and resting states is of therapeutic significance, it remains a challenge. Recently, our group has demonstrated that breadth of signal amplitudes in measured electrical signatures as an ensemble of individual protein molecules is driven through solid state nanopores and correlates with protein conformational dynamics. Here, we extend our study to resolve subtle flexibility variation in dihydrofolate reductase mutants from unlabeled single molecules in solution. We first demonstrate using a canonical protein system, adenylate kinase, that both size and flexibility changes can be observed upon binding to a substrate that locks the protein in a closed conformation. Next, we investigate the influence of voltage bias and pore geometry on the measured electrical pulse statistics during protein transport. Finally, using the optimal experimental conditions, we systematically study a series of wild-type and mutant dihydrofolate reductase proteins, finding a good correlation between nanopore-measured protein conformational dynamics and equilibrium bulk fluorescence probe measurements. Our results unequivocally demonstrate that nanopore-based measurements reliably probe conformational diversity in native protein ensembles. PMID- 29630825 TI - Multishelled Si@Cu Microparticles Supported on 3D Cu Current Collectors for Stable and Binder-free Anodes of Lithium-Ion Batteries. AB - Silicon has proved to be a promising anode material of high-specific capacity for the next-generation lithium ion batteries (LIBs). However, during repeated discharge/charge cycles, Si-based electrodes, especially those in microscale size, pulverize and lose electrical contact with the current collectors due to large volume expansion. Here, we introduce a general method to synthesize Cu@M (M = Si, Al, C, SiO2, Si3N4, Ag, Ti, Ta, SnIn2O5, Au, V, Nb, W, Mg, Fe, Ni, Sn, ZnO, TiN, Al2O3, HfO2, and TiO2) core-shell nanowire arrays on Cu substrates. The resulting Cu@Si nanowire arrays were employed as LIB anodes that can be reused via HCl etching and H2-reduction. Multishelled Cu@Si@Cu microparticles supported on 3D Cu current collectors were further prepared as stable and binder-free LIB anodes. This 3D Cu@Si@Cu structure allows the interior conductive Cu network to effectively accommodate the volume expansion of the electrode and facilitates the contact between the Cu@Si@Cu particles and the current collectors during the repeated insertion/extraction of lithium ions. As a result, the 3D Cu@Si@Cu microparticles at a high Si-loading of 1.08 mg/cm2 showed a capacity retention of 81% after 200 cycles. In addition, charging tests of 3D Cu@Si@Cu-LiFePO4 full cells by a triboelectric nanogenerator with a pulsed current demonstrated that LIBs with silicon anodes can effectively store energy delivered by mechanical energy harvesters. PMID- 29630826 TI - Eco-Efficient Process Improvement at the Early Development Stage: Identifying Environmental and Economic Process Hotspots for Synergetic Improvement Potential. AB - We present here a new eco-efficiency process-improvement method to highlight combined environmental and costs hotspots of the production process of new material at a very early development stage. Production-specific and scaled-up results for life cycle assessment (LCA) and production costs are combined in a new analysis to identify synergetic improvement potentials and trade-offs, setting goals for the eco-design of new processes. The identified hotspots and bottlenecks will help users to focus on the relevant steps for improvements from an eco-efficiency perspective and potentially reduce their associated environmental impacts and production costs. Our method is illustrated with a case study of nanocellulose. The results indicate that the production route should start with carrot pomace, use heat and solvent recovery, and deactivate the enzymes with bleach instead of heat. To further improve the process, the results show that focus should be laid on the carrier polymer, sodium alginate, and the production of the GripX coating. Overall, the method shows that the underlying LCA scale-up framework is valuable for purposes beyond conventional LCA studies and is applicable at a very early stage to provide researchers with a better understanding of their production process. PMID- 29630827 TI - Response to Comment on "Laser Desorption/Ionization Coupled to FTICR Mass Spectrometry for Studies of Natural Organic Matter". PMID- 29630828 TI - NADPH-Driven Organohalide Reduction by a Nonrespiratory Reductive Dehalogenase. AB - Reductive dehalogenases are corrinoid and iron-sulfur cluster-dependent enzymes that mostly act as the terminal oxidoreductases in the bacterial organohalide respiration process. This process often leads to detoxification of recalcitrant organohalide pollutants. While low cell yields and oxygen sensitivity hamper the study of many reductive dehalogenases, this is not the case for the nonrespiratory reductive dehalogenase NpRdhA from Nitratireductor pacificus. We here report in vitro and in vivo reconstitution of an NADPH-dependent reducing system for NpRdhA. Surprisingly, NpRdhA mediated organohalide reduction could not be supported using N. pacificus ferredoxin-NAD(P)H oxidoreductase and associated ferredoxins. Instead, we found a nonphysiological system comprised of the Escherichia coli flavodoxin reductase (EcFldr) in combination with spinach ferredoxin (SpFd) was able to support NADPH-dependent organohalide reduction by NpRdhA. Using this system, organohalide reduction can be performed under both anaerobic and aerobic conditions, with 1.1 +/- 0.1 and 3.5 +/- 0.3 equiv of NADPH consumed per product produced, respectively. No significant enzyme inactivation under aerobic conditions was observed, suggesting a Co(I) species is unlikely to be present under steady state conditions. Furthermore, reduction of the Co(II) resting state was not observed in the absence of substrate. Only the coexpression of EcFldr, SpFd, and NpRdhA in Bacillus megaterium conferred the latter with the ability to reduce brominated NpRdhA substrates in vivo, in agreement with our in vitro observations. Our work provides new insights into biological reductive dehalogenase reduction and establishes a blueprint for the minimal functional organohalide reduction module required for bioremediation in situ. PMID- 29630829 TI - Post-Synthesis Modifications of Two-Dimensional MoSe2 or MoTe2 by Incorporation of Excess Metal Atoms into the Crystal Structure. AB - Phase engineering has extensively been used to achieve metallization of two dimensional (2D) semiconducting materials, as it should boost their catalytic properties or improve electrical contacts. In contrast, here we demonstrate compositional phase change by incorporation of excess metals into the crystal structure. We demonstrate post-synthesis restructuring of the semiconducting MoTe2 or MoSe2 host material by unexpected easy incorporation of excess Mo into their crystal planes, which causes local metallization. The amount of excess Mo can reach values as high as 10% in MoTe2 thus creating a significantly altered material compared to its parent structure. The incorporation mechanism is explained by density functional theory in terms of the energy difference of Mo atoms incorporated in the line phases as compared to Mo ad-clusters. Angle resolved photoemission spectroscopy reveals that the incorporated excess Mo induces band gap states up to the Fermi level causing its pinning at these electronic states. The incorporation of excess transition metals in MoTe2 and MoSe2 is not limited to molybdenum, but other transition metals can also diffuse into the lattice, as demonstrated experimentally by Ti deposition. The mechanism of incorporation of transition metals in MoSe2 and MoTe2 is revealed, which should help to address the challenges in synthesizing defect-free single layer materials by, for example, molecular beam epitaxy. The easy incorporation of metal atoms into the crystal also indicates that the previously assumed picture of a sharp metal/2D-material interface may not be correct, and at least for MoSe2 and MoTe2, in-diffusion of metals from metal-contacts into the 2D material has to be considered. Most importantly though, the process of incorporation of transition metals with high concentrations into pristine 2D transition-metal dichalcogenides enables a pathway for their post-synthesis modifications and adding functionalities. PMID- 29630830 TI - Synthesis of 1-Cyanoalkynes and Their Ruthenium(II)-Catalyzed Cycloaddition with Organic Azides to Afford 4-Cyano-1,2,3-triazoles. AB - A new method to convert terminal alkynes under relatively mild conditions to 1 cyanoalkynes using in situ formed cyanogen is described. 1-Cyanoalkynes have a higher reactivity than terminal alkynes in the ruthenium(II)-catalyzed regiospecific azide-alkyne cycloaddition to afford 4-cyano-1,2,3-triazoles. A mechanistic proposal different from the one that terminal alkynes adopt under the same reaction conditions is proposed. This work provides a new and convenient two step sequence to prepare 4-cyano-1,2,3-triazoles from terminal alkynes and organic azides. PMID- 29630831 TI - Parametrization of Molybdenum Cofactors for the AMBER Force Field. AB - Molybdenum-containing enzymes have been receiving significant attention from the scientific community since they participate in important biological processes and in the global biogeochemical cycles of carbon, nitrogen, and sulfur. Molecular modeling studies of these metalloproteins with classical force fields are, however, often hampered by the "missing parameter" problem. In this article, a set of parameters have been determined for the AMBER force field from nine different molybdenum cofactors. All of these cofactors were optimized and parametrized using a bonded model approach. All of the bonds and angles involving the Mo ion were parametrized. The Restrained Electrostatic Potential charges of the coordination sphere of each cofactor were also determined. Finally, we demonstrated the stability of our parameters in a showcase of nine enzymes. The parameters presented in this work provide a valuable resource for the molecular simulation community as they extend the range of metal ions that can be studied using classical approaches while also providing a starting point for subsequent parametrization of similar metal centers. All of the developed parameters can be found in the Supporting Information . PMID- 29630832 TI - N-Doped Dual Carbon-Confined 3D Architecture rGO/Fe3O4/AC Nanocomposite for High Performance Lithium-Ion Batteries. AB - To address the issues of low electrical conductivity, sluggish lithiation kinetics and dramatic volume variation in Fe3O4 anodes of lithium ion battery, herein, a double carbon-confined three-dimensional (3D) nanocomposite architecture was synthesized by an electrostatically assisted self-assembly strategy. In the constructed architecture, the ultrafine Fe3O4 subunits (~10 nm) self-organize to form nanospheres (NSs) that are fully coated by amorphous carbon (AC), formatting core-shell structural Fe3O4/AC NSs. By further encapsulation by reduced graphene oxide (rGO) layers, a constructed 3D architecture was built as dual carbon-confined rGO/Fe3O4/AC. Such structure restrains the adverse reaction of the electrolyte, improves the electronic conductivity and buffers the mechanical stress of the entire electrode, thus performing excellent long-term cycling stability (99.4% capacity retention after 465 cycles relevant to the second cycle at 5 A g-1). Kinetic analysis reveals that a dual lithium storage mechanism including a diffusion reaction mechanism and a surface capacitive behavior mechanism coexists in the composites. Consequently, the resulting rGO/Fe3O4/AC nanocomposite delivers a high reversible capacity (835.8 mA h g-1 for 300 cycles at 1 A g-1), as well as remarkable rate capability (436.7 mA h g-1 at 10 A g-1). PMID- 29630833 TI - Bioavailability of Antibiotics at Soil-Water Interfaces: A Comparison of Measured Activities and Equilibrium Partitioning Estimates. AB - There are growing concerns that antibiotic pollution impacts environmental microbiota and facilitates the propagation of antibiotic resistance. However, the prediction or analytical determination of bioavailable concentrations of antibiotics in soil is still subject to great uncertainty. Biological assays are increasingly recognized as valuable complementary tools that allow a more direct determination of the residual antibiotic activity. This study assessed the bioavailability of structurally diverse antibiotics at a soil-water interface applying activity-based analyses in conjunction with equilibrium partitioning (EqP) modeling. The activity against Gram-positive and Gram-negative bacteria of nine antibiotics from different classes was determined in the presence and absence of standard soil (LUFA St. 2.2). The addition of soil affected the activity of different antibiotics to highly varying degrees. Moreover, a highly significant correlation ( p < 0.0001) between the experimentally observed and the EqP-derived log EC50 (half-maximal effective concentration) values was observed. The innovative experimental design of this study provided new insights on the bioavailability of antibiotics at soil-water interfaces. EqP appears to be applicable to a broad range of antibiotics for the purpose of screening-level risk assessment. However, EqP estimates cannot replace soil-specific ecotoxicity testing in higher-tier assessments, since their accuracy is still compromised by a number of factors. PMID- 29630834 TI - Comment on "Laser Desorption/Ionization Coupled to FTICR Mass Spectrometry for Studies of Natural Organic Matter". PMID- 29630835 TI - Allosteric Control of Peroxidase-Mimicking DNAzyme Activity with Cationic Copolymers. AB - Control of protein conformation and function, induced by the binding of an effector, plays significant roles in modulating biochemical reaction. Although the DNAzymes catalytic activity is similar to protein-based enzymes, reports of allosterically controlled DNAzymes are still limited except for aptamer-DNAzymes hybrrids. Here, we report allosteric control of peroxidase-mimicking DNAzyme activity using cationic copolymers. The DNAzyme requires a structured G quadruplex core and hemin for activity, and the DNAzyme with a parallel G quadruplex core has higher DNAzyme activity than DNAzymes based on other types of structure. We previously reported that a cationic copolymer composed of a cationic backbone and hydrophilic dextran side chains selectively stabilizes parallel G-quadruplex structures. In this study, we investigated effects of the cationic copolymer on peroxidase-mimicking DNAzyme activity. The cationic copolymer enhanced the DNAzyme activity by more than 30-fold by stabilizing the parallel G-quadruplex structure. Furthermore, reversible allosteric control of DNAzyme activity was achieved by adding cationic and anionic polymers. PMID- 29630836 TI - One-Dimensional Projection of Collective Variables for Effective Sampling of Complex Chemical Reaction Coordinates. AB - A one-dimensional projection (ODP) technique is introduced to overcome the challenges in multidimensional sampling. With the help of a projected "advancement of reaction (xi)" control parameter, it was demonstrated that multidimensional samplings could be performed with a single parameter, thus dramatically reducing the computational overhead. In our test studies, the ODP technique successfully yielded the free energy surface of the double proton transfer reaction of the acetic acid dimer and the hydrolysis of the methyl diazonium ion. In short, the ODP can be a promising protocol for the samplings of complex chemical reaction dynamics. PMID- 29630837 TI - Facile, Fluorogenic Assay for Protein Histidine Phosphatase Activity. AB - Although the importance of protein histidine phosphorylation in mammals has been a subject of increasing interest, few chemical probes are available for monitoring and manipulating PHP activity. Here, we present an optimized and validated protocol for assaying the activity of PHPT1 using the fluorogenic substrate DiFMUP. The kinetic parameters of our optimized assay are significantly improved as compared with other PHPT1 assays in the literature, with a kcat of 0.39 +/- 0.02 s-1, a Km of 220 +/- 30 MUM, and a kcat/ Km of 1800 +/- 200 M-1 s 1. In addition, the assay is significantly more sensitive as a result of using a fluorescent probe, requiring only 109 nM enzyme as compared with 2.4 MUM as required by previously published assays. In the process of assay optimization, we discovered that PHPT1 is sensitive to a reducing environment and inhibited by transition-metal ions, with one apparent Cu(II) binding site with IC50 value of 500 +/- 20 MUM and two apparent Zn(II) binding sites with IC50 values of 25 +/- 1 and 490 +/- 20 MUM. PMID- 29630838 TI - Structure and Crystallization of Alkaline-Earth Aluminosilicate Glasses: Prevention of the Alumina-Avoidance Principle. AB - Aluminosilicate glasses are considered to follow the Al-avoidance principle, which states that Al-O-Al linkages are energetically less favorable, such that, if there is a possibility for Si-O-Al linkages to occur in a glass composition, Al-O-Al linkages are not formed. The current paper shows that breaching of the Al avoidance principle is essential for understanding the distribution of network forming AlO4 and SiO4 structural units in alkaline-earth aluminosilicate glasses. The present study proposes a new modified random network (NMRN) model, which accepts Al-O-Al linkages for aluminosilicate glasses. The NMRN model consists of two regions, a network structure region (NS-Region) composed of well-separated homonuclear and heteronuclear framework species and a channel region (C-Region) of nonbridging oxygens (NBOs) and nonframework cations. The NMRN model accounts for the structural changes and devitrification behavior of aluminosilicate glasses. A parent Ca- and Al-rich melilite-based CaO-MgO-Al2O3-SiO2 (CMAS) glass composition was modified by substituting MgO for CaO and SiO2 for Al2O3 to understand variations in the distribution of network-forming structural units in the NS-region and devitrification behavior upon heat treating. The structural features of the glass and glass-ceramics (GCs) were meticulously assessed by advanced characterization techniques including neutron diffraction (ND), powder X ray diffraction (XRD), 29Si and 27Al magic angle spinning (MAS)-nuclear magnetic resonance (NMR), and in situ Raman spectroscopy. ND revealed the formation of SiO4 and AlO4 tetrahedral units in all the glass compositions. Simulations of chemical glass compositions based on deconvolution of 29Si MAS NMR spectral analysis indicate the preferred formation of Si-O-Al over Si-O-Si and Al-O-Al linkages and the presence of a high concentration of nonbridging oxygens leading to the formation of a separate NS-region containing both SiO4 and AlO4 tetrahedra (Si/Al) (heteronuclear) in addition to the presence of Al[4]-O-Al[4] bonds; this region coexists with a predominantly SiO4-containing (homonuclear) NS-region. In GCs, obtained after heat treatment at 850 degrees C for 250 h, the formation of crystalline phases, as revealed from Rietveld refinement of XRD data, may be understood on the basis of the distribution of SiO4 and AlO4 structural units in the NS-region. The in situ Raman spectra of the GCs confirmed the formation of a Si/Al structural region, as well as indicating interaction between the Al/Si region and SiO4-rich region at higher temperatures, leading to the formation of additional crystalline phases. PMID- 29630839 TI - Photo- and Reduction-Responsive Polymersomes for Programmed Release of Small and Macromolecular Payloads. AB - We report on the preparation of photo- and reduction-responsive diblock copolymers through reversible addition-fragmentation chain transfer (RAFT) polymerization of a coumarin-based disulfide-containing monomer (i.e., CSSMA) using a poly(ethylene oxide) (PEO)-based macroRAFT agent. The resulting amphiphilic PEO- b-PCSSMA copolymers self-assembled into polymersomes with hydrophilic PEO shielding coronas and hydrophobic bilayer membranes. Upon irradiating the polymersomes with visible light (e.g., 430 nm), the coumarin moieties within the bilayer membranes were cleaved with the generation of primary amine groups, which spontaneously underwent inter/intrachain amidation reactions with the ester moieties, thereby tracelessly cross-linking and permeating the bilayer membranes. Notably, this process only gave rise to the release of small molecule payloads (e.g., doxorubicin hydrochloride, DOX) while large molecule encapsulants (e.g., Texas red-labeled dextran, TR-dextran) were retained within the cross-linked polymersomes due to the preservation of the integrity of the vesicular nanostructures. However, cross-linked polymersomes undergo further structural disintegration upon incubation with glutathione (GSH) due to the scission of disulfide linkages, resulting in the release of macromolecular payloads. Thus, dual-stimuli responsive polymersomes with tracelessly cross linkable characteristics enable sequential release of payloads with spatiotemporal precision, which could be of promising applications in synergistic loading and programmed release of therapeutics. PMID- 29630840 TI - Improved Substrate Scope in the Potassium Hexacyanoferrate(II)-Based Cyanation for the Synthesis of Benzonitriles and Their Heterocyclic Analogues. AB - The use of Pd(DPEPhos)Cl2 (P26) as a catalyst for the formation of benzonitriles and their heterocyclic analogues provides excellent complementarity to existing catalysts, allowing highly electron-deficient heterocyclic aryl halides to be efficiently converted to the corresponding nitriles using K4[Fe(CN)6]) as cyanide source. This catalyst significantly enhances the scope of this reaction to include a number of substrates that are highly relevant for pharmaceutical and agrochemical applications. Importantly, not only does this cyanation method employ a nontoxic cyanide source, simple semiquantitative testing suggests that, unlike many other methods, no free cyanide is present in the reaction mixture or during a variety of potential workups, thus improving the safety aspects of this method from initial setup through to product isolation. Finally, developing and testing a series of convenient cyanation kits has allowed facile application and broader adoption of this method in our laboratories. PMID- 29630841 TI - The Evolution of Electronic and Magnetic Properties of the Chain and Sheet Assemblies Based on Planar Tetracoordinate Carbon C2Al4(CH3)8. AB - The new planar tetracoordinate carbon (ptC) compounds have received significant research attention in recent years. The present study is devoted to investigating the structural, electronic, and magnetic features of one-dimensional chains and two-dimensional sheets composed of C2Al4(CH3)8 building blocks. All possible condensations were studied, and the stabilities of different ptC assemblies were compared. Several properties such as energy gap, dipole polarizability, electronic excitation energies, and nucleus chemical shift were computed for chains up to 7 and sheets up to 16 units. A systematic analysis was performed to assess the impact of condensation pattern and number of units on the calculated properties. Topological analysis of density and electron localization functions reveals that Al-C bonds in the considered ptCs have mixed covalent/ionic character with larger ionic contribution. It is found that the electronic spectra of the condensed ptCs exhibit red shift toward larger wavelengths when compared to the C2Al4(CH3)8 building block. The amount of red shift enhances with increasing number of units. We show that the stability trend, predicted by electronic and magnetic descriptors, are in qualitative agreement with the thermodynamic stability obtained through Gibbs free energy change of condensation reaction. PMID- 29630843 TI - Strength of pi-Stacking, from Neutral to Cation: Precision Measurement of Binding Energies in an Isolated pi-Stacked Dimer. AB - pi-Stacking interactions are ubiquitious across chemistry and biochemistry, impacting areas from organic materials and photovoltaics to biochemistry and DNA. However, experimental data is lacking regarding the strength of pi-stacking forces-an issue not settled even for the simplest model system, the isolated benzene dimer. Here, we use two-color appearance potential measurements to determine the binding energies of the isolated, pi-stacked dimer of fluorene (C13H10) in ground, excited, and ionic states. Our measurements provide the first precise values for pi-stacking interaction energies in these states, which are key benchmarks for theory. Indeed, theoretical predictions using ab initio and carefully benchmarked DFT methods are in excellent agreement with experiment. PMID- 29630842 TI - Application of a Salt Coformer in a Co-Amorphous Drug System Dramatically Enhances the Glass Transition Temperature: A Case Study of the Ternary System Carbamazepine, Citric Acid, and l-Arginine. AB - The use of co-amorphous systems containing a combination of low molecular weight drugs and excipients is a relatively new technology in the pharmaceutical field to improve the solubility of poorly water-soluble drugs. However, some co amorphous systems show a lower glass transition temperature ( Tg) than many of their polymeric solid dispersion counterparts. In this study, we aimed at designing a stable co-amorphous system with an elevated Tg. Carbamazepine (CBM) and citric acid (CA) were employed as the model drug and the coformer, respectively. co-amorphous CBM-CA at a 1:1 molar ratio was formed by ball milling, but a transition from the glassy to the supercooled melt state was observed under ambient conditions, due to the relatively low Tg of 38.8 degrees C of the co-amorphous system and moisture absorption. To improve the Tg of the coformer, salt formation of a combination of l-arginine (ARG) with CA was studied. First, ball milling of CA-ARG at molar ratios of 1:1, 1:2, and 1:3 forming co-amorphous systems was performed and led to a dramatic enhancement of the Tg, depending on the CA-ARG ratio. Salt formation between CA and ARG was observed by infrared spectroscopy. Next, ball milling of CBM-CA-ARG at molar ratios of 1:1:1, 1:1:2, and 1:1:3 resulted in co-amorphous blends, which had a single Tg at 77.8, 105.3, and 127.8 degrees C, respectively. These ternary co amorphous samples remained in a solid amorphous form for 2 months at 40 degrees C. From these results, it can be concluded that blending of the salt coformer with a drug is a promising strategy to design stable co-amorphous formulations. PMID- 29630844 TI - Synthesis of Zinc Oxide Nanorods via the Formation of Sea Urchin Structures and Their Photoluminescence after Heat Treatment. AB - A protocol for the aqueous synthesis of ca. 1-MUm-long zinc oxide (ZnO) nanorods and their growth at intermediate reaction progression is presented, together with photoluminescence (PL) characteristics after heat treatment at temperatures of up to 1000 degrees C. The existence of solitary rods after the complete reaction (60 min) was traced back to the development of sea urchin structures during the first 5 s of the precipitation. The rods primarily formed in later stages during the reaction due to fracture, which was supported by the frequently observed broken rod ends with sharp edges in the final material, in addition to tapered uniform rod ends consistent with their natural growth direction. The more dominant rod growth in the c direction (extending the length of the rods), together with the appearance of faceted surfaces on the sides of the rods, occurred at longer reaction times (>5 min) and generated zinc-terminated particles that were more resistant to alkaline dissolution. A heat treatment for 1 h at 600 or 800 degrees C resulted in a smoothing of the rod surfaces, and PL measurements displayed a decreased defect emission at ca. 600 nm, which was related to the disappearance of lattice imperfections formed during the synthesis. A heat treatment at 1000 degrees C resulted in significant crystal growth reflected as an increase in luminescence at shorter wavelengths (ca. 510 nm). Electron microscopy revealed that the faceted rod structure was lost for ZnO rods exposed to temperatures above 600 degrees C, whereas even higher temperatures resulted in particle sintering and/or mass redistribution along the initially long and slender ZnO rods. The synthesized ZnO rods were a more stable Wurtzite crystal structure than previously reported ball-shaped ZnO consisting of merging sheets, which was supported by the shifts in PL spectra occurring at ca. 200 degrees C higher annealing temperature, in combination with a smaller thermogravimetric mass loss occurring upon heating the rods to 800 degrees C. PMID- 29630845 TI - Non-dairy probiotic food products: An emerging group of functional foods. AB - The functional food sector has shown tremendous growth in recent years with the application of probiotic bacteria as "food additives". The utilization of probiotic bacteria in food presents many challenges related to their growth, survival, viability, stability and functionality in food processing, storage and consumption as well as changes of sensory characteristics of probiotic foods. Although dairy foods are currently the most common food carrier to deliver probiotics, an increasing number of non-dairy food matrices exhibit potential for delivery of probiotics. This review provides more recent insight into the emergence of non-dairy probiotics products, the interactions between probiotics and different food matrices and the challenges in developing such products. Some of the technical issues are also reviewed and discussed. These issues include the efficacy of probiotic bacteria in non-chilled, low pH or high water activity foods; the potential loss of bacterial viability, additionally unwanted fermentation and changes of the sensory characteristics of food products which may result in poor microbiological quality and low acceptability to consumers. PMID- 29630846 TI - Inflammatory Bacteriome and Oral Squamous Cell Carcinoma. AB - Results from microbiome studies on oral cancer have been inconsistent, probably because they focused on compositional analysis, which does not account for functional redundancy among oral bacteria. Based on functional prediction, a recent study revealed enrichment of inflammatory bacterial attributes in oral squamous cell carcinoma (OSCC). Given the high relevance of this finding to carcinogenesis, we aimed here to corroborate them in a case-control study involving 25 OSCC cases and 27 fibroepithelial polyp (FEP) controls from Sri Lanka. DNA extracted from fresh biopsies was sequenced for the V1 to V3 region with Illumina's 2 * 300-bp chemistry. High-quality nonchimeric merged reads were classified to the species level with a prioritized BLASTN-based algorithm. Downstream compositional analysis was performed with QIIME (Quantitative Insights into Microbial Ecology) and linear discriminant analysis effect size, while PICRUSt (Phylogenetic Investigation of Communities by Reconstruction of Unobserved States) was utilized for bacteriome functional prediction. The OSCC tissues tended to have lower species richness and diversity. Genera Capnocytophaga, Pseudomonas, and Atopobium were overrepresented in OSCC, while Lautropia, Staphylococcus, and Propionibacterium were the most abundant in FEP. At the species level, Campylobacter concisus, Prevotella salivae, Prevotella loeschii, and Fusobacterium oral taxon 204 were enriched in OSCC, while Streptococcus mitis, Streptococcus oral taxon 070, Lautropia mirabilis, and Rothia dentocariosa among others were more abundant in FEP. Functionally, proinflammatory bacterial attributes, including lipopolysaccharide biosynthesis and peptidases, were enriched in the OSCC tissues. Thus, while the results in terms of species composition significantly differed from the original study, they were consistent at the functional level, substantiating evidence for the inflammatory nature of the bacteriome associated with OSCC. PMID- 29630847 TI - Screening for Inhibitors of Acetaldehyde Dehydrogenase (AdhE) from Enterohemorrhagic Escherichia coli (EHEC). AB - Acetaldehyde dehydrogenase (AdhE) is a bifunctional acetaldehyde-coenzyme A (CoA) dehydrogenase and alcohol dehydrogenase involved in anaerobic metabolism in gram negative bacteria. This enzyme was recently found to be a key regulator of the type three secretion (T3S) system in Escherichia coli. AdhE inhibitors can be used as tools to study bacterial virulence and a starting point for discovery of novel antibacterial agents. We developed a robust enzymatic assay, based on the acetaldehyde-CoA dehydrogenase activity of AdhE using both absorption and fluorescence detection models (Z' > 0.7). This assay was used to screen ~11,000 small molecules in 384-well format that resulted in three hits that were confirmed by resynthesis and validation. All three compounds are noncompetitive with respect to acetaldehyde and display a clear dose-response effect with hill slopes of 1-2. These new inhibitors will be used as chemical tools to study the interplay between metabolism and virulence and the role of AdhE in T3S regulation in gram-negative bacteria, and as starting points for the development of novel antibacterial agents. PMID- 29630848 TI - The Role of the Human Immune System in Chronic Hypoxic Pulmonary Hypertension. PMID- 29630849 TI - Gaps Up To 9 Months Between HIV Primary Care Visits Do Not Worsen Viral Load. AB - Current guidelines specify that visit intervals with viral monitoring should not exceed 6 months for HIV patients. Yet, gaps in care exceeding 6 months are common. In an observational cohort using US patients, we examined the association between gap length and changes in viral load status and sought to determine the length of the gap at which significant increases in viral load occur. We identified patients with gaps in care greater than 6 months from 6399 patients from six US HIV clinics. Gap strata were >6 to <7, 7 to <8, 8 to <9, 9 to <12, and >=12 months, with viral load measurements matched to the opening and closing dates for the gaps. We examined visit gap lengths in association with two viral load measurements: continuous (log10 viral load at gap opening and closing) and dichotomous (whether patients initially suppressed but lost viral suppression by close of the care gap). Viral load increases were nonsignificant or modest when gap length was <9 months, corresponding to 10% or fewer patients who lost viral suppression. For gaps >=12 months, there was a significant increase in viral load as well as a much larger loss of viral suppression (in 23% of patients). Detrimental effects on viral load after a care gap were greater in young patients, black patients, and those without private health insurance. On average, shorter gaps in care were not detrimental to patient viral load status. HIV primary care visit intervals of 6 to 9 months for select patients may be appropriate. PMID- 29630850 TI - Health System Features That Enhance Access to Comprehensive Primary Care for Women Living with HIV in High-Income Settings: A Systematic Mixed Studies Review. AB - Women living with HIV in high-income settings continue to experience modifiable barriers to care. We sought to determine the features of care that facilitate access to comprehensive primary care, inclusive of HIV, comorbidity, and sexual and reproductive healthcare. Using a systematic mixed studies review design, we reviewed qualitative, mixed methods, and quantitative studies identified in Ovid MEDLINE, EMBASE, and CINAHL databases (January 2000 to August 2017). Eligibility criteria included women living with HIV; high-income countries; primary care; and healthcare accessibility. We performed a thematic synthesis using NVivo. After screening 3466 records, we retained 44 articles and identified 13 themes. Drawing on a social-ecological framework on engagement in HIV care, we situated the themes across three levels of the healthcare system: care providers, clinical care environments, and social and institutional factors. At the care provider level, features enhancing access to comprehensive primary care included positive patient-provider relationships and availability of peer support, case managers, and/or nurse navigators. Within clinical care environments, facilitators to care were appointment reminder systems, nonidentifying clinic signs, women and family spaces, transportation services, and coordination of care to meet women's HIV, comorbidity, and sexual and reproductive healthcare needs. Finally, social and institutional factors included healthcare insurance, patient and physician education, and dispelling HIV-related stigma. This review highlights several features of care that are particularly relevant to the care-seeking experience of women living with HIV. Improving their health through comprehensive care requires a variety of strategies at the provider, clinic, and greater social and institutional levels. PMID- 29630851 TI - Project THANKS: Examining HIV/AIDS-Related Barriers and Facilitators to Care in African American Women: A Community Perspective. AB - Project THANKS, (Turning HIV/AIDS into Knowledge for Sisters), is an evidence based intervention that utilizes a community-based participatory and empowerment building approach for African American female substance abusers living with HIV and other chronic diseases. This qualitative study sought to gain insight from women living with HIV on how to improve Project THANKS. African American women living with substance abuse disorders, HIV, and other comorbidities were recruited from three community based health centers in New Jersey (N = 31). Ninety minute focus group sessions were implemented in each health center. The focus group sessions were designed to understand the perceived factors influencing the participants' ability to self-manage their health conditions and challenges they are currently facing regarding their diagnoses. The barriers and suggestions presented by participants included addressing stigmatization, managing mental health symptoms, improving physician-patient trust, accessing health education, educating community members, and proper nutrition. In addition, an engaged and trusting relationship with their healthcare provider and having positive sources of support were cited as motivators to adhering to their HIV treatment regimen. Participants living with HIV/AIDS also expressed more concern with difficulty treating their comorbidities than participants with only HIV/AIDS. Receiving input from African American women living with HIV related comorbidities was essential in improving the intervention to include a behavioral and primary health approach. Future programmatic interventions of Project THANKS will include a targeted focus on addressing mental health needs in women by offering meditation services and mental health referrals. In addition, Project THANKS will incorporate activities to improve communication with physicians, families, and media outlets to empower women to take an active role in their primary and social support needs. PMID- 29630852 TI - The Max Clinic: Medical Care Designed to Engage the Hardest-to-Reach Persons Living with HIV in Seattle and King County, Washington. AB - The Max Clinic in Seattle, Washington is designed to engage patients who have extensive barriers to HIV care. In this article, we describe the clinic's evolution and outcomes of patients enrolled in the first 2 years. The clinic is a high-intensity, low-threshold, incentivized care model that includes walk-in access to primary care in a Sexually Transmitted Disease Clinic. Patients who have failed to engage in care and achieve viral suppression with lower intensity support are referred by clinicians, case managers, and the health department Data to Care program. The clinic offers food vouchers, cash incentives, no-cost bus passes, and cell phones, as well as intensive case management with cross-agency coordinated care. The primary evaluation outcome was the percentage of patients who achieved viral suppression (HIV RNA <200 copies/mL) at least once after enrollment. Secondary outcomes were continuous viral suppression (>=2 suppressed results in a row >=60 days apart) and engagement in care (>=2 completed medical visits >=60 days apart). During January 2015-December 2016, 263 patients were referred; 170 (65%) were eligible, and 95 (56% of eligible) were enrolled. Most patients used illicit drugs or hazardous levels of alcohol (86%) and had diagnosed psychiatric illness (72%) and unstable housing (65%). During the year after enrollment, 90 (95%) patients engaged in care. As of the end of 2016, 76 (80%) had achieved viral suppression, and 54% had continuous viral suppression. The Max Clinic successfully treated HIV in high-need patients and, to date, has been sustainable through a combination of federal, state, and local funding. PMID- 29630853 TI - Role of Country of Birth, Testing Site, and Neighborhood Characteristics on Nonlinkage to HIV Care Among Latinos. AB - The objective of this study was to estimate disparities in linkage to human immunodeficiency virus (HIV) care among Latinos by country/region of birth, HIV testing site, and neighborhood characteristics. A retrospective study was conducted using Florida HIV surveillance records of Latinos/Hispanics aged >=13 diagnosed during 2014-2015. Linkage to HIV care was defined as a laboratory test (HIV viral load or CD4) within 3 months of HIV diagnosis. Multi-level Poisson regression models were used to estimate adjusted prevalence ratios (aPR) for nonlinkage to care. Of 2659 Latinos, 18.8% were not linked to care within 3 months. Compared with Latinos born in mainland United States, those born in Cuba [aPR 0.60, 95% confidence interval (CI) 0.47-0.76] and Puerto Rico (aPR 0.61, 95% CI 0.41-0.90) had a decreased prevalence of nonlinkage. Latinos diagnosed at blood banks (aPR 2.34, 95% CI 1.75-3.12), HIV case management and screening facilities (aPR 1.76, 95% CI 1.46-2.14), and hospitals (aPR 1.42, 95% CI 1.03 1.96) had an increased prevalence of nonlinkage compared with outpatient general, infectious disease, and tuberculosis/sexually transmitted diseases/family planning clinics. Latinos who resided in the lowest (aPR 1.57, 95% CI 1.19-2.07) and third lowest (aPR 1.33, 95% CI 1.01-1.76) quartiles of neighborhood socioeconomic status compared with the highest quartile were at increased prevalence. Latinos who resided in neighborhoods with <25% Latinos also had increased prevalence of nonlinkage (aPR 1.23, 95% CI 1.01-1.51). Testing site at diagnosis may be an important determinant of HIV care linkage among Latinos due to neighborhood or individual-level resources that determine location of HIV testing. PMID- 29630854 TI - International Medical Graduates in Psychiatry: Cultural Issues in Training and Continuing Professional Development. AB - A position paper developed by the Canadian Psychiatric Association's Education Committee and approved by the CPA's Board of Directors on August 15, 2016. PMID- 29630856 TI - CD147 Induces Epithelial-to-Mesenchymal Transition by Disassembling Cellular Apoptosis Susceptibility Protein/E-Cadherin/beta-Catenin Complex in Human Endometriosis. AB - Epithelial-to-mesenchymal transition (EMT) is postulated to be a prerequisite for the establishment of endometriosis (EMS), a common reproductive disorder in women. Our previous studies have demonstrated the elevated expression of transmembrane glycoprotein CD147 and its prosurvival effect on abnormal cells in endometriosis. Intriguingly, CD147 is known to promote EMT in cancers. However, the involvement of CD147 in EMT during the establishment of endometriosis remains incompletely understood. We found that CD147 promotes EMT in human endometrial adenocarcinoma cell line Ishikawa. We identified a novel CD147-interacting partner, cellular apoptosis susceptibility protein (CAS), which stabilized the interaction between E-cadherin (E-cad) and beta-catenin (beta-cat) by forming the CAS/E-cad/beta-cat complex. Down-regulation of CAS led to the release and nuclear translocation of beta-cat from E-cad, resulting in the overexpression of the EMT promoting gene SNAIL. Interestingly, overexpression of CD147 impaired the interaction between CAS and E-cad and triggered the release of beta-cat from the CAS/E-cad/beta-cat complex, which in turn led to EMT. Furthermore, CAS was down regulated in EMS, with elevated levels of CD147 and nuclear beta-cat. These findings suggest a previously undefined role of CAS in regulating EMT and reveal the involvement of a CD147-induced EMT signaling pathway in pathogenic progression of EMS. PMID- 29630858 TI - Antioxidant supplementation upregulates calbindin expression in cerebellar Purkinje cells of rat pups subjected to post natal exposure to sodium arsenite. AB - Optimal cytoplasmic calcium (Ca2+) levels have been associated with adequate cell functioning and neuronal survival. Altered intracellular Ca2+ levels following impaired Ca2+ homeostasis could induce neuronal degeneration or even cell death. There are reports of arsenite induced oxidative stress and the associated disturbances in intracellular calcium homeostasis. The present study focused on determining the strategies that would modulate tissue redox status and calcium binding protein (CaBP) (Calbindin D28k-CB) expression affected adversely by sodium arsenite (NaAsO2) exposure (postnatal) of rat pups. NaAsO2 alone or along with antioxidants (AOXs) (alpha lipoic acid or curcumin) was administered by intraperitoneal (i.p.) route from postnatal day (PND) 1-21 (covering rapid brain growth period - RBGP) to experimental groups and animals receiving sterile water by the same route served as the controls. At the end of the experimental period, the animals were subjected to euthanasia and the cerebellar tissue obtained therefrom was processed for immunohistochemical localization and western blot analysis of CB protein. CB was diffusely expressed in cell body as well as dendritic processes of Purkinje cells (PCs) along the PC Layer (PCL) in all cerebellar folia of the control and the experimental animals. The multilayered pattern of CB +ve cells along with their downregulated expression and low packing density was significantly evident in the arsenic (iAs) alone exposed group as against the controls and AOX supplemented groups. The observations are suggestive of AOX induced restoration of CaBP expression in rat cerebellum following early postnatal exposure to NaAsO2. PMID- 29630857 TI - The Role of Microglia and Peripheral Monocytes in Retinal Damage after Corneal Chemical Injury. AB - Eyes that have experienced alkali burn to the surface are excessively susceptible to subsequent severe glaucoma and retinal ganglion cell loss, despite maximal efforts to prevent or slow down the disease. Recently, we have shown, in mice and rabbits, that such retinal damage is neither mediated by the alkali itself reaching the retina nor by intraocular pressure elevation. Rather, it is caused by the up-regulation of tumor necrosis factor-alpha (TNF-alpha), which rapidly diffuses posteriorly, causing retinal ganglion cell apoptosis and CD45+ cell activation. Herein, we investigated the involvement of peripheral blood monocytes and microglia in retinal damage. Using CX3CR1+/EGFP::CCR2+/RFP reporter mice and bone marrow chimeras, we show that peripheral CX3CR1+CD45hiCD11b+MHC-II+ monocytes infiltrate into the retina from the optic nerve at 24 hours after the burn and release further TNF-alpha. A secondary source of peripheral monocyte response originates from a rare population of patrolling myeloid CCR2+ cells of the retina that differentiate into CX3CR1+ macrophages within hours after the injury. As a result, CX3CR1+CD45loCD11b+ microglia become reactive at 7 days, causing further TNF-alpha release. Prompt TNF-alpha inhibition after corneal burn suppresses monocyte infiltration and microglia activation, and protects the retina. This study may prove relevant to other injuries of the central nervous system. PMID- 29630860 TI - Targeting mitochondrial respiration as a therapeutic strategy for cervical cancer. AB - Targeting mitochondrial respiration has been documented as an effective therapeutic strategy in cancer. However, the impact of mitochondrial respiration inhibition on cervical cancer cells are not well elucidated. Using a panel of cervical cancer cell lines, we show that an existing drug atovaquone is active against the cervical cancer cells with high profiling of mitochondrial biogenesis. Atovaquone inhibited proliferation and induced apoptosis with varying efficacy among cervical cancer cell lines regardless of HPV infection, cellular origin and their sensitivity to paclitaxel. We further demonstrated that atovaquone acts on cervical cancer cells via inhibiting mitochondrial respiration. In particular, atovaquone specifically inhibited mitochondrial complex III but not I, II or IV activity, leading to respiration inhibition and energy crisis. Importantly, we found that the different sensitivity of cervical cancer cell lines to atovaquone were due to their differential level of mitochondrial biogenesis and dependency to mitochondrial respiration. In addition, we demonstrated that the in vitro observations were translatable to in vivo cervical cancer xenograft mouse model. Our findings suggest that the mitochondrial biogenesis varies among patients with cervical cancer. Our work also suggests that atovaquone is a useful addition to cervical cancer treatment, particularly to those with high dependency on mitochondrial respiration. PMID- 29630859 TI - A comparison of the orexin receptor distribution in the brain between diurnal Nile grass rats (Arvicanthis niloticus) and nocturnal mice (Mus musculus). AB - The neuropeptide orexin/hypocretin regulates a wide range of behaviors and physiology through its receptors OX1R and OX2R, or HCRTR-1 and HCRTR-2. Although the distributions of these receptors have been established in nocturnal rodents, their distributions in the brain of diurnal species have not been studied. In the present study, we examined spatial patterns of OX1R and OX2R mRNA expression in diurnal Nile grass rats (Arvicanthis niloticus) by in situ hybridization and compared them with those in nocturnal mice (Mus musculus). Both receptors showed similar spatial patterns between species in most brain regions. However, species specific expression was found in several regions that are mainly implicated in regulation of sleep/wakefulness, emotion and cognition. OX1R expression was detected in the caudate putamen and ventral tuberomammillary nucleus only in grass rats, while it was detected in the bed nucleus of the stria terminalis, medial division, posteromedial part only in mice. The distribution of OX2R mRNA was mostly consistent between the two species, although it was more widely expressed in the ventral tuberomammillary nucleus in grass rats compared to mice. These results suggest that neuronal pathways of the orexin system differ between chronotypes, and these differences could underlie the distinct profiles in behaviors and physiology between diurnal and nocturnal species. PMID- 29630861 TI - Caught in the Act: Thrombus Wedged in a Patent Foramen Ovale. PMID- 29630863 TI - Reply by Authors. PMID- 29630864 TI - Editorial Comment. PMID- 29630862 TI - Interactions between NRP1 and VEGFR2 molecules in the plasma membrane. AB - Here we use a quantitative FRET approach, specifically developed to probe membrane protein interactions, to study the homo-association of neuropilin 1 (NRP1) in the plasma membrane, as well as its hetero-interactions with vascular endothelial growth factor receptor 2 (VEGFR2). Experiments are performed both in the absence and presence of the soluble ligand vascular endothelial growth factor A (VEGFA), which binds to both VEGFR2 and NRP1. We demonstrate the presence of homo-interactions between NRP1 molecules, as well as hetero-interactions between NRP1 and VEGFR2 molecules, in the plasma membrane. Our results underscore the complex nature of the interactions between self-associating receptors, co receptors, and their ligands in the plasma membrane. They also highlight the need for new methodologies that capture this complexity, and the need for precise physiological measurements of local receptor surface densities in the membrane of cells. This article is part of a Special Issue entitled: Emergence of Complex Behavior in Biomembranes edited by Marjorie Longo. PMID- 29630865 TI - Doublecortin expression in CD8+ T-cells and microglia at sites of amyloid-beta plaques: A potential role in shaping plaque pathology? AB - INTRODUCTION: One characteristic of Alzheimer's disease is the formation of amyloid-beta plaques, which are typically linked to neuroinflammation and surrounded by inflammatory cells such as microglia and infiltrating immune cells. METHODS: Here, we describe nonneurogenic doublecortin (DCX) positive cells, DCX being generally used as a marker for young immature neurons, at sites of amyloid beta plaques in various transgenic amyloid mouse models and in human brains with plaque pathology. RESULTS: The plaque-associated DCX+ cells were not of neurogenic identity, instead most of them showed coexpression with markers for microglia (ionized calcium-binding adapter molecule 1) and for phagocytosis (CD68 and TREM2). Another subpopulation of plaque-associated DCX+ cells was negative for ionized calcium-binding adapter molecule 1 but was highly positive for the pan-leukocyte marker CD45. These hematopoietic cells were identified as CD3-and CD8-positive and CD4-negative T-cells. DISCUSSION: Peculiarly, the DCX+/ionized calcium-binding adapter molecule 1+ microglia and DCX+/CD8+ T-cells were closely attached, suggesting that these two cell types are tightly interacting and that this interaction might shape plaque pathology. PMID- 29630867 TI - Phyto and endocannabinoids exert complex actions on calcium and zinc signaling in mouse cortical neurons. AB - Live-cell imaging experiments were performed with the fluorescent Ca2+ and Zn2+ probes Fluo-4 and FluoZin-3 on cultured cortical neurons dissociated from embryonic mice to investigate the effects of the cannabinoids anandamide (AEA), cannabidiol (CBD), and N-arachidonoyl glycine (NAGly) on neuronal store-operated Ca2+ entry (SOCE). When tested individually AEA, CBD or NAGly inhibited SOCE. CBD and NAGly also released Ca2+ from the endoplasmic reticulum. Furthermore, NAGly mobilized Zn2+ from a store distinct from the endoplasmic reticulum and mitochondria, and up-regulated the thapsigargin-evoked Ca2+ release. All these effects developed in a cannabinoid receptor CB1/2 independent manner via an intracellular pathway sensitive to the GPR55 antagonist ML193. Evidence is presented that cannabinoids influence Ca2+ and Zn2+ signaling in central nervous system neurons. The lipid sensing receptor GPR55 seems to be a central actor governing these responses. In addition, the alteration of the cytosolic Zn2+ levels produced by NAGly provides support for the existence of a connection between endocannabinoids and Zn2+ signaling in the brain. PMID- 29630866 TI - Canal neuromast position prefigures developmental patterning of the suborbital bone series in Astyanax cave- and surface-dwelling fish. AB - Developmental patterning is a complex biological phenomenon, involving integrated cellular and molecular signaling across diverse tissues. In Astyanax cavefish, the lateral line sensory system is dramatically expanded in a region of the cranium marked by significant bone abnormalities. This system provides the opportunity to understand how facial bone patterning can become altered through sensory system changes. Here we investigate a classic postulation that mechanosensory receptor neuromasts seed intramembranous facial bones in aquatic vertebrates. Using an in vivo staining procedure across individual life history, we observed infraorbital canal neuromasts serving as sites of ossification for suborbital bones. The manner in which cavefish departed from the stereotypical and symmetrical canal neuromast patterns of closely-related surface-dwelling fish were associated with specific changes to the suborbital bone complex. For instance, bony fusion, rarely observed in surface fish, was associated with shorter distances between canal neuromasts in cavefish, suggesting that closer canal neuromasts result in bony fusions. Additionally, cavefish lacking the sixth suborbital bone (SO6) uniformly lacked the associated (sixth) canal neuromast. This study suggests that patterning of canal neuromasts may impact spatial position of suborbital bones across development. The absence of an eye and subsequent orbital collapse in cavefish appears to influence positional information normally inherent to the infraorbital canal. These alterations result in coordinated changes to adult neuromast and bone structures. This work highlights complex interactions between visual, sensory and bony tissues during development that explain certain abnormal craniofacial features in cavefish. PMID- 29630868 TI - Drug-DNA adducts as biomarkers for metabolic activation of the nitro-aromatic nitrogen mustard prodrug PR-104A. AB - PR-104A is a clinical-stage nitrogen mustard prodrug that is activated for DNA alkylation by reduction of a nitro group to the corresponding hydroxylamine (PR 104H) or amine (PR-104M). Metabolic reduction is catalysed by flavoreductases such as cytochrome P450 oxidoreductase (POR) under hypoxia, or by aldo ketoreductase 1C3 (AKR1C3) independently of hypoxia. The unstable reduced metabolites are challenging to measure in biological samples, and biomarkers of the metabolic activation of PR-104A have not been used in the clinical evaluation of PR-104 to date. Here, we employ a selected reaction monitoring mass spectrometry assay for DNA crosslinks to assess the capacity of human cancer cells to bioactivate PR-104A. We also test whether the more abundant DNA monoadducts could be used for the same purpose. DNA monoadducts and crosslinks from PR-104A itself, and from its reduced metabolites, accumulated over 4 h in AKR1C3-expressing TF1 erythroleukaemia cells under hypoxia, whereas intracellular concentrations of unstable PR-104H and PR-104M reached steady state within 1 h. We then varied rates of PR-104A reduction by manipulating hypoxia or reductase expression in a panel of cell lines, in which AKR1C3 and POR were quantified by targeted proteomics. Hypoxia or reductase overexpression induced large increases in PR-104A sensitivity (inhibition of proliferation), DNA damage response (gammaH2AX formation), steady-state concentrations of PR-104H/M and formation of reduced drug-DNA adducts but not DNA adducts retaining the dinitro groups of PR 104A. The fold-change in the sum of PR-104H and PR-104M correlated with the fold change in reduced crosslinks or monoadducts (R2 = 0.87 for both), demonstrating their potential for assessing the capacity of cancer cells to bioactivate PR 104A. PMID- 29630869 TI - Can inhibition of retinoic acid biosynthesis function as a non-hormonal female contraceptive? AB - OBJECTIVE: Vitamin A deficient females have reduced fertility due to decreased retinoic acid production. WIN 18,446 inhibits retinoic acid biosynthesis and functions as a contraceptive in males. We tested whether WIN 18,446 treatment would suppress fertility in female mice. STUDY DESIGN: Female mice were treated with WIN 18,446 and mated. Pregnancy rates were compared using Fisher's exact test. RESULTS: WIN 18,446 reduced pregnancy compared with control (p=.03). However, one animal became pregnant with malformed embryos. CONCLUSIONS: WIN 18,446 treatment significantly reduces fecundity, but teratogenicity in the setting of contraceptive failure limits the appeal of this approach to female contraception. PMID- 29630870 TI - Human epididymis protein 4 in endometrial cancer: A meta-analysis. AB - BACKGROUND: Serum human epididymis protein 4 (HE4) is a potential marker for endometrial cancer (EC), however, the diagnostic value of HE4 for EC remains controversial. In this study, we performed a meta-analysis to estimate the diagnostic accuracy of serum HE4 for EC. METHODS: Literature reports of the diagnostic accuracy of serum HE4 for EC were systematically identified using online data-bases. The meta-analysis was performed using STATA 12.0, Meta-Disc 1.4, and Review Manager 5.2. RESULTS: A total of 4182 participants and 23 studies were included in our meta-analysis. The pooled sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), diagnostic odds ratio (DOR), and area under the curve (AUC) were 0.65 (95% CI: 0.56-0.73), 0.91 (95% CI: 0.84-0.95), (95% CI: 4.38-12.64), 0.38 (95% CI: 0.31 0.47), 19.46 (95% CI: 11.61-32.62) and 0.84 (95% CI: 0.81 to 0.87), respectively. Our overall analysis suggested that HE4 is a useful diagnostic marker for EC. Subgroup analysis indicated that studies with benign disease controls showed higher diagnostic accuracies than those with healthy controls. CONCLUSION: Serum HE4 may serve as a potential biomarker for EC diagnosis. Due to certain limitations, this conclusion should to be cautiously interpreted. PMID- 29630871 TI - Development of an alpha-fetoprotein and Golgi protein 73 multiplex detection assay using xMAP technology. AB - AIM OF THE STUDY: Development of a new method to simultaneously detect Alpha fetoprotein (AFP) and Golgi protein 73 (GP73) from peripheral blood. MATERIAL AND METHODS: Anti human AFP and GP73 monoclonal antibodies was used to develop a sandwich immunity reaction using xMAP technology for the simultaneous detection of plasma AFP and GP73. The assay evaluated the sensitivity, cross reactivity, range of detection, precision, recovery and linearity dilution effect. The assay utilized plasma samples and compared its performance with commercially available Enzyme Linked Immunosorbent Assay (ELISA) kits. RESULTS: The assay was successful in detecting AFP and GP73 simultaneously. Validation experiments demonstrated the limit of detection was AFP 0.006 MUg/l and GP73 0.482 MUg/l. The functional sensitivity was AFP 0.010 MUg/l and GP73 0.640 MUg/l. The range of detection was AFP 0.01-50 MUg/l and GP73 0.64-100 MUg/l. No cross reactivity was observed. The intra- and inter-assay variation for AFP was 0.19-3.46% and 3.1-5.8% and for GP73 was 1.5-3.2% and 1.1-7.6% respectively. The recovery for AFP was 96-106% and GP73 was 89-110%. 80 clinical plasma samples from healthy controls, and patients with liver cirrhosis and Hepatocellular Carcinoma (HCC) were evaluated. For healthy controls (n = 25), the AFP was 2.40 (1.55, 3.30) MUg/l and GP73 was 42.60 (39.10, 57.40) MUg/l. For patients with liver cirrhosis (n = 19), the AFP was 2.60 (1.70, 4.20) MUg/l and GP73 was 136.10 (92.10, 261.70) MUg/l, and for HCC patients (n = 36), the AFP was 13.65 (3.35, 158.88) MUg/l and GP73 was 186.25 (96.73, 262.03) MUg/l. The new assay demonstrated a good correlation with commercially available ELISA kits (correlation coefficients (r) were 0.997 (AFP, p < 0.001) and 0.959 (GP73, p < 0.001). CONCLUSIONS: The method demonstrated a sensitive, effective and accurate method for the simultaneous detection of AFP and GP73, and could be used clinically for routine detection and monitoring of patients with chronic hepatitis B. PMID- 29630872 TI - Embolization of Bleeding Pulmonary Arterial Pseudoaneurysm in a Woman With Infective Endocarditis. AB - Pulmonary arterial pseudoaneurysm is a rare but life-threatening complication of infective endocarditis. This report describes a case of bleeding pulmonary arterial pseudoaneurysm in a young, drug-addicted woman with tricuspid annuloplasty after infective endocarditis that was promptly identified by computed tomography pulmonary angiography and successfully treated using coil embolization. Perfusion scintigraphy at 30 days confirmed the safety of endovascular treatment. PMID- 29630873 TI - The Incidence and Consequence of Prosthesis-Patient Mismatch After Surgical Aortic Valve Replacement. AB - BACKGROUND: The goal of this study was to determine the relationship of prosthesis-patient mismatch (PPM) with long-term survival and to assess whether growing concern about PPM has resulted in a decreased incidence over time. METHODS: Using The Society of Thoracic Surgeons Adult Cardiac Surgery Database, we identified 59,779 patients >=65 years old who underwent isolated surgical aortic valve replacement (AVR) between 2004 and 2014. The degree of PPM was calculated using literature-derived effective orifice areas for commonly used valves. Outcomes to 10 years were stratified by degree of PPM. RESULTS: The distribution of PPM was as follows: 35%, none (n = 21,053); 54%, moderate (n = 32,243); and 11%, severe (n = 6,483). Compared with patients with no PPM, patients with moderate or severe PPM had a significantly increased risk of readmission for heart failure (hazard ratio [HR], 1.15; 95% confidence interval [CI], 1.09 to 1.21; HR, 1.37; 95% CI, 1.26 to 1.48) and redo AVR (HR, 1.41; 95% CI, 1.13 to 1.77; HR, 2.68; 95% CI, 2.01 to 3.56) for moderate or severe PPM, respectively. Survival was significantly worse for any degree of PPM (moderate to none: HR, 1.08; 95% CI, 1.05 to 1.12; severe to none: HR, 1.32; 95% CI, 1.25 to 1.39), with 10-year adjusted survival rates of 46%, 43%, and 35% for none, moderate, and severe, respectively (p < 0.001). The incidence of severe PPM decreased by 55% over the study period, from 13.8% in 2004 to 6.2% in 2014. CONCLUSIONS: Any degree of PPM significantly decreased long-term survival and increased readmission rates for both heart failure and reoperation for AVR. Temporal trends show a significant decrease in the incidence of PPM over the past decade. PMID- 29630874 TI - Hybrid Strategy for Neonates With Ductal-Dependent Systemic Circulation at High Risk for Norwood. AB - BACKGROUND: Hypoplastic left heart syndrome and other cardiac lesions with ductal dependent systemic circulation continue to be challenging to manage, especially in high-risk (HR) populations (those with prematurity, multiple congenital anomalies, moderate to severe tricuspid regurgitation, hemodynamic instability, intact atrial septum). METHODS: A retrospective study on our institution's experience implementing a hybrid strategy as initial palliation in HR patients with ductal-dependent systemic circulation in HR patients undergoing Norwood versus hybrid procedure. From July 2004 to May 2008, 16 HR patients underwent stage I Norwood procedure. After implementation of a hybrid strategy in 2008, 24 HR patients underwent hybrid procedure from May 2008 to November 2015. RESULTS: There was no difference in gestational age, age at procedure, or hospital length of stay. The HR Hybrid group had lower mean weight (2.6 kg vs 3.1 kg, p = 0.026). Thirty-day mortality was lower in the HR Hybrid group (4% vs 31%, p = 0.019), although there was no difference in interstage mortality (17% vs 9%, p = 0.396). Catheter-based reintervention was more prevalent in the HR Hybrid group, but did not have a negative impact on survival. One-year transplant-free survival was similar (p = 0.416). HR Hybrid patients weighing less than 2.6 kg had higher overall survival (83% vs 25%, p = 0.013), as did patients who were premature (70% vs 0%, p = 0.003). CONCLUSIONS: In high-risk patients, the hybrid procedure appears to have lower 30-day mortality and may have a survival benefit in premature patients and those less than 2.6 kg. Long-term attrition in this high risk population is ongoing regardless of early strategy. PMID- 29630875 TI - Systematic Compared With Targeted Staging With Endobronchial Ultrasound in Patients With Lung Cancer. AB - BACKGROUND: To evaluate the accuracy of systematic mediastinal staging by endobronchial ultrasound transbronchial needle aspiration (EBUS-TBNA) (sampling of all visible nodes measuring >=5 mm from stations N3 to N1 regardless of their positron emission tomography/computed tomography [PET/CT] features) and compare this staging approach with targeted EBUS-TBNA staging (sampling only 18F fluorodeoxyglucose [FDG]-avid nodes) in patients with N2 non-small cell lung cancer on PET/CT. METHODS: Retrospective study of 107 patients who underwent systematic EBUS-TBNA mediastinal staging. The results were compared with those of a hypothetical scenario where only FDG-avid nodes on PET/CT would be sampled. RESULTS: Systematic EBUS-TBNA sampling demonstrated N3 disease in 3 patients, N2 disease in 60 (42 single-station or N2a, 18 multiple-station or N2b) and N0/N1 disease in 44. Of these 44, 7 underwent mediastinoscopy, which did not show mediastinal disease; 6 of the 7 proceeded to lung resection, which also showed no mediastinal disease. Thirty-four N0/N1 patients after EBUS-TBNA underwent lung resection directly: N0/N1 was found in 30 and N2 in 4 (1 N2b with a PET/CT showing N2a disease, 3 N2a). Sensitivity, specificity, negative predictive value, positive predictive value, and overall accuracy of systematic EBUS-TBNA were 94%, 100%, 90%, 100% and 96%, respectively. Compared with targeted EBUS-TBNA, systematic EBUS-TBNA sampling provided additional important clinical information in 14 cases (13%): 3 N3 cases would have passed unnoticed, and 11 N2b cases would have been staged as N2a. CONCLUSIONS: In clinical practice, systematic sampling of the mediastinum by EBUS-TBNA, regardless of PET/CT features, is to be recommended over targeted sampling. PMID- 29630876 TI - Successful Surgical Stabilization of Rib Fractures Despite Candida Colonization of the Mediastinum. AB - Pleural space or chest wall infection is a contraindication to surgical stabilization of rib fractures (SSRF) because of the risk of hardware infection. However, the exact degree of risk is uncertain. SSRF is associated with a decreased need for mechanical ventilation and pneumonia. This case report describes a patient with polytrauma and Candida colonization of the mediastinum who successfully underwent SSRF. PMID- 29630877 TI - Impact of fluoride and a static magnetic field on the gene expression that is associated with the antioxidant defense system of human fibroblasts. AB - Fluoride cytotoxicity has been associated with apoptosis, oxidative stress, general changes in DNA and RNA and protein biosynthesis, whereas the results of studies on the effect of SMF on antioxidant activity of cells are contradictory. Therefore, the aim of our study was to evaluate the simultaneous exposure of human cells to fluoride SMF that are generated by permanent magnets on the expression profile of the genes that are associated with the antioxidant defense system. Control fibroblasts and fibroblasts that had been treated with fluoride were subjected to the influence of SMF with a moderate induction. In order to achieve our aims, we applied modern molecular biology techniques such as the oligonucleotide microarray. Among the antioxidant defense genes, five (SOD1, PLK3, CLN8, XPA, HAO1), whose expression was significantly altered by the action of fluoride ions and the exposure to SMF were normalized their expression was identified. We showed that fluoride ions cause oxidative stress, whereas exposure to SMF with a moderate induction can suppress their effects by normalizing the expression of the genes that are altered by fluoride. Our research may explain the molecular mechanisms of the influence of fluoride and SMF that are generated by permanent magnets on cells. PMID- 29630878 TI - 3-Chloro-4,5-dihydroxybenzaldehyde inhibits adipogenesis in 3T3-L1 adipocytes by regulating expression of adipogenic transcription factors and AMPK activation. AB - Obesity is a serious health issue in many industrialized countries. It is a medical condition with excessive levels of fat accumulated in adipocytes. The objective of the present study was to determine the inhibitory effect of 3-chloro 4,5-dihydroxybenzaldehyde (CDB) on adipogenesis in 3T3-L1 adipocyte cells. CDB suppressed the differentiation and decreased lipid accumulation and triglycerides contents in 3T3-L1 adipocytes. Its suppression effect on fat accumulation was mediated via expression of adipogenesis factors (C/EBPalpha, SREBP-1c, PPARgamma, and adiponectin) during adipocyte differentiation in white adipocyte cells. CDB's ability to suppress fat accumulation was increased in a concentration-dependent manner. It inhibited fatty acid synthesis related proteins including FAS, FABP4, leptin, and perilipin. It also increased expression of phosphorylated AMPK in adipocytes cells. These observations suggest that CDB has potential anti-obesity effect with ability to improve metabolic diseases. PMID- 29630879 TI - Atorvastatin induces MicroRNA-145 expression in HEPG2 cells via regulation of the PI3K/AKT signalling pathway. AB - The use of statins as a potential cancer drug has been investigated; however the molecular mechanisms involved in their anti-oxidant, anti-proliferative and anti cancer effects remain elusive. In our study, we investigated the involvement of downstream mevalonate products that mediate the anti-oxidant and anti proliferative effects of Atorvastatin (Ato), and its effect on microRNA-145 expression in HepG2 hepatocellular carcinoma cells. An amorphous soluble form of Ato was prepared and found to be cytotoxic in vitro [IC50 (1.2 mM); 48 h]. Atorvastatin induced a dose-dependent increase in cell mortality with a concomitant depletion of intracellular ATP levels (p = 0.005); significantly increased extracellular nitrite levels (p = 0.001) and decreased lipid peroxidation (p = 0.0097) despite a decrease in GSH. The intrinsic apoptotic pathway was activated via increased caspase -9 (p < 0.0001) and -3/7 (p = 0.0003) activities. Increased protein expression of pGSK3-(alpha/beta) (p = 0.0338), p53 (p = 0.0032), Mdm2 (p < 0.0001), with significantly diminished levels of PI3K (p = 0.0013), pAKT (p = 0.0035), and Akt (p = 0.0077), indicated that Ato-mediated cell death occurred via inhibition of the PI3K/Akt pathway. Additionally, the expression of PI3K (p = 0.0001) and c-myc (p = 0.0127) were also downregulated, whilst and miRNA-145 (p = 0.0156) was upregulated. In conclusion our data strongly indicates a plausible mechanism involved in the cytotoxic effects of Ato and is the first study to show that Ato modulates miR-145 expression in hepatocytes. <= . PMID- 29630880 TI - 3'-Hydroxy-3,4'-dimethoxyflavone-induced cell death in human leukaemia cells is dependent on caspases and reactive oxygen species and attenuated by the inhibition of JNK/SAPK. AB - Flavonoids are phenolic substances that appear to exert beneficial effects in several chronic diseases, including cancer. Structure-activity relationships of the cytotoxic activity of a series of flavonols and their 3-methyl ether derivatives established that 3'-hydroxy-3,4'-dimethoxyflavone (flavonoid 11) displayed strong cytotoxicity against human leukaemia cell lines (HL-60, U-937 and MOLT-3), and cells that over-express the anti-apoptotic proteins, Bcl-2 and Bcl-xL, and against P-glycoprotein-overexpressing K-562/ADR cells. This compound induced G2-M cell cycle arrest and it was a potent apoptotic inducer on HL-60, MOLT-3, U-937 and U-937/Bcl-2 cell lines. Cell death was (i) mediated by caspase activation, since it was prevented by the non-specific caspase inhibitor z-VAD fmk and reduced by a selective caspase-9 inhibitor, (ii) associated with cytochrome c release, the dissipation of the inner mitochondrial membrane potential (DeltaPsim) and the activation of the mitogen-activated protein kinase pathway and (iii) partially blocked by the inhibition of c-jun NH2 terminal kinases/stress activated protein kinases (JNK/SAPK) signalling and by the free radical scavenger N-acetyl-l-cysteine. PMID- 29630882 TI - Physical activity for primary dysmenorrhea: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Primary dysmenorrhea is cramping abdominal pain associated with menses. It is prevalent, affects quality of life, and can cause absenteeism. Although evidence-based medical treatment options exist, women may not tolerate these or may prefer to use nonmedical treatments. Physical activity has been recommended by clinicians for primary dysmenorrhea since the 1930s, but there is still no high-quality evidence on which to recommend its use. OBJECTIVE: We sought to determine the effectiveness of physical activity for the treatment of primary dysmenorrhea. STUDY DESIGN: Systematic literature searches of MEDLINE, Embase, Cochrane, Web of Science, CINAHL, PsycINFO, SPORTDiscus, PEDro, Allied and Complimentary Medicine Database, World Health Organization International Clinical Trials Registry Platform, Clinicaltrials.gov, and OpenGrey were performed, from database inception to May 24, 2017. Google searches and citation searching of previous reviews were also conducted. Studies were selected using the following PICOS criteria: participants were nonathlete females experiencing primary dysmenorrhea; intervention was physical activity delivered for at least 2 menstrual cycles; comparator was any comparator; outcomes were pain intensity or pain duration; and study type was randomized controlled trials. Study quality was assessed using the Cochrane risk of bias tool. Random effects meta-analyses for pain intensity and pain duration were conducted, with prespecified subgroup analysis by type of physical activity intervention. Strength of the evidence was assessed using GRADE. RESULTS: Searches identified 15 eligible randomized controlled trials totaling 1681 participants. Data from 11 studies were included in the meta-analyses. Pooled results demonstrated effect estimates for physical activity vs comparators for pain intensity (-1.89 cm on visual analog scale; 95% CI, -2.96 to -1.09) and pain duration (-3.92 hours; 95% CI, -4.86 to -2.97). Heterogeneity for both of these results was high and only partly mitigated by subgroup analysis. Primary studies were of low or moderate methodological quality but results for pain intensity remained stable during sensitivity analysis by study quality. GRADE assessment found moderate-quality evidence for pain intensity and low-quality evidence for pain duration. CONCLUSION: Clinicians can inform women that physical activity may be an effective treatment for primary dysmenorrhea but there is a need for high-quality trials before this can be confirmed. PMID- 29630881 TI - Aldose reductase inhibitor protects mice from alcoholic steatosis by repressing saturated fatty acid biosynthesis. AB - Alcoholic liver injury results in morbidity and mortality worldwide, but there are currently no effective and safe therapeutics. Previously we demonstrated that aldose reductase (AR) inhibitor ameliorated alcoholic hepatic steatosis. To clarify the mechanism whereby AR inhibitor improves alcoholic hepatic steatosis, herein we investigated the effect of AR inhibitor on hepatic metabolism in mice fed a Lieber-DeCarli liquid diet with 5% ethanol. Nontargeted metabolomics showed carbohydrates and lipids were characteristic categories in ethanol diet-fed mice with or without AR inhibitor treatment, whereas AR inhibitor mainly affected carbohydrates and peptides. Ethanol-induced galactose metabolism and fatty acid biosynthesis are important for the induction of hepatic steatosis, while AR inhibitor impaired galactose metabolism without perturbing fatty acid biosynthesis. In parallel with successful treatment of steatosis, AR inhibitor suppressed ethanol-activated galactose metabolism and saturated fatty acid biosynthesis. Sorbitol in galactose metabolism and stearic acid in saturated fatty acid biosynthesis were potential biomarkers responsible for ethanol or ethanol plus AR inhibitor treatment. In vitro analysis confirmed that exogenous addition of sorbitol augmented ethanol-induced steatosis and stearic acid. These findings not only reveal metabolic patterns associated with disease and treatment, but also shed light on functional biomarkers contribute to AR inhibition therapy. PMID- 29630883 TI - Perhaps cerclage is the ideal treatment for the cervix <1 cm. PMID- 29630884 TI - Recommended standardized terminology of the anterior female pelvis based on a structured medical literature review. AB - BACKGROUND: The use of imprecise and inaccurate terms leads to confusion amongst anatomists and medical professionals. OBJECTIVE: We sought to create recommended standardized terminology to describe anatomic structures of the anterior female pelvis based on a structured review of published literature and selected text books. STUDY DESIGN: We searched MEDLINE from its inception until May 2, 2016, using 11 medical subject heading terms to identify studies reporting on anterior female pelvic anatomy; any study type published in English was accepted. Nine textbooks were also included. We screened 12,264 abstracts, identifying 200 eligible studies along with 13 textbook chapters from which we extracted all pertinent anatomic terms. RESULTS: In all, 67 unique structures in the anterior female pelvis were identified. A total of 59 of these have been previously recognized with accepted terms in Terminologia Anatomica, the international standard on anatomical terminology. We also identified and propose the adoption of 4 anatomic regional terms (lateral vaginal wall, pelvic sidewall, pelvic bones, and anterior compartment), and 2 structural terms not included in Terminologia Anatomica (vaginal sulcus and levator hiatus). In addition, we identified 2 controversial terms (pubourethral ligament and Grafenberg spot) that require additional research and consensus from the greater medical and scientific community prior to adoption or rejection of these terms. CONCLUSION: We propose standardized terminology that should be used when discussing anatomic structures in the anterior female pelvis to help improve communication among researchers, clinicians, and surgeons. PMID- 29630885 TI - Vaginal progesterone is as effective as cervical cerclage to prevent preterm birth in women with a singleton gestation, previous spontaneous preterm birth, and a short cervix: updated indirect comparison meta-analysis. AB - BACKGROUND: An indirect comparison meta-analysis published in 2013 reported that both vaginal progesterone and cerclage are equally efficacious for preventing preterm birth and adverse perinatal outcomes in women with a singleton gestation, previous spontaneous preterm birth, and a sonographic short cervix. The efficacy of vaginal progesterone has been challenged after publication of the OPPTIMUM study. However, this has been resolved by an individual patient-data meta analysis (Am J Obstet Gynecol. 2018;218:161-180). OBJECTIVE: To compare the efficacy of vaginal progesterone and cerclage in preventing preterm birth and adverse perinatal outcomes in women with a singleton gestation, previous spontaneous preterm birth, and a midtrimester sonographic short cervix. DATA SOURCES: MEDLINE, EMBASE, LILACS, and CINAHL (from their inception to March 2018); Cochrane databases, bibliographies, and conference proceedings. STUDY ELIGIBILITY CRITERIA: Randomized controlled trials comparing vaginal progesterone to placebo/no treatment or cerclage to no cerclage in women with a singleton gestation, previous spontaneous preterm birth, and a sonographic cervical length <25 mm. STUDY APPRAISAL AND SYNTHESIS METHODS: Updated systematic review and adjusted indirect comparison meta-analysis of vaginal progesterone vs cerclage using placebo/no cerclage as the common comparator. The primary outcomes were preterm birth <35 weeks of gestation and perinatal mortality. Pooled relative risks (RRs) with 95% confidence intervals were calculated. RESULTS: Five trials comparing vaginal progesterone vs placebo (265 women) and 5 comparing cerclage vs no cerclage (504 women) were included. Vaginal progesterone, compared to placebo, significantly reduced the risk of preterm birth <35 and <32 weeks of gestation, composite perinatal morbidity/mortality, neonatal sepsis, composite neonatal morbidity, and admission to the neonatal intensive care unit (RRs from 0.29 to 0.68). Cerclage, compared to no cerclage, significantly decreased the risk of preterm birth <37, <35, <32, and <28 weeks of gestation, composite perinatal morbidity/mortality, and birthweight <1500 g (RRs from 0.64 to 0.70). Adjusted indirect comparison meta-analyses did not show statistically significant differences between vaginal progesterone and cerclage in the reduction of preterm birth or adverse perinatal outcomes. CONCLUSION: Vaginal progesterone and cerclage are equally effective for preventing preterm birth and improving perinatal outcomes in women with a singleton gestation, previous spontaneous preterm birth, and a midtrimester sonographic short cervix. The choice of treatment will depend on adverse events and cost-effectiveness of interventions and patient/physician's preferences. PMID- 29630886 TI - Antenatal corticosteroids: an assessment of anticipated benefits and potential risks. AB - Antenatal corticosteroids are standard of care for pregnancies at risk of preterm delivery between 24-34 weeks' gestational age. Recent trials demonstrate modest benefits from antenatal corticosteroids for late preterm and elective cesarean deliveries, and antenatal corticosteroids for periviable deliveries should be considered with family discussion. However, many women with threatened preterm deliveries receive antenatal corticosteroids but do not deliver until >34 weeks or at term. The net effect is that a substantial fraction of the delivery population will be exposed to antenatal corticosteroids. There are gaps in accurate assessments of benefits of antenatal corticosteroids because the randomized controlled trials were performed prior to about 1990 in pregnancies generally >28 weeks. The care practices for the mother and infant survival were different than today. The randomized controlled trial data also do not strongly support the optimal interval from antenatal corticosteroid treatment to delivery of 1-7 days. Epidemiology-based studies using large cohorts with >85% of at-risk pregnancies treated with antenatal corticosteroids probably overestimate the benefits of antenatal corticosteroids. Although most of the prematurity associated mortality is in low-resource environments, the efficacy and safety of antenatal corticosteroids in those environments remain to be evaluated. The short term benefits of antenatal corticosteroids for high-risk pregnancies in high resource environments certainly justify antenatal corticosteroids as few risks have been identified over many years. However, cardiovascular and metabolic abnormalities have been identified in large animal models and cohorts of children exposed to antenatal corticosteroids that are consistent with fetal programming for adult diseases. These late effects of antenatal corticosteroids suggest caution for the expanded use of antenatal corticosteroids beyond at-risk pregnancies at 24-34 weeks. A way forward is to develop noninvasive fetal assessments to identify pregnancies across a wider gestational age that could benefit from antenatal corticosteroids. PMID- 29630887 TI - Opioid prescribing patterns among postpartum women. AB - BACKGROUND: Women commonly receive opioid prescriptions following hospitalization. The rise of the opioid epidemic in the United States underscores the importance of a better understanding of prescribing patterns. Although delivery is the most frequent reason for hospitalization in the United States, there is inadequate knowledge regarding opioid prescribing at postpartum hospital discharge. OBJECTIVE: We sought to describe opioid prescribing patterns at the time of discharge following delivery in a large, diverse cohort, and to describe the relationship of these patterns with objective and subjective measures of pain prior to discharge. STUDY DESIGN: This is a retrospective cohort study of all deliveries at a single, high-volume tertiary care center over a 1-year period. Women were excluded from analysis if they had evidence of recent opioid use, or their labor, delivery, or postpartum course was notable for rare, nonroutine events anticipated to increase pain. Medical records were queried for demographic and clinical data, including whether an opioid prescription was provided at discharge, and if so, details of that prescription. The primary outcome was amount of opioid morphine milligram equivalents prescribed at discharge, described separately for women after vaginal and cesarean deliveries. Among women who received a prescription, we additionally assessed associations between prescription quantity and subjective (patient-reported pain score) and objective (inpatient opioid requirement during the final 24 hours of hospitalization) assessments of pain. Descriptive and bivariable analyses were performed. RESULTS: Of the total 12,611 women, 12,326 were eligible for inclusion. Of 9038 women postvaginal delivery and 3288 women postcesarean delivery, 30.4% and 86.7% received an opioid prescription at discharge, respectively. Of women receiving discharge opioid prescriptions, median morphine milligram equivalents received was 200 (interquartile range: 120-300) following vaginal and 300 (interquartile range: 200-300) following cesarean delivery. Nearly half (45.7%) of women postvaginal delivery and 18.5% of women postcesarean delivery who received an opioid prescription used 0 morphine milligram equivalent during the final hospital day. Similarly, 26.5% and 18.5% of women after vaginal and cesarean delivery, respectively, reported a pain score of 0 of 10 prior to discharge. Regardless of delivery mode, the amount of opioids prescribed did not differ between those who reported a pain score of 0 of 10 and those who reported a pain score of >0 of 10 immediately prior to discharge. Similarly, for women who underwent cesarean delivery, the morphine milligram equivalents prescribed did not differ between those who used 0 morphine milligram equivalents and those who used >0 in the 24 hours prior to hospital discharge. CONCLUSION: Postpartum women are commonly prescribed opioids at the time of postpartum hospital discharge. There is a wide range of morphine milligram equivalents prescribed at hospital discharge following delivery, highlighting a lack of standardization. Furthermore, regardless of objective and subjective measures of pain prior to discharge, women received similar amounts of prescription morphine milligram equivalents following either vaginal or cesarean deliveries. PMID- 29630888 TI - Long-term mortality risk and life expectancy following recurrent hypertensive disease of pregnancy. AB - BACKGROUND: Women with a history of hypertensive disease of pregnancy have increased risks for early mortality from multiple causes. The effect of recurrent hypertensive disease of pregnancy on mortality risk and life expectancy is unknown. OBJECTIVE: We sought to determine whether recurrent hypertensive disease of pregnancy is associated with increased mortality risks. STUDY DESIGN: In this retrospective cohort study, we used birth certificate data to determine the number of pregnancies affected by hypertensive disease of pregnancy for each woman delivering in Utah from 1939 through 2012. We assigned women to 1 of 3 groups based on number of affected pregnancies: 0, 1, or >=2. Exposed women had >=1 affected singleton pregnancy and lived in Utah for >=1 year postpartum. Exposed women were matched 1:2 to unexposed women by age, year of childbirth, and parity. Underlying cause of death was determined from death certificates. Mortality risks by underlying cause of death were compared between exposed and unexposed women as a function of number of affected pregnancies. Cox regressions controlled for infant sex, gestational age, parental education, ethnicity, and marital status. RESULTS: We identified 57,384 women with >=1 affected pregnancy (49,598 women with 1 affected pregnancy and 7786 women with >=2 affected pregnancies). These women were matched to 114,768 unexposed women. As of 2016, 11,894 women were deceased: 4722 (8.2%) exposed and 7172 (6.3%) unexposed. Women with >=2 affected pregnancies had increased mortality from all causes (adjusted hazard ratio, 2.04; 95% confidence interval, 1.76-2.36), diabetes (adjusted hazard ratio, 4.33; 95% confidence interval, 2.21-8.47), ischemic heart disease (adjusted hazard ratio, 3.30; 95% confidence interval, 2.02-5.40), and stroke (adjusted hazard ratio, 5.10; 95% confidence interval, 2.62-9.92). For women whose index pregnancy delivered from 1939 through 1959 (n = 10,488), those with >=2 affected pregnancies had shorter additional life expectancies than mothers who had only 1 or 0 hypertensive pregnancies (48.92 vs 51.91 vs 55.48 years, respectively). CONCLUSION: Hypertensive diseases of pregnancy are associated with excess risks for early all-cause mortality and some cause-specific mortality, and these risks increase further with recurrent disease. PMID- 29630890 TI - Risk factors for explantation due to infection after sacral neuromodulation: a multicenter retrospective case-control study. AB - BACKGROUND: Sacral neuromodulation is an effective therapy for overactive bladder, urinary retention, and fecal incontinence. Infection after sacral neurostimulation is costly and burdensome. Determining optimal perioperative management strategies to reduce the risk of infection is important to reduce this burden. OBJECTIVE: We sought to identify risk factors associated with sacral neurostimulator infection requiring explantation, to estimate the incidence of infection requiring explantation, and identify associated microbial pathogens. STUDY DESIGN: This is a multicenter retrospective case-control study of sacral neuromodulation procedures completed from Jan. 1, 2004, through Dec. 31, 2014. We identified all sacral neuromodulation implantable pulse generator implants as well as explants due to infection at 8 participating institutions. Cases were patients who required implantable pulse generator explantation for infection during the review period. Cases were included if age >=18 years old, follow-up data were available >=30 days after implantable pulse generator implant, and the implant was performed at the institution performing the explant. Two controls were matched to each case. These controls were the patients who had an implantable pulse generator implanted by the same surgeon immediately preceding and immediately following the identified case who met inclusion criteria. Controls were included if age >=18 years old, no infection after implantable pulse generator implant, follow-up data were available >=180 days after implant, and no explant for any reason <180 days from implant. Controls may have had an explant for reasons other than infection at >180 days after implant. Fisher exact test (for categorical variables) and Student t test (for continuous variables) were used to test the strength of the association between infection and patient and surgery characteristics. Significant variables were then considered in a multivariable logistic regression model to determine risk factors independently associated with infection. RESULTS: Over a 10-year period at 8 academic institutions, 1930 sacral neuromodulator implants were performed by 17 surgeons. In all, 38 cases requiring device explant for infection and 72 corresponding controls were identified. The incidence of infection requiring explant was 1.97%. Hematoma formation (13% cases, 0% controls; P = .004) and pocket depth of >=3 cm (21% cases, 0% controls; P = .031) were independently associated with an increased risk of infection requiring explant. On multivariable regression analysis controlling for significant variables, both hematoma formation (P = .006) and pocket depth >=3 cm (P = .020, odds ratio 3.26; 95% confidence interval, 1.20-8.89) remained significantly associated with infection requiring explant. Of the 38 cases requiring explant, 32 had cultures collected and 24 had positive cultures. All 5 cases with a hematoma had a positive culture (100%). Of the 4 cases with a pocket depth >=3 cm, 2 had positive cultures, 1 had negative cultures, and 1 had a missing culture result. The most common organism identified was methicillin-resistant Staphylococcus aureus (38%). CONCLUSION: Infection after sacral neuromodulation requiring device explant is low. The most common infectious pathogen identified was methicillin-resistant S aureus. Demographic and health characteristics did not predict risk of explant due to infection, however, having a postoperative hematoma or a deep pocket >=3 cm significantly increased the risk of explant due to infection. These findings highlight the importance of meticulous hemostasis as well as ensuring the pocket depth is <3 cm at the time of device implant. PMID- 29630889 TI - Use of raloxifene and tamoxifen by breast cancer risk level in a Medicare eligible cohort. AB - BACKGROUND: Raloxifene and tamoxifen are Food and Drug Administration-approved for breast cancer risk reduction; in 2013, the US Preventive Services Task Force recommended these drugs for breast cancer risk reduction in high-risk women. Information on the use of raloxifene and tamoxifen for breast cancer risk reduction in the general population indicates that the risk is believed to be low; however, there is little literature. OBJECTIVE: The purpose of this study was to assess the use of breast cancer risk reduction medications by breast cancer risk level in an older cohort of women. STUDY DESIGN: Women who were enrolled in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial were assessed for the use of raloxifene, tamoxifen, and other medications. The data sources for use of the drugs were a mailed medication use questionnaire in 2013 and linked Medicare Part D claims files from 2010-2014. Estimated breast cancer risk within 5 years was assessed with the use of the modified Gail model and self-reported breast cancer risk factors; comorbidities were assessed through a questionnaire. RESULTS: A total of 22,235 women completed the medication use questionnaire; of these, 13,640 women (61%) had linked Part D data. In 2013, 45% of the women were 65-74 years old, and 55% of the women were 75-84 years old. From the medication use questionnaire, raloxifene use (past month) was 1.8%, 2.5%, and 4.0% for women with breast cancer risk within 5 years of <1.66%, 1.66 3.0%, and >=3%, respectively (probability value trend, <.0001). From Part D, for any use during the period among women with coverage, raloxifene rates were 3.3%, 4.0%, and 6.6% for the 3 categories for breast cancer risk within 5 years (probability value trend, <.0001); use was 7.4% and 3.3% in women with and without osteoporosis, respectively. Raloxifene use significantly decreased from 2010-2014, and specifically from 2012-2014, both for all women and for women with breast cancer risk within 5 years of >=3%. Tamoxifen use from Part D was 0.36%, 0.45%, and 0.85% for the 3 categories for breast cancer risk within 5 years (probability value trend, .009). CONCLUSION: Raloxifene use was low overall but increased modestly with breast cancer risk, and usage decreased from 2010-2014. Tamoxifen use was very low. PMID- 29630892 TI - Long-Standing Abdominal Complaints and Hyperamylasemia Due to Foreign Body Ingestion. PMID- 29630891 TI - Membrane plasticity facilitates recognition of the inhibitor oligomycin by the mitochondrial ATP synthase rotor. AB - Enzymes in the respiratory chain are increasingly seen as potential targets against multi-drug resistance of human pathogens and cancerous cells. However, a detailed understanding of the mechanism and specificity determinants of known inhibitors is still lacking. Oligomycin, for example, has been known to be an inhibitor of the membrane motor of the mitochondrial ATP synthase for over five decades, and yet little is known about its mode of action at the molecular level. In a recent breakthrough, a crystal structure of the S. cerevisiae c-subunit ring with bound oligomycin revealed the inhibitor docked on the outer face of the proton-binding sites, deep into the transmembrane region. However, the structure of the complex was obtained in an organic solvent rather than detergent or a lipid bilayer, and therefore it has been unclear whether this mode of recognition is physiologically relevant. Here, we use molecular dynamics simulations to address this question and gain insights into the mechanism of oligomycin inhibition. Our findings lead us to propose that oligomycin naturally partitions into the lipid/water interface, and that in this environment the inhibitor can indeed bind to any of the c-ring proton-carrying sites that are exposed to the membrane, thereby becoming an integral component of the proton-coordinating network. As the c-ring rotates within the membrane, driven either by downhill proton permeation or ATP hydrolysis, one of the protonated, oligomycin-bound sites eventually reaches the subunit-a interface and halts the rotary mechanism of the enzyme. PMID- 29630893 TI - Regulation of VDAC1 contributes to the cardioprotective effects of penehyclidine hydrochloride during myocardial ischemia/reperfusion. AB - Penehyclidine hydrochloride (PHC) preconditioning can alleviate myocardial ischemia/reperfusion (I/R) injury and inhibits the upregulation of voltage dependent anion channel 1 (VDAC1) during I/R. To validate that VDAC1 is a bona fide target of PHC for the protection against myocardial I/R injury, VDAC1 expression construct was delivered by lentiviruses into rat left ventricular myocardium before PHC preconditioning and myocardial I/R. Overexpression of VDAC1 exacerbated cardiac dysfunction and myocardial injury following I/R, and abolished the cardioprotective effect of PHC during I/R injury. Moreover, VDAC1 overexpression with myocardial I/R further increased cytochrome c release from mitochondria to cytoplasm, elevated the levels of cleaved caspase-3 and Bax, and decreased the level of Bcl-2 as compared with I/R alone, and PHC-mediated inhibition of mitochondria-dependent apoptosis during myocardial I/R was abolished by VDAC1 overexpression. In addition, VDAC1 was overexpressed in H9c2 cardiomyocytes undergoing anoxia/reoxygenation (A/R) with or without PHC pretreatment. The in vitro results showed that overexpression of VDAC1 further reduced mitochondrial membrane potential, increased mitochondrial membrane permeability and enhanced mitochondria-dependent apoptosis in H9c2 cells after A/R, and VDAC1 overexpression abrogated the protective effect of PHC on the mitochondrial function and integrity during A/R. In conclusion, exogenous overexpression of VDAC1 during myocardial I/R inhibits the cardioprotective effects of PHC. These effects may be associated with the suppression of VDAC1 expression. PMID- 29630894 TI - Better With Ultrasound: Paracentesis. AB - Paracentesis is a commonly performed procedure and generally considered to be low risk. Despite its overall favorable safety profile, use of ultrasound has been demonstrated to reduce the incidence of complications, especially in higher risk patients. Many individual ultrasound techniques have been described in the literature, each with the goal of making paracentesis safer. This article presents a systematic approach for incorporating many of these tools into bedside practice and includes a series of illustrative figures and narrated video presentations to demonstrate the techniques described. PMID- 29630895 TI - Adverse childhood experiences and HPA axis function in pregnant women. PMID- 29630896 TI - Plains zebra (Equus quagga) adrenocortical activity increases during times of large aggregations in the Serengeti ecosystem. AB - Adverse environmental stimuli (stressors) activate the hypothalamic-pituitary adrenal axis and contribute to allostatic load. This study investigates the contribution of environmental stressors and life history stage to allostatic load in a migratory population of plains zebras (Equus quagga) in the Serengeti ecosystem, in Tanzania, which experiences large local variations in aggregation. We expected higher fGCM response to the environmental stressors of feeding competition, predation pressure and unpredictable social relationships in larger than in smaller aggregations, and in animals at energetically costly life history stages. As the study was conducted during the 2016 El Nino, we did not expect food quality of forage or a lack of water to strongly affect fGCM responses in the dry season. We measured fecal glucocorticoid metabolite (fGCM) concentrations using an enzyme immunoassay (EIA) targeting 11beta-hydroxyetiocholanolone and validated its reliability in captive plains zebras. Our results revealed significantly higher fGCM concentrations 1) in large aggregations than in smaller groupings, and 2) in band stallions than in bachelor males. Concentrations of fGCM were not significantly higher in females at the energetically costly life stage of late pregnancy/lactation. The higher allostatic load of stallions associated with females, than bachelor males is likely caused by social stressors. In conclusion, migratory zebras have elevated allostatic loads in large aggregations that probably result from their combined responses to increased feeding competition, predation pressure and various social stressors. Further research is required to disentangle the contribution of these stressors to allostatic load in migratory populations. PMID- 29630897 TI - Brain pericyte activation occurs early in Huntington's disease. AB - Microvascular changes have recently been described for several neurodegenerative disorders, including Huntington's disease (HD). HD is characterized by a progressive neuronal cell loss due to a mutation in the Huntingtin gene. However, the temporal and spatial microvascular alterations in HD remain unclear. Also, knowledge on the implication of pericytes in HD pathology is still sparse and existing findings are contradictory. Here we examine alterations in brain pericytes in the R6/2 mouse model of HD and in human post mortem HD brain sections. To specifically track activated pericytes, we crossbred R6/2 mice with transgenic mice expressing the Green fluorescent protein gene under the Regulator of G-protein signaling 5 (Rgs5) promoter. We demonstrate an increase in activated pericytes in the R6/2 brain and in post mortem HD brain tissue. Importantly, pericyte changes are already detected before striatal neuronal cell loss, weight loss or behavioural deficits occur in R6/2 mice. This is associated with vascular alterations, whereby striatal changes precede cortical changes. Our findings suggest that pericyte activation may be one of the initial steps contributing to the observed vascular modifications in HD. Thus, pericytes may constitute an important target to address early microvascular changes contributing to disease progression in HD. PMID- 29630899 TI - IKK1/2 protect human cells from TNF-mediated RIPK1-dependent apoptosis in an NF kappaB-independent manner. AB - TNF signaling is directly linked to cancer development and progression. A broad range of tumor cells is able to evade cell death induced by TNF impairing the potential anti-cancer value of TNF in therapy. Although sensitizing cells to TNF induced death therefore has great clinical implications, detailed mechanistic insights into TNF-mediated human cell death still remain unknown. Here, we analyzed human cells by applying CRISPR/Cas9n to generate cells deficient of IKK1, IKK2, IKK1/2 and RELA. Despite stimulation with TNF resulted in impaired NF kappaB activation in all genotypes compared to wildtype cells, increased cell death was observable only in IKK1/2-double-deficient cells. Cell death could be detected by Caspase-3 activation and binding of Annexin V. TNF-induced programmed cell death in IKK1/2-/- cells was further shown to be mediated via RIPK1 in a predominantly apoptotic manner. Our findings demonstrate the IKK complex to protect from TNF-induced cell death in human cells independently to NF-kappaB RelA suggesting IKK1/2 to be highly promising targets for cancer therapy. PMID- 29630898 TI - Gut Microbiota Promotes Tumor Growth in Mice by Modulating Immune Response. AB - We studied the effects of gut microbiome depletion by oral antibiotics on tumor growth in subcutaneous and liver metastases models of pancreatic cancer, colon cancer, and melanoma. Gut microbiome depletion significantly reduced tumor burden in all the models tested. However, depletion of gut microbiome did not reduce tumor growth in Rag1-knockout mice, which lack mature T and B cells. Flow cytometry analyses demonstrated that gut microbiome depletion led to significant increase in interferon gamma-producing T cells with corresponding decrease in interleukin 17A and interleukin 10-producing T cells. Our results suggest that gut microbiome modulation could emerge as a novel immunotherapeutic strategy. PMID- 29630900 TI - IP3R3 silencing induced actin cytoskeletal reorganization through ARHGAP18/RhoA/mDia1/FAK pathway in breast cancer cell lines. AB - Cell morphology is altered in the migration process, and the underlying cytoskeleton remodeling is highly dependent of intracellular Ca2+ concentration. Many calcium channels are known to be involved in migration. Inositol 1,4,5 trisphosphate receptor (IP3R) was demonstrated to be implicated in breast cancer cells migration, but its involvement in morphological changes during the migration process remains unclear. In the present work, we showed that IP3R3 expression was correlated to cell morphology. IP3R3 silencing induced rounding shape and decreased adhesion in invasive breast cancer cell lines. Moreover, IP3R3 silencing decreased ARHGAP18 expression, RhoA activity, Cdc42 expression and Y861FAK phosphorylation. Interestingly, IP3R3 was able to regulate profilin remodeling, without inducing any myosin II reorganization. IP3R3 silencing revealed an oscillatory calcium signature, with a predominant oscillating profile occurring in early wound repair. To summarize, we demonstrated that IP3R3 is able to modulate intracellular Ca2+ availability and to coordinate the remodeling of profilin cytoskeleton organization through the ARHGAP18/RhoA/mDia1/FAK pathway. PMID- 29630902 TI - Repurposing and repositioning neurosteroids in the treatment of traumatic brain injury: A report from the trenches. AB - The field of neuroprotection after brain injuries has been littered with failed clinical trials. Finding a safe and effective treatment for acute traumatic brain injury remains a serious unmet medical need. Repurposing drugs that have been in use for other disorders is receiving increasing attention as a strategy to move candidate drugs more quickly to trial while reducing the very high cost of new drug development. This paper describes our own serendipitous discovery of progesterone's neuroprotective potential, and the strategies we are using in repurposing and developing this hormone for use in brain injuries-applications very different from its classical uses in treating disorders of the reproductive system. We have been screening and testing a novel analog that maintains progesterone's therapeutic properties while overcoming its physiochemical challenges, and testing progesterone in combination treatment with another pleiotropic hormone, vitamin D. Finally, our paper, in the context of the problems and pitfalls we have encountered, surveys some of the factors we found to be critical in the clinical translation of repurposed drugs. PMID- 29630903 TI - Lifelong environmental enrichment in the absence of exercise protects the brain from age-related cognitive decline. AB - Environmental manipulations enhance neuroplasticity, with enrichment-induced cognitive improvements linked to increased expression of growth factors and enhanced hippocampal neurogenesis. Environmental enrichment (EE) is defined as the addition of social, physical and somatosensory stimulation into an animal's environment via larger group housing, extra objects and, often, running wheels. Previous studies from our laboratory report that physical activity is a potent memory enhancer but that long-term environmental stimulation can be as effective as exercise at ameliorating age-related memory decline. To assess the effects of EE, in the absence of exercise, rats were housed in continuous enriched conditions for 20 months and memory assessed at young, middle aged and aged timepoints. MRI scans were also performed at these timepoints to assess regional changes in grey matter and blood flow with age, and effects of EE upon these measures. Results show an age-related decline in recognition, spatial and working memory that was prevented by EE. A parallel reduction in betaNGF in hippocampus, and cell proliferation in the dentate gyrus, was prevented by EE. Furthermore, EE attenuated an age-related increase in apoptosis and expression of pro inflammatory markers IL-1beta and CD68. Long-term EE induced region-specific changes in grey matter intensity and partially rescued age-related reductions in cerebral blood flow. This study demonstrates that sensory enrichment alone can ameliorate many features typical of the ageing brain, such as increases in apoptosis and pro-inflammatory markers. Furthermore, we provide novel data on enrichment-induced regional grey matter alterations and age-related changes in blood flow in the rat. PMID- 29630901 TI - NFE2L2, PPARGC1alpha, and pesticides and Parkinson's disease risk and progression. AB - OBJECTIVE: To investigate three expression-altering NFE2L2 SNPs and four PPARGC1alpha previously implicated SNPs and pesticides on Parkinson's disease (PD) risk and symptom progression. METHODS: In 472 PD patients and 532 population based controls, we examined variants and their interactions with maneb and paraquat (MB/PQ) pesticide exposure on PD onset (logistic regression) and progression of motor symptoms and cognitive decline (n = 192; linear repeated measures). RESULTS: NFE2L2 rs6721961 T allele was associated with a reduced risk of PD (OR = 0.70, 95% CI = 0.53, 0.94) and slower cognitive decline (beta = 0.095; p = 0.0004). None of the PPARGC1alpha SNPs were marginally associated with PD risk. We estimate statistical interactions between MB/PQ and PPARGC1alpha rs6821591 (interaction p = 0.009) and rs8192678 (interaction p = 0.05), such that those with high exposure and the variant allele were at an increased risk of PD (OR >= 1.30, p <= 0.05). PPARGC1alpha rs6821591 was also associated with faster motor symptom progression as measured with the UPDRS-III (beta = 0.234; p = 0.001). CONCLUSION: Our study provides support for the involvement of both NFE2L2 and PPARGC1alpha in PD susceptibility and progression, marginally and through pathways involving MB/PQ exposure. PMID- 29630904 TI - Spontaneous Coronary Artery Dissection: Cardiac Manifestations of Vascular Disease. AB - Spontaneous coronary artery dissection (SCAD) is an increasingly recognized cause of acute coronary syndrome (ACS) in young women who otherwise do not have traditional risk factors for coronary artery disease. Though previously considered to be a rare occurrence and primarily associated with pregnancy, contemporary series have demonstrated that SCAD may account for 35% of ACS in women under the age of 50 years, and peripartum SCAD accounts for the minority of cases. Importantly, an association between SCAD and arterial abnormalities in non coronary arterial distributions has been described. The most common of these arterial abnormalities is fibromuscular dysplasia. This manuscript will briefly review the epidemiology, diagnosis, and treatment of SCAD and provide an overview of how SCAD may be a cardiac manifestation of an underlying vascular disease in the majority of patients. PMID- 29630905 TI - Introduction to the Vascular Medicine Issue of Progress in Cardiovascular Diseases. PMID- 29630907 TI - Mathematical modelling of pressure-driven micropolar biological flow due to metachronal wave propulsion of beating cilia. AB - In this paper, we present an analytical study of pressure-driven flow of micropolar non-Newtonian physiological fluids through a channel comprising two parallel oscillating walls. The cilia are arranged at equal intervals and protrude normally from both walls of the infinitely long channel. A metachronal wave is generated due to natural beating of cilia and the direction of wave propagation is parallel to the direction of fluid flow. Appropriate expressions are presented for deformation via longitudinal and transverse velocity components induced by the ciliary beating phenomenon with cilia assumed to follow elliptic trajectories. The conservation equations for mass, longitudinal and transverse (linear) momentum and angular momentum are reduced in accordance with the long wavelength and creeping Stokesian flow approximations and then normalized with appropriate transformations. The resulting non-linear moving boundary value problem is solved analytically for constant micro-inertia density, subject to physically realistic boundary conditions. Closed-form expressions are derived for axial velocity, angular velocity, volumetric flow rate and pressure rise. The transport phenomena are shown to be dictated by several non-Newtonian parameters, including micropolar material parameter and Eringen coupling parameter, and also several geometric parameters, viz eccentricity parameter, wave number and cilia length. The influence of these parameters on streamline profiles (with a view to addressing trapping features via bolus formation and evolution), pressure gradient and other characteristics are evaluated graphically. Both axial and angular velocities are observed to be substantially modified with both micropolar rheological parameters and furthermore are significantly altered with increasing volumetric flow rate. Free pumping is also examined. An inverse relationship between pressure rise and flow rate is computed which is similar to that observed in Newtonian fluids. The study is relevant to hemodynamics in narrow capillaries and also bio-inspired micro-fluidic devices. PMID- 29630906 TI - Elevated stress hormone levels and antidepressant treatment starting before pregnancy affect maternal care and litter characteristics in an animal model of depression. AB - Many women who take antidepressant medications become pregnant while taking their medication; however, the impact of depression and antidepressant medication on fetal development is not well understood. This study used a translational animal model of maternal depression to investigate the consequences of discontinuing antidepressant medication during pregnancy. First, rats received corticosterone (CORT; 40 mg/kg, s.c.) or vehicle to induce a depressive-like phenotype. After 16 days of treatment with CORT or vehicle, animals were treated with sertraline (a selective serotonin reuptake inhibitor, SSRI; 20 mg/kg) or vehicle via gavage. Following 21 days of CORT or oil treatment, rats were mated. One group receiving sertraline was discontinued from treatment on gestational day 16, and another group continued sertraline treatment throughout pregnancy to assess the effects of discontinuation. After weaning, dams were sacrificed via perfusion to investigate neurogenesis. As intended, CORT administration created a depressive like phenotype with increased immobility in the Forced Swim Test and reduced body weight. Interestingly, sertraline treatment could not rescue these altered features. Pre-conceptional CORT exposure resulted in smaller litters and CORT dams that received sertraline until the end of gestation spent more time off of the nest compared to CORT dams that received vehicle or discontinued sertraline during gestation. There was no difference in hippocampal neurogenesis between any of the groups. Our results suggest that treatment with antidepressants may have different effects in healthy or depressed dams, however, we need more research to investigate the detailed and long-term effects of maternal depression and its treatment in translational animal models. PMID- 29630909 TI - Paleovirology of bornaviruses: What can be learned from molecular fossils of bornaviruses. AB - Endogenous viral elements (EVEs) are virus-derived sequences embedded in eukaryotic genomes formed by germline integration of viral sequences. As many EVEs were integrated into eukaryotic genomes millions of years ago, EVEs are considered molecular fossils of viruses. EVEs can be valuable informational sources about ancient viruses, including their time scale, geographical distribution, genetic information, and hosts. Although integration of viral sequences is not required for replications of viruses other than retroviruses, many non-retroviral EVEs have been reported to exist in eukaryotes. Investigation of these EVEs has expanded our knowledge regarding virus-host interactions, as well as provided information on ancient viruses. Among them, EVEs derived from bornaviruses, non-retroviral RNA viruses, have been relatively well studied. Bornavirus-derived EVEs are widely distributed in animal genomes, including the human genome, and the history of bornaviruses can be dated back to more than 65 million years. Although there are several reports focusing on the biological significance of bornavirus-derived sequences in mammals, paleovirology of bornaviruses has not yet been well described and summarized. In this paper, we describe what can be learned about bornaviruses from endogenous bornavirus-like elements from the view of paleovirology using published results and our novel data. PMID- 29630908 TI - The sub-chronic toxicity of a naphthenic hydrocarbon solvent in rats. AB - Cycloalkanes/naphthenes are constituents of complex hydrocarbon solvents, and hence an understanding of their toxicological profile is critical to establish safe limits for occupational exposures to these solvents. Although naphthenes are structurally related to and share a common metabolic fate with the straight and branched chain analogues, some toxicokinetic differences have been noted. The acute central nervous system response to volatile naphthenes in rodents has been shown to be slightly different compared to other alkane analogues. To determine whether these differences may extend to systemic effects with less volatile naphthenes, rats were exposed to 1500, 3000 or 6000 mg/m3 of a C9-C11 aliphatic solvent containing 70% naphthenes, for 90 days. Effects were limited to adaptive liver enlargement in both sexes and kidney toxicity in the male rat. For comparative purposes, the results from this study were compared to published reports of a complex hydrocarbon solvent with a higher proportion of volatile C5/C6 naphthenes and a mono-constituent naphthene (decahydronaphthalene). The results indicate that the systemic effects of naphthenes are similar to the straight and branched chain analogues and that the effects that are most relevant for human health evaluations of alkanes are acute central nervous system effects. PMID- 29630911 TI - Somatic polymerase epsilon mutations as another route leading to loss of DNA MMR protein expression in endometrial carcinoma-reply. PMID- 29630910 TI - Discovery of Mwinilunga alphavirus: A novel alphavirus in Culex mosquitoes in Zambia. AB - Mosquito-borne alphaviruses are disseminated globally and cause febrile illness in humans and animals. Since the prevalence and diversity of alphaviruses has not been previously investigated in Zambia, reverse transcription PCR was employed as a broad-spectrum approach for the detection of alphaviruses in mosquitoes. From 552 mosquito pools, a novel alphavirus, tentatively named Mwinilunga alphavirus (MWAV), was discovered from a single Culex quinquefasciatus mosquito pool. The full genome of MWAV was subsequently determined, and pairwise comparisons demonstrated that MWAV represented a new alphavirus species. Phylogenetic analyses and a linear discriminant analysis based on the dinucleotide ratios in various virus sequences indicated that MWAV is related to a mosquito-specific alphavirus distinct from other known mosquito-borne alphaviruses due to its inability to replicate in vertebrate cell lines. Further analyses of these novel alphaviruses will help to facilitate a greater understanding of the molecular determinants of host range restriction and the evolutionary relationships of alphaviruses. PMID- 29630912 TI - Transcriptome analyses reveal FOXA1 dysregulation in mammary and extramammary Paget's disease. AB - Paget's disease (PD) is an uncommon intraepithelial adenocarcinoma with unknown pathogenesis. There are two anatomic subtypes: mammary (MPD) and extramammary (EMPD). Little is known about their molecular characteristics. Our objective was to discover novel molecular markers for PD and its subtypes. In the discovery phase, we used transcriptome analyses to uncover the most differentially expressed genes and pathways in EMPD biopsies compared with normal skin. In the validation phase, we performed immunohistochemistry analyses on the most promising marker (FOXA1) and other markers selected from a literature review (GATA3, estrogen receptor [ER], and androgen receptor [AR]) on independent biopsies of MPD (n = 86), EMPD (n = 59), and normal skin (n = 21). Transcriptome analyses revealed 210 genes differentially expressed more than 10-fold between EMPD and normal skin. These genes are involved in mammary and sweat gland development (FOXA1) and immune regulation, as well as epidermal differentiation. Immunohistochemistry staining revealed that FOXA1 was positive in 88% of both MPD and EMPD, whereas GATA3 was positive in 67% of MPD and 77% of EMPD, and ER was positive in 9% of MPD and 19% of EMPD. Finally, AR was positive in 33% of PD and 54% of EMPD. Mammary Paget's disease and EMPD share dysregulation of the glandular developmental regulator gene FOXA1, suggesting similarity in cell specific transcriptional regulation. Further, FOXA1 may be a useful molecular target for developing PD therapies. PMID- 29630913 TI - A multi-disciplinary educational programme for the management of a carbapenem resistant Klebsiella pneumoniae outbreak: an Italian experience. PMID- 29630915 TI - Electrophysiological evidence of an attentional bias in crossmodal inhibition of return. AB - Inhibition of return (IOR) refers to a delay in responding to targets when they appear at recently attended locations, relative to unattended locations. Within the visual modality, this attentional bias has been associated with a reduction in the N2pc event-related potential (ERP) component at previously attended locations. The present study examined whether a similar attentional bias was observed in crossmodal audio-visual IOR. Our results demonstrate that for visual targets, the attentional component of IOR behaves similarly for both unimodal and crossmodal target pairs, as indexed by a reduction in the N2pc component for targets appearing at previously attended locations. Further, similar IOR-related modulations on the auditory-evoked N2ac indicated that an attentional bias can be observed for auditory targets as well. Finally, we identified two additional ERP components - the ACOP and VCAN - that appear to reflect biasing of attention in the currently unattended sensory modality. These results suggest that the inhibitory attentional bias that underlies the IOR effect may be supramodal and bias attention away from previously attended locations regardless of sensory modality. PMID- 29630914 TI - Reduced maternal behavior caused by gestational stress is predictive of life span changes in risk-taking behavior and gene expression due to altering of the stress/anti-stress balance. AB - Exposure of the mother to adverse events during pregnancy is known to induce pathological programming of the HPA axis in the progeny, thereby increasing the vulnerability to neurobehavioral disorders. Maternal care plays a crucial role in the programming of the offspring, and oxytocin plays a key role in mother/pup interaction. Therefore, we investigated whether positive modulation of maternal behavior by activation of the oxytocinergic system could reverse the long-term alterations induced by perinatal stress (PRS; gestational restraint stress 3 times/day during the last ten days of gestation) on HPA axis activity, risk taking behavior in the elevated-plus maze, hippocampal mGlu5 receptor and gene expression in Sprague-Dawley rats. Stressed and control unstressed dams were treated during the first postpartum week with an oxytocin receptor agonist, carbetocin (1 mg/kg, i.p.). Remarkably, reduction of maternal behavior was predictive of behavioral disturbances in PRS rats as well as of the impairment of the oxytocin and its receptor gene expression. Postpartum carbetocin corrected the reduction of maternal behavior induced by gestational stress as well as the impaired oxytocinergic system in the PRS progeny, which was associated with reduced risk-taking behavior. Moreover, postpartum carbetocin had an anti-stress effect on HPA axis activity in the adult PRS progeny and increased hippocampal mGlu5 receptor expression in aging. In conclusion, the activation of the oxytocinergic system in the early life plays a protective role against the programming effect by adverse experiences and could be considered as a novel and powerful potential therapeutic target for stress-related disorders. PMID- 29630916 TI - The physiological effects of transcranial electrical stimulation do not apply to parameters commonly used in studies of cognitive neuromodulation. AB - Transcranial direct current stimulation (tDCS) and transcranial random noise stimulation (tRNS) have been claimed to produce many remarkable enhancements in perception, cognition, learning and numerous clinical conditions. The physiological basis of the claims for tDCS rests on the finding that 1 mA of unilateral anodal stimulation increases cortical excitation and 1 mA of cathodal produces inhibition. Here we show that these classic excitatory and inhibitory effects do not hold for the bilateral stimulation or 2 mA intensity conditions favoured in cognitive enhancement experiments. This is important because many, including some of the most salient claims are based on experiments using 2 mA bilateral stimulation. The claims for tRNS are also based on unilateral stimulation. Here we show that, again the classic excitatory effects of unilateral tRNS do not extend to the bilateral stimulation preferred in enhancement experiments. Further, we show that the effects of unilateral tRNS do not hold when one merely doubles the stimulation duration. We are forced to two conclusions: (i) that even if all the data on TES enhancements are true, the physiological explanations on which the claims are based are at best not established but at worst false, and (ii) that we cannot explain, scientifically at least, how so many experiments can have obtained data consistent with physiological effects that may not exist. PMID- 29630917 TI - Nucleic acids delivering nucleic acids. AB - Nucleic acid therapeutics, including siRNAs, miRNAs/antimiRs, gRNAs and ASO, represent innovative and highly promising molecules for the safe treatment of a wide range of pathologies. The efficiency of systemic treatments is impeded by 1) the need to overcome physical and functional barriers in the organism, and 2) to accumulate in the intracellular active site at therapeutic concentrations. Although oligonucleotides either as modified naked molecules or complexed with delivery carriers have revealed to be effectively delivered to the affected target cells, this is restricted to topic treatments or to a few highly vascularized tissues. Therefore, the development of effective strategies for therapeutic nucleic acid selective delivery to target tissues is of primary importance in order to reduce the occurrence of undesired effects on non-target healthy tissues and to permit their translation to clinic. Due to their high affinity for specific ligands, high tissue penetration and chemical flexibility, short single-stranded nucleic acid aptamers are emerging as very attractive carriers for various therapeutic oligonucleotides. Yet, different aptamer-based bioconjugates, able to provide accumulation into target tissues, as well as efficient processing of therapeutic oligonucleotides, have been developed. In this respect, nucleic acid aptamer-mediated delivery strategies represent a powerful approach able to increase the therapeutic efficacy also highly reducing the overall toxicity. In this review, we will summarize recent progress in the field and discuss achieved objectives and optimization of aptamers as delivery carriers of short oligonucleotides. PMID- 29630918 TI - Effects of anoxia on survival and gene expression in Bactrocera dorsalis. AB - The oriental fruit fly (Bactrocera dorsalis) larvae may commonly experience a hypoxia microenvironment and have evolved the ability to survive in the low oxygen condition with some physiological and biochemical mechanisms. However, little is known about the response of B. dorsalis to hypoxia or anoxia. In this study, the effect of anoxia on the survival of B. dorsalis was investigated. The results showed that the B. dorsalis larvae were quite tolerant to anoxia conditions and can tolerate up to 24 h of anoxia exposure without a significant reduction in survival, 100% mortality was reached after 84 h of anoxia exposure. The cDNA of hypoxia inducible factor (HIF) 1alpha and HIF-1beta is 2912 and 3618 bp in length, encoding 766 and 648 amino acid residues, respectively. Both HIF 1alpha and HIF-1beta contain conserved basic helix-loop-helix (bHLH) domain and Per-Arnt-Sim (PAS) domain. HIF-1alpha can be induced by hypoxia, whereas HIF 1beta expression was not significantly changed with the oxygen concentration. Three major heat shock proteins (Hsps) expression increased significantly during anoxia and recovery and Hsp70 was the most responsive to anoxia. Four superoxide dismutase (SOD) genes expression were also up-regulated during anoxia exposure. These data suggest that B. dorsalis has a strategy to induce HIF-1alpha and HIF-1 responsive genes to survive in the low oxygen condition. PMID- 29630919 TI - Vowel-speech versus pure-tone processing in healthy subjects. AB - To investigate the characteristics of speech perception, we evaluated the differences in mismatch negativity (MMN) between vowel change and frequency change. Additionally, we examined the effects of gender, age, and educational length on MMN. Forty healthy adults (21 females), who were native Japanese speakers, participated in the study. A Japanese vowel-speech pair (standard/a/vs. deviant/o/) and a pure-tone pair (standard 1000 Hz vs. deviant 1050 Hz) were constructed. MMN elicited by vowel-speech sounds was larger and earlier compared with pure-tone sounds. Larger and earlier MMNs for vowel-speech sounds than for pure-tone sounds suggest different processing of linguistically relevant information at the early stage in the auditory cortex. In conclusion, the factors influencing on MMN are different between vowel-speech sounds and pure-tone sounds. PMID- 29630920 TI - Resin cements formulated with thio-urethanes can strengthen porcelain and increase bond strength to ceramics. AB - OBJECTIVES: The use of thio-urethane oligomers has been shown to significantly improve the mechanical properties of resin cements (RCs). The aim of this study was to use thio-urethane-modified RC to potentially reinforce the porcelain-RC structure and to improve the bond strength to zirconia and lithium disilicate. METHODS: Six oligomers were synthesized by combining thiols - pentaerythritol tetra-3-mercaptopropionate (PETMP, P) or trimethylol-tris-3-mercaptopropionate (TMP, T) - with di-functional isocyanates - 1,6-Hexanediol-diissocyante (HDDI) (aliphatic, AL) or 1,3-bis(1-isocyanato-1-methylethyl)benzene (BDI) (aromatic, AR) or Dicyclohexylmethane 4,4'-Diisocyanate (HMDI) (cyclic, CC). Thio-urethanes (20 wt%) were added to a BisGMA/UDMA/TEGDMA organic matrix. Filler was introduced at 60 wt%. The microshear bond strength (MUSBS), Weibull modulus (m), and failure pattern of RCs bonded to zirconia (ZR) and lithium disilicate (LD) ceramics was evaluated. Biaxial flexural test and fractographic analysis of porcelain discs bonded to RCs were also performed. The biaxial flexural strength (sigmabf) and m were calculated in the tensile surfaces of porcelain and RC structures (Z = 0 and Z = -t2, respectively). RESULTS: The MUSBS was improved with RCs formulated with oligomers P_AL or T_AL bonded to LD and P_AL, P_AR or T_CC bonded to zirconia in comparison to controls. Mixed failures predominated in all groups. sigmabf had superior values at Z = 0 with RCs formulated with oligomers P_AL, P_AR, T_AL, or T_CC in comparison to control; sigmabf increased with all RCs composed by thio urethanes at Z = -t2. Fractographic analysis revealed all fracture origins at Z = 0. CONCLUSION: The use of specific thio-urethane oligomers as components of RCs increased both the biaxial flexural strength of the porcelain-RC structure and the MUSBS to LD and ZR. CLINICAL SIGNIFICANCE: The current investigation suggests that it is possible to reinforce the porcelain-RC pair and obtain higher bond strength to LD and ZR with RCs formulated with selected types of thio-urethane oligomers. PMID- 29630921 TI - Association of sleep disturbances with obesity, insulin resistance and the metabolic syndrome. AB - Insufficient sleep, which has become endemic in recent years, has been variably associated with increased risk of obesity, disorders of glucose and insulin homeostasis, and the metabolic syndrome; to a lesser degree, so has excessive sleep. This review summarizes recent epidemiological and pathophysiological evidence linking sleep disturbances (primarily abnormalities of sleep duration) with obesity, insulin resistance, type 2 diabetes and the metabolic syndrome in children and adults. PMID- 29630922 TI - Delivery of femtolitre droplets using surface acoustic wave based atomisation for cryo-EM grid preparation. AB - Cryo-Electron Microscopy (cryo-EM) has become an invaluable tool for structural biology. Over the past decade, the advent of direct electron detectors and automated data acquisition has established cryo-EM as a central method in structural biology. However, challenges remain in the reliable and efficient preparation of samples in a manner which is compatible with high time resolution. The delivery of sample onto the grid is recognized as a critical step in the workflow as it is a source of variability and loss of material due to the blotting which is usually required. Here, we present a method for sample delivery and plunge freezing based on the use of Surface Acoustic Waves to deploy 6-8 um droplets to the EM grid. This method minimises the sample dead volume and ensures vitrification within 52.6 ms from the moment the sample leaves the microfluidics chip. We demonstrate a working protocol to minimize the atomised volume and apply it to plunge freeze three different samples and provide proof that no damage occurs due to the interaction between the sample and the acoustic waves. PMID- 29630923 TI - Validation of the Proxy Version of Symptom Screening in Pediatrics Tool in Children Receiving Cancer Treatments. AB - OBJECTIVES: Primary objectives were to evaluate the interrater reliability and validity of proxy-report Symptom Screening in Pediatrics Tool (SSPedi) in children with cancer and pediatric hematopoietic stem cell transplant (HSCT) recipients. Secondary objective was to describe the interrater reliability of each SSPedi item. METHODS: Respondents were children aged eight to 18 years with cancer or HSCT recipients, and their parents or guardians. We enrolled two pediatric respondent groups. The more symptomatic group was receiving active treatment for cancer, admitted to hospital, and expected to be in a hospital three days later. The less symptomatic group either was in maintenance therapy for acute lymphoblastic leukemia or had completed cancer treatments. Convergent validity was evaluated by comparing proxy-reported mucositis, nausea and vomiting, pain, and total SSPedi scores, with child self-reported validated scales, and we hypothesized fair correlations. Discriminant validity was evaluated by comparing proxy-reported total SSPedi scores between groups. Interrater reliability of each SSPedi item was evaluated. RESULTS: Four hundred thirty-nine child and parent or guardian pairs were recruited. Mean difference in proxy-reported SSPedi scores between the more and less symptomatic groups was 8.2, 95% CI 6.6-9.8. All hypothesized relationships among measures were observed. Intraclass correlation coefficients for SSPedi items ranged from 0.34 (problems with thinking) to 0.80 (diarrhea). CONCLUSION: Proxy-report SSPedi is reliable and valid in children aged 8 years to 18 years with cancer and HSCT recipients. Future work should support proxy-reported symptom assessment in clinical settings where children are not able to self-report or communicate bothersome symptoms. PMID- 29630924 TI - Reaction time in healthy elderly is associated with chronic low-grade inflammation and advanced glycation end product. AB - Chronic inflammation and Advanced Glycation End products (AGE) are associated with sarcopenia. Decreased voluntary muscle activation and increased antagonist coactivation can contribute to age-related muscle weakness. The influence of chronic inflammation and AGE in these neuromuscular mechanisms is not clear. We studied whether a relation exists between circulating levels of inflammatory cytokines and AGEs as well as the interplay between agonist and antagonist muscle activation. We studied 64 community-dwelling old subjects, during a maximal isometric voluntary contraction (MVC) and a reaction-time (RT) test of the upper limb. Twenty-five circulating inflammatory biomarkers were determined. Linear regression showed significant relationships between chronic inflammation and six muscle activation parameters. MIP-1beta showed a significant negative relation with antagonist coactivation (during MVC) and antagonist muscle activity during pre-movement time (PMT) and movement time (MT) (during RT). A higher level of pentosidine (AGE) was predictive for a longer PMT. We conclude that in older relatively healthy persons antagonist muscle activation is influenced by chronic inflammation, contributing to age-related muscle weakness. Our results also suggest a mechanical and inflammatory influence of pentosidine in upper limb slowing of movement. These findings show novel insight in underlying mechanisms of age-related muscle weakness. PMID- 29630926 TI - High Incidence of Autoimmune Disease after Hematopoietic Stem Cell Transplantation for Chronic Granulomatous Disease. AB - There is a lack of consensus regarding the role and method of hematopoietic stem cell transplantation (HSCT) on patients with chronic granulomatous disease (CGD). Long-term follow-up after HSCT in these patient population is essential to know its potential complications and decide who will benefit the most from HSCT. We report the outcome of HSCT and long-term follow-up in 24 patients with CGD, transplanted in our center from either related (n = 6) or unrelated (n = 18) donors, over a 12-year period (2003 to 2015), using high-dose alemtuzumab in the preparative regimen. We evaluated the incidence and timing of adverse events and potential risk factors. We described in detailed the novel finding of increased autoimmunity after HSCT in patients with CGD. At a median follow-up of 1460 days, 22 patients were full donor chimeras, and 2 patients had stable mixed chimerism. All assessable patients showed normalization of their neutrophil oxidative burst test. None of the patients developed grades II to IV acute graft-versus-host disease, and no patient had chronic graft-versus-host disease. Twelve of 24 patients developed 17 autoimmune diseases (ADs). Severe ADs (cytopenia and neuropathy) occurred exclusively in the unrelated donor setting and mainly in the first year after HSCT, whereas thyroid AD occurred in the related donor setting as well and more than 3 years after HSCT. Two patients died due to infectious complications after developing autoimmune cytopenias. One additional patient suffered severe brain injury. The remaining 21 patients have long-term Lansky scores >= 80. The outcome of HSCT from unrelated donors is comparable with related donors but might carry an increased risk of developing severe AD. A lower dose of alemtuzumab may reduce this risk and should be tested in further studies. PMID- 29630927 TI - Indigofera oblongifolia regulates the hepatic gene expression profile induced by blood stage malaria. AB - Malaria is still a major health problem worldwide. This study aimed to investigate the hepatoprotective role of Indigofera oblongifolia leaf extracts (ILE) against mice hepatic injury induced by Plasmodium chabaudi. Female C57BL/6 mice were treated with 100 mg/kg of ILE after infection with erythrocytes parasitized by P. chabaudi. On day 7 post-infection, the extract improved the histological alteration induced by the parasite. This was evidenced by the decreased histological index induced by ILE. Moreover, ILE was able to increase the hepatic antioxidant capacity and could significantly improve the decrease in erythrocyte count and hemoglobin content in mice blood plasma due to infection. ILE was also able to upregulate the expression of 24 genes related to metabolism and of 3 genes related to the immune response. Furthermore, the extract was able to downregulate the expression of 35 genes related to metabolism and of 82 genes related to immune response. Moreover, the microarray study showed that ILE regulated the change in gene expression induced by the parasite. Among these genes, we quantified the expression of cd209f, cyp7a1, Hsd3b5, Sult2a3, Lcn2, CcI8, Nos2, and saa3-mRNAs. These genes were regulated by ILE. Therefore, our results revealed the protective role of Indigofera oblongifolia against hepatic injury induced by blood stage malaria. PMID- 29630928 TI - Redox biosensors in a context of multiparameter imaging. AB - A wide variety of genetically encoded fluorescent biosensors are available to date. Some of them have already contributed significantly to our understanding of biological processes occurring at cellular and organismal levels. Using such an approach, outstanding success has been achieved in the field of redox biology. The probes allowed researchers to observe, for the first time, the dynamics of important redox parameters in vivo during embryogenesis, aging, the inflammatory response, the pathogenesis of various diseases, and many other processes. Given the differences in the readout and spectra of the probes, they can be used in multiparameter imaging in which several processes are monitored simultaneously in the cell. Intracellular processes form an extensive network of interactions. For example, redox changes are often accompanied by changes in many other biochemical reactions related to cellular metabolism and signaling. Therefore, multiparameter imaging can provide important information concerning the temporal and spatial relationship of various signaling and metabolic processes. In this review, we will describe the main types of genetically encoded biosensors, the most frequently used readout, and their use in multiplexed imaging mode. PMID- 29630925 TI - Covalent labeling-mass spectrometry with non-specific reagents for studying protein structure and interactions. AB - Using mass spectrometry (MS) to obtain information about a higher order structure of protein requires that a protein's structural properties are encoded into the mass of that protein. Covalent labeling (CL) with reagents that can irreversibly modify solvent accessible amino acid side chains is an effective way to encode structural information into the mass of a protein, as this information can be read-out in a straightforward manner using standard MS-based proteomics techniques. The differential reactivity of proteins under two or more conditions can be used to distinguish protein topologies, conformations, and/or binding sites. CL-MS methods have been effectively used for the structural analysis of proteins and protein complexes, particularly for systems that are difficult to study by other more traditional biochemical techniques. This review provides an overview of the non-specific CL approaches that have been combined with MS with a particular emphasis on the reagents that are commonly used, including hydroxyl radicals, carbenes, and diethylpyrocarbonate. We describe the reagent and protein factors that affect the reactivity of amino acid side chains. We also include details about experimental design and workflow, data analysis, recent applications, and some future prospects of CL-MS methods. PMID- 29630929 TI - Urban vs rural residency and allergy prevalence among adult women: Iowa Women's Health Study. PMID- 29630930 TI - Polymorphisms in genes implicated in base excision repair (BER) pathway are associated with susceptibility to Paget's disease of bone. AB - Paget's disease of bone (PDB) is a chronic bone metabolic disorder. Currently, PDB is the second most frequent bone disorder. PDB is a focal disorder affecting the skeleton segmentally but the cause of which is unknown. It has been hypothesised that somatic mutations could be responsible for the mosaicism described in PDB patients. Therefore, our hypothesis is that defective response to DNA damage may lead to somatic mutations favouring an increased risk of PDB. So that we have analysed polymorphisms in DNA repair genes involved in the BER, NER and DSBR pathways in order to evaluate the role of these variants in modulating PDB risk. We found statistically significant differences in genotypic and allelic distribution for polymorphisms in genes implicated in the BER pathway. Our results showed that carrying the allele T of XRCC1 rs1799782 polymorphism and the allele G of APEX rs1130409 polymorphism increased the risk of developing PDB. These polymorphisms could cause a lower DNA repair efficiency and this might lead to local somatic mutations favouring bone metabolic alterations characteristic of PDB. This is the first report showing an association between polymorphism in genes implicated in the BER pathway with PDB. PMID- 29630931 TI - Development of a scale for grading pre-plus and plus disease using retinal images: A pilot study. AB - When screening infants for retinopathy of prematurity, evaluating posterior pole vascular characteristics (ie, the presence or absence of pre-plus or plus disease) is subjective and prone to error. ROPtool, a semiautomated computer program, measures retinal vessel tortuosity and dilation. In this pilot study, we created an abbreviated pictorial scale of varying vascular tortuosity and dilation based on expert perception of vascular characteristics. We used ROPtool to evaluate the experts' ability to arrange these images in order of increasing vascular tortuosity and dilation. ROPtool values confirmed successful arrangement of images in order of increasing vascular tortuosity and dilation. This pictorial scale could serve as a reference to decrease subjectivity when diagnosing pre plus or plus disease. PMID- 29630932 TI - Intravitreal injection of ranibizumab in severe retinopathy of incontinentia pigmenti. AB - Incontinentia pigmenti (IP) is a rare X-linked multisystem disorder that mainly affects females and is usually lethal to males in utero. Mutations in the NEMO gene on chromosome Xq28 (IKBKG, inhibitor of kB kinase gamma) have been shown to cause IP. Approximately 35% of patients have ophthalmic manifestations, and 20% develop vision-threatening diseases. Retinal vascular abnormalities, from peripheral retinal avascularity to neovascular proliferation, have been described in IP patients. Laser photocoagulation and cryotherapy are traditionally effective therapy for retinopathy of IP. However, some cases still progress to retinal detachment. We report 2 cases of IP infants treated with intravitreal ranibizumab with subsequent resolution of the vasculopathy. PMID- 29630933 TI - Robustness of barrier membrane coated metoprolol tartrate matrix tablets: Drug release evaluation under physiologically relevant in vitro conditions. AB - Robust in vitro drug release behavior is an important feature of extended release (ER) hydrophilic matrix formulations for accurate prediction of in vivo drug release. In this study, ER hydrophilic matrix tablets of metoprolol tartrate were formulated using a high viscosity grade of hypromellose as a rate-limiting polymer. Expectedly, this formulation showed an undesirable initial burst release followed by controlled drug release. Application of a barrier membrane (BM) coating of ethylcellulose with a pore former (hypromellose) resulted in the elimination of the burst effect. The aim of this study was to investigate the robustness of in vitro metoprolol release from BM-coated hydrophilic matrix tablets by simulating the physicochemical properties of gastrointestinal fluids and mechanical stress in the fasted- and fed state human gastrointestinal (GI) tract. Uncoated and BM-coated matrices were subjected to various dissolution studies simulating the varying pH conditions and additional physicochemical parameters, and the mechanical stress that can be caused by GI motility during both fasted and fed state GI passage. The BM-coated formulation showed robust drug release without an initial burst in all test scenarios. BM-coated matrix formulations thus represent a very promising approach for obtaining a highly controlled and robust drug release from oral ER formulations. PMID- 29630934 TI - Microparticle preparation by a propylene carbonate emulsification-extraction method. AB - The use of various harmful organic solvents for microparticle formulations is still widespread. Here, an alternative low toxicity solvent (propylene carbonate; PC) is proposed for the preparation of poly(lactic-co-glycolic-acid) (PLGA) microparticles. Based on the classical emulsification-solvent extraction methodology, the use of PC offers the unique advantage of an additional solvent extraction step using hydrolytic solvent cleavage during microparticle preparation. Spherical, rough-surfaced microparticles were obtained with a volume median diameter range from 20 to 60 um. The residual PC content has been identified to be the major factor for the solidification hindrance, leading to polymeric Tg shifting due to a plasticizing effect. When applying the enhanced PC extraction step, the residual PC content was lowered from 8.8% to 2.7% and subsequently Tg values shifted from 8.2 to 37.7 degrees C. Additionally, the hydrolytic solvent cleavage confirmed to have no impact on the PLGA stability. This method presents a significant advancement towards replacing of conventional solvents in the microparticle preparation due to more efficient solvent extraction. PMID- 29630935 TI - Real time monitoring and quantification of reactive oxygen species in breast cancer cell line MCF-7 by 2',7'-dichlorofluorescin diacetate (DCFDA) assay. AB - The detection of reactive oxygen species (ROS) using 2',7'-dichlorofluorescin diacetate (DCFDA) is commonly performed by a single measurement of fluorescence but this fails to capture a profile of ROS generation over time. This study aimed to develop a real-time monitoring method to increase the utility of the assay, to incorporate cytotoxicity screening and to describe the combined effects of DCFDA and the ROS generator, Ter-butyl hydrogen peroxide (TBHP). Breast cancer MCF-7 cells were loaded with DCFDA (0-50 MUM) for 45 min, and then exposed to TBHP (0 50 MUM). Fluorescence was recorded according to three different schedules: every hour for 6 h, or once after 6 h or 24 h. Viability was assessed in a crystal violet assay and cell morphology was examined by microscopy. TBHP caused a time and dose-dependent increase in ROS and the magnitude of the fluorescent signal was affected by the loading concentration of DCFDA. Reading the fluorescence every hour for 6 h did not diminish the emission signal. The most sensitive and reliable combination for this ROS assay was 10 MUM DCFDA with 25 MUM TBHP; since higher concentrations of DCFDA compromised cell viability. In conclusion we adapted a single point ROS assay to enable production of a profile of ROS generation over an extended 6 h period, and related this to cell viability and morphology. PMID- 29630936 TI - The rabbit vagina as an in vivo model for vaginal fenticonazole permeability and toxicity. AB - INTRODUCTION: Vaginal route is often used in topical antifungal formulations. Vaginal permeability assays are generally performed as in vitro tests. METHOD: An in vivo vaginal permeability assay was developed using female rabbits. Fenticonazole permeability was evaluated by assessing fenticonazole bioavailability in plasma by liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS). Toxicity was monitored histopathologically after 8 consecutive days of antifungal treatment (20 mg/animal). RESULTS: The method of quantification was linear with a lower limit of quantification (LLOQ) of (0.1 ng/mL). The area-under-the-curves (AUC) of fenticonazole on day 1 and 8 of treatment were 280.3 +/- 86.1 ng/mL * h and 805.7 +/- 252.4 ng/mL * h, respectively. The calculated systemic bioavailability was 12.73% +/- 0.14%. No signs of toxicity were observed both macroscopically and histologically after 8 days fenticonazole treatment. DISCUSSION: The plasma levels of fenticonazole observed in rabbits are similar to that observed in human. Rabbit vagina may be a suitable model to evaluate vaginal antifungal formulations. PMID- 29630937 TI - Genotypic diversity of Mycobacterium tuberculosis in Buenos Aires, Argentina. AB - Buenos Aires is an overpopulated port city historically inhabited by people of European descent. Together with its broader metropolitan area, the city exhibits medium tuberculosis rates, and receives migrants, mainly from tuberculosis highly endemic areas of Argentina and neighboring countries. This work was aimed to gain insight into the Mycobacterium tuberculosis population structure in two suburban districts of Buenos Aires which are illustrative of the overall situation of tuberculosis in Argentina. The Lineage 4 Euro-American accounted for >99% of the 816 isolates analyzed (one per patient). Frequencies of spoligotype families were T 35.9%, LAM 33.2%, Haarlem 19.5%, S 3.2%, X 1.5%, Ural 0.7%, BOV 0.2%, Beijing 0.2%, and Cameroon 0.2%. Unknown signatures accounted for 5.3% isolates. Of 55 spoligotypes not matching any extant shared international type (SIT) in SITVIT database, 22 fitted into 15 newly-issued SITs. Certain autochthonous South American genotypes were found to be actively evolving. LAM3, which is wild type for RDrio, was the predominant LAM subfamily in both districts and the RDrio signature was rare among autochthonous, newly created, SITs and orphan patterns. Two genotypes that are rarely observed in neighboring countries SIT2/H2 and SIT159/T1 Tuscany were conspicuously represented in Argentina. The infrequent Beijing patterns belonged to Peruvian patients. We conclude that the genotype diversity observed reflects the influence of the Hispanic colonization and more recent immigration waves from Mediterranean and neighboring countries. Unlike in Brazil, the RDrio type does not play a major role in the tuberculosis epidemic in Buenos Aires. PMID- 29630938 TI - Gallic acid loaded PEO-core/zein-shell nanofibers for chemopreventive action on gallbladder cancer cells. AB - Coaxial electrospinning was used to develop gallic acid (GA) loaded poly(ethylene oxide)/zein nanofibers in order to improve its chemopreventive action on human gallbladder cancer cells. Using a Plackett-Burman design, the effects of poly(ethylene oxide) and zein concentration and applied voltage on the diameter and morphology index of nanofibers were investigated. Coaxial nanofibers were characterized by scanning electron microscopy (SEM), transmission electron microscopy (TEM), Fourier transform infrared spectroscopy (FTIR), thermogravimetric analysis (TGA) and differential scanning calorimetry (DSC). GA loading efficiency as high as 77% was obtained under optimal process conditions. The coaxial nanofibers controlled GA release in acid and neutral pH medium. Cytotoxicity and reactive oxygen species (ROS) production on gallbladder cancer cell lines GB-d1 and NOZ in the presence of GA-nanofibers were assessed. GA nanofibers triggered an increase in the cellular cytotoxicity compared with free GA on GB-d1 and NOZ cells. Statistically significant differences were found in ROS levels of GA-nanofibers compared with free GA on NOZ cells. Differently, ROS production on GB-d1 cell line was similar. Based on these results, the coaxial nanofibers obtained in this study under optimized operational conditions offer an alternative for the development of a GA release system with improved chemopreventive action on gallbladder cancer cells. PMID- 29630940 TI - Ultrasound-guided bilateral erector spinae plane block could provide effective postoperative analgesia in laparoscopic cholecystectomy in paediatric patients. PMID- 29630939 TI - Gastric retention pellets of edaravone with enhanced oral bioavailability: Absorption mechanism, development, and in vitro/in vivo evaluation. AB - Absorption mechanism of edaravone (EDR) was studied to inform the preparation of gastric retention pellets with the aim to enhance its oral bioavailability. Three different models, namely, Caco-2 cells model, in situ single-pass intestinal perfusion model, and everted gut sac model in rats, were employed to characterize the gastrointestinal absorption kinetics of EDR. And it was found that passive transfer plays a vital role for the transport of EDR, and acidic condition is preferable for EDR absorption. Further, it is likely that EDR acts as a substrate for P-glycoprotein and multidrug-resistance protein. And hence, an orally available gastric retention pellets were developed accordingly. Pharmacokinetic experiments performed with rats and beagles showed that the absolute bioavailability of EDR solution and enteric-coated pellets following oral administration were 33.85% +/- 2.45% and 7.64% +/- 1.03%, indicating that stomach absorption is better than intestinal adsorption for EDR. However, the gastric retention pellets resulted in 68.96% absolute bioavailability and about 200% relative bioavailability in comparison to EDR solution, which was 9 times that of enteric-coated pellets. The present work demonstrates that gastric retention pellets has excellent potential as oral administration route for EDR. PMID- 29630941 TI - Optimal systemic grapevine fanleaf virus infection in Nicotiana benthamiana following agroinoculation. AB - One of the greatest hindrances to the study of grapevine fanleaf virus (GFLV) is the dearth of robust protocols for reliable, scalable, and cost-effective inoculation of host plants, especially methods which allow for rapid and targeted manipulation of the virus genome. Agroinoculation fulfills these requirements: it is a relatively rapid, inexpensive, and reliable method for establishing infections, and enables genetic manipulation of viral sequences by modifying plasmids. We designed a system of binary plasmids based on the two genomic RNAs [RNA1 (1) and RNA2 (2)] of GFLV strains F13 (F) and GHu (G) and optimized parameters to maximize systemic infection frequency in Nicotiana benthamiana via agroinoculation. The genomic make-up of the inoculum (G1-G2 and reassortant F1 G2), the identity of the co-infiltrated silencing suppressor (grapevine leafroll associated virus 2 p24), and temperature at which plants were maintained (25 degrees C) significantly increased systemic infection, while high optical densities of infiltration cultures (OD600nm of 1.0 or 2.0) increased the consistency of systemic infection frequency in N. benthamiana. In contrast, acetosyringone in the bacterial culture media, regardless of concentration, had no effect. Plasmids in this system are amenable to rapid and reliable manipulation by one-step site-directed mutagenesis, as shown by the creation of infectious RNA1 chimeras of the GFLV-F13 and GHu strains. The GFLV agroinoculation plasmids described here, together with the optimized protocol for bacterial culturing and plant maintenance, provide a robust system for the establishment of systemic GFLV infection in N. benthamiana and the rapid generation of GFLV mutants, granting a much-needed tool for investigations into GFLV-host interactions. PMID- 29630942 TI - Discovery of an Australian Chelonia mydas papillomavirus via green turtle primary cell culture and qPCR. AB - The number of reptilian viruses detected are continuously increasing due to improvements and developments of new diagnostic techniques. In this case we used primary cell culture and qPCR to describe the first Australian Chelonia mydas papillomavirus. Commercial chelonian cell lines are limited to one cell line from a terrestrial turtle (Terrapene Carolina). To establish primary cultures from green turtles (Chelonia mydas), turtle eggs were collected from Heron Island, Queensland, Australia. From day 35 of incubation at 29 degrees , the embryos were harvested to establish primary cultures. The primary cell cultures were grown in Dulbecco's Modified Eagle Medium, 90% and foetal bovine serum, 10%. The cells became uniformly fibroblastic-shaped after 15 passages. The growth rate resembled that of cells originating from other cold-blooded animals and the average doubling time was ~5 days from the 20th passage. Karyotyping and molecular analysis of mitochondrial DNA D-loop gene were carried out for cell authentication. The primary cell cultures were screened to exclude mycoplasma contamination. Two primary cell lineages were found to be susceptible to Bohle iridovirus. The primary cell cultures were used to screen samples from green turtles foraging along the East Coast of Queensland for the presence of viruses. Homogenates from eight skin tumour samples caused cytopathic effects and were confirmed by qPCR to be infected with papillomavirus. PMID- 29630944 TI - Occupational exposure to polybrominated diphenyl ethers (PBDEs) and other flame retardant foam additives at gymnastics studios: Before, during and after the replacement of pit foam with PBDE-free foams. AB - Coaches spend long hours training gymnasts of all ages aided by polyurethane foam used in loose blocks, mats, and other padded equipment. Polyurethane foam can contain flame retardant additives such as polybrominated diphenyl ethers (PBDEs), to delay the spread of fires. However, flame retardants have been associated with endocrine disruption and carcinogenicity. The National Institute for Occupational Safety and Health (NIOSH) evaluated employee exposure to flame retardants in four gymnastics studios utilized by recreational and competitive gymnasts. We evaluated flame retardant exposure at the gymnastics studios before, during, and after the replacement of foam blocks used in safety pits with foam blocks certified not to contain several flame retardants, including PBDEs. We collected hand wipes on coaches to measure levels of flame retardants on skin before and after their work shift. We measured flame retardant levels in the dust on window glass in the gymnastics areas and office areas, and in the old and new foam blocks used throughout the gymnastics studios. We found statistically higher levels of 9 out of 13 flame retardants on employees' hands after work than before, and this difference was reduced after the foam replacement. Windows in the gymnastics areas had higher levels of 3 of the 13 flame retardants than windows outside the gymnastics areas, suggesting that dust and vapor containing flame retardants became airborne. Mats and other padded equipment contained levels of bromine consistent with the amount of brominated flame retardants in foam samples analyzed in the laboratory. New blocks did not contain PBDEs, but did contain the flame retardants 2-ethylhexyl 2,3,4,5-tetrabromobenzoate and 2 ethylhexyl 2,3,4,5-tetrabromophthalate. We conclude that replacing the pit foam blocks eliminated a source of PBDEs, but not 2-ethylhexyl 2,3,4,5 tetrabromobenzoate and 2-ethylhexyl 2,3,4,5-tetrabromophthalate. We recommend ways to further minimize employee exposure to flame retardants at work and acknowledge the challenges consumers have identifying chemical contents of new products. PMID- 29630943 TI - A highly sensitive aptamer-based HIV reverse transcriptase detection assay. AB - Although many new assays for HIV have been developed, several labs still use simple and reliable radioactivity-based reverse transcriptase (RT) nucleotide incorporation assays for detection and quantification. We describe here a new assay for detection and quantitation of HIV RT activity that is based on a high affinity DNA aptamer to RT. The aptamer is sequestered on 96-well plates where it can bind to RT and other constituents can be removed by extensive washing. Since the aptamer mimics a primer-template, upon radiolabeled nucleotide addition, bound RT molecules can extend the aptamer and the radioactive signal can be detected by standard methods. In addition to being procedurally simple, the assay demonstrated high sensitivity (detection limits for RT and virions were <=6400 molecules (~4 * 10-8 units) and ~100-300 virions, respectively) and was essentially linear over a range of at least 104. Both wild type and drug resistant forms of HIV-1 RT were detectable as was HIV-2 RT, although there were some modest differences in sensitivity. PMID- 29630945 TI - Grape seed procyanidin extract protects against Pb-induced lung toxicity by activating the AMPK/Nrf2/p62 signaling axis. AB - Lead (Pb) is one of the most relevant heavy metals contaminants which cause oxidative stress and threaten human health. The lung is one of the organs most severely damaged by Pb. In this study, we investigated the protective effect of grape seed procyanidin extract (GSPE) on Pb-induced lung injury in rats. We found that GSPE alleviated Pb-induced lung injury by relieving oxidative stress, reducing release of inflammatory factors, and inhibiting apoptosis. Furthermore, GSPE enhanced the antioxidant defense systems by activating the nuclear factor erythroid-2-related factor (Nrf2) signaling pathway to promote downstream expression of heme oxygenase 1 and NAD(P)H quinone oxidoreductase 1. The subsequent ubiquitin-binding protein p62 (sequestosome 1), a downstream target of Nrf2, formed a positive feedback loop with Nrf2 during oxidative stress responses. GSPE treatment resulted in activation of adenosine monophosphate activated protein kinase (AMPK), which was highly involved in Nrf2 activation. Overall, our findings demonstrate that theprotective effect of GSPE on Pb-induced lung injury arises from activation of the AMPK/Nrf2/p62 signaling pathway, thus providing a new approach for treatment of Pb intoxication. PMID- 29630946 TI - Photodegradation of tetracycline and sulfathiazole individually and in mixtures. AB - Antibiotics in environment can be of concern as they can enter the food chain posing risks to ecosystems and human health. Photodegradation has been considered as a promising way of naturally degrading antibiotics in environment. Antibiotics are usually present in mixtures in environment; however, previous studies focused on individual compounds. Therefore, this study investigated the effect of UV irradiation on the degradation of tetracycline (TC) and sulfathiazole (STH) in individual solutions and mixtures. Under dark conditions, the initial masses of TC and STH were reduced by about 35% and 26%, respectively, over a 35 d-reaction period. With UV irradiation TC and STH were completely removed within 14 d and 35 d, respectively, regardless of the initial concentrations. Both the TC and STH removals were faster (i.e., 2-4 times) when they were in mixtures. This may be partly attributed to the byproducts such as sulfate that can promote indirect photolysis and partly to the enhanced hydrolysis due to changes in the solution pH. Overall, this study suggests that when photodegradation is used to remove antibiotics in water, the removal kinetics of antibiotics individually and in mixtures can be considered to develop more efficient treatment technologies. PMID- 29630948 TI - Genipin inhibits the invasion and migration of colon cancer cells by the suppression of HIF-1alpha accumulation and VEGF expression. AB - Hypoxia-inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF) play important roles in cancer progression in various cancer cell lines. Although genipin, a constituent of Gardenia fruit, has been shown to have anti-tumor activity, its role in the suppression of HIF-1 and its downstream target genes is not well understood. We examined the effect of genipin on the intracellular level of HIF-1alpha and extracellular level of VEGF using the colon cancer cell line HCT116. We observed that genipin suppressed the accumulation of HIF-1alpha under hypoxia in various cancer cell lines, including HCT116, via the modulation of protein degradation. Genipin also suppressed the expression of VEGF and the invasion of colon cancer cells by blocking the extracellular signal-regulated kinase signaling pathway. Taken together, our results provide new insights into the potential role of genipin in suppressing colon cancer progression. PMID- 29630949 TI - The expression of fgfr3 in the zebrafish head. AB - Fibroblast growth factor (FGF) signaling is essential for many developmental processes and plays a pivotal role in skeletal homeostasis, regeneration and wound healing. FGF signals through one of five tyrosine kinase receptors: Fgfr1a, -1b, -2, -3, -4. To characterize the expression of zebrafish fgfr3 from the larval stage to adulthood, we used RNAscope in situ hybridization on paraffin sections of the zebrafish head. Our study revealed spatial and temporal distribution of fgfr3 transcript in chondrocytes of the head cartilages, osteoblasts involved in bone formation, ventricular zone of the brain, undifferentiated mesenchymal cells of the skin, and lens epithelium of the eye. In general, the expression pattern of zebrafish fgfr3 is similar to the expression observed in higher vertebrates. PMID- 29630947 TI - Novel dual-targeting anti-proliferative dihydrotriazine-chalcone derivatives display suppression of cancer cell invasion and inflammation by inhibiting the NF kappaB signaling pathway. AB - Chalcones present in edible plants possess anti-cancer and anti-inflammatory properties, with the Michael acceptor moiety reported to be responsible for their biological activities. In this study, two novel dihydrotriazine-chalcone compounds previously identified to exert anti-proliferative effects through dual targeting of dihydrofolate reductase (DHFR) and thioredoxin reductase (TrxR), were evaluated for their anti-invasive and anti-inflammatory abilities. At non lethal concentrations, the compounds suppressed in vitro migration of MDA-MB-231 breast carcinoma cells, which was correlated with a dose-dependent downregulation of phorbol 12-myristate 13-acetate (PMA)-induced matrix metalloproteinase-9 (MMP 9) expression and secretion. At similar concentrations, these chalcone-based compounds suppressed expression of inflammatory mediators inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) in lipopolysaccharides (LPS) stimulated murine macrophage-like RAW 264.7 cells, as well as tumor necrosis factor alpha (TNF-alpha) in LPS-stimulated human monocytes isolated from healthy donors. Mechanistically, inhibition of cancer cell invasion and inflammation by the compounds were mediated through suppression of the nuclear factor-kappaB (NF kappaB) signaling pathway, which corroborated with the reported mechanism of action of chalcones. Their abilities to target multiple biological mediators relevant to multi-step carcinogenesis and with bioactivities stronger than those of the parent chalcone scaffold have warranted dihydrotriazine-chalcone compounds as promising candidates for use in pharmacological intervention of aggressive cancers. PMID- 29630950 TI - Auditory system dysfunction in Alzheimer disease and its prodromal states: A review. AB - Recent findings suggest that both peripheral and central auditory system dysfunction occur in the prodromal stages of Alzheimer Disease (AD), and therefore may represent early indicators of the disease. In addition, loss of auditory function itself leads to communication difficulties, social isolation and poor quality of life for both patients with AD and their caregivers. Developing a greater understanding of auditory dysfunction in early AD may shed light on the mechanisms of disease progression and carry diagnostic and therapeutic importance. Herein, we review the literature on hearing abilities in AD and its prodromal stages investigated through methods such as pure-tone audiometry, dichotic listening tasks, and evoked response potentials. We propose that screening for peripheral and central auditory dysfunction in at-risk populations is a low-cost and effective means to identify early AD pathology and provides an entry point for therapeutic interventions that enhance the quality of life of AD patients. PMID- 29630951 TI - The multiple functions of melatonin in regenerative medicine. AB - Melatonin research has been experiencing hyper growth in the last two decades; this relates to its numerous physiological functions including anti-inflammation, oncostasis, circadian and endocrine rhythm regulation, and its potent antioxidant activity. Recently, a large number of studies have focused on the role of melatonin in the regeneration of cells or tissues after their partial loss. In this review, we discuss the recent findings on the molecular involvement of melatonin in the regeneration of various tissues including the nervous system, liver, bone, kidney, bladder, skin, and muscle, among others. PMID- 29630952 TI - Shock-wave Lithotripsy for Pediatric Patients: Which Nomogram Can Better Predict Postoperative Outcomes? AB - OBJECTIVE: To evaluate and to compare the accuracy of the Onal and Dogan nomograms for prediction of stone-free rate after shock-wave lithotripsy (SWL) in children. MATERIALS AND METHODS: We retrospectively analyzed the medical records of children <18 years old who had been treated with SWL for kidney stone in our department between January 2014 and December 2016. A single observer reviewed the records and both Onal and Dogan nomograms were calculated and compared with respect to their predictive capability for stone-free status. RESULTS: A total of 219 patients with a mean age of 82.7 months fulfilled the study inclusion criteria. In patients who were stone free and those with residual stones after completion of the first session, the mean Onal score was 2.83 and 4.12 (P = .01), and the mean Dogan score was 120.87 and 167.44 (P = .01), respectively. In patients who were stone free and those with residual stones after the third session, the mean Onal score was 3.02 and 4.14 (P = .01), respectively. Multivariate regression analysis identified both Onal and Dogan nomograms as independent preoperative factors for SWL outcome in pediatric patients (P = .001 and P = .001) CONCLUSION: Our study demonstrates that Onal and Dogan nomograms are independent predictors of stone-free rate following SWL in pediatric patients. PMID- 29630953 TI - Impact of Subinguinal Varicocelectomy on Serum Testosterone to Estradiol Ratio in Male Patients With Infertility. AB - OBJECTIVE: To assess the effect of varicocele and subsequent varicocelectomy on testosterone-estradiol ratio in patients presented with infertility or testicular pain. MATERIALS AND METHODS: In this prospective, controlled, clinical study, 135 men were assigned to 3 equal groups (n = 45 per group). The varicocele-treated "varicocelectomy" group included patients with varicocele who underwent loupe assisted subinguinal varicocelectomy for infertility or testicular pain; the varicocele-not-treated "positive control" group included patients with varicocele who refused or who wished to postpone varicocelectomy; and the no-varicocele "negative control" group included fertile men without varicocele. The varicocele treated patients underwent loupe-assisted subinguinal varicocelectomy for infertility or testicular pain. Semen analysis, serum testosterone, estradiol, follicle stimulating hormone, luteinizing hormone, prolactin, calculation of testosterone to estradiol ratio (T:E ratio), and scrotal Doppler ultrasound were assessed at baseline and 6 months later. RESULTS: Total testosterone levels and T:E ratio were in the normal range in all groups. Men with varicocele had significantly lower levels of total testosterone and T:E ratio than men without varicocele (P <.001 for each). Testosterone levels were 4.9, 4.6, and 7.3 ng/mL, and T:E ratios were 19, 17.4, and 28.1 in the treated, positive, and negative control groups, respectively. Testosterone level and T:E ratio were significantly higher in the negative control group than the other 2 groups at baseline assessment (P <.001 for each). These parameters improved significantly 6 months after varicocelectomy in the treated group; whereas, they remained unchanged in the 2 control groups. CONCLUSION: Varicocele is associated with the diminishing of total testosterone and T:E ratio, which were significantly improved after subsequent subinguinal varicocelectomy. PMID- 29630954 TI - The Influence of Ethnic Heterogeneity on Prostate Cancer Mortality After Radical Prostatectomy in Hispanic or Latino Men: A Population-based Analysis. AB - OBJECTIVE: To determine if recently found disparities in prostate cancer-specific mortality (PCSM) among Mexican and Puerto Rican men remained true in patients undergoing radical prostatectomy (RP), where the true grade and extent of cancer are known and can be accounted for. MATERIALS AND METHODS: Men diagnosed with localized-regional prostate cancer who had undergone RP as primary treatment were identified (N = 180,794). Patients were divided into the following racial and ethnic groups: non-Hispanic white (NHW) (n = 135,358), non-Hispanic black (NHB) (n = 21,882), Hispanic or Latino (n = 15,559), and Asian American or Pacific Islander (n = 7995). Hispanic or Latino men were further categorized into the following subgroups: Mexican (n = 3323) and South or Central American, excluding Brazilian (n = 1296), Puerto Rican (n = 409), and Cuban (n = 218). A multivariable analysis was conducted using competing risk regression in the prediction of PCSM. RESULTS: This analysis revealed hidden disparities in surgical outcomes for prostate cancer. In the multivariable analysis, Hispanic or Latino men (hazard ratio [HR] = 0.88, P = .207) did not show a significant difference in PCSM compared with NHW men. When breaking Hispanic or Latino men into their country of origin or ancestry, Puerto Rican men were found to have significantly worse PCSM than NHW men (HR = 2.55, P = .004) and NHB men (HR = 2.33, P = .016). CONCLUSION: Our findings reveal higher rates of PCSM for Puerto Rican men after RP than for both NHW and NHB men. At a minimum, these findings need further validation and should be considered in the screening and management of these men. PMID- 29630956 TI - Mirabegron 25 mg Monotherapy Is Safe but Less Effective in Male Patients With Overactive Bladder and Bladder Outlet Obstruction. AB - OBJECTIVE: To compare the therapeutic efficacy and safety of mirabegron monotherapy in male patients with overactive bladder (OAB) with and without bladder outlet obstruction (BOO). MATERIALS AND METHODS: Male patients with OAB aged >=20 years, with or without BOO, receiving mirabegron 25 mg monotherapy once daily, were prospectively enrolled. The treatment results were assessed using global response assessment, international prostate symptom score and subscores, overactive bladder symptom score, patient perception on intensity of urgency scale, patient perception of bladder condition, and quality of life index at 1 and 3 months after treatment. RESULTS: Of the 289 enrolled patients (mean age, 71.2 years), 207 did not have BOO (71.6%) and 82 had BOO (28.4%). The baseline OAB symptoms were similar between patients with and without BOO. After mirabegron treatment, the satisfactory rate (global response assessment score ?1) were similar between those without BOO (61.3%) and with BOO (57.1%). The improvement of quality of life index and patient perception of bladder condition was also found in both groups. However, only patients without BOO had significantly improved international prostate symptom score and subscores, overactive bladder symptom score, and patient perception on intensity of urgency scale. Although most adverse events (AEs) were mild, patients with BOO had significantly higher AEs rate (18.6%) than those without BOO (8.2%, P = .026). CONCLUSION: Mirabegron monotherapy in male patients with OAB and BOO was safe. However, the storage symptoms improvement was less in patients with BOO and AEs rate was higher. PMID- 29630955 TI - Multi-institutional Evaluation of Upper Urinary Tract Biopsy Using Backloaded Cup Biopsy Forceps, a Nitinol Basket, and Standard Cup Biopsy Forceps. AB - OBJECTIVE: To compare the performance of 3 contemporary ureteroscopic biopsy devices for the histopathologic diagnosis of upper tract urothelial carcinoma (UTUC). METHODS: We retrospectively reviewed 145 patients who underwent 182 urothelial biopsies using 2.4F backloaded cup biopsy forceps, a nitinol basket, or 3F standard cup biopsy forceps at 3 tertiary academic centers between 2011 and 2016. Experienced genitourinary pathologists provided an assessment of each specimen without knowledge of the device used for biopsy. For patients who underwent nephroureterectomy without neoadjuvant chemotherapy within 3 months of biopsy-proven UTUC diagnosis, the biopsy grade was compared with both the grade and stage of the surgical specimen. RESULTS: Biopsy utilization varied among the 3 institutions (P <.0001). Significant variabilities in specimen size (P = .001), the presence of intact urothelium (P = .008), and crush artifact (P = .028) were found among the biopsy devices. The quality of specimens from backloaded cup forceps was rated similarly to the nitinol basket (P >.05) and was favored over standard cup forceps specimens. Grade concordance was not affected by specimen size (P >.05), morphology (P >.1), or location (P >.5). No difference existed among the devices in the rate of acquiring a grade concordant biopsy; however, the backloaded cup forceps provided concordant biopsies that could be distinguished as low- and high-grade (P = .02). CONCLUSION: The backloaded cup forceps and nitinol basket obtained a higher quality urothelial specimen compared with standard cup forceps. Ureteroscopic biopsy device selection did not significantly impact the accuracy of the histologic diagnosis of UTUC. PMID- 29630957 TI - Impact of Accountable Care Organizations on Diagnostic Testing for Prostate Cancer. AB - OBJECTIVE: To determine if Accountable Care Organizations (ACOs) have the potential to accelerate the impact of prostate cancer screening recommendations. METHODS: We performed a retrospective cohort study using Medicare data evaluating the rates of PSA testing and prostate biopsy among men without prostate cancer between 2011 and 2014. We assessed PSA testing and biopsy rates before and after policy implementation among patients of ACO and non-ACO-aligned physicians. To control for secular trends, difference-in-differences methods were used to determine the effects of ACO implementation. RESULTS: We identified 1.1 million eligible men without prostate cancer. From 2011 to 2014, the rates of PSA testing and biopsy declined by 22.3% and 7.0%, respectively. PSA testing declined similarly regardless of ACO participation-from 618 to 530 tests per 1000 beneficiaries among ACO-aligned physicians and from 607 to 516 tests per 1000 beneficiaries among non-ACO-aligned physicians (difference-in-differences P = .11). Whereas rates of prostate biopsy remained constant for patients of non-ACO aligned physicians at 12 biopsies per 1000 beneficiaries, these rates increased from 11.6 to 12.5 biopsies per 1000 beneficiaries of patients of ACO-aligned physicians (difference-in-differences P = .03). CONCLUSION: PSA testing and prostate biopsy rates decreased significantly between 2011 and 2014. The rate of PSA testing was not differentially affected by ACO participation. Conversely, there was an increase in the rate of prostate biopsy among patients of ACO aligned physicians. ACOs did not accelerate deimplementation of PSA testing for eligible Medicare beneficiaries without prostate cancer. PMID- 29630958 TI - Porous synthetic hectorite clay-alginate composite beads for effective adsorption of methylene blue dye from aqueous solution. AB - The present study deals with the preparation and characterization of mesoporous synthetic hectorite (MSH) clay which further encapsulated with Na-alginate for the preparation of mesoporous synthetic hectorite-alginate beads (MSH-AB) where Ca2+ act as a cross-linking agent. The detail characterization of MSH and MSH-AB were carried out by various physicochemical techniques. The thermogravimetric analysis study showed better thermal stability results for MSH-AB. The textural properties results of MSH and MSH-AB showed the high surface area 468, 205m2/g, and the pore volume of 0.34, 0.29cm3/g respectively. The applicability of powder MSH and MSH-AB in wet (W) and dry (D) forms were assessed for the removal of cationic dye, methylene blue (MB) by optimizing various batch adsorption parameters. The Langmuir monolayer adsorption capacity obtained for MSH-AB-W showed significant high adsorption efficacy (i.e., 785.45mgMB/g) compared to the MSH-AB-D (357.14mgMB/g) and powder MSH materials (196.00mgMB/g). The adsorption isotherm studies showed that the Langmuir isotherm model was best suitable for MSH, whereas the Freundlich model was utilised to describe the adsorption behavior of organized hydrogel composite beads. The pseudo-second-order kinetics model was observed best for MB sorption onto MSH, whereas pseudo-first order useful to describe the kinetic behavior of MSH-AB. The regeneration experimental results revealed that MSH-AB-W could be recycled more than six cycles with high MB removal efficiency. Furthermore, the adsorption property of the MSH-AB-W was examined for the binary mixture of MB with other dye solutions such as Methyl Red (MR), Methyl Orange (MO), Alizarine Yellow (AY), and Remazol Brilliant Blue (RBB) to evaluate the selective adsorption efficiency. The MSH composite beads were found potentially suitable as an efficient, selective and recyclable adsorbent for the removal of MB from the aqueous solutions. PMID- 29630959 TI - False flax (Camelina sativa) seed oil as suitable ingredient for the enhancement of physicochemical and biological properties of chitosan films. AB - To overcome the drawbacks of synthetic films in food packaging industry, researchers are turned to natural bio-based edible films enriched with various plant additives. In current study chitosan blend films were produced by incorporating Camelina sativa seed oil at varying concentrations to chitosan matrix. The chitosan blend films were characterized both physicochemically (structural, morphological, thermal, optical and mechanical) and biologically (antimicrobial and antioxidant activity). The incorporation of C. sativa seed oil notably enhanced thermal stability, antioxidative, anti-quorum sensing and antimicrobial activity. Except elongation at break, other mechanical properties of the blend films were not affected by incorporation of C. sativa seed oil. The surface morphology of blend films was recorded as slightly rough, non-porous and fibre-free surface. As it was expected the optical transmittance in visible region was gradually decreased with increasing fraction of seed oil. Interestingly the hydrophilicity of the blend films revealed a swift increase which can be explained by the formation of micelle between glycerol and Tween 40 in blend films. This study provides valuable information for C. sativa seed oil to be used as a blending ingredient in chitosan film technology. PMID- 29630960 TI - Physico-chemical characterization and beneficial effects of seaweed sulfated polysaccharide against oxydatif and cellular damages caused by alloxan in diabetic rats. PMID- 29630961 TI - Surface temperature elevated by chronic and intermittent stress. AB - Stress in homeothermic animals is associated with raised body core temperature and altered patterns of peripheral blood flow. During acute stress, peripheral vasoconstriction causes a short-lived drop in surface temperature that can be detected non-invasively using infrared thermography (IRT). Whether and how skin temperature changes under chronic stress, and hence the potential of IRT in chronic stress detection, is unknown. We explored the impact of withdrawing environmental enrichments and intermittent routine handling on long-term skin temperature in laying hens (Gallus gallus domesticus). Immediately following enrichment withdrawal, comb, face and eye temperature dropped, suggesting this was acutely stressful. In the 3 weeks that followed, barren-housed hens displayed behavioural markers of frustration. Whilst control birds, housed in enriched conditions, showed a decline over weeks in both comb temperature and baseline corticosterone levels, barren-housed hens had no change in comb temperature and an increase in corticosterone. By the trial end, comb temperature (but not corticosterone) was significantly higher in barren-housed hens. This change in parameters over time may reflect cumulative impacts of enrichment withdrawal in barren pens and/or, as hens were young and maturing, age-related changes in controls. Comb, face and eye temperature were also higher on days following routine handling, and comb temperature higher on other days in hens that were regularly handled for blood sampling than for a less intensive weighing protocol. Together, these data support comb, face and eye surface temperature increase as a long-term marker of stress exposure in laying hens. It is important to recognise that the strength and even direction of these effects may vary with thermoregulatory and energetic context. However, in laboratory and indoor-reared farm animals that live in carefully managed environments, IRT of the skin can potentially be used to non-invasively monitor chronic and intermittent stress exposure. PMID- 29630962 TI - The cooperative economy of food: Implications for human life history and physiology. AB - The human diet has undergone substantial modifications since the emergence of modern humans and varies considerably in today's traditional societies. Despite these changes and cross-cultural differences, the human diet can be characterized by several common elements. These include diverse, high quality foods, technological complexity to acquire and process food, and the establishment of home bases for storage, processing and consumption. Together these aspects of the human diet challenge any one individual to independently meet all of his or her daily caloric needs. Humans solve this challenge through food sharing, labor exchange and the division of labor. The cooperative nature of the human diet is associated with many downstream effects on our life history and physiology. This paper overviews the constellation of traits that likely led to a cooperative economy of food, and draws on ethnographic examples to illustrate its effects on human life history and physiology. Two detailed examples using body composition, time allocation and food acquisition data show how cooperation among Savanna Pume hunter-gatherers affects activity levels, sexual dimorphism in body fat, maturational pace and age at first birth. PMID- 29630963 TI - Making time for family meals: Parental influences, home eating environments, barriers and protective factors. AB - Frequent family mealtimes have been associated with numerous positive dietary, health, and behavioral outcomes for children and families. This review article summarizes some of the beneficial outcomes associated with having frequent family dinners. Current trends in family dinner frequency are discussed in the context of barriers that influence how often families eat dinner together, including time issues, work issues, and distractions in the home environment. Next, several parental influences and home environment factors that promote healthy and consistent family dinners are outlined. Finally, limitations are discussed and a few practical suggestions are mentioned to help encourage families, employers, and policy-makers to make family mealtimes a regular practice for as many families as possible. PMID- 29630964 TI - The 5alpha-reductase inhibitor finasteride increases suicide-related aggressive behaviors and blocks clozapine-induced beneficial effects in an animal model of schizophrenia. AB - Death by suicide is 5 times higher among schizophrenia patients than in the general population. There is now compelling evidence suggesting that the pathophysiology of suicide in schizophrenia does not involve central serotonergic neurotransmission disturbances, as has been shown in other contexts. We recently developed and characterized a murine Two-Hit Model of Suicide-related behavior in a schizophrenia-like context (THMS) (gestational inflammation with polyI:C at gestational day 12 followed by post-weaning social isolation). In this THMS model, we have recently shown that the atypical antipsychotic clozapine normalized the prepulse inhibition (PPI) deficits as well suicide-related, impulsive aggressive and anxiety-like behaviors. While the mechanisms underlying the suicide-reducing benefits of clozapine in schizophrenic patients are not well understood, previous works have revealed that clozapine alters brain levels of neurosteroids, such as allopregnanolone. In the present study, we thus investigated the role of endogenous neurosteroids in clozapine action by evaluating whether the 5alpha-reductase inhibitor finasteride could overturn the ability of clozapine to reduce suicide-related behaviors. We found that clozapine significantly improved the PPI deficits in THMS mice, which could not be reversed by finasteride treatment. However, finasteride counteracted the ability of clozapine to decrease the exploratory behaviors in the open-field test. In the resident-intruder test, THMS mice showed exacerbated aggressiveness and impulsivity following finasteride alone. In this resident-intruder paradigm, clozapine alone effectively blocked the finasteride-enhanced effects on aggression and impulsivity. Altogether, these findings support the existence of a complex interaction between clozapine and neurosteroids in THMS mice. Further investigations are now required to clarify the details of the molecular mechanisms involved. PMID- 29630965 TI - Fast food in the diet: Implications and solutions for families. AB - Fast food is omnipresent in the United States (U.S.) and contributes to poor dietary quality and poor health among youth and adults alike. Children need adults to teach them good eating habits to attain and maintain good health by introducing them to healthful foods and being good role models. The fast food industry, through vast funds and advertising, contribute to challenges parents face to provide healthful foods for their families and thwart our best efforts to meet health goals. Research shows fast food consumption is influenced by lack of cooking confidence, time pressures, and perceptions of ease and convenience. We need practical strategies to help parents and children make healthier food choices. As a product of conference proceedings, this paper provides a non exhaustive narrative summary of the fast food marketplace and marketing, the contributions of fast food to diet and health, struggles with healthful eating among families, and possible solutions of how we can help children and parents empower themselves to have healthier lives. PMID- 29630966 TI - Potential of near infrared (NIR) spectroscopy and dual energy X-ray absorptiometry (DXA) in predicting pork belly softness. AB - Pork bellies (n = 198) were scanned with dual energy X-ray absorptiometry (DXA). Visible and near-infrared reflectance (Vis-NIR) spectra were collected from the lean (latissimus dorsi), subcutaneous fat and intermuscular fat layers. Belly flop angle and subjective belly scores were collected as measures of pork belly softness. Vis-NIR spectra from a single fat layer could explain between 72.7 and 81.1% of the variation in pork belly softness (43.6-72.4% in validation set). The combination of the lean and subcutaneous layers improved the calibration model fit to 79.7-99.9% (66.3-71.5% in validation set). The DXA estimates explained 62.3% of variation in pork belly softness (65.2% in validation set). Results indicated that DXA and NIR technologies could potentially be utilized for pork belly softness sorting in the pork industry. PMID- 29630967 TI - Inducible disruption of the c-myb gene allows allogeneic bone marrow transplantation without irradiation. AB - Allogeneic bone marrow (BM) transplantation enables the in vivo functional assessment of hematopoietic cells. As pre-conditioning, ionizing radiation is commonly applied to induce BM depletion, however, it exerts adverse effects on the animal and can limit experimental outcome. Here, we provide an alternative method that harnesses conditional gene deletion to ablate c-myb and thereby deplete BM cells, hence allowing BM substitution without other pre-conditioning. The protocol results in a high level of blood chimerism after allogeneic BM transplantation, whereas immune cells in peripheral tissues such as resident macrophages are not replaced. Further, mice featuring a low chimerism after initial transplantation can undergo a second induction cycle for efficient deletion of residual BM cells without the necessity to re-apply donor cells. In summary, we present an effective c-myb-dependent genetic technique to generate BM chimeras in the absence of irradiation or other methods for pre-conditioning. PMID- 29630968 TI - Antimicrobial agent triclosan disrupts mitochondrial structure, revealed by super resolution microscopy, and inhibits mast cell signaling via calcium modulation. AB - The antimicrobial agent triclosan (TCS) is used in products such as toothpaste and surgical soaps and is readily absorbed into oral mucosa and human skin. These and many other tissues contain mast cells, which are involved in numerous physiologies and diseases. Mast cells release chemical mediators through a process termed degranulation, which is inhibited by TCS. Investigation into the underlying mechanisms led to the finding that TCS is a mitochondrial uncoupler at non-cytotoxic, low-micromolar doses in several cell types and live zebrafish. Our aim was to determine the mechanisms underlying TCS disruption of mitochondrial function and of mast cell signaling. We combined super-resolution (fluorescence photoactivation localization) microscopy and multiple fluorescence-based assays to detail triclosan's effects in living mast cells, fibroblasts, and primary human keratinocytes. TCS disrupts mitochondrial nanostructure, causing mitochondria to undergo fission and to form a toroidal, "donut" shape. TCS increases reactive oxygen species production, decreases mitochondrial membrane potential, and disrupts ER and mitochondrial Ca2+ levels, processes that cause mitochondrial fission. TCS is 60 * more potent than the banned uncoupler 2,4 dinitrophenol. TCS inhibits mast cell degranulation by decreasing mitochondrial membrane potential, disrupting microtubule polymerization, and inhibiting mitochondrial translocation, which reduces Ca2+ influx into the cell. Our findings provide mechanisms for both triclosan's inhibition of mast cell signaling and its universal disruption of mitochondria. These mechanisms provide partial explanations for triclosan's adverse effects on human reproduction, immunology, and development. This study is the first to utilize super-resolution microscopy in the field of toxicology. PMID- 29630969 TI - Systematic developmental neurotoxicity assessment of a representative PAH Superfund mixture using zebrafish. AB - Superfund sites often consist of complex mixtures of polycyclic aromatic hydrocarbons (PAHs). It is widely recognized that PAHs pose risks to human and environmental health, but the risks posed by exposure to PAH mixtures are unclear. We constructed an environmentally relevant PAH mixture with the top 10 most prevalent PAHs (SM10) from a Superfund site derived from environmental passive sampling data. Using the zebrafish model, we measured body burden at 48 hours post fertilization (hpf) and evaluated the developmental and neurotoxicity of SM10 and the 10 individual constituents at 24 hours post fertilization (hpf) and 5 days post fertilization (dpf). Zebrafish embryos were exposed from 6 to 120 hpf to (1) the SM10 mixture, (2) a variety of individual PAHs: pyrene, fluoranthene, retene, benzo[a]anthracene, chrysene, naphthalene, acenaphthene, phenanthrene, fluorene, and 2-methylnaphthalene. We demonstrated that SM10 and only 3 of the individual PAHs were developmentally toxic. Subsequently, we constructed and exposed developing zebrafish to two sub-mixtures: SM3 (comprised of 3 of the developmentally toxicity PAHs) and SM7 (7 non-developmentally toxic PAHs). We found that the SM3 toxicity profile was similar to SM10, and SM7 unexpectedly elicited developmental toxicity unlike that seen with its individual components. The results demonstrated that the overall developmental toxicity in the mixtures could be explained using the general concentration addition model. To determine if exposures activated the AHR pathway, spatial expression of CYP1A was evaluated in the 10 individual PAHs and the 3 mixtures at 5 dpf. Results showed activation of AHR in the liver and vasculature for the mixtures and some individual PAHs. Embryos exposed to SM10 during development and raised in chemical-free water into adulthood exhibited decreased learning and responses to startle stimulus indicating that developmental SM10 exposures affect neurobehavior. Collectively, these results exemplify the utility of zebrafish to investigate the developmental and neurotoxicity of complex mixtures. PMID- 29630970 TI - Similar structural stabilities of 3-isopropylmalate dehydrogenases from the obligatory piezophilic bacterium Shewanella benthica strain DB21MT-2 and its atmospheric congener S. oneidensis strain MR-1. AB - We previously found that the enzymatic activity of 3-isopropylmalate dehydrogenase from the obligatory piezophilic bacterium Shewanella benthica strain DB21MT-2 (SbIPMDH) was pressure-tolerant up to 100 MPa, but that from its atmospheric congener S. oneidensis strain MR-1 (SoIPMDH) was pressure-sensitive. Such characteristics were determined by only one amino acid residue at position 266, serine (SoIPMDH) or alanine (SbIPMDH) [Y. Hamajima et al. Extremophiles 20: 177, 2016]. In this study, we investigated the structural stability of these enzymes. At pH 7.6, SoIPMDH was slightly more stable against hydrostatic pressure than SbIPMDH, contrary to the physiological pressures of their normal environments. Pressure unfolding of these IPMDHs followed a two-state unfolding model between a native dimer and two unfolded monomers, and the dimer structure was pressure-tolerant up to 200 MPa, employing a midpoint pressure of 245.3 +/- 0.1 MPa and a volume change of -225 +/- 24 mL mol-1 for the most unstable mutant, SbIPMDH A266S. Thus, their pressure-dependent activity did not originate from structural perturbations such as unfolding or dimer dissociation. Conversely, urea-induced unfolding of these IPMDHs followed a three-state unfolding model, including a dimer intermediate. Interestingly, the first transition was strongly pH-dependent but pressure-independent; however, the second transition showed the opposite pattern. Obtained volume changes due to urea-induced unfolding were almost equal for both IPMDHs, approximately +10 and -30 mL mol-1 for intermediate formation and dimer dissociation, respectively. These results indicated that both IPMDHs have similar structural stability, and a pressure-adaptation mechanism was provided for only the enzymatic activity of SbIPMDH. PMID- 29630971 TI - Effect of altered solution conditions on tau conformational dynamics: Plausible implication on order propensity and aggregation. AB - Intrinsically disordered protein tau plays a central role in maintaining neuronal network by stabilizing microtubules in axon. Tau reportedly possesses random coil architecture, which is largely inert to alteration in solution conditions. However, the presence of transient compact conformers and residual structure has been evident from previous reports. Also, during Alzheimer's disease, misfolded tau detaches from microtubule and forms ordered filaments, which is the hallmark of the disease. Despite its fundamental role in neuronal physiology and in pathological cascade of several fatal neurodegenerative diseases, tau conformational dynamics remains poorly understood. In the present study, we have explored the effect of ionic strength, temperature and solvent polarity on tau40 conformational preferences using ion mobility mass spectrometry. Investigation of collision cross section revealed that while low ionic strength, elevated temperature and reduced solvent polarity mostly induced partial collapse in tau40 conformers, higher ionic strength led to an expansion of the molecule. Limited proteolysis identified segments of tau40 projection domain and proline-rich region having high order propensity and a C-terminal region having vulnerability for further expansion at altered solution conditions. The high susceptibility for disorder-to-order transition in the above region of the protein might have crucial implication on its role as microtubule spacers, and in cellular signaling cascade. The conformational adaptation of tau40 did not enhance the heparin induced aggregation proclivity of the protein. Nevertheless, the observed correlation of electrostatic interaction with fibrillation propensity of tau40 might indicate plausible link between hyperphosphorylation at diseased state with tau conformation and self-assembly. PMID- 29630972 TI - The ranking of scientists: Computational calculation of Z-score. PMID- 29630973 TI - Anti-angiogenic effect of a humanized antibody blocking the Wnt/beta-catenin signaling pathway. AB - PURPOSE: Our previous study demonstrated that Mab2F1, a murine monoclonal antibody blocking the Wnt/beta-catenin signaling pathway, has beneficial effects on experimental diabetic retinopathy and choroidal neovascularization (NV). The aforementioned antibody has been humanized. This study evaluated effects of the humanized antibody, H1L1, on NV. METHODS: H1L1 was evaluated in the alkali burn induced corneal NV rat model. Rats with corneal NV were injected subconjunctivally with Mab2F1 or H1L1 using non-specific mouse or human IgG as controls. Corneal NV and opacity were evaluated using corneal NV area and inflammatory index. Expression of angiogenic and inflammatory factors and components of the Wnt/beta-catenin pathway in both the corneas of the animal model and human corneal epithelial (HCE) cells exposed to Wnt3a conditioned medium (WCM) were determined by Western blotting and a luciferase-based promoter assay. Cytotoxicities of these antibodies were evaluated by MTT assay. RESULTS: H1L1 reduced the area of corneal NV and opacity, similar to Mab2F1. Both Mab2F1 and H1L1 down-regulated the overexpression of angiogenic and inflammatory factors including VEGF, TNF-alpha and ICAM-1, and blocked the aberrant activation of the Wnt/beta-catenin pathway as shown by down-regulation of phosphorylated LRP6, total LRP6 and non-phosphorylated beta-catenin in the cornea of the NV model and cultured HCE cells exposed to WCM. Both antibodies also inhibited the transcriptional activity of beta-catenin induced by WCM in HCE cells. No toxic effects of the antibodies were observed in cultured HCE cells. CONCLUSIONS: H1L1 exhibits anti-angiogenic activities through blocking the Wnt/beta-catenin pathway. PMID- 29630974 TI - Hepatitis B virus rtA181T/sW172non-stop mutation may increase resistance fold to adefovir- and entecavir-resistant mutants compared to rtA181T/sW172* mutation. AB - The study aimed to characterize rtA181T/sW172stop (*) and rtA181T/sW172non-stop mutations of hepatitis B virus (HBV). Total of 22,009 patients who visited Beijing 302 Hospital from 2007 to 2016 were enrolled. These patients all received nucleos(t)ide analogues (NAs) treatment and their serum samples were collected for sequence analysis of HBV reverse-transcriptase (RT) and S regions. The rtA181T mutation was detected in 5.37% (1182/22,009) of the patients' samples. The rtA181T-causative sW172*, sW172non-stop (sW172 L/S), and mixed sW172*/non stop mutations occupied 82.91%, 7.70%, and 9.39%, respectively. The patients with rtA181T/sW172non-stop mutants had a higher HBV DNA level compared to those with rtA181T/sW172* mutants. 44.33% (524/1182) rtA181T-positive samples were detected with signature drug-resistant mutations, including 325 with adefovir-resistant mutation rtA181V/N236T, 57 with lamivudine-resistant mutation rtM204V/I, 99 with entecavir-resistant mutation rtM204V/I plus rt184/202/250 substitution(s), and 43 with multidrug-resistant mutation rtA181V/N236T + rtM204V/I +/- rt184/202/250 substitution(s). The rtA181T/sW172non-stop mutation had a higher ratio of coexistence with adefovir-resistant mutation compared to rtA181T/sW172* mutation (42.86% vs. 24.59%, P < 0.05). rtA181T/sW172S + rtN236T and rtA181T/sW172L + rtN236T mutants exhibited higher HBV DNA production and adefovir resistance fold than that of rtA181T/sW172* + rtN236T mutant (98.02% and 85.5% vs. 42.1% in HBV DNA production, and 7.38-fold and 5.49-fold vs. 3.69-fold in half maximal effective concentration of wild-type strain); rtA181T/sW172L + rtS202G + rtM204V strain exhibited higher HBV DNA production and entecavir resistance fold than that of rtA181T/sW172* + rtS202G + rtM204V strain (50.98% vs. 34.49%, 524.00-fold vs. 69.33-fold). In conclusion, rtA181T/sW172non-stop mutation may increase resistance fold of adefovir- and entecavir-resistant mutants compared to rtA181T/sW172* mutation and might influence clinical presentation of NAs-treated patients. PMID- 29630976 TI - Inhibition of dengue virus infection by mannoside glycolipid conjugates. AB - Dengue virus (DENV), a mosquito-borne flavivirus, causes severe and potentially fatal symptoms in millions of infected individuals each year. Although dengue fever represents a major global public health problem, the vaccines or antiviral drugs proposed so far have not shown sufficient efficacy and safety, calling for new antiviral developments. Here we have shown that a mannoside glycolipid conjugate (MGC) bearing a trimannose head with a saturated lipid chain inhibited DENV productive infection. It showed remarkable cell promiscuity, being active in human skin dendritic cells, hepatoma cell lines and Vero cells, and was active against all four DENV serotypes, with an IC50 in the low micromolar range. Time of-addition experiments and structure-activity analyses revealed the importance of the lipid chain to interfere with an early viral infection step. This, together with a correlation between antiviral activity and membrane polarization by the lipid moiety indicated that the inhibitor functions by blocking viral envelope fusion with the endosome membrane. These finding establish MGCs as a novel class of antivirals against the DENV. PMID- 29630975 TI - Adipocytes impair efficacy of antiretroviral therapy. AB - Adequate distribution of antiretroviral drugs to infected cells in HIV patients is critical for viral suppression. In humans and primates, HIV- and SIV-infected CD4 T cells in adipose tissues have recently been identified as reservoirs for infectious virus. To better characterize adipose tissue as a pharmacological sanctuary for HIV-infected cells, in vitro experiments were conducted to assess antiretroviral drug efficacy in the presence of adipocytes, and drug penetration in adipose tissue cells (stromal-vascular-fraction cells and mature adipocytes) was examined in treated humans and monkeys. Co-culture experiments between HIV-1 infected CD4 T cells and primary human adipocytes showed that adipocytes consistently reduced the antiviral efficacy of the nucleotide reverse transcriptase inhibitor tenofovir and its prodrug forms tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF). In HIV-infected persons, LC-MS/MS analysis of intracellular lysates derived from adipose tissue stromal-vascular fraction cells or mature adipocytes suggested that integrase inhibitors penetrate adipose tissue, whereas penetration of nucleoside/nucleotide reverse transcriptase inhibitors such as TDF, emtricitabine, abacavir, and lamivudine is restricted. The limited distribution and functions of key antiretroviral drugs within fat depots may contribute to viral persistence in adipose tissue. PMID- 29630977 TI - The Correlation between Serial Ultrasound and Diuretic Renography in Children with Severe Unilateral Hydronephrosis. AB - PURPOSE: While serial renal ultrasound is often used as an alternative to functional renal imaging in children followed for hydronephrosis, it is unclear whether a lack of hydronephrosis progression safeguards against loss of renal function. In this study we characterize the association between findings on serial renal ultrasound and diuretic renography in children with severe unilateral hydronephrosis. MATERIALS AND METHODS: We retrospectively reviewed imaging among patients younger than 18 years old with a history of severe unilateral hydronephrosis, 2 renal ultrasounds and 2 diuretic renograms. Each pair of renal ultrasounds was interpreted by an independent blinded diagnostic radiologist and compared to a contemporaneous diuretic renogram. Change in hydronephrosis was considered as 1) a change in hydronephrosis grade or 2) any change by radiologist interpretation. A 5% or greater change in split differential function was considered significant. Chi-square and Spearman correlation analyses were performed. RESULTS: A total of 85 children were evaluated. Increased hydronephrosis was noted in 11.8% of children by grade and 32.9% by radiologist interpretation. Split differential renal function worsened by 5% or more in 17.6% of children. Overall, 13.3% of children with stable or decreased hydronephrosis demonstrated worsening split differential function at an average of 11.8 months. When renal ultrasound and diuretic renograms were directly compared, the Spearman correlation was poor (r = 0.24, 95% CI 0.03 to 0.43). CONCLUSIONS: The overall correlation between imaging modalities was poor, and 13.3% of children with stable or decreased hydronephrosis had worsening of split differential renal function. These findings are important to consider when counseling nonoperatively managed children followed without diuretic renography. PMID- 29630978 TI - The IMAAGEN Study: Effect of Abiraterone Acetate and Prednisone on Prostate Specific Antigen and Radiographic Disease Progression in Patients with Nonmetastatic Castration Resistant Prostate Cancer. AB - PURPOSE: We evaluated the use of abiraterone acetate (1,000 mg) plus prednisone (5 mg) in patients with high risk, nonmetastatic, castration resistant prostate cancer. MATERIALS AND METHODS: Patients considered at high risk for progression to metastatic disease (prostate specific antigen 10 ng/ml or greater, or prostate specific antigen doubling time 10 months or less) received abiraterone acetate plus prednisone daily in 28-day cycles. The primary study end point was the proportion of patients in whom a 50% or greater prostate specific antigen reduction was achieved during cycles 1 to 6. Secondary end points included time to prostate specific antigen progression, time to radiographic evidence of disease progression and safety. RESULTS: Of the 131 enrolled patients 44 (34%) remained on treatment with a median followup of 40.0 months. Median age was 72 years (range 48 to 90). Of the patients 82.4% were white and 14.5% were black. Median screening prostate specific antigen was 11.9 ng/dl and median prostate specific antigen doubling time was 3.4 months. Prostate specific antigen was significantly reduced (p <0.0001) with a 50% or greater prostate specific antigen reduction in 86.9% of cases and a 90% or greater reduction in 59.8%. Median time to prostate specific antigen progression was 28.7 months (95% CI 21.2-38.2). Median time to radiographic evidence of disease progression was not reached but on sensitivity analysis in 15 patients it was estimated to be 41.4 months (95% CI 27.6-not estimable). Baseline testosterone 12.5 ng/dl or greater and a 90% or greater prostate specific antigen reduction at cycle 3 were associated with longer time to prostate specific antigen progression and radiographic evidence of disease progression. Outcomes in black patients were similar to those in other patients. Adverse events, grade 3 or greater adverse events and serious adverse events were reported in 96.2%, 61.1% and 43.5% of patients, respectively. CONCLUSIONS: In patients with high risk, nonmetastatic, castration resistant prostate cancer treatment with abiraterone acetate plus prednisone demonstrated a significant 50% or greater prostate specific antigen reduction with encouraging results for the secondary end points, including the safety of 5 mg prednisone. PMID- 29630979 TI - Specific Changes in Brain Activity during Urgency in Women with Overactive Bladder after Successful Sacral Neuromodulation: A Functional Magnetic Resonance Imaging Study. AB - PURPOSE: The mechanism of sacral neuromodulation is poorly understood. We compared brain activity during urgency before and after sacral neuromodulation in women with overactive bladder and according to the response to treatment. MATERIALS AND METHODS: Women with refractory overactive bladder who elected sacral neuromodulation were invited to undergo functional magnetic resonance imaging before and after treatment. During imaging the bladder was filled until urgency was experienced. Regions of interest were identified a priori and brain activity in these regions of interest was compared before and after treatment as well as according to the treatment response. Whole brain exploratory analysis with an uncorrected voxel level threshold of p <0.001 was also performed to identify additional brain regions which changed after sacral neuromodulation. RESULTS: Of the 12 women who underwent a pretreatment functional magnetic resonance imaging examination 7 were successfully treated with sacral neuromodulation and underwent a posttreatment examination. After sacral neuromodulation brain activity decreased in the left anterior cingulate cortex, the bilateral insula, the left dorsolateral prefrontal cortex and the bilateral orbitofrontal cortex (each p <0.05). No new brain regions showed increased activity after sacral neuromodulation. Pretreatment brain activity levels in the bilateral anterior cingulate cortex, the right insula, the bilateral dorsolateral prefrontal cortex, the right orbitofrontal cortex, the right supplementary motor area and the right sensorimotor cortex were higher in women who underwent successful treatment (each p <0.05). CONCLUSIONS: Brain activity during urgency changes after successful sacral neuromodulation. Sacral neuromodulation may be more effective in women with higher levels of pretreatment brain activity during urgency. PMID- 29630980 TI - The Research Implications of Prostate Specific Antigen Registry Errors: Data from the Veterans Health Administration. AB - PURPOSE: We sought to characterize the effects of prostate specific antigen registry errors on clinical research by comparing cohorts based on cancer registry prostate specific antigen values with those based directly on results in the electronic health record. MATERIALS AND METHODS: We defined sample cohorts of men with prostate cancer using data from the Veterans Health Administration, including those with a prostate specific antigen value less than 4.0, 4.0 to 10.0, 10.0 to 20.0 and 20.0 to 98.0 ng/ml, respectively. We compared the composition of each cohort and overall patient survival when using prostate specific antigen values from the Veteran Affairs Central Cancer Registry vs the gold standard electronic health record laboratory file results. RESULTS: There was limited agreement among cohorts when defined by cancer registry prostate specific antigen values vs the laboratory file of the electronic health record. The least agreement of 58% was seen in patients with prostate specific antigen less than 4.0 ng/ml and greatest agreement of 89% was noted among patients with prostate specific antigen between 4.0 and 10.0 ng/ml. In each cohort patients assigned to a cohort based only on the cancer registry prostate specific antigen value had significantly different overall survival when compared with patients assigned based on registry and laboratory file prostate specific antigen values. CONCLUSIONS: Cohorts based exclusively on cancer registry prostate specific antigen values may have high rates of misclassification that can introduce concerning differences in key characteristics and result in measurable differences in clinical outcomes. PMID- 29630982 TI - Predatory Publishing in Pediatric Urology. PMID- 29630981 TI - Nerve Growth Factor Levels are Associated with Overactive Bladder Symptoms and Long-Term Treatment Outcome after Transurethral Resection of the Prostate in Patients with Benign Prostatic Hyperplasia. AB - PURPOSE: We investigated changes in urinary nerve growth factor in patients with benign prostatic hyperplasia after transurethral prostate resection. We also assessed the association between nerve growth factor and changes of overactive bladder symptoms and long-term treatment outcomes after surgery. MATERIALS AND METHODS: This was a prospective study of 178 patients at Peking University People's Hospital with benign prostatic hyperplasia between January 2011 and January 2013. Urinary nerve growth factor levels were determined preoperatively using a commercial enzyme-linked immunosorbent assay kit. We also determined prostate volume, I-PSS (International Prostate Symptom Score), quality of life, OABSS (Overactive Bladder Symptom Score), ultrasound estimated post-void residual urine and urodynamics before surgery. Urinary nerve growth factor levels, I-PSS and OABSS were assessed again 1 year after transurethral prostate resection. RESULTS: Urinary nerve growth factor/creatinine levels differed between patients with moderate and severe lower urinary tract symptoms (mean +/- SD 10.513 +/- 4.255 vs 12.334 +/- 4.048 pg/MUmol, p = 0.002). There was no significant difference between patients with grades III/IV and V/VI bladder outlet obstruction (mean 11.285 +/- 4.069 vs 11.781 +/- 4.437 pg/MUmol, p = 0.354). However, differences were significant for urinary nerve growth factor/creatinine levels in patients without overactive bladder, and mild, moderate and severe overactive bladder (mean 8.132 +/- 3.489, 10.128 +/- 3.817, 13.232 +/- 3.290 and 14.029 +/- 3.820 pg/MUmol, respectively, p <0.001). One year after transurethral prostate resection we noted a decrease vs baseline in mean urinary nerve growth factor/creatinine (8.978 +/- 4.022 pg/MUmol, p <0.001), and I-PSS and OABSS (10.2 +/- 5.4 and 4.3 +/- 3.7, respectively, each p <0.001). Compared with the good outcome group, the fair/poor group had higher mean baseline urinary nerve growth factor/creatinine (12.319 +/- 4.017 vs 11.015 +/- 4.298 pg/MUmol, p = 0.045), higher mean 1-year urinary nerve growth factor/creatinine (10.847 +/- 4.267 vs 7.850 +/- 3.419 pg/MUmol, p <0.001) and a lesser mean postoperative change in urinary nerve growth factor/creatinine (1.472 +/- 4.928 vs 3.165 +/- 4.863 pg/MUmol, p = 0.031). CONCLUSIONS: Nerve growth factor was associated with overactive bladder symptoms in patients with benign prostatic hyperplasia as well as with the assessment of successful long-term treatment outcome of bladder outlet obstruction with symptoms of overactive bladder. PMID- 29630983 TI - A National Contemporary Analysis of Perioperative Outcomes of Open versus Minimally Invasive Sacrocolpopexy. AB - PURPOSE: We evaluated the perioperative morbidity of open abdominal sacrocolpopexy and minimally invasive sacrocolpopexy using data on a contemporary nationwide cohort. MATERIALS AND METHODS: We used the ACS (American College of Surgeons) NSQIP(r) (National Surgical Quality Improvement Program) database to identify women who underwent abdominal or minimally invasive sacrocolpopexy from 2010 to 2016. Associations of surgical approach with 30-day complications, blood transfusion, prolonged hospitalization and reoperation were evaluated by logistic regression. Hospital readmission within 30 days was calculated by the person years method and Cox proportional hazard models. RESULTS: A total of 4,362 women underwent sacrocolpopexy, including abdominal sacrocolpopexy in 1,179 (27%) and minimally invasive sacrocolpopexy in 3,183 (73%). The proportion of minimally invasive sacrocolpopexy increased during the study period from 70% in 2010 to 82% in 2016. Baseline characteristics were similar between the treatment groups aside from a higher rate of chronic obstructive pulmonary disease (p = 0.03) and higher preoperative albumin (p <0.0001) among abdominal sacrocolpopexy cases. Compared to abdominal sacrocolpopexy, minimally invasive sacrocolpopexy was associated with lower rates of 30-day complications (p = 0.001), deep vein thrombosis/pulmonary embolism (p = 0.02), surgical site infections (p <0.0001), shorter hospitalization (p <0.0001) and fewer blood transfusions (p = 0.01). Minimally invasive sacrocolpopexy was also associated with a lower 30 person-days readmission rate (2% vs 2.7%, p <=0.0001) and 30-day reoperation rate (1.1% vs 1.4%, p <0.0001). On multivariable analysis minimally invasive sacrocolpopexy was independently associated with a reduced risk of 30-day complications (OR 0.46, 95% CI 0.28, 0.76, p = 0.002), blood transfusion (OR 0.33, 95% CI 0.15, 0.74, p = 0.007), prolonged hospitalization (OR 0.16, 95% CI 0.12, 0.23, p <0.001) and readmission (HR 0.62, 95% CI 0.41, 0.96, p = 0.03). CONCLUSIONS: Minimally invasive sacrocolpopexy was associated with reduced rates of 30-day complications, blood transfusion, prolonged hospitalization and hospital readmission compared to abdominal sacrocolpopexy. PMID- 29630984 TI - Co-evolutionary interactions between host resistance and pathogen avirulence genes in rice-Magnaporthe oryzae pathosystem. AB - Rice and Magnaporthe oryzae constitutes an ideal pathosystem for studying host pathogen interaction in cereals crops. There are two alternative hypotheses, viz. Arms race and Trench warfare, which explain the co-evolutionary dynamics of hosts and pathogens which are under continuous confrontation. Arms race proposes that both R- and Avr- genes of host and pathogen, respectively, undergo positive selection. Alternatively, trench warfare suggests that either R- or Avr- gene in the pathosystem is under balanced selection intending to stabilize the genetic advantage gained over the opposition. Here, we made an attempt to test the above stated hypotheses in rice-M. oryzae pathosystem at loci of three R-Avr gene pairs, Piz-t-AvrPiz-t, Pi54-AvrPi54 and Pita-AvrPita using allele mining approach. Allele mining is an efficient way to capture allelic variants existing in the population and to study the selective forces imposed on the variants during evolution. Results of nucleotide diversity, neutrality statistics and phylogenetic analyses reveal that Piz-t, Pi54 and AvrPita are diversified and under positive selection at their corresponding loci, while their counterparts, AvrPiz-t, AvrPi54 and Pita are conserved and under balancing selection, in nature. These results imply that rice-M. oryzae populations are engaged in a trench warfare at least at the three R/Avr loci studied. It is a maiden attempt to study the co-evolution of three R-Avr gene pairs in this pathosystem. Knowledge gained from this study will help in understanding the evolutionary dynamics of host-pathogen interaction in a better way and will also aid in developing new durable blast resistant rice varieties in future. PMID- 29630985 TI - Theranostic size-reducible and no donor conjugated gold nanocluster fabricated hyaluronic acid nanoparticle with optimal size for combinational treatment of breast cancer and lung metastasis. AB - The size of nanoparticles plays a key role in utilizing enhanced permeability and retention (EPR) effect of tumor, where large-sized nanoparticles possess good retention but poor penetration, while small-sized nanoparticles are on the contrary. Although size-reducible nanoparticles have been designed to partially overcome this dilemma, the initial size and complicated tumor microenvironment remain restricting the tumor distribution of nanoparticles. Herein, we employed tumor-specific CD44 targeted, hyaluronidase-degradable hyaluronic acid (HA) and small-sized, renal-clearable, red emission, cationic bovine serum albumin protected gold nanocluster (AuNC@CBSA) to successfully construct size-reducible nanoplatform (AuNC@CBSA@HA). By changing the ratio of HA and AuNC@CBSA, different initial sizes of AuNC@CBSA@HA were prepared and their tumor targeting efficiencies, pharmacokinetic profiles were evaluated. Then 200 nm of AuNC@CBSA@HA with optimal EPR effect was screened out to further load paclitaxel (PTX) and indocyanine green (ICG) for chemo- photothermal therapy and nitric oxide (NO) for modulating tumor microenvironment and enhancing drug delivery. The AuNC@CBSA-PTX-ICG@HA-NO3 showed size-reducible ability under triggering by hyaluronidase and high accumulation in breast cancer with homogenous intra-tumor distribution, suppressed 95.3% of in-situ tumor growth and inhibited 88.4% of lung metastasis growth. In conclusion, we provide a strategy that fully satisfied the concerns in drug delivery to tumor for improved antitumor effect. PMID- 29630986 TI - Camptothecin-loaded fusogenic nanodroplets as ultrasound theranostic agent in stem cell-mediated drug-delivery system. AB - Adipose-derived stem cells (ADSCs) have been utilized in cellular delivery systems to carry therapeutic agents into tumors by migration. Drug-loaded nanodroplets release drugs and form bubbles after acoustic droplet vaporization (ADV) triggered by ultrasound stimulation, providing a system for ultrasound induced cellular delivery of theranostic agents. In order to improve the efficiency of drug release, fusogenic nanodroplets were designed to go from nano to micron size upon uptake by ADSCs for reducing ADV threshold. The purpose of our study was to demonstrate the utility of camptothecin-loaded fusogenic nanodroplets (CPT-FNDs) as ultrasound theranostic agents in an ADSCs delivery system. CPT-FNDs showed an increase in size from 81.6 +/- 3.5 to 1043.5 +/- 28.3 nm and improved CPT release from 22.0 +/- 1.8% to 37.6 +/- 2.1%, demonstrating the fusion ability of CPT-FNDs. CPT-FNDs-loaded ADSCs demonstrated a cell viability of 77 +/- 4%, and the in vitro migration ability was 3.2 +/- 1.2-fold for the tumor condition compared to the cell growth condition. Ultrasound enhancement imaging showed intratumoral ADV-generated bubble formation (increasing 3.24 +/- 0.47 dB) triggered by ultrasound after CPT-FNDs-loaded ADSCs migration into B16F0 tumors. Histological images revealed intratumoral distribution of CPT-FNDs-loaded ADSCs and tissue damage due to the ADV. The CPT FNDs can be used as theranostic agents in an ADSCs delivery system to provide the ultrasound contrast imaging and deliver combination therapy of drug release and physical damage after ADV. PMID- 29630987 TI - Preclinical evaluation of mRNA trimannosylated lipopolyplexes as therapeutic cancer vaccines targeting dendritic cells. AB - Clinical trials with direct administration of synthetic mRNAs encoding tumor antigens demonstrated safety and induction of tumor-specific immune responses. Their proper delivery to dendritic cells (DCs) requires their protection against RNase degradation and more specificity for dose reduction. Lipid-Polymer-RNA lipopolyplexes (LPR) are attractive mRNA delivery systems and their equipment with mannose containing glycolipid, specific of endocytic receptors present on the membrane of DCs is a valuable strategy. In this present work, we evaluated the capacity of LPR functionalized with a tri-antenna of alpha-d-mannopyranoside (triMN-LPR) concerning (i) their binding to CD209/DC-SIGN and CD207/Langerin expressing cell lines, human and mouse DCs and other hematopoietic cell populations, (ii) the nature of induced immune response after in vivo immunization and (iii) their therapeutic anti-cancer vaccine efficiency. We demonstrated that triMN-LPR provided high induction of a local inflammatory response two days after intradermal injection to C57BL/6 mice, followed by the recruitment and activation of DCs in the corresponding draining lymph nodes. This was associated with skin production of CCR7 and CXCR4 at vaccination sites driving DC migration. High number of E7-specific T cells was detected after E7 encoded mRNA triMN-LPR vaccination. When evaluated in three therapeutic pre clinical murine tumor models such as E7-expressing TC1 cells, OVA-expressing EG7 cells and MART-1-expressing B16F0 cells, triMN-LPR carrying mRNA encoding the respective antigens significantly exert curative responses in mice vaccinated seven days after initial tumor inoculation. These results provide evidence that triMN-LPR give rise to an efficient stimulatory immune response allowing for therapeutic anti-cancer vaccination in mice. This mRNA formulation should be considered for anti-cancer vaccination in Humans. PMID- 29630988 TI - Effects of psychological interventions on systemic levels of inflammatory biomarkers in humans: A systematic review and meta-analysis. AB - The purpose of the present investigation was to systematically review randomized controlled trials examining the effects of psychological interventions on inflammatory biomarkers in adult populations and to quantitatively analyze those effects by meta-analysis. Two researchers independently searched key electronic databases, selected eligible publications, extracted data, and evaluated methodological quality. Nineteen randomized controlled trials examining a total of 1510 participants were included. The overall combined effect size from pre to post psychological intervention on pro-inflammatory biomarker levels was statistically significant, showing an attenuating effect, although of a small magnitude (s' g = 0.15, p = .008, CI [0.04-0.26]). However, this effect was not maintained into the follow-up period (g < -0.01, p = .964, CI [-0.19-0.18]). Looking at the individual biomarkers assessed across studies, only C-reactive protein (CRP) was found to significantly decrease following psychological intervention. A number of moderation analyses were conducted, none of which reached statistical significance. However, the numerically largest - and significant - within-group effect size was obtained for the group of studies that had preselected participants based on elevated psychological distress (g = 0.29, p = .047). In conclusion, psychological interventions appear efficacious in reducing pro-inflammatory biomarker levels. Future studies are recommended to carefully select individuals based on inflammatory (e.g., the presence of low grade inflammation) and/or psychological (e.g., psychological distress) criteria. PMID- 29630989 TI - Age-dependent neurodegeneration and organelle transport deficiencies in mutant TDP43 patient-derived neurons are independent of TDP43 aggregation. AB - TAR DNA-binding protein 43 (TDP43) plays a significant role in familiar and sporadic amyotrophic lateral sclerosis (ALS). The diverse postulated mechanisms by which TDP43 mutations cause the disease are not fully understood. Human wildtype and TDP43 S393L and G294V mutant spinal motor neuron cultures were differentiated from patient-derived iPSCs. Mutant hTDP43 and wildtype motor neuron cultures did not differ in neuron differentiation capacity during early maturation stage. During aging we detected a dramatic neurodegeneration including neuron loss and pathological neurofilament abnormalities only in TDP43 mutant cultures. Additionally mitochondria and lysosomes of aging spinal motor neurons revealed robust TDP43 mutation dependent abnormal phenotypes in size, shape, speed and motility which all appeared without TDP43 mislocalization or aggregation formation. Furthermore, D-sorbitol - known to induce stress granules and cytoplasmic mislocalization of TDP43 - rescued axonal trafficking phenotypes without signs of TDP43 mislocalization or aggregation formation. Our data indicate TDP43 mutation-dependent but cytosolic aggregation-independent mechanisms of motor neuron degeneration in TDP43 ALS. PMID- 29630991 TI - Additivity of pairwise perturbations in food webs: Topological effects. AB - Food webs dynamically react to perturbations and it is an open question how additive are the effects of single-species perturbations. Network structure may have topological constraints on additivity and this influences community response. Better understanding the relationships between single-species and multi species perturbations can be useful for systems-based conservation management. Here we study a single model food web by (1) characterising the positional importance of its nodes, (2) building a dynamical network simulation model and performing sensitivity analysis on it, (3) determining community response to each possible single-species perturbation, (4) determining community response to each possible pairwise species perturbation and (5) quantifying the additivity of effects for particular types of species pairs. We found that perturbing pairs of species that are either competitors or have high net status values in the network is less additive: their combined effect is dampened. PMID- 29630990 TI - The KASH-containing isoform of Nesprin1 giant associates with ciliary rootlets of ependymal cells. AB - Biallelic nonsense mutations of SYNE1 underlie a variable array of cerebellar and non-cerebellar pathologies of unknown molecular etiology. SYNE1 encodes multiple isoforms of Nesprin1 that associate with the nuclear envelope, with large cerebellar synapses and with ciliary rootlets of photoreceptors. Using two novel mouse models, we determined the expression pattern of Nesprin1 isoforms in the cerebellum whose integrity and functions are invariably affected by SYNE1 mutations. We further show that a giant isoform of Nesprin1 associates with the ciliary rootlets of ependymal cells that line brain ventricles and establish that this giant ciliary isoform of Nesprin1 harbors a KASH domain. Whereas cerebellar phenotypes are not recapitulated in Nes1gSTOP/STOP mice, these mice display a significant increase of ventricular volume. Together, these data fuel novel hypotheses about the molecular pathogenesis of SYNE1 mutations and support that KASH proteins may localize beyond the nuclear envelope in vivo. PMID- 29630992 TI - Nutrient-limited growth with non-linear cell diffusion as a mechanism for floral pattern formation in yeast biofilms. AB - Previous experiments have shown that mature yeast mat biofilms develop a floral morphology, characterised by the formation of petal-like structures. In this work, we investigate the hypothesis that nutrient-limited growth is the mechanism by which these floral patterns form. To do this, we use a combination of experiments and mathematical analysis. In mat formation experiments of the yeast species Saccharomyces cerevisiae, we observe that mats expand radially at a roughly constant speed, and eventually undergo a transition from circular to floral morphology. To determine the extent to which nutrient-limited growth can explain these features, we adopt a previously proposed mathematical model for yeast growth. The model consists of a coupled system of reaction-diffusion equations for the yeast cell density and nutrient concentration, with a non linear, degenerate diffusion term for cell spread. Using geometric singular perturbation theory and numerics, we show that the model admits travelling wave solutions in one dimension, which enables us to infer the diffusion ratio from experimental data. We then use a linear stability analysis to show that two dimensional planar travelling wave solutions for feasible experimental parameters are linearly unstable to non-planar perturbations. This provides a potential mechanism by which petals can form, and allows us to predict the characteristic petal width. There is good agreement between these predictions, numerical solutions to the model, and experimental data. We therefore conclude that the non linear cell diffusion mechanism provides a possible explanation for pattern formation in yeast mat biofilms, without the need to invoke other mechanisms such as flow of extracellular fluid, cell adhesion, or changes to cellular shape or behaviour. PMID- 29630993 TI - Evolutionary bistability of life history decision in male masu salmon. AB - Within the salmonid species, some male juveniles after spawning in fresh water stream migrate to the ocean and return to their natal streams after maturation, while others stay and mature in the fresh water stream only. Migration is relative to the size of the individuals. This is an evolutionary outcome according to the status-dependent strategy model, which assumes that the juveniles exhibit the optimal tactic based on their status. In this paper, we consider the case in which the density of adult residents suppresses juvenile growth, and explore the dynamics of alternative tactics and the evolution of threshold size. We show that a fraction of the migratory tactic that might converge into a stable state or continue to fluctuate wildly, and that the evolutionary outcome might be evolutionarily bistable, resulting in a clearly different threshold size. In the case of evolutionary bistability, two threshold sizes differ in ecological dynamics either by stable fraction of migratory tactic or showing two-year periodic fluctuation. PMID- 29630994 TI - Representation of steady-state visual evoked potentials elicited by luminance flicker in human occipital cortex: An electrocorticography study. AB - Despite the widespread use of steady-state visual evoked potentials (SSVEPs) elicited by luminance flicker in clinical and research settings, their spatial and temporal representation in the occipital cortex largely remain elusive. We performed intracranial-EEG recordings in response to targets flickering at frequencies from 11 to 15 Hz using a subdural electrode grid covering the entire right occipital cortex of a human subject, and we were able to consistently locate the gazed stimulus frequency at the posterior side of the primary visual cortex (V1). Peripheral flickering, undetectable in scalp-EEG, elicited activations in the interhemispheric fissure at locations consistent with retinotopic maps. Both foveal and peripheral activations spatially coincided with activations in the high gamma band. We detected localized alpha synchronization at the lateral edge of V2 during stimulation and transient post-stimulation theta band activations at the posterior part of the occipital cortex. Scalp-EEG exhibited only a minor occipital post-stimulation theta activation, but a strong transient frontal activation. PMID- 29630995 TI - Music processing in preterm and full-term newborns: A psychophysiological interaction (PPI) approach in neonatal fMRI. AB - Neonatal Intensive Care Units (NICU) provide special equipment designed to give life support for the increasing number of prematurely born infants and assure their survival. More recently NICU's strive to include developmentally oriented care and modulate sensory input for preterm infants. Music, among other sensory stimuli, has been introduced into NICUs, but without knowledge on the basic music processing in the brain of preterm infants. In this study, we explored the cortico-subcortical music processing of different types of conditions (Original music, Tempo modification, Key transposition) in newborns shortly after birth to assess the effective connectivity of the primary auditory cortex with the entire newborn brain. Additionally, we investigated if early exposure during NICU stay modulates brain processing of music in preterm infants at term equivalent age. We approached these two questions using Psychophysiological Interaction (PPI) analyses. A group of preterm infants listened to music (Original music) starting from 33 weeks postconceptional age until term equivalent age and were compared to two additional groups without music intervention; preterm infants and full-term newborns. Auditory cortex functional connectivity with cerebral regions known to be implicated in tempo and familiarity processing were identified only for preterm infants with music training in the NICU. Increased connectivity between auditory cortices and thalamus and dorsal striatum may not only reflect their sensitivity to the known music and the processing of its tempo as familiar, but these results are also compatible with the hypothesis that the previously listened music induces a more arousing and pleasant state. Our results suggest that music exposure in NICU's environment can induce brain functional connectivity changes that are associated with music processing. PMID- 29630996 TI - Excessive endoplasmic reticulum stress and decreased neuroplasticity-associated proteins in prefrontal cortex of obese rats and the regulatory effects of aerobic exercise. AB - Studies have shown high fat diet induced obesity may cause cognition impairment and down-regulation of neuroplasticity-associated proteins, while aerobic exercise could improve that damage. Endoplasmic reticulum stress (ERS) has been reported to play a key role in regulating neuroplasticity-associated proteins expression, folding and post-translational modification in hippocampus of obese rodent models, however, the effects of ERS on neuroplasticity-associated proteins and possible underlying mechanisms in prefrontal cortex are not fully clear. In order to clarify changes of neuroplasticity-associated proteins and ERS in the prefrontal cortex of obese rats, male SD rats were fed on high fat diet for 8 weeks to establish the obese model. Then, 8 weeks of aerobic exercise treadmill intervention was arranged for the obese rats. Results showed that high fat diet induced obesity caused hyperlipidemia, and significantly promoted FATP1 expression in the prefrontal cortex, meanwhile, we found up-regulation of GRP78, p-PERK, p-eIF2alpha, caspase-12, CHOP, and Bax/Bcl-2, reflecting the activation of ERS and ERS-mediated apoptosis. Moreover, reduced BDNF and SYN was found in obese rats. However, FATP1, GRP78, p-PERK, p-eIF2alpha, caspase-12, CHOP, and Bax/Bcl-2 expressions were obviously reversed by aerobic exercise intervention. These results suggested that dietary obesity could induce Prefrontal ERS in SD rats and excessive ERS may play a critical role in decreasing the levels of neuroplasticity-associated proteins. Moreover, aerobic exercise could relieve ERS, thus promoted the expression of neuroplasticity-associated proteins. PMID- 29630997 TI - Neurocognitive testing in West African children 3-6 years of age: Challenges and implications for data analyses. AB - OBJECTIVE: When testing African children with developmental and cognitive standardized tests from high-income countries (HIC), investigators are uncertain as to whether to apply the HIC norms for these tests when standardizing a child's raw-score performance on the basis of age. The present study compared the construct validity of both raw and HIC-based standardized scores for the Mullen Scales of Early Learning (MSEL) and the Kaufman Assessment Battery in Children - 2nd edition (KABC-II) for Beninese children in a rural setting from three to six years of age. METHODS: Seventy-four children 3-4 yrs of age were assessed with the MSEL, and 61 eligible older children (5-6 yrs of age) were assessed with the KABC-II. Assessors spoke the instructions to the children and caregivers for the assessment items in the local language. The developmental quality of the home environment was evaluated with the Caldwell Home Observation for Measurement of the Environment (HOME) inventory, and a material possessions and housing quality checklist was used as a measure of socio-economic status (SES). Children's mothers were given the Raven's Progressive Matrices test (nonverbal cognitive ability), and the Edinburgh Postpartum Depression Scale (EPDS) (emotional wellbeing). RESULTS: For the MSEL, the 4-yr old group performed significantly better than the 3-yr old group on both the raw and standardized score comparisons for all scales. These differences were attenuated when using standardized scores, although the MSEL standardized cognitive composite score was still highly significant between years of age. When comparing 5- to 6-yr olds on KABC-II subtest and global scale performance, comparisons between the raw and standardized mean score performances were much less consistent. Generally, 6-yr olds performed significantly better than 5-yr olds on the raw score comparisons on the KABC-II subtests, but not so for standardized scores. Parent-child interactions assessed through the HOME measure was associated with both raw and standardized MSEL cognitive composite score outcomes on a multiple regression analysis. SES was the only significant predictor for KABC-II raw and standardized outcomes. CONCLUSION: Standardization using HIC norms was not optimal, resulting in minimal impact to account for age when using the MSEL, and lower scores for oldest children compared with youngest children when using the KABC2. This is likely due to children in Benin drifting away from HIC-based norms with each passing year of age, systematically lowering standardized performance measures. These findings support the importance of having a local comparison group of reference or control children to allow for adjusted (for age, HOME, and SES) raw score comparisons when using western-based tests for developmental and neuropsychological evaluation. PMID- 29630999 TI - Calpain modulates fear memory consolidation, retrieval and reconsolidation in the hippocampus. AB - It has been proposed that long-lasting changes in dendritic spines provide a physical correlate for memory formation and maintenance. Spine size and shape are highly plastic, controlled by actin polymerization/depolymerization cycles. This actin dynamics are regulated by proteins such as calpain, a calcium-dependent cysteine protease that cleaves the structural cytoskeleton proteins and other targets involved in synaptic plasticity. Here, we tested whether the pharmacological inhibition of calpain in the dorsal hippocampus affects memory consolidation, retrieval and reconsolidation in rats trained in contextual fear conditioning. We first found that post-training infusion of the calpain inhibitor PD150606 impaired long-term memory consolidation, but not short-term memory. Next, we showed that pre-test infusion of the calpain inhibitor hindered memory retrieval. Finally, blocking calpain activity after memory reactivation disrupted reconsolidation. Taken together, our results show that calpain play an essential role in the hippocampus by enabling memory formation, expression and reconsolidation. PMID- 29630998 TI - Akebia quinata Decaisne aqueous extract acts as a novel anti-fatigue agent in mice exposed to chronic restraint stress. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Akebia quinata Decaisne extract (AQE; Lardizabalaceae) is used in traditional herbal medicine for stress- and fatigue related depression, improvement of fatigue, and mental relaxation. AIM OF THE STUDY: To clarify the effects of AQE on stress-induced fatigue, we investigated the neuroprotective pharmacological effects of A. quinata Decaisne in mice exposed to chronic restraint stress. MATERIALS AND METHODS: Seven-week old C57BL/6 mice chronically stressed by immobilization for 3 h daily for 15 d and non-stressed control mice underwent daily oral administration of AQE or distilled water. The open field, sucrose preference, and forced swimming behavioral tests were carried out once weekly, and immunohistochemical analyses of NeuN, brain derived neurotrophic factor (BDNF), phosphorylated cAMP response element-binding (CREB) protein, and BDNF receptor tropomyosin receptor kinase B (TrkB) in striatum and hippocampus were performed at the end of the experimental period. Brain levels of serotonin, adrenaline, and noradrenaline as well as serum levels of corticosterone were measured. RESULTS: Behavioral tests showed that treatment with AQE improved all lethargic behaviors examined. AQE significantly attenuated the elevated levels of adrenaline, noradrenaline, and serotonin in the brain and corticosterone, alanine transaminase, and aspartate transaminase levels in the serum. Histopathological analysis showed that AQE reduced liver injury and lateral ventricle size in restraint-stress mice via inhibition of neuronal cell death. Immunohistochemical analysis showed increased phosphorylation of CREB and expression of BDNF and its receptor TrkB in striatum and hippocampus. Chlorogenic acid, isochlorogenic acid A, and isochlorogenic acid C were identified as the primary components of AQE. All three agents increased expression of BDNF in SH SY5Y cells and PC12 cells with H2O2-induced neuronal cell damage. CONCLUSIONS: AQE may have a neuroprotective effect and ameliorate the effects of stress and fatigue-associated brain damage through mechanisms involving regulation of BDNF TrkB signaling. PMID- 29631001 TI - The human pain system exhibits higher-order plasticity (metaplasticity). AB - The human pain system can be bidirectionally modulated by high-frequency (HFS; 100 Hz) and low-frequency (LFS; 1 Hz) electrical stimulation of nociceptors leading to long-term potentiation or depression of pain perception (pain-LTP or pain-LTD). Here we show that priming a test site by very low-frequency stimulation (VLFS; 0.05 Hz) prevented pain-LTP probably by elevating the threshold (set point) for pain-LTP induction. Conversely, prior HFS-induced pain LTP was substantially reversed by subsequent VLFS, suggesting that preceding HFS had primed the human nociceptive system for pain-LTD induction by VLFS. In contrast, the pain elicited by the pain-LTP-precipitating conditioning HFS stimulation remained unaffected. In aggregate these experiments demonstrate that the human pain system expresses two forms of higher-order plasticity (metaplasticity) acting in either direction along the pain-LTD to pain-LTP continuum with similar shifts in thresholds for LTD and LTP as in synaptic plasticity, indicating intriguing new mechanisms for the prevention of pain memory and the erasure of hyperalgesia related to an already established pain memory trace. There were no apparent gender differences in either pain-LTP or metaplasticity of pain-LTP. However, individual subjects appeared to present with an individual balance of pain-LTD to pain-LTP (a pain plasticity "fingerprint"). PMID- 29631000 TI - Extinction of aversive taste memory homeostatically prevents the maintenance of in vivo insular cortex LTP: Calcineurin participation. AB - Accumulating evidence indicates that homeostatic plasticity mechanisms dynamically adjust synaptic strength to promote stability that is crucial for memory storage. Our previous studies have shown that prior training in conditioned taste aversion (CTA) prevents the subsequent induction of long-term potentiation (LTP) in the projection from the basolateral nucleus of the amygdala (Bla) to the insular cortex (IC) in vivo. We have also reported that induction of LTP in the Bla-IC pathway modifies the CTA extinction. Memoryextinction involves the formation of a new associativememorythat inhibits a previously conditioned association. The aim of the present study was to analyze the effect of CTA extinction on the ability to induce subsequent LTP in the Bla-IC projection in vivo. Thus, 48 h after CTA extinction animals received high frequency stimulation in order to induce IC-LTP. Our results show that extinction training allows the induction but not the maintenance of IC-LTP. In addition, with the purpose of exploring part of the mechanisms involved in this process and since a body of evidence suggests that protein phosphatase calcineurin (CaN) is involved in the extinction of some behavioral tasks, we analyzed the participation of this phosphatase. The present results show that extinction training increases the CaN expression in the IC, as well as that the inhibition of this phosphatase reverts the effects of the CTA-extinction on the IC-LTP. These findings reveal that CTA extinction promotes a homeostatic regulation of subsequent IC synaptic plasticity maintenance through increases in CaN levels. PMID- 29631002 TI - Placebo analgesia persists during sleep: An experimental study. AB - Although placebo analgesia is a well-recognized phenomenon with important clinical implications, the possibility that placebo effects occur during sleep has received little attention. This experimental study examined whether responsiveness to acute heat pain stimuli applied during sleep could be reduced following a placebo conditioning procedure administered before sleep. Healthy individuals (n = 9) underwent polysomnographic recordings for one habituation night followed by one placebo analgesia night and one control night in counterbalanced order. Conditioning induced robust analgesia expectations before the placebo night. In the morning after the placebo night, participants reported less nocturnal pain, anxiety, and associated sleep disturbance (all p's < 0.05) compared to the control night. Furthermore, placebo induction produced a 10% reduction in brain arousals evoked by noxious stimuli during rapid-eye-movement (REM) sleep (p = 0.03), consistent with our previous findings suggesting that analgesia expectations are reprocessed during REM sleep. In contrast, arousals increased by 14% during slow wave sleep (SWS) (p = 0.02). In the morning after the last recording night, placebo testing administered as a manipulation check confirmed that typical placebo analgesic responses were produced during waking (p's < 0.05). These results suggest that analgesia expectations developed before sleep reduced nocturnal pain perception and subjective sleep disturbances and activated brain processes that modulate incoming nociceptive signals differentially according to sleep stage. These results need to be replicated in future studies exploring how analgesia expectations may be reactivated during different sleep stages to modulate nociceptive responses. PMID- 29631004 TI - Out-of-hospital cardiac arrest with Do-Not-Resuscitate orders signed in hospital: Who are the survivors? AB - BACKGROUND: Signing Do-Not-Resuscitate orders is an important element contributing to a worse prognosis for out-of-hospital cardiac arrest (OHCA). However, our data showed that some of those OHCA patients with Do-Not-Resuscitate orders signed in hospital survived to hospital discharge, and even recovered with favorable neurological function. In this study, we described their clinical features and identified those factors that were associated with better outcomes. METHODS: A retrospective, observational analysis was performed on all adult non traumatic OHCA who were enrolled in the Resuscitation Outcomes Consortium (ROC) PRIMED study but signed Do-Not-Resuscitate orders in hospital after admission. We reported their demographics, characteristics, interventions and outcomes of all enrolled cases. Patients surviving and not surviving to hospital discharge, as well as those who did and did not obtain favorable neurological recovery, were compared. Logistic regression models assessed those factors which might be prognostic to survival and favorable neurological outcomes at discharge. RESULTS: Of 2289 admitted patients with Do-Not-Resuscitate order signed in hospital, 132(5.8%) survived to hospital discharge and 28(1.2%) achieved favorable neurological recovery. Those factors, including witnessed arrest, prehospital shock delivered, Return of Spontaneous Circulation (ROSC) obtained in the field, cardiovascular interventions or procedures applied, and no prehospital adrenaline administered, were independently associated with better outcomes. CONCLUSIONS: We suggest that some factors should be taken into considerations before Do-Not Resuscitate decisions are made in hospital for those admitted OHCA patients. PMID- 29631005 TI - Association of race and socioeconomic status with automatic external defibrillator training prevalence in the United States. AB - AIM OF THE STUDY: Automated external defibrillators (AEDs) improve survival from out-of-hospital cardiac arrest (OHCA), however bystander use remains low. Limited AED training may contribute to infrequent use of these devices, yet no studies have assessed AED training nationally. Given previously documented racial disparities among Latinos in CPR provision and OHCA outcomes, we hypothesized that racial and socioeconomic differences exist in AED training, with Whites having increased training compared to Latinos and higher socioeconomic status being associated with increased training. METHODS: We administered a random digit dial survey to a nationally-representative adult sample. Using survey-weighted logistic regression adjusted for location, we assessed race and socioeconomic status of individuals trained in AEDs compared to never-trained individuals. RESULTS: From 09/2015-11/2015, 9022 individuals completed the survey. Of those, 68% had never been AED trained. Self-identified Whites and Blacks were more likely to have AED training compared to Latinos (OR: 1.90, 95% CI: 1.43-2.53 and OR: 1.73, 95% CI: 1.39-2.15, respectively). Higher educational attainment was associated with an increased likelihood of training, with an OR of 4.36 (95% CI: 2.57-7.40) for graduate school compared to less than high school education. Increased household income was not associated with an increase in AED training (p = .08). CONCLUSIONS: The minority of respondents reported AED training. Whites and Blacks were more likely to be trained than Latinos. Higher educational attainment was associated with an increased likelihood of training. These findings highlight an important opportunity to improve training disparities and layperson response to OHCA. PMID- 29631006 TI - The SlNAC8 gene of the halophyte Suaeda liaotungensis enhances drought and salt stress tolerance in transgenic Arabidopsis thaliana. AB - NAC (NAM, ATAF1/2 and CUC) transcription factors play an important role in resisting abiotic stress in plants. In this study, a novel NAC gene, designated SlNAC8 from Suaeda liaotungensis K. was characterized. SlNAC8 protein is localized in the nucleus, and the yeast one-hybrid screening showed that it contains an activation domain in its C-terminus and functions as a transcriptional activator. Gene expression analysis revealed that it is induced by drought and salt stress. Arabidopsis plants overexpressing SlNAC8 demonstrated enhanced tolerance to drought and salt stress, showing significant advantages in seed germination, root growth, shoot growth, and survival rate compared with controls. Moreover, transgenic plants had a significantly higher proline concentration, antioxidant enzyme activity (superoxide dismutase, peroxidase, and catalase), and level of chlorophyll fluorescence than wild-type, and a significantly lower malondialdehyde concentration and electrolyte leakage under drought and salt stress. The overexpression of SlNAC8 in transgenic plants also enhanced the expression of stress-responsive genes such as RD20, GSTF6, COR47, RD29A, RD29B, and NYC1. In summary, SlNAC8, as a transcription factor, may change the physiological-biochemical characteristic of plants by regulating the expression of stress-responsive genes and enhance the drought and salt stress tolerance of plants. SlNAC8 can be utilized for developing drought and salinity tolerance in crop plants through genetic engineering. PMID- 29631007 TI - Novel miRNA genes deregulated by aberrant methylation in ovarian carcinoma are involved in metastasis. AB - Methylation of promoter CpG islands may suppress the function of miRNAs by inhibiting their expression. Our work analyzes the role of promoter methylation in altering the expression of 12 miRNAs associated with epithelial ovarian cancer (EOC): miR-124-3p, -125b-5p, -127-5p, -129-5p, -132-3p, -137, -148a-3p, -191-5p, 193a-5p, -203a, -339-3p, and -375. The role of methylation in the deregulation of these miRNAs has not been previously assessed in a representative set of EOC samples. Using 76 paired (tumor/matched normal) ovarian samples and methylation specific PCR, we demonstrated significant aberrations in the methylation patterns of 11 miRNA genes and identified 8 novel hypermethylated miRNA genes (MIR-124-1, 124-2, -124-3, -127, -132, -137, -193A, and -339) as well as one hypomethylated miRNA gene (MIR-191). Quantitative PCR on a subset of 29 paired EOC samples allowed us to establish a strong correlation between methylation status and alterations in expression levels for all 12 miRNAs studied. These findings demonstrate the functional role of aberrant methylation of examined miRNA genes in EOC. Moreover, we showed a significant association of hypermethylation of 10 miRNA genes (MIR-124-2, -124-3, -125B-1, -127, -129-2, -137, -193A, -203A, -339, 375) with EOC metastasis to lymph nodes, peritoneum, and distant organs. Interestingly, MIR-203A and MIR-375 were hypermethylated only in disseminated ovarian tumors, implying that non-suppressor miR-203a and miR-375 have anti metastatic properties. Hypermethylation of 10 miRNA genes in EOC metastases was validated using an additional sample set of 13 primary tumors and matched peritoneal metastases. Together, these results show the impact of aberrant methylation on deregulation of 12 miRNAs in EOC, the involvement of 10 hypermethylated miRNA genes in metastasis (including peritoneal macro metastases), and suggest novel potential biomarkers. PMID- 29631009 TI - Hysteroscopic Management of Partial Hydatidiform Mole: A Novel Approach to an Old Disease. PMID- 29631008 TI - Differential expression of miR-34a, miR-141, and miR-9 in MPP+-treated differentiated PC12 cells as a model of Parkinson's disease. AB - Parkinson's disease (PD) is a debilitating neurodegenerative condition characterized by the loss of dopaminergic neurons in substantia nigra. MPP+ as a dopaminergic neurotoxin induces many parkinsonian-like symptoms in cell culture. MicroRNAs are noncoding RNAs which their deregulation participates in neurodegeneration by affecting most of the mechanisms responsible for neurodegenerative diseases. Differentiated PC12 cells impaired by MPP+ were served as an in vitro model of PD. The aim of present research is to evaluate expression of several miRNAs and possible target genes in MPP+-treated differentiated PC12 cells. PC12 cells were differentiated by induction of NGF. Neurite outgrowth was quantified using image analysis software. MTS assay was served to assess cell viability. DCFH-DA assay and Annexin v staining were used to detect reactive oxygen species (ROS) levels and apoptosis, respectively. An in silico study was performed to make interaction analysis between selected mRNAs and microRNAs. The expression levels of microRNAs and target genes were examined by RT-qPCR. NGF induced differentiation led to a substantial increase in neurite lengths means and percentage of the neurite-bearing cells. NGF-differentiated PC12 cells substantially expressed TH and retained their dopaminergic characteristic after differentiation. NGF treatment enhanced TH gene expression. MPP+ exposure caused loss of cell viability and induced apoptosis and ROS overproduction. SIRT1, BCL2, and BDNF were down-regulated after MPP+-treatment. In contrast, MPP+ toxicity significantly caused up-regulation in miR-34a, miR 141, and miR-9. The present study showed altered levels of selected microRNAs in response to MPP+ for the first time, suggesting that perturbed expression of them may contribute to the PD-related pathogenic processes, probably by affecting the expression of BCL2, BDNF, and SIRT1 as potential targets. PMID- 29631010 TI - Laparoscopic Uterosacral Suture Sacrohysteropexy: LUSSH Procedure. AB - STUDY OBJECTIVE: To demonstrate a mesh-free laparoscopic uterosacral suture sacrohysteropexy (LUSSH). DESIGN: Technical video demonstrating LUSSH for uterine prolapse (Canadian Task Force classification III). SETTING: University hospital. PATIENT: A 37-year-old woman with grade 3 uterine descent requested uterine sparing surgery for symptomatic prolapse. The patient declined all mesh procedures. INTERVENTION: Mesh-free laparoscopic uterosacral suture sacrohysteropexy (LUSSH). MEASUREMENTS AND MAIN RESULTS: Laparoscopic sacrohysteropexy is a uterine-preserving technique for uterine prolapse with high cure rates (92%) but with a mesh erosion risk of up to 2.5% [1,2]. Complications have resulted in reclassification of transvaginal meshes as restricted-use high risk medical devices [3,4]. Sacrospinous hysteropexy and uterosacral ligament suspension are mesh-free alternatives, but they have increased rates of anterior compartment failures and a 20% recurrence rate in the latter [5,6]. Laparoscopic suture sacrohysteropexy has been described with reported success rates of 95% [7]. This video demonstrates a modified-technique offering a simple, robust, and reproducible mesh-free approach to uterine-preserving prolapse surgery. We used 2 horizontal loop mattress sutures acting as a pulley to distribute the force evenly throughout the suture strand, leading to a significantly stronger and more secure hold and reducing risk of avulsion [8]. The technique starts with a careful dissection of the peritoneum from the sacral promontory to the cervix. Two permanent sutures are used, taking bites at the anterior longitudinal ligament, the uterosacral, a loop mattress in the midline at the cervix, the uterosacral on the way back, and finally at the sacral promontory. Damage to the uterine vessels is minimized by maintaining a central uterine position. The stitch is tied with caudal pressure on the uterus, applied via the uterine manipulator, approximating the cervix to the sacral promontory. The peritoneum is closed with dissolvable sutures, burying the Ethibond to prevent exposure and bowel obstruction. CONCLUSION: Post-procedure, the uterus was well supported with a vaginal length of 15 cm. PMID- 29631003 TI - Developmental manganese, lead, and barren cage exposure have adverse long-term neurocognitive, behavioral and monoamine effects in Sprague-Dawley rats. AB - Developmental stress, including low socioeconomic status (SES), can induce dysregulation of the hypothalamic-pituitary-adrenal axis and result in long-term changes in stress reactivity. Children in lower SES households experience more stress and are more likely to be exposed to environmental neurotoxins such as lead (Pb) and manganese (Mn) than children in higher SES households. Co-exposure to stress, Pb, and Mn during early development may increase the risk of central nervous system dysfunction compared with unexposed children. To investigate the potential interaction of these factors, Sprague-Dawley rats were bred, and litters born in-house were culled on postnatal day (P)1 to 6 males and 6 females. One male and female within each litter were assigned to one of the following groups: 0 (vehicle), 10 mg/kg Pb, 100 mg/kg Mn, or 10 mg/kg Pb + 100 mg/kg Mn (PbMn), water gavage, and handled only from P4-28 with half the litters reared in cages with standard bedding (29 litters) and half with no bedding (Barren; 27 litters). Mn and PbMn groups had decreased anxiety, reduced acoustic startle, initial open-field hypoactivity, increased activity following (+) methamphetamine, deficits in egocentric learning in the Cincinnati water maze (CWM), and deficits in latent inhibition conditioning. Pb increased anxiety and reduced open-field activity. Barren-reared rats had decreased anxiety, CWM deficits, increased startle, and initial open-field hyperactivity. Mn, PbMn, Pb Barren-reared groups had impaired Morris water maze performance. Pb altered neostriatal serotonin and norepinephrine, Mn increased hippocampal serotonin in males, Mn + Barren-rearing increased neostriatal serotonin, and Barren-rearing decreased neostriatal dopamine in males. At the doses used here, most effects were in the Mn and PbMn groups. Few interactions between Mn, Pb, and rearing stress were found, indicating that the interaction of these three variables is not as impactful as hypothesized. PMID- 29631011 TI - Author's Reply. PMID- 29631012 TI - Identification of Leiomyoma Cell Sheets in Peritoneal Washings Retrieved by an Intraoperative Red Blood Cell Salvage Device during Laparoscopic-Assisted Myomectomy with in-Bag Manual Tissue Extraction: A Pilot Study. AB - STUDY OBJECTIVE: To examine whether peritoneal washings during laparoscopic assisted myomectomy with in-bag manual tissue extraction can contain spilled leiomyoma cell sheets. DESIGN: Retrospective observational study (Canadian Task Force classification II-2). SETTING: Departments of Obstetrics and Gynecology and Diagnostic Pathology at a general hospital. PATIENTS: Twenty-four women. INTERVENTIONS: Hysterotomy followed by complete enucleation by blunt and sharp dissection was performed. Enucleated myomas were placed into a retriever bag and extracted through a suprapubic or umbilical mini-laparotomic incision by manual morcellation with a surgical scalpel. A histological examination was performed to identify the dispersed leiomyoma cell sheets in trapped tissues on the surface of a defoaming sponge equipped in the reservoir of an intraoperative red blood cell salvage device, which was used to collect peritoneal washing fluid along with blood. MEASUREMENTS AND MAIN RESULTS: Bag rupture was not observed in any case; however, apparent leiomyoma cell sheets were identified in 20 of 24 cases (83.3%). No devices or procedures that were used for myomectomy could completely prevent leiomyoma cells from appearing in the peritoneal washing fluid. CONCLUSION: Even when careful in-bag tissue extraction of myomas was performed in laparoscopic-assisted myomectomy, dispersion of leiomyoma cell was identified in most cases. Further study is needed to show that the feasibility of rigorous washing to reduce the potential risk of leiomyoma cell dissemination. PMID- 29631013 TI - Order and polarity in character state transformation models that root the tree of life. AB - Harish and Kurland recently compared two evolutionary models that root the tree of life. Both models make use of unordered phylogenetic characters. Here we show that they confused one of their models with models that use Wagner ordered characters. In addition, we also show that these Wagner characters should be polarized a posteriori with the generality criterion and not with external outgroup hypotheses. These facts question the rationale of their comparative phylogenomic exercise. PMID- 29631014 TI - Reply to Caetano-Anolles et al. comment on "Empirical genome evolution models root the tree of life". AB - We recently analyzed the robustness of competing evolution models developed to identify the root of the Tree of Life: 1) An empirical Sankoff parsimony (ESP) model (Harish and Kurland, 2017), which is a nonstationary and directional evolution model; and 2) An a priori ancestor (APA) model (Kim and Caetano Anolles, 2011) that is a stationary and reversible evolution model. Both Bayesian model selection tests as well as maximum parsimony analyses demonstrate that the ESP model is, overwhelmingly, the better model. Moreover, we showed that the APA model is not only sensitive to artifacts, but also that the underlying assumptions are neither empirically grounded nor biologically realistic. PMID- 29631015 TI - Design, synthesis and in vitro anti-mycobacterial activities of homonuclear and heteronuclear bis-isatin derivatives. AB - A series of novel homonuclear and heteronuclear bis-isatin derivatives tethered through ethylene were designed, synthesized and evaluated for their in vitro anti mycobacterial activities against MTB H37Rv and MDR-TB. All hybrids exhibited potential anti-mycobacterial activities against MTB H37Rv and MDR-TB with MIC ranging from 16 to 256 MUg/mL. In particular, the heteronuclear bis-isatin 4i (MIC: 25 and 16 MUg/mL) was most active against MTB H37Rv and MDR-TB strains, and could act as a lead for further optimization. PMID- 29631016 TI - Design, synthesis and antifungal activity evaluation of coumarin-3-carboxamide derivatives. AB - A series of coumarin-3-carboxamides/hydrazides have been designed and synthesized, all the target compounds were evaluated in vitro for their antifungal activity against Botrytis cinerea, Alternaria solani, Gibberella zeae, Rhizoctorzia solani, Cucumber anthrax and Alternaria leaf spot, some of the designed compounds 4a-4g exhibited potential activity in the primary assays, this highlighted by the compounds 4a, 4d, 4e and 4f, EC50 values of which against Rhizoctorzia solani were as low as 1.80 MUg/mL, 2.50 MUg/mL, 2.25 MUg/mL and 2.10 MUg/mL, respectively, exhibiting more effective control with that of the positive control than Boscalid. Furthermore, compounds 4a and 4e represented equivalent antifungal activity with Boscalid against Botrytis cinerea. PMID- 29631017 TI - Electron transport chains in organohalide-respiring bacteria and bioremediation implications. AB - In situ remediation employing organohalide-respiring bacteria represents a promising solution for cleanup of persistent organohalide pollutants. The organohalide-respiring bacteria conserve energy by utilizing H2 or organic compounds as electron donors and organohalides as electron acceptors. Reductive dehalogenase (RDase), a terminal reductase of the electron transport chain in organohalide-respiring bacteria, is the key enzyme that catalyzes halogen removal. Accumulating experimental evidence thus far suggests that there are distinct models for respiratory electron transfer in organohalide-respirers of different lineages, e.g., Dehalococcoides, Dehalobacter, Desulfitobacterium and Sulfurospirillum. In this review, to connect the knowledge in organohalide respiratory electron transport chains to bioremediation applications, we first comprehensively review molecular components and their organization, together with energetics of the organohalide-respiratory electron transport chains, as well as recent elucidation of intramolecular electron shuttling and halogen elimination mechanisms of RDases. We then highlight the implications of organohalide respiratory electron transport chains in stimulated bioremediation. In addition, major challenges and further developments toward understanding the organohalide respiratory electron transport chains and their bioremediation applications are identified and discussed. PMID- 29631018 TI - Trafficking mechanisms of synaptogenic cell adhesion molecules. AB - Nearly every aspect of neuronal function, from wiring to information processing, critically depends on the highly polarized architecture of neurons. Establishing and maintaining the distinct molecular composition of axonal and dendritic compartments requires precise control over the trafficking of the proteins that make up these cellular domains. Synaptic cell adhesion molecules (CAMs), membrane proteins with a critical role in the formation, differentiation and plasticity of synapses, require targeting to the correct pre- or postsynaptic compartment for proper functioning of neural circuits. However, the mechanisms that control the polarized trafficking, synaptic targeting, and synaptic abundance of CAMs are poorly understood. Here, we summarize current knowledge about the sequential trafficking events along the secretory pathway that control the polarized surface distribution of synaptic CAMs, and discuss how their synaptic targeting and abundance is additionally influenced by post-secretory determinants. The identification of trafficking-impairing mutations in CAMs associated with various neurodevelopmental disorders underscores the importance of correct protein trafficking for normal brain function. PMID- 29631019 TI - Tetraspanins shape the synapse. AB - Tetraspanins are a family of proteins largely expressed in mammals. These proteins share very similar structures and are involved in several biological processes spanning from the immune system to cancer growth regulation. Moreover, tetraspanins are scaffold proteins that are able to interact with each other and with a subset of proteins involved in the regulation of the central nervous system, including synapse formation, function and plasticity. In this review, we will focus on the analysis of the literature on tetraspanins, highlighting their involvement in synapse formation and function through direct or indirect modulation of synaptic proteins. PMID- 29631020 TI - Brain Structural Networks in Mouse Exposed to Chronic Maternal Undernutrition. AB - Brain structural connectivity is known to be altered in cases of intrauterine growth restriction and premature birth, although the specific effect of maternal nutritional restriction, a common burden in human populations, has not been assessed yet. Here we analyze the effects of maternal undernutrition during pregnancy and lactation by establishing three experimental groups of female mice divided according to their diet: control (Co), moderate calorie-protein restriction (MCP) and severe protein restriction (SP). Nutritionally restricted dams gained relatively less weight during pregnancy and the body weight of the offspring was also affected by maternal undernutrition, showing global growth restriction. We performed magnetic resonance imaging (MRI) of the offspring's brains after weaning and analyzed their connectivity patterns using complex graph theory. In general, changes observed in the MCP group were more subtle than in SP. Results indicated that brain structures were not homogeneously affected by early nutritional stress. In particular, the growth of central brain regions, such as the temporo-parietal cortex, and long integrative myelinated tracts were relatively preserved, while the frequency of short tracts was relatively reduced. We also found a differential effect on network parameters: network degree, clustering, characteristic path length and small-worldness remained mainly unchanged, while the rich-club index was lower in nutritionally restricted animals. Rich-club decrease reflects an impairment in the structure by which brain regions with large number of connections tend to be more densely linked among themselves. Overall, the findings presented here support the hypothesis that chronic nutritional stress produces long-term changes in brain structural connectivity. PMID- 29631021 TI - Characterizing Microstructural Tissue Properties in Multiple Sclerosis with Diffusion MRI at 7 T and 3 T: The Impact of the Experimental Design. AB - The recent introduction of advanced magnetic resonance (MR) imaging techniques to characterize focal and global degeneration in multiple sclerosis (MS), like the Composite Hindered and Restricted Model of Diffusion, or CHARMED, diffusional kurtosis imaging (DKI) and Neurite Orientation Dispersion and Density Imaging (NODDI) made available new tools to image axonal pathology non-invasively in vivo. These methods already showed greater sensitivity and specificity compared to conventional diffusion tensor-based metrics (e.g., fractional anisotropy), overcoming some of its limitations. While previous studies uncovered global and focal axonal degeneration in MS patients compared to healthy controls, here our aim is to investigate and compare different diffusion MRI acquisition protocols in their ability to highlight microstructural differences between MS and control tissue over several much used models. For comparison, we contrasted the ability of fractional anisotropy measurements to uncover differences between lesion, normal-appearing white matter (WM), gray matter and healthy tissue under the same imaging protocols. We show that: (1) focal and diffuse differences in several microstructural parameters are observed under clinical settings; (2) advanced models (CHARMED, DKI and NODDI) have increased specificity and sensitivity to neurodegeneration when compared to fractional anisotropy measurements; and (3) both high (3 T) and ultra-high fields (7 T) are viable options for imaging tissue change in MS lesions and normal appearing WM, while higher b-values are less beneficial under the tested short-time (10 min acquisition) conditions. PMID- 29631022 TI - Genomic and transcriptomic characterization of the mitochondrial-rich oncocytic phenotype on a thyroid carcinoma background. AB - We conducted the first systematic omics study of the oncocytic phenotype in 488 papillary thyroid carcinomas (PTC) from The Cancer Genome Atlas. Oncocytic phenotype is secondary to PTC, being unrelated to several pathologic scores. The nuclear genome had low impact on this phenotype (except in specific copy number variation), which was mostly driven by the significant accumulation of mitochondrial DNA non-synonymous and frameshift mutations at high heteroplasmy levels. Energy and mitochondrial-related pathways were significantly enriched in oncocytic tumors that also displayed increased levels of expression for genes involved in autophagy and fusion of mitochondria. Our in vitro tests confirmed that autophagy is increased and functional while mitophagy is decreased in these tumors. PMID- 29631024 TI - Applications of transcriptomics and proteomics in understanding fish immunity. AB - With the development of intensive aquaculture, economic losses increasingly result from fish mortality due to pathogen infection. In recent years, a growing number of researchers have used transcriptomic and proteomic analyses to study fish immune responses to exogenous pathogen infection. Integrating transcriptomic and proteomic analyses provides a better understanding of the fish immune system including gene expression, regulation, and the intricate biological processes underlying immune responses against infection. This review focuses on the recent advances in the fields of transcriptomics and proteomics, which have contributed to our understanding of fish immunity to exogenous pathogens. PMID- 29631025 TI - Under control: The innate immunity of fish from the inhibitors' perspective. AB - The innate immune response involves a concerted network of induced gene products, preformed immune effectors, biochemical signalling cascades and specialised cells. However, the multifaceted activation of these defensive measures can derail or overshoot and, if left unchecked, overwhelm the host. A plenty of regulatory devices therefore mediate the fragile equilibrium between pathogen defence and pathophysiological manifestations. Over the past decade in particular, an almost complete set of teleostean sequences orthologous to mammalian immunoregulatory factors has been identified in various fish species, which prove the remarkable conservation of innate immune-control concepts among vertebrates. This review will present the current knowledge on more than 50 teleostean regulatory factors (plus additional fish-specific paralogs) that are of paramount importance for controlling the clotting cascade, the complement system, pattern-recognition pathways and cytokine-signalling networks. A special focus lies on those immunoregulatory features that have emerged as potential biomarker genes in transcriptome-wide research studies. Moreover, we report on the latest progress in elucidating control elements that act directly with immune gene-encoding nucleic acids, such as transcription factors, hormone receptors and micro- and long noncoding RNAs. Investigations into the function of teleostean inhibitory factors are still mainly based on gene-expression profiling or overexpression studies. However, in support of structural and in-vitro analyses, evidence from in-vivo trials is also available and revealed many biochemical details on piscine immune regulation. The presence of multiple gene copies in fish adds a degree of complexity, as it is so far hardly understood if they might play distinct roles during inflammation. The present review addresses this and other open questions that should be tackled by fish immunologists in future. PMID- 29631023 TI - Regulation and function of neurogenesis in the adult mammalian hypothalamus. AB - Over the past two decades, evidence has accumulated that neurogenesis can occur in both the juvenile and adult mammalian hypothalamus. Levels of hypothalamic neurogenesis can be regulated by dietary, environmental and hormonal signals. Since the hypothalamus has a central role in controlling a broad range of homeostatic physiological processes, these findings may have far ranging behavioral and medical implications. However, many questions in the field remain unresolved, including the cells of origin of newborn hypothalamic neurons and the extent to which these cells actually regulate hypothalamic-controlled behaviors. In this manuscript, we conduct a critical review of the literature on postnatal hypothalamic neurogenesis in mammals, lay out the main outstanding controversies in the field, and discuss how best to advance our knowledge of this fascinating but still poorly understood process. PMID- 29631026 TI - High level of dietary soybean oil depresses the growth and anti-oxidative capacity and induces inflammatory response in large yellow croaker Larimichthys crocea. AB - Increasing demand, uncertain availability and high price of fish oil with the expansion of aquaculture made it essential to search alternative lipid sources. Vegetable oil has been proved to be the best candidate for the replacement of fish oil in aquafeeds. However, this replacement especially in high level potentially has some negative effects on fish. The present study was conducted to investigate the growth performance, anti-oxidative and inflammatory responses of large yellow croaker to replacement of dietary fish oil by soybean oil. Three isonitrogenous (46% crude protein) and isolipidic (13% crude lipids) diets were formulated to feed fish (initial body weight: 36.80 +/- 0.39 g) for 12 weeks. The control diet was designed to contain 6.5% of fish oil, and named as FO. On the basis of the control diet, the fish oil was 50% and 100% replaced by soybean oil, and these two diets were named as FS and SO, respectively. Results showed that the specific growth rate significantly decreased in the SO group. Crude lipid contents in muscle and liver of fish fed SO diet were significantly higher than those in the FO group. The ratio of n-3 poly-unsaturated fatty acids (PUFAs) to identified fatty acids in liver decreased significantly, while n-6 PUFAs increased significantly with increasing dietary soybean oil inclusion. The levels of triacylglycerol, non-esterified fatty acid and tumour necrosis factor alpha, and the activity of aspartate aminotransferase in serum significantly increased in SO group. The total anti-oxidative capacity and expressions of the anti oxidation-related genes (superoxide dismutase 1 and 2, catalase, glutathion peroxidase and nuclear factor erythroid 2-related factor 2) were significantly decreased by dietary soybean inclusion. Dietary soybean oil significantly decreased the gene expressions of the anti-inflammatory cytokines (arginase I and interleukin 10), and increased the pro-inflammatory cytokines (tumour necrosis factor alpha and interleukin 1beta). The replacement of dietary fish oil by soybean oil also induced an over-expression of toll-like receptor 22 and myeloid differentiation factor 88 in liver. In conclusion, dietary soybean oil could suppress growth performance and liver anti-oxidative capacity, and induce inflammatory responses of large yellow croaker. PMID- 29631027 TI - Kaolin incorporated diet on growth and immune response in Ctenopharyngodon idellus against Aeromonas hydrophila. AB - The effect of kaolin enriched diet on growth, hematology, and immune response in the grass carp Ctenopharyngodon idellus against Aeromonas hydrophila is reported. Both the infected and uninfected groups fed with kaolin enriched diet gained better weight, protein efficiency ratio (PER) and feed conversion ratio (FCR). The survival rate was 98.3% in control (C) and uninfected (UI) fed with 2 g kg-1 kaolin diet, whereas it was 95.0% in uninfected (UI) fed with 1 g kg-1 or infected (I) fed with 1 g kg-1 kaolin diets. In both groups the red blood cell (RBC) and white blood cell (WBC) counts, percentage of lymphocytes and eosinophils, level of albumin and globulin increased in uninfected (UI) fed with 1, 2, and 3 g kg-1 diets. The serum Ig level significantly increased in both groups when fed with 3 g kg-1 diet, whereas the phagocytic activity did not increase significantly. Further the respiratory burst activity in both groups significantly increased with any supplemented diet. The serum superoxide dismutase (SOD) activity increased significantly in the infected group fed with 2 g kg-1 diet and the uninfected group fed with 1 g kg-1 diet. The complement activity was significantly enhanced in both groups when fed with 1 and 2 g kg-1 diets; the lysozyme activity increased with 2 g kg-1 diet; besides the group was 5% mortality whereas 10% mortality was observed when fed with 1 or 3 g kg-1 diets. The present results suggest that C. idellus fed with kaolin enriched diet promotes growth, hematology, innate and adaptive immune response against Aeromonas hydrophila infection. PMID- 29631029 TI - Elevated expression of TSLP and IL-33 in Behcet's disease skin lesions: IL-37 alleviate inflammatory effect of TSLP. AB - The release of TSLP and IL-33 affect the skin integrity, which unsettled transcription factor regulators. We investigate TSLP and IL-33 in Behcet disease (BD) and we prove the effect of the anti-inflammatory cytokine IL-37 in BD skin lesions on TSLP production. TSLP, IL-33 and GATA-3/T-bet, were measured using PCR in BD skin lesions. We tested the suppressive effect of IL-37 on skin samples stimulated with a cytokine mixture inducing TSLP expression. TSLP and IL-33 were increased in BD patients particularly in patients having skin manifestations and correlate with indexed skin lesions. TSLP expression in BD with skin lesions correlates significantly with the transcription factors GATA3/Tbet ratio. The anti-inflammatory mediator IL-37 acted as a suppressor of TSLP-skin synthesis. The microenvironment in cutaneous lesions of BD patients' skin lesions is dominated by the expression of IL-33 and TSLP along an inflammatory Th2-type current. IL-37 acts as a booster to restore homeostasis. PMID- 29631028 TI - Regenerative tissue remodeling in planarians - The mysteries of morphallaxis. AB - Biologists have long marveled at the ability of planarian flatworms to regenerate any parts of their bodies in just a little over a week. While great progress has been made in deciphering the mechanisms by which new tissue is formed at sites of amputation, we know relatively little about the complementary remodeling response that occurs in uninjured tissues to restore anatomical scale and proportion. This review explores the mysterious biology of this process, first described in hydra by the father of experimental zoology, Abraham Trembley, and later termed 'morphallaxis' by the father of experimental genetics, Thomas Hunt Morgan. The perceptive work of these early pioneers, together with recent studies using modern tools, has revealed some of the key features of regenerative tissue remodeling, including repatterning of the body axes, reproportioning of organs like the brain and gut, and a major increase in the rate of cell death. Yet a mechanistic solution to this longstanding problem in the field will require further study by the next generation of planarian researchers. PMID- 29631030 TI - Would I do it again? Reflections on a career in academia and electrophysiology. PMID- 29631031 TI - Chronic thromboembolic pulmonary hypertension. What we are missing? PMID- 29631032 TI - Proteomic content of circulating exosomes in dairy cows with or without uterine infection. AB - In the past few decades, there has been a global decrease in dairy cow reproductive performance. An activated inflammatory system, due to uterine infection, has been associated with decreased cow fertility and as such, there is a need to detect uterine disease earlier. Early detection could be achieved by identifying biomarkers for uterine disease. Exosomes are small nanovesicles known to package and deliver protein, mRNA, and miRNAs to near and distant sites. Therefore, the content of circulating exosomes may have the potential to carry biomarkers for earlier diagnosis of disease. We hypothesized that circulating exosomes from cows with and without uterine infection may contain information representative of endometrial health or disease. We compared the proteomic content of circulating exosomes derived from plasma of dairy cows with (n = 10) or without (n = 10) induced uterine infection, using high-performance liquid chromatography tandem mass spectrometry (HPLC MS/MS). Our results demonstrate that there were a total of 103 bovine and 9 Trueperella pyogenes proteins found in plasma exosomes derived from infected cows (infected exosomes), and 90 bovine and 5 T. pyogenes proteins found in exosomes derived from plasma of non-infected cows (non-infected exosomes). 71 bovine proteins were found to be unique to the infected exosomes while only 4 bovine proteins were found to be unique to the non infected exosomes. 8 unique T. pyogenes proteins were identified in infected exosomes and 4 were found to be unique to the non-infected exosomes. Pathway analysis showed that infected exosomes had more proteins involved in structural molecule activity and immune system processes than non-infected exosomal protein. Additionally, proteins from infected exosomes were involved in unique pathways: angiogenesis and integrin signaling pathway. Our data provide preliminary evidence of a potential role for exosomes in the early diagnosis of uterine infection in dairy cows. PMID- 29631033 TI - An Acquired NRAS Q61K Mutation in BRAF V600E-Mutant Lung Adenocarcinoma Resistant to Dabrafenib Plus Trametinib. PMID- 29631034 TI - Small Cell Lung Cancer Presenting as Carcinocythemia. PMID- 29631035 TI - Safety and Efficacy of PD-1 Inhibitors Among HIV-Positive Patients With Non-Small Cell Lung Cancer. AB - INTRODUCTION: Despite widespread administration of programmed death receptor 1 (PD-1) pathway inhibitors among individuals with NSCLC, little is known about the safety and activity of these agents among human immunodeficiency virus (HIV) - infected patients since this population has largely been excluded from immunotherapy clinical trials. METHODS: Here, we describe seven patients with metastatic NSCLC and HIV infection who were treated with PD-1 inhibitors nivolumab (two cases) or pembrolizumab (five cases with three in the first-line setting). RESULTS: Partial responses to immune checkpoint inhibitors were observed in three of seven cases. Among four patients with a programmed death ligand-1 tumor proportion score >=50%, three partial responses were observed. All patients received antiretroviral therapy while on anti-PD-1 treatment. None of the patients experienced grade 3 or 4 immune-related adverse events or immune reconstitution inflammatory syndrome, and none required PD-1 inhibitor dose interruption or discontinuation due to toxicity. CONCLUSIONS: Nivolumab and pembrolizumab can be safe and effective among patients with NSCLC and HIV. Larger studies will be needed to determine the overall safety and efficacy of immune checkpoint inhibitors among cancer patients with HIV. PMID- 29631036 TI - A Case of Adenocarcinoma of the Lung With EGFR T790 Mutation Presenting With Chylous Ascites. PMID- 29631037 TI - Self-Efficacy for Pain Communication Moderates the Relation Between Ambivalence Over Emotional Expression and Pain Catastrophizing Among Patients With Osteoarthritis. AB - : Pain catastrophizing (ie, the tendency to focus on and magnify pain sensations and feel helpless in the face of pain) is one of the most important and consistent psychological predictors of the pain experience. The present study examined, in 60 patients with osteoarthritis pain who were married or partnered: 1) the degree to which ambivalence over emotional expression and negative network orientation were associated with pain catastrophizing, and 2) whether self efficacy for pain communication moderated these relations. Hierarchical multiple linear regression analyses revealed a significant main effect for the association between ambivalence over emotional expression and pain catastrophizing; as ambivalence over emotional expression increased, the degree of pain catastrophizing increased. In addition, the interaction between ambivalence over emotional expression and self-efficacy for pain communication was significant, such that as self-efficacy for pain communication increased, the association between ambivalence over emotional expression and pain catastrophizing became weaker. Negative network orientation was not significantly associated with pain catastrophizing. Findings suggest that higher levels of self-efficacy for pain communication may help weaken the effects of ambivalence over emotional expression on pain catastrophizing. In light of these results, patients may benefit from interventions that target pain communication processes and emotion regulation. PERSPECTIVE: This article examines interpersonal processes involved in pain catastrophizing. This study has the potential to lead to better understanding of maladaptive pain coping strategies and possibly better prevention and treatment strategies. PMID- 29631038 TI - Rabies antibody response after two intradermal pre-exposure prophylaxis immunizations: An observational cohort study. AB - BACKGROUND: Rabies is a lethal, but vaccine preventable disease. Vaccination uptake is however hampered by the time-consuming three-dose, 21/28-day schedule. The aim of this study was to examine whether adequate rabies antibody titers are reached after two intradermal (ID) doses of rabies vaccine, with a seven-day window. METHOD: We conducted an observational cohort study with military personnel. A titer was assessed by RFFIT, on the day of the third vaccination, to ensure an adequate rabies antibody response after ID immunization. RESULTS: After this abbreviated two-dose, seven-day ID schedule, seroconversion was reached in 99.3% (427/430) with a geometric mean titer of 7.59 IU/mL (95% CI 7.04-8.17). CONCLUSIONS: Implementation of this two-dose schedule will protect more people against Rabies. Travelers and military personnel under time constraints, who otherwise would remain unvaccinated, can be considered adequately protected after this two-dose schedule. For populations in endemic areas, local application of a two-dose schedule could provide an opportunity to vaccinate more people with less vaccine. Given the paucity of published data, this study adds relevant evidence in support of the new policy (2017) of WHO, concerning a two-dose, seven-day schedule is approved for all healthy individuals. PMID- 29631040 TI - Derivation and characterization of the NIH registry human stem cell line NYSCF100 line under defined feeder-free conditions. AB - The human embryonic stem cell line NYSCFe001-A was derived from a day 6 blastocyst in feeder-free and antibiotic free conditions. The blastocyst was voluntarily donated for research as surplus after in vitro fertilization treatment following informed consent. The NYSCFe001-A line, registered as NYSCF100 on the NIH registry, presents normal karyotype, is mycoplasma free, expresses all the pluripotency markers and has the potential to differentiate into all three germ layers in vitro. PMID- 29631039 TI - Open chromatin dynamics reveals stage-specific transcriptional networks in hiPSC based neurodevelopmental model. AB - Chromatin accessibility to transcription factors (TFs) strongly influences gene transcription and cell differentiation. However, a mechanistic understanding of the transcriptional control during the neuronal differentiation of human induced pluripotent stem cells (hiPSCs), a promising cellular model for mental disorders, remains elusive. Here, we carried out additional analyses on our recently published open chromatin regions (OCRs) profiling at different stages of hiPSC neuronal differentiation. We found that the dynamic changes of OCR during neuronal differentiation highlighted cell stage-specific gene networks, and the chromatin accessibility at the core promoter region of a gene correlates with the corresponding transcript abundance. Within the cell stage-specific OCRs, we identified the binding of cell stage-specific TFs and observed a lag of a neuronal TF binding behind the mRNA expression of the corresponding TF. Interestingly, binding footprints of NEUROD1 and NEUROG2, both of which induce high efficient conversion of hiPSCs to glutamatergic neurons, were among those most enriched in the relatively mature neurons. Furthermore, TF network analysis showed that both NEUROD1 and NEUROG2 were present in the same core TF network specific to more mature neurons, suggesting a pivotal mechanism of epigenetic control of neuronal differentiation and maturation. Our study provides novel insights into the epigenetic control of glutamatergic neurogenesis in the context of TF networks, which may be instrumental to improving hiPSC modeling of neuropsychiatric disorders. PMID- 29631041 TI - Exploring the representational basis of response-effect compatibility: Evidence from bilingual verbal response-effect mappings. AB - The ideomotor principle states that actions are represented by their anticipated sensory effects. This notion is often tested using the response-effect compatibility (REC) paradigm, where participants' responses are followed either by a compatible or incompatible response effect (e.g., an effect on the right side after a right-hand response is considered R-E compatible due to the spatial overlap, whereas an effect on the left side after the right-hand response is considered incompatible). Shorter reaction times are typically observed in the compatible condition compared to the incompatible condition (i.e., REC effect), suggesting that effect anticipation plays a role in action control. Previous evidence from verbal REC suggested that effect anticipation can be due to conceptual R-E overlap, but there was also phonological overlap (i.e., anticipated reading of a word preceded by the vocal response of saying that very word). To examine the representational basis of REC, in three experiments, we introduced a bilingual R-E mapping to exclude phonological R-E overlap (i.e., in the R-E compatible condition, the translation equivalent of the response word is presented as an effect word in a different language). Our findings show that the REC effect is obtained when presenting the effect word in the same language as the response (i.e., monolingual condition), but the compatibility effect was not found when the semantically same word is presented in a different language, suggesting no conceptually generalized REC in a bilingual setting. (232 words). PMID- 29631042 TI - The coma in glaucoma: Retinal ganglion cell dysfunction and recovery. AB - Retinal ganglion cell (RGC) degeneration causes vision loss in patients with glaucoma, and this has been generally considered to be irreversible due to RGC death. We question this assertion and summarise accumulating evidence that points to visual function improving in glaucoma patients with treatment, particularly in the early stages of disease. We propose that prior to death, RGCs enter periods of dysfunction but can recover with relief of RGC stress. We first summarise the clinical evidence for vision improvement in glaucoma and then detail our experimental work that points to the underlying processes that underpin clinical improvement. We show that functional recovery can occur following a prolonged course of RGC dysfunction and demonstrate how the capacity for recovery can be modified. Detecting RGC dysfunction and augmenting recovery of such 'comatosed' RGCs holds clinical potential to improve early detection of glaucoma and improve visual function. PMID- 29631043 TI - Efficient degradation of imipramine by iron oxychloride-activated peroxymonosulfate process. AB - Synthesized iron oxychloride (FeOCl) was firstly applied to activate peroxymonosulfate (PMS) to degrade imipramine (IMI), a tricyclic antidepressant. Compared to some other Fe-based materials including zero valent iron, Fe2O3, Fe3O4 and ferric ions, FeOCl presented an impressive catalytic activity on PMS at near-neutral condition due to its unique structure containing abundant unsaturated iron atoms and oxo-bridged configuration. With an increase of FeOCl dose, PMS dose or initial pH in ranges of 0.02 - 0.5 g/L, 0.1 - 2.5 mM and 4.0 - 8.0, the degradation efficiency of IMI was effectively raised by 64.0%, 48.5% and 50.6%, respectively. The presence of either bicarbonate or chloride stimulated the removal of IMI. Moreover, 70.4% of IMI was degraded under the background of real water with 2 mM PMS. The possible reactive species were identified as sulfate and hydroxyl radicals. The formed hypochlorite through the reaction of PMS and the released chloride ions may also contribute to the degradation of IMI. Among the oxidants, sulfate radical was proven to be the dominate one in the system. Additionally, the FeOCl/PMS system can overall effectively degrade six other organic compounds including amitriptyline, desipramine, propranolol, nitrobenzene, methyl-paraben and ethyl-paraben, further suggesting the possible application of this system in treatment of vast aquatic micro-organic pollutants. PMID- 29631045 TI - Microstructure of ultra high performance concrete containing lithium slag. AB - Lithium slag (LS) is discharged as a byproduct in the process of the lithium carbonate, and it is very urgent to explore an efficient way to recycle LS in order to protect the environments and save resources. Many available supplementary cementitious materials for partial replacement of cement and/or silica fume (SF) can be used to prepare ultra high performance concrete (UHPC). The effect of LS to replace SF partially by weight used as a supplementary cementitious material (0%, 5%, 10% and 15% of binder) on the compressive strengths and microstructure evolution of UHPC has experimentally been studied by multi-techniques including mercury intrusion porosimetry, scanning electron microscope and nanoindentation technique. The results show that the use of LS degrades the microstructure of UHPC at early ages, and however, the use of LS with the appropriate content improves microstructure of UHPC at later ages. The hydration products of UHPC are mainly dominated by ultra-high density calcium silicate-hydrate (UHD C-S-H) and interfacial transition zone (ITZ) in UHPC has similar compact microstructure with the matrix. The use of LS improves the hydration degree of UHPC and increases the elastic modulus of ITZ in UHPC. LS is a promising substitute for SF for preparation UHPC. PMID- 29631044 TI - Ferrocene-catalyzed heterogeneous Fenton-like degradation mechanisms and pathways of antibiotics under simulated sunlight: A case study of sulfamethoxazole. AB - Readily-available and efficient catalyst is essential for activating oxidants to produce reactive species for deeply remediating water bodies contaminated by antibiotics. In this study, Ferrocene (Fc) was introduced to establish a heterogeneous photo-Fenton system for the degradation of sulfonamide antibiotics, taking sulfamethoxazole as a representative. Results showed that the removal of sulfamethoxazole was effective in Fc-catalyzed photo-Fenton system. Electron spin resonance and radical scavenging experiments verified that there was a photoindued electron transfer process from Fc to H2O2 and dissolved oxygen resulting in the formation of OH that was primarily responsible for the degradation of sulfamethoxazole. The reactions of OH with substructure model compounds of sulfamethoxazole unveiled that aniline moiety was the preferable reaction site of sulfamethoxazole, which was verified by the formation of hydroxylated product and the dimer of sulfamethoxazole in Fc-catalyzed photo Fenton system. This heterogeneous photo-Fenton system displayed an effective degradation efficiency even in a complex water matrices, and Fc represented a long-term stability by using the catalyst for multiple cycles. These results demonstrate that Fc-catalyzed photo-Fenton oxidation may be an efficient approach for remediation of wastewater containing antibiotics. PMID- 29631046 TI - Silver nanoparticle modulates gene expressions, glyoxalase system and oxidative stress markers in fluoride stressed Cajanus cajan L. AB - Application of engineered nanomaterials has increased these days due to their beneficial impacts on several sectors of the economy, including agriculture. Silver nanoparticles (AgNP) are commonly used to improve rate of seed germination, and growth and development of plants. The present study was aimed to monitor the role of engineered AgNP (non-dialysed) in the amelioration of fluoride (F)-induced oxidative injuries in Cajanus cajan L. Experimental results revealed that F-exposure inhibited growth and membrane stability index, while were enhanced with the augmentation of AgNP. The results also demonstrated that F treatment enhanced the accumulations of reactive oxygen species, malondialdehyde and oxidized glutathione, gene expression of NADPH oxidase, and activity of lipoxygenase, but were decreased by the addition of AgNP. The results indicated that exogenous application of AgNP provided tolerance against F-toxicity via enhancing the levels of proline, total and reduced glutathione, glyoxalase I and II activities, and expression of pyrroline-5-carboxylate synthetase gene. Conducted study uniquely suggested potential role of AgNP in the remediation of F toxicity, at least in the Cajanus cajan L. radicles. Further research would be intended to unravel the molecular mechanism(s) involved precisely in the AgNP mediated alleviation of F-toxicity. PMID- 29631047 TI - Effective degradation of phenol via Fenton reaction over CuNiFe layered double hydroxides. AB - A series of CuNiFe layered double hydroxides (LDHs) with various Cu/Ni molar ratios were synthesized as catalysts for Fenton degradation of phenol. It is found that Cu+, Cu2+, Ni2+, Ni3+ and Fe3+ are present on LDHs, owing to an electron transfer from Ni2+ to Cu2+ via metal-oxo-metal bridges. At lower Cu/Ni ratios, the highly dispersed MO6 octahedra and the electron donation effect of Ni facilitate such electron transfer and thus increase the percentage of Cu+. The catalytic activity increases with the decrease in Cu/Ni ratio. The most active Cu0.5Ni2.5Fe LDH can mineralize 98.9% phenol at ambient pH and less excessive H2O2 dosage ( [Formula: see text] /Mphenol = 37). Even at the H2O2 dosage close to the theoretical value, around 90% phenol can be mineralized. The structure activity correlation indicates Cu+ which can readily react with H2O2 to produce hydroxyl radicals may dominate the reaction. The regeneration of Cu+ could be achieved by the electron transfer between Cu2+ and Ni2+ in LDHs. Moreover, Fe3+ can also act as Fenton-like active sites. The special structure of CuNiFe LDHs could offer surface-enriched and easily regenerated Cu+ species, leading to the complete mineralization of phenol and the efficient use of H2O2. PMID- 29631048 TI - Anisotropic biodegradable lipid coated particles for spatially dynamic protein presentation. AB - : There has been growing interest in the use of particles coated with lipids for applications ranging from drug delivery, gene delivery, and diagnostic imaging to immunoengineering. To date, almost all particles with lipid coatings have been spherical despite emerging evidence that non-spherical shapes can provide important advantages including reduced non-specific elimination and increased target-specific binding. We combine control of core particle geometry with control of particle surface functionality by developing anisotropic, biodegradable ellipsoidal particles with lipid coatings. We demonstrate that these lipid coated ellipsoidal particles maintain advantageous properties of lipid polymer hybrid particles, such as the ability for modular protein conjugation to the particle surface using versatile bioorthogonal ligation reactions. In addition, they exhibit biomimetic membrane fluidity and demonstrate lateral diffusive properties characteristic of natural membrane proteins. These ellipsoidal particles simultaneously provide benefits of non-spherical particles in terms of stability and resistance to non-specific phagocytosis by macrophages as well as enhanced targeted binding. These biomaterials provide a novel and flexible platform for numerous biomedical applications. STATEMENT OF SIGNIFICANCE: The research reported here documents the ability of non-spherical polymeric particles to be coated with lipids to form anisotropic biomimetic particles. In addition, we demonstrate that these lipid-coated biodegradable polymeric particles can be conjugated to a wide variety of biological molecules in a "click-like" fashion. This is of interest due to the multiple types of cellular mimicry enabled by this biomaterial based technology. These features include mimicry of the highly anisotropic shape exhibited by cells, surface presentation of membrane bound protein mimetics, and lateral diffusivity of membrane bound substrates comparable to that of a plasma membrane. This platform is demonstrated to facilitate targeted cell binding while being resistant to non specific cellular uptake. Such a platform could allow for investigations into how physical parameters of a particle and its surface affect the interface between biomaterials and cells, as well as provide biomimetic technology platforms for drug delivery and cellular engineering. PMID- 29631049 TI - Mechanics of a two-fiber model with one nested fiber network, as applied to the collagen-fibrin system. AB - : The mechanical behavior of collagen-fibrin (col-fib) co-gels is both scientifically interesting and clinically relevant. Collagen-fibrin networks are a staple of tissue engineering research, but the mechanical consequences of changes in co-gel composition have remained difficult to predict or even explain. We previously observed fundamental differences in failure behavior between collagen-rich and fibrin-rich co-gels, suggesting an essential change in how the two components interact as the co-gel's composition changes. In this work, we explored the hypothesis that the co-gel behavior is due to a lack of percolation by the dilute component. We generated a series of computational models based on interpenetrating fiber networks. In these models, the major network component percolated the model space but the minor component did not, instead occupying a small island embedded within the larger network. Each component was assigned properties based on a fit of single-component gel data. Island size was varied to match the relative concentrations of the two components. The model predicted that networks rich in collagen, the stiffer component, would roughly match pure collagen gel behavior with little additional stress due to the fibrin, as seen experimentally. For fibrin-rich gels, however, the model predicted a smooth increase in the overall network strength with added collagen, as seen experimentally but not consistent with an additive parallel model. We thus conclude that incomplete percolation by the low-concentration component of a co gel is a major determinant of its macroscopic properties, especially if the low concentration component is the stiffer component. STATEMENT OF SIGNIFICANCE: Models for the behavior of fibrous networks have useful applications in many different fields, including polymer science, textiles, and tissue engineering. In addition to being important structural components in soft tissues and blood clots, these protein networks can serve as scaffolds for bioartificial tissues. Thus, their mechanical behavior, especially in co-gels, is both interesting from a materials science standpoint and significant with regard to tissue engineering. PMID- 29631050 TI - Reducing immunoreactivity of porcine bioprosthetic heart valves by genetically deleting three major glycan antigens, GGTA1/beta4GalNT2/CMAH. AB - : Bioprosthetic heart valves (BHVs) originating from pigs are extensively used for heart valve replacement in clinics. However, recipient immune responses associated with chronic calcification lead to structural valve deterioration (SVD) of BHVs. Two well-characterized epitopes on porcine BHVs have been implicated in SVD, including galactose-alpha1,3-galactose (alphaGal) and N glycolylneuraminic acid (Neu5Gc) whose synthesis are catalyzed by alpha(1,3) galactosyltransferase (encoded by the GGTA1 gene) and CMP-Neu5Ac hydroxylase (encoded by the CMAH gene), respectively. It has been reported that BHV from alphaGal-knockout pigs are associated with a significantly reduced immune response by human serum. Moreover, valves from alphaGal/Neu5Gc-deficient pigs could further reduce human IgM/IgG binding when compared to BHV from alphaGal knockout pigs. Recently, another swine xenoantigen, Sd(a), produced by beta-1,4-N acetyl-galactosaminyl transferase 2 (beta4GalNT2), has been identified. To explore whether tissue from GGTA1, CMAH, and beta4GalNT2 triple gene-knockout (TKO) pigs would further minimize human antibody binding to porcine pericardium, TKO pigs were successfully produced by CRISPR/Cas9 mediated gene targeting. Our results showed that the expression of alphaGal, Neu5G and Sd(a) on TKO pigs was negative, and that human IgG/IgM binding to pericardium was minimal. Moreover, the analysis of collagen composition and physical characteristics of porcine pericardium from the TKO pigs indicated that elimination of the three xenoantigens had no significant impact on the physical proprieties of porcine pericardium. Our results demonstrated that TKO pigs would be an ideal source of BHVs. STATEMENT OF SIGNIFICANCE: Surgical heart valve replacement is an established lifesaving treatment for diseased heart valve. Bioprosthetic heart valves (BHVs) made from glutaraldehyde-fixed porcine or bovine tissues are widely used in clinics but exhibit age-dependent structural valve degeneration (SVD) which is associated with the immune response against BHVs. Three major xenoantigens present on commercial BHVs, Galactosea alpha1,3 galactose (alphaGal), N-glycolylneuraminic acid (Neu5Gc) and glycan products of beta-1,4-N acetyl-galactosaminyl transferase 2 (beta4GalNT2) are eliminated through CRISPR/Cas9 mediated gene targeting in the present study. The genetically modified porcine pericardium showed reduced immunogenicity but comparable collagen composition and physical characteristics of the pericardium from wild type pigs. Our data suggested that BHVs from TKO pigs is a promising alternative for currently available BHVs from wild-type pigs. PMID- 29631051 TI - Phylogenetic relationships of rollers (Coraciidae) based on complete mitochondrial genomes and fifteen nuclear genes. AB - The rollers (Coraciidae) constitute a relative small avian family with ca. 12 species distributed in Africa, western and southern Eurasia, and eastern Australia. In this study we examine the phylogenetic relationships of all species currently recognized in the family, including two taxa whose taxonomic status is currently contested. By using shotgun sequencing on degraded DNA from museum study skins we have been able to recover complete mitochondrial genomes as well as 15 nuclear genes for in total 16 taxa. The gene sequences were analyzed both concatenated in a maximum likelihood framework as well in a species tree approach using MP-EST. The different analytical approaches yield similar, highly supported trees and support the current division of the rollers into two genera, Coracias and Eurystomus. The only conflict relates to the placement of the Blue-bellied Roller (C. cyanogaster), where the mitochondrial, and the concatenated nuclear and mitochondrial data set, place this taxon as sister to the other Coracias species, whereas nuclear data and the species tree analysis place it as the sister taxon of C. naevia and C. spatulatus. All analyses place the Eurasian roller (C. garrulus) with the two African species, Abyssinian Roller (C. abyssinica) and Liliac-breasted Roller (C. caudatus), and place this clade as the sister group to the Asian Coracias rollers. In addition, our results support a sister group relationship between the morphologically rather dissimilar Purple Roller (C. naevia) and Racquet-tailed Roller (C. spatulatus) and also support the division of Eurystomus in an African and an Asian clade. However, within the Asian clade the Azure Roller (E. azureus) from Halmahera appears to be nested within the Dollarbird (E. orientalis), indicating that that this taxon is a morphological divergent, but a rather recent offshoot, of the widespread Dollarbird. Similarly, the Purple-winged Roller (C. temminickii) from Sulawesi group together with C. benghalensis affinis from Southeast Asia and these two in turn comprises the sister group to C. benghalensis benghalensis from India and western Asia. PMID- 29631052 TI - Resolving relationships and phylogeographic history of the Nyssa sylvatica complex using data from RAD-seq and species distribution modeling. AB - Nyssa sylvatica complex consists of several woody taxa occurring in eastern North America. These taxa were recognized as two or three species including three or four varieties by different authors. Due to high morphological similarities and complexity of morphological variation, classification and delineation of taxa in the group have been difficult and controversial. Here we employ data from RAD-seq to elucidate the genetic structure and phylogenetic relationships within the group. Using the genetic evidence, we evaluate previous classifications and delineate species. We also employ Species Distribution Modeling (SDM) to evaluate impacts of climatic changes on the ranges of the taxa and to gain insights into the relevant refugia in eastern North America. Results from Molecular Variance Analysis (AMOVA), STRUCTURE, phylogenetic analyses using Maximum likelihood, Bayesian Inference, and Splittree methods of RAD-seq data strongly support a two clade pattern, largely separating samples of N. sylvatica from those of N. biflora-N. ursina mix. Divergence time analysis with BEAST suggests the two clades diverged in the mid Miocene. The ancestor of the present trees of N. sylvatica was suggested to be in the Pliocene and that of N. biflora-N. ursina mix in the end of the Miocene. Results from SDM predicted a smaller range in the southern part of the species present range of each clade during the Last Glacial Maximum (LGM). A northward expansion of the ranges during interglacial period and a northward shift of the ranges in the future under a model of global warming were also predicted. Our results support the recognition of two species in the complex, N. sylvatica and N. biflora, following the phylogenetic species concept. We found no genetic evidence supporting recognitions of intraspecific taxa. However, we propose subsp. ursina and subsp. biflora within N. biflora due to their distinction in habits, distributions, and habitats. Our results further support movements of trees in eastern North America in response to climatic changes. Finally, our study demonstrates that RAD-seq data and a combination of population genomics and SDM are valuable in resolving relationship and biogeographic history of closely related species that are taxonomically difficult. PMID- 29631053 TI - Phylogenetic signature of lateral exchange of genes for antibiotic production and resistance among bacteria highlights a pattern of global transmission of pathogens between humans and livestock. AB - The exchange of bacterial virulence factors driven by lateral gene transfer (LGT) can help indicate possible bacterial transmission among different hosts. Specifically, overlaying the phylogenetic signal of LGT among bacteria onto the distribution of respective isolation sources (hosts) can indicate patterns of transmission among these hosts. Here, we apply this approach towards a better understanding of patterns of bacterial transmission between humans and livestock. We utilize comparative genomics to trace patterns of LGT for an 11-gene operon responsible for the production of the antibiotic nisin and infer transmission of bacteria among respective host species. A total of 147 bacterial genomes obtained from NCBI were determined to contain the complete operon. Isolated from human, porcine and bovine hosts, these genomes represented six Streptococcus and one Staphylococcus species. Phylogenetic analyses of the operon sequences revealed a signature of frequent and recent lateral gene transfer that indicated extensive bacterial transmission between humans and pigs. For 11 isolates, we detected a Tn916-like transposon inserted into the operon. The transposon contained the tetM gene (tetracycline resistance) and additional phylogenetic analyses indicated transmission among human and animal hosts. The bacteria possessing the nisin operon and transposon were isolated from hosts distributed globally. These findings possibly reflect both the globalization of the food industry and an increasingly mobile and expanding human population. In addition to concerns regarding zoonosis, these findings also highlight the potential threat to livestock worldwide due to reverse zoonosis. PMID- 29631054 TI - Complete species-level phylogeny of the leaf warbler (Aves: Phylloscopidae) radiation. AB - The leaf warbler radiation (Aves: Phylloscopidae) has undergone a c. 50% increase in the number of recognised species over the last three decades, mainly as a result of analyses of vocalisations and DNA. Using a multilocus dataset for all of the species in this family, and multispecies coalescent-based as well as concatenation methods, we provide the first complete species-level phylogeny for this important group, as well as an estimate of the timing of diversification. The most recent common ancestor for the family was dated at 11.7 million years ago (mya) (95% highest posterior density 9.8-13.7 mya), and divergence times between sister species ranged from 0.5 mya (0.3-0.8 mya) to 6.1 mya (4.8-7.5 mya). Based on our results, we support synonymising Seicercus with Phylloscopus, which results in a monogeneric Phylloscopidae. We discuss the pros and cons of this treatment,and we argue againstproliferation of taxonomic names,and conclude that a large monogeneric Phylloscopidae leads to the fewest taxonomic changes compared to traditional classifications. We briefly discuss morphological evolution in the light of the phylogeny. The time calibrated phylogeny is a major improvement compared to previous studies based on a smaller number of species and loci and can provide a basis for future studies of other aspects of phylloscopid evolution. PMID- 29631055 TI - Retained duplications and deletions of CYP2C genes among primates. AB - The human genome encodes about 60 functional enzymes of the cytochrome P450 superfamily, including four functional enzymes of the cytochrome P450 2C (CYP2C) subfamily. These enzymes have been shown to metabolize drugs and xenobiotic toxins, such as those in the diet, and are therefore of great importance for biomedical research and applications. While the pharmacology of P450 enzymes has been studied extensively, our understanding of molecular evolution of this gene family is incomplete, in part because a great variation exists in the number of CYP2C homologs across genomes. In humans, the enzymes encoded by these genes are responsible for the metabolism of more than 20% of clinical drugs, but this is not the naturalistic function of these enzymes, which is the metabolism of xenobiotics such as plant secondary metabolites. In this paper, we sought to correlate evolutionary relationships among primate CYP2C genes with known dietary profiles from these species, testing the hypothesis that these genes have evolved under the pressure of dietary toxins. Aside from a small number of deeply divergent genes, primate CYP2C paralogs form three separate clades: CYP2C18, CYP2C9/CYP2C19, and CYP2C8/CYP2C20. Our results showed that the CYP2C18 gene has been separately lost in Nomascus leucogenys and the Panini genomes, and there is no evidence that this gene has been under any positive selection among primates. While CYP2C20 has been retained in cercopithecoids, orthologous loci were separately lost in platyrrhines and hominoids. Notably, nine codons exhibited signature of positive selection. Finally, the CYP2C19 locus was duplicated in basal catarrhines, resulting in the birth of CYP2C9; but the ancestral locus was only retained in hominoid taxa. Overall, our findings support the hypothesis that primate CYP2C genes have evolved in response to selective pressures provided by dietary toxins, although not all gene clusters have evolved in the same manner. Our results may indicate an evolutionarily deep difference in ecology or physiology among higher-order primate taxa. PMID- 29631056 TI - Investigation into the intracellular fates, speciation and mode of action of selenium-containing neuroprotective agents using XAS and XFM. AB - BACKGROUND: A variety of selenium compounds have been observed to provide protection against oxidative stress, presumably by mimicking the mechanism of action of the glutathione peroxidases. However, the selenium chemistry that underpins the action of these compounds has not been unequivocally established. METHODS: The synchrotron based techniques, X-ray absorption spectroscopy and X ray fluorescence microscopy were used to examine the cellular speciation and distribution of selenium in SH-SY5Y cells pretreated with one of two diphenyl diselenides, or ebselen, followed by peroxide insult. RESULTS: Bis(2 aminophenyl)diselenide was shown to protect against oxidative stress conditions which mimic ischemic strokes, while its nitro analogue, bis(2 nitrophenyl)diselenide did not. This protective activity was tentatively assigned to the reductive cleavage of bis(2-aminophenyl)diselenide inside human neurocarcinoma cells, SH-SY5Y, while bis(2-nitrophenyl)diselenide remained largely unchanged. The distinct chemistries of the related compounds were traced by the changes in selenium speciation in bulk pellets of treated SH-SY5Y cells detected by X-ray absorption spectroscopy. Further, bis(2-aminophenyl)diselenide, like the known stroke mitigation agent ebselen, was observed by X-ray fluorescence imaging to penetrate into the nucleus of SH-SY5Y cells while bis(2 nitrophenyl)diselenide was observed to be excluded from the nuclear region. CONCLUSIONS: The differences in activity were thus attributed to the varied speciation and cellular localisation of the compounds, or their metabolites, as detected by X-ray absorption spectroscopy and X-ray fluorescence microscopy. SIGNIFICANCE: The work is significant as it links, for the first time, the protective action of selenium compounds against redox stress with particular chemical speciation using a direct measurement approach. PMID- 29631057 TI - High affinity sugar ligands of C-type lectin receptor langerin. AB - BACKGROUND: Langerin, a C-type lectin receptor (CLR) expressed in a subset of dendritic cells (DCs), binds to glycan ligands for pathogen capture and clearance. Previous studies revealed that langerin has an unusual binding affinity toward 6-sulfated galactose (Gal), a structure primarily found in keratan sulfate (KS). However, details and biological outcomes of this interaction have not been characterized. Based on a recent discovery that the disaccharide L4, a KS component that contains 6-sulfo-Gal, exhibits anti inflammatory activity in mouse lung, we hypothesized that L4-related compounds are useful tools for characterizing the langerin-ligand interactions and their therapeutic application. METHODS: We performed binding analysis between purified long and short forms of langerin and a series of KS disaccharide components. We also chemically synthesized oligomeric derivatives of L4 to develop a new high affinity ligand of langerin. RESULTS: We show that the binding critically requires the 6-sulfation of Gal and that the long form of langerin displays higher affinity than the short form. The synthesized trimeric (also designated as triangle or Tri) and polymeric (pendant) L4 derivatives displayed over 1000-fold higher affinity toward langerin than monomeric L4. The pendant L4, but not the L4 monomer, was found to effectively transduce langerin signaling in a model cell system. CONCLUSIONS: L4 is a specific ligand for langerin. Oligomerization of L4 unit increased the affinity toward langerin. GENERAL SIGNIFICANCE: These results suggest that oligomeric L4 derivatives will be useful for clarifying the langerin functions and for the development of new glycan-based anti-inflammatory drugs. PMID- 29631058 TI - Synergistic cellular responses to heavy metal exposure: A minireview. AB - BACKGROUND: Metal-responsive transcription factor 1 (MTF-1) induces the expression of metallothioneins (MTs) which bind and sequester labile metal ions. While MTF-1 primarily responds to excess metal exposure, additional stress response mechanisms are activated by excess metals. Evidence suggests potential crosstalk between responses mediated by MTF-1 and stress signaling enhances cellular tolerance to metal exposure. SCOPE OF REVIEW: This review aims to summarize the current understanding of interaction between the stress response mediated by MTF-1 and other cellular mechanisms, notably the nuclear factor kappaB (NF-kappaB) and heat shock response (HSR). MAJOR CONCLUSIONS: Crosstalk between MTF-1 mediated metal response and NF-kappaB signaling or HSR can modulate expression of stress proteins in response to metal exposure via effects on precursor signals or direct interaction of transcriptional activators. The interaction between stress signaling pathways can enhance cell survival and tolerance through a unified response system. GENERAL SIGNIFICANCE: Elucidating the interactions between MTF-1 and cell stress response mechanisms is critical to a comprehensive understanding of metal-based cellular effects. Co-activation of HSR and NF-kappaB signaling allows the cell to detect metal contamination in the environment and improve survival outcomes. PMID- 29631059 TI - Quantitative biochemical characterization and biotechnological production of caspase modulator, XIAP: Therapeutic implications for apoptosis-associated diseases. AB - BACKGROUND: Regulating apoptosis is a common and essential therapeutic strategy for cancer and neurodegenerative disorders. Based on basic studies of apoptotic mechanisms, various researches have attempted to overcome the pathogenesis of such diseases by activating or inhibiting apoptosis. Generally, the biochemical characteristics of the target molecules should be evaluated along with understanding of their mechanisms of action during drug development. Among apoptotic regulators, XIAP serves as a potent negative regulator to block apoptosis through the inhibition of caspase (CASP)-9 and -3/7. Although XIAP is an attractive target with such apoptotic-modulating property, biochemical and biophysical studies of XIAP are still challenging. METHODS: In this study, the CASP-9 and -3/7 inhibitors XIAP, 242Delta and Delta230 were prepared using the pGEX expression system and biochemically characterized. RESULTS: These inhibitors were expressed in Escherichia coli at a concentration of >=20 mg/L culture under a native condition with 0.01 mM IPTG induction. Notably, using a simple and rapid affinity purification technique, these CASP-9 and -3/7 inhibitors have been purified, yielding >=5 mg/L culture at approximately 90% purity. CONCLUSIONS: We have determined that HtrA2 specifically binds to the BIR2 and BIR3 of XIAP at a 1:1 molecular ratio. Moreover, in vitro cell-free CASP-9 and -3/7 activation apoptosis assays have demonstrated that these purified XIAP proteins dramatically inhibit CASP-9 and -3/7 action. GENERAL SIGNIFICANCE: Our system is suitable for biochemical studies, such as quantitation of the number of molecules acting on the apoptosis regulation, and provides a basis and insights that can be applied to the development of therapeutic agents for neurodegenerative disorders and cancer. PMID- 29631060 TI - Comparison of adult spinal deformity patients with and without rheumatoid arthritis undergoing primary non-cervical spinal fusion surgery: a nationwide analysis of 52,818 patients. AB - BACKGROUND CONTEXT: Numerous studies have analyzed the impact of rheumatoid arthritis (RA) on the cervical spine and its related surgical interventions. However, there is a paucity of literature available conducting the same analyses in patients with non-cervical spine involvement. PURPOSE: The objective of this study was to compare patient characteristics, comorbidities, and complications in patients with and without RA undergoing primary non-cervical spinal fusions. STUDY DESIGN/SETTING: This is a retrospective national database review. PATIENT SAMPLE: A total of 52,818 patients with adult spinal deformity undergoing non cervical spinal fusions (1,814 patients with RA and 51,004 patients without RA). OUTCOME MEASURES: The outcome measures in the study include patient characteristics, as well as complication and mortality rates. MATERIALS AND METHODS: Using the Nationwide Inpatient Sample from 2003 to 2014, International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnosis and procedure codes were used to identify patients aged >=18 years old with and without RA undergoing primary non-cervical spinal fusions. Univariate analysis was used to determine patient characteristics, comorbidities, and complication values for each group. Bivariate analysis was used to compare the two groups. Significance was set at p<.05. RESULTS: Patients with RA were older (p<.001), were more likely to be women (p<.001), had increased rates of osteoporosis (p<.001), had a greater percentage of their surgeries reimbursed by Medicare (p<.001), and more often had weekend admissions (p=.014). There was no difference in all the other characteristics. Patients with RA had higher rates of iron deficiency anemia, congestive heart failure, chronic pulmonary disease, depression, and fluid and electrolyte disorders (all, p<.001). Patients without RA had higher rates of alcohol abuse (p=.027). There was no difference in all the other complications. There was no difference in mortality rate (p=.99). Total complications were greater in patients with RA (p<.001). Patients with RA had higher rates of infection (p=.032), implant-related complications (p=.010), incidental durotomies (p=.001), and urinary tract infections (p<.001). No difference existed among the other complications. CONCLUSIONS: Patients with RA have an increased number of comorbidities and complication rates compared with patients without RA. Such knowledge can help surgeons and patients with RA have beneficial preoperative discussions regarding outcomes. PMID- 29631061 TI - Does approach matter? A comparative radiographic analysis of spinopelvic parameters in single-level lumbar fusion. AB - BACKGROUND CONTEXT: Lumbar fusion is a popular and effective surgical option to provide stability and restore anatomy. Particular attention has recently been focused on sagittal alignment and radiographic spinopelvic parameters that apply to lumbar fusion as well as spinal deformity cases. Current literature has demonstrated the effectiveness of various techniques of lumbar fusion; however, comparative data of these techniques are limited. PURPOSE: This study aimed to directly compare the impact of various lumbar fusion techniques (anterior lumbar interbody fusion [ALIF], lateral lumbar interbody fusion [LLIF], transforaminal lumbar interbody fusion [TLIF], and posterolateral fusion [PLF]) based on radiographic parameters. STUDY DESIGN/SETTING: A single-center retrospective study examining preoperative and postoperative radiographs was carried out. PATIENT SAMPLE: A consecutive list of lumbar fusion surgeries performed by multiple spine surgeons at a single institution from 2013 to 2016 was identified. OUTCOME MEASURES: Radiographic measurements used included segmental lordosis (SL), lumbar lordosis (LL), pelvic incidence (PI), pelvic incidence-lumbar lordosis (PI-LL) mismatch, anterior and posterior disc height (DH-A, DH-P, respectively), and foraminal height (FH). METHODS: Radiographic measurements were performed on preoperative and postoperative lateral lumbar radiographs on all single-level lumbar fusion cases. Demographic data were collected including age, gender, approach, diagnosis, surgical level, and implant lordosis. Paired sample t test, one-way analysis of variance (ANOVA), McNemar test, and independent sample t test were used to establish significant differences in the outcome measures. Multiple linear regression was performed to determine a predictive model for lordosis from implant lordosis, fusion technique, and surgical level. RESULTS: There were 164 patients (78 men, 86 women) with a mean age of 60.1 years and average radiographic follow-up time of 9.3 months. These included 34 ALIF, 23 LLIF, 63 TLIF, and 44 PLF surgeries. ALIF and LLIF significantly improved SL (7.9 degrees and 4.4 degrees ), LL (5.5 degrees and 7.7 degrees ), DH-A (8.8 mm and 5.8 mm), DH-P (3.4 mm and 2.3 mm), and FH (2.8 mm and 2.5 mm), respectively (p<=.003). TLIF significantly improved these parameters, albeit to a lesser extent: SL (1.7 degrees ), LL (2.7 degrees ), DH-A (1.1 mm), DH-P (0.8 mm), and FH (1.1 mm) (p<=.02). PLF did not significantly alter any of these parameters while significantly reducing FH (-1.3 mm, p=.01). One-way ANOVA showed no significant differences between ALIF and LLIF other than ALIF with greater DeltaDH-A (3.0 mm, p=.02). Both ALIF and LLIF significantly outperformed PLF in preoperative to postoperative changes in all parameters p<=.001. Additionally, ALIF significantly outperformed TLIF in the change in SL (6.2 degrees , p<.001), and LLIF significantly outperformed TLIF in the change in LL (5.0 degrees , p=.02). Both outperformed TLIF in DeltaDH-A (7.7 mm and 4.7 mm) and DeltaDH-P (2.6 mm and 1.5 mm), respectively (p<=.02). ALIF was the only fusion technique that significantly improved the proportion of patients with a PI-LL<10 degrees (0.410.66, p=.02). Lordotic cages had superior improvement of all parameters compared with non-lordotic cages (p<.001). Implant lordosis (m=1.1), fusion technique (m=6.8), and surgical level (m=6.9) significantly predicted postoperative SL (p<.001, R2=0.56). CONCLUSIONS: This study demonstrated that these four lumbar fusion techniques yield divergent radiographic results. ALIF and LLIF produced greater improvements in radiographic measurements postoperatively compared with TLIF and PLF. ALIF was the most successful in improving PI-LL mismatch, an important parameter relating to sagittal alignment. Lordotic implants provided better sagittal correction and surgeons should be cognizant of the impact that these differing implants and techniques produce after surgery. Surgical technique is an important determinant of postoperative alignment and has ramifications upon sagittal alignment in lumbar fusion surgery. PMID- 29631062 TI - Behcet's disease: New insights into pathophysiology, clinical features and treatment options. AB - Behcet's disease (BD) is a rare systemic vasculitis characterized by oral aphthous ulcers, genital ulcers, ocular lesions and other systemic manifestations. BD occurs most frequently in Eurasian populations along the ancient trading route known as the "Silk Road" which extends from eastern Asia to the Mediterranean basin. The causes of BD are unknown: it is believed to be due to an autoimmune process triggered by an infectious or environmental agent in genetically predisposed individuals. HLA-B51 allele located in the MHC locus, on chromosome 6p, has been the most strongly associated risk factor for BD in areas along the Old Silk Route. Herpes simplex virus-1 and Streptococcus have been postulated as possible environmental triggers of BD. T cell homeostasis perturbation, especially Th1 and Th17 expansion and decreased regulation by Tregs are now supposed to be the cornerstone of BD pathogenesis. The histology shows vasculitis that involves both arteries and veins, and vessels of any size. BD is a systemic vasculitis with significant neutrophil infiltration, endothelial cell swelling, and fibrinoid necrosis. The diagnosis of BD is only supported by clinical criteria and requires the exclusion of other diagnoses based on clinical presentation. There are no pathognomonic laboratorial findings of BD. This rare disease often leads to blindness and fatal systemic involvement. Main causes of death include major vessel disease and central nervous system involvement. Corticosteroids are commonly used to treat clinical manifestations of BD in combination with immunosuppressant drugs. Tumor necrosis factor (TNF)-blocking agents such as Infliximab, Etanercept, and Adalimumab have been reported to have success in patients with BD. PMID- 29631063 TI - The association of solid-phase assays to immunofluorescence increases the diagnostic accuracy for ANA screening in patients with autoimmune rheumatic diseases. PMID- 29631065 TI - The confidence of rheumatologists about switching to biosimilars for their patients. PMID- 29631064 TI - Autoimmune phenomena and disease in cancer patients treated with immune checkpoint inhibitors. AB - The discovery and approved treatment with immune checkpoint inhibitors (ICIs) for a variety of cancers has changed dramatically the morbidity and mortality rates for these patients. Despite the obvious benefits, their use is associated with unique immune-related adverse effects (irAEs), including autoimmune conditions such as: inflammatory arthritis, myositis, vasculitis and Sicca syndrome. The appearance of ICIs-induced autoimmune irAE requires from oncologists and rheumatologists a different approach to the identification and treatment of these conditions, which may differ from the classic and traditional approach to rheumatologic diseases. It should be taken into consideration that ICIs therapy in patients with preexisting autoimmunity could be possible, but with a cost of causing disease exacerbation. In this extensive review, we present the autoimmune irAEs, mostly as phenomena, but also as classic autoimmune diseases as well as therapeutic options for the side effects. PMID- 29631066 TI - Cannabis for musculoskeletal pain and arthritis: Evidence is needed. PMID- 29631067 TI - Bone metastases from lung cancer: A paradigm for multidisciplinary onco rheumatology management. AB - Bone is the third metastatic site after liver and lungs. Bone metastases occur in one out of three lung cancers and are usually of osteolytic aspect. Osteolytic bone metastases are responsible of long bone and vertebral fractures leading to restricted mobility, surgery and medullar compression that severely alter quality of life and that have a huge medico-economic impact. In the recent years, Bone Metastatic Multidisciplinary Tumour Board (BM2TB) have been developed to optimize bone metastases management for each patient in harmony with oncology program. In this review, we will go through all the different aspects of bone metastases management including diagnosis and evaluation (CT scan, Tc 99m-MDP bone scan, 18FDG-PET scan and biopsy for molecular diagnosis), systemic bone treatments (zoledronic acid and denosumab) and local treatments (interventional radiology and radiotherapy). Surgical strategies will be discussed elsewhere. Based on the last 2017-Lung Cancer South East French Guidelines, we present a practical decision tree to help the physicians for decision making in order to reach a personalized locomotor strategy for every patient. PMID- 29631068 TI - Hydroxychloroquine for the prevention of fetal growth restriction and prematurity in lupus pregnancy: A systematic review and meta-analysis. AB - OBJECTIVES: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that primarily affects women of childbearing age. While the impact of hydroxychloroquine (HCQ) on SLE activity and neonatal lupus occurrence has been evaluated in several studies, its role on prematurity and intrauterine growth restriction (IUGR) remains uncertain. The aim of this study was to assess the impact of HCQ exposure on prematurity and IUGR during pregnancy in women with SLE. METHODS: We conducted a systematic review and a meta-analysis comparing prematurity and IUGR in SLE pregnancies exposed or not exposed to HCQ. The odds ratio of IUGR and prematurity were calculated and compared between pregnancies in each group according HCQ treatment. RESULTS: Six studies were included (3 descriptive cohort studies and 3 case series) totalling 870 pregnancies. Of the SLE pregnancies, 308 were exposed to HCQ and were compared to 562 not exposed to HCQ. There was no statistical difference for prematurity or IUGR between groups. CONCLUSION: This meta-analysis failed to prove the efficacy of HCQ in the prevention of prematurity as well as IUGR during SLE pregnancies. Due to the heterogeneity of the studies, these results should be interpreted cautiously. PMID- 29631069 TI - Evaluation of bone quality with trabecular bone score in active spondyloarthritis. AB - OBJECTIVE: Many patients with spondyloarthritis (SpA) are at risk of fracture due to bone fragility, whereas their bone mineral density (BMD) is not significantly diminished. Other tools, such as trabecular bone score (TBS), evaluating other characteristics of bone tissue are therefore necessary in order to evaluate bone changes in these patients. Therefore we evaluated TBS as a bone quality marker, in a cohort of patients with SpA and investigated which clinical and biological factors were correlated with TBS values. METHODS: Patients fulfilling ASAS criteria of SpA with a BMD assessment and visiting our department for initiation or switch of a biologic treatment were selected. The clinical and biological data were collected at the time of BMD measurement. RESULTS: Ninety-five patients were included in the study, with a mean age of 40.2 and a mean disease duration of 8.2 years. Lumbar BMD T-score was <-1 and <-2.5 in 17% and 3% of patients, respectively. On average, TBS value was 1.34+/-0.12. Lumbar BMD was positively correlated with TBS (r=0.61), while disease duration, disease activity score and serum PTH levels were negatively correlated with TBS (r=-0.24, r=-0.33, and r= 0.27, respectively). These correlations persisted in a multivariate analysis. Furthermore, more than half of the patients with a BMD level above -2.5 T-score had a low TBS value. CONCLUSION: Our results show that TBS provides information additional to BMD on the bone status of patients with SpA. They suggest that TBS may help in identifying those patients at risk of fracture. PMID- 29631070 TI - Prevalence of shoulder calcification in pseudoxanthoma elasticum patients. PMID- 29631071 TI - Biological agents in the management of adult-onset Still's disease. PMID- 29631072 TI - Public open space characteristics influencing adolescents' use and physical activity: A systematic literature review of qualitative and quantitative studies. AB - The objective of this systematic review was to provide insight into the specific characteristics of public open spaces (POS) associated with adolescents' POS visitation and physical activity (PA). Qualitative research suggests many characteristics to be associated with POS visitation and PA. Quantitative evidence confirmed a positive association between presence of trails, playgrounds and specific types of sports fields (e.g. basketball) with POS visitation and PA, whereas safety and aesthetics seemed subordinate. Suggestions for future research, as well as some methodological recommendations are provided. PMID- 29631074 TI - Discovery, identification and mitigation of isobaric sulfate metabolite interference to a phosphate prodrug in LC-MS/MS bioanalysis: Critical role of method development in ensuring assay quality. AB - Metabolite interferences represent a major risk of inaccurate quantification when using LC-MS/MS bioanalytical assays. During LC-MS/MS bioanalysis of BMS-919194, a phosphate ester prodrug, in plasma samples from rat and monkey GLP toxicology studies, an unknown peak was detected in the MRM channel of the prodrug. This peak was not observed in previous discovery toxicology studies, in which a fast gradient LC-MS/MS method was used. We found out that this unknown peak would co elute with the prodrug peak when the discovery method was used, therefore, causing significant overestimation of the exposure of the prodrug in the discovery toxicology studies. To understand the nature of this interfering peak and its impact to bioanalytical assay, we further investigated its formation and identification. The interfering compound and the prodrug were found to be isobaric and to have the same major product ions in electrospray ionization positive mode, thus, could not be differentiated using a triple quadrupole mass spectrometer. By using high-resolution mass spectrometry (HRMS), the interfering metabolite was successfully identified to be an isobaric sulfate metabolite of BMS-919194. To the best of our knowledge, this is the first report that a phosphate prodrug was metabolized in vivo to an isobaric sulfate metabolite, and this metabolite caused significant interference to the analysis of the prodrug. This work demonstrated the presence of the interference risk from isobaric sulfate metabolites to the bioanalysis of phosphate prodrugs in real samples. It is critical to evaluate and mitigate potential metabolite interferences during method development, therefore, minimize the related bioanalytical risks and ensure assay quality. Our work also showed the unique advantages of HRMS in identifying potential metabolite interference during LC-MS/MS bioanalysis. PMID- 29631073 TI - A prospective validation of the Bova score in normotensive patients with acute pulmonary embolism. AB - BACKGROUND: The Bova score has shown usefulness in the identification of intermediate-high risk patients with acute pulmonary embolism (PE), but lacks prospective validation. The aim of this study was to prospectively validate the Bova score in different settings from the original derivation cohort. METHODS: Consecutive, normotensive patients with acute PE recruited at 13 academic or general hospitals were stratified, using their baseline data, into the three Bova risk stages (I-III). The primary outcome was the 30-day composite of PE-related mortality, hemodynamic collapse and non-fatal PE recurrences in the three risk categories. RESULTS: In the study period, 639 patients were enrolled. The primary end point occurred in 45 patients (7.0%; 95% Confidence Intervals, 5.2%-9.3%). Risk stage correlated with the PE-related complication rate (stage I, 2.9%; stage II, 17%; stage III, 27%). Patients classified as stage III by the Bova score had a 6.5-fold increased risk for adverse outcomes (3.1-13.5, p < 0.001) compared with stages I and II combined. Rescue thrombolysis increased from stage I to stage III (0.6%, 12% and 15% respectively). All-cause mortality (5.3%) did not substantially differ among the stages. CONCLUSIONS: The Bova score accurately stratifies normotensive patients with acute PE into stages of increasing risk of 30-day PE-related complications. PMID- 29631075 TI - Activation of choline kinase drives aberrant choline metabolism in esophageal squamous cell carcinomas. AB - Esophageal squamous cell carcinoma (ESCC) is a major health threat worldwide. Research focused on molecular events associated with ESCC carcinogenesis for diagnosis, treatment and prevention is needed. Our goal is to discover novel biomarkers and investigate the underlying molecular mechanisms of ESCC progression by employing a global metabolomic approach. Sera from 34 ESCC patients and 32 age and sex matched healthy controls were profiled using two dimensional liquid chromatography-mass spectrometry (2D LC-MS). We identified 120 differential metabolites in ESCC patient serums compared to healthy controls. Several amino acids, serine, arginine, lysine and histidine were significantly changed in ESCC patients. Most importantly, we found dysregulated lipid metabolism as an important characteristic in ESCC patients. Several free fat acids (FFA) and carnitines were found down-regulated in ESCC patients. Choline was significantly increased and phosphatidylcholines (PC) were significantly decreased in ESCC serum. The high expression of choline and low expression of total PC in patient serum were associated with the high expression of choline kinase (Chok) and activated Kennedy pathway in ESCC cells. Chok expression can serve as a significant biomarker for ESCC prognosis. In conclusion, metabolite profiles in the ESCC patient serum were significantly different from those in the healthy controls. Phosphatidylcholines and Chok, the key enzyme in the PC metabolism pathway, may serve as novel biomarkers for ESCC. PMID- 29631076 TI - Metabolic profiling of corylin in vivo and in vitro. AB - Corylin, an phenolic compound from Psoralea corylifolia, has been reported with various pharmacological properties but has poor bioavailability due to massive metabolism. In this study, twelve metabolites of corylin mainly involving in oxidation, hydration, glucuronidation and sulfation were detected in mice. Furthermore, the oxidation and hydration of corylin (M4) in human liver microsomes (HLM) and human intestine microsomes (HIM) were both efficient with high CLint (intrinsic clearance) values of 24.29 and 42.85 MUL/min/mg, respectively. CYP1A1, 1B1 and 2C19 contributed most for M4 with the CLint values of 26.63, 33.09 and 132.41 MUL/min/mg, respectively. Besides, M4 was strongly correlated with phenacetin-N-deacetylation (r = 0.885, p = 0.0001) and tolbutamide-4-oxidation (r = 0.727, p = 0.001) in twelve individual HLMs, respectively. In addition, corylin was efficiently glucuronidated (M7) in HLM (125.33 MUL/min/mg) and in HIM (108.74 MUL/min/mg). UGT1A1 contributed the most for M7 with the CLint value of 122.32 MUL/min/mg. Meanwhile, M7 was significantly correlated with beta-estradiol-3-O-glucuronidation (r = 0.742, p = 0.006) in twelve individual HLMs. Moreover, the metabolism of corylin showed marked species differences. Taken together, corylin was subjected to massive first-pass metabolism in liver and intestine, while CYP1A1, 1B1, 2C19 and UGT1A1 were the main contributors. Finally, the proposed metabolic pathway of corylin involed CYP and UGT isoforms were summarized, which could help to understand the metabolic fate of corylin in vivo. PMID- 29631077 TI - Simultaneous quantification of twelve compounds in ethyl acetate extracts of Euphorbia kansui before and after fry-baked with vinegar by UPLC-MS/MS and its toxic effect on zebrafish. AB - The dried roots of Euphorbia kansui T.N. Liou ex T.P. Wang have been traditionally used for edema in China. However, the severe toxicity caused by Euphorbia kansui has seriously restricted its clinical application. Therefore, in order to study the material basis of the toxicity attenuation effect of processing with vinegar, a rapid, sensitive, validated and reliable UPLC-MS/MS method was developed to determine twelve compounds in ethyl acetate extracts of Euphorbia kansui before and after fry-baked with vinegar simultaneously. Meanwhile, the study of their toxic effect on zebrafish was conducted. Chromatographic separation was accomplished on Waters BEH C18 UPLC column. 0.3% formic acid in water and acetonitrile were used as mobile phase with a flow rate of 0.40 mL/min and a temperature at 30 degrees C. The analysis was performed in multiple reaction monitoring (MRM) mode using positive electrospray ionization (ESI). Furthermore, the toxic research results indicated that the toxicity of Euphorbia kansui was decreased after vinegar-processed, which might because of the increase in the content of 5-O-benzoyl-20-deoxyingenol and the decrease in the contents of the remaining terpenoids in ethyl acetate extracts of Euphorbia kansui fry-baked with vinegar. This study demonstrated that the method used is a powerful approach to determine the content of twelve compounds that responsible for the toxic effect of Euphorbia kansui at the same instant. And provided the experimental evidence for the rationale behind the reduction of toxicity. PMID- 29631078 TI - Pure Acute-on-Chronic Subdural Hematoma Due to Ruptured Posterior Communicating Artery Aneurysm: Unsuspecting Entity. AB - BACKGROUND: Even though rarely reported as a cause of pure subdural hematoma (SDH), aneurysmal rupture should be suspected in patients with spontaneous SDH without coagulopathy. CASE DESCRIPTION: We report a case of acute-on-chronic SDH in a 55-year-old lady with cerebral herniation due to a ruptured posterior communicating artery aneurysm. She was managed with single-stage SDH evacuation along with clipping of the aneurysm. CONCLUSIONS: Computed tomography angiography of the head is advisable in patients with spontaneous SDH without coagulopathy. Pure SDH as compared with SDH associated with subacute hemorrhage, intraventricular hemorrhage, or intracerebral hemorrhage due to aneurysmal rupture has a good outcome. PMID- 29631079 TI - Stent-Retriever Thrombectomy Across Circle of Willis. AB - OBJECTIVE: Endovascular thrombectomy has become the gold standard for acute ischemic stroke intervention in appropriate patients. Occasionally, thrombectomy through the standard craniocervical artery related to the affected territory is not technically feasible due to patient-specific anatomic issues. METHODS: This is a retrospective review of cases where intracranial access was achieved via an unaffected circulation across the Circle of Willis. RESULTS: A technically successful thrombectomy is described in detail in 3 cases along with technical challenges encountered. CONCLUSIONS: Thrombectomy across the Circle of Willis is a potential bailout technique for select, complex cases. Further investigation is warranted. PMID- 29631080 TI - Uninstrumented Posterior Lumbar Interbody Fusion: Have Technological Advances in Stabilizing the Lumbar Spine Truly Improved Outcomes? AB - BACKGROUND: Since the 1980s, numerous operations have replaced posterior lumbar interbody fusion (PLIF) with human bone. These operations often involve expensive implants and complex procedures. Escalating expenditures in lumbar fusion surgery warrant re-evaluation of classical PLIF with allogeneic ilium and without instrumentation. The purpose of this study was to determine the long-term fusion rate and clinical outcomes of PLIF with allogeneic bone (allo-PLIF). METHODS: Between 1981 and 2006, 321 patients aged 12-80 years underwent 339 1-level or 2 level allo-PLIFs for degenerative instability and were followed for 1-28 years. Fusion status was determined by radiographs and as available, by computed tomography scans. Clinical outcome was assessed by the Economic/Functional Outcome Scale. RESULTS: Of the 321 patients, 308 were followed postoperatively (average 6.7 years) and 297 (96%) fused. Fusion rates were lower for patients with substance abuse (89%, P = 0.007). Clinical outcomes in 87% of patients were excellent (52%) or good (35%). Economic/Functional Outcome Scale scores after initial allo-PLIF on average increased 5.2 points. Successful fusion correlated with nearly a 2-point gain in outcome score (P = 0.001). A positive association between a patient characteristic and outcome was observed only with age 65 years and greater, whereas negative associations in clinical outcomes were observed with mental illness, substance abuse, heavy stress to the low back, or industrial injuries. The total complication rate was 7%. CONCLUSIONS: With 3 decades of follow-up, we found that successful clinical outcomes are highly correlated with solid fusion using only allogeneic iliac bone. PMID- 29631081 TI - Reconstruction of Dural Defects in Endoscopic Transnasal Approaches for Intradural Lesions Using Multilayered Fascia with a Pressure-Control Spinal Drainage System. AB - OBJECTIVE: Nasoseptal flap reconstruction is a widely accepted method for reducing cerebrospinal fluid (CSF) leakage after endoscopic transnasal surgeries (ETSs). However, this method is associated with nasal complications and is difficult to apply repeatedly in recurrent cases. Therefore, alternative methods are needed. METHODS: Layers of autologous fascia lata were placed on the inside and outside of the dural defect to sufficiently cover it, and the grafts were compressed with an inflated balloon. A lumbar drainage system with a pressure control valve was used for 72 hours postoperatively. We retrospectively analyzed data on patients with skull base lesions showing intracranial extensions that required wide opening of the ventral dura in ETS. Fifty cases (47 skull base tumors and 3 others) were included, 28 of which were recurrent cases. RESULTS: In 21 cases (42%), the nasal septum was not intact because of the previous ETS. Seventeen patients (34%) had a history of radiotherapy and 9 (18%) had undergone multisession radiotherapies. None of the 50 patients required additional surgery for postoperative CSF rhinorrhea, and 2 had intermittent CSF leakage that resolved with prolonged lumbar drainage placement for a week. Previous multisession radiotherapy was the only significant risk factor for the need of prolonged drainage (P = 0.029). CONCLUSIONS: The multilayer closure method with a pressure-control spinal drainage system is a simple, safe, and effective method for preventing postoperative CSF leakage, which can be readily applied to dural defects in any parts of the skull base regions and in patients with various conditions. PMID- 29631082 TI - Pediatric Spinal Ependymomas: An Epidemiologic Study. AB - OBJECTIVE: Pediatric intramedullary spinal cord ependymomas represent a rare central nervous system neoplasm with few available data regarding incidence and outcomes. To this end, large population-based studies are needed to assess the epidemiology and survival risk factors associated with these tumors in the hope of better understanding these tumors as well as improving outcomes. This retrospective study was undertaken to explore factors that may influence survival in pediatric patients with intramedullary spinal cord ependymomas. METHODS: Using the SEER (Surveillance Epidemiology and End Results) database, a prospective cancer registry, we retrospectively assessed survival in histologically confirmed spinal ependymomas in patients 17 years of age and younger. Survival was described with Kaplan-Meier curves, and a multivariate regression analysis was used to assess the association of several variables with survival, controlling for confounding variables. RESULTS: Invasive tumor extension (P < 0.001) was associated with decreased survival, whereas gross total resection (P = 0.028) correlated with better rates of survival. Age, gender, tumor size, tumor extension, the use and sequence of radiation therapy, or use of chemotherapy were not found to have a statistically significant association with survival outcomes. CONCLUSIONS: Invasive ependymomas occurring in the spine have a worse prognosis, whereas higher tumor grades do not clearly show worse rates of survival. Early diagnosis and surgery seem to be associated with improved survival and outcomes, whereas radiation therapy and chemotherapy have an unclear role. PMID- 29631084 TI - Acridine Orange as a Novel Photosensitizer for Photodynamic Therapy in Glioblastoma. AB - BACKGROUND: Photodynamic therapy combines the effects of a chemical agent with the physical energy from light or radiation to result in lysis of cells. Acridine orange (AO) is a molecule with fluorescence properties that has been demonstrated to possess photosensitizing properties. The objective of this study was to investigate the photodynamic effect of AO on glioblastoma cell viability and growth. METHODS: Glioblastoma cells (N = 8000 cells/well at 0 hours) were exposed to AO followed by white unfiltered light-emitting diode light. Cultures were exposed to either 10 or 30 minutes of light. The cell number per well was determined at 0, 24, 48, and 72 hours after exposure. RESULTS: A dramatic cytocidal effect of AO after exposure to 10 minutes of white light was observed. There was almost complete eradication of glioblastoma cells over a 72-hour period. Although AO or light alone exhibited some effect on cell growth, it was not as pronounced as the combination of AO and light. CONCLUSIONS: This is the first study to our knowledge to demonstrate the photodynamic effect of AO in glioblastoma cells. These data support the need for further studies to characterize and evaluate whether this striking cytotoxic effect can be achieved in vivo. The combination of AO and exposure to white unfiltered light-emitting diode light may have potential future applications in management of glioblastoma. PMID- 29631083 TI - Glioblastoma Survival Outcomes at a Tertiary Hospital in Appalachia: Factors Impacting the Survival of Patients Following Implementation of the Stupp Protocol. AB - BACKGROUND: Glioblastoma is a fatal brain cancer with low median and yearly survival rates. Standard of care for treating glioblastoma is gross total resection (GTR) coupled with the Stupp protocol, but various factors influence the interventions undertaken and survival achieved. As health disparities exist in rural areas, survival in these areas needs to be assessed to understand which factors detract from the successes of these standard medical interventions. METHODS: We retrospectively determined impact of age at diagnosis, number of lesions, the molecular marker O6-methylguanine methyltransferase (MGMT), extent of surgery, and completion of the Stupp protocol on survival in patients treated at West Virginia University Hospitals. We also compared our findings with a pre Stupp protocol study done in West Virginia in 1996. RESULTS: Age <60 years at diagnosis, having the MGMT gene methylated, having a unifocal tumor, receiving GTR, adhering to the Stupp protocol, and undergoing a treatment course of GTR followed by the Stupp protocol significantly increased survival. Comparison with the 1996 study showed that although overall median survival has not increased, all interventions involving GTR have resulted in a significantly higher survival. CONCLUSIONS: We can serve our patient population by offering GTR to all adult patients with glioblastoma when no contraindications exist and ensuring that patients follow the Stupp protocol. After discharge, the Stupp protocol may not be followed or completed for a variety of reasons. In the future, we aim to assess these reasons and analyze other significant interventional and socioeconomic factors that influence survival. PMID- 29631085 TI - Surgical Treatment of Lower Cervical Fracture-Dislocation with Spinal Cord Injuries by Anterior Approach: 5- to 15-Year Follow-Up. AB - BACKGROUND: Lower cervical fracture-dislocations frequently occur with spinal cord injuries. There is no clear consensus on best treatment option. Anterior approach surgery with direct decompression and reduction has become widely accepted. We assessed clinical outcomes of anterior approach surgery in a retrospective cohort study. METHODS: From January 2001 to January 2011, 312 patients with lower cervical spine fracture-dislocation with spinal cord injuries who were treated by the anterior approach were retrospectively analyzed. Of 312 patients, 218 (70%; 121 men and 97 women) met inclusion criteria. Clinical efficacy was evaluated using Odom's criteria and statistical analysis based on Cobb angle of kyphosis and Neck Disability Index and Japanese Orthopedic Association scores. Neurofunctional recovery of patients was assessed by the American Spinal Injury Association system. RESULTS: Average follow-up was 8.9 +/- 2.9 years (range, 5-15 years). Kyphosis angle and Neck Disability Index and Japanese Orthopaedic Association scores were significantly changed from preoperative values of 10.6 degrees +/- 8.9 degrees and 39.7 +/- 4.3 and 7.6 +/ 2.4 to last follow-up values of -5.2 degrees +/- 8.6 degrees and 10.8 +/- 4.6 and 15.6 +/- 1.2 (P < 0.05). Of patients, 197 (90.4%) had good to excellent outcomes, 14 (6.4%) had satisfactory outcomes, and 7 (3.2%) had poor outcomes. Varying degrees of neurologic function recovery were shown by 143 of the original 218 patients (65.6%) and 140 of 191 patients with incomplete paralysis (73.3%). CONCLUSIONS: For lower cervical fracture-dislocation with spinal cord injuries, satisfactory clinical outcomes can be obtained with an anterior approach. The anterior approach restored normal cervical spine structure and promoted functional recovery to achieve a good long-term curative effect. PMID- 29631087 TI - Willingness to revise own testimony: 3- and 4-year-olds' selective trust in unexpected testimony from accurate and inaccurate informants. AB - Prior work has shown that young children trust single accurate and inaccurate individuals to a similar extent in their endorsement of novel information. However, it remains unknown to what extent children trust a credible or noncredible individual when given information that is pitted against their own beliefs. The current study examined whether children, when given unexpected testimony that contradicted their initial beliefs but was not completely unbelievable, would selectively revise their beliefs depending on the informant's past history of accuracy. The participants (3- and 4-year-olds; N = 100) were familiarized with an informant who labeled a series of common objects either accurately or inaccurately. Following that, all children saw a picture of an ambiguous hybrid artifact that consisted of features of two typical common artifacts and were asked to identify the hybrid object with their own label. Subsequently, children watched the previously accurate or inaccurate informant give the same hybrid object a different but plausible label. Children expressed a greater tendency to override their initial judgments and endorse the unexpected testimony from a previously accurate informant than from someone who had consistently made naming errors. The findings provide novel understandings of the circumstances under which 3- and 4-year-old preschoolers may or may not rely on the informant's prior reliability in their selective learning. PMID- 29631086 TI - The Diagnostic Properties of Intraoperative Ultrasound in Glioma Surgery and Factors Associated with Gross Total Tumor Resection. AB - OBJECTIVE: In glioma operations, we sought to analyze sensitivity, specificity, and predictive values of intraoperative 3-dimensional ultrasound (US) for detecting residual tumor compared with early postoperative magnetic resonance imaging (MRI). Factors possibly associated with radiologic complete resection were also explored. METHODS: One hundred forty-four operations for diffuse supratentorial gliomas were included prospectively in an unselected, population based, single-institution series. Operating surgeons answered a questionnaire immediately after surgery, stating whether residual tumor was seen with US at the end of resection and rated US image quality (e.g., good, medium, poor). Extent of surgical resection was estimated from preoperative and postoperative MRI. RESULTS: Overall specificity was 85% for "no tumor remnant" seen in US images at the end of resection compared with postoperative MRI findings. Sensitivity was 46%, but tumor remnants seen on MRI were usually small (median, 1.05 mL) in operations with false-negative US findings. Specificity was highest in low-grade glioma operations (94%) and lowest in patients who had undergone prior radiotherapy (50%). Smaller tumor volume and superficial location were factors significantly associated with gross total resection in a multivariable logistic regression analysis, whereas good ultrasound image quality did not reach statistical significance (P = 0.061). CONCLUSIONS: The specificity of intraoperative US is good, but sensitivity for detecting the last milliliter is low compared with postoperative MRI. Tumor volume and tumor depth are the predictors of achieving gross total resection, although ultrasound image quality was not. PMID- 29631088 TI - Leading approaches in synthetic epigenetics for novel therapeutic strategies. AB - In recent years, our knowledge of the epigenetic functions regulated by post translational modifications (PTMs) of histones, and their role in various diseases, has expanded rapidly, opening the way to novel therapeutic strategies that treat epigenetic abnormalities. Many of the current approaches have been focusing on the chemical inhibition of histone-modifying enzymes to modulate histone PTM states for attaining therapeutic effects. However, recent developments in chemistry and molecular biology have contributed to the emergence of new methods that introduce histone PTMs entirely through artificial means, without reliance on endogenous enzymes. In this review article, we summarize several state-of-the-art approaches for the introduction of synthetic epigenetic modifications in cells, and discuss both their therapeutic potential and the possible challenges in developing novel therapeutic strategies utilizing them. PMID- 29631089 TI - Instrument detection and pose estimation with rigid part mixtures model in video assisted surgeries. AB - Localizing instrument parts in video-assisted surgeries is an attractive and open computer vision problem. A working algorithm would immediately find applications in computer-aided interventions in the operating theater. Knowing the location of tool parts could help virtually augment visual faculty of surgeons, assess skills of novice surgeons, and increase autonomy of surgical robots. A surgical tool varies in appearance due to articulation, viewpoint changes, and noise. We introduce a new method for detection and pose estimation of multiple non-rigid and robotic tools in surgical videos. The method uses a rigidly structured, bipartite model of end-effector and shaft parts that consistently encode diverse, pose-specific appearance mixtures of the tool. This rigid part mixtures model then jointly explains the evolving tool structure by switching between mixture components. Rigidly capturing end-effector appearance allows explicit transfer of keypoint meta-data of the detected components for full 2D pose estimation. The detector can as well delineate precise skeleton of the end-effector by transferring additional keypoints. To this end, we propose effective procedure for learning such rigid mixtures from videos and for pooling the modeled shaft part that undergoes frequent truncation at the border of the imaged scene. Notably, extensive diagnostic experiments inform that feature regularization is a key to fine-tune the model in the presence of inherent appearance bias in videos. Experiments further illustrate that estimation of end-effector pose improves upon including the shaft part in the model. We then evaluate our approach on publicly available datasets of in-vivo sequences of non-rigid tools and demonstrate state of-the-art results. PMID- 29631090 TI - Mercury bonds with carbon (OC and EC) in small aerosols (PM1) in the urbanized coastal zone of the Gulf of Gdansk (southern Baltic). AB - PM1 aerosols were collected at the coastal station in Gdynia between 1st January and 31st December 2012. The main purpose of the study was to determine the variability in concentrations of mercury Hg(p), organic carbon (OC) and elemental carbon (EC) in PM1 aerosols under varying synoptic conditions in heating and non heating periods. Additionally, sources of origin and bonds of mercury with carbon species were identified. The highest concentrations of Hg(p), OC and EC were found during the heating period. Then all analyzed PM1 components had a common, local origin related to the consumption of fossil fuels for heating purposes under conditions of lower air temperatures and poor dispersion of pollutants. Long periods without precipitation also led to the increase in concentration of all measured PM1 compounds. In heating period mercury correlated well with elemental carbon and primary and secondary organic carbon when air masses were transported from over the land. At that time, the role of transportation was of minor importance. In the non-heating period, the concentration of all analyzed compounds were lower than in the heating period, which could be associated with the reduced influence of combustion processes, higher precipitation and, in the case of mercury, also the evaporation of aerosols at higher air temperatures. However, when air masses were transported from over the sea or from the port/shipyard areas the mercury concentration increased significantly. In the first case higher air humidity, solar radiation and ozone concentration as well as the presence of marine aerosols could further facilitate the conversion of gaseous mercury into particulate mercury and its concentration increase. In the second case Hg(p) could be adsorbed on particles rich in elemental carbon and primary organic carbon emitted from ships. PMID- 29631091 TI - Superior removal of Co2+, Cu2+ and Zn2+ contaminants from water utilizing spongy Ni/Fe carbonate-fluorapatite; preparation, application and mechanism. AB - Spongy Ni/Fe carbonate - fluorapatite was synthesized from natural phosphorite enriched with iron impurities. The morphological, chemical and structural features of the product were estimated using several techniques as XRD, SEM, EDX, and FT-IR. It exhibits spongy structure of nano and micro-pores. The average crystallite size is about 8.27 nm. The suitability of the product for considerable decontamination of Zn2+, Co2+, and Cu2+, ions from water was studied based on several reacting parameters. The equilibrium was attained after 240 min for Zn2+ and Co2+ ions while the adsorption equilibrium of Cu2+ reached after 120 min. The adsorption data for the selected metals was represented well by a pseudo second-order model which revealed chemisorption uptake. The equilibrium studies were appraised based on traditional models and two advanced models were designed according to the statistical physical theories. The adsorption results highly fitted with Langmuir model followed rather than the other models. This indicated a monolayer adsorption for the metal ions by spongy Ni/Fe carbonate - fluorapatite. The estimated qmax values are 149.25 mg/g, 106.4 mg/g and 147.5 mg/g for the uptake of Zn2+, Co2+, and Cu2+, respectively. Based on monolayer models of one energy and two energies, the number of receptor adsorption sites, number of adsorbed metal ions per active site, the average number of sites which occupied by ions, mono layer adsorption quantity and the adsorption quantity after total saturation were calculated for the first time for such materials. PMID- 29631092 TI - Toxicity assessment of arsenate and arsenite on growth, chlorophyll a fluorescence and antioxidant machinery in Nostoc muscorum. AB - The present study deals with impact of varied doses of arsenite (AsIII; 50, 100 and 150 uM) and arsenate (AsV; 50, 100 and 150 mM) on growth, photosynthetic pigments, photochemistry of photosystem II, oxidative biomarkers, (O2*-, H2O2 and MDA equivalents contents) and activity of antioxidant enzymes in diazotrophic cyanobacterium Nostoc muscorum after 48 and 96 h of the treatments. The reduction in growth, pigment contents (Chl a, Phy and Car) and PS II photochemistry was found to increase with enhanced accumulation of test metal in cells, and the damaging effect on photosynthetic pigments showed the order (Phy > chl a> Car). The negative effect on PS II photochemistry was due to significant decrease in the value of JIP kinetics phiP0, FV/F0, phiE0,Psi0 and PIABS except F0/FV and significant rise in values of energy flux parameters such as ABS/RC, TR0/RC, ET0/RC and DI0/RC. Both the species of arsenic caused significant rise in oxidative biomarkers as evident by in vitro and in vivo analysis of (O2*-, H2O2 and MDA equivalents contents) despite of appreciable rise in the activity antioxidative enzymes such as SOD, POD, CAT and GST. The study concludes that in among both forms of arsenic, arsenite effect was more dominant on growth, photosynthetic pigments; oxidative stress biomarkers as evident by weak induction of anti-oxidative defense system to overcome the stress as compared to arsenate. PMID- 29631093 TI - Anxiety sensitivity moderates drug cravings in response to induced negative affect in opioid dependent outpatients. PMID- 29631094 TI - Social cognitive mediators of the relationship between impulsivity traits and adolescent alcohol use: Identifying unique targets for prevention. PMID- 29631095 TI - Negative attentional bias for positive recovery-related words as a predictor of treatment success among individuals with an alcohol use disorder. AB - INTRODUCTION: This study assessed relationships between clients' attentional bias (AB) for different types of stimuli and their treatment outcomes. Alcohol AB during detoxification has previously been shown to predict relapse, but further research was needed to clarify this relationship. The current study determined whether AB for recovery-related words would also predict treatment outcome. METHODS: Participants were 45 clients undergoing alcohol detoxification, and a control group of 36 staff members. They rated words for personal relevance in four categories (alcohol-related, neutral, positive change-related, and negative change-related). Participants completed an individualized Stroop task containing their chosen words. They were also assessed on readiness-to-change, difficulties with emotion regulation, drinking problems, anxiety, and depression. Clients were interviewed at a three-month follow-up to determine their treatment outcome. RESULTS: As predicted, questionnaire measures did not predict clients' treatment outcome (p > .05). A logistic regression model indicated that the best predictor of treatment outcome was AB for positive change-related words (p = .048), with successful individuals having less AB for these words than for the other word categories. Although this finding was unexpected, it was supported by significant relationships between positive change-related interference scores and continuous measures of drinking at follow-up [i.e. number of units drunk (p = .039) and number of drinking days (p = .018)]. CONCLUSIONS: The results suggest that positive change-related words are a better predictor of treatment outcome than are either alcohol-related words or negative change-related words. PMID- 29631096 TI - Genetic variation in human carboxylesterase CES1 confers resistance to hepatic steatosis. AB - Obesity often leads non-alcoholic fatty liver disease, insulin resistance and hyperlipidemia. Expression of carboxylesterase CES1 is positively correlated with increased lipid storage and plasma lipid concentration. Here we investigated structural and metabolic consequences of a single nucleotide polymorphism in CES1 gene that results in p.Gly143Glu amino acid substitution. We generated a humanized mouse model expressing CES1WT (control), CES1G143E and catalytically dead CES1S221A (negative control) in the liver in the absence of endogenous expression of the mouse orthologous gene. We show that the CES1G143E variant exhibits only 20% of the wild-type lipolytic activity. High-fat diet fed mice expressing CES1G143E had reduced liver and plasma triacylglycerol levels. The mechanism by which decreased CES1 activity exerts this hypolipidemic phenotype was determined to include decreased very-low density lipoprotein secretion, decreased expression of hepatic lipogenic genes and increased fatty acid oxidation as determined by increased plasma ketone bodies and hepatic mitochondrial electron transport chain protein abundance. We conclude that attenuation of human CES1 activity provides a beneficial effect on hepatic lipid metabolism. These studies also suggest that CES1 is a potential therapeutic target for non-alcoholic fatty liver disease management. PMID- 29631097 TI - HER2-positive breast cancer: Current and new therapeutic strategies. AB - Since the identification of the HER2 receptor amplification as an adverse prognostic factor that defined a special subtype of metastatic breast cancer, there has been a substantial improvement in survival of patients affected with this disease due to the development of anti-HER2 targeted therapies. The approval of trastuzumab and pertuzumab associated to a taxane in first line and subsequent treatment with the antibody-drug conjugate T-DM1 has certainly contributed to achieve these outcomes. The Tyrosine Kinase Inhibitor lapatinib was also approved in the basis of an improvement in progression free survival, becoming another commonly used treatment in combination with capecitabine. Inevitably, despite these therapeutic advances most patients progress on therapy due to primary or acquired resistance or because of an incorrect HER2 positivity assessment. Hence, it is crucial to correctly categorize HER2 amplified tumors and define mechanisms of resistance to design effective new treatment approaches. In addition, identifying biomarkers of response or resistance permits to tailor the therapeutic options for each patient sparing them from unnecessary toxicity as well as improving their outcomes. The aim of this review is to examine new strategies in development to treat HER2-positive metastatic breast cancer referring to the mechanisms of action of new drugs and new combinations including results reported so far. PMID- 29631098 TI - Breast reconstruction with Alloderm Ready to Use: A meta-analysis of nine observational cohorts. AB - BACKGROUND: AlloDerm-RTU is a new member of human acellular dermal matrix (HADM) which was launched in 2012. The present meta-analysis aimed to investigate whether AlloDerm-RTU was superior compared with previous HADMs. METHODS: All available databases were searched for retrospective or prospective studies regarding breast reconstruction with AlloDerm-RTU compared with other HADMs. The primary outcome was the incidence of complications among different HADMs. RESULTS: Two prospective and seven retrospective studies with a total of 1406 patients were enrolled. There was no significant difference in any of the complications, including the incidence of hematoma (RR 0.78, 95%CI 0.19 to 3.19; P = 0.73), seroma (RR 0.98, 95%CI 0.43 to 2.26; P = 0.97), cellulitis (RR 0.82, 95%CI 0.32 to 2.11; P = 0.68), necrosis (RR 0.69, 95%CI 0.44 to 1.10; P = 0.12), infection (RR 0.68, 95%CI 0.37 to 1.25; P = 0.22), explantation (RR 0.61, 95%CI 0.35 to 1.06; P = 0.08), and total complications (RR 0.91, 95%CI 0.55 to 1.52; P = 0.73). Subgroup analysis showed that AlloDerm-RTU demonstrated no superiority compared with FD AlloDerm, AlloMax, or DermACELL. Sensitivity analysis indicated that the outcomes were stabilized. No publication bias existed in the present meta-analysis. CONCLUSION: Four HADM products, AlloDerm-RTU, FD AlloDerm, AlloMax, and DermACELL, showed similar risks of complications. However since most of the included studies had a low level of evidence, further random trials with large numbers of patients are needed. PMID- 29631099 TI - Extraction of information on macromolecular interactions from fluorescence micro spectroscopy measurements in the presence and absence of FRET. AB - Investigations of static or dynamic interactions between proteins or other biological macromolecules in living cells often rely on the use of fluorescent tags with two different colors in conjunction with adequate theoretical descriptions of Forster Resonance Energy Transfer (FRET) and molecular-level micro-spectroscopic technology. One such method based on these general principles is FRET spectrometry, which allows determination of the quaternary structure of biomolecules from cell-level images of the distributions, or spectra of occurrence frequency of FRET efficiencies. Subsequent refinements allowed combining FRET frequency spectra with molecular concentration information, thereby providing the proportion of molecular complexes with various quaternary structures as well as their binding/dissociation energies. In this paper, we build on the mathematical principles underlying FRET spectrometry to propose two new spectrometric methods, which have distinct advantages compared to other methods. One of these methods relies on statistical analysis of color mixing in subpopulations of fluorescently tagged molecules to probe molecular association stoichiometry, while the other exploits the color shift induced by FRET to also derive geometric information in addition to stoichiometry. The appeal of the first method stems from its sheer simplicity, while the strength of the second consists in its ability to provide structural information. PMID- 29631101 TI - Pseudolaric acid B attenuates atherosclerosis progression and inflammation by suppressing PPARgamma-mediated NF-kappaB activation. AB - AIMS/OBJECTIVE: Atherosclerosis is a progressive disease of large arteries characterized with chronic inflammation and aberrant immune response. Pseudolaric acid B (PB) has been found to exert multiple effects by inhibiting inflammatory response. However, there is no comprehensive assessment of the effects of PB on atherosclerosis using relevant in vivo and in vitro models. MATERIAL AND METHODS: Male ApoE-/- mice were treated with PB orally with a high fat diet (HFD) to clarify its anti-atherosclerotic activities. RAW264.7 macrophage line, a well accepted cell model of atherosclerosis, was used to investigate anti-inflammatory effects and molecular mechanisms of PB. RESULTS: PB significantly attenuated atherosclerotic lesions by modulating plasma lipid profiles as well as inhibiting inflammatory responses in macrophages of atherosclerotic mice. Meanwhile, PB markedly suppressed the expression of pro-inflammatory cytokines, and regulated cholesterol efflux related genes in oxidative low density lipoprotein (ox-LDL) loaded macrophages. The cellular uptake of Dil-labeled ox-LDL was significantly inhibited by PB either. Moreover, the ability of PB to suppress nuclear factor kappa B (NF-kappaB) and activate peroxisome proliferator-activated receptor gamma (PPARgamma) was confirmed using luciferase reporter assays. Conversely, the selective PPARgamma antagonist GW9662 reversed the influence of PB in macrophages. CONCLUSION: Together, these findings indicate that PB exerts its protective effects on atherosclerosis by inhibiting macrophage-mediated inflammatory response and cellular ox-LDL uptake, and promoting cholesterol efflux by suppressing NF-kappaB activation PPARgamma-dependently. Therefore, PB may be a promising agent for inflammatory and atherosclerotic diseases. PMID- 29631102 TI - Rational design and identification of immuno-oncology drug combinations. AB - BACKGROUND: Clinical trials investigating immuno-oncology (IO) drug combinations are largely based on empiricism or limited non-clinical evaluations. This study identified the current combination IO drug clinical trials and investigated how tumour molecular profiling can help rationalise IO drug combinations. METHODS: IO targets were identified via PubMed search and expert opinion. IO drugs were compiled by searching the National Cancer Institute Drug Dictionary and pharmaceutical pipelines, August 2016. Combination IO trials were obtained by searching doublet IO drug combinations in www.clinicaltrials.gov from September to November 2016. IO target gene expressions were extracted from The Cancer Genome Atlas (TCGA) data set and compared with normal tissues from the Genotype Tissue Expression database. Differentially expressed genes for each cancer were determined using the Wilcoxon rank-sum test, and p-values were corrected for multiple testing. RESULTS: In total, 178 IO targets were identified; 90 targets have either regulatory approved or investigational therapeutics. In total, 410 combination trials involving >=2 IO drugs were identified: skin (n = 102) and genitourinary (n = 41) malignancies have the largest number of combination IO trials; 109 trials involved >2 disease sites. Summative patient accrual estimates among all trials are 71,345. Trials combining cytotoxic T lymphocyte antigen 4 (CTLA4) with programmed cell death protein 1 (n = 79) and CTLA4 with programmed cell death ligand 1 (n = 44) are the most common. Gene expression data from TCGA were mined to extract the 178 IO targets in 9089 tumours originating from 19 cancer types. IO target expression-clustered heatmap analysis identified several promising drug combinations. CONCLUSION: Our review highlights the great interest in combination IO clinical trials. Our analysis can enrich IO combination therapy selection. PMID- 29631100 TI - SA inhibits complex III activity to generate reactive oxygen species and thereby induces GA overproduction in Ganoderma lucidum. AB - Ganoderma lucidum has high commercial value because it produces many active compounds, such as ganoderic acids (GAs). Salicylic acid (SA) was previously reported to induce the biosynthesis of GA in G. lucidum. In this study, we found that SA induces GA biosynthesis by increasing ROS production, and further research found that NADPH oxidase-silenced strains exhibited a partial reduction in the response to SA, resulting in the induction of increased ROS production. Furthermore, the localization of ROS shows that mitochondria are sources of ROS production in response to SA treatment. An additional analysis focused on the relationship between SA-induced ROS production and mitochondrial functions, and the results showed that inhibitors of mitochondrial complexes I and II exert approximately 40-50% superimposed inhibitory effects on the respiration rate and H2O2 content when co-administered with SA. However, no obvious superimposed inhibition effects were observed in the sample co-treated with mitochondrial complex III inhibitor and SA, implying that the inhibitor of mitochondrial complex III and SA might act on the same site in mitochondria. Additional experiments revealed that complex III activity was decreased 51%, 62% and 75% after treatment with 100, 200, and 400 uM SA, respectively. Our results highlight the finding that SA inhibits mitochondrial complex III activity to increase ROS generation. In addition, inhibition of mitochondrial complex III caused ROS accumulation, which plays an essential role in SA-mediated GA biosynthesis in G. lucidum. This conclusion was also demonstrated in complex III-silenced strains. To the best of our knowledge, this study provides the first demonstration that SA inhibits complex III activity to increase the ROS levels and thereby regulate secondary metabolite biosynthesis. PMID- 29631103 TI - Diterpenes from buds of Wikstroemia chamaedaphne showing anti-hepatitis B virus activities. AB - Phytochemical study of the buds of Wikstroemia chamaedaphne Meisn. led to the isolation of seven previously undescribed diterpenes, including one tigliane diterpene (wikstchalide A), two daphnane diterpenes (wikstroelides W-X), and four lathyrane diterpenes (laurifoliosides A-B and 2-epi-laurifoliosides A-B), along with four known diterpenes. The structures of these compounds were established by extensive spectroscopic evidence and electronic circular dichroism (ECD) calculations. Wikstchalide A possesses a 5,6-epoxy ring in the tigliane skeleton. Two compounds exhibited potential anti-hepatitis B virus activities, with IC50 values of 46.5 and 88.3 MUg/mL against hepatitis B virus (HBV) surface antigen (HBsAg), and six compounds showed certain inhibitory effects on HBV-DNA replication with the inhibition ratios ranging from 2.0% to 33.0% at the concentrations ranging from 0.39 to 6.25 MUg/mL. PMID- 29631105 TI - Use of fatty acids in the chemotaxonomy of the family Selenastraceae (Sphaeropleales, Chlorophyceae). AB - The family Selenastraceae includes many species of freshwater green microalgae with morphological characteristics that are so subtly different that it is difficult to discriminate species within it. Therefore, the use of the diacritical characteristics of traditional morphological taxonomy may be ineffective at differentiating among many species of the family. Chemotaxonomy based on fatty acid methyl ester (FAME) can help resolve uncertainties not completely addressed by other approaches, such as molecular studies of some species within the Selenastraceae. Here, we first tested three techniques for the analysis of microalgal FAME to choose the one that would provide the best profiles for chemotaxonomy: 1) direct transesterification (DT) of the biomass followed by gas chromatography coupled to mass spectrometry analysis (GC-MS); 2) extraction using chloroform and methanol, followed by transesterification (T) and then analysis by gas chromatography/flame ionization detector (GC-FID); and 3) extraction with chloroform and methanol and then separation into lipid classes using thin-layer chromatography (TLC) using the Iatroscan-Chromarod system. The tests were conducted on 12 strains (11 species) of Selenastraceae and one outgroup strain. The fatty acid profiles produced by the DT-GC-MS technique yielded the best results for the chemotaxonomy of the Selenastraceae species using 12 FAME. The proportion of the variance in the fatty acid profiles obtained with DT-GC-MS analysis explained by species was 85%, whereas the differences explained by strains was 92%. Therefore, DT-GC-MS was used to analyze other microalgae strains, totaling 15 species of 8 genera of green coccoid microalgae, including the recently described Curvastrum. The results with all strains showed that fatty acid profiles obtained by DT-GC-MS were significantly different (p < 0.001) among strains and among species. The variance in fatty acids profiles explained by separation into strains was 97%, whereas the separation into species explained 93% of the variance. Statistical analyses showed that, for our dataset, the C18 fatty acids 18:3omega3 and 18:4omega6 were indicative of the Selenastraceae. Therefore, fatty acid profiles are a useful auxiliary chemotaxonomic tool for species identification in Selenastraceae. PMID- 29631104 TI - Seasonality effect on the composition of oxindole alkaloids from distinct organs of Uncaria tomentosa from the Caribbean region of Costa Rica. AB - Uncaria tomentosa (Willd.) D.C. (Rubiaceae), commonly known as "Una de Gato" or "Cat's Claw", is a tropical vine from the rainforest used in traditional medicine and spread through Central and South America, including Costa Rica. There is an increasing demand for medicinal extracts with biological activity attributed mainly to oxindole alkaloids (OA), where the ratio between tetracyclic (TOA) and pentacyclic oxindole alkaloids (POA) determines its feasibility for medicinal applications. The ratio is affected by distinct factors including the dynamics of environmental conditions during seasons. The purpose of the study was to assess the seasonality effect in oxindole alkaloids content in relation to plant organs from U. tomentosa grown in the Caribbean region of Costa Rica. Young leaves followed by mature leaves presented the highest amount of total OA during seasons; for these, isoryncophylline, pteropodine and isomitraphylline, were the predominant OA. The POA/TOA ratio of both leaf materials was nearly 1:1 (3.2 mg g 1: 3.1 mg g-1). Bark and root material showed a pentacyclic chemotype in all seasons with a ratio of 6:1 (6.7 mg g-1: 1.3 mg g-1) with pteropodine and isomitraphylline as the predominant POA. The POA content presented seasonality with a significant increase from rainy to dry season in young leaves, bark and roots. In contrast, TOA amount remained virtually unchanged in all plant parts. Humidity and temperature between the studied seasons were constant except for precipitation, reflecting that differences of water content had an effect in the POA amounts. Further studies of abiotic factors, like water stress, could explain the variation of POA content due to seasonality. PMID- 29631106 TI - Protein supplementation enhances cerebral oxygenation during exercise in elite basketball players. AB - OBJECTIVE: The aim of the present study was to examine cerebral oxygenation during high-intensity exercise in elite basketball players who consumed supplements with different whey protein contents after a short postexercise recovery to determine whether changing whey protein content in carbohydrate-based supplementation influences cerebral hemodynamic response when the supplement was consumed during a 2-h recovery after a 1-h exercise challenge. METHODS: This was a randomized, counterbalanced crossover study. Fifteen Division 1 collegiate basketball players (18-20 y) consumed 6.25 kcal/kg of either high-protein (36% protein in total calorie) or an isocaloric low-protein (12% protein in total calorie) control supplement in a carbohydrate-based drink immediately after a 1-h cycling (70% of maximal oxygen consumption [VO2max]). After a 2-h rest, the athletes were challenged on a cycloergometer at 80% VO2max. Blood perfusion (total hemoglobin) and oxygen saturation of frontal brain were continuously measured by near-infrared spectroscopy during the cycling. RESULTS: Before the cycloergometer test, high-protein supplementation increased peak insulin response and lowered glucose increases during the recovery compared with the low-protein trial. High-protein supplementation enhanced increases in cerebral oxygen saturation (P < 0.01) and attenuated increases in cerebral blood perfusion (total hemoglobin; P < 0.01) during the cycloergometer exercise; and resulted in a 16% longer cycling time (from 474 +/- 49 s to 553 +/- 78 s, P < 0.05), compared with the low-protein trial. CONCLUSION: Enhanced fatigue recovery after consumption of a high-protein supplement is associated with enhanced cerebral oxygenation against exercise challenge, which spares brain blood demand for periphery. PMID- 29631107 TI - New psychoactive substances in oral fluid of French and Belgian drivers in 2016. AB - BACKGROUND: Driving under the influence of drugs (DUID) is a worldwide problem with potentially major judiciary and life-threatening consequences. Up to now, only classical drugs of abuse (DOA) are tested for DUID detection. A challenging issue for drafting up-dated international drug policies is to take into account the recent and expanding new psychoactive substances (NPS) market. NPS consist in various narcotic or psychotropic drugs, most of them having a "legal" status, that replicate chemical structures and/or pharmacological effects of classical DOA. Although it is obvious that NPS can lead to impaired driving, the prevalence of NPS use in a DUID context is unknown since the applied roadside screening tests are not yet adapted for these compounds. METHODS: Between January and December 2016, a total of 391 oral fluid specimens were obtained from used roadside immunochemical test devices for DOA (Drugwipe-5S(r) device). These specimens were analyzed using liquid chromatography coupled with tandem mass spectrometry and high resolution mass spectrometry. RESULTS: NPS (mainly cathinone derivatives) were detected in 33 out of the 391 oral fluid samples. This NPS positivity rate of 8.4% in oral fluid of drivers who were submitted to a roadside drug testing in 2016 in France and in Belgium is comparable to the available blood data (NPS positivity rate of 7%) observed in 2015 in similar populations. CONCLUSION: Our results demonstrate the reality of driving after NPS use in French and Belgian drivers who were submitted to a roadside DOA test. As there is a lack of on-site detection methods to screen for NPS, the detection of NPS in a rapid and cost-effective DUID detection strategy is currently impossible. The expanding use of NPS, notably by drivers as reported here, and the inability of currently used drug detection tests, should be urgently addressed by road safety and law enforcement authorities. PMID- 29631108 TI - Genome organization at different scales: nature, formation and function. AB - Since the discovery of chromosome territories, it has been clear that DNA within the nucleus is spatially organized. During the last decade, a tremendous body of work has described architectural features of chromatin at different spatial scales, such as A/B compartments, topologically associating domains (TADs), and chromatin loops. These features correlate with domains of chromatin marking and gene expression, supporting their relevance for gene regulation. Recent work has highlighted the dynamic nature of spatial folding and investigated mechanisms of their formation. Here we discuss current understanding and highlight key open questions in chromosome organization in animals. PMID- 29631109 TI - Improvement of health related quality of life in patients with recurrent glioma treated with bevacizumab plus daily temozolomide as the salvage therapy. AB - OBJECTIVES: Bevacizumab (BEV) plus daily temozolomide (TMZ) as a salvage therapy have been recommended to recurrent glioma. The objective of this retrospective study was to evaluate the effect of the combined regimen on health related quality of life (HRQL) and treatment response in patients with recurrent glioma. PATIENTS AND METHODS: Twenty patients with recurrent glioma were treated with BEV (5-10 mg/kg, i.v. every 2 weeks) plus daily TMZ (daily, 50 mg/m2). The treatment response was evaluated via the RANO criteria. HRQL were measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire core 30 (QLQ-C30) and Brain Module (QLQ-BN20). RESULTS: Twenty patients received a total of 85 cycles of BEV with a median number of 4 cycles (range: 2-10). No patients showed complete response (CR) to treatment. Twelve patients had partial response (PR), stable disease (SD) in 5 patients with, and 3 patients showed progressive disease (PD). In the functioning domains of QLQ-C30, physical functioning, cognitive functioning and emotional functioning significantly improved after the second cycle of BEV compared to baseline, with the mean score of 45.0 vs. 64.0 (p = 0.020), 55.8 vs. 71.7 (p = 0.020) and 48.3 vs. 67.5 (p = 0.015), respectively. In the symptom scales, the scores of pain and nausea/vomiting significantly decreased compared to baseline from the mean score of 39.1 to 20.0 (p = 0.020) and 29.2 to 16.7 (p = 0.049), respectively. Score of global health status also increased from 47.5 to 63.3 (p = 0.001). As determined with the QLQ-BN20, motor dysfunction (43.3 vs. 25.0, p = 0.021), weakness of legs (36.7 vs. 18.3, p = 0.049), headache (38.3 vs. 20.0, p = 0.040), and drowsiness (50.0 vs. 30.0, p = 0.026) after the second cycle of BEV also significantly improved compared to baseline. CONCLUSION: BEV plus daily TMZ as a salvage therapy improved HRQL in patients with recurrent glioma. PMID- 29631110 TI - Does postoperative PI-LL mismatching affect surgical outcomes in thoracolumbar kyphosis associated with ankylosing spondylitis patients? AB - OBJECTIVE: To investigate if pelvic incidence (PI) and lumbar lordosis (LL) mismatching affects surgical outcomes for ankylosing spondylitis (AS) related kyphosis following 1-level lumbar pedicle subtraction osteotomy (PSO). PATIENTS AND METHODS: AS patients with thoracolumbar kyphosis, who underwent 1-level lumbar PSO from March 2006 and February 2014 in our institution, were retrospectively reviewed. The radiographic measurements and health-related quality of life (HRQoL) scores, including Oswestry Disability Index (ODI) and Visual Analogue Scale (VAS) for pain, were recorded at baseline and the last follow-up. Patients were divided into 2 groups according to PI-LL matching or not postoperatively (Match Group, Mismatch Group), and comparison of the aforementioned parameters between the two groups was performed. RESULTS: Seventy patients were enrolled with a mean age of 34.60 +/- 9.45 years (range, 17 yrs.-59 yrs.). Among them, 44 were included in the Match Group and 26 in the Mismatch Group. At baseline, patients in the Match Group had larger LL (p = 0.014) and smaller pelvic tilt (PT, p < 0.001) than patients in the Mismatch Group. At the last follow-up, along with larger LL (p = 0.004) and smaller PT (p = 0.001), Match Group patients also had significantly smaller sagittal vertical axis (SVA, 3.31 cm vs 6.27 cm, p = 0.001) than those in the Mismatch Group. Seventy-five percent (33/44) of the patients in the Match Group had a SVA < 5 cm at the last follow-up, while in the Mismatch Group, only 35% (9/26) of the patients did. However, no significant difference was found between the two groups regarding HRQoL scores. CONCLUSION: Patients with postoperative PI-LL matching were more likely to have a better correction of SVA; they also tended to have a smaller preoperative PT. However, PI-LL mismatching didn't affect HRQoL scores at the last follow-up, which was different from the results of previous studies in the settings of ASD. PMID- 29631111 TI - Bilateral continuous erector spinae plane blocks for sternotomy in a pediatric cardiac patient. PMID- 29631112 TI - Ultrasound-guided erector spinae plane block elicits sensory loss around the lateral, but not the parasternal, portion of the thorax. PMID- 29631113 TI - Effects of life-time exposure to waterborne copper on the somatotropic axis of the viviparous fish Poecilia vivipara. AB - Reduced fish growth following chronic exposure to dissolved copper (Cu) is well reported in the literature. Nevertheless, information on the mechanism(s) involved in this process is scarce. Therefore, we evaluated growth, gene expression and concentrations of proteins related to growth regulation in the viviparous guppy Poecilia vivipara chronically exposed to dissolved Cu. Newborn (<24 h after birth) fish were kept under control conditions or exposed to environmentally relevant concentrations of Cu (5 and 9 MUg/L) in salt water (24 ppt) for 345 days. After exposure, fish growth was evaluated based on body weight and length. Also, growth hormone (gh) mRNA expression was evaluated in brain, while growth hormone receptor 1 (ghr1) and 2 (ghr2) mRNA expressions were analyzed in brain, skeletal muscle and liver. In turn, insulin-like growth factor 1 (igf1) and 2 (igf2) mRNA expressions were evaluated in skeletal muscle and liver. Additionally, Gh concentration was assessed in brain, while Ghr concentration was evaluated in skeletal muscle and liver. Exposure to 9 MUg/L Cu reduced fish body weigh and length. Metal exposure affected mRNA expression only in skeletal muscle. Reduced ghr2 mRNA expression was observed in guppies exposed to 5 and 9 MUg/L Cu. Additionally, reduced igf1 and igf2 mRNA expressions were observed in guppies exposed to 9 MUg/L Cu. However, no significant change in Ghr concentration was observed. The reduced ghr2 mRNA expression suggests that chronic Cu exposure induced an insensitivity of the skeletal muscle to Gh, thus resulting in reduced igf1 and igf2 mRNA expression which lead to reduced fish growth. These findings indicate that chronic exposure to dissolved Cu disrupts the somatotropic axis regulation, thus helping to elucidate the mechanism underlying the Cu-dependent inhibition of growth observed in the viviparous fish P. vivipara. PMID- 29631114 TI - Effects of tributyltin on early life-stage, reproduction, and gonadal sex differentiation in Japanese medaka (Oryzias latipes). AB - Tributyltin, an organotin compound, was used worldwide as an antifouling agent in aquatic environments and there has been much concern about the toxicological and ecotoxicological properties of organotin compounds. Even though it has been prohibited worldwide, tributyltin is still detected at low concentrations in aquatic environments. Here we investigated the effects of tributyltin on the early life-stage, reproduction, and gonadal sex differentiation in Japanese medaka (Oryzias latipes). In adults, exposure to tributyltin at 3.82 MUg/L suppressed fecundity and fertility and increased mortality. At 10.48 MUg/L all medaka died by the sixth day of exposure. Exposure to tributyltin during early life-stages induced no significant differences in mortality or embryonic development, but growth was suppressed in groups exposed to 0.13 and 0.68 MUg/L. Furthermore, there was no abnormal gonadal development in Japanese medaka exposed to tributyltin. These results provide evidence of the negative effects of tributyltin on reproduction in a teleost fish. Tributyltin did not affect gonadal sex differentiation in Japanese medaka, but fecundity and fertility were suppressed, although it is not clear whether this suppression resulted from the endocrine-disrupting action of tributyltin or its toxicity. PMID- 29631115 TI - Health risk assessment of the workers exposed to the heavy metals in e-waste recycling sites of Chandigarh and Ludhiana, Punjab, India. AB - Investigations were made to analyze the effects of heavy metals on the adults and children working in informal e-waste recycling sectors of Chandigarh and Ludhiana, Punjab, India. Soil samples of the ground where recycling was being done, dust from the platform where recycling activities were done and dermal samples of workers were collected to estimate the presence of heavy metals (As, Cu, Co, Cd, Cr, Ni, Fe, Zn, Pb, Ba) in them. High concentration of Ba, Cu, Pb and Zn was observed in the soil and dust samples. Cr, Pb and Zn were observed in high concentrations in dermal samples. These heavy metals could cause serious health effects. Therefore, human health risk assessment was also done using carcinogenic (cancer risk potency factor) and non-carcinogenic (health hazard index) health risk assessment. Carcinogenic hazards were not reported in children however, hazard index, for soil and dust contamination for some heavy metals, was found significant (Soil samples: As = 1.69, Cr = 1.38, Cu = 4.5 and Pb = 5.82 and dust samples: Pb = 2.97). Carcinogenic hazards were reported in adults from Cr contamination in soil samples (3.4E-03). PMID- 29631116 TI - The Hot Spot in a Cold Environment: Puzzling Parvodinium (Peridiniopsidaceae, Peridiniales) from the Polish Tatra Mountains. AB - Because of a great variety of remote localities and cold habitats, the Tatra Mountains are home to many freshwater protist lineages. Dinophytes have been subjected to a number of studies from this area dating mostly to the first half of the 20th century, but their true diversity remains elusive until today. We collected water tow samples at five lakes in the Tatra Mountains in order to establish monoclonal strains. We found four lineages that were distinctive in terms of morphology and DNA sequence data and that could be assigned to peridinialean Parvodinium. These four species can be readily distinguished based on a general shape, size, thecal plate tabulation pattern and presence or absence of an antapical protuberance. The plate overlap pattern is considered conserved at higher taxonomic levels, and the divergent keystone Plate 3' in Parvodinium marciniakii, sp. nov., thus appears as a striking diagnostic character. For taxonomic conclusion, we describe two species new to science and validate three old scientific names (i.e., one species and two varieties). Our study underlines that the biodiversity assessment, particularly of species adapted to cold environments, is anything but completed as shown from remote and unexplored European landscapes such as the Tatra Mountains. PMID- 29631117 TI - Torque, power and muscle activation of eccentric and concentric isokinetic cycling. AB - This study aimed to establish the effect of cycling mode and cadence on torque, external power output, and lower limb muscle activation during maximal, recumbent, isokinetic cycling. After familiarisation, twelve healthy males completed 6 * 10 s of maximal eccentric (ECC) and concentric (CON) cycling at 20, 40, 60, 80, 100, and 120 rpm with five minutes recovery. Vastus lateralis, medial gastrocnemius, rectus femoris, and biceps femoris surface electromyography was recorded throughout. As cadence increased, peak torque linearly decreased during ECC (350-248 N.m) and CON (239-117 N.m) and peak power increased in a parabolic manner. Crank angle at peak torque increased with cadence in CON (+13 degrees ) and decreased in ECC (-9.0 degrees ). At all cadences, peak torque (mean +129 N.m, range 111-143 N.m), and power (mean +871 W, range 181-1406 W), were greater during ECC compared to CON. For all recorded muscles the crank angle at peak muscle activation was greater during ECC compared to CON. This difference increased with cadence in all muscles except the vastus lateralis. Additionally, peak vastus laterallis and biceps femoris activation was greater during CON compared to ECC. Eccentric cycling offers a greater mechanical stimulus compared to concentric cycling but the effect of cadence is similar between modalities. Markers of technique (muscle activation, crank angle at peak activation and torque) were different between eccentric and concentric cycling and respond differently to changes in cadence. Such data should be considered when comparing between, and selecting cadences for, recumbent, isokinetic, eccentric and concentric cycling. PMID- 29631118 TI - Acute neuromechanical modifications and 24-h recovery in quadriceps muscle after maximal stretch-shortening cycle exercise. AB - In the present study we investigated the acute and the delayed changes in corticospinal excitability and in the neuromechanical properties of the quadriceps muscle after maximal intensity stretch-shortening cycle exercise. Ten young males performed 150 jumps to provoke fatigue and muscle damage. Voluntary force, various electrically evoked force variables, and corticospinal excitability were measured at baseline, immediately (IP) and at 24 h post exercise. Voluntary force, single twitch force, and low frequency force decreased at IP (p < 0.05) but recovered at 24 h, although mild soreness developed in the quadriceps. High frequency force, voluntary activation, and corticospinal excitability remained unchanged. However, vastus lateralis myoelectric activity increased from baseline to IP (p < 0.05). The jumps selectively induced low frequency peripheral fatigue, and central mechanisms did not mediate the acute loss of voluntary force. Because soreness developed at 24 h post-exercise, all force variables recovered, and vastus lateralis electric activity increased, we argue that a dual process of muscle damage, and early neural adaptation as a compensation mechanism took place after the maximal stretch-shortening cycle exercise. PMID- 29631119 TI - Effectiveness of movement control exercise on patients with non-specific low back pain and movement control impairment: A systematic review and meta-analysis. AB - BACKGROUND: Patients with low back pain (LBP) and movement control impairment (MVCI) show altered spinal movement patterns. Treatment that aims to change movement behaviour could benefit these patients. OBJECTIVE: To assess the effectiveness of movement control exercise (MVCE) in terms of clinically relevant measures (disability and pain) on patients with NSLBP. METHODS: A systematic review and meta-analysis were conducted. CINAHL, MEDLINE, PUBMED and PEDro databases were searched for RCT's evaluating MVCE treatment in patients with NSLBP from review inception to April 2017. Authors were contacted to obtain missing data and outcomes. PEDro was used to assess methodological quality of the studies and the GRADE approach was used to assess the overall quality of evidence Data were combined using a random effects meta-analysis and reported as standardized mean differences (SMD). RESULTS: Eleven eligible RCT's including a total of 781 patients were found. Results show 'very low to moderate quality' evidence of a positive effect of MVCE on disability, both at the end of treatment and after 12 months (SMD -0.38 95%CI -0.68, -0.09 respectively 0.37 95%CI -0.61, 0.04). Pain intensity was significantly reduced after MVCE at the end of treatment (SMD -0.39 95%CI -0.69, -0.04), but not after 12 months (SMD -0.27, 95%CI -0.62, 0.09). CONCLUSIONS: MVCE intervention for people with NSLBP and MVCI appears to be more effective in improving disability compared to other interventions, both over the short and long term. Pain was reduced only in the short term. An important factor is the initial identification of patients with MVCI. Registration of the study: The study protocol registration number is CRD42016036662 on PROSPERO. PMID- 29631121 TI - Molecular imaging agents for ultrasound. AB - Ultrasound (US) imaging is a safe, sensitive and affordable imaging modality with a wide usage in the clinic. US signal can be further enhanced by using echogenic contrast agents (UCAs) which amplify the US signal. Developments in UCAs which are targeted to sites of disease allow the use of US imaging to provide molecular information. Unfortunately, traditional UCAs are too large to leave the vascular space limiting the application of molecular US to intravascular markers. In this mini review, we highlight the most recent reports on the application of molecular US imaging in the clinic and summarize the latest nanoparticle platforms used to develop nUCAs. We believe that the highlighted technologies will have a great impact on the evolution of the US imaging field. PMID- 29631120 TI - Recent progress in photoacoustic molecular imaging. AB - By acoustically detecting the optical absorption contrast, photoacoustic (PA) tomography (PAT) has broken the penetration limits of traditional high-resolution optical imaging. Through spectroscopic analysis of the target's optical absorption, PAT can identify a wealth of endogenous and exogenous molecules and thus is inherently capable of molecular imaging with high sensitivity. PAT's molecular sensitivity is uniquely accompanied by non-ionizing radiation, high spatial resolution, and deep penetration in biological tissues, which other optical imaging modalities cannot achieve yet. In this concise review, we summarize the most recent technological advancements in PA molecular imaging and highlight the novel molecular probes specifically made for PAT in deep tissues. We conclude with a brief discussion of the opportunities for future advancements. PMID- 29631123 TI - Attachment and psychoneuroimmunology. AB - In this review, I outline how attachment experiences in adulthood are thought to be related to the immune system. After a brief primer on the two branches of the immune system, I describe a theoretical model that explains how adults' attachment orientation could influence various immune processes. I then review recent findings documenting novel associations between attachment orientation and measures of the immune system, including inflammatory processes and cellular immunity. I conclude with a discussion about future directions focused on how we can advance our understanding about the role of attachment in shaping immune processes in ways that could shape our health over the lifespan. PMID- 29631122 TI - Emergence of two near-infrared windows for in vivo and intraoperative SERS. AB - Two clear windows in the near-infrared (NIR) spectrum are of considerable current interest for in vivo molecular imaging and spectroscopic detection. The main rationale is that near-infrared light can penetrate biological tissues such as skin and blood more efficiently than visible light because these tissues scatter and absorb less light at longer wavelengths. The first clear window, defined as light wavelengths between 650nm and 950nm, has been shown to be far superior for in vivo and intraoperative optical imaging than visible light. The second clear window, operating in the wavelength range of 1000-1700nm, has been reported to further improve detection sensitivity, spatial resolution, and tissue penetration because tissue photon scattering and background interference are further reduced at longer wavelengths. Here we discuss recent advances in developing biocompatible plasmonic nanoparticles for in vivo and intraoperative surface enhanced Raman scattering (SERS) in both the first and second NIR windows. In particular, a new class of 'broad-band' plasmonic nanostructures is well suited for surface Raman enhancement across a broad range of wavelengths allowing a direct comparison of detection sensitivity and tissue penetration between the two NIR window. Also, optimized and encoded SERS nanoparticles are generally nontoxic and are much brighter than near-infrared quantum dots (QDs), raising new possibilities for ultrasensitive detection of microscopic tumors and image-guided precision surgery. PMID- 29631124 TI - Paleoparasitology and pathoecology in Russia: Investigations and perspectives. AB - Russia, both as the USSR and the Russian federation, provided a source of parasitological theory for decades. A key figure in Russian parasitology was Yevgeny Pavlovsky. He developed the nidus concept of Pavlovsky provided the conceptual basis for the field of pathoecology. He also coined the term "Paleoparasitology". Pathoecology is a foundation concept in archaeological parasitology. Paleoparasitology, as defined by Pavlovsky, is an avenue for understanding of host parasite evolution over very long time periods. These contributions are not fully recognized internationally. Similarly, the long history of Russian paleontological and archaeological investigations are not fully known. Most recently, discoveries from archaeological sites show that a pattern of zoonotic infection prevailed among archaeological populations in central Russia. This included a case of apparent host switching of beef tapeworm infection to reindeer. This latter discovery raises the possibility that archaeological parasitology can contribute to the new Stockholm Paradigm of ecological fitting, host switching, and emergent disease. This review covers all of the parasitological discoveries from ancient Russia and illustrates how Russian models and discoveries defined parasitological theory in the past and present. PMID- 29631125 TI - Depressive symptoms and weight loss behaviors in U.S. adults. AB - OBJECTIVE: We sought to determine whether depressive symptoms are associated with attempting to lose weight and engaging in weight loss behaviors in a large, diverse sample of adults representative of the U.S. POPULATION: METHODS: Respondents were 23,106 adults, free of cardiovascular disease and diabetes, who participated in the 2005-2014 years of the National Health and Nutrition Examination Survey (NHANES). Depressive symptoms were measured using the Patient Health Questionnaire-9 (PHQ-9), and weight loss variables were obtained from a Weight History Questionnaire. RESULTS: PHQ-9 total was not associated with attempting to lose weight in the past year (OR = 1.03, 95%CI = 1.00-1.06, p = 0.074; n = 23,106). Among respondents who attempted to lose weight (n = 9582), PHQ-9 total was associated with a lower odds of exercising (OR = 0.84, 95%CI = 0.79-0.89, p < 0.001) and a greater odds of skipping meals (OR = 1.31, 95%CI = 1.22-1.41, p < 0.001), eating diet foods/products (OR = 1.16, 95%CI = 1.08-1.24, p < 0.001), eating less food (OR = 1.09, 95%CI = 1.04-1.15, p < 0.001), taking non-prescription supplements (OR = 1.31, 95%CI = 1.23-1.41, p < 0.001), taking prescription diet pills (OR = 1.28, 95%CI = 1.10-1.49, p = 0.001), and taking laxatives/vomiting (OR = 1.55, 95%CI = 1.28-1.88, p < 0.001). CONCLUSIONS: Although depressive symptoms were not associated with attempting to lose weight in the past year, adults who attempted to lose weight tended to employ potentially ineffective/unhealthy weight loss behaviors and avoid effective behaviors. This pattern of behaviors may be another mechanism that explains the excess risk of obesity in depressed adults and may be a modifiable target for future interventions. Given the cross-sectional nature of this study, reverse causality is a possibility. Future studies should investigate the prospective associations between depressive symptoms and weight loss behaviors. PMID- 29631126 TI - Activity of bromodomain protein inhibitors/binders against asexual-stage Plasmodium falciparum parasites. AB - Bromodomain-containing proteins (BDPs) are involved in the regulation of eukaryotic gene expression. Compounds that bind and/or inhibit BDPs are of interest as tools to better understand epigenetic regulation, and as possible drug leads for different diseases, including malaria. In this study, we assessed the activity of 42 compounds demonstrated or predicted (using virtual screening of a pharmacophore model) to bind/inhibit eukaryotic BDPs for activity against Plasmodium falciparum malaria parasites. In silico docking studies indicated that all compounds are predicted to participate in a typical hydrogen bond interaction with the conserved asparagine (Asn1436) of the P. falciparum histone acetyltransferase (PfGCN5) bromodomain and a conserved water molecule. Only one compound (the dimethylisoxazole SGC-CBP30; a selective inhibitor of CREBBP (CBP) and EP300 bromodomains) is also predicted to have a salt-bridge between the morpholine nitrogen and Glu1389. When tested for in vitro activity against asynchronous asexual stage P. falciparum Dd2 parasites, all compounds displayed 50% growth inhibitory concentrations (IC50) >10 MUM. Further testing of the three most potent compounds using synchronous parasites for 72 h showed that SGC-CBP30 was the most active (IC50 3.2 MUM). In vitro cytotoxicity assays showed that SGC CBP30 has ~7-fold better selectivity for the parasites versus a human cell line (HEK 293). Together these data provide a possible starting point for future investigation of these, or related compounds, as tools to understand epigenetic regulation or as potential new drug leads. PMID- 29631128 TI - The role of microwave radiometry in carotid artery disease. Diagnostic and clinical prospective. AB - Atherosclerosis of the internal carotid artery is an important cause of disabling ischemic stroke and therefore constitutes a major medical, social, and economic issue. Although advances in vascular imaging modalities during the last decades allow to risk stratify patients not solely on the degree of carotid artery stenosis but also based on 'high risk' features, there still remains a controversy over patient selection for carotid artery revascularization. Among other features of plaque vulnerability, there is an increasing body of evidence that inflammation is a key factor in the initiation, progression and destabilization of atherosclerotic plaques. Microwave radiometry (MWR) is a new imaging method that is based on the ability to detect noninvasively, with high accuracy, the relative changes of temperature in human tissues reflecting inflammatory activation. This review article aims to: (1) give an overview of current clinical experience with MWR in carotid arteries and (2) present its potential role for risk stratification. PMID- 29631127 TI - Synergistic combination of alkylphosphocholines with peptaibols in targeting Leishmania infantum in vitro. AB - Anti-leishmanial treatment increasingly encounters therapeutic limitations due to drug toxicity and development of resistance. The effort for new therapeutic strategies led us to work on combinations of chemically different compounds that could yield enhanced leishmanicidal effect. Peptaibols are a special type of antimicrobial peptides that are able to form ion channels in cell membranes and potentially affect cell viability. We assayed the antileishmanial activity of two well studied helical peptaibols, the 16-residue antiamoebin and the 20-residue alamethicin-analogue suzukacillin, and we evaluated the biological effect of their combination with the alkylphosphocholine miltefosine and its synthetic analogue TC52. The peptaibols tested exhibited only moderate antileishmanial activity, however their combination with miltefosine had a super-additive effect against the intracellular parasite (combination index 0.83 and 0.43 for antiamoebin and suzukacillin respectively). Drug combinations altered the redox stage of promastigotes, rapidly dissipated mitochondrial membrane potential and induced concatenation of mitochondrial network promoting spheroidal morphology. These results evidenced a potent and specific antileishmanial effect of the peptaibols/miltefosine combinations, achieved with significantly lower concentrations of the compounds compared to monotherapy. Furthermore, they revealed the importance of exploring novel classes of bioactive compounds such as peptaibols and demonstrated for the first time that they can act in synergy with currently used antileishmanial drugs to improve the therapeutic outcome. PMID- 29631129 TI - Evaluation of anticonvulsant and analgesic activity of new hybrid compounds derived from N-phenyl-2-(2,5-dioxopyrrolidin-1-yl)-propanamides and -butanamides. AB - Epilepsy is a chronic neurological disorder that is associated with various types of recurrent seizures, which are drug-resistant in about one third of patients. Moreover, anticonvulsant drugs are used to treat a wide range of non-epileptic conditions, including chronic pain. Here, we investigated the anticonvulsant activity of six new hybrid compounds based on the pyrrolidine-2,5-dione scaffold in the 6 Hz corneal stimulation test with 44 mA stimulus intensity in mice, which is the model of pharmacoresistant seizures. We demonstrated that two molecules, DK-10 (11) and DK-14 (14) show higher anticonvulsant activity and similar safety profile in comparison with valproic acid and much higher in comparison with levetiracetam in the aforementioned test. The second aim of this study was to examine analgesic activity of these compounds. For this purpose, the hot plate test, the formalin test, and the oxaliplatin-induced peripheral neuropathy model were performed. Among tested agents DK-11 (12) revealed prominent antinociceptive activity at non-sedative doses in the second (inflammatory) phase of the formalin test, which is the model of tonic pain and antiallodynic activity in the oxaliplatin-induced neuropathic pain, the model of painful chemotherapy-induced peripheral neuropathy. No cytotoxic effect on hepatoma cells was observed. Compound DK-10 (11) had high affinity for voltage-gated sodium channels, whereas compound DK-11 (12) showed weak binding toward sodium and calcium voltage-gated channels and the NMDA receptor. As a result, hybrid compounds reported herein seem to be very promising broad spectrum anticonvulsant molecules with collateral analgesic activity. PMID- 29631130 TI - Potential delays in referral and assessment for epilepsy surgery in children with drug-resistant, early-onset epilepsy. AB - OBJECTIVE: To study potential delays in epilepsy surgery in children with drug resistant epilepsy (DRE) of early-onset. METHODS: Medical records were reviewed from 87 children with DRE and seizure onset before age 3 years who underwent epilepsy surgery between 2006 and 2015. Information was obtained about each child's epilepsy, treatment and specific time points in management. Time intervals along diagnostic, investigative, treatment and referral pathways were calculated. RESULTS: Median ages at seizure onset, when seen in the epilepsy surgery program and surgery were 5.9 (IQR 10), 19 (IQR 29) and 36 (IQR 67) months; the median delay from seizure onset to surgery was 30 (IQR 67) months. Most children were promptly diagnosed, treated, investigated and seen by a pediatric neurologist. Focal abnormalities were reported on initial EEGs and MRIs in most children, and DRE developed within a median of 6.3 months from commencement of medication. There were median durations of 6.2 months between seeing a neurologist and being seen in the epilepsy surgery program, and then 6.1 months in determining surgical candidacy. Median durations from potential indications for a surgical evaluation to agreed surgical candidacy were 10 (DRE), 12 (focal MRI) and 17 (focal EEG) months. Children received a median of six antiepileptic drugs prior to surgery. Median interval from agreed surgical candidacy to surgery was only 3 months. There were longer durations from seizure onset to surgery in children needing PET (p = 0.001) and in children with seizure free periods (p < 0.001), and shorter durations in children with a history of infantile spasms (p = 0.01). SIGNIFICANCE: Delays in referral of children for epilepsy surgery are reported. Delays in assessment may be specific to centralized children's hospitals in public health systems. PMID- 29631131 TI - Antiepileptic drugs-induced hyponatremia: Review and analysis of 560 hospitalized patients. AB - Recent evidence suggests that eslicarbazepine acetate (ESL) might be an appropriate alternative to carbamazepine (CBZ) and oxcarbazepine (OXC) due to its better safety profile. Hyponatremia may be one of the limiting safety problems in CBZ and OXC whereas it has been indicated that ESL is less sensitive for the adverse event. Since our clinical experience is different we investigated the incidence of hyponatremia in 560 consecutive adult inpatients treated at our center in 2015 by reviewing their medical records. Only CBZ, OXC and ESL were associated with hyponatremia. The incidence of hyponatremia induced by ESL was not statistically different from that induced by OXC (43% of patients with OXC and 33% with ESL, p > 0.05). Both were associated with hyponatremia more often than CBZ (16%). OXC-induced hyponatremia was dose-related, ESL-induced hyponatremia was not. Furthermore, both OXC- and ESL-induced hyponatremia occurred particularly often in elderly epilepsy patients. Thus, for elderly patients, both OXC and ESL should be considered with caution. PMID- 29631132 TI - The development of Bruton's tyrosine kinase (BTK) inhibitors from 2012 to 2017: A mini-review. AB - Bruton's tyrosine kinase (BTK) has emerged as a promising drug target for multiple diseases, particularly haematopoietic malignancies and autoimmune diseases related to B lymphocytes. This review focuses on the diverse, small molecule inhibitors of BTK kinase that have shown good prospects for clinical application. Individual examples of these inhibitors, including both reversible and irreversible inhibitors and a recently developed reversible covalent inhibitor of BTK, are discussed. Considerable progress has been made in the development of irreversible inhibitors, most of which target the SH3 pocket and the cysteine 481 residue of BTK. The present review also surveys the pharmacological advantages and deficiencies of both reversible and irreversible BTK drugs, with a focus on the structure-activity relationship (SARs) and binding modes of representative drugs, which could inspire critical thinking and new ideas for developing potent BTK inhibitors with less unwanted off-target effects. PMID- 29631133 TI - Probabilistic risk assessment of nitrate groundwater contamination from greenhouses in Albenga plain (Liguria, Italy) using lysimeters. AB - The use of fertilizers in greenhouse-grown crops can pose a threat to groundwater quality and, consequently, to human beings and subterranean ecosystem, where intensive farming produces pollutants leaching. Albenga plain (Liguria, Italy) is an alluvial area of about 45km2 historically devoted to farming. Recently the crops have evolved to greenhouses horticulture and floriculture production. In the area high levels of nitrates in groundwater have been detected. Lysimeters with three types of reconstituted soils (loamy sand, sandy clay loam and sandy loam) collected from different areas of Albenga plain were used in this study to evaluate the leaching loss of nitrate (NO3-) over a period of 12weeks. Leaf lettuce (Lactuca sativa L.) was selected as a representative green-grown crop. Each of the soil samples was treated with a slow release fertilizer, simulating the real fertilizing strategy of the tillage. In order to estimate the potential risk for aquifers as well as for organisms exposed via pore water, nitrate concentrations in groundwater were evaluated by applying a simplified attenuation model to the experimental data. Results were refined and extended from comparison of single effects and exposure values (Tier I level) up to the evaluation of probabilistic distributions of exposure and related effects (Tier II, III IV levels). HHRA suggested HI >1 and about 20% probability of exceeding RfD for all the greenhouses, regardless of the soil. ERA suggested HQ>100 for all the greenhouses; 93% probability of PNEC exceedance for greenhouses containing sand clay loam. The probability of exceeding LC50 for 5% of the species was about 40% and the probability corresponding to DBQ of DEC/EC50>0.001 was >90% for all the greenhouses. The significantly high risk, related to the detected nitrate leaching loss, can be attributed to excessive and inappropriate fertigation strategies. PMID- 29631134 TI - Balancing macronutrient stoichiometry to alleviate eutrophication. AB - Reactive nitrogen (N) and phosphorus (P) inputs to surface waters modify aquatic environments, affect public health and recreation. Source controls dominate eutrophication management, whilst biological regulation of nutrients is largely neglected, although aquatic microbial organisms have huge potential to process nutrients. The stoichiometric ratio of organic carbon (OC) to N to P atoms should modulate heterotrophic pathways of aquatic nutrient processing, as high OC availability favours aquatic microbial processing. Heterotrophic microbial processing removes N by denitrification and captures N and P as organically complexed, less eutrophying forms. With a global data synthesis, we show that the atomic ratios of bioavailable dissolved OC to either N or P in rivers with urban and agricultural land use are often distant from a "microbial optimum". This OC deficiency relative to high availabilities of N and P likely overwhelms within river heterotrophic processing. We propose that the capability of streams and rivers to retain N and P may be improved by active stoichiometric rebalancing. Although autotrophic OC production contributes to heterotrophic rates substantial control on nutrient processing from allochthonous OC is documented for N and an emerging field for P. Hence, rebalancing should be done by reconnecting appropriate OC sources such as wetlands and riparian forests that have become disconnected from rivers concurrent with agriculture and urbanisation. However, key knowledge gaps require research prior to the safe implementation of this approach in management: (i) to evaluate system responses to catchment inputs of dissolved OC forms and amounts relative to internal production of autotrophic dissolved OC and aquatic and terrestrial particulate OC and (ii) evaluate risk factors in anoxia-mediated P desorption with elevated OC scenarios. Still, we find stoichiometric rebalancing through reconnecting landscape beneficial OC sources has considerable potential for river management to alleviate eutrophication, improve water quality and aquatic ecosystem health, if augmenting nutrient source control. PMID- 29631135 TI - Urbanization gradient of selected pharmaceuticals in surface water at a watershed scale. AB - Ubiquitous detection of pharmaceuticals in the aquatic environment around the world raises a great public concern. Aquatic residuals of pharmaceuticals have been assumed to relate to land use patterns and various human activities within a catchment or watershed. This study generated a gradient of human activity in the Jiulong River watershed, southeastern China by urban land use percentage in 20 research subwatersheds. Thirty-three compounds from three-category pharmaceuticals [26 compounds of 5 antibiotic groups, 6 compounds of non steroidal anti-inflammatory drugs (NSAIDs), and 1 compound of respiratory system drugs (RSDs)] were quantified in stream water before the research subwatershed confluences with two sampling events in dry and wet seasons. In total, 27 out of the 33 pharmaceutical compounds of interest were found in stream waters. Seasonality of instream pharmaceuticals was observed, with less compounds and lower concentrations in the wet season sampling event than in the dry season one. Urban land use in the research subwatershed was identified as the main factor influencing in stream pharmaceutical concentrations and composition regardless of season. Rural land uses contributed a mixture of human and veterinary pharmaceuticals possibly from agricultural application of manure and sewage sludge and aquaculture in the research subwatersheds. Erythromycin in both sampling events showed medium to high risks to aquatic organisms. Results of this study suggest that urban pharmaceutical management, such as a strict prescription regulations and high-efficient removal of pharmaceuticals in wastewater treatment, is critical in reducing aquatic pharmaceutical loads. PMID- 29631136 TI - Mudbank off Alleppey, India: A bane for foraminifera but not so for carbon burial. AB - Calm conditions and extensive fishing, during monsoon season in the mudbank off Alleppey (Kerala), India creates a unique environment, associated with high suspended particulate matter. The effect of processes associated with mudbank formation, on benthic foraminifera, however, has not been documented. We have studied, seasonal foraminiferal distribution, to understand foraminiferal response to physico-chemical changes associated with the mudbank formation. Additionally, seasonal changes in total carbon, calcium carbonate (CaCO3), organic carbon (Corg) and Corg/nitrogen (Corg/N) were also measured to understand the effect of mudbank formation on carbon burial. We report a low foraminiferal abundance in the mudbank. Benthic foraminiferal diversity is also low in the mudbank, during both pre-monsoon and monsoon season, clearly suggesting a stressed environment. Agglutinated foraminifera dominate the living benthic foraminiferal population in the mudbank, suggesting that the area is carbonate undersaturated and under fresh-water influence. Ammobaculites dilatatus and Ammobaculites exiguus are the dominant agglutinated species abundant in the mudbank and thus can be used to reconstruct past changes in the mudbank. The CaCO3 is consistently low during all seasons, at one of the core mudbank stations. The %Corg is, however, higher in the core mudbank as well as the northern peripheral region. The Corg/N is consistently uniform at all the stations indicating a similar source of organic matter in all the seasons. The higher %Corg and constant Corg/N suggest, that food availability and its source is not a major factor affecting benthic foraminifera in the mudbank. Instead, increased turbidity and low bottom water salinity are the main cause of seasonally stressed environment in the mudbank. Additionally, Corg degradation coupled with fresh water influx induced drop in bottom water pH is responsible for low foraminiferal population in mudbank region, in all the seasons. The reduced calcareous benthic foraminiferal abundance, however, does not affect the carbon burial in the mudbank, due to higher %Corg. PMID- 29631137 TI - Distribution of trifluoroacetic acid in gas and particulate phases in Beijing from 2013 to 2016. AB - Trifluoroacetic acid (TFA) was measured at an urban site in Beijing from April 2013 to April 2016 and examined its characteristics and particle/gas distributions. The average monthly atmospheric TFA concentration fluctuated significantly and presented marked seasonal variations. The concentration levels of gas-phase TFA were significantly higher in spring and summer than in fall and winter. The PM2.5 mass concentration and ambient temperature were important factors affecting the concentration of particulate-phase TFA. Hence, at higher PM2.5 concentrations and lower temperatures, atmospheric TFA tended to be enriched in particulate matter. Our findings suggest that the percentage of gas phase TFA in Beijing is higher than that in the steady state; thus, gas-phase TFA can still be transformed to the particulate phase and increase the contribution of TFA to haze formation. PMID- 29631138 TI - Mechanisms of developmental toxicity in zebrafish embryos (Danio rerio) induced by boscalid. AB - Boscalid has been widely used for controlling various plant diseases. It is one of the most frequently detected pesticides in main coastal estuaries in California, with concentrations as high as 36MUg/L, but its ecotoxicology information is scarce. To assess the aquatic risk of boscalid, acute toxicity and sub-lethal developmental toxicity toward zebrafish embryos were determined in the present study. In the acute toxicity test, a series of toxic symptoms of embryos were observed, including abnormal spontaneous movement, slow heartbeat, yolk sac oedema, pericardial oedema, spine deformation and hatching inhibition, and 96-h LC50 (50% lethal concentration) of boscalid toward zebrafish embryos was 2.65 (2.506-2.848)mg/L. From the results of the sub-lethal developmental toxicity test, boscalid was confirmed to have a great impact on development mechanisms of zebrafish embryos. Cell apoptosis in embryos was induced by boscalid with upregulation of genes in the cell apoptosis and an increase of capspase-3 and caspase-9 activity in the present study. Lipid metabolism was affected in embryos due to changes in gene expression and the contents of total triacylglyceride and cholesterol. Melanin synthesis and deposition was caused in embryos due to alterations in related gene expression. Overall, changes in cell apoptosis, lipid metabolism and melanin synthesis and deposition might be responsible for developmental toxicity of boscalid to zebrafish embryos. PMID- 29631139 TI - Variations in the denitrifying microbial community and functional genes during mesophilic and thermophilic anaerobic digestion of cattle manure. AB - In this study, the anaerobic digestion (AD) of cattle manure was conducted at two temperatures (mesophilic: 35 degrees C; thermophilic: 55 degrees C) to analyze the dynamics of the denitrifying functional microbial community and functional genes. The cumulative N2O production under thermophilic conditions was 130.3% higher than that under mesophilic conditions. Thermophilic AD decreased the abundance of nosZ, which was more functional than other denitrifying genes. Firmicutes, Proteobacteria, and Bacteroidetes were the main phyla, and they were also related to denitrification during AD. Redundancy analysis indicated that pH, temperature, and NH4+-N mainly affected the functional bacterial community. Temperature altered the co-occurrence patterns of the bacterial community and the keystone genera in AD. Desulfovibrio in mesophilic AD and Thiobacillus in thermophilic AD were closely related to nitrogen transformation among the keystone genera. The variations in the abundances of members of the denitrifying microbial community and functional genes during AD suggest that thermophilic AD may have caused greater nitrogen losses. PMID- 29631140 TI - Level changes and human dietary exposure assessment of halogenated flame retardant levels in free-range chicken eggs: A case study of a former e-waste recycling site, South China. AB - To assess the impacts of e-waste regulations on environmental pollution, we built on a previous study from 2010 to investigate the levels and human dietary exposure of halogenated flame retardants (HFRs) in free-range chicken eggs from Baihe village in 2013 and 2016. The concentrations of PBDEs, PBBs, HBCDs, and DBDPE showed a significant decrease (p<0.05) from 2010 to 2013/2016, suggesting the efficacy of regulatory policies. The relative contribution of BDE209 were higher in 2013 and 2016 than in 2010, accounting for 67.8%, 61.4%, and 27.7%, respectively. The concentration ratios of PBB209:PBB153 were much lower in 2013 (1.51) and 2016 (1.32) than in 2010 (29.5). These observed different profiles likely due to the different environmental behaviors of HFRs (e.g. the different atmospheric migration abilities of PBDE congeners and degradation of PBB209). Our exposure estimates suggested high dietary intake of HFRs via home-produced eggs. As for PBDEs, considering the worst situation (highly polluted eggs were consumed), the margin of exposure (MOE) of BDE99 for both adults and children were 1.5 and 0.3 in 2013, and 1.1 and 0.2 in 2016, respectively, which were below 2.5. According to the CONTAM panel, an MOE larger than 2.5 indicates no health concern. Therefore, these MOE values represent a significant potential health concern due to the adverse impacts of PBDEs on human neurodevelopment and fertility. PMID- 29631141 TI - Low concentrations of Al(III) accelerate the formation of biofilm: Multiple effects of hormesis and flocculation. AB - Residual Al(III) (at low concentration) is common in water treatment plants (WTPs) and is associated with bacteria. We hypothesize that Al(III) accelerate biofouling due to its hydrolysis and hormesis characteristics, as compared with other cations. To verify this, we elaborated the roles of Al(III) at low concentrations on the biofilm formation. Al(III) hormesis (<2.0mg/L) stimulated bacteria growth increased by ~3.7 times, and extracellular polymeric substances production also enhanced. Al(III) flocculation resulted in the suspended cells precipitation instantly, for Al(III) dosages of 0.6 and 2.0mg/L and the concentration of Al(III) decreased by 0.07 and 0.14mg/L, respectively. Al(III) poisoned the bridged bacterial cells and decreased their ATP by 22.36% and 55.91%, respectively. Al(III) formed polymer presented strong affinity with bacterial outer membrane, and this damaged the bacterial outer membrane. This caused proteins to leak at the combined point. Al-polymer bound to NH2 and/or NH on the leaked protein, contributed to biofilm formation. Biofilm maturity was aided by polysaccharides, which shielded Al(III) toxicity for the formed biofilm. Thus, the biofilm exhibited a distinguished double-layer microstructure, principally with proteins and inactivated cells at the bottom, polysaccharides and activated cells at the top. Thus, hormesis and flocculation caused by low concentration Al(III) mutually promoted each other, and together accelerated biofilm formation. PMID- 29631142 TI - Navy and black bean supplementation attenuates colitis-associated inflammation and colonic epithelial damage. AB - The enriched levels of nondigestible fermentable carbohydrates and phenolic compounds found in common beans can exert immunomodulatory effects within the colon that improve gut health and mitigate the severity of colitis-associated inflammatory pathology. Prior to acute colitis onset, C57Bl/6 mice were prefed isocaloric 20% cooked navy bean (NB) or black bean (BB) diets for 3 weeks and switched to control basal diet (BD) 24 h prior to colitis induction via 5-day exposure to dextran sodium sulfate (2% w/v in drinking water)+3 days of fresh water. The severity of the acute colitis phenotype was attenuated by bean prefeeding, evidenced by reduced colon tissue inflammatory transcription factor activation (NFkappaB, STAT3) and inflammatory mediator levels in the colon (IL 1beta, IL-6, IL-18 and MCP-1) and serum (TNFalpha, IL-6, IL-1beta, MCP-1) versus BD (P<=.05). Additionally, biomarkers of enhanced wound repair responses were increased by bean prefeeding including colon tissue protein levels of IL-22, IL 27 and activated (i.e., GTP-bound) Cdc42 and Rac1 versus BD (P<=.05). mRNA expressions of genes involved in normal colonic epithelial function and the promotion of epithelial barrier integrity, defense and/or restitution and wound closure including MUC1, RELMbeta, IgA and REG3gamma were all increased in NB and BB prefed mice versus BD (P<=.05). Collectively, bean supplementation prior to colitis induction (i.e., mimicking disease relapse) primes the colonic microenvironment to attenuate the severity of the colitis inflammatory phenotype and maintain aspects of epithelial barrier function. PMID- 29631144 TI - Enhancing the evidential value of textile fibres: Part 1: Development of a spectral database and evaluative comparison strategy. AB - In numerous major crime cases undertaken at our laboratory the recovery of large numbers of fibres (>1000), particularly in cases with no known source, presented several challenges. These included the inability to effectively manage the data (i.e. combination of MSP spectra, microscopic characteristics, composition, etc.) and perform comparisons in an efficient manner. To address these challenges, and in response to a growing need for performing fibre comparisons, we developed a database of textile fibre microspectrophotometric (MSP) spectra. The database, designed to compare MSP spectra using a modified Pearson method of correlation, currently contains over 20,000 normalised and first derivative spectra of casework, validation and reference textile fibres. A comparison strategy for cases with a large number of questioned samples was devised, involving identification of critical fibres in the casework data set, development of preliminary fibre groups classified according to their corresponding/similar MSP spectra, and verification of the preliminary groups via brightfield and fluorescence comparison microscopy. The database has successfully been utilised for proficiency trials and casework with small questioned fibre sets. Furthermore, in a case involving a larger dataset (>4000 "unknown" fibres) the database assisted in the efficient classification of 156 distinct groups of interest, highlighting its utility in providing investigative leads for the identification of potential sources of the recovered fibres. PMID- 29631143 TI - Grape pomace extract induced beige cells in white adipose tissue from rats and in 3T3-L1 adipocytes. AB - This study investigated the effects of a grape pomace extract (GPE) rich in phenolic compounds on brown-like adipocyte induction and adiposity in spontaneously hypertensive (SHR) and control normotensive Wistar-Kyoto (WKY) rats fed a high-fat diet (HFD). HFD consumption for 10 weeks significantly increased epididymal white adipose tissue (eWAT) in WKY but not in SHR rats. Supplementation with GPE (300 mg/kg body weight/day) reduced adipocyte diameter and increased levels of proteins that participate in adipogenesis and angiogenesis, i.e., peroxisome-proliferator activated receptor gamma (PPARgamma), vascular endothelial grow factor-A (VEGF-A) and its receptor 2 (VEGF-R2), and partially increased the uncoupling protein 1 (UCP-1) in WKY. In both strains, GPE attenuated adipose inflammation. In eWAT from SHR, GPE increased the expression of proteins involved in adipose tissue "browning," i.e., PPARgamma-coactivator 1alpha (PGC-1alpha), PPARgamma, PR domain containing 16 (PRDM16) and UCP-1. In primary cultures of SHR adipocytes, GPE-induced UCP-1 up-regulation was dependent on p38 and ERK activation. Accordingly, in 3T3-L1 adipocytes treated with palmitate, the addition of GPE (30 MUM) activated the beta-adrenergic signaling cascade (PKA, AMPK, p38, ERK). This led to the associated up-regulation of proteins involved in mitochondrial biogenesis (PGC-1alpha, PPARgamma, PRDM16 and UCP-1) and fatty acid oxidation (ATGL). These effects were similar to those exerted by (-)-epicatechin and quercetin, major phenolic compounds in GPE. Overall, in HFD-fed rats, supplementation with GPE promoted brown-like cell formation in eWAT and diminished adipose dysfunction. Thus, winemaking residues, rich in bioactive compounds, could be useful to mitigate the adverse effects of HFD-induced adipose dysfunction. PMID- 29631145 TI - Warm-needle moxibustion for spasticity after stroke: A systematic review of randomized controlled trials. AB - BACKGROUND: Spasticity is a common post-stroke complication, and it results in substantial deterioration in the quality of life of patients. Although potential positive effects of warm-needle moxibustion on spasticity after stroke have been observed, evidence on its definitive effect remains uncertain. OBJECTIVES: This study aimed to summarize clinical evidence pertaining to therapeutic effects and safety of warm-needle moxibustion for treating spasticity after stroke. DESIGN: Randomized controlled trials were reviewed systematically on the basis of the Cochrane Handbook for Systematic Reviews of Interventions. The report follows the PRISMA statement. METHODS: Ten electronic databases (PubMed, CENTRAL, EMBASE, AMED, CINAHL, Web of Science, CBM, CNKI, WanFang, and VIP) were explored, and articles were retrieved manually from two Chinese journals (The Journal of Traditional Chinese Medicine and Zhong Guo Zhen Jiu) through retrospective search. Randomized controlled trials with warm-needle moxibustion as treatment intervention for patients with limb spasm after stroke were included in this review. The risk of bias assessment tool was utilized in accordance with Cochrane Handbook 5.1.0. All included studies reported spasm effect as primary outcome. Effect size was estimated using relative risk, standardized mean difference, or mean difference with a corresponding 95% confidence interval. Review Manager 5.3 was utilized for meta-analysis. RESULTS: Twelve randomized controlled trials with certain methodological flaws and risk of bias were included, and they involved a total of 878 participants. Warm-needle moxibustion was found to be superior to electroacupuncture or acupuncture in reducing spasm and in promoting motor function and daily living activities. Pooled results for spasm effect and motor function were significant when warm-needle moxibustion was compared with electroacupuncture or acupuncture. A comparison of daily living activities indicated significant differences between warm-needle moxibustion and electroacupuncture. However, no difference was observed between warm-needle moxibustion and acupuncture. CONCLUSIONS: Warm-needle moxibustion may be a promising intervention to reduce limb spasm as well as improve motor function and daily living activities for stroke patients with spasticity. However, evidence was not conclusive. Rigorously designed randomized controlled trials with sample sizes larger than that in the included trials should be conducted for verification. PMID- 29631146 TI - Technology-enhanced teacher development in rural Bangladesh: A critical realist evaluation of the context. AB - This study arose in response to the complexity of implementing technology enhanced learning for teacher development in a developing country. Bangladesh is a country with growing technological capacity including mobile phone network coverage, yet it faces vast challenges of utilising these facilities in the education sector. As educational change and technological innovation do not happen in a vacuum, the researcher used a critical realist approach to understand the layers of the rural Bangladesh context where technology-enhanced learning will take place. Findings have been drawn from survey data (n = 207) and a series of six focus group sessions with the same six stakeholders, informing future technology-enhanced teacher development programmes. The implications of the study are to suggest principles for pedagogical change and a methodological approach which attends to context. PMID- 29631147 TI - Paroxetine induced galactorrhoea - A case report. PMID- 29631148 TI - Shame as a cultural index of illness and recovery from psychotic illness in Java. AB - OBJECTIVE: Most studies of shame have focused on stigma as a form of social response and a socio-psychological consequence of mental illness. This study aims at exploring more complex Javanese meanings of shame in relation to psychotic illness. METHOD: Six psychotic patients and their family members participated in this research. Ethnographic fieldwork was conducted in Yogyakarta, Indonesia. RESULT: Thematic analysis of the data showed that participants used shame in three different ways. First, as a cultural index of illness and recovery. Family members identified their member as being ill when they had lost their sense of shame. If a patient exhibited behavior that indicated the reemergence of shame, the family saw this as an indication of recovery. Second, as an indication of relapse. Third, as a barrier toward recovery. CONCLUSIONS: Shame is used as a cultural index of illness and recovery because it associated with the moral behavioral control. Shame may also be regarded as a form of consciousness associated with the emergence of insight. Further study with a larger group of sample is needed to explore shame as a 'socio-cultural marker' for psychotic illness in Java. PMID- 29631149 TI - Extent and pattern of problematic internet use among school students from Delhi: Findings from the cyber awareness programme. AB - The student population is likely to be vulnerable to problems associated with increased online activity. We present the findings on extent and pattern of problematic internet use based on observations from a cyber awareness initiative undertaken in national capital city of New Delhi. A total of 25 schools were enrolled in the first phase of the initiative. The students in the middle, high, secondary and senior secondary grades were eligible for inclusion in the initiative. The Generalized Problematic Internet Use Scale 2 was used to assess problematic internet use. Correlation analysis was done using Pearson's correlation. A binary logistic regression was carried to see how various variables predicted the GPIUS scores. The level of statistical significance was kept at p < 0.05 for all the tests. A total of 6291 students participated in first phase. Around 19% of study participants reported problematic internet use and 37% used internet for mood regulation. Male gender, older age, studying in senior grades, and owning a personal device were associated with higher rates of problematic internet use. Use of internet for accessing social media, online gaming, and recreational surfing is associated with problematic internet use, while use of internet for educational activities was associated with lesser problems. There is a need to cover all students under cyber awareness program in order to facilitate safe and healthy use of internet. PMID- 29631150 TI - Migration of spinal pedicle screw with aerodigestive perforation and subsequent device expectoration. AB - INTRODUCTION: Spinal fixation is a common surgical procedure. Frequently, fixation for spinal stabilization requires use of instrumentation such as pedicle screws and fixation plates. Aerodigestive and vascular perforations from such procedures are infrequent albeit known complications from these procedures. PRESENTATION OF CASE: This case details an uncommon situation in which a patient with anterior cervical spine fixation in the distant past was found to have a migratory pedicle screw. The patient had symptoms of neck pain and dysphagia. Radiographic studies were helpful in demonstrating the problem. While undergoing a physical examination, the patient was witnessed to expectorate the screw. Further work up with panendoscopy was undertaken and the patient managed conservatively. DISCUSSION: The upper aerodigestive system rarely experiences perforation from spinal stabilization hardware. When it occurs, management should include a dedicated investigation of the involved portions of the digestive system to avoid further complication. CONCLUSION: This case presents an rare occurrence of aerodigestive perforation of a spinal pedicle screw which was self removed. PMID- 29631151 TI - Molecular dynamics analysis of stabilities of the telomeric Watson-Crick duplex and the associated i-motif as a function of pH and temperature. AB - This work deals with a molecular dynamics analysis of the protonated and deprotonated states of the natural sequence d[(CCCTAA)3CCCT] of the telomeric DNA forming the intercalated i-motif or paired with the sequence d[(CCCTAA)3CCCT] and forming the Watson-Crick (WC) duplex. By utilizing the amber force field for nucleic acids we built the i-motif and the WC duplex either with native cytosines or using their protonated forms. We studied, by applying molecular dynamics simulations, the role of hydrogen bonds between cytosines or in cytosine-guanine pairs in the stabilization of both structures in the physiological fluid. We found that hydrogen bonds exist in the case of protonated i-motif and in the standard form of the WC duplex. They, however, vanish in the case of the deprotonated i-motif and protonated form of the WC duplex. By determining potentials of mean force in the enforced unwrapping of these structures we found that the protonated i-motif is thermodynamically the most stable. Its deprotonation leads to spontaneous and observed directly in the unbiased calculations unfolding of the i-motif to the hairpin structure at normal temperature. The WC duplex is stable in its standard form and its slight destabilization is observed at the acidic pH. However, the protonated WC duplex unwraps very slowly at 310 K and its decomposition was not observed in the unbiased calculations. At higher temperatures (ca. 400 K or more) the WC duplex unwraps spontaneously. PMID- 29631152 TI - Thiamethoxam induced hepatic energy changes in silver catfish via impairment of the phosphoryl transfer network pathway: Toxicological effects on energetics homeostasis. AB - Precise coupling of spatially separated intracellular adenosine triphosphate (ATP)-producing and ATP-consuming processes exerts a pivotal role in bioenergetic homeostasis of living organisms, and the phosphotransfer network pathway, catalyzed by adenylate kinase (AK) and pyruvate kinase (PK), is fundamental in cellular and tissue energetic homeostasis. Measurement of the phosphotransfer network can provide new information for understanding the alterations in hepatic energetic metabolism during exposition to insecticides, such as thiamethoxam. Therefore, the aim of this study was to evaluate whether exposition to thiamethoxam negatively affects the hepatic enzymes of the phosphotransfer network in silver catfish (Rhamdia quelen). Hepatic AK and PK activities were inhibited at 3.75 MUg L-1 after 24 h of exposure and at 1.125 and 3.75 MUg L-1 after 96 h of exposure compared with the control group. The hepatic ATP levels were decreased following 3.75 MUg L-1 thiamethoxam treatment after 24 h of exposure and at 1.125 and 3.75 MUg L-1 after 96 h of exposure compared with the control group. The enzymatic activity of the phosphotransfer network and ATP levels did not recover after 48 h of recovery in clean water. Thus, the inhibition of hepatic AK and PK activities by thiamethoxam caused impairment of energy homeostasis in liver tissue, decreasing hepatic ATP availability. Moreover, the absence of a mutual compensatory mechanism between these enzymes directly contributes to ATP depletion and to a severe energetic dysregulation, which may contribute to toxic effects caused by thiamethoxam. PMID- 29631153 TI - Regional variation in percutaneous absorption in the tree frog Litoria caerulea. AB - Frog skin structure and physiology differs between skin regions, however little is known about how these differences affect transdermal absorption of chemicals. Further, no information is available regarding how the relative lipophilicity of a chemical influences its transdermal pharmacokinetics in frog skin. This study investigated the in vitro percutaneous absorption of three model chemicals - benzoic acid, caffeine, and ibuprofen - through dorsal and ventral skin of the tree frog Litoria caerulea. Flux was significantly higher through the ventral skin for all chemicals. Relative lipophilicity affected flux differently in different skin regions. These differences are likely due to significantly thicker dorsal skin increasing absorption path length, and also possibly owing to lipoid secretions on the dorsum providing an additional diffusional barrier. This knowledge can advise risk mitigation of xenobiotics in agricultural and industrial settings, and also guide selection of chemicals and doses when considering transdermal drug therapy in captive frogs. PMID- 29631154 TI - Golgi bypass for local delivery of axonal proteins, fact or fiction? AB - Although translation of cytosolic proteins is well described in axons, much less is known about the synthesis, processing and trafficking of transmembrane and secreted proteins. A canonical rough endoplasmic reticulum or a stacked Golgi apparatus has not been detected in axons, generating doubts about the functionality of a local route. However, axons contain mRNAs for membrane and secreted proteins, translation factors, ribosomal components, smooth endoplasmic reticulum and post-endoplasmic reticulum elements that may contribute to local biosynthesis and plasma membrane delivery. Here we consider the evidence supporting a local secretory system in axons. We discuss exocytic elements and examples of autonomous axonal trafficking that impact development and maintenance. We also examine whether unconventional post-endoplasmic reticulum pathways may replace the canonical Golgi apparatus. PMID- 29631155 TI - Epilepsy surgery in the underserved Hispanic population improves depression, anxiety, and quality of life. AB - OBJECTIVE: The objective of this study was to investigate the effect of epilepsy surgery on depression, anxiety, and quality of life (QOL) in a Hispanic, primarily immigrant, Spanish-speaking population with intractable epilepsy (IE). METHODS: Patients with IE from a comprehensive epilepsy treatment center in an urban, public healthcare setting who underwent resective brain surgery between 2008 and 2014 (N=47) and completed presurgical and postsurgical neuropsychological evaluation were retrospectively identified. Presurgical and 1 year postsurgical Beck Depression Inventory-II (BDI-II), Beck Anxiety Inventory (BAI), and QOLIE-31 ratings were analyzed as postsurgical outcome measures. One tailed paired sample t-tests were used to evaluate whether scores improved postoperatively. Established severity level classifications of depression and anxiety (i.e., minimal, mild, moderate, or severe) were used to analyze changes in occurrence of depression and anxiety. RESULTS: Medium to large improvements on the BDI-II and most QOLIE-31 subscales, with a smaller effect on the BAI and remaining QOLIE-31 subscales, were noted 1-year postsurgery. Levels of depression and anxiety were significantly reduced 1-year postsurgery. Depression, anxiety, and QOL improvements were robust and unaffected by gender, levels of education, or hemisphere of surgery. CONCLUSIONS: This study supports the positive benefits of epilepsy surgery on depression, anxiety, and QOL in Hispanic, primarily undocumented immigrant, Spanish-speaking people with epilepsy (PWE) in the US. These results are useful for educating this particular population about the possible benefits of surgery for IE and can enhance presurgical counseling. PMID- 29631156 TI - Tuberous sclerosis complex: Concerns and needs of patients and parents from the transitional period to adulthood. AB - INTRODUCTION: Transitioning into adulthood and from pediatric services to adult healthcare are both challenging processes for young adults with rare chronic disorders such as tuberous sclerosis complex (TSC) and their parents. Adult healthcare systems are often less family-oriented and lack multidisciplinary care and experience with TSC, which can result in increased health risks and morbidity. Patient-driven data on care needs are necessary to optimize support for this vulnerable patient group. AIM: The aim of this study was to explore the concerns and care needs of young adult patients with TSC in medical, psychological, and socioeconomical domains. METHOD: A qualitative study was performed using semistructured interviews with 16 patients (median age: 21years; range: 17 to 30) and 12 parents. Concerns and care needs were organized using the International Classification of Functioning, Disability, and Health (ICF). RESULTS: Main concerns involved mental and physical health, participation, self management skills, family planning, and side effects of medications. Patients expressed the need for multidisciplinary care that is well-informed, easily accessible, and focused on the patient as a whole, including his/her family. Parents reported high stress levels. CONCLUSION: The current study provides patient-driven information, allowing recommendations to facilitate the (transition of) care for young adults with TSC. In addition to seizures, tumor growth, and TSC-associated neuropsychiatric disorders (TAND), more attention is needed for concerns and care needs specific to the transitional period, participation, and environmental factors. Adult healthcare providers should offer expert multidisciplinary care for adult patients with TSC, including attention for parental stress. PMID- 29631157 TI - Presurgical depression and anxiety are not associated with worse epilepsy surgery outcome five years postoperatively. AB - PURPOSE: Anxiety and depression have been associated with poor seizure control after epilepsy surgery. This study explored the effect of presurgical anxiety or depression on two- and five-year seizure control outcomes. METHODS: Adult subjects were enrolled between 1996 and 2001 in a multicenter prospective study to evaluate outcomes of resective epilepsy surgery. A Poisson regression was used to analyze the association of depression and anxiety with surgical outcome, while adjusting for gender, age, ethnicity, number of years with seizures, and presence of mesial temporal sclerosis. RESULTS: The relative risk (RR) of presurgical depression on two-year seizure-free outcome in this cohort is 1.12 (95% confidence interval (CI), 0.84-1.49) and 1.06 (CI, 0.73-1.55) on five-year seizure free outcome. The RR of presurgical anxiety on two-year seizure outcome is 0.73 (CI, 0.50-1.07) and 0.70 (CI, 0.43-1.17) on five-year seizure outcome. When including Engel classes I and II, the RRs of presurgical depression, anxiety, or both two years after surgery were 0.96 (p=0.59), 0.73 (p<0.05), and 0.97 (p=0.70), respectively, and they were 0.97 (p=0.82), 0.84 (p=0.32), and 0.89 (p=0.15), respectively, five years after surgery. Only presurgical anxiety was associated with worse epilepsy surgery outcome two year after surgery but not at five years postsurgery. Depression was not a risk factor for poor epilepsy surgical outcome in the long term. CONCLUSION: These findings from a prospective study that utilized a standardized protocol for psychiatric and seizure outcome assessment suggest that presurgical mood disorders have no substantial impact on postsurgical seizure outcome for up to five years after surgery. PMID- 29631158 TI - Molecularly imprinted polymer based quartz crystal microbalance sensor system for sensitive and label-free detection of synthetic cannabinoids in urine. AB - Herein, we prepared a novel quartz crystal microbalance (QCM) sensor for synthetic cannabinoids (JWH-073, JWH-073 butanoic acid, JWH-018 and JWH-018 pentanoic acid,) detection. Firstly, the synthetic cannabinoid (SCs) imprinted (MIP) and non-imprinted (NIP) nanoparticles were synthesized by mini-emulsion polymerization system. The SCs-imprinted nanoparticles were first characterized by SEM, TEM, zeta-size and FTIR-ATR analysis and then were dropped onto the gold QCM surface. The SCs-imprinted QCM sensor was characterized by an ellipsometer, contact angle, and AFM. The limit of detection was found as 0.3, 0.45, 0.4, 0.2 pg/mL JWH-018, JWH-073, JWH-018 pentanoic acid and JWH-073 butanoic acid, respectively. The selectivity of the SCs-imprinted QCM sensor was shown by using JWH-018, JWH-018 pentanoic acid, JWH-073 and JWH-073 butanoic acid. According to the results, the SCs-imprinted QCM sensors show highly selective and sensitive in a broad range of synthetic cannabinoid concentrations (0.0005-1.0 ng/mL) in both aqueous and synthetic urine solutions. PMID- 29631159 TI - Advanced biosensors for monitoring astronauts' health during long-duration space missions. AB - Long-duration space missions pose important health concerns for astronauts, especially regarding the adverse effects of microgravity and exposure to high energy cosmic rays. The long-term maintenance of crew health and performance mainly relies on prevention, early diagnoses, condition management, and medical interventions in situ. In-flight biosensor diagnostic devices and medical procedures must use few resources and operate in a microgravity environment, which complicates the collection and management of biological samples. Moreover, the biosensors must be certified for in-flight operation according to strict design and safety regulations. Herein, we report on the state of the art and recent advances in biosensing diagnostic instrumentation for monitoring astronauts' health during long-duration space missions, including portable and wearable biosensors. We discuss perspectives on new-format biosensors in autonomous space clinics. We also describe our own work in developing biosensing devices for non-invasively diagnosing space-related diseases, and how they are used in long-duration missions. Finally, we discuss the benefits of space exploration for Earth-based medicine. PMID- 29631160 TI - A new carbon paste electrode modified with MWCNTs and nano-structured molecularly imprinted polymer for ultratrace determination of trimipramine: The crucial effect of electrode components mixing on its performance. AB - A novel carbon nanocomposite paste electrode was prepared and used as a voltammetric sensor for ultratrace determination of trimipramine (TRI) which currently used for the treatment of psychiatric disorders. For this aim, nanoparticles of molecularly imprinted polymer (MIP), synthesized by precipitation polymerization method, and multi-walled carbon nanotubes (MWCNTs) were embedded in a nanocomposite paste electrode. The nanocomposite mixing style demonstrated a significant influence on the final electrode performance. The sensor exhibited linear response range of 1.0 * 10-10-2.5 * 10-8 mol L-1 and very high sensitivity of 2131 MUA MU mol L-1. The lower detection limit of the sensor was calculated to be 4.5 * 10-11 mol L-1 (S/N = 3). This sensor was applied successfully for highly selective determination of TRI in pharmaceutical formulations, urine and serum samples without applying any sample pretreatment. PMID- 29631161 TI - A novel electrochemical immunosensor based on PG for early screening of depression markers-heat shock protein 70. AB - In this study, a novel electrochemical immunosensor for early screening of depression markers-heat shock protein 70 (HSP70) was successfully developed based on the porous graphene (PG) with huge specific surface area and excellent structure. Benefiting from the strong adsorption and good bioactivity of PG which was initially prepared via a simple pyrolysis process, a variety of heat shock protein70 (HSP70) can be firmly loaded on the PG to construct the basic electrode (HSP70/PG/GCE),which was characterized by the cyclic voltammetry (CV) and electrochemical impedance spectroscopy (EIS), respectively. Due to the HSP70 fixed on the surface of basic electrode and the HSP70 in the samples can competitively combine with the horseradish peroxidase labeled human HSP 70 antibody (HRP-Strept-Biotin-Ab). As a result, it presented a negative correlation between the concentration of HSP70 in samples and the detection signal of the proposed electrochemical immunosensor (HRP-Strept-Biotin-Ab-HSP70/PG/GCE) in the test liquid. The application of PG with excellent electrical conductivity in construction of immunosensor remarkably improved the sensitivity of the immunosensor for detection of HSP70. The proposed immunosensor demonstrated a wide linear range of 0.0448 ~ 100 ng/mL with a low detection limit of 0.02 ng/mL at 3sigma. Moreover, the proposed immunosensor could be applied for the sensitive and efficient detection of HSP70 in real samples with good precision, acceptable stability, reproducibility and satisfactory results. Therefore, the HSP70 immunosensor provides a novel and convenient method for early clinical screening of depression markers-heat shock protein 70. PMID- 29631162 TI - Surface plasmon aided high sensitive non-enzymatic glucose sensor using Au/NiAu multilayered nanowire arrays. AB - A novel plasmon aided non-enzymatic glucose sensor was first constructed based on the unique half-rough Au/NiAu multilayered nanowire arrays. These multilayered and half-rough nanowires provide high chemical activity and large surface area for glucose oxidation in an alkaline solution. Under visible light irradiation, the surface plasmons originated from Au part enhance the electron transfer in the vertically aligned nanowires, leading to high sensitivity and wide detection range. The resulting sensor exhibits a wide glucose detection concentration range, low detection limit, and high sensitivity for plasmon aided non-enzymatic glucose sensor. Moreover, the detection sensitivity is enhanced by almost 2 folds compared to that in the dark, which significantly enhanced the performance of Au/NiAu multilayered nanowire arrays sensor. An excellent selectivity and acceptable stability were also achieved. These results indicate that surface plasmon aided nanostructures are promising new platforms for the construction of non-enzymatic glucose sensors. PMID- 29631163 TI - Nanoparticle co-delivery of wortmannin and cisplatin synergistically enhances chemoradiotherapy and reverses platinum resistance in ovarian cancer models. AB - Most ovarian cancer patients respond well to initial platinum-based chemotherapy. However, within a year, many patients experience disease recurrence with a platinum resistant phenotype that responds poorly to second line chemotherapies. As a result, new strategies to address platinum resistant ovarian cancer (PROC) are needed. Herein, we report that NP co-delivery of cisplatin (CP) and wortmannin (Wtmn), a DNA repair inhibitor, synergistically enhances chemoradiotherapy (CRT) and reverses CP resistance in PROC. We encapsulated this regimen in FDA approved poly(lactic-co-glycolic acid)-poly(ethylene glycol) (PLGA PEG) NPs to reduce systemic side effects, enhance cellular CP uptake, improve Wtmn stability, and increase therapeutic efficacy. Treatment of platinum sensitive ovarian cancer (PSOC) and PROC murine models with these dual-drug loaded NPs (DNPs) significantly reduced tumor burden versus treatment with combinations of free drugs or single-drug loaded NPs (SNPs). These results support further investigation of this NP-based, synergistic drug regimen as a means to combat PROC in the clinic. PMID- 29631165 TI - Ultra-thin, aligned, free-standing nanofiber membranes to recapitulate multi layered blood vessel/tissue interface for leukocyte infiltration study. AB - Leukocyte infiltration plays critical roles in tissue inflammation for pathogen clearance and tumor eradication. This process is regulated by complex microenvironments in blood vessels, including inflamed endothelium, blood flow, and perivascular components. The role of perivascular components in leukocyte infiltration has not been systematically investigated until recently mostly due to lack of technology. In this work, we developed a three-dimensional multi layered blood vessel/tissue model with a nanofiber membrane, enabling real-time visualization of dynamic leukocyte infiltration and subsequent interaction with perivascular macrophages. We directly fabricated a highly aligned, free-standing nanofiber membrane with an ultra-thin thickness of ~1 MUm in microfluidic systems. Coating the nanofiber membrane with matrigel showed synergetic topographical and biochemical effects on the reconstitution of a well-aligned endothelial monolayer on the membrane. Our 3D multi-layered blood vessel/tissue model will offer a powerful and versatile tool for investigating the mechanism of leukocyte tissue infiltration and subsequent immune responses. PMID- 29631164 TI - Injectable hyaluronic acid based microrods provide local micromechanical and biochemical cues to attenuate cardiac fibrosis after myocardial infarction. AB - Repairing cardiac tissue after myocardial infarction (MI) is one of the most challenging goals in tissue engineering. Following ischemic injury, significant matrix remodeling and the formation of avascular scar tissue significantly impairs cell engraftment and survival in the damaged myocardium. This limits the efficacy of cell replacement therapies, demanding strategies that reduce pathological scarring to create a suitable microenvironment for healthy tissue regeneration. Here, we demonstrate the successful fabrication of discrete hyaluronic acid (HA)-based microrods to provide local biochemical and biomechanical signals to reprogram cells and attenuate cardiac fibrosis. HA microrods were produced in a range of physiological stiffness and shown to degrade in the presence of hyaluronidase. Additionally, we show that fibroblasts interact with these microrods in vitro, leading to significant changes in proliferation, collagen expression and other markers of a myofibroblast phenotype. When injected into the myocardium of an adult rat MI model, HA microrods prevented left ventricular wall thinning and improved cardiac function at 6 weeks post infarct. PMID- 29631166 TI - Second near-infrared emissive lanthanide complex for fast renal-clearable in vivo optical bioimaging and tiny tumor detection. AB - In vivo optical imaging by using a new imaging window located at short-wavelength infrared region (1000-1700 nm, named as NIR II) presents an unprecedented improvement in imaging sensitivity and spatial resolution over the traditional visible and near-infrared light. However, the most developed NIR II-emitters are hardly excreted from live animals, leading to unknown long-term toxicity concerns, which hinder the widespread applications of this advanced imaging technology. Here, we developed a new generation molecular NIR II-emitting probe based on Nd-diethylene triamine pentacetate acid (DTPA) complex. The designed molecular Nd-DTPA probe with bright narrow band emission at 1330 nm is successfully used for highly sensitive in vivo NIR II bioimaging with rapid renal excretion, high biocompatibility and optical-guided tiny tumor (down to ~3 mm) detection for the first time. Moreover, the Nd-DPTA complex also holds great promise as an X-ray contrast agent. These findings open up the possibility for designing a new generation of multi-modal small molecular probe for early tumor diagnosis and favor the clinic translation of the advanced NIR II imaging method. PMID- 29631167 TI - Programmed 'triple-mode' anti-tumor therapy: Improving peritoneal retention, tumor penetration and activatable drug release properties for effective inhibition of peritoneal carcinomatosis. AB - Peritoneal carcinomatosis (PC) is a fatal condition arising in the gastrointestinal tract. PC patients administered drugs locally in the tumor region, such as in intraperitoneal chemotherapy (IPCh), suffer from low drug retention time and tumor penetration. Herein, we synthesized a lithocholic acid (LCA)-conjugated disulfide-linked polyethyleneimine (ssPEI) micelle (LAPMi) nanoconstruct by covalently conjugating ssPEI and LCA, thereby forming positive charged nanomicellar structures loaded with paclitaxel (PTX) (LAPMi-PTX) for IPCh. The incorporation of a positive surface charge aided in prolonging the peritoneal retention time, presumably via ascites-induced protein corona formation, and the subsequent size expansion caused resistance against undesired clearance through lymphatic openings. Furthermore, preferential tumor penetration by LAPMi-PTX is attributable to the permeation-enhancing properties of LCA, and the subsequent tumor activatable drug release was induced by the presence of disulfide linkages. By integrating these properties, LAPMi exhibited prolonged peritoneal residence time, enhanced tumor permeation and chemotherapeutic effect evidenced by in vitro, tumor spheroid and in vivo studies. Importantly, our strategy enabled significant PC inhibition and increased the overall survival rate of tumor-bearing mice. In conclusion, we provided a new paradigm of intractable PC treatment by enabling the prolonged residence time of the nanoconstruct, thereby enhancing tumor penetration and anti-tumor therapy. PMID- 29631168 TI - Decellularized materials derived from TSP2-KO mice promote enhanced neovascularization and integration in diabetic wounds. AB - Decellularized biologic scaffolds are gaining popularity over synthetic biomaterials as naturally derived materials capable of promoting improved healing. Nevertheless, the most widely used biologic material - acellular dermal matrix (ADM) - exhibits slow repopulation and remodeling, which prevents integration. Additionally, engineering control of these materials is limited because they require a natural source for their production. In the current report, we demonstrate the feasibility of using genetically engineered animals to create decellularized biologic scaffolds with favorable extracellular matrix (ECM) properties. Specifically, we utilized skin from thrombospondin (TSP)-2 KO mice to derive various decellularized products. Scanning electron microscopy and mechanical testing showed that TSP-2 KO ADM exhibited an altered structure and a reduction in elastic modulus and ultimate tensile strength, respectively. When a powdered form of KO ADM was implanted subcutaneously, it was able to promote enhanced vascularization over WT. Additionally, when implanted subcutaneously, intact slabs of KO ADM were populated by higher number of host cells when compared to WT. In vitro studies confirmed the promigratory properties of KO ADM. Specifically, degradation products released by pepsin digestion of KO ADM induced greater cell migration than WT. Moreover, cell-derived ECM from TSP-2 null fibroblasts was more permissive to fibroblast migration. Finally, ADMs were implanted in a diabetic wound model to examine their ability to accelerate wound healing. KO ADM exhibited enhanced remodeling and vascular maturation, indicative of efficient integration. Overall, we demonstrate that genetic manipulation enables engineered ECM-based materials with increased regenerative potential. PMID- 29631169 TI - Qualitative postural control differences in Idiopathic Parkinson's Disease vs. Progressive Supranuclear Palsy with dynamic-on-static platform tilt. AB - OBJECTIVES: We aimed to assess whether postural abnormalities in Progressive Supranuclear Palsy (PSP) and Idiopathic Parkinson's Disease (IPD) are qualitatively different by analysing spontaneous and reactive postural control. METHODS: We assessed postural control upon platform tilts in 17 PSP, 11 IPD patients and 18 healthy control subjects using a systems analysis approach. RESULTS: Spontaneous sway abnormalities in PSP resembled those of IPD patients. Spontaneous sway was smaller, slower and contained lower frequencies in both PSP and IPD as compared to healthy subjects. The amount of angular body excursions as a function of platform angular excursions (GAIN) in PSP was qualitatively different from both IPD and healthy subjects (GAIN cut-off value: 2.9, sensitivity of 94%, specificity of 72%). This effect was pronounced at the upper body level and at low as well as high frequencies. In contrast, IPD patients' stimulus-related body excursions were smaller compared to healthy subjects. Using a systems analysis approach, we were able to allocate these different postural strategies to differences in the use of sensory information as well as to different error correction efforts. CONCLUSIONS: While both PSP and IPD patients show abnormal postural control, the underlying pathology seems to be different. SIGNIFICANCE: The identification of disease-specific postural abnormalities shown here may be helpful for diagnostic as well as therapeutic discriminations of PSP vs. IPD. PMID- 29631170 TI - Effects of reflection on clinical decision-making of intensive care unit nurses. AB - BACKGROUND: Nurses are one of the most influential factors in overcoming the main challenges faced by health systems throughout the world. Every health system should, hence, empower nurses in clinical judgment and decision-making skills. OBJECTIVE: This study evaluated the effects of implementing Tanner's reflection method on clinical decision-making of nurses working in an intensive care unit (ICU). DESIGN: This study used an experimental, pretest, posttest design. SETTING: The setting was the intensive care unit of Amin Hospital Isfahan, Iran. PARTICIPANTS: The convenience sample included 60 nurses working in the ICU of Amin Hospital (Isfahan, Iran). METHODS: This clinical trial was performed on 60 nurses working in the ICU of Amin Hospital (Isfahan, Iran). The nurses were selected by census sampling and randomly allocated to either the case or the control group. Data were collected using a questionnaire containing demographic characteristics and the clinical decision-making scale developed by Laurie and Salantera (NDMI-14). The questionnaire was completed before and one week after the intervention. The data were analyzed using SPSS 21.0. RESULTS: The two groups were not significantly different in terms of the level and mean scores of clinical decision-making before the intervention (P = 0.786). Based on the results of independent t-test, the mean score of clinical decision-making one week after the intervention was significantly higher in the case group than in the control group (P = 0.009; t = -2.69). The results of Mann Whitney test showed that one week after the intervention, the nurses' level of clinical decision making in the case group rose to the next level (P = 0.001). CONCLUSION: Reflection could improve the clinical decision-making of ICU nurses. It is, thus, recommended to incorporate this method into the nursing curriculum and care practices. PMID- 29631171 TI - Importance of the subcellular location of protein deposits in neurodegenerative diseases. AB - Alzheimer's disease, Parkinson's, Huntington's, amyotrophic lateral sclerosis (ALS) and prion disorders are devastating neurodegenerative diseases of increasing prevalence in aging populations. Although clinically different, they share similar molecular features: the accumulation of one or two proteins in abnormal conformations inside or outside neurons. Enhancing protein quality control systems could be a useful strategy to neutralize the abnormal proteins causing neurodegenerative diseases. This review emphasizes the subcellular location of protein deposits in neurodegenerative diseases and the need to tailor strategies aimed at boosting protein quality control systems to the affected subcellular compartment. Inhibition of a protein phosphatase terminating the unfolded protein response will be discussed as a strategy to protect from diseases associated with misfolded proteins in the endoplasmic reticulum. PMID- 29631172 TI - The role of geriatrician-hospitalists in the care of older adults: A retrospective cohort study. AB - INTRODUCTION: Medicare patients account for over 50% of hospital days at a cost of over $1 trillion per year. Yet, hospitalization of older adults often results in poor outcomes. We evaluated the role of geriatrician-hospitalists in the care of older adults. Materials and methods A retrospective cohort study was conducted in a 764-bed tertiary care hospital with patients 65 and older admitted to medicine. Geriatrician-hospitalists care was compared to usual care by non geriatrician hospitalists (staff and non-staff). Outcome measures included length of stay (LOS) and 30-day readmissions. Process measures included geriatric focused care practices, such as early mobilization, safety precautions, delirium management, use of potentially inappropriate medications and documentation of advanced directives as well as discharge disposition. RESULTS: Of the 10,529 patients, 2949 (28.0%) were cared for by staff hospitalists, 7181 (68.2%) by non staff hospitalists and 399 (3.79%) by geriatrician-hospitalists. Patients cared for by geriatrician-hospitalists were significantly older with more comorbidities than those admitted to staff and non-staff hospitalists (average age: 86.3, 79.7, and 80.3, respectively, p < 0.0001; Charlson Comorbidity Index: 7.46, 7.01, and 7.17, respectively, p = 0.0005). Multivariate analysis showed no difference in LOS, 30-day readmissions, and discharge disposition. In terms of care practices, significant differences were found for the following: time to PT (p < 0.0001), duration of indwelling bladder catheters (p = 0.018), documentation of Do-Not Resuscitate (p < 0.0001), benzodiazepine use (p < 0.0001) and anticholinergics (p = 0.0029), respectively. CONCLUSIONS: As the population continues to age at unprecedented rates and hospitals struggle to meet the demands and expectations, geriatrician-hospitalists may improve care practices important for older adult care management. PMID- 29631173 TI - Molecular characterization of a novel mycovirus in Alternaria alternata manifesting two-sided effects: Down-regulation of host growth and up-regulation of host plant pathogenicity. AB - A double-stranded RNA (dsRNA) mycovirus was detected in a strain of Alternaria alternata showing impaired growth phenotypes. The A. alternata strain is the Japanese pear pathotype, which produces a host-specific AK-toxin. Sequence analysis of the viral genome dsRNAs revealed that this mycovirus consists of five dsRNAs and is evolutionarily related to members of the family Chrysoviridae; the virus was named Alternaria alternata chrysovirus 1 (AaCV1). AaCV1-ORF2 protein accumulated in dsRNA-high-titer sub-isolates with severely impaired phenotypes; heterologous AaCV1-ORF2 overexpression in Saccharomyces cerevisiae caused growth inhibition. In contrast to this yeast growth inhibition phenomenon, the dsRNA high-titer isolates displayed enhanced pathogenicity against Japanese pear plants, in accordance with a 13-fold increase in AK-toxin level in one such isolate. These findings indicated that AaCV1 is a novel mycovirus that exhibits two contrasting effects, impairing growth of the host fungus while rendering the host 'hypervirulent' to the plant. PMID- 29631176 TI - High-frequency, high-intensity electromagnetic field effects on Saccharomyces cerevisiae conversion yields and growth rates in a reverberant environment. AB - Studies of the effects of electromagnetic waves on Saccharomyces cerevisiae emphasize the need to develop instrumented experimental systems ensuring a characterization of the exposition level to enable unambiguous assessment of their potential effects on living organisms. A bioreactor constituted with two separate compartments has been designed. The main element (75% of total volume) supporting all measurement and control systems (temperature, pH, agitation, and aeration) is placed outside the exposure room whereas the secondary element is exposed to irradiation. Measurements of the medium dielectric properties allow the determination of the electromagnetic field at any point inside the irradiated part of the reactor and are consistent with numerical simulations. In these conditions, the growth rate of Saccharomyces cerevisiae and the ethanol yield in aerobic conditions are not significantly modified when submitted to an electromagnetic field of 900 and 2400 MHz with an average exposition of 6.11 V.m 1 and 3.44 V.m-1 respectively. PMID- 29631175 TI - Polymorphisms affecting the gE and gI proteins partly contribute to the virulence of a newly-emergent highly virulent Chinese pseudorabies virus. AB - An outbreak of a highly virulent pseudorabies virus strain, ZJ01, occurred in PRV vaccinated pigs in China in 2011. In this study, ZJ01 caused fatal diseases, while the Chinese prototypic PRV strain LA caused mild respiratory disorders. Full-genome sequencing results indicate the two viruses can be classified into two sub-clusters that distinct from traditional European and US strains. To examine the potential role of the gE and gI proteins in ZJ01 virulence, we generated several recombinant viruses. In two chimeric viruses (rZJ01-LA/gEI and rLA-ZJ01/gEI), the gE and gI genes were swapped using corresponding genes from ZJ01 and LA. rZJ01-LA/gEI and the parental virus rZJ01 retained high virulence in piglets, although the survival time for rZJ01-LA/gEI infected piglets was obviously prolonged. In contrast, rLA-ZJ01/gEI exhibited higher virulence than its parental virus rLA. We conclude that changes in gE and gI proteins partly contribute to the enhanced virulence of ZJ01 strain. PMID- 29631174 TI - Recombinant Flag-tagged E1E2 glycoproteins from three hepatitis C virus genotypes are biologically functional and elicit cross-reactive neutralizing antibodies in mice. AB - Hepatitis C virus (HCV) is a globally disseminated human pathogen for which no vaccine is currently available. HCV is highly diverse genetically and can be classified into 7 genotypes and multiple sub-types. Due to this antigenic variation, the induction of cross-reactive and at the same time neutralizing antibodies is a challenge in vaccine production. Here we report the analysis of immunogenicity of recombinant HCV envelope glycoproteins from genotypes 1a, 1b and 2a, with a Flag tag inserted in the hypervariable region 1 of E2. This modification did not affect protein expression or conformation or its capacity to bind the crucial virus entry factor, CD81. Importantly, in immunogenicity studies on mice, the purified E2-Flag mutants elicited high-titer, cross-reactive antibodies that were able to neutralize HCV infectious particles from two genotypes tested (1a and 2a). These findings indicate that E1E2-Flag envelope glycoproteins could be important immunogen candidates for vaccine aiming to induce broad HCV-neutralizing responses. PMID- 29631177 TI - Sodium thiosulphate induced immobilized bacterial disintegration of sludge: An energy efficient and cost effective platform for sludge management and biomethanation. AB - The present study aimed to gain better insights into profitable biomethanation through sodium thiosulphate induced immobilized protease secreting bacterial disintegration (STS-IPBD) of sludge. STS disperse the flocs at 0.08 g/g SS of dosage and assists the subsequent bacterial disintegration. Immobilization of bacteria increases the hydrolytic activity of cells towards effective liquefaction of sludge. A higher liquefaction of 22% was accomplished for STS IPBD when compared to immobilized protease secreting bacterial disintegration (IPBD alone). The kinetic parameters of Line Weaver Burk plot analysis revealed a maximal specific growth rate (umax) of 0.320 h-1 for immobilized cells when compared to suspended free cells showing the benefit of immobilization. Floc dispersion and immobilization of bacteria imparts a major role in biomethanation as the methane generation (0.32 gCOD/g COD) was higher in STS-IPBD sample. The cost analysis showed that STS - IPBD was a feasible process with net profit of 2.6 USD/Ton of sludge. PMID- 29631178 TI - Effects of bean dregs and crab shell powder additives on the composting of green waste. AB - Composting is an effective and economic technology for the recycling of organic waste. In this study, bean dregs (BD) (at 0, 35, and 45%) and crab shell powder (CSP) (at 0, 15, and 25%) were evaluated as additives during the two-stage composting of green waste (GW). The GW used in this experiment mainly consisted of branch cuttings collected during the maintenance of the urban green landscape. Combined additions of BD and CSP improved composting conditions and compost quality in terms of composting temperature, specific surface area, average pore diameter, pH and EC values, carbon dioxide release, ammonia and nitrous oxide emissions, E4/E6 ratio, elemental composition and atomic ratios, organic matter degradation, microbial numbers, enzyme activities, compost phytotoxicity, and environmental and economic benefits. The combined addition of 35% BD and 25% CSP to the two-stage composting of GW resulted in the highest quality compost product in only 22 days. PMID- 29631179 TI - Environmentally persistent free radicals mediated removal of Cr(VI) from highly saline water by corn straw biochars. AB - Heavy metal ions coexisting with salts in the contaminant water are difficult to remove due to the interference of salts. Herein, biochars were pyrolyzed by corn straw at different temperatures, aiming to remove Cr(VI) in the presence of salts. Results show that biochars had surprisingly selective adsorption of Cr(VI). X-ray photoelectron and X-ray absorption near edge spectra revealed that Cr(VI) was reduced to Cr(III). All the adsorption was conducted at pH ~ 7, which differed from the previous studies that Cr(VI) could only be reduced at pH 2-4. Environmental persistent free radicals (EPFRs) on biochars were found to play the role in reducing Cr(VI) in neutral solutions, which was confirmed by electron spin resonance and free radical quenching. The biochar with EPFRs reveals a highly selective removal of Cr(VI), which has implications for the remediation of contaminated water. This work provides a new insight into biochar's properties and potential environmental applications. PMID- 29631180 TI - Synthetic Escherichia coli-Corynebacterium glutamicum consortia for l-lysine production from starch and sucrose. AB - In the biorefinery concept renewable feedstocks are converted to a multitude of value-added compounds irrespective of seasonal or other variations of the complex biomass substrates. Conceptionally, this can be realized by specialized single microbial strains or by co-culturing various strain combinations. In the latter approach strains for substrate conversion and for product formation can be combined. This study addressed the construction of binary microbial consortia based on starch- and sucrose-based production of l-lysine and derived value-added compounds. A commensalism-based synthetic consortium for l-lysine production from sucrose was developed combining an l-lysine auxotrophic, naturally sucrose negative E. coli strain with a C. glutamicum strain able to produce l-lysine that secretes fructose when grown with sucrose due to deletion of the fructose importer gene ptsF. Mutualistic synthetic consortia with an l-lysine auxotrophic, alpha-amylase secreting E. coli strain and naturally amylase-negative C. glutamicum strains was implemented for production of valuable fine chemicals from starch. PMID- 29631181 TI - Novel micronized woody biomass process for production of cost-effective clean fermentable sugars. AB - Thermo-chemical pretreatments of biomass typically result in environmental impacts from water use and emission. The degradation byproducts in the resulting sugars can be inhibitory to the activities of enzymes and yeasts. The results of this study showed that combining existing commercial comminution technology can reduce total energy consumption with improved saccharification yield while eliminating chemical use. Impact mill was found to be the most efficient milling for size reduction of forest residual chips from ca. 2 mm to a specific value below 100 um. The further micronization effectively disrupted the recalcitrance of the woody biomass and produced the highly saccharifiable substrates for downstream processing. In addition, extrusion can be integrated into a clean cellulosic sugar process for further fibrillation in place of the conventional mixing processing. The highest energy efficiency was observed on the impact milled samples with 0.515 kg sugars kWh-1. PMID- 29631182 TI - Paracoccus versutus KS293 adaptation to aerobic and anaerobic denitrification: Insights from nitrogen removal, functional gene abundance, and proteomic profiling analysis. AB - A novel strain KS293 exhibiting excellent aerobic and anaerobic denitrification performance was isolated and identified as Paracoccus versutus KS293. Nitrate nitrogen and total organic carbon could be effectively removed by P. versutus KS293 without nitrite accumulation, whilst 82% and 85% of total nitrogen was converted into gaseous products under aerobic and anaerobic conditions (P > .05), respectively. Based on the ratio of anaerobic to aerobic, relative abundance values were increased 1.41, 1.45, and 2.31 folds for nirS, nosZ, and narG, respectively. A comparison of the two-dimensional gel electrophoresis and principal component analysis showed significant differences in proteomic profiles between aerobic and anaerobic conditions. In total, 78 proteins that displayed fluctuations in relative expression were observed. 10 proteins including nitrate reductase, maintenance of cell membrane (TolA), and RNA polymerase-binding transcription factor (DksA) were differentially expressed. These findings demonstrated that P. versutus KS293 was effective for nitrogen removal under aerobic or anaerobic conditions. PMID- 29631183 TI - The impact of opioid analgesic prescription uptake on the costs of recovery from injury: Evidence from compensable orthopaedic road trauma patients. AB - Long-term opioid prescribing after compensable orthopaedic injury may contribute to the 'long right tail' in the cost of recovery. The aim of this study was to estimate the effect of prescription opioid uptake on injury compensation cost, using orthopaedic road traffic injury claims data from Victoria, Australia. We used a maximum likelihood estimation that accounts for potential endogeneity associated with opioid uptake, utilizing information on the doctor's differential propensity to prescribe opioids when treating other compensable injury patients. Our results suggest that opioid recipients incurred significantly greater hospital costs, income compensation payments, and medical and paramedical expenses. Overall, income compensation was the primary driver of the claim cost difference between opioid recipients and non-recipients. The findings imply that there is scope to impose restrictions on long-term opioid usage, and to encourage the use of alternative pain relief medicines. PMID- 29631184 TI - Modulation of innate and adaptive immunity by P2X ion channels. AB - Extracellular ATP is a major component of the inflammatory microenvironment where it accumulates following cell and tissue injury but also as a consequence of non lytic release from activated inflammatory cells. In the inflammatory microenvironment ATP binds and activates nucleotide receptors of the P2Y and P2X subfamilies expressed by immune cells. P2Y receptors are G-protein-coupled, while P2X receptors are cation-selective channels. Changes in the intracellular ion homeostasis triggered by P2X receptor stimulation trigger multiple key responses crucial for initiation, propagation, and resolution of inflammation. In the P2X receptor family, the P2X7 subtype has an important role in the activation of lymphocyte, granulocyte, macrophage and dendritic cell responses. Although clinical studies have been so far rather inconclusive, it is believed that P2X7 receptor targeting might offer novel perspectives for anti-inflammatory therapy. PMID- 29631185 TI - Risk of infection from Legionella associated with spray irrigation of reclaimed water. AB - Legionella pneumophila has been detected in reclaimed water used for spray irrigation of turfgrass in public parks and golf courses. This study determined the risks of infection from exposure to various levels of Legionella in reclaimed waters considering: the method of spray application; and the duration and frequency of exposure. Evaluation of these factors resulted in a risk of infection greater than 1:10,000 for several scenarios when the number of Legionella in the reclaimed water exceeded 1000 colony-forming units (CFU) per ml. Most current guidelines for control of Legionella in distribution systems recommend that increased monitoring or remedial action be taken when Legionella levels exceed 1000 to 10,000 CFU/ml. Based upon our risk assessment, these guidelines seem appropriate for reclaimed water systems where spray irrigation is practiced. PMID- 29631186 TI - Declining ambient water phosphorus concentrations in Massachusetts' rivers from 1999 to 2013: Environmental protection works. AB - Over the last century, nutrient concentrations in streams, rivers, lakes and ponds have increased substantially in the United States. Elevated phosphorus levels are a concern due to their ability to cause changes in freshwater ecosystems that are detrimental to humans and wildlife. In the present study, long-term trends in total phosphorus (TP) concentrations from 20 rivers in central Massachusetts from 1999 to 2013 were investigated. Kendall's correlation coefficients were used to demonstrate that 18 of the 20 rivers had significant reductions in TP concentrations (P < 0.05). A similar trend was found when flow adjusted TP concentrations were analyzed. At the beginning of monitoring activities, the average TP concentration in 9 of the 20 rivers was greater than 0.05 mg/L and 6 of these 9 rivers contained TP concentrations greater than 0.1 mg/L; about fifteen years later, only 3 rivers contained TP greater than 0.05 mg/L and none had concentrations> 0.1 mg/L. TP decreases were greater in rivers with more anthropogenic inputs. Principal component analysis (PCA) revealed that the decline of TP in these Massachusetts streams is likely the result of advancements in wastewater treatment and implementation of effective non-point source management practices. PMID- 29631187 TI - Evaluation of advanced oxidation processes for water and wastewater treatment - A critical review. AB - This study provides an overview of established processes as well as recent progress in emerging technologies for advanced oxidation processes (AOPs). In addition to a discussion of major reaction mechanisms and formation of by products, data on energy efficiency were collected in an extensive analysis of studies reported in the peer-reviewed literature enabling a critical comparison of various established and emerging AOPs based on electrical energy per order (EEO) values. Despite strong variations within reviewed EEO values, significant differences could be observed between three groups of AOPs: (1) O3 (often considered as AOP-like process), O3/H2O2, O3/UV, UV/H2O2, UV/persulfate, UV/chlorine, and electron beam represent median EEO values of <1 kWh/m3, while median energy consumption by (2) photo-Fenton, plasma, and electrolytic AOPs were significantly higher (EEO values in the range of 1-100 kWh/m3). (3) UV-based photocatalysis, ultrasound, and microwave-based AOPs are characterized by median values of >100 kWh/m3 and were therefore considered as not (yet) energy efficient AOPs. Specific evaluation of 147 data points for the UV/H2O2 process revealed strong effects of operational conditions on reported EEO values. Besides water type and quality, a major influence was observed for process capacity (lab-vs. pilot-vs. full-scale applications) and, in case of UV-based processes, of the lamp type. However, due to the contribution of other factors, correlation of EEO values with specific water quality parameters such as UV absorbance and dissolved organic carbon were not substantial. Also, correlations between EEO and compound reactivity with OH-radicals were not significant (photolytically active compounds were not considered). Based on these findings, recommendations regarding the use of the EEO concept, including the upscaling of laboratory results, were derived. PMID- 29631188 TI - Tire wear particles in the aquatic environment - A review on generation, analysis, occurrence, fate and effects. AB - Tire wear particles (TWP), generated from tire material during use on roads have gained increasing attention as part of organic particulate contaminants, such as microplastic, in aquatic environments. The available information on properties and generation of TWP, analytical techniques to determine TWP, emissions, occurrence and behavior and ecotoxicological effects of TWP are reviewed with a focus on surface water as a potential receptor. TWP emissions are traffic related and contribute 5-30% to non-exhaust emissions from traffic. The mass of TWP generated is estimated at 1,327,000 t/a for the European Union, 1,120,000 t/a for the United States and 133,000 t/a for Germany. For Germany, this is equivalent to four times the amount of pesticides used. The mass of TWP ultimately entering the aquatic environment strongly depends on the extent of collection and treatment of road runoff, which is highly variable. For the German highways it is estimated that up to 11,000 t/a of TWP reach surface waters. Data on TWP concentrations in the environment, including surface waters are fragmentary, which is also due to the lack of suitable analytical methods for their determination. Information on TWP properties such as density and size distribution are missing; this hampers assessing the fate of TWP in the aquatic environment. Effects in the aquatic environment may stem from TWP itself or from compounds released from TWP. It is concluded that reliable knowledge on transport mechanism to surface waters, concentrations in surface waters and sediments, effects of aging, environmental half-lives of TWP as well as effects on aquatic organisms are missing. These aspects need to be addressed to allow for the assessment of risk of TWP in an aquatic environment. PMID- 29631189 TI - Systematic feature selection improves accuracy of methylation-based forensic age estimation in Han Chinese males. AB - Estimating individual age from biomarkers may provide key information facilitating forensic investigations. Recent progress has shown DNA methylation at age-associated CpG sites as the most informative biomarkers for estimating the individual age of an unknown donor. Optimal feature selection plays a critical role in determining the performance of the final prediction model. In this study we investigate methylation levels at 153 age-associated CpG sites from 21 previously reported genomic regions using the EpiTYPER system for their predictive power on individual age in 390 Han Chinese males ranging from 15 to 75 years of age. We conducted a systematic feature selection using a stepwise backward multiple linear regression analysis as well as an exhaustive searching algorithm. Both approaches identified the same subset of 9 CpG sites, which in linear combination provided the optimal model fitting with mean absolute deviation (MAD) of 2.89 years of age and explainable variance (R2) of 0.92. The final model was validated in two independent Han Chinese male samples (validation set 1, N = 65, MAD = 2.49, R2 = 0.95, and validation set 2, N = 62, MAD = 3.36, R2 = 0.89). Other competing models such as support vector machine and artificial neural network did not outperform the linear model to any noticeable degree. The validation set 1 was additionally analyzed using Pyrosequencing technology for cross-platform validation and was termed as validation set 3. Directly applying our model, in which the methylation levels were detected by the EpiTYPER system, to the data from pyrosequencing technology showed, however, less accurate results in terms of MAD (validation set 3, N = 65 Han Chinese males, MAD = 4.20, R2 = 0.93), suggesting the presence of a batch effect between different data generation platforms. This batch effect could be partially overcome by a z-score transformation (MAD = 2.76, R2 = 0.93). Overall, our systematic feature selection identified 9 CpG sites as the optimal subset for forensic age estimation and the prediction model consisting of these 9 markers demonstrated high potential in forensic practice. An age estimator implementing our prediction model allowing missing markers is freely available at http://liufan.big.ac.cn/AgePrediction. PMID- 29631191 TI - Prevalence and predictors of postdisaster major depression: Convergence of evidence from 11 disaster studies using consistent methods. AB - The objective of this study was to examine predictors of postdisaster major depression in two separate datasets of survivors of various disasters. Postdisaster major depression was examined in two disaster databases using consistent research methodology, permitting combination of databases into a combined dataset including 1181 survivors of 11 disasters representing all major disaster typologies with full diagnostic assessment using structured diagnostic interviews from two databases. The first database includes 808 directly-exposed survivors of 10 disasters. The second includes 373 survivors of the September 11, 2001 attacks on New York City's World Trade Center, recruited from employees of eight organizations affected by the disaster. This rich dataset permitted comparison of predictors of postdisaster major depression between databases and across survivors of different disasters. Identical models applied to both databases found postdisaster major depression to be independently associated with pre-existing major depression, indirect exposure to disaster trauma through family/friends, and disaster-related PTSD. In a final model limited to directly exposed disaster across both databases, postdisaster major depression was independently associated with terrorism in addition to the 3 variables that predicted postdisaster major depression in the two separate databases. Replication of findings from one model to the next across different types of disasters and populations in this study suggests that these three variables could potentially provide a powerful tool for estimating likelihood of postdisaster major depression. PMID- 29631190 TI - Posttraumatic stress disorder and nonadherence to medications prescribed for chronic medical conditions: A meta-analysis. AB - BACKGROUND: Patients with posttraumatic stress disorder (PTSD) are at increased risk for adverse consequences from comorbid medical conditions. Nonadherence to medications prescribed to treat those comorbid conditions may help explain this increased risk. We sought to determine the association between PTSD and medication nonadherence and whether it varied according to the type of event inducing the PTSD. METHODS: Prospective observational cohort or cross-sectional studies relating PTSD and nonadherence among adults prescribed medications for a chronic medical illness were identified by searching MEDLINE, EMBASE, PsycINFO, the Cochrane Library, CINAHL, SCOPUS, and the PILOTS Database and by hand searching bibliographies from selected articles. Individual estimates of odds ratios were pooled using random effects meta-analysis with inverse variance weighting. Articles were pooled separately according to whether PTSD was induced by a medical versus non-medical event. OUTCOMES: Sixteen articles comprising 4483 patients met eligibility criteria. The pooled effect size of the risk of PTSD to medication nonadherence was OR 1.22 (95% CI, 1.06-1.41). Among the 6 studies of medical event-induced PTSD, the OR was 2.08 (95% CI, 1.03-4.18); p = 0.04. Among the 8 studies in which PTSD was not induced by a medical event, the OR was 1.10 (95% CI, 0.99-1.24); p = 0.09. INTERPRETATION: Patients with PTSD were more likely to be nonadherent to medications prescribed for chronic medical conditions - an association that may exist specifically when PTSD was induced by a medical event. Medications may serve as aversive reminders among survivors of acute medical events, magnifying avoidance behaviors characteristic of PTSD. FUNDING: NHLBI. PMID- 29631192 TI - Daytime microsleeps during 7 days of sleep restriction followed by 13 days of sleep recovery in healthy young adults. AB - We investigated the consequences of sleep restriction (SR) on maintenance of wakefulness capacities and diurnal sleepiness through microsleeps monitoring. 12 healthy males (20-36 years old) were sleep restricted (4 h per night) during 7 nights followed by 13 nights of recovery sleep. Participants completed Karolinska Sleepiness Scale (KSS) and Maintenance of Wakefulness Test (MWT) at baseline (B), during SR (SR1, SR4 and SR7) and during recovery (R3 and R13), while continuously recorded for EEG analysis. During SR, MWT latencies decreased (SR7: -24.4%), whereas the number, the cumulative duration of microsleeps and KSS scores increased. Recovery nights allowed MWT latencies, KSS scores and all sleep values to return to baseline levels, while a rebound in N3, N3% and REM% sleep stages occurred. During SR, the maintenance of N3 sleep duration seems not sufficient to reduce daytime sleepiness and MWT results did not reflect the sleepiness levels characterized by persistent sleep attacks. PMID- 29631193 TI - Role of implicit learning abilities in metaphor understanding. AB - Although the use of metaphors is a central component of language, the processes that sustain their comprehension have yet to be specified. Work in the fields of both metaphors and implicit learning suggests that implicit learning abilities facilitate the comprehension of metaphors. However, to date, no study has directly explored the relationships between the understanding of metaphors and so called implicit learning tasks. We used a meaning decision task comparing literal, metaphorical and meaningless expressions to assess metaphor understanding and a probabilistic serial reaction time task for assessing implicit learning. Our results show that implicit learning positively predicts the time gap between responses to literal and metaphorical expressions and negatively predicts the difference between metaphorical and meaningless expressions. Thus, when confronted with novel metaphors, participants with higher implicit learning abilities are better able to identify that the expressions have some meaning. These results are interpreted in the context of metaphor understanding and psycholinguistic theories. PMID- 29631194 TI - Boredom: Under-aroused and restless. AB - Boredom is a common experience associated with a range of negative outcomes. Debate remains as to whether boredom should be considered a high or low arousal state. We employed passages of text to induce either boredom or interest and probed self-reported levels of boredom, arousal, and restlessness. Results replicated known associations between mind-wandering and state boredom (i.e., mind-wandering was highest for the boredom mood induction). Reports of sleepiness (a proxy for arousal level) were highest for the boring induction. While restlessness was not different for the boring and interesting inductions when they were performed first, restlessness was significantly higher for the boredom induction when it was experienced last. We discuss these results within the context of the debate regarding boredom and arousal. PMID- 29631195 TI - Vaccine options for influenza: thinking small. AB - Vaccines that direct the immune response towards conserved B cell epitopes of influenza viruses can provide broad protection. In many instances, this requires the design of vaccine antigens that stimulate the immune system to levels that far exceed the natural responses towards such antigens. Here we focus on the matrix protein 2 ectodomain (M2e) as a 'universal' influenza A vaccine candidate. Thanks to its small size and high solubility, M2e can be expressed and delivered in almost any format. Protection against experimental influenza A virus challenge by M2e-based vaccines has been demonstrated in natural host of influenza and clinical studies demonstrated that such vaccines are safe and immunogenic. M2e specific antibodies protect mainly by Fc receptor-mediated antibody-dependent cellular phagocytosis activity, which is reminiscent to how antibodies directed against the hemagglutinin stalk protect in vivo. Fighting influenza with a broadly protective influenza vaccine will likely require a blend of conserved antigens. M2e deserves its place in such a blend. PMID- 29631197 TI - The social-cognitive basis of infants' reference to absent entities. AB - Recent evidence suggests that infants as young as 12 month of age use pointing to communicate about absent entities. The tacit assumption underlying these studies is that infants do so based on tracking what their interlocutor experienced in a previous shared interaction. The present study addresses this assumption empirically. In three experiments, 12-month-old infants could request additional desired objects by pointing to the location in which these objects were previously located. We systematically varied whether the adult from whom infants were requesting had previously experienced the former content of the location with the infant. Infants systematically adjusted their pointing to the now empty location to what they experienced with the adult previously. These results suggest that infants' ability to communicate about absent referents is based on an incipient form of common ground. PMID- 29631196 TI - Outlooks on Epstein-Barr virus associated gastric cancer. AB - Epstein-Barr virus associated gastric cancer (EBVaGC) comprises approximately 10% of gastric carcinomas. Multiple factors contribute to tumorigenesis, including EBV driven hypermethylation of tumor suppressor genes, inflammatory changes in gastric mucosa, host immune evasion by EBV and changes in cell cycle pathways. The unique molecular characteristics of EBVaGC, such as programmed death ligand 1 (PD-L1) overexpression, highlight the potential for using EBV as a biomarker for response to immunotherapy. Few studies have reported benefit from immunotherapy in EBV positive cancers, and clinical trials investigating the impact of checkpoint inhibitors in EBVaGC are currently underway. This review provides the most recent updates on molecular pathophysiology, epidemiology, clinical features and treatment advances pertaining to EBVaGC. PMID- 29631198 TI - Doing patient-centredness versus achieving public health targets: A critical review of interactional dilemmas in ART adherence support. AB - Anti-retroviral Therapy (ART) transformed HIV into a chronic disease but its individual and public health benefits depend on high levels of adherence. The large and rising number of people on ART, now also used as prevention, puts considerable strain on health systems and providers in low and middle as well as high-income countries, which are our focus here. Delivering effective adherence support is thus crucial but challenging, especially given the promotion of patient-centredness and shared decision making in HIV care. To illuminate the complexities of ART adherence support delivered in and through clinical encounters, we conducted a multi-disciplinary interpretative literature review. We reviewed and synthesized 82 papers published post 1997 (when ART was introduced) belonging to three bodies of literature: public health and psychological studies of ART communication; anthropological and sociological studies of ART; and conversation analytic studies of patient-centredness and shared decision-making. We propose three inter-related tensions which make patient-centredness particularly complex in this infectious disease context: achieving trust versus probing about adherence; patient-centredness versus reaching public health targets; and empowerment versus responsibilisation as 'therapeutic citizens'. However, there is a dearth of evidence concerning how precisely ART providers implement patient-centredness, shared-decision making in practice, and enact trust and therapeutic citizenship. We show how conversation analysis could lead to new, actionable insights in this respect. PMID- 29631199 TI - Does welfare stigma exist in China? Policy evaluation of the Minimum Living Security System on recipients' psychological health and wellbeing. AB - This paper analyzes the policy effects of China's largest social assistance program on the psychological health and wellbeing of the recipients by the regression discontinuity approach based on the 2014 China Family Panel Studies Survey (CFPS). By excluding other confounding factors and addressing the endogeneity problems, this paper shows that China's minimum living security system (MLSS) has produced significant welfare stigmatizing effects which have negatively influenced recipients' psychological health and wellbeing. The MLSS reduces recipients' self-satisfaction towards life, decreases the levels of happiness and self-confidence, and results in poorer interpersonal relationships and self-evaluations. It also increases the probabilities of feeling depressed, helpless and hopeless. The frequencies reporting having the difficulties of doing something are significantly higher among the MLSS recipients. Corresponding strategies and professional services are required for reducing the welfare stigmatizing effects on recipients' psychological health and wellbeing. PMID- 29631200 TI - Bereaved relatives' decision about deceased organ donation: An integrated psycho social study conducted in Spain. AB - RATIONALE: Family refusal to organ donation of a deceased relative represents one of the most important barriers to organ transplantation. Although a large literature about family decisions has amassed, the existing evidence needs further integration and structuring. OBJECTIVE: This study seeks to analyse relationships between bereaved relatives' decisions and a wide range of factors that converge in the family decision process, including interactions and complex relationship patterns, and taking psychosocial theoretical frameworks as reference to conceptualize empirical findings. METHOD: This observational study examined 16 Spanish hospitals during a 36-month period. Transplant coordination teams collected data of 421 cases of family decision processes about donation (338 donations/83 refusals) through a previously validated instrument. Indicators of the following factors were collected: deceased's characteristics; circumstances of death; bereaved relatives' characteristics, beliefs, and expressions; behaviour of health and coordination staff; and family's emotional responses. Three global hypotheses related to bivariate and multivariate relations of factors with family decisions and relationships/interactions among factors were tested. RESULTS: Relatives' beliefs about the deceased's wishes concerning donation are the strongest predictor of family decisions. However, family decisions are also related to the deceased's characteristics, relatives' characteristics, satisfaction with medical attention, satisfaction with personal treatment and relatives' emotional responses, and other factors. Relatives' emotional reactions are related to satisfaction with health-staff interventions and condition family decision, even if deceased's will concerning donation is known and positive. Relatives' beliefs about deceased's wishes concerning donation vary as a function of deceased's characteristics and according to relatives' characteristics. CONCLUSIONS: Understanding of family decisions underlying organ donation may greatly benefit from a more complex, integrated, and theoretically based approach. Educational efforts should stress the need to register or simply communicate own willingness to donate organs. However, an adequate training and performance of the health-staff involved in the organ donation process may generate substantive differences in consent rates. PMID- 29631201 TI - "This baby came up and then he said, "I give up!": The interplay between unintended pregnancy, sexual partnership dynamics and social support and the impact on women's well-being in KwaZulu-Natal, South Africa. AB - BACKGROUND: Unintended pregnancy is associated with poor maternal and child health outcomes. To improve the health and wellbeing of women during the antenatal period, additional research in settings where unintended pregnancies are common is required to better understand the impact of the pregnancy on women's emotional health, relationships, and support structures. OBJECTIVE: To examine the personal, social and economic factors shaping the antenatal experiences of women in a resource-constrained setting with high rates of unintended pregnancy and HIV. RESEARCH DESIGN AND SETTING: Qualitative, semi structured interviews were conducted with 30 women from an urban informal settlement in KwaZulu-Natal, South Africa, who had given birth within the last six weeks. FINDINGS: Most participants (n = 27, 90%) reported that their pregnancy had not been planned. Unintended pregnancy marked a period of heightened stress and vulnerability for many participants due to increased financial strain, HIV status, and trauma associated with past or current violence. Family members and sexual partners could mitigate financial stress and be sources of emotional and material support during the antenatal period. However, participants frequently experienced increased instability and conflict in sexual partner and family relationships due to the unintended pregnancy, exacerbating women's stress. KEY CONCLUSIONS: A nuanced understanding of the factors shaping women's emotional responses to an unintended pregnancy may aid in identification of women who are most likely to experience high levels of antenatal stress and to prioritize these women for intervention in order to prevent associated poor maternal and child health outcomes. PMID- 29631202 TI - Neurochemical differences between bipolar disorder type I and II in superior temporal cortices: A proton magnetic resonance spectroscopy study. AB - BACKGROUND: Despite the diagnostic challenges in categorizing bipolar disorder subtypes, bipolar I and II disorders (BD-I and BD-II respectively) are valid indices for researchers. Subtle neurobiological differences may underlie clinical differences between mood disorder subtypes. The aims of this study were to investigate neurochemical differences between bipolar disorder subtypes. METHODS: Euthymic BD-II patients (n = 21) are compared with BD-I (n = 28) and healthy comparison subjects (HCs, n = 30). Magnetic Resonance Imaging (MRI) and proton spectroscopy (1H MRS) were performed on a 3T Siemens Tim Trio system. MRS voxels were located in the left/right superior temporal cortices, and spectra acquired with the single voxel Point REsolved Spectroscopy Sequence (PRESS). The spectroscopic data were analyzed with LCModel (Version 6.3.0) software. RESULTS: There were significant differences between groups in terms of glutamate [F = 6.27, p = 0.003], glutamate + glutamine [F = 6.08, p = 0.004], inositol containing compounds (Ino) (F = 9.25, p < 0.001), NAA [F = 7.63, p = 0.001] and creatine + phosphocreatine [F = 11.06, p < 0.001] in the left hemisphere and Ino [F = 5.65, p = 0.005] in the right hemisphere. Post-hoc comparisons showed that the BD-I disorder group had significantly lower metabolite levels in comparison to the BD-II and the HC groups. LIMITATIONS: This was a cross-sectional study with a small sample size. In addition, patients were on various psychotropic medications, which may have impacted the results. CONCLUSIONS: Neurochemical levels, in the superior temporal cortices, measured with 1H-MRS discriminated between BD-II and BD-I. Although further studies are needed, one may speculate that the superior temporal cortices (particularly left hemispheric) play a critical role, whose pathology may be related to subtyping bipolar disorder. PMID- 29631203 TI - Cognitive outcomes of TMS treatment in bipolar depression: Safety data from a randomized controlled trial. AB - BACKGROUND: Bipolar depression (BD) is a highly prevalent condition associated with marked cognitive deficits that persist even in the euthymic phase of the illness. Pharmacological treatments for BD might further aggravate cognitive impairment, highlighting the need of developing interventions that present cognitive safety. In this study, we evaluated the cognitive effects of H1-coil (deep) transcranial magnetic stimulation (TMS) in patients with treatment resistant bipolar depression. METHODS: Fourty-three patients were randomized to receive 20 sessions of active (55 trains, 18 Hz, 120% resting motor threshold intensity) or sham rTMS within a double-blind, sham-controlled trial. A battery of 20 neuropsychological assessments, grouped in 6 domains (attention and processing speed, working memory and executive function, inhibitory control, language, immediate verbal memory, and long-term verbal memory) was performed at baseline and after 4 and 8 weeks of trial onset. Depressive symptoms were assessed with the 17-item Hamilton Rating Scale for Depression. RESULTS: Cognitive improvement was shown for all cognitive domains. It occurred regardless of intervention group and depression improvement. For the language domain, greater improvement was observed in the sham group over time. No correlations between depression (at baseline or during treatment) and cognitive improvement were found. LIMITATIONS: Absence of healthy control group. CONCLUSION: The results of this exploratory study provide evidence on the cognitive safety of H1 coil TMS for BD patients. Putative pro-cognitive effects of rTMS in BD were not observed and thus should be further investigated. PMID- 29631205 TI - Glycosyl glycerides from the aerial parts of Malva verticillata and their chemopreventive effects. AB - A new glycosyl glyceride (5) along with twelve known ones (1-4 and 6-13) including two sulfoquinovosyl glycerides (1 and 2) were isolated from the aerial parts of Malva verticillata. Based on several spectroscopic methods, compound 5 was identified to be (2S)-1-O-beta-d-galactopyranosyl-3-O-isostearoyl glyceride, and named malvaglycolipid A. Compounds 1 and 2 contained a unique sugar, (6-deoxy 6-sulfo)-alpha-d-glucopyranose, which very rarely occurs in natural sources. This is the first report for the isolation of compounds 1 and 2 from natural sources and the structure determination using NMR experiment. It was also of note that no glycosyl glyceride has previously been isolated from the family of Malvaeae. Most glycosyl glycerides showed cytotoxicity to HepG2, AGS, HCT-15, and A549 human cancer cells. Especially, compounds 1, 2, and 11 exhibited significant cytotoxicity to AGS cells, with IC50 values of 33.7 +/- 0.64 MUM, 11.1 +/- 0.07 MUM, and 10.6 +/- 0.10 MUM, respectively. The n-BuOH fraction and compounds 1, 2, and 11 increased the number of apoptotic cells in the Tali assay and had a significant effect on the levels of proteins related to apoptosis including PARP, caspase-3, Bcl-2, Bax, and beta-actin. PMID- 29631204 TI - Social cognition moderates the relationship between neurocognition and community functioning in bipolar disorder. AB - BACKGROUND: Schizophrenia (SZ) studies suggest that neurocognition predicts functional outcome and that social cognition mediates this relationship. Bipolar disorder (BD) patients also have cognitive, social, and functional impairments but the relationship among these factors in BD is not well established. We assessed whether social cognition modulates the influence of neurocognition on community functioning in BD, as found in SZ. METHODS: 200 BD patients and 49 healthy controls (HC) were administered and compared on a battery of tests assessing neurocognition, social cognition, and community functioning. We conducted a series of regression analyses to investigate potential mediation or moderation of social cognition on the relationship between neurocognition and community functioning. RESULTS: BD patients performed worse on neurocognitive domains of processing speed, attention, verbal learning, and global neurocognition. Also, BD patients performed worse on theory of mind, the social cognition composite score, and community functioning. Neurocognition did not significantly predict functional outcome in our BD sample. However, we found a moderating effect of social cognition: among patients with poor social cognition, better neurocognition was associated with better community functioning, a relationship not seen in BD patients with good social cognition. LIMITATIONS: The study was limited by a relatively small HC group and assessing one subtype of functioning status. CONCLUSIONS: The relationship between neurocognition and community functioning in BD may be dependent on social cognition status, implying the presence of social cognitive heterogeneity. Results may be relevant to choosing proper treatment interventions depending on the patient's social cognitive level. PMID- 29631206 TI - The development of functional network organization in early childhood and early adolescence: A resting-state fNIRS study. AB - Early childhood (7-8 years old) and early adolescence (11-12 years old) constitute two landmark developmental stages that comprise considerable changes in neural cognition. However, very limited information from functional neuroimaging studies exists on the functional topological configuration of the human brain during specific developmental periods. In the present study, we utilized continuous resting-state functional near-infrared spectroscopy (rs fNIRS) imaging data to examine topological changes in network organization during development from early childhood and early adolescence to adulthood. Our results showed that the properties of small-worldness and modularity were not significantly different across development, demonstrating the developmental maturity of important functional brain organization in early childhood. Intriguingly, young children had a significantly lower global efficiency than early adolescents and adults, which revealed that the integration of the distributed networks strengthens across the developmental stages underlying cognitive development. Moreover, local efficiency of young children and adolescents was significantly lower than that of adults, while there was no difference between these two younger groups. This finding demonstrated that functional segregation remained relatively steady from early childhood to early adolescence, and the brain in these developmental periods possesses no optimal network configuration. Furthermore, we found heterogeneous developmental patterns in the regional nodal properties in various brain regions, such as linear increased nodal properties in the frontal cortex, indicating increasing cognitive capacity over development. Collectively, our results demonstrated that significant topological changes in functional network organization occurred during these two critical developmental stages, and provided a novel insight into elucidating subtle changes in brain functional networks across development. PMID- 29631207 TI - Controlled synthesis of mixed molecular nanostructures from folate and deferrioxamine-Ga(III) on gold and tuning their performance for cancer cells. AB - A new strategy is developed for construction of the mixed molecular nanostructures from folic acid (FOA), a targeting agent, and deferrioxamoine Ga(III), (DFO-Ga(III)), a theranostic agent, on gold-mercaptopropionic acid surface, Au-MPA. The strategy is focused to achieve a system in which all the active constituents of FOA; i.e., pteridine rings, p-aminobenzoeic acid, and the glutamic acid, having high affinity for folate receptor overexpressed on cancer cells; remain unreacted in adjacent to DFO-Ga(III), Au-MPA-[DFO-Ga(III)]||-[FOA]. For this purpose, the NH2 groups of FOA and DFO-Ga(III) were attached covalently and separately to COOH of Au-MPA surface allowing all the active groups of FOA to be available for drug delivery purposes. The data obtained through several electrochemical and surface analysis techniques, supported successful construction of the designed mixed molecular nanostructures system. In addition, the results showed that the system is stable, and Ga(III) ion does not leave DFO Ga(III) complex. The prepared surface was successfully tested for capturing of the breast cancer cells 4T1 as a model. The measurements showed a rapid uptake kinetics (t1/2 of ~6.0min) and efficient accessibility of the system by the cancer cells; the Rct was significantly increased in the presence of 4T1 cells compared with blank PBS (DeltaRct ~420kOmega). PMID- 29631208 TI - Construction of photo-driven bioanodes using thylakoid membranes and multi-walled carbon nanotubes. AB - A photo-driven bioanode was constructed using the thylakoid membrane from spinach, carbon nanotubes, and an artificial mediator. By considering a linear free-energy relationship in the electron transfer from the thylakoid membrane to the mediators, and the oxygen resistance of the reduced mediators, 1,2 naphthoquinone was selected as the most suitable mediator for the photo-driven bioanode. Water-dispersed multi-walled carbon nanotubes served as scaffolds to hold the thylakoid membrane on a porous electrode. The constructed photo-driven bioanode exhibited a photocurrent density of over 100MUAcm-2 at a photon flux density of 1500MUmolm-2s-1. PMID- 29631209 TI - Systematic review of maternal Placental Growth Factor levels in late pregnancy as a predictor of adverse intrapartum and perinatal outcomes. AB - AIM: This systematic review evaluates the utility of maternal Placental Growth Factor (PlGF) when measured in late pregnancy (>20 weeks) as a predictor of adverse obstetric and perinatal outcomes. METHODS: Pubmed and Embase were searched using the term "placental growth factor" in combination with relevant perinatal outcomes. Studies were included if they measured PlGF levels in pregnant women after 20 + 0 weeks gestation and reported relevant adverse obstetric or perinatal outcomes related to placental insufficiency (excluding pre eclampsia). RESULTS: Twenty-six studies were eligible for inclusion with 21 studies investigating the relationship between PlGF and small for gestational age (SGA) and 7 studies investigating PlGF for the prediction of other adverse perinatal outcomes. In all studies, maternal PlGF levels were significantly lower in the SGA group compared to controls. Other outcomes investigated included caesarean section (CS) for fetal compromise, low Apgar score, neonatal intensive care unit (NICU) admission, neonatal acidosis, stillbirth, and intrapartum fetal compromise. The results generally showed a significant association between low PlGF levels and CS for fetal compromise, NICU admission and stillbirth. CONCLUSION: Low maternal PlGF levels in late pregnancy are strongly associated with SGA. Findings across studies were variable in relation to PlGF and the prediction of other adverse intrapartum and perinatal outcomes, however there was a consistent association between low PlGF levels and CS for fetal compromise, NICU admission and stillbirth. This review suggests that the use of PlGF for the prediction of adverse outcomes is promising. Its predictive value may potentially be enhanced if used in combination with other biomarkers or biophysical measures of fetal well-being. PMID- 29631210 TI - Listeria monocytogenes strains show large variations in competitive growth in mixed culture biofilms and suspensions with bacteria from food processing environments. AB - Interactions and competition between resident bacteria in food processing environments could affect their ability to survive, grow and persist in microhabitats and niches in the food industry. In this study, the competitive ability of L. monocytogenes strains grown together in separate culture mixes with other L. monocytogenes (L. mono mix), L. innocua (Listeria mix), Gram-negative bacteria (Gram- mix) and with a multigenera mix (Listeria + Gram- mix) was investigated in biofilms on stainless steel and in suspensions at 12 degrees C. The mixed cultures included resident bacteria from processing surfaces in meat and salmon industry represented by L. monocytogenes (n = 6), L. innocua (n = 5) and Gram-negative bacteria (n = 6; Acinetobacter sp., Pseudomonas fragi, Pseudomonas fluorescens, Serratia liquefaciens, Stenotrophomonas maltophilia). Despite hampered in growth in mixed cultures, L. monocytogenes established in biofilms with counts at day nine between 7.3 and 9.0 log per coupon with the lowest counts in the Listeria + G- mix that was dominated by Pseudomonas. Specific L. innocua inhibited growth of L. monocytogenes strains differently; inhibition that was further enhanced by the background Gram-negative microbiota. In these multispecies and multibacteria cultures, the growth competitive effects lead to the dominance of a strong competitor L. monocytogenes strain that was only slightly inhibited by L. innocua and showed strong competitive abilities in mixed cultures with resident Gram-negative bacteria. The results indicates complex patterns of bacterial interactions and L. monocytogenes inhibition in the multibacteria cultures that only partially depend on cell contact and likely involve various antagonistic and bacterial tolerance mechanisms. The study indicates large variations among L. monocytogenes in their competitiveness under multibacterial culture conditions that should be considered in further studies towards understanding of L. monocytogenes persistence in food processing facilities. PMID- 29631211 TI - Tyramine and tyrosine decarboxylase gene contributes to the formation of cyanic blotches in the petals of pansy (Viola * wittrockiana). AB - Tyrosine decarboxylase (TYDC) can catalyze tyrosine into tyramine. Several studies demonstrated its roles in the acidity, salidroside and defense response. Here we found that TYDC from Viola * wittrockiana Gam (VwTYDC) may contribute to the formation of cyaninc blotches in the petal. VwTYDC gene were cloned from Viola * wittrockiana and the cDNA full-length sequences were 1634 bp encoding 494 amino acids. Gene expression of VwTYDC in different tissues and developmental stages showed that they were significantly higher expressed in flowers than stems, leaves and roots. In addition, VwTYDC expression were higher in cyanic blotches than those observed in acyanic blotches of petal. Metabolites analysis showed the contents of tyramine in cyanic blotches were also higher than that in acyanic areas. Furthermore, in vitro assay revealed the absorption peak of anthocyanins had a red shift and an increase when fed tyramine. We speculated that tyramine might contribute to flower color expression of pansy as co-pigment. Our study demonstrated for the first time that the contents of tyramine led to flower blotches formation in cyanic blotches of the petals in plant flowers, and this may due to the higher expression of VwTYDC gene. PMID- 29631212 TI - Transcriptome analysis of Jatropha curcas L. flower buds responded to the paclobutrazol treatment. AB - Jatropha seeds can be used to produce high-quality biodiesel due to their high oil content. However, Jatropha produces low numbers of female flowers, which limits seed yield. Paclobutrazol (PCB), a plant growth retardant, can increase number of Jatropha female flowers and seed yield. However, the underlying mechanisms of flower development after PCB treatment are not well understood. To identify the critical genes associated with flower development, the transcriptome of flower buds following PCB treatment was analyzed. Scanning Electron Microscope (SEM) analysis revealed that the flower developmental stage between PCB-treated and control flower buds was similar. Based on the presence of sex organs, flower buds at 0, 4, and 24 h after treatment were chosen for global transcriptome analysis. In total, 100,597 unigenes were obtained, 174 of which were deemed as interesting based on their response to PCB treatment. Our analysis showed that the JcCKX5 and JcTSO1 genes were up-regulated at 4 h, suggesting roles in promoting organogenic capacity and ovule primordia formation in Jatropha. The JcNPGR2, JcMGP2-3, and JcHUA1 genes were down-regulated indicating that they may contribute to increased number of female flowers and amount of seed yield. Expression of cell division and cellulose biosynthesis-related genes, including JcGASA3, JcCycB3;1, JcCycP2;1, JcKNAT7, and JcCSLG3 was decreased, which might have caused the compacted inflorescences. This study represents the first report combining SEM-based morphology, qRT-PCR and transcriptome analysis of PCB-treated Jatropha flower buds at different stages of flower development. PMID- 29631213 TI - Label-Free Quantitative Proteomics Unravels Carboxypeptidases as the Novel Biomarker in Pancreatic Ductal Adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers, with a high mortality rate and poor prognosis. However, little is known concerning the molecular mechanism of PDAC at the proteomics level. Here we report a proteomics analysis of PDAC tumor and adjacent tissues by shotgun proteomics followed by label-free quantification, and in total, 3031 and 3306 proteins were identified in three pairs of PDAC tumor and adjacent tissues, respectively; 40 of them were differentially expressed for at least three-fold in PDAC tumor tissues. Ontological and interaction network analysis highlighted the dysregulation of a set of four proteins in the carboxypeptidase family: carboxypeptidase A1 (CPA1), A2 (CPA2), B1 (CPB1), and chymotrypsin C (CTRC). Western blotting confirmed the downregulation of the carboxypeptidase network in PDAC. Immunohistochemistry of tissue microarray from 90 PDAC patients demonstrated that CPB1 was downregulated 7.07-fold (P<.0001, n=81) in tumor comparing with the peritumor tissue. Further 208 pancreatic tissues from PDAC tumor, peritumor, and pancreatis confirmed the downregulation of CPB1 in the PDAC patients. In summary, our results displayed that the expression of carboxypeptidase is significantly downregulated in PDAC tumor tissues and may be novel biomarker in the patient with PDAC. PMID- 29631214 TI - Identification of Prognostic Biomarkers by Combined mRNA and miRNA Expression Microarray Analysis in Pancreatic Cancer. AB - Pancreatic cancer is the fourth leading cause for cancer-related death, and early diagnosis is one key to improve the survival rate of this disease. Molecular biomarkers are an important method for diagnostic use in pancreatic cancer. We used data from three mRNA microarray datasets and a microRNA dataset (GSE16515, GSE15471, GSE28735, and GSE41372) to identify potential key genes. Differentially expressed genes (DEGs) and microRNAs (DEMs) were identified. Functional, pathway enrichment, and protein-protein interaction analyses were performed on common DEGs across all datasets. The target genes of the DEMs were identified. DEMs targets that were also DEGs were further scrutinized using overall survival analysis. A total of 236 DEGs and 21 DEMs were identified. There were a total of four DEGs (ECT2, NR5A2, NRP2, and TGFBI), which were also predicted target genes of DEMs. Overall survival analysis showed that high expression levels of three of these genes (ECT2, NRP2, and TGFBI) were associated with poor overall survival for pancreatic cancer patients. The basic expression of DEGs in pancreas stood lower level in various organ tissues. The expression of ECT2 and NRP2 was higher in different pancreatic cancer cell lines than normal pancreas cell line. Knockout of ECT2 by Crispr Cas9 gene editing system decreased proliferation and migration ability in pancreatic cancer cell line MiaPaCa2. In conclusion, we think that data mining method can do well in biomarker screening, and ECT2 and NRP2 can play as potential biomarker or therapy target by Crispr Cas9 in pancreatic cancer. PMID- 29631216 TI - Psychosocial factors associated with intended use of automated vehicles: A simulated driving study. AB - This study applied the Theory of Planned Behavior (TPB) and the Technology Acceptance Model (TAM) to assess drivers' intended use of automated vehicles (AVs) after undertaking a simulated driving task. In addition, this study explored the potential for trust to account for additional variance to the psychosocial factors in TPB and TAM. Seventy-four participants (51% female) aged between 25 and 64 years (M = 42.8, SD = 12.9) undertook a 20 min simulated experimental drive in which participants experienced periods of automated driving and manual control. A survey task followed. A hierarchical regression analysis revealed that TPB constructs; attitude toward the behavior, subjective norms, and perceived behavioral control, were significant predictors of intentions to use AV. In addition, there was partial support for the test of TAM, with ease of use (but not usefulness) predicting intended use of AV (SAE Level 3). Trust contributed variance to both models beyond TPB or TAM constructs. The findings provide an important insight into factors that might reflect intended use of vehicles that are primarily automated (longitudinal, lateral, and manoeuvre controls) but require and allow drivers to have periods of manual control. PMID- 29631215 TI - Caloric restriction mitigates age-associated hippocampal differential CG and non CG methylation. AB - Brain aging is marked by cognitive decline and susceptibility to neurodegeneration. Calorie restriction (CR) increases neurogenesis, improves memory function, and protects from age-associated neurological disorders. Epigenetic mechanisms, including DNA methylation, are vital to normal central nervous system cellular and memory functions and are dysregulated with aging. The beneficial effects of CR have been proposed to work through epigenetic processes, but this is largely unexplored. We therefore tested whether life long CR prevents age-related hippocampal DNA methylation changes. Hippocampal DNA from young (3 months) and old (24 months) male mice fed ad libitum and 24-month-old mice fed a 40% calorie-restricted diet from 3 months of age were examined by genome-wide bisulfite sequencing to measure methylation with base specificity. Over 27 million CG and CH (non-CG) sites were examined. Of the ~40,000 differentially methylated CG and ~80,000 CH sites with aging, >1/3 were prevented by CR and were found across genomic regulatory regions and gene pathways. CR also caused alterations to CG and CH methylation at sites not differentially methylated with aging, and these CR-specific changes demonstrated a different pattern of regulatory element and gene pathway enrichment than those affected by aging. CR specific DNA methyltransferase 1 and Tet methylcytosine dioxygenase 3 promoter hypermethylation corresponded to reduced gene expression. These findings demonstrate that CR attenuates age-related CG and CH hippocampal methylation changes, in combination with CR-specific methylation that may also contribute to the neuroprotective effects of CR. The prevention of age-related methylation alterations is also consistent with the prolongevity effects of CR working through an epigenetic mechanism. PMID- 29631217 TI - High-throughput assessment of oxidative respiration in fish embryos: Advancing adverse outcome pathways for mitochondrial dysfunction. AB - Mitochondrial dysfunction is a prevalent molecular event that can result in multiple adverse outcomes. Recently, a novel high throughput method to assess metabolic capacity in fish embryos following exposure to chemicals has been adapted for environmental toxicology. Assessments of oxygen consumption rates using the Seahorse XF(e) 24/96 Extracellular Flux Analyzer (Agilent Technologies) can be used to garner insight into toxicant effects at early stages of development. Here we synthesize the current state of the science using high throughput metabolic profiling in zebrafish embryos, and present considerations for those wishing to adopt high throughput methods for mitochondrial bioenergetics into their research. Chemicals that have been investigated in zebrafish using this metabolic platform include herbicides (e.g. paraquat, diquat), industrial compounds (e.g. benzo-[a]-pyrene, tributyltin), natural products (e.g. quercetin), and anti-bacterial chemicals (i.e. triclosan). Some of these chemicals inhibit mitochondrial endpoints in the MUM-mM range, and reduce basal respiration, maximum respiration, and spare capacity. We present a theoretical framework for how one can use mitochondrial performance data in zebrafish to categorize chemicals of concern and prioritize mitochondrial toxicants. Noteworthy is that our studies demonstrate that there can be considerable variation in basal respiration of untreated zebrafish embryos due to clutch-specific effects as well as individual variability, and basal oxygen consumption rates (OCR) can vary on average between 100 and 300 pmol/min/embryo. We also compare OCR between chorionated and dechorionated embryos, as both models are employed to test chemicals. After 24 h, dechorionated embryos remain responsive to mitochondrial toxicants, although they show a blunted response to the uncoupling agent carbonylcyanide-4-trifluoromethoxyphenylhydrazone (FCCP); dechorionated embryos are therefore a viable option for investigations into mitochondrial bioenergetics. We present an adverse outcome pathway framework that incorporates endpoints related to mitochondrial bioenergetics. High throughput bioenergetics assays conducted using whole embryos are expected to support adverse outcome pathways for mitochondrial dysfunction. PMID- 29631218 TI - Phase behaviour, micellar structure and linear rheology of tetrablock copolymer Tetronic 908. AB - Tetronics are X-shaped block-copolymers of polyethylene oxide and polypropylene oxide, which self-assemble into micelles and can undergo a sol-gel transition; these transitions are dependent on temperature, concentration but also pH, due to the central diamine group of the tetrablock. We report the nanoscale morphologies underlying these different phases and the rheology of the systems for a very large, highly hydrophilic block copolymer, Tetronic 908, through the combined use of oscillatory rheology, steadyblock-state and time-resolved fluorescence, small angle neutron scattering (SANS), dynamic light scattering (DLS) and Fourier transform infrared attenuated total reflectance (FTIR-ATR). At low concentrations, SANS reveal core-shell micelles of ca. 10 nm radius, presenting a dehydrated core and a highly hydrated shell, with relatively small aggregation numbers (Nagg ~ 13). The micelles are notably affected by the pH, due to the protonation of the central amine spacer at low pH (pH ~ 2), which shifts micellization to higher temperature, with smaller micelles than at natural pH. In the intermediate concentration regime (10-15%), micelles become smaller (Nagg ~ 5), and present a higher hydration of the core. In the high concentration regime, Tetronic 908 undergoes a sol-gel transition above a threshold temperature, which is fully inhibited at acidic pH. SANS data from the gel phase reveal a BCC order of tightly packed spheres. Temperature sweeps in oscillatory rheology show a shift of the onset of gelation towards lower temperatures as concentration increases, an increase in the elastic modulus G' and an expansion of gel region over a larger range of temperatures. SANS and rheology reveal that at pH below the natural pH (ca. 8), gelation is shifted to higher temperatures, but the morphology of the gels is similar, while under highly acidic conditions the gelation is fully suppresed. PMID- 29631219 TI - Rapid and tunable selective adsorption of dyes using thermally oxidized nanodiamond. AB - In the present study, capability of nanodiamond (ND) for the adsorption of anionic (methyl orange, MO) and cationic (methylene blue, MB) dyes from aqueous solution was investigated. Employing fourier transform infrared (FTIR) spectroscopy, Boehm titration method and zeta potential, it was found that the simple thermal oxidation of ND at 425 degrees C, increased the content of carboxylic acid of ND and accordingly the zeta potential of ND decreased considerably. Therefore, a series of oxidized NDs (OND) at various oxidation times and as-received untreated ND (UND) was used as adsorbents of MO and MB. The adsorption experiments exhibited that UND had large adsorption capacity, very fast adsorption kinetics and excellent selectivity for MO over MB. These results suggested that the adsorption tendency of UND toward anionic MO dye followed not only by electrostatic interactions but also via the chemical interaction caused by the strong hydrogen bond between the sulfonate groups of MO and the oxygen containing groups on the surface of UND. In contrast, ONDs exhibited higher adsorption capacity for cationic MB whose tendency toward MB increased by increasing the thermal oxidation time due to the promotion of the negative charge on the surface of OND leading to the higher electrostatic attraction. The adsorption rate of MB on ONDs was also very high. Kinetics data was well fitted with the pseudo- second-order model for most of the adsorbents. The adsorption selectivity analysis revealed that ONDs displayed more adsorption capacity for MB compared with MO which was also attributed to high electrostatic interactions of cationic dye with negative charges of ONDs. Finally, the release behavior of NDs was also demonstrated after soaking in ethanol and acetone. PMID- 29631220 TI - In situ structural study of the surface complexation of lead(II) on the chemically mechanically polished hematite (11-02) surface. AB - A structural study of the surface complexation of Pb(II) on the (11-02) surface of hematite was undertaken using crystal truncation rod (CTR) X-ray diffraction measurements under in situ conditions. The sorbed Pb was found to form inner sphere (IS) complexes at two types of edge-sharing sites on the half layer termination of the hematite (11-02) surface. The best fit model contains Pb in distorted trigonal pyramids with an average PbO bond length of 2.27(4) A and two characteristic Pb-Fe distances of 3.19(1) A and 3.59(1) A. In addition, a site coverage model was developed to simulate coverage as a function of sorbate sorbate distance. The simulation results suggest a plausible Pb-Pb distance of 5.42 A, which is slightly larger than the diameter of Pb's first hydration shell. This relates the best fit surface coverage of 0.59(4) Pb per unit cell at monolayer saturation to steric constraints as well as electrostatic repulsion imposed by the hydrated Pb complex. Based on the structural results we propose a stoichiometry of the surface complexation reaction of Pb(II) on the hematite (11 02) surface and use bond valence analysis to assign the protonation schemes of surface oxygens. Surface reaction stoichiometry suggests that the proton release in the course of surface complexation occurs from the Pb-bound surface O atoms at pH 5.5. PMID- 29631221 TI - pH-sensitive charge-conversional and NIR responsive bubble-generating liposomal system for synergetic thermo-chemotherapy. AB - A charge-conversional and NIR responsive rapid release liposomal system (PSD/DOX/Cypate-BTSL) was developed to enhance therapeutic efficacy of cancer therapy. The cationic liposomes containing Cypate, doxorubicin (DOX) and NH4HCO3 were shielded by pH-sensitive poly(methacryloyl sulfadimethoxine) (PSD) through electrostatic interaction at pH 7.4. At the tumor site (pH 6.5), PSD was deshielded and the liposomes displayed pH-sensitive charge reversal capability. The DOX released from PSD/DOX/Cypate-BTSL with irradiation was markedly higher than the other groups, indicating NIR irradiation and NH4HCO3 had a significant effect on the drug release. After irradiation, the hyperthermia induced by Cypate could produce CO2 bubbles quickly on account of the decomposition of NH4HCO3, achieving the rapid drug release. In 4T1 cells, PSD/DOX/Cypate-BTSL improved cellular uptake and cytotoxicity with irradiation at pH 6.5. In vivo results implied that the liposomes with irradiation could efficiently enhance the tumor accumulation and antitumor efficacy, and reduce systemic side effects of DOX. In conclusion, PSD/DOX/Cypate-BTSL is a promising candidate as a carrier for synergistic effects of PTT and chemotherapy. PMID- 29631222 TI - Synthesis and properties of a biodegradable polymer-drug conjugate: Methotrexate poly(glycerol adipate). AB - Polymer-drug conjugates have been actively developed as potential anticancer drug delivery systems. In this study, we report the first polymer-anticancer drug conjugate with poly(glycerol adipate) (PGA) through the successful conjugation of methotrexate (MTX). MTX-PGA conjugates were controllably and simply fabricated by carbodiimide-mediated coupling reaction with various high molar ratios of MTX. The MTX-PGA conjugate self-assembled into nanoparticles with size dependent on the amount of conjugated MTX and the pH of medium. Change in particle size was attributed to steric hindrance and bulkiness inside the nanoparticle core and dissociation of free functional groups of the drug. The MTX-PGA nanoparticles were physically stable in media with pH range of 5-9 and ionic strength of up to 0.15 M NaCl and further chemically stable against hydrolysis in pH 7.4 medium over 30 days but enzymatically degradable to release unchanged free drug. Although 30%MTX-PGA nanoparticles exhibited only slightly less potency than free MTX in 791T cells in contrast to previously reported human serum albumin-MTX conjugates which had >300 times lower potency than free MTX. However, the MTX nanoparticles showed 7 times higher toxicity to Saos-2 cells than MTX. Together with the enzymic degradation experiments, these results suggest that with a suitable biodegradable polymer a linker moiety is not a necessary component. These easily synthesised PGA drug conjugates lacking a linker moiety could therefore be an effective new pathway for development of polymer drug conjugates. PMID- 29631223 TI - Combined effects of warming and acidification on accumulation and elimination dynamics of paralytic shellfish toxins in mussels Mytilus galloprovincialis. AB - Harmful algal blooms (HAB) have been increasing in frequency and intensity most likely due to changes on global conditions, which constitute a significant threat to wild shellfish and its commercial farming. This study evaluated the impact of increasing seawater temperature and acidification on the accumulation/elimination dynamics of HAB-toxins in shellfish. Mytilus galloprovincialis were acclimated to four environmental conditions simulating different climate change scenarios: i) current conditions, ii) warming, iii) acidification and iv) interaction of warming with acidification. Once acclimated, mussels were exposed to the paralytic shellfish toxins (PSTs) producing dinoflagellate Gymnodinium catenatum for 5 days and to non-toxic diet during the subsequent 10 days. High toxicity levels (1493 ug STX eq. kg-1) exceeding the safety limits were determined under current conditions at the end of the uptake period. Significantly lower PSP toxicity levels were registered for warming- and acidification-acclimated mussels (661 and 761 ug STX eq. kg-1). The combined effect of both warming and acidification resulted in PSP toxicity values slightly higher (856 MUg STX eq. kg 1). A rapid decrease of toxicity was observed in mussels at the current conditions after shifting to a non-toxic diet, which was not noticed under the predicted climate change scenarios. Variability of each PST analogue, measured throughout the experiment, highlighted different mechanisms are associated with changes of each environmental factor, although both resulting in lower toxicity. Warming-acclimated mussels showed lower accumulation/elimination rates, while acidification-acclimated mussels showed higher capability to accumulate toxins, but also a higher elimination rate preventing high toxicity levels. As different mechanisms are triggered by warming and acidification, their combined effect not leads to a synergism of their individual effects. The present work is the first assessing the combined effect of climate change drivers on accumulation/elimination of PSTs, in mussels, indicating that warming and acidification may lead to lower toxicity values but longer toxic episodes. PSTs are responsible for the food poisoning syndrome, paralytic shellfish poisoning (PSP) in humans. This study can be considered as the first step to build models for predicting shellfish toxicity under climate change scenarios. PMID- 29631224 TI - Cytotoxicity measurement of Bisphenol A (BPA) and its substitutes using human keratinocytes. AB - Bisphenol-A (BPA) was first synthesized in the 1890s and has been used in many plastic products. However, BPA is known to act as an endocrine disruptor and has been found to be toxic to human health. Many alternative substances have been developed to replace BPA, but it is still widely used worldwide. In this study, we identified the potential cytotoxicity of BPA by evaluating toxicity using human keratinocytes. Also, we evaluated cytotoxicity of BPA substitutes to determine their suitability as an alternative to BPA. The proliferation assay using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, flow cytometry and western blot analysis showed that BPA significantly affect cell viability, induction of apoptotic fraction and increased activation of DNA-damage marker protein. In addition, through the same experiments, the substitutes of BPA were shown to be significantly less toxic than BPA, and the least toxicity was observed with 1,4-cyclohexanedimethanol (CHDM) and terephthalic acid (TPA). In conclusion, this study suggests that cytotoxicity of BPA induces apoptosis of human keratinocytes, and that CHDM and TPA are the most suitable substitutes for BPA. PMID- 29631225 TI - Relationships between physical-geographical factors and soil degradation on agricultural land. AB - It is a well-known fact that soil degradation is dramatically increasing and currently threatens agricultural soils all around the world. The objective of this study was to reveal the possible connection between soil degradation and seven physical-geographical factors - slope steepness, altitude, elevation differences, rainfall, temperature, soil texture and solar radiation - in the form of threshold values (if these exist), where soil degradation begins and ends. The analysis involved the whole area of the Czech Republic which consists of 13,027 cadasters (78,866 km2). The greatest total degradation threat occurs in areas with slope steepness >7 degrees, average annual temperature <5.9 degrees C, elevation differences >10.54, altitude >766 m a.s.l. Similarly, the results for water erosion, wind erosion, soil compaction, loss of organic matter, acidification and heavy metal contamination were processed. The results enable us to identify the relationships of different levels of threats which could consequently be used in various ways - for classification of threatened areas, for more effective implementation of anti-degradation measures, or purely for a better understanding of the role of physical geographical factors in soil degradation in the Czech Republic, and thus could increase the chances of reducing vulnerability to land degradation not only in the Czech Republic. PMID- 29631226 TI - Diurnal temperature range in relation to death from stroke in China. AB - BACKGROUND: Stroke is the second leading cause of death in the world. It has multiple risk factors of which some, such as ambient temperature, are less well documented. OBJECTIVE: We aimed to examine the association between diurnal temperature range (DTR) and stroke mortality, and to test the possible effect modification of this association according to gender, age and educational level. METHODS: Daily data on weather and stroke mortality from 16 provincial capital cities in China for the years 2007-2013 were obtained, with a total of 788,783 deaths from stroke. A quasi-Poisson generalized linear regression combined with a distributed lag non-linear model was used to examine the city-specific DTR effect on stroke mortality. The pooled effects of DTR on stroke mortality were then obtained using a meta-analysis, which was based on restricted maximum likelihood estimation. RESULTS: The DTR impacts were generally limited to a period of eight days, while significant effects during lag 0-8 days were only found in the cities of Beijing, Zhengzhou, Nanjing, Hefei, Chongqing and Changsha. The DTR effects were significantly and negatively associated with latitudes at lag 0-10 days (rs = - 0.640, P = 0.008). An increase of 1 degrees C in DTR was associated with pooled estimate of 0.66% (95%CI: 0.28-1.05%), 0.12% (- 0.26% to 0.51%) and 0.67% (0.26-1.07%) increases in stroke mortality at lag 0-10 days during the total, hot and cold days, respectively. The impact of DTR was much higher in southern China than in northern China [1.02% (0.62% to 1.43%) versus 0.10% (-0.27% to 0.47%) ]. For the individual characteristics, only females, the elderly aged >= 65 years, and those with lower educational attainment were vulnerable to DTR. CONCLUSIONS: DTR has considerable effects on risk of mortality from stroke in various cities in China, especially among the elderly, females, those with low educational level, and people living in southern China. The results can inform decisions on developing programs to protect vulnerable subpopulations from adverse impacts of DTR. PMID- 29631227 TI - Formulation of vitamin D encapsulated cinnamon oil nanoemulsion: Its potential anti-cancerous activity in human alveolar carcinoma cells. AB - Cinnamon oil is used for medicinal purpose since ancient time because of its antioxidant activity. Oil-in-water nanoemulsion (NE) of cinnamon oil was formulated using cinnamon oil, nonionic surfactant Tween 80 and water by ultrasonication technique. Phase diagram was constructed to investigate the influence of oil, water and surfactant concentration. Vitamin D encapsulated cinnamon oil NE was fabricated by wash out method followed by ultrasonication in similar fashion. The hydrodynamic size of cinnamon oil NE and vitamin D encapsulated cinnamon oil NE was observed as 40.52 and 48.96 nm in complete DMEM F12 media respectively. We focused on the cytotoxic and genotoxic responses of NEs in A549 cells in concentration dependent manner. We observed that both NEs induce DNA damage along with corresponding increase in micronucleus frequency that is evident from the comet and CBMN assay. Both the NEs arrested the cell cycle progression in G0/G1 phase, showed increased expression of Bax, capase-3 and caspase-9 and decrease expression of BcL2 proteins along with significant (p < 0.05) increase in apoptotic cell population and loss of mitochondrial membrane potential. NEs were also evaluated for bactericidal efficacy against E. coli. Thus, both NEs have cytotoxic, genotoxic and antibacterial potential and hence can also be used in food industry with cinnamon oil as carrier for lipophilic nutraceutical like vitamin D. PMID- 29631228 TI - Region-specific foot pain and plantar pressure in people with rheumatoid arthritis: A cross-sectional study. AB - BACKGROUND: It is unclear whether region-specific foot pain may influence plantar pressure in people with established rheumatoid arthritis. The aim was to determine the association between region-specific foot pain and region-specific plantar pressure. METHODS: Twenty-one people with rheumatoid arthritis and 19 age and sex-matched controls participated in this study. Self-reported foot pain in the toes, forefoot, midfoot and rearfoot was assessed using foot diagrams. Peak pressure and pressure time integrals for the toes, forefoot, midfoot and rearfoot were calculated using a pressure mat system. Differences in foot pain and pressure between the groups were calculated using appropriate regression models. To determine associations between region-specific pain and pressure, linear regression models were used while adjusting for body mass and participant group. FINDINGS: Participants with rheumatoid arthritis were primarily elderly female with long disease duration. Compared to controls, participants with rheumatoid arthritis had higher odds of foot pain at the toes (Odds Ratio (OR) = 10.4, P = 0.001), forefoot (OR = 6.3, P = 0.006) and rearfoot (OR = 10.1, P = 0.011). Participants with RA had higher peak pressure at the rearfoot (P = 0.003) and higher pressure time integrals at the forefoot (P = 0.005), midfoot (P = 0.016) and rearfoot (P < 0.001). After adjusting for body mass and participant group, peak pressure was significantly higher at the toes in those with midfoot pain and rearfoot pain. INTERPRETATION: People with rheumatoid arthritis experience region wide foot pain and demonstrate differences in pressure distribution compared to people without rheumatoid arthritis. Foot pain at the midfoot and rearfoot is also associated with increases in plantar pressure at the toes. PMID- 29631229 TI - Left adrenal ganglioneuroma: Report of a new case. AB - INTRODUCTION: Adrenal ganglioneuroma (AGN) represents about 20% of the reported cases. PRESENTATION OF CASE: We present a 37-year-old man referred to our institution for a history of abdominal discomfort and a left adrenal solid mass incidentally discovered in CT abdominal scan (24 * 20 mm). Patient underwent laparoscopic surgical excision of the tumor. CONCLUSION: The histopathology examination showed areas of spindle cells and scattered mature ganglionic cells compatible with AGN. PMID- 29631230 TI - 3-D segmentation of lung nodules using hybrid level sets. AB - Lung nodule segmentation in CT images and its subsequent volume analysis can help determine the malignancy status of a lung nodule. While several efficient segmentation schemes have been proposed, only a few studies evaluated the segmentation's performance for large nodules. In this research, we contribute a semi-automatic system which is capable of performing robust 3-D segmentations on both small and large nodules with good accuracy. The target CT volume is de noised with an anisotropic diffusion filter and a region of interest is selected around the target nodule on a reference slice. The proposed model performs nodule segmentation by incorporating a mean intensity based threshold in Geodesic Active Contour model in level sets. We also devise an adaptive technique using image intensity histogram to estimate the desired mean intensity of the nodule. The proposed system is validated on both lung nodules and phantoms collected from publicly available diverse databases. Quantitative and visual comparative analysis of the proposed work with the Chan-Vese algorithm and statistic active contour model of 3D Slicer platform is also presented. The resulting mean spatial overlap between segmented nodules and reference nodules is 0.855, the mean volume bias is 0.10+/-0.2 ml and the algorithm repeatability is 0.060 ml. The achieved results suggest that the proposed method can be used for volume estimations of small as well as large-sized nodules. PMID- 29631231 TI - Linking source characterisation and human health risk assessment of metals to rainfall characteristics. AB - Metals deposited on urban road surfaces and incorporated in stormwater runoff are discharged into receiving waters, influencing their quality and can pose human health risks. Effective design of stormwater treatment measures is closely dependent on the in-depth understanding of stormwater pollutant sources and the associated health risks. The study discussed in this paper has linked the sources of metals in stormwater runoff and the accompanying human health risk to rainfall characteristics. The study outcomes confirmed that the metal contributions to stormwater runoff from the primary sources were in the order of sea salt > soil > traffic. Although traffic contributes a relatively lower percentage to wash-off, the human health risks posed by traffic sourced metals were relatively much higher. This implies that traffic sources should receive particular attention in treating stormwater. These outcomes have the potential to contribute to enhancing effective source control measures in order to safeguard natural waterways from polluted road wash-off. PMID- 29631232 TI - How do people in different places experience different levels of air pollution? Using worldwide Chinese as a lens. AB - Air pollution, being especially severe in the fast-growing developing world, continues to post a threat to public health. Yet, few studies are capable of quantifying well how different groups of people in different places experience different levels of air pollution at the global scale. In this paper, we use worldwide Chinese as a lens to quantify the spatiotemporal variations and geographic differences in PM2.5 exposures using unprecedented mobile phone big data and air pollution records. The results show that Chinese in South and East Asia suffer relatively serious PM2.5 exposures, where the Chinese in China have the highest PM2.5 exposures (52.8 MUg/m3/year), which is fourfold higher than the exposures in the United States (10.7 MUg/m3/year). Overall, the Chinese in Asian cities (35.5 MUg/m3/year) experienced the most serious PM2.5 exposures when compared with the Chinese in the cities of other continents. These results, partly presented as a spatiotemporally explicit map of PM2.5 exposures for worldwide Chinese, help researchers and governments to consider how to address the effects of air pollution on public health with respect to different population groups and geographic locations. PMID- 29631233 TI - Comparison of the impacts of acid and nitrogen additions on carbon fluxes in European conifer and broadleaf forests. AB - Increased reactive nitrogen (N) loadings to terrestrial ecosystems are believed to have positive effects on ecosystem carbon (C) sequestration. Global "hot spots" of N deposition are often associated with currently or formerly high deposition of sulphur (S); C fluxes in these regions might therefore not be responding solely to N loading, and could be undergoing transient change as S inputs change. In a four-year, two-forest stand (mature Norway spruce and European beech) replicated field experiment involving acidity manipulation (sulphuric acid addition), N addition (NH4NO3) and combined treatments, we tested the extent to which altered soil solution acidity or/and soil N availability affected the concentration of soil dissolved organic carbon (DOC), soil respiration (Rs), microbial community characteristics (respiration, biomass, fungi and bacteria abundances) and enzyme activity. We demonstrated a large and consistent suppression of soil water DOC concentration driven by chemical changes associated with increased hydrogen ion concentrations under acid treatments, independent of forest type. Soil respiration was suppressed by sulphuric acid addition in the spruce forest, accompanied by reduced microbial biomass, increased fungal:bacterial ratios and increased C to N enzyme ratios. We did not observe equivalent effects of sulphuric acid treatments on Rs in the beech forest, where microbial activity appeared to be more tightly linked to N acquisition. The only changes in C cycling following N addition were increased C to N enzyme ratios, with no impact on C fluxes (either Rs or DOC). We conclude that C accumulation previously attributed solely to N deposition could be partly attributable to their simultaneous acidification. PMID- 29631234 TI - Abundance, composition, and distribution of microplastics larger than 20 MUm in sand beaches of South Korea. AB - To support microplastic management, the abundance, composition, and spatial distribution of microplastics on a national scale must be known. Hence, we studied the baseline level of microplastic pollution at 20 sandy beaches along the South Korean coast. All microplastic particles extracted from the sand samples were identified down to 20 MUm in size using Fourier transform infrared spectroscopy. The abundances of large microplastics (L-MPs; 1-5 mm) and small microplastics (S-MPs; 0.02-1 mm) were in the range of 0-2088 n/m2 and 1400-62800 n/m2, respectively. Maximum microplastic abundance was in the size range of 100 150 MUm, and particles smaller than 300 MUm accounted for 81% of the total abundance. Expanded polystyrene (EPS) accounted for 95% of L-MPs, whereas S-MPs were predominantly composed of polyethylene (49%) and polypropylene (38%). The spatial distribution of L-MPs, excluding EPS, was significantly related to population, precipitation, proximity to a river mouth and abundance of macroplastic debris on beach. However, there were no relationships between S-MPs and other environmental and source-related factors, except for macroplastic debris and L-MPs excluding EPS. These results imply that S-MPs are mainly produced on beaches by weathering, whereas L-MPs other than EPS are mainly introduced from land-based sources and are also partly produced on beaches. PMID- 29631235 TI - A life cycle assessment of liquid pig manure transport in line with EU regulations: A case study from Germany. AB - The transport of excess manure to crop farming systems is a core measure of livestock farmers to comply with environmental regulations like the EU Nitrates Directive. The German implementation of the directive has recently been revised and will lead to a distinct increase of manure transport. We quantify the environmental impact of 1 m3 of pig manure excreted in scenarios with and without manure transport by life cycle assessment, focusing on farming systems in North West Germany. Furthermore, we assess how the environmental impact is linked to the regulation which is causing the transport. Compared to a reference scenario without transport, manure transport lowers all assessed impact categories and no trade-off between environmental impacts is found. Major reductions are realized for global warming (39%), freshwater (61%) and marine eutrophication (54%) as well as particulate matter formation (10%). Furthermore, the depletion of fossil fuels and phosphate is lowered. Reductions are mainly caused by an increase of nutrient use efficiency and the savings in chemical fertilizer. However, in a scenario where manure transport is caused by strict regulations regarding phosphate, needed nitrogen leaves the exporting farm likewise and chemical fertilizer use rises at the exporting farm. Caused by the increased fertilizer use, the positive environmental effect of manure transport diminishes, even leading to a rise of fossil fuel depletion by 20% and slight rise of global warming potential by 3%. However, we find that the use of lorries which combine manure and grain transport and, thereby, reduce empty drives, can prevent this trade-off. Our results show the potential of manure transport to reduce the environmental burden caused by the geographical concentration of livestock production. However, the impact of manure transport on global warming and fossil fuel depletion highly depends on the transport distance. Agronomic measures are needed to prevent the increase of chemical N fertilizer use on the exporting farms and policy makers should be aware of possible trade-offs between strict regulations regarding phosphorus and fossil fuel depletion. PMID- 29631236 TI - l-cysteine intercalated layered double hydroxide for highly efficient capture of U(VI) from aqueous solutions. AB - l-cysteine intercalated Mg/Al layered double hydroxide (Cys-LDH) composites were fabricated and applied for treating the U(VI) contaminated wastewater under various conditions. Interaction mechanisms and adsorption properties were investigated by using batch experiments with spectroscopy analysis. The adsorption isotherms and kinetics were fitted perfectly with the Langmuir isotherm and the pseudo-second-order model, respectively. The significant maximum adsorption capacity of Cys-LDH (211.58 mg/g) compared to LDH was attributed to the larger number of functional groups on Cys-LDH. The presence of humic acid (HA) decreased U(VI) elimination on Cys-LDH at high pH but increased U(VI) removal at low pH. Typically, the presence of various anions (such as NO3-, Cl-, ClO4- and SO42-) did not obviously affect U(VI) adsorption on Cys-LDH, while the coexisted CO32- significantly affected U(VI) elimination. The predominate adsorption were determined to be the formation of Cys-U(VI)-Cys complexes with cysteine in the Cys-LDH interlayers. The results demonstrated that the Cys-LDH are promising adsorbents for efficient elimination and extraction of radionuclides in actual environmental contamination management. PMID- 29631237 TI - Deep exploitation of refractory organics in anaerobic dynamic membrane bioreactor for volatile fatty acids production from sludge fermentation: Performance and effect of protease catalysis. AB - Volatile fatty acids (VFAs) production from waste activated sludge fermentation could be improved in anaerobic dynamic membrane bioreactor (ADMBR) by retaining residual organics within the reactor and prolonging their reaction time. However, the accumulation of refractory organics made it operate unstably. Therefore, protease catalysis was adopted to deeply exploit those refractory organics in sludge. By combining with dynamic membrane retention, protease catalysis indeed presented a good performance. VFAs yield was further enhanced by over 40% in ADMBR. Membrane fouling was slightly relieved due to protein and polysaccharide degradations in the sludge of dynamic membrane. It was also interestingly found that not only protease activity of sludge was improved from 5 to 21 U/ml, but also beta-GLC activity was enhanced from 13 to 20 MUmoL/L/h. Microbial community analysis showed protease addition could reduce bacterial richness and evenness in sludge, and accelerate the growth of polysaccharides-hydrolyzing bacteria, as well as inhibit some proteolytic bacteria. PMID- 29631238 TI - Extending the SLEUTH model to integrate habitat quality into urban growth simulation. AB - This study aims to support sustainable urban and environmental planning by using urban growth simulation models, in which environmental quality is employed as one of the inputs. We proposed an extended SLEUTH urban growth model (UGM) for the regions threatened by environmental quality degradation caused by uncontrolled urban expansion. In this model, habitat quality is assessed by the InVEST model and is used to represent environmental quality, which is utilized in urban growth simulation. The habitat quality map is used to replace the slope layer as input for the SLEUTH model's urban growth simulation for cities where relatively flat topography makes this layer of minimal explanatory value. The extended SLEUTH UGM was calibrated using data for Changzhou city, China in 1990, 2000, 2010, and 2014. The best value of the Optimal SLEUTH Metric (OSM) was calculated for both the standard SLEUTH UGM and the extended SLEUTH UGM independently. The OSM value for the latter model was much higher than that of the former model, which indicated that the extended model provided a better explanation of urban growth in the study area. The calibrated extended SLEUTH UGM was applied to predict growth in Changzhou city from 2014 to 2030. The result showed that the urban area is expected to expand about 626 km2 by 2030. Comparison with the prediction result by using standard SLEUTH UGM showed that the area with high habitat quality could be reserved and the urban expansion could be limited by using our model. The findings demonstrate that the extended SLEUTH UGM could be a valuable tool for sustainable urban and environmental planning and management in developing regions where environmental protection should be considered as one of the major land-use objectives in their rapid urbanization process. PMID- 29631239 TI - Microalgae harvesting techniques: A review. AB - Microalgae with wide range of commercial applications have attracted a lot of attention of the researchers in the last few decades. However, microalgae utilization is not economically sustainable due to high cost of harvesting. A wide range of solid - liquid separation techniques are available for microalgae harvesting. The techniques include coagulation and flocculation, flotation, centrifugation and filtration or a combination of various techniques. Despite the importance of harvesting to the economics and energy balance, there is no universal harvesting technique for microalgae. Therefore, this review focuses on assessing technical, economical and application potential of various harvesting techniques so as to allow selection of an appropriate technology for cost effectively harvesting of microalgae from their culture medium. Various harvesting and concentrating techniques of microalgae were reviewed to suggest order of suitability of the techniques for four main microalgae applications i.e biofuel, human and animal food, high valued products, and water quality restoration. For deciding the order of suitability, a comparative analysis of various harvesting techniques based on the six common criterions (i.e biomass quality, cost, biomass quantity, processing time, species specific and toxicity) has been done. Based on the order of various techniques vis-a-vis various criteria and preferred order of criteria for various applications, order of suitability of harvesting techniques for various applications has been decided. Among various harvesting techniques, coagulation and flocculation, centrifugation and filtration were found to be most suitable for considered applications. These techniques may be used alone or in combination for increasing the harvesting efficiency. PMID- 29631240 TI - Modification of properties of energy crops under Polish condition as an effect of sewage sludge application onto degraded soil. AB - Energy crops are one of the possible solutions for reclamation of degraded or contaminated terrain. Their cultivation requires adequate fertilization typically containing high content of organic matter, nitrogen and phosphorous. While sewage sludge may be one source of these necessary nutrients, it may also modify some plant biomass properties, such as total carbon content. In our study, we determined whether sewage sludge (containing different value of heavy metals) could be an effective fertilizer to obtain good quality energy crops (such as Miscanthus x gigantheus and reed canary grass, Phalaris arundinacea) and simultaneously play positive role for improvement of phytoremediation. The 3-year experiment was performed on degraded soil from terrain of steel mill of Czestochowa (Silesian region, Poland). During the study, it was confirmed that sewage sludge (also in combination with urea, CH4N2O) influences the mobility of Pb, Zn, Cd in soil solution, however the intensity of the process can be limited by plant species and time. Both miscanthus, and reed canary grass were characterized by the low value of bioconcentration factor (BCF), but because biomass was high, the total concentration of heavy metals in crops was comparable with hyperaccumulators. Additionally, modification of the fertilization affected energetic parameters, such as the content of carbon, S/Cl ratio, unitary CO2 emission. However, this effect was not statistically significant. PMID- 29631241 TI - Using natural biomass microorganisms for drinking water denitrification. AB - Among the methods that are studied to eliminate nitrate from drinking water, biological denitrification is an attractive strategy. Although several studies report the use of denitrifying bacteria for nitrate removal, they usually involve the use of sewage sludge as biomass to obtain the microbiota. In the present study, denitrifying bacteria was isolated from bamboo, and variable parameters were controlled focusing on optimal bacterial performance followed by physicochemical analysis of water adequacy. In this way, bamboo was used as a source of denitrifying microorganisms, using either Immobilized Microorganisms (IM) or Suspended Microorganisms (SM) for nitrate removal. Denitrification parameters optimization was carried out by analysis of denitrification at different pH values, temperature, nitrate concentrations, carbon sources as well as different C/N ratios. In addition, operational stability and denitrification kinetics were evaluated. Microorganisms present in the biomass responsible for denitrification were identified as Proteus mirabilis. The denitrified water was submitted to physicochemical treatment such as coagulation and flocculation to adjust to the parameters of color and turbidity to drinking water standards. Denitrification using IM occurred with 73% efficiency in the absence of an external carbon source. The use of SM provided superior denitrification efficiency using ethanol (96.46%), glucose (98.58%) or glycerol (98.5%) as carbon source. The evaluation of the operational stability allowed 12 cycles of biomass reuse using the IM and 9 cycles using the SM. After physical-chemical treatment, only SM denitrified water remained within drinking water standards parameters of color and turbidity. PMID- 29631242 TI - Global effectiveness of group decision-making strategies in coping with forage and price variabilities in commercial rangelands: A modelling assessment. AB - This paper presents a modelling study that evaluated the global effectiveness of a range of group decision-making strategies for commercial farming areas in rangelands affected by temporal variations in forage production. The assessment utilised an integrated system dynamics model (86 equations) to examine the broad and long-term group decision outcomes. This model considers aspects usually neglected in related studies, such as the dynamics of the main local prices, the dynamics of the number of active farmers, the supplementary feeding of livestock, and certain behavioural traits of farmers and traders. The assessment procedure was based on an analysis of the outcomes of the model under 330,000 simulation scenarios. The results indicated that only if all the farmers in an area are either opportunistic or conservative that is, are either responsive or unresponsive to expected profits, the exploitation of the grazing resources were optimal in some senses. A widespread opportunism proved optimal only from an economic viewpoint. However, it is very unlikely that most of the farmers would agree to be opportunistic in practice. By contrast, a widespread conservatism, which in principle is perfectly feasible, proved optimal from economic, social, and ecological perspectives. Notably, it was found that the presence of a relatively small number of opportunistic farmers would suffice to considerably reduce the economic results of widespread conservatism. PMID- 29631244 TI - Are there clinical differences between inner, outer or dual spatial locations of auditory verbal hallucinations? AB - The aim of the present exploratory study was to examine the clinical differences of Auditory Verbal Hallucinations (AVHs) according to their spatial localization. Sixty-six outpatients were divided into three separate groups: inner, external and dual AVHs. The three groups were compared on sociodemographic variables (age, gender, education, marital status, living situation, employment, social disability), on clinical psychiatric characteristics (diagnosis, medication, comorbidities, illness onset, illness duration and hospitalizations) and on the measure yielded by the clinical assessments (Brief Psychiatric Rating Scale Expanded, version 4.0; Maastricht Voices Interview for Adults; Belief About Voices Questionnaire Revised, the Clinical Global Impression, the Global Assessment Functioning Self-Esteem Rating Short Form, the World Health Organisation Quality of Life-Bref). Gender, living situation, social quality of life and some items regarding beliefs about AVHs raised significant difference, however most of the other comparisons failed to reach significance. Taken together, our findings suggest that all AVHs subtypes have equal clinical significance in patients presenting a chronic mental illness. However, the power of the study limits the generalization of the findings. Clinical implications of the findings are proposed. PMID- 29631243 TI - Severe CNS inflammation after discontinuation of natalizumab and start of daclizumab successfully treated with alemtuzumab. AB - Natalizumab is highly effective in the treatment of relapsing multiple sclerosis patients. Unfortunately, after stopping natalizumab, there is an increased risk of inflammation in the central nervous system and relapses. Switching from natalizumab to an alternative sufficient drug may prevent disease reactivation. Here we present a case of a patient who experienced a dramatic course with severe central nervous system inflammation after discontinuation of natalizumab and treatment initiation with daclizumab. During a treatment of 36 days, 20 g intravenous methylprednisolone in total and ten courses of plasmapheresis were not able to control the severe CNS inflammation. Alemtuzumab, which targets the whole lymphocyte population, was able to stabilize the devastating disease course in our case. PMID- 29631245 TI - Maintenance ECT in schizophrenia: A systematic review. AB - Relapse after discontinuation of ECT is significant in patients with schizophrenia. The purpose of this systematic review was to examine use of M-ECT in schizophrenia to guide clinical decision making for relapse prevention in schizophrenia. We reviewed studies examining the role of continuation (C-ECT) and maintenance electroconvulsive therapy (M-ECT) in schizophrenia. Following PRISMA guidelines, we included randomized controlled trials, open label trials, retrospective chart reviews, case reports, and case series in this review. We evaluated adjunctive pharmacological regimens; ECT treatment parameters, including frequency, duration of continued treatment, electrode placement; clinical outcomes including cognitive side effects and relapse rates from included studies. Our findings suggest M-ECT could provide an effective form of relapse prevention in these patients and persistent cognitive side effects are minimal. PMID- 29631246 TI - The effects of perceived torture controllability on symptom severity of posttraumatic stress, depression and anger in refugees and asylum seekers: A path analysis. AB - Torture is associated with greater psychopathology, however, the specific mechanisms underlying the effects of torture remain unclear. Research suggests that the perceived uncontrollable nature of, rather than the exposure to, torture, influences the development of psychological disorders. Perceived distress during torture has also been shown to influence psychological outcomes. This cross-sectional study explored the relationship between perceived torture controllability, emotions (i.e., anger and fear) during torture, and current posttraumatic stress (PTS), depression and anger symptoms, controlling for the effects of post-migration living difficulties. Data were collected from 108 refugees and asylum seekers in treatment at two psychiatric clinics in Zurich, Switzerland. Path analyses revealed negative correlations between PTS, depression and anger symptoms, and perceived torture controllability, and positive correlations with anger and fear during torture. Furthermore, the effects of perceived torture controllability on PTS and depression symptoms were mediated by fear during torture, and on anger symptoms via anger during torture. This was over and above the effects of post-migration living difficulties on psychological symptoms. The study provides preliminary evidence that perceived uncontrollability and distress during torture might be significant risk factors for current mental health of torture survivors. These findings may have implications for informing interventions for torture survivors. PMID- 29631247 TI - Non-adherence to antipsychotic medication in first-episode psychosis patients. AB - This study evaluated the influence of attitudes and beliefs towards antipsychotics on adherence, and aimed to understand how satisfaction with information impacts adherence in first-episode psychosis. Fifty randomly selected out-patients attending the COAST Early Intervention service completed a survey comprised of the Selwood Compliance Scale, Beliefs about Medicines Questionnaire, and the Satisfaction with Information about Medicines Scale. Thirty-four percent of patients reported non-adherence to antipsychotic medication, and they were significantly younger than adherent patients. Adherent patients were more satisfied with medication information than non-adherent patients (65.7% and 34.3% respectively), suggesting that providing better information about antipsychotics may improve adherence. PMID- 29631248 TI - Psychosocial well-being over the two years following cardiac rehabilitation initiation & association with heart-health behaviors. AB - OBJECTIVE: To track psychosocial well-being over 2 years following cardiac rehabilitation (CR) initiation, and its' association with heart-health behaviors. METHODS: Patients from 3 CR programs were approached at their first visit, and consenters completed a survey. Participants were emailed surveys again 6 months, 1 and 2 years later. Depressive symptoms (PHQ-8) and quality of life were assessed at each point, as were exercise, nutrition, smoking and medication adherence, among other well-being indicators. RESULTS: Of 411 participants, 46.7% were retained at 2 years. Post-CR, there was 70% concordance between participants' desired and actual work status. Depressive symptoms were consistently minimal over time (mean = 3.17 +/- 0.37); Quality of life was high, and increased over time (p = .01). At 2 years, 56.9% participants met exercise recommendations, and 5.4% smoked. With adjustment, greater self-regulation was associated with significantly greater exercise at intake; greater exercise self efficacy was significantly associated with greater exercise at 1 year; greater disease management self-efficacy was significantly associated with greater exercise at 2 years; greater environmental mastery (actual) was significantly associated with greater exercise at 2 years. Lower depressive symptoms were significantly associated with better nutrition at 2 years. CONCLUSION: CR initiators are thriving, and this relates to better exercise and diet. PMID- 29631249 TI - Short-term treatment with hepatoselective NO donor V-PYRRO/NO improves blood flow in hepatic microcirculation in liver steatosis in mice. AB - BACKGROUND: The impairment of liver sinusoidal endothelial cells (LSECs) function and diminished nitric oxide (NO) production has been regarded as an important pathogenic factor in liver steatosis. Restoring NO-dependent function was shown to counteract liver steatosis, obesity, and insulin resistance. However, it is not known whether restored liver perfusion and improvement in hepatic blood flow contributes to the anti-steatotic effects of NO. Taking advantage of in vivo MRI, we have examined the effects of short-term treatment with the hepatoselective NO donor V-PYRRO/NO on hepatic microcirculation in advanced liver steatosis. METHODS: Male C57BL/6 mice fed for six months a high fat diet (HFD; 60 kcal% of fat) were treated for 3 weeks with V-PYRRO/NO (twice a day 5mg/kg b.w. ip). An MRI assessment of liver perfusion using the FAIR-EPI method and a portal vein blood flow using the FLASH method were performed. Blood biochemistry, glucose tolerance tests, a histological evaluation of the liver, and liver NO concentrations were also examined. RESULTS: Short-term treatment with V-PYRRO/NO releasing NO selectively in the liver improved liver perfusion and portal vein blood flow. This effect was associated with a slight improvement in glucose tolerance but there was no effect on liver steatosis, body weight, white adipose tissue mass, plasma lipid profile, or aminotransferase activity. CONCLUSION: Short-term treatment with V-PYRRO/NO-derived NO improves perfusion in hepatic microcirculation and this effect may also contribute to the anti-steatotic effects of hepatoselective NO donors linked previously to the modulation of glucose and lipid metabolism in the liver. PMID- 29631250 TI - A target-group-change strategy based on the UPLC-Q-TOF-MSE method for the metabolites identification of Fufang-Xialian-Capsule in rat's plasma. AB - Fufang-Xialian-Capsule (FXL) is a traditional Chinese medicine (TCM) formula which was utilized to treat chronic atrophic gastritis. Despite the chemical constituents have been clarifying by our previous studies, but the metabolism of FXL after oral was still unclear. In order to clarify the mechanism of these absorbed components, a target-group-change (TGC) strategy was utilized to analysis the collected data. This strategy include five steps: (1) acquired the mass spectra data and tandem mass spectra data simultaneously; (2) confirmed the prototype absorbed into blood and the tandem mass behavior of prototype; (3) clarified the potential group change of prototypes after metabolism by Metabolynx XS software; (4) confirmed the target group change acquired by compare the tandem mass behavior of metabolites with their prototypes; (5) inferred the position of group change occurred and metabolic pathways of each prototypes. Based on the TGC strategy, the structure of metabolites and the metabolic pathways of FXL were confirmed. The main group change behaviors on the prototypes after metabolism include demethylation, methylation, hydroxylation and glucuronide conjugation. As the results, there were 33 metabolites transformed from 11 prototypes confirmed, these 11 prototypes include 4 flavones, 5 alkaloids and 2 ginsenosides. All the metabolites could be identified or tentatively characterized according to the structure of metabolites and previous reports. PMID- 29631251 TI - Perturbations in amino acids and metabolic pathways in osteoarthritis patients determined by targeted metabolomics analysis. AB - Osteoarthritis (OA) is a degenerative synovial joint disease affecting people worldwide. However, the exact pathogenesis of OA remains unclear. Metabolomics analysis was performed to obtain insight into possible pathogenic mechanisms and diagnostic biomarkers of OA. Ultra-high performance liquid chromatography-triple quadrupole mass spectrometry (UPLC-TQ-MS), followed by multivariate statistical analysis, was used to determine the serum amino acid profiles of 32 OA patients and 35 healthy controls. Variable importance for project values and Student's t test were used to determine the metabolic abnormalities in OA. Another 30 OA patients were used as independent samples to validate the alterations in amino acids. MetaboAnalyst was used to identify the key amino acid pathways and construct metabolic networks describing their relationships. A total of 25 amino acids and four biogenic amines were detected by UPLC-TQ-MS. Differences in amino acid profiles were found between the healthy controls and OA patients. Alanine, gamma-aminobutyric acid and 4-hydroxy-l-proline were important biomarkers distinguishing OA patients from healthy controls. The metabolic pathways with the most significant effects were involved in metabolism of alanine, aspartate, glutamate, arginine and proline. The results of this study improve understanding of the amino acid metabolic abnormalities and pathogenic mechanisms of OA at the molecular level. The metabolic perturbations may be important for the diagnosis and prevention of OA. PMID- 29631252 TI - Studies on the metabolism of paeoniflorin in human intestinal microflora by high performance liquid chromatography/electrospray ionization/Fourier transform ion cyclotron resonance mass spectrometry and quadrupole time-of-flight mass spectrometry. AB - In this study, a high performance liquid chromatography/electrospray ionization/Fourier transform ion cyclotron resonance mass spectrometry and quadrupole time-of-flight mass spectrometry (HPLC-ESI-FT-ICR MS and HPLC-ESI-QTOF MS2) based on chemical profiling method was established to study the metabolites of paeoniflorin in human intestinal microflora (HIM). By virtue of the high resolution, high speed of HPLC and the accurate mass measurement of FT-ICR MS and QTOF MS2, 31 metabolites in methyl tert-butyl ether (MTBE) layer were detected, and the structures of 16 metabolites were identified. Among them, 13 metabolites (including two new compounds) were found for the first time in HIM transformation in vitro. The results indicated that metabolic pathways of paeoniflorin in HIM contained extensive metabolic reactions. The hydrolysis, oxidization and conjugation were major metabolic pathways, and the glycosidic linkage, ester bond, benzene ring and pinane of the structure were metabolic sites. These results would contribute to better understanding the metabolic mechanism of paeoniflorin, thereby to in-depth study and development of paeoniflorin in medicine. PMID- 29631254 TI - Common components of evidence-based parenting programs for preventing maltreatment of school-age children. AB - Child maltreatment can lead to a variety of negative outcomes in childhood including physical and mental health problems that can extend into adulthood. Given the transactional nature of child maltreatment and the difficulties that many maltreating families experience, child protection services typically offer various kinds of programs to maltreated children, their parents, and/or their families. Although the specific difficulties experienced by these families may vary, sub-optimal parenting practices are typically part of the picture and may play a central role in maltreated children's development. Hence, to deal with child maltreatment, programs that focus on parenting practices are essential, and identifying the common components of effective programs is of critical importance. The objectives of the present study were to: 1) describe the components of evidence-based parenting programs aimed at parents who have maltreated their elementary school-aged children or are at-risk for doing so and 2) identify the components that are common to these programs, using the approach proposed by Barth and Liggett-Creel (2014). Fourteen evidence-based parenting programs aimed at parents who had maltreated their elementary school-aged children (ages 6-12) or were at-risk for doing so were identified using both a review of relevant online databases of evidence-based programs (California Evidence-Based Clearinghouse for Child Welfare, Blueprints for Healthy Youth Development, Youth.gov, and the National Registry of Evidence-based Programs and Practices). Common components were identified (operationalized as components present in two thirds of programs) and discussed. The identification of common components of evidence-based programs may help clinicians choose the best intervention methods. PMID- 29631255 TI - The complex experience of child pornography survivors. AB - This research explores the complex experiences of survivors of child pornography production. The study was conducted among a convenience sample of child pornography adult survivors (N = 133), using an online survey which included a series of open-ended questions. Nearly half of respondents reported that they felt the production of sexual images caused specific problems that were different from the problems caused by other aspects of the abuse. Nearly half of the sample worried all the time that people would think they were willing participants or that people would recognize them, one-third refused to talk about the images and 22% denied there were images. The qualitative analysis identified three major themes which emerged from the survivor's perspective as adults: Guilt and shame, their ongoing vulnerability and an empowerment dimension the images sometimes brought. Recommendations for further research and additional implications are discussed. PMID- 29631253 TI - Synergistic effects of H3 and H4 nucleosome tails on structure and dynamics of a lesion-containing DNA: Binding of a displaced lesion partner base to the H3 tail for GG-NER recognition. AB - How DNA lesions in nucleosomes are recognized for global genome nucleotide excision repair (GG-NER) remains poorly understood, and the roles that histone tails may play remains to be established. Histone H3 and H4 N-terminal tails are of particular interest as their acetylation states are important in regulating nucleosomal functions in transcription, replication and repair. In particular the H3 tail has been the focus of recent attention as a site for the interaction with XPC, the GG-NER lesion recognition factor. Here we have investigated how the structure and dynamics of the DNA lesion cis-B[a]P-dG, derived from the environmental carcinogen benzo[a]pyrene (B[a]P), is impacted by the presence of flanking H3 and H4 tails. This lesion is well-repaired by GG-NER, and adopts a base-displaced/intercalated conformation in which the lesion partner C is displaced into the major groove. We used molecular dynamics simulations to obtain structural and dynamic characterizations for this lesion positioned in nucleosomal DNA so that it is bracketed by the H3 and H4 tails. The H4 tail was studied in unacetylated and acetylated states, while the H3 tail was unacetylated, its state when it binds XPC (Kakumu, Nakanishi et al., 2017). Our results reveal that upon acetylation, the H4 tail is released from the DNA surface; the H3 tail then forms a pocket that induces flipping and capture of the displaced lesion partner base C. This reveals synergistic effects of the behavior of the two tails. We hypothesize that the dual capability of the H3 tail to sense the displaced lesion partner base and to bind XPC could foster recognition of this lesion by XPC for initiation of GG-NER in nucleosomes. PMID- 29631256 TI - Influence of childhood abuse and neglect subtypes on late-life suicide risk beyond depression. AB - The association of childhood maltreatment and suicide has been extensively examined within the population. Depression figures as a main cause for the elevated suicide rate in advanced ages and is often related to childhood maltreatment. The purpose of the present study was to examine the relationship between childhood maltreatment subtypes and suicide risk, testing geriatric depression as a moderator. This is a cross-sectional study looking at a sample of 449 individuals 60 year s old or older from the Multidimensional Study of the Elderly of Porto Alegre Family Health Strategy, Brazil (EMI-SUS/POA). Childhood maltreatment (Childhood Trauma Questionnaire), geriatric depressive symptoms (Geriatric Depression Scale), and suicide risk (Mini International Neuropsychiatric Interview) were assessed. The subtypes of childhood abuse and neglect were significantly associated with suicide risk. In the multivariate analysis, controlling for age, gender, income, marital status, ethnicity, smoking, and geriatric depression symptoms, all trauma subtypes remained associated with suicide risk with the exception of physical neglect (EA = 3.65; PA = 3.16; SA = 5.1; EN = 2.43; PN = 1.76). The present study showed that childhood maltreatment subtypes predicted suicide risk, and geriatric depression does not directly mediate this relation. PMID- 29631257 TI - Anti-Angiogenics: Their Value in Lung Cancer Therapy. AB - Lung cancer is the second most common cancer and the leading cause of cancer related deaths. Different targeted therapies and the introduction of immunotherapy have successfully improved outcome for patients with non-small lung cancer (NSCLC). Anti-angiogenic drugs are an essential component in the treatment of NSCLC patients. The vascular endothelial growth factor (VEGF)-A antibody bevacizumab is approved for first-line treatment of advanced-stage patients in combination with platinum-based chemotherapy. Ramucirumab, a VEGF receptor antibody, and nintedanib, an anti-angiogenic multi-tyrosine kinase inhibitor, are approved for second-line treatment in combination with docetaxel. This review provides a summary of pivotal trials with anti-angiogenic drugs in NSCLC in different settings. We give an overview of how to position anti-angiogenic therapy in the current treatment algorithms and highlight future directions. The identification of predictive biomarkers for patient selection could improve the success of anti-angiogenic drugs and represents an important area of research. In addition, novel therapeutic targets including endothelial metabolomic intermediates and cellular components of the tumor microenvironment could lead to the identification of innovative new targets besides the VEGF axis. PMID- 29631258 TI - Meetings and Conferences. PMID- 29631259 TI - Ethnographic Approaches in Primatology. AB - The shared evolutionary histories and anatomical similarities between humans and non-human primates create dynamic interconnections between these alloprimates. In this foreword to Folia Primatologica's special issue on "Ethnographic Approaches in Primatology," we review the ethnographic method and existing literature at the intersection of primatology and ethnography. We summarize, compare and contrast the 5 contributions to this special issue to highlight why the human-non-human primate interface is a compelling area to investigate via ethnographic approaches and to encourage increased incorporation of ethnography into the discipline of primatology. Ethnography is a valuable and increasingly popular tool with its use no longer limited to anthropological practitioners investigating traditional, non Western peoples. Scholars from many disciplines now use ethnographic methods to investigate all members of our globalised world, including non-humans. As our closest living relatives, non-human primates (hereafter "primates") are compelling subjects and thus appear in a range of contexts within ethnographic investigations. The goal of this special issue is to highlight the trajectory of research at the intersection of primatology and ethnography and to illustrate the importance of ethnographic methods for the advancement of primatology as a discipline. PMID- 29631260 TI - On the Rocks: Using Discourse Analysis to Examine Relationships between Barbary Macaques (Macaca sylvanus) and People on Gibraltar. AB - Primates are difficult to categorise due to some of the human-like characteristics they possess. Here, we examine the complexities that exist in a commensal relationship between an introduced population of Barbary macaques and local human populations on Gibraltar. In Western culture, much has been done to recognise primates' human characteristics while simultaneously focusing on keeping them at a metaphorical distance. In the context of Gibraltar's Barbary macaques, the anomalous status of primates causes a duality of perception whereby the macaques' position makes them both more frustrating and perceived as more worthy of protection. We examine the language used by Gibraltar residents about the macaques, interpreting statements using discourse analysis to reveal the complexities of people's perceptions of the macaques. Our results indicate that Barbary macaques on Gibraltar occupy a perceptual context of internal conflict in which they are viewed both with pride and a sense of ownership as well as with mistrust and fear. The relationship between people and Barbary macaques on Gibraltar is complex, and while sensitisation programmes and awareness-raising efforts exist, we recommend greater collaboration with residents to prevent the development of more intense negative human-macaque interactions. PMID- 29631261 TI - Slow Loris Trade in Vietnam: Exploring Diverse Knowledge and Values. AB - Wildlife trade can present a major threat to primate populations. In Vietnam, slow lorises (genus Nycticebus) are subject to local, regional and international demand for diverse uses including as medicine, as meat and for pets. Ethnographic approaches explore the nuances of human-primate interactions in complex sociocultural contexts. We combined ethnographic interviews of key informants with information from questionnaires, focus groups and a movie broadcast on Vietnamese television to explore diverse knowledge and values related to slow lorises and their use in trade in Vietnam. We infer prices, uses and networks for expanding targeted regional and international markets as compared to the opportunistic local one. We highlight key findings related to gendered knowledge about slow lorises and more-than-human ontologies of slow lorises as active participants in human-slow loris interactions. We suggest that conservation efforts should pay attention to the clarification of vernacular names, and use names that highlight ecological or behavioural qualities of slow lorises, rather than other names that could be confused with medicinal remedies. Our results confirm the dynamic complexity of trade in Vietnam, highlighting the importance of ethnographic methods to explore diverse knowledge and values for place-based or site-appropriate conservation management of primates and other highly traded taxa. PMID- 29631262 TI - Identity Construction and Symbolic Association in Farmer-Vervet Monkey (Chlorocebus aethiops sabaeus) Interconnections in St. Kitts. AB - Primates occupy a liminal space between humans and animals. On the Caribbean island of St. Kitts, translocated vervet monkeys (Chlorocebus aethiops sabaeus) are respected creatures, yet they cause problems. Vervets regularly consume crops on farms and are considered "pests"; still, Kittitians express empathy and understanding for them based largely on the monkeys' display of human-like behaviours. Using data from interviews with 64 Kittitian farmers, we deconstruct the symbolism of the vervet monkey in St. Kitts and analyse how farmers give the monkeys identities that are meaningful only within human social expectations. Our findings reveal that Kittitian farmers consider monkeys to be clever and emotive, displaying complex intentions such as revenge and remorse. Yet, crop-foraging behaviour is a regular and negative experience for the majority of farmers in this study, and the monkeys' presence itself is a constant reminder of the multitude of challenges farmers face in a newly adopted tourism economy that no longer prioritises agriculture. Our results reveal that while vervet crop consumption is a significant problem in St. Kitts, it is the monkeys' boundary crossing status that drives the growing mentality that "the monkey problem" is completely out of control. PMID- 29631263 TI - Exploring the Role of Wealth and Religion on the Ownership of Captive Lemurs in Madagascar Using Qualitative and Quantitative Data. AB - Primates are kept as pets for various reasons including as indicators of wealth. Ownership of primates can also be influenced by religion. In Madagascar, thousands of lemurs are kept as pets, but the roles of wealth and religion in the ownership of captive lemurs have not been explored. We use quantitative and qualitative data to examine these aspects of ownership. Quantitative data were collected (July to August 2016) in households (n = 596) of 12 urban and rural towns in Madagascar using semi-structured interviews. International standards for research ethics were followed. Research was approved by an ethics oversight committee. We also opportunistically visited 13 religious facilities. Qualitative data were used to frame the context of the quantitative data. We found that pet lemur owners do not speak about their lemurs as a symbol of wealth, but non owners associate pet lemurs with wealth. Therefore, status/wealth may be a motivating factor in the ownership of pet lemurs. We also found evidence that Catholic entities in Madagascar sometimes take in captive lemurs when the owner can no longer care for the animal (being viewed as animal-friendly institutions). However, we did not find evidence of religion (institutional or traditional) influencing the ownership of pet lemurs. PMID- 29631265 TI - Understanding Human-Animal Relations in the Context of Primate Conservation: A Multispecies Ethnographic Approach in North Morocco. AB - Strategies for conserving species threatened with extinction are often driven by ecological data. However, in anthropogenic landscapes, understanding and incorporating local people's perceptions may enhance species conservation. We examine the relationships shepherds, living on the periphery of the mixed oak forest of Bouhachem in northern Morocco, have with animals in the context of a conservation project for Barbary macaques (Macaca sylvanus). We analyse ethnographic data to provide insights into shepherds' conceptions of Barbary macaques and the species which bring the shepherds into the forest - goats (Capra hircus), domestic dogs (Canis lupus familiaris), and the African wolf (Canis lupus lupaster). We interpret these data within the framework of boundary theory. Our multispecies ethnographic approach illuminates the different and, in the case of the domestic dog and the Barbary macaque, complex ways shepherds perceive each species. Some shepherds show intrinsic interest in the macaques, revealing potential recruits to conservation activities. As with any ethnographic study, our interpretations of human-animal relations in Bouhachem may not extrapolate to other areas of the Barbary macaque's distribution because of the unique nature of both people and the place. We recommend that conservationists examine complex place-based relations between humans and animals to improve wildlife conservation efforts. PMID- 29631266 TI - Evidence-Based Medicine and Clinical Research: Both Are Needed, Neither Is Perfect. AB - Currently, it is impossible to think of modern healthcare that ignores evidence based medicine (EBM), a concept which relies on 3 pillars: individual clinical expertise, the values and desires of the patient, and the best available research. However, EBM is not perfect. Clinical research is also far from being perfect. This article provides an overview of the basic principles, opportunities, and controversies offered by EBM. It also summarizes current discussions on clinical research. Potential solutions to the problems of EBM and clinical research are discussed as well. If there were specific issues related to pediatric nutrition, an attempt was made to discuss the basic principles and limitations in this context. However, the conclusions are applicable to EBM and clinical research in general. In the future, considering that new ways of obtaining health data will continue to emerge, the world of EBM and clinical research is likely to change. The ultimate goal, however, will remain the same: improving health outcomes for patients. PMID- 29631268 TI - Foreword. PMID- 29631269 TI - Nutrition for the Next Generation: Older Children and Adolescents. AB - This paper reviews information on why the nutrition of older children (5-9 years) and adolescents (10-19 years) is important and the consequences that it can have over generations. Developing countries still face a high burden of undernutrition and anemia, while the burden of overweight and obesity is on the rise in both developing and developed countries. There are evidence-based interventions which can improve the nutritional status and these include interventions for a balanced and diverse diet and micronutrient supplementation, especially iron and multiple micronutrient supplementation where there is sufficient evidence to reduce anemia. There is mixed evidence for the effective strategies to prevent and control obesity and a dearth of evidence from developing countries. Adolescent pregnancy also poses greater challenges to the health of mother and child, and advocacy should be rampant to delay the age of marriage and pregnancy. Interventions targeted to improving the nutritional status among "pregnant adolescents" have shown improvement in birth weight and a reduction in low birth weight and preterm delivery. Traditional platforms including school-based and community-based approaches offer a mixed picture of effectiveness, but emerging avenues of mHealth and social media could also be channelized to reach this population. The population of this age group is on the rise globally, and failure to invest in improving the nutrition of older children and adolescents will further increase the number of dependents in coming generations and negatively influence the health of future generations and progress of nations. PMID- 29631267 TI - The Effect of SH2B1 Variants on Expression of Leptin- and Insulin-Induced Pathways in Murine Hypothalamus. AB - OBJECTIVE: We aimed to determine the effect of human SH2B1 variants on leptin and insulin signaling, major regulators of energy homeostasis, on the RNA level. METHODS: We analyzed the expression of infrequent alleles of seven SH2B1 variants (Arg67Cys, Lys150Arg, Thr175Ala, Thr343Met, Thr484Ala, Ser616Pro and Pro689Leu) in response to insulin or leptin cell stimulation. Two of these were identified in own mutation screens, the others were predicted to be deleterious or to serve as controls. The variants were analyzed in a homologous system of mouse hypothalamic cells. Changes in expression of downstream genes were measured. Student's t-test for independent samples was applied and effect sizes using Cohen's d were calculated. RESULTS: In 34 of 54 analyzed genes involved in leptin (JAK/STAT or AKT) signaling, variants nominally changed expression. The expression of three genes was considerably increased (p values <= 0.001: Gbp2b (67Cys; d = 25.11), Irf9 (689Leu; d = 44.65) and Isg15 (150Arg; d = 20.35)). Of 32 analyzed genes in the insulin signaling pathway, the expression of 10 genes nominally changed (p <= 0.05), three resulted in p values <= 0.01 (Cap1 (150Arg; d = 7.48), Mapk1(343Met; d = -6.80) and Sorbs1 (689Leu; d = 7.82)). CONCLUSION: The increased expression of genes in leptin (JAK/STAT or AKT) signaling implies that the main mode of action for human SH2B1 mutations might affect leptin signaling rather than insulin signaling. PMID- 29631270 TI - Lifetime Self-Harm Behaviors Are Not More Prevalent in Bariatric Surgery Candidates than in Community Controls with Obesity. AB - OBJECTIVE: The study aimed at investigating the lifetime prevalence of 22 self harm behaviors in bariatric surgery candidates (pre-bariatric surgery group; PSG) compared to community controls with obesity (obese community group; OCG). METHODS: The Self-Harm Inventory (SHI) was administered to the PSG (n = 139, BMI >= 35 kg/m2) and to the OCG (n = 122, BMI >= 35 kg/m2). RESULTS: Group comparison of cumulative SHI scores indicated a trend towards less endorsed SHI items in the PSG compared to the OCG (medianPSG = 1.00, IQRPSG = 2.00, medianOCG = 1.00, IQROCG = 2.25, U = 7.241, p = 0.033, eta2 = 0.02). No significant group differences were found with regard to the rate of suicide attempts (12.4% vs. 9.4% for OCG vs. PSG). At least one type of lifetime self-harm behavior was admitted by 51.8% of the PSG and 63.9% of the OCG (chi2(1) = 3.91, p = 0.048). The results of logistic regressions using Firth's bias reduction method with at least one SHI item endorsed as dependent variable, group as categorical predictor (PSG as baseline), and age or BMI or PHQ-4 as continuous control variable indicated that only PHQ-4 had a positive effect on the odds ratio. CONCLUSION: The results suggest that self-harm (including suicidal attempts) is not more prevalent in bariatric surgery candidates than in community control participants with obesity. Further studies are needed to investigate self-harm in bariatric surgery patients, prior and following surgery, compared to non-operated patients with obesity. PMID- 29631271 TI - Health-Related Quality of Life in Children and Adolescents with Severe Obesity after Intensive Lifestyle Treatment and at 1-Year Follow-Up. AB - OBJECTIVE: To examine changes in generic and weight-related, health-related quality of life (HRQoL) in children and adolescents with severe obesity participating in intensive lifestyle treatment, and to examine whether changes in SDS-BMI were associated with changes in HRQoL. METHODS: In this prospective observational study, a referred sample of 120 children and adolescents (8-19 years) with severe obesity (SDS-BMI >= 3.0, or >= 2.3 in combination with obesity related comorbidity) received an intensive 1-year lifestyle treatment with an inpatient period in a specialized childhood obesity center. A weight-related (IWQOL-Kids) and three generic (KIDSCREEN-52, PedsQL 4.0, and EuroQol) HRQoL questionnaires were administered at baseline (T0), after treatment (T1), and 1 year later (T2). Generalized Linear Mixed Models and partial correlations were used to analyze changes in HRQoL and associations with changes in SDS-BMI. RESULTS: Statistically significant improvements in generic and weight-related HRQoL overall and domain scores were observed at T1and at T2 in comparison with T0, despite partial weight regain from T1 to T2. Larger weight loss at T2 was correlated with larger improvements in physical HRQoL domains. CONCLUSION: Children and adolescents with severe obesity experienced long-term improvements in generic and weight-related HRQoL after participating in intensive lifestyle treatment, despite partial weight regain. PMID- 29631273 TI - Focus/Summary. PMID- 29631272 TI - Editorial. PMID- 29631274 TI - Food Allergy Prevention and Treatment by Targeted Nutrition. AB - In view of the dramatic rise in the prevalence of food allergy globally, effective prevention strategies have become a public health priority. Several models have emerged around the etiology of food allergy, including the hygiene hypothesis, dual allergen exposure hypothesis, and vitamin D hypothesis. These form the basis for current and potential prevention strategies. Breastfeeding remains a key pillar of primary allergy prevention. Other nutritional interventions, including the use of whey-based, partially hydrolyzed formula in non-breastfed infants, also play an important role. In recent years, there has been a shift away from prolonged food allergen avoidance to the proactive allergen introduction from 4 months of age. This approach is supported by 2 pivotal randomized clinical trials showing that the early introduction of peanut and other food allergens significantly reduces the risk of food allergy. However, the implementation of this strategy at the population level still raises significant logistic problems, including patient selection and development of suitable food formats for young infants. Other prevention strategies, including vitamin D supplementation, are currently under evaluation. Maternal elimination diets during pregnancy and lactation are not recommended for allergy prevention. The treatment of food allergies has also seen major transformations. While strict allergen avoidance is still the key treatment principle, there is a greater focus on desensitization and tolerance induction by oral and epicutaneous immunotherapy. In addition, specialized hypoallergenic infant formulas for the treatment of infants with cow's milk allergy have undergone reformulation, including the addition of lactose and probiotics in order to modulate the gut microbiome and early immune responses. Further research is needed to inform the most effective food allergy prevention strategies at the population level. In addition, the wider application of food allergen immunotherapy may provide better health outcomes and improved quality of life for families affected by food allergies. PMID- 29631275 TI - Effects of a Weight Loss Program on Metabolic Syndrome, Eating Disorders and Psychological Outcomes: Mediation by Endocannabinoids? AB - OBJECTIVE: To evaluate the effects of weight loss on endocannabinoids, cardiometabolic and psychological parameters, eating disorders (ED) as well as quality of life (QoL) and to elucidate the role of endocannabinoids in metabolic syndrome (MS). METHODS: In total, 114 patients with obesity were prospectively included in a 12-month weight loss program. Plasma endocannabinoids were measured by mass spectrometry; ED, psychological and QoL-related parameters were evaluated by self-reported questionnaires; physical activity was measured by accelerometer. Nutritional assessment was done by a 3-day food diary. RESULTS: Among completers (n = 87), body weight decreased in 35 patients (-9.1 +/- 8.6 kg), remained stable in 39 patients, and increased in 13 patients (+5.8 +/- 3.4 kg). 75% of patients with MS at baseline were free of MS at follow-up, and their baseline plasma N palmitoylethanolamide (PEA) values were significantly lower when compared to patients with persisting MS. At baseline, there was a positive relationship between PEA and waist circumference (p = 0.005, R2 = 0.08), fasting glucose (p < 0.0001, R2 = 0.12), total cholesterol (p = 0.001, R2 = 0.11), triglycerides (p = 0.001, R2 = 0.11), LDL-cholesterol (p = 0.03, R2 = 0.05) as well as depression score (p = 0.002, R2 = 0.29). CONCLUSION: Plasma PEA might play a role in metabolic improvement after weight loss. Even in subjects without weight loss, a multidisciplinary intervention improves psychological outcomes, ED, and QoL. PMID- 29631276 TI - Associations of Personality with Body Mass Index and Obesity in a Large Late Midlife Community Sample. AB - OBJECTIVE: The study examined cross-sectional associations of personality with BMI and obesity among men and women in a large late midlife community sample. METHODS: The sample comprised 5,286 Danish individuals aged 49-63 years from the Copenhagen Ageing and Midlife Biobank (CAMB) with complete information on measured BMI, personality assessed by the NEO Five Factor Inventory (NEO FFI), and sociodemographic factors including sex, age and educational length. Analysis of variance and logistic regression models were used to investigate associations between personality and BMI as well as obesity. Personality traits were analyzed separately and combined in the same model. RESULTS: All personality traits except for neuroticism were significantly associated with BMI, with extraversion (p value ranged from <0.001 to 0.012) and agreeableness (p value ranged from 0.001 to 0.002) being the most consistent predictors of BMI among men and women, respectively. Furthermore, extraversion among men (high scores) (p = 0.016) and agreeableness among women (low scores) (p = 0.026) were the only personality traits significantly associated with obesity when adjusting for duration of education. CONCLUSION: Personality was significantly associated with BMI and to a lesser extent with obesity, and these associations differed between men and women. Also, it was suggested that the interrelations of the five personality traits should be considered in future research of personality and health outcomes. PMID- 29631277 TI - The Aesthetics of the Upper Face: Forehead, Brow, and Upper Eyelid. PMID- 29631278 TI - Surgical Anatomy of the Upper Face and Forehead. AB - Aesthetic ideals regarding proportion and balance of the face have existed for centuries. The upper third of the face, including the brow, forehead, and temple, provides an important contribution to the overall facial aesthetic. This is especially true given how the brow frames the eyes, and the eyes serve as the key focal point in our interactions with others. There exists a variety of surgical and nonsurgical procedures aimed at improving the aesthetic of the upper portion of the face, and a thorough knowledge of the surgical anatomy of the upper face and forehead is critical to their successful execution. PMID- 29631279 TI - The Aesthetics of the Upper Face and Brow: Male and Female Differences. AB - A hallmark of the modern era of facial plastic surgery is the increasing demand for upper facial rejuvenation by both genders and the growing variety of such options, including both surgical and non-surgical modalities. Thus, now more than ever, differentiating these aesthetic ideals between the two genders and understanding their nuances has become a necessity for the facial cosmetics community. In this article, a detailed comparison of the the pertinent anatomical and topographical differences is presented, followed by a review of the historical evolution of these aesthetic trends. PMID- 29631280 TI - Rejuvenation of the Upper Face and Brow: Neuromodulators and Fillers. AB - Facial aging involves a combination of volume loss and descent, loss of skin elasticity, dynamic lines due to facial mimetic muscle action, and development of static rhytids. Although surgery remains an option for treatment, minimally invasive aesthetic procedures continue to gain popularity with the use of neuromodulators and soft tissue fillers being the most sought-after procedures. Although these may be used in isolation to treat specific concerns, they are often combined to address multiple facets of aging. Multiple different neuromodulators and fillers are commercially available. Although relatively effective and safe, a thorough understanding of their indications, compositions, and potential adverse effects is paramount. This article will review the available aesthetic products for minimally invasive periorbital rejuvenation with botulinum toxin and injectable fillers. Although it will not focus on other therapies aimed at facial rejuvenation, such as resurfacing techniques or surgical interventions, it is important to note that an individualized treatment plan may combine multiple therapies to optimize patient outcomes and satisfaction. PMID- 29631281 TI - The Open Browlift. AB - The eyes and periorbital areas are critical components for the harmonious treatment of the aging face. The authors prefer the open browlift for rejuvenation of the forehead area. The open browlift is the most versatile, effective, and long-lasting method for the treatment of the forehead. The analysis of the forehead area, alternative treatments, variations in incisions, and key components of the surgical procedure are to be reviewed. PMID- 29631282 TI - Endoscopic Browplasty. AB - The endoscopic brow lift has become an established procedure that can safely and reliably rejuvenate the upper third of the face. The authors discuss relevant anatomy and considerations for patient selection to optimize surgical outcomes. A detailed review of surgical technique is presented, and the potential complications and means to reduce them are discussed. PMID- 29631283 TI - Scalp Advancement and the Pretrichial Brow Lift. AB - This article will review considerations for scalp advancement, or forehead shortening, when done in combination with a brow lift. The author's technique for anterior hairline reshaping is presented with particular focus on simultaneous reduction of temporal recession. PMID- 29631284 TI - The Trichophytic and Lateral Temporal Lifts: Application to the Focal Elevation of the Aging Lateral Eyebrow. AB - Rejuvenation of the upper face is a key component of overall facial rejuvenation. The upper face is probably the most important purveyor of our sense of well-being and our primary transmittal of nonverbal social interaction. There are many aspects to the aging changes in the area. Central to these concerns is the level and shape of the eyebrow. Ptosis of the lateral brow begins at a relatively young age and tends to worsen over time. This article describes an adaptation of modifiable techniques to address focal issues of the lateral eyebrow. PMID- 29631285 TI - Hairline Restoration: Difference in Men and Woman-Length and Shape. AB - Hair restoration has become increasingly popular in recent years with both men and women. New technologies such as follicular unit extraction and grafting have made it possible for patients to get a natural looking result with minimal downtime. Men usually experience hairline recession as a result of androgenic alopecia, while women most commonly experience thinning of the crown and vertex, with the preservation of the hairline. However, there is a growing population of women who wish to advance their hairline forward because of congenital high hairline, traction alopecia, or previous facial cosmetic surgery. There are several key differences between the female and male hairline. Understanding such differences and following certain guidelines will help the facial plastic surgeon to obtain beautiful and natural appearing results. PMID- 29631286 TI - Aesthetics and Rejuvenation of the Temple. AB - The temples are an often overlooked, but important element of facial rejuvenation. The anatomy of the temple should be understood prior to any intervention in this location. Multimodal treatment to re-establish youthful convexity, proper hairline position, and correct actinic damage is recommended for optimal results. Important anatomy, aesthetic goals, and methods of rejuvenation are reviewed in detail. PMID- 29631287 TI - Fat Grafting Volume Restoration to the Brow and Temporal Regions. AB - Primary manifestations of facial aging are the reduction in subcutaneous tissue volume, especially the atrophy of fat as well as bone volume depletion which directly contribute to loss of support and laxity of the skin. Depressions and hollows develop with a visible disruption of the cosmetic facial aesthetic units resulting in harsh shadows. This is especially evident in the eyebrow and temporal regions which accentuate the appearance of brow ptosis and a hollow, almost cadaveric look to the temple. Restoration of volume to these areas has been shown to rejuvenate the upper face creating a softer, fuller, and more youthful appearance. Fat grafting by itself or in combination with upper facial surgical procedures plays a major role in the restoration of youthful facial qualities in this region. PMID- 29631288 TI - Halos and Asymmetric Triangles: Designing the Eyelids with Volume Using Fillers and/or Fat. AB - Periorbital aging is mainly a product of volume loss, which can be addressed with fillers and/or fat grafting. This stands in contrast to the lower face where a lifting procedure can be the principal method to improve moderate-to-significant aging. New models to explain these concepts of periorbital rejuvenation to both the surgeon and the prospective patient are outlined herein, namely, three facial halos (around the eyes, around the perimeter of the face, and around the mouth) and asymmetric triangles around the eyes. Specific techniques for fillers and fat grafting are also covered separately in detail in this article. PMID- 29631289 TI - Effect of Orbicularis Muscle Resection during Blepharoplasty on the Position of the Eyebrow. AB - Dermatochalasis is a skin excess in the upper eyelid which may be associated with either an aesthetic and functional defect, blocking the peripheral vision. Upper blepharoplasty is the gold standard procedure for correction of dermatochalasis and to restore youthful contours to the periorbita. It is one of the most commonly performed procedures in aesthetic plastic surgery; however, there is still a lack of consensus about this procedure. The excess skin is sometimes removed alone or in conjunction with a strip of orbicularis oculi muscle. The rationale for both muscle and skin resection or skin alone preserving the muscle is uncertain. Some authors have studied the aging influence in brow position, and a few studies pointed out the influence of the upper blepharoplasty on brow height. The true effects, regarding the position of the eyebrow, of both techniques, with or without resection of the preseptal orbicularis oculi muscle, are unclear. The authors present a review of the literature to find the rationale for resecting or preserving the orbicularis oculi muscle in upper eyelid blepharoplasty and its relation to eyebrow position. PMID- 29631290 TI - Upper Blepharoplasty: Management of the Upper Eyelid and Brow Complex via Transblepharoplasty Approach. AB - Upper blepharoplasty is one of the more common facial plastic procedures. The upper lid and brow complex are managed together. Whether upper blepharoplasty is performed for medical or cosmetic reasons, the aim is to improve appearance while retaining natural shape and maintaining (or improving) function. For optimal results, it is important to understand relevant eyelid anatomy and the concept of maintaining youthful volume and position of the eyelid brow orbit complex. Management of patient expectations, meticulous planning, and a degree of surgical finesse all contribute to the desired outcome. The article will focus on the assessment, techniques, and complications of upper blepharoplasty, which involve management of the skin, orbicularis oculi, preaponeurotic fat, levator aponeurosis and muscle as related to concomitant ptosis, and lateral brow complex via transblepharoplasty (internal) brow lift and fixation. PMID- 29631291 TI - Manipulation of the Periorbital Musculature. AB - The resting and expressive states of the periorbital region contribute to perceived age, emotion, gender, race, and countenance. A thorough understanding of the periorbital musculature is essential for comprehensive facial rejuvenation. Surgical and nonsurgical manipulation of these muscles can lead to alterations in brow elevation, resting brow position, and dynamic periorbital rhytids. Both surgical and nonsurgical techniques can produce desired effects, and they are often used concomitantly to obtain optimal results. PMID- 29631292 TI - An Unexpected Donor Site Complication after Aesthetic Rhinoplasty: Arteriovenous Fistula of the Superficial Temporal Artery. PMID- 29631293 TI - 2018 Eberhard F. Mammen Award Announcements: Part I-Most Popular Articles. PMID- 29631294 TI - Editorial Compilation V. PMID- 29631295 TI - Clinical Pharmacology Considerations for Development of beta Lactamase Inhibitor Combination with Antibiotics. AB - The shrinking drug pipeline for antibacterial drugs has made it very precious to discover and develop novel drugs in this space. In this context, the recent approvals of beta lactamase inhibitors with either cephalosporin or penem as combination drugs are welcome news to the community. There are number of beta lactamase inhibitors with suggested partnered drugs that are currently in various stages of drug development. The focus of this manuscript is to provide some perspectives on clinical pharmacology considerations that may aid in the successful development of such combination drugs. In this regard, a broad framework which includes pharmacokinetics (PK), pharmacodynamics (PD) and PK/PD guided surrogate strategies are provided to enable an informed dosing decision of the combination agent. PMID- 29631296 TI - Nanocrystalization of Pioglitazone by Precipitation Method. AB - BACKGROUND: Poor solubility in aqueous medium limits the use of many drugs. Different methods have been adopted to promote the rate of dissolution of slightly water soluble drugs. Crystallization improves solubility, and bioavailability by increasing the surface area of slightly water soluble drugs. Pioglitazone (PGZ), which is a class II Biopharmaceutical Classification System drug has a slight solubility in water and a slow rate of dissolution, which may have a negative effect on its metabolism leading to a therapeutic failure. AIM: The aim of this study was to improve the solubility of PGZ-HCl; an antidiabetic drug using precipitation method. MATERIALS AND METHODS: Formulations were prepared with polyethylene glycol 6000 and isomalt using different speed of homogenizer and quantity of solvent by precipitation method. Drug-polymer interactions were examined using differential scanning calorimetry (DSC), and Powder X-Ray Diffraction (PXRD). Surface structure were shown by SEM photographs. RESULTS: The particle size was significantly decreased and solubility was enhanced with increase speed, ethanol solvent and increase stabilizer, however very high amount of stabilizer resulted in a decrease in solubility. CONCLUSION: This result however showed that solid dispersion technique is a potential method for increasing dissolution profile of a poorly aqueous soluble agent. PMID- 29631297 TI - Preparation and Evaluation of Midazolam Rectal Gel in vitro and in vivo. AB - Midazolam has been successfully used for sedation, which the tablets, injections and oral solutions were available in market. However, the oral bioavailability of midazolam is less due to the first effect, while injection formulation has a low patient compliance. The purpose of this study was to obtain midazolam rectal gel to meet the production and market requirements. We evaluated the in vitro release behavior of midazolam powder, a physical mixture of midazolam and HPMC, and midazolam gel. The results showed that the midazolam gel has superior release degree compared to the other. Correspondingly, midazolam gel produced relevant plasma concentrations result in the rats. At the same dose (1 mg/kg), the Cmax and AUC (0-t) of midazolam after administration of the midazolam rectal gel were 8-10 times higher than that of the oral solution. The midazolam rectal gel was evaluated for physico-chemical tests including pH, viscosity, drug content at 40 degrees C /75%RH (relative humidity) for 180 days (6 months). It provides information about the shelf lives of medicine, as well as the conditions for their storage. Rectum irritation test demonstrated that frequent application of midazolam rectal gel did not induce rectal mucosal damage. In conclusion, midazolam rectal gel was a potential new dosage form, which could alleviate the feeling of alien, discomfort and refusal during application of the patients. It was likely to be a more convenient and effective sedative medicine form specifically for infants and children. PMID- 29631298 TI - [Adverse Effects of Psychotherapy in Depressed Patients - First Application of the Positive and Negative Effects of Psychotherapy Scale (PANEPS)]. AB - BACKGROUND: The Positive and Negative Effects of Psychotherapy Scale (PANEPS), a self report questionnaire to measure positive effects (PE) and unwanted events (UE) during the last psychotherapy (PT), was applied for the first time within a sample of patients with depression. The questionnaires applicability was tested and delivered first empirical results about PE and UE of a PT within this population. METHODS: The 43 items of the PANEPS were completed during an online survey by 135 persons with a current or previous depressive disorder. UE were further divided into side effects (SE), malpractice (MP) and unethical misconduct (UM). In addition, sociodemographic information (age, sex, state of relationship), details about previous psychotherapeutic treatment and the last therapy were collected. The PANEPS was tested and revised using a principal components analysis with varimax rotation. RESULTS: A four-factor solution was determined, reflecting the previously defined scales (PE, SE, MP, UM) and allowed for further reduction of the PANEPS. The final version of the PANEPS showed satisfactory to excellent internal consistency with Cronbach's alpha between 0.72 and 0.92 A total of 95.6% of the participants reported at least one PE (range=0 5, M=3.3, SD=1.4) and 52.6% at least one UE (range=0-14, M=1.8, SD=2.9). From the sample, 38.5% reported at least one SE (range=0-6, M=0.8, SD=1.3), 26.7% at least one experience of MP (range=0-10, M=0.9, SD=1.9) und 8.1% at least one case of UM (range=0-4, M=0.1, SD=0.5). PE were negatively correlated with MP, but not with SE and UM. We found associations between characteristics of the sample and occurrence of WE and UE. DISCUSSION: Over half of the participants in our study confirmed presence of at least one UE as measured with the PANEPS, with unexpected high approval of at least one MP or UM. Especially the current symptomatology (PHQ-9) seems to be relevant for the approval of PE and UE of a PT. The negative association between PE and MP underlines the importance of guideline-oriented treatment for successful psychotherapy. CONCLUSION: Side effects of psychotherapy are common in patients with depression and should be measured regularly. PMID- 29631299 TI - Epileptic Encephalopathy in Adams-Oliver Syndrome Associated to a New DOCK6 Mutation: A Peculiar Behavioral Phenotype. AB - Adams-Oliver syndrome (AOS) is characterized by a combination of congenital scalp defects (aplasia cutis congenita) and terminal transverse limb malformations of variable severity. When neurological findings are present, patients are reported as AOS variants. We describe a child with compound heterozygosity of the DOCK6 gene, aplasia cutis, terminal transverse limb defects, cardiovascular impairment, intellectual disability, and brain malformations with intracranial calcifications. He suffers from a severe refractory epileptic encephalopathy characterized by polymorphic seizures with prolonged periods of electroencephalogram (EEG), continuous epileptiform activity related to clinical inactivity, and closure of eyes with an "ON-OFF" behavior. PMID- 29631300 TI - Correction: Pancreatoscopy-guided laser lithotripsy in a patient with difficult ductal stone. PMID- 29631301 TI - Magnetic compression anastomosis for biliary obstruction after partial hepatectomy. PMID- 29631302 TI - Severe peritonitis after successful endoscopic ultrasound-guided gallbladder drainage for acute gangrenous cholecystitis. PMID- 29631303 TI - Rendezvous recanalization of a postoperative coloanal anastomotic dehiscence with a lumen-apposing metal stent. PMID- 29631304 TI - A rare case of gastric wall abscess arising after endoscopic ultrasound-guided fine-needle aspiration of solid pancreatic mass. PMID- 29631306 TI - A Comparison of GFR Estimation Formulae in Pediatric Oncology. AB - BACKGROUND: Application of potentially nephrotoxic chemotherapy requires continuous monitoring of renal function for toxicity and dosing. Novel pediatric glomerular filtration rate (GFR) estimating equations including cystatin C have been proposed to enhance the reliability of GFR calculation. MATERIALS AND METHODS: We examined a pediatric oncologic data set with a total of 363 GFR measurements. An analysis of distribution characteristics and comparison of medians was performed to compare creatinine and cystatin C-based GFR estimating formulae. Furthermore, we investigated the clinical impact of different equations in regard to therapeutic consequences. RESULTS: Significant differences in estimated GFR values were calculated depending on the applied formula (range of median GFR from 94.8 to 180.9 mL/min per 1.73 m2) which may result in different therapeutic consequences for the use of potentially nephrotoxic chemotherapeutic agents. Significant correlation for all examined formulae was identified, however there were large fluctuations among the correlation coefficients ranging from 0.254 to 1.0. CONCLUSION: This study compares proposed pediatric GFR estimating equations in a clinical setting. It underlines the current limitations and difficulties of GFR estimation including potential dosing errors. Cystitis C based equations can be used as alternatives to creatinine-based estimations when the appropriate laboratory method has been applied. A comparative calculator for pediatric GFR estimating equations along with background information is provided at http://gfr.pedz.de and may support clinical decision-making. PMID- 29631307 TI - [Individual Motivational Interventions after Alcohol-Related Event Treated in Hospital - Effective Option for Secondary Prevention in Adolescence?] AB - Individual Motivational Interventions after alcohol-related event treated in Hospital - Effective Option for Secondary Prevention in Adolescence? In a prospective, randomized, single-blind study 48 adolescents between 13 and 17 years answered a standardized questionnaire about their behavior of alcohol consumption after an alcohol-related event with hospitalization. They were divided in 2 groups by randomization: Group A (n=28) took part in an individual motivational intervention (HaLT-Praventionsprojekt), Group B (n=20) did not get any intervention. Six and 12 weeks after the hospitalization the same questionnaire was answered again by telephone-based interviews. The interviewer did not know to which group the interview-partner belonged. 58% (n=28) of all adolescents drank less alcohol or in a lower frequency than before the alcohol related event. 17% (n=8) did not drink any alcohol in that period of 12 weeks. 54% (n=26) explained, that they had no events of drunkenness in that period. 38% (n=18) did not change their behavior in consumption of alcohol. 6% (n=3) drank more or in higher frequency than before. We could not find any significant difference in the behavior of alcohol-consumption of both groups: 58% (A) resp. 65% (B) drank less than the time before the alcohol-related event (chi2=0,6269; p=0,4285). An influence of the individual motivational intervention could not be shown. Further studies should include interventions for parents and peers. PMID- 29631305 TI - Endoscopic management of acute necrotizing pancreatitis: European Society of Gastrointestinal Endoscopy (ESGE) evidence-based multidisciplinary guidelines. AB - 1: ESGE suggests using contrast-enhanced computed tomography (CT) as the first line imaging modality on admission when indicated and up to the 4th week from onset in the absence of contraindications. Magnetic resonance imaging (MRI) may be used instead of CT in patients with contraindications to contrast-enhanced CT, and after the 4th week from onset when invasive intervention is considered because the contents (liquid vs. solid) of pancreatic collections are better characterized by MRI and evaluation of pancreatic duct integrity is possible. Weak recommendation, low quality evidence. 2: ESGE recommends against routine percutaneous fine needle aspiration (FNA) of (peri)pancreatic collections. Strong recommendation, moderate quality evidence. FNA should be performed only if there is suspicion of infection and clinical/imaging signs are unclear. Weak recommendation, low quality evidence. 3: ESGE recommends initial goal-directed intravenous fluid therapy with Ringer's lactate (e. g. 5 - 10 mL/kg/h) at onset. Fluid requirements should be patient-tailored and reassessed at frequent intervals. Strong recommendation, moderate quality evidence. 4: ESGE recommends against antibiotic or probiotic prophylaxis of infectious complications in acute necrotizing pancreatitis. Strong recommendation, high quality evidence. 5: ESGE recommends invasive intervention for patients with acute necrotizing pancreatitis and clinically suspected or proven infected necrosis. Strong recommendation, low quality evidence.ESGE suggests that the first intervention for infected necrosis should be delayed for 4 weeks if tolerated by the patient. Weak recommendation, low quality evidence. 6: ESGE recommends performing endoscopic or percutaneous drainage of (suspected) infected walled-off necrosis as the first interventional method, taking into account the location of the walled-off necrosis and local expertise. Strong recommendation, moderate quality evidence. 7: ESGE suggests that, in the absence of improvement following endoscopic transmural drainage of walled-off necrosis, endoscopic necrosectomy or minimally invasive surgery (if percutaneous drainage has already been performed) is to be preferred over open surgery as the next therapeutic step, taking into account the location of the walled-off necrosis and local expertise. Weak recommendation, low quality evidence. 8: ESGE recommends long-term indwelling of transluminal plastic stents in patients with disconnected pancreatic duct syndrome. Strong recommendation, low quality evidence. Lumen-apposing metal stents should be retrieved within 4 weeks to avoid stent-related adverse effects.Strong recommendation, low quality evidence. PMID- 29631308 TI - [S2-Guideline: Pediatric Flat Foot]. AB - In pediatric flat foot a differentiation has to be made between the flexible and the rigid form. The diagnosis is based on the history, clinical examination as well as pedobarography, gait analysis and imaging techniques. It is important to rule out neuropediatric conditions such as muscular dystrophies, Ehlers-Danlos- or Marfan syndrome. In children six years of age and younger a flexible flat foot is nearly always physiological (97% of all 19 months old children). Up to the age of ten years the medial column of the foot is developing. Only a minority of children (4% in ten year olds) has a persistent or progressive deformity. Beyond to age of ten there is a danger of deformity decompensation as well as an increased rigidity. Only a minority of children develops some pain (< 2%). A clear risk factor for persistent pediatric flat foot is obesity (62% of six year old children with flat foot are obese). Pathogenetic factors include muscular, bony or soft tissue conditions. However, there specific rule is still unclear. Prevention consists in a thorough parent information about the normal development as well as encouragement of regular sportive activities. Soft and large enough shoes should be carried as a protection. Barfoot walking has to be encouraged on uneven grounds. If physiotherapy is needed different methods can be applied. Orthosis treatment should include a proprioceptive approach. Surgical interventions in children are rare. If surgical treatment is planned a detailed algorhythm should be used before utilizing one of the many different surgical methods. PMID- 29631309 TI - History of Foot-and-mouth disease in North African countries. AB - Foot-and-mouth disease (FMD) is a highly infectious and contagious transboundary viral disease of domesticated and wild cloven-hoofed animals. Wide prevalence of FMD in Asia and Africa associated with huge economic losses to livestock farming and industry prompted global concern. The present review summarizes the state of the art research in epidemiology, diagnosis, and surveillance of FMD in the North African countries. Even if the situation varies across the North African states, FMD is still a key factor affecting livestock production in this part of the world. Historically, 4 serotypes have circulated in North Africa (O, A, SAT2, and C) with type O being the most prevalent serotype, followed by serotype A. However, the rapid spread of SAT2 lineages from Libya to Egypt in 2012 and the O lineages from Libya to Tunisia, Algeria, and Morocco between 2014 and 2015 demonstrated the need for a robust surveillance system to detect and respond effectively to exotic infections. Emergence and re-emergence of FMD virus genotypes/lineages have been detected engendering the need to replace vaccine strains quite frequently. PMID- 29631310 TI - Spatial clustering of pathology submissions during the initial introduction and spread of avian influenza H5N1 in poultry in Nigeria in 2006-2007. AB - Highly pathogenic avian influenza (HPAI) virus H5N1 spread throughout Nigeria between 2006 and 2007. Bird samples collected across the country were submitted through the free-of-charge (FOC) program to the National Veterinary Research Institute, Vom (NVRI-Vom) laboratory. The present article describes the spatial distributions and evaluated clustering of the FOC submissions from poultry farms at the global, local, and focal levels between 2006 and 2007 epidemic in Nigeria. Spatial statistics evaluating clustering of the FOC submissions were implemented using the Moran's I test, the purely spatial cluster analysis with the SaTScan Poisson model, and the Bithell's linear score test. A significant global clustering of the FOC submissions was observed. Significant local clusters of submissions were observed in the North-East, North-Central, and South-West zones. There was significant decline in FOC submissions with increasing distance from NVRI-Vom. These results indicated that the geographic area of influence of the FOC submission program in Nigeria was limited to regions closer to the diagnostic laboratory. This work provides a detailed insight into the surveillance activities during the HPAI outbreaks in Nigeria, and should assist policy-makers and field veterinarians to improve the effectiveness of national eradication plans in the face of any outbreak of animal diseases. PMID- 29631311 TI - Estimating the prevalence of Brucellosis in cattle in Zimbabwe from samples submitted to the Central Veterinary Laboratory between 2010 and 2014. AB - Brucellosis is a disease caused by bacteria belonging to the genus Brucella, which is endemic in sub-Saharan African countries, including Zimbabwe. Zimbabwe has a widespread dairy industry with peri-urban dairy establishments built in order to improve milk availability to rural communities. This study has been the first attempt to estimate the prevalence of brucellosis in Zimbabwe as a whole, using samples submitted to the Central veterinary laboratory between 2010 and 2014. A total of 156 farms were tested with Rose Bengal Test (RBT), Complement Fixation Test (CFT) and Milk Ring Test (MRT). Parallel testing was used to determine whether or not a farm was to be considered positive: 30.1% (95% C.I.: 23.5% - 37.8%) of the farms tested were found positive (47/156). Harare district had the highest number of sample submissions with 6 out of 17 farms testing positive (P = 37.5%; 95% C.I.: 18.4% - 61.7%). Awareness of milk-borne zoonoses is reportedly generally low in farmers (41.5%). This is even more the case in small-holder farmers who have higher likelihoods of selling or ingesting raw milk compared with dairy farmers. The results show the need to carry out surveillance of brucellosis in cattle in Zimbabwe to understand the spatial distribution of the disease in the country. This is particularly relevant given the zoonotic and economic implications of this disease. PMID- 29631312 TI - Kisspeptin and bovine follicular cysts. AB - The aim of this study was to investigate kisspeptin (Kp) and sexual hormone blood concentrations in healthy dairy cows (H) and in cows diagnosed with ovarian follicular cysts (FC). Forty dairy cows were enrolled in this study and divided in 2 groups of 20 subjects each. All cows underwent blood collection on the day of diagnosis and on that of heat detection, respectively. Kisspeptin 10, estradiol, and progesterone blood concentrations were assessed. All the parameters were higher in Group FC than in Group H. These results suggest that the higher steroid levels found may have determined the increase in Kp secretion in the cystic cows. This, in turn, may have directly or indirectly stimulated the sustained Luteinizing Hormone (LH) release, known to occur in dairy cystic disease. PMID- 29631313 TI - Evaluation of factors affecting the efficacy of treatment against Fascioloides magna in wild red deer population. AB - Deer fascioloidosis is a serious and potentially fatal disease caused by the non native trematode Fascioloides magna. Infections of red deer with F. magna in Croatia have been reported for the first time in 2000 in the Baranja region. Subsequently, the disease spread throughout the Eastern parts of the country, involving all 3 deer species (red, roe, and fallow) and mouflons. Within the disease control programme (DCP), livers from all shot deer were thoroughly analysed and all detected trematodes and gross lesions were counted and categorized. Prevalence of positive animals, in this study for Spacva region, in the period ranging from 2007 to 2012 was 36.42% (46.39% when fawns are not considered). Epidemiological analysis was applied to evaluate risk factors and disease patterns at the population level with the aim to understand factors with negative influence on therapeutic effect. Each demographic variable was tested at the seasonal, individual and location level. Model for pathological lesions suggested that the likelihood of lesions was dependent on age (p = 0.003). We did not find any locality or sex related significant differences. Finally, environmental characteristics and migratory patterns were analysed using Geographic Information System (GIS) and showed that Spacva region represents an epidemiological unit for red deer fascioloidosis. PMID- 29631314 TI - Radiostrontium accumulation in animal bones: development of a radiochemical method by ultra low-level liquid scintillation counting for its quantification. AB - Strontium-90 (90Sr) is a fission product, resulting from the use of uranium and plutonium in nuclear reactors and weapons. Consequently, it may be found in the environment as a consequence of nuclear fallouts, nuclear weapon testing, and not correct waste management. When present in the environment, strontium-90 may be taken into animal body by drinking water, eating food, or breathing air. The primary health effects are bone tumors and tumors of the blood-cell forming organs, due to beta particles emitted by both 90Sr and yttrium-90 (90Y). Moreover, another health concern is represented by inhibition of calcification and bone deformities in animals. Actually, radiometric methods for the determination of 90Sr in animal bones are lacking. This article describers a radiochemical method for the determination of 90Sr in animal bones, by ultra low level liquid scintillation counting. The method precision and trueness have been demonstrated through validation tests (CV% = 12.4%; mean recovery = 98.4%). Detection limit and decision threshold corresponding to 8 and 3 mBecquerel (Bq) kg-1, respectively, represent another strong point of this analytical procedure. This new radiochemical method permits the selective extraction of 90Sr, without interferences, and it is suitable for radiocontamination surveillance programs, and it is also an improvement with respect to food safety controls. PMID- 29631315 TI - Validation of the Italian version of the UNESP-Botucatu multidimensional composite pain scale for the assessment of postoperative pain in cats. AB - The study described in this paper had the goal to validate the Italian version of the UNESP-Botucatu multidimensional composite pain scale (UNESP-Botucatu MCPS) to assess postoperative pain in cats using video analysis and psycometric testing. The English version of the scale was translated into Italian. Thirty videos of the perioperative period of ovariohysterectomy surgery were analysed by 5 Italian observers with the aim to determine the pain score using the Italian version of the scale and to verify the need for analgesic treatment for each cat. Obtained scores were submitted to psycometric validity, responsiveness, and reliability tests. Of the 3 domains identified by factor analysis, the internal consistency was excellent for 'Psychomotor changes' and 'Protection of the painful area and vocal expressions of pain', while 'Physiological variables' showed moderate internal consistency. Significant changes in pain scores in response to surgery and analgesics confirmed content and construct validity. The agreement between the 'gold standard' and the blinded observers supported the criterion validity. Inter- and intra-rater reliability ranged from good to very good for all scale items. The cut-off point for rescue analgesia was > 7. The study concluded that the Italian version of the UNESP-Botucatu MCPS is a valid and reliable instrument for assessing postoperative pain in cats. The cut-off point for rescue analgesia provides an additional tool for guiding analgesic therapy. PMID- 29631316 TI - Bartonella infections in humans dogs and cats. AB - Bartonellae are emerging vector-borne pathogens distributed worldwide that can cause various clinical symptoms in humans and animals, ranging from a mild flu like illness to more severe manifestations such as endocarditis, myocarditis, arthritis, hepatitis, and arthralgia. Numerous mammalian species, including domestic animals such as dogs, cats, as well as humans, serve as reservoir hosts for various Bartonella species. The vectors play a central role in the transmission of these bacteria and pets and their ectoparasites can pose a serious risk of zoonoses. This paper reviews selected literature on important bartonellosis of dogs, cats, and humans with notes on transmission, vectors, pathogenesis, and diagnosis. PMID- 29631317 TI - Anaplasma phagocytophilum infection in thrombocytopenic dogs. AB - Anaplasma and Ehrlichia spp. are tick-transmitted bacteria of clinical relevance in European dogs. The diagnosis of infection is often difficult due to the wide spectrum of disease caused by them. During infection, reduction in platelet count is considered the most common haematological abnormality, frequently representing the sole alteration in asymptomatic dogs. In this study, the presence of bacteria belonging to the genera Anaplasma and Ehrlichia was investigated in Northern Italy in blood samples from 159 thrombocytopenic dogs using a polymerase chain reaction (PCR) assay amplifying a portion of the heat shock gene (groEL). Obtained amplicons were sequenced and analysed. Two dogs were positive for A. phagocytophilum, while A. platys and E. canis were not detected. None of the PCR positive dogs were diagnosed at the time of hospital admission, even in the presence of clinical signs and clinicopathological abnormalities potentially related to A. phagocytophilum infection. Nucleotide sequence analysis showed that the 2 detected strains belonged to the cluster Europe 1 and were different from each other. This study confirms the presence of A. phagocytophilum infections in dogs of Northern Italy, causing clinical signs and laboratory abnormalities that could not be properly diagnosed and treated. PMID- 29631318 TI - Detection and characterization of Distemper virus in a mink (Neovison vison) in Turkey. AB - In this study a mink showing hard pad disease like symptoms was euthanised. Heart blood and various tissue samples collected during necroscopy and tested by specific RT-PCR were found positive for CDV. H and F gene segments of the CDV strain was also partially sequenced using the appropriate primers, and subsequently the sequences were analysed and compared with same gene fragment sequence of other CDV isolates from different countries. The results of the phylogenetic analysis showed that the Turkish-Mink distemper strain is closely related to European CDV strains of lineage 1. Additionally, the distemper antigen was also detected when the tissue samples were examined by histology or immunohistochemistry. PMID- 29631319 TI - Epizootic haemorrhagic disease virus circulation in Tunisia. AB - Epizootic haemorrhagic disease virus (EHDV) was detected for the first time in Tunisia and in other Northern African countries in 2006. The objective of the present study was to investigate whether EHDV circulated in Tunisian livestock before and after the officially-reported outbreak of 2006. Thus, serum samples from cattle and dromedaries collected in different time periods (before and after 2006) and from different regions of Tunisia were screened for the presence of EHDV antibodies. Serological investigations conducted on cattle and dromedary sera collected in 2000 and 2001 demonstrated no virus circulation on these dates. However, viral circulation was evidenced in 2012 and 2013, although no EHDV cases were officially reported in these years. Serum-neutralization assessed on few ELISA positive samples, confirmed the presence of antibodies against EHDV serotype 6, which was the serotype involved in the EHDV outbreak in the Maghreb region in 2006. PMID- 29631321 TI - Dendrites of the dorsal and ventral hippocampal CA1 pyramidal neurons of singly housed female rats exhibit lamina-specific growths and retractions during adolescence that are responsive to pair housing. AB - Adolescence is accompanied by increased vulnerability to psychiatric illnesses, including anxiety, depression, schizophrenia, and eating disorders. The hippocampus is important for regulating emotional state through its ventral compartment and spatial cognition through its dorsal compartment. Previous animal studies have examined hippocampal development at stages before, after or at single time points during adolescence. However, only one study has investigated morphological changes at multiple time points during adolescence, and no study has yet compared developmental changes of dorsal versus ventral hippocampi. We analyzed the dorsal and ventral hippocampi of rats to determine the developmental trajectory of Golgi-stained hippocampal CA1 neurons by sampling at five time points, ranging from postnatal day (P) 35 (puberty) to 55 (end of adolescence). We show that the dorsal hippocampus undergoes transient dendritic retractions in stratum radiatum (SR), while the ventral hippocampus undergoes transient dendritic growths in SR. During adulthood, stress and hormonal fluctuations have been shown to alter the physiology and morphology of hippocampal neurons, but studies of the impact of these factors upon adolescent hippocampi are scarce. In addition, we show that female-female pair housing from P 36-44 significantly increases branching in the dorsal SR and reduces branching in the ventral SR. Taken together with data on spine density, these results indicate that pyramidal cells in the dorsal and ventral CA1 of female adolescents are remodeled differently following single housing. Social housing during adolescence elicits pathway-specific changes in the hippocampus that may underlie behavioral benefits, including stability of emotion regulation and superior cognition. PMID- 29631320 TI - A Facile Method for Producing Selenocysteine-Containing Proteins. AB - Selenocysteine (Sec, U) confers new chemical properties on proteins. Improved tools are thus required that enable Sec insertion into any desired position of a protein. We report a facile method for synthesizing selenoproteins with multiple Sec residues by expanding the genetic code of Escherichia coli. We recently discovered allo-tRNAs, tRNA species with unusual structure, that are as efficient serine acceptors as E. coli tRNASer . Ser-allo-tRNA was converted into Sec-allo tRNA by Aeromonas salmonicida selenocysteine synthase (SelA). Sec-allo-tRNA variants were able to read through five UAG codons in the fdhF mRNA coding for E. coli formate dehydrogenase H, and produced active FDHH with five Sec residues in E. coli. Engineering of the E. coli selenium metabolism along with mutational changes in allo-tRNA and SelA improved the yield and purity of recombinant human glutathione peroxidase 1 (to over 80 %). Thus, our allo-tRNAUTu system offers a new selenoprotein engineering platform. PMID- 29631322 TI - Lewis Base Free Oxophosphonium Ions: Tunable, Trigonal-Planar Lewis Acids. AB - Oxophosphonium ions (R2 P=O)+ are fascinating chemical intermediates related to the well-known acylium cations (RC=O)+ , and comprise a tricoordinate phosphorus(V) center with a phosphorus-oxygen double bond. Here, we report the synthesis of two oxophosphonium ions stabilized by bulky imidazolin-2-imine and imidazolin-2-olefin substituents attached to phosphorus. The novel species were characterized by NMR spectroscopy and single-crystal X-ray diffraction analysis, and the bonding situation was probed by DFT calculations. Determination of the acceptor number and the fluoride ion affinity revealed that the choice of the substituents has a strong influence on the electrophilicity of the phosphorus center. Additionally, the formation of Lewis base adducts with pyridine derivatives and the reactivity with isopropyl alcohol was explored. PMID- 29631323 TI - Latent risk assessment tool for health care leaders. AB - Efforts to improve quality of care and patient safety have concentrated on provider practice and frontline care processes. Little attention has focused on understanding the role that leadership decisions play in creating risk within a health care system. The framework and tool described in this article builds on Reason's construct of latent organizational failure, by assessing the latent risks of leadership decisions, and identifying appropriate mitigation strategies before the implementation of a change. Stakeholders who will be involved in or impacted by the change are engaged in the assessment to more thoroughly explore both technical and cultural risks. PMID- 29631324 TI - Multiple admissions for acetaminophen overdose: Acetaminophen frequent fliers, a new entity? PMID- 29631325 TI - Reply. PMID- 29631326 TI - Evidence-based dosing of maintenance subcutaneous immunotherapy: a contemporary review of state-of-the-art practice. AB - BACKGROUND: Subcutaneous immunotherapy is an effective allergy treatment only if properly dosed. In this article we review the data on the probable effective dose range for subcutaneous immunotherapy and convert the recommended doses into a clinically relevant format. METHODS: A comprehensive literature search of dose response subcutaneous immunotherapy studies was done of EBM databases, Medline database, PreMedline, and the National Guideline Clearinghouse for the period 1980-2016. Recommended doses were converted to the volume of allergen extract that should be added to a 5-mL maintenance vial. RESULTS: A safe and effective dose for subcutaneous immunotherapy is likely 5-20 MUg of major allergen per injection. A 0.5-mL injection from a 5-mL maintenance vial containing 0.2 mL of manufacturer's extract of each allergen should reach the lower end of the probable effective dose range for most allergens. A larger volume of extract is required to reach that range when treatment includes cat, dog, or only 1 dust mite. Increasing beyond the commonly prescribed 0.2 mL of manufacturer's extract added to a 5-mL treatment vial is reasonable for nearly all allergens to achieve a maintenance dose higher in the probable effective dose range. CONCLUSION: Current otolaryngic allergy practice usually escalates patients to 0.5-mL injections from 5-mL maintenance vials containing 0.2 mL of manufacturer's extract of each allergen. With the main exceptions of cat and dog, those injections administered 1 or 2 times per month likely provide an efficacious dose of allergen and are consistent with published guidelines. A larger volume of extract should be considered in certain clinical situations. PMID- 29631327 TI - Analysis of the first-time pass rate of the American College of Veterinary Emergency and Critical Care certifying examination (2010-2015). AB - OBJECTIVES: To disseminate information regarding the annual pass rates for the American College of Veterinary Emergency and Critical Care (ACVECC) certifying examination. To compare the first-time pass rates (FTPR) of ACVECC residents trained in academic and private practice settings. DESIGN: Retrospective study. SETTING: ACVECC examination. ANIMALS: None. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Anonymized ACVECC examination performance data from 2010-2015 inclusive were analyzed. Overall pass rates and FTPR were calculated for all candidates and categorized by type of residency training program. The overall pass rate for all candidates was 64.3%. The median pass rate for the 6-year period was 63.8% [IQR 59.3-67.3%]. The FTPR for residents trained in academic programs was significantly higher than for residents trained in private practice (77.1% vs 47.2%, P < 0.0001). When residents were subdivided by species-focus of training program, there was no significant difference between academic versus private practice training programs for large-animal candidates (P = 0.2), but there remained a significant difference between residency training programs for small-animal candidates (P < 0.0001). CONCLUSIONS: Between 2010 and 2015 residents trained in academic training programs were significantly more likely to pass the ACVECC certifying examination compared to those trained in private practice training programs. The causes of this difference are uncertain, are likely multifactorial and warrant further investigation. PMID- 29631328 TI - Training cognitive control to reduce emotional vulnerability in breast cancer. AB - OBJECTIVES: Breast cancer enhances anxiety and depressive vulnerability, profoundly impairing the quality of life in survivors. Hinging on recent research that training attentional control can reduce emotional vulnerability, we assess how improving cognitive function could reduce emotional vulnerability in female survivors of breast cancer. METHODS: Participants took part in a course of adaptive dual n-back cognitive training (Training Group) or a non-adaptive active control group (Active Control) for 12 days across a 2-week period. Transfer related training gains were assessed immediately after the intervention, at a shorter 1-month follow-up and at a longer follow-up time of approximately 15 months post intervention, to assess sustainability of training effects. RESULTS: Adaptive cognitive training reduced anxiety and rumination with effects evident at shorter and longer term follow-up assessments. CONCLUSIONS: Our results are among the first to suggest that adaptive cognitive training can reduce emotional vulnerability in breast cancer, with the potential to enhance quality of life in survivorship. Our findings have profound implications for designing interventions targeting cognitive function in populations who have suffered from cancer. PMID- 29631329 TI - Curious about the Future. AB - "... We must excite people about the value and possibilities of science. For this we need ambitious plans that push the boundaries of what is possible. They can unleash a passion for discovery and a desire to pursue the new and the unknown. I am convinced that groundbreaking innovation is possible. Responsible entrepreneurship and scientific curiosity can still take us a lot further ..." Read more in the Editorial by Stefan Oschmann. PMID- 29631330 TI - Spotlights on our sister journals: Angew. Chem. Int. Ed. 16/2018. PMID- 29631331 TI - Winners of the Emanuel Merck Lectureship and the Heinrich Emanuel Merck Award. PMID- 29631334 TI - Reply to the comments on "Improving physical fitness and health status perception in community-dwelling older adults through a structured program for physical activity promotion in the city of Naples, Italy: A randomized controlled trial". PMID- 29631333 TI - A commercial soy-based phospholipid emulsion accelerates clot formation in normal canine whole blood and induces hemolysis in whole blood from normal and dogs with inflammatory leukograms. AB - OBJECTIVE: To compare lipid emulsion-induced hemolysis in blood from dogs with inflammatory leukograms to blood from healthy dogs, and determine the impact of a prototypical soy-based phospholipid emulsion on coagulation in whole blood from healthy dogs. DESIGN: Ex vivo study using EDTA and citrated whole blood from healthy dogs and EDTA anticoagulated whole blood from dogs with inflammatory leukograms. SETTING: University research laboratory. ANIMALS: Healthy dogs (total of 16, 9 for hemolysis assays and 6 for thromboelastography) included student- and staff-owned animals. Blood samples from dogs with inflammatory leukograms (8) were obtained from the clinical pathology laboratory after the complete blood count was performed as part of patient care. For the purposes of this study, an inflammatory leukogram was defined as a neutrophilia with a left-shift (minimum of 3% band neutrophils) and evidence of toxic change. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Hemolysis was measured via spectrophotometric quantification of released hemoglobin and expressed as a percent of a water-lysed control. The soy emulsion caused hemolysis in blood from healthy dogs, ranging from 3.6% to 16.4% as the dose increased, and 4.1% to 25.0% in blood from dogs with inflammatory leukograms. Hemolysis between these patient groups was significantly different at the highest dose. Coagulation was assessed by native thromboelastography. Treatment of whole blood with the lipid emulsion caused a significant decrease in the time to clot formation (R) and a shorter time to reach a clot amplitude of 20 mm (K). CONCLUSIONS: Soy-based lipid emulsions cause hemolysis that is more severe in blood from dogs with inflammatory leukograms and accelerate clot formation in canine blood. The in vivo significance of these findings is not clear at this time, but warrants additional investigation given the use of these emulsions in clinical practice. PMID- 29631332 TI - Neutrophil extracellular traps promote inflammation and development of hepatocellular carcinoma in nonalcoholic steatohepatitis. AB - : Nonalcoholic steatohepatitis (NASH) is a progressive, inflammatory form of fatty liver disease. It is the most rapidly rising risk factor for the development of hepatocellular carcinoma (HCC), which can arise in NASH with or without cirrhosis. The inflammatory signals promoting the progression of NASH to HCC remain largely unknown. The propensity of neutrophils to expel decondensed chromatin embedded with inflammatory proteins, known as neutrophil extracellular traps (NETs), has been shown to be important in chronic inflammatory conditions and in cancer progression. In this study, we asked whether NET formation occurs in NASH and contributes to the progression of HCC. We found elevated levels of a NET marker in serum of patients with NASH. In livers from STAM mice (NASH induced by neonatal streptozotocin and high-fat diet), early neutrophil infiltration and NET formation were seen, followed by an influx of monocyte-derived macrophages, production of inflammatory cytokines, and progression of HCC. Inhibiting NET formation, through treatment with deoxyribonuclease (DNase) or using mice knocked out for peptidyl arginine deaminase type IV (PAD4-/- ), did not affect the development of a fatty liver but altered the consequent pattern of liver inflammation, which ultimately resulted in decreased tumor growth. Mechanistically, we found that commonly elevated free fatty acids stimulate NET formation in vitro. CONCLUSION: Our findings implicate NETs in the protumorigenic inflammatory environment in NASH, suggesting that their elimination may reduce the progression of liver cancer in NASH. (Hepatology 2018). PMID- 29631335 TI - Simple chart for practical screening of low muscle mass in well-functioning middle-aged and older men and women. PMID- 29631336 TI - Frailty index from routine laboratory measurements correlates with leukocyte telomere length. PMID- 29631337 TI - Changes in attitude of medical students toward home care during a required 2-week home care clinical clerkship program. PMID- 29631338 TI - Vitamin B12 deficiency can be a cause of acute reversible parkinsonism and cognitive impairment in older adults. PMID- 29631339 TI - Ulcerated colonic mass mimicking malignancy in an elderly patient. PMID- 29631340 TI - Severe acute hepatic failure in older adults with treatment-naive small lymphocytic lymphoma. PMID- 29631341 TI - Comments on: Improving physical fitness and health status perception in community dwelling older adults through a structured program for physical activity promotion in the city of Naples, Italy: A randomized controlled trial. PMID- 29631344 TI - Chemical colitis caused by hydrogen peroxide enema in a child: case report and literature review. PMID- 29631342 TI - Disruption of Renal Arginine Metabolism Promotes Kidney Injury in Hepatorenal Syndrome in Mice. AB - : Tubular dysfunction is an important feature of renal injury in hepatorenal syndrome (HRS) in patients with end-stage liver disease. The pathogenesis of kidney injury in HRS is elusive, and there are no clinically relevant rodent models of HRS. We investigated the renal consequences of bile duct ligation (BDL) induced hepatic and renal injury in mice in vivo by using biochemical assays, real-time polymerase chain reaction (PCR), Western blot, mass spectrometry, histology, and electron microscopy. BDL resulted in time-dependent hepatic injury and hyperammonemia which were paralleled by tubular dilation and tubulointerstitial nephritis with marked upregulation of lipocalin-2, kidney injury molecule 1 (KIM-1) and osteopontin. Renal injury was associated with dramatically impaired microvascular flow and decreased endothelial nitric oxide synthase (eNOS) activity. Gene expression analyses signified proximal tubular epithelial injury, tissue hypoxia, inflammation, and activation of the fibrotic gene program. Marked changes in renal arginine metabolism (upregulation of arginase-2 and downregulation of argininosuccinate synthase 1), resulted in decreased circulating arginine levels. Arginase-2 knockout mice were partially protected from BDL-induced renal injury and had less impairment in microvascular function. In human-cultured proximal tubular epithelial cells hyperammonemia per se induced upregulation of arginase-2 and markers of tubular cell injury. CONCLUSION: We propose that hyperammonemia may contribute to impaired renal arginine metabolism, leading to decreased eNOS activity, impaired microcirculation, tubular cell death, tubulointerstitial nephritis and fibrosis. Genetic deletion of arginase-2 partially restores microcirculation and thereby alleviates tubular injury. We also demonstrate that BDL in mice is an excellent, clinically relevant model to study the renal consequences of HRS. (Hepatology 2018; 00:000-000). PMID- 29631345 TI - Comparative study of oxidative stress caused by anthracene and alkyl-anthracenes in Caenorhabditis elegans. AB - Oxidative stress was evaluated for anthracene (Ant) and alkyl-Ants (9 methylanthracene [9-MA] and 9,10-dimethylanthracene [9,10-DMA]) in Caenorhabditis elegans to compare changes in toxicity due to the degree of alkylation. Worms were exposed at 1) the same external exposure concentration and 2) the maximum water-soluble concentration. Formation of reactive oxygen species, superoxide dismutase activity, total glutathione concentration, and lipid peroxidation were determined under constant exposure conditions using passive dosing. The expression of oxidative stress-related genes (daf-2, sir-2.1, daf-16, sod-1, sod 2, sod-3 and cytochrome 35A/C family genes) was also investigated to identify and compare changes in the genetic responses of C. elegans exposed to Ant and alkyl Ant. At the same external concentration, 9,10-DMA induced the greatest oxidative stress, as evidenced by all indicators, except for lipid peroxidation, followed by 9-MA and Ant. Interestingly, 9,10-DMA led to greater oxidative stress than 9 MA and Ant when worms were exposed to the maximum water-soluble concentration, although the maximum water-soluble concentration of 9,10-DMA is the lowest. Increased oxidative stress by alkyl-Ants would be attributed to higher lipid water partition coefficient and the pi electron density in aromatic rings by alkyl substitution, although this supposition requires further confirmation. PMID- 29631347 TI - Our Valuable Contributors: Reviewers of 2017. PMID- 29631346 TI - An Analysis of Infectious Disease Research Trends in Medical Journals From North Korea. AB - Objectives: This study aimed to investigate the current status of infectious disease research in North Korea by analyzing recent trends in medical journals from North Korea in comparison with research from South Korea. Methods: Three medical journals (Preventive Medicine, Basic Medicine, and Chosun Medicine) were analyzed from 2012 to 2016. Articles on tuberculosis (TB), malaria, and parasitic diseases were selected and classified by their subtopics and study areas. Two medical journals published in the South Korea were selected for a comparative analysis of research trends. Results: Of the 2792 articles that were reviewed, 93 were extracted from North Korea journals. TB research in North Korea was largely focused on multi-drug resistant TB and extrapulmonary TB, whereas research in South Korea more frequently investigated non-tuberculous mycobacteria. Research on parasitic diseases in North Korea was focused on protozoan and intestinal nematodes, while the corresponding South Korea research investigated various species of parasites. Additionally, the studies conducted in North Korea were more likely to investigate the application of traditional medicine to diagnosis and treatment than those conducted in South Korea. Conclusions: This study presents an analysis of research trends in preventive medicine in North Korea focusing on infectious diseases, in which clear differences were observed between South and North Korea. Trends in research topics suggest a high prevalence of certain parasitic diseases in North Korea that are no longer widespread in South Korea. The large proportion of studies examining traditional medicine implies a lack of affordable medicine in North Korea. PMID- 29631348 TI - Areca Nut Chewing and the Risk of Re-hospitalization and Mortality Among Patients With Acute Coronary Syndrome in Pakistan. AB - Objectives: Areca nut is widely consumed in many parts of the world, especially in South and Southeast Asia, where cardiovascular disease (CVD) is also a huge burden. Among the forms of CVD, acute coronary syndrome (ACS) is a major cause of mortality and morbidity. Research has shown areca nut chewing to be associated with diabetes, hypertension, oropharyngeal and esophageal cancers, and CVD, but little is known about mortality and re-hospitalization secondary to ACS among areca nut users and non-users. Methods: A prospective cohort was studied to quantify the effect of areca nut chewing on patients with newly diagnosed ACS by categorizing the study population into exposed and non-exposed groups according to baseline chewing status. Cox proportional hazards models were used to examine the associations of areca nut chewing with the risk of re-hospitalization and 30 day mortality secondary to ACS. Results: Of the 384 ACS patients, 49.5% (n=190) were areca users. During 1-month of follow-up, 20.3% (n=78) deaths and 25.1% (n=96) re-hospitalizations occurred. A higher risk of re-hospitalization was found (adjusted hazard ratio [aHR], 2.05; 95% confidence interval [CI], 1.29 to 3.27; p=0.002) in areca users than in non-users. Moreover, patients with severe disease were at a significantly higher risk of 30-day mortality (aHR, 2.77; 95% CI, 1.67 to 4.59; p<0.001) and re-hospitalization (aHR, 2.72; 95% CI, 1.73 to 4.26; p<0.001). Conclusions: The 30-day re-hospitalization rate among ACS patients was found to be significantly higher in areca users and individuals with severe disease. These findings suggest that screening for a history of areca nut chewing may help to identify patients at a high risk for re-hospitalization due to secondary events. PMID- 29631349 TI - Family Members of Cancer Patients in Korea Are at an Increased Risk of Medically Diagnosed Depression. AB - Objectives: Family members are often cancer patients' primary source of social and emotional support and make a major contribution to how well patients manage their illness. We compared the prevalence of depression in the family members of cancer patients and the general population. Methods: This study used the data from the fourth, fifth, and sixth rounds of the Korea National Health and Nutrition Examination Survey. The variable of interest was the presence of a cohabitating cancer patient in the family and the dependent variable was the presence of diagnosed depression. Results: The odds of having medically diagnosed depression in those with a cohabitating cancer patient in the family were significantly higher than among those who did not have cancer patients in their families (odds ratio [OR], 1.56; 95% confidence interval [CI], 1.12 to 2.17; p=0.009). The OR for females was 1.59, and this increase was statistically significant (95% CI, 1.09 to 2.31; p=0.02). Conclusions: We need to invest more effort into diagnosing and managing depression in the family members of cancer patients. This will have an impact both on their quality of life and on the well being of patients, as supporters and caregivers play an instrumental role in helping patients manage their illness. PMID- 29631350 TI - Differential Association of Vitamin D Deficiency With Albuminuria by Sex in the Korean General Population: A Cross-sectional Study of the Korea National Health and Nutrition Examination Survey 2011-2012. AB - Objectives: Albuminuria has emerged as a biomarker for several medical conditions, and vitamin D has received attention due to its associations with various disorders. We evaluated the association between low serum vitamin D levels and prevalent albuminuria by sex in the Korean general population. Methods: We analyzed 9823 participants (4401 males, 5422 females) from the Korea National Health and Nutrition Examination Survey 2011-2012 (KNHANES V-2), and categorized them as having a normal range of vitamin D levels, vitamin D insufficiency, or vitamin D deficiency. A multivariable logistic regression model was used to compare the risk of albuminuria across these groups. Stratified analyses were conducted by smoking status, obesity, and renal function. Results: Albuminuria was found in 325 of the 4401 male participants (7.4%) and in 455 of the 5422 female participants (8.4%). Among the males, vitamin D deficiency was associated with an odds ratio (OR) for albuminuria of 1.78 (95% confidence interval [CI], 1.07 to 2.97, p<0.05). However, such an association was not found in females. The association was stronger in male current smokers (OR, 3.54; 95% CI, 1.47 to 8.50; p=0.005). Conclusions: The findings of this study suggest that sex differences exist in the association between serum vitamin D deficiency and albuminuria. Additionally, we observed that the association was stronger in current smokers than in the overall male population, but was not seen in non smokers. Therefore, different approaches by sex and smoking status might be needed when considering using vitamin D as a biomarker for renal function. PMID- 29631351 TI - Barriers to Health Service Utilization Among Iranian Female Sex Workers: A Qualitative Study. AB - Objectives: In most countries around the world, sex work is an illegal activity. Female sex workers (FSWs) in Iran hide their identities, and they are known to be a hard-to-reach population. Despite free access to HIV testing, fewer than half of FSWs receive HIV testing. The purpose of this study was to characterize the reasons for which FSWs do not seek testing at drop-in centers (DICs) and voluntary counseling and testing (VCT) centers in Iran. Methods: A qualitative study was conducted in 2016. The participants were 24 FSWs who received services at VCT centers and DICs for vulnerable females in the north of Iran and 9 males who were the clients of FSWs. In this study, we made use of purposive sampling and carried out a thematic analysis. Results: We found 4 major and 6 minor themes. The major themes were: fear of being infected (with HIV), stigma, indifference, and knowledge. Conclusions: Despite the significant efforts made by the government of Iran to establish and expand DICs for vulnerable females, the number of FSWs receiving services at these centers has not been very considerable. Consequently, by introducing and implementing training programs for peer groups, it may be possible to take steps toward establishing strategic programs for the control and prevention of HIV/AIDS. PMID- 29631352 TI - Effects of Iranian Economic Reforms on Equity in Social and Healthcare Financing: A Segmented Regression Analysis. AB - Objectives: One of the main objectives of the Targeted Subsidies Law (TSL) in Iran was to improve equity in healthcare financing. This study aimed at measuring the effects of the TSL, which was implemented in Iran in 2010, on equity in healthcare financing. Methods: Segmented regression analysis was applied to assess the effects of TSL implementation on the Gini and Kakwani indices of outcome variables in Iranian households. Data for the years 1977-2014 were retrieved from formal databases. Changes in the levels and trends of the outcome variables before and after TSL implementation were assessed using Stata version 13. Results: In the 33 years before the implementation of the TSL, the Gini index decreased from 0.401 to 0.381. The Gini index and its intercept significantly decreased to 0.362 (p<0.001) 5 years after the implementation of the TSL. There was no statistically significant change in the gross domestic product or inflation rate after TSL implementation. The Kakwani index significantly increased from -0.020 to 0.007 (p<0.001) before the implementation of the TSL, while we observed no statistically significant change (p=0.81) in the Kakwani index after TSL implementation. Conclusions: The TSL reform, which was introduced as part of an economic development plan in Iran in 2010, led to a significant reduction in households' income inequality. However, the TSL did not significantly affect equity in healthcare financing. Hence, while measuring the long-term impact of TSL is paramount, healthcare decision-makers need to consider the efficacy of the TSL in order to develop plans for achieving the desired equity in healthcare financing. PMID- 29631353 TI - Expression of the B splice variant of NBCe1 (SLC4A4) in the mouse kidney. AB - Sodium-coupled bicarbonate transporters are critical for renal electrolyte transport. The electrogenic, sodium-coupled bicarbonate cotransporter, isoform 1 (NBCe1), encoded by the SLC4A4 geneencoded by the SLC4A4 gene has five multiple splice variants; the A splice variant, NBCe1-A, is the primary basolateral bicarbonate transporter in the proximal convoluted tubule. This study's purpose was to determine if there is expression of additional NBCe1 splice variants in the mouse kidney, their cellular distribution, and their regulation by metabolic acidosis. In wild-type mice, an antibody reactive only to NBCe1-A showed basolateral immunolabel only in cortical proximal tubule (PT) segments, whereas an antibody reactive to all NBCe1 splice variants (pan-NBCe1) showed basolateral immunolabel in PT segments in both the cortex and outer medulla. In mice with NBCe1-A deletion, the pan-NBCe1 antibody showed basolateral PT immunolabel in both the renal cortex and outer stripe of the outer medulla, and immunoblot analysis showed expression of a ~121-kDa protein. RT-PCR of mRNA from NBCe1-A knockout mice directed at splice variant-specific regions showed expression of only NBCe1-B mRNA. In wild-type kidney, RT-PCR confirmed expression of mRNA for the NBCe1-B splice variant and absence of mRNA for the C, D, and E splice variants. Finally, exogenous acid loading increased expression in the proximal straight tubule in the outer stripe of the outer medulla. These studies demonstrate that the NBCe1-B splice variant is present in the PT, and its expression increases in response to exogenous acid loading, suggesting it participates in the PT contribution to acid-base homeostasis. PMID- 29631355 TI - Vimentin expression is required for the development of EMT-related renal fibrosis following unilateral ureteral obstruction in mice. AB - Most renal transplants ultimately fail secondary to chronic allograft nephropathy (CAN). Vimentin (vim) is a member of the intermediate filament family of proteins and has been shown to be important in the development of CAN. One of the pathways leading to chronic renal fibrosis after transplant is thought to be epithelial to mesenchymal transition (EMT). Even though vim expression is one of the main steps of EMT, it is unknown whether vim expression is required for EMT leading to renal fibrosis and allograft loss. To this end, the role of vim in renal fibrosis was determined via unilateral ureteral obstruction (UUO) in vim knockout mice (129 svs6 vim -/-). Following UUO, kidneys were recovered and analyzed via Western blotting, immunofluorescence, and transcriptomics. Cultured human proximal renal tubular (HK-2) cells were subjected to lentiviral-driven inhibition of vim expression and then treated with transforming growth factor (TGF)-beta to undergo EMT. Immunoblotting as well as wound healing assays were used to determine development of EMT. Western blotting analyses of mice undergoing UUO reveal increased levels of vim soon after UUO. As expected, interstitial collagen deposition increased in control mice following UUO but decreased in vim -/- kidneys. Immunofluorescence analyses also revealed altered localization of beta catenin in vim -/- mice undergoing UUO without significant changes in mRNA levels. However, RNA sequencing revealed a decrease in beta-catenin-dependent genes in vim -/- kidneys. Finally, vim-silenced HK-2 cell lines undergoing EMT were shown to have decreased cellular migration during wound healing. We conclude that vim inhibition decreases fibrosis following UUO by possibly altering beta catenin localization and downstream signaling. PMID- 29631354 TI - Sphingosine-1-phosphate pathway in renal fibrosis. AB - Renal fibrosis is defined as the excessive deposition and modification of extracellular matrix (ECM) in the renal parenchyma in response to injury and inflammation, resulting in renal function loss. This condition is common to many chronic kidney diseases occurring under diverse pathological conditions, such as diabetic and hypertensive nephropathy. Sphingosine-1-phosphate (S1P) is a bioactive sphingolipid metabolite involved in the regulation of cardiovascular functions and the pathogenesis of various cardiovascular diseases. S1P has also been considered an important regulator of fibrotic diseases, playing significant roles in the differentiation of fibroblasts to myofibroblasts and in the induction of inflammatory responses during the early stages of fibrotic diseases. This minireview summarizes recent research findings regarding the importance of the sphingosine kinase-1-S1P-S1P receptor axis and its interactions with other classic fibrotic signaling pathways and the immune inflammatory response to reveal novel therapeutic targets for the treatment or prevention of renal fibrosis. PMID- 29631356 TI - Comparison of potential dietary and urinary risk factors for ammonium urate nephrolithiasis in two bottlenose dolphin ( Tursiops truncatus) populations. AB - Dietary and urinary risk factors have been implicated in conditions favoring ammonium urate nephrolithiasis in managed dolphins compared with free-ranging dolphins. In this study, urine samples were collected from 16 dolphins (8 cases, 8 controls) from the U.S. Navy Marine Mammal Program for the purposes of assessing changes in urinary biomarkers after a large meal. Urinary biomarkers and nephrolithiasis presence were assessed opportunistically in 15 long-term resident free-ranging dolphins living in Sarasota Bay, Florida. Additionally, the total purine contents of fish commonly consumed by each dolphin population were measured to evaluate potential dietary risk factors. Populations were compared for total dietary purine composition, recently fed status, nephrolithiasis presence, and differences in urinary biochemical, acid-base, and physicochemical parameters via Wilcoxon rank sum analysis and least square means. Managed dolphins had higher urinary pH and ammonium ([Formula: see text]) in both pre- and postprandial conditions and higher urinary uric acid and saturation indices of NH4U in the postprandial condition compared with free-ranging dolphins ( P < 0.05). The purine content was greater ( P < 0.0001) in the diet consumed by managed dolphins [7 mmol/Mcal metabolizable energy (ME)] than in the free-ranging dolphin diet (4 mmol/Mcal ME). Free-ranging dolphins did not show evidence of nephrolithiasis. Observed differences in urinary biomarkers and dietary purine content in these two dolphin populations suggest a pathophysiologic basis for the role of fish types on the risk of NH4U stone formation. Future research should investigate fish type and feeding frequency, inhibitors and promoters, and alkalinizing therapy for reducing NH4U nephrolithiasis in dolphins. PMID- 29631357 TI - Loss of biliverdin reductase-A promotes lipid accumulation and lipotoxicity in mouse proximal tubule cells. AB - Obesity and increased lipid availability have been implicated in the development and progression of chronic kidney disease. One of the major sites of renal lipid accumulation is in the proximal tubule cells of the kidney, suggesting that these cells may be susceptible to lipotoxicity. We previously demonstrated that loss of hepatic biliverdin reductase A (BVRA) causes fat accumulation in livers of mice on a high-fat diet. To determine the role of BVRA in mouse proximal tubule cells, we generated a CRISPR targeting BVRA for a knockout in mouse proximal tubule cells (BVRA KO). The BVRA KO cells had significantly less metabolic potential and mitochondrial respiration, which was exacerbated by treatment with palmitic acid, a saturated fatty acid. The BVRA KO cells also showed increased intracellular triglycerides which were associated with higher fatty acid uptake gene cluster of differentiation 36 as well as increased de novo lipogenesis as measured by higher neutral lipids. Additionally, neutrophil gelatinase-associated lipocalin 1 expression, annexin-V FITC staining, and lactate dehydrogenase assays all demonstrated that BVRA KO cells are more sensitive to palmitic acid-induced lipotoxicity than wild-type cells. Phosphorylation of BAD which plays a role in cell survival pathways, was significantly reduced in palmitic acid-treated BVRA KO cells. These data demonstrate the protective role of BVRA in proximal tubule cells against saturated fatty acid-induced lipotoxicity and suggest that activating BVRA could provide a benefit in protecting from obesity-induced kidney injury. PMID- 29631358 TI - Na+-Cl- cotransporter-mediated chloride uptake contributes to hypertension and renal damage in aldosterone-infused rats. AB - Recently, in addition to epithelial sodium channel alpha-subunit (alphaENaC), the thiazide-sensitive sodium-chloride cotransporter (NCC) and pendrin, also known as sodium-independent chloride/iodide transporter, were reported to be activated by aldosterone. Here, we investigated whether chloride (Cl-) is responsible for hypertension, inflammation, and renal damage in aldosterone-infused rats. Following left nephrectomy, 8-wk-old male Sprague-Dawley rats were allocated into four groups: 1) drinking 1.0% sodium chloride solution with aldosterone infusion (Aldo/NaCl rats); 2) drinking 1.44% sodium bicarbonate solution with aldosterone infusion (Aldo/NaHCO3 rats); 3) drinking distilled water with aldosterone infusion (Aldo/water rats); and 4) drinking distilled water without aldosterone infusion (sham rats). Additionally, heminephrectomized rats with aldosterone infusion were fed a 0.26% NaCl diet (control); 8.0% NaCl diet (high-Na/high-Cl); or a 4.0% NaCl 6.67% sodium citrate diet (high-Na/half-Cl). Last, Aldo/NaCl rats were treated with or without hydrochlorothiazide. Blood pressure in the Aldo/NaCl rats was significantly higher than in the Aldo/NaHCO3 rats, which was associated with the increased expression of NCC. Expression of markers of inflammation (CD3, CD68, interleukin-17A) and fibrosis (alpha-smooth muscle actin, collagen 1) were also increased in Aldo/NaCl rats. Similarly, aldosterone-infused rats fed a high Na/half-Cl diet had lower blood pressure than those fed a high-Na/high-Cl diet, with a reduction of phosphorylated NCC, but not alphaENaC and pendrin. NCC inhibition with hydrochlorothiazide attenuated interleukin-17A protein expression along with the phosphorylation of NCC in Aldo/NaCl rats. These findings suggest that NCC-mediated Cl- uptake plays important roles in the development of aldosterone-induced hypertension and renal injury. PMID- 29631359 TI - The vagal ganglia transcriptome identifies candidate therapeutics for airway hyperreactivity. AB - Mainstay therapeutics are ineffective in some people with asthma, suggesting a need for additional agents. In the current study, we used vagal ganglia transcriptome profiling and connectivity mapping to identify compounds beneficial for alleviating airway hyperreactivity (AHR). As a comparison, we also used previously published transcriptome data from sensitized mouse lungs and human asthmatic endobronchial biopsies. All transcriptomes revealed agents beneficial for mitigating AHR; however, only the vagal ganglia transcriptome identified agents used clinically to treat asthma (flunisolide, isoetarine). We also tested one compound identified by vagal ganglia transcriptome profiling that had not previously been linked to asthma and found that it had bronchodilator effects in both mouse and pig airways. These data suggest that transcriptome profiling of the vagal ganglia might be a novel strategy to identify potential asthma therapeutics. PMID- 29631360 TI - Carbonic anhydrase IX is a critical determinant of pulmonary microvascular endothelial cell pH regulation and angiogenesis during acidosis. AB - Carbonic anhydrase IX (CA IX) is highly expressed in rapidly proliferating and highly glycolytic cells, where it serves to enhance acid-regulatory capacity. Pulmonary microvascular endothelial cells (PMVECs) actively utilize aerobic glycolysis and acidify media, whereas pulmonary arterial endothelial cells (PAECs) primarily rely on oxidative phosphorylation and minimally change media pH. Therefore, we hypothesized that CA IX is critical to PMVEC angiogenesis because of its important role in regulating pH. To test this hypothesis, PMVECs and PAECs were isolated from Sprague-Dawley rats. CA IX knockout PMVECs were generated using the CRISPR-Cas9 technique. During serum-stimulated growth, mild acidosis (pH 6.8) did not affect cell counts of PMVECs, but it decreased PAEC cell number. Severe acidosis (pH 6.2) decreased cell counts of PMVECs and elicited an even more pronounced reduction of PAECs. PMVECs had a higher CA IX expression compared with PAECs. CA activity was higher in PMVECs compared with PAECs, and enzyme activity was dependent on the type IX isoform. Pharmacological inhibition and genetic ablation of CA IX caused profound dysregulation of extra- and intracellular pH in PMVECs. Matrigel assays revealed impaired angiogenesis of CA IX knockout PMVECs in acidosis. Lastly, pharmacological CA IX inhibition caused profound cell death in PMVECs, whereas genetic CA IX ablation had little effect on PMVEC cell death in acidosis. Thus CA IX controls PMVEC pH necessary for angiogenesis during acidosis. CA IX may contribute to lung vascular repair during acute lung injury that is accompanied by acidosis within the microenvironment. PMID- 29631361 TI - Endocannabinoids in the Islets of Langerhans: the ugly, the bad, and the good facts. AB - The endocannabinoid system (ECS) regulates cellular homeostasis and whole-body metabolism. There is an autonomous ECS in the endocrine pancreas, including the cannabinoid 1 receptor (CB1R) that is present in beta-cells. Here, we discuss conflicts that have arisen with regard to the function(s) of the ECs in the endocrine pancreas and that have caused confusion when defining the role of the ECS in islets of Langerhans, especially the role(s) of CB1R in beta-cells. We also discuss the latest data published concerning the ECS in islets. CB1R in particular is not simply a negative modulator of insulin secretion as it is also involved in intra-islet inflammation during high fat-high sugar intake and it is a negative regulator of beta-cell viability and turnover. We also discuss the feasibility of using CB1R as a target for the treatment of diabetes. PMID- 29631363 TI - Role of the saturated fatty acid palmitate in the interconnected hypothalamic control of energy homeostasis and biological rhythms. AB - The brain, specifically the hypothalamus, controls whole body energy and glucose homeostasis through neurons that synthesize specific neuropeptides, whereas hypothalamic dysfunction is linked directly to insulin resistance, obesity, and type 2 diabetes mellitus. Nutrient excess, through overconsumption of a Western or high-fat diet, exposes the hypothalamus to high levels of free fatty acids, which induces neuroinflammation, endoplasmic reticulum stress, and dysregulation of neuropeptide synthesis. Furthermore, exposure to a high-fat diet also disrupts normal circadian rhythms, and conversely, clock gene knockout models have symptoms of metabolic disorders. While whole brain/animal studies have provided phenotypic end points and important clues to the genes involved, there are still major gaps in our understanding of the intracellular pathways and neuron-specific components that ultimately control circadian rhythms and energy homeostasis. Because of its complexity and heterogeneous nature, containing a diverse mix cell types, it is difficult to dissect the critical hypothalamic components involved in these processes. Of significance, we have the capacity to study these individual components using an extensive collection of both embryonic- and adult derived, immortalized hypothalamic neuronal cell lines from rodents. These defined neuronal cell lines have been used to examine the impact of nutrient excess, such as palmitate, on circadian rhythms and neuroendocrine signaling pathways, as well as changes in vital neuropeptides, leading to the development of neuronal inflammation; the role of proinflammatory molecules in this process; and ultimately, restoration of normal signaling, clock gene expression, and neuropeptide synthesis in disrupted states by beneficial anti-inflammatory compounds in defined hypothalamic neurons. PMID- 29631362 TI - Gonadotropin-releasing hormone agonist in premenopausal women does not alter hypothalamic-pituitary-adrenal axis response to corticotropin-releasing hormone. AB - Sex hormones appear to play a role in the regulation of hypothalamic-pituitary adrenal (HPA) axis activity. The objective was to isolate the effects of estradiol (E2) on central activation of the HPA axis. We hypothesized that the HPA axis response to corticotropin-releasing hormone (CRH) under dexamethasone (Dex) suppression would be exaggerated in response to chronic ovarian hormone suppression and that physiologic E2 add-back would mitigate this response. Thirty premenopausal women underwent 20 wk of gonadotropin-releasing hormone agonist therapy (GnRHAG) and transdermal E2 (0.075 mg per day, GnRHAG + E2, n = 15) or placebo (PL) patch (GnRHAG + PL, n = 15). Women in the GnRHAG + PL and GnRHAG + E2 groups were of similar age (38 (SD 5) yr vs. 36 (SD 7) yr) and body mass index (27 (SD 6) kg/m2 vs. 27 (SD 6) kg/m2). Serum E2 changed differently between the groups ( P = 0.01); it decreased in response to GnRHAG + PL (77.9 +/- 17.4 to 23.2 +/- 2.6 pg/ml; P = 0.008) and did not change in response to GnRHAG + E2 (70.6 +/- 12.4 to 105 +/- 30.4 pg/ml; P = 0.36). The incremental area under the curve (AUCINC) responses to CRH were different between the groups for total cortisol ( P = 0.03) and cortisone ( P = 0.04) but not serum adrenocorticotropic hormone (ACTH) ( P = 0.28). When examining within-group changes, GnRHAG + PL did not alter the HPA axis response to Dex/CRH, but GnRHAG + E2 decreased the AUCINC for ACTH (AUCINC, 1,623 +/- 257 to 1,211 +/- 236 pg/ml.min, P = 0.004), cortisone (1,795 +/- 367 to 1,090 +/- 281 ng/ml.min, P = 0.009), and total cortisol (7,008 +/- 1,387 to 3,893 +/- 1,090 ng/ml.min, P = 0.02). Suppression of ovarian hormones by GnRHAG therapy for 20 wk did not exaggerate the HPA axis response to CRH, but physiologic E2 add-back reduced HPA axis activity compared with preintervention levels. PMID- 29631364 TI - Tricellular tight junction-associated angulins in the gill epithelium of rainbow trout. AB - Molecular physiology of the tricellular tight junction (tTJ)-associated proteins lipolysis-stimulated lipoprotein receptor ( lsr, = angulin-1) and an immunoglobulin-like domain-containing receptor ( ildr2, ~angulin-3) was examined in model trout gill epithelia. Transcripts encoding lsr and ildr2 are broadly expressed in trout organs. A reduction in lsr and ildr2 mRNA abundance was observed during and after confluence in flask-cultured gill cells. In contrast, as high-resistance and low-permeability characteristics developed in a model gill epithelium cultured on permeable polyethylene terephthalate membrane inserts, lsr and ildr2 transcript abundance increased. However, as epithelia entered the developmental plateau phase, lsr abundance returned to initial values, while ildr2 transcript abundance remained elevated. When mitochondrion-rich cells were introduced to model preparations, lsr mRNA abundance was unaltered and ildr2 mRNA abundance significantly increased. Transcript abundance of ildr2 was not altered in association with corticosteroid-induced tightening of the gill epithelium, while lsr mRNA abundance decreased. Transcriptional knockdown of the tTJ protein tricelluin (Tric) reduced Tric abundance, increased gill epithelium permeability, and increased lsr without significantly altering ildr2 transcript abundance. Data suggest that angulins contribute to fish gill epithelium barrier properties but that Lsr and Ildr2 seem likely to play different roles. This is because ildr2 typically exhibited increased abundance in association with decreased model permeability, while lsr abundance changed in a manner that suggested a role in Tric recruitment to the tTJ. PMID- 29631365 TI - Lipidated connexin mimetic peptides potently inhibit gap junction-mediated Ca2+ wave propagation. AB - Connexin (Cx) mimetic peptides (e.g., Gap27: SRPTEKTIFII; Peptide5: VDCFLSRPTEKT) reversibly inhibit hemichannel (HCh) and gap junction channel (GJCh) function in a concentration- and time-dependent manner (HCh: ~5 uM, <1 h; GJCh: ~100 uM, > 1 h). We hypothesized that addition of a hexadecyl tail to SRPTEKT (SRPTEKT- Hdc) would improve its ability to concentrate in the plasma membrane and consequently increase its inhibitory efficacy. We show that SRPTEKT- Hdc inhibited intercellular Ca2+-wave propagation in Cx43-expressing MDCK and rabbit tracheal epithelial cells in a time (61-75 min)- and concentration (IC50: 66 pM)-dependent manner, a concentration efficacy five orders of magnitude lower than observed for the nonlipidated Gap27. HCh-mediated dye uptake was inhibited by SRPTEKT- Hdc with similar efficacy. Following peptide washout, HCh-mediated dye uptake was restored to control levels, whereas Ca2+-wave propagation was only partially restored. Scrambled and reverse sequence lipidated peptides had no detectable inhibitory effect on Ca2+-wave propagation or dye uptake. Cx43 expression was unchanged by SRPTEKT- Hdc incubation; however, Triton-insoluble Cx43 was reduced by SRPTEKT- Hdc exposure and reversed following washout. In summary, our results show that SRPTEKT- Hdc blocked HCh function and intercellular Ca2+ signaling at concentrations that minimally affected dye coupling. Selective inhibition of intercellular Ca2+ signaling, likely indicative of channel conformation-specific SRPTEKT- Hdc binding, could contribute significantly to the protective effects of these mimetic peptides in settings of injury. Our data also demonstrate that lipidation represents a paradigm for development of highly potent, efficacious, and selective mimetic peptide inhibitors of hemichannel and gap junction channel mediated signaling. PMID- 29631366 TI - Pharmacological regulation of outflow resistance distal to Schlemm's canal. AB - The trabecular meshwork (TM) and Schlemm's canal generate the majority of outflow resistance; however, the distal regions of the conventional outflow pathway account for 25-50% of total resistance. Sections of distal vessels are surrounded by alpha-smooth muscle actin-containing cells, indicating that they may be vasoregulated. This study examined the effect of a potent vasodilator, nitric oxide (NO), and its physiological antagonist, endothelin-1 (ET-1), on the regulation of outflow resistance in the distal regions of the conventional outflow pathway. Using a physiological model of the conventional outflow pathway, human and porcine anterior segments were perfused in organ culture under constant flow conditions, while intrachamber pressure was continually monitored. For porcine anterior segments, a stable baseline outflow facility with TM intact was first achieved before anterior segments were removed and a trabeculotomy was performed. For human anterior segments, a trabeculotomy was immediately performed. In human anterior segments, 100 nM ET-1 significantly decreased distal outflow facility from 0.49 +/- 0.26 to 0.31 +/- 0.18 (mean +/- SD) ul.min 1.mmHg, P < 0.01. Perfusion with 100 uM diethylenetriamine-NO in the presence of 1 nM ET-1 immediately reversed ET-1 effects, significantly increasing distal outflow facility to 0.54 +/- 0.35 ul.min-1.mmHg, P = 0.01. Similar results were obtained in porcine anterior segment experiments. Therefore, data show a dynamic range of resistance generation by distal vessels in both the human and the porcine conventional outflow pathways. Interestingly, maximal contraction of vessels in the distal outflow tract of trabeculotomized eyes generated resistance very near physiological levels for both species having an intact TM. PMID- 29631367 TI - Long noncoding RNA MALAT1 contributes to inflammatory response of microglia following spinal cord injury via the modulation of a miR-199b/IKKbeta/NF-kappaB signaling pathway. AB - Long noncoding RNA (lncRNA) metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) was widely recognized to be implicated in human cancer, vascular diseases, and neurological disorders. This study was to explore the role and underlying mechanism of MALAT1 in acute spinal cord injury (ASCI). ASCI models in adult rats were established and demonstrated by a numerical decrease in BBB scores. Expression profile of MALAT1 and miR-199b following ASCI in rats and in vitro was determined using quantitative real-time PCR. RNA pull-down assays combined with RIP assays were performed to explore the interaction between MALAT1 and miR-199b. In the present study, MALAT1 expression was significantly increased (2.4-fold that of control) in the spinal cord of the rat contusion epicenter accompanied by activation of IKKbeta/NF-kappaB signaling pathway and an increase in the level of proinflammatory cytokines TNF-alpha and IL-1beta. Upon treatment with LPS, MALAT1 expression dramatically increased in the microglia in vitro, but knockdown of MALAT1 attenuated LPS-induced activation of MGs and TNF-alpha and IL 1beta production. Next, we confirmed that LPS-induced MALAT1 activated IKKbeta/NF kappaB signaling pathway and promoted the production of proinflammatory cytokines TNF-alpha and IL-1beta through downregulating miR-199b. More importantly, MALAT1 knockdown gradually improved the hindlimb locomotor activity of ASCI rats as well as inhibited TNF-alpha, IL-1beta levels, and Iba-1 protein, the marker of activated microglia in injured spinal cords. Our study demonstrated that MALAT1 was dysregulated in ASCI rats and in LPS-activated MGs, and MALAT1 knockdown was expected to attenuate ASCI through repressing inflammatory response of MGs. PMID- 29631370 TI - Vagal stimulation mimics preconditioning and postconditioning of ischemic myocardium in mice by activating different protection mechanisms. AB - Vagal stimulation (VS) during myocardial ischemia and reperfusion has beneficial effects. However, it is not known whether short-term VS applied before ischemia or at the onset of reperfusion protects the ischemic myocardium. This study was designed to determine whether short-term VS applied before ischemia or at the onset of reperfusion reduces myocardial infarct size (IS), mimicking classic preconditioning and postconditioning. A second objective was to study the participation of muscarinic and nicotinic receptors in the protection of both preischemic and reperfusion stimulation. FVB mice were subjected to 30 min of regional myocardial ischemia followed by 2 h of reperfusion without VS, with 10 min preischemic VS (pVS), or with VS during the first 10 min of reperfusion (rVS). pVS reduced IS, and this effect was abolished by atropine and wortmannin. rVS also reduced IS in a similar manner, and this effect was abolished by the alpha7-nicotinic acetylcholine receptor blocker methyllycaconitine. pVS increased Akt and glycogen synthase kinase (GSK)-3beta phosphorylation. No changes in Akt and GSK-3beta phosphorylation were observed in rVS. Stimulation-mediated IS protection was abolished with the JAK2 blocker AG490. rVS did not modify IL-6 and IL-10 levels in the plasma or myocardium. Splenic denervation and splenectomy did not abolish the protective effect of rVS. In conclusion, pVS and rVS reduced IS by different mechanisms: pVS activated the Akt/GSK-3beta muscarinic pathway, whereas rVS activated alpha7-nicotinic acetylcholine receptors and JAK2, independently of the cholinergic anti-inflammatory pathway. NEW & NOTEWORTHY Our data suggest, for the first time, that vagal stimulation applied briefly either before ischemia or at the beginning of reperfusion mimics classic preconditioning and postconditioning and reduces myocardial infarction, activating different mechanisms. We also infer an important role of alpha7-nicotinic receptors for myocardial protection independent of the cholinergic anti-inflammatory pathway. PMID- 29631369 TI - Klf4 has an unexpected protective role in perivascular cells within the microvasculature. AB - Recent smooth muscle cell (SMC) lineage-tracing studies have revealed that SMCs undergo remarkable changes in phenotype during development of atherosclerosis. Of major interest, we demonstrated that Kruppel-like factor 4 (KLF4) in SMCs is detrimental for overall lesion pathogenesis, in that SMC-specific conditional knockout of the KLF4 gene ( Klf4) resulted in smaller, more-stable lesions that exhibited marked reductions in the numbers of SMC-derived macrophage- and mesenchymal stem cell-like cells. However, since the clinical consequences of atherosclerosis typically occur well after our reproductive years, we sought to identify beneficial KLF4-dependent SMC functions that were likely to be evolutionarily conserved. We tested the hypothesis that KLF4-dependent SMC transitions play an important role in the tissue injury-repair process. Using SMC specific lineage-tracing mice positive and negative for simultaneous SMC-specific conditional knockout of Klf4, we demonstrate that SMCs in the remodeling heart after ischemia-reperfusion injury (IRI) express KLF4 and transition to a KLF4 dependent macrophage-like state and a KLF4-independent myofibroblast-like state. Moreover, heart failure after IRI was exacerbated in SMC Klf4 knockout mice. Surprisingly, we observed a significant cardiac dilation in SMC Klf4 knockout mice before IRI as well as a reduction in peripheral resistance. KLF4 chromatin immunoprecipitation-sequencing analysis on mesenteric vascular beds identified potential baseline SMC KLF4 target genes in numerous pathways, including PDGF and FGF. Moreover, microvascular tissue beds in SMC Klf4 knockout mice had gaps in lineage-traced SMC coverage along the resistance arteries and exhibited increased permeability. Together, these results provide novel evidence that Klf4 has a critical maintenance role within microvascular SMCs: it is required for normal SMC function and coverage of resistance arteries. NEW & NOTEWORTHY We report novel evidence that the Kruppel-like factor 4 gene ( Klf4) has a critical maintenance role within microvascular smooth muscle cells (SMCs). SMC-specific Klf4 knockout at baseline resulted in a loss of lineage-traced SMC coverage of resistance arteries, dilation of resistance arteries, increased blood flow, and cardiac dilation. PMID- 29631371 TI - Spheroids of cardiomyocytes derived from human-induced pluripotent stem cells improve recovery from myocardial injury in mice. AB - The microenvironment of native heart tissue may be better replicated when cardiomyocytes are cultured in three-dimensional clusters (i.e., spheroids) than in monolayers or as individual cells. Thus, we differentiated human cardiac lineage-induced pluripotent stem cells in cardiomyocytes (hiPSC-CMs) and allowed them to form spheroids and spheroid fusions that were characterized in vitro and evaluated in mice after experimentally induced myocardial infarction (MI). Synchronized contractions were observed within 24 h of spheroid formation, and optical mapping experiments confirmed the presence of both Ca2+ transients and propagating action potentials. In spheroid fusions, the intraspheroid conduction velocity was 7.0 +/- 3.8 cm/s on days 1- 2 after formation, whereas the conduction velocity between spheroids increased significantly ( P = 0.003) from 0.8 +/- 1.1 cm/s on days 1- 2 to 3.3 +/- 1.4 cm/s on day 7. For the murine MI model, five-spheroid fusions (200,000 hiPSC-CMs/spheroid) were embedded in a fibrin patch and the patch was transplanted over the site of infarction. Later (4 wk), echocardiographic measurements of left ventricular ejection fraction and fractional shortening were significantly greater in patch-treated animals than in animals that recovered without the patch, and the engraftment rate was 25.6% or 30% when evaluated histologically or via bioluminescence imaging, respectively. The exosomes released from the spheroid patch seemed to increase cardiac function. In conclusion, our results established the feasibility of using hiPSC CM spheroids and spheroid fusions for cardiac tissue engineering, and, when fibrin patches containing hiPSC-CM spheroid fusions were evaluated in a murine MI model, the engraftment rate was much higher than the rates we have achieved via the direct intramyocardial injection. PMID- 29631372 TI - Actin polymerization contributes to ROS- and Rho-dependent Ca2+ sensitization in pulmonary arteries from chronic hypoxic rats. PMID- 29631368 TI - Elastin, arterial mechanics, and cardiovascular disease. AB - Large, elastic arteries are composed of cells and a specialized extracellular matrix that provides reversible elasticity and strength. Elastin is the matrix protein responsible for this reversible elasticity that reduces the workload on the heart and dampens pulsatile flow in distal arteries. Here, we summarize the elastin protein biochemistry, self-association behavior, cross-linking process, and multistep elastic fiber assembly that provide large arteries with their unique mechanical properties. We present measures of passive arterial mechanics that depend on elastic fiber amounts and integrity such as the Windkessel effect, structural and material stiffness, and energy storage. We discuss supravalvular aortic stenosis and autosomal dominant cutis laxa-1, which are genetic disorders caused by mutations in the elastin gene. We present mouse models of supravalvular aortic stenosis, autosomal dominant cutis laxa-1, and graded elastin amounts that have been invaluable for understanding the role of elastin in arterial mechanics and cardiovascular disease. We summarize acquired diseases associated with elastic fiber defects, including hypertension and arterial stiffness, diabetes, obesity, atherosclerosis, calcification, and aneurysms and dissections. We mention animal models that have helped delineate the role of elastic fiber defects in these acquired diseases. We briefly summarize challenges and recent advances in generating functional elastic fibers in tissue-engineered arteries. We conclude with suggestions for future research and opportunities for therapeutic intervention in genetic and acquired elastinopathies. PMID- 29631373 TI - Small-conductance Ca2+-activated K+ channel activation deteriorates hypoxic ventricular arrhythmias via CaMKII in cardiac hypertrophy. AB - The molecular and electrophysiological mechanisms of acute ischemic ventricular arrhythmias in hypertrophied hearts are not well known. We hypothesized that small-conductance Ca2+-activated K+ (SK) channels are activated during hypoxia via the Ca2+/calmodulin-dependent protein kinase II (CaMKII)-dependent pathway. We used normotensive Wistar-Kyoto (WKY) rats and spontaneous hypertensive rats (SHRs) as a model of cardiac hypertrophy. The inhibitory effects of SK channels and ATP-sensitive K+ channels on electrophysiological changes and genesis of arrhythmias during simulated global hypoxia (GH) were evaluated. Hypoxia-induced abbreviation of action potential duration (APD) occurred earlier in ventricles from SHRs versus. WKY rats. Apamin, a SK channel blocker, prevented this abbreviation in SHRs in both the early and delayed phase of GH, whereas in WKY rats only the delayed phase was prevented. In contrast, SHRs were less sensitive to glibenclamide, a ATP-sensitive K+ channel blocker, which inhibited the APD abbreviation in both phases of GH in WKY rats. SK channel blockers (apamin and UCL-1684) reduced the incidence of hypoxia-induced sustained ventricular arrhythmias in SHRs but not in WKY rats. Among three SK channel isoforms, SK2 channels were directly coimmunoprecipitated with CaMKII phosphorylated at Thr286 (p-CaMKII). We conclude that activation of SK channels leads to the APD abbreviation and sustained ventricular arrhythmias during simulated hypoxia, especially in hypertrophied hearts. This mechanism may result from p-CaMKII-bound SK2 channels and reveal new molecular targets to prevent lethal ventricular arrhythmias during acute hypoxia in cardiac hypertrophy. NEW & NOTEWORTHY We now show a new pathophysiological role of small-conductance Ca2+-activated K+ channels, which shorten the action potential duration and induce ventricular arrhythmias during hypoxia. We also demonstrate that small-conductance Ca2+ activated K+ channels interact with phosphorylated Ca2+/calmodulin-dependent protein kinase II at Thr286 in hypertrophied hearts. PMID- 29631375 TI - Spontaneous and alpha-adrenoceptor-induced contractility in human collecting lymphatic vessels require chloride. AB - Human lymphatic vessels are myogenically active and respond to sympathetic stimulation. The role of various cations in this behavior has recently been investigated, but whether the anion Cl- is essential is unclear. With ethical approval and informed consent, human thoracic duct and mesenteric lymphatic vessels were obtained from surgical patients. Spontaneous or norepinephrine induced isometric force production from isolated vessels was measured by wire myography; the transmembrane Cl- gradient and Cl- channels were investigated by substitution of extracellular Cl- with the impermeant anion aspartate and inhibition of Cl- transport and channels with the clinical diuretics furosemide and bendroflumethiazide as well as DIDS and 5-nitro-2-(3 phenylpropylamino)benzoic acid. The molecular expression of Ca2+-activated Cl- channels was investigated by RT-PCR, and proteins were localized using immunoreactivity. Spontaneous and norepinephrine-induced contractility in human lymphatic vessels was highly abrogated after Cl- substitution with aspartate. About 100-300 uM DIDS or 5-nitro-2-(3-phenylpropylamino)benzoic acid inhibited spontaneous contractile behavior. Norepinephrine-stimulated tone was furthermore markedly abrogated by 200 uM DIDS. Furosemide lowered only spontaneous constrictions, whereas bendroflumethiazide had nonspecific inhibitory effects. Consistent expression of transmembrane member 16A [TMEM16A (anoctamin-1)] was found in both the thoracic duct and mesenteric lymphatic vessels, and immunoreactivity with different antibodies localized TMEM16A to lymphatic smooth muscle cells and interstitial cells. The significant change in contractile function observed with inhibitors and anion substitution suggests that Cl- movement over the plasma membrane of lymphatic myocytes is integral for spontaneous and alpha-adrenoceptor-evoked contractility in human collecting lymphatic vessels. Consistent detection and localization of TMEM16A to myocytes suggests that this channel could play a major functional role. NEW & NOTEWORTHY In this study, we report the first observations of Cl- being a critical ionic component of spontaneous and agonist-evoked contractility in human lymphatics. The most consistently expressed Ca2+-activated Cl- channel gene in the human thoracic duct and mesenteric lymphatic vessels appears to be transmembrane member 16A, suggesting that this channel plays a major role. PMID- 29631374 TI - KLF2-mediated disruption of PPAR-gamma signaling in lymphatic endothelial cells exposed to chronically increased pulmonary lymph flow. AB - Lymphatic abnormalities associated with congenital heart disease are well described, yet the underlying mechanisms remain poorly understood. Using a clinically relevant ovine model of congenital heart disease with increased pulmonary blood flow, we have previously demonstrated that lymphatic endothelial cells (LECs) exposed in vivo to chronically increased pulmonary lymph flow accumulate ROS and have decreased bioavailable nitric oxide (NO). Peroxisome proliferator-activated receptor-gamma (PPAR-gamma), which abrogates production of cellular ROS by NADPH oxidase, is inhibited by Kruppel-like factor 2 (KLF2), a flow-induced transcription factor. We hypothesized that chronically increased pulmonary lymph flow induces a KLF2-mediated decrease in PPAR-gamma and an accumulation of cellular ROS, contributing to decreased bioavailable NO in LECs. To better understand the mechanisms that transduce the abnormal mechanical forces associated with chronically increased pulmonary lymph flow, LECs were isolated from the efferent vessel of the caudal mediastinal lymph node of control ( n = 5) and shunt ( n = 5) lambs. KLF2 mRNA and protein were significantly increased in shunt compared with control LECs, and PPAR-gamma mRNA and protein were significantly decreased. In control LECs exposed to shear forces in vitro, we found similar alterations to KLF2 and PPAR-gamma expression. In shunt LECs, NADPH oxidase subunit expression was increased, and bioavailable NO was significantly lower. Transfection of shunt LECs with KLF2 siRNA normalized PPAR-gamma, ROS, and bioavailable NO. Conversely, pharmacological inhibition of PPAR-gamma in control LECs increased ROS equivalent to levels in shunt LECs at baseline. Taken together, these data suggest that one mechanism by which NO-mediated lymphatic function is disrupted after chronic exposure to increased pulmonary lymph flow is through altered KLF2-dependent PPAR-gamma signaling, resulting in increased NADPH oxidase activity, accumulation of ROS, and decreased bioavailable NO. NEW & NOTEWORTHY Lymphatic endothelial cells, when exposed in vivo to chronically elevated pulmonary lymph flow in a model of congenital heart disease with increased pulmonary blood flow, demonstrate Kruppel-like factor 2-dependent disrupted peroxisome proliferator-activated receptor-gamma signaling that results in the accumulation of reactive oxygen species and decreased bioavailable nitric oxide. PMID- 29631376 TI - Insulin-like growth factor-binding protein-4 inhibits epithelial growth and proliferation in the rodent intestine. AB - Insulin-like growth factor-binding protein-4 (IGFBP-4) is a binding protein that modulates the action of insulin-like growth factor-1 (IGF-1), a growth factor whose presence is required for the intestinotrophic effects of glucagon-like peptide-2 (GLP-2). GLP-2 is a gut hormone that uses both IGF-1 and epidermal growth factor (EGF) as intermediary factors to promote intestinal growth. Therefore, to elucidate the mechanism through which IGFBP-4 regulates IGF-1 activity in the intestine, proliferation assays were conducted using rat intestinal epithelial cells (IEC-6). IGF-1 and EGF synergistically enhanced proliferation, an effect that was dose-dependently decreased by IGFBP-4 ( P < 0.05-0.001) in an IGF-1 receptor (R)- and MEK1/2- but not a phosphatidylinositol 3-kinase-dependent manner ( P > 0.05 for IGFBP-4 effects with IGF-1R and MEK1/2 inhibitors). Intestinal organoids derived from IGFBP-4 knockout mice demonstrated significantly greater Ki-67 expression and an enhanced surface area increase in response to IGF-1 treatment, compared with organoids from control mice ( P < 0.05 0.01). GLP-2 is also known to increase the mucosal expression of IGFBP-4 mRNA. To investigate whether this occurs through the actions of its intermediaries, IGF-1 and EGF, inducible intestinal epithelial-IGF-1R knockout and control mice were treated for 10 days with and without the pan-ErbB inhibitor, CI-1033. However, no differences in mucosal IGFBP-4 mRNA expression were found for any of the treatment groups ( P > 0.05). Consistently, IEC-6 cells treated with IGF-1 and/or EGF displayed no alteration in IGFBP-4 mRNA or in cellular and secreted IGFBP-4 protein ( P > 0.05). Overall, this study establishes that endogenous IGFBP-4 plays an important role in inhibiting IGF-1-induced intestinal epithelial proliferation and that mucosal IGFBP-4 expression is independent of IGF-1 and EGF. NEW & NOTEWORTHY This study demonstrates, for the first time, the inhibitory role of locally expressed insulin-like growth factor-binding protein-4 (IGFBP-4) on the intestinal proliferative actions of IGF-1 and supports the notion of the synergistic roles of IGF-1 and EGF in promoting intestinal epithelial growth. In turn, intestinal IGFBP-4 expression was not found to be regulated by IGF-1 and/or EGF. PMID- 29631377 TI - Epimorphin regulates the intestinal stem cell niche via effects on the stromal microenvironment. AB - Stem cell therapy is a potential therapeutic approach for disorders characterized by intestinal injury or loss of functional surface area. Stem cell function and proliferation are mediated by the stem cell niche. Stromal cells such as intestinal subepithelial myofibroblasts (ISEMFs) are important but poorly studied components of the stem cell niche. To examine the role of ISEMFs, we have previously generated mice with deletion of epimorphin ( Epim), an ISEMF protein and member of the syntaxin family of intracellular vesicle docking proteins that regulate cell secretion. Herein we explore the mechanisms for previous observations that Epim deletion increases gut crypt cell proliferation, crypt fission, and small bowel length in vivo. Stem cell-derived crypt culture techniques were used to explore the interaction between enteroids and myofibroblasts from Epim-/- and WT mice. Enteroids cocultured with ISEMFS had increased growth and crypt-like budding compared with enteroids cultured without stromal support. Epim deletion in ISEMFs resulted in increased enteroid budding and surface area compared with cocultures with wild-type (WT) ISEMFs. In primary crypt cultures, Epim-/- enteroids had significantly increased surface area and budding compared with WTs. However, stem cell assays comparing the number of Epim /- vs. WT colony-forming units after first passage showed no differences in the absence of ISEMF support. Epim-/- vs. WT ISEMFs had increased Wnt4 expression, and addition of Wnt4 to WT cocultures enhanced budding. We conclude that ISEMFs play an important role in the stem cell niche. Epim regulates stem cell proliferation and differentiation via stromal contributions to the niche microenvironment. NEW & NOTEWORTHY The role of subepithelial intestinal myofibroblasts (ISEMFs) in the gut stem cell niche is controversial. We provide novel evidence supporting ISEMFs as important niche contributors. We show that the in vivo intestinal effects of deletion of myofibroblast Epim can be recapitulated in crypt stem cell cultures in vitro. ISEMFs support cocultured stem cell proliferation and enteroid growth, and these effects are augmented by deletion of Epim, a syntaxin that regulates myofibroblast cell secretion. PMID- 29631378 TI - Cytosolic phosphoenolpyruvate carboxykinase as a cataplerotic pathway in the small intestine. AB - Cytosolic phosphoenolpyruvate carboxykinase (PEPCK) is a gluconeogenic enzyme that is highly expressed in the liver and kidney but is also expressed at lower levels in a variety of other tissues where it may play adjunct roles in fatty acid esterification, amino acid metabolism, and/or TCA cycle function. PEPCK is expressed in the enterocytes of the small intestine, but it is unclear whether it supports a gluconeogenic rate sufficient to affect glucose homeostasis. To examine potential roles of intestinal PEPCK, we generated an intestinal PEPCK knockout mouse. Deletion of intestinal PEPCK ablated ex vivo gluconeogenesis but did not significantly affect glycemia in chow, high-fat diet, or streptozotocin treated mice. In contrast, postprandial triglyceride secretion from the intestine was attenuated in vivo, consistent with a role in fatty acid esterification. Intestinal amino acid profiles and 13C tracer appearance into these pools were significantly altered, indicating abnormal amino acid trafficking through the enterocyte. The data suggest that the predominant role of PEPCK in the small intestine of mice is not gluconeogenesis but rather to support nutrient processing, particularly with regard to lipids and amino acids. NEW & NOTEWORTHY The small intestine expresses gluconeogenic enzymes for unknown reasons. In addition to glucose synthesis, the nascent steps of this pathway can be used to support amino acid and lipid metabolisms. When phosphoenolpyruvate carboxykinase, an essential gluconeogenic enzyme, is knocked out of the small intestine of mice, glycemia is unaffected, but mice inefficiently absorb dietary lipid, have abnormal amino acid profiles, and inefficiently catabolize glutamine. Therefore, the initial steps of intestinal gluconeogenesis are used for processing dietary triglycerides and metabolizing amino acids but are not essential for maintaining blood glucose levels. PMID- 29631380 TI - Technical Consideration for Coiling of Ruptured Proximal Posterior Inferior Cerebellar Artery Aneurysm. AB - OBJECTIVE: Surgical obliteration of ruptured aneurysm of the proximal posterior inferior cerebellar artery (PICA) is challenging because of limited surgical accessibility. In recent years, coil embolization is the first-choice treatment for these lesions. However, coil embolization is not always easy in ruptured PICA aneurysm owing to the variable anatomical diversity of its shapes, its relationship to the parent artery, its low incidence, and accordingly, lesser neurointerventionist experience. METHODS: The parent artery and microcatheter for easier navigation and the embolization technique for stable coiling were identified. RESULTS: This study aimed to identify the more appropriate approach route, microcatheter, and strategies for an easier and safer, and more durable coil embolization in the treatment of lesions in the proximal PICA. CONCLUSION: Coil embolization for aneurysmal subarachnoid hemorrhage due to a ruptured proximal PICA remains a challenge, but with the appropriate coiling plan, it can be treated successfully. PMID- 29631379 TI - Tumor necrosis factor alpha reduces intestinal vitamin C uptake: a role for NF kappaB-mediated signaling. AB - Sodium-dependent vitamin C transporter-1 (SVCT-1) is the major transporter mediating intestinal vitamin C uptake. Intestinal inflammation and prolonged infection are associated with increased serum and intestinal mucosa levels of tumor necrosis factor-alpha (TNF-alpha), which also exerts profound effects on the intestinal absorption process. Elevated levels of TNF-alpha have been linked to the pathogenesis of inflammatory bowel disease (IBD) and malabsorption of nutrients, and patients with this condition have low levels of vitamin C. To date, little is known about the effect of TNF-alpha on intestinal absorption of vitamin C. We studied the impact of TNF-alpha on ascorbic acid (AA) transport using a variety of intestinal preparations. The expression level of human SVCT-1 mRNA is significantly lower in patients with IBD. TNF-alpha treated Caco-2 cells and mice showed a significant inhibition of intestinal 14C-AA uptake. This inhibition was associated with significant decreases in SVCT-1 protein, mRNA, and heterogeneous nuclear RNA levels in TNF-alpha treated Caco-2 cells, mouse jejunum, and enteroids. Also, TNF-alpha caused a significant inhibition in the SLC23A1 promoter activity. Furthermore, treatment of Caco-2 cells with celastrol (NF-kappaB inhibitor) blocked the inhibitory effect caused by TNF-alpha on AA uptake, SVCT-1 protein, and mRNA expression, as well as the activity of SLC23A1 promoter. Treatment of TNF-alpha also led to a significant decrease in the expression of hepatocyte nuclear factor-1-alpha, which drives the basal activity of SLC23A1 promoter, and this effect was reversed by celastrol. Together, these findings show that TNF-alpha inhibits intestinal AA uptake, and this effect is mediated, at least in part, at the level of transcription of the SLC23A1 gene via the NF-kappaB pathway. NEW & NOTEWORTHY Our findings show that tumor necrosis factor-alpha inhibits intestinal ascorbic acid uptake in both in vitro and in vivo systems, and this inhibitory effect is mediated, at least in part, at the level of transcription of the SLC23A1 (sodium-dependent vitamin C transporter-1) gene via the NF-kappaB pathway. PMID- 29631381 TI - Modified Orbitozygomatic Approach without Orbital Roof Removal for Middle Fossa Lesions. AB - OBJECTIVE: The purpose of the present study was to describe an OrBitoZygomatic (OBZ) surgical variant that implies the drilling of the orbital roof and lateral wall of the orbit without orbitotomy. METHODS: Design : cross-sectional study. Between January 2010 and December 2014, 18 patients with middle fossa lesions underwent the previously mentioned OBZ surgical variant. Gender, age, histopathological diagnosis, complications, and percentage of resection were registered. The detailed surgical technique is described. RESULTS: Of the 18 cases listed in the study, nine were males and nine females. Seventeen cases (94.5%) were diagnosed as primary tumoral lesions, one case (5.5%) presented with metastasis of a carcinoma, and an additional one had a fibrous dysplasia. Age ranged between 27 and 73 years. Early complications were developed in four cases, but all of these were completely resolved. None developed enophthalmos. CONCLUSION: The present study illustrates a novel surgical OBZ approach that allows for the performance of a simpler and faster procedure with fewer complications, and without increasing surgical time or cerebral manipulation, for reaching lesions of the middle fossa. Thorough knowledge of the anatomy and surgical technique is essential for successful completion of the procedure. PMID- 29631382 TI - Rare Intractable Cervicalgia Related to Exaggerated Disc Height Distraction : Report of Two Cases and Literature Review. AB - We present two cases of unexpected postoperative intractable cervicalgia due to over-sized implant insertion during simple anterior cervical decompression and fusion (ACDF) or artificial disc replacement (ADR). These patients experienced severe cervicalgia mostly related to their neck motion even after standard cervical operations. In both cases, the restored disc heights after the operations were prominently greater than the preoperative disc heights. The patients had not responded to any of the conservative treatments, and unloading of these excessively distracted segments through ultimate revision surgery led to dramatic pain relief. This report emphasizes the increase in distractional forces that takes place after a standard ACDF or ADR, as well as the importance of a proper sized implant. It also includes the reviews of other biomechanical or clinical reports dealing with this issue, thereby cautioning the surgeons not to disregard these factors, which might have an adverse effect in patients with cervicalgia even after radiographically successful cervical procedures. PMID- 29631383 TI - Endovascular Treatment with Intravenous Thrombolysis versus Endovascular Treatment Alone for Acute Anterior Circulation Stroke : A Meta-Analysis of Observational Studies. AB - Objective: The aim of this study was to determine outcome of ischemic stroke patients in the anterior circulation treated with endovascular treatment (EVT) with intravenous thrombolysis (IVT) versus EVT alone group. Methods: A systemic literature review was performed using online database from January 2004 to January 2017. Primary outcomes were successful recanalization seen on finial angiography and good outcome at three months. Secondary outcomes were mortality and the development of symptomatic intracranial hemorrhage (S-ICH) after the procedure. A fixed effect model was used when heterogeneity was less than 50%. Egger's regression test was used to assess publication bias. Results: Five studies were included for final analysis. Between EVT with IVT and EVT alone group, successful recanalization (odds ratio [OR] 1.467, p=0.216), good clinical outcome at three months (OR 1.199, p=0.385), mortality (OR 0.776, p=0.371), and S ICH (OR 1.820, p=0.280) did not differ significantly. Egger's regression intercept with 95% confidence interval (CI) was 1.99 (95% CI -2.91 to 6.89) in successful recanalization and -0.27 (95% CI -6.35 to 5.80) in good clinical outcome, respectively. Conclusion: The two treatment modalities, EVT with IVT and EVT alone, could be comparable in treating acute anterior circulation stroke. Studies to find specific beneficiary group for EVT alone, without primary IVT, are needed further. PMID- 29631384 TI - Instrumentation Failure after Partial Corpectomy with Instrumentation of a Metastatic Spine. AB - OBJECTIVE: To identify the perioperative factors associated with instrument failure in patients undergoing a partial corpectomy with instrumentation (PCI) for spinal metastasis. METHODS: We assessed the one hundred twenty-four patients with who underwent PCI for a metastatic spine from 1987 to 2011. Outcome measure was the risk factor related to implantation failure. The preoperative factors analyzed were age, sex, ambulation, American Spinal Injury Association grade, bone mineral density, use of steroid, primary tumor site, number of vertebrae with metastasis, extra-bone metastasis, preoperative adjuvant chemotherapy, and preoperative spinal radiotherapy. The intraoperative factors were the number of fixed vertebrae, fixation in osteolytic vertebrae, bone grafting, and type of surgical approach. The postoperative factors included postoperative adjuvant chemotherapy and spinal radiotherapy. This study was supported by the National Research Foundation grant funded by government. There were no study-specific biases related to conflicts of interest. RESULTS: There were 15 instrumentation failures (15/124, 12.1%). Preoperative ambulatory status and primary tumor site were not significantly related to the development of implant failure. There were no significant associations between insertion of a bone graft into the partial corpectomy site and instrumentation failure. The preoperative and operative factors analyzed were not significantly related to instrumentation failure. In univariable and multivariable analyses, postoperative spinal radiotherapy was the only significant variable related to instrumentation failure (p=0.049 and 0.050, respectively). CONCLUSION: When performing PCI in patients with spinal metastasis followed by postoperative spinal radiotherapy, the surgeon may consider the possibility of instrumentation failure and find other strategies for augmentation than the use of a bone graft for fusion. PMID- 29631385 TI - Cerebral Aneurysms in Judicial Precedents. AB - Objective: From November 30, 2016, the Korean Government carried the revised Medical Dispute Mediation and Arbitration Act into effect. Mediation will start automatically without agreements of the defendant, when the outcome of the patient was death, coma more than a month or severe disability. Cerebral aneurysm has a definite risk of bad outcome, especially in the worst condition. Any surgical intervention to this lesion has its own high risk of complications. Recently, Seoul central district court decided 50% responsibility of the doctors who made a rupture of the aneurysm during coiling (2015Ga-Dan5243104). We reviewed judicial precedents related to cerebral aneurysms in lawsuit using a web search. Methods: We searched judicial precedents at a web search of the Supreme Court, using the key words, "cerebral aneurysm". Results: There were 15 precedents, six from the Supreme Court, seven from the High Court, and two from district courts. Seven precedents were related to the causation analysis, such as work-relationship. Five precedents were malpractice suits related bad results or complications. Remaining three precedents were related to the insurance payment. In five malpractice precedents, two precedents of the Supreme Court reversed former two precedents of the High Court. Conclusion: Judicial precedents on the cerebral aneurysm included not only malpractice suits, but also causation analysis or insurance payment. Attention to these subjects is needed. We also need education of the independent medical examination. To avoid medical disputes, shared decision making seems to be useful, especially in cases of high risk condition or procedures. PMID- 29631386 TI - Protected versus Unprotected Carotid Artery Stenting : Meta-Analysis of the Current Literature. AB - Objective: To compare peri-operative any symptomatic stroke after carotid angioplasty and stenting (CAS), based on the application or absence of a cerebral protection device. Methods: A systematic literature review using PubMed, Embase, and the Cochrane Central was done across an online data base from January 1995 to October 2016. Procedures which were performed due to carotid dissection or aneurysm, procedures using covered stents or conducted in an emergency, were excluded. The primary endpoint was perioperative any symptomatic stroke within 30 days after the procedure. A fixed effect model was used in cases of heterogeneity less than 50%. Results: In the 25 articles included in this study, the number of stroke events was 326 (2.0%) in protected CAS and 142 (3.4%) in unprotected CAS. The use of cerebral protection device significantly decreased stroke after CAS (odds ratio [OR] 0.633, 95% confidence interval [CI] 0.479-0.837, p=0.001). In the publication bias analysis, Egger's regression test disclosed that the intercept was -0.317 (95% CI -1.015-0.382, p=0.358). Regarding symptomatic patients (four studies, 539 CAS procedures), the number of stroke was six (1.7%) in protected CAS and 11 (5.7%) in unprotected CAS. The protective effect against stroke events by cerebral protection device did not have a statistical significance (OR 0.455, 95% CI 0.151-1.366, p=0.160). Conclusion: The use of protection device significantly decreased stroke after CAS. However, its efficacy was not demonstrated in symptomatic patients. Routine use of protection device during CAS should be critically assessed before mandatory use. PMID- 29631387 TI - Liver transplantation: indications and outcomes. PMID- 29631388 TI - The Potential Usefulness of Magnetic Resonance Guided Focused Ultrasound for Obsessive Compulsive Disorders. AB - Obsessive compulsive disorder is a debilitating condition characterized by recurrent obsessive thoughts and compulsive reactions. A great portion of the obsessive compulsive disorder (OCD) patients are managed successfully with psychiatric treatment such as selective serotonin-reuptake inhibitor and cognitive behavioral psychotherapy, but more than 10% of patients are remained as nonresponder who needs neurosurgical treatments. These patients are potential candidates for the neurosurgical management. There had been various kind of operation, lesioning such as leucotomy or cingulotomy or capsulotomy or limbic leucotomy, and with advent of stereotaxic approach and technical advances, deep brain stimulation was more chosen by neurosurgeon due to its characteristic of reversibility and adjustability. Gamma knife radiosurgery are also applied to make lesion targeting based on magnetic resonance (MR) imaging, but the complication of adverse radiation effect is not predictable. In the neurosurgical field, MR guided focused ultrasound has advantage of less invasiveness, real-time monitored procedure which is now growing to attempt to apply for various brain disorder. In this review, the neurosurgical treatment modalities for the treatment of OCD will be briefly reviewed and the current state of MR guided focused ultrasound for OCD will be suggested. PMID- 29631389 TI - Requirements for Cerebrovascular Surgery in Comprehensive Stroke Centers in South Korea. AB - Objective: Cerebrovascular disease (CVD) was the third most common cause of death in South Korea in 2014. Evidence from abroad suggests that comprehensive stroke centers play an important role in improving the mortality rate of stroke. However, surgical treatment for CVD is currently slightly neglected by national policy, and there is still regional imbalance in this regard. For this reason, we conducted a survey on the necessity of, and the requirements for, establishing regional comprehensive cerebrovascular surgery centers (CCVSCs). Methods: This investigation was performed using the questionnaire survey method. The questionnaire was consisted with two sections. The first concerned the respondent's opinion regarding the current status of demand and the regional imbalance of cerebrovascular surgery in South Korea. The second section asked about the requirements for establishing regional CCVSCs. We sent the questionnaire to 100 board members of the Korean Society of Cerebrovascular Surgeons. Results: Most experts agreed that cerebrovascular surgery patients were concentrated in large hospitals in the capital area, and 83.6% of respondents agreed that it was necessary to alleviate the regional imbalance of cerebrovascular surgery. With regards to personnel, over 90% of respondents answered that at least two neuro-vascular surgeons and two neuro-interventionists are necessary to establish a CCVSC. Regarding facilities, almost all respondents stated that each CCVSC would require a neuro-intensive care unit and hybrid operating room. The survey asked the respondents about 13 specific neurovascular surgical procedures and whether they were necessary for a regional CCVSC. In the questions about the necessity of cerebrovascular surgical equipment, all seven pieces of equipment were considered essential by all respondents. A further five pieces of equipment were considered necessary on site: computed tomographic angiography, magnetic resonance angiography, conventional angiography, surgical microscope, and surgical navigation. Our results may provide a basis for future policy regarding treatment of cerebrovascular disease, including surgery. Conclusion: Raising the comprehensiveness of treatment at a regional level would lower the national disease burden. Policies should be drafted regarding comprehensive treatment including surgery for cerebrovascular disease, and related support plans should be implemented. PMID- 29631390 TI - Urine Cotinine Should Be Involved in Initial Evaluation of Tinnitus in Adolescents. AB - OBJECTIVES: Smoking is associated with hearing loss, while the correlation between tinnitus and smoking is not fully elucidated. This study aimed to evaluate risk factors of tinnitus in adolescents in terms of smoking, and we identified a rectifiable parameter that can be serially monitored. METHODS: A cross-sectional study was conducted using data from the Korea National Health and Nutrition Examination Survey, with 2,782 participants aged 12 to 18 years, from 2008 through 2011. Participants with history of ear disease, hearing loss, and inadequate responses to questionnaires were excluded. We investigated the prevalence of tinnitus and tinnitus-related annoyance by questionnaire and sought potential risk factors in blood and urine tests and smoking history. RESULTS: The prevalence of tinnitus in the 12- to 18-year-old population was 17.5%, with 3.3% reporting tinnitus-related annoyance. On univariate analysis, the prevalence of tinnitus increased with age (P<0.001) and was higher among girls (P=0.012). Blood tests and urinalysis showed significant correlation between tinnitus and red blood cell count, alkaline phosphatase levels, and urine cotinine (P=0.002, P<0.001, P=0.018, respectively). In multivariate analysis, the urine cotinine level was the only parameter associated with tinnitus (odds ratio, 1.000; 95% confidence interval, 0.999 to 1.000; P=0.038). Smoking was also significantly correlated with tinnitus (P=0.043), and amount of smoking with tinnitus-related annoyance (P=0.045). However, current smoking and past smoking were not correlated with tinnitus. CONCLUSION: Urine cotinine may be a rectifiable marker for management of tinnitus in adolescents. This suggests that smoking cessation should be incorporated in the management of tinnitus in adolescents. PMID- 29631392 TI - Competitive Adsorption between Nanoparticles and Surface Active Ions for the Oil Water Interface. AB - Nanoparticles (NPs) can add functionality (e.g., catalytic, optical, rheological) to an oil-water interface. Adsorption of ~10 nm NPs can be reversible; however, the mechanisms for adsorption and its effects on surface pressure remain poorly understood. Here we demonstrate how the competitive reversible adsorption of NPs and surfactants at fluid interfaces can lead to independent control of both the adsorbed amount and surface pressure. In contrast to prior work, both species investigated (NPs and surfactants) interact reversibly with the interface and without the surface active species binding to NPs. Independent measurements of the adsorption and surface pressure isotherms allow determination of the equation of state (EOS) of the interface under conditions where the NPs and surfactants are both in dynamic equilibrium with the bulk phase. The adsorption and surface pressure measurements are performed with gold NPs of two different sizes (5 and 10 nm), at two pH values, and across a wide concentration range of surfactant (tetrapentylammonium, TPeA+) and NPs. We show that free surface active ions compete with NPs for the interface and give rise to larger surface pressures upon the adsorption of NPs. Through a competitive adsorption model, we decouple the contributions of NPs wetting at the interface and their surface activity on the measured surface pressure. We also demonstrate reversible control of adsorbed amount via changes in the surfactant concentration or the aqueous phase pH. PMID- 29631393 TI - Chiral Bronsted Acid Catalyzed Enantioselective Dehydrative Nazarov-Type Electrocyclization of Aryl and 2-Thienyl Vinyl Alcohols. AB - An efficient chiral Bronsted acid-catalyzed enantioselective dehydrative Nazarov type electrocyclization (DNE) of electron-rich aryl- and 2-thienyl-beta-amino-2 en-1-ols is described. The 4pi conrotatory electrocyclization reaction affords access to a wide variety of the corresponding 1 H-indenes and 4 H-cyclopenta[ b]thiophenes in excellent yields of up to 99% and enantiomeric excess (ee) values of up to 99%. Experimental and computational studies based on a proposed intimate contact ion-pair species that is further assisted by hydrogen bonding between the amino group of the substrate cation and chiral catalyst anion provide insight into the observed product enantioselectivities. PMID- 29631394 TI - Flexible Memristive Devices Based on InP/ZnSe/ZnS Core-Multishell Quantum Dot Nanocomposites. AB - The effects of the ZnS shell layer on the memory performances of flexible memristive devices based on quantum dots (QDs) with an InP/ZnSe/ZnS core multishell structure embedded in a poly(methylmethacrylate) layer were investigated. The on/off ratios of the devices based on QDs with an InP/ZnSe core shell structure and with an InP/ZnSe/ZnS core-multishell structure were approximately 4.2 * 102 and 8.5 * 103, respectively, indicative of enhanced charge storage capability in the latter. After bending, the memory characteristics of the memristive devices based on QDs with the InP/ZnSe/ZnS structure were similar to those before bending. In addition, those devices maintained the same on/off ratios for retention time of 1 * 104 s, and the number of endurance cycles was above 1 * 102. The reset voltages ranged from -2.3 to 3.1 V, and the set voltages ranged from 1.3 to 2.1 V, indicative of reliable electrical characteristics. Furthermore, the possible operating mechanisms of the devices are presented on the basis of the electron trapping and release mode. PMID- 29631391 TI - Effects and Mechanisms of Taurine as a Therapeutic Agent. AB - Taurine is an abundant, beta-amino acid with diverse cytoprotective activity. In some species, taurine is an essential nutrient but in man it is considered a semi essential nutrient, although cells lacking taurine show major pathology. These findings have spurred interest in the potential use of taurine as a therapeutic agent. The discovery that taurine is an effective therapy against congestive heart failure led to the study of taurine as a therapeutic agent against other disease conditions. Today, taurine has been approved for the treatment of congestive heart failure in Japan and shows promise in the treatment of several other diseases. The present review summarizes studies supporting a role of taurine in the treatment of diseases of muscle, the central nervous system, and the cardiovascular system. In addition, taurine is extremely effective in the treatment of the mitochondrial disease, mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), and offers a new approach for the treatment of metabolic diseases, such as diabetes, and inflammatory diseases, such as arthritis. The review also addresses the functions of taurine (regulation of antioxidation, energy metabolism, gene expression, ER stress, neuromodulation, quality control and calcium homeostasis) underlying these therapeutic actions. PMID- 29631396 TI - Carbon-13 Cross-Polarization Magic-Angle Spinning Nuclear Magnetic Resonance for Measuring Proanthocyanidin Content and Procyanidin to Prodelphinidin Ratio in Sainfoin ( Onobrychis viciifolia) Tissues. AB - A procedure based on 13C CPMAS NMR was developed to study procyanidins (PCs) and prodelphinidins (PDs) directly in milled sainfoin plant tissues. Blackcurrant and Tilia samples enabled reference spectra of purified proanthocyanidin (PA) fractions, crude extracts, and milled plant tissues, with characteristic resonances at 155, 144, and 132 ppm. PC/PD ratios were estimated from the I132/I155 intensity ratio and differed by 2.5 to 5.9% compared to thiolysis data. Normalization to the 155 ppm signal intensity from reference spectra enabled analysis of PA contents with an error of ca. 8 g PAs/100 g plant tissue. The procedure estimates the lignin contribution and allows for a correction of the PA content. In six sainfoin accessions, estimated PA contents were 1.6- to 20.8-fold higher than the thiolysis and 1.4- to 2.6-fold higher than the HCl-butanol acetone results. Method differences may reflect the presence of unextractable, possibly high molecular weight PAs in sainfoin. PMID- 29631395 TI - Identification of the First Diketomorpholine Biosynthetic Pathway Using FAC-MS Technology. AB - Filamentous fungi are prolific producers of secondary metabolites with drug-like properties, and their genome sequences have revealed an untapped wealth of potential therapeutic leads. To better access these secondary metabolites and characterize their biosynthetic gene clusters, we applied a new platform for screening and heterologous expression of intact gene clusters that uses fungal artificial chromosomes and metabolomic scoring (FAC-MS). We leverage FAC-MS technology to identify the biosynthetic machinery responsible for production of acu-dioxomorpholine, a metabolite produced by the fungus, Aspergilllus aculeatus. The acu-dioxomorpholine nonribosomal peptide synthetase features a new type of condensation domain (designated CR) proposed to use a noncanonical arginine active site for ester bond formation. Using stable isotope labeling and MS, we determine that a phenyllactate monomer deriving from phenylalanine is incorporated into the diketomorpholine scaffold. Acu-dioxomorpholine is highly related to orphan inhibitors of P-glycoprotein targets in multidrug-resistant cancers, and identification of the biosynthetic pathway for this compound class enables genome mining for additional derivatives. PMID- 29631397 TI - Formation of Liquid Marbles Using pH-Responsive Particles: Rolling vs Electrostatic Methods. AB - Aqueous dispersions of micrometer-sized, monodisperse polystyrene (PS) particles carrying pH-responsive poly[2-(diethylamino)ethyl methacrylate] (PDEA) colloidal stabilizer on their surfaces were dried under ambient conditions at pH 3.0 and 10.0. The resulting dried cake-like particulate materials were ground into powders and used as a stabilizer to fabricate liquid marbles (LMs) by rolling and electrostatic methods. The powder obtained from pH 3.0 aqueous dispersion consisted of polydisperse irregular-shaped colloidal crystal grains of densely packed colloids which had hydrophilic character. On the other hand, the powder obtained from pH 10.0 aqueous dispersion consisted of amorphous and disordered colloidal aggregate grains with random sizes and shapes, which had hydrophobic character. Reflecting the hydrophilic-hydrophobic balance of the dried PDEA-PS particle powders, stable LMs were fabricated with distilled water droplets by rolling on the powders prepared from pH 10.0, but the water droplets were adsorbed into the powders prepared from pH 3.0. In the electrostatic method, where an electric field assists transport of powders to a droplet surface, the PDEA-PS powders prepared from pH 3.0 jumped to an earthed pendant distilled water droplet to form a droplet of aqueous dispersion. Conversely the larger powder aggregates prepared from pH 10.0 did not jump due to cohesion between the hydrophobic PDEA chains on the PS particles, resulting in no LM formation. PMID- 29631398 TI - Fluorescence Modulation of Graphene Quantum Dots Near Structured Silver Nanofilms. AB - Here, we study the plasmonic metal-enhanced fluorescence properties of blue emitting graphene quantum dots (GQDs) and green-emitting graphene oxide quantum dots (GOQDs) using fluorescence lifetime imaging microscopy. Reactive ion sputtered silver (Ag) on zinc oxide (ZnO) thin films deposited on silicon (Si) wafers are used as the substrates. The morphology of the sputtered Ag gradually changes from nanoislands, via and elongated network and a continuous film with nanoholes, to a continuous film with increasing sputtering time. The fluorescence properties of GQD and GOQD on the Ag are modulated in terms of the intensities and lifetimes as the morphology of the Ag layers changes. Although both GQD and GOQD show similar fluorescence modulation on the Ag nanofilms, the fluorescence of GQD is enhanced, whereas that of GOQD is quenched due to the charge transfer process from GOQD to ZnO. Moreover, the GQD and GOQD exhibit different fluorescence lifetimes due to the effect of their electronic configurations. The theoretical calculation explains that the fluorescence amplification on the Ag nanofilms can largely be attributed to the enhanced absorption mechanism arising from accumulated optical fields around nanogaps and nanovoids in the Ag nanofilms. PMID- 29631399 TI - Direct Visualization of Thermal Conductivity Suppression Due to Enhanced Phonon Scattering Near Individual Grain Boundaries. AB - Understanding the impact of lattice imperfections on nanoscale thermal transport is crucial for diverse applications ranging from thermal management to energy conversion. Grain boundaries (GBs) are ubiquitous defects in polycrystalline materials, which scatter phonons and reduce thermal conductivity (kappa). Historically, their impact on heat conduction has been studied indirectly through spatially averaged measurements, that provide little information about phonon transport near a single GB. Here, using spatially resolved time-domain thermoreflectance (TDTR) measurements in combination with electron backscatter diffraction (EBSD), we make localized measurements of kappa within few MUm of individual GBs in boron-doped polycrystalline diamond. We observe strongly suppressed thermal transport near GBs, a reduction in kappa from ~1000 W m-1 K-1 at the center of large grains to ~400 W m-1 K-1 in the immediate vicinity of GBs. Furthermore, we show that this reduction in kappa is measured up to ~10 MUm away from a GB. A theoretical model is proposed that captures the local reduction in phonon mean-free-paths due to strongly diffuse phonon scattering at the disordered grain boundaries. Our results provide a new framework for understanding phonon-defect interactions in nanomaterials, with implications for the use of high-kappa polycrystalline materials as heat sinks in electronics thermal management. PMID- 29631400 TI - Modular Synthesis of beta-Amino Boronate Peptidomimetics. AB - Herein, we describe the synthesis of novel beta-amino boronate peptidomimetics from amphoteric alpha-borylaldehydes in the Ugi multicomponent reaction. A mild deprotection method provided the free and stable boronic acid forms of the target molecules, which display notable stability toward protodeborylation. Despite the presence of Lewis acidic boron, there is no evidence for hydrolysis of the adjacent amide via a 5- or 6-membered ring intermediate. This methodology should facilitate the development of libraries of new boron-containing antibiotics and antifungal agents. PMID- 29631401 TI - Bifunctionality of Iminodiacetic Acid-Modified Lysozyme on Inhibiting Zn2+ Mediated Amyloid beta-Protein Aggregation. AB - Aggregation of amyloid beta-proteins (Abeta) mediated by metal ions such as Zn2+ has been suggested to be implicated in the progression of Alzheimer's disease (AD). Hence, development of bifunctional agents capable of inhibiting Abeta aggregation and modulating metal-Abeta species is an effective strategy for the treatment of AD. In this work, we modified iminodiacetic acid (IDA) onto human lysozyme (hLys) surface to create an inhibitor of Zn2+-mediated Abeta aggregation and cytotoxicity. The IDA-modified hLys (IDA-hLys) retained the stability and biocompatibility of native hLys. Extensive biophysical and biological analyses indicated that IDA-hLys significantly attenuated Zn2+-mediated Abeta aggregation and cytotoxicity due to its strong binding affinity for Zn2+, whereas native hLys showed little effect. Stopped-flow fluorescence spectroscopy showed that IDA-hLys could protect Abeta from Zn2+-induced aggregation and rapidly depolymerize Zn2+ Abeta aggregates. The research indicates that IDA-hLys is a bifunctional agent capable of inhibiting Abeta fibrillization and modulating Zn2+-mediated Abeta aggregation and cytotoxicity as a strong Zn2+ chelator. PMID- 29631402 TI - A Protein Standard That Emulates Homology for the Characterization of Protein Inference Algorithms. AB - A natural way to benchmark the performance of an analytical experimental setup is to use samples of known composition and see to what degree one can correctly infer the content of such a sample from the data. For shotgun proteomics, one of the inherent problems of interpreting data is that the measured analytes are peptides and not the actual proteins themselves. As some proteins share proteolytic peptides, there might be more than one possible causative set of proteins resulting in a given set of peptides and there is a need for mechanisms that infer proteins from lists of detected peptides. A weakness of commercially available samples of known content is that they consist of proteins that are deliberately selected for producing tryptic peptides that are unique to a single protein. Unfortunately, such samples do not expose any complications in protein inference. Hence, for a realistic benchmark of protein inference procedures, there is a need for samples of known content where the present proteins share peptides with known absent proteins. Here, we present such a standard, that is based on E. coli expressed human protein fragments. To illustrate the application of this standard, we benchmark a set of different protein inference procedures on the data. We observe that inference procedures excluding shared peptides provide more accurate estimates of errors compared to methods that include information from shared peptides, while still giving a reasonable performance in terms of the number of identified proteins. We also demonstrate that using a sample of known protein content without proteins with shared tryptic peptides can give a false sense of accuracy for many protein inference methods. PMID- 29631404 TI - Observation of Quasi-Two-Dimensional Polar Domains and Ferroelastic Switching in a Metal, Ca3Ru2O7. AB - Polar domains arise in insulating ferroelectrics when free carriers are unable to fully screen surface-bound charges. Recently discovered binary and ternary polar metals exhibit broken inversion symmetry coexisting with free electrons that might be expected to suppress the electrostatic driving force for domain formation. Contrary to this expectation, we report the first direct observation of polar domains in single crystals of the polar metal Ca3Ru2O7. By a combination of mesoscale optical second-harmonic imaging and atomic-resolution scanning transmission electron microscopy, the polar domains are found to possess a quasi two-dimensional slab geometry with a lateral size of ~100 MUm and thickness of ~10 nm. Electronic structure calculations show that the coexistence of electronic and parity-lifting orders arise from anharmonic lattice interactions, which support 90 degrees and 180 degrees polar domains in a metal. Using in situ transmission electron microscopy, we also demonstrate a strain-tuning route to achieve ferroelastic switching of polar metal domains. PMID- 29631405 TI - Hierarchical Porous Protein Scaffold Templated from High Internal Phase Emulsion Costabilized by Gelatin and Gelatin Nanoparticles. AB - Recently, three-dimensional (3D) scaffolds produced using poly-Pickering high internal phase emulsions (polyHIPEs) technology are particularly attractive in biomedical application. However, until now the most investigated polyHIPEs are hydrophobic composites originating from synthetic polymers. Here we present an investigation of a hierarchical porous protein scaffold templated from oil-in water (O/W) HIPEs costabilized by fully natural materials, gelatin, and gelatin nanoparticles. Fairly monodispersed gelatin nanoparticles were first synthesized through a two-step desolvation method, and then they were used as emulsifiers together with gelatin to fabricate stable HIPEs with adjustable droplet size distribution and rheology. Monolithic scaffolds were formed by cross-linking the HIPEs with polymers as low as 2.5 wt % in the continuous phase, which appropriately presented a general high porosity and had an interconnected porous morphology with smooth pore walls and textured structures. Furthermore, the scaffolds were degradable and showed reasonably good biocompatibility; L929 cells could adhere to the surface of the materials and exhibited intensive growth and well-spread morphology. This hierarchical porous protein scaffold could, therefore, have important application as a 3D scaffold that offers enhanced cell adhesion and functionality. PMID- 29631406 TI - [Predictive diagnosis in breast cancer - Whats new in 2018?] AB - Detection of predictive markers in breast carcinoma has undergone significant changes, the most important ones - at least in the context of Czech Republic - are related to the detection of HER2 - detection of both over-expression of oncoprotein HER-2/neu and amplification of the c-erbB-2 gene, respectively. In the Czech Republic, immunohistochemical testing is performed as a method of first choice, followed, if needed, by in situ hybridization. The update of the guidelines published in 2013 decreased the threshold for positive tumor cells from 30% to 10%, shifted the threshold for gene amplification (HER2/CEP17 ratio) from 2.2 to 2.0 and slightly changed criteria for classification of expression as 2+. These changes resulted in relatively significant increase of cases classified as "borderline" or "equivocal", requiring confirmation by in situ hybridization. In order to reduce the risk of false results, the cases diagnosed as positive in small (primary) laboratories, have to be confirmed in one of the large central laboratories. This confirmation of HER2 positivity is required before targeted therapy can be started. HER2 testing is recommended in core-cut biopsies virtually always; it is absolutely essential in patients undergoing neoadjuvant systemic therapy. In patients treated primarily by surgery can be the testing performed either in the core cut biopsy or in the final resection specimen. However, it should be kept in mind that the accuracy of some parameters in the core-cut biopsies may be limited, even in cases not influenced by the neoadjuvant chemotherapy (NACHT). The degree of concordance between results of molecular tests in the core-cut biopsy and resection specimen can achieve only 67 % and the precise concordance of histological typing reaches only 84 %, respectively; the concordance of HER2 expression, on the other hand, reaches more than 90%. In patients with positive HER2 result in core-cut biopsy, it is no longer required to repeat the testing in the resection specimen, whereas in case of HER2 negative core-cut biopsy, it is required to repeat the test from resection specimen to minimize the risk of false negative result. The probability of pathological complete response (pCR) varies in individual breast carcinoma subtypes - it reaches 27-51% in triple-negative and HER2+ cases, while in hormone-dependent tumors, namely in those with low proliferative activity, it is significantly lower. Even within the HER2+ carcinoma subgroup, the probability of pCR varies. HER2+ tumors co-expressing ER and PR have a lower rate of pCR than HER2+ carcinomas without co-expression of hormonal receptors. Carcinomas expressing high-molecular weight keratins (CK14, CK 5/6) with basal phenotype or tumors with mutations of HER2/AKT signal pathway (PI3K, PTEN) have also lower response to treatment and worse prognosis. PMID- 29631403 TI - Substrate Recognition by a Colistin Resistance Enzyme from Moraxella catarrhalis. AB - Lipid A phosphoethanolamine (PEtN) transferases render bacteria resistant to the last resort antibiotic colistin. The recent discoveries of pathogenic bacteria harboring plasmid-borne PEtN transferase ( mcr) genes have illustrated the serious potential for wide dissemination of these resistance elements. The origin of mcr-1 is traced to Moraxella species co-occupying environmental niches with Enterobacteriaceae. Here, we describe the crystal structure of the catalytic domain of the chromosomally encoded colistin resistance PEtN transferase, ICR Mc (for intrinsic colistin resistance) of Moraxella catarrhalis. The ICR Mc structure in complex with PEtN reveals key molecular details including specific residues involved in catalysis and PEtN binding. It also demonstrates that ICR Mc catalytic domain dimerization is required for substrate binding. Our structure guided phylogenetic analysis provides sequence signatures defining potentially colistin-active representatives in this enzyme family. Combined, these results advance the molecular and mechanistic understanding of PEtN transferases and illuminate their origins. PMID- 29631407 TI - [Prediction of EGFR blockade responses in metastatic colorectal carcinoma]. AB - The combination of modern systemic chemotherapy and anti-EGFR monoclonal antibodies improves overall survival and the quality of life for patients with metastatic colorectal cancer. By contrast, the addition of anti-EGFR therapy to the treatment regime of resistant patients may lead to worse progression-free and overall survival. Therofore, identifying sensitive and resistant patients is key during initial decision-making. A number of clinical trials show that primary resistance to EGFR blockade is in most cases caused by constitutive activation of signalling pathways downstream of EGFR. Of the many biomarkers studied, only the KRAS and NRAS mutation status has reached clinical relevance in routine practice. The other markers (BRAF and PIK3CA mutations, PTEN and TP53 inactivation, EGFR and HER-2 amplification, epiregulin and amphiregulin overexpression, microRNA miR 31-3p and miR-31-5p etc.) still need to be validated. The accuracy of predictive diagnostic tools could also be increased by a combination of predictive markers on the next generation sequencing platform. PMID- 29631408 TI - [Predictive diagnostics of gastric cancer in 2018]. AB - Anti-HER2 monoclonal antibody trastuzumab remains the only targeted therapy of gastric carcinoma based on histopathological predictive diagnostics used in current routine clinical practice. In the Czech Republic only the adenocarcinomas with HER2 immunohistochemical score of 3+, together with HER2 amplification detected with in situ hybridization are indicated for treatment with trastuzumab. There has been recent progress in our understanding of the molecular biology of gastric cancer, the role of its tumor microenvironment and vascular supply points to PD-1/PD-L1 and VEGFR2 as possible future targets of targeted therapy. Unfortunately, the interpretation of the results of pharmacological studies, as well as establishing new algorithms of predictive diagnostics are complicated by insufficient molecular stratification of tumors enrolled in the study groups. PMID- 29631409 TI - [Evaluation of inflammatory cells (tumor infiltrating lymphocytes - TIL) in malignant melanoma]. AB - The evaluation of inflammatory infiltrate (tumor infiltrating lymphocytes - TIL) should be a standard part of biopsy examination for malignant melanoma. Currently, the most commonly used assessment method according to Clark is not optimal and there have been attempts to find an alternative system. Here we present an overview of possible approaches involving five different evaluation methods based on hematoxylin-eosin staining, including the recent suggestion of unified TIL evaluation method for all solid tumors. The issue of methodology, prognostic and predictive significance of TIL determination as well as the importance of immunohistochemical subtyping of inflammatory infiltrate is discussed. PMID- 29631410 TI - Dedifferentiated carcinoma of the ovary. A case report. AB - We report the case of a 54-year-old female with dedifferentiated carcinoma of the ovary. Grossly, both ovaries were affected by a tumor of up to 25 mm (right ovary) and 220 mm (left ovary) in diameter. Microscopically, the tumors of both ovaries showed features of well differentiated endometrioid carcinoma with mucinous differentiation. Moreover, in the left ovary there was an undifferentiated solid component consisting of larger cells. Immunohistochemically, the undifferentiated component showed diffuse vimentin positivity and focal expression of cytokeratin 18. Other markers examined including PAX8, estrogen receptors and progesterone receptors were all negative. Dedifferentiated carcinomas consist of an undifferentiated epithelial component and a component of endometrioid carcinoma of FIGO grade 1 or 2. Clinically, they represent aggressive tumors with unfavorable prognosis mostly occurring in the endometrium. To the best of our knowledge, thus far only 6 cases arising in the ovary have been reported in the literature. PMID- 29631411 TI - Nonfunctioning parathyroid carcinoma associated with parathyromatosis. A case report. AB - We report on the case of a 39-year old man who underwent a thyroidectomy and a parathyroidectomy with misdiagnosed medullary carcinoma of the thyroid in 2013. During the operation the thyroid gland and parathyroid glands were artificially damaged due to the complicated surgical access to the glands because of the obesity of the patient as well as the deep placement of the enlarged parathyroid glands. Three years later, the neck ultrasound showed bilateral nodules on the neck, suspected to be metastases of the medullary carcinoma. Microscopically, the nodules were found to be focuses of parathyromatosis, and there was also an infiltrating carcinoma. This lesion was reclassified after clinico-pathological correlation and immunohistochemical examination as nonfunctioning parathyroid carcinoma. This article discusses morphological and immunohistochemical features of parathyromatosis and parathyroid carcinoma and its separation from lesions with which it may be misdiagnosed. PMID- 29631412 TI - Comparing Visual and Statistical Analysis of Multiple Baseline Design Graphs. AB - A growing number of statistical analyses are being developed for single-case research. One important factor in evaluating these methods is the extent to which each corresponds to visual analysis. Few studies have compared statistical and visual analysis, and information about more recently developed statistics is scarce. Therefore, our purpose was to evaluate the agreement between visual analysis and four statistical analyses: improvement rate difference (IRD); Tau-U; Hedges, Pustejovsky, Shadish (HPS) effect size; and between-case standardized mean difference (BC-SMD). Results indicate that IRD and BC-SMD had the strongest overall agreement with visual analysis. Although Tau-U had strong agreement with visual analysis on raw values, it had poorer agreement when those values were dichotomized to represent the presence or absence of a functional relation. Overall, visual analysis appeared to be more conservative than statistical analysis, but further research is needed to evaluate the nature of these disagreements. PMID- 29631413 TI - Nanotized PPARalpha Overexpression Targeted to Hypertrophied Myocardium Improves Cardiac Function by Attenuating the p53-GSK3beta-Mediated Mitochondrial Death Pathway. AB - AIMS: Metabolic remodeling of cardiac muscles during pathological hypertrophy is characterized by downregulation of fatty acid oxidation (FAO) regulator, peroxisome proliferator-activated receptor alpha (PPARalpha). Thereby, we hypothesized that a cardiac-specific induction of PPARalpha might restore the FAO related protein expression and resultant energy deficit. In the present study, consequences of PPARalpha augmentation were evaluated for amelioration of chronic oxidative stress, myocyte apoptosis, and cardiac function during pathological cardiac hypertrophy. RESULTS: Nanotized PPARalpha overexpression targeted to myocardium was done by a stearic acid-modified carboxymethyl-chitosan (CMC) conjugated to a 20-mer myocyte-targeted peptide (CMCP). Overexpression of PPARalpha ameliorated pathological hypertrophy and improved cardiac function. Augmented PPARalpha in hypertrophied myocytes revealed downregulated p53 acetylation (lys 382), leading to reduced apoptosis. Such cells showed increased binding of PPARalpha with p53 that in turn reduced interaction of p53 with glycogen synthase kinase-3beta (GSK3beta), which upregulated inactive phospho GSK3beta (serine [Ser]9) expression within mitochondrial protein fraction. Altogether, the altered molecular milieu in PPARalpha-overexpressed hypertrophy groups restored mitochondrial structure and function both in vitro and in vivo. INNOVATION: Cardiomyocyte-targeted overexpression of a protein of interest (PPARalpha) by nanotized plasmid has been described for the first time in this study. Our data provide a novel insight towards regression of pathological hypertrophy by ameliorating mitochondrial oxidative stress in targeted PPARalpha overexpressed myocardium. CONCLUSION: PPARalpha-overexpression during pathological hypertrophy showed substantial betterment of mitochondrial structure and function, along with downregulated apoptosis. Myocardium-targeted overexpression of PPARalpha during pathological cardiac hypertrophy led to an overall improvement of cardiac energy deficit and subsequent cardiac function, thereby, opening up a potential avenue for cardiac tissue engineering during hypertrophic cardiac pathophysiology. PMID- 29631414 TI - Comparative Assessment of Small and Large Intestine Biopsies for Ex Vivo HIV-1 Pathogenesis Studies. AB - Ex vivo mucosal explants have become a mainstay of HIV-1 studies using human tissue. In this study, we examine the baseline phenotypic and virologic differences between biopsies derived from the small intestine (SI) and large intestine (LI) for use in ex vivo explant studies. To do this, we collected endoscopic mucosal biopsies from both SI and LI from the same healthy, HIV seronegative participants. Mucosal mononuclear cell phenotypes and quantity were compared using flow cytometry. Comparative HIV-1 infectibility of the explants was assessed using an ex vivo explant HIV-1 infection assay. We found that all biopsies had similar numbers of T cells per biopsy. While the percentage of CD4+ T cells from SI biopsies expressed significantly more activation markers (CD38, HLA-DR) and HIV coreceptors (CXCR4, CCR5), the absolute numbers of activated CD4+ T cells were similar between both sites. LI explants, however, supported more efficient HIV-1 infection, as evidenced by earlier rise in p24 accumulation and greater percent of infected explants at limiting infectious doses. These results suggest that explants from LI biopsies support more efficient HIV-1 infection than SI biopsies, despite similar numbers of available, activated HIV-1 target cells. These findings highlight important differences in LI and SI explants, which must be considered in designing and interpreting ex vivo HIV-1 infection studies, and suggest that factors within the tissue other than target cell number and activation state may play a role in regulating HIV-1 infection. PMID- 29631415 TI - The Perinatal Biopsychosocial Consequences of Various Levels of Gestational Hyperglycemia. AB - This study was to compare biopsychosocial consequences among three groups of women with gestational hyperglycemia. We conducted a repeated-measures study at five time points among 132 women with gestational hyperglycemia. Women's physiological indicators and their psychosocial indicators were measured. There were 22.7% of participants had gestational diabetes mellitus (GDM), 11.4% had gestational impaired glucose tolerance (G-IGT), and 65.9% had mild gestational hyperglycemia (MGH). Women with GDM had higher fasting blood glucose and systolic/diastolic blood pressure than women with MGH. Women with GDM had higher diastolic blood pressure compared to women with G-IGT. Significant differences were found between the five time points regarding women's fasting blood glucose, diastolic blood pressure, depression, and health status. Health care providers should conduct early screening for predictors of metabolic syndrome in women with any degree of gestational hyperglycemia. Nursing interventions could be offered as early as the perinatal period to promote women's health. PMID- 29631416 TI - A Qualitative Study Exploring Perceptions of Patients With Gout. AB - Gout is a chronic disease that is on a rising trend and greatly affects one's physical and psychosocial well-being. The aim of this study was to explore patients' perceptions of living with gout. A descriptive qualitative study was conducted and 15 adults with gout were interviewed face-to-face between December 2014 and January 2015. Thematic analysis was used to analyze the transcribed data. The experiences of patients with gout were found to revolve around four themes: emotional experiences with gout, disruptions in daily lives, interactions with doctor, and coping with gout using internal and external resources. The in depth understanding of the patients' experiences indicates a need to provide holistic patient education and to involve family members to create nurse-led support groups and to raise public awareness regarding gout. PMID- 29631417 TI - Early Detection and Prevention of Osteoporosis Among Pre- and Postmenopausal Women in Saudi Arabia. AB - Osteoporosis is difficult to treat and is still incurable, and thus prevention is critically important. The aim of this study was to find out the high-risk women for osteoporosis and to correlate their bone mineral density (BMD) with their investigated risk factors. Cross-sectional design was used and it was conducted among 200 pre- and postmenopausal Saudi women. The study documented that postmenopausal females had high prevalence of osteopenia and majority of them had low serum calcium. Significant correlation was found between low BMD and family history of osteoporosis; increased BMD was seen in women, who consumed calcium rich foods, exposure to sun light, and longer fertility period. Majority of the women 94.5% had inadequate knowledge on preventive measures of osteoporosis. The high prevalence of osteopenia in postmenopausal women indicates the ultimate importance of early intervention to prevent development of osteoporosis in later life. PMID- 29631418 TI - Robustness of Percutaneously Completed Coronary Revascularization in Stable Coronary Artery Disease: Obstructive Versus Occlusive Lesions. AB - Our study sought to assess long-term outcomes of percutaneously completed coronary revascularization (CCR) in patients with obstructive coronary artery disease (CAD) comprising chronic total occlusions (CTOs). Between 2010 and 2014, percutaneous coronary interventions (PCIs) of the CTOs were attempted in 213 patients: the CCR was achieved in 125 patients (group 1), while the PCI failed in 88 patients (group 2). They were matched against 252 patients (group 3) with the CCR obtained by the non-CTO PCIs. In the 5-year follow-up, more adverse cardiovascular (CV) events occurred in group 2 (29.5% vs 4.8% in group 1 vs 3.5% in group 3, P = .0001), mainly due to recurrent severe symptoms and additional revascularization of the CTOs; CV mortality did not seem to be significantly affected. Survival curves for the successful CTO and non-CTO PCIs appeared indistinguishable. Stent thromboses were infrequent in the CCR groups. In conclusion, long-term outcomes of the patients with the obstructive CAD containing the CTOs showed a favorable outcome if the CCR had been achieved percutaneously. PMID- 29631419 TI - Combination of Mean Platelet Volume and Neutrophil to Lymphocyte Ratio Predicts Long-Term Major Adverse Cardiovascular Events After Percutaneous Coronary Intervention. AB - We hypothesized that the combination of a high neutrophil to lymphocyte ratio (NLR) and mean platelet volume (MPV) would be a stronger predictor of future cardiovascular events after percutaneous coronary intervention (PCI). Both NLR and MPV were measured in 364 consecutive patients undergoing PCI. The primary end point was the incidence of major adverse cardiovascular events (MACEs), including cardiac death, nonfatal myocardial infarction, and stent thrombosis. The median values of NLR and MPV were 2.8 and 8.2 fL, respectively. There were 26 MACEs during a median follow-up duration of 29.3 months. Kaplan-Meier analysis revealed that the higher NLR group had a significantly higher MACE rate than the lower NLR group and that the higher MPV group had a significantly higher MACE rate than the lower MPV group (log-rank: P = .0064 and P = .0004, respectively). The cumulative MACE-free survival can be further stratified by the combination of NLR and MPV. This value was especially useful in patients with acute coronary syndrome (ACS). By multivariate Cox proportional hazards model, the combination of high NLR and high MPV was independently associated with MACE ( P = .026). The combination of a high NLR and high MPV is an independent predictor of MACE after PCI, especially in patients with ACS. PMID- 29631420 TI - Prevalence of Integrase Strand Transfer Inhibitors Resistance Mutations in Integrase Strand Transfer Inhibitors-Naive and -Experienced HIV-1 Infected Patients: A Single Center Experience. AB - Integrase strand transfer inhibitor (InSTI) resistance rates are low. However, genotypic resistance test (GRT) is not routinely performed in many centers. The aim of this study is to evaluate the prevalence of InSTI-related mutations in our large cohort. We examined all integrase GRTs performed as part of routine clinical practice at Spedali Civili General Hospital, University of Brescia from 2011 to 2016. Analysis was performed through the Stanford HIV Drug Resistance Database. A total of 341 patients were included. Genotypic resistance assays were performed in naive (48), ART-experienced but InSTI-naive (114), and both ART experienced/InSTI-experienced (179) patients. No major resistance-associated mutations (RAMs) were detected in patients never exposed to InSTIs. Of 179 samples from patients exposed to InSTIs (mostly to raltegravir [RAL]), the overall prevalence of major RAMs was 11.7%. Among them, 10 harbored N155H, 4 Q148H, 2 Q148R, 2 Y143C/S, and 2 T66A/I/T, respectively. A novel mutation at a recognized resistance site (E92K) was identified in one RAL-experienced patient. The overall prevalence of InSTI mutations in our cohort was low, particularly in naive patients indicating no transmitted RAMs, although in InSTIs-experienced patients the rate of RAMs was high (11.7%). We support an implementation of surveillance of InSTI resistance. PMID- 29631421 TI - In Vivo Imaging of the Intra- and Extracellular Redox Status in Rat Stomach with Indomethacin-Induced Gastric Ulcers Using Overhauser-Enhanced Magnetic Resonance Imaging. AB - AIMS: Repeated use of nonsteroidal anti-inflammatory drugs can induce changes in the redox status, including production of reactive oxygen species (ROS), but the specific details of these changes remain unknown. Overhauser-enhanced magnetic resonance imaging (OMRI) has been used in vivo to monitor the redox status in several diseases and map tissue oxygen concentrations. We monitored the intra- and extracellular redox status in the stomach of rats with indomethacin-induced gastric ulcers using OMRI and investigated the relationship with gastric mucosal damage. RESULTS: One hour after oral administration of indomethacin (30 mg/kg), OMRI measurements in the stomach were made following nitroxyl probe administration. OMRI with the membrane-permeable nitroxyl probe, 4-hydroxy 2,2,6,6-tetramethyl-piperidine-1-oxyl (TEMPOL), demonstrated a redox change toward oxidation, which was reversed by a membrane-permeable antioxidant. Conversely, imaging with the impermeable probe, 4-trimethylammonium-2,2,6,6 tetramethyl-piperidine-1-oxyl (CAT-1), demonstrated little redox change. Redox imbalance imaging of a live rat stomach with indomethacin-induced gastric ulcers was produced by dual imaging of 15N-labeled TEMPOL and 14N-labeled CAT-1, in addition to imaging with another membrane-permeable 15N-labeled probe, 3 methoxycarbonyl-2,2,5,5-tetramethyl-pyrrolidine-1-oxyl (MC-PROXYL), and 14N labeled CAT-1. Pretreatment with MC-PROXYL suppressed gastric mucosal damage, whereas pretreatment with CAT-1 did not suppress ulcer formation. INNOVATION: OMRI combined with a dual probe is a less invasive imaging technique for evaluation of intracellular ROS production contributing to the formation of gastric ulcers in the stomach of indomethacin-treated rats, which cannot be done with other methods. CONCLUSION: This method may be a very powerful tool for characterizing the pathogenesis of various diseases and may have medical applications. Antioxid. Redox Signal. 00, 000-000. PMID- 29631422 TI - How resources determine pulmonary rehabilitation programs: A survey among Belgian chest physicians. AB - Despite overwhelming evidence of its benefits, a widespread implementation of pulmonary rehabilitation (PR) is lacking and the landscape of multidisciplinary programs remains very scattered. The objective of this study is to assess how PR is organized in specialized care centres in Belgium and to identify which barriers may exist according to respiratory physicians. A telephone and online survey was developed by a Belgian expert panel and distributed among all active Belgian chest physicians ( n = 492). Data were obtained from 200 respondents (40%). Seventy-five percentage of the chest physicians had direct access to an ambulatory rehabilitation program in their hospital. Most of these programs are organized bi or triweekly for an average period of 3-6 months. Programs focus strongly on chronic obstructive pulmonary disease patients from secondary care, have a multidisciplinary approach and provide exercise capacity and quality of life measures as main outcomes. Yet large differences were observed in process and outcome indicators between the programs of centres with standard funding and those of specialized centres with a larger allocated budget. We conclude that multidisciplinary PR programs are available in the majority of Belgian hospitals. Differences in funding determine the quality of the team, the diversity of the interventions and the monitoring of outcomes. More resources for rehabilitation will directly improve the utilization and quality of this essential treatment option in respiratory diseases. PMID- 29631423 TI - Adherence to long-term oxygen therapy in patients with chronic obstructive pulmonary disease. AB - Long-term oxygen therapy (LTOT) has beneficial effects on survival in patients with chronic obstructive pulmonary disease (COPD) and severe hypoxemia at rest. Two landmark trials suggested that these benefits depend on the time of exposure to oxygen. Patients are usually prescribed LTOT for at least 15-18 hours/day. The primary objective of this study was to determine the average daily exposure to supplemental oxygen in patients with severely hypoxemic COPD who were newly prescribed LTOT and the proportion of patients who were adherent to their prescription. The secondary objective was to identify predictors of compliance to LTOT. We performed a retrospective observational study of patients newly registered in a regional home oxygen program in Quebec, Canada, between July 1, 2013, and December 31, 2014. Daily exposure to oxygen was objectively measured from the concentrator's counter clock. From 196 patients registered in the program during the study period, 115 contributed to the analysis. Most patients ( n = 84; 73%) were prescribed oxygen for >=18 hours/day. Overall, the 115 patients were exposed to home oxygen for 17.8 hours/day; 60% of the patients were compliant according to our definition. Increasing age and ambulatory oxygen utilization predicted adherence to oxygen therapy. Adherence to home oxygen therapy is suboptimal. Behavioral and psychological interventions to improve compliance to LTOT should be investigated. PMID- 29631424 TI - [Interventions in medical practice to reduce tobacco use among adolescents]. AB - Interventions to facilitate prevention of tobacco use and smoking cessation are the most cost-effective health care measures. They are invaluable among adolescents, since adult smokers start smoking in adolescence. There is evidence that early smoking initiation makes cessation difficult and it is associated with lifelong health risks. Our study aims at reviewing current approaches and interventions that can help health care professionals involved in paediatric care to reduce tobacco use in adolescence. International guidelines include short, practical interventions that are easy to apply by health care professionals in the primary and paediatric care. In tobacco use prevention, the role of health care professionals is of special importance. They have social respect, therefore they can provide credible information on tobacco use and cessation. Studies have found that short, goal-oriented counselling can further reduce the prevalence of smoking among adolescents presenting to their health care professional. Reduction of tobacco use is one of the primary health care goals in the 21st century, which should be started as early as childhood and adolescence. There have been several evidence-based approaches, which are essential for health care professionals involved in adolescent care. Orv Hetil. 2018; 159(15): 593-602. PMID- 29631425 TI - [Randomized, controlled clinical trials with observational follow-up investigations for evaluating efficacy of antihyperglycaemic treatment. I. Main results of the studies]. AB - The effect of antihyperglycaemic (antidiabetic) treatment on the late diabetic complications is one of the most important research areas in clinical diabetology. The relationship between glycaemic control and late micro- and macrovascular complications was highlighted by the results of the DCCT (Diabetes Control and Complications Trial) with type 1 and by the UKPDS (United Kingdom Prospective Diabetes Study) with type 2 diabetic patients. In these studies, observational follow-up investigations were also performed after the close-out of the randomized phase of the trial. In addition to these landmark studies, other randomized, controlled efficacy trials were also performed with observational follow-up investigations resulting in the development of the concept of metabolic memory or metabolic legacy. In this article, the main results of the studies are summarized. Orv Hetil. 2018; 159(15): 575-582. PMID- 29631426 TI - [Multiplex ligation-dependent probe amplification in oncohematological diagnostics and research]. AB - Genetic abnormalities associated with the development, progression and treatment resistance of hematological malignancies are extensively characterized. Rapid, reliable and cost-efficient techniques are needed to screen the clinically relevant aberrations in routine diagnostics. Multiplex ligation-dependent probe amplification is an efficient tool to analyze genomic copy number aberrations at 55-60 different genomic loci. The method allows the profiling of prognostic and predictive markers; thus, it can efficiently be combined with karyotyping and fluorescence in situ hybridization, the most commonly used diagnostic techniques to detect cytogenetic lesions. Furthermore, the method can interrogate methylation status and unravel point mutations at specific sites, providing results in 24 hours. Here, we describe the technical background of multiplex ligation-dependent probe amplification, summarize its advantages and limitations as well as discuss its role in oncohematological diagnostics and research. Finally, future outlook is provided, with emphasis on recent technological advances related to next-generation sequencing. Orv Hetil. 2018; 159(15): 583 592. PMID- 29631428 TI - [Investigation and treatment of prefibrotic/early primary myelofibrosis. A case study]. AB - Moderate thrombocytosis can accompany several diseases (bleeding, inflammation, iron deficiency, or autoimmune diseases), but hematologic examination is strongly recommended in a patient with persistent platelet count above 450 G/L unless reactive origin can be confirmed. The 47-year-old woman's medical history included hypertonia, asthma bronchiale, and endometriosis. In March 2015, she underwent laboratory examination due to weight loss and lack of appetite. Her results showed elevated thrombocyte count (617 G/L), but no iron deficiency. She presented in our clinic on 07. 04. 2015 with acute pain below her left hypochondrial region, but simple imaging examinations showed no difference to explain it. Abdominal CT revealed a 4.5 cm thrombus which protruded into the left renal artery, blocking it. We started APTI- (activated partial thromboplastin time) monitored continuous intravenous treatment with unfractionated heparin. The JAK2V617F mutation analysis came back positive. Subsequent bone marrow examination revealed prefibrotic/early stage myelofibrosis, prompting treatment with hydroxyurea. The applied treatments led to the disappearance of the patient's symptoms accompanied by the gradual normalisation of the thrombocyte count. Moderate thrombocytosis is often secondary, but if it persists and is accompanied by mainly thromboembolic events, the risk of diseases of the haematopoietic system, primarily Philadelphia chromosome negative chronic myeloproliferative disease should also be considered. Clinically, essential thrombocythaemia and the prefibrotic/early stage of myelofibrosis can be very similar. Differential diagnosis is only possible through the histological examination of the bone marrow, which becomes indispensible due to the difference in prognosis and treatment options. Orv Hetil. 2018; 159(15): 603-609. PMID- 29631430 TI - Bioflocculation in natural and engineered systems: current perspectives. AB - Microorganisms have the tendency to accumulate at interfaces through the release of extracellular polymeric substances to form aggregates such as films or flocs. This physical association leads to different modes of interactions among cells and the subsequent development of functionally and metabolically diverse consortia. Aggregation of cells in aqueous suspensions often results in the formation of flocs, which are hotspots of enhanced microbial processes. This has important implications for the dynamics of organic and inorganic matter in varied ecosystems. These microbial flocs are not only important components in nutrient turnover, decomposition, and sinking flux but also facilitate contaminant removal and treatment of wastewater and biomass harvesting. Greater insight into the multitude of interactions between microorganisms in flocs would be useful to enhance the efficiency of bioflocculation processes. This review covers the fundamental aspects and outlines the role of bioflocculation in controlled industrial processes and in nature. PMID- 29631429 TI - Engineering microbes for direct fermentation of cellulose to bioethanol. AB - Consolidated bioprocessing (CBP) by micro-organisms is desired for efficient conversion of lignocellulosic biomass to bioethanol fuels. Potential candidates have been discovered, including cellulolytic bacteria and filamentous fungi. Genetic and metabolic manipulation of these organisms further promotes their fermentation capacities and the ethanol tolerance. In addition, Saccharomyces cerevisiae and several other yeasts were genetically modified to express recombinant cellulases in media or display them on the cell surface for CBP of cellulose. To compensate the insufficient capacity of a single strain, various microbial consortia have also been developed. In this article, we reviewed the recent advances in CBP microbes and focused on the efforts in strain improvement employing genetic engineering. PMID- 29631431 TI - Transformation of animal genomics by next-generation sequencing technologies: a decade of challenges and their impact on genetic architecture. AB - For more than a quarter of a century, sequencing technologies from Sanger's method to next-generation high-throughput techniques have provided fascinating opportunities in the life sciences. The continuing upward trajectory of sequencing technologies will improve livestock research and expedite the development of various new genomic and technological studies with farm animals. The use of high-throughput technologies in livestock research has increased interest in metagenomics, epigenetics, genome-wide association studies, and identification of single nucleotide polymorphisms and copy number variations. Such studies are beginning to provide revolutionary insights into biological and evolutionary processes. Farm animals, such as cattle, swine, and horses, have played a dual role as economically and agriculturally important animals as well as biomedical research models. The first part of this study explores the current state of sequencing methods, many of which are already used in animal genomic studies, and the second part summarizes the state of cattle, swine, horse, and chicken genome sequencing and illustrates its achievements during the last few years. Finally, we describe several high-throughput sequencing approaches for the improved detection of known, unknown, and emerging infectious agents, leading to better diagnosis of infectious diseases. The insights from viral metagenomics and the advancement of next-generation sequencing will strongly support specific and efficient vaccine development and provide strategies for controlling infectious disease transmission among animal populations and/or between animals and humans. However, prospective sequencing technologies will require further research and in field testing before reaching the marketplace. PMID- 29631432 TI - Early warning biomarkers in major depressive disorder: a strategic approach to a testing question. AB - PURPOSE: Identification of biomarkers in major depressive disorder (MDD) has proceeded in an extemporised manner. No single biomarker has been identified with utility in screening, diagnosis, prognosis, or monitoring, and screening tests have different characteristics than the other functions. Using chaos, bifurcation, and perturbation (CBP) theories, the aim is to identify biomarkers to aid clinicians in screening for MDD. MATERIALS AND METHODS: MDD is a complex disorder; consequently, a reductionist approach to characterize the complex system changes found in MDD will be inchoate and unreliable. A holistic approach is used to identify biomarkers reflecting the tipping points seen before the catastrophic bifurcation that results in MDD. RESULTS: Applying CBP theories revealed skew, resistance to change, flickering, increased variance and autocorrelation as patterns of biomarkers. Integrals and differentials of extracellular and intracellular biomarkers were identified, specifically focussed on hypothalamo-pituitary axis (HPA) dysfunction, metabolic dysfunction, inflammation and mitochondrial oxidative stress, and tryptophan metabolism. CONCLUSIONS: Applying CBP theories to the dysfunctional complex biological systems in MDD led to development of integrals and differentials of biomarkers that can be used in screening for MDD and planning future biomarker research, targeting intracellular and extracellular inflammation, HPA axis dysfunction, and tryptophan metabolism. PMID- 29631433 TI - Two new labdane diterpenoids from aerial parts of Leonurus japonicus and their anti-inflammatory activity. AB - Two new labdane diterpenoids, Leojaponin E (1) and F (2), together with three known compounds were isolated from the dried herb of Leonurus japonicus Houtt., Lamiaceae. Their structures were determined based on extensive spectroscopic analyses. The absolute configurations of 1 and 2 were elucidated on the basis of experimental and calculated electronic circular dichroism spectra. In addition, compounds 1 and 2 exerted inhibition of LPS-induced PGE2 production in a dose dependent manner at concentrations ranging from 5 to 20 MUM. PMID- 29631434 TI - Eluvia drug-eluting vascular stent system for the treatment of symptomatic femoropopliteal lesions. AB - Endovascular options are increasingly recognized as primary treatments for lower extremity peripheral arterial disease inadequately responsive to noninvasive therapy. Options include balloon angioplasty and stent implantation, and newer technologies incorporate drug coatings to prevent restenosis and reduce the need for reintervention. The Eluvia drug-eluting vascular stent system (Boston Scientific, MA, USA) was designed with a biocompatible fluoropolymer coating to allow for drug elution over time. Initial clinical results demonstrate promising efficacy in terms of sustained femoropopliteal artery patency along with a good safety profile. This review summarizes the existing clinical literature on treatment of femoropopliteal artery lesions with Eluvia, and outlines the continuing research program. PMID- 29631435 TI - A 12-month, multicenter, parallel group comparison of dexamethasone intravitreal implant versus ranibizumab in branch retinal vein occlusion. AB - PURPOSE:: Dexamethasone intravitreal implant and intravitreal ranibizumab are indicated for the treatment of macular edema secondary to retinal vein occlusion. This non-inferiority study compared dexamethasone with ranibizumab in patients with branch retinal vein occlusion. METHODS:: In this randomized, 12-month head to-head comparison, subjects with branch retinal vein occlusion were assigned to dexamethasone 0.7 mg at day 1 and month 5 with the option of retreatment at month 10 or 11, or ranibizumab 0.5 mg at day 1 and monthly through month 5 with subsequent as-needed injections at month 6-month 11. The primary efficacy outcome was the mean change from baseline in best-corrected visual acuity at month 12; secondary outcomes included average change in best-corrected visual acuity, proportion of eyes with >=10- and >=15-letter gain/loss, change in central retinal thickness, and change in Vision Functioning Questionnaire-25 score. RESULTS:: In all, 307 of a planned 400 patients were enrolled in the study and received (mean) 2.5 dexamethasone injections (n = 154) and 8.0 ranibizumab injections (n = 153) over 12 months. The mean change from baseline in best corrected visual acuity at month 12 was 7.4 letters for dexamethasone versus 17.4 letters for ranibizumab (least-squares mean difference (dexamethasone minus ranibizumab), -10.1 letters; 95% confidence interval, -12.9, -7.2; p = 0.0006). CONCLUSION:: Dexamethasone and ranibizumab improved best-corrected visual acuity and anatomical outcomes; however, dexamethasone did not show non-inferiority to ranibizumab in this under-powered study. Dexamethasone was associated with an increased risk of intraocular pressure elevation and cataract progression, but a lower injection burden, compared to ranibizumab. PMID- 29631436 TI - Engagement in community activities and trust in local leaders as concomitants of psychological distress among Israeli civilians exposed to prolonged rocket attacks. AB - BACKGROUND AND OBJECTIVES: Present study, conducted in the aftermath of the 2014 Israel-Gaza conflict, investigated psychological toll of exposure to rockets attacks in a sample of residents of central and southern Israel. Analyses focused on the distress-protective functions of collectively grounded resources: engagement in community activities and trust in local leadership. DESIGN: This cross-sectional study was conducted between 2 and 3 months after the hostilities. METHOD: Participants (N = 764) were recruited by an online survey company that distributed a questionnaire assessing, in addition to focal predictors, sociodemographic factors and prior exposure to trauma. The outcome variables were post-traumatic stress disorder (PTSD) and nonspecific distress symptoms. RESULTS: Conservative regression analyses revealed that greater exposure to rocket attacks was predictive of higher levels of posttraumatic stress symptoms. Higher engagement in community activities exhibited a partial trauma-buffering function. However, higher levels of trust in local leaders appeared to exacerbate, rather than diminish, negative impact of rocket exposure on PTSD. Symptoms of psychological distress were not influenced neither by trauma exposure nor by stressor interactions with resources. Trust in local leadership exerted a beneficial main effect on distress. CONCLUSIONS: Collectively based resources are important for coping in times of community-wide stressors, yet their role is complex. PMID- 29631437 TI - Improving Lentiviral Transduction of CD34+ Hematopoietic Stem and Progenitor Cells. AB - The delivery of therapeutic genes for treatment of inherited or infectious diseases frequently requires lentiviral transduction of CD34+ hematopoietic stem and progenitor cells (HSC). Optimized transduction protocols with a therapeutic goal aim to maximize the number of transduction-positive cells while limiting the vector copy number that reach each individual cell. Importantly, the transduced HSC should maintain their "stem-like" properties. Here, we analyzed LentiBOOSTTM reagent, a membrane-sealing poloxamer, with respect to enhancing lentiviral transduction of CD34+ peripheral blood stem cells. We demonstrate that inclusion of LentiBOOSTTM in a standard HSC transduction protocol yields high transduction efficiencies while preserving the ability of the transduced HSC to differentiate into various hematopoietic lineages. Thus, LentiBOOSTTM reagent can significantly improve lentiviral CD34+ HSC transduction protocols with the potential to improve production of gene-modified cell products. PMID- 29631439 TI - Editorial Comment on: Conservative Management of Staghorn Calculi: When Is It Safe? by Morgan et al. PMID- 29631438 TI - Development of a Patient-Based Model for Estimating Operative Times for Robot Assisted Radical Prostatectomy. AB - OBJECTIVES: To develop a methodology for predicting operative times for robot assisted radical prostatectomy (RARP) using preoperative patient, disease, procedural, and surgeon variables to facilitate operating room (OR) scheduling. METHODS: The model included preoperative metrics: body mass index (BMI), American Society of Anesthesiologists score, clinical stage, National Comprehensive Cancer Network risk, prostate weight, nerve-sparing status, extent and laterality of lymph node dissection, and operating surgeon (six surgeons were included in the study). A binary decision tree was fit using a conditional inference tree method to predict operative times. The variables most associated with operative time were determined using permutation tests. Data were split at the value of the variable that results in the largest difference in mean for surgical time across the split. This process was repeated recursively on the resultant data. RESULTS: A total of 1709 RARPs were included. The variable most strongly associated with operative time was the surgeon (surgeons 2 and 4-102 minutes shorter than surgeons 1, 3, 5, and 6, p < 0.001). Among surgeons 2 and 4, BMI had the strongest association with surgical time (p < 0.001). Among patients operated by surgeons 1, 3, 5, and 6, RARP time was again most strongly associated with the surgeon performing RARP. Surgeons 1, 3, and 6 were on average 76 minutes faster than surgeon 5 (p < 0.001). The regression tree output in the form of box plots showed operative time median and ranges according to patient, disease, procedural, and surgeon metrics. CONCLUSION: We developed a methodology that can predict operative times for RARP based on patient, disease and surgeon variables. This methodology can be utilized for quality control, facilitate OR scheduling, and maximize OR efficiency. PMID- 29631440 TI - Effect of maltodextrin reduction and native agave fructans addition on the physicochemical properties of spray-dried mango and pineapple juices. AB - The effects of the partial replacement of maltodextrin by native agave fructans on the characteristics of spray-dried pineapple and mango powder were evaluated in this study. An experimental 33 design, three concentrations of maltodextrin (5, 7, and 10%), three concentrations of native agave fructans (0, 2, and 4%), and three feed temperatures (110, 115, and 120 C) were used. The results using the treatment in which only maltodextrin was used as a reference indicated that an increment in the inlet temperature decreases the moisture content, aw, and solubility. Likewise, an increase (more than 2%) in fructans concentration generates products with increased aw, moisture, hygroscopicity, wettability, and greater solubility. Additionally, no modification of storage stability was observed. Mango and pineapple powder color were affected mainly by the inlet temperature, causing an increase in luminosity (L*) and a decrease in parameter ( a*). A scanning electron microscopy showed spherical powder particles with certain contractions; powder stability in treatments with native agave fructans was not modified in the treatment at 2%. Finally, the addition of 2% agave fructans as carrier material was able to reduce the maltodextrin concentration of the spray drying process. PMID- 29631441 TI - Intraocular light scatter in patients on topical intraocular pressure-lowering medication. AB - PURPOSE:: To quantify ocular light scattering in patients under treatment with intraocular pressure-lowering eye-drops. METHODS:: In this prospective, observational, cross-sectional case series study, 160 eyes of 160 patients with primary open angle glaucoma or primary ocular hypertension were consecutively recruited from our Glaucoma Department over 7 months. In total, 46 eyes of 46 healthy volunteers matched for age and sex served as the control group. The variables recorded in a single visit were as follows: drug and number of drops per day, treatment duration, OXFORD corneal staining grade, lower tear meniscus height as measured by spectral domain optical coherence tomography, ocular redness and non-invasive tear breakup time measured with the Oculus Keratograph 5M, ocular surface disease index questionnaire score and objective scatter index through a double-pass technique (Optical Analysis System II). RESULTS:: Objective scatter index was higher in the patient group (3.1, interquartile range = 1.8 5.47) than in the control group (1.95; interquartile range = 0.7-5; p = 0.017). In a multiple linear regression model, non-invasive tear breakup time was identified as the most influential variable on light scatter (mean ratio = 1.015; p = 0.003; 95% confidence interval = -1.025 to -1.005). No correlation with objective scatter index was observed for number of daily eye-drops, preservative concentration or treatment duration. CONCLUSION:: Participants on anti-glaucoma medication showed a significantly higher objective scatter index than control group individuals. In the treated patient group, a lower non invasive tear breakup time was associated with a higher objective scatter index. This suggests that lubricating eye-drops to improve tear breakup time could also improve vision quality in these patients by diminishing light scattering. PMID- 29631442 TI - Examination of the Origin and Branching Direction of the Anterior Medial Malleolar Artery From the Anterior Tibial Artery: A Cadaveric Study. AB - BACKGROUND: This study characterized the anterior medial malleolar artery (AMMA) branching from the anterior tibial artery (ATA) to identify problems in anterior ankle arthroscopy possibly contributing to injury to the AMMA. METHODS: Barium was injected into 12 adult cadaveric feet via the external iliac artery and the origin and branching direction of the AMMA were identified on computed tomography. RESULTS: The AMMA originated from the level of the ankle joint and below and above the ankle joint line (AJL) in 4 (33.3%), 6 (50.0%), and 1 (8.3%) specimen, respectively. Mean distance from the AJL to the branching point of the AMMA on the sagittal plane was 2.5 mm distal to the AJL. Mean angle between the distal longitudinal axis of the ATA and AMMA was 83.2 degrees . CONCLUSIONS: This study established the origin and branching of the AMMA from the ATA. The AMMA should be examined carefully during ankle arthroscopy. LEVELS OF EVIDENCE: Level IV: Cadaveric study. PMID- 29631443 TI - Assessment of humoral, innate, and T-cell immune responses to adeno-associated virus vectors. AB - Adeno-associated virus (AAV)-based gene therapy is being applied to treat a wide array of diseases. Pre-existing host immune responses to AAV and immune responses elicited by AAV vector administration remain a problem that needs to be further studied. Here, we present a series of protocols to assess immune responses before and after AAV vector administration that is applicable to multiple animal models and Phase I clinical trials. More specifically, to evaluate: 1) the humoral immune response, through levels of AAV-neutralizing and binding antibodies; 2) the innate immune response, through the acute induction of inflammatory cytokines; and 3) the T-cell immune response, through the activation of transgene and vector-specific CD8 and CD4 T cells. PMID- 29631444 TI - Changes in Self-Efficacy and Outcome Expectations From Child Participation in Bicycle Trains for Commuting to and From School. AB - BACKGROUND: Active commuting to school (ACS) is associated with increased physical activity and lowered risk of obesity. In observational studies, ACS was associated with child self-efficacy, parent self-efficacy, and parent outcome expectations, although few experiments have assessed changes in these behavioral constructs. AIM: This study examined the effects of a bicycle train intervention (BTI) on child self-efficacy, parent self-efficacy, and parent outcome expectations in a diverse, low socioeconomic status population. METHOD: Data were from a 2014 BTI pilot randomized controlled trial (RCT) on fourth to fifth graders aged 9 to 12 years, n = 54, from four schools serving low-income populations in Seattle, Washington. The BTI was a group of children and study staff who cycled together to/from school daily, while controls received no intervention. Responses to validated child self-efficacy, parent self-efficacy, and parent outcome expectations questionnaires ranged from 1 to 3. Adjusted linear mixed effects models estimated standardized coefficients for child self efficacy, parent self-efficacy, and parent outcome expectations comparing intervention and controls from Time 1 (preintervention) to Time 2 (final 4-6 weeks of intervention). RESULTS: The intervention group had increases in child self-efficacy of 0.84 standard deviations (95% confidence interval [CI] [0.37, 1.31]), parent self-efficacy of 0.46 standard deviations (95% CI [0.05, 0.86]), and parent outcome expectations of 0.47 standard deviations (95% CI [0.17, 0.76]) compared with controls from Times 1 to 2 (all ps <.05). CONCLUSION: A BTI improved child self-efficacy, parent self-efficacy, and parent outcome expectations, which warrants a larger RCT to examine long-term changes to these behavioral constructs and ACS. PMID- 29631445 TI - Prostatic Urethral Lift: Does Size Matter? AB - OBJECTIVES: To assess if prostatic urethral lift (PUL) can be as effective on larger prostates. PUL is an endoscopic device that retracts prostatic tissue to relieve benign prostatic hypertrophy (BPH) obstruction. In 2013, PUL was approved for patients with a prostate size of <80 g and no median lobes. The approval was primarily based on the L.I.F.T. study, which only evaluated patients with prostates between 30 and 80 g in size. MATERIALS AND METHODS: Seventy-four patients underwent PUL between April 2, 2014, and December 2, 2015, for BPH management. Fifty-one patients were in the <80 g prostate group (median: 46 g, range: 20-78 g) and 23 in the >80 g prostate group (median: 112 g, range: 81-254 g). Student t-tests and Fisher's exact tests were used to compare continuous and categorical variables. p-Value of <0.05 was considered statistically significant. RESULTS: Median time between PUL and follow-up AUA symptom score (AUASS) was 144 days. A difference between the numbers of PUL implants used was seen. A significant improvement in AUASSs was seen in both groups following the procedure. There was no significant difference in age, AUASS before or after the procedure, or need for an additional outlet procedure between the two groups. CONCLUSION: Early experience finds that a sufficient number of men with larger prostates appear to benefit from PUL. Patients with >80 g prostate size were more likely to have a median lobe and may benefit from resection of the median lobe at time of the PUL. Long-term follow-up is needed to evaluate the durability of the PUL procedure. PMID- 29631446 TI - Editorial Comment on: Utilizing Machine Learning and Automated Performance Metrics to Evaluate Robot-Assisted Radical Prostatectomy Performance and Predict Outcomes by Hung et al. PMID- 29631447 TI - Diagnostic Performance and Utility of Quantitative EEG Analyses in Delirium: Confirmatory Results From a Large Retrospective Case-Control Study. AB - BACKGROUND: The lack of objective disease markers is a major cause of misdiagnosis and nonstandardized approaches in delirium. Recent studies conducted in well-selected patients and confined study environments suggest that quantitative electroencephalography (qEEG) can provide such markers. We hypothesize that qEEG helps remedy diagnostic uncertainty not only in well defined study cohorts but also in a heterogeneous hospital population. METHODS: In this retrospective case-control study, EEG power spectra of delirious patients and age-/gender-matched controls (n = 31 and n = 345, respectively) were fitted in a linear model to test their performance as binary classifiers. We subsequently evaluated the diagnostic performance of the best classifiers in control samples with normal EEGs (n = 534) and real-world samples including pathologic findings (n = 4294). Test reliability was estimated through split-half analyses. RESULTS: We found that the combination of spectral power at F3-P4 at 2 Hz (area under the curve [AUC] = .994) and C3-O1 at 19 Hz (AUC = .993) provided a sensitivity of 100% and a specificity of 99% to identify delirious patients among normal controls. These classifiers also yielded a false positive rate as low as 5% and increased the pretest probability of being delirious by 57% in an unselected real-world sample. Split-half reliabilities were .98 and .99, respectively. CONCLUSION: This retrospective study yielded preliminary evidence that qEEG provides excellent diagnostic performance to identify delirious patients even outside confined study environments. It furthermore revealed reduced beta power as a novel specific finding in delirium and that a normal EEG excludes delirium. Prospective studies including parameters of pretest probability and delirium severity are required to elaborate on these promising findings. PMID- 29631448 TI - Relationship of troponin to incident atrial fibrillation occurrence, recurrence after radiofrequency ablation and prognosis: a systematic review, meta-analysis and meta-regression. AB - OBJECTIVE: To explore the association between the levels of troponin (Tn) and incident atrial fibrillation (AF) occurrence, AF recurrence after radiofrequency ablation (RFA), and the risk trend of AF related prognosis (stroke, major bleeding and mortality). METHODS: Twenty-seven studies were included after a systematic search in PubMed from 2005 to 2017, including 13 associated with incident AF occurrence, 8 associated with AF recurrence after RFA and 6 studies evaluating the risk trend of AF-related prognosis with increased Tn levels. RESULTS: Compared with 'no incident AF occurrence' patients, the incident AF occurrence group had similar baseline troponin I (TnI) levels (standardized mean differences [SMD] = 0.42, 95% CI: -0.02-0.86, p = 0.06; I2 = 87.0%, N = 6), but higher troponin T (TnT) levels (SMD = 3.77, 2.13-5.42, p <0.001; I2=99.7%, N = 8). AF recurrence patients had similar peri-ablation TnI levels, but higher peri ablation TnT levels compared to the 'no AF recurrence' group with pooled SMD. (TnI: SMD: -0.61, -1.22to 0, p = 0.049; I2 = 87.1%; TnT: 0.38, 0.14-0.62, p = 0.002; I2 = 64.7%). On meta-regression, there was an increased risk trend for stroke/systemic embolism (SE) (r2 = 0.93, p = 0.04) or major bleeding (r2 = 0.99, p < .0001) with the increasing TnT levels. Mortality was not significantly related to TnI (r2 = 0.09, p = 0.25) or TnT (r2 = 0.20, p = 0.31), and stroke/SE (r2 = 0.02, p = 0.74) or major bleeding (r2 = 0.002, p = 0.92) was non significantly related to increasing TnI levels. CONCLUSIONS: In our systematic review, meta-analysis and meta-regression, TnT was associated with both incident AF occurrence and AF recurrence after RFA, as well as stroke/SE and major bleeding. In contrast, TnI was not associated with incident AF occurrence, AF recurrence after RFA or prognosis (stroke/SE, major bleeding). PMID- 29631449 TI - Dyadic resources in the return to work of cancer survivors: exploring supervisor employee perspectives. AB - PURPOSE: The number of working-age people recovering from cancer is gradually on the rise; yet, cancer survivors have higher rates of unemployment compared to other employees. Cancer survivors returning to work cope with symptoms of fatigue, distress, cognitive difficulties and physical limitations. The present article addresses the supervisor-cancer survivor dyad as the unit of analysis, in an attempt to identify the dyadic resources that underlie the coping of the supervisor-employee unit with return to work. MATERIALS AND METHODS: In-depth, semi-structured individual interviews were conducted with 12 dyads of cancer survivors and their supervisors, representing successful return to work, followed by comparative content analysis of the data. RESULTS: Four themes were revealed: (1) Congruent supervisor-cancer survivor views regarding personalized/standard management of cancer survivors' returning to work; (2) Return to work as a team work approach; (3) Commitment and persistence in the face of obstacles, and (4) Supervisor and cancer survivor mutual appreciation. CONCLUSIONS: Joint coping of supervisors and cancer survivors with the difficulties of the return to work process is perceived to contribute significantly to the success of return to work. Training of cancer survivors and supervisors conducted by rehabilitation professionals regarding aspects of the orientation toward return to work is suggested. Implication for rehabilitation Cancer survivors have different preferences regarding standard versus exceptional organizational treatment following return to work. Organizational acknowledgment of the cancer survivor's value for the organizations supports cancer survivors' return to work. Cancer survivors can benefit from a sense of responsibility and involvement in decision making regarding the process of return to work. PMID- 29631450 TI - Carbon, nitrogen and phosphorus removal mechanisms of aerobic granules. AB - Aerobic granules are the potential tools to develop modern wastewater treatment technologies with improved nutrient removal efficiency. These granules have several promising advantages over conventional activated sludge-based wastewater treatment processes. This technology has the potential of reducing the infrastructure and operation costs of wastewater treatment by 25%, energy requirement by 30%, and space requirement by 75%. The nutrient removal mechanisms of aerobic granules are slightly different from that of the activated sludge. For instance, unlike activated sludge process, according to some reports, as high as 70% of the total phosphorus removed by aerobic granules were attributed to precipitation within the granules. Similarly, aerobic granule-based technology reduces the total amount of sludge produced during wastewater treatment. However, the reason behind this observation is unknown and it needs further explanations based on carbon and nitrogen removal mechanisms. Thus, as a part of the present review, a set of new hypotheses have been proposed to explain the peculiar nutrient removal mechanisms of the aerobic granules. PMID- 29631451 TI - Hypoechoic liver in fetuses with trisomy 21. AB - The association between hypoechoic hepatomegaly in the third trimester and transient abnormal myelopoiesis (TAM) was reported previously in six fetuses with trisomy 21 (T21). We report a series of three cases of T21 in which hypoechoic liver (HL) was found in the second trimester but without evidence of TAM on both hematological and histological examination. We postulate that the hypo echogenicity may be due to liver congestion secondary to hemodynamic disturbances seen in T21 fetuses. All three cases had negative first trimester Down syndrome screening and one case was detected solely because of the isolated finding of HL. HL per se may be associated with T21 and more positive cases are required to support this association. PMID- 29631452 TI - Children's biological responsivity to acute stress predicts concurrent cognitive performance. AB - Although prior research has characterized stress system reactivity (i.e. hypothalamic-pituitary-adrenal axis, HPAA; autonomic nervous system, ANS) in children, it has yet to examine the extent to which biological reactivity predicts concurrent goal-directed behavior. Here, we employed a stressor paradigm that allowed concurrent assessment of both stress system reactivity and performance on a speeded-response task to investigate the links between biological reactivity and cognitive function under stress. We further investigated gender as a moderator given previous research suggesting that the ANS may be particularly predictive of behavior in males due to gender differences in socialization. In a sociodemographically diverse sample of young children (N = 58, M age = 5.38 yrs; 44% male), individual differences in sociodemographic covariates (age, household income), HPAA (i.e. cortisol), and ANS (i.e. respiratory sinus arrhythmia, RSA, indexing the parasympathetic branch; pre ejection period, PEP, indexing the sympathetic branch) function were assessed as predictors of cognitive performance under stress. We hypothesized that higher income, older age, and greater cortisol reactivity would be associated with better performance overall, and flexible ANS responsivity (i.e. RSA withdrawal, PEP shortening) would be predictive of performance for males. Overall, females performed better than males. Two-group SEM analyses suggest that, for males, greater RSA withdrawal to the stressor was associated with better performance, while for females, older age, higher income, and greater cortisol reactivity were associated with better performance. Results highlight the relevance of stress system reactivity to cognitive performance under stress. Future research is needed to further elucidate for whom and in what situations biological reactivity predicts goal-directed behavior. PMID- 29631453 TI - Assessing the impact of a home-based stroke rehabilitation programme: a cost effectiveness study. AB - BACKGROUND: Stroke is often a severe and debilitating event that requires ongoing rehabilitation. The Community Stroke Rehabilitation Teams (CSRTs) offer home based stroke rehabilitation to individuals for whom further therapy is unavailable or inaccessible. The objective of this study was to evaluate the cost effectiveness of the CSRT programme compared with a "Usual Care" cohort. METHODS: We collected data on CSRT clients from January 2012 to February 2013. Comparator data were derived from a study of stroke survivors with limited access to specialised stroke rehabilitation. Literature-derived values were used to inform a long-term projection. Using Markov modelling, we projected the model for 35 years in six-month cycles. One-way, two-way, and probabilistic sensitivity analyses were performed. Results were discounted at 3% per year. RESULTS: Results demonstrated that the CSRT programme has a net monetary benefit (NMB) of $43,655 over Usual Care, and is both less costly and more effective (incremental cost = $17,255; incremental effect = 1.65 Quality Adjusted Life Years [QALYs]). Results of the probabilistic sensitivity analysis revealed that incremental cost effectiveness of the CSRT programme is superior in 100% of iterations when compared to Usual Care. CONCLUSIONS: The study shows that CSRT model of care is cost-effective, and should be considered when evaluating potential stroke rehabilitation delivery methods. Implications for Rehabilitation Ongoing rehabilitation following stroke is imperative for optimal recovery. Home-based specialised stroke rehabilitation may be an option for individuals for whom ongoing rehabilitation is unavailable or inaccessible. The results of this study demonstrated that home-based rehabilitation is a cost-effective means of providing ongoing rehabilitation to individuals who have experienced a stroke. PMID- 29631454 TI - Acute kidney injury in preterm infants with necrotizing enterocolitis. AB - PURPOSE: Acute kidney injury (AKI) is an independent predictor of morbidity and mortality in critically ill infants and children. AKI develops in an estimated one-third of the neonatal intensive care unit (NICU) population; however, literature on the incidence of AKI in premature infants with a diagnosis of necrotizing enterocolitis (NEC) is limited. The objectives of this study were to describe the incidence of AKI in infants with radiographically confirmed NEC, assess these infants for independent risk factors associated with development of AKI and evaluate if the presence of AKI is associated with increased mortality. STUDY DESIGN: We conducted a retrospective chart review of premature infants, gestational age (GA) 23-34 weeks, who developed modified Bell's level 2 or 3 NEC while admitted to two tertiary NICUs within our health system between 2010 and 2015. AKI was defined and staged according to modified Kidney Disease: Improving Global Outcomes (KDIGO) criteria. RESULTS: 77 infants with Bell's level II (63.6%) and III (36.4%) NEC were studied. AKI occurred in 42.9% of infants (Stage 1: 18.2%; Stage 2: 13%; Stage 3: 11.7%). Bell's Stage III NEC, lower GA, maternal preeclampsia/eclampsia, gentamicin/vancomycin exposure, and empiric antibiotic use were independently associated with AKI. AKI was strongly associated with mortality (HR 20.3 95%CI 2.5-162.8, p = .005) in an adjusted Cox model. CONCLUSIONS: AKI is common in premature infants who develop NEC. More severe NEC was found to be an independent risk factor for AKI. Additionally, AKI in infants with NEC increases mortality risk significantly. PMID- 29631455 TI - The influence of massage on neonatal hyperbilirubinemia: a meta-analysis of randomized controlled trials. AB - INTRODUCTION: The efficacy of massage to treat neonatal hyperbilirubinemia remains controversial. We conducted a systematic review and meta-analysis to explore the influence of massage on the neonatal hyperbilirubinemia. METHODS: We search PubMed, Embase, Web of science, EBSCO, and Cochrane Library databases through November 2017 for randomized controlled trials (RCTs) assessing the effect of massage on neonatal hyperbilirubinemia. This meta-analysis is performed using the random-effect model. RESULTS: Six RCTs involving 357 patients are included in the meta-analysis. Overall, compared with the control group in neonatal hyperbilirubinemia, massage therapy is associated with substantially reduced serum bilirubin level within 4 d (mean difference (MD) = -2.31; 95% CI = 2.92 to -1.70; p < .00001) and transcutaneous bilirubin level within 4 d for neonatal hyperbilirubinemia (MD = -1.97; 95% CI = -2.55 to -1.39; p < .00001), but results no remarkable impact on serum bilirubin level on 2 d (MD = -0.82; 95% CI = -2.16-0.52; p = .23), transcutaneous bilirubin level on 2 d (MD = -0.17; 95% CI = -1.34 to 1.00; p = .77), frequency of defecation daily on 2 d (MD = 0.57; 95% CI = -0.03 to 1.16; p = .06), and frequency of defecation daily within 4 d (MD = 0.83; 95% CI = -0.11 to 1.76; p = .08). CONCLUSIONS: Massage therapy can significantly reduce serum bilirubin level and transcutaneous bilirubin level within 4 d, but demonstrates no influence on serum bilirubin level and transcutaneous bilirubin level on 2 d, frequency of defecation daily on 2 and 4 d for neonatal hyperbilirubinemia. PMID- 29631456 TI - Targeted delivery at 34 versus 35 weeks in women with preterm prelabor rupture of membranes. AB - OBJECTIVE: To compare planned delivery at 34 versus 35 weeks for women with preterm prelabor rupture of membranes (PPROM). MATERIALS AND METHODS: We performed a retrospective cohort study of singleton pregnancies with PPROM after 24 weeks delivered from 2006 to 2014. In 2009, an institutional practice change established 35 weeks as the target gestational age before induction of labor was initiated after PPROM. Demographic and outcome measures were compared for two cohorts: women delivered 2006-2008 - target 34 weeks (T34) and women delivered 2009-2014 - target 35 weeks (T35). The primary outcome was neonatal intensive care unit (NICU) admission. RESULTS: Of the 382 women with PPROM, 153 (40%) comprized the T34 cohort and 229 (60%) comprized the T35 cohort. Demographic characteristics were similar between groups. There were no differences between groups in gestational age at PPROM (31.0 +/- 3.3 weeks versus 31.2 +/- 3.1 weeks; p = .50) or maternal complications. The mean gestational age at delivery was earlier in the T34 group (31.8 +/- 3.2 weeks versus 32.4 +/- 2.7 weeks; p = .04). The median predelivery maternal length of stay (LOS) was 1 day longer in the T35 group (p = .03); the total and postpartum LOS were similar between groups (p > .05). There were no differences in the rate of NICU admission (T34 89.5% versus T35 92.1%; p = .38) or median neonatal LOS (T34 14 days versus T35 17 days; p = .15). In those patients who reached their target gestational age, both maternal predelivery LOS and total LOS were longer in the T35 group (p > .05). The frequency of NICU admission in those reaching their target gestational age was similar between groups (T34 83.37% versus T35 76.19%; p = .46). CONCLUSIONS: A 35 week target for delivery timing for women with PPROM does not decrease NICU admissions or neonatal LOS. This institutional change increased maternal predelivery LOS, but did not increase maternal or neonatal complications. PMID- 29631457 TI - Effects of Kinesio taping in rectus femoris activity and sit-to-stand movement in children with unilateral cerebral palsy: placebo-controlled, repeated-measure design. AB - BACKGROUND: Although it has been commonly used in rehabilitation sets, there is a lack of studies verifying the effects of Kinesio taping to improve functionality in children with Cerebral Palsy (CP). This information would promote evidence based practice. PURPOSE: To verify the effects of Kinesio taping in the performance of sit-to-stand movement in children with unilateral CP. METHODS AND MATERIALS: A blinded, single placebo-controlled and repeated-measure design. The setting was the rehabilitation clinic of the university and care facilities. A total of 11 children from 6 to 12 years of age (mean: 10.5 years; standard deviation: 2.8 years) and classified as levels I and II by the Gross Motor Function Classification System were included. Kinesio taping was applied over the rectus femoris of the affected limb. Three taping conditions were used: Kinesio taping, without Kinesio taping and placebo. Three seat heights were used: neutral (100%), lowered (80%), and elevated (120%). Muscle activity (electromyography) and trunk and lower limb alignment (kinematics) were evaluated as body structures and function measures. The time required to perform sit-to-stand was used as a functionality measure. Mixed analysis of variation (ANOVA) measured angular variables of the hip, knee, ankle, and rectus femoris activity. Repeated ANOVA measured angular variables of trunk and pelvis and total duration. Significance was accepted for values of p <= 0.05. RESULTS: Kinesio taping increased rectus femoris activity, decreased peak flexion of the trunk, knee, hip, and ankle, and increased trunk extension in the end of sit-to-stand when compared with without Kinesio taping and placebo. Total duration was decreased with lower effect sizes. CONCLUSIONS: Immediate application of Kinesio taping modified body structures and function measures during sit-to-stand in children with unilateral CP, but it did not alter functionality. Implications for Rehabilitation Evidence-based practice about the use of Kinesio taping in Cerebral Palsy. Knowledge about alternative rehabilitation techniques in Cerebral Palsy. Knowledge about sensory stimulation in Cerebral Palsy. Effectiveness of Kinesio taping in muscle activation. PMID- 29631458 TI - Preparation of ordered mesoporous and macroporous thermoplastic polyurethane surfaces for potential medical applications. AB - Thermoplastic polyurethanes are widely used in medical devices. In order to limit some of their shortfalls, like microbial attachment, surfaces modifications can be required. In this work, a two-step replication method was used to create ordered macroporous and mesoporous thermoplastic polyurethane surfaces using anodic aluminum oxide as master template. The intermediate mould materials that were tested were polystyrene and a polyacrylate resin with inorganic filler. All obtained surfaces were characterized by scanning electron microscopy. The initial anodic aluminum oxide surfaces possessed macro or mesopores, function of anodization conditions. The intermediate mould structure correctly replicated the pattern, but the polystyrene surface structures (pillars) were less resistant than the polyacrylate resin ones. The thermoplastic polyurethane pattern possessed macropores or mesopores of about 130 nm or 46 nm diameter and of about 300 nm or 99 nm interpore distances, respectively, in accordance with the initial pattern. Thermoplastic polyurethanes pore depth was however less than initial anodic aluminum oxide pore depth, linked to an incomplete replication during intermediate mould preparation (60 to 90% depth replication). The correct replication of the original pattern confirms that this novel fabrication method is a promising route for surface patterning of thermoplastic polyurethanes that could be used for medical applications. PMID- 29631460 TI - Maternal and perinatal outcomes of uterine rupture in a tertiary care hospital: a cross-sectional study. AB - OBJECTIVE: The current study aims to evaluate the incidence, maternal and perinatal outcomes in cases presented with uterine rupture (UR) and to explore the differences in presentation, management and outcome of UR in patients with scarred versus unscarred uterus. MATERIALS AND METHODS: A cross-sectional study conducted in a tertiary care hospital over a period of 2 years. The study included all women diagnosed with UR and admitted to the emergency unit between January 2016 and December 2017. A structured questionnaire was used to collect the preoperative demographic and clinical data. An observation checklist was used for intraoperative findings and management. Postoperative data were collected about maternal and fetal outcomes. Data were analyzed using SPSS software. Qualitative variables were compared between groups using chi-square test while quantitative variables were compared using the Mann-Whitney test. RESULTS: Sixty two women were diagnosed with uterine rupture (0.32% of all deliveries). The mean age of the included patients was 29.6 +/- 5.6 years while the mean parity was 3.0 +/- 1.8. Uterine repair was successful in 52 cases (83.9%). There were four (6.5%) maternal deaths and 42 (67.8%) perinatal deaths. Ten patients (16.1%) were transferred to the postoperative intensive care unit (ICU). Re-exploration was carried out in three cases. The most common complication of UR was disseminated intravascular coagulopathy (DIC) occurred in eight women (12.9%). Maternal and perinatal mortality were significantly higher in patients with unscarred uterus (p = .0001 and .026, respectively). CONCLUSIONS: The incidence of UR is 32/10,000 deliveries in our tertiary hospital. Rupture of unscarred uterus is associated with more maternal and fetal mortality. However, rupture of scarred uterus was more common due to the rising rate of cesarean sections. PMID- 29631459 TI - Anti-interleukin-6 receptor antibody prevents loss of bone structure and bone strength in collagen-induced arthritis mice. AB - OBJECTIVE: Rheumatoid arthritis (RA) is a disease that typically induces secondary osteoporosis, which increases the risk of bone fractures. Anti interleukin-6 (IL-6) receptor antibody is used to treat RA; however, its effect on bone strength is not clear. Therefore, we investigated the influence of MR16 1, an anti-mouse IL-6 receptor antibody, on bone structure and femoral strength in a collagen-induced arthritis (CIA) mouse model. METHOD: DBA/1J mice were immunized by intradermal injection of bovine type II collagen. MR16-1 was administered intraperitoneally at the same time as immunization. Thirty-five days after the first immunization, bone structure and bone strength were measured by micro-computed tomography and the three-point bending test. RESULTS: In the CIA group, most bone mineral density and bone structure parameters in the foot, femur, and lumbar spine were significantly lower than in the normal group. Moreover, the maximum load of the femoral shaft in the CIA group was significantly lower than in the normal group. MR16-1 treatment significantly prevented the CIA-induced deterioration of bone structure and loss of bone strength. CONCLUSION: These results suggest that CIA systemically induces a deterioration of bone structure and loss of bone strength, and that IL-6 signalling plays an important role in these processes. PMID- 29631461 TI - The impact of time of delivery on gestations complicated by preterm premature rupture of membranes: daytime versus nighttime. AB - BACKGROUND: Perinatal death, in particular intrapartum stillbirth and short-term neonatal death, as well as neonatal short-term and long-term morbidity have been associated with the time of day that the birth occurs. Indeed, evening and nighttime deliveries were associated with an increased risk of an adverse perinatal outcome when compared to similar daytime deliveries. Impact of shift change, as well as time of day delivery have been extensively studied in the context of maternal and neonatal complications of cesarean delivery, however, no studies were previously performed on timing of delivery and its effect on the outcome of pregnancies complicated by preterm premature rupture of membranes. OBJECTIVE: Our objective was to compare obstetric, neonatal as well as long-term outcomes between women delivered in the daytime versus nighttime, in singleton gestations whose pregnancies were complicated by preterm premature rupture of membranes. STUDY DESIGN: This was a secondary analysis of a trial of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Maternal Fetal Medicine Units Network "A Randomized Clinical Trial of the Beneficial Effects of Antenatal Magnesium Sulfate for the Prevention of Cerebral Palsy." For this analysis, the time of delivery was divided into the daytime, from 07:01 to 19:00, and the nighttime, from 19:01 to 07:00. Epidemiological, obstetric characteristics as well as neonatal and long-term outcomes were compared between deliveries occurring during the daytime versus the nighttime periods. Inclusion criteria consisted of singleton gestations diagnosed with preterm premature rupture of membranes (PPROM). Multifetal gestations and pregnancies with preterm labor without preterm premature rupture of membranes were excluded. RESULTS: A total of 1752 patients met inclusion criteria, 881 delivering during the daytime, while 871 during the nighttime. There were no differences in demographic maternal variables. There were no differences in the number of patients receiving steroids and the doses of steroids. Antibiotic prophylaxis was also equal in both groups. Postpartum endometritis, chorioamnionitis, and the latency to delivery were also equivalent between both the groups. Cesarean delivery for distress was the only different outcome, more prevalent in daytime deliveries (157 (44.7%) versus 108 (35.9%) of the nighttime ones p = .02). Neonatal adverse outcomes as well as long term outcomes were similar between the two groups. CONCLUSIONS: In the setting of delivery at a tertiary care center, and in the era of universal use of steroids, and latency antibiotics for the management of preterm premature of membranes, there is no marked difference in pregnancy, neonatal as well as long-term outcomes for infants delivered in the daytime versus nighttime. PMID- 29631462 TI - Maternal factors influencing late entry into prenatal care: a stratified analysis by race or ethnicity and insurance status. AB - OBJECTIVE: Examine factors influencing late (> sixth month of gestation) entry into prenatal care by race/ethnicity and insurance payer. METHODS: The study population was drawn from singleton live births in California from 2007 to 2012 in the birth cohort file maintained by the California Office of Statewide Health Planning and Development, which includes linked birth certificate and mother and infant hospital discharge records. The sample was restricted to infants delivered between 20 and 44 weeks gestation. Logistic regression was used to calculate relative risks (RR) and 95% confidence intervals (CI) for factors influencing late entry into prenatal care. Maternal age, education, smoking, drug or alcohol abuse/dependence, mental illness, participation in the Women, Infants and Children's program and rural residence were evaluated for women entering prenatal care > sixth month of gestation compared with women entering < fourth month. Backwards stepwise logistic regression was used to create final multivariable models of risk and protective factors for late prenatal care entry for each race or ethnicity and insurance payer. RESULTS: The sample included 2,963,888 women. The percent of women with late entry into prenatal care was consistently higher among women with public versus private insurance. Less than 1% of white non Hispanic and Asian women with private insurance entered prenatal care late versus more than 4% of white non-Hispanic and black women with public insurance. After stratifying by race or ethnicity and insurance status, women less than 18 years of age were more likely to enter prenatal care late, with young Asian women with private insurance at the highest risk (15.6%; adjusted RR 7.4, 95%CI 5.3-10.5). Among all women with private insurance, > 12-year education or age >34 years at term reduced the likelihood of late prenatal care entry (adjusted RRs 0.5-0.7). Drugs and alcohol abuse/dependence and residing in a rural county were associated with increased risk of late prenatal care across all subgroups (adjusted RRs 1.3 3.8). Participation in the Women, Infants, and Children's program was associated with decreased risk of late prenatal care for women with public insurance (adjusted RRs 0.6-0.7), but increased risk for women with private insurance (adjusted RRs 1.4-2.1). CONCLUSIONS: The percent of women with late entry into prenatal care was consistently higher among women with public insurance. Younger women, women with <12-year education, those who used drugs or alcohol or resided in rural counties were more likely to enter prenatal care late, with Asian women <18 years at especially high risk. Participation in the Women, Infants, and Children's program and maternal age >34 years at delivery increased the likelihood of late prenatal care for some subgroups of women and decreased the likelihood for others. These findings can inform institutional factors influencing late prenatal care, especially among lower income women, and may assist efforts aimed at encouraging earlier entry into prenatal care. RATIONALE: Optimal prenatal care includes initiation before the 14th week of gestation. Beginning care in the first trimester provides an opportunity for sonographic pregnancy dating or confirmation with best accuracy, which can later prove critical for management of preterm labor, maternal or fetal complications, or prolonged pregnancy. In order to improve maternal and infant health by increasing the number of women seeking prenatal care in the first trimester, it is important to examine the drivers for late entry. Here, we examine factors influencing late (> sixth month of gestation) entry into prenatal care by race/ethnicity and insurance payer. We found the percent of women with late entry into prenatal care was consistently higher among women with public insurance. Younger women, women with <12-year education, those who used drugs or alcohol or resided in rural counties were more likely to enter prenatal care late, with Asian women <18 years at especially high risk. These findings can inform institutional factors influencing late prenatal care, especially among lower income women, and may assist efforts aimed at encouraging earlier entry into prenatal care. PMID- 29631463 TI - Risk of preeclampsia in of women who underwent chorionic villus sampling. AB - OBJECTIVE: To assess the risk of preeclampsia in women who underwent chorionic villus sampling (CVS). STUDY DESIGN: This is a retrospective, single-center, cohort study. All consecutive singleton gestations who underwent chorionic villus sampling from January 2014 to January 2016 were included in the study. The primary outcome was the incidence of preeclampsia. Subgroup analysis in women with beta thalassemic trait was performed. Logistic regression, presented as adjusted odds ratio (aOR) with the 95% of confidence interval (CI), was performed. RESULTS: Five hundred forty-seven women who underwent CVS, and 1532 women who did not were analyzed. Women who underwent CVS had a significantly lower risk of preeclampsia (4.4 versus 8.0%; aOR 0.53, 95%CI 0.34-0.83), and late onset preeclampsia (3.3 versus 6.1%; aOR 0.52, 95%CI 0.31-0.87). No statistically significant differences were found in preeclampsia with severe features, early onset preeclampsia, and preterm birth (PTB). Women who underwent CVS due to thalassemic trait had a lower incidence of preeclampsia compare to those women who did not undergo CVS (3.3 versus 8.0%; aOR 0.39, 95%CI 0.14-0.87), while no differences were found comparing women who underwent CVS due to thalassemic trait with women who underwent CVS due to other reasons. CONCLUSIONS: Women who underwent first trimester CVS had a lower risk of preeclampsia compared to those who did not. PMID- 29631464 TI - Adverse events associated with opioid-containing cough and cold medications in children. AB - BACKGROUND: Until recently most of the scrutiny of opioid-containing cough and cold medications (CCMs) by the US Food and Drug Administration (FDA) was focused on codeine, only recently shifting equal focus to those containing hydrocodone. We characterized adverse events (AEs) in children <12 years old associated with CCMs that include both an opioid and over-the-counter (OTC) ingredient. METHODS: US cases from multiple sources collected as part of a safety surveillance program were included if AEs followed exposure to combination CCMs containing codeine or hydrocodone between January 2008 and December 2015. An expert panel reviewed cases to identify causal relationship between exposure and AEs and identify contributing factors. Each AE term was coded using the Medical Dictionary for Regulatory Activities with preferred terms reported. RESULTS: One hundred and fourteen of the 7035 (2%) cases reviewed involved an opioid-containing product. Ninety-eight cases involved an AE at least potentially related to the opioid ingredient (38 (39%) codeine; 60 (61%) hydrocodone). All three fatality cases involved hydrocodone with an antihistamine. Among non-fatalities, somnolence, lethargy, and/or respiratory depression were more commonly reported among hydrocodone cases than codeine cases (86% vs. 61%; p = .005). DISCUSSION: These safety surveillance data support the FDA's expanded label changes limiting opioid CCMs for children. PMID- 29631465 TI - A model of motivation for physical activity in individuals diagnosed with multiple sclerosis. AB - PURPOSE: Multiple sclerosis (MS) is an incurable chronic degenerative autoimmune disease of the central nervous system that presents with limited physical and/or cognitive functioning. Physical activity has been shown effective to aid in symptom management resulting in increased overall quality of life (QoL), yet this population is highly inactive. Understanding motivation for physical activity in individuals diagnosed with MS is the first step in developing an effective, sustainable, and physical activity intervention for disease management. Therefore, the aim of this study was to model the relationship among motivation for physical activity, physical activity participation, and QoL in individuals diagnosed with MS. METHODS: Using Path analysis, this study explored potential predictors of motivation for physical activity in 215 individuals diagnosed with MS; examining self-determined motivation, in conjunction with self-efficacy, as predictors of physical activity participation, and self-efficacy and physical activity participation as predictors of QoL. RESULTS: In the model, self-efficacy and identified regulation predicted physical activity participation, and physical activity participation predicted QoL, chi2(1) = 0.02, p = 0.867; RMSEA = 0.00; CFI = 1.0; SRMR = 0.002. CONCLUSIONS: The findings and resulting model may be used to develop more effective interventions to promote physical activity participation in individuals diagnosed with MS and consequently enhance long-term QoL. Implications for Rehabilitation Regular physical activity aids in symptom management and disease control in individuals diagnosed with multiple sclerosis, yet this population is consistently highly physically inactive. The complexity of the psychological factors influencing physical activity participation in individuals diagnosed with MS needs to be considered when developing physical activity interventions. Interventions that focus on increasing self-efficacy and identified regulation during physical activity are a means to increase long-term physical activity participation in individuals diagnosed with MS. Long-term increases in physical activity levels may directly contribute to increases in overall quality of life and should, therefore, be a priority for health care professionals when developing overall disease management protocols. PMID- 29631466 TI - Radiofrequency ablation (RFA)-induced systemic tumor growth can be reduced by suppression of resultant heat shock proteins. AB - PURPOSE: To determine the role of hepatic radiofrequency ablation (RFA) heating parameters and their activation of heat shock proteins (HSPs) in modulating distant tumor growth. METHODS AND MATERIALS: First, to study the effects of RFA dose on distant tumor growth, rats with subcutaneous R3230 adenocarcinoma (10 +/- 1 mm) were assigned to 3 different hepatic RF doses (60 degrees C * 10 min, 70 degrees C * 5 min or 90 degrees C * 2 min) that induced identical sized ablation or sham (n = 6/arm). Post-RFA tumor growth rates, cellular proliferation (Ki-67) and microvascular density (MVD) were compared at 7d. Next, the effect of low and high power doses on local HSP70 expression and cellular infiltration (alpha-SMA + myofibroblasts and CD68 + macrophages), cytokine (IL-6) and growth factor (HGF and VEGF) expression was assessed. Finally, 60 degrees C * 10 min and 90 degrees C * 2 min RFA were combined with anti-HSP micellar quercetin (MicQ, 2 mg/ml). A total of 150 animals were used. RESULTS: Lower RF heating (70 degrees C * 5 min and 60 degrees C * 10 min) resulted in larger distant tumors at 7d (19.2 +/- 0.8 mm for both) while higher RF heating (90 degrees C * 2) led to less distant tumor growth (16.7 +/- 1.5 mm, p < .01 for both), though increased over sham (13.5 +/- 0.5 mm, p < .01). Ki-67 and MVD correlated with tumor growth (p < .01 for all). Additionally, lower dose 60 degrees C * 10 min hepatic RFA had more periablational HSP70 compared to 90 degrees C * 2 min (rim: 1.106 +/- 163 um vs. 360 +/- 18 um, p < .001), with similar trends for periablational alpha SMA, CD68 and CDC47 (p < .01 for all). Anti-HSP70 MicQ blocked distant tumor growth for lower dose (60 degrees C * 10: RF/MicQ 14.6 +/- 0.4 mm vs. RF alone: 18.1 +/- 0.4 mm, p < .01) and higher dose RFA (90 degrees C * 2 min: RF/MicQ 14.6 +/- 0.5 mm vs. RF alone: 16.4 +/- 0.7 mm, p < .01). CONCLUSION: Hepatic RF heating parameters alter periablational HSP70, which can influence and stimulate distant tumor growth. Modulation of RF heating parameters alone or in combination with adjuvant HSP inhibition can reduce unwanted, off-target systemic tumorigenic effects. PMID- 29631467 TI - Papulonodules, malar rash, and arthritis in a male. PMID- 29631468 TI - Improving the topical ocular pharmacokinetics of lyophilized cyclosporine A loaded micelles: formulation, in vitro and in vivo studies. AB - Dry eye syndrome (DES) is one of the most common disorders of the eye for which combined treatment includes modification of the ocular environment and pathogenic therapies. Cyclosporine A (CsA), a immunosuppressive agent, has been demonstrated to be effective for the treatment of DES but is limited clinically by its low ocular bioavailability due to poor water solubility. In this paper, methoxy poly (ethylene glycol)-poly (lactide) polymer (mPEG-PLA) micelles were investigated as alternative vehicles for the solubilization and delivery of CsA to the eye. The in vitro stability indicated that CsA-loaded micellar lyophilized powder was stable for at least 3 months and the release profile showed a sustained release manner of CsA from micelles physically. In vivo ocular distribution studies demonstrated that the micellar formulations exhibited a 4.5-fold increase in retention effect at eyes compared with 0.05% CsA emulsion. In addition, the in vivo pharmacokinetics profile showed that the CsA-loaded micelles could enhance the retention time, achieving longer effect toward the DES. These studies proposed an effective micelle formulation as a novel ocular drug delivery system to improve solubility and bioavailability of ophthalmic CsA-controlled delivery. PMID- 29631469 TI - The relationship between fear of movement, pain and fatigue severity, dyspnea level and comorbidities in patients with chronic obstructive pulmonary disease. AB - PURPOSE: Dyspnea, sedentary lifestyle, and comorbid diseases may reduce the desire to engage in physical movement in chronic obstructive pulmonary disease (COPD). The aims of this study were to assess levels of kinesiophobia among stable COPD patients and evaluate the relationship between kinesiophobia and pain and fatigue severity, dyspnea level, and comorbidities in this patient group. MATERIAL AND METHODS: Thirty-one patients with moderate/severe COPD and thirty one age- and sex-matched healthy controls participated in the study. All participants were assessed using Visual Analog Scale for pain severity, Fatigue Severity Scale, modified Medical Research Council Dyspnea Scale, Charlson Comorbidity Index, and Tampa Scale of Kinesiophobia. RESULTS: Ninety-three percent of the patients with COPD had a high degree of kinesiophobia (Tampa Scale of Kinesiophobia score >37). The modified Medical Research Council Dyspnea Scale, Charlson Comorbidity Index, and Tampa Scale of Kinesiophobia scores of patients with COPD was significantly higher than those of healthy subjects (p < 0.001). Tampa Scale of Kinesiophobia score was significantly associated with modified Medical Research Council Dyspnea Scale score (r = 0.676, p < 0.001), Charlson Comorbidity Index score (r = 0.746, p < 0.001) and fatigue severity level (r = 0.524, p = 0.005). CONCLUSION: Most moderate/severe COPD patients express fear of movement. Kinesiophobia is strongly associated with dyspnea perception, fatigue severity, multisystemic comorbidities in COPD. Further studies are needed to determine the effects of kinesiophobia on the success of pulmonary rehabilitation. Implications for rehabilitation Most of moderate-to-severe chronic obstructive pulmonary disease patients have fear of movement. Increase fear of movement in moderate-severe chronic obstructive pulmonary disease is associated with increased dyspnea perception and fatigue severity and multisystemic comorbidities. PMID- 29631471 TI - Effectiveness and safety of late midtrimester cervical cerclage. AB - OBJECTIVES: To evaluate the safety and effectiveness of late cervical cerclage performed beyond 17 weeks of gestation. The outcomes of interest were effectiveness of late cerclage in prolongation of pregnancy and evaluation of pregnancy outcome including maternal and fetal complications. STUDY DESIGN: A total of 30 patients underwent late cervical cerclage during the study period. Of them, two were twin pregnancies. A late cerclage was performed after the diagnosis of cervical shortening or dilatation in 20 patients. We performed a retrospective case series review. One case was lost to follow up (delivery in another medical center). Medical information was retrieved from all cases of patients who underwent a late cervical cerclage between the years 2010 and 2016 at the Soroka University Medical Center, a tertiary medical center. Continuous variables were expressed as mean +/- standard deviation. Categorical variables were expressed as proportions. RESULTS: The average gestational age at birth was 35 +/- 5.1 weeks of gestation. The mean interval between cerclage and delivery in the study population was 17 +/- 5.62 weeks. Nine cases (32.1%) resulted in preterm deliveries, three of them below 34 weeks of gestation (one twin pregnancy and two pregnancies diagnosed with cervical dilation prior to cerclage). Among all the preterm deliveries, there were four cases of preterm prelabor rupture of membranes (13.3%). Of the 28 deliveries, 24 women (85.7%) had a vaginal delivery, while four women (14.3%) underwent a cesarean section. No cases of cervical tear were described. The cerclage was sent to bacteriology after removal, showing positive cultures for Candida species in nine cases (31%). CONCLUSIONS: In our study population, late cervical cerclage was found to be a safe procedure resulting in almost 90% of successful vaginal deliveries without maternal or fetal complications. This procedure might be effective in the prolongation of pregnancy in women with cervical dynamics in the late second trimester. PMID- 29631470 TI - Contribution of APCs to mucosal-associated invariant T cell activation in infectious disease and cancer. AB - APCs such as monocytes and dendritic cells are among the first cells to recognize invading pathogens and initiate an immune response. The innate response can either eliminate the pathogen directly, or through presentation of Ags to T cells, which can help to clear the infection. Mucosal-associated invariant T (MAIT) cells are among the unconventional T cells whose activation does not involve the classical co-stimulation during Ag presentation. MAIT cells can be activated either via presentation of unconventional Ags (such as riboflavin metabolites) through the evolutionarily conserved major histocompatibility class I-like molecule, MR1, or directly by cytokines such as IL-12 and IL-18. Given that APCs produce cytokines and can express MR1, these cells can play an important role in both pathways of MAIT cell activation. In this review, we summarize evidence on the role of APCs in MAIT cell activation in infectious disease and cancer. A better understanding of the interactions between APCs and MAIT cells is important in further elucidating the role of MAIT cells in infectious diseases, which may facilitate the design of novel interventions such as vaccines. PMID- 29631472 TI - Vacuum extraction failure is associated with a large head circumference. AB - OBJECTIVE: To determine whether large head circumference increases the risk of vacuum extraction failure. STUDY DESIGN: This EMR-based study included all attempted vacuum extractions performed in a tertiary center between January 2010 and June 2015. All term singleton live births were eligible. Cases were divided into four groups: head circumference >=90th percentile both with birth weight >=90th percentile and <90th percentile and fetal head circumference <90th percentile with birth weight >=90th and <90th percentile. Risk of failed vacuum extraction was compared among these groups. Other neonatal and maternal parameters were also evaluated as potential risk factors. Multinomial multivariable regression provided adjusted odds ratio for vacuum extraction failure while controlling for potential confounders. RESULTS: During the study period, 48,007 deliveries met inclusion criteria, of which 3835 had an attempt at vacuum extraction. We identified 215 (5.6%) cases of vacuum extraction failure. The adjusted odds ratios (aOR) for vacuum extraction failure in cases of large fetal head circumference was 2.31 (95%CI, 1.7-3.15, p < .001). Primiparity, prolonged second stage and occipito-posterior presentation were also found to be significant risk factors for failed vacuum extraction. COMMENTS: In this study, we found that large head circumference was associated with vacuum extraction failure rather than high birth weight. PMID- 29631473 TI - Identification of a Novel Polymorphism in Bovine lncRNA ADNCR Gene and Its Association with Growth Traits. AB - Adipocyte differentiation-associated long noncoding RNA (ADNCR) is a newly discovered lncRNA. It plays function by targeting miR-204 to significantly regulates the expression of the target SIRT1 gene in preadipocytes both at the level of mRNA and protein, thereby inhibiting adipogenesis. The tetra-primer amplification refractory mutation system PCR (T-ARMS-PCR) strategy is fast and accuracy at a negligible cost for SNP genotyping in large samples. In the study, a novel SNP g.1263T>A in intron 1 of bovine ADNCR gene was found. Herein, the T ARMS-PCR assay was applied to detect the genotypes of the novel SNP of bovine ADNCR gene in 1017 individuals from seven cattle breeds and validated the accuracy by DNA sequencing assay of ninety animals representing three different genotypes. The concordance between two different methods was 100%. The association analysis indicated that this locus was significantly associated with the body weight (P = 0.010), chest girth (P = 0.014) and rump length (P = 0.038) in Jinnan cattle, hucklebone width (P = 0.032) in Qinchuan cattle, the cannon circumference (P = 0.019) in Jinjiang cattle, respectively. These novel findings may be used for marker-assisted selection (MAS) and contribute to the performance of beef cattle in the future. PMID- 29631474 TI - Brazilian Portuguese Version of the Amputee Body Image Scale: Cultural Adaptation and a Psychometric Analysis. AB - Body image adjustments after a limb loss are essential to rehabilitation. This study evaluated the psychometric properties of the Brazilian Portuguese version of the Amputee Body Image Scale (ABIS). We analyzed data from a nonprobability sample of 100 participants (71% men, mean age 48.26 +/- 18.35 years) by using a confirmatory factor analysis with partial least square path modeling. We evaluated the structural model by using Pearson's coefficient of determination, path coefficients, indicator of Stone-Geisser, and Cohen's indicator. We evaluated item factor loadings and average variance extracted for model measurement. We tested the internal consistency with Cronbach's alpha test and composite reliability and evaluated the discriminant validity by adopting Fornell and Larcker (1981) criteria. We tested the original and a new three-factor model and performed correlational and variance analyses as additional tests. The new three-factor theoretical model had stronger structural support and better discriminant and convergent validities than the original three-factor model. The ABIS total score was inversely correlated with body appreciation. There were significant body image score differences between the groups of sedentary and physically active amputees and among those with differences in years since amputation, but there were no differences between those with different causes of amputation nor for those with different amputated limbs. PMID- 29631476 TI - Thyroid Dysfunction and Anemia: A Prospective Cohort Study and a Systematic Review. AB - BACKGROUND: Even though the association between thyroid dysfunction and anemia is commonly described, it is not known whether it is clinically relevant. This study set out to quantify the association of thyroid dysfunction on hemoglobin (Hb) concentration and risk of anemia. A systematic review (MEDLINE and EMBASE, from inception until May 15, 2017) was conducted to interpret the findings in context. METHODS: Participants from the EPIC-Norfolk cohort with available baseline thyrotropin (TSH), free thyroxine (fT4), and Hb were included. Euthyroidism was defined as TSH 0.45-4.49 mIU/L (reference category), hypothyroidism as TSH >=4.50 mIU/L (subclinical [SHypo] with normal fT4 or overt [OHypo] with low fT4), and hyperthyroidism as TSH <=0.44 mIU/L (subclinical [SHyper] with normal fT4 or overt [OHyper] with elevated fT4). Anemia was defined as Hb <12 g/dL in women and Hb <13 g/dL in men. In the cross-sectional analyses, multiple linear regression was used to compare Hb across TSH categories. In the prospective analysis, participants with OHypo/OHyper at baseline were excluded, as it was assumed that they were treated for overt thyroid disease. A covariance model was used to determine change in Hb concentration from baseline to last follow-up, and multivariable Cox regression was used to analyze anemia risk. RESULTS: In the cross-sectional population (n = 12,337), the adjusted Hb was 0.22 g/dL lower [confidence interval (CI) 0.07-0.38] in OHypo compared to euthyroids, and 0.08 g/dL lower [CI -0.23 to 0.38] in OHyper. In the prospective analysis, 460/7031 participants developed anemia over a median follow-up of 4.7 years. The adjusted mean Hb change over time was -0.04 g/dL in SHypo [CI -0.14 to 0.06] and 0.05 g/dL in SHyper [CI -0.10 to 0.20]. The adjusted hazard ratio for anemia was 0.99 [CI 0.67-1.48] in SHypo, and 0.52 [CI 0.23-1.16] in SHyper. The systematic review returned no other prospective studies on this association, but cross-sectional and case-control studies showed comparable results. CONCLUSION: In this first prospective population-based cohort, subclinical thyroid dysfunction was not associated with a change in Hb concentration during follow-up and was not an independent risk factor for developing anemia; variations in Hb concentration in patients with overt thyroid dysfunction were not clinically relevant. PMID- 29631475 TI - Weight Changes After Thyroid Surgery for Patients with Benign Thyroid Nodules and Thyroid Cancer: Population-Based Study and Systematic Review and Meta-Analysis. AB - BACKGROUND: A key concern among patients who undergo thyroid surgery is postoperative weight gain. Yet, the impact of thyroid surgery on weight is unclear. METHODS: The population-based Rochester Epidemiology Project was used to examine weight and body mass index (BMI) changes at one, two, and three years of follow-up in (i) patients with thyroid cancer and benign thyroid nodules after thyroid surgery, and (ii) patients with thyroid nodules who did not have surgery. A comprehensive systematic review of the published literature from inception to February 2016 was also conducted. The results were pooled across studies using a random effects model. RESULTS: A total of 435 patients were identified: 181 patients with thyroid cancer who underwent surgery (group A), 226 patients with benign thyroid nodules without surgery (group B), and 28 patients with benign thyroid nodules undergoing surgery (group C). Small changes in mean weight, BMI, and the number of patients whose weight increased between 5 and 10 kg were similar during each year of follow-up between patients in groups A and B. Furthermore, age >50 years, female sex, baseline BMI >25 kg/m2, and thyrotropin value at one to two years were not predictors of a 5% weight change. In the meta analysis, 11 studies were included. One to two years after surgery for thyroid cancer or thyroid nodules, patients gained on average 0.94 kg [confidence interval (CI) 0.58-1.33] and 1.07 kg [CI 0.26-1.87], respectively. Patients with benign thyroid nodules who did not have surgery gained 1.50 kg [CI 0.60-2.4] at the longest follow-up. CONCLUSIONS: On average, patients receiving care for thyroid nodules or cancer gain weight, but existing evidence suggests that surgery for these conditions does not contribute significantly to further weight gain. Clinicians and patients can use this information to discuss what to expect after thyroid surgery. PMID- 29631477 TI - Reprogramming p53-Deficient Germline Stem Cells Into Pluripotent State by Nanog. AB - Cultured mouse spermatogonial stem cells (SSCs), also known as germline stem cells (GSCs), revert back to pluripotent state either spontaneously or upon being modified genetically. However, the reprogramming efficiencies are low, and the underlying mechanism remains poorly understood. In the present study, we conducted transcriptomic analysis and found that many transcription factors and epigenetic modifiers were differentially expressed between GSCs and embryonic stem cells. We failed in reprogramming GSCs to pluripotent state using the Yamanaka 4 Factors, but succeeded when Nanog and Tet1 were included. More importantly, reprogramming was also achieved with Nanog alone in a p53-deficient GSC line with an efficiency of 0.020/00. These GSC-derived-induced pluripotent stem cells possessed in vitro and in vivo differentiation abilities despite the low rate of chimera formation, which might be caused by abnormal methylation in certain paternally imprinted genes. Together, these results show that GSCs can be reprogrammed to pluripotent state via multiple avenues and contribute to our understanding of the mechanisms of GSC reprogramming. PMID- 29631478 TI - Reducing the Time from Surgery to Adjuvant Radiation Therapy: An Institutional Quality Improvement Project. AB - Objective The National Comprehensive Cancer Network guidelines recommend an interval between surgery and adjuvant radiation therapy of less than 6 weeks, but only 44% of patients meet this metric nationally. We sought to identify key components of an improvement process focused on starting adjuvant radiation therapy within 6 weeks of surgery. Methods This project used an A3 model to improve a defined process measure. We studied a consecutive sample of 56 patients with oral cavity carcinoma who were treated at our institution with upfront surgical resection followed by adjuvant radiation therapy. Twelve proposed interventions tested during the study period focused on 3 key drivers of delays: delayed dental evaluation and teeth extraction, delayed radiation oncology consults, and inadequate patient engagement. The primary outcome measure was the number of days from surgery to the start of radiation therapy. Results Prior to the intervention, 62% of patients received adjuvant radiation within 6 weeks of surgery. Following the intervention, 73% of patients achieved this metric. The percentage of patients with avoidable delays decreased from 24% to 9%. The percentage of patients with unavoidable delays was relatively constant before and after the intervention (15% and 18%, respectively). Discussion Defining disease specific metrics is critical to improving care in our head and neck cancer patient population. We demonstrate several key components to develop and improve self-defined metrics. Implications for Practice As we transition to a system of value-based care, structured quality improvement projects can have a measurable impact on cancer patient process measures. PMID- 29631479 TI - alpha-Lipoic Acid Vaginal Administration Contrasts Inflammation and Preterm Delivery in Rats. AB - alpha-Lipoic acid (ALA) is a safe natural molecule involved in the immunomodulation of many physiological processes. Orally administered ALA has been reported to treat several inflammatory pathologies and support pregnancy. Our study aimed at testing ALA vaginal administration in female Wistar rats evaluating its tissue distribution (experiment I), impact on implantation process (experiment II), and effectiveness in contrasting induced preterm birth (experiment III). In experiment I, rats were intravaginally treated with 50 mg/kg or 500 mg/kg ALA, or with a physiologic solution, for 4 days. alpha-Lipoic acid distribution in uterus and cervical tissues was evaluated by immunohistochemical analyses. In experiment II, rats received intravaginally the above treatments for 5 days, then they were mated and, if pregnant, included in the experiment to evaluate both implantation rate and the content of implantation mediators in uterus tissues. In experiment III, pregnant rats were pretreated with placebo or with vaginal ALA for 4 days and then induced to delivery with mifepristone plus PGE2 on the 19th day of pregnancy. The delivery time was recorded, and the messenger RNA (mRNA) levels of pro-inflammatory cytokines were detected in the uterine tissues by real-time polymerase chain reaction. Immunohistochemistry was also performed. Results showed that vaginal ALA was well absorbed and distributed. The treatment did not affect the implantation process and was able to significantly revert mifepristone plus prostaglandin E2 effects, delaying the timing of delivery and significantly decreasing mRNA synthesis and release of pro inflammatory cytokines. We provide for the first time new information on vaginal ALA use, even during pregnancy, opening a perspective for further studies. PMID- 29631481 TI - The Woman in Red: Examining the Effect of Ovulatory Cycle on Women's Perceptions of and Behaviors Toward Other Women. AB - Previous research has shown that during her monthly peak fertile window, a woman competes with other women for a suitable mate. Drawing upon research on ovulation and socially constructed meanings of the color red, we examine how a woman's fertility status and red clothing worn by a target woman change perceptions of the target, as well as behaviors toward the target. Following previous research on the ovulatory status and color red effects, we rely on both hormonal and self reported fertility data. Across six studies, our research fails to provide support for the prediction that an ovulating woman is less likely to trust another woman wearing red compared with a nonovulating woman. PMID- 29631482 TI - In Vitro Survival of Human Mesenchymal Stem Cells is Enhanced in Artificial Endolymph with Moderately High Concentrations of Potassium. AB - While mesenchymal stem cells (MSCs) are promising candidates for inner ear hair cell regeneration, to date, there have been no convincing reports indicating whether MSCs can survive in the cochlea for more than a few weeks, as the high levels of potassium (K+) in the endolymph (EL) are thought to be toxic to transplanted stem cells. For conditioning the EL for MSC transplantation, we conducted this in vitro study to examine the effects of artificial EL with altered K+ concentration levels, in the range of 5-153.8 mM, on proliferation, apoptosis, and morphological changes in MSCs derived from various human tissues. Our findings demonstrate that altering the K+ concentration in artificial EL could significantly influence the survival of MSCs in vitro. We discovered that K+ concentrations of 55-130 mM in artificial EL could enhance the survival of MSCs in vitro. However, MSCs exhibited reduced proliferation regardless of K+ concentration. PMID- 29631483 TI - Isolating Pediatric Mesenchymal Stem Cells with Enhanced Expansion and Differentiation Capabilities. AB - Mesenchymal stem cells/marrow stromal cells (MSCs) are attractive for applications ranging from research and development to use in clinical therapeutics. However, the most commonly studied MSCs, adult bone marrow MSCs (A MSCs), are limited by significant donor variation resulting in inconsistent expansion rates and multilineage differentiation capabilities. We have recently obtained permission to isolate pediatric MSCs (P-MSCs) from surplus iliac crest bone chips. Here, we developed a simple and easily replicable isolation protocol yielding P-MSCs, which adhere to MSC defining guidelines. After confirming immunophenotypic marker expression, we compared expansion rates, senescence, morphology, and trilineage differentiation of P-MSCs to A-MSCs for multiple donors. We found P-MSCs have faster in vitro replication, consistently show significantly lower senescence, and are capable of more reproducible multilineage differentiation than A-MSCs. We, therefore, believe P-MSCs are a promising candidate for use in research applications and potentially as part of an allogeneic therapeutic treatment. PMID- 29631485 TI - Sarcopenia Measured Using Masseter Area Predicts Early Mortality following Severe Traumatic Brain Injury. AB - Sarcopenia is strongly associated with poor outcomes and mortality following injury among the geriatric population. Diagnosis using psoas area is most common but may be unavailable given limited radiographic evaluation following low-impact injuries. Masseter area has recently been identified as an available alternative and associated with 2-year mortality following injury. We sought to validate this measure and its association with early mortality following severe traumatic brain injury (sTBI) using a retrospective analysis of all geriatric trauma patients with sTBI admitted from 2011-2016 to our trauma center. Admission Glasgow Coma Scale (GCS) score <=8 was used to identify sTBI. Bilateral masseter area was measured 2 cm below the zygomatic arch and the mean used for analysis. Sarcopenia was defined as mean masseter area one standard deviation or less from the sex based mean. Multivariate models with logistic regression and Cox proportional hazards test followed univariate analysis. Kaplan-Meier survival curves were generated and evaluated by log rank. The primary outcome of interest was 30-day mortality. A total of 108 patients were identified for inclusion. Twenty-five patients, 16 male and nine female, had sarcopenia with mean masseter areas of 2.81 +/- 0.45 cm2 and 2.24 +/- 0.42 cm2, respectively. Patients with sarcopenia had significantly increased rates of 30-day mortality (80.0% vs. 50.6%; p = 0.01). Sarcopenia (odds ratio [OR], 2.95; 95% confidence interval [CI] 1.03-8.49) and decreasing masseter area were significantly associated with 30-day mortality (OR, 0.66; 95% CI 0.46-0.95) in multivariate modeling. Masseter area is a readily available and objective measure to determine sarcopenia, which is significantly associated with in-creased 30-day mortality following sTBI. PMID- 29631484 TI - Quantitative Proteomic Profiling of the Human Ovary from Early to Mid-Gestation Reveals Protein Expression Dynamics of Oogenesis and Folliculogenesis. AB - The in vivo gene networks involved in coordinating human fetal ovarian development remain obscure. In this study, quantitative mass spectrometry was conducted on ovarian tissue collected at key stages during the first two trimesters of human gestational development, confirming the expression profiling data using immunofluorescence, as well as in vitro modeling with human oogonial stem cells (OSCs) and human embryonic stem cells (ESCs). A total of 3,837 proteins were identified in samples spanning developmental days 47-137. Bioinformatics clustering and Ingenuity Pathway Analysis identified DNA mismatch repair and base excision repair as major pathways upregulated during this time. In addition, MAEL and TEX11, two key meiosis-related proteins, were identified as highly expressed during the developmental window associated with fetal oogenesis. These findings were confirmed and extended using in vitro differentiation of OSCs into in vitro derived oocytes and of ESCs into primordial germ cell-like cells and oocyte-like cells, as models. In conclusion, the global protein expression profiling data generated by this study have provided novel insights into human fetal ovarian development in vivo and will serve as a valuable new resource for future studies of the signaling pathways used to orchestrate human oogenesis and folliculogenesis. PMID- 29631486 TI - South African Research Ethics Committee Review of Standards of Prevention in HIV Vaccine Trial Protocols. AB - HIV prevention trials provide a prevention package to participants to help prevent HIV acquisition. As new prevention methods are proven effective, this raises ethical and scientific design complexities regarding the prevention package or standard of prevention. Given its high HIV incidence and prevalence, South Africa has become a hub for HIV prevention research. For this reason, it is critical to study the implementation of relevant ethical-legal frameworks for such research in South Africa. This qualitative study used in-depth interviews to explore the practices and perspectives of eight members of South African research ethics committees (RECs) who have reviewed protocols for HIV vaccine trials. Their practices and perspectives are compared with ethics guideline requirements for standards of prevention. PMID- 29631487 TI - Development and Preliminary Testing of the Perceived Benefit and Burden Scales for Cancer Clinical Trial Participation. AB - We developed measures of benefits and burdens of research participation in cancer clinical trials using a sequential mixed methods design with a qualitative ( n = 32) and quantitative sample ( n = 110) of cancer clinical trial participants. Benefit-burden items (22 for benefits, 23 for burdens) were subsequently developed and assessed through cognitive interviewing for content, clarity, and meaning. Preliminary psychometric analyses support the internal consistency reliability and construct validity of Benefit (alpha = .90) and Burden (alpha = .87) research participation scales. Item response theory models supported the discrimination ability of the items on the scales. Participants who had thoughts of dropping out had lower Benefit scale scores ( p < .001) and higher Burden scores ( p < .001) than those who had no thoughts of dropping out, supporting construct validity. With further psychometric testing, the scale can be used to develop appropriate interventions to address recruitment and retention of human participants in clinical research. PMID- 29631488 TI - Understanding of International Committee of Medical Journal Editors Authorship Criteria Among Faculty Members of Pharmacy and Other Health Sciences in Jordan. AB - Authorship represents a critical element of scientific research. This study evaluated the perceptions, attitudes, and practices of Jordanian researchers toward the International Committee of Medical Journal Editors (ICMJE) authorship criteria. An anonymous questionnaire was distributed to health sciences faculty ( n = 986), with 272 participants completing the questionnaire. Only 27.2% reported awareness of ICMJE guidelines, yet, 76.8% agreed that all ICMJE criteria must be met for authorship, and 55.9% believed that it is easy to apply the guidelines. Unethical authorship practices were reported by 16.5% to 31.3% of participants. A majority (73%) agreed that violation of authorship criteria is scientific misconduct. Well-defined criteria for authorship need to be disseminated and emphasized in less developed countries through training to avoid authorship disputes and unethical conduct. PMID- 29631489 TI - Intraoperative Construct Preparation: A Practical Route for Cell-Based Bone Regeneration. AB - Stem cell-based bone tissue engineering based on the combination of a scaffold and expanded autologous mesenchymal stem cells (MSCs) represents the current state-of-the-art treatment for bone defects and fractures. However, the procedure of such construct preparation requires extensive ex vivo manipulation of patient's cells to achieve enough stem cells. Therefore, it is impractical and not cost-effective compared to other therapeutic interventions. For these reasons, a more practical strategy circumventing any ex vivo manipulation and an additional surgery for the patient would be advantageous. Intraoperative concept based bone tissue engineering, where constructs are prepared with easily accessible autologous cells within the same surgical procedure, allows for such a simplification. In this study, we discuss the concept of intraoperative construct preparation for bone tissue engineering and summarize the available cellular options for intraoperative preparation. Furthermore, we propose methods to prepare intraoperative constructs, and review data of currently available preclinical and clinical studies using intraoperatively prepared constructs for bone regenerative applications. We identify several obstacles hampering the application of this emerging approach and highlight perspectives of technological innovations to advance the future developments of intraoperative construct preparation. PMID- 29631490 TI - Diagnostic Value of Gains and Corrective Saccades in Video Head Impulse Test in Vestibular Neuritis. AB - Objectives We investigated changes in video head impulse test (vHIT) gains and corrective saccades (CSs) at the acute and follow-up stages of vestibular neuritis to assess the diagnostic value of vHIT. Study Design Case series with chart review. Setting Tertiary medical center. Subjects and Methods Sixty-three patients with vestibular neuritis who underwent vHIT at an initial presentation and an approximately 1-month follow-up were included. vHIT gains, gain asymmetry (GA), peak velocities of CS, and interaural difference of CS (CSD) were analyzed. Results Mean vHIT gains increased significantly from the acute stage to the follow-up exam. The mean GA, peak velocities of CS, and CSD had decreased significantly at the follow-up. The incidence of CSs was also significantly decreased at the follow-up. The abnormal rate (87%) considering both gain and CS value was significantly higher than that (62%) considering vHIT gain only at the follow-up, although the abnormal rates did not differ at the acute stage (97% vs 87%). Conclusion The abnormal rates based on both vHIT gains and CS measurements are similar at the acute stage of VN but are considerably higher at the follow-up stage compared with the abnormal rates based on vHIT gains alone. It is thus advisable to check both CS and vHIT gain while performing vHIT to detect vestibular hypofunction. PMID- 29631492 TI - mHealth applications as an educational and supportive resource for family carers of people with dementia: An integrative review. AB - Family carers encounter several challenges related to caring for people with dementia, and they need support in managing care recipients' health needs. This study aims to identify, appraise and synthesise the existing evidence on the use of mHealth/smartphone applications as an educational and supportive resource for family carers of people with dementia. An integrative literature review approach was used. Seven databases were searched. The search generated 117 articles, with seven meeting the inclusion criteria. Three categories and their attendant sub categories emerged from the literature. The categories are 'carer support', 'evaluation strategies' and 'barriers and challenges'. mHealth applications appear to be a feasible intervention for family carers of people with dementia despite the limited available research and barriers for their development and implementation. Further research on mHealth applications with strong methodological rigour and more research on mHealth applications as an educational and supportive resource for carers of people with dementia are needed. PMID- 29631491 TI - The Evolution of Polystyrene as a Cell Culture Material. AB - Polystyrene (PS) has brought in vitro cell culture from its humble beginnings to the modern era, propelling dozens of research fields along the way. This review discusses the development of the material, fabrication, and treatment approaches to create the culture material. However, native PS surfaces poorly facilitate cell adhesion and growth in vitro. To overcome this, liquid surface deposition, energetic plasma activation, and emerging functionalization methods transform the surface chemistry. This review seeks to highlight the many potential applications of the first widely accepted polymer growth surface. Although the majority of in vitro research occurs on two-dimensional surfaces, the importance of three dimensional (3D) culture models cannot be overlooked. The methods to transition PS to specialized 3D culture surfaces are also reviewed. Specifically, casting, electrospinning, 3D printing, and microcarrier approaches to shift PS to a 3D culture surface are highlighted. The breadth of applications of the material makes it impossible to highlight every use, but the aim remains to demonstrate the versatility and potential as both a general and custom cell culture surface. The review concludes with emerging scaffolding approaches and, based on the findings, presents our insights on the future steps for PS as a tissue culture platform. PMID- 29631493 TI - The development and use of the assessment of dementia awareness and person centred care training tool in long-term care. AB - Policy and practice guidelines recommend person-centred care to support people to live well with dementia in long-term care. Therefore, staff working in long-term care settings need to be trained in dementia awareness and person-centred care. However, the access to, content of and reach of training across long-term care settings can be varied. Data on current and ongoing access to person-centred care training can form an important component of data gathered on usual care in research studies, in particular clinical trials within long-term care. However, no suitable assessment tools are available to measure dementia awareness and person-centred care training availability, content and reach. This paper describes the development of a training audit tool to meet this need for a usual care measure of dementia awareness and person-centred care training. The 'Assessment of Dementia Awareness and Person-centred care Training' tool was based on a review of published person-centred care literature and consultation with dementia and aged care experts. The Assessment of Dementia Awareness and Person-centred care Training tool was piloted in 13 long-term care facilities the UK and Australia, before being used to assess the content of dementia and person centred care awareness training in 50 UK settings in a randomized controlled trial as part of usual care recording. Following pilot testing, modifications to the Assessment of Dementia Awareness and Person-centred care Training tool's wording were made to enhance item clarity. When implemented in the randomized controlled trial, pre-baseline training assessment data showed that the Assessment of Dementia Awareness and Person-centred care Training tool was able to differentiate between the training in different long-term care settings and identify settings where further dementia awareness training was required. The Assessment of Dementia Awareness and Person-centred care Training tool was then used as a method of recording data on dementia awareness and person-centred care training as part of ongoing usual care data collection. The Assessment of Dementia Awareness and Person-centred care Training tool is suitable for use by researchers to establish the availability, content and reach of dementia and person-centred care awareness training to staff within research studies. PMID- 29631495 TI - Broadening the debate on creativity and dementia: A critical approach. AB - In recent years there has been a growing interest in person-centred, 'living well' approaches to dementia, often taking the form of important efforts to engage people with dementia in a range of creative, arts-based interventions such as dance, drama, music, art and poetry. Such practices have been advanced as socially inclusive activities that help to affirm personhood and redress the biomedical focus on loss and deficit. However, in emphasizing more traditional forms of creativity associated with the arts, more mundane forms of creativity that emerge in everyday life have been overlooked, specifically with regard to how such creativity is used by people living with dementia and by their carers and family members as a way of negotiating changes in their everyday lives. In this paper, we propose a critical approach to understanding such forms of creativity in this context, comprised of six dimensions: everyday creativity; power relations; ways to operationalise creativity; sensory and affective experience; difference; and reciprocity. We point towards the potential of these dimensions to contribute to a reframing of debates around creativity and dementia. PMID- 29631497 TI - Assessing rugby place kick performance from initial ball flight kinematics: development, validation and application of a new measure. AB - The appropriate determination of performance outcome is critical when appraising a performer's technique. Previous studies of rugby place kicking technique have typically assessed performance based on ball velocity, but this is not the sole requirement. Therefore, a mathematical model of rugby place kick ball flight was developed to yield a single measure more representative of true performance. The model, which requires only initial ball flight kinematics, was calibrated and validated using empirical place kick data, and found to predict ball position with a mean error of 4.0% after 22 m of ball flight. The model was then applied to the performances of 33 place kickers. The predicted maximum distance, a single performance measure which accounted for initial ball velocity magnitude and direction, and spin, was determined using the model and was compared against ball velocity magnitude. A moderate association in the rank-order of the kicks between these two measures (rho = 0.52) revealed that the relative success of the kicks would be assessed differently with each measure. The developed model provides a representative measure of place kick performance that is understandable for coaches, and can be used to predict changes in performance outcome under different ball launch or environmental conditions. PMID- 29631496 TI - Megakaryocyte and Osteoblast Interactions Modulate Bone Mass and Hematopoiesis. AB - Emerging evidence demonstrates that megakaryocytes (MK) play key roles in regulating skeletal homeostasis and hematopoiesis. To test if the loss of MK negatively impacts osteoblastogenesis and hematopoiesis, we generated conditional knockout mice where Mpl, the receptor for the main MK growth factor, thrombopoietin, was deleted specifically in MK (Mplf/f;PF4cre). Unexpectedly, at 12 weeks of age, these mice exhibited a 10-fold increase in platelets, a significant expansion of hematopoietic/mesenchymal precursors, and a remarkable 20-fold increase in femoral midshaft bone volume. We then investigated whether MK support hematopoietic stem cell (HSC) function through the interaction of MK with osteoblasts (OB). LSK cells (Lin-Sca1+CD117+, enriched HSC population) were co cultured with OB+MK for 1 week (1wk OB+MK+LSK) or OB alone (1wk OB+LSK). A significant increase in colony-forming units was observed with cells from 1wk OB+MK cultures. Competitive repopulation studies demonstrated significantly higher engraftment in mice transplanted with cells from 1wk OB+MK+LSK cultures compared to 1wk OB+LSK or LSK cultured alone for 1 week. Furthermore, single-cell expression analysis of OB cultured+/-MK revealed adiponectin as the most significantly upregulated MK-induced gene, which is required for optimal long term hematopoietic reconstitution. Understanding the interactions between MK, OB, and HSC can inform the development of novel treatments to enhance both HSC recovery following myelosuppressive injuries, as well as bone loss diseases, such as osteoporosis. PMID- 29631498 TI - "White Thyroid" on Unenhanced Computed Tomography in Amiodarone-Induced Thyrotoxicosis Type 2. AB - Amiodarone-induced thyrotoxicosis is a common complication of long-term amiodarone treatment. In a patient with amiodarone-induced lung toxicity and amiodarone-induced thyrotoxicosis type 2 (AIT2), a "white thyroid" was incidentally observed on an unenhanced chest computed tomography (CT) scan. This "white thyroid" resembled a thyroid image on a contrast-enhanced CT scan. Therefore, the thyroid density was prospectively evaluated on unenhanced CT scans in cases of AIT2, in euthyroid patients on amiodarone (AEuth), and in unexposed controls. The aim was to test the hypothesis of a higher thyroid density in AIT2 compared to AEuth. The thyroid density, as measured in Hounsfield Units on unenhanced CT scans, is higher in AIT2 compared to AEuth and much higher than in controls. The causality of this association and its potential diagnostic use require further study. PMID- 29631499 TI - Cochlear helix and duct length identification - Evaluation of different curve fitting techniques. AB - OBJECTIVE: Within the field of cochlear implantation (CIs), the role of utilizing patient-specific cochlear anatomy for choosing the optimal implant electrode is becoming increasingly important. Unfortunately, performing detailed anatomical measurements of a cochlea using clinical imaging data is rather time consuming and hence difficult to implement into the clinical routine. In order to accelerate clinical cochlear anatomy evaluations, previously developed mathematical models can be adjusted to the patient-specific anatomy by measuring just a few overall cochlear dimensions. However, the accuracy of model-based cochlear anatomy estimations is unclear, and incorrect evaluations may lead to false conclusions regarding the suitability of specific implant electrodes. METHODS: Based on 10 cochleae, an error evaluation of various commonly used curve fitting approaches for cochlear shape and duct length approximation was conducted. Spline tracings of the cochlear contours were used as reference values for the various approximations. RESULTS: Parameterized average cochlear helix models and two of five analytical approaches were found to be suitable for reconstructing the cochlear helical shape and estimating its length. DISCUSSION: Spline curve reconstructions are the most accurate and reliable method for assessing patient-specific cochlear geometry, especially in the case of anatomical irregularities. The most accurate results within the group of model based evaluations still resulted in mean overall cochlear length deviations of approximately 5%. CONCLUSION: Spline curve reconstructions appear to be the best option for anatomical diagnostics in clinical practice. Retrospective studies can be performed to further evaluate model-based evaluations. PMID- 29631500 TI - Not the Sum of Its Parts: A Critical Review of the MacDonald Triad. AB - The MacDonald triad posits that animal cruelty, fire setting, and bed wetting in childhood is indicative of later aggressive and violent behavior in adults. Researchers refer to this phenomenon as a precursor to later antisocial behaviors including serial and sexual murder; while practitioners cite the triad in clinical formulations and risk assessments. However, there is yet to be a critical review and consolidation of the literature that establishes whether there is empirical support. This article explores the validity of the triad. We conducted a narrative review of the relevant studies examining the MacDonald triad and its individual constituents. There is evidence that any one of the triad behaviors could predict future violent offending, but it is very rare to find all three behaviors together as predictors. Thus, the empirical research on the MacDonald triad does not fully substantiate its premise. Rather, it would appear that the triad, or its individual constituents, is better used as an indicator of dysfunctional home environments, or poor coping skills in children. Future research is needed with robust and rigorous methodologies (e.g., adequate control groups, longitudinal designs) to fully establish the MacDonald triad's validity. Finally, further consideration is needed as to whether the triad behaviors are more indicative of other problematic outcomes (e.g., maladaptive coping to life stressors). PMID- 29631501 TI - Efficient Embedded Decoding of Neural Network Language Models in a Machine Translation System. AB - Neural Network Language Models (NNLMs) are a successful approach to Natural Language Processing tasks, such as Machine Translation. We introduce in this work a Statistical Machine Translation (SMT) system which fully integrates NNLMs in the decoding stage, breaking the traditional approach based on [Formula: see text]-best list rescoring. The neural net models (both language models (LMs) and translation models) are fully coupled in the decoding stage, allowing to more strongly influence the translation quality. Computational issues were solved by using a novel idea based on memorization and smoothing of the softmax constants to avoid their computation, which introduces a trade-off between LM quality and computational cost. These ideas were studied in a machine translation task with different combinations of neural networks used both as translation models and as target LMs, comparing phrase-based and [Formula: see text]-gram-based systems, showing that the integrated approach seems more promising for [Formula: see text] gram-based systems, even with nonfull-quality NNLMs. PMID- 29631503 TI - Deep Neural Architectures for Mapping Scalp to Intracranial EEG. AB - Data is often plagued by noise which encumbers machine learning of clinically useful biomarkers and electroencephalogram (EEG) data is no exemption. Intracranial EEG (iEEG) data enhances the training of deep learning models of the human brain, yet is often prohibitive due to the invasive recording process. A more convenient alternative is to record brain activity using scalp electrodes. However, the inherent noise associated with scalp EEG data often impedes the learning process of neural models, achieving substandard performance. Here, an ensemble deep learning architecture for nonlinearly mapping scalp to iEEG data is proposed. The proposed architecture exploits the information from a limited number of joint scalp-intracranial recording to establish a novel methodology for detecting the epileptic discharges from the sEEG of a general population of subjects. Statistical tests and qualitative analysis have revealed that the generated pseudo-intracranial data are highly correlated with the true intracranial data. This facilitated the detection of IEDs from the scalp recordings where such waveforms are not often visible. As a real-world clinical application, these pseudo-iEEGs are then used by a convolutional neural network for the automated classification of intracranial epileptic discharges (IEDs) and non-IED of trials in the context of epilepsy analysis. Although the aim of this work was to circumvent the unavailability of iEEG and the limitations of sEEG, we have achieved a classification accuracy of 68% an increase of 6% over the previously proposed linear regression mapping. PMID- 29631504 TI - Influence of Cholecystokinin-8 on Compound Nerve Action Potentials from Ventral Gastric Vagus in Rats. AB - OBJECTIVE: Vagus Nerve Stimulation (VNS) has shown great promise as a potential therapy for a number of conditions, such as epilepsy, depression and for Neurometabolic Therapies, especially for treating obesity. The objective of this study was to characterize the left ventral subdiaphragmatic gastric trunk of vagus nerve (SubDiaGVN) and to analyze the influence of intravenous injection of gut hormone cholecystokinin octapeptide (CCK-8) on compound nerve action potential (CNAP) observed on the same branch, with the aim of understanding the impact of hormones on VNS and incorporating the methods and results into closed loop implant design. METHODS: The cervical region of the left vagus nerve (CerVN) of male Wistar rats was stimulated with electric current and the elicited CNAPs were recorded on the SubDiaGVN under four different conditions: Control (no injection), Saline, CCK1 (100[Formula: see text]pmol/kg) and CCK2 (1000[Formula: see text]pmol/kg) injections. RESULTS: We identified the presence of A[Formula: see text], B, C1, C2, C3 and C4 fibers with their respective velocity ranges. Intravenous administration of CCK in vivo results in selective, statistically significant reduction of CNAP components originating from A and B fibers, but with no discernible effect on the C fibers in [Formula: see text] animals. The affected CNAP components exhibit statistically significant ([Formula: see text] and [Formula: see text]) higher normalized stimulation thresholds. CONCLUSION: This approach of characterizing the vagus nerve can be used in closed loop systems to determine when to initiate VNS and also to tune the stimulation dose, which is patient-specific and changes over time. PMID- 29631505 TI - Using Dictionary Pair Learning for Seizure Detection. AB - Automatic seizure detection is extremely important in the monitoring and diagnosis of epilepsy. The paper presents a novel method based on dictionary pair learning (DPL) for seizure detection in the long-term intracranial electroencephalogram (EEG) recordings. First, for the EEG data, wavelet filtering and differential filtering are applied, and the kernel function is performed to make the signal linearly separable. In DPL, the synthesis dictionary and analysis dictionary are learned jointly from original training samples with alternating minimization method, and sparse coefficients are obtained by using of linear projection instead of costly [Formula: see text]-norm or [Formula: see text]-norm optimization. At last, the reconstructed residuals associated with seizure and nonseizure sub-dictionary pairs are calculated as the decision values, and the postprocessing is performed for improving the recognition rate and reducing the false detection rate of the system. A total of 530[Formula: see text]h from 20 patients with 81 seizures were used to evaluate the system. Our proposed method has achieved an average segment-based sensitivity of 93.39%, specificity of 98.51%, and event-based sensitivity of 96.36% with false detection rate of 0.236/h. PMID- 29631502 TI - Identification of Retinal Ganglion Cell Firing Patterns Using Clustering Analysis Supplied with Failure Diagnosis. AB - An important goal in visual neuroscience is to understand how neuronal population coding in vertebrate retina mediates the broad range of visual functions. Microelectrode arrays interface on isolated retina registers a collective measure of the spiking dynamics of retinal ganglion cells (RGCs) by probing them simultaneously and in large numbers. The recorded data stream is then processed to identify spike trains of individual RGCs by efficient and scalable spike detection and sorting routines. Most spike sorting software packages, available either commercially or as freeware, combine automated steps with judgment calls by the investigator to verify the quality of sorted spikes. This work focused on sorting spikes of RGCs into clusters using an integrated analytical platform for the data recorded during visual stimulation of wild-type mice retinas with whole field stimuli. After spike train detection, we projected each spike onto two feature spaces: a parametric space and a principal components space. We then applied clustering algorithms to sort spikes into separate clusters. To eliminate the need for human intervention, the initial clustering results were submitted to diagnostic tests that evaluated the results to detect the sources of failure in cluster assignment. This failure diagnosis formed a decision logic for diagnosable electrodes to enhance the clustering quality iteratively through rerunning the clustering algorithms. The new clustering results showed that the spike sorting accuracy was improved. Subsequently, the number of active RGCs during each whole field stimulation was found, and the light responsiveness of each RGC was identified. Our approach led to error-resilient spike sorting in both feature extraction methods; however, using parametric features led to less erroneous spike sorting compared to principal components, particularly for low signal-to-noise ratios. As our approach is reliable for retinal signal processing in response to simple visual stimuli, it could be applied to the evaluation of disrupted physiological signaling in retinal neurodegenerative diseases. PMID- 29631506 TI - Formulation and Implementation of Nonlinear Integral Equations to Model Neural Dynamics Within the Vertebrate Retina. AB - Existing computational models of the retina often compromise between the biophysical accuracy and a hardware-adaptable methodology of implementation. When compared to the current modes of vision restoration, algorithmic models often contain a greater correlation between stimuli and the affected neural network, but lack physical hardware practicality. Thus, if the present processing methods are adapted to complement very-large-scale circuit design techniques, it is anticipated that it will engender a more feasible approach to the physical construction of the artificial retina. The computational model presented in this research serves to provide a fast and accurate predictive model of the retina, a deeper understanding of neural responses to visual stimulation, and an architecture that can realistically be transformed into a hardware device. Traditionally, implicit (or semi-implicit) ordinary differential equations (OES) have been used for optimal speed and accuracy. We present a novel approach that requires the effective integration of different dynamical time scales within a unified framework of neural responses, where the rod, cone, amacrine, bipolar, and ganglion cells correspond to the implemented pathways. Furthermore, we show that adopting numerical integration can both accelerate retinal pathway simulations by more than 50% when compared with traditional ODE solvers in some cases, and prove to be a more realizable solution for the hardware implementation of predictive retinal models. PMID- 29631507 TI - Sudden Sensorineural Hearing Loss in the Department of Defense. AB - Objective The American Academy of Otolaryngology-Head and Neck Surgery Foundation clinical practice guideline (CPG) proposes recommendations regarding sudden sensorineural hearing loss (SSNHL). SSNHL is managed by primary care, emergency medicine, and otolaryngology providers in the Department of Defense (DoD). However, their adherence to this CPG is unknown. We sought to determine provider compliance and identify areas for improvement. Study Design Case series with chart review. Setting DoD's electronic medical record. Subjects and Methods Patients with SSNHL (N = 204) were treated between March 1, 2012, and September 30, 2015. Time from onset of symptoms to evaluation by primary care, emergency department, audiology, and otolaryngology providers and treatments were analyzed. Results The average interval from onset of symptoms to evaluation by a primary care or emergency department provider was 4.86 days (95% CI, 3.46-6.26). Time from presentation to ear, nose, and throat and audiologic evaluation was 15.26 days (95% CI, 12.34-18.20) and 14.16 days (95% CI, 11.31-17.01), respectively. Diagnostic workup included magnetic resonance imaging (n = 150, 73.5%), computed tomography (n = 28, 13.7%), and laboratory testing (n = 50, 24.5%). Oral steroids were used in 137 (67.2%) patients, with 78.8% treated with the recommended dose. Intratympanic steroids were utilized in 65 (31.9%) patients, with variable dosing. Conclusion The DoD is uniquely positioned to evaluate adherence to CPGs on national and international levels given the robust and standardized electronic medical record. Areas of improvement include timely identification of SSNHL with rapid referral to ear, nose, and throat and audiology providers; minimizing unnecessary imaging, laboratory testing, and medications; and correct dosing of oral and intratympanic steroids. PMID- 29631508 TI - Different laparoscopic treatment modalities for splenic artery aneurysms: about 3 cases with review of the literature. AB - INTRODUCTION: The first laparoscopic treatment of splenic artery aneurysm (SAA) was performed in 1993. Since then, many papers have been published mentioning different laparoscopic treatment modalities, including splenectomy, aneurysmectomy, ligation or even occlusion. PATIENTS AND METHODS: An updated literature review of the English medical literature using the following MeSH, 'Lapaorscopic splenic artery aneurysm', 'laparoscopic aneurysectomy', 'Laparoscopic Splenic artery Aneurysm Ligation' and 'Laparoscopic Splenic artery aneurysm excision' was done. Also three cases performed at our institutions are discussed, in terms of techniques, morbidity, mortality and postoperative outcomes. RESULTS: About eight case series and 16 case reports were retrieved from the literature. Different techniques were described by the authors, including splenectomy, aneurysmectomy, splenic aneurysm ligation or even occlusion. Few morbidity cases were reported and none of the authors has mentioned a single mortality case. In our three cases, the postoperative course was uneventful, with good long-term results. CONCLUSIONS: Despite the variations in the adopted operative techniques, the laparoscopic approach seems to be harmless. However, no treatment algorithm or consensus has been published. PMID- 29631509 TI - Prevalence of Mycoplasma genitalium and mutations associated with macrolide and fluoroquinolone resistance in Finland. AB - The aim was to examine the prevalence of Mycoplasma genitalium and to determine the prevalence of mutations leading to resistance to macrolides and fluoroquinolones in a sexually transmitted infection clinic setting in Finland, and as a service evaluation, to validate the performance of a commercial Aptima(r) Mycoplasma genitalium assay. Urogenital samples were studied for M. genitalium with an automated commercial Aptima(r) Mycoplasma genitalium assay on the Panther(r) system (Hologic), and with an in-house real-time polymerase chain reaction (PCR) (mgpB). Positive specimens were further studied for mutations associated with macrolide resistance within the 23S rRNA gene and the known quinolone resistance-determining regions within genes gyrA, gyrB and parC. Altogether 17/303 (5.6%) of samples contained M. genitalium by either test. Two of the samples positive by the Aptima assay were not detected by the in-house PCR assay, although the internal control (beta-globin gene) was amplified. The Aptima assay gave an invalid result for five samples, all of which were negative by the in-house PCR. Mutations resulting in macrolide resistance were detected in 30.8% of M. genitalium-positive specimens. Prevalence of M. genitalium infections in the specimens tested is similar to that in other parts of Europe, 5.6%. The Aptima(r) Mycoplasma genitalium assay detected slightly more positives than the in-house PCR assay. Mutations resulting in macrolide resistance were common in M. genitalium and detection of these mutations is recommended in diagnostic laboratories to assist in selection of treatment. PMID- 29631510 TI - Evidence That Graves' Ophthalmopathy Immunoglobulins Do Not Directly Activate IGF 1 Receptors. AB - BACKGROUND: Graves' ophthalmopathy (GO) pathogenesis involves thyrotropin (TSH) receptor (TSHR)-stimulating autoantibodies. Whether there are autoantibodies that directly stimulate insulin-like growth factor 1 receptors (IGF-1Rs), stimulating insulin-like growth factor receptor antibodies (IGFRAbs), remains controversial. This study attempted to determine whether there are stimulating IGFRAbs in patients with GO. METHODS: Immunoglobulins (Igs) were purified from normal volunteers (NV-Igs) and patients with GO (GO-Igs). The effects of TSH, IGF-1, NV Igs, and GO-Igs on pAKT and pERK1/2, members of pathways used by IGF-1R and TSHR, were compared in orbital fibroblasts from GO patients (GOFs) and U2OS-TSHR cells overexpressing TSHRs, and U2OS cells that express TSHRs at very low endogenous levels. U2OS-TSHR and U2OS cells were used because GOFs are not easily manipulated using molecular techniques such as transfection, and U2OS cells because they express TSHRs at levels that do not measurably stimulate signaling. Thus, comparing U2OS-TSHR and U2OS cells permits specifically distinguishing signaling mediated by the TSHR and IGF-1R. RESULTS: In GOFs, all GO-Igs stimulated pERK1/2 formation and 69% stimulated pAKT. In U2OS-TSHR cells, 15% of NV-IGs and 83% of GO-Igs stimulated increases in pERK1/2, whereas all NV-Igs and GO-Igs stimulated increases in pAKT. In U2OS cells, 70% of GO-Igs stimulated small increases in pAKT. Knockdown of IGF-1R caused a 65 +/- 6.3% decrease in IGF 1-stimulated pAKT but had no effect on GO-Igs stimulation of pAKT. Thus, GO-Igs contain factor(s) that stimulate pAKT formation. However, this factor(s) does not directly activate IGF-1R. CONCLUSIONS: Based on the findings analyzing these two signaling pathways, it is concluded there is no evidence of stimulating IGFRAbs in GO patients. PMID- 29631511 TI - Vision rehabilitation interventions following mild traumatic brain injury: a scoping review. AB - PURPOSE: To broadly examine the literature to identify vision interventions following mild traumatic brain injury. Objectives are to identify: (1) evidence informed interventions for individuals with visual dysfunction after mild traumatic brain injury; (2) professions providing these interventions; (3) gaps in the literature and areas for further research. METHODS: A scoping review was conducted of four electronic databases of peer-reviewed literature from the databases earliest records to June 2017. Articles were included if the study population was mild traumatic brain injury/concussion and a vision rehabilitation intervention was tested. Two independent reviewers screened articles for inclusion, extracted data, and identified themes. RESULTS: The initial search identified 3111 records. Following exclusions, 22 articles were included in the final review. Nine studies evaluated optical devices, such as corrective spectacles, contact lenses, prisms, or binasal occlusion. Two studies assessed vision therapy. Ten studies examined vision therapy using optical devices. One study investigated hyperbaric oxygen therapy. Optometrists performed these interventions in most of the studies. Future research should address quality appraisal of this literature, interventions that include older adult and pediatric populations, and interdisciplinary interventions. CONCLUSIONS: There are promising interventions for vision deficits following mild traumatic brain injury. However, there are multiple gaps in the literature that should be addressed by future research. Implications for Rehabilitation Mild traumatic brain injury may result in visual deficits that can contribute to poor concentration, headaches, fatigue, problems reading, difficulties engaging in meaningful daily activities, and overall reduced quality of life. Promising interventions for vision rehabilitation following mild traumatic brain injury include the use of optical devices (e.g., prism glasses), vision or oculomotor therapy (e.g., targeted exercises to train eye movements), and a combination of optical devices and vision therapy. Rehabilitation Professionals (e.g., optometrists, occupational therapists, physiotherapists) have an important role in screening for vision impairments, recommending referrals appropriately to vision specialists, and/or assessing and treating functional vision deficits in individuals with mild traumatic brain injury. PMID- 29631512 TI - Infections in hospitalized lupus nephritis patients: characteristics, risk factors, and outcomes. AB - Background There are limited studies documenting infection epidemiology in lupus nephritis (LN) patients. We aimed to study infection incidences and risk characteristics and ascertain possible predictors of infective outcomes in a multiethnic Asian population. Methods This retrospective study from 2006 to 2012 included newly diagnosed LN patients. We collected admissions, immunosuppression, and infection data until end-stage renal failure, death, last follow-up, or the year 2015. The infection incidence rates were evaluated and a generalized linear latent and mixed models (GLLAMM) analysis was carried out to evaluate potential predictors of infection. Results Our cohort of 101 patients consisted of mainly Chinese (75.2%), females (78.2%), and a median age of 38 years (IQR 26-49). The median time of follow-up was 72.8 months (IQR 49.5-94.0). Six out of 14 patient deaths were infection related. Seventy-eight out of 200 admissions, with a total of 102 episodes of infection, occurred in 46 patients. The incidence of infection rates leading to admissions was 10.3 per 100 person-years and the incidence of infection episodes rates was 17.6 per 100 person-years. Cytomegalovirus (CMV) was the most common organism identified. Univariate GLLAMM analysis showed Malay compared to Chinese ethnicity (HR 2.833 (95% CI 1.088-7.373)), use of oral cyclophosphamide (HR 6.618 (95% CI 1.015-43.154)) and rituximab (HR 3.967 (95% CI 1.157-13.603)) as predictors of infection-related admissions. Malay ethnicity and rituximab remained significant in the multivariate GLLAMM analysis. Conclusions Our study highlights substantial infection incidences in patients with LN and its contribution to deaths. PMID- 29631513 TI - The devil's in the dosing: severe drug-induced liver injury in a hydroxychloroquine-naive patient with subacute cutaneous lupus erythematosus and porphyria cutanea tarda. AB - A 29-year-old woman with a 1.5 year history of photosensitive skin lesions on her hands presented with a malar rash, bullous lesions on her hands, and was diagnosed with subacute lupus erythematosus after serologies revealed a positive antinuclear antibody test (1:2560), and antibodies to Ro/SSA and dsDNA. Hydroxychloroquine (400 mg/day) was prescribed and the patient developed severe drug-induced liver injury. Biopsy of her bullous skin lesions was consistent with porphyria cutanea tarda, as were her serological and urinary exams. She was successfully treated with therapeutic phlebotomy. This case identifies porphyria cutanea tarda as an important differential diagnosis for the rheumatologist to consider when evaluating patients with bullous skin lesions. Hydroxychloroquine in lower doses is an effective treatment for porphyria cutanea tarda; at doses used to treat systemic lupus erythematosus and subacute cutaneous lupus, there is a potentially life-threatening complication of hepatotoxicity. PMID- 29631514 TI - Mesenchymal stem cell transplantation in systemic lupus erythematous, a mesenchymal stem cell disorder. AB - Systemic lupus erythematosus (SLE) is a chronic autoimmune and inflammatory disorder with involvement of several organs and systems such as the kidney, lung, brain and the hematopoietic system. As the most prevailing organ manifestation, lupus nephritis is the major cause of mortality and morbidity in SLE patients. The most classically and widely administered immunosuppressive medications, namely corticosteroids and cyclophosphamide, have eventuated in a remarkable amelioration in disease complications over the last few years and reduced the progression to end-stage multiorgan failure. Mesenchymal stem cells (MSCs) are considered as non-hematopoietic and multipotential progenitor cells, which are able to differentiate into multiple cell lineages such as chondrocytes, osteoblasts, myoblasts, endothelial cells, adipocytes, neuron-like cells, hepatocytes and cardiomyocytes. MSCs from SLE patients have demonstrated defects such as aberrant cytokine production. Moreover, impaired phenotype, growth and immunomodulatory functions of MSCs from patients with SLE in comparison to healthy controls have been reported. Therefore, it is hypothesized that SLE is potentially an MSC-mediated disease and, as a result, allogeneic rather than autologous MSC transplantation can be argued to be a potentially advantageous therapy for patients with SLE. On the other hand, the MSC senescence phenomenon may meet the current therapeutic approaches with challenges and demand more attention. Here, we discuss MSC transplantations to date in animal models and humans and focus on the MSC senescence complications in SLE patients. PMID- 29631515 TI - Watch Peripheral Arterial Tonometry in the Diagnosis of Pediatric Obstructive Sleep Apnea. AB - Objective To assess the accuracy and clinical reliability of watch peripheral arterial tonometry (PAT) compared with polysomnography (PSG) for the diagnosis of pediatric obstructive sleep apnea (OSA). Study Design Prospective, diagnostic test study. Setting National tertiary referral hospital. Subjects and Methods Patients aged 8 to 15 years with clinically suspected OSA were recruited. All participants underwent PSG and PAT simultaneously in the sleep laboratory. Results Thirty-six patients were included, with a mean age of 10.2 +/- 1.8 years. Median (interquartile range) of the apnea hypopnea index (AHI) was 8.0 (5.5-12) and 2.9 (0.5-7.5) events/h, median oxygen desaturation index (ODI) was 2.5 (1.4 8.3) and 1.3 (0.2-3.8) events/h, mean +/- standard deviation total sleep time was 398.4 +/- 38.3 and 401.9 +/- 36.1 minutes, and mean minimum oxygen saturation was 87.1% +/- 8.1% and 89.4% +/- 7.1% for PSG and PAT sleep parameter results, respectively. Agreement between methods was excellent for the AHI (intraclass correlation coefficient [ICC]: 0.89; 95% CI, 0.40-0.96; P < .001) and ODI (ICC: 0.87; 95% CI, 0.69-0.94; P < .001). Correlation between methods was very good for the ODI ( r = 0.83; 95% CI, 0.67-0.90; P < .001) and moderate for the AHI ( r = 0.64; 95% CI, 0.30-0.85; P < .001). From the receiver operating characteristic curve constructed to assess PAT diagnostic capability, AHI of PAT (W-AHI) at a cutoff of 3.5 events/h provided the highest accuracy (76.9% sensitivity, 78.3% specificity), while W-AHI at 10 events/h yielded 91.3% specificity for diagnosing severe OSA. Conclusion PAT correlated well and had good agreement with PSG. Children with W-AHI >=10 had high specificity for the diagnosis of severe OSA. Larger studies with PAT designed for children across all age ranges and with a normal control group are still needed. PMID- 29631516 TI - Simplifying the use of prognostic information in traumatic brain injury. Part 1: The GCS-Pupils score: an extended index of clinical severity. AB - OBJECTIVE Glasgow Coma Scale (GCS) scores and pupil responses are key indicators of the severity of traumatic brain damage. The aim of this study was to determine what information would be gained by combining these indicators into a single index and to explore the merits of different ways of achieving this. METHODS Information about early GCS scores, pupil responses, late outcomes on the Glasgow Outcome Scale, and mortality were obtained at the individual patient level by reviewing data from the CRASH (Corticosteroid Randomisation After Significant Head Injury; n = 9,045) study and the IMPACT (International Mission for Prognosis and Clinical Trials in TBI; n = 6855) database. These data were combined into a pooled data set for the main analysis. Methods of combining the Glasgow Coma Scale and pupil response data varied in complexity from using a simple arithmetic score (GCS score [range 3-15] minus the number of nonreacting pupils [0, 1, or 2]), which we call the GCS-Pupils score (GCS-P; range 1-15), to treating each factor as a separate categorical variable. The content of information about patient outcome in each of these models was evaluated using Nagelkerke's R2. RESULTS Separately, the GCS score and pupil response were each related to outcome. Adding information about the pupil response to the GCS score increased the information yield. The performance of the simple GCS-P was similar to the performance of more complex methods of evaluating traumatic brain damage. The relationship between decreases in the GCS-P and deteriorating outcome was seen across the complete range of possible scores. The additional 2 lowest points offered by the GCS-Pupils scale (GCS-P 1 and 2) extended the information about injury severity from a mortality rate of 51% and an unfavorable outcome rate of 70% at GCS score 3 to a mortality rate of 74% and an unfavorable outcome rate of 90% at GCS-P 1. The paradoxical finding that GCS score 4 was associated with a worse outcome than GCS score 3 was not seen when using the GCS-P. CONCLUSIONS A simple arithmetic combination of the GCS score and pupillary response, the GCS-P, extends the information provided about patient outcome to an extent comparable to that obtained using more complex methods. The greater range of injury severities that are identified and the smoothness of the stepwise pattern of outcomes across the range of scores may be useful in evaluating individual patients and identifying patient subgroups. The GCS-P may be a useful platform onto which information about other key prognostic features can be added in a simple format likely to be useful in clinical practice. PMID- 29631517 TI - Simplifying the use of prognostic information in traumatic brain injury. Part 2: Graphical presentation of probabilities. AB - OBJECTIVE Clinical features such as those included in the Glasgow Coma Scale (GCS) score, pupil reactivity, and patient age, as well as CT findings, have clear established relationships with patient outcomes due to neurotrauma. Nevertheless, predictions made from combining these features in probabilistic models have not found a role in clinical practice. In this study, the authors aimed to develop a method of displaying probabilities graphically that would be simple and easy to use, thus improving the usefulness of prognostic information in neurotrauma. This work builds on a companion paper describing the GCS-Pupils score (GCS-P) as a tool for assessing the clinical severity of neurotrauma. METHODS Information about early GCS score, pupil response, patient age, CT findings, late outcome according to the Glasgow Outcome Scale, and mortality were obtained at the individual adult patient level from the CRASH (Corticosteroid Randomisation After Significant Head Injury; n = 9045) and IMPACT (International Mission for Prognosis and Clinical Trials in TBI; n = 6855) databases. These data were combined into a pooled data set for the main analysis. Logistic regression was first used to model the combined association between the GCS-P and patient age and outcome, following which CT findings were added to the models. The proportion of variability in outcomes "explained" by each model was assessed using Nagelkerke's R2. RESULTS The authors observed that patient age and GCS-P have an additive effect on outcome. The probability of mortality 6 months after neurotrauma is greater with increasing age, and for all age groups the probability of death is greater with decreasing GCS-P. Conversely, the probability of favorable recovery becomes lower with increasing age and lessens with decreasing GCS-P. The effect of combining the GCS-P with patient age was substantially more informative than the GCS-P, age, GCS score, or pupil reactivity alone. Two-dimensional charts were produced displaying outcome probabilities, as percentages, for 5-year increments in age between 15 and 85 years, and for GCS-Ps ranging from 1 to 15; it is readily seen that the movement toward combinations at the top right of the charts reflects a decreasing likelihood of mortality and an increasing likelihood of favorable outcome. Analysis of CT findings showed that differences in outcome are very similar between patients with or without a hematoma, absent cisterns, or subarachnoid hemorrhage. Taken in combination, there is a gradation in risk that aligns with increasing numbers of any of these abnormalities. This information provides added value over age and GCS-P alone, supporting a simple extension of the earlier prognostic charts by stratifying the original charts in the following 3 CT groupings: none, only 1, and 2 or more CT abnormalities. CONCLUSIONS The important prognostic features in neurotrauma can be brought together to display graphically their combined effects on risks of death or on prospects for independent recovery. This approach can support decision making and improve communication of risk among health care professionals, patients, and their relatives. These charts will not replace clinical judgment, but they will reduce the risk of influences from biases. PMID- 29631518 TI - Over- and Under-Treatment of Hypothyroidism Is Associated with Excess Mortality: A Register-Based Cohort Study. AB - OBJECTIVE: This study investigated the association between hypothyroidism and mortality in both treated and untreated hypothyroid patients, and the consequences of over- and under-treatment with respect to mortality. PATIENTS AND METHODS: This was a register-based cohort study of 235,168 individuals who had at least one serum thyrotropin (TSH) during 1995-2011 (median follow-up 7.2 years). Hypothyroidism was defined as at least two measurements of TSH >4.0 mIU/L within a half year spaced by at least 14 days, or one measurement of TSH >4.0 mIU/L and two filled prescriptions of levothyroxine the following year. All-cause mortality rates were calculated using multivariable Cox regression analysis adjusted for age, sex, and comorbidities using the Charlson Comorbidity Index. RESULTS: Mortality was increased in untreated hypothyroid individuals (n = 673; hazard ratio [HR] = 1.46 [confidence interval (CI) 1.26-1.69]; p < 0.001) compared to euthyroid controls. Results remained significant even when subdividing according to mild (TSH >4.0 mIU/L and <=10 mIU/L; p < 0.001) and marked hypothyroidism (TSH >10 mIU/L; p = 0.002). Mortality was increased in both treated and untreated hypothyroid individuals for each six months a patient had increased TSH (HR = 1.05 [CI 1.02-1.07], p < 0.0001, and HR = 1.05 [CI 1.02-1.07], p = 0.0009, respectively). In patients who received levothyroxine, the HR for mortality increased by a factor 1.18 ([CI 1.15-1.21]; p < 0.0001) for each six months a patient exhibited decreased TSH. This finding was essentially unchanged after stratification by disease severity (mild or marked hypothyroidism) and age (older and younger than 65 years). CONCLUSIONS: Mortality was increased in untreated but not in treated hypothyroid individuals, independently of age and severity of hypothyroidism. Duration of decreased TSH in treated individuals had a greater impact on mortality than did duration of elevated TSH. These results stress the need for close monitoring of treatment in individuals receiving thyroid hormone replacement therapy. PMID- 29631519 TI - Combining the Post-Cue Task and the Perceptual Identification Task to Assess Parallel Activation and Mutual Facilitation of Related Primes and Targets. AB - Recent theories assume a mutual facilitation in case of semantic overlap for concepts being activated simultaneously. We provide evidence for this claim using a semantic priming paradigm. To test for mutual facilitation of related concepts, a perceptual identification task was employed, presenting prime-target pairs briefly and masked, with an SOA of 0 ms (i.e., prime and target were presented concurrently, one above the other). Participants were instructed to identify the target. In Experiment 1, a cue defining the target was presented at stimulus onset, whereas in Experiment 2 the cue was not presented before the offset of stimuli. Accordingly, in Experiment 2, a post-cue task was merged with the perceptual identification task. We obtained significant semantic priming effects in both experiments. This result is compatible with the view that two concepts can both be activated in parallel and can mutually facilitate each other if they are related. PMID- 29631520 TI - Are You Taking the Fastest Route to the RESTAURANT? AB - Most words in books and digital media are written in lowercase. The primacy of this format has been brought out by different experiments showing that common words are identified faster in lowercase (e.g., molecule) than in uppercase (MOLECULE). However, there are common words that are usually written in uppercase (street signs, billboards; e.g., STOP, PHARMACY). We conducted a lexical decision experiment to examine whether the usual letter-case configuration (uppercase vs. lowercase) of common words modulates word identification times. To this aim, we selected 78 molecule-type words and 78 PHARMACY-type words that were presented in lowercase or uppercase. For molecule-type words, the lowercase format elicited faster responses than the uppercase format, whereas this effect was absent for PHARMACY-type words. This pattern of results suggests that the usual letter configuration of common words plays an important role during visual word processing. PMID- 29631521 TI - Investigating Deviance Distraction and the Impact of the Modality of the To-Be Ignored Stimuli. AB - It has been suggested that deviance distraction is caused by unexpected sensory events in the to-be-ignored stimuli violating the cognitive system's predictions of incoming stimuli. The majority of research has used methods where the to-be ignored expected (standards) and the unexpected (deviants) stimuli are presented within the same modality. Less is known about the behavioral impact of deviance distraction when the to-be-ignored stimuli are presented in different modalities (e.g., standard and deviants presented in different modalities). In three experiments using cross-modal oddball tasks with mixed-modality to-be-ignored stimuli, we examined the distractive role of unexpected auditory deviants presented in a continuous stream of expected standard vibrations. The results showed that deviance distraction seems to be dependent upon the to-be-ignored stimuli being presented within the same modality, and that the simplest omission of something expected; in this case, a standard vibration may be enough to capture attention and distract performance. PMID- 29631522 TI - Moral Judgment in Old Age. AB - Younger (21-39 years) and older (63-90 years) adults were presented with scenarios illustrating either harmful or helpful actions. Each scenario provided information about the agent's intention, either neutral or valenced (harmful/helpful), and the outcome of his or her action, either neutral or valenced. Participants were asked to rate how morally good or bad the agent's action was. In judging harmful actions, older participants relied less on intentions and more on outcomes compared to younger participants. This age related difference was associated with a decline in older adults' theory of mind abilities. However, we did not find evidence of any significant age-related difference in the evaluations of helpful actions. We argue that the selective association of aging with changes in the evaluation of harmful but not helpful actions may be due also to motivational factors and highlight some implications of the present findings for judicial systems. PMID- 29631523 TI - Interference Between Number Magnitude and Parity. AB - Interference between number magnitude and other properties can be explained by either an analogue magnitude system interfering with a continuous representation of the other properties or by discrete, categorical representations in which the corresponding number and property categories interfere. In this study, we investigated whether parity, a discrete property which supposedly cannot be stored on an analogue representation, could interfere with number magnitude. We found that in a parity decision task the magnitude interfered with the parity, highlighting the role of discrete representations in numerical interference. Additionally, some participants associated evenness with large values, while others associated evenness with small values, therefore, a new interference index, the dual index was introduced to detect this heterogeneous interference. The dual index can be used to reveal any heterogeneous interference that were missed in previous studies. Finally, the magnitude-parity interference did not correlate with the magnitude-response side interference (Spatial-Numerical Association of Response Codes [SNARC] effect) or with the parity-response side interference (Markedness Association of Response Codes [MARC] effect), suggesting that at least some of the interference effects are not the result of the stimulus property markedness. PMID- 29631524 TI - The effect of sodium hyaluronate-carboxymethyl cellulose membrane in the prevention of parenchymal air leaks: an experimental and manometric study in rats. AB - Introduction: We aimed to examine effectiveness of sodium hyaluronate carboxymethly cellulose (NaH/CMC) for sealing pulmonary air leaks during postoperative period. Materials and Methods: The study was conducted in 16 male Sprague-Dawley rats. A linear insicion (length= 0.2 cm, depth= 0.1 cm) to the lung parenchyma on the inflated by a cutter was made. The animals were randomly divided; the control group (n= 8) and NaH/CMC-treated group (the study group, n= 8). Control group was left for physiologic healing while a NaH/CMC membrane was applied over the the incisional area in the study group. Then the pressure point where the air leakage observed was noted. Result: No polymorphonucleer leucocytes (PMNL) infiltration was detected in control group, whereas PMNL infiltration was 0.38 +/- 0.5 cell per 100 high field in study group (p= 0.234). The degree of macrophage, lymphocyte infiltration and the mean fibroblast count were found to be higher in study group compared with control group (p= 0.007, p= 0.02, p= 0.05, respectively). The mean pressure value for air leak to occur in the control group was 43.50 +/- 9.55 mmHg whereas it was 73.75 +/- 16.68 mmHg in the study group (p< 0.001). Conclusions: The data revealed that bioabsorbable NaH/CMC membrane accelerates healing with preserving the expansile character of lung parenchyma even in high ventilation pressures. However, further studies are required to assess the prevent impact of the pulmonary air-leak for NaH/CMC membrane. PMID- 29631525 TI - Evaluation of nephrotoxicity and prognosis in patients treated with colistin due to hospital-acquired pneumonia. AB - Introduction: Colistimethate sodium (CMS) is frequently used in the treatment of nosocomial multidrug-resistant gram-negative infections. Nephrotoxicity is the most important side effect. The aim of this study is to evaluate the effect of colistin on nephrotoxicity and to assess prognosis in patients treated with CMS due to hospital-acquired pneumonia (HAP). Materials and Methods: Patients treated with CMS for HAP due to multidrug-resistant Pseudomonas aeruginosa or Acinetobacter baumannii were included in this cohort study. Result: We evaluated 281 patients treated with two different brands of CMS whose administration dose is different: imported (n= 58, low dose/kg) and domestic (n= 223, high dose/kg). Nephrotoxicity developed in 175 patients (62.3%). The median age (73 vs. 66 years, p= 0.004) and mortality rates were higher (66.9% vs. 52.8%, p= 0.022) in patients having nephrotoxicity. The patients receiving high dose/kg had higher nephrotoxicity rate (67.7% vs. 41.4%, p< 0.001). The clinical, bacteriological response and mortality rates of the whole group were 52.0%, 61.0%, 61.6%, respectively. The clinical and bacteriological response rates were similar in the different dose groups. Multivariate analysis showed that nephrotoxicity was associated with domestic brand depending on use of high dose (OR= 3.97), advanced age (beta= 0.29, p= 0.008), male gender (OR= 2.60), hypertension (OR= 2.50), red blood cells transfusion (OR= 2.54), absence of acute kidney injury (OR= 10.19), risk stage of RIFLE (OR= 11.9). Conclusions: Nephrotoxicity is associated with the use of high dose colistin, age, gender, hypertension, red blood cells replacement and RIFLE stage. The mortality rate is higher in patients developing nephrotoxicity. PMID- 29631526 TI - Does eosinophilia and neutrophil to lymphocyte ratio affect hospital re-admission in cases of COPD exacerbation? AB - Introduction: We aimed to assess the relationship between peripheral eosinophilia and neutrophil/lymphocyte ratio with hospital admissions and re-admissions with chronic obstructive pulmonary disease (COPD) exacerbations. Materials and Methods: An observational cohort study was carried out in a tertiary teaching hospital. Subjects with previously diagnosed COPD and who were admitted as outpatients with acute exacerbations were included. The subjects' characteristics, complete blood count (CBC) parameters, neutrophil to lymphocyte rate (NLR), C-reactive protein (CRP), mean platelet volume (MPV) on admission and re-admission within the first 28 days. Patients were grouped according to their peripheral blood eosinophilia levels; group 1, > 2% (eosinophilic), group 2, <= 2% (non-eosinophilic or neutrophilic). The recorded data from the two groups were compared. Result: 1490 eligible COPD subjects were enrolled. Approximately 42% were classified as eosinophilic. The non-eosinophilic group had a significantly higher leukocyte count, neutrophil percentage, and NLR than the eosinophilic group. The NLR value in patients with repeat re-admissions was higher than the average, i.e., 4.50 (p= 0.001). MPV and CRP measured on admission and re admission were similar in both groups. The rate of hospital re-admission within 28 days was significantly higher in patients with a non-eosinophilic attack. Conclusions: When a patient is admitted to outpatients with a NLR greater than 4.50 and with a non-eosinophilic exacerbation they have an increased risk of re admission in the first month. Higher NLR values and non-eosinophilic exacerbations may be helpful for the early detection of potential acute attacks in COPD patients, and may be indicators for antibiotic management. PMID- 29631527 TI - Lung cancer diagnosed with Mycobacterium tuberculosis or nontuberculosis mycobacteria concomitantly. AB - Introduction: The concomitant occurrence of disease of Mycobacterium tuberculosis or nontuberculosis mycobacteria (NTM) and lung cancer has been reported in previous studies. We aimed to determine characteristics of the patients with lung cancer diagnosed with M. tuberculosis or NTM concomitantly. Materials and Methods: From 2010 to 2015, the patients diagnosed with lung cancer and M. tuberculosis or NTM concomitantly were enrolled in the study. Patient data were collected retrospectively. Result: Concomitant M. tuberculosis or NTM and lung cancer were diagnosed in 17 cases (1.2% of total lung cancer cases, 0.9% of total tuberculosis cases). M. tuberculosis was isolated from 11 (64.8%) patients and NTM disease was from 6 (35.2%) patients. Squamous cell carcinoma was the most common histological type. Tumoral stage was often advanced as stage III- IV (76.5%). Bronchial lavage smear positivity foracid-fast bacilli was found only in 4 (23.5%) patients. Tuberculosis treatment therapy was started only in 4 (23.5%) patients who had bronchial lavage smear positivity for acid-fast bacilli. So tuberculosis treatment was delayed for other 13 (76.5%) patients with bronchial lavage smear negative for acid-fast bacilli. Seven out of 17 (41.1%) patients died. Conclusions: Physicians should consider concomitant M. tuberculosis or NTM when managing lung cancer. Tuberculosis patients may be mis diagnosed as lung cancer or vice versa. PMID- 29631528 TI - The cough frequency among call center workers: "call center cough". AB - Introduction: Call centers are places where numerous people work together always speaking in a closed environment, and the most common complaint about admission to a doctor by call center employees is a cough and other respiratory system symptoms. Materials and Methods: In this study, we aimed to demonstrate the relationship of call center employees between work and cough complaints and cough incidence with a questionnaire that consists of eleven questions and evaluates epidemiologic features, cough complaints of call center employees. Result: 132 people were accrued to this study and the female/male ratio was 102/30. Mean age was 26.4 +/- 2.7 (min-max; 21-39) years, mean working time at the call center was 2.6 +/- 1.2 (min-max; 0.1-8) year and mean daily working hours was 8.1 +/- 1.1 hour. 40 (30.3%) participants had cough complaint before beginning, 89 (67.4%) participants had cough complaint after to work at a call center work (p= 0.004). Conclusions: Cough is more prevalent in call center employees. Pulmonary medicine specialist and occupational medicine practioner keep their mind unexplaned cough with infections or other reasons might be a warning and early symptoms of sick building syndrome or other building related diseases or voice abusing on call center operators. PMID- 29631529 TI - [Evaluation of the approaches and knowledge level of tuberculosis diagnosis and treatment of infectious disease research assistants and specialist physicians]. AB - Introduction: This study aims to evaluate approaches and knowledge level for tuberculosis (TB) diagnosis and treatment among infectious diseases and clinical microbiology research assistants and specialist physicians. Materials and Methods: This was a descriptive study on the research assistants and specialist physicians. A questionnaire consisting of 24 questions prepared by the researchers was used. Data were analyzed using SPSS, version 22.0. Result: In this study, 116 physicians participated. The average age of participants was 41.07 +/- 8.65 years, and 64.7% were female. The proportion of physicians with no pulmonary and non-pulmonary TB experience was calculated as 6.9% and 3.4%, respectively. Acid-fast-bacilli (AFB) tests were most frequently used in the diagnosis of pulmonary TB. On the other hand, the tuberculin skin test (TST) + chest radiography (CR) was most frequently used for latent TB in immunosuppressed subjects (91.4% and 69%, respectively). The most common non-pulmonary TB clinic form encountered was lymphadenitis (88.8%); the most common treatment problem was drug side effects (75%); and the most common drug resistance was to isoniazid (25.9%). It was determined that physicians encountered HIV and TB coinfection in 62.9% of patients, and standard TB treatment was applied for most patients (48.3%). The most frequent yearly TST + CR + AFB trials (69%) were performed in the screenings of health workers who were in contact with TB patients. It was observed that 44% of physicians used a negative pressurized chamber and/or isolation chamber in the institution, and 72.4% used a N95/FFP3 mask during examination. It was determined that the participants were mostly correct about TB. Conclusions: Infectious diseases and clinical microbiology physicians continue to encounter TB patients. This group of physicians often has a good level of knowledge and experience with TB, although special training for this disease is low. PMID- 29631530 TI - [Which factors effects patients belief and attitudes about influenza vaccination?] AB - Introduction: Despite its proven efficacy, vaccination rates with influenza vaccine are considerably low. This study aimed to investigate the vaccination rates with influenza-vaccine and the factors affecting attitude toward vaccination. Materials and Methods: A questionnaire was applied to patients presenting to outpatient clinic between October 2011-January 2012. Result: Of these 1251 (671 F, 580 M) patients with a mean age of 47.7 +/- 15.1, 61.9% had an indication for influenza-vaccination. The rate of vaccination was 33.4%. Among the vaccinated patients, the ratio of patients with an educational level of high school or above (60.6%) was greater than that of patients with a lower educational level (39.4%) (p= 0.01). The vaccination rates were greater among those with chronic lung disease (43.6%), heart disease (21.2%), and diabetes (19.3%) (p< 0.001, p= 0.02, and p= 0.03, respectively). A multivariate regression analysis revealed that the independent variables associated with vaccination were considering the vaccine protective (OR, 2.13; CI, 1.85-4.24, p= 0.03), getting vaccinated to protect oneself (OR, 6.31; CI, 3.25-12.63, p< 0.001), getting vaccinated to protect one's family against influenza (OR, 5.42; CI, 3.11-9.54, p= 0.02), the vaccine being recommended by a physician (OR, 4.15; CI, 2.03-7.45, p< 0.001), being regularly-vaccinated (OR, 5.32; CI, 3.24-6.35, p< 0.001), and suffering from chronic lung disease (OR, 2.21; CI, 1.64-4.32, p< 0.001). The reasons of not getting vaccinated were considering the vaccine useless (OR, 2.46; CI, 0.77-3.98; p= 0.01),having concerns about side-effects (OR, 2.14; CI, 0.16 3.25; p= 0.02),and having inadequate knowledge (OR, 7.12; CI, 4.23-12.56; p< 0.001). Men, as compared to women, had a significantly greater rate of considering the vaccine useful (p< 0.001), getting vaccinated during campaigns held by workplaces (p= 0.002), and obtaining information through bills, brochures, or bulletins (p= 0.003). Patients vaccinated with the influenza vaccine significantly more commonly consider the pneumococcal-vaccine useful (p= 0.02), and they had a significantly greater rateofvaccination with pneumococcal vaccine (p< 0.001). Conclusions: The vaccination rate remains low. Opinions about the vaccine that had favourable effect on vaccination rate were that the vaccine was beneficial and that it would protect one's family against the disease. The unvaccinated patients had inadequate knowledge of the vaccine. Obtaining information from a physician boosts vaccination rate. Men having a greater rate of vaccination through campaigns of workplaces as well as a greater rate of being informed can be explained by a higher employment rate in men. PMID- 29631531 TI - [Lung cancer and intensive care: which patient how long?] AB - Lung cancer still remains the leading cause of cancer death among all the cancer types. Early diagnosis is the most important factor for efficient treatment and disease management. Nowadays, several new methodologies are being used in clinical practise for diagnosis, staging and treatment of disease. Therefore, survival is prolonged even in patients who are not eligible for surgery. This has led to increase in the acceptance of lung cancer patients in intensive care units (ICU) due to both the disease and the treatments applied and also due to the comorbidity of the patients. However, it is unclear which lung cancer patient will benefit from intensive treatment. In this review, we shared the ICU admission reasons and prognosis of the early stage and advanced stage lung cancer patients and when these patients were referred to ICU and treatment modalities in ICU were discussed. PMID- 29631532 TI - [The pilgrimage and the burden of pneumococcal disease in adults]. AB - Pneumococcal disease is responsible for significant morbidity and mortality. All over the world, 1.6 million people die of pneumococcal disease every year; this estimate includes the deaths of 1 million children aged less than 5 years and the deaths of 600.000- 800.000 adults. The burden of pneumococcal disease is high in adults. Increasing age and the presence of comorbidity has a significant affected of the risk of developing the disease. During mass gatherings, such as pilgrimage individuals, is exposed to severe community-acquired pneumococcal infections. Individuals who has Streptococcus pneumoniae in nasopharynx, have the potential to infection and leave exposed to the risk of pneumococcal disease the other Individuals with sneezing, coughing or out of breath, given breath through droplets of these microorganisms. In the present review, the relationship of pneumococcal disease in adults and pilgrimage, vaccination strategies will be considered and then during a visit to Pilgrimate and Umrah pilgrims against the current vaccine recommendations will be summarised. PMID- 29631533 TI - A rare cause of noninvasive ventilation failure: tracheal stenosis. AB - Noninvasive ventilation is the first line treatment of choice in acute respiratory failure in many diseases including post-extubation respiratory failure. Herein we report a case unresponsive to noninvasive ventilation due to tracheal stenosis. A 49- year -old female was admitted to intensive care unit after successful resuscitation of cardiac arrest. During the follow-up, she was extubated on 16th day and then transferred to the coronary ward. Four days later, she started to have progressive dyspnea and difficulty in breathing. Arterial blood gas evaluation showed respiratory acidosis with moderate hypercapnia. Noninvasive ventilation was initiated with the diagnosis of cardiogenic pulmonary edema however she did not respond to noninvasive ventilation therapy. Pulmonary consultation revealed that she had a new onset stridor. She had an urgent fiberoptic bronchoscopy which revealed severe tracheal stenosis. Tracheal stenosis should be considered in patients who do not respond to noninvasive ventilation after extubation like in our case. PMID- 29631534 TI - [A rare case: Kikuchi-Fujimoto disease]. AB - Kikuchi-Fujimoto's disease (CFD) is a disease that usually exhibits self-limited benign lymph node involvement. Etiology of illness is not fully understood.Differential diagnosis should be performed well because lymph node involvement can be confused with lymphoma type diseases. A 35-year-old male patient with weakness, joint aches, fever, loss of appetite, weight loss, night sweating symptoms presented with the literature. PMID- 29631535 TI - Pleural tumor simulating localized pleural fluid. PMID- 29631536 TI - Clinical characteristics of nontuberculosis mycobacterial pulmonary infection in immunocompetent adult patients: 6 cases. PMID- 29631537 TI - The importance of lifestyle changes in patients with uncontrolled asthma. PMID- 29631538 TI - Bronchial atresia in an adult misdiagnosed as pulmonary mass. PMID- 29631540 TI - The effect of trauma and alcohol on the relationship between level of cytokines and depression among patients entering psychiatric treatment. AB - BACKGROUND: Depression is associated with immunological responses as reflected by altered levels of circulating cytokines. Alcohol use and trauma may modulate immune activity, and few studies have investigated these factors in depressed patients. We aimed to explore the association between circulating peripheral cytokine levels and degree of depressive symptoms, taking trauma and alcohol into account. METHODS: The study was a cross-sectional assessment of patients at admission to a specialized psychiatric center in Norway. A total of 128 patients were included. Information was gathered using the self-administered questionnaires Beck Depression Inventory-II (BDI-II) and the Alcohol Use Disorders Identification Test (AUDIT), in addition to clinical interviews recording childhood or adult life trauma. Serum levels of the cytokines Interleukin-1beta (IL-1beta), Interleukin-1 Receptor Antagonist (IL-1RA), Tumor Necrosis Factor-alpha (TNF-alpha) and the chemokine Monocyte Chemoattractant Protein-1 (MCP-1) were assessed. A Luminex bead-based multiplex assay was used for cytokine measurements. Patient cytokine levels were compared to those of healthy volunteers by the Mann-Whitney U test. RESULTS: Levels of cytokines did not differ across patients with mild, moderate and severe depression. AUDIT score was not related to cytokine levels, but to level of depression. A history of trauma was related to higher levels of IL-1RA and TNF-alpha (p = 0.048 and p = 0.033, respectively), especially among the severely depressed. Serum levels of MCP-1 and TNF-alpha were significantly higher among psychiatric patients than in healthy volunteers. CONCLUSIONS: Findings indicate that depression was not related to levels of circulating cytokines among patients in treatment, but that traumatized patients had higher levels of IL-1RA and TNF-alpha than patients without trauma experience. The lack of relationship between cytokine level and depression was evident both in those without and with trauma. PMID- 29631539 TI - Planning for globally coordinated cessation of bivalent oral poliovirus vaccine: risks of non-synchronous cessation and unauthorized oral poliovirus vaccine use. AB - BACKGROUND: Oral polio vaccine (OPV) containing attenuated serotype 2 polioviruses was globally withdrawn in 2016, and bivalent OPV (bOPV) containing attenuated serotype 1 and 3 polioviruses needs to be withdrawn after the certification of eradication of all wild polioviruses to eliminate future risks from vaccine-derived polioviruses (VDPVs). To minimize risks from VDPVs, the planning and implementation of bOPV withdrawal should build on the experience with withdrawing OPV containing serotype 2 polioviruses while taking into account similarities and differences between the three poliovirus serotypes. METHODS: We explored the risks from (i) a failure to synchronize OPV cessation and (ii) unauthorized post-cessation OPV use for serotypes 1 and 3 in the context of globally-coordinated future bOPV cessation and compared the results to similar analyses for serotype 2 OPV cessation. RESULTS: While the risks associated with a failure to synchronize cessation and unauthorized post-cessation OPV use appear to be substantially lower for serotype 3 polioviruses than for serotype 2 polioviruses, the risks for serotype 1 appear similar to those for serotype 2. Increasing population immunity to serotype 1 and 3 poliovirus transmission using pre-cessation bOPV supplemental immunization activities and inactivated poliovirus vaccine in routine immunization reduces the risks of circulating VDPVs associated with non-synchronized cessation or unauthorized OPV use. CONCLUSIONS: The Global Polio Eradication Initiative should synchronize global bOPV cessation during a similar window of time as occurred for the global cessation of OPV containing serotype 2 polioviruses and should rigorously verify the absence of bOPV in immunization systems after its cessation. PMID- 29631541 TI - Increasing nontuberculous mycobacteria reporting rates and species diversity identified in clinical laboratory reports. AB - BACKGROUND: Nontuberculous Mycobacteria (NTM) are environmental microorganisms that can affect human health. A 2009-2010 occurrence survey of NTM in potable tap water samples indicated an increased recovery rate for many clinically significant species such as M. avium (30%) and M. abscessus (12%). To determine if these trends by species were mirrored in human infections, isolation rates of NTM species identified in clinical laboratory reports from four states were evaluated. METHOD: Clinical laboratory reports from the Mississippi, Missouri, Ohio, and Wisconsin Health Departments were used to investigate the species of NTM isolated from human specimens in 2014. The NTM positive specimen reports were tabulated for each species and complex/group. The number of reports by month were used to investigate seasonal trends. The 2014 isolation rates were compared to historic values to examine longitudinal trends. RESULTS: The positive rate of NTM specimens increased from 8.2 per 100,000 persons in 1994 to 16 per 100,000 persons in 2014 (or 13.3 per 100,000 after excluding Mycobacterium gordonae). Changes in NTM diversity were observed in complex/groups known to be clinically significant. Between 1994 and 2014 the rate implicating M. abscesses-chelonae group and M. avium complex increased by 322 and 149%, respectively. CONCLUSIONS: Based on public health data supplied by the four State's Health Departments and the 2014 U.S. population, 50,976 positive NTM specimen reports per year were projected for the nation; serving as an indicator for the national potential disease burden that year. PMID- 29631542 TI - Fat soluble vitamin levels in children with newly diagnosed celiac disease, a case control study. AB - BACKGROUND: In children diagnosed with celiac disease, fat soluble vitamin levels were aimed to be evaluated and it was intended to determine whether fat soluble vitamin levels were needed to be assessed routinely in these patients during diagnosis. METHODS: Between May 2015-May 2016, diagnosis symptoms of celiac patients (CD) in newly diagnosed pediatric group were questioned, fat soluble vitamin levels simultaneous with intestinal biopsies were evaluated. Vitamin levels were compared with those of healthy control group. RESULTS: A total of 52 patients involving 27 female (51.9%), 25 male (48.1%); and a total of 50 healthy control group including 25 female (50%), 25 male (50%) were evaluated. The average age of patients was 9 +/- 4.3 years, and their average weight was determined as 16.2 +/- 6.3 kg. Growth retardation was the most frequent symptom in our patients (61.5%). Abdominal pain (51.9%) and diarrhea (11.5%) are among the other most commonly seen symptoms. In the histological examination of patients, Marsh 3B n = 23 (45.1%) was mostly established. Vitamin A and vitamin D levels of patients were determined significantly lower compared to those of control group. Vitamin A and vitamin D deficiencies were identified significantly higher compared to those of healthy control group. Vitamin D insufficiency was observed in 48 patients (92.3%) and vitamin D deficiency was determined in 32 (61.5%) out of 48. Vitamin A deficiency was established in 17 (32.7%) patients. Vitamin E and vitamin K1 deficiency were determined in no patients. In the healthy control group, vitamin D deficiency was seen in 2 (4%) patients, vitamin D insufficiency was determined in 9 (18%) patients. Other vitamin levels were identified at normal levels in the healthy group. CONCLUSIONS: In newly diagnosed children with CD, a significant lowness was established in vitamin D and A. The evaluation of vitamin A and D levels will be helpful in the course of diagnosis in these patients. PMID- 29631543 TI - Investigation of the physical and psychosocial outcomes after living kidney donation - a multicenter cohort study (SoLKiD - Safety of Living Kidney Donors). AB - BACKGROUND: Over the last years, living kidney donation (LKD) has been established for patients with endstage renal failure as an alternative to post mortem donation, which is limited by organ scarcity and long lasting waiting periods. From an ethical perspective, the increase in LKD requires that donors' physical, psychological, and social harm has to be minimized as much as possible and the risk should not exceed the generally expected consequences of nephrectomy. Despite of numerous, mainly retrospective studies about the postoperative outcome of LKD over the last years from different countries, it becomes apparent that there is a lack of comprehensive prospective multicenter research in this field worldwide. Therefore, the main aim of the study is to examine the physical and psychosocial outcome of living kidney donors in a prospective design before and after transplantation in an interdisciplinary approach (surgery, nephrology, psychosocial medicine). METHODS/DESIGN: The goal of the study is to investigate such aspects as the impact of gender- and age specific factors on LKD outcome, donor outcome in correlation to the health status of the recipient, the medical and psychosocial risk of a healthy subject undergoing the LKD procedure. The study is carried out as a nationwide multicenter study. All adult living kidney donors with sufficient knowledge in the German, Russian, or Turkish language, informed consent, and place of residence in Germany are included. In a naturalistic design (cohort study), clinical data and self-report measures (questionnaires) of 320 donors are collected before and 8 weeks, 6 and 12 months after donation. Primary outcome parameters are the kidney function (estimated GFR) and the quality of life (SF 36) of the donor. Secondary outcome parameters are data about physical (e.g., wound healing, blood pressure) and psychosocial (fatigue, depression, anxiety, somatization) outcome after donation. DISCUSSION: Previous studies on the postoperative outcome of living kidney donors have methodological limitations and/or were carried out in countries with different healthcare systems, e.g. United States, Norway, Canada, United Kingdom. Thus, results cannot be generalized and are not particularly applicable to the risks of mainly caucasian living kidney donors in the German healthcare system. The study design overcomes these disadvantages in that it provides a prospective multicenter design. TRIAL REGISTRATION: German Clinical Trials Register DRKS00006552 (22 September 2014). PMID- 29631544 TI - Progressive multifocal leukoencephalopathy associated with thymoma with immunodeficiency: a case report and literature review. AB - BACKGROUND: The development of progressive multifocal leukoencephalopathy (PML) is associated with severe cellular immunosuppression. Good's syndrome (GS) is a rare immunodeficiency syndrome related to thymoma, with the development of humoral as well as cellular immunosuppression; however, there are few reports of PML due to GS. One report suggested that the neurological symptoms of PML related to thymoma may be improved by a reduction of immunosuppressive therapy for myasthenia gravis (MG). It is therefore necessary to identify the cause of immunodeficiency in patients with PML to enable an appropriate treatment strategy to be adopted. CASE PRESENTATION: A 47-year-old Japanese woman was admitted with aphasia and gait difficulty. She had an invasive thymoma that had been treated with repeated chemotherapy, including cyclophosphamide. She had also previously been diagnosed with MG (Myasthenia Gravis Foundation of America clinical classification IIa), but her ptosis and limb weakness had completely recovered. On admission, neurological examination revealed motor aphasia and central facial weakness on the right side. Laboratory studies showed severe lymphopenia, decreased CD4+ and CD8+ T cell and CD19+ B cell counts, and reduced levels of all subclasses of immunoglobulins, suggesting GS. Serology for human immunodeficiency virus (HIV) infection was negative. Brain magnetic resonance imaging showed asymmetric multifocal white matter lesions without contrast enhancement. Cerebrospinal fluid real-time polymerase chain reaction for JC virus was positive, showing 6,283,000 copies/mL. We made a diagnosis of non-HIV-related PML complicated with GS and probable chemotherapy-induced immunodeficiency. She then received intravenous immunoglobulin therapy, mirtazapine, and mefloquine, but died of sepsis 46 days after admission. CONCLUSIONS: It is necessary to consider the possibility of immunodeficiency due to GS in patients with PML related to thymoma. Neurologists should keep in mind the risk of PML in MG patients with thymoma, even if the MG symptoms are in remission, and should thus evaluate the immunological status of the patient accordingly. PMID- 29631545 TI - Significant proportion of acute hepatitis B in Poland in 2010-2014 attributed to hospital transmission: combining surveillance and public registries data. AB - BACKGROUND: Efficient control of acute hepatitis B requires identification of current transmission routes. Countries in Central-Eastern Europe including Poland attribute an important fraction of cases to nosocomial transmission, as opposed to Western European countries. However, due to possible multiple exposures during the incubation time such assignment may be debatable. This study aimed at assessing of most affected groups and current transmission pattern of acute hepatitis B. METHODS: We investigated exposures reported by acute hepatitis B cases notified to routine surveillance system in Poland in 2010-2014 in comparison to data on hospitalization rates in general population. RESULTS: Hospitalization during incubation time significantly increased the risk of HBV infection (RR 3.13, 95%CI 2.58-3.80). Overall hospitalization population attributable risk (PAR%) was 25.7% (95% CI 20.3%-31.1%) as compared to 35% of acute cases assigned to hospital transmission in surveillance database. PAR% increased from 9.5% (1.12%-17.8%) in the age group 25-34 to 41.1% (28.2% - 53.9%) among those 65 +. In addition, cases < 40 more frequently than the older ones reported history of injecting drugs and risky sexual contacts (25% vs 5%). 27% of men < 40 did not report any exposure at all, drawing attention to possible underreporting of risk behaviors. CONCLUSIONS: The distribution of probable transmission routes differed by age and gender. Further improvement of HBV control requires better coverage of vaccination in risk groups but also strengthening the blood-borne infections control in hospitals. PMID- 29631546 TI - Neural correlates of socio-emotional perception in 22q11.2 deletion syndrome. AB - BACKGROUND: Social impairments are described as a common feature of the 22q11.2 deletion syndrome (22q11DS). However, the neural correlates underlying these impairments are largely unknown in this population. In this study, we investigated neural substrates of socio-emotional perception. METHODS: We used event-related functional magnetic resonance imaging (fMRI) to explore neural activity in individuals with 22q11DS and healthy controls during the visualization of stimuli varying in social (social or non-social) or emotional (positive or negative valence) content. RESULTS: Neural hyporesponsiveness in regions of the default mode network (inferior parietal lobule, precuneus, posterior and anterior cingulate cortex and frontal regions) in response to social versus non-social images was found in the 22q11DS population compared to controls. A similar pattern of activation for positive and negative emotional processing was observed in the two groups. No correlation between neural activation and social functioning was observed in patients with the 22q11DS. Finally, no social * valence interaction impairment was found in patients. CONCLUSIONS: Our results indicate atypical neural correlates of social perception in 22q11DS that appear to be independent of valence processing. Abnormalities in the social perception network may lead to social impairments observed in 22q11DS individuals. PMID- 29631547 TI - Lower vitamin D levels in Saudi pregnant women are associated with higher risk of developing GDM. AB - BACKGROUND: Gestational diabetes mellitus (GDM) has serious consequences such as increased risks of preeclampsia, macrosomia and cesarean delivery. Even though the mechanistic basis of GDM has not been completely understood, several risk factors have been identified and one of these is vitamin D. However, the link between vitamin D deficiency and development of GDM is yet to be proven with certainty. METHODS: This study aimed to investigate the link between the incidence of GDM and serum vitamin D level in pregnant women of Saudi Arabia. 515 Saudi women (ages 18-46) in their 24-28th week of pregnancy, visiting various hospitals of Riyadh, participated in this study. Serum vitamin D and various biochemical and anthropometric parameters were determined in the first trimester and the recruits were screened for GDM by OGTT according to IADPSG criteria in their 2nd trimester. The association between vitamin D deficiency and development of GDM was calculated based on odds ratio of the incidence of GDM among vitamin D deficient and normal women. RESULTS: In this study cohort of 515 pregnant women, in the first trimester vitamin D deficiency (< 50 nmol/l) was detected in 425 (82.5%). On their 2nd visit (2nd trimester), 116 (27.7%) were diagnosed with GDM out of 419 with OGTT, according to IADPSG criteria. GDM risk was significantly higher among vitamin D deficient than non-deficient women (Odds Ratio: 2.87; Confidence Interval: 1.32-6.25; P = 0.008) even after adjusting for season, sun exposure and vitamin D intake (OR: 2.9; CI: 1.07-7.89). Of the various anthropometric and biochemical parameters, the GDM women differed significantly from non-GDM women with respect to serum levels of triglycerides (in mmol/l) (1.3 +/- 0.6; 1.5 +/- 0.6, p = 0.018) and fasting glucose (in mmol/l) [4.7 (4.3-5.2); 5.1 (4.6-5.6), p < 0.01]. Also, fasting glucose level in the 2nd trimester correlated inversely to serum vitamin D level determined during the 1st trimester (r = - 0.121; p = 0.014). CONCLUSIONS: Results of our study reveal a significantly higher risk of development of GDM among pregnant women having deficient vitamin D status. PMID- 29631548 TI - A novel mutation in the BCHE gene and phenotype identified in a child with low butyrylcholinesterase activity: a case report. AB - BACKGROUND: Butyrylcholinesterase (BChE), an ester hydrolase produced mainly by the liver, hydrolyzes certain short-acting neuromuscular blocking agents, like succinylcholine and mivacurium that are widely used during anesthesia. Patients with BChE deficiency are possibly in danger of postanesthetic apnea. Hereditary BChE deficiency results from the mutations of BCHE gene located on chromosome 3, 3q26.1-q26.2, between nucleotides 165,490,692-165,555,260. CASE PRESENTATION: This study describes a novel mutation in a child with BChE deficiency. In general, this child appeared healthy and well-developed with a normal appearance. However, the results of Wechsler Intelligence Scale showed that the full-scale intelligence quotient (FIQ) was 53, classified into the group with the minor defect. The BChE activity was 32.0 U/L, considerably lower than the normal lower limit (reference range: 5000-12,000 U/L). Sanger sequencing showed that there were 2 mutations in the exon 2 of BCHE gene of this child. One is a heterozygous mutation rs764588882 (NM_000055.3: c.401_402insA, p.Asn134Lysfs*23). The other one is a heterozygous mutation (NM_000055.3: c.73A > T, p.Lys25Ter) that has never been reported before. The two mutations lead to a premature stop of transcription. CONCLUSIONS: Double heterozygous recessive mutations are the cause of BChE deficiency of this boy in this study, including a novel mutation c.73A > T. Intellectual disability is a new phenotype that is probably associated with this mutation. PMID- 29631549 TI - Factors influencing choice of skilled birth attendance at ANC: evidence from the Kenya demographic health survey. AB - BACKGROUND: In Kenya, skilled attendance at delivery is well below the international target of 90% and the maternal mortality ratio is high at 362 (CI 254-471) per 100,000 live births despite various interventions. The preventative role of skilled attendance at delivery makes it a benchmark indicator for safe motherhood. METHODS: Maternal health data from the Service Provision Assessment Survey, a subset of the 2010 Kenya Demographic Health Survey was analyzed. Logistic regression models were employed using likelihood ratio test to explore association between choice of skilled attendance and predictor variables. RESULTS: Overall, 94.8% of women are likely to seek skilled attendance at delivery. Cost, education level, number of antenatal visits and sex of provider were strongly associated with client's intention to deliver with a skilled birth attendant at delivery. Women who reported having enough money set aside for delivery were 4.34 (p < 0.002, 95% CI: 1.73; 10.87) times more likely to seek skilled attendance. Those with primary education and above were 6.6 times more likely to seek skilled attendance than those with no formal education (p < 0.001, 95% CI: 3.66; 11.95). Women with four or more antenatal visits were 5.95 (p < 0.018, 95% CI: 1.35; 26.18) times more likely to seek skilled attendance. Compared to men, female providers impacted more on the client's plan (OR = 2.02 (p < 0.014, 95% CI: 1.35; 3.53). CONCLUSION: Interventions aimed at improving skilled attendance at delivery should include promotion of formal education of women and financial preparation for delivery. Whenever circumstances permit, women should be allowed to choose gender of preferred professional attendant at delivery. PMID- 29631550 TI - A rare case of spontaneous hepatic rupture in a pregnant woman. AB - BACKGROUND: Spontaneous hepatic rupture in pregnancy is a rare and life threatening event during the perinatal period. CASE PRESENTATION: We report a case of a 33-year-old woman with 36 + 6 weeks' gestation that present with elevated blood pressure before delivery, who was admitted to our hospital due to irregular abdominal pain. Diagnosed with abdominal paracentesis, the emergent caesarean section and laparotomy were performed. Postoperatively, the patient experienced 22-day intensive therapy in ICU and was transferred to the General Surgery Department in good physical condition without post-operative complications. CONCLUSIONS: This case indicates that making an accurate and timely diagnosis and taking multidisciplinary approach contribute to a successful clinical outcome. PMID- 29631551 TI - Trauma exposure and the mediating role of posttraumatic stress on somatic symptoms in civilian war victims. AB - BACKGROUND: It has been well documented that the exposure to war has a negative effect on the psychological health of civilian. However, little is known on the impact of war exposure on the physical health of the civilian population. In addition, the link between trauma exposure and somatic symptoms remain poorly understood. This cross-sectional study examined levels of somatic symptoms in the aftermath of war, and the mediating role of posttraumatic stress symptoms in the relationship between trauma exposure and somatic symptoms. METHODS: Civilian war survivors (N = 142) from Kosovo were assessed for potentially traumatic events, posttraumatic stress symptoms, and somatic symptoms. Data were analyzed using mediation analyses. Posttraumatic stress disorder (PTSD) symptoms were categorized based on King's four factor model (Psychol Assessment. 10: 90-96, 1998). RESULTS: Participants reported on average more than 5 types of traumatic exposure. The cut-off indicative for PTSD was exceeded by 26.1% of participants. Symptom levels of PTSD were associated with somatic symptoms. The relationship between trauma exposure and somatic symptoms was partly mediated by the active avoidance and hyperarousal symptom clusters of PTSD. CONCLUSION: Active avoidance and hyperarousal symptoms seem to play a key role in traumatized people suffering from somatic symptoms. PMID- 29631552 TI - Choroidal perfusion abnormalities associated with Acute Posterior Multifocal Placoid Pigment Epitheliopathy: a case report. AB - BACKGROUND: Indocyanine Green Angiography (ICG-A) and Enhanced Depth Imaging Spectral-Domain Optical Coherence Tomography (EDI-OCT) are essential imaging techniques for diagnosis, management and understanding of the pathophysiology of many chorioretinal diseases. Herein, we report the ICG-A and EDI-OCT findings from a case of Acute Posterior Multifocal Placoid Pigment Epitheliopathy (APMPPE), in which these imaging techniques enable the visualization of more diagnostic details than those observable with other widely used diagnostic tools. CASE PRESENTATION: A 60-year-old white female presented with bilateral blurred vision for few days. Fundus examination showed multiple, yellow-white placoid lesions at the posterior pole of both eyes. The placoid lesions were also evident on Spectral-Domain Optical Coherence Tomography (SD-OCT), Fluorescein Angiography (FA), Fundus Autofluorescence (AF), and ICG-A. A complete ophthalmologic examination was performed and the diagnosis of APMPPE was made based on imaging and clinical features. Notably, all the lesions detected by FA, AF and OCT corresponded to focal areas of hypofluorescence seen on ICG-A, whereas several additional hypofluorescent areas that were not associated with FA, AF or OCT abnormalities, were also detected with ICG-A. On follow-up, the regression of outer retinal abnormalities detected on OCT preceded the restoration of choroidal perfusion abnormalities in the corresponding locations on ICG-A. This long standing choroidal perfusion defect could not be detected with OCT. EDI-OCT scans revealed characteristic choriocapillaris changes beneath the placoid lesions and an increase in choroidal thickness during the acute phase, with subsequent decrease in the inactive stage of the disease. CONCLUSION: Our findings show that ICG-A and EDI-OCT provide detailed morphologic information of choroidal abnormalities in APMPPE and allow accurate evaluation of definitive resolution of the lesions. Moreover, they support the acute choroidal hypoperfusion as the primary mechanism overlying the pathogenesis of the disease, and suggest that the non-perfused areas may extend beyond the damage of the outer retina. PMID- 29631553 TI - Prospective, randomized, double-blind, placebo-controlled phase IIa clinical trial on the effects of an estrogen-progestin combination as add-on to inpatient psychotherapy in adult female patients suffering from anorexia nervosa. AB - BACKGROUND: There is a need for novel treatment approaches in anorexia nervosa (AN). While there is broad knowledge with regard to altered appetite regulation and neuropsychological deficits in AN patients on the one hand, and the effects of estrogen replacement upon neuropsychological performance in healthy subjects on the other, up to now, no study has implemented estrogen replacement in AN patients, in order to examine its effects upon AN-associated and general psychopathology, neuropsychological performance and concentrations of peptide components of the hypothalamus-pituitary-adrenal (HPA) axis and within appetite regulating circuits. METHODS: This is a randomized placebo-controlled clinical trial on the effects of a 10-week oral estrogen replacement (combination of ethinyl estradiol 0.03 mg and dienogest 2 mg) in adult female AN patients. The primary target is the assessment of the impact of sex hormone replacement upon neuropsychological performance by means of a neuropsychological test battery consisting of a test for verbal intelligence, the Trail making test A and B, a Go/No-go paradigm with food cues and the Wisconsin Card Sorting Test. Secondary targets include a) the examination of safety and tolerability (as mirrored by the number of adverse events), b) assessments of the impact upon eating disorder specific psychopathology by means of the Eating Disorder Examination Questionnaire (EDE-Q) and the Eating Disorder Inventory-2 (EDI-2), c) the influence upon anxiety using the State-Trait-Anxiety Inventory (STAI), d) assessments of plasma cortisol levels during a dexamethasone-suppression test and appetite-regulating plasma peptides (ghrelin, leptin, insulin, glucose) during an oral glucose tolerance test and, e) a possible impact upon the prescription of antidepressants. DISCUSSION: This is the first study of its kind. There are no evidence-based psychopharmacological options for the treatment of AN. Thus, the results of this clinical trial may have a relevant impact on future treatment regimens. Novel approaches are necessary to improve rates of AN symptom remission and increase the rapidity of treatment response. Identifying the underlying biological (e.g. neuroendocrinological) factors that maintain AN or may predict patient treatment response represent critical future research directions. Continued efforts to incorporate novel pharmacological aspects into treatments will increase access to evidence-based care and help reduce the burden of AN. TRIAL REGISTRATION: European Clinical Trials Database, EudraCT number 2015-004184 36, registered November 2015; ClinicalTrials.gov Identifier: NCT03172533 , retrospectively registered May 2017. PMID- 29631555 TI - Gender-specific contribution of cardiometabolic index and lipid accumulation product to left ventricular geometry change in general population of rural China. AB - BACKGROUND: Despite current interest in the unfavorable impact of cardiometabolic index (CMI) and lipid accumulation product (LAP) on diabetes and cardiovascular risk, information regarding the relation of CMI and LAP to left ventricular (LV) geometry has not been specifically addressed. We aimed to examine the hypothesis: (1) CMI and LAP represent an independent determinant of LV remodeling in general population of rural China; (2) there are gender differences in obesity-related alterations in terms of LV morphology. METHODS: The sample for this cross sectional analysis included 11,258 participants (mean age 53.9 years; 54.0% females) who underwent assessment of basic metabolic and anthropometric parameters in rural areas of northeast China. Comprehensive echocardiography defined LV geometric pattern was determined according to left ventricular mass index and relative wall thickness. RESULTS: The prevalence rate of eccentric and concentric LV hypertrophy (LVH) presented a proportional increase with elevated quartiles of CMI and LAP in a dose-response manner (all P < 0.005). When CMI and LAP were entered as a continuous variable in multivariable adjusted model, we observed the independent effect of 1 SD increment in CMI and LAP with the probability of eccentric and concentric LVH, while this relationship was more pronounced in females than in males. Likewise, the odds ratio comparing the top versus bottom quartiles of CMI were 2.105 (95%CI:1.600-2.768) for eccentric LVH and 2.236 (95%CI:1.419-3.522) for concentric LVH in females. Males in the highest CMI quartile exhibited a nearly doubled (OR:1.724, 95%CI:1.287-2.311) and 1.523 fold (95%CI:1.003-2.313) greater risk of eccentric and concentric LVH, respectively. Increasing LAP entailed a higher possibility of eccentric LVH by a factor of 3.552 and 1.768 in females and males, respectively. In contrast to females, where LAP fourth quartile and concentric LVH were positively associated (OR:2.544, 95%CI:1.537-4.209), higher LAP did not correlate with concentric LVH in males (OR:1.234, 95%CI:0.824-1.849). CONCLUSIONS: CMI and LAP give rise to a new paradigm of accounting for gender difference in obesity-related abnormal LV geometry, an effect that was substantially greater in females. These two indices, acting in concert, may also be advantageous prognostically for refining cardiovascular risk stratification in individuals with LV remodeling. PMID- 29631556 TI - Clostridium perfringens panophthalmitis and orbital cellulitis: a case report. AB - BACKGROUND: Clostridium perfringens is an uncommon pathogen in endophthalmitis, causing rapid destruction of ocular tissues. Clostridium perfringens infection typically occurs after penetrating injury with soil-contaminated foreign bodies. CASE REPORT: Here, we describe the case of a 17-year-old male who sustained a penetrating injury with a metallic intraocular foreign body and who rapidly developed severe C. perfringens panophthalmitis with orbital cellulitis. He was managed by systemic and intravitreal antibiotics, resulting in preservation of the globe, but a poor visual outcome. CONCLUSION: Clostridial endophthalmitis secondary to penetrating injuries is a fulminant infection, almost always resulting in loss of the globe in the case of advanced infection. When feasible, early vitrectomy and intravitreal antibiotics should be considered in patients with penetrating eye injuries with contaminated foreign bodies. PMID- 29631554 TI - CTHRC1 induces non-small cell lung cancer (NSCLC) invasion through upregulating MMP-7/MMP-9. AB - BACKGROUND: The strong invasive and metastatic nature of non-small cell lung cancer (NSCLC) leads to poor prognosis. Collagen triple helix repeat containing 1 (CTHRC1) is involved in cell migration, motility and invasion. The object of this study is to investigate the involvement of CTHRC1 in NSCLC invasion and metastasis. METHODS: A proteomic analysis was performed to identify the different expression proteins between NSCLC and normal tissues. Cell lines stably express CTHRC1, MMP7, MMP9 were established. Invasion and migration were determined by scratch and transwell assays respectively. Clinical correlations of CTHRC1 in a cohort of 230 NSCLC patients were analysed. RESULTS: CTHRC1 is overexpressed in NSCLC as measured by proteomic analysis. Additionally, CTHRC1 increases tumour cell migration and invasion in vitro. Furthermore, CTHRC1 expression is significantly correlated with matrix metalloproteinase (MMP)7 and MMP9 expression in sera and tumour tissues from NSCLC. The invasion ability mediated by CTHRC1 were mainly MMP7- and MMP9-dependent. MMP7 or MMP9 depletion significantly eradicated the pro-invasive effects mediated by CTHRC1 on NSCLC cells. Clinically, patients with high CTHRC1 expression had poor survival. CONCLUSIONS: CTHRC1 serves as a pro-metastatic gene that contributes to NSCLC invasion and metastasis, which are mediated by upregulated MMP7 and MMP9 expression. Targeting CTHRC1 may be beneficial for inhibiting NSCLC metastasis. PMID- 29631557 TI - Relationship between combination antiretroviral therapy regimens and diabetes mellitus-related comorbidities among HIV patients in Gaborone Botswana. AB - BACKGROUND: Combination antiretroviral therapy (cARTs) regiments are known to prolong the recipients' life even though they are risk factors for diabetes mellitus-related comorbidities (DRCs). We sought to: (i) examine cART relationship with DRCs among patients attending HIV clinics in Gaborone, Botswana (which cART regimens are associated with shorter/longer time to the event), (ii) characterize patients' underlying biomedical and demographic risk factors of DRC and identify the most important, (iii) investigate survival of patients on different cART regimens in the presence of these risk factors. METHODS: Data from two major HIV clinics in Botswana were reviewed. Relationships between different cART regimens and DRCs were investigated among 531 recipients. Recipients' DRC risk factors were identified. Cox regression model was run. Unadjusted and adjusted hazard ratios were computed, and hazard and survival functions for different cART regimens were plotted. RESULTS: Major findings were: patients on second- and third-line cART were less likely to develop DRCs earlier than those on first-line cART. Patients with CD4 count <= 200 cells/mm3 at cART initiation were more likely to develop DRCs earlier than those who had CD4 count > 200 cells/mm3. Overweight patients at cART initiation had a higher risk of developing DRCs earlier than those who had normal body mass index. Males had a lower risk of developing DRCs earlier than females. CONCLUSION: The risk of new onset of DRC among cART recipients is a function of the type of cART regimen, duration of exposure and patients' underlying biomedical and demographic DRC risk factors. The study has provided a survival model highlighting DRCs' significant prognostic factors to guide clinical care, policy and management of recipients of cARTs. Further studies in the same direction will likely improve the survival to the development of DRC of every cART recipient in this community. PMID- 29631558 TI - Patients' experiences and perceptions on associates of TB treatment adherence: a qualitative study on DOTS service in public health centers in Addis Ababa, Ethiopia. AB - BACKGROUND: Ethiopia is one of the countries with the highest TB burdens in the world. There are multitude of challenges related to the implementation of DOTS and adherence to treatment. This study aimed to assess patients' experiences and perceptions on associates of TB treatment adherence in Addis Ababa, Ethiopia. METHODS: A phenomenological approach was employed to generate qualitative data through the in-depth interview of TB patients attending DOTS in two public health centers. A total of ten participants, who were purposively selected till conceptual saturation was reached, were interviewed using topic guides prepared in line with the study objectives. Interviews were tape-recorded, transcribed verbatim, and translated to English. Open Code software was used to facilitate analysis. Themes pertaining to patient, health service, therapeutic, and socioeconomic factors were developed, and findings were presented accordingly. RESULTS: Experience of missing medications was reported by a single participant. Most informants pointed out that TB is transmitted through coughing and expectorate, and prevented by letting in open air in public gatherings. However, most of them stated cold air and few mentioned contaminated food as causes of TB. Perceived risk of non-adherence to medication was among recounted reasons behind treatment adherence. Some informants also recalled to have had the intention of withdrawing medication due to perceived wellness, which they actually did not change into action. Most of the participants generally had smooth relationships with their DOTS service providers. Even if more than half of the patients preferred follow-ups by the same professional, most received DOTS service by two or more service providers. CONCLUSIONS: TB treatment non-adherence was not found to be a major challenge among the study participants. Perceived risk and wellness were implied to be responsible factors for adherence. Albeit the fact that few informants encountered unethical behaviors by some health professionals, interviewed patients generally had positive evaluation of the patient-provider relationship and the DOTS service obtained. There is a need to train and monitor DOTS service providers and ensure the provision of DOTS service by the same provider throughout the treatment period of a given patient. PMID- 29631559 TI - Subsistence difficulties are associated with more barriers to quitting and worse abstinence outcomes among homeless smokers: evidence from two studies in Boston, Massachusetts. AB - BACKGROUND: Three-quarters of homeless people smoke cigarettes. Competing priorities for shelter, food, and other subsistence needs may be one explanation for low smoking cessation rates in this population. We analyzed data from two samples of homeless smokers to examine the associations between subsistence difficulties and 1) smoking cessation readiness, confidence, and barriers in a cross-sectional study, and 2) smoking abstinence during follow-up in a longitudinal study. METHODS: We conducted a survey of homeless smokers (N = 306) in 4/2014-7/2014 and a pilot randomized controlled trial (RCT) for homeless smokers (N = 75) in 10/2015-6/2016 at Boston Health Care for the Homeless Program. In both studies, subsistence difficulties were characterized as none, low, or high based on responses to a 5-item scale assessing the frequency of past month difficulty finding shelter, food, clothing, a place to wash, and a place to go to the bathroom. Among survey participants, we used linear regression to assess the associations between subsistence difficulty level and readiness to quit, confidence to quit, and a composite measure of perceived barriers to quitting. Among RCT participants, we used repeated-measures logistic regression to examine the association between baseline subsistence difficulty level and carbon monoxide-defined brief smoking abstinence assessed 14 times over 8 weeks of follow-up. Analyses adjusted for demographic characteristics, substance use, mental illness, and nicotine dependence. RESULTS: Subsistence difficulties were common in both study samples. Among survey participants, greater subsistence difficulties were associated with more perceived barriers to quitting (p < 0.001) but not with cessation readiness or confidence. A dose-response relationship was observed for most barriers, particularly psychosocial barriers. Among RCT participants, greater baseline subsistence difficulties predicted less smoking abstinence during follow-up in a dose-response fashion. In adjusted analyses, individuals with the highest level of subsistence difficulty had one-third the odds of being abstinent during follow-up compared to those without subsistence difficulties (OR 0.33, 95% CI 0.11-0.93) despite making a similar number of quit attempts. CONCLUSIONS: Homeless smokers with greater subsistence difficulties perceive more barriers to quitting and are less likely to do so despite similar readiness, confidence, and attempts. Future studies should assess whether addressing subsistence difficulties improves cessation outcomes in this population. TRIAL REGISTRATION: ClinicalTrials.gov: NCT02565381 . PMID- 29631560 TI - Bleeding in patients who underwent scheduled second-look endoscopy 5 days after endoscopic submucosal dissection for gastric lesions. AB - BACKGROUND: Bleeding after endoscopic submucosal dissection (ESD) in antithrombotic drug users is still one of the important issues to be solved. We performed scheduled second-look endoscopy (SLE) 5 days after ESD, when the resumption of antithrombotic agents is assumed to have achieved a steady state, rather than on the day after ESD. We investigated bleeding incidence and the status of ulcers. METHODS: A total of 299 lesions in 299 patients subjected to ESD for gastric neoplasms were enrolled. A double dose of proton pump inhibitors was administered after ESD. SLE was planned 5 days after ESD. Post-ESD bleeding occurring before SLE was defined as early phase post-ESD bleeding, whereas bleeding after SLE was defined as later phase post-ESD bleeding. Forrest IIa and IIb ulcers are defined as high-risk ulcers requiring prophylactic hemostasis. We investigated risk factors for post-ESD bleeding, particularly focusing on the use of antithrombotic agents and the presence of high-risk ulcers requiring prophylactic hemostasis during SLE. RESULTS: Under a double dose of proton pump inhibitors, early phase post-ESD bleeding occurred in 2.3% of non-users (5/218) and 6.2% of users of antithrombotic agents (5/81). High-risk ulcers were found in 19.0% of the cases during scheduled SLE (55/289). Later phase bleeding occurred in 5.5% of cases [2.8% of non-users (6/213) and 13.2% of users of antithrombotic agents (10/76)]. Cox regression analysis revealed that the risk factor for post ESD bleeding was antithrombotic treatment (HR: 3.56; 95% CI: 1.63-8.02, p = 0.002) alone. Among patients with high-risk ulcers, a statistically significant increase in bleeding was observed in the later phase in patients under antithrombotic therapy, compared to those not receiving any antithrombotic agents (p = 0.001). CONCLUSIONS: Antithrombotic treatment is a risk factor for post-ESD bleeding despite SLE being scheduled 5 days after ESD. Later phase post-ESD bleeding was observed in 13.2% of the patients under antithrombotic treatment even after prophylactic hemostasis for high-risk ulcers. TRIAL REGISTRATION: This study was registered in the UMIN Clinical Trials Registry System ( 000023306 ). Retrospectively registered on 23rd July 2016. PMID- 29631561 TI - Comparative effectiveness of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in chemoprevention of hepatocellular carcinoma: a nationwide high-risk cohort study. AB - BACKGROUND: Research has revealed that angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) may prevent cancers such as hepatocellular carcinoma (HCC). The comparative chemopreventive effects of ACEIs and ARBs in high-risk populations with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection have yet to be investigated. METHODS: From 2005 to 2014, high-risk HBV and HCV cohorts of hypertensive patients without HCC history were recruited from three linked national databases of Taiwan, and were classified into two groups based on the ACEI or ARB exposure within the initial six months after initiating antiviral agent. Intergroup differences in clinical characteristics and duration of drug exposure within study period were evaluated. HCC-free survival was compared using the log-rank test. Multivariate Cox regression including time-dependent variables for the use of ACEIs or ARBs and other medications was applied to adjust for confounders. RESULTS: Among the 7724 patients with HBV and 7873 with HCV, 46.3% and 42.5%, respectively, had an initial exposure to ACEIs or ARBs. The median durations of exposure were 36.4 and 38.9 months for the HBV and HCV cohorts, respectively. The median durations of ACEI or ARB use during study period between initial exposure and nonexposure groups were 41.8 vs. 18.3 months and 46.4 vs. 22.7 months for the HBV and HCV cohorts, respectively. No significant difference was observed in HCC risk within 7 years between the initial exposure and non-exposure groups. After adjustment for comorbidities, namely liver cirrhosis, diabetes mellitus (DM), and hyperlipidemia, and medications, namely aspirin, metformin, and statins, the hazard ratios (HRs) for ACEI or ARB exposure for HCC risk were 0.97 (95% confidence interval [CI]: 0.81-1.16) and 0.96 (0.80-1.16) in the HBV and HCV cohorts, respectively. In the HCV cohort, the increased HCC risk was associated with ACEI or ARB use in patients without cirrhosis, DM, and hyperlipidemia (HR: 4.53, 95% CI: 1.46-14.1). CONCLUSION: Compared with other significant risk and protective factors for HCC, ACEI or ARB use in the HBV and HCV cohorts was not associated with adequate protective effectiveness under standard dosages and may not be completely safe. PMID- 29631562 TI - Comparative analysis of histologically classified oligodendrogliomas reveals characteristic molecular differences between subgroups. AB - BACKGROUND: Molecular data of histologically classified oligodendrogliomas are available offering the possibility to stratify these human brain tumors into clinically relevant molecular subtypes. METHODS: Gene copy number, mutation, and expression data of 193 histologically classified oligodendrogliomas from The Cancer Genome Atlas (TCGA) were analyzed by well-established computational approaches (unsupervised clustering, statistical testing, network inference). RESULTS: We applied hierarchical clustering to tumor gene copy number profiles and revealed three molecular subgroups within histologically classified oligodendrogliomas. We further screened these subgroups for molecular glioma markers (1p/19q co-deletion, IDH mutation, gain of chromosome 7 and loss of chromosome 10) and found that our subgroups largely resemble known molecular glioma subtypes. We excluded glioblastoma-like tumors (7a10d subgroup) and derived a gene expression signature distinguishing histologically classified oligodendrogliomas with concurrent 1p/19q co-deletion and IDH mutation (1p/19q subgroup) from those with predominant IDH mutation alone (IDHme subgroup). Interestingly, many signature genes were part of signaling pathways involved in the regulation of cell proliferation, differentiation, migration, and cell-cell contacts. We further learned a gene regulatory network associated with the gene expression signature revealing novel putative major regulators with functions in cytoskeleton remodeling (e.g. APBB1IP, VAV1, ARPC1B), apoptosis (CCNL2, CREB3L1), and neural development (e.g. MYTIL, SCRT1, MEF2C) potentially contributing to the manifestation of differences between both subgroups. Moreover, we revealed characteristic expression differences of several HOX and SOX transcription factors suggesting the activity of different glioma stemness programs in both subgroups. CONCLUSIONS: We show that gene copy number profiles alone are sufficient to derive molecular subgroups of histologically classified oligodendrogliomas that are well-embedded into general glioma classification schemes. Moreover, our revealed novel putative major regulators and characteristic stemness signatures indicate that different developmental programs might be active in these subgroups, providing a basis for future studies. PMID- 29631563 TI - Alterations of serum macro-minerals and trace elements are associated with major depressive disorder: a case-control study. AB - BACKGROUND: Major depressive disorder (MDD) is a mixed disorder with the highly irregular course, inconsistent response to treatment and has no well-known mechanism for the pathophysiology. Major causes of depression are genetic, neurobiological, and environmental. However, over the past few years, altered serum levels of macro-minerals (MM) and trace elements (TE) have been recognized as major causative factors to the pathogenesis of many mental disorders. The purpose of this study was to determine the serum levels of MM (calcium and magnesium) and TE (copper, iron, manganese, selenium, and zinc) in MDD patients and find out their associations with depression risk. METHODS: This prospective case-control study recruited 247 patients and 248 healthy volunteers matched by age and sex. The serum levels of MM and TE were analyzed by atomic absorption spectroscopy (AAS). Statistical analysis was performed with independent sample t tests and Pearson's correlation test. RESULTS: We found significantly decreased concentrations of calcium and magnesium, iron, manganese, selenium, and zinc in MDD patients compared with control subjects (p < 0.05). But the concentration of copper was significantly increased in the patients than control subjects (p < 0.05). Data obtained from different inter-element relations in MDD patients and control subjects strongly suggest that there is a disturbance in the element homeostasis. CONCLUSION: Our study suggests that altered serum concentrations of MM and TE are major contributing factors for the pathogenesis of MDD. Alterations of these elements in serum levels of MDD patients arise independently and they may provide a prognostic tool for the assessment of depression risk. PMID- 29631564 TI - The analgesic efficacy of subcostal transversus abdominis plane block with Mercedes incision. AB - BACKGROUND: Conventional perioperative analgesic modalities (e.g. opioids, epidural analgesia) have their own drawbacks, which limit their clinical application. This study investigated the opioid-sparing effectsof the oblique subcostal transversus abdominis plane (OSTAP) blockade with ropivacaine for the patients undergoing open liver resection with a Mercedes incision. METHODS: 126 patients who were scheduled for open liver resection were enrolled in this study. Patients were randomly assigned to receive bilateral ultrasound-guided OSTAPblocks with either 0.375% ropivacaine (groupT) or 0.9% isotonic saline (group C). Both groups also received intravenous patient-controlled analgesia and intravenous 40 mg parecoxib every 12 h for a total of 3 days. Preoperative and intraoperative parameters, plus intraoperative and postoperative cumulative sufentanil consumption, were recorded. RESULTS: 70 patients were enrolled in the study finally. There were no significant differences between the two groups with respect to preoperative parameters, and surgical and anesthetic characteristics. The intraoperative sufentanil use, cumulative sufentanil consumption at 5 min after extubation, 2 h, 4 h,12 h and 24 h after operation in group T was significantly less than that in group C (P = 0.001, 0.001, 0.000, 0.000, 0.001 and 0.044, respectively). Compared with group C, postoperative NRS pain scores at rest were significantly lower at 2 h and 4 h postoperatively in group T (P = 0.04and 0.02, respectively); NRS scores at the time of coughing were also significantly lower in group T than in group C at all time points except 5 min after extubation (all P < 0.001). Furthermore, compared with group C, the number of intraoperative vasodilator use, the extubation time and the incidence of nausea was reduced in group T. CONCLUSION: Ultrasound-guided OSTAP block with ropivacaine can significantly decrease the perioperative cumulative dosage of analgesics and improve analgesic effect without obvious side effects for the patients who underwent an open liver resection with Mercedes incision when compared tothe ultrasound-guided OSTAP block with saline. TRIAL REGISTRATION: The study protocol was registered at http://www.chictr.org.cn (ChiCTR-TRC- 14004827) on February 19, 2014. PMID- 29631565 TI - MDR1 overexpression combined with ERG11 mutations induce high-level fluconazole resistance in Candida tropicalis clinical isolates. AB - BACKGROUND: Marked increases in fluconazole resistance in Candida tropicalis have been recently reported. In this study, the molecular mechanisms behind fluconazole resistance were investigated. METHODS: Twenty-two C. tropicalis clinical isolates, including 12 fluconazole-resistant isolates and 10 fluconazole susceptible isolates, were collected from a tertiary care teaching hospital in Beijing between 2013 and 2017. Antifungal susceptibility testing, multilocus sequence typing, ERG11 amplification and sequencing, quantitative real-time reverse transcription-polymerase chain reaction (ERG11, UPC2, MDR1, and CDR1), and clinical data collection were performed for all C. tropicalis isolates. RESULTS: Multilocus sequence typing revealed that the 10 fluconazole-susceptible isolates and 12 fluconazole-resistant isolates were divided into nine and seven diploid sequence types, respectively. Of the 12 patients with fluconazole resistant isolates, six had been previously exposed to azole and four had a fatal outcome. Y132F and S154F amino acid substitutions in Erg11p were found in all fluconazole-resistant isolates except one. MDR1 gene overexpression was identified in fluconazole-resistant isolates. In particular, seven high-level fluconazole resistant isolates (minimum inhibitory concentration >= 128 mg/L) and three pan-azole resistant isolates were identified. CDR1, ERG11, and UPC2 gene expression levels in fluconazole-resistant isolates were not significantly different from the control isolates (P = 0.262, P = 0.598, P = 0.114, respectively). CONCLUSIONS: This study provides evidence that the combination of MDR1 gene overexpression and ERG11 missense mutations is responsible for high level fluconazole resistance and pan-azole resistance in C. tropicalis clinical isolates. To the best of our knowledge, this is the first study investigating the relationship between MDR1 gene overexpression and increased fluconazole resistance. PMID- 29631566 TI - Transcriptomic analysis reveals vacuolar Na+ (K+)/H+ antiporter gene contributing to growth, development, and defense in switchgrass (Panicum virgatum L.). AB - BACKGROUND: Intracellular Na+ (K+)/H+ antiporters (NHXs) have pivotal functions in regulating plant growth, development, and resistance to a range of stresses. To gain insight into the molecular events underlying their actions in switchgrass (Panicum virgatum L.), we analyzed transcriptomic changes between PvNHX1 overexpression transgenic lines and wild-type (WT) plants using RNA sequencing (RNA-seq) technology. RESULTS: The comparison of transcriptomic data from the WT and transgenic plants revealed a large number of differentially expressed genes (DEGs) in the latter. Gene ontology (GO) and KEGG pathway analyses showed that these DEGs were associated with a wide range of functions, and participated in many biological processes. For example, we found that PvNHX1 had an important role in plant growth through its regulation of photosynthetic activity and cell expansion. In addition, PvNHX1 regulated K+ homeostasis, cell expansion and pollen development, indicating that it has unique and specific roles in flower development. We also found that transgenic switchgrass exhibited a higher level of transcription of defense-related genes, especially those involved in disease resistance. CONCLUSION: We showed that PvNHX1 had an important role in plant growth and development through its regulation of photosynthetic activity, cell expansion, K+ homeostasis, and pollen development. Additionally, PvNHX1 overexpression activated a complex signal transduction network in response to various biotic and abiotic stresses. In relation to plant growth, development, and defense responses, PvNHX1 also had a vital regulatory role in the formation of a series of plant hormones and transcription factors (TFs). The reliability of the RNA-seq data was confirmed by quantitative real-time PCR. Our data provide a valuable foundation for further research into the molecular mechanisms and physiological roles of NHXs in plants. PMID- 29631567 TI - Is sleep disturbance in patients with chronic pain affected by physical exercise or ACT-based stress management? - A randomized controlled study. AB - BACKGROUND: Most people suffering chronic pain are plagued by sleeping difficulties. Cognitive behaviour therapy has produced promising results for insomnia comorbid with chronic pain, but the access to such treatment is often limited. Over the last ten years, interventions aiming to increase cognitive flexibility and physical activity have been assumed to be effective treatments for a variety of conditions, including insomnia and chronic pain. If proven effective, these treatments could constitute the first steps in a stepped care model for chronic pain and insomnia. METHODS: Two hundred ninety-nine chronic pain subjects were randomized to Exercise, ACT-based stress management (ACT-bsm), or an active control group. Two hundred thirty-two participants (78%) received their allocated intervention at least to some extent. These participants were evaluated using mixed model analyses for changes in sleep (Insomnia Severity Index, ISI), pain intensity, depression, and anxiety immediately after treatment, six months and twelve months after treatment. RESULTS: The mixed model analyses revealed that Exercise had a positive effect on insomnia compared with the control group and the effect remained after 12 months. No clear effect (i.e., both for completers and for completers together with treatment non-completers) upon ISI was found for the ACT-bsm. Pain intensity decreased significantly both in the exercise group and in the control group. For the two psychological variables (i.e., symptoms of anxiety and depression) were found significant improvements over time but no group differences. The treatment effects for ISI and pain intensity did not reach clinical significance per definitions presented in other relevant studies. CONCLUSIONS: Beneficial significant effects on insomnia was confirmed in the exercise condition. However, these changes were probably not clinically important. For pain intensity a general decrease was found in the Exercise condition and in the control condition, while no change occurred in ACT-bsm. No group differences were found for the two psychological variables. TRIAL REGISTRATION: The study was registered in Clinical Trials (Trial registration: ClinicalTrials.gov Id: NCT02399644 , 21 January 2015, retrospectively registered). PMID- 29631568 TI - A school-based interdisciplinary approach to promote health and academic achievement among children in a deprived neighborhood: study protocol for a mixed methods evaluation. AB - BACKGROUND: The large number of children that grow up in poverty is concerning, especially given the negative developmental outcomes that can persist into adulthood. Poverty has been found as a risk factor to negatively affect academic achievement and health outcomes in children. Interdisciplinary interventions can be an effective way to promote health and academic achievement. The present study aims to evaluate a school-based interdisciplinary approach on child health, poverty, and academic achievement using a mixed-method design. Generally taken, outcomes of this study increase the knowledge about effective ways to give disadvantaged children equal chances early in their lives. METHODS: An observational study with a mixed-methods design including both quantitative and qualitative data collection methods will be used to evaluate the interdisciplinary approach. The overall research project exists of three study parts including a longitudinal study, a cross-sectional study, and a process evaluation. Using a multi-source approach we will assess child health as the primary outcome. Child poverty and child academic achievement will be assessed as secondary outcomes. The process evaluation will observe the program's effects on the school environment and the program's implementation in order to obtain more knowledge on how to disseminate the interdisciplinary approach to other schools and neighborhoods. DISCUSSION: The implementation of a school-based interdisciplinary approach via primary schools combining the cross-sectoral domains health, poverty, and academic achievement is innovative and a step forward to reach an ethnic minority population. However, the large variety of the interventions and activities within the approach can limit the validity of the study. Including a process evaluation will therefore help to improve the interpretation of our findings. In order to contribute to policy and practice focusing on decreasing the unequal chances of children growing up in deprived neighborhoods, it is important to study whether the intervention leads to positive developmental outcomes in children. TRIAL REGISTRATION: ( NTR 6571 ) (retrospectively registered on August 4, 2017). PMID- 29631569 TI - Avicequinone B sensitizes anoikis in human lung cancer cells. AB - BACKGROUND: During metastasis, cancer cells require anokis resistant mechanism to survive until reach the distant secondary tissues. As anoikis sensitization may benefit for cancer therapy, this study demonstrated the potential of avicequinone B, a natural furanonaphthoquinone found in mangrove tree (Avicenniaceae) to sensitize anoikis in human lung cancer cells. METHODS: Anoikis inducing effect was investigated in human lung cancer H460, H292 and H23 cells that were cultured in ultra-low attachment plate with non-cytotoxic concentrations of avicequinone B. Viability of detached cells was evaluated by XTT assay at 0-24 h of incubation time. Soft agar assay was performed to investigate the inhibitory effect of avicequinone B on anchorage-independent growth. The alteration of anoikis regulating molecules including survival and apoptosis proteins were elucidated by western blot analysis. RESULTS: Avicequinone B at 4 MUM significantly induced anoikis and inhibited proliferation under detachment condition in various human lung cancer cells. The reduction of anti-apoptotic proteins including anti apoptotic protein B-cell lymphoma 2 (Bcl-2) and myeloid cell leukemia 1 (Mcl-1) associating with the diminution of integrin/focal adhesion kinase (FAK)/Proto oncogene tyrosine-protein kinase (Src) signals were detected in avicequinone B treated cells. CONCLUSIONS: Avicequinone B sensitized anoikis in human lung cancer cells through down-regulation of anti-apoptosis proteins and integrin mediated survival signaling. PMID- 29631570 TI - Pediatric admissions that include intensive care: a population-based study. AB - BACKGROUND: Pediatric admissions to intensive care outside children's hospitals are generally excluded from registry-based studies. This study compares pediatric admission to specialist pediatric intensive care units (PICU) with pediatric admissions to intensive care units (ICU) in general hospitals in an Australian population. METHODS: We undertook a population-based record linkage cohort study utilizing longitudinally-linked hospital and death data for pediatric hospitalization from New South Wales, Australia, 2010-2013. The study population included all new pediatric, post-neonatal hospital admissions that included time in ICU (excluding neonatal ICU). RESULTS: Of 498,466 pediatric hospitalizations, 7525 (1.5%) included time in an intensive care unit - 93.7% to PICU and 6.3% to ICU in a general (non-PICU) hospital. Non-PICU admissions were of older children, in rural areas, with shorter stays in ICU, more likely admitted for acute conditions such as asthma, injury or diabetes, and less likely to have chronic conditions, receive continuous ventilatory support, blood transfusion, parenteral nutrition or die. CONCLUSIONS: A substantial proportion of children are admitted to ICUs in general hospitals. A comprehensive overview of pediatric ICU admissions includes these admissions and the context of the total hospitalization. PMID- 29631572 TI - The effect of multitasking on the communication skill and clinical skills of medical students. AB - BACKGROUND: Mental workload is an abstract concept that perceives cognition as the brain having a small and finite capacity to process information, with high levels of workload associated with poor performance and error. While an individual may be able to complete two different tasks individually, a combination of tasks may lead to cognitive overload and poor performance. In many high-risk industries, it is common to measure mental workload and then to redesign tasks until cognitive overload is avoided. This study aimed to measure the effect of multitasking on the mental workload and performance of medical students completing single and combined clinical tasks. METHODS: Medical students who had completed basic clinical skills training in a single undergraduate Medical School completed four standardised tasks for a total of four minutes each, consisting of: inactivity, listening, venepuncture and a combination of listening and venepuncture. Task performance was measured using standard binary checklists and with mental workload measured using a secondary task method. RESULTS: The tasks were successfully completed by 40 subjects and as expected, mental workload increased with task complexity. Combining the two tasks showed no difference in the associated mental workload and performance at venepuncture (p = 0.082) However, during the combined task, listening appeared to deteriorate (p < 0.001). CONCLUSIONS: If staff are expected to simultaneously complete multiple tasks then they may preferentially shed communication tasks in order to maintain their performance of physical tasks, leading to the appearance of poor communication skills. Although this is a small-scale study in medical students it suggests that the active assessment and management of clinician workload in busy clinical settings may be an effective strategy to improve doctor-patient communication. PMID- 29631571 TI - The innate immune response to ischemic injury: a multiscale modeling perspective. AB - BACKGROUND: Cell death as a result of ischemic injury triggers powerful mechanisms regulated by germline-encoded Pattern Recognition Receptors (PRRs) with shared specificity that recognize invading pathogens and endogenous ligands released from dying cells, and as such are essential to human health. Alternatively, dysregulation of these mechanisms contributes to extreme inflammation, deleterious tissue damage and impaired healing in various diseases. The Toll-like receptors (TLRs) are a prototypical family of PRRs that may be powerful anti-inflammatory targets if agents can be designed that antagonize their harmful effects while preserving host defense functions. This requires an understanding of the complex interactions and consequences of targeting the TLR mediated pathways as well as technologies to analyze and interpret these, which will then allow the simulation of perturbations targeting specific pathway components, predict potential outcomes and identify safe and effective therapeutic targets. RESULTS: We constructed a multiscale mathematical model that spans the tissue and intracellular scales, and captures the consequences of targeting various regulatory components of injury-induced TLR4 signal transduction on potential pro-inflammatory or pro-healing outcomes. We applied known interactions to simulate how inactivation of specific regulatory nodes affects dynamics in the context of injury and to predict phenotypes of potential therapeutic interventions. We propose rules to link model behavior to qualitative estimates of pro-inflammatory signal activation, macrophage infiltration, production of reactive oxygen species and resolution. We tested the validity of the model by assessing its ability to reproduce published data not used in its construction. CONCLUSIONS: These studies will enable us to form a conceptual framework focusing on TLR4-mediated ischemic repair to assess potential molecular targets that can be utilized therapeutically to improve efficacy and safety in treating ischemic/inflammatory injury. PMID- 29631573 TI - The relationship between low back pain and professional driving in young military recruits. AB - BACKGROUND: Episodes of low back pain (LBP) are very common among workers. A number of occupational risk factors have been shown to increase the risk for LBP. One of these risk factors is exposure to whole body vibration, which is a known characteristic in driving professions. The aim of this study was to assess the impact of driving on LBP amongst young professional drivers. METHODS: This is an historical-prospective cohort study based on the Israel Defense Forces (IDF) database of male soldiers drafted between the years 1997-2006. Subjects' medical history with specific reference to LBP medical history, clinical and radiographic findings were taken as part of the recruitment process to the IDF. The study group included subjects (n = 80,599) from three occupational groups: administrative units (AU), car drivers (CD) and truck drivers (TD) that were followed for 3 years. The incidence and recrudescence rates of LBP were calculated based on standardized LBP severity tiers. RESULTS: The total incidence rate for LBP was 0.65%, 0.7% and 0.34% for AU, CD and TD respectively. In a comparison between subjects without a history of LBP (category 1) to subjects with a history of LBP without clinical findings (category 2) and subjects with a history of LBP with mild clinical / radiographic findings (category 3), the relative risk (RR) for severe LBP exacerbation was 1.4 (p < 0.001) and 3.8 (p < 0.01), respectively. The LBP exacerbation rates within different severity tiers yielded a similar trend amongst all profession groups. CONCLUSIONS: This study included 80,000 soldiers who represent a population of driving and administrative occupations aged 18-21. The significant risk factors for developing LBP were a previous history of LBP and presence of LBP symptoms at the start of work. A correlation was identified between severity of LBP at the initial examination and further exacerbation of LBP in all examined occupations. Driving as a profession in our (young) age-group was not identified as a risk factor for LBP. PMID- 29631574 TI - Challenges and opportunities of integration of community based Management of Acute Malnutrition into the government health system in Bangladesh: a qualitative study. AB - BACKGROUND: Severe acute malnutrition (SAM) in children is the most serious form of malnutrition and is associated with very high rates of morbidity and mortality. For sustainable SAM management, United Nations recommends integration of community based management of acute malnutrition (CMAM) into the health system. The objective of the study was to assess the preparedness of the health system to implement CMAM in Bangladesh. METHODS: The assessment was undertaken during January to May 2014 by conducting document review, key informant interviews, and direct observation. A total of 38 key informant interviews were conducted among government policy makers and program managers (n = 4), nutrition experts (n = 2), health and nutrition implementing partners (n = 2), development partner (n = 1), government health system staff (n = 5), government front line field workers (n = 22), and community members (n = 2). The assessment was based on: workforce, service delivery, financing, governance, information system, medical supplies, and the broad socio-political context. RESULTS: The government of Bangladesh has developed inpatient and outpatient guidelines for the management of SAM. There are cadres of community health workers of government and non-government actors who can be adequately trained to conduct CMAM. Inpatient management of SAM is available in 288 facilities across the country. However, only 2.7% doctors and 3.3% auxiliary staff are trained on facility based management of SAM. In functional facilities, uninterrupted supply of medicines and therapeutic diet are not available. There is resistance and disagreement among nutrition stakeholders regarding import or local production of ready-to-use therapeutic food (RUTF). Nutrition coordination is fragile and there is no functional supra-ministerial coordination platform for multi-sectoral and multi stakeholder nutrition. CONCLUSION: There is an enabling environment for CMAM intervention in Bangladesh although health system strengthening is needed considering the barriers that have been identified. Training of facility based health staff, government community workers, and ensuring uninterrupted supply of medicines and logistics to the functional facilities should be the immediate priorities. Availability of ready-to-use therapeutic food (RUTF) is a critical component of CMAM and government should promote in-country production of RUTF for effective integration of CMAM into the health system in Bangladesh. PMID- 29631575 TI - The genetics of smoking in individuals with chronic obstructive pulmonary disease. AB - BACKGROUND: Smoking is the principal modifiable environmental risk factor for chronic obstructive pulmonary disease (COPD) which affects 300 million people and is the 3rd leading cause of death worldwide. Most of the genetic studies of smoking have relied on self-reported smoking status which is vulnerable to reporting and recall bias. Using data from the Lung Health Study (LHS), we sought to identify genetic variants associated with quantitative smoking and cessation in individuals with mild to moderate COPD. METHODS: The LHS is a longitudinal multicenter study of mild-to-moderate COPD subjects who were all smokers at recruitment. We performed genome-wide association studies (GWASs) for salivary cotinine (n = 4024), exhaled carbon monoxide (eCO) (n = 2854), cigarettes per day (CPD) (n = 2706) and smoking cessation at year 5 follow-up (n = 717 quitters and 2175 smokers). The GWAS analyses were adjusted for age, gender, and genetic principal components. RESULTS: For cotinine levels, SNPs near UGT2B10 gene achieved genome-wide significance (i.e. P < 5 * 10- 8) with top SNP rs10023464, P = 1.27 * 10- 11. For eCO levels, one significant SNP was identified which mapped to the CHRNA3 gene (rs12914385, P = 2.38 * 10- 8). A borderline region mapping to KCNMA1 gene was associated with smoking cessation (rs207675, P = 5.95 * 10- 8). Of the identified loci, only the CHRNA3/5 locus showed significant associations with lung function but only in heavy smokers. No regions met genome-wide significance for CPD. CONCLUSION: The study demonstrates that using objective measures of smoking such as eCO and/or salivary cotinine can more precisely capture the genetic contribution to multiple aspects of smoking behaviour. The KCNMA1 gene association with smoking cessation may represent a potential therapeutic target and warrants further studies. TRIAL REGISTRATION: The Lung Health Study ClinicalTrials.gov Identifier: NCT00000568 . Date of registration: October 28, 1999. PMID- 29631576 TI - Quantitative MR thermometry based on phase-drift correction PRF shift method at 0.35 T. AB - BACKGROUND: Noninvasive magnetic resonance thermometry (MRT) at low-field using proton resonance frequency shift (PRFS) is a promising technique for monitoring ablation temperature, since low-field MR scanners with open-configuration are more suitable for interventional procedures than closed systems. In this study, phase-drift correction PRFS with first-order polynomial fitting method was proposed to investigate the feasibility and accuracy of quantitative MR thermography during hyperthermia procedures in a 0.35 T open MR scanner. METHODS: Unheated phantom and ex vivo porcine liver experiments were performed to evaluate the optimal polynomial order for phase-drift correction PRFS. The temperature estimation approach was tested in brain temperature experiments of three healthy volunteers at room temperature, and in ex vivo porcine liver microwave ablation experiments. The output power of the microwave generator was set at 40 W for 330 s. In the unheated experiments, the temperature root mean square error (RMSE) in the inner region of interest was calculated to assess the best-fitting order for polynomial fit. For ablation experiments, relative temperature difference profile measured by the phase-drift correction PRFS was compared with the temperature changes recorded by fiber optic temperature probe around the microwave ablation antenna within the target thermal region. RESULTS: The phase-drift correction PRFS using first-order polynomial fitting could achieve the smallest temperature RMSE in unheated phantom, ex vivo porcine liver and in vivo human brain experiments. In the ex vivo porcine liver microwave ablation procedure, the temperature error between MRT and fiber optic probe of all but six temperature points were less than 2 degrees C. Overall, the RMSE of all temperature points was 1.49 degrees C. CONCLUSIONS: Both in vivo and ex vivo experiments showed that MR thermometry based on the phase-drift correction PRFS with first-order polynomial fitting could be applied to monitor temperature changes during microwave ablation in a low-field open-configuration whole-body MR scanner. PMID- 29631577 TI - Perception of Cervical Cancer Patients on their Financial Challenges in Western Kenya. AB - BACKGROUND: The number of cervical cancer cases is reported to increase among women of reproductive age in the recent past with patients facing challenges with care and management of the illness. However, little is known about the financial challenges these patients undergo in contexts such as western Kenya. This study assessed financial challenges and sources of financial assistance for cervical cancer patients in western Kenya. METHODS: A cross-sectional study involving 334 cervical cancer patients was conducted in Jaramogi Oginga Odinga Teaching and Referral Hospital (JOOTRH) in Kisumu from September 2014 to February 2015. Structured questionnaire, in-depth interview guide and key informant interview guide were used to collect data. Quantitative data was analyzed using Statistical Package for Social Scientists (SPSS) Version 20 at a statistical significance of P <= 0.05, descriptive statistics and crosstabulations were performed. For qualitative data, the responses were transcribed verbatim and the content was then analyzed by searching for emerging themes on the financial challenges faced by cervical cancer patients. Qualitative data was presented in textual form with verbatim reports for illustrations. RESULTS: The key financial challenges from the study were costs of medication 291 (87%), cost of travel 281 (84%) and cost of diagnostic tests 250 (75%). Other costs incurred by the patients were cost of cloths and wigs 91 (27%), and cost of home and child care 80 (24%). Most 304 (91%) of the cervical cancer patients admitted and referred to JOOTRH did not have insurance cover and only 30 (9%) had National Hospital Insurance Fund cover which catered for only bed component of inpatient costs. Results showed that no patient received any assistance from well-wishers. Only a few received assistance from charity organizations 43 (13%), friends 91 (27%) and colleagues 31 (9%). Some patients received some assistance from relatives 32 (10%) and church 32 (10%). CONCLUSION: Cervical cancer patients experience several financial challenges yet only few of them had insurance cover which catered for only bed component of inpatient costs. There is a need for the Kenyan health care system to develop mechanisms for provision of financial support for cervical cancer patients. PMID- 29631578 TI - The perceived organizational impact of the gender gap across a Canadian department of medicine and proposed strategies to combat it: a qualitative study. AB - BACKGROUND: Despite the gender parity existing in medical schools for over three decades, women remain underrepresented in academic medical centers, particularly in senior ranks and in leadership roles. This has consequences for patient care, education, research, and workplace culture within healthcare organizations. This study was undertaken to explore the perspectives of faculty members at a single department of medicine on the impact of the existing gender gap on organizational effectiveness and workplace culture, and to identify systems-based strategies to mitigate the gap. METHODS: The study took place at a large university department of medicine in Toronto, Canada, with six affiliated hospitals. In this qualitative study, semi-structured individual interviews were conducted between May and September 2016 with full-time faculty members who held clinical and university-based appointments. Transcripts of the interviews were analyzed using thematic analysis. Three authors independently reviewed the transcripts to determine a preliminary list of codes and establish a coding framework. A modified audit consensus coding approach was applied; a single analyst reviewed all the transcripts and a second analyst audited 20% of the transcripts in each round of coding. Following each round, inter-rater reliability was determined, discrepancies were resolved through discussion, and modifications were made as needed to the coding framework. The analysis revealed faculty members' perceptions of the gender gap, potential contributing factors, organizational impacts, and possible solutions to bridge the gap. RESULTS: Of the 43 full-time faculty members who participated in the survey (29 of whom self-identified as female), most participants were aware of the existing gender gap within academic medicine. Participants described social exclusion, reinforced stereotypes, and unprofessional behaviors as consequences of the gap on organizational effectiveness and culture. They suggested improvements in (1) the processes for recruitment, hiring, and promotion; (2) inclusiveness of the work environment; (3) structures for mentorship; and (4) ongoing monitoring of the gap. CONCLUSION: The existing gender gap in academic medicine may have negative consequences for organizational effectiveness and workplace culture but many systems-based strategies to mitigate the gap exist. Although these solutions warrant rigorous evaluation, they are feasible to institute within most healthcare organizations immediately. PMID- 29631579 TI - Implementation of modified team-based learning within a problem based learning medical curriculum: a focus group study. AB - BACKGROUND: While Problem Based Learning (PBL) has long been established internationally, Team-based learning (TBL) is a relatively new pedagogy in medical curricula. Both PBL and TBL are designed to facilitate a learner-centred approach, where students, in interactive small groups, use peer-assisted learning to solve authentic, professionally relevant problems. Differences, however, exist between PBL and TBL in terms of preparation requirements, group numbers, learning strategies, and class structure. Although there are many similarities and some differences between PBL and TBL, both rely on constructivist learning theory to engage and motivate students in their learning. The aim of our study was to qualitatively explore students' perceptions of having their usual PBL classes run in TBL format. METHODS: In 2014, two iterations in a hybrid PBL curriculum were converted to TBL format, with two PBL groups of 10 students each, being combined to form one TBL class of 20, split into four groups of five students. At the completion of two TBL sessions, all students were invited to attend one of two focus groups, with 14 attending. Thematic analysis was used to code and categorise the data into themes, with constructivist theory used as a conceptual framework to identify recurrent themes. RESULTS: Four key themes emerged; guided learning, problem solving, collaborative learning, and critical reflection. Although structured, students were attracted to the active and collaborative approach of TBL. They perceived the key advantages of TBL to include the smaller group size, the preparatory Readiness Assurance Testing process, facilitation by a clinician, an emphasis on basic science concepts, and immediate feedback. The competitiveness of TBL was seen as a spur to learning. These elements motivated students to prepare, promoted peer assisted teaching and learning, and focussed team discussion. An important advantage of PBL over TBL, was the opportunity for adequate clinical reasoning within the problem solving activity. CONCLUSION: Students found their learning experience in TBL and PBL qualitatively different. There were advantages and disadvantages to both. This suggests a hybrid approach utilising the strengths of both methods should be considered for wide scale implementation. PMID- 29631580 TI - A survey of cariology teaching in Australia and New Zealand. AB - BACKGROUND: The Australian and New Zealand chapter of the Alliance for a Cavity Free Future was launched in 2013 and one of its primary aims was to conduct a survey of the local learning and teaching of cariology in dentistry and oral health therapy programs. METHODS: A questionnaire was developed using the framework of the European Organisation for Caries Research (ORCA)/Association of Dental Education in Europe (ADEE) cariology survey conducted in Europe in 2009. The questionnaire was comprised of multiple choice and open-ended questions exploring many aspects of the cariology teaching. The survey was distributed to the cariology curriculum coordinator of each of the 21 programs across Australia and New Zealand via Survey Monkey in January 2015. Simple analysis of results was carried out with frequencies and average numbers of hours collated and open-ended responses collected and compiled into tables. RESULTS: Seventeen responses from a total of 21 programs had been received including 7 Dentistry and 10 Oral Health programs. Key findings from the survey were - one quarter of respondents indicated that cariology was identified as a specific discipline with their course and 41% had a cariology curriculum in written format. With regard to lesion detection and caries diagnosis, all of the program coordinators who responded indicated that visual/tactile methods and radiographic interpretation were recommended with ICDAS also being used by over half them. Despite all respondents teaching early caries lesion management centred on prevention and remineralisation, many taught operative intervention at an earlier stage of lesion depth than current evidence supports. Findings showed over 40% of respondents still teach operative intervention for lesions confined to enamel. CONCLUSION: Despite modern theoretical concepts of cariology being taught in Australia and New Zealand, they do not appear to be fully translated into clinical teaching at the present time. PMID- 29631581 TI - Successful pulmonary arterial embolization followed by curative surgery for a lepidic predominant lung adenocarcinoma with severe hypoxemia. AB - BACKGROUND: Lepidic predominant adenocarcinoma is characterized by frequent refractory hypoxemia due to intrapulmonary shunting. Severe hypoxemia can induce perioperative complications in case of thoracic surgery. CASE PRESENTATION: We report a case of a 67 year-old woman with localized lepidic adenocarcinoma in the right lower lobe with severe hypoxemia. A selective arterial lung embolization allowed an instantaneous correction of the hypoxemia, and a curative lobectomy was safely performed 1 week after without any complication. The staging was pT3N0M0, and the patient received adjuvant chemotherapy. CONCLUSIONS: This is the first case-report of successful endovascular embolization before curative surgery for a lepidic predominant lung adenocarcinoma. PMID- 29631582 TI - Predictive values of diagnostic codes for identifying serious hypocalcemia and dermatologic adverse events among women with postmenopausal osteoporosis in a commercial health plan database. AB - BACKGROUND: Post-marketing safety studies of medicines often rely on administrative claims databases to identify adverse outcomes following drug exposure. Valid ascertainment of outcomes is essential for accurate results. We aim to quantify the validity of diagnostic codes for serious hypocalcemia and dermatologic adverse events from insurance claims data among women with postmenopausal osteoporosis (PMO). METHODS: We identified potential cases of serious hypocalcemia and dermatologic events through ICD-9 diagnosis codes among women with PMO within claims from a large US healthcare insurer (June 2005-May 2010). A physician adjudicated potential hypocalcemic and dermatologic events identified from the primary position on emergency department (ED) or inpatient claims through medical record review. Positive predictive values (PPVs) and 95% confidence intervals (CIs) quantified the fraction of potential cases that were confirmed. RESULTS: Among 165,729 patients with PMO, medical charts were obtained for 40 of 55 (73%) potential hypocalcemia cases; 16 were confirmed (PPV 40%, 95% CI 25-57%). The PPV was higher for ED than inpatient claims (82 vs. 24%). Among 265 potential dermatologic events (primarily urticaria or rash), we obtained 184 (69%) charts and confirmed 128 (PPV 70%, 95% CI 62-76%). The PPV was higher for ED than inpatient claims (77 vs. 39%). CONCLUSION: Diagnostic codes for hypocalcemia and dermatologic events may be sufficient to identify events giving rise to emergency care, but are less accurate for identifying events within hospitalizations. PMID- 29631583 TI - Cost of antenatal care for the health sector and for households in Rwanda. AB - BACKGROUND: Rwanda has made tremendous progress in reduction of maternal mortality in the last twenty years. Antenatal care is believed to have played a role in that progress. In late 2016, the World Health Organization published new antenatal care guidelines recommending an increase from four visits during pregnancy to eight contacts with skilled personnel, among other changes. There is ongoing debate regarding the cost implications and potential outcomes countries can expect, if they make that shift. For Rwanda, a necessary starting point is to understand the cost of current antenatal care practice, which, according to our knowledge, has not been documented so far. METHODS: Cost information was collected from Kigali City and Northern province of Rwanda through two cross sectional surveys: a household-based survey among women who had delivered a year before the interview (N = 922) and a health facility survey in three public, two faith-based, and one private health facility. A micro costing approach was used to collect health facility data. Household costs included time and transport. Results are reported in 2015 USD. RESULTS: The societal cost (household + health facility) of antenatal care for the four visits according to current Rwandan guidelines was estimated at $160 in the private health facility and $44 in public and faith-based health facilities. The first visit had the highest cost ($75 in private and $21 in public and faith-based health facilities) compared to the three other visits. Drugs and consumables were the main input category accounting for 54% of the total cost in the private health facility and for 73% in the public and faith-based health facilities. CONCLUSIONS: The unit cost of providing antenatal care services is considerably lower in public than in private health facilities. The household cost represents a small proportion of the total, ranging between 3% and 7%; however, it is meaningful for low-income families. There is a need to do profound equity analysis regarding the accessibility and use of antenatal care services, and to consider ways to reduce households' time cost as a possible barrier to the use of antenatal care. PMID- 29631584 TI - Effects of endogenous sex hormones on lung function and symptom control in adolescents with asthma. AB - BACKGROUND: Although pre-puberty asthma is more prevalent in males, after puberty through middle-age, asthma is more prevalent in females. The surge of sex hormones with puberty might explain this gender switch. METHODS: To examine the effects of sex hormones on lung function and symptoms with puberty, Tanner stage was assessed in 187 children 6-18 years of age (59% severe) enrolled in the NIH/NHLBI Severe Asthma Research Program (SARP). The effects of circulating sex hormones (n = 68; testosterone, dehydroepiandrosterone sulfate (DHEA-S), estrogen, and progesterone) on lung function and 4 week symptom control (ACQ6) in cross-section were tested by linear regression. RESULTS: From pre-/early to late puberty, lung function did not change significantly but ACQ6 scores improved in males with severe asthma. By contrast females had lower post-BD FEV1% and FVC% and worse ACQ6 scores with late puberty assessed by breast development. In males log DHEA-S levels, which increased by Tanner stage, associated positively with pre- and post-BD FEV1%, pre-BD FVC %, and negatively (improved) with ACQ6. Patients treated with high-dose inhaled corticosteroids had similar levels of circulating DHEA-S. In females, estradiol levels increased by Tanner stage, and associated negatively with pre-BD FEV1% and FVC %. CONCLUSIONS: These results support beneficial effects of androgens on lung function and symptom control and weak deleterious effects of estradiol on lung function in children with asthma. Longitudinal data are necessary to confirm these cross-sectional findings and to further elucidate hormonal mechanisms informing sex differences in asthma features with puberty. TRIAL REGISTRATION: ClinicalTrials.gov registration number: NCT01748175 . PMID- 29631585 TI - Empagliflozin influences blood viscosity and wall shear stress in subjects with type 2 diabetes mellitus compared with incretin-based therapy. AB - BACKGROUND: Cardiovascular protection following empagliflozin therapy is not entirely attributable to the glucose lowering effect. Increased hematocrit might influence the shear stress that is the main force acting on the endothelium, regulating its anti-atherogenic function. OBJECTIVE: We designed the study with the aim of investigating the effect of empagliflozin on blood viscosity and shear stress in the carotid arteries. A secondary endpoint was the effect of empagliflozin on carotid artery wall thickness. METHODS: The study was a non randomized, open, prospective cohort study including 35 type 2 diabetic outpatients who were offered empagliflozin or incretin-based therapy (7 liraglutide, 8 sitagliptin) in combination with insulin and metformin. Blood viscosity, shear stress and carotid wall thickness were measured at baseline and at 1 and 3 months of treatment. Blood viscosity was measured with a viscometer, and shear stress was calculated using a validated formula. Intima-media thickness (IMT) of the carotid artery was detected by ultrasound and was measured with dedicated software. RESULTS: Blood viscosity (4.87 +/- 0.57 vs 5.32 +/- 0.66 cP, p < 0.02) and shear stress significantly increased in the Empagliflozin group while no change was detected in the Control group (4.66 +/- 0.56 vs 4.98 +/- 0.73 cP, p = NS). IMT significantly decreased in the Empagliflozin group after 1 and 3 months (baseline: 831 +/- 156, 1-month 793 +/- 150, 3-month 766 +/- 127 MUm; p < 0.0001), while in the liraglutide group, IMT significantly decreased only after 3 months (baseline 879 +/- 120; 1-month 861 +/- 163; 3-month 802 +/- 114 MUm; p < 0.001). In the sitagliptin group, IMT remained almost unchanged (baseline 901 +/- 135; 1-month 902 +/- 129; 3-month 880 +/- 140 MUm; p = NS). CONCLUSIONS: This study is the first to describe a direct effect of empagliflozin on blood viscosity and wall shear stress. Furthermore, IMT was markedly reduced early on in the Empagliflozin group. PMID- 29631586 TI - Withania somnifera modulates cancer cachexia associated inflammatory cytokines and cell death in leukaemic THP-1 cells and peripheral blood mononuclear cells (PBMC's). AB - BACKGROUND: Cancer and inflammation are associated with cachexia. Withania somnifera (W. somnifera) possesses antioxidant and anti-inflammatory potential. We investigated the potential of an aqueous extract of the root of W. somnifera (WRE) to modulate cytokines, antioxidants and apoptosis in leukaemic THP-1 cells and peripheral blood mononuclear cells (PBMC's). METHODS: Cytotoxcity of WRE was determined at 24 and 72 h (h). Oxidant scavenging activity of WRE was evaluated (2, 2-diphenyl-1 picrylhydrazyl assay). Glutathione (GSH) levels, caspase (- 8, - 9, - 3/7) activities and adenosine triphosphate (ATP) levels (Luminometry) were thereafter assayed. Tumour necrosis factor-alpha (TNF-alpha), interleukin (IL)-6, IL-1beta and IL-10 levels were also assessed using enzyme-linked immunosorbant assay. RESULTS: At 24 h, WRE (0.2-0.4 mg/ml) decreased PBMC viability between 20 and 25%, whereas it increased THP-1 viability between 15 and 23% (p < 0.001). At 72 h, WRE increased PBMC viability by 27-39% (0.05, 0.4 mg/ml WRE) whereas decreased THP-1 viability between 9 and 16% (0.05-0.4 mg/ml WRE) (p < 0.001). Oxidant scavenging activity was increased by WRE (0.05-0.4 mg/ml, p < 0.0001). PBMC TNF-alpha and IL-10 levels were decreased by 0.2-0.4 mg/ml WRE, whereas IL 1beta levels were increased by 0.05-0.4 mg/ml WRE (p < 0.0001). In THP-1 cells, WRE (0.05-0.4 mg/ml) decreased TNF-alpha, IL-1beta and IL-6 levels (p < 0.0001). At 24 h, GSH levels were decreased in PBMC's, whilst increased in THP-1 cells by 0.2-0.4 mg/ml WRE (p < 0.0001). At 72 h, WRE (0.1-0.4 mg/ml) decreased GSH levels in both cell lines (p < 0.0001). At 24 h, WRE (0.2-0.4 mg/ml) increased PBMC caspase (-8, -3/7) activities whereas WRE (0.05, 0.1, 0.4 mg/ml) increased THP-1 caspase (-9, -3/7) activities (p < 0.0001). At 72 h, PBMC caspase (-8, -9, -3/7) activities were increased at 0.05-0.1 mg/ml WRE (p < 0.0001). In THP-1 cells, caspase (-8, -9, -3/7) activities and ATP levels were increased by 0.1-0.2 mg/ml WRE, whereas decreased by 0.05 and 0.4 mg/ml WRE (72 h, p < 0.0001). CONCLUSION: In PBMC's and THP-1 cells, WRE proved to effectively modulate antioxidant activity, inflammatory cytokines and cell death. In THP-1 cells, WRE decreased pro-inflammatory cytokine levels, which may alleviate cancer cachexia and excessive leukaemic cell growth. PMID- 29631588 TI - Malakit: an innovative pilot project to self-diagnose and self-treat malaria among illegal gold miners in the Guiana Shield. AB - BACKGROUND: Illegal gold miners in French Guiana, a French overseas territory ('departement') located in Amazonia, often carry malaria parasites (up to 46.8%). While the Guiana Shield Region aims at malaria elimination, the high prevalence of Plasmodium in this hard-to-reach population in conjunction with frequent incorrect use of artemisinin-based anti-malarials could favour the emergence of resistant parasites. Due to geographical and regulatory issues in French Guiana, usual malaria control strategies cannot be implemented in this particular context. Therefore, new strategies targeting this specific population in the forest are required. METHODS: Numerous discussions among health institutions and scientific partners from French Guiana, Brazil and Suriname have led to an innovative project based on the distribution of kits for self-diagnosis and self treatment of Plasmodium infections. The kit-distribution will be implemented at "resting sites", which are areas across the border of French Guiana regularly frequented by gold miners. The main objective is to increase the appropriate use and complete malaria treatment after a positive malaria diagnosis with a rapid test, which will be evaluated with before-and-after cross-sectional studies. Monitoring indicators will be collected from health mediators at the time of kit distribution and during subsequent visits, and from illegal gold miners themselves, through a smartphone application. The project funding is multisource, including Ministries of Health of the three countries, WHO/PAHO, and the European Union. RESULTS: This project will start in April 2018 as a 18 month pilot study led by the Clinical Investigation Centre of Cayenne. Results should be available at the end of 2019. DISCUSSION: This innovative approach may have several limitations which should be taken into account, as potential side effects, kit misuse or resale, declarative main criteria, or no Plasmodium vivax curative treatment. Close monitoring is thus needed. CONCLUSIONS: This project may be the best available solution to a specific and important public health challenge in the Guiana Shield. If the use of self-diagnosis and self-treatment approach is effective, this strategy could be sustained by health institutions in the region. PMID- 29631587 TI - Evaluation of the implementation of a clinical pharmacy service on an acute internal medicine ward in Italy. AB - BACKGROUND: Successful implementation of clinical pharmacy services is associated with improvement of appropriateness of prescribing. Both high clinical significance of pharmacist interventions and their high acceptance rate mean that potential harm to patients could be avoided. Evidence shows that low acceptance rate of pharmacist interventions can be associated with lack of communication between pharmacists and the rest of the healthcare team. The objective of this study was to evaluate the effect of a structured communication strategy on acceptance rate of interventions made by a clinical pharmacist implementing a ward-based clinical pharmacy service targeting elderly patients at high risk of drug-related problems. Characteristics of interventions made to improve appropriateness of prescribing, their clinical significance and intervention acceptance rate by doctors were recorded. METHODS: A clinical pharmacy intervention study was conducted between September 2013 and December 2013 in an internal medicine ward of a teaching hospital. A trained clinical pharmacist provided pharmaceutical care to 94 patients aged over 70 years. The clinical pharmacist used the following communication and marketing tools to implement the service described: Strengths, Weaknesses, Opportunities and Threats (SWOT) analysis; Specific, Measurable, Achievable, Realistic and Timely (SMART) goals; Awareness, Interest, Desire, Action (AIDA) model. RESULTS: A total of 740 interventions were made by the clinical pharmacist. The most common drug classes involved in interventions were: antibacterials for systemic use (11.1%) and anti parkinson drugs (10.8%). The main drug-related problem categories triggering interventions were: no specific problem (15.9%) and prescription writing error (12.0%). A total of 93.2% of interventions were fully accepted by physicians. After assessment by an external panel 63.2% of interventions (96 interventions/ per month) were considered of moderate clinical significance and 23.4% (36 interventions/ per month) of major clinical significance. The most frequent interventions were to educate a healthcare professional (20.4%) and change dose (16.1%). CONCLUSIONS: To our knowledge this is the first study evaluating the effect of a structured communication strategy on acceptance rate of pharmacist interventions. Pharmaceutical care delivered by the clinical pharmacist is likely to have had beneficial outcomes. Clinical pharmacy services like the one described should be implemented widely to increase patient safety. PMID- 29631589 TI - Retention of medical doctors at the district level: a qualitative study of experiences from Tanzania. AB - BACKGROUND: Retention of Human Resources for Health (HRH), particularly doctors at district level is a big challenge facing the decentralized health systems in poorly resourced countries. Tanzania, with 75% of its population in rural areas, has only 26% of doctors serving in rural areas. We aimed to analyze the experiences regarding the retention of doctors at district level in Tanzania from doctors' and district health managers' perspectives. METHODS: A qualitative study was carried out in three districts from June to September 2013. We reviewed selected HRH documents and then conducted 15 key informant interviews with members of the District Health Management teams and medical doctors working at the district hospitals. In addition, we conducted three focus group discussions with Council Health Management Team members in the three districts. Incentive package plans, HRH establishment, and health sector development plans from the three districts were reviewed. Data analysis was performed using qualitative content analysis. RESULTS: None of the districts in this study has the number of doctors recommended. Retention of doctors in the districts faced the following challenges: unfavourable working conditions including poor working environment, lack of assurance of career progression, and a non-uniform financial incentive system across districts; unsupportive environment in the community, characterized by: difficulty in securing houses for rent, lack of opportunities to earn extra income, lack of appreciation from the community and poor social services. Health managers across districts endeavour to retain their doctors through different retention strategies, including: career development plans, minimum financial incentive packages and avenues for private practices in the district hospitals. However, managers face constrained financial resources, with many competing priorities at district level. CONCLUSIONS: Retention of doctors at district level faces numerous challenges. Assurance of career growth, provision of uniform minimum financial incentives and ensuring availability of good social services and economic opportunities within the community are among important retention strategies. PMID- 29631590 TI - The effects of seed from Linum usitatissimum cultivar with increased phenylpropanoid compounds and hydrolysable tannin in a high cholesterol-fed rabbit. AB - BACKGROUND: Dietary fat is considered one of the most important factors associated with blood lipid metabolism and plays a significant role in the cause and prevention of atherosclerosis that has been widely accepted as an inflammatory disease of the vascular system. The aim of the present study was to evaluate the effect of genetically modified flaxseed (W86) rich in phenylpropanoid compounds and hydrolysable tannin in high cholesterol-induced atherosclerosis rabbit models compared to parental cultivar Linola. METHODS: Twenty-Eight White New Zealand white rabbits aged 6 months were randomly divided into four groups, control group, high cholesterol group (10 g/kg), Linola flaxseed group (100 g/kg) and W86 flaxseed group (100 g/kg). The rabbits were fed a normal diet or a high cholesterol diet for 10 weeks. Levels of blood lipids, hematological values, total antioxidative status and superoxide dismutase activity in serum were determined. Moreover, body weight and feed intake were measured after sixth and tenth weeks. After each stage of the experiment atherogenic indexes (non-HDL-C/HDL-C, LDL-C/HDL-C, and atherogenic index of plasma) was calculated. RESULTS: The intake of a dyslipidaemic diet negatively influenced lipid profile in rabbits at the 10 weeks of feeding. W86 flaxseed significantly decreased total cholesterol, LDL-C, VLDL-C and TG serum levels in cholesterolemic rabbits compared with parental Linola after 10 weeks. Atherogenic indexes decreased over time with a significant difference between the diets and they were the best for W86 flaxseed. Similarly, the experimental addition of W86 significantly decreased atherogenic predictors such as heterophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and the mean platelet volume-to-lymphocyte ratio. In rabbits, W86 flaxseed increased the activity of superoxide dismutase and total antioxidative status compared to Linola. CONCLUSIONS: Results of the presented study suggest that the addition of W86 flaxseed alleviate serum lipid changes in high cholesterolemic diet-administered rabbits. W86 flaxseed significantly reduced atherogenic indexes, as compared with the Linola and indicate that W86 flaxseed more effectively red CVD risk factors during hypercholesterolemia. Moreover, the presented result suggested that W86 flaxseed can be a part of a heart-healthy and antiatherogenic diet for the human. PMID- 29631591 TI - Condition-specific promoter activities in Saccharomyces cerevisiae. AB - BACKGROUND: Saccharomyces cerevisiae is widely studied for production of biofuels and biochemicals. To improve production efficiency under industrially relevant conditions, coordinated expression of multiple genes by manipulating promoter strengths is an efficient approach. It is known that gene expression is highly dependent on the practically used environmental conditions and is subject to dynamic changes. Therefore, investigating promoter activities of S. cerevisiae under different culture conditions in different time points, especially under stressful conditions is of great importance. RESULTS: In this study, the activities of various promoters in S. cerevisiae under stressful conditions and in the presence of xylose were characterized using yeast enhanced green fluorescent protein (yEGFP) as a reporter. The stresses include toxic levels of acetic acid and furfural, and high temperature, which are related to fermentation of lignocellulosic hydrolysates. In addition to investigating eight native promoters, the synthetic hybrid promoter P3xC-TEF1 was also evaluated. The results revealed that P TDH3 and the synthetic promoter P3xC-TEF1 showed the highest strengths under almost all the conditions. Importantly, these two promoters also exhibited high stabilities throughout the cultivation. However, the strengths of P ADH1 and P PGK1 , which are generally regarded as 'constitutive' promoters, decreased significantly under certain conditions, suggesting that cautions should be taken to use such constitutive promoters to drive gene expression under stressful conditions. Interestingly, P HSP12 and P HSP26 were able to response to both high temperature and acetic acid stress. Moreover, P HSP12 also led to moderate yEGFP expression when xylose was used as the sole carbon source, indicating that this promoter could be used for inducing proper gene expression for xylose utilization. CONCLUSION: The results here revealed dynamic changes of promoter activities in S. cerevisiae throughout batch fermentation in the presence of inhibitors as well as using xylose. These results provide insights in selection of promoters to construct S. cerevisiae strains for efficient bioproduction under practical conditions. Our results also encouraged applications of synthetic promoters with high stability for yeast strain development. PMID- 29631593 TI - Correction to: Risk factors associated with academic difficulty in an Australian regionally located medical school. AB - Following publication of the original article [1], one of the authors reported that prior to publication her surname had changed from 'Kerlen' to 'van der Kruk', but that this change had not been incorporated in the final version. PMID- 29631592 TI - Crocin attenuates cigarette smoke-induced lung injury and cardiac dysfunction by anti-oxidative effects: the role of Nrf2 antioxidant system in preventing oxidative stress. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) has been emerging as a great health problem in world. Cigarette smoke is known to cause oxidative stress and deplete glutathione (GSH) levels. Nuclear erythroid-related factor 2 (Nrf2) is involved in transcriptional regulation of glutamate-cysteine ligase catalytic subunit (GCLc). Antioxidant compounds may be of therapeutic value in monitoring disease progression. Crocin demonstrates antioxidant and anti-inflammatory functions. The aim of this study was to investigate the protective role of crocin against CSE-mediated oxidative stress, inflammatory process, Nrf2 modifications and impairment of cardiac function in rats with COPD. METHODS: Eighty rats were divided into four groups: Control, Cigarette smoke exposure (CSE), Crocin, Crocin+CS. Each group was divided into the two parts: 1) to evaluate lung inflammatory and oxidative process, 2) to evaluate the effect of Cigarette smoke induced-lung injuries on cardiac electrocardiogram (such as heart rate and QRS complex) and hemodynamic parameters (such as perfusion pressure and left ventricular developed pressure). RESULTS: CSE rats showed a significant increase in cotinine concentration (17.24 ng/ml), and inflammatory parameters and a decrease in PO2 (75.87 mmHg) and expression of PKC (0.86 fold), PI3K (0.79 fold), MAPK (0.87 fold), Nrf2 (0.8 fold) and GCLc (0.75 fold) genes, antioxidant activity, and finally cardiac abnormalities in electrocardiogram and hemodynamic parameters. Co-treatment whit crocin could restore all these values to normal levels. CONCLUSIONS: CS induced-COPD in rat model provides evidence that chronic CS exposure leads to lung injury and mediated cardiac dysfunction. Crocin co treatment by modulating of Nrf2 pathway protected lung injury caused by COPD and its related cardiac dysfunction. In this study, we showed the importance of Nrf2 activators as a therapeutic target for the development of novel therapy for lung oxidative injuries. PMID- 29631594 TI - Alternative splicing of human telomerase reverse transcriptase in gliomas and its modulation mediated by CX-5461. AB - BACKGROUND: Glioma is a heterogeneous, invasive primary brain tumor with a wide range of patient survival and a lack of reliable prognostic biomarkers. Human telomerase reverse transcriptase (hTERT) has been reported in the presence of multiple transcripts in various tumor systems. The biological function and precise regulatory mechanisms of hTERT transcripts remain uncertain. METHODS: Alternative splicing of hTERT and telomerase activity were examined in 96 glioma specimens, including 38 glioblastomas (GBMs), 23 oligodendrogliomas (ODMs), and 35 oligoastrocytomas (OAMs). The correlation between telomerase activity or hTERT transcripts and patient clinical characteristics was investigated. We examined the regulation of alternative splicing of hTERT and telomerase activity by G quadruplex stabilizer CX-5461 in GBM cells. The biological effects of CX-5461 on GBM cell lines, including inhibition of cell proliferation, effects on cell cycle/apoptosis, and telomere DNA damage were further explored. RESULTS: The beta splicing was verified in human gliomas and hTERT+beta was significantly correlated with higher telomerase activity, higher KPS, larger tumor size, and higher tumor grades. Meanwhile, glioma patients lacking hTERT+beta expression or telomerase activity showed a significant survival benefit. Notably, CX-5461 altered hTERT splicing patterns, leading to an increase of hTERT-beta transcript and a decrease of hTERT+beta transcript expression, which inhibits telomerase activity. In addition, CX-5461 had cytotoxic effects on GBM cells and caused telomere DNA damage response, induced G2/M arrest and apoptosis. CONCLUSIONS: The hTERT+beta is verified to be correlated with clinical parameters in gliomas, and could serve as a prognostic marker or possibly therapeutic target for gliomas. CX 5461 can regulate the splicing pattern of hTERT, inhibit telomerase activity, and kill GBM cells. PMID- 29631595 TI - Safety, effectiveness, and impact on quality of life of self-administration with plasma-derived nanofiltered C1 inhibitor (Berinert(r)) in patients with hereditary angioedema: the SABHA study. AB - BACKGROUND: Hereditary angioedema with C1 inhibitor deficiency is a disabling, potentially fatal condition characterized by recurrent episodes of swelling. Self treatment is recommended, in order to reduce admissions to the Emergency Room and the time between the onset of the attack and the treatment, resulting in a better treatment outcome and an improved quality of life (QoL). The purpose of this study is to assess the safety, tolerability, and effect on QoL of self administration of pnf C1-INH for IV use (Berinert(r)). METHODS: An observational, monocenter, prospective study was designed. Patients referring to a center for angioedema that attended two sessions of self-infusion training course in the period March 2014-July 2015 were enrolled in the study. The primary endpoint was to monitor the safety and feasibility of pnf C1-INH self-infusion. The secondary endpoint was to evaluate the effect of self-infusion on the QoL, by means of the HAE-QoL questionnaire and the need for access to Emergency Room for infusion of Berinert(r). Patients' medical history data were collected upon the first visit and questionnaires were filled after each attack treated with Berinert(r) (diary and Treatment Satisfaction Questionnaire for Medication) and upon the first visit and the follow-ups (HAE-QoL). RESULTS: Twenty patients were enrolled (median age = 42, IQR: 39-49; 60% females). Fifteen patients completed the study. A total of 189 attacks were recorded (annual median rate of 4 attacks/patient). Patients waited a median of 2 h (IQR: 1-4) before self-administration, and the resolution of the attack occurred after a median of 6 h (IQR: 4-11). Most attacks were abdominal (39%) and peripheral (22%). 92% of the attacks were treated through self-/caregiver-administration. In most attacks no side effects were reported. The number of attacks with side effects decreased over time, from 37% to 13%. Global satisfaction grew over time during the study period, reaching statistical significance over the first 6 months. The median total HAE-QoL score at baseline was 86 (IQR: 76-103) and improved in a non-significant manner throughout the study period. 8% of the attacks treated with Berinert(r) required ER admission/healthcare professional help in the study period, compared with 100% in the 3 years before enrollment (p < 0.0001). CONCLUSIONS: Self-administration of pnf C1-INH is safe, and increases patients' confidence in the treatment, showing also a trend towards an improvement in QoL. It reduces the need for ER admission/healthcare professionals help for the acute attacks, as well as the related costs. PMID- 29631596 TI - Association of genetic polymorphisms in genes involved in Ara-C and dNTP metabolism pathway with chemosensitivity and prognosis of adult acute myeloid leukemia (AML). AB - BACKGROUND: Cytarabine arabinoside (Ara-C) has been the core of chemotherapy for adult acute myeloid leukemia (AML). Ara-C undergoes a three-step phosphorylation into the active metabolite Ara-C triphosphosphate (ara-CTP). Several enzymes are involved directly or indirectly in either the formation or detoxification of ara CTP. METHODS: A total of 12 eQTL (expression Quantitative Trait Loci) single nucleotide polymorphisms (SNPs) or tag SNPs in 7 genes including CMPK1, NME1, NME2, RRM1, RRM2, SAMHD1 and E2F1 were genotyped in 361 Chinese non-M3 AML patients by using the Sequenom Massarray system. Association of the SNPs with complete remission (CR) rate after Ara-C based induction therapy, relapse-free survival (RFS) and overall survival (OS) were analyzed. RESULTS: Three SNPs were observed to be associated increased risk of chemoresistance indicated by CR rate (NME2 rs3744660, E2F1 rs3213150, and RRM2 rs1130609), among which two (rs3744660 and rs1130609) were eQTL. Combined genotypes based on E2F1 rs3213150 and RRM2 rs1130609 polymorphisms further increased the risk of non-CR. The SAMHD1 eQTL polymorphism rs6102991 showed decreased risk of non-CR marginally (P = 0.055). Three SNPs (NME1 rs3760468 and rs2302254, and NME2 rs3744660) were associated with worse RFS, and the RRM2 rs1130609 polymorphism was marginally associated with worse RFS (P = 0.085) and OS (P = 0.080). Three SNPs (NME1 rs3760468, NME2 rs3744660, and RRM1 rs183484) were associated with worse OS in AML patients. CONCLUSION: Data from our study demonstrated that SNPs in Ara-C and dNTP metabolic pathway predict chemosensitivity and prognosis of AML patients in China. PMID- 29631597 TI - A cross-sectional survey and follow up study on major dairy health problems in large and small scale urban farms in Mekelle, Tigray, Ethiopia. AB - OBJECTIVE: This study was conducted with the objective of estimating the incidence of major dairy health problems in the area. RESULT: From a cross sectional survey (n = 475) and follow up study (n = 68), an overall incidence of 43.00 and 29.02% was reported respectively. This study showed biting fly (9.51%), respiratory problems (7.80%), mastitis (5.13%), actinomycosis (5.12%), dystocia (4.42%), endoparasites (3.81%), retention fetal membrane (3.63%), tick infestation (2.91%), lameness (2.94%), vaginal and uterine prolepses (2.51%), skin related problem (1.70%) and abortion (1.70%) were the main dairy health problems identified. In addition, the follow up study revealed; retention fetal membrane (5.91%), tick infestation (5.91%), respiratory problem (2.91%), mastitis (2.94%), endoparasites (2.94%), lameness (2.94%), dystocia (2.94%), actinomycosis (1.53%) and skin related problems (1.53%). The incidence of dairy reproductive problems showed statistically significant variation among local and cross breeds (P < 0.05). Incidence of infectious diseases among dairy cows managed under intensive and semi-intensive management systems showed a significant difference (P < 0.05). Moreover, incidence of physical injury was also showed a significant difference among animal breeds and management system (P < 0.05). However, reproductive problems among management system and infectious diseases among breeds showed a significant difference (P > 0.05). Overall, this study showed dairy animals are exposed to various type of diseases. PMID- 29631598 TI - The monocyte counts to HDL cholesterol ratio in obese and lean patients with polycystic ovary syndrome. AB - BACKGROUND: Women with polycystic ovary syndrome are more likely to suffer from obesity, insulin resistance, and chronic low-grade inflammation. In fact, the excessive activation of monocytes exacerbates oxidative stress and inflammation. However, high-density lipoprotein cholesterol neutralizes the pro-inflammatory and pro-oxidant effects of monocytes. The aim of this study is to investigate whether monocyte counts to high-density lipoprotein cholesterol ratio can predict the inflammatory condition in patients with polycystic ovary syndrome. METHODS: In this cross-sectional study, a total of 124 women (61 of them with polycystic ovary syndrome and 63 age-matched healthy volunteers) were included in the study population. Obese polycystic ovary syndrome patients (n = 30) with a body mass index of >=25 kg/m2 and lean polycystic ovary syndrome patients (n = 31) with a body mass index of < 25 kg/m2 were compared to age-and body mass index-matched healthy subjects (30 obese and 33 non-obese). RESULTS: The monocyte counts to high density lipoprotein cholesterol values in women with polycystic ovary syndrome were significantly higher than in control subjects (p = 0.0018). Moreover, a regression analysis revealed that body mass index, the homeostasis model assessment of insulin resistance and the high sensitivity C-reactive protein levels were confounding factors that affected the monocyte counts to high density lipoprotein cholesterol values. Additionally, a univariate and multivariate logistic regression analysis demonstrated that the increased monocyte counts to high density lipoprotein cholesterol values were more sensitive than the other known risk factors (such as increased body mass index, homeostasis model assessment of insulin resistance and high sensitive C-reactive protein levels) in the prediction of the inflammation in patients with polycystic ovary syndrome. CONCLUSION: The present study demonstrated that the monocyte count to high density lipoprotein cholesterol may be a novel and useful predictor of the presence of polycystic ovary syndrome. PMID- 29631599 TI - Ebola virus disease outbreak in Guinea: what effects on prevention of mother-to child transmission of HIV services? AB - BACKGROUND: An unprecedented epidemic of Ebola virus disease (EVD) affected Guinea in 2014 and 2015. It weakened the already fragile Guinean health system. This study aimed to assess the effects of the outbreak on Prevention of Mother-to Child Transmission of HIV (PMTCT) services in 2014. METHODS: We conducted a cross sectional retrospective study. Data was collected from 60 public health centers (30 in the EVD affected areas and 30 in the unaffected areas). The comparison of PMTCT indicators between the period before Ebola (2013) and during Ebola (2014) was done using the t- test for the means and the Chi-square test for the proportions. RESULTS: This study showed a substantial and significant reduction in the mean number of antenatal care visits (ANC) in the affected localities, 1617 +/- 53 in 2013 versus 1065 +/- 29 in 2014, p = 0.0004. This would represent 41% drop in health facilities' performance. On the other hand, in the unaffected localities, the fall was not significant. The same observations were made about the number of HIV tests performed for pregnant women and the number of HIV positive pregnant women initiating ARVs. The study also noted an increase in the proportion of women tested HIV+ but who did not receive ARVs (12% in 2013 versus 44% in 2014) and HIV+ pregnant women who delivered at home (18% in 2014 versus 7% in 2013). CONCLUSION: This study showed that PMTCT services, which are one of the key services to improve maternal and child health, were affected in Guinea during this Ebola outbreak in 2014 compared to 2013. PMID- 29631600 TI - Revisiting the need for virtue in medical practice: a reflection upon the teaching of Edmund Pellegrino. AB - Edmund Pellegrino considered medicine as a skill, art, and perhaps most importantly, a moral enterprise. In this essay, I attempt to exemplify how the legacy and contributions of Edmund Pellegrino, as a teacher and a physician, could allow for a renaissance of medical practice in which physicians engage intellectual and moral virtue to both effect sound care, and do so in a humanitarian way, rather than in simple accordance with a business model of medicine. The virtues are viewed in a renewed light as being key characteristics of physicians, and important to patient centered care. PMID- 29631601 TI - Biological function of Lemur tyrosine kinase 2 (LMTK2): implications in neurodegeneration. AB - Neurodegenerative disorders are frequent, incurable diseases characterised by abnormal protein accumulation and progressive neuronal loss. Despite their growing prevalence, the underlying pathomechanism remains unclear. Lemur tyrosine kinase 2 (LMTK2) is a member of a transmembrane serine/threonine-protein kinase family. Although it was described more than a decade ago, our knowledge on LMTK2's biological functions is still insufficient. Recent evidence has suggested that LMTK2 is implicated in neurodegeneration. After reviewing the literature, we identified three LMTK2-mediated mechanisms which may contribute to neurodegenerative processes: disrupted axonal transport, tau hyperphosphorylation and enhanced apoptosis. Moreover, LMTK2 gene expression is decreased in an Alzheimer's disease mouse model. According to these features, LMTK2 might be a promising therapeutic target in near future. However, further investigations are required to clarify the exact biological functions of this unique protein. PMID- 29631602 TI - Primary blood-hosts of mosquitoes are influenced by social and ecological conditions in a complex urban landscape. AB - BACKGROUND: Temperate urban landscapes support persistent and growing populations of Culex and Aedes mosquito vectors. Large urban mosquito populations can represent a significant risk for transmission of emergent arboviral infection. However, even large mosquito populations are only a risk to the animals they bite. The purpose of this study is to identify and assess spatial patterns of host-use in a temperate urban landscape with heterogeneous socio-economic and ecological conditions. RESULTS: Mosquito blood meals were collected from neighborhoods categorized along a socio-economic gradient in Baltimore, MD, USA. Blood meal hosts were identified for two Aedes (Ae. albopictus and Ae. japonicus) and three Culex (Cx. pipiens, Cx. restuans and Cx. salinarius) species. The brown rat (Rattus norvegicus) was the most frequently detected host in both Aedes species and Cx. salinarius. Human biting was evident in Aedes and Culex species and the proportion of human blood meals from Ae. albopictus varied significantly with neighborhood socio-economic status. Aedes albopictus was most likely to feed on human blood hosts (at 50%) in residential blocks categorized as having income above the city median, although there were still more total human bites detected from lower income blocks where Ae. albopictus was more abundant. Birds were the most frequently detected Culex blood hosts but were absent from all Aedes sampled. CONCLUSIONS: This study highlights fine-scale variation in host-use by medically important mosquito vectors and specifically investigates blood meal composition at spatial scales relevant to urban mosquito dispersal and human exposure. Further, the work emphasizes the importance of neighborhood economics and infrastructure management in shaping both the relative abundance of vectors and local blood feeding strategies. The invasive brown rat was an important blood source across vector species and neighborhoods in Baltimore. We show that social and economic conditions can be important predictors of transmission potential in urban landscapes and identify important questions about the role of rodents in supporting urban mosquito populations. PMID- 29631603 TI - Heat shock protein 70 promotes lipogenesis in HepG2 cells. AB - BACKGROUND: The increasing prevalence of non-alcoholic fatty liver disease (NAFLD) has followed the international rise in obesity rates. Multiple mechanisms are involved in NAFLD, including endoplasmic reticulum stress and oxidative stress. Heat shock protein 70 (HSP70), which is abundant in most organisms, is sensitive to stress. However, the role of HSP70 in NAFLD has not been investigated. Here, we investigated the possible role of HSP70 in lipid synthesis. METHODS: C57BL/6 mice were fed a high-fat diet, and HepG2 cells were treated with 0.5 mM palmitic acid (PA). HSP70 expression was detected by qPCR, Western blot and immunohistochemistry. Total cholesterol (TC) and triglyceride (TG) levels were detected by enzyme-linked immunosorbent assay (ELISA). After Hsp70 overexpression and knockdown, TC and TG levels and FAS, SCD, and ACC expression were detected. RESULTS: HSP70 expression was significantly increased in the livers of obese mice. In vitro, HSP70 expression was markedly induced by PA in HepG2 cells. Notably, HSP70 overexpression in HepG2 cells enhanced TC and TG synthesis, in parallel with the upregulation of lipogenic genes, including FAS, SCD and ACC. By contrast, HSP70 knockdown decreased the levels of cellular lipids and the expression of FAS, SCD, and ACC in HepG2 cells. Together, our results suggest that HSP70 may promote lipogenesis in HepG2 cells. CONCLUSIONS: Heat shock protein 70 promotes lipogenesis in HepG2 cells. PMID- 29631604 TI - Polymorphism of CONNEXIN37 gene is a risk factor for ischemic stroke in Han Chinese population. AB - BACKGROUND: Stroke has a high fatality and disability rate, and is one of the main burdens to human health. It is thus very important to identify biomarkers for the development of effective approaches for the prevention and treatment of stroke. Connexin37 is an anti-inflammatory cytokine and is involved in chronic inflammation and atherosclerosis. Recent studies have found that CONNEXIN37 gene variations are associated with atherosclerosis diseases, such as coronary heart disease and stroke, but its association with stroke in distinct human populations remains to be determined. We report here the analysis of the association of the single nucleotide polymorphisms (SNPs) of CONNEXIN37 with ischemic stroke in Han Chinese population. METHODS: Two SNPs of CONNEXIN37 gene were analyzed in 385 ischemic stroke patients and 362 hypertension control patients using ligase detection reaction (LDR) method. RESULTS: Logistic regression analysis demonstrated that, AG and GG genotypes of SNP rs1764390 and CC genotype of rs1764391 of CONNEXIN37 were associated with an increased risk of ischemic stroke, and that G allele of rs1764390 is a risk factor for ischemic stroke. Further, we found that SNP rs1764390 and SNP rs1764391 in CONNEXIN37 were associated with ischemic stroke under additive/dominant model, and recessive/dominant model, respectively. CONCLUSION: Our results indicate that CONNEXIN37 gene polymorphism is an ischemic stroke risk factor in Northern Han Chinese. PMID- 29631605 TI - Fabry disease in the Spanish population: observational study with detection of 77 patients. AB - BACKGROUND: Fabry disease is a multisystemic lysosomal storage disorder caused by the impairment of alpha-galactosidase A. The incidence of this rare disease is underestimated due to delayed diagnosis. Moreover, the management of the identified subjects is often complicated by the detection of variants of unclear diagnostic interpretation, usually identified in screening studies. We performed an observational study based on biochemical and genetic analysis of 805 dried blood spot samples from patients with clinical symptoms or family history of this pathology, which were collected from 109 Spanish hospitals, all over the country. RESULTS: We identified 77 new diagnosed patients with mutations related to classical Fabry disease, as well as 2 subjects with c.374A > T; p.His125Leu, a possible new mutation that need to be confirmed. Additionally, we detected 8 subjects carrying genetic variants possibly linked to late onset Fabry disease (p.Arg118Cys and p.Ala143Thr), 4 cases with polymorphism p.Asp313Tyr and 36 individuals with single nucleotide polymorphisms in intronic regions of GLA. Five of the identified mutations (c.431delG; c.1182delA; c.374A > T; c.932 T > C; c.125 T > A; c.778G > A), which were associated with a classical phenotype have not been previously described. Moreover 3 subjects presenting complex haplotypes made up by the association of intronic variants presented impaired levels of GLA transcripts and Gb3 deposits in skin biopsy. CONCLUSIONS: Enzymatic screening for Fabry Disease in risk population (2 or more clinical manifestations or family history of the disease) helped to identify undiagnosed patients and unravel the impairment of GLA expression in some subjects with complex haplotypes. PMID- 29631607 TI - Endoscopic submucosal injection of adipose-derived mesenchymal stem cells ameliorates TNBS-induced colitis in rats and prevents stenosis. AB - BACKGROUND: Mesenchymal stem cells have potential applications in inflammatory bowel disease due to their immunomodulatory properties. Our aim was to evaluate the feasibility, safety and efficacy of endoscopic administration of adipose derived mesenchymal stem cells (ASCs) in a colitis model in rats. METHODS: Colitis was induced in rats by rectal trinitrobenzenesulfonic acid (TNBS). After 24 h ASCs (107 cells) or saline vehicle were endoscopically injected into the distal colon. Rats were followed for 11 days. Daily weight, endoscopic score at days 1 and 11, macroscopic appearance at necropsy, colon length and mRNA expression of Foxp3 and IL-10 in mesenteric lymph nodes (MLN) were analyzed. RESULTS: Endoscopic injection was successful in all the animals. No significant adverse events or mortality due to the procedure occurred. Weight evolution was significantly better in the ASC group, recovering initial weight by day 11 (- 0.8% +/- 10.1%, mean +/- SD), whereas the vehicle group remained in weight loss ( 6.7% +/- 9.2%, p = 0.024). The endoscopic score improved in the ASC group by 47.1% +/- 5.3% vs. 21.8% +/- 6.6% in the vehicle group (p < 0.01). Stenosis was less frequent in the ASC group (4.8% vs. 41.2%, p < 0.01). Colon length significantly recovered in the ASC group versus the vehicle group (222.6 +/- 17.3 mm vs. 193.6 +/- 17.9 mm, p < 0.001). The endoscopic score significantly correlated with weight change, macroscopic necropsy score and colon length. Foxp3 and IL-10 mRNA levels in MLN recovered with ASC treatment. CONCLUSIONS: ASC submucosal endoscopic injection is feasible, safe and ameliorates TNBS-induced colitis in rats, especially stenosis. PMID- 29631606 TI - What can we learn from interventions that aim to increase policy-makers' capacity to use research? A realist scoping review. AB - BACKGROUND: Health policy-making can benefit from more effective use of research. In many policy settings there is scope to increase capacity for using research individually and organisationally, but little is known about what strategies work best in which circumstances. This review addresses the question: What causal mechanisms can best explain the observed outcomes of interventions that aim to increase policy-makers' capacity to use research in their work? METHODS: Articles were identified from three available reviews and two databases (PAIS and WoS; 1999-2016). Using a realist approach, articles were reviewed for information about contexts, outcomes (including process effects) and possible causal mechanisms. Strategy + Context + Mechanism = Outcomes (SCMO) configurations were developed, drawing on theory and findings from other studies to develop tentative hypotheses that might be applicable across a range of intervention sites. RESULTS: We found 22 studies that spanned 18 countries. There were two dominant design strategies (needs-based tailoring and multi-component design) and 18 intervention strategies targeting four domains of capacity, namely access to research, skills improvement, systems improvement and interaction. Many potential mechanisms were identified as well as some enduring contextual characteristics that all interventions should consider. The evidence was variable, but the SCMO analysis suggested that tailored interactive workshops supported by goal-focused mentoring, and genuine collaboration, seem particularly promising. Systems supports and platforms for cross-sector collaboration are likely to play crucial roles. Gaps in the literature are discussed. CONCLUSION: This exploratory review tentatively posits causal mechanisms that might explain how intervention strategies work in different contexts to build capacity for using research in policy-making. PMID- 29631608 TI - Transcriptional activator DOT1L putatively regulates human embryonic stem cell differentiation into the cardiac lineage. AB - BACKGROUND: Commitment of pluripotent stem cells into differentiated cells and associated gene expression necessitate specific epigenetic mechanisms that modify the DNA and corresponding histone proteins to render the chromatin in an open or closed state. This in turn dictates the associated genetic machinery, including transcription factors, acknowledging the cellular signals provided. Activating histone methyltransferases represent crucial enzymes in the epigenetic machinery that cause transcription initiation by delivering the methyl mark on histone proteins. A number of studies have evidenced the vital role of one such histone modifier, DOT1L, in transcriptional regulation. Involvement of DOT1L in differentiating pluripotent human embryonic stem (hES) cells into the cardiac lineage has not yet been investigated. METHODS: The study was conducted on in house derived (KIND1) and commercially available (HES3) human embryonic stem cell lines. Chromatin immunoprecipitation (ChIP) was performed followed by sequencing to uncover the cardiac genes harboring the DOT1L specific mark H3K79me2. Following this, dual immunofluorescence was employed to show the DOT1L co occupancy along with the cardiac progenitor specific marker. DOT1L was knocked down by siRNA to further confirm its role during cardiac differentiation. RESULTS: ChIP sequencing revealed a significant number of peaks characterizing H3K79me2 occupancy in the proximity of the transcription start site. This included genes like MYOF, NR2F2, NKX2.5, and HAND1 in cardiac progenitors and cardiomyocytes, and POU5F1 and NANOG in pluripotent hES cells. Consistent with this observation, we also show that DOT1L co-localizes with the master cardiac transcription factor NKX2.5, suggesting its direct involvement during gene activation. Knockdown of DOT1L did not alter the pluripotency of hES cells, but it led to the disruption of cardiac differentiation observed morphologically as well as at transcript and protein levels. CONCLUSIONS: Collectively, our data suggests the crucial role of H3K79me2 methyltransferase DOT1L for activation of NKX2.5 during the cardiac differentiation of hES cells. PMID- 29631609 TI - Use of lymphoscintigraphy to differentiate primary versus secondary lower extremity lymphedema after surgical lymphadenectomy: a retrospective analysis. AB - BACKGROUND: When managing patients with cancer, lymphedema of the lower limbs (LLL) is commonly reported as secondary to the surgical excision and/or irradiation of lymph nodes (LNs). In the framework of lymphoscintigraphic imaging performed to evaluate secondary LLL, some lympho-nodal presentations have been observed that could not be explained by the applied treatments, suggesting that these LLL might be primary. Therefore, all our lymphoscintigraphic examinations that were performed in patients for LLL after surgery for gynecological or urological cancer were retrospectively analyzed in order to evaluate the frequency in which these LLL might not be secondary (either completely or partially) but primary in origin. METHODS: Lymphoscintigraphies performed in 33 patients who underwent LN dissection (limited to the intra-abdominal LN) with or without radiotherapy for histologically confirmed ovarian cancer (n = 6), uterine cancer (n = 14 with cervical cancer and n = 7 with endometrial cancer), or prostate cancer (n = 6) were compared to lymphoscintigraphies obtained in primary LLL. RESULTS: In 12 (33% of the) patients (3 men plus 9 women, 4 with cervical cancer and 5 with endometrial cancer), scintigraphy of the lower limbs revealed lympho-nodal presentation that did not match with the expected consequences of the surgical and/or radiological treatments and were either suggestive or typical of primary lymphedema. CONCLUSIONS: This retrospective analysis of a limited but well-defined series of patients suggests that the appearance of LLL might not be related to cancer treatment(s) but that these LLL may represent the development of a primary lymphatic disease latent prior to the therapeutic interventions. PMID- 29631610 TI - Amendment of the OMERACT ultrasound definitions of joints' features in healthy children when using the DOPPLER technique. AB - BACKGROUND: Recently preliminary ultrasonography (US) definitions, in B mode, for normal components of pediatric joints have been developed by the OMERACT US group. The aim of the current study was to include Doppler findings in the evaluation and definition of normal joint features that can be visualized in healthy children at different age groups. METHODS: A multistep approach was used. Firstly, new additional definitions of joint components were proposed during an expert meeting. In the second step, these definitions, along with the preliminary B-mode-US definitions, were tested for feasibility in an exercise in healthy children at different age groups. In the last step, a larger panel of US experts were invited to join a web-based consensus process in order to approve the developed definitions using the Delphi methodology. A Likert scale of 1-5 was used to assess agreement. RESULTS: Physiological vascularity and fat pad tissue were identified and tested as two additional joint components in healthy children. Since physiological vascularity changes over the time in the growing skeleton, the final definition of Doppler findings comprised separate statements instead of a single full definition. A total of seven statements was developed and included in a written Delphi questionnaire to define and validate the new components. The final definitions for fat pad and physiological vascularity agreed by the group of experts reached 92.9% and 100% agreement respectively in a web survey. CONCLUSION: The inclusion of these two additional joints components which are linked to detection of Doppler signal in pediatric healthy joints will improve the identification of abnormalities in children with joint pathologies. PMID- 29631611 TI - Association of polymorphisms in MALAT1 with risk of coronary atherosclerotic heart disease in a Chinese population. AB - BACKGROUND: Metastasis associated lung adenocarcinoma transcript 1 (MALAT1) plays an important role in vascular remodeling. Down-regulation of MALAT1 can inhibit the proliferation of vascular endothelial cells and vascular smooth muscle cells, reduce cardiomyocyte apoptosis and improve left ventricular function, which is closely linked to numerous pathological processes such as coronary atherosclerotic heart disease (CAD). The aim of this study was to investigate whether polymorphisms in MALAT1 were associated with the susceptibility to CAD. METHODS: A total of 508 CAD patients and 562 age-, gender-, and ethnicity-matched controls were enrolled in this study. Four polymorphisms in MALAT1 (i.e., rs11227209, rs619586, rs664589, and rs3200401) were genotyped using a TaqMan allelic discrimination assay. RESULTS: The rs619586 AG/GG genotypes and G allele were associated with a reduced risk of CAD (AG/GG vs. AA: adjusted OR = 0.66, 95% CI: 0.48-0.91; G vs. A: adjusted OR = 0.68, 95% CI: 0.51-0.90). Stratification analyses showed that CAD patients with rs11227209 CG/GG, rs619586 AG/GG, and rs3200401 CT/TT genotypes exhibited lower levels of TCH (P = 0.02, 0.04, and 0.02, respectively). Moreover, CGCC haplotype was associated with a decreased risk of CAD (OR = 0.28, 95% CI: 0.16-0.48). Multivariate logistic regression analysis identified some independent risk factors for CAD, including rs619586 and rs664589. Subsequent combined analysis showed that the combined genotypes of rs619586AG/GG and rs664589CC were associated with a reduced risk of CAD (OR = 0.29; 95%CI, 0.16-0.53). CONCLUSIONS: These findings indicate that rs619586AG/GG genotypes in MALAT1 may protect against the occurrence of CAD. PMID- 29631613 TI - 'Worth the test?' Pragmatism, pill testing and drug policy in Australia. AB - BACKGROUND: Recent deaths of young Australian music festival attendees from 'party-drug' overdoses have sparked debate about the effectiveness of drug policies. Australia is widely lauded for its harm minimisation approach to drugs, and yet, over the last 30 years, it can be argued its policies have been fragmented, sometimes inconsistent and contradictory. The present article examines the root of this inconsistency, using it as a foundation to advocate for drug policy reform. In keeping with the goals of the National Drug Strategy to promote policy innovation, there is an opportunity to learn from international studies which have shown promising findings in the reduction of party-drug use and its harms through application of pill testing. METHOD: This paper evaluates Australia's National Drug Strategy and pill testing through a lens of pragmatism, to determine whether there is space for testing practices in contemporary policy. Specifically, the paper analyses current drug policy literature and research studies, examining a range of key drug use indicators, social and political debate and research evidence. RESULTS: The need for policy reform, attitudinal and cultural shifts and development of stronger cross-sectoral partnerships is highlighted, to ensure a rational and logical approach that genuinely tackles drug policy-making and strategy from a broad public health perspective. CONCLUSIONS: Using a theoretical frame of pragmatism and drawing from national and international research evidence, this paper recommends the integration of pill testing into Australia's harm minimisation strategy. PMID- 29631612 TI - Stromal TRIM28-associated signaling pathway modulation within the colorectal cancer microenvironment. AB - BACKGROUND: Stromal gene expression patterns predict patient outcomes in colorectal cancer. TRIM28 is a transcriptional co-repressor that regulates an abundance of genes through the KRAB domain family of transcription factors. We have previously shown that stromal expression of TRIM28 is a marker of disease relapse and poor survival in colorectal cancer. Here, we perform differential epithelium-stroma proteomic network analyses to characterize signaling pathways associated with TRIM28 within the tumor microenvironment. METHODS: Reverse phase protein arrays were generated from laser capture micro-dissected carcinoma and stromal cells from fresh frozen colorectal cancer tissues. Phosphorylation and total protein levels were measured for 30 cancer-related signaling pathway endpoints. Strength and direction of associations between signaling endpoints were identified using Spearman's rank-order correlation analysis and compared to TRIM28 levels. Expression status of TRIM28 in tumor epithelium and stromal fibroblasts was assessed using IHC in formalin fixed tissue and the epithelium to stroma protein expression ratio method. RESULTS: We found distinct proteomic networks in the epithelial and stromal compartments which were linked to expression levels of TRIM28. Low levels of TRIM28 in tumor stroma (high epithelium: stroma ratio) were found in 10 out of 19 cases. Upon proteomic network analyses, these stromal high ratio cases revealed moderate signaling pathway similarity exemplified by 76 significant Spearman correlations (rho >= 0.75, p <= 0.01). Furthermore, low levels of stromal TRIM28 correlated with elevated MDM2 levels in tumor epithelium (p = 0.01) and COX-2 levels in tumor stroma (p = 0.002). Low TRIM28 epithelium to stroma ratios were associated with elevated levels of caspases 3 and 7 in stroma (p = 0.041 and p = 0.036) and an increased signaling pathway similarity in stromal cells with 81 significant Spearman correlations (rho >= 0.75, p <= 0.01). CONCLUSIONS: By dissecting TRIM28 associated pathways in stromal fibroblasts and epithelial tumor cells, we performed comprehensive proteomic analyses of molecular networks within the tumor microenvironment. We found modulation of several signaling pathways associated with TRIM28, which may be attributed to the pleiotropic properties of TRIM28 through its translational suppression of the family of KRAB domain transcription factors in tumor stromal compartments. PMID- 29631614 TI - Neurofilament light as a blood biomarker for neurodegeneration in Down syndrome. AB - BACKGROUND: Down syndrome (DS) may be considered a genetic form of Alzheimer's disease (AD) due to universal development of AD neuropathology, but diagnosis and treatment trials are hampered by a lack of reliable blood biomarkers. A potential biomarker is neurofilament light (NF-L), due to its association with axonal damage in neurodegenerative conditions. METHODS: We measured blood NF-L concentrations in 100 adults with DS using Simoa NF-light(r) assays, and we examined relationships with age as well as cross-sectional and longitudinal dementia diagnosis. RESULTS: NF-L concentrations increased with age (Spearman's rho = 0.789, p < 0.001), with a steep increase after age 40, and they were predictive of dementia status (p = 0.022 adjusting for age, sex, and APOE4), but they showed no relationship with long-standing epilepsy or premorbid ability. Baseline NF-L concentrations were associated with longitudinal dementia status. CONCLUSIONS: NF-L is a biomarker for neurodegeneration in DS with potential for use in future clinical trials to prevent or delay dementia. PMID- 29631615 TI - Efficacy and long-term longitudinal follow-up of bone marrow mesenchymal cell transplantation therapy in a diabetic patient with recurrent lower limb bullosis diabeticorum. AB - : Bullosis diabeticorum is a rare presentation of cutaneous manifestation most commonly affecting the lower limbs in patients with diabetes. The appearance, often as insidious as its resolution, is characterized by tense blisters on the skin surfaces of the lower limbs and the feet. The cause still remains unclear, but it may relate to microangiopathy and neuropathy. In this report, we present a case of a 64-year-old male with multiple episodes of blistering in the left lateral lower limb after a traumatic fall who was subsequently diagnosed with type 2 diabetes mellitus. The patient had a history of poorly controlled blood glucose and subsequently developed vasculopathy and peripheral neuropathy. Despite appropriate glycemic control and antibiotics therapy, the patient developed recurrent bullosis diabeticorum on five separate occasions during a 2 year span from 2005 to 2007. Building on our success with ischemic diabetic foot, we used bone marrow mesenchymal stem cell (BMMSC) transplantation therapy for bullosis diabeticorum. After a 9-month treatment, this patient developed another episode of cellulitis in the same lower limb which was successfully treated with antibacterial therapy. It is interesting that the patient reported no recurrence in the next 10-year follow-up span. This study demonstrates that bullosis diabeticorum could appear even before the onset of diabetes, and vascular insufficiency predisposes to the occurrence of bullosis diabeticorum. Our findings suggest that autologous BMMSC transplantation therapy may be an effective measure for recurrent bullosis diabeticorum; however, this will require further investigation to be conclusive. Early identification of diabetes and its complications and appropriate treatment may improve clinical outcomes and prevent lower limb amputation. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00955669 . Registered on August 10, 2009. PMID- 29631616 TI - Health-related quality of life in pediatric and adolescent patients with transfusion-dependent beta-thalassemia in upper Egypt (single center study). AB - BACKGROUND: Thalassemia is a major health problem that disturbs the lifestyle of the affected patient. The aim of this work is to detect the impact of thalassemia on the quality of life regarding physical, social, emotional, psychological scored assessment. METHODS: A case-control survey was conducted in Minia University children's hospital on 64 patients recruiting pediatric hematology outpatient clinic from July 2014 to February 2017. PedsQLTM 4.0 Generic Core Scale (Arabic version) was used to assess HRQOL in 64 thalassemia patients between 8 and 18 years of ages. Other related clinical data of the involved patients were collected from the pediatric hematology records. RESULTS: Mean physical, emotional, social, school performance, psychological and total scores ( 36.9 +/- 20.9, 49.4 +/- 17, 47.2 +/- 21.3, 38.5 +/- 15.5, 45.3 +/- 13.8, 47.9 +/ 38.8 respectively) were significantly decreased compared with control (p = 0.001 for all). The younger age group had better scores regarding social, emotional, psychological and total scores compared to older ones (p = 0.01, 0.03, 0.01 and 0.009 respectively). Older age of starting transfusion was statistically significant protecting factor from poor physical QOL in thalassemia patients (OR = 0.96, p = 0.03). The presence of hepatomegaly was a statistically significant predictor for poor physical QOL (OR = 8.5, p = 0.02). Household income was the statistically significant predictor for poor emotional QOL (OR = 5.03, p = 0.04). High serum ferritin was the statistically significant predictor for poor social QOL (OR = 1.1, CI 95%=, p = 0.04). Regarding poor psychological QOL (OR = 0.94, p = 0.01) and total QOL (OR = 0.94, p = 0.01) scores, older age of starting transfusion was the statistically significant protecting factor. CONCLUSION: Scheduled programs giving psychosocial help and a network connecting between the patients, school officials, thalassemia caregivers and the physician is required especially in developing countries where the health services are not integrated with social organizations. Special school services for thalassemia patients are required to deal with the repeated absence and anemia induced low mental performance of thalassemia children. PMID- 29631617 TI - Neural stem cells for disease modeling and evaluation of therapeutics for infantile (CLN1/PPT1) and late infantile (CLN2/TPP1) neuronal ceroid lipofuscinoses. AB - BACKGROUND: Infantile and late infantile neuronal ceroid lipofuscinoses (NCLs) are lysosomal storage diseases affecting the central nervous system (CNS). The infantile NCL (INCL) is caused by mutations in the PPT1 gene and late-infantile NCL (LINCL) is due to mutations in the TPP1 gene. Deficiency in PPT1 or TPP1 enzyme function results in lysosomal accumulation of pathological lipofuscin-like material in the patient cells. There is currently no small-molecular drug treatment for NCLs. RESULTS: We have generated induced pluripotent stem cells (iPSC) from three patient dermal fibroblast lines and further differentiated them into neural stem cells (NSCs). Using these new disease models, we evaluated the effect of delta-tocopherol (DT) and hydroxypropyl-beta-cyclodextrin (HPBCD) with the enzyme replacement therapy as the control. Treatment with the relevant recombinant enzyme or DT significantly ameliorated the lipid accumulation and lysosomal enlargement in the disease cells. A combination therapy of delta tocopherol and HPBCD further improved the effect compared to that of either drug used as a single therapy. CONCLUSION: The results demonstrate that these patient iPSC derived NCL NSCs are valid cell- based disease models with characteristic disease phenotypes that can be used for study of disease pathophysiology and drug development. PMID- 29631618 TI - Agreement between parent and child report of physical activity, sedentary and dietary behaviours in 9-12-year-old children and associations with children's weight status. AB - BACKGROUND: To date, population based surveys aimed at gaining insight in health related behaviour of children have often used either child self-reports or parent proxy reports. It remains unclear however, if surveys using different sources of information from either parents or children are comparable. In addition, (over)weight status of children can lead to under- and over reporting by parents and children as a result of social desirability bias. We aimed at gaining insight in the level of agreement between parents and child reports regarding aspects of certain dietary, physical activity and sedentary behaviours, and whether there are differences in agreement between parents and child reports in healthy-weight and overweight children. METHODS: Weighted kappa was used to determine the level of agreement between child and parent reports on health-related behaviour in 1998 parent-child dyads. We also stratified for weight status of the children. Information on children's health related behaviours was obtained by parental and children's questionnaires, and children's height and weight were measured. Associations between children's weight status and children reporting less, reporting more and reporting the same amount of health behaviour as their parents were investigated with multinomial logistic regression analysis. RESULTS: The Cohen's kappa coefficients ranged from almost perfect agreement for the variable means of transportation, fair for the variables breakfast consumption and frequency of outside play to slight for the variables duration of outside play, frequency and duration of TV/DVD viewing and family dinner. Overweight children were significantly more likely to report less breakfast consumption (OR = 2.6 (95% CI: 1.3 - 5.1)) and lower frequency of outside play than their parents (OR = 1.8 (95% CI: 1.1 - 2.9)). CONCLUSION: There can be considerable disagreement between the health related behaviours of children as reported by parents or the children themselves. Based on the present study, it cannot be concluded whether parents' or children's reports are more accurate. For future studies, social desirability and recall bias would be best demonstrated in a validation study comparing child and parent self-reports with more objective measures of physical activity and food intake. PMID- 29631619 TI - Histone hypo-acetylation of Sox9 mediates nicotine-induced weak cartilage repair by suppressing BMSC chondrogenic differentiation. AB - BACKGROUND: Nicotine has negative effects on tissue repair, little research concerns its effect on the cartilage repair of tissue engineering stem cells. The present study aimed to investigate the effects of nicotine on the bone marrow derived mesenchymal stem cells' (BMSCs) chondrogenic repair function of cartilage defects and explored the molecular mechanism. METHODS: A cartilage defect model of rat was repaired by BMSC transplantation, and treated with nicotine or saline at 2.0 mg/kg/d in 12 weeks. Nicotine's effect on chondrogenic differentiation was studied by exposing BMSCs to nicotine at 0.1, 1, 10, and 100 MUM, and methyllycaconitine (MLA), which is a selective alpha7-nicotinic acetylcholine receptor (nAChR) inhibitor and si-RNA of nuclear factor of activated T cells 2 (NFATc2), were used to verify the molecular mechanism of nicotine's effect. RESULTS: Data showed that nicotine inhibited cartilage repair function by suppressing SRY-type high-mobility group box 9 (Sox9) in regenerated tissues. Further in vitro study demonstrated that nicotine enhanced intracellular Ca2+ and activity of calcineurin (CaN) through alpha7-nAChR, increased the nucleic expressions of NFATc2 and the bindings to SOX9 promoter, and thus reduced the acetylation of H3K9 and H3K14 in SOX9 promoter. CONCLUSIONS: Findings from this study demonstrated that nicotine suppressed the chondrogenic differentiation of BMSCs in vivo and in vitro, which offers insight into the risk assessment of cartilage defect repair in a nicotine exposure population and its therapeutic target. PMID- 29631620 TI - Low sequence diversity of the prion protein gene (PRNP) in wild deer and goat species from Spain. AB - The first European cases of chronic wasting disease (CWD) in free-ranging reindeer and wild elk were confirmed in Norway in 2016 highlighting the urgent need to understand transmissible spongiform encephalopathies (TSEs) in the context of European deer species and the many individual populations throughout the European continent. The genetics of the prion protein gene (PRNP) are crucial in determining the relative susceptibility to TSEs. To establish PRNP gene sequence diversity for free-ranging ruminants in the Northeast of Spain, the open reading frame was sequenced in over 350 samples from five species: Iberian red deer (Cervus elaphus hispanicus), roe deer (Capreolus capreolus), fallow deer (Dama dama), Iberian wild goat (Capra pyrenaica hispanica) and Pyrenean chamois (Rupicapra p. pyrenaica). Three single nucleotide polymorphisms (SNPs) were found in red deer: a silent mutation at codon 136, and amino acid changes T98A and Q226E. Pyrenean chamois revealed a silent SNP at codon 38 and an allele with a single octapeptide-repeat deletion. No polymorphisms were found in roe deer, fallow deer and Iberian wild goat. This apparently low variability of the PRNP coding region sequences of four major species in Spain resembles previous findings for wild mammals, but implies that larger surveys will be necessary to find novel, low frequency PRNP gene alleles that may be utilized in CWD risk control. PMID- 29631621 TI - Postoperative infection caused by Acinetobacter baumannii misdiagnosed as a free living amoeba species in a humeral head hemiarthroplasty patient: a case report. AB - BACKGROUND: Acinetobacter baumannii is ubiquitous, facultative intracellular, and opportunistic bacterial pathogen. Its unique abilities allow it to survive in a diverse range of environments, including health care settings, leading to nosocomial infections. And its exceptional ability to develop resistance to multiple antibiotics leaves few drug options for treatment. It has been recognized as a leading cause of nosocomial pneumonia and bacteremia over the world. CASE PRESENTATION: In this case, a 73-year-old woman presented with a Neer Group VI proximal humeral fracture. Six hours after a successfully performed hemiarthroplasty, she developed continuous fever. Clinical examination revealed that the vitals were regular. Laboratory and radiographic examinations revealed only elevated procalcitonin levels. Blood culture revealed no bacterial or fungal growth. Cooling treatment and empirical broad-spectrum antibiotic therapy showed no apparent effect. CONCLUSIONS: We report a postoperative infection caused by Acinetobacter baumannii. The infectious pathogen was identified via molecular DNA sequencing and was initially misidentified as a free-living amoeba species upon microscopic examinations. The patient was mistreated with antiamebic combination therapy. Her symptoms persisted for over 4 months and were eventually followed by her death. PMID- 29631622 TI - Relational continuity with primary and secondary care doctors: a qualitative study of perceptions of users of the Catalan national health system. AB - BACKGROUND: In the current context of increasingly fragmented healthcare systems where patients are seen by multiple doctors in different settings, patients' relational continuity with one doctor is regaining relevance; however little is known about relational continuity with specialists. The aim of this study is to explore perceptions of relational continuity with primary care and secondary care doctors, its influencing factors and consequences from the viewpoint of users of the Catalan national health system (Spain). METHODS: We conducted a descriptive interpretative qualitative study using a two-stage theoretical sample; (i) contexts: three healthcare areas in the Catalan national health system with differing characteristics; (ii) informants: users 18 years or older attended to at both care levels. Sample size (n = 49) was reached by saturation. Data were collected by individual semi-structured interviews, which were audio recorded and transcribed. A thematic content analysis was carried out segmenting data by study area, and leaving room for new categories to emerge from the data. RESULTS: Patients across the areas studied generally experienced consistency of primary care doctors (PCD), alongside some inconsistency of specialists. Consistency of specialists did not seem to be relevant to some patients when their clinical information was shared and used. Patients who experienced consistency and frequent visits with the same PCD or specialist described and valued having established an ongoing relationship characterised by personal trust and mutual accumulated knowledge. Identified consequences were diverse and included, for example, facilitated diagnosis or improved patient-doctor communication. The ascription to a PCD, a health system-related factor, facilitated relational continuity with the PCD, whereas organizational factors (for instance, the size of the primary care centre) favoured consistency of PCD and specialists. Doctor related factors (for example, high technical competence or commitment to patient care) particulary fostered the development of an ongoing relationship. CONCLUSIONS: Consistency of doctors differs depending on the care level as does the relevance attributed to it. Most influencing factors can be applied to both care levels and might be addressed by healthcare managers to foster relational continuity. More research is needed to fully understand the relevance patients assign to relational continuity with specialists. PMID- 29631623 TI - Reproducible protocols for metagenomic analysis of human faecal phageomes. AB - BACKGROUND: Recent studies have demonstrated that the human gut is populated by complex, highly individual and stable communities of viruses, the majority of which are bacteriophages. While disease-specific alterations in the gut phageome have been observed in IBD, AIDS and acute malnutrition, the human gut phageome remains poorly characterised. One important obstacle in metagenomic studies of the human gut phageome is a high level of discrepancy between results obtained by different research groups. This is often due to the use of different protocols for enriching virus-like particles, nucleic acid purification and sequencing. The goal of the present study is to develop a relatively simple, reproducible and cost-efficient protocol for the extraction of viral nucleic acids from human faecal samples, suitable for high-throughput studies. We also analyse the effect of certain potential confounding factors, such as storage conditions, repeated freeze-thaw cycles, and operator bias on the resultant phageome profile. Additionally, spiking of faecal samples with an exogenous phage standard was employed to quantitatively analyse phageomes following metagenomic sequencing. Comparative analysis of phageome profiles to bacteriome profiles was also performed following 16S rRNA amplicon sequencing. RESULTS: Faecal phageome profiles exhibit an overall greater individual specificity when compared to bacteriome profiles. The phageome and bacteriome both exhibited moderate change when stored at + 4 degrees C or room temperature. Phageome profiles were less impacted by multiple freeze-thaw cycles than bacteriome profiles, but there was a greater chance for operator effect in phageome processing. The successful spiking of faecal samples with exogenous bacteriophage demonstrated large variations in the total viral load between individual samples. CONCLUSIONS: The faecal phageome sequencing protocol developed in this study provides a valuable additional view of the human gut microbiota that is complementary to 16S amplicon sequencing and/or metagenomic sequencing of total faecal DNA. The protocol was optimised for several confounding factors that are encountered while processing faecal samples, to reduce discrepancies observed within and between research groups studying the human gut phageome. Rapid storage, limited freeze-thaw cycling and spiking of faecal samples with an exogenous phage standard are recommended for optimum results. PMID- 29631624 TI - Hemorrhagic stroke after Epley maneuver: a case report. AB - BACKGROUND: This is the first case to our knowledge of a serious adverse event following the Epley maneuver, which is the treatment of choice for benign paroxysmal positional vertigo (BPPV), the most common vestibular disorder in adults. CASE PRESENTATION: A 77 year old female presented for outpatient evaluation of vertigo at a tertiary otolaryngology clinic. She was found to have BPPV clinically, and elected to have a particle repositioning maneuver (Epley maneuver) performed in clinic. Immediately following Epley maneuver, she had severe nausea and vomiting, with evolving visual changes. A CT angiogram of the brain was performed urgently through the emergency department and demonstrated an acute intraparenchymal hemorrhage in the occipital lobe. After medical stabilization and rehabilitation, the patient continues to have a permanent visual field deficit. CONCLUSION: The Epley maneuver is safe and effective, and there are no prior reports of serious adverse events associated with its use. This case, in which a patient experienced a hemorrhagic stroke after undergoing the Epley maneuver, is the first and sole case in the medical literature of an Epley-associated serious adverse event. The indirect causation and extreme rarity of this event do not warrant any change to patterns of practice. PMID- 29631625 TI - Molecular characterization of exonic rearrangements and frame shifts in the dystrophin gene in Duchenne muscular dystrophy patients in a Saudi community. AB - BACKGROUND: In individuals with Duchenne muscular dystrophy (DMD), exon skipping treatment to restore a wild-type phenotype or correct the frame shift of the mRNA transcript of the dystrophin (DMD) gene are mutation-specific. To explore the molecular characterization of DMD rearrangements and predict the reading frame, we simultaneously screened all 79 DMD gene exons of 45 unrelated male DMD patients using a multiplex ligation-dependent probe amplification (MLPA) assay for deletion/duplication patterns. Multiplex PCR was used to confirm single deletions detected by the MLPA. RESULTS: There was an obvious diagnostic delay, with an extremely statistically significant difference between the age at initial symptoms and the age of clinical evaluation of DMD cases (t value, 10.3; 95% confidence interval 5.95-8.80, P < 0.0001); the mean difference between the two groups was 7.4 years. Overall, we identified 147 intragenic rearrangements: 46.3% deletions and 53.7% duplications. Most of the deletions (92.5%) were between exons 44 and 56, with exon 50 being the most frequently involved (19.1%). Eight new rearrangements, including a mixed deletion/duplication and double duplications, were linked to seven cases with DMD. Of all the cases, 17.8% had duplications with no hot spots. In addition, confirmation of the reading frame hypothesis helped account for new DMD rearrangements in this study. We found that 81% of our Saudi patients would potentially benefit from exon skipping, of which 42.9% had a mutation amenable to skipping of exon 51. CONCLUSIONS: Our study could generate considerable data on mutational rearrangements that may promote future experimental therapies in Saudi Arabia. PMID- 29631626 TI - First study of correlation between oleic acid content and SAD gene polymorphism in olive oil samples through statistical and bayesian modeling analyses. AB - BACKGROUND: Virgin olive oil is appreciated for its particular aroma and taste and is recognized worldwide for its nutritional value and health benefits. The olive oil contains a vast range of healthy compounds such as monounsaturated free fatty acids, especially, oleic acid. The SAD.1 polymorphism localized in the Stearoyl-acyl carrier protein desaturase gene (SAD) was genotyped and showed that it is associated with the oleic acid composition of olive oil samples. However, the effect of polymorphisms in fatty acid-related genes on olive oil monounsaturated and saturated fatty acids distribution in the Tunisian olive oil varieties is not understood. METHODS: Seventeen Tunisian olive-tree varieties were selected for fatty acid content analysis by gas chromatography. The association of SAD.1 genotypes with the fatty acids composition was studied by statistical and Bayesian modeling analyses. RESULTS: Fatty acid content analysis showed interestingly that some Tunisian virgin olive oil varieties could be classified as a functional food and nutraceuticals due to their particular richness in oleic acid. In fact, the TT-SAD.1 genotype was found to be associated with a higher proportion of mono-unsaturated fatty acids (MUFA), mainly oleic acid (C18:1) (r = - 0.79, p < 0.000) as well as lower proportion of palmitic acid (C16:0) (r = 0.51, p = 0.037), making varieties with this genotype (i.e. Zarrazi and Tounsi) producing more monounsaturated oleic acid (C18: 1) than saturated acid. These varieties could be thus used as nutraceuticals and functional food. CONCLUSION: The SAD.1 association with the oleic acid composition of olive oil was identified among the studied varieties. This correlation fluctuated between studied varieties, which might elucidate variability in lipidic composition among them and therefore reflecting genetic diversity through differences in gene expression and biochemical pathways. SAD locus would represent an excellent marker for identifying interesting amongst virgin olive oil lipidic composition. PMID- 29631627 TI - Acute lung injury by gastric fluid instillation: activation of myofibroblast apoptosis during injury resolution. AB - BACKGROUND: Gastric contents aspiration in humans has variable consequences depending on the volume of aspirate, ranging from subclinical pneumonitis to respiratory failure with up to 70% mortality. Several experimental approaches have been used to study this condition. In a model of single orotracheal instillation of gastric fluid we have shown that severe acute lung injury evolves from a pattern of diffuse alveolar damage to one of organizing pneumonia (OP), that later resolves leaving normal lung architecture. Little is known about mechanisms of injury resolution after a single aspiration that could be dysregulated with repetitive aspirations. We hypothesized that, in a similar way to cutaneous wound healing, apoptosis may participate in lung injury resolution by reducing the number of myofibroblasts and by affecting the balance between proteases and antiproteases. Our aim was to study activation of apoptosis as well as MMP-2/TIMP-2 balance in the sub-acute phase (4-14 days) of gastric fluid induced lung injury. METHODS: Anesthesized Sprague-Dawley rats received a single orotracheal instillation of gastric fluid and were euthanized 4, 7 and 14 days later (n = 6/group). In lung tissue we studied caspase-3 activation and its location by double immunofluorescence for cleaved caspase-3 or TUNEL and alpha SMA. MMP-2/TIMP-2 balance was studied by zymography and Western blot. BALF levels of TGF-beta1 were measured by ELISA. RESULTS: An OP pattern with Masson bodies and granulomas was seen at days 4 and 7 that was no longer present at day 14. Cleaved caspase-3 increased at day 7 and was detected by immunofluorescence in Masson body-alpha-SMA-positive and -negative cells. TUNEL-positive cells at days 4 and 7 were located mainly in Masson bodies. Distribution of cleaved caspase-3 and TUNEL-positive cells at day 14 was similar to that in controls. At the peak of apoptosis (day 7), an imbalance between MMP-2 activity and TIMP-2 expression was produced by reduction in TIMP-2 expression. CONCLUSIONS: Apoptosis is activated in Masson body-alpha-SMA-positive and -negative cells during the sub acute phase of gastric fluid-induced lung injury. This mechanism likely contributes to OP resolution, by reducing myofibroblast number and new collagen production. In addition, pre-formed collagen degradation is favored by an associated MMP-2/TIMP-2 imbalance. PMID- 29631628 TI - Characterizing oral microbial communities across dentition states and colonization niches. AB - METHODS: The present study aimed to identify patterns and processes in acquisition of oral bacteria and to characterize the microbiota of different dentition states and habitats. Mucosal, salivary, supragingival, and subgingival biofilm samples were collected from orally and systemically healthy children and mother-child dyads in predentate, primary, mixed, and permanent dentitions. 16S rRNA gene sequences were compared to the Human Oral Microbiome Database (HOMD). Functional potential was inferred using PICRUSt. RESULTS: Unweighted and weighted UniFrac distances were significantly smaller between each mother-predentate dyad than infant-unrelated female dyads. Predentate children shared a median of 85% of species-level operational taxonomic units (s-OTUs) and 100% of core s-OTUs with their mothers. Maternal smoking, but not gender, mode of delivery, feeding habits, or type of food discriminated between predentate microbial profiles. The primary dentition demonstrated expanded community membership, structure, and function when compared to the predentate stage, as well as significantly lower similarity between mother-child dyads. The primary dentition also included 85% of predentate core s-OTUs. Subsequent dentitions exhibited over 90% similarity to the primary dentition in phylogenetic and functional structure. Species from the predentate mucosa as well as new microbial assemblages were identified in the primary supragingival and subgingival microbiomes. All individuals shared 65% of species between supragingival and subgingival habitats; however, the salivary microbiome exhibited less than 35% similarity to either habitat. CONCLUSIONS: Within the limitations of a cross-sectional study design, we identified two definitive stages in oral bacterial colonization: an early predentate imprinting and a second wave with the eruption of primary teeth. Bacterial acquisition in the oral microbiome is influenced by the maternal microbiome. Personalization begins with the eruption of primary teeth; however, this is limited to phylogeny; functionally, individuals exhibit few differences, suggesting that microbial assembly may follow a defined schematic that is driven by the functional requirements of the ecosystem. This early microbiome forms the foundation upon which newer communities develop as more colonization niches emerge, and expansion of biodiversity is attributable to both introduction of new species and increase in abundance of predentate organisms. PMID- 29631631 TI - Evaluation of the reinforced integrated disease surveillance and response strategy using short message service data transmission in two southern regions of Madagascar, 2014-15. AB - BACKGROUND: The Integrated Disease Surveillance and Response (IDSR) strategy was introduced in Madagascar in 2007. Information was collected by Healthcare structures (HS) on paper forms and transferred to the central level by post or email. Completeness of data reporting was around 20% in 2009-10. From 2011, in two southern regions data were transmitted through short messages service using one telephone provider. We evaluated the system in 2014-15 to determine its performance before changing or expanding it. METHODS: We randomly selected 80 HS and interviewed their representatives face-to-face (42) or by telephone (38). We evaluated knowledge of surveillance activities and selected case definitions, number of SMS with erroneous or missing information among the last ten transferred SMS, proportion of weekly reports received in the last 4 weeks and of the last four health alerts notified within 48 h, as well as mobile phone network coverage. RESULTS: Sixty-four percent of 80 interviewed HS representatives didn't know their terms of reference, 83% were familiar with the malaria case definition and 32% with that of dengue. Ninety percent (37/41) of visited HS had five or more errors and 47% had missing data in the last ten SMS they transferred. The average time needed for weekly IDSR data compilation was 24 min in the Southern and 47 in the South-eastern region. Of 320 expected SMS 232 (73%) were received, 136 (43%) of them in time. Out of 38 alerts detected, four were notified on time. Nine percent (7/80) of HS had no telephone network with the current provider. CONCLUSIONS: SMS transfer has improved IDSR data completeness, but timeliness and data quality remain a problem. Healthcare staff needs training on guidelines and case definitions. From 2016, data are collected and managed electronically to reduce errors and improve the system's performance. PMID- 29631630 TI - Oncolytic activity of a coxsackievirus B3 strain in human endometrial cancer cell lines. AB - BACKGROUND: Endometrial cancer (EC) is one of the most common gynecological malignancies globally. Although progress has been made in surgical and other adjuvant therapies, there is still a great need to develop new approaches to further reduce the incidence and mortality of EC. Oncolytic virotherapy offers a novel promising option of cancer treatment and has demonstrated good efficacy in preclinical models and clinical trials. However, only few oncolytic viruses have been tested for EC treatment. In this study, the potential of an oncolytic coxsackievirus B3 (CV-B3) strain 2035A (CV-B3/2035A) was investigated as a novel biotherapeutic agent against EC. METHODS: Human EC cell lines (Ishikawa, HEC-1-A and HEC-1-B) were infected with CV-B3/2035A, and viral replication and cytotoxic effects were evaluated in vitro. CV-B3/2035A-induced oncolysis was also investigated in nude mice bearing EC xenografts in vivo and in patient-derived EC samples ex vivo. RESULTS: Human EC cell lines expressing different levels of CAR and DAF were all susceptible to infection by CV-B3/2035A and supported efficient viral replication in vitro. In the EC xenograft/nude mouse model, both intratumoral and intravenous administrations of CV-B3-2035A exerted significant therapeutic effects against pre-established EC tumors without causing significant treatment-related toxicity and mortality in nude mice. Moreover, CV-B3/2035A treatment resulted in decreased viability of patient-derived EC samples ex vivo. CONCLUSIONS: CV-B3/2035A showed oncolytic activity in human EC cell lines both in vitro and in vivo as well as in patient-derived EC samples ex vivo and thus could be used as an alternative virotherapy agent for the treatment of EC. PMID- 29631629 TI - Flagellin-fused protein targeting M2e and HA2 induces potent humoral and T-cell responses and protects mice against various influenza viruses a subtypes. AB - BACKGROUND: Current influenza vaccines are mainly strain-specific and have limited efficacy in preventing new, potentially pandemic, influenza strains. Efficient control of influenza A infection can potentially be achieved through the development of broad-spectrum vaccines based on conserved antigens. A current trend in the design of universal flu vaccines is the construction of recombinant proteins based on combinations of various conserved epitopes of viral proteins (M1, M2, HA2, NP). In this study, we compared the immunogenicity and protective action of two recombinant proteins which feature different designs and which target different antigens. RESULTS: Balb/c mice were immunized subcutaneously with Flg-HA2-2-4M2ehs or FlgSh-HA2-2-4M2ehs; these constructs differ in the location of hemagglutinin's HA2-2(76-130) insertion into flagellin (FliC). The humoral and T-cell immune responses to these constructs were evaluated. The simultaneous expression of different M2e and HA2-2(76-130) in recombinant protein form induces a strong M2e-specific IgG response and CD4+/ CD8+ T-cell response. The insertion of HA2-2(76-130) into the hypervariable domain of flagellin greatly increases antigen-specific T-cell response, as evidenced by the formation of multi-cytokine-secreting CD4+, CD8+ T-cells, Tem, and Tcm. Both proteins provide full protection from lethal challenge with A/H3N2 and A/H7N9. CONCLUSION: Our results show that highly conserved M2e and HA2-2(76-130) can be used as important targets for the development of universal flu vaccines. The location of the HA2 2(76-130) peptide's insertion into the hypervariable domain of flagellin had a significant effect on the T-cell response to influenza antigens, as seen by forming of multi-cytokine-secreting CD4+ and CD8+ T-cells. PMID- 29631632 TI - "We are like co-wives": Traditional healers' views on collaborating with the formal Child and Adolescent Mental Health System in Uganda. AB - BACKGROUND: Early identification and management of mental illness in childhood and adolescence helps to avert debilitating mental illness in adulthood but the attention given to Child and Adolescent Mental Health (CAMH) has until recently been low. Traditional healers are often consulted by patients with mental illness and in Uganda, up to 60% of patients attending traditional healers have moderate to severe mental illness. Poor access to CAMH care in Uganda creates a treatment gap that could be met through enhanced collaboration between traditional healers and biomedical health systems. The aim of this study was to explore traditional healers' views on their collaboration with biomedical health systems so as to inform the implementation of strategies to improve access to CAMH services in Uganda. METHODS: In-depth interviews with 20 purposively selected traditional healers were conducted in November 2015. A semi-structured interview guide was used to explore: 1) The experiences of traditional healers with mental ill-health in children and adolescents; 2) their willingness to collaborate with the formal health system; and 3) their perception of clinicians' willingness to collaborate with them. Interviews were conducted in local languages and tape recorded. Data were analysed using thematic analysis. RESULTS: Traditional healers described several experiences managing children and adolescents with mental illness, which they ascribed to spiritual and physical causes. The spiritual explanations were a consequence of unhappy ancestral spirits, modern religions and witchcraft, while physical causes mentioned included substance abuse and fevers. No traditional healer had received a patient referred to them from a medical clinic although all had referred patients to clinics for non-mental health reasons. Traditional healers expressed distrust in biomedical health systems and believed their treatments were superior to medical therapies in alleviating mental suffering. They expressed willingness to collaborate with biomedical providers. However, traditional healers believe clinicians disregard them and would not be willing to collaborate with them. CONCLUSION: Potential for collaboration between traditional healers and biomedical health systems for improving access to CAMH services in Uganda exists, but is undermined by mutual mistrust and competition between traditional healers and clinicians. PMID- 29631633 TI - Potential benefits of combining transfluthrin-treated sisal products and long lasting insecticidal nets for controlling indoor-biting malaria vectors. AB - BACKGROUND: Transfluthrin vapour prevents mosquito bites by disrupting their host seeking behaviors. We measured the additional benefits of combining transfluthrin treated sisal decorations and long-lasting insecticidal nets (LLINs) with an aim of extending protection against early evening, indoor-biting malaria vectors when LLINs are ineffective. METHODS: We investigated the indoor protective efficacy of locally made sisal decorative baskets (0.28 m2) treated with 2.5 ml and 5.0 ml transfluthrin, in terms of mosquito density, exposure to bites and 24 h mortality. Experiments were conducted in experimental huts, located in Lupiro village, Ulanga District, south-eastern Tanzania. Human landing catches (HLC) were used to measure exposure to bites between 19:00-23:00 h. Each morning, at 06:00 h, mosquitoes were collected inside huts and in exit traps and monitored for 24 h mortality. RESULTS: Sisal decorative baskets (0.28 m2) treated with 2.5 ml and 5.0 ml transfluthrin deterred three-quarters of Anopheles arabiensis mosquitoes from entering huts (relative rate, RR = 0.26, 95% confidence interval, CI: 0.20-0.34, P < 0.001 and RR= 0.29, 95% CI: 0.22-0.37, P < 0.001, respectively). Both treatments induced a 10-fold increase in 24 h mortality of An. arabiensis mosquitoes (odds ratio, OR = 12.26, 95% CI: 7.70-19.51, P < 0.001 and OR = 18.42, 95% CI: 11.36-29.90, P < 0.001, respectively). CONCLUSIONS: Sisal decorative items treated with spatial repellents provide additional household and personal protection against indoor biting malaria and nuisance mosquitoes in the early evening, when conventional indoor vector control tools, such as LLINs, are not in use. We recommend future studies to investigate the epidemiological relevance of combining LLINs and transfluthrin decorated baskets in terms of their effect on reduction in malaria prevalence. PMID- 29631634 TI - Safety and tracking of intrathecal allogeneic mesenchymal stem cell transplantation in healthy and diseased horses. AB - BACKGROUND: It is currently unknown if the intrathecal administration of a high dose of allogeneic mesenchymal stem cells (MSCs) is safe, how MSCs migrate throughout the vertebral canal after intrathecal administration, and whether MSCs are able to home to a site of injury. The aims of the study were: 1) to evaluate the safety of intrathecal injection of 100 million allogeneic adipose-derived MSCs (ASCs); 2) to assess the distribution of ASCs after atlanto-occipital (AO) and lumbosacral (LS) injection in healthy horses; and 3) to determine if ASCs homed to the site of injury in neurologically diseased horses. METHODS: Six healthy horses received 100 * 106 allogeneic ASCs via AO (n = 3) or LS injection (n = 3). For two of these horses, ASCs were radiolabeled with technetium and injected AO (n = 1) or LS (n = 1). Neurological examinations were performed daily, and blood and cerebrospinal fluid (CSF) were evaluated prior to and at 30 days after injection. Scintigraphic images were obtained immediately postinjection and at 30 mins, 1 h, 5 h, and 24 h after injection. Three horses with cervical vertebral compressive myelopathy (CVCM) received 100 * 106 allogeneic ASCs labeled with green fluorescent protein (GFP) via AO injection and were euthanized 1-2 weeks after injection for a full nervous system necropsy. CSF parameters were compared using a paired student's t test. RESULTS: There were no significant alterations in blood, CSF, or neurological examinations at any point after either AO or LS ASC injections into healthy horses. The radioactive signal could be identified all the way to the lumbar area after AO ASC injection. After LS injection, the signal extended caudally but only a minimal radioactive signal extended further cranially. GFP-labeled ASCs were not present at the site of disease at either 1 or 2 weeks following intrathecal administration. CONCLUSIONS: The intrathecal injection of allogeneic ASCs was safe and easy to perform in horses. The AO administration of ASCs resulted in better distribution within the entire subarachnoid space in healthy horses. ASCs could not be found after 7 or 15 days of injection at the site of injury in horses with CVCM. PMID- 29631635 TI - Autophagy is increased following either pharmacological or genetic silencing of mGluR5 signaling in Alzheimer's disease mouse models. AB - Alzheimer's disease (AD) is characterized by neurotoxicity mediated by the accumulation of beta amyloid (Abeta) oligomers, causing neuronal loss and progressive cognitive decline. Genetic deletion or chronic pharmacological inhibition of mGluR5 by the negative allosteric modulator CTEP, rescues cognitive function and reduces Abeta aggregation in both APPswe/PS1DeltaE9 and 3xTg-AD mouse models of AD. In late onset neurodegenerative diseases, such as AD, defects arise at different stages of the autophagy pathway. Here, we show that mGluR5 cell surface expression is elevated in APPswe/PS1DeltaE9 and 3xTg-AD mice. This is accompanied by reduced autophagy (accumulation of p62) as the consequence of increased ZBTB16 expression and reduced ULK1 activity, as we have previously observed in Huntington's disease (HD). The chronic (12 week) inhibition of mGluR5 with CTEP in APPswe/PS1DeltaE9 and 3xTg-AD mice prevents the observed increase in mGluR5 surface expression. In addition, mGluR5 inactivation facilitates the loss of ZBTB16 expression and ULK1 activation as a consequence of ULK-Ser757 dephosphorylation, which promotes the loss of expression of the autophagy marker p62. Moreover, the genetic ablation of mGluR5 in APPswe/PS1DeltaE9 mice activated autophagy via similar mechanisms to pharmacological blockade. This study provides further evidence that mGluR5 overactivation contributes to inhibition of autophagy and can result in impaired clearance of neurotoxic aggregates in multiple neurodegenerative diseases. Thus, it provides additional support for the potential of mGluR5 inhibition as a general therapeutic strategy for neurodegenerative diseases such as AD and HD. PMID- 29631636 TI - Epidemiology of Sanfilippo syndrome: results of a systematic literature review. AB - BACKGROUND: Sanfilippo syndrome (mucopolysaccharidosis [MPS] III subtypes A, B, C, and D) is a rare autosomal recessive inherited metabolic disorder that causes progressive neurocognitive degeneration. This systematic literature review was undertaken to compile and assess published epidemiological data, including various frequency measures and geographical variation on Sanfilippo syndrome. METHODS: The following databases were systematically searched for terms related to Sanfilippo syndrome epidemiology: Medline, Embase, Cochrane Database of Systematic Reviews, Academic Search Complete, Cumulative Index to Nursing and Allied Health Literature, and the Centre for Reviews and Dissemination. Qualitative synthesis of research findings was performed. RESULTS: Of 2794 publications found in the initial search, 116 were deemed eligible after title and abstract screening. Following full-text review, 46 papers were included in the qualitative synthesis. Results of this systematic literature review indicate that lifetime risk at birth ranges from 0.17-2.35 per 100,000 live births for all 4 subtypes of MPS III together, and from 0.00-1.62 per 100,000 live births for the most frequent subtype, MPS IIIA. CONCLUSION: All 4 subtypes of MPS III are exceptionally rare, but they each have devastating effects on children. Higher quality epidemiological data are needed to appropriately target resources for disease research and management. PMID- 29631638 TI - Breast-feeding duration and child eating characteristics in relation to later vegetable intake in 2-6-year-old children in ten studies throughout Europe. AB - OBJECTIVE: Breast-feeding is thought to facilitate young children's acceptance of new foods, including vegetables, but the evidence for this relationship appears inconsistent across studies. Increasing children's vegetable intake remains challenging; therefore the present study aimed to investigate whether breast feeding duration predicts vegetable intake in 2-6-year-old children. DESIGN: Actual vegetable intake was measured in studies across three European countries. General linear model analyses with breast-feeding duration, sex and age of the child and maternal education as variables were used to predict children's vegetable intake per country. Additionally, the relationships between child eating behaviour characteristics (asked through the Child Eating Behaviour Questionnaire) and vegetable intake were investigated via Pearson correlations. SETTING: Daycare centres, schools and home settings in Denmark, Greece and the Netherlands. SUBJECTS: Children aged 2-6 years (n 750). RESULTS: Breast-feeding duration was positively associated with children's vegetable intake at 2-6 years old in Denmark (P<0.01) and the Netherlands (P<0.05), but not in Greece (P=0.17). Age of the child, maternal education and sex of the child did not predict vegetable intake in our sample. All countries showed an inverse relationship between food neophobia and children's vegetable intake and a positive relationship between vegetable liking and intake. CONCLUSIONS: The present study found that breast-feeding duration is a predictor of later vegetable intake, but that current child eating behaviour characteristics, such as vegetable liking, food neophobia and enjoyment of food, also influence vegetable intake. Besides encouragement of breast-feeding duration, strategies that support vegetable liking and food enjoyment and decrease food neophobia are needed to support young children's vegetable intake. PMID- 29631637 TI - A guideline for placement of an infra-acetabular screw based on anatomic landmarks via an intra-pelvic approach. AB - BACKGROUND: Due to demographic changes, more and more fracture patterns involving anterior acetabular structures occur. The infra-acetabular screw is seen a useful tool to increase stability in fixation of the acetabular cup. However, the exact position of this screw in relation to anatomic landmarks which are intra operatively palpable via an intra-pelvic approach has not yet been determined. METHODS: This biomorphometric experimental study references the ideal screw position of an infra-acetabular screw to anatomic landmarks palpable via an intra pelvic approach. Therefore, we created a computer tomography-based 3D-model of 40 patients (20 women, 20 men) who received a computer tomography (CT) scan of the pelvis for any other reason than an acetabular fracture. RESULTS: The entry point of an ideal infra-acetabular was of high constancy. At mean, this point was 10.2 mm caudal and 10.4 mm medial of the ilio-pubic/ilio-pectineal eminence. This reference is independent of age, gender, or physical dimensions. However, we found gender-dependent differences for the angulation and the length of the screw. CONCLUSIONS: This study provides a comprehensive guideline to determine the ideal entry point for an infra-acetabular screw via an intra-pelvic approach. The entry point is located 10.2 mm caudal and 10.4 mm medial of the ilio pubic/ilio-pectineal eminence. TRIAL REGISTRATION: Clinical Trial Registry University of Regensburg Z-2017-0930-1 . Registered 04. Dec 2017. PMID- 29631639 TI - Integrated Care Approaches Used for Transitions from Hospital to Community Care: A Scoping Review. AB - ABSTRACTIntegrated care is a promising approach for improving care transitions for older adults, but this concept is inconsistently defined and applied. This scoping review describes the size and nature of literature on integrated care initiatives for transitions from hospital to community care for older adults (aged 65 and older) and how this literature conceptualizes integrated care. A systematic search of literature from the past 10 years yielded 899 documents that were screened for inclusion by two reviewers. Of the 48 included documents, there were 26 journal articles and 22 grey literature documents. Analysis included descriptive statistics and a content analysis approach to summarize features of the integrated care initiatives. Results suggest that clinical and service delivery integration is being targeted rather than integration of funding, administration, and/or organization. To promote international comparison of integrated care initiatives aiming to improve care transitions, detailed descriptions of organizational context are also needed. PMID- 29631640 TI - Social anxiety in the eating disorders: a systematic review and meta-analysis. AB - Social anxiety disorder is one of the most common comorbid conditions in eating disorders (EDs). The aim of the current review and meta-analysis is to provide a qualitative summary of what is known about social anxiety (SA) in EDs, as well as to compare levels of SA in those with EDs and healthy controls. Electronic databases were systematically searched for studies using self-report measures of SA in ED populations. In total, 38 studies were identified, 12 of which were included in the meta-analyses. For both anorexia nervosa (AN) and bulimia nervosa, there were significant differences between ED groups and HCs, with medium to large effect sizes. Findings from the qualitative review indicate that levels of SA are similar across the ED diagnoses, and SA improves with treatment in AN. In addition, high levels of SA are associated with more severe ED psychopathology, but not body mass index. These findings add to the wider literature on socio-emotional functioning in EDs, and may have implications for treatment strategies. PMID- 29631641 TI - The transgenerational effect of maternal and paternal F1 low birth weight on bone health of second and third generation offspring. AB - Low birth weight programs diseases in adulthood, including adverse bone health. These diseases can have intergenerational and transgenerational origins, whereby transmission to subsequent generations occurs via both parental lines. Uteroplacental insufficiency surgery (Restricted) or sham surgery (Control) was performed on gestational day 18, in F0 Wistar-Kyoto rats. F1 Restricted males and females mated with breeders in order to generate F2 offspring of maternal and paternal lineages. F2 males and females were randomly selected for breeding to generate F3 offspring. F2 and F3 offspring did not have differences in birth weight irrespective of F1 low birth weight and parental line. Maternal line females had minor alterations to trabecular content and density at 6 months, these differences were not sustained at 12 months. Maternal line males had changes to trabecular content at 6 and 12 months; however, differences were no longer present at 16 months. Despite altered bone geometry at 12 and 16 months, bending strength remained unaffected at both ages. Bone health of paternal line females was not affected at 6 and 12 months. Paternal line males at 6 months had changes to trabecular and cortical content; cortical thickness, periosteal circumference and bending strength; however, these differences were no longer sustained at 12 and 16 months. Our data demonstrate that there is no transgenerational transmission of adverse bone health in F2 and F3 offspring, derived from low F1 birth weight females and males. Our results are novel, as bone health across generations and both parental lines has not been investigated in a model of low birth weight due to uteroplacental insufficiency. PMID- 29631642 TI - Organ and tissue donation from poisoned patients in the emergency department: A Canadian emergency physician survey. AB - CLINICIAN'S CAPSULE What is known about the topic? Patients who die from poisoning are potential organ or tissue donors but may represent an under referred population. What did this study ask? Do Canadian emergency physicians under-refer patients who die from poisoning for organ or tissue donation, and what characteristics influence referral rates? What did this study find? In a simulated context, poisoned patients were under-referred as potential organ or tissue donors, and both environmental and clinician characteristics influenced rates. Why does this study matter to clinicians? Understanding factors that affect donor referral may decrease the morbidity and mortality for patients waiting for organ or tissue donation. PMID- 29631643 TI - Pets, Social Participation, and Aging-in-Place: Findings from the Canadian Longitudinal Study on Aging. AB - ABSTRACTThe objective of this study was to assess whether pet ownership contributes to social participation and life satisfaction for older adults. We used baseline data from the Canadian Longitudinal Study on Aging (CLSA) for this purpose, and logistic regression models to estimate associations between social participation and life satisfaction for pet owners and non-owners. One third of all older adults (>= 65 years, n = 7,474) in our sample reported pet ownership. Pet owners were less likely than non-pet owners to report life satisfaction and to participate frequently in social, recreational, or cultural activities, but pet owners were no less satisfied than were non-owners with their current levels of social participation. For pet owners experiencing barriers to social participation, pets appeared protective of life satisfaction in some circumstances. Both individual characteristics and structural factors linked to the World Health Organization's age-friendly communities framework were relevant to understanding these findings. PMID- 29631644 TI - Review: Applications and benefits of sexed semen in dairy and beef herds. AB - The use of sexed semen in dairy and beef cattle production provides a number of benefits at both farm and industry levels. There is an increasing demand for dairy and beef products across the globe, which will necessitate a greater focus on improving production efficiency. In dairy farming, there is surplus production of unwanted male calves. Male dairy calves increase the risk of dystocia compared with heifer calves, and as an unwanted by-product of breeding with conventional semen, they have a low economic value. Incorporating sexed semen into the breeding programme can minimise the number of unwanted male dairy calves and reduce dystocia. Sexed semen can be used to generate herd replacements and additional heifers for herd expansion at a faster rate from within the herd, thereby minimising biosecurity risks associated with bringing in animals from different herds. Furthermore, the use of sexed semen can increase herd genetic gain compared with use of non-sorted semen. In dairy herds, a sustainable breeding strategy could combine usage of sexed semen to generate replacements only, and usage of beef semen on all dams that are not suitable for generating replacements. This results in increased genetic gain in dairy herd, increased value of beef output from the dairy herd, and reduced greenhouse gas emissions from beef. It is important to note, however, that even a small decrease in fertility of sexed semen relative to conventional semen can negate much of the economic benefit. A high fertility sexed semen product has the potential to accelerate herd expansion, minimise waste production, improve animal welfare and increase profitability compared with non-sorted conventional semen. PMID- 29631645 TI - Faculty mentorship during residency and professional development among practising emergency physicians. AB - CLINICIAN'S CAPSULE What is known about the topic? Mentorship is perceived to be an important component of residency education; however, evidence on its influence in emergency medicine is lacking. What did this study ask? We surveyed emergency physicians in Canada to identify the association between mentorship during residency and professional development and attitudes regarding mentorship. What did this study find? While many participants consulted their mentor regarding their first job, fewer contacted their mentor regarding subspecialty training or research. Why does this study matter to clinicians? Mentorship during residency may have a greater association with the location of practice than with academic scholarship or subspecialty training. PMID- 29631646 TI - Dissociation in victims of childhood abuse or neglect: a meta-analytic review. AB - Childhood abuse and neglect are associated with dissociative symptoms in adulthood. However, empirical studies show heterogeneous results depending on the type of childhood abuse or neglect and other maltreatment characteristics. In this meta-analysis, we systematically investigated the relationship between childhood interpersonal maltreatment and dissociation in 65 studies with 7352 abused or neglected individuals using the Dissociative Experience Scale (DES). We extracted DES-scores for abused and non-abused populations as well as information about type of abuse/neglect, age of onset, duration of abuse, and relationship to the perpetrator. Random-effects models were used for data synthesis, and meta regression was used to predict DES-scores in abused populations from maltreatment characteristics. The results revealed higher dissociation in victims of childhood abuse and neglect compared with non-abused or neglected subsamples sharing relevant population features (MAbuse = 23.5, MNeglect = 18.8, MControl = 13.8) with highest scores for sexual and physical abuse. An earlier age of onset, a longer duration of abuse, and parental abuse significantly predicted higher dissociation scores. This meta-analysis underlines the importance of childhood abuse/neglect in the etiology of dissociation. The identified moderators may inform risk assessment and early intervention to prevent the development of dissociative symptoms. PMID- 29631647 TI - A Qualitative Study of Paramedic Duty to Treat During Disaster Response. AB - OBJECTIVES: Disasters place unprecedented demands on emergency medical services and can test paramedics personal commitment as health care professionals. Despite this challenge, guidelines and codes of ethics are largely silent on the issue, providing little to no guidance on what is expected of paramedics or how they ought to approach their duty to treat in the face of risk. The objective of this research is to explore how paramedics view their duty to treat during disasters. METHODS: The authors employed qualitative methods to gather Australian paramedic perspectives. RESULTS: Our findings suggest that paramedic decisions around duty to treat will largely depend on individual perception of risk and competing obligations. A code of ethics for paramedics would be useful, but ultimately each paramedic will interpret these suggested guidelines based on individual values and the situational context. CONCLUSIONS: Coming to an understanding of the legal issues involved and the ethical-social expectations in advance of a disaster may assist paramedics to respond willingly and appropriately. (Disaster Med Public Health Preparedness. 2018;page 1 of 6). PMID- 29631649 TI - Review: Animal health and sustainable global livestock systems. AB - This paper discusses the sustainability of livestock systems, emphasising bidirectional relations with animal health. We review conventional and contrarian thinking on sustainability and argue that in the most common approaches to understanding sustainability, health aspects have been under-examined. Literature review reveals deep concerns over the sustainability of livestock systems; we recognise that interventions are required to shift to more sustainable trajectories, and explore approaches to prioritising in different systems, focusing on interventions that lead to better health. A previously proposed three tiered categorisation of 'hot spots', 'cold spots' and 'worried well' animal health trajectories provides a mental model that, by taking into consideration the different animal health status, animal health risks, service response needs and key drivers in each system, can help identify and implement interventions. Combining sustainability concepts with animal health trajectories allows for a richer analysis, and we apply this to three case studies drawn from North Africa and the Middle East; Bangladesh; and the Eastern Cape of South Africa. We conclude that the quest for sustainability of livestock production systems from the perspective of human and animal health is elusive and difficult to reconcile with the massive anticipated growth in demand for livestock products, mainly in low- and middle-income countries, as well as the aspirations of poor livestock keepers for better lives. Nevertheless, improving the health of livestock can contribute to health sustainability both through reducing negative health impacts of livestock and increasing efficiency of production. However, the choice of the most appropriate options must be under-pinned by an understanding of agro ecology, economy and values. We argue that a new pillar of One Health should be added to the three traditional sustainability pillars of economics, society and environment when addressing livestock systems. PMID- 29631661 TI - Quality Aspects in Industrial Chemistry. PMID- 29631648 TI - Associations between maternal prenatal cortisol and fetal growth are specific to infant sex: findings from the Wirral Child Health and Development Study. AB - Recent findings highlight that there are prenatal risks for affective disorders that are mediated by glucocorticoid mechanisms, and may be specific to females. There is also evidence of sex differences in prenatal programming mechanisms and developmental psychopathology, whereby effects are in opposite directions in males and females. As birth weight is a risk for affective disorders, we sought to investigate whether maternal prenatal cortisol may have sex-specific effects on fetal growth. Participants were 241 mothers selected from the Wirral Child Health and Development Study (WCHADS) cohort (n=1233) using a psychosocial risk stratifier, so that responses could be weighted back to the general population. Mothers provided saliva samples, which were assayed for cortisol, at home over 2 days at 32 weeks gestation (on waking, 30-min post-waking and during the evening). Measures of infant birth weight (corrected for gestational age) were taken from hospital records. General population estimates of associations between variables were obtained using inverse probability weights. Maternal log of the area under the curve cortisol predicted infant birth weight in a sex-dependent manner (interaction term P=0.029). There was a positive and statistically significant association between prenatal cortisol in males, and a negative association in females that was not statistically significant. A sex interaction in the same direction was evident when using the waking (P=0.015), and 30-min post-waking (P=0.013) cortisol, but not the evening measure. There was no interaction between prenatal cortisol and sex to predict gestational age. Our findings add to an emerging literature that suggests that there may be sex specific mechanisms that underpin fetal programming. PMID- 29631662 TI - Improving Process Quality by Means of Accurate and Traceable Calibration of Flow Devices with Process-oriented Liquids. AB - Calibration of flow devices is important in several areas of pharmaceutical, flow chemistry and health care applications where volumetric dosage or delivery at given flow rates are crucial for the process. Although most of the flow devices are measuring flow rates of process-oriented liquids, their calibrations are often performed with water as calibration liquid. It is recommended to perform the calibrations of the flow devices with process-oriented liquids as the liquid itself might influence the performance of the flow devices. Therefore, METAS has developed facilities with METAS flow generators to address the issue of measuring with process-oriented liquids for flow rates from 400 ml/min down to 50 nl/min with uncertainties from 0.07-0.9 %. Traceability is guaranteed through the calibration of the generated flow rates of the METAS flow generators by means of the dynamic gravimetric method where a liquid of well-known density and a well controlled evaporation rate is used. The design of the milli-flow facility will be discussed as well as first measurement results of the METAS flow generators in the range of micro-flow and milli-flow using water and other liquids. PMID- 29631663 TI - Quality Aspects in Production of Electronic Grade Chemicals in Multipurpose Plants. AB - Electronic devices and displays require electronic grade chemicals for their manufacturing process. As miniaturisation in the electronics industry has pushed the boundaries of physics, no contamination can be tolerated in the production of microchips or display panels. Electronic grade chemicals need to be of highest purity and quality consistency. After giving an introduction to the quality requirements in the electronics industry, this article describes the path from laboratory synthesis to a capable production process of a small volume electronic specialty material in a multipurpose plant. The upscaling of an electronic chemical for electronic device manufacturing is one of the examples of how products with high quality requirements can be successfully produced in an existing production infrastructure. PMID- 29631664 TI - The Use of Lean Six Sigma Methodology in Increasing Capacity of a Chemical Production Facility at DSM. AB - Lean Six Sigma is an improvement method, combining Lean, which focuses on removing 'waste' from a process, with Six Sigma, which is a data-driven approach, making use of statistical tools. Traditionally it is used to improve the quality of products (reducing defects), or processes (reducing variability). However, it can also be used as a tool to increase the productivity or capacity of a production plant. The Lean Six Sigma methodology is therefore an important pillar of continuous improvement within DSM. In the example shown here a multistep batch process is improved, by analyzing the duration of the relevant process steps, and optimizing the procedures. Process steps were performed in parallel instead of sequential, and some steps were made shorter. The variability was reduced, giving the opportunity to make a tighter planning, and thereby reducing waiting times. Without any investment in new equipment or technical modifications, the productivity of the plant was improved by more than 20%; only by changing procedures and the programming of the process control system. PMID- 29631665 TI - FT-NIR: A Tool for Process Monitoring and More. AB - With ever-increasing pressure to optimize product quality, to reduce cost and to safely increase production output from existing assets, all combined with regular changes in terms of feedstock and operational targets, process monitoring with traditional instruments reaches its limits. One promising answer to these challenges is in-line, real time process analysis with spectroscopic instruments, and above all Fourier-Transform Near Infrared spectroscopy (FT-NIR). Its potential to afford decreased batch cycle times, higher yields, reduced rework and minimized batch variance is presented and application examples in the field of fine chemicals are given. We demonstrate that FT-NIR can be an efficient tool for improved process monitoring and optimization, effective process design and advanced process control. PMID- 29631666 TI - Recent Regulatory Trends in Pharmaceutical Manufacturing and their Impact on the Industry. AB - The pharmaceutical industry is one of the most regulated industries in Switzerland. Though the concept of good manufacturing practises (GMP) was implemented for chemical production in the early 1990s, the rules and regulations for our industry are in constant evolution. In this article we will highlight the impact of these changes to the industry using three recent guideline up-dates as examples: the implementation of ICH Q3D 'Guideline for elemental impurities', the EU-GMP Guideline Part III Chapter 'Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities' from 01. June 2015, and the new guidelines to data integrity such as 'PIC/S 041-1 Good Practices for Data Management and Integrity in regulated GMP/GDP environments'. These examples show how scientific approaches help to modernize the control strategies for our products and increase product quality for a better patient safety. The requirements of data integrity regulations are also of interest to industries and universities not working under GxP requirements as they also support the business to improve data quality (traceability) for patent applications, and reduce risk of data falsification. PMID- 29631670 TI - Tumor Targeting with Small Molecule-Drug Conjugates (SMDCs) - Can They be Better than ADCs? PMID- 29631671 TI - Tolerating Toxins: Grasshoppers that Feast on Pyrrolizidine Alkaloids S. AB - The elegant grasshopper (Zonocerus elegans) and the variegated grasshopper (Z. variegatus) are among insects that deliberately consume and store pyrrolizidine alkaloids which are subsequently used in defence mechanisms. PMID- 29631672 TI - Synthesis of Advanced Mesoporous Materials by Partial Pseudomorphic Transformation. AB - The structure of porous silica particles can be reorganized without alteration of the particle size and shape by the process of pseudomorphic transformation. Partial pseudomorphic transformation leads to ordered mesoporous silica with bimodal pore size distributions and bottleneck pores. Compared to the classical pathways of mesoporous silica synthesis, pseudomorphic transformation implies less compromise between pore structure and particle shape, while enabling the preparation of complex pore architectures. PMID- 29631673 TI - 2018 International Symposium on Chemical Biology of the NCCR Chemical Biology Campus Biotech, Geneva 10.-12.01.2018. PMID- 29631674 TI - SwissSnowSymposium 2018. PMID- 29631676 TI - Chimia Report/company News. PMID- 29631675 TI - ZHAW Waedenswil: A new Approach in the Fight against Cancer. AB - A happy coincidence brought Dr Markus Rimann from ZHAW Waedenswil together with Dr Andreas Meyer from the start-up FGen and PD Dr Emanuela Felley-Bosco, Molecular Oncologist at Zurich University Hospital, to develop a technology platform for the manufacture and high throughput analysis of single mesothelioma spheroids. Armin Picenoni, former student in Chemistry for the Life Sciences at ZHAW, confirmed everything in writing his Master Thesis on this Innosuisse project. PMID- 29631677 TI - Inhibition of the oxidative stress-induced miR-125b protects glucose metabolic disorders of human retinal pigment epithelium (RPE) cells. AB - The dysfunction of retinal pigment epithelium (RPE) with aging leads to age related macular degeneration (AMD). Oxidative stress has been demonstrated as one of the causes of retinal pathological conditions. This study was conducted to investigate the mechanism of hydrogen peroxide (H2O2) induced human retinal pigment epithelial (RPE) cell dysfunction. We report miR-125b is induced by H2O2 treatments in RPE cells. In addition, we observed inhibited glucose metabolism under oxidative stress. Overexpression of miR-125b promotes the disorders of cellular glucose metabolism through direct targeting Hexokinase 2 (HK2). Restoration of HK2 in H2O2 treated RPE cells prevents the oxidative stress suppressed glucose metabolism. Inhibition of the H2O2-induced miR-125b by inhibitor significantly prevented disorders of glucose metabolism. This study will contribute to the development of the miRNA based therapeutic approaches for against the oxidative stress-mediated human AMD. PMID- 29631678 TI - TW37 enhances the pro-apoptosis and anti-migration ability of gefitinib in Non Small Cell Lung Cancer. AB - B cell leukemia-2 (Bcl-2) plays important roles in the development of tumor and drug resistance. The growth of tumor cells can be inhibited by downregulating the abnormal expression of Bcl-2 protein. TW37, an effective inhibitor of Bcl-2 protein, has now been widely studied in many tumors. In our study, it was found that TW37 exerted a significant effect on the proliferation, apoptosis and migration of Non-Small Cell Lung Cancer cells. Bcl-2 is also a key downstream factor of many signaling pathways such as Epidermal Growth Factor Receptor (EGFR). TW37 enhanced the inhibition of tumorigenesis by gefitinib, an EGFR Tyrosine Kinase Inhibitor drug. Moreover, TW37 can promote apoptosis ability by inhibiting the phosphorylation level of EGFR protein in H1975 cells. Overall, TW37 enhances the pro-apoptosis and anti-migration ability of gefitinib in Non Small Cell Lung Cancer. PMID- 29631679 TI - Chemical characterization and biological activities of Simmondsia chinensis (Link) C. K. Schneid seeds oil. AB - The chemical composition, main physicochemical properties, and biological activities of Simmondsia chinensis (S. chinensis) seeds oil were studied. The results revealed that the physiochemical characteristics of S. chinensis seeds oil were as follows: acid values 1.15 mg KOH/g, peroxide values 8.00 meq O2 Kg-1, iodine values 80.00 g/100 g of oil and saponification values 92.00 mg KOH/g, phenolic content 50.91 mg gallic acid equivalents/g extract. Gas chromatography analysis indicated that eicosenoic (55.50 %), erucic (20.43 %) and oleic (19.01 %) acids were the most abundant, saturated and unsaturated, fatty acids in the oil. Moreover, the evaluation of their antioxidant (DPPH, TAC), antibacterial, antidiabetic and acetylcholinesterase evinced interesting results. Seeds of S. chinensis constitute a substitute source for stable vegetable oil and protein with regard to nutritional and industrial applications. PMID- 29631680 TI - An investigation of NIS expression in gastric tissue of obese individuals. AB - Obesity is seen as one of the top ten (10) illness's listed by World Health Organization (WHO). It is a global problem that can affect people of all ages. Obesity is identified one of the most important factors leading to diabetes, heart disease and hypertension. Individuals with a Body Mass Index (BMI) above 40 kg/m2 are defined with morbid obesity. Sodium Iodide Symporter (NIS) gene is a plasma membrane glycoprotein that mediates iodide uptake in thyroid glands, stomach, salivary glands, lactating mammary glands and intestine. NIS gene transports iodide from the blood to the gastric epithelial cells. NIS gene expression and regulatory role of NIS gene in gastrointestinal tract, hasn't been studied yet in the individuals with obesity (i.e., BMI >40 kg/m2). In this study, gastric tissues were obtained by laparoscopic sleeve gastrectomy from 33 individuals diagnosed with obesity. Control group consisted of gastric tissue of 21 subjects with normal BMI obtained by endoscopy. RNA isolation, cDNA synthesis and qRT-PCR analyses were performed on the samples to determine NIS gene expression. Expression levels of NIS gene were compared between obese and control individuals, although an increase was observed in obese patients this difference was not found to be statistically important (p>0.05). PMID- 29631681 TI - Modulation of S100 and smooth muscle actin-alpha immunoreactivity in the wall of aorta after vitamin D administration in rats with high fat diet. AB - High fat diet is a risk factor for the development of atherosclerosis. Hence, research studies are important to understand the cellular and molecular mechanisms of atherosclerosis pathogenesis. The current study was conducted to evaluate the role of vitamin D in modulation of aortic histopathological, immunohistochemical alterations and biochemical changes induced by high fat diet in male albino rats. Forty adult rats were divided into three major groups; group I (control), group II (High fat diet) and group III (High fat diet with vitamin D). At the end of the experiment, blood cholesterol and triglycerides were determined. Aortic arches specimens were collected for histopathological study and immunohistochemical staining. Aorta of high fat diet group showed intimal thickening with vacuolated endothelial cells. The tunica media showed areas of fibrosis and irregular vacuolated smooth muscle cells. Many inflammatory cells were detected in the tunica adventitia. Significant reduction in area percentage of smooth muscle actin-alpha (SMA-alpha) immunoreactivity and increase in number of S100 positive dendritic cells (DCs) with significant increase in serum cholesterol and triglycerides were also detected. Concomitant vitamin D supplementation, with high fat diet, showed amelioration in histopathological aortic changes with significant increase in SMA-alpha immunoreactivity and decrease in S100 positive (DCs). However, serum cholesterol and triglyceride showed non-significant decrease after vitamin D supplementation. In conclusion, vitamin D administration ameliorates aortic wall histoopathological changes induced by high fat diet most probably through local modulation of S100 and SMA alpha immunoreactivity. Hence, vitamin D could be suggested as a protective agent against aortic atherosclerotic changes. PMID- 29631682 TI - Fertility enhancing efficacy of Cicer arietinum in male albino mice. AB - The present study was conducted to investigate the effect of incorporating Cicer arietinum in the diet on the testicular functions of the male mice. Seventy-two mice were divided equally into four groups that were daily fed a diet containing 0, 20, 30 and 50% of C. arietinum seeds, respectively. After 7, 14 and 21 days of starting the experiments, the mice were anesthetized and euthanized to collect the blood, testes, epididymis and seminal vesicles. The present results showed that the increased percentage of C. arietinum in the diet caused significant elevations in the serum levels of testosterone and luteinizing hormone (LH), sperm concentration, sperm motility as well as the testicular levels of antioxidants including glutathione (GSH), glutathione peroxidase (GPx) and catalase (CAT), in comparison to the controls. On the other hand, marked reductions in the sperm abnormality, testicular levels of malondialdehyde (MDA), the percentage of DNA damage in tail and tail moment (TM) were observed in the mice that received a diet containing C. arietinum as compared to the controls. Both the sperms and testes of the mice fed a diet containing C. arietinum in the diet showed a normal intact appearance of the electrophoresed genomic DNA on agarose, as those of the controls. In conclusion, C. arietinum is not only a safe ingredient in the fast-food but also an enhancer of the testicular functions. PMID- 29631683 TI - Up-regulation of receptor interaction protein 140 promotes glucolipotoxicity induced damage in MIN6 cells. AB - The receptor interaction protein 140 (RIP140) cofactor is a key regulator of metabolic balance, but its function in glucose- and lipid-mediated damage in islet beta cells is unknown and was investigated in this study. RIP140 expression and distribution was evaluated in MIN6 cells under high glucose and lipid conditions using real-time Polymerase Chain Reaction (PCR), western blotting and confocal laser scanning microscopy. Cells were separately treated with 500 MUM palmitic acid and 25 mM glucose when RIP140 expression was upregulated or downregulated, and cell viability, apoptosis rate, the level of oxidative stress and insulin secretion was assessed, as was the expression of related genes. Increased glucose and palmitic acid elevated RIP140 expression and distribution in nuclei. Overexpression of RIP140 promoted apoptosis but inhibited cell viability in MIN6 cells, and basal insulin secretion and glucose-stimulated insulin secretion levels were altered following treatment with glucose and palmitic acid. In addition, oxidative stress was elevated, phosphorylated extracellular signal-regulated kinases 1/2 and uncoupling protein 2 messenger RNA (mRNA) abundance were increased, B-cell lymphoma-2 protein levels were decreased, and peroxisome proliferators activated receptor gamma co-activator 1 alpha, phosphoenolpyruvate carboxykinase , and pancreatic and duodenal homeobox-1 mRNA levels were downregulated. Furthermore, glucolipotoxicity-induced damage was reversed when RIP140 expression was downregulated by small interfering RNA (SiRNA). RIP140 promotes islet beta cells damage caused by glucolipotoxicity. PMID- 29631684 TI - Physiological and biochemical responses of durum wheat under mild terminal drought stress. AB - The effects of mild terminal drought stress on physiological parameters and activities of peroxidase (POX), catalase (CAT) and superoxide dismutase (SOD) were investigated in ten durum wheat genotypes using two field experiments under rain-fed (terminal drought stress) and irrigated (non-stress) conditions. Stress intensity was calculated to be 0.1 indicating mild water deficit stress. Based on combined analysis of variance, the mild terminal drought stress increased the activity of CAT while, POX and SOD content decreased significantly. Rain-fed durum wheat plants showed non-significant increases in photochemical efficiency of PS II (Fv/Fm) as compared to the irrigated plants. Chlorophyll concentration in the flag leaves of the plants under terminal drought decreased slightly than normal conditions. The interaction of cultivar and environment was significant for enzyme activities, indicating different biochemical reaction of durum wheat plants in the two conditions. PMID- 29631685 TI - DNA repair and apoptosis: Roles in radiotherapy-related acute reactions in breast cancer patients. AB - Normal tissue reactions are therapy limiting factor for the effectiveness of the radiotherapy in cancer patients. DNA repair and apoptosis are estimated to be critical players of adverse effects in response to radiotherapy. Our aim was to define the association of DNA repair (ERCC1 and XPC) and apoptotic (BCL2, CASP3 and NFKB1) gene expression, DNA damage levels, apoptosis changes and DNA repair gene variations with the risk of acute side effects in breast cancer patients. The study included 100 women with newly diagnosed breast cancer; an experimental case group (n=50) with acute side effects and the control group (n=50) without side effects. Gene expression was analyzed by reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR). Micronucleus (MN) and 8-hydroxy-2' deoxyguanosine (8-OHdG) assays were performed to compare the DNA damage levels. Apoptosis was examined by TDT-mediated dUTP-biotin nick end-labeling (TUNEL) staining. ERCC1 rs3212986 and XPC rs3731055 polymorphisms were genotyped by real time PCR technique. No significantly correlation of DNA repair and apoptosis gene expression and DNA damage levels with acute side effects in response to radiotherapy. Also, there was no association between apoptosis levels and acute effects. ERCC1 rs3212986 CC genotype showed a protective effect against radiotherapy-induced acute reactions (p<0.001; OR: 0.21; 95% CI= 0.08-0.52). Our results suggest that apoptosis and DNA damage levels are not associated with acute radiosensitivity. DNA repair may affect the risk of acute reactions. Further studies are needed to validate the current findings. PMID- 29631686 TI - Anti-obesity effects of Laminaria japonica fermentation on 3T3-L1 adipocytes are mediated by the inhibition of C/EBP-alpha/beta and PPAR-gamma. AB - Obesity is global problem that contributes to disease, and is partly caused by fast-food, high-fat diets. Much attention has been focused on developing anti obesity foods and chemical materials from natural sources. Seaweed has bioactive properties that influence immune activity and have anti-cancer and anti-obesity effects. Laminaria japonica is a widely consumed seaweed, and has been promoted as a health food in Korea. The bioactive properties of L. japonica include anti cancer, anti-diabetic, and anti-inflammation effects. Most Laminaria japonica are distributed in a simple processing form such as drying, and their availability is very low. Therefore, various types of functional products can be developed if they can be applied to foods through functionalization using fermentation techniques. It is a structural problem that is the most problematic in seaweed processing. In this study, we used fermented Laminaria japonica. To increase physiological activity, fermentation treatment was performed to loosen the structure, thereby increasing the activity of the glycoprotein. First, we screened the anti-obesity potential of an L. japonica fermentation extract (LJF) using 3T3-L1 adipocyte cells. We determined cytotoxicity using an MTS assay and measured LJF for its ability to affect adipogenesis through glucose uptake, triglyceride levels, and Oil Red O staining. We confirmed that LJF inhibited adipocyte differentiation. CCAAT/enhancer-binding proteins alpha/beta (C/EBP alpha/beta) and peroxisome proliferator-activated receptor-gamma (PPAR-gamma) are involved in the early and late stages of adipocyte differentiation. LJF significantly reduced the expression levels of C/EBP-alpha/beta and PPAR-gamma and decreased the concentration of adiponectin. Thus, our results suggest that LJF inhibits adipogenesis in 3T3-L1 cells, and may be valuable for its anti obesity effects. PMID- 29631687 TI - Relation of MPO, MnSOD, NQO1 gene variants in endometrial carcinoma in the line of PCR-RFLP methods. AB - Reactive oxygen species (ROS) have been shown to be responsible for inducing DNA damage leading to mutagenesis, carcinogenesis, and cell death if the capacity of the protective antioxidant system is impaired. Endometrial carcinoma is the primary cancer type in the female genital system. The enhanced cell lipid peroxidation and impaired antioxidant enzyme activities observed in patients with endometrial cancer indicate the potential for oxidative injury to cells and cell membranes in such patients. The aim of the study was to investigate the possible association between gene variants of superoxide dismutase (SOD), myeloperoxidase (MPO), and NADPH quinone oxido reductase (NQO1), and their possible role in endometrial cancer in Turkish patients. According to results, MPO G+ genotype and AG genotype were significantly increased in patients compared with controls (P<0.001). We suggest that the MPO polymorphism might be a risk for endometrial cancer. PMID- 29631688 TI - Isolation and identification of two extremely halophilic archaea from sebkhas in the Algerian Sahara. AB - In Algeria, many salt lakes are to be found spread from southern Tunisia up to the Atlas Mountains in northern Algeria. Oum Eraneb and Ain El beida sebkhas (salt lakes), are located in the Algerian Sahara. The aim of this study was to explore the diversity of the halobacteria in this type of habitats. The physicochemical properties of these shallow saline environments were examined and compared with other hypersaline and marine ecosystems. Both sites were relatively alkaline with a pH around 8.57- 8.74 and rich in salt at 13% and 16% (w/v) salinity for Oum Eraneb and Ain El beida, respectively, with dominant ions of sodium and chloride. The microbial approach revealed the presence of two halophilic archaea, strains JCM13561 and A33T in both explored sebkhas. Growth occurred between 10 and 25% (w/v) NaCl and the isolates grow optimally at 20% (w/v) NaCl. The pH range for growth was 6 to 9.5 with an optimum at pH 7.5 for the first strain and 7 to 9.5 with an optimum pH at 8.5-9 for the second strain. On the basis of 16S rRNA gene sequence analysis, strains JCM13561 and A33T were most closely related to Halorubrum litoreum and Natronorubrum bangense (99% and 96% similarity, respectively). PMID- 29631689 TI - Grape seed extract effects on serum amylase levels and immunohistochemical alterations in Streptozotocin-induced diabetic rats. AB - In this study, serum amylase activity and structural changes of the pancreatic tissue in rats under the effects of grape seed extract were investigated. Thirty two female Wistar albino rats were divided into 4 groups. First one was the control group. The second group was the streptozotocin (STZ)-induced diabetes mellitus (DM) group (45 mg/kg), while the third group was the grape seed extract (GSE) group, where the GSE was administrated intragastrically for 20 days (at 0.6 ml/rat). Lastly, the fourth group was the diabetes mellitus+GSE (DM+GSE) group. Blood samples were taken and analyzed for amylase activity. Caspase 3 expressions were inspected with immunohistochemistry. Amylase levels in the diabetic group were found to be the lowest (794.00+/-44.85 U/L, p<0.001), while the GSE group had the highest value (1623.63+/-80.04 U/L, p<0.001) Number of apoptotic cells was increased in Langerhans islets of the diabetic group. In the control and GSE groups, the apoptotic cells were found to be almost entirely absent. Increased number of apoptotic cells was found in the DM group, while decreased number of apoptotic cells was found in the DM+GSE group. Furthermore, atrophy in Langerhans islets, hyperemia in capillary veins, hydropic degeneration and necrosis in islet cells were determined in the diabetic group. Only mild hydropic degeneration in islet cells of Langerhans was observed in the DM+GSE group. Histopathologically beneficial changes in the pancreases were detected when grape seed extract was given to diabetic rats. As a conclusion, GSE was determined to have positive effects on the function and structure of the pancreas, improving enzyme activities and the structure of the Langerhans islets. PMID- 29631690 TI - Effects of grape seed extract, quercetin and vitamin C on ovine oocyte maturation and subsequent embryonic development. AB - The present study aimed to evaluate the effects of grape seed extract (GSE) versus quercetin and vitamin C on in vitro oocyte maturation and embryo development in sheep. The free radical scavenging activity of different concentrations of each product was measured by 1, 1- diphenyl-2-picryl hydrazyl (DPPH). Oocytes were collected from ovaries of slaughtered ewes and matured in TCM-199 medium containing fetal calf serum, follicle stimulating hormone (FSH), estradiol-17 beta, sodium pyruvate, and gentamicin sulfate. The in vitro fertilization and culture were performed using Bracket and Oliphant's (BO) medium and modified Charles Rosenkrans medium with amino acids (mCR2aa), respectively. The results showed that the hydroalcoholic extract of grape seed had free radical scavenging activity. IC50 value for GSE, vitamin C, and quercetin was found to be 585 ug/mL, 53 ug/mL, and 43 ug/mL, respectively. The concentrations, which showed beneficial effects on oocyte maturation and early development based on the mean number of cleavage, morula and blastocyst rates, were 25-200 ug/mL, 5 or 15 ug/mL, and 800 ug/mL, respectively, for vitamin C, quercetin and GSE. However, there were no significant differences between different concentrations of GSE and control. Findings also highlight the great effect on blastocyst rate while adding GSE at 800 ug/mL. However, the best rate of blastocyst production was obtained in presence of quercetin. Findings suggested the need for further studies on special molecules derived from GSE. PMID- 29631691 TI - Silencing mutations in JAG1 gene may play crucial roles in the pathogenesis of Tetralogy of Fallot. AB - JAG1 gene through Notch signaling is implicated in cell fate decisions in early cardiac development, and mutations in several proteins in the pathway have been involved in various disorders. Tetralogy of Fallot (TOF) is the most frequent form of complicated congenital heart disease. The abnormality of TOF begins through the first eight weeks of fetal growth and is confused with ventricular septal defects, obstruction to right ventricular outflow tract, aortic dextroposition, and right ventricular hypertrophy. Hence the existence of mutations in JAG1 gene in Iranian patients with TOF is evaluated. The clinical data and peripheral blood samples were collected from 44 sporadic nonsyndromic patients with TOF and compared to 44 healthy individuals. DNA was extracted, and the exon 6 of the JAG1 gene was amplified by PCR then the PCR products were purified and sequenced. The age range in patients and the control group was 2-36 years, and the mean and standard deviation (SD) of the age in patients was (11.69 +/- 7.85 years) and in control group (11.63 +/- 7.99 years). Finally, the samples were successfully sequenced, then analyzed and one synonymous variant (c.765C>T; p.Y255Y) was observed in 38 patients with frequency (86.4%) and three controls with frequency (6.8%). The c.765C>T variant is significantly associated with the pathogenesis of TOF in Iranian population. PMID- 29631692 TI - Effect of Tunceli garlic on some immunological parameters in Cyprinus carpio exposed to chlorpyrifos. AB - In this study, the effect of Tunceli garlic (Allium tuncelianium) on hemoglobin (Hb) level, oxidative radical production of neutrophils (Nitoblue tetrazolium assay-NBT activity) and total immunoglobulin (TI) content in carp (Cyprinus carpio) exposed to chlorpyrifos (CPF) was investigated. The 96 hour LC50 value of CPF on C. carpio was calculated to as 0.230 mg/L. The fishes were exposed to sublethal concentration of chlorpyrifos (1/8 of LC50 value: 0.029 mg/L), and Tunceli garlic (20 and 40 g/kg diet) was simultaneously administered for 21 days. Blood samples were taken from the fishes at 7, 14 and 21 days and analysed to determine the Hb levels, the NBT activity and the TI content. There was a significant decrease in the Hb level, the NBT activity and the TI content of CPF treated fish. However, Tunceli garlic reversed the Hb level, the NBT activity and the TI content. In conclusion, this study demonstrated that CPF had a negative effect on the immunological values of the fish. The simultaneous administration of Tunceli garlic was neutralised CPF-induced toxicity. PMID- 29631693 TI - Validation of expression stability of reference genes in response to herbicide stress in wild oat (Avena ludoviciana). AB - Weeds are serious problem in crop production and wild oat is a grass weed of economic and agronomic significance. We need to extend our basic knowledge of weeds especially in molecular genetics and gene expression. For study of gene expression by semi-quantitative and quantitative PCR, it is recommended that normalization of reference genes be carried out in order to select the most stable reference gene for a precise gene expression study. The purpose of this research was evaluation of four reference genes in response to treated and untreated (control) by herbicide in two tissues (stem and leaf) of non-target site resistance wild oat (A. ludoviciana). Four candidate reference genes including Actin, Ef1alpha (elongation factor 1 alpha), GAPDH (glyceraldehyde 3 phosphate dehydrogenase) and TBP (TATA-box-binding protein) were used to determine stable reference gene exposed to the herbicide using the statistical methods of NormFinder, BestKeeper and delta-Ct. NormFinder indicated that TBP and Actin genes are the best combination of two genes for normalizing calculations (with a combined gene stability value of 0.012) for qPCR analysis under herbicide stress in different tissues of non-target site resistance wild oat. Based on the statistical results, the Ef1alpha gene was identified as the unstable reference gene. Totally, according to results of this study, TBP gene is the most stable reference gene and therefore, this gene can be used as a reference gene for future studies of quantitative PCR analysis of herbicide stress-responsive gene expression in wild oat and potentially in other grass weed species. PMID- 29631694 TI - A candidate single nucleotide polymorphism in the 3' untranslated region (rs17878624) of survivin gene for NSCLC. AB - Survivin is a gene that locates on human chromosome 17q25 and contains 142 amino acid. Survivin (BIRC5) is the first one of the found inhibitors of apoptosis proteins (IAPs) that is an important protein family and regulates apoptosis. It is expressed particularly in cancer cells. 3'UTR region of gene has components that is necessary for gene function and this region plays a critical role in the regulation of posttranscriptional regulation of the gene expression. Therefore, polymorphisms in this region may affect the function of the gene. The purpose of the study is to investigate possible relationship, that is associated with development and prognosis of the disease, between the 3 'UTR region (rs17878624) polymorphism and NSCLC in a Turkish society. PMID- 29631695 TI - Large-scale replication study reveals a limit on probabilistic prediction in language comprehension. AB - Do people routinely pre-activate the meaning and even the phonological form of upcoming words? The most acclaimed evidence for phonological prediction comes from a 2005 Nature Neuroscience publication by DeLong, Urbach and Kutas, who observed a graded modulation of electrical brain potentials (N400) to nouns and preceding articles by the probability that people use a word to continue the sentence fragment ('cloze'). In our direct replication study spanning 9 laboratories (N=334), pre-registered replication-analyses and exploratory Bayes factor analyses successfully replicated the noun-results but, crucially, not the article-results. Pre-registered single-trial analyses also yielded a statistically significant effect for the nouns but not the articles. Exploratory Bayesian single-trial analyses showed that the article-effect may be non-zero but is likely far smaller than originally reported and too small to observe without very large sample sizes. Our results do not support the view that readers routinely pre-activate the phonological form of predictable words. PMID- 29631696 TI - Glutamatergic drive along the septo-temporal axis of hippocampus boosts prelimbic oscillations in the neonatal mouse. AB - The long-range coupling within prefrontal-hippocampal networks that account for cognitive performance emerges early in life. The discontinuous hippocampal theta bursts have been proposed to drive the generation of neonatal prefrontal oscillations, yet the cellular substrate of these early interactions is still unresolved. Here, we selectively target optogenetic manipulation of glutamatergic projection neurons in the CA1 area of either dorsal or intermediate/ventral hippocampus at neonatal age to elucidate their contribution to the emergence of prefrontal oscillatory entrainment. We show that despite stronger theta and ripples power in dorsal hippocampus, the prefrontal cortex is mainly coupled with intermediate/ventral hippocampus by phase-locking of neuronal firing via dense direct axonal projections. Theta band-confined activation by light of pyramidal neurons in intermediate/ventral but not dorsal CA1 that were transfected by in utero electroporation with high-efficiency channelrhodopsin boosts prefrontal oscillations. Our data causally elucidate the cellular origin of the long-range coupling in the developing brain. PMID- 29631699 TI - An Update on Colorectal Cancer. PMID- 29631700 TI - Special issue: molecular and cellular biology of helminth parasites XI. PMID- 29631701 TI - Women and kidney disease: reflections on World Kidney Day 2018. PMID- 29631703 TI - Reflections of an Editor-Two Decades Later. PMID- 29631704 TI - Mothers, Children, and Eating: Past, Present, and Future. PMID- 29631702 TI - [Cyclophosphamide in idiopathic nephrotic syndrome: Outcome and outlook]. AB - INTRODUCTION: Cyclophosphamide (CYP) has been used for over 40 years in patients with steroid-sensitive nephrotic syndrome (NSSS) presenting frequent relapses (NSRF) or steroid dependence (NSSD). However, the long-term success of treatment with cyclophosphamide is difficult to predict. The objectives of this study are to determine long-term outcomes of cyclophosphamide and identify the factors associated with sustained remission. METHODS: We retrospectively studied the data from 50 patients with idiopathic nephrotic syndrome, treated by oral cyclophosphamide and followed at service of pediatric for more than 8 years for idiopathic nephrotic syndrome and related factors for survival without relapse were evaluated by univariate analysis. RESULTS: The median age at the time of diagnosis was 4.3 years, and median follow-up time was 1.7 years with the median of 8 years at the first use of CYC. Patients had received a median cumulative dose of 168mg/kg. At the end of follow-up, 38% of patients entered into remission after using CYC while 62% failed to respond and further relapses then occur. The median time of stopping corticosteroid therapy was three month. The survival without relapse was respectively 56% (28 patients), 52% (26 patients), 48% (24 patients), and 38% (19 patients), at 6 months, one year, two years and more than two years. In univariate analysis, the survival without relapse was related to the age at the moment of starting the therapy par CYC (the median was 5 months for an age < 8 years and 41 months for an age>=8 years; P=0.049), the type of nephrotic syndrome [36 months for SNRF, 4 months for NSSD and nephrothic syndrome steroid resistant (NSSR); P=0.068], and the histological lesion (6 months for diffuse mesangial proliferation, 2 months for segmental glomerulosclerosis; P=0.009). The age at the moment of diagnosis, the sex and the cumulative dose of CYC did not have significant influence. CONCLUSION: The results presented in this study suggest the use of oral cyclophosphamide for short period remain second line effective therapy. Further well-designed trials are required to evaluate the efficacy of other steroid-sparing agents. PMID- 29631705 TI - "That's His Choice Not Mine!" Parents' Perspectives on Providing a Packed Lunch for Their Children in Primary School. AB - OBJECTIVE: To examine factors influencing parents' selection of packed lunches over a school lunch, their choices in food preparation, and the role of children within these. DESIGN: A qualitative approach using semistructured focus group and individual interviews. SETTING: Four primary schools in a UK local authority. PARTICIPANTS: Twenty parents providing a packed lunch for their children (aged 5 11 years). ANALYSIS: An inductive thematic approach was used to identify categories and themes. The researchers maintained rigor in the data analysis through internal discussion and review until consensus was reached. RESULTS: Children emerged as active decision makers exerting substantial power particularly in the initial decision to have a packed lunch, and then in influencing the lunch's contents. The packed lunch could be a source of anxiety for some parents; however, ultimately parents' attitudes and perceptions revolved around the key requirement that the lunch was eaten. Providing a packed lunch was a means of achieving this. CONCLUSIONS: This study highlights children's growing authority over everyday food decisions. Further research is needed to explore children's perceptions of their role in food provision. The study's findings have implications for school food, nutrition education, and school-based interventions. Frameworks that look to improve children's nutrition in this area should reflect children's growing status as food decision makers and consider how this can be employed to support and sustain positive changes. PMID- 29631706 TI - From the Editor's desk....: May 2018. PMID- 29631707 TI - EASL Recognition Award Recipient 2018: Prof. Didier Samuel. PMID- 29631708 TI - EASL Recognition Award Recipient 2018: Prof. Mario Mondelli. PMID- 29631709 TI - EASL International Recognition Award Recipient 2018: Prof. Anna Lok. PMID- 29631710 TI - Evaluation for therapeutic measures to small gastric stromal tumor: A retrospective study of 90 cases. AB - Surgery and regular follow-up are two main measures for small gastric stromal tumors (sGST) less than 2cm in diameter, while there is no sound evidence to prove which treatment is more beneficial to sGST patients. In this study, we reviewed the clinical and pathological features of patients with sGST receiving surgery and discussed the value of surgical intervention. In all, 90 patients who were diagnosed as sGST(less than 2cm) and accepted surgical treatment were enrolled, correspondently, another 104 patients with GSTs between 2-5cm and 74 patients with GSTs >5cm were collected as Control groups 1 and 2, respectively, and all of them received surgical treatment. Results showed that there were no significant difference among 3 groups in terms of gender, age, clinical features, tumor locations, and mutations of the exon 9 or 11 in C-kit gene, and immunohistochemical results of CD117, CD34, and DOG-1 proteins (P > 0.05). However, we observed growing percentage of medium-/high-risk GSTs and nucleus mitotic counts >5/50 HPF in Control groups (P < 0.05). Patients with sGST were more suitable for minimally invasive procedures than the other 2 groups, with shorter hospital stay (P < 0.05). During the follow-up period (medium 45.4 months), the recurrence rate was also associated with tumor size, which surged from 1.11% in sGST group to 7.69% and 17.56% in Control groups 1 and 2, respectively. In all, we concluded that patients with sGST experienced low proportions of medium-/high-risk tumors; however, they still suffered from potential risk of tumor progression. Due to satisfied surgical outcome, surgical treatment could be suggested for sGST. PMID- 29631711 TI - The importance of quality-of-life management in patients with advanced pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) carries a poor prognosis, and as such, a focus on quality of life is vital. This review will discuss various aspects of quality of life in patients with PDAC and their treatment. Pancreatic exocrine and endocrine insufficiency may result in issues related to nutrition, and pain and fatigue are other common symptoms, and may be managed with pharmaceutical or nonpharmaceutical methods. It has also been reported that low mood is a particular problem for patients with PDAC compared to patients with other cancers; however, the data supporting this is inconsistent. Data regarding improvements in quality of life in patients with PDAC receiving chemotherapy is also reviewed, which in some cases suggests a benefit to chemotherapy, particularly in the presence of a radiological response. Furthermore, the importance of early palliative care is discussed and the benefits reported including improved quality of life and mood, reduced aggressive interventions at the end of life and improved survival. Areas for future development may include increased use of quality of life as a trial outcome and the use of patient reported outcomes to improve symptomatic care of patients, and particularly in those receiving active systemic treatment. PMID- 29631712 TI - The history and development of the journal from the view of a founding editor. PMID- 29631713 TI - Stop Chasing One's Tail: Resist the Practice of Treating Serial Side-Effects. PMID- 29631722 TI - Complete Spontaneous Regression of the Primary Tumor in Merkel Cell Carcinoma. PMID- 29631723 TI - Histologic Diagnosis of Melanocytic Lesions and Melanoma: Real Challenges. PMID- 29631724 TI - Preventive effects of car safety seat use on clinical outcomes in infants and young children with road traffic injuries: A 7-year observational study. AB - INTRODUCTION: Road traffic injury (RTI) is one of the major mechanisms of injury leading to high disability and case-fatality in infants and children. Proper car safety seat use can reduce fatal outcomes in pediatric patients with RTI; however, the use rate is still low. This study aimed to measure the preventive effects of car safety seat use on clinical outcomes among infants and young children injured from RTI. METHODS: A multicenter cross-sectional study was conducted using the Emergency Department-based Injury In-depth Surveillance (EDIIS) registry from 23 EDs between Jan 2010 and Dec 2016. All pediatric patients who were under 6 years of age and who sustained RTI in a vehicle with fewer than 10-seats were eligible. Primary and secondary endpoints were intracranial injury and mortality. We calculated the adjusted odds ratio (AOR) of the car safety seat for related outcomes adjusting for potential confounders. RESULTS: Among 5545 eligible patients, 1452 (26.2%) patients were in car safety seats at the time of the crash (12.5% in 2010 to 33.9% in 2016, p-for-trend <0.01), and 104 (1.9%) patients had intracranial injuries. The patients using car safety seats were less likely to have intracranial injuries compared with the patients not using car safety seats (0.8% vs. 2.2%, AOR: 0.31 (0.17-0.57)). However, there was no significant difference in mortality between the two groups (0.4% vs. 0.6%, AOR: 0.50 (0.20-1.25)). CONCLUSION: Use of the car safety seat has significant preventive effects on intracranial injury. Public health efforts to increase use of car safety seats for infants and young children are needed to reduce the burden of RTI. PMID- 29631725 TI - 4-1BB expression on MAIT cells is associated with enhanced IFN-gamma production and depends on IL-2. AB - The role of MAIT cells in immunity against Mycobacterium tuberculosis infection in humans is still largely unexplored. In this study, we investigated the functional role of 4-1BB on MAIT cells. We found that 4-1BB was highly up regulated on MAIT cells from tuberculous pleural effusions following Mtb antigen stimulation and its level of expression correlated with IFN-gamma and IL-17 production. 4-1BB expression on MAIT cells in response to Mtb antigens was partially dependent on IL-2 and was associated with common gamma chain receptor. By transcriptome sequencing, we identified numerous differentially expressed genes between 4-1BB- and 4-1BB+ MAIT cells. GO enrichment and KEGG pathway analysis of differentially expressed genes identified enriched pathways that included T-cell receptor and NF-kappaB signaling pathways. It is concluded that 4 1BB has the potential to be used as a biomarker to identify MAIT cells with enhanced IFN-gamma and IL-17 responses that might be associated with tuberculosis infection control. PMID- 29631726 TI - Impact of non-invasive follicular thyroid neoplasm with papillary-like nuclear features on the Bethesda system for reporting thyroid cytopathology: a multi institutional study in five Asian countries. AB - Several Western studies showed that the recent introduction of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) significantly decreased risk of malignancy for cytological diagnostic categories. We aimed to determine the impact of NIFTP on risk of malignancy within a cohort of thyroid nodules from Asian countries, and to compare distribution of diagnostic categories between NIFTP and invasive encapsulated follicular variant of papillary thyroid carcinoma (eFV-PTC). Consecutive thyroid fine-needle aspirates from six institutions were retrospectively analysed. Histopathology slides with a diagnosis of eFV-PTC were reviewed and reclassified into invasive eFV-PTC and NIFTP. The risk of malignancy was calculated with and without NIFTP. Of 11,372 thyroid nodules, 2044 had available surgical follow-up. NIFTP was diagnosed in 59 cases, which constituted 2.9% of all excised nodules, and 5.3% of malignant nodules. Preoperative cytological diagnoses for NIFTP were non diagnostic (10.2%), benign (18.6%), atypia of undetermined significance/follicular lesion of undetermined significance (22.0%), follicular neoplasm/suspicious for follicular neoplasm (FN/SFN) (32.2%), suspicious for malignancy (SM) (11.9%), and malignant (5.1%). The only category which showed a relative reduction in risk of malignancy after reclassification of more than 20%, was FN/SFN (24.4%). There was a significantly higher prevalence of benign cytology in NIFTP (p = 0.04) and SM/malignant in invasive eFV-PTC (p = 0.05). A majority of NIFTP cases were classified in indeterminate categories, which decreased the corresponding risk of malignancy. However, the magnitude of NIFTP impact was much lower than in the Western reports. Asian countries may not experience significant effects of NIFTP reclassification on the practice of thyroid cytopathology. PMID- 29631727 TI - 'Her cry is my cry': resettlement experiences of refugee women at risk recently resettled in Australia. AB - OBJECTIVES: Refugee women entering resettlement countries on woman-at-risk visas represent a particularly vulnerable population. While their specific gender-based resettlement will likely differ from the general refugee population, little is known about their experiences of early resettlement, with which to inform resettlement policy and practice. This research aimed to explore lived experiences of recently resettled refugee women at risk in Australia. STUDY DESIGN: Qualitative research used focus groups and a framework approach to identify and explicate common themes in participants' experience. METHODS: Two focus groups with a purposive sample of African and Afghan refugee women at risk (N = 10), aged 22-53 years, were conducted in South East Queensland, Australia (October 2016), recruited with the assistance of a local resettlement service. Discussions were audiotaped, transcribed, and themes explicated. RESULTS: Six superordinate themes emerged: (1) sentiment of gratitude; (2) sense of loneliness and disconnection; (3) feeling incapable; (4) experiencing distress and help seeking; (5) experiencing financial hardship; and (6) anticipating the future. CONCLUSIONS: Findings indicate that resettlement policy, programs, and practice that explicitly target the needs of women-at-risk refugees are warranted, including a longer period of active service provision with specific attention to strategies that address the women's social connection, self-efficacy, emotional well-being, and financial hardships. PMID- 29631728 TI - Mechanisms and Biomarkers of Exercise-Induced Bronchoconstriction. AB - Exercise is a common trigger of bronchoconstriction. In recent years, there has been increased understanding of the pathophysiology of exercise-induced bronchoconstriction. Although evaporative water loss and thermal changes have been recognized stimuli for exercise-induced bronchoconstriction, accumulating evidence points toward a pivotal role for the airway epithelium in orchestrating the inflammatory response linked to exercise-induced bronchoconstriction. Overproduction of inflammatory mediators, underproduction of protective lipid mediators, and infiltration of the airways with eosinophils and mast cells are all established contributors to exercise-induced bronchoconstriction. Sensory nerve activation and release of neuropeptides maybe important in exercise-induced bronchoconstriction, but further research is warranted. PMID- 29631729 TI - Exercise-Induced Bronchoconstriction and the Air We Breathe. AB - An association between airway dysfunction and airborne pollutant inhalation exists. Volatilized airborne fluorocarbons in ski wax rooms, particulate matter, and trichloromines in indoor environments are suspect to high prevalence of exercise-induced bronchoconstriction and new-onset asthma in athletes competing in cross-country skiing, ice rink sports, and swimming. Ozone is implicated in acute decreases in lung function and the development of new-onset asthma from exposure during exercise. Mechanisms and genetic links are proposed for pollution related new-onset asthma. Oxidative stress from airborne pollutant inhalation is a common thread to progression of airway damage. Key pollutants and mechanisms for each are discussed. PMID- 29631730 TI - Exercise-Induced Bronchoconstriction: Background, Prevalence, and Sport Considerations. AB - The transient airway narrowing that occurs as a result of exercise is defined as exercise-induced bronchoconstriction (EIB). The prevalence of EIB has been reported to be up to 90% in asthmatic patients, reflecting the level of disease control. However, EIB may develop even in subjects without clinical asthma, particularly in children, athletes, patients with atopy or rhinitis, and following respiratory infections. The intensity, duration, and type of training have been associated with the occurrence of EIB. In athletes, EIB seems to be only partly reversible, and exercise seems to be a causative factor of airway inflammation and symptoms. PMID- 29631731 TI - Testing for Exercise-Induced Bronchoconstriction. AB - Exercise-induced bronchoconstriction (EIB) is a form of airway hyperresponsiveness that occurs with or without current symptoms of asthma. EIB is an indicator of active and treatable pathophysiology in persons with asthma. The objective documentation of EIB permits the identification of an individual who may be at risk during a recreational sporting activity or when exercising as an occupational duty. EIB can be identified with laboratory exercise testing or surrogate tests for EIB. These include eucapnic voluntary hyperpnea and osmotic stimuli (eg, inhaled mannitol) and offer improved diagnostic sensitivity to identify EIB and improved standardization when compared with laboratory exercise. PMID- 29631732 TI - Pharmacologic Strategies for Exercise-Induced Bronchospasm with a Focus on Athletes. AB - Exercise-induced bronchoconstriction (EIB) is the transient narrowing of the airways during and after exercise that occurs in response to increased ventilation in susceptible individuals. It occurs across the age spectrum in patients with underlying asthma and can occur in athletes without baseline asthma. The inflammatory mechanisms underlying EIB in patients without asthma may be distinct from those underlying EIB in patients with asthma. This review summarizes mechanistic and clinical data that can guide the choice of chronic and acute pharmacologic therapies targeting control of EIB. Relevant regulations from the World Anti-Doping Agency are also discussed. PMID- 29631733 TI - Nonpharmacologic Strategies to Manage Exercise-Induced Bronchoconstriction. AB - Pharmacologic management of exercise-induced bronchoconstriction (EIB) is the mainstay of preventative therapy. There are some nonpharmacologic interventions, however, that may assist the management of EIB. This review discusses these nonpharmacologic interventions and how they may be applied to patients and athletes with EIB. PMID- 29631734 TI - Exercise and Sinonasal Disease. AB - Physical exercise requires proper function of the upper and lower airways in order to meet exertional ventilatory requirements. Athletes performing frequent intensive exercise experience more sino-nasal symptoms and demonstrate objective decreases in sino-nasal function when compared with the general population. Sino nasal dysfunction is known to interfere with sport performance. Nasal epithelial injury, neutrophilic influx, and decreased mucociliary clearance have been associated with intensive training. In this review, the authors provide a comprehensive overview of the prevalence of sino-nasal disease in athletes, the possible underlying pathophysiologic mechanisms, and a summary of diagnostic and treatment options. PMID- 29631735 TI - Exercise-Induced Laryngeal Obstruction-An Overview. AB - Exertional dyspnea is common in health and disease. Despite having known for centuries that breathlessness can arise from the larynx, exercise-induced laryngeal obstruction is a more prevalent condition than previously assumed. This article provides a brief overview of the history, epidemiology, and pathophysiology of exercise-induced laryngeal obstruction. PMID- 29631736 TI - Working Towards a Common Transatlantic Approach for Evaluation of Exercise Induced Laryngeal Obstruction. AB - Exertional dyspnea can be a manifestation of dysfunction in a variety of organ systems. Exercise-induced laryngeal obstruction (EILO), a condition previously known as vocal cord dysfunction and paradoxic vocal fold motion, is defined as inappropriate, reversible narrowing of the larynx during vigorous exercise. EILO is usually characterized by typical symptoms, which nevertheless frequently are confused with those of other conditions, including asthma. Laryngoscopy performed as symptoms evolve from rest to peak exercise is pivotal in patient work-up. Moving forward, laryngoscopy findings that definitively characterize EILO need to be defined as do objective measures that can quantitate absolute laryngeal measurements during exercise. PMID- 29631737 TI - Speech-Language Pathology as a Primary Treatment for Exercise-Induced Laryngeal Obstruction. AB - Exercise-induced laryngeal obstruction is a condition that restricts respiration during exercise via inappropriate glottic or supraglottic obstruction. The literature supports behavioral treatment provided by a speech-language pathologist as an effective means of treating exercise-induced laryngeal obstruction. Treatment includes educating the patient, training on relaxation, instruction on paced exercise, and use of various breathing techniques to optimize laryngeal aperture. Intervention for patients with exercise-induced laryngeal obstruction may be delivered by a speech-language pathologist, given their clinical skill of facilitating long-term behavioral change and expertise in the laryngeal mechanism. PMID- 29631738 TI - Exercise-Induced Laryngeal Obstruction and Performance Psychology: Using the Mind as a Diagnostic and Therapeutic Target. AB - Exercise-induced laryngeal obstruction causes severe shortness of breath during exercise. Episodes are associated with severe distress. These patients and those with inducible laryngeal obstruction triggered by other factors have been noted to demonstrate mental health disorders, personality features that may be associated with symptoms, and dysfunctional stress responses. This literature review calls attention to the observation that patients with isolated exercise induced laryngeal obstruction are generally mentally healthy. We review available metrics to assess traits and stress responses in performance psychology. We also discuss a therapeutic performance psychology framework. PMID- 29631739 TI - Surgical Intervention for Exercise-Induced Laryngeal Obstruction. AB - Respiratory distress during exercise can be caused by exercise-induced laryngeal obstruction (EILO). The obstruction may appear at the level of the laryngeal inlet (supraglottic), similar to supraglottic collapse observed in infants with congenital laryngomalacia (CLM). This observation has encouraged surgeons to treat supraglottic EILO with procedures proven efficient for severe CLM. This article summarizes key features of the published experience related to surgical treatment of EILO. Supraglottoplasty is an irreversible procedure with potential complications. Surgery should be restricted to cases where the supraglottic laryngeal obstruction significantly affects the quality of life in patients for whom conservative treatment modalities have failed. PMID- 29631740 TI - Exertional Dyspnea and Excessive Dynamic Airway Collapse. AB - Excessive dynamic airway collapse is a relatively new diagnosis separate from tracheobronchomalacia that is manifested by functional collapse of the large airways. Most commonly described in patients with underlying obstructive lung disease such as chronic obstructive pulmonary disease and asthma, it may contribute to increased dyspnea, cough, or exacerbations. There are few data published on the role of excessive dynamic airway collapse as related specifically to exercise. It was recently described as the cause for exertional dyspnea in individuals without underlying lung disease. PMID- 29631741 TI - The Future of Exertional Respiratory Problems: What Do We Know About the Total Airway Approach and What Do We Need to Know? AB - Exercise is increasingly viewed as a preventative and therapeutic modality for medical and behavioral health disorders. Therefore, it is imperative that the medical and scientific communities minimize barriers that discourage exercise. This issue of Immunology and Allergy Clinics of North America details a "total airway approach" to the evaluation of exertional respiratory problems. Reviews guide clinicians through evaluation and therapy. Moving forward, there is much room for growth with respect to research in each of these areas as well as for common inflammatory pathways and neurophysiologic coupling across all airway segments. PMID- 29631742 TI - Food Allergy Point of Care Pearls. AB - Food allergy should be suspected in individuals with a history of immediate reactivity following ingestion (ie, typically within 20 minutes and almost always within 2 hours) with typical symptoms of immunoglobulin E-mediated reactivity (eg, urticaria, angioedema, coughing, wheezing, vomiting). Testing for food allergy should focus on the most likely allergen to provoke the reaction based on the patient's history. Safe introduction of peanut-containing foods into the diet of an infant at high risk of developing peanut allergy at 4 to 6 months is likely to reduce the risk of peanut allergy. PMID- 29631743 TI - Exercise-Induced Airway Dysfunction in Athletes. PMID- 29631744 TI - Exercise and the Total Airway: A Call to Action. PMID- 29631745 TI - Response to the Letter to the Editor. PMID- 29631746 TI - Regenerative Endodontic Treatment with Orthodontic Treatment in a Tooth with Dens Evaginatus: A Case Report with a 4-year Follow-up. AB - Dens evaginatus is a developmental tooth anomaly in which an extra cusp or tubercle protrudes on the occlusal surface of the tooth along with some pulpal tissue. Because of the fragile nature of the protrusion, these teeth are often at risk of pulpal exposure. When this occurs in an immature tooth, regenerative endodontic treatment may be a good treatment approach to promote root formation. There is limited literature that documents the occurrence of orthodontic treatment in teeth that have undergone regenerative endodontic therapy using triple antibiotic paste. Here we present a case of an immature premolar tooth with dens evaginatus that was diagnosed with pulp necrosis and chronic apical abscess. The tooth was treated with regenerative endodontic treatment; after which, the patient received orthodontic treatment with fixed appliances for 2 years. The tooth responded favorably to the regenerative endodontic treatment and orthodontic tooth movement. Clinically and radiographically, all the follow-up examinations revealed an asymptomatic tooth with evidence of periapical healing with stunted root development. The tooth remained asymptomatic even after 4 years. The regenerative endodontic procedure (REP) was successful in treating an immature permanent premolar with pulp necrosis and apical periodontitis with dens evaginatus. In this case, the tooth treated with an REP responded to orthodontic treatment similar to the nonendodontically treated teeth. Further studies are recommended to clarify the precise effects of orthodontic treatment on teeth treated with an REP. PMID- 29631747 TI - Tube patency: Is there a difference following otic drop administration? AB - PURPOSE: Many surgeons instill peri-operative otic drops to maintain tube patency. A post-hoc analysis of three randomized, controlled studies involving a one-time administration of ciprofloxacin (OTO-201) given instead of otic drops perioperatively was conducted to evaluate tube patency in patients who did and did not receive otic drops as defined within the study protocol. MATERIALS AND METHODS: Post-hoc, retrospective analysis from three prospective, randomized, double-blind trials, (Phase 1b study [n = 83] and two Phase 3 studies [n = 532]) which enrolled children with confirmed middle ear effusion on the day of tympanostomy tube surgery and then randomized to placebo/sham (tubes alone) or OTO-201 and studied over a 28-day observation period. Patients with observed otorrhea post-tube were provided otic drops in the studies. An analysis was performed on the combined studies to evaluate tube patency, determined by pneumatic otoscopy and tympanometry, at four defined study visits over 28 days after the initial tube placement. RESULTS: The analysis included 591 total patients with similar baseline demographics across groups. Tube patency ranged from 87 to 95% for patients who received otic drops, and from 96 to 99% for patients who did not receive otic drops. CONCLUSION: Based on a retrospective post-hoc analysis from three randomized controlled trials in nearly 600 patients, tympanostomy tube occlusion rates was not increased in patients who did not receive otic drops. From this analysis, occlusion is likely caused primarily by peri-operative otorrhea since patency rates approached 99% in the absence of this complication. PMID- 29631749 TI - Cell penetrating peptide modulation of membrane biomechanics by Molecular dynamics. AB - The efficacy of a pharmaceutical treatment is often countered by the inadequate membrane permeability, that prevents drugs from reaching their specific intracellular targets. Cell penetrating peptides (CPPs) are able to route across cells' membrane various types of cargo, including drugs and nanoparticles. However, CPPs internalization mechanisms are not yet fully understood and depend on a wide variety of aspects. In this contest, the entry of a CPP into the lipid bilayer might induce molecular conformational changes, including marked variations on membrane's mechanical properties. Understanding how the CPP does influence the mechanical properties of cells membrane is crucial to design, engineer and improve new and existing penetrating peptides. Here, all atom Molecular Dynamics (MD) simulations were used to investigate the interaction between different types of CPPs embedded in a lipid bilayer of dioleoyl phosphatidylcholine (DOPC). In a greater detail, we systematically highlighted how CPP properties are responsible for modulating the membrane bending modulus. Our findings highlighted the CPP hydropathy strongly correlated with penetration of water molecules in the lipid bilayer, thus supporting the hypothesis that the amount of water each CPP can route inside the membrane is modulated by the hydrophobic and hydrophilic character of the peptide. Water penetration promoted by CPPs leads to a local decrease of the lipid order, which emerges macroscopically as a reduction of the membrane bending modulus. PMID- 29631748 TI - Genome-wide association identifies a novel locus for delirium risk. AB - We aimed to identify common genetic variations associated with delirium through genome-wide association testing in a hospital biobank. We applied a published electronic health record-based definition of delirium to identify cases of delirium, and control individuals with no history of delirium, from a biobank spanning 2 Boston academic medical centers. Among 6035 individuals of northern European ancestry, including 421 with a history of delirium, we used logistic regression to examine genome-wide association. We identified one locus spanning multiple genes, including 3 interleukin-related genes, associated with p = 1.41e 8, and 5 other independent loci with p < 5e-7. Our results do not support previously reported candidate gene associations in delirium. Identifying common variant associations with delirium may provide insight into the mechanisms responsible for this complex and multifactorial outcome. Using standardized claims-based phenotypes in biobanks should allow the larger scale investigations required to confirm novel loci such as the one we identify. PMID- 29631751 TI - Transverse ileocolic invagination: An infrequent cause of nonspecific abdominal pain in the adult. PMID- 29631750 TI - Steroid Withdrawal Using Everolimus in ABO-Incompatible Kidney Transplant Recipients With Post-Transplant Diabetes Mellitus. AB - BACKGROUND: The effectiveness of everolimus (EVR) for ABO-incompatible (ABOi) kidney transplantation is unknown. We evaluated outcomes of conversion from steroid to EVR in ABOi kidney transplant recipients. METHODS: We performed a retrospective observational cohort study of 33 de novo consecutive adult ABOi living donor kidney transplant recipients. Desensitization was performed using 0 to 4 sessions of plasmapheresis and 1 to 2 doses of 100 mg rituximab according to the anti-A/B antibody titer. ABOi recipients were administered a combination of tacrolimus, mycophenolate mofetil, and methylprednisolone. Diabetic patients were converted from methylprednisolone to EVR at 1 to 15 months post-transplantation to prevent diabetes progression. Graft outcomes, hemoglobin A1c (HbA1c) levels, and cytomegalovirus infection rates were compared between the EVR (n = 11) and steroid (n = 22) groups. RESULTS: Mean postoperative duration was 814 and 727 days in the EVR and steroid groups, respectively (P = .65). Between the 2 groups, graft survival rate (100% vs 95.5%, P > .99), acute rejection rate (9.1% vs 18.2%, P = .64), and serum creatinine levels (1.46 mg/dL vs 1.68 mg/dL, P = .66) were comparable. Although HbA1c levels were elevated in the steroid group (5.47%, 5.87%; P = .003), no significant deterioration was observed in the EVR group without additional insulin administration (6.10%, 6.47%; P = .21). Cytomegalovirus infection rate was significantly lower in the EVR group than in the steroid group (18.2% vs 63.6%, P = .026). CONCLUSION: Conversion from steroid to EVR in ABOi kidney transplant recipients maintained excellent graft outcomes and avoided diabetes progression and cytomegalovirus infection. PMID- 29631752 TI - Homogeneous photocatalytic Fe3+/Fe2+ redox cycle for simultaneous Cr(VI) reduction and organic pollutant oxidation: Roles of hydroxyl radical and degradation intermediates. AB - The sustained oxidation of aqueous organic pollutants using hydroxyl radicals (HO) generated in the UV-irradiated solution of ferric ions was investigated in the presence of Cr(VI). The synergistic effect of simultaneous 4-chlorophenol (4 CP) oxidation and Cr(VI) reduction is explained in terms of the various roles of OH radical, degradation intermediates, and Fe3+/Fe2+ redox cycle. The photolysis of FeIII(OH)2+ generates OH radical which degrades the organic substrate. The reduction of Cr(VI) was inhibited by the OH radical-induced re-oxidation of Cr(III) in the absence of 4-CP. The complete removal of Cr(VI) was achieved only in the presence of phenolic substrates which not only reacts with OH radical (hence inhibiting the reoxidation of Cr(III)) but also generates reducing intermediates which effectively reduce Cr(VI). Fe2+ also converted Cr(VI) to Cr(III) with regenerating Fe3+, which makes the overall process photocatalytic. The photocatalytic activity for the simultaneous removal of 4-CP and Cr(VI) was largely maintained up to five cycles. Such simultaneous and synergic photoactivity was also observed for other phenolic compounds (4-bromophenol, 4 nitrophenol, phenol). The simultaneous and synergic removal of phenolic compounds and Cr(VI) can be enabled through the redox couple of Fe3+/Fe2+ working as a homogeneous photocatalyst. PMID- 29631753 TI - Intrinsically motivated reinforcement learning for human-robot interaction in the real-world. AB - For a natural social human-robot interaction, it is essential for a robot to learn the human-like social skills. However, learning such skills is notoriously hard due to the limited availability of direct instructions from people to teach a robot. In this paper, we propose an intrinsically motivated reinforcement learning framework in which an agent gets the intrinsic motivation-based rewards through the action-conditional predictive model. By using the proposed method, the robot learned the social skills from the human-robot interaction experiences gathered in the real uncontrolled environments. The results indicate that the robot not only acquired human-like social skills but also took more human-like decisions, on a test dataset, than a robot which received direct rewards for the task achievement. PMID- 29631754 TI - Beyond readmission: improving patient-centered care. PMID- 29631755 TI - Lung adenocarcinoma presenting as intramedullary spinal cord metastasis: Case report and review of literature. AB - Intramedullary spinal cord metastasis (IMSCM) is a rare entity which lacks well defined treatment guidelines, yet sees rising incidence. We report a case of a 67 year-old man who presented with severe neck pain and numbness in his right fourth and fifth digits, and was found to have a C5-7 IMSCM of previously unknown lung adenocarcinoma. He underwent gross total resection of the IMSCM, afatinib, and radiation treatment. He had full reversal of his pain and sensory deficit, and remained ambulatory without any focal neurological deficit. Additionally, we conducted a literature review of original case series of IMSCM published between 1983 and 2016, representing 138 unique cases, and discuss various treatments with a focus on surgical resection and general treatment of stage IV lung adenocarcinoma. 18.75% of cases of IMSCM were an initial presentation of underlying malignancy. Rapidly progressive pain and weakness was the most common presentation, often compromising ambulatory status. Median survival ranged from 3.8 to 11.6 months after treatment in patients who were deceased at time of publication. Treatments included corticosteroids, chemotherapy, various radiotherapies, and surgical resection. Surgical resection was found to greatly improve symptoms and preserve ambulatory status, and was associated with increased survival time up to double that of non-surgical treatments. Most authors recommended surgical resection only in symptomatic patients with reversible deficits, to palliate symptoms and preserve ambulation. IMSCM can herald an underlying malignancy, and surgical resection can preserve ambulatory status and palliate symptoms as well increase survival time in a subset of patients. PMID- 29631756 TI - Role of early partial recanalization and intravenous thrombolysis for acute ischemic stroke. PMID- 29631757 TI - The link between COPD and ankylosing spondylitis: A population based study. AB - BACKGROUND: Ankylosing spondylitis (AS) is one of the most common and severe subtypes of the spondyloarthropathies. Extra-articular involvement among AS patients, including lung disease, has been described widely. Chronic obstructive pulmonary disease (COPD) has been linked to several autoimmune diseases, however, very few studies have investigated the association between AS and COPD. OBJECTIVE: To assess whether an association exists between AS and COPD. MATERIAL AND METHODS: A population-based cross-sectional study was conducted using data retrieved from the largest electronic medical records database in Israel, the Clalit Health Services (CHS). Patients were defined as having AS or COPD when there was at least one such documented diagnosis in their medical records. The proportion of COPD was compared between AS patients and controls. A logistic regression model was used to estimate the association between AS and COPD in a multivariate analysis adjusted for age, gender and smoking status. RESULTS: The study included 4076 patients with AS and 20,290 age- and sex-frequency matched controls. The proportion of COPD in AS patients was higher than in controls (46% vs. 18%, respectively, p < .001). Multivariate logistic regression demonstrated a robust independent association between AS and COPD (OR 1.225, p = .031). CONCLUSION: Our study supports an association between AS and COPD, further extending the link between COPD and autoimmune diseases. This finding highlights the importance of smoking cessation in AS patients and raises the question of whether COPD screening may be warranted. PMID- 29631758 TI - Is Nutrition Specific Quality of Life Associated With Nutritional Status? AB - OBJECTIVE: The study purpose was to explore the relationship between nutritional status, as measured by Subjective Global Assessment (SGA), and Health Related Quality of Life measured using the Nutrition Specific Quality of Life (NS-QoL), tool among participants on maintenance hemodialysis (MHD). The study aim was to determine if NS-QoL may be an adjuvant tool for detecting changes in nutritional status among patients on MHD. DESIGN, SETTING, AND SUBJECTS: This is a cross sectional, secondary analysis of data from a multi-center study. Participants were adult (>18) men and women on MHD (n = 145) recruited from 3 institutions in the Northeastern United States. METHODS: Statistical tests were conducted to determine the relationship between key demographic characteristics (age, sex, dialysis vintage, gender, and ethnicity) and SGA and NS-QoL. Spearman's correlation examined the relationship between the independent variable, SGA and the dependent variable, NS-QoL. A univariate general linear model was conducted to adjust for confounding variables. MAIN OUTCOME MEASURE: The relationship between overall SGA score and composite NS-QoL score. RESULTS: The sample consisted of 85 men (58.6%), with a mean age of 55.3 +/- 11.9 years, who were largely African-American (84.1%) and non-Hispanic (77.2%). Mean SGA score was 5.5 +/- 1.0, and the mean NS-QoL composite score was 9.51 +/- 3.77. No key demographic characteristics had a statistically significant relationship with SGA, whereas sex (P < .001) and race (P = .015) both had statistically significant relationships with NSQoL. After adjusting for the variables of race and sex, NS-QoL score was positively correlated with SGA composite score (P = .042); as NS-QoL score increased so did the SGA score. CONCLUSION: The present study found a positive linear correlation between NS-QoL composite score and SGA, as well as 5 SGA subcomponent scores and NS-QoL. These findings indicate that NS QoL can complement the SGA to provide information about a patient's nutritional status. PMID- 29631759 TI - Dose calculation of dynamic trajectory radiotherapy using Monte Carlo. AB - PURPOSE: Using volumetric modulated arc therapy (VMAT) delivery technique gantry position, multi-leaf collimator (MLC) as well as dose rate change dynamically during the application. However, additional components can be dynamically altered throughout the dose delivery such as the collimator or the couch. Thus, the degrees of freedom increase allowing almost arbitrary dynamic trajectories for the beam. While the dose delivery of such dynamic trajectories for linear accelerators is technically possible, there is currently no dose calculation and validation tool available. Thus, the aim of this work is to develop a dose calculation and verification tool for dynamic trajectories using Monte Carlo (MC) methods. METHODS: The dose calculation for dynamic trajectories is implemented in the previously developed Swiss Monte Carlo Plan (SMCP). SMCP interfaces the treatment planning system Eclipse with a MC dose calculation algorithm and is already able to handle dynamic MLC and gantry rotations. Hence, the additional dynamic components, namely the collimator and the couch, are described similarly to the dynamic MLC by defining data pairs of positions of the dynamic component and the corresponding MU-fractions. For validation purposes, measurements are performed with the Delta4 phantom and film measurements using the developer mode on a TrueBeam linear accelerator. These measured dose distributions are then compared with the corresponding calculations using SMCP. First, simple academic cases applying one-dimensional movements are investigated and second, more complex dynamic trajectories with several simultaneously moving components are compared considering academic cases as well as a clinically motivated prostate case. RESULTS: The dose calculation for dynamic trajectories is successfully implemented into SMCP. The comparisons between the measured and calculated dose distributions for the simple as well as for the more complex situations show an agreement which is generally within 3% of the maximum dose or 3mm. The required computation time for the dose calculation remains the same when the additional dynamic moving components are included. CONCLUSION: The results obtained for the dose comparisons for simple and complex situations suggest that the extended SMCP is an accurate dose calculation and efficient verification tool for dynamic trajectory radiotherapy. This work was supported by Varian Medical Systems. PMID- 29631760 TI - [Digital myxoid (mucous) cyst of toe: Association with osteoarthritis and nail deformity]. PMID- 29631761 TI - Rab22a: A novel regulator of immune functions. AB - Dendritic cells (DCs) trigger CD8 + T cell responses after the internalization of exogenous antigens in a process called cross-presentation. Multiple intracellular transport events within the endocytic and secretory routes take place in order to accomplish this fundamental immunological process. The endomembrane system can be envisioned as a complex network of membrane domains coordinately working in the fusion of organelles, the budding of vesicles and tubules, and modifying the molecular composition of the limiting membranes. In this context of tightly regulated and dynamic endomembrane transport, small GTPases of the Rab family display a pivotal role by organizing membrane microdomains and defining specific identities to the different intracellular compartments. In this review, we synthesize and update the current knowledge about Rab22a, which has been involved in several immune functions. In this way, we analyze the intracellular localization of Rab22a and its important role in the endocytic recycling, including its relevance during MHC-I trafficking, antigen cross-presentation by DCs and the formation of T cell conjugates. We also describe how different pathogenic microorganisms hijack Rab22a functions to achieve efficient infection and intracellular survival strategies. Furthermore, we examine the oncogenic properties of Rab22a and how its expression determines the progression of many tumors. In summary, we highlight the role of Rab22a as a key effector of the intracellular trafficking that could be exploited in future therapies to modulate the immune system. PMID- 29631762 TI - Can I reach that? Blind reaching as an accurate measure of estimated reachable distance. AB - Judgments of one's reach extent have been repeatedly found to be overestimated by about 10%. In 3 studies, a new dependent measure was employed in which participants viewed targets, closed their eyes, and then touched the location of the remembered target or pointed to its location if out of reach. This experimental paradigm yielded a much smaller but still present bias to over estimate by about 2%. In addition, participants often reached for and touched target locations that were actually out of reach in a manner indicative of the typical 10% over-estimation bias. Surprisingly, participant response accuracy improved significantly and consistently across experimental trials even without visual or tactile feedback. This suggests that the proprioceptive information about the arm in space coupled with the remembered visual information about target location were sufficient to facilitate learning. PMID- 29631763 TI - Iatrogenic pulmonary lesions. AB - Treatment of patients often includes the administration of medications and sometimes radiation. While the intent is to treat an underlying condition, in some cases, adverse effects occur due to these agents. Most of these adverse effects are mild, however, some can be severe and life-threatening. Furthermore, while these effects are often reversible upon cessation of exposure, especially if the inciting agent is recognized and withdrawn early, others might be permanent or even progressing. Most common histopathologic findings in drug induced interstitial lung disease include nonspecific interstitial pneumonia (cellular and/or fibrotic), organizing pneumonia with or without bronchiolitis, eosinophilic pneumonia, pulmonary edema, diffuse alveolar damage, hypersensitivity pneumonitis, granulomatous interstitial lung disease, chronic bronchiolitis, and pulmonary hemorrhage. Pulmonary vascular changes or constrictive bronchiolitis can also occur. Drugs that are more commonly associated with lung toxicity include nitrofurantoin, amiodarone, and chemotherapeutic agents such as bleomycin and methotrexate. More recently introduced immune modulating agents including rituximab and immune checkpoint inhibitors such as anti-CTLA4, anti-PD-1 and anti-PD-L1 agents have also been associated with adverse effects in the lung. Radiation therapy to the chest can trigger acute or chronic lung toxicity. While newer radiation techniques are aimed to decrease and minimize side effects other risk factors such as additional chemotherapy, oxygen, and older age may be rising. Foreign substances such as talc, hydrogel, and medical devices such as hydrophilic polymer coated catheter may rarely also lead to pulmonary complications. It is important that clinicians and pathologists are aware of these potential adverse effects of drugs, radiation and medical devices and raise the possibility of drug-induced lung toxicity after exclusion of other differential diagnoses. It is the role of the clinician to provide the pathologist with an appropriate drug history. Early intervention to a drug-induced lung toxicity might prevent progression of side effects and permanent changes. PMID- 29631764 TI - Correlation Between Skin Temperature Over Myofascial Trigger Points in the Upper Trapezius Muscle and Range of Motion, Electromyographic Activity, and Pain in Chronic Neck Pain Patients. AB - OBJECTIVE: The purpose of this study was to assess the correlation between skin temperature over a myofascial trigger point in the upper trapezius muscle and range of motion of the cervical spine, electromyographic activity, and pain in patients with chronic neck pain. METHODS: This is a single-blind cross-sectional study. Forty participants of both sexes, aged 18 to 45 years, with chronic neck pain and myofascial trigger points in the upper trapezius muscle were included in the study. The participants were assessed using the Numeric Rating Scale, the Neck Disability Index, infrared thermography, algometry, fleximetry, and electromyographic activity. RESULTS: A positive association was observed between skin temperature to the right with the range of motion of cervical flexion (r = 0.322, P = .043), the median frequency of isometrics to the right (r = 0.341, P = .032), and the median frequency of rest to the left (rs = 0.427, P = .006); as were a negative association between skin temperature to the right and the root mean square of rest to the right (rs = -0.447, P = .004), and a positive association of skin temperature to the left with the median frequency of isometrics to the right (r = 0.365, P = .020), and the median frequency of rest to the left (rs = 0.573, P < .001). CONCLUSION: Patients with chronic neck pain who had reduction of skin temperature over myofascial trigger points in the upper trapezius muscle had reduced cervical range of motion for flexion, reduced median frequency at rest and during isometric contraction, and increased root mean square at rest. PMID- 29631765 TI - Prevalence and clinical characteristics of non-alcoholic fatty liver disease in newly diagnosed patients with ketosis-onset diabetes. AB - AIM: As the prevalence and clinical characteristics of non-alcoholic fatty liver disease (NAFLD) are still unknown in ketosis-onset diabetes, the present study compared the characteristics of NAFLD in type 1 diabetes (T1D), ketosis-onset and non-ketotic type 2 diabetes (T2D) patients. METHODS: This cross-sectional study was performed with newly diagnosed Chinese patients with diabetes, including 39 T1D, 165 ketosis-onset and 173 non-ketotic T2D, with 30 non-diabetics included as controls. NAFLD was determined by hepatic ultrasonography, then its clinical features were analyzed and its associated risk factors evaluated. RESULTS: NAFLD prevalence in patients with ketosis-onset diabetes (61.8%) was significantly higher than in controls (23.3%; P=0.003) and in T1D patients (15.4%; P<0.001). However, there was no difference in prevalence between ketosis-onset and non ketotic T2D patients (52.6%; P=0.229), although BMI and alanine aminotransferase (ALT) proved to be independent risk factors for the presence of NAFLD in both these groups whereas, in T1D patients, serum uric acid levels were independent risk factors. CONCLUSION: NAFLD prevalence and risk factors in ketosis-onset diabetes were similar to those in non-ketotic T2D, but different from those in T1D. These data provide further evidence that ketosis-onset diabetes should be classified as a subtype of T2D rather than idiopathic T1D. PMID- 29631766 TI - Ethics Authorization for Research Reporting. PMID- 29631767 TI - Modified Healthy Eating Index and Incidence of Metabolic Syndrome in Children and Adolescents: Tehran Lipid and Glucose Study. AB - OBJECTIVE: To assess the relationship between modified healthy eating index (mHEI) with the development of metabolic syndrome (MetS) among children and adolescents. STUDY DESIGN: Dietary data were collected using a food frequency questionnaire among 424 healthy subjects, aged 6-18 years. The components of mHEI were grains, vegetables and fruits, dairy, red to white meat ratio, butter, sweet snacks, sweetened beverages, salty snacks, and fast food. Multivariable logistic regression models were used to estimate the incidence of MetS after 3.6 years of follow-up in each quartile of the mHEI score, adjusted for baseline age, sex, total energy intake, physical activity, and body mass index. RESULTS: The mean +/ SD age and mHEI scores of participants were 13.6 +/- 3.7 years and 55.9 +/- 10.0, respectively, at baseline. MetS developed in 11% of the participants at the end of follow-up. After adjustment for confounders, the occurrences of MetS decreased in the highest quartile compared with the lowest quartile of the mHEI score (OR = 0.35, 95% CI 0.13-0.98, P for trend = .025). In addition, higher scores of mHEI components including fruits, salty snacks, and fast food were associated with lower risk of MetS. CONCLUSIONS: Higher scores of mHEI as an indicator of diet quality may hinder the development of MetS among children and adolescents. PMID- 29631768 TI - Prevalence of Childhood Permanent Hearing Loss after Early Complex Cardiac Surgery. AB - OBJECTIVES: To estimate the prevalence of childhood permanent hearing loss (PHL) after early cardiac surgery. STUDY DESIGN: This prospective observational (1996 2015) study after complex cardiac surgery with cardiopulmonary bypass at <=6 weeks of life reports audiology follow-up by registered pediatric-experienced audiologists at 6-8 months postsurgery, age 2 years, and as required throughout and thereafter to complete diagnoses. PHL at any frequency (500-4000 Hz) is defined as responses of >25-decibel hearing level in either ear. PHL was evaluated by type (conductive or sensorineural), pattern (flat or sloping), and severity (mild to profound). RESULTS: Survival rate was 83.4% (706 of 841 children) with a 97.9% follow-up rate (691 children); 41 children had PHL, 5.9% (95% CI 4.3%, 8.0%). By cardiac defect, prevalence was biventricular, 4.0% (95%CI 2.5%, 6.1%); single ventricle, 10.8% (95%CI 6.8%, 16.1%). Eighty-seven (12.6%) of 691 had syndromes/genetic abnormalities with known association with PHL; of these, 17 (41.5%) had PHL. Of 41 children, 4 had permanent conductive, moderate to severe loss (1 bilateral); 37 had moderate to profound sensorineural loss (29 bilateral with 20 sloping and 9 flat), 6 with cochlear implant done or recommended. CONCLUSIONS: Infants surviving complex cardiac surgery are at high risk for PHL. Over 40% with PHL have known syndromes/genetic abnormalities, but others do not have easily identifiable risk indicators. Early cardiac surgery should be considered a risk indicator for PHL. PMID- 29631769 TI - Characteristics Associated with Confidential Consultation for Adolescents in Primary Care. AB - OBJECTIVE: To examine how provider report of confidential consultation in the electronic health record is associated with adolescent characteristics, health risk factors, and provider training. STUDY DESIGN: This prospective cohort study was conducted as part of a larger study implementing computerized clinical decision support in 2 urban primary care clinics. Adolescents used tablets to complete screening questions for specified risk factors in the waiting room. Adolescent-reported risk factors included sexual activity, substance use, and depressive symptoms. Providers were prompted on encounter forms to address identified risk factors and indicate whether confidential consultation was provided. Provider types included adolescent medicine board certified pediatrics and general pediatrics. Differences in proportions of adolescents reporting risk factors by provider type were assessed using chi2 tests. Associations between adolescent characteristics, risk factors, and provider-reported confidential consultation were examined using logistic regression analyses. RESULTS: The sample included 1233 English and Spanish-speaking adolescents 12-20 years of age (52% female; 60% black; 50% early adolescent). Patients seen by adolescent medicine board certified providers reported sexual activity, depressive symptoms, and substance use significantly more often than those seen by general pediatric providers. Among patients seen by board certified adolescent medicine providers, confidential consultation was provided to 90%. For those seen by general pediatric providers, confidential consultation was provided to 53%. Results of multiple logistic regression demonstrated that female sex, later adolescence, and clinic location were significantly associated with confidential consultation. CONCLUSIONS: Provider training is needed to reinforce the importance of confidential consultation for all adolescents. PMID- 29631770 TI - Statewide Initiative to Reduce Postnatal Growth Restriction among Infants <31 Weeks of Gestation. AB - OBJECTIVE: To decrease the incidence of postnatal growth restriction, defined as discharge weight <10th percentile for postmenstrual age, among preterm infants cared for in New York State Regional Perinatal Centers. STUDY DESIGN: The quality improvement cohort consisted of infants <31 weeks of gestation admitted to a New York State Regional Perinatal Center within 48 hours of birth who survived to hospital discharge. Using quality improvement principles from the Institute for Healthcare Improvement and experience derived from successfully reducing central line-associated blood stream infections statewide, the New York State Perinatal Quality Collaborative sought to improve neonatal growth by adopting better nutritional practices identified through literature review and collaborative learning. New York State Regional Perinatal Center neonatologists were surveyed to characterize practice changes during the project. The primary outcome-the incidence of postnatal growth restriction-was compared across the study period from baseline (2010) to the final (2013) years of the project. Secondary outcomes included differences in z-score between birth and discharge weights and head circumferences. RESULTS: We achieved a 19% reduction, from 32.6% to 26.3%, in postnatal growth restriction before hospital discharge. Reductions in the difference in z-score between birth and discharge weights were significant, and differences in z-score between birth and discharge head circumference approached significance. In survey data, regional perinatal center neonatologists targeted change in initiation of feedings, earlier breast milk fortification, and evaluation of feeding tolerance. CONCLUSIONS: Statewide collaborative quality improvement can achieve significant improvement in neonatal growth outcomes that, in other studies, have been associated with improved neurodevelopment in later infancy. PMID- 29631771 TI - Parent-Child Sexual Communication Among Middle School Youth. AB - Middle school youth (N = 1472) in Central Indiana completed a survey about parent adolescent sexual communication. Being older, female, mixed race, ever had sex, ever arrested, and higher HIV knowledge were associated with more frequent sexual communication. PMID- 29631772 TI - In-Hospital Outcomes in Large for Gestational Age Infants at 22-29 Weeks of Gestation. AB - OBJECTIVE: To estimate the risks of mortality and morbidities in large for gestational age (LGA) infants relative to appropriate for gestational age infants born at 22-29 weeks of gestation. STUDY DESIGN: Data on 156 587 infants were collected between 2006 and 2014 in 852 US centers participating in the Vermont Oxford Network. We defined LGA as sex-specific birth weight above the 90th centile for gestational age measured in days. Generalized additive models with smoothing splines on gestational age by LGA status were fitted on mortality and morbidity outcomes to estimate adjusted relative risks and their 95% CIs. RESULTS: Compared with appropriate for gestational age infants, being born LGA was associated with decreased risks of mortality, respiratory distress syndrome, patent ductus arteriosus, necrotizing enterocolitis, late-onset sepsis, severe retinopathy of prematurity, and chronic lung disease. Early onset sepsis and severe intraventricular hemorrhage were increased among LGA infants, but these risks were not homogeneous across the gestational age range. CONCLUSIONS: Being born LGA was associated with lower risks for all the examined outcomes except for early onset sepsis and severe intraventricular hemorrhage. PMID- 29631774 TI - Children with cystic fibrosis demonstrate no respiratory immunological, infective or physiological, consequences of vitamin D deficiency. AB - BACKGROUND: Vitamin D has health benefits in many respiratory diseases but the evidence in CF is unclear. Induction of the antimicrobial peptides cathelicidin (LL37) and human-beta-defensin-2 (HBD-2) may be the mechanism of any benefit. We hypothesised that antimicrobial peptide levels would be decreased, and airway infection and inflammation greater, in CF children with vitamin D deficiency. The objective of the study was to explore relationships between vitamin D, LL37 and HBD-2, and airway infection, inflammation and physiology in children with CF. METHODS: Bronchoalveolar lavage (BALF) and blood were obtained from children undergoing fibreoptic bronchoscopy. Serum vitamin D, BALF HBD-2 and LL37, cultured bacteria and inflammatory markers were measured. Clinical parameters were recorded. RESULTS: 113 patients with CF, 23 with non-CF chronic suppurative lung disease (CSLD) and 6 healthy controls were included. We found no relationship between serum vitamin D and BALF HBD-2 or LL-37. There were no differences in infective or inflammatory markers between vitamin D sufficient and deficient groups. Vitamin D deficient patients (<50 nmol/L) did not have a worse FEV1 (CF: 66 (58-71)% vs. 71.5 (61-76)%, ns; non-CF CSLD: 69 (36-88)% vs. 70 (62 95)%, ns). CONCLUSIONS: In the first bronchoscopic study exploring this question, we demonstrate that vitamin D deficiency is not associated with immunological, infective or clinical markers of disease severity in patients with CF or CSLD. PMID- 29631773 TI - In-frame Val216-Ser217 deletion of KIT in mild piebaldism causes aberrant secretion and SCF response. AB - BACKGROUND: Piebaldism is a pigmentary disorder characterized by a white forelock and depigmented patches. Although the loss-of-function mutations in the KIT gene underlie the disease, the intracellular dynamics of the mutant KIT are largely unknown. We herein report a Japanese family with piebaldism in which the affected members showed a mild phenotype. OBJECTIVE: The objective of this study is to investigate the functions and intracellular dynamics of the mutant KIT protein. METHODS: We performed genetic analyses of the KIT gene using peripheral blood cells. We analyzed the intracellular localization of the mutant KIT protein in HEK293T cells transfected with wild-type (Wt) and/or mutant KIT genes. Immunoprecipitation analyses, immunoblotting and immunofluorescence studies were performed using antibodies against KIT and downstream signaling proteins. Glycosidase digestion analysis was performed to clarify the intracellular localization of KIT protein. RESULTS: A genetic analysis revealed a novel heterozygous mutation c.645_650delTGTGTC which results in the in-frame deletion of Val216 and Ser217 in the extracellular domain of KIT. Immunoprecipitation analyses confirmed that the wild and mutant KIT formed a heterodimer after treatment with stem cell factor (SCF); however, the phosphorylation of the downstream signaling factors was decreased. In an immunofluorescence study, the mutant KIT accumulated predominantly in the endoplasmic reticulum (ER) and was sparsely expressed on the cell surface. A glycosidase digestion study revealed that the mutant KIT is predominantly localized in the ER. CONCLUSION: These data reveal an aberrant function and intracellular localization of mutant KIT protein in piebaldism. PMID- 29631775 TI - MECP2 mutation in a boy with severe apnea and sick sinus syndrome. AB - Rett syndrome is a neurodevelopmental disorder caused by mutations in the MECP2 gene, which encodes methyl-CpG-binding protein 2 (MECP2). It almost exclusively affects the female sex and is considered lethal in the male sex. However, an increasing number of male patients with MECP2 mutations have been reported, including patients who suddenly died of unknown causes. We report a case of MECP2 mutation in a male patient who exhibited neonatal encephalopathy. He developed severe apnea, epilepsy, and psychomotor developmental delay and died suddenly of sick sinus syndrome at 17 months of age. Severe bradycardia had been noticed since 16 months of age. His older brother followed a similar clinical course and died at 30 months of age. The brother had also experienced severe bradycardia. This familial case might help to clarify the causes of sudden death in cases of MECP2 mutations. PMID- 29631776 TI - Nerve ultrasound of small nerves in the hand. PMID- 29631777 TI - Differential modulation of prepulse inhibition of the blink reflex in peripersonal versus extrapersonal space. AB - OBJECTIVE: Threatening stimuli encountered in peripersonal space (PPS) are processed differently from those encountered in extrapersonal space (EPS). This phenomenon is attributed to tonic top-down modulation. We hypothesized that prepulse inhibition (PPI) of a reflex, which has a protective function, may change according to whether the conditioning stimulus appears in PPS or EPS. We aimed to compare the strength of the PPI according to whether stimulation was delivered in PPS or EPS. METHODS: The study included 23 healthy subjects with a mean age of 36.8+/-9.1years. Recordings of blink reflex (BR) after supraorbital stimulation (so-BR) were performed. Recordings of BR after prepulse stimulation to the median nerve 100ms prior to the supraorbital stimulation were acquired with the ipsilateral hand 50-60cm from the face (EPS) and approximately 3-4cm from the face (PPS). Changes of response magnitudes were compared between PPS and EPS conditions. RESULTS: R2 area-under-the curve of so-BR was reduced after prepulse stimulation of median nerve in all subjects while the hand was in EPS. Although the R2 magnitude was also decreased after prepulse stimulation while the hand was in PPS, the percentage of reduction with the hand in PPS was significantly smaller compared to that with the hand in EPS. CONCLUSION: Reduction in R2 magnitude after prepulse stimulation 100ms prior to test pulse is recognized (PPI). Although PPI was observed under both conditions, PPI of so-BR was attenuated when the stimulus was presented in the PPS. Therefore, our study provides evidence for modulation of PPI of so-BR in PPS and may suggest top-down modulation of the neural circuitry underlying PPI. PMID- 29631778 TI - Concurrent gradients of ribbon volume and AMPA-receptor patch volume in cochlear afferent synapses on gerbil inner hair cells. AB - The Mongolian gerbil is a classic animal model for age-related hearing loss. As a prerequisite for studying age-related changes, we characterized cochlear afferent synaptic morphology in young adult gerbils, using immunolabeling and quantitative analysis of confocal microscopic images. Cochlear wholemounts were triple-labeled with a hair-cell marker, a marker of presynaptic ribbons, and a marker of postsynaptic AMPA-type glutamate receptors. Seven cochlear positions covering an equivalent frequency range from 0.5 - 32 kHz were evaluated. The spatial positions of synapses were determined in a coordinate system with reference to their individual inner hair cell. Synapse numbers confirmed previous reports for gerbils (on average, 20-22 afferents per inner hair cell). The volumes of presynaptic ribbons and postsynaptic glutamate receptor patches were positively correlated: larger ribbons associated with larger receptor patches and smaller ribbons with smaller patches. Furthermore, the volumes of both presynaptic ribbons and postsynaptic receptor patches co-varied along the modiolar-pillar and the longitudinal axes of their hair cell. The gradients in ribbon volume are consistent with previous findings in cat, guinea pig, mouse and rat and further support a role in differentiating the physiological properties of type I afferents. However, the positive correlation between the volumes of pre- and postsynaptic elements in the gerbil is different to the opposing gradients found in the mouse, suggesting species-specific differences in the postsynaptic AMPA receptors that are unrelated to the fundamental classes of type I afferents. PMID- 29631779 TI - The different methods of assessing glycemic variability, quality of glycemic control and glycemic risk cannot be interpreted as equivalent in clinical practice. AB - OBJECTIVE: Several methods are available to calculate glycemic variability (GV), quality of glycemic control (QGC) and glycemic risk (GR). However, clinicians do not easily interpret these data. This study evaluates whether the results of the different methods can be interpreted as equivalent. METHODS: A prospective study was performed including outpatients with DMT2 evaluated at the San Ignacio Hospital and the Colombian Diabetes Association in Bogota, Colombia. From six-day continuous glucose monitoring data, GV (SD, CV, IQR, MODD, MAGE), QGC (M-value, J index) and GR (LBGI, HBGI) were calculated. Reference values were generated, classifying the patients according to GV control quartiles (excellent, good, fair or poor). The concordance between the different indices was evaluated. RESULTS: In total, 140 patients (68.9 +/- 11.2 years) were included. The agreement levels (Kappa) between GV indices were moderate, 0.40 (CI 95%:0.29-0.51), 0.42 (CI 95%:0.31-0.53) and 0.39 (CI 95%:0.28-0.50), for CV versus SD, IQR and CONGA respectively. The levels of agreement between GV and QGC indices were minimal (Kappa CV vs. M-value, 0.15CI 95%:0.046-0.26) and weak between the GV and GR indices (Kappa CVvs.LBGI 0.37CI95%:0.26-0.48). The estimators did not improve significantly when the analysis was performed with linearly weighted or quadratic weighted Kappa. CONCLUSIONS: The present study demonstrates that the concordance between the clinical interpretation of the different GV, QGC and GR indices is poor, suggesting that they cannot be assumed as equivalent, so different indices evaluating different concepts, must be evaluated simultaneously to analyze adequately each patient. New studies are needed to evaluate which of the methods better predicts hypoglycemia and microvascular or macrovascular complications. PMID- 29631780 TI - Out-of-pocket costs, primary care frequent attendance and sample selection: Estimates from a longitudinal cohort design. AB - This paper examines the effect of out-of-pocket costs on subsequent frequent attendance in primary care using data from the Personality and Total Health (PATH) Through Life Project, a representative community cohort study from Canberra, Australia. The analysis sample comprised 1197 respondents with two or more GP consultations, and uses survey data linked to administrative health service use (Medicare) data which provides data on the number of consultations and out-of-pocket costs. Respondents identified in the highest decile of GP use in a year were defined as Frequent Attenders (FAs). Logistic regression models that did not account for potential selection effects showed that out-of-pocket costs incurred during respondents' prior two consultations were significantly associated with subsequent FA status. Respondents who incurred higher costs ($15 $35; or >$35) were less likely to become FAs than those who incurred no or low (=7.5 mg prednisone daily, or equivalent) for at least 3 months (glucocorticoid continuing) or less than 3 months (glucocorticoid initiating) before screening. Patients younger than 50 years needed to have a history of osteoporosis-related fracture; glucocorticoid-continuing patients aged 50 years or older needed a lumbar spine, total hip, or femoral neck bone mineral density T score of -2.0 or less, or -1.0 or less if they had a history of osteoporosis-related fracture. Participants were randomly assigned (1:1) to either 60 mg subcutaneous denosumab every 6 months and oral placebo daily for 24 months, or 5 mg oral risedronate daily and subcutaneous placebo every 6 months for 24 months. Randomisation was stratified by sex within each subpopulation, and was done with an interactive voice-response system. Active drugs and corresponding placebos had identical packaging, labels, and appearance. The primary outcome was non-inferiority of denosumab to risedronate in terms of percentage change from baseline in lumbar spine bone mineral density at 12 months based on non-inferiority margins (-0.7 and -1.1 percentage points for the glucocorticoid-continuing and glucocorticoid-initiating subpopulations, respectively). Superiority was also assessed as a secondary outcome. The primary efficacy set included all randomly assigned participants who had a baseline and postbaseline lumbar spine bone mineral density measurement, and was analysed according to randomised treatment assignment. The safety analysis set included all randomly assigned participants who received at least one dose of investigational product, and was analysed by actual treatment received. This study is registered with ClinicalTrials.gov (NCT01575873) and is completed. FINDINGS: Between March 28, 2012, and June 30, 2015, 795 patients, 505 of whom were glucocorticoid continuing and 290 of whom were glucocorticoid initiating, were enrolled and randomly assigned (398 to denosumab, 397 to risedronate). Denosumab was both non-inferior and superior to risedronate at 12 months for effect on bone mineral density at the lumbar spine in both glucocorticoid continuing (4.4% [95% CI 3.8-5.0] vs 2.3% [1.7-2.9]; p<0.0001) and glucocorticoid initiating (3.8% [3.1-4.5] vs 0.8% [0.2-1.5]; p<0.0001) subpopulations. Incidence of adverse events, serious adverse events (including infections), and fractures was similar between treatment groups. The most common adverse events were back pain (17 [4%] patients in the risedronate group and 18 [5%] in the denosumab group) and arthralgia (21 [5%] patients in the risedronate group and 17 [4%] in the denosumab group). Serious infection occurred in 15 (4%) patients in the risedronate group and 17 (4%) patients in the denosumab group. INTERPRETATION: Denosumab could be a useful treatment option for patients newly initiating or continuing glucocorticoids who are at risk of fractures. FUNDING: Amgen. PMID- 29631783 TI - Denosumab: a new treatment option for glucocorticoid-induced osteoporosis. PMID- 29631784 TI - Combination cancer treatment through photothermally controlled release of selenous acid from gold nanocages. AB - Selenite, one of the inorganic forms of selenium, is emerging as an attractive chemotherapeutic agent owing to its selectivity in eradicating cancer cells. Here we demonstrate a new formulation of nanomedicine based on selenous acid, which is mixed with lauric acid (a phase-change material with a melting point around 43 degrees C) and then loaded into the cavities of Au nanocages. The Au nanocages can serve as a carrier during cell endocytosis and then as a photothermal agent to melt the lauric acid upon the irradiation with a near-infrared laser, triggering the swift release of selenous acid. The photothermal and chemo therapies can also work synergistically, leading to enhanced destruction of cancer cells relative to normal cells. Our systematic study suggests that the impaired mitochondrial function arising from the ROS generated through combination treatment is responsible for the cell death. This study offers an appealing candidate that holds great promise for synergistic cancer treatment. PMID- 29631785 TI - Innovations in Emergency Nursing: Transforming Emergency Care Through a Novel Nurse-Driven ED Telehealth Express Care Service. AB - PROBLEM: Emergency department overcrowding and acuity are significant challenges to patients and staff. Low-acuity patients have extended wait times, and decreased satisfaction can have a negative effect on patient flow. METHODS: A multidisciplinary ED team developed and launched the first ED-based Telehealth Express Care Service, where patients who present to the emergency department with minor complaints are offered a "virtual visit" with a board-certified emergency physician located remotely. RESULTS: More than 6 months into the program, more than 1,300 patients have been treated. These patients experienced decreased length of stay (2.5 hours to 38 minutes) and increased satisfaction. The program is very well received by staff members who appreciate its efficiency. DISCUSSION: Telehealth has the potential to optimize ED efficiency, increase patient satisfaction, and promote safe, high-quality provision of care. PMID- 29631786 TI - Design, synthesis and biological evaluation of novel tetrahydroisoquinoline derivatives as P-glycoprotein-mediated multidrug resistance inhibitors. AB - Multidrug resistance (MDR) is one of the main obstacles of clinical chemotherapy. A great deal of research shows that the occurrence of drug resistance in various malignant tumors is closely related to the expression of P-glycoprotein (P-gp) on the surface of the cell membrane. In this paper, based on the structure-activity relationship of phenylethyl tetrahydroisoquinoline, we choose tariquidar as the lead compound for the design and synthesis of 17 novel tetrahydroisoquinoline P gp inhibitors. Additionally, in vitro and in vivo cytotoxicity assays and reversed MDR activity assays were evaluated. Among them, compound 3 had a good reversal of MDR activity and the reversal mechanism study of it was carried out. All of these results demonstrated that compound 3 was considered to be a promising P-gp-mediated MDR reversal candidate. PMID- 29631787 TI - Discovery and biological evaluation of novel pyrazolopyridine derivatives as potent and orally available PI3Kdelta inhibitors. AB - Phosphatidylinositol-3-kinase (PI3K)delta inhibition is one of the most attractive approaches to the treatment of autoimmune diseases and leukocyte malignancies. Through the exploration of pyrazolopyridine derivatives as potential PI3Kdelta inhibitors, compound 12a was identified as a potent PI3Kdelta inhibitor but suffered from poor oral exposure in mice. With a modified amide linkage group, compound 15a was developed as an orally available PI3Kdelta inhibitor with reduced selectivity against other PI3Ks. To improve the trade-off between selectivity and PK profile, structure-activity relationship (SAR) studies of terminal substituents on the pyrolidine ring were conducted. As a result, we developed potent PI3Kdelta inhibitors with good oral availability. In particular, the representative compound 15j showed excellent selectivity for PI3Kdelta over other PI3Ks with good oral exposure in mice. PMID- 29631789 TI - Oncologists burnout in the spotlight. PMID- 29631788 TI - Design and discovery of thioether and nicotinamide containing sorafenib analogues as multikinase inhibitors targeting B-Raf, B-RafV600E and VEGFR-2. AB - New sorafenib derivatives containing thioether and nicotinamide moiety were designed and synthesized as B-Raf, B-RafV600E and VEGFR-2 multikinase inhibitors. Their in vitro enzymatic inhibitory activities against B-Raf, B-RafV600E and VEGFR-2 and their antiproliferative activities against HCT-116 and B16BL6 cell lines were evaluated and described. Most of the compounds showed potent activities against both cell lines and specific kinases. Compounds a1, b1 and c4, which exhibited the most potent inhibitory activities against B-Raf with IC50 of 21 nM, 27 nM and 17 nM, B-RafV600E with IC50 of 29 nM, 28 nM and 16 nM, VEGFR-2 with IC50 of 84 nM, 46 nM and 63 nM, respectively, and good antiproliferative activities, also demonstrated competitive antiangiogenic activities to sorafenib in in vitro HUVEC tube formation assay. PMID- 29631790 TI - Short vs long course adjuvant chemotherapy for colon cancer. PMID- 29631791 TI - Lawsuit filed against FDA for not reviewing e-cigarettes. PMID- 29631792 TI - Health care for cancer survivors in the USA. PMID- 29631793 TI - Short-term and mid-term results of lateral condyle sliding osteotomy in the treatment of valgus total knee arthroplasty: A successful therapy option in Grade 2 valgus total knee arthroplasty. AB - BACKGROUND: Different methods exist for deformity correction and ligament balancing in total knee arthroplasty (TKA) of valgus knees, the sliding osteotomy being one of them. The objective of the current study was to analyze the clinical and radiological short-term and mid-term results of this technique in a larger series. METHODS: Between June 2007 and May 2014, 98 patients were treated with 98 TKAs and a simultaneous sliding osteotomy. All of them had a Grade 2 fixed valgus deformity (between 10 degrees and 20 degrees ). All patients received a mobile bearing, non-constrained (CR) implant. After prospective inclusion (T1), patients were clinically assessed after one (T2) and 4.5years (+/-2.1years) (T3), and radiological and Oxford Knee Score (OKS), Knee Society Knee Score (KSS) and the Knee Society Function Score (KSF) were obtained. RESULTS: All knees were corrected to a mechanical leg alignment within three degrees. Significant improvement of all scores could be measured at T2 and T3. Seven revisions needed to be performed; three of them were procedure-related. In two of them, a problem of capsular closure occurred, while in one the slided epicondyle dislocated after three months. All other revisions were performed because of non-procedure-related problems (e.g. infection). CONCLUSIONS: Sliding osteotomy of the lateral condyle is a successful option for the treatment of Grade 2 fixed valgus deformity. Due to this technique, higher constraint could be avoided. The results stayed constant over time. The procedure-related complications need to be kept in mind. Long-term results still need to be awaited. PMID- 29631794 TI - Hormonal contraceptives and breast cancer: Clinical data. AB - The endocrine background of breast cancer has raised questions about the increase in risk that might bear the use of hormonal contraceptives. This has been a particular issue in the case of young women, who constitute the population of contraceptive consumers. Observational studies have been the main source of evidence, which has mainly limited to the combined estrogen-progestogen preparations, the popular pill. Studies in the 80's and 90's of the past century found a small, around a 20%, increase in risk. The translation in absolute number of excess cases has been exiguous because the prevalence of the disease is relatively small in premenopausal women. Moreover, the risk slowly seemed to disappear after 5-10 years of use. The more sophisticated analyses provided by new technologies, together with the powerful central registries in some countries, has confirmed increased risk of similar size. Recent preparations, with lower doses of estrogens and new progestogenic molecules, have not substantially modified the risk size. The impact of progestogen only alternatives, either pills or progestogen-loaded intrauterine devices, seems to be similar, but the evidence is still insufficient. Whether there is a preferential effect on histological or molecular subtypes of breast tumours is being debated yet. The data on women at higher risk, either with mutations of the BRCA1/2 genes or with familial weight, have not found specific response patterns, but the experience is still meagre. It is of interest that long-term follow up data on women who enrolled in the initial cohorts, like that of the Royal College of General Practitioners', have shown a considerable protection against cancer of the ovary (relative risk, RR 0.67), endometrium (RR 0.66), or colorectum (RR 0.81). PMID- 29631795 TI - Autoimmune Addison's disease - An update on pathogenesis. AB - Autoimmunity against the adrenal cortex is the leading cause of Addison's disease in industrialized countries, with prevalence estimates ranging from 93-220 per million in Europe. The immune-mediated attack on adrenocortical cells cripples their ability to synthesize vital steroid hormones and necessitates life-long hormone replacement therapy. The autoimmune disease etiology is multifactorial involving variants in immune genes and environmental factors. Recently, we have come to appreciate that the adrenocortical cell itself is an active player in the autoimmune process. Here we summarize the complex interplay between the immune system and the adrenal cortex and highlight unanswered questions and gaps in our current understanding of the disease. PMID- 29631796 TI - Politically-focused intrusive thoughts and associated ritualistic behaviors in a community sample. AB - A significant proportion of the U.S. population report increased stress attributed to the political climate following the controversial 2016 United States (U.S.) Presidential election. The political stressors paired with the growth in news consumption and social media-use could be a potential trigger for obsessive-compulsive-like symptoms specific to politics in some individuals. This study aimed to elucidate the rate of Politically-focused Intrusive Thoughts and associated Ritualistic Behaviors (PITRB), their demographic and clinical correlates, and the degree of association with political ideology. Survey data were collected using the crowdsourcing platform Mechanical Turk. A total of N = 484 individuals completed the survey. Measures of politically-focused intrusive thoughts and ritualistic behaviors, general obsessive-compulsive symptoms, depression, anxiety, anxiety control, worry, and disability were administered, as well as a measure of social and economic conservative affiliation. Results showed that a quarter of the sample (25.2%) had at least one PITRB more than once a day. PITRB was associated with all measures of psychopathology and disability. Finally, anxiety control moderated the relationship between PITRB and both anxiety and depression. No differences in psychopathology were found between major party affiliations. The findings suggest that politically-focused intrusive thoughts and ritualistic behaviors are associated with psychopathology domains in a manner comparable to general obsessive-compulsive symptoms. PMID- 29631798 TI - Fentanyl related overdose in Indianapolis: Estimating trends using multilevel Bayesian models. AB - INTRODUCTION: The opioid epidemic has been largely attributed to changes in prescribing practices over the past 20 years. Although current overdose trends appear driven by the opioid fentanyl, heroin has remained the focus of overdose fatality assessments. We obtained full toxicology screens on lethal overdose cases in a major US city, allowing more accurate assessment of the time-course of fentanyl-related deaths. METHODS: We used coroner data from Marion County, Indiana comprising 1583 overdose deaths recorded between January 1, 2010 and April 30, 2017. Bayesian multilevel models were fitted to predict likelihood of lethal fentanyl-related overdose using information about the victim's age, race, sex, zip code, and date of death. RESULTS: Three hundred and seventy-seven (23.8%) overdose deaths contained fentanyl across the seven-year period. Rates rose exponentially over time, beginning well below 15% from 2010 through 2013 before rising to approximately 50% by 2017. At the beginning of the study period, rates of fentanyl overdose were lowest among Black persons but increased more rapidly, eventually surpassing Whites. Currently, White females are at particularly low risk of fentanyl overdose whereas Black females are at high risk. Rates were highest for younger and middle-aged groups. Over time, fentanyl was more likely detected without the presence of other opioids. CONCLUSIONS: Fentanyl has increasingly been detected in fatal overdose deaths in Marion County. Policy and program responses must focus on education for those at highest risk of fentanyl exposure and death. These responses should also be tailored to meet the unique needs of high-risk demographics. PMID- 29631797 TI - Diffusion of medication drop-boxes in North Carolina from 2007 to 2016. AB - INTRODUCTION: A permanent drug donation box ("drop-box") is one strategy implemented in communities across the United States to reduce the availability of excess controlled medications, including prescription opioids, for diversion. The objective of this study was to examine correlates of the diffusion and implementation of drop-boxes in North Carolina. METHODS: We assessed the number and location of drop-boxes implemented in North Carolina. Cox proportional hazards models were used to examine covariates associated with drop-box implementation in NC counties (n = 100) between 2007 and 2016. RESULTS: There were 311 drop-boxes implemented in 91 (out of 100) counties. Most drop-boxes were in law enforcement agencies (78.8%) and a growing number were in pharmacies (14.5%). Counties with a higher percentage of whites, more educated residents, a substance abuse prevention coalition, higher rates of controlled medications dispensed and prescription opioid overdose, and that were Appalachian were more likely to be early adopters. Rural counties were less likely to have a drop-box. In the multivariate model, only higher rate of controlled medicines dispensed was significant. CONCLUSIONS: A growing number of drop-boxes are being implemented in law enforcement offices and pharmacies. Given that communities with higher rates of controlled medication dispensing likely have the highest need for disposal opportunities, it is promising that they are early adopters of drop-boxes. Future research should assess the effectiveness of drop-boxes as they become more widespread in a variety of locations. PMID- 29631799 TI - Microsatellite instability associated with durable complete response to PD-L1 inhibitor in head and neck squamous cell carcinoma. PMID- 29631800 TI - Contrast-Enhanced Ultrasound-Guided Fine-Needle Aspiration for Sentinel Lymph Node Biopsy in Early-Stage Breast Cancer. AB - The purpose of this study was to assess whether translymphatic contrast-enhanced ultrasound (CEUS) combined with fine-needle aspiration (FNA) can be used pre operatively to assess the status of axillary lymph nodes in early-stage breast cancer patients. Furthermore, we wanted to determine whether this less invasive method could potentially be a pre-operative surgical strategy. One hundred sixty four sentinel lymph nodes (SLNs) were detected by CEUS after intradermal injection of microbubbles in 126 cases. One hundred twenty of 126 cases (95.24%) were accurately diagnosed with the SLN-FNA method. All 6 false-negative cases were due to micrometastasis or macrometastasis. There were no false-positive results after CEUS-guided FNA biopsy based on post-operative histopathological results. In conclusion, translymphatic CEUS combined with SLN-FNA is a less traumatic approach that has high accuracy in the pre-operative evaluation of axillary lymph node status. It might have the potential to be as reliable an indicator for axillary lymph node dissection as SLN biopsy. PMID- 29631801 TI - Hypoplastic left heart syndrome management. PMID- 29631802 TI - Relation of Use of Red Blood Cell Transfusion After Acute Coronary Syndrome to Long-Term Mortality. AB - Registry studies have associated red blood cell (RBC) transfusion with increased in-hospital mortality in patients with acute coronary syndrome (ACS). The impact on long-term mortality after 1-year follow-up remains unknown. Consecutive patients with ACS (n = 2,009) of a prospective Genetic Predisposition of Coronary Artery Disease cohort were followed for a median of 8.6 years (95% confidence interval [CI] 8.59 to 8.69). After discharge, 1,937 (96%) patients survived for over 30 days. Of those survivors, a subgroup of previously transfusion-naive patients 85/1,937 (4.4%) who had received at least 1 RBC transfusion during hospitalization were compared with 1,278/1,937 patients (66.0%) who had not received any transfusion either during the hospitalization or the entire follow up. Unadjusted long-term mortality was significantly higher in the patients transfused with RBC compared with their counterparts not transfused with RBC (58.8% vs 20.3%, p <0.001). The results remained significant for hazard ratio (HR) 1.91, 95% CI 1.39 to 2.63, p <0.001, after multivariate Cox proportional hazards model analysis and were similar after 1-year landmark analysis (HR 1.90, 95% CI 1.34 to 2.70, p <0.001). The higher all-cause mortality was largely explained by cancer mortality (15.3% vs 4.1%, p <0.001) and cardiovascular mortality (34.1% vs 12.1%, p <0.001). After 1:1 propensity score matching (n = 65 vs 65), the association of RBC transfusion with worse survival remained significant (HR 2.70, 95% CI 1.48 to 4.95, p = 0.001). Inverse probability weighted Cox analyses turned out similar results (HR 2.07, 95% CI 1.38 to 3.11, p <0.001). In conclusion, the strong association of need for RBC transfusion with increased mortality continued for patients with ACS even after a 1-year follow up. PMID- 29631803 TI - Feasibility of Left Atrial Appendage Occlusion for Left Atrial Appendage Thrombus in Patients With Persistent Atrial Fibrillation. AB - This study sought to investigate the safety of percutaneous left atrial appendage (LAA) occlusion for stroke prevention in patients with nonvalvular atrial fibrillation who have LAA thrombus. From October 2010 to October 2016, LAA occlusions were performed in facilities within a Korean multicenter registry in patients without (n = 132) or with (n = 10) LAA thrombus (detected during preprocedural assessments). The incidences of periprocedural complications, including stroke, pericardial tamponade, major bleeding, and device embolization, were assessed and compared between the groups. The incidence of periprocedural complications was not significantly different between patients with and without LAA thrombus (0% vs 5% [6 of 132]; p = 0.49). During the mean 23.2 +/- 17.5-month follow-up duration, 7 major adverse cardiac events occurred (1 cardiovascular death, 6 ischemic strokes), but overall event rates were not significantly different between the groups (14% vs 9%; p = 0.47). In conclusion, percutaneous LAA occlusion in nonvalvular atrial fibrillation patients with LAA thrombus may be a safe and feasible alternative to anticoagulation in select patients at a high risk of bleeding or contraindication to anticoagulation, or in whom anticoagulation failed to prevent stroke. PMID- 29631805 TI - Relation of High Serum Bilirubin to Short-Term Mortality Following a Myocardial Infarction Complicated by Left Ventricular Systolic Dysfunction (from the High Risk Myocardial Infarction Database Initiative). AB - Higher serum bilirubin has been associated with poorer prognosis in patients with heart failure (HF). We examined the association between serum bilirubin and clinical outcomes in patients with clinical signs of HF and/or left ventricular systolic dysfunction after acute myocardial infarction (MI). A total of 7,467 patients from the High-Risk Myocardial Infarction Database Initiative with an available baseline total bilirubin concentration were studied. The association between baseline bilirubin concentrations and the composite outcome of cardiovascular mortality (CVM), nonfatal stroke, nonfatal MI or hospitalization for HF, CVM, and all-cause mortality were assessed using Cox proportional hazards models. An interaction with time was observed with associations present only in the first 90 days after randomization. The median (percentile25-75) baseline total bilirubin concentration was 11 (8 to 14) umol/L and was above the "normal" range (>17.1 umol/L) in 1,053 (14.1%) patients. In multivariable analysis, with adjustment for baseline characteristics (demographic, co-morbidities, Killip score, left ventricular ejection fraction, and laboratory variables), patients with a bilirubin concentration of >17.1 umol/L had a significantly higher risk of all the studied outcomes at 90 days (e.g., CVM: adjusted hazard ratio 1.45, 95% confidence interval 1.14 to 1.86, p = 0.003). The addition of bilirubin to a validated survival model modestly improved the risk reclassification to predict 90-day events (continuous net reclassification improvement for CVM 6.4%, 95% confidence interval 0.7% to 9.6%, p = 0.04). In patients with MI complicated with HF and/or systolic dysfunction, bilirubin concentration is an independent predictor of mortality and may improve risk stratification. PMID- 29631804 TI - Influence of Aortic Stiffness on Aortic-Root Growth Rate and Outcome in Patients With the Marfan Syndrome. AB - The Pediatric Heart Network randomized trial of atenolol versus losartan in the Marfan syndrome showed no treatment differences in the rates of aortic-root growth or clinical outcomes. In this report we present treatment effects on aortic stiffness and determine whether baseline aortic stiffness predicts aortic root growth and clinical outcomes. Echocardiograms at 0, 6, 12, 24, and 36 months from 608 subjects (6 months to 25 years) who met original Ghent criteria and had a maximum aortic-root z-score (ARz) >3 were centrally reviewed. Stiffness index (SI) and elastic modulus (EM) were calculated for aortic root and ascending aorta. Data were analyzed using multivariable mixed effects modeling and Cox regression. Heart rate-corrected aortic-root SI over 3 years decreased with atenolol but did not change with losartan (-0.298 +/- 0.139 vs 0.141 +/- 0.139/year, p = 0.01). In the entire cohort, above-median aortic-root SI (>9.1) and EM (>618 mm Hg) predicted a smaller annual decrease in ARz (p <=0.001). Upper quartile aortic-root EM (>914 mm Hg) predicted the composite outcome of aortic root surgery, dissection, or death (hazard ratio 2.17, 95% confidence interval 1.02 to 4.63, p = 0.04). Crude 3-year event rates were 10.4% versus 3.2% for higher versus lower EM groups. In conclusion, atenolol was associated with a decrease in aortic-root SI, whereas losartan was not. Higher baseline aortic-root SI and EM were associated with a smaller decrease in ARz and increased risk for clinical outcomes. These data suggest that noninvasive aortic stiffness measures may identify patients at higher risk of progressive aortic enlargement and adverse clinical outcomes, potentially allowing for closer monitoring and more aggressive therapy. PMID- 29631807 TI - Quality transitivity and traceability system of herbal medicine products based on quality markers. AB - BACKGROUND: Due to a variety of factors to affect the herb quality, the existing quality management model is unable to evaluate the process control. The development of the concept of "quality marker" (Q-marker) lays basis for establishing an independent process quality control system for herbal products. HYPOTHESIS/PURPOSE: To ensure the highest degree of safety, effectiveness and quality process control of herbal products, it is aimed to establish a quality transitivity and traceability system of quality and process control from raw materials to finished herbal products. STUDY DESIGN: Based on the key issues and challenges of quality assessment, the current status of quality and process controls from raw materials to herbal medicinal products listed in Pharmacopoeia were analyzed and the research models including discovery and identification of Q markers, analysis and quality management of risk evaluation were designed. METHODS: Authors introduced a few new technologies and methodologies, such as DNA barcoding, chromatographic technologies, fingerprint analysis, chemical markers, bio-responses, risk management and solution for quality process control. RESULTS: The quality and process control models for herbal medicinal products were proposed and the transitivity and traceability system from raw materials to the finished products was constructed to improve the herbal quality from the entire supply and production chain. CONCLUSION: The transitivity and traceability system has been established based on quality markers, especially on how to control the production process under Good Engineering Practices, as well as to implement the risk management for quality and process control in herbal medicine production. PMID- 29631808 TI - Reimagining Clinical Documentation With Artificial Intelligence. PMID- 29631806 TI - Determination of quality markers of Xuezhiling tablet for hyperlipidemia treatment. AB - BACKGROUND: The massive number of ingredients in traditional Chinese medicines (TCMs) makes quality control very difficult. The concept of quality markers (Q marker) was recently proposed to evaluate the quality of TCMs. Xuezhiling tablets (XZL) are widely used for the treatment of hyperlipidemia in China owing to its noticeable effectiveness and mild adverse effects, but there are no proper Q markers for this Chinese patent medicine. PURPOSE: The aim of the present study was to determine the Q-markers of XZL against hyperlipidemia through an integration of investigations on its lipid-lowering effect, metabolomics, content determination and pharmacokinetics. METHODS: XZL was prepared in accordance with the method described in the Chinese pharmacopoeia (Ch.P.). Hyperlipidemia was induced in rats through the administration of a high-fat diet (HFD). The hypolipidemic effect of XZL was investigated through the detection of the blood levels of total glyceride (TG), total cholesterol (TC), and low density lipoprotein cholesterol (LDL-C). A metabolomics study was conducted to analyze the overall effects of XZL on the regulation of lipid metabolism. The main bioactive compounds of XZL were identified and determined in the XZL preparation and the medicated plasma of hyperlipidemic rats. RESULTS: XZL lowered the levels of TG, TC, and LDL-C through alterations of metabolic patterns. 2,3,5,4' Tetrahydroxystilbene-2-O-beta-D-glucopyranoside (THSG), chrysophanol-1-O-beta glucopyranosyl-(1->3)-O-beta-D-glucopyranosy1-(1->6)-O-beta-D-glucopyranosyl-(1 >6)-O-beta-D-glucopyranoside (SHJ), cassiaside, rubrofusarin gentiobioside, aurantio-obtusin, chryso-obtusin, and obtusinfolin were identified and determined both in the preparation and the blood of hyperlipidemic rats. CONCLUSION: SHJ, obtusinfolin, THSG, rubrofusarin gentiobioside, and aurantio-obtusin, which are more abundant in the preparation, leading to greater exposure in vivo, were suitable Q-markers to guarantee the medicinal quality of XZL and ensure the clinical effectiveness on hyperlipidemia. PMID- 29631809 TI - Intracellular complement activation-An alarm raising mechanism? AB - It has become increasingly apparent that the complement system, being an ancient defense mechanism, is not operative only in the extracellular milieu but also intracellularly. In addition to the known synthetic machinery in the liver and by macrophages, many other cell types, including lymphocytes, adipocytes and epithelial cells produce selected complement components. Activation of e.g. C3 and C5 inside cells may have multiple effects ranging from direct antimicrobial defense to cell differentiation and possible influence on metabolism. Intracellular activation of C3 and C5 in T cells is involved in the maintenance of immunological tolerance and promotes differentiation of T helper cells into Th1-type cells that activate cell-mediated immune responses. Adipocytes are unique in producing many complement sensor proteins (like C1q) and Factor D (adipsin), the key enzyme in promoting alternative pathway amplification. The effects of complement activation products are mediated by intracellular and cell membrane receptors, like C3aR, C5aR1, C5aR2 and the complement regulator MCP/CD46, often jointly with other receptors like the T cell receptor, Toll-like receptors and those of the inflammasomes. These recent observations link complement activation to cellular metabolic processes, intracellular defense reactions and to diverse adaptive immune responses. The complement components may thus be viewed as intracellular alarm molecules involved in the cellular danger response. PMID- 29631811 TI - Sorafenib and hepatic arterial infusion chemotherapy: another failed combination. PMID- 29631813 TI - Superimposition of 3D digital models: A case report. AB - INTRODUCTION: Superimposition of digital models may be performed to assess tooth movement in three dimensions. Detailed analysis of changes in tooth position after treatment may be achieved by this method. AIM: This article describes the method of superimposing digital models with a clinical case. It emphasizes the difficult procedure of superimposing 3D models in the lower arch. A methodology for superimposing mandibular models acquired with a structured light 3D scanner is discussed. CONCLUSION: Superimposition of digital models is useful to analyse tooth movement in the three planes of space, presenting advantages over the method of cephalogram superimposition. It seems feasible to superimpose digital models in the lower arch in patients without growth by using a coordinate system based on the palatal rugae and occlusion. The described method aims to advance the difficult procedure of superimposing digital models in the mandibular arch, but further research is nonetheless required in this field. PMID- 29631810 TI - Sorafenib plus low-dose cisplatin and fluorouracil hepatic arterial infusion chemotherapy versus sorafenib alone in patients with advanced hepatocellular carcinoma (SILIUS): a randomised, open label, phase 3 trial. AB - BACKGROUND: Hepatic arterial infusion chemotherapy plus sorafenib in phase 2 trials has shown favourable tumour control and a manageable safety profile in patients with advanced, unresectable hepatocellular carcinoma. However, no randomised phase 3 trial has tested the combination of sorafenib with continuous arterial infusion chemotherapy. We aimed to compare continuous hepatic arterial infusion chemotherapy plus sorafenib with sorafenib alone in patients with advanced, unresectable hepatocellular carcinoma. METHODS: We did an open-label, randomised, phase 3 trial (SILIUS) at 31 sites in Japan. Eligible patients were aged 20 years or older, with advanced hepatocellular carcinoma not suitable for resection, local ablation, or transarterial chemoembolisation; Eastern Cooperative Oncology Group (ECOG) performance status 0-1; Child-Pugh score 7 or lower; and adequate bone marrow, liver, and renal function. Patients were randomly assigned (1:1) via an interactive web response system with a computer generated sequence to receive 400 mg sorafenib orally twice daily or 400 mg sorafenib orally twice daily plus hepatic arterial infusion chemotherapy (cisplatin 20 mg/m2 on days 1 and 8 and fluorouracil 330 mg/m2 continuously on days 1-5 and 8-12 of every 28-day cycle via an implanted catheter system). The primary endpoint was overall survival. The primary efficacy analysis comprised all randomised patients (the intention-to-treat population), and the safety analysis comprised all randomised patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01214343. FINDINGS: Between Nov 4, 2010, and June 10, 2014, 206 patients were randomly assigned (103 to the sorafenib group, 103 to the sorafenib plus hepatic arterial infusion chemotherapy group). One patient in the sorafenib plus hepatic arterial infusion chemotherapy group withdrew after randomisation. Median overall survival was similar in the sorafenib plus hepatic arterial infusion chemotherapy (n=102) and sorafenib monotherapy (n=103) groups (11.8 months [95% CI 9.1-14.5] vs 11.5 months [8.2-14.8]; hazard ratio 1.009 [95% CI 0.743-1.371]; p=0.955). Grade 3-4 adverse events that were more frequent in the sorafenib plus hepatic arterial infusion chemotherapy group than in the sorafenib monotherapy group included anaemia (15 [17%] of 88 vs six [6%] of 102), neutropenia (15 [17%] vs one [1%]), thrombocytopenia (30 [34%] vs 12 [12%]), and anorexia (12 [14%] vs six [6%]). INTERPRETATION: Addition of hepatic arterial infusion chemotherapy to sorafenib did not significantly improve overall survival in patients with advanced hepatocellular carcinoma. FUNDING: Japanese Ministry of Health, Labour and Welfare. PMID- 29631812 TI - Regional anaesthesia with extracorporeal membrane oxygenation backup for caesarean section in a parturient with neck and mediastinal masses. AB - Mediastinal mass in pregnancy is a rare condition that presents significant anaesthetic challenges. We present a woman with relapsed Hodgkin's lymphoma during pregnancy who declined to have chemotherapy because of concerns for her unborn child. She failed to attend follow-up clinic appointments and presented at 33 weeks' gestation with tracheal deviation and narrowing down to the level of the carina, as a result of large neck and mediastinal masses. She required delivery of the baby to allow her to receive urgent chemotherapy. We describe successful management of a caesarean section under combined spinal-epidural anaesthesia, at which bilateral femoral vein access was gained in case of the need for urgent extracorporeal membrane oxygenation. PMID- 29631814 TI - ? PMID- 29631815 TI - ? PMID- 29631816 TI - ? PMID- 29631817 TI - The effect of prior sandblasting of the wire on the shear bond strength of two different types of lingual retainers. AB - PURPOSE: The aim of this study was to evaluate the effect of total surface sandblasting on the shear bond strength of two different retainer wires. The null hypothesis was that there is no difference in the bond strength of the two types of lingual retainer wires when they are sandblasted. MATERIALS AND METHODS: One hundred and sixty human premolar teeth were equally divided into four groups (n=40). A pair of teeth was embedded in self-curing acrylic resin and polished. Retainer wires were applied on the etched and rinsed surfaces of the teeth. Four retainers were used: group 1: braided retainer (0.010*0.028", Ortho Technology); group 2: sandblasted braided retainer (0.010*0.028", Ortho Technology); group 3: coaxial retainer (0.0215" Coaxial, 3M) and group 4: sandblasted coaxial retainer (0.0215" Coaxial, 3M). The specimens were tested using a universal test machine in shear mode with a crosshead speed of one mm/min. RESULTS: One-way analysis of variance (Anova) was used to determine the significant differences among the groups. There was no significant difference (P=0.117) among the groups according to this test. CONCLUSIONS: The null hypothesis was accepted. There was no statistically significant difference among the shear bond strength values of the four groups. PMID- 29631818 TI - Effects of autoclaving versus cold chemical (glutaraldehyde) sterilization on load-deflection characteristics of aesthetic coated archwires. AB - INTRODUCTION: The effect of any sterilization methods (cold [chemical] or hot) on load-deflection characteristics of aesthetic coated archwires has not yet been investigated. Thus, we assessed it. METHODS: In this experimental in vitro study, 90-coated archwires from 3 brands were purchased. Ten wires from each brand (n=30) underwent cold and 10 underwent hot sterilization, while 10 left unsterilized as negative controls. Load-deflection curves were established for each wire (as five 0.2mm intervals between 1.0 and 1.8mm displacements), using a three-bracket test. After determining the plateau phase that was present in all wires, the averages of plateau phase pertaining to loading and unloading curves and their discrepancies (hysteresis) were calculated for each subgroup (n=10). Average plateau values were compared using two-way ANOVA, Tukey, and independent samples t-test (alpha=0.05). RESULTS: Average loading and unloading values were 906.6+/-129.7 and 295.9+/-84.5g respectively (t-test P<0.0001). Comparing loading plateaus, ANOVA indicated significant difference among wire brands (P<0.0001) but not among sterilization types (P=0.4793). Comparing unloading plateaus, ANOVA showed significant differences among wire brands (P<0.0001) and sterilization types (P=0.0008). Tukey showed that only cold sterilization and negative control differed significantly (P<0.001); cold and hot sterilization methods, or control and autoclaving were not significantly different (P>0.05). Comparing hysteresis plateaus, ANOVA indicated difference among wire brands (P<0.0053) but not among sterilization types (P=0.9166). CONCLUSIONS: Cold sterilization might reduce unloading plateau of orthodontic wires, but sterilization in general might not affect loading or hysteresis plateaus. Different brands had different plateaus of loading, unloading and hysteresis. PMID- 29631819 TI - Short wavelengths filtering properties of sunglasses on the Canadian market: are we protected? AB - BACKGROUND: Exposure to solar radiation is a risk factor for multiple ocular pathologies. Ultraviolet (UV) radiation is involved in ocular diseases, including pterygium, ocular surface squamous neoplasia, and cataracts. High-energy visible light (HEV) is associated with age-related macular degeneration. Ocular protection against solar radiation seems essential to protect our eyes against the adverse effects of those harmful rays. Australia, New Zealand, Europe, and the United States are the only regions with mandatory standards for UV transmission for sunglasses. Adherence to Canadian standards by sunglasses manufacturers is not mandatory. In this study, we evaluated the UV and visible transmission of sunglasses in the Canadian market to test their compliance with Canadian standards. METHODS: The transmittance of 207 pairs of sunglasses, divided in 3 categories according to their price range, was measured. RESULTS: We show that close to 100% of the sunglasses tested respect the Canadian standards. The average HEV transmittance is around 10%, regardless the price range. CONCLUSIONS: Our study demonstrated that even if following Canadian standards is optional, most sunglasses sold on the Canadian market follow national and international standards. We also found that sunglasses filter around 90% of HEV. With the recent findings on the potential effects of HEV in retinal pathologies, we can ask whether this filtering capacity is sufficient to protect eyes from harmful HEV light. More work needs to be done to determine acceptable HEV light transmission limits to the existing Canadian standards. PMID- 29631820 TI - Patient satisfaction with wait times at an emergency ophthalmology on-call service. AB - OBJECTIVE: To assess patient satisfaction with emergency ophthalmology care and determine the effect provision of anticipated appointment wait time has on scores. DESIGN: Single-centre, randomized control trial. PARTICIPANTS: Fifty patients triaged at the Hamilton Regional Eye Institute (HREI) from November 2015 to July 2016. METHODS: Fifty patients triaged for next-day appointments at the HREI were randomly assigned to receive standard-of-care preappointment information or standard-of-care information in addition to an estimated appointment wait time. Patient satisfaction with care was assessed postvisit using the modified Judgements of Hospital Quality Questionnaire (JHQQ). In determining how informing patients of typical wait times influenced satisfaction, the Mann-Whitney U test was performed. As secondary study outcomes, we sought to determine patient satisfaction with the intervention material using the Fisher exact test and the effect that wait time, age, sex, education, mobility, and number of health care providers seen had on satisfaction scores using logistic regression analysis. RESULTS: The median JHQQ response was "very good" (4/5) and between "very good" and "excellent" (4.5/5) in the intervention and control arms, respectively. There was no difference in patient satisfaction between the cohorts (Mann-Whitney U = 297.00, p = 0.964). Logistic regression analysis demonstrated that wait times influenced patient satisfaction (OR = 0.919, 95% CI 0.864-0.978, p = 0.008). Of the intervention arm patients, 92.0% (N = 23) found the preappointment information useful, whereas only 12.5% (N = 3) of the control cohort patients noted the same (p < 0.001). CONCLUSION: Provision of anticipated wait time information to patients in an emergency on-call ophthalmology clinic did not influence satisfaction with care as captured by the JHQQ. PMID- 29631821 TI - Treatment of herpes zoster ophthalmicus: a systematic review and Canadian cost comparison. AB - OBJECTIVE: A systematic review and cost comparison were conducted to determine the optimal treatment of active herpes zoster ophthalmicus (HZO) in immunocompetent adults. DESIGN: A literature search of MEDLINE, EMBASE, CINAHL, Cochrane Library, BIOSIS Previews and Web of Science, ClinicalTrials.gov, International Clinical Trials Registry Platform, Networked Digital Library of Theses and Dissertations, and Canadian Health Research Collection was performed. The search period was from January 1990 to March 2017. PARTICIPANTS: Collectively, 516 immunocompetent patients with active HZO treated with oral antivirals were included. METHODS: Randomized controlled trials (RCTs) investigating treatment of active HZO in immunocompetent adults, with one oral acyclovir monotherapy arm, were included. Studies fulfilling inclusion criteria were subjected to quality assessment and data extraction. Provincial drug formularies were consulted to extrapolate cost comparison for investigated treatment regimens. RESULTS: A total of 1515 titles and abstracts and 9 full-text articles were assessed. Three RCTs met the inclusion criteria. Treatment with oral acyclovir (800 mg 5 times daily for 10 days) was superior to placebo in the prevention of ocular manifestations. Oral famciclovir (500 mg 3 times daily for 7 days) and valacyclovir (1000 mg 3 times daily for 7 days) resulted in comparable rates of ocular manifestations relative to oral acyclovir (800 mg 5 times daily for 7 days). According to provincial drug formulary data, famciclovir and valacyclovir are more affordable across Canada with the recommended dosing schedules. CONCLUSIONS: Oral famciclovir and valacyclovir are reasonable alternatives to oral acyclovir for treatment of active HZO in immunocompetent individuals. Their simpler dosing schedules are associated with a cost benefit that is consistent across Canada. PMID- 29631822 TI - Comparison of the Ahmed and Baerveldt glaucoma shunts with combined cataract extraction. AB - OBJECTIVE: To compare the surgical outcomes of combined phacoemulsification with either Ahmed glaucoma valve (AGV) or Baerveldt glaucoma implant (BGI). DESIGN: Retrospective cohort study. PARTICIPANTS: A total of 104 eyes that underwent combined phacoemulsification with either AGV (PhacoAGV; n = 57) or BGI (PhacoBGI; n = 47) implantation. METHODS: Failure was defined as uncontrolled intraocular pressure (IOP; <5 mm Hg, >=18 mm Hg, or <20% reduction), additional glaucoma surgery, vision-threatening complications, or progression to no-light-perception vision. RESULTS: The PhacoAGV group was older (p = 0.03), had poorer baseline visual acuity (VA; p = 0.001), and had fewer previous glaucoma surgeries (p = 0.04). Both groups had similar baseline IOP (PhacoAGV: 26.4 +/- 8.3 mm Hg; PhacoBGI: 25.7 +/- 7.3; p = 0.66) and glaucoma medications (PhacoAGV: 3.8 +/- 1.0; PhacoBGI: 3.6 +/- 1.5; p = 0.54). At 2 years, failure rates were 44% in the PhacoAGV group and 23% in the PhacoBGI group (p = 0.02). Both groups had similar mean IOP reduction (PhacoAGV: 45%; PhacoBGI: 47%, p = 0.67) and medication use reduction (PhacoAGV: 47%; PhacoBGI: 58%, p = 0.38). The PhacoBGI group had higher IOP and medication use up to 1 month (p < 0.05). Both groups improved in VA from baseline (p < 0.05) and had similar overall complication rates (p = 0.31). The PhacoBGI group required more overall interventions (p < 0.0005). CONCLUSIONS: This comparative study found no difference in IOP, glaucoma medications, or complication rates between PhacoAGV and PhacoBGI at 2 years, despite BGIs being implanted in patients at higher risk for failure. The PhacoAGV group had higher failure rates at 2 years. Both groups had significant improvements in VA due to removal of their cataracts. The PhacoBGI group required more interventions, but most of these were minor slit-lamp procedures. PMID- 29631823 TI - Prednisolone versus dexamethasone for prevention of pseudophakic cystoid macular edema. AB - OBJECTIVE: Prevention of cystoid macular edema (CME) is important to achieve good surgical outcomes after cataract surgery. Although many options for management exist, control of postoperative inflammation with topical steroids is one of the most commonly employed. We evaluated the difference in incidence of pseudophakic CME in patients treated with prednisolone or dexamethasone topical steroids. METHODS: The study was a retrospective chart review of patients who had undergone phacoemulsification at the Cole Eye Institute of the Cleveland Clinic. Reviewable patient charts had to indicate the topical steroid used and whether or not an additional medication (e.g., nonsteroidal anti-inflammatory drugs [NSAIDs]) was used after surgery. Excluded were patients who underwent combination procedures (e.g., trabeculectomy), perioperative anti-vascular endothelial growth factor or intraocular steroid, eyes with epiretinal membrane or prior retinal vein occlusion, those who developed postoperative endophthalmitis, patients with less than 3 months of follow-up, and patients who received topical NSAIDs. Pseudophakic CME was defined as new or worsening macular edema on optical coherence tomography within the first 3 months after cataract extraction. RESULTS: In total, 1135 patient charts were included in the analysis; 721 patients were treated with prednisolone acetate, and 414 were treated with dexamethasone. Patient characteristics were similar between the 2 treatment groups. No significant difference was found in the rate of postoperative CME for patients receiving prednisolone or dexamethasone (4.0% vs 4.1%, p = 0.94). CONCLUSIONS: There was no significant difference in the rate of pseudophakic CME when either prednisolone acetate or dexamethasone sodium phosphate was used after cataract surgery. PMID- 29631824 TI - Influence of soft contact lens material on corneal warpage: prevalence and time to resolution. AB - OBJECTIVE: Corneal warpage represents a reversible distortion of the corneal surface induced by soft contact lens (SCL) wear. The aim of the study is to assess the influence of SCL materials, age, wearing duration, cylindrical refraction, and spherical equivalence on the prevalence and time to resolution of corneal warpage. METHODS: This is an interventional prospective study in which SCL wearers volunteered to remove their SCLs and underwent, on each visit, a corrected distance visual acuity and anterior and posterior segment evaluation, along with keratometry measurement and corneal topography. Visits were scheduled 30 minutes after SCL removal, on day 4, day 7, and then weekly after SCL removal until warpage resolution. RESULTS: A total of 17 volunteers (34 eyes) were included, with 9 (18 eyes) in the hydrogel SCL group and 8 (16 eyes) in the silicone hydrogel SCL group. The difference in warpage prevalence between the hydrogel group (28%, 5 eyes) and silicone hydrogel group (31%, 5 eyes) was not statistically significant (p > 0.90). Duration necessary for warpage resolution ranged from 7 to 21 days with no statistically significant difference between the 2 groups (p = 0.12). CONCLUSIONS: Both types of SCL had similar corneal warpage prevalence and time to resolution, with slightly longer mean time to resolution with silicone hydrogel. All eyes had resolution of warpage by 3 weeks. It seems more cautious to wait longer than the usual 1-week interval before performing refractive surgery, especially in patients wearing SCL for long periods and regardless of the type of material. PMID- 29631825 TI - Surgical loupe usage among oculoplastic surgeons in North America. AB - OBJECTIVE: To study the patterns of usage and perception among U.S. oculoplastic surgeons regarding surgical loupes. METHODS: An anonymous 20-question survey was emailed out to the American Society of Ophthalmic Plastic and Reconstructive Surgery listserv. Data were compiled in Google Forms. SPSS was used for statistical analyses. This study was approved by the institutional review board. RESULTS: Of the 609 members contacted, 239 (39%) completed the survey; 95% of respondents owned loupes and 78% regularly used them. No association was observed between frequency of loupe usage and sex or years in practice. The most common magnification and brand were 2.5* and Designs for Vision, respectively. The most common problems associated with loupes were limited vision (33%) and lack of comfort (24%), with 11% citing neck and cervical spinal disorders. The most common benefits were magnification (93%) and increased visual accuracy (68%). Of the respondents, 56% believed improved patient care to be a benefit and 76% believed that loupes enhance surgical outcome. With regard to training, 67% supported incorporating loupes into residency, 35% believed in mandating loupe purchase, and 25% wanted residencies to provide loupes at no cost. Respondent support for the use of loupes in practice and training was directly correlated with how frequently they used loupes. CONCLUSIONS: The vast majority of respondents owned loupes. Although most loupe owners used loupes regularly, a sizable proportion operated with limited vision and lack of comfort. Overall, just over half of respondents believed that loupes improve patient care and should be integrated into residency. PMID- 29631826 TI - The International Council of Ophthalmology 360-degree assessment tool: development and validation. AB - BACKGROUND: The Accreditation Council for Graduate Medical Education and other organizations recommend 360-degree assessments for evaluation of interpersonal and communication skills, professional behaviours, and some aspects of patient care and system-based practice. No such tool has been developed for ophthalmology or received international content validation. OBJECTIVE: To develop a valid, internationally applicable, ophthalmology-specific 360-degree assessment tool. DESIGN: Exploratory study. METHODS: A literature review was conducted. Individual 360-degree evaluation items from several publications were catalogued and classified according to different groups of assessors. A panel of international authors reviewed the list and voted on items that were most appropriate for international use. The list was trimmed to reduce redundancy and to make it as brief as possible while still capturing the essential components for each category. A second panel of international ophthalmic educators reviewed the international applicability and appropriateness of this collated list; relevant comments and suggestions were incorporated. RESULTS: A tool for the evaluation of interpersonal and communication skills, professionalism, and system-based practice was developed. The tool has face and content validity. CONCLUSION: This assessment tool can be used internationally for giving formative feedback based on the opinions of the different groups of people who interact with residents. PMID- 29631827 TI - Ability of novice clinicians to interpret high-resolution optical coherence tomography for ocular surface lesions. AB - OBJECTIVE: To assess the ability of novice clinicians to use a commercially available high-resolution anterior segment optical coherence tomography (HR-OCT) device to diagnose various lesions of the ocular surface and cornea. METHODS: Cross-sectional study. Twenty-six black-and-white HR-OCT images were projected, and clinicians were asked to determine whether the lesions represented ocular surface squamous neoplasia (OSSN) or another ocular surface pathology. A 20 minute instructional lecture was given on HR-OCT interpretation, and the same 26 images were shown. The clinicians were asked to repeat their assessment of the lesions. Thirty-four novice clinicians at the Bascom Palmer Eye Institute, Miami, FL, participated. A commercially available device (RTVue, Optovue, Fremont, Calif.) was specifically chosen for this study. RESULTS: The mean frequency of correct identification of the 26 lesions was 70% (standard deviation [SD] 15%) before instruction; after a short lecture, the frequency of correct identification improved to 84% (SD 9%, p = 0.002). Novice clinicians were more accurate in correctly determining that a lesion was not an OSSN (ruling it out as a diagnosis) than in determining that a lesion was an OSSN (p = 0.001). Some lesions (both OSSN and not OSSN), however, were more difficult to interpret than others. CONCLUSION: This study demonstrated that all levels of novice clinicians can quickly improve diagnostic accuracy with a commercially available HR-OCT after a short training session. PMID- 29631828 TI - Unsuspected and misdiagnosed posterior uveal melanoma following enucleation and evisceration in Ottawa-Gatineau. AB - OBJECTIVE: There is a gap in the recent literature on the topic of clinically misdiagnosed and unsuspected posterior uveal melanomas (PUM) with a calculation of the frequency of these events for a specific geographical area. As the only ophthalmic pathology laboratory in our region, we determined the rate of these outcomes over a 16-year period. METHODS: We retrospectively reviewed 2558 consecutive ophthalmic pathologic specimens in the Ottawa-Gatineau region, of which 334 were eviscerations and 227 were enucleations. We calculated the frequency of clinically misdiagnosed PUM and of clinically unsuspected PUM. We also determined the rate of uveal melanoma undergoing enucleation. RESULTS: From 100 diagnoses of PUM, 2 (2.0%) cases were clinically unsuspected and 2 (2.0%) cases were clinically misdiagnosed. The rate of uveal melanoma undergoing enucleation was 5.6 cases per 1 000 000 of population per annum. From 2009 to 2012, the incidence of this event was 3.8 cases per 1 000 000 per annum, which was lower than the previous three 4-year increments. CONCLUSIONS: We present the first and only single-centred, population-based data on the rates of unsuspected PUM and of clinical misdiagnosis of PUM in the era of modern diagnostic imaging. Our rate of clinical misdiagnosis is within the range of recent reports of this event. Unsuspected PUM occurred at a rate substantially lower than previously published. The incidence of uveal melanoma undergoing enucleation has decreased despite an increase in population, which reflects a shift in management from enucleation to radiation therapy. PMID- 29631829 TI - Cost analysis of remote telemedicine screening for retinopathy of prematurity. AB - OBJECTIVE: To compare costs of 2 screening modalities for retinopathy of prematurity (ROP): telemedicine imaging with remote interpretation versus in person binocular indirect ophthalmoscopy (BIO). DESIGN: Retrospective chart review. PARTICIPANTS: Infants from an existing telemedicine screening program at 2 cities in Ontario, Canada. METHODS: We conducted a cost analysis comparison from the perspective of the Ministry of Health. Patient level data was used for the telemedicine group. A hypothetical control group consisted of the minimum number of BIO and interhospital transfers if the existing patients were screened in person. Costs included in-person examinations, transfers, setting up, and ongoing costs of telemedicine screening. Costs were compared using the Mann Whitney U test and are reported in 2014 Canadian dollars. RESULTS: A total of 102 and 72 infants were screened from Sudbury and Barrie, respectively; 3% and 2% of infants in the telemedicine group were transferred for BIO from Sudbury and Barrie, respectively. All infants in the control group would have required at least one transfer for BIO. The average total cost per eye examination was $4855 +/- $5616 and $4540 +/- $3129 for the telemedicine group and $19 834 +/- $13 814 and $2429 +/- $1664 for the control group from Sudbury and Barrie, respectively (p < 0.001). Interhospital transfer cost for the control group was $19 489 +/- $13 605 and $2055 +/- $1471 compared to $635 +/- $3968 and $30 +/- $197 for the telemedicine group (p < 0.001) in Sudbury and Barrie, respectively. CONCLUSIONS: Telemedicine appears to be an economically attractive option depending on the location and number of infants screened. This information is useful for planning similar ROP screening programs. PMID- 29631830 TI - Metamorphopsia and vision-related quality of life among patients with age-related macular degeneration. AB - OBJECTIVE: To assess subjective and quantified metamorphopsia, as well as vision related quality of life (QOL), in patients with age-related macular degeneration (AMD) to determine whether there is a correlation between quantified metamorphopsia and vision-related QOL in patients with AMD. METHODS: A cross sectional study of patients with AMD. Patients who had a best-corrected visual acuity less than 20/200, vitreomacular adhesion, vitreomacular traction, epiretinal membrane, macular hole, macular edema by causes other than AMD, diabetic retinopathy, retinal detachment, previous retinal surgery, glaucoma, amblyopia, or strabismus were excluded. Subjective perceptions of metamorphopsia were captured by a validated 10-item questionnaire. M-CHARTS (Inami, Japan) was used to detect quantified metamorphopsia. Quantified metamorphopsia was scored horizontally and vertically. The mean values of 3 repeated examinations were used for data analysis. The 25-item National Eye Institute Visual Functioning Questionnaire (VFQ-25) was used to assess vision-related QOL. RESULTS: Among 102 eyes with AMD, the most commonly reported subjective perception of metamorphopsia included lines of words on books, newspapers, or computer displays (45.1%), followed by frames of windows or bookshelves (22.6%), lines of tiles on bathroom wall (21.6%), and people's faces (18.6%). Eyes with wet AMD had significantly higher horizontal and vertical metamorphopsia scores compared with eyes with dry AMD (p < 0.0001). The higher horizontal metamorphopsia score and the higher vertical metamorphopsia score between the 2 eyes were both negatively correlated with the NEI VFQ-25 composite score (Spearman rank correlation r = -0.3207, p = 0.0010; Spearman rank correlation r = -0.3190, p = 0.0011). CONCLUSIONS: In our study, the most common subjective metamorphopsia was distortion of lines of words on books, newspapers, or computer displays. Compared to eyes with dry AMD, those with wet AMD had higher quantified horizontal and vertical metamorphopsia. Between the 2 eyes, both the higher horizontal and vertical metamorphopsia scores were correlated with the NEI VFQ-25 composite score. PMID- 29631831 TI - Comparative cost evaluation of brand name and generic ophthalmology medications in Ontario. AB - Medication cost for the same indication can vary considerably and can affect patient compliance. In this comparative cost analysis of commonly prescribed ophthalmology medications, the differences in cost between generic and brand name medications as well as different medications within an individual drug class were evaluated. Eye preparations from the Ontario Drug Benefit Formulary were identified, and further agents commonly prescribed by ophthalmologists were included. The standardized prescription drug cost, which includes the cost of the medication, mark-up, and dispensing cost, was provided by Ontario Shoppers Drug Mart stores in July 2016 for 103 common medications using typical dosages and durations. Based on medication class, the highest and lowest cost medications were antiallergy agents (Zaditor [ketotifen], Vasocon [naphazoline]), antibiotic ophthalmic solutions (Vigamox [moxifloxacin], generic ciprofloxacin), oral antibiotics (Cipro [ciprofloxacin], generic cephalexin), antibiotic ophthalmic ointments (generic erythromycin, Tobrex [tobramycin]), antiviral treatment (Valtrex [oral valacyclovir], Viroptic [topical trifluridine]), blepharitis treatment (Zithromax [oral azithromycin], generic oral tetracycline), beta adrenergic inhibitors (Timoptic [topical timolol], generic topical timolol), topical prostaglandin analogues (Xalatan [latanoprost], generic travoprost), oral carbonic anhydrase inhibitors (methazolamide, acetazolamide), topical carbonic anhydrase solutions (Trusopt preservative-free [dorzolamide], Azopt [brinzolamide]), topical alpha-adrenergic agonists (Alphagan [brimonidine], generic brimonidine), topical muscarinic agonists (Isopto carpine [pilocarpine], Diocarpine [pilocarpine]), topical combination glaucoma agents (Cosopt [dorzolamide-timolol], generic dorzolamide-timolol), topical lubricants (Lacri lube, Isopto tears), topical nonsteroidal anti-inflammatory drugs (Acuvail [ketorolac], Ilevro [nepafenac]), and steroids (Durezol [difluprednate], Pred mild [prednisolone]). Substantial cost differences exist between ophthalmology medications of the same class. We encourage ophthalmologists to be aware of the associated costs of the medications they prescribe and to use this information in their decision making. PMID- 29631832 TI - Metalens ophthalmic devices: the new world of optics is flat. PMID- 29631833 TI - Incidence of endophthalmitis after intravitreal injections at a tertiary care hospital. AB - OBJECTIVE: To report the incidence of endophthalmitis after the use of intravitreal injection for anti-vascular endothelial growth factor therapy. METHODS: This was a single-centre retrospective study conducted at the Aga Khan University Hospital, Pakistan. A total of 11 128 injections were administered to 2054 patients between January 2013 and December 2015. All procedures were performed in an operating room setting, and postinjection antibiotics were prescribed. RESULTS: Three cases of endophthalmitis occurred during the study period, with the per-injection risk of endophthalmitis being 0.027%. CONCLUSION: The results highlight the benefit of administering intravitreal injections in a surgical setting in addition to enforcing quality protocols. We also recommend further investigation to scrutinize the role of antibiotics prescribed after deploying intravitreal injections so that unnecessary use of such may be curtailed. PMID- 29631834 TI - Major FDA medical device recalls in ophthalmology from 2003 to 2015. AB - OBJECTIVE: To assess recent high-risk ophthalmic medical device recalls. METHODS: The publicly available Food and Drug Administration Center for Devices and Radiological Health database was mined for Class I (high-risk) ophthalmic device recalls from January 1, 2003 to December 31, 2015. The number of Class I ophthalmic device recalls was quantified. Additionally, recall characteristics and market entry data were determined for each device. RESULTS: Twelve Class I ophthalmic device recall events were identified, collectively affecting over 68 million units in distribution. A median of 147,491 units (range 20 to 57,252,581) were recalled per event. 9 out of 12 recalls (75%) had at least one documented occurrence of an adverse event to a patient. Pre-market related issues accounted for one device recall (8%), post-market related issues accounted for nine device recalls (75%), and two device recalls (17%) were indeterminate. 510(k) clearance was the most common pathway to market, accounting for 50% of Class I recalls. Three devices were approved through pre-market approval (PMA) pathway, two devices were exempt from review, and one device failed to register with the FDA. CONCLUSION: Class I recalls surrounding ophthalmology are relatively infrequent compared to other medical specialties. However, given the impact of Class I recalls in the field, ophthalmologists have an impetus to advocate for stronger device regulation particularly in the context of post-marketing surveillance. PMID- 29631835 TI - Heavy metal--not just hard on the ears: siderosis following retained intraocular foreign body. PMID- 29631836 TI - Epithelial basement membrane dystrophy after femtosecond laser-assisted laser in situ keratomileusis. PMID- 29631837 TI - Sutureless amniotic membrane transplantation with a modified ocular surface ring. PMID- 29631838 TI - Pythium insidiosum keratitis: a pictorial essay of natural history. PMID- 29631839 TI - Expulsive aniridia following remote radial keratotomy. PMID- 29631840 TI - Nine syndrome in a patient with systemic lupus erythematosus. PMID- 29631841 TI - Ocular myasthenia gravis and idiopathic orbital inflammatory disease: double the trouble! PMID- 29631843 TI - Conjunctival angiomyxoma-rare but needs observation. PMID- 29631842 TI - Early orbital infantile hemangioma that emphasizes the importance of glucose transporter-1 (GLUT-1). PMID- 29631844 TI - De novo ossification of the choroid in a case of multifocal fibrosclerosis. PMID- 29631846 TI - Bilateral intratarsal dystrophic calcification and ossification in localized immunoglobulin light chain amyloid. PMID- 29631845 TI - Ocular self-mutilation: a case series. PMID- 29631847 TI - Bilateral neuroretinitis due to Bartonella henselae in a child. PMID- 29631848 TI - Perimacular drusenoid deposits in a child with IgA nephropathy. PMID- 29631849 TI - Exudative retinal detachment, a primary presentation in retinopathy of prematurity. PMID- 29631850 TI - Delayed transient corneal edema after intravitreal injection of ocriplasmin. PMID- 29631851 TI - Analysis of helicoidal peripapillary chorioretinal degeneration progression in an elderly Chinese female patient. PMID- 29631852 TI - Patients with suspected hip fracture in the chain of emergency care: An integrative review of the literature. PMID- 29631853 TI - Association between zinc nutritional status and glycemic control in individuals with well-controlled type-2 diabetes. AB - BACKGROUND/OBJECTIVE: Interest in healthy properties of food and nutrients as co adjuvant in type-2 diabetes therapy has increased in recent years. Zinc supplementation trials have shown improvements in glycemic control in these patients, although it seems dependent on zinc status of the individuals. The objective of this study was to evaluate the relationship between zinc nutritional status and glucose homeostasis in patients with type-2 diabetes. SUBJECTS/METHODS: Eighty patients with well controlled type-2 diabetes were recruited and clinical, anthropometric and dietary evaluations were performed. One week after, insulin sensitivity and beta cell function were assessed by a modified Frequently Sampled Intravenous Glucose Tolerance Test. Zinc status was assessed by plasma zinc and the size of rapidly Exchangeable Zinc Pool (EZP); zinc intake was also determined. Glucagon concentration was evaluated in a subsample of 36 patients. RESULTS: Patients presented a normal zinc status although zinc intake was lower than recommended. Overall, no associations were observed between zinc status and glycemic control markers. Nevertheless, positive correlations were observed between EZP and fasting insulin concentration (rho = 0.393, p = 0.021) and HOMA-IR (rho = 0.386, p = 0.024) in women, and between plasma zinc concentration and HbA1c (rho = 0.342, p = 0.020) in men. CONCLUSIONS: No significant associations were found between zinc status and glycemic control parameters in patients with well-controlled type 2 diabetes and normal zinc status, although low-degree gender-dependent associations were observed. Further research is required to assess the role of zinc status in zinc deficient patients. PMID- 29631854 TI - Pretreatment of corn straw using the alkaline solution of ionic liquids. AB - In the present work, the pretreatment of corn stalk with the solution of 1-ethyl 3-methylimidazolium acetate ([Emim]Ac) ionic liquid containing NaOH was explored for its lignin removal. The effects of reaction temperature, reaction time, and solid-liquid ratio on the lignin removal efficiency were determined by the response surface methodology (RSM). The pretreatment conditions were optimized by the Box-Behnken design and the comparative study of the composition and structure of corn straw before and after the pretreatment to be: reaction temperature 98.5 degrees C, reaction time 1.31 h, and solid-liquid ratio 1:8.7. Under the optimized conditions, the cellulose and hemicellulose contents of the corn straw were increased to 85.69% and 9.1%, respectively, and the lignin content was reduced to 2.27% with the lignin removal efficiency up to 87.4%. PMID- 29631855 TI - Stroke and syphilis: A retrospective study of 53 patients. AB - OBJECTIVE: The aim of this study was to describe the clinical, biological and radiological characteristics of patients with syphilitic vasculitis, and to assess the outcome after treatment. METHODOLOGY: A retrospective review was carried out based on the records of patients with ischemic stroke, and reactive CSF TPHA and VDRL results. None of these patients showed symptoms of any other diseases or had received high doses of penicillin. RESULTS: A total of 53 patients with stroke met the diagnostic criteria for syphilitic arteritis. Their average age was 41+/-12 years. Nine patients had a history of genital ulcer (17%), and the median duration of illness after presenting a chancre was 8 [range: 1-14] years. A prodromal syndrome was seen in 27 patients (50.9%) and included changes in mental status in 14 patients (26.4%), seizures in 10 cases (18.9%), headache in eight (15.1%) and memory loss in seven (13.2%). Neurological events included focal motor deficits in 29 cases (54.7%), ataxia in 11 (20.8%) and movement disorders in 15 (28.3%). HIV serology was performed in 31 patients and proved negative in every case. Disease evolution was generally favorable: 12 patients (22.6%) were autonomous at the time of hospital discharge; 29 (54.7%) had partially recovered; and only seven (13.2%) still had signs of severe sequelae. CONCLUSION: A diagnosis of syphilitic stroke should be suspected in young patients as a manifestation of syphilis, and tests for neurosyphilis should be routine in neurology departments to make a prompt diagnosis, thereby preventing psychological sequelae. PMID- 29631856 TI - How do we best prevent influenza in young children? PMID- 29631857 TI - Efficacy, immunogenicity, and safety evaluation of an MF59-adjuvanted quadrivalent influenza virus vaccine compared with non-adjuvanted influenza vaccine in children: a multicentre, randomised controlled, observer-blinded, phase 3 trial. AB - BACKGROUND: Young children have immature immune systems and respond poorly to standard influenza vaccines. The oil-in-water emulsion adjuvant MF59 can increase antigen uptake, macrophage recruitment, lymph node migration, and avidity to influenza virus. Therefore, we aimed to assess the relative efficacy, immunogenicity, and safety of an MF59-adjuvanted, quadrivalent, inactivated (subunit) influenza vaccine (aIIV4) compared with a US-licensed non-adjuvanted influenza vaccine in children. METHODS: We did a multicentre, randomised controlled, observer-blinded, phase 3 trial of 146 sites including hospitals, clinics, and clinician offices in nine countries over two influenza seasons. We included children of either sex aged 6 months through 5 years. We stratified eligible participants and randomly assigned them (1:1), using a block size of four, to receive either aIIV4 or non-adjuvanted inactivated influenza vaccine (ie, trivalent inactivated influenza vaccine [IIV3] or quadrivalent inactivated influenza vaccine [IIV4]). We masked participants, parents or guardians, and outcome assessors to the administered vaccine. Designated personnel who were not masked administered aIIV4 in both seasons, or IIV3 in season one and IIV4 in season two. All vaccinations were administered intramuscularly. Children aged 6 through 35 months received one or two 0.25 mL doses, whereas those aged 3 through 5 years received one or two doses of 0.5 mL. The number of doses was dependent on previous vaccination status: vaccine-naive participants received a total of two doses of study vaccine, the first on day 1 and the second on day 29, whereas non naive participants received only one dose on day 1. The primary outcome was relative vaccine efficacy assessed by RT-PCR-confirmed influenza due to any influenza strain in the overall study population and in prespecified age and dose subgroups. Immunogenicity against homologous and heterologous strains of influenza and safety were also measured. This study is registered with ClinicalTrials.gov, number NCT01964989. FINDINGS: Between Nov 3, 2013, and March 5, 2014 (season one), and between Sept 30, 2014, and March 29, 2015 (season two), 10 644 participants were enrolled in this study. Of these participants, 10 612 were vaccinated (n=5338 with aIIV4 and n=5274 with comparator). Relative vaccine efficacy was not different between aIIV4 and the comparator vaccines in the overall study population (relative vaccine efficacy -0.67, 95% CI -19.81 to 15.41). The relative vaccine efficacy in the 6 through 23-month subgroup was significantly greater for aIIV4 than for the comparator vaccine (relative vaccine efficacy 31.37, 95% CI 3.14-51.38). aIIV4 elicited superior immunogenic response compared with the comparator for all four vaccine strains (geometric mean titre ratios 1.91 [95% CI 1.8-2.0] for A/H1N1, 1.71 [1.6-1.8] for A/H3N2, 2.19 [2.0 2.4] for B/Yamagata, and 2.27 [2.0-2.6] for B/Victoria) and three heterologous strains (1.94 [1.6-2.3] for A/H3N2, 2.17 [1.8-2.6] for B/Yamagata, and 2.12 [1.6 2.7] for B/Victoria) in participants aged 6 months through 5 years. The highest geometric mean titre ratios were observed in participants aged 6 through 23 months. Safety profiles were similar but more frequent solicited adverse events were reported with aIIV4 than with the comparator (3748 [73%] of 5138 vs 3242 [64%] of 5056). INTERPRETATION: Although there was no additional benefit of aIIV4 compared with the US-licensed non-adjuvanted influenza vaccines in the overall study population, in the youngest and most vulnerable population of children in this trial, aIIV4 provided greater protection against influenza than a non adjuvanted vaccine when assessed in this prespecified age group of 6 through 23 months. Additional clinical benefit was also apparent early after first vaccination in vaccine-naive participants aged 6 months through 5 years. Finally, aIIV4 and comparator had similar efficacy and vaccine safety profiles in children aged 6 months through 5 years. FUNDING: Seqirus UK Ltd. PMID- 29631858 TI - Hormone Levels and Sexual Functioning After Risk-Reducing Salpingo-Oophorectomy. AB - INTRODUCTION: Women after risk-reducing salpingo-oophorectomy (RRSO) can have impaired sexual functioning, but whether there is an association between hormone levels and sexual functioning is unclear. AIM: To determine whether hormone levels are associated with sexual functioning in women after RRSO. METHODS: This is a retrospective cohort study of 198 sexually active and 91 inactive women after RRSO. Participants completed the Sexual Activity Questionnaire, questionnaires concerning hormone replacement therapy (HRT), quality of life, care from partner, body image, and comorbidity and provided blood samples. Associations between sexual functioning scores and covariates were examined by linear regression. Variables associated with sexual activity were examined by logistic regression. MAIN OUTCOME MEASURES: Associations with sexual pleasure and sexual discomfort scores were expressed by multivariable regression coefficients and associations with sexual activity were expressed by odds ratios. RESULTS: None of the hormone levels were associated with sexual pleasure in contrast to age (P = .032), current use of systemic HRT (P = .002), and more care form partner (P < .001). Increased free androgen index (P = .016), more care from partner (P = .017), systemic HRT (P = .002), and no history of cardiovascular disease (P = .001) were associated with less sexual discomfort. The odds ratio of being sexually active increased with younger age, no breast cancer, better quality of life, and more care from partner. CONCLUSIONS: Our results indicate that other factors than hormone levels are important for sexual functioning, although systemic HRT can have a positive impact on sexual functioning in women who have undergone RRSO. Testosterone therapy could improve women's sexual functioning after RRSO; however, the inverse association between free androgen levels and sexual discomfort should be addressed in future studies. Johansen N, Liavaag AH, Morkird L, Michelsen TM. Hormone Levels and Sexual Functioning After Risk-Reducing Salpingo-Oophorectomy. Sex Med 2018;6:143-153. PMID- 29631859 TI - Complications and Obesity in Arthroplasty-A Hip is Not a Knee. AB - BACKGROUND: Obesity has previously been demonstrated to be an independent risk factor for increased complications after total hip and knee arthroplasties (THA and TKA). The purpose of this study was to compare the effects of obesity and body mass index (BMI) to determine whether the magnitude of the effect was similar for both procedures. METHODS: We queried the American College of Surgeons National Surgical Quality Improvement Program database to identify patients who underwent primary THA or TKA between 2010 and 2014. Patients were stratified by procedure and classified as nonobese, obese, or morbidly obese according to BMI. Thirty-day rates of wound complications, deep infection, total complications, and reoperation were compared using univariate and multivariate logistic regression analyses. RESULTS: We identified 64,648 patients who underwent THA and 97,137 patients who underwent TKA. Obese THA patients had significantly higher rates of wound complications (1.53% vs 0.96%), deep infection (0.31% vs 0.17%), reoperation rate (2.11% vs 1.02%), and total complications (5.22% vs 4.63%) compared with TKA patients. Morbidly obese patients undergoing THA were also found to have significantly higher rates of wound complications (3.25% vs 1.52%), deep infection (0.84% vs 0.23%), reoperation rate (3.65% vs 1.60%), and total complications (7.36% vs 5.57%). Multivariate regression analysis identified increasingly higher odds of each outcome measure as BMI increased. CONCLUSION: This study demonstrates that the impact of obesity on postoperative complications is more profound for THA than TKA. This emphasizes the importance of considering patient comorbidities in the context of the specific procedure when assessing risks of surgery. PMID- 29631860 TI - What Is the Optimal Criteria to Use for Detecting Periprosthetic Joint Infections Before Total Joint Arthroplasty? AB - BACKGROUND: The purposes of this study were to (1) test the accuracy of alpha defensin and combined alpha-defensin-aspiration cultures in diagnosing periprosthetic joint infection (PJI) before revision total knee and hip arthroplasty and (2) evaluate Musculoskeletal Infection Society (MSIS) criteria and alpha-defensin as predictors of successful reimplantation (second-stage) at 1 year after surgery. METHODS: We retrospectively evaluated a total of 97 synovial fluid aspirations performed between August 2014 and September 2016 before revision due to septic or aseptic failures (n = 70) or before second-stage (n = 27) joint arthroplasty. Revisions were categorized as either septic or aseptic according to the MSIS criteria. Synovial fluid was tested for alpha-defensin, cell count with differential, and cultures. Reimplantations were assessed for success or failure (defined as the need for reoperation due to infection) within 1 year after surgery. RESULTS: For septic and aseptic revision arthroplasty, the sensitivity, specificity, positive predictive value, and negative predicted value of alpha-defensin was 97% while for the combined alpha-defensin and aspiration culture, it was 96%, 100%, 100%, and 97%. Despite being performed with negative MSIS criteria and alpha-defensin test results, 11% (3/27) of reimplantations (second-stage) failed within 1 year postoperatively because of infection. CONCLUSION: Alpha-defensin is an accurate diagnostic test for the diagnosis of PJI before revision arthroplasty. The combination of alpha-defensin and aspiration cultures has higher specificity and positive predictive value. MSIS criteria and alpha-defensin may help predict the success of reimplantations within 1 year after surgery. PMID- 29631861 TI - The Role of the Tourniquet and Patella Position on the Compartmental Loads During Sensor-Assisted Total Knee Arthroplasty. AB - BACKGROUND: An inflated tourniquet may diminish the natural excursion of the extensor mechanism and alter compartmental loads, affecting the surgeon's ability to accurately assess ligament balance during total knee arthroplasty (TKA). In addition, patella position (reduced, lateralized, or everted) has also been known to affect compartmental loads. This study used intraoperative sensing to assess how a combination of tourniquet inflation and patella position may affect medial and lateral compartmental loads during sensor-assisted TKA. METHODS: Fifty-six patients (13 men) with a mean age of 66 years (standard deviation, 8.66) and mean BMI of 31 kg/m2 (standard deviation, 6.66) undergoing primary cemented TKA for primary osteoarthritis were enrolled. After final prosthetic implantation, with the tourniquet inflated, medial and lateral compartment loads were obtained in the 10 degrees , 45 degrees , and 90 degrees of flexion with the patella in reduced, lateralized, or everted positions. The tourniquet was deflated and this process repeated. Surgeons were blinded to the values as to not influence medial and lateral stressing of the knee. Linear regression was used to evaluate absolute loads. RESULTS: Tourniquet inflation did not significantly alter compartmental loads regardless of knee flexion or patella position. Lateral compartment loads significantly increased as the patella moved from the reduced, to the lateralized, to the everted position with the tourniquet inflated or deflated. CONCLUSION: Tourniquet inflation did not significantly alter compartmental loads during sensor-assisted TKA. However, irrespective of tourniquet use, a lateralized or everted patellar position significantly increased lateral compartment loads. PMID- 29631862 TI - Corrigendum to 'Eight Hundred Twenty-Five Medial Mobile-Bearing Unicompartmental Knee Arthroplasties: The First 10-Year US Multi-Center Survival Analysis' [Journal of Arthroplasty 33 (2018) 677-683]. PMID- 29631863 TI - Parkinson's disease, epileptic seizures, and sudden death: Three faces of the same coin. PMID- 29631864 TI - Venous thromboembolism controversies. PMID- 29631865 TI - WITHDRAWN: Tool for predicting Caligus rogercresseyi abundance on salt ater salmon farms in Chile. PMID- 29631867 TI - The use of out-of-plane high Z patient shielding for fetal dose reduction in computed tomography: Literature review and comparison with Monte-Carlo calculations of an alternative optimisation technique. AB - When performing CT examinations on pregnant patients, great effort should be dedicated towards optimising the exposure of the mother and the conceptus. For this purpose, many radiology departments use high-Z garments to be wrapped around the patient's lower abdomen for out-of-plane organ shielding to protect the fetus. To assess their current protection efficiency, we performed a literature review and compared the efficiencies mentioned in the literature to Monte-Carlo calculations of CT protocols for which the overall scan length was reduced. We found 11 relevant articles, all of them reporting uterus exposure due to CT imaging performed for exclusion of pulmonary embolism, one of the leading causes of peripartum deaths in western countries. Uterus doses ranged between 60 and 660 uGy per examination, and relative dose reductions to the uterus due to high-Z garments were between 20 and 56%. Calculations showed that reducing the scan length by one to three centimetres could potentially reduce uterus dose up to 24% for chest imaging, and even 47% for upper abdominal imaging. These dose reductions were in the order of those achieved by high-Z garments. However, using the latter may negatively influence the diagnostic image quality and even interfere with the automatic exposure control system thus increasing patient dose if positioned in the primary beam, for example in the overranging length in helical acquisition. We conclude that efforts should be concentrated on positioning the patient correctly in the gantry and optimising protocol parameters, rather than using high-Z garments for out-of-plane uterus shielding. PMID- 29631868 TI - Functional Interaction between Melatonin Signaling and Noncoding RNAs. AB - Melatonin was discovered in the pineal gland and first came to be known as a biochemical synchronizer of circadian rhythm. The molecular mechanisms underlying the broad-spectrum actions of melatonin are not restricted to its interaction with proteins but it also has functional effects after influencing RNA species that have no protein-coding potential. In this review we discuss the current understanding of the melatonin-mediated modulation of noncoding RNA (ncRNA) pathways under different physiological and pathological conditions. We also delineate the impact of specific ncRNAs in controlling the synthesis of melatonin. The information compiled herein will serve as a solid foundation to formulate ideas for future mechanistic studies on melatonin and to better explore the emerging functions of the noncoding transcriptome. PMID- 29631866 TI - Consensus document. Management of non-alcoholic fatty liver disease (NAFLD). Clinical practice guideline. AB - Non-alcoholic fatty liver disease (NAFLD) is the main cause of liver diseases in Spain and the incidence is raising due to the outbreak of type 2 diabetes and obesity. This CPG suggests recommendation about diagnosis, mainly non-invasive biomarkers, and clinical management of this entity. Life-style modifications to achieve weight loss is the main target in the management of NAFLD. Low caloric Mediterranean diet and 200 minutes/week of aerobic exercise are encouraged. In non-responders patients with morbid obesity, bariatric surgery or metabolic endoscopy could be indicated. Pharmacological therapy is indicated in patients with NASH and fibrosis and non-responders to weight loss measures. NAFLD could influence liver transplantation, as a growing indication, the impact of steatosis in the graft viability, de novo NAFLD rate after OLT and a raised cardiovascular risk that modify the management of this entity. The current CPG was the result of the First Spanish NAFLD meeting in Seville. PMID- 29631869 TI - Novel application of virtual reality in patient engagement for deep brain stimulation: A pilot study. PMID- 29631870 TI - Geometrical accuracy of metallic objects produced with additive or subtractive manufacturing: A comparative in vitro study. AB - OBJECTIVE: To evaluate the accuracy and precision of objects produced by additive manufacturing systems (AM) for use in dentistry and to compare with subtractive manufacturing systems (SM). METHODS: Ten specimens of two geometrical objects were produced by five different AM machines and one SM machine. Object A mimics an inlay-shaped object, while object B imitates a four-unit bridge model. All the objects were sorted into different measurement dimensions (x, y, z), linear distances, angles and corner radius. RESULTS: None of the additive manufacturing or subtractive manufacturing groups presented a perfect match to the CAD file with regard to all parameters included in the present study. Considering linear measurements, the precision for subtractive manufacturing group was consistent in all axes for object A, presenting results of <0.050mm. The additive manufacturing groups had consistent precision in the x-axis and y-axis but not in the z-axis. With regard to corner radius measurements, the SM group had the best overall accuracy and precision for both objects A and B when compared to the AM groups. SIGNIFICANCE: Within the limitations of this in vitro study, the conclusion can be made that subtractive manufacturing presented overall precision on all measurements below 0.050mm. The AM machines also presented fairly good precision, <0.150mm, on all axes except for the z-axis. Knowledge regarding accuracy and precision for different production techniques utilized in dentistry is of great clinical importance. The dental community has moved from casting to milling and additive techniques are now being implemented. Thus all these production techniques need to be tested, compared and validated. PMID- 29631871 TI - Frequency of Use and Smoking Status of U.S. Adolescent E-Cigarette Users in 2015. AB - INTRODUCTION: E-cigarette use by adolescents is an important issue for public health. This study analyzed the frequency of e-cigarette use and its association with smoking status among U.S. adolescents. METHODS: The National Youth Tobacco Survey 2015 was analyzed in 2017, focusing on frequency of past 30-day e cigarette use according to smoking status of participants. Smoking status was classified as never smoker, ever/not a past 30-day smoker, and past 30-day smoker. Infrequent and frequent smoking and e-cigarette use was defined as use for <20 and >=20 of the past 30 days, respectively. RESULTS: Past 30-day e cigarette use was reported by 54.5% (95% CI=47.8%, 61.0%) of past 30-day smokers, 26.5% (95% CI=23.2%, 30.1%) of ever/not past 30-day smokers, and 4.6% (95% CI=4.0%, 5.2%) of never smokers (p<0.001). No past 30-day e-cigarette use was reported by 94.5% and frequent e-cigarette use by 0.3% of never smokers. Past 30 day e-cigarette use was reported by 50.4% (95% CI=43.6%, 57.3%) of infrequent and 64.7% (95% CI=54.4%, 73.8%) of frequent past 30-day smokers (p<0.001). E cigarette use frequency correlated with both smoking status and tobacco cigarette consumption (rho=0.42, p<0.001 and rho=0.40, p<0.001, respectively). Past 30-day smokers were more likely to report past 30-day e-cigarette use (OR=11.42, 95% CI=9.06, 14.40) compared with adolescents reporting no past 30-day smoking. CONCLUSIONS: E-cigarette use is more prevalent among ever and past 30-day smoking adolescents compared with never smoking adolescents. Frequent e-cigarette use is rare among never smoking adolescents. PMID- 29631872 TI - Should people with psychosis be supported in choosing cognitive therapy as an alternative to antipsychotic medication: A commentary on a commentary. PMID- 29631873 TI - Letter to the Editor on "Kidney transplantation: A new era of laparoscopic living donor nephrectomy in Indonesia." Evolution of laparoscopic living donor nephrectomy for kidney transplantation: Laparoscopic donor nephrectomy for kidney transplantation. PMID- 29631874 TI - Study design and recruitment for a prospective controlled study of diabesity: Taiwan Diabesity Study. AB - BACKGROUND: Strong evidence has shown that metabolic surgery is more effective than medical treatment in the treatment of type 2 diabetic patients. However, no study demonstrated a survival benefit and reduction of diabetes-related end-organ damage. Here, we describe the study design of a large prospective cohort study, the Taiwan Diabesity Study (TDS) which would compare the long-term survival rate and end-organ damage between overweight/obese type 2 diabetic patients receiving metabolic surgery and medical treatment. METHODS: Eligibility criteria include type 2 diabetic patients with duration > 6 months, body mass index (BMI) over 25 kg/m2 and age between 20 and 67 years. Exclusion criteria are serum creatinine over 2.0 mg/dL, C-peptide below 1.0 ng/ml, recent history of cancer, and major diabetic complications. Eligible participants were recruited from six medical centers in Taiwan. The survival rate and diabetes-related end organ damage will be compared between the metabolic surgery group and medical group after follow-up for 10 years. RESULTS: In 3 years, 1016 participants were identified from 38,751 patients. The average BMI of patients was 30.6 (+/-2.6) kg/m2 and the average hemoglobin A1c was 8.2% (+/-1.5%) with 18% of them receiving insulin treatment. Among them, 126 patients received metabolic surgery and 890 patients received conventional medical treatment. The metabolic surgery group are younger, have a higher proportion of females, higher BMI and blood lipids as compared to the medical group. CONCLUSION: The TDS recruited 1016 overweight/obese type 2 diabetic patients including 126 patients receiving metabolic surgery and 890 patients receiving medical treatment. PMID- 29631875 TI - [Effect of table tilt and spine flexion-rotation on the acoustic window of the lumbar spine in pregnant women]. AB - STUDY OBJECTIVE: The purpose of this study was to assess whether application of dorsal table tilt and body rotation to a parturient seated for neuraxial anesthesia increased the size of the paramedian target area for neuraxial needle insertion. SETTING: Labor and Delivery Room. PATIENTS: Thirty term pregnant women, ASA I-II, scheduled for an elective C-section delivery. INTERVENTIONS: Lumbar ultrasonography was performed in four seated positions: (F) lumbar flexion; (FR) as in position F with right shoulder rotation; (FT) as in position F with dorsal table-tilt; (FTR) as in position F with dorsal table-tilt combined with right shoulder rotation. MEASUREMENTS: For each position, the size of the 'target area', defined as the visible length of the posterior longitudinal ligament was measured at the L3-L4 interspace. MAIN RESULTS: The mean posterior longitudinal ligament was 18.4+/-4mm in position F, 18.9+/-5.5mm in FR, 19+/ 5.3mm in FT, and 18+/-5.2mm in FTR. Mean posterior longitudinal ligament length was not significantly different in the four positions. CONCLUSIONS: These data show that the positions studied did not increase the target area as defined by the length of the posterior longitudinal ligament for the purpose of neuraxial needle insertion in obstetric patients. The maneuvers studied will have limited use in improving spinal needle access in pregnant women. PMID- 29631876 TI - [The effects of transversus abdominis plane block on analgesic and anesthetic consumption during total abdominal hysterectomy: a randomized controlled study]. AB - BACKGROUND AND OBJECTIVES: A transversus abdominis plane block is a peripheral block method that has been used successfully for pain relief after total abdominal hysterectomy. However, the effects of the combination of the transversus abdominis plane block and general anesthesia on analgesic and anesthetic requirements remain unclear. This randomized placebo-controlled study is aimed to evaluate the effects of transversus abdominis plane block on analgesic and anesthetic consumption during total abdominal hysterectomy under general anesthesia. METHODS: Sixty-six women undergoing total abdominal hysterectomy were randomized into two groups to receive general anesthesia alone (control group) or with transversus abdominis plane block using 20mL of 0.25% bupivacaine (transversus abdominis plane group). Intraoperative remifentanil and sevoflurane consumption were recorded. We also evaluated the postoperative pain, nausea, quality of recovery scores and rescue analgesic requirement during postoperative 24hours. RESULTS: The total remifentanil and sevoflurane consumption is significantly lower in transversus abdominis plane group; respectively mean (SD) 0.130 (0.25) vs. 0.094 (0.02) mcg.kg-1.min-1; p<0.01 and 0.295 (0.05) vs. 0.243 (0.06) mL.min-1; p<0.01. In the postoperative period, pain scores were significantly reduced in transversus abdominis plane group soon after surgery; median (range) 6 (2-10) vs. 3 (0-5); p<0.001, at 2h (5 [3-9] vs. 2.5 [0 6]; p<0.001), at 6h (4 [2-7] vs. 3[0-6], p<0.001), at 12h (3.5 [1-6] vs. 2 [1-5]; p=0.003). The patients in the transversus abdominis plane group had significantly higher QoR-40 scores 190.5 (175-197) vs. 176.5 (141-187); p<0.001). CONCLUSION: Combining transversus abdominis plane block with general anesthesia can provide reduced opioid and anesthetic consumption and can improve postoperative pain and quality of recovery scores in patients undergoing total abdominal hysterectomy. PMID- 29631877 TI - [The use of flumazenil for benzodiazepine associated respiratory depression in postanesthesia recovery: risks and outcomes]. AB - BACKGROUND AND OBJECTIVES: The primary aim was to determine risk factors for flumazenil administration during postanesthesia recovery. A secondary aim was to describe outcomes among patients who received flumazenil. METHODS: Patients admitted to the postanesthesia recovery room at a large, academic, tertiary care facility after surgery under general anesthesia from January 1, 2010, to April 30, 2015, were identified and matched to 2 controls each, by age, sex, and surgical procedure. Flumazenil was administered in the recovery phase immediately after general anesthesia, according to the clinical judgment of the anesthesiologist. Demographic, procedural, and outcome data were extracted from the electronic health record. Conditional logistic regression, accounting for the 1:2 matched-set case-control study designs, was used to assess characteristics associated with flumazenil use. RESULTS: The incidence of flumazenil administration in the postanesthesia care unit was 9.9 per 10,000 (95% CI, 8.4 11.6) general anesthetics. History of obstructive sleep apnea (Odds Ratio [OR]=2.27; 95% CI 1.02-5.09), longer anesthesia (OR=1.13; 95% CI 1.03-1.24 per 30minutes), use of total intravenous anesthesia (OR=6.09; 95% CI 2.60-14.25), and use of benzodiazepines (OR=8.17; 95% CI 3.71-17.99) were associated with risk for flumazenil administration. Among patients who received midazolam, cases treated with flumazenil received a higher median (interquartile range) dose than controls: 3.5mg (2.0-4.0mg) vs. 2.0mg (2.0-2.0mg), respectively (p<0.001). Flumazenil use was correlated with a higher rate of unanticipated noninvasive positive pressure ventilation, longer postanesthesia care unit stay, and increased rate of intensive care unit admissions. CONCLUSIONS: Patients who required flumazenil postoperatively had received a higher dosage of benzodiazepines and utilized more postoperative health care resources. More conservative perioperative use of benzodiazepines may improve postoperative recovery and use of health care resources. PMID- 29631878 TI - [Waste anesthetic gas exposure: the risks extend outside the operating room]. PMID- 29631879 TI - [Sugammadex to prevent postoperative nausea and vomiting?] PMID- 29631880 TI - [Acquiring skills in malignant hyperthermia crisis management: comparison of high fidelity simulation versus computer-based case study]. AB - INTRODUCTION: The primary purpose of this study was to compare the effect of high fidelity simulation versus a computer-based case solving self-study, in skills acquisition about malignant hyperthermia on first year anesthesiology residents. METHODS: After institutional ethical committee approval, 31 first year anesthesiology residents were enrolled in this prospective randomized single blinded study. Participants were randomized to either a High Fidelity Simulation Scenario or a computer-based Case Study about malignant hyperthermia. After the intervention, all subjects' performance in was assessed through a high fidelity simulation scenario using a previously validated assessment rubric. Additionally, knowledge tests and a satisfaction survey were applied. Finally, a semi structured interview was done to assess self-perception of reasoning process and decision-making. RESULTS: 28 first year residents finished successfully the study. Resident's management skill scores were globally higher in High Fidelity Simulation versus Case Study, however they were significant in 4 of the 8 performance rubric elements: recognize signs and symptoms (p = 0.025), prioritization of initial actions of management (p = 0.003), recognize complications (p = 0.025) and communication (p = 0.025). Average scores from pre- and post-test knowledge questionnaires improved from 74% to 85% in the High Fidelity Simulation group, and decreased from 78% to 75% in the Case Study group (p = 0.032). Regarding the qualitative analysis, there was no difference in factors influencing the student's process of reasoning and decision-making with both teaching strategies. CONCLUSION: Simulation-based training with a malignant hyperthermia high-fidelity scenario was superior to computer-based case study, improving knowledge and skills in malignant hyperthermia crisis management, with a very good satisfaction level in anesthesia residents. PMID- 29631881 TI - [The unnecessary application of central venous catheterization in surgical patients]. AB - BACKGROUND AND OBJECTIVES: Perioperative physicians occasionally encounter situations where central venous catheters placed preoperatively turn out to be unnecessary. The purpose of this retrospective study is to identify the unnecessary application of central venous catheter placement and determine the factors associated with the unnecessary application of central venous catheter placement. METHODS: Using data from institutional perioperative central venous catheter surveillance, we analysed data from 1,141 patients who underwent central venous catheter placement. We reviewed the central venous catheter registry and medical charts and allocated registered patients into those with the proper or with unnecessary application of central venous catheter according to standard indications. Multivariate analysis was used to identify factors associated with the unnecessary application of central venous catheter placement. RESULTS: In 107 patients, representing 9.38% of the overall population, we identified the unnecessary application of central venous catheter placement. Multivariate analysis identified emergencies at night or on holidays (odds ratio [OR] 2.109, 95% confidence interval [95% CI] 1.021-4.359), low surgical risk (OR=1.729, 95% CI 1.038-2.881), short duration of anesthesia (OR=0.961/10min increase, 95% CI 0.945-0.979), and postoperative care outside of the intensive care unit (OR=2.197, 95% CI 1.402-3.441) all to be independently associated with the unnecessary application of catheterization. Complications related to central venous catheter placement when the procedure consequently turned out to be unnecessary were frequently observed (9/107) compared with when the procedure was necessary (40/1034) (p=0.032, OR=2.282, 95% CI 1.076-4.842). However, the subsequent multivariate logistic model did not hold this significant difference (p=0.0536, OR=2.115, 95% CI 0.988-4.526). CONCLUSIONS: More careful consideration for the application of central venous catheter is required in cases of emergency surgery at night or on holidays, during low risk surgery, with a short duration of anesthesia, or in cases that do not require postoperative intensive care. PMID- 29631882 TI - Predictive ability of Guy's stone score in pediatric patients undergoing percutaneous nephrolithotomy. AB - BACKGROUND: Several authors have evaluated, in a number of external validation and predominantly adult studies, Guy's stone score (GSS) as a predictive tool for the assessment of stone clearance after percutaneous nephrolithotomy (PCNL). However, there are limited and conflicting data investigating whether GSS could be a potential independent factor associated with residual stone rates and complications of PCNL for children. OBJECTIVE: The aim of the current study was to evaluate the ability of GSS, as an independent factor, to predict residual stone rates and complications in pediatric patients undergoing PCNL. STUDY DESIGN: The records of the pediatric patients who had undergone PCNL for stone disease at the current department were retrospectively reviewed. Variables included patient, stone, and treatment parameters. The GSS was used for assessment of stone complexity. Univariate and multivariate analyses were performed to evaluate factors associated with residual stone rates and complications of pediatric PCNL. RESULTS: The study group consisted of 114 children (63 boys and 51 girls) with a median (interquartile range) age of 6 (3 11) years and who had undergone 122 PCNLs (eight bilateral). Multivariate logistic regression analysis (Summary Table) demonstrated that the independent risk factors for increased residual stone rate following pediatric PCNL monotherapy were GSS (OR 3.14, 95% CI 1.31-7.49, P = 0.01) and number of calyces involved (OR 4.02, 95% CI 1.11-14.53, P = 0.033). Multivariate logistic regression analysis demonstrated that the independent risk factors for complications following pediatric PCNL were surgical experience (OR 2.72, 95% CI 1.09-6.82, P = 0.032), and operation time (OR 1.01, 95% CI 1.00-1.03, P = 0.040). DISCUSSION: A prediction model is needed to pre-operatively counsel patients and evaluate outcomes for measuring treatment success of PCNL. The GSS provides a simple, reliable and reproducible tool for describing the complexity of PCNL while predicting postoperative stone-free status, despite its limitations. However, little research has been conducted on the applicability of GSS in pediatric patients undergoing PCNL. In addition, conflicting results have been reported about its association with complications of pediatric PCNL. CONCLUSIONS: The current study found that although GSS had a significant predictive ability for residual stone rates after pediatric PCNL revealed by multivariate logistic regression, the results did not conclude that complexity of GSS was directly proportional to complications of pediatric PCNL. The factors, including calyceal involvement and surgeon experience, may need to be incorporated in GSS to further improve its ability to predict outcomes of pediatric PCNL. IRB APPROVED PROTOCOL NUMBER: 1422. PMID- 29631884 TI - A rare case of septic shock due to Neisseria meningitidis serogroup B infection despite prior vaccination in a young adult with paroxysmal nocturnal haemoglobinuria receiving eculizumab. AB - Paroxysmal nocturnal haemoglobinuria (PNH) is a rare acquired haematopoietic stem cell disease which causes defects in complement inhibiting proteins. The disease presents classically with the triad of haemolytic anaemia, pancytopenia and thrombosis. Eculizumab, a humanized antibody that blocks the cleavage of complement factor 5, was approved for PNH treatment in 2007 and has improved patients' survival since then. However, several cases of invasive meningococcal disease (IMD) have been reported in eculizumab-treated patients, mostly caused by serogroup B infection which was not covered by the previously administered vaccine (MenACWY). We report a rare case of septic shock due to infection with Neisseria meningitis serogroup B despite prior vaccination with 4CMenB in a young PNH patient treated with eculizumab. There are increasing doubts over whether vaccination ensures sufficient immunoprotection against IMD in patients receiving eculizumab. Therefore, besides monitoring the immune response, lifelong chemoprophylaxis should be considered. PMID- 29631883 TI - Evaluation of HPV-16 and HPV-18 specific antibody measurements in saliva collected in oral rinses and merocel(r) sponges. AB - BACKGROUND: Current Human papillomavirus (HPV) L1 VLP vaccines protect against HPV-16 and HPV-18-associated cancers, in females and males. Although correlates of protection have not been identified, HPV-specific antibodies at sites of infection are thought to be the main mechanism of protection afforded by vaccination. Oral sampling has gained increased attention as a potential alternative to serum in monitoring immunity to vaccination and understanding local immunity in oral cancers. METHODS: Serum was collected via venipuncture, and saliva was collected via oral rinses and Merocel(r) sponges from healthy volunteers: 16 unvaccinated females, 6 females (ages 24-41) and 6 mid-adult aged males (ages 27-45) recipients of three doses of the HPV-16/18/6/11 vaccine (Gardasil(r)). Mid-adult male vaccine trial participants were compared to female participants. Samples were tested for anti-HPV-16 and anti-HPV-18 immunoglobulin G levels by an L1 virus-like particle-based enzyme-linked immunosorbent assay (ELISA). RESULTS: All vaccinated participants had detectable serum anti-HPV-16 and anti-HPV-18 antibodies. Optimal standard concentration range and sample serial dilutions for oral rinses were determined. The standard curve was not affected by the type of solution examined. Reproducibility of HPV-16 and HPV-18 antibody titers in mouthwash (overall CV < 10%) or in Merocel(r) extraction buffer was robust (CV < 13%). Excellent assay linearity (R2 > 0.9) was observed for sera spiked controls in both solutions. HPV-16 and HPV-18 specific antibodies were detectable in saliva from vaccine recipients, both in mouthwash and in Merocel(r) sponges but levels were several logs lower than those in serum. CONCLUSIONS: This study confirms the application of HPV-16 and HPV-18 ELISAs currently used in sero-epidemiological studies of immunogenicity of HPV vaccines for use with oral samples. Oral samples may be a useful resource for the detection of HPV-16 and HPV-18-specific antibodies in saliva following vaccination. PMID- 29631885 TI - Two B-cell epitope vaccines based on uPA effectively inhibit fertility in male mice. AB - uPA, a trypsin-like serine protease, was found to take active part in male reproduction. Our previous work had demonstrated the antifertility effects of its full length protein immunization, but with immune tolerance and other latent side effects. Here we discovered two effective B-cell epitopes of uPA for male contraception in growth factor-like domain and kringle domain respectively. Together with carrier protein, immunization of these two epitope peptides could induce high titers of specific antibodies in male mice. Significant reduction of fertility was observed in these two groups in mating trial without evident systemic illness or abnormal mating behavior. Epididymal sperms of immunized males exhibited impaired progressive motility and ability to fertilize eggs in vitro. The immunization of another predicted epitope in serine protease domain and the control groups showed no similar positive results. Importantly, T cells were not activated after the challenge of these B-cell epitopes itself, which suggests that these vaccines do not induce cell-mediated autoimmunity. Taken together, our study discovered two uPA B-cell epitopes as novel targets for male immunocontraception with minimum side effects. Considering their high identity with human uPA protein, these two epitope vaccines hold great promise to be developed for man use in the future. PMID- 29631886 TI - Antibody profiling using a recombinant protein-based multiplex ELISA array accelerates recombinant vaccine development: Case study on red sea bream iridovirus as a reverse vaccinology model. AB - Predicting antigens that would be protective is crucial for the development of recombinant vaccine using genome based vaccine development, also known as reverse vaccinology. High-throughput antigen screening is effective for identifying vaccine target genes, particularly for pathogens for which minimal antigenicity data exist. Using red sea bream iridovirus (RSIV) as a research model, we developed enzyme-linked immune sorbent assay (ELISA) based RSIV-derived 72 recombinant antigen array to profile antiviral antibody responses in convalescent Japanese amberjack (Seriola quinqueradiata). Two and three genes for which the products were unrecognized and recognized, respectively, by antibodies in convalescent serum were selected for recombinant vaccine preparation, and the protective effect was examined in infection tests using Japanese amberjack and greater amberjack (S. dumerili). No protection was provided by vaccines prepared from gene products unrecognized by convalescent serum antibodies. By contrast, two vaccines prepared from gene products recognized by serum antibodies induced protective immunity in both fish species. These results indicate that ELISA array screening is effective for identifying antigens that induce protective immune responses. As this method does not require culturing of pathogens, it is also suitable for identifying protective antigens to un-culturable etiologic agents. PMID- 29631887 TI - Tailoring immunisation service delivery in a disadvantaged community in Australia; views of health providers and parents. AB - In 2014 the Australian immunisation target was raised from 90% to 95% of children to be fully immunised. A national priority is to identify geographic areas of low coverage and implement strategies to improve immunisation rates. Using The World Health Organization's Tailoring Immunization Programmes (TIP) Guidelines, the aim of this study was to identify areas of low immunisation coverage for children in the Hunter New England Local Health District, New South Wales, and to gain a deeper understanding of the factors influencing immunisation in those areas in order to develop tailored strategies for increasing immunisation coverage. Data from the Australian Immunisation Register was used to identify geographic areas of low coverage. Data from interviews and focus groups with parents and service providers were used to gain a deeper understanding of the factors influencing immunisation in those areas. The regional city of Maitland in New South Wales was identified as having a persistently high number and relatively high proportion of children not fully immunised (n = 427, 15.4% in 2016). Themes from 59 stakeholder interviews and focus groups included; (i) limited engagement with health services unless the need is urgent, (ii) multi-dimensional access barriers to immunisation services in Maitland, (iii) a flexible, supportive family centred, primary health care approach, utilising strong partnerships, is most likely to be effective in increasing childhood immunisation rates in Maitland, (iv) data can be used more effectively to inform service providers about trends and individual children not fully immunised. TIP guidelines proved useful for identifying areas of low coverage and providing an understanding of determining factors and the strategies most likely to be effective. Understanding the complex problems many parents face and the access barriers that contribute to low immunisation coverage is essential in developing appropriate solutions. Finding ways to support parents and remove those barriers can contribute to higher coverage. In Maitland, targeted outreach and home visiting has been implemented in consultation with community and health service representatives to ensure that the children from socially disadvantaged populations identified do not miss out on vaccination. PMID- 29631888 TI - Prevalence, incidence, and mortality of sarcoidosis in Korea, 2003-2015: A nationwide population-based study. AB - BACKGROUND: The prevalence and incidence of sarcoidosis, a granulomatous disorder involving multiple organ systems, varies among geographical regions and ethnicities. This study evaluated the incidence, prevalence, and mortality of sarcoidosis in a large nationwide population-based cohort in Korea. METHODS: We used data of the National Health Insurance Service database, which is an extensive health-related database including most Korean residents. Adults with a primary diagnosis of sarcoidosis, as determined by International Classification of Disease-Tenth Revision coding (D86), were identified between 2003 and 2015. The incidence, prevalence, and mortality of sarcoidosis were analysed by sex and age. RESULTS: A total of 6376 individuals had a primary diagnosis of sarcoidosis. Their mean age was 48.8 years, and 58.6% were women. The age-adjusted incidence and prevalence of sarcoidosis were 1.3 and 3.4 per 100,000 population respectively; both tended to increase between 2003 and 2015. The all-cause mortality rate was 13.1 per 1000 sarcoidosis patients. The standardised mortality ratio of sarcoidosis patients to the general population was 1.7 (95% confidence interval, 1.5 to 1.8). CONCLUSIONS: This is the largest epidemiologic study of sarcoidosis in an Asian population to date. In Korea, the annual incidence and prevalence of sarcoidosis were relatively low but tended to increase over the 13 years of the study period. Importantly, the overall mortality rate of patients with sarcoidosis was higher than that of the general population. PMID- 29631889 TI - Bacterial interspecies quorum sensing in the mammalian gut microbiota. AB - The mammalian gastrointestinal tract harbors a diverse and complex resident bacterial community, which interacts with the host in many beneficial processes required for optimal host health. We are studying the importance of bacterial cell-cell communication mediated by the interspecies quorum-sensing signal autoinducer-2 (AI-2) in the beneficial properties of the gut microbiota. Our recent work provided the first evidence that AI-2 produced by Escherichia coli can influence the species composition of this community in the mouse gut. We showed that, under conditions of microbiota imbalances induced by antibiotic treatments, E. coli, which increases intestinal AI-2 levels, not only had an effect on the overall structure of the microbiota community, but specifically favored the expansion of the Firmicutes phylum. Because the Firmicutes are very important for many gut functions and were the group of bacteria most severely affected by antibiotic treatment with streptomycin, we are addressing the possibility that AI-2 can influence the balance of the major bacterial groups in the gut and promote recovery of gut homeostasis. Overall, we want to understand how bacterial chemical signaling shapes the multi-species bacterial communities in the mammalian gut and how these communities affect host physiology. PMID- 29631890 TI - The microbiota, a necessary element of immunity. AB - The intestinal microbiota is essential for digestion, the production of physiological metabolites, and defense. More than 1013 bacteria are present in the intestine, inspiring awe as well as fear of potential infections. By definition, the immune system protects us from infection, and is given the task to recognize dangerous pathogens from useful mutualists. Nevertheless, the definition of pathogens and mutualists is often contextual, and the immune system reacts to all types of microbes. In fact, immune reactivity to microbiota is necessary for the development of the immune system. If the host-microbe cross talk is perturbed before birth or weaning, the immune system develops "pathological imprinting" and increased susceptibility to inflammatory pathology later in life. Reactivity to microbiota is also important in adulthood to regulate immune responses and maintain homeostasis. PMID- 29631891 TI - The impact of the intestinal microbiota in therapeutic responses against cancer. AB - Accumulating evidence points to the impact of the gut microbiota in regulating various chronic inflammatory disorders such as cancers. The intestinal microbiome is not only influencing the spontaneous course of colon malignancies but also acts at distant sterile sites of neoplasia, mostly playing a detrimental role. By providing microbial-associated molecular patterns and potentially antigens sharing molecular mimicry with tumor antigens, our commensals modulate the local and the systemic immune tonus, eventually influencing tumor microenvironment. Complicating this algorithm, therapeutic interventions alter the delicate balance between the epithelium, the microbial community, and the intestinal immunity, governing the final clinical outcome. This seminar focused on the impact of the intestinal composition on the immunomodulatory and therapeutic activities of distinct compounds (alkylating agents, platinum salts and immunotherapies) used in oncology. This research opens up "the era of anticancer probiotics" aimed at restoring gut eubiosis for a better clinical outcome in cancer patients. PMID- 29631892 TI - The potential of compounds isolated from Xylaria spp. as antifungal agents against anthracnose. AB - Anthracnose is a crop disease usually caused by fungi in the genus Colletotrichum or Gloeosporium. These are considered one of the main pathogens, causing significant economic losses, such as in peppers and guarana. The current forms of control include the use of resistant cultivars, sanitary pruning and fungicides. However, even with the use of some methods of controlling these cultures, the crops are not free of anthracnose. Additionally, excessive application of fungicides increases the resistance of pathogens to agrochemicals and cause harm to human health and the environment. In order to find natural antifungal agents against guarana anthracnose, endophytic fungi were isolated from Amazon guarana. The compounds piliformic acid and cytochalasin D were isolated by chromatographic techniques from two Xylaria spp., guided by assays with Colletotrichum gloeosporioides. The isolated compounds were identified by spectrometric techniques, as NMR and mass spectrometry. This is the first report that piliformic acid and cytochalasin D have antifungal activity against C. gloeosporioides with MIC 2.92 and 2.46MUmolmL-1 respectively. Captan and difenoconazole were included as positive controls (MIC 16.63 and 0.02MUmolmL-1, respectively). Thus, Xylaria species presented a biotechnological potential and production of different active compounds which might be promising against anthracnose disease. PMID- 29631893 TI - Illumina sequencing and assessment of new cost-efficient protocol for metagenomic DNA extraction from environmental water samples. AB - In this study, the development and assessment of a modified, efficient, and cost efficient protocol for mDNA (metagenomic DNA) extraction from contaminated water samples was attempted. The efficiency of the developed protocol was investigated in comparison to a well-established commercial kit (Epicentre, Metagenomic DNA Isolation Kit for Water). The comparison was in terms of degree of shearing, yield, purity, duration, suitability for polymerase chain reaction and next generation sequencing in addition to the quality of next-generation sequencing data. The DNA yield obtained from the developed protocol was 2.6 folds higher than that of the commercial kit. No significant difference in the alpha (Observed species, Chao1, Simpson and PD whole tree) and beta diversity was found between the DNA samples extracted by the commercial kit and the developed protocol. The number of high-quality sequences of the samples extracted by the developed method was 20% higher than those obtained by the samples processed by the kit. The developed economic protocol successfully yielded high-quality pure mDNA compatible with complex molecular applications. Thus we propose the developed protocol as a gold standard for future metagenomic studies investigating a large number of samples. PMID- 29631895 TI - Characterization of a null TPOX allele for AmpFlSTR(r) Identifiler(r) Plus kit. PMID- 29631896 TI - Comparison of long-term functional results between standard supracricoid laryngectomy and modified technique with sternohyoid muscle. AB - INTRODUCTION: Laryngeal cancer is the most common cancer of the upper respiratory tract. The main methods of treatment included surgery (partial laryngectomy and total laryngectomy) and radiation therapy. Laryngeal dysfunction is seen after both treatment modalities. OBJECTIVE: The aim of the study is to compare postoperative functional results of the standard supracricoid partial laryngectomy technique and a modified supracricoid partial laryngectomy technique using the sternohyoid muscle. METHODS: In total, 29 male patients (average years 58.20+/-9.00 years; range 41-79 years) with laryngeal squamous cell carcinoma who underwent supra cricoid partial laryngectomy were included. The patients were divided into two groups in terms of the surgical techniques. In Group A, all patients underwent standard supracricoid partial laryngectomy technique between January 2007 and November 2011. In Group B, all patients underwent modified supracricoid partial laryngectomy between August 2010 and November 2011. Fiberoptic endoscopic evaluation of swallowing test, short version of the voice handicap index scores, and the MD Anderson dysphagia inventory, the time of oral feeding and the decanulation of the patients after surgery of each groups were compared. RESULTS: The mean maximum phonation time was 8.68+/-4.21s in Group A and 15.24+/-6.16s in Group B (p>0.05). The S/Z (s/s) ratio was 1.23+/-0.35 in Group A and 1.08+/-0.26 in Group B (p>0.05); the voice handicap index averages were 9.86+/-4.77 in Group A and 12.42+/-12.54 in Group B (p>0.05); the fiberoptic endoscopic evaluation of swallowing test averages were calculated as 12.73+/-3.08 in Group A and 13.64+/-1.49 in Group B (p>0.05). In the MD Anderson dysphagia inventory, evaluation of swallowing, the emotional, physical, and functional scores were 29.21+/-4.11, 32.21+/-6.85, and 20.14+/-2.17 in the Group B, and 29.20+/-2.54, 32.4+/-4.79, and 19+/-1.92 in Group A, respectively. CONCLUSION: Although there is no statistical difference in functional outcome comparisons, if rules are adhered to in preoperative patient selection, modified supracricoid partial laryngectomy can be applied safely and meaningful gains can be achieved in functional outcomes. PMID- 29631894 TI - Variations in culturable bacterial communities and biochemical properties in the foreland of the retreating Tianshan No. 1 glacier. AB - As a glacier retreats, barren areas are exposed, and these barren areas are ideal sites to study microbial succession. In this study, we characterized the soil culturable bacterial communities and biochemical parameters of early successional soils from a receding glacier in the Tianshan Mountains. The total number of culturable bacteria ranged from 2.19*105 to 1.30*106CFUg-1dw and from 9.33*105 to 2.53*106CFUg-1dw at 4 degrees C and 25 degrees C, respectively. The number of culturable bacteria in the soil increased at 25 degrees C but decreased at 4 degrees C along the chronosequence. The total organic carbon, total nitrogen content, and enzymatic activity were relatively low in the glacier foreland. The number of culturable bacteria isolated at 25 degrees C was significantly positively correlated with the TOC and TN as well as the soil urease, protease, polyphenoloxidase, sucrase, catalase, and dehydrogenase activities. We obtained 358 isolates from the glacier foreland soils that clustered into 35 groups using amplified ribosomal DNA restriction analysis. These groups are affiliated with 20 genera that belong to six taxa, namely, Alphaproteobacteria, Betaproteobacteria, Gammaproteobacteria, Actinobacteria, Bacteroides, and Deinococcus-Thermus, with a predominance of members of Actinobacteria and Proteobacteria in all of the samples. A redundancy analysis showed that the bacterial succession was divided into three periods, an early stage (10a), a middle stage (25-74a), and a late stage (100-130a), with the total number of culturable bacteria mainly being affected by the soil enzymatic activity, suggesting that the microbial succession correlated with the soil age along the foreland. PMID- 29631897 TI - Preservation of residual hearing after cochlear implant surgery: an exploration of residual hearing function in a group of recipients at cochlear implant units. AB - INTRODUCTION: The preservation of residual hearing is becoming increasingly important in cochlear implant surgery. Conserving residual hearing is a positive prognostic indicator for improved hearing abilities. OBJECTIVE: The primary aim of the study was to explore the preservation of residual hearing following cochlear implantation in a group of recipients at two major cochlear implant centers. METHODS: A quantitative paradigm was adopted and exploratory research conducted within a retrospective data review design. The sample consisted of 50 surgical records and 53 audiological records from 60 observations (53 patients, seven of whom were implanted bilaterally). The records were selected using purposive sampling and consisted of records from participants ranging from six to 59 years of age. The average time of when the postoperative audiograms were performed in the current study was 24.7 months (s.d.=+/-9.0). Data were analyzed through both qualitative and inferential statistics and a comparative analysis of unaided pre- and postoperative audiological test results was conducted. RESULTS: Results indicated a high success rate of 92% preservation of residual hearing with half of the sample exhibiting complete preservation in cochlear implant recipients across all frequencies postoperatively. A total postoperative hearing loss was found in only 8% of cochlear implantees across all frequencies. There was no relationship between preoperative hearing thresholds and preservation of hearing postoperatively. The two main surgical techniques used in the current study were the contour on stylet and the advance off-stylet techniques, with the majority of surgeons utilizing a cochleostomy approach. From the findings, it became apparent that the majority of cases did not have any reported intraoperative complications. This is a positive prognostic indicator for the preservation of residual hearing. CONCLUSION: Findings suggest improved cochlear implant surgical outcomes when compared to previous studies implying progress in surgical techniques. The surgical skill and experience of the surgeon are evidenced by the minimal intraoperative complications and the high success rate of hearing preservation. This is a positive prognostic indicator for individuals with preoperative residual hearing as the preserved residual hearing allows for the potential of electro-acoustic stimulation, which in turn has its own hearing benefits. PMID- 29631898 TI - The effect of a geriatric evaluation on treatment decisions and outcome for older cancer patients - A systematic review. AB - AIM: The aim of this systematic review is to summarise all available data on the effect of a geriatric evaluation on the multidisciplinary treatment of older cancer patients, focussing on oncologic treatment decisions, the implementation of non-oncologic interventions and the impact on treatment outcome. METHODS: A systematic search in MEDLINE and EMBASE for studies on the effect of a geriatric evaluation on oncologic and non-oncologic treatment decisions and outcome for older cancer patients. RESULTS: 36 publications from 35 studies were included. After a geriatric evaluation, the oncologic treatment plan was altered in a median of 28% of patients (range 8-54%), primarily to a less intensive treatment option. Non-oncologic interventions were recommended in a median of 72% of patients (range 26-100%), most commonly involving social issues (39%), nutritional status (32%) and polypharmacy (31%). Effect on treatment outcome was varying, with a trend towards a positive effect on treatment completion (positive effect in 75% of studies) and treatment-related toxicity/ complications (55% of studies). CONCLUSION: A geriatric evaluation affects oncologic and non-oncologic treatment and appears to improve treatment tolerance and completion for older cancer patients. Fine-tuning the decision-making process for this growing patient population will require more specific and robust data on the effect of a geriatric evaluation on relevant oncologic and non-oncologic outcomes such as survival and quality of life. PMID- 29631899 TI - Beyond the black box of geriatric assessment: Understanding enhancements to care by the geriatric oncology clinic. AB - OBJECTIVE: Comprehensive geriatric assessment (CGA) of older adults with cancer aids treatment decision-making and prognostication. Much less is known about the supportive care elements or enhancements to care afforded by the CGA. We characterized the enhancements to care provided by a geriatric oncology clinic and determined how these vary by indication for referral. MATERIALS AND METHODS: All patients age 65 or older referred to a single academic geriatric oncology clinic between July 2015 (clinic opening) and June 2017 were included. Treatment enhancements were prospectively recorded in 5 categories: educational support, comorbidity management, symptom management, oncologic treatment delivery, and peri-operative management recommendations. Indications for referral were categorized into 3 groups: pre-treatment (n = 97, 44%), on active treatment (n = 89, 41%), and survivorship phase (n = 33, 15%). Data were analyzed using descriptive statistics and multivariable logistic regression. RESULTS: 219 patients were seen during the study period (mean age 79.7 years, 69% male). Overall, educational support (96%) and comorbidity management (95%) were the most common enhancements, whereas peri-operative management (10%) was the least common and provided only to pre-treatment patients. Enhancements to cancer treatment delivery were offered more often to patients pre-treatment than on active treatment (61% versus 41%, p < 0.001). Other enhancements to care did not vary by indication for referral. CONCLUSION: Educational support and comorbidity management are nearly universally offered. Most enhancements to care do not vary by indication for referral. Understanding the enhancements to care provided by geriatric oncology clinics can help with resource planning and program design. PMID- 29631900 TI - Posterior Vitreous Detachment as Observed by Wide-Angle OCT Imaging. AB - PURPOSE: Posterior vitreous detachment (PVD) plays an important role in vitreoretinal interface disorders. Historically, observations of PVD using OCT have been limited to the macular region. The purpose of this study is to image the wide-angle vitreoretinal interface after PVD in normal subjects using montaged OCT images. DESIGN: An observational cross-sectional study. PARTICIPANTS: A total of 144 healthy eyes of 98 normal subjects aged 21 to 95 years (51.4+/-22.0 [mean +/- standard deviation]). METHODS: Montaged images of horizontal and vertical OCT scans through the fovea were obtained in each subject. MAIN OUTCOME MEASURES: Montaged OCT images. RESULTS: By using wide-angle OCT, we imaged the vitreoretinal interface from the macula to the periphery. PVD was classified into 5 stages: stage 0, no PVD (2 eyes, both aged 21 years); stage 1, peripheral PVD limited to paramacular to peripheral zones (88 eyes, mean age 38.9+/-16.2 years, mean +/- standard deviation); stage 2, perifoveal PVD extending to the periphery (12 eyes, mean age 67.9+/-8.4 years); stage 3, peripapillary PVD with persistent vitreopapillary adhesion alone (7 eyes, mean age 70.9+/-11.9 years); stage 4, complete PVD (35 eyes, mean age 75.1+/-10.1 years). All stage 1 PVDs (100%) were observed in the paramacular to peripheral region where the vitreous gel adheres directly to the cortical vitreous and retinal surface. After progression to stage 2 PVD, the area of PVD extends posteriorly to the perifovea and anteriorly to the periphery. Vitreoschisis was observed in 41.2% at PVD initiation (stage 1a). CONCLUSIONS: Whereas prior work suggests that PVD originates in the perifoveal region and after the sixth decade, our observations demonstrate that (1) PVD first appears even in the third decade of life and gradually appears more extensively throughout life; (2) more than 40% of eyes without fundus diseases at their PVD initiation are associated with vitreoschisis; and (3) PVD is first noted primarily in the paramacular-peripheral region where vitreous gel adheres to the retinal surface and is noted to be more extensive in older ages to ultimately involve the fovea. PMID- 29631901 TI - Contact Lens Correction of Aphakia in Children: A Report by the American Academy of Ophthalmology. AB - PURPOSE: To review the published literature to assess the visual outcomes and adverse events associated with the 2 most commonly used contact lenses for treating aphakia in children: silicone elastomer (SE) and rigid gas permeable (RGP). METHODS: Literature searches were last conducted in January 2018 in the PubMed, Cochrane Library, and ClinicalTrials.gov databases with no date or language restrictions. These combined searches yielded 167 citations, 27 of which were reviewed in full text. Of these, 10 articles were deemed appropriate for inclusion in this assessment and subsequently assigned a level of evidence rating by the panel methodologist. RESULTS: The literature search identified 4 level II studies and 6 level III studies. There were insufficient data to compare visual outcomes for eyes treated using SE lenses versus RGP lenses. Silicone elastomer lenses have the advantage that they can be worn on an extended-wear basis, but they were associated with more adverse events than RGP lenses. These adverse events included microbial keratitis, corneal infiltrates, corneal edema, corneal scars, lenses adhering to the cornea, superficial punctate keratopathy, lid swelling, and conjunctival hyperemia. The lens replacement rate was approximately 50% higher for RGP lenses in the only study that directly compared SE and RGP lenses. CONCLUSIONS: Limited evidence was found in the literature on this topic. Silicone elastomer and RGP contact lenses were found to be effective for treating aphakia in children. Silicone elastomer lenses are easier to fit and may be worn on an extended-wear basis. Rigid gas permeable lenses must be removed every night and require a more customized fit, but they are associated with fewer adverse events. The choice of which lens a practitioner prescribes should be based on the particular needs of each patient. PMID- 29631903 TI - Laparoscopic distal gastrectomy for clinical stage I gastric adenocarcinoma: Techniques evolution and oncological outcomes of the first 100 cases. AB - BACKGROUND/PURPOSE: While gaining more acceptance, the use of laparoscopic distal gastrectomy (LDG) to treat gastric cancer were still limited in Taiwan. This study reviewed our experience about the technique evolution and outcome of using LDG for the patients with clinical stage (c-stage) I gastric cancers. METHODS: A retrospective review of the patients undergoing LDG for c-stage I gastric cancers at a medical center of Taiwan was performed. The demographics, peri-operative parameters, reconstruction methods, morbidities, pathologic and oncological outcomes were analyzed. RESULTS: A total of 100 patients with c-stage I gastric cancers between October 2005 and September 2016 were enrolled. Laparoscopy assisted distal gastrectomy (LADG) was performed in the initial 69 cases. Total laparoscopic distal gastrectomy (TLDG) was done in the following 31 cases. There was no conversion of procedures, nor surgical mortality. The surgical morbidity rate was 13%, including 3 major complications. The ratio of using Billroth I reconstruction (83.9% versus 43.5%, p < 0.01) and the mean number of harvested lymph nodes (38.6 +/- 14.8 versus 31.2 +/- 15.2, p = 0.02) were both higher in the TLDG group than in the LADG group. The pathologic examination confirmed 78 patients were stage I, while 22 were stage II disease. Seven of the 24 patients with lymph node metastasis received adjuvant chemotherapy. Two patients had recurrence of diseases. The 3-year recurrence-free and overall survival were 93.3% and 95.8% separately. CONCLUSION: These results suggested that laparoscopic gastrectomy could be performed safely and feasibly for patients with early gastric cancers. LADG is recommended for the establishment of the demanding technique. PMID- 29631902 TI - Transcription factor 7-like 2 gene links increased in vivo insulin synthesis to type 2 diabetes. AB - Transcription factor 7-like 2 (TCF7L2) is the main susceptibility gene for type 2 diabetes, primarily through impairing the insulin secretion by pancreatic beta cells. However, the exact in vivo mechanisms remain poorly understood. We performed a family study and determined if the T risk allele of the rs7903146 in the TCF7L2 gene increases the risk of type 2 diabetes based on real-time stable isotope measurements of insulin synthesis during an Oral Glucose Tolerance Test. In addition, we performed oral minimal model (OMM) analyses to assess insulin sensitivity and beta cell function indices. Compared to unaffected relatives, individuals with type 2 diabetes had lower OMM indices and a higher level of insulin synthesis. We found a T allele-dosage effect on insulin synthesis and on glucose tolerance status, therefore insulin synthesis was higher among T-allele carriers with type 2 diabetes than in wild-type individuals. These results suggest that hyperinsulinemia is not only an adaptation to insulin resistance, but also a direct cause of type 2 diabetes. PMID- 29631904 TI - Corrigendum to 'Investigation of 8-OHdG, CYP1A, HSP70 and transcriptional analyses of antioxidant defence system in liver tissues of rainbow trout exposed to eprinomectin' [Fish & Shellfish Immunology 65 (2017) 136-144]. PMID- 29631905 TI - Pattern of use of clozapine in Spain. Variability and under-prescription. AB - INTRODUCTION: International studies on clozapine use usually show lower than expected prescription proportions, under-dosing and delayed initiation of treatment, which has led to a number of initiatives aimed at improving its use and reducing the striking variability observed among practitioners. There are no similar studies on the Spanish population. Therefore we planned initial data collection from 4 territorial samples. We hypothesized that clozapine prescription would also be low and variable in our country. If this hypothesis were confirmed, a reflection on possible strategies would be necessary. MATERIAL AND METHODS: We accessed data on clozapine prescription in Catalonia, Castile and Leon, the Basque Country and the Clinical Management Area of the Hospital 12 de Octubre (Madrid). RESULTS: Patients diagnosed with schizophrenia under treatment in these territories comprise around .3% of their total population; treatment with clozapine ranges between 33.0 and 57.0 per 10000 inhabitants; patients diagnosed with schizophrenia on current treatment with clozapine range between 13.7% and 18.6% of the total number of patients with this diagnosis. The coefficient of variation between centres and prescribers is often higher than 50%. CONCLUSIONS: Although below the figures suggested as desirable in the literature, global prescribing data for clozapine in the areas we studied are not as low as the data collected in other international studies, and are in the range of countries in our environment. However, the variability in prescription is large and apparently not justified; this heterogeneity increases as we focus on smaller areas, and there is great heterogeneity at the level of individual prescription. PMID- 29631906 TI - Corrigendum to "Atg7 Activates an Autophagy-Essential Ubiquitin-like Protein Atg8 through Multi-step Recognition" [J. Mol. Biol. 430 (3) (Feb 2, 2018) 249-257]. PMID- 29631907 TI - Efficacy and Tolerability of Second-line Nab-paclitaxel and Gemcitabine After Failure of First-line FOLFIRINOX for Advanced Pancreas Cancer: A Single institution Experience. AB - BACKGROUND: Advanced pancreatic cancer (APC) has a poor prognosis. Current first line chemotherapy options include FOLFIRINOX (5-fluorouracil, irinotecan, oxaliplatin), NG (nab-paclitaxel, gemcitabine), and GEM (gemcitabine) alone. The optimal second-line regimen is unclear. For patients with disease progression with FOLFIRINOX who have a good performance status, NG might be a reasonable second-line option. PATIENTS AND METHODS: Patients in whom APC was diagnosed from 2012 to 2016 who underwent chemotherapy at CancerCare Manitoba were identified from the Manitoba Cancer Registry. Pharmacy records were used to identified those patients who had received first-line FOLFIRINOX, followed by second-line NG, GEM alone, or best supportive care. A retrospective analysis was performed to identify the patient and treatment characteristics, toxicity, radiologic response, and survival. Edmonton Symptom Assessment System, revised, scores were analyzed to assess symptom control. RESULTS: A total of 146 patients had received first-line FOLFIRINOX. Of those with disease progression who were offered second line therapy, 30 received NG, 8 GEM alone, and 22 best supportive care. NG was more toxic than GEM alone; however, the dose intensity was similar between the 2 groups. The median progression-free survival was 3.61 months in the NG group and 2.51 months in the GEM-alone group. The median overall survival was 5.69 months in the NG group and 3.82 months in the GEM-alone group. No significant differences were found in the Edmonton Symptom Assessment System, revised, scores when stratified by the treatment received. CONCLUSION: For select patients with APC in whom first-line FOLFIRINOX fails, a role might exist for second-line NG. In our institution, second-line NG was associated with improvement in survival compared with second-line GEM alone, with a manageable toxicity profile. PMID- 29631908 TI - External validation of the Cairns Prediction Model (CPM) to predict conversion from laparoscopic to open cholecystectomy. AB - BACKGROUND: Valid and user-friendly prediction models for conversion to open cholecystectomy allow for proper planning prior to surgery. The Cairns Prediction Model (CPM) has been in use clinically in the original study site for the past three years, but has not been tested at other sites. METHODS: A retrospective, single-centred study collected ultrasonic measurements and clinical variables alongside with conversion status from consecutive patients who underwent laparoscopic cholecystectomy from 2013 to 2016 in The Townsville Hospital, North Queensland, Australia. An area under the curve (AUC) was calculated to externally validate of the CPM. RESULTS: Conversion was necessary in 43 (4.2%) out of 1035 patients. External validation showed an area under the curve of 0.87 (95% CI 0.82 0.93, p = 1.1 * 10-14). CONCLUSIONS: In comparison with most previously published models, which have an AUC of approximately 0.80 or less, the CPM has the highest AUC of all published prediction models both for internal and external validation. PMID- 29631909 TI - Safety and feasibility of single-port laparoscopic low anterior resection for upper rectal cancer. AB - BACKGROUND: Single-port surgery for rectal cancer is challenging and controversial. The aim of this study was to compare the short-term outcomes of single-port laparoscopic low anterior resection (S-LAR) to multi-port laparoscopic low anterior resection (M-LAR) for upper rectal cancer. METHODS: From January 2011 to December 2015, a total of 93 patients who underwent S-LAR (n = 44) or M-LAR (n = 49) without protective diverting ileostomy for upper rectal cancer were identified. Tumors were located between the inferior margin of the second sacral vertebra and the peritoneal reflection. Short-term outcomes were compared between groups. RESULTS: S-LAR was successful in 75% of cases: 25% of cases required one additional port. Operative factors, perioperative outcomes, oncological outcomes did not differ significantly between groups. In patients with stage I-III disease, the 3-year relapse-free survival rate was significantly higher in the S-LAR group than in the M-LAR group (p = 0.032). The 3-year overall survival rate was similar between groups. CONCLUSIONS: S-LAR is safe, feasible and can provide satisfactory oncological outcomes in selected patients with upper rectal cancer. PMID- 29631910 TI - Recent Advances in the Pathogenesis of Mucormycoses. AB - PURPOSE: The purposes of this review are to describe the pathogenesis of mucormycosis and to address recent research advances in understanding the mechanisms of fungal invasion and dissemination. METHODS: Studies and reviews published in the PubMed and ClinicalTrials.gov databases until December 2017 that explored or reported recent advances in the understanding of the pathogenesis of mucormycosis were reviewed. FINDINGS: To cause disease, fungal spores need to evade the innate immune system and germinate, leading to angioinvasion and tissue destruction. Recent studies have found that Mucorales are able to downregulate several host defense mechanisms and have identified the specific receptors through which Mucorales attach to the endothelium, facilitating their endocytosis and subsequent angioinvasion. In addition, certain conditions found to act through various mechanisms and pathways in experimental and animal studies, such as hyperglycemia, elevated iron concentrations, and acidosis (particularly diabetic ketoacidosis), increase the virulence of the fungi and enhance their attachment to the endothelium, rendering patients with uncontrolled diabetes and patients with iron overload susceptible to mucormycosis. The role and various antifungal functions of platelets and natural killer cells are highlighted, and the potential contribution of alternative therapies, such as manipulating the innate immune host defenses with granulocyte transfusions or administration of growth factors and using the antifungal effects of calcineurin inhibitors, are presented. Finally, directions and possible implications for future research are provided. IMPLICATIONS: This article provides a comprehensive overview of research advances in the pathogenesis of infections caused by Mucorales and helps future studies develop effective treatment strategies and improve patient outcomes. PMID- 29631911 TI - Phytochemical characterization of polyphenolic compounds with HPLC-DAD-ESI-MS and evaluation of lipid-lowering capacity of aqueous extracts from Saharan plant Anabasis aretioides (Coss & Moq.) in normal and streptozotocin-induced diabetic rats. AB - OBJECTIVE: Anabasis aretioides (Coss & Moq.), a Saharan plant belonging to Chenopodiaceae family, is widely distributed in semi-desert areas from the Tafilalet region of Morocco. This plant is extensively used by local population against diabetes and cardiovascular disorders. The purpose of the study was to investigate the effect of the aqueous A. aretioides extract on lipid metabolism in normal and streptozotocin (STZ)-induced diabetic rats and to identify the polyphenolic compounds present. In addition, the in vitro antioxidant activity of the aqueous A. aretioides extract was also evaluated. METHODS: The effect of an aerial part aqueous extract (APAE) of A. aretioides (5 mg/kg of lyophilized A. aretioides APAE) on plasma lipid profile was investigated in normal and STZ induced diabetic rats (n = 6) after once daily oral administration for 15 days. The aqueous extract was tested for its 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging activity. Polyphenolic compounds in the extracts were definitively characterized by high-performance liquid chromatography-diode array detection-electrospray ionization-mass spectrometry. RESULTS: In diabetic rats, oral administration of A. aretioides APAE provoked a significant decrease in both plasma cholesterol and triglyceride levels from the first to the second week (P < 0.01). A significant decrease on plasma triglyceride levels was also observed in normal rats (P < 0.01), where the reduction was 53%. In addition, the phytochemical analysis revealed the presence of 12 polyphenolic compounds. Moreover, according to the DPPH radical-scavenging activity, the aqueous extract showed an in vitro antioxidant activity. CONCLUSION: Aqueous A. aretioides APAE exhibits lipid-lowering and in vitro antioxidant activities. Many polyphenols were present in this extract and these phytoconstituents may be involved in the pharmacological activity of this plant. PMID- 29631912 TI - Postsurgical complications in patients with renal tumours with venous thrombosis treated with surgery. AB - BACKGROUND AND OBJECTIVE: Surgery on renal tumours with venous thrombosis suffers a high rate of complications and non-negligible perioperative mortality. Our objective was to analyse the postoperative complications, their relationship with the level of the thrombus and its potential predisposing factors. MATERIALS AND METHODS: A retrospective analysis was conducted of 101 patients with renal tumours with venous thrombosis operated on between 1988 and 2017. Two patients were excluded because of intraoperative pulmonary thromboembolism and exitus (2%). The postsurgical complications were classified according to Clavien-Dindo. To compare the qualitative variables, we employed the chi-squared test. We performed a multivariate analysis using binary logistic regression to identify the independent predictors. RESULTS: Some type of postsurgical complication occurred in 34 (34.3%) patients, 11 (11.1%) of which were severe (Clavien III-V). There were significant differences in the total complications (P=.003) and severe complications (Clavien>=III; P=.03) depending on the level of the tumour thrombus. PMID- 29631913 TI - Long-term oncological results of treatment for high-risk prostate cancer using radical prostatectomy in a cancer hospital. AB - OBJECTIVES: To analyse the most relevant oncologic results of treatment using radical prostatectomy (RP) for high-risk prostate cancer (HRPC) in a specialist cancer hospital. MATERIAL AND METHODS: A descriptive retrospective study of RP was conducted at our centre from 1986 to 2017 on HRPC whose primary objective was to determine overall survival (OS) and cancer-specific survival (CSS). The study's secondary objectives were to determine biochemical progression-free survival (BPFS), metastasis-free survival (MFS), rescue therapy-free survival (RTFS), hormone therapy-free survival (HTFS) and the development of castration resistant prostate cancer. We performed a Cox regression analysis to establish predictive models and to better understand the weight of each variable that defines high risk. RESULTS: A total of 2093 RPs were performed, 480 (22.9%) of which were for HRPC. The median follow-up for the overall series was 79.57 months (P25-75 37.92-135.16). Lymphadenectomy was not performed in 6.5% of the cases. The lymphadenectomy was of the obturator type in 51.2% of the cases and extended in 42.3%. Overall survival at 5, 10 and 15 years was 89.8% (95% CI 86.7-92.9%), 73.3% (95% CI 68-78.6%) and 51.4% (95% CI 43.8-59%), respectively. CSS at 5, 10 and 15 years was 94.8% (95% CI 92.4-97.2%), 84.0% (95% CI 79.3-88.7%) and 75.5% (95% CI 68.8-82.2%), respectively. MFS at 5, 10 and 15 years was 87.4% (95% CI 84.1-90.7%), 72.2% (95% CI 66.7-77.7%) and 61.7% (95% CI 54.3-69.1%), respectively. A total of 120 patients of 477 analysed (25.1%) required rescue radiation therapy, and 293/477 never required hormone therapy (61.4%). Of the 93 pN1 patients, 33 (35.5%) did not require hormone therapy. The time from RP to biochemical progression was the variable with the greatest prognostic weight for MFS, CSS and overall survival. CONCLUSIONS: RP plus extended lymphadenectomy should be the first therapeutic manoeuvre when feasible within a multimodal strategy. A longer follow-up of the series is needed to validate the hypothesis of better oncologic results based on the earlier implementation of rescue radiation therapy, extended lymphadenectomy and drugs that prolong survival in the CRPC phase. PMID- 29631914 TI - hTERT mRNA expression in urine as a useful diagnostic tool in bladder cancer. Comparison with cytology and NMP22 BladderCheck Test(r). AB - INTRODUCTION: To study the relationship between quantitative mRNA determination (hTERT) in patients with bladder tumor, history of bladder tumor, and in subjects without a history of this neoplasia. MATERIAL AND METHODS: A prospective randomized controlled study with 91 subjects included. The value of mRNA-hTERTN was determined in 63 patients with a history or suspicion of bladder tumor and in 28 controls. Urine samples were sent for evaluation of the mRNA level (hTERT), the cytological study and the NMP22 result. RESULTS: Differences were observed in mean hTERTN levels in each of the groups: tumor presence 21.33+/- 40.66, tumor history 2.16+/- 2.67, controls 0.9+/- 1, 75 (p<0.001). In patients with tumor, there was no difference in mean hTERTN levels between the different grades and stages, although there was a tendency: low grade tumor 9.04+/- 16.95, high grade 28.95+/- 48.36 (p=.069), stage Ta 10.33+/- 19.39, T1 17.88+/- 27.14, T2 54.8+/- 74.05 (p=.056). In addition, the sensitivity of hTERTN was superior to that of other test (76%), although specificity and positive and negative predictive values were better for cytology (94%, 88.4% and 72.3% respectively) and NMP22 (88%, 80.6% and 73.3% respectively). CONCLUSIONS: hTERTN mRNA levels in urine were higher in patients with bladder tumors compared to patients with a history of bladder tumor and with negative cystoscopy, as well as in the control group. This determination showed a higher diagnostic yield compared with the detection of NMP22 and urinary cytology. PMID- 29631915 TI - A two-step approach for mining patient treatment pathways in administrative healthcare databases. AB - Clustering electronic medical records allows the discovery of information on healthcare practices. Entries in such medical records are usually composed of a succession of diagnostics or therapeutic steps. The corresponding processes are complex and heterogeneous since they depend on medical knowledge integrating clinical guidelines, the physician's individual experience, and patient data and conditions. To analyze such data, we are first proposing to cluster medical visits, consultations, and hospital stays into homogeneous groups, and then to construct higher-level patient treatment pathways over these different groups. These pathways are then also clustered to distill typical pathways, enabling interpretation of clusters by experts. This approach is evaluated on a real-world administrative database of elderly people in Quebec suffering from heart failures. PMID- 29631916 TI - Conformational changes of antibodies upon adsorption onto hydrophobic interaction chromatography surfaces. AB - Differential scanning calorimetry was established for in-situ measurement of the transition temperatures of antibodies when adsorbed on hydrophobic interaction chromatography media. This method is also suitable for non-transparent media, which is an advantage over spectroscopic methods that cannot be used in many cases due to large background signals. The three transition temperatures of an antibody were lowered when the molecule was adsorbed onto Phenyl and Butyl functionalized Toyopearl particles as well as on Phenyl Sepharose 6 Fast Flow when bound at moderate to high salt concentration compared to the values in free solution. The first two melting points, representing the CH2 domain and the Fab fragment, are more affected than the highest melting point, which corresponds to the CH3 domain. It is obvious that domains which are less stable are more likely to undergo conformational change upon adsorption. It could be shown that the conformational changes occurring in antibodies upon adsorption to HIC media are directly proportional to the hydrophobicity of the stationary phase and that they are reversible. Upon elution, the protein returns to its original conformation. For all four tested resins, a negative value for both DeltaH as well as DeltaS was calculated, leading to opposing contributions to DeltaG. PMID- 29631917 TI - [Editorial]. PMID- 29631918 TI - Histopathology of locally advanced colorectal carcinoma, with emphasis on tumor invasion of adherent peritoneal membranes. AB - Locally advanced colorectal carcinomas are characterized by neoplastic cells that invade beyond the colon and directly into surrounding organs and structures that include the retroperitoneum and abdominopelvic sidewall. These aggressive tumors are prognostically adverse and are categorized with highest possible tumor stage in current cancer staging systems. Recognizing colorectal carcinoma with extensive locoregional invasion is typically straightforward, but some cases can be diagnostically challenging. These include tumors with limited invasion of extracolonic tissue such as the subserosa in which there are no cells or structures that are histologically or architecturally distinct from the colonic primary. Tumor-associated injury of the colonic peritoneum often precedes invasion by the neoplastic cells and can cause the peritoneal membrane of the colon to adhere and subsequently fuse to the peritoneal membrane of a neighboring organ or structure, thereby creating a trans-peritoneal bridge through which a tumor can directly invade the adherent extracolonic tissue. Hence, locally advanced colorectal carcinoma can be narrowly defined by neoplastic cells that completely invade through the fused peritoneal membrane and into the subserosa of the adherent extracolonic tissue. The evaluation of tumor invasion of the fused peritoneal membrane, which is enhanced by the combined use of an elastic stain and an immunostain for pan-keratin, is essential for the proper staging of locally advanced colorectal carcinoma and its clinical management. PMID- 29631919 TI - MR-guided laser ablation for the treatment of hypothalamic hamartomas. AB - Hypothalamic hamartoma is an archetypal example of subcortical epilepsy that can be associated with intractable gelastic epilepsy, secondary epilepsy, and epileptic encephalopathy. The history of its surgical treatment is fraught with mislocalization of the seizure focus, modest efficacy and a high complication rate. Many minimally invasive techniques have been described to mitigate this high complication profile of which MR-guided laser ablation is one. The technology combines instant effect of thermal coagulation with stereotactic precision and guidance with real time MR thermography. This article presents a series of 71 hypothalamic hamartoma patients operated with laser ablation. Ninety three percent (93%) were free of gelastic seizures at one year with 23% of the patients requiring more than one ablation. One patient experienced a significant memory deficit and one patient experienced worsening diabetes insipidus. Stereotactic laser ablation appears to be a safe and effective surgical option in the treatment of hypothalamic hamartoma. PMID- 29631920 TI - Guided self-help for mental health disorders in children and young people with chronic neurological conditions: A qualitative evaluation. AB - OBJECTIVE: Children with neurological conditions such as epilepsy are at high risk of developing mental health disorders. Guided self-help can be used to increase access to psychological therapies. When developing and evaluating interventions, it is important to obtain the views of service-users about their acceptability. A telephone-guided self-help intervention was used to treat common mental health difficulties in children and young people with neurological conditions. The intervention was not adapted in content to account for chronic illness. This study therefore reports on qualitative interviews with participants to determine the acceptability of the intervention. METHODS: Semi-structured interviews were conducted with 27 participants (25 parents and 2 young people) who had undertaken a telephone-delivered guided self-help intervention for common mental health difficulties in the context of a paediatric neurological condition. Transcripts were analysed thematically using the framework approach. RESULTS: Thirteen themes were extracted, organised into three main domains, which covered: the practicalities of telephone guided self-help treatment; the outcomes of the intervention; and the extent to which adaptation was needed for chronic illness. Most families found the intervention helpful in working towards their specific goals and noticed changes for the child and/or parents and family. CONCLUSIONS: Participants had a positive experience of the intervention and the majority of parents found the standard intervention with individualised goals sufficient to meet the young person's mental health needs. PMID- 29631921 TI - RapidRhino herniation causing airway obstruction. AB - Epistaxis is commonly managed with RapidRhino in emergency departments. We report a case of RapidRhino herniation during air inflation in a 99-year-old female, leading to significant airway obstruction. Upon re-inflation of the RapidRhino for persistent epistaxis, our patient suddenly developed acute respiratory distress. Throat examination revealed a large clot-like circular mass occluding the oropharynx. Initially mistaken as a massive blood clot, the mass was identified as the distal end of the RapidRhino. Immediate deflation of the RapidRhino results in spontaneous resolution of the respiratory distress. We hypothesise that the RapidRhino has herniated posteriorly into the oropharynx through excessive air inflation, potentially compounded by a product defect. Our case highlights a fatal consequence of RapidRhino application where emergency physicians should be cautious of, especially among inexperienced users. PMID- 29631922 TI - Should paramedics use automated external defibrillators? Preliminary data. PMID- 29631923 TI - Consequences of the 48-h rule: A lens into the psychiatric patient flow through an emergency department. AB - OBJECTIVE: Psychiatric patient boarding in emergency department (ED) is a severe and growing problem. In July 2013, Minnesota implemented a law requiring jailed persons committed to state psychiatric facilities be transferred within 48-h of commitment. This study aims to quantify the effect of this law on a large ED's psychiatric patient flow. METHODS: A pre- and post- comparison of 2011-2015 ED length of stay (LOS) for adult psychiatric patients was performed using electronic medical record data. Comparisons of the median LOS were assessed using a segmented regression model with time series error, and risk differences (RD) were used to determine changes in the proportion of patients with LOS >=3 and >=5days. Changes in patient disposition proportions were assessed using risk ratios. RESULTS: The median ED LOS for patients admitted for psychiatric care increased by 5.22h from 2011 to 2015 (95% CI: (4.33, 7.15)), while the frequency of patient encounters remained constant. Although no significant difference in the rate of ED LOS increase was found pre- and post- implementation, the proportion of adults with LOS >=3days and >=15days increased (RD 0.017 (95% CI: (0.013, 0.021)); 0.002 (95% CI: (0.001,0.004)), respectively). CONCLUSIONS: The proportion of ED adult psychiatric patients experiencing prolonged LOS increased following the implementation of a statewide law requiring patients committed through the criminal justice system be transferred to a state psychiatric hospital within 48h. Identifying characteristics of subsets of psychiatric patients disproportionally affected could suggest focused healthcare system improvements to improve ED psychiatric care. PMID- 29631924 TI - Cardiopulmonary resuscitation on television: The TVMD study. PMID- 29631925 TI - Management of hypercalcaemic crisis in adults: Current role of renal replacement therapy. AB - : Neoplasms and hematologic diseases are the predominant etiologies of hypercalcemic crisis in adults and the immediate treatment is mainly medical and symptomatic. The use of renal replacement therapy (RRT) is often necessary to correct the hypercalcemia, uremia and electrolyte disturbances related to Acute Kidney Injury (AKI). The aim of this work was to determine the etiologies and the place of RRT in treating patients with hypercalcaemic crisis. We conducted a retrospective study for 36months at the Nephrology Unit, University Hospital, Oujda, eastern of Morocco. We included all adult patients diagnosed with hypercalcemic crisis that was defined as corrected total serum calcium of >3.5mmol/l. RESULTS: 12 patients were collected. All patients were female and 5 patients were elderly (>=65years). Three patients had a serum calcium value of >4mmol/l and the highest calcium value was 5.8mmol/l. Electrocardiographic abnormalities were observed in 8 cases. AKI was observed in 8 cases. Three patients had chronic kidney disease on hemodialysis. Neoplasm was noted in 9 cases. All patients received venous rehydration, glucocorticoids and biphosphonates. The use of RRT with low calcium dialysate was performed in 11 cases. Three patients died during the first 24h of hospitalization. CONCLUSION: RRT must play its full role as first line treatment of hypercalcemia crisis. Improvements in hemodialysis techniques and the use of low calcium or calcium free dialysates currently allows this therapeutic measure to be prescribed safely, and the benefit-risk balance is positive for the great benefit provided by dialysis. PMID- 29631926 TI - What Is Health Services Research? PMID- 29631927 TI - Radiology "Hits Refresh" with Artificial Intelligence. PMID- 29631928 TI - Musculoskeletal Radiology Fellowship Application and Selection Process: Perceptions of Residents, Fellows, and Fellowship Directors. AB - RATIONAL AND OBJECTIVES: This study aimed to assess resident, fellow, and fellowship director perceptions of the musculoskeletal (MSK) radiology fellowship application process. MATERIALS AND METHODS: A task group constructed three surveys with questions about current and "ideal" fellowship application and selection processes. Surveys were distributed to MSK fellowship directors, who were also asked to give separate surveys to current fellows. US and Canadian radiology residency directors were asked to distribute surveys to current R3 and R4 residents. Responses were tabulated and analyzed. RESULTS: Responses were received from 47 MSK fellowship directors, 73 MSK fellows, and 147 residents. Fellowship directors and fellows reported that most fellowship offers occur between July and September of the R3 year, although 19% of directors made offers as early as the R2 year. Of the 43 director respondents, 31 (72%) noted "pressure from other programs" as the main driving force behind their policies, but 28 (65%) felt that their timelines were "too early." A formal match was supported by 55% of responding fellowship directors, 57% of fellows, and 61.9% of residents, citing "fairness" as a major justification. CONCLUSIONS: MSK radiology fellowship selection occurs as early as the R2 year, before many residents have had substantial exposure to different subspecialties. An "arms race" has developed with programs moving their timelines earlier in response to the actions of other programs, presumably to avoid missing the best candidates. Although a majority of respondents would support a formalized match to increase fairness, there is not universal agreement that it would be the best approach. PMID- 29631929 TI - First case of renal abscess by Parvimonas micra. PMID- 29631930 TI - Molecular characterization of OXA-48 carbapenemase-producing Klebsiella pneumoniae strains after a carbapenem resistance increase in Catalonia. AB - INTRODUCTION: To characterize OXA-48 carbapenemase-producing Klebsiella pneumoniae strains isolated after an increase in carbapenem resistance in Catalonia. METHODOLOGY: K. pneumoniae identification, antimicrobial susceptibility studies, the Modified Hodge Test method, amplification of antimicrobial resistance genes (against beta-lactamases, quinolones and aminoglycosides), molecular typing (by PFGE and MLST), conjugation assays, plasmid characterization (PBRT-PCR and Southern blot), a description of mobile genetic elements and statistical analysis were done. RESULTS: OXA-48 was the only carbapenemase detected, with a prevalence of 1.9%. The blaOXA-48 gene was located in an IncL conjugative plasmid of 62kb and integrated into the transposons Tn1999.2 (91.7%) or Tn1999.1. Five PFGE profiles (A to E) were found, which exactly matched the MLST: ST101, ST17, ST1233, ST14 and ST405, respectively. ST1233 is described here for the first time. K. pneumoniae OXA-48-producing strains were also CTX-M-15 carriers, some producing OXA-1 and TEM-1 penicillinases. The acquired qnrB66 and qnrB1 and aac(3')-IIa, aac(6')-Ib genes were also identified. CONCLUSION: The K. pneumoniae ST405 clone has played an important role in the growing prevalence of OXA-48 in Catalonia. All clones described preserved the blaOXA-48 genetic environment and mobile genetic elements (Tn1999). Notably, the three strains with minor sequence types in this study are not multiresistant strains. These strains are expanding in elderly patients (average age of 76 years) with serious underlying diseases, mainly women (61.2%). PMID- 29631931 TI - Beyond Homophobia: How Do Jamaican Men Who Have Sex with Men Build Communities, Affirm Identity, and Mitigate Homophobia? AB - Jamaican men who have sex with men (MSM) have experienced widespread stigma and discrimination. Much of the research on Jamaican MSM has focused on HIV risk behaviors. We examined the social and romantic relationships of Jamaican MSM and how these factors fostered a sense of community in an antihomosexual environment. Qualitative in-depth interviews were conducted with 30 MSM ages 18 to 29 years. Women and familial matriarchal figures were more likely to accept someone identified as homosexual and provide protection against homophobia. Jamaican MSM affirmed their identity by providing emotional support and safe spaces, which aided in building a sense of community. Relationships with friends and intimate partners were a source of love and validation as opposed to simply sexual gratification. The social and romantic relationships of Jamaican MSM transcended the social boundaries of homophobia, affirmed sexual identity and orientation, and served as facilitators across most general societal and cultural interactions. PMID- 29631932 TI - Role of adjuvant external beam radiotherapy and chemotherapy in one versus two or more node-positive vulvar cancer: A National Cancer Database study. AB - BACKGROUND AND PURPOSE: Inguinal lymph node involvement is considered the most important prognostic risk factor for survival in vulvar cancer. However, controversy exists concerning the optimal adjuvant therapy for node-positive disease. This study sought to identify the optimal adjuvant therapy for each subset of women with node-positive disease. MATERIAL AND METHODS: The National Cancer Database (NCDB) was queried to identify women with inguinal node positive vulvar cancer. Survival analysis was performed using log-rank test, the Kaplan Meier estimates, and Cox proportional hazards to both clarify prognosis and identify the benefit of each treatment modality in individual subsets of women. RESULTS: A total of 2779 women with inguinal node positive vulvar cancer were identified. On multivariate Cox model hazard ratio, radiotherapy yielded a survival advantage for women with one positive node (HR 0.81, p = 0.027) and two or more positive nodes (HR = 0.59, p < 0.001). The addition of chemotherapy to radiotherapy yielded an incremental improvement in survival for women with 2 or more positive nodes (HR = 0.79, p = 0.022) but not women with 1 positive node (HR = 0.93, p = 0.605). CONCLUSIONS: All patients with node positive disease benefited from radiotherapy. By contrast, only those with 2 or more positive nodes benefited from the addition of chemotherapy to radiotherapy. PMID- 29631933 TI - Physician assessed and patient reported lower limb edema after definitive radio(chemo)therapy and image-guided adaptive brachytherapy for locally advanced cervical cancer: A report from the EMBRACE study. AB - BACKGROUND/PURPOSE: To evaluate the pattern of manifestation and risk factors for lower limb edema (LLE) within the prospective, observational, multi-center EMBRACE study on radiochemotherapy and MRI-guided brachytherapy in locally advanced cervical cancer (LACC). MATERIAL/METHODS: LLE was prospectively assessed according to the physician-reported CTCAE v.3 and patient-reported EORTC QLQ-CX24 questionnaire at baseline and regular follow-up. RESULTS: In total, 1176 patients were evaluated with a median follow-up of 27 months. Actuarial analyses revealed 3/5-year estimates of 27%/31% of CTCAE G >= 1, 6.1%/6.6% of G >= 2 and 0.5%/0.5% for G >= 3. Prevalence rates for G >= 1 LLE at 3 months, 1, 3 and 5 years after end of treatment were 7%, 12%, 12%, 15% for physician-assessed and 25%, 30%, 30%, 34% for any patient-reported symptoms and showed a steady increase over time. Invasive lymph node staging and obesity at diagnosis are independent significant risk factors for G >= 1 LLE, whereas nodal boost has no impact. Extended radiation fields including para-aortic and/or inguinal nodes show a tendency to increase the risk. CONCLUSION: Severe LLE after definitive radiochemotherapy in LACC is rare. However, the risk for mild LLE is considerable, and related to patient-, diagnostic- and treatment characteristics. Less invasive diagnostic surgical procedures or non-invasive assessment, less invasive radiotherapy management and active rehabilitation are important pathways for future developments. PMID- 29631934 TI - A contemporary analysis of radiotherapy effect in surgically treated retroperitoneal sarcoma. AB - BACKGROUND AND PURPOSE: Contemporary data regarding the benefit of radiotherapy in surgically treated retroperitoneal sarcoma are scarce. The aim of the study was to evaluate the effect of radiotherapy on cancer specific mortality in surgically treated patients according to tumor size, histological subtype and grade. MATERIAL AND METHODS: Within Surveillance, Epidemiology, and End Results database (2004-2014), we identified 1226 patients with non-metastatic retroperitoneal sarcoma. Univariable and multivariable logistic regression models tested for predictors of radiotherapy delivery. Univariable and multivariable Cox regression models tested the effect of radiotherapy on cancer specific mortality in the overall population. Subgroup analyses explored the result of tumor grade and tumor size on radiotherapy effect. All analyses were repeated after adjustment according to inverse probability of treatment. Additionally, all analyses were subjected to 1000 bootstrap resamples for internal validation. RESULTS: Radiotherapy was delivered in 372 patients (30.3%). In univariable and multivariable logistic regression models high grade (OR: 1.46, CI:1.12-1.90; p = 0.006), and leiomyosarcoma histologic subtype (OR: 2.14, CI: 1.55-2.95; p < 0.001) predicted radiotherapy delivery. In the overall population multivariable Cox regression models showed lower cancer specific mortality (HR: 0.73, CI: 0.55 0.96; p = 0.025) with radiotherapy. In subgroup analyses multivariable Cox regression models showed radiotherapy benefit predominantly in high grade, large tumor size retroperitoneal sarcomas (HR 0.51: C.I.: 0.30-0.86; p = 0.02). CONCLUSIONS: In this retrospective report, delivery of radiotherapy was associated with lower cancer specific mortality in high grade, large tumor size retroperitoneal sarcoma patients. Our findings are predominantly representative of liposarcomas and leiomyosarcomas that accounted for 90% of study population. Further study is needed to evaluate the role of radiotherapy in retroperitoneal sarcoma patients. PMID- 29631935 TI - Tumor Treating Fields Technology: Alternating Electric Field Therapy for the Treatment of Solid Tumors. AB - OBJECTIVE: To provide an overview of Tumor Treating Fields (TTFields) and the Optune device in the treatment of glioblastoma multiforme as well as discuss the evolution of TTFields technology for the treatment of different tumor types. DATA SOURCES: Peer reviewed publications, proceedings, and Internet-based resources. CONCLUSION: TTFields represent a unique technological modality for the effective treatment of glioblastoma multiforme and potentially other solid tumors. Oncology nurses are situated to play important roles as educators and advocates for patients and caregivers on the adherent use and management of this new and evolving treatment technology. IMPLICATIONS FOR NURSING PRACTICE: The increasing use of TTFields in cancer treatment draws attention to the expanding role for oncology nurses in the administration of this unique therapy. As an educator and advocate, the oncology nurse guides the cancer patient and caregiver through understanding the mechanism of action, initiation of TTFields treatment, and adjusting to the daily challenges of treatment administration, management of side effects, and optimizing compliance to treatment adherence to maximize treatment outcomes. PMID- 29631936 TI - C-11 Choline and F-18 Fluciclovine PET/CT demonstration of annular pancreas. PMID- 29631937 TI - The Nasal Musculature as a Control Panel for Singing-Why Classical Singers Use a Special Facial Expression? AB - OBJECTIVES: This study aimed to explain the possible reason why classical singers seem to spread their nostrils and raise their cheeks before starting to sing. STUDY DESIGN: This is an experimental study. METHODS: Five subjects (three classical singers, two nonsingers) were investigated with nasofiberoscopy holding their breath after inhalation. The subjects were instructed to have a neutral expression first and then to take the singers' expression characterized by nostril flaring. In case of nonsingers, the special expression was rehearsed beforehand, guided by a classical singer. The following measurements were made: (1) height of soft palate, (2) area of the hypopharynx, (3) area of the epilaryngeal tube inlet (Aditus laryngis), and (4) dimensions of the (visible) glottis (length, width, and length-to-width ratio). RESULTS: All subjects raised the palate and widened the pharyngeal inlet, epilaryngeal inlet, and the glottis during "singer's expression." CONCLUSIONS: The results suggest that classical singers may take advantage of breathing- and smelling-related connections between nasal and facial muscles and the larynx to avoid a hard glottal attack and pressed phonation and possibly also to assist the production of mixed register (head voice), characterized by a relatively low adduction between the vocal folds. PMID- 29631938 TI - Distinct Acoustic Features and Glottal Changes Define Two Modes of Singing in Peking Opera. AB - OBJECTIVE: We aimed to delineate the acoustic characteristics of the Laodan and Qingyi role in Peking Opera and define glottis closure states and mucosal wave changes during singing in the two roles. METHODS: The range of singing in A4 (440 Hz) pitch in seven female Peking Opera singers was determined using two classic pieces of Peking Opera. Glottal changes during singing were examined by stroboscopic laryngoscope. The fundamental frequency of /i/ in the first 15 seconds of the two pieces and the /i/ pitch range were determined. The relative length of the glottis fissure and the relative maximum mucosal amplitude were calculated. RESULTS: Qingyi had significantly higher mean fundamental frequency than Laodan. The long-term average spectrum showed an obvious formant cluster near 3000 Hz in Laodan versus Qingyi. No formant cluster was observed in singing in the regular mode. Strobe laryngoscopy showed complete glottal closure in Laodan and incomplete glottal closure in Qingyi in the maximal glottis closure phase. The relative length of the glottis fissure of Laodan was significantly lower than that of Qingyi in the singing mode. The relative maximum mucosal amplitude of Qingyi was significantly lower than that of Laodan. CONCLUSION: The Laodan role and the Qingyi role in Peking Opera sing in a fundamental frequency range compatible with the respective use of da sang (big voice) and xiao sang (small voice). The morphological patterns of glottal changes also indicate that the Laodan role and the Qingyi role sing with da sang and xiao sang, respectively. PMID- 29631940 TI - Assessing the Readability of Online Information About Hip Arthroscopy. AB - PURPOSE: To investigate the current readability of online information pertaining to hip arthroscopy. METHODS: The terms "hip arthroscopy" and "hip scope" were entered into the advanced search functions of Google, Yahoo!, and Bing on March 25, 2017, and results from the first 3 pages were analyzed. Results were required to be unique, accessible websites with information about hip arthroscopy conveyed primarily via analyzable text. Two reviewers applied inclusion criteria to the initial 97 results, discussing to reach consensus in cases of disagreement. Overall, 60 unique results were reviewed with 48 meeting inclusion criteria. Websites were categorized as physician-sponsored, academic, commercial, governmental and nonprofit organization (NPO), or unspecified. Readability was measured via 6 different indices: the Flesch-Kincaid grade level (FKGL), Flesch Reading Ease (FRE), Gunning Fog Score, SMOG Index, Coleman-Liau Index (CLI), and Automated Readability Index (ARI) along with an average grade level and readability classification score. RESULTS: Forty-eight unique websites were assessed for readability, with physician-sponsored webpages composing the majority (47.92%) followed by academic sources (35.42%). The webpages' average grade level, incorporating information from all 6 metrics, was 12.79 +/- 1.98. CONCLUSIONS: The current readability of online information pertaining to hip arthroscopy is at an inappropriately high reading level compared with the sixth grade level recommended by the American Medical Association and National Institutes of Health, thus introducing significant barriers to understanding for many patients. Online materials should be edited to reduce word and sentence length and complexity, use simpler terms, and minimize use of passive voice to facilitate patient knowledge acquisition and understanding of online information about hip arthroscopy. CLINICAL RELEVANCE: This study shows that the current readability of online information on hip arthroscopy exceeds the suggested sixth grade reading level. It also emphasizes the need for simplifying written materials and offers specific suggestions on doing so to increase accessibility of information for patients. PMID- 29631939 TI - HBsAg-redirected T cells exhibit antiviral activity in HBV-infected human liver chimeric mice. AB - BACKGROUND: Chronic hepatitis B virus (HBV) infection remains incurable. Although HBsAg-specific chimeric antigen receptor (HBsAg-CAR) T cells have been generated, they have not been tested in animal models with authentic HBV infection. METHODS: We generated a novel CAR targeting HBsAg and evaluated its ability to recognize HBV+ cell lines and HBsAg particles in vitro. In vivo, we tested whether human HBsAg-CAR T cells would have efficacy against HBV-infected hepatocytes in human liver chimeric mice. RESULTS: HBsAg-CAR T cells recognized HBV-positive cell lines and HBsAg particles in vitro as judged by cytokine production. However, HBsAg-CAR T cells did not kill HBV-positive cell lines in cytotoxicity assays. Adoptive transfer of HBsAg-CAR T cells into HBV-infected humanized mice resulted in accumulation within the liver and a significant decrease in plasma HBsAg and HBV-DNA levels compared with control mice. Notably, the fraction of HBV core positive hepatocytes among total human hepatocytes was greatly reduced after HBsAg-CAR T cell treatment, pointing to noncytopathic viral clearance. In agreement, changes in surrogate human plasma albumin levels were not significantly different between treatment and control groups. CONCLUSIONS: HBsAg CAR T cells have anti-HBV activity in an authentic preclinical HBV infection model. Our results warrant further preclinical exploration of HBsAg-CAR T cells as immunotherapy for HBV. PMID- 29631941 TI - Utility of diagnostic imaging in the diagnosis of extra adrenal myelolipoma. PMID- 29631943 TI - Anesthesia Care of Patients With Left Ventricular Assist Devices Undergoing Minor Noncardiac Surgery: Training General Anesthesiologists May Expedite Patient Care Without Negative Outcomes. PMID- 29631944 TI - Successful Use of a Double Lumen Endotracheal Tube and Bronchial Blocker for Lung Isolation in Pulmonary Mucormycosis. PMID- 29631942 TI - Double-layer closure techniques after bone surgery of medication-related osteonecrosis of the jaw - A single center cohort study. AB - INTRODUCTION: Mucosal wound closure plays a key role after surgery of manifested medication-related osteonecrosis of the jaw (MRONJ). Additional soft tissue layers promise better vascularization and mechanical stability. The objectives of this study were to examine success rates of double-layer closure techniques in MRONJ patients, namely the mylohyoideus muscle flap (MMF) for the lower jaw and the pedicled buccal fat flap (BFF) for the upper jaw. MATERIALS AND METHODS: We designed and implemented a restrospective cohort study and enrolled a sample of patients diagnosed with MRONJ that were treated between 2015 and 2017 with either the MMF or the BFF after removal of the necrotic bone areal. Success was assessed as the maintenance of full mucosal coverage without signs of residual infection at (T0) four weeks (T1), four months (T2), and eight months (T3) after operation. The occurrence of side effects was evaluated. RESULTS: A total of 87 (MMF n = 57; BFF n = 30) patients with 104 MRONJ (MMF 68 = ; BFF n = 36) lesions were included. At the time of the last follow-up, 88.0% (44 of 50) of patients in the MMF group and 93.1% (27 of 29) of patients in the BFF group showed mucosal integrity. No serious side effects were reported. Overall treatment of earlier lesions (stage I and II) showed a better outcome than more severe necrosis (stage III). CONCLUSION: Double-layer closure techniques after surgery in MRONJ patients provide a mechanically stable, well-vascularized covering of the bone defect and should be considered as an option in the standard protocol for all degrees of severity of the disease. PMID- 29631945 TI - Late Clinical Presentation of Prosthesis-Patient Mismatch Following Transcatheter Aortic Valve Replacement. AB - Prosthesis-patient mismatch (PPM) is relatively common after aortic valve replacement (AVR) and generally is associated with reduced regression of left ventricular (LV) mass. PPM after valve-in-valve transcatheter aortic valve replacement (TAVR) was reported to be 38%. PPM generally is manifested clinically by dyspnea and echocardiographically by high transvalvular gradients. In this E Challenge, the authors will review a case of a late clinical presentation of PPM 1-year following a valve-in-valve TAVR. PMID- 29631946 TI - Intrapulmonary Milrinone for Cardiac Surgery Provides Insight Into Precision Delivery of Aerosolized Vasodilators. PMID- 29631947 TI - Skin preparation for abdominal surgery. AB - INTRODUCTION: Surgical site infections (SSI) are a public health issue. The purpose of this review is to review the literature on methods of pre-operative skin preparation for the prevention of SSI in abdominal surgery. METHODS: In order to obtain the best level of evidence, only meta-analyses and randomized controlled clinical trials were selected from the Cochrane Library and PubMed databases. High-powered non-randomized studies were included when results were not available for the questions asked. The primary endpoint was the rate of SSI within 30 days. RESULTS: Analysis of the 20 selected studies suggested that hair removal in the operative field is not recommended except when it interferes with surgery; in this case, hair clipping or chemical depilation is recommended and shaving should be banned. For the pre-operative shower, the choice of a detergent product with or without antiseptic does not seem to matter, and there were no published data on the required number of showers or the interval before surgery. Application of an alcohol-based solution to the operative field for cutaneous disinfection is recommended; the products used seem to be equivalent, and there is no need for pre-operative detergent scrubbing. There is no strong evidence to recommend adhesive plastic drapes for clean or contaminated surgery. CONCLUSION: Some recommendations on skin preparation before abdominal surgery to reduce the rate of SSI are based on a high level of evidence. Other recommendations such as the number and duration of pre-operative showers or use of adhesive plastic skin drapes are less well supported. PMID- 29631948 TI - Mid-term outcomes after biologic mesh use: Does their performance meet our expectations? AB - INTRODUCTION: The indications for use of biological mesh prostheses are very limited because of their high cost, but include parietal repair in a contaminated setting. Their efficacy has been questioned by several recent studies. We therefore studied the results of all of our patients who received a biological prosthesis, including hernia recurrence and infectious complications. PATIENTS AND METHODS: We retrospectively reviewed the outcomes of 68 patients who underwent biological prosthesis placement from 2009 to 2015 in a single center. RESULTS: The site of implantation was on the anterior abdominal wall in 49 (72%) of cases, in the pelvis in 19 (28%). The median follow-up was 19 months. In the early post-operative period, 22 (32.3%) of patients presented with wall abscess; eight (11.7%) underwent surgical revision and seven (10.2%) underwent interventional radiological drainage. In the medium term, 41/56 (73%) had a late complication; 32 (57%) of the patients developed recurrent herniation and 15 (26.7%) of them were re-operated. In addition, nine (16%) of patients developed a late surgical site infection and eight (14.2%) a chronic residual infection. In multivariate analysis, the risk factors for recurrence were parastomal hernia (P=0.007) and a history of recurrent hernia (P=0.002). CONCLUSION: A majority of patients developed recurrent incisional herniation in the medium term. This puts the use of biological prostheses into question. These results need to be compared to those of semi-absorbable prostheses. PMID- 29631949 TI - Genome-wide screening for smallest regions of overlaps in cryptorchidism. AB - Cryptorchidism is a urogenital abnormality associated with increased rates of testicular neoplasia and impaired spermatogenesis. The field is facing expansion of genomics data; however, it lacks protocols for biomarker prioritization. Identification of smallest regions of overlap (SRO) presents an approach for candidate gene identification but has not yet been systematically conducted in cryptorchidism. The aim of this study was to conduct a genome-wide screening for SRO (GW-SRO) associated with cryptorchidism development. We updated the Cryptorchidism Gene Database to version 3, remapped genomic coordinates of loci from older assemblies to the GRCh38 and performed genome-wide screening for overlapping regions associated with cryptorchidism risk. A total of 73 chromosomal loci (68 involved in chromosomal mutations and five copy number variations) described in 37 studies associated with cryptorchidism risk in humans were used for SRO identification. Analysis resulted in 18 SRO, based on deletions, duplications, inversions, derivations and copy number variations. Screening for SRO was challenging owing to heterogeneous reporting of genomic locations. To our knowledge, this is the first GW-SRO study for cryptorchidism and it presents the basis for further narrowing of critical regions for cryptorchidism and planning functional experiments. The developed protocol could also be applied to other multifactorial diseases. PMID- 29631950 TI - Response: Impact of androgen supplementation on the follicular endocrine milieu in women with hypoandrogenism. PMID- 29631951 TI - Proximal anchoring distal trapping technique in a chronic total occlusion unable to cross. PMID- 29631952 TI - Disruption of sleep-wake continuum in myotonic dystrophy type 1: Beyond conventional sleep staging. AB - Sleep disruption and excessive daytime sleepiness are well recognised symptoms in myotonic dystrophy type 1 (DM1), where a central dysfunction of sleep-wake regulation may play a pivotal role. Few studies evaluated sleep macrostructure in DM1, but none investigated more refined sleep variables. Eight DM1 patients (6 male, aged 20-50 years) and 10 healthy controls (7 male, aged 22-67 years) underwent nocturnal polysomnography and multiple sleep latency test. Sleep stages and events were scored according to standard criteria; sleep microstructure was analyzed through cyclic alternating pattern. Relative and absolute delta powers were computed for whole non REM and each non REM period. DM1 patients showed increased REM sleep and decreased N2. N3, although not significantly, was increased. Three patients, but no controls, had sleep-onset REM period in nocturnal sleep. DM1 patients showed slower delta power dissipation across the night, and increased sleep instability (CAP rate). Multiple sleep latency tests showed shorter sleep latencies, five patients presenting at least one sleep-onset REM period and, when including also night sleep, two sleep-onset REM periods. Our data confirm a narcoleptic-like phenotype in DM1 with a prominent REM sleep dysregulation, that may account for daytime sleepiness, together with increased sleep instability and impaired delta power dissipation that seem peculiar of the disease. PMID- 29631953 TI - Muscle biopsy technical safety and quality using a self-contained, vacuum assisted biopsy technique. AB - Muscle sampling via percutaneous biopsy has been shown to be safe and effective using a Bergstrom needle; however, the use of a single-operator, self-contained, vacuum-assisted biopsy technique has not been explored. We performed a retrospective chart review of muscle biopsy samples obtained using the Vacora(r) self-contained vacuum-assisted biopsy system between 2013 and 2016, at the Toronto General Hospital. During this period, 102 single-operator muscle biopsies were performed using the Vacora(r) system. 54/102 showed normal or non-specific findings, while 39/102 were suggestive or diagnostic of a neuromuscular condition. 8 samples did not provide sufficient muscle tissue for diagnosis, and complications (intramuscular hematoma) occurred in 3/102 cases. Mean sample weight was 0.19 grams, which exceeded reported mean sample weights using the suction-modified Bergstrom technique (0.125 grams). We therefore conclude that the Vacora(r) vacuum-assisted biopsy system provides a safe and effective method to obtain diagnostic muscle biopsy samples; although complication rates are slightly higher than reported using the Bergstrom technique, possibly related to more vigorous suction or a sharp needle tip. PMID- 29631954 TI - Low dystrophin levels are insufficient to normalize the neuromuscular synaptic abnormalities of mdx mice. AB - Dystrophin is a sub-sarcolemmal component of skeletal muscle fibres and is enriched at the postsynaptic membrane of the neuromuscular junction (NMJ). In the mdx mouse, dystrophin absence not only causes muscle damage but also mild synaptic dysfunctions and clear morphological aberrations at NMJs. In particular, reduction of postsynaptic sensitivity for the neurotransmitter acetylcholine and extra exhaustion of presynaptic acetylcholine release during intense synaptic activity exists. Current experimental therapeutic approaches in Duchenne muscular dystrophy aim to restore dystrophin expression. An important question is what dystrophin levels are needed to improve muscle function. Recent experimental and clinical studies suggested that levels as low as a few percent of normal can be beneficial. Similarly, it is of interest to know how dystrophin levels relate to NMJ function and morphology. We investigated NMJs of a series of mdx-XistDeltahs mice, which expressed dystrophin between ~2% and 19% of normal. Most functional and morphological NMJ parameters of these mice remained comparable to mdx. On the other hand, mdx+/- mice (expressing ~50% dystrophin) showed normal NMJ features. Thus, the minimal dystrophin level required for normal NMJ function and morphology lies between 19% and 50% of normal when expression of dystrophin is not uniform. PMID- 29631955 TI - Patterns in Vulvodynia Treatments and 6-Month Outcomes for Women Enrolled in the National Vulvodynia Registry-An Exploratory Prospective Study. AB - BACKGROUND: Vulvodynia is a poorly characterized condition with multiple treatment options that have been described as largely ineffective in research settings. AIM: To describe treatment patterns in women enrolled in the National Vulvodynia Registry and determine if there is an association between selected treatments and patient-reported outcomes such as pain, sexual function, and psychological distress after 6 months of treatment. METHODS: Participants completed questionnaires on general medical history and patient-reported outcomes using the short-form McGill Pain Questionnaire, the Female Sexual Function Index, the Short Form-12 quality-of-life questionnaire, the Coping Strategies Questionnaire, and the State-Trait Anxiety Inventory. The evaluation also included pain sensitivity assessment of the vaginal mucosa using a cotton-tipped applicator and the vaginal muscles using a single-digit. In this prospective cohort study, all measurements were collected at baseline and again at 6 months after treatment. OUTCOMES: Type of treatment, number of treatments, self-reported pain intensity, dyspareunia, and pain-related psychological distress measures are reported at baseline and 6 months. RESULTS: Of 344 women enrolled, 282 received treatment; 78 different treatments were identified and categorized by type (eg, topical, oral, physical therapy) and number. The most commonly used treatments were topical (85%, n = 241), physical therapy (52%, n = 147), and oral medications (45%, n = 128). Notably, 73% of participants received >=2 treatments. There was no association between type or number of treatments and patient characteristics. At 6 months, women reported improvements in general pain (P = .001), pain during intercourse (P = .001), catastrophizing (P = .000), and anxiety (P = .000). The Short Form-12 quality-of-life questionnaire showed improvements in physical limitations (P = .024), emotional limitations (P = .003), well-being (P = .025), and social function (P = .010). However, all domains of the Female Sexual Function Index indicated worsening in sexual function (P = .000) except for pain. CLINICAL TRANSLATION: Multi-modal treatments were most commonly used in clinical practice and improvements in patient-reported outcomes such as quality of life, distress, and pain were noted; however, participants who returned at 6 months continued to report poor sexual function. CONCLUSIONS: Strengths include a prospective and long-term study design that evaluated women in clinical settings. Limitations include a high rate of loss to follow-up for certain measures and inability to evaluate efficacy of individual treatments. In a setting where women were receiving highly specialized care, we found wide variation in the type and number of treatments used to treat vulvodynia. Despite this heterogeneity in treatment selection, women reported significant improvements in all study measures except sexual function. Lamvu G, Alappattu M, Witzeman K, et al. Patterns in Vulvodynia Treatments and 6-Month Outcomes for Women Enrolled in the National Vulvodynia Registry-An Exploratory Prospective Study. J Sex Med 2018;15:705-715. PMID- 29631956 TI - Comparison of Correlated Comorbidities in Male and Female Sexual Dysfunction: Findings From the Third National Survey of Sexual Attitudes and Lifestyles (Natsal-3). AB - BACKGROUND: Many of the same mechanisms involved in the sexual arousal-response system in men exist in women and can be affected by underlying general medical conditions. AIM: To assess whether sexual function in men and women is correlated with similar comorbidities. METHODS: This study was a secondary analysis of the 3rd National Survey of Sexual Attitudes and Lifestyles (Natsal-3), a prospective stratified probability sample of British individuals 16 to 74 years old interviewed from 2010 to 2012. We assessed for an association between sexual function and the following comorbidities: heart attack, heart disease, hypertension, stroke, diabetes, chronic lung disease, depression, other mental health conditions, other neurologic conditions, obesity, menopause, incontinence, smoking status, and age. OUTCOME: An association was found between multiple medical comorbidities and sexual dysfunction in women and in men. RESULTS: 6,711 women and 4,872 men responded to the survey, were in a relationship, and reported sexual activity in the past year. The average age of the women was 35.4 +/- 14.1 and that of the men was 36.8 +/- 15.6. There was an association between sexual function and all variables assessed except for chronic lung disease, heart attack, and incontinence in women compared with stroke, other neurologic conditions, incontinence, and smoking status in men. Comorbidities associated with erectile dysfunction included depression, diabetes, and other heart disease, whereas comorbidities associated with difficulty with lubrication included depression and other heart disease. Menopause was predictive of sexual dysfunction. Male sexual function appeared to decline after 45.5 years of age. CLINICAL IMPLICATIONS: Physicians should be aware of the correlation between medical comorbidities and sexual dysfunction in women and men and should ask patients about specific symptoms that might be associated with underlying medical conditions. STRENGTHS AND LIMITATIONS: Use of a stratified probability sample compared with a convenience sample results in capturing of associations representative of the population. Inclusion of multiple comorbidities in the multivariate analysis allows us to understand the effects of several variables on sexual function. Although this study shows only an association, further research could determine whether there is a causal relation between comorbidities and sexual dysfunction in women. CONCLUSION: Multiple medical comorbidities are associated with sexual dysfunction not only in men but also in women. Polland A, Davis M, Zeymo A, et al. Comparison of Correlated Comorbidities in Male and Female Sexual Dysfunction: Findings From the Third National Survey of Sexual Attitudes and Lifestyles (Natsal-3). J Sex Med 2018;15:678-686. PMID- 29631957 TI - Prognostic value of postoperative complication for early recurrence after curative resection of hepatocellular carcinoma. AB - BACKGROUND: Postoperative complications may adversely affect oncological outcomes. The aim of this study was to evaluate the impact of postoperative complications on early-phase recurrence after curative resection for hepatocellular carcinoma (HCC). METHODS: We included 145 HCC patients who underwent initial and curative resection between January 2004 and December 2013. Postoperative complications of grade III or higher based on Clavien-Dindo classification were defined as clinically relevant postoperative complications. Recurrence within two years after hepatectomy was defined as early-phase recurrence. RESULTS: Thirty-eight patients (26%) developed postoperative complications. The only predictive factor for postoperative complication was longer operative duration (P = 0.037). The disease-specific survival rate of patients with complication was lower than that of patients without complications (P = 0.015). Early-phase recurrence was observed in 20/38 (53%) patients who suffered postoperative complications and 36/107 (34%) patients with no complications, which was statistically significant (P = 0.039). Multivariate analysis identified four factors contributing to early-phase recurrence: high serum AFP level (P = 0.042), multiple tumors (P < 0.001), poor differentiation (P = 0.036) and presence of postoperative complication (P = 0.039). CONCLUSIONS: Postoperative complication is an independent prognostic factor for early-phase recurrence after curative resection of HCC. Close observation of patients with postoperative complications may be a necessary treatment strategy for HCC. PMID- 29631958 TI - Anticomplement compounds from Polygonum chinense. AB - Five new compounds including two phenyldilactones (1, 2), two coumarins (3, 4) and a dimer of N-E-feruloyl tyramine (5) together with twenty-three known compounds (6-28) were isolated from a medicinal plant Polygonum chinense. The structures of the new compounds were established by detailed spectral analysis. The absolute configurations of 1 and 5 were elucidated by Mosher's method, Mo2(OAc)4-induced electronic circular dichroism (ECD) data, and ECD calculation. All the compounds were found to show potent anticomplement activity with CH50 and AP50 values ranging from 0.18 to 1.45 mM, and 0.26 to 2.80 mM, respectively. Phenyldilactones and phenylpropionic tyramines were firstly reported as anticomplement agents. The targets of compounds 1, 3, 5 and 10 in complement activation cascade were identified as well. PMID- 29631959 TI - Synthesis of 3-(3-hydroxyphenyl)pyrrolidine dopamine D3 receptor ligands with extended functionality for probing the secondary binding pocket. AB - A series of 3-(3-hydroxyphenyl)pyrrolidine analogues which incorporate N-alkyl groups and N-butylamide-linked benzamide functionality have been synthesized and their in vitro binding affinities at human dopamine receptors have been evaluated. Our ligand design strategy was to take the 3-(3 hydroxyphenyl)pyrrolidine scaffold and extend functionality from the orthosteric binding site to the secondary binding pocket for enhancing affinity and selectivity for the D3 receptor. The N-alkyl analogues constitute a homologous series from N-pentyl to N-decyl to probe the length/bulk tolerance of the secondary binding pocket of the D3 receptor. Enantiomeric 3-(3 hydroxyphenyl)pyrrolidine analogues were also prepared in order to test the chirality preference of the orthosteric binding site for this scaffold. Benzamide analogues were prepared to enhance affinity and/or selectivity based upon the results of the homologous series. PMID- 29631960 TI - The design, synthesis and structure-activity relationships associated with C28 amine-based betulinic acid derivatives as inhibitors of HIV-1 maturation. AB - The design and synthesis of a series of C28 amine-based betulinic acid derivatives as HIV-1 maturation inhibitors is described. This series represents a continuation of efforts following on from previous studies of C-3 benzoic acid substituted betulinic acid derivatives as HIV-1 maturation inhibitors (MIs) that were explored in the context of C-28 amide substituents. Compared to the C-28 amide series, the C-28 amine derivatives exhibited further improvements in HIV-1 inhibitory activity toward polymorphisms in the Gag polyprotein as well as improved activity in the presence of human serum. However, plasma exposure of basic amines following oral administration to rats was generally low, leading to a focus on moderating the basicity of the amine moiety distal from the triterpene core. The thiomorpholine dioxide (TMD) 20 emerged from this study as a compound with the optimal antiviral activity and an acceptable pharmacokinetic profile in the C-28 amine series. Compared to the C-28 amide 3, 20 offers a 2- to 4-fold improvement in potency towards the screening viruses, exhibits low shifts in the EC50 values toward the V370A and DeltaV370 viruses in the presence of human serum or human serum albumin, and demonstrates improved potency towards the polymorphic T371A and V362I virus variants. PMID- 29631961 TI - Callyspongiamides A and B, sterol O-acyltransferase inhibitors, from the Indonesian marine sponge Callyspongia sp. AB - Callyspongiamides A (1) and B (2), two new sterol O-acyltransferase (SOAT) inhibitors, were isolated from the Indonesian marine sponge Callyspongia sp. together with a known congener, dysamide A (3). The structures of 1 and 2 were elucidated to be polychlorine-containing modified dipeptides based on their spectroscopic data. Compounds 1-3 inhibited both of the SOAT isozymes, SOAT1 and SOAT2, in cell-based and enzyme-based assays. PMID- 29631962 TI - Identification and biological evaluation of thiazole-based inverse agonists of RORgammat. AB - The nuclear receptor retinoic acid receptor-related orphan receptor gamma t (RORgammat) is a transcription factor that drives Th17 cell differentiation and IL-17 production in both innate and adaptive immune cells. The IL-23/IL-17 pathway is implicated in major autoimmune and inflammatory diseases. RORgammat lies at the core of this pathway and represents an attractive opportunity for intervention with a small molecule. Despite diverse chemical series having been reported, combining high potency and nuclear receptor selectivity with good physicochemical properties remains a challenging endeavor in the field of RORgammat drug discovery. We describe the discovery and evaluation of a new class of potent and selective RORgammat inverse agonists based on a thiazole core. Acid analog 1j demonstrated oral bioavailability in rats and was potent in a human whole blood assay, suggesting potential utility in treating autoimmune and inflammatory diseases such as psoriasis. X-ray crystallographic data helped to elucidate the molecular mechanism for RORgammat inhibition with this series. PMID- 29631963 TI - Platelet and TRALI: From blood component to organism. AB - Even though used systematically with leukocyte reduction, platelet transfusions still cause adverse reactions in recipients. They include Transfusion-Related Acute Lung Injury (TRALI), respiratory distress that occurs within six hours of the transfusion. The pathophysiology of this transfusion complication brings complex cellular communication into play. The role, particularly inflammatory, played by blood platelets in TRALI pathophysiology has been demonstrated, but is still under debate. Blood platelets play a role in inflammation, particularly via the CD40/CD40L (sCD40L) immunomodulator complex. In this study, we examine in particular the specific involvement of the CD40/CD40L (sCD40L) complex in the inflammatory pathogenesis of TRALI. This molecular complex could be a major target in a TRALI prevention strategy. Improving the conditions in which the platelet concentrates (PC) are prepared and stored would contribute to controlling partly the risks of non-immune TRALI. PMID- 29631964 TI - Insights Into Hypertrophic Cardiomyopathy Evaluation Through Follow-up of a Founder Pathogenic Variant. AB - INTRODUCTION AND OBJECTIVES: Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiac disease. The current challenge relies on the accurate classification of the pathogenicity of the variants. Transthoracic echocardiography (TTE) is recommended at initial evaluation and cardiac magnetic resonance (CMR) imaging should also be considered. We aimed to reappraise the penetrance and clinical expression of the MYBPC3 p.G263* variant. METHODS: Three hundred and eighty-four HCM probands and a control cohort of 450 individuals were studied for the main sarcomere genes by next-generation sequencing. All MYBPC3 p.G263* carriers were identified and family screening was performed. Clinical information was recorded retrospectively before 2015 and prospectively thereafter. Extra effort was invested in performing CMR in all carriers, despite TTE results. RESULTS: Thirteen HCM probands and none of the controls were carriers of the MYBPC3 p.G263* pathogenic variant (according to the American College of Medical Genetics and Genomics and the Association for Molecular Pathology). A total of 39 carriers were identified with family screening. Most patients with HCM were asymptomatic at the time of diagnosis and showed late onset disease. Despite having a relatively benign course in the young, late HCM related complications could occur. Penetrance was around 70% when evaluated by TTE and was 87.2% with TTE plus CMR. Penetrance was age-dependent, reaching 100% in carriers older than 55 years. CONCLUSIONS: MYBPC3 p.G263* shares with most truncating pathogenic variants in this gene a late onset, relatively benign clinical course in the young, and high penetrance. Cardiac magnetic resonance could be a useful tool to evaluate carriers despite TTE results. PMID- 29631965 TI - Phase Ib Study of Bavituximab With Carboplatin and Pemetrexed in Chemotherapy Naive Advanced Nonsquamous Non-Small-Cell Lung Cancer. AB - INTRODUCTION: Bavituximab is an immunomodulatory chimeric monoclonal antibody that inhibits phosphatidylserine signaling, which promotes innate and adaptive immune responses. In this phase Ib trial we evaluated the safety, tolerability, and preliminary antitumor activity of pemetrexed, carboplatin, bavituximab in advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with advanced nonsquamous NSCLC and performance status 0 or 1 were treated with pemetrexed 500 mg/m2 and carboplatin area under the curve 6 once every 3 weeks for up to 6 cycles, with concurrent bavituximab (0.3, 1, or 3 mg/kg) intravenously weekly, using a standard 3+3 design. At the maximum identified dose, additional patients were enrolled to further characterize the safety profile. The primary objective was to characterize the safety, determine the dose limiting toxicities (DLTs), and establish the recommended phase II dose of bavituximab in combination with pemetrexed and carboplatin in incurable stage IV nonsquamous NSCLC. RESULTS: Between March 29, 2011 and December 30, 2013, 26 patients were enrolled. Three patients each were enrolled into dose escalation cohorts of bavituximab (0.3, 1, and 3 mg/kg). Therapy was well tolerated with no DLTs, and toxicities were consistent with those expected from pemetrexed/carboplatin. Overall response was 28%, with a median progression-free and overall survival of 4.8 months and 12.2 months, respectively. CONCLUSION: The combination of pemetrexed, carboplatin, bavituximab is well tolerated. However, with toxicities and preliminary efficacy signal similar to pemetrexed/carboplatin alone, further studies of bavituximab should focus on ways to enhance its immunomodulatory role. PMID- 29631966 TI - MET Expression in Advanced Non-Small-Cell Lung Cancer: Effect on Clinical Outcomes of Chemotherapy, Targeted Therapy, and Immunotherapy. AB - BACKGROUND: The receptor tyrosine kinase MET is implicated in malignant transformation, tumor progression, metastasis, and acquired treatment resistance. We conducted an analysis of the effect of MET expression and MET genomic aberrations on the outcome of patients with advanced or metastatic pulmonary adenocarcinomas prospectively enrolled in an institutional precision oncology program. PATIENTS AND METHODS: Standardized immunohistochemistry (IHC) analyses of MET and markers of pathway activation were available in 384 patients, and next generation sequencing-based MET hotspot mutation analyses were available from 892 patients. Clinical data were retrieved with a median follow-up from initial diagnosis of 37 months. RESULTS: High MET expression, defined as MET IHC 3+ or MET H-Score in the upper quartile, was observed in 102 of 384 patients (26.6%). MET exon 14 mutations were only detected in 7 of 892 patients (0.78%). High MET expression correlated with activation markers of the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathways only in cases without Kirsten rat sarcoma viral oncogene homolog (KRAS), epidermal growth factor receptor (EGFR), v-Raf murine sarcoma viral oncogene homolog B (BRAF), anaplastic lymphoma kinase (ALK) and proto-oncogene tyrosine protein kinase ROS (ROS1) aberrations. There was no association of MET expression with outcome during chemotherapy. High MET expression negatively affected the outcome during EGFR-targeting therapy but was associated with more favorable results with programmed death 1/programmed death ligand 1 (PD-L1)-directed therapy, independent of smoking history, PD-L1 expression or KRAS mutation. Two patients with MET exon 14 mutation and high PD-L1 expression failed to respond to pembrolizumab. CONCLUSION: MET expression affects the outcomes of targeted therapies in non-small-cell lung cancer, thus supporting the development of biomarker-informed combination strategies. The interaction of MET expression and MET mutation with immune checkpoint inhibitor therapy is novel and merits further investigation. PMID- 29631967 TI - Surgical Treatment of Bone Marrow Lesion Associated with Recurrent Plantar Fasciitis: A Case Report Describing an Innovative Technique Using Subchondroplasty(r). AB - Plantar fasciitis is one of the most common chief complaints seen in the foot and ankle clinic. With a relatively benign course, most cases are self-limiting or amendable to conservative therapy; ~90% of all plantar fasciitis cases will respond to these methods. When conservative treatment and time fail, surgical intervention can be necessary to improve outcomes. We present a novel method using Subchondroplasty(r) (SCP(r); Zimmer Holdings, Inc.; Warsaw, IN) and revision fasciotomy in a case in which initial fasciotomy had failed. After the patient had failed to improve, a worsening underlying bone marrow lesion was identified at the origin of the plantar fascia; thus, SCP(r) was used with repeat fasciotomy. SCP(r) involves injecting calcium phosphate into bone marrow lesions to stimulate long-term bone repair. At 10 months after SCP(r), the patient remained pain free and had returned to running at the final follow-up examination. This surgical treatment should be considered as an adjunctive procedure for those patients with plantar fasciitis, identifiable bone marrow lesions on magnetic resonance imaging, and continued pain when other treatment modalities have failed. PMID- 29631968 TI - Symptomatic Os Intercuneiform: A Case Report. AB - We encountered a case of an accessory bone in the foot in the distal portion of the tarsal navicular and the proximal portion of the intermediate cuneiform, namely an os intercuneiform. The patient presented with a history of pain on the dorsal aspect of the left foot, with tenderness and swelling. Perioperative findings revealed a synfibrotic connection between the accessory bone and the navicular and intermediate cuneiform. After unsuccessful conservative treatment, the accessory bone was excised, leading to postoperative symptomatic relief. PMID- 29631969 TI - Thirteen-Year Follow-Up Reverse Sural Artery Flap for Plantar Calcaneal Wound: A Case Report. AB - Reconstruction of soft tissue defects in the lower leg and foot after traumatic injury is a challenging problem owing to lack of locally reliable flaps. The traditional options for wound coverage often do not provide feasible or adequate treatment for many of these wounds. The lack of skin laxity in the lower leg and foot often make local flaps unavailable. Split-thickness skin grafts will not be robust enough. Free tissue flaps have a litany of potential complications and guaranteed comorbidities. The present case reinforces that appropriately selected patients with significant open bony and soft tissue trauma to the foot and ankle can be treated with a reverse sural artery fasciocutaneous flap. The reverse sural artery flap allows for full-thickness skin coverage with its own blood supply, maximizing the healing potential and should be considered a viable first option for soft tissue coverage. PMID- 29631970 TI - Spontaneous Fracture of the Os Peroneum With Rupture of the Peroneus Longus Tendon. AB - Rupture of the peroneus longus tendon with or without an associated os peroneum fracture is rare and uncommonly encountered in the published data. Owing to the infrequent nature, a high index of suspicion is required. Otherwise, the opportunity for the injury to result in a delayed or missed diagnosis is increased. We report the case of a 39-year-old male with spontaneous rupture of the peroneus longus tendon and associated fracture of the os peroneum. The spontaneous rupture and fracture were diagnosed from the history, physical examination, and imaging findings. The patient elected to undergo operative repair, with excellent results, full recovery, and full return to normal function. PMID- 29631971 TI - Minimally Invasive Tendon Release for Symptomatic Accessory Soleus Muscle in an Athlete: A Case Report. AB - The accessory soleus muscle can pose a diagnostic dilemma for exertional ankle pain, especially in athletes. Once diagnosed, the current treatment options require an extensile approach and can be associated with substantial risk and a slow recovery. We describe a minimally invasive, safe method that has proved successful in our practice. PMID- 29631972 TI - Surgical Management of Plantar Melanoma: A Retrospective Study in One Center. AB - Cutaneous melanoma is a highly malignant skin tumor, and in China, the planta pedis is a commonly involved site. The sites of plantar melanomas are a challenge to reconstruct after wide excision. Our experience with surgical management of melanomas was based on the 4 different anatomic subunits of the planta pedis. From January 1, 2002 to December 31, 2016, 35 patients who had had plantar melanoma had undergone surgical treatment in our clinic. The tumor locations were as follows: the toe in 6, the ball of the foot in 5, the arch in 15, and the heel in 9. Surgical management involved extended resection of the tumor, repair of defects with skin grafts or flaps, and inguinal lymphadenectomy. The skin flaps included a residual toe flap, an anterograde or retrograde medial plantar flap, and a retrograde sural neurocutaneous vascular flap. Of the 35 cases of flaps and skin grafts, 33 (94.29%) survived, and the wounds had healed by first intention. After a follow-up period of 6 months to 7 years, 24 patients (68.57%) were free of local and systemic disease and 30 patients (85.71%) were ambulatory using shoes, and all the flaps and skin grafts showed a good appearance. The personalized surgical treatments we used for melanoma in the planta pedis resulted in overall satisfactory outcomes and adequate disease clearance, and allowed the patients to resume normal lives. The function of the foot was maintained or restored to the greatest possible degree, and the patients' quality of life improved postoperatively. PMID- 29631973 TI - Impact of fused computed tomography and fluoroscopy in the catheterization laboratory. AB - The development of structural interventional catheterization for acquired or congenital heart disease was made possible through concomitant advances in catheterization techniques/tools and imaging techniques (fluoroscopy, ultrasound, magnetic resonance imaging and computed tomography). Imaging should provide an accurate view of the lesions and the surrounding cardiac structures, as well as the medical devices and catheters used. Here, we address the subject of image fusion. The principle of image fusion is based on the superposition of several imaging techniques: real-time fluoroscopy and multislice imaging performed offline or ultrasound imaging performed simultaneously. The goals are to improve the overall visualization of the organ and the surrounding structures, and to help the interventional cardiologist to interpret fluoroscopy images. PMID- 29631974 TI - Kinesiotape and quadriceps strengthening with elastic band in women with knee osteoarthritis and overweight or obesity. A randomized clinical trial. AB - BACKGROUND: The beneficial effects of exercise in the treatment of Osteoarthritis (OA) of the knee have been verified in several studies. Kinesiotaping (KT) has been popularized due to its reducing local pressure and increasing circulation, resulting in decreased pain. OBJECTIVE: Determine the clinical effectiveness of strengthening therapy with KT in women with knee OA for pain reduction. METHODS: Thirty two women with knee OA, aged 50-70 years, with overweight or obesity grade I, who were randomized into two groups: one with exercise and KT, and the other, with exercise and placebo technique. Both groups performed stretching and quadriceps strengthening exercise with the elastic band 3 days weekly for 6 weeks. Measurement of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain subscale was taken as primary outcome. Stiffness and functionality of the same index and the Visual Analog Scale (VAS) for pain intensity were measured. RESULTS: At the end of the study, there were no significant differences between the groups. Both groups had a difference of 2.7 points with respect to the baseline measurement, change percentage of 32.2% and 31.1% for placebo and experimental respectively (p=0.2). CONCLUSIONS: KT plus quadriceps strengthening exercise does not offer advantages for improvement of pain compared with quadriceps strengthening exercise alone in knee OA. PMID- 29631975 TI - Racial Differences in Pregnancy Intention, Reproductive Coercion, and Partner Violence among Family Planning Clients: A Qualitative Exploration. AB - BACKGROUND: Unintended pregnancy (UIP) is a persistent public health concern in the United States disproportionately experienced by racial/ethnic minorities and women of low socioeconomic status. UIP often occurs with experiences of reproductive coercion (RC) and intimate partner violence (IPV). The purpose of the study was to qualitatively describe and compare contexts for UIP risk between low-income Black and White women with histories of IPV/RC. STUDY DESIGN: Semistructured interviews were conducted with low-income Black and White women with histories of IPV or RC, ages 18 to 29 years, recruited from family planning clinics in Pittsburgh, Pennsylvania. RESULTS: Interviews with 10 non-Hispanic Black women and 34 non-Hispanic White women (N = 44) were included in the analysis. Differences between White and Black women emerged regarding IPV/RC experiences, gender roles in intimate relationships, and trauma histories, including childhood adversity. Fatal threats and IPV related to childbearing were most influential among White women. Among Black women, pregnancy was greatly influenced by RC related to impending incarceration, subfertility, and condom nonuse, and decisions about contraception were often dependent on the male. Sexual abuse, including childhood sexual assault, in the context of sexual/reproductive health was more prominent among White women. Childhood experiences of neglect impacted pregnancy intention and love-seeking behaviors among Black women. CONCLUSIONS: Racial differences exist in experiences of IPV/RC with regard to UIP even among women with similar economic resources and health care access. These findings provide much-needed context to the persistent racial/ethnic disparities in UIP and illustrate influences beyond differential access to care and socioeconomic status. PMID- 29631977 TI - Application of chromosome microarray analysis in patients with unexplained developmental delay/intellectual disability in South China. AB - BACKGROUND AND METHODS: Chromosome microarray analysis (CMA) is currently the first-tier diagnostic assay for the evaluation of developmental delay (DD) and intellectual disability (ID) with unknown etiology. Here, we present our clinical experience in implementing whole-genome high-resolution single nucleotide polymorphism (SNP) arrays to investigate 489 patients with unexplained DD/ID in whom standard karyotyping analyses showed normal karyotypes. This study aimed to assess the usefulness of CMA for clinical diagnostic testing in the Chinese population. RESULTS: A total of 489 children were classified into three groups: isolated DD/ID (n = 358), DD/ID with epilepsy (n = 49), and DD/ID with other structural anomalies (n = 82). We identified 126 cases (25.8%, 126/489) of pathogenic copy number variants (CNVs) by CMA, including 89 (24.9%, 89/358) with isolated DD/ID, 13 (26.5%, 13/49) with DD/ID with epilepsy, and 24 (29.3%, 24/82) with DD/ID with other structural anomalies. Among the 126 cases of pathogenic CNVs, 79 cases were identified as microdeletion/microduplication syndromes, among which 76 cases were classified as common syndromes, and 3 cases were classified as rare syndromes, including 15q24 microdeletion syndrome, Xq28 microduplication syndrome and Lowe syndrome. Additionally, there were forty-seven cases of non syndromic pathogenic CNVs. The ABAT, FTSJ1, DYNC1H1, and SETBP1 genes were identified as DD/ID candidate genes. CONCLUSION: Our findings suggest the necessity of CMA as a routine diagnostic test for unexplained DD/ID in South China. PMID- 29631976 TI - Effects of Legislation Regulating Abortion in Arizona. AB - INTRODUCTION: Abortion is a common and safe procedure in the United States, the regulation of which varies by state. Since 2011, hundreds of state-level abortion restrictions have been enacted by legislatures across the country. This study describes the effects of two such regulations enacted in 2011 in Arizona, (A.R.S.) 36-2153 and 36-2155, that imposed a 24-hour waiting period requiring two separate in-person clinic visits before obtaining an abortion and banned advanced practice clinicians such as physician assistants, nurse practitioners, and nurse midwives from inducing medication abortions by prescribing mifepristone. MATERIALS AND METHODS: We conducted a pre-post study to describe the effect of Arizona's scope of practice law on abortion provision by county. Using publicly available data, we compared patterns of abortion provision in 2009 and 2010 (before the laws) with 2012 and 2013. Our primary objective was to compare the proportion of abortions performed with medication by prescription of mifepristone (versus abortions performed surgically, known as aspiration abortions) before and after the laws were enacted. Our secondary objectives were to report the number of counties that lost an abortion provider and the change in the proportion of abortions performed before 14 weeks' gestation of pregnancy after the enactment of the laws. RESULTS: After enactment of the laws, the proportion of Arizona's 15 counties with abortion clinics decreased from 33% to 13%. Over this time, the proportion of abortions performed with medication in Arizona decreased by 17.4% (95% CI, 16.6%-18.3%; p = .0002), from 47.6% to 30.2%. Similarly, the proportion of abortions performed before 14 weeks' gestation in Arizona decreased by 3.3% (95% CI, 2.8%-3.8%; p = .0002) after the enactment of these laws. DISCUSSION: The proportion of abortions performed with medication and the proportion of abortion performed before 14 weeks' gestation in Arizona were negatively affected by the enactment of these laws. These findings are not explained by national temporal trends in abortion, because the proportion of abortions performed with medication increased and early abortions remained stable over the same time period in the United States as a whole. CONCLUSIONS: Proponents of laws restricting the provision of abortion such as these claim to improve the safety of abortion, but they actually seem to decrease access to abortion, as defined by the number of counties with abortion providers, and subsequently lead to delays in abortion. These data should inform future policies by providing an example of how such laws affect women seeking abortion. PMID- 29631978 TI - Suppression of Cavernosal Fibrosis in a Rat Model. AB - INTRODUCTION: Cavernosal fibrosis is an important pathologic condition leading to erectile dysfunction (ED). The etiologies of cavernosal fibrosis include aging, diabetes mellitus, castration, cavernosal nerve injury during radical prostatectomy, hypertension, and Peyronie disease. AIMS: To summarize published studies investigating suppression of cavernosal fibrosis in rat models of ED of various etiologies. METHODS: A literature search was conducted using PubMed. Relevant studies were identified using search terms such as erectile dysfunction, penis, fibrosis, and rat models. MAIN OUTCOME MEASURES: We reviewed representative literature studies on the mechanisms and suppression of cavernosal fibrosis in rat models of ED. RESULTS: The underlying mechanisms and potential therapeutic strategies suggested thus far for cavernosal fibrosis in rat models of ED were as follows. For age-related ED involving oxidative stress and tumor growth factor-beta1 (TGF-beta1)-driven pathways such as RhoA-ROCK1-LIMK2-cofilin or p42-44 and mitogen-activated protein kinase, proposed therapeutic strategies included phosphodiesterase type 5 inhibitors (PDE5Is), kallikrein-kinin system stimulators, and calorie restriction. For diabetes-related ED involving angiotensin-II- and TGF-beta1-driven Smad and non-Smad pathways, TGF-beta1 Wnt10b, and histone deacetylase (HDAC)-TGF-beta1 pathways, positive therapeutic results were obtained with PDE5Is, TGF-beta1 antagonists, HDAC inhibitors, antioxidants, sphingosine-1-phosphate receptor modulators (fingolimod), angiotensin-II antagonists, stem cell therapy, and antidiabetic drugs. For cavernosal nerve injury-associated ED involving TGF-beta1-driven pathways (Smad or RhoA-ROCK1-LIMK2-cofilin), Sonic hedgehog signaling, angiotensin-II-Smad, and HDAC4-TGF-beta1-Smad signaling triggered by cavernosal hypoxia, PDE5Is, angiotensin-II antagonists, stem cell therapy, HDAC inhibitors, Sonic hedgehog administration, ROCK inhibitors, and LIMK2 inhibitors have shown positive results. For testosterone deficiency-associated ED, TGF-beta1-driven pathways were found to be responsive to testosterone supplementation. For hypertensive ED, positive therapeutic results were obtained with angiotensin-II antagonists. For Peyronie disease involving TGF-beta1 or myostatin signaling, proposed therapeutic strategies included intra-tunical injection of TGF-beta receptor inhibitors or adipose tissue-derived stem cells and HDAC2 small hairpin RNA. CONCLUSION: Several signaling pathways appear to be responsible for the development of cavernosal fibrosis related to ED of various etiologies. Some therapeutic success has been achieved in animal models, but further research focusing on mechanism specific targeted therapies is needed. Cho MC, Song WH, Paick J-S. Suppression of Cavernosal Fibrosis in a Rat Model. Sex Med Rev 2018;6:572-582. PMID- 29631979 TI - Penile Traction Therapy and Vacuum Erection Devices in Peyronie's Disease. AB - INTRODUCTION: Peyronie's disease (PD) has historically been managed by at least 1 treatment, including oral supplements or medications, intralesional injections, or surgery. Adjunctive mechanical therapies also have been described, including penile traction therapy (PTT) and vacuum erection devices (VEDs), although relatively limited data are available on their use with PD. AIM: To review and summarize the published literature on the role and efficacy of PTT and VED in men with PD. METHODS: A PubMed search was performed of all publications on PTT and VED in men with PD from inception through September 2017. MAIN OUTCOME MEASURES: Changes in penile curvature, length, girth, erectile function, and adverse events with PTT or VED. RESULTS: PTT and VED exhibit mechanisms to improve aspects of PD, although clinical outcomes data are limited. Based on current data, PTT likely has a potential role as a primary lengthening therapy (modest improvements), in curvature correction (acute phase; unclear role in chronic phase), before penile prosthesis insertion, and after surgical correction of PD. The role of PTT as a combination therapy during collagenase Clostridium histolyticum injections is unclear. Fewer and lower level-of-evidence studies are available on VEDs and suggest potential roles in curvature correction, before penile prosthesis placement, or after PD surgery. Guideline statements from the American Urological Association and International Consultation on Sexual Medicine also support the potential role of PTT and VED in managing PD. CONCLUSIONS: PTT and VED represent viable therapeutic options for managing PD, with more data currently available on PTT. Because all PTT studies used a similar style of traction device, it is unclear whether results reflect outcomes of these particular devices or traction more broadly. Further studies are required to better delineate the benefits of PTT and VED, particularly in relation to other established treatments. Avant RA, Ziegelman M, Nehra A, et al. Penile Traction Therapy and Vacuum Erection Devices in Peyronie's Disease. Sex Med Rev 2018;X:XXX XXX. PMID- 29631980 TI - Stem Cell Therapy for Erectile Dysfunction. AB - INTRODUCTION: The prevalence of erectile dysfunction (ED) is substantial and continues to rise. Current therapeutics for ED consist of oral medications, intracavernosal injections, vacuum erection devices, and penile implants. While such options may manage the disease state, none of these modalities, however, restore function. Stem cell therapy has been evaluated for erectile restoration in animal models. These cells have been derived from multiple tissues, have varied potential, and may function via local engraftment or paracrine signaling. Bone marrow-derived stem cells (BMSC) and adipose-derived stem cells (ASC) have both been used in these models with noteworthy effects. AIM: Herein, we will review the pathophysiology of ED, animal models, current and novel stem-cell based therapeutics, clinical trials and areas for future research. METHODS: The relevant literature and contemporary data using keywords, "stem cells and erectile dysfunction" was reviewed. MAIN OUTCOME MEASURE: Examination of evidence supporting the association between erectile dysfunction and adipose derived stem cells, bone marrow derived stem cells, placental stem cells, urine stem cells and stem cell therapy respectively. RESULTS: Placental-derived stem cells and urine derived stem cells possess many similar properties as BMSC and ASC, but the methods of acquisition are favorable. Human clinical trials have already demonstrated successful use of stem cells for improvement of erectile function. CONCLUSION: The future of stem cell research is constantly being evaluated, although, the evidence suggests a place for stem cells in erectile dysfunction therapeutics. Matz EL, Terlecki R, Zhang Y, et al. Stem Cell Therapy for Erectile Dysfunction. Sex Med Rev 2018;XX:XXX-XXX. PMID- 29631981 TI - Role of Androgens in Female Genitourinary Tissue Structure and Function: Implications in the Genitourinary Syndrome of Menopause. AB - INTRODUCTION: Genitourinary conditions in women increase in prevalence with age. Androgens are prerequisite hormones of estrogen biosynthesis, are produced in larger amounts than estrogens in women, and decrease throughout adulthood. However, research and treatment for genitourinary complaints have traditionally focused on estrogens to the exclusion of other potential hormonal influences. AIM: To summarize and evaluate the evidence that androgens are important for maintaining genitourinary health in women and that lack of androgenic activity can contribute to the development of symptoms of the genitourinary syndrome of menopause. METHODS: The role of androgens in the pathophysiology, diagnosis, and treatment of genitourinary syndrome of menopause was discussed by an international and multidisciplinary panel during a consensus conference organized by the International Society for the Study of Women's Sexual Health. A subgroup further examined publications from the PubMed database, giving preference to clinical studies or to basic science studies in human tissues. MAIN OUTCOME MEASURES: Expert opinion evaluating trophic and functional effects of androgens, their differences from estrogenic effects, and regulation of androgen and estrogen receptor expression in female genitourinary tissues. RESULTS: Androgen receptors have been detected throughout the genitourinary system using immunohistochemical, western blot, ligand binding, and gene expression analyses. Lower circulating testosterone and estradiol concentrations and various genitourinary conditions have been associated with differential expression of androgen and estrogen receptors. Supplementation of androgen and/or estrogen in postmenopausal women (local administration) or in ovariectomized animals (systemic administration) induces tissue-specific responses that include changes in androgen and estrogen receptor expression, cell growth, mucin production, collagen turnover, increased perfusion, and neurotransmitter synthesis. CONCLUSION: Androgens contribute to the maintenance of genitourinary tissue structure and function. The effects of androgens can be distinct from those of estrogens or can complement estrogenic action. Androgen-mediated processes might be involved in the full or partial resolution of genitourinary syndrome of menopause symptoms in women. Traish AM, Vignozzi L, Simon JA, et al. Role of Androgens in Female Genitourinary Tissue Structure and Function: Implications in the Genitourinary Syndrome of Menopause. Sex Med Rev 2018;6:558-571. PMID- 29631982 TI - Radiologic, endoscopic, and functional patterns in patients with symptomatic gastroesophageal reflux disease after Roux-en-Y gastric bypass. AB - BACKGROUND: Roux-en-Y gastric bypass (RYGB) is considered the gold standard in treatment of morbid obesity and gastroesophageal reflux disease (GERD). Resolution of GERD symptoms is reported to be approximately 85% to 90%. OBJECTIVE: To evaluate patients with persistent GERD symptoms after RYGB and to identify contributing factors. SETTING: University hospital, cross-sectional study. METHODS: Data of patients evaluated for persistent GERD with a history of RYGB between January 2012 and December 2015 were reviewed. GERD was assessed with questionnaires, endoscopy, 24-hour pH-impendance manometry, and barium swallow. RESULTS: Of 47 patients, 44 (93.6%) presented with typical GERD, 18 (38.3%) with obstruction, 8 (17%) with pulmonary symptoms, and 21 (44.7%) with pain. The interval between RYGB and evaluation was a median of 3.8 years (range .8-12.6); median patient age was 36.5 years (19.1-67.2). Median body mass index was 30.3 kg/m2 (20.3-47.2). Pouch gastric fistulas were seen in 2 (5.1%), enlarged pouches in 5 (10.6%), and hiatal hernias in 25 patients (53.2%). Twelve (23.4%) had esophagitis>Los Angeles (LA) grade B. Manometry was performed in 45 (95.7%) and off-proton pump inhibitor 24-hour pH-impedance-metry in 44 patients (94.6%). Seventeen patients (37.8%) had esophageal hypomotility or aperistalsis; hypotensive lower esophageal sphincter was seen in 26 patients (57.8%). Increased esophageal acid exposure (>4% pH<4) was found in 27 (61.4%), an increased number of reflux episodes (>53) in 30 patients (68.2%). Symptoms were deemed as functional in 6 (12.8%). CONCLUSION: The evaluation for persistent GERD after RYGB revealed a high percentage of hiatal hernias, hypotensive lower esophageal sphincter, and severe esophageal motility disorders. These findings might have an influence on hiatal hernia closure concomitant with RYGB and the role of pH manometry in the preoperative bariatric assessment. PMID- 29631983 TI - Mesenteric visceral lipectomy using tissue liquefaction technology reverses insulin resistance and causes weight loss in baboons. AB - BACKGROUND: Visceral obesity is associated with diabetogenic and atherogenic abnormalities, including insulin resistance and increased risk for cardiometabolic diseases and mortality. Rodent lipectomy studies have demonstrated a causal link between visceral fat and insulin resistance, yet human omentectomy studies have failed to replicate this metabolic benefit, perhaps owing to the inability to target the mesentery. OBJECTIVES: We aimed to demonstrate that safe and effective removal of mesenteric fat could be achieved in obese insulin-resistant baboons using tissue liquefaction technology. SETTING: Southwest National Primate Research Center, San Antonio, Texas. METHODS: Tissue liquefaction technology has been developed to enable mesenteric visceral lipectomy (MVL) to be safely performed without disturbing the integrity of surrounding nerves and vessels in the mesentary. After an initial MVL optimization study (n = 3), we then performed MVL (n = 4) or sham surgery (n = 2) in a cohort of insulin-resistant baboons, and the metabolic phenotype was assessed via hyperinsulinemic-euglycemic clamps at baseline and 6 weeks later. RESULTS: MVL led to a 75% improvement in glucose disposal at 6-weeks follow-up (P = .01). Moreover, despite removing only an average of 430 g of mesenteric fat (~1% of total body mass), MVL led to a 14.4% reduction in total weight (P = .001). Thus, these data demonstrate that mesenteric fat can be safely targeted for removal by tissue liquefaction technology in a nonhuman primate, leading to substantial metabolic improvements, including reversal of insulin resistance and weight loss. CONCLUSIONS: These data provide the first demonstration of successful adipose tissue removal from the mesentery in a mammal. Importantly, we have demonstrated that when MVL is performed in obese, insulin-resistant baboons, insulin resistance is reversed, and significant weight loss occurs. Therefore, trials performing MVL in humans with abdominal obesity and related metabolic sequelae should be explored as a potential clinical tool to ameliorate insulin resistance and treat type 2 diabetes. PMID- 29631984 TI - Jejunal long noncoding RNAs are associated with glycemic control via gut-brain axis after bariatric surgery in diabetic mice. AB - BACKGROUND: Metabolic and bariatric surgery is effective in ameliorating type 2 diabetes, although its underlying mechanisms are largely unknown. Our previous study indicated that the distinctly expressed duodenal long noncoding RNAs (lncRNAs) induced by the duodenal-jejunal bypass (DJB) might play a role in improving glycemic control via the enteropancreatic axis. Therefore, the physiologic role of the jejunum in metabolic regulation after DJB requires investigation. OBJECTIVES: To investigate the alterations in the jejunal Roux limb lncRNA expression signatures after DJB and analyze the functional pathways associated with metabolic improvement on a genome-wide scale in high-fat diet induced diabetic mice. SETTING: University medical center. METHODS: Diabetic mice induced by high-fat diet were randomly assigned into 2 groups undergoing either DJB or sham surgery. The lncRNA and messenger (m)RNA expression profiles of the Roux limb segment of the jejunum in both groups were investigated using microarray. To identify the functional characteristics of the distinctly expressed lncRNAs, gene ontology and Kyoto Encyclopedia of Genes and Genomes pathway analysis were conducted. The lncRNA-mRNA and lncRNA-transcription factor interaction networks were constructed based on Pearson correlation analysis. RESULTS: Compared with the sham group, 827 dysregulated (fold change >=2.0) jejunal lncRNAs were identified in the DJB group. Both Kyoto Encyclopedia of Genes and Genomes pathway and gene ontology enrichment analysis revealed that 601 lncRNA-co-expressed mRNAs (fold change >=2.0) were associated with neuromodulation-related pathways or biological processes, including serotonergic, glutamatergic, and dopaminergic synapses. In addition, hormonal regulation related pathways, especially steroid biosynthesis, were also enriched. The results were further confirmed by bioinformatic analysis of target genes or transcription factors predicted on the basis of dysregulated jejunal lncRNAs. Furthermore, the NONMMUT023781 lncRNA may simultaneously target the Adcy8 mRNA both in cis and in trans and participate in neuromodulation and hormonal regulation. CONCLUSION: Alterations of jejunal Roux limb lncRNA and mRNA expression profiles trigger both neuromodulation and endocrine-related pathways, which play a critical role in type 2 diabetes remission after metabolic and bariatric surgery via the gut-brain axis. NONMMTU023781 and Adcy8 were identified as potential targets, which warrant further research. PMID- 29631986 TI - Surgery-first/early-orthognathic approach may yield poorer postoperative stability than conventional orthodontics-first approach: a systematic review and meta-analysis. AB - OBJECTIVE: There are conflicting views on the postoperative stability of surgery first and surgery-early approaches in orthognathic surgery. We systematically reviewed the literature to compare the difference in postoperative stability between a surgery-first/early orthognathic approach (SFEA) and a conventional orthodontics-first approach (COA). STUDY DESIGN: PubMed, Embase, and Cochrane Library were searched for studies related to the postoperative stability of SFEA. The primary outcome was the horizontal relapse at the pogonion. Weighted mean differences with 95% confidence intervals were pooled using a random-effects model. RESULTS: We analyzed 12 studies (total of 498 participants). The pooled estimate suggested that the SFEA group manifested less postoperative stability than COA group (weighted mean difference, 1.50; P < .00001), with moderate heterogeneity (I2 = 53%). The result of subgroup analysis yielded no subgroup difference. Sensitivity analysis conducted by omitting one study at a time further validated the robustness of the result. CONCLUSIONS: Based on the meta analysis, the mandible tends to rotate counterclockwise more in the SFEA group, which indicate a poorer postoperative stability than in the COA group. Patient screening and treatment plans should be reviewed carefully to compensate for possible postoperative relapse when adopting SFEA. PMID- 29631985 TI - Noninvasive diagnostic adjuncts for the evaluation of potentially premalignant oral epithelial lesions: current limitations and future directions. AB - Potentially premalignant oral epithelial lesions (PPOELs) are a group of clinically suspicious conditions, of which a small percentage will undergo malignant transformation. PPOELs are suboptimally diagnosed and managed under the current standard of care. Dysplasia is the most well-established marker to distinguish high-risk PPOELs from low-risk PPOELs, and performing a biopsy to establish dysplasia is the diagnostic gold standard. However, a biopsy is limited by morbidity, resource requirements, and the potential for underdiagnosis. Diagnostic adjuncts may help clinicians better evaluate PPOELs before definitive biopsy, but existing adjuncts, such as toluidine blue, acetowhitening, and autofluorescence imaging, have poor accuracy and are not generally recommended. Recently, in vivo microscopy technologies, such as high-resolution microendoscopy, optical coherence tomography, reflectance confocal microscopy, and multiphoton imaging, have shown promise for improving PPOEL patient care. These technologies allow clinicians to visualize many of the same microscopic features used for histopathologic assessment at the point of care. PMID- 29631987 TI - Estimating the Risk of Influenza-Like Illness Transmission Through Social Contacts: Web-Based Participatory Cohort Study. AB - BACKGROUND: Epidemiological studies on influenza have focused mostly on enhancing vaccination coverage or promoting personal hygiene behavior. Few studies have investigated potential effects of personal health behaviors and social contacts on the risk of getting influenza-like illness (ILI). OBJECTIVE: Taking advantage of an online participatory cohort, this study aimed to estimate the increased risk of getting ILI after contact with infected persons and examine how personal health behaviors, weather, and air pollution affect the probability of getting ILI. METHODS: A Web-based platform was designed for participants to record daily health behaviors and social contacts during the influenza season of October 1, 2015 to March 31, 2016, in Taiwan. Data on sleep, diet, physical activity, self reported ILI, and contact with infected persons were retrieved from the diaries. Measurements of weather and air pollutants were used for calculating environmental exposure levels for the participants. We fitted a mixed-effects logistic regression model to the daily measurements of the diary keepers to estimate the effects of these variables on the risk of getting ILI. RESULTS: During the influenza season, 160 participants provided 14,317 health diaries and recorded 124,222 face-to-face contacts. The model estimated odds ratio of getting ILI was 1.87 (95% CI 1.40-2.50) when a person had contact with others having ILI in the previous 3 days. Longer duration of physical exercise and eating more fruits, beans, and dairy products were associated with lower risk of getting ILI. However, staying up late was linked to an elevated risk of getting ILI. Higher variation of ambient temperature and worse air quality were associated with increased risk of developing ILI. CONCLUSIONS: Developing a healthier lifestyle, avoiding contact with persons having ILI symptoms, and staying alert with respect to temperature changes and air quality can reduce the risk of getting ILI. PMID- 29631988 TI - Identification of Users for a Smoking Cessation Mobile App: Quantitative Study. AB - BACKGROUND: The number of mobile apps that support smoking cessation is growing, indicating the potential of the mobile phone as a means to support cessation. Knowledge about the potential end users for cessation apps results in suggestions to target potential user groups in a dissemination strategy, leading to a possible increase in the satisfaction and adherence of cessation apps. OBJECTIVE: This study aimed to characterize potential end users for a specific mobile health (mHealth) smoking cessation app. METHODS: A quantitative study was conducted among 955 Dutch smokers and ex-smokers. The respondents were primarily recruited from addiction care facilities and hospitals through Web-based media via websites and forums. The respondents were surveyed on their demographics, smoking behavior, and personal innovativeness. The intention to use and the attitude toward a cessation app were determined on a 5-point Likert scale. To study the association between the characteristics and intention to use and attitude, univariate and multivariate ordinal logistic regression analyses were performed. RESULTS: The multivariate ordinal logistic regression showed that the number of previous quit attempts (odds ratio [OR] 4.1, 95% CI 2.4-7.0, and OR 3.5, 95% CI 2.0-5.9) and the score on the Fagerstrom Test of Nicotine Dependence (OR 0.8, 95% CI 0.8-0.9, and OR 0.8, 95% CI 0.8-0.9) positively correlates with the intention to use a cessation app and the attitude toward cessation apps, respectively. Personal innovativeness also positively correlates with the intention to use (OR 0.3, 95% CI 0.2-0.4) and the attitude towards (OR 0.2, 95% CI 0.1-0.4) a cessation app. No associations between demographics and the intention to use or the attitude toward using a cessation app were observed. CONCLUSIONS: This study is among the first to show that demographic characteristics such as age and level of education are not associated with the intention to use and the attitude toward using a cessation app when characteristics related specifically to the app, such as nicotine dependency and the number of quit attempts, are present in a multivariate regression model. This study shows that the use of mHealth apps depends on characteristics related to the content of the app rather than general user characteristics. PMID- 29631989 TI - Managing Patient-Generated Health Data Through Mobile Personal Health Records: Analysis of Usage Data. AB - BACKGROUND: Personal health records (PHRs) and mHealth apps are considered essential tools for patient engagement. Mobile PHRs (mPHRs) can be a platform to integrate patient-generated health data (PGHD) and patients' medical information. However, in previous studies, actual usage data and PGHD from mPHRs have not been able to adequately represent patient engagement. OBJECTIVE: By analyzing 5 years' PGHD from an mPHR system developed by a tertiary hospital in South Korea, we aimed to evaluate how PGHD were managed and identify issues in PGHD management based on actual usage data. Additionally, we analyzed how to improve patient engagement with mPHRs by analyzing the actively used services and long-term usage patterns. METHODS: We gathered 5 years (December 2010 to December 2015) of log data from both hospital patients and general users of the app. We gathered data from users who entered PGHD on body weight, blood pressure (BP), blood glucose levels, 10-year cardiovascular disease (CVD) risk, metabolic syndrome risk, medication schedule, insulin, and allergy. We classified users according to whether they were patients or general users based on factors related to continuous use (>=28 days for weight, BP, and blood glucose, and >=180 days for CVD and metabolic syndrome), and analyzed the patients' characteristics. We compared PGHD entry counts and the proportion of continuous users for each PGHD by user type. RESULTS: The total number of mPHR users was 18,265 (patients: n=16,729, 91.59%) with 3620 users having entered weight, followed by BP (n=1625), blood glucose (n=1374), CVD (n=764), metabolic syndrome (n=685), medication (n=252), insulin (n=72), and allergy (n=61). Of those 18,256 users, 3812 users had at least one PGHD measurement, of whom 175 used the PGHD functions continuously (patients: n=142, 81.14%); less than 1% of the users had used it for more than 4 years. Except for weight, BP, blood glucose, CVD, and metabolic syndrome, the number of PGHD records declined. General users' continuous use of PGHD was significantly higher than that of patients in the blood glucose (P<.001) and BP (P=.03) functions. Continuous use of PGHD in health management (BP, blood glucose, and weight) was significantly greater among older users (P<.001) and men (P<.001). In health management (BP, weight, and blood glucose), overall chronic disease and continuous use of PGHD were not statistically related (P=.08), but diabetes (P<.001) and cerebrovascular diseases (P=.03) were significant. CONCLUSIONS: Although a small portion of users managed PGHD continuously, PGHD has the potential to be useful in monitoring patient health. To realize the potential, specific groups of continuous users must be identified, and the PGHD service must target them. Further evaluations for the clinical application of PGHD, feedback regarding user interfaces, and connections with wearable devices are needed. PMID- 29631990 TI - Diabetes-Specific Formulae Versus Standard Formulae as Enteral Nutrition to Treat Hyperglycemia in Critically Ill Patients: Protocol for a Randomized Controlled Feasibility Trial. AB - BACKGROUND: During critical illness, hyperglycemia is prevalent and is associated with adverse outcomes. While treating hyperglycemia with insulin reduces morbidity and mortality, it increases glycemic variability and hypoglycemia risk, both of which have been associated with an increase in mortality. Therefore, other interventions which improve glycemic control, without these complications should be explored. Nutrition forms part of standard care, but the carbohydrate load of these formulations has the potential to exacerbate hyperglycemia. Specific diabetic-formulae with a lesser proportion of carbohydrate are available, and these formulae are postulated to limit glycemic excursions and reduce patients' requirements for exogenous insulin. OBJECTIVE: The primary outcome of this prospective, blinded, single center, randomized controlled trial is to determine whether a diabetes-specific formula reduces exogenous insulin administration. Key secondary outcomes include the feasibility of study processes as well as glycemic variability. METHODS: Critically ill patients will be eligible if insulin is administered whilst receiving exclusively liquid enteral nutrition. Participants will be randomized to receive a control formula, or a diabetes-specific, low glycemic index, low in carbohydrate study formula. Additionally, a third group of patients will receive a second diabetes-specific, low glycemic index study formula, as part of a sub-study to evaluate its effect on biomarkers. This intervention group (n=12) will form part of recruitment to a nested cohort study with blood and urine samples collected at randomization and 48 hours later for the first 12 participants in each group with a secondary objective of exploring the metabolic implications of a change in nutrition formula. Data on relevant medication and infusions, nutrition provision and glucose control will be collected to a maximum of 48 hours post randomization. Baseline patient characteristics and anthropometric measures will be recorded. A 28-day phone follow-up will explore weight and appetite changes as well as blood glucose control pre and post intensive care unit (ICU) discharge. RESULTS: Recruitment commenced in February 2015 with an estimated completion date for data collection by May 2018. Results are expected to be available late 2018. CONCLUSIONS: This feasibility study of the effect of diabetes-specific formulae on the administration of insulin in critically ill patients and will inform the design of a larger, multi-center trial. TRIAL REGISTRATION: Australian New Zealand Clinical Trial Registry (ANZCTR):12614000166673; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=1261400016667 (Archived by WebCite at http://www.webcitation.org/6xs0phrVu). PMID- 29631991 TI - Patient Adherence to Scheduled Vital Sign Measurements During Home Telemonitoring: Analysis of the Intervention Arm in a Before and After Trial. AB - BACKGROUND: In a home telemonitoring trial, patient adherence with scheduled vital signs measurements is an important aspect that has not been thoroughly studied and for which data in the literature are limited. Levels of adherence have been reported as varying from approximately 40% to 90%, and in most cases, the adherence rate usually dropped off steadily over time. This drop is more evident in the first few weeks or months after the start. Higher adherence rates have been reported for simple types of monitoring and for shorter periods of intervention. If patients do not follow the intended procedure, poorer results than expected may be achieved. Hence, analyzing factors that can influence patient adherence is of great importance. OBJECTIVE: The goal of the research was to present findings on patient adherence with scheduled vital signs measurements in the recently completed Commonwealth Scientific and Industrial Research Organisation (CSIRO) national trial of home telemonitoring of patients (mean age 70.5 years, SD 9.3 years) with chronic conditions (chronic obstructive pulmonary disease, coronary artery disease, hypertensive diseases, congestive heart failure, diabetes, or asthma) carried out at 5 locations along the east coast of Australia. We investigated the ability of chronically ill patients to carry out a daily schedule of vital signs measurements as part of a chronic disease management care plan over periods exceeding 6 months (302 days, SD 135 days) and explored different levels of adherence for different measurements as a function of age, gender, and supervisory models. METHODS: In this study, 113 patients forming the test arm of a Before and After Control Intervention (BACI) home telemonitoring trial were analyzed. Patients were required to monitor on a daily basis a range of vital signs determined by their chronic condition and comorbidities. Vital signs included noninvasive blood pressure, pulse oximetry, spirometry, electrocardiogram (ECG), blood glucose level, body temperature, and body weight. Adherence was calculated as the number of days during which at least 1 measurement was taken over all days where measurements were scheduled. Different levels of adherence for different measurements, as a function of age, gender, and supervisory models, were analyzed using linear regression and analysis of covariance for a period of 1 year after the intervention. RESULTS: Patients were monitored on average for 302 (SD 135) days, although some continued beyond 12 months. The overall adherence rate for all measurements was 64.1% (range 59.4% to 68.8%). The adherence rates of patients monitored in hospital settings relative to those monitored in community settings were significantly higher for spirometry (69.3%, range 60.4% to 78.2%, versus 41.0%, range 33.1% to 49.0%, P<.001), body weight (64.5%, range 55.7% to 73.2%, versus 40.5%, range 32.3% to 48.7%, P<.001), and body temperature (66.8%, range 59.7% to 73.9%, versus 55.2%, range 48.4% to 61.9%, P=.03). Adherence with blood glucose measurements (58.1%, range 46.7% to 69.5%, versus 50.2%, range 42.8% to 57.6%, P=.24) was not significantly different overall. Adherence rates for blood pressure (68.5%, range 62.7% to 74.2%, versus 59.7%, range 52.1% to 67.3%, P=.04), ECG (65.6%, range 59.7% to 71.5%, versus 56.5%, range 48.7% to 64.4%, P=.047), and pulse oximetry (67.0%, range 61.4% to 72.7%, versus 56.4%, range 48.6% to 64.1%, P=.02) were significantly higher in males relative to female subjects. No statistical differences were observed between rates of adherence for the younger patient group (70 years and younger) and older patient group (older than 70 years). CONCLUSIONS: Patients with chronic conditions enrolled in the home telemonitoring trial were able to record their vital signs at home at least once every 2 days over prolonged periods of time. Male patients maintained a higher adherence than female patients over time, and patients supervised by hospital-based care coordinators reported higher levels of adherence with their measurement schedule relative to patients supervised in community settings. This was most noticeable for spirometry. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN12613000635763; https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=364030&isReview= rue (Archived by WebCite at http://www.webcitation.org/6xPOU3DpR). PMID- 29631992 TI - The Validity of Online Patient Ratings of Physicians: Analysis of Physician Peer Reviews and Patient Ratings. AB - BACKGROUND: Information from ratings sites are increasingly informing patient decisions related to health care and the selection of physicians. OBJECTIVE: The current study sought to determine the validity of online patient ratings of physicians through comparison with physician peer review. METHODS: We extracted 223,715 reviews of 41,104 physicians from 10 of the largest cities in the United States, including 1142 physicians listed as "America's Top Doctors" through physician peer review. Differences in mean online patient ratings were tested for physicians who were listed and those who were not. RESULTS: Overall, no differences were found between the online patient ratings based upon physician peer review status. However, statistical differences were found for four specialties (family medicine, allergists, internal medicine, and pediatrics), with online patient ratings significantly higher for those physicians listed as a peer-reviewed "Top Doctor" versus those who were not. CONCLUSIONS: The results of this large-scale study indicate that while online patient ratings are consistent with physician peer review for four nonsurgical, primarily in-office specializations, patient ratings were not consistent with physician peer review for specializations like anesthesiology. This result indicates that the validity of patient ratings varies by medical specialization. PMID- 29631993 TI - Application of Behavior Change Techniques in a Personalized Nutrition Electronic Health Intervention Study: Protocol for the Web-Based Food4Me Randomized Controlled Trial. AB - BACKGROUND: To determine the efficacy of behavior change techniques applied in dietary and physical activity intervention studies, it is first necessary to record and describe techniques that have been used during such interventions. Published frameworks used in dietary and smoking cessation interventions undergo continuous development, and most are not adapted for Web-based delivery. The Food4Me study (N=1607) provided the opportunity to use existing frameworks to describe standardized Web-based techniques employed in a large-scale, internet based intervention to change dietary behavior and physical activity. OBJECTIVE: The aims of this study were (1) to describe techniques embedded in the Food4Me study design and explain the selection rationale and (2) to demonstrate the use of behavior change technique taxonomies, develop standard operating procedures for training, and identify strengths and limitations of the Food4Me framework that will inform its use in future studies. METHODS: The 6-month randomized controlled trial took place simultaneously in seven European countries, with participants receiving one of four levels of personalized advice (generalized, intake-based, intake+phenotype-based, and intake+phenotype+gene-based). A three phase approach was taken: (1) existing taxonomies were reviewed and techniques were identified a priori for possible inclusion in the Food4Me study, (2) a standard operating procedure was developed to maintain consistency in the use of methods and techniques across research centers, and (3) the Food4Me behavior change technique framework was reviewed and updated post intervention. An analysis of excluded techniques was also conducted. RESULTS: Of 46 techniques identified a priori as being applicable to Food4Me, 17 were embedded in the intervention design; 11 were from a dietary taxonomy, and 6 from a smoking cessation taxonomy. In addition, the four-category smoking cessation framework structure was adopted for clarity of communication. Smoking cessation texts were adapted for dietary use where necessary. A posteriori, a further 9 techniques were included. Examination of excluded items highlighted the distinction between techniques considered appropriate for face-to-face versus internet-based delivery. CONCLUSIONS: The use of existing taxonomies facilitated the description and standardization of techniques used in Food4Me. We recommend that for complex studies of this nature, technique analysis should be conducted a priori to develop standardized procedures and training and reviewed a posteriori to audit the techniques actually adopted. The present framework description makes a valuable contribution to future systematic reviews and meta-analyses that explore technique efficacy and underlying psychological constructs. This was a novel application of the behavior change taxonomies and was the first internet-based personalized nutrition intervention to use such a framework remotely. TRIAL REGISTRATION: ClinicalTrials.gov NCT01530139; https://clinicaltrials.gov/ct2/show/NCT01530139 (Archived by WebCite at http://www.webcitation.org/6y8XYUft1). PMID- 29631994 TI - Hamman's crunch: a forgotten clue to the diagnosis of spontaneous pneumomediastinum. PMID- 29631996 TI - Who's Who of Pulmonary Hypertension: Redefining Classification to Advance Precision Care. PMID- 29631997 TI - GP trainee facing deportation must be allowed to stay, says BMA. PMID- 29631995 TI - Exome Sequencing in Children With Pulmonary Arterial Hypertension Demonstrates Differences Compared With Adults. AB - BACKGROUND: Pulmonary arterial hypertension (PAH) is a rare disease characterized by pulmonary arteriole remodeling, elevated arterial pressure and resistance, and subsequent heart failure. Compared with adult-onset disease, pediatric-onset PAH is more heterogeneous and often associated with worse prognosis. Although BMPR2 mutations underlie ~70% of adult familial PAH (FPAH) cases, the genetic basis of PAH in children is less understood. METHODS: We performed genetic analysis of 155 pediatric- and 257 adult-onset PAH patients, including both FPAH and sporadic, idiopathic PAH (IPAH). After screening for 2 common PAH risk genes, mutation negative FPAH and all IPAH cases were evaluated by exome sequencing. RESULTS: We observed similar frequencies of rare, deleterious BMPR2 mutations in pediatric- and adult-onset patients: ~55% in FPAH and 10% in IPAH patients in both age groups. However, there was significant enrichment of TBX4 mutations in pediatric- compared with adult-onset patients (IPAH: 10/130 pediatric versus 0/178 adult onset), and TBX4 carriers had younger mean age-of-onset compared with BMPR2 carriers. Mutations in other known PAH risk genes were infrequent in both age groups. Notably, among pediatric IPAH patients without mutations in known risk genes, exome sequencing revealed a 2-fold enrichment of de novo likely gene damaging and predicted deleterious missense variants. CONCLUSIONS: Mutations in known PAH risk genes accounted for ~70% to 80% of FPAH in both age groups, 21% of pediatric-onset IPAH, and 11% of adult-onset IPAH. Rare, predicted deleterious variants in TBX4 are enriched in pediatric patients and de novo variants in novel genes may explain ~19% of pediatric-onset IPAH cases. PMID- 29631999 TI - Correction: Fat body glycogen serves as a metabolic safeguard for the maintenance of sugar levels in Drosophila (doi:10.1242/dev.158865). PMID- 29632000 TI - Association of antenatal steroid and risk of retinopathy of prematurity: a systematic review and meta-analysis. AB - BACKGROUND: Retinopathy of prematurity (ROP) is one of the leading causes of childhood blindness. Use of antenatal steroid can reduce neonatal morbidity and mortality in preterm births, but its effect on ROP remained controversial. We aim to determine the association between antenatal steroid and risk of ROP by a systematic review and meta-analysis. METHODS: Reported studies on the association between antenatal steroid and risk of ROP or severe ROP were identified from MEDLINE and Embase databases from their inception to November 2016. Outcome measures were ORs with 95% CIs. Extracted data were pooled using a random-effect model or fixed-effect model where appropriate. Heterogeneity was assessed, and sensitivity analysis was performed. RESULTS: A total of 434 relevant studies were identified, and 28 studies were eligible for the meta-analysis, involving 20 731 neonates with 4202 cases of ROP. Among the 28 studies included, 13 studies provided data evaluating the association between antenatal steroid use and severe ROP, involving 4999 neonates with 792 cases of severe ROP. Antenatal steroid administration was associated with a reduced risk of ROP development (ORunadjusted=0.82, 95% CI 0.68 to 0.98; ORadjusted=0.67, 95% CI 0.47 to 0.94) and progression to severe ROP (ORunadjusted=0.58, 95% CI 0.40 to 0.86). CONCLUSION: Antenatal steroid administration is associated with a reduced risk of ROP development and progression to severe ROP. Our results strengthened the indications of antenatal steroid therapy to high-risk mothers giving preterm births, especially in low-income and middle-income countries where antenatal steroid are not yet widely used. PMID- 29632001 TI - Long-term reconstruction of foveal microstructure and visual acuity after idiopathic macular hole repair: three-year follow-up study. AB - AIMS: To evaluate long-term reconstructive changes in foveal microstructures and their associations with visual improvement in eyes with surgically closed macular holes (MHs). METHODS: Twenty-eight eyes of 28 patients who underwent successful idiopathic MH repair were retrospectively studied. Best-corrected visual acuity (BCVA) and spectral-domain optical coherence tomography images were examined preoperatively and 1, 3, 6, 12, 24 and 36 months postoperatively. Correlations between postoperative BCVA and parameters relating to the reconstruction of the foveal photoreceptor layer including the external limiting membrane (ELM), ellipsoid zone (EZ) and cone interdigitation zone (CIZ) as well as changes in glial cells were evaluated. RESULTS: Logarithm of the minimum angle of resolution BCVA improved continuously during 3-year follow-up (baseline 0.70+/-0.27, 1 month 0.36+/-0.34, 3 months 0.29+/-0.30, 6 months 0.22+/-0.24, 12 months 0.18+/-0.25, 24 months 0.14+/-0.22, 36 months 0.10+/-0.19) (p=0.015). Continuous reconstruction of the foveal microstructure was apparent throughout the 3-year follow-up. The reconstruction process was initiated by glial proliferation, followed by ELM bridging, glial elimination with EZ reconstruction and CIZ reconstruction. Better BCVA at the 3-year time-point was significantly associated with early ELM bridging, early glial disappearance and photoreceptor integrity defined as complete reconstruction of the ELM, EZ and CIZ. CONCLUSIONS: Integrity of the photoreceptor layer was correlated with better long-term visual outcomes after MH repair. Reconstruction of the foveal ELM and disappearance of glial proliferation in the early postoperative period predicted better visual recovery. PMID- 29632002 TI - Inter-relationship between ageing, body mass index, diabetes, systemic blood pressure and intraocular pressure in Asians: 6-year longitudinal study. AB - BACKGROUND: To investigate the biological effect of ageing on intraocular pressure (IOP) and risk factors in a population-based cohort study of Malay and Indian adults. METHODS: Participants aged 40-80 years were recruited for baseline and 6-year follow-up visits between 2004-2009 and 2010-2015, respectively. Blood pressure (BP) was measured with an automatic BP monitor and IOP were obtained by Goldmann applanation tonometry. Main outcome was change in IOP, defined as the difference between the 6-year IOP and the baseline IOP. Linear regression models were used to investigate the association of changes in IOP with risk factors. RESULTS: Participants without a history of glaucoma or cataract surgery at baseline were included (n = 3188; mean age: 54+/-9 years) . Their average IOP was reduced (-0.5+/-3.1 mm Hg), except for those who developed hypertension at follow up (0.0+/-3.1 mm Hg). After adjusting for covariates, changes in IOP were negatively associated with age (beta=-0.07, 95% CI -0.13 to -0.01) and positively associated with body mass index, diabetes, hypertension (normotensive as reference group; newly developed hypertensive (beta=0.67, 95% CI 0.39 to 0.95) and chronic hypertensive (beta=0.46, 95% CI 0.22 to 0.70)), baseline systolic BP (SBP) (beta=0.20, 95% CI 0.14 to 0.26) and diastolic BP (DBP) (beta=0.33, 95% CI 0.22 to 0.44), as well as with 6-year increases in SBP (beta=0.27, 95% CI 0.21 to 0.33) and DBP (beta=0.52, 95% CI 0.41 to 0.63). CONCLUSIONS: Normal ageing and reduced systemic BP are associated with reduced IOP in Malay and Indian adults. Given that high IOP is a risk factor for glaucoma, our finding highlights the importance of controlling hypertension in older adults, where hypertension and glaucoma incidences are on a rise. PMID- 29632003 TI - Abdominal symptoms and cancer in the abdomen: prospective cohort study in European primary care. AB - BACKGROUND: Different abdominal symptoms may signal cancer, but their role is unclear. AIM: To examine associations between abdominal symptoms and subsequent cancer diagnosed in the abdominal region. DESIGN AND SETTING: Prospective cohort study comprising 493 GPs from surgeries in Norway, Denmark, Sweden, Scotland, Belgium, and the Netherlands. METHOD: Over a 10-day period, the GPs recorded consecutive consultations and noted: patients who presented with abdominal symptoms pre-specified on the registration form; additional data on non-specific symptoms; and features of the consultation. Eight months later, data on all cancer diagnoses among all study patients in the participating general practices were requested from the GPs. RESULTS: Consultations with 61 802 patients were recorded and abdominal symptoms were documented in 6264 (10.1%) patients. Malignancy, both abdominal and non-abdominal, was subsequently diagnosed in 511 patients (0.8%). Among patients with a new cancer in the abdomen (n = 251), 175 (69.7%) were diagnosed within 180 days after consultation. In a multivariate model, the highest sex- and age-adjusted hazard ratio (HR) was for the single symptom of rectal bleeding (HR 19.1, 95% confidence interval = 8.7 to 41.7). Positive predictive values of >3% were found for macroscopic haematuria, rectal bleeding, and involuntary weight loss, with variations according to age and sex. The three symptoms relating to irregular bleeding had particularly high specificity in terms of colorectal, uterine, and bladder cancer. CONCLUSIONS: A patient with undiagnosed cancer may present with symptoms or no symptoms. Irregular bleeding must always be explained. Abdominal pain occurs with all types of abdominal cancer and several symptoms may signal colorectal cancer. The findings are important as they influence how GPs think and act, and how they can contribute to an earlier diagnosis of cancer. PMID- 29632004 TI - Weight loss as a predictor of cancer in primary care: a systematic review and meta-analysis. AB - BACKGROUND: Weight loss is a non-specific cancer symptom for which there are no clinical guidelines about investigation in primary care. AIM: To summarise the available evidence on weight loss as a clinical feature of cancer in patients presenting to primary care. DESIGN AND SETTING: A diagnostic test accuracy review and meta-analysis. METHOD: Studies reporting 2 * 2 diagnostic accuracy data for weight loss (index test) in adults presenting to primary care and a subsequent diagnosis of cancer (reference standard) were included. QUADAS-2 was used to assess study quality. Sensitivity, specificity, positive likelihood ratios, and positive predictive values were calculated, and a bivariate meta-analysis performed. RESULTS: A total of 25 studies were included, with 23 (92%) using primary care records. Of these, 20 (80%) defined weight loss as a physician's coding of the symptom; the remainder collected data directly. One defined unexplained weight loss using objective measurements. Positive associations between weight loss and cancer were found for 10 cancer sites: prostate, colorectal, lung, gastro-oesophageal, pancreatic, non-Hodgkin's lymphoma, ovarian, myeloma, renal tract, and biliary tree. Sensitivity ranged from 2% to 47%, and specificity from 92% to 99%, across cancer sites. The positive predictive value for cancer in male and female patients with weight loss for all age groups >=60 years exceeded the 3% risk threshold that current UK guidance proposes for further investigation. CONCLUSION: A primary care clinician's decision to code for weight loss is highly predictive of cancer. For such patients, urgent referral pathways are justified to investigate for cancer across multiple sites. PMID- 29632005 TI - Development of a prediction tool for patients presenting with acute cough in primary care: a prognostic study spanning six European countries. AB - BACKGROUND: Accurate prediction of the course of an acute cough episode could curb antibiotic overprescribing, but is still a major challenge in primary care. AIM: The authors set out to develop a new prediction rule for poor outcome (re consultation with new or worsened symptoms, or hospital admission) in adults presenting to primary care with acute cough. DESIGN AND SETTING: Data were collected from 2604 adults presenting to primary care with acute cough or symptoms suggestive of lower respiratory tract infection (LRTI) within the Genomics to combat Resistance against Antibiotics in Community-acquired LRTI in Europe (GRACE; www.grace-lrti.org) Network of Excellence. METHOD: Important signs and symptoms for the new prediction rule were found by combining random forest and logistic regression modelling. Performance to predict poor outcome in acute cough patients was compared with that of existing prediction rules, using the models' area under the receiver operator characteristic curve (AUC), and any improvement obtained by including additional test results (C-reactive protein [CRP], blood urea nitrogen [BUN], chest radiography, or aetiology) was evaluated using the same methodology. RESULTS: The new prediction rule, included the baseline Risk of poor outcome, Interference with daily activities, number of years stopped Smoking (> or <45 years), severity of Sputum, presence of Crackles, and diastolic blood pressure (> or <85 mmHg) (RISSC85). Though performance of RISSC85 was moderate (sensitivity 62%, specificity 59%, positive predictive value 27%, negative predictive value 86%, AUC 0.63, 95% confidence interval [CI] = 0.61 to 0.67), it outperformed all existing prediction rules used today (highest AUC 0.53, 95% CI = 0.51 to 0.56), and could not be significantly improved by including additional test results (highest AUC 0.64, 95% CI = 0.62 to 0.68). CONCLUSION: The new prediction rule outperforms all existing alternatives in predicting poor outcome in adult patients presenting to primary care with acute cough and could not be improved by including additional test results. PMID- 29632006 TI - Identification and Validation of a 3-Gene Methylation Classifier for HPV-Based Cervical Screening on Self-Samples. AB - Purpose: Offering self-sampling of cervico-vaginal material for high-risk human papillomavirus (hrHPV) testing is an effective method to increase the coverage in cervical screening programs. Molecular triage directly on hrHPV-positive self samples for colposcopy referral opens the way to full molecular cervical screening. Here, we set out to identify a DNA methylation classifier for detection of cervical precancer (CIN3) and cancer, applicable to lavage and brush self-samples.Experimental Design: We determined genome-wide DNA methylation profiles of 72 hrHPV-positive self-samples, using the Infinium Methylation 450K Array. The selected DNA methylation markers were evaluated by multiplex quantitative methylation-specific PCR (qMSP) in both hrHPV-positive lavage (n = 245) and brush (n = 246) self-samples from screening cohorts. Subsequently, logistic regression analysis was performed to build a DNA methylation classifier for CIN3 detection applicable to self-samples of both devices. For validation, an independent set of hrHPV-positive lavage (n = 199) and brush (n = 287) self samples was analyzed.Results: Genome-wide DNA methylation profiling revealed 12 DNA methylation markers for CIN3 detection. Multiplex qMSP analysis of these markers in large series of lavage and brush self-samples yielded a 3-gene methylation classifier (ASCL1, LHX8, and ST6GALNAC5). This classifier showed a very good clinical performance for CIN3 detection in both lavage (AUC = 0.88; sensitivity = 74%; specificity = 79%) and brush (AUC = 0.90; sensitivity = 88%; specificity = 81%) self-samples in the validation set. Importantly, all self samples from women with cervical cancer scored DNA methylation positive.Conclusions: By genome-wide DNA methylation profiling on self-samples, we identified a highly effective 3-gene methylation classifier for direct triage on hrHPV-positive self-samples, which is superior to currently available methods. Clin Cancer Res; 24(14); 3456-64. (c)2018 AACR. PMID- 29632007 TI - Complete and Durable Responses in Primary Central Nervous System Posttransplant Lymphoproliferative Disorder with Zidovudine, Ganciclovir, Rituximab, and Dexamethasone. AB - Purpose: Primary central nervous system posttransplant lymphoproliferative disorder (PCNS-PTLD) is a complication of solid organ transplantation with a poor prognosis and typically associated with Epstein-Barr virus (EBV). We hypothesized EBV lytic-phase protein expression would allow successful treatment with antiviral therapy.Patients and Methods: Thirteen patients were treated with zidovudine (AZT), ganciclovir (GCV), dexamethasone, and rituximab in EBV+ PCNS PTLD. Twice-daily, intravenous AZT 1,500 mg, GCV 5 mg/kg, and dexamethasone 10 mg were given for 14 days. Weekly rituximab 375 mg/m2 was delivered for the first 4 weeks. Twice-daily valganciclovir 450 mg and AZT 300 mg started day 15. Lytic and latent protein expression was assessed using in situ hybridization and immunohistochemistry. Immunoblot assay assessed lytic gene activation. Cells transfected with lytic kinase vectors were assessed for sensitivity to our therapy using MTS tetrazolium and flow cytometry.Results: The median time to response was 2 months. Median therapy duration was 26.5 months. Median follow-up was 52 months. The estimated 2-year overall survival (OS) was 76.9% (95% CI, 44.2%-91.9%). Overall response rate (ORR) was 92% (95% CI, 64%-100%). BXLF1/vTK and BGLF4 expression was found in the seven tumor biopsies evaluated. Lytic gene expression was induced in vitro using the four-drug regimen. Transfection with viral kinase cDNA increased cellular sensitivity to antiviral therapy.Conclusions: EBV+ PCNS-PTLD expressed lytic kinases and therapy with AZT, GCV, rituximab and dexamethasone provided durable responses. Induction of the lytic protein expression and increased cellular sensitivity to antiviral therapy after transfection with viral kinase cDNA provides a mechanistic rationale for our approach. Clin Cancer Res; 24(14); 3273-81. (c)2018 AACR. PMID- 29632008 TI - Imidazopyridine Compounds Inhibit Mycobacterial Growth by Depleting ATP Levels. AB - The imidazopyridines are a promising new class of antitubercular agents with potent activity in vitro and in vivo We isolated mutants of Mycobacterium tuberculosis resistant to a representative imidazopyridine; the mutants had large shifts (>20-fold) in MIC. Whole-genome sequencing revealed mutations in Rv1339, a hypothetical protein of unknown function. We isolated mutants resistant to three further compounds from the series; resistant mutants isolated from two of the compounds had single nucleotide polymorphisms in Rv1339 and resistant mutants isolated from the third compound had single nucleotide polymorphisms in QcrB, the proposed target for the series. All the strains were resistant to two compounds, regardless of the mutation, and a strain carrying the QcrB T313I mutation was resistant to all of the imidazopyridine derivatives tested, confirming cross resistance. By monitoring pH homeostasis and ATP generation, we confirmed that compounds from the series were targeting QcrB; imidazopyridines disrupted pH homeostasis and depleted ATP, providing further evidence of an effect on the electron transport chain. A representative compound was bacteriostatic against replicating bacteria, consistent with a mode of action against QcrB. The series had a narrow inhibitory spectrum, with no activity against other bacterial species. No synergy or antagonism was seen with other antituberculosis drugs under development. In conclusion, our data support the hypothesis that the imidazopyridine series functions by reducing ATP generation via inhibition of QcrB. PMID- 29632009 TI - A Novel Polyaminocarboxylate Compound To Treat Murine Pulmonary Aspergillosis by Interfering with Zinc Metabolism. AB - Aspergillus fumigatus can cause pulmonary aspergillosis in immunocompromised patients and is associated with a high mortality rate due to a lack of reliable treatment options. This opportunistic pathogen requires zinc in order to grow and cause disease. Novel compounds that interfere with fungal zinc metabolism may therefore be of therapeutic interest. We screened chemical libraries containing 59,223 small molecules using a resazurin assay that compared their effects on an A. fumigatus wild-type strain grown under zinc-limiting conditions and on a zinc transporter knockout strain grown under zinc-replete conditions to identify compounds affecting zinc metabolism. After a first screen, 116 molecules were selected whose inhibitory effects on fungal growth were further tested by using luminescence assays and hyphal length measurements to confirm their activity, as well as by toxicity assays on HeLa cells and mice. Six compounds were selected following a rescreening, of which two were pyrazolones, two were porphyrins, and two were polyaminocarboxylates. All three groups showed good in vitro activity, but only one of the polyaminocarboxylates was able to significantly improve the survival of immunosuppressed mice suffering from pulmonary aspergillosis. This two-tier screening approach led us to the identification of a novel small molecule with in vivo fungicidal effects and low murine toxicity that may lead to the development of new treatment options for fungal infections by administration of this compound either as a monotherapy or as part of a combination therapy. PMID- 29632011 TI - Insight into the Significance of Aspergillus fumigatus cyp51A Polymorphisms. AB - Triazole antifungal compounds are the first treatment choice for invasive aspergillosis. However, in the last decade the rate of azole resistance among Aspergillus fumigatus strains has increased notoriously. The main resistance mechanisms are well defined and mostly related to point mutations of the azole target, 14-alpha sterol demethylase (cyp51A), with or without tandem repeat integrations in the cyp51A promoter. Furthermore, different combinations of five Cyp51A mutations (F46Y, M172V, N248T, D255E, and E427K) have been reported worldwide in about 10% of all A. fumigatus isolates tested. The azole susceptibility profile of these strains shows elevated azole MICs, although on the basis of the azole susceptibility breakpoints, these strains are not considered azole resistant. The purpose of the study was to determine whether these cyp51A polymorphisms (single nucleotide polymorphisms [SNPs]) are responsible for the azole susceptibility profile and whether they are reflected in a poorer azole treatment response in vivo that could compromise patient treatment and outcome. A mutant with a cyp51A deletion was generated and became fully susceptible to all azoles tested. Also, three cyp51A gene constructions with different combinations of SNPs were generated and reintroduced into an azole susceptible wild-type (WT) strain (the DeltaakuBKU80 strain). The alternative model host Galleria mellonella was used to compare the virulence and voriconazole response of G. mellonella larvae infected with A. fumigatus strains with WT cyp51A or cyp51A with SNPs. All strains were pathogenic in G. mellonella larvae, although they did not respond similarly to voriconazole therapeutic doses. Finally, the full genomes of these strains were sequenced and analyzed in comparison with those of A. fumigatus WT strains, revealing that they belong to different strain clusters or lineages. PMID- 29632010 TI - Polymyxin B in Combination with Enrofloxacin Exerts Synergistic Killing against Extensively Drug-Resistant Pseudomonas aeruginosa. AB - Polymyxins are increasingly used as a last-resort class of antibiotics against extensively drug-resistant (XDR) Gram-negative bacteria. However, resistance to polymyxins can emerge with monotherapy. As nephrotoxicity is the major dose limiting factor for polymyxin monotherapy, dose escalation to suppress the emergence of polymyxin resistance is not a viable option. Therefore, novel approaches are needed to preserve this last-line class of antibiotics. This study aimed to investigate the antimicrobial synergy of polymyxin B combined with enrofloxacin against Pseudomonas aeruginosa Static time-kill studies were conducted over 24 h with polymyxin B (1 to 4 mg/liter) and enrofloxacin (1 to 4 mg/liter) alone or in combination. Additionally, in vitro one-compartment model (IVM) and hollow-fiber infection model (HFIM) experiments were performed against P. aeruginosa 12196. Polymyxin B and enrofloxacin in monotherapy were ineffective against all of the P. aeruginosa isolates examined, whereas polymyxin B enrofloxacin in combination was synergistic against P. aeruginosa, with >=2 to 4 log10 kill at 24 h in the static time-kill studies. In both IVM and HFIM, the combination was synergistic, and the bacterial counting values were below the limit of quantification on day 5 in the HFIM. A population analysis profile indicated that the combination inhibited the emergence of polymyxin resistance in P. aeruginosa 12196. The mechanism-based modeling suggests that the synergistic killing is a result of the combination of mechanistic and subpopulation synergy. Overall, this is the first preclinical study to demonstrate that the polymyxin enrofloxacin combination is of considerable utility for the treatment of XDR P. aeruginosa infections and warrants future clinical evaluations. PMID- 29632012 TI - High Levels of Intrinsic Tetracycline Resistance in Mycobacterium abscessus Are Conferred by a Tetracycline-Modifying Monooxygenase. AB - Tetracyclines have been one of the most successful classes of antibiotics. However, its extensive use has led to the emergence of widespread drug resistance, resulting in discontinuation of use against several bacterial infections. Prominent resistance mechanisms include drug efflux and the use of ribosome protection proteins. Infrequently, tetracyclines can be inactivated by the TetX class of enzymes, also referred to as tetracycline destructases. Low levels of tolerance to tetracycline in Mycobacterium smegmatis and Mycobacterium tuberculosis have been previously attributed to the WhiB7-dependent TetV/Tap efflux pump. However, Mycobacterium abscessus is ~500-fold more resistant to tetracycline than M. smegmatis and M. tuberculosis In this report, we show that this high level of resistance to tetracycline and doxycycline in M. abscessus is conferred by a WhiB7-independent tetracycline-inactivating monooxygenase, MabTetX (MAB_1496c). The presence of sublethal doses of tetracycline and doxycycline results in a >200-fold induction of MabTetX, and an isogenic deletion strain is highly sensitive to both antibiotics. Further, purified MabTetX can rapidly monooxygenate both antibiotics. We also demonstrate that expression of MabTetX is repressed by MabTetRx, by binding to an inverted repeat sequence upstream of MabTetRx; the presence of either antibiotic relieves this repression. Moreover, anhydrotetracycline (ATc) can effectively inhibit MabTetX activity in vitro and decreases the MICs of both tetracycline and doxycycline in vivo Finally, we show that tigecycline, a glycylcycline tetracycline, not only is a poor substrate of MabTetX but also is incapable of inducing the expression of MabTetX. This is therefore the first demonstration of a tetracycline-inactivating enzyme in mycobacteria. It (i) elucidates the mechanism of tetracycline resistance in M. abscessus, (ii) demonstrates the use of an inhibitor that can potentially reclaim the use of tetracycline and doxycycline, and (iii) identifies two sequential bottlenecks-MabTetX and MabTetRx-for acquiring resistance to tigecycline, thereby reiterating its use against M. abscessus. PMID- 29632013 TI - Understanding Echinocandin Resistance in the Emerging Pathogen Candida auris. AB - Candida auris has simultaneously emerged on five continents as a fungal pathogen causing nosocomial outbreaks. The challenges in the treatment of C. auris infections are the variable antifungal susceptibility profiles among clinical isolates and the development of resistance to single or multiple classes of available antifungal drugs. Here, the in vitro susceptibility to echinocandin antifungal drugs was determined and FKS1 sequencing was performed on 106 C. auris clinical isolates. Four isolates were identified to be resistant to all tested echinocandins (MIC >= 4 mg/liter) and harbored an S639F mutation in FKS1 hot spot region 1. All remaining isolates were FKS1 wild type (WT) and echinocandin susceptible, with micafungin being the most potent echinocandin (MIC50 = 0.125 mg/liter). Antifungal susceptibility testing with caspofungin was challenging due to the fact that all FKS1 WT isolates exhibited an Eagle effect (also known as the paradoxical growth effect), which occurred at various intensities. To assess whether the Eagle effect resulted in pharmacodynamic resistance, 8 representative isolates were evaluated for their in vivo drug response in a murine model of invasive candidiasis. All isolates were susceptible to caspofungin at a human therapeutic dose, except for those harboring the S639F mutation. The data suggest that only isolates carrying mutations in FKS1 are echinocandin resistant and that routine in vitro testing of C. auris isolates for susceptibility to caspofungin by the broth microdilution method should be viewed cautiously or avoided. PMID- 29632015 TI - Report of erm(B)+ Campylobacter jejuni in the United States. PMID- 29632014 TI - Alterations of Metabolic and Lipid Profiles in Polymyxin-Resistant Pseudomonas aeruginosa. AB - Multidrug-resistant Pseudomonas aeruginosa presents a global medical challenge, and polymyxins are a key last-resort therapeutic option. Unfortunately, polymyxin resistance in P. aeruginosa has been increasingly reported. The present study was designed to define metabolic differences between paired polymyxin-susceptible and -resistant P. aeruginosa strains using untargeted metabolomics and lipidomics analyses. The metabolomes of wild-type P. aeruginosa strain K ([PAK] polymyxin B MIC, 1 mg/liter) and its paired pmrB mutant strains, PAKpmrB6 and PAKpmrB12 (polymyxin B MICs of 16 mg/liter and 64 mg/liter, respectively) were characterized using liquid chromatography-mass spectrometry, and metabolic differences were identified through multivariate and univariate statistics. PAKpmrB6 and PAKpmrB12, which displayed lipid A modifications with 4-amino-4 deoxy-l-arabinose, showed significant perturbations in amino acid and carbohydrate metabolism, particularly the intermediate metabolites from 4-amino-4 deoxy-l-arabinose synthesis and the methionine salvage cycle pathways. The genomics result showed a premature termination (Y275stop) in speE (encoding spermidine synthase) in PAKpmrB6, and metabolomics data revealed a decreased intracellular level of spermidine in PAKpmrB6 compared to that in PAKpmrB12 Our results indicate that spermidine may play an important role in high-level polymyxin resistance in P. aeruginosa Interestingly, both pmrB mutants had decreased levels of phospholipids, fatty acids, and acyl-coenzyme A compared to those in the wild-type PAK. Moreover, the more resistant PAKpmrB12 mutant exhibited much lower levels of phospholipids than the PAKpmrB6 mutant, suggesting that the decreased phospholipid level was associated with polymyxin resistance. In summary, this study provides novel mechanistic information on polymyxin resistance in P. aeruginosa and highlights its impacts on bacterial metabolism. PMID- 29632016 TI - Defining Substrate Specificity in the CTX-M Family: the Role of Asp240 in Ceftazidime Hydrolysis. AB - The natural diversification of CTX-M beta-lactamases led to the emergence of Asp240Gly variants in the clinic that confer reduced susceptibility to ceftazidime (CAZ). In this study, we compared the impact of this substitution on CAZ and ceftazidime-avibactam (CZA) MICs against isogenic Escherichia coli strains with different porin deficiencies. Our results show a noticeable increase in CAZ resistance in clones expressing Asp240Gly-harboring CTX-M when combined with OmpF porin deficiency. Kinetic analysis revealed that the kcat/Km for CAZ was 5- to 15-fold higher for all Asp240Gly variants but remained 200- to 725-fold lower than that for cefotaxime (CTX). In vitro selection of CAZ-resistant clones yielded nonsusceptible CTX-M producers (MIC of >16 MUg/ml) only after overnight incubation; the addition of avibactam (AVI) decreased MICs to a susceptible range against these variants. In contrast, the use of CZA as a selective agent did not yield resistant clones. AVI inactivated both CTX-M-12 and CTX-M-96, with an apparent inhibition constant comparable to that of SHV-2 and 1,000-fold greater than that of PER-2 and CMY-2, and k2/K for CTX-M-12 was 24- and 35-fold higher than that for CTX-M-96 and CTX-M-15, respectively. Molecular modeling suggests that AVI interacts similarly with CTX-M-96 and CTX-M-15. We conclude that the impact of Asp240Gly in resistance may arise when other mechanisms are also present (i.e., OmpF deficiency). Additionally, CAZ selection could favor the emergence of CAZ-resistant subpopulations. These results define the role of Asp240 and the impact of the -Gly substitution and allow us to hypothesize that the use of CZA is an effective preventive strategy to delay the development of resistance in this family of extended-spectrum beta-lactamases. PMID- 29632017 TI - Measurement of Skeletal Muscle Area Improves Estimation of Aminoglycoside Clearance across Body Size. AB - A consistent approach to the dosing of aminoglycosides across the modern body size distribution has been elusive. We evaluated whether radiologically derived measures of body composition could explain more of the interpatient variability in aminoglycoside pharmacokinetics (PK) than standard body size metrics. This retrospective study included adult patients treated with gentamicin or tobramycin with at least three drug concentrations and computed tomography (CT) imaging available. Aminoglycoside volume and clearance (CL) estimates were computed using a two-compartment model by Bayesian analysis. Morphomic data were extracted from CT images using a custom algorithm. Bivariable and multivariable linear regression were used to assess relationships between PK parameters and covariates. A total of 335 patients were included with a median (minimum, maximum) of 4 (3, 16) aminoglycoside concentrations per patient. The median (minimum, maximum) age, height, and weight of included patients were 57 (21, 93) years, 170 (145, 203) centimeters, and 81 (42, 187) kilograms. Both standard and morphomic measures poorly explained variability in volume (R2 < 0.06). Skeletal muscle area and volume explained more of the interpatient variability in CL than weight or sex. Higher precision was observed using a modified Cockcroft-Gault equation with skeletal muscle area at L3 (R2= 0.38) or L4 (R2= 0.37) than the standard Cockcroft-Gault equation using lean (R2= 0.23), adjusted (R2= 0.23), or total (R2= 0.22) body weights. These results highlight that skeletal muscle measurements from CT images obtained in the course of care can improve the precision of aminoglycoside CL estimation over current body size scalars. PMID- 29632020 TI - April 9th Question. PMID- 29632022 TI - Donor telomere length and causes of death after unrelated hematopoietic cell transplantation in patients with marrow failure. AB - Previous studies have suggested that longer donor leukocyte telomere length (TL) is associated with improved survival after hematopoietic cell transplantation (HCT) in severe aplastic anemia (SAA). This study aimed to determine whether cell specific lymphocyte TL is associated with certain post-HCT causes of death. We used flow cytometry and fluorescence in situ hybridization to measure TL in donor total lymphocytes and subsets: naive enriched T cells (CD45RA+CD20-), memory enriched T cells (CD45RA-CD20-), natural killer (NK) fully differentiated T cells (CD45RA+CD57+), and B cells (CD45RA+CD20+). Competing risk survival regression was used for cause-specific death analyses. Clinical data and biospecimens were available from the Center for International Blood and Marrow Transplant Research database and biorepository. The study included 197 patients who underwent unrelated-donor HCT for SAA between 1988 and 2004. The median age at HCT was 15 years (range, 0.5-40 years), and the median follow-up was 5 years (range, <1 month to 20.7 years). Longer donor TL in all cell subsets was associated with lower risk of all-cause mortality (P < .01). In cause-specific mortality analyses, longer TL in B cells (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.46-0.87; P = .006) and possibly NK fully differentiated T cells (HR, 0.7; 95% CI, 0.51 to 0.97; P = .03) was associated with lower risk of infection related death. Donor TL in other tested lymphocyte subsets was not statistically significantly associated with death resulting from graft-versus-host disease or graft failure (P > .05). However, a trend toward excess risk of graft-versus-host mortality was noted (HR for total lymphocyte TL, 1.26; P = .15). In conclusion, longer donor TL was associated with reduced rate of infection-related deaths after HCT for SAA. PMID- 29632021 TI - Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency. AB - Opa1 participates in inner mitochondrial membrane fusion and cristae morphogenesis. Here, we show that muscle-specific Opa1 ablation causes reduced muscle fiber size, dysfunctional mitochondria, enhanced Fgf21, and muscle inflammation characterized by NF-kappaB activation, and enhanced expression of pro-inflammatory genes. Chronic sodium salicylate treatment ameliorated muscle alterations and reduced the muscle expression of Fgf21. Muscle inflammation was an early event during the progression of the disease and occurred before macrophage infiltration, indicating that it is a primary response to Opa1 deficiency. Moreover, Opa1 repression in muscle cells also resulted in NF-kappaB activation and inflammation in the absence of necrosis and/or apoptosis, thereby revealing that the activation is a cell-autonomous process and independent of cell death. The effects of Opa1 deficiency on the expression NF-kappaB target genes and inflammation were absent upon mitochondrial DNA depletion. Under Opa1 deficiency, blockage or repression of TLR9 prevented NF-kappaB activation and inflammation. Taken together, our results reveal that Opa1 deficiency in muscle causes initial mitochondrial alterations that lead to TLR9 activation, and inflammation, which contributes to enhanced Fgf21 expression and to growth impairment. PMID- 29632023 TI - Eltrombopag mobilizes iron in patients with aplastic anemia. PMID- 29632025 TI - Effects of neuromedin B on steroidogenesis, cell proliferation and apoptosis in porcine Leydig cells. AB - Neuromedin B (NMB), a mammalian bombesin-related peptide, has numerous physiological functions, including regulating hormone secretions, cell growth, and reproduction, by binding to its receptor (NMBR). In this study, we investigated the effects of NMB on testosterone secretion, steroidogenesis, cell proliferation, and apoptosis in cultured primary porcine Leydig cells. NMBR was mainly expressed in the Leydig cells of porcine testes, and a specific dose of NMB significantly promoted the secretion of testosterone in the primary Leydig cells; moreover, NMB increased the expression of mRNA and/or proteins of NMBR and steroidogenic mediators (steroidogenic acute regulatory (STAR), CYP11A1, and HSD3B1) in the Leydig cells. In addition, specific doses of NMB promoted the proliferation of Leydig cells and increased the expression of proliferating cell nuclear antigen and Cyclin B1 proteins, while suppressing Leydig cell apoptosis and decreasing BAX and Caspase-3 protein expression. These results suggest that the NMB/NMBR system might play an important role in regulating boar reproductive function by modulating steroidogenesis and/or cell growth in porcine Leydig cells. PMID- 29632026 TI - Prolactin protects against cytokine-induced beta-cell death by NFkappaB and JNK inhibition. AB - Type 1 diabetes is caused by an autoimmune assault that induces progressive beta cell dysfunction and dead. Pro-inflammatory cytokines, such as interleukin 1 beta (IL1B), tumor necrosis factor (TNF) and interferon gamma (IFNG) contribute for beta-cell death, which involves the activation of the nuclear factor kappa B (NFkappaB) and c- Jun N-terminal kinase (JNK). Prolactin (PRL), a physiological mediator for beta-cell proliferation, was shown to protect beta cells against cytokines pro-apoptotic effects. We presently investigated the mechanisms involved in the protective effects of prolactin against cytokine-induced beta cell death. The findings obtained indicate that STAT3 activation is involved in the anti-apoptotic role of PRL in rat beta cells. PRL prevents the activation of JNK via AKT and promotes a shift from expression of pro- to anti-apoptotic proteins downstream of the JNK cascade. Furthermore, PRL partially prevents the activation of NFkappaB and the transcription of its target genes IkBa, Fas, Mcp1, A20 and Cxcl10 and also decreases NO production. On the other hand, the pro survival effects of PRL do not involve modulation of cytokine-induced endoplasmic reticulum stress. These results suggest that the beneficial effects of PRL in beta cells involve augmentation of anti-apoptotic mechanisms and, at the same time, reduction of pro-apoptotic effectors, rendering beta cells better prepared to deal with inflammatory insults. The better understanding of the pro-survival mechanisms modulated by PRL in beta cells can provide tools to prevent cell demise during an autoimmune attack or following islet transplantation. PMID- 29632024 TI - Genetic and mechanistic diversity in pediatric hemophagocytic lymphohistiocytosis. AB - The HLH-2004 criteria are used to diagnose hemophagocytic lymphohistiocytosis (HLH), yet concern exists for their misapplication, resulting in suboptimal treatment of some patients. We sought to define the genomic spectrum and associated outcomes of a diverse cohort of children who met the HLH-2004 criteria. Genetic testing was performed clinically or through research-based whole-exome sequencing. Clinical metrics were analyzed with respect to genomic results. Of 122 subjects enrolled over the course of 17 years, 101 subjects received genetic testing. Biallelic familial HLH (fHLH) gene defects were identified in only 19 (19%) and correlated with presentation at younger than 1 year of age (P < .0001). Digenic fHLH variants were observed but lacked statistical support for disease association. In 28 (58%) of 48 subjects, research whole-exome sequencing analyses successfully identified likely molecular explanations, including underlying primary immunodeficiency diseases, dysregulated immune activation and proliferation disorders, and potentially novel genetic conditions. Two-thirds of patients identified by the HLH-2004 criteria had underlying etiologies for HLH, including genetic defects, autoimmunity, and malignancy. Overall survival was 45%, and increased mortality correlated with HLH triggered by infection or malignancy (P < .05). Differences in survival did not correlate with genetic profile or extent of therapy. HLH should be conceptualized as a phenotype of critical illness characterized by toxic activation of immune cells from different underlying mechanisms. In most patients with HLH, targeted sequencing of fHLH genes remains insufficient for identifying pathogenic mechanisms. Whole-exome sequencing, however, may identify specific therapeutic opportunities and affect hematopoietic stem cell transplantation options for these patients. PMID- 29632027 TI - Active and inactive beta1 integrins segregate into distinct nanoclusters in focal adhesions. AB - Integrins are the core constituents of cell-matrix adhesion complexes such as focal adhesions (FAs) and play key roles in physiology and disease. Integrins fluctuate between active and inactive conformations, yet whether the activity state influences the spatial organization of integrins within FAs has remained unclear. In this study, we address this question and also ask whether integrin activity may be regulated either independently for each integrin molecule or through locally coordinated mechanisms. We used two distinct superresolution microscopy techniques, stochastic optical reconstruction microscopy (STORM) and stimulated emission depletion microscopy (STED), to visualize active versus inactive beta1 integrins. We first reveal a spatial hierarchy of integrin organization with integrin molecules arranged in nanoclusters, which align to form linear substructures that in turn build FAs. Remarkably, within FAs, active and inactive beta1 integrins segregate into distinct nanoclusters, with active integrin nanoclusters being more organized. This unexpected segregation indicates synchronization of integrin activities within nanoclusters, implying the existence of a coordinate mechanism of integrin activity regulation. PMID- 29632029 TI - Sudden unexpected death in epilepsy in children: a focused review of incidence and risk factors. AB - Sudden unexpected death in epilepsy (SUDEP) in children, although rare, needs critical attention given the tragic nature and devastating consequences for families and caregivers. True incidence is unknown and risk factors are not completely understood, more so in children compared with adults. A focused narrative review of available studies on paediatric SUDEP was undertaken to comprehend its risk factors and to develop strategies to recognise and where possible modify SUDEP risk and ultimately reduce incidence. We reviewed 16 population-based studies from various settings. We found overlapping risk factors from different studies. The prime risk factor is uncontrolled seizures. This review supports the view that children entering adolescence with optimal seizure control could be a key aspect in reducing adult mortality related to SUDEP. Ideally, clinicians would want to be able to predict prospective, individualised SUDEP risk, which is challenging due to a myriad of risk factors and an inherent non-homogeneous paediatric epilepsy population. Nevertheless, an adequate evidence base exists as evidenced by this review to support information giving and communication to support young people with epilepsy and their families in being active partners in recognising and reducing their SUDEP risk. More work particularly in the form of prospective studies and registries are needed to further clarify true incidence which may have been previously underestimated and to update risk factors. PMID- 29632028 TI - A quantitative map of human Condensins provides new insights into mitotic chromosome architecture. AB - The two Condensin complexes in human cells are essential for mitotic chromosome structure. We used homozygous genome editing to fluorescently tag Condensin I and II subunits and mapped their absolute abundance, spacing, and dynamic localization during mitosis by fluorescence correlation spectroscopy (FSC) calibrated live-cell imaging and superresolution microscopy. Although ~35,000 Condensin II complexes are stably bound to chromosomes throughout mitosis, ~195,000 Condensin I complexes dynamically bind in two steps: prometaphase and early anaphase. The two Condensins rarely colocalize at the chromatid axis, where Condensin II is centrally confined, but Condensin I reaches ~50% of the chromatid diameter from its center. Based on our comprehensive quantitative data, we propose a three-step hierarchical loop model of mitotic chromosome compaction: Condensin II initially fixes loops of a maximum size of ~450 kb at the chromatid axis, whose size is then reduced by Condensin I binding to ~90 kb in prometaphase and ~70 kb in anaphase, achieving maximum chromosome compaction upon sister chromatid segregation. PMID- 29632030 TI - Study on the influence of pregnancy-induced hypertension on neonatal birth weight. AB - To explore the effect of pregnancy-induced hypertension (PIH) on neonatal birth weight and provide the necessary reference value for the maternal and children health service. A cross-sectional study was carried out in Shaanxi Province of China in 2013. And a total of 28 045 singleton live infants and their mothers were recruited using a stratified, multistage, probability-proportional-to-size sampling method. Among the 28 045 women of childbearing age surveyed, multiple linear regression and quantile regression analysis all showed that the birth weight of newborns whose mothers had suffered from PIH during pregnancy was significantly lower than those whose mothers had not suffered from PIH during pregnancy from very low to higher birth weight percentiles (q=0-0.85), an average decrease of 137.45 g (beta=-137.45, t=-5.77 and p<0.001). When birth weight was at q=0.90-1.00 percentiles, there was no birth weight difference between two groups. The present cross-sectional study indicated that PIH had an effect of on neonatal birth weight. When pregnant women with PIH are identified then the healthcare professional initiates a closer supervision of their pregnancy in order to ameliorate the status of BP and provide a good intrauterine environment for the fetus. In addition, the gynecologists should admonish the pregnant women that their health is related to the health of their fetus, then gravidas may be more engaged to alert their physician and accept early or preventative interventions. And the healthcare professional should ask and be alert to the issues of hypertension during pregnancy. PMID- 29632031 TI - Analysis of circulating tumor cells in patients with hepatocellular carcinoma recurrence following liver transplantation. AB - Although studies have shown that detection of peripheral circulating tumor cells (CTCs) is an important tool for monitoring prognosis and therapeutic response in patients with cancer, few studies have analyzed their role in patients with hepatocellular carcinoma (HCC) following liver transplantation (LTx). The present study examined whether CTC levels were associated with HCC recurrence in patients with HCC after LTx. This prospective study included 47 patients who received LTx between October 2014 and May 2016 and who underwent analysis for peripheral CTCs at least twice using the CanPatrol system. Baseline Edmondson stage, T stage, accumulated tumor diameter, microvascular cancer embolus, and alpha-fetoprotein (AFP) levels were greater in patients with recurrence (all p<0.05). In addition, 70.2% of patients with HCC were CTC-positive. Although the proportion of CTC subtypes changes following LTx and over the follow-up period with increased epithelial and interstitial CTC levels, no significant associations were observed between change in total CTCs or CTC subtype and HCC recurrence (all p>0.05). In conclusion, baseline Edmondson stage, T stage, accumulated tumor diameter, microvascular cancer embolus, and AFP levels may be predictive of HCC recurrence following LTx; however, CTC levels and subtypes were not. Further large, multicenter studies are necessary to confirm these results. PMID- 29632033 TI - New generic pricing scheme maintains high prices and risks of shortages. PMID- 29632034 TI - Focused policy is needed to reduce inequities in primary health care access for children. PMID- 29632032 TI - Drosophila Glypicans Regulate Follicle Stem Cell Maintenance and Niche Competition. AB - Adult stem cells reside in specialized microenvironments called niches, which provide signals for stem cells to maintain their undifferentiated and self renewing state. To maintain stem cell quality, several types of stem cells are known to be regularly replaced by progenitor cells through niche competition. However, the cellular and molecular bases for stem cell competition for niche occupancy are largely unknown. Here, we show that two Drosophila members of the glypican family of heparan sulfate proteoglycans (HSPGs), Dally and Dally-like (Dlp), differentially regulate follicle stem cell (FSC) maintenance and competitiveness for niche occupancy. Lineage analyses of glypican mutant FSC clones showed that dally is essential for normal FSC maintenance. In contrast, dlp is a hypercompetitive mutation: dlp mutant FSC progenitors often eventually occupy the entire epithelial sheet. RNA interference knockdown experiments showed that Dally and Dlp play both partially redundant and distinct roles in regulating Jak/Stat, Wg, and Hh signaling in FSCs. The Drosophila FSC system offers a powerful genetic model to study the mechanisms by which HSPGs exert specific functions in stem cell replacement and competition. PMID- 29632035 TI - Can we improve on Wilson and Jungner's principles of screening for disease? PMID- 29632036 TI - Risk of ketoacidosis in children at the time of diabetes mellitus diagnosis by primary caregiver status: a population-based retrospective cohort study. AB - BACKGROUND: Diabetic ketoacidosis is the leading cause of death among children with type 1 diabetes mellitus, and is an avoidable complication at first-time diagnosis of diabetes. Because having a usual provider of primary care is important in improving health outcomes for children, we tested the association between having a usual provider of care and risk of diabetic ketoacidosis at onset of diabetes. METHODS: Using linked health administrative data for the province of Quebec, we conducted a population-based retrospective cohort study of children aged 1-17 years in whom diabetes was diagnosed from 2006 to 2015. We estimated adjusted risk ratios (RRs) for an episode of diabetic ketoacidosis at the time of diabetes diagnosis in relation to usual provider of care (family physician, pediatrician or none) using Poisson regression models with robust error variance. RESULTS: We identified 3704 new cases of diabetes in Quebec children from 2006 to 2015. Of these, 996 (26.9%) presented with diabetic ketoacidosis. A decreased risk of this complication was associated with having a usual provider of care; the association was stronger with increasing age, reaching statistical significance among those aged 12-17 years. Within this age group, those who had a family physician or a pediatrician were 31% less likely (adjusted RR 0.69, 95% confidence interval [CI] 0.56-0.85) or 38% less likely (adjusted RR 0.62, 95% CI 0.45-0.86), respectively, to present with diabetic ketoacidosis, relative to those without a usual provider of care. INTERPRETATION: For children with newly diagnosed diabetes, having a usual provider of care appears to be important in decreasing the risk of diabetic ketoacidosis at the time of diabetes diagnosis. Our results provide further evidence concerning the need for initiatives that promote access to primary care for children. PMID- 29632037 TI - Consolidated principles for screening based on a systematic review and consensus process. AB - BACKGROUND: In 1968, Wilson and Jungner published 10 principles of screening that often represent the de facto starting point for screening decisions today; 50 years on, are these principles still the right ones? Our objectives were to review published work that presents principles for population-based screening decisions since Wilson and Jungner's seminal publication, and to conduct a Delphi consensus process to assess the review results. METHODS: We conducted a systematic review and modified Delphi consensus process. We searched multiple databases for articles published in English in 1968 or later that were intended to guide population-based screening decisions, described development and modification of principles, and presented principles as a set or list. Identified sets were compared for basic characteristics (e.g., number, categorization), a citation analysis was conducted, and principles were iteratively synthesized and consolidated into categories to assess evolution. Participants in the consensus process assessed the level of agreement with the importance and interpretability of the consolidated screening principles. RESULTS: We identified 41 sets and 367 unique principles. Each unique principle was coded to 12 consolidated decision principles that were further categorized as disease/condition, test/intervention or program/system principles. Program or system issues were the focus of 3 of Wilson and Jungner's 10 principles, but comprised almost half of all unique principles identified in the review. The 12 consolidated principles were assessed through 2 rounds of the consensus process, leading to specific refinements to improve their relevance and interpretability. No gaps or missing principles were identified. INTERPRETATION: Wilson and Jungner's principles are remarkably enduring, but increasingly reflect a truncated version of contemporary thinking on screening that does not fully capture subsequent focus on program or system principles. Ultimately, this review and consensus process provides a comprehensive and iterative modernization of guidance to inform population-based screening decisions. PMID- 29632039 TI - Retained intrauterine devices in pregnancy. PMID- 29632040 TI - Hypervirulent (hypermucoviscous) Klebsiella pneumoniae causing pyogenic liver abscess. PMID- 29632041 TI - The overall culture of residency selection needs fixing. PMID- 29632038 TI - Managing premature atherosclerosis in patients with chronic inflammatory diseases. PMID- 29632042 TI - Surgery for obstructive sleep apnea. PMID- 29632043 TI - Depression guideline written "by patients for patients" a first for Canada. PMID- 29632044 TI - Reducing physician suicides requires system change, not just self-care tips. PMID- 29632045 TI - Doctors who retire early often met with scorn. PMID- 29632046 TI - Ranking the Contribution of Ankylosing Spondylitis-associated Endoplasmic Reticulum Aminopeptidase 1 (ERAP1) Polymorphisms to Shaping the HLA-B*27 Peptidome. AB - The Endoplasmic reticulum aminopeptidase I (ERAP1) trims peptides to their optimal size for binding to Major Histocompatibility Complex class I proteins. The natural polymorphism of this enzyme is associated with ankylosing spondylitis (AS) in epistasis with the major risk factor for this disease, HLA-B*27, suggesting a direct relationship between AS and HLA-B*27-bound peptides. Three polymorphisms that affect peptide trimming protect from AS: K528R, D575N/R725Q, and Q730E. We characterized and ranked the effects of each mutation, and their various combinations, by quantitative comparisons of the HLA-B*27 peptidomes from cells expressing distinct ERAP1 variants. Five features were examined: peptide length, N-terminal flanking residues, N-terminal residues of the natural ligands, internal sequences and affinity for B*27:05. Polymorphism at residue 528 showed the largest influence, affecting all five features regardless of peptide length. D575N/R725Q showed a much smaller effect. Yet, when co-occurring with K528R, it further decreased ERAP1 activity. Polymorphism at residue 730 showed a significant influence on peptide length, because of distinct effects on trimming of nonamers compared with longer peptides. Accordingly, multiple features were affected by the Q730E mutation in a length-dependent way. The alterations induced in the B*27:05 peptidome by natural ERAP1 variants with different K528R/Q730E combinations reflected separate and additive effects of both mutations. Thus, the influence of ERAP1 on HLA-B*27 is very diverse at the population level, because of the multiplicity and complexity of ERAP1 variants, and to the distinct effects of their co-occurring polymorphisms, leading to significant modulation of disease risk among HLA-B*27-positive individuals. PMID- 29632048 TI - Correction: Formation of COPI-coated vesicles at a glance (doi:10.1242/jcs.209890). PMID- 29632047 TI - Identification of Novel Response and Predictive Biomarkers to Hsp90 Inhibitors Through Proteomic Profiling of Patient-derived Prostate Tumor Explants. AB - Inhibition of the heat shock protein 90 (Hsp90) chaperone is a promising therapeutic strategy to target expression of the androgen receptor (AR) and other oncogenic drivers in prostate cancer cells. However, identification of clinically relevant responses and predictive biomarkers is essential to maximize efficacy and treatment personalization. Here, we combined mass spectrometry (MS)-based proteomic analyses with a unique patient-derived explant (PDE) model that retains the complex microenvironment of primary prostate tumors. Independent discovery and validation cohorts of PDEs (n = 16 and 30, respectively) were cultured in the absence or presence of Hsp90 inhibitors AUY922 or 17-AAG. PDEs were analyzed by LC-MS/MS with a hyper-reaction monitoring data independent acquisition (HRM-DIA) workflow, and differentially expressed proteins identified using repeated measure analysis of variance (ANOVA; raw p value <0.01). Using gene set enrichment, we found striking conservation of the most significantly AUY922-altered gene pathways between the discovery and validation cohorts, indicating that our experimental and analysis workflows were robust. Eight proteins were selectively altered across both cohorts by the most potent inhibitor, AUY922, including TIMP1, SERPINA3 and CYP51A (adjusted p < 0.01). The AUY922-mediated decrease in secretory TIMP1 was validated by ELISA of the PDE culture medium. We next exploited the heterogeneous response of PDEs to 17-AAG in order to detect predictive biomarkers of response and identified PCBP3 as a marker with increased expression in PDEs that had no response or increased in proliferation. Also, 17 AAG treatment led to increased expression of DNAJA1 in PDEs that exhibited a cytostatic response, revealing potential drug resistance mechanisms. This selective regulation of DNAJA1 was validated by Western blot analysis. Our study establishes "proof-of-principle" that proteomic profiling of drug-treated PDEs represents an effective and clinically-relevant strategy for identification of biomarkers that associate with certain tumor-specific responses. PMID- 29632051 TI - Standing Together or Alone. PMID- 29632052 TI - Letter to the Editor: Panax Ginseng for Cancer-Related Fatigue. PMID- 29632053 TI - Concurrent BRAF/MEK Inhibitors in BRAF V600-Mutant High-Grade Primary Brain Tumors. AB - BRAF V600 mutations are being identified in patients with primary brain tumors more often as molecular testing becomes widely available. Targeted treatment with BRAF inhibitors has been attempted in individual cases with some responses, whereas others showed no response or developed resistance. Preclinical work suggests that gliomas could be more responsive to the concurrent use of BRAF and MEK inhibition for MAP kinase pathway suppression. This report presents 2 cases of malignant brain tumors with BRAF V600E mutations that were resistant to radiation and temozolomide, and reports on their response to targeted treatment with the BRAF and MEK inhibitors dabrafenib and trametinib. One patient with an anaplastic pleomorphic xanthoastrocytoma experienced a partial response for 14 months, demonstrated by progressive tumor shrinkage and clinical improvement; however, this was followed by clinical and radiographic progression. The patient with glioblastoma continued to have stable disease after 16 months of treatment. These cases are encouraging in a disease that urgently needs new treatments. Further work is necessary to understand response rates, duration, and survival in primary brain tumors. PMID- 29632054 TI - Biallelic TSC2 Mutations in a Patient With Chromophobe Renal Cell Carcinoma Showing Extraordinary Response to Temsirolimus. AB - mTOR inhibitors are used to treat renal cell carcinoma (RCC). Treatment response is variable and appears to correlate with genetic alterations that activate mTOR signaling. Recently, everolimus was suggested to be more effective than sunitinib in chromophobe RCC (chRCC), a tumor with frequent mTOR pathway defects. This report presents the genomic and functional characterization of a metastatic chRCC that showed complete response at metastatic sites and 80% reduction in primary tumor size upon temsirolimus treatment. After surgery, the patient remained disease-free for 8 years after temsirolimus therapy. Whole-exome sequencing (WES) revealed 2 somatic variants in TSC2, a critical negative regulator of mTOR: a splicing defect (c.5069-1G>C) and a novel missense variant [c.3200_3201delinsAA; p.(V1067E)]. In vitro functional assessment demonstrated that the V1067E substitution disrupted TSC2 function. Immunohistochemistry in the tumor tissues revealed increased phosphorylated S6 ribosomal protein, indicating mTOR pathway activation. In conclusion, WES revealed TSC2 inactivation as the likely mechanism for this extraordinary response to temsirolimus. These findings support high efficacy of mTOR inhibitors in a subset of patients with chRCC and propose sequencing of mTOR pathway genes to help guide therapy. PMID- 29632056 TI - Trends in Incidence and Factors Affecting Survival of Patients With Cholangiocarcinoma in the United States. AB - Background: Cholangiocarcinoma (CCA) includes cancers arising from the intrahepatic and extrahepatic bile ducts. The etiology and pathogenesis of CCA remain poorly understood. This is the first study investigating both incidence patterns of CCA from 1973 through 2012 and demographic, clinical, and treatment variables affecting survival of patients with CCA. Patients and Methods: Using the SEER database, age-adjusted incidence rates were evaluated from 1973-2012 using SEER*Stat software. A retrospective cohort of 26,994 patients diagnosed with CCA from 1973-2008 was identified for survival analysis. Cox proportional hazards models were used to perform multivariate survival analysis. Results: Overall incidence of CCA increased by 65% from 1973-2012. Extrahepatic CCA (ECC) remained more common than intrahepatic CCA (ICC), whereas the incidence rates for ICC increased by 350% compared with a 20% increase seen with ECC. Men belonging to non-African American and non-Caucasian ethnicities had the highest incidence rates of CCA. This trend persisted throughout the study period, although African Americans and Caucasians saw 50% and 59% increases in incidence rates, respectively, compared with a 9% increase among other races. Median overall survival (OS) was 8 months in patients with ECC compared with 4 months in those with ICC. Our survival analysis found Hispanic women to have the best 5-year survival outcome (P<.0001). OS diminished with age (P<.0001), and ECC had better survival outcomes compared with ICC (P<.0001). Patients who were married, were nonsmokers, belonged to a higher income class, and underwent surgery had better survival outcomes compared with others (P<.0001). Conclusions: This is the most up-to-date study of CCA from the SEER registry that shows temporal patterns of increasing incidence of CCA across different races, sexes, and ethnicities. We identified age, sex, race, marital status, income, smoking status, anatomic location of CCA, tumor grade, tumor stage, radiation, and surgery as independent prognostic factors for OS in patients with CCA. PMID- 29632055 TI - NCCN Guidelines Insights: Colon Cancer, Version 2.2018. AB - The NCCN Guidelines for Colon Cancer provide recommendations regarding diagnosis, pathologic staging, surgical management, perioperative treatment, surveillance, management of recurrent and metastatic disease, and survivorship. These NCCN Guidelines Insights summarize the NCCN Colon Cancer Panel discussions for the 2018 update of the guidelines regarding risk stratification and adjuvant treatment for patients with stage III colon cancer, and treatment of BRAF V600E mutation-positive metastatic colorectal cancer with regimens containing vemurafenib. PMID- 29632057 TI - Single-Arm Longitudinal Study to Evaluate a Decision Aid for Women Offered Neoadjuvant Systemic Therapy for Operable Breast Cancer. AB - Background: Neoadjuvant systemic therapy (NAST) is an increasingly used treatment option for women with large operable or highly proliferative breast cancer. With equivalent survival outcomes between NAST and up-front surgery, the situation specific preference-sensitive nature of the decision makes it suitable for a decision aid (DA). This study aimed to develop and evaluate a DA for this population. Methods: A DA booklet was developed according to international standards, including information about adjuvant and neoadjuvant treatment, outcome probabilities, and a values clarification exercise. Eligible women, considered by investigators as candidates for NAST, were enrolled in a multi institutional, single-arm, longitudinal study. Patient-reported outcome measure questionnaires were completed pre- and post-DA, between chemotherapy and surgery, and at 12 months. Outcomes were feasibility (percentage of eligible patients accessing the DA); acceptability to patients (percentage who would recommend it to others) and clinicians (percentage who would use the DA in routine practice); and decision-related outcomes. Results: From 77 eligible women, 59 were enrolled, of whom 47 (79.7%; 95% CI, 69.4-89.9) reported having read the DA; 51 completed the first post-DA questionnaire. Of these 51, 41 participants (80.4%; 95% CI, 69.5-91.3) found the DA useful for their decision about NAST. Of 18 responding investigators, 16 (88.9%; 95% CI, 74.4-103.4) indicated they would continue to use the DA in routine practice. Post-DA, decisional conflict decreased significantly (P<.01); anxiety and distress decreased significantly; and 86.3% (95% CI, 73.7-94.3) achieved at least as much decisional control as they desired. Conclusions: This DA was feasible and acceptable to patients and clinicians, and improvement in decision-related outcomes was demonstrated when used in combination with clinical consultations. This DA could safely be implemented into routine practice for women considering NAST for operable breast cancer. PMID- 29632058 TI - Treating Second Breast Events After Breast-Conserving Surgery for Ductal Carcinoma in Situ. AB - Background: Because of screening mammography, the number of ductal carcinoma in situ (DCIS) survivors has increased dramatically. DCIS survivors may face excess risk of second breast events (SBEs). However, little is known about SBE treatment or its relationship to initial DCIS care. Methods: Among a prospective cohort of women who underwent breast-conserving surgery (BCS) for DCIS from 1997 to 2008 at institutions participating in the NCCN Outcomes Database, we identified SBEs, described patterns of care for SBEs, and examined the association between DCIS treatment choice and SBE care. Using multivariable regression, we identified features associated with use of mastectomy, radiation therapy (RT), or antiestrogen therapy (AET) for SBEs. Results: Of 2,939 women who underwent BCS for DCIS, 83% received RT and 40% received AET. During the median follow-up of 4.2 years, 200 women (6.8%) developed an SBE (55% ipsilateral, 45% invasive). SBEs occurred in 6% of women who underwent RT for their initial DCIS versus 11% who did not. Local treatment for these events included BCS (10%), BCS/RT (30%), mastectomy (53%), or none (6%); only 28% of patients received AET. Independent predictors of RT or mastectomy for SBEs included younger age, shorter time to SBE diagnosis, and RT or AET for the initial DCIS. Conclusions: A sizable proportion of patients with SBEs were treated with mastectomy, most especially those who previously received RT for their initial DCIS and those who developed an ipsilateral SBE. Despite the occurrence of an SBE, relatively few patients received AET. Future studies should investigate optimal treatment approaches for SBEs, including the benefit of mastectomy versus lumpectomy for an ipsilateral SBE and the benefit of AET for a hormone-receptor-positive SBE contingent on AET use for the initial DCIS diagnosis. PMID- 29632050 TI - The triple helix of collagens - an ancient protein structure that enabled animal multicellularity and tissue evolution. AB - The cellular microenvironment, characterized by an extracellular matrix (ECM), played an essential role in the transition from unicellularity to multicellularity in animals (metazoans), and in the subsequent evolution of diverse animal tissues and organs. A major ECM component are members of the collagen superfamily -comprising 28 types in vertebrates - that exist in diverse supramolecular assemblies ranging from networks to fibrils. Each assembly is characterized by a hallmark feature, a protein structure called a triple helix. A current gap in knowledge is understanding the mechanisms of how the triple helix encodes and utilizes information in building scaffolds on the outside of cells. Type IV collagen, recently revealed as the evolutionarily most ancient member of the collagen superfamily, serves as an archetype for a fresh view of fundamental structural features of a triple helix that underlie the diversity of biological activities of collagens. In this Opinion, we argue that the triple helix is a protein structure of fundamental importance in building the extracellular matrix, which enabled animal multicellularity and tissue evolution. PMID- 29632059 TI - High Variability in Lymph Node Counts Among an International Cohort of Pathologists: Questioning the Scientific Validity of Node Counts. AB - Background: The enumeration of lymph nodes (LNs) from surgical specimens plays a critical role in the staging of patients with cancer. LN count (LNC) can affect prognosis, staging, adequacy of resection, and/or eligibility for clinical trials. However, there is no standard method for counting LNs. Most studies in the literature site the pathology report as the source of LN data, without discussion of the counting criteria. Patients and Methods: Four microscopic slides from separate pelvic LN dissections were digitally scanned and uploaded with their gross descriptions to an online library and an online survey. Respondents were asked how many LNs they would count per slide as part of a staging procedure. The survey was distributed to an international cohort of pathologists. Results: A total of 122 surveys were returned: 79 from practicing pathologists and 43 from residents/fellows. There was no statistical difference between the groups. All slides showed significant individual variability. The LNC range for each slide was as follows: slide 1, 1-3; slide 2, 0-13; slide 3, 1-8; slide 4, 1-11. The intraclass correlation (ICC) for all responders was 0.26 (95% CI, 0.05=65 years). Results: Total and net costs were consistently highest for lung cancer and lowest for prostate cancer. Net costs were higher across all cancer sites for patients aged <65 years than those aged >=65 years. Medical care costs for all cancers increased with advanced stage at diagnosis. Conclusions: This study improves understanding of medical care costs for the 4 most common invasive cancers in the United States. Higher costs among patients aged <65 years highlight limitations of relying on SEER-Medicare data alone to understand the national burden of cancer, whereas higher costs for patients with advanced-stage cancer underscore the importance of early detection to curtail high long-term costs. These cost estimates can be used in the development and evaluation of interventions and policies across the cancer care continuum. PMID- 29632061 TI - Lung Cancer Screening, Version 3.2018, NCCN Clinical Practice Guidelines in Oncology. AB - Lung cancer is the leading cause of cancer-related mortality in the United States and worldwide. Early detection of lung cancer is an important opportunity for decreasing mortality. Data support using low-dose computed tomography (LDCT) of the chest to screen select patients who are at high risk for lung cancer. Lung screening is covered under the Affordable Care Act for individuals with high-risk factors. The Centers for Medicare & Medicaid Services (CMS) covers annual screening LDCT for appropriate Medicare beneficiaries at high risk for lung cancer if they also receive counseling and participate in shared decision-making before screening. The complete version of the NCCN Guidelines for Lung Cancer Screening provides recommendations for initial and subsequent LDCT screening and provides more detail about LDCT screening. This manuscript focuses on identifying patients at high risk for lung cancer who are candidates for LDCT of the chest and on evaluating initial screening findings. PMID- 29632062 TI - NCCN Guidelines as a Model of Extended Criteria for Lung Cancer Screening. AB - Background: This review assessed the performance of patients in NCCN high-risk group 2 in a clinical CT lung screening (CTLS) program. Methods: We retrospectively reviewed screening results for all patients from our institution undergoing clinical CTLS from January 2012 through December 2016, with follow-up through June 2017. To qualify for screening, patients had to meet the NCCN Guidelines high-risk criteria for CTLS, have a physician order for screening, be asymptomatic, be lung cancer-free for 5 years, and have no known metastatic disease. We compared demographics and screening performance of NCCN high-risk groups 1 and 2 across >4 rounds of screening. Screening metrics assessed included rates of positive and suspicious examinations, significant incidental and infectious/inflammatory findings, false negatives, and cancer detection. We also compared cancer stage and histology detected in each NCCN high-risk group. Results: A total of 2,927 individuals underwent baseline screening, of which 698 (24%) were in NCCN group 2. On average, group 2 patients were younger (60.6 vs 63.1 years), smoked less (38.8 vs 50.8 pack-years), had quit longer (18.1 vs 6.3 years), and were more often former smokers (61.4% vs 44.2%). Positive and suspicious examination rates, false negatives, and rates of infectious/inflammatory findings were equivalent in groups 1 and 2 across all rounds of screening. An increased rate of cancer detection was observed in group 2 during the second annual (T2) screening round (2.7% vs 0.5%; P=.005), with no difference in the other screening rounds: baseline (T0; 2% vs 2.3%; P=.61), first annual (T1; 1.2% vs 1.7%; P=.41), and third annual and beyond (>=T3; 1.2% vs 1.1%; P=1.00). Conclusions: CTLS appears to be equally effective in both NCCN high-risk groups. PMID- 29632063 TI - BRAF-Targeted Therapy in the Treatment of BRAF-Mutant High-Grade Gliomas in Adults. PMID- 29632065 TI - WITHDRAWN: Very low density lipoprotein receptor deficiency prevents obesity induced cardiac lipotoxicity. AB - This article has been withdrawn by the authors. We have become aware of errors in the construction of Figs 1 and 2. In Fig 1D, the tIRS1 immunoblot from untreated cardiomyocytes was inadvertently reused from Fig 2A of PLOS One 2016 May 19;11(5):e0155611. Also in Fig 1D, there were undeclared gel splices with no line indicating the assemblage of two parts in the pIRS1 immunoblot from insulin stimulated cardiomyocytes. In Fig 2B, lanes 1-3 and lanes 5-7 of the actin immunoblot were mistakenly duplicated. Because some of the original data are no longer available, the authors wish to withdraw this article. However, the authors have full confidence in the findings and conclusions of this paper, and will repeat the missing immunoblots to complete the paper. PMID- 29632066 TI - TOR complex 2 in fission yeast is required for chromatin-mediated gene silencing and assembly of heterochromatic domains at subtelomeres. AB - The conserved serine/threonine protein kinase target of rapamycin (TOR) is a major regulator of eukaryotic cellular and organismal growth and a valuable target for drug therapy. TOR forms the core of two evolutionary conserved complexes, TOR complex 1 (TORC1) and TORC2. In the fission yeast Schizosaccharomyces pombe, TORC2 responds to glucose levels and, by activating the protein kinase Gad8 (an orthologue of human AKT), is required for well regulated cell cycle progression, starvation responses, and cell survival. Here, we report that TORC2-Gad8 is also required for gene silencing and the formation of heterochromatin at the S. pombe mating-type locus and at subtelomeric regions. Deletion of TORC2-Gad8 resulted in loss of the heterochromatic modification of histone 3 lysine 9 dimethylation (H3K9me2) and an increase in euchromatic modifications, including histone 3 lysine 4 trimethylation (H3K4me3) and histone 4 lysine 16 acetylation (H4K16Ac). Accumulation of RNA polymerase II (Pol II) at subtelomeric genes in TORC2-Gad8 mutant cells indicated a defect in silencing at the transcriptional level. Moreover, a concurrent decrease in histone 4 lysine 20 dimethylation (H4K20me2) suggested elevated histone turnover. Loss of gene silencing in cells lacking TORC2-Gad8 is partially suppressed by loss of the anti silencer Epe1 and fully suppressed by loss of the Pol II-associated Paf1 complex, two chromatin regulators that have been implicated in heterochromatin stability and spreading. Taken together, our findings suggest that TORC2-Gad8 signaling contributes to epigenetic stability at subtelomeric regions and the mating-type locus in S. pombe. PMID- 29632067 TI - CD38 produces nicotinic acid adenosine dinucleotide phosphate in the lysosome. AB - Nicotinic acid adenosine dinucleotide phosphate (NAADP) is a Ca2+-mobilizing second messenger that regulates a wide range of biological activities. However, the mechanism of its biogenesis remains controversial. CD38 is the only enzyme known to catalyze NAADP synthesis from NADP and nicotinic acid. CD38-mediated catalysis requires an acidic pH, suggesting that NAADP may be produced in acidic endolysosomes, but this hypothesis is untested. In this study, using human cell lines, we specifically directed CD38 to the endolysosomal system and assessed cellular NAADP production. First, we found that nanobodies targeting various epitopes on the C-terminal domain of CD38 could bind to cell surface-localized CD38 and induce its endocytosis. We also found that CD38 internalization occurred via a clathrin-dependent pathway, delivered CD38 to the endolysosome, and elevated intracellular NAADP levels. We also created a CD38 variant for lysosome specific expression, which not only withstood the degradative environment in the lysosome, but was also much more active than WT CD38 in elevating cellular NAADP levels. Supplementing CD38-expressing cells with nicotinic acid substantially increased cellular NAADP levels. These results demonstrate that endolysosomal CD38 can produce NAADP in human cells. They further suggest that CD38's compartmentalization to the lysosome may allow for its regulation via substrate access, rather than enzyme activation, thereby providing a reliable mechanism for regulating cellular NAADP production. PMID- 29632068 TI - Eleven residues determine the acyl chain specificity of ceramide synthases. AB - Lipids display large structural complexity, with ~40,000 different lipids identified to date, ~4000 of which are sphingolipids. A critical factor determining the biological activities of the sphingolipid, ceramide, and of more complex sphingolipids is their N-acyl chain length, which in mammals is determined by a family of six ceramide synthases (CerS). Little information is available about the CerS regions that determine specificity toward different acyl CoA substrates. We previously demonstrated that substrate specificity resides in a region of ~150 residues in the Tram-Lag-CLN8 domain. Using site-directed mutagenesis and biochemical analyses, we now narrow specificity down to an 11 residue sequence in a loop located between the last two putative transmembrane domains (TMDs) of the CerS. The specificity of a chimeric protein, CerS5(299-309 >CerS2), based on the backbone of CerS5 (which generates C16-ceramide), but containing 11 residues from CerS2 (which generates C22-C24-ceramides), was altered such that it generated C22-C24 and other ceramides. Moreover, a chimeric protein, CerS4(291-301->CerS2), based on CerS4 (which normally generates C18-C22 ceramides) displayed significant activity toward C24:1-CoA. Additional data supported the notion that substitutions of these 11 residues alter the specificities of the CerS toward their cognate acyl-CoAs. Our findings may suggest that this short loop may restrict adjacent TMDs, leading to a more open conformation in the membrane, and that the CerS acting on shorter acyl-CoAs may have a longer, more flexible loop, permitting TMD flexibility. In summary, we have identified an 11-residue region that determines the acyl-CoA specificity of CerS. PMID- 29632069 TI - Extracellular alpha-synuclein drives sphingosine 1-phosphate receptor subtype 1 out of lipid rafts, leading to impaired inhibitory G-protein signaling. AB - alpha-Synuclein (alpha-Syn)-positive intracytoplasmic inclusions, known as Lewy bodies, are thought to be involved in the pathogenesis of Lewy body diseases, such as Parkinson's disease (PD). Although growing evidence suggests that cell-to cell transmission of alpha-Syn is associated with the progression of PD and that extracellular alpha-Syn promotes formation of inclusion bodies, its precise mechanism of action in the extracellular space remains unclear. Here, as indicated by both conventional fractionation techniques and FRET-based protein protein interaction analysis, we demonstrate that extracellular alpha-Syn causes expulsion of sphingosine 1-phosphate receptor subtype 1 (S1P1R) from the lipid raft fractions. S1P1R regulates vesicular trafficking, and its expulsion involved alpha-Syn binding to membrane-surface gangliosides. Consequently, the S1P1R became refractory to S1P stimulation required for activating inhibitory G-protein (Gi) in the plasma membranes. Moreover, the extracellular alpha-Syn also induced uncoupling of the S1P1R on internal vesicles, resulting in the reduced amount of CD63 molecule (CD63) in the lumen of multivesicular endosomes, together with a decrease in CD63 in the released exosomes from alpha-Syn-treated cells. Furthermore, cholesterol-depleting agent-induced S1P1R expulsion from the rafts also resulted in S1P1R uncoupling. Taken together, these results suggest that extracellular alpha-Syn-induced expulsion of S1P1R from lipid rafts promotes the uncoupling of S1P1R from Gi, thereby blocking subsequent Gi signals, such as inhibition of cargo sorting into exosomal vesicles in multivesicular endosomes. These findings help shed additional light on PD pathogenesis. PMID- 29632070 TI - Histone deacetylase 4 shapes neuronal morphology via a mechanism involving regulation of expression of vascular endothelial growth factor D. AB - Nucleo-cytoplasmic shuttling of class IIa histone deacetylases (i.e HDAC4, -5, 7, and -9) is a synaptic activity- and nuclear calcium-dependent mechanism important for epigenetic regulation of signal-regulated gene expression in hippocampal neurons. HDAC4 in particular has been linked to the regulation of genes important for both synaptic structure and plasticity. Here, using a constitutively nuclear-localized, dominant-active variant of HDAC4 (HDAC4 3SA), we demonstrate that HDAC4 accumulation in the nucleus severely reduces both the length and complexity of dendrites of cultured mature hippocampal neurons, but does not affect the number of dendritic spines. This phenomenon appeared to be specific to HDAC4, as increasing the expression of HDAC3 or HDAC11, belonging to class I and class IV HDACs, respectively, did not alter dendritic architecture. We also show that HDAC4 3SA decreases the expression of vascular endothelial growth factor D (VEGFD), a key protein required for the maintenance of dendritic arbors. The expression of other members of the VEGF family and their receptors was not affected by the nuclear accumulation of HDAC4. VEGFD overexpression or administration of recombinant VEGFD, but not VEGFC, the closest VEGFD homologue, rescued the impaired dendritic architecture caused by the nuclear-localized HDAC4 variant. These results identify HDAC4 as an epigenetic regulator of neuronal morphology that controls dendritic arborization via the expression of VEGFD. PMID- 29632071 TI - The F domain of estrogen receptor alpha is involved in species-specific, tamoxifen-mediated transactivation. AB - Estrogen receptor alpha (ERalpha) is a major transducer of estrogen-mediated physiological signals. ERalpha is a member of the nuclear receptor superfamily, which encompasses ligand-dependent transcription factors. The C terminus of nuclear receptors, termed the F domain, is the least homologous region among the members of this family. The ERalpha F domain possesses 45 amino acids; however, its function remains unclear. We noticed that the homology of the F domains between mouse and human ERalphas is remarkably lower (75.6% similarity) than that between the entire proteins (94.7% similarity). To assess the functionality of the ERalpha F domains, here we generated chimeric ERalpha expression constructs with mouse-human-exchanged F domains. Using cell-based in vitro assays, we analyzed the transcriptional coactivator interaction and ligand-binding domain dimerization activities of these mouse-human F domain-swapped ERalphas. We found that the transcriptional activity of the mouse WT ERalpha is more potent than that of the human WT ERalpha in the human hepatoma cell line HepG2. 4 Hydroxytamoxifen (4OHT)-mediated transcriptional activity of mouse-human F domain swapped ERalphas was the inverse of the WT ERalpha activities but not estradiol mediated transcriptional activities. Further experiments with constructs containing deletion or point mutations of a predicted beta-strand region within the F domain suggested that this region governs the species-specific 4OHT mediated transcriptional activity of ERalpha. We conclude that the ERalpha F domain has a species-specific function in 4OHT-mediated receptor transactivation and that mouse-human F domain-swapped ERalpha mutants enable key insights into ERalpha F domain structure and function. PMID- 29632072 TI - Cyanobacteriochrome-based photoswitchable adenylyl cyclases (cPACs) for broad spectrum light regulation of cAMP levels in cells. AB - Class III adenylyl cyclases generate the ubiquitous second messenger cAMP from ATP often in response to environmental or cellular cues. During evolution, soluble adenylyl cyclase catalytic domains have been repeatedly juxtaposed with signal-input domains to place cAMP synthesis under the control of a wide variety of these environmental and endogenous signals. Adenylyl cyclases with light sensing domains have proliferated in photosynthetic species depending on light as an energy source, yet are also widespread in nonphotosynthetic species. Among such naturally occurring light sensors, several flavin-based photoactivated adenylyl cyclases (PACs) have been adopted as optogenetic tools to manipulate cellular processes with blue light. In this report, we report the discovery of a cyanobacteriochrome-based photoswitchable adenylyl cyclase (cPAC) from the cyanobacterium Microcoleus sp. PCC 7113. Unlike flavin-dependent PACs, which must thermally decay to be deactivated, cPAC exhibits a bistable photocycle whose adenylyl cyclase could be reversibly activated and inactivated by blue and green light, respectively. Through domain exchange experiments, we also document the ability to extend the wavelength-sensing specificity of cPAC into the near IR. In summary, our work has uncovered a cyanobacteriochrome-based adenylyl cyclase that holds great potential for the design of bistable photoswitchable adenylyl cyclases to fine-tune cAMP-regulated processes in cells, tissues, and whole organisms with light across the visible spectrum and into the near IR. PMID- 29632073 TI - Phosphorylation of Tau protein correlates with changes in hippocampal theta oscillations and reduces hippocampal excitability in Alzheimer's model. AB - Tau hyperphosphorylation at several sites, including those close to the microtubule domain region (MDr), is considered a key pathological event in the development of Alzheimer's disease (AD). Recent studies indicate that at the very early stage of this disease, increased phosphorylation in Tau's MDr domain correlates with reduced levels of neuronal excitability. Mechanistically, we show that pyramidal neurons and some parvalbumin-positive interneurons in 1-month-old triple-transgenic AD mice accumulate hyperphosphorylated Tau protein and that this accumulation correlates with changes in theta oscillations in hippocampal neurons. Pyramidal neurons from young triple-transgenic AD mice exhibited less spike accommodation and power increase in subthreshold membrane oscillations. Furthermore, triple-transgenic AD mice challenged with the potassium channel blocker 4-aminopyridine had reduced theta amplitude compared with 4-aminopyridine treated control mice and, unlike these controls, displayed no seizure-like activity after this challenge. Collectively, our results provide new insights into AD pathogenesis and suggest that increases in Tau phosphorylation at the initial stages of the disease represent neuronal responses that compensate for brain circuit overexcitation. PMID- 29632074 TI - The yeast protein Gdt1p transports Mn2+ ions and thereby regulates manganese homeostasis in the Golgi. AB - The uncharacterized protein family 0016 (UPF0016) is a family of secondary ion transporters implicated in calcium homeostasis and some diseases. More precisely, genetic variants of the human UPF0016 ortholog transmembrane protein 165 (TMEM165) have been linked to congenital disorders of glycosylation (CDG). The Saccharomyces cerevisiae ortholog Gdt1p has been shown to be involved in calcium homeostasis and protein glycosylation. Moreover, plant and bacterial UPF0016 members appear to have putative roles in Mn2+ homeostasis. Here, we produced the yeast UPF0016 member Gdt1p in the bacterial host Lactococcus lactis Using Mn2+ induced quenching of Fura-2-emitted fluorescence, we observed that Gdt1p mediates Mn2+ influx, in addition to its previously reported regulation of Ca2+ influx. The estimated Km values of Gdt1p of 15.6 +/- 2.6 MUm for Ca2+ and 83.2 +/- 9.8 MUm for Mn2+ indicated that Gdt1p has a higher affinity for Ca2+ than for Mn2+ In yeast cells, we found that Gdt1p is involved in the resistance to high Mn2+ concentration and controls total Mn2+ stores. Lastly, we demonstrated that GDT1 deletion affects the activity of the yeast Mn2+-dependent Sod2p superoxide dismutase, most likely by modulating cytosolic Mn2+ concentrations. Taken together, we obtained first evidence that Gdt1p from yeast directly transports manganese, which strongly reinforces the suggested link between the UPF0016 family and Mn2+ homeostasis and provides new insights into the molecular causes of human TMEM165-associated CDGs. Our results also shed light on how yeast cells may regulate Golgi intraluminal concentrations of manganese, a key cofactor of many enzymes involved in protein glycosylation. PMID- 29632075 TI - A consensus-guided approach yields a heat-stable alkane-producing enzyme and identifies residues promoting thermostability. AB - Aldehyde-deformylating oxygenase (ADO) is an essential enzyme for production of long-chain alkanes as drop-in biofuels, which are compatible with existing fuel systems. The most active ADOs are present in mesophilic cyanobacteria, especially Nostoc punctiforme Given the potential applications of thermostable enzymes in biorefineries, here we generated a thermostable (Cts)-ADO based on a consensus of ADO sequences from several thermophilic cyanobacterial strains. Using an in silico design pipeline and a metagenome library containing 41 hot-spring microbial communities, we created Cts-ADO. Cts-ADO displayed a 3.8-fold increase in pentadecane production on raising the temperature from 30 to 42 degrees C, whereas ADO from N. punctiforme (Np-ADO) exhibited a 1.7-fold decline. 3D structure modeling and molecular dynamics simulations of Cts- and Np-ADO at different temperatures revealed differences between the two enzymes in residues clustered on exposed loops of these variants, which affected the conformation of helices involved in forming the ADO catalytic core. In Cts-ADO, this conformational change promoted ligand binding to its preferred iron, Fe2, in the di-iron cluster at higher temperature, but the reverse was observed in Np-ADO. Detailed mapping of residues conferring Cts-ADO thermostability identified four amino acids, which we substituted individually and together in Np-ADO. Among these substitution variants, A161E was remarkably similar to Cts-ADO in terms of activity optima, kinetic parameters, and structure at higher temperature. A161E was located in loop L6, which connects helices H5 and H6, and supported ligand binding to Fe2 at higher temperatures, thereby promoting optimal activity at these temperatures and explaining the increased thermostability of Cts-ADO. PMID- 29632076 TI - The antibiotic cyclomarin blocks arginine-phosphate-induced millisecond dynamics in the N-terminal domain of ClpC1 from Mycobacterium tuberculosis. AB - Mycobacterium tuberculosis can remain dormant in the host, an ability that explains the failure of many current tuberculosis treatments. Recently, the natural products cyclomarin, ecumicin, and lassomycin have been shown to efficiently kill Mycobacterium tuberculosis persisters. Their target is the N terminal domain of the hexameric AAA+ ATPase ClpC1, which recognizes, unfolds, and translocates protein substrates, such as proteins containing phosphorylated arginine residues, to the ClpP1P2 protease for degradation. Surprisingly, these antibiotics do not inhibit ClpC1 ATPase activity, and how they cause cell death is still unclear. Here, using NMR and small-angle X-ray scattering, we demonstrate that arginine-phosphate binding to the ClpC1 N-terminal domain induces millisecond dynamics. We show that these dynamics are caused by conformational changes and do not result from unfolding or oligomerization of this domain. Cyclomarin binding to this domain specifically blocked these N terminal dynamics. On the basis of these results, we propose a mechanism of action involving cyclomarin-induced restriction of ClpC1 dynamics, which modulates the chaperone enzymatic activity leading eventually to cell death. PMID- 29632077 TI - IreA controls endoplasmic reticulum stress-induced autophagy and survival through homeostasis recovery. AB - The Unfolded Protein Response (UPR) is an adaptive pathway that restores cellular homeostasis after endoplasmic reticulum (ER) stress. The ER-resident kinase/ribonuclease Ire1 is the only UPR sensor conserved during evolution. Autophagy, a lysosomal degradative pathway, also contributes to the recovery of cell homeostasis after ER-stress but the interplay between these two pathways is still poorly understood. We describe the Dictyostelium discoideum ER-stress response and characterize its single bonafide Ire1 orthologue, IreA. We found that tunicamycin (TN) triggers a gene-expression reprogramming that increases the protein folding capacity of the ER and alleviates ER protein load. Further, IreA is required for cell-survival after TN-induced ER-stress and is responsible for nearly 40% of the transcriptional changes induced by TN. The response of Dictyostelium cells to ER-stress involves the combined activation of an IreA dependent gene expression program and the autophagy pathway. These two pathways are independently activated in response to ER-stress but, interestingly, autophagy requires IreA at a later stage for proper autophagosome formation. We propose that unresolved ER-stress in cells lacking IreA causes structural alterations of the ER, leading to a late-stage blockade of autophagy clearance. This unexpected functional link may critically affect eukaryotic cell survival under ER-stress. PMID- 29632079 TI - Management of recurrent pancreatic cancer after surgical resection: a protocol for systematic review, evidence mapping and meta-analysis. AB - INTRODUCTION: Although recurrence rate among cases of resected pancreatic cancer are as high as 85%, an optimal treatment for recurrent pancreatic cancer (RePC) has not been established. Previous evidence regarding RePC is scarce, and randomised controlled trials (RCTs) are particularly lacking. The evidence mapping (EM) method has been introduced as a tool intended to complement the conventional systematic review (SR) and meta-analysis (MA) and is suitable for this issue. This review aims to investigate the optimal treatment options for RePC, using a newly developed automatic EM tool. METHOD AND ANALYSIS: All study types, including RCTs, non-randomised studies and other forms of observational studies will be included in the SR-EM. The Medline, Embase, Cochrane library and Scopus databases will be searched for reports of five treatment options for local and metastatic recurrences, including re-resection, chemotherapy, radiotherapy, best supportive care and other novel treatments, published from database inception to 30 April 2017. References from relevant studies will be searched manually. If meta-analysis is feasible, the primary outcome measure will be median overall survival. Two independent authors will select the studies and assess the risk of bias, and a third author will resolve discrepancies in consensus meeting. To visualise EM, we will use a novel web-based and open-access mapping programme, Plotting E-Map (PLOEM) (http://plotting-e-map.com). If eligible combinations of interventions for quantitative comparison are identified, we will conduct subgroup MAs using random-effect models and I2 statistics. Publication bias will be visualised using funnel plots. ETHICS AND DISSEMINATION: This study will not use primary data, and therefore formal ethical approval is not required. The findings will be disseminated through peer-reviewed journals and committee conferences. PROSPEROREGISTRATION NUMBER: CRD42016049178. PMID- 29632078 TI - Regulation of Intestinal Epithelial Barrier Function by Long Noncoding RNA uc.173 through Interaction with MicroRNA 29b. AB - The mammalian intestinal epithelium establishes a selectively permeable barrier that supports nutrient absorption and prevents intrusion by noxious luminal substances and microbiota. The effectiveness and integrity of the barrier function are tightly regulated via well-controlled mechanisms. Long noncoding RNAs transcribed from ultraconserved regions (T-UCRs) control diverse cellular processes, but their roles in the regulation of gut permeability remain largely unknown. Here we report that the T-UCR uc.173 enhances intestinal epithelial barrier function by antagonizing microRNA 29b (miR-29b). Decreasing the levels of uc.173 by gene silencing led to dysfunction of the intestinal epithelial barrier in cultured cells and increased the vulnerability of the gut barrier to septic stress in mice. uc.173 specifically stimulated translation of the tight junction (TJ) claudin-1 (CLDN1) by associating with miR-29b rather than by binding directly to CLDN1 mRNA. uc.173 acted as a natural decoy RNA for miR-29b, which interacts with CLDN1 mRNA via the 3' untranslated region and represses its translation. Ectopically expressed uc.173 abolished the association of miR-29b with CLDN1 mRNA and restored claudin-1 expression to normal levels in cells overexpressing miR-29b, thus rescuing the barrier function. These results highlight a novel function of uc.173 in controlling gut permeability and define a mechanism by which uc.173 stimulates claudin-1 translation, by decreasing the availability of miR-29b to CLDN1 mRNA. PMID- 29632082 TI - Effect of Tai Chi for the prevention or treatment of osteoporosis in elderly adults: protocol for a systematic review and meta-analysis. AB - INTRODUCTION: Osteoporosis (OP) has been defined as a degenerative bone disease characterised by low bone mass and microstructural deterioration of bone tissue, leading to fragility and an increased risk of fractures, especially of the hip, spine and wrist. Exercise has been shown to benefit the maintenance of bone health and improvement of muscle strength, balance and coordination, thereby reducing the risk of falls and fractures. However, prior findings regarding the optimal types and regimens of exercise for treating low bone mineral density (BMD) in elderly people are not consistent. As an important component of traditional Chinese Qigong exercises, Tai Chi (TC) is an ancient art and science of healthcare derived from the martial arts. The objective of this study is to attempt to conduct a systematic review and meta-analysis of the existing studies on TC exercise as an intervention for the prevention or treatment of OP in elderly adults and to draw more useful conclusions regarding the safety and the effectiveness of TC in preventing or treating OP. METHODS AND ANALYSIS: Eight electronic databases (Science Citation Index, PubMed Database, Embase (Ovid) Database, the Cochrane Central Register of Controlled Trials, and Chinese databases, including Chinese BioMedical Database, China National Knowledge Infrastructure, Wanfang database and the Chongqing VIP Chinese Science and Technology Periodical Database) will be searched from the beginning of each database to 1 April 2018. Potential outcomes of interest will include rates of fractures or falls, BMD at the total hip and the total spine, bone formation biomarkers, bone resorption biomarkers, bone biomarkers, health-related quality of life and adverse events. Only randomised controlled trials comparing TC exercise against each other or non-intervention will be included. The Cochrane risk of bias assessment tool will be used for quality assessment. ETHICS AND DISSEMINATION: Ethical approval is not required as the study will be a review of existing studies. This review may help to elucidate whether TC exercise is effective for the prevention or treatment of OP in elderly adults. The findings of the study will be published in a peer-reviewed publication and will be disseminated electronically or in print. We will share the findings in the fourth quarter of 2018. TRIAL REGISTRATION NUMBER: CRD42018084950. PMID- 29632081 TI - A randomised controlled trial of a facilitated home-based rehabilitation intervention in patients with heart failure with preserved ejection fraction and their caregivers: the REACH-HFpEF Pilot Study. AB - INTRODUCTION: Home-based cardiac rehabilitation may overcome suboptimal rates of participation. The overarching aim of this study was to assess the feasibility and acceptability of the novel Rehabilitation EnAblement in CHronic Hear Failure (REACH-HF) rehabilitation intervention for patients with heart failure with preserved ejection fraction (HFpEF) and their caregivers. METHODS AND RESULTS: Patients were randomised 1:1 to REACH-HF intervention plus usual care (intervention group) or usual care alone (control group). REACH-HF is a home based comprehensive self-management rehabilitation programme that comprises patient and carer manuals with supplementary tools, delivered by trained healthcare facilitators over a 12 week period. Patient outcomes were collected by blinded assessors at baseline, 3 months and 6 months postrandomisation and included health-related quality of life (primary) and psychological well-being, exercise capacity, physical activity and HF-related hospitalisation (secondary). Outcomes were also collected in caregivers.We enrolled 50 symptomatic patients with HF from Tayside, Scotland with a left ventricular ejection fraction >=45% (mean age 73.9 years, 54% female, 100% white British) and 21 caregivers. Study retention (90%) and intervention uptake (92%) were excellent. At 6 months, data from 45 patients showed a potential direction of effect in favour of the intervention group, including the primary outcome of Minnesota Living with Heart Failure Questionnaire total score (between-group mean difference -11.5, 95% CI 22.8 to 0.3). A total of 11 (4 intervention, 7 control) patients experienced a hospital admission over the 6 months of follow-up with 4 (control patients) of these admissions being HF-related. Improvements were seen in a number intervention caregivers' mental health and burden compared with control. CONCLUSIONS: Our findings support the feasibility and rationale for delivering the REACH-HF facilitated home-based rehabilitation intervention for patients with HFpEF and their caregivers and progression to a full multicentre randomised clinical trial to test its clinical effectiveness and cost-effectiveness. TRIAL REGISTRATION NUMBER: ISRCTN78539530. PMID- 29632080 TI - Laparoscopic excision of deep rectovaginal endometriosis in BSGE endometriosis centres: a multicentre prospective cohort study. AB - OBJECTIVE: To estimate the effectiveness and safety of laparoscopic surgical excision of rectovaginal endometriosis. DESIGN: A multicentre, prospective cohort study. SETTING: 51 hospitals accredited as specialist endometriosis centres. PARTICIPANTS: 5162 women of reproductive age with rectovaginal endometriosis of which 4721 women had planned laparoscopic excision. INTERVENTIONS: Laparoscopic surgical excision of rectovaginal endometriosis requiring dissection of the pararectal space. MAIN OUTCOME MEASURES: Standardised symptom questionnaires enquiring about chronic pelvic pain, bladder and bowel symptoms, analgesia use and quality of life (EuroQol) completed prior to surgery and at 6, 12 and 24 months postoperatively. Serious perioperative and postoperative complications including major haemorrhage, infection and visceral injury were recorded. RESULTS: At 6 months postsurgery, there were significant reductions in premenstrual, menstrual and non-cyclical pelvic pain, deep dyspareunia, dyschezia, low back pain and bladder pain. In addition, there were significant reductions in voiding difficulty, bowel frequency, urgency, incomplete emptying, constipation and passing blood. These reductions were maintained at 2 years, with the exception of voiding difficulty. Global quality of life significantly improved from a median pretreatment score of 55/100 to 80/100 at 6 months. There was a significant improvement in quality of life in all measured domains and in quality-adjusted life years. These improvements were sustained at 2 years. All analgesia use was reduced and, in particular, opiate use fell from 28.1% prior to surgery to 16.1% at 6 months. The overall incidence of complications was 6.8% (321/4721). Gastrointestinal complications (enterotomy, anastomotic leak or fistula) occurred in 52 (1.1%) operations and of the urinary tract (ureteric/bladder injury or leak) in 49 (1.0%) procedures. CONCLUSION: Laparoscopic surgical excision of rectovaginal endometriosis appears to be effective in treating pelvic pain and bowel symptoms and improving health-related quality of life and has a low rate of major complications when performed in specialist centres. PMID- 29632083 TI - Sepsis recognition tools in acute ambulatory care: associations with process of care and clinical outcomes in a service evaluation of an Emergency Multidisciplinary Unit in Oxfordshire. AB - OBJECTIVE: To assess the performance of currently available sepsis recognition tools in patients referred to a community-based acute ambulatory care unit. DESIGN: Service evaluation of consecutive patients over a 4-month period. SETTING: Community-based acute ambulatory care unit. DATA COLLECTION AND OUTCOME MEASURES: Observations, blood results and outcome data were analysed from patients with a suspected infection. Clinical features at first assessment were used to populate sepsis recognition tools including: systemic inflammatory response syndrome (SIRS) criteria, National Early Warning Score (NEWS), quick Sequential Organ Failure Assessment (qSOFA) and National Institute for Health and Care Excellence (NICE) criteria. Scores were assessed against the clinical need for escalated care (use of intravenous antibiotics, fluids, ongoing ambulatory care or hospital treatment) and poor clinical outcome (all-cause mortality and readmission at 30 days after index assessment). RESULTS: Of 533 patients (median age 81 years), 316 had suspected infection with 120 patients requiring care escalated beyond simple community care. SIRS had the highest positive predictive value (50.9%, 95% CI 41.6% to 60.3%) and negative predictive value (68.9%, 95% CI 62.6% to 75.3%) for the need for escalated care. Both NEWS and SIRS were better at predicting the need for escalated care than qSOFA and NICE criteria in patients with suspected infection (all P<0.001). While new-onset confusion predicted the need for escalated care for infection in patients >=85 years old (n=114), 23.7% of patients >=85 years had new-onset confusion without evidence for infection. CONCLUSIONS: Acute ambulatory care clinicians should use caution in applying the new NICE endorsed criteria for determining the need for intravenous therapy and hospital-based location of care. NICE criteria have poorer performance when compared against NEWS and SIRS and new-onset confusion was prevalent in patients aged >=85 years without infection. PMID- 29632084 TI - Protocol for development and validation of a context-appropriate tool for assessing organisational readiness for change in primary health clinics in South Africa. AB - INTRODUCTION: A large treatment gap for common mental disorders (such as depression) exists in South Africa. Comorbidity with other chronic diseases, including HIV and diseases of lifestyle, is an increasing public health concern globally. Currently, primary health facilities as points of care for those with chronic disease provide limited services for common mental disorders. Assessing organisational readiness for change (ORC) towards adopting health innovations (such as mental health services) using contextually appropriate measures is needed to facilitate implementation of these services. This study aims to investigate the validity of the Texas Christian University Organisational Readiness for Change (TCU-ORC) scale in the South African context. Subsequently, we will develop a shortened version of this scale. This study is nested within Project MIND, a multiyear randomised controlled trial that is testing two different approaches for integrating counselling for common mental disorders into chronic disease care. Although the modified, contextually appropriate ORC measure resulting from the proposed study will be developed in the context of integrating mental health into primary healthcare services, the potential for the tool to be generalised to further understanding barriers to any change being implemented in primary care settings is high. METHODS AND ANALYSIS: We will establish internal consistency (Cronbach's alpha coefficients), test-retest reliability (intraclass correlation coefficient) and construct validity of the long-form TCU-ORC questionnaire. Survey data will be collected from 288 clinical, management and operational staff from 24 primary health facilities where the Project MIND trial is implemented. A modified Delphi approach will assess the content validity of the TCU-ORC items and identify areas for potential adaptation and item reduction. ETHICS AND DISSEMINATION: Ethical approval has been granted by the South African Medical Research Council (Protocol ID EC004-2-2015, amendment of 20 August 2017). Results will be submitted to peer-reviewed journals relevant to implementation and health systems strengthening. PMID- 29632085 TI - Increased HOXA5 expression provides a selective advantage for gain of whole chromosome 7 in IDH wild-type glioblastoma. AB - Glioblastoma is the most frequently occurring and invariably fatal primary brain tumor in adults. The vast majority of glioblastomas is characterized by chromosomal copy number alterations, including gain of whole chromosome 7 and loss of whole chromosome 10. Gain of whole chromosome 7 is an early event in gliomagenesis that occurs in proneural-like precursor cells, which give rise to all isocitrate dehydrogenase (IDH) wild-type glioblastoma transcriptional subtypes. Platelet-derived growth factor A (PDGFA) is one gene on chromosome 7 known to drive gliomagenesis, but, given its location near the end of 7p, there are likely several other genes located along chromosome 7 that select for its increased whole-chromosome copy number within glioblastoma cells. To identify other potential genes that could select for gain of whole chromosome 7, we developed an unbiased bioinformatics approach that identified homeobox A5 (HOXA5) as a gene whose expression correlated with gain of chromosome 7 and a more aggressive phenotype of the resulting glioma. High expression of HOXA5 in glioblastoma was associated with a proneural gene expression pattern and decreased overall survival in both human proneural and PDGF-driven mouse glioblastoma. Furthermore, HOXA5 overexpression promoted cellular proliferation and potentiated radioresistance. We also found enrichment of HOXA5 expression in recurrent human and mouse glioblastoma at first recurrence after radiotherapy. Overall, this study implicates HOXA5 as a chromosome 7-associated gene-level locus that promotes selection for gain of whole chromosome 7 and an aggressive phenotype in glioblastoma. PMID- 29632086 TI - Athymic mice reveal a requirement for T-cell-microglia interactions in establishing a microenvironment supportive of Nf1 low-grade glioma growth. AB - Pediatric low-grade gliomas (LGGs) frequently do not engraft in immunocompromised mice, limiting their use as an experimental platform. In contrast, murine Neurofibromatosis-1 (Nf1) optic LGG stem cells (o-GSCs) form glioma-like lesions in wild-type, but not athymic, mice following transplantation. Here, we show that the inability of athymic mice to support o-GSC engraftment results from impaired microglia/macrophage function, including reduced expression of Ccr2 and Ccl5, both of which are required for o-GSC engraftment and Nf1 optic glioma growth. Impaired Ccr2 and Ccl5 expression in athymic microglia/macrophages was restored by T-cell exposure, establishing T-cell-microglia/macrophage interactions as critical stromal determinants that support NF1 LGG growth. PMID- 29632087 TI - In-depth characterization of the cisplatin mutational signature in human cell lines and in esophageal and liver tumors. AB - Cisplatin reacts with DNA and thereby likely generates a characteristic pattern of somatic mutations, called a mutational signature. Despite widespread use of cisplatin in cancer treatment and its role in contributing to secondary malignancies, its mutational signature has not been delineated. We hypothesize that cisplatin's mutational signature can serve as a biomarker to identify cisplatin mutagenesis in suspected secondary malignancies. Knowledge of which tissues are at risk of developing cisplatin-induced secondary malignancies could lead to guidelines for noninvasive monitoring for secondary malignancies after cisplatin chemotherapy. We performed whole genome sequencing of 10 independent clones of cisplatin-exposed MCF-10A and HepG2 cells and delineated the patterns of single and dinucleotide mutations in terms of flanking sequence, transcription strand bias, and other characteristics. We used the mSigAct signature presence test and nonnegative matrix factorization to search for cisplatin mutagenesis in hepatocellular carcinomas and esophageal adenocarcinomas. All clones showed highly consistent patterns of single and dinucleotide substitutions. The proportion of dinucleotide substitutions was high: 8.1% of single nucleotide substitutions were part of dinucleotide substitutions, presumably due to cisplatin's propensity to form intra- and interstrand crosslinks between purine bases in DNA. We identified likely cisplatin exposure in nine hepatocellular carcinomas and three esophageal adenocarcinomas. All hepatocellular carcinomas for which clinical data were available and all esophageal cancers indeed had histories of cisplatin treatment. We experimentally delineated the single and dinucleotide mutational signature of cisplatin. This signature enabled us to detect previous cisplatin exposure in human hepatocellular carcinomas and esophageal adenocarcinomas with high confidence. PMID- 29632088 TI - Borrelia burgdorferi SpoVG DNA- and RNA-Binding Protein Modulates the Physiology of the Lyme Disease Spirochete. AB - The SpoVG protein of Borrelia burgdorferi, the Lyme disease spirochete, binds to specific sites of DNA and RNA. The bacterium regulates transcription of spoVG during the natural tick-mammal infectious cycle and in response to some changes in culture conditions. Bacterial levels of spoVG mRNA and SpoVG protein did not necessarily correlate, suggesting that posttranscriptional mechanisms also control protein levels. Consistent with this, SpoVG binds to its own mRNA, adjacent to the ribosome-binding site. SpoVG also binds to two DNA sites in the glpFKD operon and to two RNA sites in glpFKD mRNA; that operon encodes genes necessary for glycerol catabolism and is important for colonization in ticks. In addition, spirochetes engineered to dysregulate spoVG exhibited physiological alterations.IMPORTANCEB. burgdorferi persists in nature by cycling between ticks and vertebrates. Little is known about how the bacterium senses and adapts to each niche of the cycle. The present studies indicate that B. burgdorferi controls production of SpoVG and that this protein binds to specific sites of DNA and RNA in the genome and transcriptome, respectively. Altered expression of spoVG exerts effects on bacterial replication and other aspects of the spirochete's physiology. PMID- 29632089 TI - Characterization of the Trehalose Utilization Operon in Streptococcus mutans Reveals that the TreR Transcriptional Regulator Is Involved in Stress Response Pathways and Toxin Production. AB - Streptococcus mutans, the organism most frequently associated with the development of dental caries, is able to utilize a diverse array of carbohydrates for energy metabolism. One such molecule is trehalose, a disaccharide common in human foods, which has been recently implicated in enhancing the virulence of epidemic strains of the pathogen Clostridium difficile In this study, mutants with deletions of all three genes in the putative S. mutans trehalose utilization operon were characterized, and the genes were shown to be required for wild-type levels of growth when trehalose was the only carbohydrate source provided. Interestingly, the TreR transcriptional regulator appeared to be critical for responding to oxidative stress and for mounting a protective stress tolerance response following growth at moderately acidic pH. mRNA sequencing (RNA-seq) of a treR deletion mutant suggested that in S. mutans, TreR acts as a trehalose sensing activator of transcription of the tre operon, rather than as a repressor, as described in other species. In addition, deletion of treR caused the downregulation of a number of genes involved in genetic competence and bacteriocin production, supporting the results of a recent study linking trehalose and the S. mutans competence pathways. Finally, deletion of treR compromised the ability of S. mutans to inhibit the growth of the competing species Streptococcus gordonii and Lactococcus lactis Taking the results together, this study solidifies the role of the S. mutans tre operon in trehalose utilization and suggests novel functions for the TreR regulator, including roles in the stress response and competitive fitness.IMPORTANCES. mutans is the primary etiologic agent of dental caries, which globally is the most common chronic disease. S. mutans must be able to outcompete commensal organisms in its dental plaque niche in order to establish persistence and pathogenesis. To that end, S. mutans metabolizes a diverse array of carbohydrates to generate acid and impede its acid-sensitive neighbors. Additionally, S. mutans utilizes quorum signaling through genetic competence-associated pathways to induce production of toxins to kill its rivals. This study definitively shows that the S. mutans trehalose utilization operon is required for growth in trehalose. Furthermore, this study suggests that the S. mutans TreR transcriptional regulator has a novel role in virulence through regulation of genes involved in genetic competence and toxin production. PMID- 29632090 TI - cAMP and Vfr Control Exolysin Expression and Cytotoxicity of Pseudomonas aeruginosa Taxonomic Outliers. AB - The two-partner secretion system ExlBA, expressed by strains of Pseudomonas aeruginosa belonging to the PA7 group, induces hemorrhage in lungs due to disruption of host cellular membranes. Here we demonstrate that the exlBA genes are controlled by a pathway consisting of cAMP and the virulence factor regulator (Vfr). Upon interaction with cAMP, Vfr binds directly to the exlBA promoter with high affinity (equilibrium binding constant [Keq] of ~2.5 nM). The exlB and exlA expression was diminished in the Vfr-negative mutant and upregulated with increased intracellular cAMP levels. The Vfr binding sequence in the exlBA promoter was mutated in situ, resulting in reduced cytotoxicity of the mutant, showing that Vfr is required for the exlBA expression during intoxication of epithelial cells. Vfr also regulates function of type 4 pili previously shown to facilitate ExlA activity on epithelial cells, which indicates that the cAMP/Vfr pathway coordinates these two factors needed for full cytotoxicity. As in most P. aeruginosa strains, the adenylate cyclase CyaB is the main provider of cAMP for Vfr regulation during both in vitro growth and eukaryotic cell infection. We discovered that the absence of functional Vfr in the reference strain PA7 is caused by a frameshift in the gene and accounts for its reduced cytotoxicity, revealing the conservation of ExlBA control by the CyaB-cAMP/Vfr pathway in P. aeruginosa taxonomic outliers.IMPORTANCE The human opportunistic pathogen Pseudomonas aeruginosa provokes severe acute and chronic human infections associated with defined sets of virulence factors. The main virulence determinant of P. aeruginosa taxonomic outliers is exolysin, a membrane-disrupting pore forming toxin belonging to the two-partner secretion system ExlBA. In this work, we demonstrate that the conserved CyaB-cAMP/Vfr pathway controls cytotoxicity of outlier clinical strains through direct transcriptional activation of the exlBA operon. Therefore, despite the fact that the type III secretion system and exolysin are mutually exclusive in classical and outlier strains, respectively, these two major virulence determinants share similarities in their mechanisms of regulation. PMID- 29632091 TI - Convergence of PASTA kinase and two-component signaling in response to cell wall stress in Enterococcus faecalis. AB - Two common signal transduction mechanisms used by bacteria to sense and respond to changing environments are two-component systems (TCSs) and eukaryotic-like Ser/Thr kinases and phosphatases (eSTK/Ps). Enterococcus faecalis is a Gram positive bacterium and serious opportunistic pathogen that relies on both a TCS and an eSTK/P pathway for intrinsic resistance to cell wall-targeting antibiotics. The TCS consists of a histidine kinase (CroS) and response regulator (CroR) that become activated upon exposure of cells to cell wall-targeting antibiotics, leading to modulation of gene expression. The eSTK/P pathway consists of a transmembrane kinase (IreK) and its cognate phosphatase (IreP), which act antagonistically to mediate antibiotic resistance through an unknown mechanism. Because both CroS/R and IreK/P contribute to enterococcal resistance towards cell wall-targeting antibiotics, we hypothesized these signaling systems are intertwined. To test this hypothesis, we analyzed CroR phosphorylation and CroS/R-dependent gene expression to probe the influence of IreK and IreP on CroS/R signaling. In addition, we analyzed the phosphorylation state of CroS which revealed IreK-dependent phosphorylation of a Thr residue important for CroS function. Our results are consistent with a model in which IreK positively influences CroR-dependent gene expression through phosphorylation of CroS to promote antimicrobial resistance in E. faecalisImportance Two-component signaling systems (TCSs) and eukaryotic-like Ser/Thr kinases (eSTKs) are used by bacteria to sense and adapt to changing environments. Understanding how these pathways are regulated to promote bacterial survival is critical for a more complete understanding of bacterial stress responses and physiology. The opportunistic pathogen Enterococcus faecalis relies on both a TCS (CroS/R) and an eSTK (IreK) for intrinsic resistance to cell wall-targeting antibiotics. We probed the relationship between CroS/R and IreK, revealing convergence of IreK and the sensor kinase CroS to enhance signaling through CroS/R and increase antimicrobial resistance in E. faecalis This newly described example of eSTK/TCS convergence adds to our understanding of the signaling networks mediating antimicrobial resistance in E. faecalis. PMID- 29632092 TI - Salt-Induced Stress Stimulates a Lipoteichoic Acid-Specific Three Component Glycosylation System in Staphylococcus aureus. AB - Lipoteichoic acid (LTA) in Staphylococcus aureus is a poly-glycerophosphate polymer anchored to the outer surface of the cell membrane. LTA has numerous roles in cell envelope physiology, including regulating cell autolysis, coordinating cell division, and adapting to environmental growth conditions. LTA is often further modified with substituents including D-alanine and glycosyl groups to alter cellular function. While the genetic determinants of D alanylation have been largely defined, the route of LTA glycosylation and its role in cell envelope physiology has remained unknown in part due to the low levels of basal LTA glycosylation in S. aureus Herein we demonstrate S. aureus utilizes a membrane associated three component glycosylation system composed of an undecaprenol (Und) N-acetylglucosamine (GlcNAc) charging enzyme (CsbB; SAOUHSC_00713), a putative flippase to transport loaded substrate to the outside surface of the cell (GtcA; SAOUHSC_02722), and finally a LTA specific glycosyltransferase that adds alpha-GlcNAc moieties to LTA (YfhO; SAOUHSC_01213). We demonstrate that this system is specific for LTA with no cross recognition of the structurally similar polyribitol phosphate containing wall teichoic acids. We show that while wild-type S. aureus LTA has only a trace of GlcNAcylated LTA under normal growth conditions, amounts are raised upon either overexpressing CsbB, reducing endogenous D-alanylation activity, expressing the cell envelope stress responsive alternative sigma factor SigB, or by exposure to environmental stress-inducing culture conditions including high sodium chloride containing growth media.Importance The role of glycosylation in the structure and function of Staphylococcus aureus LTA is largely unknown. By defining key components of the lipoteichoic acid three component glycosylation pathway and uncovering stress induced regulation by the alternative sigma factor SigB, the role of N acetylglucosamine tailoring during adaptation to environmental stresses can now be elucidated. As the dlt and glycosylation pathways compete for the same sites on LTA and induction of glycosylation results in decreased D-alanylation, the interplay between the two modification systems holds implications for resistance to antibiotics and antimicrobial peptides. PMID- 29632093 TI - Endoribonuclease YbeY Is Linked to Proper Cellular Morphology and Virulence in Brucella abortus. AB - The YbeY endoribonuclease is one of the best-conserved proteins across the kingdoms of life. In the present study, we demonstrated that YbeY in Brucella abortus is linked to a variety of important activities, including proper cellular morphology, mRNA transcript levels, and virulence. Deletion of ybeY in B. abortus led to a small-colony phenotype when the bacteria were grown on agar medium, as well as to significant aberrations in the morphology of the bacterial cell as evidenced by electron microscopy. Additionally, compared to the parental strain, the DeltaybeY strain was significantly attenuated in both macrophage and mouse models of infection. The DeltaybeY strain also showed increased sensitivities to several in vitro-applied stressors, including bile acid, hydrogen peroxide, SDS, and paraquat. Transcriptomic analysis revealed that a multitude of mRNA transcripts are dysregulated in the DeltaybeY strain, and many of the identified mRNAs encode proteins involved in metabolism, nutrient transport, transcriptional regulation, and flagellum synthesis. We subsequently constructed gene deletion strains of the most highly dysregulated systems, and several of the YbeY-linked gene deletion strains exhibited defects in the ability of the bacteria to survive and replicate in primary murine macrophages. Taken together, these data establish a clear role for YbeY in the biology and virulence of Brucella; moreover, this work further illuminates the highly varied roles of this widely conserved endoribonuclease in bacteria.IMPORTANCEBrucella spp. are highly efficient bacterial pathogens of animals and humans, causing significant morbidity and economic loss worldwide, and relapse of disease often occurs following antibiotic treatment of human brucellosis. As such, novel therapeutic strategies to combat Brucella infections are needed. Ribonucleases in the brucellae are understudied, and these enzymes represent elements that may be potential targets for future treatment approaches. The present work demonstrates the importance of the YbeY endoribonuclease for cellular morphology, efficient control of mRNA levels, and virulence in B. abortus Overall, the results of this study advance our understanding of the critical roles of YbeY in the pathogenesis of the intracellular brucellae and expand our understanding of this highly conserved RNase. PMID- 29632094 TI - Evolution of a Vegetarian Vibrio: Metabolic Specialization of Vibrio breoganii to Macroalgal Substrates. AB - While most Vibrionaceae are considered generalists that thrive on diverse substrates, including animal-derived material, we show that Vibrio breoganii has specialized for the consumption of marine macroalga-derived substrates. Genomic and physiological comparisons of V. breoganii with other Vibrionaceae isolates revealed the ability to degrade alginate, laminarin, and additional glycans present in algal cell walls. Moreover, the widely conserved ability to hydrolyze animal-derived polymers, including chitin and glycogen, was lost, along with the ability to efficiently grow on a variety of amino acids. Ecological data showing associations with particulate algal material but not zooplankton further support this shift in niche preference, and the loss of motility appears to reflect a sessile macroalga-associated lifestyle. Together, these findings indicate that algal polysaccharides have become a major source of carbon and energy in V. breoganii, and these ecophysiological adaptations may facilitate transient commensal associations with marine invertebrates that feed on algae.IMPORTANCE Vibrios are often considered animal specialists or generalists. Here, we show that Vibrio breoganii has undergone massive genomic changes to become specialized on algal carbohydrates. Accompanying genomic changes include massive gene import and loss. These vibrios may help us better understand how algal biomass is degraded in the environment and may serve as a blueprint on how to optimize the conversion of algae to biofuels. PMID- 29632095 TI - Association of omega with the C-Terminal Region of the beta' Subunit Is Essential for Assembly of RNA Polymerase in Mycobacterium tuberculosis. AB - The omega subunit is the smallest subunit of bacterial RNA polymerase (RNAP). Although homologs of omega are essential in both eukaryotes and archaea, this subunit has been known to be dispensable for RNAP in Escherichia coli and in other bacteria. In this study, we characterized an indispensable role of the omega subunit in Mycobacterium tuberculosis Unlike the well-studied E. coli RNAP, the M. tuberculosis RNAP core enzyme cannot be functionally assembled in the absence of the omega subunit. Importantly, substitution of M. tuberculosis omega with omega subunits from E. coli or Thermus thermophilus cannot restore the assembly of M. tuberculosis RNAP. Furthermore, by replacing different regions in M. tuberculosis omega with the corresponding regions from E. coli omega, we found a nonconserved loop region in M. tuberculosis omega essential for its function in RNAP assembly. From RNAP structures, we noticed that the location of the C terminal region of the beta' subunit (beta'CTD) in M. tuberculosis RNAP but not in E. coli or T. thermophilus RNAP is close to the omega loop region. Deletion of this beta'CTD in M. tuberculosis RNAP destabilized the binding of M. tuberculosis omega on RNAP and compromised M. tuberculosis core assembly, suggesting that these two regions may function together to play a role in omega-dependent RNAP assembly in M. tuberculosis Sequence alignment of the omega loop and the beta'CTD regions suggests that the essential role of omega is probably restricted to mycobacteria. Together, our study characterized an essential role of M. tuberculosis omega and highlighted the importance of the omega loop region in M. tuberculosis RNAP assembly.IMPORTANCE DNA-dependent RNA polymerase (RNAP), which consists of a multisubunit core enzyme (alpha2betabeta'omega) and a dissociable sigma subunit, is the only enzyme in charge of transcription in bacteria. As the smallest subunit, the roles of omega remain the least well studied. In Escherichia coli and some other bacteria, the omega subunit is known to be nonessential for RNAP. In this study, we revealed an essential role of the omega subunit for RNAP assembly in the human pathogen Mycobacterium tuberculosis, and a mycobacterium-specific omega loop that plays a role in this function was also characterized. Our study provides fresh insights for further characterizing the roles of bacterial omega subunit. PMID- 29632096 TI - RNase III Processing of rRNA in the Lyme Disease Spirochete Borrelia burgdorferi. AB - The rRNA genes of Borrelia (Borreliella) burgdorferi are unusually organized; the spirochete has a single 16S rRNA gene that is more than 3 kb from a tandem pair of 23S-5S rRNA operons. We generated an rnc null mutant in B. burgdorferi that exhibits a pleiotropic phenotype, including decreased growth rate and increased cell length. Here, we demonstrate that endoribonuclease III (RNase III) is, as expected, involved in processing the 23S rRNA in B. burgdorferi The 5' and 3' ends of the three rRNAs were determined in the wild type and rncBb mutants; the results suggest that RNase III in B. burgdorferi is required for the full maturation of the 23S rRNA but not for the 5S rRNA nor, curiously, for the 16S rRNA.IMPORTANCE Lyme disease, the most common tick-borne zoonosis in the Northern Hemisphere, is caused by the bacterium Borrelia (Borreliella) burgdorferi, a member of the deeply branching spirochete phylum. B. burgdorferi carries a limited suite of ribonucleases, enzymes that cleave RNA during processing and degradation. Several ribonucleases, including RNase III, are involved in the production of ribosomes, which catalyze translation and are a major target of antibiotics. This is the first study to dissect the role of an RNase in any spirochete. We demonstrate that an RNase III mutant is viable but has altered processing of rRNA. PMID- 29632097 TI - Important Late-Stage Symbiotic Role of the Sinorhizobium meliloti Exopolysaccharide Succinoglycan. AB - Sinorhizobium meliloti enters into beneficial symbiotic interactions with Medicago species of legumes. Bacterial exopolysaccharides play critical signaling roles in infection thread initiation and growth during the early stages of root nodule formation. After endocytosis of S. meliloti by plant cells in the developing nodule, plant-derived nodule-specific cysteine-rich (NCR) peptides mediate terminal differentiation of the bacteria into nitrogen-fixing bacteroids. Previous transcriptional studies showed that the intensively studied cationic peptide NCR247 induces expression of the exo genes that encode the proteins required for succinoglycan biosynthesis. In addition, genetic studies have shown that some exo mutants exhibit increased sensitivity to the antimicrobial action of NCR247. Therefore, we investigated whether the symbiotically active S. meliloti exopolysaccharide succinoglycan can protect S. meliloti against the antimicrobial activity of NCR247. We discovered that high-molecular-weight forms of succinoglycan have the ability to protect S. meliloti from the antimicrobial action of the NCR247 peptide but low-molecular-weight forms of wild-type succinoglycan do not. The protective function of high-molecular-weight succinoglycan occurs via direct molecular interactions between anionic succinoglycan and the cationic NCR247 peptide, but this interaction is not chiral. Taken together, our observations suggest that S. meliloti exopolysaccharides not only may be critical during early stages of nodule invasion but also are upregulated at a late stage of symbiosis to protect bacteria against the bactericidal action of cationic NCR peptides. Our findings represent an important step forward in fully understanding the complete set of exopolysaccharide functions during legume symbiosis.IMPORTANCE Symbiotic interactions between rhizobia and legumes are economically important for global food production. The legume symbiosis also is a major part of the global nitrogen cycle and is an ideal model system to study host-microbe interactions. Signaling between legumes and rhizobia is essential to establish symbiosis, and understanding these signals is a major goal in the field. Exopolysaccharides are important in the symbiotic context because they are essential signaling molecules during early-stage symbiosis. In this study, we provide evidence suggesting that the Sinorhizobium meliloti exopolysaccharide succinoglycan also protects the bacteria against the antimicrobial action of essential late-stage symbiosis plant peptides. PMID- 29632098 TI - Performance of a Blood Pressure Smartphone App in Pregnant Women: The iPARR Trial (iPhone App Compared With Standard RR Measurement). AB - : Hypertensive disorders are one of the leading causes of maternal death worldwide. Several smartphone apps claim to measure blood pressure (BP) using photoplethysmographic signals recorded by smartphone cameras. However, no single app has been validated for this use to date. We aimed to validate a new, promising smartphone algorithm. In this subgroup analysis of the iPARR trial (iPhone App Compared With Standard RR Measurement), we tested the Preventicus BP smartphone algorithm on 32 pregnant women. The trial was conducted based on the European Society of Hypertension International Protocol revision 2010 for validation of BP measuring devices in adults. Each individual received 7 sequential BP measurements starting with the reference device (Omron-HBP-1300) and followed by the smartphone measurement, resulting in 96 BP comparisons. Validation requirements of the European Society of Hypertension International Protocol revision 2010 were not fulfilled. Mean (+/-SD) systolic BP disagreement between the test and reference devices was 5.0 (+/-14.5) mm Hg. The number of absolute differences between test and reference device within 5, 10, and 15 mm Hg was 31, 53, and 64 of 96, respectively. A Bland-Altman plot showed an overestimation of smartphone-determined systolic BP in comparison with reference systolic BP in low range but an underestimation in medium-range BP. The Preventicus BP smartphone algorithm failed the accuracy criteria for estimating BP in pregnant women and was thus not commercialized. Pregnant women should be discouraged from using BP smartphone apps, unless there are algorithms specifically validated according to common protocols. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02552030. PMID- 29632100 TI - Orthostatic Hypotension in the First Minute After Standing Up: What Is the Clinical Relevance and Do Symptoms Matter? PMID- 29632099 TI - Simultaneously Measured Interarm Blood Pressure Difference and Stroke: An Individual Participants Data Meta-Analysis. AB - We conducted individual participant data meta-analysis to examine the validity of interarm blood pressure difference in simultaneous measurement as a marker to identify subjects with ankle-brachial pressure index <0.90 and to predict future cardiovascular events. We collected individual participant data on 13 317 Japanese subjects from 10 cohorts (general population-based cohorts, cohorts of patients with past history of cardiovascular events, and those with cardiovascular risk factors). Binary logistic regression analysis with adjustments identified interarm blood pressure difference >5 mm Hg as being associated with a significant odds ratio for the presence of ankle-brachial pressure index <0.90 (odds ratio, 2.19; 95% confidence interval, 1.60-3.03; P<0.01). Among 11 726 subjects without a past history of cardiovascular disease, 249 developed stroke during the average follow-up period of 7.4 years. Interarm blood pressure difference >15 mm Hg was associated with a significant Cox stratified adjusted hazard ratio for subsequent stroke (hazard ratio, 2.42; 95% confidence interval, 1.27-4.60; P<0.01). Therefore, interarm blood pressure differences, measured simultaneously in both arms, may be associated with vascular damage in the systemic arterial tree. These differences may be useful for identifying subjects with an ankle-brachial pressure index of <0.90 in the overall study population, and also a reliable predictor of future stroke in subjects without a past history of cardiovascular disease. These findings support the recommendation to measure blood pressure in both arms at the first visit. PMID- 29632102 TI - Thymosin beta4 Deficiency Exacerbates Renal and Cardiac Injury in Angiotensin-II Induced Hypertension. AB - Thymosin beta4 (Tbeta4), a ubiquitous peptide, regulates several cellular processes that include cell morphology, wound healing, and inflammatory response. Administration of exogenous Tbeta4 is protective in diabetic nephropathy and in a unilateral ureteral obstruction model. However, the role of endogenous Tbeta4 in health and disease conditions remains unclear. To elucidate the pathophysiological role of endogenous Tbeta4 in hypertension, we examined angiotensin-II (Ang-II)-induced renal and cardiac damage in Tbeta4 knockout (Tbeta4 KO) mice. Tbeta4 KO and wild-type C57BL/6 mice were infused continuously for 6 weeks with either vehicle or Ang-II (980 ng/kg per minute). At baseline, Tbeta4 deficiency did not affect renal and cardiac function. Systolic blood pressure in the Ang-II group was similar in wild-type and Tbeta4 KO mice (wild type Ang-II, 179.25+/-10.11 mm Hg; Tbeta4 KO Ang-II, 169.81+/-6.54 mm Hg). Despite the similar systolic blood pressure after Ang-II infusion, Tbeta4 deficient mice had dramatically increased albuminuria and decreased nephrin expression in the kidney (P<0.005). In the heart of Tbeta4 KO mice, Ang-II reduced ejection fraction and shortening fraction (ejection fraction: wild-type Ang-II 77.95%+/-1.03%; Tbeta4 KO Ang-II 62.58%+/-3.25%; P<0.005), which was accompanied by cardiac hypertrophy and left ventricular dilatation. In addition, renal and cardiac infiltration of CD68 macrophages, intercellular adhesion molecule-1, and total collagen content were increased after Ang-II infusion in Tbeta4 KO mice (P<0.005). Overall, our data indicate that endogenous Tbeta4 is crucial in preventing tissue injury from Ang-II-induced hypertension. This study gives new insights into the protective role of endogenous Tbeta4 in hypertensive end-organ damage. PMID- 29632103 TI - Longitudinal Association Between Orthostatic Hypotension at 30 Seconds Post Standing and Late-Life Depression. AB - There is an established cross-sectional association between orthostatic hypotension (OH) and late-life depression. The aim of this observational study was to clarify the longitudinal association between baseline symptomatic OH (sOH 30) and incident depression in a sample of >3000 older people without baseline depression (mean age: 62 years at baseline). This study was embedded within the Irish Longitudinal Study on Ageing using data from waves 1 to 3, collected between 2009 and 2014. At 2- and 4-year follow-up, a score >=9 on the 8-item Center for Epidemiological Studies Depression Scale was used to define incident depression. sOH-30 was defined as a drop in systolic blood pressure >=20 mm Hg or diastolic blood pressure >=10 mm Hg at 30 seconds post-standing in conjunction with orthostatic symptoms, such as dizziness, using beat-to-beat measurements. Almost one fifth (proportion, 18%; 95% confidence interval [CI], 16-20) of the study sample had sOH-30. One tenth (proportion, 10%; 95% CI, 9-12) had incident depression. Participants with incident depression were twice as likely to have sOH-30 at baseline compared with those without incident depression (linear regression, 13% [95% CI, 8-19] versus 7% [95% CI, 6-8]). Weighted logistic regression models demonstrated that sOH-30 predicted incident depression with an odds ratio of 1.90 (95% CI, 1.15-3.15) after controlling for covariates, including subthreshold depression, hypotension, cognitive impairment, and antidepressant use. Asymptomatic OH at 30 seconds and initial OH did not predict depression. This study demonstrates that sOH-30 predicts incident depression in a population-representative sample of older people and may, therefore, represent a potentially modifiable risk factor for late-life depression. PMID- 29632101 TI - Vascular Function Is Improved After an Environmental Enrichment Program: The Train the Brain-Mind the Vessel Study. AB - : Environmental enrichment may slow cognitive decay possibly acting through an improvement in vascular function. Aim of the study was to assess the effects of a 7-month cognitive, social, and physical training program on cognitive and vascular function in patients with mild cognitive impairment. In a single-center, randomized, parallel-group study, 113 patients (age, 65-89 years) were randomized to multidomain training (n=55) or usual care (n=58). All participants underwent neuropsychological tests and vascular evaluation, including brachial artery flow mediated dilation, carotid-femoral pulse wave velocity, carotid distensibility, and assessment of circulating hematopoietic CD34+ and endothelial progenitor cells. At study entry, an age-matched control group (n=45) was also studied. Compared with controls, patients had at study entry a reduced flow-mediated dilation (2.97+/-2.14% versus 3.73+/-2.06%; P=0.03) and hyperemic stimulus (shear rate area under the curve, 19.1+/-15.7 versus 25.7+/-15.1*10-3; P=0.009); only the latter remained significant after adjustment for confounders (P=0.03). Training improved Alzheimer disease assessment scale cognitive (training, 14.0+/ 4.8 to 13.1+/-5.5; nontraining, 12.1+/-3.9 to 13.2+/-4.8; P for interaction visit*training=0.02), flow-mediated dilation (2.82+/-2.19% to 3.40+/-1.81%, 3.05+/-2.08% to 2.24+/-1.59%; P=0.006; P=0.023 after adjustment for diameter and shear rate area under the curve), and circulating hematopoietic CD34+ cells and prevented the decline in carotid distensibility (18.4+/-5.3 to 20.0+/-6.6, 23.9+/ 11.0 to 19.5+/-7.1 Pa-1; P=0.005). The only clinical predictor of improvement of cognitive function after training was established hypertension. There was no correlation between changes in measures of cognitive and vascular function. In conclusion, a multidomain training program slows cognitive decline, especially in hypertensive individuals. This effect is accompanied by improved systemic endothelial function, mobilization of progenitor CD34+ cells, and preserved carotid distensibility. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01725178. PMID- 29632106 TI - What's happening in Neurology(r). PMID- 29632105 TI - Discovery of New Blood Pressure Phenotypes and Relation to Accuracy of Cuff Devices Used in Daily Clinical Practice. AB - Cuff blood pressure (BP) is the reference standard for management of high BP, but the method is inaccurate and can lead to BP misclassification. The aims of this study were to determine whether distinctive BP phenotypes exist based on BP transmission (amplification) variability from central-to-peripheral arteries and whether applying one standard cuff BP measurement approach (eg, oscillometry) to all people could discriminate the BP phenotypes. Intra-arterial BP was measured at the ascending aorta and brachial and radial arteries in 126 participants (61+/ 10 years; 69% male) after coronary angiography. Central-to-peripheral systolic BP (SBP) transmission (SBP amplification) was defined by >=5 mm Hg SBP increase between the aorta-to-brachial or brachial-to-radial arteries. Standard cuff BP was measured 4 different times using 3 different devices. Three independent investigators also provided data (n=255 from 4 studies) using another 3 separate cuff BP devices. Four distinct BP phenotypes were discovered based on variability in SBP amplification: phenotype 1, both aortic-to-brachial and brachial-to-radial SBP amplification; phenotype 2, only aortic-to-brachial SBP amplification; phenotype 3, only brachial-to-radial SBP amplification; and phenotype 4, neither aortic-to-brachial nor brachial-to-radial SBP amplification. Aortic SBP was significantly higher among phenotypes 3 and 4 compared with phenotypes 1 and 2 (P=0.00074), but this was not discriminated using any standard cuff BP measures (P=0.31). Data from independent investigators confirmed the key findings. This is the first-in-human discovery of BP phenotypes that have significantly different BPs, but which are not discriminated by standard cuff BP devices used in daily clinical practice. Improved BP device accuracy may be achieved by considering individual phenotypic BP differences. PMID- 29632104 TI - History of Asthma From Childhood and Arterial Stiffness in Asymptomatic Young Adults: The Bogalusa Heart Study. AB - Asthma is related to various cardiovascular risk. Whether a history of asthma from childhood contributes to arterial stiffness in adulthood, a noninvasive surrogate for cardiovascular events, is unknown. Prospective analyses were performed among 1746 Bogalusa Heart Study participants aged 20 to 51 years with data on self-report asthma collected since childhood. Aorta-femoral pulse wave velocity (af-PWV, m/s) was repeatedly assessed among adults >=aged 18 years. Generalized linear mixed models and generalized linear models were fitted for the repeated measurements of af-PWV and its changes between the last and the first measurements, respectively. After a median follow-up of 11.1 years, participants with a history of asthma from childhood had a higher af-PWV (6.78 versus 6.13; P=0.048) and a greater increase in af-PWV (8.99 versus 2.95; P=0.043) than those without asthma, adjusted for age, sex, race, smoking status, heart rate, body mass index, systolic blood pressure, lipids, and glycemia. In addition, we found significant interactions of asthma with body mass index and systolic blood pressure on af-PWV and its changes (P for interaction <0.01). The associations of asthma with af-PWV and its changes appeared to be stronger among participants who were overweight and obese (body mass index >=25 kg/m2) or with prehypertension and hypertension (systolic blood pressure >=120 mm Hg) compared with those with a normal body mass index or systolic blood pressure. Our findings indicate that a history of asthma from childhood is associated with higher af-PWV and greater increases in af-PWV, and such associations are stronger among young adults who are overweight or with elevated blood pressure. PMID- 29632107 TI - What's happening in Neurology(r)Clinical Practice. PMID- 29632108 TI - What's happening in Neurology(r)Genetics. PMID- 29632110 TI - What's happening in Without Borders. PMID- 29632109 TI - What's happening in Neurology(r)Neuroimmunology & Neuroinflammation. PMID- 29632111 TI - Acute amnesia associated with damaged fiber tracts following anterior fornix infarction. PMID- 29632112 TI - Education Research: The current state of neurophysiology education in selected neurology residency programs. AB - OBJECTIVE: Prior research has illustrated there is a knowledge gap in neurology residents' neurophysiology education (EEG and EMG), and we sought to understand whether this is still an issue and to recognize the barriers in order to create solutions and improve education. METHODS: Surveys were developed for adult neurology residents and one for program directors asking about confidence in neurophysiology knowledge, percent of graduates reaching level 4 ACGME (American Council of Graduate Medical Education) milestones in EEG and EMG, methods of learning used, interest in the subjects, and suggestions for improvements. RESULTS: Twenty-six program directors (19% responder rate) and 55 residents (from at least 16 different programs) completed the survey. Program directors thought that 85% of graduating residents met level 4 milestones in EEG and only 75% in EMG. Structured rotations and more time allocated to education of these topics were frequent barriers mentioned. Postgraduate year 4 residents were 60% and 67% confident in EEG and 64%, 59%, and 62.3% in EMG level 4 milestones. Learning to read EEGs was considered important throughout residents' training; however, this interest and value decreased over time with EMG. CONCLUSION: In our study, program directors suspect up to a quarter of residents may graduate not meeting level 4 ACGME milestones, and residents expressed lack of confidence in these areas. The educational methods used to instruct residents in EEG and EMG were similar as were the barriers they face across programs. This information hopefully will help fuel curriculum design and interest in these important neurology techniques. PMID- 29632113 TI - Editors' note: Wrist sensor reveals sympathetic hyperactivity and hypoventilation before probable SUDEP. PMID- 29632114 TI - Reader response: Wrist sensor reveals sympathetic hyperactivity and hypoventilation before probable SUDEP. PMID- 29632115 TI - Author response: Wrist sensor reveals sympathetic hyperactivity and hypoventilation before probable SUDEP. PMID- 29632116 TI - Editors' note: Mystery Case: A case of fulminant encephalopathy in a 69-year-old woman. PMID- 29632118 TI - Author response: Mystery Case: A case of fulminant encephalopathy in a 69-year old woman. PMID- 29632117 TI - Reader response: Mystery Case: A case of fulminant encephalopathy in a 69-year old woman. PMID- 29632119 TI - Clinical Reasoning: A 30-year-old man with acute paraplegia and left foot gangrene. PMID- 29632120 TI - Teaching NeuroImages: Varicella-zoster virus-related hemorrhagic encephalomyelitis. PMID- 29632121 TI - Teaching NeuroImages: A cutaneous vascular malformation hides giant cerebral aneurysms. PMID- 29632122 TI - An unusual cause of thunderclap headache after eating the hottest pepper in the world - "The Carolina Reaper". PMID- 29632123 TI - Letter: there is too much traffic for Alex to walk to school, so we drive. A call to action based on a 42-year trend. PMID- 29632124 TI - There is too much traffic for Alex to walk to school, so we drive: a call to action based on a 42-year trend. PMID- 29632125 TI - Full-Size Cardiac Troponin I and Its Proteolytic Fragments in Blood of Patients with Acute Myocardial Infarction: Antibody Selection for Assay Development. AB - BACKGROUND: In the blood of patients with acute myocardial infarction (AMI), cardiac troponin I (cTnI) presents as an intact molecule with a repertoire of proteolytic fragments. The degradation of cTnI might negatively influence its precise immunodetection. In this study we identified cTnI fragments and calculated their ratio in the blood of patients at different times after AMI to discriminate the most stable part(s) of cTnI. METHODS: Serial serum samples were collected from AMI patients within 1 to 36 h after the onset of chest pain both before and after stenting. cTnI and its fragments were immunoextracted from serum samples and analyzed by Western blotting with monoclonal antibodies (mAbs) specific to the different epitopes of cTnI and by 2 in-house immunoassays specific to the central and terminal portions of cTnI. RESULTS: Intact cTnI and its 11 major fragments were detected in blood of AMI patients. The ratio of the fragments in serial samples did not show large changes in the period 1-36 h after AMI. mAbs specific to the epitopes located approximately between amino acid residues (aar) 34 and 126 stained all extracted cTnI. mAbs specific to aar 23-36 and 126-196 recognized approximately 80% to 90% (by abundance) of cTnI. CONCLUSIONS: In addition to mAbs specific to the central part of cTnI (approximately aar 34-126), antibodies specific to the adjacent epitopes (approximately aar 23-36 and 126-196) could be used in assays because they recognize >=80% of cTnI in patients' blood samples within the first 36 h after AMI. PMID- 29632126 TI - Development of Immunochromatographic Assays for the Selective Detection of Zika Virus or Dengue Virus Serotypes in Serum. PMID- 29632128 TI - What's New in Laboratory Test Utilization Management? PMID- 29632127 TI - Accurate Pan-Cancer Molecular Diagnosis of Microsatellite Instability by Single Molecule Molecular Inversion Probe Capture and High-Throughput Sequencing. AB - BACKGROUND: Microsatellite instability (MSI) is an emerging actionable phenotype in oncology that informs tumor response to immune checkpoint pathway immunotherapy. However, there remains a need for MSI diagnostics that are low cost, highly accurate, and generalizable across cancer types. We developed a method for targeted high-throughput sequencing of numerous microsatellite loci with pan-cancer informativity for MSI using single-molecule molecular inversion probes (smMIPs). METHODS: We designed a smMIP panel targeting 111 loci highly informative for MSI across cancers. We developed an analytical framework taking advantage of smMIP-mediated error correction to specifically and sensitively detect instability events without the need for typing matched normal material. RESULTS: Using synthetic DNA mixtures, smMIPs were sensitive to at least 1% MSI positive cells and were highly consistent across replicates. The fraction of identified unstable microsatellites discriminated tumors exhibiting MSI from those lacking MSI with high accuracy across colorectal (100% diagnostic sensitivity and specificity), prostate (100% diagnostic sensitivity and specificity), and endometrial cancers (95.8% diagnostic sensitivity and 100% specificity). MSI-PCR, the current standard-of-care molecular diagnostic for MSI, proved equally robust for colorectal tumors but evidenced multiple false-negative results in prostate (81.8% diagnostic sensitivity and 100% specificity) and endometrial (75.0% diagnostic sensitivity and 100% specificity) tumors. CONCLUSIONS: smMIP capture provides an accurate, diagnostically sensitive, and economical means to diagnose MSI across cancer types without reliance on patient matched normal material. The assay is readily scalable to large numbers of clinical samples, enables automated and quantitative analysis of microsatellite instability, and is readily standardized across clinical laboratories. PMID- 29632129 TI - Urine Lipoarabinomannan for Tuberculosis Diagnosis: Evolution and Prospects. PMID- 29632130 TI - Effectiveness of face masks used to protect Beijing residents against particulate air pollution. AB - OBJECTIVES: Many residents in Beijing use disposable face masks in an attempt to protect their health from high particulate matter (PM) concentrations. Retail masks may be certified to local or international standards, but their real-life performance may not confer the exposure reduction potential that is marketed. This study aimed to evaluate the effectiveness of a range of face masks that are commercially available in China. METHODS: Nine masks claiming protection against fine PM (PM2.5) were purchased from consumer outlets in Beijing. The masks' filtration efficiency was tested by drawing airborne diesel exhaust through a section of the material and measuring the PM2.5 and black carbon (BC) concentrations upstream and downstream of the filtering medium. Four masks were selected for testing on volunteers. Volunteers were exposed to diesel exhaust inside an experimental chamber while performing sedentary tasks and active tasks. BC concentrations were continuously monitored inside and outside the mask. RESULTS: The mean per cent penetration for each mask material ranged from 0.26% to 29%, depending on the flow rate and mask material. In the volunteer tests, the average total inward leakage (TIL) of BC ranged from 3% to 68% in the sedentary tests and from 7% to 66% in the active tests. Only one mask type tested showed an average TIL of less than 10%, under both test conditions. CONCLUSIONS: Many commercially available face masks may not provide adequate protection, primarily due to poor facial fit. Our results indicate that further attention should be given to mask design and providing evidence-based guidance to consumers. PMID- 29632131 TI - EIF2B2 mutations in vanishing white matter disease hypersuppress translation and delay recovery during the integrated stress response. AB - Mutations in eIF2B genes cause vanishing white matter disease (VWMD), a fatal leukodystrophy that can manifest following physical trauma or illness, conditions that activate the integrated stress response (ISR). EIF2B is the guanine exchange factor for eIF2, facilitating ternary complex formation and translation initiation. During the ISR, eIF2alpha is phosphorylated and inhibits eIF2B, causing global translation suppression and stress-induced gene translation, allowing stress adaptation and recovery. We demonstrate that VWMD patient cells hypersuppress translation during the ISR caused by acute ER stress, delaying stress-induced gene expression and interrupting a negative feedback loop that allows translational recovery by GADD34-mediated dephosphorylation of phospho eIF2alpha. Thus, cells from VWMD patients undergo a prolonged state of translational hyperrepression and fail to recover from stress. We demonstrate that small molecules targeting eIF2B or the eIF2alpha kinase PERK rescue translation defects in patient cells. Therefore, defects in the ISR could contribute to white matter loss in VWMD. PMID- 29632133 TI - Ketamine for military prehospital analgesia and sedation in combat casualties. AB - Ketamine is an effective drug for battlefield analgesia. Recent evidence suggests that it can be safely and effectively used by Level 6 Pre-Hospital Emergency Care (PHEC) practitioners. This article presents a review of the evidence, and outlines the future use of ketamine for provision of analgesia and sedation in combat casualties. PMID- 29632132 TI - Sex Differences in Recombination in Sticklebacks. AB - Recombination often differs markedly between males and females. Here we present the first analysis of sex-specific recombination in Gasterosteus sticklebacks. Using whole-genome sequencing of 15 crosses between G. aculeatus and G. nipponicus, we localized 698 crossovers with a median resolution of 2.3 kb. We also used a bioinformatic approach to infer historical sex-averaged recombination patterns for both species. Recombination is greater in females than males on all chromosomes, and overall map length is 1.64 times longer in females. The locations of crossovers differ strikingly between sexes. Crossovers cluster toward chromosome ends in males, but are distributed more evenly across chromosomes in females. Suppression of recombination near the centromeres in males causes crossovers to cluster at the ends of long arms in acrocentric chromosomes, and greatly reduces crossing over on short arms. The effect of centromeres on recombination is much weaker in females. Genomic differentiation between G. aculeatus and G. nipponicus is strongly correlated with recombination rate, and patterns of differentiation along chromosomes are strongly influenced by male-specific telomere and centromere effects. We found no evidence for fine scale correlations between recombination and local gene content in either sex. We discuss hypotheses for the origin of sexual dimorphism in recombination and its consequences for sexually antagonistic selection and sex chromosome evolution. PMID- 29632134 TI - Severe rhabdomyolysis induced by quetiapine and mirtazapine in a French military soldier. AB - Rhabdomyolysis is a potential complication of psychotropic drugs use and may potentially lead to life-threatening complications, such as an acute renal failure. We describe the case of a 40-year-old military soldier suffering from post-traumatic stress disorder was admitted for an adaptation of his treatment. Mirtazapine was introduced and quetiapine increased. Two days later, the patient presented with severe rhabdomyolysis syndrome. Mirtazapine administration was paused and intravenous hydration commenced. Shortly after the creatine kinase levels decreased enabling mirtazapine to be reintroduced without complication. It is our opinion that 5-hydroxytryptamine 2a serotonergic receptors inhibition (related to mirtazapine and quetiapine) associated with muscle training was responsible for inducing rhabdomyolysis. This must be kept in mind when psychotropic medications are adjusted, especially in an athletic population such as military. PMID- 29632138 TI - Effects of dietary salt on gene and protein expression in brain tissue of a model of sporadic small vessel disease. AB - BACKGROUND: The effect of salt on cerebral small vessel disease (SVD) is poorly understood. We assessed the effect of dietary salt on cerebral tissue of the stroke-prone spontaneously hypertensive rat (SHRSP) - a relevant model of sporadic SVD - at both the gene and protein level. Methods: Brains from 21-week old SHRSP and Wistar-Kyoto rats, half additionally salt-loaded (via a 3-week regime of 1% NaCl in drinking water), were split into two hemispheres and sectioned coronally - one hemisphere for mRNA microarray and qRT-PCR, the other for immunohistochemistry using a panel of antibodies targeting components of the neurovascular unit. Results: We observed differences in gene and protein expression affecting the acute phase pathway and oxidative stress (ALB, AMBP, APOH, AHSG and LOC100129193, up-regulated in salt-loaded WKY versus WKY, >2 fold), active microglia (increased Iba-1 protein expression in salt-loaded SHRSP versus salt-loaded WKY, p<0.05), vascular structure (ACTB and CTNNB, up-regulated in salt-loaded SHRSP versus SHRSP, >3-fold; CLDN-11, VEGF and VGF down-regulated >2-fold in salt-loaded SHRSP versus SHRSP) and myelin integrity (MBP down regulated in salt loaded WKY rats versus WKY, >2.5-fold). Changes of salt-loading were more pronounced in SHRSP and occurred without an increase in blood pressure in WKY rats. CONCLUSION: Salt exposure induced changes in gene and protein expression in an experimental model of SVD and its parent rat strain in multiple pathways involving components of the glio-vascular unit. Further studies in pertinent experimental models at different ages would help clarify the short- and long-term effect of dietary salt in SVD. PMID- 29632139 TI - Thermoregulation-Independent Regulation of Sleep by Serotonin Revealed in Mice Defective in Serotonin Synthesis. AB - A role for 5-hydroxytryptamine (5-HT) or serotonin in sleep has been known for decades but was challenged by recent papers that concluded that the apparent sleep phenotype was secondary to defective thermoregulation. Those studies used mice lacking serotonergic neurons resulting from the loss of function mutations in the gene encoding the LIM homeobox transcription factor 1 (Lmx1b). Here we show that, while Lmx1b mutants failed to keep the physiologic body temperature, they exhibited more activities at the room and elevated temperatures. More importantly, we used mice deficient in the gene encoding tryptophan hydroxylase 2 (Tph2), which could not synthesize 5-HT in the brain. Tph2 mutants were capable of thermoregulation and keeping physiologic body temperature when the environmental temperature was reduced and exhibited significantly more activities at both the room and elevated temperatures. Electroencephalographic (EEG) recording also showed decreased sleep in Tph2-deficient mice. Our results indicate that 5-HT is important for sleep regulation but not thermoregulation. PMID- 29632135 TI - Hiding in Plain Sight: Rediscovering the Importance of Noncoding RNA in Human Malignancy. AB - At the time of its construction in the 1950s, the central dogma of molecular biology was a useful model that represented the current state of knowledge for the flow of genetic information after a period of prolific scientific discovery. Unknowingly, it also biased many of our assumptions going forward. Whether intentional or not, genomic elements not fitting into this paradigm were deemed unimportant and emphasis on the study of protein-coding genes prevailed for decades. The phrase "Junk DNA," first popularized in the 1960s, is still used with alarming frequency to describe the entirety of noncoding DNA. It has since become apparent that RNA molecules not coding for protein are vitally important in both normal development and human malignancy. Cancer researchers have been pioneers in determining noncoding RNA function and developing new technologies to study these molecules. In this review, we will discuss well known and newly emerging species of noncoding RNAs, their functions in cancer, and new technologies being utilized to understand their mechanisms of action in cancer. Cancer Res; 78(9); 2149-58. (c)2018 AACR. PMID- 29632136 TI - Slow calcium waves mediate furrow microtubule reorganization and germ plasm compaction in the early zebrafish embryo. AB - Zebrafish germ plasm ribonucleoparticles (RNPs) become recruited to furrows of early zebrafish embryos through their association with astral microtubules ends. During the initiation of cytokinesis, microtubules are remodeled into a furrow microtubule array (FMA), which is thought to be analogous to the mammalian midbody involved in membrane abscission. During furrow maturation, RNPs and FMA tubules transition from their original distribution along the furrow to enrichments at the furrow distal ends, which facilitates germ plasm mass compaction. We show that nebel mutants exhibit reduced furrow-associated slow calcium waves (SCWs), caused at least in part by defective enrichment of calcium stores. RNP and FMA distal enrichment mirrors the medial-to-distal polarity of SCWs, and inhibition of calcium release or downstream mediators such as Calmodulin affects RNP and FMA distal enrichment. Blastomeres with reduced or lacking SCWs, such as early blastomeres in nebel mutants and wild-type blastomeres at later stages, exhibit medially bundling microtubules similar to midbodies in other cell types. Our data indicate that SCWs provide medial-to distal directionality along the furrow to facilitate germ plasm RNP enrichment at the furrow ends. PMID- 29632140 TI - Multiple Homozygous Variants in the STING-Encoding TMEM173 Gene in HIV Long-Term Nonprogressors. AB - Among HIV-infected individuals, long-term nonprogressor (LTNP) patients experience slow CD4 T cell decline and almost undetectable viral load for several years after primary acquisition of HIV. Type I IFN has been suggested to play a pathogenic role in HIV pathogenesis, and therefore diminished IFN responses may underlie the LTNP phenotype. In this study, we examined the presence and possible immunological role of multiple homozygous single-nucleotide polymorphisms in the stimulator of IFN genes (STING) encoding gene TMEM173 involved in IFN induction and T cell proliferation in HIV LTNP patients. We identified LTNPs through the Danish HIV Cohort and performed genetic analysis by Sanger sequencing, covering the R71H-G230A-R293Q (HAQ) single-nucleotide polymorphisms in TMEM173 This was followed by investigation of STING mRNA and protein accumulation as well as innate immune responses and proliferation following STING stimulation and infection with replication-competent HIV in human blood-derived cells. We identified G230A-R293Q/G230A-R293Q and HAQ/HAQ homozygous TMEM173 variants in 2 out of 11 LTNP patients. None of the 11 noncontrollers on antiretroviral treatment were homozygous for these variants. We found decreased innate immune responses to DNA and HIV as well as reduced STING-dependent inhibition of CD4 T cell proliferation, particularly in the HAQ/HAQ HIV LTNP patients, compared with the age- and gender-matched noncontrollers on antiretroviral treatment. These findings suggest that homozygous HAQ STING variants contribute to reduced inhibition of CD4 T cell proliferation and a reduced immune response toward DNA and HIV, which might result in reduced levels of constitutive IFN production. Consequently, the HAQ/HAQ TMEM173 genotype may contribute to the slower disease progression characteristic of LTNPs. PMID- 29632141 TI - Early Antiretroviral Therapy Preserves Functional Follicular Helper T and HIV Specific B Cells in the Gut Mucosa of HIV-1-Infected Individuals. AB - HIV-1 infection is associated with B cell dysregulation and dysfunction. In HIV-1 infected patients, we previously reported preservation of intestinal lymphoid structures and dendritic cell maturation pathways after early combination antiretroviral therapy (e-ART), started during the acute phase of the infection, compared with late combination antiretroviral therapy started during the chronic phase. In this study, we investigated whether the timing of combination antiretroviral therapy initiation was associated with the development of the HIV 1-specific humoral response in the gut. The results showed that e-ART was associated with higher frequencies of functional resting memory B cells in the gut. These frequencies correlated strongly with those of follicular Th cells in the gut. Importantly, frequencies of HIV-1 Env gp140-reactive B cells were higher in patients given e-ART, in whom gp140-reactive IgG production by mucosal B cells increased after stimulation. Moreover, IL-21 release by PBMCs stimulated with HIV 1 peptide pools was greater with e-ART than with late combination antiretroviral therapy. Thus, early treatment initiation helps to maintain HIV-1-reactive memory B cells in the gut as well as follicular Th cells, whose role is crucial in the development of potent affinity-matured and broadly neutralizing Abs. PMID- 29632142 TI - Netting Neutrophils Activate Autoreactive B Cells in Lupus. AB - Lupus erythematosus (LE) patients develop autoantibodies that form circulating immune complexes (ICs) with extracellular self-nucleic acids. These ICs are deposited into peripheral tissues, where they trigger detrimental organ inflammation. Recent evidence suggests that ICs contain LL37-DNA complexes derived from neutrophil extracellular traps (NETs) and that LE patients develop pathogenic autoantibodies against these structures, including Abs to LL37. However, the mechanism that leads to the generation of these Abs is unknown. In this study, we show that NETs directly trigger Ab production by human memory B cells. This occurs via LL37-DNA complexes present in NETs, which have the unique ability to gain access to endosomal compartments of B cells and to trigger TLR9 activation. In LE patients, NET-derived LL37-DNA complexes trigger polyclonal B cell activation via TLR9, but also specifically expand self-reactive memory B cells producing anti-LL37 Abs in an Ag-dependent manner. These findings suggest a unique link between neutrophils and B cells in which NETs trigger a concerted activation of TLR9 and BCR leading to anti-NET autoantibody production in lupus. PMID- 29632143 TI - TCF-1 Inhibits IL-17 Gene Expression To Restrain Th17 Immunity in a Stage Specific Manner. AB - T cell factor 1 (TCF-1) is expressed in both developing and mature T cells and has been shown to restrain mature T cell-mediated Th17 responses by inhibiting IL 17 expression. However, it is not clear when TCF-1 is required in vivo to restrain the magnitude of peripheral Th17 responses and what the molecular mechanisms responsible for TCF-1-regulated IL-17 gene expression are. In this study, we showed that conditional deletion of TCF-1 at the early but not later CD4+CD8+ double-positive stage in mice enhanced Th17 differentiation and aggravated experimental autoimmune encephalomyelitis, which correlates with abnormally high IL-17 expression. Expression of TCF-1 in TCF-1-deficient thymocytes but not TCF-1-deficient Th17 cells inhibited IL-17 expression. TCF-1 binds to IL-17 promoter regions, and deletion of two TCF-1 binding sites relieves TCF-1-mediated inhibition of IL-17 promoter activity. Lastly, wild-type TCF-1, but not a TCF-1 mutant that has no intrinsic histone deacetylase activity, was able to inhibit IL-17 expression in TCF-1 deficient mouse thymocytes. Thus, our study demonstrates the requirement of TCF-1 in vivo at stages earlier than double positive cells to restrain peripheral Th17 immunity by directly binding and inhibiting IL-17 promoter in its intrinsic histone deacetylase-dependent manner. PMID- 29632144 TI - HLA-B*39:06 Efficiently Mediates Type 1 Diabetes in a Mouse Model Incorporating Reduced Thymic Insulin Expression. AB - Type 1 diabetes (T1D) is characterized by T cell-mediated destruction of the insulin-producing beta cells of the pancreatic islets. Among the loci associated with T1D risk, those most predisposing are found in the MHC region. HLA-B*39:06 is the most predisposing class I MHC allele and is associated with an early age of onset. To establish an NOD mouse model for the study of HLA-B*39:06, we expressed it in the absence of murine class I MHC. HLA-B*39:06 was able to mediate the development of CD8 T cells, support lymphocytic infiltration of the islets, and confer T1D susceptibility. Because reduced thymic insulin expression is associated with impaired immunological tolerance to insulin and increased T1D risk in patients, we incorporated this in our model as well, finding that HLA B*39:06-transgenic NOD mice with reduced thymic insulin expression have an earlier age of disease onset and a higher overall prevalence as compared with littermates with typical thymic insulin expression. This was despite virtually indistinguishable blood insulin levels, T cell subset percentages, and TCR Vbeta family usage, confirming that reduced thymic insulin expression does not impact T cell development on a global scale. Rather, it will facilitate the thymic escape of insulin-reactive HLA-B*39:06-restricted T cells, which participate in beta cell destruction. We also found that in mice expressing either HLA-B*39:06 or HLA A*02:01 in the absence of murine class I MHC, HLA transgene identity alters TCR Vbeta usage by CD8 T cells, demonstrating that some TCR Vbeta families have a preference for particular class I MHC alleles. PMID- 29632146 TI - Antigen-Induced but Not Innate Memory CD8 T Cells Express NKG2D and Are Recruited to the Lung Parenchyma upon Viral Infection. AB - The pool of memory-phenotype CD8 T cells is composed of Ag-induced (AI) and cytokine-induced innate (IN) cells. IN cells have been described as having properties similar to those of AI memory cells. However, we found that pathogen induced AI memory cells can be distinguished in mice from naturally generated IN memory cells by surface expression of NKG2D. Using this marker, we described the increased functionalities of AI and IN memory CD8 T cells compared with naive cells, as shown by comprehensive analysis of cytokine secretion and gene expression. However, AI differed from IN memory CD8 T cells by their capacity to migrate to the lung parenchyma upon inflammation or infection, a process dependent on their expression of ITGA1/CD49a and ITGA4/CD49d integrins. PMID- 29632145 TI - Inflammatory Macrophage Expansion in Pulmonary Hypertension Depends upon Mobilization of Blood-Borne Monocytes. AB - Pulmonary inflammation, which is characterized by the presence of perivascular macrophages, has been proposed as a key pathogenic driver of pulmonary hypertension (PH), a vascular disease with increasing global significance. However, the mechanisms of expansion of lung macrophages and the role of blood borne monocytes in PH are poorly understood. Using multicolor flow cytometric analysis of blood in mouse and rat models of PH and patients with PH, an increase in blood monocytes was observed. In parallel, lung tissue displayed increased chemokine transcript expression, including those responsible for monocyte recruitment, such as Ccl2 and Cx3cl1, accompanied by an expansion of interstitial lung macrophages. These data indicate that blood monocytes are recruited to lung perivascular spaces and differentiate into inflammatory macrophages. Correspondingly, parabiosis between congenically different hypoxic mice demonstrated that most interstitial macrophages originated from blood monocytes. To define the actions of these cells in PH in vivo, we reduced blood monocyte numbers via genetic deficiency of cx3cr1 or ccr2 in chronically hypoxic male mice and by pharmacologic inhibition of Cx3cl1 in monocrotaline-exposed rats. Both models exhibited decreased inflammatory blood monocytes, as well as interstitial macrophages, leading to a substantial decrease in arteriolar remodeling but with a less robust hemodynamic effect. This study defines a direct mechanism by which interstitial macrophages expand in PH. It also demonstrates a pathway for pulmonary vascular remodeling in PH that depends upon interstitial macrophage dependent inflammation yet is dissociated, at least in part, from hemodynamic consequences, thus offering guidance on future anti-inflammatory therapeutic strategies in this disease. PMID- 29632149 TI - Cytosolic reverse CrAT activity in cardiac tissue: potential importance for fuel selection. AB - The movement of lipids across mitochondrial membranes represents a rate-limiting step in fatty acid oxidation within the heart. A key regulatory point in this process is flux through carnitine palmitoyltransferase-I (CPT-I), an enzyme located on the outer mitochondrial membrane. Malonyl-CoA (M-CoA) is a naturally occurring inhibitor of CPT-I; therefore, the abundance of M-CoA has long been considered a major regulator of fatty acid oxidation. A recent paper published in the Biochemical Journal by Altamimi et al. (Biochem. J. (2018) 475, 959-976) provides evidence for a novel mechanism to produce M-CoA. Specifically, these authors identified carnitine acetyltransferase within the cytosol and further show that flux in the reverse direction forms acetyl-CoA, which is the necessary substrate for the subsequent synthesis of M-CoA. The elegant study design and intriguing data presented by Altamimi et al. provide further insights into the reciprocal regulation of substrate selection within the heart, with implications for fuel utilization and the development of cardiac diseases. PMID- 29632150 TI - Obesity as a Disease, Not a Behavior. PMID- 29632148 TI - In vivo bioassay to test the pathogenicity of missense human AIP variants. AB - BACKGROUND: Heterozygous germline loss-of-function mutations in the aryl hydrocarbon receptor-interacting protein gene (AIP) predispose to childhood-onset pituitary tumours. The pathogenicity of missense variants may pose difficulties for genetic counselling and family follow-up. OBJECTIVE: To develop an in vivo system to test the pathogenicity of human AIP mutations using the fruit fly Drosophila melanogaster. METHODS: We generated a null mutant of the Drosophila AIP orthologue, CG1847, a gene located on the Xchromosome, which displayed lethality at larval stage in hemizygous knockout male mutants (CG1847exon1_3 ). We tested human missense variants of 'unknown significance', with 'pathogenic' variants as positive control. RESULTS: We found that human AIP can functionally substitute for CG1847, as heterologous overexpression of human AIP rescued male CG1847exon1_3 lethality, while a truncated version of AIP did not restore viability. Flies harbouring patient-specific missense AIP variants (p.C238Y, p.I13N, p.W73R and p.G272D) failed to rescue CG1847exon1_3 mutants, while seven variants (p.R16H, p.Q164R, p.E293V, p.A299V, p.R304Q, p.R314W and p.R325Q) showed rescue, supporting a non-pathogenic role for these latter variants corresponding to prevalence and clinical data. CONCLUSION: Our in vivo model represents a valuable tool to characterise putative disease-causing human AIP variants and assist the genetic counselling and management of families carrying AIP variants. PMID- 29632151 TI - Will His Bundle Pacing Make Cardiac Resynchronization Therapy Obsolete? PMID- 29632147 TI - The Synergy between Palmitate and TNF-alpha for CCL2 Production Is Dependent on the TRIF/IRF3 Pathway: Implications for Metabolic Inflammation. AB - The chemokine CCL2 (also known as MCP-1) is a key regulator of monocyte infiltration into adipose tissue, which plays a central role in the pathophysiology of obesity-associated inflammation and insulin resistance. It remains unclear how CCL2 production is upregulated in obese humans and rodents. Because elevated levels of the free fatty acid (FFA) palmitate and TNF-alpha have been reported in obesity, we studied whether these agents interact to trigger CCL2 production. Our data show that treatment of THP-1 and primary human monocytic cells with palmitate and TNF-alpha led to a marked increase in CCL2 production compared with either treatment alone. Mechanistically, we found that cooperative production of CCL2 by palmitate and TNF-alpha did not require MyD88, but it was attenuated by blocking TLR4 or TRIF. IRF3-deficient cells did not show synergistic CCL2 production in response to palmitate/TNF-alpha. Moreover, IRF3 activation by polyinosinic-polycytidylic acid augmented TNF-alpha-induced CCL2 secretion. Interestingly, elevated NF-kappaB/AP-1 activity resulting from palmitate/TNF-alpha costimulation was attenuated by TRIF/IRF3 inhibition. Diet induced C57BL/6 obese mice with high FFAs levels showed a strong correlation between TNF-alpha and CCL2 in plasma and adipose tissue and, as expected, also showed increased adipose tissue macrophage accumulation compared with lean mice. Similar results were observed in the adipose tissue samples from obese humans. Overall, our findings support a model in which elevated FFAs in obesity create a milieu for TNF-alpha to trigger CCL2 production via the TLR4/TRIF/IRF3 signaling cascade, representing a potential contribution of FFAs to metabolic inflammation. PMID- 29632152 TI - Ezetimibe: Likely to Be Beneficial For All. PMID- 29632153 TI - Arrhythmogenic Cardiomyopathy: Mechanotransduction Going Wrong. PMID- 29632154 TI - Leptin-Aldosterone-Neprilysin Axis: Identification of Its Distinctive Role in the Pathogenesis of the Three Phenotypes of Heart Failure in People With Obesity. AB - Obesity (especially visceral adiposity) can be associated with 3 different phenotypes of heart failure: heart failure with a reduced ejection fraction, heart failure with a preserved ejection fraction, and high-output heart failure. All 3 phenotypes are characterized by an excessive secretion of aldosterone and sodium retention. In addition, obesity is accompanied by increased signaling through the leptin receptor, which can promote activation of both the sympathetic nervous system and the renin-angiotensin system and can directly stimulate the secretion of aldosterone. The deleterious interaction of leptin and aldosterone is potentiated by the simultaneous action of adiposity and the renal sympathetic nerves to cause overactivity of neprilysin; the loss of the counterbalancing effects of natriuretic peptides is exacerbated by an additional effect of both obesity and heart failure to interfere with adiponectin signaling. This intricate neurohormonal interplay leads to plasma volume expansion as well as to adverse ventricular remodeling and cardiac fibrosis. Furthermore, the activity of aldosterone and neprilysin is not only enhanced by obesity, but these mechanisms can also promote adipogenesis and adipocyte dysfunction, thereby enhancing the positive feedback loop. Last, in elderly obese women, changes in quantity and biology of epicardial adipose tissue further enhances the release of leptin and other proinflammatory adipokines, thereby leading to cardiac and systemic inflammation, end-organ fibrosis, and multiple comorbidities. Regardless of the phenotypic expression, activation of the leptin-aldosterone-neprilysin axis appears to contribute importantly to the evolution and progression of heart failure in people with obesity. Efforts to interfere with the detrimental interactions of this distinctive neurohormonal ecosystem with existing or novel therapeutic agents are likely to yield unique clinical benefits. PMID- 29632156 TI - Wide QRS Complex After Catheter Ablation. PMID- 29632158 TI - Letter by Katritsis Regarding Article, "Preprints and Cardiovascular Science: Prescient or Premature?" PMID- 29632159 TI - Response by Nallamothu and Hill to Letter Regarding Article, "Preprints and Cardiovascular Science: Prescient or Premature?" PMID- 29632160 TI - Letter by Chertoff et al Regarding Article, "The Effects of Public Access Defibrillation on Survival After Out-of-Hospital Cardiac Arrest: A Systematic Review of Observational Studies". PMID- 29632161 TI - Letter by El-Battrawy et al Regarding Article, "The Effects of Public Access Defibrillation on Survival After Out-of-Hospital Cardiac Arrest: A Systematic Review of Observational Studies". PMID- 29632157 TI - Sudden Cardiovascular Arrest During Sexual Intercourse. PMID- 29632162 TI - Letter by Karam et al Regarding Article, "The Effects of Public Access Defibrillation on Survival After Out-of-Hospital Cardiac Arrest: A Systematic Review of Observational Studies". PMID- 29632163 TI - Response by Baekgaard et al to Letters Regarding Article, "The Effects of Public Access Defibrillation on Survival After Out-of-Hospital Cardiac Arrest: A Systematic Review of Observational Studies". PMID- 29632164 TI - Letter by Jin-shan and Xue-bin Regarding Article, "Acute Coronary Syndrome: What Is the Affected Artery? Where Is the Occlusion Located? And How Important Is the Myocardial Mass Involved?" PMID- 29632165 TI - Response by Fiol-Sala and Bayes de Luna to Letter Regarding Article, "Acute Coronary Syndrome: What Is the Affected Artery? Where Is the Occlusion Located? And How Important Is the Myocardial Mass Involved?" PMID- 29632166 TI - BACE1 Mediates HIV-Associated and Excitotoxic Neuronal Damage Through an APP Dependent Mechanism. AB - HIV-associated neurocognitive disorders (HANDs) share common symptoms with Alzheimer's disease (AD), which is characterized by amyloid-beta (Abeta) plaques. Plaques are formed by aggregation of Abeta oligomers, which may be the toxic species in AD pathogenesis, and oligomers are generated by cleavage of amyloid precursor protein (APP) by beta-site amyloid precursor protein cleaving enzyme 1 (BACE1). BACE1 inhibitors reverse neuronal loss and cognitive decline in animal models of AD. Although studies have also found evidence of altered APP processing in HIV+ patients, it is unknown whether increased BACE1 expression or Abeta oligomer production is a common neuropathological feature of HAND. Moreover, it is unknown whether BACE1 or APP is involved in the excitotoxic, NMDAR-dependent component of HIV-associated neurotoxicity in vitro Herein, we hypothesize that HIV-associated neurotoxicity is mediated by NMDAR-dependent elevation of BACE1 and subsequent altered processing of APP. Supporting this, we observed elevated levels of BACE1 and Abeta oligomers in CNS of male and female HIV+ patients. In a model of HIV-associated neurotoxicity in which rat neurons are treated with supernatants from HIV-infected human monocyte-derived macrophages, we observed NMDAR-dependent elevation of BACE1 protein. NMDA treatment also increased BACE1 and both pharmacological BACE1 inhibition and genetic loss of APP were partially neuroprotective. Moreover, in APP knock-out (APP-/-) mouse neurons, NMDA-induced toxicity was BACE1 independent, indicating that cytotoxicity of BACE1 is dependent upon APP cleavage. Our findings suggest that increased BACE1 and the resultant Abeta oligomer production may contribute to HIV-associated neuropathogenesis and inhibition of BACE1 could have therapeutic potential in HANDs.SIGNIFICANCE STATEMENT HIV-associated neurocognitive disorders (HANDs) represent a range of cognitive impairments affecting ~50% of HIV+ individuals. The specific causes of HAND are unknown, but evidence suggests that HIV-infected macrophage infiltration into the brain may cause neuronal damage. Herein, we show that neurons treated with conditioned media from HIV-infected macrophages have increased expression of beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), a protein implicated in Alzheimer's disease pathogenesis. Moreover, inhibition of BACE1 prevented neuronal loss after conditioned media exposure, but had no effect on HIV-associated neurotoxicity in neurons lacking its cleavage target amyloid precursor protein. We also observed increased BACE1 expression in HIV+ patient brain tissue, confirming the potential relevance of BACE1 as a therapeutic target in HANDs. PMID- 29632167 TI - Matrix Metalloproteinase-Mediated Blood-Brain Barrier Dysfunction in Epilepsy. AB - The blood-brain barrier is dysfunctional in epilepsy, thereby contributing to seizure genesis and resistance to antiseizure drugs. Previously, several groups reported that seizures increase brain glutamate levels, which leads to barrier dysfunction. One critical component of barrier dysfunction is brain capillary leakage. Based on our preliminary data, we hypothesized that glutamate released during seizures mediates an increase in matrix-metalloproteinase (MMP) expression and activity levels, thereby contributing to barrier leakage. To test this hypothesis, we exposed isolated brain capillaries from male Sprague Dawley rats to glutamate ex vivo and used an in vivo/ex vivo approach of isolated brain capillaries from female Wistar rats that experienced status epilepticus as an acute seizure model. We found that exposing isolated rat brain capillaries to glutamate increased MMP-2 and MMP-9 protein and activity levels, and decreased tight junction protein levels, which resulted in barrier leakage. We confirmed these findings in vivo in rats after status epilepticus and in brain capillaries from male mice lacking cytosolic phospholipase A2 Together, our data support the hypothesis that glutamate released during seizures signals an increase in MMP-2 and MMP-9 protein expression and activity levels, resulting in blood-brain barrier leakage.SIGNIFICANCE STATEMENT The mechanism leading to seizure-mediated blood-brain barrier dysfunction in epilepsy is poorly understood. In the present study, we focused on defining this mechanism in the brain capillary endothelium. We demonstrate that seizures trigger a pathway that involves glutamate signaling through cytosolic phospholipase A2, which increases MMP levels and decreases tight junction protein expression levels, resulting in barrier leakage. These findings may provide potential therapeutic avenues within the blood-brain barrier to limit barrier dysfunction in epilepsy and decrease seizure burden. PMID- 29632168 TI - Ultradian rhythmicity of plasma cortisol is necessary for normal emotional and cognitive responses in man. AB - Glucocorticoids (GCs) are secreted in an ultradian, pulsatile pattern that emerges from delays in the feedforward-feedback interaction between the anterior pituitary and adrenal glands. Dynamic oscillations of GCs are critical for normal cognitive and metabolic function in the rat and have been shown to modulate the pattern of GC-sensitive gene expression, modify synaptic activity, and maintain stress responsiveness. In man, current cortisol replacement therapy does not reproduce physiological hormone pulses and is associated with psychopathological symptoms, especially apathy and attenuated motivation in engaging with daily activities. In this work, we tested the hypothesis that the pattern of GC dynamics in the brain is of crucial importance for regulating cognitive and behavioral processes. We provide evidence that exactly the same dose of cortisol administered in different patterns alters the neural processing underlying the response to emotional stimulation, the accuracy in recognition and attentional bias toward/away from emotional faces, the quality of sleep, and the working memory performance of healthy male volunteers. These data indicate that the pattern of the GC rhythm differentially impacts human cognition and behavior under physiological, nonstressful conditions and has major implications for the improvement of cortisol replacement therapy. PMID- 29632169 TI - Unique organization of photosystem I-light-harvesting supercomplex revealed by cryo-EM from a red alga. AB - Photosystem I (PSI) is one of the two photosystems present in oxygenic photosynthetic organisms and functions to harvest and convert light energy into chemical energy in photosynthesis. In eukaryotic algae and higher plants, PSI consists of a core surrounded by variable species and numbers of light-harvesting complex (LHC)I proteins, forming a PSI-LHCI supercomplex. Here, we report cryo-EM structures of PSI-LHCR from the red alga Cyanidioschyzon merolae in two forms, one with three Lhcr subunits attached to the side, similar to that of higher plants, and the other with two additional Lhcr subunits attached to the opposite side, indicating an ancient form of PSI-LHCI. Furthermore, the red algal PSI core showed features of both cyanobacterial and higher plant PSI, suggesting an intermediate type during evolution from prokaryotes to eukaryotes. The structure of PsaO, existing in eukaryotic organisms, was identified in the PSI core and binds three chlorophylls a and may be important in harvesting energy and in mediating energy transfer from LHCII to the PSI core under state-2 conditions. Individual attaching sites of LHCRs with the core subunits were identified, and each Lhcr was found to contain 11 to 13 chlorophylls a and 5 zeaxanthins, which are apparently different from those of LHCs in plant PSI-LHCI. Together, our results reveal unique energy transfer pathways different from those of higher plant PSI-LHCI, its adaptation to the changing environment, and the possible changes of PSI-LHCI during evolution from prokaryotes to eukaryotes. PMID- 29632170 TI - Tradeoffs between immune function and childhood growth among Amazonian forager horticulturalists. AB - Immune function is an energetically costly physiological activity that potentially diverts calories away from less immediately essential life tasks. Among developing organisms, the allocation of energy toward immune function may lead to tradeoffs with physical growth, particularly in high-pathogen, low resource environments. The present study tests this hypothesis across diverse timeframes, branches of immunity, and conditions of energy availability among humans. Using a prospective mixed-longitudinal design, we collected anthropometric and blood immune biomarker data from 261 Amazonian forager horticulturalist Shuar children (age 4-11 y old). This strategy provided baseline measures of participant stature, s.c. body fat, and humoral and cell-mediated immune activity as well as subsample longitudinal measures of linear growth (1 wk, 3 mo, 20 mo) and acute inflammation. Multilevel analyses demonstrate consistent negative effects of immune function on growth, with children experiencing up to 49% growth reduction during periods of mildly elevated immune activity. The direct energetic nature of these relationships is indicated by (i) the manifestation of biomarker-specific negative immune effects only when examining growth over timeframes capturing active competition for energetic resources, (ii) the exaggerated impact of particularly costly inflammation on growth, and (iii) the ability of children with greater levels of body fat (i.e., energy reserves) to completely avoid the growth-inhibiting effects of acute inflammation. These findings provide evidence for immunologically and temporally diverse body fat-dependent tradeoffs between immune function and growth during childhood. We discuss the implications of this work for understanding human developmental energetics and the biological mechanisms regulating variation in human ontogeny, life history, and health. PMID- 29632171 TI - Exolytic and endolytic turnover of peptidoglycan by lytic transglycosylase Slt of Pseudomonas aeruginosa. AB - beta-Lactam antibiotics inhibit cell-wall transpeptidases, preventing the peptidoglycan, the major constituent of the bacterial cell wall, from cross linking. This causes accumulation of long non-cross-linked strands of peptidoglycan, which leads to bacterial death. Pseudomonas aeruginosa, a nefarious bacterial pathogen, attempts to repair this aberrantly formed peptidoglycan by the function of the lytic transglycosylase Slt. We document in this report that Slt turns over the peptidoglycan by both exolytic and endolytic reactions, which cause glycosidic bond scission from a terminus or in the middle of the peptidoglycan, respectively. These reactions were characterized with complex synthetic peptidoglycan fragments that ranged in size from tetrasaccharides to octasaccharides. The X-ray structure of the wild-type apo Slt revealed it to be a doughnut-shaped protein. In a series of six additional X-ray crystal structures, we provide insights with authentic substrates into how Slt is enabled for catalysis for both the endolytic and exolytic reactions. The substrate for the exolytic reaction binds Slt in a canonical arrangement and reveals how both the glycan chain and the peptide stems are recognized by the Slt. We document that the apo enzyme does not have a fully formed active site for the endolytic reaction. However, binding of the peptidoglycan at the existing subsites within the catalytic domain causes a conformational change in the protein that assembles the surface for binding of a more expansive peptidoglycan between the catalytic domain and an adjacent domain. The complexes of Slt with synthetic peptidoglycan substrates provide an unprecedented snapshot of the endolytic reaction. PMID- 29632172 TI - Human hydroxymethylbilane synthase: Molecular dynamics of the pyrrole chain elongation identifies step-specific residues that cause AIP. AB - Hydroxymethylbilane synthase (HMBS), the third enzyme in the heme biosynthetic pathway, catalyzes the head-to-tail condensation of four molecules of porphobilinogen (PBG) to form the linear tetrapyrrole 1-hydroxymethylbilane (HMB). Mutations in human HMBS (hHMBS) cause acute intermittent porphyria (AIP), an autosomal-dominant disorder characterized by life-threatening neurovisceral attacks. Although the 3D structure of hHMBS has been reported, the mechanism of the stepwise polymerization of four PBG molecules to form HMB remains unknown. Moreover, the specific roles of each of the critical active-site residues in the stepwise enzymatic mechanism and the dynamic behavior of hHMBS during catalysis have not been investigated. Here, we report atomistic studies of HMB stepwise synthesis by using molecular dynamics (MD) simulations, mutagenesis, and in vitro expression analyses. These studies revealed that the hHMBS active-site loop movement and cofactor turn created space for the elongating pyrrole chain. Twenty seven residues around the active site and water molecules interacted to stabilize the large, negatively charged, elongating polypyrrole. Mutagenesis of these active-site residues altered the binding site, hindered cofactor binding, decreased catalysis, impaired ligand exit, and/or destabilized the enzyme. Based on intermediate stages of chain elongation, R26 and R167 were the strongest candidates for proton transfer to deaminate the incoming PBG molecules. Unbiased random acceleration MD simulations identified R167 as a gatekeeper and facilitator of HMB egress through the space between the enzyme's domains and the active-site loop. These studies identified the specific active-site residues involved in each step of pyrrole elongation, thereby providing the molecular bases of the active-site mutations causing AIP. PMID- 29632173 TI - A Mesoproterozoic iron formation. AB - We describe a 1,400 million-year old (Ma) iron formation (IF) from the Xiamaling Formation of the North China Craton. We estimate this IF to have contained at least 520 gigatons of authigenic Fe, comparable in size to many IFs of the Paleoproterozoic Era (2,500-1,600 Ma). Therefore, substantial IFs formed in the time window between 1,800 and 800 Ma, where they are generally believed to have been absent. The Xiamaling IF is of exceptionally low thermal maturity, allowing the preservation of organic biomarkers and an unprecedented view of iron-cycle dynamics during IF emplacement. We identify tetramethyl aryl isoprenoid (TMAI) biomarkers linked to anoxygenic photosynthetic bacteria and thus phototrophic Fe oxidation. Although we cannot rule out other pathways of Fe oxidation, iron and organic matter likely deposited to the sediment in a ratio similar to that expected for anoxygenic photosynthesis. Fe reduction was likely a dominant and efficient pathway of organic matter mineralization, as indicated by organic matter maturation by Rock Eval pyrolysis combined with carbon isotope analyses: Indeed, Fe reduction was seemingly as efficient as oxic respiration. Overall, this Mesoproterozoic-aged IF shows many similarities to Archean-aged (>2,500 Ma) banded IFs (BIFs), but with an exceptional state of preservation, allowing an unprecedented exploration of Fe-cycle dynamics in IF deposition. PMID- 29632174 TI - GHSR-D2R heteromerization modulates dopamine signaling through an effect on G protein conformation. AB - The growth hormone secretagogue receptor (GHSR) and dopamine receptor (D2R) have been shown to oligomerize in hypothalamic neurons with a significant effect on dopamine signaling, but the molecular processes underlying this effect are still obscure. We used here the purified GHSR and D2R to establish that these two receptors assemble in a lipid environment as a tetrameric complex composed of two each of the receptors. This complex further recruits G proteins to give rise to an assembly with only two G protein trimers bound to a receptor tetramer. We further demonstrate that receptor heteromerization directly impacts on dopamine mediated Gi protein activation by modulating the conformation of its alpha subunit. Indeed, association to the purified GHSR:D2R heteromer triggers a different active conformation of Galphai that is linked to a higher rate of GTP binding and a faster dissociation from the heteromeric receptor. This is an additional mechanism to expand the repertoire of GPCR signaling modulation that could have implications for the control of dopamine signaling in normal and physiopathological conditions. PMID- 29632175 TI - Physical interaction of junctophilin and the CaV1.1 C terminus is crucial for skeletal muscle contraction. AB - Close physical association of CaV1.1 L-type calcium channels (LTCCs) at the sarcolemmal junctional membrane (JM) with ryanodine receptors (RyRs) of the sarcoplasmic reticulum (SR) is crucial for excitation-contraction coupling (ECC) in skeletal muscle. However, the molecular mechanism underlying the JM targeting of LTCCs is unexplored. Junctophilin 1 (JP1) and JP2 stabilize the JM by bridging the sarcolemmal and SR membranes. Here, we examined the roles of JPs in localization and function of LTCCs. Knockdown of JP1 or JP2 in cultured myotubes inhibited LTCC clustering at the JM and suppressed evoked Ca2+ transients without disrupting JM structure. Coimmunoprecipitation and GST pull-down assays demonstrated that JPs physically interacted with 12-aa residues in the proximal C terminus of the CaV1.1. A JP1 mutant lacking the C terminus including the transmembrane domain (JP1DeltaCT) interacted with the sarcolemmal/T-tubule membrane but not the SR membrane. Expression of this mutant in adult mouse muscles in vivo exerted a dominant-negative effect on endogenous JPs, impairing LTCC-RyR coupling at triads without disrupting JM morphology, and substantially reducing Ca2+ transients without affecting SR Ca2+ content. Moreover, the contractile force of the JP1DeltaCT-expressed muscle was dramatically reduced compared with the control. Taken together, JPs recruit LTCCs to the JM through physical interaction and ensure robust ECC at triads in skeletal muscle. PMID- 29632176 TI - Aspect controls the survival of ice cliffs on debris-covered glaciers. AB - Supraglacial ice cliffs exist on debris-covered glaciers worldwide, but despite their importance as melt hot spots, their life cycle is little understood. Early field observations had advanced a hypothesis of survival of north-facing and disappearance of south-facing cliffs, which is central for predicting the contribution of cliffs to total glacier mass losses. Their role as windows of energy transfer suggests they may explain the anomalously high mass losses of debris-covered glaciers in High Mountain Asia (HMA) despite the insulating debris, currently at the center of a debated controversy. We use a 3D model of cliff evolution coupled to very high-resolution topographic data to demonstrate that ice cliffs facing south (in the Northern Hemisphere) disappear within a few months due to enhanced solar radiation receipts and that aspect is the key control on cliffs evolution. We reproduce continuous flattening of south-facing cliffs, a result of their vertical gradient of incoming solar radiation and sky view factor. Our results establish that only north-facing cliffs are recurrent features and thus stable contributors to the melting of debris-covered glaciers. Satellite observations and mass balance modeling confirms that few south-facing cliffs of small size exist on the glaciers of Langtang, and their contribution to the glacier volume losses is very small ([Formula: see text]1%). This has major implications for the mass balance of HMA debris-covered glaciers as it provides the basis for new parameterizations of cliff evolution and distribution to constrain volume losses in a region where glaciers are highly relevant as water sources for millions of people. PMID- 29632178 TI - Spontaneous oscillation and fluid-structure interaction of cilia. AB - The exact mechanism to orchestrate the action of hundreds of dynein motor proteins to generate wave-like ciliary beating remains puzzling and has fascinated many scientists. We present a 3D model of a cilium and the simulation of its beating in a fluid environment. The model cilium obeys a simple geometric constraint that arises naturally from the microscopic structure of a real cilium. This constraint allows us to determine the whole 3D structure at any instant in terms of the configuration of a single space curve. The tensions of active links, which model the dynein motor proteins, follow a postulated dynamical law, and together with the passive elasticity of microtubules, this dynamical law is responsible for the ciliary motions. In particular, our postulated tension dynamics lead to the instability of a symmetrical steady state, in which the cilium is straight and its active links are under equal tensions. The result of this instability is a stable, wave-like, limit cycle oscillation. We have also investigated the fluid-structure interaction of cilia using the immersed boundary (IB) method. In this setting, we see not only coordination within a single cilium but also, coordinated motion, in which multiple cilia in an array organize their beating to pump fluid, in particular by breaking phase synchronization. PMID- 29632177 TI - beta-Amyloid accumulation in the human brain after one night of sleep deprivation. AB - The effects of acute sleep deprivation on beta-amyloid (Abeta) clearance in the human brain have not been documented. Here we used PET and 18F-florbetaben to measure brain Abeta burden (ABB) in 20 healthy controls tested after a night of rested sleep (baseline) and after a night of sleep deprivation. We show that one night of sleep deprivation, relative to baseline, resulted in a significant increase in Abeta burden in the right hippocampus and thalamus. These increases were associated with mood worsening following sleep deprivation, but were not related to the genetic risk (APOE genotype) for Alzheimer's disease. Additionally, baseline ABB in a range of subcortical regions and the precuneus was inversely associated with reported night sleep hours. APOE genotyping was also linked to subcortical ABB, suggesting that different Alzheimer's disease risk factors might independently affect ABB in nearby brain regions. In summary, our findings show adverse effects of one-night sleep deprivation on brain ABB and expand on prior findings of higher Abeta accumulation with chronic less sleep. PMID- 29632179 TI - E3 ubiquitin ligase SOR1 regulates ethylene response in rice root by modulating stability of Aux/IAA protein. AB - Plant hormones ethylene and auxin synergistically regulate plant root growth and development. Ubiquitin-mediated proteolysis of Aux/IAA transcriptional repressors by the E3 ubiquitin ligase SCFTIR1/AFB triggers a transcription-based auxin signaling. Here we show that rice (Oryza sativa L.) soil-surface rooting 1 (SOR1), which is a RING finger E3 ubiquitin ligase identified from analysis of a rice ethylene-insensitive mutant mhz2/sor1-2, controls root-specific ethylene responses by modulating Aux/IAA protein stability. SOR1 physically interacts with OsIAA26 and OsIAA9, which are atypical and canonical Aux/IAA proteins, respectively. SOR1 targets OsIAA26 for ubiquitin/26S proteasome-mediated degradation, whereas OsIAA9 protects the OsIAA26 protein from degradation by inhibiting the E3 activity of SOR1. Auxin promotes SOR1-dependent degradation of OsIAA26 by facilitating SCFOsTIR1/AFB2-mediated and SOR1-assisted destabilization of OsIAA9 protein. Our study provides a candidate mechanism by which the SOR1 OsIAA26 module acts downstream of the OsTIR1/AFB2-auxin-OsIAA9 signaling to modulate ethylene inhibition of root growth in rice seedlings. PMID- 29632180 TI - Correlating structural and photochemical heterogeneity in cyanobacteriochrome NpR6012g4. AB - Phytochrome photoreceptors control plant growth, development, and the shade avoidance response that limits crop yield in high-density agricultural plantings. Cyanobacteriochromes (CBCRs) are distantly related photosensory proteins that control cyanobacterial metabolism and behavior in response to light. Photoreceptors in both families reversibly photoconvert between two photostates via photoisomerization of linear tetrapyrrole (bilin) chromophores. Spectroscopic and biochemical studies have demonstrated heterogeneity in both photostates, but the structural basis for such heterogeneity remains unclear. We report solution NMR structures for both photostates of the red/green CBCR NpR6012g4 from Nostoc punctiforme In addition to identifying structural changes accompanying photoconversion, these structures reveal structural heterogeneity for residues Trp655 and Asp657 in the red-absorbing NpR6012g4 dark state, yielding two distinct environments for the phycocyanobilin chromophore. We use site-directed mutagenesis and fluorescence and absorbance spectroscopy to assign an orange absorbing population in the NpR6012g4 dark state to the minority configuration for Asp657. This population does not undergo full, productive photoconversion, as shown by time-resolved spectroscopy and absorption spectroscopy at cryogenic temperature. Our studies thus elucidate the spectral and photochemical consequences of structural heterogeneity in a member of the phytochrome superfamily, insights that should inform efforts to improve photochemical or fluorescence quantum yields in the phytochrome superfamily. PMID- 29632182 TI - Profile of Alexander Y. Rudensky, winner of the 2018 Vilcek Prize in Biomedical Science. PMID- 29632181 TI - PARP-1 protects against colorectal tumor induction, but promotes inflammation driven colorectal tumor progression. AB - Colorectal cancer (CRC) is one of the most common tumor entities, which is causally linked to DNA repair defects and inflammatory bowel disease (IBD). Here, we studied the role of the DNA repair protein poly(ADP-ribose) polymerase-1 (PARP 1) in CRC. Tissue microarray analysis revealed PARP-1 overexpression in human CRC, correlating with disease progression. To elucidate its function in CRC, PARP 1 deficient (PARP-1-/-) and wild-type animals (WT) were subjected to azoxymethane (AOM)/ dextran sodium sulfate (DSS)-induced colorectal carcinogenesis. Miniendoscopy showed significantly more tumors in WT than in PARP-1-/- mice. Although the lack of PARP-1 moderately increased DNA damage, both genotypes exhibited comparable levels of AOM-induced autophagy and cell death. Interestingly, miniendoscopy revealed a higher AOM/DSS-triggered intestinal inflammation in WT animals, which was associated with increased levels of innate immune cells and proinflammatory cytokines. Tumors in WT animals were more aggressive, showing higher levels of STAT3 activation and cyclin D1 up regulation. PARP-1-/- animals were then crossed with O6-methylguanine-DNA methyltransferase (MGMT)-deficient animals hypersensitive to AOM. Intriguingly, PARP-1-/-/MGMT-/- double knockout (DKO) mice developed more, but much smaller tumors than MGMT-/- animals. In contrast to MGMT-deficient mice, DKO animals showed strongly reduced AOM-dependent colonic cell death despite similar O6 methylguanine levels. Studies with PARP-1-/- cells provided evidence for increased alkylation-induced DNA strand break formation when MGMT was inhibited, suggesting a role of PARP-1 in the response to O6-methylguanine adducts. Our findings reveal PARP-1 as a double-edged sword in colorectal carcinogenesis, which suppresses tumor initiation following DNA alkylation in a MGMT-dependent manner, but promotes inflammation-driven tumor progression. PMID- 29632183 TI - Molecular mechanism of activation of human musk receptors OR5AN1 and OR1A1 by (R) muscone and diverse other musk-smelling compounds. AB - Understanding olfaction at the molecular level is challenging due to the lack of crystallographic models of odorant receptors (ORs). To better understand the molecular mechanism of OR activation, we focused on chiral (R)-muscone and other musk-smelling odorants due to their great importance and widespread use in perfumery and traditional medicine, as well as environmental concerns associated with bioaccumulation of musks with estrogenic/antiestrogenic properties. We experimentally and computationally examined the activation of human receptors OR5AN1 and OR1A1, recently identified as specifically responding to musk compounds. OR5AN1 responds at nanomolar concentrations to musk ketone and robustly to macrocyclic sulfoxides and fluorine-substituted macrocyclic ketones; OR1A1 responds only to nitromusks. Structural models of OR5AN1 and OR1A1 based on quantum mechanics/molecular mechanics (QM/MM) hybrid methods were validated through direct comparisons with activation profiles from site-directed mutagenesis experiments and analysis of binding energies for 35 musk-related odorants. The experimentally found chiral selectivity of OR5AN1 to (R)- over (S) muscone was also computationally confirmed for muscone and fluorinated (R) muscone analogs. Structural models show that OR5AN1, highly responsive to nitromusks over macrocyclic musks, stabilizes odorants by hydrogen bonding to Tyr260 of transmembrane alpha-helix 6 and hydrophobic interactions with surrounding aromatic residues Phe105, Phe194, and Phe207. The binding of OR1A1 to nitromusks is stabilized by hydrogen bonding to Tyr258 along with hydrophobic interactions with surrounding aromatic residues Tyr251 and Phe206. Hydrophobic/nonpolar and hydrogen bonding interactions contribute, respectively, 77% and 13% to the odorant binding affinities, as shown by an atom-based quantitative structure-activity relationship model. PMID- 29632184 TI - New class of transcription factors controls flagellar assembly by recruiting RNA polymerase II in Chlamydomonas. AB - Cells have developed regulatory mechanisms that underlie flagellar assembly and maintenance, including the transcriptional regulation of flagellar genes, an initial step for making flagella. Although transcriptional regulation of flagellar gene expression is required for flagellar assembly in Chlamydomonas, no transcription factor that regulates the transcription of flagellar genes has been identified. We report that X chromosome-associated protein 5 (XAP5) acts as a transcription factor to regulate flagellar assembly in Chlamydomonas While XAP5 proteins are evolutionarily conserved across diverse organisms and play vital roles in diverse biological processes, nothing is known about the biochemical function of any member of this important protein family. Our data show that loss of XAP5 leads to defects in flagellar assembly. Posttranslational modifications of XAP5 track flagellar length during flagellar assembly, suggesting that cells possess a feedback system that modulates modifications to XAP5. Notably, XAP5 regulates flagellar gene expression via directly binding to a motif containing a CTGGGGTG-core. Furthermore, recruitment of RNA polymerase II (Pol II) machinery for transcriptional activation depends on the activities of XAP5. Our data demonstrate that, through recruitment of Pol II, XAP5 defines a class of transcription factors for transcriptional regulation of ciliary genes. This work provides insights into the biochemical function of the XAP5 family and the fundamental biology of the flagellar assembly, which enhance our understanding of the signaling and functions of flagella. PMID- 29632185 TI - Conformational sampling of membranes by Akt controls its activation and inactivation. AB - The protein kinase Akt controls myriad signaling processes in cells, ranging from growth and proliferation to differentiation and metabolism. Akt is activated by a combination of binding to the lipid second messenger PI(3,4,5)P3 and its subsequent phosphorylation by phosphoinositide-dependent kinase 1 and mechanistic target of rapamycin complex 2. The relative contributions of these mechanisms to Akt activity and signaling have hitherto not been understood. Here, we show that phosphorylation and activation by membrane binding are mutually interdependent. Moreover, the converse is also true: Akt is more rapidly dephosphorylated in the absence of PIP3, an autoinhibitory process driven by the interaction of its PH and kinase domains. We present biophysical evidence for the conformational changes in Akt that accompany its activation on membranes, show that Akt is robustly autoinhibited in the absence of PIP3 irrespective of its phosphorylation, and map the autoinhibitory PH-kinase interface. Finally, we present a model for the activation and inactivation of Akt by an ordered series of membrane binding, phosphorylation, dissociation, and dephosphorylation events. PMID- 29632186 TI - Programmed self-assembly of peptide-major histocompatibility complex for antigen specific immune modulation. AB - A technology to prime desired populations of T cells in the body-particularly those that possess low avidity against target antigen-would pave the way for the design of new types of vaccination for intractable infectious diseases or cancer. Here, we report such a technology based on positive feedback-driven, programmed self-assembly of peptide-major histocompatibility complex (pMHC) directly on the membrane of cognate T cells. Our design capitalizes on the unique features of the protein annexin V (ANXA5), which-in a concerted and synergistic manner-couples the early onset of TCR signaling by cognate pMHC with a surge in pMHC-TCR affinity, with repeated pMHC encounters, and with widespread TCR cross-linking. In our system, ANXA5 is linked to pMHC and firmly engages the plasma membrane of cognate T cells upon (and only upon) the early onset of TCR signaling. ANXA5, in turn, exerts a mechanical force that stabilizes interactions at the TCR-pMHC interface and facilitates repeated, serial pMHC encounters. Furthermore, ANXA5 quickly arranges into uniform 2D matrices, thereby prompting TCR cross-linking. Fusion of ANXA5 to pMHC augments lymphocyte activation by several orders of magnitude (>1,000-fold), bypasses the need for costimulation, and breaks tolerance against a model self-antigen in vivo. Our study opens the door to the application of synthetic, feedback-driven self-assembly platforms in immune modulation. PMID- 29632187 TI - Long-wavelength (reddish) hues induce unusually large gamma oscillations in the primate primary visual cortex. AB - Gamma oscillations (~30-80 Hz) are a prominent signature of electrophysiological signals, with a purported role in natural vision. Previous studies in the primary visual cortex (area V1) have shown that achromatic gratings or gabor stimuli generate salient gamma oscillations, whose strength and frequency depend on stimulus properties such as their size, contrast, and orientation. Surprisingly, although natural images are rarely achromatic, the effect of chromatic input on gamma has not been thoroughly investigated. Recording from primate V1, we show that gamma oscillations of extremely high magnitude (peak increase of ~300-fold in some cases), far exceeding the gamma generated by optimally tuned achromatic gratings, are induced in the local field potentials by full-field color stimuli of different hues. Furthermore, gamma oscillations are sensitive to the hue of the chromatic input, with the strongest oscillations for long-wavelength (reddish) hues and another, smaller gamma response peak for hues in the short wavelength (bluish) range, which lie approximately on the two cardinal chromatic response axes of the upstream lateral geniculate nucleus neurons. These oscillations depended critically on the purity of the hue, decreasing with hue desaturation, but remained robust for pure hue stimuli even at reduced luminance. Importantly, the magnitude of gamma oscillations was highly correlated with positive L-M cone contrast produced by the stimuli, suggesting that gamma could be a marker of the specific mechanisms underlying this computation. These findings provide insights into the generation of gamma oscillations, as well as the processing of color along the visual pathway. PMID- 29632188 TI - Genomic insights into the origin and diversification of late maritime hunter gatherers from the Chilean Patagonia. AB - Patagonia was the last region of the Americas reached by humans who entered the continent from Siberia ~15,000-20,000 y ago. Despite recent genomic approaches to reconstruct the continental evolutionary history, regional characterization of ancient and modern genomes remains understudied. Exploring the genomic diversity within Patagonia is not just a valuable strategy to gain a better understanding of the history and diversification of human populations in the southernmost tip of the Americas, but it would also improve the representation of Native American diversity in global databases of human variation. Here, we present genome data from four modern populations from Central Southern Chile and Patagonia (n = 61) and four ancient maritime individuals from Patagonia (~1,000 y old). Both the modern and ancient individuals studied in this work have a greater genetic affinity with other modern Native Americans than to any non-American population, showing within South America a clear structure between major geographical regions. Native Patagonian Kaweskar and Yamana showed the highest genetic affinity with the ancient individuals, indicating genetic continuity in the region during the past 1,000 y before present, together with an important agreement between the ethnic affiliation and historical distribution of both groups. Lastly, the ancient maritime individuals were genetically equidistant to a ~200-y-old terrestrial hunter-gatherer from Tierra del Fuego, which supports a model with an initial separation of a common ancestral group to both maritime populations from a terrestrial population, with a later diversification of the maritime groups. PMID- 29632191 TI - Correction for Kobayashi et al., B and T lymphocyte attenuator inhibits LPS induced endotoxic shock by suppressing Toll-like receptor 4 signaling in innate immune cells. PMID- 29632189 TI - Genome-wide CRISPR screen identifies FAM49B as a key regulator of actin dynamics and T cell activation. AB - Despite decades of research, mechanisms controlling T cell activation remain only partially understood, which hampers T cell-based immune cancer therapies. Here, we performed a genome-wide CRISPR screen to search for genes that regulate T cell activation. Our screen confirmed many of the known regulators in proximal T cell receptor signaling and, importantly, also uncovered a previously uncharacterized regulator, FAM49B (family with sequence similarity 49 member B). FAM49B deficiency led to hyperactivation of Jurkat T cells following T cell receptor stimulation, as indicated by enhancement of CD69 induction, PAK phosphorylation, and actin assembly. FAM49B directly interacted with the active form of the small GTPase Rac, and genetic disruption of the FAM49B-Rac interaction compromised FAM49B function. Thus, FAM49B inhibits T cell activation by repressing Rac activity and modulating cytoskeleton reorganization. PMID- 29632190 TI - Individually addressable and dynamic DNA gates for multiplexed cell sorting. AB - The ability to analyze and isolate cells based on the expression of specific surface markers has increased our understanding of cell biology and produced numerous applications for biomedicine. However, established cell-sorting platforms rely on labels that are limited in number due to biophysical constraints, such as overlapping emission spectra of fluorophores in FACS. Here, we establish a framework built on a system of orthogonal and extensible DNA gates for multiplexed cell sorting. These DNA gates label target cell populations by antibodies to allow magnetic bead isolation en masse and then selectively unlock by strand displacement to sort cells. We show that DNA gated sorting (DGS) is triggered to completion within minutes on the surface of cells and achieves target cell purity, viability, and yield equivalent to that of commercial magnetic sorting kits. We demonstrate multiplexed sorting of three distinct immune cell populations (CD8+, CD4+, and CD19+) from mouse splenocytes to high purity and show that recovered CD8+ T cells retain proliferative potential and target cell-killing activity. To broaden the utility of this platform, we implement a double positive sorting scheme using DNA gates on peptide-MHC tetramers to isolate antigen-specific CD8+ T cells from mice infected with lymphocytic choriomeningitis virus (LCMV). DGS can potentially be expanded with fewer biophysical constraints to large families of DNA gates for applications that require analysis of complex cell populations, such as host immune responses to disease. PMID- 29632192 TI - Crystal structures of a pentameric ion channel gated by alkaline pH show a widely open pore and identify a cavity for modulation. AB - Pentameric ligand-gated ion channels (pLGICs) constitute a widespread class of ion channels, present in archaea, bacteria, and eukaryotes. Upon binding of their agonists in the extracellular domain, the transmembrane pore opens, allowing ions to go through, via a gating mechanism that can be modulated by a number of drugs. Even though high-resolution structural information on pLGICs has increased in a spectacular way in recent years, both in bacterial and in eukaryotic systems, the structure of the open channel conformation of some intensively studied receptors whose structures are known in a nonactive (closed) form, such as Erwinia chrysanthemi pLGIC (ELIC), is still lacking. Here we describe a gammaproteobacterial pLGIC from an endo-symbiont of Tevnia jerichonana (sTeLIC), whose sequence is closely related to the pLGIC from ELIC with 28% identity. We provide an X-ray crystallographic structure at 2.3 A in an active conformation, where the pore is found to be more open than any current conformation found for pLGICs. In addition, two charged restriction rings are present in the vestibule. Functional characterization shows sTeLIC to be a cationic channel activated at alkaline pH. It is inhibited by divalent cations, but not by quaternary ammonium ions, such as tetramethylammonium. Additionally, we found that sTeLIC is allosterically potentiated by aromatic amino acids Phe and Trp, as well as their derivatives, such as 4-bromo-cinnamate, whose cocrystal structure reveals a vestibular binding site equivalent to, but more deeply buried than, the one already described for benzodiazepines in ELIC. PMID- 29632193 TI - Symbiont selection via alcohol benefits fungus farming by ambrosia beetles. AB - Animal-microbe mutualisms are typically maintained by vertical symbiont transmission or partner choice. A third mechanism, screening of high-quality symbionts, has been predicted in theory, but empirical examples are rare. Here we demonstrate that ambrosia beetles rely on ethanol within host trees for promoting gardens of their fungal symbiont and producing offspring. Ethanol has long been known as the main attractant for many of these fungus-farming beetles as they select host trees in which they excavate tunnels and cultivate fungal gardens. More than 300 attacks by Xylosandrus germanus and other species were triggered by baiting trees with ethanol lures, but none of the foundresses established fungal gardens or produced broods unless tree tissues contained in vivo ethanol resulting from irrigation with ethanol solutions. More X. germanus brood were also produced in a rearing substrate containing ethanol. These benefits are a result of increased food supply via the positive effects of ethanol on food fungus biomass. Selected Ambrosiella and Raffaelea fungal isolates from ethanol responsive ambrosia beetles profited directly and indirectly by (i) a higher biomass on medium containing ethanol, (ii) strong alcohol dehydrogenase enzymatic activity, and (iii) a competitive advantage over weedy fungal garden competitors (Aspergillus, Penicillium) that are inhibited by ethanol. As ambrosia fungi both detoxify and produce ethanol, they may maintain the selectivity of their alcohol rich habitat for their own purpose and that of other ethanol-resistant/producing microbes. This resembles biological screening of beneficial symbionts and a potentially widespread, unstudied benefit of alcohol-producing symbionts (e.g., yeasts) in other microbial symbioses. PMID- 29632195 TI - Neural precursors of future liking and affective reciprocity. AB - Why do certain group members end up liking each other more than others? How does affective reciprocity arise in human groups? The prediction of interpersonal sentiment has been a long-standing pursuit in the social sciences. We combined fMRI and longitudinal social network data to test whether newly acquainted group members' reward-related neural responses to images of one another's faces predict their future interpersonal sentiment, even many months later. Specifically, we analyze associations between relationship-specific valuation activity and relationship-specific future liking. We found that one's own future (T2) liking of a particular group member is predicted jointly by actor's initial (T1) neural valuation of partner and by that partner's initial (T1) neural valuation of actor. These actor and partner effects exhibited equivalent predictive strength and were robust when statistically controlling for each other, both individuals' initial liking, and other potential drivers of liking. Behavioral findings indicated that liking was initially unreciprocated at T1 yet became strongly reciprocated by T2. The emergence of affective reciprocity was partly explained by the reciprocal pathways linking dyad members' T1 neural data both to their own and to each other's T2 liking outcomes. These findings elucidate interpersonal brain mechanisms that define how we ultimately end up liking particular interaction partners, how group members' initially idiosyncratic sentiments become reciprocated, and more broadly, how dyads evolve. This study advances a flexible framework for researching the neural foundations of interpersonal sentiments and social relations that-conceptually, methodologically, and statistically-emphasizes group members' neural interdependence. PMID- 29632194 TI - In vivo CRISPR screening unveils histone demethylase UTX as an important epigenetic regulator in lung tumorigenesis. AB - Lung cancer is the leading cause of cancer-related death worldwide. Inactivation of tumor suppressor genes (TSGs) promotes lung cancer malignant progression. Here, we take advantage of the clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated somatic gene knockout in a KrasG12D/+ mouse model to identify bona fide TSGs. From individual knockout of 55 potential TSGs, we identify five genes, including Utx, Ptip, Acp5, Acacb, and Clu, whose knockout significantly promotes lung tumorigenesis. These candidate genes are frequently down-regulated in human lung cancer specimens and significantly associated with survival in patients with lung cancer. Through crossing the conditional Utx knockout allele to the KrasG12D/+ mouse model, we further find that Utx deletion dramatically promotes lung cancer progression. The tumor-promotive effect of Utx knockout in vivo is mainly mediated through an increase of the EZH2 level, which up-regulates the H3K27me3 level. Moreover, the Utx-knockout lung tumors are preferentially sensitive to EZH2 inhibitor treatment. Collectively, our study provides a systematic screening of TSGs in vivo and identifies UTX as an important epigenetic regulator in lung tumorigenesis. PMID- 29632197 TI - Chemical trends in ocean islands explained by plume-slab interaction. AB - Earth's surface shows many features, of which the genesis can be understood only through their connection with processes in Earth's deep interior. Recent studies indicate that spatial geochemical patterns at oceanic islands correspond to structures in the lowermost mantle inferred from seismic tomographic models. This suggests that hot, buoyant upwellings can carry chemical heterogeneities from the deep lower mantle toward the surface, providing a window to the composition of the lowermost mantle. The exact nature of this link between surface and deep Earth remains debated and poorly understood. Using computational models, we show that subducted slabs interacting with dense thermochemical piles can trigger the ascent of hot plumes that inherit chemical gradients present in the lowermost mantle. We identify two key factors controlling this process: (i) If slabs induce strong lower-mantle flow toward the edges of these piles where plumes rise, the pile-facing side of the plume preferentially samples material originating from the pile, and bilaterally asymmetric chemical zoning develops. (ii) The composition of the melt produced reflects this bilateral zoning if the overlying plate moves roughly perpendicular to the chemical gradient in the plume conduit. Our results explain some of the observed geochemical trends of oceanic islands and provide insights into how these trends may originate. PMID- 29632196 TI - Macrophages impede CD8 T cells from reaching tumor cells and limit the efficacy of anti-PD-1 treatment. AB - In a large proportion of cancer patients, CD8 T cells are excluded from the vicinity of cancer cells. The inability of CD8 T cells to reach tumor cells is considered an important mechanism of resistance to cancer immunotherapy. We show that, in human lung squamous-cell carcinomas, exclusion of CD8 T cells from tumor islets is correlated with a poor clinical outcome and with a low lymphocyte motility, as assessed by dynamic imaging on fresh tumor slices. In the tumor stroma, macrophages mediate lymphocyte trapping by forming long-lasting interactions with CD8 T cells. Using a mouse tumor model with well-defined stromal and tumor cell areas, macrophages were depleted with PLX3397, an inhibitor of colony-stimulating factor-1 receptor (CSF-1R). Our results reveal that a CSF-1R blockade enhances CD8 T cell migration and infiltration into tumor islets. Although this treatment alone has minor effects on tumor growth, its combination with anti-PD-1 therapy further increases the accumulation of CD8 T cells in close contact with malignant cells and delays tumor progression. These data suggest that the reduction of macrophage-mediated T cell exclusion increases tumor surveillance by CD8 T cells and renders tumors more responsive to anti-PD-1 treatment. PMID- 29632198 TI - Expressway to partially oxidized phosphorene. PMID- 29632199 TI - New insight into the early stages of biofilm formation. PMID- 29632200 TI - Fermentation of dihydroxyacetone by engineered Escherichia coli and Klebsiella variicola to products. AB - Methane can be converted to triose dihydroxyacetone (DHA) by chemical processes with formaldehyde as an intermediate. Carbon dioxide, a by-product of various industries including ethanol/butanol biorefineries, can also be converted to formaldehyde and then to DHA. DHA, upon entry into a cell and phosphorylation to DHA-3-phosphate, enters the glycolytic pathway and can be fermented to any one of several products. However, DHA is inhibitory to microbes due to its chemical interaction with cellular components. Fermentation of DHA to d-lactate by Escherichia coli strain TG113 was inefficient, and growth was inhibited by 30 g?L 1 DHA. An ATP-dependent DHA kinase from Klebsiella oxytoca (pDC117d) permitted growth of strain TG113 in a medium with 30 g?L-1 DHA, and in a fed-batch fermentation the d-lactate titer of TG113(pDC117d) was 580 +/- 21 mM at a yield of 0.92 g?g-1 DHA fermented. Klebsiella variicola strain LW225, with a higher glucose flux than E. coli, produced 811 +/- 26 mM d-lactic acid at an average volumetric productivity of 2.0 g-1?L-1?h-1 Fermentation of DHA required a balance between transport of the triose and utilization by the microorganism. Using other engineered E. coli strains, we also fermented DHA to succinic acid and ethanol, demonstrating the potential of converting CH4 and CO2 to value-added chemicals and fuels by a combination of chemical/biological processes. PMID- 29632201 TI - New zoning laws enforced by glucagon. PMID- 29632202 TI - NATure of actin amino-terminal acetylation. PMID- 29632204 TI - Facet-specific interaction between methanol and TiO2 probed by sum-frequency vibrational spectroscopy. AB - The facet-specific interaction between molecules and crystalline catalysts, such as titanium dioxides (TiO2), has attracted much attention due to possible facet dependent reactivity. Using surface-sensitive sum-frequency vibrational spectroscopy, we have studied how methanol interacts with different common facets of crystalline TiO2, including rutile(110), (001), (100), and anatase(101), under ambient temperature and pressure. We found that methanol adsorbs predominantly in the molecular form on all of the four surfaces, while spontaneous dissociation into methoxy occurs preferentially when these surfaces become defective. Extraction of Fermi resonance coupling between stretch and bending modes of the methyl group in analyzing adsorbed methanol spectra allows determination of the methanol adsorption isotherm. The isotherms obtained for the four surfaces are nearly the same, yielding two adsorbed Gibbs free energies associated with two different adsorption configurations singled out by ab initio calculations. They are (i) ~-20 kJ/mol for methanol with its oxygen attached to a low-coordinated surface titanium, and (ii) ~-5 kJ/mol for methanol hydrogen-bonded to a surface oxygen and a neighboring methanol molecule. Despite similar adsorption energetics, the Fermi resonance coupling strength for adsorbed methanol appears to depend sensitively on the surface facet and coverage. PMID- 29632203 TI - Cell-specific discrimination of desmosterol and desmosterol mimetics confers selective regulation of LXR and SREBP in macrophages. AB - Activation of liver X receptors (LXRs) with synthetic agonists promotes reverse cholesterol transport and protects against atherosclerosis in mouse models. Most synthetic LXR agonists also cause marked hypertriglyceridemia by inducing the expression of sterol regulatory element-binding protein (SREBP)1c and downstream genes that drive fatty acid biosynthesis. Recent studies demonstrated that desmosterol, an intermediate in the cholesterol biosynthetic pathway that suppresses SREBP processing by binding to SCAP, also binds and activates LXRs and is the most abundant LXR ligand in macrophage foam cells. Here we explore the potential of increasing endogenous desmosterol production or mimicking its activity as a means of inducing LXR activity while simultaneously suppressing SREBP1c-induced hypertriglyceridemia. Unexpectedly, while desmosterol strongly activated LXR target genes and suppressed SREBP pathways in mouse and human macrophages, it had almost no activity in mouse or human hepatocytes in vitro. We further demonstrate that sterol-based selective modulators of LXRs have biochemical and transcriptional properties predicted of desmosterol mimetics and selectively regulate LXR function in macrophages in vitro and in vivo. These studies thereby reveal cell-specific discrimination of endogenous and synthetic regulators of LXRs and SREBPs, providing a molecular basis for dissociation of LXR functions in macrophages from those in the liver that lead to hypertriglyceridemia. PMID- 29632205 TI - Alpha-v-containing integrins are host receptors for the Plasmodium falciparum sporozoite surface protein, TRAP. AB - Malaria-causing Plasmodium sporozoites are deposited in the dermis by the bite of an infected mosquito and move by gliding motility to the liver where they invade and develop within host hepatocytes. Although extracellular interactions between Plasmodium sporozoite ligands and host receptors provide important guidance cues for productive infection and are good vaccine targets, these interactions remain largely uncharacterized. Thrombospondin-related anonymous protein (TRAP) is a parasite cell surface ligand that is essential for both gliding motility and invasion because it couples the extracellular binding of host receptors to the parasite cytoplasmic actinomyosin motor; however, the molecular nature of the host TRAP receptors is poorly defined. Here, we use a systematic extracellular protein interaction screening approach to identify the integrin alphavbeta3 as a directly interacting host receptor for Plasmodium falciparum TRAP. Biochemical characterization of the interaction suggests a two-site binding model, requiring contributions from both the von Willebrand factor A domain and the RGD motif of TRAP for integrin binding. We show that TRAP binding to cells is promoted in the presence of integrin-activating proadhesive Mn2+ ions, and that cells genetically targeted so that they lack cell surface expression of the integrin alphav-subunit are no longer able to bind TRAP. P. falciparum sporozoites moved with greater speed in the dermis of Itgb3-deficient mice, suggesting that the interaction has a role in sporozoite migration. The identification of the integrin alphavbeta3 as the host receptor for TRAP provides an important demonstration of a sporozoite surface ligand that directly interacts with host receptors. PMID- 29632206 TI - Neddylation mediates ventricular chamber maturation through repression of Hippo signaling. AB - During development, ventricular chamber maturation is a crucial step in the formation of a functionally competent postnatal heart. Defects in this process can lead to left ventricular noncompaction cardiomyopathy and heart failure. However, molecular mechanisms underlying ventricular chamber development remain incompletely understood. Neddylation is a posttranslational modification that attaches ubiquitin-like protein NEDD8 to protein targets via NEDD8-specific E1-E2 E3 enzymes. Here, we report that neddylation is temporally regulated in the heart and plays a key role in cardiac development. Cardiomyocyte-specific knockout of NAE1, a subunit of the E1 neddylation activating enzyme, significantly decreased neddylated proteins in the heart. Mice lacking NAE1 developed myocardial hypoplasia, ventricular noncompaction, and heart failure at late gestation, which led to perinatal lethality. NAE1 deletion resulted in dysregulation of cell cycle regulatory genes and blockade of cardiomyocyte proliferation in vivo and in vitro, which was accompanied by the accumulation of the Hippo kinases Mst1 and LATS1/2 and the inactivation of the YAP pathway. Furthermore, reactivation of YAP signaling in NAE1-inactivated cardiomyocytes restored cell proliferation, and YAP deficient hearts displayed a noncompaction phenotype, supporting an important role of Hippo-YAP signaling in NAE1-depleted hearts. Mechanistically, we found that neddylation regulates Mst1 and LATS2 degradation and that Cullin 7, a NEDD8 substrate, acts as the ubiquitin ligase of Mst1 to enable YAP signaling and cardiomyocyte proliferation. Together, these findings demonstrate a role for neddylation in heart development and, more specifically, in the maturation of ventricular chambers and also identify the NEDD8 substrate Cullin 7 as a regulator of Hippo-YAP signaling. PMID- 29632207 TI - Live-cell analysis of endogenous GFP-RPB1 uncovers rapid turnover of initiating and promoter-paused RNA Polymerase II. AB - Initiation and promoter-proximal pausing are key regulatory steps of RNA Polymerase II (Pol II) transcription. To study the in vivo dynamics of endogenous Pol II during these steps, we generated fully functional GFP-RPB1 knockin cells. GFP-RPB1 photobleaching combined with computational modeling revealed four kinetically distinct Pol II fractions and showed that on average 7% of Pol II are freely diffusing, while 10% are chromatin-bound for 2.4 seconds during initiation, and 23% are promoter-paused for only 42 seconds. This unexpectedly high turnover of Pol II at promoters is most likely caused by premature termination of initiating and promoter-paused Pol II and is in sharp contrast to the 23 minutes that elongating Pol II resides on chromatin. Our live-cell-imaging approach provides insights into Pol II dynamics and suggests that the continuous release and reinitiation of promoter-bound Pol II is an important component of transcriptional regulation. PMID- 29632209 TI - Translation initiation in bacterial polysomes through ribosome loading on a standby site on a highly translated mRNA. AB - During translation, consecutive ribosomes load on an mRNA and form a polysome. The first ribosome binds to a single-stranded mRNA region and moves toward the start codon, unwinding potential mRNA structures on the way. In contrast, the following ribosomes can dock at the start codon only when the first ribosome has vacated the initiation site. Here we show that loading of the second ribosome on a natural 38-nt-long 5' untranslated region of lpp mRNA, which codes for the outer membrane lipoprotein from Escherichia coli, takes place before the leading ribosome has moved away from the start codon. The rapid formation of this standby complex depends on the presence of ribosomal proteins S1/S2 in the leading ribosome. The early recruitment of the second ribosome to the standby site before translation by the leading ribosome and the tight coupling between translation elongation by the first ribosome and the accommodation of the second ribosome can contribute to high translational efficiency of the lpp mRNA. PMID- 29632208 TI - KELCH F-BOX protein positively influences Arabidopsis seed germination by targeting PHYTOCHROME-INTERACTING FACTOR1. AB - Seeds employ sensory systems that assess various environmental cues over time to maximize the successful transition from embryo to seedling. Here we show that the Arabidopsis F-BOX protein COLD TEMPERATURE-GERMINATING (CTG)-10, identified by activation tagging, is a positive regulator of this process. When overexpressed (OE), CTG10 hastens aspects of seed germination. CTG10 is expressed predominantly in the hypocotyl, and the protein is localized to the nucleus. CTG10 interacts with PHYTOCHROME-INTERACTING FACTOR 1 (PIF1) and helps regulate its abundance in plantaCTG10-OE accelerates the loss of PIF1 in light, increasing germination efficiency, while PIF1-OE lines fail to complete germination in darkness, which is reversed by concurrent CTG10-OE Double-mutant (pif1 ctg10) lines demonstrated that PIF1 is epistatic to CTG10. Both CTG10 and PIF1 amounts decline during seed germination in the light but reaccumulate in the dark. PIF1 in turn down regulates CTG10 transcription, suggesting a feedback loop of CTG10/PIF1 control. The genetic, physiological, and biochemical evidence, when taken together, leads us to propose that PIF1 and CTG10 coexist, and even accumulate, in the nucleus in darkness, but that, following illumination, CTG10 assists in reducing PIF1 amounts, thus promoting the completion of seed germination and subsequent seedling development. PMID- 29632212 TI - Harmonics added to a flickering light can upset the balance between ON and OFF pathways to produce illusory colors. AB - The neural signals generated by the light-sensitive photoreceptors in the human eye are substantially processed and recoded in the retina before being transmitted to the brain via the optic nerve. A key aspect of this recoding is the splitting of the signals within the two major cone-driven visual pathways into distinct ON and OFF branches that transmit information about increases and decreases in the neural signal around its mean level. While this separation is clearly important physiologically, its effect on perception is unclear. We have developed a model of the ON and OFF pathways in early color processing. Using this model as a guide, we can produce imbalances in the ON and OFF pathways by changing the shapes of time-varying stimulus waveforms and thus make reliable and predictable alterations to the perceived average color of the stimulus-although the physical mean of the waveforms does not change. The key components in the model are the early half-wave rectifying synapses that split retinal photoreceptor outputs into the ON and OFF pathways and later sigmoidal nonlinearities in each pathway. The ability to systematically vary the waveforms to change a perceptual quality by changing the balance of signals between the ON and OFF visual pathways provides a powerful psychophysical tool for disentangling and investigating the neural workings of human vision. PMID- 29632210 TI - TMEM59 potentiates Wnt signaling by promoting signalosome formation. AB - Wnt/beta-catenin signaling controls development and adult tissue homeostasis by regulating cell proliferation and cell fate decisions. Wnt binding to its receptors Frizzled (FZD) and low-density lipoprotein-related 6 (LRP6) at the cell surface initiates a signaling cascade that leads to the transcription of Wnt target genes. Upon Wnt binding, the receptors assemble into large complexes called signalosomes that provide a platform for interactions with downstream effector proteins. The molecular basis of signalosome formation and regulation remains elusive, largely due to the lack of tools to analyze its endogenous components. Here, we use internally tagged Wnt3a proteins to isolate and characterize activated, endogenous Wnt receptor complexes by mass spectrometry based proteomics. We identify the single-span membrane protein TMEM59 as an interactor of FZD and LRP6 and a positive regulator of Wnt signaling. Mechanistically, TMEM59 promotes the formation of multimeric Wnt-FZD assemblies via intramembrane interactions. Subsequently, these Wnt-FZD-TMEM59 clusters merge with LRP6 to form mature Wnt signalosomes. We conclude that the assembly of multiprotein Wnt signalosomes proceeds along well-ordered steps that involve regulated intramembrane interactions. PMID- 29632211 TI - Stoichiometry and compositional plasticity of the yeast nuclear pore complex revealed by quantitative fluorescence microscopy. AB - The nuclear pore complex (NPC) is an eightfold symmetrical channel providing selective transport of biomolecules across the nuclear envelope. Each NPC consists of ~30 different nuclear pore proteins (Nups) all present in multiple copies per NPC. Significant progress has recently been made in the characterization of the vertebrate NPC structure. However, because of the estimated size differences between the vertebrate and yeast NPC, it has been unclear whether the NPC architecture is conserved between species. Here, we have developed a quantitative image analysis pipeline, termed nuclear rim intensity measurement (NuRIM), to precisely determine copy numbers for almost all Nups within native NPCs of budding yeast cells. Our analysis demonstrates that the majority of yeast Nups are present at most in 16 copies per NPC. This reveals a dramatic difference to the stoichiometry determined for the human NPC, suggesting that despite a high degree of individual Nup conservation, the yeast and human NPC architecture is significantly different. Furthermore, using NuRIM, we examined the effects of mutations on NPC stoichiometry. We demonstrate for two paralog pairs of key scaffold Nups, Nup170/Nup157 and Nup192/Nup188, that their altered expression leads to significant changes in the NPC stoichiometry inducing either voids in the NPC structure or substitution of one paralog by the other. Thus, our results not only provide accurate stoichiometry information for the intact yeast NPC but also reveal an intriguing compositional plasticity of the NPC architecture, which may explain how differences in NPC composition could arise in the course of evolution. PMID- 29632213 TI - Extracting neuronal functional network dynamics via adaptive Granger causality analysis. AB - Quantifying the functional relations between the nodes in a network based on local observations is a key challenge in studying complex systems. Most existing time series analysis techniques for this purpose provide static estimates of the network properties, pertain to stationary Gaussian data, or do not take into account the ubiquitous sparsity in the underlying functional networks. When applied to spike recordings from neuronal ensembles undergoing rapid task dependent dynamics, they thus hinder a precise statistical characterization of the dynamic neuronal functional networks underlying adaptive behavior. We develop a dynamic estimation and inference paradigm for extracting functional neuronal network dynamics in the sense of Granger, by integrating techniques from adaptive filtering, compressed sensing, point process theory, and high-dimensional statistics. We demonstrate the utility of our proposed paradigm through theoretical analysis, algorithm development, and application to synthetic and real data. Application of our techniques to two-photon Ca2+ imaging experiments from the mouse auditory cortex reveals unique features of the functional neuronal network structures underlying spontaneous activity at unprecedented spatiotemporal resolution. Our analysis of simultaneous recordings from the ferret auditory and prefrontal cortical areas suggests evidence for the role of rapid top-down and bottom-up functional dynamics across these areas involved in robust attentive behavior. PMID- 29632214 TI - Molecular spherical nucleic acids. AB - Herein, we report a class of molecular spherical nucleic acid (SNA) nanostructures. These nano-sized single molecules are synthesized from T8 polyoctahedral silsesquioxane and buckminsterfullerene C60 scaffolds, modified with 8 and 12 pendant DNA strands, respectively. These conjugates have different DNA surface densities and thus exhibit different levels of nuclease resistance, cellular uptake, and gene regulation capabilities; the properties displayed by the C60 SNA conjugate are closer to those of conventional and prototypical gold nanoparticle SNAs. Importantly, the C60 SNA can serve as a single entity (no transfection agent required) antisense agent to efficiently regulate gene expression. The realization of molecularly pure forms of SNAs will open the door for studying the interactions of such structures with ligands and living cells with a much greater degree of control than the conventional polydisperse forms of SNAs. PMID- 29632215 TI - Soluble Klotho causes hypomineralization in Klotho-deficient mice. AB - The type I transmembrane protein alphaKlotho (Klotho) serves as a coreceptor for the phosphaturic hormone fibroblast growth factor 23 (FGF23) in kidney, while a truncated form of Klotho (soluble Klotho, sKL) is thought to exhibit multiple activities, including acting as a hormone, but whose mode(s) of action in different organ systems remains to be fully elucidated. FGF23 is expressed primarily in osteoblasts/osteocytes and aberrantly high levels in the circulation acting via signaling through an FGF receptor (FGFR)-Klotho coreceptor complex cause renal phosphate wasting and osteomalacia. We assessed the effects of exogenously added sKL on osteoblasts and bone using Klotho-deficient (kl/kl) mice and cell and organ cultures. sKL induced FGF23 signaling in bone and exacerbated the hypomineralization without exacerbating the hyperphosphatemia, hypercalcemia and hypervitaminosis D in kl/kl mice. The same effects were seen in rodent bone models in vitro, in which we also detected formation of a sKL complex with FGF23 FGFR and decreased Phex (gene responsible for X-linked hypophosphatemic rickets (XLH)/osteomalacia) expression. Further, sKL-FGF23-dependent hypomineralization in vitro was rescued by soluble PHEX. These data suggest that exogenously added sKL directly participates in FGF23 signaling in bone and that PHEX is a downstream effector of the sKL-FGF23-FGFR axis in bone. PMID- 29632217 TI - Projected Costs of Informal Caregiving for Cardiovascular Disease: 2015 to 2035: A Policy Statement From the American Heart Association. AB - INTRODUCTION: In a recent report, the American Heart Association estimated that medical costs and productivity losses of cardiovascular disease (CVD) are expected to grow from $555 billion in 2015 to $1.1 trillion in 2035. Although the burden is significant, the estimate does not include the costs of family, informal, or unpaid caregiving provided to patients with CVD. In this analysis, we estimated projections of costs of informal caregiving attributable to CVD for 2015 to 2035. METHODS: We used data from the 2014 Health and Retirement Survey to estimate hours of informal caregiving for individuals with CVD by age/sex/race using a zero-inflated binomial model and controlling for sociodemographic factors and health conditions. Costs of informal caregiving were estimated separately for hypertension, coronary heart disease, heart failure, stroke, and other heart disease. We analyzed data from a nationally representative sample of 16 731 noninstitutionalized adults >=54 years of age. The value of caregiving hours was monetized by the use of home health aide workers' wages. The per-person costs were multiplied by census population counts to estimate nation-level costs and to be consistent with other American Heart Association analyses of burden of CVD, and the costs were projected from 2015 through 2035, assuming that within each age/sex/racial group, CVD prevalence and caregiving hours remain constant. RESULTS: The costs of informal caregiving for patients with CVD were estimated to be $61 billion in 2015 and are projected to increase to $128 billion in 2035. Costs of informal caregiving of patients with stroke constitute more than half of the total costs of CVD informal caregiving ($31 billion in 2015 and $66 billion in 2035). By age, costs are the highest among those 65 to 79 years of age in 2015 but are expected to be surpassed by costs among those >=80 years of age by 2035. Costs of informal caregiving for patients with CVD represent an additional 11% of medical and productivity costs attributable to CVD. CONCLUSIONS: The burden of informal caregiving for patients with CVD is significant; accounting for these costs increases total CVD costs to $616 billion in 2015 and $1.2 trillion in 2035. These estimates have important research and policy implications, and they may be used to guide policy development to reduce the burden of CVD on patients and their caregivers. PMID- 29632216 TI - Associations of Fitness, Physical Activity, Strength, and Genetic Risk With Cardiovascular Disease: Longitudinal Analyses in the UK Biobank Study. AB - BACKGROUND: Observational studies have shown inverse associations among fitness, physical activity, and cardiovascular disease. However, little is known about these associations in individuals with elevated genetic susceptibility for these diseases. METHODS: We estimated associations of grip strength, objective and subjective physical activity, and cardiorespiratory fitness with cardiovascular events and all-cause death in a large cohort of 502 635 individuals from the UK Biobank (median follow-up, 6.1 years; interquartile range, 5.4-6.8 years). Then we further examined these associations in individuals with different genetic burden by stratifying individuals based on their genetic risk scores for coronary heart disease and atrial fibrillation. We compared disease risk among individuals in different tertiles of fitness, physical activity, and genetic risk using lowest tertiles as reference. RESULTS: Grip strength, physical activity, and cardiorespiratory fitness showed inverse associations with incident cardiovascular events (coronary heart disease: hazard ratio [HR], 0.79; 95% confidence interval [CI], 0.77-0.81; HR, 0.95; 95% CI, 0.93-0.97; and HR, 0.68; 95% CI, 0.63-0.74, per SD change, respectively; atrial fibrillation: HR, 0.75; 95% CI, 0.73-0.76; HR, 0.93; 95% CI, 0.91-0.95; and HR, 0.60; 95% CI, 0.56-0.65, per SD change, respectively). Higher grip strength and cardiorespiratory fitness were associated with lower risk of incident coronary heart disease and atrial fibrillation in each genetic risk score group (Ptrend <0.001 in each genetic risk category). In particular, high levels of cardiorespiratory fitness were associated with 49% lower risk for coronary heart disease (HR, 0.51; 95% CI, 0.38 0.69) and 60% lower risk for atrial fibrillation (HR, 0.40; 95%, CI 0.30-0.55) among individuals at high genetic risk for these diseases. CONCLUSIONS: Fitness and physical activity demonstrated inverse associations with incident cardiovascular disease in the general population, as well as in individuals with elevated genetic risk for these diseases. PMID- 29632218 TI - The Capacity of Primary Care for Improving Evidence-Based Care: Early Findings From AHRQ's EvidenceNOW. PMID- 29632219 TI - EvidenceNOW: Balancing Primary Care Implementation and Implementation Research. AB - The mission of the Agency for Healthcare Research and Quality (AHRQ) is to generate knowledge about how America's health care delivery system can provide high-quality care, and to ensure that health care professionals and systems understand and use this evidence. In 2015 AHRQ invested in the largest primary care research project in its history. EvidenceNOW is a $112 million effort to disseminate and implement patient-centered outcomes research evidence in more than 1,500 primary care practices and to study how quality-improvement support can build the capacity of primary care practices to understand and apply evidence.EvidenceNOW comprises 7 implementation research grants, each funded to provide external quality-improvement support to primary care practices to implement evidence-based cardiovascular care and to conduct rigorous internal evaluations of their work. An independent, external evaluator was funded to conduct an overarching evaluation using harmonized outcome measures and pooled data. The design of EvidenceNOW required resolving tensions between implementation and implementation research goals.EvidenceNOW is poised to develop a blueprint for how stakeholders can invest in strengthening the primary care delivery system and to offer a variety of resources and tools to improve the capacity of primary care to deliver evidence-based care. Federal agencies must maximize the value of research investments to show improvements in the lives and health of Americans and the timeliness of research results. Understanding the process and decisions of a federal agency in designing a large clinical practice transformation initiative may provide researchers, policy makers, and clinicians with insights into future implementation research, as well as improve responsiveness to funding announcements and the implementation of evidence in routine clinical care. PMID- 29632220 TI - Technical Assistance for Primary Care Practice Transformation: Free Help to Perform Unpaid Labor? PMID- 29632221 TI - Finding a Parsimonious Path for Primary Care Practice Transformation. PMID- 29632222 TI - Quality of Cardiovascular Disease Care in Small Urban Practices. AB - PURPOSE: We wanted to describe small, independent primary care practices' performance in meeting the Million Hearts ABCSs (aspirin use, blood pressure control, cholesterol management, and smoking screening and counseling), as well as on a composite measure that captured the extent to which multiple clinical targets are achieved for patients with a history of arteriosclerotic cardiovascular disease (ASCVD). We also explored relationships between practice characteristics and ABCS measures. METHODS: We conducted a cross-sectional, bivariate analysis using baseline data from 134 practices in New York City. ABCS data were extracted from practices' electronic health records and aggregated to the site level. Practice characteristics were obtained from surveys of clinicians and staff at each practice. RESULTS: The proportion of at-risk patients meeting clinical goals for each of the ABCS measures was 73.0% for aspirin use, 69.6% for blood pressure, 66.7% for cholesterol management, and 74.2% screened for smoking and counseled. For patients with a history of ASCVD, only 49% were meeting all ABC (aspirin use, blood pressure control, cholesterol management) targets (ie, composite measure). Solo practices were more likely to meet clinical guidelines for aspirin (risk ratio [RR] =1.17, P =.007) and composite (RR=1.29, P = .011) than practices with multiple clinicians. CONCLUSION: Achieving targets for ABCS measures varied considerably across practices; however, small practices were meeting or exceeding Million Hearts goals (ie, 70% or greater). Practices were less likely to meet consistently clinical targets that apply to patients with a history of ASCVD risk factors. Greater emphasis is needed on providing support for small practices to address the complexity of managing patients with multiple risk factors for primary and secondary ASCVD. PMID- 29632223 TI - Organizational Leadership and Adaptive Reserve in Blood Pressure Control: The Heart Health NOW Study. AB - PURPOSE: Our purpose was to assess whether a practice's adaptive reserve and high leadership capability in quality improvement are associated with population blood pressure control. METHODS: We divided practices into quartiles of blood pressure control performance and considered the top quartile as the benchmark for comparison. Using abstracted clinical data from electronic health records, we performed a cross-sectional study to assess the association of top quartile hypertension control and (1) the baseline practice adaptive reserve (PAR) scores and (2) baseline practice leadership scores, using modified Poisson regression models adjusting for practice-level characteristics. RESULTS: Among 181 practices, 46 were in the top quartile, which averaged 68% or better blood pressure control. Practices with higher PAR scores compared with lower PAR scores were not more likely to reside in the top quartile of performance (prevalence ratio [PR] = 1.92 for highest quartile; 95% CI, 0.9-4.1). Similarly, high quality improvement leadership capability compared with lower capability did not predict better blood pressure control performance (PR = 0.94; 95% CI, 0.57-1.56). Practices with higher proportions of commercially insured patients were more likely than practices with lower proportions of commercially insured patients to have top quartile performance (37% vs 26%, P =.002), whereas lower proportions of the uninsured (8% vs 14%, P =.055) were associated with better performance. CONCLUSIONS: Our findings show that adaptive reserve and leadership capability in quality improvement implementation are not statistically associated with achieving top quartile practice-level hypertension control at baseline in the Heart Health NOW project. Our findings, however, may be limited by a lack of patient-related factors and small sample size to preclude strong conclusions. PMID- 29632225 TI - Effect of Practice Ownership on Work Environment, Learning Culture, Psychological Safety, and Burnout. AB - PURPOSE: Physicians have joined larger groups and hospital systems in the face of multiple environmental challenges. We examine whether there are differences across practice ownership in self-reported work environment, a practice culture of learning, psychological safety, and burnout. METHODS: Using cross-sectional data from staff surveys of small and medium-size practices that participated in EvidenceNOW in Virginia, we tested for differences in work environment, culture of learning, psychological safety, and burnout by practice type. We conducted weighted multivariate linear regression of outcomes on ownership, controlling for practice size, specialty mix, payer mix, and whether the practice was located in a medically underserved area. We further analyzed clinician and staff responses separately. RESULTS: Participating were 104 hospital-owned and 61 independent practices and 24 federally qualified health centers (FQHCs). We analyzed 2,005 responses from practice clinicians and staff, a response rate of 49%. Working in a hospital-owned practice was associated with favorable ratings of work environment, psychological safety, and burnout compared with independent practices. When we examined separately the responses of clinicians vs staff, however, the association appears to be largely driven by staff. CONCLUSIONS: Hospital ownership was associated with positive perceptions of practice work environment and lower burnout for staff relative to independent ownership, whereas clinicians in FQHCs perceive a more negative, less joyful work environment and burnout. Our findings are suggestive that clinician and nonclinician staff perceive practice adaptive reserve differently, which may have implications for creating the energy for ongoing quality improvement work. PMID- 29632224 TI - Use of Quality Improvement Strategies Among Small to Medium-Size US Primary Care Practices. AB - PURPOSE: Improving primary care quality is a national priority, but little is known about the extent to which small to medium-size practices use quality improvement (QI) strategies to improve care. We examined variations in use of QI strategies among 1,181 small to medium-size primary care practices engaged in a national initiative spanning 12 US states to improve quality of care for heart health and assessed factors associated with those variations. METHODS: In this cross-sectional study, practice characteristics were assessed by surveying practice leaders. Practice use of QI strategies was measured by the validated Change Process Capability Questionnaire (CPCQ) Strategies Scale (scores range from -28 to 28, with higher scores indicating more use of QI strategies). Multivariable linear regression was used to examine the association between practice characteristics and the CPCQ strategies score. RESULTS: The mean CPCQ strategies score was 9.1 (SD = 12.2). Practices that participated in accountable care organizations and those that had someone in the practice to configure clinical quality reports from electronic health records (EHRs), had produced quality reports, or had discussed clinical quality data during meetings had higher CPCQ strategies scores. Health system-owned practices and those experiencing major disruptive changes, such as implementing a new EHR system or clinician turnover, had lower CPCQ strategies scores. CONCLUSION: There is substantial variation in the use of QI strategies among small to medium-size primary care practices across 12 US states. Findings suggest that practices may need external support to strengthen their ability to do QI and to be prepared for new payment and delivery models. PMID- 29632226 TI - The Alarming Rate of Major Disruptive Events in Primary Care Practices in Oklahoma. AB - PURPOSE: In primary care practices, sustainability of performance improvements and ability to deliver continuity of care to patients can be adversely affected by major disruptive events, such as relocations and changes in ownership, clinicians, and key staff. This study documented the rates of major disruptive events in a cohort of primary care practices in Oklahoma. METHODS: Practices were included if they had existed for 1 year before enrollment and remained in the project for at least 1 year after enrollment. Practice characteristics for 208 practices and major disruptive events during the preenrollment year were collected by survey. Postenrollment major disruptive events were prospectively collected by practice facilitators. We compiled frequency statistics and conducted bivariate analyses for each data set. RESULTS: Of 208 eligible practices, 81 (39%) were clinician owned, and 51 (25%) were health system owned. One hundred nine practices (52%) were in nonmetropolitan counties. One hundred seventy-five major disruptive events occurred in 120 (58%) practices during the preenrollment year, with 42 practices having experienced multiple events. During the first year of the project, 89 major disruptive events occurred in 67 (32%) practices, with 20 practices experiencing multiple events. The major disruptive events reported most often during both periods were loss of personnel and implementation of electronic health records and billing systems. Practice size was associated with occurrence of these events. CONCLUSIONS: During a 2-year period, major disruptive events occurred at an alarming rate, adversely affecting quality improvement efforts. Most reported events involved losses of clinicians and staff. More research is needed to identify and address the root causes of these events. PMID- 29632227 TI - A Community Engagement Method to Design Patient Engagement Materials for Cardiovascular Health. AB - PURPOSE: EvidenceNOW Southwest is a cluster-randomized trial evaluating the differential impact on cardiovascular disease (CVD) care of engaging patients and communities in practice transformation in addition to standard practice facilitation support. The trial included development of locally tailored CVD patient engagement materials through Boot Camp Translation (BCT), a community engagement process that occurred before practice recruitment but after cluster randomization. METHODS: We introduce a cluster randomization method performed before recruitment of small to medium-size primary care practices in Colorado and New Mexico, which allowed for balanced study arms while minimizing contamination. Engagement materials for the enhanced study arm were developed by means of BCT, which included community members, practice members, and public health professionals from (1) metropolitan Denver, (2) rural northeast Colorado, (3) Albuquerque, and (4) rural southeast New Mexico. Outcome measures were messages and materials from BCTs and population characteristics of study arms after using geographic-based covariate constrained randomization. RESULTS: The 4 BCTs' messages and materials developed by the BCT groups uniquely reflected each community and ranged from family or spiritual values to early prevention or adding relevance to CVD risk. The geographic-based covariate of a cluster randomization method constrained randomization-assigned regions to study arms, allowing BCTs to precede practice recruitment, reduce contamination, and balance populations. CONCLUSIONS: Cluster-randomized trials with community-based interventions present study design and implementation challenges. The BCTs elicited unique contextual messages and materials, suggesting that interventions designed to help primary care practices decrease CVD risk may not be one size fits all. PMID- 29632228 TI - Practice Facilitators' and Leaders' Perspectives on a Facilitated Quality Improvement Program. AB - PURPOSE: Practice facilitation is a promising approach to helping practices implement quality improvements. Our purpose was to describe practice facilitators' and practice leaders' perspectives on implementation of a practice facilitator-supported quality improvement program and describe where their perspectives aligned and diverged. METHODS: We conducted interviews with practice leaders and practice facilitators who participated in a program that included 35 improvement strategies aimed at the ABCS of heart health (aspirin use in high risk individuals, blood pressure control, cholesterol management, and smoking cessation). Rapid qualitative analysis was used to collect, organize, and analyze the data. RESULTS: We interviewed 17 of the 33 eligible practice leaders, and the 10 practice facilitators assigned to those practices. Practice leaders and practice facilitators both reported value in the program's ability to bring needed, high-quality resources to practices. Practice leaders appreciated being able to set the schedule for facilitation and select among the 35 interventions. According to practice facilitators, however, relying on practice leaders to set the pace of the intervention resulted in a lower level of program intensity than intended. Practice leaders preferred targeted assistance, particularly electronic health record documentation guidance and linkages to state smoking cessation programs. Practice facilitators reported that the easiest interventions were those that did not alter care practices. CONCLUSIONS: The dual perspectives of practice leaders and practice facilitators provide a more holistic picture of enablers and barriers to program implementation. There may be greater opportunities to assist small practices through simple, targeted practice facilitator-supported efforts rather than larger, comprehensive quality improvement projects. PMID- 29632229 TI - Engaging Primary Care Practices in Studies of Improvement: Did You Budget Enough for Practice Recruitment? AB - PURPOSE: The methods and costs to enroll small primary care practices in large, regional quality improvement initiatives are unknown. We describe the recruitment approach, cost, and resources required to recruit and enroll 500 practices in the Northwest and Midwest regional cooperatives participating in the Agency for Healthcare Research and Quality (AHRQ)-funded initiative, EvidenceNOW: Advancing Heart Health in Primary Care. METHODS: The project management team of each cooperative tracked data on recruitment methods used for identifying and connecting with practices. We developed a cost-of-recruitment template and used it to record personnel time and associated costs of travel and communication materials. RESULTS: A total of 3,669 practices were contacted during the 14- to 18-month recruitment period, resulting in 484 enrolled practices across the 6 states served by the 2 cooperatives. The average number of interactions per enrolled practice was 7, with a total of 29,100 hours and a total cost of $2.675 million, or $5,529 per enrolled practice. Prior partnerships predicted recruiting almost 1 in 3 of these practices as contrasted to 1 in 20 practices without a previous relationship or warm hand-off. CONCLUSIONS: Recruitment of practices for large-scale practice quality improvement transformation initiatives is difficult and costly. The cost of recruiting practices without existing partnerships is expensive, costing 7 times more than reaching out to familiar practices. Investigators initiating and studying practice quality improvement initiatives should budget adequate funds to support high-touch recruitment strategies, including building trusted relationships over a long time frame, for a year or more. PMID- 29632230 TI - Disruption is the Norm. PMID- 29632231 TI - Do wild-caught urban house sparrows show desensitized stress responses to a novel stressor? AB - While urbanization exposes individuals to novel challenges, urban areas may also constitute stable environments in which seasonal fluctuations are buffered. Baseline and stress-induced plasma corticosterone (cort) levels are often found to be similar in urban and rural populations. Here we aimed to disentangle two possible mechanisms underlying such pattern: (i) urban environments are no more stressful or urban birds have a better ability to habituate to stressors; or (ii) urban birds developed desensitized stress responses. We exposed wild-caught urban and rural house sparrows (Passer domesticus) to combined captivity and diet treatments (urban versus rural diet) and measured corticosterone levels both in natural tail feathers and in regrown homologous ones (cortf). Urban and rural house sparrows showed similar cortf levels in the wild and in response to novel stressors caused by the experiment, supporting the growing notion that urban environments are no more stressful during the non-breeding season than are rural ones. Still, juveniles and males originating from urban populations showed the highest cortf levels in regrown feathers. We did not find evidence that cortf was consistent within individuals across moults. Our study stresses the need for incorporating both intrinsic and environmental factors for the interpretation of variation in cortf between populations. PMID- 29632232 TI - Correction for Sharadamma et al., "Defining the Functionally Important Domain and Amino Acid Residues in Mycobacterium tuberculosis Integration Host Factor for Genome Stability, DNA Binding, and Integrative Recombination". PMID- 29632233 TI - Workforce planners need data on NHS usage, say royal colleges. PMID- 29632234 TI - Risk of recurrent venous thromboembolism according to baseline risk factor profiles. AB - The optimal duration of anticoagulation for venous thromboembolism (VTE) is uncertain. In this prespecified analysis, we used data from 2 randomized trials, which compared once-daily rivaroxaban (20 mg or 10 mg) with aspirin (100 mg) or placebo for extended VTE treatment to estimate the risk of recurrence according to baseline risk factor profiles. Index VTE events were centrally classified as unprovoked, or provoked by major transient or persistent, or minor transient or persistent risk factors, and rates of recurrence at 1 year were calculated. A total of 2832 patients received rivaroxaban; 1131 received aspirin, and 590 received placebo. With unprovoked VTE, rates of recurrence in the 1173 patients given rivaroxaban, the 468 given aspirin, and the 243 given placebo were 2.0%, 5.9%, and 10.0%, respectively. There were no recurrences in patients with VTE provoked by major transient risk factors. With VTE provoked by minor persistent risk factors, recurrence rates in the 1184 patients given rivaroxaban, the 466 given aspirin, and the 248 given placebo were 2.4%, 4.5%, and 10.7%, respectively. For patients with minor transient risk factors, recurrence rates were 0.4% in the 268 patients given rivaroxaban, 4.2% in the 121 given aspirin, and 7.1% in the 56 given placebo. Recurrence rates in patients with VTE provoked by minor persistent or minor transient risk factors were not significantly lower than that with unprovoked VTE (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.56-1.16; and HR, 0.68; 95% CI, 0.32-1.30, respectively). Therefore, such patients may also benefit from extended anticoagulation therapy. PMID- 29632235 TI - Defective RAB1B-related megakaryocytic ER-to-Golgi transport in RUNX1 haplodeficiency: impact on von Willebrand factor. AB - Patients with RUNX1 haplodeficiency have thrombocytopenia, platelet dysfunction, and deficiencies of alpha-granules and dense granules. Platelet expression profiling of a patient with a heterozygous RUNX1 mutation (c.969-323G>T) revealed decreased RAB1B, which encodes a small G protein. RAB GTPases regulate vesicle trafficking, and RAB1B is implicated in endoplasmic reticulum (ER)-to-Golgi transport in nonhematopoietic cells, but its role in megakaryocytes (MK) is unknown. We addressed the hypothesis that RAB1B is a transcriptional target of RUNX1 and that RAB1B regulates ER-to-Golgi transport in MK cells. Chromatin immunoprecipitation studies and electrophoretic mobility shift assay using phorbol 12-myristate 13-acetate (PMA)-treated human erythroleukemia cells revealed RUNX1 binding to RAB1B promoter region RUNX1 consensus sites, and their mutation reduced the promoter activity. RAB1B promoter activity and protein expression were inhibited by RUNX1 siRNA and enhanced by RUNX1 overexpression. These indicate that RAB1B is a direct RUNX1 target, providing a mechanism for decreased RAB1B in patient platelets. Vesicle trafficking from ER to Golgi in PMA treated human erythroleukemia cells was impaired along with Golgi disruption on siRNA downregulation of RUNX1 or RAB1B. The effects of RUNX1 knockdown were reversed by RAB1B reconstitution. Trafficking of von Willebrand factor (vWF), an alpha-granule MK synthesized protein, was impaired with RUNX1 or RAB1B downregulation and reconstituted by ectopic RAB1B expression. Platelet vWF was decreased in patients with RUNX1 mutations. Thus, ER-to-Golgi transport, an early critical step in protein trafficking to granules, is impaired in megakaryocytic cells on RUNX1 downregulation, secondary to decreased RAB1B expression. Impaired RAB1B mediated ER-to-Golgi transport contributes to platelet alpha-granule defects in RUNX1 haplodeficiency. PMID- 29632236 TI - Anti-inflammatory Properties of Cannabidiol, a Nonpsychotropic Cannabinoid, in Experimental Allergic Contact Dermatitis. AB - Phytocannabinoids modulate inflammatory responses by regulating the production of cytokines in several experimental models of inflammation. Cannabinoid type-2 (CB2) receptor activation was shown to reduce the production of the monocyte chemotactic protein-2 (MCP-2) chemokine in polyinosinic-polycytidylic acid [poly (I:C)]-stimulated human keratinocyte (HaCaT) cells, an in vitro model of allergic contact dermatitis (ACD). We investigated if nonpsychotropic cannabinoids, such as cannabidiol (CBD), produced similar effects in this experimental model of ACD. HaCaT cells were stimulated with poly-(I:C), and the release of chemokines and cytokines was measured in the presence of CBD or other phytocannabinoids (such as cannabidiol acid, cannabidivarin, cannabidivarinic acid, cannabichromene, cannabigerol, cannabigerolic acid, cannabigevarin, tetrahydrocannabivarin, and tetrahydrocannabivarinic acid) and antagonists of CB1, CB2, or transient receptor potential vanilloid type-1 (TRPV1) receptors. HaCaT cell viability following phytocannabinoid treatment was also measured. The cellular levels of endocannabinoids [anandamide (AEA), 2-arachidonoylglycerol] and related molecules (palmitoylethanolamide, oleoylethanolamide) were quantified in poly-(I:C) stimulated HaCaT cells treated with CBD. We show that in poly-(I:C)-stimulated HaCaT cells, CBD elevates the levels of AEA and dose-dependently inhibits poly (I:C)-induced release of MCP-2, interleukin-6 (IL-6), IL-8, and tumor necrosis factor-alpha in a manner reversed by CB2 and TRPV1 antagonists 6-iodopravadoline (AM630) and 5'-iodio-resiniferatoxin (I-RTX), respectively, with no cytotoxic effect. This is the first demonstration of the anti-inflammatory properties of CBD in an experimental model of ACD. PMID- 29632238 TI - Incidence, Predictors, and Outcomes of Acquired Thrombocytopenia After Percutaneous Coronary Intervention: A Pooled, Patient-Level Analysis of the CHAMPION Trials (Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition). AB - BACKGROUND: The influence of cangrelor on the incidence and outcomes of post percutaneous coronary intervention (PCI) thrombocytopenia is not defined. We aimed to explore the incidence, predictors, and clinical impact of thrombocytopenia after PCI in cangrelor-treated patients. METHODS AND RESULTS: This was a pooled, patient-level analysis of the CHAMPION trials (Cangrelor Versus Standard Therapy to Achieve Optimal Management of Platelet Inhibition), which compared cangrelor with clopidogrel for prevention of thrombotic complications during and after PCI. Acquired thrombocytopenia was defined as either a drop in platelet count to <100 000 after PCI or a drop of >50% between baseline and a follow-up. The main efficacy outcome was major adverse cardiac events. The primary safety outcome was noncoronary artery bypass grafting-related Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries-defined severe bleeding at 48 hours. Patients (23 783) were enrolled, and 3009 (12.7%) received a GPI (glycoprotein IIb/IIIa inhibitor). Acquired thrombocytopenia occurred in 200 patients (0.8%). The adjusted rate of major adverse cardiovascular events at 48 hours was significantly higher in patients who developed thrombocytopenia compared with those who did not (odds ratio, 3.00; 95% confidence interval, 1.89-4.69; P<0.001), as was major bleeding (odds ratio, 14.71; 95% confidence interval, 5.96-36.30; P<0.001). GPI use was the strongest independent predictor of acquired thrombocytopenia (odds ratio, 2.93; 95% confidence interval, 2.15-3.97; P<0.0001). There was no difference in the rate of acquired thrombocytopenia in patients randomized to cangrelor or clopidogrel. CONCLUSIONS: Acquired thrombocytopenia after PCI is strongly associated with substantial early morbidity and mortality, as well as major bleeding. GPI use is a significant predictor of thrombocytopenia. Cangrelor is not associated with acquired thrombocytopenia, and its clinical efficacy and safety is consistent irrespective of thrombocytopenia occurrence. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifiers: NCT00305162, NCT00385138, and NCT01156571. PMID- 29632239 TI - Hobson's Choice: Platelet Inhibition and Thrombocytopenia. PMID- 29632240 TI - Acute HSF1 depletion induces cellular senescence through the MDM2-p53-p21 pathway in human diploid fibroblasts. AB - Heat shock transcription factor 1 (HSF1) regulates the expression of a wide array of genes, controls the expression of heat shock proteins (HSPs) as well as cell growth. Although acute depletion of HSF1 induces cellular senescence, the underlying mechanisms are poorly understood. Here, we report that HSF1 depletion induced senescence (HDIS) of human diploid fibroblasts (HDFs) was independent of HSP-mediated proteostasis but dependent on activation of the p53-p21 pathway, partly because of the increased expression of dehydrogenase/reductase 2 (DHRS2), a putative MDM2 inhibitor. We observed that HDIS occurred without decreased levels of major HSPs or increased proteotoxic stress in HDFs. Additionally, VER155008, an inhibitor of HSP70 family proteins, increased proteotoxicity and suppressed cell growth but failed to induce senescence. Importantly, we found that activation of the p53-p21 pathway resulting from reduced MDM2-dependent p53 degradation was required for HDIS. Furthermore, we provide evidence that increased DHRS2 expression contributes to p53 stabilization and HDIS. Collectively, our observations uncovered a molecular pathway in which HSF1 depletion-induced DHRS2 expression leads to activation of the MDM2-p53-p21 pathway required for HDIS. PMID- 29632237 TI - Network-Based Analysis of Bortezomib Pharmacodynamic Heterogeneity in Multiple Myeloma Cells. AB - The objective of this study is to evaluate the heterogeneity in pharmacodynamic response in four in vitro multiple myeloma cell lines to treatment with bortezomib, and to assess whether such differences are associated with drug induced intracellular signaling protein dynamics identified via a logic-based network modeling approach. The in vitro pharmacodynamic-efficacy of bortezomib was evaluated through concentration-effect and cell proliferation dynamical studies in U266, RPMI8226, MM.1S, and NCI-H929 myeloma cell lines. A Boolean logic-based network model incorporating intracellular protein signaling pathways relevant to myeloma cell growth, proliferation, and apoptosis was developed based on information available in the literature and used to identify key proteins regulating bortezomib pharmacodynamics. The time-course of network-identified proteins was measured using the MAGPIX protein assay system. Traditional pharmacodynamic modeling endpoints revealed variable responses of the cell lines to bortezomib treatment, classifying cell lines as more sensitive (MM.1S and NCI H929) and less sensitive (U266 and RPMI8226). Network centrality and model reduction identified key proteins (e.g., phosphorylated nuclear factor-kappaB, phosphorylated protein kinase B, phosphorylated mechanistic target of rapamycin, Bcl-2, phosphorylated c-Jun N-terminal kinase, phosphorylated p53, p21, phosphorylated Bcl-2-associated death promoter, caspase 8, and caspase 9) that govern bortezomib pharmacodynamics. The corresponding relative expression (normalized to 0-hour untreated-control cells) of proteins demonstrated a greater magnitude and earlier onset of stimulation/inhibition in cells more sensitive (MM.1S and NCI-H929) to bortezomib-induced cell death at 20 nM, relative to the less sensitive cells (U266 and RPMI8226). Overall, differences in intracellular signaling appear to be associated with bortezomib pharmacodynamic heterogeneity, and key proteins may be potential biomarkers to evaluate bortezomib responses. PMID- 29632241 TI - A fragment of adhesion molecule L1 is imported into mitochondria, and regulates mitochondrial metabolism and trafficking. AB - The cell adhesion molecule L1 (also known as L1CAM) plays important roles in the mammalian nervous system under physiological and pathological conditions. We have previously reported that proteolytic cleavage of L1 by myelin basic protein leads to the generation of a 70 kDa transmembrane L1 fragment (L1-70) that promotes neuronal migration and neuritogenesis. Here, we provide evidence that L1-70 is imported from the cytoplasm into mitochondria. Genetic ablation of L1, inhibition of mitochondrial import of L1-70 or prevention of myelin basic protein-mediated generation of L1-70 all lead to reduced mitochondrial complex I activity, and impaired mitochondrial membrane potential, fusion, fission and motility, as well as increased retrograde transport. We identified NADH dehydrogenase ubiquinone flavoprotein 2 as a binding partner for L1, suggesting that L1-70 interacts with this complex I subunit to regulate complex I activity. The results of our study provide insights into novel functions of L1 in mitochondrial metabolism and cellular dynamics. These functions are likely to ameliorate the consequences of acute nervous system injuries and chronic neurodegenerative diseases. PMID- 29632242 TI - Congress Gives NIH $3 Billion Increase. AB - The federal budget for fiscal year 2018 includes $3 billion in increased funding for the NIH and $275 million for the NCI. This boost in funding will allow the NCI to fund more cancer research at institutions across the country. In addition, this support for the NIH sends a strong message to future scientists that cancer research is a promising field. PMID- 29632243 TI - Disentangling the molecular determinants for Cenp-F localization to nuclear pores and kinetochores. AB - Cenp-F is a multifaceted protein implicated in cancer and developmental pathologies. The Cenp-F C-terminal region contains overlapping binding sites for numerous proteins that contribute to its functions throughout the cell cycle. Here, we focus on the nuclear pore protein Nup133 that interacts with Cenp-F both at nuclear pores in prophase and at kinetochores in mitosis, and on the kinase Bub1, known to contribute to Cenp-F targeting to kinetochores. By combining in silico structural modeling and yeast two-hybrid assays, we generate an interaction model between a conserved helix within the Nup133 beta-propeller and a short leucine zipper-containing dimeric segment of Cenp-F. We thereby create mutants affecting the Nup133/Cenp-F interface and show that they prevent Cenp-F localization to the nuclear envelope, but not to kinetochores. Conversely, a point mutation within an adjacent leucine zipper affecting the kinetochore targeting of Cenp-F KT-core domain impairs its interaction with Bub1, but not with Nup133, identifying Bub1 as the direct KT-core binding partner of Cenp-F. Finally, we show that Cenp-E redundantly contributes together with Bub1 to the recruitment of Cenp-F to kinetochores. PMID- 29632245 TI - Adipocyte Model of Mycobacterium tuberculosis Infection Reveals Differential Availability of Iron to Bacilli in the Lipid-Rich Caseous Environment. AB - Mycobacterium tuberculosis, a successful human pathogen, utilizes multiple carbon sources from the host but adapts to a fatty-acid-rich environment in vivo We sought to delineate the physiologic response of M. tuberculosis to a lipid-rich environment by using differentiated adipocytes as a model system. Global transcriptome profiling based on RNA sequencing was performed for bacilli from infected adipocytes and preadipocytes. Genes involved in de novo fatty acid synthesis were downregulated, while those predicted to be involved in triglyceride biosynthesis were upregulated, in bacilli isolated from adipocytes, indicating reliance on host-derived fatty acids. Transcription factor network analysis indicated suppression of IdeR-regulated genes, suggesting decreased iron uptake by M. tuberculosis in the adipocyte model. This suppression of iron uptake coincided with higher ferritin and iron levels in adipocytes than in preadipocytes. In accord with the role of iron in mediating oxidative stress, we observed upregulation of genes involved in mitigating oxidative stress in M. tuberculosis isolated from adipocytes. We provide evidence that oleic acid, a major host-derived fatty acid, helps reduce the bacterial cytoplasm, thereby providing a safe haven for an M. tuberculosis mutant that is sensitive to iron mediated oxidative stress. Via an independent mechanism, host ferritin is also able to rescue the growth of this mutant. Our work highlights the inherent synergy between macronutrients and micronutrients of the host environment that converge to provide resilience to the pathogen. This complex synergy afforded by the adipocyte model of infection will aid in the identification of genes required by M. tuberculosis in a caseous host environment. PMID- 29632246 TI - Heightened Systemic Levels of Neutrophil and Eosinophil Granular Proteins in Pulmonary Tuberculosis and Reversal following Treatment. AB - Granulocytes are activated during Mycobacterium tuberculosis infection and act as immune effector cells, and granulocyte responses are implicated in tuberculosis (TB) pathogenesis. Plasma levels of neutrophil and eosinophil granular proteins provide an indirect measure of degranulation. In this study, we wanted to examine the levels of neutrophil and eosinophil granular proteins in individuals with pulmonary tuberculosis (PTB) and to compare them with the levels in individuals with latent TB (LTB). Hence, we measured the plasma levels of myeloperoxidase (MPO), neutrophil elastase, proteinase 3, major basic protein (MBP), eosinophil derived neurotoxin (EDN), eosinophil cationic protein (ECP), and eosinophil peroxidase (EPX) in these individuals. Finally, we also measured the levels of all of these proteins in PTB individuals following antituberculosis treatment (ATT). Our data reveal that PTB individuals are characterized by significantly higher plasma levels of MPO, elastase, proteinase 3, as well as MBP and EDN in comparison to those in LTB individuals. Our data also reveal that ATT resulted in the reversal of all of these changes, indicating an association with TB disease. Finally, our data show that the systemic levels of MPO and proteinase 3 can significantly discriminate PTB from LTB individuals. Thus, our data suggest that neutrophil and eosinophil granular proteins could play a potential role in the innate immune response and, therefore, the pathogenesis of pulmonary TB. PMID- 29632244 TI - Cross-talk between monocyte invasion and astrocyte proliferation regulates scarring in brain injury. AB - Scar formation after brain injury is still poorly understood. To further elucidate such processes, here, we examine the interplay between astrocyte proliferation taking place predominantly at the vascular interface and monocyte invasion. Using genetic mouse models that decrease or increase reactive astrocyte proliferation, we demonstrate inverse effects on monocyte numbers in the injury site. Conversely, reducing monocyte invasion using CCR2-/- mice causes a strong increase in astrocyte proliferation, demonstrating an intriguing negative cross regulation between these cell types at the vascular interface. CCR2-/- mice show reduced scar formation with less extracellular matrix deposition, smaller lesion site and increased neuronal coverage. Surprisingly, the GFAP+ scar area in these mice is also significantly decreased despite increased astrocyte proliferation. Proteomic analysis at the peak of increased astrocyte proliferation reveals a decrease in extracellular matrix synthesizing enzymes in the injury sites of CCR2 /- mice, highlighting how early key aspects of scar formation are initiated. Taken together, we provide novel insights into the cross-regulation of juxtavascular proliferating astrocytes and invading monocytes as a crucial mechanism of scar formation upon brain injury. PMID- 29632247 TI - MicroRNA-216a Inhibits NF-kappaB-Mediated Inflammatory Cytokine Production in Teleost Fish by Modulating p65. AB - Inflammation is the host self-protection mechanism to eliminate pathogen invasion. The excessive inflammatory response can result in uncontrolled inflammation, autoimmune diseases, or pathogen dissemination. Recent studies have widely shown that microRNAs (miRNAs) contribute to the regulation of inflammation in mammals by repressing gene expression at the posttranscriptional level. However, the miRNA-mediated mechanism in the inflammatory response in fish remains hazy. In the present study, the regulatory mechanism of the miR-216a mediated inflammatory response in teleost fish was addressed. We found that the expression of miR-216a could be significantly upregulated in the miiuy croaker after challenge with Vibrio anguillarum and lipopolysaccharide. Bioinformatics predictions demonstrated a potential binding site of miR-216a in the 3' untranslated region of the p65 gene, and the result was further confirmed by luciferase assay. Moreover, both the mRNA and protein levels of p65 in macrophages were downregulated by miR-216a. Deletion mutant analysis of the miR 216a promoter showed that the Ap1 and Sp1 transcription factor binding sites are indispensable for the transcription of miR-216a. Further study revealed that overexpression of miR-216a suppresses inflammatory cytokine expression and negatively regulates NF-kappaB signaling, which inhibit an excessive inflammatory response. The collective results indicate that miR-216a plays a role as a negative regulator involved in modulating the bacterium-induced inflammatory response. PMID- 29632248 TI - Are Sphingolipids and Serine Dipeptide Lipids Underestimated Virulence Factors of Porphyromonas gingivalis? AB - The keystone periodontal pathogen Porphyromonas gingivalis produces phosphorylated dihydroceramide lipids (sphingolipids) such as phosphoethanolamine dihydroceramide (PE DHC) and phosphoglycerol dihydroceramide (PG DHC) lipids. Phosphorylated DHCs (PDHCs) from P. gingivalis can affect a number of mammalian cellular functions, such as potentiation of prostaglandin secretion from gingival fibroblasts, promotion of RANKL-induced osteoclastogenesis, promotion of apoptosis, and enhancement of autoimmunity. In P. gingivalis, these lipids affect anchoring of surface polysaccharides, resistance to oxidative stress, and presentation of surface polysaccharides (anionic polysaccharides and K-antigen capsule). In addition to phosphorylated dihydroceramide lipids, serine dipeptide lipids of P. gingivalis are implicated in alveolar bone loss in chronic periodontitis through interference with osteoblast differentiation and function and promotion of osteoclast activity. As a prerequisite for designation as bacterial virulence factors, bacterial sphingolipids and serine dipeptide lipids are recovered in gingival/periodontal tissues, tooth calculus, human blood, vascular tissues, and brain. In addition to P. gingivalis, other bacteria of the genera Bacteroides, Parabacteroides, Porphyromonas, Tannerella, and Prevotella produce sphingolipids and serine dipeptide lipids. The contribution of PDHCs and serine dipeptide lipids to the pathogenesis of periodontal and extraoral diseases may be an underappreciated area in microbe-host interaction and should be more intensively investigated. PMID- 29632250 TI - Comment on "Type I CD20 Antibodies Recruit the B Cell Receptor for Complement Dependent Lysis of Malignant B Cells". PMID- 29632249 TI - Clostridium difficile Toxoid Vaccine Candidate Confers Broad Protection against a Range of Prevalent Circulating Strains in a Nonclinical Setting. AB - Clostridium difficile infection (CDI) is a leading cause of nosocomial and antibiotic-associated diarrhea. A vaccine, based on formalin-inactivated toxins A and B purified from anaerobic cultures of C. difficile strain VPI 10463 (toxinotype 0), has been in development for the prevention of symptomatic CDI. We evaluated the breadth of protection conferred by this C. difficile toxoid vaccine in cross-neutralization assessments using sera from vaccinated hamsters against a collection of 165 clinical isolates. Hamster antisera raised against the C. difficile toxoid vaccine neutralized the cytotoxic activity of culture supernatants from several toxinotype 0 strains and heterologous strains from 10 different toxinotypes. Further assessments performed with purified toxins confirmed that vaccine-elicited antibodies can neutralize both A and B toxins from a variety of toxinotypes. In the hamster challenge model, the vaccine conferred significant cross-protection against disease symptoms and death caused by heterologous C. difficile strains from the most common phylogenetic clades, including the most prevalent toxinotypes. PMID- 29632251 TI - Response to Comment on "Type I CD20 Antibodies Recruit the B Cell Receptor for Complement-Dependent Lysis of Malignant B Cells". PMID- 29632252 TI - The Impact of Maternal Microbes and Microbial Colonization in Early Life on Hematopoiesis. AB - All body surfaces are colonized by microbes, which occurs through a dynamic process over the first few years of life. Initial colonizing microbes are transferred from the maternal microbiota to the newborn through vertical transmission. Postnatal maturation of the immune system is heavily influenced by these microbes, particularly during early life. Although microbial-mediated education of the immune system is better understood at mucosal sites, recent data indicate that the systemic immune system is also shaped by the microbiota. Bacterial products and metabolites produced through microbial metabolism can reach distal sites, and metabolites derived from the maternal microbiota can cross the placenta and are present in milk. Recent studies show that the microbiota can even influence immune development in primary lymphoid organs like the bone marrow. This review outlines our current knowledge of how the microbiota can impact hematopoiesis, with a focus on the effects of maternal and early-life microbiota. PMID- 29632253 TI - Developmental Trajectory of Language From 2 to 13 Years in Children Born Very Preterm. AB - OBJECTIVES: The objective of this study was to describe language functioning at 13 years of age and examine its developmental trajectory from 2 to 13 years of age in children born very preterm (VP) compared with term controls. METHODS: Two hundred and twenty-four children born VP (<30 weeks' gestation) and 77 term controls had language skills assessed by using performance-based and/or parent report measures at 2, 5, 7, and 13 years of age. Regression models were used to compare verbal memory, grammar, semantics, and pragmatic skills between the VP and term groups at 13 years of age. Linear mixed effects regression models were used to assess language trajectories from 2 to 13 years of age. RESULTS: Compared with term controls, children born VP had poorer functioning across all components of language (mean group differences ranged from -0.5 SD to -1 SD; all P < .05) at 13 years of age. At each follow-up age, the VP group displayed poorer language functioning than the term controls, with the groups exhibiting similar developmental trajectories (slope difference = -0.01 SD per year; P = .55). CONCLUSIONS: Children born VP continue to display language difficulties compared with term controls at 13 years of age, with no evidence of developmental "catch up." Given the functional implications associated with language deficits, early language-based interventions should be considered for children born VP. PMID- 29632255 TI - Early Childhood Behavioral Health: Can the Medical Neighborhood Move Us Forward? PMID- 29632254 TI - Reading Aloud, Play, and Social-Emotional Development. AB - OBJECTIVES: To determine impacts on social-emotional development at school entry of a pediatric primary care intervention (Video Interaction Project [VIP]) promoting positive parenting through reading aloud and play, delivered in 2 phases: infant through toddler (VIP birth to 3 years [VIP 0-3]) and preschool-age (VIP 3 to 5 years [VIP 3-5]). METHODS: Factorial randomized controlled trial with postpartum enrollment and random assignment to VIP 0-3, control 0 to 3 years, and a third group without school entry follow-up (Building Blocks) and 3-year second random assignment of VIP 0-3 and control 0 to 3 years to VIP 3-5 or control 3 to 5 years. In the VIP, a bilingual facilitator video recorded the parent and child reading and/or playing using provided learning materials and reviewed videos to reinforce positive interactions. Social-emotional development at 4.5 years was assessed by parent-report Behavior Assessment System for Children, Second Edition (Social Skills, Attention Problems, Hyperactivity, Aggression, Externalizing Problems). RESULTS: VIP 0-3 and VIP 3-5 were independently associated with improved 4.5-year Behavior Assessment System for Children, Second Edition T scores, with effect sizes (Cohen's d) ~-0.25 to -0.30. Receipt of combined VIP 0 3 and VIP 3-5 was associated with d = -0.63 reduction in Hyperactivity (P = .001). VIP 0-3 resulted in reduced "Clinically Significant" Hyperactivity (relative risk reduction for overall sample: 69.2%; P = .03; relative risk reduction for increased psychosocial risk: 100%; P = .006). Multilevel models revealed significant VIP 0-3 linear effects and age * VIP 3-5 interactions. CONCLUSIONS: Phase VIP 0-3 resulted in sustained impacts on behavior problems 1.5 years after program completion. VIP 3-5 had additional, independent impacts. With our findings, we support the use of pediatric primary care to promote reading aloud and play from birth to 5 years, and the potential for such programs to enhance social-emotional development. PMID- 29632256 TI - Preventive Behavioral Health Programs in Primary Care: A Systematic Review. AB - CONTEXT: Early childhood is a critical period for socioemotional development. Primary care is a promising setting for behavioral health programs. OBJECTIVES: To identify gaps in the literature on effectiveness and readiness for scale-up of behavioral health programs in primary care. DATA SOURCES: PubMed, PsycINFO, Cumulative Index to Nursing and Allied Health Literature, Embase, Evidence-Based Medicine Reviews, and Scopus databases were searched for articles published in English in the past 15 years. Search terms included terms to describe intervention content, setting, target population, and names of specific programs known to fit inclusion criteria. STUDY SELECTION: Inclusion criteria were: (1) enrolled children 0 to 5 years old, (2) primary care setting, (3) measured parenting or child behavior outcomes, and (4) clinical trial, quasi-experimental trial, pilot study, or pre-post design. DATA EXTRACTION: Data were abstracted from 44 studies. The rigor of individual studies and evidence base as a whole were compared with the Society of Prevention Research's standards for efficacy, effectiveness, and scale-up research. RESULTS: Gaps in the literature include: study findings do not always support hypotheses about interventions' mechanisms, trust in primary care as a mediator has not been sufficiently studied, it is unclear to which target populations study findings can be applied, parent participation remains an important challenge, and the long-term impact requires further evaluation. LIMITATIONS: Potential limitations include publication bias, selective reporting within studies, and an incomplete search. CONCLUSIONS: Targeting gaps in the literature could enhance understanding of the efficacy, effectiveness, and readiness for scale-up of these programs. PMID- 29632257 TI - Self-organization: the fundament of cell biology. AB - Self-organization refers to the emergence of an overall order in time and space of a given system that results from the collective interactions of its individual components. This concept has been widely recognized as a core principle in pattern formation for multi-component systems of the physical, chemical and biological world. It can be distinguished from self-assembly by the constant input of energy required to maintain order-and self-organization therefore typically occurs in non-equilibrium or dissipative systems. Cells, with their constant energy consumption and myriads of local interactions between distinct proteins, lipids, carbohydrates and nucleic acids, represent the perfect playground for self-organization. It therefore comes as no surprise that many properties and features of self-organized systems, such as spontaneous formation of patterns, nonlinear coupling of reactions, bi-stable switches, waves and oscillations, are found in all aspects of modern cell biology. Ultimately, self organization lies at the heart of the robustness and adaptability found in cellular and organismal organization, and hence constitutes a fundamental basis for natural selection and evolution.This article is part of the theme issue 'Self organization in cell biology'. PMID- 29632258 TI - Reverse and forward engineering of protein pattern formation. AB - Living systems employ protein pattern formation to regulate important life processes in space and time. Although pattern-forming protein networks have been identified in various prokaryotes and eukaryotes, their systematic experimental characterization is challenging owing to the complex environment of living cells. In turn, cell-free systems are ideally suited for this goal, as they offer defined molecular environments that can be precisely controlled and manipulated. Towards revealing the molecular basis of protein pattern formation, we outline two complementary approaches: the biochemical reverse engineering of reconstituted networks and the de novo design, or forward engineering, of artificial self-organizing systems. We first illustrate the reverse engineering approach by the example of the Escherichia coli Min system, a model system for protein self-organization based on the reversible and energy-dependent interaction of the ATPase MinD and its activating protein MinE with a lipid membrane. By reconstituting MinE mutants impaired in ATPase stimulation, we demonstrate how large-scale Min protein patterns are modulated by MinE activity and concentration. We then provide a perspective on the de novo design of self organizing protein networks. Tightly integrated reverse and forward engineering approaches will be key to understanding and engineering the intriguing phenomenon of protein pattern formation.This article is part of the theme issue 'Self organization in cell biology'. PMID- 29632259 TI - Evolutionary trade-offs and the structure of polymorphisms. AB - Populations of organisms show genetic differences called polymorphisms. Understanding the effects of polymorphisms is important for biology and medicine. Here, we ask which polymorphisms occur at high frequency when organisms evolve under trade-offs between multiple tasks. Multiple tasks present a problem, because it is not possible to be optimal at all tasks simultaneously and hence compromises are necessary. Recent work indicates that trade-offs lead to a simple geometry of phenotypes in the space of traits: phenotypes fall on the Pareto front, which is shaped as a polytope: a line, triangle, tetrahedron etc. The vertices of these polytopes are the optimal phenotypes for a single task. Up to now, work on this Pareto approach has not considered its genetic underpinnings. Here, we address this by asking how the polymorphism structure of a population is affected by evolution under trade-offs. We simulate a multi-task selection scenario, in which the population evolves to the Pareto front: the line segment between two archetypes or the triangle between three archetypes. We find that polymorphisms that become prevalent in the population have pleiotropic phenotypic effects that align with the Pareto front. Similarly, epistatic effects between prevalent polymorphisms are parallel to the front. Alignment with the front occurs also for asexual mating. Alignment is reduced when drift or linkage is strong, and is replaced by a more complex structure in which many perpendicular allele effects cancel out. Aligned polymorphism structure allows mating to produce offspring that stand a good chance of being optimal multi-taskers in at least one of the locales available to the species.This article is part of the theme issue 'Self-organization in cell biology'. PMID- 29632260 TI - Emergence of evolutionary driving forces in pattern-forming microbial populations. AB - Evolutionary dynamics are controlled by a number of driving forces, such as natural selection, random genetic drift and dispersal. In this perspective article, we aim to emphasize that these forces act at the population level, and that it is a challenge to understand how they emerge from the stochastic and deterministic behaviour of individual cells. Even the most basic steric interactions between neighbouring cells can couple evolutionary outcomes of otherwise unrelated individuals, thereby weakening natural selection and enhancing random genetic drift. Using microbial examples of varying degrees of complexity, we demonstrate how strongly cell-cell interactions influence evolutionary dynamics, especially in pattern-forming systems. As pattern formation itself is subject to evolution, we propose to study the feedback between pattern formation and evolutionary dynamics, which could be key to predicting and potentially steering evolutionary processes. Such an effort requires extending the systems biology approach from the cellular to the population scale.This article is part of the theme issue 'Self-organization in cell biology'. PMID- 29632261 TI - Self-organization principles of intracellular pattern formation. AB - Dynamic patterning of specific proteins is essential for the spatio-temporal regulation of many important intracellular processes in prokaryotes, eukaryotes and multicellular organisms. The emergence of patterns generated by interactions of diffusing proteins is a paradigmatic example for self-organization. In this article, we review quantitative models for intracellular Min protein patterns in Escherichia coli, Cdc42 polarization in Saccharomyces cerevisiae and the bipolar PAR protein patterns found in Caenorhabditis elegans By analysing the molecular processes driving these systems we derive a theoretical perspective on general principles underlying self-organized pattern formation. We argue that intracellular pattern formation is not captured by concepts such as 'activators', 'inhibitors' or 'substrate depletion'. Instead, intracellular pattern formation is based on the redistribution of proteins by cytosolic diffusion, and the cycling of proteins between distinct conformational states. Therefore, mass conserving reaction-diffusion equations provide the most appropriate framework to study intracellular pattern formation. We conclude that directed transport, e.g. cytosolic diffusion along an actively maintained cytosolic gradient, is the key process underlying pattern formation. Thus the basic principle of self organization is the establishment and maintenance of directed transport by intracellular protein dynamics.This article is part of the theme issue 'Self organization in cell biology'. PMID- 29632262 TI - Discovery of functional interactions among actin regulators by analysis of image fluctuations in an unperturbed motile cell system. AB - Cell migration is driven by propulsive forces derived from polymerizing actin that pushes and extends the plasma membrane. The underlying actin network is constantly undergoing adaptation to new mechano-chemical environments and intracellular conditions. As such, mechanisms that regulate actin dynamics inherently contain multiple feedback loops and redundant pathways. Given the highly adaptable nature of such a system, studies that use only perturbation experiments (e.g. knockdowns, overexpression, pharmacological activation/inhibition, etc.) are challenged by the nonlinearity and redundancy of the pathway. In these pathway configurations, perturbation experiments at best describe the function(s) of a molecular component in an adapting (e.g. acutely drug-treated) or fully adapted (e.g. permanent gene silenced) cell system, where the targeted component now resides in a non-native equilibrium. Here, we propose how quantitative live-cell imaging and analysis of constitutive fluctuations of molecular activities can overcome these limitations. We highlight emerging actin filament barbed-end biology as a prime example of a complex, nonlinear molecular process that requires a fluctuation analytic approach, especially in an unperturbed cellular system, to decipher functional interactions of barbed-end regulators, actin polymerization and membrane protrusion.This article is part of the theme issue 'Self-organization in cell biology'. PMID- 29632264 TI - Fluid flows shaping organism morphology. AB - A dynamic self-organized morphology is the hallmark of network-shaped organisms like slime moulds and fungi. Organisms continuously reorganize their flexible, undifferentiated body plans to forage for food. Among these organisms the slime mould Physarum polycephalum has emerged as a model to investigate how an organism can self-organize their extensive networks and act as a coordinated whole. Cytoplasmic fluid flows flowing through the tubular networks have been identified as the key driver of morphological dynamics. Inquiring how fluid flows can shape living matter from small to large scales opens up many new avenues for research. This article is part of the theme issue 'Self-organization in cell biology'. PMID- 29632263 TI - The Min-protein oscillations in Escherichia coli: an example of self-organized cellular protein waves. AB - In the rod-shaped bacterium Escherichia coli, selection of the cell centre as the division site involves pole-to-pole oscillations of the proteins MinC, MinD and MinE. This spatio-temporal pattern emerges from interactions among the Min proteins and with the cytoplasmic membrane. Combining experimental studies in vivo and in vitro together with theoretical analysis has led to a fairly good understanding of Min-protein self-organization. In different geometries, the system can, in addition to standing waves, also produce travelling planar and spiral waves as well as coexisting stable stationary distributions. Today it stands as one of the best-studied examples of cellular self-organization of proteins.This article is part of the theme issue 'Self-organization in cell biology'. PMID- 29632265 TI - Self-organization across scales: from molecules to organisms. AB - Creating ordered structures from chaotic environments is at the core of biological processes at the subcellular, cellular and organismic level. In this perspective, we explore the physical as well as biological features of two prominent concepts driving self-organization, namely phase transition and reaction-diffusion, before closing with a discussion on open questions and future challenges associated with studying self-organizing systems.This article is part of the theme issue 'Self-organization in cell biology'. PMID- 29632266 TI - Ordering of myosin II filaments driven by mechanical forces: experiments and theory. AB - Myosin II filaments form ordered superstructures in both cross-striated muscle and non-muscle cells. In cross-striated muscle, myosin II (thick) filaments, actin (thin) filaments and elastic titin filaments comprise the stereotypical contractile units of muscles called sarcomeres. Linear chains of sarcomeres, called myofibrils, are aligned laterally in registry to form cross-striated muscle cells. The experimentally observed dependence of the registered organization of myofibrils on extracellular matrix elasticity has been proposed to arise from the interactions of sarcomeric contractile elements (considered as force dipoles) through the matrix. Non-muscle cells form small bipolar filaments built of less than 30 myosin II molecules. These filaments are associated in registry forming superstructures ('stacks') orthogonal to actin filament bundles. Formation of myosin II filament stacks requires the myosin II ATPase activity and function of the actin filament crosslinking, polymerizing and depolymerizing proteins. We propose that the myosin II filaments embedded into elastic, intervening actin network (IVN) function as force dipoles that interact attractively through the IVN. This is in analogy with the theoretical picture developed for myofibrils where the elastic medium is now the actin cytoskeleton itself. Myosin stack formation in non-muscle cells provides a novel mechanism for the self-organization of the actin cytoskeleton at the level of the entire cell.This article is part of the theme issue 'Self-organization in cell biology'. PMID- 29632267 TI - Guided by curvature: shaping cells by coupling curved membrane proteins and cytoskeletal forces. AB - Eukaryote cells have flexible membranes that allow them to have a variety of dynamical shapes. The shapes of the cells serve important biological functions, both for cells within an intact tissue, and during embryogenesis and cellular motility. How cells control their shapes and the structures that they form on their surface has been a subject of intensive biological research, exposing the building blocks that cells use to deform their membranes. These processes have also drawn the interest of theoretical physicists, aiming to develop models based on physics, chemistry and nonlinear dynamics. Such models explore quantitatively different possible mechanisms that the cells can employ to initiate the spontaneous formation of shapes and patterns on their membranes. We review here theoretical work where one such class of mechanisms was investigated: the coupling between curved membrane proteins, and the cytoskeletal forces that they recruit. Theory indicates that this coupling gives rise to a rich variety of membrane shapes and dynamics, while experiments indicate that this mechanism appears to drive many cellular shape changes.This article is part of the theme issue 'Self-organization in cell biology'. PMID- 29632268 TI - Rhythmicity and waves in the cortex of single cells. AB - Emergence of dynamic patterns in the form of oscillations and waves on the cortex of single cells is a fascinating and enigmatic phenomenon. Here we outline various theoretical frameworks used to model pattern formation with the goal of reducing complex, heterogeneous patterns into key parameters that are biologically tractable. We also review progress made in recent years on the quantitative and molecular definitions of these terms, which we believe have begun to transform single-cell dynamic patterns from a purely observational and descriptive subject to more mechanistic studies. Specifically, we focus on the nature of local excitable and oscillation events, their spatial couplings leading to propagating waves and the role of active membrane. Instead of arguing for their functional importance, we prefer to consider such patterns as basic properties of dynamic systems. We discuss how knowledge of these patterns could be used to dissect the structure of cellular organization and how the network centric view could help define cellular functions as transitions between different dynamical states. Last, we speculate on how these patterns could encode temporal and spatial information.This article is part of the theme issue 'Self organization in cell biology'. PMID- 29632269 TI - Lipid self-assembly and lectin-induced reorganization of the plasma membrane. AB - The plasma membrane represents an outstanding example of self-organization in biology. It plays a vital role in protecting the integrity of the cell interior and regulates meticulously the import and export of diverse substances. Its major building blocks are proteins and lipids, which self-assemble to a fluid lipid bilayer driven mainly by hydrophobic forces. Even if the plasma membrane appears globally speaking-homogeneous at physiological temperatures, the existence of specialized nano- to micrometre-sized domains of raft-type character within cellular and synthetic membrane systems has been reported. It is hypothesized that these domains are the origin of a plethora of cellular processes, such as signalling or vesicular trafficking. This review intends to highlight the driving forces of lipid self-assembly into a bilayer membrane and the formation of small, transient domains within the plasma membrane. The mechanisms of self-assembly depend on several factors, such as the lipid composition of the membrane and the geometry of lipids. Moreover, the dynamics and organization of glycosphingolipids into nanometre-sized clusters will be discussed, also in the context of multivalent lectins, which cluster several glycosphingolipid receptor molecules and thus create an asymmetric stress between the two membrane leaflets, leading to tubular plasma membrane invaginations.This article is part of the theme issue 'Self-organization in cell biology'. PMID- 29632270 TI - Joining forces: crosstalk between biochemical signalling and physical forces orchestrates cellular polarity and dynamics. AB - Dynamic processes like cell migration and morphogenesis emerge from the self organized interaction between signalling and cytoskeletal rearrangements. How are these molecular to sub-cellular scale processes integrated to enable cell-wide responses? A growing body of recent studies suggest that forces generated by cytoskeletal dynamics and motor activity at the cellular or tissue scale can organize processes ranging from cell movement, polarity and division to the coordination of responses across fields of cells. To do so, forces not only act mechanically but also engage with biochemical signalling. Here, we review recent advances in our understanding of this dynamic crosstalk between biochemical signalling, self-organized cortical actomyosin dynamics and physical forces with a special focus on the role of membrane tension in integrating cellular motility.This article is part of the theme issue 'Self-organization in cell biology'. PMID- 29632271 TI - Controlling compartmentalization by non-membrane-bound organelles. AB - Compartmentalization is a characterizing feature of complexity in cells, used to organize their biochemistry. Membrane-bound organelles are most widely known, but non-membrane-bound liquid organelles also exist. These have recently been shown to form by phase separation of specific types of proteins known as scaffolds. This forms two phases: a condensate that is enriched in scaffold protein separated by a phase boundary from the cytoplasm or nucleoplasm with a low concentration of the scaffold protein. Phase separation is well known for synthetic polymers, but also appears important in cells. Here, we review the properties of proteins important for forming these non-membrane-bound organelles, focusing on the energetically favourable interactions that drive condensation. On this basis we make qualitative predictions about how cells may control compartmentalization by condensates; the partition of specific molecules to a condensate; the control of condensation and dissolution of condensates; and the regulation of condensate nucleation. There are emerging data supporting many of these predictions, although future results may prove incorrect. It appears that many molecules may have the ability to modulate condensate formation, making condensates a potential target for future therapeutics. The emerging properties of condensates are fundamentally unlike the properties of membrane-bound organelles. They have the capacity to rapidly integrate cellular events and act as a new class of sensors for internal and external environments.This article is part of the theme issue 'Self-organization in cell biology'. PMID- 29632272 TI - Understanding breast cancer screening--past, present, and future. AB - This article provides an up-to-date overview of breast cancer mammography screening and briefly discusses its history, controversies, current guidelines, practices across Asia, and future directions. An emphasis is made on shared decision-making--instead of giving just a 'yes' or 'no' answer to patients, the focus should be on providing sufficient information about the pros and cons of screening to help women make a personal, informed choice. Frontline experts, including breast surgeons, oncologists, breast radiologists, and their representative professional associations should all participate in guideline panels, with the goal of improving cancer detection, reducing mortality, and improving patient outcome. PMID- 29632273 TI - Outcomes and morbidities of patients who survive haemoglobin Bart's hydrops fetalis syndrome: 20-year retrospective review. AB - INTRODUCTION: Haemoglobin Bart's hydrops fetalis syndrome was once considered a fatal condition. However, advances over the past two decades have enabled survival of affected patients. Data relating to their morbidities and outcomes will help medical specialists formulate a management plan and parental counselling. METHODS: All babies with the syndrome who survived beyond the neonatal period and were subsequently managed long-term in eight public hospitals in Hong Kong from 1 January 1996 to 31 December 2015 were included. Patient and parent characteristics, antenatal care, reasons for continuation of pregnancy, intrauterine interventions, perinatal course, presence of congenital malformations, stem-cell transplantation details, and long-term neurodevelopmental outcomes were reviewed. RESULTS: A total of nine patients were identified, of whom five were female and four male. The median follow-up duration was 7 years. All were Chinese and were homozygous for the Southeast Asian alpha thalassaemia deletion. Five of the nine mothers received antenatal care at a public hospital and opted to continue the pregnancy after antenatal diagnosis and counselling. Despite intrauterine transfusions, all babies were born with respiratory depression and required intubation and mechanical ventilation during the neonatal period. Hypospadias was identified in all four male infants. Growth retardation, global developmental delay, and residual neurological deficits were noted in two-thirds of the patients. Haematopoietic stem-cell transplantation was performed in two patients, who became transfusion-independent. CONCLUSIONS: Survival of patients with Bart's hydrops fetalis syndrome is possible but not without short- and long-term complications; local epidemiology is comparable to that documented for an international registry. Detailed antenatal counselling of parents with a non-judgemental attitude and cautious optimism are imperative. PMID- 29632274 TI - Reduction of operative mortality after implementation of Surgical Outcomes Monitoring and Improvement Programme by Hong Kong Hospital Authority. AB - INTRODUCTION: Since 2008, the Hong Kong Hospital Authority has implemented a Surgical Outcomes Monitoring and Improvement Programme (SOMIP) at 17 public hospitals with surgical departments. This study aimed to assess the change in operative mortality rate after implementation of SOMIP. METHODS: The SOMIP included all Hospital Authority patients undergoing major/ultra-major procedures in general surgery, urology, plastic surgery, and paediatric surgery. Patients undergoing liver or renal transplantation or who had multiple trauma or massive bowel ischaemia were excluded. In SOMIP, data retrieval from the Hospital Authority patient database was performed by six full-time nurse reviewers following a set of precise data definitions. A total of 230 variables were collected for each patient, on demographics, preoperative and operative variables, laboratory test results, and postoperative complications up to 30 days after surgery. In this study, we used SOMIP cumulative 5-year data to generate risk-adjusted 30-day mortality models by hierarchical logistic regression for both emergency and elective operations. The models expressed overall performance as an annual observed-to-expected mortality ratio. RESULTS: From 2009/2010 to 2015/2016, the overall crude mortality rate decreased from 10.8% to 5.6% for emergency procedures and from 0.9% to 0.4% for elective procedures. From 2011/2012 to 2015/2016, the risk-adjusted observed-to-expected mortality ratios showed a significant downward trend for both emergency and elective operations: from 1.126 to 0.796 and from 1.150 to 0.859, respectively (Mann- Kendall statistic = -0.8; P<0.05 for both). CONCLUSION: The Hospital Authority's overall crude mortality rates and risk-adjusted observed-to-expected mortality ratios for emergency and elective operations significantly declined after SOMIP was implemented. PMID- 29632275 TI - Management of complications of ketamine abuse: 10 years' experience in Hong Kong. AB - Ketamine is an N-methyl-d-aspartate receptor antagonist, a dissociative anaesthetic agent and a treatment option for major depression, treatment resistant depression, and bipolar disorder. Its strong psychostimulant properties and easy absorption make it a favourable candidate for substance abuse. Ketamine entered Hong Kong as a club drug in 2000 and the first local report of ketamine associated urinary cystitis was published in 2007. Ketamine-associated lower urinary tract symptoms include frequency, urgency, nocturia, dysuria, urge incontinence, and occasionally painful haematuria. The exact prevalence of ketamine-associated urinary cystitis is difficult to assess because the abuse itself and many of the associated symptoms often go unnoticed until a very late stage. Additionally, upper-urinary tract pathology, such as hydronephrosis, and other complications involving neuropsychiatric, hepatobiliary, and gastrointestinal systems have also been reported. Gradual improvement can be expected after abstinence from ketamine use. Sustained abstinence is the key to recovery, as relapse usually leads to recurrence of symptoms. Both medical and surgical management can be used. The Youth Urological Treatment Centre at the Prince of Wales Hospital, Hong Kong, has developed a four-tier treatment protocol with initial non-invasive investigation and management for these patients. Multidisciplinary care is essential given the complex and diverse psychological factors and sociological background that underlie ketamine abuse and abstinence status. PMID- 29632276 TI - [Pathomechanism of Autoantibody Production in the Nervous System Diseases]. AB - Antibodies to different brain and peripheral nerve proteins have recently been found to be associated with several different autoimmune diseases. They can bind to either neuronal or non-neuronal antigens and may have a pathogenic role by themselves or in synergy with other inflammatory mediators after penetrating the blood-brain barrier or the blood-nerve barrier. In this review, we will describe the association with the impairment of immune tolerance, innate immunity, and autoantibody production of myasthenia gravis (MG), systemic lupus erythematosus (SLE), and Guillain-Barre syndrome (GBS). Impairment of central tolerance, which is characterized by the repertoire selection of immature T-lymphocytes in the thymus, is seen in patients with MG who are positive for anti-Ach R antibodies. Impairment of peripheral tolerance due to activation of autoreactive T-cells and suppression of regulatory T-cells is seen in SLE. In addition, molecular mimicry between the lipooligosaccharides of Campylobacter jejuni and gangliosides of the peripheral nerves results in the production of anti-gangliosides antibodies in GBS. Next, we will describe the antibody-mediated pathology in neuromyelitis optica and anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. The binding of anti-aquaporin-4 antibodies or anti-NMDAR antibodies to their respective targets initiates target internalization and complement- or antibody-dependent cellular cytotoxicity of the target cells. Further understanding of antibody mediated pathology may suggest novel therapeutic strategies. PMID- 29632277 TI - [Anti-Glutamate Receptor Antibodies: Focusing on Anti-N-methyl-D-aspartate Receptor Encephalitis]. AB - The most frequent antibody-mediated autoimmune encephalitis is anti-N-methyl-D aspartate receptor (NMDAR) encephalitis, which presents unique clinical features. Antibodies directly affect the cognitive function of patients with anti-NMDAR encephalitis, and immunotherapy is required to ameliorate their symptoms. The antibody binding is conformational, and antibody detection requires cell surface expression of receptor antigens. There are many unresolved questions surrounding autoimmune encephalitis, such as determination of the triggers of immune reactions against central nervous system antigens, the involved brain lesions responsible for the patients' variable symptoms, the mechanism of neuronal dysfunction, the most effective treatment strategy, and how long the medication should be continued. These questions should be investigated in the future. PMID- 29632278 TI - [Autoantibodies in Neuromyelitis Optica Spectrum Disorders]. AB - Neuromyelitis optica was previously considered a subtype of multiple sclerosis until a specific serum antibody, NMO-IgG, was discovered in 2004. In 2012, anti MOG antibody was found specifically in the serum of patients whose presentation was similar to those with neuromyelitis optica. These autoantibodies are pathogenic and are important disease markers when reaching a diagnosis. PMID- 29632279 TI - [Hashimoto's Encephalopathy and Autoantibodies]. AB - Encephalopathy occasionally occurs in association with thyroid disorders, most of which are treatable. These encephalopathies include a neuropsychiatric disorder associated with hypothyroidism named myxedema encephalopathy. Moreover, Hashimoto's encephalopathy (HE) has been recognized as a new clinical disease based on an autoimmune mechanism associated with Hashimoto's thyroiditis, and can be successfully treated using steroids. Recently, we discovered that the serum autoantibodies against the NH2-terminal of alpha-enolase (NAE) were a highly specific diagnostic biomarker for HE. We analyzed the serum anti-NAE autoantibodies and the clinical features in many cases of HE from institutions across Japan and other countries. About half the patients with HE had anti-NAE antibodies. Patient age was widely distributed with two peaks (around 20-30 years old and 60-80 years old). Most patients with HE were in euthyroid states and all patients had anti-thyroid antibodies. The common neuropsychiatric features include disturbance of consciousness, psychosis, cognitive dysfunction, involuntary movements, seizures, and ataxia. Electroencephalograph (EEG) abnormalities and decreased cerebral blood flow on brain single positron emission computed tomography are common findings, whereas abnormalities on brain magnetic resonance imaging are rare. Patients with HE present with various clinical phenotypes such as an acute encephalopathy form and chronic psychiatric form. Other clinical forms include limbic encephalitis, progressive cerebellar ataxia, and Creutzfeldt-Jakob disease (CJD)-mimic forms. The cerebellar ataxia form of HE clinically mimics spinocerebellar degeneration (SCD) and is characterized by the absence of nystagmus, absent or mild cerebellar atrophy, and lazy background activity on EEG. Taken together, clinicians should pay attention to the possibility of encephalopathy associated with thyroid disorders. PMID- 29632280 TI - [Current Perspective on Voltage-gated Potassium Channel Complex Antibody Associated Diseases]. AB - Voltage-gated potassium channel (VGKC) complex auto-antibodies were initially identified in Isaacs' syndrome (IS), which is characterized by muscle cramps and neuromyotonia. These antibodies were subsequently identified in patients with Morvan's syndrome (MoS), which includes IS in conjunction with psychosis, insomnia, and dysautonomia. The antibodies have also been detected in a patient with limbic encephalopathy (LE) presenting with prominent amnesia and frequent seizures. Typical cases of LE have adult-onset, with frequent, brief dystonic seizures that predominantly affect the arms and ipsilateral face, and has recently been termed faciobrachial dystonic seizures. Autoantibodies against the extracellular domains of VGKC complex proteins, leucine-rich glioma-inactivated 1 (LGI1), and contactin-associated protein-2 (Caspr2), occur in patients with IS, MoS, and LE. However, routine testing has detected VGKC complex antibodies without LGI1 or Caspr2 reactivities (double-negative) in patients with other diseases, such as Creutzfeldt-Jakob disease and amyotrophic lateral sclerosis. Furthermore, double-negative VGKC complex antibodies are often directed against cytosolic epitopes of Kv1 subunits. Therefore, these antibodies should no longer be classified as neuronal-surface antibodies and lacking pathogenic potential. Novel information has been generated regarding autoantibody disruption of the physiological functions of target proteins. LGI1 antibodies neutralize the interaction between LGI1 and ADAM22, thereby reducing the synaptic AMPA receptors. It may be that the main action is on inhibitory neurons, explaining why the loss of AMPA receptors causes amnesia, neuronal excitability and seizures. PMID- 29632281 TI - [Autoantibodies in Paraneoplastic Neurological Syndrome]. AB - Paraneoplastic neurological syndromes (PNS) are caused by immune responses against neuronal antigens expressed by the tumor. Based on the immunological pathomechanisms and responsiveness of treatments, onconeuronal antibodies are divided into two categories: 1) antibodies against neural intracellular antigens and 2) antibodies against neuronal surface or synaptic antigens. The recent discovery of onconeuronal antibodies have radically changed concepts of CNS autoimmunity, including PNS. The recognition of PNS provides a foundation for the early detection of underlying tumors and initiations of prompt treatments, which can result in substantial improvement. We here review the characteristic onconeuronal antibodies, including anti-Hu, anti-Ma2, and anti-N-methyl-D aspartate receptor, and discuss the algorithm for the diagnosis of PNS. PMID- 29632282 TI - [P/Q-type Calcium Channel Antibodies in Lambert-Eaton Myasthenic Syndrome]. AB - Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disease of the neuromuscular junction. Approximately 50-60% of patients with LEMS have a tumor, most often small cell lung cancer (SCLC), making LEMS a paraneoplastic neurological syndrome. In Japan, the clinical picture is a male: female ratio of 3:1; mean age, 62 years (17-80 years); and 61% of LEMS patients have SCLC (SCLC LEMS), with the remainder of patients having no cancer. Patients with LEMS develop a unique set of clinical characteristics, which include proximal muscle weakness, depressed tendon reflexes with post-tetanic potentiation, and autonomic symptoms. Interestingly, less than 10% of patients with LEMS have cerebellar ataxia (LEMS with paraneoplastic cerebellar degeneration). Considering its pathomechanisms, LEMS is a presynaptic disorder of neuromuscular transmission in which quantal release of acetylcholine is impaired by autoantibodies against P/Q type voltage-gated calcium channels (P/Q-VGCCs) at active zones reducing quantal release of acetylcholine, although an animal model using immunization with purified P/Q-VGCCs has not yet been established. The diagnosis can be confirmed by finding a reduced compound muscle action potential amplitude that increases by over 60% following maximum voluntary activation or 50 Hz nerve stimulation. Approximately 90% of patients who satisfy the above electrophysiological diagnostic criteria are positive for P/Q-VGCC antibodies have their diagnosis confirmed. Specific tumor therapy in SCLC-LEMS will often improve the neurologic deficit. Tumor removal is the primary treatment for LEMS. If primary tumor screening is negative, screening should be repeated after 3-6 months, followed by screening every 6 months until 2 years post diagnosis. Most patients benefit from 3,4-diaminopyridine being administered with pyridostigmine. In those with severe weakness, high-dose intravenous gamma-globulin (IVIg) or plasmapheresis confers short-term benefits. Prednisone, alone or combined with immunosuppressive drugs, can achieve long-term control of the disorder. The results of a prospective cohort study showed that the presence of LEMS with SCLC had a significant survival advantage independent of other prognostic factors including disease extent, age, sex, performance status, and serum sodium values. PMID- 29632283 TI - [Stiff-Person Syndrome and Related Autoantibodies]. AB - Stiff-person syndrome (SPS) is a disorder characterized by fluctuating muscle rigidity and painful spasms that occur spontaneously or are triggered by diverse stimuli. Partial or segmental forms of the disorder, such as stiff-limb syndrome (SLS) and a more severe disease called progressive encephalomyelitis with rigidity and myoclonus (PERM), are usually considered within the spectrum of SPS. SPS responds to immunotherapies, and several autoantigens have been identified. Most patients with SPS have a high-titer of antibodies against glutamic acid decarboxylase (GAD), the rate-limiting enzyme for the synthesis of gamma aminobutyric acid (GABA), and up to 15% have antibodies to the glycine receptor alpha-subunit. This review explains milestones in defining SPS including autoantibodies. PMID- 29632284 TI - [Autoantibodies Associated with Autoimmune Basal Ganglia Disorders]. AB - Autoimmune basal ganglia disorders (ABGDs) are presumed autoimmune encephalitides characterized by movement disorders and basal ganglia lesions on neuroimaging. The most common type of autoimmune encephalitis manifesting as movement disorders is anti-N-methyl-D-aspartate (NMDA) receptor encephalitis. Anti-phospholipid antibody syndrome and neuropsychiatric lupus may present with chorea or other involuntary movements. In childhood, Sydenham's chorea is an important differential diagnosis. Although autoantibodies directed against the surface antigens on basal ganglia neurons are assumed to cause ABGDs, few autoantibodies have been demonstrated to be relevant to certain clinical syndromes except for anti-NMDA receptor antibodies. However, recent studies have identified autoantibodies to the dopamine D2 receptor and collapsin response mediator proteins in patients with ABGDs. It remains to be elucidated, however, whether these autoantibodies to basal ganglia antigens play pathogenic roles in ABGDs. PMID- 29632285 TI - [Cerebellar Ataxia and Autoantibodies]. AB - The cerebellum is one of the main targets in the central nervous system for autoimmunity. Immune-mediated cerebellar ataxias include gluten ataxia, GAD antibody-associated cerebellar ataxia, Hashimoto's encephalopathy, and paraneoplastic cerebellar degeneration. Autoimmune cerebellar ataxia may be of either insidious or subacute onset, and vertigo or transient neurological symptoms occur in some patients before the onset of the disease, in contrast to spinocerebellar degeneration. If autoimmune cerebellar ataxia is suspected, early diagnosis and introduction of treatment are very important. For diagnosis, testing for gliadin antibody, TG6 antibody, GAD antibody, thyroid antibody, and anti-neuronal antibodies, including mGluR1, is useful. Magnetic resonance imaging voxel-based morphometry is also useful because it can detect cortical cerebellar atrophy of autoimmune cerebellar ataxia, different from spinocerebellar ataxia. As for treatment, it is important to remove autoimmune triggering factors (e.g.,dietary gluten or neoplasm). When the ataxia symptoms are causing hindrances in the daily life, it is worth considering immunotherapy including IVIg, steroid therapy and so on. PMID- 29632286 TI - [Anti-Ganglionic Acetylcholine Receptor Antibodies, Autoimmune Autonomic Ganglionopathy, and Related Disorders]. AB - The clinical associations of the anti-ganglionic acetylcholine receptor (gAChR) have not yet been described fully. It is not known whether central nervous system (CNS) involvement and endocrine disorders are the extra-autonomic features of autoimmune autonomic ganglionopathy (AAG), or whether it is related to circulating anti-gAChR antibodies (Abs). The present study prospectively identified 123 Abs-positive AAG patients in Japan and collated their clinical features, investigations, and immunotherapy responses. Luciferase immunoprecipitation systems were used to detect anti-alpha3 and -beta4 gAChR Abs. A gradual mode of onset was more common among the 123 seropositive AAG patients examined. Patients with AAG demonstrated widespread autonomic dysfunction. In particular, orthostatic hypotension and lower gastrointestinal tract dysfunction were frequently observed. Approximately 80% of patients with seropositive AAG exhibited extra-autonomic manifestations, including CNS involvement, endocrine disorders, other autoimmune disease, and tumors. Additionally, the majority exhibited a marked improvement in clinical status and the levels of anti-gAChR Abs with immunotherapy. CNS involvement and endocrine disorders were frequent among the seropositive patients with AAG, indicating that seropositivity for AAG may be associated with underlying conditions such as autoimmune diseases or tumors. PMID- 29632287 TI - [Autoantibodies in Chronic Inflammatory Demyelinating Polyneuropathy]. AB - Recent reserch has successfully identified several autoantibodies in chronic inflammatory demyelinating polyneuropathy (CIDP). Most of those identified were IgG4 antibodies targeting cell adhesion molecules around the node of Ranvier of myelinated fibers. In particular, much has been learned concerning the pathogenic roles of antibodies against neurofascin 155. Growing evidence has revealed that patients with CIDP with these antibodies are characterized by IVIg-resistance and lack typical demyelinating findings on biopsied nerve fibers, both of which could make diagnosis and treatment difficult without autoantibody measurement. Clinicians should recognize that it is now essential to measure autoantibodies in CIDP and utilize antibody testing. PMID- 29632288 TI - [A New Aspect of Anti-Glycolipid Antibodies in Guillain-Barre Syndrome: Ca2+-Dependent Antibody in Fisher Syndrome-Related Disorders]. AB - Anti-glycolipid antibodies are key to revealing the pathomechanisms of Guillain Barre syndrome (GBS). There are correlations between the antigen specificities of the antibodies, clinical features, and preceding infectious agents. It has also been found that some glycoantigens are localized in human peripheral nervous tissues, corresponding to the clinical features. Antibody-detection methods are still evolving. The discovery of antibodies against glycolipid complexes expanded the horizon of anti-glycolipid research in GBS, which had started from isolated antigens. Recently, IgG antibodies against ganglioside GQ1b-related antigens that required Ca2+ cations in the antigen-antibody reaction (Ca2+-dependent anti-GQ antibody) have also been detected in patients with Fisher syndrome, or other related disorders, who were GQ1b-seronegative in conventional assays without adding Ca2+. It is suggested that Ca2+ interacts with disialosyl groups [NeuAc (a2-8) NeuAc (a2-)] in gangliosides, and that the Ca2+-dependent antibodies recognize the Ca2+-bound conformation of GQ1b. PMID- 29632289 TI - [Autoantibodies in Myasthenia Gravis]. AB - Myasthenia gravis (MG) is one of the autoantibody-mediated neuroimmunological diseases. Autoantibodies to the muscle-type nicotinic acetylcholine receptor (AChR) were detected in more than 80% of MG patients. The gene structure and pathogenicity of some AChR antibodies produced in MG have already been identified and elucidated, respectively. Therefore, the AChR antibody is similar in nature to innovative drug development targets with respect to MG treatment. Here, we discuss the development of molecular target drugs for AChR antibody-positive MG. PMID- 29632290 TI - [Dermatomyositis and Autoantibodies]. AB - Recent studies have identified novel dermatomyositis-specific autoantibodies and revealed that disease-specific autoantibodies become positive at a high rate in this disease. Moreover, these autoantibodies have been demonstrated to show a strong correlation with distinct clinical manifestations and complications such as interstitial lung disease and malignancy. Thus, these autoantibodies are now recognized as useful tools to classify this varied disease into more homogeneous subsets. In this review, the clinical significance of five dermatomyositis specific autoantibodies, anti-Mi-2, anti-MDA5, anti-TIF1, anti-NXP2, and anti SAE, was described. PMID- 29632291 TI - [Idiopathic Inflammatory Myopathy and Anti-aminoacyl-tRNA Synthetase Antibody]. AB - Anti-aminoacyl-tRNA synthetase (ARS) antibodies (anti-Jo-1, anti-PL-7, anti-PL 12, anti-EJ, anti-KS, anti-OJ, anti-Ha, and anti-Zo antibodies) are found in 25 to 40% of myositis patients. The patients with these antibodies have anti synthetase syndrome with one or more of the following clinical features: myositis, interstitial lung disease, arthritis, fever, Raynaud's phenomenon, and mechanic's hands. In Japan, health insurance coverage of treatments for patients in whom the "anti-ARS antibodies," anti-Jo-1, anti-PL-7, anti-PL-12, anti-EJ, and anti-KS are detected by enzyme-linked immunosorbent assay was approved by the Ministry of Health, Labour and Welfare in 2014. Recently, clinical features have been discovered to be heterogeneous. Patients with the anti-PL-7, anti-PL-12, anti-KS, and anti-OJ antibodies exhibit interstitial lung disease rather than myositis. Interstitial lung disease is related to the prognosis of this syndrome. Regarding histopathological findings of the muscle, perimysial connective tissue fragmentation with positive staining for alkaline phosphatase is the characteristic feature. Myonuclear actin filament inclusions are also detected. A recent work demonstrated that immunization of mice with histidyl-tRNA synthetase results in muscle inflammation consistent with myositis. These findings promote understanding of the pathological mechanism of the development of myositis associated with anti-ARS antibodies. PMID- 29632292 TI - [Sporadic Inclusion Body Myositis and Autoantibodies]. AB - Sporadic inclusion body myositis (sIBM) is a chronically progressing inflammatory myopathy most common in the aged population. Asymmetric muscle weakness and waste of the quadriceps and finger and wrist flexor muscles are characteristic features of sIBM. Histological findings suggest the involvement of a crosstalk of inflammatory and myodegenerative mechanisms in the pathogenesis of sIBM. As an etiological clue to sIBM, identification of autoantibodies against cytosolic 5' nucleotidase 1A (NT5C1A) in plasma and serum samples from patients with sIBM has been attracting attention. So far, various methods with clinical utility have been established to detect anti-NT5C1A autoantibodies. The measurement of the autoantibodies is useful for the diagnosis of sIBM due to its high specificity. Moreover, the autoantibodies may have pathogenic roles in the development of the disease by stimulating catabolic conditions and/or causing dysfunction in protein degradation of skeletal muscles; however, the molecular mechanisms by which the sarcoplasmic autoantigen is recognized and involved in the degeneration of myofibers remain unclear. PMID- 29632293 TI - [Immune Checkpoint Inhibitors and Neuromuscular Adverse Events]. AB - Neuromuscular adverse events (AEs) in cancer patients treated with immune checkpoint inhibitors (ICIs) are characterized by diverse clinical subsets. The general features of neuromuscular AEs have remained elusive due to its low frequency, ranging from 1-2% of cancer patients undergoing ICIs therapy. The diseases affect the central nervous system, peripheral nerves, neuromuscular junction, and muscle. Disease onset and progression may be rapid with a critical clinical course. The clinical presentation may differ from that of patients whose symptoms are unrelated to drugs. Headache, dizziness, and dysgeusia are relatively common and mild treatment-related AEs. In contrast, immune-related AEs, such as autoimmune encephalitis, demyelinating polyneuropathy, myasthenia, and myositis are more serious conditions. There is a strong correlation between ICIs and myasthenia, myositis, and myocarditis. Immune-modulating medication is generally effective for neuromuscular AEs. However, there are guidelines for treatment, and checkpoint inhibitor therapy should be withheld until the pathophysiology of the AEs is defined. Both CD8+ cytotoxic T cells and autoantibodies are involved in the pathogenesis of neuromuscular AEs. Therefore, understanding the mechanisms of neuromuscular AEs is necessary to alleviate the symptoms associated with ICIs therapy in cancer patients. PMID- 29632294 TI - [Diagnosis of Subjective Tinnitus]. AB - Subjective tinnitus is one of the most common diseases in industrialized countries; however, the mechanisms of tinnitus generation and maintenance remain elusive. Currently, there are no objective parameters in the diagnosis of tinnitus. In order to meet the overwhelming demand for evidence-based tinnitus therapy, an objective measurement of subjective tinnitus is necessary. Here, we discuss the possible objective diagnosis of tinnitus from different perspectives. PMID- 29632295 TI - Corneal Opacity Leading to Multiple Myeloma Diagnosis: A Case Report and Literature Review. AB - BACKGROUND A multiple myeloma patient presenting with corneal opacity and blurred vision as chief complaint is rare. CASE REPORT A 54-year-old woman with a 9-month history of blurred vision without other systemic symptoms consulted an ophthalmologist. The patient had bilateral diffuse corneal opacity at the corneal epithelium and anterior stroma under slit-lamp examination. Decreased corneal endothelial cells density was found by microscopy. During consultation, the patient was noted to have an anemic face. Laboratory analysis and bone marrow were investigated. Serum protein electrophoresis revealed a raised serum kappa paraprotein band (12.4 g/L). The erythrocyte sedimentation rate (ESR) was accelerated to 49 mm/h (normal <20mm/h). There was mild kidney impairment. The blood urea increased to 8.1 mmol/L (normal <7.1 mmol/L) and creatinine increased to 158 MUmol/L (normal <133 MUmol/L). Then, a bone marrow biopsy was performed, showing 26% pleomorphic plasma cells (normal <15%). The patient was eventually diagnosed as having MM and was treated with systemic chemotherapy. CONCLUSIONS Blurred vision due to corneal opacity can be an initial presentation of MM, of which ophthalmologists should be aware. PMID- 29632296 TI - Low Mean Arterial Blood Pressure is Independently Associated with Postoperative Acute Kidney Injury After Living Donor Liver Transplantation: A Propensity Score Weighing Analysis. AB - BACKGROUND As end-stage liver disease progresses, renal blood flow linearly correlates with mean arterial blood pressure (MBP) due to impaired autoregulation. We investigated whether the lower degree of postoperative MBP would predict the occurrence of postoperative acute kidney injury (AKI) after liver transplantation. MATERIAL AND METHODS This retrospective study enrolled 1,136 recipients with normal preoperative kidney function. Patients were categorized into two groups according to the averaged postoperative MBP: <90 mmHg (MBPbelow90) and >=90 mmHg (MBPover90). The primary endpoint was occurrence of postoperative AKI, defined by the creatinine criteria of the Kidney Disease Improving Global Outcomes. The logistic regression model with inverse probability treatment weighting (IPTW) of propensity score was used to compare the risk of postoperative AKI between two groups. RESULTS MBPbelow90 group (83.0+/-5.1 mmHg) showed higher prevalence and risk of postoperative AKI (74.2% versus 62.6%, p<0.001; IPTW-OR 1.34 [1.12-1.61], p=0.001) compared with MBPover90 group (97.3+/ 5.2 mmHg). When stratified by quartiles of baseline cystatin C glomerular filtration ratio (GFR), the association between MBPbelow90 and postoperative AKI remained significant only with the lowest quartile (cystatin C GFR <=85 mL/min/1.73 m2; IPTW-OR 2.24 [1.53-3.28], p<0.001), but not with 2nd-4th quartiles. CONCLUSIONS Our results suggest that maintaining supranormal MBP over 90 mmHg may be beneficial to reduce the risk of post-LT AKI, especially for liver transplant recipients with cystatin C GFR <=85 mL/min/1.73 m2. PMID- 29632297 TI - Baicalin, a Chinese Herbal Medicine, Inhibits the Proliferation and Migration of Human Non-Small Cell Lung Carcinoma (NSCLC) Cells, A549 and H1299, by Activating the SIRT1/AMPK Signaling Pathway. AB - BACKGROUND Baicalin is a flavonoid derived from Scutellaria baicalensis, used in Chinese herbal medicine. Activation of the sirtuin 1 gene (SIRT1) and adenosine monophosphate (AMP)-activated protein kinase gene (AMPK), the SIRT1/AMPK signaling pathway, is associated with human malignant tumors. The aim of this study was to investigate the effects of baicalin on the cell viability, apoptosis, proliferation, and migration of human non-small cell lung cancer (NSCLC) cells, A549 and H1299, in vitro. MATERIAL AND METHODS Human NSCLC cells, A549 and H1299, were treated with serial doses of baicalin. Small interfering RNA (siRNA) silencing of the SIRT1 and AMPK genes was performed using cell transfection. The MTT assay was used to determine cell viability, flow cytometry was used to measure cell apoptosis, wound healing and transwell assays were used to assess cell migration of A549 and H1299 cells. Western blotting was used to measure protein expression and phosphorylation levels in untreated A549 and H1299 cells, and cells treated with increasing doses of baicalin. RESULTS Baicalin inhibited the viability, migration, and invasion of A549 and H1299 cells, and increased cell apoptosis in a dose-dependent manner. Baicalin activated the SIRT1/AMPK and mechanistic target of rapamycin (mTOR), and SIRT1/AMPK and matrix metalloproteinase (MMP) signaling in A549 and H1299 cells in a dose-dependent manner. siRNA silencing of SIRT1 and AMPK reduced the effects of baicalin on cell proliferation and migration. CONCLUSIONS Baicalin, a flavonoid used in Chinese herbal medicine, inhibited the proliferation and migration of human NSCLC cells, A549 and H1299, by activating the SIRT1/AMPK signaling pathway. PMID- 29632298 TI - Recurrent acquisition of cytosine methyltransferases into eukaryotic retrotransposons. AB - Transposable elements are in a constant arms race with the silencing mechanisms of their host genomes. One silencing mechanism commonly used by many eukaryotes is dependent on cytosine methylation, a covalent modification of DNA deposited by C5 cytosine methyltransferases (DNMTs). Here, we report how two distantly related eukaryotic lineages, dinoflagellates and charophytes, have independently incorporated DNMTs into the coding regions of distinct retrotransposon classes. Concomitantly, we show that dinoflagellates of the genus Symbiodinium have evolved cytosine methylation patterns unlike any other eukaryote, with most of the genome methylated at CG dinucleotides. Finally, we demonstrate the ability of retrotransposon DNMTs to methylate CGs de novo, suggesting that retrotransposons could self-methylate retrotranscribed DNA. Together, this is an example of how retrotransposons incorporate host-derived genes involved in DNA methylation. In some cases, this event could have implications for the composition and regulation of the host epigenomic environment. PMID- 29632300 TI - Endocycle-related tubular cell hypertrophy and progenitor proliferation recover renal function after acute kidney injury. AB - Acute kidney injury (AKI) is considered largely reversible based on the capacity of surviving tubular cells to dedifferentiate and replace lost cells via cell division. Here we show by tracking individual tubular cells in conditional Pax8/Confetti mice that kidney function is recovered after AKI despite substantial tubular cell loss. Cell cycle and ploidy analysis upon AKI in conditional Pax8/FUCCI2aR mice and human biopsies identify endocycle-mediated hypertrophy of tubular cells. By contrast, a small subset of Pax2+ tubular progenitors enriches via higher stress resistance and clonal expansion and regenerates necrotic tubule segments, a process that can be enhanced by suitable drugs. Thus, renal functional recovery upon AKI involves remnant tubular cell hypertrophy via endocycle and limited progenitor-driven regeneration that can be pharmacologically enhanced. PMID- 29632301 TI - Designable ultra-smooth ultra-thin solid-electrolyte interphases of three alkali metal anodes. AB - Dendrite growth of alkali metal anodes limited their lifetime for charge/discharge cycling. Here, we report near-perfect anodes of lithium, sodium, and potassium metals achieved by electrochemical polishing, which removes microscopic defects and creates ultra-smooth ultra-thin solid-electrolyte interphase layers at metal surfaces for providing a homogeneous environment. Precise characterizations by AFM force probing with corroborative in-depth XPS profile analysis reveal that the ultra-smooth ultra-thin solid-electrolyte interphase can be designed to have alternating inorganic-rich and organic rich/mixed multi-layered structure, which offers mechanical property of coupled rigidity and elasticity. The polished metal anodes exhibit significantly enhanced cycling stability, specifically the lithium anodes can cycle for over 200 times at a real current density of 2 mA cm-2 with 100% depth of discharge. Our work illustrates that an ultra-smooth ultra-thin solid-electrolyte interphase may be robust enough to suppress dendrite growth and thus serve as an initial layer for further improved protection of alkali metal anodes. PMID- 29632299 TI - Genome-wide association study identifies susceptibility loci for B-cell childhood acute lymphoblastic leukemia. AB - Genome-wide association studies (GWAS) have advanced our understanding of susceptibility to B-cell precursor acute lymphoblastic leukemia (BCP-ALL); however, much of the heritable risk remains unidentified. Here, we perform a GWAS and conduct a meta-analysis with two existing GWAS, totaling 2442 cases and 14,609 controls. We identify risk loci for BCP-ALL at 8q24.21 (rs28665337, P = 3.86 * 10-9, odds ratio (OR) = 1.34) and for ETV6-RUNX1 fusion-positive BCP-ALL at 2q22.3 (rs17481869, P = 3.20 * 10-8, OR = 2.14). Our findings provide further insights into genetic susceptibility to ALL and its biology. PMID- 29632302 TI - Stimulus dependent diversity and stereotypy in the output of an olfactory functional unit. AB - Olfactory inputs are organized in an array of functional units (glomeruli), each relaying information from sensory neurons expressing a given odorant receptor to a small population of output neurons, mitral/tufted (MT) cells. MT cells respond heterogeneously to odorants, and how the responses encode stimulus features is unknown. We recorded in awake mice responses from "sister" MT cells that receive input from a functionally characterized, genetically identified glomerulus, corresponding to a specific receptor (M72). Despite receiving similar inputs, sister MT cells exhibit temporally diverse, concentration-dependent, excitatory and inhibitory responses to most M72 ligands. In contrast, the strongest known ligand for M72 elicits temporally stereotyped, early excitatory responses in sister MT cells, consistent across a range of concentrations. Our data suggest that information about ligand affinity is encoded in the collective stereotypy or diversity of activity among sister MT cells within a glomerular functional unit in a concentration-tolerant manner. PMID- 29632303 TI - Palladium gates for reproducible quantum dots in silicon. AB - We replace the established aluminium gates for the formation of quantum dots in silicon with gates made from palladium. We study the morphology of both aluminium and palladium gates with transmission electron microscopy. The native aluminium oxide is found to be formed all around the aluminium gates, which could lead to the formation of unintentional dots. Therefore, we report on a novel fabrication route that replaces aluminium and its native oxide by palladium with atomic-layer deposition-grown aluminium oxide. Using this approach, we show the formation of low-disorder gate-defined quantum dots, which are reproducibly fabricated. Furthermore, palladium enables us to further shrink the gate design, allowing us to perform electron transport measurements in the few-electron regime in devices comprising only two gate layers, a major technological advancement. It remains to be seen, whether the introduction of palladium gates can improve the excellent results on electron and nuclear spin qubits defined with an aluminium gate stack. PMID- 29632304 TI - Response of Aquatic Bacterial Communities to Hydraulic Fracturing in Northwestern Pennsylvania: A Five-Year Study. AB - Horizontal drilling and hydraulic fracturing extraction procedures have become increasingly present in Pennsylvania where the Marcellus Shale play is largely located. The potential for long-term environmental impacts to nearby headwater stream ecosystems and aquatic bacterial assemblages is still incompletely understood. Here, we perform high-throughput sequencing of the 16 S rRNA gene to characterize the bacterial community structure of water, sediment, and other environmental samples (n = 189) from 31 headwater stream sites exhibiting different histories of fracking activity in northwestern Pennsylvania over five years (2012-2016). Stream pH was identified as a main driver of bacterial changes within the streams and fracking activity acted as an environmental selector for certain members at lower taxonomic levels within stream sediment. Methanotrophic and methanogenic bacteria (i.e. Methylocystaceae, Beijerinckiaceae, and Methanobacterium) were significantly enriched in sites exhibiting Marcellus shale activity (MSA+) compared to MSA- streams. This study highlighted potential sentinel taxa associated with nascent Marcellus shale activity and some of these taxa remained as stable biomarkers across this five-year study. Identifying the presence and functionality of specific microbial consortia within fracking impacted streams will provide a clearer understanding of the natural microbial community's response to fracking and inform in situ remediation strategies. PMID- 29632305 TI - New Common and Rare Variants Influencing Metabolic Syndrome and Its Individual Components in a Korean Population. AB - To identify novel loci for susceptibility to MetS, we conducted genome-wide association and exome wide association studies consisting of a discovery stage cohort (KARE, 1946 cases and 6427 controls), and a replication stage cohort (HEXA, 430 cases and 3,264 controls). For finding genetic variants for MetS, with its components, we performed multivariate analysis for common and rare associations, using a standard logistic regression analysis for MetS. From the discovery and replication GWA studies, we confirmed 21 genome-wide signals significantly associated with MetS. Of these 21, four were previously unreported to associate with any MetS components: rs765547 near LPL; rs3782889 in MYL2; and rs11065756 and rs10849915 in CCDC63. Using exome chip variants, gene-based analysis of rare variants revealed three genes, CETP, SH2B1, and ZFP2, in the discovery stage, among which only CETP was confirmed in the replication stage. Finally, CETP D442G (rs2303790) associated, as a less common variant, with decreased risk of MetS. In conclusion, we discovered a total of five new MetS associated loci, and their overlap with other disease-related components, suggest roles in the various etiologies of MetS, and its possible preventive strategies. PMID- 29632306 TI - Greater mindful eating practice is associated with better reversal learning. AB - Mindfulness-based interventions are thought to reduce compulsive behavior such as overeating by promoting behavioral flexibility. Here the main aim was to provide support for mindfulness-mediated improvements in reversal learning, a direct measure of behavioral flexibility. We investigated whether an 8-week mindful eating intervention improved outcome-based reversal learning relative to an educational cooking (i.e., active control) intervention in a non-clinical population. Sixty-five healthy participants with a wide BMI range (19-35 kg/m2), who were motivated to change their eating habits, performed a deterministic reversal learning task that enabled the investigation of reward- and punishment based reversal learning at baseline and following the intervention. No group differences in reversal learning were observed. However, time invested in the mindful eating, but not the educational cooking intervention correlated positively with changes in reversal learning, in a manner independent of outcome valence. These findings suggest that greater amount of mindfulness practice can lead to increased behavioral flexibility, which, in turn, might help overcome compulsive eating in clinical populations. PMID- 29632307 TI - Compromised functionality of monocyte-derived dendritic cells in multiple myeloma patients may limit their use in cancer immunotherapy. AB - Dendritic cells (DCs) have the potential to elicit long-lasting anti-tumour immune responses. Most of the clinical trials of anti-cancer DC vaccines are based on monocyte-derived DCs (Mo-DCs). However, their outcomes have shown limited promise especially in multiple myeloma (MM) patients. Here, we investigated whether in vitro generated Mo-DCs from MM patients (MM-DCs) possess impaired functionality, thus contributing to the limited success of DC vaccines. We generated MM-DCs and compared them with DCs from healthy donors (HD-DCs). The yield of DCs in MM was 3.5 fold lower than in HD sets. However morphology, phenotype, antigen uptake and allo-T cell stimulation were comparable. Migration and secretion of IL12p70 and IFN-gamma (in DC-T cell co-cultures) were significantly reduced in MM-DCs. Thus, MM-DCs were compromised in functionality. This impairment could be attributed to autocrine secretion of IL6 by MM-monocytes and activation of their P38 MAPK pathway. This indicates a need to look for alternative sources of DCs. PMID- 29632308 TI - The oscillation of intracellular Ca2+ influx associated with the circadian expression of Piezo1 and TRPV4 in the bladder urothelium. AB - We previously showed that bladder functions are controlled by clock genes with circadian rhythm. The sensation of bladder fullness (SBF) is sensed by mechano sensor such as Piezo1 and TRPV4 in the mouse bladder urothelium. However, functional circadian rhythms of such mechano-sensors remain unknown. To investigate functional circadian changes of these mechano-sensors, we measured circadian changes in stretch-evoked intracellular Ca2+ influx ([Ca2+] i ) using mouse primary cultured urothelial cells (MPCUCs). Using Ca2+ imaging, stretch evoked [Ca2+] i was quantified every 4 h in MPCUCs derived from wild-type (WT) and Clock Delta19/Delta19 mice, which showed a nocturia phenotype. Furthermore, a Piezo1 inhibitor GsMTx4 and a TRPV4 inhibitor Ruthenium Red were applied and stretch-evoked [Ca2+] i in MPCUCs was measured to investigate their contribution to SBF. Stretch-evoked [Ca2+] i showed a circadian rhythm in the WT mice. In contrast, Clock Delta19/Delta19 mice showed disrupted circadian rhythm. The administration of both GsMTx4 and Ruthenium Red eliminated the circadian rhythm of stretch-evoked [Ca2+] i in WT mice. We conclude that SBF may have a circadian rhythm, which is created by functional circadian changes of Piezo1 and TRPV4 being controlled by clock genes to be active during wakefulness and inactive during sleep. Abnormalities of clock genes disrupt SBF, and induce nocturia. PMID- 29632309 TI - Analysis of DNAs associated with coconut foliar decay disease implicates a unique single-stranded DNA virus representing a new taxon. AB - The unique ecology, pathology and undefined taxonomy of coconut foliar decay virus (CFDV), found associated with coconut foliar decay disease (CFD) in 1986, prompted analyses of old virus samples by modern methods. Rolling circle amplification and deep sequencing applied to nucleic acid extracts from virion preparations and CFD-affected palms identified twelve distinct circular DNAs, eleven of which had a size of about 1.3 kb and one of 641 nt. Mass spectrometry based protein identification proved that a 24 kDa protein encoded by two 1.3 kb DNAs is the virus capsid protein with highest sequence similarity to that of grabloviruses (family Geminiviridae), even though CFDV particles are not geminate. The nine other 1.3 kb DNAs represent alphasatellites coding for replication initiator proteins that differ clearly from those encoded by nanovirid DNA-R. The 641 nt DNA-gamma is unique and may encode a movement protein. Three DNAs, alphasatellite CFDAR, capsid protein encoding CFDV DNA-S.1 and DNA-gamma share sequence motifs near their replication origins and were consistently present in all samples analysed. These DNAs appear to be integral components of a possibly tripartite CFDV genome, different from those of any Geminiviridae or Nanoviridae family member, implicating CFDV as representative of a new genus and family. PMID- 29632310 TI - A Multi-scale Biophysical Approach to Develop Structure-Property Relationships in Oral Biofilms. AB - Over the last 5-10 years, optical coherence tomography (OCT) and atomic force microscopy (AFM) have been individually applied to monitor the morphological and mechanical properties of various single-species biofilms respectively. This investigation looked to combine OCT and AFM as a multi-scale approach to understand the role sucrose concentration and age play in the morphological and mechanical properties of oral, microcosm biofilms, in-vitro. Biofilms with low (0.1% w/v) and high (5% w/v) sucrose concentrations were grown on hydroxyapatite (HAP) discs from pooled human saliva and incubated for 3 and 5 days. Distinct mesoscale features of biofilms such as regions of low and high extracellular polymeric substances (EPS) were identified through observations made by OCT. Mechanical analysis revealed increasing sucrose concentration decreased Young's modulus and increased cantilever adhesion (p < 0.0001), relative to the biofilm. Increasing age was found to decrease adhesion only (p < 0.0001). This was due to mechanical interactions between the indenter and the biofilm increasing as a function of increased EPS content, due to increasing sucrose. An expected decrease in EPS cantilever contact decreased adhesion due to bacteria proliferation with biofilm age. The application OCT and AFM revealed new structure-property relationships in oral biofilms, unattainable if the techniques were used independently. PMID- 29632311 TI - Intercomparison of phenological transition dates derived from the PhenoCam Dataset V1.0 and MODIS satellite remote sensing. AB - Phenology is a valuable diagnostic of ecosystem health, and has applications to environmental monitoring and management. Here, we conduct an intercomparison analysis using phenological transition dates derived from near-surface PhenoCam imagery and MODIS satellite remote sensing. We used approximately 600 site-years of data, from 128 camera sites covering a wide range of vegetation types and climate zones. During both "greenness rising" and "greenness falling" transition phases, we found generally good agreement between PhenoCam and MODIS transition dates for agricultural, deciduous forest, and grassland sites, provided that the vegetation in the camera field of view was representative of the broader landscape. The correlation between PhenoCam and MODIS transition dates was poor for evergreen forest sites. We discuss potential reasons (including sub-pixel spatial heterogeneity, flexibility of the transition date extraction method, vegetation index sensitivity in evergreen systems, and PhenoCam geolocation uncertainty) for varying agreement between time series of vegetation indices derived from PhenoCam and MODIS imagery. This analysis increases our confidence in the ability of satellite remote sensing to accurately characterize seasonal dynamics in a range of ecosystems, and provides a basis for interpreting those dynamics in the context of tangible phenological changes occurring on the ground. PMID- 29632312 TI - Vms1 and ANKZF1 peptidyl-tRNA hydrolases release nascent chains from stalled ribosomes. AB - Ribosomal surveillance pathways scan for ribosomes that are transiently paused or terminally stalled owing to structural elements in mRNAs or nascent chain sequences1, 2. Some stalls in budding yeast are sensed by the GTPase Hbs1, which loads Dom34, a catalytically inactive member of the archaeo-eukaryotic release factor 1 superfamily. Hbs1-Dom34 and the ATPase Rli1 dissociate stalled ribosomes into 40S and 60S subunits. However, the 60S subunits retain the peptidyl-tRNA nascent chains, which recruit the ribosome quality control complex that consists of Rqc1-Rqc2-Ltn1-Cdc48-Ufd1-Npl4. Nascent chains ubiquitylated by the E3 ubiquitin ligase Ltn1 are extracted from the 60S subunit by the ATPase Cdc48-Ufd1 Npl4 and presented to the 26S proteasome for degradation3-9. Failure to degrade the nascent chains leads to protein aggregation and proteotoxic stress in yeast and neurodegeneration in mice10-14. Despite intensive investigations on the ribosome quality control pathway, it is not known how the tRNA is hydrolysed from the ubiquitylated nascent chain before its degradation. Here we show that the Cdc48 adaptor Vms1 is a peptidyl-tRNA hydrolase. Similar to classical eukaryotic release factor 1, Vms1 activity is dependent on a conserved catalytic glutamine. Evolutionary analysis indicates that yeast Vms1 is the founding member of a clade of eukaryotic release factor 1 homologues that we designate the Vms1-like release factor 1 clade. PMID- 29632315 TI - Retraction of the dissolution front in natural porous media. AB - The dissolution of porous materials in a flow field controls the fluid pathways through rocks and soils and shapes the morphology of landscapes. Identifying the dissolution front, the interface between the reactive and the unreactive volumes in a dissolving medium, is a prerequisite for describing dissolution-induced structure emergence and transformation. Despite its fundamental importance, the report on the dynamics of a dissolution front in an evolving natural microstructure is scarce. Here we show an unexpected, spontaneous migration of the dissolution front against the flow direction. This retraction stems from infiltration instability induced surface generation, which leads to an increase in reactive surface area when a porous medium dissolves in an imposing flow field. There is very good agreement between observations made with in situ, X-ray tomography and model predictions. Both show that the value of reactive surface area reflects a balance between flow-dependent surface generation and destruction, i.e. the "dry" geometric surface area of a porous material, measured without a flow field, is not necessarily the upper limit of its reactive surface area when in contact with reactive flow. This understanding also contributes to reconciling the discrepancies between field and laboratory derived solid-fluid reaction kinetics. PMID- 29632314 TI - Unravelling the inhibitory activity of Chlamydomonas reinhardtii sulfated polysaccharides against alpha-Synuclein fibrillation. AB - alpha-Synuclein (alpha-Syn) is an intrinsically disordered presynaptic protein, whose aggregation is critically involved in Parkinson's disease (PD). Many of the currently available drugs for the treatment of PD are not sufficiently effective in preventing progress of the disease and have multiple side-effects. With this background, efficient drug candidates, sulfated polysaccharides from Chlamydomonas reinhardtii (Cr-SPs) were isolated and investigated for their effect on inhibition of alpha-Syn fibrillation and dissolution of preformed alpha Syn fibrillar structures through a combination of spectroscopic and microscopic techniques. The kinetics of alpha-Syn fibrillation demonstrates that Cr-SPs are very effective in inhibiting alpha-Syn fibrillation. Sodium dodecyl sulphate polyacrylamide gel electrophoresis gel-image shows presence of soluble protein in the presence of Cr-SPs after completion of the fibrillation process. The morphological changes associated with fibrillation monitored by transmission electron microscopy showed that Cr-SPs efficiently bind with alpha-Syn and delay the conversion of alpha-helical intermediate into beta-sheet rich structures. Cr SPs are also effective even if onset of alpha-Syn fibrillation has already started and they also have the ability to dissolve pre-formed fibrils. Thus, the current work has substantial therapeutic implications towards unlocking the immense potential of algal products to function as alternative therapeutic agents against PD and other protein aggregation related disorders. PMID- 29632313 TI - Discretized Theta-Rhythm Perception Revealed by Moving Stimuli. AB - Despite the subjective continuity of perception over time, increasing evidence suggests that the human nervous system samples sensory information periodically, a finding strongly exemplified by discretized perception in the alpha-rhythm frequency band. More recently, studies have revealed a theta-band cyclic process that manifests itself as periodical fluctuations in behavioral performance. Here, we used a simple stimulus to demonstrate that the theta-cyclic system can produce a vivid experience of slow discrete visual sampling: a Gabor texture pattern appears as a series of flickering snapshots if its spatial window moves continuously over a carrier grating that remains still or drifts continuously in the opposite direction. While the perceptual magnitude of this illusory saltation varied with the speed difference between grating and window components in head centered coordinates, the perceived rhythm of saltation remained nearly constant (3-8 Hz) over a wide range of stimulus parameters. Results provide further evidence that the slow cyclic neural processes play a critical role not only in attentional task performance but also in conscious perception. PMID- 29632316 TI - Sunlight-Induced photochemical synthesis of Au nanodots on alpha-Fe2O3@Reduced graphene oxide nanocomposite and their enhanced heterogeneous catalytic properties. AB - In this present study, we report the synthesis of Au nanodots on alpha Fe2O3@reduced graphene oxide (RGO) based hetero-photocatalytic nanohybrids through a chlorophyll mediated photochemical synthesis. In this process, chlorophyll induces a rapid reduction (30 min) of Au3+ ions to Au degrees metallic nanodots on alpha-Fe2O3@RGO surface under sunlight irradiation. The nucleation growth process, photo-induced electron-transfer mechanism and physico chemical properties of the Au@alpha-Fe2O3@RGO ternary nanocomposites were systematically studied with various analytical techniques. This novel photochemical synthesis process is a cost-effective, convenient, surfactant-less, and scalable method. Moreover, the prepared ternary nanocomposites enhanced catalytic activity as compared to pure alpha-Fe2O3 and alpha-Fe2O3@RGO. The advantages and synergistic effect of Au@alpha-Fe2O3@RGO exhibit, (i) a broader range of visible-light absorption due to visible light band gap of alpha-Fe2O3, (ii) lower recombination possibility of photo-generated electrons and holes due to effect of Au and (iii) faster electron transfer due to higher conductivity of RGO. Therefore, the prepared Au@alpha-Fe2O3@RGO hetero-photocatalytic nanohybrids exhibited a remarkable photocatalytic activity, thus enabling potential active hetero-photocatalyst for industrial and environmental applications. PMID- 29632317 TI - Plac1 Is a Key Regulator of the Inflammatory Response and Immune Tolerance In Mammary Tumorigenesis. AB - Plac1 is an X-linked trophoblast gene expressed at high levels in the placenta, but not in adult somatic tissues other than the testis. Plac1 however is re expressed in several solid tumors and in most human cancer cell lines. To explore the role of Plac1 in cancer progression, Plac1 was reduced by RNA interference in EO771 mammary carcinoma cells. EO771 "knockdown" (KD) resulted in 50% reduction in proliferation in vitro and impaired tumor growth in syngeneic mice; however, tumor growth in SCID mice was equivalent to tumor cells expressing a non silencing control RNA, suggesting that Plac1 regulated adaptive immunity. Gene expression profiling of Plac1 KD cells indicated reduction in several inflammatory and immune factors, including Cxcl1, Ccl5, Ly6a/Sca-1, Ly6c and Lif. Treatment of mice engrafted with wild-type EO771 cells with a Cxcr2 antagonist impaired tumor growth, reduced myeloid-derived suppressor cells and regulatory T cells, while increasing macrophages, dendritic cells, NK cells and the penetration of CD8+ T cells into the tumor bed. Cxcl1 KD phenocopied the effects of Plac1 KD on tumor growth, and overexpression of Cxcl1 partially rescued Plac1 KD cells. These results reveal that Plac1 modulates a tolerogenic tumor microenvironment in part by modulating the chemokine axis. PMID- 29632318 TI - Ion Permeation Mechanism in Epithelial Calcium Channel TRVP6. AB - Calcium is the most abundant metal in the human body that plays vital roles as a cellular electrolyte as well as the smallest and most frequently used signaling molecule. Calcium uptake in epithelial tissues is mediated by tetrameric calcium selective transient receptor potential (TRP) channels TRPV6 that are implicated in a variety of human diseases, including numerous forms of cancer. We used TRPV6 crystal structures as templates for molecular dynamics simulations to identify ion binding sites and to study the permeation mechanism of calcium and other ions through TRPV6 channels. We found that at low Ca2+ concentrations, a single calcium ion binds at the selectivity filter narrow constriction formed by aspartates D541 and allows Na+ permeation. In the presence of ions, no water binds to or crosses the pore constriction. At high Ca2+ concentrations, calcium permeates the pore according to the knock-off mechanism that includes formation of a short-lived transition state with three calcium ions bound near D541. For Ba2+, the transition state lives longer and the knock-off permeation occurs slower. Gd3+ binds at D541 tightly, blocks the channel and prevents Na+ from permeating the pore. Our results provide structural foundations for understanding permeation and block in tetrameric calcium-selective ion channels. PMID- 29632319 TI - Too many targets, not enough patients: rethinking neuroblastoma clinical trials. AB - Neuroblastoma is a rare solid tumour of infancy and early childhood with a disproportionate contribution to paediatric cancer mortality and morbidity. Combination chemotherapy, radiation therapy and immunotherapy remains the standard approach to treat high-risk disease, with few recurrent, actionable genetic aberrations identified at diagnosis. However, recent studies indicate that actionable aberrations are far more common in relapsed neuroblastoma, possibly as a result of clonal expansion. In addition, although the major validated disease driver, MYCN, is not currently directly targetable, multiple promising approaches to target MYCN indirectly are in development. We propose that clinical trial design needs to be rethought in order to meet the challenge of providing rigorous, evidence-based assessment of these new approaches within a fairly small patient population and that experimental therapies need to be assessed at diagnosis in very-high-risk patients rather than in relapsed and refractory patients. PMID- 29632320 TI - Ocular Blood Flow in Rabbits under Deep Anesthesia: A Real-Time Measurement Technique and Its Application in Characterizing Retinal Ischemia. AB - In this study, we reported a new technique based on laser speckle flowgraphy to record the ocular blood flow in rabbits under deep anesthesia, and proposed parameters to characterize retinal ischemia. We applied the proposed technique to study the correlation of blood flow between the eyes of normal non-anesthetized animals, and to characterize the occlusion of the internal carotid artery (ICA) and external carotid artery (ECA). We established a correlation in blood flow between the eyes of non-anesthetized animals, and derived two new parameters, namely, the laterality index and vascular perfusion estimate (VPE). Our experimental results from 16 eyes (of 13 New Zealand white rabbits) showed a reduction in ocular blood flow with a significant decrease in the VPE after the occlusion of the ECA (p < 0.001). A low/minimal effect on blood flow was observed with the occlusion of the ICA. In conclusion, we demonstrated a means for the real-time measurement of the ocular blood flow in rabbits under deep anesthesia by using laser speckle flowgraphy and the VPE as an indicator of successful occlusion. The proposed technique might be applicable in quantifying the efficacy of new drugs and interventions for the treatment of retinal ischemia. PMID- 29632321 TI - Metabolic profiling of sourdough fermented wheat and rye bread. AB - Sourdough fermentation by lactic acid bacteria is commonly used in bread baking, affecting several attributes of the final product. We analyzed whole-grain wheat and rye breads and doughs prepared with baker's yeast or a sourdough starter including Candida milleri, Lactobacillus brevis and Lactobacillus plantarum using non-targeted metabolic profiling utilizing LC-QTOF-MS. The aim was to determine the fermentation-induced changes in metabolites potentially contributing to the health-promoting properties of whole-grain wheat and rye. Overall, we identified 118 compounds with significantly increased levels in sourdough, including branched-chain amino acids (BCAAs) and their metabolites, small peptides with high proportion of BCAAs, microbial metabolites of phenolic acids and several other potentially bioactive compounds. We also identified 69 compounds with significantly decreased levels, including phenolic acid precursors, nucleosides, and nucleobases. Intensive sourdough fermentation had a higher impact on the metabolite profile of whole-grain rye compared to milder whole-grain wheat sourdough fermentation. We hypothesize that the increased amount of BCAAs and potentially bioactive small peptides may contribute to the insulin response of rye bread, and in more general, the overall protective effect against T2DM and CVD. PMID- 29632322 TI - Variability of the Indonesian Throughflow in the Makassar Strait over the Last 30 ka. AB - The hydrological characteristics, including temperatures and salinities, of the upper water over the last 30 ka from two sites connected by the Indonesian Throughflow (ITF) across the Makassar Strait are reconstructed and compared. The thermocline hydrological gradient in the strait was larger during 13.4~19 ka BP and 24.2~27 ka BP than that in the Holocene. The weakened ITF during those periods in the last glacial period, corresponding to the decreased trade wind stress under an El Nino-like climate mean state, likely accounts for the increased thermocline gradient. The thermocline water temperature variabilities of the two sites, in particular the highest peaks at ~7 ka BP, are different from the records of the open western Pacific. Reoccurrence of the South China Sea Throughflow and thus a decreased surface throughflow along the Makassar Strait perhaps led to a warmer peak of thermocline temperature at ~7 ka BP than at ~11 ka BP. PMID- 29632323 TI - Inter-laboratory testing of the effect of DNA blocking reagent G2 on DNA extraction from low-biomass clay samples. AB - Here we show that a commercial blocking reagent (G2) based on modified eukaryotic DNA significantly improved DNA extraction efficiency. We subjected G2 to an inter laboratory testing, where DNA was extracted from the same clay subsoil using the same batch of kits. The inter-laboratory extraction campaign revealed large variation among the participating laboratories, but the reagent increased the number of PCR-amplified16S rRNA genes recovered from biomass naturally present in the soils by one log unit. An extensive sequencing approach demonstrated that the blocking reagent was free of contaminating DNA, and may therefore also be used in metagenomics studies that require direct sequencing. PMID- 29632324 TI - Activation of Calcium-Sensing Receptor increases intracellular calcium and decreases cAMP and mTOR in PKD1 deficient cells. AB - Clinical and fundamental research suggest that altered calcium and cAMP signaling might be the most proximal events in ADPKD pathogenesis. Cells from ADPKD cysts have a reduced resting cytosolic calcium [Ca2+]i and increased cAMP levels. CaSR plays an essential role in regulating calcium homeostasis. Its activation is associated with [Ca2+]i increase and cAMP decrease, making CaSR a possible therapeutic target. Human conditionally immortalized Proximal Tubular Epithelial cells (ciPTEC) with stable knockdown of PKD1 (ciPTEC-PC1KD) and ciPTEC generated from an ADPKD1 patient (ciPTEC-PC1Pt) were used as experimental tools. CaSR functional expression was confirmed by studies showing that the calcimimetic NPS R568 induced a significant increase in [Ca2+]i in ciPTEC-PC1KD and ciPTEC-PC1Pt. Resting [Ca2+]i were significantly lower in ciPTEC-PC1KD with respect to ciPTECwt, confirming calcium dysregulation. As in native cyst cells, significantly higher cAMP levels and mTOR activity were found in ciPTEC-PC1KD compared to ciPTECwt. Of note, NPS-R568 treatment significantly reduced intracellular cAMP and mTOR activity in ciPTEC-PC1KD and ciPTEC-PC1Pt. To conclude, we demonstrated that selective CaSR activation in human ciPTEC carrying PKD1 mutation increases [Ca2+]i, reduces intracellular cAMP and mTOR activity, reversing the principal dysregulations considered the most proximal events in ADPKD pathogenesis, making CaSR a possible candidate as therapeutic target. PMID- 29632325 TI - Speciation in the presence of gene flow: population genomics of closely related and diverging Eucalyptus species. AB - Speciation is a complex process that is fundamental to the origins of biological diversity. While there has been considerable progress in our understanding of speciation, there are still many unanswered questions, especially regarding barriers to gene flow in diverging populations. Eucalyptus is an appropriate system for investigating speciation mechanisms since it comprises species that are rapidly evolving across heterogeneous environments. We examined patterns of genetic variation within and among six closely related Eucalyptus species in subgenus Eucalyptus section Eucalyptus in south-eastern Australia (commonly known as the "green ashes"). We used reduced representation genome sequencing to genotype samples from populations across altitudinal and latitudinal gradients. We found one species, Eucalyptus cunninghamii, to be highly genetically differentiated from the others, and a population of mallees from Mount Banks to be genetically distinct and therefore likely to be a new undescribed species. Only modest levels of differentiation were found between all other species in the study. There was population structure within some species (e.g., E. obstans) corresponding to geographical factors, indicating that vicariance may have played a role in the evolution of the group. Overall, we found that lineages within the green ashes are differentiated to varying extents, from strongly diverged to much earlier stages of the speciation continuum. Furthermore, our results suggest the green ashes represent a group where a range of mechanisms (e.g., reticulate evolution and vicariance) have been operating in concert. These findings not only offer insights into recent speciation mechanisms in Eucalyptus, but also other species complexes. PMID- 29632326 TI - Drought drives rapid shifts in tropical rainforest soil biogeochemistry and greenhouse gas emissions. AB - Climate change models predict more frequent and severe droughts in the humid tropics. How drought will impact tropical forest carbon and greenhouse gas dynamics is poorly understood. Here we report the effects of the severe 2015 Caribbean drought on soil moisture, oxygen, phosphorus (P), and greenhouse gas emissions in a humid tropical forest in Puerto Rico. Drought significantly decreases inorganic P concentrations, an element commonly limiting to net primary productivity in tropical forests, and significantly increases organic P. High frequency greenhouse gas measurements show varied impacts across topography. Soil carbon dioxide emissions increase by 60% on slopes and 163% in valleys. Methane (CH4) consumption increases significantly during drought, but high CH4 fluxes post-drought offset this sink after 7 weeks. The rapid response and slow recovery to drought suggest tropical forest biogeochemistry is more sensitive to climate change than previously believed, with potentially large direct and indirect consequences for regional and global carbon cycles. PMID- 29632327 TI - Surface display of PbrR on Escherichia coli and evaluation of the bioavailability of lead associated with engineered cells in mice. AB - Human exposure to lead mainly occurs by ingestion of contaminated food, water and soil. Blocking lead uptake in the gastrointestinal tract is a novel prevention strategy. Whole-cell biosorbent for lead was constructed with PbrR genetically engineered on the cell surface of Escherichia coli (E. coli), a predominant strain among intestinal microflora, using lipoprotein (Lpp)-OmpA as the anchoring protein. In vitro, the PbrR displayed cells had an enhanced ability for immobilizing toxic lead(II) ions from the external media at both acidic and neutral pH, and exhibited a higher specific adsorption for lead compared to other physiological two valence metal ions. In vivo, the persistence of recombinant E. coli in the murine intestinal tract and the integrity of surface displayed PbrR were confirmed. In addition, oral administration of surface-engineered E. coli was safe in mice, in which the concentrations of physiological metal ions in blood were not affected. More importantly, lead associated with PbrR-displayed E. coli was demonstrated to be less bioavailable in the experimental mouse model with exposure to oral lead. This is reflected by significantly lower blood and femur lead concentrations in PbrR-displayed E. coli groups compared to the control. These results open up the possibility for the removal of toxic metal ions in vivo using engineered microorganisms as adsorbents. PMID- 29632328 TI - Strategic Design and Fabrication of Biomimetic 3D Scaffolds: Unique Architectures of Extracellular Matrices for Enhanced Adipogenesis and Soft Tissue Reconstruction. AB - The higher rate of soft tissue impairment due to lumpectomy or other trauma greatly requires the restoration of the irreversibly lost subcutaneous adipose tissues. The nanofibers fabricated by conventional electrospinning provide only a superficial porous structure due to its sheet like 2D structure and thereby hinder the cell infiltration and differentiation throughout the scaffolds. Thus we developed a novel electrospun 3D membrane using the zwitterionic poly (carboxybetaine-co-methyl methacrylate) co-polymer (CMMA) through electrostatic repulsion based electrospinning for soft tissue engineering. The inherent charges in the CMMA will aid the nanofiber to directly transform into a semiconductor and thereby transfer the immense static electricity from the grounded collector and will impart greater fluffiness to the scaffolds. The results suggest that the fabricated 3D nanofiber (CMMA 3NF) scaffolds possess nanofibers with larger inter connected pores and less dense structure compared to the conventional 2D scaffolds. The CMMA 3NF exhibits significant cues of soft tissue engineering such as enhanced biocompatibility as well as the faster regeneration of cells. Moreover the fabricated 3D scaffolds greatly assist the cells to develop into its stereoscopic topographies with an enhanced adipogenic property. PMID- 29632329 TI - Peptide-specific recognition of human cytomegalovirus strains controls adaptive natural killer cells. AB - Natural killer (NK) cells are innate lymphocytes that lack antigen-specific rearranged receptors, a hallmark of adaptive lymphocytes. In some people infected with human cytomegalovirus (HCMV), an NK cell subset expressing the activating receptor NKG2C undergoes clonal-like expansion that partially resembles anti viral adaptive responses. However, the viral ligand that drives the activation and differentiation of adaptive NKG2C+ NK cells has remained unclear. Here we found that adaptive NKG2C+ NK cells differentially recognized distinct HCMV strains encoding variable UL40 peptides that, in combination with pro inflammatory signals, controlled the population expansion and differentiation of adaptive NKG2C+ NK cells. Thus, we propose that polymorphic HCMV peptides contribute to shaping of the heterogeneity of adaptive NKG2C+ NK cell populations among HCMV-seropositive people. PMID- 29632330 TI - A transmission electron microscope study of Neel skyrmion magnetic textures in multilayer thin film systems with large interfacial chiral interaction. AB - Skyrmions in ultrathin ferromagnetic metal (FM)/heavy metal (HM) multilayer systems produced by conventional sputtering methods have recently generated huge interest due to their applications in the field of spintronics. The sandwich structure with two correctly-chosen heavy metal layers provides an additive interfacial exchange interaction which promotes domain wall or skyrmion spin textures that are Neel in character and with a fixed chirality. Lorentz transmission electron microscopy (TEM) is a high resolution method ideally suited to quantitatively image such chiral magnetic configurations. When allied with physical and chemical TEM analysis of both planar and cross-sectional samples, key length scales such as grain size and the chiral variation of the magnetisation variation have been identified and measured. We present data showing the importance of the grain size (mostly < 10 nm) measured from direct imaging and its potential role in describing observed behaviour of isolated skyrmions (diameter < 100 nm). In the latter the region in which the magnetization rotates is measured to be around 30 nm. Such quantitative information on the multiscale magnetisation variations in the system is key to understanding and exploiting the behaviour of skyrmions for future applications in information storage and logic devices. PMID- 29632332 TI - Effects of oil-film layer and surfactant on the siphonal respiration and survivorship in the fourth instar larvae of Aedes togoi mosquito in laboratory conditions. AB - Mosquitoes transmit various diseases; thus, controlling them is necessary to prevent mosquito-borne infections. Unlike flying adult mosquitoes, those in the immature stages are easy to control because of being restricted to their habitats found in an aquatic environment. In this study, we aimed to evaluate of respiration and survivorship in the larvae of Aedes togoi. The mechanism of actions of the oil-film layer and the surfactant as well as their effects on the siphonal respiration of submerged Aedes togoi larvae were analyzed by checking the survival time of mosquito larvae against oil-film layer and surfactant, and conducting experiments using a siphon-model. Compared with an impermeable membrane used for reference (762.4 min; average time in all cases), the survival time of mosquito larvae was 5% longer for the oil-film layer (808.1 min) and 40% longer for the surfactant (1086.9 min). The surface of the siphon was changed from hydrophobic to hydrophilic by addition of a surfactant. In addition, the surface tension and wettability have a significant influence on the opening and closing of siphon. This study would be helpful for understanding the basic mechanism of physical control measures for disturbing the siphonal respiration of mosquito larvae in a way of dissolved oxygen and surface tension. The present results would guide the establishment of effective control measures for mosquitoes. PMID- 29632331 TI - Quantitative 3D determination of self-assembled structures on nanoparticles using small angle neutron scattering. AB - The ligand shell (LS) determines a number of nanoparticles' properties. Nanoparticles' cores can be accurately characterized; yet the structure of the LS, when composed of mixture of molecules, can be described only qualitatively (e.g., patchy, Janus, and random). Here we show that quantitative description of the LS' morphology of monodisperse nanoparticles can be obtained using small angle neutron scattering (SANS), measured at multiple contrasts, achieved by either ligand or solvent deuteration. Three-dimensional models of the nanoparticles' core and LS are generated using an ab initio reconstruction method. Characteristic length scales extracted from the models are compared with simulations. We also characterize the evolution of the LS upon thermal annealing, and investigate the LS morphology of mixed-ligand copper and silver nanoparticles as well as gold nanoparticles coated with ternary mixtures. Our results suggest that SANS combined with multiphase modeling is a versatile approach for the characterization of nanoparticles' LS. PMID- 29632333 TI - Structural, magnetic, and electronic properties of Fe82Si4B10P4 metallic glass. AB - The structural, magnetic, and electronic properties of Fe82Si4B10P4 metallic glass were systemically investigated by theoretical simulations. Strong atomic interaction between Fe and metalloid atoms can be observed, while the direct metalloid-metalloid atomic bonds are rare due to the solute-solute avoidance effect. The calculated value of saturation magnetic flux density (B S ) is ~1.65 T, approaching to experimental result, which is contributed by not only the electron exchange between Fe and metalloid atoms, but also the p-d orbital hybridization of Fe atoms. Moreover, Fe atoms with neighboring P atom behaving larger magnetic moments reveals the important role of P element for promoting the B S value. The potential correlation between magnetic behaviors and the local atomic packing in this study sheds some light on the structural origin of the soft magnetic properties and, thereby the theoretical guidance for the development of new soft-magnetic metallic glasses. PMID- 29632334 TI - A [4Fe-4S]-Fe(CO)(CN)-L-cysteine intermediate is the first organometallic precursor in [FeFe] hydrogenase H-cluster bioassembly. AB - Biosynthesis of the [FeFe] hydrogenase active site (the 'H-cluster') requires the interplay of multiple proteins and small molecules. Among them, the radical S adenosylmethionine enzyme HydG, a tyrosine lyase, has been proposed to generate a complex that contains an Fe(CO)2(CN) moiety that is eventually incorporated into the H-cluster. Here we describe the characterization of an intermediate in the HydG reaction: a [4Fe-4S][(Cys)Fe(CO)(CN)] species, 'Complex A', in which a CO, a CN- and a cysteine (Cys) molecule bind to the unique 'dangler' Fe site of the auxiliary [5Fe-4S] cluster of HydG. The identification of this intermediate-the first organometallic precursor to the H-cluster-validates the previously hypothesized HydG reaction cycle and provides a basis for elucidating the biosynthetic origin of other moieties of the H-cluster. PMID- 29632335 TI - O2-O2 and O2-N2 collision-induced absorption mechanisms unravelled. AB - Collision-induced absorption is the phenomenon in which interactions between colliding molecules lead to absorption of light, even for transitions that are forbidden for the isolated molecules. Collision-induced absorption contributes to the atmospheric heat balance and is important for the electronic excitations of O2 that are used for remote sensing. Here, we present a theoretical study of five vibronic transitions in O2-O2 and O2-N2, using analytical models and numerical quantum scattering calculations. We unambiguously identify the underlying absorption mechanism, which is shown to depend explicitly on the collision partner-contrary to textbook knowledge. This explains experimentally observed qualitative differences between O2-O2 and O2-N2 collisions in the overall intensity, line shape and vibrational dependence of the absorption spectrum. It is shown that these results can be used to discriminate between conflicting experimental data and even to identify unphysical results, thus impacting future experimental studies and atmospheric applications. PMID- 29632337 TI - Boxing up food poverty. PMID- 29632338 TI - Metal transceptor. PMID- 29632336 TI - Fine Needle-Diathermy Regresses Pathological Corneal (Lymph)Angiogenesis and Promotes High-Risk Corneal Transplant Survival. AB - Pathological corneal hem- and lymphangiogenesis are prime risk factors for corneal graft rejection. Fine needle-diathermy (FND) is an option to regress corneal blood vessels; however, whether this treatment besides clinically visible blood vessels also affects invisible lymphatic vessels is so far unknown. Here we test the hypothesis that FND destroys not only blood but also lymphatic vessels, thereby promotes corneal high-risk graft survival. The effect of FND was studied in vivo using BALB/c mice and the model of suture-induced corneal neovascularization. Mice were divided into three groups: FND, ANTI (anti inflammatory therapy) and NON (control). Five, 7, 10 and 20 days after cauterization, corneas were harvested and stained with LYVE-1, CD31 to quantify (lymph)angiogenesis. The long-term survival of allografts was compared between the three groups. FND caused significant regression of both blood and lymphatic vessels compared to the control group at all time points (p < 0.05) with the most obvious effect at day 7 (p < 0.01). Graft survival was significantly prolonged when transplants were placed into the FND pretreated group (p < 0.0001). The effect of the anti-inflammatory therapy alone was less effective compared to FND (p < 0.05). This novel lymphangioregressive effect of FND can be used clinically to precondition high-risk recipients to promote graft survival. PMID- 29632339 TI - Contraction of basal filopodia controls periodic feather branching via Notch and FGF signaling. AB - Branching morphogenesis is a general mechanism that increases the surface area of an organ. In chicken feathers, the flat epithelial sheath at the base of the follicle is transformed into periodic branches. How exactly the keratinocytes are organized into this pattern remains unclear. Here we show that in the feather follicle, the pre-branch basal keratinocytes have extensive filopodia, which contract and smooth out after branching. Manipulating the filopodia via small GTPases RhoA/Cdc42 also regulates branch formation. These basal filopodia help interpret the proximal-distal FGF gradient in the follicle. Furthermore, the topological arrangement of cell adhesion via E-Cadherin re-distribution controls the branching process. Periodic activation of Notch signaling drives the differential cell adhesion and contraction of basal filopodia, which occurs only below an FGF signaling threshold. Our results suggest a coordinated adjustment of cell shape and adhesion orchestrates feather branching, which is regulated by Notch and FGF signaling. PMID- 29632341 TI - Germline alterations in a consecutive series of acute myeloid leukemia. PMID- 29632340 TI - Targeting the MALAT1/PARP1/LIG3 complex induces DNA damage and apoptosis in multiple myeloma. AB - Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is a highly conserved long non-coding RNA (lncRNA). Overexpression of MALAT1 has been demonstrated to related to poor prognosis of multiple myeloma (MM) patients. Here, we demonstrated that MALAT1 plays important roles in MM DNA repair and cell death. We found bone marrow plasma cells from patients with monoclonal gammopathy of undetermined significance (MGUS) and MM express elevated MALAT1 and involve in alternative non-homozygous end joining (A-NHEJ) pathway by binding to PARP1 and LIG3, two key components of the A-NHEJ protein complex. Degradation of the MALAT1 RNA by RNase H using antisense gapmer DNA oligos in MM cells stimulated poly-ADP ribosylation of nuclear proteins, defected the DNA repair pathway, and further provoked apoptotic pathways. Anti-MALAT1 therapy combined with PARP1 inhibitor or proteasome inhibitor in MM cells showed a synergistic effect in vitro. Furthermore, using novel single-wall carbon nanotube (SWCNT) conjugated with anti MALAT1 oligos, we successfully knocked-down MALAT1 RNA in cultured MM cell lines and xenograft murine models. Most importantly, anti-MALAT1 therapy induced DNA damage and cell apoptosis in vivo, indicating that MALAT1 could serve as a potential novel therapeutic target for MM treatment. PMID- 29632342 TI - Author Correction: Local generation of fumarate promotes DNA repair through inhibition of histone H3 demethylation. AB - In the version of this Article originally published, the authors mistakenly used the same images for three different time points in Fig. 2d: images for 24 h post IR WT were also used for 0 h post-IR WT (top row, left panels) and for 1 h post IR, T236A mutant (2nd row from the top, right panels). The correct images from these experiments have now been inserted in the figure in all online versions of the Article. In addition, results from this experiment and from two additional independent experiments have been uploaded to Figshare and the sentence 'Additional repeats of this experiment have been uploaded to Figshare28.' has been added to the figure legend to highlight this fact. The Figshare doi has been added as reference 28. The new reference and corrected Fig. 2d are shown below. PMID- 29632343 TI - Correcting B0 Field Distortions in MRI Caused by Stainless Steel Orthodontic Appliances at 1.5 T Using Permanent Magnets - A Head Phantom Study. AB - Susceptibility artifacts caused by stainless steel orthodontic appliances (braces) pose significant challenges in clinical brain MRI examinations. We introduced field correction device (FCD) utilizing permanent magnets to cancel the induced B0 inhomogeneity and mitigate geometric distortions in MRI. We evaluated a prototype FCD using a 3D-printed head phantom in this proof of concept study. The phantom was compartmented into anterior frontal lobe, temporal lobe, fronto-parieto-occipital lobe, basal ganglia and thalami, brain stem, and cerebellum and had built-in orthogonal gridlines to facilitate the quantification of geometric distortions and volume obliterations. Stainless steel braces were mounted on dental models of three different sizes with total induced magnetic moment 0.15 to 0.17 A.m2. With braces B0 standard deviation (SD) ranged from 2.8 to 3.7 ppm in the temporal and anterior frontal lobes vs. 0.2 to 0.3 ppm without braces. The volume of brain regions in diffusion weighted imaging was obliterated by 32-38% with braces vs. 0% without braces in the cerebellum. With the FCD the SD of B0 ranged from 0.3 to 1.2 ppm, and obliterated volume ranged from 0 to 6% in the corresponding brain areas. These results showed that FCD can effectively decrease susceptibility artifacts from orthodontic appliances. PMID- 29632345 TI - Corrigendum: Quantitative clinical characteristics of 53 patients with MPS VII: a cross-sectional analysis. AB - This corrects the article DOI: 10.1038/gim.2017.10. PMID- 29632348 TI - Kidney cancer: Antibody pincer movement challenges sunitinib as standard therapy. PMID- 29632347 TI - Positive Surgical Margins in the 10 Most Common Solid Cancers. AB - A positive surgical margin (PSM) following cancer resection oftentimes necessitates adjuvant treatments and carries significant financial and prognostic implications. We sought to compare PSM rates for the ten most common solid cancers in the United States, and to assess trends over time. Over 10 million patients were identified in the National Cancer Data Base from 1998-2012, and 6.5 million had surgical margin data. PSM rates were compared between two time periods, 1998-2002 and 2008-2012. PSM was positively correlated with tumor category and grade. Ovarian and prostate cancers had the highest PSM prevalence in women and men, respectively. The highest PSM rates for cancers affecting both genders were seen for oral cavity tumors. PSM rates for breast cancer and lung and bronchus cancer in both men and women declined over the study period. PSM increases were seen for bladder, colon and rectum, and kidney and renal pelvis cancers. This large-scale analysis appraises the magnitude of PSM in the United States in order to focus future efforts on improving oncologic surgical care with the goal of optimizing value and improving patient outcomes. PMID- 29632349 TI - Supraorbital morphology and social dynamics in human evolution. AB - Uniquely, with respect to Middle Pleistocene hominins, anatomically modern humans do not possess marked browridges, and have a more vertical forehead with mobile eyebrows that play a key role in social signalling and communication. The presence and variability of browridges in archaic Homo species and their absence in ourselves have led to debate concerning their morphogenesis and function, with two main hypotheses being put forward: that browridge morphology is the result of the spatial relationship between the orbits and the brain case; and that browridge morphology is significantly impacted by biting mechanics. Here, we virtually manipulate the browridge morphology of an archaic hominin (Kabwe 1), showing that it is much larger than the minimum required to fulfil spatial demands and that browridge size has little impact on mechanical performance during biting. As browridge morphology in this fossil is not driven by spatial and mechanical requirements alone, the role of the supraorbital region in social communication is a potentially significant factor. We propose that conversion of the large browridges of our immediate ancestors to a more vertical frontal bone in modern humans allowed highly mobile eyebrows to display subtle affiliative emotions. PMID- 29632350 TI - Trouble on the dating scene. PMID- 29632351 TI - Satellite passive microwaves reveal recent climate-induced carbon losses in African drylands. AB - The African continent is facing one of the driest periods in the past three decades as well as continued deforestation. These disturbances threaten vegetation carbon (C) stocks and highlight the need for improved capabilities of monitoring large-scale aboveground carbon stock dynamics. Here we use a satellite dataset based on vegetation optical depth derived from low-frequency passive microwaves (L-VOD) to quantify annual aboveground biomass-carbon changes in sub Saharan Africa between 2010 and 2016. L-VOD is shown not to saturate over densely vegetated areas. The overall net change in drylands (53% of the land area) was 0.05 petagrams of C per year (Pg C yr-1) associated with drying trends, and a net change of -0.02 Pg C yr-1 was observed in humid areas. These trends reflect a high inter-annual variability with a very dry year in 2015 (net change, -0.69 Pg C) with about half of the gross losses occurring in drylands. This study demonstrates, first, the applicability of L-VOD to monitor the dynamics of carbon loss and gain due to weather variations, and second, the importance of the highly dynamic and vulnerable carbon pool of dryland savannahs for the global carbon balance, despite the relatively low carbon stock per unit area. PMID- 29632353 TI - Pulling faces. PMID- 29632352 TI - Homo sapiens in Arabia by 85,000 years ago. AB - Understanding the timing and character of the expansion of Homo sapiens out of Africa is critical for inferring the colonization and admixture processes that underpin global population history. It has been argued that dispersal out of Africa had an early phase, particularly ~130-90 thousand years ago (ka), that reached only the East Mediterranean Levant, and a later phase, ~60-50 ka, that extended across the diverse environments of Eurasia to Sahul. However, recent findings from East Asia and Sahul challenge this model. Here we show that H. sapiens was in the Arabian Peninsula before 85 ka. We describe the Al Wusta-1 (AW 1) intermediate phalanx from the site of Al Wusta in the Nefud desert, Saudi Arabia. AW-1 is the oldest directly dated fossil of our species outside Africa and the Levant. The palaeoenvironmental context of Al Wusta demonstrates that H. sapiens using Middle Palaeolithic stone tools dispersed into Arabia during a phase of increased precipitation driven by orbital forcing, in association with a primarily African fauna. A Bayesian model incorporating independent chronometric age estimates indicates a chronology for Al Wusta of ~95-86 ka, which we correlate with a humid episode in the later part of Marine Isotope Stage 5 known from various regional records. Al Wusta shows that early dispersals were more spatially and temporally extensive than previously thought. Early H. sapiens dispersals out of Africa were not limited to winter rainfall-fed Levantine Mediterranean woodlands immediately adjacent to Africa, but extended deep into the semi-arid grasslands of Arabia, facilitated by periods of enhanced monsoonal rainfall. PMID- 29632355 TI - Joining the dots. PMID- 29632356 TI - Protecting intact forests requires holistic approaches. PMID- 29632354 TI - Multicopy plasmids allow bacteria to escape from fitness trade-offs during evolutionary innovation. AB - Understanding the mechanisms governing innovation is a central element of evolutionary theory. Novel traits usually arise through mutations in existing genes, but trade-offs between new and ancestral protein functions are pervasive and constrain the evolution of innovation. Classical models posit that evolutionary innovation circumvents the constraints imposed by trade-offs through genetic amplifications, which provide functional redundancy. Bacterial multicopy plasmids provide a paradigmatic example of genetic amplification, yet their role in evolutionary innovation remains largely unexplored. Here, we reconstructed the evolution of a new trait encoded in a multicopy plasmid using TEM-1 beta lactamase as a model system. Through a combination of theory and experimentation, we show that multicopy plasmids promote the coexistence of ancestral and novel traits for dozens of generations, allowing bacteria to escape the evolutionary constraints imposed by trade-offs. Our results suggest that multicopy plasmids are excellent platforms for evolutionary innovation, contributing to explain their extreme abundance in bacteria. PMID- 29632357 TI - The evolution of immunity in relation to colonization and migration. AB - Colonization and migration have a crucial effect on patterns of biodiversity, with disease predicted to play an important role in these processes. However, evidence of the effect of pathogens on broad patterns of colonization and migration is limited. Here, using phylogenetic analyses of 1,311 species of Afro Palaearctic songbirds, we show that colonization events from regions of high (sub Saharan Africa) to low (the Palaearctic) pathogen diversity were up to 20 times more frequent than the reverse, and that migration has evolved 3 times more frequently from African- as opposed to Palaearctic-resident species. We also found that resident species that colonized the Palaearctic from Africa, as well as African species that evolved long-distance migration to breed in the Palaearctic, have reduced diversity of key immune genes associated with pathogen recognition (major histocompatibility complex class I). These results suggest that changes in the pathogen community that occur during colonization and migration shape the evolution of the immune system, potentially by adjusting the trade-off between the benefits of extensive pathogen recognition and the costs of immunopathology that result from high major histocompatibility complex class I diversity. PMID- 29632358 TI - Baby brains reflect maternal inflammation. PMID- 29632359 TI - A hypothalamic circuit for the circadian control of aggression. AB - 'Sundowning' in dementia and Alzheimer's disease is characterized by early evening agitation and aggression. While such periodicity suggests a circadian origin, whether the circadian clock directly regulates aggressive behavior is unknown. We demonstrate that a daily rhythm in aggression propensity in male mice is gated by GABAergic subparaventricular zone (SPZGABA) neurons, the major postsynaptic targets of the central circadian clock, the suprachiasmatic nucleus. Optogenetic mapping revealed that SPZGABA neurons receive input from vasoactive intestinal polypeptide suprachiasmatic nucleus neurons and innervate neurons in the ventrolateral part of the ventromedial hypothalamus (VMH), which is known to regulate aggression. Additionally, VMH-projecting dorsal SPZ neurons are more active during early day than early night, and acute chemogenetic inhibition of SPZGABA transmission phase-dependently increases aggression. Finally, SPZGABA recipient central VMH neurons directly innervate ventrolateral VMH neurons, and activation of this intra-VMH circuit drove attack behavior. Altogether, we reveal a functional polysynaptic circuit by which the suprachiasmatic nucleus clock regulates aggression. PMID- 29632360 TI - Tbr1 instructs laminar patterning of retinal ganglion cell dendrites. AB - Visual information is delivered to the brain by >40 types of retinal ganglion cells (RGCs). Diversity in this representation arises within the inner plexiform layer (IPL), where dendrites of each RGC type are restricted to specific sublaminae, limiting the interneuronal types that can innervate them. How such dendritic restriction arises is unclear. We show that the transcription factor Tbr1 is expressed by four mouse RGC types with dendrites in the outer IPL and is required for their laminar specification. Loss of Tbr1 results in elaboration of dendrites within the inner IPL, while misexpression in other cells retargets their neurites to the outer IPL. Two transmembrane molecules, Sorcs3 and Cdh8, act as effectors of the Tbr1-controlled lamination program. However, they are expressed in just one Tbr1+ RGC type, supporting a model in which a single transcription factor implements similar laminar choices in distinct cell types by recruiting partially non-overlapping effectors. PMID- 29632362 TI - From cooperative to uncorrelated clogging in cross-flow microfluidic membranes. AB - The operational lifetime of filtration membranes is reduced by the clogging of pores and subsequent build-up of a fouling or cake layer. Designing membrane operations in which clogging is delayed or even mitigated completely, requires in depth insight into its origins. Due to the complexity of the clogging process, simplified model membranes fabricated in microfluidic chips have emerged as a powerful tool to study how clogs emerge and deteriorate membrane efficiency. However, to date, these have focussed solely on dead-end filtration, while cross flow filtration is of greater practical relevance at the industrial scale. As such, the microscopic mechanisms of clogging in crossflow geometries have remained relatively ill-explored. Here we use a microfluidic filtration model to probe the kinetics and mechanisms of clogging in crossflow. Our study exposes two findings: (i) the primary clogging rate of individual pores depends only on the trans-membrane flux, whose strong effects are explained quantitatively by extending existing models with a term for flux-controlled flow-enhanced barrier crossing, (ii) cross-membrane flow affects the pore-pore communication, leading to a transition from correlated to uncorrelated clogging of the membrane, which we explain qualitatively by deriving a dimensionless number which captures two essential regimes of clogging at the microscale. PMID- 29632361 TI - Maternal IL-6 during pregnancy can be estimated from newborn brain connectivity and predicts future working memory in offspring. AB - Several lines of evidence support the link between maternal inflammation during pregnancy and increased likelihood of neurodevelopmental and psychiatric disorders in offspring. This longitudinal study seeks to advance understanding regarding implications of systemic maternal inflammation during pregnancy, indexed by plasma interleukin-6 (IL-6) concentrations, for large-scale brain system development and emerging executive function skills in offspring. We assessed maternal IL-6 during pregnancy, functional magnetic resonance imaging acquired in neonates, and working memory (an important component of executive function) at 2 years of age. Functional connectivity within and between multiple neonatal brain networks can be modeled to estimate maternal IL-6 concentrations during pregnancy. Brain regions heavily weighted in these models overlap substantially with those supporting working memory in a large meta-analysis. Maternal IL-6 also directly accounts for a portion of the variance of working memory at 2 years of age. Findings highlight the association of maternal inflammation during pregnancy with the developing functional architecture of the brain and emerging executive function. PMID- 29632363 TI - Temporal and spatial changes of macrobenthos community in the regions frequently occurring black water aggregation in Lake Taihu. AB - Seasonal survey was performed from August 2015 to May 2016 at 50 sampling sites in Lake Taihu to determine the spatial and temporal changes in macrobenthos community and their relationships with environmental variables. A total of 58 macrobenthos species were collected and identified, including 28 species of annelids, 17 species of molluscs, and 12 species of arthropods. Both the community composition and the dominant species changed temporally and spatially. Correspondingly, the macrobenthos biodiversity differed among regions and seasons. The macrobenthos density decreased with increased sediment depth, which is the first report about the vertical distribution of macrobenthos in Lake Taihu. The majority of benthic animals were located within the sediment depth of 0-5 cm and 5-10 cm, accounting for 39.25% and 24.87% of the total abundance respectively. Redundancy discriminate analysis revealed that the main environmental factors affecting the most contributing macrobenthos species were temperature in summer, transparency, dissolved oxygen and pH in autumn, and water depth and dissolved oxygen in winter. Particularly, salinity and conductivity showed high correlation with the macrobenthos community through the whole sampling period. The investigation reveals the inherent spatiotemporal variation of macrobenthos community, and provides references for the biological assessment of water quality in Lake Taihu. PMID- 29632365 TI - Mining for novel bacterial defence systems. PMID- 29632366 TI - Structural insight into the assembly of the type II secretion system pilotin secretin complex from enterotoxigenic Escherichia coli. AB - Secretin is a large outer-membrane channel found in secretion systems of Gram negative bacteria, facilitating the last step for transfer of proteins into the extracellular environment. In the type II secretion system, a lipoprotein called pilotin is essential to bind and target its corresponding secretin to the outer membrane. However, there is only limited structural information available about the interaction and assembly of the pilotin-secretin complex. Here we report the first near-atomic-resolution structure of a full-length Vibrio-type pilotin secretin (AspS-GspD) complex from enterotoxigenic Escherichia coli by cryo electron microscopy, which reveals the detailed assembly mode of the full-length pilotin-secretin complex. The AspS subunits attach to the secretin channel surface with a 15:15 stoichiometric ratio to GspD subunits, and insert their amino terminus into the outer membrane. The AspS subunits interact with all three secondary structural elements of the S domain of GspD, including strong interaction with the carboxy-terminal alpha-helix and weak interactions with another two elements, an alpha-helix and a loop. These structural and biochemical details provide a deeper insight to pilotin-secretin interaction and their assembly mode. PMID- 29632367 TI - Proteotype profiling unmasks a viral signalling network essential for poxvirus assembly and transcriptional competence. AB - To orchestrate context-dependent signalling programmes, poxviruses encode two dual-specificity enzymes, the F10 kinase and the H1 phosphatase. These signalling mediators are essential for poxvirus production, yet their substrate profiles and systems-level functions remain enigmatic. Using a phosphoproteomic screen of cells infected with wild-type, F10 and H1 mutant vaccinia viruses, we systematically defined the viral signalling network controlled by these enzymes. Quantitative cross-comparison revealed 33 F10 and/or H1 phosphosites within 17 viral proteins. Using this proteotype dataset to inform genotype-phenotype relationships, we found that H1-deficient virions harbour a hidden hypercleavage phenotype driven by reversible phosphorylation of the virus protease I7 (S134). Quantitative phosphoproteomic profiling further revealed that the phosphorylation dependent activity of the viral early transcription factor, A7 (Y367), underlies the transcription-deficient phenotype of H1 mutant virions. Together, these results highlight the utility of combining quantitative proteotype screens with mutant viruses to uncover proteotype-phenotype-genotype relationships that are masked by classical genetic studies. PMID- 29632369 TI - A type VI secretion system effector delivery mechanism dependent on PAAR and a chaperone-co-chaperone complex. AB - The type VI secretion system (T6SS) is used by many Gram-negative bacteria as a molecular weapon to modulate neighbouring bacterial and eukaryotic cells, thereby affecting the dynamics of community structure in multiple species environments. The T6SS injects its inner-needle Hcp tube, the sharpening tip complex consisting of VgrG and PAAR, and toxic effectors into neighbouring cells. Its functions are largely determined by the activities of its delivered effectors. Six mechanisms of effector delivery have been described: two mediated by the inner tube and the others mediated by the VgrG and PAAR tip complex. Here, we report an additional effector delivery mechanism that relies on interaction with a chaperone complex and a PAAR protein as a carrier. The Pseudomonas aeruginosa PAO1 TOX-REase-5 domain-containing effector TseT directly interacts with PAAR4 and the chaperone TecT for delivery, and an immunity protein, TsiT, for protection from its toxicity. TecT forms a complex with its co-chaperone, co-TecT, which is disrupted by the carboxy-terminal tail of PAAR4. In addition, we delineate a complex, multilayered competitive process that dictates effector trafficking. PAAR delivery provides an additional tool for engineering cargo protein translocation. PMID- 29632368 TI - Topical application of aminoglycoside antibiotics enhances host resistance to viral infections in a microbiota-independent manner. AB - Antibiotics are widely used to treat infections in humans. However, the impact of antibiotic use on host cells is understudied. Here we identify an antiviral effect of commonly used aminoglycoside antibiotics. We show that topical mucosal application of aminoglycosides prophylactically increased host resistance to a broad range of viral infections including herpes simplex viruses, influenza A virus and Zika virus. Aminoglycoside treatment also reduced viral replication in primary human cells. This antiviral activity was independent of the microbiota, because aminoglycoside treatment protected germ-free mice. Microarray analysis uncovered a marked upregulation of transcripts for interferon-stimulated genes (ISGs) following aminoglycoside application. ISG induction was mediated by Toll like receptor 3, and required Toll/interleukin-1-receptor-domain-containing adapter-inducing interferon-beta signalling adaptor, and Interferon regulatory factors 3 and 7, transcription factors that promote ISG expression. XCR1+ dendritic cells, which uniquely express Toll-like receptor 3, were recruited to the vaginal mucosa upon aminoglycoside treatment and were required for ISG induction. These results highlight an unexpected ability of aminoglycoside antibiotics to confer broad antiviral resistance in vivo. PMID- 29632370 TI - A cynomolgus macaque model for Crimean-Congo haemorrhagic fever. AB - Crimean-Congo haemorrhagic fever (CCHF) is the most medically significant tick borne disease, being widespread in the Middle East, Asia, Africa and parts of Europe 1 . Increasing case numbers, westerly movement and broadly ranging case fatality rates substantiate the concern of CCHF as a public health threat. Ixodid ticks of the genus Hyalomma are the vector for CCHF virus (CCHFV), an arbovirus in the genus Orthonairovirus of the family Nairoviridae. CCHFV naturally infects numerous wild and domestic animals via tick bite without causing obvious disease2,3. Severe disease occurs only in humans and transmission usually happens through tick bite or contact with infected animals or humans. The only CCHF disease model is a subset of immunocompromised mice4-6. Here, we show that following CCHFV infection, cynomolgus macaques exhibited hallmark signs of human CCHF with remarkably similar viral dissemination, organ pathology and disease progression. Histopathology showed infection of hepatocytes, endothelial cells and monocytes and fatal outcome seemed associated with endothelial dysfunction manifesting in a clinical shock syndrome with coagulopathy. This non-human primate model will be an invaluable asset for CCHFV countermeasures development. PMID- 29632364 TI - Multimodal and Multiscale Deep Neural Networks for the Early Diagnosis of Alzheimer's Disease using structural MR and FDG-PET images. AB - Alzheimer's Disease (AD) is a progressive neurodegenerative disease where biomarkers for disease based on pathophysiology may be able to provide objective measures for disease diagnosis and staging. Neuroimaging scans acquired from MRI and metabolism images obtained by FDG-PET provide in-vivo measurements of structure and function (glucose metabolism) in a living brain. It is hypothesized that combining multiple different image modalities providing complementary information could help improve early diagnosis of AD. In this paper, we propose a novel deep-learning-based framework to discriminate individuals with AD utilizing a multimodal and multiscale deep neural network. Our method delivers 82.4% accuracy in identifying the individuals with mild cognitive impairment (MCI) who will convert to AD at 3 years prior to conversion (86.4% combined accuracy for conversion within 1-3 years), a 94.23% sensitivity in classifying individuals with clinical diagnosis of probable AD, and a 86.3% specificity in classifying non-demented controls improving upon results in published literature. PMID- 29632371 TI - Gain of toxic apolipoprotein E4 effects in human iPSC-derived neurons is ameliorated by a small-molecule structure corrector. AB - Efforts to develop drugs for Alzheimer's disease (AD) have shown promise in animal studies, only to fail in human trials, suggesting a pressing need to study AD in human model systems. Using human neurons derived from induced pluripotent stem cells that expressed apolipoprotein E4 (ApoE4), a variant of the APOE gene product and the major genetic risk factor for AD, we demonstrated that ApoE4 expressing neurons had higher levels of tau phosphorylation, unrelated to their increased production of amyloid-beta (Abeta) peptides, and that they displayed GABAergic neuron degeneration. ApoE4 increased Abeta production in human, but not in mouse, neurons. Converting ApoE4 to ApoE3 by gene editing rescued these phenotypes, indicating the specific effects of ApoE4. Neurons that lacked APOE behaved similarly to those expressing ApoE3, and the introduction of ApoE4 expression recapitulated the pathological phenotypes, suggesting a gain of toxic effects from ApoE4. Treatment of ApoE4-expressing neurons with a small-molecule structure corrector ameliorated the detrimental effects, thus showing that correcting the pathogenic conformation of ApoE4 is a viable therapeutic approach for ApoE4-related AD. PMID- 29632373 TI - Archean phosphorus liberation induced by iron redox geochemistry. AB - The element phosphorus (P) is central to ecosystem growth and is proposed to be a limiting nutrient for life. The Archean ocean may have been strongly phosphorus limited due to the selective binding of phosphate to iron oxyhydroxide. Here we report a new route to solubilizing phosphorus in the ancient oceans: reduction of phosphate to phosphite by iron(II) at low (<200 degrees C) diagenetic temperatures. Reduction of phosphate to phosphite was likely widespread in the Archean, as the reaction occurs rapidly and is demonstrated from thermochemical modeling, experimental analogs, and detection of phosphite in early Archean rocks. We further demonstrate that the higher solubility of phosphite compared to phosphate results in the liberation of phosphorus from ferruginous sediments. This phosphite is relatively stable after its formation, allowing its accumulation in the early oceans. As such, phosphorus, not as phosphate but as phosphite, could have been a major nutrient in early pre-oxygenated oceans. PMID- 29632372 TI - Improving treatment outcome assessment in a mouse tuberculosis model. AB - Preclinical treatment outcome evaluation of tuberculosis (TB) occurs primarily in mice. Current designs compare relapse rates of different regimens at selected time points, but lack information about the correlation between treatment length and treatment outcome, which is required to efficiently estimate a regimens' treatment-shortening potential. Therefore we developed a new approach. BALB/c mice were infected with a Mycobacterium tuberculosis Beijing genotype strain and were treated with rifapentine-pyrazinamide-isoniazid-ethambutol (RpZHE), rifampicin-pyrazinamide-moxifloxacin-ethambutol (RZME) or rifampicin-pyrazinamide moxifloxacin-isoniazid (RZMH). Treatment outcome was assessed in n = 3 mice after 9 different treatment lengths between 2-6 months. Next, we created a mathematical model that best fitted the observational data and used this for inter-regimen comparison. The observed data were best described by a sigmoidal Emax model in favor over linear or conventional Emax models. Estimating regimen-specific parameters showed significantly higher curative potentials for RZME and RpZHE compared to RZMH. In conclusion, we provide a new design for treatment outcome evaluation in a mouse TB model, which (i) provides accurate tools for assessment of the relationship between treatment length and predicted cure, (ii) allows for efficient comparison between regimens and (iii) adheres to the reduction and refinement principles of laboratory animal use. PMID- 29632375 TI - FAIR to the community. PMID- 29632374 TI - Short cryptic exons mediate recursive splicing in Drosophila. AB - Many long Drosophila introns are processed by an unusual recursive strategy. The presence of ~200 adjacent splice acceptor and splice donor sites, termed ratchet points (RPs), were inferred to reflect 'zero-nucleotide exons', whose sequential processing subdivides removal of long host introns. We used CRISPR-Cas9 to disrupt several intronic RPs in Drosophila melanogaster, some of which recapitulated characteristic loss-of-function phenotypes. Unexpectedly, selective disruption of RP splice donors revealed constitutive retention of unannotated short exons. Assays using functional minigenes confirm that unannotated cryptic splice donor sites are critical for recognition of intronic RPs, demonstrating that recursive splicing involves the recognition of cryptic RP exons. This appears to be a general mechanism, because canonical, conserved splice donors are specifically enriched in a 40-80-nt window downstream of known and newly annotated intronic RPs and exhibit similar properties to a broadly expanded class of expressed RP exons. Overall, these studies unify the mechanism of Drosophila recursive splicing with that in mammals. PMID- 29632377 TI - Repeat expansions in myoclonic epilepsy. PMID- 29632376 TI - Highly parallel genome variant engineering with CRISPR-Cas9. AB - Understanding the functional effects of DNA sequence variants is of critical importance for studies of basic biology, evolution, and medical genetics; however, measuring these effects in a high-throughput manner is a major challenge. One promising avenue is precise editing with the CRISPR-Cas9 system, which allows for generation of DNA double-strand breaks (DSBs) at genomic sites matching the targeting sequence of a guide RNA (gRNA). Recent studies have used CRISPR libraries to generate many frameshift mutations genome wide through faulty repair of CRISPR-directed breaks by nonhomologous end joining (NHEJ) 1 . Here, we developed a CRISPR-library-based approach for highly efficient and precise genome wide variant engineering. We used our method to examine the functional consequences of premature-termination codons (PTCs) at different locations within all annotated essential genes in yeast. We found that most PTCs were highly deleterious unless they occurred close to the 3' end of the gene and did not affect an annotated protein domain. Unexpectedly, we discovered that some putatively essential genes are dispensable, whereas others have large dispensable regions. This approach can be used to profile the effects of large classes of variants in a high-throughput manner. PMID- 29632378 TI - Evaluating tumor-suppressor gene combinations. PMID- 29632379 TI - Regulatory variants at KLF14 influence type 2 diabetes risk via a female-specific effect on adipocyte size and body composition. AB - Individual risk of type 2 diabetes (T2D) is modified by perturbations to the mass, distribution and function of adipose tissue. To investigate the mechanisms underlying these associations, we explored the molecular, cellular and whole-body effects of T2D-associated alleles near KLF14. We show that KLF14 diabetes-risk alleles act in adipose tissue to reduce KLF14 expression and modulate, in trans, the expression of 385 genes. We demonstrate, in human cellular studies, that reduced KLF14 expression increases pre-adipocyte proliferation but disrupts lipogenesis, and in mice, that adipose tissue-specific deletion of Klf14 partially recapitulates the human phenotype of insulin resistance, dyslipidemia and T2D. We show that carriers of the KLF14 T2D risk allele shift body fat from gynoid stores to abdominal stores and display a marked increase in adipocyte cell size, and that these effects on fat distribution, and the T2D association, are female specific. The metabolic risk associated with variation at this imprinted locus depends on the sex both of the subject and of the parent from whom the risk allele derives. PMID- 29632380 TI - Heritability enrichment of specifically expressed genes identifies disease relevant tissues and cell types. AB - We introduce an approach to identify disease-relevant tissues and cell types by analyzing gene expression data together with genome-wide association study (GWAS) summary statistics. Our approach uses stratified linkage disequilibrium (LD) score regression to test whether disease heritability is enriched in regions surrounding genes with the highest specific expression in a given tissue. We applied our approach to gene expression data from several sources together with GWAS summary statistics for 48 diseases and traits (average N = 169,331) and found significant tissue-specific enrichments (false discovery rate (FDR) < 5%) for 34 traits. In our analysis of multiple tissues, we detected a broad range of enrichments that recapitulated known biology. In our brain-specific analysis, significant enrichments included an enrichment of inhibitory over excitatory neurons for bipolar disorder, and excitatory over inhibitory neurons for schizophrenia and body mass index. Our results demonstrate that our polygenic approach is a powerful way to leverage gene expression data for interpreting GWAS signals. PMID- 29632381 TI - Plain-language medical vocabulary for precision diagnosis. PMID- 29632384 TI - The Scientific Basis and Advantage of Human Experiential Assessment in the quality control of Chinese Herbal Medicines exampling as Schisandrae Chinensis Fructus. AB - Experiential quality assessment(EQA) is an important sensory analysis for judging herbal quality grades. Because of the high empirical utility of expert experience, the consistency, science and inheritance of such experience are continuously in dispute. To explore the scientific evidence for this subjective method, we designed a Delphi expert investigation coupled with chemical analysis to evaluate the quality of Schisandrae Chinensis Fructus (SCF). Initially, 13 experts were invited to independently evaluate the grades of 11 batches of SCF. After screening the consistency and repeatability of the evaluation results, typical samples of all quality levels were identified. Seven significant physical characters were detected; colour and size were found to be the key parameters for identifying SCF quality. Based on this correlation, a decision tree model was ultimately established and converted to a quality evaluation card. Over 80% consistency in a novice test demonstrated the technical advantages and application characteristics of the model. Further correlation analysis revealed that EQA quality grades of SCF were positively correlated to the content of polysaccharides and polyphenols, while negatively correlated to the content of lignans. Biological activities were also approving it. In summary, our study proves that subjective EQA is consistency, repeatability and could be inherited. PMID- 29632385 TI - Systematic design and experimental demonstration of bianisotropic metasurfaces for scattering-free manipulation of acoustic wavefronts. AB - Recent advances in gradient metasurfaces have shown that by locally controlling the bianisotropic response of the cells one can ensure full control of refraction, that is, arbitrarily redirect the waves without scattering into unwanted directions. In this work, we propose and experimentally verify the use of an acoustic cell architecture that provides enough degrees of freedom to fully control the bianisotropic response and minimizes the losses. The versatility of the approach is shown through the design of three refractive metasurfaces capable of redirecting a normally incident plane wave to 60 degrees , 70 degrees , and 80 degrees on transmission. The efficiency of the bianisotropic designs is over 90%, much higher than the corresponding generalized Snell's law based designs (81%, 58%, and 35%). The proposed strategy opens a new way of designing practical and highly efficient bianisotropic metasurfaces for different functionalities, enabling nearly ideal control over the energy flow through thin metasurfaces. PMID- 29632383 TI - Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights. AB - Genome-wide association studies (GWAS) have identified over 100 risk loci for schizophrenia, but the causal mechanisms remain largely unknown. We performed a transcriptome-wide association study (TWAS) integrating a schizophrenia GWAS of 79,845 individuals from the Psychiatric Genomics Consortium with expression data from brain, blood, and adipose tissues across 3,693 primarily control individuals. We identified 157 TWAS-significant genes, of which 35 did not overlap a known GWAS locus. Of these 157 genes, 42 were associated with specific chromatin features measured in independent samples, thus highlighting potential regulatory targets for follow-up. Suppression of one identified susceptibility gene, mapk3, in zebrafish showed a significant effect on neurodevelopmental phenotypes. Expression and splicing from the brain captured most of the TWAS effect across all genes. This large-scale connection of associations to target genes, tissues, and regulatory features is an essential step in moving toward a mechanistic understanding of GWAS. PMID- 29632386 TI - Metabolomics and proteomics reveal drought-stress responses of leaf tissues from spring-wheat. AB - To reveal the integrative biochemical networks of wheat leaves in response to water deficient conditions, proteomics and metabolomics were applied to two spring-wheat cultivars (Bahar, drought-susceptible; Kavir, drought-tolerant). Drought stress induced detrimental effects on Bahar leaf proteome, resulting in a severe decrease of total protein content, with impairments mainly in photosynthetic proteins and in enzymes involved in sugar and nitrogen metabolism, as well as in the capacity of detoxifying harmful molecules. On the contrary, only minor perturbations were observed at the protein level in Kavir stressed leaves. Metabolome analysis indicated amino acids, organic acids, and sugars as the main metabolites changed in abundance upon water deficiency. In particular, Bahar cv showed increased levels in proline, methionine, arginine, lysine, aromatic and branched chain amino acids. Tryptophan accumulation via shikimate pathway seems to sustain auxin production (indoleacrylic acid), whereas glutamate reduction is reasonably linked to polyamine (spermine) synthesis. Kavir metabolome was affected by drought stress to a less extent with only two pathways significantly changed, one of them being purine metabolism. These results comprehensively provide a framework for better understanding the mechanisms that govern plant cell response to drought stress, with insights into molecules that can be used for crop improvement projects. PMID- 29632388 TI - New awards aim to celebrate women in science. PMID- 29632389 TI - Peptide signal alerts plants to drought. PMID- 29632387 TI - The focal alteration and causal connectivity in children with new-onset benign epilepsy with centrotemporal spikes. AB - The aim of the current study was to find the epileptic focus and examine its causal relationship to other brain regions in children with new-onset benign childhood epilepsy with centrotemporal spikes (BECTS). Resting-state functional magnetic resonance imaging (fMRI) was performed in 66 children with BECTS and 37 matched control children. We compared the amplitude of low frequency fluctuation (ALFF) signals between the two groups to find the potential epileptogenic zone (EZ), then used Granger causality analysis (GCA) to explore the causal effects of EZ on the whole brain. Children with BECTS had significantly increased ALFF in the right Broca's area, and decreased ALFF in bilateral fusiform gyrus. The patients also showed increased driving effect from the EZ in Broca's area to the right prefrontal lobe, and decreased effects to the frontal lobe and posterior parts of the language network. The causal effect on left Wernicke's area negatively correlated with verbal IQ (VIQ) score. Our research on new-onset BECTS patients illustrates a possible compensatory mechanism in the language network at early stages of BECTS, and the negative correlation of GCA and VIQ suggest the disturbance of epileptiform activity on language. These findings shed light on the mechanisms of and language dysfunction in BECTS. PMID- 29632390 TI - Backbone of RNA viruses uncovered. PMID- 29632391 TI - All-Optical Reinforcement Learning In Solitonic X-Junctions. AB - Ethology has shown that animal groups or colonies can perform complex calculation distributing simple decision-making processes to the group members. For example ant colonies can optimize the trajectories towards the food by performing both a reinforcement (or a cancellation) of the pheromone traces and a switch from one path to another with stronger pheromone. Such ant's processes can be implemented in a photonic hardware to reproduce stigmergic signal processing. We present innovative, completely integrated X-junctions realized using solitonic waveguides which can provide both ant's decision-making processes. The proposed X-junctions can switch from symmetric (50/50) to asymmetric behaviors (80/20) using optical feedbacks, vanishing unused output channels or reinforcing the used ones. PMID- 29632392 TI - Targeting the polyadenylation factor EhCFIm25 with RNA aptamers controls survival in Entamoeba histolytica. AB - Messenger RNA 3'-end polyadenylation is an important regulator of gene expression in eukaryotic cells. In our search for new ways of treating parasitic infectious diseases, we looked at whether or not alterations in polyadenylation might control the survival of Entamoeba histolytica (the agent of amoebiasis in humans). We used molecular biology and computational tools to characterize the mRNA cleavage factor EhCFIm25, which is essential for polyadenylation in E. histolytica. By using a strategy based on the systematic evolution of ligands by exponential enrichment, we identified single-stranded RNA aptamers that target EhCFIm25. The results of RNA-protein binding assays showed that EhCFIm25 binds to the GUUG motif in vitro, which differs from the UGUA motif bound by the homologous human protein. Accordingly, docking experiments and molecular dynamic simulations confirmed that interaction with GUUG stabilizes EhCFIm25. Incubating E. histolytica trophozoites with selected aptamers inhibited parasite proliferation and rapidly led to cell death. Overall, our data indicate that targeting EhCFIm25 is an effective way of limiting the growth of E. histolytica in vitro. The present study is the first to have highlighted the potential value of RNA aptamers for controlling this human pathogen. PMID- 29632382 TI - Refining the accuracy of validated target identification through coding variant fine-mapping in type 2 diabetes. AB - We aggregated coding variant data for 81,412 type 2 diabetes cases and 370,832 controls of diverse ancestry, identifying 40 coding variant association signals (P < 2.2 * 10-7); of these, 16 map outside known risk-associated loci. We make two important observations. First, only five of these signals are driven by low frequency variants: even for these, effect sizes are modest (odds ratio <=1.29). Second, when we used large-scale genome-wide association data to fine-map the associated variants in their regional context, accounting for the global enrichment of complex trait associations in coding sequence, compelling evidence for coding variant causality was obtained for only 16 signals. At 13 others, the associated coding variants clearly represent 'false leads' with potential to generate erroneous mechanistic inference. Coding variant associations offer a direct route to biological insight for complex diseases and identification of validated therapeutic targets; however, appropriate mechanistic inference requires careful specification of their causal contribution to disease predisposition. PMID- 29632393 TI - Coarse particulate matter (PM2.5-10) in Los Angeles Basin air induces expression of inflammation and cancer biomarkers in rat brains. AB - Air pollution is linked to brain inflammation, which accelerates tumorigenesis and neurodegeneration. The molecular mechanisms that connect air pollution with brain pathology are largely unknown but seem to depend on the chemical composition of airborne particulate matter (PM). We sourced ambient PM from Riverside, California, and selectively exposed rats to coarse (PM2.5-10: 2.5-10 um), fine (PM<2.5: <2.5 um), or ultrafine particles (UFPM: <0.15 um). We characterized each PM type via atomic emission spectroscopy and detected nickel, cobalt and zinc within them. We then exposed rats separately to each PM type for short (2 weeks), intermediate (1-3 months) and long durations (1 year). All three metals accumulated in rat brains during intermediate-length PM exposures. Via RNAseq analysis we then determined that intermediate-length PM2.5-10 exposures triggered the expression of the early growth response gene 2 (EGR2), genes encoding inflammatory cytokine pathways (IL13-Ralpha1 and IL-16) and the oncogene RAC1. Gene upregulation occurred only in brains of rats exposed to PM2.5-10 and correlated with cerebral nickel accumulation. We hypothesize that the expression of inflammation and oncogenesis-related genes is triggered by the combinatorial exposure to certain metals and toxins in Los Angeles Basin PM2.5-10. PMID- 29632394 TI - SPL6 represses signalling outputs of ER stress in control of panicle cell death in rice. AB - Inositol-requiring enzyme 1 (IRE1) is the most conserved transducer of the unfolded protein response that produces either adaptive or death signals depending on the amplitude and duration of its activation. Here, we report that SQUAMOSA PROMOTER-BINDING PROTEIN-LIKE 6 (SPL6)-deficient plants displayed hyperactivation of the endoplasmic reticulum (ER) stress sensor IRE1, leading to cell death in rice panicles, indicating that SPL6 is an essential survival factor for the suppression of persistent or intense ER stress conditions. Importantly, knockdown of the hyperactivated mRNA level of IRE1 rescues panicle apical abortion in the spl6-1 transgenic plants harbouring the IRE1-RNAi constructs, establishing the genetic linkage between the hyperactivation of IRE1 and cell death in spl6-1. Our findings reveal a novel cell survival machinery in which SPL6 represses the transcriptional activation of the ER stress sensor IRE1 in control of ER stress signalling outputs that hinge on a balance between adaptive and death signals for determining cell fates during ER stress. PMID- 29632396 TI - Believe in the force. PMID- 29632395 TI - Improvement of Storage Medium for Cultured Human Retinal Pigment Epithelial Cells Using Factorial Design. AB - Storage of human retinal pigment epithelium (hRPE) can contribute to the advancement of cell-based RPE replacement therapies. The present study aimed to improve the quality of stored hRPE cultures by identifying storage medium additives that, alone or in combination, contribute to enhancing cell viability while preserving morphology and phenotype. hRPE cells were cultured in the presence of the silk protein sericin until pigmentation. Cells were then stored for 10 days in storage medium plus sericin and either one of 46 different additives. Individual effects of each additive on cell viability were assessed using epifluorescence microscopy. Factorial design identified promising additive combinations by extrapolating their individual effects. Supplementing the storage medium with sericin combined with adenosine, L-ascorbic acid and allopurinol resulted in the highest cell viability (98.6 +/- 0.5%) after storage for three days, as measured by epifluorescence microscopy. Flow cytometry validated the findings. Proteomics identified 61 upregulated and 65 downregulated proteins in this storage group compared to the unstored control. Transmission electron microscopy demonstrated the presence of melanosomes after storage in the optimized medium. We conclude that the combination of adenosine, L-ascorbic acid, allopurinol and sericin in minimal essential medium preserves RPE pigmentation while maintaining cell viability during storage. PMID- 29632397 TI - Quantitative assessment of intermolecular interactions by atomic force microscopy imaging using copper oxide tips. AB - Atomic force microscopy is an impressive tool with which to directly resolve the bonding structure of organic compounds1-5. The methodology usually involves chemical passivation of the probe-tip termination by attaching single molecules or atoms such as CO or Xe (refs 1,6-9). However, these probe particles are only weakly connected to the metallic apex, which results in considerable dynamic deflection. This probe particle deflection leads to pronounced image distortions, systematic overestimation of bond lengths, and in some cases even spurious bond like contrast features, thus inhibiting reliable data interpretation8-12. Recently, an alternative approach to tip passivation has been used in which slightly indenting a tip into oxidized copper substrates and subsequent contrast analysis allows for the verification of an oxygen-terminated Cu tip13-15. Here we show that, due to the covalently bound configuration of the terminal oxygen atom, this copper oxide tip (CuOx tip) has a high structural stability, allowing not only a quantitative determination of individual bond lengths and access to bond order effects, but also reliable intermolecular bond characterization. In particular, by removing the previous limitations of flexible probe particles, we are able to provide conclusive experimental evidence for an unusual intermolecular N-Au-N three-centre bond. Furthermore, we demonstrate that CuOx tips allow the characterization of the strength and configuration of individual hydrogen bonds within a molecular assembly. PMID- 29632398 TI - A semi-floating gate memory based on van der Waals heterostructures for quasi-non volatile applications. AB - As conventional circuits based on field-effect transistors are approaching their physical limits due to quantum phenomena, semi-floating gate transistors have emerged as an alternative ultrafast and silicon-compatible technology. Here, we show a quasi-non-volatile memory featuring a semi-floating gate architecture with band-engineered van der Waals heterostructures. This two-dimensional semi floating gate memory demonstrates 156 times longer refresh time with respect to that of dynamic random access memory and ultrahigh-speed writing operations on nanosecond timescales. The semi-floating gate architecture greatly enhances the writing operation performance and is approximately 106 times faster than other memories based on two-dimensional materials. The demonstrated characteristics suggest that the quasi-non-volatile memory has the potential to bridge the gap between volatile and non-volatile memory technologies and decrease the power consumption required for frequent refresh operations, enabling a high-speed and low-power random access memory. PMID- 29632399 TI - A bio-hybrid DNA rotor-stator nanoengine that moves along predefined tracks. AB - Biological motors are highly complex protein assemblies that generate linear or rotary motion, powered by chemical energy. Synthetic motors based on DNA nanostructures, bio-hybrid designs or synthetic organic chemistry have been assembled. However, unidirectionally rotating biomimetic wheel motors with rotor stator units that consume chemical energy are elusive. Here, we report a bio hybrid nanoengine consisting of a catalytic stator that unidirectionally rotates an interlocked DNA wheel, powered by NTP hydrolysis. The engine consists of an engineered T7 RNA polymerase (T7RNAP-ZIF) attached to a dsDNA nanoring that is catenated to a rigid rotating dsDNA wheel. The wheel motor produces long, repetitive RNA transcripts that remain attached to the engine and are used to guide its movement along predefined ssDNA tracks arranged on a DNA nanotube. The simplicity of the design renders this walking nanoengine adaptable to other biological nanoarchitectures, facilitating the construction of complex bio-hybrid structures that achieve NTP-driven locomotion. PMID- 29632400 TI - Experimental observation of chiral magnetic bobbers in B20-type FeGe. AB - Chiral magnetic skyrmions1,2 are nanoscale vortex-like spin textures that form in the presence of an applied magnetic field in ferromagnets that support the Dzyaloshinskii-Moriya interaction (DMI) because of strong spin-orbit coupling and broken inversion symmetry of the crystal3,4. In sharp contrast to other systems5,6 that allow for the formation of a variety of two-dimensional (2D) skyrmions, in chiral magnets the presence of the DMI commonly prevents the stability and coexistence of topological excitations of different types 7 . Recently, a new type of localized particle-like object-the chiral bobber (ChB) was predicted theoretically in such materials 8 . However, its existence has not yet been verified experimentally. Here, we report the direct observation of ChBs in thin films of B20-type FeGe by means of quantitative off-axis electron holography (EH). We identify the part of the temperature-magnetic field phase diagram in which ChBs exist and distinguish two mechanisms for their nucleation. Furthermore, we show that ChBs are able to coexist with skyrmions over a wide range of parameters, which suggests their possible practical applications in novel magnetic solid-state memory devices, in which a stream of binary data bits can be encoded by a sequence of skyrmions and bobbers. PMID- 29632401 TI - Non-invasive, transdermal, path-selective and specific glucose monitoring via a graphene-based platform. AB - Currently, there is no available needle-free approach for diabetics to monitor glucose levels in the interstitial fluid. Here, we report a path-selective, non invasive, transdermal glucose monitoring system based on a miniaturized pixel array platform (realized either by graphene-based thin-film technology, or screen printing). The system samples glucose from the interstitial fluid via electroosmotic extraction through individual, privileged, follicular pathways in the skin, accessible via the pixels of the array. A proof of principle using mammalian skin ex vivo is demonstrated for specific and 'quantized' glucose extraction/detection via follicular pathways, and across the hypo- to hyper glycaemic range in humans. Furthermore, the quantification of follicular and non follicular glucose extraction fluxes is clearly shown. In vivo continuous monitoring of interstitial fluid-borne glucose with the pixel array was able to track blood sugar in healthy human subjects. This approach paves the way to clinically relevant glucose detection in diabetics without the need for invasive, finger-stick blood sampling. PMID- 29632402 TI - Bordetella pseudohinzii targets cilia and impairs tracheal cilia-driven transport in naturally acquired infection in mice. AB - Several species of the Gram-negative genus Bordetella are the cause of respiratory infections in mammals and birds, including whooping cough (pertussis) in humans. Very recently, a novel atypical species, Bordetella pseudohinzii, was isolated from laboratory mice. These mice presented no obvious clinical symptoms but elevated numbers of neutrophils in bronchoalveolar lavage fluid and inflammatory signs in histopathology. We noted that this species can occur at high prevalence in a mouse facility despite regular pathogen testing according to the FELASA-recommendations. Affected C57BL/6 J mice had, in addition to the reported pulmonary alterations, tracheal inflammation with reduced numbers of ciliated cells, slower ciliary beat frequency, and largely (>50%) compromised cilia-driven particle transport speed on the mucosal surface, a primary innate defence mechanism. In an in vitro-model, Bordetella pseudohinzii attached to respiratory kinocilia, impaired ciliary function within 4 h and caused epithelial damage within 24 h. Regular testing for this ciliotropic Bordetella species and excluding it from colonies that provide mice for lung research shall be recommended. On the other hand, controlled colonization and infection with Bordetella pseudohinzii may serve as an experimental model to investigate mechanisms of mucociliary clearance and microbial strategies to escape from this primary innate defence response. PMID- 29632403 TI - A death pheromone, oleic acid, triggers hygienic behavior in honey bees (Apis mellifera L.). AB - Eusocial insects live in teeming societies with thousands of their kin. In this crowded environment, workers combat disease by removing or burying their dead or diseased nestmates. For honey bees, we found that hygienic brood-removal behavior is triggered by two odorants - beta-ocimene and oleic acid - which are released from brood upon freeze-killing. beta-ocimene is a co-opted pheromone that normally signals larval food-begging, whereas oleic acid is a conserved necromone across arthropod taxa. Interestingly, the odorant blend can induce hygienic behavior more consistently than either odorant alone. We suggest that the volatile beta-ocimene flags hygienic workers' attention, while oleic acid is the death cue, triggering removal. Bees with high hygienicity detect and remove brood with these odorants faster than bees with low hygienicity, and both molecules are strong ligands for hygienic behavior-associated odorant binding proteins (OBP16 and OBP18). Odorants that induce low levels of hygienic behavior, however, are weak ligands for these OBPs. We are therefore beginning to paint a picture of the molecular mechanism behind this complex behavior, using odorants associated with freeze-killed brood as a model. PMID- 29632404 TI - Formation of trihalomethanes as disinfection byproducts in herbal spa pools. AB - Herbal spa treatments are favorite recreational activities throughout the world. The water in spas is often disinfected to control pathogenic microorganisms and guarantee hygiene. However, chlorinated water may cause the formation of disinfection byproducts (DBPs). Although there have been many studies on DBP formation in swimming pools, the role of organic matter derived from herbal medicines applied in herbal spa water has been largely neglected. Accordingly, the present study investigated the effect of herbal medicines on the formation of trihalomethanes (THMs) in simulated herbal spa water. Water samples were collected from a spa pool, and then, disinfection and herbal addition experiments were performed in a laboratory. The results showed that the organic molecules introduced by the herbal medicines are significant precursors to the formation of THMs in spa pool water. Since at least 50% of THMs were produced within the first six hours of the reaction time, the presence of herbal medicines in spa water could present a parallel route for THM exposure. Therefore, despite the undeniable benefits of herbal spas, the effect of applied herbs on DBP formation in chlorinated water should be considered to improve the water quality and health benefits of spa facilities. PMID- 29632405 TI - Combined effect of renal function and serum potassium level in sudden cardiac death in aging hypertensive subjects. AB - In patients with chronic kidney disease, serum potassium level is a factor influencing sudden cardiac death (SCD). The aim of our analysis was to study the combined effect of serum potassium level and renal function on the onset of SCD in elderly hypertensive subjects. Data from the 3620 hypertensive patients aged over 70 years were extracted from three randomized clinical trials included in the INDANA database. During a mean follow up of 4.5 years, 81 patients (2.24%) died from SCD. Mean serum potassium levels and prevalence of chronic kidney disease were not different in patients who died from SCD. In addition to serum potassium and creatinine levels, 14 clinical and biological variables linked to cardiovascular diseases recorded at baseline were analyzed using a Bayesian network. The area under the receiver operating characteristic curve of the Bayesian model reached 0.91. Bayesian inference was used to simulate the combined effects of serum potassium and creatinine levels on SCD. Our analysis, using simulated data from Bayesian model, showed that the estimated probabilities of SCD was significantly increased in case of hyperkalemia (>5.0 mmol/l) and in case of hypokalemia (<3.5 mmol/l) and in case of chronic kidney disease. Combined effects of serum potassium level and renal function revealed that chronic kidney disease increased the probability of SCD whatever the serum potassium level. Our results using a Bayesian model confirm the deleterious effects of hypokalemia, hyperkalemia and chronic kidney disease on SCD in elderly hypertensive patients. PMID- 29632406 TI - Deformable inorganic semiconductor. PMID- 29632407 TI - Room-temperature ductile inorganic semiconductor. AB - Ductility is common in metals and metal-based alloys, but is rarely observed in inorganic semiconductors and ceramic insulators. In particular, room-temperature ductile inorganic semiconductors were not known until now. Here, we report an inorganic alpha-Ag2S semiconductor that exhibits extraordinary metal-like ductility with high plastic deformation strains at room temperature. Analysis of the chemical bonding reveals systems of planes with relatively weak atomic interactions in the crystal structure. In combination with irregularly distributed silver-silver and sulfur-silver bonds due to the silver diffusion, they suppress the cleavage of the material, and thus result in unprecedented ductility. This work opens up the possibility of searching for ductile inorganic semiconductors/ceramics for flexible electronic devices. PMID- 29632408 TI - Electrostrain in excess of 1% in polycrystalline piezoelectrics. AB - Piezoelectric actuators transform electrical energy into mechanical energy, and because of their compactness, quick response time and accurate displacement, they are sought after in many applications. Polycrystalline piezoelectric ceramics are technologically more appealing than single crystals due to their simpler and less expensive processing, but have yet to display electrostrain values that exceed 1%. Here we report a material design strategy wherein the efficient switching of ferroelectric-ferroelastic domains by an electric field is exploited to achieve a high electrostrain value of 1.3% in a pseudo-ternary ferroelectric alloy system, BiFeO3-PbTiO3-LaFeO3. Detailed structural investigations reveal that this electrostrain is associated with a combination of several factors: a large spontaneous lattice strain of the piezoelectric phase, domain miniaturization, a low-symmetry ferroelectric phase and a very large reverse switching of the non 180 degrees domains. This insight for the design of a new class of polycrystalline piezoceramics with high electrostrains may be useful to develop alternatives to costly single-crystal actuators. PMID- 29632409 TI - Large local lattice expansion in graphene adlayers grown on copper. AB - Variations of the lattice parameter can significantly change the properties of a material, and, in particular, its electronic behaviour. In the case of graphene, however, variations of the lattice constant with respect to graphite have been limited to less than 2.5% due to its well-established high in-plane stiffness. Here, through systematic electronic and lattice structure studies, we report regions where the lattice constant of graphene monolayers grown on copper by chemical vapour deposition increases up to ~7.5% of its relaxed value. Density functional theory calculations confirm that this expanded phase is energetically metastable and driven by the enhanced interaction between the substrate and the graphene adlayer. We also prove that this phase possesses distinctive chemical and electronic properties. The inherent phase complexity of graphene grown on copper foils revealed in this study may inspire the investigation of possible metastable phases in other seemingly simple heterostructure systems. PMID- 29632410 TI - Molecular basis of GID4-mediated recognition of degrons for the Pro/N-end rule pathway. AB - The N-end rule pathway senses the N-terminal destabilizing residues of degradation substrates for the ubiquitin-proteasome system, whose integrity shields against various human syndromes including cancer and cardiovascular diseases. GID4, a subunit of the ubiquitin ligase GID complex, has been recently identified as the N-recognin of the new branch of the N-end rule pathway responsible for recognizing substrates bearing N-terminal proline residues (Pro/N degrons). However, the molecular mechanism of GID4-mediated Pro/N-degron recognition remains largely unexplored. Here, we report the first crystal structures of human GID4 alone and in complex with various Pro/N-degrons. Our complex crystal structures, together with biophysical analyses, delineate the GID4-mediated Pro/N-degron recognition mechanism and substrate selection criteria for the Pro/N-end rule pathway. These mechanistic data on the Pro/N-recognin activity of GID4 will serve as a foundation to facilitate the identification of authentic physiological substrates as well as the development of inhibitors of therapeutic values for the Pro/N-end rule pathway. PMID- 29632411 TI - Ligand-receptor co-evolution shaped the jasmonate pathway in land plants. AB - The phytohormone jasmonoyl-isoleucine (JA-Ile) regulates defense, growth and developmental responses in vascular plants. Bryophytes have conserved sequences for all JA-Ile signaling pathway components but lack JA-Ile. We show that, in spite of 450 million years of independent evolution, the JA-Ile receptor COI1 is functionally conserved between the bryophyte Marchantia polymorpha and the eudicot Arabidopsis thaliana but COI1 responds to different ligands in each species. We identified the ligand of Marchantia MpCOI1 as two isomeric forms of the JA-Ile precursor dinor-OPDA (dinor-cis-OPDA and dinor-iso-OPDA). We demonstrate that AtCOI1 functionally complements Mpcoi1 mutation and confers JA Ile responsiveness and that a single-residue substitution in MpCOI1 is responsible for the evolutionary switch in ligand specificity. Our results identify the ancestral bioactive jasmonate and clarify its biosynthetic pathway, demonstrate the functional conservation of its signaling pathway, and show that JA-Ile and COI1 emergence in vascular plants required co-evolution of hormone biosynthetic complexity and receptor specificity. PMID- 29632412 TI - Profiling and genetic control of the murine immunoglobulin G glycome. AB - Immunoglobulin G (IgG) glycosylation is essential for function of the immune system, but the genetic and environmental factors that underlie its inter individual variability are not well defined. The Collaborative Cross (CC) genetic resource harnesses over 90% of the common genetic variation of the mouse. By analyzing the IgG glycome composition of 95 CC strains, we made several important observations: (i) glycome variation between mouse strains was higher than between individual humans, despite all mice having the same environmental influences; (ii) five genetic loci were found to be associated with murine IgG glycosylation; (iii) variants outside traditional glycosylation site motifs affected glycome variation; (iv) bisecting N-acetylglucosamine (GlcNAc) was produced by several strains although most previous studies have reported the absence of glycans containing the bisecting GlcNAc on murine IgGs; and (v) common laboratory mouse strains are not optimal animal models for studying effects of glycosylation on IgG function. PMID- 29632413 TI - A selective peptide inhibitor of Frizzled 7 receptors disrupts intestinal stem cells. AB - Regeneration of the adult intestinal epithelium is mediated by a pool of cycling stem cells, which are located at the base of the crypt, that express leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR5). The Frizzled (FZD) 7 receptor (FZD7) is enriched in LGR5+ intestinal stem cells and plays a critical role in their self-renewal. Yet, drug discovery approaches and structural bases for targeting specific FZD isoforms remain poorly defined. FZD proteins interact with Wnt signaling proteins via, in part, a lipid-binding groove on the extracellular cysteine-rich domain (CRD) of the FZD receptor. Here we report the identification of a potent peptide that selectively binds to the FZD7 CRD at a previously uncharacterized site and alters the conformation of the CRD and the architecture of its lipid-binding groove. Treatment with the FZD7-binding peptide impaired Wnt signaling in cultured cells and stem cell function in intestinal organoids. Together, our data illustrate that targeting the lipid-binding groove holds promise as an approach for achieving isoform-selective FZD receptor inhibition. PMID- 29632414 TI - The cyanobacterial ornithine-ammonia cycle involves an arginine dihydrolase. AB - Living organisms have evolved mechanisms for adjusting their metabolism to adapt to environmental nutrient availability. Terrestrial animals utilize the ornithine urea cycle to dispose of excess nitrogen derived from dietary protein. Here, we identified an active ornithine-ammonia cycle (OAC) in cyanobacteria through an approach combining dynamic 15N and 13C tracers, metabolomics, and mathematical modeling. The pathway starts with carbamoyl phosphate synthesis by the bacterial- and plant-type glutamine-dependent enzyme and ends with conversion of arginine to ornithine and ammonia by a novel arginine dihydrolase. An arginine dihydrolase deficient mutant showed disruption of OAC and severely impaired cell growth when nitrogen availability oscillated. We demonstrated that the OAC allows for rapid remobilization of nitrogen reserves under starvation and a high rate of nitrogen assimilation and storage after the nutrient becomes available. Thus, the OAC serves as a conduit in the nitrogen storage-and-remobilization machinery in cyanobacteria and enables cellular adaptation to nitrogen fluctuations. PMID- 29632415 TI - The role of hydrophobic silane coating on Si stamps in nanoimprint lithography. AB - Hydrophobic silane coatings have been successfully applied to the surface of Si stamps to improve demolding in nanoimprint lithography (NIL). However, the role of the silane coating has only been studied either indirectly, by measuring adhesion or friction coefficients for Si and substrate surfaces without patterns, or collectively, by measuring the overall demolding force that does not differentiate contributions of friction dissipation, stored elastic energy, and adhesion. Here, for the first time, we present experimental evidence on the role of the silane coating in improving demolding in UV-NIL by using different silane coatings. The silane coatings were characterized by x-ray photoelectron spectroscopy, water contact angle, and friction force measurements. Then, the work of demolding was systematically measured for different silane coatings using stamps with the same micropattern but different pattern depths. Comparison of the results to the theoretical model developed for fiber-matrix debonding energy by Sutcu and Hillig [Acta Metall. Mater. 38(12), 2653-2662] indicated that with a hydrophobic silane coating, the main parameter contributing to overall demolding work shifts from adhesion to stored elastic energy and frictional dissipation as surface adhesion keeps decreasing. The results confirm that the main role of the silane coating in reducing the demolding is to reduce surface adhesion rather than friction at the stamp/substrate interface. PMID- 29632416 TI - Arsenic methylation by a genetically engineered Rhizobium-legume symbiont. AB - Background and aims: Arsenic (As) is one of the most widespread environmental contaminants. The aim of our study was to test a novel bioremediation system based on the symbiosis between leguminous plant and genetically engineered rhizobia. Methods: The arsenite [As(III)] S-adenosylmethionine methyltransferase gene (CrarsM) from the alga Chlamydomonas reinhardtii was inserted into the chromosome of Rhizobium leguminosarum bv. trifolii strain R3. The As methylation ability of the recombinant Rhizobium was tested under free living conditions and in symbiosis with red clover plants. Arsenic speciation was determined using high performance liquid chromatography-inductively coupled plasma mass spectrometry. Results: Under free-living conditions, CrarsM-recombinant R. leguminosarum gained the ability to methylate As(III) to methylated arsenicals, including methylarsenate [MAs(V)], dimethylarsenate [DMAs(V)] and trimethylarsine oxide [TMAs(V)O]. Red clover plants were inoculated with either control (non recombinant) or CrarsM-recombinant R. leguminosarum and exposed to 5 or 10 MUM arsenite. No methylated As species were detected in red clover plants inoculated with control R. leguminosarum. In contrast, all three methylated species were detected in both the nodules and the shoots when the recombinant Rhizobium established symbiosis with red clover, accounting for 74.7-75.1% and 29.1-42.4% of the total As in the two plant tissues, respectively. The recombinant symbiont also volatilized small amounts of As. Conclusions: The present study demonstrates that engineered rhizobia expressing an algal arsM gene can methylate and volatilize As, providing a proof of concept for potential future use of legume rhizobia symbionts for As bioremediation. PMID- 29632417 TI - Resolving the Lophiostoma bipolare complex: Generic delimitations within Lophiostomataceae. AB - Lophiostoma bipolare was taxonomically revised based on the morphological observations and phylogenetic analyses of molecular data from nuclear rDNA SSU ITS-LSU, TUB, tef1, and rpb2 genes. Twenty-nine strains were morphologically similar to Lo. bipolare. A total of 174 sequences were generated from the Lo. bipolare complex. Phylogenetic analyses based on TUB sequence revealed 11 distinct species within the Lo. bipolare complex. Morphological features of the ascospores and the anatomical structure of the ascomata from both field collections as well as axenic culture, which have been reported previously as variable features at intraspecific levels, were compared to evaluate the taxonomic reliability of these features. To clarify the generic position of the 11 species, phylogenetic analyses were done on SSU-ITS-LSU-tef1-rpb2 gene sequences. The Lo. bipolare complex shared phylogenetic relationships with Pseudolophiostoma and Vaginatispora, and formed an additional five distinct clades from other members of Lophiostomataceae. According to its phylogenetic position, Lo. bipolare sensu stricto was distantly related to Lophiostoma s. str., and formed an independent clade within Lophiostomataceae. Lophiostoma bipolare s. str. could be distinguished from the other lophiostomataceous genera by the clypeus around the ostiolar neck and by the thin and uniformly thick peridium. A novel genus described as Lentistoma was established to accommodate this species, and the epitypification of Lentistoma bipolare (basionym: Massarina bipolaris) was proposed. Other lineages of the Lo. bipolare complex could not be separated on the basis of the ascospore size and sheath variations, but were distinguished based on ascomatal features, such as the existence of the clypeus, brown hyphae surrounding the peridium, and the contexture of the peridium, which were stable indicators of generic boundaries in Lophiostomataceae. Four additional new genera with five new species were recognised based on these morphological differences: Crassiclypeus (C. aquaticus), Flabellascoma (F. cycadicola and F. minimum), Leptoparies (Lep. palmarum), and Pseudopaucispora (Pseudop. brunneospora). Three new species were added to Pseudolophiostoma (Pseudol. cornisporum, Pseudol. obtusisporum, and Pseudol. tropicum) and two new species were added to Vaginatispora (V. amygdali and V. scabrispora). The re evaluation of the validity of several previously recognised genera resulted in the introduction of two new genera with new combinations for Lophiostoma pseudoarmatisporum as Parapaucispora pseudoarmatispora and Vaginatispora fuckelii as Neovaginatispora fuckelii. PMID- 29632418 TI - A Comparison of Phenomenologic Growth Laws for Myocardial Hypertrophy. AB - The heart grows in response to changes in hemodynamic loading during normal development and in response to valve disease, hypertension, and other pathologies. In general, a left ventricle subjected to increased afterload (pressure overloading) exhibits concentric growth characterized by thickening of individual myocytes and the heart wall, while one experiencing increased preload (volume overloading) exhibits eccentric growth characterized by lengthening of myocytes and dilation of the cavity. Predictive models of cardiac growth could be important tools in evaluating treatments, guiding clinical decision making, and designing novel therapies for a range of diseases. Thus, in the past 20 years there has been considerable effort to simulate growth within the left ventricle. While a number of published equations or systems of equations (often termed "growth laws") can capture some aspects of experimentally observed growth patterns, no direct comparisons of the various published models have been performed. Here we examine eight of these laws and compare them in a simple test bed in which we imposed stretches measured during in vivo pressure and volume overload. Laws were compared based on their ability to predict experimentally measured patterns of growth in the myocardial fiber and radial directions as well as the ratio of fiber-to-radial growth. Three of the eight laws were able to reproduce most key aspects of growth following both pressure and volume overload. Although these three growth laws utilized different approaches to predict hypertrophy, they all employed multiple inputs that were weakly correlated during in vivo overload and therefore provided independent information about mechanics. PMID- 29632419 TI - Dissecting the molecular pathophysiology of drug-induced liver injury. AB - Drug-induced liver injury (DILI) has become a major topic in the field of Hepatology and Gastroenterology. DILI can be clinically divided into three phenotypes: hepatocytic, cholestatic and mixed. Although the clinical manifestations of DILI are variable and the pathogenesis complicated, recent insights using improved preclinical models, have allowed a better understanding of the mechanisms that trigger liver damage. In this review, we will discuss the pathophysiological mechanisms underlying DILI. The toxicity of the drug eventually induces hepatocellular damage through multiple molecular pathways, including direct hepatic toxicity and innate and adaptive immune responses. Drugs or their metabolites, such as the common analgesic, acetaminophen, can cause direct hepatic toxicity through accumulation of reactive oxygen species and mitochondrial dysfunction. The innate and adaptive immune responses play also a very important role in the occurrence of idiosyncratic DILI. Furthermore, we examine common forms of hepatocyte death and their association with the activation of specific signaling pathways. PMID- 29632421 TI - Systems pharmacology approach reveals the antiinflammatory effects of Ampelopsis grossedentata on dextran sodium sulfate-induced colitis. AB - AIM: To investigate the protective effects of Ampelopsis grossedentata (AMP) on dextran sulfate sodium (DSS)-induced colitis in mice based on systems pharmacology approach. METHODS: Systems pharmacology approach was used to predict the active ingredients, candidate targets and the efficacy of AMP on ulcerative colitis (UC) using a holistic process of active compound screening, target fishing, network construction and analysis. A DSS-induced colitis model in C57BL/6 mice (n = 10/group) was constructed and treated with 5-aminosalicylic acid (100 mg/kg/d) and AMP (400 mg/kg/d) to confirm the underlying mechanisms and effects of AMP on UC with western blot analyses, polymerase chain reaction, histological staining and immunohistochemistry. RESULTS: The therapeutic effects of AMP against DSS-induced colitis were determined in the beginning, and the results showed that AMP significantly improved the disease in general observations and histopathology analysis. Subsequent systems pharmacology predicted 89 corresponding targets for the four candidate compounds of AMP, as well as 123 candidate targets of UC, and protein-protein interaction networks were constructed for the interaction of putative targets of AMP against UC. Enrichment analyses on TNF-alpha and RANKL/RANK, a receptor activator of NF kappaB signaling pathways, were then carried out. Experimental validation revealed that inflammation-related signaling pathways were activated in the DSS group, and AMP significantly suppressed DSS-induced high expression of IRAK1, TRAF6, IkappaB and NF-kappaB, and inhibited the elevated expression levels of TNF alpha, IL-1beta, IL-6 and IL-8. CONCLUSION: AMP could exert protective effects on UC via suppressing the IRAK1/TRAF6/NF-kappaB-mediated inflammatory signaling pathways. PMID- 29632420 TI - Thrombocytopenia after liver transplantation: Should we care? AB - Transient thrombocytopenia is a common phenomenon after liver transplantation. After liver transplantation (LT), platelet count decreases and reaches a nadir on postoperative days 3-5, with an average reduction in platelet counts of 60%; platelet count recovers to preoperative levels approximately two weeks after LT. The putative mechanisms include haemodilution, decreased platelet production, increased sequestration, medications, infections, thrombosis, or combination of these processes. However, the precise mechanisms remain unclear. The role of platelets in liver transplantation has been highlighted in recent years, and particular attention has been given to their effects beyond hemostasis and thrombosis. Previous studies have demonstrated that perioperative thrombocytopenia causes poor graft regeneration, increases the incidence of postoperative morbidity, and deteriorates the graft and decreases patient survival in both the short and long term after liver transplantation. Platelet therapies to increase perioperative platelet counts, such as thrombopoietin, thrombopoietin receptor agonist, platelet transfusion, splenectomy, and intravenous immunoglobulin treatment might have a potential for improving graft survival, however clinical trials are lacking. Further studies are warranted to detect direct evidence on whether thrombocytopenia is the cause or result of poor graft function and postoperative complications, and to determine who needs platelet therapies in order to prevent postoperative complications and thus improve post-transplant outcomes. PMID- 29632422 TI - Potential triggering factors of acute liver failure as a first manifestation of autoimmune hepatitis-a single center experience of 52 adult patients. AB - AIM: To investigate potential triggering factors leading to acute liver failure (ALF) as the initial presentation of autoimmune hepatitis (AIH). METHODS: A total of 565 patients treated at our Department between 2005 and 2017 for histologically-proven AIH were retrospectively analyzed. However, 52 patients (9.2%) fulfilled the criteria for ALF defined by the "American Association for the Study of the Liver (AASLD)". According to this definition, patients with "acute-on-chronic" or "acute-on-cirrhosis" liver failure were excluded. Following parameters with focus on potential triggering factors were evaluated: Patients' demographics, causation of liver failure, laboratory data (liver enzymes, MELD score, autoimmune markers, virus serology), liver histology, immunosuppressive regime, and finally, outcome of our patients. RESULTS: The majority of patients with ALF were female (84.6%) and mean age was 43.6 +/- 14.9 years. Interestingly, none of the patients with ALF was positive for anti-liver kidney microsomal antibody (LKM). We could identify potential triggering factors in 26/52 (50.0%) of previously healthy patients presenting ALF as their first manifestation of AIH. These were drug-induced ALF (57.7%), virus-induced ALF (30.8%), and preceding surgery in general anesthesia (11.5%), respectively. Unfortunately, 6 out of 52 patients (11.5%) did not survive ALF and 3 patients (5.7%) underwent liver transplantation (LT). Comparing data of survivors and patients with non recovery following treatment, MELD-score (P < 0.001), age (P < 0.05), creatinine (P < 0.01), and finally, ALT-values (P < 0.05) reached statistical significance. CONCLUSION: Drugs, viral infections, and previous surgery may trigger ALF as the initial presentation of AIH. Advanced age and high MELD-score were associated with lethal outcome. PMID- 29632423 TI - Helicobacter pylori infection in subjects negative for high titer serum antibody. AB - AIM: To investigate the clinicopathological features of the patients testing negative for high titer serum anti-Helicobacter pylori (H. pylori) antibody. METHODS: The antibody titers were measured using antigens derived from Japanese individuals. 13C-urea breath test-positive individuals were defined as having H. pylori infection. We investigated the demographic characteristics, laboratory data, endoscopic findings including Kyoto classification of gastritis, and histology in negative-high titer patients without H. pylori eradication therapy. Kyoto classification consisted of scores for gastric atrophy, intestinal metaplasia, enlarged folds, nodularity, and redness. RESULTS: Of the 136 subjects enrolled, 23 (17%) had H. pylori infection. Kyoto classification had an excellent area under the receiver operating characteristics curve (0.886, 95% confidence interval: 0.803-0.968, P = 3.7 * 10-20) for predicting H. pylori infection with a cut-off value of 2. Further, Kyoto classification, H. pylori density, and neutrophil activity had high accuracies (89.7%, 96.3%, and 94.1%, respectively). Kyoto classification was independent of the demographic and laboratory parameters in multivariate analysis. CONCLUSION: Endoscopic Kyoto classification of gastritis is a useful predictor of H. pylori infection in negative-high titer antibody patients. PMID- 29632424 TI - Impact of postoperative TNM stages after neoadjuvant therapy on prognosis of adenocarcinoma of the gastro-oesophageal junction tumours. AB - AIM: To compare prognostic relevance of postoperative tumour/node/metastasis (TMN) stages between patients with and without neoadjuvant treatment. METHODS: Data from patients with adenocarcinoma of the gastro-oesophageal junction (AEG) who had undergone surgical resection at a single German university centre were retrospectively analysed. Patients with or without neoadjuvant preoperative treatment were selected by exact matching based on preoperative staging. Standard assessment of preoperative (c)TNM stage was based on endoscopic ultrasound and computed tomography of the thorax and abdomen, according to the American Joint Committee on Cancer/Union for International Cancer Control classification system. Patients with cT1cN0cM0 and cT2cN0cM0 stages were excluded from the study, as these patients are generally not recommended for pretreatment. Long-term survival among the various postoperative TNM stages was compared between the groups of patients with or without neoadjuvant treatment. For statistical assessments, a P value of <= 0.05 was considered significant. RESULTS: The study included a total of 174 patients. The group of patients who had received preoperative neoadjuvant treatment included more cases of AEG (Siewert) type 1 carcinoma (P < 0.001), and consequently oesophagectomy was performed more frequently among these patients (P < 0.001). The two groups (with or without preoperative neoadjuvant treatment) had comparable preoperative T stages, but the group of patients with preoperative neoadjuvant treatment presented a higher rate of preoperative N-positive disease (P = 0.020). Overall long-term survival was not different between the two groups of patients according to tumours of different AEG classifications, receipt of oesophagectomy or gastrectomy, nor between patients with similar postoperative TNM stage, resection margin and grading. However, an improvement of long-term survival was found for patients with nodal down-staging after neoadjuvant therapy (P = 0.053). CONCLUSION: The prognostic relevance of postoperative TNM stages is similar for AEG in patients with or without neoadjuvant preoperative treatment, but treatment-related nodal down-staging prognosticates longer-term survival. PMID- 29632425 TI - Mild drinking habit is a risk factor for hepatocarcinogenesis in non-alcoholic fatty liver disease with advanced fibrosis. AB - AIM: The impact of mild drinking habit (less than 20 g/d of ethanol) on the clinical course of non-alcoholic fatty liver disease (NAFLD) has not been determined. We examined the influence of a mild drinking habit on liver carcinogenesis from NAFLD. METHODS: A total of 301 patients who had been diagnosed as having NAFLD by liver biopsy between 2003 and 2016 [median age: 56 years, 45% male, 56% with non-alcoholic steatohepatitis, 26% with advanced fibrosis (F3-4)] were divided into the mild drinking group with ethanol consumption of less than 20 g/d (mild drinking group, n = 93) and the non drinking group (n = 208). Clinicopathological features at the time of liver biopsy and factors related to hepatocellular carcinoma (HCC) occurrence were compared between the groups. RESULTS: We observed significant differences in male prevalence (P = 0.01), platelet count (P = 0.04), and gamma-glutamyl transpeptidase (P = 0.02) between the test groups. Over 6 years of observation, the HCC appearance rate was significantly higher in the mild drinking group (6.5% vs 1.4%, P = 0.02). Multivariate survival analysis using Cox's regression model revealed that hepatic advanced fibrosis (F3-4) (P < 0.01, risk ratio: 11.60), diabetes mellitus (P < 0.01, risk ratio: 89.50), and serum triglyceride (P = 0.04, risk ratio: 0.98) were factors significantly related to HCC in all NAFLD patients, while the effect of a drinking habit was marginal (P = 0.07, risk ratio: 4.43). In patients with advanced fibrosis (F3-4), however, a drinking habit (P = 0.04, risk ratio: 4.83), alpha-fetoprotein (P = 0.01, risk ratio: 1.23), and diabetes mellitus (P = 0.03, risk ratio: 12.00) were identified as significant contributors to HCC occurrence. CONCLUSION: A mild drinking habit appears to be a risk factor for hepatocarcinogenesis in NAFLD patients, especially those with advanced fibrosis. PMID- 29632426 TI - Prognostic significance of combined preoperative fibrinogen and CA199 in gallbladder cancer patients. AB - AIM: To investigate the prognostic value of the combination of preoperative plasma fibrinogen and CA199 in patients with gallbladder carcinoma (GBC). METHODS: The clinicopathological data of 154 GBC patients were retrospectively reviewed after surgery. A receiver operating characteristic (ROC) curve was plotted to verify the optimum cut-off values for plasma fibrinogen and CA199. Univariate and multivariate survival analyses were performed to identify the factors associated with GBC prognosis. Based on the HRs calculated via multivariate survival analyses, patients with elevated plasma fibrinogen and CA199 levels were allocated a score of 2.1; those with an elevated plasma fibrinogen level only were allocated a score of 1, those with an elevated CA199 level only were allocated a score of 1.1, and those with neither of these abnormalities were allocated a score of 0. RESULTS: ROC curve analysis showed that the optimum cut-off values for preoperative plasma fibrinogen and CA199 were 3.47 g/L and 25.45 U/mL, respectively. Multivariate analysis indicated that elevated preoperative plasma fibrinogen and CA199 levels were significantly correlated with worse overall survival (OS) (HR = 1.711, 95%CI: 1.114-2.627, P = 0.014, and HR = 1.842, 95%CI: 1.111-3.056, P = 0.018). When we combined these two parameters, the area under the ROC curve increased from 0.735 (for preoperative plasma fibrinogen only) and 0.729 (for preoperative CA199 only) to 0.765. When this combined variable was added to the multivariate analysis, the combination of plasma fibrinogen and CA199 (P < 0.001), resection margin (P < 0.001) and TNM stage (P = 0.010) were independent prognostic factors for GBC. CONCLUSION: The combination of plasma fibrinogen and CA199 may serve as a more efficient independent prognostic biomarker for postoperative GBC patients than either parameter alone. PMID- 29632427 TI - Fecal microbial dysbiosis in Chinese patients with inflammatory bowel disease. AB - AIM: To analyze the alterations of fecal microbiota in Chinese patients with inflammatory bowel disease (IBD). METHODS: Fecal samples from 15 patients with Crohn's disease (CD) (11 active CD, 4 inactive CD), 14 patients with active ulcerative colitis (UC) and 13 healthy individuals were collected and subjected to 16S ribosomal DNA (rDNA) gene sequencing. The V4 hypervariable regions of 16S rDNA gene were amplified from all samples and sequenced by the Illumina MiSeq platform. Quality control and operational taxonomic units classification of reads were calculated with QIIME software. Alpha diversity and beta diversity were displayed with R software. RESULTS: Community richness (chao) and microbial structure in both CD and UC were significantly different from those in normal controls. At the phyla level, analysis of the microbial compositions revealed a significantly greater abundance of Proteobacteria in IBD as compared to that in controls. At the genera level, 8 genera in CD and 23 genera in UC (in particular, the Escherichia genus) showed significantly greater abundance as compared to that in normal controls. The relative abundance of Bacteroidetes in the active CD group was markedly lower than that in the inactive CD group. The abundance of Proteobacteria in patients with active CD was nominally higher than that in patients with inactive CD; however, the difference was not statistically significant after correction. Furthermore, the relative abundance of Bacteroidetes showed a negative correlation with the CD activity index scores. CONCLUSION: Our study profiles specific characteristics and microbial dysbiosis in the gut of Chinese patients with IBD. Bacteroidetes may have a negative impact on inflammatory development. PMID- 29632428 TI - Hepatocellular carcinoma or interferon-based therapy history attenuates sofosbuvir/ribavirin for Japanese genotype 2 hepatitis C virus. AB - AIM: To investigate the real-world efficacy and safety of sofosbuvir/ribavirin (SOF/RBV) therapy for Japanese patients with genotype 2 hepatitis C virus (GT2 HCV). METHODS: A total of 182 patients with GT2-HCV infection who received SOF/RBV therapy for 12 wk at our hospital were enrolled. The patients comprised 122 men and 60 women (age range: 17-84 years; mean age +/- SD: 60.1 +/- 12.1 years). Relationships between virological response and clinical data were examined by logistic regression analyses. RESULTS: The proportions of patients with liver cirrhosis and history of hepatocellular carcinoma (HCC) were 29.0% and 17.3%, respectively. The proportion of patients with prior interferon (IFN)-based therapy was 25.6%. SOF/RBV therapy rapidly decreased HCV RNA levels. Several patients required RBV dose reduction because of anemia or fatigue. Four patients discontinued the therapy. The rates of sustained virological response at 12 wk after the end of treatment were 87.9% (intention to treat: 160/182) and 94.1% (per protocol: 159/169). Multivariate analyses showed that history of HCC or IFN based therapy independently reduced the efficacy of SOF/RBV therapy. CONCLUSION: SOF/RBV therapy for GT2-HCV is safe, highly tolerated, and effective. History of HCC or IFN-based therapy independently reduces the efficacy of this treatment. PMID- 29632429 TI - Gilbert syndrome combined with prolonged jaundice caused by contrast agent: Case report. AB - This case highlights a patient with Gilbert syndrome who underwent endoscopic retrograde cholangiopancreatography (ERCP) with removal of bile duct stones, who then experienced an unexplained increase in bilirubin, with total bilirubin (TBIL) levels increasing from 159.5 MUmol/L to 396.2 MUmol/L and to a maximum of 502.8 MUmol/L after 9 d. Following the decrease in the TBIL level, enhanced magnetic resonance cholangiopancreatography (MRCP) was performed to exclude any possible remaining choledocholithiasis. Nevertheless, the serum bilirubin level increased again, with TBIL levels rising from 455.7 MUmol/L to 594.8 MUmol/L and a maximum level of 660.3 MUmol/L with no remaining bile duct stones. A liver biopsy showed severe bile duct cholestasis with no inflammation. Based on the exclusion of other potential causes of hyperbilirubinemia and the fact that both instances of increased bilirubin occurred after ERCP and MRCP, the contrast agents iopromide and gadoterate meglumine were suspected to be the causes of the hyperbilirubinemia. As of the writing of this report, the patient's bilirubin levels have spontaneously returned to baseline levels. In summary, ERCP and MRCP utilizing the contrast agents iopromide and gadoterate meglumine may possibly induce prolonged hyperbilirubinemia. PMID- 29632430 TI - Perceived Risks and Benefits in a Text Message Study of Substance Abuse and Sexual Behavior. AB - To inform ethical procedures for human subjects research using mobile health (mHealth), we examined perceived risks and benefits of study participation among emerging adults (N=54) with drug use who completed text message assessments of substance use and sexual behaviors. Most participants reported comfort with participation and some reported perceived benefits, such as improved relationships. Perceived risks were infrequently reported, including negative emotions, and legal or financial concerns. In conclusion, participants from a vulnerable population reported few perceived harms of participation in longitudinal mHealth assessments of sensitive behaviors. Researchers should continue characterizing participants' perspectives on ethical aspects of mHealth research. PMID- 29632431 TI - Using Metaphor to Find Meaning in Life. AB - Pursuing meaning in life confronts the individual with abstract ideas about the connections between experiences and identities over time (continuity), the ends that life serves (purpose), and its worth (value). Conceptual metaphor theory is helpful to explain the cognitive strategies people use to understand these ideas. This theory posits that metaphor is a cognitive tool for understanding abstractions in terms of superficially dissimilar, relatively more concrete concepts. Early empirical tests of this claim focused on how activated metaphors influence judgments of other people, events, and social issues. Going further, an emerging area of research examines metaphor's roles in perceptions of life's continuity, purpose, and value. This article provides the first overview of this development. Specific aims are to organize previous findings, identify questions for future research, and discuss theoretical implications for the meaning of meaning. PMID- 29632432 TI - Development of High-Resolution Dynamic Dust Source Function -A Case Study with a Strong Dust Storm in a Regional Model. AB - A high-resolution dynamic dust source has been developed in the NASA Unified Weather Research and Forecasting (NU-WRF) model to improve the existing coarse static dust source. In the new dust source map, topographic depression is in 1-km resolution and surface bareness is derived using the Normalized Difference Vegetation Index (NDVI) data from Moderate Resolution Imaging Spectroradiometer (MODIS). The new dust source better resolves the complex topographic distribution over the Western United States where its magnitude is higher than the existing, coarser resolution static source. A case study is conducted with an extreme dust storm that occurred in Phoenix, Arizona in 02-03 UTC July 6, 2011. The NU-WRF model with the new high-resolution dynamic dust source is able to successfully capture the dust storm, which was not achieved with the old source identification. However the case study also reveals several challenges in reproducing the time evolution of the short-lived, extreme dust storm events. PMID- 29632433 TI - Sensitivity analysis of the near-road dispersion model RLINE - an evaluation at Detroit, Michigan. AB - The development of accurate and appropriate exposure metrics for health effect studies of traffic-related air pollutants (TRAPs) remains challenging and important given that traffic has become the dominant urban exposure source and that exposure estimates can affect estimates of associated health risk. Exposure estimates obtained using dispersion models can overcome many of the limitations of monitoring data, and such estimates have been used in several recent health studies. This study examines the sensitivity of exposure estimates produced by dispersion models to meteorological, emission and traffic allocation inputs, focusing on applications to health studies examining near-road exposures to TRAP. Daily average concentrations of CO and NOx predicted using the Research Line source model (RLINE) and a spatially and temporally resolved mobile source emissions inventory are compared to ambient measurements at near-road monitoring sites in Detroit, MI, and are used to assess the potential for exposure measurement error in cohort and population-based studies. Sensitivity of exposure estimates is assessed by comparing nominal and alternative model inputs using statistical performance evaluation metrics and three sets of receptors. The analysis shows considerable sensitivity to meteorological inputs; generally the best performance was obtained using data specific to each monitoring site. An updated emission factor database provided some improvement, particularly at near road sites, while the use of site-specific diurnal traffic allocations did not improve performance compared to simpler default profiles. Overall, this study highlights the need for appropriate inputs, especially meteorological inputs, to dispersion models aimed at estimating near-road concentrations of TRAPs. It also highlights the potential for systematic biases that might affect analyses that use concentration predictions as exposure measures in health studies, e.g., to estimate health impacts. PMID- 29632434 TI - Energy Profiles of an Agricultural Frontier: The American Great Plains, 1860 2000. AB - Agro-ecosystem energy profiles reveal energy flows into, within, and out of U.S. Great Plains farm communities across 140 years. This study evaluates external energy inputs such as human labor, machinery, fuel, and fertilizers. It tracks the energy content of land produce, including crops, grazed pasture, and firewood, and also accounts unharvested energy that remains available for wildlife. It estimates energy redirected through livestock feed into draft power, meat, and milk, and estimates the energy content of final produce available for local consumption or market sale. The article presents energy profiles for three case studies in Kansas in 1880, 1930, 1954, and 1997. Two energy transformations occurred during that time. The first, agricultural colonization, saw farm communities remake the landscape, turning native grassland into a mosaic of cropland and pasture, a process that reduced overall landscape energy productivity. A second energy transition occurred in the mid-twentieth century, characterized by fossil fuel energy imports. That outside energy raised harvested and unharvested energy flows, reused biomass energy, and also final produce. This socio-ecological transition increased landscape energy productivity by 33 to 45 percent above pre-settlement conditions in grain-growing regions. These energy developments were not uniform across the plains. Variations in rainfall and soil quality constrained or favored energy productivity in different places. The case studies reveal the spatial variation of energy profiles in Great Plains agro ecosystems, while the longitudinal approach tracks temporal change. PMID- 29632435 TI - Perceptions of perioperative nursing competence: a cross-country comparison. AB - Background: Throughout many countries, professional bodies rely on yearly self assessment of competence for ongoing registration; therefore, nursing competence is pivotal to safe clinical practice. Our aim was to describe and compare perioperative nurses' perceptions of competence in four countries, while examining the effect of specialist education and years of experience in the operating room. Methods: We conducted a secondary analysis of cross-sectional surveys from four countries including; Australia, Canada, Scotland, and Sweden. The 40-item Perceived Perioperative Competence Scale-Revised (PPCS-R), was used with a total sample of 768 respondents. We used a factorial design to examine the influence of country, years of experience in the operating room and specialist education on nurses' reported perceived perioperative competence. Results: Regardless of country origin, nurses with specialist qualifications reported higher perceived perioperative competence when compared to nurses without specialist education. However, cross-country differences were dependent on nurses' number of years of experience in the operating room. Nurses from Sweden with 6-10 years of experience in the operating room reported lower perceived perioperative competence when compared to Australian nurses. In comparing nurses with > 10 years of experience, Swedish nurses reported significantly lower perceived perioperative competence when compared to nurses from Australia, Canada and Scotland. Conclusion: Researchers need to consider educational level and years of experience in the perioperative context when examining constructs such as competence. PMID- 29632436 TI - MiR-144-3p promotes the tumor growth and metastasis of papillary thyroid carcinoma by targeting paired box gene 8. AB - Background: Paired box gene 8 (PAX8) is expressed in and indispensable to thyroid development. MiR-144-3p is found dys-regulated in cancers, and it can block the expression of target gens. This study sought to understand the effect of MiR-144 3p in papillary thyroid carcinoma (PTC) as well as the associated mechanisms. Materials and methods: Real-time PCR, immunohistochemical and Western blot assays were performed to examine the expression of target miRNA and/or genes. CCK-8 and flow cytometry analysis was used to respectively test cell growth, cell cycle progression and apoptosis. Luciferase reporter assay was performed to find out whether miR-144-3p could bind to the 3' untranslated region of PAX8 or not. Results: We found that PAX8 decreased in PTC, while miR-144-3p increased in PTC. Over-expression of miR-144-3p promoted the cell viability and cell cycle progression. The expressions of cell-cycle-related genes, cyclin D1, cyclin dependent kinase 2 and CDC25A were modulated by miR-144-3p. Meanwhile, the presence or absence of miR-144-3p both affected epithelial-mesenchymal transition of PTC by regulating the expression of E-cadherin, N-cadherin and vimentin. Moreover, PAX8 may be a potential direct target of miR-144-3p. Mechanically, the activation of extracellular signal-regulated kinases 1/2, Akt and c-Jun N terminal kinases may be associated with the tumor-promoting effect of miR-144-3p. In addition, the blockage of miR-144-3p forced the anti-tumor effect delivered by X-ray exposure or paclitaxel. Conclusion: MiR-144-3p promoted the growth of tumor and the metastasis of PTC by targeting PAX 8. The study provided promising prognosis markers and valuable treatment strategy for PTC. PMID- 29632437 TI - Practicing what we preach: developing a data sharing policy for the Journal of the Medical Library Association. AB - Providing access to the data underlying research results in published literature allows others to reproduce those results or analyze the data in new ways. Health sciences librarians and information professionals have long been advocates of data sharing. It is time for us to practice what we preach and share the data associated with our published research. This editorial describes the activity of a working group charged with developing a research data sharing policy for the Journal of the Medical Library Association. PMID- 29632439 TI - An historical overview of the National Network of Libraries of Medicine, 1985 2015. AB - The National Network of Libraries of Medicine (NNLM), established as the Regional Medical Library Program in 1965, has a rich and remarkable history. The network's first twenty years were documented in a detailed 1987 history by Alison Bunting, AHIP, FMLA. This article traces the major trends in the network's development since then: reconceiving the Regional Medical Library staff as a "field force" for developing, marketing, and distributing a growing number of National Library of Medicine (NLM) products and services; subsequent expansion of outreach to health professionals who are unaffiliated with academic medical centers, particularly those in public health; the advent of the Internet during the 1990s, which brought the migration of NLM and NNLM resources and services to the World Wide Web, and a mandate to encourage and facilitate Internet connectivity in the network; and the further expansion of the NLM and NNLM mission to include providing consumer health resources to satisfy growing public demand. The concluding section discusses the many challenges that NNLM staff faced as they transformed the network from a system that served mainly academic medical researchers to a larger, denser organization that offers health information resources to everyone. PMID- 29632440 TI - Evaluating the impact of clinical librarians on clinical questions during inpatient rounds. AB - Objective: The investigation sought to determine the effects of a clinical librarian (CL) on inpatient team clinical questioning quality and quantity, learner self-reported literature searching skills, and use of evidence-based medicine (EBM). Methods: Clinical questioning was observed over 50 days of inpatient pediatric and internal medicine attending rounds. A CL was present for 25 days and absent for 25 days. Questioning was compared between groups. Question quality was assessed by a blinded evaluator, who used a rubric adapted from the Fresno Test of Competence in Evidence-Based Medicine. Team members were surveyed to assess perceived impacts of the CL on rounds. Results: Rounds with a CL (CLR) were associated with significantly increased median number of questions asked (5 questions CLR vs. 3 NCLR; p<0.01) and answered (3 CLR vs. 2 NCLR; p<0.01) compared to rounds without a CL (NCLR). CLR were also associated with increased mean time spent asking (1.39 minutes CLR vs. 0.52 NCLR; p<0.01) and answering (2.15 minutes CLR vs. 1.05 NCLR; p=0.02) questions. Rounding time per patient was not significantly different between CLR and NCLR. Questions during CLR were 2 times higher in adapted Fresno Test quality than during NCLR (p<0.01). Select participants described how the CL's presence improved their EBM skills and care decisions. Conclusions: Inpatient CLR were associated with more and improved clinical questioning and subjectively perceived to improve clinicians' EBM skills. CLs may directly affect patient care; further study is required to assess this. CLs on inpatient rounds may be an effective means for clinicians to learn and use EBM skills. PMID- 29632441 TI - A qualitative analysis of the information science needs of public health researchers in an academic setting. AB - Objectives: The University of Minnesota (UMN) Health Sciences Libraries conducted a needs assessment of public health researchers as part of a multi-institutional study led by Ithaka S+R. The aims of the study were to capture the evolving needs, opportunities, and challenges of public health researchers in the current environment and provide actionable recommendations. This paper reports on the data collected at the UMN site. Methods: Participants (n=24) were recruited through convenience sampling. One-on-one interviews, held November 2016 to January 2017, were audio-recorded. Qualitative analyses were conducted using NVivo 11 Pro and were based on the principles of grounded theory. Results: The data revealed that a broad range of skill levels among participants (e.g., literature searching) and areas of misunderstanding (e.g., current publishing landscape, open access options). Overall, data management was an afterthought. Few participants were fully aware of the breadth of librarian knowledge and skill sets, although many did express a desire for further skill development in information science. Conclusions: Libraries can engage more public health researchers by utilizing targeted and individualized marketing regarding services. We can promote open science by educating researchers on publication realities and enhancing our data visualization skills. Libraries might take an institution-wide leadership role on matters of data management and data policy compliance. Finally, as team science emerges as a research priority, we can offer our networking expertise. These support services may reduce the stresses that public health researchers feel in the current research environment. PMID- 29632442 TI - It takes longer than you think: librarian time spent on systematic review tasks. AB - Introduction: The authors examined the time that medical librarians spent on specific tasks for systematic reviews (SRs): interview process, search strategy development, search strategy translation, documentation, deliverables, search methodology writing, and instruction. We also investigated relationships among the time spent on SR tasks, years of experience, and number of completed SRs to gain a better understanding of the time spent on SR tasks from time, staffing, and project management perspectives. Methods: A confidential survey and study description were sent to medical library directors who were members of the Association of Academic Health Sciences Libraries as well as librarians serving members of the Association of American Medical Colleges or American Osteopathic Association. Results: Of the 185 participants, 143 (77%) had worked on an SR within the last 5 years. The number of SRs conducted by participants during their careers ranged from 1 to 500, with a median of 5. The major component of time spent was on search strategy development and translation. Average aggregated time for standard tasks was 26.9 hours, with a median of 18.5 hours. Task time was unrelated to the number of SRs but was positively correlated with years of SR experience. Conclusion: The time required to conduct the librarian's discrete tasks in an SR varies substantially, and there are no standard time frames. Librarians with more SR experience spent more time on instruction and interviews; time spent on all other tasks varied widely. Librarians also can expect to spend a significant amount of their time on search strategy development, translation, and writing. PMID- 29632443 TI - Environmental scan and evaluation of best practices for online systematic review resources. AB - Objective: Online training for systematic review methodology is an attractive option due to flexibility and limited availability of in-person instruction. Librarians often direct new reviewers to these online resources, so they should be knowledgeable about the variety of available resources. The objective for this project was to conduct an environmental scan of online systematic review training resources and evaluate those identified resources. Methods: The authors systematically searched for electronic learning resources pertaining to systematic review methods. After screening for inclusion, we collected data about characteristics of training resources and assigned scores in the domains of (1) content, (2) design, (3) interactivity, and (4) usability by applying a previously published evaluation rubric for online instruction modules. We described the characteristics and scores for each training resource and compared performance across the domains. Results: Twenty training resources were evaluated. Average overall score of online instructional resources was 61%. Online courses (n=7) averaged 73%, web modules (n=5) 64%, and videos (n=8) 48%. The top 5 highest scoring resources were in course or web module format, featured high interactivity, and required a longer (>5hrs) time commitment from users. Conclusion: This study revealed that resources include appropriate content but are less likely to adhere to principles of online training design and interactivity. Awareness of these resources will allow librarians to make informed recommendations for training based on patrons' needs. Future online systematic review training resources should use established best practices for e learning to provide high-quality resources, regardless of format or user time commitment. PMID- 29632444 TI - Accepting the challenge: what academic health sciences library directors do to become effective leaders. AB - Objective: This study sought to better understand effective leadership through the lived experiences of academic health sciences library directors. Methods: Phenomenological interviews were conducted with eight academic health sciences library directors to capture the essence of their shared leadership experiences. The research question that guided the study was: How do academic health sciences library directors understand their leadership effectiveness? The interviews were transcribed and coded, and the data were analyzed thematically. Results: Three main themes emerged from data after analysis: assessment of the environment, strategies and decisions, and critical skills. Assessment of the environment includes awareness not only of trends in libraries and technology, but also the trends in health information, higher education, and current events and politics of their institutions and states. The strategies and decisions theme is about the ability to think both in the long-term and short-term when leading the library. Finally, critical skills are those leadership skills that the research participants identified as most important to their leadership effectiveness. Conclusions: The study identified three main themes capturing the essence of the research participants' leadership experiences. The three themes constitute a wide array of leadership skills that are important to learn, understand, and develop to increase leadership effectiveness. Effective leadership is fundamental to obtaining long-term strategic goals and is critical to the long-term future of the libraries. PMID- 29632445 TI - Has Embase replaced MEDLINE since coverage expansion? AB - Objectives: The research tested the authors' hypothesis that more researchers from the academic medicine community in the United States and Canada with institutional access to Embase had started using Embase to replace MEDLINE since Embase was expanded in 2010 to cover all MEDLINE records. Methods: We contacted libraries of 140 and 17 medical schools in the United States and Canada, respectively, to confirm their subscriptions to Embase 5 years before and 5 years after 2010. We searched the names of institutions with confirmed Embase access in Ovid MEDLINE and Embase to retrieve works authored by affiliates of those institutions. We then examined 100 randomly selected records from each of the 5 years before and 5 years after the Embase coverage expansion in 2010. We hypothesized that studies that used Embase but not MEDLINE would increase due to the Embase coverage expansion. Results: The number of studies that used Embase but not MEDLINE did not change between the pre-2010 and post-2010 periods. Conclusion: Our hypothesis was refuted. Studies that used Embase but not MEDLINE did not increase post-2010. Our results suggest the academic medicine community in the United States and Canada that had access did not use Embase to replace MEDLINE, despite the Embase coverage expansion. PMID- 29632447 TI - The hidden benefits of helping students with systematic reviews. AB - Helping students with systematic reviews goes against the instinct of many librarians, who see it as their duty to talk researchers out of these projects rather than to assist them. My perspective on helping students with systematic reviews changed after meeting with one student a few years ago. However, the question of whether the finished product will be publication-worthy or entirely free of error is secondary, in my view, to other potential benefits to the student in completing the assignment. PMID- 29632446 TI - Health sciences libraries' subscriptions to journals: expectations of general practice departments and collection-based analysis. AB - Objective: The aims of this study were to (i) assess the expectations of general practice departments regarding health sciences libraries' subscriptions to journals and (ii) describe the current general practice journal collections of health sciences libraries. Methods: A cross-sectional survey was distributed electronically to the thirty-five university general practice departments in France. General practice departments were asked to list ten journals to which they expected access via the subscriptions of their health sciences libraries. A ranked reference list of journals was then developed. Access to these journals was assessed through a survey sent to all health sciences libraries in France. Adequacy ratios (access/need) were calculated for each journal. Results: All general practice departments completed the survey. The total reference list included 44 journals. This list was heterogeneous in terms of indexation/impact factor, language of publication, and scope (e.g., patient care, research, or medical education). Among the first 10 journals listed, La Revue Prescrire (96.6%), La Revue du Praticien-Medecine Generale (90.9%), the British Medical Journal (85.0%), Pedagogie Medicale (70.0%), Exercer (69.7%), and the Cochrane Database of Systematic Reviews (62.5%) had the highest adequacy ratios, whereas Family Practice (4.2%), the British Journal of General Practice (16.7%), Medecine (29.4%), and the European Journal of General Practice (33.3%) had the lowest adequacy ratios. Conclusions: General practice departments have heterogeneous expectations in terms of health sciences libraries' subscriptions to journals. It is important for librarians to understand the heterogeneity of these expectations, as well as local priorities, so that journal access meets users' needs. PMID- 29632448 TI - Is there a place for undergraduate and graduate students in the systematic review process? AB - Systematic reviews are a well-established and well-honed research methodology in the medical and health sciences fields. As the popularity of systematic reviews has increased, disciplines outside the sciences have started publishing them. This increase in familiarity has begun to trickle down from practitioners and faculty to graduate students and recently undergraduates. The amount of work and rigor that goes into producing a quality systematic review may make these types of research projects seem unattainable for undergraduate or graduate students, but is this an accurate assumption? This commentary discusses whether there is a place for undergraduate and graduate students in the systematic review process. It explains the possible benefits of having undergraduate and graduate students engage in systematic reviews and concludes with ideas for creating basic education or training opportunities for researchers and students who are new to the systematic review process. PMID- 29632449 TI - Health sciences library outreach to family caregivers: a call to service. AB - This commentary discusses the information needs of family caregivers and care recipients in the United States. Health sciences library services and outreach activities that support family caregivers include: (1) advocacy, (2) resource building, and (3) programming and education. Ethical issues related to the privacy and confidentiality of clients are outlined in the commentary for information service providers. Also, continuing professional education resources are identified to assist librarians in providing high-quality information services for this special family caregiver population, such as those designed by the National Library of Medicine (NLM) through the NLM 4 Caregivers program. PMID- 29632450 TI - Finding a silver lining: the importance of documenting medical tragedies. AB - The radiation overexposure tragedy at a Columbus, Ohio, hospital impacted hundreds of patient lives and made a lasting impression on the regulation and oversight of the use of radiation medicine on a national level. Archival documentation of the incident and the current-day importance of the data collected during and after the event is discussed and highlights many of the reasons why the history of past medical disasters matters to us today. PMID- 29632451 TI - Taking publication date into consideration: a response to the review of Mobile Technologies for Every Library. PMID- 29632452 TI - Prediction equation for estimating total daily energy requirements of special operations personnel. AB - Background: Special Operations Forces (SOF) engage in a variety of military tasks with many producing high energy expenditures, leading to undesired energy deficits and loss of body mass. Therefore, the ability to accurately estimate daily energy requirements would be useful for accurate logistical planning. Purpose: Generate a predictive equation estimating energy requirements of SOF. Methods: Retrospective analysis of data collected from SOF personnel engaged in 12 different SOF training scenarios. Energy expenditure and total body water were determined using the doubly-labeled water technique. Physical activity level was determined as daily energy expenditure divided by resting metabolic rate. Physical activity level was broken into quartiles (0 = mission prep, 1 = common warrior tasks, 2 = battle drills, 3 = specialized intense activity) to generate a physical activity factor (PAF). Regression analysis was used to construct two predictive equations (Model A; body mass and PAF, Model B; fat-free mass and PAF) estimating daily energy expenditures. Results: Average measured energy expenditure during SOF training was 4468 (range: 3700 to 6300) Kcal.d-1. Regression analysis revealed that physical activity level (r = 0.91; P < 0.05) and body mass (r = 0.28; P < 0.05; Model A), or fat-free mass (FFM; r = 0.32; P < 0.05; Model B) were the factors that most highly predicted energy expenditures. Predictive equations coupling PAF with body mass (Model A) and FFM (Model B), were correlated (r = 0.74 and r = 0.76, respectively) and did not differ [mean +/ SEM: Model A; 4463 +/- 65 Kcal.d- 1, Model B; 4462 +/- 61 Kcal.d- 1] from DLW measured energy expenditures. Conclusion: By quantifying and grouping SOF training exercises into activity factors, SOF energy requirements can be predicted with reasonable accuracy and these equations used by dietetic/logistical personnel to plan appropriate feeding regimens to meet SOF nutritional requirements across their mission profile. PMID- 29632453 TI - Criterion validity of self-reports of alcohol, cannabis, and methamphetamine use among young men in Cape Town, South Africa. AB - Valid measurement of substance use is necessary to evaluate preventive and treatment interventions. Self-report is fast and inexpensive, but its accuracy can be hampered by social desirability bias and imperfect recall. We examined the agreement between self-report of recent use and rapid diagnostic tests for three substances (alcohol, cannabis, and methamphetamine) among 904 young men living in Cape Town, South Africa. Rapid diagnostic tests detected the respective substances in 32%, 52%, and 22% of men. Among those who tested positive, 61% (95% CI [56%, 66%]), 70% ([67%, 74%]), and 48% ([42%, 54%]) admitted use. Men were moderately more willing to admit use of cannabis than alcohol (log OR 0.42) or admit use of alcohol than methamphetamine (log OR 0.53). Our findings show that self-report has reasonable criterion validity in this population, but criterion validity can vary substantially depending on the substance. PMID- 29632454 TI - Contract Design: Risk Management and Evaluation. AB - Introduction: Effective risk adjustment is an aspect that is more and more given weight on the background of competitive health insurance systems and vital healthcare systems. The risk structure of the providers plays a vital role in Pay for Performance. A prerequisite for optimal incentive-based service models is a (partial) dependence of the agent's returns on the provider's gain level. Integrated care systems as well as accountable care organisations (ACOs) in the US and similar concepts in other countries are advocated as an effective method of improving the performance of healthcare systems. These systems outline a payment and care delivery model that intends to tie provider reimbursements to predefined quality metrics. By this the total costs of care shall be reduced. Methods: Little is known about the contractual design and the main challenges of delegating "accountability" to these new kinds of organisations and/or contracts. The costs of market utilisation are highly relevant for the conception of healthcare contracts; furthermore information asymmetries and contract-specific investments are an obstacle to the efficient operation of ACOs. A comprehensive literature review on methods of designing contracts in Integrated Care was conducted. The research question in this article focuses on how reimbursement strategies, evaluation of measures and methods of risk adjustment can best be integrated in healthcare contracting. Results: Each integrated care contract includes challenges for both payers and providers without having sufficient empirical data on both sides. These challenges are clinical, administrative or financial nature. Risk adjusted contracts ensure that the reimbursement roughly matches the true costs resulting from the morbidity of a population. If reimbursement of care provider corresponds to the actual expenses for an individual/population the problem of risk selection is greatly reduced. The currently used methods of risk adjustment have widely differing model and forecast accuracy. For this reason, it is necessary to clearly regulate the method of risk adjustment in the integrated care contract. Conclusions and discussion: The series of three articles on contract design has shown that coordination and motivation problems in designing healthcare contracts cannot be solved at no-costs. Moreover, it became clear, that complete contracts in healthcare are unrealistic and that contracts do always include certain uncertainties. These are based on the risk of random, and no contracting party can control these risks completely. It is also not possible to fully integrate these risks in the contract or to eliminate these risks by the parties. PMID- 29632455 TI - Barriers to the Integration of Care in Inter-Organisational Settings: A Literature Review. AB - Introduction: In recent years, inter-organisational collaboration between healthcare organisations has become of increasingly vital importance in order to improve the integration of health service delivery. However, different barriers reported in academic literature seem to hinder the formation and development of such collaboration. Theory and methods: This systematic literature review of forty studies summarises and categorises the barriers to integrated care in inter organisational settings as reported in previous studies. It analyses how these barriers operate. Results: Within these studies, twenty types of barriers have been identified and then categorised in six groups (barriers related to administration and regulation, barriers related to funding, barriers related to the inter-organisational domain, barriers related to the organisational domain, barriers related to service delivery, and barriers related to clinical practices). Not all of these barriers emerge passively, some are set up intentionally. They are not only context-specific, but are also often related and influence each other. Discussion and conclusion: The compilation of these results allows for a better understanding of the characteristics and reasons for the occurrence of barriers that impede collaboration aiming for the integration of care, not only for researchers but also for practitioners. It can help to explain and counteract the slow progress and limited efficiency and effectiveness of some of the inter-organisational collaboration in healthcare settings. PMID- 29632456 TI - The SUSTAIN Project: A European Study on Improving Integrated Care for Older People Living at Home. AB - Introduction: Integrated care programmes are increasingly being put in place to provide care to older people who live at home. Knowledge of how to further develop integrated care and how to transfer successful initiatives to other contexts is still limited. Therefore, a cross-European research project, called Sustainable Tailored Integrated Care for Older People in Europe (SUSTAIN), has been initiated with a twofold objective: 1. to collaborate with local stakeholders to support and monitor improvements to established integrated care initiatives for older people with multiple health and social care needs. Improvements focus on person-centredness, prevention orientation, safety and efficiency; 2. to make these improvements applicable and adaptable to other health and social care systems, and regions in Europe. This paper presents the overall structure and approach of the SUSTAIN project. Methods: SUSTAIN uses a multiple embedded case study design. In three phases, SUSTAIN partners: (i) conduct interviews and workshops with stakeholders from fourteen established integrated care initiatives to understand where they would prefer improvements to existing ways of working; (ii) collaborate with local stakeholders to support the design and implementation of improvement plans, evaluate implementation progress and outcomes per initiative, and carry out overarching analyses to compare the different initiatives, and; (iii) translate knowledge and experience to an online roadmap. Discussion: SUSTAIN aims to generate evidence on how to improve integrated care, and apply and transfer the knowledge gained to other health and social care systems, and regions. Lessons learned will be brought together in practical tools to inform and support policy-makers and decision-makers, as well as other stakeholders involved in integrated care, to manage and improve care for older people living at home. PMID- 29632457 TI - Development of a Customizable Programme for Improving Interprofessional Team Meetings: An Action Research Approach. AB - Introduction: Interprofessional teamwork is increasingly necessary in primary care to meet the needs of people with complex care demands. Needs assessment shows that this requires efficient interprofessional team meetings, focusing on patients' personal goals. The aim of this study was to develop a programme to improve the efficiency and patient-centredness of such meetings. Methods: Action research approach: a first draft of the programme was developed, and iteratively used and evaluated by three primary care teams. Data were collected using observations, interviews and a focus group, and analysed using directed content analysis. Results: The final programme comprises a framework to reflect on team functioning, and training activities supplemented by a toolbox. Training is intended for the chairperson and a co-chair, and aims at organizing and structuring meetings, and enhancing patient-centredness. Our findings emphasize the essential role of the team's chairperson, who, in addition to technically structuring meetings, should act as a change agent guiding team development. Conclusion: Findings show that the programme should be customizable to each individual team's context and participants' learning objectives. Becoming acquainted with new structures can be considered a growth process, in which teams have to find their way, with the chairperson as change agent. PMID- 29632459 TI - The Sixth FESCC Continuous Postgraduate Course in Clinical Chemistry: New Trends in Classification, Monitoring and Management of Metabolic Syndrome. PMID- 29632460 TI - The 6th FESCC Continuous Postgraduate Course in Clinical Chemistry: New Trends in Classification, Monitoring and Management of Metabolic Syndrome: Under the Auspices of IFCC. PMID- 29632458 TI - Feasibility and Acceptability of Text Messaging to Assess Daily Substance Use and Sexual Behaviors among Urban Emerging Adults. AB - Background: Daily process research can help distinguish causal relationships between substance use and sexual risk behaviors in high-risk groups, such as urban emerging adults. We employed text messaging to assess 18-25 year-olds' daily substance use and sexual risk behaviors over 28 days. We describe the implementation of this method, attitudes regarding the daily surveys, and correlates of survey completion. Method: We recruited 111 emerging adults from an urban Emergency Department in a resource-limited area who reported recent drug use and unprotected sex (Mage=22.0; 53.2% female; 45.1% African American; 43.2% receiving public assistance). Results: Respondents completed M=18.0 (SD = 8.7) of 28 daily surveys (27 items each). Participants completing a 1-month follow-up found the surveys not at all/only a little annoying (90.3%) and were comfortable with questions about drugs/alcohol (97.9%) and sex (94.6%). Completion was higher on weekdays versus weekends, and earlier in the study. Daily survey completion was unrelated to same-day substance use measured by the Timeline Follow Back at follow-up; polysubstance use and drinks consumed were associated with lower odds of next-day completion. School enrollment, public assistance, unlimited texting plan, lower baseline alcohol use, and depression symptoms at follow-up were associated with higher completion. Technology difficulties were commonly mentioned barriers to completion. Conclusions: Participants in this urban, resource-constrained sample found the daily text message methodology acceptable for reporting sensitive information. With rapid advancements in technologies and increased accessibility, text messaging remains a promising methodology for the study of daily processes in substance use and HIV risk behaviors. Keywords: text messaging; assessment; emerging adults; substance use; risky sex; mobile technology. PMID- 29632461 TI - Pathophysiology of Metabolic Syndrome. PMID- 29632462 TI - Genetic Succeptibility to Metabolic Syndrome. PMID- 29632463 TI - How is the Metabolic Syndrome Related to the Dyslipidemia? PMID- 29632464 TI - Coronary Disease and Metabolic Syndrome. PMID- 29632465 TI - Insulin Resistance and Metabolic Syndrome. PMID- 29632466 TI - Pro-Inflammatory and Prothrombotic Factors and Metabolic Syndrome. PMID- 29632467 TI - Evidence Based Laboratory Medicine in the Diagnosis of Metabolic Syndrome. PMID- 29632468 TI - Hypertension and the Metabolic Syndrome. PMID- 29632469 TI - Approach to the Treatement of Metabolic Syndrome. PMID- 29632470 TI - Properties and Units in the Clinical Laboratory Sciences. AB - This document describes the introduction of the concept of property in the field of clinical and environmental human toxicology for the presentation of results of clinical laboratory investigations. It follows the IFCC-IUPAC systematic terminological rules and attempts to create a common base for communication between the clinical chemist, the medical practitioner, the human toxicologist, and the environmental toxicologist. The term designating a substance being a toxicant may be an international nonproprietary name (INN), a generic name, a registered trade name, a fantasy name, or other. This causes difficulties in the transmission of requests and reports on properties involving such substances in biological fluids and environmental media to and from laboratories, to the end user, and in the collating of this information from different sources. The document comprises a list of properties of human and environmental systems involving toxicants for use in transmitting medical laboratory data. The document recommends terms based on the format developed by the IFCC and IUPAC to facilitate interaction between disciplines and unambiguous interpretation of data, e.g. for purposes of risk interpretation. Systematic terms are presented together with a code (identified by the letters NPU) for each. The complete C-NPU Database may be found at: http://dior.imt.liu.se/C-NPU. PMID- 29632471 TI - A Bayesian Spatial Model to Predict Disease Status Using Imaging Data From Various Modalities. AB - Relating disease status to imaging data stands to increase the clinical significance of neuroimaging studies. Many neurological and psychiatric disorders involve complex, systems-level alterations that manifest in functional and structural properties of the brain and possibly other clinical and biologic measures. We propose a Bayesian hierarchical model to predict disease status, which is able to incorporate information from both functional and structural brain imaging scans. We consider a two-stage whole brain parcellation, partitioning the brain into 282 subregions, and our model accounts for correlations between voxels from different brain regions defined by the parcellations. Our approach models the imaging data and uses posterior predictive probabilities to perform prediction. The estimates of our model parameters are based on samples drawn from the joint posterior distribution using Markov Chain Monte Carlo (MCMC) methods. We evaluate our method by examining the prediction accuracy rates based on leave-one-out cross validation, and we employ an importance sampling strategy to reduce the computation time. We conduct both whole-brain and voxel-level prediction and identify the brain regions that are highly associated with the disease based on the voxel-level prediction results. We apply our model to multimodal brain imaging data from a study of Parkinson's disease. We achieve extremely high accuracy, in general, and our model identifies key regions contributing to accurate prediction including caudate, putamen, and fusiform gyrus as well as several sensory system regions. PMID- 29632472 TI - tDCS Over DLPFC Leads to Less Utilitarian Response in Moral-Personal Judgment. AB - The profound nature of moral judgment has been discussed and debated for centuries. When facing the trade-off between pursuing moral rights and seeking better consequences, most people make different moral choices between two kinds of dilemmas. Such differences were explained by the dual-process theory involving an automatic emotional response and a controlled application of utilitarian decision-rules. In neurocognitive studies, the bilateral dorsolateral prefrontal cortex (DLPFC) has been demonstrated to play an important role in cognitive "rational" control processes in moral dilemmas. However, the profile of results across studies is not entirely consistent. Although one transcranial magnetic stimulation (TMS) study revealed that disrupting the right DLPFC led to less utilitarian responses, other TMS studies indicated that inhibition of the right DLPFC led to more utilitarian choices. Moreover, the right temporoparietal junction (TPJ) is essential for its function of integrating belief and intention in moral judgment, which is related to the emotional process according to the dual-process theory. Relatively few studies have reported the causal relationship between TPJ and participants' moral responses, especially in moral dilemmas. In the present study, we aimed to demonstrate a direct link between the neural and behavioral results by application of transcranial direct current stimulation (tDCS) in the bilateral DLPFC or TPJ of our participants. We observed that activating the right DLPFC as well as inhibiting the left DLPFC led to less utilitarian judgments, especially in moral-personal conditions, indicating that the right DLPFC plays an essential role, not only through its function of moral reasoning but also through its information integrating process in moral judgments. It was also revealed that altering the excitability of the bilateral TPJ using tDCS negligibly altered the moral response in non-moral, moral impersonal and moral-personal dilemmas, indicating that bilateral TPJ may have little influence over moral judgments in moral dilemmas. PMID- 29632473 TI - Endothelial Monocyte-Activating Polypeptide-II Induces BNIP3-Mediated Mitophagy to Enhance Temozolomide Cytotoxicity of Glioma Stem Cells via Down-Regulating MiR 24-3p. AB - Preliminary studies have shown that endothelial-monocyte-activating polypeptide II (EMAP-II) and temozolomide (TMZ) alone can exert cytotoxic effects on glioma cells. This study explored whether EMAP-II can enhance the cytotoxic effects of TMZ on glioma stem cells (GSCs) and the possible mechanisms associated with Bcl 2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)-mediated mitophagy facilitated by miR-24-3p regulation. The combination of TMZ and EMAP-II significantly inhibited GSCs viability, migration, and invasion, resulting in upregulation of the autophagy biomarker microtubule-associated protein one light chain 3 (LC3)-II/I but down-regulation of the proteins P62, TOMM 20 and CYPD, changes indicative of the occurrence of mitophagy. BNIP3 expression increased significantly in GSCs after treatment with the combination of TMZ and EMAP-II. BNIP3 overexpression strengthened the cytotoxic effects of EMAP-II and TMZ by inducing mitophagy. The combination of EMAP-II and TMZ decreased the expression of miR-24-3p, whose target gene was BNIP3. MiR-24-3p inhibited mitophagy and promoted proliferation, migration and invasion by down-regulating BNIP3 in GSCs. Furthermore, nude mice subjected to miR-24-3p silencing combined with EMAP-II and TMZ treatment displayed the smallest tumors and the longest survival rate. According to the above results, we concluded that EMAP-II enhanced the cytotoxic effects of TMZ on GSCs' proliferation, migration and invasion both in vitro and in vivo. PMID- 29632474 TI - Melatonin Regulates Apoptosis and Autophagy Via ROS-MST1 Pathway in Subarachnoid Hemorrhage. AB - Compelling evidence has indicated that imbalance between apoptosis and autophagy may be involved in subarachnoid hemorrhage (SAH). We aimed to investigate the effects and mechanisms of melatonin in the homeostasis of apoptosis and autophagy. One-hundred and forty-eight male Sprague-Dawley rats were intraperitoneally injected with melatonin or vehicle 2 h after SAH induction. Western blotting and an immunofluorescent assay were performed to detect the expression of apoptosis- and autophagy-related proteins. The neuroprotective effect of melatonin attenuating SAH-induced neurological deficit and brain edema may be associated with the suppression of SAH-induced neuronal apoptosis and autophagy. Furthermore, melatonin inhibited the cleavage of mammalian sterile 20 like kinase 1 (MST1) protein by reducing reactive oxygen species (ROS) content. These effects of melatonin on regulating the homeostasis between apoptosis and autophagy could be reversed by an MST1 agonist, chelerythrine, via enhancement of MST1 cleavage. In conclusion, exogenous melatonin alleviates SAH-induced early brain injury (EBI) by suppressing excessive neuronal apoptosis and autophagy. The underlying mechanism may, at least in part, involve the ROS-MST1 pathway. PMID- 29632475 TI - The Enlightened Brain: Novel Imaging Methods Focus on Epileptic Networks at Multiple Scales. AB - Epilepsy research is rapidly adopting novel fluorescence optical imaging methods to tackle unresolved questions on the cellular and circuit mechanisms of seizure generation and evolution. State of the art two-photon microscopy and wide-field fluorescence imaging can record the activity in epileptic networks at multiple scales, from neuronal microcircuits to brain-wide networks. These approaches exploit transgenic and viral technologies to target genetically encoded calcium and voltage sensitive indicators to subclasses of neurons, and achieve genetic specificity, spatial resolution and scalability that can complement electrophysiological recordings from awake animal models of epilepsy. Two-photon microscopy is well suited to study single neuron dynamics during interictal and ictal events, and highlight the differences between the activity of excitatory and inhibitory neuronal classes in the focus and propagation zone. In contrast, wide-field fluorescence imaging provides mesoscopic recordings from the entire cortical surface, necessary to investigate seizure propagation pathways, and how the unfolding of epileptic events depends on the topology of brain-wide functional connectivity. Answering these questions will inform pre-clinical studies attempting to suppress seizures with gene therapy, optogenetic or chemogenetic strategies. Dissecting which network nodes outside the seizure onset zone are important for seizure generation, propagation and termination can be used to optimize current and future evaluation methods to identify an optimal surgical strategy. PMID- 29632476 TI - Heightened Salience of Anger and Aggression in Female Adolescents With Borderline Personality Disorder-A Script-Based fMRI Study. AB - Background: Anger and aggression belong to the core symptoms of borderline personality disorder. Although an early and specific treatment of BPD is highly relevant to prevent chronification, still little is known about anger and aggression and their neural underpinnings in adolescents with BPD. Method: Twenty female adolescents with BPD (age 15-17 years) and 20 female healthy adolescents (age 15-17 years) took part in this functional magnetic resonance imaging (fMRI) study. A script-driven imagery paradigm was used to induce rejection-based feelings of anger, which was followed by descriptions of self-directed and other directed aggressive reactions. To investigate the specificity of the neural activation patterns for adolescent patients, results were compared with data from 34 female adults with BPD (age 18-50 years) and 32 female healthy adults (age 18 50 years). Results: Adolescents with BPD showed increased activations in the left posterior insula and left dorsal striatum as well as in the left inferior frontal cortex and parts of the mentalizing network during the rejection-based anger induction and the imagination of aggressive reactions compared to healthy adolescents. For the other-directed aggression phase, a significant diagnosis by age interaction confirmed that these results were specific for adolescents. Discussion: The results of this very first fMRI study on anger and aggression in adolescents with BPD suggest an enhanced emotional reactivity to and higher effort in controlling anger and aggression evoked by social rejection at an early developmental stage of the disorder. Since emotion dysregulation is a known mediator for aggression in BPD, the results point to the need of appropriate early interventions for adolescents with BPD. PMID- 29632478 TI - Eye Movement Correlates of Expertise in Visual Arts. AB - The aim of this study was to search for oculomotor correlates of expertise in visual arts, in particular with regard to paintings. Achieving this goal was possible by gathering data on eye movements of two groups of participants: experts and non-experts in visual arts who viewed and appreciated the aesthetics of paintings. In particular, we were interested in whether visual arts experts more accurately recognize a balanced composition in one of the two paintings being compared simultaneously, and whether people who correctly recognize harmonious paintings are characterized by a different visual scanning strategy than those who do not recognize them. For the purposes of this study, 25 paintings with an almost ideal balanced composition have been chosen. Some of these paintings are masterpieces of the world cultural heritage, and some of them are unknown. Using Photoshop, the artist developed three additional versions of each of these paintings, differing from the original in the degree of destruction of its harmonious composition: slight, moderate, or significant. The task of the participants was to look at all versions of the same painting in pairs (including the original) and decide which of them looked more pleasing. The study involved 23 experts in art, students of art history, art education or the Academy of Fine Arts, and 19 non-experts, students in the social sciences and the humanities. The experimental manipulation of comparing pairs of paintings, whose composition is at different levels of harmony, has proved to be an effective tool for differentiating people because of their ability to distinguish paintings with balanced composition from an unbalanced one. It turned out that this ability only partly coincides with expertise understood as the effect of education in the field of visual arts. We also found that the eye movements of people who more accurately appreciated paintings with balanced composition differ from those who more liked their altered versions due to dwell time, first and average fixation duration and number of fixations. The familiarity of paintings turned out to be the factor significantly affects both the aesthetic evaluation of paintings and eye movement. PMID- 29632477 TI - Single Session Low Frequency Left Dorsolateral Prefrontal Transcranial Magnetic Stimulation Changes Neurometabolite Relationships in Healthy Humans. AB - Background: Dorsolateral prefrontal cortex (DLPFC) low frequency repetitive transcranial magnetic stimulation (LF-rTMS) has shown promise as a treatment and investigative tool in the medical and research communities. Researchers have made significant progress elucidating DLPFC LF-rTMS effects-primarily in individuals with psychiatric disorders. However, more efforts investigating underlying molecular changes and establishing links to functional and behavioral outcomes in healthy humans are needed. Objective: We aimed to quantify neuromolecular changes and relate these to functional changes following a single session of DLPFC LF rTMS in healthy participants. Methods: Eleven participants received sham controlled neuronavigated 1 Hz rTMS to the region most activated by a 7-letter Sternberg working memory task (SWMT) within the left DLPFC. We quantified SWMT performance, functional magnetic resonance activation and proton Magnetic resonance spectroscopy (MRS) neurometabolite measure changes before and after stimulation. Results: A single LF-rTMS session was not sufficient to change DLPFC neurometabolite levels and these changes did not correlate with DLPFC activation changes. Real rTMS, however, significantly altered neurometabolite correlations (compared to sham rTMS), both with baseline levels and between the metabolites themselves. Additionally, real rTMS was associated with diminished reaction time (RT) performance improvements and increased activation within the motor, somatosensory and lateral occipital cortices. Conclusion: These results show that a single session of LF-rTMS is sufficient to influence metabolite relationships and causes widespread activation in healthy humans. Investigating correlational relationships may provide insight into mechanisms underlying LF-rTMS. PMID- 29632479 TI - Retrieving Against the Flow: Incoherence Between Optic Flow and Movement Direction Has Little Effect on Memory for Order. AB - Research from multiple areas in neuroscience suggests a link between self locomotion and memory. In two free recall experiments with adults, we looked for a link between (a) memory, and (b) the coherence of movement and optic flow. In both experiments, participants heard lists of words while on a treadmill and wearing a virtual reality (VR) headset. In the first experiment, the VR scene and treadmill were stationary during encoding. During retrieval, all participants walked forward, but the VR scene was stationary, moved forward, or moved backwards. In the second experiment, during encoding all participants walked forward and viewed a forward-moving VR scene. During retrieval, all participants continued to walk forward but the VR scene was stationary, forward-moving, or backward-moving. In neither experiment was there a significant difference in the amount recalled, or output order strategies, attributable to differences in movement conditions. Thus, any effects of movement on memory are more limited than theories of hippocampal function and theories in cognitive psychology anticipate. PMID- 29632481 TI - Walking Speed Influences the Effects of Implicit Visual Feedback Distortion on Modulation of Gait Symmetry. AB - The use of visual feedback in gait rehabilitation has been suggested to promote recovery of locomotor function by incorporating interactive visual components. Our prior work demonstrated that visual feedback distortion of changes in step length symmetry entails an implicit or unconscious adaptive process in the subjects' spatial gait patterns. We investigated whether the effect of the implicit visual feedback distortion would persist at three different walking speeds (slow, self-preferred and fast speeds) and how different walking speeds would affect the amount of adaption. In the visual feedback distortion paradigm, visual vertical bars portraying subjects' step lengths were distorted so that subjects perceived their step lengths to be asymmetric during testing. Measuring the adjustments in step length during the experiment showed that healthy subjects made spontaneous modulations away from actual symmetry in response to the implicit visual distortion, no matter the walking speed. In all walking scenarios, the effects of implicit distortion became more significant at higher distortion levels. In addition, the amount of adaptation induced by the visual distortion was significantly greater during walking at preferred or slow speed than at the fast speed. These findings indicate that although a link exists between supraspinal function through visual system and human locomotion, sensory feedback control for locomotion is speed-dependent. Ultimately, our results support the concept that implicit visual feedback can act as a dominant form of feedback in gait modulation, regardless of speed. PMID- 29632480 TI - Moving Beyond ERP Components: A Selective Review of Approaches to Integrate EEG and Behavior. AB - Relationships between neuroimaging measures and behavior provide important clues about brain function and cognition in healthy and clinical populations. While electroencephalography (EEG) provides a portable, low cost measure of brain dynamics, it has been somewhat underrepresented in the emerging field of model based inference. We seek to address this gap in this article by highlighting the utility of linking EEG and behavior, with an emphasis on approaches for EEG analysis that move beyond focusing on peaks or "components" derived from averaging EEG responses across trials and subjects (generating the event-related potential, ERP). First, we review methods for deriving features from EEG in order to enhance the signal within single-trials. These methods include filtering based on user-defined features (i.e., frequency decomposition, time-frequency decomposition), filtering based on data-driven properties (i.e., blind source separation, BSS), and generating more abstract representations of data (e.g., using deep learning). We then review cognitive models which extract latent variables from experimental tasks, including the drift diffusion model (DDM) and reinforcement learning (RL) approaches. Next, we discuss ways to access associations among these measures, including statistical models, data-driven joint models and cognitive joint modeling using hierarchical Bayesian models (HBMs). We think that these methodological tools are likely to contribute to theoretical advancements, and will help inform our understandings of brain dynamics that contribute to moment-to-moment cognitive function. PMID- 29632482 TI - Closed-Loop Deep Brain Stimulation for Refractory Chronic Pain. AB - Pain is a subjective experience that alerts an individual to actual or potential tissue damage. Through mechanisms that are still unclear, normal physiological pain can lose its adaptive value and evolve into pathological chronic neuropathic pain. Chronic pain is a multifaceted experience that can be understood in terms of somatosensory, affective, and cognitive dimensions, each with associated symptoms and neural signals. While there have been many attempts to treat chronic pain, in this article we will argue that feedback-controlled 'closed-loop' deep brain stimulation (DBS) offers an urgent and promising route for treatment. Contemporary DBS trials for chronic pain use "open-loop" approaches in which tonic stimulation is delivered with fixed parameters to a single brain region. The impact of key variables such as the target brain region and the stimulation waveform is unclear, and long-term efficacy has mixed results. We hypothesize that chronic pain is due to abnormal synchronization between brain networks encoding the somatosensory, affective and cognitive dimensions of pain, and that multisite, closed-loop DBS provides an intuitive mechanism for disrupting that synchrony. By (1) identifying biomarkers of the subjective pain experience and (2) integrating these signals into a state-space representation of pain, we can create a predictive model of each patient's pain experience. Then, by establishing how stimulation in different brain regions influences individual neural signals, we can design real-time, closed-loop therapies tailored to each patient. While chronic pain is a complex disorder that has eluded modern therapies, rich historical data and state-of-the-art technology can now be used to develop a promising treatment. PMID- 29632484 TI - Light Alcohol Consumption Does Not Protect Cognitive Function: A Longitudinal Prospective Study. AB - Studies show that light to moderate alcohol consumption is related to better health and higher cognitive performance. However, it has been suggested that this association is caused by a systematic bias in the control group as many people abstain from drinking or quit because of health issues. Therefore, the group of non-drinkers is biased towards poor health and may not be suitable as a control group. The present study examined the effect of alcohol on cognitive performance while addressing this bias by excluding the non-drinkers. Thus, instead of comparing different levels of alcohol consumption to a non-drinking control group, a dose-response association was calculated between all levels of alcohol intake and cognitive performance. The study used information from a sample of people in the Swedish Twin Registry, who in their midlife (1967) participated in a survey on alcohol intake and 25 years later participated in a longitudinal study on cognitive aging (N = 486). The cognitive aging study took place on five occasions, at 2-year intervals, and included the Mini Mental State Examination (MMSE), tests of episodic memory, semantic memory and spatial ability. The association between midlife alcohol consumption and later cognitive performance was analyzed using growth curve models, adjusting for background variables. The findings showed that there was a significant negative dose-response association between alcohol intake in midlife and the MMSE, and the tests of episodic memory, such that higher intake in midlife was related to lower performance in old age. The associations between alcohol and semantic memory, and spatial ability respectively, were not significant. In contrast to findings from other studies, which show that low to moderate alcohol intake promotes cognitive function, the current study showed that alcohol intake was related to lower cognitive performance in a dose-response manner, even at low levels. The results from this study indicate that the observed benefits of moderate alcohol intake for cognitive function reported by others might be solely due to comparisons to an inappropriate control group, a group that is biased towards poor health. Hence, it is concluded that light alcohol intake may not protect cognitive function. PMID- 29632483 TI - The Retromer Complex and Sorting Nexins in Neurodegenerative Diseases. AB - The retromer complex and associated sorting nexins (SNXs) comprise a critical trafficking machinery which mediates endosomal protein sorting. Retromer and/or SNX dysfunction has been linked to several neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), and Down's syndrome (DS). In AD, deficiency of the retromer complex or its cargo proteins impairs endosomal trafficking of amyloid precursor protein (APP), resulting in the overproduction of beta-amyloid (Abeta). Several SNX components directly interact with APP or APP cleaving enzymes (beta- and gamma-secretases) to regulate amyloidogenic APP processing and Abeta generation. In addition, PD-linked mutations in retromer components cause mistrafficking of retromer cargo proteins and mitochondrial dysfunction, and dysregulation retromer-mediated trafficking has been considered as an important cause of hereditary spastic paraplegia (HSP) and neuronal ceroid lipofuscinoses (NCLs). Moreover, SNX27 deficiency is an important contributor for synaptic and cognitive impairment in DS. Here we review recent findings describing the retromer complex and/or SNXs-mediated endosomal sorting in neurodegenerative disorders. PMID- 29632485 TI - Exposure to Silver Nanospheres Leads to Altered Respiratory Mechanics and Delayed Immune Response in an in Vivo Murine Model. AB - Here we examine the organ level toxicology of both carbon black (CB) and silver nanoparticles (AgNP). We aim to determine metal-specific effects to respiratory function, inflammation and potential interactions with lung lining fluid (LLF). C57Bl6/J male mice were intratracheally instilled with saline (control), low (0.05 MUg/g) or high (0.5 MUg/g) doses of either AgNP or CB 15 nm nanospheres. Lung histology, cytology, surfactant composition and function, inflammatory gene expression, and pulmonary function were measured at 1, 3, and 7 days post exposure. Acutely, high dose CB resulted in an inflammatory response, increased neutrophilia and cytokine production, without alteration in surfactant composition or respiratory mechanics. Low dose CB had no effect. Neither low nor high dose AgNPs resulted in an acute inflammatory response, but there was an increase in work of breathing. Three days post-exposure with CB, a persistent neutrophilia was noted. High dose AgNP resulted in an elevated number of macrophages and invasion of lymphocytes. Additionally, AgNP treated mice displayed increased expression of IL1B, IL6, CCL2, and IL10. However, there were no significant changes in respiratory mechanics. At day 7, inflammation had resolved in AgNP-treated mice, but tissue stiffness and resistance were significantly decreased, which was accompanied by an increase in surfactant protein D (SP-D) content. These data demonstrate that the presence of metal alters the response of the lung to nanoparticle exposure. AgNP-surfactant interactions may alter respiratory function and result in a delayed immune response, potentially due to modified airway epithelial cell function. PMID- 29632486 TI - Transcriptomic Study Reveals Recovery of Impaired Astrocytes Contribute to Neuroprotective Effects of Danhong Injection Against Cerebral Ischemia/Reperfusion-Induced Injury. AB - Danhong Injection (DHI) is widely used in clinics for treating cardiovascular and cerebrovascular diseases in China. However, the mode of action of DHI for neuroprotection remains unclear. In the present study, we deemed to investigate the effects of DHI on a rat model of cerebral ischemia/reperfusion injury (IRI) with an emphasis on its regulated gene profile obtained from microarray assays. Firstly, we showed that a 14-day DHI treatment effectively ameliorated severity of neurological deficits, reduced size of ischemic damage, improved status of oxidation stress, as well as systemic inflammation for IRI rats, along with which was a pronounced reduced cell infiltration in the area of periaqueductal gray matter. Secondly, bioinformatic analyses for the 429 differentially expressed genes (DEGs) regulated by DHI treatment pointed out ECM-receptor interaction, neuroactive ligand-receptor interaction, and endocytosis as the top three biological processes, while Toll-like recptor 4 (TLR4) as the most relavant singaling molecule. Lastly, we provided evidences showing that DHI might directly protect primary astrocytes from oxygen and glucose deprivation/re-oxygenation (OGD/Re) injury, the effects of which was associated with LAMC2 and ADRB3, two DEGs related to the top three biological processes according to transcriptomic analysis. In conlusion, we reported that DHI might work through maintaining the integrity for brain-blood barrier and to regulate TLR4-related signaling pathway to diminish the inflammation, therefore, effectively improved the outcomes of IRI. Our findings suggested that the attenuated astrocytic dysfunction could be a novel mechanism contributing to the neuroprotective effects of DHI against cerebral ischemia/reperfusion-induced damage. PMID- 29632487 TI - Uridine Adenosine Tetraphosphate-Induced Coronary Relaxation Is Blunted in Swine With Pressure Overload: A Role for Vasoconstrictor Prostanoids. AB - Plasma levels of the vasoactive substance uridine adenosine tetraphosphate (Up4A) are elevated in hypertensive patients and Up4A-induced vascular contraction is exacerbated in various arteries isolated from hypertensive animals, suggesting a potential role of Up4A in development of hypertension. We previously demonstrated that Up4A produced potent and partially endothelium-dependent relaxation in the porcine coronary microvasculature. Since pressure-overload is accompanied by structural abnormalities in the coronary microvasculature as well as by endothelial dysfunction, we hypothesized that pressure-overload blunts the coronary vasodilator response to Up4A, and that the involvement of purinergic receptors and endothelium-derived factors is altered. The effects of Up4A were investigated using wire-myography in isolated coronary small arteries from Sham operated swine and swine with prolonged (8 weeks) pressure overload of the left ventricle induced by aortic banding (AoB). Expression of purinergic receptors and endothelium-derived factors was assessed in isolated coronary small arteries using real-time PCR. Up4A (10-9 to 10-5 M) failed to produce contraction in isolated coronary small arteries from either Sham or AoB swine, but produced relaxation in preconstricted arteries, which was significantly blunted in AoB compared to Sham. Blockade of purinergic P1, and P2 receptors attenuated Up4A induced coronary relaxation more, while the effect of P2X1-blockade was similar and the effects of A2A- and P2Y1-blockade were reduced in AoB as compared to Sham. mRNA expression of neither A1, A2, A3, nor P2X1, P2X7, P2Y1, P2Y2, nor P2Y6 receptors was altered in AoB as compared to Sham, while P2Y12 expression was higher in AoB. eNOS inhibition attenuated Up4A-induced coronary relaxation in both Sham and AoB. Additional blockade of cyclooxygenase enhanced Up4A-induced coronary relaxation in AoB but not Sham swine, suggesting the involvement of vasoconstrictor prostanoids. In endothelium-denuded coronary small arteries from normal swine, thromboxane synthase (TxS) inhibition enhanced relaxation to Up4A compared to endothelium-intact arteries, to a similar extent as P2Y12 inhibition, while the combination inhibition of P2Y12 and TxS had no additional effect. In conclusion, Up4A-induced coronary relaxation is blunted in swine with AoB, which appears to be due to the production of a vasoconstrictor prostanoid, likely thromboxane A2. PMID- 29632488 TI - Improving Docking Performance Using Negative Image-Based Rescoring. AB - Despite the large computational costs of molecular docking, the default scoring functions are often unable to recognize the active hits from the inactive molecules in large-scale virtual screening experiments. Thus, even though a correct binding pose might be sampled during the docking, the active compound or its biologically relevant pose is not necessarily given high enough score to arouse the attention. Various rescoring and post-processing approaches have emerged for improving the docking performance. Here, it is shown that the very early enrichment (number of actives scored higher than 1% of the highest ranked decoys) can be improved on average 2.5-fold or even 8.7-fold by comparing the docking-based ligand conformers directly against the target protein's cavity shape and electrostatics. The similarity comparison of the conformers is performed without geometry optimization against the negative image of the target protein's ligand-binding cavity using the negative image-based (NIB) screening protocol. The viability of the NIB rescoring or the R-NiB, pioneered in this study, was tested with 11 target proteins using benchmark libraries. By focusing on the shape/electrostatics complementarity of the ligand-receptor association, the R-NiB is able to improve the early enrichment of docking essentially without adding to the computing cost. By implementing consensus scoring, in which the R NiB and the original docking scoring are weighted for optimal outcome, the early enrichment is improved to a level that facilitates effective drug discovery. Moreover, the use of equal weight from the original docking scoring and the R-NiB scoring improves the yield in most cases. PMID- 29632489 TI - Identification of Novel Melanin Synthesis Inhibitors From Crataegus pycnoloba Using an in Vivo Zebrafish Phenotypic Assay. AB - Zebrafish has emerged as a powerful model organism for high throughput drug screening. Several morphological criteria, transgenic lines and in situ expression screens have been developed to identify novel bioactive compounds and their mechanism of action. Here, we used the inhibition of melanogenesis during early zebrafish embryo development to identify natural compounds that block melanogenesis. We identified an extract from the Greek hawthorn Crataegus pycnoloba as a potent inhibitor of melanin synthesis and used activity based subfractionation to identify active subfractions and eventually three single compounds of the same family (dibenzofurans). These compounds show reversible inhibition of melanin synthesis and do not act via inhibition of tyrosinase. We also showed that they do not interfere with neural crest differentiation or migration. We identified via in silico modeling that the compounds can bind to the aryl hydrocarbon receptor (AHR) and verified activation of the Ahr signaling pathway showing the induction of the expression of target genes. PMID- 29632490 TI - Uncovering the Mechanisms of Chinese Herbal Medicine (MaZiRenWan) for Functional Constipation by Focused Network Pharmacology Approach. AB - MaZiRenWan (MZRW, also known as Hemp Seed Pill) is a Chinese Herbal Medicine which has been demonstrated to safely and effectively alleviate functional constipation (FC) in a randomized, placebo-controlled clinical study with 120 subjects. However, the underlying pharmacological actions of MZRW for FC, are still largely unknown. We systematically analyzed the bioactive compounds of MZRW and mechanism-of-action biological targets through a novel approach called "focused network pharmacology." Among the 97 compounds identified by UPLC-QTOF MS/MS in MZRW extract, 34 were found in rat plasma, while 10 were found in rat feces. Hierarchical clustering analysis suggest that these compounds can be classified into component groups, in which compounds are highly similar to each other and most of them are from the same herb. Emodin, amygdalin, albiflorin, honokiol, and naringin were selected as representative compounds of corresponding component groups. All of them were shown to induce spontaneous contractions of rat colonic smooth muscle in vitro. Network analysis revealed that biological targets in acetylcholine-, estrogen-, prostaglandin-, cannabinoid-, and purine signaling pathways are able to explain the prokinetic effects of representative compounds and corresponding component groups. In conclusion, MZRW active components enhance colonic motility, possibly by acting on multiple targets and pathways. PMID- 29632491 TI - Selective Histone Deacetylase 6 Inhibitor 23BB Alleviated Rhabdomyolysis-Induced Acute Kidney Injury by Regulating Endoplasmic Reticulum Stress and Apoptosis. AB - Histone deacetylase 6 (HDAC6) contributed to the pathogenesis of rhabdomyolysis induced acute kidney injury (AKI) and selective inhibition of HDAC6 activity may be a promising strategy for the treatment of AKI. Compound 23BB as a highly selective HDAC6 inhibitor was designed, synthesized by our lab and exhibited therapeutic potential in various cancer models with good safety. However, it remained unknown whether 23BB as a drug candidate could offer renal protective effect against rhabdomyolysis-induced AKI. In the present study, we investigated the effect of 23BB in a murine model of glycerol (GL) injection-induced rhabdomyolysis. Following GL injection, the mice developed severe AKI as indicated by acute renal dysfunction and histologic changes, accompanied by increased HDAC6 expression in the cytoplasm of tubular epithelial cells. Pharmacological inhibition of HDAC6 by 23BB pretreatment significantly reduced serum creatinine and serum blood urea nitrogen (BUN) levels as well as attenuated renal tubular damage in GL-injured kidneys. HDAC6 inhibition also resulted in reduced TdT-mediated dUTP nick-end labeling (TUNEL)-positive tubular cells, suppressed BAX, BAK, cleaved caspase-3 levels, and preserved Bcl-2 expression, indicating that 23BB exerted potent renoprotective effects by the regulation of tubular cell apoptosis. Moreover, GL-induced kidney injury triggered multiple signal mediators of endoplasmic reticulum (ER) stress including GRP78, CHOP, IRE1alpha, p-eIF2alpha, ATF4, XBP1, p-JNK, and caspase-12. Oral administration of 23BB improved above-mentioned responses in injured kidney tissues and suggested that 23BB modulated tubular cell apoptosis via the inactivation of ER stress. Overall, these data highlighted that renal protection of novel HDAC6 inhibitor 23BB is substantiated by the reduction of ER stress-mediated apoptosis in tubular epithelial cells of rhabdomyolysis-induced AKI. PMID- 29632492 TI - Multifractal Desynchronization of the Cardiac Excitable Cell Network During Atrial Fibrillation. I. Multifractal Analysis of Clinical Data. AB - Atrial fibrillation (AF) is a cardiac arrhythmia characterized by rapid and irregular atrial electrical activity with a high clinical impact on stroke incidence. Best available therapeutic strategies combine pharmacological and surgical means. But when successful, they do not always prevent long-term relapses. Initial success becomes all the more tricky to achieve as the arrhythmia maintains itself and the pathology evolves into sustained or chronic AF. This raises the open crucial issue of deciphering the mechanisms that govern the onset of AF as well as its perpetuation. In this study, we develop a wavelet based multi-scale strategy to analyze the electrical activity of human hearts recorded by catheter electrodes, positioned in the coronary sinus (CS), during episodes of AF. We compute the so-called multifractal spectra using two variants of the wavelet transform modulus maxima method, the moment (partition function) method and the magnitude cumulant method. Application of these methods to long time series recorded in a patient with chronic AF provides quantitative evidence of the multifractal intermittent nature of the electric energy of passing cardiac impulses at low frequencies, i.e., for times (?0.5 s) longer than the mean interbeat (? 10-1 s). We also report the results of a two-point magnitude correlation analysis which infers the absence of a multiplicative time-scale structure underlying multifractal scaling. The electric energy dynamics looks like a "multifractal white noise" with quadratic (log-normal) multifractal spectra. These observations challenge concepts of functional reentrant circuits in mechanistic theories of AF, still leaving open the role of the autonomic nervous system (ANS). A transition is indeed observed in the computed multifractal spectra which group according to two distinct areas, consistently with the anatomical substrate binding to the CS, namely the left atrial posterior wall, and the ligament of Marshall which is innervated by the ANS. In a companion paper (II. Modeling), we propose a mathematical model of a denervated heart where the kinetics of gap junction conductance alone induces a desynchronization of the myocardial excitable cells, accounting for the multifractal spectra found experimentally in the left atrial posterior wall area. PMID- 29632493 TI - Growth and Stress Axis Responses to Dietary Cholesterol in Nile Tilapia (Oreochromis niloticus) in Brackish Water. AB - Six isonitrogenous and isocaloric diets were formulated to contain 0% (control), 0.4, 0.8, 1.2, 1.6, or 2.4% dietary cholesterol and fed to juvenile Nile tilapia (Oreochromis niloticus) (2.20 +/- 0.12 g) twice daily to apparent satiation for 8 weeks in triplicate at a salinity of 16. Fish fed 0.4% cholesterol showed a higher weight gain and specific growth rate and a lower feed coefficient ratio than fish fed other diets. No difference was found in the survival of Nile tilapia fed various levels of cholesterol. Cholesterol in the serum and liver and low-density lipoprotein cholesterol in the serum increased with the increase in the dietary cholesterol content. Relative to the control, no significant difference was found in the expression of head kidney P450scc mRNA between treatment groups. The expression of head kidney 11beta-HSD2 mRNA was the highest in the control group, and it decreased significantly with increasing levels of diet cholesterol. Fish fed 0.4 or 1.2% cholesterol had a higher 20beta-HSD2 mRNA expression in the head kidney than those fed other diets. Fish fed 0.8% cholesterol had higher expressions of GR1 and GR2B mRNA in the liver than other groups. Fish fed 0.4% cholesterol had the highest activity of gill Na+/K+-ATPase. Fish fed 0.8 to 2.4% cholesterol had higher serum cortisol contents than the fish in the control group and the fish fed 0.4% cholesterol. This study suggests that dietary cholesterol is not essential for Nile tilapia survival in brackish water, but 0.4% cholesterol supplementation in the Nile tilapia diet contributes to the improvement of hyperosmotic adaptation and increases in gill Na+/K+-ATPase activity and serum cortisol content by regulating the hypothalamic-pituitary interrenal stress axis. PMID- 29632494 TI - Center of Pressure Motion After Calf Vibration Is More Random in Fallers Than Non fallers: Prospective Study of Older Individuals. AB - Aging is associated with changes in balance control and elderly take longer to adapt to changing sensory conditions, which may increase falls risk. Low amplitude calf muscle vibration stimulates local sensory afferents/receptors and affects sense of upright when applied in stance. It has been used to assess the extent the nervous system relies on calf muscle somatosensory information and to rapidly change/perturb part of the somatosensory information causing balance unsteadiness by addition and removal of the vibratory stimulus. This study assessed the effect of addition and removal of calf vibration on balance control (in the absence of vision) in elderly individuals (>65 years, n = 99) who did (n = 41) or did not prospectively report falls (n = 58), and in a group of young individuals (18-25 years, n = 23). Participants stood barefoot and blindfolded on a force plate for 135 s. Vibrators (60 Hz, 1 mm) attached bilaterally over the triceps surae muscles were activated twice for 15 s; after 15 and 75 s (45 s for recovery). Balance measures were applied in a windowed (15 s epoch) manner to compare center-of-pressure (CoP) motion before, during and after removal of calf vibration between groups. In each epoch, CoP motion was quantified using linear measures, and non-linear measures to assess temporal structure of CoP motion [using recurrence quantification analysis (RQA) and detrended fluctuation analysis]. Mean CoP displacement during and after vibration did not differ between groups, which suggests that calf proprioception and/or weighting assigned by the nervous system to calf proprioception was similar for the young and both groups of older individuals. Overall, compared to the elderly, CoP motion of young was more predictable and persistent. Balance measures were not different between fallers and non-fallers before and during vibration. However, non-linear aspects of CoP motion of fallers and non-fallers differed after removal of vibration, when dynamic re-weighting is required. During this period fallers exhibited more random CoP motion, which could result from a reduced ability to control balance and/or a reduced ability to dynamically reweight proprioceptive information. These results show that non-linear measures of balance provide evidence for deficits in balance control in people who go on to fall in the following 12 months. PMID- 29632495 TI - Molecular Characterization of a Dual Domain Carbonic Anhydrase From the Ctenidium of the Giant Clam, Tridacna squamosa, and Its Expression Levels After Light Exposure, Cellular Localization, and Possible Role in the Uptake of Exogenous Inorganic Carbon. AB - A Dual-Domain Carbonic Anhydrase (DDCA) had been sequenced and characterized from the ctenidia (gills) of the giant clam, Tridacna squamosa, which lives in symbiosis with zooxanthellae. DDCA was expressed predominantly in the ctenidium. The complete cDNA coding sequence of DDCA from T. squamosa comprised 1,803 bp, encoding a protein of 601 amino acids and 66.7 kDa. The deduced DDCA sequence contained two distinct alpha-CA domains, each with a specific catalytic site. It had a high sequence similarity with tgCA from Tridacna gigas. In T. squamosa, the DDCA was localized apically in certain epithelial cells near the base of the ctenidial filament and the epithelial cells surrounding the tertiary water channels. Due to the presence of two transmembrane regions in the DDCA, one of the Zn2+-containing active sites could be located externally and the other one inside the cell. These results denote that the ctenidial DDCA was positioned to dehydrate [Formula: see text] to CO2 in seawater, and to hydrate the CO2 that had permeated the apical membrane back to [Formula: see text] in the cytoplasm. During insolation, the host clam needs to increase the uptake of inorganic carbon from the ambient seawater to benefit the symbiotic zooxanthellae; only then, can the symbionts conduct photosynthesis and share the photosynthates with the host. Indeed, the transcript and protein levels of DDCA/DDCA in the ctenidium of T. squamosa increased significantly after 6 and 12 h of exposure to light, respectively, denoting that DDCA could participate in the light-enhanced uptake and assimilation of exogenous inorganic carbon. PMID- 29632496 TI - Diet Affects Muscle Quality and Growth Traits of Grass Carp (Ctenopharyngodon idellus): A Comparison Between Grass and Artificial Feed. AB - Fish muscle, the main edible parts with high protein level and low fat level, is consumed worldwide. Diet contributes greatly to fish growth performance and muscle quality. In order to elucidate the correlation between diet and muscle quality, the same batch of juvenile grass carp (Ctenopharyngodon idellus) were divided into two groups and fed with either grass (Lolium perenne, Euphrasia pectinata and Sorghum sudanense) or artificial feed, respectively. However, the different two diets didn't result in significant differences in all the detected water quality parameters (e.g., Tm, pH, DO, NH3/[Formula: see text]-N, [Formula: see text]-N, [Formula: see text], TN, TP, and TOC) between the two experimental groups. After a 4-month culture period, various indexes and expression of myogenic regulatory factor (MRFs) and their related genes were tested. The weight gain of the fish fed with artificial feed (AFG) was nearly 40% higher than the fish fed with grass (GFG). Significantly higher alkaline phosphatase, total cholestrol, high density cholestrol and total protein were detected in GFG as compared to AFG. GFG also showed increased hardness, resilience and shear force in texture profile analysis, with significantly bigger and compact muscle fibers in histologic slices. The fat accumulation was most serious in the abdomen muscle of AFG. Additionally, the expression levels of MyoG, MyoD, IGF-1, and MSTNs were higher, whereas Myf-5, MRF4, and IGF-2 were lower in most positional muscles of GFG as compared to AFG. Overall, these results suggested that feeding grass could promote muscle growth and development by stimulating muscle fiber hypertrophy, as well as significantly enhance the expression of CoL1As. Feeding C. idellus with grass could also improve flesh quality by improving muscle characteristics, enhancing the production of collagen, meanthile, reducing fat accumulation and moisture in muscle, but at the cost of a slower growth. PMID- 29632497 TI - Urtica dioica (Stinging Nettle): A Neglected Plant With Emerging Growth Promoter/Immunostimulant Properties for Farmed Fish. AB - Urtica dioica (stinging nettle), is a perennial plant belonging to the family of Urticaceae, genus Urtica. Despite the use of nettle in folk veterinary medicine is well documented, U. dioica is today an underestimated and frequently neglected plant, considered by the contemporary agriculture as a weed to be eliminated. This mini review focus on very recent studies on dietary administration of U. dioica, both as a single herb or in combination with other herbs, to enhance growth and stimulate farmed fish immunity, thus enabling the fish to be more resistant against bacterial infections. Such an emerging feature, together with cost-effectiveness, adequate availability, and easy processing of nettle, could make this herb an excellent, inexpensive and widely used dietary supplement on intensive fish farms. PMID- 29632498 TI - Continuous Change in Membrane and Membrane-Skeleton Organization During Development From Proerythroblast to Senescent Red Blood Cell. AB - Within the context of erythropoiesis and the possibility of producing artificial red blood cells (RBCs) in vitro, a most critical step is the final differentiation of enucleated erythroblasts, or reticulocytes, to a fully mature biconcave discocyte, the RBC. Reviewed here is the current knowledge about this fundamental maturational process. By combining literature data with our own experimental evidence we propose that the early phase in the maturation of reticulocytes to RBCs is driven by a membrane raft-based mechanism for the sorting of disposable membrane proteins, mostly the no longer needed transferrin receptor (TfR), to the multivesicular endosome (MVE) as cargo of intraluminal vesicles that are subsequently exocytosed as exosomes, consistently with the seminal and original observation of Johnstone and collaborators of more than 30 years ago (Pan BT, Johnstone RM. Cell. 1983;33:967-978). According to a strikingly selective sorting process, the TfR becomes cargo destined to exocytosis while other molecules, including the most abundant RBC transmembrane protein, band 3, are completely retained in the cell membrane. It is also proposed that while this process could be operating in the early maturational steps in the bone marrow, additional mechanism(s) must be at play for the final removal of the excess reticulocyte membrane that is observed to occur in the circulation. This processing will most likely require the intervention of the spleen, whose function is also necessary for the continuous remodeling of the RBC membrane all along this cell's circulatory life. PMID- 29632499 TI - Mitochondria in Cardiac Postconditioning. AB - Mitochondria play a pivotal role in cardioprotection. Here we report some fundamental studies which considered the role of mitochondrial components (connexin 43, mitochondrial KATP channels and mitochondrial permeability transition pore) in postconditioning cardioprotection. We briefly discuss the role of mitochondria, reactive oxygen species and gaseous molecules in postconditioning. Also the effects of anesthetics-used as cardioprotective substances-is briefly considered in the context of postconditioning. The role of mitochondrial postconditioning signaling in determining the limitation of cell death is underpinned. Issues in clinical translation are briefly considered. The aim of the present mini-review is to discuss in a historical perspective the role of main mitochondria mechanisms in cardiac postconditioning. PMID- 29632500 TI - Neurological Soft Signs and Psychopathology in Chronic Schizophrenia: A Cross Sectional Study in Three Age Groups. AB - As established in a wealth of studies subtle motor and sensory neurological abnormalities or neurological soft signs (NSS) are frequently found in patients with schizophrenia at any stage of their illness. However, the potential impact of chronicity and age on NSS was scarcely investigated. Therefore, we assessed NSS in 90 patients with subchronic (n = 22) or chronic (n = 68) schizophrenia and in 60 healthy controls who were assigned to three age groups (18-29, 30-49, and +50 years). NSS were measured on the Heidelberg Scale, psychopathological symptoms including apathy were rated on established instruments. As demonstrated by analysis of variance, NSS scores in patients were significantly (p < 0.05) increased relative to healthy controls. Significant age effects arose in all NSS subscores, with older subjects scoring well above the younger ones. These age effects were more pronounced in patients than controls, indicating that NSS in chronic schizophrenia exceed age-associated changes. Moreover, the NSS scores in patients were significantly associated with duration of illness, thought disturbance, positive symptoms, and apathy. These results were confirmed after age/duration of illness and years of education were partialed out and via regression analyses. Our findings conform to the hypothesis that NSS are associated with chronicity of the disorder as indicated by the correlations of NSS with both, duration of illness and apathy. The correlations between NSS and positive symptoms/thought disturbance correspond to the fluctuation of positive symptoms during the course of the disorder. The significantly more pronounced age effects on NSS in patients may either point to ongoing cerebral changes or to a greater susceptibility of patients toward physiological age effects, which may be mediated among other factors by a lower cognitive reserve. PMID- 29632501 TI - Experience in a Climate Microworld: Influence of Surface and Structure Learning, Problem Difficulty, and Decision Aids in Reducing Stock-Flow Misconceptions. AB - Research shows that people's wait-and-see preferences for actions against climate change are a result of several factors, including cognitive misconceptions. The use of simulation tools could help reduce these misconceptions concerning Earth's climate. However, it is still unclear whether the learning in these tools is of the problem's surface features (dimensions of emissions and absorptions and cover story used) or of the problem's structural features (how emissions and absorptions cause a change in CO2 concentration under different CO2 concentration scenarios). Also, little is known on how problem's difficulty in these tools (the shape of CO2 concentration trajectory), as well as the use of these tools as a decision aid influences performance. The primary objective of this paper was to investigate how learning about Earth's climate via simulation tools is influenced by problem's surface and structural features, problem's difficulty, and decision aids. In experiment 1, we tested the influence of problem's surface and structural features in a simulation called Dynamic Climate Change Simulator (DCCS) on subsequent performance in a paper-and-pencil Climate Stabilization (CS) task (N = 100 across four between-subject conditions). In experiment 2, we tested the effects of problem's difficulty in DCCS on subsequent performance in the CS task (N = 90 across three between-subject conditions). In experiment 3, we tested the influence of DCCS as a decision aid on subsequent performance in the CS task (N = 60 across two between-subject conditions). Results revealed a significant reduction in people's misconceptions in the CS task after performing in DCCS compared to when performing in CS task in the absence of DCCS. The decrease in misconceptions in the CS task was similar for both problems' surface and structural features, showing both structure and surface learning in DCCS. However, the proportion of misconceptions was similar across both simple and difficult problems, indicating the role of cognitive load to hamper learning. Finally, misconceptions were reduced when DCCS was used as a decision aid. Overall, these results highlight the role of simulation tools in alleviating climate misconceptions. We discuss the implication of using simulation tools for climate education and policymaking. PMID- 29632502 TI - Significant Work Is About Self-Realization and Broader Purpose: Defining the Key Dimensions of Meaningful Work. AB - Research on meaningful work has proliferated in recent years, with an increasing understanding of the centrality of meaningfulness for work-related motivation, commitment, and well-being. However, ambiguity around the main construct, "meaningful work," has hindered this progress as various researchers have used partly overlapping, partly differing conceptualizations. To bring clarity to this issue, we examine a broad range of various definitions of meaningful work and come to argue that meaningfulness in the broadest sense is about work significance as an overall evaluation of work as regards whether it is intrinsically valuable and worth doing. Furthermore, we argue that there are two key sub-dimensions to this work significance: Broader purpose as work serving some greater good or prosocial goals (the intrinsic value of work beyond the person in question). And self-realization as a sense of autonomy, authenticity and self-expression at work (the intrinsic value of work for the person in question). Previous definitions of meaningful work feature typically one or two of these elements-significance, broader purpose, self-realization -, but in the future it would be beneficial to clearly acknowledge all three elements in both definitions and operationalizations of meaningful work. PMID- 29632503 TI - Seeking Systematicity in Variation: Theoretical and Methodological Considerations on the "Variety" Concept. AB - One centennial discussion in linguistics concerns whether languages, or linguistic systems, are, essentially, homogeneous or rather show "structured heterogeneity." In this contribution, the question is addressed whether and how sociolinguistically defined systems (or 'varieties') are to be distinguished in a heterogeneous linguistic landscape: to what extent can structure be found in the myriads of language variants heard in everyday language use? We first elaborate on the theoretical importance of this 'variety question' by relating it to current approaches from, among others, generative linguistics (competing grammars), sociolinguistics (style-shifting, polylanguaging), and cognitive linguistics (prototype theory). Possible criteria for defining and detecting varieties are introduced, which are subsequently tested empirically, using a self compiled corpus of spoken Dutch in West Flanders (Belgium). This empirical study demonstrates that the speech repertoire of the studied West Flemish speakers consists of four varieties, viz. a fairly stable dialect variety, a more or less virtual standard Dutch variety, and two intermediate varieties, which we will label 'cleaned-up dialect' and 'substandard.' On the methodological level, this case-study underscores the importance of speech corpora comprising both inter- and intra-speaker variation on the one hand, and the merits of triangulating qualitative and quantitative approaches on the other. PMID- 29632505 TI - The Intolerance of Uncertainty Inventory: Validity and Comparison of Scoring Methods to Assess Individuals Screening Positive for Anxiety and Depression. AB - Intolerance of Uncertainty is a fundamental transdiagnostic personality construct hierarchically organized with a core general factor underlying diverse clinical manifestations. The current study evaluated the construct validity of the Intolerance of Uncertainty Inventory, a two-part scale separately assessing a unitary Intolerance of Uncertainty disposition to consider uncertainties to be unacceptable and threatening (Part A) and the consequences of such disposition, regarding experiential avoidance, chronic doubt, overestimation of threat, worrying, control of uncertain situations, and seeking reassurance (Part B). Community members (N = 1046; Mean age = 36.69 +/- 12.31 years; 61% females) completed the Intolerance of Uncertainty Inventory with the Beck Depression Inventory-II and the State-Trait Anxiety Inventory. Part A demonstrated a robust unidimensional structure and an excellent convergent validity with Part B. A bifactor model was the best fitting model for Part B. Based on these results, we compared the hierarchical factor scores with summated ratings clinical proxy groups reporting anxiety and depression symptoms. Summated rating scores were associated with both depression and anxiety and proportionally increased with the co-occurrence of depressive and anxious symptoms. By contrast, hierarchical scores were useful to detect which facets mostly separated between for depression and anxiety groups. In sum, Part A was a reliable and valid transdiagnostic measure of Intolerance of Uncertainty. The Part B was arguably more useful for assessing clinical manifestations of Intolerance of Uncertainty for specific disorders, provided that hierarchical scores are used. Overall, our study suggest that clinical assessments might need to shift toward hierarchical factor scores. PMID- 29632504 TI - Work Stress and Depressive Symptoms in Fishermen With a Smoking Habit: A Mediator Role of Nicotine Dependence and Possible Moderator Role of Expressive Suppression and Cognitive Reappraisal. AB - This study examined pathways of influence between work stress, depressive symptoms, nicotine dependence, expressive suppression, and cognitive reappraisal in fishermen with smoking habits in Qionghai, Hainan province, China (N = 1068). These fishermen responded to multiple assessments a week before leaving on a deep sea fishing trip, including a Mental Stressor Investigation Questionnaire (MSIQ), the Center for Epidemiological Studies Depression Scale (CES-D), the Russell Reason for Smoking Questionnaire (RRSQ), and an Emotion Regulation Questionnaire (ERQ). Structural equation modeling (SEM) analyses of the collected data in Mplus 7 showed that work stress and nicotine dependence were independent predictors of depressive symptoms. The relationship between work stress and depressive symptoms was found to be partially mediated by nicotine dependence and be moderated by cognitive reappraisal. The evidence suggests it advantageous to examine the need of work stress, nicotine dependence, and cognitive reappraisal when attempting to understand depressive symptoms in fishermen with a smoking habit. These findings suggest that improving nicotine dependence through work stress management and training in cognitive reappraisal could be utilized as effective modalities for improving depressive symptoms. PMID- 29632506 TI - Divergent Perceptual Processes on Cyberbullying Between Victims and Aggressors: Construction of Explanatory Models. AB - Understanding the causes of adolescents' aggressive behavior in and through technological means and resources requires a thorough analysis of the criteria that they consider to be identifying and defining cyberbullying and of the network of relationships established between the different criteria. The present study has aimed at making a foray into the attempt to understand the underlying structures and mechanisms that determine aggressors' and victims' perceptions of the cyberbullying phenomenon. The sample consisted of 2148 adolescents (49.1% girls; SD = 0.5) of ages from 12 to 16 (M = 13.9; SD = 1.2). The data collected through a validated questionnaire for this study whose dimensions were confirmed from the data extracted from the focus groups and a CFA of the victim and aggressor subsamples. The analysis of the data is completed with CFA and the construction of structural models. The results have shown the importance and interdependence of imbalance of power and intention to harm in the aggressors' perceptual structure. The criteria of anonymity and repetition are related to the asymmetry of power, giving greater prominence to this factor. In its perceptual structure, the criterion "social relationship" also appears, which indicates that the manifestations of cyberbullying are sometimes interpreted as patterns of behavior that have become massively extended among the adolescent population, and have become accepted as a normalized and harmless way of communicating with other adolescents. In the victims' perceptual structure the key factor is the intention to harm, closely linked to the asymmetry of power and publicity. Anonymity, revenge and repetition are also present in this structure, although its relationship with cyberbullying is indirect. These results allow to design more effective measures of prevention and intervention closely tailored to addressing directly the factors that are considered to be predictors of risk. PMID- 29632507 TI - Anthropomorphism in Human-Robot Co-evolution. AB - Social robotics entertains a particular relationship with anthropomorphism, which it neither sees as a cognitive error, nor as a sign of immaturity. Rather it considers that this common human tendency, which is hypothesized to have evolved because it favored cooperation among early humans, can be used today to facilitate social interactions between humans and a new type of cooperative and interactive agents - social robots. This approach leads social robotics to focus research on the engineering of robots that activate anthropomorphic projections in users. The objective is to give robots "social presence" and "social behaviors" that are sufficiently credible for human users to engage in comfortable and potentially long-lasting relations with these machines. This choice of 'applied anthropomorphism' as a research methodology exposes the artifacts produced by social robotics to ethical condemnation: social robots are judged to be a "cheating" technology, as they generate in users the illusion of reciprocal social and affective relations. This article takes position in this debate, not only developing a series of arguments relevant to philosophy of mind, cognitive sciences, and robotic AI, but also asking what social robotics can teach us about anthropomorphism. On this basis, we propose a theoretical perspective that characterizes anthropomorphism as a basic mechanism of interaction, and rebuts the ethical reflections that a priori condemns "anthropomorphism-based" social robots. To address the relevant ethical issues, we promote a critical experimentally based ethical approach to social robotics, "synthetic ethics," which aims at allowing humans to use social robots for two main goals: self-knowledge and moral growth. PMID- 29632508 TI - Multidimensional Circadian Monitoring by Wearable Biosensors in Parkinson's Disease. AB - Parkinson's disease (PD) is associated with several non-motor symptoms that may precede the diagnosis and constitute a major source of frailty in this population. The digital era in health care has open up new prospects to move forward from the qualitative and subjective scoring for PD with the use of new wearable biosensors that enable frequent quantitative, reliable, repeatable, and multidimensional measurements to be made with minimal discomfort and inconvenience for patients. A cross-sectional study was conducted to test a wrist worn device combined with machine-learning processing to detect circadian rhythms of sleep, motor, and autonomic disruption, which can be suitable for the objective and non-invasive evaluation of PD patients. Wrist skin temperature, motor acceleration, time in movement, hand position, light exposure, and sleep rhythms were continuously measured in 12 PD patients and 12 age-matched healthy controls for seven consecutive days using an ambulatory circadian monitoring device (ACM). Our study demonstrates that a multichannel ACM device collects reliable and complementary information from motor (acceleration and time in movement) and common non-motor (sleep and skin temperature rhythms) features frequently disrupted in PD. Acceleration during the daytime (as indicative of motor impairment), time in movement during sleep (representative of fragmented sleep) and their ratio (A/T) are the best indexes to objectively characterize the most common symptoms of PD, allowing for a reliable and easy scoring method to evaluate patients. Chronodisruption score, measured by the integrative algorithm known as the circadian function index is directly linked to a low A/T score. Our work attempts to implement innovative technologies based on wearable, multisensor, objective, and easy-to-use devices, to quantify PD circadian rhythms in huge populations over extended periods of time, while controlling at the same time exposure to exogenous circadian synchronizers. PMID- 29632510 TI - The Crucial Changes of Sit-to-Stand Phases in Subacute Stroke Survivors Identified by Movement Decomposition Analysis. AB - Objective: The aim of this study was to detect the key changes during sit-to stand (STS) movement cycle in hemiparetic stroke survivors using a five-phase kinematic and kinetic analysis. Methods: Twenty-five subacute stroke survivors and 17 age-matched healthy adults participated in this study. The kinematic and kinetic parameters during STS cycle were measured using three-dimensional motion analysis system with force plates. The five standard phases of STS cycle were identified by six timing transitional points. Results: Longer total time as well as larger changes were observed at the initial phase (phase I, 0.76 +/- 0.62 VS 0.43 +/- 0.09 s; p = 0.049) and at the end of hip and knee extension phase (phase IV, 0.93 +/- 0.41 VS 0.63 +/- 0.14 s; p = 0.008) in the stroke group than healthy group. Time to maximal knee joint moment was significantly delayed in the stroke group than in the control group (1.14 +/- 1.06 VS 0.60 +/- 0.09 s, p < 0.001). The maximal hip flexion was lower during the rising phase from seated position on the affected side in the stroke group than in the control group (84.22 degrees +/- 11.64 degrees VS 94.11 degrees +/- 9.40 degrees ; p = 0.022). Ground reaction force was lower (4.61 +/- 0.73 VS 5.85 +/- 0.53 N, p < 0.001) in the affected side of the stroke group than in the control group. In addition, knee joint flexion was significantly lower at just-standing phase (T4) and at end point (T5) (5.12 degrees +/- 5.25 degrees VS 8.21 degrees +/- 7.28 degrees , p = 0.039; 0.03 degrees +/- 5.41 degrees VS 3.07 degrees +/- 6.71 degrees , p = 0.042) on the affected side than the unaffected side. Crucial decrease of knee joint moment at abrupt transitory (T2) and the maximal moment was also observed on the affected side in comparison with the unaffected side (0.39 +/- 0.29 VS 0.77 +/- 0.25 Nm/kg, p < 0.001; 0.42 +/- 0.38 VS 0.82 +/- 0.24 Nm/kg, p < 0.001). Conclusion: The findings of movement decomposition analysis provided useful information to clinical evaluation of STS performance, and may potentially contribute to the design of rehabilitation intervention program for optimum functional recovery of STS after stroke. PMID- 29632509 TI - Evaluation of Microglial Activation in Multiple Sclerosis Patients Using Positron Emission Tomography. AB - Understanding the mechanisms underlying progression in multiple sclerosis (MS) is one of the key elements contributing to the identification of appropriate therapeutic targets for this under-managed condition. In addition to plaque related focal inflammatory pathology typical for relapsing remitting MS there are, in progressive MS, widespread diffuse alterations in brain areas outside the focal lesions. This diffuse pathology is tightly related to microglial activation and is co-localized with signs of neurodegeneration. Microglia are brain-resident cells of the innate immune system and overactivation of microglia is associated with several neurodegenerative diseases. Understanding the role of microglial activation in relation to developing neurodegeneration and disease progression may provide a key to developing therapies to target progressive MS. 18-kDa translocator protein (TSPO) is a mitochondrial molecule upregulated in microglia upon their activation. Positron emission tomography (PET) imaging using TSPO binding radioligands provides a method to assess microglial activation in patients in vivo. In this mini-review, we summarize the current status of TSPO imaging in the field of MS. In addition, the review discusses new insights into the potential use of this method in treatment trials and in clinical assessment of progressive MS. PMID- 29632512 TI - Editorial: Monitoring Pathophysiology in the Injured Brain. PMID- 29632511 TI - Functional Assessment for Acute Stroke Trials: Properties, Analysis, and Application. AB - A measure of treatment effect is needed to assess the utility of any novel intervention in acute stroke. For a potentially disabling condition such as stroke, outcomes of interest should include some measure of functional recovery. There are many functional outcome assessments that can be used after stroke. In this narrative review, we discuss exemplars of assessments that describe impairment, activity, participation, and quality of life. We will consider the psychometric properties of assessment scales in the context of stroke trials, focusing on validity, reliability, responsiveness, and feasibility. We will consider approaches to the analysis of functional outcome measures, including novel statistical approaches. Finally, we will discuss how advances in audiovisual and information technology could further improve outcome assessment in trials. PMID- 29632513 TI - Risky Decision Making in Juvenile Myoclonic Epilepsy. AB - It is not known whether patients with juvenile myoclonic epilepsy (JME) differ from healthy people in decision making under risk, i.e., when the decision-making context offers explicit information about options, probabilities, and consequences already from the beginning. In this study, we adopted the Game of Dice Task-Double to investigate decision making under risk in a group of 36 patients with JME (mean age 25.25/SD 5.29 years) and a group of 38 healthy controls (mean age 26.03/SD 4.84 years). Participants also underwent a comprehensive neuropsychological assessment focused on frontal executive functions. Significant group differences were found in tests of psychomotor speed and divided attention, with the patients scoring lower than the controls. Importantly, patients made risky decisions more frequently than controls. In the patient group, poor decision making was associated with poor executive control, poor response inhibition, and a short interval since the last seizure episode. Executive control and response inhibition could predict 42% of variance in the frequency of risky decisions. This study indicates that patients with JME with poorer executive functions are more likely to make risky decisions than healthy controls. Decision making under risk is of major importance in every-day life, especially with regard to treatment decisions and adherence to long-term medical therapy. Since even a single disadvantageous decision may have long-lasting consequences, this finding is of high relevance. PMID- 29632515 TI - Novel Insights into How Overnutrition Disrupts the Hypothalamic Actions of Leptin. AB - Obesity has become a worldwide health problem, but we still do not understand the molecular mechanisms that contribute to overeating and low expenditure of energy. Leptin has emerged as a major regulator of energy balance through its actions in the hypothalamus. Importantly, obese people exhibit high circulating levels of leptin, yet the hypothalamus no longer responds normally to this hormone to suppress appetite or to increase energy expenditure. Several well-known hypotheses have been proposed to explain impaired central responsiveness to the effects of leptin in obesity, including defective transit across the blood-brain barrier at the arcuate nucleus, hypothalamic endoplasmic reticulum stress, maladaptive sterile inflammation in the hypothalamus, and overexpression of molecules that may inhibit leptin signaling. We also discuss a new explanation that is based on our group's recent discovery of a signaling pathway that we named "NSAPP" after its five main protein components. The NSAPP pathway consists of an oxide transport chain that causes a transient, targeted burst in intracellular hydrogen peroxide (H2O2) to inactivate redox-sensitive members of the protein tyrosine phosphatase gene family. The NSAPP oxide transport chain is required for full activation of canonical leptin signaling in neurons but fails to function normally in states of overnutrition. Remarkably, leptin and insulin both require the NSAPP oxide transport chain, suggesting that a defect in this pathway could explain simultaneous resistance to the appetite-suppressing effects of both hormones in obesity. PMID- 29632516 TI - Editorial: Trends in Regulatory Peptides. PMID- 29632514 TI - Olivocochlear Efferents in Animals and Humans: From Anatomy to Clinical Relevance. AB - Olivocochlear efferents allow the central auditory system to adjust the functioning of the inner ear during active and passive listening. While many aspects of efferent anatomy, physiology and function are well established, others remain controversial. This article reviews the current knowledge on olivocochlear efferents, with emphasis on human medial efferents. The review covers (1) the anatomy and physiology of olivocochlear efferents in animals; (2) the methods used for investigating this auditory feedback system in humans, their limitations and best practices; (3) the characteristics of medial-olivocochlear efferents in humans, with a critical analysis of some discrepancies across human studies and between animal and human studies; (4) the possible roles of olivocochlear efferents in hearing, discussing the evidence in favor and against their role in facilitating the detection of signals in noise and in protecting the auditory system from excessive acoustic stimulation; and (5) the emerging association between abnormal olivocochlear efferent function and several health conditions. Finally, we summarize some open issues and introduce promising approaches for investigating the roles of efferents in human hearing using cochlear implants. PMID- 29632517 TI - Maternal Thyroid Function During Pregnancy and the Child's Linguistic and Sensory Development in the Northern Finland Birth Cohort 1986. AB - Background: Maternal hypothyroidism and hypothyroxinemia are associated with poor neuropsychological development in children. Previous research is lacking on whether maternal thyroid dysfunction affects sensory and linguistic development in childhood. Methods: The Northern Finland Birth Cohort 1986 included all births within a year (9,362 women, 9,479 children) from the two northernmost Finnish provinces. Maternal serum samples (n = 5,791) were obtained in early pregnancy and analyzed for TSH, free T4, and thyroid peroxidase antibodies (TPO-Abs). Five thousand three hundred and ninety-one parents evaluated their child's sensory and linguistic development at 7 years old via a questionnaire (excluding children with an intelligence quotient <=85). The prevalence of sensory and linguistic impairments was compared between mothers with and without thyroid dysfunction. Results: There were no statistically significant differences in the prevalence of sensory or linguistic impairment between children of mothers with and without thyroid dysfunction. Children of hypothyroid and hypothyroxinemic mothers had an increased prevalence of vision impairment compared with those of euthyroid mothers (10.8 and 11.7%, respectively, versus 6.5%), but the difference was not significant. All results remained similar after excluding TPO-Ab-positive mothers and premature children. Conclusion: We did not find an association between maternal thyroid dysfunction during pregnancy and sensory and linguistic development impairment in childhood. A somewhat higher prevalence of vision impairment was seen in children of hypothyroid and hypothyroxinemic mothers, which merits further research. PMID- 29632518 TI - Diagnostic Approaches for Invasive Aspergillosis-Specific Considerations in the Pediatric Population. AB - Invasive aspergillosis (IA) is a major cause of morbidity and mortality in children with hematological malignancies and those undergoing hematopoietic stem cell transplantation. Similar to immunocompromised adults, clinical signs, and symptoms of IA are unspecific in the pediatric patient population. As early diagnosis and prompt treatment of IA is associated with better outcome, imaging and non-invasive antigen-based such as galactomannan or beta-D-glucan and molecular biomarkers in peripheral blood may facilitate institution and choice of antifungal compounds and guide duration of therapy. In patients in whom imaging studies suggest IA or another mold infection, invasive diagnostics such as bronchoalveolar lavage and/or bioptic procedures should be considered. Here we review the current data of diagnostic approaches for IA in the pediatric setting and highlight the major differences of performance and clinical utility of the tests between children and adults. PMID- 29632519 TI - A Bayesian Semiparametric Regression Model for Joint Analysis of Microbiome Data. AB - The successional dynamics of microbial communities are influenced by the synergistic interactions of physical and biological factors. In our motivating data, ocean microbiome samples were collected from the Santa Cruz Municipal Wharf, Monterey Bay at multiple time points and then 16S ribosomal RNA (rRNA) sequenced. We develop a Bayesian semiparametric regression model to investigate how microbial abundance and succession change with covarying physical and biological factors including algal bloom and domoic acid concentration level using 16S rRNA sequencing data. A generalized linear regression model is built using the Laplace prior, a sparse inducing prior, to improve estimation of covariate effects on mean abundances of microbial species represented by operational taxonomic units (OTUs). A nonparametric prior model is used to facilitate borrowing strength across OTUs, across samples and across time points. It flexibly estimates baseline mean abundances of OTUs and provides the basis for improved quantification of covariate effects. The proposed method does not require prior normalization of OTU counts to adjust differences in sample total counts. Instead, the normalization and estimation of covariate effects on OTU abundance are simultaneously carried out for joint analysis of all OTUs. Using simulation studies and a real data analysis, we demonstrate improved inference compared to an existing method. PMID- 29632520 TI - Gliding Motility and Expression of Motility-Related Genes in Spreading and Non spreading Colonies of Flavobacterium columnare. AB - Gliding motility facilitates the movement of bacteria along surfaces in many Bacteroidetes species and results in spreading colonies. The adhesins required for the gliding are secreted through a gliding motility-associated protein secretion system, known as the type IX secretion system (T9SS). The fish pathogen Flavobacterium columnare produces spreading (rhizoid [Rz], soft [S]) and non spreading (rough [R]) colony types, of which only the spreading Rz type is virulent. In this study, we explored the spreading behavior of these colony types by microscopic imaging and measured the expression of genes associated with gliding motility and T9SS (gldG, gldH, gldL, sprA, sprB, sprE, sprF, sprT, and porV) under high and low resource levels by using RT-qPCR (reverse transcription quantitative PCR). The spreading colony types responded to the low resource level with increased colony size. The non-spreading colony type, as well as the cells growing under high nutrient level expressed only moderate cell movements. Yet, a low nutrient level provoked more active gliding motility in individual cells and increased spreading by cooperative gliding. The gene expression survey demonstrated an increased expression level of sprA (a core component of T9SS) and sprF (needed for adhesin secretion) under low nutrient conditions. Surprisingly, the expression of gliding motility genes was not consistently associated with more active spreading behavior. Furthermore, no genetic differences were found between spreading and non-spreading colony types in the studied genes associated with gliding motility. Our study demonstrates that environmental nutrient level is an important regulator of both gliding motility and the expression of some of the associated genes. These results may help to understand the connections between nutrient concentration, gliding motility, and virulence of F. columnare. PMID- 29632521 TI - Prevalence, Virulence Genes, Antimicrobial Susceptibility, and Genetic Diversity of Bacillus cereus Isolated From Pasteurized Milk in China. AB - Bacillus cereus is a common and important food-borne pathogen that can be found in various food products. Due to low-temperature sterilization for a short period of time, pasteurization is not sufficient for complete elimination of B. cereus in milk, thereby cause severe economic loss and food safety problems. It is therefore of paramount importance to perform risk assessment of B. cereus in pasteurized milk. In this study, we isolated B. cereus from pasteurized milk samples in different regions of China, and evaluated the contamination situation, existence of virulence genes, antibiotic resistance profile and genetic polymorphism of B. cereus isolates. Intriguingly, 70 samples (27%) were found to be contaminated by B. cereus and the average contamination level was 111 MPN/g. The distribution of virulence genes was assessed toward 10 enterotoxigenic genes (hblA, hblC, hblD, nheA, nheB, nheC, cytK, entFM, bceT, and hlyII) and one emetic gene (cesB). Forty five percent strains harbored enterotoxigenic genes hblACD and 93% isolates contained nheABC gene cluster. The positive rate of cytK, entFM, bceT, hlyII, and cesB genes were 73, 96, 75, 54, and 5%, respectively. Antibiotic susceptibility assessment showed that most of the isolates were resistant to beta lactam antibiotics and rifampicin, but susceptible to other antibiotics such as ciprofloxacin, gentamicin and chloramphenicol. Total multidrug-resistant population was about 34%. In addition, B. cereus isolates in pasteurized milk showed a high genetic diversity. In conclusion, our findings provide the first reference on the prevalence, contamination level and characteristics of B. cereus isolated from pasteurized milk in China, suggesting a potential high risk of B. cereus to public health and dairy industry. PMID- 29632522 TI - HPV-Induced Field Cancerisation: Transformation of Adult Tissue Stem Cell Into Cancer Stem Cell. AB - Field cancerisation was originally described as a basis for multiple head and neck squamous cell carcinoma (HNSCC) and is a pre-malignant phenomenon that is frequently attributable to oncogenic human papillomavirus (HPV) infection. Our work on beta-HPV-induced cutaneous squamous cell carcinomas identified a novel Lrig1+ hair follicle junctional zone keratinocyte stem cell population as the basis for field cancerisation. Herein, we describe the ability for HPV to infect adult tissue stem cells in order to establish persistent infection and induce their proliferation and displacement resulting in field cancerisation. By review of the HPV literature, we reveal how this mechanism is conserved as the basis of field cancerisation across many tissues. New insights have identified the capacity for HPV early region genes to dysregulate adult tissue stem cell self renewal pathways ensuring that the expanded population preserve its stem cell characteristics beyond the stem cell niche. HPV-infected cells acquire additional transforming mutations that can give rise to intraepithelial neoplasia (IEN), from environmental factors such as sunlight or tobacco induced mutations in skin and oral cavity, respectively. With establishment of IEN, HPV viral replication is sacrificed with loss of the episome, and the tissue is predisposed to multiple cancer stem cell-driven carcinomas. PMID- 29632523 TI - PutA Is Required for Virulence and Regulated by PruR in Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa, a Gram-negative opportunistic pathogenic bacterium, causes acute and chronic infections. Upon entering the host, P. aeruginosa alters global gene expression to adapt to host environment and avoid clearance by the host immune system. Proline utilization A (PutA) is a bifunctional enzyme, which converts proline to glutamate. Here we report that PutA was required for the virulence of P. aeruginosa in a murine acute pneumonia model. A putA mutant was more susceptible to oxidative stress compared to the wild type strain. An AraC/XylS family protein, PruR, directly bound to the upstream of -35 box in the putA promoter and activated putA expression. High concentration of proline in bacteria up-regulated pruR expression, which led to the activation of putA expression. As a feedback regulation, glutamate produced by PutA released PruR from the putA promoter and turned off the putA expression. PruR affected bacterial virulence through the regulation of the putA expression. Altogether, these data are the first to reveal that PutA plays an important role in the pathogenesis of P. aeruginosa, as well as to describe the genetic regulation of PutA in P. aeruginosa. PMID- 29632525 TI - C-terminus Proteolysis and Palmitoylation Cooperate for Optimal Plasma Membrane Localization of RasA in Aspergillus fumigatus. AB - RasA is a major regulator of fungal morphogenesis and virulence in Aspergillus fumigatus. The proper localization of RasA to the plasma membrane is essential for the formation of invasive hyphae during infection. In yeast, the localization of Ras2p to the plasma membrane is orchestrated by several post-translational modifications (PTM) at the C-terminal CAAX box that are thought to occur in sequential order. These PTMs include: (1) CAAX motif farnesylation by the farnesyltransferase complex composed of Ram1p and Ram2p; (2) proteolysis of the AAX residues by Rce1p or Ste24p; (3) methylation of the remaining prenylated cysteine residue by Ste14p, and; (4) palmitoylation at a single conserved cysteine residue mediated by the Erf2p/Erf4p palmitoyltransferase. We previously reported that homologs of each RasA PTM enzyme are conserved in A. fumigatus. Additionally, we delineated a major role for protein farnesylation in A. fumigatus growth and virulence. In this work, we characterize the post prenylation processing enzymes of RasA in A. fumigatus. The genes encoding the RasA post-prenylation enzymes were first deleted and examined for their roles in growth and regulation of RasA. Only when strains lacked cppB, the A. fumigatus homologue of yeast RCE1, there was a significant reduction in fungal growth and conidial germination. In addition, cppB-deletion mutants displayed hypersensitivity to the cell wall-perturbing agents Calcofluor White and Congo Red and the cell wall biosynthesis inhibitor Caspofungin. In contrast to the previously published data in yeast, the deletion of post-prenylation modifying enzymes did not alter the plasma membrane localization or activation of RasA. To delineate the molecular mechanisms underlying these differences, we investigated the interplay between dual-palmitoylation of the RasA hypervariable region and CAAX proteolysis for stabilization of RasA at the plasma membrane. Our data indicate that, in the absence of proper CAAX proteolysis, RasA accumulation at the plasma membrane is stabilized by dual palmitoyl groups on the dual cysteine residues. Therefore, we conclude CAAX proteolysis and dual-palmitoylation of the hypervariable region is important for maintaining a stable attachment association of RasA with the plasma membrane to support optimal fungal growth and development. PMID- 29632524 TI - Frequency and Genetic Determinants of Tigecycline Resistance in Clinically Isolated Stenotrophomonas maltophilia in Beijing, China. AB - Stenotrophomonas maltophilia is an emerging nosocomial pathogen with high resistance to most clinically used antimicrobials. Tigecycline is a potential alternative antimicrobial for S. maltophilia infection treatment, but its resistance mechanism in clinical isolates is not fully elucidated. We investigated the antimicrobial susceptibility of 450 S. maltophilia isolated during 2012-2015 from three university hospitals in Beijing, China. These strains exhibited high susceptibility to minocycline (98.44%), sulfamethoxazole/trimethoprim (87.56%), tigecycline (77.78 %), doxycycline (81.33%), levofloxacin (67.56%), and ticarcillin/clavulanate (73.00%). The susceptibility of tigecycline-nonsusceptible strains (TNS) to doxycycline and levofloxacin was much lower than that of tigecycline-susceptible strains (TSS) (25.00% vs. 97.71% for doxycycline, P < 0.001; 17.00% vs. 82.00% for levofloxacin, P < 0.001). We further selected 48 TNS and TSS and compared the detection rate of eight tetracycline-specific genes by PCR and the expression level of six intrinsic multidrug resistance efflux pumps by real-time PCR. Only one tetB and two tetH genes in TNS and three tetH genes in TSS were detected, and the detection rate had no difference. The average expression level of smeD in TNS was higher than that in TSS [20.59 (11.53, 112.54) vs. 2.07 (0.80, 4.96), P < 0.001], while the average expression levels of smeA, smeI, smeO, smeV, and smrA were not significantly different, indicating that smeDEF was the predominant resistance genetic determinant in clinical S. maltophilia. Higher smeD expression was also observed in levofloxacin- and doxycycline-nonsusceptible isolates than in their corresponding susceptible isolates [16.46 (5.83, 102.24) vs. 2.72 (0.80, 6.25) for doxycycline, P < 0.001; 19.69 (8.07, 115.10) vs. 3.01(1.00, 6.03), P < 0.001], indicating that smeDEF was also the resistance genetic determinant to levofloxacin and doxycycline. The consistent resistance profile and common resistance genetic determinant highlight the importance of rational use of tigecycline for preventing the occurrence and spread of multidrug resistance. PMID- 29632526 TI - Editorial: Vibrionaceae Diversity, Multidrug Resistance and Management. PMID- 29632527 TI - Tissue-Resident Memory CD8+ T Cells: From Phenotype to Function. AB - Tissue-resident memory CD8+ T cells are an important first line of defense from infection in peripheral non-lymphoid tissues, such as the mucosal tissues of the respiratory, digestive, and urogenital tracts. This memory T cell subset is established late during resolution of primary infection of those tissues, has a distinct genetic signature, and is often defined by the cell surface expression of CD69, CD103, CD49a, and CD44 in both mouse and human studies. The stimuli that program or imprint the unique gene expression and cell surface phenotypes on TRM are beginning to be defined, but much work remains to be done. It is not clear, for example, when and where the TRM precursors receive these signals, and there is evidence that supports imprinting in both the lymph node and the peripheral tissue sites. In most studies, expression of CD49a, CD103, and CD69 on T cells in the tissues appears relatively late in the response, suggesting there are precise environmental cues that are not present at the height of the acute response. CD49a and CD103 are not merely biomarkers of TRM, they confer substrate specificities for cell adhesion to collagen and E-cadherin, respectively. Yet, little attention has been paid to how expression affects the positioning of TRM in the peripheral tissues. CD103 and CD49a are not mutually exclusive, and not always co-expressed, although whether they can compensate for one another is unknown. In fact, they may define different subsets of TRM in certain tissues. For instance, while CD49a+CD8+ memory T cells can be found in almost all peripheral tissues, CD103 appears to be more restricted. In this review, we discuss the evidence for how these hallmarks of TRM affect positioning of T cells in peripheral sites, how CD49a and CD103 differ in expression and function, and why they are important for immune protection conferred by TRM in mucosal tissues such as the respiratory tract. PMID- 29632528 TI - PKCdelta-Mediated Nox2 Activation Promotes Fluid-Phase Pinocytosis of Antigens by Immature Dendritic Cells. AB - Aims: Macropinocytosis is a major endocytic pathway by which dendritic cells (DCs) internalize antigens in the periphery. Despite the importance of DCs in the initiation and control of adaptive immune responses, the signaling mechanisms mediating DC macropinocytosis of antigens remain largely unknown. The goal of the present study was to investigate whether protein kinase C (PKC) is involved in stimulation of DC macropinocytosis and, if so, to identify the specific PKC isoform(s) and downstream signaling mechanisms involved. Methods: Various cellular, molecular and immunological techniques, pharmacological approaches and genetic knockout mice were utilized to investigate the signaling mechanisms mediating DC macropinocytosis. Results: Confocal laser scanning microscopy confirmed that DCs internalize fluorescent antigens (ovalbumin) using macropinocytosis. Pharmacological blockade of classical and novel PKC isoforms using calphostin C abolished both phorbol ester- and hepatocyte growth factor induced antigen macropinocytosis in DCs. The qRT-PCR experiments identified PKCdelta as the dominant PKC isoform in DCs. Genetic studies demonstrated the functional role of PKCdelta in DC macropinocytosis of antigens, their subsequent maturation, and secretion of various T-cell stimulatory cytokines, including IL 1alpha, TNF-alpha and IFN-beta. Additional mechanistic studies identified NADPH oxidase 2 (Nox2) and intracellular superoxide anion as important players in DC macropinocytosis of antigens downstream of PKCdelta activation. Conclusion: The findings of the present study demonstrate a novel mechanism by which PKCdelta activation via stimulation of Nox2 activity and downstream redox signaling promotes DC macropinocytosis of antigens. PKCdelta/Nox2-mediated antigen macropinocytosis stimulates maturation of DCs and secretion of T-cell stimulatory cytokines. These findings may contribute to a better understanding of the regulatory mechanisms in DC macropinocytosis and downstream regulation of T-cell mediated responses. PMID- 29632530 TI - Ezh2 Regulates Activation-Induced CD8+ T Cell Cycle Progression via Repressing Cdkn2a and Cdkn1c Expression. AB - Transition from resting to cell cycle in response to antigenic stimulation is an essential step for naive CD8+ T cells to differentiate to effector and memory cells. Leaving the resting state requires dramatic changes of chromatin status in the key cell cycle inhibitors but the details of these concerted events are not fully elucidated. Here, we showed that Ezh2, an enzymatic component of polycomb repressive complex 2 (PRC2) catalyzing the trimethylation of lysine 27 on histone 3 (H3K27me3), regulates activation induced naive CD8+ T cells proliferation and apoptosis. Upon deletion of Ezh2 during thymocyte development (Ezh2fl/flCd4Cre+ mice), naive CD8+ T cells displayed impaired proliferation and increased apoptosis in response to antigen stimulation. However, naive CD8+ T cells only had impaired proliferation but no increase in apoptosis when Ezh2 was deleted after activation (Ezh2fl/flGzmBCre+ mice), suggesting cell cycle and apoptosis are temporally separable events controlled by Ezh2. We then showed that deletion of Ezh2 resulted in the increase in expression of cyclin-dependent kinase inhibitors Cdkn2a (p16 and Arf) and Cdkn1c (p57) in activated naive CD8+ T cells as the consequence of reduced levels of H3K27me3 at these two gene loci. Finally, with real time imaging, we observed prolonged cell division times of naive CD8+ T cells in the absence of Ezh2 post in vitro stimulation. Together, these findings reveal that repression of Cdkn1c and Cdkn2a by Ezh2 plays a critical role in execution of activation-induced CD8+ T cell proliferation. PMID- 29632531 TI - Inhibition of Immune Complex Complement Activation and Neutrophil Extracellular Trap Formation by Peptide Inhibitor of Complement C1. AB - Two major aspects of systemic lupus erythematosus (SLE) pathogenesis that have yet to be targeted therapeutically are immune complex-initiated complement activation and neutrophil extracellular trap (NET) formation by neutrophils. Here, we report in vitro testing of peptide inhibitor of complement C1 (PIC1) in assays of immune complex-mediated complement activation in human sera and assays for NET formation by human neutrophils. The lead PIC1 derivative, PA-dPEG24, was able to dose-dependently inhibit complement activation initiated by multiple types of immune complexes (IC), including C1-anti-C1q IC, limiting the generation of pro-inflammatory complement effectors, including C5a and membrane attack complex (sC5b-9). In several instances, PA-dPEG24 achieved complete inhibition with complement effector levels equivalent to background. PA-dPEG24 was also able to dose-dependently inhibit NET formation by human neutrophils stimulated by PMA, MPO, or immune complex activated human sera. In several instances PA-dPEG24 achieved complete inhibition with NETosis with quantitation equivalent to background levels. These results suggest that PA-dPEG24 inhibition of NETs occurs by blocking the MPO pathway of NET formation. Together these results demonstrate that PA-dPEG24 can inhibit immune complex activation of the complement system and NET formation. This provides proof of concept that peptides can potentially be developed to inhibit these two important contributors to rheumatologic pathology that are currently untargeted by available therapies. PMID- 29632529 TI - Autoantibodies Associated With Connective Tissue Diseases: What Meaning for Clinicians? AB - Connective tissue diseases (CTDs) such as systemic lupus erythematosus, systemic sclerosis, myositis, Sjogren's syndrome, and rheumatoid arthritis are systemic diseases which are often associated with a challenge in diagnosis. Autoantibodies (AAbs) can be detected in these diseases and help clinicians in their diagnosis. Actually, pathophysiology of these diseases is associated with the presence of antinuclear antibodies. In the last decades, many new antibodies were discovered, but their implication in pathogenesis of CTDs remains unclear. Furthermore, the classification of these AAbs is nowadays misused, as their targets can be localized outside of the nuclear compartment. Interestingly, in most cases, each antibody is associated with a specific phenotype in CTDs and therefore help in better defining either the disease subtypes or diseases activity and outcome. Because of recent progresses in their detection and in the comprehension of their pathogenesis implication in CTD-associated antibodies, clinicians should pay attention to the presence of these different AAbs to improve patient's management. In this review, we propose to focus on the different phenotypes and features associated with each autoantibody used in clinical practice in those CTDs. PMID- 29632532 TI - Complement Receptor 3-Mediated Inhibition of Inflammasome Priming by Ras GTPase Activating Protein During Francisella tularensis Phagocytosis by Human Mononuclear Phagocytes. AB - Francisella tularensis is a remarkably infectious facultative intracellular bacterium of macrophages that causes tularemia. Early evasion of host immune responses contributes to the success of F. tularensis as a pathogen. F. tularensis entry into human monocytes and macrophages is mediated by the major phagocytic receptor, complement receptor 3 (CR3, CD11b/CD18). We recently determined that despite a significant increase in macrophage uptake following C3 opsonization of the virulent Type A F. tularensis spp. tularensis Schu S4, this phagocytic pathway results in limited pro-inflammatory cytokine production. Notably, MAP kinase/ERK activation is suppressed immediately during C3-opsonized Schu S4-CR3 phagocytosis. A mathematical model of CR3-TLR2 crosstalk predicted early involvement of Ras GTPase-activating protein (RasGAP) in immune suppression by CR3. Here, we link CR3-mediated uptake of opsonized Schu S4 by human monocytes and macrophages with inhibition of early signal 1 inflammasome activation, evidenced by limited caspase-1 cleavage and IL-18 release. This inhibition is due to increased RasGAP activity, leading to a reduction in the Ras-ERK signaling cascade upstream of the early inflammasome activation event. Thus, our data uncover a novel signaling pathway mediated by CR3 following engagement of opsonized virulent F. tularensis to limit inflammasome activation in human phagocytic cells, thereby contributing to evasion of the host innate immune system. PMID- 29632534 TI - The C3dg Fragment of Complement Is Superior to Conventional C3 as a Diagnostic Biomarker in Systemic Lupus Erythematosus. AB - Introduction/objectives: In 2012, hypocomplementemia was included in the classification criteria of systemic lupus erythematosus (SLE). The suggested measurement of C3 or C4 often reflect disease activity poorly. Our objective was to establish an assay measuring C3dg, which is generated following complement activation, and to evaluate the assay in a cross-sectional SLE cohort. Method: We included SLE patients (n = 169) and controls (n = 170) and developed a modified C3dg assay where C3dg fragments were separated from the large plasma proteins by polyethylene glycol (PEG), and the supernatant containing the C3dg fragment was used for analysis in an antibody-based sandwich-type assay. Gel permeation chromatography and western blotting were used to establish the optimal conditions for PEG precipitation. Results: 16% PEG was optimal for separating C3dg from C3 and the larger protein fragments. The assay showed a high degree of stability when using EDTA plasma, and measurements correlated well with commercially available complement activation assays. SLE patients had higher concentrations in plasma of C3dg than controls (p < 0.05). ROC analysis showed that the C3dg activation fragment of C3 with an AUC of 0.96 (CI 0.94-0.98) was superior to C3 (AUC 0.52) in differentiating between patients and controls. Conclusion: Our results present a modified assay for the measurement of C3dg. We demonstrate that C3dg was superior to conventional C3 measurements in discriminating SLE patients from controls. We suggest that C3dg should be considered as a complement activation measurement in the SLE classification criteria. PMID- 29632533 TI - Adjuvant-Associated Peripheral Blood mRNA Profiles and Kinetics Induced by the Adjuvanted Recombinant Protein Candidate Tuberculosis Vaccine M72/AS01 in Bacillus Calmette-Guerin-Vaccinated Adults. AB - Systems biology has the potential to identify gene signatures associated with vaccine immunogenicity and protective efficacy. The main objective of this study was to identify optimal postvaccination time points for evaluating peripheral blood RNA expression profiles in relation to vaccine immunogenicity and potential efficacy in recipients of the candidate tuberculosis vaccine M72/AS01. In this phase II open-label study (NCT01669096; https://clinicaltrials.gov/), healthy Bacillus Calmette-Guerin-primed, HIV-negative adults were administered two doses (30 days apart) of M72/AS01. Twenty subjects completed the study and 18 subjects received two doses. Blood samples were collected pre-dose 1, pre-dose 2, and 1, 7, 10, 14, 17, and 30 days post-dose 2. RNA expression in whole blood (WB) and peripheral blood mononuclear cells (PBMCs) was quantified using microarray technology. Serum interferon-gamma responses and M72-specific CD4+ T cell responses to vaccination, and the observed safety profile were similar to previous trials. Two different approaches were utilized to analyze the RNA expression data. First, a kinetic analysis of RNA expression changes using blood transcription modules revealed early (1 day post-dose 2) activation of several pathways related to innate immune activation, both in WB and PBMC. Second, using a previously identified gene signature as a classifier, optimal postvaccination time points were identified. Since M72/AS01 efficacy remains to be established, a PBMC-derived gene signature associated with the protective efficacy of a similarly adjuvanted candidate malaria vaccine was used as a proxy for this purpose. This approach was based on the assumption that the AS01 adjuvant used in both studies could induce shared innate immune pathways. Subjects were classified as gene signature positive (GS+) or gene signature negative (GS-). Assignments of subjects to GS+ or GS- groups were confirmed by significant differences in RNA expression of the gene signature genes in PBMCs at 14 days post-dose 2 relative to prevaccination and in WB samples at 7, 10, 14, and 17 days post-dose 2 relative to prevaccination. Hence, in comparison with a prevaccination, 7, 10, 14, and 17 days postvaccination appeared to be suitable time points for identifying potentially clinically relevant transcriptome responses to M72/AS01 in WB samples. PMID- 29632535 TI - The Inner and Outer Qualities of Extracellular Vesicles for Translational Purposes in Breast Cancer. AB - Breast cancer (BC) is the second most common cause of cancer mortality of women worldwide. BC is a systemic disease with a highly heterogeneous course of disease. Therefore, prognostic and diagnostic biomarkers are required to improve the clinical risk management. Cancer-derived or cancer-associated extracellular vesicles (EVs) procured from the bloodstream of BC patients offer a novel platform for the qualitative and quantitative screening and establishment of biomarkers. Here, we focus on common aspects of EVs, on the function of BC derived EVs and their translational potential considering the EV abundancy, intravesicular as well as outer membrane-anchored composition and current challenges of implementation in clinical practice. PMID- 29632537 TI - Modulation of Regulatory T Cell Activity by TNF Receptor Type II-Targeting Pharmacological Agents. AB - There is now compelling evidence that tumor necrosis factor (TNF)-TNF receptor type II (TNFR2) interaction plays a decisive role in the activation, expansion, and phenotypical stability of suppressive CD4+Foxp3+ regulatory T cells (Tregs). In an effort to translate this basic research finding into a therapeutic benefit, a number of agonistic or antagonistic TNFR2-targeting biological agents with the capacity to activate or inhibit Treg activity have been developed and studied. Recent studies also show that thalidomide analogs, cyclophosphamide, and other small molecules are able to act on TNFR2, resulting in the elimination of TNFR2 expressing Tregs. In contrast, pharmacological agents, such as vitamin D3 and adalimumab, were reported to induce the expansion of Tregs by promoting the interaction of transmembrane TNF (tmTNF) with TNFR2. These studies clearly show that TNFR2-targeting pharmacological agents represent an effective approach to modulating the function of Tregs and thus may be useful in the treatment of major human diseases such as autoimmune disorders, graft-versus-host disease (GVHD), and cancer. In this review, we will summarize and discuss the latest progress in the study of TNFR2-targeting pharmacological agents and their therapeutic potential based on upregulation or downregulation of Treg activity. PMID- 29632538 TI - Pathogen Recognition by CD4 Effectors Drives Key Effector and Most Memory Cell Generation Against Respiratory Virus. AB - Although much is known about the mechanisms by which pathogen recognition drives the initiation of T cell responses, including those to respiratory viruses, the role of pathogen recognition in fate decisions of T cells once they have become effectors remains poorly defined. Here, we review our recent studies that suggest that the generation of CD4 T cell memory is determined by recognition of virus at an effector "checkpoint." We propose this is also true of more highly differentiated tissue-restricted effector cells, including cytotoxic "ThCTL" in the site of infection and TFH in secondary lymphoid organs. We point out that ThCTL are key contributors to direct viral clearance and TFH to effective Ab response, suggesting that the most protective immunity to influenza, and by analogy to other respiratory viruses, requires prolonged exposure to antigen and to infection-associated signals. We point out that many vaccines used today do not provide such prolonged signals and suggest this contributes to their limited effectiveness. We also discuss how aging impacts effective CD4 T cell responses and how new insights about the response of aged naive CD4 T cells and B cells might hold implications for effective vaccine design for both the young and aged against respiratory viruses. PMID- 29632536 TI - C-Type Lectin Receptors in Antiviral Immunity and Viral Escape. AB - C-type lectin receptors (CLRs) are important pattern recognition receptors involved in recognition and induction of adaptive immunity to pathogens. Certain CLRs play an important role in viral infections as they efficiently interact with viruses. However, it has become clear that deadly viruses subvert the function of CLRs to escape antiviral immunity and promote infection. In particular, viruses target CLRs to suppress or modulate type I interferons that play a central role in the innate and adaptive defense against viruses. In this review, we discuss the function of CLRs in binding to enveloped viruses like HIV-1 and Dengue virus, and how uptake and signaling cascades have decisive effects on the outcome of infection. PMID- 29632539 TI - Factors Influencing the Differentiation of Human Monocytic Myeloid-Derived Suppressor Cells Into Inflammatory Macrophages. AB - Monocytic myeloid-derived suppressor cells (mMDSC) accumulate within tumors where they create an immunosuppressive milieu that inhibits the activity of cytotoxic T and NK cells thereby allowing cancers to evade immune elimination. The toll-like receptors 7/8 agonist R848 induces human mMDSC to mature into inflammatory macrophage (MACinflam). This work demonstrates that TNFalpha, IL-6, and IL-10 produced by maturing mMDSC are critical to the generation of MACinflam. Neutralizing any one of these cytokines significantly inhibits R848-dependent mMDSC differentiation. mMDSC cultured in pro-inflammatory cytokine IFNgamma or the combination of TNFalpha plus IL-6 differentiate into MACinflam more efficiently than those treated with R848. These mMDSC-derived macrophages exert anti-tumor activity by killing cancer cells. RNA-Seq analysis of the genes expressed when mMDSC differentiate into MACinflam indicates that TNFalpha and the transcription factors NF-kappaB and STAT4 are major hubs regulating this process. These findings support the clinical evaluation of R848, IFNgamma, and/or TNFalpha plus IL-6 for intratumoral therapy of established cancers. PMID- 29632540 TI - Decitabine Inhibits Gamma Delta T Cell Cytotoxicity by Promoting KIR2DL2/3 Expression. AB - Gamma delta (gammadelta) T cells, which possess potent cytotoxicity against a wide range of cancer cells, have become a potential avenue for adoptive immunotherapy. Decitabine (DAC) has been reported to enhance the immunogenicity of tumor cells, thereby reinstating endogenous immune recognition and tumor lysis. However, DAC has also been demonstrated to have direct effects on immune cells. In this study, we report that DAC inhibits gammadelta T cell proliferation. In addition, DAC increases the number of KIR2DL2/3-positive gammadelta T cells, which are less cytotoxic than the KIR2DL2/3-negative gammadelta T cells. We found that DAC upregulated KIR2DL2/3 expression in KIR2DL2/3-negative gammadelta T cells by inhibiting KIR2DL2/3 promoter methylation, which enhances the binding of KIR2DL2/3 promoter to Sp-1 and activates KIR2DL2/3 gene expression. Our data demonstrated that DAC can inhibit the function of human gammadelta T cells at both cellular and molecular levels, which confirms and extrapolates the results of previous studies showing that DAC can negatively regulate the function of NK cells and alphabeta T cells of the immune system. PMID- 29632542 TI - Exogenous Abscisic Acid Promotes Anthocyanin Biosynthesis and Increased Expression of Flavonoid Synthesis Genes in Vitis vinifera * Vitis labrusca Table Grapes in a Subtropical Region. AB - Hybrid (Vitis vinifera *Vitis labrusca) table grape cultivars grown in the subtropics often fail to accumulate sufficient anthocyanins to achieve good uniform berry color. Growers of V. vinifera table grapes in temperate regions generally use ethephon and, more recently, (S)-cis-abscisic acid (S-ABA) to overcome this problem. The objective of this study was to determine if S-ABA applications at different timings and concentrations have an effect on anthocyanin regulatory and biosynthetic genes, pigment accumulation, and berry color of the Selection 21 cultivar, a new V. vinifera *V. labrusca hybrid seedless grape that presents lack of red color when grown in subtropical areas. Applications of S-ABA 400 mg/L resulted in a higher accumulation of total anthocyanins and of the individual anthocyaninsanthocyanins: delphinidin-3 glucoside, cyanidin-3-glucoside, peonidin-3-glucoside, and malvidin-3-glucoside in the berry skin and improved the color attributes of the berries. Treatment with two applications at 7 days after veraison (DAV) and 21 DAV of S-ABA 400 mg/L resulted in a higher accumulation of total anthocyanins in the skin of berries and increased the gene expression of CHI, F3H, DFR, and UFGT and of the VvMYBA1 and VvMYBA2 transcription factors in the seedless grape cultivar. PMID- 29632541 TI - 5' Rapid Amplification of cDNA Ends and Illumina MiSeq Reveals B Cell Receptor Features in Healthy Adults, Adults With Chronic HIV-1 Infection, Cord Blood, and Humanized Mice. AB - Using 5' rapid amplification of cDNA ends, Illumina MiSeq, and basic flow cytometry, we systematically analyzed the expressed B cell receptor (BCR) repertoire in 14 healthy adult PBMCs, 5 HIV-1+ adult PBMCs, 5 cord blood samples, and 3 HIS-CD4/B mice, examining the full-length variable region of MU, gamma, alpha, kappa, and lambda chains for V-gene usage, somatic hypermutation (SHM), and CDR3 length. Adding to the known repertoire of healthy adults, Illumina MiSeq consistently detected small fractions of reads with high mutation frequencies including hypermutated MU reads, and reads with long CDR3s. Additionally, the less studied IgA repertoire displayed similar characteristics to that of IgG. Compared to healthy adults, the five HIV-1 chronically infected adults displayed elevated mutation frequencies for all MU, gamma, alpha, kappa, and lambda chains examined and slightly longer CDR3 lengths for gamma, alpha, and lambda. To evaluate the reconstituted human BCR sequences in a humanized mouse model, we analyzed cord blood and HIS-CD4/B mice, which all lacked the typical SHM seen in the adult reference. Furthermore, MiSeq revealed identical unmutated IgM sequences derived from separate cell aliquots, thus for the first time demonstrating rare clonal members of unmutated IgM B cells by sequencing. PMID- 29632543 TI - Heterotetramerization of Plant PIP1 and PIP2 Aquaporins Is an Evolutionary Ancient Feature to Guide PIP1 Plasma Membrane Localization and Function. AB - Aquaporins (AQPs) are tetrameric channel proteins regulating the transmembrane flux of small uncharged solutes and in particular water in living organisms. In plants, members of the plasma membrane intrinsic protein (PIP) AQP subfamily are important for the maintenance of the plant water status through the control of cell and tissue hydraulics. The PIP subfamily is subdivided into two groups: PIP1 and PIP2 that exhibit different water-channel activities when expressed in Xenopus oocytes or yeast cells. Most PIP1 and PIP2 isoforms physically interact and assemble in heterotetramers to modulate their subcellular localization and channel activity when they are co-expressed in oocytes, yeasts, and plants. Whether the interaction between different PIPs is stochastic or controlled by cell regulatory processes is still unknown. Here, we analyzed the water transport activity and the subcellular localization behavior of the complete PIP subfamily (SmPIP1;1, SmPIP2;1, and SmPIP2;2) of the lycophyte Selaginella moellendorffii upon (co-)expression in yeast and Xenopus oocytes. As observed for most of the PIP1 and PIP2 isoforms in other species, SmPIP1;1 was retained in the ER while SmPIP2;1 was found in the plasma membrane but, upon co-expression, both isoforms were found in the plasma membrane, leading to a synergistic effect on the water membrane permeability. SmPIP2;2 behaves as a PIP1, being retained in the endoplasmic reticulum when expressed alone in oocytes or in yeasts. Interestingly, in contrast to the oocyte system, in yeasts no synergistic effect on the membrane permeability was observed upon SmPIP1;1/SmPIP2;1 co-expression. We also demonstrated that SmPIP2;1 is permeable to water and the signaling molecule hydrogen peroxide. Moreover, growth- and complementation assays in the yeast system showed that heteromerization in all possible SmPIP combinations did not modify the substrate specificity of the channels. These results suggest that the characteristics known for angiosperm PIP1 and PIP2 isoforms in terms of their water transport activity, trafficking, and interaction emerged already as early as in non-seed vascular plants. The existence and conservation of these characteristics may argue for the fact that PIP2s are indeed involved in the delivery of PIP1s to the plasma membrane and that the formation of functional heterotetramers is of biological relevance. PMID- 29632544 TI - AFLP Approach Reveals Variability in Phragmites australis: Implications for Its Die-Back and Evidence for Genotoxic Effects. AB - Phragmites australis is a subcosmopolitan species typical of wetlands being studied in Europe for its disappearance from natural stands, a phenomenon called reed die-back syndrome (RDBS). Although it is conjectured that low genetic variability contributes to RDBS, this aspect remains neglected to this day. Using a molecular fingerprinting approach and a sequence analysis of the trnT-trnL/rbcL psaI regions of cpDNA, this study aimed to compare the genetic structure of stable vs. RDBS-affected P. australis stands from five wetlands of central Italy. Beforehand, in order to characterize the health condition of reed populations, the occurrence of the main macromorphological descriptors for RDBS was considered on 40 reed stands. Soil samples were also collected to examine the total content of heavy metals. The current study analyzed cpDNA in 19 samples and AFLP profiles in 381 samples to investigate the genetic structure of Phragmites populations. Based on the multinomial-Dirichlet model, an analysis of candidate loci under selective pressure was also performed. The relationships among AFLP data, RDBS descriptors and chemicals were evaluated with the use of Linear Mixed Models. The analysis of the cpDNA shows the occurrence of the haplotypes M (the most widespread), and K here recorded for the first time in Italy. Three new haplotypes were also described. The DNA fingerprinting analysis has produced a total of 322 loci (98% polymorphic) and shows the medium-to-high amount of genetic diversity. The significant genetic differentiation among wetlands (Fst = 0.337) suggests either low gene flow or small effective population size. Moreover, the low amount of outlier loci (only 5; l.5% of the total), seems to indicate the scarce occurrence of selective pressure upon the reed's genome. Genetic diversity increased in relationship to the decrease in diameter and of flowering buds of the reed, two of the trends associated with the die-back. The current study rejects the hypothesis that genetic diversity massively contributed to RDBS. Moreover, significant relationships between genetic diversity and the total concentration of some heavy metals (Cr, Cu, and Zn) were highlighted, indicating possible genotoxic effects on P. australis. The current study represents a fact-finding background useful for the conservation of common reed. PMID- 29632545 TI - Identification of Minimal p53 Promoter Region Regulated by MALAT1 in Human Lung Adenocarcinoma Cells. AB - The MALAT1 long noncoding RNA is strongly linked to cancer progression. Here we report a MALAT1 function in repressing the promoter of p53 (TP53) tumor suppressor gene. p21 and FAS, well-known p53 targets, were upregulated by MALAT1 knockdown in A549 human lung adenocarcinoma cells. We found that these upregulations were mediated by transcriptional activation of p53 through MALAT1 depletion. In addition, we identified a minimal MALAT1-responsive region in the P1 promoter of p53 gene. Flow cytometry analysis revealed that MALAT1-depleted cells exhibited G1 cell cycle arrest. These results suggest that MALAT1 affects the expression of p53 target genes through repressing p53 promoter activity, leading to influence the cell cycle progression. PMID- 29632546 TI - MAP2 - A Candidate Gene for Epilepsy, Developmental Delay and Behavioral Abnormalities in a Patient With Microdeletion 2q34. AB - Introduction: Microdeletions in the chromosomal region 2q34 and its neighboring regions lead to a phenotypic spectrum including autism, intellectual disability, and epilepsy. Up to now, only few affected patients have been reported. Therefore, the genetic pathogenesis is not completely understood. One of the most discussed candidate genes in this context is MAP2, a gene responsible for microtubule polymerization and neurite outgrowth. Materials and Methods: We present a 4.5-year-old male patient with epilepsy, mild developmental delay, and behavioral abnormalities. SNP-Array analysis was performed to search for pathogenic copy number variations. Results: SNP-Array analysis revealed a 1.5 Mb de novo microdeletion on the long arm of chromosome 2 (2q34). The identified microdeletion included the candidate genes UNC80, LANCL1, and most importantly MAP2. Discussion: The reported microdeletion identified in this patient is the smallest one described in the literature so far spanning MAP2 next to UNC80 and LANCL1. In this context MAP2 is the most important candidate gene concerning neuronal development and its function should be further examined. PMID- 29632547 TI - Critical view of anaphylaxis epidemiology: open questions and new perspectives. AB - In contrast to the majority of allergic or hypersensitivity conditions, worldwide anaphylaxis epidemiological data remain sparse with low accuracy, which hampers comparable morbidity statistics. Data can differ widely depending on a number of variables. In the current document we reviewed the forms on which anaphylaxis has been defined and classified; and how it can affect epidemiological data. With regards to the methods used to capture morbidity statistics, we observed the impact of the anaphylaxis coding utilizing the World Health Organization's International Classification of Diseases. As an outcome and depending on the anaphylaxis definition, we extracted the cumulative incidence, which may not reflect the real number of new cases. The new ICD-11 anaphylaxis subsection developments and critical view of morbidity statistics data are discussed in order to reach new perspectives on anaphylaxis epidemiology. PMID- 29632548 TI - Atopic dermatitis: a review of topical nonsteroid therapy. AB - Background: Atopic dermatitis is a chronic inflammatory skin condition that affects up to 20% of children and 3% of adults globally. Although topical corticosteroids are considered to be the first-line agents, they can be associated with cutaneous and systemic adverse effects. Since the early 2000s, two new classes of nonsteroid topical therapies, topical calcineurin inhibitors and phosphodiesterase 4 (PDE4) inhibitors, have been introduced and provide a safe treatment alternative. Method: We performed a search and review of clinical trials that examined the safety and efficacy of topical calcineurin inhibitors and PDE4 inhibitors. The search was conducted using the PubMed database as well as preselected keywords and filters. This review focuses on the safety and efficacy of each therapy. Results: Sixty-nine clinical trials identified in this study have demonstrated the efficacy and safety of topical calcineurin and a single novel PDE4 inhibitor in the treatment of atopic dermatitis. Topical calcineurin inhibitors have been shown to be effective in both achieving lesion clearance as well as reducing relapse when used long-term and proactively. Similarly, in clinical trials the PDE4 inhibitor showed success in lesion clearance and symptom management. All three therapies (pimecrolimus, tacrolimus, crisaborole) are associated with low systemic absorption. No clinical trials to date have shown an increased risk of systemic adverse events or malignancy such as lymphoma. The most commonly reported treatment-related adverse event across all three therapies was application-site discomfort, pain or pruritus. It is important to note that long-term studies are not yet available for the novel PDE4 inhibitor. Discussion: Topical calcineurin inhibitors provide a safe and effective alternative to topical corticosteroid use in the treatment of atopic dermatitis. Although the US Food and Drug Administration (FDA) black box warning for topical calcineurin inhibitors remains, studies have not shown an increased risk of malignancy. These warnings have caused a decline in use in favor of topical steroids. A novel PDE4 inhibitor has shown efficacy and safety in studies up to one year. Further long-term safety data is needed. PMID- 29632549 TI - Perceptions of northeast Thai breastfeeding mothers regarding facilitators and barriers to six-month exclusive breastfeeding: focus group discussions. AB - Background: The 6-month exclusive breastfeeding rate in the Northeast region of Thailand has recently significantly decreased in contrast to all other regions in Thailand. The factors that have influenced this decrease remain unknown. Hence, it is suggested that an investigation into factors that could improve or hinder EBF for 6 months in Northeast Thailand may be required to inform the development of relevant interventions to improve this situation. This study aimed to identify perceived facilitators and barriers to providing exclusive breastfeeding for 6 months in Northeast Thailand among breastfeeding mothers. Methods: Six focus group discussions were conducted with a total of 30 mothers aged 20 to 40 years who had children aged between 4 and 6 months and were currently breastfeeding or had breastfeeding experience. Participants were recruited through self-selection sampling from Khonkaen hospital (urban), Numphong hospital (peri-urban) and private hospitals (urban) in Khonkaen, Thailand. Thematic analysis was employed to analyse the data. Results: Five main themes, with 10 sub-themes, were identified as either facilitators (+) or barriers (-), or in some cases, as both (+/-). Breastfeeding knowledge, perceptions, maternal circumstances, support, and traditional food were the main identified themes. Mother's breastfeeding knowledge, intention to breastfeed, and social media were perceived as facilitators. Perceptions, employment, and formula milk promotion were perceived as barriers. Family, healthcare, and traditional food were perceived as both facilitators and barriers. The perception that social media was a way to access breastfeeding knowledge and support mothers in Northeast Thailand emerged as a new facilitating factor that had not previously been identified in Thai literature relating to facilitators and barriers to exclusive breastfeeding. Intention to breastfeed, family support, healthcare support and traditional food were mentioned by all groups, whereas mothers from urban areas specifically mentioned mother's breastfeeding knowledge, social media and employment sub themes. Only mothers from the peri-urban area mentioned formula milk promotion and only mothers who had delivered in public hospitals mentioned the perceptions sub-theme. Conclusions: Knowledge about these facilitators and barriers may inform the design and development of specific and relevant interventions to improve the 6-month exclusive breastfeeding rate in the Northeast region of Thailand and be useful in other contexts. Social media emerged as a newly perceived facilitator in the Thai context and may be a useful inclusion in a 6 month exclusive breastfeeding intervention model. PMID- 29632550 TI - Role of BK human polyomavirus in cancer. AB - Human polyomaviruses (HPyV), which are small DNA viruses classified into the polyomaviridae family, are widely distributed in human populations. Thirteen distinct HPyVs have been described to date. Some of these viruses have been found in human tumors, suggesting an etiological relationship with cancer. In particular, convincing evidence of an oncogenic role has emerged for a specific HPyV, the Merkel cell polyomavirus (MCPyV). This HPyV has been linked to rare skin cancer, Merkel cell carcinoma (MCC). This finding may be just the tip of the iceberg, as HPyV infections are ubiquitous in humans. Many authors have conjectured that additional associations between HPyV infections and neoplastic diseases will likely be discovered. In 2012, the International Agency for Research on Cancer (IARC) evaluated the carcinogenicity of the BK virus (BKPyV), reporting that BKPyV is "possibly carcinogenic to humans." This review explores the BKPyV infection from a historical point of view, including biological aspects related to viral entry, tropism, epidemiology and mechanisms potentially involved in BKPyV-mediated human carcinogenesis. In order to clarify the role of this virus in human cancer, more epidemiological and basic research is strongly warranted. PMID- 29632551 TI - Alcohol use in a rural district in Uganda: findings from community-based and facility-based cross-sectional studies. AB - Background: Uganda has one of the highest per capita alcohol consumption rates in sub-Saharan Africa. However, the prevalence of alcohol use disorders (AUD) remains unknown in many areas, especially in rural districts. This study aimed to estimate the prevalence of alcohol consumption and of alcohol use disorder among men, and to describe the distribution of drinking intensity, among men in in Kamuli District, Uganda. Methods: Men attending primary care clinics in Kamuli District were consecutively interviewed in a facility-based cross-sectional study, and a separate group of men were interviewed in a population-based cross sectional study. In both studies the men were administered a structured questionnaire, which included the alcohol use disorder identification test (AUDIT) to screen for AUD, as well as sections about demographic characteristics, depression screening, internalized stigma for alcohol problems and treatment seeking. Results: Among the 351 men enrolled in the Community study, 21.8% consumed alcohol in the past 12 months, compared to 39.6% of 778 men in the Facility Survey. The proportion of men who screened positive for AUD was 4.1% in the community study and 5.8% in the facility study. AUDIT scores were higher among older men, men with paid/self-employment status and higher PHQ-9 score (P < 0.05). Nearly half (47.5%) of the men with AUDIT-positive scores reported that alcohol use problems had ruined their lives. A majority (55.0%) of men with AUDIT positive scores did not seek treatment because they did not think AUD was a problem that could be treated. Conclusions: Internalized stigma beliefs among AUDIT-positive men impede treatment-seeking. As part of any efforts to increase detection and treatment services for alcohol use problems, routine screening and brief interventions for internalized stigma must be incorporated within the normal clinical routine of primary health care. PMID- 29632552 TI - Focusing the diversity of Gardnerella vaginalis through the lens of ecotypes. AB - Gardnerella vaginalis has long been associated with bacterial vaginosis, a condition that increases the risk of women to preterm birth, sexually transmitted infections, and other adverse sequelae. However, G. vaginalis is also commonly found in healthy asymptomatic women of all ages. This raises the question if genetic differences among strains might distinguish potentially pathogenic from commensal strains. To disentangle the diversity of G. vaginalis, we invoked the concept of ecotypes-lineages of genetically and ecologically distinct strains within a named species-to better understand their evolutionary history and identify functional characteristics. We compared the genomes of G. vaginalis to six species in the closely related Bifidobacterium genus and found that G. vaginalis has a large accessory genome relative to Bifidobacterium, including many unique genes possibly involved in metabolism, drug resistance, and virulence. We then performed a comparative genomic analysis of 35 strains of G. vaginalis to infer a phylogeny based on the combined analysis of the core genome, using nucleotide substitution models, and the accessory genome, using gene gain/loss models. With the inferred tree topology, we performed comparisons of functional gene content among lineages that diverged at varying depths in the phylogeny and found significant differences in the representation of genes putatively involved in pathogenicity. Our functional enrichment analysis suggests that some lineages of G. vaginalis may possess enhanced pathogenic capabilities, including genes involved in mucus degradation like sialidases, while others may be commensal strains, lacking many of these pathogenic capabilities. The combined phylogenetic evidence and functional enrichment analysis allowed us to identify distinct ecotypes that have evolved in G. vaginalis as the result of the differential gene gain/loss for specific functions, including the capability to cause disease. We finally discuss how this analysis framework could be used to gain insight into the etiology of bacterial vaginosis and improve diagnosis. PMID- 29632553 TI - Planting exotic relatives has increased the threat posed by Dothistroma septosporum to the Caledonian pine populations of Scotland. AB - To manage emerging forest diseases and prevent their occurrence in the future, it is essential to determine the origin(s) of the pathogens involved and identify the management practices that have ultimately caused disease problems. One such practice is the widespread planting of exotic tree species within the range of related native taxa. This can lead to emerging forest disease both by facilitating introduction of exotic pathogens and by providing susceptible hosts on which epidemics of native pathogens can develop. We used microsatellite markers to determine the origins of the pathogen Dothistroma septosporum responsible for the current outbreak of Dothistroma needle blight (DNB) on native Caledonian Scots pine (Pinus sylvestris) populations in Scotland and evaluated the role played by widespread planting of two exotic pine species in the development of the disease outbreak. We distinguished three races of D. septosporum in Scotland, one of low genetic diversity associated with introduced lodgepole pine (Pinus contorta), one of high diversity probably derived from the DNB epidemic on introduced Corsican pine (Pinus nigra subsp. laricio) in England and a third of intermediate diversity apparently endemic on Caledonian Scots pine. These races differed for both growth rate and exudate production in culture. Planting of exotic pine stands in the UK appears to have facilitated the introduction of two exotic races of D. septosporum into Scotland which now pose a threat to native Caledonian pines both directly and through potential hybridization and introgression with the endemic race. Our results indicate that both removal of exotic species from the vicinity of Caledonian pine populations and restriction of movement of planting material are required to minimize the impact of the current DNB outbreak. They also demonstrate that planting exotic species that are related to native species reduces rather than enhances the resilience of forests to pathogens. PMID- 29632554 TI - Metabolome- and genome-scale model analyses for engineering of Aureobasidium pullulans to enhance polymalic acid and malic acid production from sugarcane molasses. AB - Background: Polymalic acid (PMA) is a water-soluble biopolymer with many attractive properties for food and pharmaceutical applications mainly produced by the yeast-like fungus Aureobasidium pullulans. Acid hydrolysis of PMA, resulting in release of the monomer l-malic acid (MA), which is widely used in the food and chemical industry, is a competitive process for producing bio-based platform chemicals. Results: In this study, the production of PMA and MA from sucrose and sugarcane molasses by A. pullulans was studied in shake flasks and bioreactors. Comparative metabolome analysis of sucrose- and glucose-based fermentation identified 81 intracellular metabolites and demonstrated that pyruvate from the glycolysis pathway may be a key metabolite affecting PMA synthesis. In silico simulation of a genome-scale metabolic model (iZX637) further verified that pyruvate carboxylase (pyc) via the reductive tricarboxylic acid cycle strengthened carbon flux for PMA synthesis. Therefore, an engineered strain, FJ PYC, was constructed by overexpressing the pyc gene, which increased the PMA titer by 15.1% compared with that from the wild-type strain in a 5-L stirred-tank fermentor. Sugarcane molasses can be used as an economical substrate without any pretreatment or nutrient supplementation. Using fed-batch fermentation of FJ-PYC, we obtained the highest PMA titers (81.5, 94.2 g/L of MA after hydrolysis) in 140 h with a corresponding MA yield of 0.62 g/g and productivity of 0.67 g/L h. Conclusions: We showed that integrated metabolome- and genome-scale model analyses were an effective approach for engineering the metabolic node for PMA synthesis, and also developed an economical and green process for PMA and MA production from renewable biomass feedstocks. PMID- 29632555 TI - A structured understanding of cellobiohydrolase I binding to poplar lignin fractions after dilute acid pretreatment. AB - Background: Cellulase adsorption to lignin is considered a cost barrier for bioethanol production; however, its detailed association mechanism is still not fully understood. In this study, two natural poplar variants with high and low sugar release performance were selected as the low and high recalcitrant raw materials (named L and H, respectively). Three different lignin fractions were extracted using ethanol, followed by p-dioxane and then cellulase treatment from the dilute acid pretreated poplar solids (fraction 1, 2, and 3, respectively). Results: Each lignin fraction had different physicochemical properties. Ethanol extracted lignin had the lowest weight average molecular weight, while the molecular weights for the other two lignin fractions were similar. 31P NMR analysis revealed that lignin fraction with higher molecular weight contained more aliphatic hydroxyl groups and less phenolic hydroxyl groups. Semi quantitative analysis by 2D HSQC NMR indicated that the lignin fractions isolated from the natural variants had different contents of syringyl (S), guaiacyl (G) and interunit linkages. Lignin extracted by ethanol contained the largest amount of S units, the smallest amounts of G and p-hydroxybenzoate (PB) subunits, while the contents of these lignin subunits in the other two lignin fractions were similar. The lignin fraction obtained after cellulase treatment was primarily comprised of beta-O-4 linkages with small amounts of beta-5 and beta-beta linkages. The binding strength of these three lignin fractions obtained by Langmuir equations were in the order of L1 > L3 > L2 for the low recalcitrance poplar and H1 > H2 > H3 for the high recalcitrance poplar. Conclusions: Overall, adsorption ability of lignin was correlated with the sugar release of poplar. Structural features of lignin were associated with its binding to CBH. For natural poplar variants, lignin fractions with lower molecular weight and polydispersity index (PDI) exhibited more CBH adsorption ability. Lignins with more phenolic hydroxyl groups had higher CBH binding strength. It was also found that lignin fractions with more condensed aromatics adsorbed more CBH likely attributed to stronger hydrophobic interactions. PMID- 29632556 TI - Clostridium thermocellum LL1210 pH homeostasis mechanisms informed by transcriptomics and metabolomics. AB - Background: Clostridium (Ruminiclostridium) thermocellum is a model fermentative anaerobic thermophile being studied and engineered for consolidated bioprocessing of lignocellulosic feedstocks into fuels and chemicals. Engineering efforts have resulted in significant improvements in ethanol yields and titers although further advances are required to make the bacterium industry-ready. For instance, fermentations at lower pH could enable co-culturing with microbes that have lower pH optima, augment productivity, and reduce buffering cost. C. thermocellum is typically grown at neutral pH, and little is known about its pH limits or pH homeostasis mechanisms. To better understand C. thermocellum pH homeostasis we grew strain LL1210 (C. thermocellum DSM1313 Deltahpt DeltahydG Deltaldh Deltapfl Deltapta-ack), currently the highest ethanol producing strain of C. thermocellum, at different pH values in chemostat culture and applied systems biology tools. Results: Clostridium thermocellum LL1210 was found to be growth-limited below pH 6.24 at a dilution rate of 0.1 h-1. F1F0-ATPase gene expression was upregulated while many ATP-utilizing enzymes and pathways were downregulated at pH 6.24. These included most flagella biosynthesis genes, genes for chemotaxis, and other motility-related genes (> 50) as well as sulfate transport and reduction, nitrate transport and nitrogen fixation, and fatty acid biosynthesis genes. Clustering and enrichment of differentially expressed genes at pH values 6.48, pH 6.24 and pH 6.12 (washout conditions) compared to pH 6.98 showed inverse differential expression patterns between the F1F0-ATPase and genes for other ATP-utilizing enzymes. At and below pH 6.24, amino acids including glutamate and valine; long chain fatty acids, their iso-counterparts and glycerol conjugates; glycolysis intermediates 3-phosphoglycerate, glucose 6-phosphate, and glucose accumulated intracellularly. Glutamate was 267 times more abundant in cells at pH 6.24 compared to pH 6.98, and intercellular concentration reached 1.8 MUmol/g pellet at pH 5.80 (stopped flow). Conclusions: Clostridium thermocellum LL1210 can grow under slightly acidic conditions, similar to limits reported for other strains. This foundational study provides a detailed characterization of a relatively acid intolerant bacterium and provides genetic targets for strain improvement. Future studies should examine adding gene functions used by more acid-tolerant bacteria for improved pH homeostasis at acidic pH values. PMID- 29632557 TI - Flow cytometry analysis of Clostridium beijerinckii NRRL B-598 populations exhibiting different phenotypes induced by changes in cultivation conditions. AB - Background: Biobutanol production by clostridia via the acetone-butanol-ethanol (ABE) pathway is a promising future technology in bioenergetics , but identifying key regulatory mechanisms for this pathway is essential in order to construct industrially relevant strains with high tolerance and productivity. We have applied flow cytometric analysis to C. beijerinckii NRRL B-598 and carried out comparative screening of physiological changes in terms of viability under different cultivation conditions to determine its dependence on particular stages of the life cycle and the concentration of butanol. Results: Dual staining by propidium iodide (PI) and carboxyfluorescein diacetate (CFDA) provided separation of cells into four subpopulations with different abilities to take up PI and cleave CFDA, reflecting different physiological states. The development of a staining pattern during ABE fermentation showed an apparent decline in viability, starting at the pH shift and onset of solventogenesis, although an appreciable proportion of cells continued to proliferate. This was observed for sporulating as well as non-sporulating phenotypes at low solvent concentrations, suggesting that the increase in percentage of inactive cells was not a result of solvent toxicity or a transition from vegetative to sporulating stages. Additionally, the sporulating phenotype was challenged with butanol and cultivation with a lower starting pH was performed; in both these experiments similar trends were obtained viability declined after the pH breakpoint, independent of the actual butanol concentration in the medium. Production characteristics of both sporulating and non-sporulating phenotypes were comparable, showing that in C. beijerinckii NRRL B-598, solventogenesis was not conditional on sporulation. Conclusion: We have shown that the decline in C. beijerinckii NRRL B-598 culture viability during ABE fermentation was not only the result of accumulated toxic metabolites, but might also be associated with a special survival strategy triggered by pH change. PMID- 29632558 TI - Assessment of postoperative complications using E-PASS and APACHE II in patients undergoing oral and maxillofacial surgery. AB - Background: The prediction of postoperative complications is important for oral and maxillofacial surgeons. We herein aimed to evaluate the efficacy of the Estimation of Physiologic Ability and Surgical Stress (E-PASS) and Acute Physiology, Age, and Chronic Health Evaluation (APACHE) II scoring systems to predict postoperative complications in patients undergoing oral and maxillofacial surgery. Methods: Thirty patients (22 males, 8 females; mean age: 65.1 +/- 12.9 years) who underwent major oral surgeries and stayed in the intensive care unit for postoperative management were enrolled in this study. Postoperative complications were discriminated according to the necessity of the therapeutic intervention by the Medical Department, i.e. according to the Clavien-Dingo classification. E-PASS and APACHE II scores as well as laboratory test values were compared between patients with/without postoperative complications. Results: Postoperative complications were developed in seven patients. The comprehensive risk score (CRS: 1.13 +/- 0.24) and APACHE II score (13.0 +/- 2.58) were significantly higher in patients with postoperative complications than in those without ones (p < 0.01, p < 0.05, respectively). The CRS showed an appropriate discriminatory power for predicting postoperative complications (area under the curve: 0.814). Furthermore, a correlation was detected between APACHE II scores and postoperative data until C-reactive protein levels decreased to < 1.0 mg/L (r = 0.43, p < 0.05). Conclusion: The E-PASS and APACHE II scoring systems were both shown to be useful to predict postoperative complications after oral and maxillofacial surgery. PMID- 29632559 TI - What are patients' knowledge, expectation and experience of radial extracorporeal shockwave therapy for the treatment of their tendinopathies? A qualitative study. AB - Background: Extracorporeal shockwave therapy (ESWT) is used to manage different tendinopathies and appears to be effective in some tendinopathies but not others. The reasons for this are unclear. There is evidence that patient outcomes can be influenced by a patient-centred approach. There is therefore a need to qualitatively evaluate patient experiences for a treatment like ESWT where uncertainties exist. The aim of this study was to understand patients' overall perspective of ESWT to manage their tendinopathy. Methods: A qualitative semi structured face-to-face interview study design was used and the data was analysed thematically using 'Framework Analysis'. Results: Eleven participants that have had radial ESWT (rESWT) to treat a range of tendinopathies were recruited from a private London sports clinic and interviewed in person or via SkypeTM. Four main themes and 16 subthemes were identified. Subthemes included previous failed treatment, clinician factors, mechanisms of ESWT, positive aspects, negative aspects, responsibility over own health and perceived outcomes. Conclusion: The participants understood the procedural aspects of rESWT, but were largely unaware of its mechanism of action and whether it was found to be effective for their condition or not. The participants felt that self-management measures were equally or more important than rESWT to help treat their tendinopathies. Recommendations would be for rESWT providers to offer patients written information, maintain continuity of care, address patients' expectations, feedback on progress, and encourage self-management measures such as activity modification. PMID- 29632560 TI - Equivalent Recombinant Human Insulin Preparations and their Place in Therapy. AB - Recombinant human insulin was one of the first products of biotechnology. It was developed in response to the need for a consistent and sufficient worldwide supply. Recombinant human insulin replaced the animal insulins and semisynthetic insulins obtained by modification of animal insulins. Bioequivalence studies were required for regulatory approval. Three reference products were independently established during these procedures: Humulin(r) (Eli Lilly and Co), Novolin(r) (NovoNordisk) and Insuman(r) (Sanofi). Numerous brand names have been used during the commercial development of recombinant human insulin formulations. In this review, three current brand names are used for consistent identification. Human insulin for Humulin and Insuman are produced by fermentation in bacteria (Escherichia coli) and for Novolin in yeast (Saccharomyces cerevisiae). The bioequivalence of recombinant human insulin products was investigated in euglycaemic clamp studies. An overview of such bioequivalence studies is provided here. This paper will consider the relevance of human insulin formulations today and their place in therapy. PMID- 29632561 TI - Insulin Glulisine in Pregnancy - Experience from Clinical Trials and Post marketing Surveillance. AB - Pregnancies complicated by gestational diabetes or pre-existing type 1 or type 2 diabetes mellitus are associated with a higher rate of adverse outcomes compared with pregnancies in the background population. These outcomes include miscarriage, pre-term delivery, pre-eclampsia, perinatal mortality and congenital malformations. Insulin glulisine (Apidra(r), Sanofi) is a rapid-acting insulin analogue indicated for the treatment of adults, adolescents and children 6 years or older with diabetes mellitus where treatment with insulin is required. Here, all post-marketing and clinical trials safety data with insulin glulisine in pregnancy available to Sanofi up to June 2014 are summarised together with the findings of a comprehensive literature search. Cumulatively, a total of 303 pregnancy exposures to insulin glulisine were received. Of these 303 pregnancy exposures, there were 116 live births, 12 spontaneous abortions, two late foetal intra-uterine deaths (>28 weeks), three elective abortions and 170 cases without a known pregnancy outcome. There were six cases of congenital malformations; of these, there were five live births; in the other case a live birth was not confirmed. The congenital malformations reported to date do not reveal a pattern of defects. In conclusion, the evidence to date does not suggest a causal association between insulin glulisine and an increased risk of pregnancy complications or congenital malformations. PMID- 29632562 TI - GLP-1 Receptor Agonists in Type 2 Diabetes and Beyond - New Insights 2015. AB - Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) were introduced for type 2 diabetes therapy nearly 10 years ago, among them short-acting compounds on the basis of the GLP-1-like peptide exendin-4 (exenatide and lixisenatide) and a long acting GLP-1 RA based on the human GLP-1 sequence (liraglutide). Recently, two novel long-acting GLP-1 RAs on the basis of human GLP-1 sequence, for once-weekly application, have been approved for therapy of type 2 diabetes. Additionally, liraglutide has been approved for treatment of obesity at a higher dose than that used for diabetes therapy. This mini-review gives a short overview of the novel long-acting GLP-1 RAs albiglutide and dulaglutide and also reviews the studies of liraglutide in treatment of obesity leading to its approval for this use. These studies were largely presented at the annual meeting of the European Association for the Study of Diabetes (EASD) in fall 2014. PMID- 29632563 TI - Early Vascular Ageing - A Concept in Development. AB - Cardiovascular disease (CVD) is a prevalent condition in the elderly, often associated with metabolic disturbance and type 2 diabetes. For a number of years, research dedicated to understand atherosclerosis dominated, and for many good reasons, this pathophysiological process being proximal to the CVD events. In recent years, research has been devoted to an earlier stage of vascular pathology named arteriosclerosis (arterial stiffness) and the new concept of early vascular ageing (EVA), developed by a group of mostly European researchers. This overview describes recent developments in research dedicated to EVA and new emerging aspects found in studies of families at high cardiovascular risk. There are new aspects related to genetics, telomere biology and the role of gut microbiota. However, there is still no unifying definition available of EVA and no direct treatment, but rather only recommendations for conventional cardiovascular risk factor control. New interventions are being developed - not only new antihypertensive drugs, but also new drugs for vascular protection - the selective angiotensin-II (AT2) agonist Compound 21 (C21). Human studies are eagerly awaited. Even new functional food products could have the potential to positively influence cardiometabolic regulation, to be confirmed. PMID- 29632564 TI - Which One to Endorse Among the Multitude of Lipid Guidelines? AB - Dyslipidemia is the major risk factor for atherosclerotic cardiovascular diseases. A multitude of lipid guidelines exist, with several controversies, and the best approach in dyslipidemia management is not clear. The tools and lipoproteins used for risk assessment, whether to use a treatment target and implementing drugs other than statins are all controversial points. Until the time for the publication of an agreeable lipid guideline, physicians should choose their way by considering the advantages and disadvantages of the existing guidelines. PMID- 29632566 TI - Current Challenges in the Management of Prolactinomas. AB - Although the diagnosis of prolactinoma is often straightforward and the treatment strategy has been well defined in recent guidelines, several challenging issues persist in their management. The differential diagnosis of a large pituitary tumour with moderately elevated prolactin (PRL) concentrations is sometimes difficult, and prolonged treatment with a dopamine agonist may be inappropriate when the diagnosis of a prolactinoma is not sufficiently well substantiated. Also, timely withdrawal of dopamine agonist treatment and the remaining indications of transsphenoidal surgery are still matters of debate. Last but not least, the management of resistant or aggressive prolactinomas remains a challenge for the clinician, especially when they occur in young patients. PMID- 29632565 TI - Cushing's Disease - Quality of Life, Recurrence and Long-term Morbidity. AB - Cushing's disease (CD) is a rare disorder caused by an adrenocorticotropic hormone (ACTH)-secreting pituitary adenoma. Chronic exposure to hypercortisolism leads to significant morbidities, which may be only partially reversible after remission of the disease, as well as to impairment of the health-related quality of life (HRQoL) and an increase in mortality. Transsphenoidal surgery (TSS) is the treatment of choice, and recurrence rates vary widely, confirming the need for lifelong follow-up. This review summarises the studies performed on HRQoL, recurrence rates and morbidities in patients who have CD. PMID- 29632567 TI - Sarcopenia in Endocrine Disorders - The Iceberg or Its Tip? AB - Endocrine myopathies represent disorders of the musculoskeletal system that significantly impair the state of health. Sarcopenia is their pathophysiological common denominator. Recent reports have shown that endocrine disorders, even when subclinical, may also be associated with tendinopathies. It may thus be suggested that both hormones and hormonal disorders have complex actions on the musculoskeletal system and that musculoskeletal endocrinology represents a fascinating research area still awaiting exploration. PMID- 29632568 TI - Assessing Osteoporosis in the Young Adult. AB - Osteoporosis in the young adult is a relatively rare phenomenon, and its diagnosis needs careful assessment of the affected person. The emphasis in the assessment of bone health is gradually shifting from a simple quantitative assessment of bone mineral density to one that includes bone quality. This may be particularly important in the young adult, where the aetiological cause of osteoporosis may be a primary genetic condition or secondary to another chronic condition. PMID- 29632569 TI - Central Precocious Puberty - Management and Long-term Outcomes. AB - Central precocious puberty (CPP) results from premature re-activation of the gonadotropic axis. CPP is much more common in girls than in boys and is idiopathic in most cases. In boys, precocious puberty is more likely to be linked to hypothalamic lesions (~40%). Recent studies have implicated the inactivation of MKRN3 gene in 'idiopathic' CPP Gonadotropin-releasing hormone agonists are the standard treatment for progressive CPP. PMID- 29632570 TI - The International Diabetes Federation World Diabetes Congress 2015. AB - Bernard Zinman, Programme Committee Chair of the International Diabetes Federation (IDF) World Diabetes Congress 2015, talks about the scientific programme highlights, the experience of attending the Congress and his involvement in diabetes care and research. Bernard Zinman is Director of the Leadership Sinai Centre for Diabetes and holds the Sam and Judy Pencer Family Chair in Diabetes Research at Mount Sinai Hospital and the University of Toronto, Canada. He is Professor of Medicine at the University of Toronto and Senior Scientist at the Samuel Lunenfeld Tanenbaum Research Institute, Mount Sinai Hospital, Ontario, Canada. PMID- 29632571 TI - The Insulin Treatment Satisfaction Questionnaire and Assessment of Satisfaction with a Latest-generation Insulin Pump. AB - Satisfaction with the latest-generation insulin pump (LGIP) was assessed in patients with diabetes mellitus enrolled in the Comparing Perception of Insulin Therapies for T1D Patients with the Aim to Improve Quality of Care (CHOICE) study. The Insulin Treatment Satisfaction Questionnaire (ITSQ), a measure of insulin treatment satisfaction, together with additional questions assessed respondents' perceptions of glucose control, their satisfaction with major LGIP features and preference for the LGIP versus their previous treatment, was used. The LGIP (Animas(r) VibeTM) was considered to be a better method for delivering insulin compared with their therapy before switching and was rated high for treatment satisfaction. These findings should be useful to clinicians when considering the possibility of transferring a patient from their existing treatment regimen to a LGIP. PMID- 29632572 TI - The OPT2MISE Study - A Review of the Major Findings and Clinical Implications. AB - Many patients with type 2 diabetes struggle to achieve adequate glucose control despite escalation of therapy including complex insulin regimens with multiple daily injections (MDIs). Previous randomised controlled trials failed to show a significant improvement in glycaemic control with pump therapy over multiple injections. The OPT2MISE study enrolled 495 adult patients with poorly controlled type 2 diabetes despite an intensified insulin regimen using rapid and slow acting insulin analogues. After a 2-month run-in period, patients were randomised to switch to pump therapy or to maintain their MDI regimen. After 6 months, patients with pump therapy achieved a better glycaemic control than those who used multiple injections (glycated haemoglobin [HbA1c] difference of -0.7 %), and twice as many patients reached the target range of 8 % or less in the pump therapy group compared with the injection group. Patients using pump therapy had a 20 % reduction of their total daily insulin dose. A moderate weight gain was observed with both treatments, and no severe hypoglycaemia nor ketoacidosis occurred in the pump therapy group. Pump therapy may now be considered as a valuable option in type 2 diabetes patients who fail to respond to an intensified insulin regimen. PMID- 29632574 TI - Basal Insulin Inadequacy versus Failure - Using Appropriate Terminology. AB - This editorial focuses on appropriate terminology related to basal insulin therapy. The authors analyse current usage of 'basal insulin failure', and propose 'basal insulin inadequacy' as a better descriptor for persons not responding to basal insulin alone. The pharmacokinetic and pharmacodynamic differences between various basal insulin preparations are highlighted. Based upon these, a drug-specific definition for insulin inadequacy is suggested, instead of a generic class-based labelling. PMID- 29632573 TI - Reporting on Glucose Control Metrics in the Intensive Care Unit. AB - The 'diabetes of injury' typically associated with critical illness has recently been thoroughly revisited and much better characterised following major therapeutic advances. The occurrence of severe hyperglycaemia, moderate hypoglycaemia or high glycaemic variability has been associated with an increased mortality and rate of complications in large independent cohorts of acutely ill patients. Hence, current guidelines advocate the prevention and avoidance of each of these three dysglycaemic domains, and the use of a common metrics for a quantitative description of dysglycaemic events, such as the proportion of time spent in the target glycaemic range as a unifying variable. Using a common language will help to face the future challenges, including the definition of the most appropriate blood glucose (BG) target according to the category of admission, the time interval from the initial injury and the medical history. The clinical testing of technological improvements in the monitoring systems and the therapeutic algorithms should be assessed using the same metrics. PMID- 29632577 TI - Management of Craniopharyngioma - Perspectives beyond Surgery and Endocrinology. AB - The excess mortality in craniopharyngiomas is attributable to their size, site and the traditional surgical approach; aggressive resection predisposes to hypothalamic complications such as obesity, somnolence, thirst disorders and neurocognitive dysfunction. Recently, treatment has been modified to partial resection and radiotherapy. The role of the endocrinologist has expanded from identification and replacement of hormone deficits to include management of hypothalamic disease. Future treatment of craniopharyngioma with neo-adjuvant chemotherapy to minimise surgical resection may improve the outcomes for these patients. PMID- 29632578 TI - Surgical Approach to the Adrenal Glands. AB - Any surgeon treating a patient with adrenal disease should be a member of a multi disciplinary team involving dedicated specialists, including an endocrinologist, anaesthetist, radiologist, intensivist and geneticist. In an era of epidemic numbers of adrenal incidentalomas, great care must be taken to determine not only the endocrine diagnosis, but also the benefits (if any) of adrenal surgery. Finally, the surgeon must be competent in both minimally invasive and gross resectional surgical techniques and know when to adopt these two very different surgical approaches. PMID- 29632575 TI - Obstructive Sleep Apnoea and Vascular Disease in Patients with Type 2 Diabetes. AB - Obstructive sleep apnoea (OSA) is common and is associated with many vascular risk factors, such as hypertension, insulin resistance, albuminuria, dyslipidaemia, increased inflammation and endothelial dysfunction. Epidemiological studies have shown that OSA is associated with increased cardiovascular disease (CVD) and that continuous positive airway pressure (CPAP) might reduce CVD events in patients with OSA. In addition, OSA has also been shown to be associated with albuminuria, chronic kidney disease, a wide range of ocular diseases and peripheral neuropathy. Considering that CVD and microvascular complications are major contributors to the morbidity, mortality and the economic burden of diabetes and that OSA is common in patients with type 2 diabetes (T2D), it is important to understand the role of OSA in the development and/or progression of vascular disease in patients with T2D and to explore the impact of CPAP on diabetes-related vascular outcomes. The purpose of this article is to review the evidence for the relationship and impact of OSA on vascular disease and vascular risk factors particularly in patients with T2D. PMID- 29632579 TI - Management of Turner Syndrome. AB - Turner syndrome is one of the most common genetic disorders, affecting one in 2,000-2,500 live-born girls. In order to provide appropriate healthcare, a multi disciplinary team of closely cooperating endocrinologists, gynaecologists, geneticists, cardiologists, otolaryngologists, fertility specialists, psychologists, nurse educators and social workers is needed. PMID- 29632576 TI - Ghrelin - Physiological Functions and Regulation. AB - Ghrelin is an orexigenic peptide predominantly secreted from the stomach and stimulates appetite and growth hormone (GH) release. Studies have provided evidence that ghrelin exercises a wide range of functions, including regulation of food intake and energy metabolism, modulation of cardiovascular function, stimulation of osteoblast proliferation and bone formation and stimulation of neurogenesis and myogenesis. In the gastrointestinal system, ghrelin affects multiple functions, including secretion of gastric acid, gastric motility and pancreatic protein output. Most of these functions have been attributed to the actions of acylated ghrelin. The balance among its secretion rate, degradation rate and clearance rate determines the circulating level of ghrelin. This review explains what ghrelin is, its physiological functions and the factors that influence its level. PMID- 29632580 TI - Severe Hypercalcaemia - Chronic Tophaceous Gout as the Responsible Cause? AB - The association of chronic tophaceous gout with severe hypercalcaemia is exceptional. In this case, a 42-year old man with a long-standing history of gout arrived at the emergency room with altered mental status. Laboratory work up revealed a uric acid of 14.0 mg/dl, corrected calcium of 14.5 mg/dl, phosphorous of 6.3 mg/dl, parathyroid hormone (PTH) was suppressed (<3.0 pg/ml), 25 dihydroxyvitamin D 25.2 ng/ml, parathyroid hormone related-protein (PTHrP) was 45.0 pg/ml and calcitriol 19.6 pg/ml. Biopsy histopathology result showed deposits of monosodium urate crystals surrounded by granulomatous inflammation. The association of chronic tophaceous gout with severe hypercalcaemia is extremely rare and has been usually described to be secondary to 1-25 dihydroxyvitamin D (calcitriol) secretion. In this case, calcitriol levels were normal and this possibility was excluded. On the other hand, PTHrP had never been, until now, described as the responsible cause of hypercalcaemia in gout. In our case, baseline PTHrP and calcium values were elevated and after medical treatment both returned to normal values. PTHrP usually causes hypophosphataemia and in this case the abnormal renal function could have diminished this last effect. PMID- 29632581 TI - Recombinant Human Insulins - Clinical Efficacy and Safety in Diabetes Therapy. AB - Insulin replacement therapy is the standard of care for patients with type 1 and advanced type 2 diabetes mellitus. Porcine and bovine pancreatic tissue was the source of the hormone for many years, followed by semisynthetic human insulin obtained by modification of animal insulin. With the development of recombinant DNA technology, recombinant (biosynthetic) human insulin became available in large amounts by biosynthesis in microorganisms (Escherichia coli, yeast) providing reliable supplies of the hormone worldwide at affordable costs. The purity and pharmaceutical quality of recombinant human insulin was demonstrated to be superior to animal and semisynthetic insulin and patients with diabetes could be safely and effectively transferred from animal or semisynthetic human insulin to recombinant human insulin with no change expected in insulin dose. The decision for change remains a clinical objective, follow-up after any change of insulin product is recommended to confirm clinical efficacy. This review provides a summary and retrospective assessment of early clinical studies with recombinant insulins (Insuman(r), Humulin(r), Novolin(r)). PMID- 29632582 TI - The Hypoglycaemia-Hyperglycaemia Minimizer System in the Management of Type 1 Diabetes. AB - Living with type 1 diabetes (T1D) presents many challenges in terms of daily living. Insulin users need to frequently monitor their blood glucose levels and take multiple injections per day and/or multiple boluses through an insulin infusion pump, with the consequences of failing to match the insulin dose to the body's needs resulting in hypoglycaemia and hyperglycaemia. The former can result in seizures, coma and even death; the latter can have both acute and long-term health implications. Many patients with T1D also fail to meet their treatment goals. In order to reduce the burdens of self-administering insulin, and improve efficacy and safety, there is a need to at least partially remove the patient from the loop via a closed-loop 'artificial pancreas' system. The Hypoglycaemia Hyperglycaemia Minimizer (HHM) System, comprising a continuous, subcutaneous insulin infusion pump, continuous glucose monitor (CGM) and closed-loop insulin dosing algorithm, is able to predict changes in blood glucose and adjust insulin delivery accordingly to help keep the patient at normal glucose levels. Early clinical data indicate that this system is feasible, effective and safe, and has the potential to dramatically improve the therapeutic outcomes and quality of life for people with T1D. PMID- 29632584 TI - Cardiovascular Outcomes with Empagliflozin - News for Type 2 Diabetes Therapy. AB - Cardiovascular safety has to be proven for antidiabetic therapy for type 2 diabetes according to the guidance from regulatory bodies. Recently, the results of the respective study for the sodium-glucose transporter-2 (SGLT-2) inhibitor empagliflozin were published. Unlike similar studies for other antidiabetic agents that proved cardiovascular safety by non-inferiority compared with standard treatment with regard to a combined cardiovascular primary endpoint, empagliflozin showed superiority with a significantly lower incidence of cardiovascular events. PMID- 29632583 TI - The Rationale for Continuous Glucose Monitoring-based Diabetes Treatment Decisions and Non-adjunctive Continuous Glucose Monitoring Use. AB - Self-monitoring of blood glucose (SMBG) is now recognised as a core component of diabetes self-management. However, there are many limitations to SMBG use in individuals with diabetes who are treated with intensive insulin regimens. Many individuals do not test at the recommended frequencies. Additionally, because SMBG only provides a blood glucose reading at a single point in time, hypoglycaemia and hyperglycaemia can easily go undetected, limiting the user's ability to take corrective action. Inaccuracies due to user error, environmental factors and weaknesses in SMBG system integrity further limit the utility of SMBG. Real-time continuous glucose monitoring (CGM) displays the current glucose, direction and velocity of glucose change and provides programmable alarms. This trending information and 'around-the-clock' vigilance provides a significant safety advantage relative to SMBG. No published clinical studies have evaluated outcomes when CGM is used as a replacement for SMBG; however, recent in silico studies support this indication. This article reviews the limitations of SMBG and discusses recent evidence that supports CGM-based decisions as an effective approach to managing insulin-treated diabetes. PMID- 29632585 TI - Sodium-glucose Cotransporter 2 Inhibitors and Ketoacidosis - Clinical Implications in the Treatment of Patients with Type 2 Diabetes. AB - The use of sodium-glucose cotransporter 2 inhibitors is associated with an increased risk of diabetic ketoacidosis. This risk has been reported in particular in off-label use of these agents in type 1 diabetes, but reports of risks in type 2 diabetes patients also exist. In type 2 diabetes ketoacidosis is rare and is present particularly in patients who have undergone prolonged starvation, serious infection, alcohol abuse or surgery. The pleiotropic advantages of sodium-glucose cotransporter 2 inhibitors do not outweigh the risk for a diabetic ketoacidosis, but caution is warranted. PMID- 29632586 TI - Psychosocial Aspects and Diabetes Technology - Head to Head or Hand in Hand? AB - Diabetes technologies have progressed rapidly over recent years with a dedicated conference entering its 10th year, stronger and larger than ever. The long awaited automated insulin delivery systems represent the latest devices in engineering excellence however it is important that we do not lose sight of the fact that there is a person at the end of this technology, simply wanting a better life with diabetes with reduced diabetes burden. This commentary explores the relationship between technology and the psychosocial aspects of that technology in the context of user experience, clinical guidelines and the inclusion of psychosocial aspects alongside medical outcomes in research trials. PMID- 29632587 TI - The Future of Sleeve Gastrectomy. AB - The International Diabetes Federation has recently published a position statement on bariatric surgery. Facing a global diabetes crisis, it has added various types of surgery on the gastrointestinal tract as powerful options among the armamentarium to normalise glycaemia, avoid regular medications and decrease costs in severely obese patients. Laparoscopic sleeve gastrectomy has been shown to be effective for the treatment of type 2 diabetes, with extremely low mortality and acceptable morbidity. It decreases caloric consumption, modifies gut hormones, changes gastric emptying, and lowers glycaemia. In the long term, if recurrences in weight or diabetes occur, it can be converted to a duodenal switch, potentially reaching 90% of patients with partial or complete remission. PMID- 29632588 TI - The Management of Medullary Thyroid Carcinoma in the Era of Targeted Therapy. AB - Medullary thyroid cancer (MTC) is a rare cancer comprising approximately 5% of all thyroid cancers. The majority arises sporadically but around 25% are hereditary forming part of the Multiple Endocrine Neoplasia (MEN) type 2 syndromes. The initial management is surgical, the extent of resection determined by radiological stage, presence of and specific REarranged during Transfection (RET) oncogene mutation and level of serum calcitonin. External beam radiotherapy may be utilised in the adjuvant setting to improve local control rates. Conventional cytotoxic agents remain essentially futile in the management of advanced MTC with response rates of around 15-20% at best. Over the last decade, alongside a greater understanding of the molecular pathogenesis of MTC we have seen the development of small molecule agents including tyrosine kinase inhibitors targeting vascular endothelial growth factor receptors (VEGFRs) and RET with activity in advanced MTC. This review will examine the evidence for this therapeutic approach, when to consider initiating and how to manage toxicities arising from such therapies in the treatment of advanced MTC. PMID- 29632589 TI - New Developments in the Treatment of Neuroendocrine Tumours - RADIANT-4, NETTER-1 and Telotristat Etiprate. AB - Neuroendocrine tumours (NETs) are a heterogeneous group of neoplasms whose incidence has increased significantly in recent years, and whose optimal management remains controversial. We report the latest innovations in their management, in particular the results of three trials concerning the use of the mammalian target of rapamycin (mTOR) inhibitor, everolimus, in non-functional NETs of lung/ gastrointestinal (GI) origin, the first randomised trial of radiolabelled 177Lu-DOTATATE in patients with mid-gut NETs, and the use of the 5 HT synthesis inhibitor, telotristat etiprate, in patients with the carcinoid syndrome. PMID- 29632591 TI - Lessons From LEADER - All-round Leadership. AB - The large multinational, randomised, double-blind LEADER (Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results - A Long Term Evaluation) trial recently reported the cardiovascular (CV) benefits achieved with liraglutide therapy in type 2 diabetes mellitus (T2DM). This editorial analyses the primary and secondary CV outcomes (CVO) results of the LEADER trial, and discusses the impact these will have on clinical practice of diabetes in specific, and medicine in general. It delves into the evolution of clinical and biochemical outcomes used in diabetes, and discusses the role of liraglutide in shaping future outcomes. The editorial describes the potential role of liraglutide in primary, secondary and tertiary prevention of CV disease (CVD), and suggests exaptation of this molecule for use in cardiology, nephrology and neurology. PMID- 29632590 TI - Perspectives on the Search for a True Physiologic Replacement Therapy for Hypoparathyroidism. AB - Over the past two decades, we have studied various parathyroid hormone (PTH) 1-34 regimens, including once-daily and twice-daily injections without the concurrent conventional therapy. We recently studied PTH delivery by insulin pump, which produced normal, steady-state serum and urine calcium levels. The recent approval of PTH 1-84 represents an important milestone in the treatment of hypoparathyroidism. As PTH 1-84 and PTH 1-34 have similar pharmacokinetic (PK) and pharmacodynamic profiles, one can assume that many of the principles learned from studies of PTH 1-34 also apply to PTH 1-84 in the management of this rare disease. PMID- 29632592 TI - A Comparative Pulse Accuracy Study of Two Commercially Available Patch Insulin Infusion Pumps. AB - Background: Patch pumps are a relatively new method of Insulin delivery. This study explores the accuracy of patch-pumps by reporting on comparative pulse accuracy study of two patch pumps. Methods: The accuracy of two patch pumps (Cellnovo, [Cellnovo Ltd., Swansea, UK] and OmniPod(r) [Ypsomed Ltd, Escrick, UK]) was evaluated micro-gravimetrically. Pulse accuracy was analysed by comparing single and time-averaged pulses for each device. Results: Single-pulses outside accuracy thresholds +/-5%, +/-10%, +/-15%, +/-20%, +/-25% and +/-30% were: Cellnovo; 79.6%, 55.6%, 35.0%, 19.9%, 9.7% and 4.3%; OmniPod; 86.2%, 71.6%, 57.4%, 45.5%, 35.2% and 25.4%. For 10, 20 and 40 pulse-windows mean values outside +/-15% accuracy level were: Cellnovo; 7.3%, 1.5% and 0.4%, OmniPod; 37.6%, 31.8% and 25.9. Conclusions: This study showed that not all patch pumps are the same. The pumping mechanisms employed in these pumps play a significant role in the accuracy and precision of such devices. PMID- 29632593 TI - Morphological Changes Induced by Bipolar Radiofrequency Ablation in Thyroid Nodules - a Preclinical Ex Vivo Investigation. AB - Introduction: Recently, radiofrequency ablation (RFA) has been increasingly used for the treatment of thyroid nodules. However, immediate morphological changes associated with bipolar devices are poorly shown. Aims: To present the results of analysis of gross and microscopic alterations in human thyroid tissue induced by RFA delivered through the application of the original patented device. Materials and methods: In total, there were 37 surgically removed thyroid glands in females aged 32-67 at presentation: 16 nodules were follicular adenoma (labelled as 'parenchymal' solid benign nodules) and adenomatous colloid goitre was represented by 21 cases. The thyroid gland was routinely processed and the nodules were sliced into two parts - one was a subject for histological routine processing according to the principles that universally apply in surgical pathology, the other one was used for the RFA procedure. Results: No significant difference in size reduction between parenchymal and colloid nodules was revealed (p>0.1, t-test) straight after the treatment. In addition, RFA equally effectively induced necrosis in follicular adenoma and adenomatous colloid goitre (p>0.1, analysis of variance test). As expected, tumour size correlated with size reduction (the smaller the size of the nodule, the greater percentage of the nodule volume that was ablated): r=-0.48 (p<0.0001). Conclusion: The results make it possible to move from ex vivo experiments to clinical practice. PMID- 29632594 TI - Updates on Immune Therapies in Type 1 Diabetes. AB - Multiple clinical trials investigating the efficacy and safety of immunotherapeutic interventions in new onset type 1 diabetes (T1D) have failed to yield long term clinical benefit. Lack of efficacy has frequently been attributed to an incomplete understanding of the pathways involved in T1D and the use of single immunotherapeutic agents. Recent mechanistic studies have improved our knowledge of the complex etiopathogenesis of T1D. This in turn has provided the framework for new and ongoing clinical trials in new onset T1D patients and at risk subjects. Focus has also shifted towards the potential benefits of synergistic combinatorial approaches, both in terms of efficacy and the potential for reduced side effects. These efforts seek to develop intervention strategies that will preserve beta-cell function, and ultimately prevent and reverse clinical disease. PMID- 29632595 TI - Subclinical Hypothyroidism - What is Responsible for its Association with Cardiovascular Disease? AB - Subclinical hypothyroidism (SH) is a common condition, with prevalence estimates ranging from 4-20%, depending on the population demographics. Although epidemiological analysis associates it with an increased risk of cardiovascular disease, clinical practice guidelines express uncertainty about whether to monitor or to treat. As we await large-scale, well-designed randomised clinical trials regarding treatment of SH, a review of pathophysiological considerations may be informative to better understand this disorder. PMID- 29632596 TI - Neonatal Screening for Congenital Hypothyroidism with Focus on Developing an Indian Screening Programme. AB - Neonatal screening for congenital hypothyroidism, along with eradication of iodine deficiency in large parts of the world, has made it possible to prevent the development of permanent neurological impairment due to thyroid hormone deficiency in the developing brain. The first successful screening programme was demonstrated in Canada in 1973 and since then it has been standard of care in most developed societies. In India there is no national programme for neonatal screening, and screening is only done in selected larger hospitals on newborns whose parents fund it. This review summarises the current understanding of the various strategies for newborn screening that could potentially be employed in India with resource constraints. Once a case is detected, the further evaluation and determination of etiology is summarised. Treatment and long term follow-up with levothyroxine replacement is also described in detail as per current understanding. PMID- 29632597 TI - Tumour-induced Osteomalacia Secondary to a Sarcoma. AB - Tumour-induced osteomalacia (TIO), is a rare paraneoplasatic syndrome found in >95% of benign tumours that secrete fibroblast growth factor 23 - a phosphaturic circulating hormone. A rare case of a TIO secondary to a sarcoma, in a 21-year old man with history of bone fractures and distinctive physical and biochemical characteristics is presented and discussed. PMID- 29632598 TI - Letter from the Editor-in-Chief. PMID- 29632599 TI - The Cellnovo Insulin Delivery System. PMID- 29632600 TI - Latest Developments and Future Perspectives in the Field Of Obesity. AB - The prevalence of obesity is increasing exponentially worldwide, becoming an international public health issue that affects quality of life, increases the risk of illness and raises healthcare costs in countries in all parts of the world. In this editorial, we analyse the latest progress in the management of obesity and associated cardiovascular risk factors, and summarise the latest randomised controlled trials that have had the biggest influence on the current changes we are experiencing in obesity management. PMID- 29632601 TI - Progress and Problems in Bone and Mineral Disorders. AB - A number of new drugs are moving through the osteoporosis therapy pipeline. Some show great promise for patients while one has fallen by the wayside at the last hurdle. New, effective therapies are warmly welcomed but there are still uncertainties around management of osteoporosis with currently available drugs that are contributing to what is commonly being referred to as the 'treatment gap'; a differential between those patients who would benefit from treatment versus those who actually are receiving it. Furthermore, in parallel to the common public health disease of osteoporosis, there have been tangible developments in therapies available for some rare bone and calcium diseases. PMID- 29632602 TI - Recombinant Human Insulin in Global Diabetes Management - Focus on Clinical Efficacy. AB - Biosynthetic human insulin and insulin analogues are the mainstay of insulin therapy for both type 1 and type 2 diabetes although access to human insulin at affordable prices remains a global issue. The world is experiencing an exponential rise in the prevalence of diabetes presenting an urgent need to establish effective diabetes therapy in countries burdened by inadequate health care budgets, malnutrition and infectious diseases. Recombinant human insulin has replaced animal insulins and animal-based semisynthetic human insulin thereby available in sufficient quantities and at affordable prices able to provide global access to insulin therapy. In many patients, analog insulins can offer additional clinical benefit, although at a considerably higher price thus severely restricting availability in low income countries. The approval process for recombinant human insulins (i.e. biosimilars) and analogue insulins is highly variable in the developing countries in contrast to Europe and in North America, where it is well established within a strict regulatory framework. This review aims to discuss the future access to human insulin therapy in a global context with an ever increasing burden of diabetes and significant economic implications. PMID- 29632603 TI - Pilot Study of a Web-based Decision Tool on Post-operative Use of Radioactive Iodine. AB - Background: The Thyroid Cancer Care Collaborative developed a web-based clinical decision-making module (CDMM) to inform risk-adjusted decisions on post thyroidectomy radioactive iodine (RAI) use in papillary thyroid cancer (PTC). Methods: In a pilot study, we evaluated the CDMM in 19 PTC cases representing low (five), intermediate- (seven) and high-risk (seven) disease. Two PTC experts and 10 PTC physicians reviewed cases and assigned risk level and RAI recommendation. The experts used a standard approach while the others used the CDMM. We assessed agreement between responses using a weighted Kappa. Results: Between experts, risk-assignment was concordant in 100%, 57% and 86% of low-, intermediate- and high-risk cases, respectively. Between CDMM users, risk-assignment was concordant in 100%, 29% and 14% in low-, intermediate- and high-risk cases, respectively (p=0.01). CDMM-assigned risk agreed with the expert-assigned risk in 100%, 25% and 0% of low-, intermediate- and high-risk cases, respectively (Kappa=0.69). For RAI use, the experts agreed in 15 cases while CDMM users agreed in eight. On further analysis, interpretation of extrathyroidal extension and lymph node staging led to discrepancies with the CDMM. Conclusions: For a web-based CDMM to accurately inform appropriate use of RAI in PTC, standard pathological and surgical reports are necessary. PMID- 29632604 TI - Takotsubo Cardiomyopathy Associated with Levothyroxine Over-replacement. AB - Takotsubo cardiomyopathy (TC) is characterised by acute, transient left ventricular apical ballooning precipitated by emotional or physiologically stressful stimuli and has been previously associated with Grave's disease based on a few clinical reports. More recently, the association with exogenous thyrotoxicosis and radioiodine-induced thyroiditis has also been described. Iatrogenic hyperthyroidism on patients on levothyroxine replacement therapy for hypothyroidism has not been reported as a cause of TC. The authors describe two female patients with TC associated with levothyroxine over-replacement. A 74-year old and a 48-year-old female patient, medicated with levothyroxine (respectively, 2.27 MUg/kg and 1.85 MUg/kg) for autoimmune thyroiditis were admitted to our emergency room with precordial pain. The first had an electrocardiogram with ST segment elevation in the anterior precordial leads, and the latter had sinus tachycardia with deep T-wave inversion and QT interval prolongation. Further investigation revealed a mild elevation of cardiac biomarker levels and severe apical hypokinesis, but no significant coronary lesions on catheterisation. The suppressed thyroid stimulating hormone (TSH) levels were verified in the cardiac intensive care unit: 0.21 and 0.07 mIU/l (0.35-5.50) respectively. Both patients showed improvement of the apical hypokinesis on the discharge echocardiogram and normalisation of cardiac biomarker levels. Levothyroxine dose was reduced. This case report focuses on the cardiovascular risks of thyrotoxicosis, emphasises the importance of correct dose adjustment on patients under levothyroxine replacement therapy and stresses that TSH should be determined in patients presenting with acute coronary syndrome and typical findings of TC. PMID- 29632605 TI - Call for Submissions. PMID- 29632607 TI - Ten Years of Vildagliptin. AB - After many years of limited therapeutic opportunities, the treatment of type 2 diabetes has become more target and pathophysiologically driven. A typical example is represented by the development of the dipeptidyl peptidase-4 (DPP-4) inhibitors, allowing for more physiological regulation of the endocrine pancreas and leading to a previously unmet risk-to-benefit balance. Vildagliptin, one of the earliest DPP-4 inhibitors, has been tested across the entire spectrum of type 2 diabetes and has been in clinical use for 20 years. This publication critically reviews the main steps in the clinical development of this agent. PMID- 29632606 TI - Beta-cell Insufficiency. AB - 'Beta-cell failure' is a frequently used term to describe the structural and functional inability of the cells to fulfil their metabolic responsibility. This editorial reviews the anatomy and physiology of the beta cell, and describes factors which regulate this. The authors focus on semantics, comparing the phrases 'beta-cell failure', 'functional mass', and 'beta-cell insufficiency'. They suggest the use of 'beta-cell insufficiency', with descriptors such as 'partial' and 'complete', or 'reversible' and 'irreversible', to convey betacell dysfunction in type 2 diabetes. A three-phase taxonomic structure: beta-cell sufficiency, partial/reversible beta-cell insufficiency and complete/irreversible beta-cell insufficiency, is proposed as a tool to understand pathophysiology and facilitate therapeutic decision-making. PMID- 29632608 TI - The Vildagliptin Experience - 25 Years Since the Initiation of the Novartis Glucagon-like Peptide-1 Based Therapy Programme and 10 Years Since the First Vildagliptin Registration. AB - The discovery of the incretin hormone glucagon like peptide-1 (GLP-1), and its usefulness in the treatment of type 2 diabetes mellitus (T2DM) followed by the finding that dipeptidyl peptidase-4 (DPP-4) inhibition prevents GLP-1 inactivation, led to the discovery of DPP-728. In 1999, studies with DPP-728 established the first proof-of-concept that DPP-4 inhibition improves glycaemic control in patients with T2DM. Further efforts to improve the binding kinetics of DPP-728 resulted in the discovery of vildagliptin (LAF237). In the last 20 years, a plethora of studies conducted by Novartis in collaboration with external investigators has demonstrated the mechanism of action of vildagliptin and its efficacy as monotherapy and as an add-on therapy for patients with T2DM. The studies establish that vildagliptin is a selective DPP-4 inhibitor that blocks GLP-1 and glucose-dependent insulinotropic polypeptide (GIP) inactivation, thereby prolonging their action, resulting in improved glycaemic control. This review aims to discuss the discovery and development of vildagliptin, with an emphasis on mechanism of action and clinical efficacy. PMID- 29632609 TI - Dipeptidyl Peptidase-4 Inhibitor Development and Post-authorisation Programme for Vildagliptin - Clinical Evidence for Optimised Management of Chronic Diseases Beyond Type 2 Diabetes. AB - The last decade has witnessed the role of dipeptidyl peptidase-4 (DPP-4) inhibitors in producing a conceptual change in early management of type 2 diabetes mellitus (T2DM) by shifting emphasis from a gluco-centric approach to holistically treating underlying pathophysiological processes. DPP-4 inhibitors highlighted the importance of acknowledging hypoglycaemia and weight gain as barriers to optimised care in T2DM. These complications were an integral part of diabetes management before the introduction of DPP-4 inhibitors. During the development of DPP-4 inhibitors, regulatory requirements for introducing new agents underwent substantial changes, with increased emphasis on safety. This led to the systematic collection of adjudicated cardiovascular (CV) safety data, and, where 95% confidence of a lack of harm could not be demonstrated, the standardised CV safety studies. Furthermore, the growing awareness of the worldwide extent of T2DM demanded a more diverse approach to recruitment and participation in clinical trials. Finally, the global financial crisis placed a new awareness on the health economics of diabetes, which rapidly became the most expensive disease in the world. This review encompasses unique developments in the global landscape, and the role DPP-4 inhibitors, specifically vildagliptin, have played in research advancement and optimisation of diabetes care in a diverse population with T2DM worldwide. PMID- 29632610 TI - Clinical Safety and Tolerability of Vildagliptin - Insights from Randomised Trials, Observational Studies and Post-marketing Surveillance. AB - Vildagliptin is one of the most extensively studied dipeptidyl peptidase-4 (DPP 4) inhibitors in terms of its clinical utility. Over the last decade, a vast panorama of evidence on the benefit-risk profile of vildagliptin has been generated in patients with type 2 diabetes mellitus (T2DM). In this article, we review the cumulative evidence on the safety of vildagliptin from the clinical development programme, as well as reports of rare adverse drug reactions detected during the post-marketing surveillance of the drug. Across clinical studies, the overall safety and tolerability profile of vildagliptin was similar to placebo, and it was supported by real-world data in a broad population of patients with T2DM, making DPP-4 inhibitors, like vildagliptin, a safe option for managing patients with T2DM. PMID- 29632611 TI - Continuous Glucose Monitoring Adoption in the United Kingdom - An Economic and Policy Perspective. AB - Continuous glucose monitoring (CGM) technology provides real-time glucose concentration data to people with diabetes. The data enable timely treatment decisions that can lead to avoidance or mitigation of hypoglycaemia, with potential cost savings. This commentary discusses CGM implementation and funding policies in the UK, and regional disparities that confront many people with diabetes who could benefit from the technology. PMID- 29632612 TI - Is Continuous Glucose Monitoring Underappreciated in the UK? AB - INTRODUCTION: Information about continuous glucose monitoring (CGM) use in the UK is limited. We conducted an online survey of a representative sample of current CGM users in England, Scotland and Wales to address this deficit. METHODS: The 29 item online survey was conducted between 29 December 2016 and 25 January 2017. Persons with type 1 diabetes (T1D) and caregivers of T1D children/adolescents were recruited from mailing lists, using Nielsen and Harris Polling databases. RESULTS: 315 patients and caregivers responded to the survey - 170 adult patients and 145 caregivers. Among respondents, 144 received full funding for CGM use, 72 received partial funding and 83 received no funding. Most reported improvements in glycated haemoglobin (HbA1c) (67.0%), fewer hypoglycaemia episodes (70.2%), improved hypoglycaemia awareness (77.5%) and better diabetes management (92.4%). Self-funders reported significantly higher CGM use (76.1%) than those who were fully funded (58.9%) and/or partially funded (65.9%), p=0.0008. Fewer than 50% of all respondents reported receiving guidance in interpreting CGM data from their diabetes care team; 30.1% of self-funders reported receiving no CGM support from their diabetes team compared with fully funded (2.8%) and partially funded (1.4%) respondents, p<0.0001. CONCLUSIONS: Patients with T1D and their caregivers are realising benefits from CGM use but are largely unsupported by the UK healthcare system. PMID- 29632613 TI - An Economic Evaluation of Continuous Glucose Monitoring for People with Type 1 Diabetes and Impaired Awareness of Hypoglycaemia within North West London Clinical Commissioning Groups in England. AB - : To assess the economic impact of providing real time continuous glucose monitoring (CGM) for people with type 1 diabetes (T1D) and impaired awareness of hypoglycaemia (IAH) within North West (NW) London clinical commissioning groups (CCGs). METHODS: The eligible population for CGM and inputs for the economic budget impact model developed were derived from published data. The model includes cost of CGM; cost savings associated with lower hypoglycaemia related hospital admissions, accidents and emergency visits; self-monitoring of blood glucose (SMBG) strip usage; and glycated haemoglobin (HbA1c) reduction-related avoided complications and insulin pump use. RESULTS: The cost of CGM for T1D-IAH (n=3,036) in the first year is L10,770,671 and in the fourth year is L11,329,095. The combined cost off-sets related to reduced hypoglycaemia admissions, SMBG strip usage and complications are L8,116,912 and L8,741,026 in years one and four, respectively. The net budget impact within the NW London CCGs is L2,653,760; L2,588,068 in years one and four respectively. CONCLUSIONS: Introduction of CGM for T1D-IAH patients will have a minimal budget impact on NW London CCGs, driven by cost of CGM and offsets from lower hypoglycaemia-related costs, reduced SMBG strip usage, avoided HbA1c-related complications and lower insulin pump use. PMID- 29632614 TI - Antihyperglycemic Medications and Cardiovascular Risk Reduction. AB - Cardiovascular disease (CVD) remains a leading cause of death in patients with type 2 diabetes (T2D). In addition to glycemic control, a major focus of diabetes treatment involves cardiovascular (CV) risk reduction. In 2008, the US Food and Drug Administration (FDA) instituted a new requirement that new drugs developed and studied for the treatment of T2D must undergo CV safety testing. Since the advent of this new policy, canagliflozin, empagliflozin, liraglutide and semaglutide have demonstrated superior CV event reduction - via a composite of reduction in CV death, nonfatal myocardial infarction (MI), and nonfatal stroke - compared with placebo in patients with T2D and existing CVD, or at high risk of CVD. Multiple studies are underway to evaluate the CV outcomes of other antihyperglycemic agents. In a time when there are numerous drugs in the T2D armamentarium, positive CV outcomes data influence drug selection and aids practitioners in making more individualised therapeutic recommendations for their patients. PMID- 29632615 TI - Ranibizumab in Diabetic Macular Oedema - A Benefit-risk Analysis of Ranibizumab 0.5 mg PRN Versus Laser Treatment. AB - INTRODUCTION: The structured Benefit-risk Action Team (BRAT) approach aims to assist healthcare decision makers in treatment assessments. We applied BRAT to compare the benefit-risk profile of ranibizumab 0.5 mg versus laser photocoagulation for the treatment of diabetic macular oedema (DMO). METHODS: One year data for the ranibizumab 0.5 mg pro re nata (PRN) and laser arms of the phase III trials RESPOND (NCT01135914; n=220), RESTORE (NCT00687804; n=345), and REVEAL (NCT00989989; n=396) were included in the analysis. The benefit measures included >=10 letters gain/avoidance of loss in best-corrected visual acuity (BCVA), achieving central retinal thickness (CRT) <275 MUm, and 25-item Visual Function Questionnaire (VFQ-25) outcomes. The risks measures included endophthalmitis, intraocular pressure increase, hypertension, proteinuria, arterial/venous thromboembolic events and deaths. RESULTS: Ranibizumab treatment provided significant benefits compared with laser for >=10 letter BCVA gain at month 12 (387/1,000 versus 152/1,000 patients), CRT <275 MUm at 12 months (474/1,000 versus 348/1,000 patients), and improvement of >=6.06 on the VFQ-25 near activities subscale (325/1,000 versus 245/1,000 patients). Results for the risk measures were similar for both treatments. CONCLUSIONS: Superior clinically relevant outcomes were observed with ranibizumab 0.5 mg PRN compared with laser without compromising on safety. This analysis further supports the positive benefit-risk profile of ranibizumab 0.5 mg PRN. PMID- 29632616 TI - Type 2 Diabetes Decompensation as the Clinical Presentation of Thyroid Storm - Cause or Consequence? AB - This case study aims to discuss the unusual forms of hyperthyroidism presentation, the nonspecific symptoms and precipitating events. A 70-year-old male was taken to the emergency department for hyperglycaemia, nausea, vomiting and altered mental status with a week of evolution. He had a past medical history of type 2 diabetes, hypertension and dyslipidemia. He had no history of any recent intercurrent illness or infection. At the emergency room, besides hyperglycaemia, ketonemia and slightly elevated C-reactive protein, the basic laboratory panel workup was normal, as was the head computed tomography. He was admitted for metabolic compensation and to study the altered neurological status. During hospitalisation, despite the good glycemic control, he had no improvements in neurological status. At day four of hospitalisation, thyrotoxicosis with thyroid storm criteria was diagnosed. He started on adequate treatment with complete clinical recovery. The associated morbidity and mortality of thyroid storm requires immediate recognition and treatment. Elderly patients are frequently misdiagnosed or diagnosed later due to fewer and less pronounced signs and symptoms. PMID- 29632617 TI - Sarcopenia: a chronic complication of type 2 diabetes mellitus. AB - Background: Diabetics are at increased risk for impaired mobility and strength, frequently related to the disease control. Sarcopenia is the reduction of muscle mass associated with the decrease in muscle strength and/or performance, resulting in worse morbidity in chronic diseases. Methods: The objectives of this paper was to assess the prevalence of sarcopenia in patients with type 2 diabetes mellitus (T2DM) and determine its association with diabetes characteristics, progression, and complications, as well as changes in bone mineral density. The sample consisted of patients with T2DM followed at the outpatient clinics of the Servico de Endocrinologia e Metabologia do Hospital de Clinicas da Universidade Federal do Parana, from March to August 2016. Participants were men and women above 18 years with T2DM diagnosed at least 1 year earlier. Individuals with chronic diseases, users of any drug that modifies body composition, patients with body mass index (BMI) > 35 or < 18 kg/m2, and users of illicit drugs or hormonal or nutritional supplementation were excluded. The selected patients answered questionnaires about demographics, eating habits, and disease characteristics, and performed a bone densitometry exam in a dual energy absorptiometry (total body; spine and femur (total and neck)), a handgrip test by manual dynamometer, and an evaluation of the abdominal circumference (AC). The medical records were reviewed seeking diabetes data and laboratory test results. Patients were matched for sex, age, and race with healthy controls [Control Group (CG)]. The diagnosis of sarcopenia was conducted according to the criteria of the Foundation for National Institute of Health. Results: The final sample consisted of 83 patients in the DG and 83 in the CG. The DG had higher BMI, WC, past history of fractures and lower calcium and healthy diet intake (p < 0.005), compared to the CG. The DG presented a higher frequency of abnormal BMD (osteopenia in 45 (53%), and osteoporosis in 14 (19%)) and comorbidities than the CG (p < 0.005). Pre sarcopenia was not different between groups, but muscle weakness was present in 25 diabetics (18 women) and only in 5 controls (4 men) (p = 0.00036). Sarcopenia was diagnosed in 13 (16.2%) patients in the DG and 2 (2.4%) in the CG (p = 0.01168). Pre-sarcopenia and sarcopenia were associated with altered BMD (p < 0.005), with no association with diabetes duration or control. Body mass index and osteoporosis increased the likelihood to have sarcopenia, but hypertension and healthy diet decreased it. Conclusion: The DG had altered BMD associated with worse glycemic control, and a higher prevalence of sarcopenia, suggesting the need to look for their presence in diabetics. PMID- 29632618 TI - A computational reconstruction of Papio phylogeny using Alu insertion polymorphisms. AB - Background: Since the completion of the human genome project, the diversity of genome sequencing data produced for non-human primates has increased exponentially. Papio baboons are well-established biological models for studying human biology and evolution. Despite substantial interest in the evolution of Papio, the systematics of these species has been widely debated, and the evolutionary history of Papio diversity is not fully understood. Alu elements are primate-specific transposable elements with a well-documented mutation/insertion mechanism and the capacity for resolving controversial phylogenetic relationships. In this study, we conducted a whole genome analysis of Alu insertion polymorphisms unique to the Papio lineage. To complete these analyses, we created a computational algorithm to identify novel Alu insertions in next generation sequencing data. Results: We identified 187,379 Alu insertions present in the Papio lineage, yet absent from M. mulatta [Mmul8.0.1]. These elements were characterized using genomic data sequenced from a panel of twelve Papio baboons: two from each of the six extant Papio species. These data were used to construct a whole genome Alu-based phylogeny of Papio baboons. The resulting cladogram fully-resolved relationships within Papio. Conclusions: These data represent the most comprehensive Alu-based phylogenetic reconstruction reported to date. In addition, this study produces the first fully resolved Alu-based phylogeny of Papio baboons. PMID- 29632619 TI - KAT3B-p300 and H3AcK18/H3AcK14 levels are prognostic markers for kidney ccRCC tumor aggressiveness and target of KAT inhibitor CPTH2. AB - Background: Kidney cancer and clear cell renal carcinoma (ccRCC) are the 16th most common cause of death worldwide. ccRCC is often metastasized at diagnosis, and surgery remains the main treatment; therefore, early diagnosis and new therapeutic strategies are highly desirable. KAT inhibitor CPTH2 lowers histone H3 acetylation and induces apoptosis in colon cancer and cultured cerebellar granule neurons. In this study, we have evaluated the effects of CPTH2 on ccRCC 786-O cell line and analyzed drug targets expressed in ccRCC tumor tissues at different grade. Results: CPTH2 decreases cell viability, adhesion, and invasiveness in ccRCC cell line 786-O. It shows preferential inhibition for KAT3B p300 with hypoacetilating effects on histone H3 at specific H3-K18. Immunohistochemical analysis of 70 ccRCC tumor tissues compared with peritumoral normal epithelium showed a statistical significant reduction of p300/H3AcK18 paralleled by an increase of H3AcK14 in G1 grade and an opposed trend during tumor progression to worst grades. In this study, we demonstrate that these marks are CPTH2 targets and significative prognosticators of low-grade ccRCC tumor. Conclusions: ccRCC is substantially insensitive to current therapies, and the efficacy of clinical treatment is dependent on the dissemination stage of the tumor. The present study shows that CPTH2 is able to induce apoptosis and decrease the invasiveness of a ccRCC cell line through the inhibition of KAT3B. In a tumor tissue analysis, we identified new prognosticator marks in grade G1 ccRCC tumors. Low KAT3B/H3AcK18 vs. high H3AcK14 were found in G1 while an opposed trend characterized tumor progression to worst grades. Our collected results suggest that CPTH2 reducing KAT3B and H3AcK18 can be considered a promising candidate for counteracting the progression of ccRCC tumors. PMID- 29632620 TI - Experimental Hemorrhagic Shock Protocol in Swine Models: The Effects of 21 Aminosteroid on the Small Intestine. AB - Background: The protective potential of lazaroids has been reported in previous studies on ischemia/reperfusion and induced hemorrhagic shock protocols. Objectives: The present study is the first experimental protocol on the effects of the antioxidant factor U-74389G on the small intestine of swine models in a hemorrhagic shock protocol and resuscitation with 3 different types of fluids. Methods: The study included 49 Landrace breed swine that were divided into groups of 7 each. Hemorrhage was provoked 45 minutes after starting the surgical protocol (0 minutes), followed by resuscitation starting 30 minutes after haemorrhage ceased by using 3 different fluids. Three groups (Group A, resuscitation using blood; Group B, resuscitation with Ringer's lactate solution; and Group C, resuscitation with hypertonic saline solution) underwent resuscitation with fluid alone, and another 3 groups (named A', B,' and C') were administered lazaroid U-74389G in addition to fluid. Control Group S underwent all the surgical procedures without hemorrhagic shock. Vital signs, complete blood count, and biochemical markers were analyzed, and tissue samples of the small intestine were collected from all animals. Further, malondialdehyde, tumor necrosis factor-alpha, and levels of inflammation in the tissue sample were measured. Results: In Group S-A-A' and Group S-C-C', the analysis did not show statistically significant differences in the percentage changes of histopathology, malondialdehyde, and tumor necrosis factor-alpha through time. In Group S-B-B', the malondialdehyde levels in the small intestine were reduced in both the B and B' groups, without lazaroid (Group B) (P = 0.038) and lazaroid (Group B') (P = 0.011), compared with Group S (control), but the group without lazaroid (Group B) had greater reduction in malondialdehyde levels than the group treated with lazaroid (Group B'). With regard to the biochemistry results, 24% reduction was observed for alkaline phosphatase (P = 0.022) in Group A' treated with lazaroid compared with that in the untreated group. Lastly, for the complete blood count parameters, a 14% reduction in white blood cells was observed in Group B', which was treated with lazaroid in all phases (P = 0.015) (absolute value = 6.23) compared with Group B (absolute value = 13.74). Conclusions: Despite few initial findings of this study suggesting that administration of lazaroid U-74389G may have some potential in attenuation of the effects of hemorrhagic shock in the small intestine of swine models, no differences remained after correction for multiple comparisons was made. Therefore, further research is required to investigate this result thoroughly. PMID- 29632621 TI - Measurement of 8-hydroxyguanine as an oxidative stress biomarker in saliva by HPLC-ECD. AB - Introduction: Oxidative stress leads to many kinds of diseases. Currently, urinary 8-hydroxydeoxyguanosine (8-OHdG) is widely measured as an oxidative stress biomarker. There is a specific advantage if saliva can be used as the sample to measure the oxidative stress biomarker, because saliva is much easier to collect than urine. In this study, we investigated the measurement of 8 hydroxyguanine (8-OHGua) as an oxidative stress marker in saliva, by a column switching HPLC system equipped with an electrochemical detector (HPLC-ECD). Findings: The 8-OHGua in saliva could be detected as a single peak by HPLC-ECD. The average level of 8-OHGua in saliva was 3.80 ng/mL in ordinary, non-smoking subjects. The salivary 8-OHGua levels of smokers were significantly higher than those of non-smokers. Conclusions: Salivary 8-OHGua may be a useful noninvasive and promising oxidative stress biomarker.